PMID- 7830467 TI - [Modern technology permits better "look" into the brains of dangerous criminals]. PMID- 7830468 TI - Clinical applications of lasers in otolaryngology--head and neck surgery. AB - The use of lasers in otolaryngology--head and neck surgery is described from the invention of the laser in 1960, through the current uses of the laser, and concludes with a summary for the future directions of laser surgery. The various lasers, including the argon, the KTP, and the carbon dioxide lasers used in otolaryngology, are briefly described. The applications of lasers in the larynx, sinuses, and the ear are separately covered, as well as pediatric otolaryngology. In addition to a brief description of the procedure, the complications and limitations are given. Anesthetic considerations are also covered. PMID- 7830469 TI - Experimental study of CO2 laser myringotomy with a hand-held otoscope and fiberoptic delivery system. AB - CO2 laser myringotomy has previously been proven effective in patients with serous otitis media for short-term aeration of the middle ear. However, the system based on a microscope and a coaxially aligned laser is cumbersome and expensive. The advantage of CO2 laser energy is the high absorption coefficient in biological tissue, meaning minimal damage surrounding the desired lesion. The disadvantage is that conventional optical fibers do not transmit CO2 laser energy (lambda = 10.6 microns). We have developed a silver halide optical fiber of diameter 0.9 mm and lengths of several meters, with high transmission at 10.6 microns. Using a hand-held otoscope coupled to a fiberoptic delivery system, CO2 laser myringotomies were performed in guinea pigs. In the animal model the feasibility of the procedure was proven. Different irradiation parameters were studied and a "dose-dependent" relationship was found between the total energy used and the duration of a patent myringotomy. However, conventional histological studies failed to show a difference in circumferential damage with different energy parameters. CO2 laser myringotomy utilizing a hand-held otoscope coupled to an optical fiber capable of transmitting CO2 laser energy may prove simple and effective. The relationship between energy parameters and myringotomy patency may be instrumental in deciding on the optimal duration of aeration of the middle ear in secretory otitis media. PMID- 7830470 TI - New device for visual neodymium:YAG laser prostate ablation: acute and chronic canine evaluation. AB - This canine study (n = 6) evaluated the acute and chronic effects of Nd:YAG laser prostatectomy using a Prolase II fiber. The Prolase II device consists of a 1,000 microns quartz fiber which directs a cone of Nd:YAG laser energy, at 45 degrees to the axis of the fiber, into the prostatic urethra under direct visual guidance [visual laser ablation of prostate, (VLAP)]. Under visual guidance and saline irrigation, 60 seconds of 60 watts of laser power was delivered at 3, 6, 9, and 12 o'clock positions (14,400 J). One canine was instrumented but received no laser energy (control). One prostate was harvested acutely. The remaining four laser-treated dogs were evaluated at 6 to 16 weeks. The histopathology of acute laser effects shows areas of necrosis with loss of glandular structures and stromal edema. Surrounding this area was a zone of degenerative glandular structures extending up to 12.6 mm into the prostate. Two of the four dogs developed urinary retention at 6.5 and 9 weeks. On examination, both were found to have fibrotic strictures at the distal prostatic urethra with markedly dilated proximal prostatic urethral lumens (1.98 and 2.8 cm). Two other dogs showed no signs of urinary retention at sacrifice. Histopathology, both the 6 and 16 week laser-treated animals without urinary retention demonstrated dilated prostatic urethras with maximum cross-sectional diameters of 1.52 and 1.50 cm, respectively.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7830471 TI - 308 nm excimer laser ablation of cartilage. AB - This article reports the investigation of the XeCl excimer laser as a cutting ablating tool for human fibrocartilage and hyaline cartilage. Quantitative measurements were made of tissue ablation rates as a function of fluence in meniscal fibrocartilage and articular hyaline cartilage. A force of 1.47 Newtons was applied to an 800-microns fiber with the laser delivering a range of fluences (40-190 mJ/mm2) firing at a frequency of 5 Hz. To assess the effect of repetition rate on depth per pulse, a set of measurements was made at a constant fluence of 60 mJ/mm2, with the repetition rate varying from 10 to 40 Hz. Histologic and morphometric analysis of preserved specimens was performed using light microscopy. The results of these studies revealed that the ablation rate was directly proportional to fluence over the range tested. Fibrocartilage was ablated at a rate 2.56 times faster than hyaline cartilage. Repetition rate had no effect on the penetration per pulse. Adjacent tissue damage was noted to be minimal (10-70 microns). The excimer laser achieved ablation rates adequate for arthroscopic applications. PMID- 7830472 TI - SEM comparison of acid-etched, CO2 laser-irradiated, and combined treatment on dentin surfaces. AB - Research into polymer systems capable of bonding to dentin and enamel have resulted in improved bond strengths that allow more conservative restoration and strengthening of teeth. However, pretreatment of the dentin and enamel of various sorts, including exposure to laser energy, have been espoused to enhance this bonding. This study investigated the effects of two pretreatments, acid and CO2 laser exposure, both alone and in combination, on the surface topography of prepared dentin specimens as observed by scanning electron microscopy. Eighteen dentin specimens were flat-sanded with 600 grit sandpaper and exposed to 10% maleic acid and CO2 laser both alone and in combination. SEM observation suggested that laser treatment prior to acid etching could increase the resistance of the smear layer to acid removal, that laser exposure after acid treatment could expose a porous topography suggestive of the underlying dentin inorganic structure by way of vaporization of the collagen surface left after acid demineralization, and that these effects varied in degree with the laser exposure energy. PMID- 7830473 TI - Beam profile of the flashlamp pumped pulsed dye laser: support for overlap of exposure spots. AB - The degree to which individual practitioners overlap exposure spots of the flashlamp pumped pulsed dye laser when treating large vascular lesions appears to be a matter of personal preference. There are few data to support one approach over another. We have measured the beam profile of this laser at two different energy fluences using a photodiode and a digitizing storage oscilloscope. Results show that for each energy fluence, the beam intensity decreases from the center to the outside rim of the beam. A plot of beam intensity versus the radius of the treatment field approaches a truncated normal distribution with a full width at half-maximum of 4.7-4.8 mm. These results help explain why clinical overlap of exposure spots can be safely undertaken and provide a rationale for recommendations concerning the degree of overlap needed to expedite treatment while still minimizing adverse reactions. PMID- 7830474 TI - Expression of growth factors in early wound healing in rat skin. AB - Growth factors are a group of hormone-like polypeptides that have been shown to play a central role in different phases of wound healing. The expression of these growth factors in early wound healing has not been quantified, and the pattern and distribution of these growth factors in early wound healing has not been described completely. Furthermore the quantity and pattern of distribution of these growth factors have not been investigated in early wounds produced by various methods of surgical incision. Comparison of the rate of healing between the CO2 laser wound and the scalpel wound has produced conflicting results. The present immunohistochemical study uses polyclonal antibodies specific for epidermal growth factor (EGF), platelet-derived growth factor (PDGF), transforming growth factor beta (TGF-beta), and basic fibroblast growth factor (bFGF) to observe the pattern and distribution of these growth factors in rat skin wound and elucidate whether there are differences in the expression of these growth factors which might account for the delayed healing of the CO2 laser wounds compared to the scalpel as has been observed by some authors. Our results indicate that EGF, TGF-beta, PDGF, and bFGF are expressed and distributed in same areas of the early skin wound. The area of expression of these growth factors was associated with presence of wound inflammatory cells and wound fibroblasts.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7830475 TI - Histological studies on the rheumatoid synovial membrane irradiated with a low energy laser. AB - The beneficial effects of low energy laser irradiation on rheumatoid arthritis (RA) joints have been reported, but the mechanisms of action of low energy lasers in RA are unclear. The synovial membrane in cases of RA was studied histologically to observe the effects of low energy laser irradiation. Fourteen knee joints of RA cases, which had been scheduled for arthroplasty, were irradiated with a gallium-aluminium-arsenide (Ga-Al-As) laser (790 nm in wavelength and 10 mW of output power) prior to the surgical operation, at six points of the external aspect of the knee joint for 80 seconds at each points once a day for 6 days. On the day following the last irradiation, pieces of synovial membrane from the lateral irradiated area and from the median nonirradiated area as a control were resected during the arthroplasty. The histological findings of the irradiated synovial membrane showed flattening of epithelial cells, decreased villous proliferation, narrowed vascular lumen, and less infiltration of inflammatory cells compared with those of nonirradiated synovia. The evaluation of slides was done in a blinded manner, and significant differences was seen by Wilcoxon's t-test (P < 0.01). Histological findings suggested that the low energy laser irradiation induced suppression of inflammation in the synovial membrane of RA. PMID- 7830476 TI - Effect of the dynamic optical properties of water on midinfrared laser ablation. AB - Water is a primary tissue chromophore in the midinfrared. Absorption of midinfrared radiation by water is a function of temperature and pressure, both of which rise rapidly during an ablative laser pulse. Data show that the absorption coefficient of water changes, by as much as two orders of magnitude, during a high-irradiance laser pulse. We present an ablation model that is fundamentally based upon Beer's Law but considers changes in the absorption coefficient. The model predicts that Er:YAG laser cuts will be deeper than Er:YSGG laser cuts; an opposite prediction would be made based upon the static, low-intensity absorption coefficient of water. The results of in vitro ablation of skin confirm that the dynamic optical properties of tissue need to be considered in the understanding of laser ablation as well as the design, manufacture, use, and regulation of clinical laser systems. PMID- 7830477 TI - Doubling time of cancer (junk science in the courtroom). PMID- 7830478 TI - A contemporary analysis of medicolegal concerns for physician assistants and nurse practitioners. AB - The utilization of-PAs and NPs to expand the supply of traditional physician services to the public, at reduced costs, as proposed by President Nixon in 1971, has in 1994 become a national mandate. There is an increasing demand for the "traditional" physician services, which can be efficiently and cost effectively performed by nonphysician practitioners, such as PAs and NPs. Statutory changes permitting physicians "to delegate medical acts in an innovative manner" have been, at times, agonizingly slow. However, when compared to the NP statutes, the PA statutes have evolved at a rapid rate. It is postulated that this may be due to the fact that PAs who are totally dependent on physician supervision are more controllable and hence more acceptable to organized medicine than NPs who are currently flexing their political muscles in a quest for greater independence in their performance of traditional physician services. The reimbursability of the two professions is yet another important consideration. Nurse practitioners are "directly" reimbursed by third-party payors, such as Medicare and Medicade, for the traditional physician services they perform, while PA third-party reimbursement is, by law, paid directly to the employing physician or medical facility. Unlike NPs, PAs were conceived by organized medicine, the AMA, to provide a mechanism for physicians to expand their capability to treat increasing numbers of patients. Accordingly, PAs are tied to their supervising physician by the same governmental agencies that regulate physician licensure. Conversely, NPs, who derive their authority to practice from the various state nurse practice acts, have been, at times, impeded in their quest for an enlargement of their scope of practice, including independent prescriptive privileges. The NP bid for greater independence and enlargement of their scope of practice, on a national level, is viewed by organized medicine as an encroachment into the "independent" practice of medicine under the guise of providing advanced nursing care. Unlike PAs, whose professional existence depends on the supervision of a licensed physician, NPs are, by and large, independent of physician control by virtue of their status as licensed members of the nursing profession. While PAs and NPs were once thought to be virtually interchangeable, the divergence of the two professions over the past two decades has been such that all similarities have, for all intents and purposes, disappeared.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7830479 TI - Evidence destruction--legal consequences of spoliation of records. PMID- 7830480 TI - AIDS and the emergency room physician and staff. PMID- 7830481 TI - Adverse drug reactions. AB - Clearly, adverse drug reactions continue to induce injury and harm to patients, despite careful considerations, prescribing, dispensing, and administration. New drugs represent unknown risks and require intense scrutiny and monitoring in their early market stages. Deterioration of good monitoring, selection of more toxic drugs, and poor history taking from patients will continue to present challenges and increased risks from this partially reversible morbidity and mortality to patients. PMID- 7830482 TI - The learned intermediary doctrine: past, present and future. PMID- 7830483 TI - The doctrine of informed consent: the reaffirmation of the right to self determination through the exclusion of patients' nonmedical interests. PMID- 7830484 TI - Ethical and legal implications of advances in genetic testing technology. PMID- 7830485 TI - Mental disorder in the workplace. PMID- 7830486 TI - Peer review/hospital privileges/credentialing. PMID- 7830487 TI - Quality control in health care: developments in the law of medical malpractice. PMID- 7830488 TI - Endothelins urinary excretion is increased in spontaneously diabetic rats: BB/BB. AB - Previously we reported (1) an increase of endothelin-1,2 (ET) content, in urine of rats made diabetic with streptozotocin (STZ), starting three days and up to 20 weeks from diabetes induction. The increased ET excretion was considered as an early marker of endothelial damage. To ascertain if this phenomenon was present also in a strain of spontaneously diabetic rats, endothelin-1,2 urinary excretion was determined in BB/BB diabetic rats, and their control (BB/WB), at different times after the onset of diabetes, (two, four, six and twelve weeks). BB/BB diabetic rats showed elevated urinary excretion of endothelins as compared to BB/WB control rats, starting two weeks after diabetes onset, and up to twelve weeks. In the same animals, Nerve Conduction Velocity (NCV), was monitored at the same time as an index of the occurrence of a diabetes complication (peripheral neuropathy). NCV resulted to be impaired in the BB/BB diabetic rats as compared to control rats; however the increase of ET in urine, is earlier in comparison to peripheral neuropathy. These data suggest the hypothesis that endothelial damages preceed the overt manifestations of peripheral neuropathy associated to diabetes. PMID- 7830489 TI - Adrenomedullin mediates vasodilation via CGRP1 receptors. AB - Adrenomedullin is a recently discovered 52 amino acid polypeptide with potent hypotensive activity. The peptide possesses 21% homology with the amino acid sequence of human calcitonin gene-related peptide-alpha (hCGRP-alpha). In 125I hCGRP-alpha receptor binding experiments using membranes from human neuroblastoma cells (SK-N-MC) adrenomedullin is a potent competitor with a Ki of 0.37 nM. In SK N-MC cells hCGRP-alpha and adrenomedullin concentration-dependently increase cAMP levels with -logEC50 values of 9.65 and 7.75, respectively. Both responses were attenuated in the presence of 30 nM CGRP[8-37], a CGRP1 receptor antagonist. In isolated rat hearts, perfused at constant flow, bolus infusion of adrenomedullin (1 to 100 nM) resulted in a concentration-dependent, pronounced and long-lasting vasodilation with an approximate EC50 of about 3 nM. This effect was markedly attenuated in the presence of 100 nM CGRP[8-37]. In this model, bolus infusion of hCGRP-alpha (0.01 to 100 nM) evoked a comparable vasodilation with an approximate EC50 of 0.5 nM. This effect was also potently inhibited in the presence of CGRP[8 37]. These results suggest that adrenomedullin-mediated vasodilation is linked to the activation of CGRP1 receptors in the coronary vascular system. PMID- 7830490 TI - SR 142801, the first potent non-peptide antagonist of the tachykinin NK3 receptor. AB - SR 142801 is the first potent and selective non-peptide antagonist of the tachykinin NK3 receptor. It inhibited [MePhe7]NKB binding to its receptor from various species, including humans. SR 142801 was a competitive antagonist of [MePhe7]NKB-mediated contractions of guinea-pig ileum and inhibited the acetylcholine release following the activation of the guinea-pig ileum tachykinin NK3 receptor. In vivo, SR 142801 potently inhibited the turning behaviour induced by intrastriatal injection of senktide in gerbils, and appears as a powerful tool for investigation of the physiological and pathological role of NKB and its NK3 receptor. PMID- 7830491 TI - Pulmonary effects of the cocaine pyrolysis product, methylecgonidine, in guinea pigs. AB - The pulmonary effects of the cocaine pyrolysis product, methylecgonidine (MEG; anhydroecgonine methyl ester), were assessed in guinea pigs. Specific airway conductance (SGaw), which decreases during bronchoconstriction, was measured in guinea pigs exposed to atmospheres containing a condensation aerosol of MEG free base (13 +/- 1 mg/liter of air), nebulized MEG fumarate (3 and 12% in phosphate buffered saline) or nebulized acetylcholine chloride (0.2 and 0.4% in phosphate buffered saline). A decrease in SGaw to 24.0 +/- 4.2% (mean +/- 2 S.E.M.) of baseline levels was observed in guinea pigs breathing MEG free base. A decrease to 28.4 +/- 4.5% of baseline was observed following administration of 0.4% acetylcholine. No change in SGaw was measured in guinea pigs exposed to 3% MEG fumarate but SGaw was reduced to 69.3 +/- 5.3% of baseline after exposure to 12% MEG fumarate. MEG free base poses an alkaline challenge to the lung, 3% MEG fumarate is neutral (pH approximately 7.4) and 12% MEG fumarate is acidic (pH approximately 4.3); thus, MEG free-base and 12% MEG fumarate might provoke a reflex bronchoconstriction due to direct pulmonary irritant effects. These results suggest that MEG free base produced during crack pyrolysis may play a role in bronchoconstriction observed in crack smokers. PMID- 7830492 TI - Different mechanisms can activate Ca2+ entrance via cation currents in endothelial cells. AB - Effects of Endothelin-1 (ET-1) and cyclopiazonic acid (CPA) on non-specific cation channels in cultured bovine pulmonary artery endothelial cells (BPAECs) were investigated using the patch-clamp technique. In a bath solution containing Ca2+ as a permeant cation, 10 nM ET-1 increased inward and outward currents and this current reversed at -10 mV instead of -60 mV. Under similar conditions, 10 microM CPA, an inhibitor of Ca2+ pumps in the sarcoplasmic reticulum, also increased both currents which now reversed near -10 mV. An inorganic Ca2+ influx blocker, La3+ at 50 microM completely blocked ET-1 and CPA-evoked currents restoring the reversal potential to -60 mV. ET-1 and CPA evoked currents were partially blocked by 50 microM SK&F 96365 (a putative inhibitor of receptor mediated Ca2+ entry). ET-1 and CPA increased Ca2+ influx by activation of the Ca(2+)-permeable non-specific cation channels, which are gated by the depletion of intracellular Ca2+ stores in endothelial cells. These results, together with a previous study demonstrating that this Ca2+ entrance pathway can be opened directly by one vasodilator (LP-805) reveal that different mechanisms exist to activate Ca2+ entrance into endothelial cells. All may allow sustained release of endothelium-derived relaxing factor (EDRF). PMID- 7830493 TI - Vascular effects of halothane and isoflurane: cGMP dependent and independent actions. AB - This study investigated the effects of halothane and isoflurane on cGMP-dependent and independent regulation of vascular contraction of the isolated rat aorta and on NO-stimulated soluble guanylate cyclase (sGC) isolated from the perfused rat liver. For the studies of the aorta, isometric tension of isolated rings, with and without, endothelium was recorded and cGMP content measured. ACh was used to initiate endothelial-dependent relaxation of norepinephrine (NE)-contracted rings while NO was used to directly stimulate isolated aortic ring sGC which catalyzes the isolated aortic ring formation of cGMP. Both halothane and isoflurane interfered with ACh and NO relaxations and with NO-stimulated increases in cGMP. Halothane was more potent, having significant attenuating effects at 0.34 mM (1 MAC) and 0.72 mM (2 MAC) while isoflurane had effects only at 0.53 mM (2 MAC). For the isolated sGC studies, a soluble liver fraction was prepared from perfused rat livers. In the absence of NO stimulation, neither halothane nor isoflurane modified the activity of the sGC. However, during NO-stimulation halothane produced significant, concentration-dependent, inhibition of sGC activity over a wide range of NO concentrations. Isoflurane also inhibited sGC activity, but to a lesser extent than halothane. The mechanism whereby the anesthetics could interfere with sGC from liver and blood vessels is unknown. It could result from anesthetic interaction at hydrophobic sites that may exist in GC. However, the results of both the aorta and liver sGC enzyme studies support the suggestion that these anesthetics can compete with NO for its binding site on the ferrous heme of sGC, with chemical structural differences accounting for the potency variations. Both anesthetics also had cGMP independent effects, causing concentration dependent relaxations of NE-contracted vessels without endothelium. Isoflurane was about 5 times more effective at 1 MAC than halothane. Therefore, the net effects of these anesthetics involve the sum of two opposite effects on tension of vessels with intact endothelium: 1) interference with NO-stimulated cGMP relaxation and 2) direct stimulation of relaxation (not dependent on changes in cGMP). PMID- 7830494 TI - Effect of dietary cholesterol on activity and mRNA levels of hepatic lipase in rat. AB - Female lean Zucker rats were fed for four weeks with either a control diet or the same diet enriched with 2% (w/w) cholesterol and cholic acid (0.5%, w/w). This treatment resulted in a 6-fold increase in plasma total cholesterol. A 30% decrease was observed in plasma post-heparin HL activity, in contrast with lipoprotein lipase, which was unmodified in the cholesterol/cholate-fed rats. HL activity measured in liver homogenate from these rats was also decreased (-30%, p < 0.05), as was its protein mass, quantified by immunoblot analysis (-57%, (p < 0.01), whereas HL mRNA levels were 3-fold lower in the cholesterol/cholate-fed rats. We conclude that the cholesterol/cholate-enriched diet decreases the HL gene expression by acting at the transcriptional level and/or by affecting HL mRNA stability, or both. PMID- 7830495 TI - Influence of estrogen on cholesterol esterification and fatty acid composition in serum lipoproteins of castrated rats. AB - Total, free and esterified cholesterol and its fatty acid composition were measured in the serum lipoproteins of castrated rats after estradiol administration. In general, castration and treatment with estradiol led to a decrease in total esterified cholesterol content. However, estradiol induced an effect opposite to that of castration on the fatty acid composition in VLDL. The effects were variable in HDL and insignificant in LDL. Similarly, the ratios of essential fatty acid to non-essential fatty acid (EFA/NEFA) and that to monoenoic acid (EFA/ME) were affected differently in castration and estradiol treatment in VLDL, but not in HDL or LDL. The pattern of lipid metabolism in castrated and estradiol-treated rats thus appears opposite to that described in human pathology. PMID- 7830496 TI - Choline enhances scopolamine-induced acetylcholine release in dorsal hippocampus of conscious, freely-moving rats. AB - We examined the effects of exogenous choline (30, 60, 120 mg/kg, i.p.) on basal and scopolamine-evoked acetylcholine (ACh) release in awake animals, using in vivo microdialysis. After collection of 3-4 baseline dialysate samples (15 min each), rats received either saline or choline chloride and 4 additional samples were collected. All animals then received scopolamine hydrochloride (0.5 mg/kg, i.p.) and 6 additional samples were collected. Basal ACh release in animals receiving choline did not differ from that in rats given saline, nor from ACh release prior to choline administration. Scopolamine alone increased average ACh levels in dialysates from 1.22 +/- 0.54 to 11.18 +/- 3.07 pmol/15 min (mean +/- SD; p = 0.001); administration of 60 mg/kg or 120 mg/kg of choline chloride significantly enhanced maximal scopolamine responses by about 55%. These results suggest that supplemental choline enhances evoked ACh release in hippocampus of freely-moving rats. PMID- 7830497 TI - The relationship between vessel wall tension and the magnitude and frequency of oscillation in rat aorta. AB - Aortic rings from adult normotensive rats display spontaneous rhythmic activity that is enhanced by vasoconstricting agents. Graded doses of norepinephrine as well as combinations of norepinephrine and vasodilators produced levels of tension that were inversely related to the magnitude of oscillation and directly related to the frequency. A similar result occurred with KCl stimulation. Oscillations were only slightly affected by removal of the endothelium. These results, when combined with other reported studies, suggest that the oscillations in rat aorta are a manifestation of feedback control that may involve the cyclic release of one or more agents affecting calcium channels. PMID- 7830498 TI - Biomimetic pulmonary surfactants. AB - Considerable progress has been made in the development of defined mixtures of proteins or peptides with phospholipids which mimic the activity of natural pulmonary surfactants. Several of these biomimetic surfactants are active in animal models and clinical syndromes of surfactant deficiency. This review summarizes the structure and composition of natural surfactants and the development of defined mixtures of peptides and lipids that may be useful in the treatment of respiratory distress. PMID- 7830499 TI - Effect of adrenomedullin on aldosterone secretion by dispersed rat adrenal zona glomerulosa cells. AB - Adrenomedullin, a novel hypotensive peptide, was discovered in human pheochromocytoma. Although adrenomedullin exists also in normal adrenal medulla and several other organs, its effect on steroidogenesis in adrenal cortex has not been studied. We examined the effect of adrenomedullin on aldosterone secretion by the dispersed rat adrenal zona glomerulosa cells. Adrenomedullin (10(-12)-10( 7) M) did not affect basal aldosterone secretion. Adrenomedullin dose dependently inhibited aldosterone secretion stimulated by 10(-9) M angiotensin II and 10 mM potassium, whereas 10(-9) M ACTH-stimulated aldosterone was not significantly inhibited by adrenomedullin. N6,O2'-dibutyryladenosine 3':5'-cyclic monophosphate (db-cAMP, 10(-5)-10(-3) M) and Ca+ ionophore A23187 (10(-8)-10(-6) M) stimulated aldosterone secretion dose dependently, and A23187-stimulated secretion was significantly inhibited by adrenomedullin (10(-8) M), but db-cAMP-stimulated secretion was not inhibited by adrenomedullin. Our data suggest the possibility that adrenomedullin is a novel inhibitory peptide of aldosterone secretion induced by increasing concentration of intracellular free calcium. PMID- 7830500 TI - In vivo 31P nuclear magnetic resonance evidence of the salvage effect of ascorbate on the postischemic reperfused rat skeletal muscle. AB - The effect of 32 mM ascorbate on the time courses of phosphocreatine (PCr), inorganic phosphate (Pi), adenosine triphosphate (ATP) and intracellular pH in rat skeletal muscle during ischemia and reperfusion was investigated in vivo using 31P nuclear magnetic resonance (NMR) spectroscopy. Ascorbate was administered intravenously prior to induction of ischemia and at the time of reperfusion. The changes in PCr/(PCr+Pi), ATP and pH were similar in the non treated and in the treated groups during ischemia. PCr/(PCr+Pi) fell to < 10% and ATP to approximately 30% of the preischemic values after 4 hours of arrested circulation, and pH decreased considerably. Postischemic reperfusion was followed continuously for 150 minutes. At the time of reflow, treatment with ascorbate had an immediate, positive effect on the recovery of high energy phosphates and pH. The level of PCr/(PCr+Pi) was 86% higher (p < 0.001) and the ATP level was 40% higher (p < 0.001) in the treated group than in the control group by the end of the reperfusion period. The results provide in vivo evidence for a salvaging effect of ascorbate on ischemia-reperfusion injury in skeletal muscle, probably owing to its antioxidant function and other ancillary effects, mainly its provision of additional buffer capacity. PMID- 7830501 TI - Metaphit amplifies long-term potentiation (LTP) in the mouse hippocampus. AB - The influence of metaphit, a phencyclidine derivative, on the amplitude of Long Term Potentiation (LTP) in the mouse hippocampus was investigated. Mice (C57BL/6) of both sexes were injected with metaphit (80 mg/kg) and hippocampal slices were prepared at 3, 24, 48 hrs and 6 days following injection. The extracellular evoked potentials were recorded from the pyramidal cell layer following Schaffer collateral stimulation. The threshold value, defined as the minimum strength of the stimuli to evoke a 0.1 mV potential, was about 5 fold greater in metaphit slices than in control slices 3 hr following injection, and then declined to the control value within 6 days. The magnitude of LTP was also amplified by metaphit in a time-dependent fashion. The effect was visible three hours after injection, reached its maximum at 48 hr and then declined to a level slightly higher than control at 6 days following injection. These results demonstrate that metaphit, a compound known to induce audiogenic seizures, is able to modify synaptic plasticity in the hippocampus. Presented results are also in agreement with our previous data which demonstrated an interaction between the mechanisms of LTP and audiogenic seizure. PMID- 7830502 TI - Thalidomide and the immune system. 4. Down-regulation of the CD26 receptor, probably involved in the binding of HIV components to T cells in primates. AB - Thalidomide (Thd) is capable of down-regulating the CD26 receptor on CD4+ lymphocytes after treatment of healthy volunteers. Similar effects are observed when marmosets (Callithrix jacchus) are treated with Thd. The Ta1 epitope of the CD26 receptor has recently been shown to bind the HIV-1 Tat trans-activating protein, and CD26 has also been suggested to be a coreceptor for the binding of the V3 loop of the gp120 HIV envelope protein. This might provide a hint for possible therapeutic interventions. PMID- 7830503 TI - Chlorinated dibenzo-p-dioxins and dibenzofurans and the human immune system. 2. In vitro proliferation of lymphocytes from workers with quantified moderately increased body burdens. AB - Lymphocyte proliferation responses were studied in workers with moderately increased body burdens of 2,3,7,8-tetrachlorodibenzo-p-dioxin and other polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDDs/PCDFs, calculated as International Toxicity Equivalencies [I-TE]). Mitogens (pokeweed mitogen [PWM], phytohemagglutinine [PHA], concanavalin A [Con A]), as well as an anti-human monoclonal antibody against CD3 were used as proliferation stimulators in vitro. Additionally, the feasibility of using the lymphocyte response to tetanus toxoid was assessed, and the response to this recall-antigen was included in this trial. No decrease in the capacity of 3H-thymidine incorporation was observed with any of the proliferation stimulators in the group of volunteers with the increased TCDD-body burden when compared with volunteers exhibiting TCDD-concentrations in blood fat within the reference range. Regression analysis revealed a slight trend towards an increase for 3H-thymidine incorporation during the stimulation with PHA only. It can be concluded from our data that moderate increases in the TCDD- or I-TE-body burdens do not induce any medically significant changes in the capacity for proliferation of lymphocytes, measured as 3H-thymidine incorporation. PMID- 7830504 TI - Proliferative capacity of marmoset lymphocytes after tetanus vaccination and lack of 2,3,7,8-tetrachlorodibenzo-p-dioxin to reduce a booster effect. AB - Marmosets (Callithrix jacchus) were vaccinated with tetanus toxoid and boostered 3 months and 1 year following the initial immunization. During this period, the proliferative response of lymphocytes (3H-thymidine incorporation) to the recall antigen was measured in vitro in blood samples 7 times. The experimental procedure proved to be suitable to monitor a defined but complex function of the immune system, and to assess possible substance-induced alterations with minimal stress or discomfort for the non-human primates. As a first example, a possible interference by a single very small dose (100 ng/kg body weight) of 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) given at the time of the second booster was evaluated. No reduction in the in vitro response of the lymphocytes to recall antigen was observed under the experimental conditions used, and the extent of the 3H-thymidine incorporation was not significantly different in the groups. When the ratio of the responses between the first and the second booster was taken as a measure, there was a slight but statistically significant increase in this ratio for the lymphocytes of the TCDD-treated marmosets over that of reference animals. The limitations of these attempts to develop a test system and evaluate a substance-induced effect, and possible improvements of the test, e.g. with multivaccination, are discussed. It is suggested to use this approach also after routine multivaccination in children to assess possible substance-induced effects on immunological variables. This would allow an excellent comparison of experimental and clinical data obtained in primates with an identical technology. PMID- 7830505 TI - Purinergic and cholinergic components of bladder contractility and flow. AB - The role of ATP as a neurotransmitter/neuromodulator in the urinary tract has been the subject of much study, particularly whether ATP has a functional role in producing urine flow. Recent studies suggested significant species variation, specifically a variation between cat and other species. This study was performed to determine the in vivo response of cat urinary bladder to pelvic nerve stimulation (PNS) and to the exogenous administration of cholinergic and purinergic agents. In anesthetized cats, bladder contractions and fluid expulsion was measured in response to PNS and to the exogenous administration of cholinergic and purinergic agents. Fluid was instilled into the bladder and any fluid expelled by bladder contractions induced by PNS or exogenous agents was collected in a beaker. The volume was measured in a graduated cylinder and recorded. PNS, carbachol and APPCP produced sustained contractions with significant expulsion of fluid. ATP, ACh and hypogastric nerve stimulation did not produce any significant expulsion of fluid. Atropine, a cholinergic antagonist, inhibited PNS contractions and fluid expulsion with no effect on purinergic actions. There was a significant relationship between the magnitude of the contraction, duration of the contractions and volume of fluid expelled. The data and information from other studies, strongly suggests a functional role for ATP as a cotransmitter in the lower urinary tract different from ACh's role. ATP stimulation of a specific purinergic receptor plays a role in initiation of bladder contractions and perhaps in the initiation of urine flow from the bladder. ACh's role is functionally different and appears to be more involved in maintenance of contractile activity and flow. PMID- 7830506 TI - Effects of feeding lipids of different fatty acid compositions upon rat lymphocyte proliferation. AB - Weanling Wistar rats were fed for 8 weeks on a low fat (3% by weight) diet (LF) or on diets containing 15% by weight hydrogenated coconut oil (coconut oil), cocoa butter, cashew kernel oil (cashew oil), canola oil or soya bean oil (soya oil). Each of the high fat diets resulted in inhibition of spleen lymphocyte proliferation in response to concanavalin A (Con A), a T-cell mitogen. Feeding the soya oil diet caused more than 95% inhibition of proliferation, compared with feeding the LF diet. Amongst the high fat diets, feeding the cashew, canola or soya oil diets resulted in inhibition of proliferation compared with feeding the coconut oil diet while feeding the soya oil diet resulted in inhibition of proliferation compared with feeding the cocoa butter or canola oil diets. Proliferation of lymphocytes in response to Con A was also investigated using whole blood culture. Once again, feeding the soya oil diet resulted in a dramatic decrease in proliferation (80%) compared with feeding the LF diet. Feeding the soya oil diet also inhibited proliferation compared with feeding the coconut oil, cocoa butter or cashew oil diets. Feeding the canola oil diet resulted in inhibition of proliferation compared with feeding the LF or cocoa butter diets. PMID- 7830507 TI - Effect of temperature on opioid dependence and on the abstinence response in the isolated guinea pig ileum. AB - This paper explores, in the isolated guinea-pig ileum, the effects of temperature on the acute development of opioid dependence and on the precipitation of the abstinence response, using as reference the effect of temperature on the response to a standard nicotine concentration. Additionally, the influence of temperature on acute morphine neurodepression was examined. Three experimental groups were included. In the first, the bath temperature was adjusted and maintained along the experimental session (2.5 h) at one of the following values: 28, 32, 36 or 40 degrees C. In the second, the different values of bath temperature were applied only during the period of morphine exposure before testing the abstinence response at 36 degrees C. In the third, all segments were initially incubated at 36 degrees C for 1 h, and afterwards, abstinence and the nicotine response were elicited at the different temperatures mentioned. In all the series, a single challenge naloxone dose (3.1, 10, 31, 100, 316, 1000 or 3160 nM) was administered after 1h of morphine and complete naloxone concentration-response curves were obtained. The abstinence response was expressed as a percentage of the nicotine reference response. All segments showed robust nicotine responses at all the experimental protocols tested indicating that, at the temperature range studied, the contractile mechanisms were impaired. This study showed that changes in bath temperature modify the magnitude of acute morphine neurodepression, and of the abstinence response but did no affect the development of acute opioid dependence. These data, along with several lines of evidence, strongly suggest that acute neurodepression, the development of opiate dependence and antagonist-precipitated abstinence are separable. Results are discussed on the basis of drug-receptor interactions. PMID- 7830508 TI - 'All tragedy is the failure of communication' (John Wilson)--the sad saga of Christopher Clunis. PMID- 7830509 TI - Mental disorder amongst defendants in Liverpool Magistrates' Court. AB - The Home Office advocates development of court liaison schemes to divert mentally disordered offenders into the care of health and social services. No-one has yet evaluated the amount of mental disorder that existing schemes fail to identify. We interviewed 136 defendants who had been detained by the police prior to their first appearance in Liverpool Magistrates' Court for their current alleged offence. We found very little mental illness but high levels of drug and alcohol misuse. Merseyside police policy advocates diversion at the earliest possible point and local general psychiatry services are willing to assess and treat offenders. The defendants with drug and alcohol problems are, however, neglected by the current initiatives in providing for this group. Addressing this need in a population which might not otherwise come to the attention of services could have an impact on personal and public health as well as on offending behaviour. PMID- 7830510 TI - Age estimation by Chinese permanent teeth with image analysis. AB - A total of 567 human teeth except third molars were studied to estimate age, using a combined method of multiple regression analysis of data from a scoring system, direct measurements with image analyser, and logarithmic transformation. As a result, the standard errors of estimate were 4.8-5.4 years in the working sample, and 2.9-5.4 years in the control sample respectively, by using a single tooth. By testing the formulae on forensic autopsy cases in Guang Dong and Guang Xi, (People's Republic of China), it is demonstrated that the standard error of estimate is 3.7 and 2.6 years respectively for any single tooth (incisor, canine, premolar or molar) except the third molar. Age determination from multiple teeth of the same individual has also been studied. As a result, according to the different age grouping, the standard errors of estimate ranged from 0.8 to 2.6 years (2 teeth from the same individual) and 0.6 to 2.3 years (3 teeth from the same individual). It is concluded that the method presented here is helpful in improving the accuracy of age determination from teeth. PMID- 7830511 TI - Aflatoxin exposure in Singapore: blood aflatoxin levels in normal subjects, hepatitis B virus carriers and primary hepatocellular carcinoma patients. AB - Blood screening conducted on Singaporeans over 1991-1992 showed exposure to predominantly aflatoxin B1 and to a lesser extent G1. The extent of exposure to B1 among three groups of residents in Singapore, namely normal subjects (n = 423), hepatitis B virus carriers (n = 302) and primary hepatocellular carcinoma (PHC) patients (n = 58) were extensive as reflected by the positive rates of 15.1, 0.7 and 1.7 per cent respectively. However, the degree of individual exposure to this toxin among the three groups was considered low as shown by the low respective mean blood levels of 5.4 +/- 3.2 (range 3.0-17), 7.7 (range 7.5 7.9) and 7.5 picogrammes per ml of blood. It is not immediately clear whether or not such low levels would precipitate an undesirable health effect. The higher positive rate seen in normal subjects as compared with the other groups could be due to differences in dietary intake of aflatoxin B1, differences in metabolic patterns or both. About 70 per cent of PHC patients studied were carriers. The degree of aflatoxin B1 exposure among normal subjects in Singapore was a factor of 22.1 times less than that in Japan, 40.9 times less than that in Indonesia and 51.3 times less than that in the Philippines. Similarly, the extent of exposure among hepatitis B carriers in Singapore was a factor of 8.2 times, 39.6 times and 24.2 times less than those in the other three Asiatic countries respectively. The results reflected stringent Government control over the quality of food stuff imported into this country. As Singapore imports almost all of its dietary needs from elsewhere, it can afford to be selective at a cost. Aflatoxin M1, a metabolite of B1, was most commonly encountered in the liver tissues of deceased (n = 154) who died of causes other than sickness or disease in 1992-93, consistent with our blood findings of prevalence of aflatoxin B1. High performance liquid chromatography (HPLC) with fluorescence detection using one of the aflatoxins G2 or B2 as an internal standard was used for the detection and quantification of aflatoxins. The use of an internal standard structurally and chemically similar to those required to be quantified minimizes errors in quantifications. This is because differences in the quenching of fluorescence between specimen extracts and spiked-standard extracts were internally standardized and compensated for. The presence of an internal standard also helped to locate aflatoxins of interest more accurately.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7830512 TI - Scientific fraud: the McBride case--judgment. AB - Dr W G McBride, who was a specialist obstetrician and gynaecologist and the first to publish on the teratogenicity of thalidomide, has been removed from the medical register after a four-year inquiry by the Medical Tribunal of New South Wales. Of the 44 medical practice allegations made against him by the Department of Health only one minor one was found proved but 24 of the medical research allegations were found proved. Of these latter, the most serious was that in 1982 he published a scientific journal, spurious results relating to laboratory experiments on pregnant rabbits dosed with scopolamine. Had Dr McBride used any of the many opportunities available to him to make an honest disclosure of his misdemeanour, his conduct would have been excused by the Tribunal. However, he persisted in denying his fraudulent conduct for several years, including the four years of the Inquiry. The Tribunal unanimously found Dr McBride not of good character in the context of fitness to practice medicine. The decision to deregister was taken by a majority of 3 to 1. Since research science is not organized as a profession, there are no formal sanctions which can be taken against his still engaging in such research. PMID- 7830513 TI - Deaths from hanging in the eastern province of Saudi Arabia. AB - An analysis of cases of hanging in the Eastern Province of Saudi Arabia over a period of five years is presented. Of 61 victims investigated there was a high incidence of suicidal hanging among expatriate males of lower socio-economic classes especially Asians, and in particular, Indians. Two distinct patterns of suicidal hanging were observed in this series. The first used a seemingly popular plastic clothes line, with complete body suspension. This produced a narrow ligature mark, commonly deep and high up in the neck, often with internal cervical injuries. In the second, soft cotton cloth was used with partial suspension of the body, which produced a broad, low, ill-defined ligature mark with facial congestion and petechial haemorrhages, but minimal or absent deep neck injuries. Classical external injuries of asphyxial death (congestion of the face and petechial haemorrhages) were more common in cases of partial suspension than in complete suspension. While the mechanism of death in the majority of cases of partial suspension was apparently due to airways or vascular obstruction, death in cases of complete suspension appeared to result from, in addition to obstruction (airways or vascular), vagal stimulation or carotid sinus pressure, or a combination of these. No fracture of the hyoid bone, thyroid cartilage or cervical vertebrae was detected in any of the victims in this series. PMID- 7830514 TI - Serious professional misconduct: the judicial view. PMID- 7830515 TI - Supervised discharge. PMID- 7830516 TI - Employing simulated data to illustrate an important cause of the 'steepling' effect in breath alcohol analysis. AB - The 'steepling' effect (large excursions in analytical data over time) is a debated issue in forensic breath alcohol analysis with various explanations being postulated. Simulated breath alcohol data was generated according to a hypothetical kinetic model where single random samples as well as means of duplicate random samples were plotted with respect to time at 0.2 hour intervals. In addition, the simulated data was compared when both two or more digit treatment was employed. Results showed the occurrence of significant noise or 'steepling' when single, two-digit breath alcohol samples were employed as compared to a four-digit mean computed from three-digit duplicates. The magnitude of variability was quantified by means of nonlinear regression resulting in the residual sum of squares (RSS) = 0.00202 for the single analysis and RSS = 0.00053 for the mean of duplicates. The method of data collection and treatment appears to contribute significantly to the 'steepling' phenomenon. Intuitively, replicate analyses reduce variability and allow for more accurate kinetic modelling employing breath alcohol analysis. PMID- 7830517 TI - Recorded psychiatric morbidity in a large prison for male remanded and sentenced prisoners. AB - The purpose of the study was to establish the proportion of remanded and convicted prisoners who were known from their records to have a psychiatric history. The inmate medical records of 834 out of 864 inmates resident on one day at HM Prison, Leeds, were studied. There was a recorded history of 23 per cent having seen a psychiatrist, 15 per cent having taken drugs and 16 per cent having a history of depression or self-harm. Out of 43 inmates interviewed, 18 admitted to failing to report such a history upon reception. There were eight former long stay psychiatric patients, but only two of these had been in a hospital other than a special hospital or Regional Secure Unit. Out of the 36 residents of the hospital wing, 33 had psychiatric disorders and 10 were awaiting transfer to NHS or private psychiatric services. Various recommendations are made which may lead to an improvement in the medical reception procedure, more informed screening for suicide risk and mental disorder, greater understanding of the psychiatric histories of patients, an audit of prison health care and more effective planning of aftercare. PMID- 7830518 TI - Hemlock: murder before the Lord. AB - Two healthy young men were killed by a plume of hemlock (Conium maculatum) emitted when contaminated incense was vaporized during religious rites about the middle of the thirteenth century BC. PMID- 7830519 TI - Suicidal chloroquine poisoning: report of two cases. AB - Two cases of suicidal chloroquine poisoning are presented. The autopsy, toxicological findings and strategies for preventing self-destruction by this method are discussed. PMID- 7830520 TI - Two undiagnosed cases of intussusception. PMID- 7830521 TI - Fatal classic and exertional heat stroke--report of four cases. AB - Heat stroke is the outcome of impaired heat dissipation which is aggravated by hot and humid environmental conditions. The very young and debilitated on the one hand and healthy individuals under considerable physical stress on the other are vulnerable to heat stroke. Post-mortem findings will depend on the time lapse between the stroke event and death. We report on the deaths resulting from heat stroke in a 12-month-old baby and three 19-year-old soldiers. Reconstruction of the environmental conditions enables elucidation of the circumstances that precipitated exogenous hyperpyrexia. The Discomfort Index presents reliable criteria for the assessment of heat load: values above 28 units are considered as severe heat load and are life threatening. Awareness of the hazards related to severe heat load on the body is helpful in preventing avoidable calamities. PMID- 7830522 TI - Monosymptomatic hypochondriacal psychosis and prolonged solitary confinement. AB - A man previously imprisoned for 11 years developed unremitting and treatment resistant monosymptomatic hypochondriacal psychosis following a period in excess of 12 months in solitary confinement. We are unaware of any other reported incidences of this disorder arising in such circumstances. PMID- 7830523 TI - Treatment of a man with a mild learning disability who was sexually assaulted whilst in prison. AB - The aim of this study is to describe the psychological effects on a man with a mild learning disability who was sexually assaulted whilst in prison, and the treatment which was carried out. J. suffered Post-Traumatic Stress Disorder (PTSD), as defined in DSM-III-R, combined with associated features of depression and anxiety. Treatment involved imaginal exposure to the assault, followed by systematic desensitization to the traumatic experience of imprisonment preceding the assault. Activities were also carried out to develop J.'s self-esteem, coping strategies and anxiety management. The successful outcome of treatment is discussed in relation to models of emotional processing. Some discrepancies between scores on self-evaluation questionnaires and behavioural observations raise issues concerning the best way of assessing treatment outcome for people with learning disabilities. PMID- 7830524 TI - Occipital contrecoup in a case of Hallervorden-Spatz disease. AB - This case report describes the unusual complications of a simple fall in a person with a profound neurological disorder, Hallervorden-Spatz disease. The fall produced a laceration of the forehead, skull fractures and severe occipital contrecoup contusions. Such contrecoup contusions are rare and may be a feature of this case because of the abnormal limb rigidity displayed in Hallervorden Spatz disease. The mechanisms of injury are discussed. PMID- 7830525 TI - The use of the "Appropriate adult" scheme. PMID- 7830526 TI - Herpes simplex virus type 1 replication and IL-1 beta gene expression in mouse peritoneal macrophages activated in vivo by an attenuated Salmonella typhimurium vaccine or Corynebacterium parvum. AB - Activated macrophages (M phi) from mice given Salmonella typhimurium or Corynebacterium parvum were compared with resident peritoneal macrophages at the molecular level for permissiveness for herpes simplex virus type 1 (HSV-1) replication and for expression of interleukin-1 beta (IL-1 beta). Peritoneal macrophages were harvested from mice injected 7 days previously with live, avirulent S. typhimurium (Sal-PM phi) or heat-killed C. parvum (CP-PM phi) and infected with HSV-1 in vitro. Both Sal-PM phi and CP-PM phi were activated as evidenced by characteristic changes in an ectoenzyme, by increased permissiveness for infectious virus production and viral cytopathic effect, and by induction of IL-1 beta mRNA. Analysis at the molecular level revealed that both types of activated M phi demonstrated increased patterns of HSV-1 immediate-early gene expression and viral DNA replication as compared with resident cells. A novel finding was that viral infection reduced IL-1 beta mRNA in both types of activated M beta. This observation has implications for the efficacy of Salmonella vaccines given in proximity to HSV-1 infection and for potential deleterious effects of HSV-1 infection in immunosuppressed patients receiving immunotherapy. PMID- 7830527 TI - Mycobacterial cell wall components induce the production of TNF-alpha, IL-1, and IL-6 by bovine monocytes and the murine macrophage cell line RAW 264.7. AB - Johne's disease is characterized by a chronic enteritis that results in granulomatous inflammation, cachexia, and eventual death of cattle infected with Mycobacterium paratuberculosis. The cytokines tumor necrosis factor-alpha (TNF alpha), interleukin-1 (IL-1), and interleukin-6 (IL-6) have been associated with granuloma formation and wasting in other disease syndromes. The potential role of these cytokines in the development and progression of Johne's disease has not been investigated. Freshly isolated bovine peripheral blood monocytes and the murine macrophage cell line RAW 264.7 were examined for their ability to release inflammatory cytokines in response to mycobacterial cell wall components. Bovine monocytes and RAW 264.7 cells incubated with M. paratuberculosis lipoarabinomannan (LAM), muramyl dipeptide (MDP), or lipopolysaccharide (LPS) released TNF-alpha, IL-1 beta, and IL-6 as detected by appropriate bioassays. Using the RAW 264.7 cells, cytokine mRNA levels were elevated after in vitro incubation with live M. paratuberculosis or LPS as determined using a reverse transcriptase polymerase chain reaction procedure. PMID- 7830528 TI - Sialylation of lipopolysaccharide by CMP-NANA in viable gonococci is enhanced by low Mr material released from blood cell extracts but not by some UDP sugars. AB - Serum resistance of gonococci in most patients is due to sialylation of a Gal beta 1-4GlcNAc group on a conserved 4.5 kDa lipopolysaccharide (LPS) component by host cytidine 5'-monophospho-N-acetyl neuraminic acid (CMP-NANA) catalysed by a gonococcal sialyl transferase. This sialylation is enhanced by a low M(r) factor(s) which, like CMP-NANA, is released in diffusates from high M(r) fractions obtained from sonicates dialysed at 4 degrees C. Also, as shown here, this factor(s) is released when the sonicates are dialysed at 18-20 degrees C. The enhancement of sialylation, first demonstrated using enzymes in gonococcal extracts, has been shown to occur in live gonococci and hence probably to have a role in pathogenicity. Gonococci, emerging from lag phase and incubated for 2 h with CMP-14CNANA fixed up to 90% more radiolabel than controls when the second factor(s) was present; their LPS separated by SDS-PAGE contained more radiolabel than control samples and label was not detected in any other component. Fractions with enhancing activity absorbed maximally at about 260 nm but a mixture of UDP galactose (UDP-Gal), UDP-N-Acetyl galactosamine (UDP-GalNAc), UDP-glucose (UDP Glc) and UDP-N-Acetyl glucosamine (UDP-GlcNAc) showed no significant enhancing activity. The enhancing action of the low M(r) fractions was unaffected by incubation with beta-galactosidase. PMID- 7830529 TI - Development of an intraperitoneal implant chamber for the study of in vivo-grown Pasteurella haemolytica in cattle. AB - An intraperitoneal implant chamber was developed for the study of the in vivo growth of Pasteurella haemolytica in calves. The chamber had a volume of approximately 100 ml and featured an external sampling port which allowed multiple and sequential sampling of the chamber contents. A single polycarbonate diffusion membrane with a pore size of 0.22 micron allowed host peritoneal fluid to diffuse into the chamber and maintained the bacterial population free of white blood cells. Chambers were implanted into the peritoneal cavities of four five month-old dairy-cross calves, demonstrated to be sero-negative by indirect haemagglutination assay. Three days later, four different P. haemolytica isolates, of serotypes A1 or A2, were inoculated into the chambers. In all cases, there was a slow decline in the viable bacterial numbers within the chambers. Western blot analysis of the antibody content of the chamber fluids revealed IgG antibodies to P. haemolytica OMPs in the fluid prior to inoculation and both 9 and 15 days after inoculation. Furthermore, there was no significant change in the IgG antibody content of the chamber fluid, either quantitatively or qualitatively, during the course of the experiment. Analysis of the bactericidal activity of pre-inoculation chamber fluid against the corresponding bacterial isolate suggested that an antibody-dependent complement-mediated process was not responsible for the decline in bacterial numbers. Overall, the chamber design was demonstrated to be extremely effective for in vivo studies of P. haemolytica in calves, allowing easy and regular sampling of the chamber contents and maintaining bacteria free of white blood cells. Although there was a slow decline in bacterial numbers over time, sufficient numbers of cells could be obtained for analysis of cell-surface antigens. PMID- 7830530 TI - Effect of intranasal inoculation of Streptococcus pneumoniae on the structure of the surface carbohydrates of the chinchilla eustachian tube and middle ear mucosa. AB - The changes in the cell surface carbohydrates of the eustachian tube (ET) and middle ear subsequent to the intranasal (i.n.) inoculation of Streptococcus pneumoniae (Spn) type 6A were studied in the chinchilla model of otitis media (OM) using a lectin histochemical technique with six different lectins (SNA, WGA, Succ WGA, BSL II, PNA, ECL). The labeling pattern revealed not only the removal of the terminal sialic acid, but also exposure of N-acetylglucosamine (GlcNAc), a component of the trisaccharide receptor for Spn previously identified on human pharyngeal cells. The removal of sialic acid residues progressed from the nasopharyngeal to the tympanic orifice and was most pronounced in those animals from which Spn could be isolated from the middle ear. Our data indicate an alteration of the normal lectin labeling pattern and exposure of GlcNAc restricted mainly to the roof and neck portion, along the course of the eustachian tube. Exposure of part or all of a Spn adherence receptor structure by the pneumococcal enzymes, may facilitate colonization, invasion of the middle ear, and induction of OM. PMID- 7830531 TI - Vaccination with streptococcal extracellular cysteine protease (interleukin-1 beta convertase) protects mice against challenge with heterologous group A streptococci. AB - Virtually all clinical isolates of group A streptococci secrete a highly conserved extracellular cysteine protease that cleaves human fibronectin and vitronectin, and converts IL-1 beta precursor to biologically active IL-1 beta. Based on the high degree of gene conservation within the species and its role in host pathogenicity, it was postulated that antibodies to the cysteine protease would confer protective immunity against S. pyogenes infection. To test this hypothesis, Swiss CD1 mice were intraperitoneally administered either saline, rabbit IgG, or IgG from rabbits immunized with the protease, and challenged with a highly virulent (minimum lethal dose approximately 10 cfu) clinical isolate of S. pyogenes expressing a heterologous cysteine protease. The results indicate that mice administered IgG from rabbits immunized with purified cysteine protease had significantly enhanced survival when compared with mice given either non specific rabbit IgG (log rank test; chi 2; p = 0.0195) or saline (log rank test; chi 2; p = 0.0002). Moreover, mice actively immunized with the cysteine protease had a significantly longer time to death than the control group (log rank test; chi 2; p = 0.0418). The results show that the cysteine protease elicits non-type specific immunity to challenge with heterologous S. pyogenes. PMID- 7830532 TI - Lancefield group C Streptococcus milleri group strains aggregate human platelets. AB - Lancefield group C Streptococcus milleri group (SMG) strains are the only SMG types that are able to aggregate human platelets. Complete aggregation occurred within 10 min of mixing bacterial cells and platelets together in the ratio 8:1. Substances which (i) chelated cations; (ii) inhibited the cycloxygenase pathway in platelets; (iii) reduced the availability of ADP and disrupted platelet membrane stability; (iv) reduced bacterial aggregation of platelets. The platelet interacting substance on the surface of the SMG appeared to be proteinacious as digestion of bacterial cells with protease inhibited aggregation whereas treatment with lipase, periodate or antisera to Lancefield group C polysaccharide had no effect. PMID- 7830533 TI - Microvascular decompression as a therapy for trigeminal neuralgia. PMID- 7830534 TI - Combined transsylvian-subtemporal exposure of cerebral aneurysms involving the basilar apex. AB - The surgical repair of cerebral aneurysms involving the apex of the basilar artery continues to undergo refinement and evolution. The inherent difficulty in accessing the basilar apex as well as the complexities of the microanatomy render this area a notoriously hazardous and technically challenging region in which to perform microsurgical clipping of cerebral aneurysms. Several operative approaches have been described and are constantly undergoing a state of evolution in the hopes of optimizing the exposure of the distal basilar artery and minimizing the inherent risks of surgery. The consistent decline in operative morbidity has paralleled improved understanding of the microvascular anatomy, both in this region and along the various corridors of approach. No single operative approach is universally superior, considering the wide variability of individual patient anatomy and vascular configurations. Each approach has strengths, weaknesses, and potential complications that must be considered in the though process of planning an operative attack on a basilar apex aneurysm. Intimate familiarity with the microvasculature and the microsurgical anatomy of the region is an imperative prerequisite for the application of any surgical approach to this region. This paper outlines a detailed review of the microsurgical anatomy that is pertinent to microsurgery of aneurysms in this region, and describes an approach referred to as the combined transsylvian subtemporal approach. We have found this operative approach particularly useful in aneurysm surgery of the basilar apex but do not mean to imply that this single approach is suitable for all surgeons or all patients.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7830535 TI - Endoscopic techniques in neurosurgery. AB - Endoscopic techniques have been utilized in neurosurgery for nearly a century. The history of application of these techniques is reviewed. Because of recent improvements in optics, microinstrumentation, and other associated technologies endoscopy has begun to have an impact on neurosurgery. Documented uses of these techniques are reviewed. Greater experience with the techniques, along with continued improvements in the technology, has the potential to result in broadened applications. These procedures can be performed quickly, safely, and effectively, and in selected applications may reduce tissue trauma, risks associated with surgery, hospital stays, and costs. Neuroendoscopy presents exciting possibilities for the future. PMID- 7830536 TI - The medical videoscope: neurosurgery into the 21st century. PMID- 7830537 TI - Short-term response of epiphyseal plate cell populations following selective devascularization and microsurgical revascularization. AB - The distal femoral epiphyseal plates of 21 8-week-old New Zealand white rabbits were totally or partially (nutrient artery only) devascularized, or devascularized and then microsurgically revascularized. Sacrifice was at 24, 48 or 72 hours postoperatively. The heights of the proliferative and hypertrophic zones of the epiphyseal plates operated upon were compared with the contralateral control epiphyseal plates for both the central and the peripheral regions of the epiphyseal plate. Neither extent of devascularization nor revascularization had a significant effect on the height of the proliferative zone of chondrocytes at any of the follow-up intervals. Selective devascularization of the nutrient artery led to a significant increase in height of the central region of the hypertrophic zone of chondrocytes at 48 and 72 hours. Microsurgical revascularization did not lead to a significant change in the height of either the central or the peripheral regions of the hypertrophic zone of chondrocytes at any of the follow up intervals. This study is another 'building block' experiment toward vascularized epiphyseal plate transplantation in humans. PMID- 7830538 TI - A rabbit ear model for cold stress testing. AB - A rabbit ear model resembling the human digit was studied to determine the vascular response of the rabbit ear to a cold stress. Following moderate cooling (10 minutes at 5 degrees - 8 degrees C), auricular blood flow and cutaneous perfusion were reduced. This decrease was reversed by 30 minutes of warming. The response in the rabbit ear to cold stress is similar to that of normal human digits. The similarities between the control of the circulation in human digits and rabbit ears may result from the similarities in digital and auricular vascular receptors and receptor subtypes. Verification of the rabbit model provides an experimental method for obtaining important data regarding digital pathophysiology and the treatment of cold intolerance. Further study with this model will provide clinically relevant information regarding the pathophysiology of digital thermoregulatory abnormalities. PMID- 7830539 TI - Prefabricated flap size limitations utilizing an omental carrier. AB - Several researchers and clinicians have taken advantage of the omentum's rich vascular arcades to support skin grafts. We have previously described an experimental model using the omentum as a vascular carrier for prefabricated free flaps in the rat. In this study, we used this model to compare three different sizes of free flaps using the same size omental carrier. Twenty-four male Sprague Dawley rats were used for this study. A 2.5 x 4 cm patch of omentum with gastroepiploic vessels and its rich vascular arcades was transferred under a bipedicled 2.5 x 6 cm (group I), a 2.5 x 8 cm (group II), and a 4 x 10 cm (group III) right abdominal panniculocutaneous flap. On the seventh postoperative day, the skin pedicles were divided and the skin flap raised as a composite island flap vascularized only by the underlying omental patch. The composite flap was then sutured back in place. Prefabricated flaps examined 7 days postoperatively demonstrated a dye florescence index percent (DFI) of 38.19 +/- 7.52 and 98.13 +/ 3.72% flap survival (FS) in the 6 x 2.5 cm skin flap group; a DFI of 39.96 +/- 6.81% and FS 94.88 +/- 7.08% in the 8 x 2.5 skin flap group (P > 0.05) and a DFI 29.71 +/- 2.85% and FS 57.06 +/- 9.52% in the 10 x 4 cm skin flap group (P < 0.05). India ink injection study and histologic examination confirmed revascularization of the overlying skin at 7 days. This study confirms that omentum can be used as a vascular carrier for prefabricated flaps. However, there is a limit to the size of the flap. A 10 cm2 carrier can support 57% of a 40 cm2 (10 x 4 cm) flap for a total area of 22.8 cm2, more than twice the area of the carrier. PMID- 7830540 TI - Venous flap--its classification and clinical applications. AB - We previously reported pedicled venous flap survival using the rat model, as well as venovenous, arteriovenous, and arterialized flow-through venous flap survival using the rabbit ear model. For this study, we utilized these flaps clinically. Five of seven pedicled venous flaps survived, displaying superficial necrosis. The others became partially necrotic; they were transferred after dissection of a long pedicle vein. Eight of nine venovenous flow-through venous flaps survived; six displayed superficial necrosis. The nonsurviving flap became completely necrotic, possibly because only one donor vein and one recipient vein were used. Six of 10 arteriovenous flow-through venous flaps survived. The remaining four became partially necrotic, possibly because only one vein was anastomosed for outflow. The arterialized flow-through venous flap survived. The pedicled venous and venovenous groups studied seem likely to survive despite superficial necrosis. However, the draining vein should not be dissected more than 5 cm, and many draining veins should be anastomosed with recipient vessels. PMID- 7830541 TI - Hemodynamic comparison of microsurgical repairs for large arterial defects. AB - Twenty-eight femoral arteries in 14 rats were used to compare transverse closures and end-to-end anastomoses in blood vessels approximately 1 mm in diameter. The transverse closures were applied to arteriectomies created by excising one-half the circumference of the vessel over a length of 1 mm. The end-to-end anastomoses were performed after resecting a 1-mm segment. Recordings were made of pre- and postrepair flow velocity and three-point diameter measurements every 5 minutes using a 20-MHz pulsed Doppler velocimeter and digimatic caliper. Maximum reductions in flow velocity were 18% and 31% for the transverse repair and end-to end anastomosis, respectively. Otherwise, intergroup comparisons of the postrepair normalization of both flow velocity and vessel diameter showed few significant differences (P < 0.05). We conclude that arterial defects involving no more than half the diameter of the vessel can be effectively repaired in significantly less time using the transverse closure. PMID- 7830542 TI - Experimental evaluation of small intestinal submucosa as a microvascular graft material. AB - The evaluation of porcine small intestine submucosa (SIS) in a microsurgical model was conducted using an interpositional graft in the rat femoral artery. The SIS grafts were fabricated from processed porcine material that was wrapped around a glass tube and oversewn longitudinally to produce a tubular structure. Of the 42 animals studied, 7 received grafts of untreated SIS (group I), 7 of the grafts were presoaked (PSH) in heparin (Group II), 7 animals were treated with systemic heparin prior to implantation of PSH-SIS (group III), 7 animals received SIS grafts crosslinked to heparin (group IV), 7 animals received SIS grafts crosslinked to urokinase (group V), and 7 animals received untreated autologous epigastric vein grafts (group VI). Patency was assessed postoperatively and selected grafts were evaluated by histology. All SIS grafts failed to maintain patency beyond the first postoperative hour. Histologic examination of the thrombosed graft surfaces revealed a smooth luminal surface with a thick layer of attached fibrin and platelets with a central occluding thrombus. The thickness of the induced fibrin layer appears to narrow intraluminal space significantly at the microvascular level. While having excellent success at vessel diameters greater than 3 mm, and in a variety of nonporcine animal models without xenographic rejection, SIS in this model was thrombogenic despite a favorable surface morphology as demonstrated by SEM. Even with use of heparin and urokinase SIS graft thrombosis occurred. PMID- 7830543 TI - Bipolar coagulation at different energy levels: effect on patency. AB - Determining the extent of damage caused by bipolar coagulation at different levels is critical in microsurgery. If no significant damage occurs at known levels, this technique can be used instead of ligation, saving considerable time. One hundred eighty Sprague-Dawley rats were divided into six groups of 30 each. The effects of bipolar coagulation were assessed at either 2 or 10.4 watts at the junction between the common femoral artery and a branch vessel. Three common clinical settings were used: branch coagulation without interruption of blood flow in the common femoral artery; branch coagulation with interruption of blood flow for 30 minutes; and branch coagulation with arterial anastomosis 3-5 mm distal to the branch. Control procedures without coagulation were performed on the contralateral vessels. The animals were re-explored at 5-7 days. No differences occurred in patency of the coagulated vessels at 2 or 10.4 watts of delivered energy as compared with controls. Recanalization of the side branch occurred in approximately 80% (144/180) of specimens. Extensive damage to endothelium, tunica intima, and tunica media occurred for 1-2 mm around the site of the coagulated branch. The forceps pick-up test demonstrated little difference in flow of the cauterized vessel compared with controls. However, the cauterized vessel had a clinically weaker pulse stream of the transected common femoral artery. Recanalization of the coagulated side branch commonly occurred with a fibrin cap at the end of the vessel. Manipulation of the branch vessel frequently caused rebleeding. Our study shows that bipolar coagulation can be used effectively if coagulation is located at least 2 mm from the main vessel. PMID- 7830544 TI - Congenital pseudarthrosis of the tibia in adults treated by a free vascularized iliac crest graft. AB - Congenital pseudarthrosis of the tibia is a rare condition. It usually presents during early childhood, at which time the surgeon is faced with numerous challenges including difficulties in achieving union and preventing refractures and recurrences. Patients frequently end up with a severe deformity or an amputation. When an adult patient presents with previously untreated congenital pseudarthrosis of the tibia, the surgeon is faced with the additional problems of a long-standing soft tissue contracture and disuse atrophy of the limb. Two patients with congenital pseudarthrosis of the tibia were treated by free vascularized iliac crest graft. Soft tissue deformity was corrected using an external fixation device. The patients were not freely ambulatory before surgery. Union across the pseudarthrosis was achieved in both patients with a double staged operation, within a short period of time. A functional stable painless limb with good knee and ankle motion has allowed both patients to resume bipedal gait and achieve a successful rehabilitation. PMID- 7830545 TI - Modern therapeutic approaches to postmastectomy brachial lymphedema. AB - Over the past 10 years we have treated 36 patients affected by upper limb lymphedema, associated with mastectomy and axillary dissection, by either macrosurgical exeresis or microsurgical techniques. All cases had been unresponsive to prior drug or physical therapy (pressure and thermal therapy). Preoperative upper limb status was thoroughly examined by evaluating volume measurements, dynamic lymphoscintigraphy, venous Doppler fluximetry, ultrasonography, and nuclear magnetic resonance. Selected tests were repeated during follow-up to obtain more statistically significant results. Twenty-five of the 36 patients in our series presented a grade II lymphedema and underwent Degni Cordeiro's microsurgical indirect lymphatico-venous shunt (L.V.S.) surgery. Fifteen of the 25 also received fasciotomies performed along the posterior aspect of the forearm. Three of the 36 patients presented grade II lymphedema and upper limb venous hypertension. These were treated with multiple fasciotomies alone. The remaining eight patients presented grade III lymphedemas. Seven underwent Kondoleon's partial superficial lymphangectomy, and one was treated with Servelle's total superficial lymphangectomy. Of the 36 patients who underwent surgery, only 27 were checked at 6 months; 22 were seen at 18 months. The remaining patients were followed up for too short of a period of time to be considered. Results were arranged into three groups. Classification criteria were: reduction of upper limb dimensions and the presence of the pre-existing symptoms (episodes of lymphangitis, pain, functional deficits. Results were considered good (class 3), fair (class 2), or poor (class 1). A positive clinical picture (class 2-3) was seen in 74% (20/27) at 6 months and in 59% (13/22) at 18 months.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7830546 TI - A simple emergency method for improvising a lost surgical loupe's hinge screw. AB - The unexpected loss of a surgical loupe's hinge screw renders surgical loupes virtually useless, and this can have a profound effect on the performance of a tedious microsurgical procedure. The author has devised what is believed to be an extremely practical and effective method for performing an emergency repair of these glasses that utilizes common operating room suture material. This method has many distinct advantages over numerous makeshift remedies that have been attempted by surgeons over the years. To the author's knowledge, this is the first paper to appear in the literature addressing this familiar and not uncommon problem. PMID- 7830547 TI - Prokaryotic HU and eukaryotic HMG1: a kinked relationship. AB - HU and IHF proteins have long been considered the prokaryotic analogues of eukaryotic histones. Their ability to bend DNA, however, is distinctly similar to that of eukaryotic HMG-box proteins, a recently identified family of chromatin components and transcription factors. In some conditions, HU and HMG1-like proteins can even be swapped, both in vitro and in vivo. In spite of this, HU/IHF and HMG-box proteins are not evolutionarily related, and represent two independent solutions for the same biochemical problem. PMID- 7830549 TI - Proteolytic cleavage and cell wall anchoring at the LPXTG motif of surface proteins in gram-positive bacteria. AB - Many surface proteins are thought to be anchored to the cell wall of Gram positive bacteria via their C-terminus. Cell wall anchoring requires a specific sorting signal, normally located at the predicted C-terminus of surface proteins. Here we show that when placed into the middle of a polypeptide chain, the sorting signal causes the specific cleavage of the precursor as well as the cell wall anchoring of its N-terminal fragment, while the C-terminal fragment remains within the cytoplasm. N-terminal sequencing of the C-terminal cleavage fragment suggests that the cleavage site is located between threonine (T) and glycine (G) of the LPXTG motif, the signature sequence of cell wall sorting signals. All surface proteins harbouring an LPXTG sequence motif may therefore be cleaved and anchored by a universal mechanism. We also propose a novel hypothesis for the cell wall linkage of surface proteins in Gram-positive bacteria. PMID- 7830548 TI - The FeSII protein of Azotobacter vinelandii is not essential for aerobic nitrogen fixation, but confers significant protection to oxygen-mediated inactivation of nitrogenase in vitro and in vivo. AB - The FeSII protein of Azotobacter vinelandii has been proposed to mediate the 'conformational protection' of the molybdenum-dependent nitrogenase components against oxygen inactivation. We have cloned and characterized the structural gene for the FeSII protein (the fesII locus). Hybridization studies did not reveal the presence of fesII-like genes in a number of diverse species of well-studied nitrogen-fixing bacteria, with the exception of Azotobacter chroococcum. The fesII locus is transcriptionally expressed during both nitrogen fixing and non nitrogen fixing conditions, although the level of its message is upregulated by approximately 2.5-fold during nitrogen fixation. The promoter region was identified by primer extension analysis, and is similar to other sigma 70-type promoters. Mutants devoid of the FeSII protein were constructed. These mutants possessed growth characteristics on a variety of carbon substrates during non diazotrophic as well as diazotrophic growth that were essentially indistinguishable from the wild-type strain. Nevertheless, the nitrogenase activity in cell-free extracts is significantly more sensitive to irreversible oxygen inactivation in the mutants as compared with the wild type. When treated with 250 mM NaCl (a condition known to dissociate FeSII from nitrogenase components), the wild-type and mutant extracts were equally hypersensitive to oxygen inactivation. Upon energy starvation, conditions in which 'respiratory protection' is inoperable, the MoFe and Fe proteins of nitrogenase are degraded much more rapidly in vivo in the deletion mutants, compared to the wild type. Strains relying on either the vanadium or the 'iron-only' alternative nitrogenases exhibited similar growth rates irrespective of the presence or absence of the FeSII protein, and the in vitro inactivation of the vanadium nitrogenase components was not affected by the lack of the FeSII protein. All in all, these results are consistent with a model whereby 'respiratory protection' is the major physiological mechanism responsible for the protection of all three nitrogenases during energy-supplemented growth. Upon energy starvation, however, 'conformational protection', mediated by the FeSII protein is capable of temporarily protecting the conventional molybdenum nitrogenase components from inactivation and subsequent degradation. PMID- 7830550 TI - Molecular characterization of catalase from Bordetella pertussis: identification of the katA promoter in an upstream insertion sequence. AB - In this report we evaluate the role of catalase in the survival of Bordetella pertussis within human polymorphonuclear leukocytes (PMNs). Crude extracts of B. pertussis exhibited a single catalase activity when subjected to non-denaturing polyacrylamide gel electrophoresis and assayed for catalase activity. A plasmid containing B. pertussis katA was identified by complementation of UM255, a catalase-deficient strain of Escherichia coli. The nucleotide sequence of katA predicts a 55 kDa protein that shares homology with a class of haem-containing catalases found in both eubacteria and eukaryotes. Analysis of the nucleotide sequence upstream of katA revealed the presence of a copy of IS481, a B. pertussis-specific insertion sequence. The start site of transcription of katA was mapped to a T residue in IS481 by primer extension analysis performed with B. pertussis RNA and a katA-specific primer. A catalase-deficient strain of B. pertussis, DD900, was constructed by gene replacement. DD900 was more sensitive to killing by 1 and 5 mM H2O2 than the parental strain, BP339. However, there was no difference in the ability of DD900 and BP339 to survive for 2 h in human PMNs. This suggests that catalase plays no significant role in the survival of B. pertussis within PMNs. PMID- 7830551 TI - IS231A insertion specificity: consensus sequence and DNA bending at the target site. AB - In its natural host, Bacillus thuringiensis, the insertion sequence IS231A is preferentially inserted into the terminal inverted repeats of the transposon Tn4430. Using a novel transposition assay, we demonstrate that the Tn4430 ends behave as insertion hot spots for IS231A in Escherichia coli. Sequence analysis reveals that IS231A insertion sites match the 5'-GGG(N)5CCC-3' consensus. However, this consensus is not the only determinant of IS231A insertion specificity. Although both Tn4430 ends have identical sequences, one is strongly preferred to the other and the orientation of insertion into this end is not random. We demonstrate that this preference is determined by the flanking regions of the site. These regions display a conserved periodic organization of their sequence which, by conferring anisotropic flexibility, would induce the DNA to bend in a roughly 'S'-shaped structure centered on the target consensus. DNA conformation analysis by polyacrylamide gel electrophoresis indeed shows that the preferred target site of IS231A is flanked by DNA segments curved in opposite directions. We present a model in which DNA bendability and curvature would contribute to the positioning of IS231A transposase on the target DNA. PMID- 7830552 TI - Molecular analysis of the biosynthesis pathway of the alpha-2,8 polysialic acid capsule by Neisseria meningitidis serogroup B. AB - The genes encoding all enzymes necessary for capsular polysaccharide biosynthesis in Neisseria meningitidis B are located on a 5 kb DNA fragment within the chromosomal cps gene cluster. Nucleotide sequence analysis revealed four open reading frames (ORFs), which can encode proteins with molecular masses of 41.4 kDa, 24.9 kDa, 38.3 kDa, and 54.4 kDa, respectively. These ORFs constitute a transcriptional unit as demonstrated by Northern blots. Primer extension analysis revealed that the transcriptional start site is preceded by a nucleotide sequence with homologies to the sigma 70 consensus promoter sequence of Escherichia coli. Functional analysis of the proteins encoded by the ORFs indicated that ORF2 encodes the CMP-NeuNAc synthetase, ORF3 encodes the NeuNAc condensing enzyme, and ORF4 encodes the alpha-2,8 polysialyltransferase. ORF1 encodes an enzyme, which provides a precursor molecule for synthesis of monomeric NeuNAc. In E. coli the subcloned ORFs 2-4 were able to synthesize a high-molecular-weight alpha-2,8 polysialic acid. In contrast, inactivation of ORF1 in the meningococcal genome resulted in a complete loss of capsule production. A regulatory enzyme, the CMP NeuNAc hydrolase, which cleaves CMP-NeuNAc to CMP and NeuNAc, was not found as a part of the capsular polysaccharide biosynthesis gene operon or within the cps gene cluster. PMID- 7830553 TI - Escherichia coli tyrT gene transcription is sensitive to DNA supercoiling in its native chromosomal context: effect of DNA topoisomerase IV overexpression on tyrT promoter function. AB - We have investigated the in vivo DNA supercoiling sensitivity of the Escherichia coli tRNA(1tyr) gene (tyrT) promoter in its normal chromosomal location. Here, the native tyrT promoter is found to be exquisitely sensitive to mutations and to drugs which alter the level of DNA supercoiling. We show that the response of the tyrT promoter to supercoiling is qualitatively similar to that of a known supercoiling-sensitive tRNA gene promoter, hisR. Specifically, treatments which increase in vivo DNA supercoiling levels enhance transcription of these tRNA genes. Particularly striking is the strong enhancement of expression from both promoters by a transposon insertion mutation in the topA gene encoding DNA toposisomerase I. This phenotypic effect can be complemented by providing active topoisomerase I in trans from a recombinant plasmid. Interestingly, it can also be complemented by overexpression of the genes encoding the subunits of DNA topoisomerase IV. We believe that this is the first demonstration that DNA topoisomerase IV can influence gene expression and it suggests that DNA topoisomerase I is partially redundant, at least in E. coli. PMID- 7830554 TI - Repeated polyketide synthase modules involved in the biosynthesis of a heptaene macrolide by Streptomyces sp. FR-008. AB - Genes for biosynthesis of a Streptomyces sp. FR-008 heptaene macrolide antibiotic with antifungal and mosquito larvicidal activity were cloned in Escherichia coli using heterologous DNA probes. The cloned genes were implicated in heptaene biosynthesis by gene replacement. The FR-008 antibiotic contains a 38-membered, polyketide-derived macrolide ring. Southern hybridization using probes encoding domains of the type I modular erythromycin polyketide synthase (PKS) showed that the Streptomyces sp. FR-008 PKS gene cluster contains repeated sequences spanning c. 105kb of contiguous DNA; assuming c. 5 kb for each PKS module, this is in striking agreement with the expectation for the 21-step condensation process required for synthesis of the FR-008 carbon chain. The methods developed for transformation and gene replacement in Streptomyces sp. FR-008 make it possible to genetically manipulate polyene macrolide production, and may later lead to the biosynthesis of novel polyene macrolides. PMID- 7830555 TI - Transcriptional control of toxT, a regulatory gene in the ToxR regulon of Vibrio cholerae. AB - Co-ordinate expression of many virulence genes in Vibrio cholerae is under the control of the ToxR and ToxT proteins. These proteins function in a regulatory cascade in which ToxR is required to activate toxT, and ToxT activates virulence genes. The precise mechanism for ToxR activation of toxT is unknown, but data presented in this report suggest a direct involvement of ToxR. Primer extension and gene fusion analyses identified a ToxR-regulated promoter directly upstream of toxT, immediately following a region of inverted repeats capable of terminating transcription. Gel mobility shift studies indicate that ToxR binds DNA within the inverted repeat region, yet preliminary evidence suggests that ToxR binding alone is not sufficient for activation of toxT. Possible mechanisms of ToxR-dependent toxT expression are discussed. PMID- 7830556 TI - Czc/cnr efflux: a three-component chemiosmotic antiport pathway with a 12 transmembrane-helix protein. PMID- 7830557 TI - From sequence alignment to structure prediction: the case of the OmpF porin family. PMID- 7830558 TI - Mutational analysis of the pseudoknot structure of the S15 translational operator from Escherichia coli. AB - Expression of rpsO, the gene encoding the small ribosomal protein S15, is autoregulated at the translational level by S15, which binds to its mRNA in a region overlapping the ribosome-binding site. By measuring the effect of mutations on the expression of a translational rpsO-lacZ fusion and the S15 binding affinity for the translational operator, the formation of a pseudoknot in the operator site in vivo is fully demonstrated and appears to be a prerequisite for S15 binding. The mutational analysis suggests also that specific determinants for S15 binding are located in very limited regions of the structure formed by the pseudoknot. It is deduced that a specific pseudoknot conformation is a key element for autoregulation. PMID- 7830559 TI - Common features of the NAD-binding and catalytic site of ADP-ribosylating toxins. AB - Computer analysis of the three-dimensional structure of ADP-ribosylating toxins showed that in all toxins the NAD-binding site is located in a cavity. This cavity consists of 18 contiguous amino acids that form an alpha-helix bent over a beta-strand. The tertiary folding of this structure is strictly conserved despite the differences in the amino acid sequence. Catalysis is supported by two spatially conserved amino acids, each flanking the NAD-binding site. These are: a glutamic acid that is conserved in all toxins, and a nucleophilic residue, which is a histidine in the diphtheria toxin and Pseudomonas exotoxin A, and an arginine in the cholera toxin, the Escherichia coli heat-labile enterotoxins, the pertussis toxin and the mosquitocidal toxin of Bacillus sphaericus. The latter group of toxins presents an additional histidine that appears important for catalysis. This structure suggests a general mechanism of ADP-ribosylation evolved to work on different target proteins. PMID- 7830560 TI - Probing the structure-activity relationship of Escherichia coli LT-A by site directed mutagenesis. AB - Computer analysis of the crystallographic structure of the A subunit of Escherichia coli heat-labile toxin (LT) was used to predict residues involved in NAD binding, catalysis and toxicity. Following site-directed mutagenesis, the mutants obtained could be divided into three groups. The first group contained fully assembled, non-toxic new molecules containing mutations of single amino acids such as Val-53-->Glu or Asp, Ser-63-->Lys, Val-97-->Lys, Tyr-104-->Lys or Asp, and Ser-114-->Lys or Glu. This group also included mutations in amino acids such as Arg-7, Glu-110 and Glu-112 that were already known to be important for enzymatic activity. The second group was formed by mutations that caused the collapse or prevented the assembly of the A subunit: Leu-41-->Phe, Ala-45-->Tyr or Glu, Val-53-->Tyr, Val-60-->Gly, Ser-68-->Pro, His-70-->Pro, Val-97-->Tyr and Ser-114-->Tyr. The third group contained those molecules that maintained a wild type level of toxicity in spite of the mutations introduced: Arg-54-->Lys or Ala, Tyr-59-->Met, Ser-68-->Lys, Ala-72-->Arg, His or Asp and Arg-192-->Asn. The results provide a further understanding of the structure-function of the active site and new, non-toxic mutants that may be useful for the development of vaccines against diarrhoeal diseases. PMID- 7830561 TI - New clusters of genes required for gliding motility in Myxococcus xanthus. AB - Gliding is the directed movement of cells across surfaces which occurs in the absence of external organelles such as flagella. Gliding of the complex prokaryote, Myxococcus xanthus, results from the action of two independent sets of genes known as the A (adventurous motility) and S (social motility) genes. Strains with mutations in both systems (A-S-) do not spread on agar surfaces because both individual and group movement is abolished. To generate regulated, transcriptional fusions with operons including A and S genes, we introduced TN5 lac into A- and S- strains to obtain non-motile A-S::Tn5-lac and A::Tn5-lac S- double mutants. These insertions identify five separate clusters of A genes and three separate clusters of S genes on the M. xanthus genome. Some Tn5-lac insertions map near two of the five previously identified motility gene clusters, but at least five new clusters were identified in this search. Single mutations at only one locus, mglA, block motility; the mglA locus is epistatic to A and S motility genes. A- and S- Tn5-lac insertions were transduced into mgl+ and delta mgl strains. The levels of beta-galactosidase activity produced from each A- or S Tn5-lac insertion are similar in otherwise isogenic mgl+ and delta mgl strains, showing that MglA does not regulate the transcription of many A and S genes. PMID- 7830562 TI - Altered pH and lysine signalling mutants of cadC, a gene encoding a membrane bound transcriptional activator of the Escherichia coli cadBA operon. AB - The Escherichia coli CadC protein is required for activation of cadBA transcription under conditions of low external pH and exogenous lysine. cadBA encodes proteins involved in the decarboxylation of lysine to cadaverine, and cadaverine excretion. Sequence analysis suggested that CadC contains a single transmembrane segment separating a DNA-binding domain in the amino terminus from a periplasmic domain. Western analysis of subcellular fractions demonstrated that CadC is expressed and concentrated in the cytoplasmic membrane in cells grown either at an inducing pH (pH 5.8) or at a non-inducing pH (pH 7.6). Eight cadC mutants were isolated based on their ability to confer expression of a cadA-lacZ fusion independent of low external pH or exogenous lysine. Five of these mutants expressed the cadA-lacZ fusion at both pH 5.8 and pH 7.6, but retained the requirement for the lysine signal while the other three mutants displayed pH independence at pH 5.8 but not at pH 7.6. These results support a model in which CadC is a membrane-bound transcriptional activator of the cadBA operon capable of sensing (directly or indirectly) signals generated outside the cytoplasmic membrane as a consequence of acidic pH and lysine. PMID- 7830563 TI - Information essential for cell-cycle-dependent secretion of the 591-residue Caulobacter hook protein is confined to a 21-amino-acid sequence near the N terminus. AB - Recent findings suggest that axial flagellar proteins and virulence proteins of Gram-negative bacteria are exported from the cytoplasm via conserved translocation systems. To identify residues essential for secretion of flagellar axial proteins we examined the 591-residue Caulobacter crescentus flagellar hook protein. Western blot assays of the culture media of strains producing mutant hook proteins show that only residues 38-58 are essential for its secretion to the cell surface. We discuss the observation that this unprocessed 21-residue sequence is not conserved in other axial proteins and does not correspond to the SGL-, ANNLAN- and heptad repeat motifs that are located just upstream of the essential secretion information in the hook protein and are conserved near the N termini of other axial proteins. These motifs, for which an essential role in export or assembly has been proposed, are required for motility. However, we also demonstrate that hook protein can only be secreted when the flagellar basal body is present in the cell envelope. The cell-cycle regulation of hook protein secretion confirms the specificity of the assay used in these studies and suggests that the basal body itself may serve as a secretion channel for the hook protein. PMID- 7830564 TI - Expression of seven members of the gene family encoding secretory aspartyl proteinases in Candida albicans. AB - The opportunistic fungal pathogen Candida albicans produces secretory aspartyl proteinases, which are believed to be virulence factors in infection. We have studied the in vitro expression of seven known members of the SAP gene family in a range of strains and serotypes by Northern analysis. SAP1 and SAP3 were regulated during phenotypic switching between the white and opaque forms of the organism. The SAP2 mRNA, which was the dominant transcript in the yeast form, was found to be autoinduced by peptide products of Sap2 activity and to be repressed by amino acids. The expression of the closely related SAP4-SAP6 genes was observed only at neutral pH during serum-induced yeast to hyphal transition. No SAP7 mRNA was detected under any of the conditions or in any of the strains tested. Our data suggest that the various members of the SAP gene family may have distinct roles in the colonization and invasion of the host. PMID- 7830565 TI - Iron, DtxR, and the regulation of diphtheria toxin expression. AB - In recent years considerable advances have been made in the understanding of the molecular basis of iron-mediated regulation of diphtheria toxin expression. The tox gene has been shown to be regulated by the heavy metal ion-activated regulatory element DtxR. In the presence of divalent heavy metal ions, DtxR becomes activated and binds to a 9 bp interrupted palindromic sequence. The consensus-binding site has been determined by both the sequence analysis of DtxR responsive operators cloned from genomic libraries of Corynebacterium diphtheriae as well as by in vitro genetic methods using cyclic amplification of selected targets (CASTing). It is now clear that DtxR functions as a global iron-sensitive regulatory element in the control of gene expression in C. diphtheriae. In addition, the metal ion-activation domain of DtxR is being characterized by both mutational analysis and determination of the X-ray structure at 3.0 A resolution. PMID- 7830566 TI - Building bridges: disulphide bond formation in the cell. AB - Disulphides are often vital for the folding and stability of proteins. Dedicated enzymatic systems have been discovered that catalyse the formation of disulphides in the periplasm of prokaryotes. These discoveries provide compelling evidence for the actual catalysis of protein folding in vivo. Disulphide bond formation in Escherichia coli is catalysed by at least three 'Dsb' proteins; DsbA, -B and -C. The DsbA protein has an extremely reactive, oxidizing disulphide which it simply donates directly to other proteins. DsbB is required for the reoxidation of DsbA. DsbC is active in disulphide rearrangements and appears to work synergistically with DsbA. The relative rarity of disulphides in cytoplasmic proteins appears to be dependent upon a disulphide-destruction machine. One pivotal cog in this machine is thioredoxin reductase. PMID- 7830567 TI - The RTX haemolysins ApxI and ApxII are major virulence factors of the swine pathogen Actinobacillus pleuropneumoniae: evidence from mutational analysis. AB - The involvement of the RTX haemolysins (ApxI and ApxII) of the swine pathogen Actinobacillus pleuropneumoniae in virulence was investigated using haemolysin deficient mutants constructed by a mini-Tn10 mutagenesis procedure. Two types of haemolysin mutant with single insertions of the transposon were obtained from a serotype 1 strain producing both ApxI and ApxII. One presented a complete loss of haemolytic activity because of the absence of ApxI and ApxII production. The other displayed weaker haemolysis than the wild type and produced only ApxII. The chromosomal regions flanking mini-Tn10 were cloned and sequenced. In the non haemolytic mutant, the transposon had inserted in apxIB, a gene involved in the exportation of ApxI and ApxII toxins. The weakly haemolytic mutant resulted from the disruption of the structural gene for ApxI. Both mutations in the apxI operon were associated with a significant loss of virulence for mice and pigs, demonstrating that haemolysins are involved in A. pleuropneumoniae pathogenicity. The non-haemolytic mutant was apathogenic and the weakly haemolytic mutant retained some virulence for pigs, suggesting that both ApxI and ApxII are needed for full virulence. PMID- 7830568 TI - A Haemophilus influenzae IgA protease-like protein promotes intimate interaction with human epithelial cells. AB - Haemophilus influenzae represents a common cause of human disease and an important source of morbidity and mortality. Disease caused by this organism begins with colonization of the upper respiratory tract. Several studies indicate that H. influenzae is capable of binding to and entering cultured human cells, properties which are potentially of relevance to the process of colonization. In the present study, we isolated an H. influenzae gene designated hap, which is associated with the capacity for in vitro attachment and entry. Analysis of the derived amino acid sequence of hap demonstrated significant homology with the serine-type IgA1 proteases expressed by H. influenzae and Neisseria gonorrhoeae. It is notable that the hap product shares the catalytic domain of the IgA1 proteases and appears to be processed and secreted in an analogous manner. We speculate that the hap gene product is an important determinant of colonization, perhaps enabling the organism to evade the local immune response and thereby persist within the respiratory tract. PMID- 7830569 TI - Growth and viability of Streptomyces coelicolor mutant for the cell division gene ftsZ. AB - A homologue of the bacterial cell division gene ftsZ was cloned from the filamentous bacterium Streptomyces coelicolor. The gene was located on the physical map of the chromosome at about '11 o'clock' (in the vicinity of glkA, hisA and trpB). Surprisingly, a null mutant in which the 399-codon ftsZ open reading frame was largely deleted was viable, even though the mutant was blocked in septum formation. This indicates that cell division may not be essential for the growth and viability of S. coelicolor. The ftsZ mutant was able to produce aerial hyphae but was unable to produce spores, a finding consistent with the idea that ftsZ is required in order for aerial hyphae to undergo septation into the uninucleoid cells that differentiate into spores. PMID- 7830570 TI - Proximal and distal sites bind LuxR independently and activate expression of the Vibrio harveyi lux operon. AB - The LuxR regulatory protein of Vibrio harveyi as well as the autoinducer molecule, N-(3-hydroxybutanoyl) homoserine lactone, are known to be required for expression of luminescence. Although LuxR has been implicated in the activation of the promoter of the lux operon of V. harveyi, and can bind to two distinct sites upstream of the transcription initiation start site, its mode of action is unknown. In the present experiments, mobility shift assays were used to demonstrate that LuxR bound to the distal and proximal sites in an independent rather than co-operative interaction with a much tighter binding to the distal site. Deletion mutation analyses of DNA upstream of the lux promoter followed by transconjugation into V. harveyi in trans using the chloramphenicol acetyltransferase (cat) gene as a reporter demonstrated, however, that the proximal site for LuxR was absolutely critical for promoter activation while the distal LuxR site was only necessary for maximum activation. This result was confirmed by mutation of the proximal site which blocked activation of the lux promoter and binding of LuxR to this site, but did not prevent LuxR binding to the distal site. PMID- 7830571 TI - Observations on the formation of deletions on monomeric and dimeric plasmids in Escherichia coli. AB - We have studied the formation of spontaneous mutations on plasmids present in the monomeric and dimeric states in a recF strain of Escherichia coli. Two test systems were employed: (i) the precise excision of Tn5 from the tetA gene of the plasmid pBR322 and (ii) operator constitutive (Oc) mutations on the pBR322 derived plasmid pPY97. The rate of Oc mutations was increased by a factor of three when this plasmid was present in the dimeric state compared to the monomeric state and the Oc phenotype was caused by small deletions in the operator sequence. No apparent mutational hot-spot was found. The rate of Tn5 excision was increased on dimeric compared to monomeric plasmids. Excision from a dimeric plasmid usually resulted in two types of mutant plasmids; a dimeric plasmid, where the Tn5 had excised from one of the plasmid units, and a monomeric parental pBR322. A mechanisms to account for this is suggested. Complementation tests revealed that the increased mutation rate on dimeric plasmids is the result of dimers being mutaphilic per se, rather than the result of a general, trans acting increase in mutation rates of the host, induced by the presence of the dimeric plasmid. Furthermore, it was found that the rate of Tn5 excision from plasmids in the monomeric state was increased when the region carrying the inserted Tn5 was duplicated. PMID- 7830572 TI - Permeability of the cell wall of Mycobacterium smegmatis. AB - The cell wall of Mycobacterium smegmatis mc2155 was shown to be an effective permeability barrier to hydrophilic compounds. Permeability coefficients to beta lactams ranged from 10 x 10(-7) to 0.5 x 10(-7) cms-1. Cell wall proteins were solubilized with EDTA and Genapol and were tested for channel-forming activity by reconstitution into lipid bilayers. Proteins were able to induce a voltage-gated cation-selective channel. The mycobacterial porin channel appeared to be water filled since the single-channel conductance followed the mobility sequence of hydrated ions in the aqueous phase. On the basis of the Renkin equation and the single-channel conductance, the channel diameter was estimated to be around 3 nm. Model calculations showed that cation selectivity may be caused by four negative point-charges at the channel mouth. The permeability properties of the cell wall of intact cells were in good agreement with those of the reconstituted channel. Negatively charged cephalosporins, cefamandole and cephalothin, diffused at a 10- to 20-fold lower rate than the zwitterionic cephaloridine. The mycobacterial porin represents a major hydrophilic pathway of the cell wall of M. smegmatis. PMID- 7830573 TI - Analysis of the rnc locus of Coxiella burnetii. AB - A 3.2 kb EcoRI genomic DNA fragment of Coxiella burnetii was isolated by virtue of its ability to suppress mucoidy in Escherichia coli. Nucleotide sequence analysis revealed the presence of the genes homologous to rnc, era and recO of E. coli. Suppression of capsule synthesis, measured by beta-galactosidase expression in lon- cps-lac fusion strains of E. coli, is caused by gene-dosage effects of the plasmid-borne rnc genes of either C. burnetii or E. coli. The rnc gene of C. burnetii complemented rnc- E. coli hosts for lambda plaque morphology and stimulation of lambda N gene expression. We also demonstrated heterologous complementation of an E. coli strain defective for the expression of Era, an essential protein in E. coli, using the plasmid-borne C. burnetii era. Under the control of the bacteriophage lambda PL promoter, this 3.2 kb EcoRI DNA fragment directed the synthesis in E. coli of three proteins with approximate molecular masses of 35, 27 and 25 kDa. Antibodies against purified E. coli Era protein cross-reacted with the 35 kDa protein of C. burnetii on Western blots. PMID- 7830574 TI - Strain variation in the katG region of Mycobacterium tuberculosis. AB - Southern blot analysis of chromosomal DNA from clinical isolates of Mycobacterium tuberculosis using cosmid DNA probes revealed extensive strain variation in the katG region of the genome. In addition to deletion of the katG gene itself in some isoniazid-resistant strains, adjacent DNA fragments were missing or altered in a range of drug-sensitive and drug-resistant isolates. A species-specific 2kb Kpnl fragment located 10kb upstream of katG in M. tuberculosis H37Rv hybridized to fragments of differing size in different clinical isolates and was characterized in detail. Sequence analysis of this fragment in detail. Sequence analysis of this fragment showed that it comprised three tandem copies of a novel 75 bp repeat element flanked by multiple copies of the previously described 10 bp major polymorphic tandem repeat of M. tuberculosis (MPTR). The copy number of the 75 bp repeat was found to vary between strains, allowing application of a polymerase chain reaction amplification strategy for strain differentiation. These results indicate that the katG region of the M. tuberculosis genome is highly variable and unstable. The presence of repetitive sequences may contribute to instability in this region of the genome. PMID- 7830575 TI - The tail of a chaperonin: the C-terminal region of Escherichia coli GroEL protein. AB - The active form of the HSP60 molecular chaperone of Escherichia coli, GroEL, is a pair of seven-membered rings. We have used site-directed mutagenesis to construct forms of the 547-amino-acid monomer truncated at the C-terminus. We show here that forms that are 520 amino acids long or longer are close to being fully functional. Removing one further amino acid, however, results in a protein, GroEL519, which retains little function. This truncated form is metabolically stable but is not recovered from the cell in particle form. When synthesized at high levels, it prevents the normal assembly of GroEL547 present in the same cell. When synthesized at low levels, it can be included, probably at low molar ratios, in particles formed by assembly-competent forms of GroEL. This can be seen as partial complementation of the temperature-sensitive mutant groEL44. We conclude that amino acid 520 is crucial for particle assembly. GroEL516 has in vivo properties similar to those of GroEL516 has in vivo properties similar to those of GroEL519, but the still shorter form, GroEL504, appears to be inactive. PMID- 7830576 TI - Overexpression of flbA, an early regulator of Aspergillus asexual sporulation, leads to activation of brlA and premature initiation of development. AB - Aspergillus nidulans reproduces asexually by forming thousands of mitotically derived spores atop highly specialized multicellular organs termed conidiophores. We have identified a gene called flbA (for fluffy low brlA expression) that is required for initiation of A. nidulans conidiophore development. flbA mutants form abnormal colonies that have a distinct fluffy phenotype characterized by tightly interwoven aerial hyphae that autolyse as the colony matures. The requirement for flbA in conidiophore development precedes activation of brlA, a primary regulator of conidiophore development. The wild-type flbA gene was isolated and found to encode a 3.0 kb mRNA that is expressed throughout the A. nidulans asexual life cycle. Overexpression of flbA using an inducible promoter resulted in misscheduled expression of brlA in vegetative cells and caused hyphal tips to differentiate into spore-producing structures. Sequence analysis of a nearly full-length flbA cDNA clone showed that flbA is predicted to encode a 717 amino-acid polypeptide with 30% identity to the Saccharomyces cerevisiae SST2 protein. SST2 is required by yeast cells for resuming growth following prolonged exposure to yeast mating pheromone and for mating partner discrimination. We propose that flbA plays a related role in a signalling pathway for Aspergillus conidiophore development. PMID- 7830577 TI - Multiple protein-DNA and protein-protein interactions are involved in transcriptional activation by MalT. AB - The promoters of the Escherichia coli maltose regulon are positively regulated by the MalT protein, which recognizes a short asymmetric nucleotide sequence that is present as several copies in each promoter of the regulon. We report a detailed biochemical characterization of the interaction of MalT with the promoter of the malPQ operon. The MalT sites in malPp were precisely located and their occupation as a function of MalT concentration was quantified using DNase I and dimethyl sulphate footprinting experiments. The contribution of each site to malPp activity was assessed by introducing mutations that destroy them and measuring the residual in vivo and in vitro activity. Two main results were obtained. First, although the proximal MalT site is centred at -37.5, RNA polymerase is likely to establish a contact required for malPp activity with at least one base pair of the promoter -35 region; this close proximity between RNA polymerase and MalT bound to site 1 suggests that the two proteins interact. Second, even if the interaction of MalT with the three functional sites in malPp is a co-operative process, the MalT molecules bound to the two distal sites play a more subtle role than simply increasing the occupancy of the proximal site and may also contact RNA polymerase. We suggest that, in the nucleoprotein structure responsible for the initiation of transcription, MalT, RNA polymerase and malPp are held together by several weak interactions. PMID- 7830578 TI - Klebsiella pneumoniae genes for citrate lyase and citrate lyase ligase: localization, sequencing, and expression. AB - In the course of studies on anaerobic citrate metabolism in Klebsiella pneumoniae, the DNA region upstream of the gene for the sodium-dependent citrate carrier (citS) was investigated. Nucleotide sequence analysis revealed a cluster of five new genes that were oriented inversely to citS and probably form an operon. The genes were named citCDEFG. Based on known protein sequence data, the gene products derived from citD, citE and citF could be identified as the gamma-, beta-, and alpha-subunits of citrate lyase, respectively. This enzyme catalyses the cleavage of citrate to oxaloacetate and acetate. The gene product derived from citC (calculated M(r) 38,476) exhibited no obvious similarity to other proteins. In the presence of acetate and ATP, cell extracts from a citC expressing Escherichia coli strain were able to reactivate purified citrate lyase from K. pneumoniae that had been inactivated by chemical deacetylation of the prosthetic group. This represents 5-phosphoribosyl-dephospho-acetyl-coenzyme A which is covalently bound to serine-14 of the acyl carrier protein (gamma subunit). CitC was thus identified as acetate:SH-citrate lyase ligase. The function of the gene product derived from citG (M(r) 32,645) has not yet been identified. Expression of the citCDEFG gene cluster in E. coli led to the formation of citrate lyase which was active only in the presence of acetyl coenzyme A, a compound known to substitute for the prosthetic group. These and other data strongly indicated that the enzyme synthesized in E. coli lacked its prosthetic group. Thus, additional genes besides citCDEFG appear to be required for the formation of holo-citrate lyase. PMID- 7830579 TI - Mutants at conserved positions in gene IV, a gene required for assembly and secretion of filamentous phages. AB - The filamentous phage protein pIV is required for assembly and secretion of the virus and possesses regions homologous to those found in a number of Gram negative bacterial proteins that are essential components of a widely distributed extracellular protein-export system. These proteins form multimers that may constitute an outer membrane channel that allows phage/protein egress. Three sets of f1 gene IV mutants were isolated at positions that are absolutely (G355 and P375) or largely (F381) conserved amongst the 16 currently known family members. The G355 mutants were non-functional, interfered with assembly of pIV+ phage, and made Escherichia coli highly sensitive to deoxycholate. The P375 mutants were non functional and defective in multimerization. Many of the F381 mutants retained substantial function, and even those in which charged residues had been introduced supported some phage assembly. Some inferences about the roles of these conserved amino acids are made from the mutant phenotypes. PMID- 7830580 TI - Neisseria gonorrhoeae acquires mutations in analogous regions of gyrA and parC in fluoroquinolone-resistant isolates. AB - Neisseria gonorrhoeae homologues of gyrA and parC have been identified using hybridization probes generated from conserved regions of diverse gyrA genes. These genes have been tentatively identified as gyrA and parC, based on predicted amino acid sequence homologies to known GyrA homologues from numerous bacterial species and to ParC from Escherichia coli and Salmonella typhimurium. The gyrA gene maps to a physical location distant from the gyrB locus on the gonococcal chromosome, which is similar to the situation found in E. coli. The parC gene is not closely linked (i.e. greater than 9 kb) to an identifiable parE gene in N. gonorrhoeae. The gonococcal GyrA is slightly larger than its E. coli homologue and contains several small insertions near the C-terminus of the predicted open reading frame. A series of ciprofloxacin-resistant mutants were selected by passage of N. gonorrhoeae on increasing concentrations of the antibiotic. Sequential passage resulted in the selection of isolates with minimum inhibitory concentrations approximately 10,000-fold higher than the parental strain. Mutations within gyrA resulted in low to moderate levels of resistance, while strains with high-level resistance acquired analogous mutations in both gyrA and parC. Resistance mutations were readily transferred between N. gonorrhoeae strains by transformation. The frequencies of transformation, resulting in different levels of ciprofloxacin resistance, further support the notion that both gyrA and parC genes are involved in the establishment of extreme levels of ciprofloxacin resistance. PMID- 7830582 TI - Two-dimensional exchange spectroscopy of proteins. PMID- 7830581 TI - Elucidation of the mechanism of CryIIIA overproduction in a mutagenized strain of Bacillus thuringiensis var. tenebrionis. AB - NB176 is a Bacillus thuringiensis mutant derived by gamma-irradiation of NB125 Bacillus thuringiensis var. tenebrionis (Krieg). It exhibits two interesting phenotypes: (i) oligosporogeny and (ii) twofold to threefold overproduction of the CryIIIA protein. Southern profiles of the NB176 strain showed an additional copy(s) of the cryIIIA gene located on a 4 kb HindIII fragment, in addition to the expected cryIIIA gene on a 3 kb HindIII fragment. Each cryIIIA gene-bearing HindIII fragment was cloned from NB176. The restriction map of the 3 kb HindIII fragment was identical to that published by Donovan and coworkers. Sequencing of the 4 kb HindIII fragment showed no alterations in the promoter region of the cryIIIA gene but did show replacement of the region immediately following the cryIIIA open reading frame with a sequence encoding a transposase with 50% amino acid homology to that of Tn1000. These findings suggest that the overproduction phenotype of NB176 results from extra copies of the cryIIIA gene produced from a transposition event(s) induced or stabilized by gamma-irradiation. Integration of additional copies of the cryIIIA gene into the native 90 MDa plasmid of the wild type B. thuringiensis var. tenebrionis strain resulted in strains that made enormous crystals, many possessing greatly enhanced insecticidal activity. PMID- 7830583 TI - Pulsed-field gradients: theory and practice. PMID- 7830584 TI - Selective pulses and their applications to assignment and structure determination in nuclear magnetic resonance. PMID- 7830585 TI - Modifications of older model nuclear magnetic resonance console for collection of multinuclear, multidimensional spectral data. PMID- 7830586 TI - Automated and semiautomated analysis of homo- and heteronuclear multidimensional nuclear magnetic resonance spectra of proteins: the program Pronto. PMID- 7830587 TI - Practical introduction to theory and implementation of multinuclear, multidimensional nuclear magnetic resonance experiments. PMID- 7830588 TI - Automated assignment of multidimensional nuclear magnetic resonance spectra. PMID- 7830589 TI - Quantitative information from complicated nuclear magnetic resonance spectra of biological macromolecules. PMID- 7830590 TI - Multidimensional heteronuclear nuclear magnetic resonance of proteins. PMID- 7830591 TI - Chemical shifts as a tool for structure determination. PMID- 7830592 TI - Use of chemical shifts and coupling constants in nuclear magnetic resonance structural studies on peptides and proteins. PMID- 7830593 TI - Assessment of quality of derived macromolecular structures. PMID- 7830594 TI - Nuclear magnetic resonance study of antibodies: a multinuclear approach. PMID- 7830595 TI - Strategy for studying modular proteins: application to complement modules. PMID- 7830596 TI - Two-dimensional nuclear magnetic resonance spectra of paramagnetic systems. PMID- 7830597 TI - Methods to study membrane protein structure in solution. AB - Membrane protein structure is difficult to determine by any technique. NMR spectroscopy of membrane proteins in solution can proceed using methods identical to those that have been successfully applied to numerous water-soluble proteins providing suitable solubilization conditions can be found. Organic solvents and small detergent micelles have correlation times short enough for structure determination based on 1H NOEs. Although it is difficult to generalize as each system is unique, organic solvents and micelles of strong detergents such as SDS are useful for amphiphilic peptides and small membrane proteins, whereas larger proteins need milder treatment to preserve the tertiary structure. Small unilamellar phospholipid vesicles are much too large for NOE-based structure determination, but they still fall under the domain of solution-state NMR and can be useful in certain circumstances. PMID- 7830598 TI - Experimental nuclear magnetic resonance studies of membrane proteins. PMID- 7830599 TI - Investigation of protein motions via relaxation measurements. PMID- 7830600 TI - Nuclear magnetic resonance measurements of slow conformational dynamics in macromolecules. AB - The combined use of rotating-frame relaxation methods, temperature-dependent measurements of line shapes and magnetization transfer experiments allows in favorable cases the examination in some detail of exchange processes that occur on the millisecond time scale. It is possible to determine not only the rate constants, but also the activation parameters and chemical shifts even for events that are in fast exchange on the chemical shift time scale. Such measurements complement the information obtainable from heteronuclear relaxation methods that probe mainly the fast librational motions in macromolecules and may provide information important for functional studies of biological macromolecules. PMID- 7830601 TI - Protein-ligand interactions: exchange processes and determination of ligand conformation and protein-ligand contacts. PMID- 7830602 TI - Nuclear magnetic resonance studies of protein-peptide complexes. PMID- 7830603 TI - Use of nuclear magnetic resonance in probing ligand-macromolecule interactions. AB - Nuclear magnetic resonance techniques can be used to study ligand-macromolecule interactions under a wide variety of conditions. There are a number of different approaches, which are generally applicable under different conditions of exchange rate and binding constant. In the tight binding limit direct structural studies using NOE are possible using labeled ligand (13C, 15N) and/or labeled macromolecule. In the intermediate exchange regime, line broadening complicates the analysis of bound conformations of ligands. However, a good deal of information can be obtained about the binding kinetics and about the number and nature of binding modes when several are present. In such cases it is often best to use an NMR active nucleus which can be directly detected, with high sensitivity. Tritium has good characteristics in this respect, and has been effective in a number of cases. In the fast exchange limit it is often best to use the rapid dissociation of the ligand to transfer structural information from the bound form to the free, where it can be sensitively and selectively detected, often by direct observation of 1H values. There are a number of conditions on the binding kinetics which must be met, and systems with multiple binding sites generally cannot be analyzed. The large number of different NMR approaches which can be used, often only under special conditions of exchange, complicates planning of NMR studies of ligand-macromolecule interactions. However, once the characteristics of binding affinity and exchange rate have been determined, it is usually possible to apply NMR spectroscopy to obtain information about the binding. The instrumental demands for carrying out ligand-macromolecule interactions are generally not more than those required for studies of the macromolecules alone. PMID- 7830605 TI - Monoheme cytochromes. PMID- 7830604 TI - Measurement of homo- and heteronuclear J couplings from quantitative J correlation. PMID- 7830606 TI - Tetraheme cytochromes. PMID- 7830607 TI - Cytochrome c3 (M(r) 26,000) isolated from sulfate-reducing bacteria and its relationships to other polyhemic cytochromes from Desulfovibrio. PMID- 7830608 TI - Hexadecaheme cytochrome c. PMID- 7830609 TI - Ferredoxins. PMID- 7830610 TI - Flavodoxins. PMID- 7830611 TI - Rubredoxin in crystalline state. PMID- 7830612 TI - Characterization of three proteins containing multiple iron sites: rubrerythrin, desulfoferrodoxin, and a protein containing a six-iron cluster. PMID- 7830614 TI - Aldehyde oxidoreductases and other molybdenum-containing enzymes. PMID- 7830615 TI - Desulforubidin: dissimilatory, high-spin sulfite reductase of Desulfomicrobium species. PMID- 7830616 TI - Desulfofuscidin: dissimilatory, high-spin sulfite reductase of thermophilic, sulfate-reducing bacteria. PMID- 7830617 TI - Enzymology and molecular biology of sulfate reduction in extremely thermophilic archaeon Archaeoglobus fulgidus. PMID- 7830618 TI - Purification and properties of cytochrome c-555 from phototrophic green sulfur bacteria. PMID- 7830619 TI - Purification and properties of high-potential iron-sulfur proteins. PMID- 7830620 TI - Computational chemistry and molecular modeling of electron-transfer proteins. AB - The methods of computational chemistry and molecular modeling are becoming more and more accessible to biochemists with the advent of fast, inexpensive graphics workstations and well-tested computer programs. The state of the art in small molecules allows chemists to use these programs as "black boxes" and be confident of the results at an amazingly high level of precision. This is not the case, however, for biological macro-molecules at this time. Therefore, it is necessary before using the programs listed in Section I that we familiarize ourselves with their theoretical basis and limitations. It is also important that they be used in the context of the accumulated literature on their use. The survey given in this chapter is intended as an introduction to these tools and as a source for initiating the discovery process with the literature cited. PMID- 7830621 TI - Nickel-iron-selenium hydrogenase. PMID- 7830622 TI - MOM system keeps pace with practice changes. Technology key to changing recruitment environment for state's doctors. PMID- 7830623 TI - Why health system reform failed. A lighthearted view. PMID- 7830624 TI - Patient-centered care: empowering patients to achieve real health care reform. PMID- 7830625 TI - Court of appeals decision in "Premier Plus" has wide ramifications. PMID- 7830626 TI - The fifth freedom. PMID- 7830627 TI - Aerial evacuation of sick travellers. PMID- 7830628 TI - The state of medical research in Australia. PMID- 7830629 TI - Premature mortality in Australia 1983-1992, the first decade of the AIDS epidemic. AB - OBJECTIVE: To determine the trends in premature mortality due to selected causes in Australia and in selected States for the whole population and for adults aged 25 to 44 years. DESIGN: Analysis of data from the Australian Bureau of Statistics and the National AIDS Registry for the 10 years from 1983 to 1992. Premature mortality was measured in terms of years of potential life lost before the age of 75 years (YPLL-75). Trends in premature mortality due to AIDS were compared with those for lung cancer, melanoma of the skin, breast cancer, diabetes mellitus, acute myocardial infarction, cerebrovascular disease, traffic accidents and suicide. RESULTS: There have been marked increases in premature mortality due to AIDS and suicide in young men and an increase in deaths due to breast cancer in young women over the past decade. The overall number of potential years of life lost has remained constant, partially because these increases have been counterbalanced by declines in deaths from traffic accidents, acute myocardial infarction and cerebrovascular disease. The increasing trend in premature mortality due to AIDS is strongest in New South Wales, followed by Victoria and Queensland, with smaller increases in the other States and Territories. CONCLUSIONS: Apparent advances in medical care have reduced premature deaths from acute myocardial infarction and stroke and public health measures are likely to have reduced traffic accident deaths; but at the same time there have been serious increases in HIV, suicide and breast cancer among young adults. PMID- 7830630 TI - Improving the continuity of care between general practitioners and public hospitals. AB - OBJECTIVE: To improve the quality of clinical care through better continuity of services between the public hospital and general practitioners (GPs), focusing on expediting discharge of patients from hospital through improved use of resources provided by GPs. DESIGN: Stage 1: Participant observation during ward rounds and unstructured interviews to gain an understanding of the perceptions of hospital staff and GPs of the GP's role in the discharge process. Stage 2: Semi-structured interviews with registrars and GPs of 30 patients (who were admitted to a medical ward and discharged to the care of their GP) to get the participants' views of each other's roles in providing continuity of care. RESULTS: There was a general lack of trust on both sides, and poor communication owing to several structural and perceptual problems. Registrars focused on specialist care and outpatient follow-up, being almost oblivious to GP functions, apart from monitoring the management plan developed in the hospital; they made no use of GPs' knowledge of the case or their experience in treating patients within their families and social milieu, and frequently wished to do everything within the hospital. GPs, on the other hand, often felt alienated from the hospital system, although they had much to offer by being able to contribute details of the patient's background and by using their special skills, which went well beyond passively monitoring progress. RECOMMENDATIONS: 1. Information about the patient's GP should be made available to hospital staff. 2. Interns should make telephone calls to GPs after admission and when the discharge date is known. 3. Early-discharge summaries should be forwarded and include: (i) reasons for giving or altering medications; (ii) specific plans after discharge; (iii) information conveyed to the patient and family about the illness; and (iv) a summary of the case by the consultant. 4. Registrars and interns should be educated about the appropriate involvement of GPs in the discharge process and throughout the patient's stay in hospital. 5. Direct involvement of the GP with the patient during hospital stay should be encouraged. 6. A pilot study should be set up to investigate the role of a liaison person in overcoming problems of the transition of care of hospitalised patients to the community. PMID- 7830631 TI - The cholesterol-lowering effect of a breakfast cereal containing psyllium fibre. AB - OBJECTIVE: To determine the cholesterol-lowering effect of ready-to-eat cereal containing soluble fibre as psyllium (86%), oatmeal and barley on the plasma lipids of otherwise healthy men with mild hypercholesterolaemia, who were already eating a diet low in saturated fats. DESIGN: Double-blind crossover trial, lasting 12 weeks, in volunteers eating each cereal for six weeks at home, in Sydney and Newcastle (New South Wales). PARTICIPANTS: Eighty-one men (average age 50 years; range, 31-69 years) who had initial plasma (total) cholesterol concentrations of 5.8-8.8 mmol/L, but did not have major illness, obesity or diabetes, and were not on special diets or taking stool bulkers. INTERVENTION: One box of cereal was eaten each day: control, 60 g wheat/wheat bran (2 g soluble fibre); or test, 50 g of product containing psyllium/oats/barley (12 g soluble fibre). Subjects were allocated at random, when established on a low saturated fat diet, to wheat followed by psyllium cereal or psyllium followed by wheat cereal. MAIN OUTCOME MEASURES: Plasma total cholesterol, high density lipoprotein cholesterol, triglyceride and low density lipoprotein cholesterol concentrations measured twice, four to seven days apart before the start of the trial and then after six weeks of eating each cereal. RESULTS: Compliance was excellent with both cereals. There were no significant differences in subjects' macronutrient intake or body weight between the two six-week periods. Total cholesterol and low density lipoprotein cholesterol concentrations fell significantly on psyllium cereal, relative to wheat cereal, in both periods at both centres (mean -3.2% and -4.4%, respectively). There were no consistent changes in triglyceride or high density lipoprotein cholesterol concentrations. CONCLUSIONS: This type of product, which is easy to consume on a daily basis, is a useful adjunct to the dietary management of mild hypercholesterolaemia. PMID- 7830632 TI - Can patients safely read their psychiatric records? Implications of freedom of information legislation. AB - OBJECTIVE: To assess how suitable psychiatric medical records are for access by patients. DESIGN: We examined a random selection of psychiatric records to identify features which we thought might be confusing or injurious to a patient reading his or her own record. RESULTS: Potentially offensive, alarming or upsetting entries were found in most records. CONCLUSION: Clinicians need to take care in recording information in medical records lest patients be adversely affected by the experience of reading their notes. Access should always be arranged in conjunction with a medical supervisor. PMID- 7830633 TI - Pharmaceutical advertisements in Australian medical publications--have they improved? PMID- 7830634 TI - The hole in the valve: presentation with haemolytic anaemia. PMID- 7830635 TI - Medical relief in central Bosnia. PMID- 7830636 TI - Retreat to Dunkirk. PMID- 7830637 TI - Radiofrequency electric shock and burn. PMID- 7830638 TI - Rhabdomyolysis and acute renal failure after near-drowning in cold salt water. PMID- 7830639 TI - Disaster alert! The role of physician-staffed helicopter emergency medical services. PMID- 7830640 TI - A survey of emergency medical care at Uluru (Ayers Rock). AB - OBJECTIVES: To determine the emergency practice profile of the Ayers Rock population and the health risk of tourist activities. DESIGN AND PARTICIPANTS: A prospective survey of all patients presenting to the medical staff at Ayers Rock Medical Centre between 1 July 1991 and 31 December 1992. MAIN OUTCOME MEASURE: A serious incident was defined as an incident that was life threatening or required more than 1.5 hours of emergency medical attention. RESULTS: There were 255 serious incidents, 40 of which were immediately life threatening and six of which resulted in death. Most serious incidents were not associated with climbing Uluru, but nine of 13 myocardial infarcts occurred on the Rock, all involving tourists (P < 0.001). CONCLUSIONS: Living in or visiting the Ayers Rock area is associated with an increased health risk and the Uluru climb is associated with a high incidence of myocardial infarction. The emergency practice workload is higher than at other comparable rural facilities. PMID- 7830641 TI - Lymphatic flow rates and first-aid in simulated peripheral snake or spider envenomation. AB - OBJECTIVES: To demonstrate and define normal lymphatic transit times by lymphoscintigraphy and to evaluate the efficacy of the currently recommended first-aid measures for the management of snake or spider envenomation. SETTING: The nuclear medicine department of a major teaching hospital. PARTICIPANTS AND DESIGN: Twenty-four subjects received either intradermal or subcutaneous injections of 99mtechnetium antimony sulfur colloid (0.1 mL) in both hands/forearms and feet/legs. This simulated a snake or spider bite. Fifteen of the subjects had first-aid in the form of firm bandages and splints applied to an upper and a lower limb immediately after injection. MAIN OUTCOME MEASURES: The progress of the radiotracer was followed with a large field of view gamma camera. If no egress of radiotracer was seen in the bandaged limbs, the subject walked until radioactivity was detected. RESULTS: The mean (+/- SEM) periphery-to systemic circulation transit time after subcutaneous injection was 58 (+/- 7) minutes. The first-aid was found to be very effective when applied with bandage pressures ranging from 40 to 70 mmHg (5.3-9.3 kPa) in the upper limb and 55 to 70 mmHg (7.3-9.3 kPa) in the lower limb. Lower and higher bandage pressures were ineffective. However, despite first-aid measures, egress of radiotracer, even in the upper limbs, was seen in all subjects who walked for 10 minutes or more. CONCLUSIONS: Firm pressure bandaging is an effective means of restricting the lymphatic flow of toxins after envenomation, provided the bandage is applied within the defined pressure range. Strict limb immobilisation is necessary to minimise lymphatic flow, and walking after upper or lower limb envenomation will inevitably result in systemic envenomation despite first-aid measures. PMID- 7830642 TI - The pressure immobilisation technique. PMID- 7830644 TI - Snakebite in herpetologists. AB - OBJECTIVES: To define the risk of snake envenomation in herpetologists, assess factors which lead to their being bitten, assess their occupational morbidity and propose preventive stratagems. SUBJECTS AND DESIGN: Interview of 14 of the most experienced professional herpetologists in Queensland; and questionnaire to 14 members of the Cape York Peninsula Herpetological Society, Cairns, Queensland. RESULTS: The 28 herpetologists had sustained 119 bites by potentially dangerous species, and hundreds of clinically insignificant bites. Seventeen had been admitted to hospital. Only five had never been bitten by a medically dangerous snake and 14 had been bitten on two or more occasions. Correct first-aid techniques were applied in less than half the bites. Two had permanent morbidity- renal damage, and permanent tissue damage to the hands. Anaphylactic reactions from the repeated use of antivenom did not occur. The experienced herpetologists sustained a life-threatening bite every 10 years (median). Four herpetologists had been bitten by the western taipan (Oxyuranus microlepidotus), the world's most venomous snake. CONCLUSIONS: Herpetologists working with highly venomous snakes are at high risk. Prevention involves recognising the risk; possessing a first-aid certificate; applying standard first-aid if a bite is sustained; carrying a mobile telephone; and not working alone. PMID- 7830643 TI - Red-back spider envenomation in the red centre of Australia. AB - OBJECTIVE: To examine the incidence, symptoms and treatment of red-back spider envenomation at a rural hospital. METHODS: A retrospective review of all patients admitted to the intensive care unit of Alice Springs Hospital with red-back spider envenomation from 1 January 1991 until 31 December 1992. RESULTS: Thirty two patients were identified, of whom 12 were Australian Aboriginals (35%). Mean time from bite to presentation was 21 hours. Twenty-six patients required antivenom. All patients responded well to therapy and adverse reactions to the antivenom were observed. Two antivenom recipients had had previous bites requiring treatment. Aboriginals received antivenom later than non-Aboriginals (27.0 h v. 16.5 h) and this delay was associated with more sweating and fever in Aboriginals. CONCLUSION: Red-back spider envenomation is common in Central Australia. Aboriginals and non-Aboriginals are equally at risk but later presentation is more common in Aboriginals who thereby suffer greater systemic symptoms. Antivenom use is safe and effective. PMID- 7830645 TI - Epidermal ridge patterns in medicine. PMID- 7830646 TI - A psychologist in intensive care. PMID- 7830647 TI - Lymphoma--a personal experience. PMID- 7830649 TI - Radiology. PMID- 7830650 TI - Accuracy of Pap smear screening--is community expectation unrealistic? PMID- 7830651 TI - Patient-to-patient transmission of blood-borne viruses during surgery. A need to set up a sterile anaesthetic field? PMID- 7830652 TI - The true cost of blood collection. PMID- 7830653 TI - Guidelines for no-CPR orders. PMID- 7830654 TI - Measles susceptibility under one year of age and vaccination strategy. PMID- 7830655 TI - Spinal fractures in blowhole jumpers. PMID- 7830656 TI - The use of poorly validated and expensive technology. PMID- 7830657 TI - Dyskinesia presenting as a respiratory emergency. PMID- 7830658 TI - Medicolegal postmortem examination. PMID- 7830659 TI - Muscle toning may be the answer to sleep apnoea. PMID- 7830660 TI - There are days ... and moons ... and public holidays. Self-poisoning is not lunacy. PMID- 7830661 TI - Helicobacter pylori eradication: who, why and how in 1994? PMID- 7830662 TI - Pertussis vaccine--time to stop the confusion. PMID- 7830663 TI - Attitudes of Victorian vaccine providers to pertussis vaccine. AB - OBJECTIVES: To assess the attitudes of Victorian vaccine providers to the pertussis component of the diphtheria-tetanus-pertussis vaccine (DTP), and to examine differences between kinds of health professionals. Also, to assess vaccine providers' understanding of National Health and Medical Research Council (NHMRC) guidelines on childhood immunisation with DTP. METHODS: We conducted a postal survey of 765 randomly selected Victorian health professionals involved in childhood vaccination, including medical officers of health (MOHs), general practitioners (GPs), maternal child health nurses (MCHNs), paediatricians and environmental health officers (EHOs). RESULTS: Most (83%) knew that the pertussis component was most frequently responsible for adverse effects of DTP. Thirty-four per cent of all respondents (9% MCHNs, 23% paediatricians, 24% MOHs, 34% EHOs and 39% GPs) believed that pertussis vaccine causes permanent brain damage, 34% did not, and 32% were unsure; 39% believed it causes encephalopathy. Only 9% described vaccination practices entirely in accordance with NHMRC guidelines. Up to 58% of respondents would give diphtheria-tetanus vaccine (DT) in situations when DTP was indicated, and up to 54% would give DTP when it is clearly contraindicated. There was no correlation between knowledge of the safety of DTP and vaccination practices. CONCLUSION: Victorian vaccine providers have doubts about the safety of pertussis vaccine. There is a need to ensure the availability and clarity of immunisation guidelines for health workers, to educate them about the use of pertussis vaccine, and to ensure that this knowledge is put into practice. PMID- 7830664 TI - The vaccination status of aboriginal children in the North Coast Health Region of New South Wales. AB - OBJECTIVE: To determine the vaccination status of Aboriginal children resident in the North Coast Health Region of NSW. DESIGN: Cross-sectional descriptive study. SETTING AND PARTICIPANTS: The vaccination status of Aboriginal children aged 4 months to 11 years and resident in selected villages/isolated communities, small and large towns in the North Coast Health Region of NSW was determined by review of vaccination records. Data were obtained from general practitioners, the Aboriginal Health Service, Community Health Centres and Local Government Councils. MAIN OUTCOME MEASURES: Vaccination status according to the childhood immunisation schedule recommended by the National Health and Medical Research Council, defined as fully or partially documented, with a generous lag time. RESULTS: The study population comprised 1179 children--55% of the estimated Aboriginal population under 12 years of age in the North Coast Health Region. Data collection on Sabin vaccine was incomplete and was not included in the analysis. Of 1094 children whose records were analysed, 9% had fully documented and 27% fully or partially documented evidence of up-to-date vaccinations. For measles vaccination, 28% of children aged 18 months or more had fully documented and 35% fully or partially documented evidence of vaccination. There was no fully documented evidence of any vaccinations for 52% of children. CONCLUSION: The vaccination status of Aboriginal children in the North Coast Health Region is poor. The 1989-1990 National Health Survey showed overall vaccination rates for NSW and Australia to be more than twice those found for this population. PMID- 7830665 TI - Homoeopathic vaccination. What does it mean? Immunisation Interest Group of the Royal Alexandra Hospital for Children. AB - OBJECTIVE: To document and review the theoretical basis of vaccination practices and policies of homoeopaths in Sydney. METHODS: After preliminary interviews, a questionnaire was designed and mailed to all 29 homoeopaths listed in the Sydney telephone directory and practising in central Sydney. RESULTS: Six homoeopaths (21%) returned the completed questionnaire and 10 others were interviewed. Their attitudes to vaccination varied widely. The two medically qualified homoeopaths recommended orthodox vaccination routinely for most children. Five of the six respondents did not recommend routine vaccination by any method. We could not obtain any scientific data about the contents of homoeopathic vaccinations. No reports evaluating homoeopathic vaccination were found in the peer-reviewed medical literature from 1982-1993. CONCLUSIONS: Homoeopathic vaccination practices are variable, with no statutory body regulating them in Australia. Medically qualified homoeopaths frequently recommend orthodox vaccination. PMID- 7830666 TI - Percutaneous fluoroscopic gastrostomy. A safe option? AB - OBJECTIVE: To assess the safety of percutaneous fluoroscopic gastrostomy (PFG) tube insertion for enteral nutrition. DESIGN AND SETTING: The records of 70 consecutive patients who had a PFG procedure at a tertiary referral hospital (Princess Alexandra Hospital) were analysed retrospectively. MAIN OUTCOME MEASURE: Incidence of morbidity and mortality from PFG. RESULTS: Sixty-nine of 70 procedures were successfully performed. There were two deaths secondary to aspiration pneumonia and a morbidity rate of 13%. These figures are comparable with results from other series. CONCLUSION: PFG is a safe, effective procedure for enteral nutrition. PMID- 7830667 TI - Hysterectomy experience among mid-aged Australian women. AB - OBJECTIVES: To determine the rate of oophorectomy in, use of hormone replacement therapy by, and health, social and lifestyle factors of, mid-aged Australian women who have undergone hysterectomy. DESIGN AND PARTICIPANTS: A community-based cross-sectional survey by telephone interview of a random sample of 2001 Australian-born Melbourne women aged between 45 and 55 years. MAIN OUTCOME MEASURES: The health status, sociodemographic and lifestyle correlates of women who had undergone hysterectomy compared with women in the natural menopause transition. RESULTS: Twenty-two per cent of the women had undergone hysterectomy. Of these, 21% had had one ovary removed, and 20% both. Mean age at hysterectomy was 40.4 years. There was no trend in the bilateral oophorectomy rate over the last two decades. Current hormone replacement therapy use increased significantly with surgery, from 17% of non-hysterectomised women to 31% of hysterectomised women, and 49% for women who had undergone hysterectomy and bilateral oophorectomy. Hysterectomised women were significantly more likely to be of lower educational level, and to report a history of troublesome premenstrual complaints, more dilatation and curettage procedures and nongynaecological operations, and use of prescription medications. CONCLUSIONS: Social and pre existing health problems influence hysterectomy rates. Many women undergo oophorectomy at hysterectomy despite limited evidence of benefit. PMID- 7830668 TI - Training for rural general practice. AB - OBJECTIVE: To identify requirements for vocational training and continuing education programs in rural general practice. DESIGN: A questionnaire was sent to all 487 rural doctors and 140 metropolitan and 140 provincial city general practitioners (GPs) in Queensland. A sample of medical educators, health professional and consumer representatives and rural doctors was also interviewed. Responses were compared by geographical area, practice characteristics and level of postgraduate training. RESULTS: There are significant differences between rural and urban practice profiles. Rural doctors have to practise a range of clinical skills in an environment with restricted access to health professional support, although the need for advanced training in procedural or other skills depends on the type of rural practice. Rural and urban doctors want more influence in determining continuing medical education (CME) programs. Interactive learning methods were rated as the most effective education methods by both rural and urban GPs. Rural doctors were less likely to consider that they spent enough time on CME. CONCLUSION: Vocational training programs should accommodate various rural career objectives, including those requiring advanced levels of procedural work. There is a significant unmet demand for CME tailored to the needs of individual doctors, both rural and urban, but distance and isolation may make this more critical in rural practice. These issues need to be addressed as training opportunities can contribute to improved retention of the rural medical workforce. PMID- 7830669 TI - Total hepatectomy and liver transplantation as a two-stage procedure in fulminant hepatic failure. PMID- 7830670 TI - Mononeuritis multiplex after coelenterate sting. PMID- 7830671 TI - Success of a new health administration strategy. The patient-focused institute with a tripartite management. AB - As the result of the restructuring and decentralisation of the administration of St Vincent's Hospital, Sydney, I was Clinical Chief of a pilot "institute" for three years operating within a "patient-focused model" in hospital management. By the end of the trial, we had improved performance despite reductions in hospital and unit budgets. PMID- 7830672 TI - Adverse Drug Reactions Advisory Committee. Gynaecomastia in association with calcium antagonists. PMID- 7830673 TI - Gynaecology. PMID- 7830674 TI - The human toxicity of marijuana. PMID- 7830675 TI - Needlestick injury in practice. PMID- 7830676 TI - The evidence in favour of immunisation--a world without smallpox--a world without polio. PMID- 7830677 TI - Early medical journals of Australia. PMID- 7830678 TI - HTLV-I and infection control. PMID- 7830679 TI - The prevalence of tuberculosis infection among year 8 school-children in inner Sydney in 1992. PMID- 7830680 TI - Drug-induced hyperprolactinaemia. PMID- 7830681 TI - Beware of sharks. PMID- 7830682 TI - Isolated renal mucormycosis. PMID- 7830683 TI - Tachyphylaxis and oestradiol implants. PMID- 7830684 TI - The implementation of casemix in Victoria--a clinician's view. AB - Although a number of concerns remain, casemix-based funding is seen by clinicians in Victoria to be a more equitable way of determining public hospital inpatient budgets than historical allocation, and will provide a valuable source of data for service provision planning. The concerns in particular are the inadequacy of the current Australian national diagnosis-related groups 2 system to classify modern clinical practice and describe complex patients; the absence of adequate baseline data to allow an accurate assessment of the impact of casemix-based funding on quality of care; the lack of direct recognition within diagnosis related groups of the training, research and development roles of public hospitals; and the instability of a funding system which is in evolution. PMID- 7830685 TI - Casemix payment in the real world of running a hospital. AB - The Victorian casemix funding initiative has achieved initial success in implementing massive budget cuts while increasing hospital throughput and reducing waiting lists. For hospitals to survive, the relationship between casemix and resource use must be managed and this can only be achieved by the involvement of clinicians. With effective information systems and accommodating clinicians, games to maximise casemix, and hence revenue, will undoubtedly emerge. Side effects may include reduced access to "unprofitable" services, increasing pressure on "unprofitable" clinicians and the wooing of "profitable" ones, increasing difficulty in delivering continuity of care and the politicisation of the diagnosis-related groups pricing system. In the end, State governments will be left with a complex control system without resolving the fundamental dilemma inherent in being both the provider of hospital care and the payer. PMID- 7830686 TI - Quality of care under casemix. AB - The introduction of casemix funding in some States has led to concerns that hospitals, faced with budgetary problems, may be tempted to discharge patients prematurely after inadequate treatment--the "quicker and sicker syndrome". There are no significant Australian data on quality of care before and after casemix funding, but a large study in the United States found that, in general, there was no evidence of a deterioration in care. Contrary to expectation, readmission rates were unaltered. There was, however, some evidence of an increase in discharge of patients in an unstable state and more were transferred to nursing homes. There are significant reasons why these conclusions can not be readily transported to the Australian environment, and there is a need to monitor the discharge status of patients, particularly the frail elderly, with casemix funding in Australia. PMID- 7830687 TI - The casemix conundrum--trick or treat? PMID- 7830688 TI - Devolved clinical management and casemix. AB - Devolved clinical management aims at greater medical and nursing involvement in the management of health resources and focuses on achieving measurable improvements in patient care through better use of resources. It permits the major drivers of the health care system (doctors), in collaboration with the major direct care providers (nurses), to be not only effective at allocating resources but also effective resource users. Casemix is a classification of patient care episodes based principally on resource use and can assist in the process of managing health services. We discuss the relationship between devolved clinical management and casemix systems. Health care organisations must move towards devolved clinical management, with a greater focus on the patient and a greater emphasis on accountability among all clinical disciplines. PMID- 7830689 TI - Casemix classification and health care of the elderly. AB - The Australian national diagnosis-related groups (AN-DRGs) patient classification has highlighted the distinction between different categories of inpatient care and ambulatory care, and the need for an explicit definition of boundaries of associated categories. A nationally consistent definition of these patient care categories, and of episodes of care according to illness acuity, will facilitate the design of additional casemix classifications to supplement AN-DRGs. Specific features of the AN-DRGs classification will have a major impact on health care of the elderly through incentives created by funding arrangements based on this classification. The use of age as an AN-DRG classification criterion, as a surrogate for definitive secondary diagnoses, should be regarded as an interim measure pending improvement in medical record documentation, further analysis of the relationship of age partitions to these secondary diagnoses, and ongoing improvement of AN-DRG design. The complex process of development of casemix classifications for subacute and ambulatory care has commenced, and will also have a profound impact on health care of the elderly and on all specialities concerned with both acute and chronic illness, again because of financial incentives in the classification design. Funding for development and refinement of each of these casemix classifications will be required if the anticipated benefits are to occur. PMID- 7830690 TI - Are casemix developments meeting the needs of paediatrics? AB - There are many advantages in the use of casemix measures for financing acute hospitals, but there are deficiencies in the diagnosis-related groups (DRGs) classification for paediatrics. Some, such as poor measurement of severity, inability to classify appropriately some operating room procedures and an inappropriate mix of uncommon complex paediatric procedures and common straightforward adult procedures in the one DRG, are intrinsic to the system and not easy to change. Costing studies must be sufficiently sophisticated to determine the increased costs of nursing a child in hospital if cost weights are not to disadvantage children. PMID- 7830691 TI - The future of casemix in emergency medicine and ambulatory care. AB - The selection of appropriate non-inpatient casemix classification systems is pivotal to the overall success of casemix in Australia. Before implementation, an extensive review and evaluation of issues relating to non-inpatient casemix must be undertaken in conjunction with inpatient casemix to avoid adverse economic and clinical outcomes. Here, we review the background to and current status of non inpatient casemix classification systems. The current Commonwealth/State research agenda is defined and possible options for both classification and funding of non inpatient services are described. PMID- 7830692 TI - Making casemix work for psychiatry. AB - Providers of mental health and substance abuse care cannot afford to ignore the existence of casemix descriptions of their services. As casemix comes to be the predominant language used to describe the products of hospital care, its use will inevitably impinge upon psychiatric services. The psychiatric components of the Australian national diagnosis-related groups classification 1 and 2 (AN-DRG 1 and 2) do not describe the relevant products with great accuracy. We review some possible reasons for this and the effects on the homogeneity of resource consumption of technical procedures, such as trimming of data sets, in the context of the current casemix system and that proposed for AN-DRG-3. The evolution of a casemix system which does justice to current and future psychiatric services will be a complex process. Some of the crucial areas are discussed. Clinicians involved in mental health and substance abuse care must continue to advocate for the resources and effort needed to improve casemix information in their area. PMID- 7830693 TI - Casemix issues for nursing. AB - The diagnosis-related groups (DRGs) patient classification system provides information about the type and volume of acute inpatients treated, as well as the length of stay and cost of treatment. Nurses have been involved in casemix development in Australia, providing advice to government departments on nursing issues; researching the relative cost of nursing patients in one diagnosis related group compared with another; budgeting nursing resources for casemix treated; and using casemix information to change practices to achieve more efficient use of resources and maintain quality of care. Casemix information allows nurses to contribute to the management of clinical services in partnership with other clinicians and managers. PMID- 7830694 TI - Casemix--an AMA perspective. AB - The introduction of casemix payment systems into Australia's public hospitals is an inevitability which the Australian Medical Association has now begun to address. A greater involvement of clinicians in the design and implementation of casemix can add substantial quality to these systems. However, there is concern that a proliferation of separate casemix systems may be contrary to overall health policy developments and that governments will not understand the limits of casemix. Recent attempts to include medical payments within a casemix payment system in the private sector faced our united opposition. Finally, special care needs to be taken to ensure that the introduction of a casemix payment system does not further disadvantage access to high quality health care for Aborigines. PMID- 7830695 TI - Clinical representation in the development of casemix: measures and applications in Australia. AB - The Australian Casemix Clinical Committee coordinated the clinical evaluation of inpatient casemix classifications leading to the development of Australian national diagnosis-related groups 1, 2 and 3. It has provided and will continue to provide advice on clinical matters associated with casemix activities to the Commonwealth and State health authorities, public and private hospital associations, insurers and the clinical professions. In future, all clinicians will be expected to understand casemix, diagnosis-related groups and cost weights, especially those relevant to their speciality. PMID- 7830696 TI - Development of AN-DRGs: meeting the concerns of clinicians. AB - The diagnosis-related group (DRG) classification has been the centre of Commonwealth and various State initiatives to modify significantly the basis for funding of public hospitals in Australia. The classification has been extensively criticised by Australian clinicians as being out of date and inappropriate for several areas of medicine. Developments in Australia to improve the DRGs classification have led to the Australian national version, AN-DRGs. The differentiating features of AN-DRGs are summarised and priority areas for further development are suggested. Further substantial improvement in the classification can be obtained only if new approaches to classification design are considered and if it is supplemented by measures of severity of illness. PMID- 7830697 TI - [Decreasing cholesterol is life extending]. PMID- 7830698 TI - [Acute and chronic diarrhea. A differential diagnostic and therapeutic problem]. PMID- 7830699 TI - [Better health with a vegetarian diet?]. PMID- 7830700 TI - [Smoking. Public health and economic aspects of tobacco use]. PMID- 7830701 TI - Occupational silicosis--Ohio, 1989-1994. AB - Silicosis is a chronic lung disease associated with the inhalation and pulmonary deposition of dust that contains crystalline silica. Through the Sentinel Event Notification System for Occupational Risks (SENSOR)* program, CDC's National Institute for Occupational Safety and Health (NIOSH) is assessing practical models for implementing state-based surveillance of silicosis and linking follow up intervention activities to surveillance reports. From 1989 through 1992, the Ohio Department of Health (ODH) SENSOR program identified silicosis cases through reports of Bureau of Workers' Compensation (BWC) claims, physician reports, and death certificates. The addition in 1993 of hospital discharge reports as an ascertainment source resulted in a substantial increase in the number of silicosis case reports identified annually (Table 1). This report describes the investigation of a case of occupational silicosis in Ohio and summarizes the impact of hospital-based reporting on surveillance for silicosis in Ohio during 1993-1994. PMID- 7830702 TI - Update: acquired immunodeficiency syndrome--United States, 1994. AB - During 1994, state, local, and territorial health departments reported to CDC 80,691 cases of acquired immunodeficiency syndrome (AIDS) among persons in the United States, which followed the 106,618 cases reported in 1993. The number of cases reported in each of these years was greater than that reported in 1992 (47,572) and followed the expansion of the AIDS surveillance case definition for adolescents and adults implemented on January 1, 1993 (1-3). Based on analyses using consistent definitions, the rate of AIDS-related illnesses increased 3% in 1993 compared with 1992; a similar increase is expected for 1994 compared with 1993 (3). This report summarizes the characteristics of AIDS cases reported in 1994 and compares these findings with those in 1993. PMID- 7830703 TI - Acute pulmonary hemorrhage among infants--Chicago, April 1992-November 1994. AB - A cluster of cases of acute pulmonary hemorrhage of unknown etiology occurred among eight infants in Cleveland during January 1993-November 1994 (1). During the investigation of these cases, a similar cluster was identified in the Chicago area. From April 1992 through November 1994, seven infants with acute pulmonary hemorrhage of unknown etiology were admitted to hospitals in the Chicago area. Four of the infants were treated at the same hospital in which, during the preceding 3 years (1989-1991), one case of pulmonary hemorrhage among infants had been diagnosed. This report summarizes the preliminary results of the ongoing epidemiologic, clinical, and laboratory investigations of these cases by pediatric pulmonologists in Chicago, the Illinois Department of Public Health, the Chicago Department of Public Health, the Cook County Department of Public Health, and CDC. PMID- 7830704 TI - Transmission of pertussis from adult to infant--Michigan, 1993. AB - During 1993, a total of 6586 pertussis cases was reported in the United States, including 675 (10%) cases among persons aged > 19 years. However, the total number of cases probably was substantially higher because only an estimated 10% of all pertussis cases are reported (1); underreporting is greater among adults, who often have only a mild cough. This report summarizes the investigation of two cases of pertussis in which transmission occurred from an adult resident of Massachusetts who was visiting the residence of an infant in Michigan. PMID- 7830705 TI - Controlling lead toxicity in bridge workers--Connecticut, 1991-1994. AB - Workers involved in the repair of infrastructure--including bridges and roads- are at risk for exposure to lead and lead poisoning (1,2). Because of these risks, in 1990, the Yale University School of Medicine, the Connecticut Department of Public Health and Addiction Services (CDPHAS), the Connecticut Department of Transportation (CONNDOT), and CDC's National Institute for Occupational Safety and Health (NIOSH) initiated the Connecticut Road Industry Surveillance Project (CRISP) to reduce lead toxicity in bridge workers through the incorporation of protective measures into contracts in addition to the use of regulatory measures. This report describes an assessment of the impact of this program. PMID- 7830706 TI - [Analyses of PCNA and AgNOR on advanced colorectal cancer as predictive indicators of the prognosis]. AB - As part of a search for predictive indicators of the prognosis of advanced colon cancers, the significance of PCNA and AgNORs in terms of grading of biological malignancy was investigated. In 47 selected cases, which had been sufficiently followed up for the present study, PCNA labeling indices (PCNA LI) were 20.96 +/- 8.87 and 54.78 +/- 11.35 in normal colonic mucosa and colon cancer, respectively. With survival durations of more or less than 5 years, the PCNA LI values were 57.27 +/- 9.56 and 48.27 +/- 13.37, thus, suggesting a decrease with poor prognosis. PCNA LI decreased in proportion to the depth of cancer invasion and the progression of stage. In all of these cases statistically significant differences were apparent, whereas other histopathologic factors did not demonstrate any correlation. Numbers of AgNORs were 1.31 +/- 0.10 and 2.43 +/- 0.39 in normal tissues and cancers, the differences being statistically significant. However, no correlation with prognosis or histopathologic factors was noted for this parameter. In conclusion, our data suggest that PCNA LI might be an important predictive indicator of prognosis in advanced colon cancer. In contrast, AgNORs are of no assistance with this problem, although use of both or combination might facilitate differentiation between benign and malignant lesions. PMID- 7830707 TI - [The relationship between hepatoma and portal vein]. AB - Hepatic cells receive dual blood supply of the arterial and portal systems, but hepatoma has been thought to be supplied completely by hepatic artery. However, transcatheter hepatic artery embolization (TAE) has not been able to damage hepatoma entirely. For the study on the relationship between hepatoma and portal vein, I gave intraportal infusions of bromodeoxyuridine. (BrdU), an analogue of thymidine, to 10 patients with hepatoma at the time of surgery, and counted BrdU positive nuclei immunohistochemically using the anti-BrdU monoclonal antibody. The labeling index, or percentage of BrdU-labelled cells, was 2.0 +/- 1.1% (mean +/- SD) in the cases without TAE and 11.9 +/- 4.2% in the other after TAE. On the other hand, examining the specimens with Microfil injected into the portal branch showed the distribution of portal branches in the hepatoma by radiograph or microscope. It is concluded that hepatoma does not receive arterial blood supply alone but the portal vein participates in vascular distribution of hepatoma, and the participation gets larger after TAE. It is suggested that this finding could be of great importance in planing treatment of patients with hepatoma. PMID- 7830708 TI - [Study on the expression of oncogene mRNA in hepatocellular carcinoma using in situ hybridization technique]. AB - Expression of oncogene mRNA was investigated in 37 cases of hepatocellular carcinoma (HCC) surgically resected using in situ hybridization (ISH) technique. C-myc, c-Ha-ras and N-ras DNA probes labeled with biotin were used. The hybrids were detected by streptavidin-biotin alkaline phosphatase staining. Thirteen cases of liver cirrhosis and 16 cases of non-cirrhotic liver were also examined as controls. In HCC cases, c-myc mRNA was expressed in 15 of 37 cases. The c-myc positive cells were found unevenly both in cancerous regions and in non-cancerous regions, being mainly distributed near the cancer capsule. The hybrids were detected mostly in cytoplasm of cancer cells. In some cases, they were seen not only in the parenchymal cells but also in the non-parenchymal cells, such as histiocytes, Kupffer cells and fibroblastic cells. In control cases, c-myc mRNA was expressed in five of 13 cases of liver cirrhosis and in three of 16 cases of non-cirrhotic liver. The expression of c-Ha-ras mRNA could be detected in only three of 37 cases of HCC. These three cases were early staged HCC. The expression of N-ras mRNA was detected in five of 32 cases examined of HCC. These five cases were differentiated type HCC. These results suggest that c-myc gene might play an important role in evolution and progression of HCC, and that ras genes might play a role in hepatocarcinogenesis at early stage. PMID- 7830709 TI - [The effect of calcitonin gene-related peptide on the hepatic hemodynamics after releasing of hepatic ischemia]. AB - The effect of synthetic chicken calcitonin gene-related peptide (CGRP) on the hepatic circulation was studied using adult mogrel dogs. Infusion of CGRP (10(-9) M/kg) decreased the mean arterial blood pressure to 56.8% of the pre-infusion value and increased heart rates to 106.3%. 10(-10) M/kg CGRP increased blood flow of the superior mesenteric artery, hepatic artery and portal vein by 130.1%, 130.2%, and 121.2% respectively of the basal levels. The hepatic blood flow was discontinued for 20 minutes by clamping the hepato-duodenal ligament. After reestablishing effects of CGRP on the hepatic hemodynamics became more evident. These results offer the possibility that CGRP may be used to maintain the hepatic blood flow stable during and after hepatic surgery. PMID- 7830710 TI - [De novo malignancy following renal transplantation]. AB - The characteristics and incidence of de novo malignancy was analyzed in 376 renal transplant recipients transplanted between April 1970 and December 1992. Malignancies developed in 21 recipients of living related donor renal allografts. The total number of malignancies was 23, with 2 patients developing 2 malignancies. The mean age at the time of diagnosis was 42 years. The average interval from transplantation to the time of diagnosis was 129 months. Malignancy developed in 12 of 21 patients who survived 10 years with a functioning graft. Nine patients died of their malignancy. The risk of developing malignancy is increased following renal transplantation. Compared with sex- and age-matched Japanese control, the incidence is 6.1 times greater for male, 10.5 times greater for female, and 7.3 times greater overall. The risk was increased at all sites except the stomach. The risk rate of acquiring malignancies at 5-year intervals following transplantation was 6.5 times greater from 0 to 5 years, 10.0 times greater from 5 to 10 years, and 9.3 times greater from 10 to 15 years. These results suggest that annual medical examinations should be performed as part of the routine log-term follow-up of renal transplant recipients to detect malignancies in the early stage. PMID- 7830711 TI - [A case of ruptured hepatocellular carcinoma with rapid growth after the interferon therapy in chronic hepatitis]. AB - A 75-year-old man who had had a long history of chronic hepatitis C virus liver disease underwent interferon (IFN) therapy for three months. After three months of the last IFN injection, he presented with a sudden attack of epigastralgia. Abdominal US and CT revealed a tumor about 9 x 10 cm in the right lobe of the liver. Serum AFP level was 8,499 ng/ml. Spontaneous hemoperitoneum due to ruptured hepatocellular carcinoma (HCC) was suspected. Hepatectomy was carried out on 35 days postembolization. Pathological examination revealed HCC of trabecular type. Although the relation between the rapid growth and IFN is not clear, US examination should be performed once a month for the patient. PMID- 7830712 TI - [A case of angiosarcoma with von Recklinghausen's disease]. AB - We treated a patient with von Recklinghausen's disease and angiosarcoma. This combination has not been reported in Japan to the best of our knowledge. An emergency operation for massive gastrointestinal bleeding was performed on a 68 year-old woman with von Recklinghausen's disease, who had been known to have a retroperitoneal tumor; The bleeding was controlled and the tumor was also resected. Postoperative course was uneventful also but one month after operation intra-abdominal and intrathoracic bleeding developed, and the patient died of respiratory failure. Autopsy showed hemorrhagic lesions, which were diagnosed pathologically metastatic angiosarcoma. The possibility of hemorrhagic lesions in the patients with von Recklinghausen's disease should be kept in mind. PMID- 7830713 TI - [Analysis of gastric stump mucosa by immunohistochemical staining of proliferating cell nuclear antigen: preliminary report]. PMID- 7830714 TI - [Development of vascular prosthesis with excellent elasticity: preliminary report]. PMID- 7830715 TI - Genetic interactions between SIN3 mutations and the Saccharomyces cerevisiae transcriptional activators encoded by MCM1, STE12, and SWI1. AB - SIN3 was first identified by a mutation which suppresses the effects of an swi5 mutation on expression of the HO gene in Saccharomyces cerevisiae. We now show that a sin3 mutation also partially suppresses the effects of swi1 on HO transcription, and partially suppresses the growth defect and inositol requirement observed in swi1 mutants. This suggests that SIN3 and SWI1 may play opposite regulatory roles in controlling expression of many yeast genes. Yeast SIN3 has been shown to function as a negative transcriptional regulator of a number of yeast genes. However, expression of the yeast STE6 gene is reduced in a sin3 mutant strain. This suggests that SIN3 functions as a positive regulator for STE6 transcription, although this apparent activation function could be indirect. In order to understand how SIN3 functions in STE6 regulation, we have performed a genetic analysis. It has been previously demonstrated that MCM1 and STE12 are transcriptional activators of a-specific genes such as STE6, and we now show that SWI1 is also required for STE6 expression. Our data suggest that STE12 and SWI1 function in different pathways of activation, and that STE12 is epistatic to SIN3 and SWI1. We show that the activities of the Mcm1p and Ste12p activators are modestly reduced in a sin3 mutant strain, and that phosphorylation of the Ste12p activator is decreased in a sin3 mutant. Thus, it is possible that the decreased transcription of STE6 in sin3 mutants is due to the combined effect of the diminished activities of Mcm1p and Ste12p. PMID- 7830716 TI - Expression of human poly(ADP-ribose) polymerase in Saccharomyces cerevisiae. AB - The coding sequence for human poly(ADP-ribose) polymerase was expressed inducibly in Saccharomyces cerevisiae from a low-copy-number plasmid vector. Cell free extracts of induced cells had poly(ADP-ribose) polymerase activity when assayed under standard conditions; activity could not be detected in noninduced cell extracts. Induced cells formed poly(ADP-ribose) in vivo, and levels of these polymers increased when cells were treated with the alkylating agent N-methyl-N' nitro-N- nitrosoguanidine (MNNG). The cytotoxicity of this agent was increased in induced cells, and in vivo labelling with [3H]adenine further decreased their viability. Increased levels of poly(ADP-ribose) found in cells treated with the alkylating agent were not accompanied by lowering of the NAD concentration. PMID- 7830717 TI - Localization of functional domains in the Escherichia coli coprogen receptor FhuE and the Pseudomonas putida ferric-pseudobactin 358 receptor PupA. AB - Transport of ferric-siderophores across the outer membrane of gram-negative bacteria is mediated by specific outer membrane receptors. To localize the substrate-binding domain of the ferric-pseudobactin 358 receptor, PupA, of Pseudomonas putida WCS358, we constructed chimeric receptors in which different domains of PupA were replaced by the corresponding domains of the related ferric pseudobactin receptors PupB and PupX, or the coprogen receptor FhuE of Escherichia coli. None of the chimeric proteins composed of pseudobactin receptor domains facilitated growth on any of the original substrates, or they showed only an extremely low efficiency. However, these receptors enabled cells of Pseudomonas BN8 to grow on media supplemented with uncharacterized siderophore preparations. These siderophore preparations were isolated from the culture supernatant of WCS358 cells carrying plasmids that contain genes of Pseudomonas B10 required for the biosynthesis of pseudobactin B10. Hybrid proteins that contained at least the amino-terminal 516 amino acids of mature FhuE were active as a receptor for coprogen and interacted with the E. coli TonB protein. A chimeric PupA-FhuE protein, containing the amino-terminal 94 amino acids of mature PupA, was also active as a coprogen receptor, but only in the presence of Pseudomonas TonB. It is concluded that the carboxy-terminal domain of ferric pseudobactin receptors is important, but not sufficient, for ligand interaction, whereas binding of coprogen by the FhuE receptor is not dependent on this domain. Apparently, the ligand-binding sites of different receptors are located in different regions of the proteins. Furthermore, species-specific TonB binding by the PupA receptor is dependent on the amino-terminal domain of the receptor. PMID- 7830718 TI - An essential virulence protein of Agrobacterium tumefaciens, VirB4, requires an intact mononucleotide binding domain to function in transfer of T-DNA. AB - The 11 gene products of the Agrobacterium tumefaciens virB operon, together with the VirD4 protein, are proposed to form a membrane complex which mediates the transfer of T-DNA to plant cells. This study examined one putative component of that complex, VirB4. A deletion of the virB4 gene on the Ti plasmid pTiA6NC was constructed by replacing the virB4 gene with the kanamycin resistance-conferring nptII gene. The virB4 gene was found to be necessary for virulence on plants and for the transfer of IncQ plasmids to recipient cells of A. tumefaciens. Genetic complementation of the deletion strain by the virB4 gene under control of the virB promoter confirmed that the deletion was nonpolar on downstream virB genes. Genetic complementation was also achieved with the virB4 gene placed under control of the lac promoter, even though synthesis of the VirB4 protein from this promoter is far below wild-type levels. Having shown a role for the VirB4 protein in DNA transfer, lysine-439, found within the conserved mononucleotide binding domain of VirB4, was changed to a glutamic acid, methionine, or arginine by oligonucleotide-directed mutagenesis. virB4 genes bearing these mutations were unable to complement the virB4 deletion for either virulence or for IncQ transfer, showing that an intact mononucleotide binding site is necessary for the function of VirB4 in DNA transfer. The necessity of the VirB4 protein with an intact mononucleotide binding site for extracellular complementation of virE2 mutants was also shown. In merodiploid studies, lysine-439 mutations present in trans decreased IncQ plasmid transfer frequencies, suggesting that VirB4 functions within a complex to facilitate DNA transfer. PMID- 7830719 TI - Molecular cloning and analysis of CDC28 and cyclin homologues from the human fungal pathogen Candida albicans. AB - In the budding yeast Saccharomyces cerevisiae, progress of the cell cycle beyond the major control point in G1 phase, termed START, requires activation of the evolutionarily conserved Cdc28 protein kinase by direct association with G1 cyclins. We have used a conditional lethal mutation in CDC28 of S. cerevisiae to clone a functional homologue from the human fungal pathogen Candida albicans. The protein sequence, deduced from the nucleotide sequence, is 79% identical to that of S. cerevisiae Cdc28 and as such is the most closely related protein yet identified. We have also isolated from C. albicans two genes encoding putative G1 cyclins, by their ability to rescue a conditional G1 cyclin defect in S. cerevisiae; one of these genes encodes a protein of 697 amino acids and is identical to the product of the previously described CCN1 gene. The second gene codes for a protein of 465 residues, which has significant homology to S. cerevisiae Cln3. These data suggest that the events and regulatory mechanisms operating at START are highly conserved between these two organisms. PMID- 7830720 TI - The yeast SIN3 gene product negatively regulates the activity of the human progesterone receptor and positively regulates the activities of GAL4 and the HAP1 activator. AB - The activation of gene transcription in eukaryotic organisms is regulated by sequence-specific DNA-binding proteins as well as by non-DNA-binding proteins. In this report we describe the modulatory functions of a non-DNA-binding protein, SIN3 (also known as SDI1, UME4, RPD1, and GAM2) on the transactivation properties of the human progesterone receptor (hPR), GAL4, and the HAP1 activator in yeast. Our data suggest that SIN3 is a dual function protein. It negatively regulates the transcriptional activities of hPR-A and hPR-B by affecting the N-terminal activation domain (AF1). SIN3 positively regulates the transcriptional activities of GAL4 and the HAP1 activator. However, it has no effect on the transcriptional activities of the human glucocorticoid receptor (hGR) and GCN4. The SIN3 protein contains four copies of a paired amphipathic helix (PAH) motif. Deletion analysis of the SIN3 PAH motifs shows that the PAH3 motif is essential for SIN3-mediated regulation of hPR, GAL4, and the HAP1 activator. In contrast, the PAH1, PAH2, and PAH4 motifs are not required for SIN3-mediated regulation of these activators. Additionally, we examined the mechanism(s) by which the SIN3 protein modulate the activities of various activators. We are unable to demonstrate the direct interaction of SIN3 protein with these activators using the yeast two-hybrid system or co-immunoprecipitation. These data suggest that SIN3 regulates the transactivation functions of hPR, GAL4, and the HAP1 activator by an indirect mechanism. PMID- 7830721 TI - Facilitated isolation of rare recombinants by ligase chain reaction: selection for intragenic crossover events in the Drosophila optomotor-blind gene. AB - Ligase chain reaction (LCR) was evaluated as a tool for the detection of point mutations. For the mutation studied, the specificity of the method is sufficient to detect the mutant allele in the presence of a 200-fold molar excess of the wild-type sequence. LCR was therefore employed in a genetic recombination experiment as a probe for a recessive lethal point mutation. LCR greatly facilitated the isolation of a rare recombinant originating from a crossover event in the 40 kb interval separating the lethal mutation and an enhancer trap insertion in the optomotor-blind locus. The recombinant will allow the study of gene control in situ, in a largely unperturbed regulatory environment. PMID- 7830722 TI - Studies on the mechanism of reduction of UV-inducible sulAp expression by recF overexpression in Escherichia coli K-12. AB - UV-inducible sulAp expression, an indicator of the SOS response, is reduced by recF+ overexpression in vivo. Different DNA-damaging agents and amounts of RecO and RecR were tested for their effects on this phenotype. It was found that recF+ overexpression reduced sulAp expression after DNA damage by mitomycin C or nalidixic acid, recO+ and recR+ overexpression partially suppressed the reduction of UV-induced sulAp expression caused by recF+ overexpression. The requirement for ATP binding to RecF to produce the phenotype was tested by genetically altering the putative phosphate binding cleft of recF in a way that should prevent the mutant recF protein from binding ATP. It was found that a change of lysine to glutamine at codon 36 results in a mutant recF protein (RecF4115) that is unable to reduce UV-inducible sulAp expression when overproduced. It is inferred from these results that recF overexpression may reduce UV-inducible sulAp expression by a mechanism that is sensitive to the ability of RecF to bind ATP and to the levels of RecO and RecR (RecOR) in the cell, but not to the type of DNA damage per se. Models are explored that can explain how recF+ overexpression reduces UV induction of sulAp and how RecOR overproduction might suppress this phenotype. PMID- 7830723 TI - Involvement of the PS03 gene of Saccharomyces cerevisiae in intrachromosomal mitotic recombination and gene amplification. AB - Using a genetic system of haploid strains of Saccharomyces cerevisiae carrying a duplication of the his4 region on chromosome III, the pso3-1 mutation was shown to decrease the rate of spontaneous mitotic intrachromosomal recombination 2- to 13-fold. As previously found for the rad52-1 mutant, the pso3-1 mutant is specifically affected in mitotic gene conversion. Moreover, both mutations reduce the frequency of spontaneous recombination. However, the two mutations differ in the extent to which they affect recombinations between either proximally or distally located markers on the two his4 heteroalleles. In addition, amplifications of the his4 region were detected in the pso3-1 mutant. We suggest that the appearance of these amplifications is a consequence of the inability of the pso3-1 mutant to perform mitotic gene conversion. PMID- 7830724 TI - Apparent functional independence of the mitochondrial and nuclear transcription systems in cultured human cells. AB - We have constructed a series of reporter constructs which test the effects of sequence elements from the control region of human mitochondrial DNA on expression in the nucleus, as assayed by transient expression in cultured human cells. The mitochondrial heavy-strand promoter (HSP) was unable to function as a promoter in nuclear DNA. Neither the HSP, nor the binding region for the mitochondrial transcription factor mtTF1 from the light-strand promoter, had any significant or systematic modulatory effects upon transcription from strong or weak RNA polymerase II (pol II) promoters, in three different human cell lines. The same finding held true regardless of orientation with respect to the start site of transcription. Similar results were obtained with a rho 0 derivative of one of these lines, indicating that mitochondrial promoter sequences in the nucleus cannot modulate transcription in response to altered mtDNA copy number. These results support the view that the nuclear and mitochondrial transcription systems in human cells are functionally independent, and do not communicate through factors recognizing shared sequence elements, as suggested by studies in yeast. PMID- 7830726 TI - The identification of a Caenorhabditis elegans homolog of p34cdc2 kinase. AB - We have identified a Caenorhabditis elegans homolog of p34cdc2 kinase. The C. elegans homolog, ncc-1, is approximately 60% identical to p34cdc2 of Homo sapiens. When expressed from a constitutive yeast promoter, ncc-1 is capable of complementing a conditional lethal mutation in the CDC28 gene of Saccharomyces cerevisiae, indicating that this C. elegans homolog can properly regulate the cell cycle. PMID- 7830725 TI - Phylogenic relationships of the amino acid sequences of prosome (proteasome, MCP) subunits. AB - Prosomes [or proteasomes, Multi-Catalytic Proteinase (MCP) are multisubunit protein complexes, found from archaebacteria to man, the structure of which (a 4 layer cylinder) is remarkable conserved. They were first observed as subcomplexes of untranslated mRNP, and then as a multicatalytic proteinase with several proteolytic activities. A number of sequences from subunits of these complexes are now available. Analysis of the sequences shows that these subunits are evolutionarily related, and reveals three highly conserved amino acid stretches. Based on a phylogenic approach, we propose to classify the sequenced subunits into 14 families, which fall into two superfamilies, of the alpha- and beta-type. These data, together with several recently published observations, suggest that some subunits may be interchangeable within the complexes, which would thus constitute a population of heterogenous particles. PMID- 7830727 TI - Two new genes involved in signalling ambient pH in Aspergillus nidulans. AB - Two new genes, palH and palI, where mutations mimic the effects of acidic growth pH have been identified in Aspergillus nidulans. A palH mutation is phenotypically indistinguishable from mutations in the palA, palB, palC, and palF genes, whereas palI mutations differ only in that they allow some growth at pH 8. Mutations in palA, B, C, F, and H are epistatic to a palI mutation and the significance of this epistasis is discussed. Additionally, palE and palB mutations have been shown to be allelic. Thus, a total of six genes where mutations mimic acidic growth conditions has been identified. PMID- 7830728 TI - Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease. AB - BACKGROUND: Impaired endothelium-mediated relaxation contributes to vasospasm and myocardial ischemia in patients with coronary artery disease. We hypothesized that cholesterol-lowering therapy with the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor lovastatin could improve endothelium-mediated responses in patients with coronary atherosclerosis. METHODS: In a randomized, double-blind, placebo-controlled trial, we studied coronary endothelial responses in 23 patients randomly assigned to either lovastatin (40 mg twice daily; 11 patients) or placebo (12 patients) plus a lipid-lowering diet (American Heart Association Step 1 diet). Patients were studied 12 days after randomization and again at 5 1/2 months. These patients had total cholesterol levels ranging from 160 to 300 mg per deciliter (4.1 to 7.8 mmol per liter) and were undergoing coronary angioplasty. At the initial and follow-up studies, patients received serial intracoronary infusions (in a coronary artery not undergoing angioplasty) of acetylcholine to assess endothelium-mediated vasodilatation. The responses of the coronary vessels were analyzed with quantitative angiography. RESULTS: The patients in the placebo and lovastatin groups had similar responses to acetylcholine at a mean of 12 days of therapy (expressed as the percentage of change in diameter in response to acetylcholine doses of 10(-9) M, 10(-8) M, 10( 7) M, and 10(-6) M). In the placebo group, the respective mean (+/- SE) changes were 1 +/- 2, 0 +/- 2, -2 +/- 4, and -19 +/- 4 percent; in the lovastatin group, they were -2 +/- 2, -4 +/- 4, -12 +/- 5, and -16 +/- 7 percent (P = 0.32). (Coronary-artery constriction is reflected by negative numbers). The responses to acetylcholine in the placebo group after a mean of 5.5 months of therapy were -3 +/- 3, -1 +/- 2, -8 +/- 4, and -18 +/- 5 percent, respectively; there was significant improvement in the lovastatin group, which had responses of 3 +/- 3, 3 +/- 3, 0 +/- 2, and 0 +/- 3 percent (P = 0.004). CONCLUSIONS: Cholesterol lowering with lovastatin significantly improved endothelium-mediated responses in the coronary arteries of patients with atherosclerosis. Such improvement in the local regulation of coronary arterial tone could potentially relieve ischemic symptoms and signal the stabilization of the atherosclerotic plaque. PMID- 7830729 TI - The effect of cholesterol-lowering and antioxidant therapy on endothelium dependent coronary vasomotion. AB - BACKGROUND: Patients with coronary artery disease and abnormalities of serum lipids often have endothelial vasodilator dysfunction, which may contribute to ischemic cardiac events. Whether cholesterol-lowering or antioxidant therapy can restore endothelium-dependent coronary vasodilation is unknown. METHODS: We randomly assigned 49 patients (mean serum cholesterol level, 209 +/- 33 mg per deciliter [5.40 +/- 0.85 mmol per liter]) to receive one of three treatments: an American Heart Association Step 1 diet (the diet group, 11 patients); lovastatin and cholestyramine (the low-density lipoprotein [LDL]-lowering group, 21 patients); or lovastatin and probucol (the LDL-lowering-antioxidant group, 17 patients). Endothelium-dependent coronary-artery vasomotion in response to an intracoronary infusion of acetylcholine (10(-8) to 10(-6) M) was assessed at base line and after one year of therapy. Vasoconstrictor responses to these doses of acetylcholine are considered to be abnormal. RESULTS: Treatment resulted in significant reductions in LDL cholesterol levels of 41 +/- 22 percent in the LDL lowering-antioxidant group and 38 +/- 20 percent in the LDL-lowering group (P < 0.001 vs. the diet group). The maximal changes in coronary-artery diameter with acetylcholine at base line and at follow-up were -19 and -2 percent, respectively, in the LDL-lowering-antioxidant group, -15 and -6 percent in the LDL-lowering group, and -14 and -19 percent in the diet group (P < 0.01 for the LDL-lowering-antioxidant group vs. the diet group; P = 0.08 for the LDL-lowering group vs. the diet group). (The negative numbers indicate vasoconstriction). Thus, the greatest improvement in the vasoconstrictor response was seen in the LDL-lowering-antioxidant group. CONCLUSIONS: The improvement in endothelium dependent vasomotion with cholesterol-lowering and antioxidant therapy may have important implications for the activity of myocardial ischemia and may explain in part the reduced incidence of adverse coronary events that is known to result from cholesterol-lowering therapy. PMID- 7830730 TI - The risk of cancer among patients with cystic fibrosis. Cystic Fibrosis and Cancer Study Group. AB - BACKGROUND: Anecdotal reports suggest an increased frequency of certain cancers in patients with cystic fibrosis, the commonest genetic disorder of whites. One third of patients with cystic fibrosis now reach adulthood, when cancer is more frequent, implying that cancer rates in these patients will increase over time. We investigated the relation between cystic fibrosis and cancer in North American and European patients with cystic fibrosis. Methods. We performed a retrospective cohort study of the occurrence of cancer in 28,511 patients with cystic fibrosis from 1985 through 1992 in the United States and Canada. The number of cases observed was compared with the number expected, calculated from population-based data on the incidence of cancer. We also analyzed proportional incidence ratios to assess the association between specific cancers and cystic fibrosis in Europe. RESULTS: Thirty-seven cancers were observed in the North American cohort during 164,764 person-years of follow-up, as compared with an expected number of 45.6, yielding a ratio of observed to expected cancers of 0.8 (95 percent confidence interval, 0.6 to 1.1). Thirteen digestive tract tumors were observed, as compared with an expected number of two, for a ratio of observed to expected cancers of 6.5 (95 percent confidence interval, 3.5 to 11.1). In Europe, 11 of 39 cancers originated in the digestive tract, yielding a positive association between digestive tract tumors and cystic fibrosis (odds ratio, 6.4; 95 percent confidence interval, 2.9 to 14.0). CONCLUSIONS: Although the overall risk of cancer in patients with cystic fibrosis is similar to that of the general population, there is an increased risk of digestive tract cancers. Persistent or unexplained gastrointestinal symptoms in these patients should be carefully investigated. PMID- 7830731 TI - Intramuscular injections within 30 days of immunization with oral poliovirus vaccine--a risk factor for vaccine-associated paralytic poliomyelitis. AB - BACKGROUND: In Romania the rate of vaccine-associated paralytic poliomyelitis is for unexplained reasons 5 to 17 times higher than in other countries. Long ago it was noted that intramuscular injections administered during the incubation period of wild-type poliovirus infection increased the risk of paralytic disease (a phenomenon known as "provocation" poliomyelitis). We conducted a case-control study to explore the association between intramuscular injections and vaccine associated poliomyelitis in Romania. METHODS: The patients were 31 young children in whom vaccine-associated paralytic poliomyelitis developed from 1988 through 1992. Eighteen were vaccine recipients, and 13 had acquired the disease by contact with vaccine recipients. Each of these children was matched with up to five controls according to health center, age, and in the case of vaccine recipients, history of receipt of the live attenuated oral poliovirus vaccine. Data were abstracted from medical records that documented the injections administered in the 30 days before the onset of paralysis. RESULTS: Of the 31 children with vaccine-associated disease, 27 (87 percent) had received one or more intramuscular injections within 30 days before the onset of paralysis, as compared with 77 of the 151 controls (51 percent) (matched odds ratio, 31.2; 95 percent confidence interval, 4.0 to 244.2). Nearly all the intramuscular injections were of antibiotics, and the association was strongest for the patients who received 10 or more injections (matched odds ratio for > or = 10 injections as compared with no injections, 182.1; 95 percent confidence interval, 15.2 to 2186.4). The risk of paralytic disease was strongly associated with injections given after the oral polio virus vaccine, but not with injections given before or at the same time as the vaccine (matched odds ratio, 56.7; 95 percent confidence interval, 8.9 to infinity). The attributable risk in the population for intramuscular injections given in the 30 days before the onset of paralysis was 86 percent (95 percent confidence interval, 66 to 95 percent); that is, we estimate that 86 percent of the cases of vaccine-associated paralytic poliomyelitis in this population might have been prevented by the elimination of intramuscular injections within 30 days after exposure to oral poliovirus vaccine. CONCLUSIONS: Provocation paralysis, previously described only for wild type poliovirus infection, may rarely occur in a child who receives multiple intramuscular injections shortly after exposure to oral poliovirus vaccine, either as a vaccine recipient or through contact with a recent recipient. This phenomenon may explain the high rate of vaccine-associated paralytic poliomyelitis in Romania, where the use of intramuscular injections of antibiotics in infants with febrile illness is common. PMID- 7830732 TI - Brief report: lymphoma with recurrent cycles of spontaneous remission and relapse -possible role of apoptosis. PMID- 7830733 TI - Images in clinical medicine. Corticosteroid osteonecrosis. PMID- 7830734 TI - Cholesterol reduction in cardiovascular disease. Clinical benefits and possible mechanisms. PMID- 7830735 TI - Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 6-1995. A one-month-old girl with an intraabdominal mass found on prenatal ultrasonographic examination. PMID- 7830736 TI - Minimizing the risks associated with the prevention of poliomyelitis. PMID- 7830737 TI - Abortion--1995. PMID- 7830738 TI - DNA on trial--the molecular basis of DNA fingerprinting. PMID- 7830739 TI - Coronary-stent placement compared with balloon angioplasty. PMID- 7830740 TI - Clinical problem-solving: the appropriate degree of diagnostic certainty? PMID- 7830741 TI - Clinical problem-solving: the appropriate degree of diagnostic certainty? PMID- 7830743 TI - Clinical problem-solving: the appropriate degree of diagnostic certainty? PMID- 7830742 TI - Clinical problem-solving: the appropriate degree of diagnostic certainty? PMID- 7830744 TI - Clinical problem-solving: the appropriate degree of diagnostic certainty? PMID- 7830745 TI - Autologous chondrocyte transplantation. PMID- 7830746 TI - Autologous chondrocyte transplantation. PMID- 7830747 TI - Case 37-1994: juvenile chronic myelogenous leukemia. PMID- 7830748 TI - Trans fatty acids in European margarines. PMID- 7830749 TI - A space-time slide rule. PMID- 7830750 TI - Glaxo bid 'reflects changing patterns of drug research'. PMID- 7830751 TI - AIDS activists fail to block 'reasonable pricing' reform. PMID- 7830752 TI - New hominid remains found in Ethiopia. PMID- 7830753 TI - Republican warns of $35-billion cut in 1996 budget. PMID- 7830754 TI - Canada to set up genome research centre in Toronto. PMID- 7830755 TI - But France keeps EMBL guessing. PMID- 7830756 TI - Cell biology centre plans to break the mould on staffing. PMID- 7830757 TI - Animal research. PMID- 7830758 TI - Animal research. PMID- 7830759 TI - Malaria menace. PMID- 7830760 TI - The hot, dry mountains of Venus. PMID- 7830761 TI - DNA-binding proteins. A butterfly flutters by. PMID- 7830762 TI - Neuron saving schemes. PMID- 7830763 TI - Leukaemia and wartime evacuees. PMID- 7830764 TI - Structure of the NF-kappa B p50 homodimer bound to DNA. AB - The structure of a large fragment of the p50 subunit of the human transcription factor NF-kappa B, bound as a homodimer to DNA, reveals that the Rel-homology region has two beta-barrel domains that grip DNA in the major groove. Both domains contact the DNA backbone. The amino-terminal specificity domain contains a recognition loop that interacts with DNA bases; the carboxy-terminal dimerization domain bears the site of I-kappa B interaction. The folds of these domains are related to immunoglobulin-like modules. The amino-terminal domain also resembles the core domain of p53. PMID- 7830765 TI - Production and evolution of light elements in active star-forming regions. AB - Collisions between cosmic rays (energetic protons and alpha-particles) and carbon, nitrogen and oxygen in the interstellar medium have been considered to be the main source of lithium, beryllium and boron, through fragmentation of the larger nuclei. But this mechanism is unable to account for the observed Solar System abundances of the isotopes 7Li and 11B. The recent detection of an excess of gamma-rays in the direction of the star-forming region in the Orion cloud has been interpreted as arising from the excitation of carbon and oxygen nuclei ejected from supernovae when they collide with the surrounding gas, which is primarily molecular and atomic hydrogen. Here we investigate the consequences of the two-body interactions of the ejected carbon and oxygen nuclei (and the alpha particles ejected with them) with the hydrogen and helium in the surrounding gas, using a model developed previously. We show that these interactions offer a way to make lithium, beryllium and boron that is independent of the abundance of heavy elements in the surrounding medium. Such supernova-driven interactions, combined with the effect of galactic cosmic rays, can explain the observed Solar System abundances of these light elements. PMID- 7830766 TI - Protection and repair of the nigrostriatal dopaminergic system by GDNF in vivo. AB - Glial-cell-line-derived neurotrophic factor (GDNF), a recently cloned new member of the transforming growth factor-beta superfamily, promotes survival of cultured fetal mesencephalic dopamine neurons and is expressed in the developing striatum. There have, however, been no reports about effects of GDNF in situ. We have used the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which produces parkinsonian symptoms in man, to determine whether GDNF might exert protective or regenerative effects in vivo in the adult nigrostriatal dopamine system in C57/B1 mice. GDNF injected over the substantia nigra or in striatum before MPTP potently protects the dopamine system, as shown by numbers of mesencephalic dopamine nerve cell bodies, dopamine nerve terminal densities and dopamine levels. When GDNF is given after MPTP, dopamine levels and fibre densities are significantly restored. In both cases, motor behaviour is increased above normal levels. We conclude that intracerebral GDNF administration exerts both protective and reparative effects on the nigrostriatal dopamine system, which may have implications for the development of new treatment strategies for Parkinson's disease. PMID- 7830767 TI - Mesencephalic dopaminergic neurons protected by GDNF from axotomy-induced degeneration in the adult brain. AB - Glial-cell-line-derived neurotrophic factor (GDNF) promotes survival of embryonic dopaminergic neurons in culture, and its expression pattern suggests a role as a transient target-derived trophic factor for dopaminergic neurons of the substantia nigra. These neurons participate in the control of motor activity, emotional status and cognition, and they degenerate in Parkinson's disease for unknown reasons. To test whether GDNF has a trophic effect on dopaminergic neurons in the adult brain, we used a rat model in which these neurons are induced to degenerate by transecting their axons within the medial forebrain bundle. We report here that axotomy resulted in loss of half the tyrosine hydroxylase-expressing neurons in the substantia nigra. This loss was largely prevented by repeated injections of GDNF adjacent to the substantia nigra. Our findings suggest that GDNF or related molecules may be useful for the treatment of Parkinson's disease. PMID- 7830768 TI - In vivo neurotrophic effects of GDNF on neonatal and adult facial motor neurons. AB - Motor neurons require neurotrophic factor(s) for their survival during development and for maintenance of function in adulthood. In vivo studies have shown that motor neurons respond to a variety of molecules, including ciliary neurotrophic factor, members of the neurotrophin family, and the insulin growth factor IGF-1 (refs 3-13). Here we investigate the potential motor neuron neurotrophic effects of glial-cell-line-derived neurotrophic factor (GDNF), initially identified as a neurotrophic factor for substantia nigra dopaminergic neurons. We find that GDNF is retrogradely transported, in a receptor-mediated fashion, by spinal cord motor neurons in neonatal rats. Local application of GDNF to the transected facial nerve prevents the massive motor neuron cell death and atrophy that normally follows axotomy in the neonatal period. In adult rats, GDNF administered locally or systemically can markedly attenuate the lesion-induced decrease of choline acetyltransferase immunoreactivity in the facial nucleus. Our data indicate that GDNF has very profound neurotrophic effects in vivo on developing as well as on adult motor neurons, and is the most potent motor neuron trophic factor found so far. PMID- 7830769 TI - Developing motor neurons rescued from programmed and axotomy-induced cell death by GDNF. AB - During normal development of the vertebrate nervous system, large numbers of neurons in the central and peripheral nervous system undergo naturally occurring cell death. For example, about half of all spinal motor neurons die over a period of a few days in developing avian, rat and mouse embryos. Previous studies have shown that extracts from muscle and brain, secreted factors from glia, as well as several growth factors and neurotrophic agents, including muscle-derived factors, can promote the survival of developing motor neurons in vitro and in vivo. But because neurotrophins and other known trophic agents administered alone or in combination are insufficient to rescue all developing motor neurons from cell death, other neurotrophic molecules are probably essential for the survival and differentiation of motor neurons. Here we report that glial-cell-line-derived neurotrophic factor (GDNF), a potent neurotrophic factor that enhances survival of mammalian midbrain dopaminergic neurons, rescues developing avian motor neurons from natural programmed cell death in vivo and promotes the survival of enriched populations of cultured motor neurons. Furthermore, treatment with this agent in vivo also prevents the induced death and atrophy of both avian and mouse spinal motor neurons following peripheral axotomy. PMID- 7830770 TI - Developmental control point in induction of thymic cortex regulated by a subpopulation of prothymocytes. AB - T lymphocytes of the alpha/beta T-cell receptor (TCR) lineage mature in the thymus, where they undergo a series of differentiation, expansion and selection events. For normal T-cell ontogeny to occur, thymocytes must interact physically with cortical and medullary thymic stroma cells. In parallel, interactions of the thymic stromal cells with TCR-positive thymocytes are necessary for the development of the thymic medulla. Comparable requirements for the differentiation of the cortex have not been defined, however. Here we analyse mutant mouse strains to assess the function of early prothymocytes in the induction of the thymic cortex. We find that animals with a developmental block at the earliest stage of T-lineage commitment lack a functional thymic cortex. This abnormality could be corrected in fetal but not adult animals by transplantation of either fetal or adult wild-type haematopoietic stem cells. Thus a developmentally restricted interaction of fetal stromal cells with early prothymocytes is required for the induction of a cortical microenvironment. In addition, a normal thymic architecture is necessary for sustained T-cell ontogeny. PMID- 7830771 TI - CD8 modulation of T-cell antigen receptor-ligand interactions on living cytotoxic T lymphocytes. AB - Thymocytes and class I major histocompatibility complex (MHC)-restricted cytotoxic T lymphocytes express predominantly heterodimeric alpha/beta CD8. By interacting with non-polymorphic regions of MHC class I molecules CD8 can mediate adhesion or by binding the same MHC molecules that interact with the T-cell antigen receptor (TCR) function as coreceptor in TCR-ligand binding and T-cell activation. Using TCR photoaffinity labelling with a soluble, monomeric photoreactive H-2Kd-peptide derivative complex, we report here that the avidity of TCR-ligand interactions on cloned cytotoxic T cells is very greatly strengthened by CD8. This is primarily explained by coordinate binding of ligand molecules by CD8 and TCR, because substitution of Asp 227 of Kd with Lys severely impaired the TCR-ligand binding on CD8+, but not CD8- cells. Kinetic studies on CD8+ and CD8- cells further showed that CD8 imposes distinct dynamics and a remarkable temperature dependence on TCR-ligand interactions. We propose that the ability of CD8 to act as coreceptor can be modulated by CD8-TCR interactions. PMID- 7830772 TI - Neisseria PilC protein identified as type-4 pilus tip-located adhesin. AB - Type-4 pilus-mediated adherence of Neisseria gonorrhoeae and Neisseria meningitidis is considered to be a crucial early event in neisserial infections. In addition to the principal pilus subunit (pilin or PilE), both pathogens produce low quantities of a phase-variable PilC protein which is implicated in pilus biogenesis and pilus-mediated epithelial cell adherence. The identity, however, of the pilus adhesin has remained obscure. Here we describe the isolation of a PilC protein from a gonococcal overproducing strain and demonstrate its specific interaction with human epithelial cells. Our results are consistent with the cell and species tropisms of neisserial infections. Binding of PilC effectively competes with pilus-mediated, but not Opa-mediated, attachment of N. gonorrhoeae and of N. meningitidis, indicating that both pathogens interact with identical or very similar epithelial cell receptors. Immunogold electron microscopy using antisera raised against purified PilC and synthetic peptides locates PilC at the tip of gonococcal pili. PilC thus represents an essential pilus-associated adhesin, providing a rationale for selective protection against neisserial infections. PMID- 7830773 TI - A Rosetta stone of mammalian genetics. AB - The Mammalian Comparative Database provides genetic maps of mammalian species. Comparative maps are valuable aids for predicting linkages, developing animal models and studying genome organization and evolution. PMID- 7830774 TI - A space-time slide rule. PMID- 7830776 TI - NIH selects new alternative medicine head. PMID- 7830775 TI - Names for hi-jacking. PMID- 7830777 TI - UK firms buy into drug design skills of US start-ups. PMID- 7830779 TI - US technology support under the microscope. PMID- 7830778 TI - US accused of 'cover-up' in defence of Gallo claims. PMID- 7830780 TI - Threat to German medical research. PMID- 7830781 TI - Patent system gets vote of support from gene workers. PMID- 7830782 TI - Sparks continue to fly in Taq patent dispute. PMID- 7830784 TI - Apoptosis forever. PMID- 7830783 TI - Randomized trials. PMID- 7830785 TI - Female ensoulment: late but durable. PMID- 7830786 TI - Female ensoulment: late but durable. PMID- 7830787 TI - The rise of neurogenetic determinism. AB - Dramatic advances in neuroscience are changing and enriching our understanding of brain and behaviour. But reductionist interpretations of these advances can cause great harm. PMID- 7830788 TI - Diabetes. Causes of insulin resistance. PMID- 7830789 TI - Nuclear DNA from primate dung. PMID- 7830790 TI - Back to front. PMID- 7830791 TI - Chromosome correction. PMID- 7830792 TI - Photodesorption from low-temperature water ice in interstellar and circumsolar grains. AB - Dust grains in the interstellar medium and the outer Solar System commonly have a coating of water ice, which affects their optical properties and surface chemistry. The thickness of these icy mantles may be determined in part by the extent of photodesorption (photosputtering) by background ultraviolet radiation. But this process is poorly understood, with theoretical estimates of the photodesorption rate spanning several orders of magnitude. Here we report measurements of the absolute ultraviolet photodesorption yield of low-temperature water ice. Our results indicate that the rate of photodesorption is appreciable. In particular, it can account for the absence of icy mantles on grains in diffuse interstellar clouds, it exceeds solar-wind ion erosion and sublimation in the outer Solar System, and it is important in determining the lifetimes of icy mantles in dense molecular clouds. PMID- 7830793 TI - Corticotropin-releasing hormone deficiency reveals major fetal but not adult glucocorticoid need. AB - The body responds to stress by activation of the hypothalamic-pituitary-adrenal (HPA) axis and release of glucocorticoids. Glucocorticoid production in the adult regulates carbohydrate and amino-acid metabolism, maintains blood pressure, and restrains the inflammatory response. In the fetus, exogenous glucocorticoids accelerate maturation of lung and gastrointestinal enzyme systems and promote hepatic glycogen deposition. Corticotropin-releasing hormone (CRH), a 41-amino acid neuropeptide produced in the paraventricular nucleus of the hypothalamus and many regions of the cerebral cortex, has been implicated in both the HPA axis and behavioural responses to stress. To define the importance of CRH in the response of the HPA axis to stress and fetal development, we have constructed a mammalian model of CRH deficiency by targeted mutation in embryonic stem (ES) cells. We report here that corticotropin-releasing hormone-deficient mice reveal a fetal glucocorticoid requirement for lung maturation. Postnatally, despite marked glucocorticoid deficiency, these mice exhibit normal growth, fertility and longevity, suggesting that the major role of glucocorticoid is during fetal rather than postnatal life. PMID- 7830794 TI - Absence of blood formation in mice lacking the T-cell leukaemia oncoprotein tal 1/SCL. AB - Chromosomal translocations associated with malignancies often result in deregulated expression of genes encoding transcription factors. In human T-cell leukaemias such regulators belong to diverse protein families and may normally be expressed widely (for example, Ttg-1/rbtn1, Ttg-2/rbtn2), exclusively outside the haematopoietic system (for example, Hox11), or specifically in haematopoietic cells and other selected sites (for example, tal-1/SCL, lyl-1). Aberrant expression within T cells is though to interfere with programmes of normal maturation. The most frequently activated gene in acute T-cell leukaemias, tal-1 (also called SCL), encodes a candidate regulator of haematopoietic development, a basic-helix-loop-helix protein, related to critical myogenic and neurogenic factors. Here we show by targeted gene disruption in mice that tal-1 is essential for embryonic blood formation in vivo. With respect to embryonic erythropoiesis, tal-1 deficiency resembles loss of the erythroid transcription factor GATA-1 or the LIM protein rbtn2. Profound reduction in myeloid cells cultured in vivo from tal-1 null yolk sacs suggests a broader defect manifest at the myelo-erythroid or multipotential progenitor cell level. PMID- 7830795 TI - Quantal-like current fluctuations induced by odorants in olfactory receptor cells. AB - Many sensory systems have evolved signal detection capabilities that are limited only by the physical attributes of the stimulus. For example, 'hair' cells of the inner ear can detect displacements of atomic dimensions. Likewise, both in vertebrates and in invertebrates photoreceptors can detect a single photon. The olfactory stimulus also has a quantal unit, the single odorant molecule. Insects are reportedly able to detect a single pheromone molecule, whereas quantal responses in vertebrate olfactory receptor cells have not been reported yet. Psychophysical measurements indicate that a minimum of 50 odorant molecules are necessary for human olfactory detection, suggesting that an individual receptor may be activated by a single odorant molecule. We report here measurements of current fluctuations induced by odorants that suggest a quantal event of about 0.3-1 pA, presumably triggered by the binding of a single odorant molecule. PMID- 7830796 TI - Membrane glycoprotein PC-1 and insulin resistance in non-insulin-dependent diabetes mellitus. AB - Most patients with non-insulin-dependent diabetes mellitus are resistant to both endogenous and exogenous insulin. Insulin resistance precedes the onset of this disease, suggesting that it may be an initial abnormality. Insulin-receptor kinase activity is impaired in muscle, fibroblasts and other tissues of many patients with non-insulin-dependent diabetes mellitus, but abnormalities in the insulin-receptor gene do not appear to be the cause of this decreased kinase activity. Skin fibroblasts from certain insulin-resistant patients contain an inhibitor of insulin-receptor tyrosine kinase. Here we show that this inhibitor is a membrane glycoprotein, termed PC-1 (refs 10, 11). We find that PC-1 activity is increased in fibroblasts from seven of nine patients with typical non-insulin dependent diabetes mellitus. In addition, overexpression of PC-1 in transfected cultured cells reduces insulin-stimulated tyrosine kinase activity. These studies raise the possibility that PC-1 has a role in the insulin resistance of non insulin-dependent diabetes mellitus. PMID- 7830797 TI - Evolution of homeotic gene regulation and function in flies and butterflies. PMID- 7830798 TI - [Scientific aspects of raw materials in medicine]. AB - Metallic, ceramic, and polymeric materials are applied in all disciplines of surgical and dental medicine. The biocompatibility is determined by the chemical composition, the mechanical and electronic structures of the material's surface, the properties of the interface to the specific body electrolyte as well as by reactions, which occur between the solid and the liquid phase. The development of biomaterials, considering the sensitive biological environment, requires knowledge from all fields of the natural sciences and knowledge of manufacturing methods derived from the key technologies. PMID- 7830799 TI - [4 patients with painless diarrhea and weight loss]. PMID- 7830800 TI - [Locally acting glucocorticoids in chronic intestinal inflammation]. PMID- 7830801 TI - [Possibilities of drug treatment in inflammatory intestinal diseases]. PMID- 7830802 TI - [Is 'gluten-free' outlawed?]. PMID- 7830803 TI - [A new biscuit free of cow's milk, chicken egg protein, lactose and gluten for children with food hypersensitivity]. AB - OBJECTIVE: Evaluation of the clinical reaction of 10 children with food allergy, including allergy to cow's milk protein, to the introduction of a new biscuit, free of cow's milk protein, chicken egg protein, lactose and gluten. DESIGN: Descriptive prospective study. SETTING: Outpatient clinic, Beatrix Children's Hospital, University Hospital Groningen. METHOD: In 10 patients (mean age 28 months, range 13-78 months) with a proven cow's milk protein allergy the new biscuit (25 biscuits of 15.5 g each in 2 weeks) was introduced without otherwise changing the diet. The clinical symptoms, total serum IgE, the IgE radio allergosorbent test (RAST), the skin test, the intestinal permeability (measured with the sugar absorption test), and energy and nutrient intake were determined before and after the introduction of the biscuits. Results were evaluated by the Wilcoxon test. RESULTS: Laboratory results were not significantly different between the groups. A recurrent clinical reaction was seen in one patient after consumption of a biscuit (probably due to a potato component). During the period of biscuit consumption energy and nutrient intake were increased in all children when a maximum of 1.5 biscuit per day was consumed. CONCLUSION: No problems were seen in 9/10 children following introduction of the new biscuit. Energy and nutrient intake were improved. An allergic reaction was seen in 1/10 children, probably due to the potato component. PMID- 7830804 TI - [Methotrexate as possible treatment in refractory chronic inflammatory intestinal disease]. AB - OBJECTIVE: To determine the value of low dose methotrexate therapy in chronic inflammatory bowel disease. SETTING: Catharina Hospital and Diaconessenhuis, Eindhoven, and St. Joseph Hospital, Veldhoven. DESIGN: Descriptive. METHOD: From 1988 until 1993 we treated 15 patients 16 times (one patient was treated twice) with methotrexate 25 mg i.m. once a week during 12 weeks, followed by a tapering oral dose. Our population consisted of 4 men and 11 women with a mean age of 31 year. The diagnosis was Crohn ileitis (1 patient), Crohn colitis (8), ileocolitis (4) and ulcerative colitis (2). The indication for methotrexate was resistance to therapy (9) and steroid dependency (7). Retrospectively the disease activity was determined after 1, 2 and 3 months of therapy. RESULTS: The mean defaecation frequency went down from 7 to 2 times daily after 12 weeks, the ESR from 47 to 17 mm/1st hour, the thrombocytes from 436 x 10(9)/l to 325 x 10(9)/l and the prednisone dose could be lowered from 22 mg to 15 mg after 3 months. In 13/16 treatment cases there was a subjective positive response to methotrexate. Initial response was seen within 4 weeks. No serious side effects were seen. After 10 of the 13 response episodes the disease recurred. CONCLUSION: Methotrexate 25 mg once a week i.m. was associated with a subjective and objective improvement in 12/15 patients, but the risk of recurrence after tapering appears to be large. PMID- 7830805 TI - [Tubulointerstitial nephritis caused by mesalazine (5-ASA) agents]. AB - In five patients (4 men aged 34, 20, 22 and 29 years, and a woman of 34 years) tubulo-interstitial nephritis developed during treatment with 5-aminosalicylic acid (5-ASA) containing drugs for colitis ulcerosa, proctocolitis or Crohn's disease. Two patients had an impaired renal function before treatment with 5-ASA medication. In all patients there was only an incomplete recovery of renal function after cessation of the therapy. It is therefore necessary to monitor renal function regularly in patients receiving 5-ASA containing preparations. PMID- 7830806 TI - [Information and consent in health care; current developments]. PMID- 7830807 TI - [Current bronchoscopic techniques in the diagnosis of various forms of pneumonia]. PMID- 7830808 TI - [Normal cerebrospinal fluid in clinical suspicion of bacterial meningitis]. PMID- 7830809 TI - [Treatment of bleeding ulcers in stomach or duodenum]. PMID- 7830810 TI - ['Finally dry']. PMID- 7830811 TI - [Copolymer 1 in the treatment of multiple sclerosis]. PMID- 7830812 TI - [The status of standards and recommendations by the Dutch Family Practitioners Society]. PMID- 7830813 TI - [Practical significance of bone density measurement in osteoporosis]. PMID- 7830814 TI - [Family physician and gatekeeper]. PMID- 7830815 TI - [The loyalty of Belgian patients to their family practitioner]. AB - OBJECTIVE: To determine the effect of a non-committal registration specifying the intention of patients to contact a particular general practitioner, on patient loyalty in Belgium. SETTING: Antwerp and Liege DESIGN: Case control study. METHOD: Medical consumption was registered during one year by two health insurance companies for a group of 4000 participating patients (experimental group) and 4000 non-participants (control group) within two selected areas (Antwerp and Liege). Patient loyalty was measured by means of the normalised usual provider continuity index. RESULTS: No relevant differences were found between the experimental group and the control group. Even when taking into account that a general practitioner is not available 20% of the time, the proportion of loyal patients hardly reached 70%. CONCLUSION: A non-committal registration had no influence on patient loyalty. There is a clear difference between intention and actual behaviour. More coercive measures are needed to reach a more loyal behaviour. PMID- 7830817 TI - [Who decides on hospital admission of nursing home patients?]. AB - OBJECTIVE: To examine how the decision making to hospitalize nursing home patients proceeds, who takes the initiative, which participants are involved and how much time the consultation and decision making take. DESIGN: Prospective. METHOD: Analysis of registration data about decisions to hospitalize nursing home patients, collected from nursing home physicians in 30 nursing homes. RESULTS: In 76% of the cases the nursing home physician took the initiative to hospitalize. 38% of the patients had been consulted, which influenced the decision. 22% of the patients did not participate in the decision, mostly because of poor mental condition. Consultation of family members and nurses compensated only partly for this limited consultation of patients. With the other patients there had been contact, but without influence on the decision. Medical specialists to nursing home physicians were the most important participants in the decision making. Over 40% of the decisions were taken within 1 h, almost 25% between 1 h and 1 day. The duration of the decision making and the possibilities for consultation were mostly dependent of the urgency of hospitalisation. CONCLUSIONS: Because of the limited possibilities for consultation of nursing home patients when hospitalisation is considered, it is important to anticipate early on such situations by discussing this with patients and family members, and to write down the patients' wishes. PMID- 7830816 TI - [Hospital admission of nursing home patients: patient characteristics and purpose of admission]. AB - OBJECTIVE: To establish how many hospitalisations of nursing home patients are realised annually, the characteristics of these patients and the diagnoses and the purposes for which they are hospitalised. DESIGN: Retrospective and prospective. METHOD: Analysis of national data for the 5-year period 1986-1990 obtained from the registration of nursing home patients (SIVIS) of the Dutch Centre of Health Care information (SIG) and analysis of 385 separately gathered registration data from 30 nursing homes. RESULTS: More than 9000 hospitalisations of nursing home patients were realised annually, over 10% of those who stay in a nursing home for a shorter or longer time. Somatic patients were hospitalised nearly twice as often as psychogeriatric patients, and men about 1.25 times more often than women. The probability of hospitalisation decreased with advancing age. The most frequent reasons for hospitalisation were cardiovascular diseases, digestive tract diseases and femoral neck fractures. The most important purposes of hospitalisation are: to ward off threat to life (31%), to remedy complaints and burdens (29%), to improve the general condition (16%) and diagnostics (16%). The probability of hospitalisation was 2.5 times as large for the elderly living at home as for older nursing home patients. CONCLUSIONS: Hospitalisations are an important part of medical treatment and care of nursing home patients. There is a variation in hospitalisation rates for different categories of patients. Objectives of hospitalisation are diverse. There is a need for research into the effects of hospitalisation on the quality of life. PMID- 7830818 TI - [Hospital admission of nursing home patients: a difficult decision?]. AB - OBJECTIVE: To examine how difficult decisions to hospitalize nursing home patients are considered by the physicians and to what patient characteristics this is related. DESIGN: Prospective and descriptive. METHOD: Analysis of registration data about 387 decisions to hospitalize nursing home patients collected among nursing home physicians in 30 nursing homes. RESULTS: The degree of difficulty of hospitalisation was associated primarily with poor physical condition and much less with the mental condition. It was not related to patient age (apart from physical condition and the reason for hospitalisation). Referrals were difficult for e.g. infections and respiratory tract disorders, which may be further complicated by the short time available for the decision making because of the life threatening nature of the disorders. With malignancies, feeding, urogenital and skin disorders, decisions to hospitalize also proved difficult to make. These disorders usually allowed more time for consultation. CONCLUSION: About half the decisions to hospitalize were considered hard to make. Only when there is better insight into the effects of hospitalisation on patient functioning and quality of life will it be possible to determine correctness and professional obviousness of such decisions. PMID- 7830819 TI - [The family physician as gatekeeper]. PMID- 7830820 TI - [Adrenal cortex suppression attributed to the use of budesonide]. PMID- 7830821 TI - [Alarming admission rates for schizophrenia in migrants from Surinam, the Netherlands Antilles and Morocco]. PMID- 7830822 TI - [Skull and brain injuries in adults]. PMID- 7830823 TI - [Prices and values]. PMID- 7830824 TI - [Transfer copyright to Tijdschrift changed; no charges for authorized reprints]. PMID- 7830825 TI - [Early coronary heart disease together with tyoe II diabetes mellitus in persons of Hindustani origin]. AB - OBJECTIVE: To investigate the association between early coronary heart disease and non insulin dependent diabetes mellitus in South Asian patients in the Netherlands, a homogeneous population which descends from Indian immigrants to Surinam in the late nineteenth century. DESIGN: Case control study. SETTING: University hospital Leiden. METHOD: South Asian patients (n = 38) and control patients (n = 76) were identified in an automated data base comprising all patients who had aortocoronary surgery in the period January 1st 1990 to January 1st 1993. Control patients were from the general population and matched for calendar time. Patients' characteristics such as the onset of coronary heart disease and the presence of non insulin dependent diabetes mellitus were obtained from the medical records at the time of surgery. RESULTS: The onset of coronary heart disease in South Asian patients occurred about eight years earlier than in control patients (49.8 versus 58.2 years; 95% confidence interval of the difference: 4.3-12.5). Non insulin dependent diabetes mellitus was about four times more frequent in South Asian patients (50% versus 13%; 19-54). This difference was the same after correction for differences in sex, age, and body mass index. CONCLUSION: Diabetes mellitus caused by insulin resistance significantly contributes to early coronary heart disease in South Asian immigrant patients, in accordance with the literature on the present population of India. These findings strengthen the belief that genetic factor are important in the development of insulin resistance and atherosclerosis. PMID- 7830826 TI - [Breast feeding among autochthonous and allochthonous mothers in Amsterdam, 1992 1993]. AB - OBJECTIVE: To investigate whether breast feeding is related to family type, family size, maternal education, maternal occupational status and ethnic origin. DESIGN: Descriptive study. SETTING: Six child health centres in Amsterdam, the Netherlands. METHOD: In the period 1992-1993 the feeding practices of 961 children of 3 months were investigated by interviewing their mothers. RESULTS: In Amsterdam 21% of infants were exclusively breast-fed, 15% of infants were breast and formula fed and 64% of infants were exclusively formula fed. After adjustment for potential confounding variables, breast-feeding was associated with mother's educational level and ethnic origin. The breast feeding rate was 49% for mothers with a high education and 26% for mothers with a low education. Among Dutch mothers the frequency of breast-feeding was 37%, and among Surinam, Moroccan and Turkish mothers the frequencies of breast feeding were 16%, 34% and 43% respectively. CONCLUSION: These results suggest that besides socioeconomic factors cultural factors also play a part in the breast feeding practices of mothers. To promote breast feeding culture-based perceptions with respect to feeding and nursing of infants should be considered. PMID- 7830827 TI - [Disappointing results of postanal repair in the treatment of fecal incontinence]. AB - OBJECTIVE: To evaluate the long-term results after postanal repair in patients with faecal incontinence. DESIGN: Retrospective study. LOCATION: Rotterdam. METHODS: Thirty-seven patients, who underwent postanal repair during the period 1984-1992, were approached by telephone to determine the current functional status. RESULTS: The median duration of follow-up was 38 months (range: 4-94). One year after the operation 24 patients (65%) were continent. In 22 patients this successful outcome was observed within the first half year. In seven patients (29%) incontinence recurred. In 13 patients (35%) the functional results were disappointing from the very beginning. The final outcome, which was good in 46% of the patients, was not influenced by the underlying aetiology. CONCLUSION: Postanal repair is not beneficial for the majority of patients with faecal incontinence. Therefore, it should be considered if other treatment modalities, such as biofeedback and the electrically stimulated M. gracilis neosphincter might not be preferable. PMID- 7830828 TI - [Muscle weakness as initial symptom of bronchial carcinoma]. AB - Lambert-Eaton myasthenic syndrome was diagnosed in three patients, two men aged 55 and 57 and one woman aged 66 years. After a variable time interval a small cell carcinoma of the lung was detected in all three patients. Two already had metastases outside the thorax and died, the other patient was doing well after treatment with chemotherapy and radiotherapy. The short survival of patients with a small cell carcinoma requires early diagnosis, and paraneoplastic phenomena such as the Lambert-Eaton myasthenic syndrome can be the earliest presenting sign. The syndrome can be diagnosed by electromyography. PMID- 7830829 TI - [Type II diabetes mellitus in Hindus; new manifestations of old disease pictures]. PMID- 7830830 TI - [Final terms for university medical education: "General Plan 1994 medical education']. PMID- 7830831 TI - [Need for and financing of 'workplaces' outside academic and affiliated hospitals in medical education]. PMID- 7830832 TI - [Selective decontamination of the digestive tract in patients with artificial respiration in an intensive care unit: more arguments for than against]. PMID- 7830833 TI - [Selective decontamination of the digestive tract in patients with artificial respiration in an intensive care unit: more arguments for than against]. PMID- 7830835 TI - [Consensus hemorrhoids]. PMID- 7830834 TI - [Consensus hemorrhoids]. PMID- 7830837 TI - Physician discipline--concerns and misconceptions. PMID- 7830836 TI - [Sex differences in the diagnosis and treatment of coronary heart diseases]. PMID- 7830838 TI - Epinephrine for anaphylaxis. PMID- 7830839 TI - Health care maintenance for the asymptomatic HIV infected individual. PMID- 7830840 TI - Gastrointestinal motility tests--when to call the motility lab? PMID- 7830841 TI - Management strategies in transposition of the great vessels; 1994. PMID- 7830842 TI - Metatarsophalangeal joint subluxation. PMID- 7830843 TI - Ask a lawyer. Anatomical gifts. PMID- 7830844 TI - Acute tumour lysis syndrome and the kidney. PMID- 7830845 TI - Bone mineral density in healthy Dutch women: spine and hip measurements using dual-energy X-ray absorptiometry. AB - OBJECTIVE: To investigate in healthy normal Dutch women the age-associated changes in bone mineral density (BMD) and the effect on bone mass of the menopause and potential risk factors. METHODS: In 260 healthy Dutch women BMD was measured in the lumbar spine and three regions of the proximal femur (Ward's triangle, femoral neck and trochanter), using dual energy X-ray absorptiometry (DXA). The subjects were interviewed using a structured questionnaire on age, reproductive history and gynaecological status, height, weight and consumption of tobacco and alcohol. RESULTS: In 125 premenopausal women a small age-related bone loss was observed at both the lumbar spine and proximal femur, while in postmenopausal women (n = 135) a 2-3 times higher age-related loss was observed. Expressed in years since the menopause this postmenopausal loss was found to be exponential (p < 0.001). After adjustment for age there appears to be a relationship between actual age of menopause and BMD at the lumbar spine and femoral neck. After adjustment for age and actual age of menopause we observed a small negative effect of breastfeeding, whereas parity, current alcohol use and smoking showed no additional effect on BMD in this cohort. For all women (n = 260) a highly significant correlation between BMD and body mass index was found. CONCLUSIONS: In healthy Dutch women we observed a small premenopausal and an accelerated postmenopausal bone loss in both the lumbar spine and proximal femur. Except for breastfeeding, no other risk factors could be identified. PMID- 7830846 TI - Antithrombin III concentrate in the treatment of DIC: a retrospective follow-up study. AB - OBJECTIVE: To assess the clinical utility of antithrombin III (AT-III) substitution in adults with septicaemia in an intensive care unit. METHODS: A retrospective follow-up study was performed in the adult intensive care unit of a large teaching hospital. Adults with septicaemia and AT-III levels less than 0.45 IU/ml were identified. AT-III administration, consisting of an intravenous bolus injection of 20 IU/kg, followed by continuous infusion of 20 IU/kg per 24 h, was given to 21 patients, while this was withheld in 21 age- and sex-matched controls. The severity of diffuse intravascular coagulation (DIC), APACHE II score, and type of septicaemia were analysed. The odds ratio was calculated for survival. RESULTS: The base-line characteristics with regards to severity of DIC, APACHE scores and types of sepsis were comparable for the patients who received AT-III concentrates and those who did not. Mortality in the treated and non treated groups was 76% (95% CI: 53-92%) and 57% (95% CI: 34-78%), respectively (p = 0.24). The odds ratio for survival was 2.4 if no AT-III concentrate was administered (95% CI: 0.537-11.5; p = 0.24). CONCLUSIONS: The use of AT-III concentrates in the doses applied in adult intensive care patients with septicaemia does not appear to improve outcome in terms of mortality. PMID- 7830847 TI - Tumour lysis syndrome and acute renal failure in Burkitt's lymphoma. Description of 2 cases and a review of the literature on prevention and management. AB - Two patients with Burkitt's lymphoma and acute renal failure are described, one with acute uric acid nephropathy and the other with acute renal failure due to hyperphosphataemia. Renal insufficiency caused by the precipitation of calcium phosphate salts only occurs after starting treatment of the lymphoma; uric acid nephropathy can also be present in an untreated patient. A uric acid/creatinine ratio in a random urine sample may help to confirm the diagnosis of acute uric acid nephropathy. Vigorous hydration, allopurinol and alkalinization of the urine have been advocated to prevent uric acid nephropathy. However, alkalinization may accelerate phosphate precipitation in the kidneys and thereby induce renal failure. Xanthine nephropathy may develop as a consequence of high doses of allopurinol. The administration of large volumes of fluid therefore remains the keystone in prevention of the tumour lysis syndrome. PMID- 7830848 TI - Acute renal failure as first presentation of acute lymphoblastic leukaemia. AB - A 26-year-old man presented with acute renal failure, which appeared to be due to uric acid nephropathy occurring as a metabolic complication of acute lymphoblastic leukaemia with T-cell immunophenotype. At presentation there were neither other manifestations of leukaemic disease nor signs of a large leukaemic cell burden, which is very uncommon. PMID- 7830849 TI - Successful renal autotransplantation for renal failure with prolonged oliguria in a Jehovah's Witness with fibromuscular dysplasia of the renal arteries. AB - A young female presented with hypertension and oliguric renal insufficiency caused by fibromuscular dysplasia of the renal arteries. There was a left kidney remnant and a normal-sized right kidney with a retrograde blood supply through capsular arteries. Reconstruction of the occluded right renal artery with autotransplantation of the kidney after 60 days of oliguric renal insufficiency was followed by complete functional repair. Erythropoietin treatment was a great help in the management of this patient who refused blood transfusions because she was a Jehovah's Witness. PMID- 7830850 TI - Digitalis in congestive heart failure. AB - The indications for digitalis glycosides in the treatment of congestive heart failure with sinusrhythm have been disputed since early in this century. In the last decade several well designed studies have been published that have established the effectiveness of digitalis in this condition. However, new groups of drugs have been introduced in the treatment of heart failure and have been compared with digitalis. Ibopamine appeared to be an effective alternative for digitalis in patients with heart failure of low NYHA class. Because of their proven favourable effect on patient survival, ACE inhibitors are replacing digitalis as first-line drug--after diuretics--in the treatment of congestive heart failure. In this review of the literature the present place of digitalis in the treatment of heart failure is discussed. PMID- 7830851 TI - Genesis and significance of hypertension in autosomal dominant polycystic kidney disease. PMID- 7830852 TI - Acquired aortic stenosis in dialysis patients. PMID- 7830853 TI - Effect of an acute oral protein load on microalbuminuria in uninephrectomized patients in relation to the time since nephrectomy. AB - To evaluate the effect of an acute oral protein load (OPL) on urinary albumin excretion (UAE) in uninephrectomized subjects with a negative Albustix test, in relation to the time since nephrectomy, the UAE was determined by a double antibody 125I radioimmunoassay in 3-hour urine collections before and after 150 g OPL under conditions of moderate physical activity in 18 subjects who underwent unilateral nephrectomy more than 10 years (346.5 +/- 178.60 months) before evaluation and had a mean basal creatinine clearance (CCr) of 45.3 +/- 14 ml/min (group 1), in 21 subjects who underwent unilateral nephrectomy less than 10 years (31.5 +/- 28 months) before evaluation and had a mean basal CCr of 76.0 +/- 22 ml/min (group 2), and in 16 normal volunteers (controls) with a mean basal CCr of 103.1 +/- 12 ml/min. The UAE was higher in group 1 as compared with either group 2 or controls at both basal state (90.8 +/- 65, 19.6 +/- 17, and 11.0 +/- 5 micrograms/min/100 CCr for groups 1 and 2 and controls, respectively; p < 0.001) and after OPL (92.0 +/- 65, 43.6 +/- 24, and 12.0 +/- 5 micrograms/min/100 CCr for groups 1 and 2 and controls, respectively; p < 0.001). However, the increase in UAE following OPL was significant (p < 0.001) only in group 2 patients. In all patients, the basal UAE was negatively correlated with basal CCr (r = 0.63; p < 0.001) and positively correlated with the time since nephrectomy (r = 0.73; p < 0.001) and with both systolic (r = 0.57; p < 0.001) and diastolic blood pressures (r = 0.69; p < 0.001). CCr calculated using 3-hour urine collections increased more in controls (11.2 +/- 44.2%) than in patient groups 1 (1.6 +/- 0.89) and 2 (7.7 +/- 3.7%; p < 0.001). Basal CCr calculated using 24-hour urine collections the day before the test was negatively correlated with the time since nephrectomy in group 1 (r = -0.69; p < 0.001) and positively correlated with the time since nephrectomy in group 2 (r = 0.89; p < 0.001). Multiple regression analysis revealed that the relationship between CCr and duration of uninephric state was independent of age or systolic and diastolic blood pressures in both patient groups. These results suggest that UAE increase significantly after an OPL in subjects who have been nephrectomized less than 10 years before the study and have basal CCr values higher than 50% of normal.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7830854 TI - Chemical preservation of urine sediment for phase-contrast microscopic examination. AB - A major difficulty in diagnostic urinary microscopy is the need to observe a freshly passed urine specimen. This study illustrates the use of glutaraldehyde (GA) and formaldehyde (FA) to preserve urinary sediment for diagnostic microscopy. GA and FA in whole urine cause a precipitate to form if there is a trace or more of proteinuria. This can be eliminated by centrifugation and fixation of urine sediment. Red blood cells (RBC) and casts are adequately preserved for diagnostic microscopy for at least 3 months. However, subtle changes in RBC morphology consisting of hexagonal distortion and wrinkling of cell margins are seen in some cells. White blood cells (WBC) are less reliably preserved. Diagnostic phase-contrast microscopy can be performed on urine sediment stored at room temperature for up to 3 months after fixation with GA or FA. PMID- 7830855 TI - Hemorheological and hemostatic parameters in children with nephrotic syndrome undergoing steroid therapy. AB - Disturbances in hemostatic and hemorheological parameters have been investigated in a group of 29 children with nephrotic syndrome: 23 children classified as steroid-sensitive and 6 as steroid-resistant. Studies were performed before prednisone treatment and 3 weeks later, after initiation of steroid therapy. Before treatment, the alterations in hemostatic system involved moderate thrombocytosis with spontaneous aggregation in 19 patients. High levels of fibrinogen, factor VIII, Willebrand factor, protein C, protein S and alpha 2 macroglobulin (alpha 2M) were observed. Factor XII and alpha 1-antitrypsin (alpha 1AT) were lower than normal. Antithrombin III (ATIII) level was normal in the majority of patients. A plasma and blood hyperviscosity syndrome was also observed as well as an increase in erythrocyte aggregation. During treatment, an improvement in the hemostatic parameters was observed in the patients who responded to prednisone. The expected increase in factor VIII (frequently described in the literature) was not observed, while there was a significant increase in protein C. In the steroid-resistant patients, the only significant changes observed were decreased fibrinogen and increased protein C. The hemorheological parameters showed a tendency towards normality regardless of whether or not the treatment provided remission of NS. The relationship between hemorheological and hemostatic factors changes are discussed. PMID- 7830856 TI - Effect of calcium supplement preparation containing small amounts of citrate on the absorption of aluminium in normal subjects and in renal failure patients. AB - It is well known that Al absorption is markedly enhanced by citrate. The aim of the study was to document whether low-dose citrate ingestion (4 g/day) contained in a well-known effervescent calcium supplement was sufficient to increase Al absorption in 16 normal volunteers and 15 subjects with stable chronic renal failure under conditions of either Ca carbonate or Al hydroxide supplementation. Serum and urine Al levels were measured using flameless atomic absorption spectrophotometry as previously described. After Ca carbonate plus Ca citrate ingestion, there was no rise over baseline (Ca Carbonate alone) serum or urine Al levels in either group. Ca carbonate and Al hydroxide taken together produced a significant rise in serum and urine Al levels in both groups. Maintaing Al hydroxide but substituting Ca citrate for the carbonate (same dose of elemental Ca) produced a further significant increment in serum Al (0.47 +/- 0.28-1.15 +/- 0.8 mumol/l; p < 0.001) and in urine Al(1.37 +/- 0.46-5.77 +/- 5.21 mumol/l; p < 0.001) in the chronic renal failure group as well as in serum Al (0.42 +/- 0.2 0.76 +/- 0.48 mumol/l; p < 0.001) and urine Al (2.70 +/- 1.24-8.24 +/- 3.96 mumol/l; p < 0.001 in the normal volunteer group. Due to decreased urine excretion, the increment in serum Al in the CRF group was significantly greater than in the normal subjects (p < 0.02). Thus small quantities of citrate present in effervescing Ca supplements can significantly enhance intestinal Al absorption even in normal subjects. All citrate-containing preparations are totally contra indicated in chronic renal failure patients ingesting Al-containing compounds.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7830857 TI - Pharmacokinetics of a low molecular weight heparin (reviparine) in hemodialyzed patients. AB - Low-molecular-weight heparins (LMWHs) are used to prevent clotting in hemodialysis extracorporeal blood circuits. In order to test the possibility of using reviparine (a LMWH of 3,900 D) in this indication, we studied the pharmacokinetics of the drug after a mean dose of 3,300 IU anti-Xa in 10 hemodialyzed patients. Reviparine was administered subcutaneously between two dialysis sessions and intravenously at the start of 20 dialysis sessions performed either with high (HP) or low-permeability (LP) membranes. We observed a moderate increase of the elimination half-life of reviparine (T1/2: 5 +/- 1.6 h between dialysis, 3.6 +/- 1.3 during dialysis with an HP membrane and 4.7 +/- 1.8 during dialysis with an LP membrane) versus 3.3 +/- 1 in healthy volunteers. Dialysis procedures with an HP or an LP membrane do not importantly modify the pharmacokinetics of reviparin compared with data observed in healthy volunteers. During the sessions, we observed no clotting in the extracorporeal circuit, no hemorrhagic event and no prolongation of the fistula compression times. Further clinical studies are required to define the optimal dosage of reviparine to prevent coagulation in hemodialysis blood circuits. PMID- 7830858 TI - Renal handling of albumin and beta-2-microglobulin in neonates. AB - Urinary albumin and beta 2-microglobulin (B2M) were measured during the neonatal period. Urinary albumin decreased postnatally in term neonates, while it remained almost constant in preterm neonates. Urinary B2M showed a peak level on day 7 both in term and preterm neonates. There was some trend towards higher levels of albumin and B2M with decreasing gestation, showing that glomerular permeability increases and proximal tubular protein reabsorption decreases with increasing degrees of prematurity. In sick preterms who were depressed at birth and had respiratory failure, both parameters were elevated during the first 2 weeks, indicating the presence of glomerular and tubular damage in this period. The changes in B2M with gestation or clinical condition were more pronounced than those in albumin. PMID- 7830859 TI - Tertiary hyperparathyroidism treated by ultrasonically guided percutaneous fine needle ethanol injection. AB - Advanced renal failure is often accompanied by secondary and tertiary hyperparathyroidism. In tertiary hyperparathyroidism it is necessary to reduce the gland mass. The present study describes the response to treatment with percutanous injection of ethanol of enlarged parathyroid nodules in 9 uremic patients. All had hypercalcemia, severely elevated serum levels of parathyroid hormone and ultrasonically detectable enlarged parathyroid glands. Three patients did not respond to the treatment. In the remaining 6 patients, serum values of total and ionized calcium were normalized and the serum values of parathyroid hormone were reduced at least 30% after 18 months. Seven of the patients experienced an improvement of symptoms. No complications were seen. We conclude that treatment with ethanol injection can be used as an alternative to conventional parathyroidectomy to improve parathyroid status in selected patients. PMID- 7830860 TI - Serial evaluation of parathyroid size by ultrasonography is another useful marker for the long-term prognosis of calcitriol pulse therapy in chronic dialysis patients. AB - To clarify whether the changes of parathyroid size have any correlations with the long-term prognosis of calcitriol pulse therapy, we examined the time course of serum levels of parathyroid hormone (PTH) and size of parathyroid glands in 14 chronic dialysis patients during and after the oral calcitriol pulse therapy. In 5 patients without any detectable glands, secondary hyperparathyroidism was easily controlled by calcitriol pulse therapy and then by conventional oral active vitamin D therapy. In 2 patients with detectable gland(s) in whom size of all parathyroid glands as well as PTH hypersecretion regressed to normal by calcitriol pulse therapy, secondary hyperparathyroidism could then remain controlled at least for 12 months after switching to conventional oral active vitamin D therapy. In contrast, in 7 patients in whom size of all parathyroid glands did not regress to normal by calcitriol pulse therapy, secondary hyperparathyroidism relapsed after switching to the conventional therapy, even if PTH hypersecretion could be controlled temporarily. Our findings suggest that the time course of parathyroid hyperplasia detected by ultrasonography is an important determinant of the efficacy and the prognosis of calcitriol pulse therapy. Thus, the change of parathyroid gland size as well as PTH hypersecretion should be taken into account for the management of secondary hyperparathyroidism. PMID- 7830861 TI - The effect of ultrafiltered dialysate on the cellular content of interleukin-1 receptor antagonist in patients on chronic hemodialysis. AB - We investigated the effect of dialysate ultrafiltration on the content of IL-1 receptor antagonist (IL-1Ra) in mononuclear cells (PBMC) as a marker of the inflammatory response. 11 patients on Cuprophan dialyzers were randomly assigned to treatment with standard bicarbonate dialysate first and then to ultrafiltered dialysate or the reverse order in a crossover design. In each treatment period (at least 4 weeks) weekly separations of PBMC were performed before the start of dialysis. Cellular content of IL-1Ra was determined in PBMC that were frozen immediately after separation; all values of IL-1Ra in each treatment period were averaged. The dialysate contained a median of 148 (range, 61-400) colony-forming units without dialysate filter; no bacterial growth was detected in ultrafiltered dialysate. The median endotoxin content was 80 pg/ml in nonfiltered dialysate; endotoxin was below 5 pg/ml in all ultrafiltered dialysate samples. Cellular content of IL-1Ra decreased in all but 1 patient with the use of ultrafiltered dialysate (mean +/- SEM: 1,467 +/- 113 pg/ml without dialysate filter vs. 1,166 +/- 104 pg/ml with filter, p = 0.016). The present study demonstrates that the bacterial contamination of the dialysate induces a systemic inflammatory response in hemodialysis patients. PMID- 7830862 TI - Regulation of proximal renal tubular K+ conductance by intracellular pH. AB - Conventional electrophysiology and 2', 7'-bis-(2-carboxyethyl)-5-(and 6) carboxyfluorescein fluorescence have been applied to elucidate the effects of metabolic acidosis on straight proximal tubules of the mouse kidney. Reduction of extracellular bicarbonate concentration from 20 to 10 mmol/l leads to a decline of intracellular pH from 7.00 +/- 0.06 to 6.85 +/- 0.05, a depolarization of the cell membrane (PDbl) from -72 +/- 1 to -59 +/- 2 mV, a decrease of the basolateral transference number for potassium (tK) from 0.80 +/- 0.01 to 0.54 +/- 0.03, an increase of the basolateral transference number for bicarbonate (tb) from 0.16 +/- 0.02 to 0.42 +/- 0.03 and an increase of the fractional resistance of the basolateral over the luminal cell membrane (Rb/Ra) by 64 +/- 8%. Upon return to 20 mmol/l bicarbonate after a 5-min exposure to 10 mmol/l bicarbonate, the intracellular pH approached a more alkaline value (7.28 +/- 0.08) than before exposure to acidosis. Despite the intracellular alkalosis, PDbl (-67 +/- 1 mV) and tK (0.73 +/- 0.02) remained significantly below, and tb (0.26 +/- 0.02) and Rb/Ra (32 +/- 8%) significantly above the respective values before induction of acidosis. Even transient exposure of the tubules to 40 mmol/l extracellular bicarbonate did not restore the original electrophysiological properties of the tubule cells. It is concluded that both a rapidly reversible and a long-lasting decrease of proximal tubular K+ conductance follows cellular acidosis. PMID- 7830863 TI - Hereditary nephrotic syndrome with progression to renal failure in a mouse model (ICGN strain): clinical study. AB - The clinical course of murine hereditary nephrotic syndrome (ICGN strain) was determined by examining 201 animals under different conditions. In the early stage, significant hypoproteinemia and hypoalbuminemia developed (p < 0.001) in parallel with a progressive rise in urinary protein concentration (p < 0.001). In the middle stage, the concentrations of total cholesterol, triglyceride, and beta lipoprotein markedly increased (p < 0.01, p < 0.001, and p < 0.001, respectively), suggesting that type IIb hyperlipoproteinemia developed as in human nephrotic patients. Systemic edema appeared in 8 of 24 animals. In the terminal stage, both BUN and creatinine values greatly increased (p < 0.001), indicating rapid deterioration of renal function. The present study suggests that ICGN mice could be a useful model to study the pathophysiology of human nephrotic syndrome and its progression to renal failure. PMID- 7830864 TI - A quantitative assessment of renal blood flow autoregulation in experimental diabetes. AB - Several approaches have been utilized to describe renal blood flow (RBF) autoregulation in normal and pathological conditions. When describing the relation between RBF and stepwise decrements in renal perfusion pressure (RPP), these methods have several limitations, including: the necessity for predetermining a pressure 'break-point', and establishing constraints on changes in flow. To circumvent these limitations, we successfully utilized a third order polynomial, the cubical parabola, to characterize the autoregulatory responses in untreated streptozotocin (STZ) diabetic and control rats. The nonlinear relationship occurring between RBF and RPP was estimated from individual observations using the equation RBF = a + b x 10(-6) (RPP-c)3. Variables a and c represent RBF and RPP at the inflection point of the curve, respectively; variable b represents the rate of fall of RBF as RPP decreases (shape factor). Variable c was significantly lower in the diabetic group than in the control group whereas variable b was greater in the diabetic group. RBF (a) did not differ between the two groups. In conclusion, we determined that the range of RBF autoregulation in untreated diabetic rats is reset to a lower RPP. Furthermore, the curve below the inflection point declines more rapidly in diabetic rats than in controls. We propose that the equation described herein constitutes a promising and reproducible method for describing RBF autoregulation in vivo. PMID- 7830865 TI - Severe hyponatremia in a patient with renovascular hypertension: case report. AB - We report a 2-year-old boy with renovascular hypertension caused by stenosis of the left renal artery that was successfully treated by percutaneous transluminal angioplasty (PTA). He initially presented with severe hyponatremia, hypokalemia, polyuria, transient proteinuria and weight loss. This phenomenon is known to occur in patients with renovascular and malignant hypertension, called hyponatremia hypertensive syndrome, but was thought to be rare in children. Renovascular hypertension should be considered as a cause of hyponatremia in children. In addition, PTA is an appropriate treatment even in very young children with renovascular hypertension. PMID- 7830866 TI - Bilateral renal angiomyolipomatosis in tuberous sclerosis presenting with chronic renal failure: case report and review of the literature. AB - A 45-year-old patient with tuberous sclerosis and bilateral renal angiomyolipomas who presented with chronic renal failure is reported. Although bilateral renal angiomyolipomas are commonly associated with tuberous sclerosis, the occurrence of chronic renal failure in the absence of associated cystic disease of the kidneys as seen in this patient is very rare. PMID- 7830867 TI - Recurrent nephrotic syndrome associated with Kimura's disease in a young non Oriental male. AB - Kimura's disease (KD) is an angiolymphoid proliferative disorder of soft tissue with eosinophilia, with a predilection for head and neck regions in young Oriental men. Renal disease is rarely associated with it. We describe a young non Oriental male with KD and relapsing steroid-responsive minimal-change nephrotic syndrome. This case of KD associated nephrotic syndrome is unique in the relapsing nature of the nephropathy and the non-Oriental origin of the patient. We comment on KD and nephrotic syndrome and on treatment strategy. PMID- 7830868 TI - Syndrome of inappropriate antidiuretic hormone secretion and herpes zoster infection: 1. Report of this association in a patient suffering from AIDS. AB - The syndrome of inappropriate secretion of antidiuretic hormone is a common consequence of neurologic and pulmonary infections as well as drug intake and many other clinical situations. Its association with herpes varicella-zoster virus infections is scarcely reported in the literature. It generally appears in immunosuppressed patients suffering from serious underlying diseases. There are also a few cases of syndrome of inappropriate secretion of antidiuretic hormone related to vidarabine use. We report the case of a man infected by human immunodeficiency virus who developed a disseminated herpes varicella-zoster virus infection and symptoms due to hyponatremia caused by antidiuretic hormone excess. The patient was cured with saline hypertonic infusion, water restriction, and intravenous administration of acyclovir. To the best of our knowledge, this is the first case of this association in a human immunodeficiency virus infected patient. We propose the use of acyclovir instead of vidarabine in the management of these situations. PMID- 7830869 TI - Elective rather than emergency intervention for acute renal artery occlusion with anuria. AB - We describe a case in which surgical revascularisation was electively delayed until 27 days after acute renal artery occlusion, allowing surgery to be performed after a period of haemodialysis and pre-operative cardiac assessment. Owing to the collateral blood supply to the kidney, emergency surgery in cases of acute renal artery occlusion may not be necessary, and may be hazardous. PMID- 7830870 TI - Thrombocyte alpha-2-adrenoceptors and hypotension in hemodialyzed patients. PMID- 7830871 TI - Conflicting results on peripheral adrenoceptor function in hypotension of hemodialyzed patients. PMID- 7830872 TI - Evaluation of magnetic resonance imaging for the assessment of renal vein thrombosis in the nephrotic syndrome. PMID- 7830873 TI - Sodium nitroprusside increases renal synthesis of cGMP and reduces free water clearance in human. PMID- 7830874 TI - Toxic and vascular nephropathy associated with orotic acid administration in laboratory cats. PMID- 7830875 TI - Obstruction of the subclavian vein due to placement of a hemodialysis catheter in a subject with thoracic outlet syndrome. PMID- 7830876 TI - Methylguanidine synthase from rat kidney is identical to long-chain L-2-hydroxy acid oxidase. PMID- 7830877 TI - Major role of hydroxyl radical in the conversion of creatinine to creatol. PMID- 7830878 TI - Transient suppression of erythropoietin synthesis in hydronephrosis. PMID- 7830879 TI - Detection of serum IL-6 in patients with diabetic nephropathy. PMID- 7830880 TI - Metronidazole-associated hepatotoxicity in a hemodialyzed patient. PMID- 7830881 TI - Decreased choline acetyltransferase activity in nerve growth factor-transgenic mice during brain development. AB - Activity of the synthetic enzyme for acetylcholine, choline acetyltransferase was investigated during development and in adult nerve growth factor-transgenic mice. A conspicuous reduction of choline acetyltransferase activity was observed in the anterior brain of nerve growth factor-transgenic embryos from embryonic days 13 to 16 (E13 to E16). Choline acetyltransferase activity levels subsequently resumed to normal levels, with the exception of a 15% increase in the adult hippocampus. Nerve growth factor contents followed a similar time-course and regional distribution in normal and nerve growth factor-transgenic animals and displayed significantly higher values from E14 to the early postnatal period. Nerve growth factor contents were normal in the adult brain. In vitro experiments confirmed the involvement of nerve growth factor in the decrease of choline acetyltransferase activity levels observed in transgenic neurons during development. These results suggest a role for nerve growth factor in the initial phase of the phenotypic differentiation of cholinergic neurons. They show that nerve growth factor may, under specific development conditions, lead to a paradoxical down-regulation of choline acetyltransferase activity. PMID- 7830882 TI - Comparison of prostaglandin E1- and prostaglandin E2-induced hyperalgesia in the rat. AB - We have studied prostaglandin E1-induced mechanical hyperalgesia in the rat hindpaw, by assessing paw-withdrawal thresholds, before and after injecting prostaglandin E1 alone or with other agents, in normal and streptozotocin-induced diabetic rats. In normal and diabetic rats, prostaglandin E1 (1-1000 ng) produced a dose-dependent decrease in mechanical nociceptive threshold. In diabetic rats, prostaglandin E1 was more potent than in normal rats, in producing hyperalgesia, whereas prostaglandin E2 hyperalgesia was not changed in normal and diabetic rats. Prostaglandin E1-induced hyperalgesia was not inhibited by E-type 1 prostaglandin receptor antagonists, SC19220 or SC51089, either in normal or diabetic rats. In fact, in the presence of SC19220, prostaglandin E1 produced enhanced hyperalgesia, in normal rats. Prostaglandin E1 hyperalgesia was not significantly modified by sympathectomy or indomethacin. Unlike prostaglandin E2, prostaglandin E1 hyperalgesia was not blocked by the inhibitor of the stimulatory guanine nucleotide-binding regulatory protein, guanosine 5'-O-(2 thiodiphosphate). It is suggested that prostaglandin E1 decreases primary afferent nociceptive threshold directly, by activating a prostaglandin receptor other than the E-type 1 prostaglandin receptor, and that this receptor is not coupled to a stimulatory guanine nucleotide-binding regulatory protein. PMID- 7830883 TI - Trophic factors from chromaffin granules promote survival of peripheral and central nervous system neurons. AB - Chromaffin cells of the adrenal medulla were used to study the release of neurotrophic factors operationally defined by their capacity to promote the in vitro survival of embryonic neurons from the peripheral and central nervous system. Chromaffin cells are closely related to sympathetic neurons in terms of their transmitters and specific proteins and, like sympathetic neurons, receive preganglionic cholinergic, aminergic and peptidergic neuronal inputs. The issue of whether chromaffin cells store and secrete neurotrophic factors is therefore pertinent to the question whether trophic mechanisms may be involved in neuronal interactions and what modes of secretion are employed to liberate neurotrophic factors from neurons. Cell culture media conditioned by purified bovine chromaffin cells supported several neuron populations in vitro. Stimulation of the chromaffin cells with the cholinergic agonist carbachol (10(-4) M) increased in parallel the output of neurotrophic factor activity (assayed on chick ciliary ganglionic neurons) as well as two components specifically located in chromaffin granules, chromogranin A and catecholamines. The release of all three components was partially blocked by the Ca2+ channel blocker verapamil (10(-5) M), suggesting co-storage and -release of neurotrophic factors, chromogranin A and catecholamines in/from chromaffin granules. Neurotrophic factor activity for ciliary ganglionic neurons accumulating in the medium of unstimulated chromaffin cells decreased with time, and so did catecholamines. In contrast, amounts of neurotrophic factors and catecholamines released by challenging cells with carbachol did not significantly decline up to 62 h. The neurotrophic factor activity tested on chick ciliary, sensory and spinal cord neurons as well as on rat hippocampal neurons was heat- and trypsin-labile and could not be blocked by polyclonal antibodies against bovine nerve growth factor and the chromogranin A, B, and C. Defined fragments of chromogranin A and pancreastatin were devoid of neurotrophic activity. Our results suggest the presence of one or several neurotrophic factors in chromaffin granules, which can be released by exocytosis and may be potentially relevant for the maintenance of neurons innervating the adrenal medulla. PMID- 7830884 TI - Imaging cell volume changes and neuronal excitation in the hippocampal slice. AB - Brain cell swelling is a consequence of seizure, ischemia or excitotoxicity. Changes in light reflectance from cortical surface are now used to monitor brain activity but these intrinsic signals are poorly understood. The objectives of this study were first, to show that changes in light transmittance were correlated with cell volume and second, to image increases in light transmittance as they related to neuronal activation. Transverse hippocampal slices from the rat were used for the study. Brief exposure (4-6 min) to hypo-osmotic artificial cerebrospinal fluid (-40 mOsm) elevated light transmittance consistently and reversibly in most regions of the slice and particularly in CA1 dendritic regions. Neither zero-Ca2+ artificial cerebrospinal fluid nor tetrodotoxin altered the transmittance increase and its subsequent reversal, suggesting that it was dependent on osmolality but independent of synaptic transmission and neuronal firing. The amplitude of the CA1 population spike evoked from Schaffer collaterals increased concomitantly with the hypo-osmotic increase in light transmittance, providing evidence that the extracellular tissue resistance increased. Hyper-osmotic artificial cerebrospinal fluid (+40 mOsm) containing impermeant mannitol consistently lowered light transmittance and the amplitude of the population spike. Glycerol (+40 mOsm), which is cell permeant, did not have an affect. Taken together these observations indicate that osmotic challenge alters light transmittance by inducing changes in cell volume. Transmittance increases induced by hypo-osmotic artificial cerebrospinal fluid or 10 microM kainate were small in the CA1 cell body region compared to dendritic regions. Similarly, orthodromic stimulation of axons terminating in stratum oriens or in stratum radiatum evoked transmittance increases only in their respective postsynaptic areas. In contrast, the cell body region and its adjacent proximal apical dendrites (both sites of action potential initiation) could display dramatic increases in light transmittance upon brief exposure to 20 mM K+. The response, which may represent neuronal damage, was blocked in tetrodotoxin. Antidromic stimulation evoked a weak response in these same proximal areas. We conclude that activity-dependent increases in light transmittance across brain slices primarily reveal glial and neuronal swelling associated with excitatory synaptic input and action potential discharge. The signal can be imaged in real time to reveal neuronal activation, not only among hippocampal areas, but among neuronal regions. Cell swelling is a known consequence of excessive neuronal discharge. Therefore, the imaging of changes in light transmittance across brain slices should prove useful in monitoring epileptiform and excitotoxic states. PMID- 7830885 TI - Endogenous adenosine modulates long-term potentiation in the hippocampus. AB - The effect of endogenous adenosine on frequency-induced long-term potentiation of the responses evoked by stimulation of the Schaffer fibres and recorded in the CA1 area was studied in hippocampal slices of the rat. Long-term potentiation was facilitated in the presence of the selective A1 adenosine receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (10-20 nM), and was reduced in the presence of the adenosine uptake blocker, nitrobenzylthioinosine (5 microM), suggesting that endogenous adenosine exerted a tonic inhibitory role on long-term potentiation, which was mediated through adenosine A1 receptors. We also found that long-term potentiation was increased in the presence of the selective A2 receptor agonist, CGS 21680 (30 nM), suggesting that the activation of adenosine A2 receptors may have excitatory effects on long-term potentiation. We suggest that, endogenous adenosine is able to modulate mechanisms of synaptic plasticity, such as long term potentiation, in the hippocampus. PMID- 7830886 TI - Interaction between paired-pulse facilitation and long-term potentiation in area CA1 of guinea-pig hippocampal slices: application of quantal analysis. AB - The aim of the study was to further specify mechanisms of maintenance of hippocampal long-term potentiation. Previous analysis of excitatory postsynaptic potentials showed increases in quantal content (mean number of neurotransmitter quanta released by every testing pulse) with smaller increases in quantal size (effect of one transmitter quantum) following long-term potentiation induction. Here we recorded intracellularly excitatory postsynaptic potentials from CA1 pyramidal neurons of guinea-pig hippocampal slices after minimal paired-pulse stimulation of monosynaptic inputs. Statistical parameters underlying excitatory postsynaptic potential fluctuations were estimated by a deconvolution procedure using a quantal model. The parameters of excitatory postsynaptic potentials following paired-pulse stimulation were studied before and after induction of long-term potentiation. Under both conditions, paired-pulse facilitation was found to be accompanied by increases in quantal content and quantal size. During long-term potentiation, paired-pulse facilitation of amplitude and quantal content was lower. The respective changes in the paired-pulse facilitation ratios correlated with long-term potentiation magnitude. In contrast, the paired-pulse facilitation of quantal size did not change significantly following long-term potentiation induction. The results are compatible with the existence of two separate mechanisms of long-term potentiation maintenance. They support the suggestion that changes in quantal content are mainly due to presynaptic mechanisms which are shared by long-term potentiation and paired-pulse facilitation. The mechanisms underlying changes in quantal size are of a different nature for long-term potentiation and paired-pulse facilitation. For long-term potentiation they might be located postsynaptically. PMID- 7830887 TI - The putative essential nutrient pyrroloquinoline quinone is neuroprotective in a rodent model of hypoxic/ischemic brain injury. AB - Pyrroloquinoline quinone is a ubiquitous redox cofactor and putative essential nutrient in mammals. Pyrroloquinoline quinone has recently been demonstrated to depress N-methyl-D-asparate induced electrical responses and is neuroprotective in vitro. In addition, pyrroloquinoline quinone has been demonstrated to act as a free radical scavenger in mammalian tissues. In this study, we demonstrate a neuroprotective effect of pyrroloquinoline quinone in an in vivo cerebral hypoxia/ischemia model in the rodent. Significant reduction in infarct size resulted from pyrroloquinoline quinone pretreatment and also when pyrroloquinoline quinone was administered following induction of hypoxia/ischemia. The neuroprotective effect was not dependent on change in core or cranial temperatures, as there was no difference between temperature measurements in pyrroloquinoline quinone-treated and vehicle-treated controls. No changes in electroencephalographic activity were observed at neuroprotective doses. These findings suggest that pyrroloquinoline quinone may represent a novel class of quinoid reagents of potential use in the treatment of neurological disorders that involve excitotoxicity. This study demonstrates a protective effect of the novel essential nutrient pyrroloquinoline quinone on brain injury in a rodent model of cerebral hypoxia/ischemia. Pyrroloquinoline quinone was neuroprotective when administered before and even after the insult, and did not appear to have significant neurobehavioral side effects. Pyrroloquinoline quinone represents a new class of agents with potential use in the therapy of stroke. PMID- 7830888 TI - Temporal changes in the messenger RNA levels of cellular immediate early genes and neurotransmitter/receptor genes in the rat neostriatum and substantia nigra after acute treatment with eticlopride, a dopamine D2 receptor antagonist. AB - The cellular immediate early genes are involved in the transcriptional events associated with the dopaminergic regulation of neurotransmitter expression within neurons of the neostriatum. To characterize these events in detail, quantitative in situ hybridization histochemistry was used to assess the temporal effects of acute dopamine receptor blockade with eticlopride, a dopamine D2 receptor antagonist, on the messenger RNA expression of the immediate early genes and neurotransmitters/receptors in the caudate-putamen and ventral tegmental area/substantia nigra pars compacta of the rat. Groups of rats were injected with a single dose of either isotonic saline or eticlopride (0.5 mg/kg i.p.) and killed at various time intervals ranging from 5 min to 24 h and frozen brain sections processed by in situ hybridization histochemistry. Using computerized image analysis, the changes in messenger RNA expression for c-fos, c-jun, jun B, jun D, nerve growth factor I-A and nerve growth factor I-B and for neurotensin, glutamate decarboxylase, proenkephalin, the dopamine D1 receptor and the short and long isoforms of the D2 receptor were examined in the caudate-putamen. In the ventral tegmental area and substantia nigra pars compacta, the messenger RNA expression of the above early response genes and that for neurotensin, tyrosine hydroxylase, cholecystokinin and the D2 receptor isoforms were also examined. In the neostriatum, eticlopride caused a rapid increase in c-fos messenger RNA with significantly increased levels at 10 min (P < 0.01). The levels peaked at 30 min and thereafter declined to control levels. A similar profile was observed for jun B messenger RNA, although levels were still significantly (P < 0.01) elevated at 1 h and declined to basal levels thereafter. No significant changes were observed for c-jun, jun D, nerve growth factor I-A and nerve growth factor I-B messenger RNAs. In the dorsolateral neostriatum, there was an increase in proneurotensin messenger RNA 10 min after eticlopride, this increase becoming significant (P < 0.01) at 60 min. Levels were maximal at 2-6 h and decreased after 12 h to basal levels. There were small increases in proenkephalin messenger RNA, but these were not significant (P < 0.05) until 6 h after the injection. Eticlopride did not have any significant effects on the messenger RNA levels for glutamate decarboxylase, the D1 receptor and the short and long isoforms of the D2 receptor.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7830889 TI - Response of striatal astrocytes to neuronal deafferentation: an immunocytochemical and ultrastructural study. AB - This ultrastructural and light microscopic immunocytochemical study describes the time course of anatomical changes that occur in striatal astrocytes in response to neuronal deafferentation in young adult rats and the coordinate distribution of two astrocytic proteins involved in reactive synaptogenesis, glial fibrillary acidic protein and clusterin. We found that following a unilateral lesion of the cerebral cortex, striatal astrocytes undergo a rapid ultrastructural transformation from a protoplasmic to a reactive type of astroglia and are the primary cells involved in the removal of degenerating axon terminals, but not axons of passage, from the neuropil. In addition, at 10 and 27 days postlesion, processes of reactive astrocytes are also seen to occupy vacant postsynaptic spines after degenerating presynaptic terminals are removed, suggesting that they may also participate in the reinnervation of the deafferented neurons. By immunocytochemistry, reactive astrocytes were characterized by a significant increase in the intensity of glial fibrillary acidic protein staining beginning at three days postlesion and lasting for at least 27 days postlesion. Reactive astrocytes were characterized by cellular hypertrophy and an increase in the density of immunoreactive processes distributed throughout the deafferented striatum. However, our analysis of astrocyte cell number found no evidence of astrocyte proliferation in response to the deafferentation lesion. Although previous in situ hybridization studies have reported elevated clusterin messenger RNA in reactive astrocytes after decortication, clusterin immunoreactivity was not seen in the cell soma of reactive astrocytes but was distributed as punctate deposits, ranging from 1 to 2 microns in diameter, within the neuropil of the deafferented striatum. At 10 days postlesion, the distribution of clusterin staining appeared as large aggregates of immunoreactive deposits adjacent to neurons. However, by 27 days postlesion, the aggregates of clusterin reaction product were replaced by a fine scattering of individual punctate deposits distributed evenly over the dorsal part of the deafferented striatum. These data support the notion that reactive astrocytes serve multiple, time-dependent roles in response to brain injury and are involved in both the removal of degenerative debris from the lesion site as well as in reforming the synaptic circuitry of the damaged brain. Our data suggest that, in response to decortication, reactive astrocytes are the primary cells responsible for removing degenerating axon terminals, but not axons of passage, from the deafferented striatum and that the coordinate increase in glial fibrillary acidic protein may serve to stabilize the extension of reactive astrocytic processes during phagocytosis.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7830890 TI - Cholinergic stimulation of rostral and caudal substantia nigra pars compacta produces opposite effects on circling behavior and striatal dopamine release measured by brain microdialysis. AB - Turning in circles is among the behaviors elicited by unilateral cholinergic stimulation of the substantia nigra. Recent studies have shown that microinjection of cholinergic agonists into the substantia nigra pars compacta increases dopamine release and turnover in the striatum of anesthetized rats [Hernandez-Lopez et al. (1992) Brain. Res. 598, 114-120; Blaha and Winn (1993) J. Neurosci, 13, 1035-1044]. In this study, the relationship between circling behavior and striatal dopamine release following cholinergic stimulation of the substantia nigra pars compacta neurons was assessed by brain microdialysis in awake rats. The results indicate that cholinergic stimulation of the substantia nigra pars compacta with the mixed nicotinic-muscarinic cholinergic agonist carbachol modulates striatal dopamine release, and this effect is accompanied by circling behavior and stereotypies. Microinjection of carbachol (109 nmol) in the caudal portions of the substantia nigra pars compacta induced contralateral circling associated with an increase of dopamine release in neostriatum. On the contrary, ipsilateral circling and reduction of striatal dopamine release was elicited when the same dose of the drug was applied in the rostral portions of the substantia nigra pars compacta. The above findings are in accordance with recent electrophysiological studies suggesting the existence of sub-populations of nigrostriatal dopaminergic neurons, and indicate that the substantia nigra pars compacta is functionally compartmentalized. We conclude that the cholinergic input to the substantia nigra pars compacta could modulate the motor behavior through regulating the firing rate of nigrostriatal dopaminergic neurons and dopamine release in the neostriatum. PMID- 7830891 TI - Immunohistochemical study of catechol-O-methyltransferase in the human mesostriatal system. AB - The cellular localization of catechol-O-methyltransferase was analysed in the mesostriatal system of human brain post mortem by means of immunohistochemistry. In the human nigral complex, catechol-O-methyltransferase immunostaining was not detected in melanized dopaminergic neurons, except in the ventral tegmental area and substantia nigra pars lateralis, where few neurons displayed intense immunolabelling. In the striatum, catechol-O-methyltransferase immunostaining was found in numerous cell bodies and in the neuropile. Observations at the electron microscope level revealed that catechol-O-methyltransferase immunoreactivity was present in the cell bodies of neurons and their processes, including the dendritic spines. No catechol-O-methyltransferase immunolabelling was observed in striatal nerve terminals in contact with dendritic spines, indicating that dopaminergic nerve terminals do not exhibit catechol-O-methyltransferase immunoreactivity. Catechol-O-methyltransferase-immunoreactive cell bodies and processes of glial cells were also detected in the striatum. The data suggest that catechol-O-methyltransferase is either not expressed or only slightly expressed by the dopaminergic nigrostriatal neurons, whereas it is clearly present in striatal neurons and glial cells. Thus, the catabolic degradation of striatal released dopamine by its O-methylation may involve postsynaptic neurons rather than dopaminergic presynaptic neurons. The presence of catechol-O methyltransferase in some dopaminergic neurons of the ventral tegmental area and substantia nigra pars lateralis suggests that methylation of dopamine may occur in these neurons, which may consequently be better protected against dopamine auto-oxidation than those of the substantia nigra pars compacta. PMID- 7830892 TI - Transients in the inhibitory driving of neurons and their postsynaptic consequences. AB - The presynaptic fiber at an inhibitory synapse on a pacemaker neuron was forced to generate transients, defined here as spike trains with a trend, unceasingly accelerating or slowing. Experiments were on isolated crayfish stretch receptor organs. Spike train analyses used tools and notions from conventional point processes and from non-linear dynamics. Pre- and postsynaptic discharges contrasted clearly in terms of rates and interspike intervals. The inhibitory train evolved monotonically and smoothly, following tightly the simple prescribed curves; it was uniform, exhibiting throughout a single and simple discharge form (i.e. interval patterning). The inhibited postsynaptic train alternately accelerated and slowed, not following tightly any simple curve; it was heterogeneous, exhibiting in succession several different and often complex discharge forms, and switching abruptly from one to another. The inhibited trains depended on the inhibitory transient's span, range and average slope. Accordingly, transients separated (not cuttingly) into categories with prolonged spans (over 1 s) and slow slopes (around 1/s2) and those with short spans (under 1 s) and fast slopes (around 30/s2). Special transients elicited postsynaptic discharges that reproduced it faithfully, e.g. accelerated with the transient and proportionately; no transient elicited postsynaptic discharges faithful to its mirror image. Crayfish synapses are prototypes, so these findings should be expected in any other junction, as working hypotheses at least. Implications involve the operation of neural networks, including the role of distortions and their compensation, and the underlying mechanisms. Transients have received little attention, most work on synaptic coding concentrating on stationary discharges. Transients are inherent to the changing situations that pervade everyday life, however, and their biological importance is self-evident. The different discharges encountered during a transient had strong similarities to the stationary forms reported for different pacemaker drivings that are called locking, intermittency, erratic and stammering; they were, in fact, trendy versions of these. Such forms appear with several synaptic drivings in the same order along the presynaptic rate scale; they may constitute basic building blocks for synaptic operation. In terms of non-linear science, it is as if the attractors postulated for stationary drivings remained strongly influential during the transients, though affected by the rate of change. PMID- 7830893 TI - The anatomical substrates subserving the pupillary light reflex in rats: origin of the consensual pupillary response. AB - While the olivary pretectal nucleus has been shown to be central to the pupillary constriction response in rats, it is not at all clear at which level the consensual response is generated. To examine this we have investigated the efferent projections of this nucleus, as well as the effect of unilateral lesions of the olivary pretectal nucleus, on the direct and consensual pupillary light reflexes. The results demonstrate that the olivary pretectal nucleus projects bilaterally to the Edinger-Westphal nucleus, as well as to the nucleus of the posterior commissure, which itself projects bilaterally to the Edinger-Westphal nucleus. The olivary pretectal nucleus also projects to the ipsilateral ventral lateral geniculate nucleus. Unilateral lesions of the olivary pretectal nucleus decrease, but do not abolish, the direct and consensual pupillary light reflexes by as much as 66%. Since some degree of consensual response remains, this is likely to be due to the bilateral projection from the olivary pretectal nucleus, either directly or indirectly through the nucleus of the posterior commissure, to the Edinger-Westphal nucleus. These results show that while the bilateral projection from the olivary pretectal nucleus to the Edinger-Westphal nucleus contributes to the consensual pupillary light reflex, the bilateral retinal projection to the olivary pretectal nucleus is the more determinant component of the pathway. In addition to providing insights into the anatomical substrates of the pupillary response, this work also provides a background to ongoing studies of the retinal graft-mediated pupillary light reflex, as well as serving as a model of a relatively simple reflex system. PMID- 7830894 TI - Facilitation of 5-hydroxytryptamine3 receptor desensitization by fluoxetine. AB - Effect of fluoxetine on the desensitization of the inward current mediated by 5 hydroxytryptamine3 receptors in rat nodose ganglion neurons was investigated with whole cell patch-clamp recording. 5-Hydroxytryptamine3 current desensitization was best fitted in most experiments by a single exponential function and showed little dependence on membrane potential. Fluoxetine greatly facilitated the rate of 5-hydroxytryptamine3 current desensitization in a dose-dependent manner. The effect of fluoxetine was gradual, long-lasting, voltage-independent and the recovery was incomplete. The IC50 value for the decrease of the desensitization time-constant by fluoxetine was 0.171 microM and the Hill coefficient was 1.1. Fluoxetine also inhibited the peak and steady-state 5-hydroxytryptamine3 current with the latter being more sensitive to fluoxetine. The IC50 value for the effect of fluoxetine on peak current was 1.27 microM and that on steady-state current was 0.172 microM. There is a highly significant correlation between the two effects of fluoxetine on current desensitization and on current amplitudes: r values for the correlation between the decrease in time-constant and the reduction in peak and steady-state current amplitudes were 0.82 and 0.88, respectively (P < 0.001). This action of fluoxetine on 5-hydroxytryptamine3 receptors may be involved in the behavioral effects of fluoxetine. PMID- 7830895 TI - Activation of adenylate cyclase attenuates the hyperpolarization following single action potentials in brain noradrenergic neurons independently of protein kinase A. AB - Afterhyperpolarizations that follow action potentials are a prominent mechanism for the control of neuronal excitability. Such afterhyperpolarizations in many neurons are modulated by a variety of second messenger systems. Here, we examined the regulation of afterhyperpolarizations in noradrenergic locus coeruleus neurons by the adenylate cyclase system. Although superfusion of the adenylate cyclase activator, forskolin, had no effect on hyperpolarizations following trains of action potentials, both forskolin and a membrane permeable analog of cyclic AMP, 8-bromo-cyclic AMP, attenuated the amplitude of afterhyperpolarizations which followed single action potentials of locus coeruleus neurons recorded intracellularly in brain slices. In contrast, superfusion of 1,9-dideoxyforskolin, the forskolin analog that does not activate adenylate cyclase, had no effect on these single action potential afterhyperpolarizations. Co-application of a protein kinase inhibitor (H8, KT5720, staurosporin or Rp-cAMPS) with either forskolin or 8-bromo-cyclic AMP failed to block the reduction of afterhyperpolarization amplitude, but blocked the cyclic AMP-dependent enhancement of opiate responses in the same locus coeruleus neurons. Furthermore, application of a membrane permeable analog of 5' AMP, 8-bromo-5'-AMP, the cyclic AMP metabolite that does not activate a protein kinase, potently reduced the amplitudes of single action potential afterhyperpolarizations. The afterhyperpolarization amplitude was also reduced in locus coeruleus neurons taken from chronically morphine-treated rats, a treatment known to increase adenylate cyclase activity. These results indicate that elevation of intracellular cyclic AMP or 5'-AMP reduces the single action potential afterhyperpolarization in locus coeruleus neurons. This action may be mediated through a mechanism independent of protein kinase activation. PMID- 7830896 TI - The role of tonic preganglionic neuron firing in the turnover of the large dense cored vesicle store in sympathetic preganglionic nerve terminals. AB - Large dense-cored vesicles are transported centrifugally in the cervical sympathetic trunk and are depleted in a calcium-dependent manner from synaptic boutons of the cat superior cervical ganglion during orthodromic stimulation at 20-40 Hz [P. Weldon et al. (1993) Neuroscience 55, 1045-1054]. In the present study, we tested in awake cats whether the normal tonic firing of the sympathetic preganglionic neuron contributes to the turnover of large dense-cored vesicles in synaptic boutons of the superior cervical ganglion. Tetrodotoxin was applied with a mini-osmotic pump to one cervical sympathetic trunk, while vehicle alone was applied to the contralateral cervical sympathetic trunk, for two, four or seven days. The appearance of Horner syndrome ipsilateral to the tetrodotoxin application demonstrated block of action potential propagation. Both superior cervical ganglia were excised and processed for electron microscopy. The number of large dense-cored vesicles per bouton cross-section was higher in the ganglion with tetrodotoxin-treated input than in the control. The content at four days was higher than at two days; the content at seven days was similar to that at four days. The number of lysosomes per bouton profile also increased in the ganglion with tetrodotoxin-treated input. No changes were observed in size of bouton profiles, number of boutons or of synapses per grid square and length of the presynaptic densities in the ganglion with tetrodotoxin-treated input.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7830897 TI - In vitro autoradiographic localization of amylin binding sites in rat brain. AB - Amylin is a recently discovered 37 amino acid peptide which is co-secreted from the pancreas with insulin and acts to modulate carbohydrate metabolism. Recently, high-affinity binding sites for [125I]rat amylin have been identified in the rat central nervous system. These sites also have high affinity for the structurally related peptides calcitonin gene-related peptide and salmon calcitonin. In the present study we have used in vitro autoradiography to map the distribution of these [125I]rat amylin binding sites in rat brain. High to moderate levels of binding were present in mid-caudal accumbens nucleus, fundus striati and parts of the bed nucleus of the stria terminalis and substantia inominata. This binding extended caudally into parts of the amygdalostriatal transition zone and the central and medial amygdaloid nuclei. High to moderate levels of binding also occurred in much of the hypothalamus including the medial preoptic, dorsomedial hypothalamic and medial tuberal nuclei as well as the ventrolateral subnucleus of the ventromedial hypothalamic nucleus. Other regions of high level binding included the subfornical organ, the vascular organ of the lamina terminalis, area postrema, locus coeruleus, dorsal raphe and caudal parts of the nucleus of the solitary tract. The subfornical organ, vascular organ of the lamina terminalis and area postrema, which display some of the highest binding densities, lack a patent blood-brain barrier and thus could be responsive to blood-borne amylin. In conclusion we have mapped, in detail, the distribution of amylin binding sites in rat brain. The location of binding is consistent with potential roles for these sites in appetite, fluid and electrolyte homeostasis, autonomic function and regulation of mood. PMID- 7830898 TI - Interactions of anticholinesterases with Achatina fulica acetylcholine responses and electrogenic sodium pump. AB - The dose-dependent effects of the anticholinesterases, neostigmine and mycotoxin territrem-B, were determined on: (i) Cl(-)-responses of voltage clamped Achatina fulica neurons to microperfused acetylcholine; (ii) the 4 K(+)-induced outward currents evoked by an electrogenic sodium pump in the same neuron; and (iii) acetylcholinesterase activity of Achatina fulica ganglionic homogenates. Both compounds at low doses potentiated the peak acetylcholine responses. However, they had different effects at higher (> 1 microM) doses in that neostigmine now antagonized acetylcholine responses, while territrem-B still produced a maximal potentiation. At all doses neostigmine produced a dose-dependent inhibition of acetylcholinesterase activity. The cholinolytic effect of high doses of neostigmine was associated with the inhibition of 4 K(+)-induced current in the same neuron, while territrem-B neither altered the K(+)-induced current nor antagonized acetylcholine responses. The cholinolytic effect of neostigmine was completely antagonized by the inhibition of electrogenic sodium pump by ouabain or by perfusion with K(+)-free solution. These results suggest that neostigmine at high concentrations inhibits the electrogenic sodium pump and that the cholinolytic effect of high doses of neostigmine is secondary to this action. Territrem-B, on the other hand, had no effect on the electrogenic sodium pump and had no effect on the neuronal membrane properties other than to inhibit acetylcholinesterase. Thus, territrem-B may be a useful tool for studying the interaction between acetylcholinesterase and acetylcholine receptors. PMID- 7830899 TI - Developmental changes in the localization of the synaptic vesicle protein rab3A in rat brain. AB - Rab3A is a protein associated with the membrane of synaptic vesicles and is involved in the control of the targeting or docking of these vesicles at the presynaptic membrane for the release of neurotransmitters. Here, we have examined the expression and localization of this protein during the development of the rat brain. Relative to total protein, the concentration of rab3A greatly increased during brain development. Both the intracellular localization of the protein and its cerebral distribution showed an age-dependent shift. In contrast to other synaptic vesicle proteins, rab3A was heavily concentrated in cell bodies when immature neurons were migrating and during early differentiation. Later, the protein disappeared from perikarya and had a diffuse distribution in the neuropil, indicating a redistribution to nerve terminals, its exclusive localization in the adult. In the developing somatosensory cortex, rab3A delimited the modular organization of the barrels well after the afferents have arrived but just around the time that mature synaptic activity has been observed. In the hippocampus, rab3A defined a novel "blob-like" organization of the mossy fibre terminals and its appearance in terminal fields closely preceded the known onset of long-term potentiation. The appearance of rab3A in specific terminal fields during the period of increased physiological activity suggests that this small GTP-binding protein may be an important late element in the establishment of the mature characteristics of the presynaptic terminal. PMID- 7830901 TI - Trends in Cerebral Resuscitation Pathophysiology, Therapy and Ethics. Sicily, Italy, March 8-13, 1993. PMID- 7830900 TI - Postnatal ontogeny of GABAB binding in rat brain. AB - The postnatal development of GABAB binding sites in rat brain was studied by quantitative receptor autoradiography using [3H]GABA under selective conditions. Binding levels peak at regionally specific times during the first three weeks of life and then decline to adult levels. GABAB binding peaked in the globus pallidus, vestibular and spinal trigeminal nuclei, and the CA3 region of the hippocampus at postnatal day 3; in the striatum, nucleus accumbens, inferior olive, septum, dentate gyrus and CA1 region of the hippocampus at postnatal day 7; in the neocortex and thalamus at postnatal day 14; and in the medial geniculate at postnatal day 21. Following these regionally specific peaks, binding decreased to postnatal day 28 levels. Further significant decreases in binding were observed in all regions examined between postnatal day 28 and adulthood. Comparisons of binding site pharmacology reveal equipotent displacement of GABAB binding by several competitive agonists and antagonists in postnatal day 7 and adult rat brain, indicating that immature and adult binding sites have similar pharmacological properties with regard to these compounds. The GABAB receptor antagonist CGP 54626A, however, inhibited binding more potently in the postnatal day 7 thalamus and neocortex than in these areas in the adult brain. The guanyl nucleotide analogue guanosine 5'-O-(3-thiotriphasphate) inhibited GABAB binding extensively in both postnatal day 7 and adult brain. The non-competitive antagonist zinc also inhibited GABAB binding at both ages and was more potent in postnatal day 7 brain than in adult brain. Saturation analyses reveal two binding sites with similar affinities in both immature and adult rat brain, indicating that postnatal modulation of GABAB binding reflects changes in binding site density rather than modulation of binding site affinity. While immature GABAB binding sites share most pharmacological characteristics with adult binding sites and appear to be coupled to G-proteins at an early age, their interactions with zinc and CGP 54626A suggest that GABAB binding sites in immature brain may have a distinct pharmacological profile. Our data suggest significant regional and pharmacological changes in GABAB binding during development. The implications of these findings are discussed with regards to a possible role of GABAB receptors in the development of the central nervous system. PMID- 7830902 TI - Reanimatology as a neurological science. PMID- 7830903 TI - Past, present and future of cardiopulmonary-cerebral resuscitation (CPCR). PMID- 7830904 TI - Selective vulnerability of the CNS in the hypoxic insults (an onto-phylogenetic approach). PMID- 7830906 TI - Structural bases of cerebral integrative activity in postresuscitation period. PMID- 7830905 TI - 31P NMR spectroscopic investigation of brain resuscitation: global reversible ischemia of rat brain. PMID- 7830907 TI - Role of neurophysiological mechanisms in postresuscitation pathology and postresuscitation restoration of CNS functions. PMID- 7830908 TI - Cortico+subcortical interactions in acute brain ischemia. PMID- 7830909 TI - Energy state of hypoxic brain. PMID- 7830910 TI - Oxygen-derived free radicals and excitatory amino-acids in the pathogenesis of ischemic neuronal death. PMID- 7830911 TI - Oxygen radicals in central nervous system injury. PMID- 7830912 TI - Brain glucose metabolism in the comatose state and in post-comatose syndromes. PMID- 7830913 TI - Tissue acidosis and cerebral resuscitation. PMID- 7830914 TI - Hypothermia and multifaceted therapies for cardiac arrest. PMID- 7830915 TI - Clinical application of mild hypothermia in neurological disorders. PMID- 7830916 TI - Antioxidant drugs in cerebral and spinal ischemia. PMID- 7830917 TI - Heparin and 21-aminosteroids in post-anoxic cerebral resuscitation. PMID- 7830918 TI - Severe head injury: towards a target therapy? PMID- 7830919 TI - Postresuscitation pathology. A syndrome or a disease? PMID- 7830920 TI - Brain edema: secondary consequence of cerebral damage. PMID- 7830921 TI - The postresuscitation syndrome. Role of extracerebral organ derangements in cerebral recovery. PMID- 7830922 TI - Quality of life in long term conscious cardiac arrest survivors and related impact on the social support network. PMID- 7830923 TI - An early approach to brain death diagnosis using multimodality evoked potentials and electroretinography. PMID- 7830924 TI - Diagnostic aspects of brain death. PMID- 7830925 TI - Multimodal neuromonitoring in impending brain death. PMID- 7830926 TI - Significance of different levels of the Edinburgh-2 coma scale and pupillary reactivity. PMID- 7830927 TI - Multimodality evoked potentials in coma and brain death. PMID- 7830928 TI - Ethical dilemmas in resuscitation medicine. PMID- 7830929 TI - Death, brain death, brainstem death: the evolution of a concept. PMID- 7830930 TI - Brain death and organ transplantation: confusion and its consequences. PMID- 7830931 TI - A historical overview of Japanese brain death criteria and medical and social arguments against brain death in Japan. PMID- 7830932 TI - Determination of brain death in Italy. PMID- 7830933 TI - Determination of brain death in children. PMID- 7830935 TI - Distribution of immediate early gene zif-268, c-fos, c-jun and jun-D mRNAs in the adult cat with special references to brain region related to vision. AB - The distribution of immediate early gene zif-268, c-fos, c-jun and jun-D mRNAs was investigated in the visual cortex, dorsal lateral geniculate nucleus and hippocampus of the adult cat brain with in situ hybridization. In area 17, zif 268, c-jun and jun-D were found predominantly in layers II-III and VI, while c fos mRNA was abundant in layer VI. In area 18, the zif-268, c-fos and c-jun labelling pattern was identical to that of area 17, this was not true for jun-D. In area 19, only c-jun retained the lamination pattern of areas 17 and 18, while zif-268, c-fos and jun-D were homogeneously distributed. In the dorsal lateral geniculate nucleus, only c-fos and jun-D resulted in labelling. In the pyramidal layer of hippocampus, zif-268 was found in CA1-4, c-jun in CA1-3, and jun-D in CA2-4. In the dentate gyrus, c-jun was abundant, jun-D moderate and zif-268 faint. C-fos labelling was absent in the hippocampal formation. PMID- 7830934 TI - Microglial interleukin-1 alpha expression in human head injury: correlations with neuronal and neuritic beta-amyloid precursor protein expression. AB - Activated microglia containing IL-1 alpha-immunoreactive (IL-1 alpha +) product were increased 3-fold in number in the acute phase following head injury, a risk factor for later development of Alzheimer's disease, and this increase was correlated with a 7-fold increase in the number of neurons with elevated beta amyloid precursor protein (beta-APP) levels (R = 0.78; P < 0.05). Furthermore, clusters of beta-APP+ dystrophic neurites present in these patients were invariably associated with activated IL-1 alpha + microglia. These findings suggest that early overexpression of IL-1 alpha and beta-APP is a priming event for later neuropathological changes evident at end stages of Alzheimer's disease. PMID- 7830936 TI - Presence of alpha-bungarotoxin-sensitive nicotinic acetylcholine receptors in rat olfactory bulb neurons. AB - The presence of a functional nicotinic acetylcholine receptor (nAChR) in rat olfactory bulb (OB) neurons was investigated using the whole-cell patch-clamp technique. Acetylcholine (ACh) or other nicotinic agonists elicited fast-decaying whole-cell currents in cultured OB neurons. ACh-evoked currents could be blocked by the highly selective competitive nicotinic antagonists alpha-bungarotoxin (alpha-BGT, 10 nM) and methyllycaconitine (MLA, 1 nM) and exhibited strong inward rectification in the presence of intracellular Mg2+. The properties of the nicotinic currents in OB neurons were similar to those of type IA currents elicited by nicotinic agonists in rat hippocampal neurons. The present results suggest that the fast-decaying nicotinic currents evoked in OB neurons are subserved by nAChRs containing alpha 7 subunits. PMID- 7830937 TI - Dilatation of cerebral microvessels mediated by endothelin ETB receptor and nitric oxide in cats. AB - The functional role of the endothelin (ET)B receptor in the cerebral microvessels was examined in seven anesthetized cats. The effects of intracarotidly injected IRL1620, a selective ETB receptor agonist, on the cerebral blood volume (CBV) in the cortex were examined by a photoelectric method. CBV reflects the cumulative dimensions of the cerebral microvessels. High doses of IRL1620 (0.1-1 nmol/kg) elicited a transient fall in CBV, followed by a marked and dose-related increase of CBV (P < 0.01). The CBV increase was significantly inhibited (P < 0.01) by simultaneous administration of 0.35 mg/kg/min NG-monomethyl-L-arginine (L-NMMA), an inhibitor of nitric oxide synthesis. The marked, but transient, depressor effect of IRL1620 was also attenuated (P < 0.01) by L-NMMA. The ETB receptor subtype and production of nitric oxide, probably in the endothelium, mediate the vasodilatory action of ET in the cerebral microvessels. PMID- 7830938 TI - Nerve growth factor and epidermal growth factor rescue PC12 cells from programmed cell death induced by etoposide: distinct modes of protection against cell death by growth factors and a protein-synthesis inhibitor. AB - A rat pheochromocytoma cell line (PC12 cells) died within 24 h in the presence of etoposide (1-40 micrograms/ml), an inhibitor of topoisomerase II. This cytotoxic effect was prevented by either nerve growth (NGF) or epidermal growth factor (EGF). Cycloheximide and actinomycin D also suppressed the cell death as well. Furthermore, a difference among protective modes against etoposide-induced death by growth factors and a protein-synthesis inhibitor was observed: the protective effect of either NGF or EGF remained rather constant as a function of incubation time with etoposide whereas that of cycloheximide declined. These results indicate that etoposide induces programmed death in PC12 cells and that prevention of the programmed cell death by both NGF and EGF is mainly due to inactivation of molecules involved in the death processes rather than suppression of specific protein and/or mRNA synthesis. PMID- 7830939 TI - Phosphoinositide kinase activities in synaptosomes prepared from brains of patients with Alzheimer's disease and controls. AB - Previously, phosphatidylinositol (PI) kinase activity in cytosolic fractions prepared from postmortem tissue of the cerebral cortex from patients with Alzheimer's disease (AD) appeared to be lower than that of age-matched controls [Jolles et al., J. Neurochem., 58 (1992) 2326-2329]. In the study presented here, PI and PIP (phosphatidylinositol phosphate) kinase activities were studied in synaptosomes prepared from postmortem brain tissue of AD patients and age-matched controls. Firstly, PI kinase activity in synaptosomes prepared from the frontal superior gyrus of AD brain was 30% lower than in synaptosomes prepared from postmortem tissue of control brain. PIP kinase activity was the same in AD and control synaptosomes. Secondly, the yield of synaptosomal protein (micrograms protein per mg tissue wet weight) was lower in preparations from AD brain than in preparations from control brain, which could be a manifestation of a loss of presynaptic terminals in the frontal cortex. These results suggest that the difference in PI kinase activity between AD and control brain tissue may originate from differences in intact neurons in view of the fact that synaptosomes can originate only from intact neurons. PMID- 7830940 TI - Electrical stimulation of the kindled hippocampus briefly increases extracellular dopamine in the nucleus accumbens. AB - The effect of electrical stimulation of the dorsal hippocampus on accumbens dopamine release was examined. Stimulation of the kindled hippocampus that produced stage 3 seizures evoked a brief increase in extracellular DA and DOPAC levels in the contralateral nucleus accumbens. In contrast, similar stimulation early in the development of kindling producing a stage 1 seizure did not evoke this increase. PMID- 7830941 TI - Altered synaptophysin-immunoreactive pattern in human olivary hypertrophy. AB - We examined the inferior olivary nucleus from four cases of olivary hypertrophy and six control cases immunohistochemically with an anti-synaptophysin (SYP) antibody. Our study revealed the altered SYP-immunoreactive pattern in the hypertrophied olives, consisting of an increased number of SYP-immunoreactive dots on neuronal cell bodies in spite of its decreased immunoreactivity in the neuropil. Because SYP is a marker protein for presynaptic vesicles, presynaptic terminals in the inferior olivary nucleus seem to change their distribution during the course of olivary hypertrophy. PMID- 7830942 TI - Potassium and calcium channel involvement in induction of long-lasting synaptic enhancement by calyculin A, a protein phosphatase inhibitor, in rat hippocampal CA1 region. AB - In the Schaffer collateral-CA1 pathway in rat hippocampal slices, exposure to calyculin A induced a long-lasting potentiation of the extracellular field potentials with a transient increase in glutamate release. The synaptic enhancement produced by calyculin A was blocked by staurosporine and nicardipine, but not by D,L-2-amino-5-phosphonovalerate. In dissociated CA1 pyramidal cells, calyculin A blocked the action-potential repolarization and fast after hyperpolarization, and increased spike frequency. These results suggest that calyculin A-induced long-lasting potentiation is triggered by the blockade of Ca(2+)-activated K+ channels, the transient increase of glutamate release and the consequent activation of voltage-gated Ca2+ channels, and is maintained by increases in protein kinases activities. PMID- 7830943 TI - omega-Conotoxin GVIA binds to and blocks rat neuromuscular junction. AB - The effect of omega-conotoxin GVIA, a specific blocker of N-type calcium channels, on the synaptic transmission at the mammalian neuromuscular junction is controversial. We have found that 125I-omega-conotoxin binds to rat tibialis muscle end-plate; that omega-conotoxin blocks the neuromuscular transmission both in vivo, in the sciatic nerve-tibialis anterior muscle, and in vitro in the isolated phrenic nerve-diaphragm preparation; and does not affect muscle nicotinic receptors. We conclude that in rat neuromuscular junctions N-type calcium channels are important for neurotransmitter secretion. PMID- 7830944 TI - Propentofylline enhances the formation of long-term potentiation in guinea pig hippocampal slices. AB - The postsynaptic field potential (population spike; PS) was recorded in the CA1 area of guinea pig hippocampal slices in response to electrical stimulation of Schaffer's collateral. After tetanic stimulation (100 Hz for 1 s) to Schaffer's collateral, the PS amplitude increased to 127.9 +/- 7.7% (mean +/- S.E.M.) of the original level at 20 min and 140.1 +/- 7.7% at 60 min, and formed long-term potentiation (LTP). After application of 10 nM propentofylline, a synthetic xanthine derivative, which did not enhance the amplitude of the PS evoked by the test stimulus, the tetanic stimulation increased the amplitude to 160.3 +/- 3.8% at 20 min and 173.3 +/- 4.3% at 60 min. Thus, propentofylline enhances the formation of LTP in hippocampal slices. PMID- 7830945 TI - Pituitary adenylate cyclase-activating polypeptide-like immunoreactivity in autonomic regulatory areas of the rat medulla oblongata. AB - Pituitary adenylate cyclase-activating polypeptide-like immunoreactivity (PACAP LI) was mapped immunohistochemically in the rat medulla oblongata. We found the majority of perikarya with PACAP-LI in the visceral areas of the solitary nucleus, dorsal motor vagal nucleus, nucleus ambiguus, ventrolateral medulla, ventral medullary surface, and caudal raphe nuclei. Medium densities of labeled fibers were detected in the area postrema, solitary nucleus, dorsal vagal and raphe pallidus nuclei. Our morphological data support the hypothesis that PACAP is a central regulator of visceral functions. PMID- 7830946 TI - Structural dimorphism in the mammillary bodies of the rat. AB - Diverse structures of the CNS show sexual differences in the anatomical and functional organization. In particular, many dimorphic nuclei have been found in the hypothalamus: the preoptic area, suprachiasmatic nucleus and ventromedial hypothalamus. Our investigation has shown a statistically significant difference in relation to volume of the medial mammillary and left lateral nuclei, and the number of glial cells of the medial mammillary nucleus. The volume and glial cell population is greater in the male than in the female. Thus, the existence of dimorphic functions in which this structure could be involved are discussed herein. PMID- 7830947 TI - Colocalization of prolyl endopeptidase and amyloid beta-peptide in brains of senescence-accelerated mouse. AB - Prolyl endopeptidase-like immunoreactivity (PEP-LI) was detected and compared with amyloid beta-peptide-like immunoreactivity (A beta-LI) in the brains of senescence-accelerated mouse (SAM). Granular structures of PEP-LI in the hippocampus appeared progressively, and age- and strain-dependently to form deposits which distributed morphologically similar and closely to those of A beta LI. These results suggest that PEP has functional relevance to amyloidgenesis in brains of SAM. PMID- 7830948 TI - The pattern of neuronal injury following seizures induced by intranigral kainic acid. AB - The substantia nigra pars reticulosa (SNpr) is involved in the initiation and propagation of seizures within the limbic system (cingulate and parahippocampal gyri and associated connections in the brain stem, e.g. amygdala, hypothalamus, some thalamic nuclei, and parts of basal ganglia). We have investigated the pattern of neuronal injury (using heat shock protein (HSP) expression) and cell death (acid-fuchsin (AF) staining) in SNpr and limbic structures following seizures evoked by bilateral intranigral injection of kainic acid. Affected cells were observed predominantly in piriform cortex, amygdala, hippocampal formation, and thalamic nuclei; massive necrosis or hemorrhage occurred in bilateral piriform cortices following prolonged seizures. The piriform cortex may play an important role in the activation of limbic seizures under the regulation of the SNpr. PMID- 7830949 TI - High extracellular GABA levels in hippocampus--as a mechanism of neuronal protection in cerebral ischemia in adrenalectomized gerbils. AB - Adrenalectomy protects the brain from delayed neuronal damage that occurs following transient forebrain ischemia in gerbils. Gamma-amino butyric acid (GABA) and GABA-mimetic drugs also have a neuro-protective effect. In this study we estimated the extracellular glutamate and GABA levels in the hippocampus during transient forebrain ischemia in adrenelectomized gerbils (n = 8) compared to controls (n = 6). Duration of ischemia was 10 min, and glutamate and GABA levels were measured with in vivo microdialysis. Microdialysis was started 2 h after the placement of a probe (to stabilise baseline) and samples were collected at 10-min intervals. The pattern of glutamate release did not show any difference between adrenelectomized animals and controls. Adrenelectomized animals showed marked increase in GABA levels during ischemia and upto 30 min after ischemia (P = 0.0287, 2-way ANOVA for repeated measurements). The enhanced GABA release may be one of the possible mechanisms of neuronal protection against ischemia in adrenelectomized gerbils. PMID- 7830950 TI - Reduction of electrical coupling between Necturus taste receptor cells, a possible role in acid taste. AB - Cytoplasmic acidification in taste receptor cells is thought to be involved, at least in part, in acid taste transduction. Since in taste buds about 20% of the receptor cells are electrically coupled, we have tested whether reduction in intracellular pH affects these lateral synaptic interactions. By applying the patch clamp technique to a slice preparation of Necturus lingual epithelium, we found that electrical coupling between taste receptor cells was strongly reduced by cytoplasmic acidification. Therefore, electrical coupling in taste buds might be modified during acid stimulation. PMID- 7830951 TI - Differences between adrenaline and noradrenaline cells in cellular association with supporting cells in the adrenal medulla of the pig: an immunohistochemical study. AB - Location and morphology of glial supporting cells in the pig adrenal medulla were examined immunohistochemically by the ABC method using antibody to S-100 protein. In noradrenaline (NA)-cell regions, S-100-positive cells were located in both marginal and internal portions of the parenchyma, extending fine cytoplasmic processes between NA cells and/or enveloping large surface areas of NA cells. In adrenaline (A)-cell regions, S-100-positive cells were present less frequently than in NA-cell regions, mostly in the marginal portion of the parenchyma. It is surmised that differences between A cells and NA cells in cellular association with supporting cells reflect those in biological characteristics. PMID- 7830952 TI - Influence of physical exercise on 5-HT1A receptor- and anxiety-related behaviours. AB - Treadmill exercise (1 h at 20 m/min) has been shown to increase brain serotonin (5-HT) synthesis/metabolism in 4-day trained rats. This work has analysed whether these changes are associated with (5-HT-dependent or -independent) alterations in pre- and postsynaptic 5-HT1A receptor-mediated behaviours; in addition, the controversial hypothesis that exercised rats are less anxious than sedentary rats was tested in the elevated plus-maze and the social interaction models. Acute administration of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n propylamino)tetralin (8-OH-DPAT; 0.125-0.5 mg/kg) triggered hyperphagia, forepaw treading, and flat body posture, the amplitude of which were not affected by training or acute exercise. In the elevated plus-maze, training, but not acute exercise, reduced the number of total arm entries. In the social interaction test, trained and acutely exercised rats displayed increased locomotion and decreased defecation, compared to resting rats, but social interaction and rearings were not affected. It is suggested that the aforementioned effects of acute exercise upon 5-HT synthesis/metabolism in short-term trained rats are not associated with changes in 5-HT1A receptor- and anxiety-related behaviours. PMID- 7830953 TI - Role of the nucleus raphe obscurus in the inhibition of rostral ventrolateral medullary neurones induced by stimulation in the ventrolateral periaqueductal grey matter of the rabbit. AB - Experiments have been carried out to investigate the pathways which mediate the inhibitory influence of the ventrolateral periaqueductal grey matter (vlatPAG) on neurones in the rostral ventrolateral medulla (RVLM). In anaesthetized rabbits, 20-ms trains of electrical stimulation in the vlatPAG inhibited ongoing activity of neurones in the RVLM to < 30% of the control level. The inhibition was blocked after microinjections of 500-1000 nl local anaesthetic (4% lignocaine, n = 9) or 0.2 M glycine (n = 4) into nucleus raphe obscurus (NRO). We suggest that the inhibitory influence of the vlatPAG on neurones in the RVLM is mediated by a relay in NRO. PMID- 7830954 TI - Sex-related effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine treatment may be related to differences in monoamine oxidase B. AB - Effects of the parkinsonism inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) on striatal dopamine metabolism and the influence of sex on the recovery were investigated in adult (2-month-old) male and female C57/BL mice. We present here evidence that MPTP treatment (2 doses of 30 mg/kg i.p., each at 24 h interval) produced a similar reduction (-65% to -70%) of striatal dopamine in both sexes 24 h after the last injection of MPTP, and a greater loss of the metabolites in the female group. In contrast to the partial recovery observed in the male group, an increased dopamine loss occurred in the female group within 10 days following the last injection of MPTP. This impairment in recovery appears to be different to the one already observed in aged (24-month old) male mice treated in similar conditions. As the neurotoxic effects of MPTP depend on its conversion to the 1-methyl-4-phenylpyridinium ion (MPP+) by monoamine oxidase B (MAO B), the presence of a different peripheral or central MAO B type in female mice could be in part responsible for these sex related effects. To investigate this possibility, MAO A and B activities were characterized in liver and brain of adult female control mice during the different steps of the oestrous cycle and compared to those of adult control male mice. Significant differences in MAO A and MAO B activities could be detected during the oestrous cycle and between the adult male and female groups. It is concluded that MAO B may be involved in the sex related effects of MPTP. PMID- 7830955 TI - Sulfhydryl groups essential for the volume-sensitive release of taurine from astrocytes. AB - The volume-sensitive [3H]taurine efflux from cultured astrocytes was found to be strongly inhibited by the sulfhydryl group-modifying reagent N-ethylmaleimide (NEM). This maleimide inhibited taurine efflux evoked by 50% hyposmotic solutions with an IC50 of 54 microM. The inhibition by NEM followed pseudo-first order reaction kinetics. A double log plot of the pseudo-first order constant against NEM concentration gave a linear relationship with a slope of 1.2. The data are consistent with a simple bimolecular reaction mechanism in which one molecule of NEM reacts with one sulfhydryl group per transport unit. The membrane-impermeant maleimide derivative 5-eosin maleimide did not affect the volume-stimulated taurine efflux. The sulfhydryl-modifying mercurial reagents mersalyl and p-chloro mercuribenzenesulfonate (0.5-1 mM) increased [3H]taurine efflux under isosmotic conditions and concomitantly decreased the hyposmolarity-evoked efflux. The results demonstrate an essential requirement for sulfhydryl groups for the volume sensitive taurine efflux. PMID- 7830956 TI - Survival and transmitter expression of rat cholinergic medial septal neurons despite removal of hippocampus in the early postnatal period. AB - It has been shown that target-derived neurotrophins are not necessary for the survival of septohippocampal cholinergic neurons in adult rats. In this study, we have removed the hippocampus in early postnatal rats by unilateral excitotoxic N methyl-D-aspartate lesions at postnatal days 5, 10 and 20. At postnatal day 70, numerous cholinergic neurons (60% of controls) were present in the medial septum on the lesioned side. This suggests that there is only a limited influence of target-derived neurotrophic factors to these cells also in development. PMID- 7830957 TI - Lipid hydroperoxides induce changes in palmitate uptake across the rat blood retina and blood-brain barrier. AB - The blood-retina and blood-brain transport of fatty acids was studied in control and lipid hydroperoxide-treated rats by measuring the permeability-surface area product (PS) to [1-14C]palmitate. An in situ carotid perfusion method was used. PS values were evaluated: (1) just after intracarotid injection of hydroperoxides; or (2) after a short-term systemic treatment for 1 week with sonicated emulsion of phospholipids-linoleate peroxidized mixture. Compared with saline-treated rats, PS remarkably decreased in the retina and most brain regions studied after acute, arterial injection of hydroperoxide preparations. On the contrary, the transport index significantly increased in the retina and almost all the brain areas after 7 days i.v. treatment with hydroperoxide emulsion. It is suggested that hydroperoxides acutely administered before transport radiotracer brought about a reinforcement of microvasculature junctional area or hampered substrate diffusion across endothelial membrane. On the other hand, upon short-term i.v. administration, hydroperoxides presumably triggered a lipid structure derangement of endothelial cell membranes and zonulae occludens due to their local accumulation and/or high capability of generating oxygen-free radicals. PMID- 7830958 TI - NMDA receptors on adult frog spinal motoneurons in culture. AB - Whole-cell membrane currents induced by superfusion of NMDA were examined in cultured motoneurons from the spinal cord of the adult frog in Mg(2+)-free Ringer solution containing 10 microM glycine. The amplitude of the response to 100 microM NMDA was 280 +/- 37 pA (mean +/- S.D.; n = 24) with a reversal potential +6.1 +/- 3.0 mV (mean +/- S.D.; n = 6). At a membrane potential of -60 mV, the response to 100 microM NMDA was blocked by 0.1 mM Mg2+ or 100 microM AP5. From the dose-response curve, the estimated EC50 was 77 microM and the calculated Hill coefficient was 1.6. NMDA receptors on frog motoneurons appear to have properties similar to those of mammals but may be expressed at lower density. PMID- 7830959 TI - Intra-amygdala kinase inhibitors disrupt retention of a learned avoidance response in rats. AB - To assess the involvement of intra-amygdala kinase activity in aversively motivated learning, rats received intracranial injections of polymixin B sulfate (PMXB)--a protein kinase C (PKC) and calcium/calmodulin-dependent kinase II inhibitor--immediately after inhibitory avoidance training. When tested 48 h later, retention was significantly impaired relative to vehicle-injected controls. Delayed injections (2 h posttraining) and injections made dorsal to the amygdala were ineffective. Immediate posttraining injections of the more selective PKC inhibitor, NPC 15437, also impaired retention. These results suggest that intra-amygdala protein phosphorylation must occur soon after training for learned avoidance responses to be successfully retained. PMID- 7830960 TI - Direct in vivo evidence that D2 dopamine receptors can modulate dopamine uptake. AB - In vivo electrochemistry was used to determine the effects of locally applied raclopride (a D2 receptor antagonist) and SCH-23390 (a D1 receptor antagonist) on the clearance of locally applied dopamine in the striatum, nucleus accumbens, and medial prefrontal cortex of rats. Chronoamperometric recordings were continuously made at 5 Hz using Nafion-coated, single carbon fiber electrodes. When a calibrated amount of dopamine was pressure ejected at 5-min intervals from a micropipette adjacent (280-310 microns) to the electrode, transient and reproducible dopamine signals were detected in all three regions. Local application of raclopride from a second micropipette, prior to pressure ejection of dopamine, increased the amplitude and time course of the dopamine signals, indicating significant inhibition of the dopamine transporter. In contrast, local application of SCH-23390 or saline had no effect on the dopamine signals. These data indicate that D2, but not D1, dopamine receptors can modulate the activity of the dopamine transporter. PMID- 7830961 TI - Endogenous excitatory amino acids tonically stimulate striatal acetylcholine release through NMDA but not AMPA receptors. AB - The effect of stimulation and blockade of excitatory amino acid receptors on striatal acetylcholine release was examined using in vivo microdialysis in awake, freely moving rats. Local perfusion with the NMDA receptor antagonists CPP and MK 801 reduced striatal acetylcholine release, while NMDA itself enhanced striatal acetylcholine release. Co-perfusion with MK-801 blocked the NMDA-induced increase in acetylcholine release. The AMPA/kainate antagonists NBQX and GYKI 52466 alone did not decrease striatal acetylcholine release, although AMPA increased acetylcholine release. Co-perfusion with NBQX reduced the AMPA-induced elevation in acetylcholine release. These findings suggest that endogenous excitatory amino acids tonically stimulate striatal acetylcholine release through NMDA but not AMPA receptors. PMID- 7830962 TI - Effects of aporphine isomers on rat prolactin. AB - S(+)-aporphines are partial agonists at D2 dopamine receptors. High selectivity of anti-dopaminergic action in limbic vs. extrapyr amidal regions of rat brain and lack of induction of dopaminergic supersensitivity have suggested their potential as atypical antipsychotic drugs. Now, in testing for effects on circulating prolactin, a typical D2 antagonist haloperidol elevated, and potent agonist R(-)-11-hydroxy-N-propylnoraporphine lowered, serum prolactin levels in gentled male rats, while S(+)-N-propylnorapomorphine and its 11-monohydroxy analog had little or no effect, even at high doses. Lack of hyperprolactinemia adds to characteristics of S(+)-aporphines that are desirable in improved antipsychotics. PMID- 7830963 TI - Intracranial action of corticosterone facilitates the development of behavioral inhibition in the adrenalectomized preweanling rat. AB - We tested the hypothesis that in preweanling rats central administration of exogenous corticosterone (CORT) is sufficient to facilitate the development of behavioral inhibition. 28-gauge cannulae containing varying concentrations of CORT (0, 25, 50 and 100%) were implanted unilaterally into the lateral ventricles of 9-day-old rat pups. After a 24-h postoperative recovery period, pups were adrenalectomized. At 14 days of age, pups were tested for behavioral inhibition which consisted of removing the pup from the nest and exposing it to an unfamiliar adult male rat. Pups implanted with cannulae containing 0, 25 and 50% concentrations of CORT spent significantly less time in freezing postures than pups implanted with cannulae containing 100% CORT. These freezing pups also tended to emit fewer ultrasonic vocalizations than pups in the other three implant conditions, albeit the level obtained was not statistically significant. RIAs indicated that, in general, hormone-filled cannulae produced no detectable concentrations of plasma CORT on the day of the test or on days preceding testing. Results suggest that in the early postnatal period endogenous CORT acts centrally to facilitate the development of neural pathways involved in the ontogenetic expression of behavioral inhibition. PMID- 7830964 TI - Has GM1 ganglioside been shown to be effective in the restoration of neurologic function in persons with chronic spinal cord injury? A critique of an article by Judith B. Walker and Michelle Harris. PMID- 7830965 TI - Achieving gender equality. PMID- 7830966 TI - If ever there was a time in the profession of nursing to break the glass ceiling. PMID- 7830967 TI - CNO to CEO: Barbara A. Donaho and Irma E. Goertzen--they broke the glass ceiling. Interview by Barbara J Brown. AB - Two nurse executives who broke the glass ceiling to become chief executives of health care systems are interviewed. Irma Goertzen and Barbara Donaho are asked key, candid questions comparing chief nurse officer (CNO) with chief executive officer (CEO); special skills needed; being a woman in a traditional man's role; and advice to colleagues for becoming a CEO. PMID- 7830968 TI - Shake the kaleidoscope: one woman's response to gender-related barriers in health care management. AB - The term "glass ceiling" is an apt metaphor for the challenges executive women face as they advance in health care management. Women who break through this glass ceiling are those who see their opportunities, sense the looming barriers to advancement, choose carefully whether to stay within an environment unfriendly to women or to seek advancement elsewhere, and use their talents as women to bring a focus on outcomes to the organization, as well as empowerment to the people within it. PMID- 7830969 TI - Hardball for nuns. AB - Women are constantly challenged to lead and succeed in business based on male rules. This article outlines how women religious (sisters), who have been perceived as non-gendered, have learned to use the rules outlined in the book Hardball for Women to become successful health care leaders. PMID- 7830970 TI - Developing glass-breaking skills. AB - The glass ceiling cannot be cracked and broken until nurses realize a sense of personal and professional empowerment. Issues are discussed from corporate structures to male-female communication. Information from the seven steps will assist the nurse executive to accept the challenge and change the world for future generations of women. PMID- 7830971 TI - Ending the silent conspiracy: sexual harassment in nursing. AB - Sexual harassment in health care institutions presents a formidable challenge for nurse leaders as solutions and accountabilities get mired in power, politics, and a historical tradition of secrecy and silence. Harassment is devastating to all individuals, but especially to women because it blatantly violates the victim's personal autonomy and individual sense of equality. Sexual harassment lingers in the corridors of all types of organizations, preying on women as they struggle to overcome cultural and socially imposed barriers. Nurse executives must learn the subtle complexities surrounding harassment, voice strong opposition against harassment, and take swift and comprehensive action to prevent sexual harassment. PMID- 7830972 TI - Reverse discrimination in nursing leadership: hitting the concrete ceiling. AB - Discrimination has many facets. In nursing there is as much discrimination as there is in any other group. Reverse discrimination, that is discrimination toward men in nursing, is evident even though it is well hidden. There are many situations and opportunities for the minority group in nursing (men) to experience the vagaries of gender prejudice in the same concentration as women experience in their attempt to integrate in more male-dominated professions. It is valuable to take time to denote the characteristics of gender bias in nursing and to identify mechanisms for handling it. PMID- 7830973 TI - Getting beyond "she said, he said". AB - Men and women grow up in different cultures and as a result learn different lessons about "appropriate" adult behaviors. But these lessons are invisible to us and that creates a variety of work-related problems. This article addresses the double blind and hidden expectations that nursing executives face as a member of the male-dominated administration team. PMID- 7830974 TI - Hidden advantages for men in nursing. AB - Men comprise a small minority of professional nurses in the United States. Yet men in nursing earn more money than women on average, and they are overrepresented in administration and other prestigious specialties. This article explores the hidden advantages for men in the profession, focusing on (1) hiring and promotions, (2) relationships with physicians and colleagues, and (3) relationships with patients. Data from in-depth interviews with male nurses throughout the United States are used to demonstrate that cultural and social stereotypes about masculinity pressure men into some of the best-paying and most prestigious nursing specialties. Administrators are encouraged to develop more gender-sensitive criteria for evaluating performance that reward both reputedly "masculine" and "feminine" qualities. PMID- 7830975 TI - Taking a sledgehammer to the glass ceiling. PMID- 7830976 TI - Development and initial assessment of the Tiffany/Lutjens Planned Change Theory Evaluation Instrument. PMID- 7830977 TI - Cutaneous manifestations of renal transplantation in a New Zealand population. AB - AIM: To document the skin manifestations of renal transplant recipients. METHODS: The findings in 52 patients (27 males; mean age 43.5 yr; range 22-74 yr; SD 12.0) with a stable renal transplant for a mean of 115.6 mth (range 3-258; SD 70.6). Thirty seven patients were on prednisone and azathioprine and 18 on prednisone, azathioprine and cyclosporin. RESULTS: Including prior observations, 48 cutaneous malignancies were identified in nine patients, with the ratio of squamous cell to basal cell carcinoma being 1.2:1. No metastases were detected. Actinic keratoses were present in 20 patients and tended to be multiple and present on sun exposed skin. A wide range of nonneoplastic lesions was documented, including warts in 75%. Human papillomavirus was isolated from 43% of warts. CONCLUSIONS: Renal transplant recipients require regular skin examination. Patients with high recreational or work related sun exposure prior to, or after transplantation, and those who have had a previous skin malignancy, should be identified as high risk patients for skin cancer and have regular dermatological follow up. PMID- 7830979 TI - The costs of mammography screening in New Zealand: evidence from the pilot programmes. AB - AIMS: To measure the public health service costs associated with New Zealand's pilot mammography screening programmes. To compare the early evidence on cost per woman screened and per cancer detected in those programmes to that of overseas screening programmes. To estimate the cost of introducing a national screening programme in New Zealand. METHODS: Costs in each screening centre were obtained by a careful examination of screening budgets and public health service accounts; these were inflation adjusted using a consumers price index, and analysed in terms of equivalent annual operating costs. RESULTS: In the first year of screening the cost per woman screened (in $1991) was $182 in Waikato and $178 in Otago/Southland. The cost per woman screened in the third year of screening (with an assumed full screening throughput of 8,000 women per annum) is estimated to fall to $106 and $113 for the Waikato and Otago/Southland programmes respectively. The cost per cancer detected in the first screening round differs between the two programmes. In the first year of screening the cost per cancer detected was $35,975 in Waikato and $21,908 in Otago/Southland. The difference was primarily attributable to a lower cancer detection rate in Waikato in that period (0.51% of women screened compared with 0.81% in Otago/Southland). CONCLUSIONS: The initial performance of the New Zealand pilot programmes, both in terms of cost per woman screened and cost per cancer detected, falls within the range indicated from overseas experience. An established national screening programme is estimated to add between $9.3 and $9.9 million dollars (in 1991 dollar terms) to health service costs each year. These costs will be partly offset by savings resulting from the earlier detection of cancers. PMID- 7830978 TI - Computed tomography scanning and minor head injuries. PMID- 7830980 TI - Investigation of subjects with abnormal iron studies: role of the hepatic iron index. AB - AIM: Genetic haemochromatosis is a common disorder resulting in increased iron deposition in the liver and other organs but can be difficult to diagnose. The aim of this study was to assess the diagnostic value of the conventional tests for iron overload (percentage saturation of transferrin, serum ferritin and grading of iron staining on liver biopsy) and compare these with the newer quantitative biochemical measurements of liver iron. METHOD: A retrospective analysis was made of 108 consecutive patients referred for quantitative liver iron measurements. Iron studies were obtained in 66 of the 108 subjects of whom 60 had abnormal screening tests defined as percent saturation of transferrin (> 60%) and/or ferritin > 350 micrograms/L for females and > 450 micrograms/L for males. Based on clinical features, biochemical data and treatment outcome these 60 subjects were classified as either genetic haemochromatosis, nongenetic haemochromatosis or indeterminate. One patient with treated genetic haemochromatosis was excluded from subsequent analysis. RESULTS: Although the serum ferritin (p < 0.002), percentage saturation of transferrin (p < 0.001), histological iron grade (p < 0.0001) were significantly higher in the genetic haemochromatosis than nongenetic haemochromatosis group there was considerable overlap. Similarly for the hepatic iron concentration (HIC) (p < 0.0001) overlap occurred. The hepatic iron index (HIC/age) gave the best separation with only three cases being misclassified. A correlation between the HII and histological iron index (visualised iron score corrected for age) in 15 subjects gave an r value of 0.72. CONCLUSION: Based on this study we feel that in addition to visual grading of iron in liver biopsies, the hepatic iron index is helpful in establishing a diagnosis of genetic haemochromatosis. PMID- 7830981 TI - When does middle ear effusion signify nasopharyngeal cancer? AB - AIM: To analyse the presenting symptoms of patients with nasopharyngeal carcinoma seen in Auckland, New Zealand, with emphasis on the significance of otological symptoms. METHOD: The records of 85 patients with nasopharyngeal carcinoma seen in the department between 1980-93 were reviewed. RESULTS: Twenty eight of patients were Pacific Island Polynesian, 21 caucasian, and 18 Chinese. The youngest patient was 11 years old. The most prominent symptoms were neck mass (53), deafness/otalgia (45), nasal obstruction (35) and epistaxis (30). The ear symptoms, representing middle ear effusion were evident for more than 9 months, on average, before a diagnosis was made. Most patients presented with multiple symptoms: 95% of patients had one or more of the above four cardinal symptoms. Only two patients presented with middle ear effusion alone: 95 of the patients with middle ear effusion had another, accompanying, cardinal symptom. Nineteen patients had cranial nerve involvement. CONCLUSIONS: Neck mass, deafness/otalgia, progressive nasal obstruction and epistaxis are the cardinal symptoms of nasopharyngeal carcinoma. A persisting middle ear effusion in people over 10 years of age must be examined for nasopharyngeal carcinoma, if an accompanying cardinal symptom is also present, or develops. PMID- 7830982 TI - Readability of subject information leaflets for medical research. AB - AIM: To compare the readability of adult subject information leaflets prepared for medical research projects with the readability scores of a range of New Zealand newspaper editorials and popular magazine articles. METHODS: Of the 134 research projects approved by the Auckland Area Health Board in 1991, 99 were analysed together with nine randomly selected newspaper editorials and nine randomly selected articles from popular magazines. The Flesch reading ease index, the Flesch-Kincaid index and the Gunning fog index were calculated using a computerised grammar checker. RESULTS: Subject information leaflets were easier to read than newspaper editorials but significantly more difficult to read than articles in popular magazines. The Flesch reading ease index showed that information leaflets had a median readability score of 53 compared with magazines which had a score of 67 and newspaper editorials which had a score of 48. The level of secondary school education required to read information leaflets was equivalent to about 2 years or form 4, whereas a level of about form 5 appears to be required to read newspaper editorials and a level of about form 1 for magazine articles. CONCLUSIONS: The readability level of information leaflets prepared for participants in medical research in the Auckland area appears satisfactory and the process for reviewing this component of the research protocol appears consistent and effective. Readability scores may be a useful tool in assessing the overall ease with which written information can be read. PMID- 7830983 TI - Medical manslaughter. PMID- 7830984 TI - The red eye. PMID- 7830985 TI - Core services for 1995/6: cardiac surgery. PMID- 7830986 TI - Child psychotherapy for sexual abuse. PMID- 7830987 TI - Problems with herbal treatments. PMID- 7830988 TI - The post mortem. PMID- 7830989 TI - Changes in histological structure and microvasculature of the rat tongue after transection of the hypoglossal nerve. AB - This investigation was made on sequential changes in the tongue caused by unilateral transection of the hypoglossal nerve in the rat. These changes were examined on the basis of gross inspection of the lingual dorsal surface, histological aspects of the intrinsic muscle and interstitial tissues, morphological changes in the capillary loops of the filiform papillae utilizing plastic microcorrosion casts, and blood flux and number of erythrocytes in the lingual dorsum as determined by laser Doppler flowmetry. The period of examination following denervation of the hypoglossal nerve was divided into 3-5 days, 1, 2-3, 4-5, 6-7 and 66 weeks. The initial sign of histological change was an edematous change that later developed to atrophic change of the muscular element. This pathological change caused a change in volume on the lesion side of the tongue and finally formed a depression on the dorsal surface and a scallop like lateral margin. Four to five weeks after denervation, the lesion half swelled, and its lingual apex elongated forward with a coving of the lingual median groove. The filiform papillae showed decreased keratinization, and interpapillary intervals were somewhat widened. Capillary loops in the papillae began to change, showing slight twistings at the tips of loops. Additionally, bulging, coiling and tortuosity were observed on both crura. The loops showed more complicated transformation, and little recovery was observed even 66 weeks after denervation. Blood flux in the dorsal mucosa decreased very slowly after a slight increase. This process seemed to be in proportion to the transformational complexity of the capillary loops in the filiform papillae. In conclusion, unilateral transection of the hypoglossal nerve, which is composed almost entirely of efferent neurons, caused edema and atrophic change in the intrinsic lingual muscle fibers with interstitial fibrosis in the lesion half of the tongue. Capillary loops in the filiform papillae were transformed markedly and successively by transection of the hypoglossal vasomotor neuron together with a slight decrease in blood flow in the dorsal mucosa. None of these changes recovered even at 66 weeks after transection. PMID- 7830990 TI - Three-dimensional architecture of collagen fibrils in the mouse testicular capsule. AB - The three-dimensional architecture of collagen fibrils in the mouse testicular capsule was studied after digestion of cellular and some extracellular elements by 10% NaOH. In the tunica vaginalis, the collagen fibrils were interwoven in an irregular and complex pattern. The tunica albuginea consisted of successively stacked lamellae of collagen bundles, which were arranged parallel to the testicular surface and ran across their neighbors at almost right angles. This arrangement of collagen fibrils appears to be effective in giving the testis its rigidity. Further, the collagen bundles in the tunica albuginea showed more or less undulating courses. It is suggested that the bundles undergo alteration from straight to undulate, to permit contraction of the testicular capsule. PMID- 7830991 TI - Scanning electron microscopy of elastic system fibers in the articular disc of the rat mandibular joint. AB - Elastic system fibers (ESFs), i.e., microfibrils (putative oxytalan fibers), elaunin and elastic (true elastin) fibers, in the rat mandibular joint were studied mainly using scanning electron microscopy (SEM) and light microscopy (LM) with the aid of image processing. The present quantitative analysis using LM showed that the articular disc and capsule, which are the sites that receive physical compressive force during mastication, contained more ESFs than the articular cartilage of the mandibular joint. In addition, oxytalan fibers were the principal ESFs in all the articular components (capsule, articular disc, supraossous layer of articular surfaces and articular cartilage). Subsequently, ESFs in the articular disc, which contained more thick ESFs, were closely examined by SEM using both collagen- and elastin-digestion methods. SEM showed networks of microfibrils beneath the articular surfaces (superior and inferior layers) in the thin central portion of the articular disc; the principal microfibrils ran at nearly right angles to the collagen fibers. The microfibrils were cemented with amorphous elastin, thickened and shifted towards interconnecting oblique fibers and many main ESF trunks, which were oriented in the direction of the layered wavy collagen fibers and parallel to the direction of applied force, to sustain the mechanical force. From the superior and inferior layers, the main ESFs shifted towards the middle portion of the disc, transitional zone (synovial osteochondral junction) and the other articular components, showing no specific directivity. Transmission mission electron microscopy revealed that the thick main ESFs in the elastic network were elaunin fibers. The present study indicated that ESFs unite, branch and therefore construct an extensive and complicated protective stretchable network, which is interposed with the less tensible collagen network in the mandibular articular disc. PMID- 7830992 TI - Morphological changes of human mandibular bone during fetal periods. AB - Standardized photographs (lateral and basal view) of fetal mandibles (n = 80) were taken. Outline segments (from gnathion to condylion, on the coronoid process and from infradentale to gnathion in lateral view; and on the inferior margin in basal view) were analyzed into sine curves, according to Fourier series. Using the calculated Fourier coefficients, we statistically examined how mandibular shape changed with fetal growth. Materials were classified into four groups on the basis of the body length (BL): 100 < or = BL < 200 mm (BL1, n = 20); 200 < or = BL < 300 mm (BL2, n = 20); 300 < or = BL < 400 mm (BL3, n = 20); and 400 < or = BL < or = 500 mm (BL, 4 = 20). Statistical analyses were all done on these stature groups. On the outline from gnathion to condylion, the constant and the first term phase showed statistically greater values in BL4 than in the other groups, as assessed by t-test. The first term phase for the coronoid process significantly decreased with increments in stature in the canonical disciminant analysis. On the outline from infradentale to gnathion, although the cumulative contributions of the first two terms were constant (about 85%) in all four groups, the relative contributions with growing stature decreased in the first term and increased in the second term. The mean of the phase in the first term indicated slightly more than -90 degrees in BL1, and was less than -90 degrees in BL2 to BL4. The averages of the second term phases presented little change from BL1 to BL3, and were close to -100 degrees. From the canonical discriminant analysis, the constant was great and the first term amplitude was small in BL1 and BL4, and the constant was small and the first term amplitude was great in BL2 and BL3. Also, the second term amplitude in BL4 indicated a significantly bigger volume than in BL3. The constant for the inferior margin manifested statistically significant increments in BL2 to BL4, as assessed by t-test. We interpret the results as follows: 1. On the outline from gnathion to condylion, anteroinferior shift occurs in BL4, resulting in an acute gonial angle. The change of angle during the prenatal period precedes the postnatal findings that bring about a progressive decrease in the gonial angle. 2. The tip of the coronoid process indicates a forward shift with increasing fetal body stature.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7830993 TI - A study on the projection patterns of aberrant retinal ganglion cells in the albino rat. AB - Injecting the retrograde fluorescent neuronal tracer fluoro-gold into the dorsal nucleus of the lateral geniculate body (dLGN), the olivary pretectal nucleus (OPN), and the superior colliculus (SC) revealed the existence of some ganglion cells (RGCs) scattered outside the temporoventral crescent of the ipsilateral retina in the adult albino rats. We studied the projection patterns, topographic distribution, number, and the soma size of these aberrant RGCs in 12 adult albino rats. We estimated a mean of 50 aberrant cells projecting to the dLGN. Their soma size ranged from 40.6 to 211.0 microns2, with an average of 108.6 microns2. The soma size of the 45.5 aberrant cells projecting to the OPN ranged from 41.5 to 312.5 microns2, with an average of 147.2 microns2. The SC received projection from 38.3 aberrant cells whose soma size ranged from 42.0 to 315.1 microns2, with an average of 120.7 microns2. These cells were almost equally distributed between the central and peripheral portions of the ipsilateral nasal retina. The mean cell count of the SC-projecting population was significantly lower than those of the other 2 groups. The mean soma size of the OPN-projecting aberrant cells was larger, and their soma size histogram was significantly different from those of the other 2 groups, whose histograms were almost alike. Though their physiological role in processing visual information is not fully understood, the aberrant RGCs might project their axons to--in addition to the dLGN, OPN, and SC- other visual centers. PMID- 7830994 TI - Microvasculature of the lingual papillae in primates and insectivores--fungiform, vallate and foliate papillae. AB - The microvascular architecture of the fungiform, vallate and foliate papillae was investigated under scanning electron microscope in man, common squirrel monkeys, common marmosets, common tree shrews (primates), large Japanese moles and dwarf shrews (insectivores) utilizing microvascular corrosion casts. The fungiform papilla of the lingual apex in man was supplied by an intrapapillary capillary network with a globular pattern. It was composed of 10-15 capillary loops in a circular arrangement and 5-7 thick capillaries in the center. The fungiform papilla of the lingual body was supplied by a dense capillary network on the top and lateral surfaces. That in other primates was supplied by a cylindrical capillary network and loop formation was seen on the top surface. That in insectivores was supplied by a thin cylindrical network with coarse meshes, at the tips of which were observed 2 or 3 capillary rings in the mole and only one in the dwarf shrew. The vallate papilla in primates was supplied by an intrapapillary capillary network with a globular pattern, and showed irregularly tortuous capillary loops on its top surface. The vallum was supplied by a capillary network in man and usually one or two rows of loops arranged in a circle in other primates. The vallate papilla in insectivores was supplied by a doughnut-like capillary network with a recess on the top surface, and an indistinctly low vallum by a low undulating network. The foliate papillae were most developed in man, and each lobule was supplied by capillaries passing longitudinal to it and capillary loops in 5-10 regular rows on the top, but 3-5 rudimentary lobules in the squirrel monkey and marmoset. In the two species, each lobule was supplied by one arteriole, one venule and a coarse capillary network continuing from the interpapillary network. No foliate papilla was observed, but large conical papillae were noted in the tree shrew and insectivores. In conclusion, the intrapapillary vasculature appeared most complicated in man, simplified in the squirrel monkey and marmoset, and was much more simplified in the insectivores, where it was quite different from that in the primates. The pattern of the intrapapillary vasculature in the tree shrew was transitional between primates and insectivores. PMID- 7830995 TI - Major refractive surgical techniques. PMID- 7830996 TI - Prospective comparison of the Heine retinometer with the Mentor Guyton-Minkowski potential acuity meter for the assessment of potential visual acuity before cataract surgery. AB - Various techniques and devices have been developed to aid in the assessment of potential visual acuity prior to cataract surgery. We report a prospective comparison of two such assessments, one made using a new instrument, the hand held Heine retinometer (HR) (Heine Instruments, Germany), and the other using the Mentor Guyton-Minkowski potential acuity meter (PAM) (Mentor, Inc, Norwell, Mass). A total of 37 eyes were assessed using both instruments just before cataract surgery. Three eyes were excluded from analysis due to postoperative complications affecting visual acuity that could not have been predicted with either instrument. The false-negative rate was 44% for the PAM and 32% for the HR. There were no false-positive results with either instrument. Neither instrument was particularly accurate in predicting actual final visual acuity (r2 = 0.290 and 0.144 for the PAM and HR, respectively). The HR was deemed easier to use. PMID- 7830997 TI - Surgical removal of congenital pupillary-iris-lens membrane. AB - A pupillary membrane in a case of congenital pupillary-iris-lens membrane with goniodysgenesis was surgically peeled from the lens without causing cataract formation. Histopathology revealed ectopic iris. The ectopic iris found in this condition differentiates congenital pupillary-iris-lens membrane with goniodysgenesis as an entity from persistent pupillary membrane, hereditary goniodysgenesis, and Rieger's anomaly. We suggest that congenital pupillary-iris lens membrane with goniodysgenesis is a neurocristopathy. The finding of ectopic iris muscle is consistent with avian chimera experiments that have suggested that iris sphincter muscle is derived from the neural crest, not neural ectoderm. Membranes in this condition can be successfully removed when they cause vision loss and amblyopia. PMID- 7830998 TI - Postoperative chronic pressure abnormalities in the vitreon study. AB - Perfluoroperhydrophenanthrene (Vitreon) was used as an intraoperative hydrokinetic retinal manipulator, followed by C3F8 or SF6 gases, silicone oil, or Vitreon as postoperative tamponading agents in 234 eyes. Two chronic intraoperative pressure abnormalities were defined: hypotony (5 mm Hg or less) and elevated intraocular pressure (IOP) (25 mm Hg or more at three or more postoperative visits). Postoperatively, 28 eyes (12%) had chronically elevated IOP, and 41 (18%) had chronic hypotony. There was no significant difference in the incidence of abnormal IOP among the groups of eyes in which the various tamponading agents had been used. In particular, the use of Vitreon as an intraoperative tool or as a short-term tamponade did not affect the incidence of chronic abnormal IOP any more than did the use of silicone oil, C3F8, or SF6 as tamponading agents. PMID- 7830999 TI - Air pump for retinal detachment with macular hole. AB - From 1984 to 1992, 128 eyes with substantial retinal detachment due to macular hole underwent vitrectomy at the Ideta Eye Hospital. In the first 76 eyes treated, air was injected by syringe after removal of the vitreous (group A); in the subsequent 52 eyes, air was injected by a pump while subretinal fluid was aspirated through the macular hole (group B). The rates of retinal reattachment after the first surgery were 63.2% in group A and 82.7% in group B (P < .05). Thus, using the air pump was more effective than air injection. PMID- 7831000 TI - Chemosis following blepharoplasty: an unusual complication. AB - We observed four cases of chemosis associated with otherwise uneventful four-lid blepharoplasty. These patients experienced postoperative conjunctival chemosis (without associated globe injection), varied types of congestion, subconjunctival hemorrhage, retrobulbar hematoma, or corneal involvement. Postoperatively, the patients were treated with some combination of patching, topical and/or systemic steroids, decongestant eye drops, and observation. Regardless of the treatment, the chemosis resolved by 5 months, without permanent complication. Probable causes were blockage of orbital or eyelid lymphatics and excessive cautery during surgery. PMID- 7831002 TI - Trans-nasal flap for medial canthal reconstruction. AB - The trans-nasal flap is an effective method for repairing medial canthal defects following Mohs' surgery. This procedure transposes redundant skin from the nasal bridge into the defect. The construction of the flap, which minimizes the risk of medial canthal webbing, yielded excellent cosmetic results in 22 patients. PMID- 7831001 TI - The effect of silicone intubation on failure and infection rates after dacryocystorhinostomy. AB - Of 388 cases of dacryocystorhinostomy eligible for silicone intubation, intubation was used in 238 (61%) and not used in 150 (39%). The indications for intubation were canalicular disease or sac characteristics predisposing to failure. No significant difference was found in the rate of failure (.5 < P < 1.0) or soft-tissue infection (.25 < P < .5) for either primary or repeated surgery. Antibiotic prophylaxis did not alter these risks in relation to silicone intubation. PMID- 7831003 TI - The entropion patch: a method of temporarily correcting involutional entropion with adhesive tape. AB - A simply designed entropion patch provided effective temporary preoperative relief of the symptoms of lid malposition in lower lid involutional entropion in six patients. The patch is easily fashioned and used after appropriate instruction, with its design taking into account lid mechanics and the pathophysiology of involutional entropion. PMID- 7831004 TI - Diode and Nd:YAG laser contact transscleral cyclophotocoagulation in a human eye: a comparative histopathologic study of the lesions produced using a new fiber optic probe. AB - We compared the contact cyclodestructive effects (both gross and histologic) achieved with diode and Nd:YAG laser wavelengths (810 and 1064 nm, respectively), using equivalent energy doses, released by means of a new optical delivery system in a human eye that was soon to be enucleated because of a choroidal melanoma. For both lasers, a fiber optic system (400 microns) with a focusing microlens placed at the end of the fiber was used. The center of the beam was placed 1.5 mm from the corneoscleral limbus. At medium (5.2 to 6.6 J) and higher (7.8 J) energy levels, the cyclodestructive thermal damage produced by the diode laser appeared more widespread than that created by the Nd:YAG laser. At lower levels (3.6 to 3.9 J), both laser treatments produced similar lesions. The new delivery system proved to be safe and effective in achieving the desired cyclodestructive effects at both wavelengths. PMID- 7831005 TI - Effect of the concentration and duration of application of mitomycin C in trabeculectomy. AB - Ninety-three consecutive trabeculectomies in which mitomycin C (MMC) was applied intraoperatively, either at a concentration of 0.5 mg/mL for 5 minutes (n = 48) or at a concentration of 0.4 mg/mL for 3 minutes (n = 45), were reviewed to determine whether there was a significant difference between the two groups in terms of intraocular pressure (IOP) control and the incidence of complications. Preoperative and postoperative IOPs in the two groups did not differ significantly (P = .817 and .131, respectively). The 5-minute group had a higher incidence of serous choroidal detachments (P = .001). The incidence of postoperative hypotony and filtration failure with uncontrolled IOP in the two groups did not significantly differ (P = .177 and .582, respectively). Thus, intraoperative application of MMC at a concentration of 0.4 mg/mL for 3 minutes controlled postoperative IOP as effectively as MMC at a concentration of 0.5 mg/mL for 5 minutes, with a significantly lower incidence of choroidal detachments. PMID- 7831006 TI - Trabeculectomy with mitomycin C in glaucoma associated with uveitis. AB - Twenty-four trabeculectomies performed in 24 patients for control of uveitic glaucoma were retrospectively evaluated to analyze the effect of intraoperative application of mitomycin C (MMC) on the short-term outcome of trabeculectomy for glaucoma associated with uveitis. Success rates, postoperative levels of intraocular pressure (IOP), and complications were studied. After a mean follow up of 9.87 months (range, 3 to 27 months), 18 eyes (75%) achieved an IOP of 21 mm Hg or less without antiglaucoma medications. The same IOP level with one antiglaucoma medication was achieved in four eyes (16.6%). Statistical analysis demonstrated a significant reduction in IOP postoperatively during the period studied (P = .0001). Complications observed included exacerbation of the uveitis (12.5%), choroidal detachment (12.5%), hypotony (8.3%), postoperative shallow anterior chamber (4.2%), wound leak (4.2%), hyphema (4.2%), and macular edema (4.2%). The results of this retrospective and uncontrolled study suggest that intraoperative application of MMC may be a good option for enhancement of short term trabeculectomy success rates in cases of uveitic glaucoma. PMID- 7831007 TI - Results of trabeculectomy combined with phacoemulsification versus trabeculectomy combined with extracapsular cataract extraction in patients with advanced glaucoma. AB - We compared the results of trabeculectomy combined with phacoemulsification (n = 16) with those of trabeculectomy combined with extracapsular cataract extraction (n = 18). There was no significant difference between the two groups in terms of early or chronic postoperative intraocular pressure (IOP) control or in terms of the number of glaucoma medications prescribed postoperatively. However, by 12 weeks postoperatively, bleb height and extent were significantly greater in the phacoemulsification group. There was no significant difference between the groups in terms of postoperative spheroequivalent, astigmatism, or cylindrical axis. The mean final visual acuity, however, was less in the extracapsular group. We conclude that phacoemulsification combined with trabeculectomy offers a safe and effective technique to control postoperative IOP in patients with glaucoma. PMID- 7831008 TI - Respiratory arrest after 0.75% bupivacaine retrobulbar block. AB - Respiratory arrest is an uncommon complication of retrobulbar anesthesia. We present a case in which it occurred following a 0.75% bupivacaine and 2% lidocaine retrobulbar block and analyze the possible causes. We conclude that the most important of these were the relatively high concentration and volume of the anesthetic and a faulty technique. PMID- 7831009 TI - Computerized topography of a full-thickness corneal laceration. AB - A full-thickness corneal laceration was studied by computerized topography. Measurements taken preoperatively and during healing allowed the effects of the injury, its repair, and subsequent suture removal to be isolated and separately analyzed. PMID- 7831010 TI - Ultrasound biomicroscopy for the assessment of Molteno tube position. AB - Due to anatomic distortion or surgical complications, it may be difficult to determine the precise position of an implanted Molteno tube. We performed ultrasound biomicroscopy (high-resolution ultrasound) to test the usefulness of this modality in localizing implanted Molteno tubes in 10 patients with Molteno tubes. A 50-megahertz transducer with a penetration of approximately 4 mm was used to produce a magnified image of the anterior segment. The Molteno tube was visualized without complication in all of these cases. PMID- 7831011 TI - Treatment of postfiltration bleb leak by bleb injection of autologous blood. AB - We treated a persistent, brisk bleb-leak after trabeculectomy with mitomycin C by bleb injection of autologous blood. Following preparation with povidone iodine, approximately 0.5 cc of whole autologous blood was injected into the bleb at the slit lamp. The leak resolved after 36 hours, and after 9 months' follow up, continued to function well. PMID- 7831012 TI - Conjunctival ulcer in a patient with Crohn's disease. AB - A 38-year-old woman with documented Crohn's disease (CD) had uniocular nodular episcleritis and a limbal nodule with surrounding infiltrate, which, when healed, left residual pannus. The episcleral nodule was abnormally large (7 x 5 x 3 mm). A localized conjunctival ulceration, a rare manifestation, to our knowledge not previously reported, developed later in the same eye. Impression cytology of the ulcer showed pyknotic conjunctival epithelium and absence of goblet cells, together with the presence of a few plasma cells, lymphocytes, and macrophages. These features are comparable to those seen in the intestinal mucosa of patients with CD. The unilaterality of the ocular infection together with the good response to local therapy suggests that a local antigen-antibody immune complex reaction was involved. We recommend local therapy as a first treatment option. PMID- 7831013 TI - Herpes simplex keratitis following argon laser trabeculoplasty. AB - Many complications have been reported with argon laser trabeculoplasty (ALT). In the following article, we report the first case of Herpes simplex keratitis recurrence being triggered after ALT. PMID- 7831014 TI - Trabecular aspiration: clinical results of a new surgical approach to improve trabecular facility in glaucoma capsulare. AB - The main reason for elevated intraocular pressure (IOP) in glaucoma capsulare is secondary plugging of the intertrabecular spaces by pigment and fibrillous material. The goal of this study was to evaluate the clinical results of "trabecular aspiration," a new surgical technique designed to improve trabecular facility in pseudoexfoliative glaucoma (PEG). Trabecular aspiration was performed under the operating microscope prior to extracapsular cataract extraction (ECCE) over half of the chamber-angle circumference using a specially designed irrigation-aspiration device in 12 eyes diagnosed with PEG and cataract. Trabecular debris and pigment were cleared with a suction force of 100 to 200 mm Hg. The mean preoperative IOP (with and without antiglaucoma medications) was 33.0 +/- 6.27 mm Hg; on postoperative day 5, 16.25 +/- 4.5 mm Hg; at 1 month, 18.1 +/- 2.68 mm Hg; at 3 months, 18.33 +/- 2.69 mm Hg; and at 6 months, 19.0 +/- 6.26 mm Hg. The mean number of antiglaucoma medications per day decreased from 3.77 preoperatively to 0.67 at 6 months postoperatively. Trabecular aspiration substantially lowered the IOP in all 12 patients. Removal of intertrabecular and pretrabecular debris prior to ECCE reduced IOP 42% from baseline at 6 months postoperatively, a clinically significant decrease. Additionally, routine preoperative and postoperative gonioscopy in most cases revealed a significant reduction of pigmentation in the area of treatment. More patients and longer follow up are required to substantiate these results. PMID- 7831015 TI - The blepharoplasty rotational flap. AB - Patients with large benign upper eyelid lesions and dermatochalasis are optimally treated with excision of their lesions and a blepharoplasty. I have devised a myocutaneous flap to reconstruct defects created by excising upper eyelid lesions peripheral to the blepharoplasty incision lines. The flap is created from skin and muscle that would normally be excised during the blepharoplasty. This technique results in a well-defined upper eyelid crease, without eyelid retraction or epicanthal fold formation. PMID- 7831016 TI - Procedures involving star-shaped capsulectomy for managing congenital cataracts in developing nations. AB - The management of congenital cataracts is still challenging, especially in developing nations, where surgical facilities are limited. Congenital cataracts were extracted from 22 patients (26 eyes): a procedure consisting of a star shaped anterior capsulectomy and wash-out of lens material (STARWO) was performed in 16 of them (18 eyes) (group A); a procedure consisting of a star-shaped anterior capsulectomy, wash-out, anterior vitrectomy through the posterior capsulotomy, and repeated tearing of remnants of the anterior capsule (STARWAR) was performed in six patients (eight eyes) (group B). Intraocular lenses were implanted in both groups. In group A, secondary membranes (27.7%) developed in five eyes, postoperative uveitis in four (22.2%), and a late Elschnig pearl in 1 (5.5%). In group B, there was one case of secondary membrane formation (12.5%), and one of postoperative uveitis; neither required subsequent intervention. The inexpensive instrumentation used and the low rate of perioperative complications encountered in these patients make these two techniques attractive alternatives for managing congentital cataracts in developing nations. PMID- 7831017 TI - A 74-year-old woman with epiphora. PMID- 7831018 TI - Mentor Guyton-Minkowski potential acuity meter. PMID- 7831019 TI - Intraocular lens placement after removal of a subluxated lens. PMID- 7831020 TI - Bimanual cortex removal. PMID- 7831021 TI - Avoiding air bubbles in Viscoat. PMID- 7831022 TI - Histopathology of macular holes. PMID- 7831023 TI - Primary intraocular lens implantation in the setting of penetrating ocular trauma. AB - PURPOSE: To evaluate the clinical outcome of patients who underwent lensectomy and intraocular lens (IOL) implantation at the time of primary repair of a penetrating ocular injury. METHODS: A review of 14 patients who sustained cataracts and lens rupture in the setting of a corneal laceration to determine anatomic and visual outcome, in addition to complications related to the primary IOL. RESULTS: The IOL remained anatomically stable in all 14 patients with no complications encountered at implantation or after surgery. Final visual acuity in 9 of the 14 patients was 20/40 or better. Six patients underwent pars plana vitrectomy for removal of an intraocular foreign body. CONCLUSION: Intraocular lens implantation at the time of lensectomy and primary repair of a corneal laceration allows good visual rehabilitation with restoration of binocular function and serves as an alternative to contact lens correction in select patients. PMID- 7831024 TI - Prevalence and risk factors of lens opacities in the elderly in Finland. A population-based study. AB - PURPOSE: The distribution and prevalence of lens opacities and visual impairment caused by cataract were studied in an epidemiologic cross-sectional population study of inhabitants 70 years of age or older in three communities in Oulu County, Finland. METHODS: Of the 560 eligible subjects, 500 (89.3%) were examined. The best-corrected visual acuity for distance in both eyes was determined. The diagnosis of lens opacities was based on clinical biomicroscopy. The findings were compared with standardized photographs of the Lens Opacities Classification System II. RESULTS: One hundred sixty-five (33.0%) persons in the study population had a clear lens in both eyes. Cataract, aphakia, or pseudophakia was recorded in one or both of the eyes in 64.4% (322 persons) of the participants. The prevalence increased with age from 44.6% of persons (n = 88) in the 70- to 74-year-old age group to 97.6% of persons (n = 41) in the 85- to 89-year-old age group. A total of 56.4% of persons had cataract, aphakia, or pseudophakia in both eyes. Nuclear, cortical, and posterior subcapsular opacities were detected in 38.5%, 37.6%, and 27.7% of the participants, respectively. Exfoliation was present in one or both eyes in 22.1% of the participants. There was no difference in the prevalence of cataract between the sexes when age was considered. Visual impairment to 20/50 or worse was at least partly due to cataract in 23.8% of the right eyes and 22.4% of the left eyes. Significant risk factors for cataract were age and the presence of exfoliation in men and age, occupational exposure to sunlight, and current cigarette smoking in women. CONCLUSIONS: Almost two thirds of the population 70 years of age or older had lens opacities, and in 23.1% of the eyes visual impairment to 20/50 or worse was at least partly due to cataract. Including the patients who had undergone surgery, 30.3% of all the eyes of persons 70 years of age or older can be considered for cataract surgery. PMID- 7831025 TI - Tear flow in cyclosporine recipients. AB - PURPOSE: To measure tear flow in renal allograft recipients who received oral cyclosporine as immunosuppressive therapy. PATIENTS: Control subjects were from the staff of various clinics, dialysis patients were recruited, and one group of kidney transplant recipients took oral cyclosporine, whereas another group took azathioprine. Written informed consent was obtained for an institutionally approved protocol. METHODS: A 4-minute Schirmer test with topical anesthetic was performed in both eyes of each person, and the average score was used in calculations. RESULTS: The tear flow rate was 10.6 mm/4 minutes in the control subjects, 13.6 mm/4 minutes in the dialysis patients, 10.4 mm/4 minutes in kidney transplant recipients taking azathioprine, and 19.0 mm/4 minutes in kidney transplant recipients taking cyclosporine. Kidney transplant recipients taking cyclosporine had significantly increased tear flow compared with the other three groups (P < 0.05); dialysis patients, kidney transplant recipients taking azathioprine, and control subjects showed statistically indistinguishable tear flow. Within-group comparisons (male versus female, black versus white, and all combinations) showed no statistically significant differences. CONCLUSION: Medications used by dialysis patients or the azathioprine group did not significantly increase tear flow compared with control subjects. The addition of cyclosporine (plus prednisone) enhanced tear flow in kidney transplant recipients compared with all other groups. Systemic cyclosporine appears to increase tear flow even when no lacrimal autoimmune disease exists. PMID- 7831026 TI - The use of propofol and mivacurium anesthetic technique for the immediate postoperative adjustment of sutures in strabismus surgery. AB - PURPOSE: Adjustable suture techniques have become increasingly popular over the last decade and may reduce the re-operation rate after strabismus surgery. The adjustment usually is made in the hospital or office 5 to 24 hours after surgery, when the patient has fully recovered from general anesthesia. The ability to perform suture adjustment in the operating room, immediately after completion of surgery, would be an attractive alternative with respect to patient monitoring, sterility, comfort, and timing. The purpose of this study is to compare the alignment of patients in the operating room adjusted immediately after surgery with their alignment the morning after surgery. METHODS: Patients with strabismus who have good vision in each eye and who were judged to be appropriate candidates for adjustable sutures were invited to enroll in a study using propofol and mivacurium total intravenous anesthetic technique. Patients underwent strabismus surgery in which one or more muscles were placed on adjustable sutures. Immediately after extubation, these patients were awakened in the operating room, assisted in sitting upright, and asked to fixate on a 20/400 Snellen E target on the operating room wall. Sutures were adjusted, when necessary, to obtain the desired postoperative alignment. Prism and alternate cover measurements, taken after the sutures were permanently tied, were compared with measurements taken the morning after surgery. RESULTS: Twenty-nine patients qualified for inclusion. Measurements of horizontal and vertical alignment in the operating room were all within 12 prism diopters (PD) of the measurements taken 18 to 24 hours after surgery (mean variation, 4 PD horizontally and 2 PD diopters vertically). The measured deviation changed less than or equal to 6 PD horizontally in 78% of patients and less than or equal to 3 PD vertically in 70% of patients. CONCLUSION: For some adult patients with strabismus, a total intravenous general anesthesia technique using an infusion of propofol and mivacurium may provide the opportunity for accurate suture adjustment in the operating room, immediately after completion of surgery. PMID- 7831027 TI - Burkitt lymphoma presenting as a conjunctival mass. AB - PURPOSE: A sporadic Burkitt lymphoma, which presented as a primary conjunctival mass, demonstrates the approach to clinical diagnosis, staging, and current management of this rapidly growing malignant tumor, as well as newer concepts of its pathogenesis. PATIENT AND METHODS: A 16-year-old girl had rapid development of a conjunctival mass 6 weeks after an infectious mononucleosis-like illness, associated with a positive monospot test. A biopsy of the tumor was immunostained for lymphocyte markers. Additional clinical workup included computed tomographic scanning, nasopharyngeal biopsy, and studies of blood, bone marrow, and spinal fluid. In situ hybridization for Epstein-Barr virus (EBV)-encoded nuclear RNA was performed on the tumor and adenoidal tissue. RESULTS: The conjunctival biopsy showed a typical Burkitt lymphoma with markers positive for predominantly B lymphocytes. Computed tomographic scans indicated residual tumor in the anterior orbit. Biopsy of thickened adenoidal tissue showed only benign lymphoid hyperplasia. Evidence of EBV infection was found in the adenoidal tissue but not in the tumor cells. The patient was treated with combined chemotherapy on a Pediatric Oncology Group Study protocol for localized non-Hodgkin lymphoma, and is disease-free 4 1/2 years after diagnosis. CONCLUSIONS: A sporadic Burkitt lymphoma arising in the conjunctiva appears to be the first reported in this site. The lymphoma responded well to chemotherapy, which is now the usual course in stage 1 disease. A direct role for EBV in the oncogenesis of this sporadic tumor, similar to that in the endemic form, could not be supported because EBV encoded nuclear RNA was absent in the tumor cells. PMID- 7831028 TI - Congenital orbital cysts associated with the common sheath of superior rectus and levator palpebrae superioris muscles. AB - PURPOSE: To review the clinical and operative features of a subgroup of superior congenital orbital cysts that intimately are associated with the common sheath of the superior rectus and levator palpebrae superioris muscles. METHODS: Records from four eligible patients were reviewed retrospectively. RESULTS: All four patients had ptosis or lid swelling at initial presentation and were found at surgery to have large cysts within the common tendon sheath of the superior rectus and levator palpebrae superioris muscles. The lining of these cysts resembled that of conjunctiva. There was no precedent conjunctival disease or surgery. CONCLUSIONS: The authors propose that these cysts are congenital and arise as misdirected cleavage of mesoderm during formation of the superior fornix. As such, this type of cyst has not been described previously and may represent a third group of congenital orbital cysts distinct from both conjunctival inclusion and dermoid cysts. Particular caution is required in their excision. PMID- 7831029 TI - Long-term follow-up of patients with familial subepithelial amyloidosis of the cornea. AB - PURPOSE: To investigate the clinical course of patients with familial subepithelial amyloidosis of the cornea (FSA). METHODS: The authors retrospectively investigated the clinical course of seven Japanese patients with FSA. Corneal specimens obtained at the time of keratoplasty were examined histopathologically. RESULTS: The mean follow-up period was 20.6 years, including four patients followed for more than 25 years. In all patients, the initial symptoms of photophobia and epiphora started in the first decade of life. All except one patient had their first keratoplasty before 30 years of age. The seven Japanese patients with FSA had a total of 35 keratoplasties, each of which was followed by a severe recurrence of disease. In each patient, subepithelial haziness developed in the graft within 1 year of keratoplasty (mean, 7.9 months). Amyloid deposition typically recurred within a few years (mean, 26.6 months) followed by a deterioration of vision. There was a high incidence of postkeratoplasty complications such as wound dehiscence, glaucoma, and cataract. Histopathologic findings demonstrated that, in the early phase of recurrence, amyloid was deposited between the basal cell of the epithelium and Bowman's layer. CONCLUSION: Patients with FSA have ocular symptoms with a deterioration in vision from an early decade of life. Conventional surgical approaches were complicated by subepithelial haziness in the first postoperative year, which was followed by a severe recurrence in each patient. New surgical approaches may be indicated in FSA. PMID- 7831031 TI - Disease relapse in patients with ocular manifestations of Wegener granulomatosis. AB - PURPOSE: To evaluate possible factors associated with disease relapse in patients with ocular manifestations of Wegener granulomatosis. METHODS: Eight patients with ocular manifestations of Wegener granulomatosis were longitudinally followed for a mean period of 34 months. Serial antineutrophil cytoplasmic antibody (ANCA) levels were determined on all patients. RESULTS: All eight patients had either scleritis alone or scleritis combined with peripheral ulcerative keratitis. Clinical disease remission was achieved in all patients using immunosuppressive chemotherapy. Five patients had subsequent relapse after treatment withdrawal. The serum ANCA level had failed to revert to normal during remission in four of the five patients who had had relapses. The ANCA levels for all three patients who remained in remission without therapy converted to normal. There was no significant difference in the initial serum ANCA level (P = 0.35) or the mean cumulative cyclophosphamide dose (P = 0.13) between those who had a relapse and those who did not. CONCLUSION: Failure of ANCA titers to revert to normal levels may be associated with the potential for relapse in patients with ocular manifestations of Wegener granulomatosis. PMID- 7831030 TI - Serum antibodies reactive with eye muscle membrane antigens are detected in patients with nonspecific orbital inflammation. AB - PURPOSE: Nonspecific orbital inflammation, also called "orbital pseudotumor," has many of the features of thyroid-associated ophthalmopathy, especially when localized to the eye muscle. The purpose of this study is to test for circulating autoantibodies against eye muscle antigens and features of possible thyroid autoimmunity in patients with nonspecific orbital inflammation. METHODS: The authors studied eight patients with diffuse or localized nonspecific orbital inflammation. The presence of autoantibodies reactive with pig eye muscle membrane antigens and 1D, a recombinant 64 kilodaltons (kd) thyroid and eye muscle protein, were tested in sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blotting. RESULTS: The most frequently detected antibodies were those reactive with eye muscle membrane proteins of 55 and 64 kd, which were demonstrated in 62.5% and 62.5%, respectively, of patients with nonspecific orbital inflammation; antibodies against 95- and 45-kd proteins were each detected in 50% of patients. In health subjects, antibodies reactive with the 55- and 64-kd proteins were detected in 16% and 20% of patients, respectively; those reactive with the 95-kd protein were detected in 24% of patients and with the 45-kd protein in 20% of patients. On the other hand, antibodies to 1D were demonstrated in only one patient with nonspecific orbital inflammation and not at all in healthy subjects. The prevalence of positive tests were significantly greater in patients with nonspecific orbital inflammation than healthy patients only for antibodies reactive with a 55-kd protein. Of the four antigens, only the 55-kd protein was expressed in other (systemic) skeletal muscle. No patient had overt thyroid disease or detectable serum antibodies reactive with the thyroid-stimulating hormone receptor, and only one had antibodies reactive with the thyroid microsomal antigen. CONCLUSION: Serum autoantibodies reactive with eye muscle membrane proteins are demonstrated in the majority of patients with nonspecific orbital inflammation. Although the pathogenesis of this condition is unknown, autoimmunity against eye muscle antigens is a likely mechanism. While antibodies reactive with the thyroid microsomal antigen were detected in only one patient and anti-thyroid-stimulating hormone receptor antibodies in none of the patients, a possible association of nonspecific orbital inflammation with thyroid autoimmunity has not been excluded. PMID- 7831032 TI - Coralline hydroxyapatite spheres as secondary orbital implants in anophthalmos. AB - BACKGROUND: Secondary reconstruction of the anophthalmic socket is frequently challenging. A number of surgical techniques are described to improve the cosmetic and functional outcome. Recently, the use of hydroxyapatite as a primary orbital implant after enucleation has gained popularity and yielded encouraging surgical results. There are no published reports concerning the use of hydroxyapatite as a secondary orbital implant in anophthalmos. METHODS: The authors reviewed the charts of 17 patients who received a secondary hydroxyapatite orbital implant to rehabilitate the anophthalmic socket. Each patients' preoperative and postoperative photographs, socket appearance, implant and prosthetic motility, and overall impressions of the surgical outcome were analyzed. Complications of surgery and secondary procedures were reviewed. RESULTS: All except one patient attained an improved prosthetic appearance postoperatively and 76% achieved improved implant and prosthetic motility. Four patients undergoing surgery early in the series had worsening of pre-existing ptosis. In two patients, implant exposure developed; a socket infection with subsequent loss of the implant developed in one of these patients. Eight patients underwent additional eyelid and orbital surgery at the time of secondary implant surgery, whereas nine patients required additional staged procedures. CONCLUSION: Secondary orbital implantation with the coralline hydroxyapatite sphere is an encouraging alternative to traditional secondary orbital implant surgery. Surgical outcomes in this study were excellent with few complications and high patient satisfaction. PMID- 7831034 TI - Exophthalmometry. PMID- 7831033 TI - Lens-sparing vitrectomy with perfluorocarbon liquid for the primary treatment of giant retinal tears. AB - PURPOSE: To evaluate the surgical success of vitrectomy without initial lensectomy in the primary treatment of retinal detachment associated with giant tears without proliferative vitreoretinopathy. METHODS: Thirty-four consecutive phakic eyes with idiopathic giant retinal tears underwent vitrectomy, injection of perfluorocarbon liquid, endolaser, and gas tamponade. Encircling scleral buckling was performed in 14 of 34 patients. Preoperative visual acuity ranged from 20/25 to hand motions. Giant tear size ranged from 90 degrees to 330 degrees. Follow-up ranged from 10 to 64 months. RESULTS: Anatomic retinal re attachment was achieved intraoperatively in all eyes. The re-operation rate was 14% for eyes that underwent scleral buckling with the initial vitrectomy and 45% in eyes without primary scleral buckling. In 59% of eyes with cataract formation, 32% underwent cataract surgery with or without intraocular lens implantation. Best-corrected final visual acuity ranged from 20/15 to 20/400. CONCLUSION: Most phakic eyes with giant retinal tear not associated with proliferative vitreoretinopathy can be re-attached successfully with initial preservation of the lens. PMID- 7831035 TI - Exophthalmometry. PMID- 7831036 TI - Automated perimetry detects visual field loss before manual Goldmann perimetry. AB - PURPOSE: To determine if automated perimetry detects visual field defects before manual Goldmann perimetry. METHODS: Subjects with ocular hypertension without field loss on detailed manual perimetry were followed prospectively with annual automated and manual perimetry. Subjects with field loss on manual perimetry were age-matched post hoc to subjects who did not have field loss. The automated fields 1 year before the development of field loss on manual perimetry were compared between the two groups. Subjects were recruited from ophthalmologists' offices, eye clinics, and a population-based glaucoma survey in the Baltimore area. Abnormal results detected on the Humphrey Field Analyzer were defined using the glaucoma hemifield test, mean defect, and corrected-pattern standard deviation. RESULTS: Forty subjects who had field loss during 8 years of follow-up were compared with 145 control subjects with ocular hypertension who did not have defects. Seventy-five percent of converters had abnormal results of the glaucoma hemifield test 1 year before field loss on manual perimetry, whereas 22% of controls had abnormal results of the glaucoma hemifield test (odds ratio, 13.4). The odds ratio of field loss developing on manual perimetry within 12 months was 3.3 for those with borderline results of the glaucoma hemifield test relative to the control subjects. The odds ratio was 6.0 for corrected-pattern standard deviation (P < 0.05) and 3.9 for mean deviation (P < 0.05). CONCLUSIONS: Those with field loss on manual perimetry were more likely to have had an abnormal automated field 1 year before conversion than those who did not convert. However, 22% of subjects in whom definitive field loss did not develop on manual perimetry during the study had abnormal automated fields at one visit and 15% had abnormal automated fields on two consecutive visits. PMID- 7831037 TI - Automated perimetry and malingerers. Can the Humphrey be outwitted? AB - BACKGROUND: Through detailed strategies and sophisticated analysis, the Humphrey automated visual field analyzer attempts to indicate if visual field loss is artefactual. Can these measures be outwitted by malingerers? METHODS: The author investigated the ease with which motivated individuals (such as are malingerers) could simulate visual field defects consistent with organic neurologic disease on the Humphrey visual field analyzer. Visual field test results were analyzed for characteristic features and compared with visual field tests from patients with documented pituitary tumors. RESULTS: Volunteers, given only broad suggestions as to the visual field they were to simulate, produced consistent, convincing, neurologic-type field defects, according to textbook descriptions of such fields. These plotted fields were only distinguishable from genuine pituitary tumor Humphrey field tests, in that they more convincingly fitted the classic descriptions of visual fields seen with chiasmal compression. CONCLUSIONS: The author concludes that single routine Humphrey visual field tests do not show malingerers. An incidental finding of this study was the extent to which Humphrey visual fields from patients with genuine neurologic disease contain field defects with characteristics different from those of the (kinetic) visual field test appearances described in the textbooks. PMID- 7831038 TI - Exophthalmometry. PMID- 7831039 TI - Scanning slit confocal microscopic observation of cell morphology and movement within the normal human anterior cornea. AB - PURPOSE: Noninvasive in vivo observations of the anterior human cornea were performed to study cell structure and dynamics. Cellular elements were identified by their location, morphology, and pattern of movement. The hypothesis that cells in the epithelial layer of the normal cornea migrate centripetally was tested. METHODS: Using a scanning slit confocal microscope with a new 0.75-numeric aperture contact objective, individual cells of normal human corneas were observed over time, quantifying the velocity and direction of cellular movement within the basal epithelial layer. RESULTS: Basal epithelial cells, wing cells, the basal epithelial nerve plexus, and the subepithelial nerve plexus were identified readily. Centripetal motion was observed for three corneal cell types: basal epithelial cells, basal epithelial nerves, and unidentified cellular elements (possibly Langerhans cells). The unidentified cellular elements moved along the length of the basal epithelial nerves. The basal epithelial nerve plexus maintained a roughly stable topology as it slid centripetally. New nerve material appeared at the site of entry of the nerve into the epithelium. No growth cones were present at the distal termini of the growing epithelial nerves. CONCLUSION: In the midperiphery of the normal human cornea, basal epithelial cells and nerves slide centripetally, probably in concert. Unidentified cellular elements used the basal epithelial nerve plexus as a pathway for intraepithelial movement. Observations in this study suggest that neurite growth occurred by the addition of new membrane material along the length of the axon rather than at a distal growth cone. PMID- 7831040 TI - Relation of visual symptoms to topographic ablation zone decentration after excimer laser photorefractive keratectomy. AB - BACKGROUND: The authors used computer-assisted videokeratoscopy to analyze the relation of photorefractive keratectomy ablation zone decentration to subjective patient assessments of disturbing visual symptoms. METHODS: Ablation zone decentration was measured 1 month postoperatively. The study population was divided into two groups: group 1, patients whose ablation zone decentrations were less than 0.50 mm; group 2, patients whose ablation zone decentrations were greater than 0.50 mm. Visual symptoms including glare, rings or halos around lights and problems with night driving were scored preoperatively and 6 months postoperatively. The Hotelling T-square and chi-square tests were used. RESULTS: The mean decentration from the center of the ablation zone to the pupillary center was 0.30 mm and 190 degrees for group 1 compared with 0.66 mm and 198 degrees for group 2. The Hotelling T-square test showed a significant statistical preoperative/postoperative difference in group 1 (P < 0.03) for the halo symptom category. No other symptom category showed a significant statistical difference in either group for the mean scores. The Hotelling T-square test did not show a statistically significant difference between the two groups preoperatively to postoperatively regarding the mean scores of the individual patient differences for the three symptoms. The only significant statistical difference for the individual patient ratings preoperatively to postoperatively was for the halo symptom category (chi-square = 7.756; P < 0.03). CONCLUSIONS: Multivariate analysis did not show a significant statistical difference preoperatively between the two groups or postoperatively except for group 1 with regard to the halo symptom category. It appears from this study that ablation zone decentrations less than 0.89 mm from the pupillary center do not necessarily produce unwanted visual symptoms 6 months postoperatively. PMID- 7831041 TI - Diabetes, intraocular pressure, and primary open-angle glaucoma in the Baltimore Eye Survey. AB - BACKGROUND: The association of diabetes with primary-open angle glaucoma (POAG) has been controversial and often confused by varying definitions of both diabetes and POAG. The purpose of this study is to evaluate this association in a population-based sample of subjects from the Baltimore Eye Survey. METHODS: A stratified sample of residents in 16 cluster areas of east Baltimore was recruited for a detailed ophthalmologic screening examination. A total of 5308 black subjects and white subjects participated. Of these participants, 161 received a diagnosis of POAG. During a detailed interview with each subject, diabetes was defined based on a reported history of diabetes. Persons with diabetes were classified as "insulin-users" and "noninsulin-users" based on their current method of treatment. RESULTS: Diabetes was highly prevalent in this population, with 10.6% of white subjects and 17.2% of black subjects reporting a positive history. Diabetes was associated with higher intraocular pressure, but differences were not large (means, 17.4, 18.0, and 17.8 mmHg) among subjects without diabetes, those with diabetes who were not using insulin, and those with diabetes who were using insulin, respectively. Diabetes was not associated with POAG (age-race-adjusted odds ratio, 1.03; 95% confidence interval, 0.85, 1.25). This was true for both types of diabetes. Persons whose POAG had been diagnosed before the examination showed a positive association with diabetes (odds ratio, 1.7, 95% confidence interval, 1.03, 2.86), indicating that selection bias could explain the positive results of previous clinic-based investigations. CONCLUSION: There is no evidence from this population-based investigation that supports an association between diabetes and POAG. PMID- 7831042 TI - Primary open-angle glaucoma, intraocular pressure, and systemic blood pressure in the general elderly population. The Rotterdam Study. AB - PURPOSE: The purpose of this study is to investigate the association of primary open-angle glaucoma (POAG), intraocular pressure (IOP), and systemic blood pressure. METHODS: Subjects participating in the Rotterdam Study (n = 4187, 55 years of age and older) were examined according to standard protocols, including a medical history interview, IOP measurement, perimetry, funduscopy, and blood pressure measurement. Primary open-angle glaucoma was defined by the presence of a glaucomatous visual field defect. Additionally, the distinction was made between high-tension glaucoma, defined as POAG with an IOP of more than 21 mmHg, and normal-tension glaucoma, defined as POAG with an IOP of 21 mmHg or less. The relation between blood pressure and hypertension with IOP, POAG, high-tension glaucoma, and normal-tension glaucoma was studied by means of regression analysis. RESULTS: A systolic blood pressure or diastolic blood pressure that was 10 mmHg higher was associated with an IOP that was, on average, 0.23 mmHg (95% confidence interval [CI], 0.19-0.27) or 0.24 mmHg (95% CI, 0.16-0.32) higher, respectively. The presence of hypertension was associated with a higher mean IOP of 0.66 mmHg (95% CI, 0.39-0.93). A higher systolic blood pressure of 10 mmHg was associated with an odds ratio of 1.22 (95% CI, 1.03-1.46) for high-tension glaucoma and 0.90 (95% CI, 0.72-1.12) for normal-tension glaucoma. Hypertension was associated with an odds ratio of 2.33 (95% CI, 0.99-5.47) for high-tension glaucoma and 0.77 (95% CI, 0.22-2.72) for normal-tension glaucoma. CONCLUSION: Systemic blood pressure and hypertension are associated with IOP and high-tension glaucoma. No association was found between blood pressure or hypertension and normal-tension glaucoma. PMID- 7831043 TI - Ambulatory blood pressure monitoring in glaucoma. The nocturnal dip. AB - PURPOSE: Hypoperfusion of the optic nerve head may be among the significant factors relating to glaucoma damage. The physiologic nocturnal blood pressure "dip" may be exaggerated in some patients and may compromise local vascular supply. METHODS: Twenty-four-hour ambulatory blood pressure recording was performed on 38 patients with normal-tension glaucoma and on 46 with primary open angle glaucoma. Eleven control subjects of similar age also were tested. The means of the systolic and diastolic blood pressures, mean arterial pressure, and pulse pressure for 24 hours, taken during the daytime (6 AM-10 PM) and night (10 PM-6 AM) periods were determined. The percentage nocturnal dip for each patient was calculated. A masked assessment of Humphrey visual fields for progression or stability was done on those 52 patients who had numerous fields plotted for more than 2 years. RESULTS: The results of the control subjects confirmed that the authors' technique produces values similar to cardiologic studies from large healthy populations. The mean results from all the authors' patients with glaucoma were within the ranges reported for control subjects in the literature. The blood pressure parameters of the normal-tension glaucoma and primary open angle glaucoma groups did not differ significantly. All nocturnal pressure parameters (except pulse pressure) were lower in the 37 patients with progressive field defects compared with the 15 patients whose pressure parameters were stable, whereas the systolic, diastolic, and mean arterial pressure dips were significantly larger (systolic dip, P = 0.001). CONCLUSION: The nocturnal reduction in blood pressure may be an additional risk factor in patients with glaucoma. PMID- 7831044 TI - The Wisconsin Epidemiologic Study of Diabetic Retinopathy. XV. The long-term incidence of macular edema. AB - BACKGROUND: As part of a population-based study of diabetes mellitus, the incidence of macular edema over a 10-year period and its relation to various risk factors are examined. METHODS: There were 891 younger-onset people with a diagnosis of having had diabetes before 30 years of age who were taking insulin at baseline examination and 987 older-onset people with a diagnosis of having had diabetes at 30 years of age or older who participated in baseline and 4-year examinations. Of these, 765 younger-onset and 533 older-onset people also participated in a 10-year examination. The presence of macular edema at baseline and follow-up examinations was determined from gradings of stereoscopic fundus photographs. RESULTS: The incidence of macular edema over the 10-year period was 20.1% in the younger-onset group, 25.4% in the older-onset group taking insulin, and 13.9% in the older-onset group not taking insulin. The incidence of macular edema over the 10-year period was associated with higher levels of glycosylated hemoglobin and more severe retinopathy in both younger- and older-onset groups, and with being female and increased diastolic blood pressure in the older-onset group. CONCLUSIONS: These data suggest a relatively high incidence of macular edema. The authors' data also suggest that a reduction in hyperglycemia may result in a beneficial decrease in the incidence of macular edema. PMID- 7831045 TI - 5-Fluorouracil and mitomycin C in pseudophakic patients. AB - PURPOSE: Previous studies have shown that 5-fluorouracil (5-FU) and mitomycin C enhance the success rate of filtration surgery in aphakic eyes. However, eyes with posterior chamber implants have not been specifically studied. This study was performed to compare the safety and efficacy of 5-FU with that of mitomycin C in eyes that have posterior chamber implants and undergo filtration surgery for uncontrolled glaucoma. METHODS: Eighty eyes of 74 patients who had previous cataract surgery with posterior chamber implants and who subsequently required trabeculectomy for uncontrolled open-angle glaucoma were randomized to receive either subconjunctival postoperative 5-FU or intraoperative mitomycin C. RESULTS: Twelve months after surgery, intraocular pressures (IOPs) averaged 12.8 +/- 5.5 mmHg (mean +/- standard deviation) in the mitomycin C group and 14.8 +/- 3.8 mmHg in the 5-FU group (P = 0.001). Mitomycin C-treated eyes received an average of 0.6 medications for IOP control, and 5-FU-treated eyes received an average of 1.05 medications (P = 0.03). There was no significant difference in complications between the two groups. CONCLUSION: Mitomycin C appears to be a viable alternative to 5-FU in patients with posterior chamber implants with uncontrolled glaucoma who require filtration surgery. PMID- 7831046 TI - One-year follow-up results of combined mitomycin C trabeculectomy and extracapsular cataract extraction. AB - PURPOSE: When patients with glaucoma require cataract surgery, combined procedures offer important advantages over cataract surgery alone. Because mitomycin C has improved the success rate of a trabeculectomy in patients at high risk for filtration failure, the authors investigated whether it also would increase the survival rate of functioning filters in combined procedures. METHODS: Patients with both cataract and glaucoma underwent combined mitomycin C trabeculectomy, extracapsular cataract extraction, and intraocular lens implantation. Mitomycin C (0.5 mg/ml) was applied topically to the trabeculectomy site for 5 minutes before the cataract extraction. Intraocular pressure (IOP), visual acuity, and astigmatism were measured preoperatively and postoperatively. One-year results are available for 74 patients. RESULTS: At 1 year, 54 (73%) of 74 patients had IOPs of 15 mmHg or less without glaucoma medications. Visual acuity was 20/40 or better in 44 (60%) of 74 patients. Ten (15%) patients had a shift of more than 2 diopters of astigmatism against the rule compared with preoperative values. No notable corneal epithelial toxicity was present. Postoperative symptomatic hypotony with the wound construction occurred in 3 (4%) of 74 patients, with 1 patient requiring surgical revision. Other potential complications of mitomycin C include endothelial toxicity (1 patient had decreased vision due to endothelial folds) and wound stability (1 patient had wound rupture after direct ocular trauma). CONCLUSION: The 1-year survival rate of a functioning trabeculectomy using mitomycin C in combined glaucoma and cataract surgery is encouraging. The longer-term benefits and possible adverse effects of mitomycin C in combined procedures are unknown and continue to be investigated. PMID- 7831047 TI - The effect of reducing the exposure time of mitomycin C in glaucoma filtering surgery. AB - BACKGROUND: The use of adjunctive intraoperative mitomycin C has considerably improved the success rate of glaucoma filtering surgery. However, the ideal concentration and exposure time of mitomycin C is unknown. The purpose of this study is to determine whether a satisfactory surgical outcome can be achieved with a lower incidence of adverse side effects by using a shorter exposure time of mitomycin C than has been recommended previously. METHODS: Twenty-five eyes of 25 consecutive patients who were considered to be at high risk for surgical failure because of their age (< 55 years), previous failure of trabeculectomy, previous cataract surgery, or traumatic glaucoma received a single intraoperative application of mitomycin C (0.2 mg/ml for 2 minutes). They were case-matched with a group of 48 consecutive patients who received a single intraoperative application of mitomycin C (0.2 mg/ml for 5 minutes) by using age, race, type of refractory glaucoma, and preoperative intraocular pressure (IOP) as variables. RESULTS: Eighteen months after surgery, 22 (88%) patients in the 2-minute group and 21 (84%) patients in the 5-minute group had an IOP less than 21 mmHg with or without treatment. No significant differences were found in the complication rate: in 2 (8%) of 25 eyes of the 2-minute group, chronic hypotony developed compared with 3 (12%) of 25 eyes in the 5-minute group. Hypotony-related maculopathy developed in one eye in the 5-minute group. A cystic bleb was found in 15 (60%) eyes in the 2-minute group compared with 19 (76%) eyes in the 5 minute group, although this difference was not statistically significant. Two (8%) eyes in the 2-minute group and one eye (4%) in the 5-minute group had a bleb related infection. In one (4%) patient in each group, late severe endophthalmitis developed. CONCLUSION: These results suggest that a 2-minute intraoperative application of 0.2 mg/ml mitomycin C is as effective as a 5-minute exposure, but the complication rate remains unaltered. PMID- 7831048 TI - Adjunctive mitomycin C in Molteno implant surgery. AB - PURPOSE: The authors assessed the efficacy of adjunctive intraoperative mitomycin C to produce lower intraocular pressures (IOPs) in patients with complicated glaucoma who underwent double-plate Molteno implantation. METHODS: A pilot series of 21 consecutive patients who underwent double-plate Molteno implantation with adjunctive intraoperative mitomycin C (0.5 mg/ml) for 5 minutes was compared with a historical control group who received Molteno implants without mitomycin C (n = 18). With failure defined as an IOP greater than 21 or less than 6 mmHg at two observations 1 month apart, the addition of medication, re-operation for glaucoma, or tube removal, a life-table analysis of IOP was performed on patients with at least 3 months' follow-up. RESULTS: Success in the mitomycin C group was higher (68% at 1 year) than the control group (17% at 1 year; P = 0.006). Loss of more than one line of vision (33%) and re-operation for complications (including flat anterior chamber, choroidal detachment, and tube blockage) (38%) were slightly but not significantly more frequent in the mitomycin C group than in the control group. CONCLUSION: This study suggests that intraoperative mitomycin C in conjunction with Molteno implant may offer a better chance of achieving target IOPs in the low teens in patients with complicated glaucoma than Molteno implantation alone. PMID- 7831049 TI - Iris retraction syndrome after intraocular surgery. AB - BACKGROUND: The authors report the postoperative development of iris retraction syndrome in two individuals. This is a rare syndrome that can present with pupillary block after an unrepaired rhegmatogenous retinal detachment. PATIENTS: The authors report two patients who had the iris retraction syndrome shortly after intraocular surgery. One patient had pupillary block that developed 6 months after cataract extraction and posterior chamber intraocular lens implantation. A second patient had uveitis, hypotony, and pupillary seclusion 4 weeks after pars plana vitrectomy. RESULTS: Both patients were treated successfully with a scleral buckling procedure and peripheral iridectomy. CONCLUSION: Postoperative uveitis that occurs with iris retraction and pupillary seclusion should alert the physician of an occult retinal detachment and warrant a thorough dilated funduscopic examination. Features unique to this report include the development of iris retraction syndrome in the presence of a pseudophakos, the rapidity of onset of this disorder after retinal detachment, and its masquerade as a persistent postoperative uveitis. PMID- 7831050 TI - [Bone transplantation in diaphyseal defects of the long bones]. AB - The treatment of large diaphyseal defects has remained in the domain of autologous bone transplantation, but has been substantially complemented by the Ilazarow technique. Bone formation following transplantation or segmental transport is controlled by three interacting mechanisms involving osteoregeneration, osteovascularization and osteostabilization. All three components are equally important in the healing process of large cortical defects. Osteoregeneration is inseparably linked to an intact bone matrix. Therefore, entirely inorganic bone substitutes are not suitable for difficult conditions such as is the case diaphyseal defects. PMID- 7831052 TI - [Plastic surgery in soft tissue reconstruction in large extremity defects]. AB - Soft-tissue defects in the extremities vary greatly, depending on the trauma mechanism, localization and a number of factors related to the patient's physical condition. We offer an overview of the plastic surgery methods in reconstruction of different soft-tissue defects in the extremities, beginning with the diagnostic, clinical and radiological measures that make classification of soft tissue defects possible, and then giving a concentrated view of the appropriate reconstruction methods. Collaboration between traumatology and plastic surgery seems to be especially important in lesions in the extremities. PMID- 7831051 TI - [Stabilization procedures in large soft-tissue and bone defects]. AB - When stabilizing fractures with large soft tissue and bone defects, the primary concern is to avoid additional vascularization damage. Therefore, external fixation is still the standard method. In metaphysical fractures, joint transfixation should be avoided if possible. Concerning closed comminuted fractures of femoral and tibial shaft fractures, interlocking nailing shows the lowest complication rate. The introduction of unreamed nailing of open fractures shows the same low infection rate as external fixation, so it can be considered an alternative method. Early plate fixation is applied for fractures of the upper extremities as well as the proximal and distal femur, if secure covering with vital tissue can be provided. As this is not guaranteed in the case of the tibial shaft, plate fixation remains the absolute last resort. Concerning distal and proximal fractures of the tibial pylon and tibia head, plate fixation is very often applied for definitive stabilization. However, the secondary application represents a considerably lower infection and fracture-healing risk. PMID- 7831053 TI - [Possibilities in the reconstruction of bone defects]. AB - The importance of the functional unit "bone-soft-tissue" for the treatment of bone defects is discussed. A division is made between non-vascular and vascular bone transport. The individual methods are explained and their clinical significance is illustrated partly using case material. In general, the best way to fill small defects in vital soft tissue is to use cancellous autografts. For bridging longer bone defects callus distraction is the method of first choice, but in individual cases vascularized bone transfer can be taken from the iliac crest or the fibula. Homo- or heterografts should only be used in cases where no autologic bone material is available or when there is not enough. PMID- 7831054 TI - [Treatment in septic and aseptic bone defects of the spine]. AB - Today it is possible to cure septic or non-septic defects of the spine with the help of diverse, specially designed implants for spinal surgery. The replacement of bone defects is realized by autologous bone grafts from the iliac crest, ribs or fibula pieces. Tumorous defects are preferably filled with bone cement and plates. A prerequisite for such operations is exact knowledge and operative experience with suitable approaches to the different levels of the spine. PMID- 7831055 TI - [Stabilizing procedures in tumor-induced bone defects of the pelvis and extremities]. AB - With malignant tumors of the skeleton the same therapeutic limb-saving guidelines must apply for the proximal sections of the locomotor system--the shoulder and pelvic girdles--as for the limbs themselves, especially since amputation here can hardly be surpassed by other resectional interventions with respect to operative risk, disfigurement and functional loss. The possibilities of surgical therapy for tumorous invasion of the pelvic girdle and the extremities are considered in some detail. PMID- 7831056 TI - [Bone defects as complication following total hip endoprosthesis implant]. AB - The authors present a relatively short followup study of 129 patients who were treated with cementless revision for loosened previous arthroplasties. Elderly patients with a first revision and good bone stock condition were excluded as were septic failures. All patients were treated with cementless, hollow-designed implants. Following previous THA and, also repeated revisions--nearly all of them using a cemented technique--many of the patients developed mostly acetabular, but also femoral loss of bone stock of various quality. Many of these cases required extensive allogenic bone grafting; some of the cases with severe loss of bone stock in young patients necessitated two-stage surgery. Despite this high rate of allografts, no infection occurred. Five patients were revised again for loosening or for femoral fracture; two patients showed sinking of the femoral component and clinical deterioration. The possibilities and advantages of restoration of the implant bed in destructive, aseptic loosening with demanding bone graft and cementless techniques are encouraged by the early results of the patients remobilization and radiologically recognizable revitalization of bone stock. Long term follow-up will be necessary to evaluate allograft incorporation exactly. PMID- 7831057 TI - [Treatment concept in infected bone and soft-tissue defects]. AB - The first priority when treating infected bone and soft-tissue defects is the maintenance or reconstruction of vitality, vascularity and stability. This means that when signs of infection are apparent, this is an immediate indication for operative revision with protective preparations on the tissue and radical debridement. Treatment of the soft-tissue damage is carried out with local or microsurgically connected muscle flaps. As for stability, in early infection the retention of well-bonded implants is often possible. If not, it is often necessary to change over to external fixation. Reconstruction of bone damage is carried out after the infection recedes, and complete healing is finally achieved by further treatment changes to conservative means or further stabilizing treatment. PMID- 7831058 TI - Mitochondrial abnormalities in nigral neurons of the marmoset and Macaca fascicularis treated with MPTP. AB - In a previous study we observed the processes determining the cellular death in nigral neurons of Macaca fascicularis and common Marmoset treated with MPTP. The purpose of this study is to consider, in substantia nigra neurons of the same animals, mitochondrial abnormalities caused by neurotoxin. Three Macaca fascicularis and 5 common Marmosets, respectively treated with 3 and 4 mg/kg of MPTP dissolved in saline + 10% ethanol, were suppressed by means of an i.v. injection phenobarbital. The substantia nigra, isolated from the mesencephalon, has been examined under Electron Microscope. Different mitochondrial abnormalities have been observed in nigral neurons: crystal abnormalities occur more frequently than other alterations. They are correlated with various degrees of mitochondrial enlargement. Dissolution of the matrix induces formation of spherical highly electron-dense inclusions of various volume and in different number; they are probably lipoprotein. Laminar bodies and myelin-like figures are determined by alterations of the external membrane. Particular roundish organules, placed near normal mitochondria, are limited by fragments of membrane with a granular material, occasionally flowing in the cytoplasm. The biochemical hypothesis concerning the genesis of the observed abnormalities is discussed in the present study. PMID- 7831059 TI - A clinical study on the postoperative prognosis of 168 cases of surgical hyperbilirubinemia. AB - It's universally acknowledged that the mortality rate of postoperative patients with obstructive jaundice is higher than that of the non-icteric. Opinions, however, differ as to whether the mortality rate goes up with the worsening of jaundice. Some even regard hyperbilirubinemia as a contraindication in operation. The present article through a clinical research of 168 cases suggested that postoperative mortality registered no increase because of bilirubin level in plasma and the degree of severity of bilirubinemia was not a major factor affecting the postoperative prognosis. The 4 preoperative complications: hypoproteinemia, hepatocirrhosis, portal hypertension and acute cholangitis were responsible for postoperative prognosis, the conclusion is hyperbilirubinemia is not a contraindication in operation. A great portion of the patients should be given active operation to intercept persistent injury on liver and prevent the occurrence of acute cholangitis. To reduce the postoperative mortality, the treatment to be adopted is not to arrange biliary drainage before operation but to improve the patients general conditions by eliminating the complications mentioned above. PMID- 7831060 TI - The role of surgery in stage IIIa non-small cell lung cancer. Surgery in IIIa NSCLC. AB - The authors have reviewed the records of 50 consecutive patients resected for stage IIIa non-small cell lung cancer and included in a long-term follow-up study at the 1st Department of Surgery, University of Rome "La Sapienza". Overall survival was 60-20-16.6-16.6% at 1-5-7-10 years with an incidence of recurrence and/or metastasis respectively of 56-80-85.6-85.6%. These percentages were not influenced by the histological type. Tumours with the best prognosis were those classified as T1N2 and T3N0 (7-year survival rate: 33.3 and 29.4% respectively). Tumours with the worst prognosis were those classified as T3N2 with the highest incidence of relapse after 6 months (T3N0 vs T3N2 0.01 < p < 0.025) and no survival after 3 years (T3N0 vs T3N2 0.005 < p < 0.01). Regarding T3 tumours, infiltration of mediastinal pleura or pericardium was a negative prognostic factor implying no survival at 30 months. Involvement of chest wall or parietal pleura showed better survival overall although not statistically significant (10 year survival rate: 37.4 vs 24% respectively). PMID- 7831061 TI - Cronobiologic analysis of abortions in two related populations of teenager girls during two decades. AB - STUDY OBJECTIVE: To identify and compare the time dynamics of artificial abortions in two (Czech and Slovak) ethnically, historically and socially closely related populations. DESIGN: Data have been taken separately for 12-15 and 16-18 year age girls from official exhaustive statistical sources and processed by advanced procedures of time series analysis. SETTING: Czech and Slovak Republics. PARTICIPANTS: All girls of the given age. INTERVENTIONS: Legislative liberalization of abortions 1987. MAIN OUTCOME MEASURES: Estimated starting values of relative numbers of abortions by 1971, increasing linear trends, period lengths of fluctuation, coefficients of determination and those of cross correlation. Level of significance alpha = 0.05. RESULTS: The Czech figures are significantly higher than the Slovak. Thus, estimated abortion percentage (from pregnancies) for 1971 was for younger Czech girls 53%, and for those from Slovakia 29%. All estimated trends were increasing significantly in all cases for the Czech population (by 1.5% per year in the younger group) and in one case for Slovakia. The estimated period lengths were usually 10-12 years. Czech and Slovak data display significant positive mutual cross-correlation, the delay being 1-3 years in Slovak girls. Surprisingly, all data significantly cross-correlate with the geomagnetic index value Ap, acting as lead-lag, with 3-6-year delay for abortions. CONCLUSIONS: Despite living in the same federal state--the former Czechoslovak Republic, both Czech and Slovak populations do differ in starting values and general trends of abortions in teenagers. This can be due to historical, racial and religious peculiarities as well as a more advanced process of industrialization in the western part--the Czech Republic. The latter hypothesis is corroborated by strong dynamism of changes and by the time delay in Slovakia. The periodicity exhibits a frequency resembling that known for solar motion round barycenter of solar system, for sunspots and geomagnetism. PMID- 7831062 TI - Possible role of beta-blockers in the prevention of sudden cardiac death (SCD) in patients with coronary heart disease (CHD). AB - The prevention of sudden cardiac death remains one of the greatest challenges in the field of cardiovascular medicine today. Despite the difficulty in predicting which individuals are going to die suddenly, much knowledge has accumulated in recent years in regard to independent risk factors for SCD and moreover, different pharmacological interventions have been evaluated for the prevention of sudden coronary death. Currently, the beta-blockers are the only pharmacological agents that have been shown to reduce sudden cardiac deaths in clinical trials. The reduction in sudden death may involve several mechanisms that include antiatherosclerotic effects, antithrombotic effects, cardiac anti-ischemic effects and antifibrillatory effects. PMID- 7831063 TI - The importance of vitamins in relation to the presence of heavy metals in food. AB - Heavy metals are among the most widespread potential chemical contaminants in the environment and may be transferred to man through diet. Cadmium, mercury and lead are those which are most dangerous to human health. The nutritional status of exposed subjects is of particular interest in the study of the biochemical and morphological changes linked to heavy metal intoxication. Some vitamins play an efficacious protective role through direct or indirect mechanisms which interfere with the intestinal absorption of heavy metals by increasing urinary excretion or creating a synergic effect on the chelating element. It is important to underline the importance of an adequate vitamin intake in the prevention and treatment of cadmium, mercury and lead intoxications. PMID- 7831064 TI - Treatment of intermittent claudication with defibrotide or mesoglycan. A double blind study. AB - Forty-four patients with intermittent claudication were included and randomised in two groups respectively treated with oral defibrotide (one 400 mg tablet bid) or oral mesoglycan (one 24 mg tablet bid) for 6 months. Twenty-two subjects completed the study in the defibrotide group and 20 in the mesoglycan group. The two treatments were well tolerated and the two drop outs in the mesoglycan group were not due to medical causes. In the defibrotide group, after 1 month the pain free walking distance (PFWD) increased from 473 +/- 96 m to 586 +/- 84 (p < 0.05). The walking distance (WD) increased from 767 +/- 125 m to 898 +/- 109 (p < 0.05). After 6 months the posterior tibial pressure (PTP) at the end of the treadmill exercise test also increased from 40 +/- 19 to 63 +/- 12 (p < 0.05). No variations in PFWD, WD and PTP were observed in the mesoglycan group. The improvement in walking was possibly due to the action of defibrotide increasing local fibrinolysis and decreasing the distal vasospasm present in subjects with peripheral vascular disease and intermittent claudication. PMID- 7831065 TI - Acute effects of TTFCA on capillary filtration in severe venous hypertension. AB - The acute variation in capillary filtration [CF] was evaluated with strain-gauge plethysmography in patients with severe venous hypertension due to deep venous disease. Two groups were selected and randomly treated with a single oral dose or TTFCA (60 mg or 120 mg). CF was assessed again after 5 and 10 hours. Eleven patients were randomised in the 60 mg group and 9 in the 120 mg group. Also 5 normal subjects were studied with the same procedure to act as controls. No variations in CF were observed in normal limbs. In both groups of patients there was a significant decrease in CF after 5 and 10 hours. The percent decrease in CF after 10 hours was higher in the high dose group. These results indicate that TTFCA is acutely effective in reducing CF and oedema in subjects with venous hypertensive microangiopathy. The effects of TTFCA on CF appear to be dose related. PMID- 7831066 TI - Osteonecrosis of the femoral head associated with pregnancy. Report of two cases. AB - Osteonecrosis of the femoral head developed in two patients, that had taken oral contraceptives for four and eight years respectively, during pregnancy. There were non demonstrable predisposing factors. The symptoms were first noted during the last trimester, and after the delivery improved significantly. Results of examinations, radiography and scanning were consistent with diagnosis of avascular osteonecrosis of the femoral head. The possibility that the long term use of oral contraceptives, might have played a role in the development of femoral head necrosis is stressed by the authors. PMID- 7831067 TI - Lingual thyroid and hypothyroidism. Report of a case in a middle aged woman. AB - There are approximately 400 reported cases of lingual thyroid (LT) with a clear cut prevalence in paediatric age. These glands are probably quantitatively deficient and function at marginal levels. Thyro-stimulating hormone (TSH) causes hypertrophy producing local symptoms and in younger patients may induce dangerous obstruction. The presumptive diagnosis is usually made by indirect laryngoscopy and thyroscintigraphy. The authors describe a case of LT in a middle aged patient in whom the anomaly remained undiscovered, being without local symptoms, and permitting a normal life. The discovery was made possible by the development in the last four years of a progressive, frank hypothyroidism, probably induced by silent thyroiditis into the ectopic gland. PMID- 7831068 TI - Physiological costs of reciprocal gait in FES assisted walking. PMID- 7831069 TI - Pathology of spinal cord injuries due to fracture and fracture-dislocations of the cervical spine. AB - Autopsy was performed on 31 patients with spinal cord injuries at Chugoku Rosai Hospital between 1957 and 1987. The pathology of intervertebral disc injuries and hyperextension injuries of the cervical spine have been reported previously. This paper describes and discusses the pathological features of spinal cord injuries of 11 patients with fracture and fracture-dislocations of the cervical spine. Sex, age, cause of injuries, bone injuries seen on roentgenograms, level and grade of neurological deficits, survival time, and findings of postmortem studies are presented in the table. Roentgenograms and pathological features of five cases are illustrated in color. PMID- 7831070 TI - Ejaculation induced by penile vibratory stimulation in men with spinal cord injuries. The importance of the vibratory amplitude. AB - A total of 66 men with a spinal cord injury (SCI) and ejaculatory dysfunction were included in two different but comparable study populations I (n = 25) and II (n = 41). The level of lesion ranged from C2 to L1 (44 complete). Penile vibratory stimulation (PVS) to induce ejaculation was performed with two different types of vibrators in population I and considerably different ejaculation rates (antegrade+retrograde) occurred depending on the vibrator used. Our experience suggested discrepancies between the manufacturers' specifications and the actual vibrator outputs concerning frequencies and peak-to-peak amplitudes. Retrospectively performed determinations revealed that the manufacturers' specifications regarding the frequencies were accurate whereas the peak-to-peak amplitudes were inaccurate. With a frequency of 100 Hz and determined peak-to-peak amplitudes of 1 mm and 2.5 mm, ejaculation rates of 32% and 96%, respectively, were obtained in population I. This indicates that an adequate peak-to-peak amplitude is essential to exceed an 'ejaculatory threshold' in the majority of SCI men. Furthermore, an ejaculation rate of 83% obtained in a subsequent prospective study of 41 SCI men (population II) verified that a frequency of 100 Hz and a peak-to-peak amplitude of 2.5 mm seems to approach the ideal vibrator output. The ejaculation responses obtained by JS (first author) were reproduced when the PVS was performed by the patient or his partner, indicating that the vibrator output is more important than PVS experience. No major adverse reactions due to autonomic dysreflexia were observed. The lowest level of SCI where antegrade or retrograde ejaculation occurred was T9 and L1, respectively. No absolute predictors for ejaculatory success or failure in relation to patient age, years since lesion, completeness of SCI, urinary bladder management method, hip flexion and bulbocavernous reflexes were observed. Therefore, most SCI men with ejaculatory dysfunction should be considered candidates for PVS. PMID- 7831071 TI - Use of intracavernous injection of prostaglandin E1 for neuropathic erectile dysfunction. AB - The administration and suitability of intracavernous PGE-1 in men with neuropathic erectile dysfunction is reported herein. Twenty-seven men with neuropathic erectile dysfunction (SCI, 14; multiple sclerosis, 7; discogenic disease, 6) were evaluated and treated with intracavernous PGE-1. An average of 3.2 office sessions were required to learn adequate self-injection technique and determine optimal dosage requirement. Initial dosage for SCI men was 2.5 micrograms and increased in 2.5 micrograms increments to a mean maintenance dose of 6.2 micrograms. Quarterly monitoring up to 28 months demonstrated satisfactory erectile rigidity and duration of erection in all patients electing to pursue home administration of PGE-1. During this interval, over 40% of patients dropped out of the treatment program. No priapism or changes in serum chemistries, CBC, or platelets were observed during this period. Corporal fibrosis although not palpable, was detected subclinically by penile ultrasound in two men. This study confirms the safety and efficacy of self-administered intracavernous PGE-1 for neuropathic impotence. However, because of a significant rate of voluntary cessation, patients should be counseled regarding the full range of therapeutic alternatives to intracavernous therapy. PMID- 7831072 TI - Surveillance of spinal cord injuries in Utah, USA. AB - From 1989 through 1991, we conducted surveillance of spinal cord injury (SCI) among residents of Utah. We found an annual incidence rate of 4.3 per 100,000, with the highest rates occurring among males 15-24 years of age. Motor vehicles were the leading cause of injury, followed by falls, and sports and recreation. We also examined the accuracy and completeness of reporting in this surveillance system. We found the predictive value positive of SCI diagnoses reported in hospital discharge data to be only 61%. When we considered only patients who received acute hospital care in-state, we found that the sensitivity of hospital discharge data 89%. These findings indicate serious problems in the reporting of spinal cord injury diagnoses in hospital discharge data and the need to verify case reports based on these data. There is also a need to study this problem in other jurisdictions to determine if overreporting is widespread. PMID- 7831073 TI - Management of pharmacologically induced prolonged penile erection with oral terbutaline in traumatic paraplegics. AB - Intracavernosal administration of papaverine or prostaglandin E1 for erectile impotence in paraplegics is being practised widely. One of the complications of this therapeutic regimen is prolonged erection which is at present being treated by aspiration of corporeal blood and intracavernosal administration of alpha adrenergic agonist such as phenylephrine. We report successful management of pharmacologically-induced prolonged erection in three traumatic paraplegics with oral terbutaline therapy. The indications for oral terbutaline therapy were (1) absence of significant coronary artery disease and (2) full erection persisting for more than 2 1/2 h, but less than 4 h duration. The initial dose of terbutaline was 5 mg and the same dose was repeated after 15 min as full erection persisted. Within the next 15 min, penile detumescence was achieved in two paraplegics with papaverine-induced prolonged erection. However, full erection still persisted 15 min after the second dose of terbutaline in the third patient who had received intracavernosal administration of 3.25 micrograms of prostaglandin E1. Therefore, he was given the third and final dose of 5 mg of terbutaline under cardiac monitoring. Penile detumescence was achieved within the next 15 min. It was ensured before administration of the third dose of terbutaline that (1) his blood pressure was within the normal range (for his paralysed status), (2) the heart rate was less than 100 per min and (3) there was no cardiac arrhythmia. Occasional premature ventricular contraction was observed only in the patient who received the third dose of terbutaline, but it was transient, self-limiting and did not warrant any treatment.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7831074 TI - A longitudinal investigation into anxiety and depression in the first 2 years following a spinal cord injury. AB - This study is a 1 year extension of a controlled 1 year follow up study of spinal cord injured persons. The study assessed the extent of spinal cord injury (SCI) persons' depression and anxiety in comparison to an able bodied control group matched for age, sex, education and as far as possible, occupation. Psychological adjustment to SCI was assessed in terms of scores on the Trait Anxiety Inventory and the Beck Depression Inventory. Results obtained at the 2 year follow up were not significantly changed from those obtained over the first year. There was no significant improvement in anxiety and depression scores in the SCI group 2 years post injury. Examination of the SCI scores suggest that psychological morbidity was confined to a group of approximately 30% of persons, whilst the remaining persons were not severely anxious or depressed. Traditional stage models of adjustment to SCI which suggest that the passage of time is associated with better adjustment were not supported by the present data. PMID- 7831075 TI - Physiologic costs of reciprocal gait in FES assisted walking. AB - This study reports the velocity and physiologic cost index (PCI) of ambulation using a functional electrical stimulation (FES) system for ambulation in paraplegic spinal cord injured subjects. Using established techniques, average velocity and heart rate (HR) were measured on five subjects trained with the Parastep system. PCI was reported for the four subjects who achieved a steady state during ambulation with the Parastep system. It was found that walking performance varied greatly between subjects, and was correlated to frequency of use of the system. Velocity of walking with the Parastep system ranged from 4.6 to 24.3 m/min. In the four subjects where steady state was achieved, PCI ranged from 2.30 to 6.26 beats/m. The average walking speed and PCI were similar to the values reported using alternative mechanical or hybrid systems available to the spinal cord injured for restoration of upright locomotion. PMID- 7831076 TI - Tracheostomy ventilation versus diaphragmatic pacemaker ventilation in high spinal cord injury. AB - We have made a retrospective comparative study of patients with spinal cord injury, nine with a diaphragmatic pacemaker and 13 with mechanical ventilation. Clinical outcome, cost and subjective satisfaction with both modalities have been evaluated. The functional status was the same with both types of treatment. Proper management of an electric wheelchair and optimal phonation were attained, respectively, in 100% and 89% of pacers and in 77% and 77% of mechanically ventilated. The rate of hospital discharge and satisfaction with the treatment were significantly better for pacers. The time devoted to ventilatory assistance and cost were also more favourable in this group. PMID- 7831078 TI - Car driving for the severely physically disabled: the American experience. PMID- 7831077 TI - Severe exacerbation of post traumatic syringomyelia after lithotripsy. Case report. AB - A case of post traumatic thoracic syringomyelia is reported which presented with an acute and severe worsening of the spinal cord condition after extracorporeal shock wave lithotripsy was performed for ureteral stone. The worsening was probably caused by the shock waves reverberating the fluid within the intramedullary cavity producing further damage to the spinal cord. PMID- 7831079 TI - Nutritional aspects of the orthopaedic trauma patient. AB - The metabolic response to trauma is related to a variety of factors, including severity of injury, age, and previous state of health and nutrition (Cardona et al., 1994). This article addresses nutritional considerations of an orthopaedic trauma patient. A case study has been developed with common findings associated with malnutrition, including postoperative infection. Three concepts are discussed: (a) pretrauma nutritional status, (b) post-trauma metabolism, and (c) nutritional assessment parameters. A brief comment on nursing diagnoses related to nutrition concludes this article. PMID- 7831080 TI - Early identification of chronic posttraumatic stress disorder by nurse clinicians. AB - Posttraumatic Stress Disorder (PTSD), generally agreed to be a discrete and insidious psychopathologic entity, commonly develops in victims of extreme trauma. It is known that some trauma victims recover quickly and naturally in the acute phase of the disorder while others develop a debilitating and life threatening chronic phase. Early detection and treatment can enhance opportunities for recovery by preventing development of the chronic phase, but posttrauma identification of patients who may be vulnerable to the development of chronic PTSD is clinically difficult. However, there is evidence for the existence of predisposing factors that may predict susceptibility to chronic PTSD. Nurse clinicians may be in the best position to identify potential victims of chronic PTSD and make referrals for appropriate psychiatric evaluation and treatment. PMID- 7831081 TI - Behavioral and cognitive sequelae of head trauma. AB - Traumatic brain injury accounts for many deaths each year. Those who survive stand a high chance of sustaining permanent cognitive and behavioral sequelae that will impact not only their own lives, but those of family and friends. The most frequently observed cognitive manifestations include memory loss, decreased rates of information processing, and cognitive rigidity. The most common behavioral manifestations are lack of impulse control, increased agitation, and mood lability. While these deficits are often permanent, cognitive retraining and behavioral management can modulate responses. The focus of care is on reorganization of existing abilities rather than modification of abnormal responses. PMID- 7831082 TI - Traction basics: Part III. Types of traction. AB - Traction is a treatment modality used for the reduction or immobilization of fractures or dislocations. It is used to maintain alignment, decrease muscle spasms, relieve pain, correct, lessen or prevent deformities, expand joint spaces prior to surgery, promote rest to diseased or injured body parts and to promote exercise. Nurses need a working knowledge of the various types of traction along with its rationale, correct setup, and maintenance. They must become familiar with potential complications and use nursing diagnoses to work with patients to strive to achieve expected patient outcomes. PMID- 7831083 TI - Clinical exemplars to recognize excellence in nursing practice. AB - Nursing is a dynamic, challenging, rewarding profession. It is important that we take opportunities to tell the world and each other about the richness of caring, which is the essence of our practice. Clinical exemplars are a way to capture this true nature of nursing. It is through sharing of clinical exemplars that we celebrate our own practice and share our uniqueness with others. This article defines clinical exemplars, describes their importance to nursing practice, and discusses their benefit to identify skill acquisition and recognition in nursing. PMID- 7831084 TI - Posthospital convalescence in older women with hip fracture. AB - Women who had lived at home before hip fracture repair (N = 120, M age = 79.9) were interviewed before hospital discharge and at 2, 8, and 14 weeks postdischarge to determine (a) early recovery patterns in function and mood, (b) factors predictive of assistance needed in mobility and perceived mobility compared to prefracture status, (c) problems faced, and (d) advice to others. The mobility pattern was that of a relatively rapid gain until 8 weeks, with a smaller gain from 8 to 14 weeks. Affective mood distress was low except in those going to nursing homes. Somatic mood distress was high, decreasing only gradually. Factors predictive of needed assistance in mobility and of perceived mobility included both those without potential for nursing intervention (age, prefracture mobility, how fell, and type of surgical procedure), and those with the potential for intervention (affective distress, fatigue, and urinary problems). Persistent problems related to limitations in mobility, especially in dressing. Overwhelmingly, subjects advised the need for maintaining a good mental attitude. PMID- 7831085 TI - Injury prevention. PMID- 7831086 TI - Informed consent: the consent component. AB - Individuals who participate in treatment or research protocols should perceive that their decision is a free choice and that they are acting of their own accord. However, these persons may feel as if they are being pressured to participate in the protocol being described. The author discusses the two components of consent: voluntariness and authorization and offers suggestions to nurses to fulfill their moral responsibility to be patient advocates. PMID- 7831088 TI - Depuytren fracture, LeFort fracture. PMID- 7831087 TI - Injury prevention: a nursing responsibility. AB - Injury represents a major health care problem in the United States today. The rise in the number of violent crimes as well as unintentional injuries has touched Americans of all ages and in all socieconomic groups. Advances in prehospital care, acute care, and rehabilitation provided to trauma victims have helped to decrease the toll that trauma takes, but the most effective intervention is to prevent these deaths and injuries from ever occurring. Nurses are in key positions to educate the public on prevention practices, identify injury trends, influence the passage of prevention legislation, and help decrease the number of traumatic deaths and injuries occurring in our society. PMID- 7831089 TI - Relationships between Plasmodium falciparum infection and morbidity in a highly endemic area. AB - A total of 736 outpatients diagnosed as having malaria using clinical criteria at a health centre in a highly endemic area of Papua New Guinea were investigated parasitologically. Plasmodium falciparum-attributable fractions were determined using a logistic regression model to compare parasite densities in cases with those of healthy individuals in community surveys. Thirty-seven percent of presumptive cases were found to have raised P. falciparum parasitaemia. This corresponds to an average reporting rate for the population of 0.53 attributable episodes per annum. Whilst the maximum prevalence of parasitaemia in the community was in children aged 5-9 years, the maximum age-specific incidence of attributable cases at the outpatient clinic was 2 cases per annum in the 2- to 4 year-old age group. The procedure for estimating attributable fractions makes it possible to compare morbidity rates between age groups, and to examine how the relationship between morbidity risk and parasite density changes with age, without diagnosing individual episodes. The average tolerance of parasites in an age group was measured by considering the level of parasitaemia associated with a given risk of malaria-attributable morbidity. In contrast to anti-parasite immunity, tolerance of parasites declines with age since at parasite isodensity the probability of being symptomatic increases with age. PMID- 7831090 TI - Maternal transfer of antibodies induced by infection with Eimeria maxima partially protects chickens against challenge with Eimeria tenella. AB - Infection of breeding hens with Eimeria maxima induces production of Eimeria specific IgG antibodies which are transferred to hatchlings via the egg yolk and confer a high degree of maternal immunity against homologous challenge and partial immunity to infection with another important species, Eimeria tenella. As an example, in an experiment using hatchlings from eggs collected between days 28 and 39 after infection of the hens with 20,000 sporulated E. maxima oocysts, control chicks (challenged with 100 sporulated oocysts) excreted 6.8 +/- 1.2 million (mean +/- S.E., n = 10) or 5.8 +/- 1.2 million (n = 8) oocysts of E. maxima or E. tenella, respectively, compared to 0.9 +/- 0.4 million (n = 5) E. maxima oocysts or 2.2 +/- 0.4 million (n = 9) E. tenella oocysts excreted by hatchlings of infected hens. This represents an 87% reduction in oocyst excretion with regard to E. maxima and a 62% reduction in oocyst excretion with regard to E. tenella in the progeny of the infected hens. In another experiment, eggs were collected from days 28 to 37 and again from days 114 to 123 after infection of the hens with E. maxima and hatchling oocyst excretion rates were 82% and 62%, respectively, reduced for E. maxima and 43% and 41%, respectively, reduced for E. tenella in the progeny of hens infected with E. maxima compared to the progeny of uninfected hens. ELISA and Western blot analyses of maternally-derived IgG revealed a high degree of cross-reactivity to antigens of E. maxima and E. tenella.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7831091 TI - Attenuation of Schistosoma mansoni cercariae with a molluscicide derived from Millettia thonningii. AB - A chloroform extract of molluscicidal plant secondary compounds from the seeds of a West African legume Millettia thonningii was used to attenuate cercariae of Schistosoma mansoni prior to infection of NMRI female mice. Exposure of cercariae to 0.3, 0.6, 1.3, 2.5, 10 or 20 mg/l concentrations of extract for 30 min, immediately before standardized infection, was associated with a concentration dependent decline in worm establishment at 55 days post-infection. The mean numbers of adult worms established declined from about 17 worms/mouse with control cercariae and those exposed to 0.3 mg/l Millettia to 0.1 worms/mouse after 10 mg/l pre-treatment. Mice exposed to cercariae after 20 mg/l pre treatment had no adult worms at 55 days post-infection. The activities of cercariae 30 min after exposure to Millettia extract at concentrations up to 2.5 mg/l were similar to those of control larvae: none was immobile. Exposure to higher concentrations of Millettia progressively reduced swimming activity and increased the proportion of immobile cercariae. After pretreatment with 20 mg/l Millettia the majority of larvae were immobile. Levels of anti-parasite antibodies (estimated by ELISA assay using an adult worm-based antigen preparation) rose between 21 and 55 days p.i. with control cercariae and those pre-treated with 2.5 mg/l Millettia. After 5 mg/l pre-treatment, cercariae induced a reduced antibody rise, while mice exposed to cercariae after 10 mg/l pre-treatment showed no rise in anti-parasite antibody levels. These results are discussed in the context of protocols which could possibly use Millettia attenuated cercariae to induce useful levels of protection in mice towards further cercarial challenge. PMID- 7831092 TI - Tissue expression of the Schistosoma mansoni 28 kDa glutathione S-transferase. AB - The expression of the Schistosoma mansoni 28 kDa glutathione S-transferase (Sm28) was studied using molecular (PCR, in situ hybridization), and immunocytochemical techniques. The presence of Sm28 was demonstrated in all developmental stages of the parasite except the intra-uterine immature egg. In the parenchyma of male and female adult worms the distribution of Sm28 was limited to a subpopulation of parenchymal cells and to the dorsal tubercles of the male. The tegument, the muscles, the digestive tract, the neural mass, the vitelline glands, and mature gametes were not immunoreactive. Immature germinal cells in both sexes, and the ootype in the female genital system, were found to express Sm28. Deposits of immunoreactive material on host skin following cercarial penetration, exfoliation from the male tubercles, and especially emission of Sm28 from eggs in hepatic granulomas are suspected to be a source of antigen during the parasite infection. The reduction in worm fecundity previously observed in immunization experiments may result from an antibody response directed against Sm28 present in the ootype. There was no cross-reactivity observed, under the experimental conditions used, between the anti-Sm28 sera and either vertebrate or invertebrate host tissue. PMID- 7831093 TI - Molecular characterization of Theileria parasites: application to the epidemiology of theileriosis in Zimbabwe. AB - Forty Theileria schizont-infected lymphocyte culture isolates from Zimbabwe were characterized using a panel of antischizont monoclonal antibodies (MAbs) and 4 Theileria parva DNA probes containing cloned extrachromosomal element, Tpr repetitive, ribosomal and telomeric sequences. The Theileria isolates were assigned as T. parva or T. taurotragi on the basis of reactivities with MAbs and restriction fragment length polymorphisms (RFLPs) detected using the extra chromosomal element probe. Cattle-derived T. parva isolates were relatively homogeneous on the basis of reactivities with MAbs and RFLPs detected using Tpr repetitive and ribosomal DNA probes. In contrast to previous results from Kenya, most of the cattle-derived isolates from Zimbabwe exhibited very similar Tpr restriction fragment patterns, although the Tpr genotypes of buffalo-derived isolates were heterogeneous. This suggests that selection for a particular Tpr genotype may be occurring in cattle. Many isolates with similar Tpr genotypes were differentiated by RFLPs detected using the telomeric DNA probe. The T. parva Boleni immunizing stock was distinguished from all other isolates by telomeric RFLPs. The T. parva Boleni Tpr repetitive DNA probe cross-hybridized with T. taurotragi DNA and detected RFLPs between different T. taurotragi isolates. PMID- 7831094 TI - The effect of Toxoplasma gondii and other parasites on activity levels in wild and hybrid Rattus norvegicus. AB - Using both correlational and experimental evidence, the relationship between parasite load and host activity was assessed in brown rats, Rattus norvegicus. Two hypotheses were tested--(1) that parasites with indirect life-cycles, involving transmission between a prey and its predator, will alter the activity of the intermediate host so as to increase its susceptibility to predation by the definitive host and (2) that activity levels in parasitized rats would be increased rather than decreased. Four groups of rats (n = 140) were examined. One group (n = 50) were wild brown rats trapped from 3 UK farmsteads, with naturally occurring parasites. The others were purpose-bred wild/laboratory hybrid rats with experimentally induced parasitic infections of either (n = 15) adult acquired or (n = 15) congenitally-acquired Toxoplasma gondii (an indirect life cycle parasite), or (n = 15) Syphacia muris (a direct life-cycle parasite). Uninfected hybrid rats ( n = 45), matched for sex, age and weight, served as controls. Rats were housed individually in outdoor cages, and their activities were recorded on video-tapes for 6 non-consecutive 10 h nights. Exercise wheels were also available for the hybrid rats. Out of 6 parasite species detected in the wild rats, T. gondii was the only one which required predation by a definitive host to complete its life-cycle, and was also the only parasite to be associated with higher activity levels in infected than uninfected rats. Hybrid rats infected with T. gondii were also more active than those uninfected, whereas there were no differences in activity levels between S. muris infected and uninfected rats. This study shows that the indirect life-cycle parasite T. gondii can influence the activity of its intermediate host the rat. I suggest that this may facilitate its transmission to the cat definitive host. PMID- 7831095 TI - Modification of macrophage -T cell interaction during infection of mice with Mesocestoides corti (Cestoda). AB - Peritoneal macrophages from Mesocestoides corti-infected mice showed a marked and progressive loss of ability to act as accessory cells for syngeneic Con A stimulated mesenteric lymph node lymphocytes. The same effect on the macrophages could be induced by intraperitoneal injection of M. corti culture supernatant, despite a concurrent increase in numbers of peritoneal adhesive macrophages. The findings are used to compare and contrast the known immunomodulatory effects of M. corti and taeniid metacestodes, the latter differing chiefly in their potential for modifying T-cell as well as macrophage behaviour. PMID- 7831096 TI - Cleavage of immunoglobulin G by excretory-secretory cathepsin S-like protease of Spirometra mansoni plerocercoid. AB - When immunoglobulin G (IgG) was incubated with Spirometra mansoni plerocercoid (sparganum), it was cleaved into Fab and Fc fragments. Fab/c fragments were also hydrolysed. The digestion was accelerated by dithiothreitol (DTT), indicating that cleavage of IgG heavy chain was due to a cysteine protease secreted into the medium. The responsible enzyme, of M(r) 27 (+/- 0.8) kDa, was purified by a series of thiopropyl affinity, Sephacryl S-300 HR and DEAE-anion exchange chromatographies, either from worm extracts or from excretory-secretory products (ESP). The purified, thiol-dependent protease showed an optimal activity at pH 5.7 with 0.1 M sodium acetate but was active over the pH range 4.5-8.0. Its activity was inhibited completely by 10(-5) M L-trans-epoxysuccinylleucylamido(4 guanidino) butane (E-64) and 1 mM iodoacetamide (IAA), but by only 53% using the specific cathepsin L inhibitor, Z-Phe-Phe-CHN2 (5 x 10(-5) M). Partial NH2 terminal amino acid sequence was Leu-Pro-Asp-Ser-Val-Asn-Trp-Arg-Glu-Gly-Ala-Val Thr-Ala-Val which showed 80% homology to human cathepsin S. Immunoblot analysis showed that sera from infected patients exhibited IgE antibody reaction. It is proposed that cleavage of immunoglobulin by an excreted-secreted, cathepsin S like, allergenic protease is a mechanism of immune evasion used by the sparganum. PMID- 7831097 TI - Characterization of peptidases of adult Trichuris muris. AB - Excretory/secretory (E/S) material of Trichuris muris was found to contain 2 major peptidases, M(r) 85 and 105 kDa, which degrade gelatin optimally at pH 6.0 in sodium dodecyl sulphate-polyacrylamide gels. The peptidases were inactivated by diisopropylfluorophosphate, leupeptin and soybean trypsin inhibitor, but were unaffected by inhibitors of aspartic-, cysteine- and metallo-peptidases, indicating that they are serine peptidases. Both enzymes were detectable within 5 h after incubation of worms in culture medium and showed a time-dependent increase in levels. Neither peptidase was detected in worm extracts, suggesting that they are activated during or following secretion from worms. Live worms degraded a radio-isotope labelled extracellular matrix protein substratum derived from mammalian cells. Aminopeptidase activities capable of catalysing hydrolysis of amino acyl aminomethylcoumarin (MCA) substrates and a Z-Phe-Arg-MCA hydrolysing cysteine peptidase activity, were detected in extracts of adult worms but not in E/S material. PMID- 7831098 TI - The interaction of Trypanosoma congolense with endothelial cells. AB - Factors which affect adhesion of cultured Trypanosoma congolense bloodstream forms to mammalian feeder cells have been examined. Using an in vitro binding assay, the initial events following interaction of trypanosomes with bovine aorta endothelial (BAE) cells were monitored by both light- and electron microscopy. Metabolic inhibitors and other biochemicals were incubated with either cells or parasites, to test whether any inhibited the process. Our findings suggest that adhesion of the parasites is an active process requiring metabolic energy from the trypanosomes, but not from endothelial cells. We also provide data suggesting that T. congolense bloodstream forms possess a lectin-like domain, localized at distinct sites on their flagellar surface, which interacts with specific carbohydrate receptors, most likely sialic acid residues, on the endothelial cell plasma membrane. We also suggest that the cytoskeletal protein actin is probably involved in this interaction. PMID- 7831099 TI - Development in vitro of free-living infective larvae to the parasitic stage of Strongyloides venezuelensis by temperature shift. AB - Free-living infective larvae Strongyloides venezuelensis were cultured in Dulbecco's modified Eagle's medium at 25 and 37 degrees C, and development to the parasitic stage was evaluated using morphological, protein and antigenicity criteria. Few larvae cultured at 25 degrees C showed development whereas, in most of the larvae cultured at 37 degrees C, there appeared characteristic changes such as a bulb-like head and droplets under the cuticle with an increase of body width of the larvae. The results obtained from two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) revealed that the protein spot patterns of the larvae cultured at 25 and 37 degrees C were differentiated by 17 specific spots. In addition, Western blot analysis combined with 2D-PAGE for reaction with serum obtained from an infected rat revealed that protein spots showing immunodominant antigen at 37 degrees C were almost the same as those of the larvae recovered from the rats rather than those of the larvae at 25 degrees C. These results strongly suggested that a temperature shift from 25 to 37 degrees C has an important role in the development of free-living infective larvae to the parasitic stage of S. venezuelensis. The culture system established in the present study was useful for biological and biochemical studies in the development from/of the free-living to the parasitic stage of Strongyloides species. PMID- 7831100 TI - Induction of the prophenoloxidase-activating system of Simulium (Diptera: Simuliidae) following Onchocerca (Nematoda: Filarioidea) infection. AB - Trials were carried out to study the humoral immune response of blackflies to filariae following infection using the intrathoracic injection technique. An induced 66 kDa protein was abundant in the haemolymph of the European species Simulium ornatum following infection with bovine Onchocerca lienalis. This protein was apparently at higher concentrations in the haemolymph of sham inoculated flies, i.e. flies that received sterile medium without the parasites. A molecule of the same size was also observed in the haemolymph of infected S. damnosum s.l. following infection with human O. volvulus or bovine O. ochengi. However, the level of this protein was lower in blackflies injected with microfilariae of bovine O. dukei. Unlike O. volvulus and O. ochengi this species is not transmitted by S. damnosum s.l. under natural conditions. No such reaction was observed if the African blackflies had received a sham inoculation. Feeding experiments with wild-caught nulliparous S. damnosum sl. on Onchocerca-infected cattle supported the results of the injection trials. The 66 kDa protein could only be found in the haemolymph of specimens infected via a blood meal. This 66 kDa molecule was identified as phenoloxidase. It appeared in the haemolymph due to the activation of the prophenoloxidase system following the filarial infection and we hypothesize that it may be sequestered by the parasites, as part of a non self recognition system. PMID- 7831101 TI - [What happens behind closed doors when physicians become problems? Informal mechanism revealed in a case study]. AB - Problem doctors are a heterogeneous group, and it is sometimes difficult to determine whether a doctor is incompetent or simply makes repeated mistakes hard to avoid completely under pressure of the clinical work-load. The profession has a small repertoire of informal methods for dealing with situations where a colleague has become a problem. An interview study, carried out in Britain and Sweden, revealed the approaches most commonly used. It also showed that the problem doctor's colleagues often hesitate too long in taking the informal approach that the problem is much more difficult to resolve by the time department heads and administrators become involved. PMID- 7831102 TI - [What do medical societies do to help physicians in crisis?]. PMID- 7831103 TI - [A fragile network]. PMID- 7831104 TI - [Physicians who are drug addicts should be taken care of together]. PMID- 7831105 TI - [Estimated consumption of anabolic steroids among athletes in Denmark]. AB - In an attempt to ascertain the types and quantities of anabolic steroids used by athletes in Denmark, a questionnaire was distributed at nine weight-training centres during the winter of 1986-1987. By comparing the results of the non representative questionnaire study with the overall consumption of anabolic steroids in the country as a whole, the annual consumption was estimated to be the equivalent of at least 6,500 10-week courses of anabolic steroids at daily dosages eight times the recommended therapeutic level. In addition, the not inconsiderable illegal use of anabolic steroids seems to increase. The annual consumption of anabolic steroids by athletes in Denmark is estimated to be 2 million daily doses. PMID- 7831106 TI - [Future collaboration in medical education in Scandinavia]. AB - The Nordic Federation for Medical Education is in the process of re-organisation. Owing to increasing cooperation with the remainder of Europe, it is desirable that the Nordic countries unite to preserve the structure of Nordic medical education. PMID- 7831107 TI - [Entry requirements for medical education in Scandinavia]. PMID- 7831108 TI - [The great Scandinavian Medical Jahre Prize 1994. Role of lipoprotein lipase in lipoprotein metabolism]. AB - Each day more than 150 g of triglycerides are transported from the intestine in chylomicrons and from the liver in VLDL. The triglycerides are hydrolyzed by lipoprotein lipase at the vascular endothelium in extrahepatic tissues. This releases fatty acids and monoglycerides which can move across aqueous barriers and cell membranes to reach metabolic sites in tissue cells. At the endothelial cell the enzyme is anchored to heparin sulfate proteoglycans. The enzyme is located in a position where it can freely interact with lipoproteins from the circulating blood. The hydrolysis is a rapid and efficient process. A chylomicron containing more than a million triglyceride molecules can be unloaded in less than 10 minutes. As a consequence of triglyceride hydrolysis the lipoproteins are reduced to remnant particles. Some of these are rapidly removed from plasma but some are remodeled into LDL and HDL, lipoproteins that are catabolized slowly and therefore dominate in plasma. The activity of LPL is regulated in a tissue specific manner and this directs the destination of triglyceride transport. The enzyme binds fatty acids which provides a mechanism for product control of the reaction. When the tissue can no longer assimilate the fatty acids, the lipase reaction is stopped and the lipoprotein returns to the circulating blood. In addition to its catalytic action, lipoprotein lipase can also serve as a ligand for binding of lipoproteins to cell surfaces and to receptors. Hence, the lipase has a dual role in lipoprotein metabolism, mediating both unloading of triglycerides in extrahepatic tissues and particle catabolism in the liver. PMID- 7831110 TI - Wound care. The role of the nurse. Part 2. PMID- 7831111 TI - Mercy or murder? PMID- 7831109 TI - [Antibiotic prophylaxis in diagnostic and therapeutic urological interventions]. AB - An enquiry into the use of antibiotic prophylaxis in conjunction with diagnostic or therapeutic urological procedures at hospitals in four Scandinavian countries showed manifest national differences to exist for most procedures. In transurethral resection, for instance, antibiotic cover was used at 79 percent of Finnish hospitals, but at only nine percent of Danish hospitals. Not only were dosage regimens characterized by wide national variation, but also the spectrum of antibiotics used, quinolones being most frequently used in Sweden, but ampicillin and pivampicillin in Denmark. For some procedures policy was more uniform in all countries, antibiotic cover rarely being used in connection with ureterocystoscopy (5 percent of hospitals), but often in conjunction with percutaneous stone surgery (72 per cent). In certain procedures where there is strong evidence suggesting the necessity of antibiotic prophylaxis, it was not always used-e.g., in transrectal prostate biopsy where it was used at only 62 per cent of hospitals. The interpretation of published findings and clinical experience would appear to differ markedly, and local traditions would seem to be strong determinants of clinical routines. The wide variation suggests that all patients do not receive optimal treatment. To improve routines, our knowledge of antibiotic preparations needs to be expanded by well executed studies, followed by general implementation of the results at the various centres. A series of consensus conferences should be arranged and the recommendations published as a first step toward a more uniform and probably better use of antibiotic prophylaxis in conjunction with diagnostic and therapeutic urological procedures. PMID- 7831112 TI - Birth rite. PMID- 7831113 TI - Buying power. PMID- 7831114 TI - Work-related hazards for the occupational health nurse. AB - Occupational health nursing is frequently poorly understood, even by users of the service. This paper introduces a new series which has been written to increase awareness of the specialty. PMID- 7831116 TI - Retaining the care. PMID- 7831115 TI - Healthy staff, healthy profits. AB - This article discusses the development and contemporary scope for practice of occupational health nurses whose names appear on Part 1 of the Professional Register of the UK Central Council for Nursing Midwifery and Health Visiting (UKCC) and who hold a post-registration qualification in occupational health nursing recorded with the UKCC. PMID- 7831117 TI - The NT/Regent survey results. AB - This paper describes the findings of the NT/Regent national survey of occupational health nurses, which was conducted during the summer and autumn of 1994, and looked at staffing, workload, budget responsibility and income generation. PMID- 7831119 TI - Systems of life: blood: 7. PMID- 7831118 TI - The obsolete measurement of pulse deficit by nurses. AB - Measurement of the pulse deficit, the discrepancy between the pulse rate which can be felt at the wrist and actual ventricular contraction, is a common nursing observation. However, this procedure is time-consuming, usually needing to be carried out by two nurses at the same time. How useful this measurement is and whether nurses know why they are carrying it out is questioned in this paper. PMID- 7831120 TI - A special approach. PMID- 7831121 TI - Happy retirement. PMID- 7831122 TI - Family traditions. PMID- 7831123 TI - A lottery for the elderly. PMID- 7831124 TI - Treating bacterial wound infection. PMID- 7831125 TI - Detecting infection. PMID- 7831127 TI - Dressing choices. PMID- 7831126 TI - Vital ingredients. PMID- 7831128 TI - Using locus of control to empower student nurses to be professional. AB - The author examines locus of control as a factor in some educational problems. Characteristics and implications of internal and external locus of control are identified; and strategies are presented to promote assertiveness, accountability, and independence in students who previously avoided risking taking behaviors. PMID- 7831129 TI - The value of mentoring in nursing leadership: a descriptive study. AB - The author of this descriptive study explores the general characteristics of mentoring relationships and their effects on professional lives as perceived by nurse administrators. An adult developmental theoretical framework was used. The sample consisted of 367, members of the California Society for Nursing Service Administrators, a group of top-level nurse administrators. The overwhelmingly positive responses supported the literature, which described a variety of significant positive developments as a result of mentoring relationships. Ninety seven percent (n = 356) indicated changes had occurred in their lives, with a change in self-confidence indicated most frequently. More than eighty percent (n = 294) indicated the relationship was valuable. Enhancing formal and informal mentoring relationships particularly in the nursing leadership arena is important. PMID- 7831130 TI - Call me a nurse. PMID- 7831131 TI - TQM/CQI: providing a steady supply of nurses for the future. AB - The recent emphasis on total quality management and continuous quality improvement (TQM/CQI) is a positive way to improve the professional status of nurses and minimize repetitive cycles of nursing shortages. The author reviews the history and the current status of the supply and demand for nursing personnel, and suggests solutions for preventing shortages that incorporate TQM/CQI strategies. PMID- 7831132 TI - The myth of independent practice. PMID- 7831133 TI - Computer technology: implications for nurse educators. AB - The purpose of this paper is to discuss implications of computer technology for nursing education. Effects of computer anxiety and strategies to minimize them are presented. Computer assisted instruction (CAI) and interactive videodisc (IVD) are alternative instructional strategies for content dissemination and learning enhancement. Faculty must be cognizant of design factors facilitating usage when selecting programs. Issues of privacy, confidentiality, information security, and impact on nursing practice have risen with increased computer usage. PMID- 7831134 TI - Let's pretend: a hospital teaches children about health care. AB - A college of nursing and a hospital offer a "pretend hospital" to approximately 3,000 first graders each spring. The community service project, which has quadrupled in attendance over nine years, teaches first graders about health maintenance and the role of health care in their lives, and helps decrease their anxiety related to the hospital experience. Realistic and nonthreatening multisensory experiences of the simulated hospital prepare children for the healthcare consumer role. The simulation also provides nursing students an opportunity to translate concepts of growth, development, and communication into practice. PMID- 7831136 TI - Fluoride dosage alert. PMID- 7831135 TI - Excessive fluoride. PMID- 7831137 TI - Recognition of bite marks in child abuse cases. AB - Health professionals must be attentive to any and all signs of child maltreatment. Bite marks are one of several visual expressions of active child abuse. The efforts of forensic odontologists, in conjunction with recent technical advancements in bite mark analysis, support the uniqueness of the human dentition and have contributed to the conviction of numerous child abusers. Through recognition, proper documentation, and reporting dentists can help the forensic community use bite marks to solve cases of child maltreatment. PMID- 7831138 TI - Fluoride exchange from glass ionomer preventive resin restorations. AB - The purposes of this in vivo study were to determine if placing a sealant over a glass ionomer restoration modifies its fluoride release, and to examine the effect on glass ionomer of a 4-min application of topical fluoride. Fluoride release from glass ionomer preventive resin restorations placed in 21 bovine teeth was measured before and after removing their sealants. Fuji II, Ketac Silver, and Fuji LC were evaluated, representing the three generations of glass ionomers. Fluoride was extracted from the restorations by incubating the specimens in 5 ml deionized water and was measured by specific ion electrodes at 1 and 2 days, then once weekly for 7 weeks. The results indicated that fluoride release was not significantly different in pattern or quantity in the three types of ionomer (P > 0.05). A significant reduction in fluoride release occurred when the restorations were covered with a sealant when compared with control restorations of the same materials (P < 0.001). After removing the sealant from the glass ionomer preventive resin restorations, a significant release of fluoride occurred when compared with sealed restorations (P < 0.001). After 63 days in water, the unsealed restorations were subjected to a 4-min topical APF treatment and reimmersed in water for an additional 27 days to examine the ability of the various materials to absorb fluoride. The fluoride-depleted restorations treated with fluoride released significantly more fluoride than fresh, untreated ionomer restorations (P < 0.001) or amalgam restorations. As a result of fluoride release, the glass ionomer preventive resin restoration may afford chemical protection to the tooth if sealant loss occurs. PMID- 7831139 TI - Growth inhibition of glass ionomer cements on mutans streptococci. AB - This study was conducted to identify the factors involved in the antibacterial activity of glass ionomer cement (GIC) on mutans streptococci. The antibacterial effect of GIC was estimated using agar plates infected with strains of S. mutans and S. sobrinus. The effect of pH and fluoride release of GIC on mutans streptococci was studied under acid and neutral pH. Strains of S. sobrinus were more sensitive to GIC antibacterial activity, the difference being statistically significant (P < 0.001). The GIC Fuji II LC, Fuji II type II, Vitremer, Vitrebond, and Ketac-Cem were the most active materials in this study. The inhibition activity was associated with GIC fluoride release; 140 +/- 25 ppm were required to inhibit S. sobrinus 6715. Inhibition activity was not associated with changes in pH after setting of these materials. PMID- 7831141 TI - Survival of different types of space maintainers. PMID- 7831140 TI - Evaluation of two dosages of oral midazolam as a conscious sedation for physically and neurologically compromised pediatric dental patients. AB - Physically and neurologically handicapped pediatric dental patients are often a challenge to treat and may require the use of pharmacological agents for behavior modification. The purpose of this study was to investigate the safety, in terms of vital sign changes and complications, and the effectiveness, in terms of behavioral changes, of two dosages of oral midazolam as a conscious sedative agent for this unique population. Participating in this study were 31 patients of Texas Scottish Rite Hospital for Children, who were uncooperative (as rated on the Frankl scale) at a previous dental appointment. The patients, 3-18 years old, were randomly selected to receive one of the two dosage regimens; Group A received 0.3 mg/kg oral midazolam and Group B received 0.5 mg/kg. Physiologic parameters and behavior were recorded throughout the appointment and overall safety and success were determined. Although clinically insignificant, Group A's pulse rates 20 min into treatment were significantly higher than at baseline or treatment start, and oxygen saturations were lower during treatment than at baseline and start of treatment. Intratreatment systolic and diastolic blood pressures and pulse rates of Group B were significantly higher than the baseline figures; however, these changes were not clinically significant. No clinical or postoperative complications were noted for either dosage. The regimen of 0.3 mg/kg of oral midazolam was successful 75% of the time, and the regimen of 0.5 mg/kg of oral midazolam was successful 60% of the time in providing adequate sedation to allow operative treatment to be safely and efficiently performed.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7831142 TI - A survey of parents whose children had full-mouth rehabilitation under general anesthesia regarding subsequent preventive dental care. PMID- 7831143 TI - Prevalence and racial distribution of primary canine hypoplasia of the maxillary canine. PMID- 7831145 TI - The relationship between learned resourcefulness and coping with crying in pediatric dentistry: a pilot study. PMID- 7831144 TI - The effect of acid and fluoride release on the antimicrobial properties of four glass ionomer cements. PMID- 7831146 TI - Pre-eruptive coronal resorption of permanent teeth: report of three cases and their treatments. PMID- 7831147 TI - Acquired toxoplasmosis of a submandibular lymph node in a 13-year-old boy: case report. AB - Toxoplasmosis is a parasitic infection divided into congenital and acquired forms. In the latter form, malaise, fatigue, and lymphadenopathy are commonly found, and submandibular lymphadenopathy is sometimes a manifestation. In children, cervical lymph nodes usually are affected. This is a case of a 13-year old boy suffering from acquired toxoplasmosis, in which submandibular lymphadenopathy was the only clinical sign of the disease. Meticulous history taking, clinical examination, and specific serological tests should be performed in these cases. Positive serological results will confirm toxoplasmosis infections. Conservative treatment must be attempted initially. PMID- 7831148 TI - American Board of Pediatric Dentistry recertification section examination. PMID- 7831149 TI - Cardiomyopathy in childhood and adult life, with emphasis on hypertrophic cardiomyopathy. AB - Over 60 entries in the genetic catalog have cardiomyopathy features--32 autosomal dominant, 35 autosomal recessive and X-linked. Over 40 present in, or can have survival into, adult life. Major clinicopathologic categories of these cardiomyopathic disorders included: sudden death (13 entities); cardiac conduction disturbance important feature; associated myopathy or motor dysfunction; storage diseases with cardiac involvement; cardiac amyloidoses; and, other categories. Genes, abnormality of which can cause hypertrophic cardiomyopathy (HCM), have been identified on chromosomes 1, 14 and 15, the locus on chromosome 14 involving the B-myosin heavy chain gene, but at least one unidentified locus is known to exist and there is a suggestive locus on chromosome 16, so that HCM is not a single disease but a group of disorders with clinicopatholopic similarities. To investigate these aspects of HCM in some detail, sixty-six patients with "sharply demarcated" differential myocardial fiber bundle hypertrophy (DMBH), considered to be of significant degree, from a pediatric autopsy data base of approximately 8,000 cases, were reviewed. Twenty three of the patients died suddenly, without antecedent significant cardiac dysfunction, seven had clinical congestive heart failure of varying duration, three were stillborn, six showed evidence of aspiration of amniotic sac content (three had history of fetal distress), five had ischemic bowel disease, three (two with clinical cerebral palsy and one with Ondine's curse syndrome) had cerebral atrophy and sclerosis and one had extensive more acute encephalomalacia, and a variety of other major "causes of death" were present. Whether all infants and children with DMBH meeting the criteria used, who do not have congenital heart disease, have dominant hypertrophic cardiomyopathy (HCM) cannot be established by studies of this type, but the "concentration" of a gene or genes for HCM in pediatric autopsy series because the strong effect of HCM on life expectancy is relevant to this possibility. The data raise the question that stillbirth, fetal distress with aspiration of amniotic sac content, ischemic bowel disease and cerebral atrophy and sclerosis may be hitherto underappreciated features of HCM in childhood, and that patients with HCM may be peculiarly liable to die with certain types of septic shock, such as acute meningococcemia. In the material of this study, sudden death was statistically more frequent in females than in males in childhood (p < .029). PMID- 7831150 TI - Bone metastasizing renal tumor of childhood. A clinicopathological study of eleven cases from the Prague Pediatric Tumor Registry. AB - Eleven patients with bone metastasizing renal tumor of childhood (BMRTCh) who were diagnosed and treated in our departments over a 20-year period were reviewed. The incidence among all malignant renal tumors in children up to 15 years of age in our files was 3.7%. The male to female ratio was 10:1. The morphology had a uniform, predominantly clear cell finely vascularized pattern in all of them. Various previously recognized variations of the classic pattern such as hyalinization, nuclear palisading and cyst formation were observed in some patients. Electron microscopy showed that coarse vacuolization of the tumor seen at the light microscopic level was due to distended extracellular spaces surrounded by tumor cells and their cytoplasmic processes. Immunohistochemistry of the tumor cells revealed positive vimentin in all cases, and focally positive muscle specific actin in one. A prominent feature was fascicles of perivascular spindle cells. They were considered to be tumor cells rather than stromal elements since their morphology was close to the appearance of the polygonal tumor cells. The follow up data were available for ten patients. Four developed bone metastases, three of them died of the disease progression. Another patient died of lymph node dissemination and gastrointestinal bleeding. Six patients survived for a period of 29 months to 14 years following the diagnosis. PMID- 7831151 TI - Lysosomal storage diseases in adults. AB - Most lysosomal storage disorders are known as pediatric diseases. In recent years late onset and adult forms of these disorders have been recognized. The adult form of a given lysosomal storage disorder differs from the childhood disease in several respects. Adult disorders are, with some exceptions, less common than the childhood diseases. The clinical picture is not only less severe, but often shows quite different clinical signs and symptoms than the early onset form. Metachromatic leucodystrophy, GM1 and GM2 gangliosidoses, Gaucher disease and aspartylglucosaminuria are presented as examples of lysosomal storage disorders manifesting as adult diseases. The differences of the early and late onset disorders are discussed in the light of recent results of molecular genetics, residual enzyme activity and pseudodeficiency. PMID- 7831152 TI - Mycosis fungoides: expression of C-myc p62 p53, bcl-2 and PCNA proteins and absence of association with Epstein-Barr virus. AB - The expression of C-myc p62, bcl-2, p53, PCNA and EBV-encoded LMP-1 proteins was studied by immunohistochemistry on paraffin-embedded skin specimens from 14 patients with early stage (premycotic erythema and second stage plaques) mycosis fungoides (MF), 21 patients with advanced stage MF (third stage plaques and tumors), 3 patients with Sezary's syndrome (SS) and 3 patients with pleomorphic medium and large cell cutaneous T-cell lymphomas (PML-CTCL). All 41 cases were also screened for the presence of EBV by using RNA in situ hybridization with EBER 1/2 oligonucleotides. Increased expression of C-myc p62, p53 and PCNA proteins was found in PML-CTCL and advanced stages of MF as compared to early stages of MF. These results suggest a relationship between levels of C-myc p62, p53 and PCNA proteins and aggressiveness of the cutaneous T-cell lymphomas. Furthermore, C-myc p62 and bcl-2 proteins were found to be frequently coexpressed in the present series. In view of the background information from in vitro findings and animal models that cooperation of C-myc and bcl-2 is important for lymphomagenesis, our results suggest that coexpression of these oncogenes may be implicated in the pathogenesis and/or the progression of cutaneous T-cell lymphomas. Neither LMP-1 expression nor EBV EBER l/2 transcripts were detected in our series suggesting that EBV is not involved in the pathogenesis of cutaneous T cell lymphomas. PMID- 7831153 TI - Pathology of Toxoplasma gondii infection in the nude rat. An experimental model of toxoplasmosis in the immunocompromised host? AB - Genetically athymic nu/nu (nude) rats, deficient in T cells, die from infection with various Toxoplasma gondii strains, including RH and Prugniaud strains. In contrast, these strains cause chronic infections without apparent symptoms in immunocompetent non-nude rats. We show here that nude rats die in two to three weeks after RH infection and three to four weeks after Prugniaud infection. Histological examination of brains from nude rats at different time points after infection, revealed an absence of lesions after RH strain infection and cysts with usually no inflammation after Prugniaud infection. Lungs from nude rats developed a fibrin alveolitis using either strain, whereas myocarditis with focal areas of necrosis were observed only after Prugniaud infection. Cysts and, in some cases, tachyzoites in the necrotic lesions were easily identifiable. The two strains of T. gondii elicited in nude rats a granulomatous hepatitis that only differed in intensity. Spleen and mesenteric lymph nodes appeared totally non reactive in both cases. This model allows immunological and parasitological studies by comparison with immunocompetent rat infection. Published data concerning toxoplasma pathology in AIDS, therefore, suggest that acute toxoplasma infection in nude rats may be a useful model for studying disseminated forms of toxoplasma infection found in AIDS patients. PMID- 7831154 TI - Demonstration of mycobacterial antigens in skin biopsies fron suspected leprosy cases in the absence of bacilli. AB - Skin-biopsies from fifty-six patients suspected of early leprosy from Bahia State, Brazil, were examined histopathologically. The Fite-Faraco staining failed to demonstrate acid-fast bacilli in this material. The prominent features of the lesions were inflammation of the neurovascular bundles and sometimes inflammation of the skin appendages. The non-specific infiltrate was predominantly composed of histiocytes and lymphocytes. In 41 cases (73.2%) epidermal atrophy was also present. The avidin-biotin peroxidase technique was used with primary antibodies to detect bacillary antigens (anti-BCG serum) and nerve branches (anti-S-100 protein serum). Immunohistochemical detection of bacillary antigens using the anti-BCG serum was positive in 28 cases (50%). A positive staining for S-100 protein was observed in 40 cases (71.4%) in dendritic antigen-presenting cells of the skin. The detection of bacillary antigens, together with the clear demonstration of nerve bundles enhanced our capacity to fulfill morphologic criteria for the diagnosis of early leprosy. Our observations indicate that the use of immunohistochemical methods represent a useful tool for the early diagnosis of leprosy. PMID- 7831155 TI - The proliferating cell nuclear antigen index in breast carcinomas does not correlate with mitotic index and estrogen receptor immunoreactivity. AB - To investigate the expression of a marker of cell proliferation (PCNA/Cyclin) and its putative relationship with histological grading, mitotic index and estrogen receptor immunoreactivity, we studied twenty-seven cases of invasive breast carcinoma in formalin-fixed, paraffin-embedded tissue sections. The PCNA and estrogen receptor were detected by the PC 10 and H 222 monoclonal antibodies respectively, using an avidin-biotin-peroxidase method. The median value of PCNA index was 20.9% with a range from 1.4 to 84.2%. We did not find any significant relationship between PCNA index and the histological grading, mitotic index and estrogen receptor immunoreactivity. We conclude that PCNA detected by the monoclonal antibody PC 10 in formalin-fixed material looks at present unreliable as a proliferation marker in breast carcinoma. PMID- 7831156 TI - Histological findings in breast tissue specimens from reduction mammoplasties. AB - Tissue specimens from 55 consecutive reduction mammoplasty operations were studied histologically for changes considered to be associated to an increased risk in the development of invasive breast cancer. A thorough sampling of all removed tissues was performed and nearly all solid parts were processed for histological evaluation. We found that in 47 specimens, most of which belonged to women younger than 40 years of age (39), both breasts presented either no proliferative changes or mild hyperplastic lesions of the usual type and thus the women had no increased risk for breast cancer development. In 7 breast specimens, all of them from women older than 30 years, the changes observed ranged from florid hyperplasia to atypical ductal or lobular hyperplasia, which are lesions considered to be associated to a relatively increased risk of invasive carcinoma. Finally we present a case of infiltrative ductal carcinoma with extensive lesions of atypical hyperplasia and combined ductal and lobular carcinoma in situ in both breasts, which developed 3 years after reduction mammoplasty in which changes of atypical hyperplasia were found. We suggest that reduction mammoplasty specimens should be handled with particular care and according to the women's age. PMID- 7831157 TI - Quantitative computerized image analysis of immunostained lymphocytes. A methodological approach. AB - A methodological approach by computerized image analysis to quantify immunostained objects in histological sections is described. We have investigated antibodies against CD4, CD8, CD20, CD23 and CD25 in frozen sections of human nasal mucosa; however, the methodology of standardization is of general validity. The study was designed particularly to investigate the following points: 1) light intensity, 2) the grey level for counter staining intensity, 3) the grey level threshold value for positive objects, 4) the minimal acceptable size of a positive object, 5) the influence of the brightness of the light on both the number and the area of objects. Furthermore, random sampling and determination of 6) the area per section, and 7) the number of histological sections to be measured per biopsy. Finally, a study of reproducibility of immunostaining intensity was performed. The influence of the different parameters mentioned above was studied and the values (eg. threshold value) for our particular setting of microscope, image analysis equipment, computer software etc, were defined. The method was then tested for intra- and interindividual variation which was found to be less than 5%. Correlation analysis of the reproducibility gave coefficients of correlation of 0.99, both concerning number of immunopositive objects and immunopositive area. We emphasize the importance of a highly standardized methodology if the numeric data obtained from computer assisted image analysis are to be more accurate than semiquantitative assessments by experienced observers. With a thorough standardization as described in this method it is possible to obtain numeric values, and data with low deviations, which are two obvious and important advantages. PMID- 7831158 TI - Placental vascular malformation with mesenchymal hyperplasia and a localized chorioangioma. A rarity simulating partial mole. AB - We here report a case of placental vascular malformation with mesenchymal hyperplasia of the villi and a localized chorioangioma. After an uneventful pregnancy our patient delivered a non-malformed live female infant. The placenta was grossly enlarged, and macroscopically it was characterized by strongly enlarged varicous chorionic vessels. On the maternal plate vesicle-like structures, giving the impression of partial mole, were seen. At microscopy level, areas of normal looking tissue alternated with areas of excessively enlarged villi, in which the ground substance contained large amounts of acid mucopolysaccharide, corresponding to "mesenchymal hyperplasia". Moreover, a localized chorioangioma was found. In none of the histological sections were cisterns, abnormal trophoblastic proliferation, stunted ramification or stromal trophoblastic inclusions observed. In week 15 maternal se-AFP was elevated to 3.03 multiples of the median. Genetic analyses revealed a normal female karyotype and biparental genomic contributions to 7 unlinked loci. Placental vascular malformation with mesenchymal hyperplasia is a differential diagnosis to partial mole which should be considered when vesicle like placental enlargement is observed along with a living fetus. PMID- 7831159 TI - How to achieve optimal diabetic control in patients with insulin-dependent diabetes. PMID- 7831160 TI - Human papillomavirus and skin cancer. PMID- 7831162 TI - Hyperoxaluria and renal calculi. PMID- 7831161 TI - Salt, hypertension and renal disease: comparative medicine, models and real diseases. AB - Dogs are well established as experimental animals for the study of both renal disease and hypertension, but most work is based on surgical or pharmacological models and relatively little on spontaneous diseases. This review argues for the latter as an underexploited aspect of comparative medicine. The most important feature of canine hypertension may not be the ease with which models can be produced but the fact that dogs are actually rather resistant to hypertension, and perhaps to its effects, even when they have chronic renal failure. The importance of natural models of chronic renal failure is strengthened by the evidence that self-sustaining progression is a consequence of extreme nephron loss, that is, a late event, rather than the dominant feature of the course of the disease. The role of salt in hypertension is discussed and emphasis given to the importance of understanding the physiological basis of nutritional requirement and recognizing that it is unlikely to exceed 0.6 mmol/kg/day for most healthy adult mammals except during pregnancy or lactation. Such a perspective is essential to the evaluation of experiments, whether in animals or humans, in order to avoid arbitrary definitions of 'high' or 'low' sodium intake, and the serious misinterpretations of data which result. An age-related rise in arterial pressure may well be a warning of excess salt intake, rather than a normal occurrence. Problems of defining hypertension in the face of variability of arterial pressure are also discussed. PMID- 7831163 TI - Unstable angina and exposure to carbon monoxide. AB - Inhalation of small amounts of carbon monoxide diminishes the pain threshold in patients with stable angina pectoris. The aim of this study was to identify and describe patients who had been exposed unknowingly to toxic inhalations of this gas and subsequently presented to hospital with a clinical picture of unstable angina. Blood carboxyhaemoglobin levels of 104 patients referred with unstable angina to a coronary care unit were determined on admission. The likely source of carbon monoxide was identified in all patients. Three patients had definite carbon monoxide intoxication. Another five patients had evidence of minor exposure. When the three cases with carbon monoxide poisoning were excluded, the mean carboxyhaemoglobin level was 2.5% (+/- 1.3) for smokers (n = 30) and 0.6% (+/- 0.5) for non-smokers (n = 71). Use of fossil fuel combustion in an enclosed environment was responsible for the three most serious intoxications and one of the minor cases. We suggest that a number of patients admitted for coronary care with unstable angina may have significant carbon monoxide poisoning. This intoxication is often overlooked by attending physicians with the result that high concentration oxygen therapy is not administered, when it is in fact a necessary part of treatment. PMID- 7831164 TI - Cardiac tamponade as the initial presentation of malignancy: is it as rare as previously supposed? AB - Advanced malignant disease frequently involves the heart and pericardium, and pericardial effusion is a common postmortem finding in such patients. Identification of pericardial effusions in life is uncommon, however, even when symptomatic. Cardiac tamponade occurring as the first presentation of malignancy appears to be uncommon. We present five cases of cardiac tamponade due to undiagnosed malignancy which presented to a general medical unit over 18 months. The availability of echocardiography was an important factor in correct diagnosis, since clinical features were non-specific. Bronchial adenocarcinoma was the cause in three of the five cases. Review of the literature confirms adenocarcinomas of the bronchus as the most common cause of this complication. The majority of cases have presented with large volume, haemorrhagic effusions, and cytology (with or without carcinoembryonic antigen measurement) was diagnostic in most patients. Immediate treatment with subxiphoid pericardiotomy is recommended; the role of balloon catheter pericardiotomy remains to be established. Combined chemotherapy and radiotherapy appears to extend survival, which in some cases may be prolonged. We recommend that early echocardiography should be obtained in all patients presenting with apparent cardiac failure, since early treatment of malignant effusions provides symptomatic relief. PMID- 7831166 TI - Back to basics in health care. PMID- 7831165 TI - Continuing clinically severe vitamin D deficiency in Asians in the UK (Leicester). AB - Deprivational vitamin D deficiency began to be noted in immigrant Asians in the early 1960s. Although there have been suggestions that the level of this problem may be declining, we describe a number of clinical cases seen over a consecutive 3 1/2 year period. Musculoskeletal symptoms were the commonest though there were a variety of medical presentations requiring hospital referral. Most of the cases were Hindu vegetarians. There is likely to be significant underdiagnosis of this condition. In spite of the extensive medical, social and political attention this condition has received, our study shows that vitamin D deficiency continues to persist in certain Asians in a clinically florid fashion. An effective preventative policy is long overdue. PMID- 7831167 TI - Health services research: what is being done, why do it at all? PMID- 7831168 TI - A comparative study of postgraduate medical education in North East Thames Region. AB - As a prelude to more detailed formal contracting, North East Thames Region undertook a review to examine whether the content of postgraduate medical education (PGME) varies according to the type of hospital in which junior doctors are trained. The study covered a sample of 83 trainees at different grades in four types of hospital (postgraduate, university, district general hospital involved in off-site undergraduate medical education, and district general hospital with no formal involvement in undergraduate medical education) and was designed as a qualitative comparative study. The results of the study point to a perceived lack of structure in PGME and indicate that hospital type alone does not determine a trainees' PGME experience. Moreover, different training grades have different educational needs, which will need to be addressed under more formal contracting arrangements. The Region plans to take this work forward by convening one or more consensus conferences to examine how a more structured approach to PGME could be implemented. PMID- 7831169 TI - The history of postgraduate medicine education. PMID- 7831170 TI - Continuing medical education for the trained physician. Recommendations for the introduction and implementation of a CME system. PMID- 7831171 TI - Treatment of methyl bromide poisoning with haemodialysis. AB - Acute accidental methyl bromide poisoning was treated with haemodialysis. The treatment was successful in removing bromide from the blood but the patient persists with severe neuropsychiatric sequelae. To the best of our knowledge haemodialysis has not been used previously for the treatment of organic bromide poisoning. PMID- 7831172 TI - Emphysematous pyelonephritis. PMID- 7831173 TI - Effect of acute cytomegalovirus infection on drug-induced SLE. AB - A 58 year old woman developed systemic symptoms, interstitial lung disease, splenomegaly, leukopenia and anti-histone and anti-nuclear antibodies (ANA), while treated with hydralazine for hypertension. Five months after presentation she was admitted with high fever, skin rash and atypical lymphocytosis due to acute cytomegalovirus (CMV) infection. Worsening leukopenia and increased ANA were found, and high titres of anti-DNA antibodies, anti-cardiolipin antibodies and rheumatoid factors appeared. Hydralazine was stopped and the patient gradually became asymptomatic. All autoantibodies spontaneously disappeared (over 16 weeks), and the white cell count and spleen size became normal. The patient was found to be a slow acetylator and to have both HLA-DR4 and selective IgA deficiency. Thus, a multifactorial genetic susceptibility to develop drug-induced lupus was brought out in stages first by hydralazine and then by CMV, yet all manifestations and autoantibodies resolved spontaneously, demonstrating the complex interplay of varied environmental factors with a genetic predisposition in the pathogenesis of autoimmunity. PMID- 7831175 TI - A small cell bronchogenic carcinoma associated with tumoral hypophosphataemia and inappropriate antidiuresis. AB - A patient is described with small cell carcinoma of the lung, associated with profound hypophosphataemia and hyponatraemia. Increased phosphate excretion and inappropriately high urine osmolality were observed. The abnormalities are consistent with tumoral hypophosphataemia and inappropriate antidiuresis. These tumour-related metabolic abnormalities have only been described once before with this malignancy. PMID- 7831174 TI - The association of systemic lupus erythematosus and myasthenia gravis. AB - Two women with the rare association of systemic lupus erythematosus (SLE) and myasthenia gravis (MG) are reported. The first patient developed SLE (arthritis, severe thymectomy for MG. The second patient developed SLE (oral ulcers, arthritis, serositis, leukopenia, high titres of anti-DNA and anti-nuclear antibodies) 4 years prior to the clinical and serological onset of MG. Lymphocyte subsets and in vitro proliferative responses of peripheral blood mononuclear cells to mitogens were normal in both patients. A review of the literature revealed 26 additional patients with definite SLE coexisting with MG. Besides the theoretical interest of this association, the differential diagnosis of fatigue in patients with SLE should always include the possibility of MG. PMID- 7831176 TI - Pseudohyperkalaemia associated with hereditary spherocytosis in four members of a family. AB - Pseudohyperkalaemia was detected in four members of a family all of whom have hereditary spherocytosis with normal white blood cells and platelets counts. The degree of pseudohyperkalaemia was related to the time between sampling and cell separation, and inversely related to the temperature in which the sample was left to stand before cell separation. A fifth member of this family was free from both conditions. The association suggests linkage at a membrane level. PMID- 7831177 TI - A virilized patient with congenital hemihypertrophy. AB - An 18 year old woman with congenital hemihypertrophy of her left side, presented with the rapid onset of virilism, hypertension and a cushingoid appearance. A computed tomographic examination revealed adrenal and hepatic masses. Adrenocortical carcinoma was confirmed by surgical pathology. Hemihypertrophy is linked to a variety of benign and malignant disorders that usually appear during childhood. These disorders include adrenocortical carcinoma and hepatoblastoma. We bring this case to clinical attention to increase awareness that adult patients with congenital hemihypertrophy are still at a significant risk of developing neoplasms. PMID- 7831178 TI - Microembolism from aortic aneurysm and ventricular thrombus: a complication of intravenous streptokinase. AB - Two patients sustained the rare complication of skin infarction following administration of intravenous streptokinase for acute myocardial infarction. We report evidence that dissolution of thrombus from an unsuspected source and subsequent microembolization of the skin may be responsible for this complication. In patients known to have an aortic aneurysm or ventricular thrombus, careful consideration should be given to the use of intravenous streptokinase following myocardial infarction. PMID- 7831179 TI - Aggressive management of doxorubicin-induced cardiomyopathy associated with 'low' doses of doxorubicin. AB - There is a dose-effect relationship between doxorubicin and the incidence of symptomatic cardiac failure. It is generally thought that doses below 500-550 mg/m2 are safe but, when objective measures of cardiac function are used, it becomes apparent that degrees of cardiac failure occur at doses below this. We present here the case histories of two patients who developed very severe cardiac failure at cumulative doses well below 500 mg/m2 but who survived their initial cardiac illness due to aggressive intervention. In one case, the patient was successfully treated by orthotopic cardiac transplantation. PMID- 7831180 TI - Bilateral foot drop, weight loss and rectal bleeding as an acute presentation of Crohn's disease. AB - We report a 71 year old lady who presented with weight loss, rectal bleeding and bilateral foot drop having been previously fit and well. Clinical examination, laboratory investigation and postmortem examination confirmed the diagnosis of active Crohn's disease and acute peripheral neuropathy. The clinical course of this patient suggests that the peripheral neuropathy might have resulted from the common pathogenesis for Crohn's disease. PMID- 7831181 TI - Cerebellar dysfunction following dextropropoxyphene-induced carbamazepine toxicity. PMID- 7831182 TI - Heavy metal intoxication from homeopathic and herbal remedies. PMID- 7831183 TI - Selenium deficiency, reversible cardiomyopathy and short-term intravenous feeding. PMID- 7831184 TI - Oesophageal carcinoma presenting as isolated malignant hypercalcaemia. PMID- 7831185 TI - Watermelon stomach in the CREST syndrome. PMID- 7831186 TI - Cardioprotective therapeutics--drugs used in hypertension, hyperlipidaemia, thromboembolization, arrhythmias, postmenopausal state and as anti-oxidants. PMID- 7831187 TI - An unusual case of dysphagia. PMID- 7831188 TI - Polycythaemia rubra vera presenting with severe glossitis. PMID- 7831189 TI - A case of recurrent eclampsia. PMID- 7831190 TI - Balance between cortical 5-HT1A and 5-HT2 receptor function: hypothesis for a faster antidepressant action. PMID- 7831191 TI - Regulation of interleukin 6 production by cAMP-protein kinase-A pathway in rat cortical astrocytes. AB - In this study we analysed the involvement of the cAMP-protein kinase-A system in the regulation of interleukin 6 production by cultured cortical astrocytes. Vasoactive intestinal peptide strongly increased, in a dose-dependent manner, interleukin 6 production. This effect was reduced when protein kinase A was blocked by KT-5720; it was not affected by calphostin C, a protein kinase C inhibitor. Forskolin caused a concentration-dependent increase in interleukin 6 release, that was also inhibited by KT-5720. Since prostaglandins are believed to play a role in interleukin 6 production, we tried to determine whether the stimulatory effects of vasoactive intestinal peptide and forskolin on cytokine release might be mediated by stimulation of prostaglandin production in cortical astrocytes. Vasoactive intestinal peptide did not increase the production of either prostaglandin E2 or F2 alpha. Conversely, forskolin concentration dependently stimulated the production of both prostaglandins, an effect that was blocked by indomethacin. Indomethacin did not affect either vasoactive intestinal peptide- or forskolin-stimulated interleukin 6 production. To exclude the possibility that prostaglandins participate in interleukin 6 production induced by forskolin, we tested the effect of prostaglandins E2 and F2 alpha on the cytokine production. The former was completely ineffective in eliciting the cytokine production, while prostaglandin F2 alpha slightly increase interleukin 6 only at the highest concentration. 8-Br-cAMP and (BU)2- cAMP stimulated interleukin 6 production to a lesser extent than vasoactive intestinal peptide and forskolin. In conclusion, we provide evidence that vasoactive intestinal peptide increases interleukin 6 production by astrocytes through the stimulation of the cAMP-protein kinase-A pathway, an effect that is reproduced by cAMP analogues. In addition, we point out that prostaglandins are not involved in vasoactive intestinal peptide- and forskolin-mediated induction of interleukin 6 production in cultured astrocytes. PMID- 7831192 TI - Interleukin-1 beta- and tumour-necrosis-factor-induced inhibition of rat gastric fundus motility in vitro. AB - In this study, we compared the effects of interleukin-1 beta (IL-1 beta) and tumour necrosis factor (TNF) on in vitro rat gastric fundus motility. IL-1 beta and TNF produced rapid, concentration-dependent relaxation of the rat gastric fundus strips with maximal effect at 300 pg ml-1 and 10 ng ml-1, and estimated EC50S at 10 and 450 pg ml-1, respectively. The relaxant effects of IL-1 beta and TNF were not influenced by the inhibition of cyclo-oxygenase or NO-synthase activities. IL-1 beta- and TNF-induced gastric relaxations were inhibited by BW 755c, which inhibits both cyclo-oxygenase and lipoxygenase (LO), BW A4c, which selectively inhibits the 5-LO pathway, and SC 41930, a selective leukotriene B4 (LTB4) receptor antagonist, providing pharmacological evidence that LTB4 is involved in the relaxant effects of both cytokines. The IL-1 beta- and TNF induced activation of 5-LO pathway did not appear to be triggered by phospholipase A2. An alternative pathway could involve the activation of a phospholipase C, specific for phosphatidylcholine, from which, in sequence: the formation of diacylglycerol (DAG), DAG-induced activation of protein kinase C and the formation of free arachidonic acid from DAG would ensue. This mechanism is suggested by the finding that LTB4 is able to mimic cytokine-induced strip relaxation only in the presence of phorbol 12-myristate 13-acetate, which selectively activates protein kinase C. PMID- 7831193 TI - Cytokines, glucocorticoids and neuroendocrine function. AB - Activation of the immune system is normally associated with widespread alterations in neuroendocrine activity, the profile of which depends upon the species and on the severity and duration of the stimulus. Particularly important in this regard is the activation of the hypothalamo-pituitary-adrenocortical (HPA) axis for the consequent rise in circulating glucocorticoids serves to contain the ensuing pathophysiological responses and thus to restore homeostasis. In the present study, in vivo and in vitro techniques have been used to examine the influence of various immunokines on the HPA axis and to determine whether their actions are modulated by glucocorticoids and lipocortin 1 (LC1). In vivo interleukin-1 beta (IL-1 beta), given orally or peripherally, produced increases (P < 0.01) the serum corticosterone concentration which were reversed by pretreatment with dexamethasone. IL-1 beta also produced glucocorticoid reversible increases in the release of the two corticotrophin releasing factors, CRF-41 and AVP, from the hypothalamus in vitro (P < 0.01) as also did IL-1 alpha, IL-6 and IL-8. By contrast, none of these cytokines influenced directly the release of ACTH from pituitary tissue in vitro. The inhibitory actions of the glucocorticoids on the HPA responses to cytokines observed in vivo and in vitro were mimicked by LC1 and reversed by neutralizing anti-LC1 antisera. Our results demonstrate a role of cytokines, glucocorticoids and LC1 in effecting the interplay between the brain-neuroendocrine and immune system which may be critical to host defence in conditions of both health and disease. PMID- 7831194 TI - Dexamethasone and interleukins modulate apoptosis of murine thymocytes and peripheral T-lymphocytes. AB - Glucocorticoid hormones (GCH) induce apoptotic cell death in immature thymocytes through an active process, characterized by extensive DNA fragmentation into oligonucleosomal subunits. This requires macromolecular synthesis and is inhibited by interleukins (ILs). We performed experiments to analyse the possible effect of GCH on more differentiated lymphocytes, i.e. peripheral (from lymph nodes and spleen) T-lymphocytes. The results show that in vitro dexamethasone (DEX) induces DNA fragmentation and cell death not only in thymocytes but also in mature T cells. We also tested the possible role of interleukins (ILs) in the modulation of apoptotic cell death. We show that DEX-induced apoptosis is inhibited by IL-2 and IL-4 and that the IL-4 induced inhibition correlates with induction of c-jun (a component of AP-1 transcription factor). Furthermore high doses of IL-2 are able to induce apoptosis in both thymocytes and peripheral T cells. These data indicate that both thymocytes and peripheral T cells undergo apoptosis in response to appropriate stimuli and suggest that GCH and ILs interact in regulating T-lymphocytes apoptotic death. PMID- 7831195 TI - Cytokines, glucocorticoids and lipocortins in the control of neutrophil migration. AB - By using a simple murine air-pouch technique we were able to measure an intense neutrophil infiltration in response to the local application of specific pro inflammatory stimuli such as interleukin-1 and interleukin-8. The role of endogenous and exogenous lipocortin 1 on this cellular migratory response was evaluated. Exogenously i.v. administration of human recombinant lipocortin 1 and its N-terminus peptide Ac2-26 dose-dependently inhibited IL-1-induced neutrophil migration with calculated ED50 values of 5.18 +/- 0.74 micrograms and of 88.0 +/- 13.1 micrograms per mouse, respectively. Direct injection of these agents into the pouch was ineffective. In keeping with these observations, the inhibitory action exerted by dexamethasone, in both IL-1- and IL-8-induced cell infiltration, was abrogated by passive immunisation of mice with specific anti lipocortin 1 antibodies. In conclusion, lipocortin 1 is not only a mediator of some of the anti-inflammatory actions of glucocorticoid hormones, but can also modulate the effect that specific cytokines have on the trafficking of highly specialised cells like the neutrophils. PMID- 7831196 TI - Glutamine metabolism and utilization: relevance to major problems in health care. AB - Glutamine plays an important role in normal and pathophysiological states. In this review we describe the biochemical synthesis and degradation pathways of glutamine, as well as its utilization by the immune system and in rapidly dividing cells. Also discussed are glutamine behaviour in catabolic states and the therapeutic implications of this amino acid in total parenteral nutrition, digestive diseases and cancer. PMID- 7831197 TI - Potentiation by capsaicin of lidocaine's phasic impulse block in isolated rat sciatic nerve. AB - Compound action potentials (CAPs) of A- and C-fibres were recorded from isolated sciatic nerves of the rat to determine whether lidocaine-induced phasic impulse block was affected by low doses of capsaicin. Preceding impulse activity produced phasic reductions of the amplitudes of both A- (5.7 +/- 1.3%) and C-CAPs (20.7 +/ 7.0%) in drug-free solution. Capsaicin alone (50 microM) did not change the activity-induced reductions of the heights of both CAPs (A-CAP: 6.2 +/- 1.7%, C CAP: 22.3 +/- 8.0%). Lidocaine (100 microM) caused differential phasic blocks between the A-CAP (20.1 +/- 3.7%; n = 7) and the C-CAP (33.8 +/- 4.9% n = 7). Lidocaine's phasic impulse block was potentiated after 30 min of subsequent capsaicin administration (A-CAP: 40.6 +/- 4.7%, n = 7; C-CAP: 48.8 +/- 5.5% n = 9). Capsaicin's phasic potentiating effects were reversed after 30 min of washing. These results suggest that capsaicin may be a useful agent for the reversible potentiation of phasic impulse blockade by lidocaine. PMID- 7831198 TI - Effects of 8-chloro-cyclic adenosine monophosphate on the growth and sensitivity to doxorubicin of multidrug-resistant tumour cell lines. AB - We examined the in vitro effects of 8-chloro-adenosine 3':5'-monophosphate (8-Cl cAMP), a reportedly stable, potent and site-selective analogue of cAMP, on the proliferation and sensitivity to doxorubicin (DXR) of two mouse cell lines, the B16 melanoma and Friend leukaemia, both as wild-type (B16, FLC) and DXR-resistant (B16/DXR, FLC/DXR) variants. The latter strains had characteristics of 'typical' multidrug resistance (MDR), including the over-expression of P-glycoprotein. Encouragingly, 8-Cl-cAMP affected almost equally the growth of the chemosensitive and chemoresistant variants of both cell lines. Its activity proved to be much more elevated on cells cultivated with fresh rather than heat-inactivated calf serum. In fact, the IC50 values for B16 and B16/DXR were about 4.7 microM in fresh serum and 215 microM in heat-inactivated serum; the IC50 values for FLC and FLC/DXR were about 12 microM in fresh serum and 70 microM in heat-inactivated serum. Furthermore, experiments with B16 showed that cotreatments with isobutylmethylxanthine (IBMX), a phosphodiesterase inhibitor, or adenosine deaminase (ADA) greatly reduce the activity of 8-Cl-cAMP bringing it to comparable levels in fresh and heat-inactivated serum. These results indicate that the antiproliferative effects of 8-Cl-cAMP may be due principally to metabolites formed by the enzymic activities of the serum, most probably including 8-chloro-adenosine (8-Cl-adenosine), as suggested by other authors. Moreover, the dose-response curves and the IC50 values of the latter compound for the various cell lines were compatible with those observed for 8-Cl-cAMP in fresh serum. Finally, there was no evidence that 8-Cl-cAMP, either in the presence of fresh or heat-inactivated serum, or 8-Cl-adenosine may increase the sensitivity to DXR of the MDR variants of B16 melanoma and Friend leukaemia. PMID- 7831199 TI - Fractionation of rat liver tRNA by reversed-phase high performance liquid chromatography: isolation of Iso-tRNAs(Pro). AB - This paper illustrates the fractionation of cytoplasmic transfer ribonucleic acid from rat liver by reversed-phase high performance liquid chromatography using a gradient of acetonitrile/ammonium acetate. The procedure is fast, highly reproducible, and gives an excellent resolution of the numerous tRNA population: about 50 peaks with area peak percentages ranging from 0.001 to 5 can be monitored. Uncharged tRNA preparations exhibited a chromatographic profile different from aminoacylated tRNA, thus suggesting a possible strategy to distinguish between aminoacylated and nonacylated tRNA species. Moreover, a first approach to map the HPLC peaks was attempted by chromatographing preparations of tRNA which had been aminoacylated with individual 3H-labeled aminoacids. Here is reported the case of tRNA(Pro), which gave three well separated radioactive peaks, most likely corresponding to tRNA(Pro) isoacceptor species. PMID- 7831201 TI - A novel technique for isolation of pure sperm heads from disintegrated mammalian spermatozoa. AB - The phenomenon of differential charge distribution on sperm surface membrane has been utilised here in a low e.m.f. (electro motive force) capillary electrophoresis system to effect separation of sperm heads from disintegrated mixed spermatozoal subfractions. Washed caudal sperm of goat (Black Bengal variety) and ejaculated washed human sperm were fractionated by sonication into head, mid-piece and tail portions. Routine techniques of density gradient centrifugation on Percoll and/or sucrose were performed with sonicated spermatozoa for separation into their respective subfractions. The products obtained were not free of contamination in either case. Mixed sperm fractions when subjected to the afore mentioned modified capillary electrophoresis technique only the head pieces exhibited high affinity for migration towards the cathode terminal. With this method around 50% of the total sperm heads were separated and collected in absolutely pure form at the cathode side within 2 hrs. at 150 volts (V) and 1.5 milliampere (mA) current at 37.5 degrees C. A 4 cm. long capillary tube with a bore size 1.2 mm. was used for this purpose. PMID- 7831200 TI - Fast purification of Phaseolus vulgaris isolectins. AB - Phytohemagglutinin from red kidney bean has been purified by affinity chromatography on a human alpha 1-acid glycoprotein Sepharose 4B column. Further purification of the hemagglutinin's five isolectins was achieved on a Mono S column with an 86% protein recovery. Each sequentially eluted isolectin from the ion exchange column displayed either hemagglutinating or mitogenic activity. The main activity of each fraction was the result of the combination of varying proportions of the L and E subunits. PMID- 7831202 TI - Purification and properties of cow splenic biliverdin reductase. AB - Biliverdin reductase was purified from cow spleen. The specific activity of the final enzyme preparation was 24.01 u/mg, representing 686-fold purification as measured with NADPH. The yield was 3 grams of enzyme per 100 grams of cow spleen. The purified enzyme was a monomeric protein with an apparent molecular weight of about 34,000 and an isoelectric point of about 6.2. The biliverdin reductase was specific for biliverdin and reduced IX alpha faster than the biliverdin isomers IX beta, IXr, or IX delta. The purified enzyme could utilize both NADH and NADPH, but the kinetic properties of the NADH-dependent and the NADPH-dependent enzyme activities were different: the time course of the NADPH-dependent reaction displayed a sigmoidal curve, whereas that of the NADH-dependent reaction did not. Km for biliverdin IX alpha was 4 x 10(-4) mM in the NADPH system, while it was 1.5 x 10(-3) mM in the NADH system. Both enzyme activities were inhibited by excess biliverdin, but the inhibition of the NADPH-dependent enzyme activity was more pronounced. The pH optimum was 7.0 with NADH, and 6.8 with NADPH. PMID- 7831203 TI - Purification and characterization of triokinase from porcine kidney. AB - In order to be able to use triokinase for the enzymatic assay of tissue glyceraldehyde, we purified the enzyme to homogeneity from porcine kidney and characterized its biochemical properties. The purification was performed by polyethylene glycol fractionation, anion exchange chromatography, hydroxyapatite chromatography, hydrophobic chromatography, and gel filtration. The enzyme was purified 937-fold from the crude extract with an overall yield of 28%. It had a molecular weight of 122,000 and was a dimer composed of identical subunits. The optimal pH and optimal temperature were 7.0 and 60 degrees C, respectively. This enzyme was stable when incubated at pH 7.0 at 40 degrees C for 1 h in the presence of 0.1 mg/ml bovine serum albumin. No loss of activity occurred for at least 1 month when the enzyme was stored at 4 degrees C in the presence of 1 mM dithiothreitol and 15 mM NaN3 under N2. Only three compounds, i.e., D glyceraldehyde, dihydroxyacetone, and glycolaldehyde, acted as the substrate of the enzyme, having Km's of 11, < 5, and 260 microM, respectively. The Km for ATP Mg2+ was 68 microM. These results indicate that porcine kidney triokinase has properties advantageous for the glyceraldehyde assay using glyceraldehyde-3 phosphate dehydrogenase as a coupling enzyme. PMID- 7831204 TI - Purification of rat liver glucokinase. AB - A new purification method for rat liver glucokinase was developed. Glucokinase was purified to homogeneity in a yield of 70% in 5 days. The procedure consists of DEAE-cellulose ion-exchange chromatography, QAE-Toyopearl ion-exchange chromatography, glucosamine-Sepharose affinity chromatography, and HiLoad Superdex 200 gel filtration. Purified glucokinase had a specific activity of 200 units/mg protein and was highly stable in the presence of 100 mM glucose, 300 mM KCl, and 20% glycerol. We found that some of the methionine residues of glucokinase were oxidized to methionine sulfoxide residues during dialysis in the presence of glucose. It would appear that this oxidation is caused by formation of hydroxyl radicals in the presence of glucose and contaminating transition metal(s). PMID- 7831205 TI - Joint chromatographic purification of bovine serum ceruloplasmin and amineoxidase. AB - A purification procedure leading to a joint separation of two serum copper enzymes: ceruloplasmin (EC 1.16.3.1) and amineoxidase (EC 1.4.3.6), is described. Both enzymes are obtained in electrophoretically homogeneous form and their specific activities are higher than those obtained by previously described purification techniques. Two common steps: precipitation of bovine plasma proteins with ammonium sulphate (at 35% and 55% saturation) followed by column chromatography on AE-Agarose (obtained by treatment of agarose beads with 1 chloro-2-ethylamine), lead to an electrophoretically homogeneous ceruloplasmin. At the same time, the ceruloplasmin-free protein preparation eluted in a first peak, following further Q-Sepharose and Con A-Sepharose chromatography, leads to purified bovine serum amine oxidase (BSAO) with an improved yield. The emphasis was given to a mutual improving effect as a consequence of the integration of the two enzymes purification procedures. PMID- 7831206 TI - Purification and characterization of lysine- and arginine-specific gingivain proteases from Porphyromonas gingivalis. AB - Four gingivain proteases, active in presence of L-cysteine, were purified from spent culture media of oral pathogen Porphyromonas gingivalis by ion-exchange chromatography on MonoQ and chromatofocusing on MonoP columns. Three of the purified proteases, with molecular masses of 75 kDa, 70 kDa and 55 kDa, respectively, hydrolyzed synthetic chromogenic substrates with arginine in the P1 position. One protease, with a molecular mass of 80 kDa, hydrolyzed substrates with lysine in the P1 position. It is proposed these enzymes be named: arg gingivain-75, arg-gingivain-70, arg-gingivain-55, and lys-gingivain-80, respectively, based on their molecular mass and specificity for either arginine or lysine in the P1 position. PMID- 7831207 TI - Purification and characterization of bovine heart glycogen synthase kinase-3. AB - Glycogen Synthase Kinase-3 (GSK-3) was isolated from bovine heart tissue extracts by a procedure involving ammonium sulfate fractionation, followed by chromatography on phosphocellulose, Cibacron blue 3GA-agarose, DEAE-Sephacel, CM Sepharose, heparin-agarose, myelin basic protein-Sepharose, and LiChrospher 1000 C00-. GSK-3 was identified by its activation of protein phosphatase-1i (PP-1i). The purified enzyme had a specific activity of 25,500 units of protein phosphatase-1i activated/mg protein. The enzyme is an asymmetric monomeric protein of 53 kDa. The molecular size and retention of activity after autophosphorylation indicated that the isolated enzyme was the GSK-3 alpha isoform. PMID- 7831208 TI - Improved large-scale purification of transducin, and its alpha and beta gamma subunits from frozen retinas. AB - The transducin heterotrimer and its alpha- and beta gamma-subunits have been purified from frozen bovine rod outer segments by modifying existing procedures. The methods described here are relatively simple and fast. The yield (ca. 8 mgs/100 retinas) and purity of the transducin heterotrimer and subunits from frozen retinas is equal to or larger than those previously obtained from fresh or frozen retinas. PMID- 7831209 TI - Rapid purification of yeast cytoplasmic fumarate reductase by affinity chromatography on blue sepharose CL-6B. AB - The rapid and effective purification of soluble fumarate reductase from baker's yeast achieved by Blue Sepharose CL-6B chromatography. Cibacron Blue F3GA, the chromophore of Blue Sepharose, inhibited the activity of fumarate reductase. The enzyme bound to the column was selectively eluted by flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN) or riboflavin. The purified enzyme was essentially homogeneous as indicated by polyacrylamide gel electrophoresis under nondenaturing conditions and under denaturing conditions in sodium dodecylsulfate. By this procedure, the enzyme could be rapidly purified with high yield from yeast cells. PMID- 7831210 TI - A rapid method for the purification of large amounts of an alpha-complementing peptide derived from beta-galactosidase (E. coli). AB - A DNA segment coding for residues 6-44 of beta-galactosidase was ligated to a vector with the glutathione-S-transferase gene which also contained a sequence coding for a thrombin recognition site. The fused protein, with an additional 9 amino acids coded for by the vector, was purified using a glutathione agarose affinity column. A peptide made up of residues 6-44 of beta-galactosidase and the 9 additional amino acids was then cleaved from the glutathione-S-transferase using thrombin and purified with a gel filtration column. The peptide was about 3 4 times as active for alpha-complementation as the alpha-peptide derived from CNBr digestion of wild type beta-galactosidase. PMID- 7831211 TI - [Present status and new approach to anti-parasite therapy]. AB - New highly effective molecules have been developed for the treatment of human parasites due to the development resistances and newly described types of parasitosis. In man as in animals, chemoresistant strains of parasites are rare, even for Plasmodium species where decreased sensibility has been observed basically due to monotherapies given for too short periods. Many resistance mechanisms have been elucidated. Most antiparasite drugs are metabolized in the liver and alterations in the mitochondrial oxidative system, particularly in hepatic fasciolasis and amibiasis, may limit the production of active derivatives. Modifications in the host-parasite relations may also have an effect as has been observed in patients with acquired immunodeficiency syndrome. Several approaches suggest new therapeutic perspectives. Since most protozoa require large amounts of energy to maintain motility and asexual reproduction, blocking aerobic glycolysis has been suggested but is limited by toxic effects. Blocking protein metabolism is another possibility since intracellular protozoa cannot synthesize purines. Parasites also rely on the host for cholesterol, phospholipids and other lipids and blocking their uptake into the parasite is another possibility. Promising results have been obtained in vitro against Plasmodium berghei and P. chabaudi. Other approaches include inhibiting drug outflow from the parasite incapable of metabolizing it. Nonesense oligonuclides could be coupled with active drugs and induce irreparable damage to the parasite. In addition to these new therapeutic possibilities, better use of traditional drugs should be emphasized.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7831213 TI - Sleep apnoea in acromegaly--prevalence, pathogenesis and therapy. Report on two cases. AB - It has long been known, that irregular, heavy snoring and daytime sleepiness are common features of acromegaly. Only recently has the high incidence (30-60%) and clinical relevance of the sleep apnoea underlying these symptoms been recognized. Both diseases have a group of common symptoms and prognostic features: Increased cardiovascular and respiratory mortality, elevated incidence of hypertension, daytime sleepiness, decreased vitality, headaches and depression. These are very prominent in sleep apnoea and often reversible under treatment. In acromegaly their etiology has been widely unexplained and they commonly persist even when human growth hormone (hGH) levels remain normal after operative treatment. We report on 2 patients presenting with excessive daytime sleepiness and severe obstructive sleep apnoea caused by acromegaly. Both had macroglossia and hypertrophy of hypopharyngeal tissues regressive after surgical therapy. The average hGH-levels were 20 and 31 ng/ml before and 3 and 1.7 ng/ml several months after operation respectively. Apnoea indices and minimal oxygen saturations (SO2) were 59/h and 55/h, and 60% and 58% initially and improved postoperatively to 40/h and 50/h, and 72% and 70%. Polysomnographic parameters were normalized by NCPAP-therapy pre- and postoperatively and daytime sleepiness improved dramatically. In one patient the NCPAP-pressure could be decreased postoperatively. Since patients with sleep apnoea have an increased perioperative risk of hypoxia and because transsphenoidal operation and postoperative nasal tamponade were performed, both patients were tracheostomized perioperatively.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7831212 TI - [Emergency colonic surgery. Value of intervention in delayed emergency]. AB - OBJECTIVES: Currently, there is a trend towards emergency colectomy in patients requiring immediate care for lesions involving the large bowel. However, the therapeutic indications have not been fully identified. We therefore retrospectively evaluated our experience with 123 emergency situations. METHODS: Among 745 cases requiring colonic surgery from January 1985 to August 1992, 123 were seen in emergency for intestinal obstruction (n = 69; 56.1%), peritonitis (n = 41; 33.3%) or haemorrhage (n = 13; 10.6%). The mean age of the patient was 71 years and 50% were over 75. The left colon was involved in 76.4% of the cases. Diverticulitis was seen in 43.1% and 39% had cancer of the colon. RESULTS: Emergency resection and anastomosis was performed in 55 cases (44.7%) without colostomy. In 62 patients (50.4%) a colostomy was created; 46 were later removed. In 61 cases, the patients underwent emergency surgery within 24 hours and in the other 62, delayed surgery was performed after one day of hospitalization. Overall hospital mortality was 11.4% (14/123), 20% for patients over 75 and 3.2% for those under 75. Mortality after delayed operations was lower (6.5%) than after emergency surgery (17.2%). There was also a higher rate of colon resections without colostomy in delayed procedures (62.9% vs 26.2%). CONCLUSIONS: Our experience leads us to recommend delayed surgery whenever possible in order to decrease operative mortality and number of operations. PMID- 7831214 TI - [Human herpesvirus-6 infection and hepatitis following heart transplantation]. AB - OBJECTIVES: Human Herpesvirus-6 (HHV-6) has been implicated in hepatitis and HHV 6 infections have been reported in patients receiving heart transplants. We investigated the occurrence of such infections and their possible relation with post-transplantation hepatitis in 58 heart transplanted patients. METHODS: The titre of HHV-6 antibodies was determined by anticomplement immunofluorescence assay and compared with the titre of CMV antibodies determined by using ELISA. RESULTS: HHV-6 seroprevalence after transplantation did not differ significantly between hepatitis, control patients (without hepatitis) and the healthy general population. In three controls and five hepatitis patients we observed, after transplantation, a seroconversion or a significant increase of antibody titre which suggested active HHV-6 infection. In six cases, HHV-6-specific IgM were found whereas CMV-specific IgM were not detected. CONCLUSION: These results indicate that HHV-6 infection is frequent after heart transplantation but not in relation with hepatitis. The mechanism of this infection needs to be clarified (either primo-infection or reactivation) and the question remains whether this infection is totally asymptomatic or could induce serious illness. PMID- 7831215 TI - [Hormonal regulation in breast cancer from cell lines to patients]. AB - Culture of human breast cancer cell lines has made it possible to better understand how oestrogens and anti-oestrogens interact with oestrogen receptors and thus regulate breast cancer cell growth. In addition, since human cell lines are cultured, immunologic and genetic probes can be used to compare in vitro cell behaviour with in vivo tumour development. The discovery of certain proteins, specifically induced by oestrogens and secreted in cell cultures, led us to the hypothesis that oestrogen might influence cell growth via a relay protein secreted by cancer cells. Results obtain in our laboratory over the last 15 years allowed us to define cathepsin D, an oestrogen-regulated protein now under study as a prognostic marker for metastasis. For patients, the implications of such fundamental results are great since clinicians could adapt management on the basis of a more specific prognosis. Nevertheless, it must be kept in mind that although in vitro cell cultures can provides an extremely fruitful model of cancer cell growth, in vivo breast cancer is not equivalent to a mono-layer of epithelial cancer cells growing in a Petri dish. Use of co-cultures and simplified in vivo models may be a new route to further developments. Progress, in terms of patient benefit, depends directly on rapid communications between research laboratories and clinical oncologists engaged in developing new tumour markers. PMID- 7831217 TI - [Fractionated heparins: LMWH or LMMH?]. PMID- 7831216 TI - [Veno-occlusive disease of the liver after bone marrow transplantation. Report of the symposium Autograft in France and the group of study of bone marrow transplantation. France Auto-Greffe et le Groupe d'Etude de la Greffe de Moelle osseuse]. AB - Hepatic veno-occlusive disease is a frequent complication after high-dose chemo- or radiotherapy after bone marrow transplantation and is a major cause of mortality. During the 3 weeks following transplantation, acute major hepatic vascularization is observed together with portal hypertension and weight gain, ascitis and oedema of the lower limbs due to non-thrombotic obstruction of the centrilobular hepatic veins. This report summarizes the observations presented at a French symposium of France Autogreffe and Groupe d'Etude de la Greffe de Moelle osseuse. Different pathogenic processes are implicated including endothelial mechanisms due to toxic factor related to graft preparations and immunosuppressor treatments (methotrexate, cyclosporin), physical factors related to irradiation, immunological factors related to the expression of class II antigens on endothelial cells and viral factors, in particular cytomegalovirus infection. The incidence of veno-occlusive disease varies greatly from one series to another. Two French groups reported 5 and 3 cases among 1991 and 253 autologous grafts respectively (1.2 and 2.3%) while the Seattle group observed 53% among 355 consecutive grafts, although the same clinical criteria were used. Histological criteria include fibrosis around a non-thrombotic occlusion of the centrilobular veins, cytolysis and congestion of the sinuses. Other methods for diagnosis include transjugular biopsy, the suprahepatic pressure and imaging techniques. Prophylactic continuous infusion of low-dose heparin has been associated with a lower incidence. Trials using anti-tumour necrosis drugs and prostaglandin E1 have also been undertaken and show possible effects towards decreasing prevalence.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7831218 TI - [Role of surgery in paraplegia associated with HTLV-1 infection and cervicarthritis on narrow canal]. PMID- 7831219 TI - [Cardiac metastasis of a hepatocellular carcinoma after liver transplantation]. PMID- 7831220 TI - [Severe neutropenia in dengue]. PMID- 7831221 TI - [Prognostic index of community-acquired acute pneumopathies. Validation of the Fine score in 173 hospitalized patients]. PMID- 7831222 TI - [Surgery for lung cancer in patients at the age of 75 years and over]. PMID- 7831223 TI - [Pasteurella pneumotropica skin infection in a child]. PMID- 7831224 TI - [Splenic infarction during P. falciparum and P. vivax malaria]. PMID- 7831225 TI - [Synchronous Hodgkin disease and mycosis fungoides]. PMID- 7831226 TI - [Treatment of inguinal hernia through celioscopy]. PMID- 7831227 TI - [Idiopathic CD4 lymphocytopenia]. AB - In healthy adults the CD4+ lymphocyte count in circulating blood is remarkably stable over a prolonged period. In patients infected with the human immunodeficiency virus (HIV) CD4 counts drop off sharply and can be used as a predictive marker of midterm outcome. However certain case reports of patients with out HIV infection, some reported as early as 1983, have led to a much publicized search for another immunosuppressive retrovirus. In reality no evidence of any such virus has been found and the Centers for Disease Control and the World Health Organisation have now defined the syndrome of idiopathic CD4 lymphocytopenia which includes a CD4 count below 300/mm3 or less than 20% of total lymphocytes in at least two successive counts without anti-HIV antibodies and without a known cause of immune deficiency or immunosuppressor treatment. The syndrome is extremely rare and although only recently identified, is probably not new. No endemic zone is known and there is no evidence of inter-human transmission. The clinical presentation is different from HIV infection. Although patients are susceptible to opportunistic infections, CD4 counts have relative stability and no hypergammaglobulinaemia occurs. Idiopathic CD4 lymphopenia is probably a primary immunodeficiency syndrome. PMID- 7831229 TI - [Elevation of lipoprotein(a) levels in patients following transplantation for ischemic cardiopathy]. AB - OBJECTIVES: Increased levels of serum lipoprotein (a) in heart transplant patients has been recently shown to be related to early recurrence of coronary artery disease. In order to evaluate the effect of the ischaemic origin of the heart disease we compared lipoprotein (a) levels observed in heart transplant patients who underwent transplantation due to ischaemic heart disease and non obstructive cardiomyopathy with those in healthy control subjects. METHODS: Serum levels lipoprotein (a) were measured in 62 cardiac transplantation recipients who had a hyperlipidemia. The results were compared with those of 212 control subjects matched for age and who were referred for hyperlipidemia. RESULTS: In the whole population 40 patients had been operated on for coronary heart disease and 22 for idiopathic cardiomyopathy. The two populations did not differ with regard to their cardiovascular risk factors except for the smoking status. The mean Lp(a) values were significantly higher in the subjects with coronary heart disease as compared with those with idiopathic cardiomyopathy (0.33 +/- 0.24 and 0.21 +/- 0.17 mg/dl respectively; p < 0.05). The latter were not different from the control group (0.22 +/- 0.19 mg/ml). We did not find any difference between the two populations concerning the drugs taken by the patients (especially cyclosporine), LDL-cholesterol, creatinine, fasting blood glucose and TSH. CONCLUSION: Our data confirm the relation between coronary atherosclerosis and high lipoprotein (a) levels. PMID- 7831228 TI - [Oropharyngeal flora. Epidemiologic survey of prevalence]. AB - OBJECTIVES: Epidemiological surveys which are not frequently carried out in medical practice should provide useful information for the choice of antibiotics to be prescribed in community-acquired infections particularly with the recent development of therapeutic difficulties due to resistant strains. We therefore analyzed the prevalent pharyngeal flora in a general patient population. METHODS: The study was conducted during a single 24-hour period in 1991 by 43 general practitioners and included 645 subjects consulting for benign affections. No patient selection was made. Two pharyngeal swabs were obtained from each subject and cultured in aerobic and anaerobic conditions. Internationally accepted methods for identifying bacteria in pharyngeal samples all performed by one well equipped laboratory. Beta-lactamase activity was determined with the nitrocephine technique, both directly and after culture. RESULTS: Patient age varied from 16 to 45 years; most (68.5%) consulted for reasons other than ear-nose-throat affections. Only 41 patients (4.3%) consulted for sore throat and 65.4% had not received antibiotics for at least 6 months. Haemophilus influenzae was found in 59.6% of the patients, 20% of the strains were beta-lactamase producers as were 83.7% of the Moraxella catarrhalis strains identified. CONCLUSION: These factors are indicators of potential risk of therapeutic failure when using beta-lactams unstable to beta-lactamases for the treatment of pharyngeal infections. PMID- 7831230 TI - [Cerebral protection by retrograde perfusion in the treatment of acute aortic dissection]. AB - Four consecutive patients underwent resection and graft replacement of ascending aorta or aortic arch for acute dissection. Retrograde cerebral perfusion (RCP) was used during circulatory arrest. RCP at 15 degrees C was administered through the superior vena cava. Duration of cerebral ischaemia and cardiopulmonary bypass averaged 33 and 156 minutes respectively. Retrograde perfusion flow was regulated from 100 to 800 ml/minute to maintain an internal jugular vein pressure of about 25 cm H2O. All patients survived. Three patients awoke neurologically intact. Minor neurological disturbance was found in 1 patient, he was discharged from hospital at day 11 without any detectable neurological deficit. This technique was attractive because it provided a dry operative field unencumbered by perfusion cannulas or clamps, facilitated construction of a more secure distal anastomosis, and avoided the risk of further injury resulting from the aortic cross clamp. It seems that RCP allows longer circulatory arrest time. PMID- 7831231 TI - [Echography of thyroid nodules. The echography specialist facing the clinician's requirements]. AB - The risk of malignancy in cases of unique non-functional thyroid nodules ranges from 5 to 20% and since definitive diagnosis can only be provided by the pathology examination, surgical removal could be planned in all cases. The clinician however also has the objective of proposing surgery to as few patients with benign nodules as possible and thus calls upon the echographist to help distinguish between malignant and benign nodules. Thus orders for echography carry an intrinsic request for diagnostic arguments, a precise analysis of the characteristics of the nodule and a description of possible multinodular dystrophy as well as an estimation of the probability of malignancy. The echographist's report must include a precise description of each thyroid lobe, the localization of the nodule, its size, contour, echostructure, echogenicity and calcifications. The cervical lymph node chains must also be explored. An analysis of the surrounding parenchyma can frequently confirm multinodular dystrophy. The size of the nodule is the determining factor in predicting malignancy. While for very small nodules, less than 1 cm in diameter, the malignant nature cannot be reasonably predicted, and inversely for very large nodules, invading an entire lobe, it is usually evident, for intermediate sized nodules, echography is a strategic diagnostic tool. No sign is pathognomonic but an association of arguments can favour malignancy: an unique isolated nodule, irregular contours, lymph node enlargement greater than 1 cm. Hypoechogenicity is another important characteristic with a positive predictive value of 50% to 63%. Overall, the sensitivity of echography is good at 75% with specificity of 61 to 83%.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7831232 TI - Role of muscle morphology in the development of insulin resistance and metabolic syndrome. AB - Type IIB muscle fibres are among the most insulin-insensitive muscle fibres and are not adapted to oxidation of fat during muscle work. The first characteristic of this type of muscle fibre most probably reflects or contributes to further development of insulin resistance contribute to further perpetuation of obesity and to the channeling of excess free fatty acids to the liver followed by secondary deterioration of its function. The impaired functioning of the liver is epitomized, among other changes, by impairment of insulin extraction. The increasing hyperinsulinaemia is followed by inhibition of synthesis of specific proteins such as carrier proteins for transporting testosterone (sex hormone binding globulin, SHBG). This results in an increased free testosterone concentration which induces androgenization in women and may further increase insulin insensitivity in abdominal obesity in women. The poor capillarization and changed muscle morphology in spite of great interindividual variety is observed in several pathological conditions characterised by insulin sensitivity (stroke, PCO, hypertension, diabetes, obesity). It is suggested that, in addition to the previous concept of the main role of intraabdominal adipose tissue, even muscles and liver are also important organs contributing to the pathogenesis and development of the metabolic syndrome. PMID- 7831233 TI - [Sinusitis and Bordetella bronchiseptica pneumonia in AIDS]. PMID- 7831235 TI - [Severe antiphospholipid syndrome]. PMID- 7831234 TI - [Cortico-dependent Hashimoto encephalitis]. PMID- 7831236 TI - [Association of sclerosing cholangitis and ankylosing spondylitis]. PMID- 7831237 TI - [Use of implantable chambers for intravenous chemotherapy: let us combine our talents!]. PMID- 7831238 TI - [Conservative treatment of infiltrating breast cancer smaller than 3 cm of diameter. Effect of local control on survival]. AB - Recurrence of breast tumours after conservative treatment is considered by some as a simple prognosis factor marking risk of distant metastasis. Inversely, others consider small recurrent tumours as the starting point of systemic disease and a possible cause of death. These conflicting opinions could lead to highly opposing management decisions. Following one theory, we would be prone see a new wave of mutilating breast resections and following the other, insufficient tumour resection. The question thus becomes how to treat small, < 3 cm, recurrent tumours. Several factors can help in decision making. The risk of metastasis increases with large sized primary tumours, independently of lymph node invasion. The size number of the recurrent tumour(s) also play a role. Studies of the time interval between treatment and recurrence have shown that early recurrence within 24 months is associated with high risk of metastasis suggesting that in such cases local treatment should be combined with systemic therapy. The controversy will continue to be debated, but the essential element of conservative treatment is to control local invasion of small tumours. Surgical exeresis must be complete and irradiation must be delivered with an optimal dose. It would appear reasonable to limit conservative treatment to patients with a 5-year risk of recurrence below 8% and a 10-year risk below 15%. PMID- 7831239 TI - [Chronic lupus erythematosus in lupus disease. Retrospective study of 136 patients]. AB - OBJECTIVES: The aim of this retrospective study of 136 patients was to specify the natural history and the systemic prognosis of chronic cutaneous lupus erythematosus. It has been stated that in most of the cases, the disease only affects the skin. METHODS: From 10 October 1980 to 31 December 1990, 136 patients with the following criteria were included in this retrospective study: clinical signs suggestive of chronic cutaneous lupus erythematosus, characteristic histology, insufficient evidence for the diagnosis of systemic lupus erythematosus. RESULTS: The prevalence of systemic clinical involvement in the population under study was nearly the same as in the general population. The following biologic or immunologic abnormalities were quite common: leukopenia, lymphopenia, thrombopenia (significantly more frequent among patients having widespread chronic cutaneous lupus erythematosus), low titers of complement levels, positive antinuclear antibodies (usually at a low titer). Eleven out of the 136 patients developed systemic lupus erythematosus, most often over 5 years after the onset of the cutaneous lesions. Four cases out of these 11 had poor prognosis: renal and/or neurologic involvement. CONCLUSION: This data suggests that patients with chronic cutaneous lupus erythematosus could benefit from long term follow up, since the course to systemic disease occurs in only a few. Usually, antimalarials used singly or in combination with topical steroids may lead to the clearing of the lesions. Thalidomide will occasionally be useful whenever the disease is unresponsive to the preceding measures. PMID- 7831240 TI - [Cerebral infarction in patients aged 16 to 35 years. Prospective study of 52 cases]. AB - OBJECTIVES: Aetiologies of cerebral ischemic events in young adults are various and often contraversial: atherosclerosis plays a role after age 35 years, cardioembolism is often recognized as the major cause, and numerous new predisposing conditions have been described. To evaluate very premature cerebral infarction, we studied prospectively 52 consecutive patients (34 women and 18 men) aged 16-35 years (mean 28.6 +/- 5.6 years) admitted over a 6-year period for an arterial cerebral infarct identified on CT, on MRI or both. METHODS: All patients were investigated using a standard protocol including cerebral angiography, transthoracic echocardiography, 24-hour Holter ECG monitoring, coagulation inhibitors levels, lupus anticoagulant testing, HIV and syphilitic serologies. Additional investigations were performed in a majority of patients: transesophageal echocardiography in 33, contrast echocardiography in 50, and anticardiolipin antibodies levels in 38. RESULTS: The arterial distribution of infarction did not differ from that of overall stroke patients. Sixteen cases were classified as certain aetiologies, including cardiac diseases with high embolic risk (n = 9), spontaneous arterial dissection (n = 4), moya-moya disease (n = 1), atherosclerosis (n = 1), and inherited antithrombine III deficiency (n = 1). Eighteen cases were classified as possible aetiologies including cardiac diseases with low embolic risk (n = 11) such as mitral valve prolapse or atrial septal aneurysm, miscellaneaous arteriopathies (n = 3) such as arterial dysplasia, antiphospholipid antibodies syndrome (n = 1) and migrainous stroke (n = 3). The 18 last cases were classified as unknown aetiologies, despite all patients but one had at least one vascular risk factor: this group significantly differed from the formers in that the patients were more frequently women using oral contraceptive associated with tobacco consumption, hypercholesterolemia, or both. Two patients died acutely and the survivors were followed 31 +/- 18 months. Three patients experienced recurrent stroke. Functional outcome was assessed using the Rankin scale on admission and 6 to 12 months after the onset of stroke: patients evaluated < or = 2 (no to mild handicap) were 31% on admission and 82% after recovery. Twenty six p. cent remained unable to resume a work. CONCLUSION: Despite extensive evaluation, identification and classification of aetiologies of cerebral infarction in young adults should be cautious because the risk as well as the pathogenesis of many potential causes still need to be defined. PMID- 7831241 TI - [Post-exposure antirabies vaccination. Early serological response to vaccine cultivated on VERO cells using a reduced 2-1-1 schedule]. AB - OBJECTIVES: An abbreviated 2-1-1 schedule for post-exposure rabies vaccination would theoretically lead to more rapid production of specific antibodies than the classical schedule. We measured early serological response to the 2-1-1 schedule. METHODS: Patients consulting the antirabies centre of the Epinal hospital from June 1992 to June 1993 who had never been vaccinated and whose exposure history justified antirabies vaccination were included in this study. Fifty subjects were vaccinated with PVRV (purified vero rabies vaccine, Pasteur Institute) cultured on VERO (vervet monkey origin) cells using the abbreviated 2-1-1 schedule of 2 doses (0.5 ml = 2.5 IU/dose) on day 0 and 1 dose on days 7 and 21. Antirabies antibodies were assayed using the Platelia Rage immunoenzyme method (Diagnostic Pasteur) on day 21. Titres above 0.5 IU were considered to give protection and non-protected subjects were seen again on day 28 for a supplementary dose. RESULTS: Only 34 subjects (68%) had protective antibody titres on day 21, but by day 28, 48 (96%) had acquired immunity. In this study population, the age range was from 1 to 83 years and age over 30 years appeared to delay antibody formation. CONCLUSION: These findings emphasize the importance of initial antirabies immunoglobulins if short incubation in suspected and the need for serological follow-up if delayed antibody formation is suspected (subjects over 30). PMID- 7831242 TI - A simple method to measure red blood cell deformability by centrifugation. PMID- 7831243 TI - [Fluoroquinolones in respiratory infections]. AB - Given orally, currently marketed fluoroquinolones, ciprofloxacin, ofloxacin and pefloxacin are absorbed rapidly, have an excellent diffusion coefficient. They are wide-spectrum first intention antibiotics effective against Gram negative bacilli, staphylococci and intracellular germs such as Legionella, Chlamydiae and mycoplasms. The spectrum does however not include streptococci, and in particular pneumococci, and anaerobic germs. The development of resistant strains, particularly in hospital settings, have been observed and despite their fundamental properties, the use of fluoroquinolones has been restrained for infections of the respiratory tract. Actually, the insensitivity of pneumococci or anaerobic germs means that fluoroquinolones cannot be used empirically for isolated cases of pneumonia or sinusitis. They can however be used successfully, either empirically, in a combination regimen or after identification of the bacteria, for treating infections due to Gram negative bacilli (superinfection of chronic bronchitis or cystic fibrosis, otitis) or intracellular germs (pneumonia). In the near future, when new fluoroquinolones active against pneumococci or anaerobic germs are introduced, therapeutic options will be modified. PMID- 7831244 TI - [Acquired syphilis and HIV infection]. AB - The currently observed increased prevalence of syphilis in subjects with human immunodeficiency virus (HIV) infection could be an expression of an increase in sex-related risks or could result from facilitated viral transmission via ulcerations of the genital organs. In addition, viral-immunological interactions related to HIV infection could affect the natural history of syphilis suggesting that the clinical pictures of the past may be making a comeback due to modified response to syphilis infection. These observations would suggest revising a certain number of the classical diagnostic and therapeutic criteria for syphilis in HIV positive patients. The consequence of these interactions on response to treatment may be the key to the increased number of unsuccessful treatments observed recently and to the increased frequency of early neurological and ocular manifestations of syphilis. Clinicians should revise their therapeutic schemes which have become unadapted to the new situation caused by HIV infection. PMID- 7831245 TI - [Colonic histoplasmosis in AIDS]. PMID- 7831247 TI - [Immunocytochemistry in the classification of pituitary adenoma. 1300 cases]. PMID- 7831246 TI - [Esophageal tuberculosis. A case]. PMID- 7831248 TI - [Sepsis, unknown cause of hypocalcemia]. PMID- 7831249 TI - [Asthma-allergy. Altitude: a study model]. AB - Several epidemiological studies have now established the relationship between atopy and bronchial asthma. The study of the role of altitude in sensitization, bronchial reactivity, clinical symptoms and allergen exposure in asthma is a good model for understanding the disease. It is now demonstrated that in altitude there is a major decrease in the number of mites (one of the major aeroallergens) and a low mite antigenic load (measured with monoclonal antibodies). In altitude, the climatic factor which has by far the greatest effect on the development of mites is indoor relative humidity which is much lower that at sea level. These findings explain the clinical improvement of some asthmatic patients and help understand the association between the presence of indoor allergens and asthma. PMID- 7831250 TI - [Anorectal asynchronism. Clinical, manometric and therapeutic data]. AB - OBJECTIVES: Anorectal asynchronism is a frequent and unrecognized cause of terminal constipation. The aim of this study was to describe clinical and instrumental findings, and results of biofeedback therapy. METHODS: From 1987 to 1991, 18 patients with anorectal asynchronism were studied then treated by biofeedback training. RESULTS: We found high rates of pelvic and perineal trauma (77.7%), of psychogenic factors (6.5%), of urinary incontinence (27.8%). The manometrical study confirmed puborectalis paradoxical contraction during defecation straining, and all the patients could not expel a rectal balloon containing 50 ml of air; non-specific manometrical abnormality was found in 44.5% patients. Excessive stamp of puborectalis muscle was always found at defecography; 77.7% of the patients had incomplete rectal evacuation, and 61.1% had an associated pelvic floor disorder. Biofeedback training was successful, and 88.9% of the patients were cured by 5 or 6 sessions. There was no predictive parameter in our study, but recovery rate seemed to be lower for patients from 45 to 55 years old. CONCLUSION: The diagnosis of the anorectal asynchronism is easily made with manometry and defecography. Treatment with biofeedback gives very good results in almost all patients. PMID- 7831251 TI - [Reference values of lipoprotein(a) in a French population]. AB - OBJECTIVES: The aim of this work is to study the effect of different biological factors that could affect Lp(a) level in a presumably healthy population and to establish reference limits. METHODS: We selected 723 subjects (367 men and 356 women) for the age interval 4 to 64 years for evaluation. RESULTS: The distribution of Lp(a) is not Gaussian; 50.5% of subjects had Lp(a) concentrations under 0.10 g/l and the value for the 75th percentile was 0.27 g/l and 0.57 g/l for the 90th percentile. No relationship was observed between Lp(a) concentration and cholesterolaemia, triglyceridaemia, glycaemia, inflammatory proteins (orosomucoide and CRP), overweight, tobacco consumption and oral contraceptive use. The menopause state in women was a factor correlated with increased Lp(a) but this increase was not significant. Moreover, alcohol consumption (more than 44 g per day in men and more than 22 g per day in women) was associated with lower Lp(a) values. Among familial cardiovascular risks, only paternal listing of hypertension was associated with Lp(a) concentration in men. CONCLUSION: The measurement of Lp(a) in a young subject could be used as a genetic marker of cardiovascular risk associated with abnormal lipid metabolism and thrombosis phenomena. PMID- 7831252 TI - [A new cause of prolonged fever of unknown origin: progesterone substitution therapy]. AB - OBJECTIVES: Over the last 3 years, we examined 15 patients on progesterone substitution therapy who presented prolonged fever. Many explanations had been put forward before the diagnosis was suggested. We recall the thermogenic effect of progesterone. METHODS: Based on a retrospective analysis, we reported the clinical and biological features of 15 patients with prolonged fever due to progesterone substitution therapy and prospectively followed the temperature curves of 9 menopaused women who received substitution therapy for the first time. RESULTS: The 15 case reports were quite typical. Often onset occurred with an acute infectious episode. Following this episode, the patients continued to take their temperature and discovered persistent fever. The context was often one of anxiety-depression rich in functional symptomatology. Laboratory findings included a normal sedimentation rate in all patients. Several days after treatment withdrawal temperature returned to normal. The prospective study confirmed the thermogenetic effect of almost all progesterone substitution drugs. CONCLUSION: The thermogenic effect of natural progesterone is well known but it must be recalled that all progesterone agents with 5-beta metabolites have the same effect. Since metabolic clearance is long, the thermogenic effect may persist for several days after withdrawal. PMID- 7831253 TI - [Helicobacter pylori gastric infections in children]. AB - OBJECTIVES: Numerous reports have established the association of Helicobacter pylori and recurrent abdominal pain in children. We investigated the clinical, bacteriological and therapeutic features of our patients seen over a 1 year period. METHODS: We investigated 121 children during 1992 in Hospital Saint Vincent-de-Paul, Paris. At endoscopy, biopsies were taken and sent for histology and bacteriology and urease testing. A decision regarding treatment by amoxicillin and metronidazol was made after positive results of bacteriology and/or histology. RESULTS: Heliobacter pylori was found in 47 antral biopsies after pathology examination with Giemsa staining alone 16 times, bacterial culture 9 times and both methods 22 times. Abdominal pain was the prominent symptom, occurring in 35.5% of Helicobacter pylori+patients. In 25 of the positive negative patients, a nodular gastritis was observed (53.1%) and in 27.6% of them a weight loss or a delay in weight gain. Few patients became after combined treatment with amoxicillin and metronidazol whereas eradication rates after triple therapy with amoxicillin-metronidazol and H2 antagonist or proton pump blocker were higher. CONCLUSION: Helicobacter pylori related gastritis is a common cause of abdominal complaints in children. The most common symptom is recurrent abdominal pain. Antral nodularity is a peculiar endoscopic finding in children. Two-drug therapy associating amoxicillin-metronidazol is often ineffective to eradicate the bacteria whereas eradication rates after triple therapy amoxicillin-metronidazol and H2 antagonist or proton pump blocker are higher. PMID- 7831255 TI - [Autografts and acute leukemia: 15 years later]. AB - Autologous bone marrow transplantation (ABMT) is now widely used to consolidate patients with acute leukaemia. Results presently available indicate that the leukaemia free survival for adults autografted in first remission of acute myelocytic leukaemia (AML) is in the range of 50%, with better results achieved when using marrow purged with a cyclosphosphamide derivate: mafosfamide. Results in adult patients with acute lymphocytic leukaemia (ALL) autografted in first remission are in the range of 40%. In second remission, results obtained for AML and ALL in adults are in the range of 35% and 20% respectively. In children, results are better. Because ABMT can be used up to 60 years of age and because the transplant related mortality associated with autografting is much lower than the one following allografting, ABMT is now considered as a first choice therapeutic option in the absence of an HLA identical related donor, and/or in older patients. Epidemiologic studies from the "Centre International Greffes de Moelle Osseuse, hopital St-Antoine, Paris" indicate that more than 1000 ABMT are performed each year worldwide for the treatment of acute leukaemias. PMID- 7831254 TI - [Pica. Anomalies in mother-child relations]. AB - A 3-year old boy was referred to a paediatric psychiatry out-patient clinic for major disorders consisting of hyperphagia, intolerance to frustrations and instability since the age of one year, and pica (i.e. the indigestion of non edible substances) since the age of two years. These symptoms developed in a context of greatly disturbed parent-child relations, predominantly made of ambivalence and inability to define limits and interdictions. Conversations with the family are restoring the parental roles and improving the child's symptoms. PMID- 7831256 TI - [Management of asymptomatic hyperparathyroidism]. AB - Over the last 20 years, widespread assay of serum calcium in patients with diverse and often minor symptomatology and its introduction into routine check-up lists in perfectly healthy subjects has led to the identification of asymptomatic hyperparathyroidism defined as apparently isolated hypercalcalcaemia. In most subjects, the diagnosis is easily confirmed by assaying intact parathormone 1-84. The real problem is management of this condition, particularly in elderly subjects. Due to the lack of any truely effective medical treatment, the only alternative is between abstention and surgical exeresis. A critical analysis of the literature on the risks involved in untreated asymptomatic hyperparathyroidism compared with surgery indicates that the decision can be simple in certain specific cases. Surgery is indicated in young subjects and abstention in case of patient refusal or contraindications for surgery. In all other cases, age, the possibility of prolonged follow-up and patient demands must be carefully weighed before decision making. Prospective studies comparing abstention and surgery are needed to determine prognostic criteria. PMID- 7831257 TI - [Ischemic spinal cord disorders]. AB - Infarcts in the territory of the anterior spinal artery usually are located in the Adamkiewicz artery. Onset is either sudden or progressive with clinical signs of deficit and spinal pain of short duration. The extent and distribution of the deficit depends on the extension and the level of the spinal lesions. A perfect knowledge of the spinal cord vascularization is required to discern the complex and variable clinical expression. Unlike cerebral vascular events, emboli or cardiac origin are rarely involved in spinal cord events. Aortic pathology, including surgery of the aorta, is however of major importance in ischaemic spinal cord syndromes. Several reports have shown that atheroma causing spinal cord ischaemia are not located in the perispinal arterial network but lie on the aorta and its spinal branches. Dissection of the aorta is found responsible in 2 to 8% of the cases. Isthma stenosis can also give spinal cord signs and syphylitic arteritis is exceptionally encountered. Other rare causes are gas emboli and fibrocalcium emboli. PMID- 7831258 TI - [Generalized resistance to thyroid hormones. A new familial case]. PMID- 7831259 TI - [Does the consumption of various solanaceous plants carry a risk of nicotine poisoning?]. PMID- 7831260 TI - [Horton disease-hyperthyroidism association]. PMID- 7831261 TI - [Digestive echo-endoscopy]. AB - Since its introduction into clinical practice in 1980, echo-endoscopy has greatly contributed to improving our capacity to image the digestive tract and now plays a major role in management of digestive tract diseases. Echo-endoscopy is a second intention technique reserved for further investigation of lesions previously identified by endoscopy or other imaging techniques. All five layers of the wall and surroundings of the accessible structures (oesophagus, stomach, duodenum, rectum and colon) can be visualized. Evaluation of locoregional extension of cancer invasion is one of the predominant indications. For example, since the prognosis of tumours of the oesophagus are directly related to parietal and lymph node extension, echo-endoscopy would be indicated to precisely determine the tumoural stage and thus help in adapting therapeutic management. Today, it is generally accepted that echo-endoscopy is superior to computed tomography for staging tumours of the oesophagus and the cardia. For gastric and duodenal adenocarcinomas, the performance of echo-endoscopy is similar and can identify more readily superficial lesions accessible for photocoagulation. For adenocarcinoma of the rectum, echo-endoscopy can be used to identify the tumoural stage and local extension and thus help in therapeutic decision making. Other classical indications include the evaluation of submucosal tumefaction and biliopancreatic disorders (biliary lithiasis, pancreatitis, tumours). Thus for certain well-defined indications, echo-endoscopy is now the highest performing imaging technique currently available for lesions of the digestive tract. Operator experience is however a limiting factor, emphasizing the need for clinical training. PMID- 7831262 TI - [Prevention of Pneumocystis carinii pneumonia associated with HIV infection using pentamidine aerosols. Retrospective study of 465 cases]. AB - OBJECTIVES: At least 80% of human immunodeficiency virus (HIV)-positive patients not given prophylaxis therapy against Pneumocystis carinii develop pneumonia, a major cause of morbidity and mortality. We therefore retrospectively evaluated prophylaxis protocols given from March 1988 to July 1991 at the Pasteur Institute Hospital. METHODS: Pentamidine aerosols were prescribed for 456 HIV-positive patients as primary or secondary prophylaxis. From March 1988 to November 1989 the dose was 4 mg/kg pentamidine mesylate once a month for primary prophylaxis and 4 mg/kg twice a month for secondary prophylaxis. From November 1989 pentamidine isethionate was given at the dose of 300 mg once a month. RESULTS: Tolerance was generally good, treatment had to be discontinued in only 2 of the 456 patients due to side effects. Pneumocystis carinii pneumonia was diagnosed in 4.9% of the treated patients, but in only 2.9% of those who were compliant. Pneumocystis carinii pneumonia occurred in very immunodepressed patients and radiologically appeared as an interstitial or alveolo-interstitial syndrome, often with a macronodular element, in 65% of the patients. CONCLUSION: The results of this retrospective study confirm the prophylactic value of pentamidine aerosols given after trimethoprim-sulfamethoxasol. PMID- 7831263 TI - [Bacterial epidemiology of pharyngitis in pediatric private practice]. AB - OBJECTIVES: While viruses are usually the causal agents of common sore throat in children, bacterial infections cannot be distinguished solely on the basis of clinical presentation. Thus most physicians in France prefer to prescribe antibiotics in order to prevent rheumatismal complications of group A streptococcal infections. We updated current epidemiological data on bacterial pharyngitis in paediatric out-patient clinics. METHODS: A prospective study was conducted from March 1 to June 1, 1992 by 9 physicians. Throat swabs were obtained from 102 controls and from 307 patients with acute pharyngitis. Samples were transferred to the same bacteriology laboratory for examination. RESULTS: The mean age of the children was 6.1 years for patients and 7.2 years for controls. Throat swabs were inoculated for culture within a mean delay of 22.6 hours. Cultures were performed on Columbia blood medium with nalidixic acid and colistin then incubated in CO2 enriched atmosphere and on trypticase blood soy medium + 3.5% NaCl. Group A streptococcal strains were identified by search for beta-haemolysis and latex characterisation of group A polyosides. Group A streptococcal strains were found in 8.8% of the controls and 36.8% of the patients. Groups B, C or G streptococci were found in 10.8 et 11.4% of the controls and patients respectively (NS). Arcanobacterium haemolyticum was never isolated. Clinical association of sore throat, erythematous pharyngitis, fever > 38 degrees C and cervical lymph nodes was found in only 33.63% of the sore throat cases with group A streptococcal infection and in 7.73% of those without group A streptococcal infection (p < 0.0001, sensitivity 33%, specificity 92%). CONCLUSION: These results emphasize the necessity either to treat all pharyngitis or to do throat swabs or rapid group A streptococcal tests for diagnosis. PMID- 7831264 TI - [Gastric metastases of breast cancer]. AB - Breast cancer is the most frequently encountered cancer in women and the first cause of death in the female population. Metastasis may occur ubiquitously depending on the histological type and the presence or absence of oestroprogesterone receptors. We report three cases with gastric metastasis. Signs of gastric involvement are often non-specific and should not be mistaken for simple side reactions to treatment. Hormone chemotherapy is indicated in most situations but surgery may be needed. It should be noted that gastrointestinal metastasis predominates in lobular breast cancers positive for progesterone receptors. PMID- 7831265 TI - [Kaposi's disease in a female patient with acquired HIV-negative immunodeficiency]. AB - A 79-year-old woman of Mediterranean ascent suffered from corticosteroid dependent chronic obstructive lung disease, hypogammaglobulinemia (IgG 1 and 2), decreased CD16 natural killer cell function and non-HIV related CD4 and CD8 lymphopenia. Such immunodeficiency could be either a variant of common variable immunodeficiency or an early stage of the idiopathic CD4 + T lymphocytopenia syndrome. She developed bilateral lesions of Kaposi's sarcoma on the lower extremities resembling the classic European type of the disease. The tumors contained both CD34 + and Factor XIIIa + cells. The HLA-DR5 haplotype was not found. Weekly low intravenous dosages of vinblastine improved the lesions but the patient died from pontic infarction. PMID- 7831266 TI - [Macrolides. New therapeutic prospects]. AB - The aim of the development of semisynthetic derivatives was to overcome the problem of chemical stability of erythromycin A in acid medium, with less variability in gastro-intestinal absorption and leading to renewed interest in macrolides. The new macrolides have the same antibacterial spectrum as erythromycin A including Gram-positive and Gram-negative cocci, intracellular bacteria, mycoplasma, Campylobacter sp., Helicobacter pylori, mycobacteria spp., Gram-negative bacilli including Haemophilus influenzae, Bordetella pertussis, Pasteurella multocida, Gram-positive bacilli including Corynebacterium diphtheriae and anaerobic species. In vitro activity against Haemophilus influenzae is still a controversial subject. Macrolides are among the best tolerated antibacterial agents. Theoretically, macrolides could be given to a large range of patients even those suffering from underlying diseases. The new macrolides, roxithromycin, azithromycin, clarithromycin, dirithromycin, rokitamycin and miokamycin, are indicated for the treatment of upper respiratory tract infections and lower respiratory tract infections due to intracellular bacteria or Mycoplasma pneumoniae. Macrolides could be used as first line therapy for non-gonococcal urethritis, especially those due to Chlamydia trachomatis or Ureaplasma urealyticum. In pelvic inflammatory infections in which Chlamydia trachomatis is involved macrolides could also be used. Other non-conventional indications under discussion are H. pylori and Lyme's disease. Macrolides in combination with other antibacterials could be an alternative for Mycobacterium avium-intracellulare infections. The antiparasite effect of erythromycin has been known since the 1950s. Extensive experimental work is currently underway to determine the potential use of these drugs in this setting. Research during the 80s in the macrolide field, led to enhanced pharmacokinetic properties. Current research is focused on expanding the antibacterial spectrum and to overcome cross resistance among 14-membered-ring macrolides. PMID- 7831267 TI - [Thromboembolic disease and cancer]. AB - Many anomalies in primary haemostasis, coagulation and fibrinolysis have been described which favour thrombosis in cancer patients. Cancer is often associated with other risk factors for thromboembolism which explain much of the increased frequency of thrombosis in these patients. Thromboembolism may precede cancer and sometimes is the inaugural manifestation leading to the diagnosis of cancer. Cancer occurs more frequently in patients with idiopathic recurrent venous thrombosis than in those with thrombosis due to other risk factors for thromboembolism. The results of antivitamin K therapy are disappointing: in retrospective series, recurrent thromboembolism occurred in 9% of the treated patients and severe haemorrhage in 27%. New therapies should be assessed in cancer patients with thromboembolism. PMID- 7831268 TI - [Cortico-basal degeneration: a new entity]. AB - Cortico-basal degeneration is a progressive disease comprisong characteristic features concerning both cortical and basal ganglionic dysfunction. Manifestations include akineto-rigid syndrome and apraxia strictly limited at disease onset to one hemibody, especially the left. Myoclonus, chorea a alien limb syndrome can begin within the clinicalcome. Functional exploration of the brain shows an asymmetric hypometabolism affecting both cortical and basal structures. Neuropathologic studies show pathological features including neuronal loss, gliosis and neuronal achromasia affecting the cortex (frontal and parietal), basal ganglia and locus niger. Further evaluation of this disease is needed to understand its links with the other neurological degenerative diseases especially progressive aphasia and Pick's disease. PMID- 7831269 TI - [Ascitic fluid infected by Listeria monocytogenes]. PMID- 7831270 TI - [Is p-acetylaminophenol (paracetamol) an endogenous substance produced in man?]. PMID- 7831271 TI - [Reversible hyperaluminemia induced by ingestion of didanosine in a patient under chronic hemodialysis]. PMID- 7831272 TI - [Weaning from mechanical ventilation facilitated by colostomy in a patient with colonic dilatation]. PMID- 7831273 TI - [Synthesis of nicotinamide adenine dinucleotide from exogenous precursors. Properties and regulation of enzymes]. AB - Data on the properties and regulation of the enzymes of NAD salvage synthesis and the enzymes involved in degradation of NAD and intermediates of NAD synthesis are reviewed. An elaborate system of control of NAD synthesis and a key role of ATP in this process are discussed. These data can be used intensification of NAD production. PMID- 7831274 TI - [The interaction of carriers with proteolytic enzymes used for enzymatic synthesis of peptides in organic solvents]. AB - The adsorption of some proteolytic enzymes on inorganic solvents (Silochromes C 80 and C-120, macroporous glass CPG-10, and celite 535) and the effect of sorption-desorption processes on the activity and stability of the enzymes have been studied. The ability of the enzymes to be adsorbed on the carrier depended on the specific surface of the carrier and properties of the enzyme. Adsorption desorption processes did not affect the activity of the enzymes. Acetonitrile had no noticeable effect on the activity of the enzyme adsorbed on the inorganic carrier. The enzymes adsorbed on such carriers catalysed reactions in media with a low (4-5%) content of water, since the carrier seems to protect the enzyme from inactivation with organic solvents. The loading of carrier with enzyme influenced the rate of the enzymatic reaction, the optimal loading corresponding the value of the maximum adsorption of the enzyme on the carrier. PMID- 7831275 TI - [Solid phase methods of immunoenzyme analysis of the herbicides 2,4 dichlorophenoxyacetic and 2,4,5-trichlorophenoxyacetic acids]. AB - Competitive solid-phase enzyme immunoassays for the detection of 2,4 dichlorophenoxyacetic (2,4-D) and 2,4,5-trichlorophenoxyacetic (2,4,5-T) acids have been developed and optimized. The sensitivity of the assay is 3 ng/ml for 2,4-D and 5 ng/ml for 2,4,5-T. The time of the assay is 1.5 h. The sensitivity of the assays increases after immobilization of antibodies on staphylococcus protein A, in the case of using monovalent derivatives of antibodies, and as a result of chemical modification of hapten. The detection limit for the pesticides is 0.1 ng/ml in this case, which is close to the sensitivity of the assay for the haptens conjugated with proteins. PMID- 7831276 TI - The protein threading problem with sequence amino acid interaction preferences is NP-complete. AB - In recent protein structure prediction research there has been a great deal of interest in using amino acid interaction preferences (e.g. contact potentials or potentials of mean force) to align ('thread') a protein sequence to a known structural motif. An important open question is whether a polynomial time algorithm for finding the globally optimal threading is possible. We identify the two critical conditions governing this question: (i) variable-length gaps are admitted into the alignment, and (ii) interactions between amino acids from the sequence are admitted into the score function. We prove that if both these conditions are allowed then the protein threading decision problem (does there exist a threading with a score < or = K?) is NP-complete (in the strong sense, i.e. is not merely a number problem) and the related problem of finding the globally optimal protein threading is NP-hard. Therefore, no polynomial time algorithm is possible (unless P = NP). This result augments existing proofs that the direct protein folding problem is NP-complete by providing the corresponding proof for the 'inverse' protein folding problem. It provides a theoretical basis for understanding algorithms currently in use and indicates that computational strategies from other NP-complete problems may be useful for predictive algorithms. PMID- 7831277 TI - Modelling the structure of the calcitonin gene-related peptide. AB - The calcitonin gene-related peptide (CGRP) is a 37 residue neuropeptide which causes vasodilatation, increases heart rate and inhibits bone resorption. These effects make it an interesting lead for drug discovery. We have combined current structural and biological information to model the structure of hCGRP-beta to be used as a basis for the rational design of novel analogues. Distinct regions of CGRP have been shown to be responsible for the activity of the whole molecule. Thus, the structure of the peptide was modelled in four parts which were finally combined. A random search of conformational space was performed for the fragments CGRP1-8 and CGRP30-37 which have been shown to be central for receptor activation and binding, respectively. Five low-energy hCGRP-beta structures were obtained from modelled fragments by molecular dynamics. The relevance of the approach was verified by comparing the models with NMR structures of CGRP and calcitonin. The models obtained for the N- and C-terminal fragments should enable the design of novel agonists and antagonists of the CGRP receptor, respectively. Models of the whole molecule may be used in the design of peptides with shortened spacers between the receptor-bound regions. The approach described is applicable to several related peptide hormones, like growth hormone-releasing hormone and secretin. PMID- 7831278 TI - A simple method for assessing the mutational effect on the protein-DNA interaction: application to amino acid substitutions. AB - We have developed a simple method to assess the effect of mutations on the binding affinity change in the protein-DNA interaction. In this method, we evaluate the contribution of the local geometric effect in protein-DNA recognition by calculating the change in interaction energy caused by mutations, and assess the binding activity by introducing the binding affinity index. We applied this method to the interaction between lambda repressor and DNA. In spite of the simplicity of the present method, the calculated results qualitatively agree with experimental results for a limited number of mutants of lambda repressor. The mutational effects are mostly attributed to the complementary interactions in the protein-DNA complex. Although the method is still preliminary and should be the subject of further experimental verification, it may be used effectively at the planning stage of mutagenesis experiments to narrow down the selection of mutation by excluding unreasonable mutations. PMID- 7831279 TI - Extrapolation to water of kinetic and equilibrium data for the unfolding of barnase in urea solutions. AB - Assumptions about the dependence of protein unfolding on the concentration of urea have been examined by an extensive survey of the equilibrium unfolding of barnase and many of its mutants measured by urea denaturation and differential scanning calorimetry. The free energy of equilibrium unfolding and the activation energy for the kinetics of unfolding of proteins are generally assumed to change linearly with [urea]. A slight downward curvature is detected, however, in plots of highly precise measurements of logku versus [urea] (where ku is the observed rate constant for the unfolding of barnase). The data fit the equation logku = logkuH2O* + mku*.[urea] - 0.014[urea]2, where mku* is a variable which depends on the mutation. The constant 0.014 was measured directly on four destabilized mutants and wild-type, and was also determined from a global analysis of data from > 60 mutants of barnase. Any equivalent deviations from linearity in the equilibrium unfolding are small and in the same region, as determined from measurements on 166 mutants. The free energy of unfolding of barnase, delta GU-F, appears significantly larger by 1.6 kcal mol-1 when measured by calorimetry than when determined by urea denaturation. However, the changes in delta GU-F on mutation, delta delta GU-F, determined by calorimetry and by urea denaturation are identical. We show analytically how, in general, the curvature in plots of activation or equilibrium energies against [denaturant] should not affect the changes of these values on mutation provided measurements are made over the same concentration ranges of denaturant and the curvature is independent of mutation. PMID- 7831280 TI - Synthesis and properties of the peptide corresponding to the mutant form of the leucine zipper of the transcriptional activator GCN4 from yeast. AB - A 33 membered polypeptide corresponding to the leucine zipper region of the yeast transcriptional activator GCN4 was synthesized by solid phase chemical synthesis and characterized. Asparagine in the hydrophobic core of the molecule is replaced by valine in the synthetic variant. The correctness of amino acid sequence of the preparation is corroborated by direct sequencing. High-speed equilibrium ultracentrifugation, ultraviolet circular dichroism spectroscopy and scanning microcalorimetry have been employed to demonstrate that in solution the peptide forms a highly stable triple-stranded alpha-helical coiled coil. The stability of the mutant form is 40 degrees C higher than the dimeric form of natural peptide under similar conditions. It was proposed that location of some polar groups in the 'a' and 'd' positions of natural two-stranded coiled coils may be regarded as protection against alternative triple- and multistranded conformations. PMID- 7831281 TI - Effect of amino acid deletions in the O-glycosylated region of Aspergillus awamori glucoamylase. AB - Aspergillus awamori glucoamylase (GA) contains globular catalytic and starch binding domains (residues 1-471 and 509-616, respectively). A heavily O glycosylated sequence comprises two parts. The first (residues 441-471) in the crystal structure wraps around an alpha/alpha-barrel formed by residues 1-440. The second (residues 472-508) is an extended, semi-rigid linker between the two domains. To investigate the functional role of this linker, we made internal deletions to remove residues 466-512 (GA delta 1), 485-512 (GA delta 2) and 466 483 (GA delta 3). GA delta 2 and GA delta 3 were expressed in Saccharomyces cerevisiae culture supernatants at approximately 60 and 20% the wild-type level, respectively, while GA delta 1 was almost undetectable. Western blots comparing extracellular and intracellular fractions indicated that the region deleted in GA delta 3 was critical for secretion, while the region deleted in GA delta 2 contributed to the production of a stable enzyme structure. The activities of purified GA delta 2 and GA delta 3 on soluble and insoluble starch were similar to those of wild-type GA, indicating that for soluble starch their deletions did not affect the catalytic domain and for insoluble starch the linker does not coordinate the activities of the catalytic and starch-binding domains. The deletions had a significant negative effect on GA delta 2 and GA delta 3 thermostabilities. PMID- 7831282 TI - Engineering of a metal coordinating site into human glutathione transferase M1-1 based on immobilized metal ion affinity chromatography of homologous rat enzymes. AB - Rat glutathione transferase (GST) 3-3 binds to Ni(II)-iminodiacetic acid (IDA) agarose, whereas other GSTs that are abundant in rat liver do not bind to this immobilized metal ion affinity chromatography (IMAC) adsorbent. Rat GST 3-3 contains two superficially located amino acid residues, His84 and His85, that are suitably positioned for coordination to Ni(II)-IDA-agarose. This particular structural motif is lacking in GSTs that do not bind to the IMAC matrix. Creation of an equivalent His-His structure in the homologous human GST M1-1 by protein engineering afforded a mutant enzyme that displays affinity for Ni(II)-IDA agarose, in contrast to the wild-type GST M1-1. The results identify a distinct site that is operational in IMAC and suggest an approach to the rational design of novel integral metal coordination sites in proteins. PMID- 7831283 TI - Protein engineering of the hydrophobic domain of human factor IX. AB - Vitamin K-dependent plasma proteins contain a highly conserved hydrophobic domain located between the gamma-carboxyglutamic acid (Gla) domain and the first epidermal growth factor (EGF)-like domain. Here we have used protein engineering of the hydrophobic domain in human factor IX to investigate its function in intact factor IX. Mutant proteins were generated by site-directed mutagenesis and in vitro expression in Madin-Darby canine kidney (MDCK) cells. All of our mutants, including one with a deletion of the entire hydrophobic domain, were activated by factor XIa, showing that this domain is not required for factor IX activation. The results with the mutant Phe41-->Val suggest that the hydrophobic domain interacts with the adjacent EGF-like domain. Our data for the Phe41-->Asp mutant is consistent with, but cannot prove, a role for this residue in the maintenance of a phospholipid-binding structure required for factor IX function. PMID- 7831284 TI - Sequence and structure of VH domain from naturally occurring camel heavy chain immunoglobulins lacking light chains. AB - We cloned 17 different PCR fragments encoding VH genes of camel (Camelus dromedarius). These clones were derived from the camel heavy chain immunoglobulins lacking the light chain counterpart of normal immunoglobulins. Insight into the camel VH sequences and structure may help the development of single domain antibodies. The most remarkable difference in the camel VH, consistent with the absence of the VL interaction, is the substitution of the conserved Leu45 by an Arg or Cys. Another noteworthy substitution is the Leu11 to Ser. This amino acid normally interacts with the CH1 domain, a domain missing in the camel heavy chain immunoglobulins. The nature of these substitutions agrees with the increased solubility behavior of an isolated camel VH domain. The VH domains of the camels are also characterized by a long CDR3, possibly compensating for the absence of the VL contacts with the antigen. The CDR3 lacks the salt bridge between Arg94 and Asp101. However, the frequent occurrence of additional Cys residues in both the CDR1 and CDR3 might lead to the formation of a second internal disulfide bridge, thereby stabilizing the CDR structure as in the DAW antibody. Within CDRs of the camel VH domains we observe a broad size distribution and a different amino acid pattern compared with the mouse or human VH. Therefore the camel hypervariable regions might adopt structures which differ substantially from the known canonical structures, thereby increasing the repertoire of the camel antigen binding sites within a VH. PMID- 7831285 TI - Coiled-coil molecular recognition: directed solution assembly of receptor ectodomains. AB - The high affinity interleukin-2 (IL-2) receptor is composed of at least three cell surface proteins (alpha, beta and gamma subunits), each of which is independently capable of ligand binding. Physiologically, these subunits cooperate to form dimeric and trimeric complexes that efficiently capture IL-2 and transmit the signal across the membrane. The knowledge of how each subunit functions with respect to ligand capture, signal transmission and internalization is essential for the development of ligand-based IL-2 agonists and antagonists, as well as receptor-related therapeutic and diagnostic reagents. Only one of the subunits (p55 or alpha chain) is capable of interacting with ligand in solution in a manner that resembles cell surface binding. To generate soluble multimeric complexes of the IL-2 receptor subunits that may bind ligand in solution in a fashion that mimics the same receptor complexes on the cell surface, we have added recognition sequences (coiled-coil heptad repeats) to the ectodomains of the individual receptors. Here we describe the expression and characterization of a prototype IL-2 beta receptor ectodomain-coiled-coil fusion protein and demonstrate that this is a feasible approach to the preparation of cytokine receptor solution complexes. PMID- 7831286 TI - Hyperexpression of a synthetic gene encoding a high potential iron sulfur protein. AB - A gene encoding high potential iron sulfur protein (HiPIP) iso-1 from Ectothiorhodospira halophila was constructed in one step from long synthetic oligonucleotides. The gene was inserted into a phagemid vector from which the HiPIP was expressed as a fusion protein to > 10% of the soluble protein in Escherichia coli, demonstrating that a 4Fe-4S protein can be highly expressed in E. coli. The recombinant HiPIP was purified to apparent homogeneity by affinity chromatography followed by proteolytic removal of the leader sequence and anion exchange chromatography. Approximately 180 mg of HiPIP were purified from 10 l of cell culture. CD spectra of the oxidized and reduced forms of the protein and the 1H NMR spectrum of the oxidized protein are essentially identical to those of the wild type protein, indicating that the environment of the iron sulfur cluster in the two proteins is the same and thus that the recombinant protein is folded correctly. The reduction potential of the recombinant protein was determined to be 120 +/- 6 mV versus NHE (20 mM HEPES, 0.1 M sodium chloride, pH 7.0, 25 degrees C). This efficient heterologous expression of an HiPIP enables a systematic investigation of structure-function relationships in this class of iron sulfur proteins. PMID- 7831287 TI - Getting the inside out: the transporter associated with antigen processing (TAP) and the presentation of viral antigen. PMID- 7831288 TI - Building zinc fingers by selection: toward a therapeutic application. AB - A phage display approach was utilized to modify the specificity of each of the three fingers of the murine transcription factor Zif268. Selections were performed by using the consensus binding sequence of the natural protein and a conserved sequence in the genome of the type 1 human immunodeficiency virus. By using an extensive randomization strategy, the entire 3-bp specificity of a finger has been changed. Rapid analysis of selected zinc fingers was facilitated by the development of an immunoscreening assay for DNA binding and specificity. To investigate the mechanism of binding and specificity, the binding kinetics of Zif268 and 10 selected variants were determined in real time with an assay based on surface plasmon resonance. Differential mechanisms for sequence-specific recognition were observed. No evidence in support of a single general coding relationship between zinc finger and target DNA sequence was observed. The prospects for the development of this class of proteins in human therapy are considered. PMID- 7831289 TI - Human immunodeficiency virus type 1 Nef and p56lck protein-tyrosine kinase interact with a common element in CD4 cytoplasmic tail. AB - The human immunodeficiency virus type 1 nef gene induces endocytosis of CD4 antigen and disrupts the association between CD4 and p56lck protein-tyrosine kinase (EC 2.7.1.112). We demonstrate that in T cells these effects of the viral protein require a cluster of hydrophobic amino acids in a membrane-proximal region of the CD4 cytoplasmic tail; other amino acids in the C-terminal segment of CD4 cytoplasmic tail also contribute to the interaction. Mutations in CD4 that prevent down-modulation by Nef also decrease CD4 association with p56lck and prevent Nef-induced disruption of CD4-p56lck complexes. Together, the overlap in CD4 sequences required for interaction with Nef and p56lck and the tight correlation between Nef-induced CD4 down-modulation and disruption of CD4-p56lck association suggest that Nef, or cellular factors recruited by Nef, interact with this segment of CD4 to displace p56lck from the complex and induce CD4 endocytosis. PMID- 7831290 TI - Human spleen tyrosine kinase p72Syk associates with the Src-family kinase p53/56Lyn and a 120-kDa phosphoprotein. AB - The 72-kDa spleen tyrosine kinase (Syk) and Src-family kinase p53/56Lyn (Lyn) contribute to signaling via the B-cell antigen receptor complex. Here we show that Syk and Lyn from human B lymphocytes can interact directly. Syk and Lyn coimmunoprecipitated from mature and activated B-cell lines, and gel-purified Syk and Lyn reassociated in vitro, demonstrating their direct interaction. This Syk Lyn interaction may be dependent on the stage of B-cell differentiation, since Syk-Lyn associations were not detected in pre-B and myeloma cell lines and Syk from an immature B-cell line did not reassociate with Lyn in vitro. Serine/threonine kinase activity was also associated with Syk. Crosslinking of cell surface IgM led to rapid activation of both tyrosine and serine/threonine protein kinase activities that resulted in phosphorylation in vitro of proteins coprecipitating with Syk--in particular, a serine/threonine phosphorylated protein 120 kDa in size (pp120). Several phosphoproteins, including one of 72 kDa and one of 120 kDa, coprecipitated with phospholipase C-gamma 1 (PLC gamma 1). Sequential immunoprecipitation identified the 72-kDa protein associated with PLC gamma 1 as Syk. The 120-kDa serine/threonine phosphorylated protein that coprecipitated with PLC gamma 1 resembled the Syk-associated pp120 by several criteria. Thus, pp120 may serve as a link between Syk and PLC gamma 1, coupling the B-cell antigen receptor to the phosphatidylinositol pathway. PMID- 7831291 TI - Targeting of a nuclease to murine leukemia virus capsids inhibits viral multiplication. AB - Capsid-targeted viral inactivation is an antiviral strategy in which toxic fusion proteins are targeted to virions, where they inhibit viral multiplication by destroying viral components. These fusion proteins consist of a virion structural protein moiety and an enzymatic moiety such as a nuclease. Such fusion proteins can severely inhibit transposition of yeast retrotransposon Ty1, an element whose transposition mechanistically resembles retroviral multiplication. We demonstrate that expression of a murine retrovirus capsid-staphylococcal nuclease fusion protein inhibits multiplication of the corresponding murine leukemia virus by 30- to 100-fold. Staphylococcal nuclease is apparently inactive intracellularly and hence nontoxic to the host cell, but it is active extracellularly because of its requirement for high concentrations of Ca2+ ions. Virions assembled in and shed from cells expressing the fusion protein contain very small amounts of intact viral RNA, as would be predicted for nuclease-mediated inhibition of viral multiplication. PMID- 7831292 TI - Solubilization of beta-amyloid-(1-42)-peptide: reversing the beta-sheet conformation induced by aluminum with silicates. AB - Plaques are one of the two lesions found in the brain of patients with Alzheimer disease. Using a synthetic peptide corresponding to rat beta-amyloid-(1-42) (beta A4), circular dichroism (CD) analyses were performed to examine the effect of Na4SiO4 on the conformational state produced by Al3+. A previous study on fragments of neuronal proteins involved in tangle formation had shown a conformational transition from a beta-pleated sheet to a soluble random coil upon addition of Na4SiO4. In the present study, CD measurements showed that the beta pleated sheet conformation of beta A4 induced by Al3+ was reversed to the random coil soluble form by the addition of Na4SiO4. The tight binding of SiO4(4-) with Al3+ provides the mechanism for this transition. These results provide insight into the role of aluminum in the Alzheimer diseased brain and suggests that investigation of the use of silicates as a therapeutic agent. PMID- 7831293 TI - Rapid long-range proton diffusion along the surface of the purple membrane and delayed proton transfer into the bulk. AB - The pH-indicator dye fluorescein was covalently bound to the surface of the purple membrane at position 72 on the extracellular side of bacteriorhopsin and at positions 101, 105, 160, or 231 on the cytoplasmic side by reacting bromomethylfluorescein with the sulfhydryl groups of cysteines introduced by site directed mutagenesis. At position 72, on the extracellular surface, the light induced proton release was detected 71 +/- 4 microseconds after the flash (conditions: pH 7.3, 22 degrees C, and 150 mM KCl). On the cytoplasmic side with the dye at positions 101, 105, and 160, the corresponding values were 77, 76, and 74 +/- 5 microseconds, respectively. Under the same conditions, the proton release time in the bulk medium as detected by pyranine was around 880 microseconds--i.e., slower by a factor of more than 10. The fact that the proton that is released on the extracellular side is detected much faster on the cytoplasmic surface than in the aqueous bulk phase demonstrates that it is retained on the surface and migrates along the purple membrane to the other side. These findings have interesting implications for bioenergetics and support models of local proton coupling. From the small difference between the proton detection times by labels on opposite sides of the membrane, we estimate that at 22 degrees C the proton surface diffusion constant is greater than 3 x 10(-5) cm2/s. At 5 degrees C, the proton release detection time at position 72 equals the faster of the two main rise times of the M intermediate (deprotonation of the Schiff base). At higher temperatures this correlation is gradually lost, but the curved Arrhenius plot for the proton release time is tangential to the linear Arrhenius plot for the rise of M at low temperatures. These observations are compatible with kinetic coupling between Schiff base deprotonation and proton release. PMID- 7831294 TI - Lymphoid development in mice with a targeted deletion of the interleukin 2 receptor gamma chain. AB - The interleukin 2 receptor gamma chain (IL-2R gamma) is a component of the receptors for IL-2, IL-4, IL-7, and IL-15. Mutations in IL-2R gamma in man appear responsible for the X chromosome-linked immunodeficiency SCIDX1, characterized by a defect in T-cell and natural killer (NK)-cell differentiation with the presence of poorly functioning B cells. To explore at which level IL-2R gamma affects lymphoid development in vivo, we have analyzed mice derived from embryonic stem (ES) cells with mutant IL-2R gamma loci generated by Cre/loxP-mediated recombination. In the peripheral blood of chimeric animals, lymphoid cells derived from IL-2R gamma- ES cells were not detected, although control ES cells carrying an IL-2R gamma gene with embedded loxP sites gave rise to T-, B-, and NK cell lineages. Germline IL-2R gamma-deficient male animals, however, developed some mature splenic B and T cells, although the absolute number of lymphocytes was almost 10-fold reduced. In contrast, there was a complete disappearance of NK cells (over 350-fold reduction). Development of gut-associated intraepithelial lymphocytes was also severely diminished, and Peyer's patches were not detected. In vitro mitogenic responses of thymocytes, IL-4-directed immunoglobulin class switch of splenocytes, and NK activity were defective. Thus, IL-2R gamma facilitates mainstream B- and T-cell generation and function and also appears to be essential for NK-cell development. PMID- 7831295 TI - Self-association of a synthetic peptide from the N terminus of the hepatitis delta virus protein into an immunoreactive alpha-helical multimer. AB - The formation of hepatitis delta antigen (HDAg) multimers is required for full biologic activity of this protein and for replication of the hepatitis delta virus. To determine the residues responsible for multimerization, three peptides [ delta 12-49, delta 25-60(Y), delta 12-60(Y)] from the putative coiled-coil multimer-forming domain of HDAg were chemically synthesized and biophysically characterized by circular dichroic spectroscopy, deuterium-exchange mass spectrometry, gel filtration, chemical crosslinking, and ultracentrifugation. By circular dichroism the 50-residue peptide delta 12-60(Y) was half-denatured above 80 degrees C and was 97% alpha-helical at 5 degrees C and 84% alpha-helical at 37 degrees C. By deuterium exchange, peptide delta 12-60(Y) was 93% alpha-helical at 25 degrees C. Its high alpha-helicity and melting temperature are due to the formation of an alpha-helical multimer consisting of four or more chains. All three synthetic peptides reacted with human anti-HDAg antibodies in an enzyme linked immunosorbent assay, but only peptide delta 12-60(Y) was detected in a sandwich radioimmunoassay in which successful antigens must display at least two antibody-binding sites, which correlates with the ability of this peptide to form multimers. Peptide delta 12-60(Y) also interfered with the self-association of natural HDAg into multimers. These results have significant practical implications for development of improved diagnostic tests, antiviral agents, and possibly even vaccines for prevention of hepatitis delta virus disease. PMID- 7831297 TI - Evidence for two distinct retinoic acid response pathways for HOXB1 gene regulation. AB - We have recently identified a promoter proximal retinoic acid (RA)-responsive site in the 5' region of the HOXB1 gene. In this report, we have identified the second RA-responsive site in the 3' region of the HOXB1 gene. This site also consists of a DR-2-type target of RA receptor.retinoid X receptor complex (DR-2B) and the binding site for a distinct RA-dependent coactivator termed retinoid activating protein, which shows a different tissue-specific spectrum from the 5' responsive site. This indicates that the activation of the HOXB1 gene is achieved through two distinct pathways. These data define an unusual regulatory mechanism leading to the establishment of HOXB1 gene expression. PMID- 7831296 TI - A retinoic acid-triggered cascade of HOXB1 gene activation. AB - Retinoic acid (RA) has been proposed to be a direct regulator of HOX gene complexes. However, the molecular mechanism of the RA signaling pathway during normal development is unclear. We have identified an RA-responsive element in the promoter of HOXB1 gene composed of two functionally separable sites: (i) a DR-2 sequence, which is the direct target of the RA receptor retinoid X receptor heterodimer; and (ii) a motif for an RA-inducible and tissue-specific coactivator termed retinoid-inducible protein. Through neither enhancer alone is functional, this combined element strongly activates the HOXB1 promoter in a cell-specific and retinoid-dependent manner. Finally, this activation is potentiated by a proximal autoregulatory site for HOXB1 gene itself. These data define a tripartite cascade leading to the establishment of HOXB1 gene activation. PMID- 7831298 TI - Preservation of hemostatic and structural properties of rehydrated lyophilized platelets: potential for long-term storage of dried platelets for transfusion. AB - Currently, therapeutic platelet concentrates can be stored for only 5 days. We have developed a procedure that permits long-term storage of fixed and lyophilized platelets that retain hemostatic properties after rehydration. These rehydrated lyophilized platelets (RL platelets) restore hemostasis in thrombocytopenic rats and become incorporated in the hemostatic plug of bleeding time wounds of normal dogs as well as von Willebrand disease dogs with partially replenished plasma von Willebrand factor. Ultrastructurally, these platelets are well preserved and are comparable to control normal washed platelets. Flow cytometry analysis shows that RL platelets react with antibodies to the major surface receptors, glycoprotein (GP)Ib and GPIIb/IIIa. These receptors are involved in platelet agglutination, aggregation, and adhesion. In vitro functional tests document the ability of RL platelets to adhere to denuded subendothelium and to spread on a foreign surface. Circulating RL platelets participated in carotid arterial thrombus formation induced in normal canine subjects. The participation of RL platelets in these vital hemostatic properties suggests that with further development they could become a stable platelet product for transfusion. PMID- 7831299 TI - Macrophage foam cells from experimental atheroma constitutively produce matrix degrading proteinases. AB - Monocyte-derived foam cells figure prominently in rupture-prone regions of atherosclerotic plaques. Peripheral blood monocytes in culture can produce certain enzymes that degrade extracellular matrix, known as matrix metalloproteinases (MMPs). Lipid-laden macrophages may thus contribute to weakening of extracellular matrix of rupture-prone atherosclerotic plaques. However, the spectrum and regulation of MMP production by foam cells remain unknown. To investigate this issue, we isolated lipid-laden macrophages from rabbit aortic lesions produced by a combination of hypercholesterolemia and balloon injury. Freshly isolated aortic macrophage foam cells, identified using cell-specific antibodies, contained immunoreactive stromelysin and interstitial collagenase, whereas alveolar macrophages isolated from the lungs of same rabbits did not. Macrophages from both tissue sources released gelatinolytic activity consistent with the 92-kDa gelatinase. In vitro, lipid-laden aortic macrophages, but not alveolar macrophages, synthesized de novo and released immunoprecipitable stromelysin and collagenase, with or without stimulation by phorbol ester or bacterial lipopolysaccharide. These stimuli caused foam cells to release additional gelatinolytic activity that migrated faster than a purified preparation of 92-kDa gelatinase in substrate-containing polyacrylamide gels, indicating activation of the 92-kDa gelatinase or induction of the 72-kDa gelatinase. Our results show that lipid-laden macrophages elaborate MMPs capable of degrading the major constituents of vascular extracellular matrix even without further stimulation. Therefore, these cells may contribute to remodeling of the extracellular matrix during atherogenesis and to the disruption of plaques often responsible for acute clinical manifestations of atherosclerosis. PMID- 7831300 TI - Systemin activates synthesis of wound-inducible tomato leaf polyphenol oxidase via the octadecanoid defense signaling pathway. AB - Tomato plants overexpressing a prosystemin gene that encodes the precursor of a mobile wound signal called systemin have been shown previously to constitutively synthesize extraordinarily high levels of two defensive proteinase inhibitor proteins in leaves in the absence of wounding. We herein report that leaves of these transgenic plants possess enhanced levels of another defensive protein, polyphenol oxidase (PPO) at levels that are up to 70-fold higher than levels found in leaves of wild-type plants. Supplying young wild-type tomato plants with systemin through cut stems induced PPO activity in leaves, and wounding lower leaves of young tomato plants induced PPO activity in both wounded and unwounded leaves to levels equal to those induced by systemin. Exposing young tomato plants to methyl jasmonate vapor caused an increase in PPO activity equivalent to levels found in plants overexpressing the prosystemin gene. The data indicate that PPO and proteinase inhibitor genes are coactivated systemically by wounding via the octadecanoid signal transduction pathway and that systemin has a much broader role in signaling plant defensive genes than was previously known. PMID- 7831301 TI - The orphan receptors COUP-TF and HNF-4 serve as accessory factors required for induction of phosphoenolpyruvate carboxykinase gene transcription by glucocorticoids. AB - Glucocorticoids stimulate hepatic phosphoenolpyruvate carboxykinase (PEPCK; EC 4.1.1.32) gene expression, thereby increasing the rate of gluconeogenesis. The effect of glucocorticoids on PEPCK gene expression is mediated by a set of promoter elements collectively referred to as the glucocorticoid response unit. The response unit spans a 100-bp segment and includes two glucocorticoid receptor binding sites (GR1 and GR2) and two accessory factor binding sites (AF1 and AF2), all of which are required for a maximal glucocorticoid response. The AF1 element also serves as a retinoic acid response element and may be involved in developmental and tissue-specific expression of the gene. In this study we report that COUP-TF and HNF-4, two orphan members of the nuclear receptor superfamily, bind to the AF1 element and function as accessory factors for the glucocorticoid response of the PEPCK gene. PMID- 7831302 TI - Cooperative binding of lactose and the phosphorylated phosphocarrier protein HPr(Ser-P) to the lactose/H+ symport permease of Lactobacillus brevis. AB - Lactobacillus brevis accumulates lactose and nonmetabolizable lactose analogues via sugar/H+ symport, but addition of glucose to the extracellular medium results in rapid efflux of the free sugar from the cells due to the uncoupling of sugar transport from proton transport. By using vesicles of L. brevis cells, we recently showed that these regulatory/effects could be attributed to the metabolite-activated ATP-dependent protein kinase-catalyzed phosphorylation of serine-46 in the phosphocarrier protein HPr [HPr(Ser-P)] of the phosphotransferase system and that a mutant form of HPr with the serine-46- >aspartate replacement ([S46D]HPr) is apparently locked in the seryl phosphorylated conformation. We here demonstrate that [S46D]HPr binds directly to inside-out membrane vesicles of L. brevis that contain the lactose permease. Sugar substrates of the permease markedly and specifically stimulate binding of [S46D]HPr to the membranes while certain transport inhibitors such as N ethylmaleimide block binding. The pH dependency for binding follows that for transport. Wild-type HPr and the [S46A]HPr mutant protein did not appreciably compete with [S46D]HPr for binding to the permease. These results provide evidence for the direct interaction of HPr(Ser-P) with an allosteric site on the lactose/proton symporter of L. brevis for the purpose of regulating sugar accumulation in response to the metabolic needs of the cell. PMID- 7831303 TI - Cooperative formation of high-order oligomers by retinoid X receptors: an unexpected mode of DNA recognition. AB - Nuclear hormone receptors are ligand-regulated transcription factors that function in metazoan homeostasis and differentiation. We report here that DNA recognition by at least one class of nuclear receptors, the retinoid X receptors (RXRs), can occur through an unanticipated mechanism involving the cooperative formation of protein tetramers and other high-order oligomers. Formation of these oligomeric complexes enables RXRs alpha and gamma, but not beta, to efficiently regulate transcription through response elements poorly recognized by RXR dimers. Thus, oligomer formation plays an important role in determining the specificity of DNA recognition by nuclear receptors and contributes to isoform-dependent differences in gene regulation. PMID- 7831304 TI - Variability of dopamine D4 receptor (DRD4) gene sequence within and among nonhuman primate species. AB - The dopamine D4 receptor is one of five receptors known to function in mammalian dopaminergic pathways. The DNA sequence of the human dopamine D4 receptor gene (DRD4) has previously been investigated in several populations and found to be highly polymorphic at both the DNA and amino acid levels, exhibiting at least 25 alleles. This variation results from differences in the number and DNA sequence of a 48-bp (16-amino acid) repeat unit in the coding region of DRD4. In the present study, DRD4 DNA sequence was examined in at least two individuals from each of five nonhuman primate species. All five species exhibit intraspecies variability, including both single nucleotide substitutions and variation in the number of 48-bp repeat units. No differences were found between the two alleles of one individual from a sixth nonhuman species. Within each species, all of the DRD4 alleles share species-specific features, indicating that while repeat-unit variation is nearly ubiquitous, ancestral variation has been lost and subsequently regenerated in each of the evolutionary lineages studied. Chimpanzees and gorillas share a unique 12-bp deletion in the coding region of DRD4, outside the repeat-unit segment of the gene. This suggest that the extant chimpanzee DRD4 is more closely related to the gorilla DRD4 than either is to the human DRD4. PMID- 7831305 TI - Breast and ovarian cancer-specific cytotoxic T lymphocytes recognize the same HER2/neu-derived peptide. AB - The identification of antigenic peptides presented on the tumor cell surface by HLA class I molecules and recognized by tumor-specific cytotoxic T lymphocytes may lead to a peptide vaccine capable of inducing protective cellular immunity. We demonstrate that both HLA-A2-restricted breast and ovarian tumor-specific cytotoxic T lymphocytes recognize shared antigenic peptides. At least one of these peptides is derived from the oncogene product of HER2/neu, which is overexpressed in 30-40% of all breast and ovarian cancers. T cells sensitized against this nine-amino acid sequence demonstrate significant recognition of HLA A2+, HER2/neu+ tumors. Since 50% of the tumor-cell population is HLA-A2+ and many different tumors express HER2/neu, this peptide may be widely recognized and have many clinical applications. PMID- 7831306 TI - Cyclosporin A blocks apoptosis by inhibiting the DNA binding activity of the transcription factor Nur77. AB - Engagement of T-cell receptors (TCRs) on immature thymocytes by self-antigen major histocompatibility complexes causes the death of self-reactive thymocytes via apoptosis, a phenomenon that establishes T-cell tolerance. Similarly, treatment of thymocytes with anti-TCR antibodies leads to TCR-mediated apoptosis, which can also be induced in T-cell hybridomas. TCR-mediated apoptosis in immature thymocytes and T-cell hybridomas requires the expression of a new set of genes. In particular, it has recently been shown that the expression of Nur77, a transcription factor which is a member of the steroid/thyroid receptor superfamily, is required for TCR-mediated apoptosis in T-cell hybridomas and perhaps in thymocytes. Cyclosporin A (CsA), an immunosuppressive drug, has been shown to interfere with clonal deletion of self-reactive T cells in vivo, partly by blocking TCR-mediated apoptosis. We report here that CsA inhibits the TCR mediated activation of Nur77 protein in T-cell hybridomas by blocking the DNA binding activity of Nur77 protein rather than its de novo synthesis. We also show that CsA mediates its negative effects on the Nur77 DNA binding activity through the N-terminal region of the protein. This complete inhibition of Nur77 protein DNA binding activity may explain how CsA interferes with TCR-mediated apoptosis. PMID- 7831307 TI - Angiogenin antagonists prevent tumor growth in vivo. AB - A noncytotoxic neutralizing monoclonal antibody (mAb), 26-2F, to human angiogenin (Ang), a potent inducer of neovascularization, has been reported to prevent or delay the establishment of HT-29 human tumor xenografts in athymic mice. In the present study the tumor model was modified to increase sensitivity to Ang antagonists to facilitate further investigations and comparisons of their capacity to inhibit tumor growth. An increase in the percentage of tumor-free mice from 10-25% to 65% is observed in this modified model after treatment with mAb 26-2F. An additional neutralizing mAb, 36u, that interacts with a different epitope on Ang similarly prevents the appearance of tumors, both alone and in combination with mAb 26-2F. In those tumors that develop in mice treated with these agents, the number of vascular elements is reduced. Actin, an Ang antagonist that unlike the mAbs binds both human and mouse Ang, also prevents the establishment of tumors while exhibiting no toxic effects at daily doses > 50 times the molar amount of circulating mouse Ang. Ang antagonists also inhibit the appearance of tumors derived from two other Ang-secreting human tumor cell lines- i.e., A549 lung adenocarcinoma and HT-1080 fibrosarcoma. These results demonstrate that inhibition of the action of Ang is an effective therapeutic approach for the treatment of malignant disease. PMID- 7831308 TI - Avian cellular homolog of the qin oncogene. AB - We have isolated chicken cDNA clones of the c-qin gene, the cellular counterpart of the v-qin (Chinese for "avian") oncogene of avian sarcoma virus 31. There are several differences between the cellular and the viral qin sequences: (i) two nonconservative amino acid substitutions in the Qin coding region; (ii) a truncation in the carboxyl terminus of the viral protein due to a premature stop codon; (iii) a partial Gag sequence fused to the amino terminus of viral Qin; and (iv) eight cell-coded amino acids which link the cellular Qin coding domain to the viral Gag domain. We have also characterized the expression pattern of c-qin in chicken embryos by in situ hybridization and by Northern blot analysis. c-qin is abundantly expressed in the developing brain, and this expression is restricted to the telencephalon of early embryos. PMID- 7831309 TI - A relationship between protein stability and protein function. AB - Enzymes are thought to use their ordered structures to facilitate catalysis. A corollary of this theory suggests that enzyme residues involved in function are not optimized for stability. We tested this hypothesis by mutating functionally important residues in the active site of T4 lysozyme. Six mutations at two catalytic residues, Glu-11 and Asp-20, abolished or reduced enzymatic activity but increased thermal stability by 0.7-1.7 kcal.mol-1. Nine mutations at two substrate-binding residues, Ser-117 and Asn-132, increased stability by 1.2-2.0 kcal.mol-1, again at the cost of reduced activity. X-ray crystal structures show that the substituted residues complement regions of the protein surface that are used for substrate recognition in the native enzyme. In two of these structures the enzyme undergoes a general conformational change, similar to that seen in an enzyme-product complex. These results support a relationship between stability and function for T4 lysozyme. Other evidence suggests that the relationship is general. PMID- 7831310 TI - Complementation of tobacco etch potyvirus mutants by active RNA polymerase expressed in transgenic cells. AB - A genetic complementation system was developed in which tobacco etch virus (TEV) polymerase (NIb)-expressing transgenic plants or protoplasts were inoculated with NIb-defective TEV mutants. A beta-glucuronidase (GUS) reporter gene integrated into the genomes of parental and four mutant viruses was used to assay RNA amplification. Two mutants (termed VNN and EDE) contained substitutions affecting the conserved "GDD" polymerase motif or a nuclear localization signal sequence, respectively; one (aD/b) contained a mutation debilitating the NIb N-terminal cleavage site, whereas the other (delta b) lacked the entire NIb sequence. Each mutant was unable to amplify in nontransformed tobacco protoplasts. In contrast, the VNN, EDE, and delta b mutants were complemented to various degrees in NIb expressing cells, whereas the aD/b mutant was not complemented. The VNN mutant was complemented most efficiently, reaching an average of 11-12% the level of parental TEV-GUS, although in some experiments the level was near 100%. This mutant also replicated in, and spread through, whole transgenic plants to the same level as parental virus. The EDE mutant was complemented relatively poorly, reaching 1% or less of the level of parental TEV-GUS. Despite the close proximity of the EDE substitution to the N-terminal cleavage site, proteolytic processing of NIb was unaffected in an in vitro assay. The delta b mutant was complemented to an intermediate degree in protoplasts, reaching 3.5% the level of parental virus, and replicated and moved systemically in transgenic plants. These data indicate that free NIb supplied entirely in trans can provide all NIb functions essential for RNA amplification. The relative inefficient complementation of the EDE mutant suggests that the resulting mutant protein was transinhibitory. PMID- 7831311 TI - Bioactive conformation of stromelysin inhibitors determined by transferred nuclear Overhauser effects. AB - The transferred nuclear Overhauser effect has been used to determine the biologically active conformations of two stromelysin inhibitors. Both inhibitors used in this study were hydroxamic acids generated via chemical synthesis. These structures, representing the conformation of each inhibitor bound to stromelysin, superimposed with excellent agreement. The study also provided information on the shape and orientation of the S2' and S1' pockets of the enzyme relative to thermolysin. Comparisons were made between stromelysin and thermolysin inhibitors to critically examine thermolysin as a template for stromelysin-inhibitor design. The enzyme-bound conformations of these stromelysin inhibitors were determined for use as a template in conformationally restricted drug design. PMID- 7831312 TI - Fibroblast growth factor receptor is required for in vivo cardiac myocyte proliferation at early embryonic stages of heart development. AB - In birds and mammals, cardiac myocytes terminate mitotic activity in the neonatal period and regeneration of cardiac muscle does not occur after myocardial injury in adult hearts. Even embryonic myocytes, which actively proliferate in vivo, quickly lose mitotic activity when placed in cell culture. Several growth factors, including fibroblast growth factor (FGF), have been documented in embryonic hearts and some have been shown to influence myocyte terminal differentiation in culture. However, none of these growth factors have been shown to reactivate cell division in postmitotic myocytes nor have their in vivo functions been defined satisfactorily. To clarify the role of FGF signaling in heart growth, we prepared two retroviral vectors capable of suppressing (i) functions of FGF receptors (FGFRs) with a dominant-negative mutant of receptor type 1 (FGFR1) or (ii) the translation of endogenous FGFR1 by transcribing its antisense RNA. Both vectors inhibited myocyte proliferation and/or survival during the first week of chicken embryonic development but had much less effect after the second week. No apparent alteration of myocyte growth was observed after overexpression of full-length FGFR1. These results suggest that receptor coupled FGF signaling regulates cardiac myocyte growth during tubular stages of cardiogenesis but that myocyte growth becomes FGF-independent after the second week of embryogenesis. PMID- 7831313 TI - Functional interaction of yeast and human TATA-binding proteins with an archaeal RNA polymerase and promoter. AB - TATA boxes are common structural features of eucaryal class II and archaeal promoters. In addition, a gene encoding a polypeptide with sequence similarity to eucaryal TATA-binding protein (TBP) has recently been detected in Archaea, but its relationship to the archaeal transcription factors A (aTFA) and B (aTFB) was unclear. Here, we demonstrate that yeast and human TBP can substitute for aTFB in a Methanococcus-derived archaeal cell-free transcription system. Template commitment studies show that eucaryal TBP is stably sequestered at the archaeal promoter and that this interaction is further stabilized in combination with aTFA. Binding studies revealed that recognition of an archaeal promoter by TBP involves specific binding to the TATA box. These findings demonstrate a common function of TBP and aTFB and imply a common evolutionary origin of eucaryal and archaeal transcriptional machinery. PMID- 7831314 TI - Genomic imprinting proposed as a surveillance mechanism for chromosome loss. AB - One consequence of genomic imprinting is that loss of the transcriptionally active chromosomal homologue causes a change in gene expression that might permit surveillance of chromosome-loss events. Possible selective advantages of such surveillance include protection against cancer and early elimination of monosomic and trisomic fetuses. Potential mechanisms for such surveillance are discussed. PMID- 7831315 TI - Expression of the E2F1 transcription factor overcomes type beta transforming growth factor-mediated growth suppression. AB - Inhibition of cell growth by type beta transforming growth factor (TGF-beta) occurs in mid-G1 and is associated with decreased G1 cyclin-dependent kinase activity and maintenance of the retinoblastoma tumor suppressor protein Rb in an underphosphorylated, growth-suppressive state. A variety of recent experiments suggest that a functional target of Rb is the E2F transcription factor. In addition, the growth-suppressive effects of TGF-beta can be overcome by expression of viral oncogene products that dissociate E2F from Rb and Rb-related polypeptides. These results suggest the possibility that control of E2F may be a downstream event of TGF-beta action. Consistent with that possibility is the observation that E2F1 RNA levels are drastically reduced in TGF-beta-treated cells. We have also used a recombinant adenovirus containing the human E2F1 gene to overexpress the E2F1 product in mink lung epithelial cells that were growth arrested with TGF-beta. We find that overexpression of E2F1 can overcome the TGF beta-mediated effect as measured by the activation of cellular DNA synthesis. These results suggest that a likely downstream target for the cyclin-dependent kinases, which are controlled by TGF-beta, is the activation of E2F. PMID- 7831316 TI - Determination of helix-helix interactions in membranes by rotational resonance NMR. AB - Dimerization of human glycophorin A in erythrocyte membranes is mediated by specific interactions within the helical transmembrane domain of the protein. Rotational resonance NMR provides a unique approach for obtaining high-resolution structural data in membrane systems and has been used to establish intermolecular contacts in the glycophorin A dimer by using hydrophobic peptides that correspond to the transmembrane sequence. Magnetization exchange rates were measured between [13C]methyl labels in the hydrophobic sequence -G79-V80-M81-A82-G83-V84- located in the middle of the transmembrane domain and specific [13C]carbonyl labels along the peptide backbone across the dimer interface. Significant magnetization exchange was observed only between V80 (13CH3) and G79 (13C = O) and between V84 (13CH3) and G83 (13C = O), indicating that these residues are packed in the dimer interface in a "ridges-ingrooves" arrangement. PMID- 7831317 TI - An autoregulatory region in protein kinase C: the pseudoanchoring site. AB - We have previously identified receptors for activated C kinase (RACKs) as components of protein kinase C (PKC) signaling. RACK1, a recently cloned 36-kDa RACK, has short sequences of homology to PKC. A possible explanation for the homologous sequences between the ligand (PKC) and its intracellular receptor (RACK1) may be that, similar to the pseudosubstrate autoregulatory sequence on PKC, there is also a pseudo-RACK1 binding site on the enzyme. If this is the case, peptides with these sequences (derived from either RACK1 or PKC) are expected to affect PKC binding to RACK1 in vitro and PKC-mediated functions in vivo. Here, we show that the PKC-derived peptide (pseudo-RACK1 peptide), but not its RACK1 homologue, modulated PKC function both in vitro and in vivo. Our data suggest that the pseudo-RACK1 peptide binds and activates PKC in the absence of PKC activators and thereby acts as an agonist of PKC function in vivo. Therefore, the pseudo-RACK1 sequence in PKC appears to be another autoregulatory site; when PKC is in an inactive conformation, the pseudo-RACK1 site interacts with the RACK binding site. Activation of PKC exposes the RACK-binding site, enabling the association of the enzyme with its anchoring RACK. Similar pseudoanchoring sites may regulate the function of other protein kinases. PMID- 7831318 TI - A bovine cDNA and a yeast gene (VMA8) encoding the subunit D of the vacuolar H(+) ATPase. AB - Subunit D of vacuolar H(+)-ATPase (V-ATPase) from bovine chromaffin granules was subjected to partial proteolysis and amino acid sequencing. A cDNA encoding this subunit was isolated and sequenced. The predicted open reading frame encodes a protein of 247 amino acids with a calculated molecular weight of 28,336. Northern blot analysis revealed an mRNA distribution with higher transcript amounts in tissues that are active in secretion. A homologous gene was identified as open reading frame 11 in chromosome V of Saccharomyces cerevisiae. The two proteins exhibit 55% identity with several conservative replacements. Interruption of the yeast gene, denoted as VMA8, resulted in the null mutant delta vma8::URA3 that, like all the other V-ATPase null mutants, did not grow on medium buffered at pH 7.5 and showed no accumulation of quinacrine into their vacuoles. Transformation of the null mutant with a plasmid containing the VMA8 gene restored the wild-type phenotype. This supports the conclusion that subunit D is an integral subunit of the catalytic sector of V-ATPase and its structural analysis suggests analogy to the gamma subunit of F-ATPases. PMID- 7831319 TI - A cluster of basic amino acids within an alpha-helix is essential for alpha subunit recognition by the glycoprotein hormone N acetylgalactosaminyltransferase. AB - The glycoprotein hormone N-acetylgalactosaminyltransferase is responsible for synthesis of Asn-linked oligosaccharides terminating with GalNAc-4-SO4 on lutropin, thyrotropin, and the uncombined glycoprotein hormone alpha subunit. We previously established that a recognition determinant for the N acetylgalactosaminyltransferase is contained within a 22-amino acid glycopeptide fragment of the alpha subunit. We proposed that the tripeptide Pro-Leu-Arg is an essential element of the recognition determinant. Using site-directed mutagenesis we have examined the role of individual amino acids in recognition by the glycoprotein hormone N-acetylgalactosaminyltransferase. Within the sequence Pro40 Leu41-Arg42-Ser43-Lys44-Lys45, Lys44, and Lys45, as well as Arg42 of the tripeptide, are essential for recognition. Substitution of the Leu41 with other amino acids can either increase or decrease the rate of GalNAc transfer over an 8 fold range, suggesting that the middle amino acid of the tripeptide plays a modulatory role in recognition. The critical Leu41-Arg42 and Lys44-Lys45 residues are present on the same surface of an alpha-helix, which projects from the surface of the alpha subunit. Our results indicate that an essential element of the recognition determinant consists of a cluster of basic residues and that neutral but not negatively charged residues are tolerated within this cluster. PMID- 7831320 TI - Reaction in alphavirus mRNA capping: formation of a covalent complex of nonstructural protein nsP1 with 7-methyl-GMP. AB - After the start of transcription, the 5' ends of eukaryotic mRNA molecules are modified by the addition of a guanylyl residue to form a cap structure, G(5')ppp(5')N. The guanylyltransferase (GTP:mRNA guanylyltransferase, EC 2.7.7.50) reaction responsible for cap formation usually proceeds via a covalent enzyme-GMP intermediate. We have studied the alphavirus-specific guanylyltransferase by incubating lysates from Semliki Forest and Sindbis virus infected cells with [alpha-32P]GTP, using vaccinia virus and mock-infected cells as controls. One additional 32P-labeled protein was detected in alphavirus infected cells but only in the presence of S-adenosylmethionine. This protein was identified as the nonstructural protein nsP1. The properties of the covalent enzyme-guanylate complex were studied with Semliki Forest virus nsP1 expressed in recombinant baculovirus-infected cells. S-Adenosylmethionine and divalent cations were required for the complex formation. The reaction was specific for guanylate nucleotides (GTP, dGTP) and was inhibited by pyrophosphate. nsP1 could be labeled with S-adenosyl[methyl-3H]methionine but only under conditions in which the nsP1 guanylate complex was formed. 7-Methyl-GMP was released from the nsP1-guanylate complex by treatment with acid or acidic hydroxylamine. Similar treatment of vaccinia virus capping enzyme released GMP. These findings suggest that in the capping of alphavirus mRNAs the guanine is methylated before linkage to the mRNA molecule. PMID- 7831321 TI - Visualization of the thyrotropin-releasing hormone receptor and its ligand during endocytosis and recycling. AB - Endocytosis and recycling of both thyrotropin-releasing hormone (TRH) and its G protein-coupled receptor were visualized by conventional and confocal fluorescence microscopy in pituitary cells using a rhodamine-labeled TRH analog (Rhod-TRH) and indirect immunofluorescent staining of cells stably transfected with an epitope-tagged TRH receptor (TRHR). The epitope-tagged TRHR was confined to the cell surface prior to agonist treatment. Both Rhod-TRH and TRHR were also localized on the plasma membrane after agonist binding at 0 degrees C. Ligand binding at 37 degrees C resulted in rapid endocytosis, and both Rhod-TRH and the epitope-tagged TRHR appeared in cytoplasmic vesicles within 5 min. Fluorescently labeled TRH and transferrin colocalized in the same endocytotic vesicles, and internalization of Rhod-TRH and TRHR was inhibited by hypertonic medium, suggesting that endocytosis occurred by a clathrin-dependent mechanism. Internalized TRHRs returned to the membrane within 20 min after removal of TRH, and cycloheximide did not block receptor recycling. A mutant TRHR truncated at Cys335 signaled but did not internalize Rhod-TRH, confirming the importance of the carboxyl terminus of the TRHR in receptor-mediated endocytosis. Thus, the TRH TRHR complex is endocytosed via clathrin-coated vesicles and the receptor is recycled to the plasma membrane. PMID- 7831322 TI - Leukotriene B4 plays a critical role in the progression of collagen-induced arthritis. AB - Leukotriene B4 (LTB4) is a product of the 5-lipoxygenase pathway of arachidonic acid metabolism. LTB4 is a potent chemotactic factor for neutrophils and has been postulated to play an important role in a variety of pathological conditions including rheumatoid arthritis (RA), psoriasis, and inflammatory bowel disease. The role of LTB4 in such diseases has not yet been defined but in this paper we provide direct evidence that LTB4 plays a critical role in a murine model of RA. CP-105,696, (+)-1-(3S,4R)-[3-(4-phenylbenzyl)- 4-hydroxychroman-7-yl]cyclopentane carboxylic acid, is an LTB4 receptor antagonist that inhibits LTB4 binding to human neutrophil membranes with an IC50 of 3.7 nM and inhibits LTB4-induced chemotaxis of these cells with an IC50 of 5.2 nM. CP-105,696 inhibits LTB4 induced neutrophil influx in mouse skin when administered orally with an ED50 of 4.2 mg/kg. CP-105,696 had a dramatic effect on both the clinical symptoms and histological changes of murine collagen-induced arthritis when administered at doses of 0.3-10 mg/kg. Inhibition was not associated with suppression of the humoral immune response to collagen and was equally effective if drug treatment was commenced just prior to the onset of arthritis or throughout the experiment. These results suggest that LTB4 receptor antagonists may be effective therapeutic agents for the treatment of RA. PMID- 7831324 TI - Transcytosis-associated protein (TAP)/p115 is a general fusion factor required for binding of vesicles to acceptor membranes. AB - Transcytosis-associated protein (TAP) is found on transytotic vesicles (TCVs) and is required for their fusion with the target membrane. We developed a cell-free assay capable of differentiating targeting/binding of TCVs to membrane from later fusion events. We found that TAP mediates stable association of TCVs with the target membrane. The sequence of rat liver TAP (959-amino acid open reading frame) encodes a protein that contains (i) an N-terminal region (amino acids 1 649), (ii) an internal region with several coiled-coil stretches (amino acids 650 930), and (iii) a C-terminal acidic region (amino acids 931-959). Comparisons between TAP and other sequences indicate that TAP is identical to p115, a protein involved in cis to medial Golgi transport, and homologous to Uso1p, a yeast protein involved in endoplasmic reticulum to Golgi transport. Our findings suggest that TAP/p115/Usop1 is a general factor acting within the secretory and endocytic pathways to bind transport vesicles prior to membrane fusion. PMID- 7831323 TI - p115 is a general vesicular transport factor related to the yeast endoplasmic reticulum to Golgi transport factor Uso1p. AB - A recently discovered vesicular transport factor, termed p115, is required along with N-ethylmaleimide-sensitive fusion protein (NSF) and soluble NSF attachment proteins for in vitro Golgi transport. p115 is a peripheral membrane protein found predominantly on the Golgi. Biochemical and electron microscopic analyses indicate that p115 is an elongated homodimer with two globular "heads" and an extended "tail" reminiscent of myosin II. We have cloned and sequenced cDNAs for bovine and rat p115. The predicted translation products are 90% identical, and each can be divided into three domains. The predicted 108-kDa bovine protein consists of an N-terminal 73-kDa globular domain followed by a 29-kDa coiled-coil dimerization domain, a linker segment of 4 kDa, and a highly acidic domain of 3 kDa. p115 is related to Uso1p, a protein required for endoplasmic reticulum to Golgi vesicular transport in Saccharomyces cerevisiae, which has a similar "head coil-acid" domain structure. The p115 and Uso1p heads are similar in size, have approximately 25% sequence identity, and possess two highly homologous regions (62% and 60% identity over 34 and 53 residues, respectively). There is a third region of homology (50% identity over 28 residues) between the coiled-coil and acidic domains. Although the acidic nature of the p115 and Uso1p C termini is conserved, the primary sequence is not. We discuss these results in light of the proposed function of p115 in membrane targeting and/or fusion. PMID- 7831325 TI - Model study detecting breast cancer cells in peripheral blood mononuclear cells at frequencies as low as 10(-7). AB - A flow cytometric assay was developed to detect rare cancer cells in blood and bone marrow. Multiple markers; each identified by a separate color of immunofluorescence (yellow and two shades of red), are used to reliably identify the cancer cells. Blood or bone marrow cells, which are not of interest but interfere in detecting the cancer cells, are identified by a panel of immunofluorescence markers, each of which has the same color (green). Thus, the rare cancer cells of interest are yellow and two different shades of red but not green. The requirement that the rare cancer cell be simultaneously positive for three separate colors (the specific markers) and negative for a fourth color (the exclusion color) allowed detection of as few as one cancer cell in 10(7) nucleated blood cells (a frequency of 10(-7). To test this rare-event assay prior to clinical studies, a model study was performed in which the clinical sample was simulated by mixing small numbers of cells from the breast carcinoma line BT-20 with peripheral blood mononuclear cells. We detected statistically significant numbers of BT-20 cells at mixing frequencies of 10(-5), 10(-6), and 10(-7). In control samples, no target events (BT-20) were observed when more than 10(8) cells were analyzed. For additional confirmation that the BT-20 cells in the model study were correctly identified and counted, the BT-20 cells (and only BT 20 cells) were covalently stained with a fifth fluorescence dye, 7-amino-4 chloromethylcoumarin (CMAC). CMAC fluorescence data were not used in the assay for detecting BT-20 cells. Only after the analysis using data from the specific and exclusion colors had been completed were the events identified as BT-20 cells checked for CMAC fluorescence. The putative BT-20 events were always found to be positive for CMAC fluorescence, which further increases confidence in the assay. Manual data analysis and an automated computer program were compared. Results were comparable with the manual and automated methods, but the automated "genetic algorithm" always found more BT-20 events. Cell sorting of BT-20 cells from samples that contained BT-20 at frequencies of 10(-5), 10(-6), and 10(-7) provided further evidence that these rare cells could be reliably detected. The good performance of the assay with the model system will encourage further studies on clinical samples. PMID- 7831326 TI - The neural cell adhesion molecule (N-CAM) inhibits proliferation in primary cultures of rat astrocytes. AB - Cell proliferation is a key primary process during neural development and also plays an important role in the regenerative response of neural tissue to injury. It has been reported that glial cell proliferation is, at least in part, controlled by a neuronal signal, possibly involving cell surface molecules. We report here that the addition of purified rat neural cell adhesion molecule (N CAM) to primary cultures of rat forebrain astrocytes inhibits their proliferation. This inhibitory effect can be elicited in cultures grown in chemically defined serum-free medium or in medium that had been supplemented with growth factors. Polyclonal antibodies to N-CAM or their Fab' fragments elicited a similar inhibitory effect. The magnitude of the inhibitory effect of N-CAM was dependent on cell density: it was maximal at low cell densities and weakened progressively as cells approached confluency. Synthetic peptides with sequences identical to a putative homophilic binding region of N-CAM mimicked the effect of purified N-CAM, while peptides of the same length and amino acid composition but with a randomized sequence did not. The addition of N-CAM antisense oligonucleotides to primary astrocyte cultures for 48 h resulted in reduced levels of N-CAM expression. After N-CAM levels on astrocytes were diminished by this treatment, the antiproliferative effect of N-CAM added to the medium was significantly reduced. The combined results suggest that N-CAM homophilic binding may be involved in the control of glial cell proliferation. PMID- 7831327 TI - Activation of NF-kappa B requires proteolysis of the inhibitor I kappa B-alpha: signal-induced phosphorylation of I kappa B-alpha alone does not release active NF-kappa B. AB - The transcription factor NF-kappa B is retained in the cytoplasm by its inhibitor I kappa B-alpha. Upon cellular stimulation with a variety of pathogen- or stress related agents, I kappa B-alpha is functionally inactivated and NF-kappa B translocates to the nucleus to trigger transcription of a large array of genes, many of which encode proteins critical for immune or stress responses. Here, we demonstrate that signal-induced proteolysis of I kappa B-alpha is an obligatory step for activation of NF-kappa B: calpain inhibitors I and II, which inhibit cysteine proteases, block activation of NF-kappa B by blocking degradation of I kappa B-alpha without affecting signal-induced phosphorylation of this inhibitor. This contrasts with previous models in which phosphorylation of I kappa B-alpha was postulated to be sufficient for activation. We demonstrate further that signal-induced phosphorylation of I kappa B-alpha does not by itself lead to dissociation of the inhibitor from NF-kappa B, providing a rationale for and confirmation of the need to proteolyze I kappa B-alpha in order to activate NF kappa B. Signal-controlled, target-specific proteolysis is an unexpected, yet likely more general, mechanism for regulating transcription factors. PMID- 7831328 TI - Periodic recurrence of methionines: fossil of gene fusion? AB - As we have recently shown, approximately 20% of proteins are made of uniform size units of approximately 123 aa for eukaryotes and approximately 152 aa for prokaryotes. Such regularity may reflect certain past events in protein evolution by fusion (molecular recombination) of a spectrum of standard-size protein-coding DNA segments--the early genes. Consequently, methionines, as start residues, would mark those locations in proteins that correspond to the DNA recombination sites--the borders between the fused genes. This positional preference of the methionines may still survive as a fossil of the early protein sequence organization. In this study we address the question how methionines are distributed in modern protein sequences. This analysis of eukaryotic sequences shows that methionine residues do preferentially appear at the positions corresponding to the multiples of the unit size, as predicted. PMID- 7831329 TI - Activation of the myogenin promoter during mouse embryogenesis in the absence of positive autoregulation. AB - Myogenin, a member of the MyoD family of helix-loop-helix proteins, can induce myogenesis in a wide range of cell types. In addition to activating muscle structural genes, members of the MyoD family can autoactivate their own and cross activate one another's expression in transfected cells. This has led to the hypothesis that autoregulatory loops among these factors provide a mechanism for amplifying and maintaining the muscle-specific gene expression program in vivo. Here, we make use of myogenin-null mice to directly test this hypothesis. To investigate whether the myogenin protein autoregulates the myogenin gene during embryogenesis, we introduced a myogenin-lacZ transgene into mice harboring a null mutation at the myogenin locus. Despite a severe deficiency of skeletal muscle in myogenin-null neonates, the myogenin-lacZ transgene was expressed normally in myogenic cells throughout embryogenesis. These results show that myogenin is not required for regulation of the myogenin gene and argue against the existence of a myogenin autoregulatory loop in the embryo. PMID- 7831330 TI - Effect of erythrocyte membrane on extracellular development of the erythrocytic cycle of Plasmodium falciparum. AB - We have earlier reported conditions that support the axenic development in vitro of a complete asexual erythrocytic cycle of Plasmodium falciparum. Up to 30% of merozoites showed initial differentiation into trophic forms (rings) viable at 14 hr. However, only approximately 1% of the merozoites would develop further into trophozoites and early schizonts viable at 36 hr. In efforts to increase the number of late stage parasites, we have now found a significant favorable effect of the addition of erythrocyte ghosts. Doubling the quantity of erythrocyte membrane in the erythrocyte sonicate medium resulted in approximate doubling of the number of trophozoites and early schizonts. These results indicate that components of the erythrocyte membrane are essential for the complete development of the erythrocytic cycle. PMID- 7831331 TI - Nanosecond time-resolved circular polarization of fluorescence: study of NADH bound to horse liver alcohol dehydrogenase. AB - Circularly polarized luminescence (CPL) spectroscopy provides information on the excited-state chirality of a lumiphore analogous but complementary to information regarding the ground-state chirality derived from circular dichroism. The sensitivity of CPL spectra to molecular conformation makes this technique uniquely suited for the study of biomolecular structure, as extensively demonstrated in earlier studies. Unfortunately, the CPL spectra of many biomolecules often contain significantly overlapping contributions from emitting species either because multiple lumiphores are present (e.g., tryptophan residues in a protein) or because multiple conformations of the biomolecule simultaneously exist, each with a unique CPL spectrum. Increased resolution between individual contributions to the CPL may be achieved by time-resolving this signal, thus taking advantage of the fact that, as a rule, each of the emitting species also has a characteristic decay time associated with its electronically excited state. In addition, the time resolution provides information regarding dynamics associated with the different chiral states of the system. The present study describes an instrument for the determination of time-resolved CPL (TR-CPL) with subnanosecond resolution and its application to several chiral systems. The technique was first demonstrated on a model system with a strong time-dependent CPL signal. Subsequently, the circularly polarized component in the fluorescence of reduced nicotinamide adenine dinucleotide (NADH) bound to liver alcohol dehydrogenase was time-resolved. The CPL of NADH in the binary enzyme-coenzyme complex is time-dependent, reflecting structural differences around the reduced nicotinamide possibly due to a dynamic restructuring. In contrast, the CPL of the coenzyme in the ternary complex formed with enzyme and the substrate analog isobutyramide is essentially time-independent, likely reflecting a more rigid binding domain. Since the linear polarization of the fluorescence of the two complexes did not show any local flexibility of the NADH chromophore, the excited state conformational rearrangement of the binary complex indicates a subtle change in its interactions with group(s) in direct contact with it. PMID- 7831332 TI - The force generated by a single kinesin molecule against an elastic load. AB - To probe the mechanism by which the motor protein kinesin moves along microtubules, we have developed a highly sensitive technique for measuring the force exerted by a single motor molecule. In this technique, one end of a microtubule is attached to the tip of a flexible glass fiber of calibrated stiffness. The other end of the microtubule makes contact with a surface sparsely coated with kinesin. By imaging the tip of the glass fiber on a photodiode detector, displacement of the microtubule by kinesin through as little as 1 nm can be detected and forces as small as 1 pN resolved. Using this force-fiber apparatus we have characterized the mechanical output of this molecular motor. The speed at which a molecule of kinesin moved along the surface of a microtubule decreased linearly as the elastic force was increased. The force required to stop a single kinesin molecule was 5.4 +/- 1.0 pN (mean +/- SD; n = 16), independent of the stiffness of the fiber, the damping from the fluid, and whether the ATP concentration was high or low. PMID- 7831333 TI - Cell cycle regulation of metallothionein in human colonic cancer cells. AB - Elevated levels of metallothionein (MT) found in rapidly growing tissues such as neonatal liver and various types of human tumors have suggested a role for MT in cell proliferation. To further explore this possibility we investigated the concentration of MT in human colonic cancer (HT-29) cells at different stages of proliferation by means of immunocytochemistry and competitive binding. MT is increased in subconfluent proliferating cells relative to growth-inhibited confluent cells, much as it is in growing tissues. Cycling cells synchronized with compactin, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, revealed an oscillation of cytoplasmic MT that reached a maximum in successive late G1 phases and at the G1/S transition. Individual phase of the cell cycle were assessed by [3H]thymidine incorporation and by immunofluorescence employing an antibody that detects a nuclear antigen associated with proliferation. An enzyme-linked immunosorbent assay was used to quantify the relative amounts of MT in homogenate supernatants of HT-29 cells. A 2- to 3-fold increase in MT in actively proliferating cells and the regulation of the protein during the mitotic cell cycle point to a physiological role for MT in cellular proliferation and suggest that it may also serve as a proliferation marker. PMID- 7831335 TI - Long-term effects of embryo freezing in mice. AB - Embryo cryopreservation does not induce clear-cut anomalies at detectable rates, but several mechanisms exist for nonlethal damage during the freeze-thaw process, and the risk of moderate or delayed consequences has not been extensively investigated. In a long-term study including senescence, we compared cryopreserved and control mice for several quantitative traits. Significant differences were seen in morphophysiological and behavioral features, some of them appearing in elderly subjects. Thus, apart from its immediate toxicity, embryo cryopreservation, without being severely detrimental, may have delayed effects. These results, consistent with other findings, question the neutrality of artificial reproductive technologies and draw attention to the preimplantation stages in developmental toxicology. PMID- 7831334 TI - Effects of interferon gamma and major histocompatibility complex-encoded subunits on peptidase activities of human multicatalytic proteases. AB - We have examined several peptidase activities of human multicatalytic protease (MCP) purified from the lymphoblastoid cell line 721.45 and a deletion mutant derivative, 721.174, lacking MCP subunits encoded in the major histocompatibility complex (MHC) class II region. Wild-type lymphoblast MCP hydrolyzed a specific peptide, glutaryl-Gly-Gly-Phe-4-methylcoumaryl-7-amide (-MCA), several times faster than the mutant enzyme did, suggesting that MHC-encoded subunits may provide this activity. Contrary to a recent report [Driscoll, J., Brown, M. G., Finley, D. & Monaco, J J. (1993) Nature (London) 365, 262-264], we did not detect significant aminopeptidase associated with lymphoblast MCPs. Our results also differ markedly from those of Gaczynska et al. [Gaczynska, M., Rock, K. L. & Goldberg, A L. (1993) Nature (London) 365, 264-267], who reported that gamma interferon (IFN-gamma) alters the peptidase activities of lymphoblast MCPs. We found that IFN-gamma did not produce significant differences in the peptidase activities of purified MCPs. Moreover, our measurements of Vmax and Km for succinyl-Leu-Leu-Val-Tyr-MCA hydrolysis differ 600-fold and 15-fold, respectively, from those reported by Gaczynska et al. On balance, the findings presented here do not support the idea that IFN-gamma induces major changes in the peptidase activity of purified MCPs. PMID- 7831336 TI - Seminalplasmin: recent evolution of another member of the neuropeptide Y gene family. AB - Seminalplasmin, the major basic protein of bull semen, an important regulator of calcium transport in bovine sperm and a positive modulator of the zona pellucida induced acrosome reaction, is shown to be a recently created member of the neuropeptide Y gene family. Sequence analysis of the bovine peptide YY-pancreatic polypeptide gene cluster reveals an unexpected and extensive homology between seminalplasmin and the neuropeptide Y gene family, at the level of both gene structure and primary amino acid and nucleotide sequences. The extremely high degree of homology to the peptide YY gene, in both coding and especially noncoding regions, suggests that the seminalplasmin gene has arisen by a very recent gene duplication of the bovine peptide YY gene. Despite the more than 95% nucleotide sequence identity, a few specific mutations in the seminalplasmin gene have resulted in both the loss of the amino- and carboxyl-terminal cleavage sites characteristic of all other members of the neuropeptide Y family and the acquisition of a function apparently unrelated to the neurotransmitter/endocrine role of peptide YY. PMID- 7831337 TI - Two membrane forms of guanylyl cyclase found in the eye. AB - The cDNAs for two membrane guanylyl cyclases, designated E (GC-E) and F (GC-F, were isolated from a rat eye cDNA library. Their deduced topographic structures correspond to known members of the guanylyl cyclase receptor family, containing an extracellular domain, a single membrane-spanning domain, a protein kinase-like domain, and a cyclase catalytic domain. GC-E was expressed in the eye and the pineal gland, whereas GC-F expression was confined to the eye. Overproduction of GC-E and GC-F in COS cells resulted in expression of guanylyl cyclase activity, but ligands known to activate other guanylyl cyclase receptors failed to stimulate enzyme activity. Thus, both GC-E and GC-F remain orphan receptors. Amino acid sequence similarity between GC-E and GC-F in the extracellular region and homology with a cyclase expressed in olfactory neurons and retGC, a rod outer segment-specific cyclase, suggest that there is another subfamily of guanylyl cyclase receptors, possibly restricted to sensory tissues. PMID- 7831338 TI - Pan-neurotrophin 1: a genetically engineered neurotrophic factor displaying multiple specificities in peripheral neurons in vitro and in vivo. AB - Pan-neurotrophin 1 (PNT-1) is a synthetic trophic factor engineered by combining active domains of the neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin 3 (NT-3) into an NT-3 backbone. This molecule was produced in transiently transfected COS cells or in baculovirus infected insect cells transfected COS cells or in baculovirus-infected insect cells and subsequently purified to homogeneity. Saturation binding in embryonic spinal sensory neurons demonstrated a greater number of high-affinity binding sites for PNT-1 than for its parental molecule NT-3. PNT-1 was shown to efficiently block the chemical crosslinking of NGF, BDNF, and NT-3 to their cognate Trk receptors and to the low-affintiy NGF receptor expressed on neuronal and nonneuronal cells. PNT-1 stimulated survival and proliferation of MG87 fibroblasts expressing either TrkA, TrkB, or TrkC. PNT-1 also promoted survival of a greater number of embryonic dorsal root ganglion neurons than any of the other neurotrophins alone, and its effects were equivalent to a combination of NGF, BDNF, and NT-3. Analysis of receptor-specific neurotrophic activities demonstrated that PNT-1 efficiently rescued TrkA mRNA-containing sympathetic neurons and TrkB and TrkC mRNA-containing sensory neurons from the dorsal root and nodose ganglia. Finally, PNT-1 showed robust retrograde transport to DRG neurons in vivo after injection into the sciatic nerve. Radiolabeled PNT-1 accumulated in small-, medium-, and large-sized neurons. Coinjection with different unlabeled neurotrophins inhibited PNT-1 transport in distinct subpopulations of neurons of different sizes, suggesting that this molecule affects sensory neurons of different modalities. These results indicate that PNT 1 is a potent and multispecific neurotrophic factor that may be useful in the treatment of peripheral neurophathies and nerve damage. PMID- 7831339 TI - The period clock gene is expressed in central nervous system neurons which also produce a neuropeptide that reveals the projections of circadian pacemaker cells within the brain of Drosophila melanogaster. AB - The period protein (PER) is a essential component of the circadian clock in Drosophila melanogaster. Although PER-containing pacemaker cells have been previously identified in the brain, the neuronal network that comprises the circadian clock remained unknown. Here it is shown that some PER neurons are also immunostained with an antiserum against the crustacean pigment-dispersing hormone (PDH). This antiserum reveals the entire arborization pattern of these pacemaker cells. The arborizations of these neurons are appropriate for modulation of the activity of many neurons and they might interact with PER-containing glial cells. A putative physiological role of PDH in the circadian system is discussed. PMID- 7831340 TI - Disregulation of leukosialin (CD43, Ly48, sialophorin) expression in the B-cell lineage of transgenic mice increases splenic B-cell number and survival. AB - Leukosialin (also known as Ly48, CD43, and sialophorin) is a major cell surface sialoglycoprotein found on a variety of hematopoietically derived cells. The precise function of this molecule is poorly understood but it has been implicated in cell proliferation and intercellular adhesion. We developed a transgenic mouse model to assess leukosialin's function in vivo. Our approach was to alter mouse CD43 (mCD43) expression in the B-cell lineage where it is tightly regulated, by expressing it in peripheral B cells where it is normally absent. To drive expression of leukosialin in mature B cells, the immunoglobulin heavy chain enhancer was fused to the mCD43 gene. mCD43-immunoglobulin heavy chain enhancer transgenic mice display splenomegaly due to increased numbers of B cells. Transgenic B cells show a striking increase in their ability to survive in vitro compared to B cells from nontransgenic control mice. This prolonged survival is reflected in a decreased susceptibility to apoptosis. These observations suggest that mCD43 plays an important role in the regulation of B-cell survival. The alteration of the temporal expression, or "disregulation," of a gene in transgenic mice provides a general strategy for elucidating the in vivo role of other molecules involved in cell signaling and adhesion. PMID- 7831343 TI - Evidence for intron capture: an unusual path for the evolution of proteins. PMID- 7831341 TI - Induction of antibodies to the human immunodeficiency virus type 1 by immunization of baboons with immunoglobulin molecules carrying the principal neutralizing determinant of the envelope protein. AB - The hypervariable region 3 (V3) within the disulfide-bridged loop of the envelope protein of the human immunodeficiency virus type 1 (HIV-1) contains an amino acid sequence that was defined as a principal neutralizing determinant (PND). A 19 amino acid residue consensus sequence (designated V3C) predicted from the PND sequences of 245 isolates as well as a sequence from the PND of the WMJ2 HIV-1 isolate (designated V3M) were expressed on the variable region of murine-human immunoglobulin (Ig) chimeras that were designated Ig-V3C and Ig-V3M, respectively. The HIV-1 sequences on the Ig chimeras preserved their antigenicity and interacted with antibodies specific for peptides encompassing the V3C and V3M sequences. In baboons, Ig-V3C and Ig-V3M induced antibodies that bound V3C and V3M peptides as well as the glycoprotein gp120 envelope protein of HIV-1 MN isolate. In addition, the baboons' antisera were able to prevent infection of CD4 SupT1 susceptible T cells by HIV-1 MN. Finally, Ig-V3M chimeras were able to stimulate in vitro production of antibodies specific for the HIV-1 envelope derived peptides by lymphocytes from HIV-1-infected human subjects. PMID- 7831342 TI - Cyanobacterial protein with similarity to the chlorophyll a/b binding proteins of higher plants: evolution and regulation. AB - We have isolated, from the prokaryotic cyanobacterium Synechococcus sp. strain PCC 7942, a gene encoding a protein of 72 amino acids [designated high light inducible protein (HLIP)] with similarity to the extended family of eukaryotic chlorophyll a/b binding proteins (CABs). HLIP has a single membrane-spanning alpha-helix, whereas both the CABs and the related early light inducible proteins have three membrane-spanning helices. Hence, HLIP may represent an evolutionary progenitor of the eukaryotic members of the CAB extended family. We also show that the gene encoding HLIP is induced by high light and blue/UV-A radiation. The evolution, regulation, and potential function of HLIP are discussed. PMID- 7831344 TI - The tamoxifen controversy--clinical chemopreventive agent and experimental carcinogen. PMID- 7831345 TI - Tamoxifen experimental carcinogenicity studies: implications for human effects. PMID- 7831346 TI - Tamoxifen for breast cancer prevention. PMID- 7831347 TI - Recombinant hemoglobins as blood substitutes: a biotechnology perspective. AB - Human hemoglobin can be produced in microbial and mammalian organisms using many different expression systems. It is anticipated that recombinant hemoglobins (or globin genes) will have many applications including as an infectious agent-free, inexpensive raw material for a red blood cell substitute, as a vehicle for expression or delivery of other biomolecules, and in gene therapy of inherited hemoglobinopathies. Recombinant expression, combined with site-directed mutagenesis, is facilitating the modification of the functional properties of hemoglobin. Although a functional hemoglobin molecule can be derived using many of the known expression systems, the choice of the production system for manufacturing depends on the scale, acceptable cost, and the associated environmental impact of the various processes. While the efficient bacterial production systems yield a modified, "surrogate" hemoglobin, the transgenic animal-derived product is virtually identical to the human erythrocyte-derived hemoglobin. Both the microbial fermentation, and the mammalian transgenic systems can be geared to produce the enormous quantities of hemoglobin expected to be required to meet the anticipated demand for a successful blood substitute in the future. PMID- 7831348 TI - Role of brown adipose tissue thermogenesis in control of thermoregulatory feeding in rats: a new hypothesis that links thermostatic and glucostatic hypotheses for control of food intake. AB - The hypothesis proposed in this review provides a novel view of both the control of feeding and the function of brown adipose tissue (BAT) thermogenesis. It takes into account the episodic nature of feeding in rats allowed free access to food and the necessity for episodic events in the controlling systems which govern initiation and termination of feeding. A feeding episode is proposed to occur during an episode of increased sympathetic nervous system activity that stimulates BAT thermogenesis and increases body temperature. Two different aspects of stimulated BAT metabolism, namely increased uptake of glucose and increased heat production, evoke initiation and termination of feeding, respectively. Initiation is mediated by a transient dip in blood glucose concentration caused by stimulated glucose utilization in BAT. Feeding continues while both BAT and core temperature continue to rise. Termination is induced by the high level of core temperature brought about by the episode of stimulated BAT thermogenesis. The time between initiation and termination determines the size of the meal and depends on the balance between BAT thermogenesis and heat loss, and thus on ambient temperature. The underlying cause of the episodic stimulation of sympathetic nervous system activity is a decline in core temperature to a level recognized by the hypothalamus as needing a burst of increased heat production. Thus, BAT thermogenesis is important in control of meal size, relating it to thermoregulatory needs. When this function is lost, as in many obese animal models of obesity, the animal loses its ability to remain in energy balance by precisely adjusting its intake in relation to environmental temperature and meal size increases. The hypothesis also predicts that an increase in endogenous heat production that is not due to BAT thermogenesis will prevent the matching of intake to increased expenditure via thermoregulatory feeding. This is seen, for example, in the shivering rat during the early stage of acclimation to cold. Feeding is viewed as the outcome of a thermoregulatory event. Rats do not eat to warm up; they start to eat after they have started to warm up and stop eating once they have warmed up. The phenomenon is termed thermoregulatory feeding, to distinguish it from feeding initiated by other stimuli. PMID- 7831349 TI - Potentiation of nitric oxide-mediated vascular relaxation by SC52608, a superoxide dismutase mimic. AB - Nitric oxide (NO) produced by the vascular endothelium is an endogenous contributor to the regulation of vascular relaxation and the maintenance of blood pressure. The effective half-life of NO and the relaxation of aortic rings by NO is enhanced by a reduction in the concentration of superoxide radicals with superoxide dismutase (SOD). In the current study, SC52608, a newly synthesized SOD mimic with a manganese core, was tested for its ability to potentiate the activity of NO both in vitro and in vivo. SC52608 relaxation of rat aortic segments was endothelium dependent as well as concentration dependent. The maximum relaxation following KCl contraction was 44% with 300 microM SC52608. Cyclic GMP concentrations in the segments were increased 1.6- and 3.2-fold with 5 and 300 microM SC52608, respectively. N-monomethyl-I-arginine pretreatment of aortic rings abolished the relaxation and cyclic GMP accumulation mediated by SC52608. In a smooth muscle cell reporter system of nitric oxide synthase activity, SC52608 potentiated the increase in cyclic GMP elicited by NO in a concentration-dependent manner with a maximum increase of 5.2-fold at 100 microM. Injection of SC52608 into conscious, restrained rats resulted in a dose-dependent decrease of blood pressure. Therefore, the data suggest that SC52608 potentiates the actions of nitric oxide on vascular tone, cyclic GMP, and blood pressure by enhancing the half-life of NO through a mechanism that mimics the action of SOD. PMID- 7831350 TI - Effects of N-(4-hydroxyphenyl)retinamide on vitamin A metabolism in rats. AB - Chronic administration of the anticancer drug N-(4-hydroxyphenyl)-retinamide (4 HPR) causes reductions in the plasma levels of vitamin A and its transport protein, retinol-binding protein. Here, we used model-based compartmental analysis to study effects of 4-HPR on the whole-body kinetics of vitamin A metabolism in rats. Rats (n = 8) were fed a purified diet containing vitamin A (approximately 49 nmol retinol/day) plus 0 or approximately 50 mumole 4-HPR/(kg body wt.day). Plasma retinol kinetics were monitored for 35 days after intravenous administration of [3H]retinol-labeled plasma. 4-HPR caused an 80% reduction in plasma retinol; after 40 days of treatment with 4-HPR, liver vitamin A levels were 2.33 times higher than those of control rats. A three compartment model, in which plasma retinol exchanges with two extravascular compartments, was required to fit data for both groups. Vitamin A input was via the central plasma compartment, while irreversible loss was via the larger extravascular compartment. The time retinol spent in plasma before reversible or irreversible exit was normal (1.7 hr) in 4-HPR-treated rats, but the rate of plasma retinol turnover was reduced, and the recycling of retinol to plasma was delayed and reduced. Vitamin A utilization was significantly lower in 4-HPR-treated rats (20 nmol retinol/day vs 42 nmol/day in controls). We conclude that 4-HPR partially blocks access and thus binding of retinol to retinol-binding protein and may therefore lead to vitamin A accumulation in certain cells. PMID- 7831351 TI - The effects of O- and N-linked glycosylation on the secretion and bile salt stimulation of pancreatic carboxyl ester lipase activity. AB - Pancreatic carboxyl ester lipase is a glycoprotein that requires millimolar concentrations of trihydroxy bile salts, such as cholate, for maximal catalytic activity against cholesteryl esters and triglycerides. Binding of cholate, with subsequent activation, has been proposed to occur in the carboxy-terminal region of carboxyl ester lipase, which contains multiple sites for O-linked glycosylation (1). To investigate the role of O- and N-linked glycosylation in the secretion of carboxyl ester lipase by cells and its activation by cholate, rat carboxyl ester lipase cDNA was transfected into the mutant chinese hamster ovary cell line, IdID, and the ability of the cells to modify the expressed carboxyl ester lipase by N- and O-linked glycosylation was modulated by using various incubation conditions and metabolic inhibitors. The results showed that, similar to other lipases, maximal secretion of carboxyl ester lipase activity required N-linked glycosylation. In contrast, O-linked glycosylation did not affect the secretion of carboxyl ester lipase activity. In addition, the cholate stimulation of hydrolysis was also independent of O-linked glycosylation. PMID- 7831352 TI - Lead and nickel alter the cardiorenal actions of endothelin in the rat. AB - In the current study, we have determined to what extent lead and nickel alter the cardiorenal actions of endothelin in pentobarbital anesthetized female rats. One hour following surgery, 3 x 15-min renal clearances were collected and endothelin (ET)-1 was infused iv at 110 ng/kg/min for 30 min during which time an additional two clearances were collected. Lead (infused as lead acetate throughout the experiment) at 4.8 nmoles/min and 24 nmoles/min significantly attenuated the ET induced increase in mean arterial pressure (MAP); lead infused at 0.48 nmoles/min had no effect. An ET-induced decrease in the glomerular filtration rate (GFR) in control rats was completely blocked by the higher doses of Pb2+. By contrast, Pb2+ had no effect on angiotensin II or norepinephrine induced increases in MAP. In additional experiments, calcium chloride was infused at 500 nmoles/min for 105 min, then Ca2+ + Pb2+ (4.8 nmoles/min) were infused for another 105 min; in these experiments, there was no Pb(2+)-induced inhibition of the MAP response to endothelin; the GFR response to the peptide remained blocked. NiCl2 reduced the ET-induced increase in MAP only at 24 nmoles/min; at 4.8 and 24 nmoles/min, nickel attenuated the decrease in GFR induced by ET. Finally, Ca2+ infusion had no effect on the inhibition by Ni2+ of the GFR response to ET. These data illustrate that (i) lead inhibits the cardiorenal actions of endothelin; (ii) a Ca(2+)-related process is involved the systemic but not the renal component of this inhibition; (iii) since the heavy metal does not affect angiotensin II or norepinephrine-induced increases in MAP, the inhibition by lead of the systemic response is relatively specific for endothelin; and (iv) nickel also inhibits the renal response to the peptide but higher doses are required to inhibit the systemic response. PMID- 7831353 TI - Prophylactic use of monophosphoryl lipid A in patients at risk for sepsis. PMID- 7831354 TI - Rabbit CAP18 derived peptides inhibit gram negative and gram positive bacteria. AB - CAP18 (cationic antimicrobial protein of 18 kDa) was originally isolated from rabbit granulocytes using as an assay the agglutination of Re-lipopolysaccharide coated erythrocytes. The C-terminal 37 amino acids of CAP18 comprise the LPS binding domain called RNIP, reactive nitrogen inhibitory peptide. Synthetic RNIP has broad antimicrobial activity versus both gram positive [IC50 = 130-200 nM] and gram negative bacteria [IC50 = 20-100 nM). Susceptible strains include Staphylococcus aureus, Klebsiella pneumoniae, Streptococcus pneumoniae, Escherichia coli, Pseudomonas aeruginosa, and Streptococcus pyogenes. Antimicrobial activity is highly dependent upon peptide structure. Although a 32 amino peptide resulting from truncation of five amino acids from the C terminus of RNIP is highly active, other fragments of RNIP including truncation of its N terminus do not exhibit antimicrobial activity. Unlike previously characterized antimicrobial peptides derived from granulocyte proteins RNIP is active in serum. RNIP or a derivative peptide may have therapeutic potential for bacterial sepsis. PMID- 7831355 TI - Endotoxin-binding synthetic peptides with endotoxin-neutralizing, antibacterial and anticoagulant activities. AB - Endotoxin(lipopolysaccharide = LPS), cell wall component of gram-negative bacteria, activates monocytes and macrophages to release cytokines, reactive nitrogen intermediates (RNI), and to generate tissue factor(TF) which initiate coagulation. We have purified 7kDa and 18kDa cationic antibacterial proteins (CAP 7 and CAP-18) with LPS-binding and LPS-neutralizing activities from rabbit granulocytes using as an assay the agglutination of erythrocytes coated with Re LPS. From protein sequencing, CAP-7 was identified as the C-terminal 37 amino acid fragment of CAP-18. Synthetic peptide #197 (identical sequence to CAP-7, Gly1-Try37) and #36-1 (a truncation of CAP consisting of 32 amino acid residues, Gly1-Ala32) showed LPS-binding activity. Each peptide inhibited LPS-induced tissue factor(TF) generation by murine peritoneal macrophages, even added 1-3 hours after stimulation of cells with LPS. C57BL/6 mice treated with #197 were significantly protected from lethal LPS challenge. Peptide #36 also blocked the LPS-induced lethality. These peptides had antibacterial activity to gram-negative bacteria, such as E.coli, S.typhimurium, K.pneumonia, Ps.aeruginosa and also to gram-positive S.aureus (Methicillin sensitive and resistant strains). Both peptides inhibited TF- and Xa-induced plasma clotting. Using synthetic chromotogenic substrates, both CAP7 peptides blocked the coagulation cascade at two sites, activation of factor X to Xa and conversion of Factor II (prothrombin) to factor IIa (thrombin). In vivo treatment of peptide #197 prevented acute lethality in mice injected with tissue factor (rabbit brain thromboplastin). Two other peptides, #32(Gly1-Phe9) and #50(Ile13-Typ37) failed to demonstrate LPS binding, LPS-neutralizing, antibacterial and anticoagulant activities. The active peptides but not the inactive peptide maintain a putative heparin binding domain at their N-termini. This heparin binding domain is participate in the LPS binding, LPS neutralizing, antibacterial and anticoagulant activities of CAP7. These active peptides may have a therapeutic potential for treatment for DIC due to sepsis and endotoxin shock. PMID- 7831356 TI - Hemoglobin: a newly recognized binding protein for bacterial endotoxins (LPS). AB - Administration of purified hemoglobin (Hb) as a cell-free resuscitation fluid is associated with multiple organ toxicities. Many of these toxicities are characteristic of the pathophysiological effects of bacterial endotoxins (lipopolysaccharide, LPS). To better understand the potential role of LPS in the observed in vivo toxicities of Hb, we examined mixtures of Hb and LPS for evidence of LPS-Hb complex formation. LPS-Hb complexes were demonstrated by three techniques: ultrafiltration through 300 kDa cut-off membranes, which distinguished LPS in complexes (87-89% < 300 kDa) from LPS alone (90% > 300 kDa); density centrifugation through sucrose, which distinguished denser LPS alone from LPS-Hb complexes; and precipitation by 67% ethanol, which demonstrated 2-3 fold increased precipitability of Hb in complexes compared to Hb alone. Interaction of LPS with Hb was also associated with markedly increased biological activity of LPS, as manifested by enhancement of LPS activation of Limulus amebocyte lysate (LAL), increased release of human mononuclear cell tissue factor, and enhanced production of human endothelial cell tissue factor. These results demonstrated that hemoglobin can serve as an endotoxin binding protein, and that this interaction results in the alteration of several of the physical characteristics of LPS and enhancement of the biological activities of LPS. These findings suggest that a mechanism for the toxicity of infused Hb in vivo may involve potentiation of the biological effects of LPS. In addition, these observations suggest a mechanism by which LPS-related morbidity during sepsis could be enhanced by erythrocyte hemolysis. PMID- 7831358 TI - Studies on the inflammatory-coagulant axis in the baboon response to E. coli: regulatory roles of proteins C, S, C4bBP and of inhibitors of tissue factor. AB - The baboon model of E. coli sepsis illustrates three concepts with respect to the host response and vascular endothelium. First, the endothelium is the primary target. E. coli sepsis is an acute inflammatory disease of the vascular endothelium. Second, the endothelium is not a passive target. Initially it regulates both the inflammatory and coagulopathic aspects of E. coli sepsis through membrane associated regulatory receptor/plasma protein assemblies including protein C/thrombomodulin, activated protein C/protein S, C4bBP/protein S, tissue factor pathway inhibitor/Xa, antithrombin III/glycosaminoglycans. Third, when overridden by inflammatory events, the endothelium can change its anticoagulant phenotype and mount a massive procoagulant fibrinolytic counter attack on its luminal side through the expression of tissue factor and release of tissue plasminogen activator. Fourth, again when overridden by inflammatory events, the endothelium can change its antioxidant phenotype and produce a "distal" tissue hypoxia on its abluminal side through induction of free radical generation and peroxidation of mitochondrial lipid membranes of those tissues with high metabolic rates. It has become increasingly clear that the so-called anticoagulant systems which act on the proximal factors of the clotting cascade (protein C, TFPI, AT-III, PGI2) also attenuate the amplification of the inflammatory response. Aspects of the mechanism by which this occurs are coming to light. This includes the attenuation of Il-6 response by TFPI and the attenuation of the complement effects by C4bBP/PS. The specifics of these observations in the E. coli sepsis model will be reviewed. PMID- 7831357 TI - A case for an endotoxic conformation. AB - Gram-negative bacteria express on their surface endotoxins which are essential for bacterial growth and survival. If released from the bacterial cell, endotoxins induce, in higher organisms, a variety of pathophysiological effects known as manifestations of bacterial sepsis. Chemically, endotoxins are lipopolysaccharides (LPS) composed of a polysaccharide and a lipid component, termed lipid A, which is responsible for the induction of endotoxin effects. Lipid A of all endotoxically active LPS have a similar architecture. The structural and conformational parameters endowing lipid A with its potent bioactivity have been well characterized. The toxic effects of endotoxins or their lipid A component, respectively, are initiated by the specific interaction of lipid A with macrophages/monocytes resulting in the production of peptide or lipid mediators like tumor necrosis factor alpha (TNF), the leukotrienes, and oxygen radicals. This interaction requires a unique "endotoxic conformation" of lipid A on the one hand, and specific cellular receptors on the other. The interaction and subsequent mediator production can be specifically and antagonistically inhibited by lipid A partial structures. PMID- 7831359 TI - The contact system and sepsis. PMID- 7831360 TI - Inhibition of extrinsic coagulation activation in endotoxemia; therapeutic implications. PMID- 7831362 TI - Endotoxin induced coagulation activation and protein C reduction in meningococcal septic shock. PMID- 7831363 TI - Efficacy of a recombinant amino terminal fragment of bactericidal/permeability increasing protein in rodents challenged with LPS or E. coli bacteria. PMID- 7831361 TI - Experimental and clinical evidence of leukocyte activation in trauma and sepsis. PMID- 7831364 TI - Platelet-activating factor antagonists as therapeutic strategy in sepsis. PMID- 7831365 TI - Cytokine neutralizing strategies in experimental sepsis. AB - Endotoxemia and bacteremia initiate a cytokine cascade, which may be beneficial to host defense, but in its exaggerated form may be responsible for shock and death. A large amount of experimental and clinical investigation has centered on neutralizing the cytokine cascade in order to prevent the severe pathophysiologic sequelae associated with infection and sepsis. Most of the work has been focused on systemic administration of antibodies for neutralization of specific cytokines, particularly tumor necrosis factor and interleukin-1. Both biologic and fiscal obstacles have prevented this strategy of using specific antibodies from becoming clinical practice. Of the many other strategies under investigation, four are particular exciting: 1) utilization of natural cytokine antagonists, 2) strategies for increasing cytokine clearance, 3) dietary modulation of cytokine production, and 4) gene therapy of sepsis. PMID- 7831366 TI - Pentoxifylline modulates cytokine responses in a sepsis model. PMID- 7831367 TI - Initial studies on the administration of C1-esterase inhibitor to patients with septic shock or with a vascular leak syndrome induced by interleukin-2 therapy. AB - Activation of the complement and contact systems occur in patients with septic shock and is associated with a poor outcome. Activation of both systems is regulated by a common inhibitor, C1-esterase inhibitor (C1-Inh). Functional levels of C1-Inh are normal or slightly decreased in septic patients although this inhibitor is an acute phase protein. Moreover, an increased turn-over of C1 Inh in sepsis likely occurs since levels of proteolytically inactivated ("modified") C1-Inh are increased in this syndrome. One may therefore postulate that in sepsis there is a relative deficiency of C1-Inh. Here we will summarize our preliminary studies in 11 patients with septic shock, who received high doses of C1-Inh for up to 5 days. Activation of complement and contact systems also occurs in "a human model for septic shock" i.e., the vascular leak syndrome (VLS) induced by immunotherapy with the cytokine interleukin-2 (IL-2). The similarity between VLS and sepsis is not only reflected by similar patterns of complement and contact activation, but also by comparable hemodynamic and biochemical changes, and by the involvement of a number of other inflammatory mediators, such as the release of pro-inflammatory cytokines, and activation of coagulation and fibrinolysis and of neutrophils. Here we will also summarize our initial studies of the effect of C1-Inh administration to 6 patients with the VLS induced by IL 2. Our results indicate that high doses of C1-Inh can be safely administered to patients with septic shock or with the VLS, and may attenuate complement and contact activation in these conditions. Whether this therapy may reduce mortality and or morbidity of either syndrome has to be established by double-blind controlled studies. PMID- 7831368 TI - Gene therapy for inflammatory diseases. AB - The concept of gene therapy may be broadened to include transient gene therapy (gene therapeutics) as a potential intervention in prevention and treatment of diseases which are a consequence of triggering the inflammatory response. Functioning genes can be delivered in vivo by a variety of technologies. Liposome technology is particularly attractive for gene therapeutics because plasmid DNA constructs can be delivered using liposomes which express transiently and do not readily incorporate into the host genome. In the lungs, DNA may be targeted by either intravenous or airway delivery. Airway delivery may be achieved either by direct injection into the airways or by aerosolizing liposome-DNA constructs. Expression of transgenes might also be targeted to areas of inflammation by choosing DNA constructs which contain the appropriate regulatory regions. Several genes have been cloned which are directly relevant to manipulating the inflammatory response and this technology could, in theory, by using either sense or antisense constructs, provide an opportunity to increase or decrease proteins relevant to the inflammatory response. Because of rapid progress in the technology of molecular biological techniques, and rapid progression of human trials using gene transfer methodologies, it is likely that extension of gene therapy to acute diseases such as those which are characterized by inflammation will open a new vista for pharmacological approaches to these complex diseases. PMID- 7831369 TI - Regulation of the TNF alpha gene. PMID- 7831370 TI - Endotoxin and the release of tumor necrosis factor receptors. PMID- 7831371 TI - Participation of IFN-gamma in the pathogenesis of LPS lethality. PMID- 7831372 TI - Sepsis criteria, and selection of patients for immunotherapy. PMID- 7831373 TI - The bactericidal/permeability increasing protein of neutrophils is a potent antibacterial and anti-endotoxin agent in vitro and in vivo. AB - The Bactericidal/Permeability Increasing protein (BPI) is a major constituent of the azurophilic granules of human and rabbit polymorphonuclear leukocytes (PMN). The cDNA of the highly conserved protein has been isolated from man, rabbit and cow. The ca. 50 kDa BPI and a ca. 25 kDa bioactive N-terminal fragment are cytotoxic only for Gram-negative bacteria (GNB). This target-cell specificity reflects the strong attraction of the highly cationic protein for the negatively charged lipopolysaccharides (LPS) in the bacterial envelope. Native and recombinant (r) holo-BPI and the N-terminal fragment (rBPI-23) bind with high affinity (apparent Kd 1-10 nM) to all forms of isolated LPS so far examined, and inhibit the numerous biological effects of LPS in vitro (including in whole blood ex vivo) as well as in animals. Under the same conditions the antibacterial activities of holo-BPI and rBPI-23 against GNB with rough chemotype LPS are the same, but against serum-resistant and smooth chemotype GNB rBPI-23 is up to 30 fold more potent than holo-BPI. Holo-BPI and rBPI-23 protect mice, rats and rabbits against lethal cytotoxic effects of LPS and in some cases against lethal inoculations with live GNB. PMID- 7831374 TI - The protective role of interleukin-10 in endotoxin shock. PMID- 7831375 TI - The role of tumor necrosis factor in systemic inflammatory responses in primate endotoxemia. PMID- 7831376 TI - Cost-effectiveness of HA-1A treatment for patients with sepsis. AB - The cost-effectiveness of prescribing HA-1A for sepsis patients was analyzed by comparing effectiveness and direct medical costs. Effectiveness was estimated on the basis of published data from a randomized clinical trial. Costs were determined by combining data from the same trial with expectations about hospital days. Average costs per life year gained were estimated at 25,000 Dutch guilders (1 Dutch guilder is approximately 53 US cents). Sensitivity analyses were applied and showed that the effectiveness and cost-effectiveness of treating patients with HA-1A depend a great deal on the expected duration of survival after successful treatment. If the objective is to maximize the cost-effectiveness of treatment, this means that the prognosis of the patient should be considered when deciding about the appropriateness of treatment with HA-1A. As one would expect, another way to increase cost-effectiveness would be to increase the proportion of gram-negative sepsis patients amongst those receiving treatment. PMID- 7831377 TI - Biological activity of lipid A partial structures. PMID- 7831378 TI - Anti-lipopolysaccharide core antibodies. PMID- 7831379 TI - Lipopolysaccharide-antagonizing effects of diphosphoryl lipid A from Rhodobacter sphaeroides (Rs-DPLA). PMID- 7831380 TI - Role of serotonin1A and serotonin2 receptors in the central regulation of the cardiovascular system. PMID- 7831381 TI - Peptidergic modulation of learning and memory processes. PMID- 7831382 TI - Diversity of agents that modify opioid tolerance, physical dependence, abstinence syndrome, and self-administrative behavior. PMID- 7831383 TI - Endothelins: molecular biology, biochemistry, pharmacology, physiology, and pathophysiology. PMID- 7831384 TI - Distribution of metalloporphyrin inhibitors of heme oxygenase among serum transport proteins. AB - Porphyrins are transported in the serum bound to proteins and lipoproteins; the particular component(s) to which a porphyrin is bound influences its distribution in the body. In these experiments, the fractions of serum to which several metalloporphyrin inhibitors of the microsomal enzyme heme oxygenase bind were determined. Sn-mesoporphyrin and Sn-protoporphyin were associated almost entirely with serum albumin and Sn-diiododeuteroporphyrin almost completely with the lipoprotein fraction; Zn-mesoporphyrin was associated with all fractions. Serum transport proteins may be targets of photosensitization by photoactive metalloporphyrins. A decrease in the binding constant of bilirubin to Sn mesoporphyrin-mediated photosensitized human serum albumin (HSA) was observed following illumination at 50 W/m2 in the spectral range of 520-700 nm; there were 2.0 +/- 0.2 bilirubins bound per HSA for samples illuminated < 120 min; following 180 min illumination, the stoichiometry decreased to 1.5 +/- 0.1 bilirubin per HSA. In a similar experiment with Zn-mesoporphyrin, the porphyrin was fully photooxidized to a nonphotoactive and noninhibiting product after 1 min illumination. The light reaching a porphyrin through human skin would be considerably less than that utilized under these in vitro conditions, and such effects on serum proteins, if demonstrable at all in vivo, would be expected to be far less pronounced than those measured here. PMID- 7831385 TI - Incorporation of metalloporphyrin inhibitors of heme oxygenase into micelles and liposomes. AB - Spectral and photodynamic properties of a porphyrin are sensitive to the environment in which it is localized. By comparison of absorption maxima of porphyrins bound to micelles, proteins or artificial membranes with peak wavelengths in homogeneous solutions of known dielectric constant, the relative polarity of the microenvironment surrounding a porphyrin can be estimated. We have focused our examination on the ability of two synthetic metalloporphyrin inhibitors of heme oxygenase, Sn(IV)-mesoporphyrin (SnMP) and Zn(II) mesoporphyrin (ZnMP), to partition into charged and uncharged detergent micelles and liposomes. SnMP and ZnMP are intercalated into micelles with cationic surface charges but only ZnMP into nonionic micelles, suggesting that the ionic character of the two anionic axial ligands of SnMP, as well as that of the ionized carboxylic acids of both porphyrins, is a predominant force in the interactions of these compounds. Absorbance shifts of SnMP and ZnMP bound to serum albumin suggest that both porphyrins are localized within an environment with polarity similar to that of ethanol. Spectral changes upon incubation of ZnMP into liposomes (with or without surface charges) indicate that the porphyrin is incorporated into the polar region of the bilayer, i.e. at the border between hydrophilic headgroups and hydrophobic lipids. Illumination of ZnMP within the liposomal membrane resulted in a rapid rate of oxygen uptake, consistent with lipid peroxidation occurring within the bilayer. PMID- 7831386 TI - Interaction between Helicobacter pylori and human gastric epithelial cells in culture: effect of antiulcer drugs. AB - A human in vitro model to study the interaction between Helicobacter pylori and gastric epithelial cells was developed using primary cultures of gastric mucosal cells (isolated from gastric biopsies or operative specimen and maintained in culture for 2 weeks) as well as the well-differentiated human gastric carcinoma cell line HM02, the undifferentiated gastric tumour cell line HM51, and the laryngeal epithelial cell line HEp-2. Primary cultures and all cell lines were exposed to seven isolates of H. pylori isolated from gastritis and duodenal ulcer patients. Microbial adherence was assessed by microscopical evaluation of Giemsa stained preparations and by culturing the viable bacteria attached to the epithelial cells. All H. pylori isolates adhered to the gastric cells in primary culture, to HM02 cells, and to HEp-2 cells with the greatest binding affinity found in primary gastric cells. No adherence was detected in HM51 cells. H. pylori adherence was dependent on bacterial load, incubation time, and temperature. There was no difference in microbial binding between H. pylori isolates derived from gastritis and duodenal ulcer patients. The effect of antiulcer drugs on H. pylori adherence was investigated by pre-incubating isolates of H. pylori with omeprazole, cimetidine, and bismuth subcitrate. Omeprazole and cimetidine failed to significantly influence microbial adherence. In contrast, bismuth subcitrate already in concentrations below the MIC range decreased H. pylori adherence in gastric epithelial cells and in HEp-2 cells substantially. Our study shows that primary cultured human gastric mucosal cells and the human gastric carcinoma cell line HM02 provide suitable in vitro models for the study of the interactions between H. pylori and the gastric epithelium. This gastric cell model is characterized by a high affinity for H. pylori binding. PMID- 7831387 TI - Characterization of ATP-sensitive potassium channel-blocking activity of ZENECA ZM181,037, a eukalemic diuretic. AB - ZENECA ZM181,037 is a novel eukalemic diuretic from a series of 1,1-diarylcarbin 1-01-2 amines. In contrast to the standard diuretic hydrochlorothiazide, the blood pressure-lowering effect was not observed with ZENECA ZM181,037 in spontaneously hypertensive rats. ZENECA ZM181,037 demonstrated a K+ channel blocker profile. In the isolated rat aorta stimulated with 20 mmol/l KCl, both the d- and l-enantiomer of ZENECA ZM181,037 antagonized the relaxation of cromakalim with mean pKB values of 6.4 and 6.7, respectively. In the isolated guinea-pig portal vein and urinary detrusor muscle, both enantiomers enhanced the spontaneous myogenic activity at concentrations of 1 mumol/l and higher, in addition to antagonizing the effect of cromakalim. ZENECA ZM 181,037, similar to glibenclamide, prevented a significant increase in 86Rb+ by cromakalim in both portal vein and detrusor muscle strips; however, ZENECA ZM181,037, dissimilar to glibenclamide and tolbutamide, did not increase plasma glucose when given orally to dogs. Thus, ZENECA ZM181,037 is a blocker of the ATP-sensitive K+ channel (KATP) in vascular and nonvascular tissues. In view of the profound saluresis produced by ZENECA ZM181,037, the lack of antihypertensive effect appears to result from its blocking activity on KATP in vascular tissues. PMID- 7831388 TI - Cultured endothelial cells restore vasodilator responses to coronary arteries with impaired endothelial function and alter the response to a nitric oxide donor. AB - The objective of this investigation was to determine the effect of cultured human umbilical vein endothelial cells (HUVEC) on the vascular response to canine coronary arteries in which the endothelium had been either mechanically removed or injured by multiple brief episodes of occlusion and reperfusion in vivo. The endothelium-dependent vasodilator, A23187 (10(-6) mol/l) did not cause any significant relaxation in vessels from which the endothelium had been removed. However, following addition of cultured HUVEC to the tissue bath (75 x 10(3) cells/ml), A23187 produced a significant (p < 0.05) relaxation. This effect was abolished by inhibition of nitric oxide synthase with Nw-nitro-l-arginine methyl ester (L-NAME). Vascular relaxation caused by the nitric oxide donor SIN-1 was significantly (p < 0.05) enhanced when cultured HUVEC were added to vessels mechanically denuded of endothelium. Repetitive ischemia and reperfusion significantly inhibited the relaxant response to A23187. Addition of cultured HUVEC to the tissue bath partially restored the response to A23187. In contrast to the mechanically damaged vessels the relaxant response to SIN-1 was unaffected by cultured HUVEC in reperfusion-injured vessels. These results demonstrate that cultured endothelial cells partially restore endothelium-dependent vasodilation of vessels in which the endothelium is not functional following mechanical- or reperfusion-induced damage. The differential effect of endothelial cells on the response to SIN-1 suggests that mechanical and reperfusion injury alter the coronary vascular response to SIN-1 by different mechanisms. PMID- 7831389 TI - Vascular reactivity to vasoconstrictors in aorta and renal vasculature of hyperthyroid and hypothyroid rats. AB - Vascular reactivity to vasoconstrictors in relation to altered thyroid function was studied in two preparations: aortic strips and the isolated perfused kidney. To assess whether the possible alterations in vascular reactivity were restricted to a specific agonist or whether they involved the contractile system, receptor mediated and nonspecific smooth muscle stimulants were used. Male Wistar rats were divided into three groups: control, hyperthyroid and hypothyroid rats. Aortic strips from hypothyroid rats were less sensitive to phenylephrine and KCl when the data were expressed in absolute values or as percentages of the maximum responses. Sensitivity and reactivity in strips from hyperthyroid rats were similar to those observed in control strips. Renal vasculature obtained from hypothyroid rats also showed a markedly reduced sensitivity to phenylephrine, with normal maximal responses. The response to vasopressin at 3-10(-11) mol/l was also decreased, as was the reactivity to barium chloride. In contrast, renal vasculature of hyperthyroid rats showed markedly enhanced reactivity to all agonists: the concentration-response curves were characterized by a similar threshold and a greater maximal response. These results demonstrate that hypothyroidism is accompanied by a marked decrease in sensitivity to vasoconstrictors in large arteries as well as in resistance vessels. This decrease may be secondary to a generalized alteration in the contractile system of vascular smooth muscle cells and may play a role in the decreased blood pressure in these animals. In contrast, isolated perfused kidneys of hyperthyroid rats showed increased vascular reactivity to vasoconstrictors, which may play a role in the maintenance of elevated blood pressure in these animals. PMID- 7831390 TI - Pre- and postsynaptic mechanisms involved in tetanic fade induced by pancuronium in the isolated rat muscle. AB - The mechanisms underlying the fade of the tetanic contraction induced by pancuronium were studied in vitro by means of myographical and electrophysiological techniques in the extensor digitorum longus muscle of the rat. Pancuronium (0.5 mumol/l) induced a complete fade of the tetanic contraction while leaving the twitch unaffected. At the same concentration it decreased the amplitude and increased the tetanic rundown of trains of endplate potentials (e.p.ps) evoked in the frequency of 50 Hz. The electrophysiological changes induced by pancuronium were due to decreases in both quantal sizes and quantal contents of the e.p.ps. The former effect was the result of a postsynaptic competitive action and the latter of a presynaptic inhibitory action of that compound. The decrease in quantal content affected the e.p.ps starting from the first in the train and became larger during the generation of the sequence of e.p.ps. This intensified their tetanic rundown. It is concluded that the fade of the tetanic contraction induced by pancuronium is due to a summation of pre- and postsynaptic actions and, therefore, not only to an increase in the tetanic rundown of e.p.ps. Possible explanations for the distinct abilities of neuromuscular blockers in affecting tetani and twitches in a differential manner are also discussed. PMID- 7831391 TI - Immunotoxins in the therapy of cancer: from bench to clinic. AB - This review presents only those contributions that have progressed from the bench to the clinic using murine monoclonal antibodies coupled chemically to toxins, their subunits or ribosome-inactivating proteins. The rationale and progress in the development, characterization, preclinical testing and clinical trials are discussed. PMID- 7831392 TI - Regulation of macrophage gene expression by T-cell-derived lymphokines. AB - Cytokines secreted from antigen-specific T lymphocytes provide important positive and negative control of inflammation through their effects on non-antigen specific inflammatory leukocytes. These effects often involve modulation of gene expression. Lymphokine-inducible macrophage gene expression is largely controlled at the level of transcription. Multiple cis-acting sequence motifs cooperate with one another to produce patterns of expression that are relatively unique to individual genes. Members of trans-acting transcription factor families, which recognize related regulatory sequence elements, participate frequently in complex protein-protein interactions that generate remarkable complexity in terms of the number of potential combinations and the consequential functional differences exhibited by each combination. Thus, the remarkable plasticity of immune-mediated inflammation derives from combinations of finite numbers of options at several points in the cellular and molecular sequence. PMID- 7831393 TI - Ambulatory blood pressure monitoring. AB - Non-invasive measurement of blood pressure in ambulatory humans began in the 1960s. Ambulatory devices have been modified over the years and are now pocket sized, with almost noiseless pumps. Their accuracy must be validated by independent laboratories using a standardised protocol. Twenty-four-hour ambulatory monitoring offers considerable advantages over conventional measurement, including avoidance of error associated with conventional measurement, elimination of white-coat effect and the provision of a series of blood pressure readings over the time period rather than a one-off measurement. In clinical practice, 24-hr monitoring provides valuable assistance in both the diagnosis and treatment of hypertension, in particular, in the selection of drug and dosage regimen. In the research setting, 24-hr monitoring plays an important role in establishing dose-response relationships and the duration of action of new drugs. It also has a role in the design of antihypertensive trials by ensuring that those with white-coat hypertension are excluded and by reducing the number of subjects necessary for recruitment. Although 24-hr ambulatory blood pressure is a better predictor of target organ damage, definitive evidence as to whether it is a better predictor of prognosis in hypertension awaits the results of longitudinal studies, which are now underway. PMID- 7831394 TI - Central control of breathing in mammals: neuronal circuitry, membrane properties, and neurotransmitters. PMID- 7831395 TI - Corticocortical connections in the visual system: structure and function. PMID- 7831396 TI - Gastric acid secretion. PMID- 7831397 TI - Physiology of penile erection. PMID- 7831398 TI - Physiological and molecular mechanisms involved in nutritional regulation of fatty acid synthesis. PMID- 7831399 TI - Experimental basis for neural-immune interactions. PMID- 7831400 TI - Burn prevention for the very young child. PMID- 7831401 TI - Preparing the pediatric patient for surgery. PMID- 7831402 TI - The waiting game: when do we tell? PMID- 7831403 TI - Methods of data collection. PMID- 7831404 TI - America's future and health care reform. PMID- 7831405 TI - President's message: positive changes in health care reform will only happen with our input. PMID- 7831406 TI - Pain management in children. AB - Pain management in children has only recently been described in medical and nursing literature. The lingering myth that children do not experience pain, combined with difficulties in assessing pain, hamper pain management. Various assessment tools for pediatric pain exist. Options for management include blocks, opioids, topical anesthetics, and nonpharmacological techniques. PMID- 7831407 TI - Anesthetic considerations for the pediatric plastic surgical patient. AB - An understanding of the anesthesiologist's concerns during pediatric plastic surgical procedures can facilitate the coordination of efforts between the multiple services involved in the care of these children. Prior to surgery, the child's history is obtained and physical examination is performed. The condition of the airway is the primary concern. Preoperative medication is usually given by oral routes to avoid injections. Induction intubation, maintenance, and emergence are discussed. Specific postanesthesia care is described. Special precautions are given for children having surgical repair of craniofacial anomalies. Cleft lip and palate and mandibular advancement are described. PMID- 7831408 TI - Management of vascular and premalignant nevi in the pediatric population. AB - Successful management of the pediatric patient is a challenge to plastic surgery nurses as they work in tandem with surgeons to guide the family through the treatment process. This article will discuss the treatment of a number of congenital birthmarks, specifically congenital vascular birthmarks and congenital nevi, which have a potential for malignant transformation. PMID- 7831409 TI - Understanding and managing stressors facing the pediatric craniofacial patient and family. AB - Many challenges exist for the pediatric patient with a craniofacial anomaly. The support and care nurses provide to valuable members of this child's family are of special importance. This article presents an overview of how nurses and health care team members can recognize and manage the needs of both the pediatric patient and family to ensure the desired treatment outcomes. PMID- 7831411 TI - Taking the O.R. to the office--safety and care of children during surgery. PMID- 7831410 TI - Pediatric postanesthesia care. AB - Every patient admitted to the postanesthesia care unit (PACU) requires critical assessment, monitoring and postsurgical care. The pediatric patient has additional needs based on differences in biophysical and cognitive development. These differences will significantly influence patient outcomes. PMID- 7831412 TI - A preliminary cost effectiveness analysis of an intervention to reduce homelessness among the mentally ill. AB - The Critical Time Intervention Project is a three-year clinical trial which tests a time-limited, supportive intervention to reduce recurrent homelessness among mentally ill men moving from a shelter to the community. Along with a comparison of nights spent homeless and other outcomes, the evaluation of the Critical Time Intervention includes a comparison of the relative costs of the intervention, compared to usual treatment. Such cost effectiveness analyses are difficult to perform and are rarely applied to mental health treatments. This paper presents the general scheme of this analysis and discusses critical issues in the construction and measurement of cost variables. Preliminary results which have implications for the cost analysis are presented. PMID- 7831413 TI - Assessing the outcomes of parent-and provider-designed systems of care for children with emotional and behavioral disorders. AB - There is a paucity of research on the outcomes associated with involving parents of children with emotional and behavioral problems as partners with professionals in designing and implementing a system of care. This study examines the systems, child, and family outcomes associated with providing flexible funds to two counties, one engaged in strengthening its provider-designed system and the other in developing and implementing a parent-designed system. This article describes the qualitative, network, and treatment outcome studies comprising the research. PMID- 7831414 TI - Primary prevention of conduct disorder. AB - Conduct disorders represent one of the most troubling and persistent childhood psychiatric disorders. This serious condition has a poor long-term prognosis and entails a wide range of negative consequences over the life span. No single intervention strategy has been identified that successfully alters its negative course. This article reviews developmental findings and previous intervention efforts and provides a rationale for approaching the problem of Conduct Disorder through primary preventive intervention. A comprehensive, family-based prevention model and specific clinical strategies for intervention are described. A case example is used to illustrate the integration of program components. PMID- 7831415 TI - A family history study of schizophrenia spectrum disorders suggests new candidate genes in schizophrenia and autism. AB - To limit genetic heterogeneity, this study focused on the widely extended pedigrees of Ashkenazi Jewish schizophrenic and autistic probands, to determine if similar causal mechanisms might obtain for both conditions. At least two previous epidemiological studies have demonstrated increased risk for schizophrenia in Ashkenazi Jews. The hypothesis posed is that increased prevalence of various rare autosomal recessive diseases among the Ashkenazim might contribute to the increased vulnerability to schizophrenia and to autism in this large genetic isolate. Rates of amyotrophic lateral sclerosis (ALS) and bleeding disorders were significantly increased among relatives of schizophrenic and autistic probands, compared to relatives of normal probands. These results suggest new candidate loci in schizophrenia and autism, particularly the chromosome 15q23-24 locus of the hexosaminidase A gene, causing various GM2 gangliosidoses, and the 21q22.1-q22.2 loci of the antioxidant, superoxide dismutase gene, and a cytokine receptor gene. PMID- 7831416 TI - A new five factor model of schizophrenia. AB - Schizophrenic psychopathology is heterogeneous and multidimensional. Various strategies have been developed over the past several years to assess and measure more accurately discrete domains of psychopathology. One of the more fruitful strategies to investigate more homogenous domains of psychopathology has been the positive-negative syndrome approach. However, this approach is unable to address a number of important issues. Most schizophrenics present a mixed syndrome; the criteria for what constitutes a positive and negative syndrome are variable; distinguishing primary from secondary negative symptoms can be difficult. In order to address some of these problems, we propose the introduction of a five syndrome model based on a reanalysis of factor analytic procedures used on 240 schizophrenics assessed with the Positive and Negative Syndrome Scale (PANSS). We present data on a 5-factor solution which appears to best fit the psychopathological data and which is supported by three independent and comparable factor analyses; negative, positive, excitement, cognitive and depression/anxiety domains of psychopathology give patients their individual mark. Data on internal consistency of the five factors and on initial validation using demographic and clinical variables are presented. PMID- 7831417 TI - What are the public health implications of subclinical depressive symptoms? AB - Longitudinal data from a community study of 9900 adults in the United States show that persons with depressive symptoms, as compared to those without such symptoms, were 4.4 times more likely to develop a first onset major depression over one year. The attributable risk, a measure which reflects both the relative risk associated with depressive symptoms (4.4) and the prevalence of exposure to that risk (24%) and is a useful measure for documenting burden of a risk to the community, indicated that more than 50% of first onset major depressions are associated with prior depressive symptoms. Since depressive symptoms have a high prevalence in the community, but are often unrecognized and untreated in clinical practice, we conclude that their identification and the development of effective treatments could have public health implications for the prevention of associated social morbidity, service utilization and major depression. PMID- 7831418 TI - BRL 46470A: a highly potent, selective and long acting 5-HT3 receptor antagonist with anxiolytic-like properties. AB - The novel 5-HT3 antagonist, BRL 46470A (endo-N-(8-methyl-8-azabicyclo [3.2.1]oct 3-yl)2,3-dihydro-3,3 dimethyl-indole-1-carboxamide, hydrochloride), has been investigated in a series of in vitro and in vivo tests, including the effect of the drug in models of anxiolysis. In classical tests for 5-HT3 receptor antagonism, BRL 46470A was shown to antagonise 5-HT3 mediated responses in the guinea-pig ileum [pA2 8.3 +/- 0.5, slope 0.98 +/- 0.20, mean +/- SEM (5)], the rabbit isolated heart (pA2 10.1 +/- 0.1, slope 1.2 +/- 0.2, n = 5) and the rat Bezold-Jarisch model (ID50 0.7 microgram/kg IV +/- 0.1, n = 8), with a long duration of action (> 3 h). BRL 46470A selectively displaced [3H]-BRL 43694 from 5-HT3 binding sites in rat brain membranes (Ki 0.32 nM +/- 0.04, n = 4) without displacing (at concentrations greater than 1 microM) a wide variety of ligands binding to other neurotransmitter receptors, opioid receptors and to neurotransmitter gated ion channel complexes. In vivo, BRL 46470A showed anxiolytic-like activity in two animal models predictive of antianxiety effects elevated X-maze and social interaction in rats. In both models, BRL 46470A showed significant activity over a wide dose-range following both oral (0.0001-0.1 mg/kg PO) and systemic administration. The unique level of potency of BRL 46470A was apparent in the rat social interaction test and was shown to be 100 fold more potent than the 5-HT3 receptor antagonist ondansetron, with no evidence of a bell shaped dose response curve over 4 orders of magnitude.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7831419 TI - Potency mismatch for behavioral and biochemical effects by dopamine receptor antagonists: implications for the mechanism of action of clozapine. AB - Clozapine (3.8-60.0 mumol kg-1) did not produce any alterations in DOPA accumulation (following inhibition of cerebral aromatic L-amino acid decarboxylase) in the prefrontal cortex or in three regions of the neostriatum, i.e. the ventral, the dorso-lateral and the posterior regions, in the rat. In contrast, clozapine produced a reduction in the 5-HTP accumulation in all these brain areas, except for the prefrontal cortex. Raclopride (0.08-20.0 mumol kg-1) produced a marked increase in DOPA accumulation in all four brain regions and an increase in 5-HTP accumulation in the dorso-lateral neostriatum (2.5-20.0 mumol kg-1), but not in the other forebrain regions. Treatment with SCH-23390 (0.4-1.6 mumol kg-1) resulted in increased DOPA accumulation in the ventral and posterior parts of the neostriatum. No other changes in the DOPA or 5-HTP accumulation were seen with SCH-23390. Considering the doses of these three compounds needed for suppression of conditioned avoidance behavior and for the induction of cataleptic rigidity, it is concluded that raclopride produces an increased DA synthesis at much lower doses than those needed for behavioral effects. In contrast, the behavioral effects of SCH-23390 or clozapine precedes effects on brain DA synthesis on the dose-effect curve. In fact, the only biochemical effect of clozapine, which was observed in low, yet behaviorally active doses, was a decrease in forebrain 5-HTP accumulation. In conclusion, the present results demonstrate a mismatch, in different directions for raclopride and SCH-23390, as regards to the doses needed to produce effects on brain dopamine synthesis and on behavior.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7831420 TI - Discriminative stimulus properties of a new anxiolytic, DN-2327, in rats. AB - In an operant learning lever-pressing procedure on an FR10 schedule of milk reinforcement, male Wistar rats were trained to discriminate between saline and 3 mg/kg IP DN-2327, a new anxiolytic which acts on benzodiazepine receptors, 3 mg/kg IP diazepam or 15 mg/kg IP pentylenetetrazol (PTZ). More than 80% appropriate lever responding was established after 27, 38 and 44 daily training sessions with DN-2327, diazepam and PTZ, respectively, as the training drug. Although rats trained with DN-2327 dose-dependently generalized to various doses of DN-2327 and diazepam, the cue of DN-2327 was more potent than that of diazepam: ED50 values of DN-2327 and diazepam for stimulus generalization were 0.30 and 0.66 mg/kg, respectively. These animals partially generalized to pentobarbital (1-10 mg/kg) but did not generalize to buspirone (0.1-10 mg/kg). Rats trained with diazepam dose-dependently generalized to various doses of DN 2327, diazepam and pentobarbital with ED50 values of 0.51, 0.47 and 4.5 mg/kg, respectively, but did not generalize to buspirone. In rats trained with PTZ, DN 2327 and diazepam antagonized the discriminative stimulus produced by 15 mg/kg PTZ in a dose-dependent manner with ED50 values of 0.27 and 0.83 mg/kg, respectively, but buspirone neither antagonized nor was able to substitute for the PTZ-induced stimulus. The cue of DN-2327 was antagonized by flumazenil dose dependently as was that of diazepam.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7831421 TI - Cocaine-like discriminative stimulus effects of procaine, dimethocaine and lidocaine in rats. AB - The discriminative stimulus effects of several local anesthetics and (+) amphetamine were assessed in a drug discrimination based on the psychomotor stimulant cocaine. Two groups of adult male Sprague-Dawley rats were trained in two-lever operant chambers in a cocaine versus saline discrimination, or a cocaine versus procaine or saline discrimination, using a fixed ratio 20 schedule of food reinforcement. Cocaine, (+)-amphetamine and dimethocaine all dose dependently substituted for the training dose of cocaine (10 mg/kg) in both procedures. While procaine and lidocaine showed partial substitution in the cocaine versus saline procedure, much less substitution occurred in the cocaine versus procaine or saline discrimination. These data demonstrate that it is possible to train rats to discriminate between cocaine and another local anesthetic procaine, resulting in an increased pharmacological specificity of cocaine discrimination. The fact that dimethocaine fully substituted for cocaine in both procedures indicates that this local anesthetic has more cocaine-like effects than others so far tested, which is consistent with results from other behavioral and neurochemical studies with this compound. PMID- 7831423 TI - Inhibition of antidepressant demethylation and hydroxylation by fluvoxamine in depressed patients. AB - Bidirectional drug interactions between fluvoxamine and classical antidepressants were studied in depressed patients. A column switching technique combined with high performance liquid chromatography (HPLC) enabled automated analyses of plasma for simultaneous determination of fluvoxamine, tricyclic and tetracyclic antidepressants and demethylated and major hydroxylated metabolites in a single HPLC run. The measurements revealed that fluvoxamine inhibited N-demethylation of imipramine, clomipramine, amitriptyline and maprotiline whereas interferences with hydroxylation reactions were restricted to aromatic 8-hydroxylation of clomipramine. In patients under fluvoxamine monotherapy before comedication, plasma concentrations of fluvoxamine increased after administration of a tricyclic antidepressant, thus indicating bidirectional drug interactions. The inhibitory effects of fluvoxamine on the metabolism of classical antidepressants disappeared after discontinuation of concomitant fluvoxamine treatment within at least 1-2 weeks. The reported alterations in drug metabolism observed in depressed patients who were under fluvoxamine/tricyclic antidepressant comedication suggested that careful supervision and regular drug monitoring are necessary in such patients. PMID- 7831422 TI - Pentobarbital-like discriminative stimulus effects of direct GABA agonists in rats. AB - The discriminative stimulus effects of direct and indirect-acting GABAergic drugs were investigated in rats trained to discriminate 5 mg/kg pentobarbital (PB) from saline under a two-lever fixed ratio (FR) 32 schedule of food reinforcement. PB and diazepam produced dose-dependent substitution for the training dose of PB with response rate reduction only at doses above those producing full substitution. Muscimol, thiomuscimol and 4,5,6,7-tetrahydroisoxazolo [5,4-c] pyridin-3-ol (THIP) produced intermediate levels of pentobarbital-lever responding (40-60%), accompanied by dose-dependent decreases in rates of responding following THIP and muscimol administration. The GABAA agonist progabide and its metabolite 4-([(4-chlorophenyl) (5-fluoro-2 hydroxyphenyl)methylene]amino)] butyric acid (SL 75102) also partially substituted for PB, producing means of 39-73% PB-lever responding. The GABAB agonist, baclofen, completely failed to substitute for PB even at doses that decreased rates of responding. These results show that the discriminative stimulus effects of indirect GABAA agonists, PB and diazepam, although similar to one another, differ from those of direct GABAA receptor agonists, which produced only partial substitution for PB. The GABAB agonist, baclofen, can be distinguished by lacking any ability to substitute for PB. These results contribute to a further understanding of the similarities and differences in the behavioral effects of different types of GABA agonists. PMID- 7831424 TI - The discriminative stimulus properties of legal, over-the-counter stimulants administered singly and in binary and ternary combinations. AB - Ninety-six male Sprague-Dawley rats were trained in one of seven drug versus saline (SAL) discrimination (DD) tasks under a variable-ratio 5-15 schedule of food-motivated lever press responding. Three groups of rats (n = 12/group) were trained to discriminate between one of the legal over-the-counter (OTC) stimulants--caffeine (CAF), ephedrine (EPHED), phenylpropanolamine (PPA), and SAL. Three other groups (n = 12/group) were trained to discriminate between one of three binary stimulant combinations--CAF+EPHED, CAF+PPA, EPHED+PPA, and SAL. The seventh group of rats (n = 24) was trained to discriminate between SAL and a ternary combination of the OTC stimulants, CAF+EPHED+PPA. Generalization tests were conducted with each of the OTC stimulants and the controlled stimulants- amphetamine (AMPHET) and cocaine (COC). The data suggest: 1) there is cross generalization between some OTC combinations and controlled stimulants; 2) full generalization between the OTC and controlled stimulants were demonstrated in rats trained to discriminate two of the binary stimulant combinations from SAL; 3) drug mixtures are not perceived as new entities distinct from their component elements; 4) training dose-ratio may influence the characteristics of mixture discriminations; 5) stimulus overshadowing may be a factor determining drug mixture cues, and 6) the DD properties of aggregate drug compounds may function within a euclidean metric space. We propose that some binary OTC stimulant combinations may effectively function as a methadone-like replacement therapy in cocaine dependence. PMID- 7831425 TI - Effects of daily SKF 38393, quinpirole, and SCH 23390 treatments on locomotor activity and subsequent sensitivity to apomorphine. AB - In three experiments, male Wistar rats (250-350 g) were injected (SC) daily with the D1-type dopamine receptor agonist, SKF 38393 (0.0, 4.0, 8.0, or 16.0 mg/kg), the D2-type dopamine receptor agonist, quinpirole (0.0, 0.3, or 3.0 mg/kg), and/or the D1-type dopamine receptor antagonist, SCH 23390 (0.0 or 0.5 mg/kg) for 8-10 days. After each daily injection, the rats were tested for locomotor activity in photocell arenas for 20 min. Following this subchronic pretreatment, all rats were challenged with the mixed dopamine receptor agonist apomorphine (1.0 mg/kg, SC) and tested for locomotor activity. SKF 38393 treatments produced a dose-dependent decrease in locomotor activity which did not significantly change across days. Quinpirole also depressed locomotor activity when first injected, but this quinpirole-induced inhibition of activity progressively decreased across days. When subsequently challenged with apomorphine, rats in both the SKF 38393 and the quinpirole pretreatment groups displayed greater locomotor activity than rats pretreated with only vehicle. Although SCH 23390 pretreatments did not affect subsequent sensitivity to apomorphine, SCH 23390 completely blocked the effect of quinpirole. These results suggest that although repeated D1 receptor stimulation may be sufficient to induce behavioral sensitization to apomorphine, D2 receptor stimulation also contributes to the effect. PMID- 7831426 TI - MDMA and memory: the acute and chronic effects of MDMA in pigeons performing under a delayed-matching-to-sample procedure. AB - The purpose of the present study was to examine the acute and chronic effects of (+/-)3,4-methylenedioxy-methamphetamine (MDMA) in pigeons responding under a delayed-matching-to-sample procedure with 0-, 3-, and 6-s delays. In the absence of drug, accuracy (percent correct responses) was inversely related to delay length. When administered pre-chronically, MDMA (0.32-5.6 mg/kg) generally decreased accuracy and response rates at doses of 3.2 mg/kg and above. Although humans report a distinct "hangover" when exposure to MDMA ends, performance of pigeons in the present study did not deteriorate when the chronic regimen ended, indicating an absence of behavioral dependence on the drug. Tolerance developed following chronic exposure to 3.2 mg/kg. In general, greater tolerance occurred at the 0-s delay than at longer delays. Although MDMA is reported to have neurotoxic effects, it does not inevitably produce long-lasting or cumulative behavioral impairment. PMID- 7831427 TI - Nicotine abstinence produces content-specific Stroop interference. AB - Adult, male smokers were randomly assigned to be nicotine abstinent for 12 h (n = 10) or to smoke normally for the same period of time (n = 10). Performance on a modified version of the Stroop (1935) color-naming task, where subjects named the color of ink in which each of a series of words was written, showed that abstinent smokers took significantly longer to color-name words related to cigarette smoking (e.g., Lighter) than to color-name neutral control words (e.g., Pennant). Non-abstinent smokers showed a significant difference in the opposite direction. These results suggest that nicotine abstinence decreases the ability to ignore the meaning of smoking-related information. This finding supports the hypothesis that abstinence produces a content-specific shift in attentional focus. The present pattern of results cannot be explained by a general decrease in cognitive function due to nicotine abstinence. PMID- 7831428 TI - Cigarette smoking, blood lipids, and baroreceptor-modulated nociception. AB - Activation of arterial blood pressure has been shown to influence higher central nervous activity. In animals, induction of sleep-like states and increases of seizure and pain thresholds in response to baroreceptor stimulation have been reported. In certain human groups, mechanical stimulation of the carotid baroreceptors also increases pain thresholds. The present paper examines the hypothesis that smokers show baroreceptor dependent antinociception as compared to non-smokers. It is speculated that one effect which rewards smoking is the nicotine induced phasic blood pressure increase which leads to baroreceptor stimulation and dampens pain perception. One hundred and twenty subjects were investigated using a recently developed mechanical baroreceptor stimulation technique and an electrical pain stimulus. The group of heavy smokers showed the predicted effect: their pain thresholds were enhanced during conditions of increased baroreceptor activity as compared to the control condition. The group of medium, light and non-smokers, however, did not show this effect. Neither blood lipid levels nor diastolic or systolic blood pressure paralleled the group differences on baroreceptor dependent antinociception. In heavy smokers, the nicotine induced phasic blood pressure increases might have baroreceptor dependent pain dampening effects, which might be among the reinforcing qualities of smoking. PMID- 7831429 TI - Yohimbine-facilitated acoustic startle reflex in humans. AB - Preclinical studies have suggested the acoustic startle reflex (ASR) may be a useful animal model to investigate the neurochemical basis of anxiety and fear states. This work has revealed that the anxiogenic alpha-2 receptor antagonist, yohimbine, increases the amplitude of the ASR in laboratory animals. The present investigation evaluated the effects of yohimbine on the ASR in healthy subjects. Seven healthy subjects received IV yohimbine (0.4 mg/kg) or saline placebo on two separate days in a randomized double blind placebo control design. A trial of 2 tone frequencies with varied intensity (90, 96, 102, 108, 114 dB) white noise, instantaneous rise time, was delivered binaurally through headphones. Tones were delivered every 25-60 sec, for a 30 ms duration. Startle testing was done 80 minutes post infusion and lasted 15-20 minutes. Sign rank testing indicated yohimbine caused an overall increase in startle amplitude, as well as significant augmentation of startle amplitude at 96, 102, 108, 114 decibels but not at the 90 dB intensity. Sign rank tests indicated a significant reduction of startle latency by yohimbine at only the 96 dB intensity. Significant correlations were observed between startle and peak anxiety, startle and plasma MHPG, peak anxiety and plasma MHPG. This study demonstrates in healty human subjects an excitatory effect of yohimbine on the magnitude of the ASR and a decrease in its latency. In the context of the key role of this reflex in the alarm response, this finding adds to the array of documented behavioral, biochemical and cardiovascular effects of yohimbine in humans which support the relationship between increased noradrenergic function and anxiety states. PMID- 7831430 TI - Behavioural and ligand-binding studies in rats with 1-acetyl-4-methylpiperazine, a novel nicotinic agonist. AB - The novel nicotinic agonist 1-acetyl-4-methylpiperazine (AMP) has been studied in ligand-binding and behavioural studies. AMP methiodide potently inhibited [3H]-( )-nicotine and [125I]-alpha-bungarotoxin binding to P2 membranes from rat brain and [125I]-alpha-bungarotoxin binding to rat skeletal muscles. AMP HCl also inhibited nicotinic binding, but it was 100 times less potent than AMP methiodide. In behavioural studies, AMP HCl reduced locomotor activity of experimentally naive rats and mecamylamine blocked this effect. In rats receiving (-)-nicotine chronically, AMP HCl did not increase locomotor activity consistently or to the same extent as (-)-nicotine. In rats trained to discriminate (-)-nicotine from saline in a two-bar operant conditioning procedure with food reinforcement, there was generalization to AMP HCl, but only at doses that reduced the overall rate of responding. The potency and effectiveness of AMP relative to (-)-nicotine varied across the different behavioural procedures. The results suggest that the pharmacodynamic action of AMP differs from that of (-) nicotine and that it usefully extends the range of agonists that can be used as probes for central nicotinic mechanisms. PMID- 7831431 TI - Relative roles of ventral striatal D1 and D2 dopamine receptors in responding with conditioned reinforcement. AB - Several experiments investigated the involvement of D1 and D2 dopamine receptors in the ventral striatum in the control over behaviour by a conditioned reinforcer using an acquisition of new response procedure. Intra-accumbens infusion of either the D1 receptor antagonist, SCH 23390, or the D2 receptor antagonist, raclopride, completely blocked the potentiative effects of intra-accumbens d amphetamine on responding with conditioned reinforcement and reduced responding to control levels. SCH 23390 was more potent than raclopride. At higher doses in the absence of d-amphetamine, both antagonists also blocked the preference for responding on the lever producing the conditioned reinforcer. Intra-accumbens infusions of either the D1 receptor agonist, SKF 38393, or the D2/3 receptor agonist, LY 171555 (quinpirole), selectively potentiated responding on the lever producing the conditioned reinforcer. Various combined infusions of the D1 and D2 agonists in specific low doses had additive, but not synergistic, effects on responding with conditioned reinforcement. None of the drugs affected the drinking of water in deprived subjects when infused intra-accumbens. These results suggest that both D1 and D2 receptors in the nucleus accumbens are involved in mediating the effects of dopamine in potentiating the control over behaviour by conditioned reinforcers. PMID- 7831432 TI - High 5-HT2 receptor occupancy in clozapine treated patients demonstrated by PET. AB - The clinical benefit of the atypical antipsychotic drug clozapine may be related to a combined effect on D2 and 5-HT2 receptors. To examine the basis for this hypothesis, positron emission tomography (PET) and the radioligand [11C]N methylspiperone were used to determine cortical 5-HT2 receptor occupancy in three psychotic patients treated with 125 mg, 175mg and 200mg clozapine daily. The uptake of [11C]N-methylspiperone in the frontal cortex was very low compared to that in neuroleptic naive schizophrenic patients. 5-HT2 receptor occupancy calculated in the clozapine treated patients was 84%, 87% and 90%. The results show that clinical treatment with clozapine induces a high 5-HT2 receptor occupancy in psychotic patients at a low dose level. PMID- 7831433 TI - Intravenous sodium lactate decreases plasma GABA levels in man. AB - Gamma aminobutyric acid (GABA), an inhibitory neurotransmitter, may play an important role in anxiety. We studied changes in plasma GABA levels in nine healthy subjects before and after infusions of sodium lactate and dextrose. Plasma GABA significantly decreased during infusions of sodium lactate (109.3 +/- 4.4 versus 91.6 +/- 5.1 pmol/ml; P = 0.0001) but not during infusions of dextrose. PMID- 7831434 TI - Cigarette smoking related variation of heart rate and physical activity with ad libitum smoking under field conditions. AB - A recently developed device was used in a field study to continuously assess physical activity, heart rate, and cigarette lighting during 2 workdays and 2 days off in 12 female smokers and 12 female non-smokers. Heart rates did not differ between smokers and non-smokers or between workdays and days off; however, the nonsmokers showed significantly higher physical activity during the workdays. An averaging procedure used to obtain plots for smoking related changes of activity (SRA), pulse (SRP), and the pulse-activity ratio (SRpai) revealed four observations. a) "Lighting" responses consisting of parallel increases of SRA and SRP start a few minutes before lighting, reach a maximum with lighting, and drop immediately after lighting. b) The subsequent "smoking" responses last about 6 min and are characterized by a sustained postlighting SRA depression but immediate recovery of SRP, resulting in an increased SRpai level. c) Ten minutes prelighting and 10 min postlighting SRA and SRP are highly similar. d) The pattern of this response was similar for workdays and days off. PMID- 7831435 TI - Effects of lorazepam upon recollective experience in recognition memory. AB - The effects of lorazepam (2 mg) and placebo upon recognition memory with and without conscious recollection were assessed in a cross-over study with normal volunteers. When recognising a word from study lists presented before and 1, 3 and 5 h after drug administration, subjects were required to indicate whether they could consciously recollect the word's prior occurrence or recognised it on the basis of "knowing"; in the absence of conscious recollection. Lorazepam only impaired word recognition which was accompanied by conscious recollection, and further, the level of this impairment correlated significantly with each of three different indices of subjects' arousal at the time of presentation of each list. Recognition in the absence of conscious recollection was not impaired but somewhat heightened by lorazepam, and these effects did not significantly relate to any index of arousal. These findings are interpreted as providing further support for the notion that recognition entails two distinct components, one based on contextual and associative information and related to conscious recollection, the other possibly based on a "traceless" perceptual or semantic memory system and related to feelings of knowing in the absence of conscious recollection. Implications are drawn for a contextual-encoding/retrieval account of lorazepam-induced amnesia. PMID- 7831436 TI - Automatic quantification of withdrawal from 5-day diazepam in rats: ultrasonic distress vocalizations and hyperreflexia to acoustic startle stimuli. AB - The purpose of the present work was to develop an objective and precise method to quantify withdrawal responses from anxiolytics relying on ethologically valid responses. Behavioral effects of diazepam withdrawal in rats are automatically measured that appear to correspond to clinically relevant disturbances in affective and sensory-motor functions. Ultrasonic vocalizations and startle reflexes in response to acoustic stimuli were measured as indices of withdrawal 24 h after 5 days of 2.5, 5 or 10 mg/kg diazepam, b.i.d., IP in male Long-Evans rats. About 60% of male rats emit 22-26 kHz ultrasonic calls when exposed to acoustic startle stimuli (18 presentations, 9 at 105 dB and 9 at 115 dB, each 30 s apart on average). Diazepam-withdrawn rats exhibited startle responses with larger maximal and average amplitude and emitted more frequent 22-26 kHz ultrasonic vocalizations than vehicle-treated control animals. The magnitude of the withdrawal changes in ultrasonic calls and in startle reflex amplitude increased significantly already at the low 2.5 mg/kg diazepam dose in spite of considerable individual variability. The increased ultrasound rates during diazepam withdrawal contrast with the suppressive effects of acutely administered diazepam in drug-naive rats. The current methodology offers the opportunity to more adequately characterize withdrawal from anxiolytic substances in a quantitative, objective and automated manner. PMID- 7831437 TI - Serotonin, dopamine and their interactions in schizophrenia. PMID- 7831439 TI - Differential changes in serotonin 5-HT1A and 5-HT2 receptor binding in patients with chronic schizophrenia. AB - Serotonin 5-HT1A and 5-HT2 receptors were examined in the postmortem brains of controls and patients with chronic schizophrenia. In the prefrontal cortex from patients with schizophrenia, 5-HT1A receptor binding was increased, while 5-HT2 receptor binding was decreased, when compared to controls. The increased 5-HT1A receptor binding or the decreased 5-HT2 receptor binding was observed in both the patients who had been medicated with neuroleptics at time of death and those who had not, at least 2 months prior to death. Thus, abnormalities of 5-HT receptor subtypes seem to exist in the brains of patients with chronic schizophrenia. 5-HT related agents might be beneficial for the treatment of schizophrenia. PMID- 7831441 TI - Serotonergic and dopaminergic aspects of neuroleptic-induced extrapyramidal syndromes in nonhuman primates. AB - Neuroleptic drug-induced acute extra-pyramidal syndromes are one of the major reasons why patients discontinue their antipsychotic medicines. The typical (e.g., haloperidol) neuroleptic drug produces acute extrapyramidal symptoms in the majority of patients, whereas the atypical (clozapine) neuroleptic produces only minimal motor system side effects. Serotonin S2 antagonists often reduce or prevent catalepsy in rodents, but the limited number of studies in nonhuman primates have produced conflicting results. The hypothesis of a high serotonin S2/dopamine D2 antagonism ratio as a mechanism underlying atypical neuroleptic effects in preventing acute extrapyramidal syndromes deserves further evaluation in nonhuman primate models because extrapyramidal symptoms in monkeys closely resemble those in patients. Cebus monkeys (22-28 years old) were tested with compounds that ranged from low to high S2/D2 antagonism ratios. These were haloperidol, fluphenazine, clopenthixol, melperone, tefludazine, setoperone, risperidone, and clozapine. A saline control was included with a wide dose range of each of these drugs that was tested in a once-weekly, blindly-scored random drug administration schedule. Dystonia was scored on four different symptoms by an experienced rater who was blind to drug dosage. All the compounds, with the exception of clozapine, produced clinically indistinguishable dose-related dystonia. The only difference was the dose at which dystonia appeared. In contrast to rodent studies, these nonhuman primate investigations with drugs, spanning a wide range of S2/D2 antagonism ratios, produced clinically similar extrapyramidal symptoms. Thus, adding an S2 antagonism component to neuroleptics does not appear to provide an explanation for the motor side effect profile of atypical neuroleptics, or a method for designing neuroleptic drugs that will be free of extrapyramidal symptoms. PMID- 7831438 TI - The dopamine hypothesis of schizophrenia: limbic interactions with serotonin and norepinephrine. AB - The "dopamine hypothesis" of schizophrenia has been the predominant guiding theoretical construct for driving studies of the neurobiology of schizophrenia. There has, however, been much interest in the contributions of non-dopamine systems to the clinical symptoms of schizophrenia, in particular, norepinephrine and serotonin. However, direct evidence for altered transmission in monoamine systems has been quite limited. In part this reflects a focus on specific brain regions for different transmitters, in contrast to a "neural systems" approach. Thus, evidence for the dopamine hypothesis has been derived from studies of the basal ganglia in schizophrenic cases and infrequently from other (e.g. cortical) regions. Recent studies have suggested that disturbances in the organization or development of the temporal lobe may underlie certain aspects of the symptoms of schizophrenia In particular, the hippocampus may show cellular loss or disturbances in cell orientation. These results are supported by the work that has identified neuropsychological and in vivo brain disturbances in schizophrenia specific to the medial temporal lobe. However, not all cases show such pathology and it is likely that these disorders could, in addition, involve an important afferent and/or efferent system associated with the temporal lobe. This model is based on the currently held view that parallel cortico-striatal-pallidal-thalamo circuits form an important basis for information processing in the brain. One such circuit involves the primary efferent of the hippocampus, the subiculum, and associated cortical regions that project onto the ventral striatum. Many of the cortical regions that project directly to the ventral striatum also project to the hippocampus via the entorhinal cortex. These include the anterior cingulate, posterior cingulate, superior temporal cortex, and inferior temporal cortex. The ventral striatum, made up of the nucleus accumbens, olfactory tubercle, and ventral putamen, has as its target the ventral pallidum. The ventral pallidum projects to the medial dorsal nuclei of the thalamus, which, in turn, projects to the anterior prefrontal cortical area. This loop has been referred to as the limbic loop. The patterns of innervation and expression of monoamine receptors in the brain have been delineated for the non-human primate and are being unraveled in the human. We, and other, have described the patterns of receptor expression in the limbic circuit. However, few studies have been published to date that detail what the neurochemical counterparts of the neuronal and neuropsychological disturbances in the limbic circuit might be. We have explored the possibility that monoamine systems are altered at more than one synaptic station in this circuit.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7831442 TI - Electrophysiological, biochemical and behavioral evidence for 5-HT2 and 5-HT3 mediated control of dopaminergic function. AB - Several lines of evidence have suggested a link between serotonergic and dopaminergic systems in the brain. The interpretation of much of these early data needs careful reevaluation in light of the recent understanding of the plethora of serotonin receptor subtypes, their distribution in the brain and the new findings with more selective serotonin antagonists. Electrophysiological, biochemical and behavioral evidence obtained using highly selective antagonists of the 5-HT2 or 5-HT3 receptor subtypes, MDL 100,907 or MDL 73,147EF, respectively, supports the thesis that serotonin modulates the dopaminergic system. This modulation is most evident when the dopaminergic system has been activated. PMID- 7831440 TI - The role of serotonin in schizophrenia: an overview of the nomenclature, distribution and alterations of serotonin receptors in the central nervous system. AB - Serotonin is a neurotransmitter that is widely distributed throughout the central nervous system. The role of serotonin in schizophrenia is still unclear. Postmortem studies of serotonin receptor subtypes in schizophrenia have been inconclusive for the most part. The most promising findings involve a reduction in 5-HT2 receptors and 5-HT reuptake sites in the prefrontal cortex of schizophrenic patients. In this paper we review the function, distribution and pharmacological characteristics of serotonin receptors. Postmortem studies are also reviewed, focusing upon the role of these receptors in schizophrenia. PMID- 7831443 TI - Interactions between 5-HT3 receptors and cerebral dopamine function: implications for the treatment of schizophrenia and psychoactive substance abuse. AB - This article reviews current knowledge on the interaction between 5 hydroxytryptamine (5-HT), acting at 5-HT3 receptors in the CNS, and cerebral dopamine systems. Since 1987, a growing body of behavioural, neurochemical and electrophysiological evidence from animal studies has demonstrated a clear role for 5-HT3 receptors in the modulation of activity of mesolimbic and mesocortical dopamine neurones. This evidence has led to the suggestion that 5-HT3 receptor antagonists have potential as novel antipsychotic agents and may also find use in the treatment of psychoactive substance abuse. Data emerging from clinical studies generally support this hypothesis and suggest that 5-HT3 antagonists may prove to be among the first agents available to treat schizophrenia which are not dopamine D2 antagonists and hence lack their side-effect problems. PMID- 7831445 TI - Haloperidol and clozapine treatment and their effect on M-chlorophenylpiperazine mediated responses in schizophrenia: implications for the mechanism of action of clozapine. AB - Since clozapine is, in contrast to conventional neuroleptics, effective in treatment refractory schizophrenic patients its mechanism of action may be different from that of typical neuroleptics. Clozapine has been shown to display the highest binding affinity of all neuroleptics to one of the serotonin (5 hydroxytryptamine, 5HT) receptor subtypes, i.e., the 5HT1c receptor. Furthermore, clozapine, in contrast to conventional neuroleptics, blocks the effect of 5HT agonists on ACTH and corticosterone release in animals. This study hypothesized that clozapine, but not haloperidol would block ACTH and prolactin release induced by the 5HT agonist, m-chlorophenylpiperazine (MCPP). MCPP (0.35 mg/kg PO) was administered after a 3-week drug-free period, after 5 weeks of haloperidol treatment (20 mg/day) and finally after 5 weeks of clozapine treatment (> 400 mg/day) in ten male schizophrenic patients. Clozapine, but not haloperidol, blocked the effect of MCPP on ACTH and prolactin release. These results suggest that clozapine, in contrast to haloperidol, is a functional 5HT antagonist. Since MCPP-induced ACTH and prolactin release may be (partially) 5HT1c mediated, these results suggest that clozapine is a potent antagonist at the 5HT1c receptor. PMID- 7831447 TI - Metabolic and physiologic consequences of nortriptyline treatment in the elderly. AB - The challenge in the pharmacotherapy of affective disorders is shifting to maintenance treatment. Hence, there is a need for systematic data on the somatic effects of long-term medication use. Twenty-six depressed patients (age > 60 yr) treated with therapeutic concentrations of nortriptyline were evaluated after an average of 7 months for changes in lipoproteins and cardiovascular parameters. Twelve patients were tested for debrisoquine (P450 2D6) metabolic status and creatinine clearance at these same intervals. There was no significant change in cholesterol levels, but triglycerides and very-low-density lipoproteins (VLDL) were significantly increased. Heart rate was also elevated by a mean of 15 beats per minute, and there were modest but significant increases in cardiac conduction parameters. Creatinine clearance declined significantly (by 34%), and blood pressure was unchanged. Small decrements in P450 2D6 could be quantitated. Older patients treated with maintenance psychotropic medications should be evaluated at the regular intervals, particularly with regard to the age-related complications of multiple illness and medications. PMID- 7831444 TI - Clinical investigation of monoamine neurotransmitter interactions. AB - Monoamine neurotransmitter systems are widely thought to be involved in the pathophysiology of affective disorders and schizophrenia and the mechanism of action of antidepressant and antipsychotic drugs. Previous clinical studies have focused on individual monoamine function in isolation, even though a large number of preclinical studies have demonstrated that monoamine neurotransmitter systems interact with one another. In the present paper, preclinical data on monoamine neurotransmitter interactions are reviewed, and two methods for examining monoamine neurotransmitter system interactions in clinical data are presented. One of the best replicated findings in biological psychiatry is that monoamine metabolites in CSF correlate with one another. The degree of correlation may be in part a measure of the degree of interaction between the parent monoamine neurotransmitter systems. Another approach to studying interactions is the use of HVA/5HIAA and HVA/MHPG ratios as an index of interactions between 5HT-DA and NE DA. When these methods are applied in schizophrenia, patients are found to have decreased monoamine metabolite correlations compared to normal controls. Metabolite correlations increase significantly after antipsychotic treatment, and the HVA/5HIAA and HVA/MPHG ratios also increase, suggesting that neuroleptics may act in part by strengthening interactions between monoamines. BPRS ratings are negatively correlated with HVA/5HIAA and HVA/MHPG so that patients with higher ratios have fewer symptoms, particularly after treatment. These results provide direct experimental support for hypotheses suggesting that interactions between monoamine neurotransmitters are important in schizophrenia. Some of the effects of the atypical neuroleptic, clozapine, on metabolite correlations and ratios are also discussed. PMID- 7831448 TI - Are selective serotonin reuptake inhibitors well tolerated in somatizing depressives? AB - This retrospective evaluation included 89 patients who participated in two independent clinical investigations of the antidepressant medications paroxetine and fluoxetine. Baseline gastrointestinal (GI) somatic symptoms, as indicated by the baseline scores on the Hamilton Rating Scale for Depression (HAM-D) items 11, 12, and 16, the Symptom Checklist (SCL) items 19 and 40, and the Covi Anxiety Scale somatic anxiety item were analyzed for their discriminative ability in predicting which patients would subsequently develop adverse GI side effects on medication. Subjects with baseline complaints of nausea or upset stomach (SCL #40), GI somatic symptoms (HAM-D #11 and #12, Covi somatic anxiety), or weight loss (HAM-D #16) were not statistically more likely to develop GI side effects on paroxetine or fluoxetine. Only a baseline complaint of appetite loss (SCL #19) was associated with subsequent GI side effects on paroxetine to a statistically significant degree (p < .05). PMID- 7831446 TI - The cimetidine-induced increase in prolactin secretion in schizophrenia: effect of clozapine. AB - There is considerable interest in the role of serotonin (5-HT) in the pathophysiology of schizophrenia and in the mechanism of action of clozapine, an atypical antipsychotic agent and a potent dopamine (DA), 5-HT2/5-HT1C and histamine (H) antagonist. Cimetidine, an H2 antagonist, produces robust, transient increase in plasma prolactin (PRL) levels in man following intravenous administration. This effect has been attributed, in part, to indirect central serotonergic mechanisms involving 5-HT2 receptors in the hypothalamus, but the evidence is inconclusive. This study investigated the effects of cimetidine on plasma PRL levels in unmedicated schizophrenic patients versus normal controls and the effect of chronic treatment with clozapine on the cimetidine-induced PRL response. The PRL response to cimetidine was significantly blunted in male but not female schizophrenic patients. The PRL response in male schizophrenic patients was inversely related to psychopathology. Chronic treatment with clozapine completely suppressed the plasma PRL response following cimetidine. These data are consistent with the hypothesis of an abnormality of serotonergic activity, including downregulation of 5-HT2 receptors, in male but not female schizophrenic patients. The role of antagonism of 5-HT2 receptors in the action of clozapine is discussed. PMID- 7831449 TI - The antidepressant response to tricyclics in major depressives is accelerated with adjunctive use of methylphenidate. AB - Standard tricyclic antidepressant (TCA) treatment usually entails response latencies of 2 to 4 weeks. To accelerate the antidepressant response, methylphenidate (MPH) was administered together with standard antidepressants in an open label trial. Twenty inpatients (9 females, 11 males) met DSM-III-R criteria for major depressive episode (15 unipolar and 2 bipolar), depression NOS (n = 2), or Research Diagnostic Criteria for schizoaffective illness, depressed type (n = 1). Following evaluation for depression, patients received an open label oral MPH stimulation trial (MST), in 1 or 2 dosages of 5 to 15 mg at 0900 and 1000 hours. Twenty patients with positive MST response were treated with TCAs combined with MPH (5-15 mg/d). Therapeutic response was defined as 50 percent decline in the Hamilton Rating Scale for Depression. Six of 20 (30%) patients responded after 1 week of combination TCA-MPH, and 10 of 16 (63%) after 2 weeks. Adverse effects of the combination treatment included: dizziness and orthostatic blood pressure changes (n = 3), dry mouth (n = 3), increased anxiety (n = 3), and hypomania (n = 1). The severity of adverse effects required cessation of the MPH in 3 patients. Elevated self-ratings of anxiety were associated with lack of improvement after both 1 and 2 weeks. Adjunctive MPH appears to accelerate response to tricyclics in this systematically conducted open trial, and adverse effects of the TCA-MPH combination were usually tolerable. Positive response on the MST may be predictive of beneficial therapeutic outcome, especially in depressed patients without high anxiety levels.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7831450 TI - Long-term treatment of depression with nefazodone. AB - The utility of double-blind continuation data in assessing long-term efficacy was evaluated in an analysis of data from the development program of a new antidepressant, nefazodone. The benefit of nefazodone therapy was examined during continuation treatment of patients who improved during the 6-8 week acute phase of efficacy studies. Discontinuation for lack of efficacy was used as an indicator of relapse. Pooled long-term data from the extension phases of placebo controlled, acute efficacy trials were analyzed by the Kaplan-Meier method to estimate survival curves for time to discontinuation. Both nefazodone (p < .01) and imipramine (p < .05) were more effective than placebo during long-term continuation therapy. The findings demonstrate the value of double-blind continuation data in the evaluation of long-term drug benefit and provide an early assessment of nefazodone's effectiveness in continuation treatment of major depression. PMID- 7831451 TI - Dose-response characterization of the antipanic effects of imipramine. AB - This article presents panic diary results of a dose-response study with imipramine hydrochloride in panic disorder with agoraphobia patients. Analysis of variance revealed significant time effects on panic frequency and severity measures, but group x time interaction effects were present for the severity measures only. Results also provided evidence for a positive dose-response relationship with 20 percent of patients in the placebo group, 31 percent in the low-dose group (0.5 mg/kg/day), 54 percent in the medium-dose group (1.5 mg/kg/day), and 70 percent in the high-dose (3 mg/kg/day) group being free of recurrent or severe panic attacks at posttreatment. Further stratified and logistic regression analyses revealed a direct linear relationship between total plasma tricyclic concentration and response. These findings affirm the dose dependent nature and the specificity of imipramine's antipanic effects. PMID- 7831452 TI - Discriminating placebo and drug in generalized anxiety disorder (GAD) trials: single vs. multiple clinical raters. AB - A multisite, double-blind, placebo-controlled study was made of 177 patients with the diagnosis of generalized anxiety disorder. After a 1-week placebo lead-in, they were randomized to 4 weeks of treatment by placebo or one of two doses of a novel, nonsedating compound that had demonstrated reduction of fear-avoidance behavior in animals. Efficacy was not demonstrated at a significant level. A further analysis of 142 patients who completed the treatment was undertaken to test the hypothesis that efficacy might be demonstrated by the single-rater procedure (SRP), which eliminates interrater error variance. The 80 patients who were examined by the same clinical rater for all six visits were compared with the 62 patients who had the multiple-rater procedure (MRP), ratings by two or more clinicians sequentially over the six visits. A two-way analysis of variance showed significantly greater discrimination of placebo and drug for the MRP group. The results provided no support for the frequent preference for the SRP. The MRP may include less psychotherapeutic interaction with the patient and less researcher bias in ratings. PMID- 7831453 TI - A comparison of delusional and nondelusional body dysmorphic disorder in 100 cases. AB - A controversial issue that was debated for DSM-IV is whether body dysmorphic disorder (BDD)--a preoccupation with an imagined defect in appearance--can be psychotic. BDD is classified separately from its delusional counterpart (delusional disorder, somatic type) in DSM-IV, but does it have a psychotic variant that overlaps with, and may even be the same diagnostic entity as, its delusional disorder variant? One hundred consecutive patients with DSM-III-R defined BDD or its delusional variant were assessed with a semistructured interview, the Structured Clinical Inverview for DSM-III-R, and a modified version of the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). The 48 patients with nondelusional BDD were compared with the 52 patients with delusional BDD (i.e., delusional disorder, somatic type). The two groups did not differ significantly in terms of most variables examined, including demographics, phenomenology, course, associated features, comorbidity, and treatment response. Thus, BDD may have a psychotic subtype that significantly overlaps with, and may even be the same disorder as, its delusional disorder variant. However, delusional subjects had higher total scores on the modified Y-BOCS, suggesting that the delusional variant of BDD may be a more severe form of the disorder. Although preliminary, these findings have implications for BDD's treatment and classification, suggesting that inclusion of a delusional (psychotic) subtype of BDD should be considered for future editions of DSM. PMID- 7831454 TI - Early course of new-onset tardive dyskinesia in older patients. AB - The risk of neuroleptic-induced tardive dyskinesia (TD) in older patients is known to be high, yet the course of TD in older patients has not been systematically studied. We followed 69 middle-aged and elderly outpatients newly diagnosed with TD in a naturalistic, longitudinal, prospective fashion. Standardized assessment instruments were administered to measure psychopathology, cognitive impairment, and abnormal movements. We observed a highly fluctuating early course of TD. Although the cumulative proportion of patients whose TD partially remitted was quite high (56% at 3 months, and 80% at 6 months), the cumulative proportion of patients whose TD relapsed (post-remission) was also high (33% at 3 months and 54% at 6 months). These findings may have clinical as well as theoretical implications for TD in older subjects. PMID- 7831455 TI - Scales for the assessment of neuroleptic response in schizophrenic children: specific measures derived from the CPRS. AB - This article reports the psychometric properties of two scales for rating positive and negative schizophrenic signs and symptoms. These Positive and Negative Syndrome Scales consist of items selected from the Children's Psychiatric Rating Scale (CPRS), which contains items covering a wide range of childhood psychopathology. CPRS rating data were analyzed for 19 schizophrenic children, 16 males and 3 females, mean age 8.9 years (range 5.5-11.7), evaluated in a double-blind, placebo-controlled crossover study of haloperidol. We describe the item composition and coherence of each scale, the interrater reliabilities of clinicians using the scales, and the sensitivity of the scales for resolving treatment response. Schizophrenic children showed both positive and negative signs and symptoms, and both improved with neuroleptic treatment. PMID- 7831456 TI - Naltrexone plasma levels, clinical response and effect on weight in autistic children. AB - This research measured naltrexone levels in plasma, to assess the relationship between behavioral response to naltrexone and plasma levels, and the effects of naltrexone on weight in hospitalized autistic children (n = 41). A double-blind, placebo-controlled, parallel groups design with fixed dose was used, with random assignment to naltrexone or placebo. Drug plasma levels were analyzed by gas chromatography/mass spectrometry, and weights were obtained weekly. Naltrexone levels measured in 17 children ranged from 0.12 to 5.60 ng/mL (mean = 0.71, standard error of the mean = 0.32). There was no relationship between plasma levels and age, level of intellectual functioning, scores on the 14 selected Children's Psychiatric Rating Scale (CPRS) items, Clinical Global Impressions, Global Clinical Consensus, and the CPRS hyperactivity factor. There was a trend (p = .06) for children receiving naltrexone in the highest weight percentile (> or = 90th) to lose weight (mean = -0.42 kg) but this was not the case for those in the lower weight percentiles (mean = +0.03 kg). PMID- 7831457 TI - Placebo response in aggressive children with conduct disorder. AB - Aggressiveness and explosiveness characterize a subgroup of children diagnosed with conduct disorder (CD). Few double-blind, placebo-controlled studies have been conducted in aggressive children with CD, and no study has differentiated placebo responders from nonresponders. This study examined factors that may differentiate placebo responders from nonresponders hospitalized in a structured setting. The sample consisted of 25 children, ages 6.25 to 11.95 years, with CD and a profile of aggressive and explosive behavior, who were assigned to placebo treatment as part of a double-blind study of lithium. Responders were compared to nonresponders with respect to a detrimental psychosocial environmental score, age, IQ, and baseline ratings on the Children's Psychiatric Rating Scale and Clinical Global Impressions. Responders had significantly higher detrimental psychosocial environmental scores than nonresponders; they were particularly more likely to come from violent homes and to have criminally charged parents. Demographic variables did not distinguish the two groups; however, even mild hyperactivity was associated with poorer response to placebo. PMID- 7831458 TI - The Overt Aggression Scale in a study of lithium in aggressive conduct disorder. AB - This article describes an open study of lithium carbonate in conduct-disordered children. The objective of the study was to investigate the effectiveness of lithium in reducing aggression and the usefulness of the Overt Aggression Scale (OAS), as a measure of treatment effect. The subjects, 8 children, ages 9.2 to 16.9 years (mean +/- standard deviation [SD] = 12.48 +/- 2.97), were treated for 4 weeks with lithium. Optimal dosages ranged from 1200 to 1800 mg/day (mean = 1350 +/- 227) with corresponding serum lithium levels ranging from 0.86 to 1.39 mEq/L (mean = 1.05 +/- 0.17). OAS results indicated that aggression decreased significantly over time. The findings from the OAS agreed with findings from a more general measure, the Global Clinical Consensus Rating, leading to the conclusion that the OAS is a promising outcome measure for treatment studies of aggression in children. Further placebo-controlled studies of lithium carbonate in reducing aggressive behavior in conduct-disordered children, employing a specific measure such as the OAS, are warranted. PMID- 7831459 TI - Effects of intravenous dextroamphetamine on brain metabolism in adults with attention-deficit hyperactivity disorder (ADHD). Preliminary findings. AB - The effects on brain metabolism of the intravenous (i.v.) administration of dextroamphetamine was assessed by positron emission tomography (PET) with [18F] fluorodeoxyglucose (18-FDG) in 8 adults with attention-deficit hyperactivity disorder (ADHD). During the 3-hour 18-FDG PET session, each adult underwent the initial scan following i.v. infusion of placebo and a second scan following i.v. infusion of 0.15 mg/kg dextroamphetamine in a single-blind design. All subjects showed increased systolic/diastolic blood pressure and improved continuous performance task scores after dextroamphetamine. Global and regional metabolic rates were not significantly altered by the stimulant. When regional and global rates were normalized, the metabolic rates of only three cortical regions differed significantly between conditions. Individually, global metabolism increased in 4 subjects, was unchanged in 2, and decreased in 2 after stimulant infusion. No clinical characteristics differentiated these patients. I.V. infusion of dextroamphetamine did not significantly alter brain metabolism in ADHD adults in this preliminary study. PMID- 7831460 TI - The resampling method of statistical analysis. AB - Some non-statisticians occasionally use improper statistical methodology due to a lack of appreciation for the model assumptions that underlie a particular technique. The resampling method is a recent attempt to solve statistical problems with a minimum of assumptions. In essence, resampling involves an intuitive approach to inferential statistics that obviates the need for the mathematically derived sampling distribution. The resampling approach takes advantage of readily accessible high-speed computers to do a computationally intensive Monte Carlo experiment on the available data. The resampling approach liberates the user from imposing assumptions that are sometimes dubious. It also directs one away from a black-box attitude toward statistical analysis and instead forces the user to consider the purpose of the inferential process. A particularly user-friendly implementation of resampling methods that addresses some of the problems faced by non-statisticians is found in a simple, yet powerful, computer program called "Resampling Stats," version 3.13. PMID- 7831461 TI - A note on the use of confidence intervals in psychiatric research. AB - The emphasis on hypothesis testing, which characterizes the majority of medical research, is often inappropriate because it focuses on statistical significance (the viability of the nil hypothesis) rather than substantive significance (the magnitude of the treatment effect). An alternative approach, the reporting of a treatment effect with the corresponding confidence interval, may better reflect the researcher's intent since these are the issues that are relevant to an informed clinical decision. Additionally, results reported in this format are less likely to be misinterpreted than results presented as p values since the precision with which the effect size is estimated would be reported separately from the effect size itself. PMID- 7831462 TI - Clinical sequelae of overt non-compliance with psychotropic agents. AB - A group of 487 patients admitted to Eastern State Hospital in Lexington, Kentucky, during a 3-month period were prospectively followed to determine the incidence of psychotropic medication refusal, unique characteristics of refusers, factors leading to refusal, and clinical outcome of those who refused. Patients who refused any dose(s) of psychotropic medications were identified within 24 hours of refusal. For patients who refused for 24 hours or more, the psychiatrist was asked to complete a 4-item questionnaire. Our data indicate that medication refusal leads to poorer clinical outcomes, as measured by length of hospitalization and incidence and duration of restraint episodes. PMID- 7831463 TI - Self-injurious behavior and serotonin in Prader-Willi syndrome. AB - Low central nervous system (CNS) serotonin levels have been associated with impulsive, aggressive and self-injurious behavior (SIB). Persons with Prader Willi Syndrome (PWS) often engage in self-injury by severe compulsive skin picking and gouging and often manifest compulsive eating, hoarding, and explosive outbursts. Some of the compulsive behaviors seen in patients with obsessive compulsive disorder (OCD) bear similarity to behaviors associated with PWS: Skin picking, trichotillomania, and onychophagia (nail biting). There is abundant evidence that selective serotonin reuptake inhibitors (SSRIs) are effective in treating OCD. Three cases are described in which persons with PWS responded favorably to SSRI treatment. Two persons showed a significant decrease in skin picking. The third case showed a significant decrease in hoarding and explosive outbursts. Strategies are discussed for investigating the possibility of a shared neurochemical basis for the self-injurious, aggressive, and compulsive behaviors in persons with PWS. PWS may provide a relatively homogenous model for the study of skin picking and explosive outbursts among other populations. PMID- 7831465 TI - RSNA index to imaging literature. Volumes 182-193(I), 1992-1994. PMID- 7831464 TI - Inhibition of hepatic P-450 isoenzymes by serotonin selective reuptake inhibitors: in vitro and in vivo findings and their implications for patient care. AB - The effect on hepatic isoenzymes is emerging as the major clinically important distinguishing characteristic among the selective serotonin reuptake inhibitors (SSRIs). Although this fact has only recently gained widespread attention, the knowledge that some SSRIs inhibit hepatic metabolism dates back almost 20 years. This paper will first provide an overview of hepatic isoenzymes and then present the history and our current understanding of the effects of different SSRIs on different hepatic isoenzymes. Most of the attention in this area has focused on drug-drug interactions. This paper will also review recent work indicating that genetically determined differences in hepatic isoenzyme function can be risk factors in the development of a variety of diseases. The possible implications of this work relative to the long-term use of SSRIs will be discussed. PMID- 7831466 TI - Biophysics and pathology of catheter energy delivery systems. AB - Catheter ablation has rapidly emerged as the treatment of choice for many symptomatic cardiac arrhythmias. The initial experience with catheter ablation used high-energy DC as the energy source. However, over the last several years radiofrequency (RF) catheter ablation has become the dominant mode of energy delivery. Currently, a major limitation of RF ablation is the small lesion size created by this technique that has reduced its success rate in ablation of larger arrhythmogenic substrates such as coronary artery disease-related ventricular tachycardia. Alternate energy sources such as microwave or ultrasound catheter ablation are being developed that have the potential for producing larger lesions than RF ablation. This review will discuss the biophysics and pathophysiology of the various energy modalities used in catheter ablation. PMID- 7831467 TI - Catheter ablation for the treatment of atrial tachycardia. AB - Radiofrequency (RF) catheter ablation has revolutionized the treatment of supraventricular tachycardia, particularly those caused by atrioventricular nodal reentry and Wolff-Parkinson-White syndrome. Recently, RF catheter ablation has also been used to treat atrial flutter (AFL), focal automatic atrial tachycardia, and intra-atrial reentrant tachycardia. Typical AFL is caused by reentry in the right atrium, with an area of slow conduction in the isthmus between the inferior vena cava and tricuspid valve annulus. Ablation of exit sites from the isthmus near the coronary sinus ostium, or the isthmus itself, may cure AFL in the majority of patients. Intra-atrial reentrant tachycardia also has an area of slow conduction where application of RF energy is curative in most patients. In this arrhythmia, which is particularly common after congenital heart disease surgery, the reentrant circuit may occur in the right or left atrium. Focal automatic atrial tachycardia is probably caused by abnormal automaticity and, although it may arise from the right or left atrium, is easily ablated in most patients. Thus, RF catheter ablation is a highly effective alternative to pharmacologic therapy for treating atrial tachycardia, and it is likely to be increasingly used as curative therapy in the future. PMID- 7831468 TI - Ablative therapy for ventricular arrhythmias. AB - Radiofrequency catheter ablation techniques have enjoyed successful applications in patients with a wide variety of supraventricular tachycardias, especially the Wolff-Parkinson-White syndrome and atrioventricular nodal reentry. More recent reports have shown successful applications in patients with atrial tachycardias and atrial flutter. In addition to these, there are now reports of success during attempts to use radiofrequency techniques to eliminate ventricular tachycardia (VT), both in patients without structural heart disease (idiopathic VT) and patients with structural heart disease (primarily coronary artery disease). Techniques to map sites for ablation in patients with idiopathic VT usually include identifying early endocardial activation and using pace mapping. Success rates for ablation of idiopathic VT have been very high (over 90%) in patients with VT arising from the right ventricular outflow tract. Success rates have not been quite as high when VTs arising from sites other than the right ventricular outflow tract are targeted in the patient with idiopathic VT. In patients with VT caused by coronary artery disease, early endocardial activation and pace mapping can be unreliable. In these patients, searching for mid-diastolic potentials or showing concealed entrainment have proved more reliable. When these latter techniques are applied, success rates in eliminating a single focus of VT in a patient with coronary artery disease has been reported to be as high as 60% to 80%. Future therapies will include new energy sources, new (larger and/or cooled) electrodes, and multipoint catheter mapping, possibly using body surface mapping techniques. PMID- 7831470 TI - Dopaminergic neural grafts after fifteen years: results and perspectives. PMID- 7831469 TI - Cost-effectiveness analysis in heart disease, Part II: Preventive therapies. AB - Cost-effectiveness analysis of preventive therapies are reviewed in the following categories: lipid lowering, hypertension, smoking cessation, exercise, and anticoagulation. From review of 8 analyses, cost-effectiveness of primary prevention via cholesterol lowering drugs is generally expensive, whereas that of secondary prevention generally is favorable. However, targeting by age, coexisting risk factors, and gender strongly influence results that are also sensitive to drug costs. Treatment of hypertension (5 analyses) is cost-effective in virtually all patient populations and circumstances and for a wide variety of drugs. It is more so with coexisting risk. Issues relating to compliance and drug costs are important. Smoking cessation (4 analyses) is highly cost-effective and worthwhile. However, data on recidivism are incomplete, and cessation may be more difficult to achieve in the general population versus study patients. In one analysis, an exercise program was found to be cost-effective in prevention of coronary heart disease. Anticoagulants have been analyzed in various circumstances. Their cost-effectiveness is favorable for prosthetic valves, although sensitive to imprecision in monitoring. It is also favorable for mitral stenosis in the presence of atrial fibrillation but not normal sinus rhythm. Cost effectiveness of heparinization for prosthetic valve patients undergoing surgery is rather variable and depends on type of surgery (major versus minor) and type of valve. Many topics in anticoagulant therapy remain to be explored from a cost effectiveness point of view. PMID- 7831471 TI - Transneuronal labelling of CNS neurons with herpes simplex virus. PMID- 7831472 TI - Female sex steroid hormones: from receptors to networks to performance--actions on the sensorimotor system. PMID- 7831473 TI - Nuclear magnetic resonance spectroscopy studies of the brain. PMID- 7831474 TI - Neurogenic and myogenic regulation of skeletal muscle formation: a critical re evaluation. PMID- 7831475 TI - Possible mechanisms of action of (-)deprenyl and other MAO-B inhibitors in some neurologic and psychiatric disorders. PMID- 7831476 TI - Postsynaptic integration of glutamatergic and dopaminergic signals in the striatum. AB - The aim of this study was to achieve a better understanding of the integration in striatal medium-sized spiny neurons (MSNs) of converging signals from glutamatergic and dopaminergic afferents. The review of the literature in the first section shows that these two types of afferents not only contact the same striatal cell type, but that individual MSNs receive both a corticostriatal and a dopaminergic terminal. The most common sites of convergence are dendritic shafts and spines of MSNs with a distance between the terminals of less than 1-2 microns. The second section focuses on synaptic transmission and second messenger activation. Glutamate, the candidate transmitter of corticostriatal terminals, via different types of glutamate receptors can evoke an increase in intracellular free calcium concentrations. The net effect of dopamine in the striatum is a stimulation of adenylate cyclase activity leading to an increase in cAMP. The subsequent sections present information on calcium- and cAMP-sensitive biochemical pathways and review the regional and subcellular distribution of the components in the striatum. The specific biochemical reaction steps were formalized as simplified equilibrium equations. Parameter values of the model were chosen from published experimental data. Major results of this analysis are: at intracellular free calcium concentrations below 1 microM the stimulation of adenylate cyclase by calcium and dopamine is at least additive in the steady state. Free calcium concentrations exceeding 1 microM inhibit adenylate cyclase, which is not overcome by dopaminergic stimulation. The kinases and phosphatases studied can be divided in those that are almost exclusively calcium-sensitive (PP2B and CaMPK), and others that are modulated by both calcium and dopamine (PKA and PP1). Maximal threonine-phosphorylation of the phosphoprotein DARPP requires optimal concentrations of calcium (about 0.3 microM) and dopamine (above 5 microM). It seems favourable if the glutamate signal precedes phasic dopamine release by approximately 100 msec. The phosphorylation of MAP2 is under essentially calcium-dependent control of at least five kinases and phosphatases, which differentially affect its heterogeneous phosphorylation sites. Therefore, MAP2 could respond specifically to the spatio-temporal characteristics of different intracellular calcium fluxes. The quantitative description of the calcium- and dopamine-dependent regulation of DARPP and MAP2 provides insights into the crosstalk between glutamatergic and dopaminergic signals in striatal MSNs. Such insights constitute an important step towards a better understanding of the links between biochemical pathways, physiological processes, and behavioural consequences connected with striatal function. The relevance to long term potentiation, reinforcement learning, and Parkinson's disease is discussed. PMID- 7831477 TI - Central neural mechanisms mediating excitation of sympathetic neurons by hypoxia. PMID- 7831478 TI - The psychology of perserverative and stereotyped behaviour. AB - Many forms of psychopathology in higher animals and humans include the production of maladaptive, repetitive behaviour. Behaviour which is both repetitive and excessive in amount can be described as stereotyped whereas behaviour which represents a restriction of behavioural possibilities without excessive production can be described as perseverative. Both types of repetition can result from pathology in the neural mechanisms which control either the production of motor output or the organisation of behaviour at a higher level. A number of forms of repetitive behaviour can be induced environmentally. Confinement in adulthood results in a functional disorder which rapidly dissipates when normal conditions are restored but confinement in infancy may have a permanent effect on the organism's ability to interact in a flexible and creative way with its environment. The permanence of these disorders suggests that the environment can affect the way in which the nervous system develops. Repetitive behaviour is also a feature of mental illness including schizophrenia, autism, OCD, addiction and some neurological disorders including frontal lobe lesions, Tourette's syndrome and PD. In experimental studies in animals, stereotyped behaviour seems to be related mainly to excess dopaminergic activity in the basal ganglia while perserverative behaviour can be produced by lesions of the frontal lobes. It is supposed that the level of dopamine activity in the basal ganglia affects the baseline level of behavioural activation such that excess activation results in the excessive execution of the most probable response to the environment to the exclusion of other possibilities (i.e. stereotypy) while deficient activation results in the production of only a few responses which can exceed the necessary activation level (i.e. perseveration). In either case behaviour is 'stimulus bound', being driven by only the most salient feature of the environment. The symptoms of PD result from inadequate levels of dopamine in the basal ganglia while the stimulant psychoses result from excessive availability of dopamine. The frontal lobes have a modulating effect on (i) the activation of motor activity by the basal ganglia, (ii) in the generation of self-initiated behaviour, i.e. volition, and (iii) in the neural mechanisms which permit different modes of neural function (e.g. perceiving, remembering or thinking) to be identified. Failures in these three functions could result in excessive and repetitive motor activity, stimulus-bound behaviour, the paucity of volitional and creative behaviour, and the perceptual and experiential symptoms of psychosis. PMID- 7831479 TI - Papers from a Boden Research Conference on Immunological Control of Fertility: from Gametes to Gonads. New South Wales, 9-11 February 1994. PMID- 7831480 TI - Contraceptive vaccine development. AB - Recent advances in antigen definition and production have made the development of a contraceptive vaccine more attainable. Such a vaccine must evoke an immune response that blocks an indispensable step in the reproductive process. Vaccine research involves many approaches to fertility prevention. Vaccines are being developed that could interrupt fertility by inhibition of gonadotrophin release, the function of follicle-stimulating hormone or the effects of human chorionic gonadotrophin (hCG); alternatively, they may prevent fertilization by interfering with the transport of spermatozoa or with sperm-zona pellucida binding. The most advanced prototype is a vaccine based on antibodies to beta hCG. Such vaccines are being studied for clinical efficacy. Many hurdles remain in contraceptive vaccine development. Since the antigens are peptides or small proteins, the resultant immune response is usually moderate, and better adjuvants and delivery systems must be developed to enhance and maintain the immune response. Improvement of the mucosal immune response may be necessary for vaccines incorporating sperm antigens. Research on vaccines that control fertility has resulted in a fascinating base of scientific knowledge that, it is hoped, can be converted into products that will allow another option for individuals who wish to control their fertility. PMID- 7831481 TI - Virus-vectored immunocontraception of feral mammals. AB - The potential value of immunosterilization as a means to control species of wildlife that are widespread, numerous and undesirable is assessed. Key questions about the efficacy of fertility control and the means for delivering antigens expressed in recombinant viral vectors are discussed and the legal and social concerns that relate to its possible future use are raised. PMID- 7831483 TI - Biology and structure of the zona pellucida: a target for immunocontraception. AB - Although reversible interference of sperm-egg interactions with pharmacological agents has not yet been achieved, animal models have provided increasing evidence that immunological reagents directed against mammalian gametes can effectively inhibit fertilization. One potential target of immunocontraception is the zona pellucida, an extracellular matrix that surrounds the growing oocyte and ovulated egg. Recent advances in our knowledge of the biosynthesis and molecular biology of the zona pellucida have provided much information useful in the rational design of immunocontraceptive vaccines. There remain, however, major obstacles to using immunological reagents to prevent fertilization, including potential toxic side effects, the lack of adequate delivery systems and the possibility of incomplete reversibility. This review summarizes current understanding of the production of the zona pellucida during folliculogenesis, the structure of the conserved proteins and genes in the zona pellucida, and the progress made in the development of immunocontraceptive strategies that focus on this oocyte-specific structure. PMID- 7831482 TI - Experimental strategies for the development of an immunocontraceptive vaccine for the European red fox, Vulpes vulpes. AB - The development of an immunocontraceptive vaccine to control fox populations in Australia would confer considerable advantages in controlling the long-term impact of this predator on native and endangered species. Studies are currently under way to identify sperm antigens that might be used in such a vaccine, and some of these studies are described. It is proposed that such a vaccine would be delivered orally in a bait, thereby stimulating a mucosal immune response to the foreign antigen(s). Such a vaccine requires a detailed understanding of reproductive-tract mucosal immunity in foxes, and selection of the most effective form of antigen delivery. Those under consideration include viral or bacterial vectors and microencapsulated antigens. PMID- 7831484 TI - The mammalian zona pellucida: its biochemistry, immunochemistry, molecular biology, and developmental expression. AB - Many studies of the molecular and biochemical aspects of mammalian fertilization have focused on the interaction of the spermatozoa with the zona pellucida (ZP). The zona pellucida, a unique extracellular matrix surrounding the mammalian oocyte, is formed during ovarian follicular development. Following ovulation of the mature ovum, the spermatozoa must bind to and penetrate this matrix before the fertilization process is completed and the male and female genetic information combine. Although numerous models for this interaction have been proposed, the complete process has yet to be elucidated. The precise mechanisms by which these interactions occur also vary markedly among different mammalian species, making it more difficult to establish a unified model. To a great extent, the study of the molecules involved in these interactions have been limited because small numbers of female gametes are available for these studies. The recent development of techniques to isolate large numbers of zonae pellucidae as well as advances in immunological and molecular biology techniques have permitted the detailed characterization of ZP proteins. Although there is a paucity of information on the post-translational modification and extracellular processing of these molecules which result in matrix formation, a number of properties have been elucidated allowing better correlation between the structure and function of different ZP proteins among species. This review reflects these studies in relation to protein nomenclature and the molecular complexity of ZP antigens. PMID- 7831485 TI - The common mucosal immune system: from basic principles to enteric vaccines with relevance for the female reproductive tract. AB - The realization that induction of immune responses at mucosal surfaces may prevent colonization, invasion or dissemination of pathogenic microorganisms has spurred intensive efforts to develop vaccines which elicit effective mucosal immunity. In this paper, recent results are discussed for mice given cholera toxin as both an immunogen and as an adjuvant for inducing both humoral and gastrointestinal mucosal immune responses. Oral administration of cholera toxin alone or with a co-administered protein vaccine tetanus toxoid induces a strong T helper type 2 (TH2) cell response in both Peyer's patches and spleen. Both serum IgG and secretory IgA antibodies specific for cholera toxin or for the co administered protein tetanus toxoid were induced. When administered parentally, however, no mucosal antibody responses were evident and a mixed TH1- and TH2-type CD4+ T cell response was noted in the spleen. Various vectors are being employed in an effort not only to induce mucosal immune responses but also to direct the response to a TH1-type response, thought to promote strong cell-mediated immune responses, or to a TH2-type response for maximum B cell antibody responses. The ability to manipulate the TH cell responses may provide a more rational approach for the design of vaccines. Although lymphoid tissues of the female reproductive tract differ from that of the gut, many of the strategies and evolving principles may be directly applicable to the development of vaccines designed to prevent sexually transmitted diseases. PMID- 7831486 TI - Cytokine regulation of mucosal responses: a rational basis for new vaccine delivery strategies. AB - In this review, cytokine regulation of mucosal responses is discussed in relation to the mucosal immune network and regulation of IgA responses. Based on this understanding, aspects of gene therapy for manipulation of the host environment and vaccine delivery systems are discussed. Although evidence obtained in vitro is briefly reviewed the general focus of this article is on evidence obtained from models in vivo. PMID- 7831487 TI - Enhancement of mucosal IgA responses by interleukins 5 and 6 encoded in recombinant vaccine vectors. AB - The expression of the genes for murine interleukin-5 (IL-5) or IL-6 in recombinant vaccinia virus vectors markedly increased IgA reactivity to co expressed heterologous antigen in the lungs of mice inoculated intranasally with the viruses. These elevated local IgA responses reached a peak four times higher than those elicited by control viruses 14 days after infection and these peak levels were maintained for at least four weeks. Elevated IgA responses, reaching a peak 3-4 weeks after immunization, were also observed in the lungs of mice inoculated with IL-6 expressed by another vector, fowlpox virus. The results indicate that these factors enhance the development of mucosal IgA reactivity in vivo and suggest that their expression in mucosal vaccine vectors may stimulate local immune responses. The approach described in this study may be useful in stimulating mucosal immunity to a wide range of vector-encoded antigens, not only for vaccination against disease but also for immunocontraception by the co expression of antigens involved in reproduction. PMID- 7831488 TI - Disease and fertility control in wildlife and feral animal populations: options for vaccine delivery using vectors. AB - A wide variety of vertebrates have been introduced into Australia during the 200 years of European settlement. Many have become pests causing significant environmental damage and having the potential to act as reservoirs of infectious diseases. Control of vertebrate pest species by fertility control is attractive on animal welfare grounds. Should exotic animal diseases become established in any of these feral animal populations vaccination would be an essential element in the control or eradication of disease. The only experience to date with vaccination of wildlife or feral animals has been the successful control of rabies in foxes in Europe by means of a live, attenuated rabies vaccine and a vaccinia-rabies recombinant vaccine. The feasibility of vaccination for disease control or fertility control in other vertebrate pests will depend on the development and evaluation of several vaccine vector strategies. The choice of vector, based on live viruses or bacteria, naked DNA coding for vaccine antigen or virus-like particles encapsidating genetic material coding for vaccine antigen, will depend on optimization of vector delivery strategies and immunogenicity of the vaccine antigen. Past experience from the vaccination of foxes against rabies suggests that rates of uptake of the vaccine bait and immunogenicity of the vaccine will be crucial factors in determining the success of other vaccines controlling disease or fertility. PMID- 7831489 TI - The potential of murine cytomegalovirus as a viral vector for immunocontraception. AB - Wild populations of house mice (Mus domesticus) regularly undergo population eruptions in the cereal growing regions of S.E. Australia, causing significant damage to crops. Rodenticides are costly and are of limited usefulness, and the need for a biological control agent is widely recognized. The options for the use of an infectious agent to control mouse populations are considered. The three main types are: infectious agents which establish lethal infection; those which directly interfere with fertility; and recombinant virus vectors encoding fertility-associated proteins such as zona pellucida or sperm antigens in order to induce immunocontraceptive responses in infected mice. Ectromelia, a murine pox virus, has the potential for reducing mouse populations by lethal infection but it is not present in wild mice in Australia. The disadvantages of using ectromelia are that it would pose a significant threat to colonies of laboratory mice, there appears to be substantial innate resistance in Australian wild mice and it may not be entirely mouse-specific, thus placing native rodents at risk. A number of factors influencing the selection of a virus as a vector for immunocontraception are discussed. The mouse-specific murine cytomegalovirus (MCMV) fits most of these criteria. Infection with MCMV is already widespread in Australia with 80-90% of Mus domesticus tested being seropositive. It is a large DNA virus which establishes persistent, non-lethal infection, it is a suitable vector for the insertion of foreign genes and has a number of properties, including the capacity for superinfection, that should assist the recombinant virus to persist in wild mouse populations and induce an immunocontraceptive effect. PMID- 7831490 TI - Our naked emperor. PMID- 7831491 TI - Two evaluations of combined mother-infant versus separate postnatal nursing care. AB - Combined mother-infant postnatal nursing care was compared with traditional, separate postpartum and newborn care in two studies. In Study I, self administered questionnaires were completed by 408 mothers and 63 staff nurses. Data were collected both before and after mother-infant care was implemented. Benefits of the new system included increased maternal competence and satisfaction with parent education, parent-infant contact, and the nurse-client relationship, increased staff satisfaction, with no increase in operational cost. There were no breastfeeding differences, but ways to improve duration were implied by reasons for stopping. These findings were replicated in a separate setting with similar sample sizes. However, in the latter case, low staff ratios appeared to limit the benefits of mother-infant care to multiparas rather than primiparas. PMID- 7831492 TI - Longitudinal effects of unimodal and multimodal stimulation on development and interaction of healthy infants. AB - The effects of unimodal and multimodal stimulation on mental, psychomotor, and behavioral development of healthy full-term infants were examined longitudinally. Subjects were randomly assigned to a control group or one of three experimental conditions: daily administration of a stroking procedure, placement on a multisensory hammock during sleep periods, or a combination of the two treatments. Interventions were conducted during the first 3 months of life. Data are presented on 49 infants who were available for 24-month follow up. The experimental conditions did not significantly affect scores on the Bayley Scales of Infant Development. Eyberg's Child Behavior Inventory, the Nursing Child Assessment Teaching Scales, or the HOME. These findings suggest that supplementary stimulation provided no benefits beyond those associated with natural caregiving and raise questions about the value of the interventions with nonrisk infants in middle-class families. Additional studies need to be conducted with larger samples of healthy infants to test sensory stimulation protocols before they are advocated for widespread consumer use. PMID- 7831493 TI - The PREP system of nursing interventions: a pilot test with families caring for older members. Preparedness (PR), enrichment (E) and predictability (P). AB - The PREP system of nursing interventions, designed to increase preparedness (PR), enrichment (E), and predictability (P) in families providing care to older people, was pilot tested for acceptability and preliminary effectiveness. Eleven family units were assigned to the PREP group and 11 to a standard home health control group. The PREP group scored approximately one SD higher than the control group (p < .05) on the Care Effectiveness Scale, indicating greater preparedness, enrichment, and predictability. Further, on a rating of overall usefulness, the PREP group rated their assistance from PREP nurses (M = 9.75) as significantly higher (p < .01) than the control group rated assistance from the home health nurse or physical therapist (M = 6.57). Although not statistically significant, mean hospital costs for the PREP group ($2,775) were lower than for the control group ($6,929). Results provided support for a full intervention trial. PMID- 7831494 TI - The stages of the prediagnostic period in chronic, life-threatening childhood illness: a process analysis. AB - This is one of a series of articles explicating a theory of family behavior under conditions of sustained uncertainty brought about by the diagnosis of a chronic, life-threatening illness of a child. The procedures of the grounded theory method were used to collect and analyze data. The analysis illuminated a perceptual interpretive-behavioral process that made visible the emergence and intensification of the uncertain state during the prediagnostic period. This process, which may consist of up to three stages, most frequently began with the parents' initial awareness of the child's illness cues and terminated with the diagnostic announcement. The stages were categorized as Lay Explanatory (I), Legitimating (II), and Medical Diagnostic (III). The duration of stage III was found to be a significant factor in explaining the variation in parental response to the diagnosis. PMID- 7831495 TI - Communication between continuing care organizations. AB - Communication between health care providing organizations is fundamental to discharge planning and continuity of care, but has been reported to be inadequate. Using a classic communication model, the content of communication between hospitals and home health agencies was examined in 300 closed home care records and compared to referral content desired by practitioners. Discharge planners sent about half of the referral information recommended by the literature. Referrals consisted primarily of background data, some medical data, even less nursing care data, and almost no psychosocial data. No referral form was used by the hospital in over one third of the cases. Discrepancies existed between what client care data practitioners identified as important or desirable and the data they actually received. As responsibility for providing health care is decentralized and shared by multiple organizations, communication between providers will play a greater role in ensuring continuity of care. The findings suggest that adoption of standardized, written referral forms might facilitate clear and complete communication. PMID- 7831496 TI - Implementation of the Patient Self-Determination Act: a survey of Nebraska hospitals. AB - The purpose of this survey of Nebraska hospitals (N = 79) was to describe the planning, implementation, and evaluation of the Patient Self-Determination Act (PSDA) and to explore the role of the nurse in these processes. Results indicate nurses were very involved in the planning phase but rarely in the implementing phase. Few evaluation strategies were utilized and only some respondents identified problematic issues related to the implementation of the PSDA. Clinical implications for issues related to the PSDA are discussed and framed within the American Nurses' Association Position Statement on the PSDA (1991). Future studies are suggested, especially related to evaluation of PSDA implementation. PMID- 7831497 TI - Ergonomic analysis of working posture in nursing personnel: example of modified Ovako Working Analysis System application. AB - A postural analysis system was developed using a biomechanical approach to identify low back pain related working postures of nursing personnel. The Ovako Working Analysis System (OWAS) was modified for doing postural recording. Chaffin's biomechanical model was used to calculate the associated work stress on the L5/S1. The system was applied to examine the working postures of 64 nurses of 16 departments. The frequency distribution of the trunk showed 15.9% of the 8,629 observed postures were bending more than 15 degrees. Based on the calculated stress, 17.0% of the observed postures generated forces higher than the recommended action limit of the National Institute for Occupational Safety and Health (NIOSH). In addition to patient transfers, potentially health hazardous postures were identified in nursing tasks of inspection, nursing techniques, instrumentation, physical examination, taking inventory, and documentation. PMID- 7831498 TI - Data aggregation: criteria for psychometric evaluation. AB - Criteria for the examination of data collected at the individual level and aggregated to the group are proposed. These four empirical criteria relate to content validity, representativeness, reliability, and validity of the aggregated scores as indicators of group phenomena. An example of the use of the criteria is provided using data from a large research project on the implementation of a professional practice model on nine nursing units. The use of the criteria proposed provide a systematic approach to the evaluation of individual data for use at the group level. PMID- 7831499 TI - Chronic exposure of cultured rat pancreatic islets to elevated concentrations of islet amyloid polypeptide (IAPP) causes a decrease in islet DNA content and medium insulin accumulation. AB - The biological action of islet amyloid polypeptide (IAPP) remains to be established, although a role for IAPP in causing beta-cell failure in diabetes has been proposed. Acute in vitro experiments with IAPP have given controversial results as to beta-cell insulin secretion. We have studied the effect of a long term exposure of pancreatic islets to elevated IAPP concentrations. Thus, rat pancreatic islets were cultured for 4 days in medium supplemented with 0, 0.1, 1, 10, 100 or 1000 nM of synthetic amidated rat IAPP. Islets exposed to the two highest IAPP concentrations contained about 20% less DNA, whereas the rate of DNA synthesis was unchanged. Culture with 1000 nM IAPP, but not the lower concentrations of the peptide, slightly decreased the glucose oxidation rate. There was a correlation between increasing IAPP concentrations and and a decline in the medium insulin accumulation. The preceding IAPP exposure did, however, neither significantly affect basal and glucose-stimulated insulin secretion nor (pro)insulin and total protein biosynthesis rates, when tested after the culture. The finding of a decreased islet cell DNA content after culture with elevated IAPP concentrations suggests a toxic action to islet cells, whereas a putative inhibition of the islet insulin production appears to be transient. PMID- 7831500 TI - Lack of biologic activity or specific binding of amino-terminal pro-ANP segments in the rat. AB - In addition to atrial natriuretic peptide (ANP99-126) itself, linear peptide fragments from its N-terminal prohormone segment (pro-ANP) have been reported to have biological activity. In vivo, diuresis and natriuresis, as well as hypotension have been observed. In vitro, sodium uptake into medullary collecting duct cells was inhibited, and tone of vascular smooth muscle was reduced, associated with activation of guanylate cyclase. Such previous studies have used heterologous peptides and species, e.g., human pro-ANP1-30 or pro-ANP31-67, tested in rat, pig, or dog. The present experiments were designed to test whether rat pro-ANP1-30 or pro-ANP31-67 were natriuretic and hypotensive in rats, whether the two peptides showed specific binding to plasma membranes from rat kidney cortex or aorta, and whether they affected particulate guanylate cyclase activity in rat glomerular membranes. To extend in vitro results from the literature, the effect of human pro-ANP31-67 on transport in the rat medullary collecting duct in vivo was also tested. Although rat ANP99-126, as expected, increased diuresis and natriuresis, associated with inhibition of transport in the medullary collecting duct, in identically treated rats human pro-ANP31-67 was without effect. Similarly, only the ANP99-126 infusion resulted in reduction of arterial blood pressure. Furthermore, no diuretic, natriuretic, or hypotensive responses were observed in rats infused with either rat pro-ANP31-67 or pro-ANP1-30. In plasma membranes from rat kidney cortex or aorta, neither of the rat prosegments showed specific binding, or interference with ANP99-126 receptors. Finally, in contrast to ANP99-126, neither of the prosegments was able to increase basal guanylate cyclase activity in rat glomerular membranes. Therefore, under our experimental conditions we were unable to replicate the earlier results. This study thus does not support a regulatory role for pro-ANP fragments in blood volume or blood pressure homeostasis. PMID- 7831501 TI - AT1 receptor subtype mediates the inhibitory effect of central angiotensin II on cerebrospinal fluid formation in the rat. AB - The effect of central administration of angiotensin II (AII) on cerebrospinal fluid (CSF) formation was studied in pentobarbital-anesthetized, artificially ventilated rats. CSF production was measured by the ventriculocisternal perfusion method with Blue Dextran 2000 as the indicator. Baseline value of CSF production was 3.35 +/- 0.08 microliters/min. Intracerebroventricular (i.c.v.) infusion of AII at rates of 0.5 and 5 pg/min significantly lowered (P < 0.01) CSF formation by 23% and 16%, respectively. In comparison, high peptide doses (50 and 500 pg/min) did not alter this parameter. The inhibitory effect of low AII doses on CSF formation was blocked by the i.c.v. AT1 receptor subtype antagonists, losartan and SK&F 108566 (2.4 and 2.7 ng/min, respectively), but not by the AT2 receptor subtype-specific agent, PD 123319 (3.8 ng/min). Peptide AII antagonists, [Sar1,Ile8]AII (5 ng/min), which binds to both AT1 and AT2 receptors, had a similar effect to those of AT1-specific blockers. It is concluded that AII, by controlling CSF formation, may influence the water and electrolyte balance in the brain. PMID- 7831502 TI - Differential patterns of relaxation by atrial natriuretic peptide in major blood vessels of two distantly related teleosts. AB - In order to elucidate the role of the atrial hormone in the teleost circulation, the vascular effects of atrial natriuretic peptide (ANP) have been compared in major blood vessels of the cod (Gadus morhua) and of Atlantic salmon (Salmo salar). The relaxing effects of ANP from eel (eANP) have been examined in ventral aorta (VA) versus dorsal aorta (DA) in the cod and in VA versus the coeliaco mesenteric artery (CMA), a major branch of DA, in the salmon. The vessels were precontracted by acetylcholine (ACh) and adrenaline (A) and by the mammalian endothelium-derived vasoconstrictor peptide endothelin-1 (ET-1). The role of endothelial integrity for these responses has been assessed in vessels either mechanically probed or chemically impaired by indomethacin or the L-arginine analogue, NG-monomethyl-L-arginine (L-NMMA). Adrenaline and noradrenaline (NA) failed to contract the salmon VA. In the salmon vessels, eANP was without relaxing effects in ACh-contracted VA, while completely relaxing CMA when precontracted with ACh. The eANP was also a relaxant of A-contracted CMA and of ET-1-contracted VA. The cod vessels, which were insensitive to ACh were markedly relaxed by eANP when precontracted with either A (VA) or ET-1 (DA). In DA also the resting tension was reversed, an effect of eANP that was highly potentiated in mechanical probed vessels. Otherwise the relaxing effects of eANP in these vessels were seemingly independent of endothelial factors. In conclusion ANP is not a general relaxant of the precontracted VA which in teleosts is the first possible target vessel for the myocardial release of this hormone. On the arterial side ANP serves as a relaxant both in the salmon and the cod vessels, indicating that myocardial release of ANP in teleosts may have an important role in regulation of blood flow via diverse, species-specific effects on major blood vessels on both sides of the gills. PMID- 7831503 TI - [Radon and primary bronchial cancer]. AB - Radon is a natural radioactive gas, with worldwide distribution, deriving from uranium decay products, which can be inhaled, weather in mining condition (extraction and management of uranium ores) or in domestic condition (in some high risk homes or geographic areas). The main epidemiologic studies on uranium mining workers have all confirmed an excess in relative risk of primary lung cancer. Epidemiologic studies on indoor exposure suggest a role of radon in the genesis of a certain number of primary lung cancer, although these results remain controversial and need to be confirmed. An overview of the main actual problems related to this bronchial carcinogen is presented in this paper. PMID- 7831504 TI - [How to assess the size of a clinical trial?]. AB - The interpretation of the results of a clinical trial, an experimental method now recognised as the agreed technique for studying new therapeutic modes of treatment in man, is based on a statistical study of data collected on a sample of patients enrolled in the study and treated till its fulfillment. This interpretation is often made using statistical inference techniques based on the construction of a decision rule associated with a statistical hypothesis test; this hypothesis test serves to formalize a research question in a precise manner, and allows the null hypothesis H0 to be tested against an alternative hypothesis H1. The decision rule will be constructed using a probability distribution, which assumes control against type I error, and consists of falsely rejecting the null hypothesis. However, the control of the risk of type II error, made error where one mistakenly takes a decision not to reject the null hypothesis, can only be achieved using a sufficiently large sample. The correct evaluation of the sample size is thus paramount if one does not wish to be doomed to the failure of a study, by including an insufficient number of patients to achieve the aimed objective. The aim of this report is to review how this evaluation can be due, in a practical manner without proof, in the context of simple situations which are used when Phase II or III clinical trials are put into action. PMID- 7831505 TI - [Immunopathology of cytomegalovirus pneumonia and allograft rejection in lung transplantation. Group of Pulmonary Transplantation of the University Paris-Sud]. AB - In order to better understand the immunopathology of acute complications of lung transplantation we have analysed the different parameters of cytotoxic cell and macrophage activation during the course of pulmonary allograft rejection and cytomegalovirus pneumonia. In transplanted patients presenting with an acute pulmonary allograft rejection, a cytomegalovirus pneumonia or no complication (control group), we have studied, first serum markers of immune activation: interleukin-2 soluble receptor (IL-2sR), neopterin, IL-6, TNF soluble receptors (TNF-sR55 and TNF-sR75). Secondly the intrapulmonary compartmentalisation of allogenic and antiviral responses were evaluated by studying bronchoalveolar lavage fluid (BAL). The level of IL-6 was measured in BAL supernatants and the gene expression of two cytokines (IL-1 beta and IL-6) and two markers of activated cytotoxic cells (granzyme B and perforin) were studied by in situ hybridisation on the alveolar cells. Acute pulmonary allograft rejection was characterised by the paucity of systemic stigmata of immune activation and by the intrapulmonary compartmentalisation of the inflammatory response principally expressed by an increase in alveolar concentration of IL-6, TNF-sR55 and TNF sR75, and an increased expression of the IL-1 beta gene. Cytomegalovirus pneumonia is accompanied by an intense local and systemic inflammatory activity as evidenced by the serum level of IL-2sR, neopterin, TNF-sR55 and TNF-sR75, the alveolar concentration of IL-6, TNF-sR55 and TNF-sR75, and the expression of monokine (IL-1 beta, IL-6) and of cytotoxic mediator (granzyme b, perforin) genes by BAL cells. These mediators could participate in the elaboration of an acute or chronic inflammatory response which would be potentially deleterious for the graft. PMID- 7831506 TI - [Methotrexate in the treatment of asthma. Open trial in 10 corticoid-dependent patients with severe asthma]. AB - Methotrexate was suggested as a treatment in 1976 by Mullarkey for severe steroid dependent asthma, in order to reduce the use of systemic steroids responsible for numerous undesired side-effects. The aim of this open trial was to study the efficacy and tolerance of Methotrexate in the short, medium and long term and after its cessation, in ten patients aged 49.2 (+/- 3.0) who were suffering from severe steroid-dependent asthma (18.5 +/- 4.8 mg of prednisone daily for at least one year). Methotrexate was given in a dose of 15-30 mg for 14.3 months (+/- 1.8) with a post-treatment follow-up for eight patients lasting 7.9 months (+/- 1.7). The efficacy was assessed on the daily dosage of prednisone and was also evaluated using the FEV1 (VEMS) (the variations expressed were a percentage of the variation from the predicted value). In the short term (six weeks) there was no significant change in the FEV1 nor in the dose of prednisone. In the medium term (12 weeks) there was evidence of a reduction in the average daily dosage of prednisone of 39.5% with an increase in the FEV1 of 14.1%. In the long term MTX was not found as effective in reducing the dose of prednisone (15.2 mg) as on the FEV1 (an increase of 5.1% on the theoretical values). There was a favourable outcome for two patients who maintained the benefit after stopping the MTX. Seven out of ten patients presented with side effects of MTX, in three of whom the drug has to be stopped.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7831507 TI - [Characterization by isotope method of the performance of the pneumatic nebulizer NL9 Atomizer in the production of colistin, tobramycin and amiloride aerosols]. AB - The objective of this study was to assess the performance of a new pneumatic nebuliser NL9 Atomisor. The performance was assessed in terms of particle distribution, fraction nebulised, fraction inhaled and percentage of particles of a diameter of between 1 and 4 microns for the nebulisation of physiological serum, colistin, tobramycin and amiloride. The solutions were nebulised in the approved formula for their reconstitution as used in the clinic after the addition of sodium pertechnetate. The validity of this indirect isotopic method has been shown before. The nebuliser was coupled, during the nebulisation, to a pump respirator with six settings. The fraction nebulised was defined as the percentage of the volume of the solution which had left the aerosol generator at the end of the nebulisation. The fraction inhaled was defined as a percentage of the volume of the solution which was gathered at the end of the nebulisation on a filter placed in the inspiratory circuit of the aerosol generator. The study of the distribution of aerosol particle sizes was carried out using a cascade impactor at ten stages. Each of these parameters was determined in triplicate for the four solutions studied. The nebulised fraction consisted of between 33.5 and 58.6% (mean 49.7 +/- 8.1%). The inhaled fraction consisted of between 14 and 30.4% (mean 24.5 +/- 5.5) and the duration of nebulisation was between 10 and 20 minutes. The MMAD was between 1.6 microns with tobramycin 3.5 microns with physiological serum.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7831508 TI - [Factors in quitting antituberculous treatment in Bamako (Mali)]. AB - This is a descriptive study of 33 cases with recurrent tuberculosis in patients who abandoned their treatment, admitted between March and October 1991 in the Pulmonary Tuberculosis Service of the Hospital Point G. The aim of the study was to identify the reasons for stopping treatment and to propose corrective measures. One third of the patients registered in the study were agricultural workers. Sixteen per cent of those who stopped treatment did so in the first four months of treatment. The duration and the nature of the therapeutic regime had no influence on the attendance of the patients: 42% received a standard regime for twelve months and 45% a short regime for eight months. We thought that the poor motivation of the health personnel to counsel the patients correctly was the principal factor in influencing their attendance. Sixty seven per cent did not know the nature of their disease. The distance factor between home and the place of treatment was another important point which should be improved. Concrete proposals were made to improve the supervision and follow up of tuberculous patients. PMID- 7831509 TI - [Smoking by the 11-16 years old in the Yvelines department in 1990]. AB - Smoking and its risk factors were studied in 1990 on a representative sample of 2,514 pupils in Yvelines by auto-questionnaire. A similar enquiry had been carried out in 1983 with the same methodology. It was noted that between 1983 and 1990, there was a diminution in the prevalence of smoking from 15.4 to 7.6 per cent in the young in Yvelines. Amongst those young people of French nationality, the prevalence of smoking passed from 16 to 9 per cent in boys and from 17 to 12 per cent in girls aged between 11 and 16. This diminution of prevalence affected both brothers, sisters, and best friends whether male or female. The proportion of youth who had never smoked was significantly increased. In 1990, age and smoking habits of best male or female friend had a relationship which was independent of other factors with smoking in the two sexes. In girls, religious practice and (just within the limits of significance) the attitude of parents, and in boys the absence of one parent from the home, were also linked to smoking habits. The evolution of risk factors was discussed, particularly comparing the two studies of 1983 and 1990. All health education should take account of the phenomenon of "youth groups" as initiation occurs early, health education should be made early, at primary school level. PMID- 7831510 TI - [Acute eosinophilic pneumonia and the larva migrans syndrome: apropos of a case in an adult]. AB - Toxocariasis is a frequent disease in children, but the severe clinical manifestations are rare in the literature (diffuse interstitial pneumonia with hypoxaemia and acute severe asthma). The diagnosis is made thanks to the reliability of serological techniques (the ELISA test and using antigen excretion secretion tests of the larvae of Toxocara canis). The authors report a case of acute severe eosinophilic pneumonia whose outcome was rapidly favourable following steroid therapy; the existence of positive Toxocara canis serology with a contamination risk of the patient in the domestic environment leads us to integrate the clinical picture into the larva migrans syndrome. PMID- 7831511 TI - [Associated lipid pneumonia and bronchiolo-alveolar carcinoma]. AB - The authors report a new case of bronchio-alveolar carcinoma which developed on a background of iatrogenic exogenous lipid pneumonia; this association is extremely rare (less than 20 cases in the literature) and poses the problem of possible cancer developing in the centre of the lipid pneumonia. PMID- 7831512 TI - [Major hypercalcemia revealing sarcoidosis]. AB - We reported a new case of sarcoidosis disclosed by a symptomatic severe hypercalcemia. Increase of 1,25-dihydroxyvitamin D is secondary to an extrarenal production by alveolar macrophages and sarcoid granuloma. Glucocorticoid administration produces a prompt and persistent decrease in serum and urinary levels of calcium. PMID- 7831513 TI - [Diffuse alveolar hemorrhage and myositis in icterohemorrhagic leptospirosis. Rapid control by a single bolus of corticoids]. AB - Leptospirosis is one of the commonest causes of diffuse alveolar haemorrhage. Despite good sensitivity to penicillin and current techniques of ventilation, there remains a considerable mortality which is particularly linked to the initial pulmonary disease at presentation. The authors describe a new case of a gravely ill patient with leptospirosis and sever hypoxaemia. There was diffuse alveolar haemorrhage and myositis thus a bolus of corticosteroids was used over the first 24 hours complementary to the traditional treatment. PMID- 7831514 TI - [Pulmonary lesions after inhalation of nitrous vapors]. AB - Nitrous vapours are oxidants and they create fibrosing lesions in the distal bronchioles and alveoli. The degree of oedema in the initial lesion influences the development of acute respiratory failure and the prognosis in the initial term. We have seen a case of acute hypoxic interstitial pneumonia following accidental inhalation of nitrous vapours with lesions of bronchiolitis obliterans. The outcome subsequently followed the usual pattern and there was a complete cure with steroid therapy. PMID- 7831516 TI - [Multiple pulmonary opacities with spontaneously favorable outcome]. PMID- 7831517 TI - [Measurement of nasal potential difference]. PMID- 7831515 TI - [Small cell bronchial cancer in a 17-year-old young man]. AB - We report a case of small cell lung cancer in a 17 year-old man. He was admitted to our unit suffering from a two month history of pain left shoulder. Chest X rays showed a large round mass in the left upper lobe. The chest CT scan revealed a tumor with evidence of first left rib involvement. Histological examination, after surgical biopsy revealed small cell carcinoma, confirmed by two independent pathological physicians. Small cell lung carcinoma is very rare in the under 20 year age group and we compare this case with other types of lung cancer in young patients described in the literature. PMID- 7831518 TI - The polio survivor as expert: implications for rehabilitation nursing research. AB - Clients' personal experiences with illness or tragedy can uniquely qualify them as experts in many research-relevant content areas. Nurse researchers can benefit from this expertise by involving such clients in important decision-making aspects of research planning. The advantages of consulting with client-experts in the early and subsequent stages of research are discussed in this article, which uses as an example the way such consultation has worked in the development of a study of coping in polio survivors. Consultation with client-experts is especially appropriate when research involves sensitive issues or the measurement of subjects at vulnerable periods in their lives. It is advocated as a means of helping to ensure that participants are questioned in the most ethical, sensitive way possible and that the research will address the needs and concerns of the target population. PMID- 7831519 TI - School-age children's responses to parents with disabilities. AB - Disability usually occurs unpredictably and can happen in a fraction of a second. The major physical and psychological life changes that result from disability can affect the patient's entire family. When a parent becomes disabled, the focus of a family's attention often is shifted to the parent, and the responses and needs of the children may be overlooked. Empirical data reveal that children have special needs whenever their life changes, and they share common concerns during a major life crisis. The authors' observations at a neurological rehabilitation center indicate that children appear to go through several phases of adjustment and need specialized supportive therapy when a parent becomes disabled. PMID- 7831520 TI - Concept analysis of family+health = a new definition of family health. AB - In this article, the authors explore references to family and health in the nursing literature and compare them with their own perceptions to propose a new definition of family health. Focusing on connectedness, energy, and hope for the future, this definition and its conceptual model can help nurses care for families in the rehabilitation setting. PMID- 7831521 TI - A comprehensive pediatric rehabilitation nurse internship program. AB - A comprehensive internship program was conceived at Mount Washington Pediatric Hospital in Baltimore to recruit and train new nursing employees in pediatric rehabilitation. The Pediatric Nurse Internship Program was designed to provide extensive theory relevant to pediatric rehabilitation nursing, as well as preceptor-based clinical experiences, to ease the transition of new nurses into the pediatric rehabilitation arena. The program incorporated a strong interdisciplinary team approach. The content areas included all the functional parameters of health as well as didactic information about the diagnoses specific to the pediatric population. The goal was to allow the intern to achieve clinical competence in pediatric rehabilitative nursing. Four nursing interns were enrolled in the 12-week program, which involved completing an educational project, taking a written examination, and demonstrating evidence of clinical competencies. On completion of the program, three interns transferred into full time positions at the hospital and demonstrated an extremely high level of functioning. Partial support for the program was provided through grant money from the Maryland Health Services Cost Review Commission. PMID- 7831522 TI - Nurses' attitudes toward emotional, sexual, and physical abusers of children with disabilities. AB - Some studies have linked birth defects, disability, and chronic illness with an increased incidence of child abuse. Nurses who are involved with disabled children face a challenge in preventing child abuse and intervening in cases in which abuse has occurred. Nurse must become aware of the risk factors and signs of abuse, understand the role of their personal attitudes toward abuse and abusers, and develop the skills to intervene effectively and deal with abusers. Thus, the authors of this article undertook a study to ascertain nurses' attitudes about emotional, sexual, and physical abuse of children with disabilities and to determine if nurses' anticipated level of comfort differed when dealing with abusers of children with disabilities in contrast to abusers of children without disabilities. PMID- 7831523 TI - The importance of outcome data in brain injury rehabilitation. AB - Rehabilitation nurses, rehabilitation clients and their families, and healthcare funders easily can obtain brochures about or tours of agencies that provide rehabilitation services to people with brain injuries. Less accessible are outcome data from these agencies, data that should be as readily available as the tours and the brochures--and that reveal far more about the agencies. In this article, the authors describe the system developed by a private, comprehensive postacute service provider for collecting, analyzing, and using the outcome data of its discharged clients. The importance of outcome data for funders, families, and facilities is stressed, and the article provides examples of how to use the data for decision making and program development. PMID- 7831524 TI - Spina bifida: the transition into adulthood begins in infancy. AB - Many concerns surround the preparation of a person with spina bifida for a successful transition into adult life and responsibilities. A model of intervention must be based on developmental concerns and timely issues from infancy through all stages of development to young-adult life. This article discusses, within a developmental framework, issues of transition in relation to physical, social, emotional, and educational/vocational needs; it also presents a conceptual framework for the transition into adulthood. Guidelines were developed by incorporating expected outcomes of people with spina bifida and using a philosophical framework that encompasses the achievement of a balance among dependence, independence, and interdependence. This model is based on developmental issues from infancy through all stages of development to young adult life. Using this framework for care, the rehabilitation nurse can feel confident that the needs of clients with spina bifida and similar chronic conditions are being met. PMID- 7831525 TI - The wheel that moves. PMID- 7831526 TI - A closer look at conversion paralysis. PMID- 7831527 TI - The development of stroke units: the British experience. PMID- 7831528 TI - Ductal carcinoma in situ: a proposal for a new classification. AB - Details of a proposed new classification for ductal carcinoma in situ (DCIS) are presented. This is based, primarily, on cytonuclear differentiation and, secondarily, on architectural differentiation (cellular polarisation). Three categories are defined. First is poorly differentiated DCIS composed of cells with very pleomorphic, irregularly spaced nuclei, with coarse, clumped chromatin, prominent nucleoli, and frequent mitoses. Architectural differentiation is absent or minimal. The growth pattern is solid or pseudo-cribriform and -micropapillary (without cellular polarisation). Necrosis is usually present. Calcification, when present, is amorphous. Second, at the other end of the spectrum is well differentiated DCIS, composed of cells with monomorphic, regularly spaced nuclei containing fine chromatin, inconspicuous nucleoli, and few mitoses. The cells show pronounced polarisation with orientation of their apical border towards intercellular spaces usually resulting in cribriform, micropapillary and clinging patterns, although a solid pattern of well-differentiated DCIS also occurs. Necrosis is uncommon. Calcifications, when present, are usually psammomatous. The third category, intermediately differentiated DCIS, is composed of cells showing some pleomorphism but not so marked as in the poorly differentiated group. There is, however, always evidence of polarization around intercellular spaces, although this is not so pronounced as in the well-differentiated group. These two criteria, cytonuclear differentiation and architectural differentiation, have been found to be more consistent throughout a DCIS lesion than previously employed criteria of architectural pattern or the presence or absence of necrosis. PMID- 7831529 TI - Microcalcifications associated with ductal carcinoma in situ: mammographic pathologic correlation. AB - Because of the large scale use of mammography, the incidence of ductal carcinoma in situ (DCIS) has been increased fivefold to sixfold. The majority of these tumors are detected by mammographically significant microcalcifications. Their mammographic and histologic appearance is rather characteristic for the different types of DCIS. Microcalcifications associated with poorly differentiated DCIS appear on the mammogram as either linear, often branching, or as granular microcalcifications which are usually coarse. They correspond to the amorphous type calcifications on histology. Microcalcifications associated with well differentiated DCIS appear on the mammogram usually as multiple clusters of fine granular microcalcifications, which correspond to the clusters of laminated, crystalline calcifications on histology. The distribution of DCIS is typically unicentric and segmental. In a series of 119 mastectomies, only a single case had a multicentric distribution. Based on the extent of microcalcifications, mammography usually underestimates the size of DCIS; although this discrepancy is less than 2 cm in 80% to 85% of the cases if state-of-the-art mammography, including magnification views, is used. Close co-operation between radiologist, pathologist, and surgeon is essential for the optimum management of patients with DCIS. PMID- 7831530 TI - Three dimensional imaging of mammary ductal carcinoma in situ: clinical implications. AB - The conservation treatment of ductal carcinoma in situ (DCIS) is based on the surgical excision of the tumour together with irradiation of the remaining breast. Because short-term recurrence is almost certainly caused by residual tumour, an attempt should be made to verify the adequacy of the excision by assessing the specimen margin. The reliability of histologic margin assessment is influenced by the growth pattern of DCIS within the ductal tree and by the distance between tumour foci. Using an original stereoscopic technique, the present study of 60 mastectomy specimens shows that continuous and multifocal growth patterns are usual. A multifocal distribution (defined as gap of 4 cm or more between tumour foci) was found in only a single case. The growth pattern is related to DCIS type. Poorly-differentiated DCIS shows continuous growth, in contrast to the well-differentiated DCIS, which has a multicentric distribution. Irrespective of histologic type, however, only 8% of DCIS have a multifocal distribution with gaps greater than 10 mm. Therefore, with careful assessment, the likelihood of a false free margin seems theoretically low and should encourage the use of conserving treatment for eradicable DCIS. PMID- 7831531 TI - The classification of ductal carcinoma in situ and its association with biological markers. AB - One hundred five cases of pure ductal carcinoma in situ (DCIS) seen in the Guys Hospital breast unit between 1975 and 1991 were reviewed and reclassified using a modified histologic classification based on cytological features as well as histological architecture. The expression of p53 protein, cerbB2 protein, progesterone receptor, and a proliferation antigen KiS1, all factors reported to be of prognostic significance in invasive ductal carcinoma, was also evaluated using immunohistochemical methods. The mode of presentation of these cases was noted, and its relationship to biological markers and histologic type was also assessed. Good interobserver agreement was achieved by two independent observers using the modified histologic classification. Strong correlation was seen between histologic pattern and biological markers as well as between the individual markers. Poorly differentiated DCIS was associated with a high proliferation rate, the presence of cerbB2 and p53 protein and the absence of progesterone receptors. Well-differentiated DCIS showed the reverse, and the intermediate group showed an intermediate pattern. Paget's disease of the nipple was only seen in association with poorly differentiated DCIS, but no other significant association was noted between mode of presentation and DCIS type. PMID- 7831532 TI - Mammographically-detected ductal in situ carcinoma of the breast analyzed with a new classification. A study of 127 cases: correlation with estrogen and progesterone receptors, p53 and c-erbB-2 proteins, and proliferative activity. AB - The new histologic classification proposed by Holland et al was applied to 127 cases of mammographically-detected ductal carcinoma in situ (DCIS). The relationship between histologic types and tumor cell expression of estrogen and progesterone receptors, p53 protein, c-erbB-2 oncoprotein, and proliferative activity markers was evaluated. There were 38 (30%) well differentiated, 39 (31%) intermediately differentiated and 50 (39%) poorly differentiated DCIS. Immunohistochemistry showed that 81% of the tumors were estrogen-receptor positive and 73% progesterone receptor positive. p53 protein and c-erbB-2 oncoprotein expression was identified in 40% and 57% of the cases, respectively. Growth-fraction determination with the Ki-67 antibody showed that 52% of the tumors had high proliferative activity. A highly significant association was found between the histologic types of DCIS and p53 protein, c-erB-b2 oncoprotein, and proliferative activity marker expression: these biological markers were more frequently overexpressed in less differentiated DCIS. No significant relationship with estrogen or progesterone receptor expression was noted. A strong relationship with the amount of tumor necrosis was also found. The clinical significance of these results should, however, be determined by long-term follow up studies of patients with DCIS. PMID- 7831533 TI - Evaluation of infiltrating ductal carcinomas with a DCIS component: correlation of the histologic type of the in situ component with grade of the infiltrating component. AB - Recently there has been an increase in the detection of DCIS, and there is much interest in establishing a new pathologic classification that has less subjective criteria than traditional methods and that more closely reflects the clinical behavior of the tumor. It is hoped that this will lead to a more rational approach to treatment of DCIS. In this study one such recently proposed classification has been applied to the DCIS component of 215 infiltrating ductal carcinomas, and this has been compared with the histologic grade of the tumors. There was a highly significant correlation between DCIS type and grade (chi 2 = 110.0, P < 0.0001); well- and intermediately differentiated DCIS were usually found in grade I and grade II tumors, respectively. Poorly differentiated DCIS was equally associated with grade II and grade III infiltrating carcinomas. Furthermore, in univariate analysis, the DCIS type correlated with disease-free (chi 2 = 17.1, P < 0.001) and overall survival (chi 2 = 13.97, P < 0.001). In a Cox multivariate analysis, which included histologic grade, the association between DCIS type and prognosis was lost because of the very close relationship between type and grade. These results support the validity of the new classification and reinforce the view that treatment of pure DCIS should be related to tumor type. PMID- 7831534 TI - Long-term follow-up of in situ carcinoma of the breast. AB - Eighty cases of duct carcinoma in situ (DCIS) of the breast have been investigated by a cohort-retrospective study. These consisted of 8.5 per 1,000 of 9,446 breast biopsies originally diagnosed as benign, between 1964 and 1976, with a mean follow-up of 17.5 years. There were forty-one cases (51%) of DCIS of clinging type (CC); 30 cases (37.%) of CC associated with other types of DCIS; nine cases of DCIS other than CC two of which were DCIS of comedo-type. Invasive duct carcinoma (IDC) subsequently developed in 11 patients (14%), whereas DCIS recurred in 5 (6%). The recurrence was ipsilateral in 12 of these 16 patients. IDC appeared more frequently, with high statistical significance, when the lesion present in the original biopsy showed pleomorphic (P) nuclei (ie, poorly differentiated cyto-nuclear morphology). The Standardized Morbidity Ratio (SMR) was 8.0 (95% CI; 2.9-17.5) with the general population as reference. IDC that developed following a lesion displaying P nuclei also showed a statistically significantly more aggressive behavior. It is suggested that when cases of DCIS are followed-up for a considerable length of time, a two-wave pattern of aggressiveness becomes apparent. IDC that develops after a poorly differentiated DCIS leads to death more precociously than that appearing after other types of DCIS, especially those showing more bland nuclear cytology. PMID- 7831535 TI - The pathology of community-acquired pneumonia. AB - A good understanding of pathologic processes facilitates clinical approaches to the diagnosis of respiratory disorders. The pathology of community-acquired pneumonia is reviewed. The gross appearance and microscopic features of bronchopneumonia, lobar pneumonia, interstitial pneumonia, and mixed patterns are compared. Next, features of lung injury incited by specific microbial agents are discussed. Specific histological clues to diagnosis of the causative agent are highlighted where applicable. Special techniques are available to aid the pathologist in diagnosis of specific microbial agents in biopsy materials. The benefits and pitfalls of using immunohistochemical stains and molecular biologic techniques, such as in situ hybridization and the polymerase chain reaction are briefly presented. Finally, the methods by which material for study are obtained, (open lung biopsy, fine needle aspiration, and bronchoalveolar lavage), are discussed with respect to advantages and limitations. PMID- 7831536 TI - Assessing prognosis and predicting patient outcomes in community-acquired pneumonia. AB - Community-acquired pneumonia is a common medical illness, with clinical outcomes ranging from mild illness with rapid and complete recovery to a fulminant clinical course with morbid complications followed by death. A systematic review of the literature on pneumonia prognosis has identified a variety of demographic factors, symptoms and physical examination findings, comorbid illnesses, laboratory abnormalities, and etiologic agents that are independently associated with short-term mortality in patients with this illness. By combining these prognostic factors, investigators have developed a variety of indices to predict short-term mortality. Although these predictive instruments vary with respect to the patient populations studied, number of predictor variables included, statistical methods used, and overall clinical performance, these models can assist physicians in assessing patient prognosis and in making important management decisions such as the initial site of care (ie, home v hospital). Assessment of patient prognosis has also been used by clinicians and health services researchers who use the hospital severity of illness-adjusted mortality rate as a measure of the quality of medical care provided. Because the majority of patients with this illness survive, future assessments or predictions of prognosis in patients with community-acquired pneumonia should also evaluate a spectrum of other important health outcome measures including the occurrence of morbid complications, symptom resolution, quality of life, return to work and usual activities, and patient satisfaction with care. PMID- 7831537 TI - An overview of community acquired pneumonia with lessons learned from the British Thoracic Society Study. AB - There are many factors resulting in a changing pattern of pneumonia. This varies from the impact of an aging population, patients surviving longer with underlying chronic disease, severe illness, and various causes of immunosuppression and the effect of new investigations, new antibiotics, and the recognition of new pathogens. Numerous studies have been performed over the last few years regarding the cause and outcome of community-acquired pneumonia (CAP). Marked variation in results has been seen related to the criteria used for defining and diagnosing pneumonia, the population studied, and the use of differing investigations and diagnostic criteria. This is particularly apparent when comparing the different incidence of pneumococcal infection as a cause of CAP in studies from different parts of the world. Extrapolation of the findings from the multicenter British Thoracic Society (BTS) study of pneumonia suggests that pneumococcal infection is more common than several studies suggest. Having said that, it is clear from examination of the many studies that CAP is a diverse disease and that different part of the world will have to develop individual management strategies based on a critical analysis of the best available study data appropriate to their local or national situation. PMID- 7831538 TI - Initial investigation and treatment of the patient with severe community-acquired pneumonia. AB - Approximately 5% to 10% of patients hospitalized with community-acquired pneumonia (CAP) require treatment in an intensive care unit (ICU) because of severe disease. The case fatality rates in these patients are high, between 20% and 50% in most series. Streptococcus pneumoniae, Legionella spp, Haemophilus influenzae, Staphylococcus aureus, and gram-negative enteric bacteria are the most common causes of severe CAP. However, because the spectrum of pathogens encountered in these patients is unlimited, including viruses, tuberculosis, and opportunistic pathogens, it is crucial to obtain an etiologic diagnosis. A complete diagnostic arsenal should be used, including, if possible, invasive diagnostic procedures before antibiotics are given. The initial empirical therapy must cover the most common pathogens, and in most patients this can be accomplished with a combination of a cephalosporin and a macrolide. PMID- 7831539 TI - Community-acquired pneumonia: the future of the microbiology laboratory: focused diagnosis or syndromic management? AB - The traditional classification of community-acquired pneumonia into typical and atypical pneumonia to facilitate successful empirical treatment is no longer optimal. An accurate prediction of cause and adequate empirical therapy cannot be provided with this approach in severely ill patients. There is an increasing spectrum of recognized treatable pathogens presenting as community-acquired pneumonia including Legionella species, Chlamydia pneumoniae, and Pneumocystis carinii in addition to the traditional community pathogens. The variability of presentation in severely ill or compromised hosts makes clinical prediction of cause inadequate. A more rational approach may involve the classification of patients by the severity of illness and underlying disease with little or no microbiological workup in mild illness unless the results will contribute to the epidemiological surveillance of resistance because these investigations have not been shown to affect outcome in this setting. Etiologic diagnosis should be more aggressively sought and the microbiology laboratory can be best used by providing the efficient and rapid diagnosis of this expanded range of pathogens in more severely ill patients. The mounting antimicrobial resistance of common pathogens such as Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus will require not only a critical review of empirical therapy, but an increased emphasis on epidemiological monitoring of resistance by laboratories and effective communication with clinicians. PMID- 7831540 TI - Serological diagnosis of pneumococcal pneumonia--will it ever become a clinical reality. AB - Bacterial serology is not commonly used in the etiological diagnosis of pneumococcal pneumonia. This is partly because of the lack of commercial tests for this purpose. In addition, if paired sera taken about 2 weeks apart are needed, the positive pneumococcal finding obtained after the patient has been discharged from the hospital does not help clinicians in selecting the proper antibiotic treatment for the patient. Pneumococcal serology, however, is needed in both etiologic and epidemiological surveys as well as in the studies on the clinical efficacy of pneumococcal vaccines. PMID- 7831541 TI - Empirical therapy of community-acquired pneumonia. AB - An empiric approach to the therapy of community-acquired pneumonia (CAP) is needed because of the limitations of traditional approaches to antibiotic selection. The use of sputum Gram's stain and culture tests to guide initial therapy is potentially inaccurate and of limited use. Clinical syndromes cannot be reliably used to predict microbial pathogens, primarily because host, as well as bacterial factors, contribute to the presence of specific clinical signs and symptoms. The routine use of extensive diagnostic testing on all patients with CAP is expensive and of limited clinical usefulness. An empirical approach is presented that is based on an assessment of three factors that can help to predict the likely etiologic pathogens and thus guide initial therapy. These factors are the place of therapy, the presence of advanced age and/or comorbidity, and the severity of illness on initial clinical presentation. When these factors are used to guide empirical therapy, it is important to recognize and appropriately evaluate the nonresponding patient, and it is in this setting that an extensive diagnostic evaluation may be most useful. PMID- 7831542 TI - Methicillin-resistant Staphylococcus aureus as a cause of community-acquired pneumonia--a critical review. AB - Methicillin-resistant Staphylococcus aureus (MRSA) has been recognized as a nosocomial pathogen in Europe and North America for 3 decades. More recently it has emerged as a problem in long-term care facilities. It is less frequently considered a pathogen in nonfacility, community-acquired infections, where it is most often seen in intravenous drug users. There are no studies in the literature specifically describing the clinical features of MRSA pneumonia. Presumably its presentation and outcome are similar to that of pneumonia caused by susceptible strains. Staphylococcus aureus pneumonia is more often nosocomial- or nursing home-acquired, has a variable association with influenza, has clinical and laboratory features similar to other types of community-acquired pneumonia and carries a relatively high mortality of 20% to 84%. MRSA should be considered resistant to all classes of beta-lactam (beta) antibiotics. In addition, these isolates are frequently resistant to a number of other antibiotics, with vancomycin and only antibiotic to have consistently shown activity against MRSA. Therefore, vancomycin remains the treatment of choice for infections caused by MRSA, although treatment failures have been reported. The use of alternative antibiotics should be based on results of susceptibility testing of the strain isolated from the patient. PMID- 7831543 TI - Pneumonia caused by Nocardia species. AB - There are nine species of Nocardia. Nocardia asteroides accounts for 80% of infections caused by this organism in man. N brasiliensis causes 3% to 9% of these infections, and N farcinica is being recognized with increasing frequency. We present three cases of Nocardia pneumonia two of which were caused by N asteroides and one was caused by N farcinica. These cases illustrate the diverse nature of nocardiosis and show that sometimes it is difficult to determine whether the Nocardia was community- or nosocomially-acquired. PMID- 7831544 TI - Design of outcome studies of community-acquired pneumonia. AB - This review deals with design, description, and analysis of outcome studies of pneumonia. A review of studies of mortality from pneumonia shows deficiencies in reporting in several areas including description of exclusion/inclusion criteria, information on patients not enrolled in the study, referral patterns, and statistical analysis. Very few studies have evaluated outcomes other than mortality. Recommendations are provided for studies that evaluate a broad set of outcomes in patients with pneumonia. PMID- 7831545 TI - Intradermal lignocaine injections increase blood cell flux but not flap survival in rats. AB - In four groups of six rats a random dorsal flap was raised, and 5, 20, or 200 mg/ml lignocaine or 0.9% sodium chloride, were injected intradermally. Cutaneous laser Doppler blood cell flux was measured at 12 time points over 130 minutes. In six other groups 5, 20, 100, 200, or 400 mg/ml lignocaine concentrations, or sodium chloride were tested. Blood cell flux was measured at the time that the flap was raised and 30 minutes after the injections. The area of the flap that survived was measured on day 10. Raising of the flaps resulted in a significant reduction in blood cell flux, which was followed by a significant increase at 10 minutes (p < 0.05) after the injections with all lignocaine concentrations tested. Injections of 5, 20 and 100 mg/ml lignocaine elicited a significant increase (p < 0.05) in blood cell flux compared with baseline values. There was no reduction in blood cell flux values at any concentration of lignocaine tested. Compared with sodium chloride, injections of lignocaine had no significant effect on flap survival. We conclude that, despite an increase in blood cell flux, lignocaine had no effect on flap survival in this model. PMID- 7831546 TI - Platelet accumulation and thrombus formation after microarterial injury. An experimental study in rabbits. AB - Patency rats and accumulation of 32P-labelled platelets were studied in the central ear arteries of rabbits (which were not treated with antithrombotic agents) after three types of vascular injury: End to end anastomosis, arteriotomy and superficial injury to the vessel wall to expose the lamina elastica interna/juxtaluminal parts of the tunica media, arteriotomy and deep injury to the vessel wall to expose the deeper layers of the tunica media. The superficial and deep vessel injuries were 5 mm long. Patency rates were 100% after end to end anastomosis and superficial injury, and 48% after deep injury. In a separate group of vessels with deep injuries the time course of formation of occlusive thrombi was investigated: occlusion was already present 15 minutes after reperfusion in all but one of seven occluded vessels. Platelet accumulation ratios were significantly higher after deep injury than after end to end anastomosis or superficial injury. In deeply injured patent vessels, platelet accumulation reached a maximum after about 30 minutes, which was later followed by a gradual decrease. Platelet accumulation patterns indicating sustained thrombogenicity throughout the measurement interval (embolization/reaccumulation patterns or late increases in accumulation) were encountered in only three of 22 deeply injured vessels. We conclude that: to cause formation of occlusive thrombus in otherwise healthy arteries and animals, a deep injury to the tunica media is necessary, and following reperfusion after repair of damaged vessels the time course of the thrombotic challenge is short. PMID- 7831547 TI - Cell loss in sensory ganglia after peripheral nerve injury. An anatomical tracer study using lectin-coupled horseradish peroxidase in cats. AB - In 33 adult cats the lateral superficial branch of the radial nerve was exposed and transsected on one side. In one group of animals (n = 22) the nerve-stumps were re-approximated with epineural sutures and in the other group (n = 11) the proximal nerve stump was enclosed to prevent regeneration. After survival periods ranging from 4-17 months the same nerve on both sides was exposed to an intra axonal nerve tracer to label the dorsal root ganglion neurones projecting into the nerve being investigated. In each animal the opposite side was used as control. When the transsection was followed by a nerve suture the mean proportion of labelled sensory neurones in the dorsal root ganglion, compared with the control side, was 61% at eight months after operation, but by 17 months it had increased to 70%. When regeneration was prevented by the proximal nerve stump being enclosed in a plastic envelope, the reduction in labelled cells was 45% after a survival period of 17 months. PMID- 7831548 TI - Risk of accidental exposure to blood borne infection during plastic surgical operations. AB - To find out the incidence of accidental exposure to blood borne infections by the operation team in the department of plastic surgery a three month survey was carried out. All episodes of exposure of unprotected skin or mucous membranes to blood were recorded. There were 94 accidents in 746 operations, and 17 (18%) of the injuries penetrated the skin. These were mostly self injuries, typically the surgeon injuring his non-dominant index finger. Only one injured person wanted the patient to have an HIV test after the injury, and none of the injured people wanted an HIV test. Only two reported the injury as an occupational accident. PMID- 7831549 TI - Orbital reconstruction with hydroxyapatite ceramic implants. AB - Thirteen patients with fractures of the orbital floor (inferior wall), medial and lateral walls, or so-called "blowout" fractures with or without fractures of the zygoma were treated with artificially made hydroxyapatite ceramic implants made entirely from limestone, some of which were made with computer aided design and computer aided machinery (CAD-CAM) from data obtained from helical computed tomography. Orbital reconstruction with hydroxyapatite ceramic implants is a safe technique which is superior to previous ones in which autogenous or plastic materials were used. PMID- 7831550 TI - Minimal incision palatopharyngoplasty. A preliminary report. AB - A new palatopharyngoplasty which allows good muscular reorientation as well as elongation of the soft palate with minimal morbidity and scarring has been developed, and 66 selected patients underwent the procedure during the period September 1989 to March 1993. The most important findings were reduced operative bleeding, good length and mobility of the soft palate, and minimal scarring. A total of seven fistulas (11%) developed. Twenty-three patients (mean age 6 years and 2 months at the time of operation) underwent nasopharyngoscopy and multiview videofluoroscopy; velopharyngeal insufficiency was evident in only four (17%). Dental casts were obtained in 14 patients (mean age at the time of the operation 1 year, 3 months) who were followed up for a maximum period of two years. No postoperative orthodontic treatment was required and the width and harmony of the dental arch were maintained in all cases. PMID- 7831551 TI - Effects of mandibular growth patterns on the development and configuration of the face in patients with unilateral cleft lip and palate. AB - Radiographic cephalometry has been used for the assessment of the effects of mandibular rotation and of posterior growth displacement of the temporomandibular joint on the development of the face and on overjet in 43 patients with complete unilateral cleft lip and palate between the ages of 10 and 15 years. Rotation acted mainly on vertical facial measurements and on the position of the lower jaw. The degree of posterior displacement of the temporomandibular joint exerted an influence on the position of the mandible, on the difference between the functional length of the upper and lower jaw, and on the occlusion of incisors. The direction of growth of the mandible as a whole represented the result of a combination of changes produced by the rotation of the jaw and by the degree of posterior displacement of the temporomandibular joint. The most favourable conditions for development were a combination of the neutral type of rotation with a more pronounced posterior displacement of the temporomandibular joint. PMID- 7831552 TI - Clinical evaluation of the pectoralis major flap for reconstruction in head and neck cancer. AB - Sixty two patients (7 women and 55 men) with head and neck cancer underwent 64 musculocutaneous or osteomusculocutaneous reconstructions in the Department of Head and Neck Tumours, Estonian Cancer Centre, from May 1988 to December 1991. Two men had two reconstructions. The patients were evaluated for surgical, functional, aesthetic, and also for oncological results. The flap-related complication rate was higher among women than men (6/7 (86%) compared with 19/57 (33%), p = 0.012), and in the group of osteomusculocutaneous flaps which contained a segment of the fifth or sixth rib compared with the musculocutaneous ones (5/6 (83%) compared with 20/58 (34%), p = 0.03). The functional results were good or satisfactory in 41/60 (68%) of the cases. Mean follow-up time was 32 months; 31/58 (53%) of patients operated on due to primary or recurrent cancer are alive, with or without recurrent disease. We do not recommend the inclusion of rib segments in pedicled pectoral flaps for reconstructions of head and neck defects. PMID- 7831553 TI - Persistent irritation of the soft tissue around an osseointegrated titanium implant. Case report. AB - Percutaneous implants for hearing aids which are anchored in the bone have a low incidence of skin irritation. We report here the case of a man born in 1958 who had a long period of skin irritation, which was on two occasions associated with bacterial infection with Staphylococcus aureus. Despite local treatment with steroid/antibiotic ointment and skin grafts, episodes of skin irritation recurred, often in association with a relapse of ear drainage. Tests of delayed hypersensitivity to the implant and standard allergens were negative. Morphological and immunohistochemical analysis of the skin after removal of the abutment revealed an intense inflammatory reaction, with polymorphonuclear leucocytes, macrophages, lymphocytes, and HLA-DR expressing cells. In contrast to the inflammatory reaction in the soft tissue, there was a large amount of bone and the degree of bone-implant contact was good. PMID- 7831554 TI - Large peripheral cystic schwannomas. Two case reports and a review. AB - Two patients presented with benign cystic schwannomas, which originated from the brachial plexus and the sciatic nerve, respectively. The tumours were single, egg shaped growths that were excised completely without damage to the nerve. Histopathological examination confirmed the diagnosis of encapsulated, cystic, benign schwannomas. Preoperative magnetic resonance imaging provided useful information and is recommended in the evaluation of peripheral nerve tumours. PMID- 7831555 TI - Nasal stenosis after operations on the nose: expansion and subsequent maintenance of the nasal airway. Case report. AB - Nasal stenosis after operations on the nose may cause respiratory problems. We have re-established the patency of the nasal airway by controlled expansion of the nostril and nasal vestibule in seven patients. The airway was subsequently maintained with an individually adapted retention tube which was used intermittently as necessary. PMID- 7831556 TI - [The child and his environment]. PMID- 7831558 TI - [The child's world and his family world]. AB - Interactive processes between the child's inner and outer worlds are of first rank importance for childhood psychogenesis. In this the particular family dynamic is especially important both for the creation of constructs and for ongoing semantic differentiation in the child. The diversity of modern family structures are also reflected in the child's inner world. In the light of personally observed individual case studies, the paper describes interactive processes between the child, family and professional worlds and draws possible action-oriented conclusions for everyday pediatric practice. The remarks are based on a general concept of knowledge and action in family therapy (Meilen Concept [The Meilen Concept is being developed in the Arbeitsgemeinschaft des Ausbildungsinstituts fur systemische Therapie und Beratung, Meilen. Apart from the author its other members are Rosmarie Welter-Enderlin, Bruno Hildenbrand and Robi Waschle]), which is also briefly outlined. The model is designed to make clear that the central pole of professional action is understanding of the individual case through the encounter of physician and patient system. Professional knowledge and the rules of the physician's craft serve to keep this encounter within the bounds of professionalism. PMID- 7831557 TI - [The child in our society]. AB - Peter Berger once said that children are our "hostages to history", we expect them to ensure continuity. At the same time we project our wishes on them, they are our vectors of the future. Public discourse on children in modern society- charged with historical traditions and diverse expectations--provides a seismographic reading of our hopes and fears as the 20th century draws to a close. Pessimistic attitudes, the sense of looming dangers, appear to be ever more widespread, the discourse about modern childhood takes on an apocalyptic tone, children are seen increasingly as victims or dangerous delinquents. There are complaints that childhood disappeared or would be extended more and more. The paper provides a critical review of present day attitudes to children, investigates the current situation, and discusses the dilemmas that have arisen in the conditions of life and relations between the generations in modern civilization. But a question is also asked: How can we create the conditions that will do children and adults good? Last but not least, what can the health and social services contribute to making childhood worth living? PMID- 7831559 TI - [Child rearing style in the contemporary family]. AB - The main results of a recent Swiss study on major trends in the upbringing of preadolescents in the family are reviewed. Special emphasis is placed on the goals the parents set themselves, the upbringing techniques they employ and their mode of coordination with other agents of socialisation (school, TV, peer groups, etc). Three major, upbringing styles are distinguished and related to family social background and type of family cohesion. In conclusion, the relationship between the style of upbringing and preadolescents self-esteem is examined. PMID- 7831560 TI - [Sex abuse and sexual health in children: current dilemmas for the pediatrician]. AB - Epidemiologic research in nearly two dozen countries shows that sexual abuse is a real danger for 5-20% of all children, girls being 2-3 times more at risk than boys. Sexual abuse has proved an important risk factor in many behavioral or even somatic disorders, including posttraumatic symptoms such as nightmares, phobias, nutritional problems, aggressivity and school problems. Unfortunately the problem is surrounded by shame, denials and numerous misleading prejudices which make it hard to diagnose. Diagnosis is also complicated by the frequent absence of reliable physical evidence, the lack of serious research into the child's normal sexual behavior and development, the fact that many small children express themselves awkwardly, and finally the existence of reasons for making untruthful statements, e.g. in child custody disputes. In North America experience has shown the importance of certain arrangements when public health authorities need to respond effectively to the problem of sexual abuse: these arrangements are: (1) Education of the pediatric and medical communities to ensure that the majority of personnel are thoroughly aware of the symptoms and are willing to accept the diagnosis. (2.) Training of specialists capable of interpreting the physical signs, where these are present. (3.) Interdisciplinary cooperation, in practice, of the police and social and psycho-medical institutions with medical personnel when investigating individual cases. (4.) Serious efforts must be made to ensure that children do not suffer the negative iatrogenic effects of investigations into sexual abuse: that is, by minimising the number of interviews and examinations, respecting the child's privacy, and doing everything possible to ensure positive follow-up of the child by the primary social network surrounding him/her. PMID- 7831561 TI - [The abused and neglected child in Switzerland]. AB - Pediatricians form part of children's and young people's most important extra familial relations. They are thus especially well placed: first, to discover abuse of any kind, and second to put in motion the first years of measures of assistance for the children and their families. The first years of life are decisive for effective prevention of abuse and neglect, and for the development of a healthy personality. In this part of life, pediatricians are virtually the only "social outposts". Nevertheless, in Swiss pediatrics the concept of child protection is still in the initial stages. While we should warmly welcome the fact this problem was at last the main theme of an annual meeting, it must be remembered that this was only the first time. For a long time now no one has doubted that in our, thus far socially privileged country, a frighteningly large number of children and adolescents are victims of abuse. Since the publication of the report "Mauvais traitements des enfants en Suisse" (1992) a representative questionnaire to parents has shown that in this country and now, as before, over a third of parents use corporal punishment on their children. It has been calculated that e.g. 21,800 babies aged between 0 and 2.5 years are beaten, 4800 of them even with implements. There are no data on psychological and sexual maltreatment. Despite this shocking incidence of abuse, only a total of 72 cases (6% of all recorded cases) were reported over one year by pediatric practitioners in the "1989 prospective study". We cannot accept that this reflects a lack of social concern. Many other shortcomings appear to be involved: lack of briefing on the problems of child abuse during medical training, post-graduate and continuing studies, inadequate arrangements for interdisciplinary work, discouragement and early delegation to pseudo-experts, distrust of the efficacy of available aids (but sometimes overestimation of one's own possibilities) and last but not least, a still highly idealized image of the family which prompts one to reject the possibility of abuse. The Swiss Pediatric Society is urgently called upon to focus closer attention on this subject, and in so doing to take advantage of the increasingly widespread concept that child abuse must be regarded as resulting from a disturbance of the child's social network. Here the pediatrician can find an effective, decisive and also--above all--preventive role. PMID- 7831562 TI - [The child in the hospital]. AB - Children and adolescents live in a rich emotional world of imagination and fantasies. In the hospital they are confronted with a highly complex field of transactions. This generates images and feelings within the child and the adolescent which can be either healing, illness-provoking or maintaining certain problems. If doctors, nurses and other staff-members encourage the child and his relatives to develop favorable images, this may support the process of healing and enhance the quality of life, in dying patients as well. The presentation shows some of the images children have developed in the hospital and reports constructive and destructive transactional patterns related to the hospitalized patient. PMID- 7831563 TI - [School and child health]. AB - A roundtable discussion involving 2 educators and 4 pediatricians with widely varying experience sounded out the negative (pathogenic) and positive (healthy) influences to which a child is exposed in school and which decisively shape his/her physical, mental and psychic development. Concrete case reports and a systematic compilation of harmful factors show that this institution poses major threats to children's health of which pediatricians should be aware. An important cause of childhood suffering is the discrepancy between the uniform and inflexible institutional structures and the variability of children's needs conditioned by biology and social origin. Between ideal visions and the consequent school structures on the one hand, and social reality on the other hand, there are notable contradictions which must be recognized, lived with and- if possible--resolved by reforms. If he believes in the reformability of school, the pediatrician can make essential contribution to promoting health during school age. PMID- 7831564 TI - Intrauterine growth of tiny neonates. PMID- 7831565 TI - Proper focus. PMID- 7831566 TI - "Any Willing Provider" law--current status. PMID- 7831567 TI - Molecular medicine: a primer for clinicians--Part VII: Ethical issues associated with genetic testing. AB - Previously, we described the concepts and methods of DNA-based or genetic testing. The unlimited diagnostic power of genetic testing, coupled with the reality that effective treatments for many conditions are not available, raises many ethical and legal issues. These issues are discussed as they relate to the bed-side practice of molecular medicine. PMID- 7831568 TI - Virtue and longitudinal ethics education in medical school. AB - This article advances the argument that the inherent virtue/character of the caregiver is an important element in clinical ethical decision making. Virtue should be promoted as an essential component of professional behavior, and specifically emphasized in both medical student education and professional practice. PMID- 7831569 TI - Ethics and formulary choices. PMID- 7831570 TI - What's in a name? PMID- 7831571 TI - Thrombosis and inflammation as multicellular processes: significance of cell-cell interactions. PMID- 7831572 TI - Molecular mechanisms of thrombin signaling. PMID- 7831573 TI - Role of platelet integrin GPIIb-GPIIIa, fibronectin, von Willebrand factor, and thrombin in platelet-tumor interaction in vitro and metastasis in vivo. PMID- 7831574 TI - Disintegrins and other naturally occurring antagonists of platelet fibrinogen receptors. AB - Disintegrins represent a family of low-molecular weight, cysteine-rich, RGD containing peptides that inhibit fibrinogen binding to glycoprotein IIb/IIIa complex as well as binding of other ligands to RGD-dependent integrins on the surface of other cells. Disintegrins occur in the venom of various vipers. Disintegrin domains have been identified in viper venom hemorrhagins and in sperm proteins involved in the sperm-egg fusion. Amino acid sequences of 25 disintegrins, alignment of S-S bridges in four disintegrins, and stereo models of five disintegrins are presented. Primary structures of disintegrins differ significantly from other fibrinogen receptor antagonists occurring in the venoms of Elapidae, leeches, and ticks. Several aspects of structure-function relationship of disintegrins, their biological activities, and possible clinical applications are discussed. PMID- 7831575 TI - Glanzmann thrombasthenia: new insights from an historical perspective. PMID- 7831576 TI - Scott syndrome: a disorder of platelet coagulant activity. PMID- 7831577 TI - Platelet membrane receptors for the complement component C1q. PMID- 7831578 TI - The effect of viral infections on platelets and megakaryocytes. PMID- 7831579 TI - Applications for retinoids in cancer therapy. AB - Current data suggest that the spectacular responses seen with the single-agent use of all-trans RA in APL will probably not be replicated in other diseases in the near future. Nonetheless, that experience has revealed critical information that ultimately may be generalizable to other types of cancer. Among these lessons include the observation that in APL the t(15;17) translocation appears to dominate other cytogenetic lesions, such that therapy directed against that lesion corrects the leukemic process, irrespective of the presence of other abnormalities. In addition, the concept of induced cytodifferentiation as a practical and consistently successful method of cancer treatment has been validated. Although all-trans RA itself may not prove as useful in other diseases, it is not unreasonable to expect that other retinoids (or ligands of other nuclear receptors used alone or in combination) may be effective. Finally, although the expectation of cure in patients with advanced cancers may never be realized with these compounds, they have distinct activity as cancer chemopreventive drugs, and widespread clinical testing is ongoing. Perhaps more than any other therapy, this preventive indication affords the greatest opportunity to impact favorably on public health. PMID- 7831580 TI - Pharmacokinetics of all-trans-retinoic acid: clinical implications in acute promyelocytic leukemia. AB - Continuous daily treatment with all-trans-retinoic acid (ATRA) in patients with acute promyelocytic leukemia has been associated with a marked decline in the plasma drug concentration at the time of relapse. Recent pharmacologic studies have attempted to determine the reasons for the progressive reduction of plasma concentrations of the drug. A decrease in plasma concentrations over time may be attributed to either upregulation of metabolism or downregulation of absorption. The effect of intravenous ATRA was examined in Rhesus monkeys to help differentiate between these possibilities and to better establish the metabolism of ATRA. Findings were consistent with a capacity-limited (saturable) elimination process. A subsequent study with Rhesus monkeys demonstrated that this capacity limited elimination process can be induced. Two potential ways of overcoming decreased plasma levels are suggested by the explanations for rapid elimination of ATRA: administration of a P-450 inhibitor such as ketoconazole to block oxidation of the drug, or use of an intermittent dosing schedule. Studies are currently under way to examine the effectiveness and tolerability of these methods. PMID- 7831581 TI - Potential applications of cytodifferentiation therapy in hematologic malignancies. AB - Retinoids, including retinoic acid (RA), are naturally occurring and synthetic analogs of vitamin A that inhibit cell growth and induce cell differentiation in many experimental tumor models. Differentiation of the human myelogenous leukemia cell line HL-60 by RA led to the finding that cells from patients with acute promyelocytic leukemia (APL) are terminally differentiated by RA. One mechanism for the activity of RA in a variety of cell types involves the RA nuclear receptors (RA receptors [RARs] and retinoid X receptors), which have specific high-affinity binding sites for RA and some of its metabolites. Other mechanisms may also be involved in RA-induced differentiation. Recent studies suggest that RA acylation (retinoylation) may be involved in the RA induction of differentiation in leukemia cells. Combinations of RA with cyclic adenosine monophosphate (cAMP)-elevating agents led to synergistically induced differentiation of HL-60 cells. The lower doses of RA needed in combination therapy are unlikely to lead to RA resistance, a major limitation of RA therapy in APL. In vitro studies suggest that combinations of RA with either PGE or the butyric acid (BA) prodrug tributyrin (TB) may be useful in differentiation therapy for APL and other malignancies. This is a US government work. There are no restrictions on its use. PMID- 7831582 TI - Retinoid chemoprevention of second primary tumors. AB - Retinoids, natural or synthetic derivatives of vitamin A, have been studied as cancer chemopreventive agents and as therapeutic agents in the treatment of solid tumors. Intensive clinical research has focused on the role of retinoids in preventing second primary tumors following head and neck or lung cancer. The frequent occurrence of second primary tumors in these areas provides clinical support for the hypothesis of field carcinogenesis. Based on evidence of its efficacy in reversing oral premalignancy, the synthetic retinoid 13-cis-retinoic acid (13cRA) was studied in a 1-year trial to prevent the incidence of new cancers in patients who had been treated for squamous cell carcinoma (SCC) of the head and neck. Second primary tumors developed in only 4% of 49 patients treated with 13cRA, as compared with 24% of 51 patients treated with placebo (P = .005). These findings have led to two ongoing large-scale trials of 13cRA in North America. One study, performed through the M.D. Anderson Cancer Center and its affiliated Community Clinical Oncology Program and the institutions of the Radiation Therapy Oncology Group (RTOG), will determine whether long-term administration of low-dose 13cRA will prevent second primary tumors following an initial head and neck cancer. Another intergroup study using a similar randomized double-blind design is being performed among patients who have undergone resection of a stage I non-small-cell lung cancer. In Europe, a large chemoprevention study called Euroscan is currently examining the efficacy of another retinoid, retinyl palmitate, in preventing second primary tumors following head and neck or lung cancer.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7831583 TI - Retinoic acid and interferon in human cancer: mechanistic and clinical studies. AB - Various combinations of retinoids, metabolic and synthetic derivatives of vitamin A, and interferons (IFNs) have demonstrated synergistic antiproliferative, differentiating, and antiangiogenic activity in some human hematologic and solid tumor systems. This synergistic antitumor activity may be due to enhanced gene expression. In several cell systems, the actions of IFNs are enhanced by differentiation of cells with retinoic acid (RA). Combined RA-IFN effects have been correlated with the induction of higher levels of IFN-stimulated genes than the levels induced by either agent alone. Natural and synthetic retinoids have been found to augment the antiproliferative activity of IFNs in several squamous cell carcinoma (SCC) and breast tumor cell lines. Results of recent clinical trials indicate substantial activity of 13-cis-RA (13cRA) combined with IFN against advanced SCC of the skin and cervix, and possibly against other solid tumors. Two phase II trials have confirmed activity against locally advanced SCC of the cervix. Successful integration of this regimen with radiotherapy appears to be the most probable means of optimizing clinical outcome. Further studies are needed to determine the mechanistic details of the RA-IFN interaction. PMID- 7831585 TI - Illustrated keys to the medically important mosquitos of Thailand. AB - The major mosquito-borne diseases in Thailand are malaria, dengue, Japanese encephalitis, and filariasis. The newly revised and illustrated keys to adult female and fourth instar larval mosquitos presented in this paper will enable public health workers to rapidly identify mosquito vectors of these diseases and to distinguish them from other species in the same genera. Keys are provided to identify 4 medically important genera from among any mosquito in Thailand. The 4 genera are treated in more detail with keys to 9 subgenera, 11 groups or subgroups, and 38 individual species considered to be of medical importance. PMID- 7831584 TI - All-trans-retinoic acid in acute promyelocytic leukemia and its potential in other hematologic malignancies. AB - Several phase II clinical studies of all-trans-retinoic acid (ATRA) have been conducted in acute promyelocytic leukemia (APL), an uncommon subtype of acute myeloid leukemia (AML). ATRA has been shown to induce complete remission (CR) in 64% to 96% of patients with APL, and with rapid resolution of the coagulopathy, which is a major cause of early morbidity and mortality. Although CRs induced with ATRA alone are usually not sustained and intensive antileukemic consolidation therapy is required to prolong remission, these findings indicate that a new approach of differentiation therapy is effective in treating patients with APL and may potentially be effective in other malignancies. The presence of the PML/retinoic acid receptor-alpha (PML/RAR-alpha) fusion gene, produced as a result of the unique chromosomal translocation in APL, is a marker of sensitivity to ATRA. Aside from the complications of hyperleukocytosis and the retinoic acid syndrome, ATRA therapy is generally well tolerated. An international study (Intergroup 0129), headed by the Eastern Cooperative Oncology Group, is currently under way to determine further the role of ATRA in the treatment of patients with APL. Given its success in APL, studies of ATRA in other hematologic malignancies are also being conducted. A better understanding of how retinoids modulate carcinogenesis will help determine if the results in APL can be realized in other malignancies treated with ATRA or other retinoids. PMID- 7831587 TI - Issues in regulatory protection of reproductive health in the workplace. AB - Provisions of federal laws that protect reproductive health in the workplace and information on recent federal actions that seek to enhance such protection are reviewed. California's Birth Defects Prevention Act and its Proposition 65, regulatory programs that specifically address reproductive toxicity, also are described. PMID- 7831586 TI - Introduction: rationale for an update. Reproductive hazards. AB - More than 104,000 chemical and physical agents have been identified in the workplace, but the effects on reproduction of at least 95% of them have not been assessed. Here, the editors of this volume describe changing demographics in the workplace, which underscore the need for evaluating potential hazards to reproduction. They also review findings regarding occupational reproductive hazards to men and women that have been reported over the past decade. PMID- 7831588 TI - Clinical approach to male reproductive problems. AB - This review of the currently recommended clinical and laboratory approach to the evaluation of male reproductive problems describes history-taking, physical examination, evaluation of semen, evaluation of abnormalities of the endocrine system, and specialized laboratory tests such as bioassays, biochemical tests of sperm function, and tests for antisperm antibodies. PMID- 7831589 TI - Occupational hazards to male reproduction. AB - Since the field of reproductive toxicology was firmly established a generation ago, various approaches have been used to study toxicologic effects. The authors detail the reproductive effects that have been observed in a number of population based studies, case-control studies, standardized fertility ratio studies, cohort studies, and clinical studies. PMID- 7831590 TI - Clinical approach to female reproductive problems. AB - Conditions of infertility addressed here include ovulatory dysfunction, tubal and pelvic factors, uterine and cervical factors, immunologic factors, and unexplained infertility. A discussion of recurrent loss of pregnancy and antenatal diagnosis completes the chapter. PMID- 7831592 TI - Occupational hazards to fertility and pregnancy outcome. AB - Occupational reproductive hazards to women have been studied frequently despite the fact that many female reproductive endpoints are not readily observable or routinely recorded in occupational medical records (subfertility, delayed conception, early pregnancy loss, menstrual cycle dysfunction). However, a number of outcomes are fairly readily observable (low birthweight, clinically observed SAB, preterm labor) and medically recorded although they are not generally recorded in the occupational setting. In addition, techniques for observing reproductive outcomes in women are generally less invasive than those in men, particularly with recent developments in urinary monitoring for ovarian function and early pregnancy loss. Although studies of some exposures and outcomes (risk of SAB, low birthweight, or preterm birth with exposure to VDTs or EMFs or exposure to metals and menstrual dysfunction, infertility, or SAB) have shown inconsistent results, a number of findings regarding other associations have been fairly consistent and are very suggestive of causal relationships. Occupational exposure to solvents does appear to increase the risk of dysmenorrhea and SAB, particularly with exposure to organic solvents. Increased risk of adverse reproductive outcomes has also been observed among women working in agricultural settings, but no link has been made to specific exposures. In addition, physical stressors such as shift work, long hours standing, and lifting have been fairly consistently associated with increased risk of SAB or preterm birth. Finally, while complete agreement among studies is lacking, many have observed an increased risk of subfertility or SAB associated with work in medical occupations and with some specific medical exposures, such as nitrous oxide, anesthetic gases and antineoplastic drugs. Much remains to be explored, particularly clarification of the relationship for exposures and outcomes that have shown inconsistent results. These require specific efforts to validate exposures and outcomes, to investigate and control for confounding variables, to consider the effects of multiple comparisons, to study populations of adequate size to provide meaningful statistical analyses, and to make possible the evaluation of dose-response and timing of exposure effects. PMID- 7831591 TI - Methods for evaluating reproductive health of women. AB - The use of urine as a practical sample for evaluating the reproductive health of women in population-based studies is still being developed and applied. The adaptation of enzyme-based assays for the assessment of ovarian steroids as well as simple computer algorithms for interpreting the data both simplify and increase the efficiency of modern reproductive epidemiologic studies. New statistical approaches and new assays have extended physiologic monitoring to include early pregnancy, luteal phase function, and ovulation. While urine is superior to blood sampling, it is important to remember, however, the limitations of urinary hormone measurements when applying them alone to identify specific types of reproductive failure because variations in metabolism and excretion rate still contribute some uncontrollable variation. The rate of progress in developing and refining these methods over the past 5 years indicates that urinary methods of reproductive monitoring will continue to dominate this field and eventually be used in the clinic as well. PMID- 7831593 TI - Congenital malformations related to occupational reproductive hazards. AB - Occupational and environmental agents are the suspected cause of at least some of the approximately 60% of birth defects whose etiology is unknown. The author discusses studies of birth defects published since 1988. Studies that examine associations between congenital malformations and both maternal and paternal exposures are included. PMID- 7831594 TI - Childhood cancers associated with parental occupational exposures. AB - Statistics suggest that environmental and occupational exposures may be at least partially responsible for an increased incidence of cancer in children. The authors describe the latest findings in this area of research and look at the methodologic concerns that arise and how they affect the derivation of causal inferences from such studies. PMID- 7831595 TI - Workplace policy on hazards to reproductive health. AB - At present, workplace policies regarding reproductive hazards are not regulated directly, and inappropriate policies are occasionally corrected by legal actions or union pressures on the employers. Further, information on reproductive hazards is incomplete; however, employees have a legal right to know available information about hazards, including reproductive hazards, that they face in the workplace. Occupational health personnel play a major role in communicating information about reproductive hazards in the workplace and in implementing company policy and complying with legislation. Regulatory and case law likely will continue to evolve as many issues related to safety from reproductive hazards in the workplace have not yet been resolved. PMID- 7831596 TI - Laparoscopic surgery--anesthetic implications. AB - Laparoscopic cholecystectomy is a relatively new surgical procedure which is enjoying ever-increasing popularity and presenting new anesthetic challenges. The advantages of shorter hospital stay and more rapid return to normal activities are combined with less pain associated with the small limited incisions and less postoperative ileus compared with the traditional open cholecystectomy. The efficacy of laparoscopic appendectomy and hemicolectomy has been recently evaluated. However, there have been no prospective randomized studies to date comparing laparoscopic with traditional laparotomy techniques. The physiological effects of prolonged pneumoperitoneum and the longer duration of surgery with the laparoscopic techniques are of concern. The application of laparoscopic inguinal hernia repair may be limited because, unlike traditional surgical hepair, general anesthesia is required and concerns have been expressed about the duration of surgery and the possibility of hernia recurrence. Notwithstanding case reports and series describing successful diaphragmatic and hiatus hernia repair using a laparoscopic surgical technique, the frequently encountered complications of cervical surgical emphysema, pneumothorax, and pneumomediastinum, attributed to passage of insufflating gas through weak points or defects in the diaphragm, must be of major concern. Anesthesiologists must maintain a high index of suspicion for these potential complication and must undertake appropriate monitoring. If there is clinical evidence of a tension pneumothorax, immediate chest tube decompression is indicated. Intraoperative complications of laparoscopic surgery are mostly due to traumatic injuries sustained during blind trocar insertion and physiological changes associated with patient positioning and pneumoperitoneum creation. The choice of anesthetic technique for upper abdominal laparoscopic procedures is most frequently limited to general anesthesia. Controlled ventilation avoids hypercarbia, and an anesthetic technique incorporating antiemetics and nonsteroidal anti-inflammatory agents has reduced postoperative nausea and vomiting following laparoscopic cholecystectomy. The use of nitrous oxide during laparoscopic procedures remains controversial. Laparoscopic cholecystectomy is a major advance in the management of patients with symptomatic gall-bladder disease. However, in the present era of cost containment, older and sicker patients may present for this procedure on the day of surgery without adequate preoperative evaluation. Anesthesiologists should thus be prepared to recommend deflation of the pneumoperitoneum and possibly conversion to an open procedure if hemodynamic, oxygenation, or ventilation difficulties arise during the procedure. PMID- 7831598 TI - The suturoscope. A preliminary report on the first clinical applications. AB - One of the authors has developed a special device--the suturoscope--which allows endoscopic sutures with conventional suture material. After several modifications, in order to improve the prototype, the authors began its clinical application in 1992. Five bladder operations were performed--two antireflux operations, two meatotomies with meatoplasty, and an intramural ureteric ligation. The results indicate that this device is suitable for clinical use. PMID- 7831597 TI - Comparative study of the holding strength of slipknots using absorbable and nonabsorbable ligature materials. AB - The holding and tensile characteristics of five extracorporeal slipknots in relation to absorbable and nonabsorbable ligature materials have been evaluated in a standardized in vitro test rig. The knots studied: Tayside, Roeder, Melzer (modified Roeder), Cross square, and Blood knots were tied with the following materials: silk, polyamide, Dacron, polydioxanone (PDS), and lactomer (Polysorb). Following construction and slippage (run down) to a fixed-diameter loop around a cylinder, the knots were locked (tightened) using a standardized force after which they were removed from the test rig and subjected to holding strength (force required to induce reverse slippage) and other tensile characteristics (stress, strain, elasticity) by a tensiometer. Analysis of the data has demonstrated the following: (1) The safest slip knots (resist slippage) are the Tayside, Melzer, and Roeder knots tied with lactomer and Dacron. (2) The holding strengths of the Cross square and Blood knots are weak with all ligature materials tested. (3) Polydioxanone is a safe ligature material for the Melzer and Tayside but not the Roeder knot. (4) Extracorporeal slipknots tied with silk and polyamide are less secure than the equivalent knots tied with Dacron, lactomer, and polydioxanone. PMID- 7831599 TI - Continuous esophageal pH monitoring during laparoscopic cholecystectomy. AB - Gastro-esophageal regurgitation (GER) and eventual aspiration is considered a major risk during general anesthesia. High intraperitoneal pressure produced during laparoscopic cholecystectomy (LC) is a possible source of increased GER. We investigated the incidence of GER using continuous esophageal pH monitoring in 14 patients undergoing elective LC. Only two brief episodes of acid reflux (pH < 4) occurred during LC. Apparently the high intraperitoneal pressure during LC carries no increased risk of regurgitation and aspiration. PMID- 7831600 TI - Extracorporeal shock-wave lithotripsy prior to laparoscopic cholecystectomy. Does it make sense? AB - The extraction of large gallstones in laparoscopic cholecystectomy either requires the enlargement of one of the incisions or intraoperative lithotripsy. Preoperative extracorporeal shock-wave lithotripsy (ESWL) might theoretically solve the problem and facilitate the extraction of the gallbladder. Ten patients with at least one gallstone larger than 20 mm in diameter underwent ESWL treatment within 24 h prior to laparoscopic surgery. Complete pulverization of stones was achieved in one patient. Fragmentation into pieces smaller than 10 mm could be observed in another three cases. Additional mechanical fragmentation employing forceps was necessary in seven and an enlargement of the incision in five of the 10 patients. Compared to a matched group of 10 control patients with gallstones of corresponding size receiving mechanical lithotripsy, the ESWL did not show an advantage, but rather an increase in costs. It therefore cannot be recommended. PMID- 7831601 TI - Comparison of laparoscopic and minilap cholecystectomy for acute cholecystitis. AB - The charts of all patients with acute cholecystitis undergoing either laparoscopic or minilap cholecystectomy at the Chinle Comprehensive Health Care Facility between October 1, 1991, and August 15, 1993, were retrospectively reviewed. During that period, 54 patients underwent laparoscopic cholecystectomy and 45 patients had minilap procedures. The two groups had similar mean age, sex distribution, temperature, leukocyte count, gallbladder wall thickness, and duration of preoperative symptoms. While laparoscopic cholecystectomy took an average of 16 min longer to perform than minilap cholecystectomy, patients who had laparoscopic cholecystectomy had less blood loss, reduced postoperative narcotic needs, and shorter hospital stays. PMID- 7831602 TI - Endoscopic and histological criteria for preoperative evaluation of the depth of infiltration of gastric carcinoma. AB - Because the therapeutic approach to gastric carcinoma differs according to the stage of development, a study was carried out to investigate whether there are any factors which would allow the depth of infiltration of a gastric carcinoma to be evaluated preoperatively. The criteria used were endoscopic and histological. The first provide information on size and macroscopic aspect; the second reveal the relationship between bioptic specimens that are positive for carcinoma and those that are negative. On the basis of these standards, small, benign-looking neoplasias with bioptic positivity for carcinoma lower than 30% were classified as probably early. Of the 200 gastric carcinomas investigated, 55 were considered probably early and 145 probably advanced. Surgical fragment findings confirmed the diagnosis in 169 cases (37 true negatives and 132 true positives) and failed to confirm it in the other 31 cases (13 false positives and 18 false negatives). The specificity, sensitivity, negative predictive value, positive predictive value, and total diagnostic accuracy indices were 74.00%, 88.00%, 67.27%, 91.03%, and 84.50%. PMID- 7831603 TI - Diagnosis of colorectal tumors by the endoscopic Congo red-methylene blue test. AB - The endoscopic Congo red-methylene blue test was performed on 51 tumors of the large intestine. Results revealed that colorectal adenocarcinomas and adenomas bleached the Congo red and methylene blue sprayed over their surface and so appeared in sharp contrast to the bluish red mucosa of unaffected areas. No bleaching of the dyes was observed on the surface of non-neoplastic polyps. Moderately differentiated adenocarcinomas, submucosal or advanced cancers, and adenomas with severe atypia bleached the dyes most frequently. Thus this test facilitates early detection of colorectal tumors. PMID- 7831604 TI - Laparoscopic-assisted vagotomy and distal gastrectomy. AB - This is a report of the techniques used on and outcome for three patients who underwent laparoscopic-assisted vagotomy and distal gastrectomy for complicated peptic ulcer disease. The first patient had a Billroth I anastomosis in 2 h 42 min with an estimated blood loss of 200 ml. Oral fluids were started on day 3 and the diet progressed to a soft food by day 5. The patient was discharged 11 days after his gastrectomy following a transurethal prostatic resection on day 6. The second patient had a Billroth II anastomosis. The operation was completed in 4 h 40 min with an estimated blood loss of 350 ml. Oral fluids were commenced on the 1st postoperative day and the patient was tolerating a soft diet by day 4. The patient was discharged 5 days after his gastrectomy. The third patient had a Billroth I anastomosis with an estimated blood loss of less than 150 ml. The surgery took 2 h 35 min; the patient was tolerating oral fluids on the first postoperative day and was discharged on the 4th postoperative day on soft diet. Laparoscopic-assisted vagotomy and gastrectomy has the advantages of a minimal access procedure without the risks of an intracorporeal anastomosis. PMID- 7831605 TI - Complications and recurrences associated with laparoscopic repair of groin hernias. A multi-institutional retrospective analysis. AB - Although the laparoscopic technique is a new approach to groin hernia, it is becoming more widely accepted as an alternative to traditional open techniques. This study is a preliminary review of complications and recurrences. A questionnaire specific for complications was sent to each investigator. From 12/89 to 4/93, 1,514 hernias were repaired; 119 (7.8%) were bilateral and 192 (12.7%) recurrent. There were 860 indirect, 560 direct, 43 pantaloon, 37 femoral, and 6 obturator hernias, and 8 were not specified; 553 were repaired using a transabdominal preperitoneal mesh technique (TAPP), 457 with a total extraperitoneal technique (TEP), 320 with intraperitoneal onlay mesh (IPOM), 102 by ring closure, and 82 involved plug and patch technique. Eighteen intraoperative and 188 postoperative complications were seen. The total complication rate was 13.6%, of which 1.2% were intraoperative. Of the intraoperative complications, 12 were related to the laparoscopic technique, three were related to the hernia repair, and one was related to anesthesia. The rate of conversion to open was 0.8%. Of the postoperative complications, there were 95 local, 25 neurologic, 23 testicular, 23 urinary, 10 mesh, and 12 miscellaneous. There were 34 recurrences after the 1,514 hernia repairs (2.2%). The follow-up was reported in 825 patients for an average of 13 months. The recurrence rate varied drastically with the technique: A 22% recurrence rate after the plug and patch vs 3%, 2.2%, 0.7%, and 0.4% with the ring closure, IPOM, TAPP, and TEP, respectively. Laparoscopic repair of groin hernia can be safely performed. Complications, mostly minor, diminish with experience. The recurrence rate is less with large mesh which is anchored. PMID- 7831607 TI - Laparoscopic enucleation of a renal cell carcinoma. AB - The purpose of this study was to report on the feasibility of laparoscopic excision of renal cell carcinoma. An 81-year-old female with renovascular disease underwent a laparoscopic excisional operation for a 2-cm tumor localized in the left kidney. Pathological evaluation showed a low-grade tumor without any extension through the renal capsule (grade I Hand Broder, stage I Robson). The postoperative course was uneventful; there was minimal postoperative pain. The patient was discharged home on the sixth day. Laparoscopic excision would appear to be a safe and effective technique in selected cases. PMID- 7831606 TI - The influence of the number of endoclips and of mesh incorporation on the strength of an experimental hernia patch repair. AB - The strength conferred to a mesh by fixing it with laparoscopic staples and the effects of tissue incorporation have never been quantified. Eighteen dogs were divided into three groups sacrificed at 2 days (5 dogs), 2 weeks (6 dogs), and 2 months (7 dogs). One 3.5- by 5-cm piece of abdominal wall was removed from each side through a median laparotomy, leaving the skin intact. A polypropylene mesh (5 by 7 cm) was fixed over one defect with four Endopath EMS staples (Ethicon Endo-surgery) and over the other with 16 EMS staples. At sacrifice, bursting strength (BS) was measured with an Instron tester and specimens were studied histologically. One-way analysis of variance and the Newmann-Keuls multiple comparison test were used. BS tests showed that for each period studied, the strength of the repair performed with 16 staples was significantly higher than that obtained when four staples were applied. They also showed that tensile strength increased significantly in both groups as time elapsed. Light microscopy supported the conclusion that the initial strength of the repair was related to the number of clips and was significantly increased by cellular infiltration at 2 weeks and significantly more by collagen deposition at 2 months. At 2 months, BS was significantly higher in the 16-staples group, suggesting that initial fixation still plays a significant role. PMID- 7831608 TI - Delayed gallstone abscess following laparoscopic cholecystectomy. AB - Delayed infectious complications following elective laparoscopic cholecystectomy have not been well delineated in the medical literature. Irretrievable spillage of gallbladder contents at the time of laparoscopic cholecystectomy is not rare, and has generally been felt to be of little consequence, particularly in the nonacute setting. The case presented documents an instance of delayed gallstone abscess formation after elective laparoscopic cholecystectomy. While rare, such cases highlight the need for refined techniques to prevent gallbladder, perforation during this procedure and to allow laparoscopic recovery of small gallstones spilled at the time of cholecystectomy. PMID- 7831609 TI - Liver fibrosis after extracorporeal shock-wave lithotripsy of gallbladder stones. A case report. AB - We encountered significant liver fibrosis in a healthy young patient undergoing laparoscopic cholecystectomy for symptomatic gallstone disease. Twelve months prior to cholecystectomy the patient underwent multiple extracorporeal shock-wave lithotripsy (ESWL) sessions with adjuvant oral bile-acid therapy. Since the site of fibrosis corresponded clearly to the shock-wave transmission path, which was in accordance with animal studies, it was concluded that this liver fibrosis was a side effect of biliary ESWL. Based on these findings and the literature, we conclude that further assessment of the long-term safety of ESWL is still warranted, especially in patients undergoing multiple ESWL sessions. PMID- 7831610 TI - Gastric diverticulum. Endoscopic and radiologic appearance. AB - Gastric diverticula are relatively rare findings. Although usually asymptomatic, they may cause vague epigastric pain. These lesions may be confused radiologically for gastric ulcers or cancers. Endoscopically, they may be confused for paraesophageal hernias. This report discusses the appearance and evaluation of gastric diverticula. PMID- 7831611 TI - Laparoscopy preferable to imaging procedures in detecting metastases of a pancreas carcinoma to the liver. Report of two cases. AB - In two patients a pancreatic mass, 6 and 4 cm in diameter, respectively, was detected using imaging techniques. Computed tomography, ultrasound, and angiography revealed no evidence of a metastatic lesion in the liver. In the first patient, exploration was done prior to a possible radical operation. Multiple hepatic metastases forming thin, flat lesions on the surface of the liver were present and palliative surgery only was done. In the other patient, laparoscopy was done before surgical exploration and multiple hepatic metastases on the surface of the liver were clearly evident. Laparoscopy can help to avoid unnecessary explorations in patients with large pancreas cancer. PMID- 7831612 TI - Laparoscopy in the diagnosis of bleeding Meckel's diverticulum. AB - A rare case of bleeding Meckel's diverticulum in an adult, in which Tc-99m pertechnetate scan, mesenteric angiography, and barium examination failed to establish the diagnosis, is presented. The diagnosis was made by laparoscopy, and a laparoscopically assisted resection was carried out with a smooth postoperative course, early discharge from the hospital, and rapid return to work. PMID- 7831613 TI - Technical aspects of adrenalectomy via operative laparoscopy. AB - Adrenalectomy is usually performed through a transabdominal or a posterior approach. These approaches are associated with a painful syndrome postoperatively and long hospital stay. We report a series of five successful laparoscopic adrenalectomies, performed on: a 35-year-old male with a 5-cm right nonfunctioning tumor; a 32-year-old female with a 1.8-cm right aldosterone producing adenoma; a 17-year-old female with a 4-cm right adrenocortical adenoma; and a 33-year-old female with bilateral 3.5-cm right and 4.5-cm left pheocromocytoma. Single right adrenalectomy lasted between 2 h and 2 h 30 min and bilateral adrenalectomy 5 h and 30 min. No transfusion was required. The hospital stay was between 3 and 4 days. This technique adequately removes adrenal tumors surgically and results in less postoperative pain and rapid recovery. PMID- 7831614 TI - Colonoscopic-assisted laparoscopic colectomy. AB - One of the technical difficulties during laparoscopic and laparoscopic-assisted resection of the right, transverse, and left colon is the mobilization of the splenic and hepatic flexures. We present a simple technique of colonoscopic traction of the splenic or hepatic flexure. This technique enables good exposure and facilitates dissection while laparoscopic mobilization of these segments of the colon is performed. PMID- 7831615 TI - Laparoscopic adjustable silicone gastric banding in the treatment of morbid obesity. A preliminary report. AB - A first approach to laparoscopic placement of the adjustable silicone gastric band (ASGB) was begun in our institution in 1992. This work started on an animal model first. In the animal lab, details of laparoscopic dissection around the stomach have been defined. A new prototype of the adjustable silicone band for laparoscopic use has been devised. Four voluntary patients underwent this operation on the 1st, 2nd, and 3rd of September 1993. All the patients were female and the average weight was 116 kg (102-120 kg). The mean body mass index was 43 kg/m2 (36-49 kg/m2). No major operative difficulty was encountered. Immediate postoperative outcome was uneventful. PMID- 7831616 TI - Laparoscopic cholecystectomy and gallbladder cancer. PMID- 7831617 TI - Recurrent inguinal hernia without peritoneal defect. The role of laparoscopy in the diagnosis and management. PMID- 7831618 TI - Is the retrieval of lost peritoneal gallstones worthwhile? PMID- 7831619 TI - Influenza vaccination. PMID- 7831620 TI - Carotid bodies and breathing in humans. PMID- 7831622 TI - Which patients are prescribed inhaled anti-asthma drugs? AB - BACKGROUND: Prescribing rates for inhaled anti-asthmatic drugs in the UK vary considerably from area to area and between individual practices. The objectives of this study were to determine the prevalence of patients prescribed inhaled steroids and beta agonist bronchodilators, the indications for these prescriptions, and to relate prescribing to the recorded levels of morbidity for specific respiratory disease. METHODS: Anonymised patient-specific prescription and diagnostic data were extracted from computerised general practice records for the 41 practices in the Northern region (total population 330,749) whose data had been validated for inclusion in a research databank. Patients were included if they were either prescribed an inhaled steroid or bronchodilator during a 12 month period, or had a recorded diagnosis of asthma, bronchitis or chronic obstructive pulmonary disease. Prescribing of inhalers per 1000 population was determined within age, sex, and diagnostic groups. Respiratory diagnosis rates within different patient groups were used to measure the underlying level of morbidity in the population. RESULTS: Inhaled anti-asthma drugs were prescribed for 5% of the study population. Prescribing prevalences peaked at ages 5-14 (steroids 40 per 1000 population; bronchodilators 68 per 1000) and at ages 65-74 (steroids 53 per 1000; bronchodilators 79 per 1000). Prescribing frequency for both drugs increased from two or three items per patient annually at age 0-14 to about six in the over 65 age group. Of the 39,424 respiratory patients 38% received inhalers and 7% only non-inhaler medication. Inhaler therapy was used in only 6% of patients with bronchitis, but in 66% of those with asthma, though the proportions varied with patient age and gender. Study practices differed in their overall levels of both inhaler prescribing and respiratory diagnosis, and had lower prescribing patterns of these drugs than other practices in the Northern region. CONCLUSIONS: Inhaled steroid and bronchodilator prescribing have age related and gender-related prevalences. Treatment for respiratory diagnoses varies with patient age and gender, and with the diagnosis. Prescribing differences between practices are attributable to variation in both diagnostic rates for respiratory disease and therapeutic intervention patterns. For asthma patients study practices show consensus in approach, perhaps illustrating the value of clear guidelines for asthma prescribing. PMID- 7831621 TI - Tuberculosis in the UK, 1994: current issues and future trends. PMID- 7831623 TI - Effect of acetazolamide and amiloride against sodium metabisulphite-induced bronchoconstriction in mild asthma. AB - BACKGROUND: Inhaled frusemide but not bumetanide, another loop diuretic, reduces bronchial responsiveness to sodium metabisulphite (MBS). To investigate whether the effect of frusemide could be mediated through mechanisms other than Na+/K+/Cl cotransporter inhibition, the effects of amiloride--an inhibitor of sodium channels in the airway epithelium--and of acetazolamide--a specific inhibitor of carbonic anhydrase--against MBS challenge were studied. METHODS: In two separate randomised double blind placebo controlled studies, 10 subjects with mild asthma attended on four separate occasions to inhale 7.5 mg amiloride or matched placebo, and 500 mg acetazolamide or placebo, immediately before MBS challenge. The concentration of MBS required to cause a 20% fall in baseline FEV1 (PC20) was measured. RESULTS: Amiloride and acetazolamide had no effect on baseline FEV1. Amiloride had no effect against MBS challenge, but acetazolamide increased -log PC20 from a mean (SE) of 0.75 (0.09) to 0.98 (0.06) representing a 0.77 (0.24) doubling dose increase. CONCLUSIONS: These results suggest that carbonic anhydrase activity in the airways, but not sodium flux, modulates bronchial responsiveness to MBS challenge. The action of frusemide is not likely to involve inhibition of carbonic anhydrase activity. PMID- 7831624 TI - Prevention of further bone mass loss by nasal calcitonin in patients on long term glucocorticoid therapy for asthma: a two year follow up study. AB - BACKGROUND: Injectable calcitonin is effective in reducing spinal bone loss in steroid-dependent asthma but side effects are frequent. In contrast, a nasal spray presentation has been shown to be effective and well tolerated in involutional osteoporosis. To test the efficacy of nasal calcitonin a two year prospective trial was conducted in 44 steroid-dependent asthmatic patients. METHODS: All patients received a calcium supplement of 1000 mg and were allocated randomly into two groups treated with either salmon calcitonin nasal spray (200 IU every other day, n = 22) or calcium alone (n = 22) for two years. All patients completed the first year of the study. Five patients in each group dropped out during the second year. In the calcitonin group one patient developed generalised pruritus and four lost steroid dependence, and in the calcium alone group five were no longer dependent on steroids. The efficacy of treatment was evaluated as follows: bone turnover assessed by biochemical markers, bone loss assessed by serial measurement of lumbar spine density, and rates of bone fractures. RESULTS: The bone mass in the calcitonin group increased by 2.7% in the first year while in the group receiving calcium alone it decreased by 2.8%; this difference was significant. Calcitonin prevented more bone loss during the second year while the calcium alone group continued losing bone mass (-7.8%). The difference between means was 0.1077 (95% CI 0.0381 to 0.1773). Three new fractures occurred in both groups. No changes in biochemical parameters were detected in either group. CONCLUSIONS: Calcitonin given intranasally increased spinal bone mass during the first year of treatment and maintained bone mass in a steady state during the second year. These results suggest that calcitonin may be a useful agent to prevent steroid-induced osteoporosis. However, the lack of effect of calcitonin on the rate of vertebral fractures does not permit its recommendation for routine use in preventing steroid-induced osteoporosis. PMID- 7831625 TI - Comparison of the effects of salbutamol and adrenaline on airway smooth muscle contractility in vitro and on bronchial reactivity in vivo. AB - BACKGROUND: The effect of adrenergic agonists in asthma depends on their net effect on microvascular leakage, mucosal oedema, vascular clearance of spasmogens, inhibition of cholinergic neurotransmission, and airway smooth muscle contractility. It has been postulated that adrenaline, by virtue of its alpha effects on the vasculature and cholinergic neurotransmission, may have additional useful properties in asthma compared with selective beta agonists such as salbutamol. METHODS: The airway effects of adrenaline (a non-selective adrenoreceptor agonist) were compared with the selective beta 2 agonist salbutamol. Their airway smooth muscle relaxant potencies and effect on histamine contraction in human bronchi in vitro were compared with their effects on airway calibre and histamine reactivity in asthmatic subjects in vivo. For the in vitro studies changes in tension were measured in response to these agents in thoracotomy specimens of human airways. In vivo the effects of adrenaline and salbutamol on airway calibre and histamine reactivity were measured in eight subjects with mild to moderate asthma in a randomised crossover study. RESULTS: Salbutamol and adrenaline had approximately equivalent airway smooth muscle relaxant potencies in vitro and bronchodilator potency in vivo. However, their effects on histamine induced contraction in vitro were significantly different from their effects on histamine reactivity in vivo. Salbutamol was less potent in vitro producing a mean (SE) 2.4 (0.15) doubling dose increase in the histamine EC20 and adrenaline a 5.2 (0.18) doubling dose increase (mean difference between salbutamol and adrenaline 2.8 doubling doses; 95% CI 1.1 to 4.5). Salbutamol had no effect on the maximal response to histamine whereas adrenaline reduced it by 54%. In contrast, salbutamol was more potent in vivo producing a mean (SE) increase in PD20 histamine of 1.84 (0.5) doubling doses whereas adrenaline was without effect increasing PD20 by only 0.06 (0.47) doubling doses (mean difference between adrenaline and salbutamol 1.78, 95% CI 0.26 to 3.29 doubling doses). CONCLUSIONS: These findings suggest that the alpha adrenergic airway effects of non-selective adrenoreceptor agonists such as adrenaline offer no additional protection against histamine-induced broncho-constriction in vivo than beta 2 selective drugs such as salbutamol, despite adrenaline providing greater protection against histamine-induced contraction in vitro. The differences between the effects of these agents in vitro and in vivo may be related to their opposing vascular effects in vivo. PMID- 7831626 TI - Influence of treatment on peak expiratory flow and its relation to airway hyperresponsiveness and symptoms. The Dutch CNSLD Study Group. AB - BACKGROUND: Despite effective treatments, the morbidity and mortality of obstructive airways disease (asthma and COPD) remains high. Home monitoring of peak expiratory flow (PEF) is increasingly being advocated as an aid to better management of obstructive airways disease. The few available studies describing effects of treatment on the level and variation of PEF have involved relatively small numbers of subjects and did not use control groups. METHODS: Patients aged 18-60 years were selected with PC20 < or = 8 mg/ml and FEV1 < 95% confidence interval of predicted normal. They were randomised to receive, in addition to a beta 2 agonist, either an inhaled corticosteroid (BA+CS), an anticholinergic (BA+AC), or a placebo (BA+PL). One hundred and forty one of these subjects with moderately severe obstructive airways disease completed seven periods of two weeks of morning and afternoon PEF measurements at home during 18 months of blind follow up. RESULTS: Improvements in PEF occurred within the first three months of treatment with BA+CS and was subsequently maintained: the mean (SE) increase in morning PEF was 51 (8) l/min in the BA+CS group compared with no change in the other two groups. Similarly, afternoon PEF increased by 22 (7) l/min. Diurnal variation in PEF (amplitude %mean) decreased from 18.0% to 10.2% in the first three months of treatment with BA+CS. Within-subject relations between changes in diurnal variation in PEF and changes in PC20 were found to be predominantly negative (median rho-0.40) but with a large scatter. Relations between diurnal variation in PEF and changes in symptom scores, FEV1, and bronchodilator response were even weaker. CONCLUSIONS: In patients with moderately severe obstructive airways disease, PEF rates and variation are greatly improved by inhaled corticosteroids. Since the relation of diurnal PEF variation with PC20, symptoms, FEV1, and bronchodilator response were all weak, these markers of disease severity may all provide different information on the actual disease state. PEF measurements should be used in addition to the other markers but not instead of them. PMID- 7831627 TI - Effect of oral theophylline on resting energy expenditure in normal volunteers. AB - BACKGROUND: The aim of this study was to investigate the contribution of regular treatment with oral theophylline to the increase in resting oxygen consumption observed in patients with chronic airflow limitation who are receiving bronchodilator therapy. METHODS: Resting oxygen consumption (VO2) and carbon dioxide production (VCO2) were measured in 10 normal subjects (six men, age 21-48 years, weight 50-85 kg) before and after 11 days of treatment with either placebo or theophylline in a double blind manner, in twice daily oral doses ensuring trough serum concentrations between 8.4 and 13.5 mg/l. An open canopy method was used to measure VO2 and VCO2 and in all test conditions this was extended for 60 minutes after an inhalation of 800 micrograms of salbutamol super-imposed on the background placebo or theophylline treatment. RESULTS: Resting VO2 and heart rate were increased during theophylline treatment compared with placebo by 6.5% and 8.4% respectively. Salbutamol inhalation transiently increased VO2, VCO2, and heart rate in all tests but this was not modified by background theophylline treatment. CONCLUSION: Oral theophylline treatment causes a sustained increase in resting oxygen consumption and heart rate but does not modify the metabolic response to acutely inhaled salbutamol. PMID- 7831628 TI - Measurement of transfer factor during constant exhalation. AB - BACKGROUND: Transfer factor of the lung for carbon monoxide (TLCO) was measured by a new method based on analysis of the ratio of the concentrations of carbon monoxide to an inert gas (methane) relative to lung volume during a constant exhalation. Since this new technique is based solely upon exhalation, anomalies associated with inspiration and breath holding do not affect results. Additionally, because prolonged breath holding is not required, measurements can readily be made in dyspnoeic patients. METHODS: Exhalation TLCO (TLCO,ex) was compared with the standard (Jones and Meade) 10 second breath holding TLCO (TLCO,bh) in 100 consecutive patients. Patients did not practise the exhalation manoeuvre prior to testing. RESULTS: The comparative results were very close; mean difference (bias) +/- standard deviation (precision) was 0.05 (0.84) mmol/min/kPa. The relation was equally strong in patients with severe pulmonary disease; for patients with FEV1 < 1.51 the mean difference was 0.21 (0.80) mmol/min/kPa. CONCLUSIONS: Since the results were essentially identical between the techniques, it seems that comparable pathophysiological factors affect TLCO during breath holding and constant exhalation. Constant exhalation may therefore be a useful alternative to the breath holding technique for clinical measurement of TLCO. PMID- 7831629 TI - Inspiratory muscle relaxation rate assessed from sniff nasal pressure. AB - BACKGROUND: Slowing of the maximum relaxation rate (MRR) of inspiratory muscles measured from oesophageal pressure (POES) during sniffs has been used as an index of the onset and recovery of respiratory muscle fatigue. The purpose of this study was to measure MRR at the nose (PNASAL MRR), to investigate its relationship with POES MRR, and to establish whether PNASAL MRR slows with respiratory loading. METHODS: Five normal subjects were studied. Each performed sniffs before and after two minutes of maximal isocapnic ventilation (MIV). In a separate session the subjects performed submaximal sniffs. POES and PNASAL were recorded during sniffs and the MRR (% pressure fall/10 ms) for each sniff was determined. RESULTS: Before MIV mean POES MRR was 8.9 and PNASAL MRR was 9.3. The mean (SD) difference between PNASAL MRR and POES MRR during a maximal sniff was 0.48 (0.34) (n = 64) and during submaximal sniffs was 0.28 (0.46) (n = 526). The subjects showed a mean decrease in sniff POES MRR of 27.4% (range 22.5-36%) after MIV and a similar reduction in sniff PNASAL MRR of 28.5% (range 24.1-41.3%). Both returned to control values within 5-10 minutes. CONCLUSIONS: PNASAL MRR reflects POES MRR over a wide range of sniff pressures, PNASAL MRR of maximal sniffs reflects POES MRR in normal subjects at rest and following MIV, so measurement of PNASAL MRR may be a useful non-invasive method for measuring inspiratory muscle MRR, thereby providing an index of respiratory muscle fatigue. PMID- 7831631 TI - Localisation of a pulmonary autoantigen in cryptogenic fibrosing alveolitis. AB - BACKGROUND--Cryptogenic fibrosing alveolitis (CFA) is believed to have an immunological pathogenesis with a persisting inflammatory reaction to an as yet unidentified pulmonary antigen(s). A high frequency of IgG autoantibodies has previously been found in the plasma of patients with CFA to an extractable 70-90 kDa lung antigen by Western blotting. Preliminary immunohistochemical studies with patient IgG had indicated that the target protein(s) might be associated with alveolar epithelial lining cells which have previously been suggested as the site of immunological attack in CFA. METHODS--In order to confirm this finding immunohistochemical analysis and Western blotting were performed on a human type II alveolar cell line (A549) using CFA patient plasma. In order to study further the distribution of the antigen, antibodies were raised in a rabbit to the partially purified 70-90 kDa CFA lung protein. RESULTS--The results showed that the human CFA autoantibody recognised a 70-90 kDa protein with a cytoplasmic distribution present in the A549 cells, confirming previous observations. The immune rabbit IgG recognised a protein of similar molecular weight by Western blotting of protein derived from lung biopsy samples of patients with CFA and A549 cells. In addition it immunoprecipitated protein(s) of this molecular weight from lung biopsy protein extracts from patients with CFA. The precipitated protein(s) were found to cross-react with the autoantibody found in the plasma of patients with CFA. Immunohistochemical analysis with immunised rabbit antibody revealed positive staining of type I and II alveolar epithelial lining cells in CFA. A similar pattern of epithelial staining was also observed with the rabbit IgG on biopsy specimens of lung from patients with sarcoidosis and control lung tissue, although this was more focal and less intense. No positive staining was seen on sections from a number of non-pulmonary tissues (colon, liver, kidney, tonsil, lymph node, skin, cervix). Cytoplasmic staining of the A549 cell line was also detected. CONCLUSIONS--The 70-90 kDa protein recognised by autoantibodies in patients with CFA is associated with pulmonary epithelial lining cells. The immune rabbit IgG produced appears to recognise antigen by Western blotting and immunohistochemical staining of lung tissue in a similar pattern to the patient autoantibodies. Immunohistochemical data obtained with this antibody suggest that the putative autoantigen against which patients with CFA mount a humoral immune response may be endogenous and specific to the lung. PMID- 7831630 TI - Concentration of amoxycillin and clavulanate in lung compartments in adults without pulmonary infection. AB - BACKGROUND: The efficacy of an antibiotic is usually predicted from serum levels and MIC90 values for likely pathogens, but in the lung tissue concentrations may be more informative. This study compares concentrations of amoxycillin and clavulanate in serum, epithelial lining fluid (ELF), alveolar macrophages, and bronchial mucosa in 15 adults. METHODS: Amoxycillin 500 mg and clavulanic acid 250 mg were given 1-2 hours before diagnostic bronchoscopy for haemoptysis or radiological abnormality. Mucosal biopsy samples were taken from macroscopically normal sites, alveolar macrophages harvested by lavage, and ELF volume derived from urea concentrations in bronchial lavage fluid and blood. Amoxycillin was assayed by inhibition of growth of Micrococcus lutea, and clavulanate (in serum, ELF, and bronchial mucosa) by inhibition of growth of Klebsiella pneumoniae; in macrophages clavulanate was measured by high performance liquid chromatography. RESULTS: The median concentrations in serum were 6.90 mg/l for amoxycillin and 5.25 mg/l for clavulanate. The median bronchial mucosal concentration of amoxycillin was 2.99 mg/l and of clavulanate was 1.65 mg/l; the median concentrations in ELF were 0.89 and 0.96 mg/l, and in macrophages 0 and 0.76 mg/l, respectively. In macrophages amoxycillin levels were undetectable in 10 of 14 subjects (71%); by contrast, only 6 of 14 subjects (43%) had no detectable clavulanate. CONCLUSIONS: Clavulanate levels exceeded quoted MIC90 values (around 0.25 mg/l) for Legionella pneumophila both in ELF and in macrophages. Amoxycillin clavulanate may therefore have a clinical role in infections with Legionella pneumophila. PMID- 7831632 TI - Activation of peripheral blood mononuclear cells in bronchoalveolar lavage fluid from patients with sarcoidosis: visualisation of single cell activation products. AB - BACKGROUND: Interstitial lung diseases are characterised by the recruitment of mononuclear cells to disease sites where maturation occurs and activation products, including lysozyme (LZM), are released. Analysis of in vitro cell culture supernatants for activation products masks the functional heterogeneity of cell populations. It is therefore necessary to examine the secretion of activation products by single cells to assess whether the activation of newly recruited mononuclear phagocytes at the sites of disease in the lung is uniform and controlled by the local microenvironment. METHODS: The reverse haemolytic plaque assay was used to evaluate, at a single cell level, the ability of bronchoalveolar lavage (BAL) fluid from seven patients with sarcoidosis to activate Ficoll-Hypaque-separated peripheral blood mononuclear cells by comparison with BAL fluid from six normal volunteers and nine patients with systemic sclerosis. Monolayers of peripheral blood mononuclear cells and sheep red blood cells were cultured either alone or in the presence of 20% (v/v) BAL fluid with a polyclonal anti-LZM antibody. LZM/anti-LZM complexes bound to red blood cells surrounding the secreting cells were disclosed following complement lysis of red blood cells and quantification of plaque dimensions using microscopy and image analysis. RESULTS: Bronchoalveolar lavage fluid from all the patients with sarcoidosis increased LZM secretion by peripheral blood mononuclear cells compared with unstimulated mononuclear cells. By contrast, BAL fluid from the other individuals had no effect on LZM secretion. CONCLUSIONS: Single cells activated by BAL fluid can be evaluated by the reverse haemolytic plaque assay. BAL fluid from patients with sarcoidosis, but not from patients with systemic sclerosis or normal individuals, contains components capable of activating mononuclear phagocytes to secrete lysozyme. PMID- 7831633 TI - Comparison of nucleolar organiser regions and DNA flow cytometry in the evaluation of pleural effusion. AB - BACKGROUND: In conventional cytological diagnosis of pleural effusions the assessment of morphological features plays an important part. However, false negative and false positive results may occur. In this study conventional cytology was compared with flow cytometric DNA analysis and the argyrophil staining technique for nucleolar organiser regions (AgNOR) to characterise benign and malignant effusions. METHODS: Pleural effusions from 71 patients (38 with benign lung disease, 33 with proven adenocarcinoma of lung) were studied by conventional cytology, flow cytometric DNA analysis, and the AgNOR technique. Tumour cell ploidy was determined by flow cytometry. In an attempt to detect the cell proliferative state, flow cytometric S phase fraction and the AgNOR technique were used. The correlations among conventional cytology, flow cytometric DNA ploidy, S phase fraction analysis, and nucleolar organiser regions were investigated. RESULTS: All the 38 benign pleural effusions were diploid. There were 17 (52%) aneuploid and 16 (48%) diploid malignant pleural effusions. Based on these results this type of DNA analysis had a sensitivity of 52% and a specificity of 100%. The mean (SD) numbers of flow cytometric S phase fractions of benign and malignant cases were 5.32 (1.67)% and 12.45 (3.93)% respectively. The mean numbers of S phase fractions of diploid malignant cases were higher than diploid benign cases. In each case the number of AgNORs was counted in 100 cells. The mean number of AgNOR dots per nucleus was 12.57 (3.64) for malignant pleural effusion cells and 3.96 (1.39) for benign pleural effusion cells. The mean number of AgNOR dots was 14.45 (3.36) for aneuploid malignant pleural effusion cells and 10.57 (2.82) for diploid malignant pleural effusion cells. The AgNOR numbers were higher in diploid malignant cells than in diploid benign cells. There was a significant correlation between the S phase fraction determined by flow cytometry and the mean number of AgNORs per nucleus in malignant cases. CONCLUSIONS: Both flow cytometry and the AgNOR methods provide comparable measurements in the diagnosis of pleural effusion. The study also indicates that the AgNOR method, which is rapid and easy to perform, may be a useful adjunct to flow cytometry, S phase fraction analysis and conventional cytology in the routine diagnosis of malignant pleural effusion. PMID- 7831634 TI - Tuberculous pleural effusion: experience with six months of treatment with isoniazid and rifampicin. AB - BACKGROUND: Tuberculous pleurisy is associated with small numbers of bacteria. Due to the low rate of primary resistance to antituberculous drugs a two-drug regimen was used to treat the condition. METHODS: Patients received isoniazid 5 mg/kg and rifampicin 10 mg/kg daily for six months. Clinical, radiological, and haematological assessments were performed during treatment and patients were followed up for a median period of 41 (range 6-96) months. RESULTS: One hundred and thirty patients were studied with a mean age of 27 (range 11-53) years. Seven were withdrawn due to parenchymal disease and eight were lost to follow up during the treatment period. Side effects during treatment were frequent (20.7%), but only three patients required a change in medication. No treatment failures were observed. One hundred and fifteen patients completed therapy and were followed up for 41 (range 6-96) months with no evidence of a relapse. CONCLUSIONS: Tuberculous pleurisy responds well to a two-drug regimen of antituberculous therapy given for six months. PMID- 7831635 TI - Volumatic usage: some generic salbutamol metered dose inhalers can be used. AB - BACKGROUND: The 30 minute and 24 hour post-inhalation urinary excretion of salbutamol represents the relative amount of drug deposited in the lungs and total systemic absorption, respectively. Using this method two metered dose inhalers used with a Volumatic (Allen and Hanburys Ltd, UK) large volume spacer have been compared. METHOD: Eleven healthy volunteers inhaled 4 x 100 micrograms salbutamol from either a generic salbutamol (Baker Norton, UK) or Ventolin (Allen and Hanburys Ltd, UK) metered dose inhaler with a Volumatic. The order of administration was randomised with a seven day washout period. Urine samples were collected for 0-30 minutes and then pooled up to 24 hours after inhalation. RESULTS: The mean (SD) urinary salbutamol excretion 30 minutes after inhalation with the metered dose inhalers used with the Volumatic was 22.22 (4.63) and 21.30 (5.91) micrograms for the Baker Norton and Ventolin respectively, with a mean difference (95% confidence interval (CI)) of 0.92 (-0.65 to 2.49) micrograms. Similar amounts were excreted up to 24 hours after the dose with a mean (SD) urinary excretion of 116.1 (24.3) micrograms and 114.8 (22.3) micrograms, respectively, and a mean difference (95% CI) of 1.22 (-20.39 to 22.84) micrograms. CONCLUSION: Inhalations from generic salbutamol (Baker Norton) and Ventolin metered dose inhalers with a Volumatic inhalation aid deliver similar amounts of drug to the lungs and the total systemic absorption from the two products is the same. PMID- 7831636 TI - Assessment of hyperinflation in children with cystic fibrosis. AB - BACKGROUND: Radiological estimates of hyperinflation are used in several clinical and radiographic scoring systems for cystic fibrosis, but it is not known if these estimates of hyperinflation are related to measured total lung capacity. METHODS: Comparison was made of independent clinical estimates of hyperinflation from chest radiographs with objective plethysmographic and radiographic measurements of total lung capacity in 25 children with cystic fibrosis. RESULTS: There was good agreement between plethysmographic and radiographic measurements. Clinical estimation correctly predicted the extremes of hyperinflation, but grading was no more than 50% accurate in all other groups. CONCLUSION: The degree of hyperinflation cannot be estimated by inspecting chest radiographs in many children with cystic fibrosis. This does not invalidate the scoring systems, but suggests that a better term than "hyperinflation" should be sought. PMID- 7831639 TI - Mesenchymal cystic hamartoma of the lung: a rare cause of relapsing pneumothorax. PMID- 7831637 TI - Effects of inhaled lignocaine and adrenaline on capsaicin-induced cough in humans. AB - BACKGROUND: The hypothesis that adrenaline can augment and/or prolong the antitussive effect of nebulised lignocaine was examined. METHODS: The effect of inhaled lignocaine alone (20 mg) and in combination with adrenaline (400 micrograms) was studied on capsaicin-induced cough in 10 healthy subjects. RESULTS: Cough was significantly reduced between five and 25 minutes by lignocaine. Adrenaline alone had no inhibitory effect and it neither augmented nor prolonged the antitussive effect of lignocaine. The subjective anaesthesia by lignocaine was short lasting (less than 15 minutes) and not altered by adrenaline, suggesting different sensory mechanisms for anaesthesia and cough suppression. Plasma concentrations of lignocaine were low (< 30 ng/ml), not altered by adrenaline, and did not correlate with the local anaesthetic or the antitussive effect. CONCLUSIONS: Lignocaine acts locally in the oropharynx and airways and adrenaline does not alter the effect or absorption of nebulised lignocaine on the human respiratory mucosa. PMID- 7831638 TI - Contribution of multiple inert gas elimination technique to pulmonary medicine- 4. Gas exchange abnormalities in pulmonary vascular and cardiac disease. PMID- 7831640 TI - Aortic valvulitis complicating Wegener's granulomatosis. AB - In a case of Wegener's granulomatosis aortic valve replacement was performed for worsening congestive cardiac failure secondary to aortic incompetence. Two paravalvular lesions and an isolated intraleaflet deficiency of the non-coronary cusp were identified at operation. Histological changes were consistent with a connective tissue disease. PMID- 7831641 TI - Use of a Heimlich flutter valve for pneumothorax in cystic fibrosis. AB - The use of a Heimlich flutter valve in an adult patient with cystic fibrosis with hypercapnic respiratory failure which allowed resolution of a persisting pneumothorax after failure of conventional tube drainage is reported. The patient was managed at home and avoided surgical pleurodesis which could have jeopardised transplantation at a later date. PMID- 7831642 TI - Empyema and mediastinitis complicating retropharyngeal abscess. AB - A 21 year old man with a retropharyngeal abscess complained of right sided chest pain, and chest radiography and thoracocentesis revealed an empyema. A computed tomographic scan of the chest showed a posterior mediastinal abscess communicating with the right pleural cavity. Emergency thoracotomy was performed and the mediastinal abscess and empyema were drained. PMID- 7831643 TI - Respiration in dystrophia myotonica. PMID- 7831644 TI - Sympathomimetics and airway hyperreactivity. PMID- 7831645 TI - Bronchodilators in COPD. PMID- 7831646 TI - Bioavailability of salbutamol. PMID- 7831647 TI - A database of recombinant wild-type and mutant serpins. PMID- 7831648 TI - Characterization of partial gene deletions in type III von Willebrand disease with alloantibody inhibitors. AB - von Willebrand factor gene deletions were characterized in four patients with severe type III von Wilebrand disease and alloantibodies to von Willebrand factor. A PCR-based strategy was used to characterize the boundaries of the deletions. Identical 30 kb von Willebrand factor gene deletions which include exons 33 through 38 were identified in two siblings of one family by this method. A small 5 base pair insertion (CCTGG) was sequenced at the deletion breakpoint. PCR analysis was used to detect the deletion in three generations of the family, including two family members who are heterozygous for the deletion. In a second family, two type III vWD patients, who are distant cousins, share an approximately 56 kb deletion of exons 22 through 43. The identification and characterization of large vWF gene deletions in these type III vWD patients provides further support for the association between large deletions in both von Willebrand factor alleles and the development of inhibitory alloantibodies. PMID- 7831649 TI - Comparison of once-daily subcutaneous Fragmin with continuous intravenous unfractionated heparin in the treatment of deep vein thrombosis. AB - Two hundred and four consecutive patients with venographically confirmed deep vein thrombosis (DVT) were randomised either to a low molecular weight heparin, Fragmin, administered subcutaneously (s.c.) once daily as a fixed dose of 200 IU anti-factor Xa/kg or to continuous intravenous infusion of unfractionated heparin (UFH). The UFH dose was adjusted to maintain the activated partial thromboplastin time between 1.5 and 3.0 times the upper limit of the reference value at each centre. Fragmin or UFH was given for a minimum of 5 days until anticoagulation with warfarin, given from day 1, was established (i.e. an Internation Normalised Ratio, of 2.0-3.0). A second venogram was obtained after Fragmin or UFH treatment. There were no significant differences in the change in mean Marder score before and after treatment between the two treatment groups, irrespective of thrombus localisation. No major bleeding events, symptomatic pulmonary embolism, symptomatic thrombosis progression or death occurred during hospitalisation. Eight documented venous thromboembolic events occurred before the follow-up visit 6 months after randomisation: 5 in patients treated with Fragmin and 3 in those treated with UFH. Six of these events occurred after cessation of warfarin treatment. In conclusion Fragmin given s.c. once daily in a fixed dose adjusted for body weight, is no less effective or safe than a continuous infusion of UFH in the initial treatment of acute DVT. PMID- 7831650 TI - Low molecular weight heparin versus warfarin in the prevention of recurrences after deep vein thrombosis. AB - To evaluate the role of low-molecular weight heparin (LMWH) as an alternative to oral anticoagulants in the prevention of recurrent venous thromboembolism, we compared in a randomized trial conventional warfarin treatment with a three-month course of enoxaparin 4000 anti-Xa units once a day subcutaneously. 187 patients with symptomatic deep-vein thrombosis (DVT), diagnosed by strain-gauge plethysmography plus D-dimer latex assay and confirmed by venography in most cases, were treated with full-dose subcutaneous heparin for ten days and then randomized to secondary prophylaxis. During the 3-month treatment period, 6 of the 93 patients who received LMWH (6%) and 4 of the 94 patients on warfarin (4%) had symptomatic recurrence of venous thromboembolism confirmed by objective testing (p = 0.5; 95% confidence interval [CI] for the difference, -3% to 7%). Four patients in the LMWH group had bleeding complications as compared with 12 in the warfarin group (p = 0.04; 95% CI for the difference, 4% to 14%). In the 9 month follow-up period, during which 34 patients on warfarin prolonged treatment for other 3 months and 14 up to one year, 10 patients in the enoxaparin group and 4 patients in the warfarin group suffered a documented recurrence of venous thromboembolism. Of these 14 late recurrences, just one occurred in patients with postoperative DVT. After one year there were 16 recurrences (17%) in the LMWH group and 8 (9%) in the warfarin group (p = 0.07; 95% CI for the difference, 1% to 16%).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7831651 TI - Homozygous antithrombin deficiency: report of two new cases (99 Leu to Phe) associated with arterial and venous thrombosis. AB - Inherited antithrombin deficiency is associated with an increased risk of thrombosis, primarily venous rather than arterial. Most affected individuals have inherited only a single copy of an abnormal antithrombin (AT) gene. Homozygously affected individuals, although rare, have a severe thrombotic history of early onset and often affecting the arteries. We report two new cases of type II HBS (heparin binding site) deficiency in which the propositi are homozygous for the previously reported mutation 99 Leu to Phe, and who have a severe thrombotic history. These cases are considered alongside existing homozygote and compound heterozygote cases. PMID- 7831652 TI - Hereditary protein C deficiency associated with mutations in exon IX of the protein C gene. AB - This report describes five families with symptomatic hereditary protein C deficiency. Using a polymerase chain reaction (PCR)-based method, the entire coding sequence and intron-exon boundaries of the protein C gene was amplified from genomic DNA. In each family a single point mutation in the protein C gene was identified. Two unrelated families were found to share the same mutation, while the other three had different mutations. In the first two families with type I protein C deficiency the normal cytosine residue at nucleotide position 8551 in the protein C gene was replaced by thymidine leading to substitution of the normal proline residue at amino acid position 279 by leucine. In the third family with type I deficiency a previously undescribed mutation was identified. In this family the guanosine residue at position 8559 was replaced by adenosine (glycine 282 substituted by serine). In the fourth family, also with type I deficiency, guanosine 8589 was replaced by adenosine (glycine 292 substituted by serine). The fifth family had type II deficiency and in affected members cytosine 8769 was replaced by thymidine (arginine 352 substituted by tryptophan). All these mutations lead to amino acid substitutions in the serine protease domain of the mature protein. All were able to be confirmed by restriction enzyme analysis of PCR-derived DNA. In addition the novel mutation at nucleotide position 8559 was also demonstrable using single strand conformation polymorphism (SSCP) analysis of PCR-derived DNA. These mutations were likely examples of deamination of methylated cytosine occurring in cytosine-phosphate-guanosine (CpG) dinucleotide sequences. These findings confirm the genetic heterogeneity of hereditary protein C deficiency in these families. PMID- 7831653 TI - Prevalence, follow-up and clinical significance of the anticardiolipin antibodies in normal subjects. AB - To date very few studies that analyze the prevalence of anticardiolipin antibodies (ACA) in healthy subjects have been reported. No data based on a systematic analysis of normal subjects with positive ACA is available. The aim of the present study was to evaluate the prevalence of ACA; its clinical significance and relationship to the lupus anticoagulant (LA) and other autoimmune parameters in an apparently healthy population. 552 normal blood donors from a blood bank were randomly selected. ACA positive donors who consented were monitored over a period of twelve months and tested every three months. ACA (IgG and IgM isotypes) were quantitated by enzyme linked immunoassay (ELISA). The prevalence for IgG ACA in our donor population was estimated to be 6.5%, and 9.4% for IgM ACA, which is similar to the one previously reported for IgG and slightly higher for IgM. It is worth noting that in our study ACA positive donors exhibited a progressive negativization. Eight donors with IgG ACA and seven with IgM ACA remained positive for nine months. Five donors with IgG ACA and four with IgM ACA had family history of thromboembolic disease. One donor with IgG ACA and two with IgM ACA had had unexplained miscarriages in the past. We did not find any relationship between ACA and LA, nor between ACA positivity and the clinical and laboratory data studied. Pseudopositivity for lues was not found. No thrombotic event occurred in donors that were positive for ACA during the 12-month follow-up. PMID- 7831654 TI - CD4+ counts before and after switching to monoclonal high-purity factor VIII concentrate in HIV-infected haemophilic patients. AB - Allogenic proteins that contaminate intermediate purity clotting factor concentrates may activate the immune system of HIV-infected haemophilic patients. In 37 haemophilic patients infected with HIV who had originally been treated with intermediate purity factor VIII concentrate and then changed to monoclonally purified high purity factor VIII concentrate the rates of CD4+ decline (10(9)/l per year) were 0.06 before and 0.02 after a switch to high purity products (p = 0.01). The median follow-up of patients after the switch to high purity products was 1.7 years (range 0.2 to 3 years). This significant change in the rate of CD4 decline was independent of the starting CD4 count, age and antiretroviral therapy. This result is consistent with those from randomised trials of the introduction of high-purity concentrate. Given the strong association between the CD4+ count and survival, treatment with high purity rather than intermediate purity clotting factor concentrate may confer a survival benefit for HIV-infected haemophilic patients. PMID- 7831655 TI - Changes in haematological indices, blood viscosity and inhibitors of coagulation during treatment of endometriosis with danazol. AB - The effects of treatment with danazol (600 mg daily) on haemostatic and haematological function were investigated in 18 pre-menopausal women with endometriosis. Blood samples were taken at 2 pre-treatment visits, at 6, 12 and 24 weeks on treatment, and at 6 weeks after discontinuation of the drug. Haemoglobin, red cell count, haematocrit and platelet count all rose significantly during treatment with danazol (p < 0.01 vs. baseline). Plasma fibrinogen levels fell significantly (p < 0.01), while whole blood viscosity increased during treatment and remained significantly elevated at follow-up. The prothrombin time shortened, but remained within normal limits, and there were no significant changes in factor VII:C, VIIa, or fibrinopeptide A. No significant changes were found in platelet function. Plasma B-beta 15-42 increased significantly. Functional levels of protein C, protein S, and antithrombin III, all rose significantly, above the normal range, while C4b-binding protein levels fell. We conclude that the observed changes in coagulation inhibitors and fibrinolytic activity may be considered beneficial in the context of venous thromboembolism. The rheological effects, however, indicate a degree of caution in the use of the drug in individuals considered to be at risk from arterial cardiovascular disease. PMID- 7831656 TI - Activation of blood coagulation after abrupt or stepwise withdrawal of oral anticoagulants--a prospective study. AB - The occurrence of a "rebound hypercoagulable state" in patients after dicontinuation of oral anticoagulants is still a matter of debate and no definite recommendation can be made on the best procedure for anticoagulant withdrawal. The present study investigated the changes in the levels of markers of activated blood coagulation in 32 patients (pts) in whom warfarin treatment (for venous thromboembolic disease) was randomly withdrawn abruptly (n = 17, group A) or gradually (n = 15, group B: 2/3 of initial dose the 1st week, 1/3 the 2nd weeks and nothing from the 3rd week on). Blood was sampled at baseline, once a week for the first three weeks and after 2 months. At the 1st week group A had significantly higher F1+2 and TAT values (p < 0.001); at the 2nd week F1+2 levels remained higher (p < 0.05) though INR values were not different from those of group B. After baseline, higher than normal F1+2 levels were recorded in 32/66 (48%) controls in group A vs 15/60 (25%) in group B (p < 0.01); at the 2nd week, 10/17 (59%) patients in group A vs 1/15 (7%) in group B still had higher than normal F1+2 levels (p < 0.01). The values of areas under curve (AUC) and maximum concentrations of all variables were not statistically different in the two groups; however, very high levels were observed in a few cases of group A. Thrombotic events (one DVT recurrence and one thrombophlebitis in a varicose vein) occurred in 2 pts of group A, both with high F1+2 and TAT AUC values.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7831658 TI - Displacement of fibrin-bound thrombin by r-hirudin precludes the use of 131I-r hirudin for detecting pulmonary emboli in the rabbit. AB - Pulmonary emboli are detectable by filling defects in the pulmonary vasculature upon pulmonary angiography. Emboli derived from venous thrombi are rich in fibrin to which thrombin remains bound. Hirudin, a specific thrombin inhibitor, binds to thrombin to yield a 1:1 stoichiometric complex. We examined whether 131I recombinant hirudin (r-hirudin) could be used to detect pulmonary emboli in rabbits. Clots were formed by re-calcifying rabbit plasma in vitro, and then injected (0.034 ml) into a femoral vein to lodge in the lungs. 131I-r-hirudin (29 +/- 4 microCi/kg) was injected intravenously but emboli could not be detected by gamma camera in real time. Post-mortem analysis of lung tissue showed that 131I-r hirudin did not associate with emboli prepared with 125I-fibrin. Because of these findings, we used different techniques to look at the binding of hirudin to plasma clots. Clots formed in vitro were incubated with 131I-r-hirudin in the presence of equimolar amounts of 125I-albumin; specific binding of 131I-r-hirudin was not observed. Experiments with immobilized fibrin(ogen) showed that 125I-r hirudin did not bind to and remain with fibrin-bound 131I-thrombin but did lead to the inactivation and displacement of up to 70% of bound thrombin as r-hirudin thrombin complex; residual thrombin bound to fibrin remained active. Thus, released r-hirudin-thrombin complex is probably cleared rapidly from the region of the embolus in vivo; radioiodinated r-hirudin may not, therefore, be useful as a marker for detecting emboli. PMID- 7831659 TI - Curvilinear relations between age and hemostatic parameters in Chinese. AB - The role of hemostatic factors in the pathogenesis of cardiovascular disease has gained much attention recently. Information about hemostatic factors, and their age patterns is sparse for orientals. With the data collected in the Cardiovascular Disease Risk Factor Two-township Study in Taiwan, this study shows that, in general, the older the age, the stronger the tendency toward thrombosis. With advancing age, prothrombin time, activated partial thromboplastin time, and antithrombin-III level decreased steadily; but mean values of fibrinogen, factor VIIc, and factor VIIIc increased. Gender differences in the age patterns of the above factors are carefully described. Curvilinear relations between hemostatic factors and age were demonstrated for adults aged 18 and above for all hemostatic factors studied. This curvilinearity should be taken into consideration when adjusting for the effect of age in data analysis to avoid residual confounding, particularly when the age range of the study subjects is wide. PMID- 7831657 TI - Direct thrombin inhibition with Rec-hirudin CGP 39393 as prophylaxis of thromboembolic complications after total hip replacement. AB - Hirudin is an anticoagulant originally extracted from the leech Hirudo medicinalis. Using recombinant DNA technology a new compound, recombinant desulphato hirudin CGP 39393 has now been produced. The aim of this study was to determine the maximum tolerated dose in patients undergoing elective hip replacement. This open safety trial represents, to our knowledge, the first experience of recombinant hirudin in orthopedic patients. In this study 48 patients undergoing primary total hip replacement were included and the safety of subcutaneous injections of 10, 15, 20 and 40 mg CGP 39393 twice daily, was evaluated. Prophylaxis was started immediately pre-operatively and continued for 8-10 days. A mandatory bilateral phlebography was performed at the end of the prophylactic treatment period and a clinical follow-up was done 6 weeks after surgery. A major bleeding event occurred in the first 3 patients receiving 40 mg CGP 39393 b.i.d. and the prophylaxis regimen at this dosage level was therefore discontinued. Median values of total blood loss and requirements of blood transfusion in the patients receiving 10-20 mg CGP 39393 were similar to those reported in previous studies on total hip replacement performed at the same centre, using other prophylactic drugs. Deep vein thrombosis (DVT) was confirmed by phlebography in 5 out of 12 patients in the 10 mg group (41.7%, 95% confidence limits [CL]: 15.2-72.3%), 1 out of 11 patients in the 15 mg group (9.1%, CL: 0.23 41.3%) and 2 out of 20 patients in the 20 mg group (10.0%, CL: 1.2-31.7%) during the prophylaxis period. CGP 39393 was safe and well tolerated, when administered as subcutaneous injections of 10-20 mg twice daily. The dose level of 40 mg CGP 39393 twice daily resulted in serious disturbance of the hemostasis in patients after hip prosthesis surgery. PMID- 7831660 TI - Properties of fibrinogen cleaved by Jararhagin, a metalloproteinase from the venom of Bothrops jararaca. AB - Haemorrhagic metalloproteinases from Bothrops jararaca and other venoms degrade vessel-wall and plasma proteins involved in platelet plug and fibrin clot formation. These enzymes also cause proteolytic digestion of fibrinogen which has been suggested to cause defective platelet function. Fibrinogen degradation by jararhagin, a metalloproteinase from B. jararaca, and the effect of jararhagin fibrinogenolysis on both platelet aggregation and fibrin clot formation were investigated. Jararhagin was found to cleave human fibrinogen in the C-terminal region of the A alpha-chain giving rise to a 285-290 kDa fibrinogen molecule lacking the A alpha-chain RGD 572-574 platelet-binding site. Platelet binding and aggregation of ADP-activated platelets is unaffected by this modification. This indicates that the lost site is not essential for platelet aggregation, and that the remaining platelet binding sites located in the N-terminal portion of A alpha chains (RGD 95-97) and the C-terminal of gamma chains (dodecapeptide 400-411) are unaffected by jararhagin-digestion of fibrinogen. Fibrin clot formation with thrombin of this remnant fibrinogen molecule was defective, with poor polymerization of fibrin monomers but normal release of FPA. The abnormal polymerization could be explained by the loss of one of the two complementary polymerization sites required for side-by-side association of fibrin protofibrils. Jararhagin-induced inhibition of platelet function, an important cause of haemorrhage in envenomed patients, is not caused by proteolysis of fibrinogen, as had been thought, and the mechanism remains to be elucidated. PMID- 7831661 TI - Relation of plasma coagulation factor VII and fibrinogen to carotid artery intima media thickness. AB - Plasma clotting factor VII and plasma fibrinogen have been claimed as independent risk factors for occlusive cardiovascular disease. The aim of this study was to investigate whether these coagulation parameters affect early atherosclerosis, additional to their possible effect on arterial thrombosis. We used high resolution quantitative ultrasonography to measure carotid intima-media thickness in 121 healthy volunteers, aged 18 to 56 years. It has previously been demonstrated that an increased artery wall thickness is seen in advanced atherosclerosis. To validate our methodology for relatively young individuals, we assessed the association of intima-media thickness with the risk-factor status of our subjects, by including classical cardiovascular risk factors, e.g. age, sex, serum cholesterol, smoking habits and blood pressure. Thereafter, we studied the effect of factor VII and fibrinogen plasma levels on carotid intima-media thickness, as well as that of polymorphisms of the factor VII and fibrinogen genes. All classical risk factors except smoking and family history were associated with intima-media thickness. When adjusted for by multivariate linear regression analysis, age, blood pressure and cholesterol appeared to be independent determinants of intima-media thickness. Factor VII and fibrinogen levels showed no association in multivariate analysis with intima-media thickness. We conclude that artery wall thickness measurement by ultrasound is a useful tool to investigate the role of clotting factors in early atherosclerosis. Factor VII and fibrinogen levels in young and middle-aged volunteers have no association with early artherosclerotic vessel wall changes. PMID- 7831662 TI - Multicenter evaluation of a kit for activated protein C resistance on various coagulation instruments using plasmas from healthy individuals. The APC Resistance Study Group. AB - Recently a new hemostatic disorder has been described which appears to be an important risk factor for familial thromboembolism. The disorder is characterized by a poor anticoagulant response to activated Protein C (APC) and has been shown to be due to lack of an APC cofactor activity which is a property of factor V. A kit for determining the response of plasma samples towards addition of APC in an APTT-based assay--COATEST APC Resistance-has been evaluated on 35 coagulation instruments in a multicenter study involving 32 laboratories. A lyophilized normal plasma and identical plasma aliquotes from 20 individuals, one of whom had a borderline resistance to APC, were analysed in each laboratory and the sensitivity of each plasma to APC was determined as the ratio between the clotting times obtained in the presence and absence of APC (APC ratio). The plasma from the individual with a borderline resistance to APC activity was correctly classified as the lowest responder in each laboratory, with an APC ratio in the range 1.6-2.4. In comparison, plasmas from individuals with a pronounced response to APC activity resulted in APC ratios above 3.4 in most cases. Interestingly, although the actual APT time for a plasma from a given individual showed a more than 10s difference due to the type of instrumentation used, the variation in the APC ratio was limited. A similar discrimination was also obtained from evaluation of the actual prolongation of the clotting time in the presence of APC.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7831663 TI - Results of a multicenter study assessing the status of standardization of a recombinant thromboplastin for the control of oral anticoagulant therapy. AB - An international collaborative study involving 20 laboratories was undertaken to evaluate the status of standardization of a commercial recombinant thromboplastin. The results show that the reagent fulfills the WHO requirements for thromboplastin calibration against two International Reference Preparations (IRP) from different species, because there was a linear relationship of log transformed prothrombin times as measured by the recombinant reagent and the two IRPs in normal individuals and patients stabilized on oral anticoagulants. The regression lines drawn through the patient data points passed through the normal data points in the majority of instances. The average ISI values for three different batches were close to unity. On the average, the ISI value calculated against BCT/253 (human, plain) was slightly smaller than that against RBT/79 (rabbit, plain). The between laboratory precision of calibration (CV = 5-6%) did not change whether BCT/253 or RBT/79 was used, whereas it was substantially improved when the calibrations of batches 2 and 3 were performed against batch 1, arbitrarily taken as standard (CV < or = 1.7%). Statistical analysis to test for differences between slopes revealed no significant between-batch differences in 16 of 20 laboratories. However slight differences for the third batch (2.8% less than the average ISI value of batches 1 and 2) leave room for further improvement in the standardization of the reagent. PMID- 7831664 TI - Pharmacological properties of CY 216 and of its ACLM and BCLM components in the rabbit. AB - This study compares some in vivo pharmacological properties of CY 216 and of its ACLM and BCLM components having a molecular weight above and below 5.4 kDa respectively. The anti-factor Xa/antithrombin ratio of these compounds determined in a rabbit plasma system were 2.5 and 1.2 for CY 216 and ACLM respectively while BCLM was devoid of anti-thrombin effect. After bolus intravenous injection, continous infusion and subcutaneous administration, the clearances of anti-factor Xa activity generated by ACLM were, on the average, 2 and 1.5 times higher than those generated by BCLM and CY 216 respectively. The clearances of the anti thrombin activity were comparable for CY216 and ACLM, and higher than those of the antifactor Xa activity. The duration of the antithrombotic effect was investigated in the Wessler model after a single subcutaneous injection of 1000 anti-factor Xa units of one of the compounds. Using thromboplastin as thrombogenic stimulus, the most efficient agent was ACLM and the antithrombotic activity was essentially correlated to the circulating anti-thrombin activity. Using human serum as thrombogenic stimulus, ACLM and BCLM were more efficient than CY 216 and the antithrombotic activity was mainly correlated to the anti factor Xa activity. The ability of the 3 compounds to inhibit venous thrombosis growth was compared: they were found equipotent and the antithrombotic effect was independent of the anti-thrombin activity. The prohaemorrhagic properties were compared in the rabbit ear model. The activity of the 3 compounds were comparable and significantly less prohaemorrhagic than unfractionated heparin.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7831665 TI - Characterisation of persistent anti-Xa activity following administration of the low molecular weight heparin enoxaparin sodium (Clexane). AB - It is widely reported that persistent anti-Xa activity follows administration of low molecular weight heparins. To identify the effectors of this activity we have injected 125I-labelled Enoxaparin sodium into rabbits and subsequently analysed the circulating radiolabelled material and anti-Xa activity by affinity and size exclusion chromatography. Antithrombin III-binding material derived from the injected drug was responsible for all the anti-Xa amidolytic activity. At early times after injection additional anticoagulant activity which was largely attributable to tissue factor pathway inhibitor was measured by the Heptest clotting assay after removal of glycosaminoglycans from plasma samples. Small radiolabelled fragments, including penta/hexasaccharide with affinity for antithrombin III, were detectable in the circulation 1 week later, and sulphated oligosaccharides persisted for 3-4 weeks. Significant quantities of radiolabel remained in the liver and kidney several weeks post-injection; these organs may sequester some of the injected drug and give rise to circulating biologically active material by degradation and secretion of catabolic products into the plasma. PMID- 7831666 TI - In vivo release of tissue-type plasminogen activator across the human forearm during mental stress. AB - We have previously shown that plasma levels of endothelium-derived tissue-type plasminogen activator (t-PA) increase during mental stress. The aim of the study was to investigate in vivo release in an intact human muscle vascular bed. Eleven healthy young males (22-36 yrs) were studied at rest and during 10 min of mental stress (forced arithmetic). Net release or uptake were assessed by arterio-venous (AV) concentration gradients across the forearm of t-PA antigen and t-PA activity, and plasminogen activator inhibitor antigen type 1 (PAI-1). Forearm blood flow was measured by venous occlusion plethysmography. At rest, there was a positive AV-difference of t-PA activity across the forearm indicating a net release of t-PA activity of approximately 3.7 fmol x min-1 x 100 ml-1 (Wilcoxon's signed rank test vs 0, p = 0.01). However, t-PA antigen showed a variable release pattern. On the average, there was a net release of 0.17 ng x min-1 x 100 ml-1 after 60 min of rest (Wilcoxon vs 0, p = 0.07). PAI-1 antigen showed net release at rest. In response to stress, forearm blood flow increased from 1.9 to 2.9 ml x min-1 x 100 ml-1 (ANOVA, p = 0.007), and net release of t-PA activity increased to 9.8 fmol x min-1 x 100 ml-1 (ANOVA, p = 0.01 compared with rest). Arterial and venous plasma t-PA levels also increased significantly during stress (ANOVA, p < 0.01). t-PA antigen showed a similar but less pronounced release pattern during stress.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7831667 TI - Association of increased fibrin turnover and defective fibrinolytic capacity with leg atherosclerosis. The PLAT Group. AB - Patients with peripheral arterial disease have a high risk of death from cardiovascular events. As defective fibrinolysis associated with leg atherosclerosis has been suggested as a predisposing factor, we sought a relation among decreased fibrinolysis, the presence of leg atherosclerosis and the incidence of thrombotic events in a case-control study nested in the PLAT. Fifty eight patients with coronary and/or cerebral atherothrombotic disease, free of leg atherosclerosis at Doppler examination, were compared with 50 atherosclerotic patients with leg involvement. High D-dimer (153.0 vs 81.3 ng/ml, p < 0.001) and tPA antigen before venous stasis (14.4 vs 11.8 ng/ml, p < 0.03), and low tPA antigen (6.7 vs 15.6 ng/ml, p < 0.01) and fibrinolytic activity released after venous stasis (fibrinolytic capacity: 113.2 vs 281.4 mm2, p < 0.001) were found in patients with leg atherosclerosis. D-dimer and fibrinolytic capacity, in addition to age, were selected by stepwise discriminant analysis as characterizing patients with leg atherosclerosis. Moreover, higher D-dimer and tPA inhibitor characterized patients with leg atherosclerosis who subsequently experienced thrombotic events. These findings constitute evidence of high fibrin turnover and impaired fibrinolytic potential in patients with leg atherosclerosis. Thus impaired fibrinolysis may contribute to the prothrombotic state in these patients. PMID- 7831668 TI - On the immunogenicity of recombinant staphylokinase in patients and in animal models. AB - Streptokinase and staphylokinase, the presently available thrombolytic agents of bacterial origin, are immunogenic in man; their use may cause allergic reactions and/or refractoriness to renewed administration. Infusion of 2 to 10 mg of recombinant staphylokinase (STAR) in 20 patients with acute myocardial infarction or peripheral arterial occlusion induced IgG-related neutralizing activity in plasma with a lag phase of 10 to 12 days, from a baseline of 0.2 +/- 0.06 microgram STAR neutralized per ml plasma (mean +/- SEM) to a maximum of 30 +/- 6.2 micrograms/ml after 3 to 9 weeks, which persisted at a level of 14 +/- 5.8 micrograms/ml after 18 months (n = 4). In 4 baboons with a 125I-fibrin labeled clot in an extracorporeal arteriovenous loop, i.v. administration of 63 micrograms/kg STAR over 1 h, repeated at weekly intervals, induced a progressive increase of STAR-neutralizing activity (from 0.05 +/- 0.1 microgram/ml at baseline to 4.8 +/- 1.5 micrograms/ml at week 6), which was paralleled by a reduction of in vivo clot lysis (from 60 +/- 7% to 8 +/- 3%). After temporary discontinuation of STAR-administration, neutralizing activity reverted to baseline within 7 weeks, whereafter the sensitivity of in vivo clot lysis to STAR was restored. In rabbits, i.v. administration of 250 micrograms/kg STAR over 1 h, repeated at weekly intervals, also induced a progressive increase of STAR neutralizing activity (from 0.5 +/- 0.2 microgram/ml at baseline to 6.4 +/- 1.1 micrograms/ml at week 6), which was paralleled by a reduction of in vivo clot lysis (from 68 +/- 3% to 31 +/- 7%).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7831669 TI - Platelet activation induced by interleukin-6: evidence for a mechanism involving arachidonic acid metabolism. AB - The effect of IL-6 on in vitro platelet function was investigated. Platelet-rich plasma (PRP) incubated with IL-6 showed a dose dependent enhancement of agonist induced maximum aggregation (AIMA) and secretion of thromboxane B2 (TXB2) as measured by RIA, in short term incubations. Dazoxiben (0.2 to 160 microM) pretreated PRP incubated with IL-6 and aggregated with ionophore A23187, showed a dose dependent inhibition of TXB2 secretion concomitant with a dose dependent abrogation of IL-6's enhancement of AIMA. A similar abrogation of AIMA was observed when these experiments were repeated using indomethacin. Further, PRP incubated with IL-6 showed a dose dependent increase in TXB2 and BTG secretion as measured by RIA and an increased incorporation of actin binding protein, talin, and myosin into the cytoskeletal core (triton insoluble residue) as shown by SDS PAGE. The integrin glycoprotein IIIa (GPIIIa) was also observed to be retained into the cytoskeleton by immunoblot. These results suggest that IL-6 activates platelets in vitro and enhances AIMA via a mechanism involving arachidonic acid metabolism. PMID- 7831670 TI - The calcium modulator nifedipine exerts its antiaggregatory property via a nitric oxide mediated process. AB - The in vitro effect of nifedipine, a calcium channel blocker of the dihydropyridine (DHP) type, on platelet aggregation was reinvestigated considering especially the capability of platelets to form endogenous nitric oxide (NO). We studied the dose-dependent antiaggregatory property of nifedipine in porcine platelet rich plasma. Aggregation was stimulated by collagen (7.5 micrograms/ml). Nifedipine inhibited collagen-induced platelet aggregation with an IC50 of 380 nmol/l. The antiaggregatory effect of nifedipine could be significantly diminished by N-nitro-L-arginine (NNA) in a concentration dependent manner, whereas oxy haemoglobin (4 microM), a NO scavenger, totally abolished the effect of nifedipine. L-Arginine, the precursor of NO, dose-dependently inhibited the collagen-induced platelet aggregation but did not potentiate the effects of nifedipine. Therefore, we propose that in platelet rich plasma the nifedipine induced inhibition of platelet aggregation is mediated by NO, a potent endogenous inhibitor of aggregation. We could confirm this hypothesis by measuring NO directly with a specific electrode. PMID- 7831672 TI - Guidelines for the hematologic evaluation of contrast media. For the Subcommittee on Rheology, Biomaterials, and Contact Activation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. PMID- 7831671 TI - The antiaggregating activity of clopidogrel is due to a metabolic activation by the hepatic cytochrome P450-1A. AB - Clopidogrel and ticlopidine are two well known selective anti-ADP agents which are inactive in vitro and must be administered in vivo to fully exhibit their antiaggregating and antithrombotic effects. Since previous studies have clearly demonstrated that the activation steps take place in the liver, we examined the effect of specific induction or inhibition of cytochrome P450 subfamilies on the antiaggregating activity of clopidogrel. SKF 525-A, a global cytochrome P450 inhibitor, dramatically decreased the antiaggregating effect of clopidogrel, therefore indicating that cytochrome P450 enzymes are involved in the hepatic activation of clopidogrel. The efficacy of clopidogrel was increased in animals pretreated with 3-methylcholanthrene and beta-naphthoflavone, indicating that the cytochrome P450-1A subfamily pathway was mainly involved in the activating metabolism of clopidogrel. The use of specific antibodies directed against the various cytochrome P450 subfamilies ascertained this observation. PMID- 7831673 TI - Polymorphism in the promoter region of the beta-fibrinogen gene and fibrinogen plasma levels in an in-patient population. PMID- 7831674 TI - Platelet intracellular calcium is not modified by subcutaneous administration of erythropoietin. PMID- 7831675 TI - Repeated release of the tissue factor pathway inhibitor. PMID- 7831676 TI - Cost effectiveness and ease of administration of low molecular weight heparin in deep vein thrombosis. PMID- 7831677 TI - In vitro model to test the thrombogenicity of coronary stents. AB - Thrombotic occlusion is a major complication limiting the application of stents in coronary arteries. In an in vitro model we investigated the thrombogenicity of different stent materials and several medical regimens to prevent thrombotic occlusion. Experiments were conducted in a closed system of silicon tubing with circulating citrated platelet rich plasma of healthy volunteers (n = 7) and of patients (n = 7 for each condition). Patients were either treated with phenprocoumon or with high or low dose heparin in combination with aspirin alone (100 mg) or aspirin (990 mg) plus dipyridamole (225 mg). After placement of tantalum wire stents into the system platelet aggregates were visible after 13.5 +/- 3.0 min, and occlusion occurred after 15.0 +/- 3.5 min. Similarly, with implanted stainless steel stents aggregation was seen after 13.0 +/- 3.5 min and thrombosis occurred after 14.5 +/- 3.5 min (p < 0.001 vs control without stent). Microscopic examination revealed combined platelet fibrin thrombi occluding the lumen. Platelet components predominately covered stent wires, particularly at crossing points. In all experiments high-dose heparin prevented platelet aggregate formation and stent occlusion independently of additional aspirin or aspirin plus dipyridamole; perfusion time > 60 min (p < 0.001 vs no heparin). Low dose heparin could not prevent clotting. With aspirin alone aggregates were visible after 16.0 +/- 4.0 min and clotting occurred after 23.0 +/- 5.0 min. In combination with dipyridamole aggregates were visible after 15.5 +/- 5.0 min and clotting after 21.0 +/- 4.0 min (NS vs aspirin alone). Phenprocoumon prevented platelet aggregate formation and stent occlusion; perfusion time > 60 min.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7831678 TI - Effect of different glycosaminoglycans in a guinea-pig carotid artery thrombosis model. AB - Heparin is the most frequently used drug for the prevention and treatment of thrombosis. Its use, however, is restricted by its side-effects. To study the efficacy of other glycosaminoglycans that could substitute heparin in the management of arterial thrombosis, 60 guinea-pigs were randomly allocated into 6 groups: G1 = control, G2 = heparin (150 IU/kg), G3 = heparan sulfate from beef pancreas (2.5 mg/kg), G4 = heparan sulfate from beef lung (2.5 mg/kg), G5 = N acetylated heparan from beef pancreas, G6 = dermatan sulfate from beef intestine (2.5 mg/kg). Ten minutes after intravenous injection of the drugs, thrombosis was induced by the injection of a 50% glucose solution into a segment of the right carotid artery isolated between 2 thread loops during 10 minutes. Three hours later the artery was re-exposed and if a thrombus was present it was measured, withdrawn and weighed. Thrombin time and activated partial thromboplastin time were measured in all animals. Thrombus developed in 90% of the animals in the control group, 0% in G2 and G3, 62.5% in G4, 87.5% in G5 and G6. Only in the animals treated with heparin the coagulation tests were prolonged. In conclusion, in the used dose only the heparan sulfate from beef pancreas presented an antithrombotic effect similar to heparin in this experimental model. PMID- 7831679 TI - Prothrombin fragment F 1 + 2 and oral anticoagulant therapy. AB - This study was undertaken to establish a correlation between prothrombin activation fragment F 1 + 2 and one-stage prothrombin time (PT) ratios in patients receiving oral anticoagulant therapy. One hundred consecutive patients on warfarin treatment were utilized for this study. The patients had received warfarin for not less than four days prior to entry into the study. F 1 + 2 levels and PT ratios were found to be 0.28 +/- 0.24 nM/L (mean +/- SD) ranging from 0.01 to 1.5 nM/L and 1.62 +/- 0.46 (mean +/- SD) ranging from 0.97 to 3.11, respectively. Most patients on oral anticoagulants with PT ratios between 1.2 - 1.7 exhibited decreased concentrations of F 1 + 2. Normal control values of F 1 + 2 were established for this study in 40 healthy individuals; they were 0.40 +/- 0.23 nM/L (median +/- SD) ranging from 0.11 to 1.19 nM/L. Mean plasma levels of F 1 + 2 were significantly lower in the anticoagulated patients as compared to the healthy controls (t = 2.377, p < 0.05). The relationship between F 1 + 2 levels and PT ratios in the 100 anticoagulated patients was analyzed by linear regression. No significant correlation (r = -0.208) was found between F 1 + 2 levels and PT ratios. It is concluded that the degree of reduction in F 1 + 2 levels is not proportional to the intensity of therapy reflected by the PT ratios in anticoagulated patients. PMID- 7831680 TI - Inhibitory effects of TFPI on thrombin and factor Xa generation in vitro- modulatory action of glycosaminoglycans. AB - The effect of tissue factor pathway inhibitor (TFPI) on thrombin and factor Xa generation was studied in an in vitro system using a prothrombin complex concentrate. It was found that TFPI, via the direct inhibition of factor Xa and the tissue factor/factor VIIa complex, inhibited both the further generation of factor Xa and the generation of thrombin in a concentration-dependent manner. The generation of thrombin (IC50 255 ng/ml) was more pronounced than that of factor Xa (IC50 684 ng/ml). The inhibitory activity of TFPI was significantly enhanced when unfractionated heparin was present in the assay system at a concentration of 10 micrograms/ml which did not show any inhibitory effects on protease generation in the same system. Furthermore, the influence of TFPI at subthreshold concentrations (100 ng/ml and 200 ng/ml, resp.) on the inhibitory action of unfractionated heparin (UFH), a low molecular weight heparin (LMWH), heparan sulfate (HS) and the synthetic heparin pentasaccharide (PS) was investigated. Whereas in the concentration range used (0.3-40 micrograms/ml) these glycosaminoglycans did not inhibit thrombin and factor Xa generation, after supplementation of the system with TFPI a concentration-dependent inhibition of the generation of the proteases up to 40-50% was seen for UFH, LMWH and HS. TFPI did not increase the activity of PS. PMID- 7831681 TI - At high heparin concentrations, protamine concentrations which reverse heparin anticoagulant effects are insufficient to reverse heparin anti-platelet effects. AB - Combined effects of heparin and protamine on plasma clot structure and platelet function were studied. Anticoagulant effects were monitored as changes in aPTT. Clot structure was defined in terms of fibrin fiber mass/length ratio (mu) and clot elastic modulus (EM). Platelet function was studied utilizing platelet aggregation and platelet force development (PFD) measurements. Heparin (1 U/ml) prolonged the aPTT from 30 to > 300 seconds, reduced PFD from 5,100 to 0 dynes, decreased mu (in batroxobin-induced gels) from 1.36 to 1.08 x 10(13) daltons/cm and decreased clot EM from 9,600 to 2000 dynes/cm2. Varying amounts of protamine reversed these effects: 16 micrograms/ml normalized the aPTT, 20 micrograms/ml normalized PFD, 32 micrograms/ml corrected mu, and 20 micrograms/ml returned EM to baseline. At high heparin concentrations (4 U/ml), protamine concentrations which corrected anticoagulant effects were inadequate to reverse antiplatelet effects. A protamine concentration of 40 micrograms/ml normalized the aPTT and mu, but 140 micrograms/ml of protamine was required to reverse heparin suppression of force development and clot elastic modulus. Excess protamine inhibited clotting and platelet function. In plasma containing 1 u heparin/ml, 140 micrograms protamine/ml reduced PFD by 83%, prolonged the aPTT by 63%, and reduced clot EM by 75%. In heparin free plasma, > 75 micrograms protamine/ml prolonged the aPTT. Thus, platelet function and clot structure are sensitive to protamine during heparin neutralization, and anti-platelet effects of heparin may persist when the aPTT is completely corrected. Excess protamine inhibits platelet function and compromises clot structure. PMID- 7831682 TI - Nitric oxide donors inhibit platelet spreading on surfaces coated with fibrinogen but not with fibronectin. AB - We have studied the effect of nitric oxide (NO) on the interaction of washed human platelets with fibrinogen or fibronectin adsorbed on glass. Platelet contacts were visualized by interference reflection microscopy at 37 degrees C in Tyrode's solution. The areas of spread platelets were measured, using digital video image processing techniques, at times up to 30 minutes after initial surface platelet contact. On fibrinogen spreading was inhibited by NO donors in the order of potency: S-nitroso-acetylpenicillamine > sodium nitroprusside > S nitroso-glutathione. The inhibitory action of NO donors was prevented by Oxy haemoglobin, confirming that this inhibition was due to the release of NO. In contrast, NO donors had virtually no effect on platelet spreading on fibronectin. Platelet adhesion to fibrinogen is mediated by GP IIb IIIa and the vitronectin receptor (VNR), while that to fibronectin is via GP IIb IIIa, VNR, Ic IIa and VLA 6. Our results thus indicate that NO inhibits adhesion mediated by GP IIb IIIa and/or VNR but not by the two other receptors. The mechanism of this receptor specific inhibition of platelet adhesion remains to be elucidated. PMID- 7831683 TI - Inhibition of plasminogen activation by polymerized ampicillin. AB - The polymerized beta-lactam antibiotic ampicillin inhibits the proteolytic activity of human plasmin upon 125I-labeled fibrin clots. The inhibition is dose dependent, with half-maximal inhibition occurring at 1.25 mM of the polymerized antibiotic. Polymerized ampicillin also inhibits binding of plasmin to fibrin, and 38% inhibition of binding occurs at 10 mM of the antibiotic. Furthermore, polymerized ampicillin inhibits the activation of plasminogen by either urokinase like plasminogen activator (uPA) or tissue type-plasminogen activator (tPA). At 7.5 mM of polymerized ampicillin, the uPA-mediated plasminogen activation is suppressed by 94%, and half-maximal inhibition is obtained at 0.66 mM. The direct activity of uPA on the chromogenic substrate L-pyroglutamyl-glycyl-L-arginine p nitroanilide hydrochloride (S-2444) is unaffected by polymerized ampicillin levels of up to 10 mM. The inhibitory effects of the polymerized antibiotic on the activation of plasminogen by both uPA and tPA is totally abolished in presence of fibrin. These interactions may serve as a novel model for ligands that enhance the clot-specificity of thrombolytic agents. PMID- 7831684 TI - Short-term aspirin treatment does not reduce plasma fibrinogen concentration in young healthy adults. PMID- 7831685 TI - Species specificity of ELISAs for prothrombin fragment F1.2. PMID- 7831686 TI - Dissociation of antithrombotic and thrombocytopenic effects of D-phenylalanyl-L prolyl-L-arginyl chloromethyl ketone in rabbits. PMID- 7831687 TI - Does nafamostat mesilate inhibit the tissue factor pathway? PMID- 7831688 TI - Contrast-enhanced transcranial imaging. Results of an American phase-two study. AB - BACKGROUND AND PURPOSE: Pulsed color Doppler imaging of cerebrovascular structures permits rapid visual identification of the intracranial vessels. In some patients, however, the clinical utility of transcranial ultrasound examinations is limited by poor tissue penetration and inadequate imaging of vessels. This phase-two clinical trial evaluates whether administration of an echocontrast agent in such ultrasound-refractory patients enhances image acquisition enough to yield meaningful diagnostic impressions. METHODS: This is a phase-two clinical trial of safety and efficacy of the "galactose/palmitic acid based microbubble preparation" Levovist injection (Berlex Laboratories). Thirty subjects with clinical indications for cerebrovascular imaging but refractory to transcranial Doppler studies were enrolled in a nonrandomized, single-center study. Echocontrast agent was administered intravenously in a tiered-dose protocol. Safety was determined by clinical and laboratory monitoring for 18 to 24 hours. Efficacy of contrast enhancement was determined by comparisons between each patient's precontrast (control) and postcontrast images. RESULTS: No significant patient discomfort, side effects, or adverse reactions occurred that were due to the intravenous administration of the echocontrast agent. Optimal image enhancement was obtained using the 300-mg/mL concentration (3 g bolus) of contrast. Visualization of both individual arterial segments and/or the entire circle of Willis was demonstrated. Clinical confidence of diagnostic impressions was achieved in 77% (23/30) of subjects. CONCLUSIONS: The transpulmonary ultrasound contrast agent (Levovist injection) was easily administered and found to be safe in the 30 patients studied and increased the diagnostic utility of transcranial ultrasound in 77% of the patients studied. PMID- 7831689 TI - Detection of cerebral microemboli by means of transcranial Doppler monitoring before and after carotid endarterectomy. AB - BACKGROUND AND PURPOSE: The main purpose of carotid endarterectomy (CEA) for neurologically symptomatic high-grade extracranial carotid artery stenosis is to remove the suspected source of cerebral microemboli. Transcranial Doppler (TCD) ultrasonography has the potential for detecting solid microemboli in the basal cerebral arteries. Therefore, TCD monitoring provides the opportunity to assess the rate of microemboli to the brain in patients with symptomatic high-grade carotid artery stenosis and to verify whether these phenomena have ceased after CEA. METHODS: TCD monitoring was performed in 41 patients to detect high intensity transient signals indicating microemboli in the middle cerebral artery before and after CEA. In the event that, within 1 week after CEA, TCD monitoring revealed ongoing cerebral microemboli on the side of surgery, the examination was repeated 3 months later. RESULTS: High-intensity transient signals were detected preoperatively on the side of the affected carotid artery in 22 patients (54%; mean, 10.2 per hour; range, 1 to 88). Linear regression analysis demonstrated a trend toward an inverse relationship between the number of high-intensity transient signals per hour and the time interval since the last episode of neurological symptoms (P < .1). CEA resulted in a significant reduction in the number of high-intensity transient signals per hour 7 days after surgery (mean, 6.0 versus 0.4 per hour; median, 0 versus 0; n = 37; P < .005) and 3 months later (mean, 6.3 versus 0 per hour; median, 1.3 versus 0; n = 41; P < .0001). CONCLUSIONS: Clearly, TCD monitoring can be helpful in assessing the effect of CEA in removing the suspected source of cerebral microemboli. Ongoing microemboli to the brain should prompt reassessment of the operated carotid artery or a search for other potential sources of cerebral embolism. Carotid artery plaques seem to produce cerebral microemboli for a limited period, which implies that the prophylactic effect of CEA might decrease if the operation is delayed. PMID- 7831690 TI - Transcranial Doppler sonography and magnetic resonance angiography in the assessment of collateral hemispheric flow in patients with carotid artery disease. AB - BACKGROUND AND PURPOSE: The aim of this investigation was to compare the respective efficacy of transcranial Doppler sonography (TCD) and magnetic resonance angiography (MRA) for the assessment of intracranial hemodynamics in patients with extracranial occlusion or severe stenosis of the internal carotid artery (ICA). METHODS: Twenty-five patients with unilateral ICA occlusion (n = 20) or tight stenosis (n = 5) demonstrated by duplex scanning or angiography were studied with both TCD and MRA. Three-dimensional time-of-flight MRA was used for the evaluation of extracranial-intracranial ICAs. Collateralization through the circle of Willis was investigated by means of selective two-dimensional MRA with presaturation of the carotid siphon, ophthalmic artery, or basilar artery. TCD was performed according to published standards: Anterior, middle, and posterior cerebral arteries were insonated through the temporal window, and carotid siphon and ophthalmic artery were assessed through a transorbital approach. Collateralization through the anterior circle of Willis was assumed if anterior cerebral artery flow was reversed, through the external carotid artery if ophthalmic artery flow was reversed, and through the basilar artery if the ratio of ipsilateral to contralateral posterior cerebral artery velocity was greater than 50%. TCD and MRA were performed by different investigators unaware of the results obtained with the other technique. RESULTS: In every case time-of-flight MRA demonstrated the ICA occlusion or stenosis. There was an excellent correlation (kappa = 0.64) between TCD and MRA in assessing the hemodynamic contribution of the anterior part of the circle of Willis, whereas MRA was unable to detect the anastomotic pathway of the ophthalmic artery (kappa = 0.32). The contribution of the posterior communicating artery was difficult to assess with both techniques, but in three cases only MRA showed unequivocal evidence of collateralization. In three cases of middle cerebral artery stenosis TCD was superior to MRA in demonstrating the patency of the vessel. CONCLUSIONS: TCD and MRA should be considered complementary techniques. Combining the findings of both examinations may help to better understand the changes in intracranial hemodynamics produced by extracranial carotid occlusion. The contribution of the ophthalmic pathway, although important for the intraorbital structures, is probably of limited functional significance to the hemispheric blood supply. PMID- 7831691 TI - Proximal aortic atheroma. An independent risk factor for cerebral ischemia. AB - BACKGROUND AND PURPOSE: Transesophageal echocardiography frequently demonstrates aortic atheroma in patients with cerebral and peripheral emboli. The aim of this study was to determine whether atheroma in the ascending aorta and arch is an independent risk factor for cerebral ischemia. METHODS: We studied 215 consecutive patients with a first stroke or transient ischemic attack and 202 community-based control subjects using transesophageal echocardiography to detect aortic atheroma and potential cardiac sources for embolism. Information about other stroke risk factors was obtained from a structured interview, and the presence of carotid vascular disease was assessed by means of duplex ultrasonography or digital subtraction angiography. Multiple logistic regression analysis was used to determine adjusted odds ratios for each risk factor. RESULTS: Atheroma in the ascending aorta and aortic arch was a significant risk factor for cerebral ischemia, independent of other well-established risk factors including high-grade carotid stenosis. The odds ratio for simple atheroma was 2.3 (95% confidence interval, 1.2 to 4.2) and for complex atheroma 7.1 (2.7 to 18.4). CONCLUSIONS: Ascending aortic and arch atheroma detected by transesophageal echocardiography is an important new independent risk factor for cerebral ischemia. Further characterization of the embolic potential of atheroma with different echocardiographic appearances and development of optimal management strategies are now needed. PMID- 7831692 TI - Clinical correlates of proton magnetic resonance spectroscopy findings after acute cerebral infarction. AB - BACKGROUND AND PURPOSE: We sought to determine whether lactate and N-acetyl signals measured by proton magnetic resonance spectroscopy (MRS) in the first days after stroke correlate with clinical measures of disability and functional outcome. METHODS: One-dimensional spectroscopic imaging was performed after stroke on 32 patients using a 2.1-T magnet. The Toronto Stroke Scale score at the time of the MRS study and the Barthel Index score at hospital discharge were determined from patient records. Lesion volume was estimated by a tracing algorithm from the scout magnetic resonance image obtained as part of the MRS study. The scaled lactate and N-acetyl signals from the voxel having the highest measured lactate were used to predict the clinical variables and lesion volume, as well as relative perfusion within the lesion, in those patients who underwent single-photon emission computed tomography (SPECT) blood flow imaging, using a multiple regression analysis. The correlation of lesion volume with the clinical variables was also evaluated. RESULTS: Lesion lactate signal was correlated with the Toronto Stroke Scale score, Barthel Index score, lesion volume, and SPECT score, all at P < .01. The N-acetyl level correlated with the Barthel Index score and lesion volume at P < .05. Lesion volume was also strongly correlated with the clinical variables (P < .0001). CONCLUSIONS: This is the first study to document the clinical predictive value of proton MRS measurements in patients after stroke. The association with functional outcome is stronger for lactate than for N-acetyl. Spectroscopic assessment of the metabolic status of cerebral tissues shortly after infarction may have significant clinical utility. PMID- 7831693 TI - Carotid Stenosis Index. A new method of measuring internal carotid artery stenosis. AB - BACKGROUND AND PURPOSE: Current methods of measuring carotid stenosis such as those used in the North American Symptomatic Carotid Endarterectomy Trial (NASCET) and European Carotid Surgery Trial (ECST) have limitations caused by difficulties in measuring the normal width of the distal internal carotid artery (ICA) or the carotid bulb. METHODS: We developed a new technique, the Carotid Stenosis Index (CSI), based on the known anatomic relationship between the common carotid artery (CCA) and ICA (1.2 x CCA diameter=proximal ICA diameter). The normal ICA diameter can therefore be calculated from direct measurement of the CCA. Three blinded observers evaluated the angiograms of 57 patients (114 carotid arteries), previously screened with duplex ultrasonography, using the NASCET, ECST, and CSI methods. In a subset of 30 patients undergoing carotid endarterectomy, comparison was also made to computerized carotid plaque planimetry. RESULTS: The NASCET method could only be applied correctly in 89% and the ECST method in 95% of cases because of overlying vessels or inadequate views of the distal ICA or carotid bulb. An additional 9% of NASCET cases had a "negative" stenosis, in which the stenosis is wider than the distal ICA. The CSI method was applicable in 99% of cases. Interobserver comparison using ANOVA revealed significant differences using NASCET (P < .0001) and ECST (P <.001) but not CSI (P = NS). NASCET had a sevenfold variation (P < .01) and ECST a twofold variation (P < .01) in results compared with CSI. The intraobserver reliability was 0.87 for NASCET, 0.86 for ECST, and 0.90 for CSI. However, the 95% confidence intervals for an individual measurement by an observer were +/- 30% for NASCET, +/- 19% for ECST, and +/- 15% for CSI. With linear methods of measurement there were significant differences between NASCET and CSI (P < .0001) and ECST (P < .0001) but not between CSI and ECST. A comparison of area derivations of these methods to carotid plaque planimetry revealed significant differences from NASCET (P <.0001) but not ECST, CSI, or duplex methods. A CSI nomogram was created, allowing measurement of both linear and area percent stenosis. CONCLUSIONS: CSI is the most reliable validated method of measuring carotid stenosis, and it correlates with duplex and carotid pathology. PMID- 7831694 TI - Time course of symptoms in extracranial carotid artery dissections. A series of 80 patients. AB - BACKGROUND AND PURPOSE: Cerebral infarction is the most frequent and severe manifestation of extracranial internal carotid artery dissection. However, few data exist on the precise time course of symptoms preceding the onset of stroke. METHODS: We studied 80 consecutive patients (29 retrospectively, 51 prospectively) with angiographically diagnosed extracranial internal carotid artery dissection and, during a 6-month follow-up, recorded the time elapsed between the onset of the first symptoms and the onset of any ischemic event (transient ischemic attack or stroke). We compared patients with and without ischemic events, with and without completed stroke, and, among patients who had local signs at onset, those with and without subsequent ischemic events. RESULTS: Cerebral or retinal infarction occurred in 42 patients. It was inaugural in 9 patients. In the 33 others, the time interval between the first symptoms (local signs and/or transient ischemic attacks) and the onset of stroke ranged from a few minutes to 31 days; it was < or = 7 days in 82% of the patients. No significant difference in the baseline characteristics of the patients or in the angiographic pattern of dissection was found based on the presence or absence of ischemic signs or of completed stroke. CONCLUSIONS: In carotid artery dissections, completed stroke usually occurs in the first few days after the onset of the first symptoms, whether local or ischemic, but it can occur as much as 1 month later. This suggests that any potential preventive treatment should be initiated as early as possible after the onset of the first symptoms but might also be worth initiating even 1 month later. PMID- 7831695 TI - Epidemiology of stroke in Kaunas, Lithuania. First results from the Kaunas Stroke Register. AB - BACKGROUND AND PURPOSE: In Lithuania, only routine mortality statistics have thus far provided data on the epidemiology of stroke. This study aims to assess the mortality, incidence, and case-fatality rate of stroke in the city of Kaunas, Lithuania, during 1986 to 1988. METHODS: A community-based stroke register was set up in 1986 to collect data on all suspected events of acute stroke that occurred in the population aged 35 to 64 years permanently residing in Kaunas. Crude and age-standardized attack rates, incidence, mortality, and case-fatality rates were calculated for the period studied. RESULTS: Among men, the average age standardized incidence of stroke (referring to first-ever events) was 230/100,000, the attack rate (all events) was 300/100,000, and the mortality from all strokes was 68/100,000. Among women, the corresponding rates were 131/100,000, 154/100,000, and 35/100,000, respectively. Of 973 acute stroke events registered, 80% were first-ever strokes. The age-adjusted 28-day overall case-fatality rate and the case-fatality rate of first-ever stroke were 23.3% and 19.8% in men and 21.8% and 21.3% in women, respectively. CONCLUSIONS: The findings from this first assessment of the incidence and mortality of stroke show that in the mid-1980s both were high in Kaunas compared with other countries. The case-fatality rate was similar to that reported for most other European countries. Further investigations are being carried out to assess the trends in mortality, incidence, and risk factors of stroke in the Kaunas population. PMID- 7831696 TI - Impact of race and ethnicity on ischemic stroke. The University of California at San Diego Stroke Data Bank. AB - BACKGROUND AND PURPOSE: As the US minority population continues to grow, increasing numbers of nonwhite citizens are at risk for stroke. A better understanding of how ischemic stroke differs in the minority populations may lead to more effective clinical management. METHODS: We prospectively evaluated 542 consecutive patients (416 whites, 71 Mexican Americans, 55 blacks) presenting to the University of California at San Diego Medical Center or the San Diego Veterans Affairs Hospital with presumed acute ischemic stroke or transient ischemic attack. RESULTS: Whites had a higher proportion of transient ischemic attacks (32% versus 18% and 17% for blacks and Mexican Americans, respectively) and had the lowest prevalence of diabetes mellitus (17% versus 29% and 40% for blacks and Mexican Americans, respectively). Mexican Americans had higher initial serum glucose levels (178 versus 133 and 131 mg/dL for whites and blacks, respectively). Blacks were youngest (average age, 56 years). There were no differences among the groups in the prevalence of prior stroke, hypertension, myocardial infarction, or smoking; initial systolic blood pressure, serum cholesterol levels, and functional deficit also were similar. Although it did not reach statistical significance, there was a trend toward relatively late presentation in the black stroke subpopulation: only 53% of blacks (compared with 73% of both Mexican Americans and whites) reached medical attention within 24 hours of stroke onset. All groups had similar diagnostic evaluations and functional outcome at 1 week. With the exception of a higher frequency of stroke of unknown cause in Hispanics, the distributions of stroke etiologies did not differ significantly among the groups. CONCLUSIONS: These data suggest that there are significant clinical differences in populations with ischemic stroke and transient ischemic attack that are related to race and ethnic origin, but in our population these differences did not include the extent of diagnostic evaluation undertaken or stroke severity. PMID- 7831697 TI - Where and how should elderly stroke patients be treated? A randomized trial. AB - BACKGROUND AND PURPOSE: Elderly stroke patients in particular are at risk of receiving less than optimal care. We studied the effects of the department care (medicine versus neurology) on the outcome of elderly stroke patients in a randomized controlled trial with 1-year follow-up. METHODS: A total of 243 consecutive patients aged 65 years or older with acute stroke were randomized to receive care in the Departments of Medicine or the Department of Neurology of a university teaching hospital with a referral area of 1.1 million. The outcome was assessed by mortality, length of hospital stay, ability to live at home on discharge, Barthel Index, and Rankin grades at 1 year. RESULTS: There were no differences in sex and age, severity or type of stroke, other diseases, or social factors between the two groups. One-year mortality was 21% in both patients treated by the Departments of Medicine and those treated by the Department of Neurology. Patients treated by the Department of Neurology were discharged an average of 16 days earlier (24 versus 40 days). The length of hospital stay of patients aged younger than 75 years differed significantly (P = .02). Patients randomized to neurological wards more often went directly home (75% versus 62%; P = .03), and their functional status was better as assessed with Barthel Index and Rankin grades at 1 year (P = .02 and P = .03, respectively). Independent predictors of a better functional outcome and shorter hospital stay by stepwise multivariate analysis included management by the Department of Neurology. CONCLUSIONS: Well-organized management of elderly stroke patients was associated with a better outcome. It was also the more economical alternative. PMID- 7831698 TI - Safety, tolerability, and pharmacokinetics of the N-methyl-D-aspartate antagonist dextrorphan in patients with acute stroke. Dextrorphan Study Group. AB - BACKGROUND AND PURPOSE: Dextrorphan hydrochloride is a noncompetitive N-methyl-D aspartate antagonist that is neuroprotective in experimental models of focal brain ischemia. The purpose of this study was to determine the maximum loading dose and maintenance infusion of dextrorphan hydrochloride that are well tolerated in patients with an acute stroke. METHODS: An intravenous infusion of dextrorphan or placebo was begun within 48 hours of onset of a mild-to-moderate hemispheric stroke. Initially, patients were treated with either placebo (n = 15) or dextrorphan (n = 22) using a 1-hour loading dose (60 to 150 mg) followed by a 23-hour ascending-dose maintenance infusion (maximum total dose, 3310 mg). Subsequently, 29 patients were treated with dextrorphan in an open trial using a 1-hour loading dose (145 to 260 mg) followed by an 11-hour constant rate (30 to 70 mg/h) infusion. RESULTS: Transient and reversible adverse effects, including nystagmus, nausea, vomiting, somnolence, hallucinations, and agitation, commonly occurred in dextrorphan-treated patients. Loading-dose escalation was stopped because of rapid-onset, reversible, symptomatic hypotension in 7 of 21 patients treated with doses of 200 to 260 mg/h. At the highest rates of maintenance infusion (> 90 mg/h), 3 patients developed deep stupor or apnea. The maximum tolerated loading dose was 180 mg/h, and the maximum tolerated maintenance infusion was 70 mg/h. Maximum plasma levels of 750 to 1000 ng/mL were obtained in 9 patients. There was no difference in neurological outcome at 48 hours between the dextrorphan-treated and placebo-treated patients. CONCLUSIONS: The highest doses of dextrorphan administered were associated with serious adverse experiences in some patients. Lower doses (loading doses of 145 to 180 mg, maintenance infusions of 50 to 70 mg/h) were better tolerated and rapidly produced potentially neuroprotective plasma concentrations of dextrorphan. These doses were associated with well-defined pharmacological effects compatible with N methyl-D-aspartate receptor antagonism. PMID- 7831699 TI - Decompressive craniectomy for cerebral infarction. An experimental study in rats. AB - BACKGROUND AND PURPOSE: Acute ischemia in the territory of the carotid artery can lead to massive cerebral edema with raised intracranial pressure and progression to coma and death due to uncal, cingulate, or tonsillar herniation. Thus far, only anecdotal experience with supratentorial ischemia treated by decompressive craniectomy has been reported; and there are no published experimental data dealing with this kind of therapy in acute supratentorial stroke. In this study, we present our results on the effect of decompressive craniectomy in an endovascular model of cerebral infarction in rats. METHODS: Focal cerebral ischemia was induced in 50 rats using an endovascular occlusion technique of the middle cerebral artery. Decompressive craniectomy was performed in 30 animals: in 15 animals after 1 hour and in the remaining 15 animals 24 hours after vessel occlusion. Twenty animals were not treated by decompressive craniectomy (control group). RESULTS: Mortality in the nontreated group was 35%, whereas none of the animals treated by decompressive craniectomy died. Neurological behavior, weight loss, and infarction size were all significantly better in the animals treated by decompressive craniectomy, regardless of whether they had been treated after 1 or 24 hours (P < .01). CONCLUSIONS: Our results suggest that decompressive craniectomy for cerebral ischemia not only reduces mortality but also significantly improves outcome and reduces infarction size, probably because of increased perfusion pressure through leptomeningeal collaterals. This experimental study suggests that a controlled study of decompressive craniectomy in patients with acute internal carotid or middle cerebral artery occlusion would be worthwhile. By performing decompressive craniectomy in a small, selected group of patients, neurosurgeons may play an important role in the management of these patients. PMID- 7831700 TI - Contraction of human brain endothelial cells induced by thrombogenic and fibrinolytic factors. An in vitro cell culture model. AB - BACKGROUND AND PURPOSE: Vasogenic brain edema is a frequent complication of ischemic stroke. The mechanism of the blood-brain barrier opening that underlies the edema formation is poorly understood. In the present study we examined the response of endothelial cells cultured from adult human brain to thrombogenic and fibrinolytic factors that possibly accumulate in the occluded vascular segments in ischemic stroke. METHODS: The changes in the morphology of cultured human brain microvascular endothelial cells were observed by phase-contrast light microscopy and quantified with computerized morphometry. RESULTS: Active proteases (eg, thrombin, plasmin, urokinase) as well as heparin and protamine, but not fibrinogen and antithrombin III, produced significant changes in endothelial cell morphology. Two shape patterns of contraction were observed: protamine treatment resulted in rounded cells with a decrease in both cell perimeter and area, whereas all other agents induced spiderlike cell morphology with increased perimeter and reduced area. The rate of contraction was dose dependent, and at comparable enzyme concentrations plasmin produced faster contraction than thrombin. The observed changes were reversed 3 hours after abrogating the treatment. CONCLUSIONS: In an in vitro model we have demonstrated that factors involved in thrombus formation and dissolution induce endothelial cell contraction, which could affect focally the permeability of the blood-brain barrier by opening paracellular avenues between endothelial cells in vivo. Thus, the genesis of brain edema in thromboembolic stroke or occasionally during fibrinolytic therapy can be attributed in part to the contact of these factors with the microvascular endothelium. PMID- 7831701 TI - Cat cerebral arteries are functionally innervated by serotoninergic fibers from central and peripheral origins. AB - BACKGROUND AND PURPOSE: Tryptophan hydroxylase activity and responses to tyramine were analyzed in cat cerebral arteries to investigate serotoninergic innervation. METHODS: Enzymatic activity and responses to tyramine were measured in vessels from animals subjected to cervical gangliectomy and dorsal and median raphe nuclei lesions. RESULTS: Tryptophan hydroxylase activity in cat cerebral arteries was reduced after ganglia removal and raphe nuclei destruction. Contractile responses of the middle cerebral artery after gangliectomy were decreased by ketanserine. Dorsal raphe nucleus destruction had a significant effect on the contractile response, whereas median raphe nucleus destruction had only a slight effect. CONCLUSIONS: Cat cerebral arteries receive serotoninergic innervation from central and peripheral origins. PMID- 7831702 TI - NG-nitro-L-arginine delays the development of brain injury during focal ischemia in rats. AB - BACKGROUND AND PURPOSE: The present study was designed to determine the effect of nitro-L-arginine, the inhibitor of nitric oxide synthesis, on the evolution of cytotoxic brain edema during focal cerebral ischemia. METHOD: Diffusion-weighted and contrast-enhanced, perfusion-sensitive magnetic resonance imaging was performed in anesthetized, mechanically ventilated rats at 30 minutes and 1, 2, and 3 hours after occlusion of the middle cerebral artery combined with coagulation of the basilar artery. At the onset of ischemia, the animals were infused intravenously with 0.5 mL of either 0.9% NaCl or nitro-L-arginine (30 mg/kg). The severity of cytotoxic edema was evaluated based on changes in the water apparent diffusion coefficient (ADC) derived from diffusion-weighted images. The size of the area affected by ischemia was evaluated 3 hours after occlusion using 2,3,5-triphenyltetrazolium chloride (TTC) staining. RESULTS: The percentage decrease of ADC in the striatum of rats pretreated with nitro-L arginine was significantly smaller (P < .05) than in the control group at 30 minutes and 1 and 2 hours of ischemia. The ADC in the injured cortex of nitro-L arginine-treated rats did not differ significantly from the ADC value measured in the contralateral cortex until 3 hours after the occlusion. However, at 3 hours of ischemia the percentage decrease of ADC in both the striatum and the cortex of either group of rats was similar. This transient attenuation of ADC drop during ischemia after nitro-L-arginine pretreatment occurred concurrently with a transient improvement of blood supply to the ischemic regions. The percentage of hemispheric area with abnormal TTC staining after 3 hours of ischemia did not differ between control and nitro-L-arginine-treated rats. CONCLUSIONS: Nitro-L arginine delays the development of ischemic injury by retarding cytotoxic brain edema. This effect is, at least partially, mediated by an improvement in blood supply to the ischemia tissues. PMID- 7831703 TI - Neuron-specific enolase in gerbil brain and serum after transient cerebral ischemia. AB - BACKGROUND AND PURPOSE: The sensitivity and validity of serum neuron-specific enolase as a marker of brain injury were tested after global cerebral ischemia. METHODS: Sixty-nine Mongolian gerbils were perfusion fixed after variable reperfusion after 5-minute (group 1) or 15-minute (group 2) bilateral carotid occlusion. Neuron-specific enolase was analyzed by an enzyme immunoassay in serum of control, sham-operated, and ischemic animals before euthanasia and in nonischemic gerbil brains. Brains were processed for histology, immunohistochemistry, and morphometric evaluation of ischemic neuronal damage. RESULTS: After cerebral ischemia, loss of neuronal immunoreactivity was closely associated with increased neuron-specific enolase serum levels, which were significantly elevated by 24 hours (group 1) or by 4 hours (group 2) of reperfusion (P < .001). Response of serum levels depended on the duration of preceding ischemia, and maximum concentrations were approximately 3-fold (group 1) or 20-fold (group 2) those of nonischemic control. Morphological damage became apparent 48 hours (group 1) or 12 hours (group 2) after ischemia, as indicated by histological and morphometric data. CONCLUSIONS: Significantly elevated neuron specific enolase serum levels could be demonstrated as a consequence of ischemia induced cytoplasmic loss of neuron-specific enolase in central nervous system neurons, corresponded quantitatively to the severity of cerebral ischemia, and were detectable before irreversible neuronal injury. Therefore, analysis of serum neuron-specific enolase is suggested to be both a valuable diagnostic tool in clinical management of the initial stages of global cerebral ischemia and a prognostic parameter during the postischemic course. PMID- 7831704 TI - N-acetylcysteine enhances hippocampal neuronal survival after transient forebrain ischemia in rats. AB - BACKGROUND AND PURPOSE: Free radical scavengers enhance neuronal survival in some models of transient forebrain ischemia. Recent experiments have suggested that N acetylcysteine prevents cellular injury after a reperfusion injury. No information is available regarding the neuroprotective potential of the free radical scavenger N-acetylcysteine after transient forebrain ischemia. In this study we evaluated the potential of N-acetylcysteine to improve hippocampal neuronal survival after transient forebrain ischemia in the rat. METHODS: In series A and B, ventilated, paralyzed, normothermic rats had 10 minutes of transient forebrain ischemia induced by bilateral carotid occlusion with hypotension induced by blood withdrawal (mean arterial blood pressure, 45 mm Hg). In series A, animals were administered N-acetylcysteine (163 mg/kg) 30 minutes and 5 minutes before transient forebrain ischemia. In series B, N-acetylcysteine (326 mg/kg) was administered 15 minutes after transient forebrain ischemia. In series C, N-acetylcysteine (326 mg/kg) was administered 15 minutes after transient forebrain ischemia in animals with a mean arterial blood pressure of 30 mm Hg during transient forebrain ischemia. All series had normal control, sham, and vehicle treatment groups. In all series, the rats were allowed to recover and were killed at 7 days after ischemia. The effect of forebrain ischemia was assessed by evaluating the number of viable neurons at bregma sections -3.3, 3.8, and -4.3 of the CA1 region of the hippocampus. RESULTS: The results demonstrated no physiological difference among the various treatment groups. There were no differences in the number of viable neurons between the transient forebrain ischemia with no treatment group and the vehicle (saline)-treated transient forebrain ischemic groups. Animals pretreated with N-acetylcysteine (mean number of neurons, 84 +/- 6) had a significant increase (P < .05) in neuronal survival compared with vehicle-treated animals (mean number of neurons, 43 +/- 4). Animals posttreated with N-acetylcysteine (mean number of neurons, 89 +/- 9) had a significant increase in neuronal survival compared with vehicle treated animals (mean number of neurons, 7 +/- 1). However, N-acetylcysteine protection was only partial at 45 mm Hg and did not improve neuronal survival (mean number of neurons, 22 +/- 3) in animals with a more severe ischemic insult (mean arterial blood pressure, 30 mm Hg during transient forebrain ischemia) compared with vehicle-treated animals (mean number of neurons, 10 +/- 1). CONCLUSIONS: N-Acetylcysteine partially improved neuronal survival when administered before or after ischemia following transient cerebral ischemia (mean arterial blood pressure, 45 mm Hg) but not with a more severe ischemic insult of 10 minutes of transient cerebral ischemia with a mean arterial blood pressure of 30 mm Hg. PMID- 7831705 TI - Collagenase-induced intrastriatal hemorrhage in rats results in long-term locomotor deficits. AB - BACKGROUND AND PURPOSE. Previous studies have shown that injection of the metalloproteinase collagenase directly into the caudate nucleus of rats causes an intracerebral hemorrhage. The purpose of the present study is to determine functional deficits associated with a collagenase-induced hemorrhagic lesion of the striatum. METHODS: Twelve adult rats received a 2-microL infusion of bacterial collagenase (0.5 U in saline) into the right striatum. The rotational response to apomorphine (1 mg/kg SC) administration was then examined at 1, 4, 7, 21, 35, and 70 days after the surgery. In addition to the rotational asymmetry studies, the initiation of stepping movements in each forelimb was determined 8 weeks after the collagenase injections. In the assessment of rotational asymmetry and stepping ability, an additional six control animals received unilateral injections of saline alone. After behavioral testing, brains were processed for neuropathological evaluation. RESULTS: A net ipsilateral rotation was noted at all posthemorrhage time periods. The average rotational asymmetries on these days were 14.57 +/- 2.9, 20.33 +/- 2.7, 19.99 +/- 4.4, 18.95 +/- 4.9, 17.03 +/- 4.9, and 14.4 +/- 4.7, respectively (data expressed as mean clockwise rotations per 5 minutes +/- SEM). The average number of steps initiated by the forelimb ipsilateral and contralateral to the lesion was 28.3 +/- 2.1 steps per minute and 13.6 +/- 1.5 steps per minute, respectively. This difference between left and right forelimb stepping was stable and reproducible for 3 consecutive days. Histological studies revealed a long-lasting hematoma cavity surrounded by dense reactive gliosis in the striatum. CONCLUSIONS: We conclude that collagenase induced intrastriatal hemorrhage results in long-term locomotor deficits and is therefore a useful model for developing and assessing therapeutic approaches for the restoration of neurological function after intracerebral hemorrhage. PMID- 7831706 TI - Transient increase of cytokine-induced neutrophil chemoattractant, a member of the interleukin-8 family, in ischemic brain areas after focal ischemia in rats. AB - BACKGROUND AND PURPOSE: We have indicated that neutrophils play an important role in cerebral ischemia-reperfusion injury. Neutrophils are also known to adhere to the endothelial wall through adhesion molecules and to infiltrate into the tissue, and this neutrophilic invasion correlates with the concentration gradient of chemotactic factors. The aim of the present study was to evaluate the role of cytokine-induced neutrophil chemoattractant (CINC) on brain damage in rats from transient ischemia. METHODS: The brain water content was measured to evaluate postischemic brain injury in rats with 60 minutes of middle cerebral artery occlusion with perfusion. An enzyme-linked immunosorbent assay was used to evaluate the blood and brain concentrations of CINC, and enzymatic and histological techniques were used to measure the neutrophilic infiltration into the brain. RESULTS: The increase of water content was first observed at 6 hours after reperfusion, after which this increase was gradual, with brain edema peaking from 24 to 48 hours after reperfusion. Neutrophilic infiltration into the parenchyma and myeloperoxidase activity were first noted 12 hours after reperfusion, after which a marked increase occurred from 24 to 48 hours after reperfusion. In the ischemic brain areas, CINC was first detected at 3 hours after reperfusion. The CINC level peaked at 12 hours after reperfusion (9.15 +/- 0.45 ng/g wet wt, n = 5 and then gradually reduced from 24 to 48 hours after reperfusion (5.35 +/- 0.95 ng/g wet wt, n = 5, and 1.25 +/- 0.10 ng/g wet wt, n = 5, respectively). Interestingly, the serum CINC concentration was transiently elevated from 3 to 6 hours after reperfusion. No CINC production was detected in the brain of rats subjected to 60 minutes of ischemia without reperfusion. CONCLUSIONS: A marked increase in CINC concentration was detected in brain and serum during early reperfusion. This suggests that the time course of CINC production precedes brain edema formation and neutrophilic infiltration. It thus appears that CINC may play an important role in neutrophilic infiltration in ischemic lesion and in brain edema formation after ischemia-reperfusion injury. PMID- 7831707 TI - Embolic stroke following thrombolytic therapy for myocardial infarction in a patient with preexisting ventricular thrombi. AB - BACKGROUND: Dislodging of preexisting cardiac thrombi has been a reported but unconfirmed cause of embolic strokes after thrombolytic therapy for myocardial infarction. CASE DESCRIPTION: An 82-year-old woman was admitted with congestive heart failure. Initial echocardiogram demonstrated ventricular thrombi. Three days later she experienced an inferior wall myocardial infarction, and intravenous streptokinase was administered. Six hours later she abruptly developed a global aphasia with a dense right hemiparesis. Repeat echocardiogram did not show any thrombus. CONCLUSIONS: Thrombolytic therapy may have caused embolization of ventricular thrombi. Cardiac conditions that predispose to embolic strokes are not established contraindications to thrombolytic therapy. The potential for thrombolytic therapy to produce embolization in patients with preexisting cardiac mural thrombi should be evaluated. PMID- 7831708 TI - Unilateral upper limb asterixis related to primary motor cortex infarction. AB - BACKGROUND: Unilateral upper limb asterixis related to cortical infarct is an unusual clinical picture. We found this association in two patients. Magnetic resonance imaging (MRI), somatosensory evoked potentials (SEPs), and electromyographic recording were performed. CASE DESCRIPTIONS: Two patients developed an acute upper limb ataxia with asterixis. This consisted of frequent arrhythmic loss of extensor muscle tone on instruction to maintain the wrist and fingers extended. Voluntary electromyographic activity in the left extensor digitorum communis muscle showed abrupt periods of interruption ranging from 90 to 260 milliseconds in duration in the first case and from 60 to 220 milliseconds in the second case. SEPs were normal. MRI disclosed a right cortical infarct within the primary motor cortex in both cases. CONCLUSIONS: These findings indicate that asterixis was not related to a failure in the processing of proprioceptive input controlling the regulation of postural tone of the distal upper limbs because SEPs were normal. The involvement of primary motor cortex might suggest that asterixis results from an impairment of a centrally generated motor-command signal controlling the postural tone of the distal upper limb. PMID- 7831709 TI - Stroking the stroke prevention numbers. PMID- 7831710 TI - Neuroradiology of early cerebral ischemia. PMID- 7831711 TI - Transcranial Doppler assessment of positional vertebrobasilar ischemia. PMID- 7831712 TI - Identifying clinically relevant carotid disease. PMID- 7831713 TI - Silent myocardial ischemia or pseudoischemia after ischemic stroke? PMID- 7831714 TI - Transcholedochal cholecystolithotomy for a variant of Mirizzi's syndrome. AB - Obstruction of the common bile duct by impaction of a gallstone in the neck or the cystic duct of the gallbladder results into repeated attacks of cholangitis (Mirizzi's syndrome). In suspected cases preoperative diagnosis can be made by ultrasonography and cholangiography. We report two patients of a variant of Mirizzi's syndrome. The common bile duct was obstructed by a stone impacted in the neck and causing extrinsic compression from behind. Ultrasonography and endoscopic retrograde cholangiography diagnosed the condition as common bile duct stone in both the cases. The anomaly could be diagnosed only after choledochotomy. Stones were retrieved by transcholedochal cholecystolithotomy--an innovative surgical procedure for this variant of Mirizzi's syndrome. PMID- 7831715 TI - Mechanical vs chemical therapy induced variceal ulcers. PMID- 7831716 TI - Percutaneous creation of intrahepatic portasystemic shunt with a stent--an attractive alternative to open surgery. PMID- 7831717 TI - Liver failure; varied manifestation and confusing classification. PMID- 7831718 TI - Brain edema and fulminant hepatic failure. PMID- 7831719 TI - Prevention of hepato-tropic viral infections. PMID- 7831720 TI - Medical treatment of peptic ulcer. PMID- 7831721 TI - Characterisation of the Indian strain of duck hepatitis B virus (DHBV) and development of a carrier duck colony for antiviral drug testing. AB - Duck hepatitis B virus (DHBV) infected carrier ducks serve as a useful model for testing anti-hepadnavirus drugs. This needs a well characterised duck hepatitis B virus strain. We cloned and sequenced the complete genome of duck hepatitis B virus strain of Indian origin. It was 3021 nucleotides in length and had all the recognisable open reading frames (Polymerase: 20-2530 nucletides, Surface: 693 1787 nucleotides and Core: 2518-412). Using an inoculum of 50 microliters serum containing 1 x 10(11) virus particles/ml, we could infect 80% of one day old ducklings and develop a duck colony. PMID- 7831722 TI - Oesophageal manometry in noncardiac chest pain. AB - Chest pain of oesophageal origin is an important differential diagnosis in patients with cardiac chest pain. A preliminary survey of 40 patients with noncardiac chest pain (NCCP) revealed oesophageal motility disorder in 47.5%; achalasia cardia being the most frequent disease (47.3%). 15.8% of these patients with motility disorder had features of progressive systemic sclerosis and another 15.8% had non specific oesophageal motility disorder (variants). Compared to barium swallow, oesophageal manometry was found to be superior in the diagnosis of oesophageal motility disorder. PMID- 7831724 TI - [Azithromycin--an exciting new antibiotic]. PMID- 7831723 TI - Multiple primary coexisting malignancy in young patients. AB - Two young patients with two coexisting primary malignancy are described. Both of them had colonic carcinoma. In addition, one had pancreatic carcinoma and the other duodenal carcinoma. PMID- 7831725 TI - [Dermatoscopy. An investigative method for the diagnosis of pigmented skin tumors]. AB - Dermatoscopy is a non-invasive investigative technique which makes it possible to evaluate the pigmented structures of the epidermis, the dermo-epidermal junction and the papillary dermal layer. The melanin pigmentation of the epidermal basal cell layers, the so-called pigment network is the primary target of dermatoscopy. A number of diagnostic criteria and variables for the dermatoscopy of pigmented skin lesions have been developed. Cutaneous malignant melanoma is still increasing in incidence and mortality. An early diagnosis is decisive for the prognosis. Therefore, it is urgent to develop practical investigative methods which can increase the diagnostic sensitivity. Dermatoscopy is such a method, but it demands training and experience. Lack of suspicious findings by dermatoscopy does not exclude malignancy. A safe diagnosis can only be obtained by a histological examination. PMID- 7831726 TI - [Leptospirosis]. AB - Leptospirosis is a worldwide zoonosis. When human beings are infected the clinical spectrum varies from a mild, febrile illness to severe, icteric disease with multiorgan failure and fatal outcome. The illness falls into two phases, the septicaemic and the so-called immune. The diagnosis is confirmed by culture of blood and spinal fluid during the first phase, by culture of urine during the second and by serology. It is recommended that penicillin be given as quickly as possible. Prevention is important e.g. effective rat control and individual protection such as wearing protective clothing in contaminated work areas. PMID- 7831727 TI - [Leptospirosis in the Ribe County 1980-1991]. AB - Though only 4.2% of the Danish population live in Ribe County, 12 cases of leptospirosis (22% of the Danish total) were found in the county between 1980 1991. Nine cases were associated with fresh water angling or fish farming. The patients were typically young or middle-aged formerly healthy men, who suddenly became ill with acute febrile disease. Eleven patients survived, one died. Cases were most often seen in late summer and autumn. Four patients required dialysis, and these patients also had relatively high serum levels of bilirubin. Case history and simple laboratory findings are helpful in leading to the diagnosis. Three patients were admitted with the correct diagnosis, and by the third day in hospital all 12 were being treated with relevant antibiotics, eight on suspicion of leptospirosis. Three patients had positive blood cultures on day 4, 6 and 9, and nine patients had late positive serology, two of whom also belonged to the group with positive blood cultures. In two patients the diagnosis was based on clinical findings alone. For these reasons, penicillin should be commenced on clinical suspicion alone. PMID- 7831728 TI - [Abruptio placentae--a clinical diagnosis?]. AB - The diagnosis of abruptio placentae is based on clinical symptoms and the classical presentation seldom causes diagnostic doubt. There is no significant correlation between the presenting symptoms and degree of placental abruption. Additional diagnostic parameters would be useful in cases with few symptoms. The survey describes the clinical presentation and diagnosis. The use of paraclinical tests in diagnosing, monitoring and estimating prognosis in cases with suspicion of abruptio placentae is reviewed. PMID- 7831729 TI - [Reduced concentration of beta-endorphin in cerebrospinal fluid and reduced pain tolerance in patients with functional dyspepsia]. AB - It was investigated whether central pain mechanisms including the endogenous antinociceptive system were involved in functional dyspepsia defined as: abdominal pain without abnormal findings. Pain sensitivity was measured by an ischaemic pain test comparing 21 functional dyspepsia patients with two control groups: 1) 24 patients with organic abdominal pain, and 2) 13 healthy pain-free controls. The endogenous opioids beta-endorphin, met-enkephalin immunoreactivity, and dynorphin immunoreactivity were measured in cerebrospinal fluid (CSF) from nine patients with functional dyspepsia and pain-free controls undergoing minor surgery while under spinal analgesia. There was no significant difference between the groups in pain sensitivity, but subdivision of the functional dyspepsia group showed that individuals with pain and no symptoms of irritable bowel syndrome (IBS) were significantly more sensitive to ischaemic pain than functional dyspepsia patients with IBS. The CSF beta-endorphfin concentration was significantly decreased in the functional dyspepsia group as compared with the controls. There were no significant group differences regarding met-enkephalin immunoreactivity and dynorphin immunoreactivity. Because of post-lumbar-puncture headache, this part of the investigation was suspended after nine patients. Functional dyspepsia is probably a pain syndrome with decreased central antinociceptive activity. PMID- 7831730 TI - [Late sequelae after testicular torsion]. AB - Thirty-five patients were examined six to eleven years after having been operated for torsion of the testis. Loss of testicular tissue was significantly associated with long preoperative duration of symptoms and with a low postoperative spermcount. No indications of autoimmunization affecting fertility nor evidence of bilateral defects were found. Apparently the reduced semen quality following testicular torsion is a matter of lost testicular tissue more than impairment of the quality of the remaining tissue. PMID- 7831731 TI - [Homologous intrauterine insemination as a first choice treatment of infertility]. AB - Intrauterine insemination with husband's Percoll preparated sperm was performed in 179 couples in a total of 440 treatment cycles. A total of 60 pregnancies was obtained. The pregnancy and delivery rate was 13.6% and 9.3% per insemination cycle, respectively. The cumulative probabilities of pregnancy and delivery were respectively 42% and 31% after three cycles. There was a significantly higher pregnancy rate when the number of follicles was more than three and a trend towards more pregnancies when the number of spermatozoa was increased. The study shows that this easy and non-invasive treatment gives acceptable results. We recommend an ideal maximum of three treatment cycles, and at least 1-2 million spermatozoa for each insemination. PMID- 7831732 TI - [Idiopathic pulmonary hemosiderosis. A cause of severe iron deficiency anemia in childhood]. AB - The most common cause of anaemia in childhood is iron deficiency. Anaemia due to poor dietary iron is seen most often between 9-24 months of age in infants being fed with large amounts of milk during periods of high growth rate. After the age of two years one must look for other causes of iron deficiency, particularly blood loss. In the description of three cases of idiopathic pulmonary haemosiderosis, the problems of severe chronic anaemia in childhood are discussed. Idiopathic pulmonary haemosiderosis is a rare disease in children, characterized by iron deficiency, anaemia and pulmonary symptoms. It has a high mortality, mostly due to acute pulmonary haemorrhage. However, early diagnosis is important, as some therapeutical regimens have succeeded in delaying the pulmonary haemorrhages and a few patients have possibly gained complete remission. PMID- 7831733 TI - [Azithromycin]. PMID- 7831734 TI - [AIDS in Denmark and Sweden]. PMID- 7831735 TI - Analysis of transient structures by cryo-microscopy combined with rapid mixing of spray droplets. AB - A simple method to determine transient conformations of biological molecules is described. The two reactants (e.g. protein complex and ligand) are mixed rapidly by the coalescence of spray droplets containing one component, with a thin, grid supported aqueous film containing the other. The transient state is then trapped by rapid freezing, and investigated later by cryo-microscopy. Images of conformations associated with reaction times of 1-100 ms can be achieved by adjusting the delay between the droplet impact and freezing. The droplets (typically 1 micron in diameter) are propelled onto the grid by an atomizer spray. It is shown that the droplets impinging on the liquid film spread rapidly over its surface under the influence of surface tension, and only weakly disturb the underlying film, partially displacing its contents away from the point of impact. Experiments with sprayed salt solutions, using vesicles derived from erythrocytes as micro-osmometers, indicate that rapid mixing occurs both through the film and laterally, by diffusion. The spraying process does not produce any detectable concentration changes due to drying in either the droplets or the film, and the method is applicable to high-resolution imaging. PMID- 7831737 TI - Restoration of high-tilt electron micrographs using a focus series. AB - Electron microscopy tomography requires high-tilt projections. However, the variation in defocus over a highly tilted specimen results in a blurred micrograph, where the blur is spatially varying blur can cause the micrograph to deviate from an acceptable approximation of the projection of the specimen's density function. In practice, this has been one factor limiting reconstructions of large cellular areas. We derive an algorithm to restore, or deblur, high-tilt electron micrographs using multiple defocused versions of the micrograph. This algorithm consists of digitization and registration of the micrographs, identification of the defocus blur using either a theoretical model or a zero tilt focus series, and spatially varying restoration using the multiple high-tilt defocused micrographs. Numerical results using simulated and real data are presented, demonstrating the effectiveness of this algorithm. PMID- 7831736 TI - Variable pitch in frozen-hydrated sickle hemoglobin fibers: an image analysis model study. AB - The intracellular polymerization of deoxyhemoglobin S (HbS) into helical fibers is the primary pathological event which gives rise to sickle cell disease. The structure of these fibers has previously been studied by electron microscopy of negatively stained specimens. We are extending these studies with unstained frozen-hydrated HbS fibers (cryo-EM), which afford better visualization of the internal details of the fiber structure than can be achieved by negative staining, but have lower signal-to-noise ratio images. The pitch of the HbS fiber structure varies locally along any given particle. Because rotation about the particle axis thus is partially decoupled from translation along the axis, the pitch and angular rotation of a fiber unit cell cannot be inferred by symmetry (as is the case with constant pitch helices). Image analysis procedures are presented which are capable of explicitly identifying the pitch and angular rotation of individual HbS fiber unit cells having low signal-to-noise ratios. Fiber images are divided into segments one unit cell long (63 A) which are analyzed in two steps. First each unit cell is aligned with constant pitch electron density reference models by cross-correlation. Correlation coefficients are then used to determine angular rotation and pitch. This procedure was tested, and found to be robust, using model images corrupted to simulate experimental problems normally encountered in the analysis of cryo-electron micrographs. The effects of limited resolution, low signal-to-noise ratio, scaling errors, and rotational and axial misalignment are described. PMID- 7831738 TI - Preparing for the worst: will the profession be able to cope? PMID- 7831740 TI - New species, and new perspectives, in practice. PMID- 7831739 TI - Veterinary education: should practitioners have more say? PMID- 7831741 TI - Detection of anthelmintic resistant nematodes in sheep in southern England by a faecal egg count reduction test. AB - On five farms identified by in vitro tests to have benzimidazole resistance, and on one farm with apparent anthelmintic failure, faecal egg count reduction tests were performed using benzimidazoles, levamisole and ivermectin. With benzimidazoles efficacy was less than 70 per cent on all farms, confirming the validity of the in vitro tests to detect benzimidazole resistance. On two farms levamisole had an efficacy of less than 90 per cent but laboratory tests failed to demonstrate levamisole resistance. Ivermectin reduced egg counts by 100 per cent on all farms. PMID- 7831742 TI - Influence of the beta-agonist salbutamol on claw horn lesions and walking soundness in finishing pigs. AB - The effects of feeding the beta-adrenergic agonist salbutamol to pigs at levels between 0.5 and 5.0 mg/kg feed for different periods were studied in six experiments. The feet and ability to walk of pigs weighing 30 to 100 kg were examined at intervals. False sand-crack, white-line and heel erosion lesions were classified as mild or severe, and corns and wall haemorrhages were also recorded. At each examination the pig was given a grade for the overall severity of its foot lesions. Salbutamol fed at 1.0 to 5.0 mg/kg feed, for as little as 21 to 28 days, increased the frequency (P < 0.05 to 0.001) and often the severity (P < 0.05) of the foot lesions, the higher doses tending to produce more severe lesions, and the overall foot grades deteriorated (P < 0.001). The effects on both sexes were similar. No changes were observed when 0.5 mg/kg was fed for 56 days. Despite the severity of many of the foot lesions, the pigs became lame in only one experiment. Electron microscopy indicated that salbutamol was interfering with horn production, but light microscopy revealed no changes in skin sections. These findings suggested that salbutamol was not directly affecting the function of keratinocytes. Supplementing the diet of the pigs with biotin and methionine did not delay, or prevent, the effects of salbutamol. PMID- 7831744 TI - Evidence for the transmission of the Lyme disease spirochaete to sheep in Cumbria. PMID- 7831743 TI - Brucella abortus serology in cattle naturally infected with Escherichia coli O157.H7. PMID- 7831745 TI - Isolation of a parainfluenzavirus type 2 from the prostatic fluid of a dog. PMID- 7831746 TI - Animal imports. PMID- 7831747 TI - Future of veterinary research. PMID- 7831748 TI - Equine granulocytic ehrlichiosis in the UK. PMID- 7831749 TI - Equine euthanasia. PMID- 7831750 TI - Manpower and education. PMID- 7831751 TI - Manpower and education. PMID- 7831752 TI - Unusual stomach contents in a dog. PMID- 7831753 TI - Antimicrobial effect of combinations of EDTA-Tris and amikacin or neomycin on the microorganisms associated with otitis externa in dogs. AB - Combinations of EDTA-Tris and two aminoglycoside antibiotics (amikacin and neomycin) were tested for synergistic activities against the microorganisms associated with otitis externa in dogs and for the solutions' stability over time. Synergistic activity was observed when EDTA-Tris plus amikacin and EDTA Tris plus neomycin were tested against Staphylococcus intermedius, Proteus mirabilis, Pseudomonas aeruginosa, and Escherichia coli, but not against Candida albicans. Stability studies over a 3-month period indicated that the test solutions were stable at room temperature and that their antimicrobial activity was maintained. PMID- 7831754 TI - Studies on the relationship between sway disease of bactrian camels and copper status in Gansu province. AB - The clinical signs of camel sway disease in the Hexi Corridor of Gansu province were defined. The contents of eight minerals in soils, in forage and in the blood and hair of bactrian camels from this region were determined. The related blood indices were also measured. The concentration of molybdenum in soils and forage was 4.8 +/- 0.02 and 4.8 +/- 0.25 micrograms/g (dry matter), respectively, the copper to molybdenum ratio in the forage being only 1.3. The concentration of copper in blood and hair from the camels was 0.28 +/- 0.17 micrograms/ml and 3.50 +/- 1.00 micrograms/g, respectively. There was a hypochromic microcytic anaemia and a low level of ceruloplasmin in the blood. It is therefore suggested that sway disease of bactrian camels in this region is caused by secondary copper deficiency, mainly due to the high molybdenum content in soils and forage. The copper deficiency in the camels was aggravated during reproduction. Oral administration of copper sulphate can prevent and cure the disease. PMID- 7831755 TI - Age-related storage of iron in the liver of horses. AB - The non-haem iron concentration was estimated in post-mortem liver samples from 51 horses (age range 1-25 years). Two were normal and 49 had been suffering from conditions that were not expected to have had long-term effects on iron metabolism. Muscle samples (splenius and biceps femoris) from 23 of these horses were also analysed. There was a highly significant age-related increase in the non-haem iron concentration in the liver (r = 0.635, p < 0.001), but not in the muscles, in which the iron concentration was much lower than in the liver. PMID- 7831757 TI - Prevalence and risk factors in serous arthritis in the carpal joint of Norwegian coldblooded trotters. AB - Of 508 four-year-old coldblooded trotters examined for carpitis, 135 (27%) had the condition. Thirty horses had unilateral carpitis on the left frontlimb, 52 on the right frontlimb and 53 had bilateral carpitis. Of these horses, 105 were stallions, 135 were geldings and 269 were mares. The prevalence of carpitis in these three groups was 25%, 25% and 28%, respectively. Information was obtained on the training regimes in four periods of the life of 378 horses. The odds ratios for the training variables were of the same order in all four periods. In logistic regression analyses on the training variables for the first period for the variable percentage of carpitis within each progeny group (sire index), the odds ratio corresponding to a 10% increase in sire index was 1.7 (1.4, 2.1) (95% confidence interval of the odds ratio). The odds ratios for leaving the horses out in a paddock, walking in a jogcart and fast training, or not in each case, were 0.4 (0.2, 0.9), 2.5 (1.2, 5.3) and 2.0 (0.9, 4.4), respectively. This implies a decreased risk of developing carpitis for horses left out in a paddock as a two-year-old, and a 2.5 and 2.0 times increased risk of carpitis occuring in horses exposed to walking in a jogcart and fast training, respectively. Information on the feeding regimes during the first, second and third year collected by a questionnaire revealed no association with carpitis beyond that which could be ascribed to chance. The rations offered were within normal ranges except for calcium, which was below recommended levels. PMID- 7831756 TI - Localization of glycoconjugates in dog parotid gland by lectin histochemistry. AB - Parotid glands from adult dogs were stained with a battery of seven horseradish peroxidase-conjugated lectins (PNA, UEA, LTA, DBA, SBA, WGA and ConA). In some cases (PNA and DBA) neuraminidase digestion was followed by lectin staining. Acinar cells contained conspicuous quantities of oligosaccharides with terminal sialic acid radicals. Galactosil-(beta 1-->3) N-acetylgalactosamine was the most abundant penultimate sugar linked to N-acetylneuraminic acid. Sialylated components having the terminal dimer sialic acid-N-acetylgalactosamine were found in the acinar cells. Secretory cells presented a heterogeneous distribution of glycoconjugates with terminal fucose and beta-N-acetylgalactosamine. Fucose, N acetylglucosamine and alpha-N-acetylgalactosamine were present on the apical cytoplasm and surface of the striated and interlobular duct cells. This glycosidic composition was unaffected by extensive selective breeding. The role of abundant amounts of sialic acid radicals in the oral mucosa was considered. PMID- 7831758 TI - Quantitative counter-immunoelectrophoresis for estimation of antibodies to infectious bursal disease virus. AB - Quantitative counter-immunoelectrophoresis was standardized to detect antibodies to the avian infectious bursal disease virus. This technique correlated well with the conventional quantitative agar gel precipitation test in estimating antibodies to IBDV. The use of blood dried on filter paper as an alternative to serum is discussed. QCIE is simple, easy to perform and faster than QAGP. PMID- 7831759 TI - Immunohistological demonstration of antigenicity of the various endogenous stages of Eimeria apsheronica in goats. AB - Ten naive goat kids obtained soon after birth were reared coccidia-free in cages indoors. At one month of age they were each infected with 25,000 oocysts of E. apsheronica. Infection was monitored by examining the faeces for oocysts for two and a half weeks after patency. They were then euthanized and sections of their small intestines showing gross coccidal lesions were fixed for histology. Intestinal sections were incubated in pre-infection and post-infection sera to detect any antigen-antibody reactions using diaminobenzidine (DAB) as the stain. The sections treated with pre-infection sera stained very poorly in comparison to those treated with post-infection sera. The conclusion is drawn that serum antibodies which developed after infection reacted with the endogenous stages of the parasite and were histologically demonstrable. PMID- 7831760 TI - Experimental infection of domestic goats with Leishmania major through bites of infected Phlebotomus duboscqi and needle inoculation of culture-derived promastigotes. PMID- 7831761 TI - The ability of Stomoxys calcitrans and mechanical means to transmit Trypanosoma (brucei) evansi from goats to camels in Kenya. PMID- 7831762 TI - Pharmacokinetics and dosage regimen of cefotaxime in cross-bred calves following single intramuscular administration. AB - The pharmacokinetics, penetration into erythrocytes and plasma protein binding of cefotaxime were investigated in cross-bred calves. Following a single intramuscular dose of cefotaxime (10 mg/kg), the absorption half-life and elimination half-life were 0.13 +/- 0.03 h and 2.97 +/- 0.72 h, respectively. The apparent volume of distribution and total body clearance were 3.28 +/- 0.72 L/kg and 0.78 +/- 0.08 L/kg per h, respectively. The extent of penetration into erythrocytes was 24-40% of the total blood concentration. Cefotaxime was bound to plasma proteins of calves to the extent of 25.5-33.6%. A satisfactory intramuscular dosage regimen for cefotaxime in calves would be 11 mg/kg followed by 10 mg/kg at 7 h intervals. PMID- 7831763 TI - Vagal reflex inhibition of motility in the abomasal body of sheep by antral and duodenal tension receptors. AB - Vagally-mediated regulation of motility in the abomasal body by duodenal and abomasal antral motility was demonstrated in acutely prepared anaesthetized sheep. The enteric plexuses between the abomasal body, antrum and duodenum were interrupted by transection. Antral contractions were more effective than duodenal contractions at causing inhibition of the abomasal body, and antral isometric conditions were more effective than antral isotonic conditions. Inhibition of motility in the abomasal body was reduced by unilateral cervical vagotomy, was abolished by bilateral cervical vagotomy, and was reversibly inhibited by cervical vagus cold block. The demonstration of vagal pathways in abomaso abomasal reflexes confirms a functional homology of the mechanisms in the ruminant and animals with simple forms of stomach. PMID- 7831764 TI - Transcription regulatory elements of the avian retroviral long terminal repeat. PMID- 7831765 TI - The metabolism of small cellular RNA species during productive subgroup C adenovirus infection. AB - During the late phase of subgroup C adenovirus infection, export of cellular mRNA from the nucleus to the cytoplasm is inhibited. In one approach to investigate the mechanism whereby viral late mRNAs are selected for export, we have examined the metabolism of small cellular RNA species transcribed by all three RNA polymerases during the late phase of Ad5 infection. No changes in the quantities of [3H]uridine-labeled 5S rRNA or tRNAs entering the cytoplasm were observed in infected cells. Adenovirus type 5 infection reduced the nuclear and cytoplasmic populations of the newly synthesized, snRNP-associated snRNAs U1, U2, U4, U5, and U6. Transcription of a representative snRNA, U1 RNA, was not inhibited, indicating that the post-transcriptional metabolism of snRNAs was perturbed during the late phase of infection. The increased cytoplasmic concentration of newly synthesized U1 RNA in Ad5- compared to mock-infected cells, and the greater reduction of the snRNP-associated compared to the total U1 RNA population, indicated that snRNP assembly in the cytoplasm was impaired. As adenovirus infection does not perturb export from the nucleus of small cellular mRNAs transcribed by RNA polymerases II and III, viral mRNA must be distinguished for selective export at a nuclear step upstream of translocation to the cytoplasm via nuclear pore complexes. PMID- 7831766 TI - Synthesis of an infectious full-length cDNA clone of rice yellow mottle virus and mutagenesis of the coat protein. AB - A full-length cDNA clone of rice yellow mottle sobemovirus (RYMV) was synthesized and placed adjacent to a bacteriophage T7 RNA polymerase promoter sequence. Capped-RNA transcripts produced in vitro were infectious when mechanically inoculated onto rice plants (Oryza sativa L). Individual full-length clones varied in their degree of infectivity but all were less infectious than native viral RNA. A representative clone, designated RYMV-FL5, caused a disease phenotype identical to that produced by viral RNA except that symptoms were somewhat slower to appear than those induced by viral RNA. The infectivity of RYMV-FL5 was verified by ELISA, Western blot analysis, Northern blot hybridization, RT-PCR, and Southern blot hybridization. Frameshift and deletion mutations introduced into the coat protein cistron demonstrated that the coat protein was dispensable for RNA replication in rice protoplasts. However, the coat protein was required for full infectivity in rice plants, presumably by playing a role in phloem-mediated long-distance movement and possibly in cell-to cell movement. PMID- 7831767 TI - NPI-1, the human homolog of SRP-1, interacts with influenza virus nucleoprotein. AB - We used the yeast interactive trap system to identify a cellular protein which interacts with the nucleoprotein of influenza A viruses. This protein, nucleoprotein interactor 1 (NPI-1) is the human homolog of the yeast protein SRP1. SRP1 was previously identified as a suppressor of temperature-sensitive RNA polymerase I mutations (R. Yano, M. Oakes, M. Yamaghishi, J. Dodd, and M. Nomura, Mol. Cell. Biol. 12, 5640-5651, 1992). A full-length cDNA clone of NPI-1 was generated from HeLa cell poly A + RNA. The viral nucleoprotein, which had been partially purified from influenza A/PR/8/34 virus-infected embryonated eggs, could be coprecipitated from solution by glutathione agarose beads complexed with a bacterially expressed glutathione-S-transferase-NPI-1 fusion protein, confirming the results of the yeast genetic system. Antisera raised against NPI-1 identified a 60-kDa polypeptide from total cellular extracts of both HeLa and MDBK cells. The viral nucleoprotein was coimmunoprecipitated from influenza A/WSN/33 virus-infected MDBK cells by anti-NPI-1 sera, demonstrating an interaction of these two proteins in infected cells. Similarly, NPI-1 was coimmunoprecipitated from MDBK cells by anti-NP sera. These experiments suggest that NPI-1 plays a role during influenza virus replication. PMID- 7831768 TI - Synthesis and assembly of virus-like particles of human papillomaviruses type 6 and type 16 in fission yeast Schizosaccharomyces pombe. AB - We have synthesized capsid proteins of human papillomavirus types 6 (HPV 6) and 16 (HPV 16) in fission yeast Schizosaccharomyces pombe and produced virus-like particles (VLP). The capsid proteins were localized in the nucleus by indirect immunofluorescence and cell fractionation analyses. The VLP were produced in both yeast clones synthesizing L1 alone and L/L2 and purified by sulfato-cellulofine chromatography. Electron microscopic examination showed that these VLP were similar in structure to native HPV particles. Two HPV 16 L1 variants (16 B27L1 and 16 T3L1), isolated from benign cervical samples, produced many more (68- and 14-fold) VLP than the prototype L1 (16 PL1) derived from cervical carcinoma. Coexpression of the HPV 6 L2 protein with 6 L1 and 16 B27L1 proteins increased the production level of the VLP four- and twofold, respectively. The L2 was not detected in the VLP purified with sulfato-cellulofine column, although the L2 was purified in the same fraction containing HPV 6 and 16 B27-VLP by size fractionation using Sepharose column. Interaction between 6 L2 and 6/16 L1 proteins was not detected by the coimmunoprecipitation assays with either L1 or L2 antibodies. These results suggest that the L2 is not incorporated into the VLP synthesized in yeast. PMID- 7831769 TI - Vaccinia virus serpins B13R (SPI-2) and B22R (SPI-1) encode M(r) 38.5 and 40K, intracellular polypeptides that do not affect virus virulence in a murine intranasal model. AB - A characterization of genes B13R (SPI-2) and B22R (SPI-1) from vaccinia virus strain Western Reserve (WR) is presented. These genes are transcribed early during infection and the predicted encoded proteins show similarity to the superfamily of serine protease inhibitors (serpins). The 5' transcriptional initiation site of each gene was mapped by primer extension experiments to 71-72 and 31 nucleotides upstream of the B13R and B22R open reading frames (ORFs), respectively. Each ORF was expressed in Escherichia coli and specific antisera were raised against the protein produced. These antisera were used to identify the B13R- and B22R-encoded proteins in vaccinia virus-infected cells as stable, intracellular, nonglycosylated proteins of M(r) 38.5K and M(r) 40K, respectively. The B22R gene product was detected in all orthopoxviruses tested including cowpox, rabbitpox, and vaccinia strains WR, Copenhagen, Tashkent, Tian Tan, Lister, Wyeth, IHD-J, and IHD-W. In contrast, the B13R gene product had a more limited distribution and was not detected in Copenhagen, Tashkent, Lister, and Tian Tan. Viable virus deletion mutants that lacked only B13R or B22R coding sequences (delta B13R and delta B22R) and revertant viruses in which the deleted gene was restored were constructed by transient dominant selection. The growth of the deletion mutants in cell culture was indistinguishable from that of wild-type virus. Additionally the virulence of each deletion mutant was indistinguishable from wild-type and revertant viruses in a murine intranasal model. PMID- 7831770 TI - Characterization of proteins encoded by ORFs 2 to 7 of Lelystad virus. AB - The genome of Lelystad virus (LV), a positive-strand RNA virus, is 15 kb in length and contains 8 open reading frames (ORFs) that encode putative viral proteins. ORFs 2 to 7 were cloned in plasmids downstream of the Sp6 RNA polymerase promoter, and the translation of transcripts generated in vitro yielded proteins that could be immunoprecipitated with porcine anti-LV serum. Synthetic polypeptides of 15 to 17 amino acids were selected from the amino acid sequences of ORFs 2 to 7 and antipeptide sera were raised in rabbits. Antisera that immunoprecipitated the in vitro translation products of ORFs 2 to 5 and 7 were obtained. Sera containing antibodies directed against peptides from ORFs 3 to 7 reacted positively with LV-infected alveolar lung macrophages in the immunoperoxidase monolayer assay. Using these antipeptide sera and porcine anti LV serum, we identified three structural proteins and assigned their corresponding genes. Virions were found to contain a nucleocapsid protein of 15 kDa (N), an unglycosylated membrane protein of 18 kDa (M), and a glycosylated membrane protein of 25 kDa (E). The N protein is encoded by ORF7, the M protein is encoded by ORF6, and the E protein is encoded by ORF5. The E protein in virus particles contains one or two N-glycans that are resistant to endo-beta-N-acetyl D-glucosaminidase H. This finding indicates that the high-mannose glycans are processed into complex glycans in the Golgi compartment. The protein composition of the LV virions further confirms that LV is evolutionarily related to equine arteritis virus, simian hemorrhagic fever virus, and lactate dehydrogenase elevating virus. PMID- 7831771 TI - Single cell transcript analysis of human immunodeficiency virus gene expression in the transition from latent to productive infection. AB - In the lymph nodes of individuals infected with human immunodeficiency virus (HIV), there is evidence that points to three kinds of virus-cell relationships. Virions may be associated with CD4+ lymphocytes that are actively producing virus or may be bound at the surfaces of follicular dendritic cells like other antigens. HIV is also harbored in CD4+ lymphocytes and monocytes/macrophages in a latent form as transcriptionally silenced provirus. To ultimately investigate in vivo these and other HIV-cell interactions that play such critical roles in the persistence of virus, immune dysregulation, and depletion, we have developed an in situ hybridization method that discriminates multiply spliced from singly or unspliced viral transcripts. In this report we describe the method and the results obtained with it in an analysis of the switch from latent to productive infection of chronically infected T lymphocytes in culture. We found with this single-cell technique that there are two subpopulations in the culture, a minor one of productively infected cells and a major one of latently infected cells in which only low levels of viral transcripts terminated close to the 5' end of the viral genome were detected. Shortly after activation of viral gene expression with phorbol ester, transcripts encoding Tat and Rev increase in abundancy in individual latently infected cells and this is followed by increases in and cytoplasmic export of singly or unspliced mRNAs encoding structural proteins. These studies provide insights into the regulation of HIV gene expression from a single-cell perspective and, from that perspective, transcript profiles of productively infected cells as a frame of reference for defining HIV-cell relationships in individual cells in tissue sections. PMID- 7831772 TI - Spliced HERV-H endogenous retroviral sequences in human genomic DNA: evidence for amplification via retrotransposition. AB - HERV-H elements are a large family of endogenous retrovirus-like sequences found in approximately 1000 dispersed copies in the genomes of humans and other primates. The most abundant subclass of these elements is a partially deleted form of 5.8 kb which is transcribed primarily as a 5.6-kb unit length RNA and a 3.7-kb spliced derivative. The provirus-like structure of these elements suggests that their numbers have increased in the genome through retrotransposition. However, this has not been demonstrated for HERV-H. To determine if genomic expansion of HERV-H elements involved an RNA intermediate, primate DNAs were screened by PCR for elements that were transcribed, spliced, reverse transcribed, and integrated back into the genome. This PCR screen detected several genomic HERV-H fragments that appear to be derived from spliced transcripts. Interestingly, the presence of one of these fragments is polymorphic in humans, suggesting that its integration was a relatively recent event. Another PCR strategy was used to determine that at least one of the spliced elements has an intact 5' LTR, indicating that it is not simply a "processed pseudogene" or cDNA copy of a HERV-H transcript. Genomic cloning and sequencing of a human locus harboring a spliced element revealed the expected structure, e.g., intact LTRs and flanking 5-bp direct repeats, for a virally retrotransposed element. A genomic library screening method also indicated that very few HERV-H elements (less than 1%) have the structure of processed pseudogenes. These results suggest that most HERV-H elements amplified in the genome as viral retrotransposons. PMID- 7831773 TI - Characterization of the Epstein-Barr virus Fp promoter. AB - Expression of the Epstein-Barr virus nuclear antigen-1 (EBNA-1) protein is mediated by the virus Fp promoter in Burkitt lymphoma and nasopharyngeal carcinoma. This promoter is silent in latently infected B lymphoblastoid and most Burkitt lymphoma-derived cell lines in vitro, which utilize separate promoters approximately 50 kb upstream of Fp to express EBNA proteins. Fp-mediated activation of EBNA-1 expression is also activated upon induction of the virus replication cycle. We previously demonstrated that activation of Fp in Burkitt cells requires cis-regulatory elements downstream of the site of transcription initiation. We have now mapped two positive regulatory elements within the Fp promoter. One element contains two potential binding sites for the cellular transcription factor LBP-1 between +138 and +150. A second regulatory element was mapped between +177 and +192 and can be specifically bound in vitro by protein from nuclear extracts of Burkitt cells. Although this element overlaps two partial E2F binding sites and Fp reporter plasmids could be activated in trans by the adenovirus E1A protein in cotransfection experiments, mutational analysis and DNA binding studies suggest that these are unlikely to be functional E2F response elements within Fp. We also demonstrate that Fp-directed transcription initiates at multiple sites within both the genome and the Fp reporter plasmids. However, the principal site of transcription initiation within the genome is not utilized within reporter plasmids, in which the majority of transcripts initiate at multiple sites between +150 and +200. This finding suggests that additional elements may be necessary for Fp to function normally in these assays or that the context of Fp within the viral genome is critical to its regulation. PMID- 7831775 TI - Identification and characterization of the orf virus type I topoisomerase. AB - Vaccinia virus (VV) and Shope fibroma virus (SFV), representatives of the orthopox and leporipox genera, respectively, encode type I DNA topoisomerases. Here we report that the 957-nt F4R open reading frame of orf virus (OV), a representative of the parapox genus, is predicted to encode a 318-aa protein with extensive homology to these enzymes. The deduced amino acid sequence of F4R has 54.7 and 50.6% identity with the VV and SFV enzymes, respectively. One hundred forty amino acids are predicted to be conserved in all three proteins. The F4R protein was expressed in Escherichia coli under the control of an inducible T7 promoter, partially purified, and shown to be a bona fide type I topoisomerase. Like the VV enzyme, the OV enzyme relaxed negatively supercoiled DNA in the absence of divalent cations or ATP and formed a transient covalent intermediate with cleaved DNA that could be visualized by SDS-PAGE. Both the noncovalent and covalent protein/DNA complexes could be detected in an electrophoretic mobility shift assay. The initial PCR used to prepare expression constructs yielded a mutant allele of the OV topoisomerase with a G-A transition at nt 677 that was predicted to replace a highly conserved Tyr residue with a Cys. This allele directed the expression of an enzyme which retained noncovalent DNA binding activity but was severely impaired in DNA cleavage and relaxation. Incubation of pUC19 DNA with the wild-type OV or VV enzyme yielded an indistinguishable set of DNA cleavage fragments, although the relative abundance of the fragments differed for the two enzymes. Using a duplex oligonucleotide substrate containing the consensus site for the VV enzyme, we demonstrated that the OV enzyme also cleaved efficiently immediately downstream of the sequence CCCTT. PMID- 7831774 TI - A natural antisense RNA derived from the HIV-1 env gene encodes a protein which is recognized by circulating antibodies of HIV+ individuals. AB - A naturally occurring antisense RNA, transcribed in the opposite direction and complementary to the envelope transcript, was identified in various cell lines chronically infected with HIV-1. In T cells, the antisense transcript is constitutively expressed and enhanced by activation with phorbol myristate acetate. The open reading frame corresponding to the antisense transcript, when expressed in vitro, encodes a protein with an apparent molecular mass of 19 kDa. Antibodies against this protein have been detected in several sera of HIV+ individuals and not in any of the noninfected control sera. These results indicate, for the first time, that expression of an antisense open reading frame most likely accompanies the HIV infection cycle in humans. PMID- 7831776 TI - Characterization of defective-interfering RNAs of rubella virus generated during serial undiluted passage. AB - During serial undiluted passage of rubella virus (RUB) in Vero cells, two species of defective-interfering (DI) RNAs of approximately 7000 and 800 nucleotides (nts) in length were generated (Frey, T. K., and Hemphill, M. L., Virology 164, 22-29, 1988). In this study, these DI RNAs were characterized by molecular cloning, hybridization with probes of defined sequence, and primer extension. The 7000-nt DI RNA species were found to be authentic DI RNAs which contain a single 2500- to 2700-nt deletion in the structural protein open reading frame (ORF) region of the genome. The 800-nt RNAs were found to be subgenomic DI RNAs synthesized from the large DI RNA templates. Analysis of the extent of the deletions using a reverse-transcription-PCR protocol revealed that the 3' end of the deletions did not extend beyond the 3' terminal 244 nts of the genome. The 5' end of the deletions did not extend into the nonstructural protein ORF; however, DI RNAs in which the subgenomic start site was deleted were present. Following serial undiluted passage of seven independent stocks of RUB, this was the only pattern of DI RNAs generated. DI RNAs of 2000 to 3000 nt in length were the majority DI RNA species in a persistently infected line of Vero cells, showing that other types of RUB DI RNAs can be generated and selected. However, when supernatant from the persistently infected cells was passaged, the only DI RNAs present after two passages were 7000 nts in length, indicating that this species has a selective advantage over other types of DI RNAs during serial passage. PMID- 7831777 TI - Intrachromosomal recombination mediated by the polyomavirus large T antigen. AB - We used a spleen necrosis virus-based retroviral vector to introduce the polyomavirus replication origin into rat cells and developed a system to analyze homologous recombination events that do not reconstitute a selectable marker. Introduction of the gene coding for the polyomavirus large T antigen into the cell lines by DNA transfection promoted high-frequency recombination between the two retroviral LTRs, leading to amplification and excision of DNA sequences. To analyze homology requirements, we constructed cell lines carrying only the replication origin without exogenous repeats. Most of the cell lines sustained high-frequency recombination, presumably by undergoing homologous recombination between repetitive DNA lying in the vicinity of the integrated origin. Our results indicate that homologous recombination promoted by large T antigen does not require recombination hot spots in the viral genome other than the replication origin and they explain the cytotoxicity observed in some cell types when large T antigen is expressed in the presence of a functional origin. PMID- 7831778 TI - Generation of humoral immune responses against herpes simplex virus type 2 in the murine female genital tract. AB - A murine model of genital infection with a thymidine kinase-deficient (tk-) strain of herpes simplex virus type 2 (HSV-2) was utilized to examine the local urogenital antibody response to HSV-2. Vaginal inoculation with HSV-2 tk- protected against a subsequent genital challenge with a lethal dose of virulent HSV-2. After primary vaginal infection, predominantly HSV-specific IgG antibodies were detected in serum and vaginal secretions. HSV-specific IgG antibody secreting cells (ASC) were detected first and in greatest numbers in the genital lymph nodes (gLN) after primary HSV-2 tk- inoculation. HSV-specific IgG or IgA ASC were not detected in the urogenital mucosa after primary HSV-2 vaginal infection. Vaginal HSV-2 challenge of HSV-immune mice resulted in increased HSV specific serum IgG antibody and vaginal IgA antibody titers. HSV-specific IgG ASC were detected by 4 days postchallenge in gLN and by Days 6 and 7 postchallenge in the spleen and genital mucosa. These results suggest that urogenital humoral responses originate in the gLN following HSV genital infection and that gLN may serve as the primary source of the HSV-specific IgG- and IgA-secreting cells present in the urogenital mucosa after vaginal challenge. PMID- 7831779 TI - Sequence elements of the adeno-associated virus rep gene required for suppression of herpes-simplex-virus-induced DNA amplification. AB - Herpes simplex virus (HSV) has been shown to induce DNA amplification in the host cell genome, which can be suppressed by the adeno-associated virus type 2 (AAV-2) rep gene (Heilbronn et al., 1990, J. Virol. 64, 3012-3018). In an attempt to define domains of Rep which are required for this effect a set of expression constructs was generated for Rep mutants with either N-terminal and/or C-terminal truncations, with small internal deletions, or with point mutations. In transient cotransfection assays these mutants were tested for the inhibition of HSV-induced DNA amplification and in parallel for DNA replication of a rep-defective AAV genome. Our data show that the C-terminal region of Rep where spliced and unspliced proteins differ is dispensable for both AAV DNA replication and inhibition of HSV-induced DNA amplification. The N-terminus of Rep is required for AAV DNA replication, whereas the first 174 amino acids can be deleted without loss of function for the inhibition of DNA amplification. Rep52 which starts at methionine 225 is neither sufficient, nor required for this effect. We further analyzed the region between amino acids 174 and 225: A stretch of 16 highly hydrophilic amino acids is dispensable for the inhibition of DNA amplification, but it is required for AAV DNA replication. Deletion of two short motifs spanning putative protein kinase C phosphorylation sites each strongly reduce both AAV DNA replication and inhibition of DNA amplification, whereas a single amino acid substitution of one of these sites abolished AAV DNA replication with no effect on the inhibition of DNA amplification. Our data show that most, but not all, of the sequence elements within the N-terminus of Rep78 required for AAV DNA replication coincide with those required for the inhibition of HSV-induced DNA amplification. A replication-negative version of Rep78 comprising the internal 60% of the protein still carry the entire inhibitory function for HSV-induced DNA amplification. PMID- 7831780 TI - Synergistic effects on ganglionic herpes simplex virus infections by mutations or drugs that inhibit the viral polymerase and thymidine kinase. AB - Herpes simplex virus encodes proteins, such as DNA polymerase, that are essential for its replication and proteins, such as thymidine kinase, that are not essential for replication in cell culture, but are important for pathogenesis in animal models. However, certain mutations affecting these proteins exert little or no effect on replication or pathogenesis. We tested the effects of combining two such mutations--one that alters DNA polymerase and one that decreases but does not abolish thymidine kinase activity--on replication in cultured cells and on acute and latent infections in mice. The double mutant replicated similarly to the single mutants and wild-type virus both in cell culture and acutely in the mouse eye. However, it was severely impaired for acute replication in trigeminal ganglia and for reactivatable latent infections. This impairment depended upon the polymerase mutation. Similarly, although Ro 31-5140, a thymidine kinase inhibitor, did not potentiate the antiviral effects of phosphonoacetic acid, a polymerase inhibitor, in cell culture, the two drugs in combination substantially inhibited viral reactivation from latency at concentrations that had little or no effect when used singly. These synergistic effects may have implications for viral functions during pathogenesis and for antiviral chemotherapy. PMID- 7831781 TI - Identification of the binding site for the Shc protein to the avian erythroblastosis virus (AEV-H) v-erbB protein. AB - Activation of tyrosine kinase growth factor receptors leads to autophosphorylation of specific tyrosine residues within the intracellular region of the receptor. The phosphorylated tyrosines serve as binding sites for various cytoplasmic proteins. The Shc protein is one such protein. Upon activation of the chicken c-erbB protein by ligand Shc binds to the c-erbB protein and becomes phosphorylated on tyrosine. Similarly, Shc is found bound to the constitutively phosphorylated v-erbB protein encoded by the avian erythroblastosis virus strain H, AEV-H. Utilizing various mutant forms of the v-erbB protein, the residue equivalent to tyrosine 1154 in the chicken c-erbB protein was shown to serve as a binding site for the Shc protein to the AEV-H v-erbB protein. However, binding to this site was not essential for transformation since v-erbB oncoproteins which lacked this site still transform both erythroid cells and fibroblasts. PMID- 7831782 TI - Host-specificity restriction by bromovirus cell-to-cell movement protein occurs after initial cell-to-cell spread of infection in nonhost plants. AB - The nonstructural 3a protein of the positive-strand RNA bromoviruses is required for infection spread in plants and is a crucial determinant of host specificity in systemic infection. To determine the paths of wild-type (wt) bromovirus infection spread, the step at which 3a mutants are arrested, and the nature of the host specificity associated with the 3a gene, we used in situ hybridization to examine infection spread by cowpea chlorotic mottle bromovirus (CCMV) and its derivatives at the level of individual cells in cowpea leaf epidermis. From 1 to 3 days post inoculation (dpi), wt CCMV spread from initially infected cells to adjacent cells, creating expanding infection foci whose radii grew by one additional epidermal cell diameter every 5 hr. By 3 to 4 dpi, vascular elements contacting such foci acted as conduits for further infection spread. By contrast, a 3a frameshift derivative multiplied in initially infected epidermal cells but failed to move into neighboring cells even by 4 dpi, showing that the 3a gene is essential for cell-to-cell spread. Most interestingly, a CCMV derivative with the 3a gene replaced by that of a bromovirus not adapted to cowpea, brome mosaic virus (BMV), initially spread from cell to cell in cowpea plants, but stopped spreading between 1 and 2 dpi, when most infection foci encompassed 40-80 epidermal cells. Thus, the host-specificity restriction imposed by BMV 3a protein did not result from an inability to direct the spread of infection out of initially infected cowpea cells, but from a much later block. The apparent absence of any preexisting anatomical boundary at the limit of infection spread and localized tissue changes at the infection foci suggested that induced host responses might have contributed to this block. PMID- 7831783 TI - Aggregation of VSV M protein is reversible and mediated by nucleation sites: implications for viral assembly. AB - Purified M protein of VSV has been reported to aggregate at low NaCl concentration. Using light scattering, analytical centrifugation, and electron microscopy (EM), we have studied this phenomenon. Our results demonstrate that self aggregation of M protein can be reversed by increasing the salt concentration. Below 250 mM NaCl, there is an equilibrium between aggregates and monomeric M protein. Most importantly, we demonstrate that aggregation only occurs in the presence of nucleation sites and that these sites are sensitive to trypsin. We have found conditions under which these nucleation sites can be eliminated, after which M remains soluble even at low salt concentration. Finally, using EM, we show that the aggregates of purified M protein share common structural aspects with the previously described internal "cigar" around which the nucleocapsid is wrapped. These new results help to explain why M is a soluble protein in the cytoplasm of the infected cell just up to the moment that it is integrated into the budding virion. PMID- 7831784 TI - Nucleotide sequence of the bean strain of southern bean mosaic virus. AB - The genome of the bean strain of southern bean mosaic virus (SBMV-B) comprises 4109 nucleotides and thus is slightly shorter than those of the two other sequenced sobemoviruses (southern bean mosaic virus, cowpea strain (SBMV-C) and rice yellow mottle virus (RYMV)). SBMV-B has an overall sequence similarity with SBMV-C of 55% and with RYMV of 45%. Three potential open reading frames (ORFs) were recognized in SBMV-B which were in similar positions in the genomes of SBMV C and RYMV. However, there was no analog of SBMV-C and RYMV ORF 3. From a comparison of the predicted sequences of the ORFs of these three sobemoviruses and of the noncoding regions, it is suggested that the two SBMV strains differ from one another as much as they do from RYMV and that they should be considered as different viruses. PMID- 7831785 TI - Direct evaluation of the immunodominance of a major antigenic site of foot-and mouth disease virus in a natural host. AB - The immunodominance of a major antigenic site of foot-to-mouth disease virus (FMDV) (serotype C; clone C-S8c1) in a natural host has been evaluated by serum immunoglobulin fractionation. Nineteen sera from either convalescent or vaccinated swine were fractionated by affinity chromatography using a synthetic peptide representing antigenic site A (the G-H loop of capsid protein VP1) coupled to a Sepharose matrix. Antigen-binding and neutralizing activities of serum fractions were quantitated. On average, about 57 or 27% of the virus neutralizing activity (and about 35 or 12% of the virus-binding activity) from convalescent or vaccinated swine, respectively, corresponded to antibodies against site A. The results provide direct evidence of the important contribution of site A, and also of additional sites unrelated to site A, in the evoking of neutralizing antibodies by FMDV in a natural host. The proportion of antibodies directed to site A varied greatly among individual swine. Some animals evoked remarkably low levels of antibodies specific for site A although they were competent to raise antibodies against other antigenic sites of FMDV. Thus, the major antigenic site of FMDV shows heterogeneous dominance in a natural host. Possible implications for evolution of viral quasispecies are discussed. PMID- 7831786 TI - A defective movement protein of TMV in transgenic plants confers resistance to multiple viruses whereas the functional analog increases susceptibility. AB - Transgenic tobacco plants that express a gene encoding a defective mutant of the tobacco mosaic virus (TMV) movement protein which are known to be resistant to several tobamoviruses were inoculated with viruses from different taxonomic groups to determine the breadth of resistance. There were significant delays in the time of appearance of disease symptoms and/or there was reduced systemic accumulation of virus in upper leaves of plants inoculated with tobacco rattle tobravirus, tobacco ringspot nepovirus, alfalfa mosaic alfamovirus, peanut chlorotic streak caulimovirus, and cucumber mosaic cucumovirus. Conversely, tobacco plants that express a gene encoding the functional tobacco mosaic virus wild-type movement protein accelerated symptom development, enhanced the severity of symptom formation, and/or increased the accumulation of these viruses and, additionally, TMV. Our results indicate that there are similar functions among the movement proteins of a number of plant viruses despite the apparent lack of sequence similarity between them. PMID- 7831787 TI - Expression and functional analysis of a baculovirus gene encoding a truncated protein kinase homolog. AB - Autographa californica nuclear polyhedrosis virus (AcMNPV) potentially encodes a 215-amino acid polypeptide containing 6 out of 11 motifs conserved among eukaryotic protein kinases (Morris et al., Virology 200, 360-369, 1994). We examined the expression of this gene, named pk2, at the transcriptional and translational levels and the possible role of the gene during baculovirus replication in cell culture and insect larvae. Northern (RNA) blot analysis revealed that pk2 was transcribed primarily as an early 1.2-kb RNA. Western blot analysis showed that pk2 was expressed as a 25-kDa protein, PK2, which was present both early and late during virus infection. To examine the function(s) of pk2, we constructed a mutant baculovirus, vKINdel, in which one-third of the PK2 coding region was deleted and then compared the characteristics of vKINdel with wild-type AcMNPV and a marker-rescued revertant. The pk2 deletion mutation had no discernable effect on the number, size, or appearance of plaques, the kinetics of protein synthesis or protein phosphorylation profiles during virus infection of cultured SF-21 cells. Deletion of pk2 also had no significant influence on the infectivity or virulence of the baculovirus in larval bioassays and the level of occluded virus production was normal. Thus, pk2 does not appear to have a significant influence on virus replication in the host systems examined. PMID- 7831788 TI - The Marek's disease virus (MDV) unique short region: alphaherpesvirus-homologous, fowlpox virus-homologous, and MDV-specific genes. AB - Despite its previous classification as a gammaherpesvirus, primarily due to its lymphotropism, Marek's disease virus (MDV), an oncogenic avian herpesvirus, is phylogenetically more related to the "neurotropic" alphaherpesviruses, characterized by its prototype, herpes simplex virus (HSV) (Buckmaster et al., 1988, J. Gen. Virol. 69, 2033-2042). In this report we present the DNA sequence of an 11,286-bp DNA segment encompassing the entire 11,160-bp-long Us region of the oncogenic avian herpesvirus, Marek's disease virus. Eleven open reading frames (ORFs) likely to code for proteins were identified; of these, 7 represent homologs exclusive to alphaherpesvirus S component genes. These include MDV counterparts of HSV US1 (ICP22), US2, US3 (a serine-threonine protein kinase), US6, US7, and US8 (HSV glycoproteins gD, gI, and gE, respectively), and US10. Three additional ORFs were identified with no apparent relation to any sequences currently present in the SwissProt or GenBank/EMBL databases, while a fourth was found to exhibit significant homology to an uncharacterized fowlpox virus (FPV) ORF. Having precisely identified the IRs-U(s) and U(s)-TRs junctions, we have corrected and clarified their previously reported locations. By characterizing genes encoding three new alphaherpesvirus-related homologs (US1, US8, and US10), completing the sequence for a fourth (US7), and identifying 2 new MDV-specific ORFs (SORF1 and SORF3) and a fowlpox homolog (SORF2), our sequence analysis of the "virulent" GA strain of MDV (vMDV) extends upon that of a 5255-bp segment located in the U(s) region of the "very virulent" RB1B strain of MDV (vvMDV) (Ross et al., 1991, J. Gen. Virol. 72, 939-947; 949-954). These two sequences were found to exhibit 99% identity at both nucleotide and predicted amino acid levels. Combined with the fact that MDV U(s) sequences failed to show statistically significant CpG deficiencies, our analysis is consistent with MDV bearing a closer phylogenetic relation to alphaherpesviruses than to gammaherpesviruses. Because alphaherpesvirus-specific U(s) region genes are primarily nonessential for virus replication, they are thought to be important biological property determinants. Thus, our sequence provides a foundation for further MDV studies aimed at resolving the apparent discrepancy between MDV's genetic and biologic properties. PMID- 7831789 TI - Analysis of 45 kb of DNA located at the left end of the chlorella virus PBCV-1 genome. AB - Forty-five kilobases of DNA, including the previously sequenced 2.2-kb inverted repeat region, located at the left termini of the 330-kb Chlorella virus PBCV-1 genome were sequenced and analyzed. Eighty-five complete open reading frames (ORFs) larger than 195 nucleotides were identified. Thirty-seven of the 85 ORFs, which are densely packed on both strands of the DNA, were considered major ORFs. Fifteen of the major ORFs have similarity to genes in the databases, including bacterial glycerophosphoryl diester phosphodiesterase, bacteriophage T4 endonuclease V, D-isomer specific 2-hydroxyacid dehydrogenases, and beta-alanine synthetase and bacterial nitrilases. Two major ORFs resemble the virus major capsid protein. Three major ORFs contain three or more ankyrin-like repeat elements and four ORFs encode proline-rich proteins. PMID- 7831790 TI - Transport of a lysosomally targeted Rous sarcoma virus envelope glycoprotein involves transient expression on the cell surface. AB - The details of intracellular transport pathways for glycosylated proteins remain incompletely described. We previously described a mutant Rous sarcoma virus envelope glycoprotein (gp), mu 26, with an altered membrane-spanning domain that was targeted to lysosomes after traversing the trans-Golgi. This mutant protein was not detectable on the cell surface by immunofluorescence, but its pathway for degradation remained unclear. To investigate this we have employed a second env mutation, S19, that results in a protein which is defective for normal cleavage/activation by intracellular enzymes, but remains susceptible to cleavage by extracellular proteases. Cleavage/activation of the double mutant by trypsin, which could only occur if it was exposed on the cell surface, was observed, indicating that the plasma membrane is an intermediate destination in the transport of this mutant protein. To substantiate these results, cells expressing the mu 26 glycoprotein were incubated with an antibody specific for the native protein in the presence of chloroquine. The specific accumulation of this antibody/gp complex in vesicles, as detected by internal immunofluorescence, confirmed the trypsin cleavage results. We conclude that this rapidly degraded mutant protein is transported from the trans-Golgi to the cell surface, where it is only transiently exposed, and then rapidly endocytosed and lysosomally degraded. The relevance of these results to the targeting of lysosomal proteins is discussed. PMID- 7831791 TI - Functional characterization of the proteolytic activity of the tomato black ring nepovirus RNA-1-encoded polyprotein. AB - Translation of tomato black ring virus (TBRV) RNA-1 in a rabbit reticulocyte lysate leads to the synthesis of a 250K polyprotein which cleaves itself into smaller proteins of 50, 60, 120, and 190K. Polypeptides synthesized from synthetic transcripts corresponding to different regions of TBRV RNA-1 are processed only when they encode the 23K protein delimited earlier by sequence homology with the cowpea mosaic virus 24K protease. The proteolytic activity of this protein is completely lost by mutating residues C170 (to I) or L188 (to H), residues which align with conserved residues of the viral serine-like proteases. The 120K protein is generated by cleavage of the dipeptide K/A localized in front of the VPg but is not further cleaved in vitro at the K/S site (at the C terminus of the VPg) or between the protease and polymerase domains. However, both the protein VPgProPol (120K) and the protein ProPol (117K) produced in vitro from synthetic transcripts can cleave in trans the RNA-2-encoded 150K polyprotein, but they cannot cleave in trans polypeptides containing a cleavage site expressed from RNA-1 transcripts in which the protease cistron is absent or modified. PMID- 7831792 TI - Prevention of retrovirus-induced neurological disease by infection with a nonneuropathogenic retrovirus. AB - Perinatal infection of susceptible mice with the neurotropic retrovirus CasBrE leads to a noninflammatory spongiform degeneration of the central nervous system with a long incubation period of up to 1 year. Virus replication in infected animals can be suppressed by administration of antiviral antibodies, cytotoxic T cells, or by AZT treatment, which results in partial to complete protection from neurological disease. A highly neuropathogenic chimeric retrovirus, FrCasE, which contains the envelope gene of CasBrE, induces rapid neurodegeneration within only 16 days. Here we report that this fatal disease could be prevented if a nonneuropathogenic Friend murine leukemia virus was administered to mice prior to their infection with FrCasE. This double inoculation led to a substantial reduction of the replication level of FrCasE in spleen and CNS. Only live but not heat-inactivated nonneuropathogenic virus was able to protect from FrCasE-induced neurological disease. The extent of protection was influenced by the viral envelope gene and the kinetics of replication of the nonneuropathogenic virus. These observations in addition to the rapidity of the effect make it likely that competition for replication sites through the mechanism of viral interference is responsible for the protection. Resistance was demonstrable in vivo even when the "protecting" and "challenge" virus belonged to different in vitro interference groups. However, the protection was considerably weaker than that seen between viruses belonging to the same interference group. PMID- 7831793 TI - Mutational analysis of the cucumber necrosis virus coat protein gene. AB - A series of frameshift, deletion, and inversion mutations were made in the coat protein (CP) gene of the icosahedral cucumber necrosis tombusvirus (CNV) to investigate the role of the CP protruding (P) domain in the production of virus particles and, also, to investigate the basis for the accumulation of CP deletion derivatives previously reported in plants inoculated with PD(-), a P-domainless CNV CP mutant. P-domainless coat protein subunit could be detected in extracts of CP mutant-infected plants; however, virus-like particles could not, suggesting that the P domain is essential for tombusvirus particle assembly and/or stability. In addition, each of the P-domain mutants analyzed invariably produced coat protein deletion derivatives in infected plants whereas shell domain mutants rarely produced deletion derivatives. Finally, P-domain inversion and deletion mutants accumulated deletion derivatives very rapidly in comparison to P-domain frameshift mutants. Protoplast studies show that PD(-) RNA inoculum does not undergo further deletion in infected protoplasts, suggesting that PD(-) CP deletion derivatives preferentially accumulate in plants because they have a greater capacity for cell-to-cell movement. PMID- 7831794 TI - In vitro and in vivo characterization of a second functional hairpin ribozyme against HIV-1. AB - We have constructed a hairpin ribozyme targeted to cleave a conserved sequence in the HIV-1 pol gene. The ribozyme was modified to include a structure-stabilizing tetraloop. In vitro studies revealed a cleavage efficiency unprecedented for hairpin ribozymes (Kcat/Km = 75 min-1 microM-1). Stable retroviral vector transduction of this ribozyme gene in T-cell lines resulted in long-term ribozyme expression. As compared to control vector transduced T-cells, the pol ribozyme transduced cells exhibited significant inhibition of different strains of HIV-1 virus production; this protection was greater when ribozyme expression was driven from an internal pol III promoter (adenovirus VA1) than when driven by a pol II promoter (the MMLV LTR). These results further demonstrate the potential of hairpin ribozymes as anti-HIV gene therapy agents and suggest possibilities for employing combinations of independently targeted hairpin ribozymes. PMID- 7831795 TI - Structure and biological activity of the subgenomic Mtv-6 endogenous provirus. AB - The Mtv-6 provirus has an incomplete genome, but retains a functional superantigen gene (sag) which directs the thymic deletion of CD4+ T cells expressing T cell receptors containing the V beta 3 or V beta 5 chains. To better understand the Mtv-6 superantigen, the structure and biological activity of the Mtv-6 provirus was analyzed. First, the complete nucleotide sequence was determined, and the mutation producing the subgenomic provirus was identified. Second, the nucleotide sequence of the 5' end of the sag gene transcript (including the splice junction) was determined by sequence analysis of a cDNA clone. Third, the superantigen activity of Mtv-6 was analyzed in mice carrying the Mtv-6 provirus isolated by selective breeding on a genetic background free of endogenous and exogenous mouse mammary tumor virus (MMTV). These studies demonstrate that (i) the Mtv-6 provirus contains a 6.2-kb deletion between two 12 bp direct repeats encompassing the central portion of the provirus but not affecting sag gene splicing or translation, (ii) the sag gene transcript has the structure predicted from previous S1 nuclease mapping studies, and (iii) the Mtv 6 superantigen can direct thymic deletion of target V beta 3+ and V beta 5+ T cells in the absence of gene products from full-length MMTV proviruses. PMID- 7831796 TI - Coding density of the turnip yellow mosaic virus genome: roles of the overlapping coat protein and p206-readthrough coding regions. AB - More than one-third of the turnip yellow mosaic virus (TYMV) genome simultaneously encodes two ORFs. We have investigated the functions of the overlapping coat protein ORF and readthrough domain of ORF-206 in the 3' region of the genome. TYMC-206 RNA, in which a second stop codon has been positioned to prevent ORF-206 readthrough, induced infections in protoplasts and plants that were indistinguishable from wild type. ORF-206 readthrough is thus nonessential. Nevertheless, TYMV-221 RNA, in which the ORF-206 stop codon was replaced with a tyrosine codon to force readthrough, was infectious to protoplasts, suggesting that a role for ORF-206 readthrough under certain conditions is possible. TYMV RNA variants that produce truncated or no coat protein were used to show that the coat protein is dispensable for local movement but necessary for systemic spread of virus in plants. Studies in protoplasts showed that (-) RNA levels are normal in the absence of coat protein, but (+) strand levels are decreased about 10-fold relative to wild-type infections. A mutant with a short C-terminal coat protein extension that formed virions less stable than normal demonstrated the protective role of capsids toward genomic RNA. The evolutionary implications of the dense information content of the TYMV genome are discussed. PMID- 7831798 TI - Induction of protection against Borna disease by inoculation with high-dose attenuated Borna disease virus. AB - Borna disease is a chronic neurological disease caused by an enveloped negative strand RNA virus (BDV). Experimental disease can be reproduced in rats with brain homogenates derived from infected animals or with virus derived from infected cells in culture. The virus replicates in cultured cells without evidence of cytopathic effect or production of significant levels of cell-free virus. Borna disease is caused by an immunopathological response to viral infection of neural cells. To further investigate the pathogenesis of Borna disease, rats were inoculated with different doses of BDV attenuated by culture in MDCK cells. Low doses of attenuated BDV (10(2)-10(4) TCID50) resulted in typical clinical disease and severe encephalitis; however, the lag period between inoculation and disease was considerably longer than that with virulent BDV. In contrast, animals inoculated with a high dose of attenuated BDV (10(5)-10(6) TCID50) did not develop clinical disease, although a mild encephalitic response was present that did not progress beyond the mild encephalitis. Animals inoculated with a high dose of BDV developed high titers of anti-BDV antibody and were protected against virulent challenge. Protection was correlated with the rapid induction of an immune response in the animals and the lack of any biologically detectable virus in the CNS. PMID- 7831797 TI - The role of the major tegument protein VP8 of bovine herpesvirus-1 in infection and immunity. AB - The tegument of bovine herpesvirus-1 (BHV-1) carries an abundant protein of 96 kDa, termed VP8. Immunolabeling using VP8-specific antiserum and colloidal gold labeled protein A as the electron-dense marker was used to identify VP8 in the virions and virus-infected cells. VP8 was confirmed to be a tegument protein that, like the herpes simplex virus-1 homologue VP13/14, contains O-linked carbohydrates. VP8 was found in the nucleus of virus-infected cells as early as 2 hr postinfection. Since VP8 is a gamma2 protein, this protein cannot be newly synthesized at this time and must be acquired from the inoculum. This supports the hypothesis that early during infection, VP8 has a function in modulation of alpha gene expression. Later during infection, VP8 was observed in the cytoplasm around nucleocapsids and in dense inclusions, which accumulated in the cisternae of the Golgi. In addition, de novo-synthesized VP8 continued to accumulate in the nucleus in dense areas and around nucleocapsids. In calves, VP8 stimulated T cell proliferation and antibody production, both after BHV-1 challenge and after immunization with purified VP8. These results suggest a role for VP8 in the induction of humoral and specifically cell-mediated immunity to BHV-1. PMID- 7831799 TI - Nucleotide sequence and transcriptional analysis of the DNA polymerase gene of Bombyx mori nuclear polyhedrosis virus. AB - A gene encoding a putative DNA polymerase (pol) of Bombyx mori nuclear polyhedrosis virus (BmSNPV) was cloned and sequenced. The gene included an open reading frame (ORF) encoding a polypeptide of 988 amino acids with a predicted molecular mass of 114.65 kDa. The deduced amino acid sequence of the BmSNPV pol ORF showed an overall identity of 96 and 45% to those of the Autographa californica NPV (AcMNPV) pol ORF and the Lymantria dispar NPV pol ORF, respectively, and contained sequences conserved in a variety of eukaryotic and viral replicative DNA polymerases. The BmSNPV pol lacked a canonical TATAA element but contained a G+C-rich sequence in the transcriptional initiation region. Analyses by Northern blot hybridization, RNase protection assay, primer extension, and 3' and 5' RACE (rapid amplification of cDNA ends) showed that at least seven different transcripts of approximately 3.1 kb that shared a common 3' end were expressed from the BmSNPV pol. The expression of these transcripts from BmSNPV pol was regulated differentially during virus infection. Transcription of five of the seven species initiated in the close vicinity of and within the motif 5'-GCGTGCT-3'. One transcript placed its initiation site within the motif 5' AGAGCGT-3' and the remaining one within the motif 5'-GGCGGTGG-3'. The motifs 5' GCGTGCT-3' and 5'-AGAGCGT-3' have been identified in pol and other genes of AcMNPV as conserved sequences containing transcriptional initiation sites, whereas the motif 5'-GGCGGTGG-3', which is arranged as a direct repeat in BmSNPV pol but not in AcMNPV pol, has not been defined as the sequence responsible for transcriptional initiation sites. The BmSNPV pol transcripts were detectable at 2 hr postinfection (p.i.), peaked at 10 hr p.i., and declined to a low level by 18 hr p.i. The expression of BmSNPV pol was not inhibited but delayed dramatically by the protein synthesis inhibitor cycloheximide upon treatment of infected cells, whereas aphidicolin, an inhibitor of DNA polymerase, inhibited BmSNPV pol transcription. These results suggest a complicated and unique mechanism for the regulation of BmSNPV pol expression. PMID- 7831800 TI - Activities and substrate specificity of the evolutionarily conserved central domain of retroviral integrase. AB - The retroviral integrase (IN) is a virus-encoded enzyme that is essential for insertion of viral DNA into the host chromosome. In order to map and define the properties of a minimal functional domain for this unique viral enzyme, a series of N- and C-terminal deletions of both Rous sarcoma virus (RSV) and human immunodeficiency virus (HIV) INs were constructed. The RSV IN deletion mutants were first tested for their ability to remove two nucleotides from the end of a substrate representing the terminus of viral DNA in order to assess the contribution of N and C regions towards this reaction, referred to as processing. The results suggest that C-terminal amino acids of the intact RSV protein are required to maintain specificity of the processing reaction. Though deficient for processing, the RSV deletion mutants exhibited a secondary endonucleolytic activity that was indistinguishable from that of wild-type IN, demonstrating that all retained some enzymatic activity. RSV, and a larger set of HIV-1, IN deletion mutants were then tested for their ability to perform an intramolecular, concerted cleavage-ligation reaction using an oligodeoxynucleotide substrate that mimics the intermediate viral-host DNA junction found prior to the final step of covalent closure. The composite results from such analyses define a minimal functional central region of approximately 140 amino acids for each enzyme that includes the highly conserved D,D(35)E domain. Results with HIV-1 and HIV-2 IN also indicate that the efficiency of concerted cleavage-ligation depends upon the presence of CA/GT base pairs within the viral component of the DNA substrate at the reaction site. Even the isolated central region of HIV-1 IN exhibited this sequence requirement for optimal activity. We conclude that this evolutionarily conserved central region of IN not only encodes residues that are required for the catalytic activity of the enzyme but also harbors some or all of the determinants responsible for recognition of the CA/GT dinucleotides that are present at the ends of all retroviral DNAs. PMID- 7831801 TI - Multibranched peptide constructs derived from the V3 loop of envelope glycoprotein gp120 inhibit human immunodeficiency virus type 1 infection through interaction with CD4. AB - The V3 loop of the gp120 of human immunodeficiency virus type 1 (HIV-1) is assumed to be involved in HIV-1-mediated membrane fusion. V3-derived peptides have been shown either to enhance or to prevent HIV-1 infection. Multibranched peptide constructs (MBPCs) derived from the V3 North American/European consensus sequence were designed to sort out these conflicting findings. At 5 microM, MBPC1 (8-branched GPGRAF) totally, and MBPC2 ([RKSIHIGPGRAFYT]4) partially, inhibited HIV-1LAI infection, whereas the GPGRAF monomer had only a limited effect. A peptide of the entire V3 consensus loop and a control MBPC had no detectable activity. The 5 microM MBPC1 HIV-1-inhibiting concentration was not cytotoxic, nor did it alter T lymphocyte allogeneic, antigen-, or mitogen-induced reactivities, and it was about 5- to 50-fold lower (MBPC2 and MBPC1, respectively) than that resulting in 50% cell death. Analysis of MBPC immunoreactivity showed that MBPC2, but not MBPC1, strongly reacted with human HIV-1 positive sera. Only MBPC2 elicited significant antibody responses in rabbits. The V3-derived MBPCs bound to CD4+ cells, as determined by immunofluorescence analysis. The binding was inhibited either by soluble CD4 or by CD4 monoclonal antibody (mAb) MT151, which recognizes the CDR3 region of the D1 domain of CD4, but not by other CD4 mAbs Leu3a, OKT4A, Q4021, 13B8-2, 5A8, RFT4, nor by the CD26 mAb BA5. Therefore, it appears likely that MBPCs inhibit HIV-1 infection by interacting with the CDR3 region of CD4 or with a region in its vicinity. PMID- 7831802 TI - The product of the UL6 gene of herpes simplex virus type 1 is associated with virus capsids. AB - We report on the analysis of the UL6 and UL7 open reading frames of the herpes simplex virus type 1 (HSV-1) genome. The UL6 and UL7 transcripts were identified in HSV-1-infected cells by Northern blotting and shown to be coterminal at their 3' ends. Both transcripts were synthesized in the presence of phosphonoacetic acid, although in reduced amounts, indicating that UL6 and UL7 are expressed as delayed-early or gamma-1 genes. The 5' ends of the two transcripts were mapped by S1 nuclease and primer extension analysis. A polyclonal antiserum directed against an Escherichia coli-expressed 6 x His-UL6 fusion protein identified a protein of approximate M(r) 75,000 in cells infected with either HSV-1 or with a vaccinia virus recombinant expressing the HSV-1 UL6 protein. As with the transcript, the UL6 protein was synthesized at reduced levels in the absence of viral DNA replication. Western immunoblotting showed that the UL6 protein was present in purified virions but not in L-particles of HSV-1, and that it was located exclusively in the tegument/capsid fraction of virion. Further analysis of the UL6 protein revealed that this protein was associated with virus capsids. PMID- 7831803 TI - Dual translational start motif evolutionarily conserved in the holin gene of Bacillus subtilis phage phi 29. AB - Holins represent phage encoded lysis functions required for transit of the phage murein hydrolases to the periplasm. The Lambda S, phage 21 S, and P22 13 holin genes contain a dual translational start motif, beginning with Met1-Lys2-X-Met3. In all cases both start codons at the 5' end of the respective holin gene are utilized. The resulting polypeptides have opposing functions, with the longer product acting as an inhibitor of the shorter one. The 131-codon gene 14 of Bacillus subtilis phage phi 29 encodes the holin function, whereas the downstream gene 15 codes for a lysozyme. phi 29 Gene 14 begins with Met1-Lys2-Met3. Here, we present in vitro and in vivo evidence for the expression of two protein 14 species consisting of 129 and 131 amino acids, respectively. These data suggest that the lysis control mechanism based on two holin species, which has been shown to be operational in the temperature Escherichia coli phages Lambda and 21, and in the Salmonella typhimurium phage P22, is evolutionarily conserved in the lytic B. subtilis phage phi 29. PMID- 7831804 TI - Cellular actin-binding ezrin-radixin-moesin (ERM) family proteins are incorporated into the rabies virion and closely associated with viral envelope proteins in the cell. AB - Cellular ezrin-radixin-moesin (ERM) family proteins, members of the actin-binding proteins of the band 4.1 superfamily, were detected in the virions of enveloped viruses, such as rabies, vesicular stomatitis, Newcastle disease, and influenza viruses. To elucidate the mechanism of ERM protein incorporation, we investigated possible association of ERM proteins with viral components in rabies virus infected BHK-21 cells. Double immunofluorescence studies demonstrated that the ERM proteins are concentrated in the microvilli, where the colocalized viral G protein was also seen. Viral G protein expressed in the G cDNA-transfected COS-7 cells also displayed similar distributions to those seen in the virus-infected cells. Both the ERM and viral envelope proteins were coprecipitated by anti-viral G antibody from lysates of the virus-infected cells, while the anti-ERM antibody coprecipitated viral G and ERM proteins. These observations suggest that the ERM proteins are closely associated with viral envelope proteins in the cell, which would be involved in the selective incorporation of cellular actin into the virion. PMID- 7831805 TI - Expression of a Tat-inducible herpes simplex virus-thymidine kinase gene protects acyclovir-treated CD4 cells from HIV-1 spread by conditional suicide and inhibition of reverse transcription. AB - Cellular expression of the herpes simplex virus type 1 thymidine kinase (HSV1-TK) gene promotes cell death in the presence of specific nucleoside analog substrates such as acyclovir (ACV). We have reported that lymphoid CD4+ cells harboring an HSV1-TK gene, under the transcriptional control of the HIV-1 long terminal repeat (HUT-TK), are completely protected from HIV-1 spread in the presence of 10 microM ACV. In this report we clarify the efficiency, generality, and mechanism of this protective effect. We show that the protection from HIV-1 spread in HUT-TK cells obtains from both an inhibition of HIV reverse transcription by ACV metabolites and an HIV-induced and ACV-dependent cell killing. We also demonstrate that monocytic cells harboring the HIV-1-inducible HSV1-TK gene are protected from HIV spread in the presence of ACV. These observations facilitate the design of therapeutic strategies to limit HIV replication based on HSV1-TK expression. PMID- 7831806 TI - Coat protein of the Ectocarpus siliculosus virus. AB - Ectocarpus siliculosus virus, EsV, multiplies in sporangia and gametangia of the marine brown alga Ectocarpus siliculosus. We describe an improved method for the isolation of morphologically intact and infectious virus from diseased plants. We show that treatment of virus particles with high concentrations of CsCl results in a substantial loss of structural proteins. One of the proteins which resists CsCl treatment is glycoprotein-1, the largest of the three viral glycoproteins. We have isolated an EsV genomic fragment with an open reading frame encoding glycoprotein-1. The predicted amino acid sequence is rich in hydrophilic amino acids, but contains hydrophobic regions close to the amino and carboxy termini. A discrepancy between the molecular weight predicted from the coding region and the molecular weight determined by gel electrophoresis suggests that proteolytic processing is required for the maturation of the protein. PMID- 7831807 TI - Characterization of human immunodeficiency virus type 1 mutants with decreased sensitivity to proteinase inhibitor Ro 31-8959. AB - A human immunodeficiency virus type 1 (HIV-1) variant with highly reduced susceptibility to Ro 31-8959, an inhibitor of the viral proteinase, has been selected by repeated passage of wild-type virus in CEM cells in the presence of increasing concentrations of the inhibitor. Peptide sequences of the proteinase of selected virus were obtained from proviral DNA. Sequence comparison to wild type (wt) proteinase demonstrated two amino acid substitutions in the resistant virus, a Gly to Val exchange at position 48 and a Leu to Met exchange at position 90. Furthermore, sequences of intermediate passage virus suggest contributions from positions 12, 36, 57, and 63 in early steps of resistance development. The selected virus showed a ca. 40-fold increase in 50% inhibitory concentration of Ro 31-8959. Growth kinetics of resistant virus were comparable to wild-type virus and the resistant genotype proved to be stable in the absence of inhibitor. Directed mutagenesis of the HIV-1 HXB2 proteinase at positions 48 and 90 suggested that each mutation alone led to a moderate decrease in sensitivity of the recombinant virus to proteinase inhibitor. However, a recombinant virus carrying both mutations in the proteinase gene showed a significant reduction in its sensitivity to Ro 31-8959 thus proving the importance of these exchanges for the resistance phenotype. PMID- 7831808 TI - The proteins of lymphocyte- and macrophage-tropic strains of simian immunodeficiency virus are processed differently in macrophages. AB - Since the pathogenesis of SIVmac disease complex is thought to be explained by the tropism of the infecting virus for either CD4+ T-lymphocytes or macrophages or both types of cells, we compared the infection in primary macaque macrophages with molecularly cloned, lymphocyte-tropic SIVmac239 and a cloned, macrophage tropic chimeric virus (SIVmac239/17E) whose env gene was derived from brain of a macaque (17E) dying from SIV-induced encephalopathy. SIVmac239/17E caused a productive, syncytial cytopathic infection accompanied by accumulation of virus particles within cytoplasmic vesicles of the macrophages. Pulse-chase and immune precipitation studies showed that both the viral glycoprotein precursor (gp160) and the gag precursor (p57) were cleaved into gp120 and p27, respectively, and both were released into the culture medium of infected cells, although most of the p27 remained cell associated. SIVmac239 also infected macrophages, but in comparison to SIVmac239/17E, minimal virus replication occurred. Immunocytostaining revealed that while occasional syncytia were observed in cultures, the majority of the infected cells were not associated with syncytium formation. Ultrastructural studies did not reveal the accumulation of virions within infected macrophages. Pulse-chase studies showed that both gp160 and p57 were produced but were cleaved inefficiently and only minimal amounts of gp120 and p27 were released into the culture medium, even after prolonged incubation times. The processing of proteins of the two viruses was indistinguishable in lymphocytes. Since these two viruses are identical except for changes within the env gene, these results indicate that efficient assembly and release of SIV from blood-derived macrophages is mediated by changes in the envelope glycoprotein. PMID- 7831809 TI - Vesicular stomatitis virus transcription inhibited by purified MxA protein. AB - MxA is a GTPase encoded by an interferon-inducible human gene. Its constitutive expression renders transfected mammalian cells resistant to infections with several different RNA viruses, including vesicular stomatitis virus (VSV). Differences in viral RNA levels of VSV-infected cells either expressing or lacking MxA indicated that VSV mRNA synthesis is the principal target of MxA action. We now used purified histidine-tagged MxA (His-MxA) that we produced in Escherichia coli to successfully inhibit VSV in vitro transcription, a reaction catalyzed by VSV ribonucleoprotein complexes isolated from virus-infected cells or from purified virions. MxA was inactive when added to preformed VSV mRNAs, arguing against the possibility that it has a negative effect on viral RNA stability. MxA inhibited both leader RNA and mRNA synthesis of VSV, suggesting that it interfered with transcription initiation. The degree of VSV inhibition correlated directly with the specific GTPase activities of the various wild-type MxA preparations. No inhibition of viral mRNA synthesis was observed when a C terminally truncated, GTPase-inactive variant of His-MxA was added to the transcription reactions. Purified His-MxA-E645R, a mutant of MxA with normal GTPase activity whose range of antiviral activity in vivo is altered so that it no longer inhibits VSV, showed no inhibitory effect on VSV in vitro transcription. Since MxA inhibited VSV RNA synthesis in the presence of GMP-PNP or GTP gamma S, GTP analogs that are readily accepted by the viral polymerase but cannot be hydrolyzed by MxA, the possibility was excluded that MxA acts by depleting the viral polymerase for its nucleotide substrates. Thus, binding of GTP rather than its hydrolysis seems of importance for the anti-VSV activity of MxA. PMID- 7831810 TI - Establishment of leukemic T-cell lines from mice inoculated with the MAIDS defective virus. AB - Mice inoculated with replication-competent stocks of the murine acquired immunodeficiency syndrome (MAIDS) virus are severely immunocompromised and proned to the development of T- and B-cell lymphomas. We have studied the development of T-cell lymphomas in C57BL/6 and RF/J mice inoculated with helper-free stocks of the MAIDS defective virus. We observed the expansion of T cell clones (detected by TCR gene rearrangements and by transplantation) only rarely in diseased C57BL/6 mice and slightly more frequently in RF/J mice. We succeeded in establishing four transplantable T cell tumors and malignant cell lines. The three cell lines from RF/J mice were immature T-cells (Thy-1+, CD3-, CD4+, CD8+, Mac-1+), while the line from the C57BL/6 mouse had the phenotype of mature T cells (Thy-1+, CD3+, CD4+, CD8-). All lines were virus-producers despite the fact that helper-free stocks of the virus were inoculated. These helper MuLVs most likely originated from endogenous MuLV sequences. Also, the defective viral genome was clearly detectable in one cell line and was rearranged in two other lines. These established cell lines may be useful to determine whether they share some of the characteristics of the anergic T-cells in vivo and to study the role of the MAIDS defective virus in T cell transformation. PMID- 7831811 TI - Characterization of adenovirus subgenus D fiber genes. AB - The fiber genes of human adenovirus types 8, 9, 15, and two genome types of intermediate adenovirus 15/H9, all belonging to subgenus D, were sequenced and the nucleotide and predicted amino acid sequences compared. The analyzed peptide sequences were consistent with the structural domains described for other adenoviruses: an amino-terminal tail region, an intervening shaft region composed of eight repeating 15-amino-acid segments, and a carboxy-terminal knob. Furthermore, several highly conserved sequences could be confirmed. The fiber genes of AV9 and the AV15/H9 intermediate strains were 100% identical, not only in the coding region, but also in the presented 5'- and 3'-flanking regions. These findings support the hypothesis that intermediate strains arise by recombination of two serologically different parent viruses. The predicted AV8, AV9, and AV15/H9 polypeptides showed an overall homology of 92%. In the knob regions, AV8 and AV9; AV15/H9 intermediate strains revealed nine mismatches. AV8 is the main causative agent of epidemic keratoconjunctivitis in man, whereas AV9 and the AV15/H9 intermediate strains only infrequently cause acute follicular conjunctivitis. Since the knob is the component responsible for interaction with the cell receptor, these differences in the receptor binding sites should be expected to play an important role in the differences in pathogenicity. PMID- 7831812 TI - Transcriptional inhibition of the parvovirus minute virus of mice by constitutive expression of an antisense RNA targeted against the NS-1 transactivator protein. AB - We have assessed a genetic resistance approach based on antisense RNA to interfere with the prototype Minute Virus of Mice (MVMp), an autonomous parvovirus. MVMp is a cytolytic virus when infecting the permissive A9 mouse fibroblast cell line, and its gene expression is largely regulated at the level of transcription initiation by the nonstructural transactivator NS-1 protein, a multifunctional polypeptide also involved in viral DNA replication and cytotoxicity. An NS-1 specific antisense RNA constitutively expressed in transfected A9 clones increased several fold the proliferative viability of the cells upon high multiplicity virus infection, and cultures infected at low multiplicity reached confluence overcoming virus progression. All clones shared a common phenotype of resistance characterized by a lowered synthesis of viral DNA replicative intermediates and genomic forms, a significant reduction in the accumulation of the three viral messengers in the cytoplasmic and nuclear compartments, and a specific inhibition in viral protein synthesis. These results indicate that the constitutive antisense RNA mediates an overall repression of viral macromolecular synthesis by preventing the onset of NS-1 functions. Therefore, cytocidal parvoviruses may be hampered by engineered antisense RNA targeted against early regulators of virus growth. PMID- 7831813 TI - Myxoma virus and Shope fibroma virus encode dual-specificity tyrosine/serine phosphatases which are essential for virus viability. AB - Sequence analysis of the genomes of the Leporipoxviruses myxoma virus and Shope fibroma virus (SFV) led to the discovery of open reading frames homologous to the vaccinia H1L gene encoding a soluble protein phosphatase with dual tyrosine/serine specificity. These viral phosphatase genes were subsequently localized to the myxoma BamHI-I fragment and the SFV BamHI-M fragment, and the resulting encoded proteins were designated I1L and M1L, respectively. The localization and orientation of the myxoma I1L and SFV M1L open reading frames within the well conserved central core of the viral genomes closely mirror that of the Orthopoxviruses vaccinia virus and variola virus. The myxoma I1L and SFV M1L phosphatases each contain the conserved tyrosine phosphatase signature sequence motif, (I/V)HCXAGXXR(S/T)G, including the active site cysteine, found previously to be essential for phosphotyrosine dephosphorylation. The vaccinia H1L phosphatase was originally shown to have the ability to dephosphorylate phosphotyrosyl and phosphoseryl residues in vitro. To assess whether this is a common feature of poxvirus phosphatases, myxoma I1L was expressed as a GST-fusion protein, purified, and shown to dephosphorylate substrates containing tyrosine and serine phosphorylated residues, in a similar fashion to vaccinia H1L. A myxoma I1L variant, in which the active site cysteine 110 was mutated to serine, was expressed in a parallel fashion to the wild-type I1L protein and found to be completely deficient in its ability to dephosphorylate both phosphotyrosine and phosphoserine amino acids. In an attempt to ascertain the biological requirement for the myxoma I1L phosphatase, we constructed a recombinant myxoma virus containing a disrupted I1L open reading frame. This I1L mutant virus was able to successfully propagate in tissue culture only in the presence of a wild-type complementing gene, and pure virus clones containing only the disrupted allele were not viable. Thus, we conclude that the myxoma I1L dual specificity phosphatase is an essential factor for virus viability. PMID- 7831814 TI - 5' proximal potyviral sequences mediate potato virus X/potyviral synergistic disease in transgenic tobacco. AB - The interaction of potato virus X (PVX) and potato virus Y (PVY) in tobacco causes a synergistic disease characterized by a dramatic increase in symptom severity, a change in the regulation of PVX RNA replication, and an increase in accumulation of PVX. In this study we demonstrate that PVX also interacts synergistically with three other members of the potyvirus group of plant viruses, tobacco vein mottling virus (TVMV), tobacco etch virus (TEV), and pepper mottle virus. These synergisms resemble the classic PVX/PVY synergism with respect to both the increase in host response and the change in PVX replication. To determine if the induction of PVX/potyviral synergism requires potyviral genome replication per se or if the response is mediated by expression of one or more potyviral genes, we used tobacco plants stably transformed with various subsets of the TVMV genome. PVX infections of transgenic plants expressing the 5' proximal region of the TVMV genome, including the protease-1, helper component protease, and protein-3 genes, result in symptoms resembling those of PVX/potyviral synergism. A similar synergistic-like response occurs when transgenic tobacco plants expressing the analogous but smaller region from the 5' proximal region of the TEV genome were infected with PVX. Replication of PVX RNA is altered in transgenic plants expressing 5'-proximal sequences of either TVMV or TEV, and in a manner similar to that observed in double infections. These results indicate that replication of the potyviral genome is not required for PVX/potyviral synergism and that the response is mediated by expression of potyviral sequences which have been localized to the 5'-proximal third of the genomic RNAs of both TVMV and TEV. PMID- 7831815 TI - Mapping and investigation of the role in pathogenesis of the major unique secreted 35-kDa protein of rabbitpox virus. AB - Following infection, many secreted poxvirus proteins are able to modulate the host immune response through interactions with cytokines or components of the complement pathway. A comparison of the secreted protein profiles from cells infected with vaccinia Western Reserve (VV-WR), cowpox virus Brighton strain, or rabbitpox virus (RPV) showed an abundant 35-kDa protein present only in the supernatants from RPV-infected cells. The gene encoding this protein was identified and mapped by N-terminal sequencing of the protein. Examination of the predicted amino acid sequence showed it to be identical to the 35-kDa secreted protein of the Lister strain of vaccinia virus described by Patel et al. (1990, J. Gen. Virol. 71, 2013-2021). The counterpart of this gene in the commonly studied VV-WR strain is truncated and encodes a 7.5-kDa protein under control of the well-characterized p7.5 promoter. While nonessential for replication in cell culture, conservation of this gene in at least two orthopoxvirus strains suggested that this protein might play an important role in vivo. Following intranasal inoculation of Balb/c mice at several doses (10(3), 10(4), or 10(5) PFU), a mutant of RPV lacking a functional 35-kDa gene (RPV delta 35) appeared to induce an earlier onset and more severe illness at low, sublethal doses (10(3) PFU) than was observed with wild-type (wt) RPV. At higher doses (10(4) or 10(5) PFU), the behavior of wt RPV and RPV delta 35 became indistinguishable and the overall LD50 values were similar. Intradermal infection of rabbits simultaneously, at separate sites, with RPV and RPV delta 35 showed no gross or microscopic differences between either primary skin lesions or viremic extension of each virus into the lungs. Therefore, this abundant secreted protein does not appear to play a major role in the virulence of the virus. PMID- 7831816 TI - The human foamy virus internal promoter is required for efficient gene expression and infectivity. AB - The human foamy or spumaretrovirus (HFV) is a complex retrovirus that codes for the three retroviral genes gag, pol, and env and the regulatory and accessory bel genes. A particular feature of HFV gene expression was recently described: not only does the HFV provirus contain the classical retroviral long terminal repeat promoter, a second functionally active promoter is present in the env gene upstream of the bel genes (M. Lochelt, W. Muranyi, and R. M. Flugel, 1993, Proc. Natl. Acad. Sci. USA 90, 7317-7321). Both, the HFV long terminal repeat promoter I and internal promoter II depend upon the HFV transcriptional transactivator Bel 1 for efficient gene expression. The internal promoter directs the synthesis of functionally active Bel 1 transactivator and Bet proteins that are expressed early after HFV infection. In this report, it is shown that mutation of the promoter II TATA box resulted in HFV proviral clones with a reduction in infectivity by a factor of approximately 100. Gene expression by promoter II TATA box mutant HFV proviruses was reduced. HFV proviruses with the mutated promoter II TATA box used cryptic start sites of transcription upstream of the original promoter II TATA box, resulting in an inefficient and less accurate transcriptional initiation. The reduced HFV structural gene expression by the mutated HFV proviruses was relieved by providing Bel 1 protein in trans. This demonstrates that HFV promoter II-directed Bel 1 expression is important for producing the high levels of Bel 1 that increases virus replication. PMID- 7831817 TI - Nucleotide sequence of a single-stranded RNA phage from Pseudomonas aeruginosa: kinship to coliphages and conservation of regulatory RNA structures. AB - We report the complete nucleotide sequence of the single-stranded RNA phage PP7 from Pseudomonas aeruginosa. There are three open reading frames which code for apparent protein homologues of the single-stranded RNA coliphages, i.e., maturation protein, coat protein, and replicase. A fourth overlapping reading frame exists that probably encodes a lysis protein, similar to what has been found in the group A coliphages such as MS2. The genetic map of PP7 is colinear with group A coliphages and we accordingly classify the phage as a levivirus. There is, generally speaking, no significant nucleotide sequence identity between PP7 and the coliphages except for a few regions where homologous parts of proteins are encoded, most notable in the replicase gene. In these regions the nucleotide sequence similarity between PP7 and MS2 is no greater than between PP7 and the group B coliphages such as Q beta. Surprisingly, Q beta and MS2 are no closer to each other than they are to PP7. Several regulatory RNA secondary structure features that are present in the coliphages were identified also in PP7 RNA although the sequences involved cannot be aligned. Among these are the coat protein binding helix at the start of the replicase gene, structures at the 5' and 3' terminus of the RNA, a replicase binding site, and the structure of the coat protein cistron start. Some of these features resemble MS2 type coliphages but others the Q beta type. These findings suggest that PP7 is related to the coliphages but branched off before the coliphages diverged into separate groups. PMID- 7831819 TI - Restricted replication of the HIV-1 T-lymphotropic isolate NL4-3 in HL-60 cells. AB - To understand how different cell types might influence the generation of viral variants, we have examined the differences in the viral life cycle of the HIV-1 isolate, NL4-3, in the human promyelocytic cell line, HL-60, and the human T cell line, H9. NL4-3 harvested from H9 cells productively infected and was cytopathic to H9 and HL-60 cells. However, the cytopathic effect was delayed in HL-60 cells compared to that seen in H9 cells, suggesting that NL4-3 replication was restricted in myeloid cells. This restriction was overcome by production of a variant virus, NL4-3 (M), which replicated efficiently in HL-60 cells. Measurements of the kinetics of entry of NL4-3 in H9 and HL-60 cells and NL4-3 (M) in HL-60 cells demonstrated that the timing of viral entry into each cell line was similar. However, quantitation of the amount of newly reverse transcribed NL4-3 DNA in H9 and HL-60 cells revealed that NL4-3-infected H9 cells and NL4-3 (M)-infected HL-60 cells contained consistently more newly reverse transcribed DNA than NL4-3-infected HL-60 cells. This difference was further amplified by inefficient spread of the virus throughout the HL-60 culture. Together these results suggest that the efficiency of NL4-3 infection of HL-60 cells is restricted at early steps in the viral life cycle and may be restricted at late steps as well. PMID- 7831818 TI - In situ DNA PCR and RNA hybridization detection of herpes simplex virus sequences in trigeminal ganglia of latently infected mice. AB - The presence of herpes simplex virus (HSV-1) DNA in the trigeminal ganglia of latently infected mice was detected by an in situ DNA polymerase chain reaction (PCR), which includes a DNA:DNA hybridization step (indirect in situ PCR). These results were compared to the number of neurons possessing the HSV-1 latency associated transcript (LAT), as detected by in situ RNA hybridization with LAT probes. Sensitivity assays were shown to detect a single copy cellular gene in 48% of neuronal cell bodies. The results suggest that in situ PCR is an effective method to locate and detect HSV-1 within latently infected neurons. Moreover, the number of neurons found to be harboring HSV-1, by the method of in situ PCR, which does not depend upon virus gene expression, is within threefold of the number detected by in situ hybridization for LAT. Therefore, this report describes the first detection of HSV-1 DNA in latently infected murine trigeminal ganglia by the method of indirect in situ PCR, and compares the findings to the number of neurons expressing LAT, as assessed by conventional in situ hybridization. PMID- 7831820 TI - Multiple determinants for growth of human immunodeficiency virus type 1 in monocyte-macrophages. AB - Attempts to define the genetic determinants required for efficient growth of human immunodeficiency virus type 1 (HIV-1) in monocyte-macrophages were made by constructing chimeras between two infectious clones of HIV-1 (HXB2 and LW/C), which despite only minor differences in their DNA sequence have striking differences in cell tropism. Although both of them replicate efficiently in peripheral blood mononuclear cells, HXB2 replicates extensively in permanent T cell lines but poorly in primary monocyte macrophages (T cell line tropic); the reverse is true for LW/C (macrophage tropic). The envelope proved to contain the major determinants of macrophage tropism. However, tropism determinants appeared to be scattered along the envelope. In particular, the V3 loop alone appeared to be neither necessary nor sufficient for growth in macrophages. Both vpr and nef genes appeared to play a less significant role to improve viral replication in macrophages, but only in the presence of the proper envelope sequences. HIV-1 macrophage tropism thus appears to result from the contribution of several different determinants. PMID- 7831821 TI - Synthesis and processing of bovine herpesvirus-1 glycoprotein H. AB - The translation product of the bovine herpesvirus-1 (BHV-1) gH gene was identified and characterized. Synthetic peptides were used to generate specific antisera and a glycoprotein of 108K was precipitated by one of the antisera. Cross-immunoprecipitations with monoclonal antibodies to BHV-1 glycoprotein gp108 and the anti-gH peptide antiserum demonstrated that gp108 is the translation product of the gH open reading frame. Glycoprotein gH synthesis and intracellular processing was analyzed in infected Madin-Darby bovine kidney cells using anti-gp 108 monoclonal antibodies. Glycoprotein gH is expressed as a beta-gamma protein and could be detected by radioimmunoprecipitation as early as 2 hr postinfection. Cotranslational N-glycosylation of gH is essential for the recognition by monoclonal antibodies, suggesting that N-linked glycans are involved in protein folding or that they are targets for most of monoclonal antibodies used in this study. PMID- 7831822 TI - The varicella-zoster virus origin-binding protein can substitute for the herpes simplex virus origin-binding protein in a transient origin-dependent DNA replication assay in insect cells. AB - We isolated two recombinant baculoviruses each of which expresses a varicella zoster virus (VZV) homolog of one of the seven herpes simplex virus type 1 (HSV 1) genes required for DNA replication. We performed transient origin-dependent DNA replication assays in insect cells in which we substituted a baculovirus which expresses a VZV protein for a baculovirus which expresses its HSV homolog. VZV gene 51 protein was found to be able to support origin-dependent DNA synthesis when it was substituted for UL9, the HSV-1 origin-binding protein (OBP). This occurred whether an HSV-1 or a VZV origin-containing plasmid was used in the assay. These results suggest that VZV gene 51 protein is able to interact with the HSV replication machinery, and in light of the extensive structural divergence of these proteins, it suggests that initiation of VZV and HSV-1 DNA synthesis may involve a limited number of interactions between the OBP and other replication factors. Substitution of infected-cell protein 8 (ICP8), the major single-stranded DNA-binding protein of HSV-1, with VZV gene 29 protein, however, did not result in amplification of plasmids containing either an HSV-1 or a VZV origin. In the absence of ICP8, addition of both VZV gene 51 protein and gene 29 protein was also negative for origin-dependent replication whether or not UL9 was present. Although demonstration that our baculovirus-expressed VZV gene 29 protein is functional for DNA replication will await development of a VZV replication system, our results suggest that VZV gene 29 protein is unable to interact functionally with one or more of the HSV replication proteins. This approach should contribute to efforts to define the interactions among the alphaherpesvirus DNA replication proteins. PMID- 7831823 TI - In vivo selection of long terminal repeat alterations in feline leukemia virus induced thymic lymphomas. AB - To determine what genetic changes are selected in the enhancer sequences of the feline leukemia virus (FeLV) long terminal repeat in cats that develop T cell tumors, we cloned proviral U3 sequences in cats that died with thymic lymphoma following infection with molecularly cloned FeLV. Analysis of the U3 enhancer region revealed single base changes, including point mutations in the core and FLV-1 sequences. Additionally, in clones from two of four cat tumors, portions of the enhancer including Lvb and core were duplicated with respect to the single enhancer unit of the inoculating virus. In contrast, a PCR survey of necropsy DNA samples derived from five cats that did not develop tumors revealed that all retained the single enhancer unit of the infecting virus. These results demonstrate that viruses with duplicated enhancers can be generated and selected after only a single passage in cats, and furthermore, that such viruses may be particularly selected in tumors. PMID- 7831824 TI - HIV-1 Tat protein is able to efficiently transactivate the HIV-2 LTR through a TAR RNA element lacking both dinucleotide bulge binding sites. AB - Each of the two stem-loop structures in the HIV-2 TAR (TAR-2) RNA element contains a dinucleotide bulge that specifies a binding site in vitro for the HIV 2 Tat transactivator protein. A TAR-2 RNA with both bulges deleted is very weakly transactivated in vivo by the HIV-2 Tat protein. To gain insight into general features of Tat protein:TAR RNA interactions, we have analyzed the significance of the dinucleotide bulges in TAR-2 RNA for in vitro binding and in vivo transactivation by the related HIV-1 Tat protein. The HIV-1 Tat protein has been shown previously to bind efficiently to wild-type TAR-2 RNA and fully transactivates the HIV-2 LTR. We found that the 5' proximal bulge and the 3' distal bulge appear to specify a high and low affinity binding site in vitro, respectively, for the HIV-1 Tat protein. Wild-type TAR-2 RNA was found to be able to bind HIV-1 Tat proteins simultaneously at each bulge binding site in vitro. A TAR-2 RNA with both bulges deleted was greatly defective for in vitro binding by the HIV-1 Tat protein. Surprisingly, the TAR-2 RNA with both bulges deleted was efficiently transactivated in vivo by the HIV-1 Tat protein, indicating that the HIV-1 Tat protein (but not HIV-2 Tat protein) is able to strongly activate transcription of a TAR RNA with no apparent bulge binding site. PMID- 7831825 TI - Differentiation-dependent expression of E1--E4 proteins in cell lines maintaining episomes of human papillomavirus type 31b. AB - The life cycle of human papillomaviruses (HPVs) is dependent on epithelial differentiation. Among the viral proteins expressed in differentiated epithelial cells are the viral capsid proteins, L1 and L2, as well as the E1E4 fusion proteins. In this study, the expression and intracellular localization of the E1E4 proteins of HPV type 31b were examined in both monolayer and raft cultures of the CIN-612 cell line which maintains episomal copies of HPV-31b. In this cell line, a high level of E1E4 protein expression was observed in the cytoplasm of a small percentage of cells in monolayer culture. A large increase in E1E4 protein levels was observed upon stratification of the CIN-612 cell line in raft cultures, with E1E4 protein expression limited to the uppermost layers of the epithelium. A diffuse, slightly grainy cytoplasmic localization of E1E4 protein was observed in both monolayer and raft culture systems. Although virion synthesis is entirely dependent upon phorbol ester or synthetic diacylglycerol treatment of raft cultures, E1E4 expression was observed in both treated and untreated monolayer and raft cultures of the CIN-612 cell line. In monolayer cultures of two simian virus 40-transformed cell lines, cos-7 and MK-6, transiently transfected with an E1E4 expression vector, the distribution of E1E4 protein was found to differ substantially from that in the CIN-612 cells. In these cell lines E1E4 protein was found to exhibit a total collapse into either cytoplasmic inclusion granules in the cos-7 cells or a perinuclear halo-like structure in the MK-6 cell line. The host cell, its differentiation state, and the amount of expression can therefore significantly affect the distribution of the E1E4 proteins. PMID- 7831826 TI - Highly heterogeneous fiber genes in the two closely related adenovirus genome types Ad35p and Ad34a. AB - Two adenovirus isolates from urine, Ad35p (from a bone marrow recipient) and Ad34a (from a hemorrhagic cystitis patient), were compared regarding their fiber gene organization and hemagglutinating capacity. The fiber serves as the ligand between the virus capsid and the host cell receptor. The Ad35p fiber gene encoded a 323-amino-acid protein, and the Ad34a fiber gene a 325 amino acid protein. The two fibers manifested 62.4% overall amino acid sequence homology, the differences predominantly occurring within the knob region where sequence homology was only 49.5%. The knob region of Ad34a was virtually identical to that of Ad11p which also causes hemorrhagic cystitis. Unlike all other known subgenus B adenoviruses, in the Ad35p fiber an asparagine constituted the C-terminus. Although both Ad34a and Ad35p viruses can hemagglutinate monkey erythrocytes, the hemagglutination inhibition test showed them to differ from each other in the epitopes expressed on the fibers. PMID- 7831827 TI - Characterization of an acid-resistant mutant of foot-and-mouth disease virus. AB - A foot-and-mouth disease virus mutant which is stable at pH 6.4 has been isolated from a virus of serotype A. In contrast to the parent (P) virus, which gave a mixture of large and small plaques in BHK21 cells and in a bovine kidney cell line, the acid-resistant (AR) virus gave small plaques which did not increase markedly in size after 24 hr. The infectivity titer of the acid-resistant virus was about 100-fold lower in suckling mice than in BHK21 cells, whether the inoculation was made intraperitoneally or intracerebrally, whereas the parent virus gave similar titers in both systems. Furthermore, in mice the AR virus reached its end point two to three times more slowly. The diameter of the AR virus was almost 20% less than that of the P virus and it had a more distinct topography, but the two viruses cosedimented in sucrose gradients. However, the buoyant density in CsCl of the AR virus was slightly lower (1.42 compared with 1.43 g/cc) in coruns. The RNAs and capsid proteins of the two viruses gave similar profiles in sucrose gradients and by SDS-PAGE, respectively. However, isoelectric focusing of the capsid proteins revealed considerable differences between the two viruses. Whereas the P virus gave four protein bands, corresponding to VP1-VP4, the AR virus gave one band for VP4, two for VP3, two for VP2, and four for VP1. Sequence analysis of the genes coding for the capsid protein regions of the two viruses showed four changes (one silent), resulting in an Ala-3-->Ser substitution in VP1 and Glu-131-->Lys and Asp-133-->Ser substitutions in VP2. PMID- 7831828 TI - A 14-kDa immediate-early phosphoprotein is specifically expressed in cells infected with oncogenic Marek's disease virus strains and their attenuated derivatives. AB - Previously, we reported two cDNAs derived from the Marek's disease virus (MDV) long internal repeat region. A 14-kDa polypeptide (p14) encoded by two small open reading frames (ORFs) from at least two distinct cDNAs is expressed in cells lytically infected with both oncogenic and attenuated MDV as well as in cells latently infected and transformed by MDV. In this study, we demonstrate that p14 is serotype 1 specific and highly phosphorylated. Given the degree of phosphorylation and lack of homology to known proteins, we propose the name pp14 for the polypeptide encoded by ORF1a and ORF1b. Further analysis reveals that pp14 is predominantly found in cytoplasmic fractions of MDV-infected cells and can be detected in the cytoplasm of MDV-infected cells by immunofluorescence with polyclonal antisera prepared against pp14-glutathione S-transferase fusion protein. PMID- 7831829 TI - Sequence analysis and gene content of potato mop-top virus RNA 3: further evidence of heterogeneity in the genome organization of furoviruses. AB - The complete sequence of the 2315 nucleotides in RNA 3 of potato mop-top furovirus (PMTV) isolate T was obtained by analysis of cDNA clones and by direct RNA sequencing. The sequence contains an open reading frame for the coat protein (20K) terminated by an amber codon, followed by an in-phase coding region for an additional 47K. PMTV therefore resembles soil-borne wheat mosaic (SBWMV) and beet necrotic yellow vein (BNYVV) viruses (two other fungus-transmitted viruses with rod-shaped particles) in having a coat protein-readthrough product. Comparison of the 3' untranslated regions of PMTV RNA 2 and RNA 3 reveals a long conserved block of 150 nucleotides, which contains two repeated sequences and has the potential to form consecutive pseudoknot structures. PMTV RNA 3 ends a few nucleotides downstream of this conserved block, but RNA extends for a further 140 nucleotides, which can potentially form a 3'-terminal tRNA-like structure similar to those in the RNA species of SBWMV, tymoviruses, and some tobamoviruses. PMTV coat protein has amino acid sequence identities of 30 and 28% with SBWMV and BNYVV coat proteins, respectively, and apparent structural similarities with tobacco mosaic virus coat protein. The coat protein readthrough domains of PMTV, SBWMV, and BNYVV have shared residues throughout their length but no extended sequences are conserved. The presence in RNA 3 of coding sequences for only the coat protein and readthrough domain distinguishes PMTV from SBWMV and BNYVV, both of which have them in RNA 2 along with one or more other genes. Comparison of the genomes of PMTV, BNYVV, and SBWMV shows that furoviruses exhibit considerable heterogeneity in genome organization. PMID- 7831830 TI - Analysis of African cassava mosaic virus recombinants suggests strand nicking occurs within the conserved nonanucleotide motif during the initiation of rolling circle DNA replication. AB - Intact clones containing partial repeats of the genomic components of African cassava mosaic (ACMV DNAs A and B) are infectious when mechanically coinoculated onto Nicotiana benthamiana. Monomeric genomic components may be generated either by homologous recombination or, when two copies of the origin of replication (ori) are present, by a modified rolling circle replication mechanism in which nascent single-stranded DNA is resolved by the introduction of nicks at both oris. DNA B partial repeats with duplicated common region sequences containing combinations of wild-type sequences and nonlethal mutations at nucleotides 151 and 155 within the putative stem-loop region have been constructed and introduced into plants in the presence of DNA A. Analysis of progeny indicates that monomers are generated by DNA strand nicking preferentially between nucleotides 151 and 155, suggesting a nonrandom replicative release mechanism involving the ubiquitous TAATATTAC motif (nucleotides 146-154). Viable ACMV DNA A deletion mutants are known to revert to wild-type size during systemic infection by generating tandem repeats. The recombination point in one such revertant has been mapped between nucleotides 152 and 153. Just as ori-nicking enzymes mediate recombinational events during prokaryotic rolling circle DNA replication, the result suggests that a nick has been introduced in the virion-sense strand within the nonanucleotide motif (TAATATT decreases AC) during the initiation of ACMV DNA replication. PMID- 7831831 TI - Rabies virus glycoprotein gene contains a long 3' noncoding region which lacks pseudogene properties. AB - Analysis of a limited number of laboratory strains of rabies virus had demonstrated the presence of a genome region bounded by two transcription termination and polyadenylation-like (TTP) signals (approximately 400 to 450 nucleotides apart) which was located between the end of the glycoprotein (G) coding sequence and the beginning of the L polymerase coding sequence. Although this region had been suggested to represent a remnant or pseudogene (psi), no detailed analysis had been carried out to examine this possibility. Here we present the nucleotide sequence analysis of this genome region for several laboratory rabies virus strains and a large number of diverse rabies viruses detected directly in brain tissue of naturally infected animals. Only one distinct lineage of the laboratory strains and none of the wild-type rabies viruses contained the upstream TTP-like signal, indicating that only the downstream TTP motif is the authentic G mRNA transcription termination and polyadenylation and signal. Phylogenetic analysis of sequence differences provided no evidence of laboratory strains containing the two TTP-like signals being ancestral to any of the viruses possessing only the downstream TTP sequence motif. These data indicate that this region of the rabies virus genome encodes a G mRNA with a long 3' noncoding region with no evidence of a pseudogene. PMID- 7831832 TI - Site-directed mutagenesis confirms the involvement of carboxylate groups in the disassembly of tobacco mosaic virus. AB - Electrostatic repulsion between carboxylate groups across subunit interfaces has for many years been recognized as important in the disassembly of simple plant viruses. In the coat protein of tobacco mosaic virus (TMV), the amino acids Glu50 and Asp77 have been proposed as examples of such carboxylate groups. Site directed mutagenesis has been used to replace these amino acids by Gln and Asn, respectively. Increased virion stability, together with reduced infectivity and reduced capacity for long-distance transport within the host plant confirms that the negative charges on the side chains of these amino acids are involved in the disassembly of TMV. Mixing purified mutant coat proteins with wild-type virions under appropriate conditions stabilizes the virions to alkaline disassembly and reduces their infectivity. It is suggested that transgenic plants expressing such mutant coat proteins could have enhanced resistance to virus infection. PMID- 7831833 TI - Efficient synthesis of viral nucleic acids following monocyte infection by HIV-1. AB - The replication of human immunodeficiency virus type 1 in mononuclear phagocytes (blood monocytes, tissue macrophages, and dendritic cells) is an important feature of HIV-1 pathogenesis. Although most primary HIV-1 isolates are able to productively infect monocytes, some reports suggest that rates of viral DNA synthesis and virus replication are reduced in HIV-1-infected monocytes as compared to infected T cells. In this study we compare kinetics of viral DNA synthesis in CD4+ T cells and monocytes following HIV-1 infection. Our results indicate that reverse transcription of viral nucleic acids following infection of monocytes occurs at rates equal to or greater than that observed following infection of T cells. These studies reveal no postentry restrictions to HIV-1 replication following infection in monocytes. Moreover, the results support the notion that both monocytes and CD4+ T cells are equally permissive for virus replication in infected individuals. PMID- 7831834 TI - Expression and characterization of secreted forms of rubella virus E2 glycoprotein in insect cells. AB - Two different forms of rubella virus E2 glycoproteins were expressed in insect cells: intact wild-type E2 and a soluble form of E2 (E2 delta Tm) glycoprotein, in which the C-terminal membrane-anchor domain was deleted. E2 delta Tm behaved as a secretory protein and was secreted abundantly (5 mg/liter) from insect cells. In contrast to wild-type E2 (36 kDa), E2 delta Tm was secreted into the media and was detected as two species (33 and 30 kDa). Lectin binding assays in conjunction with glycosidase analyses revealed that both intracellular wild-type E2 and E2 delta Tm contained only N-linked glycans, while the two secreted forms of E2 delta Tm were found to differ in their glycosylation, with the 30-kDa form having only N-linked glycans while the 33-kDa species had both N-linked and O linked glycans. The secreted E2 delta Tm species were purified by precipitation between 20 and 40% saturation with (NH4)2SO4 and retained full antigenicity. The levels of antibodies elicited in mice immunized with purified E2 delta Tm showed that the immunogenicity of secreted E2 delta Tm compared favorably to that of natural virion E2. PMID- 7831835 TI - Completion of the La Crosse virus genome sequence and genetic comparisons of the L proteins of the Bunyaviridae. AB - La Crosse virus is a member of the Bunyavirus genus in the family Bunyaviridae, viruses with trisegmented RNA genomes of mostly negative polarity composed of large (L), medium (M), and small (S) segments. The sequences of the La Crosse/original M and S RNA segments have been previously characterized. Using reverse transcriptase in conjunction with PCR amplification, we have obtained the nucleotide sequence of the L RNA segment, which encodes the viral polymerase in a single large open reading frame. Comparison of the amino acid sequence of the LAC L protein with the sequence of other polymerases from members of the Bunyaviridae, demonstrated the presence of several conserved motifs, some of which are characteristic of many polymerase proteins. A genetic tree comparing the available polymerase proteins of the Bunyaviridae provides insights into the phylogenetic relationships within this large family. Members of the genus Bunyavirus, which are mosquito-borne and infect mammals, have a closer relationship to the plant viruses represented by tomato spotted wilt virus (Tospovirus genus) than to viruses of other genera in the family Bunyaviridae. PMID- 7831836 TI - Pestivirus translation initiation occurs by internal ribosome entry. AB - The role of the 385 nucleotide 5' noncoding region (NCR) in the translation of the pestivirus genome was investigated. In vitro translation of an RNA transcript containing the 5' NCR of the bovine viral diarrhea virus (BVDV) genome followed by the coding sequence of the first gene product (p20) of the BVDV large open reading frame resulted in the synthesis of a 20-kDa polypeptide. Results from hybrid-arrest translation studies identified a region involving a predicted RNA stem-loop structure spanning nucleotides 154-261 within the 5' NCR that was important for p20 synthesis. An additional inhibitory oligonucleotide was complementary to the sequence at the base of this stem-loop and encompassed the initiating AUG at nucleotide 386. Antisense oligonucleotides both upstream and downstream of those that were inhibitory had no effect on p20 translation. RNA from a dicistronic expression vector in which the BVDV 5' NCR was inserted between two reporter genes, CAT and LUC, showed strong expression of the second (LUC) cistron upon in vitro translation. This expression was dramatically reduced in an analogous construct in which nucleotides 173-236 of the 5' NCR were deleted. Similar results were obtained when RNA from these same vectors was evaluated for expression after transfection into BHK cells. These results suggest that the BVDV 5' NCR contains an internal ribosome entry site for translation initiation. This translational mechanism is similar to that shown for hepatitis C virus, further demonstrating the close relationship between viruses of these two genera within the family Flaviviridae. PMID- 7831837 TI - Molecular changes in virulent mutants arising from avirulent avian influenza viruses during replication in 14-day-old embryonated eggs. AB - The emergence of virulent avian influenza viruses in poultry is unpredictable. To gain insight into the mechanism for this event, we sought to identify the molecular changes in virulent mutants that occur during replication in 14-day-old embryonated chicken eggs. After three passages in 14-day-old eggs, avirulent H5 viruses with the K/R-K-K/T-R sequence at the hemagglutinin (HA) cleavage site became virulent in chickens, concomitantly acquiring high HA cleavability, whereas those with the R-E-T-R sequence did not. None of the test viruses converted to a virulent phenotype when passaged in 10-day-old eggs. Nucleotide sequence analysis indicated that the virulent mutants either lost a glycosylation site near the HA cleavage site or acquired an additional arginine at the latter. Avirulent viruses that became virulent after passage in older eggs included an H5N2 avian strain with the R-K-T-R sequence that was isolated in 1993, indicating that viruses with this sequence motif, which are currently circulating in bird populations, should be considered potentially virulent. Failure to generate virulent mutants from viruses with R-E-T-R at the HA cleavage site underscores the pathogenic heterogeneity among avian influenza viruses. PMID- 7831838 TI - Full expression of transfected nonproducer interfering HIV-1 proviral DNA abrogates susceptibility of human He-La CD4+ cells to HIV. AB - An Hut-78 cell clone (F12) harboring a nonproducer human immunodeficiency virus-1 (HIV) variant, and showing a complete resistance to HIV-1 or HIV-2 superinfection, was previously characterized. We demonstrated that the replication of the superinfecting HIVs is blocked at the retrotranscription step, despite the CD4 down-regulation, since HIVs are able to cross the Hut-78/F12 cell membrane. In order to establish if the expression of the HIV-1 variant (F12/HIV) could be per se sufficient to induce the homologous viral interference shown in the F12 cells, the whole F12/HIV provirus was cloned and transfected in He-La CD4+ cells. In F12/HIV expressing He-La CD4+ clones, both the viral proteins expressed and the HIV nonproducer phenotype remain unmodified compared to F12 cells. Furthermore, despite the full expression of CD4 HIV receptors, the life cycle of the superinfecting HIV could be either strongly inhibited or totally abolished, depending on the cell clone considered. The inhibition of the superinfecting HIV was also reproduced when an HIV infectious molecular clone was transfected in F12/HIV He-La CD4+ clones, thus indicating that a post-cDNA synthesis block may operate against the superinfecting HIV. These data demonstrate that HIV susceptibility could be abrogated in cells expressing the F12/HIV genome, even in absence of any CD4 down-regulation. PMID- 7831839 TI - The termini of VSV DI particle RNAs are sufficient to signal RNA encapsidation, replication, and budding to generate infectious particles. AB - Infectious defective interfering (DI) particles of the negative-stranded RNA virus vesicular stomatitis virus (VSV) have been recovered from negative-sense transcripts of a plasmid that contains a full-length cDNA derived from the DI-T particle genome. In order to determine the cis-acting sequences necessary for RNA replication, encapsidation, and budding and to approximate the minimal size of RNA that can be packaged into infectious particles, we constructed a series of internal deletions in the DI cDNA to generate plasmids that could be transcribed to yield RNAs which ranged in size from 2209 nucleotides down to 102 nucleotides. All the deletion plasmids retained at least 36 nucleotides from the 5'-terminus and 51 nucleotides from the 3'-terminus of the DI genome. In cells expressing the five VSV proteins, the deleted DI RNAs were examined for their ability to be encapsidated, to replicate, and to bud to produce infectious DI particles. An RNA as small as 191 nucleotides, which contained 46 nucleotides from the 5'-end and 145 nucleotides from the 3'-end of the DI genome was encapsidated, replicated, and budded at least as efficiently as the full-length wild-type DI RNA. In contrast, a 102-nucleotide RNA that contained only the 51 nucleotides from the 5' end of the DI RNA and its perfect 51-nucleotide complement at the 3'-end replicated poorly and failed to bud infectious DI particles. However, an RNA with an insertion of 1499-nucleotide "stuffer" sequences of non-VSV origin between the two 51-nucleotide complementary termini not only replicated but also budded infectious particles. These data show that the signals necessary for RNA encapsidation, replication, and packaging into infectious DI particles are contained within the 5'-terminal 36 nucleotides and the 3'-terminal 51 nucleotides of the DI RNA genome. Furthermore, the results show that a heterologous sequence can be replicated and packaged into infectious particles if it is flanked by the DI RNA termini. PMID- 7831840 TI - Lack of LTR and ENV genetic variation during bovine leukemia virus-induced leukemogenesis. AB - Genetic variation of the Bovine Leukemia Virus (BLV) appears to be limited in vitro and during the latent phase of the disease. However, cells in tumors often harbor deleted proviruses that are defective for expression. In order to gain insight into the involvement of viral genetic variation during pathogenesis, the BLV LTR and the env proviral sequences were analyzed in tumor tissues. A sheep (M230) was injected with the cloned BLV provirus 344 and became persistently infected with circulating lymphocytes reaching 345,000/mm3. After 11 months, this infected sheep developed leukemia-lymphoma. DNA was extracted from peripheral blood leukocytes at the time of tumor development and the LTR and the env gene were amplified, using the polymerase chain reaction procedure, cloned, and sequenced. Twenty independent LTR and twenty env clones were analyzed. It appeared that the in vivo mutation rate in the env gene was 0.043% (eight mutations including seven transitions out of 18,300 bp). Five point mutations (all transitions) were identified in the LTR, corresponding to 0.041% modifications (four mutations out of 9740 bp). These mutation rate values (0.043 and 0.041) were close to those due to the Taq DNA polymerase errors (0.030%). Altogether, these data demonstrate the lack of genetic variation in the LTR and the env gene during this case of BLV-induced pathogenesis in vivo. They confirm that the defectiveness of some BLV proviruses in vivo, thus, is not a mandatory step in the leukemogenic process. PMID- 7831841 TI - The cDNA sequence of Trichomonas vaginalis virus-T1 double-stranded RNA. AB - Trichomonas vaginalis virus (TVV) is a nonsegmented double-stranded (ds) RNA virus that infects the pathogenic protozoan T. vaginalis. To study the virus, we cloned the genomic ds RNA of a TVV-T1 isolate and obtained a contiguous 4647-bp cDNA sequence. Two overlapping genes separated by a + 1 reading frame shift were identified on the plus strand but none on the complementary strand RNA in this sequence. The upstream gene probably encodes a 75-kDa capsid protein, and the downstream gene encodes an 86-kDa polypeptide which is probably the viral RNA dependent RNA polymerase (RDRP). A potential ribosomal slippage heptamer (C CUU UUU) was identified within the 14-nt overlap of the two genes. The genomic organization and RDRP sequence in TVV-T1 exhibit similarity to those of Saccharomyces cerevisiae virus and Leishmania RNA virus, suggesting that these viruses originate from common ancestry, but are only distantly related to Giardia lamblia virus. PMID- 7831842 TI - Measles virus nucleocapsid protein can function in Sendai virus defective interfering particle genome synthesis in vitro. AB - The Sendai virus P and L proteins, the viral RNA polymerase, and the nucleocapsid protein, NP, synthesized in a transient mammalian expression system support the replication of Sendai virus defective interfering particle (DI) genome RNA in vitro. We have shown that the measles virus nucleocapsid protein, N, can substitute for the Sendai NP protein in genome synthesis. The chimeric product nucleocapsids, which contained Sendai RNA encapsidated with measles N protein, were atypical since they were sensitive to micrococcal nuclease digestion, unlike wild-type Sendai or measles nucleocapsids. The utilization of measles N protein required the endogenous Sendai virus RNA polymerase, since DI nucleocapsids free of polymerase were not replicated. Although both Sendai virus NP and P proteins and measles N and P proteins formed complexes when they were coexpressed, sedimentation analysis showed that measles N protein self-assembled and did not form a complex when expressed with the Sendai P protein. Furthermore, when the Sendai P-L polymerase complex was provided separately, measles N protein alone synthesized DI genome RNA in the absence of Sendai P protein. These data suggest that the self-assembled form of measles N protein functions in Sendai DI genome synthesis. PMID- 7831843 TI - Effect of interferon-alpha and cell differentiation on Puumala virus infection in human monocyte/macrophages. AB - Pathogenesis of hantavirus infections is poorly understood. Puumala virus (PUU) is the etiologic agent of nephropathia epidemica, a form of hemorrhagic fever with renal syndrome common in Europe. We have studied PUU infection in primary human monocyte/macrophages and specifically the role of interferon alpha (IFN alpha) and cell differentiation in it. PUU infection proceeded at a low level in monocyte/macrophages, and nucleocapsid (N) protein accumulation started 2 days postinfection. IFN-induced antiviral MxA protein was detected 3 days postinfection, suggesting IFN-alpha production in culture. IFN-alpha titers remained low, proposing that PUU is a poor IFN inducer. However, the PUU-induced IFN had an inhibitory effect on virus production as was shown by the effect of anti-IFN-alpha. Pretreatment of cells with IFN-alpha caused a dose-dependent inhibition of PUU N accumulation and reduced the yield of infectious virus. Monocytic U-937 cells overexpressing MxA protein were susceptible to PUU, suggesting that, unlike in some other negative strand RNA virus infections, MxA does not mediate resistance to PUU infection. Differentiation of monocyte/macrophages in culture and treatment of THP-1 promonocytic cells with phorbol 12-myristate 13-acetate made the cells more susceptible to PUU. The increased susceptibility of mature macrophages to PUU suggests that after differentiation to tissue macrophages they might function in the spread of the virus during PUU infection. PMID- 7831844 TI - Akv murine leukemia virus enhances bone tumorigenesis in hMT-c-fos-LTR transgenic mice. AB - hMt-c-fos-LTR transgenic mice (U. Ruther, D. Komitowski, F. R. Schubert, and E. F. Wagner. Oncogene 4, 861-865, 1989) developed bone sarcomas in 20% (3/15) of females at 448 +/- 25 days and in 8% (1/12) of males at 523 days. After infection of newborns with Akv, an infectious retrovirus derived from the ecotropic provirus of the AKR mouse, 69% (20/28) of female animals and 83% (24/29) of males developed malignant fibrous-osseous tumors. The tumors in infected transgenics developed with higher frequency and a 200-days shorter mean tumor latency period. The hMt-c-fos-LTR transgene was expressed in all the fibrous-osseous tumors. They also showed newly integrated Akv proviruses, but in most tumors Akv was detected and expressed in only a small number of the tumor cells. Wild-type C3H mice infected with Akv developed benign osteomas with an incidence of 33% and a latency period of 474 days. The data indicate that Akv exerts distinct pathogenic effects on the skeleton. In hMt-c-fos-LTR transgenic mice, predisposed to bone sarcomagenesis, Akv acts synergistically with the fos transgene, resulting in the development of fibrous-osseous tumors. PMID- 7831845 TI - Akv murine leukemia virus enhances lymphomagenesis in myc-kappa transgenic and in wild-type mice. AB - The contribution of endogenous retroviruses to the multistep process of lymphomagenesis was investigated in wild-type mice and in two different myc-kappa transgenic mouse lines by infection with Akv. This retrovirus is derived from the endogenous ecotropic provirus of the AKR mouse and was previously considered to be nonlymphomagenic. The mice of the two myc-k transgenic lines are predisposed to B-cell lymphomagenesis and were therefore considered to be more susceptible to Akv. For comparison, the same mouse strains were also infected with the exogenous Moloney murine leukemia virus (MoMuLV). Both MoMuLV and Akv increased the tumor incidence and shortened the tumor latency period in wild-type mice and in the transgenic mouse lines. The differences in pathogenicity, number of provirus integrations, and level of virus expression between MoMuLV and Akv indicate different mechanisms of lymphomagenesis: while MoMuLV induced tumors apparently by insertional mutagenesis involving common integration sites similar to previous reports, the enhancement of lymphomagenesis by Akv seems to be directed by other mechanisms. PMID- 7831846 TI - [The optimization of the management of a general hospital]. PMID- 7831847 TI - [Cardiac surgery and the outlook for its development at the N. N. Burdenko Main Military Clinical Hospital]. AB - The article deals with the actual questions of modern cardiosurgery, questions of its formation and further development in the Burdenko Main Military Clinical Hospital. There are results of cardiosurgical operations and treatment of cardiosurgical patients. The article also briefly describes the question of artificial blood circulation and myocardium protection. PMID- 7831849 TI - [The pulmonary thromboembolism problem: the means for its resolution in a general clinical hospital]. AB - The article summarizes the results of clinical examination of 992 patients with thromboembolism of lung artery (TLA), its etiology, frequency of development and risk factors. The author describes clinical symptoms of TLA depending on the diameter of the obturated lung arterial vessel. The estimation of special methods was made from the point of view of its diagnostical significance: ECG, chest roentgenography, echocardiography, angiopneumography. The article contains questions concerning pathogenetical treatment and prophylaxis of TLA. PMID- 7831848 TI - [The nephrolithiasis problem in the Armed Forces of Russia]. PMID- 7831850 TI - [The use of mafusol in acute blood loss]. AB - Mafusol is a crystalloid solution, containing sodium fumarat and possessing antihypoxic bioenergetic ability. It was used for the correction of acute hypovolemia in infusion-transfusion therapy. Mafusol in a dose of 800-1600 ml reliably prevents the development of metabolic acidosis. It can be the preparation of choice in acute loss of blood and traumatic shock treatment in early stages of medical care. PMID- 7831851 TI - [The management of vomiting and nausea with zofran during the chemotherapy of malignant tumors]. PMID- 7831852 TI - [The Fahr syndrome]. PMID- 7831853 TI - [The pathomorphological aspect of modern blast trauma (a review of the literature)]. PMID- 7831854 TI - [E. I, Smirnov--the founder of the Military Medical Museum]. PMID- 7831856 TI - [The diagnosis and treatment of acute leukemias (methodological recommendations)]. AB - The article describes the modern classification of acute leukemia, gives criteria of the diagnosis of acute leukemia, and its basic clinical syndromes. The authors stress that the main task throughout medical staging (till patient's admission to the specialized hematological centre) is to prepare patient for medical staging and to deal with emergencies which appear in the beginning of illness. The article contains the list of counterindications to evacuation, and recommendations for treatment of anemic, hemorrhagic and intoxication syndromes, and also concerning the treatment of patients with agranulocytosis. A special attention is drawn on the management regimen of patient. The authors emphasize that all transportable patients with a confirmed diagnosis of acute leukemia must be immediately evacuated to the specialized centers for stationary polychemical treatment. PMID- 7831855 TI - [Fiber bronchoscopy in the diagnosis and treatment of lung diseases (methodological recommendations)]. PMID- 7831857 TI - [The clinical picture, diagnosis and treatment of injuries to the larynx and cervical trachea (methodological recommendations)]. PMID- 7831858 TI - [A method for calculating the labor outlay in outfitting medical stores kits and refitting their contents]. PMID- 7831859 TI - [The use of container bodies in the stages of medical evacuation]. PMID- 7831860 TI - [The organization of specialized emergency medical care at the N.N. Burdenko Main Military Clinical Hospital]. PMID- 7831861 TI - [The instrumentarium of the military surgeon (an historical essay)]. PMID- 7831862 TI - [The 3rd Central Consultative-Diagnostic Polyclinic of the Ministry of Defense- in service]. PMID- 7831863 TI - Has hepatitis A virus been transmitted by clotting factor concentrates among hemophiliacs in the United States? AB - Hepatitis A virus (HAV) infection occurred after administration of factor VIII concentrate in Europe associated with one manufacturing process. We determined if there was an excess prevalence of anti-HAV among hemophiliacs in the United States, and whether any infections here were potentially concentrate-associated. We observed clotting disorder patients and household members for up to 7 years at 6-month intervals. Selected specimens were titered for anti-HAV-immunoglobulin G content to distinguish whether they were passively or actively acquired. Our results show that anti-HAV prevalence was 20-25%, but males with clotting deficiencies had a 44% rate (p < 0.001). Passive anti-HAV (> or = 30 to < 950 mIU/ml) from intermediate-purity factor VIII may have protected against community HAV exposure. Factor IX concentrates, which contain no anti-HAV, did not protect and a few instances of past transmission are possible. Criteria for present-day concentrate-associated cases were developed; no subject conclusively met these criteria during the period between late 1985 and May 1993. In conclusion, the excess of anti-HAV prevalence in male clotting disorders is attributable to both passive administration in concentrate, and past therapy prior to concentrates. No untoward HAV event related to concentrate was found in our population, but measures to prevent transmission of nonenveloped viruses should be instituted. PMID- 7831864 TI - FDA perspective on and response to the risk of hepatitis A from blood products. AB - The clinical and laboratory data available on hepatitis A virus infections reported in Europe were reviewed by the Blood Products Advisory Committee of the Food and Drug Administration. The panel's consensus was that the clotting factor concentrates currently available in the United States are safe with respect to viral diseases, hepatitis A transmissions do not appear to be a significant health problem, and there is a paucity of epidemiologic data on hepatitis A in patients with hemophilia in the United States. PMID- 7831865 TI - The natural history of hepatitis A: the potential for transmission by transfusion of blood or blood products. AB - A study of the natral history and risk factors for hepatitis A can shed light on the potential for contamination of plasma concentrate with hepatitis A virus (HAV). According to the long-term Sentinel Counties Study conducted by Alter and colleagues at the Centers for Disease Control and Prevention in Atlanta, the most frequently reported risk factors for HAV infection are living with a patient who has hepatitis, homosexual activity, and close contact with young children. International travel to hepatitis A endemic areas and illicit parenteral drug use were less frequently documented risk factors, although illicit injectable drug use has been considered more significant in other hepatitis A studies. Approximately 40% of patients with hepatitis A reported no apparent risk factors. Hepatitis A occurs most often today in the 5- to 30-year-old age group. Young adults, who are also eligible donors, are thus at risk of infection. The natural history of hepatitis A was studied in New World owl monkeys. Fecal shedding of infectious virus was detected by 4 days after intravenous injection of infectious material and peaked at almost 10 million infectious particles per gram of feces just prior to onset of chemical evidence of liver disease. Viremia of substantial magnitude occurred throughout most of the 4-week incubation period and was maximal during the prodromal stage, prior to the development of clinical, chemical, or serologic manifestations of infection. Although the magnitude of hepatitis A viremia has not been well documented in humans, it is likely to reach levels of 10(4)-10(6) infectious particles per milliliter of blood.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7831866 TI - Virology of the hepatitis A epidemic in Italy. AB - We studied the virologic aspects of a hepatitis A epidemic that occurred among hemophilia patients in Italy between 1989 and 1992. Twelve lots of factor VIII concentrate manufactured by the solvent-detergent chromatographic technique and suspected of contamination by the hepatitis A virus (HAV) were analyzed by a two step, nested polymerase chain reaction (PCR) procedure. PCR was applied to 1-ml samples of factor VIII concentrate and 100-microliters serial serum samples available from 2 patients. Particular care was taken to rule out the possibility of false-positive results during analysis. Results demonstrated PCR amplification of the 3'-region of the VP3 gene in 5 of the 12 implicated lots of factor VIII and in the serial serum samples of both patients. PCR amplification also revealed that the gene sequences detected in patients' sera were identical to the sequences detected in the product they had received. In all, 3 VP3 sequences (found to be 96-99% identical) were amplified. Further characterization of the HAV found in the factor VIII concentrate and the patients' sera was attempted by PCR amplification of the VP1/2A region. Successful amplification of this region was achieved in the serum of only 1 patient and in the concentrate he received. This fourth amplified sequence was identical in both serum and factor VIII concentrate. Attempts to transmit hepatitis A from the contaminated lots to 3 chimpanzees resulted in no signs of infection after 10 months of observation. Based on the Italian experience, persons with severe hemophilia who receive large pool concentrate are at potential risk for HAV infection and should be vaccinated against HAV or use an alternative to solvent-detergent-prepared concentrate.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7831867 TI - Review of the hepatitis A epidemics in hemophiliacs in Europe. AB - A recent increased incidence of hepatitis A in the hemophilia populations of Italy, Germany, Belgium and Ireland was studied. The first well-documented outbreak occurred in Italy, where 51 patients with severe hemophilia contracted hepatitis A between the years 1989 and 1992. A case-control study by Mannucci et al. of the first 29 consecutive cases of hemophilia patients with jaundice led to the conclusion that hepatitis A was transmitted to Italian hemophilia patients by solvent-detergent-treated, ion-exchange-purified concentrate. In a retrospective serologic study of the German epidemic, Brakmann et al. isolated 18 seroconversions in a study group of 195 hemophilia patients over a 5-year period. Although several types of concentrate were used in Germany during this time, all but 1 infected patient received large doses of solvent-detergent, ion-exchange product. It was revealed that the 1 exception had a brother with hemophilia who had received solvent-detergent-prepared concentrate and had developed hepatitis A. Transmission to the study patient was therefore attributed to household contact. The Belgian experience corroborated the findings of the Italian and German investigators: several batches of factor VIII, prepared from plasma of Belgian donors in Lille, France, and Vienna, Austria, appeared to be associated with hepatitis A infection, mainly in hemophilia patients who had received large infusions. An interesting observation in the later (1993) case-control portion of the Belgian study was that hepatitis A virus antibodies were less prevalent in hemophilia patients than in age-matched controls.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7831868 TI - [The philosophical bases of medical ethics and deontology]. PMID- 7831869 TI - [The functional activity of the poly- and mononuclear leukocytes in patients with different clinical forms of ischemic heart disease]. AB - While studying the functional activity of poly- and mononuclear leucocytes in 75 patients with various clinical types of ischemic heart disease (angina of effort, angina decubitus, arrhythmias, cardiac insufficiency at the background of atherosclerotic cardiosclerosis and atherosclerotic hypertension), decline in the functional activity of the phagocytizing cells has been revealed, this being considered to be a pathogenetic prerequisite for atherosclerosis progression. PMID- 7831870 TI - [Myocardial ischemia occurring during coronary ventriculography in patients with ischemic heart disease]. AB - Analysis of myocardial ischemia that occurred during coronary ventriculography in patients suffering from ischemic heart disease (IHD) depending on the severity of the illness showed that it tended to develop in patients with the most restricted coronary reserve, clinically apparent affection of major arteries of the heart and significant dysfunction of left ventricular myocardium. While preparing patients for the invasive evaluation it is necessary that the clinical course of the disease be taken into consideration. At most risk in this respect are persons whose IHD course is aggravated by myocardial infarction and associated with hypertensive disease. PMID- 7831872 TI - [A correlational analysis of the morphometric cardiac indices in virtually healthy persons and in patients with ischemic heart disease and arterial hypertension in different age groups]. PMID- 7831871 TI - [The clinical picture of ischemic heart disease following a myocardial infarct]. AB - The course of ischemic heart disease was studied in 167 patients who had survived myocardial infarction (MI). The chief factors determining the course of the disease and prognosis after MI are the degree and number of affected coronary arteries, MI localization, functional state of myocardium and early onset of postinfarction stenocardia. PMID- 7831873 TI - [The effect of quantum hemotherapy on the plasma hemostatic indices and fibrinolysis in patients with unstable angina]. AB - An evaluation was done in 172 patients with progressive stenocardia. The use of intracardiac laser light irradiation of blood in combined treatment was found to improve the clinical course of the illness and to have a beneficial effect on the factors of plasma haemostasis and fibrinolysis which play a pathogenetic role in the destabilization of the ischemic heart disease course, this being manifest by a significant decrease in the activity of factor XIII, platelet factor 4, and an increase in fibrinolysis. PMID- 7831874 TI - [The use of 3rd-generation antacid preparations for the treatment of patients with nonulcerous dyspepsia and peptic ulcer complicated by reflux esophagitis]. AB - In the present investigation on the treatment of patients with nonulcerous dyspepsia and peptic ulcer, hiatus hernia complicated with reflux esophagitis, a mechanism has been studied of the action of topalkan, a 3rd generation aluminium magnesium antacid, that involves not only its antacid properties but in an even greater degree the availability of alginic acid in its formula which has antipeptic and protective effect with respect of the mucous membrane of the stomach and esophagus, and provides, together with the magnesium salts, a floating layer of the preparation in the stomach. In grave course of nonulcerous dyspepsia (preulcerous condition) and peptic ulcer complicated by reflux disease of the esophagus topalkan was used in combination with present-day antisecretory preparations pyrenzepine or H2-blockaders of histamine receptors capable of enhancing the antisecretory effect of topalkan as well as endowed with cytoprotective properties with respect of the mucous membrane of the stomach and duodenum promoting healing of erosions and healing and scarring of ulcerous defects. PMID- 7831875 TI - [The role of segmental analgesic mechanisms in the development of silent myocardial ischemia in patients with initial coronary atherosclerosis]. AB - In patients with ischemic heart disease (IHD) with early coronary atherosclerosis the ratio of the myocardial ischemia pain episodes (MIPE) to myocardial ischemia pain-free episodes (MIPFE) is 1:4. In IHD patients, an important role to play in the development of MIPFE has the first segmental link in the analgetic system leading to a segmental rise of the electropain sensitivity threshold. Blockade of alpha 1-adrenoreceptors with prazosinum decreases the activity of analgesic mechanisms and favours transition from MIPFE to MIPE. In patients with the initial stages of coronary atherosclerosis, prazosinum promotes a significant alleviation of both MIPFE and MIPE. PMID- 7831876 TI - [The potentials of echography in the diagnosis of chronic colitis]. AB - Ultrasonic signs of colitis were studied in 24 adults aged 20 to 53 yr and 38 children aged 3-16 yr in whom chronic colitis was diagnosed. 2 adults and three children had ulcerative colitis. The results obtained showed that with the aid of echography it is possible to detect inflammatory lesions in the large intestine as well as to observe the time course of changes in its wall during the course of treatment. Ultrasonic investigation can be of screening type in detecting an inflammatory process in the large intestine, on the one hand, and a method of profound study of changes in its wall, on the other. PMID- 7831877 TI - [An evaluation of the treatment results and prognosis in patients with chronic bronchitis]. PMID- 7831878 TI - [The use of interstitial electrophoresis in the combined treatment of acute pneumonia with a severe course in young patients]. AB - The results of employing intratissue (intraorganic) electrophoresis in a complex of therapeutic measures applied in patients with acute pneumonia with a grave course in young individuals (n = 195) versus homogeneous control group of patients (n = 50) in whom intratissue electrophoresis was not done, were as follows: the percentage of those discharged from hospital in the former group exceeded those among control by 15.9%, the average bed occupancy was reduced by 5 days, the number of persons whom sick leaves had been granted dropped by 9.9% and there were no dismissals from the Army whereas in the control group these amounted to 6%. The present method of treatment used in combination with other therapeutic modalities promotes undelayed resolution of an acute pneumonia and prevention of certain complications in this category of patients. PMID- 7831879 TI - [Local hyperthermia in the combined treatment of chronic trichomonal urethroprostatitis]. PMID- 7831880 TI - [The highly effective biological preparation biosporin]. AB - In this paper, information is given about a new original probiotic, biosporin, worked out at the D. K. Zabolotnyi Institute of Microbiology and Virology of the Academy of Sciences of the Ukraine. The preparation consists of two strains of aerobic sporiferous bacteria Bacillus subtilis and Bacillus licheniformis characterized by mutually complementary spectrum of antagonistic activity with respect to a broad range of pathogenic and conventionally pathogenic microorganisms. The mechanism of treatment and prophylactic action of biosporin was established to be of original, multifactorial and many-sided character. Along with its high antagonistic activity, ability to stimulate non-specific resistance of the macroorganism, biosporin is endowed with enzymatic properties owing to which the preparation regulates and stimulates digestion and has also a pronounced antiallergenic effect. The data obtained from the preclinical studies of the preparation in a great number of animals (including primates) were entirely supported by the results of the state clinic trials of biosporin carried out at the clinics of Kiev, Dnepropetrovsk, Moscow. Parameters characterizing microflora were found to have returned to normal in all the patients with acute intestinal infections, dysbacterioses of different etiology, non-specific ulcerative colitis (more than 800 patients having been kept under observation) during the course of treatment with biosporin, with no instance reported of deterioration in general condition or emergence of any adverse reaction. The clinical application of the preparation being permitted, the Chemicals and Pharmaceuticals Plant of Dnepropetrovsk has started producing it. PMID- 7831881 TI - [The use of Enterogel in the combined treatment of patients with viral hepatitis B and mechanical jaundice]. AB - Enterosgel was studied for its effect in the treatment of viral hepatitis B. No side reactions (allergic or dyspeptic) were noted in patients on enterosgel. The agent may be used in complex therapy of viral hepatitis B in the presence of mechanical jaundice. PMID- 7831882 TI - [The rehabilitation of patients with postneuritic contracture of the mimetic muscles by using locally applied cold action]. AB - A method is proposed for combined modality treatment of patients with postneuritic contracture of the muscles of expression of various genesis utilizing local hypothermia as well as hypo- and hyperthermic methods of treatment. Clinical effectiveness of the proposed method of treatment of patients in the acute phase of the facial nerve neuritis, non-existence of important contraindications which are usual with the medicamentous and electrophysiotherapeutic methods of treatment of this condition, and absence of supposed complications enable it to be recommended for clinical application. PMID- 7831883 TI - [The effect of pentoxifylline on the systemic and cerebral hemodynamics in patients with circulatory encephalopathy and an atherosclerotic lesion of the precerebral arteries]. AB - Studied was an effect of pentoxyfilline on systemic and cerebral haemodynamics in 33 patients with discirculatory encephalopathy in the presence of atherosclerotic lesion of the precerebral arteries, with the aid of dye-dilution methods using Evans blue (T-1824) and ultrasonic dopplerography. Pentoxyfilline was found to be associated with significant reduction of the circulating blood volume at the expense of its globular fraction, diminution of the cardiac and stroke work indices; the drug has only minor effects on the peripheral vascular resistance and linear velocity of bloodflow in the precerebral arteries; it makes for an increased number of cases of eukinetic type of blood circulation and causes regression of subjective neurologic symptomatology. On account of its antihypertensive and cardiodepressive effect the drug is contraindicated in patients with low AP and hypokinetic type of systemic haemodynamics. If intracerebral steal syndrome is detected, the institution of the pentoxyfilline therapy cannot be recommended. PMID- 7831884 TI - [The clinical characteristics and treatment results in patients with lumbago]. AB - 93 patients with lumbalgias working under adverse conditions in aviation industry were examined. The patients were divided into two groups. Group 1 (control) patients (n = 45) received medicamentous, physiotherapeutic and balneologic treatment. Group 11 patients (n = 48) underwent, in addition to the treatments above, a manual therapy (MT) to the vertebrogenic zone and "trigger spots" as well as injections of antireticular cytotoxic serum as to A. A. Bogomolets. Clinical picture in all patients was characterized by vegetovascular disturbances and a pain syndrome of three grades. The treatment resulted in recovery of the vegetovascular deficits and freedom of pain. The greater benefit from treatment occurred in group 11 patients. We conclude that giving manual therapy to the above patients and utilizing native antireticular cytotoxic serum in these is associated with both therapeutic and economic benefits and is easy in performance. PMID- 7831885 TI - [A clinico-neurophysiological analysis of the single action of laser puncture]. AB - Mechanisms were studied of a single exposure to laser puncture on the basis of clinico-neurophysiological investigations in 50 patients with cochleovestibular dysfunctions in the presence of vascular affections of the brain. In a comparative evaluation of endaural versus auricular laser puncture, more pronounced changes were revealed in all the parameters studied during the course of treatment with the former modality than they were with the latter, these parameters being the patients' general well-being as judged by subjective evidence, the ability of the points to conduct electrical current, and the findings from rheoencephalography, encephaloradiothermometry, audiovestibulometry. PMID- 7831886 TI - [The dynamics of the pathophysiological and clinical manifestations resulting from the use of noncontact massage in subjects with the late sequelae of mild closed craniocerebral trauma]. PMID- 7831887 TI - [The mechanical component in viral hepatitis]. PMID- 7831888 TI - [The energy allowance and calcium homeostasis of the cardiomyocytes in the early stages of myocardial ischemia]. AB - Morphofunctional equivalents are described of adaptive and abnormal reconstitution of CMC in acute coronary failure, using methods of light transmission optics in combination with those of electron microscopy. It has been established that the contractile myocardium cell compensatory hyperfunction is provided by mobilization of a maximum number of the CMC organelles. Documented for the first time cytochemically is a direct interrelation between the metabolic activity of oxidoreductases, ability of mitochondria to accumulate Ca2+, and the status of their membranes. Exhaustion of the CMC adaptive potential was found to be associated with inconsistencies between metabolic and Ca(2+)-binding capacity of mitochondria, sarcoplasmic reticulum (CPR), and sarcolemma, these causing desynchronization of myofibrils restricting the CMC contractile apparatus function. The above changes develop prior to the destruction of the organelle membranes, resolved with the routine electron microscopy. It has been shown that inhibition of ion-exchange functions of the basal and plasmic membranes involves redistribution of Ca2+ on these and is accompanied by a progressive impairment of the barrier properties of sarcolemmas. PMID- 7831889 TI - [The blood circulation of the rectal mucosa and the functional status of the rectal sphincter in acute infectious enterocolitis]. AB - Significant decrease in the tone of the rectal mucosa venules was to be seen at the climax of acute Proteus and Klebsiella enterocolitis, as evidenced by examinations with the aid of rheorectograph and an analyzer of intracavitary motor activity, general blood supply to the intestinal segment under study being not compromised. The tone of the rectal mucous membrane arterioles is raised at the climax of acute dysentery caused by a Flexner type of organism in erosive and haemorrhagic proctosigmoiditis. With the clinical recovery being set in, the blood supply to this area fails to return to normal. The excitability of the inner anal sphincter was noted to be on the increase at the climax of acute S. flexneri dysentery, this showing up predominantly in erosive and haemorrhagic proctosigmoiditis, ceasing to reveal itself in the period of reconvalescentia. PMID- 7831890 TI - [Disordered water-mineral metabolism in cholera patients]. AB - Clinical analysis was carried out of El Tor cholera in 100 patients, plasma concentrations of electrolytes of potassium (K) and sodium (Na) were studied as were those of trace elements of iron (Fe), copper (Cu), magnesium (Mg) and manganese (Mn) in the whole blood before and after rehydration therapy and depending on the extent of dehydration. The results were as follows: the plasma concentration of K and Na was lowered, that of Mg in the whole blood increased in stage III as well as that of Mn in st. I and II of dehydration; the concentration of Fe, Cu was decreased in st. I, II, III, and of Mn in sit. III of dehydration. The activities of transferrin and ceruloplasmin were found to be on the decrease for the duration of the illness. Rehydration promoted the return to normal of water and electrolyte metabolism, haemodynamics, without affecting to any noticeable degree the trace element metabolism. PMID- 7831891 TI - [Coagulation hemostasis and the acid-base status of the blood in pertussis patients]. PMID- 7831892 TI - [Changes in the indices of a general blood analysis depending on the histological form of cancer]. AB - Retrospective analysis has been carried out of case records of 122 patients operated on in the urological department for renal cancer. It is only in squamous cell carcinoma (SCC), keratinizing type of epidermoid carcinoma, and spindle cell variant of SCC that the diminution in red blood count, decrease in hemoglobin and increase in ESR was noted to occur in all the patients; to a lesser extent the above changes showed up in adenocarcinoma, mixed type, clear cell, granular cell variants of SCC and in transitional cell carcinoma. Increase in white blood count was noted in 80% of the patients in spindle cell variant of SCC only; whereas in other forms this was recorded in 11-33%. The results obtained will, we believe, help in broadening, to an extent, our diagnostic and prognostic potentialities in malignant neoplasia of the kidney. PMID- 7831893 TI - [The diagnosis of nonorganic neoplasms of the lesser pelvis]. AB - An analysis is presented of the data on 330 patients with extraorganic neoplasms of the small pelvis (ENSP), 110 of whom are children, 105 subjects had benign neoplasms, 225 presented with malignant neoplasia. ENSP are manifested primarily by pains in the pelvis and disturbances in physiological functions due to the adjacent organs and structures being squeezed. In applying for medical advice for the first time diagnostic procedures fail to show ENSP in each third (34.2%) patient. The diagnosis of ENSP is supposed to include several studies and it is multi-stage. The most valuable information concerning ENSP is provided by rectal and/or vaginal examination of pelvic cavity. A scheme was elaborated for establishing boundaries of the focus, determining the size of a neoplasm, as was the classification according to the stages and TNM system for the objective information to be obtained on localization, size and distribution of a neoplasm. Employed in the evaluation of patients were rectoscopy (in 158 patients), cystoscopy (123), roentgenography of bones and pelvic cavity (306), pelvic pneumography (79), excretory urography (175), rectosigmoidography (178), ultrasonography (102), computerized tomography (118), angiography (112) and other procedures, all these having been done in order to be able to make as accurate and precise a diagnosis as possible. PMID- 7831895 TI - [A case of the cutaneous form of anthrax]. PMID- 7831894 TI - [A case of Chiari's disease]. PMID- 7831896 TI - [The main trends in the work to formulate a healthy life style]. AB - Formation of a healthy life style is a complex socioeconomic task which is to be solved at the level of the state, public health care agencies as well as at the individual level. Attainment of this objective will require a complex approach to each individual taken separately. PMID- 7831897 TI - [An analysis of the organizational status of medical care for venereal disease patients]. PMID- 7831898 TI - [The electrophysiological and psychogenic correction of psychosomatic disorders in flight personnel]. PMID- 7831899 TI - [Objective control over student knowledge during instruction in a department of hospital therapy]. PMID- 7831900 TI - [The contribution of Ukrainian scientists to the development of immunology]. PMID- 7831901 TI - [The medicinal plants of Scythia]. PMID- 7831902 TI - [The molecular aspects of the immunopathology in rheumatic diseases]. AB - In this paper, low-molecular immunosuppressive lymphopeptide of molecular weight ranging from 300 to 500 daltons and anti-DNA autoantibodies have been shown to play a role in the formation of immunosuppression and development of secondary immunodeficiency states in patients with diffuse involvement of connective tissue, as evidenced by the analysis of the clinical and experimental studies. A concept of enzyme immunodeficiency in the pathogenesis of rheumatological diseases is documented. Special emphasis is put on the unsolved issues relative to this problem. PMID- 7831903 TI - [The fractional calcium composition and the content of calcium-regulating hormones in the blood plasma of hypertension patients]. AB - It has been established that the degree of ionization of serum calcium increases with the progression of hypertensive disease (HD) concurrently with the elevation of the level of calcitoninemia. Concentrations of parathyroid hormone remain unchanged at early stages of HD and it is not until hypertrophy of the left ventricle becomes clinically apparent that they begin to increase. The data obtained will, we believe, help in accounting for the features of the clinical course of variant forms of hypertrophy of left ventricle in patients with hypertensive disease. PMID- 7831904 TI - [Experience in the use of autotransfusions of laser-irradiated blood in treating hypertension patients]. AB - Autotransfusion of laser light-irradiated blood (5-7 sessions) was found to facilitate a steady arterial blood pressure fall by an average 24% of the initial level in patients with hypertensive disease. Drop in the arterial blood pressure following the course of autotransfusion of laser light-irradiated blood was accompanied by improvement in general condition of the patients, enhancement of the effectiveness of antihypertensive preparations, favourable shifts in immunological and haemorheological indices. After discharge from hospital beneficial clinical effect persisted for up to 4-8 months. The preliminary data obtained suggest that autotransfusion of laser light-irradiated blood may well be used as adjunct to a complex of therapeutic measures to be taken to control hypertensive disease. PMID- 7831905 TI - [Atrial natriuretic hormone in certain forms of arterial hypertension of endocrine origin]. AB - Atrial natriuretic peptide is shown to be a hormone having a certain part to play in the regulation of arterial blood pressure and water-salt metabolism. Results of study on the plasma content of the hormone in patients with various forms of arterial hypertension of endocrine genesis are presented. Differentially directed changes have been revealed in concentrations of immunoreactive atrial natriuretic peptide. Elucidation of the role of these in the pathogenesis of the pathology under consideration warrants further study in a comparative evaluation wtih the parameters of cardiohaemodynamics and water-salt metabolism. PMID- 7831906 TI - [The amino acid composition of the blood serum and gastric mucosa in peptic ulcer with involvement of the hepatobiliary system and intestines in patients of different ages (2)]. AB - In ulcerative disease of the stomach the pool of free amino acids (AA) in the mucous membrane of the stomach (MMS) was shown to be expanded, their amount being increased with ageing and in the involvement of the hepatobiliary system, this being a result of even more pronounced augmentation of pathological processes and a decrease in the rate of the protein synthesis. This is accompanied by ever increasing inadequacies in the assimilation of essential amino acids (particularly methionine, threonine, phenilalanine), formation of cystein, glycine, many other essential and conventionally non-essential AA, the process of incorporation of many AA (especially those of sulphur-containing) into polypeptide chain being made difficult, this affecting the synthesis of structural and specific proteins and reducing strikingly the protein-synthesizing potential of MMS. PMID- 7831907 TI - [The efficacy of the new hepatoprotector Antral' in treating patients with a chronic toxic lesion of the liver]. PMID- 7831908 TI - [Antigen-binding lymphocytes in pulmonary tuberculosis patients with the side effects of antitubercular preparations]. AB - 70 patients with pulmonary tuberculosis, experiencing side-effects associated with antibacterial preparations were examined as were 30 patients receiving similar therapy with no complications being developed, and 20 apparently healthy subjects. It was established that the level of antigen-binding lymphocytes depends on the extent of sensitization to the allergen in question and reaches the highest values in patients presenting with adverse reactions. Preliminary treatment of lymphocytes with a medicamentous preparation results in some reduction of the number of antigen-binding lymphocytes. Values for the index of restoration of stimulated expression of the receptors to the medicinal preparations by trypsinized lymphocytes are higher in patients experiencing adverse reactions than they are in patients with pulmonary tuberculosis, presenting with no ill-effects, and in donors. PMID- 7831909 TI - [The role of pulmonary surfactant in the atherogenesis process in patients with dust-induced respiratory organ diseases]. AB - There have been established opposite reactions in the cardiovascular system during formation of dust-induced pathology of lungs: a common finding in patients with pneumoconiosis is alterations in the left heart, while in chronic dust bronchitis the same is true of the right heart. In the authors' opinion, different states of pulmonary surfactant in the above conditions account for this observation. Inhibition of synthesis of the pulmonary surfactant associated with the development of the blood and tissue phospholipid deficiency makes for the evolution of atherosclerosis in patients with pneumoconiosis while enhancement of the phospholipid production by the lungs accompanied by elevation of their blood content is an important factor inhibiting the processes of atherogenesis in patients with dust bronchitis. PMID- 7831910 TI - [The cellular level of integration in the body of the workers at a poultry plant with extrinsic allergic alveolitis]. AB - Studied at the cell level of integration were the following indices for nonspecific reactivity: phagocytic activity of leucocytes (PhAL), a parameter characterizing damage to neutrophils (PDN), nitroblue tetrasolium test (NBT test), the activity of alkaline phosphatase (AlPhA) of neutrophils, and the activity of acid phosphatase (AcPhA) of lymphocytes in EAA (exogenous allergic alveolitis) workers with reference to the service duration. PDN was shown to be raised in EAA workmen who had worked at the integrated poultry farm for 6-10 and 16-20 years. The parameter characterizing damage to neutrophils did not differ from control values in the workmen with 1-5 and 11-15 yr service duration. It was found that the activity of AlPh of neutrophils was decreased in EAA workers with 1-5 and 11-15 yr service duration. The activity of AlPh did not change with 6-10- and 16-20 yr service duration. The results from NBT-test, determinations of PhAL, and the activity of AcPh of lymphocytes showed their elevation in EAA workmen with the service duration 1-20 years. In summary, study at the cell level of integration into the indices of nonspecific reactivity in workmen with 1-2-yr length of service showed a decrease in the activity of AlPh neutrophils and an increase in the activity of AcPh of lymphocytes, PhAL, PDN, NBT-test, suggesting some disturbance in metabolism in leucocytes and involvement of nonspecific mechanisms of protection of organism in EAA. PMID- 7831911 TI - [Free histamine and free serotonin in the blood plasma in symptomatic respiratory erythrocytosis]. AB - Fluorometric analysis was carried out of the blood plasma content of free histamin (FH) and free serotonin (FS) in 27 patients with chronic non-obstructive bronchitis (ChNB), 52 patients with chronic obstructive bronchitis (ChOB) presenting with symptomatic erythrocytosis (SE) and in 29 normal subjects. Comparative analysis of the results obtained showed that in SE caused by ChOB the FH and FS content is significantly higher (p < 0.001) than in ChNB and in normal subjects. The FH content increases in SE with the augmentation in erythrocytosis. Positive dynamics was noted of FH and FS during the course of the disease treatment (p < 0.001). PMID- 7831912 TI - [Radiation thermometry used in the study of normal kidney functional activity]. AB - In this paper, the results of use of active radiation heat flowmetry in the nephrological clinic are presented. Employment of rationalized loading tests permitted direct relationship to be established of radiation heat losses from the surface of the "open" kidney to the status of renal functions. Patterns of changes in the infrared radiation intensity have been ascertained in health and in the blockade of canalicular reabsorption. A hypothesis is documented about participation of autonomic system of regulation of renal bloodflow and glomerular filtration in thermostabilization of the kidney. PMID- 7831913 TI - [Satellite myocytes in postnatal ontogeny and during skeletal muscle adaptation to hyper- and hypokinesia]. AB - The authors studied the genesis of myosatellitocytes in normalcy and hypo- and hyperkinesia in skeletal muscles of albino rats. It is for the first time in the development of atrophy of the muscle fiber physiological hypertrophy that an additional mechanism has been described of the formation of myosatellitocytes from segregated nucleosarcoplasmic sites. An analysis is provided of ultrastructural reorganization of satellite cells in long-term restriction of motor activity. PMID- 7831914 TI - [The prospects for using an indirect immunoenzyme method for the diagnosis of leptospirosis]. AB - An evaluation was carried out of sensitivity and specificity of indirect enzyme immunoassay to be used for the identification of antileptospiral antibodies in the patients' sera. Ultrasonic antigenic preparations were used as an antigen. The test permits determining genus-specific antibodies as well as those of more restricted specificity including serogroup-specific ones. Time course of changes is presented of antibodies in different phases of the disease. In leptospiral patients the spectrum of the antibodies identified broadens with the use of polyvalent antigenic preparations. PMID- 7831916 TI - [Stimulating and hypobiotic therapy in cardiogenic shock]. AB - Comparative evaluation of the efficacy of stimulating and hypobiotic agents in 122 dogs with experimentally induced cardiogenic shock and 56 patients with acute myocardial infarction complicated by cardiogenic shock allowed a relationship to be established of the efficiency of therapeutic measures to the phase and rate of progression of the pathological process. In rapid progression of clinical symptoms of cardiogenic shock it is predominantly preparations of hypobiotic action that are to be prescribed whereas in slow progression of these it is advisable to use agents of stimulating action. PMID- 7831915 TI - [Morphological changes in the stomach and duodenum in chronic liver diseases of HB viral etiology]. AB - Morphologic investigation of 72 gastroduodenal biopsy samples from 29 children with chronic persistent and chronic active hepatitis, hepatic cirrhosis, revealed signs of chronic gastroduodenitis. The degree of the gastroduodenal zone lesion was directly related to severity of the primary condition. Comparative data on histopathological changes in the stomach and duodenum in concurrent pathologies suggest that chronic duodenitis may be the primary condition. PMID- 7831917 TI - [The characteristics of the accumulation of metals in the hair of children]. AB - Gender- and colour-associated quantitative features of accumulation of zinc, copper, nickel, lead, molybdenum and chromium have been studied in the hair of children aged 3-4 yr residing in different districts of Kiev. Inverse relationship was found between accumulation of lead and zinc, zinc and copper; direct proportionality between copper and lead, chromium and molibdenum. The levels of nickel detected in 34% of the hair samples did not permit establishing the pattern of this metal relations to other metallic elements. PMID- 7831918 TI - [The efficacy of replacement therapy in hypothyroidism]. AB - The use of L-thyroxin in the substitution therapy for hypothyrosis is, in our judgement, a most pathogenetically well-grounded option. In the early period of the treatment of hypothyrosis with L-thyroxin the total clearance of thyroxin is accelerated and is in inverse relationship to the initial blood hormone level. From the results of pharmacokinetic studies a specific individualized regimen is proposed of thyroxin administration in the early period of the treatment of hypothyrosis, which allows the thyroxin concentrations to be achieved within the range of 120-150 micrograms. The use of the above method results in clearing up pathognomonic symptomatology of hypothyrosis, normalization of the thyrotrophin and total cholesterin levels, improvement in central hemodynamics in 14-21 days, promotes complete rehabilitation of patients about 1 month after the initiation of treatment. PMID- 7831919 TI - [Natural killer activity--an index of the efficacy of the treatment of patients with acute leukemia]. PMID- 7831920 TI - [The blood kinin system of persons with a history of 1st-degree acute radiation sickness]. AB - There tends to be an activation of blood kinin system in individuals with a prior acute grade I radiation sickness in the period of remote sequelae (six yr after irradiation). It is suggested that changes in the proteolytic processes may play a role in the natural course of the diseases in the individuals with a history of acute radiation sickness (pathology of the gastrointestinal tract, vegetovascular dystonia etc.). The disturbances revealed are of pathological nature and require therapeutic measures to be taken aimed at clearing them up. PMID- 7831921 TI - [The rehabilitation of participants in the cleanup of the sequelae of the accident at the Chernobyl Atomic Electric Power Station with borderline mental disorders]. AB - Among ecological disasters the aftermath of the accident at the Chernobyl NPP present an undoubted chronic anthropogenic stress situation. Psychological stress is manifested by somatic, predominantly vasovegetative disorders, as well as by pre-nosological and clinical forms of mental disorders. Phasing and reconstructive principle forms a basis for the organizational and structural activity of specialized psychoneurological institutions dealing with rehabilitation and readaptation of the participants in the elimination of the ChNPP accident aftereffects. PMID- 7831922 TI - [The criteria for forming risk groups among the population exposed to ionizing radiation after the accident at the Chernobyl Atomic Electric Power Station]. AB - Studied were particular features of peripheral blood, certain immunological and biochemical indices under long-term exposure of human body to radiation after the accident at the Chernobyl Nuclear Power Plant. The study comprised 5578 individuals. The examinees were liquidators of the Chernobyl accident sequels (n = 1052), inhabitants of Pripyat evacuated from the town (n = 850), the Kiev SSBT primary donors (n = 1738). Control group consisted of 936 Kievans who had been examined before the accident between 1982-1985 by the same methods. The results obtained allowed for the most informative indices to be found in order that risk groups might be formed. PMID- 7831923 TI - [The development of methods for experimental physiotherapy in patients with altered thyroid activity after exposure to ionizing radiation]. AB - Pathogenic influence of Chernobyl-related factors was modelled with the view to study peculiarities of changes in the most important systems of the body induced by long-term low-dose ionizing radiation associated with hypo- and hyperthyroidism. Experimental rehabilitative therapy stipulated following methods of physico-pharmacological treatment: 1) course of general electrophoresis with chemical components of peloids; 2) the same course with Ethimisol added to the solution used for electrophoresis. Clinical follow-up of patients resided in the Chernobyl-stricken territories proved advisability of differentiated application of aforementioned methods according to prevailing thyroid symptoms. PMID- 7831924 TI - [The immune system indices of hypertension patients exposed to ionizing radiation]. AB - We studied immunologic status in patients with stage II hypertensive disease (HD): there were 92 Kievans and 46 subjects living in the area with excessive radiation within a 30-km radius of the Chernobyl Nuclear Power Plant; control group comprised 20 apparently healthy men (donors of the city station of blood transfusion). In HD patients the T-lymphocyte count was found to be reduced as was the content of T-suppressors and T-helpers, the activity of the B-immune system tending to be on the increase. Suppression of the T-lymphocyte suppressive function and elevation of the immunoglobulin G content result in an accelerated formation of circulating immune complexes, this indicating evolution of disturbances in immune complexes and an influence being exerted on the development of vascular affections and progression of atherosclerosis being promoted in these patients. Changes in the immune system tended to be more pronounced in st. II HB patients residing in the area with abnormal radiation than they were in the same category of patients--inhabitants of Kiev--this being supposedly a reason for disease progression in them. PMID- 7831925 TI - [The effect of the ecologically adverse factors of a Donets Basin industrial region on the clinico-immunological indices of patients with viral hepatitis A and B]. AB - Clinicoimmunological features of viral hepatitis A and B (VH A and VH B) were studied in residents of unfavorable (from the environmental standpoint) regions. 180 VH A, 86 VII B patients were examined. Clinical picture of VH was characterized by predominance of more severe forms, frequent occurrence of cholestatic variant of VH, high rate of protracted and recurrent (in VH B) course of VH, hepato- and splenomegaly of long duration. The immunologic status was characterized by more pronounced T-lymphopenia, noticeable imbalance of T-helpers and T-suppressors, decrease in the level of immunoglobulins, as well as in phagocytic activity of neutrophilic granulocytes and monocytes in peripheral blood. The use of adaptogens and antioxidants in multimodality treatment promotes rapid normalization of clinicoimmunological parameters in VH. PMID- 7831926 TI - Biochemical investigations of the dynamics of proteinase activity at different stages of trichinellosis in mice. AB - In the literature available hitherto there are many reports on enzymatic changes in tissues and a correlated rise in enzymatic activity in blood serum during experimental and human trichinellosis. In this study we were characterised proteinase activity in crude extracts from muscles of mice infected with Trichinella spiralis and T. pseudospiralis and the dynamics of their changes in different stages of disease. The activity of proteinase in muscle of mice infected with T. spiralis showed an increase in the 1st-5th week post infection, and then a slight decrease. The biggest proteinase activity was observed in 5th 6th week post infection. In the muscle of mice infected with T. pseudospiralis the increase of proteinase activity was observed in 1st-4th week post infection. In the 4th week the activity reached its maximum and in the 5th-10th week post infection there was a decrease of the activity in comparison with the control. As we could see, the dynamics of the changes of proteinase activity in mice is similar in the case of the disease with other biochemical and immunological indices observed in trichinellosis and with the increase of regeneration and transformation processes observed in histopathological studies. PMID- 7831927 TI - Parasitological appraisal of TFX-thymomodulin effect on the course of intestinal and muscular invasion in mice infected with Trichinella spiralis. AB - Studies were undertaken to evaluate by parasitological techniques the course of intestinal and muscular invasions in mice infected with Trichinella spiralis and treated with TFX-Thymomodulin (TFX-Th). Studies were conducted on 120 mice of BALB/c and SWISS strains, infected each with a mean invasive dose of 300 T. spiralis larvae. TFX-Th (Thymoorgan GmbH Pharmazie Co. KG, Vienenburg, Germany) was administered subcutaneously at 30 mg/kg body weight. Depending upon duration of TFX-Th administration and stages of intestinal and muscular invasions, three experiments were distinguished in the study. The results indicated that TFX-Th promoted eradication of larvae from muscles, whether administered at the early of the late stage of T. spiralis invasion. PMID- 7831928 TI - CD4+ and CD8+ cells in mice infected with Trichinella spiralis and treated with cyclosporine A. AB - The mice infected with 200 Trichinella spiralis larvae were injected intraperitoneally with Cyclosporine A (CyA) between 14-18 days post infection (dpi). The drug was administered in a dosis of 50 mg/kg/day. The animals were killed at 21, 28, 35, 42 and 60 dpi and the fragments of spleen, mesenteric lymph node, jejunum and musculus masseter were sectioned in a cryostat and fixed in acetone. The slides were examined with monoclonal sera by the immunofluorescent or immunoenzymatic method. It was found that the number of CD4+ cells in the control and in the CyA-treated mice was similar but in the animals receiving the drug the reaction was less intensive. The stimulation of CD8+ cells of CyA treated mice--especially in the jejunum--was stronger than in the control animals. This fact is important because the CD8+ cells are the APC cells in this organ. PMID- 7831929 TI - The influence of adriamycin on the CD4+ and CD8+ cells in the course of trichinellosis in mice. AB - The effect of adriamycin on the behaviour of CD4+ and CD8+ cells in the course of trichinellosis in mice has been studied. The animals infected with 200 larvae per mouse were administered intraperitoneally adriamycin (Adriblastin from Farmitalia) at 1st and 28th day post infection (dpi), in a dosis of 0.2 mg. The mice were killed weakly for 6 weeks and then at the 60th dpi. The examinations were made on histologic sections from the spleen, mesenteric lymph node, jejunum and masseter muscle using immunofluorescent and immunoenzymatic methods with monoclonal antibody. The mice receiving adriamycin exhibited more CD8+ cells in the intestinal mucosa and by the end of the experiment also in the muscles in comparison with the control animals, which, however, did not affect the course of the infection. PMID- 7831930 TI - Contribution of muscle cell to formation of the capsule around Trichinella spiralis larva. Ultrastructural studies. AB - In electron microscopic studies on structure of the capsule surrounding Trichinella spiralis larva the techniques have been employed which permit demonstration of proteoglycans and collagen fibers at various stages of their formation, i.e. fixation in tannic acid and staining reaction with ruthenium red. The muscle cell has been demonstrated to produce both collagen fibers and glycoproteins plus proteoglycans. The products formed inner part of the capsule, separated from the outer part by the basement membrane. The outer part of the capsule contained collagen fibers and matrix, synthesized by the interstitial tissue cells, by fibroblasts and vascular endothelium cells in particular. PMID- 7831931 TI - Focus of trichinellosis and factors determining its mild clinical course. AB - Present study aimed at analysing the set of epidemiologic, clinical and serological data in appraisal of trichinellosis focus in little town S., near Poznan. It was stressed, that parasitic testing of the consumed meat associated with biological appraisal of Trichinella spiralis represent valuable criteria, which are helpful in interpretation mild clinical signs and symptoms, serological data and in establishing management of patients. PMID- 7831932 TI - Remarks on horse trichinellosis in Poland. PMID- 7831933 TI - Trichinellosis in CIS (1989-1993). Epidemic situation. PMID- 7831934 TI - Trichinellosis in Byelorussia. PMID- 7831935 TI - Trichinellosis in Italy (1988-1993). PMID- 7831936 TI - Epidemiological data concerning T. spiralis infection in The Netherlands. PMID- 7831937 TI - Trichinellosis in France (1991-1992). PMID- 7831938 TI - Trichinellosis in Slovak Republic (1988-1992). PMID- 7831939 TI - Trichinellosis in Sweden. PMID- 7831940 TI - Trichinellosis in Bulgaria (1988-1992). PMID- 7831941 TI - Trichinellosis in Greece (1992-1993). PMID- 7831942 TI - Trichinellosis in Chile (1980-1993). PMID- 7831943 TI - [Perspectives in gene therapy in rheumatic and degenerative diseases of the spine and joints]. AB - Rheumatoid degenerative conditions of the spine and other joints are most common in elderly patients. Data by the "National Center for Health Statistics" state that approximately 500 in 1000 persons above 65 are affected. Numbers for Germany should be in the same range. Although a lot of research has been dedicated to these conditions many of the actual causes remain unclear. There is consensus about the involvement of Interleukin-1 in the development of rheumatoid arthritis RA. Recent results point towards a more refined understanding and a gene therapy approach utilizing synovial cells. The synovium will in this strategy be the locus of drug (eg hormone) synthesis antagonizing the rheumatoid disease. We believe that this new approach will have a major impact on the treatment of RA. PMID- 7831944 TI - [Organization of a bone and tissue bank]. AB - The regional bone bank offers a good foundation for covering the expanding clinical demands in tumor and revision surgery. Since 1980 the tissue bank of Munster consists of 32 cadaveric and 41 multi organ donors. In the guidelines of the tissue bank the responsibility, organisation form, donor selection, quality control, sterilisation, documentation and all questions of finances are fixed, in accordance to the American Association of Tissue Banks. A fixed staff will be helpful to offer a secure and not expensive donor tissue for the clinical demands. PMID- 7831945 TI - [Homologous blood use and possibilities for autologous hemotherapy as exemplified in hip and knee endoprostheses]. AB - In a retrospective study we documented the need for blood transfusion in total knee (TKR) and hip replacement (THR). The problems with homologous blood transfusion in orthopedic surgery and alternative techniques of autologous-blood transfusions are discussed. In this series patients with primary THR needed 1.69 (+/- 2.25) blood units, with primary TKR 1.58 (+/- 1.54) blood units, and secondary TKR 1.19 (+/- 1.47) blood units, Secondary THR required significantly more units (3.85 +/- 3.07). These procedures also asked for significantly more plasma (3.27 +/- 3.95) than all other procedures. For secondary THR 2.63 (+/- 2.45) blood units were intraoperatively used and only 1.23 (+/- 1.09) blood units postoperatively. All other procedures needed postoperatively significant more units than intraoperatively. In secondary THR the use of blood transfusions increased with age. 45% of the patients with primary THR and 15% with secondary THR were operated without additional blood transfusion. In secondary THR 36% of all patients needed more than 4 blood units and 27% more than 4 plasma units. In TKR 39% of the primary cases and 50% of the secondary cases were operated on without additional homologous blood. Based on these results we established a transfusion concept for our department. Economic, practical, as well as legal aspects were taken into account. PMID- 7831946 TI - [The use of a rapid infusion system in orthopedics]. AB - Major orthopedic surgery such as partial resection of the pelvis and subsequent implantation of a prosthesis is highly connected with massive bleeding. Therefore we tested the hypothesis that the use of a rapid infusion device, which was originally designed for liver transplantations, can prevent hypovolemic shock. We studied 20 patients: in one group (n = 10) the iv volume was given in a conventional way (37 degrees C) by use of pressure infusion bags. Patients of the second group (n = 10) received the iv volume via the Rapid Infusion system (Haemonetics Corp., Braintree, MA). We can conclude that with this new device for rapid volume replacement it is possible to keep the patient's vital functions stable even during times of excessive bleeding and to prevent from metabolic consequences following hypovolemic shock. PMID- 7831947 TI - [Joint destruction and infection in advanced age]. AB - Because of degenerative joint diseases and the reduced resistance in older patients the correct diagnoses of joint-empyema is difficult. In 29 pat (> 60 y) the mean delay of diagnoses was 5.1 months. First location of the infection have been: urinary tract 12, pneumonia 6, skin infection 10, and decubitus 3. Risk factors have been diabetes 4, polyarthritis 3, gout 3 and tuberculosis 3. The species were: s. aureus 12, s. albus 2, streptococcus 2, diphtheroid 2, e.coli 2, pseudomonas 2, proteus 4, enterobacter 3 and salmonella 1. 8 patients demonstrated mixed infections. The high mortality (3 pat.) and the frequent general sepsis (5 pat.) underline the importance of a missed joint-empyema in the elderly. PMID- 7831948 TI - [Use of ultrasonography in the diagnosis of infections in the locomotor apparatus -possibilities and limitations]. AB - Significance of sonography in the detection of soft tissue infections is unclear and discussed controversial in literature. In a retrospective study sonograms of 40 hematomas and 23 infections were evaluated to examine the possibility of detecting infections by means of sonography alone. Accumulation of fluid, however, could not be differentiated by the established sonomorphological criteria. Especially in postoperative infections with unclear clinical pattern no differentiation between hematoma and abscess could be made. Only ultrasonically guided transcutaneous needle aspiration biopsy can prove the character of sonographic findings. PMID- 7831949 TI - [Arthropathy and late changes in thalassemia major. A case report]. AB - Patients with beta-thalassemia develop a specific osteoarthropathy as they approach the second life decade. Radiological changes included osteopenia, widened medullary spaces, thin cortices with coarse reticulations, evidence of microfractures, premature epiphysiodesis of long bones and skeletal deformations. The fact that currently patients with beta-thalassemia have a longer life expectancy may explain the recent observations in this case report of this entity, which should become more familiar to orthopaedic surgeons who treat thalassemia patients in the future. PMID- 7831950 TI - [Nail-patella syndrome. A 4-generation family study]. AB - Five cases of hereditary onycho-osteodysplasie are reported. All of the family members presented dysplastic nails. Hypoplastic patella, elbow dysplasia or iliac horns were shown in variable expression. We've seen no other anomalies especially nephropathy did not occur. PMID- 7831951 TI - [Tumor-associated hypophosphatemic osteomalacia: case report and literature review]. AB - Despite the great number of neoplastic entities, which are able to cause this disease, "oncogenous osteomalacia" is hardly known as a paraneoplastic phenomenon. Without removing the not constantly malignant tumor as the underlying cause recovery is not possible. Until now pathogenesis is unknown. Together with a review of the literature a case report is presented, in which a malignant fibrous histiocytoma of soft tissue caused an untreatable osteomalacia. Because of failure of local tumor control prognosis in this case must be considered fatal. PMID- 7831952 TI - [Ultrasonography studies of the fetal hip]. AB - Recent advances in ultrasound technology, especially high-resolution sonography, now permit visualisation of the fetal hip development. Since early diagnosis and treatment of congenital hip dislocation significantly influence the outcome of the disease, ultrasound screening of the newborn infants showed to be the most effective method. In our study assessment of the fetal hip has been performed on the prenatal level in order to provide basic knowledge on fetal hip development from 14th to 40th weeks of gestation. From the 20th week of gestation bony structures are clearly visible and allow the assessment of acetabular configuration. Soft tissue and chondral acetabular components are recognizable from the 21st week. For pre- and postnatal comparative measures Graf's method and standard documentation is used. PMID- 7831953 TI - [Maturation curve of the ultrasonographic alpha angle according to Graf's untreated hip joint in the first year of life]. AB - In addition to Graf's classification into different hip-types a maturation-curve of the sonographic alpha-angle was established in order to optimize the differentiation between mature hip joints and those ones which need follow-up and those ones which need treatment at any time within the first year of life. The results obtained are confirming our present knowledge about the spontaneous maturation of physiologically immature hip joints: The mean-value of the alpha angle crosses the 60 degrees-borderline at about the age of two months, then reaches an about 64 degrees-level at about four months. This 64-degrees-level is more or less unchanged up to the end of the first year of life. PMID- 7831954 TI - [The influence of ultrasonography on the diagnosis and treatment of so-called congenital hip dislocation]. AB - By means of a retrospective analysis of the hospital reports of 107 children with 131 dislocated hips we investigated the influence of ultrasound examination on the diagnosis and therapy of congenital dislocation of the hip. We could show, that although the ultrasound examination had increased since 1985 the number of dislocated hips receded only little. However the diagnosis was made earlier in children who had been examined by ultrasound. In these children operative reposition of the dislocated hip had to be performed less frequently compared to the unexamined children. Several case reports are given to demonstrate typical faults in ultrasound diagnostics and treatment of congenital hip dislocation. Our results support the call for a general ultrasound screening of the newborn hip. PMID- 7831955 TI - [Percentile graphs in the documentation of acetabular angle in children with hip dysplasia. A tool in the diagnosis and quality control of its treatment]. AB - The acetabular index (AI; Hilgenreiner 1925) has proven to be a reliable parameter for the radiological diagnosis of developmental hip dysplasia (DDH). Age-dependent normal values and ranges of the AI are well documented. These data, however, have so far not been presented graphically in a way which would have made them suitable for patient data documentation on a routine basis (calculation of percentiles, time-axis with log scale, smoothing). We have therefore created graphs meeting these requirements, based on a previous examination of the AI of 719 girls and 428 boys (Tonnis and Brunken 1968). These graphs have meanwhile proven to be a useful and time-saving tool for the diagnosis as well as quality control of the treatment in children with DDH. PMID- 7831956 TI - [Does the type of prosthesis have an effect on the development of periarticular ossification?]. AB - We checked up the hip operations that were done by the same surgeon in the years 1974-76 and 1984-86. For this examination we had 115 Muller Charnley prosthesis and 75 anatomically straight stems type SF. The heterotopic ossifications were classified according to Arcq. The aim was to find out if the form and type of the femoral stem, the changing of the leg length and of the CCD-angle, the post operative CCD-angle and the number of blood transfusion influences the dimension of heterotopic ossifications. The groups with higher amount of periarticular ossification (Arcq grade 2 and 3) are generally smaller. In the case of SF prostheses the ossifications raised when the CCD angle difference also raised. But the Muller/Charnley prostheses showed quite the contrary. Though there was no significance in this manner. Although in the other controlled factors there were no significant differences. The difference that was found between the two types of prosthesis was equalized with another factor: Low-dose heparin. This was the only significant influence on heterotopic ossification. PMID- 7831957 TI - [Dislocation following total hip endoprosthesis. Association with surgical approach and other factors]. AB - During a period of eight years (1984 to 1992) we found 45 dislocations in 1734 patients treated by total hip arthroplasty. We compared this retrospectively evaluated group with a randomized control group of 61 patients. As a cause for an increasing number of dislocations in 1989 we found: age over 70 years, high CCD stem-angle (142 degrees), dorsal approach, abduction of the acetabular component under certain circumstances (left side). Revision operations always are a high risk procedure. Acetabular anteversion, anaesthesia, way of component fixation did not induce an increased rate of dislocation. We now left the dorsal approach and use only stems with an CCD-angle of 135 degrees or less by now. Careful positioning of the acetabular components and a better patient-instruction helped to decrease the number of dislocations. Because of these measures we reduced the THA-dislocations rate from 5.6 to 0.17 per cent (first operations) and from 12.1 to 6.5 per cent (revision operations). PMID- 7831958 TI - [Unusual late complications following total hip endoprosthesis]. AB - A cementless total hip replacement was implanted in a 52-year-old male patient with coxarthrosis. Rapid cranial migration of the cup and ectopic ossification were subsequently observed. Five years after the original operation, revisional arthroplasty had to be performed to replace the cup. At surgery a large amount of granulomatous tissue and the tip of a deep drainage tube were found. Interposed between the polyethylene inlay and the femoral head of the prosthesis, the drain had not been visible on any of the radiographic controls. The X-ray control performed immediately after the first procedure revealed that the drain had been slung around the neck of the prosthesis stem, a procedure preferred by some surgeons. When the drain was removed, the tip must have been caught between the polyethylene inlay and the femoral head of the prosthesis. It is not clear whether the loosening of the cup was ultimately caused by the increased wear due to the presence of the drain tip. However, in light of this finding we no longer sling the drain around the prosthesis shaft, but lay it along the neck of the femoral component in the same direction as it is routed out transcutaneously. PMID- 7831960 TI - [100 years Zeitschrift fur Orthopadie, Z. Orthop. 131 (1993) 195-207]. AB - The historical review of 100 years of the Zeitschrift fur Orthopadie could create the impression that the Nazi era did not have any significant impact on orthopedics in Germany. In this commentary it is shown that the Prevention of Heredopathic Offspring Act of 1933 resulted in an uncritical overemphasis on hereditary factors. This decisively influenced concepts of, research into and therapy for hip dislocation, both in Germany and other countries. PMID- 7831959 TI - [Macrodactyly of the foot--an unusual, untreated course of many years standing]. AB - This case report represents a 56-year-old patient with macrodactyly of the right foot. This congenital anomaly was not treated surgically before. We resected the gigantic phalanges and metatarsals with preservation of the three main points for walking. The patient is now able to wear fitting shoes. PMID- 7831961 TI - Physical contact with lymphocytes is required for reactivation of dormant HIV-1 in colonic epithelial cells: involvement of the HIV-1 LTR. AB - HIV-1 transmission from mucosal epithelial cells to lymphocytes is a potential mechanism of HIV-1 contamination during sexual intercourse. The human colon epithelial cell line HT-29, that is infectable by various HIV-1 strains, is a useful model for studying the molecular mechanisms involved in this process. In the present study, we show that HT-29 cells, when exposed to either HIV-1(LAI) or HIV-1(NDK) at a low multiplicity of infection, became infected but did not produce infectious virions. Using two-compartment cell culture chambers separated by a porous membrane, we showed that PBL were able to rescue infectious HIV-1 from latently infected HT-29 cells following a physical interaction between the two cell populations. In contrast, HT-29 cells, infected with the same viruses at a high multiplicity of infection, were able to produce mature viral particles that were infectious to PBL in absence of cellular contacts. Transient expression assays using an indicator gene under the control of the HIV-1 long terminal repeat revealed that cell-to-cell contact induced an activation of the HIV-1 promoter. These observations provide a putative molecular mechanism for transmission of HIV-1 from mucosal epithelial cells to lymphocytes. PMID- 7831962 TI - Consistent occurrence of hemagglutinin variants among avian influenza virus isolates of the H7 subtype. AB - Several field isolates of avian influenza virus of the H7 subtype were analyzed for the presence of hemagglutinin variants by labeling proteins in cells infected with virus clones, and reacting with monoclonal antibodies. Each strain was shown to contain two distinct electrophoretic variants of the uncleaved hemagglutinin. In the A/Tk/Ore/71 (H7N3) isolate, two variants remained in the population through 35 laboratory passages, indicating both are stable and may be important to expression of the viral phenotype. Nucleotide sequence analysis of the HA gene of these two variants demonstrated differences at several amino acid positions in the HA1 subunit including one glycosylation site. Three additional recent North American isolates were also each found to contain two electrophoretic variants occurring within populations as few as one embryo passage away from the original clinical specimen. Pulse-chase assays indicated none of the variant HA molecules were cleavable in chick embryo fibroblasts. In the highly pathogenic Australian isolate; A/Ck/Victoria/75, both HA variants are cleavable in fibroblasts, without added trypsin, and the differences are localized within the HA1 region. With all the strains tested, the slower migrating HA variant was associated with a consistently higher hemagglutinin titer in embryos. Finally, recent H7 isolates from imported birds (A/Soft Bill/Ill/92) also exhibit similar variants, indicating their occurrence is not limited to domestic poultry. This consistent presence of two distinct electrophoretic variants in several avian H7 isolates suggests multiple allelic forms of the H7 hemagglutinin. PMID- 7831963 TI - Genetic variation of foot-and-mouth disease virus during persistent infection in cattle. AB - Genetic variation of foot-and-mouth disease virus O1 Campos has been analyzed in consecutive isolates recovered over a one- or two-year period from four cattle with experimental persistent infection. Comparisons of RNase T1 two-dimensional maps and nucleotide sequences of the VP1-coding region revealed a continual, although irregular, increase in the fixation of mutations as the infection progressed. Most changes were not conserved in consecutive isolates. These results, together with the substantial rates of genomic variation observed between some pairs of strains recovered at close time periods, suggested the coexistence of heterogeneous populations in which variants evolve independently from each other, and predominate at irregular time intervals. Furthermore, non related patterns of variation were observed in the four animals. Similarly, genetic diversity of representative strains from major serotype O outbreaks in endemic disease regions of southeastern Brazil and central eastern Argentina which occurred between 1958 and 1983, suggested that outbreak strains are also likely to represent fluctuations of heterogeneous populations which evolve independently from each other. The possible role of persistent infections in the introduction of variant populations in the field is discussed. PMID- 7831964 TI - Fine mechanisms of ectromelia virus thymidine kinase-negative mutants avirulence. AB - Three independently selected spontaneous thymidine kinase-negative mutants (TK phenotype) and a recombinant with Escherichia coli beta-galactosidase gene (LacZ+ phenotype) inserted in the viral thymidine kinase gene (tk) were derived from a plaque-cloned isolate of K-1 ectromelia virus strain (TK+ phenotype). Dramatically decreased virulence of TK- variants was observed for all routes of mouse inoculation. The kinetics of TK+ and TK- variants in various target organs indicated a significant decrease of production and dissemination of TK- mutants and recombinant in the organs of mice. In the spleen and liver of intranasally or intracerebrally infected mice TK- virus was not detected during the entire period of observation. Analysis of organs homogenates of mice intranasally infected by a mixture of recombinant with TK-LacZ+ phenotype and parental isolate with TK+LacZ- phenotype on the monolayers of TK- cells indicated that only white plaques (LacZ ) with the TK+ phenotype appeared from liver and spleen homogenates. Thus, the mouse acts as a live filter much more efficiently than any other selective systems. Ultrastructural studies showed that viral damage in animals infected by TK- variants was far less than that observed in mice, infected with wild type of ectromelia virus and pathological lessions were slight and reversible. Replication of ectromelia virus TK- variants was blocked at the viroplasma stage in cells with a high level of differentiation in contrast to TK+ variants. Most likely, such restriction of target cells assortment is the general reason of reduced virulence in the case of tk-gene inactivation. PMID- 7831965 TI - Sequence analysis of the non-structural protein 2 from epizootic hemorrhagic disease viruses. AB - The non-structural protein 2 (NS2) of epizootic hemorrhagic disease virus serotype 1 (EHD-1) was cloned and sequenced. The NS2 gene was found to be 1185 bp containing a single open reading frame that encodes a 376 amino acid protein. A 97% nucleic acid identity was found between EHD-1 and a previously published NS2 sequence of EHD-2. Only a 60% nucleic acid identity was found between EHD and the bluetongue virus (BTV) serogroup. Comparison of the deduced amino acid sequences revealed 97% identity within the EHD serogroup, and less than or equal to 43% identity between serogroups. PMID- 7831966 TI - RNA splicing contributes to the generation of mature mRNAs of Borna disease virus, a non-segmented negative strand RNA virus. AB - We recently demonstrated that Borna disease virus (BDV) has a negative non segmented single stranded (NNS) RNA genome, whose organization is similar to that of other members of the Mononegavirales order. However, we have also documented that in contrast to the rest of the NNS-RNA animal viruses, BDV replication and transcription occur in the nucleus of infected cells. Here, we provide evidence that BDV uses the host nuclear splicing machinery to generate some of the viral mRNAs, representing the first documentation of RNA splicing in NNS-RNA animal viruses. Possible implications of RNA splicing for the regulation of BDV gene expression are discussed. PMID- 7831967 TI - Phylogenetic relationships of the VP2 protein of a virulent isolate of bluetongue virus (BTV-23) compared to those of 6 other BTV serotypes. AB - To determine the genetic relationship of the virulent Australian bluetongue virus serotype 23 with that of other serotypes and to identify the extent and nature of the antigenic variation among seven serotypes of bluetongue virus (BTV), the complete nucleotide sequence was determined for cDNA clones representing the L2 dsRNA of BTV-23, the gene that codes for the outer capsid neutralization antigen (VP2). The predicted amino acid sequence of the protein was compared with the VP2 sequences of the five USA serotypes (BTV-2, -10, -11, -13 and -17) as well as with an Australian isolate of BTV-1. The comparisons revealed that the VP2 of BTV 23 is most closely related to that of BTV-1, sharing 52% identical and 72% similar sequences, also that the VP2 of the two Australian serotypes are more closely related to that of BTV-2 than to the other four USA serotypes. Only 22% identical sequences are shared by all seven VP2 molecules; however, when homologous substitutions are considered the similarity index was as high as 48%. In addition, the conserved regions that have been identified previously for other VP2 molecules are also conserved in BTV-23. PMID- 7831968 TI - [The role of ultraviolet and gamma radiation in the abiogenic synthesis of nucleotides in the solid state]. AB - A possibility of abiogenic synthesis of natural nucleotides in solid state under the influence of UV and gamma radiation has been shown for a mixture of nucleosides and dihydrophosphate. Adenosine and deoxyadenosine were used as initial substances. During adenosine and deoxyadenosine phosphorylation under the action of UV radiation (lambda = 254 nm), only 5'-monophosphates were formed, a yield of 0.094 and 0.36% respectively. Under the action of gamma radiation, 2',3' cAMP (0.12%), 2'-AMP (0.08%) and 3'-AMP (0.14%) were produced together with 5'AMP (0.41%). PMID- 7831969 TI - [The pepsinogen of the gastric mucosa in the red-cheeked suslik Citellus erythrogenys]. AB - Studies have been made on the isozymic composition of pepsinogen (polyacrylamide gel electrophoresis) and peptidase activity in gastric mucosa of the ground squirrel at various stages of hibernation. Eight pepsinogen isoforms were found in acid-producing zone of the mucosa, pyloric mucosa lacks first three of them, its peptidase activity being two times lower than in other parts of the stomach. During hibernation, no significant changes were found in fractional composition of pepsinogen, peptidase activity being decreased twofold only in the fundulus of the stomach, remaining practically constant in other parts of the latter. This finding indicates that the stomach is ready for the activity irrespectively of food uptake. PMID- 7831970 TI - [The comparative action of cholinergic substances on the cervical and thoracic trachea of the rat]. AB - Different reactions were found in the cervical and thoracal parts of the trachea to application of acetylcholine, cholinomimetics and cholinolytics. The effect of acetylcholine on the cervical part is associated with muscarinic receptors in muscles. In the thoracal trachea, the effect of acetylcholine at a low concentration is associated mainly with muscle cholinoreceptors, whereas at high concentrations its effect is determined by both myogenic and neurogenic factors. Cholinergic systems of the intramural ganglia are involved in contraction and relaxation of tracheal smooth muscle in rats. PMID- 7831971 TI - [The direct connections of the auditory and limbic cortices in rats]. AB - Using axonal transport of a horseradish peroxidase, studies have been made on the connections of the limbic cortex with peripheral parts of the auditory cortex in rats. Ipsi- and contralateral projections from the rostral and caudal limbic cortex to the auditory cortex were described together with peculiarities of the distribution of neurones in fields 23 and 24 of the limbic cortex which send their axons to the auditory cortex. PMID- 7831972 TI - [Temperature-evoked long-term potentiation in hippocampal slices]. AB - The effect of temperature changes on the activity of CA1 pyramidal cells has been investigated on completely submerged rat hippocampal slices. Fast and slow increase in the temperature from 24-28 to 37-38 degrees C decreased the amplitude of population spikes (PS), but increased the number of active pyramidal cells. The decrease in PS is more evident from 32 to 37 degrees C. After cooling to 24 28 degrees C, a long (more than 30 min) and considerable (up to 12%) increase of PS was observed. Increasing the temperature from 24-28 to 37-38 degrees C does not affect double facilitation, nor the maintenance of a long post-tetanic potentiation. It is suggested that the mechanism of temperature-induced long-term potentiation is similar to that of a long post-tetanic potentiation. PMID- 7831973 TI - [The role of serotonin and noradrenaline in regulating the motor activity of the chick amnion]. AB - In experiments on chick embryos from various age groups, studies have been made of the effect of a blockader of serotonin receptors--cyproheptadine--and blockader of adrenoreceptors--propranolol--on rhythmic activity of the amnion in vivo after injection of the substances into amniotic fluid. Stimulating effect of propranolol from the 9th to the 19th day of incubation and inhibitory effect of cyproheptadine from the 5th to the 19th day of incubation were revealed. These results indicate the existence of serotonin and noradrenaline in the amniotic fluid of chick embryo. High performance liquid chromatography directly confirmed this conclusion. PMID- 7831974 TI - [The development of grooming in the ontogeny of rats and mice]. AB - Experiments have been made on rats and mice within the first month of postnatal life. Common age dynamics of grooming reactions for these animals was shown which consists of a sharp intensification of grooming movements at the 3rd week, i.e. at the period of "behavioral arousal", as well as of heterochronous onset of different types of movements which results from successive maturation of the brain structures in which rhythmic centres of these movements are located. Quantitative differences in grooming of rats and mice are presumably due to ecological peculiarities of these animals. Periodic pattern of realization of grooming, as well as the parameters of its rhythmic components suggests that stereotype behavioural reactions are governed by mechanisms of autorhythmic excitation which are typical for the early stages of the development of the nervous system. PMID- 7831975 TI - [The structural-functional organization of the endoplasmic reticulum in the neurons of the rat cerebellar cortex]. AB - Electron microscopic investigation of neuronal elements in the cerebellar cortex of rats revealed the existence of septal reticulum in axonal collaterals of Purkinje cells, in axons of basket cells and in mossy fibers. It was shown that this reticulum acts as a calcium depot. The presence in neuroplasm of the developed system of evenly distributed reticulum, which forms relatively isolated compartments and acts as the calcium depot may account for local regulation of rearrangements in the cytoskeleton. Wide presentation of the septal reticulum in the nervous cells of both invertebrates and vertebrates indicates functional determination of this structure. PMID- 7831976 TI - [The ultrastructural characteristics of the formation of the thyroid in fetuses of the pied lemming Dicrostonyx torguatus during its dynamic population cycle]. AB - Thyroid formation in lemmings takes place at earlier embryonic stages as compared to that in laboratory rodents. Two modes of follicle formation in the thyroid gland are described, i.e. by means of formation of intracellular follicules and by transformation of the apical surface of future thyrocytes. Significance of each of these ways depends on the rate of formation of the thyroid gland, which in its turn is related to the density of population. At the stage of the increase in population density, differentiation of the thyroid gland begins before the 15th day of prenatal life. Follicle formation is associated with polarization of thyrocytes and transformation of future apical surface. The definite structure of the organ is complete to the 17th day. At maximum population density, significant inhibition of cyto- and histodifferentiation of the thyroid gland is observed, folliculogenesis being accomplished to the 3rd-6th day of postnatal life. At low population density, follicular structure of the thyroid gland is achieved already in 14-day foetuses. At the 19-20th day of prenatal life, the decrease in secretory activity of the organ together with inhibition of thyroglobulin iodination are observed. PMID- 7831977 TI - [The chemosignal systems of unicellular eukaryotes and bacteria as the precursors of hormonally competent systems in higher animals]. PMID- 7831978 TI - [Digestive enzymes in the epithelial and subepithelial layers of the small intestine in different strains of rats]. AB - Studies have been made on the activity of various digestive enzymes and their distribution between the mucosal, submucosal and muscle-serosal layers of the small intestine in Wistar and Sprague-Dawley rats. Three groups of the enzymes were found, their activities being maximal either in the mucosal, or in muscular layers, or being evenly distributed between three intestinal layers. PMID- 7831979 TI - Prognosis in infants with birth asphyxia. AB - The risk of neurodevelopmental disability from birth asphyxia secondary to intrapartum complications and obstetric mismanagement is generally overestimated. Between 8-17% of all cerebral palsy is associated with adverse perinatal events suggestive of asphyxia. Less than 10% is probably due directly to birth asphyxia itself. Studies have shown that different methods of intrapartum assessment of fetal well-being (fetal heart rate monitoring, fetal scalp pH, presence of meconium) do not correlate well with each other or with neonatal parameters (acid base status at birth, Apgar scores, seizures, neurological behaviour) and outcome measures (death, cerebral palsy, mental retardation). The prevalence rate of cerebral palsy in most communities of 2.0-2.5 per 1000 children is not falling in spite of increasing use of obstetric and neonatal interventions aimed at preventing or treating birth asphyxia. Prediction of neurodevelopmental outcome of birth asphyxia is difficult because of a limited ability to measure birth asphyxia quantitatively in the antenatal and neonatal period. The terminology used to describe the condition is often confusing. It has been recommended that substantial cerebral hypoxia can only be presumed when four criteria are met: the infant has an Apgar score < or = 3 at 10 minutes, metabolic acidosis at birth, hypotonia for several hours and seizures. For the paediatrician, a number of clinical observations and laboratory investigations have been suggested as helpful in the prediction of death or disability among term infants with birth asphyxia. PMID- 7831980 TI - Allogeneic bone marrow transplantation for children with acute lymphoblastic leukemia in second remission or relapse. AB - Most children with acute lymphoblastic leukemia (ALL) are successfully treated by chemotherapy. For those patients, who relapse on therapy, bone marrow transplantation (BMT) is considered most appropriate after a subsequent remission is achieved. Three boys with ALL aged from 9 to 13 years met these criteria and received BMT from their HLA-compatible sisters after marrow ablation with total body irradiation 12 Gy plus high dose cytosine arabinoside 3 gm/m2/12h x 12 doses and graft-versus-host disease (GVHD) prophylaxis with cyclosporine plus short course methotrexate from March 10, 1989 to May 23, 1992. Filgrastim (rhG-CSF) was used to hasten the recovery of granulocyte in one patient. All three patients got full engraftment and two had grade 1 acute GVHD. None of them developed chronic GVHD. Two patients have disease-free survival over 51 and 12 months respectively post BMT without further chemotherapy. One patient died of recurrent refractory leukemia 5 months after BMT. The toxicity of this conditioning regimen included photophobia, conjunctivitis and erythematous skin rashes. One patient who received filgrastim from day 1 to 21 developed severe bone pain. However, this patient had faster recovery of granulocyte count than the other two patients. The preliminary results of this work favors BMT for children with recurrent ALL whose ultimate survival is usually poor when treated with chemotherapy. Further efforts are necessary to investigate new methods for reducing leukemic relapse in ALL patients undergoing BMT. PMID- 7831981 TI - Intracranial meningiomas in childhood. AB - Over the 10-year period from 1980 to 1990, ten pediatric patients were diagnosed at this hospital with intracranial meningiomas. The patients' diagnoses were confirmed by histological studies, including the incidence, age and sex distribution, duration of symptoms prior to diagnosis, signs and symptoms on onset, tumor locations, histologic type, presence of cyst, dural attachment of tumor, treatment, and prognosis. When comparing pediatric meningiomas with those of adults, some differences were noted such as a slight preference for males; the clinical history seemed to be shorter; a ventricular location is more frequent; predilection for cystic meningioma and absence of dural attachment are more common. PMID- 7831982 TI - Intravesical ureterocele in children. AB - Eighteen intravesical ureteroceles associated with single collecting system were found in 16 children over past 6 years. Hydronephrosis of varying severity, with hydroureter, was present in 10 patients. The ipsilateral kidney was nonfunctioning in 5 patients and normal in 1. The ureterocele was easily detected by ultrasound and usually revealed as a cystic mass in the bladder. On intravenous urogram the ureterocele usually showed a positive cobra-head dilatation. However, it may exhibit a negative filling defect when the function of the associated kidney is impaired. In this series, 9 patients were asymptomatic, and the condition was detected incidentally by ultrasound. 7 patients received surgery. The remaining 9 patients were followed up at an Outpatient Clinic. PMID- 7831983 TI - Diagnosis of I-cell disease. AB - I-cell disease (mucolipidosis II) is a rare lysosomal storage disease, with its primary defect the deficiency of an enzyme responsible for lysosomal enzyme processing, resulting in multiple lysosomal enzyme insufficiency. Diagnosis of I cell disease usually can be made by the specific patterns of enzyme distribution: deficient intracellular, but excessive extracellular, enzymes. A six month old female infant was found to have bilateral congenital dislocation of hips, developmental delay, coarsening of facial appearance and dysostosis multiplex. In view of the very early onset of disease, I-cell disease was suspected. Lysosomal enzyme tests (including alpha-mannosidase, alpha-fucosidase, beta-glucuronidase and beta-galactosidase) were performed on the leukocytes, skin fibroblasts, plasma and media from fibroblast cultures. All activities of the four enzymes were low in both leukocytes and fibroblasts, but were 10- to 70-fold higher than normal in plasma, and high in culture media. Both the clinical and laboratory findings here were consistent with a diagnosis of I-cell disease. PMID- 7831984 TI - Liver function in patients with vitamin K deficiency in infancy. AB - Liver chemistry was studied in fifteen patients with vitamin K deficiency in infancy (VKDI). All except 2 were exclusively breast fed and 4 of the 15 infants had received intramuscular vitamin K prophylaxis. A high incidence of hepatic dysfunction was found during long term follow-up in patients with VKDI. Abnormal aminotransferase was noted either at the time of onset (n = 6) or during the ensuing few weeks (n = 6). Cholestasis was documented in six cases at onset and another two in a later period. Most cases had increased serum alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), or bile acid levels regardless of hepatic enzymes and bilirubin levels. The abnormal enzymes returned to normal after 5 weeks to 23 months. This study demonstrates a close relationship between hepatic dysfunction and VKDI. Liver function impairment other than cholestasis may play some role in the pathogenesis of VKDI, but the cause of hepatic dysfunction can not be defined. Follow-up of liver chemistry is recommended in patients with VKDI. Parenteral vitamin K prophylaxis at birth may not give sustained protection against VKDI, especially in those with underlying liver disease. PMID- 7831985 TI - [The effects of anticonvulsants on the epileptiform discharges--study by 24-hour ambulatory cassette EEG system]. AB - Thirty-three epileptic children who had epileptiform discharges in conventional 16 channel EEG study were enrolled in this study. The patients have never been treated with medication at first visit. Then patient were put on ambulatory monitoring EEG with the Oxford Medilog 9-channel cassette EEG system, which included six symmetrical scalp leads, one EOG, one Chin EMG and one channel for time signal. The EEG record was processed under the rule of the international standard method in terms of 10-20 system. The 24 hours EEG cassettes which recorded before and after antiepileptic drugs therapy were reviewed by an experienced electroencephalographer on a video play back unit. The number and duration of spikes or spike wave discharges were calculated. Among those 22 cases who had studied completed, there are 11 cases with generalized spike waves (5 with irregular spike waves, 3 with regular 3 hz spike waves, 1 with multiple spike waves, 1 with slow sharp waves and 1 with abortive spike waves), and 11 cases with focal spike activities (5 with bilateral central or centrotemporal spikes, 4 with temporal spikes and 2 with occipital spike discharges). After anticonvulsants therapy, 9 cases (82%) out of those 11 cases with generalized spike waves, the spike waves were disappeared; 2 cases (18%) revealed no significant change in spike rate and duration.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7831986 TI - [The relationship between serum uric acid and the prognosis of children admitted to pediatric intensive care unit]. AB - To investigate the relationship between hyperuricemia and the prognosis of acute ill children, we evaluated the usefulness of serum uric acid (SUa) and urinary uric acid concentration on admission as prognostic indices in 94 consecutive children admitted to a pediatric intensive care unit. Patients with hyperuricemia (13.1 +/- 5.6 mg/dl) had a higher mortality (13/26, 50% vs 7/68, 10%, P < 0.001), lower blood pH (7.20 +/- 0.18 vs 7.37 +/- 0.10, p < 0.05), lower systolic blood pressure (85 +/- 24 vs 102 +/- 28 mmHg, p < 0.05) and lower body temperature (36.6 +/- 0.8 vs 37.4 +/- 1.0 degrees C, p < 0.05) than did patients with normouricemia (5.0 +/- 1.5 mg/dl). There are no significant difference in uric acid and sodium excretion between hyperuricemic and normouricemic patients. We concluded that elevated serum uric acid on admission is associated with a higher mortality in pediatric ICU patients, therefore it may be used as an important prognostic index to evaluate patients' outcome in acute ill children. Hyperuricemia should also alert physicians to the possibility of profound cell injury caused by various etiology. PMID- 7831987 TI - [Family environment of children with simple obesity]. AB - Fifty obese children aged from 6 to 15 years and 50 non-obese controls paired on the basis of age and sex were evaluated by anthropometric measurements and a parents' questionnaire. Birth weight was comparable in obese and non-obese children. The majority (78%) of the cases in the study group were becoming obese during the age among 2 and 12 years. It was found that obese children were about five times as likely to have an obese parent as controls: 44% of the obese children had obese fathers and 12% had obese mothers. There also a significant difference in the chance of having an obese sibling between the obese and control groups. However, the difference of socioeconomic status between the two groups did not reach level of significance. The results indicated that there are likely to be more obese family members at home for every obese case identified in a weight control clinic. Identification, prevention, and control of childhood obesity in at-risk families are an important pediatric issue. Further research efforts are needed to unravel the multiple factors associated with childhood obesity. PMID- 7831988 TI - Neonatal meningococcal meningitis: report of two cases. AB - Two neonates with meningococcal meningitis and meningococcemia are reported. The two, aged 28 and 16 days, respectively, presented similar symptoms of fever, poor appetite and poor activity. Both blood and cerebrospinal fluid cultures of each patient grew Neisseria meningitidis. The isolated bacteria were sensitive to penicillin, and both patients recovered completely after penicillin treatment for 22 and 15 days, respectively. In the antibiotic era, only 22 cases of neonatal meningococcal meningitis have been reported in the English literature. Among these reports, at least 7 patients survived without sequelae; 6 of those were treated with different combinations of antibiotics, including penicillin, for variable durations of 7-14 days. Therefore, effective antibiotic therapy for 14 days should be adequate in the treatment of uncomplicated neonatal meningococcal meningitis and meningococcemia. PMID- 7831989 TI - Retrograde intussusception as a complication of Roux-en-Y anastomosis for choledochal cyst--report of one case. AB - A 19 month-old girl with choledochal cyst received complete cyst excision and biliary reconstruction by Roux-en-Y hepaticojejunostomy. Three months later, intestinal obstruction developed and small bowel intussusception was diagnosed preoperatively by ultrasonography. Laparotomy revealed retrograde jejunojejunal intussusception, involving the distal end of the Roux limb. To best knowledge, this is the first case in a child and the third case having such complication after Roux-en-Y anastomosis, reported in the literature. It should be noted that, if intestinal obstruction develops in a patient who had received this procedure for choledochal cyst, retrograde intussusception, although very rare, should be considered in addition to adhesion ileus. PMID- 7831990 TI - Lesch-Nyhan Syndrome: report on two brothers. AB - Lesch-Nyhan syndrome is a rare X-linked disease characterized by over-production of uric acid and a central nervous system (CNS) disorder consisting of mental retardation, spasticity, choreoathetosis, and a compulsive form of self mutilation. A deficiency in hypoxanthine-guanine phosphoribosyl transferase (HPRT) provides the underlying metabolic basis for this disease. A 12 month-old male baby who had orange crystals over the diapers since he was 3 months old was brought to our hospital due to developmental delay. Mental retardation and athetosis were also noted. Chemical analysis revealed hyperuricemia (uric acid 8.6 mg/dl). Urine routine showed microscopic hematuria and uric acid crystals. The activity of HPRT in erythrocyte lysates of parents were both within normal limits, but that of the patient was very low (0.0547 nm/min/mg protein, < 0.05% of control). His younger brother was born 2 months after this disorder diagnosed in this patient. The younger brother was noted to have uric acid crystals over the diapers when he was 40 days old and hyperuricemia (10.6 mg/dl) showed up later. He was also a case of Lesch-Nyhan syndrome since the activity of HPRT in erythrocyte lysates was also low (0.0327 nmol/min/mg protein, < 0.05% of control). Further studies, including carrier detection and deoxyribonucleic acid (DNA) analysis, could be helpful for genetic counseling. This syndrome is rare among Chinese, and this may be due to underdiagnosis. PMID- 7831991 TI - [A liveborn infant with triploidy (69, XXX): report of one case]. AB - Triploidy is not rare and present in about 1% of all recognized human pregnancies, although most of these pregnancies end in spontaneous abortion during the first trimester. Survival of the fetus up to 20 weeks or beyond is rare. Therefore, liveborn infants with triploidy are very rare. Here is a report on a female liveborn infant with triploidy (69,XXX), who was born to a 27-year old healthy mother. The clinical features are growth retardation, head-to-body disproportion, wide posterior fontanelle, hypertelorism, micrognathia, bilateral pre-auricular polyps, syndactyly of left 3rd and 4th fingers, syndactyly of right 2nd and 3rd fingers and talipes equinovarus. The infant died 4 hours after birth. The autopsy revealed transposition of great vessels, ventricular septal defect, one lobe of left lung and 2 lobes of right lung and duodenal atresia. PMID- 7831992 TI - Psychopathology in Huntington's disease patients. AB - A retrospective study of 30 Huntington's disease families (110 patients: 75 alive and 35 dead) known to a regional genetic centre, using multiple sources of information, showed the minimum lifetime prevalence of depression to be 39% in the prodrome and the diagnosed disease phase of the illness. The frequency of symptomatic schizophrenia was found to be about 9% and significant personality changes were found in 72% of the sample, some of them leading to gross behavioural anomalies. The findings reinforce the point that depression and schizophrenia, unaccompanied or preceded by organic personality changes and/or very early neural symptoms, are unlikely to lead to the eventual manifestation of the disease. PMID- 7831993 TI - Antipsychotic medication and suicide risk among schizophrenic and paranoid inpatients. A controlled retrospective study. AB - A retrospective analysis of the psychotrophic medication, illness history and recent mental symptoms of 28 schizophrenic or paranoid inpatients who had committed suicide and the same number of matched control subjects was carried out. The groups were first compared separately for every variable, and 6 statistically most significant variables in the paired comparisons were then entered into a stepwise linear logistic regression model. Four statistically significant differences between the groups were found with the paired comparisons. The suicide group had more often previous suicide attempts, lower neuroleptic doses, more depressive symptoms and less positive schizophrenic symptoms compared to their controls. The results of the regression analysis suggested that the lower neuroleptic doses in the suicide group were more probably a consequence of the differences in the symptom profile than in a direct causal relationship to the suicides per se. PMID- 7831995 TI - Epidemiology of anorexia nervosa and bulimia nervosa in Bornholm County, Denmark, 1970-1989. AB - In a retrospective study of anorexia nervosa and bulimia nervosa, potential cases were traced, studied, and diagnosed according to ICD-10. Forty-two cases were found in Bornholm County, comprising the island of Bornholm in Denmark, in a population of 47,000 from 1970 to 1989. Less than half of these cases (n = 16) were registered in Danish psychiatric case registers, and 35% (n = 14) could be found only by search in primary care. The incidence rates were stable during most of the study period, but a significant increase occurred during the last 5 years. The prevalence rates, determined by counting the number of cases in the population year by year, also increased during the late part of the study period. In 1989 the incidence rate of the high-risk group of females 10 to 24 years of age was 136 per 100,000 for anorexia nervosa and 45 per 100,000 for bulimia nervosa, and the prevalence rate was 222 per 100,000 for anorexia nervosa and 89 per 100,000 for bulimia nervosa. PMID- 7831994 TI - Lower degree of esterification of serum cholesterol in depression: relevance for depression and suicide research. AB - Previous studies have suggested that depression and suicide are related to alterations in total cholesterol serum concentrations, and that an altered distribution of haptoglobin (Hp) phenotypes in major depression indicates that variation on chromosome 16 may be associated with that illness. Lecithin:cholesterol acyl transferase (LCAT, EC 2.3.1.43), the enzyme that catalyzes the esterifying reaction of cholesterol in serum, is located close to the Hp gene. This study examined the serum concentrations of total and free cholesterol and the esterified cholesterol ratio in 26 healthy controls, 47 unipolar depressed subjects (16 minor, 14 simple major and 17 melancholic depressed subjects) and 12 relatives of melancholic subjects. Depressed subjects (regardless of subtype) and relatives of depressed subjects had a significantly lower esterified cholesterol ratio than normal controls. No significant differences in total or free cholesterol concentrations were found between the above study groups. In depressed subjects, there were no significant relationships between the esterified cholesterol ratio, total or free cholesterol and postdexamethasone adrenocorticotropic or cortisol values, Hp phenotypes, severity of illness or suicidal symptoms. It is hypothesized that lower esterification in serum cholesterol may constitute a vulnerability factor for depression through alterations in cell membrane microviscosity. PMID- 7831996 TI - D2-dopamine receptor occupancy differs between patients with and without extrapyramidal side effects. AB - To investigate whether the occurrence of extrapyramidal side effects was related to D2 dopamine receptor occupancy, iodobenzamide single positron emission computed tomography was carried out in 27 schizophrenic patients and 10 controls. Eighteen patients were treated with haloperidol; 9 patients were treated with clozapine. Our data suggest a relationship between D2 receptor occupancy and extrapyramidal side effects as well as the existence of a neuroleptic threshold of a striatal:frontal cortex ratio of 1.2, below which drug-induced exptrapyramidal side effects can be expected. PMID- 7831997 TI - Alpha-1- and 2-adrenoceptor subsensitivity in siblings of opioid addicts with personality disorders and depression. AB - Noradrenergic receptor sensitivity of 16 healthy male siblings of heroin addicts and of 8 age and sex-matched controls was examined by administering a clonidine stimulation test and by measuring the resulting growth hormone (GH) (alpha-2 adrenoceptors) and beta-endorphin (beta-endorphin) (alpha-1-adrenoceptors) responses. Siblings were divided into two groups: A = siblings of heroin addicts with personality disorders and high aggressivity and B = siblings of heroin addicts without mental disorders. The GH and beta-endorphin responses to clonidine were blunted in group A subjects compared with controls and normal in group B. PMID- 7831998 TI - Dissociation and child abuse histories in an eating disorder cohort in Japan. AB - Dissociation and childhood abuse were studied in female eating disorder outpatients in Japan. A self-report version of the Dissociative Disorders Interview Schedule (DDIS), which includes data on physical and sexual abuse, and the Dissociative Experience Scale (DES) were used. Nine of 41 subjects who completed the DDIS reported symptoms suggesting DSM-III-R multiple personality, and 6 of the 39 subjects who completed the DES scored over 30 (reflecting a high likelihood of posttraumatic stress or multiple personality). Subjects' sexual abuse history rates were considerably greater then those in the Japanese general population. Though physical abuse history was associated with high dissociation, no difference was seen between the high and low dissociators in sexual abuse histories. PMID- 7831999 TI - Relationship between brain structure and function in disorders of the schizophrenic spectrum: single positron emission computerized tomography, computerized tomography and psychopathology of first episodes. AB - Fifty newly diagnosed, briefly treated or drug-naive patients with schizophrenia or schizophreniform disorder were examined by psychopathology scales for positive (SAPS), negative (SANS) and overall psychotic symptoms (PSE and BPRS). CT-scan and regional cerebral blood flow (rCBF) measurement by 99mTc-HMPAO SPECT during rest and mental activation by Wisconsin Card Sorting Test was performed as well. Twenty-five age-matched normal healthy volunteers served as controls. Thought disorders and fundamental symptoms correlated positively with relatively high, though subnormal prefrontal (PFC) rCBF and high rCBF in temporal cortex; positive symptoms correlated positively with high rCBF in the striatum and temporal cortex during activation. Negative symptoms correlated with high prefrontal rCBF. The patients had sulcal enlargement and smaller brain volume compared with the healthy volunteers. There were no signs of ventricular enlargement. Neither total negative symptoms, thought disorder nor fundamental symptoms correlated with any CT measurements. Total positive symptoms correlated negatively with the size of the temporal horns. The relatively high rCBF in PFC and temporal cortex of cases with pronounced positive and negative symptoms and thought disorder may imply that an aberrant cortical network has to be active to express a malattuned clinical output. The striatal hyperfunction mainly in productive cases may be a secondary phenomenon and more pronounced in cases where no signs of subcortical atrophy has (yet?) ensued. PMID- 7832000 TI - Does defense style vary with severity of mental disorder? An empirical assessment. AB - Bond's Defense Style Questionnaire was administered to control subjects from the general population (n = 50) and to psychiatric outpatients with neurosis (n = 42), high-level personality disorder (n = 37) and low-level personality disorder (n = 22). Factor analysis yielded 4 defense styles ranging on a continuum from immature to mature; the reliabilities of the subscales as measured with Cronbach's alpha were adequate. Three of the styles - the mature, neurotic and immature - were similar to the styles in Bond's original study, but the fourth style consisted of items reflecting inhibition instead of omnipotence as in the original study. The level of defense maturity varied with severity of disorder. The construct and criterion validity of the measure are discussed. PMID- 7832001 TI - Mortality during initial and during later lithium treatment. A collaborative study by the International Group for the Study of Lithium-treated Patients. AB - We have previously shown that the mortality of patients with recurrent affective disorders in long-term lithium treatment is not higher than that of the general population. In the present study on 471 patients from Denmark and Germany, we examined mortality during the initial year of lithium treatment and during later lithium treatment. During initial lithium treatment, the total mortality was twice as high as in the general population (difference not significant) and the mortality due to suicide 16 times higher. During later lithium treatment, the mortality rates did not differ from those in the general population. Our results indicate that patients with frequent, often severe recurrences, those chosen for prophylactic lithium treatment, are at risk of high mortality, which then diminishes as the prophylactic action of the treatment takes effect. PMID- 7832002 TI - Uptake of 99mTc-exametazime shown by single photon emission computerized tomography in obsessive-compulsive disorder compared with major depression and normal controls. AB - Twelve patients with obsessive-compulsive disorder (OCD) were investigated at rest using single photon emission computerized tomography with 99mTc-exametazime. The uptake of 99mTc-exametazime was expressed relative to calcarine/occipital cortex. Patients were matched for drug treatment with 12 patients with a major depressive episode and the patient groups were compared with a control group. Significant bilateral decreases in tracer uptake were confined to basal ganglia in the OCD group. There was a paradoxical positive correlation between anxiety ratings and tracer uptake to basal ganglia in the OCD group. The findings confirm that the functional topography of OCD implicates altered function in the basal ganglia. PMID- 7832003 TI - Mode of inheritance in families of patients with lithium-responsive affective disorders. AB - A better understanding of the role of genetic factors in affective disorders is likely to result from investigating more homogeneous populations. To achieve this goal, we have systematically studied patients who are excellent responders to long-term lithium treatment and their relatives. In the families of 71 such probands, we have analyzed the mode of inheritance by comparing the observed morbidity risks with the risks expected under different genetic models. The results demonstrate major-gene effects in the transmission of primary affective disorders; the polygenic model with sex-specific thresholds could be rejected. Discrimination between the autosomal and X-chromosome models was not possible, but the autosomal recessive model predicts more realistic, gender-specific frequencies of affective disorders in the general population. These results suggest that autosomal recessive inheritance deserves serious consideration in molecular genetic investigations. PMID- 7832004 TI - A multivariate evaluation of the Michigan Alcoholism Screening Test and the Drug Abuse Screening Test in a female offender population. AB - The Michigan Alcoholism Screening Test (MAST) and the Drug Abuse Screening Test (DAST) are instruments designed to detect alcohol and drug abuse, respectively. Short versions (20 self-report items) of each instrument were administered to a sample of 615 women who were in jail or on probation. Principal-components analysis (PCA) was applied to the items of each instrument. Four factors similar to those found in previous research were identified, however the instruments were essentially found to be unidimensional. Subjecting pooled MAST and DAST items to PCA did not result in the identification of an underlying factor. PMID- 7832005 TI - Motivational subtypes in an inpatient sample of substance abusers. AB - Motivational subgroups in a sample of inpatient substance abusers were identified to facilitate future development of treatment interventions aimed at enhancing compliance and involvement. The modified Stages of Change Readiness and Treatment Eagerness Scales from 165 subjects were subject to factor and cluster analyses. Results suggest the instrument assesses three dimensions: determination, action, and contemplation. Using these dimensions, three subgroups were identified: Uninvolved, Ambivalent, and Active. There were no differences on demographic or background variables or Minnesota Multiphasic Personality Inventory 2 (MMPI-2) profiles. The Uninvolved group scored significantly lower than the other two groups on measures of alcohol use and abuse. The Ambivalent and Active groups did not differ on any of the measures of alcohol use and abuse. The Ambivalent group demonstrated a high level of conflict and inaction. The Active group appeared to be aware of their dependence and were ready to change their behavior. The results have implications for treatment matching and enhancing treatment motivation. PMID- 7832006 TI - A measurement model of adolescent smoking. AB - Self report measures of smoking may contain substantial measurement error. If these errors are nonrandom, then they may be correlated with substantive variables in epidemiologic or intervention studies, thus confounding and biasing estimates of structural relations. In efforts to circumvent such bias, investigators have supplemented questionnaires with biological indicators of exposure to tobacco smoke. However, errors in biological indicators may also include systematic errors that produce biased estimates. The current study was designed to estimate the variance of systematic and random errors in self report and two biologic measures of smoking in adolescents. A linear model was fit to data from 342 males and 250 females with repeated measures separated by 1 year. Thiocyanate and self report were found to have substantial nonrandom error components that were correlated with psychosocial variables. In contrast, errors in carbon monoxide in expired air were not autocorrelated, and were uncorrelated with psychosocial variables. PMID- 7832007 TI - Drinking-related locus of control as a predictor of drinking after treatment. AB - This study evaluated the predictive utility of the drinking-related control orientation for successful treatment outcome among Finnish inpatient alcoholics (N = 106, 16% women). Using the Drinking-Related Locus of Control (DRIE) scale by Keyson and Janda (unpublished; see Lettieri, Nelson, & Sayers, 1985), it aimed to discover to what extent the DRIE scores measured at the end of treatment predict (a) the timing and severity of the first drinking occasion after treatment, and (b) the 6 and 12 months' total treatment outcome of the sample. The DRIE scores correlated with the time to the first drinking occasion (r = -.27, p < .02). Internal subjects started to drink later (p < .004), drank less on the first occasion (p < .001), and continued for fewer days (p < .005) than external subjects. Moreover, internal orientation was more common among abstinent and external orientation among unimproved subjects during the first 6 (p < .02) and 12 months (p < .05) after treatment. The results thus support the beneficial role of internal control attributions. PMID- 7832008 TI - Measuring readiness and motivation to quit smoking among women in public health clinics. AB - We conducted a pilot test of an instrument to assess stage of readiness and level of motivation to change smoking behavior among 495 women smokers in public health clinics. The stages of readiness were based on those proposed by Prochaska and DiClemente but with finer discrimination within the precontemplation stage, where a substantial minority (41%) of the target smokers were situated. Subdividing this earliest group, we found that 8% of the total sample planned no change in smoking ever; 8% were seriously thinking of cutting down; and 25% were seriously thinking of quitting but not within 6 months. Scales in the questionnaire included general motivation to change smoking behavior and confidence in one's ability to do so. The women's scores differed on these scales and on action toward quitting across the five stages of readiness, except that the lowest two groups did not differ on confidence. Pregnancy enhanced readiness to quit. The instrument accommodates the brevity and low literacy requirements for use in these applied settings and is suitable for use in either self-administered questionnaire or interview format. PMID- 7832009 TI - The effects of alcohol, expectancy, and alcohol beliefs on anxiety and self disclosure in women: do beliefs moderate alcohol effects? AB - This study investigates the effects of alcohol, expectancy, and alcohol-related beliefs on self-reported anxiety and self-disclosure behavior in a social interaction situation. Seventy-two female social drinkers were assigned to eight conditions in a 2 x 2 x 2 factorial balanced-placebo design, controlling for drink content, expectancy, and beliefs. Results show that alcohol expectancy resulted in an anxiety reduction in subjects who believed that alcohol has a positive influence on social behavior, whereas expectancy had no effect in subjects with negative alcohol beliefs. Furthermore, subjects who expected alcohol were less anxious when they had positive alcohol beliefs than when they had negative beliefs, whereas beliefs made no difference in subjects who expected tonic. Our results suggest that the effect of alcohol expectancy on social anxiety in women is moderated by differences in the content of their alcohol related beliefs. We conclude that the inconsistency in previous results about the effect of alcohol expectancy on social behavior might be explained by differences in subjects' alcohol beliefs. Finally, as neither of the three factors had any effect on self-disclosure behavior, we suggest that this behavioral measure is unrelated to self-reported anxiety. PMID- 7832010 TI - Alcohol expectancies and adolescent drinking: differential prediction of frequency, quantity, and intoxication. AB - Although alcohol expectancies have been shown to be consistently related to drinking and problematic drinking among underage youth, some studies suggest that they are more predictive of quantity than of frequency of drinking. However, this hypothesis has not been formally tested. This study examines the differential prediction hypothesis using a sample of 1,781 high school students from the San Francisco Bay Area. Measures included yearly and monthly frequency of drinking and intoxication and usual quantity consumed per drinking occasion. Alcohol expectancies were measured with 11 items asking about the likelihood that having 2 or 3 whole drinks of alcohol would lead to specific personal consequences. Structural equations analyses indicated that expectancies were better predictors of quantity than of frequency or intoxication. The results also show that positive and negative expectancy subscales were differentially associated with the drinking measures and the patterns were somewhat different for males and females. PMID- 7832011 TI - Variability in subjective responses to marijuana: initial experiences of college students. AB - A short self-report questionnaire that probed initial and most recent experiences with marijuana was administered to 197 undergraduate psychology students. Measures of Global Positive and Global Negative responses to marijuana use were obtained. There was substantial variability in the response to marijuana on both of these scales, which were moderately correlated with each other. The self reported Global Positive score for initial use of marijuana was correlated with latency to next use of marijuana and with lifetime use of the drug, suggesting that abuse potential of the drug is related to magnitude of initial positive effect. Self-reported Global Negative scores for initial use did not correlate with either of these outcome measures. These data are compared and contrasted to those from a study that examined these responses to cocaine. The findings suggest that the abuse potential for both of these drugs is related to the magnitude of the positive response to first use. PMID- 7832012 TI - Cognitive bias covaries with alcohol consumption. AB - Cognitive models of behavior led to the prediction that ambiguous stimuli would be interpreted as alcohol-relevant in heavier drinkers. Women were asked to define words that could be interpreted as alcohol-relevant or not (e.g., shot). Two measures served as indicators of a latent construct of cognitive bias: the number of words construed to be related to alcohol, and the position of the first word in the series that was defined as alcohol-relevant. Average quantity, average frequency, and maximum number of drinks imbibed in a single episode served as indicators of a latent construct of alcohol consumption. These two constructs covaried significantly (.44) in a two-factor latent variable analysis that fit the data better than alternative models. These findings support an alcohol-related interpretive bias and suggest hypotheses concerning the types of interpretive preferences that may contribute to alcohol consumption. PMID- 7832013 TI - Identifying video game addiction in children and adolescents. AB - There is a current trend of thought among some scholars of gambling that arcade video game playing in some adolescents may develop into a behavior which resembles a gambling addiction. A scale, developed to identify arcade video game addiction in adolescents, was administered to 467 secondary school children in a coastal town in the UK. Initial psychometric tests show that the scale has acceptable internal consistency reliability and factorial validity, and is significantly related to alternative means of assessing excessive video game play. The implications of the study findings are discussed together with its limitations and suggestions for future research. PMID- 7832014 TI - Risk and protective factors for alcohol use among pregnant African-American, Hispanic, and white adolescents: the influence of peers, sexual partners, family members, and mentors. AB - Factors affecting the drinking patterns of 183 pregnant, African-American, Hispanic, and White adolescents were investigated, including the influence of peers, sexual partners, family members, and mentors. Among participants who drank alcohol prior to their pregnancies, 87% quit or cut back on their drinking behaviors. Those adolescents who lived in environments where their partners, peers, and relatives were drinking and using drugs were more likely to have consumed alcohol in the previous month, while adolescents who identified mentors and/or parents who provided high levels of support were less likely to have consumed alcohol. Finally, distinct patterns of both drinking and life circumstances among the African-American, Hispanic, White adolescents were revealed. The implications of these findings for future research and intervention with pregnant adolescents are discussed. PMID- 7832015 TI - Psychosocial and personality differences in chippers and regular smokers. AB - Tobacco chippers are an anomalous group of smokers who, while having smoked regularly for years, have avoided the clutches of nicotine dependence. In an attempt to better understand the factors associated with nondependent cigarette smoking, this paper describes a study in which matched groups of regular smokers, chippers, and nonsmokers were compared on a number of personality and psychosocial variables believed relevant to drug-seeking behavior. The strongest finding indicated that sensation seeking best discriminates among the three groups, with nonsmokers clearly viewing themselves as more socially inhibited and less interested in pursuing sensations relative to both regular smokers and chippers, both of whom evidenced comparable scores. Regular smokers evidenced less self-control, or restraint, and appeared more impulsive and unable to resist temptation, compared to chippers and nonsmokers. Surprisingly, none of the groups could be differentiated on the basis of perceived stress, coping, or social support. Even among the personality variables, however, the effect sizes were relatively small, indicating that these differences in personality cannot fully account for chipper's resistance to dependence. PMID- 7832016 TI - Personality risk for alcoholism and alcohol expectancies. AB - Studies of the association between risk for alcoholism and alcohol expectancies reveal contradictory results. The link between risk and expectancies may vary with the type of expectancy and the limb of the blood alcohol curve. The current study examined the relation between personality risk for alcoholism (as measured by the MacAndrew scale) and anticipated stimulant and sedative effects of alcohol. Even when sex and drinking habits were controlled, subjects at higher risk expected fewer of the aversive, sedative effects of alcohol on both the ascending and descending limbs of the blood alcohol curve. Risk and positive, stimulant effects were orthogonal. These data suggest that high- and low-risk individuals may anticipate experiencing an equal intensity of alcohol's positive effects, but high-risk individuals anticipate negative effects that are less severe. The potential role of these risk-related expectancies in the development of problem drinking is discussed. PMID- 7832017 TI - Adolescent contraceptive use and communication: changes over a decade. AB - Sexual experiences of 186 adolescents in 1979 were compared to those of 215 adolescents in 1989 who were recruited from the same university to determine if there was an increase over the decade in "safe sex" practices. Self-reported condom use increased between 1979 and 1989 for very first intercourse as well as first intercourse with current partner, although condom use was still far from universal. For other behaviors, there were sexual career changes (i.e., changes from first to current partner) but not decade changes. The percentage of respondents using any method of contraception and the percentage who discussed contraception with their partner increased from first to current partner, but did not increase between 1979 and 1989. The very first intercourse with first partner remained especially troubling since contraceptive use was very low and discussions about contraception prior to sex were very infrequent. PMID- 7832018 TI - Sexual harassment: early adolescents' self-reports of experiences and acceptance. AB - Considerable attention has been focused on sexual harassment experiences and attitudes of older adolescents and adults. Recently, educational and judicial institutions have recognized that harassment also occurs among junior and senior high school students. The primary aim of this project was to gather information regarding early adolescents' experiences with and acceptance of sexual harassment behaviors. Results indicate a considerable proportion of females (50%) and males (37%) have been victims of sexual harassment perpetrated by their peers, even though their acceptance of these behaviors is quite low. Suggestions for a sexual harassment educational program for early adolescents are presented. PMID- 7832019 TI - Parental behavior and adolescent self-esteem in clinical and nonclinical samples. AB - This study investigated the relationships between multiple dimensions of self esteem and adolescents' perceptions of parental behaviors using nonclinical (n = 119) and clinical (n = 30) samples of adolescents. The Rosenberg Self-Esteem Scale (RSES), a modified version of Osgood's Semantic Differential (OSD), Schaefer's Children's Report of Parental Behavior Inventory (CRPBI) short form), and a demographic questionnaire were administered to participants. Scores from the self-esteem measures were empirically combined and factor analyzed, yielding four dimensions of self-esteem. Multivariate analysis of variance were used to compare self-esteem dimension scores for males and females within both samples. Correlations and partial correlations were conducted to determine the nature of the relationships between each dimension of self-esteem and perceptions of parental behaviors. Nonclinical adolescents scored higher than did clinical adolescents on all self-esteem dimensions. Males scored higher than females only on the dimension of Self-Esteem Competence. Perceptions of parental behaviors were consistently unrelated to dimensions of self-esteem among adolescents in the clinical sample. Among adolescents in the nonclinical sample, perceptions of parental support and autonomy granting were related to multiple dimensions of self-esteem. Perceptions of parental discipline were inconsistently related to dimensions of nonclinical self-esteem. PMID- 7832021 TI - School consultation and the management of obsessive-compulsive personality in the classroom. AB - The need for a comprehensive assessment involving areas of ability, personality, and motivation when young people are referred to a mental health service with problems of school failure is discussed. Traits associated with obsessive compulsive personality style are reviewed, and the impact on school performance explored. Three case examples illustrate the ways this personality style interferes with success in the classroom and the concerns and problems encountered in providing intervention. Particular classroom teaching strategies may assist teacher and student in avoiding these problems. In addition, the benefits of SQ3R, Cornell systems, and cooperative learning are discussed, and warning signals, observable by the teacher, described. The process of mental health consultation, contribution to classroom change, and difficulties encountered along with the advantages of professional partnership in the diagnosis and management of school problems are reviewed. PMID- 7832020 TI - Corporal punishment of adolescents by parents: a risk factor in the epidemiology of depression, suicide, alcohol abuse, child abuse, and wife beating. AB - Over 90% of parents of toddlers spank or use other forms of corporal punishment. Although the rate declines each year from about age five, this study of a large national sample of U.S. adults found that almost half recalled having been corporally punished during their teen years. This high prevalence indicates a need to investigate the possibility that corporal punishment puts adolescents at increased risk of developing mental health and social relationship problems later in life. The analysis, which controlled for a number of possible confounding risk factors such as low socioeconomic status, found that children who experienced corporal punishment in adolescence had an increased risk later in life of depressive symptoms, suicidal thoughts, alcohol abuse, physical abuse of children, and wife beating. The consistent association of corporal punishment with major adult problem behavior, together with the fact that at least half of all adolescents are victims of corporal punishment by their parents, indicates a need to replicate the study using longitudinal data. If the findings are confirmed, it suggests that a major step in primary prevention of violence and mental health problems can be achieved by a national effort to reduce or eliminate all use of corporal punishment. PMID- 7832022 TI - A thirteen-year comparison in patterns of attitudes toward counseling. AB - Two comparable samples of college students were administered the same survey of attitudes toward counseling in 1976 and 1989. Ratings were obtained for (1) likelihood of seeking counseling, (2) likelihood of seeking help from professional and nonprofessional helpers, (3) likelihood of seeking help for differing types of problems, (4) degree of responsibility the professional should assume, and (5) preferences for five of the major counseling approaches (Adlerian, Behavioral, Gestalt, Person-Centered, Rational-Emotive). Consistencies and changing patterns were noted within each year and between years. Findings are discussed in relation to existing research as well as to possible gender and societal determinants. PMID- 7832023 TI - Measuring the short-term mood of adolescents: reliability and validity of the state form of the Depression Adjective Check Lists. AB - Adequate reliability (internal consistency, and alternate form), and validity (concurrent, convergent, and discriminant) of the state version of Set 1 (lists A, B, C, D) and Set 2 (lists E, F, G) of the Depression Adjective Check Lists with two adolescent samples: F = 35, M = 29; F = 294, M = 244) were demonstrated. The lists also were shown to be sufficiently sensitive for use in measuring short term mood. Significant grade effect was found on two of the lists of Set 1 and a significant sex effect was found on each of the lists of Set 2. PMID- 7832024 TI - The effect of self-esteem, family structure, locus of control, and career goals on adolescent leadership behavior. AB - Since leadership in formal and informal high school activities is one possible indicator of positive social adjustment among adolescents, it is worthwhile to better understand why certain adolescents become leaders and others do not. This study was designed to investigate the relationship between leadership behavior (dependent variable) and self-esteem, locus of control, family structure, and career goals. The participants were divided into a leadership group (n = 79) and a nonleadership (comparison) group (n = 124). Adolescents in the leadership group tended to be higher in internal locus of control, to live in a two-parent family structure, and to have more prestigious career goals. There was no significant difference between the two groups in level of self-esteem, although those in the leadership group with higher self-esteem also tended to have higher career goals. PMID- 7832025 TI - The relationship between heavy metal and rap music and adolescent turmoil: real or artifact? AB - Adolescents and their parents were surveyed to investigate the association between heavy metal and rap music and adolescent psychosocial turmoil. Subjects were asked about current and past psychosocial functioning, as well as their music preferences. Adolescents who preferred heavy metal and rap music were compared with those who preferred other types of music. Results indicated that adolescents who preferred heavy metal and rap had a higher incidence of below average school grades, school behavior problems, sexual activity, drug and alcohol use, and arrests. However, when gender was controlled, only below-average current and elementary school grades and a history of counseling in elementary school for school problems remained significant. Implications of these findings are discussed. PMID- 7832026 TI - An investigation of differences in attitudes between suicidal and nonsuicidal student ideators. AB - Suicidal activity among youths has increased dramatically in recent years, yet little objective research in non-hospital settings has been conducted. The present study analyzed attitudes of suicidal ideator and nonideator groups at elementary, middle, and high school levels. Responses to the Student Attitude Measure (S.A.M.) were analyzed with a multivariate analysis of variance. Ideators' attitudes were found to be significantly more negative than those of nonideators. Some grade level and gender differences also were revealed. The ability of this instrument to differentiate potentially suicidal youths from their nonsuicidal peers has the potential for providing schools with a critical proactive strategy. PMID- 7832027 TI - Physical symptoms of stress, depression, and suicidal ideation in high school students. AB - The occurrence of minor physical symptoms of stress, but not the major psychosomatic disorders, was found to be associated with depression in high school students. Physical symptoms were not associated with suicidal preoccupation once the level of depression was taken into account. PMID- 7832028 TI - Adolescent boys and anorexia nervosa. AB - Anorexia nervosa is an eating disorder that primarily affects adolescent girls and young adult females, and is considered to be rare among males. It is estimated that one in 200 adolescents between the ages of 12 and 18 years, the high risk group, develop anorexia nervosa with 90% of those affected being females. However, there has been a steady increase in the reported incidence of male anorectics, from approximately 5% (DSM III) in 1985, to as much as 10% in 1987 (NIMH, 1987). Since educators and counselors can serve a vital role in the early identification of this disorder, the young anorectic male has a better prognosis for recovery if they receive treatment during the early stages. PMID- 7832029 TI - Do attitudinal and behavioral ratings of family members vary across familial configurations? AB - In this study 212 high school students from different familial configurations were compared regarding their descriptions of themselves and their parents, as well as how their parents interacted with each other. Findings revealed that fathers' ratings or evaluations, but not mothers' ratings or the students' self ratings, suffered in the wake of divorce. Regarding perceived "loving" actions by parents, however, students from intact families clearly had an advantage over their counterparts from reconstituted, divorced, and single-parent families. Implications of the findings are discussed. PMID- 7832030 TI - Parent-rating and self-report measures in the psychiatric assessment of adolescents. AB - Thirty adolescents who received a psychiatric diagnosis based on the DSM-III clinical criteria were compared to 28 adolescents who were free of a diagnosis using the same criteria, on a parent-completed questionnaire (Revised Behavior Problem Checklist) and self-report measures (Revised Children's Manifest Anxiety Scale, Children's Depression Inventory, SCL-90-R). The two groups of adolescents were significantly distinguished by scores from the parent questionnaire but not by self-report measures. Possible explanations for the discrepant results are discussed. It is concluded that the parent measure may be used to reliably distinguish adolescents with psychiatric disorders from those free of similar disorders. PMID- 7832031 TI - Possibilities and limitations of a gender stereotypes intervention program. AB - This study deals with an educational intervention program for elementary school teachers aimed at decreasing gender stereotypes. The limits of the educational program's effectiveness in relation to the theory of "relative autonomy of schools" is examined. The sample of sixth graders in this study was divided into two groups: the experiment group, whose teachers participated in the program's workshops, and the control group, whose teachers did not. It was hypothesized that (1) the experiment group would show greater preference for the more prestigious professions than would the control group. This hypothesis was supported in the main findings; (2) the experiment group would choose less gender biased professions than would the control group. This hypothesis was only partially supported by the findings. Since school is only one of the many socializing factors in society, the effectiveness of this research was limited, as can be expected from the theory of the relative autonomy of schools. PMID- 7832032 TI - Effect of timing of parental divorce on the vulnerability of children to depression in young adulthood. AB - The significance of a child's age at parents' divorce on later well-being was studied. In a population-based follow-up study from age 16 to 22, children who had experienced parental divorce before school age (n = 134), in latency at age 7 to 12 (n = 129), and in adolescence at age 13 to 16 (n = 71) were compared. In young adulthood, 24% of the boys who had experienced parental divorce in latency were depressive as compared with 9% and 6% in the other two groups, respectively. Interpersonal problems in adolescence predicted depression in young adulthood especially in the group of latency-aged boys. Among girls, depression was independent of the timing of parental divorce. PMID- 7832033 TI - Pubertal status, interaction with significant others, and self-esteem of adolescent girls. AB - The aim of this study was to examine the relationship between pubertal status, the quality of interactions with significant others, and the self-esteem of adolescent girls. The model which was tested, hypothesized that pubertal status affects self-esteem through girls' interactions with their parents and friends. Pubertal status was operationalized as the number of months between occurrence of the first menstrual periods and time of the investigation. The measure of self esteem was the shortened form of the Coopersmith Self-Esteem Inventory. Analyses revealed that girls who begun menstruating six months before the investigation obtained higher scores on the measure of self-esteem than did girls who had been menstruating 13 months or more. The best predictor of self-esteem, however, was the quality of interaction with their mothers. The results support the theoretical view that stresses the importance of interaction with significant others for the development of self-esteem. PMID- 7832034 TI - Adolescents' perceptions of their risk-taking behavior. AB - A questionnaire comprised of several self-report scales was administered to 440 adolescents to assess differences between high and low sports and danger risk takers on relationship and personality variables. Sports risk takers reported more danger-related risk taking and more drug use but higher self-esteem than did nonrisk takers. Danger risk takers reported greater sports-related risk taking and more drug use as well as less intimacy with their mothers, less family responsibility taking, and less depression than did their nonrisk-taking counterparts. PMID- 7832035 TI - Psychological determinants of adolescent exercise adherence. AB - The purpose of this study was to identify some psychological determinants of exercise adherence on which public school physical education programs may have an impact. Data were collected twice, once representing a structured physical education classroom setting (N = 132), and later representing an unstructured summer vacation exercise setting (N = 110). Male and female physical education students at a large suburban high school completed five questionnaires which represented four psychological variables (self-motivation, perceived control, personality/sport congruence, and perceived self-competency), and one physical activity variable (exercise adherence) in both of the two data-collection periods. The results indicated that Perceived Romantic Appeal was predictive of male exercise adherence while Perceived Athletic Competency, Perceived Global Self-Worth, and Perceived Physical Appearance were predictive of female exercise adherence. None of the psychological predictor variables was significant for competitive subjects in either exercise setting, yet Perceived Romantic Appeal and Personality/Sport Congruence were predictive of noncompetitive subjects' exercise adherence in the structured and unstructured settings, respectively. PMID- 7832036 TI - Decreasing sex bias through education for parenthood or prevention of adolescent pregnancy: a developmental model with integrative strategies. AB - This paper identifies the need for more research, education, and services for males about adolescent pregnancy and parenthood to augment their social and familial learning experiences. A case is made for more participation by schools in achieving a better balance between males and females in preparing for parenthood or prevention of pregnancy. Developmentally appropriate educational concepts and strategies that are integrated into the curriculum are described. PMID- 7832037 TI - Street youth in substance abuse treatment: characteristics and treatment compliance. AB - This study reports on the characteristics of street youth in treatment in Ontario. Data came from eleven substance abuse treatment programs. It was found that street youth in treatment had a larger number of social and drug abuse problems than did non-street youth. They were more likely to be unemployed, on welfare, and to have legal problems. They had more depression and lower self esteem, and use more alcohol and drugs. Discharged street and non-street youth had similar lengths of stay and drop-out rates in one residential program and similar, although limited, amounts of treatment in outpatient programs. However, street youth were more likely to leave outpatient programs without telling staff. The need for more experimentation in the provision of service for youth is identified. PMID- 7832038 TI - Mechanisms of fetal growth retardation in the underweight mother. PMID- 7832039 TI - Maternal anthropometry predicts benefit in lactational performance of undernourished Guatemalan women. PMID- 7832040 TI - Energy balance in pregnancy and lactation. PMID- 7832041 TI - The physiological significance of circulating transferrin receptors. AB - A soluble truncated form of the tissue transferrin receptor has been recently identified in human serum. The concentration of this serum receptor appears to reflect the total mass of tissue receptor and is consequently elevated with tissue iron deficiency and enhanced red cell production. When coupled with the serum ferritin, the serum transferrin receptor concentration provides a sensitive, quantitative index of iron status over a wide spectrum. While the physiological significance of the circulating receptor is still unknown, this new laboratory measurement will play an important role in the clinical and epidemiological detection of iron deficiency anemia. PMID- 7832042 TI - The consequences of iron deficiency and anemia in pregnancy. PMID- 7832043 TI - Folate binding proteins. Mechanisms for placental and intestinal uptake. PMID- 7832044 TI - Iron and folate supplementation during pregnancy. Maternal and fetal consequences. PMID- 7832045 TI - Folate status during pregnancy and lactation. PMID- 7832046 TI - Vitamin B12 metabolism and status during pregnancy, lactation and infancy. AB - This overview of vitamin B12 metabolism and requirements during the continuum of pregnancy and lactation has identified several gaps in our knowledge. More information is needed concerning the roles of the different transcobalamins during pregnancy and lactation, including their impact on placental and mammary transfer of cobalamin and their effect on intestinal absorption in the infant. Knowledge is needed about the relative importance of maternal stores and current dietary intake on fetal storage of the vitamin, and on its concentration in breast milk. Because there is some evidence that infant's urinary methylmalonic acid excretion is reduced by intakes slightly higher than the current RDA, the adequacy of the current RDA for vitamin B12 during infancy should be verified. Finally, it is possible that vitamin B12 deficiency is more common in pregnant and lactating women and their young children in developing countries than has been recognized previously, due primarily to malabsorption. It is important to confirm whether or not this is the case, in view of its potential impact on infant neurobehavioral development and the relative ease with which supplements of the vitamin could be provided. PMID- 7832048 TI - The role of vitamin A in child growth, development and survival. AB - Vitamin A is essential for growth, development and survival. For children in deprived settings an adequate vitamin A status may be more critical to survival protection than to growth and development. During infancy breast milk from malnourished mothers is protective against the development of xerophthalmia; it needs to be complemented after six months by other dietary sources of vitamin A to provide full health protection. Correcting the low vitamin A content of breast milk from malnourished mothers within the first four weeks of delivery by a high dose oral vitamin A supplement can be an effective short-term preventive strategy while efforts are made to improve the dietary intake for the long-term solution. PMID- 7832047 TI - The function of vitamin A in cellular growth and differentiation, and its roles during pregnancy and lactation. AB - Recent advances in the molecular biology of the retinoids have provided a mechanistic explanation for the observations, first made several decades ago, that vitamin A profoundly influences the differentiation of tissues throughout the body. A central concept has recently emerged, namely that retinoids seldom exist "free" in solution but, rather, are nearly always associated with specific retinoid-binding proteins. In plasma, these include RBP and the chylomicron whereas, in cells two distinct classes of retinoid-binding proteins exist: the cellular (cytoplasmic) proteins (CRBPs and CRABPs) and the nuclear receptors proteins (RARs and RXRs). Whereas the cellular retinoid-binding proteins serve as buffers and as chaperones during metabolism (Ross, 1993b), the nuclear receptors are now recognized to be the direct mediators of retinoid actions on the genome. Both the cytoplasmic and nuclear classes of retinoid-binding proteins are expressed early in development and are proposed to control the concentration of retinoic acid and the transcription of retinoid-responsive genes, respectively. Given the profound effects of retinoic deficiency or excess on the developing fetus, it is not surprising that mechanisms have evolved to control the placental transfer of vitamin A. Transfer is nearly uniform over a rather wide range of maternal dietary vitamin A intake. The importance of RBP in transporting retinol to tissues is suggested by the observations that the visceral yolk sac and the liver of the fetus transcribe and translate RBP. In comparison to pregnancy, vitamin A transport during lactation is much more responsive to variations in maternal vitamin A intake. The young of mothers with good vitamin A nutriture may thus accumulate significant retinol reserves during the suckling period. Conversely, young nursed by mothers with poor vitamin A status and low intake during lactation may fail to develop adequate stores and be vulnerable to vitamin A deficiency if the post-weaning diet is also poor in vitamin A. In populations with low vitamin A status, the lactation period provides an excellent window of opportunity for supplementing mothers and, indirectly, their offspring, with vitamin A to replenish the mother's vitamin A reserves and assure that the infant's growth and development are not limited by an inadequate quantity of this essential nutrient. PMID- 7832049 TI - Molecular basis for abnormal parturition in zinc deficiency in rats. PMID- 7832050 TI - Zinc supplementation and child growth in Ecuador. PMID- 7832051 TI - Whole body zinc metabolism in full-term breasted and formula fed infants. PMID- 7832052 TI - Cellular growth and differentiation during embryogenesis and fetal development. The role of vitamin D. PMID- 7832053 TI - Effect of calcium deficiency on vitamin D metabolism. PMID- 7832054 TI - Calcium intakes and bone densities of lactating women and breast-fed infants in The Gambia. AB - The calcium required for breast-milk production and infant growth can be a substantial proportion of dietary intakes especially in regions of the world were calcium consumption is low. Insufficient calcium supply might lead to maternal bone loss, reduced breast-milk calcium secretion and impaired infant bone growth. However, changes in calcium absorption and excretion may be sufficient to allow these requirements to be met without affecting maternal or infant health. A limited number of studies have investigated changes in maternal bone mineral, absorption, excretion and metabolism during lactation but few have addressed whether any changes are influenced by calcium intakes. Ongoing detailed research by the MRC Dunn Nutrition Unit in a rural area of The Gambia amongst mothers and infants with habitually low calcium intakes will provide valuable information about calcium needs during lactation and growth. PMID- 7832055 TI - Interactions between zinc, vitamins A and D and hormones in the regulation of growth. PMID- 7832056 TI - Stable isotopes for measurement of nutrient dynamics during pregnancy and lactation. AB - Only a few of the advantages of stable isotopes have been illustrated here. However, two valuable concepts have emerged in recent years; (1) the use of multiple isotopomers for comprehensive studies of a nutrient system, and (2) the use of multiple tracers for parallel investigations of different metabolic systems. These concepts provide flexibility in the conduct of clinical research, however, precautions are necessary to employ them properly. Nearly every example described here can be traced back to a pioneering study by Schoenheimer and Rittenberg. Certainly we do them faster, and more precisely, and with a deeper understanding of the biology, but the credit for this wonderful tool belongs to the original visionaries. PMID- 7832057 TI - Influence of body composition on food intake. PMID- 7832058 TI - Issues in constant tracer infusion and mineral metabolism. AB - The preceding discussion focussed on two aspects of the application of tracer kinetics to studies of endogenous metabolism. It is recognized that the discussions were more directed to theoretical aspects of tracer studies, but it is hoped that, as such, they will lead to some new experimental investigations, particularly in the area of metal metabolism. PMID- 7832059 TI - Cellular mechanisms for the regulation of adipose tissue lipid metabolism in pregnancy and lactation. PMID- 7832060 TI - Animal models for the study of adipose regulation in pregnancy and lactation. PMID- 7832061 TI - Endocrine regulation of nutrient flux in the lactating woman. Do the mechanisms differ from pregnancy? PMID- 7832062 TI - Maternal fatness in Mexican women predicts body composition changes in pregnancy and lactation. PMID- 7832063 TI - [Problems of refraction & accommodation in Japan]. PMID- 7832064 TI - [Treatment of paralytic strabismus]. AB - 1) Cases of strabismus combined with abnormalities in ocular movement were divided into three groups: paralytic nonconcomitant strabismus, special forms of strabismus, and paralytic concomitant strabismus. 977 cases of surgery for paralytic nonconcomitant strabismus were analyzed. 2) 109 cases of surgery for paralytic esotropia due to abducens palsy were performed. In cases of complete paralysis, a transposition of the vertical rectus muscle was indicated. In cases of incomplete paralysis, a resection of the lateral rectus muscle was indicated. On the basis of these indications, the same results could be achieved, and when a recession of the medial rectus muscle was concurrently performed the results were improved. 3) In oculomotor palsy, 138 cases of surgery for paralytic exotropia were performed. In cases of complete paralysis, a transposition of the superior oblique muscle was indicated. In cases of incomplete paralysis, a resection of the medial rectus muscle was indicated. On the basis of these indications, the same results could be achieved, and when a recession of the lateral rectus muscle was concurrently performed the results were improved. 4) 570 cases of surgery for superior oblique muscle palsy were performed. In cases of vertical deviation, a weakening operation on the inferior oblique muscle, the superior rectus muscle of the affected eye, and the inferior rectus muscle of the sound eye were indicated. In cases of torsional deviation, good results were obtained through an advancement of the anterior part of the superior oblique muscle and a resection of the superior oblique muscle. 5) Statistics concerning cure based on the standards for cure employed by the Japanese Association of Strabismus and Amblyopia, or from the point of view of cosmetic cure were: 85% for paralytic esotropia and superior oblique muscle palsy, 82% satisfactory for incomplete paralysis of the oculomotor nerve within paralytic exotropia, and 61% relatively unsatisfactory for complete paralysis of the oculomotor nerve within paralytic exotropia. 6) The results of 216 cases examined after period of four years or longer were: cases where a one-month postoperative cure or cosmetic cure was maintained over this period were 90% of superior oblique muscle palsy cases, 79% of paralytic esotropia, and 59% of paralytic exotropia. Paralytic exotropia showed poor results. The surgical methods were muscle transposition in cases of horizontal muscle surgery and surgery of the oblique muscles in cases of vertical muscle surgery. 7) Through the Turn-Amplitude Analysis of the amounts of EMG interference patterns in the extraocular muscle, neuropathy was classified as either complete or incomplete.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7832065 TI - [Microphthalmos and its pathogenic classification]. AB - Congenital microphthalmos is a common malformation encountered clinically. Microphthalmos in adults is here defined as eyes whose axial length is below 20.4 mm in males and 20.1 mm in females; in under 14-year-old children, it is eyes at least 3 square root of 2/3 below the mean for age-similar controls. Experimental animals with hereditary microphthalmos have been widely investigated, and many environmental factors given to pregnant animals frequently induce microphthalmos. In both clinical and experimental microphthalmos, there are conspicuous variations in size, and various kinds of ocular and systemic complications. Recently, fetal alcohol syndrome produced by alcohol intake during pregnancy has been reported. In this syndrome, microphthalmos is one of the important symptoms. Experimentally, microphthalmos also developed at a high incidence among mouse fetuses whose mothers were given ethanol during pregnancy. The present investigator established a preliminary etiological classification of microphthalmos in 1984. In this paper summing up newly obtained results, the relationship to neural crest cells and histochemical changes of glycosaminoglycan molecular species, the author presents a final pathogenic classification of microphthalmos, which consists of developmental disturbance of the optic vesicle, malformation of the optic cup, mesenchymal dysgenesis of the anterior ocular segment, maldevelopment of the lens, maldevelopment of the vitreous, faulty closure of the embryonic fissure and developmental disturbance of the wall of eyeball. PMID- 7832066 TI - [Optical characteristics of the human eye]. AB - The optical characteristics of the eyeball are caused by its non-coaxial system. We show that the refraction changes throughout an individual's life. Results were obtained by a longitudinal study for ten years on patients (from 3-year-old to 58 year-old, 254 eyes of 127 persons) with only ametropia. We also did a longitudinal study for two years of healthy 3-year-old children (54 eyes of 27). However, we could not define the factors which control the refraction change. We examined the alteration of refraction induced by examination circumstances such as the size, shape, direction of fixation targets, and brightness of the room. Only minimizing size caused an increase of deviation range of astigmatism axis with miosis. Concerning a moving target from 5 m to 0.5 m, anisometropic eyes with the retinal conjugate point nearer to the target tended to track the target more closely than isometropic eyes. PMID- 7832067 TI - [Mechanism of axial elongation and chorioretinal atrophy in high myopia]. AB - Myopic chorioretinal atrophy with axial elongation is one of the main factors of visual impairment in high myopia. To clarify the causes of this chorioretinal atrophy (CRA), the mechanism of ocular axial elongation was investigated from the effects of growth factors on experimental myopia models. From the analysis of large numbers of humans with extreme myopia, the factors causing CRA and the process of progression of this atrophy were also studied. I. Mechanism of ocular axial elongation Myopic change of 20 to 30 diopters occurred in chicks when they wore translucent or black opaque goggles for 2 weeks. But when they were fed under dark conditions for 24 hours, myopic change did not occur, and even when the goggles were worn, only slight myopic changes occurred. Thus, it appeared that light was necessary for myopic change and an increase in temperature caused by the goggles had little influence on the myopic change. In light microscopic observations, the posterior sclera of myopic chick eyes had thicker cartilaginous sclera and thinner fibrous sclera than the normal controls and abnormal proliferation of chondrocytes was seen at the border area. To investigate the changes in cell proliferation at 3 different locations (periphery, equator, posterior pole) of the sclera, the ratio of positive cells in PCNA, Decorin, b FGF, TGF-alpha, TGF-beta, IGF-II, and phosphotyrosine were studied immunohistologically. Positive ratios were higher at the posterior pole of the treated myopic eyes for all factors, except for b-FGF and TGF-alpha. We estimated that the proliferation of chondrocytes and revelation of growth factors were higher at the posterior pole of the sclera in the experimental myopic eye than in the control eyes. In electron microscopic observations, proliferation of chondrocytes in cartilaginous sclera was found and small diameter collagen fibrils with a large amount of ground substance were observed in the fibrous sclera. These observations were similar to those of the sclera before hatching. It appeared that the sclera of the experimental myopic eyes remained in the pre hatching condition. In co-culture experiments of the cultured condrocytes of cartilaginous sclera and the retina (retinal pigment epithelium (RPE) excluded), proliferation of the chondrocytes was suppressed significantly (p < 0.05). On the other hand, in the co-culture of chondrocytes and RPE-choroid, increase of the chondrocytes was induced (p < 0.05).(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7832068 TI - [Accommodation function and its clinical evaluation]. AB - One subjective examination in accommodation, we found fundamental fault in the self-selection of clear vision against stimulus target and the time control of examination. On the other hand, it was difficult to objectively judge clear vision or check subjects consciousness for the tests. In this study, we made a trial instrument called new accommodometer which was able to confirm the time limit for clear vision, and measured response time for accommodation in constriction and relaxation. Young healthy subjects could obtain clear vision within 0.5 seconds on the new accommodometer, but this took over 0.8 seconds with scattered distribution on an accommodopolyrecorder. The required time for clear vision tended to increase in diabetic cases, and also in pseudophakia corrected bifocal lenses, over 0.6 seconds. We analyzed the form of accommodative response under clear vision, using on infrared optometer with stimulus-targets prepared outside, meanwhile changing the size of targets and amplitude of accommodative stimulus. When we compare these results to those of the new accommodometer, it will be easily seen that accommodative clear vision may be acquired in a rapid response stage after a latent period of constrictive accommodation, and usually with a steady running time under 4 D stimulus. For getting clear vision in far and near objects simultaneously, in pseudophakia, moderate astigmatism plays an important part, but it tends to cause deteriorated quality of clear vision. In diffractive intraocular lenses, we can find patients who are able to see using arbitrarily both areas, the refractive or diffractive part. We analyzed microfluctuation of accommodation by the maximum entropy method, and one of the typical cases revealed three-dimensional drawings reconstructed from it. In analyzing the spectral power of young healthy subjects, the response waves tend to increase in blurred conditions for targets. PMID- 7832069 TI - [Pathogenesis and treatment of accommodative disturbance]. AB - Using a computer-assisted infrared optometer with a pupillograph, we tried to obtain basic understanding of accommodative disturbance and its by investigating tonic (dark focus) level of accommodation and quasi-static accommodative response. In normal volunteers in whom either visual fatigue, general fatigue, or drunkeness was loaded intentionally, myopic shift of refraction, increased refractive fluctuation, and miosis were induced in all cases but the effect on amplitude of accommodative response was minimal. Subjects that worked at a computer terminal all day for 2 years, but not controls, developed myopic change at a statistically significant level. The effect on tonic level of accommodation of subject age, sustained near-vision tasks, and topical application of autonomic related drugs was investigated. In subjects with severe eyestrain, myopic shift of tonic accommodation and prominent pupillary unrest were observed, suggesting increased parasympathetic excitation. One patient who was accidentally exposed to diisopropyl fluorophosphate, a potent cholinesterase inhibitor, showed a phenomenon similar to that mentioned above. Chaos attractors based upon the Shil'nikov phenomenon were introduced for evaluation of microfluctuation and pupillary unrest, as first applied by Sumida et al. Topical application of low dose cyclopentolate hydrochloride was effective for treating accommodative abnormality in professional computed workers, who sometimes develop abnormal parasympathetic excitation. Based on quasi-static accommodation measurements, accommodative abnormality after head and neck injury, including whiplash injury, was divided into two completely different states: accommodative spasm and palsy. Since quasi-static accommodation was greatly affected by satellite ganglion block, sympathetic innervation from cervical ganglions may strongly influence accommodative response. Hyperthyroidism, which may be accompanied by sympathetic hyper-excitation, showed diminished accommodative response. In patients after refractive surgery by excimer laser, there was no difference in accommodative response before and after surgery, although tonic accommodation was slightly unstable after surgery. These findings suggest that the evaluation of tonic level or a similar state of accommodation and pupillary unrest will yield extremely valuable information in regard to various accommodative disturbances. PMID- 7832070 TI - [Academic articles and ethical consideration]. PMID- 7832071 TI - [Adenovirus-induced kidney graft pyelonephritis following renal transplantation]. AB - A 16-year-old female received a kidney transplantation from her mother 13 months before she suddenly noticed gross hematuria and painful micturition, and developed high fever with chills. The serum creatinine (S-Cr) level rose from 1.5 to 2.6 mg/dl, but there was no clinical sign of acute rejection. Despite the treatment with antibiotics and gamma-globulin, the the high fever and hematuria did not improve. The adenovirus antibody titer elevated from x8 to x1,024, while adenovirus was not isolated from the urine. On the 15th day of the disease, hematuria disappeared spontaneously and on the 19th day she became afebrile. The S-Cr level also was normalized spontaneously. Histological examination of the graft biopsy on the 14th day, showed severe tubulointerstitial nephritis localized in the renal medulla and full type intranuclear inclusions were revealed in tubular epithelial cells. From these findings, we diagnosed this case as adenovirus-induced kidney graft pyelonephritis associated with acute hemorrhagic cystitis. PMID- 7832072 TI - [Prenatally diagnosed bilateral multicystic dysplastic kidneys associated with multiple anomalies: a case report]. AB - A case of bilateral multicystic dysplastic kidneys with multiple anomalies is reported. Prenatal ultrasonography showed oligohydramnios, atrial septal defect, bilateral multicystic kidneys, omphalocele, and bowel dilatation. A male baby died of respiratory insufficiency immediately after premature delivery. Autopsy showed multiple anomalies of face, fingers, lung, heart, bowels, and genitourinary tract. Seven more cases with urinary tract anomalies prenatally detected by ultrasonography are also reported. Ultrasonography is useful to diagnose anomalies of fetus. PMID- 7832073 TI - [A case of muscle metastasis of renal cell carcinoma treated by local resection and tensor fascia lata myocutaneous flaps]. AB - A 44-year-old male with a little finger tip-sized tumor palpable on the left epigastric wall and a left renal tumor detected on computerized tomography (CT) was referred to this hospital in June 1991. Nephrectomy was performed in July 1991 under the diagnosis of a left renal tumor. Histologically, the tumor was a renal cell carcinoma, grade 2, clear and granular cell type. The tumor in the left abdominal wall was not extracted. As a tumor also developed in the scapular tunica muscularis, tumors in the left musculus rectus abdominis and the scapular tunica muscularis were extracted to the extent possible in July of 1992. Histologically, these tumors were metastatic clear cell carcinomas. The tumor in the left musculus rectus abdominis recurred and another was palpable in the left lateral femur. In August of 1993, the tumors in the left musculus vastus lateralis and the left musculus abdominis were extracted together with the tunica muscularis, and the defective region on the abdominal wall was closed with a left musculus tensor fascia lata flap. No evidence of recurrence has been observed to date. PMID- 7832074 TI - [A case of sepsis caused by methicillin-resistant Staphylococcus aureus aureus (MRSA) following retropubic prostatectomy]. AB - Although severe infection caused by methicillin-resistant Staphylococcus aureus (MRSA) has become a serious social problem in medical facilities, it is relatively uncommon in the urological field. It is supposed that MRSA in the urine is asymptomatic and MRSA urinary colonization is not likely to occur compared with the other Staphylococci. We report a case of sepsis caused by MRSA that occurred in the patient following retropubic prostatectomy. He had had a urinary catheter indwelt and had received anti-bacterial agents before the operation. Factors such as the continuing use of antibiotics and urinary catheterization could contribute to MRSA infections especially following open surgery. Therefore careful management seems important for such patients. PMID- 7832075 TI - Mediastinal lymph node metastasis 38 months after surveillance for stage I seminoma: a case report. AB - We present a case report of a relapse to the mediastinal lymph node alone, 38 months after orchiectomy on surveillance for stage I typical seminoma. The patient, a 63-year-old man, was treated with high inguinal orchiectomy for left testicular tumor and close follow-up. After 38 months from the initial treatment, the chest X-ray film and CT scan revealed mediastinal tumor. Fine needle aspiration cytology performed under the bronchoscopy showed seminoma cells. Complete remission was achieved after three courses chemotherapy of cisplatin, vincristine, methotrexate, peplomycin and etoposide (COMPE). He has continued to be clinically disease-free 8 months after completion of the treatment. According to the available data in the literature, 94% of the recurrences was detected within 3 years after orchiectomy, and 92% involved retroperitoneal lymph node metastases. This is a rare case who had a late relapse in the mediastinum alone. PMID- 7832077 TI - [Two cases reports of extramammary Paget's disease with adenocarcinoma]. AB - Two patients who suffered from extramammary Paget's disease with adenocarcinoma were treated with combination chemotherapy. Both patients who complained of scrotal induration were the Paget's cells with undifferentiated adenocarcinoma in pathology. We tried CAP (cyclophosphamide, pirarubicin, cisplatin) therapy on case 1, and MEC (methotrexate, etoposide, cisplatin) therapy on case 2. The primary lesion was reduced and the metastatic lesion, showed regression. PMID- 7832076 TI - [Two cases of testicular tumor with brain metastasis]. AB - During the last 8 years, 70 cases of testicular tumor were treated in our department. Of them 2 cases had brain metastasis. Case 1; A 37-year-old male was admitted with the chief complaint of cough. Retroperitoneal lymph node and lung metastases were discovered (stage IIIB, pT4aN1M1). Resected right testis was diagnosed as embryonal carcinoma, teratoma and STGC histopathologically. After 3 courses of PVB (cisplatinum, vincristine, bleomycin) chemotherapy right hemiplegia occurred and computerized tomographic (CT) scan revealed brain metastasis. His general condition degraded rapidly and he died of brain herniation 3 months after orchiectomy. Case 2; A 32-year-old male was admitted because of right testicular swelling and lung metastases (stage IIIB, pTiN0M1). Pathological examination revealed embryonal carcinoma, yolk sac tumor and teratoma. After 4 courses of chemotherapy with cisplatinum (CDDP), vincristine, methotrexate, peplomycin, and etoposide all lung metastases were disappeared. A few months later left hemiplegia by brain metastasis appeared suddenly. Four additional courses of high dose chemotherapy and resection of brain metastasis was performed. Complete remission continued for 13 months. The prognosis of testicular tumor with brain metastasis was very poor. During the last 8 years, 21 cases of testicular tumor with brain metastasis were reported in the Japanese literature. A follow-up study of prognosis in the literature was performed and discussed. PMID- 7832078 TI - [Lymphangioma of the penis: a case report]. AB - We report a case of lymphangioma of the penis. A 45-year-old man presented with a painless mass on the dorsal penis. A soft and movable mass was excised under local anesthesia. Pathological findings demonstrated vast amounts of fluid, which did not involve any blood cells and confirmed it to be cavernous lymphangioma. After 2 years postoperatively, no evidence of recurrence was present. We review 22 reports of penile lymphangioma in Japan. PMID- 7832079 TI - [Clinical evaluation on ofloxacin administered once daily in the treatment of acute uncomplicated cystitis]. AB - A comparative study of ofloxacin (OFLX), a new oral quinolone, was carried out at the Department of Urology, Osaka University Hospital and its eighteen affiliated hospitals to evaluate the clinical efficacy and safety of daily dose of 300 mg, given either once daily dose (SID group), or in three divided doses (TID group), in the treatment of acute uncomplicated cystitis in women. Clinical efficacy was evaluated in 42 cases from the SID group, and 43 cases from TID group, respectively, according to the criteria by the Japanese UTI Committee. In the SID group, the clinical efficacy was evaluated as excellent in 29 cases, moderate in 12 and poor in 1, with an overall clinical effectiveness rate of 98%. In the TID group, it was evaluated as excellent in 25 cases, moderate in 17 and poor in 1, with an overall clinical effectiveness rate of 98%. Safety was monitored only by subjective complaints. In the SID group, no subjective side effects appeared (0%). In the TID group, one of the 43 women (2.3%) complained of borborygmus. These findings suggest that there was no significant difference between the two groups in the safety and efficacy of ofloxacin. PMID- 7832080 TI - [Clinical efficacy of sairei-to in various urinary tract diseases centering on fibrosis]. AB - A joint multi-institution study was conducted on the efficacy of Sairei-to, centering on urinary tract fibrosis. The subjects consisted of 18 patients with retroperitoneal fibrosis (including 3 women), 77 patients with plastic induration of penis, 5 patients with sclerotic lipogranuloma (all men), and 67 patients with hemorrhagic cystitis (including 6 men). As a rule, Sairei-to was administered in monotherapy for periods of 4 weeks or longer. Efficacy was most pronounced in the patients with sclerotic lipogranuloma and plastic induration of penis, with overall improvement rates (percentage of patients with ratings of effective or better) of 80% in the former and 77.9% in the latter group. The overall improvement rate in the patients with retroperitoneal fibrosis was 61.1%. In the above diseases, there were numerous patients concurrently administered drugs such as antiinflammatory enzyme preparations and corticoid preparations, and the improvement rates were somewhat higher in these patients treated concurrently with other drugs. Outstanding efficacy was also seen in hemorrhagic cystitis. Dividing the patients into irradiation and non-irradiation groups, respective overall improvement rates of 77.8% and 82.8% were obtained, with the non irradiation group showing a slightly higher rate. The non-irradiation group showed slightly higher improvement rates in the subjects treated concurrently with drugs such as antibacterial drug. Conversely, the irradiation group showed significantly superior rates for monotherapy. Side effects such as mild gastrointestinal disturbances were seen in only 13 of 167 patients (7.8%), and the utility of this drug in treatment of the above diseases should be held in high regard. PMID- 7832081 TI - [Management of voiding dysfunction in elderly patients: effectiveness of rehabilitation and familial care]. AB - We examined whether the improvement of impaired mobility correlates with the success rate in achievement of catheter-free or diaper-free status of 260 hospitalized elderly patients whose activities in daily life (ADL) were impaired and urinary tract dysfunctions including urinary incontinence were managed by indwelling catheters or diapers. The contribution of physical rehabilitation and/or care given by family to the improvement of impaired mobility was also investigated. All 154 patients whose ADL improved during the course of the treatment acquired the catheter-free or diaper-free status. Of 106 patients whose ADL did not improve, 85 patients became free of catheters or diapers. All of the remaining 19 patients who continued to be dependent upon catheter or diapers had been bed-ridden during the course of the treatment. Among 201 patients who were bed-ridden before the treatment, the success rate in the improvement of impaired ADL in 84 patients who underwent physical rehabilitation and received care given by family, was 83%. The ADL improved in 71% of the 70 who received rehabilitation and 53% of 17 bed-ridden patients who received familial care. By contrast, only 2 out of 30 patients who received neither of them were free from the bed-ridden condition. The remaining 28 patients continued to be bed-ridden, and the 19 cases who were not free of indwelling catheters or diapers were a part of this population of patients.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7832082 TI - [Management of voiding dysfunction in elderly patients: prognosis 1 year after discharge from hospital]. AB - We investigated how 293 elderly patients who had been successfully treated to be free of catheters or diapers managed to urinate one year after their discharge from our hospital. Of 192 patients who returned to their own home 154 (80%) had good activities in daily life (ADL), and of 101 who moved to a nursing home or other hospital only 7 (7%) had good ADL. Among the 192 in their own home, 151 (79%) remained free of catheters or diapers thanks to the home care services provided by trained nurses belonging to our hospital. However, among the 101 at other facilities 21 (21%) could avoid these appliances. Furthermore, those who stayed in their own home with poor ADL had a significantly higher rate of being independent of catheters or diapers (34%) compared to those who lived in facilities other than their home with poor ADL (13%). These findings indicate that the elderly patients who reside in their own home or have good ADL possess a better chance of avoiding catheters or diapers compared to those who live in other than their residence or have poor ADL, and that continued urological care coupled with the home-visiting services is effective and important in attaining these aims. PMID- 7832083 TI - [Clinical studies of renal trauma]. AB - A total of 70 patients with renal trauma were treated at the Department of Urology, Nara Medical University and Nara Prefectural Hospital, including Life Saving Emergency center, from January 1982 to June 1993. They were between 3 and 79 years old (mean 30.0) and preponded to the younger generation. The main cause of injury was traffic accident in 46 cases (65.7%). According to the Classification of Renal Injury by the Japanese Association for the Surgery of Trauma in Japan, there were 31 cases (44.3%) of type I (subcapsular injury), 18 cases (25.7%) of type II (superficial injury), 15 cases (21.4%) of type III (deep injury), and 6 cases (8.6%) of type IV (pedicle injury). Surgical treatment was performed in 17 cases (24.2%). The major associated injuries were bone fracture in 32 cases (45.7%), lung injury in 17 cases (24.2%), and liver injury in 15 cases (21.4%). Furthermore, hydronephrosis and ureteral tumors were incidentally found in 4 and 1 patient during the course of treatment for renal trauma. Post traumatic plasma renin activities (PRA) in types III and IV were significantly higher than those in types I and II. Hypertension developed in 1 case of types I and II and 4 cases of types III and IV. The mean level of PRA was significantly decreased 2 years after renal injury in both groups. We should bear in mind that renal trauma may be associated with other urological diseases such as hydronephrosis and urological malignancies, and post-traumatic PRA should be followed carefully. PMID- 7832084 TI - [Application of whole layer core biopsy of bladder wall to paravesical tumor]. AB - We have reported the usefulness of percutaneous or transurethral whole layer core biopsy (WLCB) of bladder wall for staging of invasive bladder cancer. We have applied WLCB to 3 cases of paravesical tumor with good results. The first case was in a 3-year-old boy suspected of retrovesical sarcoma. Percutaneous WLCB revealed an inflammatory tumor of the Douglas cavity which was probably caused by perforation of appendix. The tumor disappeared by antibiotics alone. The second case was in a 37-year-old female with retrovesical tumor suspected to be ovarial cancer because of the high value of CA19-9 and CA125. Transurethral WLCB showed invasion of endometriosis to bladder muscle layer. The third case was in a 75 year-old female diagnosed by transurethral WLCB as sigmoid colon cancer invading until the deep bladder muscle layer. Cold cup punch biopsy was not informative in these 3 cases. Percutaneous or transurethral WLCB is safe and easy to perform, and is a technique recommended for diagnosis of pathology and bladder invasion of paravesical tumor. PMID- 7832085 TI - [Clinical study on torsion of appendix in intrascrotal organ]. AB - We reviewed 12 cases of torsion of appendix in the intrascrotal organ treated surgically and discussed its clinical features. An accurate diagnosis could be made in 5 of the 12 patients before operation because they had a palpable localized tender nodule at the affected area, but not in the other 7 patients because their whole scrotal contents had become swollen with time. The histological study on 6 patients with testicular swelling revealed their spermatogenesis intact. Therefore, we believe that torsion of the appendix in the intrascrotal organ has little influence on future fertility, and thus, correct preoperative diagnosis may diminish the necessity for surgical treatment. PMID- 7832087 TI - Dental volunteers for Israel. PMID- 7832086 TI - [Clinical analysis of methicillin-resistant Staphylococcus aureus (MRSA) infection]. AB - In 14 patients from which methicillin-resistant Staphylococcus aureus (MRSA) was isolated at the Department of Urology, Tone Chuo Hospital June, 1992 and October, 1993, the site of infection, background of patients, and drug resistance were analyzed. The 14 patients consisted of 11 males and 3 females between 45 and 85 years old with a mean of 71.6 years. The site from which MRSA was isolated was urine in 11, wound in 2, nasal cavity in 1, pharynx in 1, and renal fistula in 1 (detected at 2 or more sites in 2). The underlying condition was prostate hyperplasia in 2, prostate cancer in 4 (after radical prostatectomy in 1, complicated by bladder stone in 1), bladder tumor in 3, (during bladder instillation of BCG in 1), perirenal abscess in 2, renal pelvic tumor in 1, neurogenic bladder in 1, and after Boari's operation in 1. Urethral catheterization had been performed in 3. A fewer of 38 degrees C or above was noted in 3. Mixed infection was observed in 10, and was caused by Escherichia coli in 2, Proteus mirabiris in 1, Candida in 1, Klebsiella in 2, Pseudomonas aeruginosa in 2, and Serratia in 2. Four patients has previously been administered antibiotics, which were third generation cephems in 3 and penicillin in 1. The drug sensitivity was 100% for vancomycin (VCM), 30% for imipenam (IMP), 31% for minomycin (MINO), 31% for amikacin (AMK), and 7% for fosfomycin (FOM). As for chemotherapy, VCM+FOM+sulbactam/cefoperazone were administered to 6, and ceftazidime+ MINO were administered to 1.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7832088 TI - The adjustable soft palate lifter. PMID- 7832090 TI - "The old will be renewed and the new will be blessed"--is this true in prosthodontics as well? PMID- 7832089 TI - Pre-implantological oral guided bone regeneration. PMID- 7832091 TI - Myocardial neutrophil infiltration, lipid peroxidation, and antioxidant activity after coronary artery thrombosis and thrombolysis. AB - Neutrophil accumulation and free radical release are implicated in the genesis of reperfusion injury. However, little is known about the changes in myocardial lipid peroxidation and antioxidant activity in relation to coronary artery thrombosis and thrombolysis. To investigate this issue, 18 dogs with electrically induced occlusive thrombus in the left anterior descending (LAD) coronary artery were given tissue-type plasminogen activator (TPA). Sustained reflow (lasting > 120 min) occurred in 4 dogs, reocclusion after initial thrombolysis (transient reflow, duration of reflow 5 to 25 min) occurred in 7 dogs, and no reperfusion was evident in 7 dogs. Myocardial neutrophil infiltration was determined by measuring myeloperoxidase (MPO) activity, lipid peroxidation by malondialdehyde (MDA) levels and antioxidant activity by superoxide dismutase (SOD) activity in the myocardial regions supplied by the nonischemic left circumflex (Cx) and the ischemic LAD coronary arteries. In dogs with ischemia alone (no reperfusion), MPO activity and MDA levels in the LAD-supplied myocardium were modestly higher and SOD activity modestly lower than in the corresponding Cx-supplied myocardium. In dogs with sustained reperfusion there was a marked increase in MPO and MDA and a marked reduction in SOD activity in the reperfused myocardium. The MPO and MDA values in the myocardium of dogs with transient reperfusion, although much higher than the corresponding normal myocardial values, were less marked than in the myocardium of dogs with sustained reperfusion, and the SOD activity was preserved in the transiently reperfused regions. Myocardial shortening fraction in the LAD region was worse in dogs with sustained reperfusion than in those with sustained ischemia or transient reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7832092 TI - Doppler guide wire flow-velocity indexes measured distal to coronary stenoses associated with reversible thallium perfusion defects. AB - A Doppler guide wire was used to measure phasic coronary blood flow velocity distal to coronary stenoses in 17 symptomatic patients with corresponding positive exercise or adenosine thallium scintigrams. Distal average peak velocity and diastolic/systolic flow-velocity ratio were obtained in 16 vessels with stenoses (55% to 85% diameter stenosis) and a corresponding reversible thallium defect and in 11 control vessels with no stenosis or thallium defect. Coronary flow-velocity reserve was obtained with intracoronary adenosine. Coronary flow reserve (2.3 +/- 0.4 vs 1.2 +/- 0.3, p < 0.01) and diastolic/systolic flow velocity ratio (1.95 +/- 0.56 vs 1.44 +/- 0.59, p < 0.04) were significantly different between normal vessels and distal to stenoses, respectively. Excellent concordance between distal coronary flow reserve and diastolic/systolic flow velocity ratio to thallium scintigraphy was noted. A coronary flow reserve of < 1.8 and a diastolic/systolic flow-velocity ratio of < 1.7 predicted a reversible thallium perfusion scintigram (concordance 96% and 88%, respectively). Distal coronary flow velocity indexes may provide an alternative means of physiologic assessment of lesion severity during coronary angiography. PMID- 7832093 TI - Postexercise systolic blood pressure response: association with the presence and extent of perfusion abnormalities on thallium-201 scintigraphy. AB - We sought to determine whether the 3-minute postexercise systolic blood pressure response (SBPR) would be an indicator of a greater extent of hypoperfusion on quantitative thallium-201 scintigraphy. Previous studies have suggested that the 3-minute postexercise SBPR, defined as the ratio of the systolic blood pressure measured 3 minutes after exercise to the systolic blood pressure at peak exercise, is an ischemic response to exercise that indicates both the presence and extent of coronary artery disease. We prospectively studied the myocardial perfusion imaging correlates of the 3-minute postexercise SBPR in 133 patients referred for symptom-limited exercise testing and quantitative thallium-201 scintigraphy. The mean 3-minute postexercise SBPR was 0.85 +/- 0.14 in patients with normal scans compared to 0.91 +/- 0.14 in patients with redistribution defects (p = 0.04) and 0.92 +/- 0.17 in patients with persistent defects (p = 0.02). Patients with > 3 abnormal scan segments had significantly higher 3-minute postexercise SBPR values compared to patients with < or = 3 abnormal scan segments (p = 0.0005). Multiple linear regression evaluating the 3-minute postexercise SBPR, exercise-induced ST depression, and the level of exercise in metabolic equivalents indicated an association only between the 3-minute postexercise SBPR and the number of abnormal scan segments (p = 0.0004). An abnormal 3-minute postexercise SBPR is reflective of myocardial perfusion abnormalities, comprising regions of ischemia and scar. Higher values of the 3 minute post-exercise SBPR are associated with greater degrees of myocardial hypoperfusion. PMID- 7832094 TI - Serum glycoproteins and severity of coronary atherosclerosis. AB - The relation of serum glycoproteins and C-reactive protein (CRP) to severity of coronary atherosclerosis was examined in 133 men and 92 women undergoing coronary angiography. The following serum glycoproteins were determined: alpha 1 antitrypsin, alpha 1-acid glycoprotein, alpha 2-macroglobulin, ceruloplasmin, haptoglobin, fibrinogen, C4b binding protein, and lipoprotein (a) [Lp(a)]. Sex- and age-adjusted levels of alpha 1-antitrypsin, alpha 1-acid glycoproteins, alpha 2-macroglobulin, ceruloplasmin, Lp(a) and CRP were significantly associated with the severity of coronary atherosclerosis as determined by the Gensini score; these associations remained significant even after adjustment for body-mass index, smoking history, hypertension, and total cholesterol, except for Lp(a) (p = 0.075). These findings suggest that certain serum glycoproteins and CRP can serve as independent indicators for the progression of coronary atherosclerosis. PMID- 7832095 TI - The time course and relation of positive signal-averaged electrocardiograms by time-domain and spectral temporal mapping analyses after infarction. AB - We evaluated the time course of development of positive signal-averaged electrocardiograms (SA-ECGs) by time-domain and Spectral Temporal Mapping (STM) analyses after myocardial infarction in 88 patients without bundle branch block. The incidence of positive SA-ECGs by time-domain analysis peaked at 4 to 8 weeks postinfarction whereas the peak incidence by STM analysis varied from 4 days to 4 to 10 months postinfarction. Positive time-domain SA-ECGs demonstrated a significantly reduced factor of normality (NF) compared with negative time-domain SA-ECGs by X, Z, or vector STM analyses, but marked overlap was present for the standard deviations of positive and negative SA-ECGs in all STM leads. Chi square analysis demonstrated a significant correlation only between X-lead STM analysis and time-domain analysis; however, the two methods were markedly discordant. Although there is a statistically significant relation between time-domain and STM analyses of SA-ECGs, the two analyses are not clinically interchangeable. PMID- 7832096 TI - A new transvenous internal cardioverter-defibrillator: implantation technique, complications, and short-term follow-up. AB - Twenty-four patients with ventricular fibrillation or sustained ventricular tachycardia underwent implantation of a new transvenous defibrillator. All patients had a device implanted without thoracotomy. High placement of a shock lead in the anonymous vein and inversion of the shock-wave polarity allowed avoidance of placement of subcutaneous patches. Implantation time decreased from 138 minutes for the first 12 patients to 82 minutes for the last 12 patients, with 4 and 11 subpectoral pockets, respectively. Three patients required a minor reintervention. No bleeding or infection occurred. One episode of pulmonary edema and one pulmonary embolism were seen in the postoperative course. No postoperative deaths were observed. During a mean follow-up period of 4.12 months, 58% of the 24 patients had symptomatic arrhythmic episodes, with shocks in 50% of the 24. Inappropriate shocks were delivered in three cases (atrial fibrillation and T-wave sensing). One episode was not terminated even with four internal shocks. One patient had ventricular fibrillation because of a sensing problem. By reprogramming of sensitivity, back-up pacing, and adjustment of drug therapy these arrhythmic complications could be prevented. Pectoral implantation of a cardioverter-defibrillator is easy and can be performed by cardiologists experienced in pacemaker implantation. Careful postoperative observation, reprogramming after the first spontaneous event, and prehospital discharge induction of ventricular fibrillation will prevent arrhythmic complications. PMID- 7832097 TI - Cardioverter-defibrillator implantation in the catheterization laboratory: initial experiences in 48 patients. AB - The exponential increase in cardioverter-defibrillator implantations has resulted in a need for safe implantations that do not require long waiting periods. We report intraoperative and follow-up results in 48 patients with ventricular tachyarrhythmias who underwent cardioverter-defibrillator implantation in the catheterization laboratory. Twenty-six (54%) patients had their first cardioverter-defibrillator implant (group 1), and 22 (46%) patients underwent pulse-generator replacement (group 2). In all patients, cardioverter defibrillator implant or pulse-generator replacement was performed with the patient under general anesthesia. In 25 (96%) of 26 patients in group 1, cardioverter-defibrillator implantation was possible with a mean defibrillation threshold of 13 +/- 8 J. One patient had a defibrillation threshold of > 25 J, and therefore cardioverter-defibrillator implant was not achieved. This patient underwent epicardial device implantation 1 day later. Another patient in group 1 had vessel rupture (vena subclavia) intraoperatively. During a mean follow-up of 2 +/- 1 months, two patients died from congestive heart failure 2 and 4 months after device implantation. An infection occurred in one patient in group 2, 3 months after generator replacement. In conclusion, these data show that in the majority of patients cardioverter-defibrillator implantation in the catheterization laboratory is safe and has a low complication rate and therefore can generally be recommended. PMID- 7832098 TI - Electrocardiographic pseudo-infarct patterns after implantation of cardioverter defibrillators. AB - Postoperative electrocardiographic (ECG) changes are frequently present after insertion of implantable cardioverter-defibrillators (ICD) and may mimic perioperative myocardial infarction (MI). The purpose of this study was to assess the incidence and clinical significance of postoperative ECG changes in relation to clinical, laboratory, and implantation data. In 25 (16%) of 156 patients undergoing ICD implantation, significant ECG changes (> or = 50% reduction in R wave amplitude in > or = 3 leads or new Q waves in > or = 2 leads) were present 1 to 3 days after the operation and persisted at hospital discharge in 12 (8%). Presence of thoracotomy, the total number of induced ventricular fibrillation episodes, and the number of defibrillation shocks required during defibrillation threshold (DFT) testing correlated with postoperative ECG changes. Other factors associated with a significant R-wave loss in the lateral precordial leads included left-sided pleural effusion, lung infiltrates or atelectasis, and large defibrillator patch electrodes over the left ventricle or the lateral chest wall. Myocardial necrosis documented by elevated cardiac enzymes occurred in 6 (5%) of 151 patients without significant ECG changes and in 3 (12%) with (p value not significant). However, postoperative ECG changes associated with elevated enzymes were indistinguishable from changes unrelated to necrosis. Therefore the sensitivity and specificity of the surface ECG for detection of MI after ICD placement is poor. Multiple factors such as thoracotomy, myocardial injury from DFT testing, electric insulation, or shielding of the heart may contribute to the development of electrocardiographic pseudo-infarct patterns. PMID- 7832099 TI - Cardiac conduction system involvement in sudden death of obese young people. AB - Involvement of the conduction system in the sudden death of obese young people has not been documented in the literature. We therefore studied the conduction system by serial section examination in 7 subjects, 5 obese and 2 mild to moderately obese, who died suddenly at ages 6, 11, 14, 16, 20, 30, and 32 years of age (5 males, 4 black and 1 white; two females, 1 black and 1 white). Three had a history of sleep apnea. The heart was hypertrophied and enlarged in 6; all 6 had a distinct ventricular septal bulge and epicardial coronary arteries were normal. All had focal mononuclear cells in and around the sinoatrial node and/or its approaches, with marked fat throughout the conduction system in 3, fibrosis of the atrioventricular (AV) bundle and/or the left bundle branch in 5, and the branching bundle sandwiched between the bulbar muscle and the summit of the ventricular septum in 5 (2 with left-sided bundle, 1 with loop formation, and 1 with a markedly fragmented bundle). The AV node was partly within the central fibrous body and/or the atrial septum in 6 patients; focal mononuclear cells were present to a varying degree, with focal fibrosis of the ventricular septum in 6 patients, arteriolosclerosis in 4, and myocardial disarray in 3. The mild to moderately obese patients demonstrated lesser amounts of fat with more fibrosis when compared with the markedly obese. In summary, there are significant pathologic findings in the conduction system in the sudden death of obese young people.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7832100 TI - Relation of left atrial V-wave/left ventricular systolic pressure ratio to mitral regurgitant volume. AB - Evaluation of mitral regurgitation is difficult whether invasive or noninvasive methods are used. The determination of the regurgitant volume itself cannot be done in clinical practice with reasonable accuracy. In six sheep with chronic mitral regurgitation, left ventricular and left atrial pressures were recorded with high-fidelity catheters. The regurgitant volume was measured directly with electromagnetic flow probes positioned at the mitral annulus and around the ascending aorta, balanced against each other. A total of 24 hemodynamic states were obtained varying preload and afterload by fluid expansion and angiotensin infusion. On the basis of these studies, the pressure ratio of the V wave divided by the left ventricular systolic pressure is proposed as an index of regurgitant volume. A good correlation was found between this ratio and the regurgitant volume (r = 0.75). The ratio is easily recorded during routine heart catheterization. PMID- 7832101 TI - Effects of passive tilt and submaximal exercise on spectral heart rate variability in ventricular fibrillation patients without significant structural heart disease. AB - It has been shown that tilt and exercise elicit significant changes in autonomic activity in normal subjects and that submaximal exercise causes a greater reduction in heart rate variability (HRV) in animals susceptible to ventricular fibrillation (VF). Whether there is an abnormal HRV response to tilt and exercise in patients at risk of sudden cardiac death (SCD) remains unknown. Short-term HRV before and during passive tilt and exercise was studied in 12 survivors of out-of hospital cardiac arrest with documented VF and compared with 12 age- and sex matched normal controls. No patient had significant structural heart disease or left ventricular dysfunction. HRV was computed as total-frequency (TF, 0.01 to 1.00 Hz), low-frequency (LF, 0.04 to 0.15 Hz) and high-frequency (HF, 0.15 to 0.40 Hz) components. There was no significant difference between normal controls and SCD survivors in HRV before or during tilt or submaximal exercise testing. The HF component was significantly decreased during tilt compared with that in the supine position in both normal controls (5.85 +/- 0.61 vs 5.08 +/- 0.95 In(msec2), p = 0.005) and patients (5.58 +/- 1.49 versus 4.74 +/- 1.18 In(msec2), p = 0.003). There was again no significant change in the TF or LF components during tilt in either patients or controls. All frequency components were significantly decreased during submaximal exercise testing in both patients and controls. However, there was no significant difference in any of these tilt- and exercise-induced changes in HRV between normal controls and SCD survivors.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7832102 TI - Intraventricular dispersion of early diastolic filling: a new marker of left ventricular diastolic dysfunction. AB - Mitral flow velocity patterns are frequently "normalized" by the alteration in the loading condition even in the presence of left ventricular (LV) diastolic dysfunction. In addition, a simple index, the ratio of mitral peak early diastolic flow velocity to mitral peak flow velocity at atrial contraction, is not obtainable in patients with atrial fibrillation (Af). Thus these limitations hamper the value of analyzing the mitral flow velocity pattern in the assessment of abnormal LV diastolic characteristics. This study was designed to elucidate the hypothesis that peak early diastolic flow velocity decreases progressively from the base to the apex in patients with LV diastolic dysfunction. Regional diastolic flow velocity patterns at 1, 2, or 3 cm from the mitral tip toward the apex were simultaneously recorded with the mitral flow velocity pattern by using multigate pulsed Doppler echocardiography in 42 subjects with normal LV function (31 normal volunteers and 11 patients with Af only), 17 patients with hypertensive heart disease, and 22 patients with dilated cardiomyopathy. In the normal subjects early diastolic flow velocity at the mitral tip was maintained at the positions 1 to 3 cm away from the tip into the LV cavity. In contrast, regional peak early diastolic flow velocity progressively decreased toward the apex in patients with hypertensive heart disease and dilated cardiomyopathy. These findings were observed even in patients with a normalized mitral flow velocity pattern or those with Af. Thus the assessment of the intraventricular decrease in peak early diastolic flow velocity may be useful in detecting LV diastolic dysfunction, particularly in patients with Af or a "normalized" mitral flow velocity pattern. PMID- 7832103 TI - Application of quantitative coronary angiography in a cineless environment: in vivo assessment of a fully automated system for clinical use. AB - The accuracy and precision of a fully automated quantitative coronary angiography (QCA) algorithm for use in a cineless environment were determined in phantom studies and in an in vivo canine preparation. Imaging studies of 118 coronary segments in six anesthetized dogs were compared with measurements of the diameters of casts of the canine coronary arteries produced in physiologic conditions. Regression analysis of phantom vessel diameters against QCA measurements revealed slopes of 0.94 to 0.96 and r values > 0.99. The results of the in vivo studies showed good correlation with the coronary cast diameter measurements, with a slope of 0.969 and an r value of 0.987 for the sets of measurements. The high degree of accuracy obtained in a model representative of the clinical situation demonstrates that QCA methods can be applied reliably in the clinical arena with current digital imaging technology and without cinefilm. PMID- 7832104 TI - Rest technetium 99m-sestamibi tomoscintigraphy in hibernating myocardium. AB - The myocardial uptake of rest-injected technetium 99m sestamibi on single-photon emission computed tomographic images was assessed in 25 patients. All had an area of myocardial dysfunction that could be related to a coronary artery stenosis. None of the patients had clinical evidence of a myocardial infarction. Three months after revascularization, viability was demonstrated by contrast angiography and center-line analysis in 21 (78%) of the 27 formerly hibernating territories. Among these, none had a transmural defect, and 38% had a normal technetium 99m-sestamibi uptake. The four transmural preoperative defects were located in territories without viability. Eight of the 9 territories that were normal at scintigraphy proved to be viable postoperatively. It is concluded that as long as some residual technetium 99m-sestamibi uptake is present, viable myocardium is also present. PMID- 7832105 TI - Anatomic explanation of mobile systolic clicks: implications for the clinical and echocardiographic diagnosis of mitral valve prolapse. AB - An echocardiogram (echo) is often ordered for suspected mitral valve prolapse (MVP). Using echo as the gold standard, we conducted a meticulous physical examination on 61 patients with this referral diagnosis. Ninety percent of patients with negative physical examination and echo results for MVP had physical examination findings likely to have been misinterpreted as MVP by the referring physician. Redundant portions of the mitral valve apparatus were found in 57% of patients with MVP on our physical examination but not on echo. A carefully performed physical examination (including dynamic auscultation) can exclude MVP. Not all mobile systolic clicks are associated with anatomic echo prolapse; they can be generated by redundant chordae tendineae and, in the absence of echo prolapse, probably by redundant leaflets. Patients with mobile systolic clicks should have an echo to determine the portion of the spectrum of echo prolapse present and to determine risk stratification and management. PMID- 7832106 TI - Thallium-201 lung uptake and peak treadmill exercise first-pass ejection fraction. AB - Increased thallium-201 lung uptake immediately after exercise has been shown (1) to be a marker for extensive coronary artery disease, (2) to correlate with low rest and exercise left ventricular ejection fraction by supine gated blood pool scintigraphy, and (3) to be a powerful independent predictor of future cardiac events. Exercise left ventricular ejection fraction measured during upright exercise by the first-pass technique has also been shown to be a powerful independent prognostic variable. Combined perfusion and exercise left ventricular ejection fraction can be acquired by using the technetium 99m-based myocardial perfusion agents and offers an alternative protocol to stress/redistribution thallium imaging. It is therefore clinically important to understand the relation between exercise lung heart thallium uptake and exercise left ventricular ejection fraction. Accordingly, both these measurements were acquired in 38 patients with documented coronary artery disease who underwent two treadmill exercise studies. Parameters obtained from the first-pass study that are known to affect lung thallium uptake were correlated with exercise lung/heart thallium ratios; lung/heart ratios were used in a model to predict exercise left ventricular ejection fraction values. Exercise left ventricular ejection fraction and peak filling rate showed significant negative correlations with thallium lung/heart ratio, but the first-pass variables examined were not independently predictive of thallium lung uptake. The chance of finding an abnormal thallium lung/heart ratio at exercise LVEF of 40% is only 52%, whereas the chance of finding an abnormal ratio at exercise LVEF of 30% is 74%.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7832107 TI - Effects of dobutamine on myocardial blood flow, contractile function, and bioenergetic responses distal to coronary stenosis: implications with regard to dobutamine stress testing. AB - To determine the effects of dobutamine stimulation on myocardium distal to a coronary stenosis, transmural spatially localized phosphorus 31 nuclear magnetic resonance measurements of myocardial high-energy phosphate compounds (adenosine triphosphate and phosphocreatine), inorganic phosphate, and blood flow and systolic wall thickening were made in 8 open-chested dogs. Data were collected under (1) control conditions, (2) after the application of a moderate coronary stenosis, (3) during infusion of dobutamine with continuing stenosis, and (4) after the release of the stenosis with continuing dobutamine. Stenosis was associated with concordant reductions of subendocardial blood flow, wall thickening, and high-energy phosphate, and mild elevation of inorganic phosphate; subepicardial measurements were essentially unchanged. During dobutamine infusion, blood flow increased in all myocardial layers. Wall thickening returned to control values in the subendocardium and increased nonsignificantly in the subepicardium. Additional loss of high-energy phosphate occurred only in the subepicardium. The data suggest that improved contractile function associated with dobutamine infusion resulted from the inotropic effects of dobutamine and was made possible by the improved blood flow it produced. The data indicate that measurements of blood flow and contractile function do not reliably predict the transmural myocardial metabolic responses to inotropic perturbations in the hypoperfused heart. Taken together, the present findings yield insights with regard to the interpretation of diagnostic dobutamine stimulation testing with single photon emission tomography, radionuclide angiography, and echocardiography. PMID- 7832108 TI - Electrophysiologic effects of antiarrhythmic drug therapy in the prediction of successful suppression of induced ventricular tachycardia. AB - Predictors of a successful outcome of serial electrophysiologic (EP) and drug studies have been identified from among baseline patient characteristics but not from among measures of baseline and drug-related EP effects. Identifying such predictors would be useful in explaining the mechanism of successful drug therapy and in guiding drug development and selection. We prospectively studied EP characteristics in 159 trials in 62 patients with ventricular tachycardia or ventricular fibrillation during antiarrhythmic therapy and compared EP measures between successful (n = 30) and failed trials (n = 129). The average age of the patients was 64 years (range 27 to 78 years); 82% were men and 18% women; and 87% had coronary artery disease. Measurements included R-R, QRS, and QT intervals during intrinsic rhythm and during pacing at cycle lengths of 600 of 400 msec; ventricular effective refractory periods (ERP) during pacing at cycle lengths of 600 and 400 msec; and changes in these measures, comparing treatment with drug free baseline. Univariate predictors of success (in order of significance) included ERP600/QRS600, sotalol versus other drugs, ERP400/QRS400, delta ERP600, delta R-R, ERP600, QRS400 (negative association), delta ERP400, QRS600 (negative association), ERP400 (all p < 0.1). In two separate multivariate models, one for each drive cycle length, only the ratio ERP600/QRS600 (p = 0.01) in the first model and ERP400/QRS400 (p = 0.01) in the second model were significantly and independently associated with achieving noninducibility with drug therapy. Therefore measures of greater refractoriness and lesser delays in conduction velocity (ie, greater "wavelength") relate to drug success.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7832109 TI - Left main coronary artery disease: assessment, diagnosis, and therapy. AB - This article reviews and updates the current literature concerning the assessment, diagnosis, and therapy of coronary disease involving the LMCA. Included is recent information regarding the natural history, congenital abnormalities, noninvasive diagnostic studies, and role of coronary bypass surgery and percutaneous coronary interventions in treating disease of the LMCA. At present, it remains that the LMCA is a difficult segment to assess angiographically. The use of noninvasive imaging does not specifically distinguish LMCA from other types of coronary disease. Coronary bypass surgery has a proven benefit in the treatment of disease of the LMCA. Currently, interventional procedures are limited by significant risks, and surgical treatment with coronary bypass surgery remains the therapy of choice. PMID- 7832110 TI - Controlled-release drug delivery systems in cardiovascular medicine. AB - Controlled-release drug delivery technology has had a significant effect on the pharmacotherapy of cardiovascular diseases. Oral and transcutaneous controlled release systems allow relatively short-acting drugs to be administered once or twice daily with comparable therapeutic efficacy and fewer adverse reactions compared with standard formulations. They can provide decreased fluctuations in drug concentrations in plasma while possibly reducing the total amount of drug necessary for a clinical response. Techniques include the diffusion, bioerosion or degradation, and generation of osmotic pressure in orally active and transcutaneous drug delivery systems. Calcium-channel blocking agents, nitrates, beta-blocking agents, antiarrhythmic agents, clonidine, and nicotinic acid can be administered by these techniques, which have greatly influenced the application of these drugs in clinical practice. PMID- 7832111 TI - Assessment of valvular heart disease by magnetic resonance imaging. AB - MRI has developed very rapidly and now provides anatomic and functional information in cases of valvular heart disease. MRI has several important attributes that make it advantageous for the evaluation of valvular heart disease. First, the natural contrast between flowing blood and surrounding cardiovascular structures provides sharp delineation of endocardial and epicardial borders without the need for contrast media. This feature in combination with the essential three-dimensional nature of this imaging technique allows precise quantification of cardiac volumes, function, and mass without the use of any assumed formulas or geometric models. Second, blood flow-sensitive GRE techniques are able to identify areas of turbulent flow caused by stenotic or regurgitant valves. With this technique regurgitant jets can be visualized and semiquantitative grading can be performed as with color Doppler. Third, recently developed velocity-encoded techniques permit measurements of blood flow velocities across stenotic native and prosthetic heart valves and retrograde flow caused by regurgitation. Moreover, the close interstudy reproducibility of measurements of cardiac dimensions and valvular regurgitation suggests a role in assessing the effect of therapeutic interventions. PMID- 7832112 TI - Endothelium, coronary vasodilation, and organic nitrates. AB - Recent investigations have suggested that the vascular endothelium is an active participant in the regulation of arterial tone and blood flow. In a state of health, the endothelium contributes to hemodynamic equilibrium; however, it rapidly becomes dysfunctional in hypercholesterolemia and diabetes mellitus or with exposure to the stress of hypertension or long-term smoking. Among the deficits observed during endothelial dysfunction is a reduction in the synthesis and release or an excessive degradation of EDRF. This potent vasorelaxant is derived from the amino acid L-arginine and has been characterized as NO or a closely related substance. EDRF relaxes vascular smooth muscle by activating guanylate cyclase. A deficiency in the activity of EDRF may be the mechanism of diminished coronary vasodilation in patients with ischemic heart disease. Organic nitrates, which are metabolized to NO or S-nitrosothiol at the cellular level, are often used in the management of myocardial ischemia; they also induce vasodilation by activating guanylate cyclase. The similarities between organic nitrates and endogenous EDRF and their interactions are discussed in this review. PMID- 7832113 TI - Temperature-guided radiofrequency catheter ablation of slow pathway in atrioventricular nodal reentrant tachycardia. PMID- 7832114 TI - Intermittent cyanosis from tricuspid obstruction resulting from aortic compression in hypertension. PMID- 7832115 TI - Surgical coronary angioplasty for left main vasospasm. PMID- 7832116 TI - Disappearance of systolic narrowing of a mural coronary artery after myocardial infarction. PMID- 7832117 TI - Intraventricular thrombus after cocaine-induced myocardial infarction. PMID- 7832118 TI - Thromboembolic complications in cardiac amyloidosis detected by transesophageal echocardiography. PMID- 7832119 TI - Cystic lymphangioma of the mediastinum. PMID- 7832120 TI - Reversibility of severe left ventricular dysfunction in patients with subarachnoid hemorrhage. PMID- 7832121 TI - Long-term evolution of right ventricular dysplasia-cardiomyopathy. The Heart Muscle Disease Study Group. PMID- 7832122 TI - Truncus arteriosus with double aortic arch: two-dimensional and color flow Doppler echocardiographic diagnosis. PMID- 7832123 TI - Angina caused by systolic compression of the left coronary artery as a result of pseudoaneurysm of the mitral-aortic intervalvular fibrosa. PMID- 7832124 TI - Familial occurrence of peripartum cardiomyopathy. PMID- 7832125 TI - Identification of viable myocardium with contrast echocardiography in patients with poor left ventricular systolic function caused by recent or remote myocardial infarction. AB - We hypothesized that viable myocardium can be identified in patients with poor left ventricular (LV) systolic function caused by recent or prior infarction using myocardial contrast echocardiography. Accordingly, 39 patients with reduced LV ejection fraction (range 0.10 to 0.40) and recent (n = 30) or remote (n = 9) myocardial infarction were studied. Echocardiography was performed at baseline and at 1 month to assess regional function (1 = normal, 5 = dyskinesia) in 12 segments/patient; the segments were also scored for contrast effect (1 = homogenous, 0.5 = partial, 0 = none) during contrast echocardiography performed in the cardiac catheterization laboratory. Four patients had unsuccessful angioplasty of occluded arteries and were treated medically, 9 were treated medically because of noncritical coronary stenoses (< 80%), and 26 underwent revascularization (16 angioplasty and 10 bypass operation). Twelve segments could not be visualized (2 each in 6 patients), and 30 segments continued to be subserved by totally occluded arteries because of unsuccessful angioplasty in 4 patients. Of the remaining 426 segments, 186 (44%) demonstrated baseline wall motion scores of > or = 3. The best correlate of 1-month wall motion score in these segments was the contrast score (p = -0.62), with better 1-month function noted in segments with more contrast. The overall perfusion status of LV myocardium also correlated (p = -0.59) with global LV systolic function at 1 month. We conclude that myocardial contrast echocardiography can be used during cardiac catheterization to define myocardial segments that are viable in patients with poor LV systolic function caused by recent or remote myocardial infarction. PMID- 7832126 TI - The utility of clinical, electrocardiographic, and roentgenographic variables in the prediction of left ventricular function. AB - To determine the clinical value of simple, widely available variables in estimating left ventricular (LV) function, we performed an analysis on 14,507 patients presenting with chest pain who were enrolled in the Coronary Artery Surgery Study registry. Of these patients, 4,034 had a normal electrocardiogram, and of these, 91.8% had an LV ejection fraction (EF) > 0.50, 7.6% had an EF of 0.36 to 0.50, and only 0.6% had an EF < or = 0.35. The presence of T-wave abnormalities (with normal QRS), left bundle branch block, electrocardiographic evidence of LV hypertrophy or myocardial infarction, cardiomegaly on chest roentgenogram, basilar rales, or third heart sound significantly decreased the likelihood of normal LVEF. Based on these clinical variables, a logistic regression model with a sensitivity of 68% and a specificity of 74% for identifying subjects with normal EF was developed. It was concluded that in patients with chest pain, consideration of such readily available clinical data provides useful information and may decrease the need for more expensive imaging methods. PMID- 7832127 TI - Relation between myocardial infarction site and pain location in Q-wave acute myocardial infarction. AB - Location, severity, duration, and time course of pain were assessed in 104 consecutive patients with either first or second, anterior or inferior Q-wave acute myocardial infarction (AMI). Pain severity was assessed using a visual analog scale. Pain location and radiation were similar in 48 patients with anterior and 56 patients with inferior wall AMI. Pain duration (6.1 +/- 6.4 vs 6.5 +/- 5.4 hours, p = NS) and severity (68 +/- 21 vs 61 +/- 21 mm, p = NS) were also similar. The pain was continuous in 34 patients with anterior (71%) and in 42 with inferior (75%) wall AMI. Among the 41 patients who did not receive thrombolytic therapy, 18 patients with continuous pain had a higher creatine kinase peak level than the remaining 23 patients with intermittent pain or preinfarction angina, or both (2,065 +/- 1,017 vs 1,162 +/- 994 IU, p < 0.01). The incidence of gastrointestinal symptoms was slightly higher in patients with inferior than anterior wall AMI (70% vs 48%, p < 0.05). Among 32 patients admitted with a second AMI, pain location was similar in 14 who had both infarcts in the same myocardial region, but was different in 12 of 18 (67%) who had a first and second infarct in different regions (p < 0.001). Thus, patients with anterior or inferior wall AMI experienced pain in similar body regions. However, in patients who presented with > 1 AMI, different locations of the infarction pain were highly predictive of ischemia occurring in different myocardial regions. Finally, patients with preinfarction angina or intermittent pain tended to have smaller infarcts. PMID- 7832128 TI - The degree of ST-segment depression on symptom-limited exercise testing: relation to the myocardial ischemic burden as determined by thallium-201 scintigraphy. AB - This study sought to determine the relation between the magnitude of exercise induced ST depression and the ischemic burden as determined by quantitative thallium-201 scintigraphy. One hundred forty-four consecutive patients were prospectively studied with symptom-limited exercise testing and thallium-201 scintigraphy. Of these patients, 37 had between 1.0 and < 2.0 mm (group 1) and 17 had > or = 2.0 mm (group 2) of exercise-induced ST depression. There were no significant differences between groups 1 and 2 with respect to all exercise parameters including peak exercise heart rate (134 +/- 21 vs 144 +/- 26 beats/min), metabolic equivalents achieved (7.9 +/- 3.0 vs 8.6 +/- 3.3), and exercise time (7.4 +/- 2.7 minutes in both groups). There was no significant difference in the prevalence of thallium-201 redistribution defects in group 1 versus group 2 patients (17 of 37 [46%] vs 8 of 17 [47%]), and in the extent of ischemia as determined by the number of redistribution defects per patient (1.2 +/- 1.8 vs 1.2 +/- 1.5, respectively). Thus, in this consecutive group of patients with exercise-induced ST depression, those with > or = 2.0 mm of ST depression, relative to patients with a lesser degree of ST depression, had comparable exercise capacity and comparable ischemic burden by thallium-201 scintigraphic assessment. We conclude that the magnitude of ST depression on symptom-limited exercise testing does not correlate with the extent of ischemia as assessed by quantitative thallium-201 scintigraphy. PMID- 7832129 TI - How do smokers differ from nonsmokers in their response to thrombolysis? (the TIMI-4 trial) AB - Smokers with acute myocardial infarction appear to have a better outcome after thrombolysis than do nonsmokers. To identify factors that could contribute to this curious finding, we analyzed data from the Thrombolysis in Myocardial Infarction (TIMI-4) trial, in which 382 patients with acute myocardial infarction were randomized to tissue plasminogen activator, anistreplase, or both. Coronary angiography was performed 90 minutes and 18 to 36 hours after randomization, a myocardial perfusion scan was performed at 18 to 36 hours and before discharge, and a radionuclide ventriculogram was obtained before discharge. Angiographic and clinical outcome variables were determined in current smokers, ex-smokers, and nonsmokers, and regression analysis was used to correct for differences in baseline characteristics. The in-hospital mortality of current smokers was lower than that of ex-smokers and nonsmokers: 2.3% versus 5.2% versus 7.0%, respectively (p = 0.04 by paired comparison, current vs nonsmokers). Ninety minutes after randomization, the incidence of TIMI grade 3 flow was significantly higher in smokers than in ex-smokers and nonsmokers (55% vs 43% and 45%, p = 0.02); this difference was no longer observed at the second angiogram, nor did smokers differ from nonsmokers with respect to residual stenosis, thrombus grade, infarct size, ejection fraction, or recurrent ischemia. Because a strong inverse relation exists between TIMI grade 3 flow at 90 minutes and mortality, our findings suggest that the lower mortality of current smokers after thrombolytic therapy may be related to a higher incidence of early, complete reperfusion. PMID- 7832130 TI - Effectiveness of percutaneous transluminal coronary angioplasty for patients with medically refractory rest angina pectoris and high risk of adverse outcomes with coronary artery bypass grafting. AB - This study was undertaken to test the hypothesis that percutaneous transluminal coronary angioplasty (PTCA) is a reasonable alternative to coronary artery bypass grafting (CABG) for some high-risk patients with medically refractory rest angina. Over a 5-year period, 1 operator at a tertiary Veterans Affairs Medical Center performed angioplasty on 624 patients, of whom 441 had unstable angina. Of these 441 patients, 288 had rest angina and 225 had medically refractory rest angina. Medically refractory unstable angina was defined as reversible myocardial ischemia occurring at rest in an intensive care unit setting with low flow oxygen despite the following medications: (1) oral aspirin, intravenous heparin, or both; (2) some combination of beta blocker, calcium blocker, and/or nitrate so that resting heart rate is < 70 beats/min or resting blood pressure < 140 mm Hg, or both. There were 207 patients with medically refractory rest angina who had > or = 1 of the following characteristics predictive of a more than twofold increased risk of operative death at CABG: age > 70 years, prior CABG, recent myocardial infarct, need for intravenous nitroglycerin, need for intraaortic balloon pump, and left ventricular ejection fraction < 0.35. Of these 207 patients, 11 died (5%) during index hospitalization, 196 (95%) were discharged, and 186 (90%) went home angina free. There were 2 emergency CABGs and 9 acute myocardial infarctions. At follow-up (3 to 60 months, average 24), there were 27 late deaths (for a total of 38 [18%]), 8 (4%) late CABGs, and 44 (21%) late PTCAs (with 17 [8%] late myocardial infarctions). The 2-year mortality of 18% for this cohort is comparable to a 21% 2-year mortality observed in a group of 1,073 "high risk" patients who underwent CABG in the Veterans Affairs Medical Center from 1987 to 1988. These data support the hypothesis that PTCA provides an alternative to CABG in some high-risk patients with medically refractory rest angina. PMID- 7832131 TI - Effect of epinephrine infusion on chest pain in syndrome X in the absence of signs of myocardial ischemia. AB - Eight female patients (aged 51 to 65 years) with New York Heart Association class II angina pectoris, normal coronary angiograms, normal hyperventilation, and abnormal exercise stress tests (chest pain and ST depression), and 5 sex- and age matched controls participated in this study. Epinephrine was given intravenously to both patients and controls at 5-minute intervals in doses of 0.1, 0.2, 0.3, 0.4, and 0.6 nmol/kg/min. After rest (15 minutes), the alpha-adrenoceptor antagonist phentolamine or placebo was administered intravenously to patients in a double-blind, crossover study on 2 separate occasions in doses of 250 micrograms/min for 5 minutes and 500 micrograms/min for the next 10 minutes; the epinephrine infusion was repeated. Blood pressure, heart rate, and electrocardiogram were monitored continuously and pain was estimated on the Borg CR-10 scale. On a third occasion, chest pain was induced in patients using the same epinephrine protocol during echocardiographic monitoring. In the control group, all patients received the maximal epinephrine dose. No chest discomfort or pain developed. In the patient group, the maximal tolerable epinephrine dose (0.39 +/- 0.19 nmol/kg/min) decreased diastolic pressure (-14 +/- 9 mm Hg, p < 0.01) and increased heart rate (+24 +/- 10 beats/min, p < 0.01), not statistically different from the control group. Pulse pressure increased in the patient group (27 +/- 17 mm Hg, p < 0.01) but not in the controls. Left ventricular ejection fraction at baseline was within reference limits (58% to 75%) and did not change during epinephrine infusion.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7832133 TI - Relevance of asystole during head-up tilt testing. AB - The prognosis of patients manifesting prolonged asystole during head-up tilt testing is unclear. In 209 consecutive patients with a history of syncope and positive head-up tilt tests, 19 had asystole lasting > 5 seconds (mean duration 15 +/- 10) (group 1a). When compared with patients without asystole (group 1b), group 1a patients were younger (32 +/- 12 vs 47 +/- 21 years, p < 0.005), but clinical manifestations were not any more dramatic (the number of episodes of syncope [7 +/- 5 vs 8 +/- 6 episodes, p = NS] and injury during syncope [2 vs 13 patients, p = NS] were similar). During follow-up (mean 2 +/- 1 year), with the patient taking pharmacologic therapy such as beta blockers, ephedrine, theophylline, or disopyramide, the recurrence rate was 11% and 8% in groups 1a and 1b (p = NS). No patient in the asystole group underwent pacemaker implantation. Additionally, of 75 normal volunteers (group 2) with no history of syncope undergoing tilt tests to define its specificity, 3 had asystole (mean duration 10 seconds). During > 1 year of follow-up, despite no treatment, all 3 are symptom free. Thus, asystole during head-up tilt testing does not predict either a more malignant outcome or a poor response to pharmacologic therapy. Moreover, an asystolic response does not enhance the specificity of the head-up tilt test because it may be present in asymptomatic "normal" volunteers. PMID- 7832132 TI - Coronary microvascular response to intracoronary administration of nicorandil. AB - Nicorandil is an antianginal drug that causes potent coronary vasodilation of both epicardial and resistance vessels. To measure the dose-response kinetics of bolus injections of intracoronary nicorandil and to compare the vasodilatory response to nicorandil with that of intracoronary papaverine in humans, coronary blood flow velocity was measured in 30 patients using a 3Fr intravascular Doppler catheter. Continuous intravenous nitroglycerin 6 to 8 micrograms/min was infused to achieve maximal vasodilation of the epicardial vessels. Bolus doses of nicorandil dissolved in warmed saline solution were injected into the left (0.1, 0.2, 0.5, 1.0, 1.5, and 2.0 mg) and right (0.1, 0.2, 0.4, 0.8, 1.0, and 1.5 mg) coronary arteries. Intracoronary nicorandil caused a dose-dependent increase in coronary flow velocity and a decrease in coronary vascular resistance. Maximal vasodilatory effects equivalent to those obtained with 12 +/- 2 mg of intracoronary papaverine were induced with nicorandil 1.5 mg in the left coronary artery, and effects similar to those of 10 +/- 2 mg of papaverine were produced with nicorandil 1.0 mg in the right coronary artery. The time from injection of nicorandil to the onset of maximal hyperemia and duration of hyperemia were significantly shorter after nicorandil than after papaverine in both coronary arteries. Each dose of nicorandil produced no clinical symptoms and fewer changes in systemic hemodynamics and electrocardiographic QT intervals than did papaverine. These results suggest that a bolus administration of intracoronary nicorandil can safely, quickly, and reliably induce maximal coronary hyperemia comparable to that achieved with intracoronary papaverine in humans. PMID- 7832134 TI - Comparison of implantation of nonthoracotomy defibrillators in the operating room versus the electrophysiology laboratory. AB - Implantable cardioverter-defibrillators (ICDs) with nonthoracotomy lead systems are widely available, and are implanted either in the electrophysiology laboratory or the operating room. The purpose of this study was to prospectively evaluate the safety and efficacy of nonthoracotomy ICD implantation in an electrophysiology laboratory versus an operating room. During a 7-month period, 62 consecutive ICDs with nonthoracotomy lead systems were implanted in patients in an electrophysiology laboratory. During the next 10 months, 110 consecutive ICDs were implanted in patients in a surgical operating room. All ICD implantations were performed under general anesthesia by electrophysiologists. There were no differences in age (58 +/- 14 vs 62 +/- 12 years, p = 0.06), gender distribution (p = 0.3), frequency of structural heart disease (97% vs 97%, p = 0.9), ejection fraction (0.31 +/- 0.15 vs 0.29 +/- 0.13, p = 0.3), or presentation with cardiac arrest (65% vs 53%, p = 0.2) between patients undergoing ICD implantation in the electrophysiology laboratory and operating room, respectively. The rate of successful implantation and of complications for systems implanted in the electrophysiology laboratory (95% and 13%, respectively) and in the operating room (98% and 14%, respectively) were similar (p = 0.4 and p = 0.8, respectively). Specifically, the rate of infection (0% vs 4%, p = 0.3) and hematoma formation (2% vs 4%, p = 0.8) were not statistically significantly different. Three patients who had undergone ICD implantation in an operating room died within 30 days. ICDs with nonthoracotomy lead systems can be implanted with a similarly high rate of success and acceptable complication rate in the electrophysiology laboratory and in the operating room. PMID- 7832136 TI - Effects of estrogen replacement therapy on peripheral vasomotor function in postmenopausal women. AB - Hormone replacement therapy is associated with a reduction in cardiovascular events in postmenopausal women. We have recently found that acute 17 beta estradiol administration improves endothelium-dependent vasodilation in both the peripheral and coronary circulations of postmenopausal women. The current study was undertaken in 33 estrogen-deficient postmenopausal women (mean age 59 +/- 7 years) to determine if short-term estrogen replacement therapy also improves endothelium-dependent vasodilation in peripheral circulation. Acute intraarterial infusion of estradiol, which increased forearm venous estradiol levels from 16 +/ 11 to 345 +/- 202 pg/ml, potentiated forearm vasodilation induced by the endothelium-dependent vasodilator acetylcholine by 49 +/- 67% (p < 0.001). Acute estradiol also potentiated vasodilation induced by the endothelium-independent vasodilator nitroprusside by 5 +/- 31% (p = 0.04). However, after 3 weeks of transdermal estradiol administration (0.1 mg/day), which achieved an estradiol level of 120 +/- 57 pg/ml, the vasodilator responses to acetylcholine and to sodium nitroprusside were unchanged from initial measurements obtained before acute administration of estradiol. Repeat intraarterial infusion of estradiol in 8 women, while receiving transdermal estradiol, increased forearm venous estradiol levels to 268 +/- 105 pg/ml and again potentiated the vasodilator response to acetylcholine to a similar degree as that observed in the initial study after acute administration of estradiol. Thus, although acute intraarterial infusion of 17 beta-estradiol potentiates endothelium-dependent vasodilation in the forearms of postmenopausal women, this effect is not maintained with a 3-week cycle of systemic estradiol administration. The different effects of acute and chronic estradiol may be due to the lower plasma levels achieved with chronic estrogen administration. PMID- 7832135 TI - Effect of doxazosin or atenolol on exercise performance in physically active, hypertensive men. AB - The effects of doxazosin or atenolol on exercise capacity in 15 male distance runners (mean age +/- SD 43 +/- 10 years) were compared in a double-blind, crossover study. Subjects performed a maximal treadmill test and a timed 2-mile run before and after each drug treatment. Cardiac output was determined by acetylene rebreathing at rest and at 30%, 50%, and 75% of maximal oxygen consumption. Oxygen consumption was determined at the above-mentioned workloads and at maximal effort. Both drugs were titrated to produce similar reductions in blood pressure and the final doses of atenolol and doxazosin were 43 +/- 22 and 6 +/- 6 mg, respectively. Atenolol reduced cardiac output (p < 0.05) and heart rate (p < 0.001) at rest and at all exercise intensities compared with the prior placebo phase, whereas doxazosin increased cardiac output at rest and at 50% effort (p < 0.05). Consequently, cardiac output was higher (p < 0.01) with doxazosin than with atenolol at rest and at 30% and 50% effort. Heart rate was higher with doxazosin (p < 0.01) during all exercise workloads. Despite these changes in cardiovascular function, there were no significant differences between the effect of the 2 study drugs on maximal oxygen consumption or 2-mile run times. We conclude that atenolol decreases rest and exercise heart rate and cardiac output compared with doxazosin, but that at modest doses neither drug adversely affects exercise performance in male hypertensive runners. PMID- 7832137 TI - The wisdom of Sir William Osler. AB - William Osler (1849-1919) was generally regarded as the greatest and most respected physician of his time. He is still considered by many in these terms. Others have questioned the relevance of Osler's teachings in recent years. This paper describes Osler's life and gives his philosophy and views in his own words. An outstanding clinician who emphasized bedside teaching and observation, he possessed extraordinary charm that inspired many disciples. As Professor of Medicine at 4 institutions in 3 countries, he exerted a profound influence on medical education. He was a prolific writer and his textbook became the most popular and widely read treatise on medicine in the world. He also was a medical historian, a classical scholar, and an avid bibliophile. He emphasized the value of hard work and ongoing education. His comparison and concern for patients and colleagues reflected his personality. Osler's wisdom is as relevant now as in his era. It is likely that he would be in the forefront of medical science if he were alive today. Osler blended the art and science of medicine perhaps better than anyone else and remains a valuable role model for students and physicians more than 75 years after his death. PMID- 7832138 TI - Failure of cholesterol treatment in patients with coronary artery disease: a cost effective solution. PMID- 7832139 TI - Lifting the smoke-screen: the enigma of better outcome in smokers after myocardial infarction. PMID- 7832140 TI - Reduction of pacing-induced myocardial ischemia by intravenous magnesium sulfate. PMID- 7832141 TI - Gaseous coronary embolism as a cause of myocardial ischemia during coronary artery bypass grafting. PMID- 7832142 TI - The physiologic meaning of relative coronary flow reserve. PMID- 7832144 TI - Effects of isosorbide dinitrate and nicardipine hydrochloride on postprandial blood pressure in elderly patients with stable angina pectoris or healed myocardial infarction. PMID- 7832143 TI - Correlation of coronary stenosis by quantitative coronary arteriography with exercise echocardiography. PMID- 7832145 TI - Response of high-density lipoproteins to hypolipidemic drugs according to their initial level. PMID- 7832146 TI - Disparate effects of interleukin-3 on serum lipoprotein(a), and low- and high density lipoprotein cholesterol levels. PMID- 7832147 TI - Radiofrequency catheter ablation for control of frequent ventricular tachycardia with healed myocardial infarction. PMID- 7832148 TI - Compartmental analysis of norepinephrine kinetics in congestive heart failure. PMID- 7832149 TI - Safety of Inoue balloon mitral commissurotomy in patients with left atrial appendage thrombi. PMID- 7832150 TI - Prevalence of extracranial carotid arterial disease and of valvular aortic stenosis and their association in the elderly. PMID- 7832151 TI - Absence of cerebrovascular events in a prospective study of coronary artery bypass patients with atrial septal aneurysms taking aspirin. PMID- 7832152 TI - Echocardiographic characteristics of diaphragmatic hiatus hernia. PMID- 7832153 TI - Woven left coronary artery disease. PMID- 7832154 TI - Electrocardiographic abnormalities suggestive of myocardial ischemia during upper gastrointestinal bleeding. PMID- 7832155 TI - Which medical journals are most frequently copied in a hospital library? PMID- 7832156 TI - A look at SRR by DHS. PMID- 7832157 TI - Association of hiatus hernia with asplenia syndrome. PMID- 7832158 TI - The ineffectiveness of a commonly recommended diet for lowering total and low density lipoprotein cholesterol levels. PMID- 7832159 TI - Effect of caffeine on ambulatory blood pressure. PMID- 7832161 TI - The School Nutrition Dietary Assessment Study. PMID- 7832160 TI - Lipoprotein(a): friend or foe? PMID- 7832162 TI - The school nutrition dietary assessment study. PMID- 7832163 TI - Background of the School Nutrition Dietary Assessment Study. AB - The National School Lunch Program (NSLP) and the School Breakfast Program (SBP) are federally sponsored nutrition programs operating daily in the nation's schools. The School Nutrition Dietary Assessment Study had three primary objectives: 1) to describe the nutrient composition of NSLP lunches and SBP breakfasts as offered to students, 2) to analyze the dietary intakes of students, and 3) to compare the dietary intakes of program participants with nonparticipants. This paper describes the school nutrition programs, discusses current program issues and policy concerns, and provides an overview of the study objectives and papers included in this journal issue. PMID- 7832164 TI - School Nutrition Dietary Assessment Study: overview of the study design. AB - The School Nutrition Dietary Assessment Study collected information from a nationally representative sample of schools and a nationally representative sample of students attending these schools. A total of 545 schools provided information about all meals served during a 1-wk period between February and May 1992, as well as information about school food service operations. Approximately 3350 students in grades 1-12 provided detailed information about the foods and beverages that they consumed during a 24-hr period that included a school day. To assess the content of both the school meals offered to students and the meals consumed by students, the study used dietary standards from three sources: the recommended dietary allowances, the Dietary Guidelines for Americans, and recommendations of the National Research Council. PMID- 7832165 TI - Meals offered in the National School Lunch Program and the School Breakfast Program. AB - This paper presents findings from the School Nutrition Dietary Assessment Study on the meals offered to students under the National School Lunch Program (NSLP) and the School Breakfast Program (SBP). On average, NSLP lunches provide the program goal of at least one-third of the recommended dietary allowance (RDA) for most nutrients. The average amounts of total fat and saturated fat as a percentage of food energy in NSLP lunches, however, exceed the Dietary Guidelines' goals. The amount of sodium exceeds National Research Council (NRC) recommendations, but the amount of cholesterol is within the recommended range. With the exception of food energy, SBP breakfasts on average provide the program goal of at least one-fourth of the RDA. They are close to the Dietary Guidelines' goal for total fat, but exceed it for saturated fat. SBP breakfasts provide amounts of cholesterol that exceed the recommendations. PMID- 7832166 TI - Factors affecting the fat content of National School Lunch Program lunches. AB - An analysis of a week's menus from a nationally representative sample of 515 National School Lunch Program schools found that < 5% of schools offer lunches that provide a 5-d average close to the Dietary Guidelines recommendation for fat. This paper examines the factors associated with schools offering meals that, on average, provided different amounts of fat: low (< 32% of food energy from fat), moderate (32-35% fat), high (35-40% fat), and very high (> 40% fat). Schools in which NSLP lunches come close, on average, to meeting the Dietary Guidelines' goal for total fat follow several menu-planning, food-purchasing, and food-preparation practices to reduce the fat content of the school lunches. PMID- 7832167 TI - Dietary intakes of students. AB - This paper relies on 24-h dietary recall data from a nationally representative sample of approximately 3350 students to analyze the dietary intakes of students. Most US students eat at least five times during the day, and nearly all eat at least three times per day. The average daily intake of vitamins and minerals at least meets the recommended dietary allowances (RDAs). Overall, students consume more food energy on average than recommended, suggesting that some may be at risk of consuming more food energy than is optimal. Students also consume more protein, total fat, saturated fat, and sodium than is recommended for good health. National School Lunch Program (NSLP) participants' mean intakes of most nutrients at lunch meet the program goal of at least one-third of the RDA. NSLP participants, however, consume more fat, saturated fat, and sodium than is recommended. School Breakfast Program (SBP) participants' mean intakes of most nutrients at breakfast also exceed the program goal of one-fourth of the RDA. However, their breakfast intakes of saturated fat as a percentage of food energy, cholesterol, and sodium exceed dietary recommendations. PMID- 7832168 TI - Participation in the National School Lunch Program and the School Breakfast Program. AB - This paper uses student-level data from the School Nutrition Dietary Assessment Study to examine participation in the National School Lunch Program (NSLP) and the School Breakfast Program (SBP). Among students attending schools offering the relevant program, the NSLP participation rate is 56% and the SBP participation rate is 19%. Students who are certified for free or reduced-price meals are more likely than noncertified students to participate in either program. Among noncertified students, participation is negatively related to meal price. NSLP participation is less likely when the lunch offered contains < 32% of food energy from fat, suggesting that policies designed to drastically reduce the fat in NSLP lunches would also reduce participation. However, the fat content could be reduced somewhat below its current mean amount of 38% of food energy without affecting participation. Finally, the availability of the SBP does not appear to influence the likelihood of students eating breakfast. PMID- 7832169 TI - Dietary effects of the National School Lunch Program and the School Breakfast Program. AB - In this paper we use 24-h dietary recall data to assess the dietary effects of participation in the National School Lunch Program (NSLP) and the School Breakfast Program (SBP). After adjustment for differences in characteristics between NSLP participants and nonparticipants, NSLP participation is associated with higher lunch intakes of vitamin A, calcium, and magnesium, and a lower intake of vitamin C. Although mean intakes of other key dietary components such as food energy, iron, cholesterol, and sodium are higher for NSLP participants than for nonparticipants, these differences appear to be due to underlying differences in unobserved characteristics (eg, food preferences, appetites, or food energy needs) rather than to the NSLP. Both at lunch and over 24 h, NSLP participation is associated with consumption of a higher percentage of food energy from fat and saturated fat. SBP participation is associated with higher breakfast intakes of food energy, calcium, riboflavin, phosphorus, and magnesium, and with a higher percentage of breakfast food energy from fat and saturated fat, and a lower percentage of food energy from carbohydrate. PMID- 7832170 TI - Sources of nutrients in students' diets. AB - This paper describes foods consumed and nutrients derived from specific foods by participants and non-participants in the National School Lunch Program (NSLP) and the School Breakfast Program (SBP). Data are from 24-h dietary intake interviews with 3350 children in grades 1-12, collected as part of the School Nutrition Dietary Assessment Study. The meal-pattern requirements of the NSLP and SBP strongly influence what participants eat. NSLP participants are more likely than nonparticipants to consume milk, meats, grain mixtures, and vegetables, leading to higher intakes of fat and sodium, but also of calcium and vitamin A, and are less likely to consume cakes and cookies, soft drinks, and fruitades, which do not count toward program requirements. SBP participants are more likely than nonparticipants to consume milk and fruit juice, leading to higher intakes of calcium and magnesium, and are three times more likely to eat meat, leading to higher intakes of fat and sodium. Nonparticipants in the SBP obtain similar amounts of vitamins and minerals at breakfast but less food energy. PMID- 7832171 TI - Perspectives on the School Nutrition Dietary Assessment Study from the Child and Adolescent Trial for Cardiovascular Health. AB - The School Nutrition Dietary Assessment Study provides current data on the nutritional quality and adequacy of the National School Lunch Program (NSLP) and the School Breakfast Program (SBP) as well as on the dietary intakes of students participating in these programs. The study demonstrates that the NSLP and SBP meals and children's total diets do not conform to the recommendations of the US Department of Agriculture and the National Research Council and confirms the need to improve the nutritional quality of the nation's school meal program and student's overall dietary intakes. In this regard, the Child and Adolescent Trial for Cardiovascular Health (CATCH) is the first collaborative, school-based field trial that tests the effectiveness of a multi-level intervention designed to reduce the fat, saturated fat, and sodium content of school meals and student's diets. This commentary highlights the findings and questions raised by the School Nutrition Dietary Assessment Study and presents an overview of CATCH, including the implications and significant questions that can be addressed by this intervention study. PMID- 7832172 TI - Why school meals are high in fat and some suggested solutions. PMID- 7832173 TI - Commentary on school meals from school food service personnel and researchers. PMID- 7832174 TI - Commentary on who participates in the National School Lunch Program and the School Breakfast Program. PMID- 7832175 TI - The School Nutrition Dietary Assessment Study: summary and discussion. AB - This paper summarizes the key findings of the School Nutrition Dietary Assessment Study and discusses the implications for policy and practice in the National School Lunch Program (NSLP) and the School Breakfast Program (SBP). Reducing total fat offered in NSLP lunches to the amount set in the Dietary Guidelines, as called for in the proposed regulations published by the US Department of Agriculture in June 1994, would be facilitated by changing the legislative requirement to serve whole milk. In addition, the following menu choices and meal preparation methods would reduce considerably the amounts of fat in NSLP lunches: reducing the average meat serving from 2 to 1.5 oz; eliminating high-fat meats, high-fat cheese, nuts, and nut butters; eliminating high-fat desserts and milk based desserts; and reducing sharply the use of added fats in food preparation. PMID- 7832176 TI - Diagnostic conundrums in substance abusers with psychiatric symptoms: variables suggestive of dual diagnosis. AB - Patients with substance dependence and psychiatric symptoms often present a diagnostic conundrum because each of these problems may mutually and reciprocally complicate the other. This may challenge the ability to identify dual-diagnosis patients who have both a substance abuse disorder and a definitive symptom-based psychiatric disorder. The main purpose of this explorative study was to identify variables suggestive of dual diagnosis in the population of substance-dependent patients with psychiatric symptoms. A secondary purpose was to examine the subgroups in this population for their distinctiveness from one another. Based upon clinical experience and the literature, seven independent variables were hypothesized as suggestive of dual diagnosis. Seventy-nine patients with substance dependence and psychiatric symptoms of depression, anxiety, and/or psychosis were assessed for symptom and disorder status generating three subgroups: I) 20 patients with psychiatric symptoms not meeting thresholds for clinical significance; II) 36 patients exhibiting a psychiatric disorder (dual diagnosis); and III) 23 patients with psychiatric symptoms meeting thresholds for clinical significance but not for a disorder. Odds ratios were calculated to examine the risk for dual diagnosis using the seven independent variables. A persistent increased risk for dual diagnosis was observed in patients who were positive for the seven variables. The seven variables were combined into an overall measure of patients' risk for dual diagnosis. Mean scores were significantly different for the three groups F(2, 76) = 8.4, p < .001. This study indicates variables that may be suggestive of dual diagnosis and finds subgroup distinctiveness in this sample. Both of these findings have treatment implications. PMID- 7832177 TI - Correlates of cocaine/crack use among inner-city incarcerated adolescents. AB - Inner-city male adolescents in jail in New York City (N = 427) were interviewed to examine correlates of cocaine or crack use. Twenty-three percent had used cocaine or crack in the month before arrest and 32% reported lifetime use. Substantial rates of robbery, murder, other violent crime, weapons possession, and drug dealing were found. However, type of crime, including violent crime, was not related either to cocaine/crack use or to drug dealing. Current cocaine/crack users were more likely to use alcohol, marijuana, and intranasal heroin; to have multiple previous arrests; to be out of school; to be psychologically distressed; to have been sexually molested as a child; to have substance abusing parents; and to have cocaine/crack-using friends. They were also more likely to have frequent sex with girls, to be gay or bisexual, and to engage in anal intercourse. The findings should be considered in developing more effective drug abuse prevention and treatment interventions, and HIV prevention education, for incarcerated at risk adolescents. PMID- 7832178 TI - Treatment research with crack-cocaine-dependent male veterans: the efficacy of different recruitment strategies. AB - Crack cocaine dependence rapidly leads to physical deterioration and severe social consequences. There is no widely accepted standard of treatment. As such, it is important to attract broad samples of patients into treatment research to improve efficacy and to establish generalizability. Better understanding of what attracts different subgroups of cocaine users into treatment, particularly research-based treatment, is needed. This article assesses the efficacy of six different recruitment strategies for attracting different populations of male veterans into treatment for crack cocaine dependence. New directions are outlined for the examination of recruitment strategies. PMID- 7832179 TI - Reduction of opiate withdrawal-like symptoms by cocaine abuse during methadone and buprenorphine maintenance. AB - In a 6-month randomized trial comparing 125 opiate-dependent patients who were assigned to four treatment groups (2 or 6 mg of buprenorphine and 35 or 65 mg of methadone), we examined the effects of cocaine use on opiate withdrawal symptoms measured on a 25-item scale on which the scores range from 0 to 75. For the methadone-maintained patients receiving the relatively low dose (35 mg), weekly withdrawal symptoms were highest when the urine toxicology for that week indicated no cocaine use. Similar associations were found for buprenorphine. Thus, when using cocaine at a low maintenance opiate dose, persistent opiate withdrawal symptoms were reduced, which is consistent with previous naloxone precipitated withdrawal studies. Interestingly, with a higher dose of buprenorphine (6 mg), cocaine may have increased opiate withdrawal symptoms, suggesting a possible mechanism for the reduction of illicit cocaine abuse also recently observed in another study in patients treated with high dose (120 mg) methadone maintenance. This has led to a two-component model for the relationship between cocaine and opiate withdrawal-like symptoms at high versus low opiate maintenance dose. This two-component model also reconciles the contradictory findings of prior studies. PMID- 7832180 TI - Developmental vicissitudes that promote drug abuse in adolescents. AB - Adolescence is a time of significant developmental transformation during which the teenager may be susceptible to experimental behaviors such as illicit drug use. This risk-taking proclivity may arise because the adolescent is just beginning to consolidate the skills of formal operations thought, including abilities to predict behavioral outcomes, weight options, select alternatives, and adopt the perspective of others. Lacking these skills, teenagers may have difficulty adjusting to pubertal status and family conflict. One technique for overcoming this cognitive deficit is previewing, which focuses the teenager on imminent outcomes. A case history concerning a teenager abusing marijuana illustrates how previewing may help overcome maladaptive patterns. PMID- 7832182 TI - Circumstances, motivation, readiness, and suitability (the CMRS scales): predicting retention in therapeutic community treatment. AB - Based upon clinical considerations, scales were developed measuring client perceptions across four interrelated domains: circumstances (external pressures), motivation (intrinsic pressures), readiness, and suitability (CMRS) for residential TC treatment. This paper, the first in a series, reports findings on the reliability of the CMRS and its validity as a predictor of retention in TC treatment in three cohorts of consecutive admissions to a long-term residential TC. The main findings show that: (a) discriminant and factor analyses confirm the face validity of the original four rationale scales; (b) scores distribute into four groups, with most clients in the moderately low to moderately high range; (c) two cross-validation studies confirm the internal consistency of the scales, and a linear relationship between the separate and total CMRS scores and short term retention in all three cohorts and long-term retention in two cohorts. The present psychometric study provides impressive findings on the reliability and validity of the CMRS scales as predictors of retention in long-term TCs. Although still considered experimental, awaiting replicational studies and firm conclusions concerning generalizability, the CMRS holds considerable promise for research, theory, and practice. PMID- 7832181 TI - Drug use among primary alcoholic veterans. AB - Many people with alcohol dependence use other drugs. However, not much is known about the relationship between their past drug use (not necessarily dependence) and their prognosis following treatment. The goal of this study is first to determine the drug use rates among primary alcoholic men and then to evaluate the possible relationship between past drug use and future alcohol or drug use relapse. As a result, 630 primary alcoholic veterans were recruited from a 28-day inpatient Alcohol and Drug Treatment Program at the San Diego VA Medical Center. Among them, almost two-thirds also had a history of drug use. Subjects were divided into the following four groups which were determined by their lifetime drug use histories: Group I (N = 226) consisted of drug abstainers, Group 2 (N = 142) was made up of alcoholics who had used only marijuana, Group 3 (N = 210) contained stimulant users who had never used opiates, and Group 4 (N = 52) included all opiate users. Comparisons of the four groups at a 3-month follow-up revealed that alcoholic men who had a history of stimulant or opiate use (Groups 3 and 4) were more likely to have had a drug use relapse. However, the four groups had similar alcohol relapse rates. PMID- 7832184 TI - Community-based facilities may be replacing hospitals for the treatment of alcoholism: the evidence from Ontario. AB - We examined hospital utilization and use of community facilities for the treatment of alcohol problems in Ontario using Statistics Canada, Hospital Medical Records Institute records, and other administrative records. Between 1974 and 1986 there was a large drop in utilization of hospital services for treatment of alcohol problems. Rates of alcohol inpatient cases in general hospitals dropped by 47% and in mental hospitals by 33%. At the same time, there was an increase in overall availability of hospital beds and bed-days of care for all medical conditions, and no change in the total number of hospital discharges (1.3 million) and occupancy rates (80-85%). Also at the same time, the number of community-based programs for the treatment of alcohol problems increased, as did the number of persons or cases treated by them. This was associated with a drop of inpatient cases treated for alcohol problems in 38 out of 48 counties in Ontario (P < .0005). Multiple regression techniques were used to take into account the effect of the slight decline in overall alcohol consumption in this period. We found that after controlling for changes in alcohol consumption, the addition of one community-based alcohol treatment program was associated with a reduction in the number of cases treated on a hospital inpatient basis for alcohol-related problems, with a short-run drop of 27.1 hospital cases within 1 year of a community facility's availability and a long-run reduction of 52.2 cases. (P < .005). PMID- 7832185 TI - Drinking practices of illicit and licit drug users in the general population across Greece. AB - This article presents the results on the patterns of alcohol consumption among illicit and licit drug users in a Greek nationwide sample of general population with 4,290 respondents aged 12 to 64. The type of survey was cross sectional and the respondents were interviewed in their homes with a multidimensional structured questionnaire. The illicit drug users of all age groups reported a higher frequency of alcohol consumption in their lifetime, past year, month, and week prior to interview than the unprescribed licit drug users and the nonusers. The majority of illicit drug users of all ages reported their reason for drinking "to feel better or to get high." Illicit drug users of all age groups had a higher frequency of episodes of drunkenness than the other categories. Finally, the higher the frequency (> or = 3 times) of illicit drug use, the more excessive drinking reported during the past year and month. Forty percent of this category of illicit drug users reported that they had two or more serious alcohol-related problems. PMID- 7832183 TI - The role of node-link mapping in individual and group counseling. AB - The value of using a visual representation strategy, called node-linking mapping, was evaluated in individual and group drug abuse counseling settings. Methadone maintenance clients were randomly assigned to counselors trained to use mapping techniques (n = 57), and those who used standard counseling (n = 51). Clients in the mapping counseling group had more favorable perceptions of their own therapeutic engagement and progress as indicated by ratings of cognitive behavioral and motivational attributes than did those in standard counseling. Overall, individual sessions were viewed by clients as being more valuable than group counseling, but the use of mapping increased the helpfulness attributed to group counseling to near the same level as individual counseling. PMID- 7832186 TI - A functional factor X deficiency. AB - A functional factor X deficiency is described which caused pronounced reduction in the in vitro activation of the extrinsic system while marginally affecting the in vitro activation of the intrinsic pathway. All studies were normal with the exception of a prolonged PT, an elevated factor X antigen, and low factor X activity. Western blot analysis revealed the presence of two factor X species. The abnormal molecule was of higher molecular weight. Interestingly, there was no bleeding associated with this deficiency. The biochemical basis of this defect is currently under investigation. PMID- 7832187 TI - Antithrombin III Kumamoto II; a single mutation at Arg393-His increased the affinity of antithrombin III for heparin. AB - Abnormal antithrombin III (AT III) was found in a 30-year-old woman who suffered from recurrent thrombosis during pregnancy and the postpartum period. Among her family members, only her father had recurrent episodes of deep vein thrombosis of the lower extremities, from his youth. The antithrombin and antifactor Xa heparin cofactor activities of the proposita's plasma were 61% and 42% of normal, respectively. The progressive antithrombin and antifactor Xa activities were also decreased to 55% and 58% of normal, respectively. The immunoreactive level of AT III was within the normal range (23.1 mg/dl). Analysis of the proposita's plasma by crossed immunoelectrophoresis in the presence or absence of heparin and by affinity chromatography on heparin-Sepharose revealed that the proposita's AT III had apparently normal affinity for heparin. Nucleotide sequencing of 7 exons of the proposita's AT III gene amplified by polymerase chain reaction (PCR) disclosed that the second base of codon 393 comprised both G and A, indicating Arg393-His conversion. The base sequences of exons 1, 2, 3a, 3b, 4, and 5 were normal, excluding any other mutation. These findings indicated that the proposita's AT III was a variant of AT III at the thrombin binding site and that the proposita was a heterozygote for the abnormality. Heparin affinity of purified abnormal AT III from the proposita's plasma was demonstrated to be increased upon affinity chromatography using heparin-Sepharose, suggesting that the mutation (Arg393-His) per se could possibly increase the affinity of antithrombin III for heparin. For this variant AT III (Arg393-His), the name AT III Kumamoto II is proposed. PMID- 7832188 TI - Sickle cell rheology is determined by polymer fraction--not cell morphology. AB - Sickle cell disease pathophysiology is mediated by acute and chronic impairment of cell flexibility due to the formation of intracellular sickle hemoglobin (Hb S) polymer as cells are partially deoxygenated in the microcirculation. We have recently developed a method to measure the relationship between the formation of intracellular polymerized Hb S and cell filtration. In this study, we have used this method to examine whether sickle cell morphology, independent of Hb S polymer fraction, had an effect on cell rheology. We primarily use sickle trait (AS) and Hb S-beta(+)-thalassemia (S-beta(+)-thal) erythrocytes with low hemoglobin F levels, which have normal membranes and few or no dense cells, to remove these confounding effects. We find that the relationship between filtration and the percentages of each "type" of morphological deformation of AS erythrocytes was different from that of the S-beta(+)-thal erythrocytes. In addition, we find that while the filtration of AS erythrocytes as a function of oxygen saturation was similar, whether measured during deoxygenation or reoxygenation, the relationship between the percentages of each type of deformed erythrocyte and oxygen saturation demonstrated hysteresis during oxygenation deoxygenation experiments. Transmission electron microscopy, for both elongated and irregularly shaped cells, showed that similarly distorted cells could have very different amounts and alignment of polymer. These results suggests that cell morphology per se is not strongly related to filtration, whereas calculated intracellular Hb S polymer fraction predicts loss of filtration of AS and S beta(+)-thal erythrocytes well. Measured or calculated polymer fraction values would appear to be a better parameter for the study of sickle cell disease pathophysiology and response to treatment than cell morphology studies. PMID- 7832189 TI - An acquired hemorrhagic disorder of fibrin crosslinking due to IgG antibodies to FXIII, successfully treated with FXIII replacement and cyclophosphamide. AB - We report a new case of severe bleeding diathesis due to an acquired inhibitor of fibrin crosslinking. The patient, an 80-year-old woman, was admitted to the hospital for a massive subcutaneous hematoma, with severe anemia requiring red cell transfusion; a subsequent retroperitoneal hematoma developed 2 weeks later. Coagulation studies were normal except for a thromboelastographic pattern suggestive of FXIII deficiency. Clot solubility test was abnormal even after 1:1 mix with normal plasma. Immunochemical studies confirmed the presence of a monoclonal IgG lambda inhibitor directed against FXIII activity (type II FXIII inhibitor). The patient IgG fraction selectively inhibited FXIII transamidating activity but did not inhibit the thrombin-mediated activation of FXIII. The patient was treated with high doses of FXIII concentrate to overcome the inhibitor and immunosuppressive therapy with cyclophosphamide and discharged in good conditions. High doses of commercially available FXIII appear to be a safe and effective method of controlling acute episodes of bleeding in patients with acquired FXIII deficiency. PMID- 7832191 TI - Copper deficiency-induced anemia and neutropenia secondary to intestinal malabsorption. AB - A patient with a history of partial gastrectomy presented with severe anemia, neutropenia, intestinal malabsorption, and was found to be severely copper deficient. The anemia and neutropenia corrected promptly with the administration of intravenous cupric chloride. This case suggests that partial gastrectomy with or without intestinal malabsorption can result in copper deficiency and should be considered in differential diagnosis of severe anemia and neutropenia. PMID- 7832190 TI - Acute promyelocytic leukaemia (M3): relapse with acute myeloblastic leukaemia (M2) and dic(5;17) (q11;p11). AB - Secondary leukaemia following treatment of M3 acute promyelocytic leukaemia (APL) is a rare event. We describe a patient in remission following chemotherapy for APL who relapsed with M2 acute non-lymphoblastic leukaemia (ANLL). The original t(15;17) (q22;q21) chromosome translocation was lost and replaced by a clone containing a dic(5;17) (q11;p11) abnormality. Southern genomic analysis demonstrated re-arrangements of the retinoic acid receptor varies; is directly proportional to (RAR varies; is directly proportional to) and PML genes in the APL blasts at presentation but not in the M2 ANLL marrow at relapse. The significance of unbalanced 5;17 translocations as markers for therapy-related secondary leukaemia is discussed. PMID- 7832192 TI - Unexpected hepatotoxicity after priming and treatment with molgramostim (rhGM CSF) in acute myeloid leukemia during induction chemotherapy. AB - The effect of supplementing induction chemotherapy with recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) was studied in a randomized trial of 18 patients with acute myeloid leukemia (AML). Ten patients received rhGM-CSF, starting on day one to three before chemotherapy and continued for a maximum of 21 days after the start of induction treatment. Unexpected adverse effects of rhGM-CSF and chemotherapy combination included a transient decline in plasma coagulation factors II, VII, and X (5 of 5 patients) and an increased transcapillary escape rate of albumin (in 3 of 3 patients tested). The decline in coagulation factors was prevented in subsequent patients by prophylactic treatment with vitamin K. Although the small number of patients studied may not allow a definite conclusion, caution with regard to liver function should be shown in combining rhGM-CSF with intensive chemotherapy. PMID- 7832193 TI - Hyperaggregation of platelets in intestinal tuberculosis: role of platelets in chronic inflammation. AB - Eighty-eight percent (38/43) patients of intestinal tuberculosis showed significant hyperaggregation of platelets (P < 0.001). Serum and plasma from 15 patients when incubated with normal platelets caused hyperaggregation. Gel filtered platelets from 2 patients suspended in normal plasma showed hyperaggregation of platelets with arachidonic acid. Tubercular protein had no effect on platelet aggregation. A role of hyperactive platelets in chronic inflammatory response is discussed. PMID- 7832194 TI - Role of interferon alpha-2a in the treatment of polycythemia vera. AB - We studied the effects of recombinant interferon alpha-2a (IFN-alpha) in 36 patients with polycythemia vera (PV) previously treated with phlebotomy and/or conventional cytostatic agents. In each patient, after at least 2 months of discontinuation of any cytotoxic therapy, the hematocrit (Hmt) was first brought to normal value by phlebotomy; IFN-alpha treatment was then begun at a starting dose of 3,000,000 IU s.c. three times a week. Response to treatment, which was assessed monthly, was defined as persistent normalization of Hmt without concomitant phlebotomy; in non-responsive patients the initial IFN-alpha weekly dosage was progressively increased. Twenty patients were responsive with a median duration of response of 7 months (range 2-25+ months); out of these, 7 patients are still under treatment and responsive at 13+, 17+, 20+, 22+, 23+, 25+, 25+ months. These findings indicate that a cohort, although small, of patients with PV (19.4%) are persistently sensitive to IFN-alpha; in this subset of patients, this cytokine can therefore provide a useful treatment option, since, contrary to conventional therapeutic approaches such as radioactive phosphorus, cytostatic agents, or phlebotomy, IFN-alpha is devoid of harmful side effects. PMID- 7832195 TI - Thrombocytosis: misdiagnosis and its prevention. PMID- 7832196 TI - Air in the bone in a case of bone marrow necrosis associated with Escherichia coli septicemia. PMID- 7832197 TI - Mobilization of myeloblasts with 5q-anomaly during treatment with macrophage colony stimulating factor (M-CSF) PMID- 7832198 TI - Chronic lymphocytic leukemia with localized extranodal prolymphocytic transformation. PMID- 7832199 TI - Cyclic thrombocytopenia successfully treated with low dose hormonal contraception. PMID- 7832200 TI - Interstitial 9q- and dyserythropoiesis in acute myeloid leukemia. PMID- 7832201 TI - Herpes simplex meningoencephalitis simulating meningeal myelomatosis. PMID- 7832202 TI - Anticardiolipin antibodies, functional protein S deficiency, and fetal loss. PMID- 7832203 TI - Multiple myeloma presenting as a manubrial mass with intracytoplasmic crystal accumulation within macrophages. PMID- 7832204 TI - Constitutional trisomy 8 mosaicism evolving to primary myelodysplastic syndrome: a new subset of biologically related patients? PMID- 7832205 TI - Does higher monocyte count predict increased alcohol consumption? PMID- 7832206 TI - Normal reticulocyte count and subtype HFR in antenatal blood. PMID- 7832207 TI - Lung cancer mortality in a French cohort of hard-metal workers. AB - A cohort mortality study was carried out among workers of a plant producing hard metals using cobalt as a binder. This study was aimed at assessing possible lung cancer risks in relation with cobalt exposure. Seven hundred nine male workers with at least 1 year of employment were included in the cohort and followed for mortality from 1956 to 1989. Job histories were provided by the administration of the plant, whereas smoking habits were collected from medical records and by interview. The causes of deaths were ascertained from hospital and general practitioner records. The observed numbers of deaths (obs) were compared with the expected based on national rates with adjustment for age, sex, and calendar time (standardized mortality ratio; SMR). The overall mortality did not differ from that expected (obs = 75, SMR = 1.05), whereas mortality due to lung cancer was in significant excess (obs = 10, SMR = 2.13). This excess was higher among workers employed in the areas with the highest exposure (obs = 6, SMR = 5.03). No trend was observed, however, with duration of employment or time since first employment. Smoking data were available for 81% of the workers and 69% of the deceased and showed that smoking alone does not account for these lung cancer excesses, yet, because of the small numbers involved, no firm conclusion should be drawn from this study. PMID- 7832209 TI - Symptoms, lung function, and diurnal variation in peak expiratory flow rate among female solderers in the electronics industry. AB - The purpose was to determine if solderers had increased diurnal variation (DV) in peak expiratory flow rate (PEFR) and chronic impairment of lung function. A cross sectional study of 150 female operators doing manual soldering using flux-cored (rosin-based) solder wire and 52 administrative staff from two electronics factories was carried out. They answered a questionnaire, had their forced expiratory volume in 1 sec (FEV1) and forced vital capacity (FVC) measured and their 3-hourly PEFR monitored for 5 working days. The DV in PEFR was the difference in the daily maximum and minimum PEFR expressed as a percentage of the maximum. Six solderers with smoking history were excluded from the analysis. Solderers had a significantly higher prevalence of work-related eye (14.6%) and nose (10.4%) irritation. The prevalence of cough, breathlessness, and wheezing was low. There was no overt case of occupational asthma. The DV in PEFR of 6.0% was not increased. The analysis of FEV1 and FVC was restricted to Chinese only (101 solderers and 51 controls): these were not significantly different. Solderers with 5 or more years of exposure had a significantly lower FEV1/FVC (%) of 88.4% after adjustment for age. In conclusion, solderers with 5 or more years of exposure may have a mild obstructive effect apart from smoking, asthma, or age. PMID- 7832208 TI - VDT-related musculoskeletal symptoms: interactions between work posture and psychosocial work factors. AB - Video display terminal (VDT) operators (n = 150) in the editorial department of a large metropolitan newspaper participated in a study of day-to-day musculoskeletal symptoms. Work posture related to the VDT workstation and psychosocial work factors were also investigated for their contributions to the severity of upper body pain, numbness, and stiffness using a representative subsample (n = 70). Self-report measures included Karasek's Job Content Instrument and the author-designed Work Interpersonal Relationships Inventory. Independent observations of work posture were performed using techniques similar to those reported by Sauter et al. [1991]. Pain during the last week was reported by 59% (n = 88) of the respondents, and 28% (n = 42) were categorized by symptom criteria potentially to have musculoskeletal disorders. More hours per day of VDT use and less decision latitude on the job were significant risk factors for potential musculoskeletal CTDs. Head rotation and relative keyboard height were significantly related to more severe pain and stiffness in the shoulders, neck, and upper back. Lower levels of co-worker support were associated with more severe hand and arm numbness. For both the region of the shoulders, neck, and upper back and the hand and arm region, however, the contributions of relative keyboard and seat back heights to symptom severity were modified by psychological workload, decision latitude, and employee relationship with the supervisor. Alternative explanations for these findings are discussed. PMID- 7832210 TI - Estimation of historical exposures to machining fluids in the automotive industry. AB - A retrospective exposure assessment study in the automotive parts industry conducted in conjunction with a cancer mortality and respiratory morbidity study [Kennedy et al. (1989): Am J Ind Med 15:627-641; Eisen et al. (1992): Am J Ind Med 22:809-824; Tolbert et al. (1992): Scand J Work Environ Health 18:351-360] describes exposure to different types of machining fluids and selected components that may contribute to the conditions investigated. A dataset of 394 industrial hygiene measurements made between 1958 and 1987 was used to estimate past machining fluid levels using a linear statistical model. The effects of different plants, machining fluid types, machining operations, and time periods were examined in the model. Separate analyses examined the effects of different sampling and analysis methods and other measurement variables. Machining fluid levels prior to 1970 were generally two to five times higher than subsequent measurements. The arithmetic mean exposure of all measurements taken before 1970 was 5.42 mg/m3. Arithmetic means for different subgroups ranged from 0.59 to 20.28 mg/m3, depending upon plant, machining fluid, and operation. The arithmetic mean exposure after 1980 was 1.82 mg/m3 with subgroups ranging from 0.45 to 2.79 mg/m3. Changes in exposure levels generally corresponded with reported changes in plant environments such as installation of enclosures and local exhaust ventilation on machines. PMID- 7832211 TI - Occupational exposure to lead, kidney function tests, and blood pressure. AB - In the present study we examined sensitive biochemical markers of kidney function and damage in 166 workers exposed to lead and in 60 control workers. The objective was to investigate the chronic renal toxicity of lead and its possible correlation with arterial pressure. Diastolic arterial pressure was higher in the exposed group (p < 0.05), but the two groups did not differ in systolic pressure. Median activity of urinary N-acetyl-beta-D-glucosaminidase was higher in the exposed group (p < 0.001), and correlated with blood lead levels (p < 0.001) and duration of exposure (p < 0.001), but not with arterial pressure. The other indicators studied, gamma-glutamyl-transpeptidase and alanine-aminopeptidase activity, urine albumin, and total urine protein, were not higher than in the control group and were not correlated with blood lead, duration of exposure, or arterial pressure. PMID- 7832212 TI - Asbestos bodies in bronchoalveolar lavage fluid in relation to occupational history. AB - Concentrations of asbestos bodies (AB) were assessed by optical microscopy of 10 ml iron-stained samples and compared with the exposure history acquired by personal interview for 156 patients. Concentrations equalling or exceeding 1 AB/ml were found in 85% of patients who had been heavily exposed to asbestos and only 7% of those who were unlikely to have been exposed. Elevated AB concentrations were observed among primary asbestos, shipyard and construction workers. Smoking was not found to affect the AB concentrations. The use of Papanicolaou-stained cytological Millipore preparations during routine screening was a less sensitive method for the assessment of AB concentrations than that involving iron-stained preparations. The expression of AB concentration as AB/ml or AB/million cells were found to be equally useful indicators of exposure. The correlation between AB concentration and exposure history was greater than in earlier studies on workers exposed to chrysotile. Concentrations exceeding 1 AB/ml were indicative of a nontrivial exposure to asbestos. Despite the observed correlation between AB concentration and exposure history, the individual variability of AB counts, methodological differences and laboratory-bound reference values are important in the interpretation of AB concentrations in bronchoalveolar lavage (BAL) fluid at individual level. PMID- 7832213 TI - Airway hyper-responsiveness and the prevalence of work-related symptoms in workers exposed to irritants. AB - The association between exposure to airway irritants and the presence of work related symptoms and whether this association was modified by airway hyper responsiveness, smoking, and allergy by history was studied in 668 workers of synthetic fiber plants. A Dutch version of the British Medical Research Council (BMRC) questionnaire with additional questions on allergy and work-related symptoms was used to assess symptoms, and a standardized histamine challenge test of airway hyper-responsiveness (AHR) was employed. Work-related symptoms were defined as having more than usual eye and respiratory symptoms during work. On the basis of job titles and working department, the exposure status of all workers was characterized into seven groups: (1) reference group; (2) white collars; (3) SO2, HCl, SO4(2-); (4) polyester vapor; (5) oil mist and oil vapor; (6) polyamide and polyester vapor; and (7) multiple exposure. The association between exposure groups and work-related symptom prevalence was estimated by means of multiple logistic regression. The overall prevalence of the work-related symptoms were: cough 9%; phlegm 6%; dyspnea 7%; wheeze 2%; eye symptoms 16%; nasal symptoms 15%. Exposure to airway irritants was significantly associated with work-related symptoms, independent of AHR, smoking, allergy by history, and chronic respiratory symptoms. The association of exposure group with work-related symptoms was stronger for subjects with AHR than for subjects with no AHR. The association with dyspnea and/or wheeze was also stronger for smokers than for nonsmokers and ex-smokers. In contrast, the association between exposure and a higher prevalence of work-related symptoms was stronger in subjects with no history of allergy than in subjects with history of allergy. This is most likely due to the relatively high prevalence of background symptoms in (nonexposed) allergic subjects. It is concluded that exposure to irritants in the working environment might lead to respiratory symptoms, even if exposure levels are relatively low. PMID- 7832214 TI - Humoral immune responses of workers occupationally exposed to wheat flour. AB - Wheat flour is a complex organic dust likely to induce immune responses when inhaled in work environment conditions. We compared the humoral status of 159 exposed workers from 11 flour mills and one industrial bakery with that of 41 workers from a salt factory. IgG, IgA, and IgM levels of antibodies to whole flour and to gliadin were assayed using ELISA tests in serum and saliva samples. Serum levels of IgG and IgA to both antigens were significantly higher (p < 0.0001) in occupationally exposed workers. Exposed workers had significantly higher levels of salivary IgG (p = 0.005) and IgA (p < 0.0001) to whole flour and of salivary IgG (p = 0.0005) to gliadin. In both groups, similar levels of anti gliadin salivary IgA antibodies were observed. These data suggest that occupational exposure to wheat flour triggers specific immune responses, most likely through stimulation of the mucosal immune system. The presence of significant levels of serum antibodies, however, indicates that a systemic immunologic response is also present among exposed individuals. PMID- 7832216 TI - Lead exposure in a tank demolition crew: implications for the new OSHA construction lead standard. AB - The Federal Occupational Safety and Health Administration (OSHA) has recently extended the basic health and safety provisions of the OSHA lead standard for general industry to workers in the construction industry. In this report we describe a tank demolition worksite that midway through the project strengthened its lead exposure control activities to a level that approximated the current lead standard. Of 12 tested ironworkers and laborers who worked at the site before the change, zinc protoporphyrin levels increased and seven developed blood lead levels (BLL) > 50 micrograms/dL. After the change these workers' BLLs declined. Six workers hired after the change did not experience increases in zinc protoporphyrin and none developed BLL > 25 micrograms/dL. The experience at this worksite demonstrates the usefulness and feasibility of implementing the current lead standard in construction settings. PMID- 7832215 TI - 60 Hertz magnetic field exposure assessment for an investigation of leukemia in telephone lineworkers. AB - The purpose of this paper is to present the assessment of magnetic field exposure conducted as a part of a nested case-control investigation of leukemia mortality in telephone lineworkers. For the purposes of exposure classification, telephone company jobs were initially divided into two classes: those with potential for working in an electric environment, referred to as linework jobs, and those not working in an electric environment, referred to as nonlinework jobs. Linework jobs were further divided into the following four categories: outside plant technicians (OPT), installation/maintenance/repair (IMR) technicians, central office technicians (COT), and cable splicing technicians (CST). These job groupings were based on similarity of work tasks and exposure environments. Emdex data-logging dosimeters were used to measure personal exposures to ELF magnetic fields for 204 telephone company workers. Three general classes of exposure indices were calculated for each exposure record: measures of central tendency, measures of peak or maximum exposure, and measures of exposure variability. CSTs had the highest full-shift mean and median exposure, 4.3 and 3.2 mG, respectively. CSTs also ranked the highest, with average peak, average 95th percentile, and average time above background equal to 99.2 mG, 11.1 mG, and 156 min, respectively. In addition, the results suggest the OPT and IMR technicians have exposures similar to nonlineworkers. Exposure classifications, therefore, which misclassify all lineworkers into one "telephone lineworker" job grouping are not appropriate and future studies should concentrate on cable splicing technicians. PMID- 7832217 TI - Occupational lead poisoning: can it be eliminated? AB - The continued occurrence of occupational lead poisoning and overexposure in the United States represents a serious challenge to the occupational health community. We outline a proposed action strategy which integrates case-based surveillance, hazard surveillance, increased requirements for biological monitoring, and targeted educational activities, with a goal of eliminating occupational lead poisoning. The system provides a simple mechanism for monitoring compliance in lead-using employers, in order to identify employers for enforcement action. Lead poisoning should be viewed as an eradicable condition; successfully solving the persistent lead overexposure problem can serve as a model for approaching other occupational diseases. PMID- 7832218 TI - Occupational lead poisoning: who should conduct surveillance and training? AB - This commentary challenges the current employer-controlled model for delivering occupational health services. Problems emanating from traditional employer-based medical surveillance and worker education programs for occupational lead poisoning are identified. A new public health model for delivering these services is proposed. This model utilizes a case-based and hazard-based method for bringing workplaces and employers into the program and features direct delivery of surveillance and training services by public health agencies. PMID- 7832219 TI - Diagnosis and clinical characteristics of ocular Lyme borreliosis. AB - PURPOSE: To establish a diagnosis, in a group of patients we studied the characteristics of ocular Lyme borreliosis. METHODS: During a two-year period, 236 patients with prolonged external ocular inflammation, uveitis, retinitis, optic neuritis, or unexplained neuro-ophthalmic symptoms were examined for Lyme borreliosis. Antibodies to Borrelia burgdorferi were measured by indirect ELISA and western blot. Cerebrospinal fluid was also analyzed by polymerase chain reaction. RESULTS: Ocular Lyme borreliosis was diagnosed in ten patients on the basis of medical history, clinical findings, and serologic test results. Results of ELISA disclosed that five patients were seropositive, two patients showed borderline reactivity, and three patients were seronegative. Four of the five patients with borderline or negative results by ELISA had a positive result by western blot analysis. In one seropositive patient, polymerase chain reaction verified a gene of B. burgdorferi endoflagellin from the vitreous and cerebrospinal fluid specimen. In five of the six patients with known onset of the Borrelia infection, the ocular disorder appeared as a late manifestation. Abnormalities of the posterior segment of the eye, such as vitreitis, retinal vasculitis, neuroretinitis, choroiditis, and optic neuropathy were seen in six patients. Bilateral paralytic mydriasis, interstitial keratitis, episcleritis, and anterior uveitis were seen in one patient each. CONCLUSIONS: Late-phase ocular Lyme borreliosis is probably underdiagnosed because of weak seropositivity or seronegativity in ELISA assays. Ocular borrelial manifestations show characteristics resembling those seen in syphilis. PMID- 7832220 TI - Retinal trypsin digest study of cystoid macular edema associated with peripheral choroidal melanoma. AB - PURPOSE: Although the association of cystoid macular edema with peripheral choroidal melanoma has been studied previously, the pathogenesis of cystoid macular edema as evaluated by light and electron microscopy remains controversial. We evaluated the cause of cystoid macular edema at the retinal capillary level. METHODS: We clinicopathologically correlated petaloidlike changes noted on fluorescein angiography with the corresponding morphologic changes, as documented by retinal trypsin digest preparation. RESULTS: The angiographic foci of fluorescein leakage were found to correspond to sites of endothelial cell proliferation that resembled intraretinal microvascular abnormalities in the retinal trypsin digest preparation. CONCLUSIONS: The source of cystoid macular edema at the level of the retinal capillary network are intraretinal microvascular abnormalities resembling endothelial cell proliferation. We examine the relationship between endothelial cell proliferation and vascular leakage. PMID- 7832221 TI - Lens changes after proton beam irradiation for uveal melanoma. AB - PURPOSE: Because limited data exist on the incidence of lens changes after therapeutic intraocular irradiation, we studied a group of patients who underwent proton irradiation for uveal melanoma, in order to estimate cumulative rates of radiation-induced posterior subcapsular opacities and age-related lens changes at specific time points. after irradiation. METHODS: Cumulative rates for each type of opacity were estimated from among the 383 patients, treated between 1987 and 1989, who had clear lenses or minimal lens changes before irradiation. Cox's proportional hazards model was used to evaluate the independent effects of tumor and treatment-related characteristics on the development of posterior subcapsular opacities in these patients. Risk factors for posterior subcapsular opacities were evaluated. RESULTS: By three years after irradiation, posterior subcapsular opacities had developed in 42% of the patients, and rates increased significantly with lens dose and with tumor height. The risk of posterior subcapsular opacities was over three times higher when the lens received a substantial dose of irradiation (adjusted relative risk, 3.25; 95% confidence interval, 1.60-6.59), as compared with minimal dose, and was three times higher when the tumor was highly elevated (adjusted relative risk, 3.05; 95% confidence interval, 1.45 6.40) as compared with minimally elevated lesions. Opacities in the other segments of the lens were age related. CONCLUSIONS: These data show that patients receiving therapeutic intraocular irradiation have a high risk of developing posterior subcapsular opacities. As expected, the leading risk determinant of posterior subcapsular change is the amount of irradiation received by the lens. PMID- 7832222 TI - Surgical techniques for repositioning a dislocated intraocular lens, repair of iridodialysis, and secondary intraocular lens implantation using innovative 25 gauge forceps. AB - PURPOSE: We developed surgical techniques for the sulcus fixation of a posteriorly dislocated or secondarily implanted posterior chamber intraocular lens, repair of an iridodialysis, and the management of a decentered intraocular lens during vitreous surgery using innovative 25-gauge forceps. METHODS: The 25 gauge forceps have a curved shaft, a tip with a distal platform for grasping a suture, and a proximal groove for gripping a haptic. The forceps are inserted through a grooved scleral incision into the plane of the ciliary sulcus, facilitating manipulations such as fastening a suture loop around a haptic, repositing an intraocular lens at the ciliary sulcus, and grasping sutures during repair of a iridodialysis or implantation of a secondary intraocular lens. Seven patients underwent vitreous surgery using the new forceps. RESULTS: In all seven patients the surgical objectives were accomplished with the 25-gauge forceps without postoperative complications such as hemorrhage, hypotony, or lens decentration. CONCLUSIONS: The 25-gauge forceps are innovative instrumentation designed specifically for anterior segment applications during vitreous surgery. PMID- 7832223 TI - Cataract in infants treated with argon laser photocoagulation for threshold retinopathy of prematurity. AB - PURPOSE: Previous studies of lens opacities occurring after argon laser photocoagulation for retinopathy of prematurity indicate that the lens in these laser-treated eyes may be at risk for cataract. We studied the occurrence of permanent, visually significant cataracts in four infants after laser therapy for retinopathy of prematurity. METHODS: The records of 51 consecutive patients (100 eyes) treated only with argon laser photocoagulation for threshold retinopathy of prematurity at our institution were reviewed. Patient characteristics and treatment variables were compared between infants who developed cataracts and those who did not. RESULTS: Complete opacification of the lens nucleus and cortex developed in six eyes of four patients between 19 and 99 days after laser therapy. An additional patient developed a transient, focal, anterior capsular, and subcapsular opacity in one eye that cleared by one month postoperatively. Eyes that developed permanent cataracts were noted to have a prominent anterior tunica vasculosa lentis at the time of treatment. After laser therapy, these eyes developed hyphema, shallowing of the anterior chamber, corneal edema, and progressive opacification of the lens. When compared with eyes that did not develop cataract, no statistically significant difference in number of burns, zone or clock hours of extraretinal proliferation, birth weight, gestational age, or age at treatment was found. CONCLUSIONS: Cataract is a potential vision threatening complication of argon laser photocoagulation that must be considered before choosing a treatment modality for infants with threshold retinopathy of prematurity. PMID- 7832224 TI - Microorganisms cultured from the anterior chamber of ruptured globes at the time of repair. AB - PURPOSE: We studied events leading to the development of posttraumatic endophthalmitis by examining the significance of 15 factors on microbial contamination of injured eyes. METHODS: A prospective study was done of 30 ruptured globes in patients admitted to an urban medical center. Cultures were taken from the conjunctiva before and after preoperative disinfection and from the anterior chamber at the beginning and end of wound repair. Twenty-five of 30 patients received a three-day regimen of intravenous antibiotics that were begun before surgery. RESULTS: Anterior chamber samples grew microorganisms in ten (33%) of 30 eyes, with positive cultures recovered from specimens taken at the beginning of wound repair in eight eyes and at the end of wound repair in six eyes. Contamination with indigenous flora may have occurred at the time of injury in one eye and during repair in another eye. Microbes recovered included Staphylococcus, Corynebacterium, and Aspergillus species. No patient developed endophthalmitis. Of the 15 factors studied, only intravenous antibiotics significantly decreased the incidence of positive anterior chamber cultures in eyes treated before wound repair compared with eyes not receiving such therapy (P = .002). CONCLUSIONS: Despite the frequency of anterior chamber microbial contamination during injury or repair of the wound, with our treatment protocol and the presence of physiologic mechanisms to reduce intraocular microbes, no eyes developed clinical endophthalmitis. With our limited sample size only intravenous antibiotic therapy was found significantly to reduce anterior chamber microorganisms at the time of surgical repair, supporting their prophylactic use against the development of posttraumatic endophthalmitis. PMID- 7832225 TI - Local therapy of corneal allograft rejection with cyclosporine. AB - PURPOSE: We evaluated the therapeutic effect of 0.5% topical cyclosporine on human corneal allograft rejection. METHODS: Sixteen patients (16 eyes) with corneal allograft rejection, refractory to the conventional treatments, were recruited and treated with 0.5% cyclosporine eyedrops in this study. RESULTS: Of 16 eyes with corneal graft rejection after penetrating keratoplasty treated with 0.5% cyclosporine eyedrops, nine eyes were completely cured, six eyes improved markedly, and treatment was ineffective in one eye. A follow-up of 12 to 24 months (three eyes for 12 months, five eyes for 18 months, and eight eyes for 24 months) disclosed that rejection recurred in three of the nine cured eyes--two eyes after suspension of cyclosporine and one eye after removal of the sutures. The recurrence of rejection resolved by resumption of the cyclosporine eyedrops. CONCLUSIONS: This study demonstrated that treatment of corneal graft rejection with 0.5% topical cyclosporine yielded good results in eyes with satisfactory preoperative corneal transplantation beds and beneficial effects in eyes with poor preoperative corneal transplantation beds. PMID- 7832226 TI - Comparison of high-pass resolution perimetry and standard automated perimetry in glaucoma. AB - PURPOSE: We sought to ascertain whether high-pass resolution perimetry would provide results comparable to those of standard perimetry. METHODS: Thirty-four eyes with primary open-angle glaucoma, 37 eyes suspected of having glaucoma, and 36 normal control eyes were matched for age and lens density. We controlled for refraction, pupil size, and learning effects. Standard and ring visual fields were obtained with the Humphrey perimeter and the Frisen ring perimeter, respectively. Each test was judged according to the Glaucoma Hemifield Test (a statistical visual field analysis method) to be outside normal limits (abnormal) or not outside normal limits (normal or borderline). RESULTS: Under these conditions, both tests identified 19 of 34 (56%) glaucoma eyes as outside normal limits. High-pass resolution perimetry determined that 34 of 36 (94%) normal eyes were not outside normal limits; standard perimetry determined that all 36 normal eyes were not outside normal limits. High-pass resolution perimetry determined 12 of 37 (32%) eyes that were glaucoma suspects were outside normal limits; standard perimetry determined three of the 37 (8%) glaucoma suspect eyes were outside normal limits. Overall agreement between the two tests was 65%. CONCLUSION: With the Glaucoma Hemifield Test, high-pass resolution perimetry was comparable to standard perimetry in sensitivity and specificity, and identified a slightly higher percentage of patients at risk for glaucoma as abnormal. These results suggest that high-pass resolution perimetry should continue to be explored as an alternative to standard perimetry for the diagnosis and treatment of glaucoma. PMID- 7832227 TI - Ophthalmologic examination of patients with seasonal affective disorder, before and after bright light therapy. AB - PURPOSE: We assessed the potential ocular hazards of bright light therapy for patients with seasonal affective disorder, after both short- and long-term treatment, and identified prospective patients with pre-existing ocular abnormalities. METHODS: Fifty patients with seasonal affective disorder received daily exposure to artificial light in the morning or evening for 30 minutes at an illuminance level of 10,000 lux (irradiant dose, 0.016 J/cm2). Ophthalmologic examinations were performed before and after short-term treatment (two to eight weeks) and after three to six years of use during the fall and winter months. Over the four years of patient intake, the eye examination included subsets of the following tests: visual acuity, intraocular pressure, slit-lamp biomicroscopy, direct and indirect ophthalmoscopy, color vision, visual field, fundus photography, Amsler grid, ocular motility, pupillary reactions, contrast sensitivity, stereopsis, and the macular stress test. RESULTS: No ocular changes were detected after short-term treatment. Long-term treatment (three to six years) of 17 patients, with cumulative exposure durations of 60 to 1,250 hours, also resulted in no ocular abnormalities. CONCLUSIONS: Light therapy yields about 75% clinical remissions. It is effective as an antidepressant and appears safe for the eyes. Current knowledge is insufficient to specify any definite ocular contraindications for bright light therapy, although we recommend that patients with preexisting ocular abnormalities and those using photosensitizing drugs undergo treatment only with periodic ophthalmologic examination. PMID- 7832228 TI - Clinical features and treatment of seven patients with carcinoid tumor metastatic to the eye and orbit. AB - PURPOSE: To understand better the clinical features, treatment, and outcome of patients with carcinoid tumors metastatic to the eye and orbit. METHODS: We studied seven patients with carcinoid tumors metastatic to the eye and orbit who were initially examined at the Mayo Clinic between 1974 and 1992. Carcinoid tumors metastasized to the choroid of six eyes of four patients and unilaterally to the orbit in three additional patients. RESULTS: Decreased vision was the most frequent initial symptom with choroidal metastases. Choroidal metastases were treated with brachytherapy only, with brachytherapy and chemotherapy, with external beam irradiation and chemotherapy, or with chemotherapy only. The duration of follow-up of these four patients ranged from seven to eight years after the diagnosis of choroidal metastases. Two of the four patients died from tumor complications 7 1/2 and seven years after the diagnosis of choroidal metastases. Proptosis and limitation of ocular motility were the most common initial signs with orbital metastases. Orbital metastases were treated with external beam irradiation and chemotherapy, with chemotherapy only, or with external beam irradiation only. Duration of follow-up of these three patients ranged from one-half to two years after the diagnosis of orbital metastases. All three patients died from tumor complications during the follow-up period. CONCLUSIONS: Because of the relatively good prospects for long-term survival in patients with carcinoid tumors metastatic to the choroid, early detection and treatment of the metastases are important. PMID- 7832229 TI - Natural course and histopathologic findings of lacrimal gland choristoma of the iris and ciliary body. AB - PURPOSE: To show a well-documented clinicopathologic correlation of lacrimal gland choristoma of the iris and ciliary body, to review the literature on the subject, and to recommend treatment of this condition. METHODS: A congenital iridociliary mass was removed by iridocyclectomy when a female infant was 19 months old because it had produced a large cyst, secondary glaucoma, a vascularized corneal pannus, focal cataract, and iris heterochromia secondary to pigment dispersion. The excised mass was studied by routine histopathologic methods. RESULTS: The mass proved histopathologically to be a lacrimal gland choristoma composed of mature lacrimal gland tissue associated with a large epithelial-lined cyst and several smaller cysts. Postoperatively, the glaucoma resolved and the child had visual acuity of 20/40 14 months after surgery. CONCLUSIONS: Lacrimal gland choristoma of the anterior uvea has typical clinical features that should indicate that correct diagnosis. It is a fleshy, often cystic, lesion with an irregular, cerebriform surface that appears identical to the lacrimal gland in the orbit. Although the mass itself is generally stable, secondary cysts in the lesion can enlarge and secondary glaucoma and other complications can develop. Consequently, affected patients should be followed up at close intervals and surgical excision performed if such complications begin to develop. PMID- 7832230 TI - Electromyographic studies of the reconstructed lower eyelid after a modified Hughes procedure. AB - PURPOSE: We evaluated quantitatively, with electromyography, the function of orbicularis oculi muscle flaps in modified Hughes reconstructions of the lower eyelids. METHODS: A modified Hughes procedure with a bipedicle orbicularis oculi flap was used to reconstruct large left lower eyelid defects after tumor excision in six consecutive patients. Standard needle electromyography and facial nerve conduction studies were performed on each reconstructed lower eyelid, and results were compared with those of the unoperated-on right lower eyelid. Electromyographic studies were performed between 143 and 517 days after division of the tarsoconjunctival flap. RESULTS: Blink reflexes and results of facial nerve studies were normal and similar on both sides. All operated-on eyelids demonstrated electromyographic activity during voluntary orbicularis contraction. The functional and cosmetic results were satisfactory in all patients. No complications of reconstruction, such as eyelid retraction, ectropion, tissue necrosis, or abnormal contour or thickness, occurred. CONCLUSIONS: A modified Hughes procedure using a bipedicle orbicularis oculi flap provides viable, electrically active muscle to the reconstructed lower eyelid and may enhance the functional results. PMID- 7832231 TI - The role of international ophthalmology in blindness prevention. PMID- 7832232 TI - Prospective incidence of photic maculopathy after cataract surgery. AB - PURPOSE/METHODS: To determine the incidence of photic retinal injury during cataract surgery, we studied 37 consecutive patients with intravenous fluorescein angiography within ten days after cataract surgery. The microscope irradiance was standardized for all cases. RESULTS/CONCLUSIONS: Fluorescein evidence of photic retinal injury did not develop in any of the 37 cataract patients. Incidence rates for photic retinal injury induced by the surgical microscope vary considerably among ophthalmologists and most likely reflect differences in microscope brightness, surgical duration, and surgical technique. PMID- 7832233 TI - Use of the Hoskins lens in needle revision of a failed bleb after filtration surgery. AB - PURPOSE/METHODS: During needle revision of a failed bleb after filtration surgery, a needle is inserted through the conjunctiva and a Hoskins lens is placed on the conjunctiva over the needle. The lens blanches the conjunctival vessels and the needle tip can be pinpointed. RESULTS/CONCLUSION: This procedure has been performed in nine eyes with no major complications. Needle revision of a failed bleb can be performed efficiently with the Hoskins lens. PMID- 7832234 TI - Bilateral Serratia marcescens keratitis after simultaneous bilateral radial keratotomy. AB - PURPOSE/METHODS: After bilateral simultaneous radial keratotomy, Serratia marcescens keratitis, which involved multiple incisions of both eyes, developed in a 46-year-old physician. The keratitis was treated with repeated wound debridement, fortified topical antibiotics, and topical povidone-iodine. RESULTS/CONCLUSIONS: Six months after radial keratotomy, uncorrected visual acuity was R.E.: 20/25 and L.E.: 20/60, both eyes correctable to 20/20. Health care workers who undergo refractive surgery may be at increased risk of acquired postoperative infections because of their work environment. Although the occurrence of simultaneous bilateral ulcerative keratitis after simultaneous bilateral radial keratotomy is rare, it is nonetheless a real possibility, making it prudent to perform radial keratotomy on one eye at a time. PMID- 7832235 TI - Increased numbers of mast cells in pterygia. AB - PURPOSE/METHODS: We examined the mast cells in 12 pterygium specimens of patients who underwent primary excisions and the conjunctival specimens of ten normal age matched control subjects. RESULTS/CONCLUSION: The mean mast cell count per cubic millimeter was twice as high in the pterygium specimens as in the control specimens. Mast cell proliferation and activation may contribute to the pathogenesis of pterygium formation. PMID- 7832236 TI - Conjunctival foreign body from a cosmetic facial scrub. AB - PURPOSE/METHODS: Foreign body sensation in four patients was caused by particles from a cosmetic facial scrub that contained small plastic spheres designed to abrade the skin. The particles were lodged in the superior palpebral conjunctiva 2 to 3 mm from the eyelid margin. RESULTS/CONCLUSIONS: Removal of the particles eliminated the foreign body sensation and there were no lasting deleterious effects. PMID- 7832237 TI - Simultaneous onset of Vogt-Koyanagi-Harada syndrome in monozygotic twins. AB - PURPOSE/METHODS: We examined monozygotic twins of Vietnamese ancestry in whom the Vogt-Koyanagi-Harada syndrome developed. RESULTS/CONCLUSIONS: Both patients demonstrated typical clinical findings of the Vogt-Koyanagi-Harada syndrome, and HLA typing disclosed HLA-DR4, an antigen that is present in a disproportionate number of patients with the Vogt-Koyanagi-Harada syndrome. Although familial cases of the Vogt-Koyanagi-Harada syndrome are rare, associations with HLA antigens may indicate that genetic factors play a role in this disease. PMID- 7832238 TI - Early stage of macular hole in a severely myopic eye. AB - PURPOSE/METHODS: A progressive early stage of macular hole developed in a severely myopic eye of a 37-year-old woman. RESULTS/CONCLUSIONS: The patient improved after pars plana vitrectomy, peeling of the posterior hyaloid, and gas fluid exchange. Biomicroscopic, ultrasonographic, and intraoperative findings support the theory of cortical vitreous traction as the cause of macular hole in severely myopic eyes. PMID- 7832239 TI - Ophthalmoscopic visualization of the inferior ophthalmic vein through a chorioretinal coloboma. AB - PURPOSE/METHODS: In a patient with a coloboma of the optic nerve, inferior retina and choroid, and deep portions of the sclera, a retrobulbar vessel moved irregularly relative to the retinal vessels, which moved contiguously with the posterior globe. RESULTS/CONCLUSION: Fluorescein angiography showed the retrobulbar vessel filling slightly later than overlying retinal vessels. We conclude that the retrobulbar vessel was a vein situated inferiorly to the optic nerve. PMID- 7832240 TI - Clinicopathologic correlation of a case of adenocarcinoma of the retinal pigment epithelium. AB - PURPOSE/METHODS: We observed a clinicopathologic correlation of a case of adenocarcinoma of the retinal pigment epithelium. RESULTS/CONCLUSIONS: The ultrasonographic findings of this tumor demonstrated a collar button profile with high internal reflectivity. The ultrasonographic characteristics in this case reflected the variable vascularity and cystic spaces within the tumor. PMID- 7832241 TI - Risk of false-positive molecular genetic diagnosis of Leber's hereditary optic neuropathy. AB - PURPOSE/METHODS: The most common pathogenic mitochondrial mutation at nucleotide 11778 in Leber's hereditary optic neuropathy is usually detected by the loss of an SfaNI restriction site. To evaluate a false-positive diagnostic error in this molecular genetic assay, we investigated SfaNI polymorphism in 120 patients with bilateral optic atrophy. RESULTS/CONCLUSIONS: The ratio of false-positive to true positive results was 1:36. Mitochondrial DNA polymorphism at nucleotide 11779 reflects a false-positive genetic error. PMID- 7832242 TI - Harm reduction--a framework for incorporating science into drug policy. PMID- 7832243 TI - The impact of drug-related deaths on mortality among young adults in Madrid. AB - The trend from 1983 to 1990 of drug-related mortality (defined as the sum of deaths from acute drug reactions and the acquired immuno-deficiency syndrome [AIDS] in drug users) among the population 15 to 39 years of age in Madrid, Spain, was studied and compared with mortality from all causes. All of the mortality rates increased from 1983 to 1990: all causes, from 101/100,000 to 148/100,000; acute drug reactions, from 3/100,000 to 15/100,000; and AIDS, from 0 to 20/100,000. Drug-related mortality represented 60% of the increase in the rate from all causes in males and 170% of the increase in females. The increases in drug-related mortality are likely to continue in the future. PMID- 7832244 TI - Drug abuse treatment experience and HIV risk behaviors among active drug injectors in Ohio. AB - This study compares the sociodemographic characteristics and human immunodeficiency virus (HIV) risk behaviors of injection drug users who had received drug abuse treatment in the previous 5 years and those who had not received treatment. The National AIDS Demonstration Research Program database provided 2001 structured interviews, representing Cleveland, Columbus, Cincinnati, and Dayton, Ohio. About 43% of the subjects reported having received treatment in the previous 5 years. Length of involvement with drugs, more frequent injection, more legal problems, and higher levels of HIV risk behaviors were associated with a history of treatment. Incorporating HIV risk reduction education in drug abuse treatment is an urgent priority. PMID- 7832245 TI - Revisiting "the origins of compulsory drug prescriptions". AB - It has been argued that today's prescription drug market originated in the arbitrary acts of the US Food and Drug Administration (FDA), which in 1938 issued regulations creating a class of drugs that could be sold by prescription only. On the basis of the FDA's administrative records, I argue that the 1938 regulations on prescription drug labeling were initiated by industry and then agreed to by the FDA; that contemporaries understood and accepted the reasons for restricting the use of certain drugs; and that the subsequent evolution of these regulations is best understood as an FDA effort to limit industry abuses of the prescription labeling system. This decade-long war of position ended when drug manufacturers persuaded the US Congress to enshrine their version of prescription labeling in law in a highly politicized struggle over government's role in the economy. PMID- 7832246 TI - Current trends in tobacco use on prime-time fictional television. PMID- 7832247 TI - Use of smokeless tobacco in the World Series, 1986 through 1993. PMID- 7832248 TI - Excess mortality in smokeless tobacco users not meaningful. PMID- 7832249 TI - Mortality among injection drug users identified as "out of treatment". PMID- 7832250 TI - The natural history of substance use as a guide to setting drug policy. PMID- 7832251 TI - Public health and medicine. PMID- 7832252 TI - The key role of nurses in local health departments. PMID- 7832253 TI - Interdisciplinary centers for tobacco-related cancer research--a health policy issue. PMID- 7832254 TI - Alcohol and longevity. PMID- 7832255 TI - Drug regulation and drug information--who should do what to whom? PMID- 7832256 TI - Dietary intake among Mexican-American women: generational differences and a comparison with white non-Hispanic women. AB - OBJECTIVES: Although Mexican Americans consume diets that may protect them against adverse health, dietary advantages may disappear with increased acculturation. This study examined whether the nutrient intake of second generation Mexican-American women of childbearing age deteriorates compared with that of first-generation Mexican-American women and approximates that of White non-Hispanic women. METHODS: Data on the absolute and relative intake of eight nutrients were obtained from a 24-hour recall and compared among 475 first generation and 898 second-generation Mexican-American women, and among 2326 White non-Hispanic women. RESULTS: Although first-generation Mexican-American women were of lower socioeconomic status than were second-generation or White non Hispanic women, they had a higher average intake of protein; vitamins A, C, and folic acid; and calcium than the other two groups. Whereas the mean adequacy ratio of the eight nutrients studied was highest in first-generation Mexican women, it was lowest in their second-generation counterparts. CONCLUSIONS: First generation Mexican women stand a markedly lower risk of eating a poor diet than second-generation Mexican women, whose nutrient intake resembles that of White non-Hispanic women. PMID- 7832257 TI - The relationship between structural and health services variables and state-level infant mortality in the United States. AB - OBJECTIVES: This study compared the relative strength of the associations of a set of structural (social, economic, and political) variables and a set of health services variables with state-level infant, neonatal, and postneonatal mortality. It also examined whether health services mediate the relationships between structural variables and state-level infant, neonatal, and postneonatal mortality. METHODS: With the state as the unit of analysis, data for all 50 states were analyzed by means of multiple regression. RESULTS: Structural variables accounted for substantially more variance in infant, neonatal, and postneonatal mortality than health services variables, and health services variables were more strongly related to infant mortality than to neonatal or postneonatal mortality. When health services variables were controlled, the strengths of the associations between the structural variables and infant, neonatal, and postneonatal mortality were reduced but remained statistically significant. CONCLUSIONS: A substantial portion of the variance in state-level infant mortality is accounted for by states' structural characteristics, which are partially mediated by health services. PMID- 7832258 TI - Fecal contamination in child day care centers: cloth vs paper diapers. AB - OBJECTIVES: Cloth diapers with front closure and all-in-one design were compared with paper diapers containing absorbent gel material for their influence on fecal contamination of the environment in licensed child day care centers. METHODS: One infant room and two toddler rooms in each of four day care centers were monitored for the presence of fecal bacteria. Microbial samples were taken from the play/sleep area, the diaper-changing area, and the hands of the caregivers and the children. Sampling was done twice weekly for two 4-week periods. Each center used either cloth or paper diapers during the first period, changing to the other diaper type during the second period. RESULTS: A total of 1722 samples were cultured, 881 during the first 4 weeks and 841 during the second 4 weeks. The frequency of isolation of fecal organisms ranged from a low of 12% of the total bacteria isolates at a center using cloth diapers, to highs of 46% and 45%, respectively, at a center using first paper and then cloth diapers. Sink faucets and the hands of the caregivers and the children were often contaminated. CONCLUSIONS: Analysis of the results of comparisons between cloth and paper diapers showed no significant difference in the frequency (F = .380, P < .535) or the intensity of fecal contamination in child day care centers. PMID- 7832259 TI - Trends in cigarette smoking among US adolescents, 1974 through 1991. AB - OBJECTIVES: The purpose of this study was to determine national trends in adolescent cigarette smoking prevalence. METHODS: We conducted trend analyses based on 1974 through 1991 current smoking prevalence data among persons aged 12 through 19 years from the National Household Surveys on Drug Abuse, High School Seniors Surveys, and National Health Interview Surveys. RESULTS: Overall smoking prevalence declined much more rapidly from 1974 through 1980 (1.9 percentage points annually among younger adolescents; the range among surveys of older adolescents was 0.2 to 2.0 percentage points annually) than from 1985 through 1991 (0 to 0.5 percentage points annually among all adolescents). Since 1980, smoking has generally declined at a slightly faster rate among older female adolescents than among male adolescents. Smoking among Black adolescents of all ages declined in nearly every survey population during each study period (range among surveys: 1974-1985 = 1.0 to 2.9 percentage points; 1985-1991 = 0.7 to 1.5 percentage points annually); for White adolescents, only minimal declines in smoking have occurred since 1985. CONCLUSIONS: Since 1974, major changes in adolescent smoking patterns have occurred, especially among Blacks. The overall slowing rate of decline in smoking prevalence since 1985 may indicate success of increased tobacco advertising and promotional activities targeted at adolescents or inadequate antitobacco education efforts. PMID- 7832260 TI - The natural history of drug use from adolescence to the mid-thirties in a general population sample. AB - OBJECTIVES: This study sought to describe patterns of initiation, persistence, and cessation in drug use in individuals from their late 20s to their mid-30s, within a broad perspective that spans 19 years from adolescence to adulthood. METHODS: A fourth wave of personal interviews was conducted at ages 34-35 with a cohort of men and women (n = 1160) representative of adolescents formerly enrolled in New York State public secondary high schools. A school survey was administered at ages 15-16, and personal interviews with participants and school absentees were conducted at ages 24-25 and 28-29. Retrospective continuous histories of 12 drug classes were obtained at each follow-up. RESULTS: There was no initiation into alcohol and cigarettes and hardly any initiation into illicit drugs after age 29, the age at which most use ceased. The largest proportion of new users was observed for prescribed psychoactives. Periods of highest use since adolescence based on relative and absolute criteria were delineated. Among daily users, the proportions of heavy users declined for alcohol and marijuana but not for cigarettes. CONCLUSIONS: Cigarettes are the most persistent of any drug used. Drug-focused interventions must target adolescents and young adults. PMID- 7832261 TI - Estimating the costs of substance abuse to the Medicaid hospital care program. AB - OBJECTIVES: The purpose of this study was to develop a model, using the epidemiologic tool of attributable risk, for estimating the cost of substance abuse to Medicaid. METHODS: Based on prior substance-use and morbidity research, population attributable risks for substance abuse-related diseases were calculated. (These risks measure the proportion of total disease cases attributable to smoking, drinking, and drug use.) The risks for each disease were applied to Medicaid hospital discharges and days on the 1991 National Hospital Discharge Survey that had these diseases as primary diagnoses. The cost of these substance abuse-related days were added to Medicaid hospital costs for direct treatment of substance abuse. RESULTS: More than 60 medical conditions involving 1100 diagnoses were identified, at least in part, as attributable to substance abuse. Factoring these substance abuse-related conditions into hospital costs, 1 out of 5 Medicaid hospital days, or 4 million days, were spent on substance abuse related care in 1991. In 1994, this would account for almost $8 billion in Medicaid expenditures. CONCLUSIONS: The use of tobacco, alcohol, and drugs contributes significantly to hospital costs. To address rising costs, substance abuse treatment and prevention should be an integral part of any health care reform effort. PMID- 7832262 TI - Trends in the treatment of alcohol problems in the US general population, 1979 through 1990. AB - OBJECTIVES: The purpose of this study was to conduct a comprehensive analysis of alcohol-treatment service utilization trends in the general population during the 1980s. METHODS: Three national surveys of the US household population (1979, 1984, and 1990) were used for trend analysis of treatment utilization. Trends in demographic characteristics of persons with lifetime treatment rates and particular types of treatment were examined by means of logistic regression analysis, controlling for alcohol problem severity and other variables. RESULTS: Substantial increases in the numbers reporting treatment were found. In all surveys, Alcoholics Anonymous was the treatment used most frequently and its use increased most, especially for women. Men were more likely than women (odds ratio [OR] = 2.01, 95% confidence interval [CI] = 1.20, 5.39) and unmarried persons were twice as likely as married persons to have been treated [corrected]. Social consequences carried more predictive power than dependence symptoms. CONCLUSIONS: From a general population perspective, while overall treatment capacity has increased, the structural changes in the public/private balance of services have not positively affected the representation of women or other characteristics of the treatment population. PMID- 7832263 TI - What if Americans drank less? The potential effect on the prevalence of alcohol abuse and dependence. AB - OBJECTIVES: Several advisory committees have recently recommended that alcohol consumption be limited to moderate levels. Moderate drinking has been defined generally as not more than two drinks per day for healthy men and not more than one drink per day for healthy, nonpregnant women. The impact of reducing alcohol consumption to within the recommended guidelines on the prevalence of two serious alcohol-related problems was examined by modeling the relationship between average daily ethanol intake and alcohol abuse and dependence. METHODS: The recommended drinking guidelines, both in their existing form and modified by a measure of impairment, were applied to the observed distribution of consumption derived from a large representative survey of the US general population. RESULTS: The results demonstrated that restricting drinking to the maximum allowable levels under the existing and the modified guidelines would reduce the prevalence of alcohol abuse and dependence by 14.2% and 47.1%, respectively, in the adult US general population. CONCLUSIONS: Implications of these findings are discussed in terms of the validity of the assumptions underlying the models and the nature and direction of future research that would form the basis of newly developed guidelines for safe drinking limits. PMID- 7832264 TI - Menthol vs nonmenthol cigarettes: effects on smoking behavior. AB - OBJECTIVES: The purpose of this study was to examine intraindividual differences in smoking behavior between smoking regular and mentholated cigarettes. METHODS: Healthy male smokers (n = 29) smoked either a regular or a mentholated cigarette in two separate sessions 1 week apart. Commercial brands with comparable tar, nicotine, and CO content were used. Smoking behavior was constrained by fixed 15 second interpuff intervals, but puff volume and number of puffs were unconstrained. RESULTS: When smoking the non-mentholated brand of cigarettes, participants smoked 22% more puffs and had 13% higher mean volumes per puff than they did when smoking the mentholated brand of cigarettes. The aggregate 39% excess exposure to cigarette smoke in the regular-cigarette condition was not accompanied by commensurate excesses in expired carbon monoxide or in physiological measures normally correlated with nicotine exposure. CONCLUSIONS: These findings parallel differences in physiological correlates of exposure to nicotine found in cross-sectional comparisons of African-American and White smokers and are consistent with the results of emerging laboratory investigations. PMID- 7832265 TI - Characteristics associated with excessive weight gain after smoking cessation in men. AB - OBJECTIVES: Data from two surveys of the National Academy of Sciences-National Research Council Twin Registry, conducted 16 years apart, were used to determine characteristics of individuals that were predictive of excessive weight gain after smoking cessation. METHODS: Over the follow-up, 2179 men quit smoking and averaged a weight gain of 3.5 kg. Quitters were grouped into four categories of weight change: lost weight, no change, gained weight, and excessive weight gain ("super-gainers"). RESULTS: In comparison with quitters reporting no change in weight, super-gainers were younger, were of lower socioeconomic status, and differed on a number of health habits before quitting (all Ps < .05). At follow up, super-gainers reported changes in health habits that were significantly different from those seen in quitters reporting stable weight (all Ps < .05). Pairwise concordance for weight change in 146 monozygotic and 111 dizygotic twin pairs in which both twins quit smoking was significantly greater in monozygotic than dizygotic pairs (P < .01). CONCLUSIONS: These results indicate that super gainers differ in important ways from those who do not gain weight after smoking cessation and that these weight changes may be influenced by underlying genetic factors. PMID- 7832266 TI - Facial wrinkling in men and women, by smoking status. AB - OBJECTIVES: This study examined the association of smoking status and pack-years of smoking with facial wrinkling in men and women. METHODS: We conducted a cross sectional study of 299 never smokers, 551 former smokers and 286 current smokers, aged 30 through 69 years, drawn from a health maintenance organization. Smoking status, pack-years of smoking, and potential confounding variables were assessed by questionnaire. Facial wrinkle category, a dichotomous variable, and facial wrinkle score, a computed continuous variable, were assessed by blinded standardized visual assessment. Wrinkling was so uncommon among 30- through 39 year-old subjects that analyses were restricted to subjects aged 40 and over (227 never smokers, 456 former smokers, and 228 current smokers). RESULTS: With age, average sun exposure, and body mass index controlled, the estimated relative risk of moderate/severe wrinkling for current smokers compared to never smokers was 2.3 (95% confidence interval [CI] = 1.2, 4.2) among men and 3.1 (95% CI = 1.6, 5.9) among women. Pack-years was positively associated with facial wrinkle score in women aged 40 through 69 years and in men aged 40 through 59 years. In both groups, the increased risk of wrinkling was equivalent to about 1.4 years of aging. CONCLUSIONS: Our results support earlier findings that risk of facial wrinkling is greater in cigarette smokers than in never smokers. PMID- 7832267 TI - Heroin use during methadone maintenance treatment: the importance of methadone dose and cocaine use. AB - OBJECTIVES: The purpose of this study was to examine factors associated with heroin use during methadone maintenance treatment. METHODS: Logistic regression statistical models were used to examine data obtained in a cross-sectional sample of 652 methadone patients. RESULTS: Heroin use during the 3 months prior to interview was shown to be greatest among (1) patients maintained on methadone dosages of less than 70 mg/day (adjusted odds ratio [OR] = 2.1, 95% confidence interval [CI] = 1.3, 3.4) and (2) patients who used cocaine during treatment (adjusted OR = 5.9, 95% CI = 3.8, 9.1). These results were independent of treatment duration, treatment compliance, alcohol use, and socioeconomic factors. Cocaine users were more likely than nonusers of cocaine to use heroin at all methadone dosage levels. CONCLUSIONS: This study confirms and extends past research showing high-dose methadone maintenance to be important to heroin abstinence. Further investigation of the independent association between heroin use and cocaine use is needed. PMID- 7832268 TI - Farm-related fatalities among children in California, 1980 to 1989. AB - To evaluate farm-related deaths among children in California and to identify specific risk factors, this study used death certificate tapes to identify 40 farm-related deaths among children under age 15 in California for 1980 to 1989. Mortality rates and odds ratios for cause-specific unintentional farm deaths were calculated. While California's farm-related mortality rate was lower than those in the midwestern states studied, the rate for Hispanic boys was 70% higher than that for non-Hispanics. The odds of death from machinery (81.3), animals (10.1), electricity (5.2), and nontraffic motor vehicles (3.4) were significantly greater than those in nonfarm locations; those from drowning were significantly lower (0.2). Specific factors associated with the lower California mortality rate need to be identified. PMID- 7832269 TI - Daylight saving time and motor vehicle crashes: the reduction in pedestrian and vehicle occupant fatalities. AB - Fatal crashes were tabulated for 6-hour periods around sunrise and sunset, from 13 weeks before the fall change to standard time until 9 weeks after the spring change to daylight saving time. Fatal-crash occurrence was related to changes in daylight, whether these changes occurred abruptly with the fall and spring time changes or gradually with the changing seasons of the year. During daylight saving time, which shifts an hour of daylight to the busier evening traffic hours, there were fewer fatal crashes. An estimated 901 fewer fatal crashes (727 involving pedestrians, 174 involving vehicle occupants) might have occurred if daylight saving time had been retained year-round from 1987 through 1991. PMID- 7832271 TI - World War II-veteran male twins who are discordant for alcohol consumption: 24 year mortality. AB - The role of genetic and shared environmental influences in the association of alcohol with mortality was studied by using the National Academy of Sciences National Research Council World War II-veteran male twin registry. An epidemiologic questionnaire administered from 1967 through 1969 permitted identification of twin pairs discordant for alcohol consumption. The subsequent 24 years of mortality follow-up yielded data on time and cause of death. Analyzing the first or only death in drinking-discordant pairs, we observed 27 deaths in abstainer twins and 14 deaths in their light- to moderate-drinker cotwins (relative risk [RR] = 1.93). Excess mortality in twin abstainers was also indicated for deaths from cardiovascular diseases (RR = 2.0) and other causes of death excluding cancers (RR = 3.2). The protective effect, however, of light to moderate drinking did not persist in twins who were smokers at baseline. PMID- 7832270 TI - Compliance with the 1992 California motorcycle helmet use law. AB - To evaluate helmet use in California before and after the introduction of an unrestricted helmet use law on January 1, 1992, observations of motorcycles and their riders were made at 60 locations in seven California counties, twice before and four times after the law was introduced. Helmet use increased from about 50% in 1991 to more than 99% throughout 1992. Compliance was achieved despite variations in helmet use by motorcycle design and road type. Seven percent of riders used nonstandard helmets after the law. With adequate enforcement, unrestricted helmet use laws can achieve almost 100% compliance and reduce the number of people riding motorcycles. PMID- 7832272 TI - Lymphangiomatosis of the limbs. Clinicopathologic analysis of a series with a good prognosis. AB - Six cases of a distinctive but poorly recognized variant of lymphangiomatosis with predominant or exclusive involvement of the soft tissues of the limb/limb girdle are described. The six patients were male and presented with slowly progressive swelling of the involved limb. The age of onset was at birth (three cases), 3 months (one case), 11 years (one case) and 12 years (one case). Five patients had involvement of the lower extremity and one of the right upper extremity. Three patients had concomitant asymptomatic bone involvement either in the affected limb (two cases) or in distant bones (one case). Only one patient had visceral involvement that was limited to the ipsilateral thorax and was associated with chylothorax. Diagnosis was confirmed in all but one patient by lymphangiography. Treatment consisted principally of surgical reduction with significant clinical improvement. No patient later developed systemic involvement and the clinical course was benign. The bone lesions did not progress in any patient. Histologically, each case was characterised by interconnecting, dilated lymphatic spaces, lined by a single, attenuated layer of endothelial cells, involving the dermis, subcutis, and occasionally, underlying fascia and skeletal muscle with characteristic and extensive "dissection" of collagen and surrounding normal adnexal structures. Despite the absence of red blood cells in the vascular spaces, interstitial hemosiderin deposition was prominent in four cases. As opposed to most cases of lymphangiomatosis, which usually have extensive visceral involvement associated with a very poor prognosis, involvement in this variant is limited almost exclusively to soft tissues of the limb and bone and is associated with good prognosis. PMID- 7832273 TI - Lymphoma of the kidney. A report of 11 cases. AB - We describe 11 patients first seen with symptoms or signs related to lymphoma predominantly or exclusively involving one or both kidneys. The patients were seven men and four women, aged 40-77 years (median, 67). Seven of them had one or more other prior (four), subsequent (two) or both simultaneous and subsequent (one) primary malignant or premalignant lesions. The presenting symptoms of the patients with lymphoma included local pain (five cases), loss of appetite or nausea (four cases), hematuria (two cases), weight loss (two cases) or malaise (two cases). One patient had renal failure at presentation. One lymphoma was an incidental finding at the time of aneurysm resection. Nine patients had unilateral disease; two patients had bilateral disease. Six unilateral cases were initially considered on clinical (five) or clinical and pathological (one) evaluation to be primary carcinomas of the kidney. Gross examination of nephrectomy specimens revealed fleshy or firm, yellow, tan, or gray tumors from 5.7 to 22 cm (median, 7.5) in greatest dimensions that frequently invaded perinephric fat and adjacent structures. The lymphomas were subclassified as diffuse large cell (seven cases), follicular and diffuse large cell (one case), small lymphocytic plasmacytoid (two cases), and small noncleaved cell lymphoma (non-Burkitt's type) (one case). Immunophenotyping in nine cases revealed that all were B-lineage tumors. Three patients had Ann Arbor stage I disease, three had stage II, and five had stage IV. On follow-up, ranging from 1 week to 169 months (median, 15 months), 5 patients were alive and free of lymphoma. Four patients died of progressive disease 1 week to 23 months after diagnosis. One patient is alive at 4 months but has not completed chemotherapy. One asymptomatic patient has not been treated. Renal lymphomas are predominantly large-cell lymphomas of B-lineage affecting middle-aged and older adults and often can be treated successfully. Both clinically and pathologically, they can be mistaken for carcinomas of the kidney. A high proportion of patients in this series had malignant tumors of other types. PMID- 7832274 TI - Tumefactions as an extravascular manifestation of Wegener's granulomatosis. AB - Wegener's granulomatosis appeared as localized or infiltrative tumefactions in six patients. The tissue swellings affected the retroperitoneum, mediastinum (two), breast, retroorbital tissue (two), and gingiva. There was extensive fibroblastic proliferation in each case with a predominantly granulocytic inflammatory component, microabscess formation, and collagen necrobiosis. In one of the mediastinal lesions and in the gingiva, there was a granulomatous component as well. In the breast were scattered multinucleated histiocytes. Necrotizing vasculitis was absent or limited in all cases. All patients responded dramatically to cyclophosphamide and/or prednisone after the diagnosis was established. These observations indicate a role for tissue destruction in Wegener's granulomatosis mediated by granulocytes without a vasculitic component. PMID- 7832275 TI - Vulvar vestibulitis. A histopathologic study of 36 cases, including human papillomavirus in situ hybridization analysis. AB - Vulvar vestibulitis is a recently described clinical condition of unknown etiology. Human papillomavirus (HPV) infection has been implicated as a causal pathogen by some investigators. Because reports on this entity are few, we studied the pathologic features of vestibulectomy specimens from 36 women with a clinical diagnosis of vulvar vestibulitis. The patients' ages ranged from 19 to 53 years (mean, 31 years). Bilateral excisions were performed in 34 patients and a unilateral excision in two. Minor vestibular glands or ducts were identified in 28 patients (78%). Chronic inflammation was present in all specimens. The inflammatory infiltrate consisted predominantly of T lymphocytes and plasma cells with smaller numbers of B lymphocytes. Lymphoid follicles were present in four patients, ulcers in two. The predominant site of inflammation was the squamous mucosa, especially the lamina propria, where the degree of inflammation was graded as mild in 11 patients, moderate in 21 patients, and severe in four patients. To a lesser degree, the inflammation also typically involved the periglandular/periductal connective tissue of the minor vestibular glands, where it was graded as mild in 25 patients and moderate in three patients. Foci of squamous metaplasia were observed in 27 of 28 patients with demonstrable vestibular ducts or glands. Nodular hyperplasia of a vestibular gland (so-called "adenoma") occurred in one patient. In six selected cases, fungi were not identified on silver stains. Morphologic findings of HPV infection, such as koilocytotic atypia or squamous dysplasia, were absent. In-situ hybridization studies for HPV types 6, 11, 16, 18, 31 and 35 were negative in all 36 cases. We conclude that (a) vestibulectomy specimens from patients with a clinical diagnosis of vulvar vestibulitis typically show a chronic inflammatory cell infiltrate that predominantly involves the mucosal lamina propria and periglandular/periductal connective tissue and (b) a pathogenetic role for HPV types 6, 11, 16, 18, 31 and 35 is not substantiated. PMID- 7832276 TI - Cutaneous pathology in Wegener's granulomatosis. A clinicopathologic study of 75 biopsies in 46 patients. AB - While no cutaneous lesion is specific for Wegener's granulomatosis (WG), several histopathologic entities, including leukocytoclastic vasculitis and necrotizing granulomatous inflammation, are characteristic. This report details the histopathologic features of 75 cutaneous biopsies from 46 patients with WG. Biopsies were subdivided into histologic groups that included leukocytoclastic vasculitis (31%), granulomatous inflammation (GI) (19%), nonspecific ulceration (4%), superficial dermal and epidermal necrosis without inflammation (2.7%), erythema nodosum (2.7%), granuloma annulare (1%), chronic inflammation (31%), and acute inflammatory lesions without vasculitis (9%). No convincing example of granulomatous vasculitis was observed. The histopathologic subgroups were correlated with clinical features, and the results were compared with those from a control group of 82 WG patients with no skin involvement. We found that the histopathologic subgroups of leukocytoclastic vasculitis and granulomatous inflammation correlated with different clinical courses. Patients with leukocytoclastic vasculitis developed WG at an earlier age (median age, 30 years) than did the control group (median age, 45 years). Leukocytoclastic vasculitis developed shortly after onset of WG (median, 15 months vs. 35 months for patients with nonspecific chronic inflammation). All lesions occurred during active disease. Active disease with leukocytoclastic vasculitis was associated with a mean erythrocyte sedimentation rate twice that of active disease in the same patient when leukocytoclastic vasculitis was absent. The patients with leukocytoclastic vasculitis had more rapidly progressive and widespread WG than patients with granulomatous skin lesions or patients without skin lesions. A marked excess of joint and musculoskeletal symptoms and renal disease was seen in patients with leukocytoclastic vasculitis. Patients with granulomatous inflammation also developed WG at an early age (median age, 30 years) when compared with the control group. Cutaneous granulomatous lesions also developed shortly after presentation (median, 12 months). Only 64% of granulomatous biopsies were from patients with active disease. These patients frequently had neither renal nor pulmonary manifestations of WG, and their disease progressed at a slower rate than that of the patients with leukocytoclastic vasculitis. These findings suggest that the cutaneous lesions characteristic of WG may correlate with the activity, distribution, and course of the disease. PMID- 7832277 TI - Immunostaining in the diagnosis of pulmonary neuroendocrine carcinomas. An immunohistochemical study with ultrastructural correlations. AB - To determine the specificity of immunostaining in the diagnosis of pulmonary neuroendocrine carcinomas, we studied 66 ultrastructurally characterized lung cancers with a panel of markers considered to be selective for neuroendocrine tumors (neuron-specific enolase, chromogranin A, Leu 7, synaptophysin) and B72.3, which is reported to be selective for non-small-cell carcinomas. Neuroendocrine tumors studied included 13 small-cell carcinomas, four low-grade neuroendocrine carcinomas, and two large-cell carcinomas with neuroendocrine differentiation. Non-neuroendocrine tumors included 26 adenocarcinomas, 10 squamous cell carcinomas, and 11 large-cell undifferentiated carcinomas. The following percentages of neuroendocrine carcinomas showing immunoreactivity for the various "neuroendocrine markers" were found: synaptophysin, 100%; neuron-specific enolase, 74%; chromogranin A, 37%; and Leu 7, 5%. However, carcinomas without morphologic features of neuroendocrine differentiation showed the following immunoreactivity: synaptophysin, 62%; neuron-specific enolase, 60%; chromogranin A, 17%; and Leu 7, 9%. B72.3 immunostaining was seen in 81% of the carcinomas without neuroendocrine features and in 31% of the small-cell carcinomas. We conclude that many of the commercially available antibodies used as neuroendocrine markers are nonspecific in the diagnosis of pulmonary neuroendocrine carcinomas. PMID- 7832278 TI - Surgical pathology of adenocarcinoma arising in Barrett's esophagus. Analysis of 67 cases. AB - Numerous reviews of adenocarcinoma arising in Barrett's esophagus have been reported, but detailed pathologic findings or survival analysis have rarely been provided. This retrospective study analyzed 67 patients (mean age, 64 years; male to-female ratio, 10:1) with an adenocarcinoma arising in Barrett's esophagus treated by surgical resection. Prevalence of smokers was 63%, alcohol users, 45%, and patients with hiatal hernia, 73%. Five patients had another synchronous cancer, and seven patients, previous esophageal surgery. Forty percent of the tumors were well differentiated, 31% moderately differentiated, 15% poorly differentiated, 7% mucinous, and 6% composed of signet-ring cells. Depth of invasion in the esophageal wall was limited to mucosa in 13% of cases and submucosa in 18%. Invasive adenocarcinomas extended to the muscular layer in 12% of cases, to adventitia in 33%, and to periesophageal tissue in 24%. Vascular and perineural neoplastic invasion was present in 67 and 38% of cases. Regional lymph node involvement and distant metastases were found in 51 and 9% of cases. Overall, 1-, 2-, and 5-year survival rates were 63, 41, and 32%, respectively. Five-year survival rate was significantly better for patients with superficial cancer limited to mucosa or submucosa (82 vs. 12%) or without regional lymph node involvement (59 vs. 10%). Tumor differentiation, vascular and perineural invasion, extranodal spread, distant metastases, and resection margins status also had a significant prognostic value on univariate analysis. In a multivariate Cox regression analysis for overall survival, depth of invasion in the esophageal wall and regional lymph node involvement were independent prognostic factors. Careful pathologic staging is of value in determining the prognosis of patients with adenocarcinoma arising in Barrett's esophagus. PMID- 7832280 TI - Sarcomatoid carcinoma of the anorectal junction with neuroendocrine and rhabdomyoblastic features. AB - A case of sarcomatoid carcinoma of the anorectal junction in a 71-year-old woman showing neuroendocrine and rhabdomyoblastic features is described. The tumor was diffusely infiltrative and metastases to regional lymph nodes were found at laparotomy. The patient died 6 months after surgery with widespread metastases. PMID- 7832279 TI - Structural integrity and identification of causes of liver allograft dysfunction occurring more than 5 years after transplantation. AB - The clinicopathologic features of liver allograft dysfunction occurring in 51 symptomatic recipients after more than 5 years' survival (mean 7.1 years) with the same hepatic allograft were compared with those of a similar group of 14 asymptomatic patients (mean survival, 9.9 years) who underwent a nonclinically indicated protocol liver biopsy evaluation. Predictably, patients who had clinically indicated biopsies more frequently showed histopathologic alterations (76% versus 36%, p < 0.002). After detailed clinicopathologic correlation, the changes in the symptomatic patients were attributed primarily to definite or presumed viral hepatitis in 17 of 51 (33%) patients, 11 of whom had recurrent viral disease; seven of 51 (14%) had nonviral recurrent original disease, three (6%) had obstructive cholangiopathy, and 11 (22%) had acute and/or chronic rejection. In 13 of 51 (25%) of the symptomatic patients, the clinical and pathologic abnormalities were minimal. Long-term liver allograft survival in nine of 14 (64%) of the asymptomatic patients was associated with minimally abnormal histologic alterations. Two of the asymptomatic patients had obstructive cholangiopathy; two others has recurrence of the original disease and one has possible viral hepatitis. Viral hepatitis types B and C, alcoholic liver disease, autoimmune hepatitis, granulomatous hepatitis (not otherwise specified), and probably primary biliary cirrhosis and primary sclerosing cholangitis were shown to recur after hepatic transplantation. The histopathologic changes associated with acute and chronic rejection frequently overlapped with other syndromes causing late dysfunction, such as chronic viral or autoimmune hepatitis, primary biliary cirrhosis, or primary sclerosing cholangitis; more than one insult could be identified in 15 cases, which made the differential diagnosis of causes of late liver allograft dysfunction much more difficult than early after hepatic transplantation. It is important to correlate the biopsy findings with the liver injury tests, the results of viral and autoimmune antibody serologic studies, and review of previous biopsies and to be aware of the original disease, recent changes in immunosuppression, and results of therapeutic intervention(s) to identify correctly the causes of liver allograft dysfunction in this patient population. PMID- 7832281 TI - Graft-versus-host-like colitis associated with malignant thymoma. AB - A case of a patient with a malignant thymoma who developed an unusual form of colitis is reported. The patient was a previously healthy 20-year-old man who was referred to the Johns Hopkins Medical Institution for biopsy and resection of a mediastinal mass, which proved to be a malignant thymoma. During this hospitalization and subsequently, the patient developed severe chronic diarrhea, the etiology of which remained uncertain after routine work-up, including cultures. Colonoscopic biopsies revealed only minimal inflammation but numerous, prominent apoptotic lesions within crypt epithelium, suggestive of an autoimmune or graft-versus-host-like colitis. The patient, who was immunocompetent and human immunodeficiency virus (HIV) negative, had no known risk factors for graft-versus host-disease (e.g., no blood transfusions, no transplantation history before diarrheal episodes). Stool cultures for pathogenic bacteria and viruses were negative. The diarrhea and histologic findings eventually improved with steroid therapy yet returned on recurrence of the thymoma. This unusual form of colitis has not been previously reported to be associated with thymoma and is interesting in light of the role the thymus plays in immune regulation. PMID- 7832282 TI - Adenoid cystic carcinoma of the uterine cervix with malignant stroma. An unusual variant of carcinosarcoma? AB - An 80-year-old woman developed vaginal bleeding caused by a large tumor of the cervix. Histologically, the tumor proved to be composed predominantly of adenoid cystic carcinoma focally associated with squamous cell carcinoma. Of special interest was the stroma, which displayed pleomorphism, multinucleated tumor giant cells, and numerous mitoses, justifying the designation of carcinosarcoma. A single similar reported case also regarded as a carcinosarcoma described a primary cervical neoplasm in a postmenopausal woman containing an admixture of heterologous sarcoma and conventional cervical adenocarcinoma, which focally demonstrated areas of adenoid cystic carcinoma. PMID- 7832283 TI - Transbronchial biopsy in pulmonary lymphangiomatosis. PMID- 7832284 TI - [Brain research as a philosophical problem]. PMID- 7832285 TI - Localization of lysosomal enzymes in the retina and retinal pigment epithelium of RCS rats. AB - Using ultrahistochemical and immunohistochemical techniques, localization of acid phosphatase and cathepsin D was demonstrated in the retina and pigment epithelium of 1 to 42 day old RCS rats and its nonaffected congenic rat strain. Both enzymes are present in the pigment epithelium of the normal and dystrophic rat eye. As early as the age of 1 week, it was found that the lysosomes in the dystrophic rat retina are less stable in releasing acid phosphatase than those of control animals. Infiltration of cathepsin D into the subretinal space could first be detected with certainty in 2-week-old animals. The fragility of the lysosomal membrane and, therefore, the release of both enzymes became more pronounced as the animals aged. The findings of this study indicate that the instability of the lysosomal membrane in the RCS rat pigment epithelium may initiate degeneration of photoreceptors and pigment epithelium. The demonstration of cathepsin D activity has proved very helpful in revealing the physiological or pathophysiological condition of retinal pigment epithelium. PMID- 7832286 TI - Alterations of the fetal extracellular matrix in the nuchal oedema of Down's syndrome. AB - Elevations in the lateral and dorsal neck region are known to be highly correlated with chromosomal aberrations in human fetuses. However, the morphology of the elevations is poorly described. Only in the case of Turner's syndrome has lymphatic vessel formation been shown to be deficient leading to swellings in the nuchal area. In Down's syndrome, non-echogenic nuchal oedemata can be visualized in ultrasound scan between the 10th and 15th week of gestation. In the present study, alterations in the extracellular matrix (ECM) of the skin in trisomy 21 fetuses were found to be the morphological basis of the nuchal oedema. The distribution of collagen type VI differs from that in normal fetuses, both in nuchal and leg skin. Collagen VI forms a denser mesh in trisomy 21 than in normal fetal skin, hyaluronan (HA) being the main glycosaminoglycan (GAG) component as judged from the appearance of the TEM precipitate after fixation in the presence of tannic acid. Nuchal oedema in Down's syndrome is therefore found to be an interstitial oedema. The interstitial fluid is bound to HA, leading to a swelling of the fetal dermis. No cysts or dilated vessels were found in the oedematous tissue. The presence of a high amount of HA during development can influence the behaviour of migrating cell populations, which might have a bearing on the pathogenesis of Down's syndrome. PMID- 7832287 TI - [Comparative studies on looking into lacertus fibrosis and aponeurosis of the bicipitis brachii muscle as well as assessment of the biceps brachii and bracialis muscles in sheep, goats and wild deer]. AB - In 34 anatomical specimens of sheep, goat and fallow deer the development of the cranial brachial and antebrachial fascia as well as the occurrence of a lacertus fibrosus and of structures, that are homologous with the aponeurosis m. bicipitis brachii hominis, were studied. Additionally, the attachments of the m. biceps brachii and the m. brachialis were dissected. In sheep, goat and fallow deer the superficial layer of the fascia brachii et antebrachii is weakly developed. Its deeper stratum, originating in the tuberositas deltoidea as well as in the crista humeri, and on the forearm interspersing with the fascia of the m. extensor carpi radialis, is of a more robust composition. In goat and fallow deer a remarkable ligamentous bracing of this fascial layer stresses its cranial aspect. The lacertus fibrosus intermingles in all three species with the cranial fascia antebrachii respectively with the tendon of the m. extensor carpi radialis. While in sheep and goat its emergence from the m. biceps brachii is obviously bipartite, in fallow deer this part of the lacertus fibrosus is undivided. Moreover, in all three species a muscular and/or tendinous connection between the m. biceps brachii and the m. pronator teres exists, that is homologous with the aponeurosis m. bicipitis brachii hominis. In sheep, goat and fallow deer the m. biceps brachii attaches with each one tendon to the tuberositas radii and the processus coronoideus med. ulnae. Frequently in sheep, but rarely in goat the ulnar tendon extends its area of attachment to the radius.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7832288 TI - Detection and localization of autofluorescent substances in thymus tissue of sheep. AB - An oxygenated sterol was detected by chemical analysis of sheep thymus lipid extracts. It was characterized as 7 beta-hydroxycholesterol, which is well known for its biological activity. Using fluorescence microscopy, attempts were made to correlate this substance to particular histological structures of the thymus tissue. Microscopy revealed an intense yellow-green primary fluorescence distributed throughout the entire thymic parenchyma, which was predominant in the cortico-medullary junction, the vicinity of the Hassall's bodies and the subcapsular space. This indicated an accumulation of the fluorogenic substance in special tissue structures of sheep thymus. This result can be assumed as specific for the thymus, since such primary fluorescence was absent from other simultaneously investigated organs, such as the adrenal. PMID- 7832289 TI - [Preparation of critical point dried specimens of mouse embryos with a laser scalpel]. AB - We investigated the use of a laser scalpel for tissue sparing demonstration of the deep structures of critical point dried specimens. A Nd:YAG-Laser emitted pico-second pulses (wavelength 1064 nm, pulse width 30 ps) at pulse energies varying from 1 microJ to 6 mJ was used. Differences in the effects on sputtered and unsputtered specimens were found. We separate the floor of the mouth and pharyngeal fornix in mouse embryos (10. developmental day). It was concluded the laser scalpel is superior to conventional mechanical dissecting methods when applied to small dried specimens. The advantages and disadvantages of the laser scalpel are discussed. PMID- 7832290 TI - Age-related changes in the secretory-dendritic cells of the pigeon bursa of Fabricius: an immunohistochemical and ultrastructural study. AB - The present study was undertaken to determine, by means of immunohistochemical techniques, image analysis and ultrastructural methods, whether the secretory dendritic cells (SDC) of the pigeon bursa of Fabricius undergo changes from hatching to the involutive stage (120 days) of the organ. A monoclonal antibody against vimentin (VIM) was used to label SDC. VIM-like immunoreactivity (VIM-L IR) was observed labelling dendritic cell profiles in all age groups. These cells are primarily localized within the medulla and at the cortico-medullary border of the lymphoid follicles. At hatching VIM-L IR was present mainly in the cell bodies, whereas during post-hatching bursal growth (7 to 75 days) it was also present in the cell processes. Conversely, the involutive period examined (90-120 days) was characterized by a progressive decrease of VIM-L IR in the SDC processes. Quantitative studies confirmed the immunohistochemical findings. At the ultrastructural level, there was a progressive increase from 0 to 90 days of age in both the number and size of secretory granules and break-down bodies, as well as in the length of the SDC processes. The involutive stage showed the reverse phenomena. The present results demonstrate that the SDC of the pigeon bursa of Fabricius undergo age-related changes parallel with that of the organ. The possible involvement of SDC in the maintenance of the bursal microenvironment and their role in the maturation of lymphoid line cells is discussed. PMID- 7832291 TI - Carbachol, norepinephrine, and hypocapnia stimulate phosphatidylinositol turnover in rat tracheal slices. AB - BACKGROUND: The intracellular mechanisms involved in the alpha-adrenoceptor- or hyperventilation-induced bronchoconstriction remain unknown. Because there is a direct relationship between phosphatidylinositol (PI) metabolism and airway smooth muscle contraction induced by muscarinic agonists, the authors examined the effects of carbachol (CCh), norepinephrine (NE), and hypocapnia on PI turnover in the airway smooth muscle. METHODS: Rat tracheal slices were incubated in Krebs-Henseleit solution containing LiCl and [3H]myo-inositol in the presence of NE, CCh, or neither. The PCO2 in the solution was 36 +/- 3 mmHg (normocapnia), 19 +/- 2 mmHg (moderate hypocapnia), or 5 +/- 2 mmHg (severe hypocapnia), respectively. [3H]inositol monophosphate (IP1) formed was counted with a liquid scintillation counter. RESULTS: Basal IP1 formed was greater at severe hypocapnia than at normocapnia. Norepinephrine- and CCh-induced IP1 formation were also greater at hypocapnia than at normocapnia. CONCLUSIONS: These results indicate that CCh, NE, and hypocapnia stimulate PI turnover in the airway smooth muscle, which would cause bronchoconstriction, and hypocapnia also augments NE- and CCh induced PI turnover, which could cause worsening of exercise-induced asthma and vagotonic asthma, respectively. PMID- 7832292 TI - Halothane, isoflurane, xenon, and nitrous oxide inhibit calcium ATPase pump activity in rat brain synaptic plasma membranes. AB - BACKGROUND: Perturbation of neuronal calcium homeostasis may alter neurotransmission in the brain, a phenomenon postulated to characterize the anesthetic state. Because of the central role of plasma membrane Ca(2+)-ATPase (PMCA) in maintaining Ca2+ homeostasis, the authors examined the effect of several inhalational anesthetics on PMCA function in synaptic plasma membranes (SPM) prepared from rat brain. METHODS: Ca(2+)-ATPase pumping activity was assessed by measurement of ATP-dependent uptake of Ca2+ by SPM vesicles. ATPase hydrolytic activity was assessed by spectrophotometric measurement of inorganic phosphate (Pi) released from ATP. For studies of anesthetic effects on PMCA activity, Ca2+ uptake or Pi release was measured in SPM exposed to halothane, isoflurane, xenon, and nitrous oxide at partial pressures ranging from 0 to 1.6 MAC equivalents. Halothane and isoflurane exposures were carried out under a gassing hood. For xenon and nitrous oxide exposures, samples were incubated in a pressure chamber at total pressures sufficient to provide anesthetizing partial pressures for each agent. RESULTS: Dose-related inhibition of Ca(2+)-ATPase pumping activity was observed in SPM exposed to increasing concentrations of halothane and isoflurane, confirmed by ANOVA and multiple comparison testing (P < 0.05). Concentrations of halothane and isoflurane equivalent to one minimum effective dose (MED) depressed PMCA pumping approximately 30%. Xenon and nitrous oxide also inhibited Ca2+ uptake by SPM vesicles. At partial pressures of these two gases equivalent to 1.3 MAC, PMCA was inhibited approximately 20%. Hydrolysis of ATP by SPM fractions was also inhibited in a dose-related fashion. An additive effect occurred when 1 vol% of halothane was added to xenon or nitrous oxide at partial pressures equivalent to 0-1.6 MAC for the latter two agents. CONCLUSIONS: Plasma membranes Ca(2+)-ATPase is significantly inhibited, in a dose-related manner, by clinically relevant partial pressures of halothane, isoflurane, xenon, and nitrous oxide. Furthermore, these anesthetics inhibit PMCA activity in accordance with their known potencies, and an additive effect was observed. How inhalational anesthetics inhibit the PMCA pump is not known at this time. It is noteworthy that the only shared characteristic of this group of agents of widely different structure is anesthetic action. The relevance of this dual commonality, anesthetic action and PMCA inhibition, to actual production of the anesthetic state remains to be determined. PMID- 7832293 TI - Stable inhibition of brain synaptic plasma membrane calcium ATPase in rats anesthetized with halothane. AB - BACKGROUND: The authors recently showed that plasma membrane Ca(2+)-ATPase (PMCA) activity in cerebral synaptic plasma membrane (SPM) is diminished in a dose related fashion during exposure in vitro to halothane, isoflurane, xenon, and nitrous oxide at clinically relevant partial pressures. They have now extended their work to in vivo studies, examining PMCA pumping in SPM obtained from control rats decapitated without anesthetic exposure, from rats decapitated during halothane anesthesia, and from rats decapitated after recovery from halothane anesthesia. METHODS: Three treatment groups were studied: 1) C, control rats that were decapitated without anesthetic exposure, 2) A, anesthetized rats exposed to 1 minimum effective dose (MED) for 20 min and then decapitated, and 3) R, rats exposed to 1 MED for 20 min and then decapitated after recovery from anesthesia, defined as beginning to groom. Plasma membrane Ca(2+)-ATPase pumping and Ca(2+)-dependent ATPase hydrolytic activity, as well as sodium-calcium exchanger activity and Na+-K+-ATPase hydrolytic activity, were assessed in cerebral SPM. In addition, halothane effect on smooth endoplasmic reticulum Ca(2+)-ATPase (SERCA) was examined. RESULTS: Plasma membrane Ca(2+)-ATPase transport of Ca2+ into SPM vesicles from anesthetized rats was reduced to 71% of control (P < 0.01) compared with 113% of control for the recovered group (NS). No depression by halothane of SERCA activity, sodium-calcium exchanger, or Na+-K+ ATPase activity was noted among the CAR treatment groups. CONCLUSIONS: Plasma membrane Ca(2+)-ATPase is selectively and stably inhibited in cerebral SPM from rats killed while anesthetized with halothane, compared with rats killed without anesthesia or after recovery from anesthesia. The studies described in this report, in conjunction with previously reported inhibition of PMCA activity in vitro by a wide range of anesthetic agents, indicate a relationship between inhibition of PMCA and action of inhalational anesthetics. PMID- 7832294 TI - Thoracic epidural anesthesia attenuates halothane-induced myocardial sensitization to dysrhythmogenic effect of epinephrine in dogs. AB - BACKGROUND: The autonomic nervous system plays a critical role in the central modulation of cardiac dysrhythmias. Because sympathetic blockade by thoracic epidural anesthesia has been documented to protect patients from various stress responses, the authors speculate that epidural anesthesia can attenuate the dysrhythmogenic interaction between halothane and epinephrine. METHODS: In adult mongrel dogs anesthetized with halothane, the dysrhythmogenic dose (DD) of epinephrine, defined as the smallest dose producing four or more premature ventricular contractions within a 15-s period, was determined in the presence of thoracic epidural mepivacaine or saline. To address the effect of circulating mepivacaine after epidural administration, the authors examined the DD of epinephrine in the presence of intravenous mepivacaine. They also investigated the effect of thoracic epidural anesthesia in bilaterally vagotomized dogs. RESULTS: Epidural mepivacaine significantly increased the DD of epinephrine compared with epidural saline. However, intravenous mepivacaine did not affect the DD of epinephrine, even when the plasma concentration of mepivacaine during the dysrhythmias was twice that in the epidural mepivacaine group. The beneficial effect of epidural mepivacaine was not seen in bilaterally vagotomized dogs. CONCLUSIONS: Thoracic epidural anesthesia attenuated the myocardial sensitization by halothane, and vagal activity had an essential role in this action. PMID- 7832295 TI - Halothane impairs the hemodynamic influence of endothelium-derived nitric oxide. AB - BACKGROUND: The endogenous vasodilator endothelium-derived nitric oxide (EDNO) contributes to the regulation of vascular tone and organ perfusion. It has been suggested that some volatile anesthetics may diminish the influence of EDNO and thereby decrease regional blood flow. METHODS: Radioactive microspheres were used to determine regional hemodynamics in rats. The authors tested the hypothesis that halothane inhibits EDNO and, therefore, should diminish the response to nitric oxide synthesis inhibition by NW-nitro-L-arginine methyl ester (L-NAME) compared with either conscious or barbiturate-anesthetized rats. RESULTS: NW nitro-L-arginine methyl ester decreased blood flow to the brain by 23% (P < 0.005) in conscious rats to a level similar to that seen with either anesthetic agent. In both conscious and barbiturate-anesthetized rats, L-NAME increased blood pressure (BP) by 24 +/- 2 (P < 0.001) and 20 +/- 1 (P < 0.001) mmHg and total peripheral resistance (TPR) by 132% (P < 0.001) and 105% (P < 0.001), respectively. In contrast, during halothane anesthesia, both the pressor response (only 7 +/- 1 mmHg) and the increase in TPR (only 22%) were greatly diminished (P < 0.001). NW-nitro-L-arginine methyl ester decreased cardiac output (CO) by 47% (P < 0.001) and heart rate (HR) by 28% (P < 0.001) in conscious rats. In barbiturate-anesthetized rats, L-NAME decreased CO by 38% (P < 0.005) and HR by 13% (P < 0.001). In halothane-anesthetized rats, L-NAME changed neither CO nor HR. Thus halothane anesthesia largely eliminated the systemic response to EDNO synthesis inhibition. In conscious rats, L-NAME decreased blood flow to the heart (30%) and kidneys (47%). In barbiturate-anesthetized rats, L-NAME did not alter blood flow to the heart but decreased renal blood flow by 35% (P < 0.005). In halothane-anesthetized rats, L-NAME did not alter blood flow to either the heart or the kidneys. Overall, halothane blunted or blocked the systemic and regional hemodynamic responses to EDNO synthesis inhibition seen in conscious and barbiturate-anesthetized rats. CONCLUSIONS: Halothane anesthesia greatly diminished or eliminated all systemic and regional hemodynamic responses to L NAME. These data indicate that halothane anesthesia inhibits EDNO-mediated regulation of systemic and organ hemodynamics. PMID- 7832296 TI - Effects of opioid microinjections in the nucleus of the solitary tract on the sleep-wakefulness cycle states in cats. AB - BACKGROUND: Previous studies have shown that the region of the nucleus of the solitary tract (NST) is involved in the control of electrocortical activity and in sleep mechanisms. It also is well known that this region contains the highest concentration of opioid receptors within the medullary brainstem. The involvement of the NST opioid system in sleep-wakefulness states were evaluated. METHODS: Ten cats were implanted with electrodes for chronic polygraphic recordings of their sleep-wakefulness states and provided with an implanted guide cannula stereotaxically aimed at the NST region. Microinjections of saline, morphine sulfate, morphiceptin (specific mu agonist), D-pen-2-D-pen-5-enkephalin (delta agonist), and U-50488H (kappa agonist) were given to the freely moving animals (doses 0.8-2.4 x 10(-9) M, in a volume of 0.05 microliters of saline). After microinjections, sleep-wakefulness recordings were obtained for 8 h. RESULTS: Morphine microinjections in NST provoked a dose-dependent enhancement of all the polygraphic and behavioral manifestations of slow wave sleep. This effect was blocked by the prior intraperitoneal administration of naloxone. The mu and delta agonists also produced a hypnotic effect by enhancing slow wave sleep. By contrast, the kappa agonist caused no changes in sleep-wakefulness states. CONCLUSIONS: These results indicate that endogenous opioids could be involved in controlling electrocortical activity generated by NST and that activation of mu and delta NST opioid receptors enhanced the electroencephalographic synchronization associated with behavioral slow wave sleep in cats. PMID- 7832297 TI - The effects of halothane on cardiovascular responses in the neuraxis of cats. Influence of background anesthetic state. AB - BACKGROUND: This study examined the effects of halothane on arterial pressure after central nervous system (CNS) pressor site stimulation in anesthetized cats, cats rendered unconscious by midcollicular transection, and conscious cats. METHODS: Two anesthetized groups and two nonanesthetized groups were used. Cats were anesthetized with either alpha-chloralose and urethane or pentobarbital. Nonanesthetized groups were cats with midcollicular transections or conscious cats with chronically implanted electrodes. Stimulating electrodes were placed into vasomotor areas of the hypothalamus (HYP), reticular formation (RF), and medulla, and arterial pressure responses to increasing stimulus currents were examined during different halothane concentrations. Two groups of cats were also anesthetized with either pentobarbital or urethane and underwent bilateral carotid artery occlusion. RESULTS: Stimulation at each CNS site produced increases in arterial pressure and heart rate. Halothane attenuated pressor responses evoked by stimulation of all loci in all groups of cats. The inhibition by halothane on these cardiovascular responses was greatest at HYP and RF sites, while the medulla was more resistant to the effects of halothane in the anesthetized animals. Midcollicular transection decreased this medullary resistance. The inhibition of pressor responses by halothane was also greater in pentobarbital-than chloralose urethane-anesthetized animals. In contrast, pressor responses elicited by bilateral carotid occlusion were attenuated by halothane similarly in both anesthetic groups. Reticular formation stimulation in conscious animals resulted in "altering responses" in addition to pressor effects, both of which were attenuated by halothane. CONCLUSIONS: Modulation of CNS cardiovascular control centers contribute to halothane-induced hemodynamic alterations. Baseline anesthesia, CNS stimulation site, and the suprabulbar system influence the effects of halothane. PMID- 7832298 TI - Halothane inhibits signaling through m1 muscarinic receptors expressed in Xenopus oocytes. AB - BACKGROUND: Interactions between volatile anesthetics and muscarinic acetylcholine receptors have been studied primarily in binding assays or in functional systems derived from tissues or cells, often containing multiple receptor subtypes. Because interactions with muscarinic signaling systems may explain some effects and side effects of anesthetics and form a model for anesthetic-protein interactions in general, the author studied anesthetic inhibition of muscarinic signaling in an isolated system. METHODS: mRNA encoding the m1 muscarinic receptor subtype was prepared in vitro and expressed in Xenopus oocytes. Effects of halothane on methylcholine-induced intracellular Ca2+ release was measured. Angiotensin II receptors were expressed to evaluate anesthetic effects on intracellular signaling. RESULTS: m1 Receptors expressed in oocytes were functional, and could be inhibited by atropine and pirenzepine. Halothane depressed m1 muscarinic signaling in a dose-dependent manner: half-maximal inhibition of 10(-7) M methylcholine was obtained with 0.3 mM halothane. The effect was reversible and could be overcome by high concentrations of muscarinic agonist. Angiotensin II signaling was unaffected by 0.34 mM halothane. CONCLUSIONS: m1 Muscarinic signaling is inhibited by halothane, and lack of halothane effect on angiotensin signaling indicates that the intracellular signaling systems of Xenopus oocytes are unaffected. Therefore, the most likely site of halothane action is the receptor and/or G protein. Oocytes provide a versatile system for detailed investigation into the molecular mechanism of anesthetic-protein interactions. PMID- 7832299 TI - Platelet factor 4 injection produces acute pulmonary hypertension in the awake lamb. AB - BACKGROUND: Reversal of heparin anticoagulation by intravenous protamine sulfate consistently produces acute pulmonary vasoconstriction mediated by the release of thromboxane in the awake lamb. Recently, recombinant platelet factor 4 (rPF4) has been cloned, expressed in Escherichia coli, and infused to reverse heparin anticoagulation in the rat, without producing adverse hemodynamic or pulmonary morphologic effects. The authors sought to learn whether intravenous administration of PF4 is devoid of side effects in the pulmonary circulation of lambs. METHODS: The authors evaluated the hemodynamic response and plasma release rates of thromboxane during intravenous challenges with heparin-rPF4 (n = 2), rPF free carrier (n = 5), rPF4 (n = 5), rPF4 after indomethacin (n = 5), protamine (n = 5) and heparin-protamine (n = 5) in 17 awake, hemodynamically monitored lambs. Each lamb underwent up to three random challenges with a 2-h recovery period between each challenge. RESULTS: In two lambs, systemic anticoagulation with heparin followed by reversal of anticoagulation with an intravenous bolus of rPF4 (4 mg/kg) led to acute pulmonary vasoconstriction and hypertension with the release of thromboxane (peak pulmonary artery pressure [Ppa] 40 and 33 mmHg and peak plasma thromboxane B2 50 and 30 ng/ml, respectively). Intravenous administration of rPF4 (1.5 mg/kg) alone increased the Ppa from 17.2 +/- 0.7 mmHg (mean +/- SEM) at baseline to 31.2 +/- 2 mmHg at 1 min (n = 5, P < 0.05). This was associated with an increase of plasma thromboxane B2 from 0.06 +/- 0.02 to 3.96 +/- 1.21 ng/ml. Acute pulmonary vasoconstriction lasted approximately 5 min and was completely prevented by pre-treatment with oral indomethacin (10 mg/kg). Intravenous bolus administration of rPF4 carrier (n = 5) or protamine (2 mg/kg) alone (n = 5) did not induce pulmonary hypertension or the release of thromboxane. In five lambs, intravenous heparin (200 U/kg) followed by protamine (2 mg/kg) consistently produced acute pulmonary vasoconstriction and hypertension. CONCLUSIONS: Intravenous injection of human rPF4 into the awake lamb produces acute pulmonary vasoconstriction and hypertension associated with thromboxane release into circulating blood. The effects of rPF4 on the pulmonary vasculature should be evaluated in primates before rPF4 is substituted for protamine in reversing heparin anticoagulation in humans. PMID- 7832300 TI - Effects of volatile anesthetics on acetylcholine-induced relaxation in the rabbit mesenteric resistance artery. AB - BACKGROUND: Vascular endothelium plays an important role in the regulation of vascular tone. Volatile anesthetics have been shown to attenuate endothelium mediated relaxation in conductance arteries, such as aorta. However, significant differences in volatile anesthetic pharmacology between these large vessels and the small vessels that regulate systemic vascular resistance and blood flow have been documented, yet little is known about volatile anesthetic action on endothelial function in resistance arteries. Furthermore, endothelium-dependent relaxation mediated by factors other than endothelium-derived relaxing factor (EDRF) has recently been recognized, and there is no information available regarding volatile anesthetic action on non-EDRF-mediated endothelium-dependent relaxation. METHODS: Employing isometric tension recording and microelectrode methods, the authors first characterized the endothelium-dependent relaxing and hyperpolarizing actions of acetylcholine (ACh) in rabbit small mesenteric arteries, and tested the sensitivities of these actions to EDRF pathway inhibitors and K+ channel blockers. They then examined the effects of the volatile anesthetics isoflurane, enflurane, and sevoflurane on ACh-induced endothelium-dependent relaxation that was sensitive to EDRF inhibitors and that which was resistant to the EDRF inhibitors but sensitive to blockers of ACh induced hyperpolarization. The effects of the volatile anesthetics on endothelium independent sodium nitroprusside (SNP)-induced relaxation were also studied. RESULTS: Acetylcholine concentration-dependently caused both endothelium dependent relaxation and hyperpolarization of vascular smooth muscle. The relaxation elicited by low concentrations of ACh (< or = 0.1 microM) was almost completely abolished by the EDRF inhibitors NG-nitro-L-arginine (LNNA), oxyhemoglobin (HbO2), and methylene blue (MB). The relaxation elicited by higher concentrations of ACh (> or = 0.3 microM) was only attenuated by the EDRF inhibitors. The remaining relaxation, as well as the ACh-induced hyperpolarization that was also resistant to EDRF inhibitors, were both specifically blocked by tetraethylammonium (TEA > or = 10 mM). Sodium nitroprusside, a NO donor, produced dose-dependent relaxation, but not hyperpolarization, in the endothelium-denuded (E[-]) strips, and the relaxation was inhibited by MB and HbO2, but not TEA (> or = 10 mM). One MAC isoflurane, enflurane, and sevoflurane inhibited both ACh relaxation that was sensitive to the EDRF inhibitors and the ACh relaxation resistant to the EDRF inhibitors and sensitive to TEA, but not SNP relaxation (in the E[-] strips). An additional finding was that the anesthetics all significantly inhibited norepinephrine (NE) contractions in the presence and absence of the endothelium or after exposure to the EDRF inhibitors. CONCLUSIONS: The results confirm that ACh has a hyperpolarizing action in rabbit small mesenteric resistance arteries that is independent of EDRF inhibitors but blocked by the K+ channel blocker TEA. The ACh relaxation in these resistance arteries thus appears to consist of distinct EDRF mediated and hyperpolarization-mediated components. Isoflurane, enflurane, and sevoflurane inhibited both components of the ACh-induced relaxation in these small arteries, indicating a more global depression of endothelial function or ACh signaling in endothelial cells, rather than a specific effect on the EDRF pathway. All these anesthetics exerted vasodilating action in the presence of NE, the primary neurotransmitter of the sympathetic nervous system, which plays a major role in maintaining vasomotor tone in vivo. This strongly indicates that the vasodilating action of these anesthetics probably dominates over their inhibitory action on the EDRF pathway and, presumably, contributes to their known hypotensive effects in vivo. Finally, the vasodilating action of these anesthetics is, at least in part, independent from endothelium. PMID- 7832301 TI - Preanesthetic medication with intranasal midazolam for brief pediatric surgical procedures. Effect on recovery and hospital discharge times. AB - BACKGROUND: The perfect preanesthesia medication and its ideal route of administration are still debated, but for pediatric surgical patients undergoing brief procedures, preanesthesia medication is frequently omitted because of the concern that it will prolong the child's recovery from anesthesia. The effects of nasally administered midazolam on anesthetic recovery and hospital discharge times were determined in 88 ASA physical status 1 and 2 ambulatory surgical patients undergoing a brief surgical procedure. METHODS: Using a randomized, double-blind, placebo-controlled design, 88 ambulatory surgical patients 10-36 months of age undergoing myringotomy and tube insertion were entered into the study. All patients were randomly assigned to one of three medication groups. One group received 0.2 mg/kg intranasal midazolam; a second group received 0.3 mg/kg intranasal midazolam; and the third group received intranasal saline drops. All patients were anesthetized with nitrous oxide, oxygen, and halothane administered via mask. The duration of anesthesia lasted between 9 and 10 min. After preanesthetic medication, the children were evaluated for ease of separation and induction of anesthesia. In addition, the time from when the anesthetic was discontinued until the child recovered from anesthesia and the time the child was discharged home were recorded by a nurse observer blinded to the patient grouping. RESULTS: Children receiving midazolam had smoother, calmer parent-child separation and anesthesia induction scores, and their anesthesia recovery times and hospital discharge times were the same as those receiving placebo. CONCLUSIONS: For children undergoing brief surgical procedures, nasal midazolam provides satisfactory anxiolysis without delaying anesthesia recovery and hospital discharge. PMID- 7832302 TI - Human chest wall function while awake and during halothane anesthesia. II. Carbon dioxide rebreathing. AB - BACKGROUND: Changes in the distribution of respiratory drive to different respiratory muscles may contribute to respiratory depression produced by halothane. The aim of this study was to examine factors that are responsible for halothane-induced depression of the ventilatory response to carbon dioxide rebreathing. METHODS: In six human subjects, respiratory muscle activity in the parasternal intercostal, abdominal, and diaphragm muscles was measured using fine wire electromyography electrodes. Chest wall motion was determined by respiratory impedance plethysmography. Electromyography activities and chest wall motion were measured during hyperpnea produced by carbon dioxide rebreathing while the subjects were awake and during 1 MAC halothane anesthesia. RESULTS: Halothane anesthesia significantly reduced the slope of the response of expiratory minute ventilation to carbon dioxide (from 2.88 +/- 0.73 (mean +/- SE) to 2.01 +/- 0.45 l.min-1.mmHg-1). During the rebreathing period, breathing frequency significantly increased while awake (from 10.3 +/- 1.4 to 19.7 +/- 2.6 min-1, P < 0.05) and significantly decreased while anesthetized (from 28.8 +/- 3.9 to 21.7 +/- 1.9 min 1, P < 0.05). Increases in respiratory drive to the phrenic motoneurons produced by rebreathing, as estimated by the diaphragm electromyogram, were enhanced by anesthesia. Anesthesia attenuated the response of parasternal electromyography and accentuated the response of the transversus abdominis electromyography to rebreathing. The compartmental response of the ribcage to rebreathing was significantly decreased by anesthesia (from 1.83 +/- 0.58 to 0.48 +/- 0.13 l.min 1.mmHg-1), and marked phase shifts between ribcage and abdominal motion developed in some subjects. However, at comparable tidal volumes, the ribcage contribution to ventilation was similar while awake and anesthetized in four of the six subjects. CONCLUSIONS: Halothane anesthesia enhances the rebreathing response of neural drive to the primary respiratory muscle, the diaphragm. These findings provide direct evidence that, at the dose examined in this study, halothane induced respiratory depression is caused by alterations in the distribution and timing of neural drive to the respiratory muscles, rather than a global depression of respiratory motoneuron drive. PMID- 7832303 TI - Ketamine inhibits glutamate-, N-methyl-D-aspartate-, and quisqualate-stimulated cGMP production in cultured cerebral neurons. AB - BACKGROUND: Glutamatergic signaling has been linked to the recently discovered neurotransmitter/neuromodulator nitric oxide (NO), and several classes of anesthetics block some step in glutamatergic signaling. This study was designed to determine whether or not ketamine would prevent NO-dependent cGMP production stimulated by glutamate (GLU) and the GLU analogs NMDA, quisqualate (QUIS), and kainate (KAIN). METHODS: Primary cultures of cortical neurons and glia (prepared from 16-day gestational rat fetuses) were used after 12-16 days in culture. Reactions were carried out in magnesium-free buffer containing 100 microM 3 isobutyl-1-methylxanthine, and cGMP content of cultures was used as a bioassay of NO production. RESULTS: Cyclic GMP production stimulated by sodium nitroprusside (100 microM) occurred predominately in neurons and not in glia. Neurons were spontaneously active in these cultures; basal cGMP production was decreased by 50% in the presence of 1 microM tetrodotoxin (TTX). Glutamate (100 microM), NMDA (100 microM), QUIS (300 microM), and KAIN (100 microM) each increased cGMP content of neuronal cultures. L-NMMA (100 microM), a NO synthase inhibitor, prevented the stimulation of cGMP production by GLU or its analogs. Pretreatment with MK-801 (1 microM) or ketamine (10-100 microM) inhibited GLU-, NMDA-, and QUIS-stimulated cGMP production. Quisqualate-stimulated responses were the most sensitive to inhibition by ketamine and NMDA-stimulated responses were the least sensitive to inhibition. MK-801 and ketamine did not significantly inhibit KAIN stimulated cGMP production. CNQX (10 microns) blocked KAIN-stimulated cGMP production only. CONCLUSIONS: The authors' data demonstrate that ketamine inhibited NO synthesis stimulated by NMDA- and non-NMDA-receptor specific analogs. Our findings indicate that blockade of QUIS- as well as NMDA-subtypes of GLU- receptor may be important in the development of ketamine-induced anesthesia. PMID- 7832304 TI - Metabolism of a new local anesthetic, ropivacaine, by human hepatic cytochrome P450. AB - BACKGROUND: Ropivacaine is a local anesthetic with a long duration of action. Although it is less toxic than bupivacaine, local anesthetic toxicity is possible when the plasma concentration is increased. Because ropivacaine is an amide-type local anesthetic, it is metabolized by cytochrome P450 (P450) in the liver, and its elimination and plasma concentration can be dependent on the level of P450. The purpose of this investigation was to elucidate the metabolism of ropivacaine by human hepatic P450. METHODS: The metabolism of ropivacaine was compared using recombinant human and purified rat hepatic P450 isozymes. An inhibition study using antibodies against rat P450 was performed using hepatic microsomes from human and rat to identify which P450s are involved in ropivacaine metabolism. RESULTS: Ropivacaine was metabolized to 2',6'-pipecoloxylidide (PPX), 3' hydroxyropivacaine (3'-OH Rop), and 4'-hydroxyropivacaine (4'-OH Rop) by hepatic microsomes from human and rat. PPX was a major metabolite of both human and rat hepatic microsomes. In a reconstituted system with rat P450. PPX was produced by CYP2C11 and 3A2, 4'-OH Rop by CYP1A2, and 3'-OH Rop by CYP1A2 and 2D1. Formation of PPX in rat hepatic microsomes was inhibited by anti CYP3A2, but not by CYP2C11 antibody, and formation of 3'-OH Rop was inhibited by CYP1A2 and 2D1 antibodies. Anti CYP3A2 and 1A2 antibodies inhibited the formation of PPX and 3'-OH Rop in human hepatic microsomes, respectively. Recombinant human P450s expressed in lymphoblast cells were used for further study. CYP3A4 and 1A2 formed the most PPX and 3'-OH Rop, respectively. Ropivacaine N-dealkylation and 3'-hydroxylation activities correlated well with the level of CYP3A4 and 1A2 in human hepatic microsomes, respectively. CONCLUSIONS: Ropivacaine was metabolized to PPX, 3'-OH Rop, and 4'-OH Rop by hepatic P450. PPX was a major metabolite in human hepatic microsomes. CYP3A4 was involved in producing PPX. CYP1A2 was involved in the formation of 3'-OH Rop in human hepatic microsomes. PMID- 7832305 TI - Endothelium-independent vasoconstricting and vasodilating actions of halothane on rat mesenteric resistance blood vessels. AB - BACKGROUND: Whether volatile anesthetics produce changes in vascular resistance and blood flow because of direct effects on vascular tissue is unclear. Direct vasoconstricting and vasodilating actions have been demonstrated in isolated conductance arteries in vitro, but there is little information regarding direct effects on the small vessels that mediate resistance and flow changes in vivo. METHODS: We investigated the actions of halothane on 50-200 microM branches of the rat mesenteric artery that were cannulated and studied in vitro. The vessels were pressurized to 60 mmHg, and vascular dimensions were continuously monitored using a computer-based real-time image analysis system. The vessel bath was perfused with HCO3(-)-buffered saline (37 degrees C) equilibrated with 95% O2/5% CO2 (+/- halothane). The vascular endothelium was mechanically removed before cannulation in some vessels. RESULTS: In unstimulated vessels, halothane had a concentration-dependent vasoconstricting action (EC50 = 0.45 mM approximately 1.5 vol% at 37 degrees C) that was largely transient and was similar to that produced by caffeine. Both halothane and caffeine constrictions were unaffected by bath [Ca2+], nifedipine (1 microM) or Cd2+ (100 microM) and were abolished by ryanodine (10 microM). In addition, caffeine responses were attenuated by halothane in a concentration-dependent manner (EC50 = 1.6 mM). In vessels preconstricted with KCl (40 mM) or phenylephrine (10(-6) M), halothane produced transient constriction followed by concentration-dependent vasodilation. Ryanodine, which abolished halothane constrictions, had little effect on the amplitude of KCl- or phenylephrine-induced constrictions or the vasodilating action of halothane. Removal of the endothelium likewise had little effect on the vasoconstricting or the vasodilating actions of halothane in unstimulated, KCl- or phenylephrine-constricted vessels. Halothane completely relaxed KCl and phenylephrine constrictions with EC50 values of 0.36 mM (1.2% at 37 degrees C) and 0.75 mM (2.5%), respectively, in intact vessels before ryanodine; 0.25 mM (0.8%) and 0.59 mM (1.9%) in intact vessels after ryanodine; and 0.52 mM (1.7%) and 0.67 mM (2.2%) in endothelium-denuded vessels. CONCLUSIONS: Halothane has endothelium-independent vasoconstricting and vasodilating actions in isolated mesenteric resistance blood vessels. The vasoconstricting action appears to involve halothane-induced Ca2+ release from caffeine/ryanodine-sensitive intracellular store(s). The vasodilating action in phenylephrine- or KC1 constricted vessels is independent of the Ca(2+)-releasing action and most likely involves an effect(s) on sarcolemmal-dependent Ca2+ signaling (e.g., extracellular Ca2+ influx) and/or Ca2+ activation of contractile proteins. The magnitude of both the vasoconstricting and the vasodilating actions of halothane in these vessels at clinically relevant concentrations suggests these direct actions contribute to the overall cardiovascular effects of halothane in vivo. PMID- 7832306 TI - The addition of 7.5% glucose does not alter the neurotoxicity of 5% lidocaine administered intrathecally in the rat. AB - BACKGROUND: Recent reports of major and minor neurologic sequelae after spinal anesthesia have generated concern regarding the safety of some currently used intrathecal agents. The role of glucose, if any, in neurotoxic injury associated with spinal anesthesia is not known. The current experiments sought to determine whether the presence of 7.5% glucose alters the neurotoxicity of intrathecally administered 5% lidocaine. METHODS: Two experiments were performed. First, 48 rats were implanted with an intrathecal catheter and randomly divided into eight equal groups. Each animal received a single intrathecal infusion of 5% lidocaine (groups P1-P4) or 5% lidocaine with 7.5% glucose (G1-G4) for 0.5, 1, 2, or 4 h at a rate of 1 microliter/min. Sensory function was assessed using the tail-flick test; a deficit was defined as a complete lack of response to the heat stimulus at the proximal, mid or distal portion of the tail persisting 4 days after the infusion. In the second experiment, 60 rats were randomly divided into two groups to receive a 1-h intrathecal infusion of 5% lidocaine or 5% lidocaine with 7.5% glucose. Animals were evaluated for increase in the latency of the tail-flick reflex 4 days after infusion. RESULTS: In the first experiment, the two lidocaine solutions produced similar dose-dependent loss of sensory function. In the second experiment, the two solutions induced similar alterations in tail-flick latency. CONCLUSIONS: The presence of 7.5% glucose does not affect the potential of intrathecally administered 5% lidocaine to induce sensory impairment. These findings provide further support for the hypothesis that recent injuries after spinal anesthesia resulted from a direct neurotoxic effect of the local anesthetic. PMID- 7832307 TI - Pulsatile versus nonpulsatile flow. No difference in cerebral blood flow or metabolism during normothermic cardiopulmonary bypass in rabbits. AB - BACKGROUND: Although pulsatile and nonpulsatile cardiopulmonary bypass (CPB) do not differentially affect cerebral blood flow (CBF) or metabolism during hypothermia, studies suggest pulsatile CPB may result in greater CBF than nonpulsatile CPB under normothermic conditions. Consequently, nonpulsatile flow may contribute to poorer neurologic outcome observed in some studies of normothermic CPB. This study compared CBF and cerebral metabolic rate for oxygen (CMRO2) between pulsatile and nonpulsatile CPB at 37 degrees C. METHODS: In experiment A, 16 anesthetized New Zealand white rabbits were randomized to one of two pulsatile CPB groups based on pump systolic ejection period (100 and 140 ms, respectively). Each animal was perfused at 37 degrees C for 30 min at each of two pulse rates (150 and 250 pulse/min, respectively). This scheme created four different arterial pressure waveforms. At the end of each perfusion period, arterial pressure waveform, arterial and cerebral venous oxygen content, CBF (microspheres), and CMRO2 (Fick) were measured. In experiment B, 22 rabbits were randomized to pulsatile (100-ms ejection period, 250 pulse/min) or nonpulsatile CPB at 37 degrees C. At 30 and 60 min of CPB, physiologic measurements were made as before. RESULTS: In experiment A, CBF and CMRO2 were independent of ejection period and pulse rate. Thus, all four waveforms were physiologically equivalent. In experiment B, CBF did not differ between pulsatile and nonpulsatile CPB (72 +/ 6 vs. 77 +/- 9 ml.100 g-1.min-1, respectively (median +/- quartile deviation)). CMRO2 did not differ between pulsatile and nonpulsatile CPB (4.7 +/- 0.5 vs. 4.1 +/- 0.6 ml O2.100 g-1.min-1, respectively) and decreased slightly (0.4 +/- 0.4 ml O2.100 g-1.min-1) between measurements. CONCLUSIONS: During CPB in rabbits at 37 degrees C, neither CBF nor CMRO2 is affected by arterial pulsation. The absence of pulsation per se is not responsible for the small decreases in CMRO2 observed during CPB. PMID- 7832308 TI - Recovery of hepatic drug extraction after hypothermic preservation. AB - BACKGROUND: To determine whether liver preservation before transplantation impairs hepatic drug metabolism, hepatic extraction of drugs with different metabolic pathways (fentanyl, morphine, and vecuronium) in isolated rat livers was measured either immediately or after 24 h of hypothermia at 4 degrees C using a standard preservation-reperfusion sequence. METHODS: Isolated rat livers were perfused via the portal vein for 30 min to document initial viability. Test livers (n = 5) were perfused with iced Belzer solution, stored for 24 h at 4 degrees C, and flushed with 6% hetastarch. After hypothermic preservation for 24 h, or in control livers (n = 5) immediately after the 30-min perfusion, livers were perfused single-pass at a constant flow rate with solutions containing fentanyl, morphine, and vecuronium at 37 degrees C. Perfusate and bile samples were obtained at regular intervals for 64 min, after which liver tissue was harvested for analysis. Drug concentrations were measured using radioimmunoassay and gas chromatography. Metabolic capacity of the liver was estimated from the extraction fraction of each drug at steady-state. RESULTS: After warming to 37 degrees C, preserved livers consumed oxygen and produced bile at rates similar to that of control livers. Hypothermic preservation did not affect extraction of fentanyl and morphine. Vecuronium extraction was initially less in preserved livers, but this difference disappeared as the preserved livers returned to 37 degrees C (< 16 min). Biliary excretion and tissue concentrations of vecuronium were similar in each group. CONCLUSIONS: Hypothermic preservation does not significantly impair extraction of these drugs in this liver preservation model. If these results apply to human liver transplantation, little danger of drug accumulation exists during the early postoperative period if hepatic function is normal. PMID- 7832309 TI - Inhibition of nociception-induced spinal sensitization by anesthetic agents. AB - BACKGROUND: Subcutaneous injection of dilute formalin in the hind paw of the rat produces a biphasic nociceptive response. Initial C-fiber activity is accompanied by flinching of the paw for about 5 min (phase 1), followed by cessation of activity and resumption of flinching beginning 15 min after injection and lasting about 40 min or more (phase 2). The second phase depends on changes in dorsal horn cell function that occur shortly after the initial C-fiber discharge. It was previously shown that isoflurane, administered during phase 1, reduced phase 2 activity, but a combination of isoflurane and nitrous oxide given throughout phase 1 did not suppress spinal sensitization. The same model was used to determine the effects of several inhalation and intravenous anesthetic agents on phase 2 of the formalin test. METHODS: The formalin test was carried out on male Sprague-Dawley rats. Animals anesthetized briefly with halothane to facilitate formalin injection, were compared to animals that received 1 MAC anesthesia from 5 min before to 6 min after formalin injection using halothane, enflurane, isoflurane, desflurane, or 70% N2O, or a combination of nitrous oxide plus 1 MAC halothane. Animals that were given intravenous saline immediately before injection of formalin were compared to animals given either 20 mg/kg intravenous thiopental just before formalin injection or 10 mg/kg intravenous propofol just before and 3 mg/kg immediately after formalin injection. Flinches/minute were counted at 1 and 5 min after formalin injection and thereafter at 5-min intervals for 1 h. The total of 1- and 5-min flinches were considered phase 1 activity and the total of 10-60-min flinches were considered phase 2. Total phase 2 activity was compared between groups using one-way analysis of variance. RESULTS: Animals that received halothane, enflurane, isoflurane, desflurane, or nitrous oxide during phase 1 demonstrated a significant decrease in phase 2 activity when compared to controls, while those that received a combination of nitrous oxide and halothane exhibited no difference. Animals that received intravenous thiopental anesthesia during phase 1 demonstrated no difference in phase 2 activity when compared to controls, whereas those that received propofol during phase 1 demonstrated a significant decrease of phase 2 activity. CONCLUSIONS: Volatile anesthetics or nitrous oxide significantly suppress spinal sensitization, whereas the combination of nitrous oxide plus halothane causes no suppression. Thiopental does not affect spinal sensitization, whereas propofol causes significant suppression. These results may have important implications regarding the development of postoperative pain. PMID- 7832310 TI - Sensitization of spinal neurons by non-noxious stimuli in the awake but not anesthetized state. AB - BACKGROUND: The observation that peripheral trauma causes enhanced spinal neuronal excitability has provided the scientific rationale for the concept of "pre-emptive analgesia." The premise has been that only noxious stimuli cause sensitization in sensory pathways, but this premise has not been tested in the conscious state. METHODS: Responses of single spinal neurons were recorded in instrumented sheep that were untrained and free from drugs or recent surgery, in either fully conscious or halothane-anesthetized states. Receptive field (RF) size was measured before and after non-noxious mechanical conditioning stimulation. RESULTS: Noxious conditioning stimuli in anesthetized sheep caused enlargement of RF areas, as expected. Conditioning with nonpainful scratching or other stimuli was without effect in anesthetized animals; in marked contrast, it caused enlargement of RF size in conscious animals, in which 29 of 33 wide dynamic range units but only 1 of 12 low-threshold mechanoreceptive neurons were affected. CONCLUSIONS: Sensitization of spinal sensory neurons evidently is a process that is not restricted to pathologic pain states but rather that occurs under normal physiologic conditions independent of painful stimuli. The significance of such sensitization processes therefore needs reevaluation. The sensitization triggered by non-nociceptive afferents is likely to be opioid resistant and therefore may contribute to the rather disappointing results seen in several clinical trials of "pre-emptive analgesia." PMID- 7832311 TI - General anesthetics modify the kinetics of nicotinic acetylcholine receptor desensitization at clinically relevant concentrations. AB - BACKGROUND: General anesthetics are thought to induce anesthesia through their actions on ligand-gated ion channels. One such channel, the nicotinic acetylcholine receptor (nAcChoR), can be found in different subtypes in the central nervous system and at the periphery in the neuromuscular junction. The latter subtype of the nAcChoR is a useful model for examining interactions between general anesthetics and ligand-gated ion channels, because it can be isolated and purified in sufficient quantities to allow for biophysical and biochemical studies. This study examines the actions of general anesthetics on agonist-induced conversion of the nAcChoR to inactive desensitized conformational states. METHODS: Nicotinic acetylcholine receptor membranes were purified from the electric organ of Torpedo nobiliana. Agonist-induced desensitization was characterized from the time-dependent increase in fluorescence intensity that results from the binding of the fluorescent acetylcholine analog, Dns-C6-Cho, to the nAcChoR. RESULTS: Mixing Dns-C6-Cho with nAcChoR-rich membranes results in an increase in fluorescence that is characterized by four rate processes. Concentrations of isoflurane and butanol, which range from subclinical to toxic increase the rates of the third and fourth components of fluorescence, corresponding to fast and slow desensitization, respectively. At concentrations that are twice their EC50s for anesthesia, isoflurane, butanol, chloroform, methanol, and cyclopentanemethanol increase the apparent rates of fast and slow desensitization by an average of 92 +/- 22% and 108 +/- 22%, respectively. CONCLUSIONS: The concentration range over which general anesthetics modify the kinetics of nAcChoR desensitization is similar to those reported for anesthetic actions on the GABAA receptor. Thus, the nAcChoR, like other members of this superfamily, is a sensitive target of general anesthetics. PMID- 7832312 TI - Prevention of kinking of a percutaneous transtracheal intravenous catheter. AB - BACKGROUND: Transtracheal jet ventilation (TTJV) through a percutaneously inserted intravenous/TTJV catheter, using a high-pressure oxygen source and noncompliant tubing is a simple and quick method of effective ventilation, especially in a patient in whom the lungs cannot be ventilated via mask and/or whose trachea cannot be intubated. TTJV becomes impossible if any part of the plastic portion of the TTJV catheter kinks; although the incidence of this problem is not known, kinking of the catheter is most likely to occur as the catheter turns from a predominantly posterior to a predominantly caudad direction. These experiments tested the hypothesis that a small-angle bend in the tip of the TTJV catheter would reduce the requirement to aim the entire TTJV catheter in a caudad-directed orientation. METHODS: A model of the trachea was designed using polyvinylchloride tubing to observe TTJV catheter insertion and plastic catheter kinking. The TTJV catheters were inserted at 0, 5 degrees, 10 degrees, 15 degrees, 20 degrees, 25 degrees, and 30 degrees angles in trials of 15 times each. Small-angle bends, placed at 2.5 cm from the distal end of the TTJV catheter, of 0, 5 degrees, 10 degrees, 15 degrees, and 20 degrees were used, and each bent TTJV catheter was inserted at each of the above insertion angles 15 times. RESULTS: Increasing the angle of insertion decreased the incidence of kinking of the TTJV catheter at every small-angle bend in the tip of the TTJV catheter. Increasing the small-angle bend in the tip of the TTJV catheter decreased the incidence of kinking with every angle of insertion. A small-angle bend in the tip of the TTJV catheter and the angle of insertion often were complementary in their ability to decrease the incidence of kinking. With a cumulative angle of 10 degrees, 98% of the plastic catheters kinked, compared to 0 in trials involving a cumulative angle of 30 degrees or more. Analysis via the chi-squared test yielded a P value of < 0.0001 when comparing incidence of kinking for cumulative angles of 10-30 degrees. CONCLUSIONS: A modest bend in the tip of the TTJV catheter greatly reduces the sharpness of the angle of insertion required to eliminate kinking of the plastic catheter. Because the risk/benefit ratio is so low, we suggest that a small-angle bend of 15 degrees should always be created and, combined with a 15 degrees angle of insertion, should result in a rare incidence of kinking. PMID- 7832313 TI - Successful treatment of a massive intrathecal morphine overdose. PMID- 7832314 TI - Reactivation of phantom limb pain after combined interscalene brachial plexus block and general anesthesia: successful treatment with intravenous lidocaine. PMID- 7832315 TI - Complete electrical failure during cardiopulmonary bypass. PMID- 7832316 TI - Epidural blood patch can cause acute neurologic deterioration. PMID- 7832317 TI - Parkinsonian symptoms during emergence from general anesthesia. PMID- 7832318 TI - What is a "replication"? Epinephrine facilitation of learning under anesthesia. PMID- 7832319 TI - Hazard of small-gauge needles. PMID- 7832320 TI - Desflurane can be used to achieve smooth and rapid induction of anesthesia. PMID- 7832321 TI - The esophageal detector device: Ellick's evacuator versus syringe. PMID- 7832322 TI - The history of immediate hypersensitivity reactions. PMID- 7832323 TI - A monitor with a mind of its own. PMID- 7832324 TI - Time required to insert laryngeal mask airway in neonates requiring resuscitation. PMID- 7832325 TI - Metal corrosion of tracheostomy apparatus. PMID- 7832326 TI - Parturients infected with human immunodeficiency virus and regional anesthesia. Clinical and immunologic response. AB - BACKGROUND: It is estimated that 1.5 million Americans are infected with the human immunodeficiency virus (HIV-1), and the consequences of HIV infection are a leading cause of death in women aged 15-44 yr. Thus, HIV-1 disease, or acquired immunodeficiency syndrome, occurs with increasing frequency in the parturient, and there is little information concerning the risks of regional anesthesia. Fear of spreading infection to the central nervous system or adverse neurologic sequelae have led some clinicians to advise against regional anesthesia. Thus, this study was undertaken to evaluate the possible problems or risks associated with regional anesthesia in parturients infected with HIV-1 and to determine whether anesthesia affected the clinical course of the disease. METHODS: The clinical course and immunologic function of 30 parturients infected with HIV-1 were evaluated prospectively. Extensive medical and laboratory evaluation before delivery and 4-6 months postpartum was undertaken. Medical problems related to HIV-1 disease and use of antiviral drugs also were monitored. The anesthetic management was dictated by the clinical situation and the patient's wishes were careful postpartum follow-up to evaluate possible neurologic changes or infection. RESULTS: Regional anesthesia was administered in 18 parturients, and 12 received small doses of opioids or no analgesia. There were no changes in the immunologic parameters studied (CD4+, p24, beta 2 microglobulins), and HIV-1 disease remained stable in the peripartum period. There were no infections, complications, or neurologic changes in the peripartum period. Sixty-eight percent of the infants were HIV-1-negative and, in 21% of infants, the HIV-1 status was indeterminate (probably negative). CONCLUSIONS: This prospective study of parturients infected with HIV-1 demonstrated that regional anesthesia can be performed without adverse sequelae. There were no neurologic or infectious complications related to the obstetric or anesthetic course. The immune function of the parturient was stable in the peripartum period. Although the number of patients studied was small, with careful medical evaluation, regional anesthesia is an acceptable choice in the parturient infected with HIV-1. PMID- 7832327 TI - Securing epidural catheters to Tuohy connectors. PMID- 7832328 TI - Flumazenil reversal of benzodiazepine sedation before electroconvulsive therapy. PMID- 7832329 TI - How many acute pain services are there in the United States, and who is managing patient-controlled analgesia? PMID- 7832330 TI - Husband-induced hypotension. PMID- 7832331 TI - The FDA protects the public by regulating the manufacture of anesthetic agents and the production devices used in anesthetic practice. PMID- 7832332 TI - Clinical characteristics of sevoflurane in children. A comparison with halothane. AB - BACKGROUND: For pediatric patients, sevoflurane may be an alternative to halothane, the anesthetic agent used most commonly for inhalational induction. The induction, maintenance, and emergence characteristics were studied in 120 unpremedicated children 1-12 yr of age randomly assigned to receive one of three anesthesia regimens: sevoflurane with oxygen (group S), sevoflurane with nitrous oxide and oxygen (group SN), or halothane with nitrous oxide and oxygen (group HN). METHODS: Anesthetic was administered (via a Mapleson D, F or Bain circuit) beginning with face mask application in incremental doses to deliver maximum inspired concentrations of 4.5% halothane or 7% sevoflurane. End-tidal concentrations of anesthetic agents and vocal cord position were noted at the time of intubation. Elapsed time intervals from face mask application to loss of the eyelash reflex, intubation, surgical incision, and discontinuation of the anesthetic were measured. Heart rate, systolic, diastolic, and mean blood pressures, and end-tidal anesthetic concentrations were measured at fixed intervals. Anesthetic MAC-hour durations were calculated. The end-tidal concentration of anesthetic was adjusted to 1 MAC (0.9% halothane, 2.5% sevoflurane) for at least the last 10 min of surgery. Intervals from discontinuation of anesthetic to hip flexion or bucking, extubation, administration of first postoperative analgesic, and attaining discharge criteria from recovery room were measured. Venous blood was sampled at anesthetic induction, at the end of anesthesia, and 1, 4, 6, 12, and 18-24 h after discontinuation of the anesthetic for determination of plasma inorganic fluoride content. RESULTS: Induction of anesthesia was satisfactory in groups SN and HN. Induction in group S was associated with a significantly greater incidence of excitement (35%) than in the other groups (5%), resulting in a longer time to intubation. The end-tidal minimum alveolar concentration multiple of potent inhalational anesthetic at the time of intubation was significantly greater in patients receiving halothane than in patients receiving sevoflurane. Induction time, vocal cord position at intubation, time to incision, duration of anesthesia, and MAC-hour duration were similar in the three groups. During emergence, the time to hip flexion was similar among the three groups, whereas the time to extubation, time to first analgesic, and time to attaining discharge criteria were significantly greater in group HN than in groups S and SN. Mean heart rate and systolic blood pressure decreased during induction in group HN but not in groups S and SN. The maximum serum fluoride concentration among all patients was 28 microM. CONCLUSIONS: Sevoflurane with nitrous oxide provides satisfactory anesthetic induction and intubating conditions; however, induction using sevoflurane without nitrous oxide is associated with a high incidence of patient excitement and prolonged time to intubation. There were greater decreases in heart rate and systolic blood pressure during induction with halothane than with sevoflurane; however, these differences may be dose-related. The more rapid emergence with sevoflurane when compared with halothane is consistent with the low solubility of sevoflurane in blood and tissues. Children receiving sevoflurane for up to 9.6 MAC-hours did not develop high serum fluoride concentrations. PMID- 7832333 TI - The dose-response relationship of ondansetron in preventing postoperative emesis in pediatric patients undergoing ambulatory surgery. AB - BACKGROUND: Postoperative nausea and vomiting is a distressing anesthetic complication that may delay discharge after ambulatory surgery. Effective prophylaxis for postoperative nausea and vomiting can be achieved in adults with lower doses of ondansetron, a 5-hydroxytryptamine subtype 3 receptor antagonist, compared with chemotherapy-induced emesis. However, the doses of ondansetron used in preventing postoperative nausea and vomiting in children are based on data from chemotherapy-induced emesis. The dose-related efficacy of intravenous ondansetron in the prophylaxis of postoperative emesis in the pediatric outpatient population was determined. METHODS: In a double-blind, randomized placebo-controlled study, 130 patients (mean age 5.7 +/- 3.4 yr) received placebo, 10, 50, or 100 micrograms/kg ondansetron during a standardized anesthetic. Episodes of postoperative vomiting or retching were recorded. RESULTS: Intravenous ondansetron in a dose of 50 micrograms/kg was more effective than placebo or a dose of 10 micrograms/kg in controlling the incidence and frequency of emesis in the hospital and during the first 24 postoperative hours. Increasing the dose of ondansetron to 100 micrograms/kg intravenously did not significantly reduce the incidence or frequency of emesis compared to 50 micrograms/kg intravenously. CONCLUSIONS: Intravenous ondansetron in a dose of 50 micrograms/kg is as effective as larger doses for the prophylaxis of emesis in children undergoing surgical procedures known to be associated with an increased risk for postoperative nausea and vomiting. PMID- 7832334 TI - Using alcohol as a standard to assess the degree of impairment induced by sedative and analgesic drugs used in ambulatory surgery. AB - BACKGROUND: There is a need for a standard by which to compare the degree of subjective and behavioral impairment caused by anesthetic drugs, because anesthesiologists may not be able to gauge how extreme or important a statistically significant change in psychomotor functioning is. This study examined the psychomotor and subjective effects of alcohol at blood concentrations equal or greater than 0.10% as a standard with which to compare those effects caused by sedative and analgesic agents commonly used in ambulatory surgery. METHODS: Twelve healthy human volunteers (11 men and 1 nonpregnant woman), with an average age of 28 yr (range 24-34 yr) and an average alcohol consumption of four drinks per week, were selected in this institutional review board-approved study. Each subject was exposed to five drug conditions (70 mg/70 kg propofol intravenously, 2 mg/70 kg midazolam intravenously, 50 micrograms/70 kg fentanyl intravenously, 0.8 g/kg alcohol orally, and placebo orally and intravenously) in a double-blind randomized fashion over five weekly sessions. Testing was done at baseline and at different intervals until 240 min after drug administration. Testing included psychomotor performance (Maddox Wing, eye-hand coordination, auditory reaction time test, and digit symbol substitution test), subjective effects (strength of drug effect scale, drug liking scale, and visual analog scale), and short-term memory. Psychomotor performance was used as an index of objective impairment, and mood was used as an index of subjective impairment. RESULTS: After consumption of the alcoholic beverage, a blood alcohol level of 0.11 +/- 0.003% (mean +/- SE) was obtained at 15 min after injection. The study drugs not only produced statistically significant impairment (i.e., impairment greater than that seen with placebo) but also, at one or more times after injection, produced impairment similar to that observed with alcohol at a blood alcohol concentration of 0.11%. Midazolam produced a similar degree of impairment to that of alcohol for a longer duration than did fentanyl and propofol. CONCLUSIONS: This study provides evidence that degree of impairment caused by sedative and analgesic drugs used in ambulatory surgery is similar to that obtained with a dose of alcohol that produces a blood alcohol concentration of 0.11%. We suggest that anesthesiologists can use alcohol as a standard by which to assess degree of impairment produced by drugs used for sedation/analgesia. PMID- 7832335 TI - Human chest wall function while awake and during halothane anesthesia. I. Quiet breathing. AB - BACKGROUND: Data concerning chest wall configuration and the activities of the major respiratory muscles that determine this configuration during anesthesia in humans are limited. The aim of this study was to determine the effects of halothane anesthesia on respiratory muscle activity and chest wall shape and motion during spontaneous breathing. METHODS: Six human subjects were studied while awake and during 1 MAC halothane anesthesia. Respiratory muscle activity was measured using fine-wire electromyography electrodes. Chest wall configuration was determined using images of the thorax obtained by three dimensional fast computed tomography. Tidal changes in gas volume were measured by integrating respiratory gas flow, and the functional residual capacity was measured by a nitrogen dilution technique. RESULTS: While awake, ribcage expansion was responsible for 25 +/- 4% (mean +/- SE) of the total change in thoracic volume (delta Vth) during inspiration. Phasic inspiratory activity was regularly present in the diaphragm and parasternal intercostal muscles. Halothane anesthesia (1 MAC) abolished activity in the parasternal intercostal muscles and increased phasic expiratory activity in the abdominal muscles and lateral ribcage muscles. However, halothane did not significantly change the ribcage contribution to delta Vth (18 +/- 4%). Intrathoracic blood volume, measured by comparing changes in total thoracic volume and gas volume, increased significantly during inspiration both while awake and while anesthetized (by approximately 20% of delta Vth, P < 0.05). Halothane anesthesia significantly reduced the functional residual capacity (by 258 +/- 78 ml), primarily via an inward motion of the end expiratory position of the ribcage. Although the diaphragm consistently changed shape, with a cephalad displacement of posterior regions and a caudad displacement of anterior regions, the diaphragm did not consistently contribute to the reduction in the functional residual capacity. Halothane anesthesia consistently increased the curvature of the thoracic spine measured in the saggital plane. CONCLUSIONS: The authors conclude that (1) ribcage expansion is relatively well preserved during halothane anesthesia despite the loss of parasternal intercostal muscle activity; (2) an inward displacement of the ribcage accounts for most of the decrease in functional residual capacity caused by halothane anesthesia, accompanied by changes in diaphragm shape that may be related to motion of its insertions on the thoracoabdominal wall; and (3) changes in intrathoracic blood volume constitute a significant fraction of delta Vth during tidal breathing. PMID- 7832336 TI - Quantitative assessment of differential sensory nerve block after lidocaine spinal anesthesia. AB - BACKGROUND: Recent technology allows for quantitative and selective measurement of A beta, A delta, and C fiber nerve transmission. To gain further insight into the physiology of differential block after lidocaine spinal anesthesia, the function of these different fibers was quantitatively measured over time, and these measurements were correlated with regression of anesthesia to pinprick, touch, cold, and tolerance of tetanic electrical current (equivalent to surgical incision). METHODS: Six volunteers received lidocaine spinal anesthesia with 50 mg lidocaine (5% in dextrose). Cutaneous current perception thresholds at 2,000, 250, and 5 Hz, which stimulate A beta, A delta, and C fibers, respectively, were determined at L2-L3 (medial aspect above knee) before and every 10 min after spinal anesthesia. Dermatomal levels to pinprick, touch, and cold were assessed every 5 min after spinal anesthesia. Tolerance to tetanic electrical stimulus was assessed at L2-L3 every 10 min after spinal anesthesia. RESULTS: Differential block was demonstrated by the sequential return of sensation to touch, pinprick, and cold at L2-L3. Recovery of function of A beta, A delta, and C fibers correlated with return of sensation to touch (R2 = 0.7, p = 0.03), pinprick (R2 = 0.75, p = 0.02), and cold (R2 = 0.67, p = 0.04) respectively. Loss of tolerance of surgical anesthesia corresponded to return of A beta current perception thresholds to baseline, whereas current perception thresholds for A delta and C fibers were still increased to greater than baseline (p = 0.025). CONCLUSIONS: Differential sensory block during spinal anesthesia is due to different recovery profiles of A beta, A delta, and C fibers. Return of A beta current perception thresholds to baseline correlated with duration of surgical anesthesia as assessed with an electrical stimulation model. PMID- 7832337 TI - Volumetric capnography in children. Influence of growth on the alveolar plateau slope. AB - BACKGROUND: Lung growth in children is associated with dramatic increases in the number and surface area of alveolated airways. Modelling studies have shown the slope of the alveolar plateau (phase III) is sensitive to the total cross sectional area of these airways. Therefore, the influence of age and body size on the phase III slope of the volumetric capnogram was investigated. METHODS: Phase III slope (alveolar dcCO2/dv) and airway deadspace (VDaw) were derived from repeated single-breath carbon dioxide expirograms collected on 44 healthy mechanically ventilated children (aged 5 months-18 yr) undergoing minor surgery. Ventilatory support was standardized (VT = 8.5 and 12.5 ml/kg, f = 8-15 breaths/min, inspiratory time = 1 s, end-tidal partial pressure of carbon dioxide = 30-45 mmHg), and measurements were recorded by computerized integration of output from a heated pneumotachometer and mainstream infrared carbon dioxide analyzer inserted between the endotracheal tube and anesthesia circuit. Experimental data were compared to simulated breath data generated from a numeric pediatric lung model. RESULTS: An increased VDaw, a smaller VDaw/VT, and flatter phase III slope were found at the larger tidal volume (P < 0.01). Strong relationships were seen at VT = 12.5 ml/kg between airway deadspace and age (R2 = 0.77), weight (R2 = 0.93), height (R2 = 0.78), and body surface area (R2 = 0.89). The normalized phase III slopes of infants were markedly steeper than that of adolescents and were reduced at both tidal volumes with increasing age, weight, height, and body surface area. Phase III slopes and VDaw generated from modelled carbon dioxide washout simulations closely matched the experimental data collected in children. CONCLUSIONS: Morphometric increases in the alveolated airway cross-section with lung growth is associated with a decrease of the phase III slope. During adolescence, normalized phase III slopes approximate those of healthy adults. The change in slope with lung growth may reflect a decrease in diffusional resistance for carbon dioxide transport within the alveolated airway resulting in diminished acinar carbon dioxide gradients. PMID- 7832338 TI - Cerebral oxygenation during pediatric cardiac surgery using deep hypothermic circulatory arrest. AB - BACKGROUND: Deep hypothermic circulatory arrest is a widely used technique in pediatric cardiac surgery that carries a risk of neurologic injury. Previous work in neonates identified distinct changes in cerebral oxygenation during surgery. This study sought to determine whether the intraoperative changes in cerebral oxygenation vary between neonates, infants, and children and whether the oxygenation changes are associated with postoperative cerebral dysfunction. METHODS: The study included eight neonates, ten infants, and eight children without preexisting neurologic disease. Cerebrovascular hemoglobin oxygen saturation (SCO2), an index of brain oxygenation, was monitored intraoperatively by near-infrared spectroscopy. Body temperature was reduced to 15 degrees C during cardiopulmonary bypass (CPB) before commencing circulatory arrest. Postoperative neurologic status was judged as normal or abnormal (seizures, stroke, coma). RESULTS: Relative to preoperative levels, the age groups experienced similar changes in SCO2 during surgery: SCO2 increased 30 +/- 4% during deep hypothermic CPB, it decreased 62 +/- 5% by the end of arrest, and it increased 20 +/- 5% during CPB recirculation (all P < 0.001); after rewarming and removal of CPB, SCO2 returned to preoperative levels. During arrest, the half life of SCO2 was 9 +/- 1 min in neonates, 6 +/- 1 min in infants, and 4 +/- 1 min in children (P < 0.001). Postoperative neurologic status was abnormal in three (12%) patients. The SCO2 increase during deep hypothermic CPB was less in these patients than in the remaining study population (3 +/- 2% versus 33 +/- 4%, P < 0.001). There were no other significant SCO2 differences between outcome groups. CONCLUSIONS: Brain oxygenation changed at distinct points during surgery in all ages, reflecting fundamental cerebral responses to hypothermic CPB, ischemia, and reperfusion. However, the changes in SCO2 half-life with age reflect developmental differences in the rate of cerebral oxygen utilization during arrest, consistent with experimental work in animals. Certain intraoperative cerebral oxygenation patterns may be associated with postoperative cerebral dysfunction and require further study. PMID- 7832339 TI - The catecholamine, cortisol, and hemodynamic responses to mild perioperative hypothermia. A randomized clinical trial. AB - BACKGROUND: Unintended hypothermia occurs frequently during surgery and may have adverse effects on the cardiovascular system. Although the mechanisms responsible for the cardiovascular manifestations of hypothermia are unclear, it is possible that they are sympathetically mediated. In this prospective study, relationships between body temperature, the neuroendocrine response, and hemodynamic changes in the perioperative period were examined. METHODS: Seventy-four elderly patients, undergoing abdominal, thoracic, or lower extremity vascular surgical procedures, were randomly assigned to either "routine care" (n = 37) or "forced-air warming" (n = 37) groups. Throughout the intraoperative and early postoperative periods, the routine care group received standard thermal care, and the forced-air warming group received forced-air skin-surface warming. Core temperature, forearm minus fingertip skin-surface temperature gradient, and plasma concentrations of epinephrine, norepinephrine, and cortisol were measured throughout the perioperative period, and the two groups were compared. In addition, heart rate and arterial blood pressure were compared between groups. RESULTS: The routine care and forced-air warming groups did not differ with regard to age, sex, type of surgical procedures, anesthetic techniques, or postoperative analgesia. Mean core temperature was lower in the routine care group on admission to the postanesthetic care unit (routine care, 35.3 +/- 0.1 degree C; forced-air warming, 36.7 +/- 0.1 degree C; P = 0.0001) and remained lower during the early postoperative period. Forearm minus fingertip skin-surface temperature gradient (an index of peripheral vasoconstriction) was greater in the routine care group in the early postoperative period. The mean norepinephrine concentration (pcg/ml) was greater in the routine care group immediately after surgery (480 +/- 70 vs. 330 +/- 30, P = 0.02) and at 60 min (530 +/- 50 vs. 340 +/- 30, P = 0.002) and 180 min (500 +/- 80 vs. 320 +/- 30, P = 0.004) postoperatively. Mean epinephrine concentrations were not significantly different between groups. Mean cortisol concentrations were increased in both groups during the early postoperative period (P < 0.01), but the differences between groups were not significant. Systolic, mean, and diastolic arterial blood pressures were significantly higher in the routine care group. CONCLUSIONS: Compared with patients in the forced-air warming group, patients receiving routine thermal care had lower core temperatures, a greater degree of peripheral vasoconstriction, higher norepinephrine concentrations, and higher arterial blood pressures in the early postoperative period. These findings suggest a possible mechanism for hypothermia related cardiovascular morbidity in the perioperative period. PMID- 7832340 TI - Analysis of strategies to decrease postanesthesia care unit costs. AB - BACKGROUND: The goal of this study was to identify interventions that anesthesiologists can make to decrease total costs of a postanesthesia care unit (PACU). METHODS: Data were collected retrospectively from patients who underwent ambulatory surgery at our tertiary care center. RESULTS: Supplies and medications accounted for only 2% of PACU charges. Personnel costs, which depend on the peak number of patients in the PACU, accounted for almost all PACU costs. If nausea and vomiting could have been eliminated in each patient who suffered this complication, without causing sedation, the total time to discharge for all patients would have been decreased by less than 4.8% (95% confidence interval < 7.3%). Arrival rates to and times to discharge from the PACU followed triangular and log-normal distributions, respectively. Computer simulations, using published times to discharge for drugs with "faster recovery," such as propofol, showed that the use of these drugs would only decrease PACU costs if operating rooms were consistently scheduled to run later each day. Such earlier discharge also might be beneficial if used at night, but only if the PACU could close after a single patient leaves. However, reasonably achievable decreases in the times to discharge for all patients undergoing general anesthesia are unlikely to substantively decrease PACU costs. In contrast, arranging an operating room schedule to optimize admission rates would greatly affect the number of PACU nurses needed. CONCLUSIONS: Anesthesiologists have little control over PACU economics via choice of anesthetic drugs. The major determinant of PACU costs is the distribution of admissions. PMID- 7832341 TI - Strengthening the in-hospital chain of survival with rapid defibrillation by first responders using automated external defibrillators: training and retention issues. AB - STUDY OBJECTIVE: To determine whether staff outside critical care areas who were proficient in basic life support (BLS) could be easily trained to use automated external defibrillators (AEDs) and whether they would retain these skills. DESIGN: Prospective, longitudinal cohort series. SETTING: Two university teaching hospitals. PARTICIPANTS: One hundred forty nurses who had previously learned BLS and constituted the staff from three medical/surgical nursing units from each study hospital. INTERVENTIONS: The nurses were taught how to use the Heartstart 1000s, a lightweight portable shock-advisory AED, in a 2-hour class with an instructor and manikin-to-student ratio of 1:5. The course emphasized hands-on practice of the BLS-AED algorithm on a computerized manikin. RESULTS: Using a similar scenario, each nurse was evaluated on the computerized manikin immediately after training (posttest). At 1 to 3, 4 to 6, and 7 to 9 months after the initial training, convenience samples of the cohort in three different groups were evaluated for retention. Satisfactory performance was defined as delivery of the first AED shock within 2 minutes of recognition of the arrest. At the posttest after training, 139 of 140 nurses (99%) demonstrated satisfactory performance. Of 77 nurses evaluated, 31 of 32 at 1 to 3 months, 18 of 18 at 4 to 6 months, and 24 of 27 at 7 to 9 months after initial training (95% overall) performed satisfactorily. CONCLUSION: As has been demonstrated with prehospital emergency personnel, nurses outside critical care areas who are proficient in BLS can easily learn and retain the knowledge and skills to use AEDs. Automated external defibrillation, a BLS skill, should be incorporated into BLS programs (BLS-AED) for all hospital personnel expected to respond to a patient in cardiac arrest, with rapid defibrillation taking priority over CPR. PMID- 7832342 TI - Accuracy of interpretation of cranial computed tomography scans in an emergency medicine residency program. AB - STUDY OBJECTIVES: To determine the concordance of emergency physicians and radiologists in interpreting cranial computed tomography (CT) scans. The study also sought to determine the clinical significance of misinterpretations of cranial CT scans by emergency physicians. DESIGN: Prospective cohort study. SETTING: A county hospital emergency medicine residency program. PARTICIPANTS: Five hundred fifty-five patients undergoing CT scanning during emergency department evaluation. RESULTS: Forty-nine percent (272) of the indications for CT scanning were for trauma, 14.2% (79) were for cerebrovascular accident, 25.1% (139) were for headache, 15.1% (84) were for seizure, and 13.7% (76) were for miscellaneous reasons. The radiologists interpreted 46.1% (256) of the CT scans as abnormal. The most frequent abnormalities were scalp hematoma, 15.2% (39); infarction, 14.1% (36); calcification, 6.3% (16); contusion, 6.3% (16); parenchymal hemorrhage, 5.1% (13); and mass, 5.1% (13). Nonconcordance between radiologists and emergency physicians was found in 38.7% (206) of the cases. Potentially clinically significant misinterpretations were found in 24.1% (131) of the total sample. These misinterpretations included 62 missed major findings (11.4% of total sample): 25 new infarcts, 10 mass lesions, 8 cases of cerebral edema, 8 parenchymal hemorrhages, 5 contusions, 4 subarachnoid hemorrhages, 1 epidural hematoma, and 1 subdural hematoma. However, on chart review, only three patients (0.6%) were found to have been managed inappropriately, and none had an adverse outcome. CONCLUSION: The misinterpretation rate of cranial CT scans by emergency physicians is of potential clinical concern. However, clinical mismanagement is rare. We recommend that more formal education in CT interpretation be included in residency training and continuing medical education programs for emergency physicians. PMID- 7832343 TI - Stabilization of rural multiple-trauma patients at level III emergency departments before transfer to a level I regional trauma center. AB - STUDY OBJECTIVE: To determine whether triage and stabilization of severely injured rural trauma victims in outlying Level III emergency departments before transfer to Level I trauma centers results in outcomes similar to national normative data. DESIGN: Retrospective review of trauma transfers and deaths during a 4-year period. SETTING: Two Level III EDs in rural, upstate New York and an urban Level I regional trauma center. PARTICIPANTS: Fifty multiple-trauma victims with a Trauma Triage Score (T-RTS) of < or = 11 or less. Forty-three patients were stabilized before transfer, and 7 died in the rural Level III ED. RESULTS: There were 45 blunt injuries and 5 penetrating injuries. Mean patient age was 34 years (range, 9 months to 97 years). The Revised Trauma Score (RTS) on admission to the Level III ED was calculated for each patient (median score, 5.97; interquartile range (IQR), 4.09 to 6.90), as was the ultimate Injury Severity Score (ISS) (median score, 23; IQR, 13 to 29). With TRISS methodology, probabilities of survival (Ps) and death (Pd) were calculated. Results were compared with the Major Trauma Outcome Study (MTOS) by use of current coefficients derived from Walker-Duncan regression analysis of MTOS data. The predicted number of deaths was 13.5, whereas the actual number was 12, Z statistic, -.710. There were two unexpected survivors and three unexpected deaths. The 43 patients who were stabilized and transferred had a median RTS of 5.97 (IQR, 4.30 to 6.90) and an ISS of 18 (IQR, 12 to 25). The median interval in the Level III ED before transfer was 1 hour 43 minutes (IQR, 1 hour 11 minutes to 2 hours 40 minutes). There were two unexpected survivors (Ps = .32, Ps = .49) and 1 unexpected death (Ps = .52). The predicted number of deaths was 8.1, whereas the actual number was 5. The 7 patients who died in the rural Level III ED had a median RTS of 4.41 (IQR, 2.98 to 4.71) and a median ISS of 50 (IQR, 44 to 65). The median interval in the Level III ED before death was 42 minutes (IQR, 41 minutes to 1 hour 20 minutes). There were 2 unexpected deaths (Ps = .66, Ps = .55). The predicted number of deaths was 5.4 whereas the actual number was 7. CONCLUSION: Triage and stabilization of severely injured rural trauma victims at Level III EDs before Level I transfer provide outcomes similar to national results. Unexpected death of severely injured trauma victims remains a problem in rural Level III EDs. PMID- 7832344 TI - Vehicle-at-scene-to-patient-access interval measured with computer-aided dispatch. AB - STUDY OBJECTIVE: To determine whether the vehicle-at-scene-to-patient-access (VSPA) interval could be measured by means of crew reporting to a computer-aided dispatch operation. DESIGN: A prospective demonstration-proof-methodology pilot study using crew reporting of access time on emergency calls. SETTING: An urban, public utility model (a type of EMS system), all-ALS system. PARTICIPANTS: Six ambulance crews (four day and two night). INTERVENTIONS: Times were collected by radio reporting. A survey was to be completed for each call. RESULTS: Two hundred ninety-two calls met study criteria; 181 had corresponding surveys. Crew reporting compliance ranged from 52.8% to 94%. Poor radio transmission was cited infrequently as a reason for noncompliance. The median VSPA interval for all calls was 1.3 minutes (interquartile range, .8 to 2.6 minutes). Twenty-five percent of calls had intervals of more than 2.5 minutes, and 10% had an interval of more than 5 minutes. CONCLUSION: Our study suggests that it is feasible for ambulance crews to report patient access times. Methods to improve the consistency and frequency of crew reporting should be considered. The VSPA access interval varies in length and is not normally distributed. PMID- 7832345 TI - Variation in air medical outcomes by crew composition: a two-year follow-up. AB - STUDY OBJECTIVE: In a previous 1-year retrospective study, we found no differences in outcomes of patients transported by physician/nurse (P/N) and nurse/nurse (N/N) air medical crews. To confirm this finding and to identify any trends in outcome that might be associated with changes in crew composition, we prospectively collected and analyzed 2 additional years of severity and outcome data. DESIGN: Prospective cohort. SETTING: University hospital-based air medical program. RESULTS: Severity measured by APACHE-II, the Revised Trauma Score, and the Therapeutic Intervention Scoring System, and outcomes measured by mortality and the number of ICU and hospital days, were gathered prospectively on all adult air medical patients between July 1, 1990, and June 30, 1992. Patients less than 16 years old or those who were delivered to other hospitals were excluded. Patients were categorized as cardiac, acute trauma, and other. Origin of transfer and transfer times were included in the analysis. In all, 1,169 patients were studied--554 in the first year of the study, 615 in the second. In the first year, there were 185 P/N (33%) and 369 N/N (67%) flights. P/N patients were older (48.8 versus 44.5 years; P = .01) and were more likely to come from a scene (14% versus 5.7%; P = .001), but no differences were found with regard to sex or disease category. Mortality, the Therapeutic Intervention Scoring System, APACHE II, number of ICU days, and number of hospital days were no different; nor were total flight times or times spent at the hospital or scene. In the second year, 89% of flights were N/N. Differences in age or origin were not observed. Severity levels and outcomes remained unchanged. Between 1987 and 1992, the proportion of cardiac patients decreased, and overall illness severity of transported patients increased. CONCLUSION: Two years of detailed prospective measurement of air medical patient characteristics and outcomes confirmed the initial finding that no significant differences in clinical outcomes could be identified between patients managed by P/N versus N/N crews. PMID- 7832346 TI - Reasons patients with chest pain delay or do not call 911. AB - STUDY OBJECTIVE: To determine the reasons patients with suspected acute myocardial infarction (AMI) delay seeking medical care or do not call 911. DESIGN: Telephone interview of patients hospitalized with suspected AMI. SETTING: Nine hospitals in King County, Washington. PARTICIPANTS: Patients admitted to a CCU or ICU between October 1, 1986, and December 31, 1987, with suspected AMI occurring out-of-hospital. Spouses of patients who met criteria but died during the hospitalization also participated. INTERVENTIONS: Hospital records were reviewed, and a 20-minute telephone interview was conducted of patients who reside in King County but do not live in an extended care facility. MEASUREMENTS: Patient demographics, cardiac history, symptoms, time of acute symptom onset, time of emergency department arrival, method of transportation, discharge diagnosis, and hospital outcome were abstracted from hospital records. Circumstances leading to the hospitalization, reasons for delay in seeking care, and reasons for not calling 911 were determined in the telephone interview. RESULTS: In a 15-month period, 5,207 patients were hospitalized for suspected AMI in King County, Washington. Twenty-seven percent had AMI. Median patient delay between symptom onset and hospital arrival was 2 hours. Paramedics transported 45% of all patients. A representative subset of patients (2,316) were interviewed. The main reasons for delay were because the patient thought that the symptoms would go away, because the symptoms were not severe enough, and because the patient thought that the symptoms were caused by another illness. The main reasons for not calling 911 were because the symptoms were not severe enough, because the patient did not think of calling 911, and because the patient thought that self-transport would be faster because of his or her close location to the hospital. CONCLUSION: Maximal benefit from thrombolytic therapy is not realized in a substantial proportion of patients with AMI because of delays in seeking medical care. Knowledge of the reasons patients delay or do not call 911 can help focus efforts on achieving more rapid treatment of patients with AMI. PMID- 7832347 TI - CPR instruction by videotape: results of a community project. AB - STUDY OBJECTIVE: To increase the rate of bystander CPR in a community by use of a free, mailed, 10-minute videotape of CPR instruction. DESIGN: Prospective, randomized intervention trial. One half of the households (8,659) received the free videotape (video-tape group) and were considered the intervention group, and one half (8,659) served as the control (no-videotape group). All households were followed from December 1991 to March 1993 to determine whether a cardiac arrest occurred and who initiated CPR. A telephone interview obtained additional information about circumstances of the arrest and whether members of the household viewed the videotape. SETTING: City of Everett and South Snohomish County, Washington. A commercial mailing list was used to identify 17,318 households with a head of the household who was more than 50 years old. PARTICIPANTS: A case was defined as a cardiac arrest in which CPR was initiated or continued by emergency medical services personnel. Only cardiac arrests due to presumed underlying heart disease were included. Arrests occurring after arrival of emergency medical services personnel were not included. INTERVENTIONS: The intervention was a free 10-minute videotape with CPR instructions mailed to the 8,659 intervention households. Paramedic run reports were reviewed and interviews were conducted with cardiac arrest bystanders to determine who initiated CPR and whether they had received and viewed the videotape. RESULTS: Sixty-five cardiac arrests occurred in the study households: 31 in households that received the videotape and 34 in households that did not review the videotape. The overall rate of bystander CPR was 47% in the videotape group and 53% in the no-videotape group (P = NS). In nine cardiac arrests, an individual was present who had watched the videotape; six of these nine cases (66%) had bystander CPR. CONCLUSION: Mass mailings of CPR instructional videos are likely to be ineffective in increasing the rate of bystander CPR in a community. PMID- 7832348 TI - Tetracaine, epinephrine (adrenalin), and cocaine (TAC) versus lidocaine, epinephrine, and tetracaine (LET) for anesthesia of lacerations in children. AB - STUDY OBJECTIVE: To compare the duration of anesthesia experienced with lidocaine, epinephrine, and tetracaine (LET) solution and that with tetracaine, epinephrine (Adrenalin), and cocaine (TAC) solution during suturing of uncomplicated lacerations on the face or scalp. DESIGN: Double-blind, randomized, controlled trial. SETTING: The emergency department of a university-affiliated private children's hospital. PARTICIPANTS: One hundred seventy-one children with lacerations on the face and scalp requiring suturing. INTERVENTIONS: After standard application of the anesthetic solution, patients were assessed for signs of discomfort before and during laceration repair. Duration of anesthesia during laceration repair was determined on the basis of the length of time after removal of the anesthetic solution to the first sign(s) of discomfort that required additional anesthesia. RESULTS: There was no statistical difference between TAC and LET in adequacy of anesthesia before suturing or in duration of anesthesia during suturing. CONCLUSION: LET is an effective alternative to TAC for topical anesthesia during suturing of uncomplicated lacerations on the face and scalp in children. PMID- 7832349 TI - A randomized, controlled trial of oral midazolam and buffered lidocaine for suturing lacerations in children (the SLIC Trial). AB - STUDY OBJECTIVE: To evaluate the efficacy of oral midazolam (0.3 mg/kg) and buffered lidocaine in reducing the anxiety associated with the repair of childhood lacerations. DESIGN: Prospective, randomized, double-blind, placebo controlled trial. SETTING: Community-based emergency department. PARTICIPANTS: Children younger than 10 years. INTERVENTIONS: Each subject was randomized into one of four treatment groups: A, midazolam and buffered lidocaine (n = 25); B, placebo and buffered lidocaine (n = 27); C, midazolam and plain lidocaine (n = 32); and D, placebo and plain lidocaine (n = 23). RESULTS: Anxiety level was scored on a scale of 1 to 4 on the basis of predetermined behavior criteria before and during repair. Parents independently rated the child's distress using a visual analog scale. Vital signs were measured on admission and at discharge. There were no significant differences among the treatment groups for age, location and length of laceration, or initial anxiety scores. Midazolam decreased the number of children with anxiety levels 3 and 4 by 24% (95% CI, 7.5% to 41.3%). There was a 33% reduction of the parents' distress rating with midazolam (P < .01). Buffered lidocaine had no effect on anxiety level. CONCLUSION: Oral midazolam (0.3 mg/kg) is a safe and effective treatment for reducing anxiety during the suturing of lacerations in children less than 10 years of age. In this study, buffered lidocaine had no effect on anxiety level. PMID- 7832350 TI - Prospective identification and triage of nonemergency patients out of an emergency department: a 5-year study. AB - STUDY OBJECTIVE: To determine whether nonemergency patients can be prospectively identified by triage nurses and safely triaged out of the emergency department without treatment. METHODS: All adult patients (16 years or older) who presented to a university ED were provided an evaluation by a triage nurse. For a patient's case to be defined as nonemergency, four criteria were required: vital signs within a specific range, presence of 1 of 50 potentially nonemergent chief complaints, absence of key indicators found on screening examination, and absence of chest pain, abdominal pain, any severe pain, and inability to walk. Between July 1988 and July 1993, patients who satisfied these criteria were defined as nonemergency, refused care in the ED, and triaged out of the ED. Patients were referred to off-site clinics. The clinics had agreed to see patients in advance of the study, and the referral lists were frequently updated. Outcome data were obtained by telephone surveys to both triaged individuals and other health care providers. RESULTS: In this 5-year study, 176,074 adults presented to the ambulatory triage area in the ED, and 31,165 (18%) were defined as nonemergency, were not treated, and were referred elsewhere. Letters and telephone calls to all referral clinics, eight local EDs, and the coroner's office identified no instances of gross mistriage and only a small number of insignificant adverse outcomes. Telephone follow-up to individuals triaged away was successful in 34% of calls and showed that 39% of persons received care elsewhere on the same day, 35% received care within 3 days, and 26% decided not to seek medical care. A group of 1.0% sought care at other hospital EDs for minor complaints. CONCLUSION: A subset of patients with nonemergency problems can be prospectively identified and triaged out of the ED without significant adverse outcomes provided there is community support for follow-up care. PMID- 7832351 TI - Health insurance status and the use of emergency and other outpatient services by adults with sickle cell disease. AB - STUDY OBJECTIVE: To evaluate insurance status and frequency of use of emergency services in adults with sickle cell disease. DESIGN: Retrospective analysis of visits. SETTING: Emergency department and outpatient clinics of an urban university hospital. PARTICIPANTS: One hundred seventy-two subjects, who made 771 visits to the ED during 1990. RESULTS: Of the 172 subjects, 31 were covered by commercial insurance, 32 were covered by Medicare, and 109 were covered by Medicaid or were uninsured. Insurance status and frequency of use of emergency services were independent (P > .05). On discriminant analysis, Medicaid-covered and uninsured subjects were correctly classified, but commercially insured and Medicare subjects were not. Medicaid and uninsured subjects were more likely to be younger and to live closer to the hospital (P < .00005). High-frequency users of emergency services were discriminated from low-frequency users. High-frequency users were more likely to be younger, to be users of primary-care services, and to live closer to the hospital (P = .0004). CONCLUSION: Provision of primary-care services or stable insurance in the form of commercial insurance or Medicare did not decrease use of emergency services in subjects with sickle cell disease in a group of patients selected from one urban academic ED. PMID- 7832352 TI - The role of emergency medicine in the future of American medical care. PMID- 7832353 TI - Recommendations for emergency medicine. PMID- 7832354 TI - Clinical emergency medicine, today and tomorrow. AB - Properly staffed and equipped EDs are essential to a modern system of health care. In a relatively brief period, emergency medicine has emerged as a major medical specialty. Despite formidable barriers, emergency medicine has substantially improved the quality of prehospital and ED care in the United States. If sufficient support for the specialty can be secured, the future of emergency medicine is bright. If not, the nature of emergency care in the United States will be profoundly changed for years to come. PMID- 7832355 TI - Medical care for chemically contaminated patients: guidelines for a difficult problem are on the way. PMID- 7832356 TI - A survey of wellness issues in emergency medicine (Part 2). PMID- 7832357 TI - Fatal clival subdural hematoma in a hemophiliac. AB - We report the case of a hemophiliac in whom developed an unusual site of intracranial bleeding, a subdural hematoma that extended in the posterior fossa anteriorly from the clivus into the upper spinal subdural space. The hematoma was delayed in onset and was fatal. We review the current management recommendations for hemophiliac patients with head injury and the clinical presentation of intracranial bleeding in hemophiliacs. The necessity for Factor VIII replacement and serial computed tomography scans is emphasized. PMID- 7832358 TI - Bilateral vocal cord paralysis following blunt trauma to the neck. AB - Blunt trauma to the anterior neck has been known to cause upper-airway obstruction requiring emergency tracheostomy. We report the case of a 26-year-old man who sustained blunt trauma to the anterior neck in whom upper-airway obstruction developed. Although computed tomography of the neck revealed a thyroid cartilage fracture and a retropharyngeal hematoma, fiberoptic examination of the larynx identified vocal cord paralysis as the primary cause of his upper airway obstruction. Emergency tracheostomy was performed, and the patient recovered uneventfully. A Medline search of the literature for the past 3 years failed to identify any individual case reports of bilateral vocal cord paralysis secondary to blunt anterior neck trauma. PMID- 7832359 TI - Emergency management of hypercyanotic crises in tetralogy of Fallot. AB - We report the case of a 3-month-old girl with tetralogy of Fallot who was resuscitated from a near-fatal hypercyanotic episode (Tet spell). While tetralogy of Fallot is rare (1 in 10,000 live births), failures of diagnosis or management may result in catastrophic outcomes for an eminently survivable condition. An understanding of the pathophysiology of hypercyanotic spells will allow the emergency specialist to understand and apply a treatment option--compression of the abdominal aorta--not previously reported in the emergency medicine literature. PMID- 7832360 TI - Zigadenus poisoning. AB - Significant toxicity can result from ingestion of certain species of the Zigadenus plant, an herb occasionally confused with nontoxic wild onions. A 50 year-old man inadvertently ingested Z paniculatus and presented to the emergency department with profound gastrointestinal toxicity, hypotension, and bradycardia. The pathophysiology and management of Zigadenus poisoning are reviewed. Emergency physicians, particularly in rural areas, should be aware of the morbidity caused by ingestion of some Zigadenus species. PMID- 7832362 TI - On turbulent times for emergency medicine. PMID- 7832361 TI - Adverse cardiac manifestations following dextropropoxyphene overdose: can naloxone be helpful? AB - Dextropropoxyphene overdose may be complicated by serious cardiovascular manifestations, including conduction abnormalities and collapse. We report two patients in whom cardiac toxicity developed. Cardiovascular depression seemed to be improved after naloxone infusion in these two cases. Possible mechanisms are briefly discussed. PMID- 7832363 TI - On turbulent times for emergency medicine. PMID- 7832364 TI - On turbulent times for emergency medicine. PMID- 7832365 TI - On turbulent times for emergency medicine. PMID- 7832366 TI - Carbon monoxide poisoning: a review of human outcome studies comparing normobaric oxygen with hyperbaric oxygen. PMID- 7832367 TI - Carbon monoxide controversies: neuropsychologic testing, mechanism of toxicity, and hyperbaric oxygen. PMID- 7832368 TI - Clinical policy for the initial approach to adults presenting with a chief complaint of chest pain, with no history of trauma. American College of Emergency Physicians. PMID- 7832369 TI - American College of Emergency Physicians: family leave of absence. PMID- 7832370 TI - American College of Emergency Physicians: physician impairment. PMID- 7832372 TI - American College of Emergency Physicians: certificate of competency in critical care medicine. PMID- 7832371 TI - American College of Emergency Physicians: pediatric equipment guidelines. PMID- 7832373 TI - Beyond the scalpel. AB - Surgical residency training should be changed to provide much needed surgical manpower to rural America. Small-town and rural surgery practices demand that surgeons see and treat their patients as people. If rural surgery could become a real option for young surgeons, it could bring about a change in the sometimes adversarial relationship between patients and their physicians. PMID- 7832374 TI - Second place winner of the Conrad Jobst Award in the gold medal paper competition. Increased antibiotic effectiveness in a model of surgical infection through continuous infusion. AB - As long as infection remains the most common cause of morbidity and mortality in severely ill patients, there exists the need for more effective anti-infective therapy. The current study was undertaken to determine whether continuous infusion (CONT) is superior to intermittent administration (INT) of an equal amount of cefazolin (CEF) in a model of surgical infection. The thigh suture model consists of the surgical placement of 1 cm of cotton suture with absorbed K. pneumoniae into the thigh muscle of mice. The experimental groups were: 1) controls (n = 20) with thigh suture inoculation and treatment with intraperitoneal (IP) sterile saline; 2) CONT infusion group that received CEF at 60 mg/kg IP 30 minutes before inoculation followed by CONT IP infusion at 180 mg/kg/day (n = 22) for 3 days; and 3) INT injection group that received CEF at 60 mg/kg IP 30 minutes before inoculation followed by INT IP injections every 8 hours at 180 mg/kg/day (n = 20) for 3 days. All CEF treated animals received identical quantities of total CEF, and all groups were followed for 10 days. The control and INT CEF groups had 20% survival, whereas the CONT CEF group had 81% survival, (P < 0.001). Continuous CEF yielded constant serum levels of 19 +/- 1 micrograms/mL, whereas INT injections resulted in peak serum level of 74 +/- 12 micrograms/mL at one minute but declined to 3.9 +/- 0.9 micrograms/mL in 2 hours. Although there was statistically significant tissue bacterial growth in the INT injection group, there was extensive tissue bacterial clearance in the CONT infusion group.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7832375 TI - Third place winner of the Conrad Jobst Award in the gold medal paper competition. Prevention of spinal cord dysfunction in a new model of spinal cord ischemia. AB - Paraplegia or paraparesis caused by temporary cross-clamping of the aorta is a devastating sequela in patients after surgery of the thoracoabdominal aorta. No effective clinical method is available to protect the spinal cord from ischemic reperfusion injury. A small animal (rat) model of spinal cord ischemia is established to better understand the pathophysiological events and to evaluate potential treatments. Eighty-one male Sprague-Dawley rats weighing 300 g to 350 g were used for model development (45) and treatment evaluation (36). The heparinized and anesthetized rat was supported by a respirator following tracheostomy. The thoracic aorta was cannulated via the left carotid artery for post-clamping intra-aortic treatment solution administration. After thoracotomy, the aorta was freed and temporarily clamped just distal to the left subclavian artery and just proximal to the diaphragm for different time intervals: 0, 5, 10, 15, 20, 25, 30, 35, and 40 minutes (five animals per group). The motor function of the lower extremities postoperatively showed consistent impairment after 30 minutes clamping (5/5 rats were paralyzed), and this time interval was used for treatment evaluation. For each treatment, six animals per group were used, and direct local intra-aortic infusion of physiologic solution (2 mL) at different temperatures with or without buffer substances was given immediately after double cross-clamp to protect the ischemic spinal cord. Arterial blood (2 mL) was infused in the control group. The data indicate that the addition of HCO3-(20 mM) to the hypothermic (15 degrees C) solution offered complete protection of the spinal cord from ischemic injury.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7832376 TI - Initial experience with laparoscopic Nissen fundoplication. AB - In an effort to explore the utility of classic Nissen fundoplication performed laparoscopically, 16 adult patients with well documented gastroesophageal reflux underwent laparoscopic Nissen fundoplication. A full gastric fundal dissection was performed, with division of at least 2 short gastric vessels. The crura were approximated with 1-3 sutures, and a loose fundoplication was performed over an esophageal dilator (minimum 46 F) with three stitches, encompassing the esophageal wall (2.5 cm in length). All patients had symptoms of reflux refractory to medical therapy, and four had an esophageal stricture requiring preoperative dilatation. Fifteen of 16 procedures were completed laparoscopically; one patient required conversion to an open procedure to control bleeding from a posterior gastric vein. There were no other operative complications. The average operative time was 180 minutes (range 120-285). Clear liquids were begun at the passage of flatus (average 2.7 days postop), and patients were discharged an average of 4.1 days postoperatively. Postoperative complications included ileus (1 patient for 6 days), severe subcutaneous emphysema (1 patient), and dysphagia requiring dilatation (5 patients). In short follow-up (mean 4.43 mo., range 1-12 mo.) 14 of 15 patients had complete abolition of reflux symptoms, but one patient with persistent heartburn had reflux demonstrated on a postoperative upper GI series. Thirteen of 16 patients returned to full function within 14 days of surgery. We conclude that standard Nissen fundoplication is possible laparoscopically, and allows a rapid recovery from surgery. However, it is difficult, time consuming, and associated with a significant rate of recurrence in the short term (6%).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7832377 TI - Aggressive use of ICP monitoring is safe and alters patient care. AB - OBJECTIVE: To identify complications and interventions resulting from fiberoptic ICP monitoring in a large series of patients with closed head injury (CHI). SETTING/DESIGN: Level I trauma center/Consecutive case series. METHODS: Of 11,962 consecutive trauma admissions from 1984-1991, 279 patients underwent fiberoptic ICP monitoring for CHI. We identified the last 100 consecutive blunt trauma patients who had received ICP monitoring. Ninety-eight of these patients had charts available and constitute the study group. We examined mortality, Glasgow Coma Score (GCS), and admission CT findings for the group. Indications, interventions, and complications (bleeding, meningitis, and wound infections) associated with ICP monitoring were identified. RESULTS: Mortality for the group was 24%. Reasons for ICP monitoring included GCS < or = 8 and/or abnormal CT findings; 83% had GCS < or = 8. Admission CT findings included subarachnoid hemorrhage (48%), intracerebral hemorrhage (47%), edema (31%), intraventricular hemorrhage (20%), subdural hematoma (18%), and epidural hematoma (9%). Eighty-one per cent of patients had interventions based on ICP monitoring: osmolar therapy (81%), emergency CT (22%), surgical decompression (3%), or pentobarbital coma (2%). No complications resulted from ICP monitoring. Mean duration of monitoring was 4 days (maximum 13 days). Twenty patients (20%) required two or more monitors. Reasons for placing a second monitor included duration > 5 days (50%), questionable accuracy (20%), and accidental removal of the first monitor (10%). CONCLUSIONS: 1) Fiberoptic intracranial pressure monitoring leads to specific interventions in the majority of patients. 2) The procedure is safe. 3) Prospective studies are needed to determine the impact of coagulopathy on the safety of fiberoptic intracranial pressure monitoring and to define those factors responsible for the low infection rate. PMID- 7832378 TI - Temporary closure of open abdominal wounds: the vacuum pack. AB - Temporary closure of abdominal surgical wounds is occasionally required when conditions of the abdominal wall or peritoneal cavity prevent closure or when early re-exploration is planned. The optimal temporary closure should contain and protect the contents of the peritoneal cavity from external contamination and injury; preserve the integrity of the abdominal wall; be simple to perform and maintain; provide ease of reentry; and have minimal adverse physiologic effects. Based on these criteria, a method of temporary abdominal wound closure (termed the vacuum pack) has been designed and evaluated. The operative technique includes 1) placement of a fenestrated polyethylene sheet between the abdominal viscera and anterior parietal peritoneum; 2) placement of a moist, sterile laparotomy towel over the polyethylene sheet; 3) placement of two closed suction drains over the towel; 4) placement of an adhesive backed drape over the entire wound, including a wide margin of surrounding skin; and 5) suction applied to the drains, creating a vacuum and rigid compression of the layers of closure material. This creates a tight, external seal of the adhesive backed drape and facilitates drainage of the peritoneal cavity. From April 1992-December 1993, this temporary abdominal wound closure was performed 56 times in 28 patients, ages 6-78 years, for periods of 1-11 days. The procedure was used in 17 trauma patients and 11 non-trauma patients. Indications for use included increased intra abdominal pressure in nine, mandatory re-exploration in 10, and a combination of these indications in nine patients. Pre- and postprocedural airway and systemic blood pressures were unaffected by this closure.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7832379 TI - Laparoscopic herniorrhaphy: technical concerns in prevention of complications and early recurrence. AB - Laparoscopic herniorrhaphy continues to gain popularity, but should be subjected to proper scrutiny before widespread acceptance. From 5/91 to 6/93, 290 transabdominal preperitoneal (TAPP) laparoscopic herniorrhaphies were performed on 244 adult patients at Georgia Baptist Medical Center. Procedures consisted of indirect (164), direct (73), femoral (5), obturator (7), and recurrent (41) hernia repairs, with a mean operative time of 81.2 minutes (range 30-193 min). The overall technical complication rate was 5.3% and includes lateral thigh paresthesias (6), inferior epigastric artery injury (4), enterotomy during adhesiolysis (1), bowel obstruction secondary to herniation through a lateral trocar site (1), and bladder injury (1). The recurrence rate is 1% (3/290), with a mean follow up of 11 months (range 2-27 months). The authors present herein a discussion of technical considerations in an attempt to help decrease complications and recurrence as others incorporate laparoscopic hernia repair into their surgical armamentarium. PMID- 7832380 TI - Increased morbidity of appendicitis with advancing age. AB - The early diagnosis of acute appendicitis before progression to gangrene or abscess formation is recognized as important to minimize morbidity from this common disease process. As our population ages, the challenge for expedient diagnosis and intervention in older age groups will become more significant. Prompted by recent unexpected complications occurring in elderly patients, we reviewed 100 consecutive admissions with the diagnosis of appendicitis to a tertiary Veterans Administration hospital. All patients were males and were arbitrarily divided into three age groups: less than 50, 50-70, and greater than 70 years of age. There were no patients less than 20 years old. Operative findings were classified as simple acute appendicitis, ruptured or perforated appendicitis, appendicitis associated with intra-abdominal abscess, and finally other when the operative diagnosis differed from appendicitis. Of the 37 patients less than 50 years of age, 28 were found to have simple acute appendicitis, making this by far the most common finding in this age group (P < 0.05). Only two of the 18 patients aged 50-70 with appendicitis demonstrated simple acute appendicitis, with the remainder having progressed to perforation or abscess formation (P < 0.05). Patients greater than 70 years of age were significantly more likely than any other age group to manifest appendicitis associated with intra-abdominal abscess (10 of 19, P < 0.05). Eight patients died in this series, six of whom were more than 70 years of age. In most cases, mortality was directly attributable to infectious complications of perforated appendicitis. There were no deaths in the under 50 age group.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7832381 TI - Stratification of mortality risk for renal artery surgery. AB - Seventy consecutive operations involving the renal arteries were reviewed to identify factors linked to perioperative mortality. Aortorenal bypass (n = 29), endarterectomy (n = 12), extraanatomic bypass (n = 12), thrombectomy (n = 4), and reimplantation (n = 13) were associated with a 16% perioperative mortality that was often secondary to multisystem organ failure. Patients who died exhibited a higher serum creatinine (3.4 vs 2.1 mg/dL; P < 0.05). Stratification of patients by risk revealed higher American Society of Anesthesiologists (ASA) (P < 0.005) and modified Acute Physiology Score, and Chronic Health Evaluation (APACHE II) (P < 0.02) score among patients who died. Higher mortality was also observed after bilateral renal artery operations (31% vs 5%; P < 0.005) or concomitant mesenteric revascularization (37% vs 12%; P < 0.05), but not simultaneous aortic procedures (18% vs 11%; P = NS). Bilateral operation (P < 0.0001), age (P < 0.001), and ASA class (P < 0.01) were independent predictors of mortality according to multivariate analysis. Because of higher mortality in these specific situations, modification or limitation of operative scope may be appropriate. PMID- 7832382 TI - Emergency cricothyrotomy: a reassessment. AB - The Medical College of Georgia Level I Trauma Center admitted 5603 adult trauma patients from January 1, 1989 through June 30, 1993. Cricothyrotomy was required in 66 of 525 patients who required emergency airway control but could not be intubated nonsurgically in an expeditious manner. There were three major complications (thyroid cartilage laceration, significant hemorrhage, and failure to obtain a surgical airway) involving two patients, but each resolved without sequelae. Twenty-six patients with cricothyrotomy survived their hospital course, of which seven had decannulation of the cricothyrotomy without further airway procedures, and 19 had conversion to tracheostomy. No patient had clinically significant morbidity from the cricothyrotomy, whether with or without a subsequent tracheostomy. Surgical cricothyrotomy remains an important technique with low morbidity for selected trauma victims needing emergency airway control. PMID- 7832383 TI - Postsurgical gout. AB - Although catabolic events are known to precipitate gout, postsurgical gout has rarely been reported. We identified the charts of 302 patients treated over a 10 year period in a university center who carried the diagnosis of gout and who also had a surgical procedure. Fifty-two patients (42 male, 10 female) were found to have had a postsurgical episode of gouty arthritis. Ages ranged from 20 to 82 years (mean 60.1 +/- 2.1). Forty-five patients had a history of gout, 22 of whom were receiving medication and 23 who were not receiving chronic therapy. In seven patients the postsurgical event was their first attack. Attacks occurred 1-17 days (mean 4.2 +/- 0.5 [SE]) after surgical admission. Most attacks were in the lower extremity, but classic podagra was uncommon. Essentially all patients were febrile (100.7 +/- 0.2 degrees F) compared with admission (99.0 +/- 0.1 degree) (P < 0.001). There was a trend toward leukocytosis in the group as a whole, but the relationship of leukocytosis to the gout attack was most clearly seen in patients admitted for noninflammatory conditions (9.4 +/- 0.7 versus 12.8 +/- 0.8 x 1000 WBC/mm3, P < 0.001). Uric acid levels were elevated but did not follow the course of the attack. Most patients underwent a variety of tests and consultative evaluations because of their undiagnosed febrile episode. Once the diagnosis was established, all patients responded quickly to nonsteroidal anti-inflammatory drugs or colchicine. Despite evidence of a significant inflammatory response, no patient proved to have a suppurative focus as the source of their febrile episode.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7832384 TI - The ramifications of immediate reconstruction in the management of breast cancer. AB - A retrospective review of 50 patients who underwent immediate postmastectomy breast reconstruction was performed to determine the effect of reconstruction on the treatment of these patients. The overall complication rate was 50% (25 of 50). Smoking statistically correlated with an increased rate of wound complications (0 = 0.0001). Obese patients had nearly twice as many wound complications; however, this finding was not statistically significant (P = 0.261). Eleven of the 50 patients underwent reconstruction with a prosthesis, with an overall complication rate of 64% (seven of 11) and a 55% (six of 11) rate of prosthesis loss. Thirty-nine of the 50 patients underwent reconstruction with autologous tissue. Forty-six per cent (18 of 39) of the patients in the autologous group developed complications, and eight required emergent reoperation to prevent flap loss. The wound complication rate was significantly lower for bipedicled transverse rectus abdominis muscle (TRAM) flap reconstructions than for other forms of autologous reconstruction (P = 0.040). total operative time (including mastectomy) was 3.11 hours (range, 2-4 hours) for the prosthetic group and 9.4 hours (range, 5-15 hours) for the autologous group. All but two patients undergoing autologous tissue reconstruction required blood transfusions; an average of 2.4 U of blood was transfused per patient (range, 0-7 U). Only two patients in the prosthetic group required a transfusion. The average hospital stay was 5 days (range, 2-7 days) for the prosthetic group and 8.3 days (range, 5 19 days) for the autologous tissue group.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7832385 TI - Nonoperative management of blunt hepatic trauma. AB - Abdominal CT scanning makes nonoperative management of liver injury possible. We reviewed medical records of 56 blunt trauma patients with hepatic injury who received initial abdominal CT scan. We examined: 1) Indications for delayed surgery; 2) Disposition or cause of death; 3) Results of follow up CT scans; 4) Long term complications. Over a 53 month period, 1597 patients were admitted for blunt trauma, of which 76 patients were found to have hepatic injury. Twenty patients presented either clinically unstable or with an acute abdomen and underwent diagnostic peritoneal lavage or immediate laparotomy without a CT scan. Abdominal CT scan was performed on 56 patients, 19 of whom had hepatic injury or associated major abdominal injury and underwent laparotomy. One patient died of cardiac arrhythmias following CT scanning. The remaining 36 patients received initial nonoperative management of their hepatic injury. Three patients in this group underwent delayed abdominal surgery. Two developed an acute abdomen. One had a planned nephrectomy. No patient required surgical treatment of their liver injury at the time of laparotomy. Four deaths occurred in the 36 patients managed nonoperatively, all due to associated extra-abdominal injuries. Nineteen patients had 27 CT scans taken as follow up examination at intervals of 1 to 94 days postinjury. All of the CT scans showed stabilization or improvement of hepatic injury. Three patients who had CT scans taken at 3 months postdischarge were asymptomatic, with radiologic resolution of their hepatic injury. Nineteen patients were followed for an average of 61.8 days (range 7-203 days) after discharge with no complications from liver injury.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7832386 TI - Major gastroenteric injuries from blunt trauma. AB - Hollow visceral injuries are far less common in blunt abdominal trauma than in penetrating abdominal trauma. From 1982 through 1993 we treated 50 patients with 57 major blunt injuries to the gut, defined as perforation, transection, or devascularization. Thirty-two patients (64%) were injured in motor vehicle collisions. Of these, 29 wore no restraints; three were wearing lap belts (none wore lap-shoulder restraints). Mean injury Severity Score (ISS) in patients wearing lap belts was 13.3, compared with 28.6 in the 29 patients who were not using restraint devices (P < 0.01). Small bowel perforations were the most frequent injuries, followed by devascularization of the small bowel, colorectal injuries, duodenal, and gastric perforations. ISS and mortality rates were lowest in small bowel injuries and higher in the less common colonic and gastroduodenal injuries. Except for those patients with perforations of the small bowel, most patients had associated injuries to the head, chest, or abdominal solid organs that were largely responsible for morbidity and mortality. Injuries to the abdominal hollow viscera are unusual following blunt trauma, but are the result of very high energy truncal trauma, and are associated with multiple additional injuries. Most alert patients had physical findings suggestive of peritoneal irritation, but when diagnostic testing was necessary, peritoneal lavage was superior to computed tomography scanning (false negatives = 6.7% versus 36%, respectively; P < 0.05). A high index of suspicion is necessary to avoid diagnostic delays that can lead to severe complications and death. PMID- 7832387 TI - Erythropoetin accelerates hematocrit recovery in post-surgical anemia. AB - We evaluated the role of recombinant human erythropoietin (RHE) for treatment of severe postsurgical anemia (Hct < 25%) in 40 Jehovah's Witness (JW) patients refusing transfusion. Twenty patients (group E) received RHE either at a loading dose of 300 U/kg iv 3 times/week for 1 week followed by 150 U/kg 3 times/week in accordance with an IRB approved protocol (N = 13), or at a dose of 100 U/kg 3 times/week for humanitarian reasons (N = 7). This group was compared to 20 similar JW patients who did not receive RHE (group C). All patients received iron restoration and nutritional support. Non-parametric analysis (Mann-Whitney) was used because of sample size. Entry hematocrit was similar for both groups: H(E)(0) = 15.8% +/- 1.1 SEM (8.5-23.4) vs HC (0) = 12.8% +/- 0.9 SEM (7.3-20.6), P = 0.09. After one week, hematocrit was significantly higher in group E (H(E)(1)) = 19.3 +/- 1.1 vs HC(1) = 12.5% +/- 0.9, P < 0.0005) as was the increase in hematocrit for group E (3.6% +/- 0.9 for E vs -0.4% +/- 0.8 for C, P < 0.005). Hematocrit change in Week 2 showed an increase for both groups (2.9 +/- 0.6 for E vs 4.9% +/- 1.2 for C, P = 0.12). CONCLUSIONS: Hct recovery shows a 1 week lag in severely anemic postsurgical patients treated without RHE. Exogenous RHE appears to accelerate hematocrit recovery in the first week. Use of RHE in the immediate postoperative period may help avoid or reduce homologous blood transfusion. PMID- 7832388 TI - Colorectal carcinoma in patients 30 years of age and younger. AB - Thirty-seven cases of colorectal cancer in patients aged 30 years or younger have been treated at the University of Virginia Health Sciences Center from 1957 through 1992. The present series, comprising patients treated from 1978 through 1992, updates a series presented from our institution comprising patients treated from 1957 through 1977. For the 36-year series, 24 patients (65%) were female, and 13 (35%) were male. Sixteen patients (43%) were black, and 21 patients (57%) were white. Sites of tumor and their frequency were rectosigmoid, 14 (38%), left colon, five (14%), splenic flexure, two (5%), transverse colon, three (9%), hepatic flexure, two (5%), right colon, two (5%), and cecum, six (16%). Twenty two patients (59%) presented with abdominal pain, whereas 15 (41%) presented with hematochezia or hemoccult positive stools. The average time of onset of symptoms to diagnosis was 2.3 months. Thirty-four of 37 patients (92%) presented with advanced stage disease. Only four patients had precancerous conditions: one each with Gardner's Syndrome, Turcot's Syndrome, ulcerative colitis, and villous adenoma. Twenty-five patients (68%) underwent surgery for cure, and ten (27%) received palliative procedures. Nothing could be done for two patients (5%). Twenty-one patients (57%) had mucinous histology, 13 (35%) had typical adenocarcinoma, one (3%) had small cell carcinoma, and histology was unavailable in two (6%). Nodes were negative in only 10 (27%) patients, of which only three had mucinous histology. There have been five 5-year survivors and three patients alive and disease free at last follow up, ranging from 30 months to 48 months.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7832389 TI - Thoracoscopy versus thoracotomy: indications and advantages. AB - Although the diagnosis and treatment of intrathoracic diseases have been affected by the use of thoracoscopy, the indications and advantages of this procedure are poorly defined. To review the indications and results in a community practice, 52 consecutive cases of thoracoscopy were reviewed and the postoperative courses were compared to a control group of 43 simultaneous thoracotomies. Operative indications for thoracoscopy included investigation or treatment of a lung mass (n = 33), spontaneous pneumothorax (n = 10), mediastinal mass (n = 4), pleural effusion (n = 2), mesothelioma (n = 2), and a ruptured hemidiaphragm (n = 1). General endotracheal anesthesia was used in each case. Overall, thoracoscopy was successful in 40 cases (77%). Conversion to formal thoracotomy was required in 14 cases (27%) secondary to poor visualization or to aid in further dissection. Compared to thoracotomy, complication rates were less (7.6 vs 16.2%), hospital stay shorter (5.5 vs 8 days), ICU stay shorter (0 vs 2 days) and pleural drainage time less (2 vs 5 days) in the thoracoscopy group. In summary, 73% of the patients in this study who formerly would have undergone thoracotomy were successfully managed with thoracoscopy alone, with acceptable morbidity and mortality. These data define the indications, morbidity, and mortality of thoracoscopy and suggest that thoracoscopy may emerge as the procedure of choice in the diagnosis and management of many thoracic diseases. PMID- 7832390 TI - Stereotactic needle biopsy for occult breast lesions: a minimally invasive alternative. AB - Women are being screened with annual mammography in increasing numbers to achieve early diagnosis and improve chances of survival. A minimally invasive and cost effective biopsy technique is needed to evaluate nonpalpable mammographically detected lesions without decreasing reliability. A technique of core biopsy with a coring needle deployed in a spring loaded gun using stereotactic localization has been developed to fulfill this need. An in-depth study of 500 consecutive stereotactic core biopsies have been analyzed and reported in this article. The study gives statistical evaluation of data and reports the breakdown of the histologic diagnosis of these cases and an analysis of detected malignancies. The study suggests that 75% of the indeterminate mammographic lesions can be judged to be benign and that no further surgery is necessary. The false negative rate is discussed in detail. The indications for stereotactic biopsy, the proper selection of patients, and the suggested follow-up are also addressed. The benign and malignant lesions are characterized in detail. PMID- 7832392 TI - [Aspects related to the safety of the workers in magnetic resonance for clinical use]. AB - Some practical items, concerning the safety of workers employed in clinical NMR sites are described. In particular, the connections between safety, and arrangement of some installations, like electric system and cryogenic system, are pointed out. The consideration of the physical properties of the cryogens used in such sites can determine different designing criteria of these plants. Furthermore, the connections among properties of cryogens, characteristics of electric system, and prevention of fire are considered. PMID- 7832393 TI - [Measurement of the magnetic field dispersed in places with installed magnetic resonance equipment. Characteristics of the control instrumentation]. AB - Among the various controls prescribed by the standards for NMR equipment installations, the measurement of dispersed magnetic field values is of utmost technical importance. The paper deals with scope, strategy and practical execution of the measurements. It also analyzes the question of measurement errors and their effect on the strategy to be adopted and on the final accuracy of isomagnetic tracings. PMID- 7832391 TI - Laparoscopy and thoracoscopy in evaluation of abdominal trauma. AB - The role of laparoscopy and thoracoscopy as diagnostic modalities in blunt and penetrating abdominal trauma was studied in 35 hemodynamically stable patients who otherwise would have undergone exploratory laparotomy because of equivocal diagnostic findings. Minimally invasive laparoscopic techniques (single 5 millimeter port) and minimal abdominal insufflation (8-10 millimeters mercury) were used with general anesthesia. Both laparoscopy and thoracoscopy appear to be safe (no complications), highly sensitive (100%), specific (88%), and accurate (91%) tools for determining the presence of surgically significant abdominal pathology and the need for therapeutic laparotomy. The appropriate application of these techniques, possibly under local anesthesia, offers potential cost savings. PMID- 7832394 TI - [Quality control in magnetic resonance for clinical use]. AB - This chapter summarizes requirements, rationale and main steps in the recent evolution of protocols adopted at international level for quality controls in clinical magnetic resonance imaging (MRI) and spectroscopy (MRS). An accurate assessment of instrumental performance in MRI and MRS is essential for enhancing the clinical value of these methodologies, both in terms of anatomical and physio pathological information. In the field of MRI, a series of Concerted Actions, carried out in the frame of the medical and health research programmes of the European Economic Communities (EEC), led to the definition of standardized methodologies and to the construction of five test objects for assessing the quality of fourteen instrumental parameters, inherent to: signal uniformity and linearity; geometry; slice position and thickness; spatial resolution; signal-to noise and contrast-to-noise ratios; T1 and T2 precision and accuracy. The first part of this paper devotes particular attention to the protocols adopted by the EEC Concerted Actions and by the National Electrical Manufacturers Association (NEMA, US), for assessing signal uniformity, geometric distortion and signal-to noise ratio in MRI. A brief description is also given of the rationale and protocols for measuring other MRI parameters. The second part is devoted to describe eleven parameters of instrumental performance, two test objects and the measuring protocols recently proposed by the EEC Concerted Actions for quality control in single-volume localized MRS, following their validation in a series of experimental multi-centre trials. PMID- 7832395 TI - [Diagnostic applications of magnetic resonance to clinical use: imaging]. AB - The widespread diagnostic applications of magnetic resonance are here reviewed. Central nervous system, cardiovascular system, articulations are emphasized. Magnetic resonance is compared with other imaging methods, as computerized tomography, echography. PMID- 7832396 TI - [Localized magnetic resonance spectroscopy: diagnostic applications]. AB - Some of the main experimental requirements limiting, till now, the clinical development of nuclear magnetic resonance (NMR) spectroscopy are discussed, with particular attention to the scarce sensitivity, low resolution and problems of spatial localization. A concise description is then given of the principal biological compounds which can be studied by this peculiar type of spectroscopy, together with the main categories of biochemical information that can be extracted from their detection, i.e. especially at the level of intermediate and energetic metabolism. In conclusion, some of the more outstanding examples selected from human clinical studies are depicted, particularly emphasizing those focused on the skeletal muscle system. PMID- 7832397 TI - [Interaction mechanisms and biological effects of the static magnetic field (B0) in magnetic resonance for clinical use]. AB - This chapter summarizes the main mechanisms of interaction of a static magnetic field with the human body, during magnetic resonance examinations. The biological effects are evaluated at the level of physiological parameters, such as neuronal conduction and blood pressure. The artifacts on ECG traces are also described in the light of the Lorentz and Faraday laws. PMID- 7832398 TI - [Interaction mechanisms and biological effects of time-variable magnetic fields (dB/dt) in magnetic resonance for clinical use]. AB - The first part of this paper is devoted to discuss the necessity of using time varying magnetic fields, with frequencies up to a few kHz, during NMR tomographic and spectroscopic clinical examinations. It is then shown that these magnetic fields induce in the biological systems an electric field, with associated current densities, whose intensities span from physiological currents to currents able to depolarize the axonal membrane. Therefore particular emphasis is given to the involvement of excitable tissues, which can produce biological responses of variable intensity, from the less hazardous, such as magnetophosphenes, to muscle twitches, to more serious phenomena, such as extrasistoles and ventricular fibrillation. The thresholds above which these effects become physiologically relevant depend upon the different conditions and modalities of stimulus administration. Regarding weak electric currents, with their associated biological effects, the more important mechanisms of action at present hypothesized, along with some better studied experimental models, have been shortly outlined. PMID- 7832399 TI - [Radiofrequency magnetic fields and SAR in magnetic resonance for clinical use]. AB - The exposure to radiofrequency (RF) electromagnetic fields is one of the main aspects to be controlled in order to ensure the safety of patients in an NMR environment. Starting from the description of the main physical characteristics of RF fields active in imaging instrumentation, a simple model is obtained which accounts for the experimental interdependence between the parameters of the stimulus and SAR values deposited on the patients. This model can yield a preliminary/approximate prediction of exposure levels for a given test. Some NMR equipment admit the estimation of the actual SAR values during the test on the basis of electrical measurements. The paper illustrates the basic principles of these measurements. The biological effects associated with the absorption of RF energy are discussed with particular attention to the physical and biological factors which may result in local heating on the body, a danger which may not be prevented by simply observing the prescribed thresholds of mean exposure. PMID- 7832400 TI - [Interactions of electromagnetic fields produced by magnetic resonance with prostheses and ferromagnetic materials]. AB - This paper accounts for coupling modes and effects that NMR-induced electromagnetic fields (B0, dB/dt, RF) produce when interacting with prostheses and ferromagnetic materials. As for prostheses specifically, the paper reports an original contribution: an in vitro test performed on the NMR equipment mod. SISCO SIS 200/183 for research purposes installed at the Istituto Superiore di Sanita. Scope of this study was the evaluation of effects and malfunctionings induced by the above-mentioned electromagnetic fields on pacemakers inside a human trunk simulator exposed to NMR field intensity. PMID- 7832401 TI - [Introduction to magnetic resonance for clinical use. Physical principles and instrumentation]. AB - The recent technological developments in nuclear magnetic resonance (NMR) have made it possible to extend the use of this methodology to the formation of body images (MRI), as well as to the in vivo detection of metabolites in tissues and organs, by means of localized magnetic resonance spectroscopy (MRS). After presenting a brief semi-classical introduction to the NMR phenomenon, this article illustrates the principles of MRI, starting from phase encoding to the most commonly used pulse sequences. The main techniques of localized MRS are then introduced, with particular attention to their major advantages and limitations. The last session is devoted to the schematic description of a system for magnetic resonance imaging and spectroscopy. PMID- 7832402 TI - [Limits of exposure to magnetic fields and national standards for the safety of the patient during magnetic resonance examination]. AB - This review summarizes experimental bases, limitations and rationale of guide lines and recommendations adopted by national health authorities for the safety of patients exposed to the magnetic fields utilized during magnetic resonance (MR) examinations: static magnetic field (B0); time-varying magnetic field gradients (dB/dt) and radiofrequency magnetic fields. Although the mechanisms of interaction of these fields with the living matter are today sufficiently understood to identify the main categories of potentially associated health hazards, epidemiological studies and dosimetric concepts are still far from the levels of definition of protection standards adopted in the field of ionizing radiations. The definition of safety thresholds and levels of exposure to magnetic fields during MR examinations has evolved in the last decade and the matter is still under study today. This article summarizes the main steps in this continuous updating process and discusses limitations and criteria, which recently suggested the adoption in some Countries (including Italy) of a two-tier system for the levels of exposure of patients to the magnetic fields generated by clinical MR equipment. PMID- 7832403 TI - [National standards: safety of the workers who work with magnetic resonance devices for clinical use]. AB - The italian regulation in force of NMR, concerning the safety of workers is resumed. In particular, the innovative criterion of the law DM 8 August 1991 is pointed out. It concerns the safety criteria which take into account both the premises and the equipment. Specific mention is made of the surveillance and inspection authorities concerned and their specific duties, as well as the general prescribed general safety criteria. PMID- 7832404 TI - [International guidelines on the diagnostic applications of magnetic resonance. International Non-Ionizing Radiation Committee of the International Radiation Protection Association]. AB - Magnetic resonance imaging has become an established diagnostic modality. The clinical usefulness of in vivo magnetic resonance spectroscopy was demonstrated in several instances and is being explored further. These techniques involve exposure of the patient to static and time-varying magnetic fields and radiofrequency electromagnetic fields. In particular exposure situations, these fields may pose a health hazard. The purpose of this paper is to provide information on the guidelines issued by the International Non-Ionizing Radiation Committee of the International Radiation Protection Association on levels of exposure and health effects from magnetic and radiofrequency electromagnetic fields associated with magnetic resonance diagnostic devices, and on precautions to be taken to minimize health hazards to patients undergoing magnetic resonance examinations. PMID- 7832405 TI - [Installation of magnetic resonance equipment: technical requirements, site suitability criteria and safety control. Aspects related to the safety of the patients and the population]. AB - This paper deals with some technical requirements for the installation of NMR equipment in health units, in particular, stray field, proximity of critical objects, magnetic shieldings, and weight of the magnet. As regards building requirements, measures and location of the site and intended use of the rooms inside and adjacent to the site are discussed. Finally, reference is made to safety controls concerning exposure levels, safety protocols, and measures adopted for the safety of patients and healthy volunteers. PMID- 7832406 TI - [Methods and instrumentation for the analysis of asbestos fibers in human organs and tissues]. PMID- 7832407 TI - Acute and chronic sulphur dioxide (SO2) exposure: an overview of its effects on humans and laboratory animals. AB - Sulphur dioxide (SO2) is a common air pollutant found both in indoor and outdoor environments. Studies of controlled human exposure as well as epidemiological and animal investigations have documented several short- and long-term effects of SO2 exposure on the respiratory and other systems. Exercise, duration and other exposure factors may potentiate the pollutant's effects, especially in sensitive individuals such as children and asthmatics. Early postnatal somatic and behavioural alterations have been shown after maternal SO2 exposure, during pregnancy and neonatal exposure. Such exposure should be considered as a complex toxic hazard which may interfere with the developmental processes in the offspring. PMID- 7832408 TI - Endogenous DNA damage and spontaneous mutagenesis in cultured mammalian cells. AB - This review describes the main molecular mechanisms of endogenous mutagenesis, with reference to the possible sources of the different DNA lesions, the types of mutation originated and the specific defense strategies employed by the cell. The analysis of mutations induced by mutagenic agents that mimic the effect of endogenous sources of damage is also considered, since it provides information on the possible effect of intracellular mutagens. Furthermore spontaneous mutational spectra of different target genes of mammalian cells are described and compared and the contribution of the different mutational sources is discussed. PMID- 7832409 TI - Molecular analysis of mutations induced by chemical carcinogens in mammalian cells. I. The use of selectable gene loci. AB - Several lines of evidence indicate the important role of mutation in the process of carcinogenesis, however our understanding of the factors that influence the formation of mutation is still limited. Recent developments in the analysis of gene mutations at selectable loci in cultured mammalian cells has allowed to accumulate a significant amount of information on the type and distribution of mutations induced by a variety of chemical and physical agents. The purpose of this review is to summarize the data relative to chemical carcinogens and to discuss how their mechanism of interaction with DNA and the repair processes active on the induced lesions affect mutational spectra. PMID- 7832410 TI - Molecular analysis of mutations induced by chemical carcinogens in mammalian cells. II. The use of recombinant DNA vectors. AB - One approach to molecular and mechanistic studies of mutagenesis in mammalian cells is to introduce a mutational target gene into the cells as part of a shuttle vector which is capable of replication in both mammalian cells and bacteria. Following mutagenesis in the mammalian cell host, the shuttle vector sequences are recovered from the mammalian cells and introduced into bacteria, where large amounts of the mutant gene can be produced for sequence analysis. The variety of shuttle vector systems which have been developed for this purpose will be described. Shuttle vectors have been widely used for the molecular analysis of mutations induced by physical and chemical agents and to investigate the factors which modulate mutation fixation. The data regarding chemically induced mutational spectra will be reviewed with particular emphasis on the studies aimed to dissect the complex process which lead from DNA lesion to mutation. PMID- 7832411 TI - [Infections associated with intra- and extravascular catheters: factors involved in microorganism-biomaterial interactions]. AB - Infections is one of the most common cause of catheter failure as well as the most difficult to manage, most often requiring catheter removal. Staphylococcus is the etiologic agent of such infections more frequently isolated, particularly Staphylococcus epidermidis. Several factors have been suggested to be involved in bacteria-biomaterial interactions such as catheter surface morphology, molecular biofilm and bacterial virulence features. Different strategies have been tried to avoid the development to catheter-associated infections: among them adsorption of antibiotic molecules to the catheter surface might represent a successful tool to improve catheter implant life. PMID- 7832412 TI - [Quantitative determination of asbestos in bulk samples]. AB - In this work, the general problems regarding asbestos determination in bulk samples are discussed. It appears that to date there are no analytical methods that can be considered satisfactory for solving these problems. The approach adopted by the Istituto Superiore di Sanita (National Health Institute) is presented herein: X-ray diffractometry (XRD), that makes use of the silver filter method, is employed for asbestos concentrations equal or higher than 1% (w/w); scanning electron microscopy (SEM) for concentrations lower than 1%. The work describes in detail and discusses the analytical procedures adopted. PMID- 7832413 TI - Urban feral cats (Felis catus L.): perspectives for a demographic control respecting the psycho-biological welfare of the species. AB - The presence of feral cats in the urban environment is creating problems of acceptance by human beings especially in relation to health aspects. In accordance with the protectionist spirit of the law 281 of 14/8/91, the new sensitivity to the general welfare of animals, and better knowledge of their natural history, some possible interventions of the Public Veterinary Services for feral cat control in the cities are proposed. These consist mainly in demographic control by means of neutering the cats, with particular attention to the psycho-biological welfare of the species. PMID- 7832414 TI - [Survey on antibiotic prescriptions in general medicine]. AB - The objectives of the survey are to describe the use of antibiotics in general practice, in order to identify inappropriate use and to estimate the exposure to different antibiotic categories in the population. The data refer to the overall drug prescriptions issued in general practice during 1991 in Rome. Four million of antibiotic prescriptions were issued, corresponding to 9% of the overall drug prescriptions and to 11% of the drug expenditure in Rome. When considering all anti-infective drugs (antibiotics plus antivirals and immunostimulating agents) the prescriptions and the expenditure increase up to 13% and 18% respectively. Three therapeutic categories (penicillins, cephalosporins and macrolides) represent more than 50% of the antibiotic prescriptions. Among the general population, 34% received at least one anti-infective drug and each patient received on average 2.7 prescriptions during the year. More than 20% of the prescriptions refers to antibiotic categories (such as aminoglycosides and chloramphenicols) which are not considered as a first choice in general practice. The analysis shows that a considerable proportion of antibiotic prescriptions refers to therapeutic categories with negative benefit/risk profile. More appropriate use of antibiotics might reduce both adverse events and drug expenditure. PMID- 7832415 TI - A pilot study on colon cancer occurrence as related to serum selenium levels. AB - A pilot study was undertaken in order to assess the relationship between selenium status and occurrence of colon cancer in a selected population group. The opportunity for starting the programme occurred in 1992 after some information attained from health control laboratories that noted human colon cancer death rates much higher than normal in a well defined geographical area of central Italy (province of Terni). Element levels in serum and healthy and neoplastic colon tissues were determined for twenty subjects affected by the disease. A hydride generation-based method with inductively-coupled plasma atomic emission spectrometry (ICP-AES) detection was developed for the determination of Se in acid-digested samples. The mean values observed in the three types of samples led to the following conclusion: i) Se levels in serum of subjects affected by colon cancer are significantly lower (0.063 +/- 0.018 microgram/ml) than those reported previously for the national average (0.089-0.093 microgram/ml); ii) there is a considerable difference in Se levels between the healthy and neoplastic tissues (0.098 +/- 0.030 microgram/g vs 0.158 +/- 0.065 microgram/g). PMID- 7832416 TI - [Dementia in Friuli-Venice Giulia: hospital diagnosis]. AB - Discharge diagnoses made in the large hospitals of Friuli-Venezia Giulia during a 3-year period (1989-91) were collected. Diagnoses with ICD-9 codes 290, 290.0-4, 290.8-9, 331, 331.0-9, and 437.0 were selected, and analyzed. Discharge diagnoses including one of the above ICD-9 codes were found in 6,647 cases. ICD-9437.0 (brain arteriosclerosis) was by far the most frequent code (4,731 cases). When the present results are examined in the light of literature data as well as of previous research performed at the Monfalcone Hospital, it emerges that in the hospitals of Friuli-Venezia Giulia, dementia is a strongly underestimated condition. In addition the present data suggest that in these hospitals most dementia cases are misdiagnosed as vascular dementias. PMID- 7832417 TI - [Malignant mesothelioma: various key aspects]. AB - Mesothelioma deserves particular attention for various reasons: 1) a dramatic increase in the incidence of this tumor has been observed in various countries; 2) diagnosis is not rarely problematic; 3) asbestos-related mesothelioma represents a nearly unique model in human cancerogenesis. Latency periods (defined as intervals between first exposure to asbestos and death) differ from one occupational category to another. These differences seem to depend not only on the intensity of the exposure, but also on other unidentified factors. The study of the mechanisms influencing the length of latency periods could open a way in preventing mesothelioma. PMID- 7832418 TI - The Neurobiology of NO Radical and OH Radical. Proceedings of a symposium. Bethesda, Maryland, November 7, 1993. PMID- 7832419 TI - Keeping reactive oxygen species (ROS) in their proper place. PMID- 7832420 TI - Transgenic glutathione peroxidase mouse models for neuroprotection studies. AB - Seleno-glutathione peroxidase (GSHPx) is considered to be the major enzymatic activity in charge of removing excess cytosolic and mitochondrial H2O2 in most tissues including brain. Intracellular GSHPx activity is therefore hypothesized to be one important factor that contributes to minimize hydroxyl radical formation via Fenton-type reactions. An animal model was developed to challenge this hypothesis in vivo and evaluate the role of GSHPx in hydroperoxide metabolism and oxidative stress homeostasis. Three lines of transgenic mice, homozygous for the integration of 1 to 3 GSHPx transgene copies, have been generated. The transgene was placed under transcriptional control of a metallothionein promoter (hMT-IIA). This promoter was chosen because metallothionein expression, normally low in most tissues, can be induced by several inflammatory cytokines, protein kinase C activators, and stress agents including heavy metals. The data reported here provide information on the constitutive expression of GSHPx mRNA and enzyme in various brain regions of healthy untreated adult tg-MT-GPx mice. Northern and/or Western analysis indicated that transgenic GSHPx was expressed constitutively in all brain regions investigated in tg-MT-GPx-6 mice, including the cerebral cortex, brainstem, hippothalamus, cerebellum, substantia nigra, and striatum. Similar results were obtained with the two other transgenic lines, tg-MT-GPx-11 and -13. Depending on the brain region, the GSHPx immunoreactivity detected in tissue extracts with an immunoaffinity-purified polyclonal antibody was about 2- to 5-fold stronger in transgenic extracts than in their non-tg counterparts (western blots). In contrast, the corresponding increase in GSHPx activity measured in these extracts was smaller, for example, about 1.5-fold in transgenic mesencephalon. Immunocytochemical data indicated that GSHPx-like staining was distinctly more intense in transgenic midbrain brain sections than in corresponding non-tg sections. Interestingly, only a subset of the cells displayed higher density staining that most likely reflects increased amounts of GSHPx protein. This observation suggests that the stained cells, not yet identified, may have larger GSHPx activity increments than the cell-average increments measured in tissue extracts. Current work is in progress to determine whether transgenic GSHPx expression may be induced by inflammatory processes or perturbations of heavy metal metabolism. PMID- 7832421 TI - Superoxide dismutase expression in Parkinson's disease. PMID- 7832422 TI - Reactive oxygen species on neural transmission. PMID- 7832423 TI - Reactive oxygen species on GABA release. PMID- 7832424 TI - Modifications of the synaptosomal dopamine uptake and release by two systems generating free radicals: ascorbic acid/Fe2+ and L-arginine/NADPH. PMID- 7832425 TI - Generation and detection of hydroxyl radical following experimental head injury. PMID- 7832426 TI - Reactive oxygen species inhibit high-affinity glutamate uptake: molecular mechanism and neuropathological implications. PMID- 7832428 TI - Evidence that nitric oxide is involved in the control of electrocortical arousal. PMID- 7832429 TI - Hydroxyl radicals, iron, oxidative stress, and neurodegeneration. PMID- 7832427 TI - Synaptic and extrasynaptic action of free radicals on cell-to-cell signaling. PMID- 7832430 TI - Antioxidant mechanism and protection of nigral neurons against MPP+ toxicity by deprenyl (selegiline). AB - The current research has demonstrated that MPP+ can induce lipid peroxidation in the nigrostriatal system of rat in vivo. Antioxidant agent U-78517F and .OH scavenger DMSO may protect against MPP+ toxicity through the inhibition of .OH radical-mediated oxidative injury in the substantia nigra. These findings indicate that the cytotoxic hydroxyl radical generated from dopamine oxidation in the iron-rich basal ganglia may contribute to the mechanism underlying the selective A9 melanized nigral degeneration in MPTP-Parkinsonism and possibly in idiopathic Parkinson's disease. In addition, the present studies also clearly demonstrate that deprenyl can substantially protect dopaminergic neurons against MPP+ toxicity in the substantia nigra zona compacta in vivo. The neuroprotective effect provided by deprenyl may not be the consequence of its inhibition of MAO-B activity or prevention of the uptake of MPP+ by dopaminergic neurons. A unique antioxidant property of deprenyl by suppressing .OH formation and associated oxidative injury induced by MPP+ may contribute to the apparent neuroprotective action. In perspective, this putative antioxidant effect of deprenyl may provide another mechanism to its overt neuroprotective effects against oxygen radical mediated oxidative injury in some neurotoxic chemicals, such as 6-OHDA and DSP-4, and probably in Alzheimer's disease and senescent changes. Finally, based on the present data, a possible neuroprotective therapeutic window of deprenyl in the treatment of early Parkinson's disease has been proposed. It is suggested that deprenyl should be introduced as early as possible in de novo Parkinsonian patients to achieve its full neuroprotective effect on nigral degeneration. Moreover, a combination of early detection of individuals at risk of developing Parkinson's disease and early intervention of deprenyl and/or other centrally active antioxidants to these patients may provide a new preventive therapeutic strategy in the future, in addition to the current conventional levodopa treatment of Parkinson's disease. PMID- 7832431 TI - Bromocriptine scavenges methamphetamine-induced hydroxyl radicals and attenuates dopamine depletion in mouse striatum. PMID- 7832432 TI - Carvedilol, a new antihypertensive drug with unique antioxidant activity: potential role in cerebroprotection. AB - The antioxidant activities of carvedilol have been demonstrated in a wide variety of test systems, including (i) physicochemical (EPR studies), (ii) biochemical (measurement of lipid peroxidation and endogenous antioxidant depletion), (iii) cellular, and (iv) in vivo. The antioxidant activity of carvedilol clearly emanates from the carbazole moiety which is unique to carvedilol. The antioxidant activity resides equally in both of the enantiomers of carvedilol, as well as in some of its metabolites which are devoid of either the alpha 1-adrenoceptor blocking activity or beta-adrenoceptor blocking activity. This novel antioxidant property of carvedilol may account, at least in part, for its cerebroprotection. The data discussed in this article suggest that carvedilol may not only provide effective and safe antihypertensive therapy and therefore reduce a major risk factor for stroke, but will also be better able to provide additional benefits to patients by protecting against oxygen free radicals generated during cerebral ischemia and stroke. PMID- 7832433 TI - In vitro and in vivo activity of a novel series of radical trapping agents in model systems of CNS oxidative damage. AB - Many laboratory and clinical studies suggest that oxygen radical formation and resultant cell damage contribute to CNS injury following stroke and neurotrauma. Accordingly, antioxidants represent a viable therapeutic approach for management of CNS oxidative damage. Recently, several investigators have reported that the spin trap PBN protects against stroked-induced damage and reduces aging associated neurological deficits. We have prepared and tested a cyclic analog of PBN, MDL 101,002, in a number of in vitro and in vivo assays designed to assess its neuroprotective properties. MDL 101,002 was found to be an effective .OH trap, to inhibit lipid peroxidation, and to decrease infarct size in a gerbil model of stroke. These results further indicate that oxidative damage arising from stroke contributes to infarct formation, and that spin traps are effective in ameliorating ischemia and reperfusion-induced CNS injury. PMID- 7832435 TI - Neuroprotection by antioxidants in models of global and focal ischemia. PMID- 7832434 TI - In vivo generation of hydroxyl radicals and MPTP-induced dopaminergic toxicity in the basal ganglia. AB - The in vivo generation of .OH free radicals in specific brain regions can be measured by intracerebral microdialysis perfusion of salicylate, avoiding many of the pitfalls inherent in systemic administration of salicylate. Direct infusion of salicylate into the brain can minimize the hepatic hydroxylation of salicylate and its contribution to brain levels of 2,5-DHBA. Levels of 2,5-DHBA detected in the brain dialysate may reflect the .OH adduct plus some enzymatic hydroxylation of salicylate in the brain. After minimizing the contribution of enzyme and/or blood-borne 2,5-DHBA, the present data demonstrate the validity of the use of 2,3 DHBA and apparently 2,5-DHBA as indices of .OH formation in the brain. Therefore, intracranial microdialysis of salicylic acid and measurement of 2,3-DHBA appears to be a useful .OH trapping procedure for monitoring the time course of .OH generation in the extracellular fluid of the brain. These results indicate that nonenzymatic and/or enzymatic oxidation of the dopamine released by MPTP analogues in the extracellular fluid may play a key role in the generation of .OH free radicals in the iron-rich basal ganglia. Moreover, a site-specific generation of cytotoxic .OH free radicals and quinone/semiquinone radicals in the striatum may cause the observed lipid peroxidation, calcium overload, and retrograde degeneration of nigrostriatal neurons. This free-radical-induced nigral injury can be suppressed by antioxidants (i.e., U-78517F, DMSO, and deprenyl) and possibly hypothermia as well. In the future, this in vivo detection of .OH generation may be useful in answering some of the fundamental questions concerning the relevance of oxidants and antioxidants in neurodegenerative disorders during aging. It could also pave the way for the research and development of novel neuroprotective antioxidants and strategies for the early or preventive treatment of neurodegenerative disorders, such as Parkinson's disease (Wu et al., this issue), amyotrophic lateral sclerosis, head trauma, and possibly Alzheimer's cognitive dysfunction as well. In conclusion, this in vivo free radical trapping procedure provides evidence to support a current working hypothesis that a site-specific formation of cytotoxic .OH free radicals in the basal ganglia may be one of the neurotoxic mechanisms underlying nigrostriatal degeneration and Parkinsonism caused by the dopaminergic neurotoxin MPTP. Addendum added in proof: The controversy concerning possible neurotoxic and/or neuroprotective roles of NO. in cell cultures was discussed and debated at the symposium (Wink et al., this issue; Dawson et al., this issue; Lipton et al., this issue).(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7832436 TI - Antioxidant properties of lipoic acid and its therapeutic effects in prevention of diabetes complications and cataracts. PMID- 7832438 TI - Neurobiology of NO. and .OH: basic research and clinical relevance. PMID- 7832437 TI - Nitric oxide protects against the cytotoxic effects of reactive oxygen species. PMID- 7832439 TI - The measurement of nitric oxide release induced by kainic acid using a novel hemoglobin-trapping technique with microdialysis. PMID- 7832440 TI - Regulation of neurotransmitter reuptake by nitric oxide. PMID- 7832441 TI - Differential glutathione peroxidase mRNA up-regulations in rat forebrain areas after transient hypoxia-ischemia. PMID- 7832442 TI - Action of trimetazidine on retina of gerbils after ischemia reperfusion insult: determination of .OH, amino acids, and electroretinogram. PMID- 7832443 TI - Role of nitric oxide in brain ischemia. AB - In order to study the role of nitric oxide (NO) in rat brain ischemia, an in vivo spin trapping technique was applied. The results showed that NO was produced not only during ischemia but also during reperfusion. The role of NO production during ischemia may be to increase cerebral blood flow. The NO production during reperfusion seems to be related to tissue damage. PMID- 7832444 TI - The role of oxidative stress in signal transduction changes and cell loss in senescence. PMID- 7832445 TI - Lipid peroxidation and lipofuscin granula in brain endothelial cell cultures during reoxygenation. PMID- 7832446 TI - Neuroprotective and neurodestructive effects of nitric oxide and redox congeners. PMID- 7832447 TI - Ferrous-citrate complex and nigral degeneration: evidence for free-radical formation and lipid peroxidation. AB - Increased nigral iron content in the parkinsonian brain is now well documented and is implicated in the pathogenesis of this movement disorder. Free iron in the pigmented DA-containing neurons catalyze DA autoxidation and Fenton reaction to produce cytotoxic .OH, initiating lipid peroxidation and consequent cell damage. The present results clearly demonstrate that a regional increase in the levels of the "labile iron pool" can result in the degeneration of dopaminergic nigral neurons as reflected by a significant inhibition in the expression of tyrosine hydroxylase mRNA and DA depletion. Iron-complex-induced damage of dopaminergic neurons in the substantia nigra, might have resulted from a sequence of cytotoxic events including the .OH generation and lipid peroxidation as demonstrated in this study. This free-radical-induced oxidative nigral injury may be a reliable free-radical model for studying parkinsonism and may be relevant to idiopathic Parkinson's disease. This apparent nigral injury stimulated by Fe(2+)-citrate is more severe than that produced by ferric iron and its citrate complex. Moreover, these data indicate that Fe(2+)-citrate is as potent as MPP+ in causing oxidative injury to the substantia nigral neurons. However, the nigral toxicity of MPTP and its congeners are not progressive, while Fe(2+)-citrate complex may produce a progressive degeneration of the nigrostriatal neurons which is similar to the progression of ideopathic Parkinson's disease. Thus, this unique Fe(2+)-citrate complex animal model could be used for studying neuroprotective treatments for retarding or halting the progressive nigrostriatal degeneration caused by free radicals in the iron-rich basal ganglia. PMID- 7832448 TI - Apoptosis and free radicals. AB - Necrotic cell death is usually a consequence of extensive insult to the cell, leading to release of intracellular contents and an inflammatory response. Apoptosis, however, is a physiological response to damaging influences that requires sufficient maintenance of homeostasis to allow execution of the pathway. Apoptosis circumvents the induction of an inflammatory response, which can be disadvantageous and, therefore, would be more beneficial than necrosis under many circumstances. The apoptotic response appears complicated and involves many factors, including the mitotic rate, the stage of differentiation, the type and strength of the initiating stimulus, and exogenous factors. Recent evidence, however, implicates free radicals as a causal agent in some types of apoptosis, both physiologically and pathologically. PMID- 7832449 TI - Serotonin binding proteins: an in vitro model system for monoamine-related neurotoxicity. PMID- 7832450 TI - Melatonin--a highly potent endogenous radical scavenger and electron donor: new aspects of the oxidation chemistry of this indole accessed in vitro. PMID- 7832451 TI - Levodopa administration to normal rats: influence on striatal oxidized glutathione concentration. PMID- 7832452 TI - Extracellular ATP may induce neuronal degeneration by a free-radical mechanism. PMID- 7832453 TI - The role of nitric oxide in glial pathology. PMID- 7832454 TI - Aging- and oxygen-induced modifications in brain biochemistry and behavior. AB - In summary, the work presented here has shown accumulation of oxidized protein with age in an animal aging model. In gerbil brain, this accumulation is associated with (1) decreased activity of oxidatively sensitive enzymes creatine kinase and glutamine synthetase; (2) decreased function of particular cytoskeletal proteins; and (3) decreased performance in a radial-arm maze task. Manipulations shown to increase the presence of reactive oxygen species in the brain increase oxidized protein, decrease the index enzyme activities and cytoskeletal protein defects, and worsen performance deficits. Moreover, intervention designed to quench ROS-mediated reactions decrease oxidized protein levels, and nearly normalize index enzyme activities and associated behavioral deficits. The precise connections between the performance deficits and protein measures are probably highly complex and likely to remain obscure for now. Currently, the behavioral measures serve as a marker for the functional consequences of the protein alterations. Our studies in humans have shown oxidized protein accumulation with age and a differential decrease of glutamine synthetase activity in the frontal lobe in AD. Further preliminary results in AD autopsy material show a striking correlation between the distribution of index enzyme inactivation and the known intensity distribution of AD pathology. These findings support the hypothesis that inability to restrain age- or pathology related increases in local ROS activity can result in AD. PMID- 7832455 TI - Advanced Maillard reaction end products, free radicals, and protein oxidation in Alzheimer's disease. PMID- 7832456 TI - Induction of production of nitric oxide in microglial cells by insoluble form of aluminium. PMID- 7832457 TI - Peroxynitrite versus hydroxyl radical: the role of nitric oxide in superoxide dependent cerebral injury. PMID- 7832458 TI - Molecular mechanisms of nitric oxide actions in the brain. PMID- 7832460 TI - Antioxidant defense mechanisms: a new thiol-specific antioxidant enzyme. PMID- 7832459 TI - Enzymatic/nonenzymatic sources of oxyradicals and regulation of antioxidant defenses. PMID- 7832462 TI - Novel concepts from novel peptides. PMID- 7832461 TI - SOD-1 transgenic mice as a model for studies of neuroprotection in stroke and brain trauma. PMID- 7832463 TI - Models of Neuropeptide Action. Proceedings of a conference. Breckenridge, Colorado, February 5-8, 1994. PMID- 7832464 TI - Study of passage of peptides across the blood-brain barrier: biological effects of cyclo(His-Pro) after intravenous and oral administration. PMID- 7832465 TI - Brain-to-blood transport of peptides and the alcohol withdrawal syndrome. AB - Brain-to-blood transport, or efflux, systems play important roles in brain functions and can affect the CNS uptake and activity of endogenous and exogenous blood-borne substances. Several efflux systems have been described for peptides. These efflux systems may play important roles in communication between the CNS and peripheral tissues and may be important in conditions such as alcoholism. PMID- 7832466 TI - Bombesin-like peptides in the regulation of ingestive behavior. PMID- 7832467 TI - TRH gene products are implicated in the antidepressant mechanisms of seizures. AB - 1. After a series of electroconvulsive seizures, levels of TRH-Gly (the immediate precursor of TRH) in four limbic regions correlate significantly and highly with increased swimming in the forced-swim test model of antidepressant efficacy. Only in hippocampus did TRH itself correlate with swimming. 2. After ECS, limbic forebrain regions differ in the relationship of TRH to its precursor peptides. This probably results from differences in the coordination of induction of TRH processing enzymes, as well as differences in the level of prepro-TRH following seizures. 3. Sprague-Dawley rats that are partially kindled with corneal stimulation swim less in the forced-swim test, opposite to the effect seen with antidepressant agents. 4. Pyriform cortex is unique among the four limbic regions examined in showing decreased amounts of the TRH precursor following swim/stress. 5. Combining ECS with the forced-swim test of antidepressant effects creates a useful model for studying the involvement of TRH and its precursor peptides in both the antidepressant and anticonvulsant effects of controlled therapeutic seizures in the treatment of major depressive disorders. Regional differences between the effects of pinnate and corneal ECS on peptides and behavior support the idea that corneal ECS is a better model than pinnate ECS for human bitemporal ECT. 6. Together with recent results in other laboratories, our results suggest that a series of generalized seizures results in prolonged and increased release and action of TRH in limbic forebrain. PMID- 7832468 TI - Alcohol-related behaviors as models for neuropeptide mediation. Introduction to Part IV. PMID- 7832469 TI - Opioid involvement in alcohol drinking. AB - A large body of evidence indicates that the endogenous opioid system plays an important role in maintaining alcohol drinking behavior. Evidence is reviewed that indicates that the reinforcing properties of alcohol that lead to continued and repeated bouts of drinking may be due, in part, to alcohol-induced activation of the endogenous opioid system. Much of this evidence is pharmacologic in nature. Blocking the action of endogenous opioid peptides via administration of opioid antagonists significantly attenuates alcohol consumption in animals under a variety of experimental conditions. In clinical trials, opioid receptor antagonists decrease alcohol consumption, relapse rates, subjective high, and alcohol craving in outpatient alcoholics. The potential clinical utility of opioid receptor antagonists in the treatment of alcoholism and alcohol dependence is discussed. PMID- 7832470 TI - Neuroadaptive functions of the neuropeptide arginine vasopressin. Ethanol tolerance. PMID- 7832471 TI - The role of corticotropin-releasing factor in the anxiogenic effects of ethanol withdrawal. AB - In summary, endogenous CRF has been demonstrated to play an important role in the endocrine but also autonomic and behavioral responses to a stressor and to mediate some of the signs and symptoms observed in human affective and anxiety disorders. These findings led to the hypothesis that the anxiety that characterizes drug withdrawal, such as ethanol withdrawal in humans, may be related in part to the action of CRF-producing neurons in the CNS. Indeed, rats made dependent on an ethanol liquid diet showed significant signs of enhanced stress responsiveness that was blocked by intracerebral administration of a CRF antagonist. At this time little is known about the specific site of action for endogenous CRF. However, recent studies using local administration of CRF antagonist and in vivo CRF microdialysis suggest that the central nucleus of the amygdala may be an important site for the increases in CRF activity associated with the anxiogenic effects of ethanol withdrawal. Although preliminary, these results propound that ethanol dependence may involve a prolonged dysregulation of the CRF system in the basal forebrain that may contribute to the increased motivational effect of ethanol withdrawal. PMID- 7832472 TI - Effects of acute and chronic ethanol administration on neurotensinergic systems. AB - A summary of pharmacogenetic studies designed to test the hypothesis that NT receptors might mediate or regulate some of the actions of ethanol is presented. Indeed, there are significant genetic correlations between ethanol-induced locomotor activation and high-affinity NT receptor densities in the FC. The results suggest that further studies are needed to determine the role of NT receptors in the FC and MPFC in regulating locomotor activity. In other studies, chronic ethanol treatment, under conditions that produced tolerance to ethanol and caused NT receptor downregulation in the NA and VMB, caused tolerance to locomotor inhibitory effects of centrally administered NT and blunted the effects of intra-VTA NT on dopamine metabolism in the NA and CP. The results show a relationship between NT receptor densities and pharmacological effects of ethanol. PMID- 7832473 TI - Fetal and neonatal models for the study of neuropeptide regulation. Introduction to Part V. PMID- 7832475 TI - Blockade of VIP during neonatal development induces neuronal damage and increases VIP and VIP receptors in brain. PMID- 7832474 TI - Psychobiological influences of stress and HPA regulation on the human fetus and infant birth outcomes. PMID- 7832476 TI - Neurotrophism, mitogenesis, and nerve regeneration as models for neuropeptide mediation. Introduction to Part VI. PMID- 7832477 TI - Bombesin receptor gene expression during mammalian development. AB - Mammalian bombesin-like peptides (gastrin-releasing peptide [GRP] and neuromedin B [NMB]) and their receptors (GRP-R and NMB-R) can stimulate growth of cultured cells, and have been shown to be part of an autocrine growth regulatory network in some human small cell lung carcinoma cells. Given the connection between bombesin receptor expression and bombesin-mediated growth regulation in cultured cells, we were interested in investigating the possibility that bombesin peptides and their receptors might be important for normal growth and differentiation during development. As a first step, we examined the distribution of expression of GRP-R and NMB-R mRNA during rat embryonic development to identify changing spatio-temporal patterns of gene expression. In situ hybridization studies show that GRP-R mRNA is expressed at early embryonic stages in various locations of the nervous, urogenital, respiratory, and gastrointestinal systems. In contrast, the distribution of expression of NMB-R mRNA is more limited (upper gastrointestinal tract, bladder, and central nervous system) and is observed at later embryonic stages. In most locations, receptor mRNA levels increased steadily throughout development after onset of expression. However, transient GRP R mRNA expression is observed in the posterior pituitary where expression increases from embryonic day 12 to 20, and abruptly disappears at birth. These studies suggest that appropriate development of several organ systems, in particular the posterior pituitary, may involve GRP-R-mediated signaling. We plan to test this hypothesis using gene targeting to inactivate the GRP-R gene in the mouse. PMID- 7832478 TI - Neuropeptide regulation of mitosis. PMID- 7832479 TI - An overview of cytokines and their associations with the brain. Introduction to Part VII. PMID- 7832480 TI - Interactions between cytokines and the hypothalamic-pituitary-adrenal axis during stress. PMID- 7832481 TI - The functional neuroanatomy of the acute-phase response. PMID- 7832482 TI - Interleukin-1 modulates GABAergic and glutamatergic function in brain. AB - Interleukin-1 is a polypeptide cytokine involved in the acute-phase response. We examined the effects of IL-1 on the major inhibitory and excitatory neurotransmitter systems in brain mediated by GABA and glutamate, respectively. IL-1 enhanced the effects of GABA as determined by GABA-dependent chloride uptake at 1 and 10 ng/ml in cortical synaptoneurosomes. This effect was attenuated by pretreatment with the IL-1 receptor antagonist. Neither IL-6 nor TNF was effective in this system. IL-1 decreased the effect of NMDA and glycine on intracellular calcium concentrations in cultured chick cortical neurons in both the presence and absence of the endogenous polyamine spermine. This effect was attenuated by pretreatment with the AMPA/kainate antagonist CNQX. These data indicate that IL-1 modulates both inhibitory and excitatory neurotransmitter function in brain. PMID- 7832483 TI - Distribution of melanocortin receptors in the lower brainstem of the rat. PMID- 7832484 TI - Identification of a specific mammalian melanocortin receptor antagonist. PMID- 7832485 TI - Immunocytochemical localization of ACTH-(4-10) in the rat spinal cord following peripheral nerve trauma. PMID- 7832486 TI - Involvement of calcium and cAMP in the mechanism of action of two melanocortins: alpha MSH and an ACTH-(4-9) analogue. PMID- 7832487 TI - Effects of glucose and food restriction on passive avoidance behavior in vasopressin-deficient rats. PMID- 7832488 TI - Predominance of pGlu-His-Pro-Gly among all TRH precursor peptides in rat limbic forebrain after electroconvulsive seizures. PMID- 7832489 TI - The combined pyridostigmine-TRH test for the evaluation of hypothalamic somatostatinergic activity in healthy, normal men. PMID- 7832490 TI - Lesions of the area postrema/adjacent nucleus of the solitary tract result in enhanced hypothalamic neuropeptide Y levels. PMID- 7832491 TI - Short-term dexamethasone treatment increases food intake, but apparently not through changes in NPY content in the PVN. PMID- 7832492 TI - Partial purification and measurement of motilin in human milk. PMID- 7832493 TI - Bombesin, gastrin-releasing peptide, and neuromedin B attenuate the salt appetite of sodium-depleted rats. PMID- 7832494 TI - Thymosin-like peptides are present in lung cancer cell lines. PMID- 7832495 TI - Identification of gastrin-releasing peptide and neuromedin B receptors on established tumors and tumor cell lines. In vitro receptor binding and receptor mRNA expression. PMID- 7832496 TI - Possible mechanisms for the powerful actions of neuropeptides. AB - In order to understand the mechanisms underlying the powerful actions of neuropeptides, the present article has emphasized the unique ability of neuropeptides to act as VT signals, which via high-affinity G-protein coupled receptors can exert long-lasting actions and control synaptic transmission via receptor-receptor interactions. Also of substantial importance is the ability of neuropeptides to act as a set of signals via the formation of different types of active fragments, which can act as negative-feedback or positive-feedback signals to modulate the response elicited by the parent peptide and to give origin to syndromic responses. Also in the actions of the fragments on the neuronal network, receptor-receptor interactions may play an important role both by modulating the parent peptide receptors and by modulating other types of VT and/or WT receptors. Future work will have to evaluate the role of neuropeptides as transcellular signals and as regulators of neuronal excitabilities after the formation of carbamates, but certainly new important developments are within the horizon of today's research. PMID- 7832497 TI - Specificity versus redundancy of melanocortins in nerve regeneration. AB - The results of the present study demonstrate that administration of the ACTH-(4 9) analogue Org 2766 acutely enhances behavioral, morphological, and biochemical recovery after nigrostriatal destruction. Animals treated with Org 2766 (10 micrograms/kg every 24 hr) demonstrated an acceleration of denervation supersensitivity and a significantly decreased ipsilateral rotational response, as compared to their saline counterparts. Upon evaluation of the mesolimbic DA system using open field behavior, peptide-treated rats demonstrated a compensatory response in their rearing behavior. Furthermore, tyrosine hydroxylase immunocytochemical analysis indicated an enhanced staining in the Org 2766-treated groups. This evaluation was confirmed and quantified using specific high-affinity dopamine uptake. The brains of animals treated with Org 2766 maintained higher uptake levels, suggesting a greater fiber density than the saline-treated animals. Although recovery via reinnervation is very unlikely in this short period of time, improved recovery may be the result of a protective effect of Org 2766 after administration of 6-OHDA into the substantia nigra. Thus, it appears that Org 2766 provides the rapid effects in this system, by both accelerating some compensatory mechanisms necessary for functional recovery and promoting cell survival by providing neuronal protection. However, it does not appear that this protection is due to NMDA receptor manipulation. Org 2766 neither mimicked the NMDA antagonist MK-801 behaviorally nor biochemically in binding displacement studies. Interestingly, other studies have suggested that only the full ACTH molecule, and fragments larger than ACTH-(1-17), demonstrated binding activity at micromolar concentrations, whereas the shorter, noncorticotropic fragments were either less active or inactive (Table 2). As for ACTH-(4-10) immunoreactivity, it appears that this neurotrophic fragment of ACTH reappears in adults following injury to the nigrostriatal system. In addition, the systemically administered ACTH-(4-9) analogue, Org 2766, seems to be gaining access to the CNS, but is only effective in the injured system. Therefore, based on the immunocytochemical localization of the ACTH-(4-10) fragment in neonatal brains and in the injured adult rat CNS, the interesting possibility may be raised that endogenous ACTH peptides appear during both ontogeny and regeneration. These studies demonstrate once again that biological responses to the family of ACTH/MSH peptides depend on the specific peptide fragment administered, its dosage, and the timing of the administration. Consequently, since early intervention is of vital importance in CNS recovery processes, synergistic administration of ACTH fragments and other neurotrophic agents may offer a viable approach with which to combat degeneration in the CNS. PMID- 7832498 TI - Dorsal root ganglia as an in vitro model for melanocortin-induced neuritogenesis. Pharmacological and mechanistic aspects. PMID- 7832499 TI - The blood-brain barrier: methods for the study of peptide transport mechanisms. Introduction to Part II. PMID- 7832500 TI - Peptides and the blood-brain barrier: the status of our understanding. AB - In this limited review, it has only been possible to highlight some of the more significant interactions of peptides with the blood-brain barrier. The literature has been reviewed extensively in recent years, and the major reviews are included in the references. Certainly one of the major outstanding problems is an elucidation of the precise mechanism(s) by which centrally active peptides produce their effects. Without question peripherally administered peptides are able to modify central nervous activity; and for a rapidly growing number of peptides, an extraction by the cerebral endothelial cells can be demonstrated. For some of these peptides, the extraction involves highly specific transporters. What is far less clear is whether this internalization of peptide into the endothelial cells is the first step in a process of transcytosis, with an eventual abluminal exocytosis into brain extracellular fluid of the intact peptide, or an active fragment or whether their entry into brain extracellular fluid is via a different route. If, on the other hand, the mechanism of central action is via the circumventricular organs, a general entry into brain extracellular fluid may not be required. Clearly for different peptides the route and mechanism of action will differ and future attention should be focused on the precise mechanisms producing the central effects of defined peptides. PMID- 7832501 TI - Minimizing the genome of Escherichia coli. Motivation and strategy. PMID- 7832502 TI - Intracellular pH responses of hybridoma and yeast to substrate addition and acid challenge. AB - The pHi responses of hybridoma and yeast cells to substrate and external acid additions were measured using the fluorescent pHi indicator, 9-aminoacridine. The pHi change, following CCCP addition, indicated by 9AA, compared very well with that indicated by BCECF. No change in pHi was observed following glucose or glutamine additions to hybridoma cells under glucose- and glutamine-absent conditions. Also, no change in pHi was observed when glucose was added in the presence of low glutamine and when glutamine was added in the presence of low glucose. However, in the presence of amiloride, the pHi of hybridoma cells decreased following glucose addition. Intracellular pH responses of hybridoma and yeast cells to decreases in external pH, effected by acid addition, were dependent on the cellular energy state and acid type. Cells controlled their pHi more tightly under energy-poor conditions compared to energy-rich conditions, and sulfuric acid (strong acid) caused larger changes in pHi compared to pyruvic acid (weak acid). In response to acid addition under energy-rich conditions, the magnitudes of pHi increases in hybridoma were smaller in the presence of amiloride compared to that in the absence of amiloride. Further, pHi responses to a decrease in external pH were slower at submetabolic temperatures. PMID- 7832503 TI - Studies of baby hamster kidney natural cell aggregation in suspended batch cultures. AB - Microcarrier cultures of animal cells of industrial relevance are known to shed aggregates into the suspension phase. For a BHK cell line, which is known to be prone to aggregate naturally, microcarrier and aggregate forms of culture are compared in spinner culture. In microcarrier cultures, it is shown that increasing initial microcarrier concentration yields decreasing concentration of smaller aggregates in suspension; roughly equivalent concentrations of total cells and single cells in suspension are obtained. In the absence of Cytodex 3, aggregate final size is hydrodynamically controlled in batch and semicontinuous suspension culture. Rate of agitation is the main variable controlling aggregate size in batch cultures. The range of agitation rates studied (20 to 70 rpm in 250 mL spinner flasks) produced aggregates with maximum sizes of 200 microns. Necrotic centers were not observed; this was confirmed by Trypan blue viability measurements after mechanical dissociation of aggregates and also by the constant productivity obtained from different aggregate sizes. Comparing aggregate and microcarrier culture conditions, it is shown that at 100 rpm maximum total cell concentration is larger in the absence of microcarriers; dead cell concentrations, most of which exist in suspension, are slightly larger in microcarrier culture. Total viable cell concentrations in aggregate, hydrodynamically controlled culture, are almost one order of magnitude higher than in microcarrier cultures. These results suggest that there might be advantages in using aggregate cultures under hydrodynamic control of aggregate size in lieu of microcarrier cultures for naturally aggregating cell lines. PMID- 7832504 TI - Novel methods to synthesize polyhydroxyalkanoates. PMID- 7832505 TI - Sf9 insect cell growth and beta-galactosidase production in serum and serum-free media. PMID- 7832506 TI - Effect of taxol and diamide on shear tolerance of hybridoma and insect cells. AB - The role of the cytoskeletal structure on the shear tolerance of hybridoma and insect cells to laminar and turbulent shear flow field was investigated. The cytoskeletal network of cells modified by taxol and diamide, which are known to alter the stability of specific cytoskeletal components, resulted in increased cell shear tolerance to both laminar and turbulent flow fields. Plasma membrane fluidity measurements revealed that modification of microtubules by taxol did not alter the fluidity state of the plasma membrane. The increase in shear tolerance by taxol treatment is attributed to its ability to stabilize microtubules in the cytoskeleton. A low concentration of taxol, 0.05 microM, did not reduce the hybridoma cell growth rate or the monoclonal antibody production rate, but both were decreased at a higher concentration, 0.25 microM. PMID- 7832507 TI - Cell attachment and motility on materials modified by surface-active RGD containing peptides. PMID- 7832508 TI - Selective adhesion of hepatocytes on patterned surfaces. AB - Successful development of cell-biased bioartificial liver devices necessitates the establishment of techniques and designs for long-term, stable hepatocellular function and efficient transport of nutrients and wastes within the device. Given the relatively large cell mass that one must consider, one possible solution involves the use of micropatterning technology to sandwich hepatocytes aligned in rows between two micropatterned surfaces. Rows of cells would alternate with hepatocyte-free areas, creating efficient transport channels for fluid flow and nutrient exchange. Ultimately, this type of device could also be used as a three dimensional construct for investigating a variety of cell-surface, cell extracellular matrix, and cell-cell interactions. To achieve this goal, one must develop techniques for selectively adhering hepatocytes to solid substrates. In this study, reproducible, selective adhesion of hepatocytes on a glass substrate with large regions of adhesive (AS) and nonadhesive (NAS) surfaces was obtained. The AS had hydrophilic characteristics, enhancing deposition of collagen molecules from an aqueous solution, and subsequent hepatocyte adhesion, whereas the NAS had hydrophobic properties and remained collagen-free and hepatocyte free. In addition, a reproducible processing technique for obtaining patterns of hepatocytes was developed and optimized, using a surface with a single AS band as a first approximation to a micropatterned device. This was achieved by spincoating an aqueous collagen type I solution (0.1 mg/mL) on a banded surface at 500 rpm for 25 seconds. The morphology and long-term function of the hepatocytes attached to AS in nonbanded and banded surface configurations was assessed by mimicking sandwich culture and was shown to be similar to stable, differentiated sandwich cultures. Mathematical modeling was used to determine critical design criteria for the hypothetical micropatterned device. The oxygen distribution and viscous pressure drop were modeled along a typical microchannel and limited to in vivo values. An optimal channel length of 0.6 cm and a flow rate of 2.0 x 10(-6) mL/s were obtained for a channel of 100 microns in width and 10 microns in height. These values were reasonable in terms of practical implementation. PMID- 7832509 TI - Alteration of the biochemical valves in the central metabolism of Escherichia coli. AB - Although E. coli central metabolism has been studied for several decades, many regulatory features are still unknown. To achieve the goal of rational manipulation of cellular metabolism, it is important to understand how E. coli responds to overexpressed enzymes. By studying the biochemical control of fluxes between PEP, pyruvate, and OAA, we have addressed some fundamental questions that may prove to be essential for applications in metabolic engineering. First, we found that simultaneous overexpression of Pck and Ppc, or Pps alone in the presence of glucose leads to phenotypes consistent with futile cycline. In contrast to our expectation, futile cycling per se does not affect the growth rate significantly. However, excessive futile cycling may cause competitive disadvantage in the natural environment. Overexpression of Pck caused growth inhibition but no futile cycling. Therefore, E. coli controls the expression of gluconeogenic enzymes not only to avoid excessive futile cycling, but also to prevent toxicity effects. In metabolic engineering, futile cycling may be used as a strategy to stimulate metabolism for either production of metabolites or digestion of toxic wastes. Second, we found that the expression levels of Pps and Pck in E. coli are not optimal for growth on pyruvate and succinate, respectively. Overexpression of these enzymes increases the growth rate on pyruvate and on succinate, respectively, indicating that the slow growth rates on these substrates are at least partially caused by the insufficient supply of PEP and its derivatives. Moreover, E. coli also has not optimized the Ppc level for optimal growth yield on glucose in uncontrolled batch cultures. These results demonstrate that the central metabolism is not optimized for growth under defined laboratory conditions. Thus, the possibility exists that adjustment of native enzyme levels in the central metabolism can improve bioreactor performance. Third, we found that overexpression of Pck affects the transcriptional levels of unrelated genes. This example indicates that physiological responses to enzyme (over)expression should be interpreted cautiously, as changing the expression level of a specific enzyme may affect many unlinked genes. Similar results have also been obtained by use of two-dimensional electrophoresis of proteins from E. coli. Although more questions remain to be answered, fast progress in the area of metabolic engineering can be expected in the near future. PMID- 7832510 TI - Nerve growth dynamics. Quantitative models for nerve development and regeneration. AB - The quantitative analysis of nerve growth dynamics is critical to our understanding of nerve development and regeneration, but only recently has a quantitative framework begun to emerge to help define key objectives and to direct experimental measurements towards achieving this goal. Conceptually, the framework centers on the dynamic processes commonly observed for individual growth cones of growing neurites at the phase microscopy level, namely lamellipodial and filopodial extension and retraction. Because these activities essentially define the position of the axon tip, understanding how they are regulated offers to yield direct insight into factors governing the growth trajectory of the axon. In addition, much biological interest and effort is focused on the lamellipodial and filopodial behavior of the growth cone, which should facilitate experimental quantitation. Characterization of lamellipodial and filopodial activity has not been straightforward, however, because their inherent randomness leads to a requirement for considerable data and for less common mathematical techniques, such as time-series analysis. The work reviewed above has identified key analytical tools and experimental parameters needed to develop an integrated model of growth cone dynamics. Detailed measurement and analysis will be required to carry this development process to the next step. The cellular model of growth cone motility resulting from the characterization of lamellipodial and filopodial dynamics represents an intermediate description that can be extended to encompass both molecular mechanisms of growth cone behavior and axonal growth in multicellular tissue environments. For example, on the molecular level, filopodia contain a central core of actin filaments whose polymerization and depolymerization is thought to correspond to filopodial extension and retraction, with significant regulation possible through receptor mediated effects on actin dynamics. By rewriting the parameters of filopodia dynamics in the current model in terms of these molecular events, one can begin to investigate their effects on growth cone behavior and to examine hypotheses of molecular mechanisms. Processes underlying lamellipodial behavior can be examined in a similar manner. At the tissue level, the effects of environmental factors on model parameters can be incorporated to yield predictions of the neurite outgrowth response to a particular environment. Such predictions offer a basis for designing microenvironments with optimal characteristics for enhancing nerve regeneration or manipulating the nerve growth response. Although the quantitative framework described here has focused on growth by peripheral nerve cells, it represents concepts known to apply to neurons of the central nervous system, as well.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7832511 TI - Acid precipitation of mammalian cell fermentation broth. AB - The broth harvested from the "fermentation" of mammalian cells contains many contaminants produced by the cells, including nucleic acids, proteins, and complex polysaccharides, in addition to the product. These contaminants can foul filtration membranes, precipitate during storage or processing steps, and interfere with the performance of chromatographic separations. Acidification of hybridoma cell fermentation broth at the time of harvest from the fermenter has been investigated as a method of selectively precipitating the major contaminants from the soluble antibody product. Between pH values of 6.0 and 4.5, precipitation of the major contaminants is rapid and independent of the temperature (4-37 degrees C), with less than 10% of the antibody coprecipitating in 4 of 5 cases. Antibody activity and physical characteristics were found to be unaltered above a pH of 3.8. Recovery of antibody at the stage of concentrated (50 x), diafiltered bulk was improved from 63% to 84% by using the acid precipitation step. An additional benefit is that retrovirus is effectively inactivated by incubation at a pH below 4.2. PMID- 7832513 TI - Use of lipid emulsions as nutritional supplements in mammalian cell culture. PMID- 7832512 TI - Electroenzymology in membrane-mimetic media. PMID- 7832515 TI - Two-phase culture system for plant cells. PMID- 7832514 TI - On-line monitoring of bacterial mass during production of recombinant exotoxin A. Using an in situ steam sterilizable sensor. PMID- 7832516 TI - Application potential of 2D protein crystals (S-layers). PMID- 7832517 TI - Biochemical engineering. VIII: Debate session. PMID- 7832518 TI - Investigation of NS0 cell metabolic behavior in monoclonal antibody producing clones. PMID- 7832520 TI - Alteration of oligosaccharide biosynthesis by genetic manipulation of glycosyltransferases. AB - The alteration of oligosaccharide structures through genetic manipulation of glycosyltransferase activities is now a reality. It is apparent that this technique has greater consequences on oligosaccharide structure when an exogenous enzyme is introduced into cells, and in particular when this enzyme is responsible for a terminal glycosylation step. By contrast, only one study has examined the effects of overexpressing an endogenous glycosyltransferase, in which there was no detectable effect on glycosylation. However, there are still other key regulatory biosynthetic enzymes, such as GlcNAc transferase V and beta 1,3 GlcNAc transferase, whose overexpression may alter glycosylation. Both of these enzymes are required for the biosynthesis of polylactosaminoglycans (polymers of N-acetyllactosamine disaccharides), and their elevation in tumor cells correlates with increased expression of polylactosaminoglycans. Recently, the gene encoding GlcNAc transferase V has been isolated, but its transfection into cells and characterization of the resulting oligosaccharides awaits further study. Alternate strategies for modifying oligosaccharide structures could involve the introduction of more than one glycosyltransferase into cells to ensure the availability of biosynthetic intermediates. Alternatively, the disruption of specific glycosyltransferase genes by homologous recombination could be used to eliminate competing glycosyltransferases that act on a common substrate. Although oligosaccharide biosynthesis is directly dependent upon the presence or absence of specific glycosyltransferases, other factors also contribute to glycosylation. For example, the transport rate of a glycoprotein through the endoplasmic reticulum and Golgi complex, the levels of processing glycosidases, the availability of substrates, the host cell, and ultimately, the peptide backbone of the particular glycoprotein of interest are important contributors to the final outcome of oligosaccharide structure. Despite these complications, further study into the manipulation of glycosyltransferase genes may ultimately allow the controlled and predictable biosynthesis of glycoprotein sugar chains. PMID- 7832519 TI - Optimization of a fed-batch process for production of a recombinant antibody. PMID- 7832521 TI - Development of an efficient bioprocess for poultry vaccines using high-density insect cell culture. PMID- 7832522 TI - Flux adaptations of citrate synthase-deficient Escherichia coli. AB - The results from the experiments performed with a mutant deficient in citrate synthase activity can be summarized as follows. (1) Totally blocking entry into the TCA cycle did not appreciably alter the cellular ATP yield. The unchanged yield suggests that for growth on abundant glucose, the sensitivity of ATP yield to TCA cycle flux is low. ATP production in the mutant is altered, in part, by modulating the relative amounts of formate and acetate produced. (2) The in vivo operation of pyruvate-formate lyase and malic enzyme corresponds to proposals developed from in vitro studies. Namely, pyruvate activates the former, and acetyl CoA inhibits the latter. Overall, the diversion of pyruvate to formate under aerobic conditions constitutes an adaptation of the mutant to the enzymatic lesion. The low alpha-ketoglutarate dehydrogenase flux estimated for the mutant indicates that the enzyme is highly repressed in cells growing rapidly on glucose, which is in accord with prior induction-repression studies. Moreover, the lack of a change in uptake flux during the bulk of batch growth is consistent with prior induction-repression studies. (3) The mutant exhibits a heightened sensitivity to CO2 as compared to wild-type counterparts. Growth rate is increased, and the production of formate, malate, glycerate, and pyruvate is reduced. This sensitivity illustrates that citrate synthase is more than an expendable component in an amphibolic pathway. Its presence in wild-type cells "immunizes" against the effect of CO2 fluctuations. (4) The effects of CO2 can be tentatively explained by assuming that the PEP carboxylase-catalyzed reaction is stimulated. PMID- 7832523 TI - Cell aggregation in a Chinese hamster ovary cell microcarrier culture affects the expression rate and N-linked glycosylation of recombinant mouse placental lactogen-1. AB - A microcarrier culture of Chinese hamster ovary (CHO) cells, expressing the N glycosylated recombinant protein mouse placental lactogen I (mPL-I), was found to form large cellular aggregates (400 to 600 microns in diameter). There was increased accumulation of lower molecular sized mPL-I glycoforms in cultures containing the large cellular aggregates at pH 7.3, but not at pH 7.6. Specific rates of mPL-I expression were found in the cultures with cellular aggregates at both pH values (7.3 and 7.6). These findings are interpreted in the light of our earlier studies that showed that extracellular pH and elevated ammonia concentrations affect both the glycosylation and the expression rates of mouse placental lactogen I. PMID- 7832524 TI - The expression of recombinant proteins on the external surface of Escherichia coli. Biotechnological applications. AB - The expression of recombinant proteins on the external surface of Gram-negative bacteria is expected to open the way for a number of significant biotechnological applications, including the development of live bacterial vaccines, the production of whole cell adsorbents, the preparation of whole cell catalysts, and the display and selection of peptide and antibody libraries. We have developed a fusion protein system for the production of active recombinant proteins on the surface of Escherichia coli. Using this system we have expressed beta-lactamase, the Cellulomonas fimi exoglucanase Cex as well as its cellulose binding domain, and an antidigoxin single chain Fv antibody fragment on the cell surface. Recently we have begun to explore some of the potential applications for cell surface expression. PMID- 7832525 TI - Chaperonins and protein folding. PMID- 7832526 TI - Biodiversity and utilization of microorganisms. PMID- 7832527 TI - Spatially resolved evolution of viruses. PMID- 7832528 TI - Extremely thermophilic microorganisms. Metabolic strategies, genetic characteristics, and biotechnological potential. PMID- 7832529 TI - Production of chemicals using genetically transformed plant organs. PMID- 7832530 TI - Shikonin production by extractive cultivation in transformed-suspension and hairy root cultures of Lithospermum erythrorhizon. AB - Effects of in situ extraction, fungal elicitation, a permeabilizing agent, and the oxygen transfer rate on shikonin production in transformed suspension and hairy root cultures of Lithospermum erythrorhizon were studied. Shikonin production with in situ extraction in transformed cell and hairy root cultures by n-hexadecane was 7.6 and 3 times higher than those of the control culture. Shikonin production of transformed L. erythrohizon increased with the enhanced gas exchange, and in situ extraction also increased sucrose consumption and shikonin production. The optimal volume of n-hexadecane in the hairy root culture was similar to that in the transformed cell cultures. In situ extraction at an earlier stage significantly enhanced shikonin production both in transformed cell and hairy root cultures. Dimethylsulfoxide used as a permeabilizing agent was harmful to cell growth and shikonin production, and permeabilizing was unnecessary when in situ extraction was applied. This occurred because with the solvent addition, most shikonin was spontaneously released from the cells and was dissolved in the solvent layer. The combined addition of n-hexadecane of the extract of the fungus Penicillium as an elicitor seemed to result in a higher production of shikonin both in cell suspensions and transformed root cultures. However, an increase of shikonin induction by fungal elicitation in a hairy root culture was not significant in comparison with that of normal cell cultures. PMID- 7832531 TI - Bioreactor engineering as an enabling technology to tap biodiversity. The case of taxol. AB - One barrier to exploiting the chemical and genetic diversity in nature is the difficulty of cultivating many organisms in a controlled manner. In some cases it is difficult to achieve growth. In many others, good growth is achieved, but the expression of the organism's genetic potential to make a desired product is not realized. The thesis of this paper is that a coupling of an understanding of reactor engineering principles with the basic knowledge of the biology is often necessary to circumvent these barriers. In many cases the construction of appropriate cultivation systems is a necessary step to better understanding of cellular physiology. In some cases the chemical of interest is of high social utility and comes from a natural source that is uncommon and difficult to secure. In these cases a method of controlled cultivation becomes a prerequisite for commercial exploitation. These points were illustrated using a taxol. Taxol is an important new anticancer drug whose development has been greatly impeded by supply problems. Taxol has been derived from the park of the pacific yew tree, a process that kills the tree. The pacific yew is a relatively uncommon tree and very slow growing. One alternative to the natural source is plant cell culture. Such cultures can produce significant levels of taxol with substantial release into the medium. Taxane products not observed in typical extracts from field grown plants can be found in cell cultures, indicating the potential unmasking of pathways. These cultures are quite responsive to changes in their environments as illustrated by the summary of initial observations. With regard to natural compounds, biochemical engineers can play a major role in the capture and preservation of producing systems, in the discovery of useful compounds, and in providing the basis for commercial production of natural compounds. PMID- 7832532 TI - Biotransformation of finasteride (MK-0906) by Selenastrum capricornutum (green algae). AB - Finasteride (MK-0906), a drug used for the treatment of benign prostatic hyperplasia, is a highly specific inhibitor of steroid 5 alpha-reductase, an enzyme that converts testosterone (T) to dihydrotestosterone (DHT) in animals and humans. In a study to evaluate the effect of finasteride on the growth of green alga, Selenastrum capricornutum, the parent drug was not detected by HPLC in the posttreatment (14 day) samples, suggesting complete biotransformation. Thermospray LC/MS, followed by NMR analysis, indicated that the major algal metabolite was 11 alpha-hydroxy-finasteride. This metabolite has negligible in vitro bioactivity against human prostatic 5 alpha-reductase; its potency is only 2% that of finasteride. The primary metabolite of finasteride produced by the green alga involved a biotransformation not previously observed in mammalian and human studies. The green alga effectively deactivates the drug, thereby mitigating any potential environmental impact. PMID- 7832533 TI - Resuscitation of starved ultramicrobacteria to improve in situ bioremediation. PMID- 7832534 TI - Polyphosphate metabolism in Escherichia coli. AB - Polyphosphate metabolism in Escherichia coli was studied in order to determine the role of polyphosphates in energy and phosphate metabolism. Phosphate-shift experiments were performed on wild-type E. coli W3110 and on an E. coli strain mutant in the genes encoding the polyphosphate-metabolizing enzymes polyphosphate kinase (PPK) and polyphosphatase (PPX). The levels of polyphosphates were measured by [31P]NMR, and the activities of PPK and PPX were measured using enzymatic assays. During phosphate starvation, the intracellular level of polyphosphate was not detectable in E. coli W3110; the activities of PPX and alkaline phosphatase were high relative to those during exponential growth. During the shift from phosphate starvation to phosphate surplus conditions, PPX activity decreased and PPK activity and intracellular polyphosphate stores increased dramatically. These results imply an important role for polyphosphates in cellular energy and phosphate storage and in adaptation to adverse growth conditions. PMID- 7832536 TI - Autologous fat injection for vocal fold paralysis: long-term histologic evaluation. AB - Many techniques have been developed for medialization of the paralyzed vocal fold. The purpose of this study is to evaluate autologous fat as an alternative to alloplastic substances for use in vocal fold medialization. Eight dogs underwent left recurrent laryngeal nerve sectioning. Autologous fat was harvested, and the paralyzed vocal fold was medialized by injecting the fat into the thyroarytenoid muscle. The animals were divided into three groups for evaluation at 1, 3, and 6 months. Videolaryngoscopy was performed prior to sacrificing the animals. The larynges were sectioned coronally, and histologic studies were performed. The studies confirmed the preservation of viable fat at the injected site in all animals. Only a minimal inflammatory response was observed in the 1-month group. It would appear that fat injection is a viable alternative to Teflon injection and thyroplasty; it eliminates the need for alloplastic materials, does not appear to migrate, and does not require an open procedure. PMID- 7832535 TI - Diversity in the ability of cultured cells to elongate and desaturate essential (n-6 and n-3) fatty acids. AB - Essential fatty acids (EFAs) cannot be synthesized by mammalian cells. Once taken in with the diet, they can undergo desaturations/saturations and chain elongations/shortenings to yield a variety of polyunsaturated fatty acids of the same family. Cells in vitro from a variety of tissues are capable of processing EFAs to varying extents. Conversion of the parent EFAs, linoleic (LA, n-6) and alpha-linolenic (LNA, n-3) acids, to the 20-carbon polyunsaturated fatty acids, arachidonic (AA, n-6) and eicosapentanoic (EPA, n-3), requires chain elongation and delta 6 and delta 5 desaturations. AA and EPA are required by many tissues for optimal biological function and are precursors of biologically active eicosanoid hormones. All cultured cells are able to elongate exogenous LA and LNA, and most can perform delta 5 desaturation, so delta 6 desaturation is the limiting step in AA and EPA production. Longer fatty acids that have more double bonds than AA or EPA are less frequently produced due to a deficiency in delta 4 desaturating ability. The process of retroconversion (chain shortening) is less extensively studied, but evidence from a variety of cells suggests that this type of metabolic conversion is normally active. The example of MCF-7 (human breast cancer cell line) and MCF-10A cells (human noncancerous breast cell line) is discussed in order to emphasize the diversity in EFA processing ability of cultured cells. Under identical culture conditions, MCF-10A cells perform extensive desaturations, elongations, and retroconversions, whereas MCF-7 cells can only elongate and retroconvert exogenous EFAs. Given the great diversity in the ability of cultured cells to process EFAs, no conclusions can be drawn regarding the mechanisms responsible for the effects of exogenous EFAs on a particular cell until that cell's EFA processing patterns have been evaluated. PMID- 7832537 TI - Benign pathologic responses of the larynx. AB - Benign laryngeal lesions were examined for patterns of injury indicated by deposition of fibronectin and collagen type IV. An immunoperoxidase technique was used to compare 33 fresh or paraffin-embedded tissues with regard to their staining of monoclonal antibodies directed against fibronectin and collagen type IV. Two types of patterns were recognized. One pattern showed intense fibronectin deposition in the superficial layer of the lamina propria, often coupled with basement membrane zone injury, indicated by thick collagen type IV bands. The other pattern showed rare basement membrane zone injury and very little fibronectin deposition. The first pattern correlated more with nodules, the second pattern more with Reinke's edema and some polyps. A better understanding of the effects of excessive deposition of structural glycoproteins such as fibronectin and of abnormal proteoglycan deposition may lead to a better characterization of vocal fold disease and its causation and, ultimately, better treatment. PMID- 7832538 TI - Calibration of endoscopic images. AB - In pediatric airway surgery, endoscopic evaluation of the lesions and treatment is important. However, there are no objective and reproducible methods for measurement. The purpose of this study was to define the optical effects of a Storz-Hopkins system and develop a method of calibration and measurement. Known geometric images (grids and circles) were viewed through the Storz-Hopkins system and recorded. These images were then analyzed morphometrically with a computer image analyzer (Jandel Scientific). The distortion of the endoscope could be identified, and the severity was found to be a function of the distance from the center of the field (r = .962). When this distortion factor (range, 0% to 25% shrinkage) was used mathematically, known circles could be measured by means of an endoscopic image. The error was reduced from 17.6% to 4.3% (p < .003). With morphometric programs the optical distortion of the bronchoscope can be calibrated. This can then be used to correct the measurement of images. PMID- 7832539 TI - Airway complications of jet ventilation in neonates. AB - Four cases of airway complications in infants surviving jet ventilation have been observed at the Children's Hospital of New Mexico. Two cases of necrotizing tracheobronchitis in preterm infants are presented: one was treated with bronchoscopy and removal of the necrotizing tissue; the second was placed on extracorporeal membrane oxygenation, prior to dilation of the affected area. A third child developed subglottic stenosis after intubation with an oversized jet endotracheal tube. A fourth child, with a history of prematurity and jet ventilation as a neonate, was found at 3 years of age to have tracheal webs in the lower third of his airway. Management and follow-up of these four cases, as well as a literature review of the known airway complications of jet ventilation, are presented. PMID- 7832540 TI - Ear surgery in Treacher Collins syndrome. AB - The autosomal dominant hereditary Treacher Collins syndrome manifests itself phenotypically in dysmorphogenesis of particularly the first, but also the second branchial arch system. Consequently, 50% of patients with Treacher Collins syndrome have a congenital, generally pure conductive hearing loss resulting from a major or minor ear anomaly. The outcome of surgery to improve patients' hearing varies and is sometimes even disappointing. Thorough analysis of 33 cases (39 operated ears) and the strict application of a classification for the anomaly to each ear enabled us to gain insight into the most suitable surgical policy and to form a prognosis for reconstructive ear surgery. PMID- 7832541 TI - Role of modern imaging technology in the implementation of pediatric cochlear implants. AB - Since 1989, 40 patients have received cochlear implants in our institution. Over the past 2 years, 17 children among these patients have undergone radiographic assessment combining magnetic resonance imaging (MRI) and high-resolution computed tomography (CT) scanning. Imaging is not essential, and is only used after assessment by a multidisciplinary team. However, the imaging results influence the choice of implant, and sometimes the side to be implanted. The first study is always CT, as it detects congenital abnormalities, and for children with a history of bacterial meningitis, it can detect signs of labyrinthine ossification that contraindicates or complicates cochlear implantation. These signs are not always visible with tomodensitometry, especially when fibrosis within the canal has not yet ossified. This examination also provides for postoperative confirmation of implant position in case of failure or complication. Over the past 3 years, MRI has been combined with tomodensitometry, especially with children having a history of meningitis. This examination provides a basis for evaluating the liquid nature of the labyrinth. A GE Signa 1.5-T unit was used by the authors, employing sequences of volumetric acquisition (steady state free precision with 1.5-mm image slices and an angle of 15 degrees to 35 degrees). Hence, modern imaging plays an important role when the decision to implant has already been made, particularly in the case of profoundly deaf children. We always use MRI in combination with a CT scanner in children with a history of meningitis. PMID- 7832542 TI - Electronic speckle pattern interferometry of the vibrating larynx. AB - Laser holography is a technique that creates a three-dimensional image of a static object. This technique can be applied to the analysis of vibrating structures. Electronic speckle pattern interferometry uses a laser for illumination of the vibrating object and solid state detectors and digital hardware technology for capturing and processing the image in real time. This was performed on a human cadaver larynx and is the first time an interferogram of vibrating vocal cords has ever been obtained. Dark and bright interference fringes are seen that represent the vibratory motion of the vocal folds. These are presented in still photos as well as real-time on videotape. This method can provide advantages over current techniques of laryngeal study: it is sensitive to motion in the vertical dimension, and the digital data can be quantitatively analyzed. Application of this technique to study the larynx should eventually be a valuable clinical tool and provide quantitative research data. PMID- 7832543 TI - Lower skull base: anatomic study with surgical implications. AB - With advances in the lateral approaches to the skull base and the increasing success of the management of jugular foramen lesions, a thorough knowledge of the anatomy of this region is needed. The purpose of the present work is to study the detailed microsurgical anatomy of the lower skull base and the jugular foramen area as seen through the lateral approaches. Forty preserved skull base specimens and 5 fresh cadavers were dissected. The shape of the jugular bulb and its relationship to nearby structures were recorded. The different venous connections of the bulb were noted. The hypoglossal canal was identified and its contents were observed. The lower cranial nerves were studied at the level of the upper neck, at their exit from the inferior skull base, and in the jugular foramen. The results of the present study showed the complex and variable anatomy of this area. The classic compartments of the jugular foramen were not always present. Cranial nerves IX through XI followed different patterns while passing through the jugular foramen, being separated from the jugular bulb by bone, thick fibrous tissue, or thin connective tissue. PMID- 7832544 TI - Vestibular and sensory interaction deficits assessed by dynamic platform posturography in patients with multiple sclerosis. AB - Vestibular impairments have not been routinely identified in patients with multiple sclerosis (MS), because of the confounding effects of deficits in other neural systems. In this study, 35 patients with MS were evaluated by means of a systematic alteration of the sensory environment (dynamic posturography) in order to identify those patients who became unstable when vestibular inputs were needed to maintain stance. Subjects were assigned to either a high-function (HF) or a low-function (LF) group on the basis of a functional status assessment score obtained prior to the posturography test. For the HF group, 30% (7/23) had abnormal posturography scores. Of those subjects, 3 had a vestibular dysfunction pattern or a somatosensory-vestibular impairment. In contrast, 58% of the LF group (7/12) had abnormal posturography scores. Nearly all of these LF patients (6/7) had a vestibular dysfunction pattern or a combined visual-vestibular or somatosensory-vestibular impairment. Posturography might serve as one method to evaluate the functional consequences of a vestibular deficit in patients with MS. PMID- 7832545 TI - Central nervous system imaging in the evaluation of children with true vocal cord paralysis. PMID- 7832546 TI - Laryngeal paraganglioma versus atypical carcinoid tumor. AB - Paraganglioma and atypical carcinoid tumor of the larynx are two neuroendocrine neoplasms that have often been confused in the past, and even in the present, in the literature. The clinicopathological profile of the two lesions is presented and the differential diagnosis is discussed. A correct diagnosis is of paramount importance, since treatment and prognosis depend on diagnostic accuracy and differ for the two lesions. Paraganglioma of the larynx is usually benign, whereas atypical carcinoid tumor is malignant and has an aggressive clinical course. PMID- 7832548 TI - [The French language of dermatology]. PMID- 7832547 TI - Microlaryngoscopic surgery for T1 glottic lesions: a cost-effective option. PMID- 7832549 TI - [For a development of dermatologic nomenclature in the French language]. PMID- 7832550 TI - [Physiological cutaneous signs in normal pregnancy: a study of 60 pregnant women]. AB - We made a prospective study of 60 pregnant women from February 1992 to July 1992. Women with pathologic pregnancies were excluded. Fifty-one women had pigmentary changes; the most frequent was linea nigra in 45. Melasma was observed in 3 women only, and the other local melanosis were rare. Vascular changes appeared in 50 women and vascular spiders in 32. Only one vascular spider was seen on a leg; all the others were on the upper part of the body. Eighteen women had a palmar erythema. New striae distensae appeared in 37 women, the more often on the abdomen. Among the other non classified skin changes, acne appeared in 14 women, oedemas of the legs in 22, oedemas of the eyelids in 3 and molluscum fibrosum gravidarum in 4. We emphasize that skin changes are a frequent and polymorphous feature in pregnancy. PMID- 7832551 TI - [Acquired cutaneous osteomatosis. A primary monomelic form]. AB - Eight cases of sporadic acquired primary osteoma cutis have been reported in the literature. Age at onset varies from 16 to 55 years with a mean of about 35 years. The sex ratio is 1 and a wide range of localizations have been reported. There is no known treatment. We report a new case of primary osteoma cutis observed in an adult. The monomelic feature of this case has not been reported previously. The patient was 76 years old and had multiple painless, stone-like formations at several sites on the left thigh and leg since the age of 40. Histological examination of skin biopsies showed a perfectly differentiated bone tissue in the dermal layer. There was no similar family history nor abnormal morphotype. Likewise, the absence of laboratory signs of pseudohypoparathyroidism, together with the late and spontaneous onset allowed us to eliminate hereditary Albright's osteodystropy or secondary osteomatosis due to a local pathological process. Despite the late onset, the monomelic character of the osteomas observed and the association of hemicorporeal hypertrophy and linear basocellular naevi reported in the literature would suggest a hamartomatous origin rather than a metaplasic process in this patient. PMID- 7832552 TI - [Fixed pigmented erythema caused by levamisole administration]. AB - INTRODUCTION: Description of a case of fixed drug eruption induced by levamisole. OBSERVATION: Fixed toxic erythema with pigmentation was observed in a patient taking levamisole as an adjuvant to 5 fluorouracil chemotherapy for cancer of the colon. The imputability of levamisole was highly likely. Epicutaneous skin tests were negative. DISCUSSION: Several types of skin eruptions have been described after intake of levamisole. It was highly likely that levamisole was implicated here and fixed pigmented erythema should be added to the list. PMID- 7832553 TI - [Allergic vasculitis in brucellosis]. AB - Brucellosis is an anthropozoonosis caused by a Gram negative bacillus of the Brucella gender. Skin manifestations have been reported in 1.5 to 11 p. 100 of the cases. Allergic vasculitis is rare. Recently a 24-year-old man was hospitalized for signs of infection. He had been treated with tetracycline. The clinical picture was suggestive of brucellosis and the Wright test was positive at 1/1,280. There were violet and purpuric papulae on the limbs, arthritis of the knee and ankle joints and renal involvement (haematuria, proteinuria). Histology revealed fibrinoid and leukocytoclastic vasculitis of the small veinules of the subpapillary plexus. Outcome was favourable with rifampicin, doxycycline and adjuvant dapsone, together with bed rest. Several types of skin manifestations have been reported in brucellosis although cases of allergic vasculitis are rare. PMID- 7832554 TI - [Disulone hypersensitivity syndrome]. AB - Hypersensitivity to dapsone (Disulone) is a rare side effect of sulfone therapy. The diagnosis is based on variable clinical manifestations and laboratory findings dominated by hyperthermia, skin eruptions and a mixed form of hepatitis. We observed a case of hypersensitivity to dapsone in a 57-year-old woman who was treated with Disulone for cicatricaial pemphigoid. Clinical manifestations and laboratory results returned to normal 3 weeks after drug withdrawal. This case is interesting because the skin eruptions classically described were not observed. In addition this is apparently the first case reported of such a hypersensitivity syndrome occurring during treatment of autoimmune bullous dermatosis. PMID- 7832555 TI - [Acquired mid-dermal elastolysis. 2 new cases]. AB - Two new cases of mid-dermal elastolysis are reported. In the first case, a 32 year-old woman, the clinical picture included the typical perifollicular protrusions of the trunk and wrinkled skin of the members. There was no prodrome and no other signs were associated. In the second case, a 39-year-old woman, after a 14-year clinical course, the skin manifestations involved the entire body with the exception of the face. Over the years, the initial follicular papules progressively formed plaques of wrinkled skin. PMID- 7832556 TI - [Microsporum langeronii dermatophytosis in a newborn infant contaminated in France]. AB - Dermatophytosis due to Microsporum langeronii was observed in a 21-day neonate born in Bordeaux, France to a mother of West African origin. A typical misleading manifestations were: non alopecic squamation of the scalp with seborrhoea associated with circineous vesiculo-squamous lesions of the forehead. The source of the contamination was undoubtedly the mother who presented squamation without alopecia of the scalp. M. langeronii were observed in the scales and the hair. Epidemiological search for tinea should be carried out in the family as well as in schools attended by the brothers and sisters. Familial contamination is more frequent. PMID- 7832557 TI - [Diagnosis of autoimmune pemphigus by immunostaining of paraffin slides with anti desmoglein antibody (32-2B)]. PMID- 7832558 TI - [Relations between basal cell carcinoma and actinic keratosis]. PMID- 7832559 TI - [Treatment of psoriasis by oral calcitriol]. PMID- 7832560 TI - [Treatment of dermatomyositis by adrenal cortex hormones. Prevention of adverse effects]. PMID- 7832561 TI - [A case for diagnosis: lupus erythematosus panniculitis]. PMID- 7832562 TI - [A case for diagnosis: dermoid cyst]. PMID- 7832563 TI - [Acquired mid-dermal elastolysis]. AB - Sixteen cases of acquired mid-dermal elastolysis have been reported in the literature. In 1977, Shelley identified this type of elastolysis as a separate entity and described three variants: post-inflammatory elastolysis with cutis laxa predominates in facial areas in African children. The initial inflammatory lesions are replaced by rough wrinkling of the skin; post-inflammatory elastolysis without cutis laxa; non-inflammatory elastolysis without cutis laxa as mid-dermal elastolysis. It is difficult nevertheless to classify certain cases reported in the literature. This would suggest that there is in reality a continuum of acquired elastolysis which could be classed according to a scale of decreasing initial inflammation. The non-inflammatory pole would represent mid dermal elastolysis. The common features of the different types of elastolysis are dominated by the absence of a causative agent in most cases, unknown pathogenesis and the fact that the empirical treatments which have been used have been ineffective. PMID- 7832564 TI - [Vulvodynia]. PMID- 7832565 TI - [Retinoids and cutaneous lupus erythematosus]. PMID- 7832566 TI - [Question of the month. What is the role of PUVA therapy in the treatment of vitiligo?]. PMID- 7832567 TI - The chemical pathology of AIDS. PMID- 7832568 TI - Lactic acidosis in paediatrics: clinical and laboratory evaluation. PMID- 7832569 TI - Methodological and clinical aspects of cyclosporin monitoring: report of the Association of Clinical Biochemists task force. PMID- 7832570 TI - Urine-free cortisol excretion: evidence of sex-dependence. AB - Measurement of urine-free (unconjugated) cortisol (UFC) excretion is widely used in the investigation of hypercortisolaemia. We have measured 24 h UFC excretion in normal healthy individuals using a radioimmunoassay (RIA) method claimed to be suitable for unextracted urine. Significantly higher rates of excretion were found in a group of 15 men compared with a group of 18 women, with median values of 230 (range 145-334) and 149 (range 67-315) nmol/24 h, respectively (P < 0.005). This method was used to reanalyse the urine samples after extraction with dichloromethane. Although values were significantly lower than those found with unextracted urine (P < 0.001), the male:female difference remained with median values of 140 (range 96-295) and 112 (range 29-196) nmol/24 h, respectively (P < 0.02). Rates of UFC excretion were measured on the same dichloromethane-extracted urine samples using a second, different RIA, which again demonstrated the male:female difference with median values of 151 (range 116-302) and 109 (range 36-205) nmol/24 h, respectively (P < 0.001). There was no significant difference between these values and those obtained with extracted urine in the first assay. The higher rates of UFC excretion in men compared to women does not appear to be due to the presence of interfering compounds since the difference is also present using extracted urine samples and with two methods using different antibodies. These results should be borne in mind by laboratories when interpreting UFC results. PMID- 7832571 TI - Normal red cell magnesium concentrations and magnesium loading tests in patients with chronic fatigue syndrome. AB - Red blood cell magnesium concentrations were measured in samples from 89 patients who fulfilled the diagnostic criteria for chronic fatigue syndrome and the results compared to those found in an age and sex matched group selected from the normal population. No significant difference was found. Six patients were further investigated using a magnesium loading test to determine if there was any evidence of magnesium deficiency associated with this disorder. None was found. There is therefore no indication for the use of magnesium therapy in the management of this condition. PMID- 7832572 TI - Use of dynamic tests of muscle function and histomorphometry of quadriceps muscle biopsies in the investigation of patients with chronic alcohol misuse and chronic fatigue syndrome. AB - Ischaemic lactate/ammonia tests, serum carnosinase and creatine kinase assays and percutaneous needle muscle biopsies were performed on 10 patients with chronic fatigue syndrome (CFS), and 10 with chronic alcohol misuse complaining of muscular symptoms. Basal serum lactate levels were significantly elevated in the alcohol misusers compared to the CFS patients, but all were within the reference range. Lactate profiles after ischaemic forearm exercise did not differ significantly for the two patient groups. In one patient previously diagnosed as having CFS, myoadenylate deaminase deficiency was identified on the basis of a flat ammonia response to ischaemia and absent muscle adenosine monophosphate deaminase activity. In addition, two further patients in the CFS group were subsequently shown to have other disorders: one had polymyositis and one had myopathy with mild type II fibre atrophy of unknown cause. Histomorphometric examination of muscle needle biopsy in the alcohol misusers showed features of chronic alcohol-induced skeletal myopathy in six patients and polymyositis in one patient. Type II fibre atrophy factors were significantly elevated in the alcohol group but were within the reference range in CFS patients. Dynamic tests of muscle function and muscle histology are valuable tools in excluding alternative pathology in CFS, whereas muscle histomorphometry is of the greatest value in the diagnosis of chronic alcoholic myopathy. PMID- 7832573 TI - A characterization of the blood lead concentrations in Saudi Arabian children. AB - The results presented in this paper are those derived from an extensive analysis of lead in 1047 children aged 2 months to 16 years attending as outpatients at a reference hospital, taking cases from all parts of the Kingdom of Saudi Arabia. Since the distribution of blood lead data in the sample suggested the existence of two mixed sub groups among the studied children, a non-linear mathematical model was used fit to the data. More than 20% of the children had blood lead concentrations above 0.608 mumol/L (12.59 micrograms/dL). PMID- 7832574 TI - Drugs of abuse screening in the West Midlands: a 6 year retrospective survey of results. AB - We describe the results of urinary drugs of abuse screening performed by the West Midlands Regional Laboratory for Toxicology, Birmingham, UK, on more than 27,800 urine specimens received between January 1988 and December 1993. The number of specimens positive for amphetamine declined from 1988 to 1990, but this was followed by a doubling of specimens testing positive from 5.7% in 1990 to 12.0% in 1993. There is very little evidence of methamphetamine or Ecstasy abuse in the West Midlands. Morphine (assumed to be from heroin abuse) is the most common opiate detected, with 11.7% of all specimens received proving to be positive in 1993. The incidence of cocaine abuse is low, less than 5% when requests are based on clinical judgement, and less than 3% in the overall population monitored. PMID- 7832575 TI - Determination of conjugated and unconjugated serum 3 alpha-OH bile acids by high performance liquid chromatography. AB - A simple reverse-phase liquid chromatographic method has been developed for the quantitative measurement of 11 3 alpha-OH bile acids in paediatric serum samples. Bile acids are enzymatically reduced to the corresponding 3-keto compound and then derivatized with the fluorophore dansyl hydrazine. Preliminary fractionation of bile acids is not required. The limit of detection is 0.1 mumol/L using a sample size of 200 microL. One hundred and twenty-three serum samples were analysed by the high-performance liquid chromatography (HPLC) method and the results compared with a commercial kit method (Enzabile) presently used in many laboratories for the measurement of total bile acids. There was a good correlation between the two methods (r = 0.96). The method is suitable for use in a clinical laboratory for the further investigation of those patients with abnormally high total bile acid levels where quantification of bile acid fractions is required. PMID- 7832576 TI - Studies on paracetamol binding to serum proteins. AB - There is a limited amount of data on the binding of paracetamol to plasma proteins. It has been suggested that binding might influence the ability of some analytical methods to quantify the total amount of drug present in the plasma fraction--the basis of clinical experience in risk assessment and antidote usage. We have investigated the binding of paracetamol to plasma proteins using an ultrafiltration technique. In overdose and spiked uraemic plasma samples the mean percentage of paracetamol bound was 24.1 (1SD = 7.0) with no significant correlation with drug levels or degree of uraemia. There is a small but significant increase in binding with increasing serum albumin concentration both in plasma (rs = 0.549, P = 0.014) and in pure serum albumin solutions (rs = 0.848, P < 0.001). PMID- 7832577 TI - Behcet's disease and hypopituitarism: a possible link. PMID- 7832578 TI - Effects of supplemental dietary calcium on quantitative and qualitative fecal fat excretion in man. AB - Oral calcium supplementation is thought to be a useful interventional agent to decrease colon cancer risk. This is supposedly due, at least in part, to the binding of bile acids and fatty acids by calcium in the colon, thus prohibiting the damaging effects of these substances to the epithelium. To determine the effects of calcium supplementation on fecal fat excretion, 24 subjects kept a fat and calcium constant diet for one week and were supplemented with either 0, 2 or 4 g elemental calcium as calcium carbonate in a double-blind fashion. At the end of the week 72-hour feces was collected, and total fat, neutral fat, fatty acids and the ratio of polyunsaturated and saturated fatty acids (P/S ratio) were measured. Calcium dose-dependently increased the percentual excretion of total fat as related to fat intake: 6.8 +/- 0.9% during 0 g, 7.4 +/- 1.0% during 2 g and 10.2 +/- 1.4% during 4 g, r = 0.44, p = 0.03. This was due to increased fatty acid excretion, excretion of neutral fat was not affected, nor was the P/S ratio. It is concluded that calcium supplementation modestly increases fecal fatty acid excretion. No adverse metabolic effects are to be expected from this in case of long-term calcium supplementation in subjects at increased risk for colon cancer. PMID- 7832579 TI - Iron status of a healthy French population: factors determining biochemical markers. AB - The iron status of a representative population sample in a district of Paris area (France) was assessed using a biochemical and dietary approach. Complete data were obtained for 1,108 subjects 6 months to 97 years old. Total iron intake increased up to adolescence and then remained stable in adult life. Iron intake was higher in men than in women. Most children and menstruating women presented a dietary iron intake below the recommended allowances. While anemia was not very common, iron deficiency (defined as the existence of at least two abnormal values in the four independent indicators of iron status: serum ferritin, erythrocyte protoporphyrin, transferrin saturation and MCV) was particularly common in infants, young children, menstruating women and elderly men. Serum ferritin, erythrocyte protoporphyrin and transferrin saturation were significantly correlated with inflammatory markers. Significant correlations were found between dietary total iron and serum ferritin (r = 0.29, p < 0.001) and hemoglobin (r = 0.44, p < 0.001). After adjustment for age, sex and inflammation, using multiple linear regression models, the relationship between both heme and nonheme iron intake and serum ferritin remained significant. Serum ferritin and hemoglobin levels were negatively correlated with calcium and phosphorus intake. PMID- 7832580 TI - Effects of dietary fibre mixtures on glucose and lipid metabolism and on mineral absorption in the rat. AB - Four diets containing different mixtures of dietary fibre (DF) were tested in the rat to verify the effects of fibre source and fibre level on plasma glucose, insulin and lipids and on apparent intestinal absorption of minerals. Diets Puri5 and Puri 10 contained 5 and 10% of total DF from pectin and cellulose. Diets Bran 5 and Bran 10 supplied 5 and 10% DF from oat bran and wheat bran. A fifth diet with 5% cellulose was used as a control. Ten rats were fed each diet for 4 weeks. On days 3, 17 and 28, feces were collected and analyzed for Fe, Zn, Ca and Mg. On day 29, blood samples were collected in portal vein and abdominal aorta in fasted and fed rats from each group. All diets had similar effects on plasma insulin and triglycerides. Compared to Bran diets, Puri diets induced higher portal glucose (p < 0.01) and lower plasma cholesterol (p < 0.03) in fed rats. The apparent absorption of Fe, Zn and Mg was higher (p < 0.05) in rats fed Puri diets than in those fed Bran diets. For Ca, the difference was significant only on day 3. In this study, only the apparent absorption of Fe was affected (p < 0.01) by fibre level (5 > 10%). This indicates that in fibre mixtures, the source rather than the amount of fibre generally affects absorptive and metabolic parameters. PMID- 7832581 TI - Liver microsomal mixed-function oxidases in response to dietary n-3 fatty acid levels in rats. AB - Phenobarbital (PB)-induced activities of the liver microsomal mixed-function oxidase (MFO) system in response to dietary levels of n-3 fatty acids were investigated in rats. The MFO activities were assessed by the contents of cytochromes P-450 and b5, and the activities of NADPH-cytochrome c reductase, aminopyrine N-demethylase and aniline hydroxylase. A linoleic acid (C18:2, n-6; LA) diet (2.0 energy % as LA) and n-3 fatty acid diets (0.3, 1.0, 1.9 or 4.8 energy % as n-3 fatty acids) were fed to rats for 16 days. The activities of MFOs except that of NADPH-cytochrome c reductase increased, as compared with the LA diet, with increasing the dietary n-3 fatty acid level, concomitant with the increase in n-3 fatty acids and decrease in n-6 fatty acids in liver microsomal lipids. The dietary LA over 1.8 energy % up to 13.8% did not increase the activities of PB-induced MFOs. Consequently, dietary n-3 fatty acids further elevated the PB-induced MFO activities effectively. These results suggest a differential response of dietary n-6 and n-3 fatty acids to the PB-induced MFO activities. PMID- 7832582 TI - Comparative effects of intestinal absorption of folic acid and methyltetrahydrofolic acid in chronic ethanol-fed rats. AB - This study concerns in vivo folic acid and methyltetrahydrofolic acid (MTHF) absorption by the whole intestinal surface after 20 weeks of 30% ethanol ingestion in drinking water. The results were compared with control rats fed ad libitum. The total intestinal serosal areas were similar in ethanol-fed and control rats. Significant increases in intestinal length, and decreases in tissue wet and dry weights were found in ethanol-fed rats. Serum folic acid concentrations were significantly less in the animals which had ingested ethanol than in the control rats. Intestinal folic acid absorption was significantly increased at lower substrate concentrations (0.5 and 1 microM), while no difference was observed at 2.5 microM in the ethanol-fed rats. Folic acid absorption relative to tissue wet weight showed significant increases at all tested concentrations in the ethanol-fed rats. Intestinal MTHF absorption showed no significant changes at 0.5 microM MTHF concentration, and an increase was observed in the absorption values at 1 and 2.5 microM concentrations in the ethanol-fed rats. When expressed as tissue wet weight, MTHF absorption values in ethanol-fed rats increased at 1 and 2.5 microM but did not differ at 0.5 microM substrate concentrations. The above results indicate compensatory responses in the folic acid and MTHF intestinal absorption after chronic ethanol ingestion. These effects are observed when the whole intestinal surface is evaluated. PMID- 7832583 TI - Effect of tea on iron absorption from the typical Tunisian meal 'couscous' fed to healthy rats. AB - Black and green tea decoctions are popular beverages in Tunisia, especially after eating. Our study was performed to examine the effect of graded amounts of black and green tea decoction prepared under realistic Tunisian conditions on nonheme iron absorption from a typical Tunisian meal, 'couscous', by extrinsic radioiron labeling in rats. Concentrations of 300, 200 and 100 micrograms/ml of black tea decreased dramatically nonheme iron bioavailability from couscous, but 50 micrograms/ml did not influence iron absorption. The inhibition of nonheme iron from couscous varied from 36 to 61% with black tea and 30.5% with green tea. Taken together, our findings show that the tea decoction in Tunisia has a great inhibitory power and may constitute an important factor for the development of iron deficiency anemia throughout Tunisia. PMID- 7832584 TI - Circadian variation and changes after a meal in volume and lipid production of human milk from rural Mexican women. AB - This research was designed to evaluate the circadian variation in the lipid content of the milk obtained from 10 lactating Mexican women as well as the effects of a meal eaten by the mother and of previous milk sampling on the milk volume and fat yield. In addition, predictions were made to determine the most appropriate sampling schedule to obtain a milk sample representative of 24-hour production. Every 4 h over a 24-hour period, the contents of the left breast of predominantly breast-feeding volunteers were completely extracted, using an Engell pump, and analysed for lipid content. In a separate experiment, 6 volunteers were sampled hourly from 9.00 to 13.00 h on 2 consecutive days, one after eating breakfast and the second while fasting. Significant circadian variations of volume (p < 0.05) and lipid yield (p < 0.001) were noted, peaking at 8.00-12.00 and 16.00-20.00 h, respectively. No effects of eating breakfast or of the volume and fat content of the preceding pumping on the actual volume or fat yield were found. In this population, sampling at 12.00, 20.00 and 24.00 h is the most representative of the 24-hour lipid yield, tending to overestimate it by 2.59 g/24 h with a predictive range of 97-124%. PMID- 7832585 TI - Assessment of the carbon tetrachloride-induced cirrhosis model for studies of nitrogen metabolism in chronic liver disease. AB - We evaluated the rat cirrhosis model obtained by repeated intraperitoneal administration of CCl4 (group C) with regard to biological and nutritional conditions in comparison to ad libitum (group AL) and pair-fed control rats. Cirrhotic rats were divided into two groups according to their clinical condition: group C1 (n = 4) represented those in good physical condition and group C2 those (n = 10) in poor physical condition. Autopsy indicated that rats in group C2 suffered from severe malnutrition as judged by body weight, carcass weight and the carcass/body weight ratio. However, all 14 treated rats presented the same micronodular cirrhosis and the same alterations in liver function, except for alkaline phosphatase activity (group C1: 110 +/- 63 IU/l, group C2: 259 +/- 110 IU/l; p < 0.05). In the cirrhosis groups, plasma levels of branched chain amino acids (BCAA) and the BCAA/aromatic amino acid (AAA) ratio were significantly reduced, but values in groups C1 and C2 were not significantly different (BCAA/AAA: 1.9 +/- 0.9 in group C1, 1.5 +/- 0.8 in group C2, 2.8 +/- 0.3 in group AL; C1 and C2, vs. AL: p < 0.05). These alterations were similar to those observed in human cirrhosis and were not solely the result of reduced food intake, as indicated by the lack of difference between pair-fed and ad libitum fed control rats. PMID- 7832586 TI - Bioenergetics: the evolution of molecular mechanisms and the development of bioenergetic concepts. AB - Possible routes for the evolution of cell energetics are considered. It is assumed that u.v. light was the primary energy source for the precursors of the primordial living cell and that primitive energetics might have been based on the use of the adenine moiety of ADP as the u.v. chromophore. It is proposed that the excitation of the adenine residue facilitated phosphorylation of its amino group with subsequent transfer of a phosphoryl group to the terminal phosphate of ADP to form ATP. ATP-driven carbohydrate synthesis is considered as a mechanism for storing u.v.-derived energy, which was then used in the dark. Glycolysis presumably produced compounds like ethanol and CO2, which easily penetrate the membrane and therefore were lost by the cell. Later lactate-producing glycolysis appeared, the end product being non-penetrant and, hence, retained inside the cell to be utilized to regenerate carbohydrates when light energy became available. Production of lactate was accompanied by accumulation of equimolar H+. To avoid acidification of the cell interior, an F0-type H+ channel was employed. Later it was supplemented with F1. This allowed the ATP energy to be used for 'uphill' H+ pumping to the medium, which was acidified due to glycolytic activity of the cells. In the subsequent course of evolution, u.v. light was replaced by visible light, which has lower energy but is less dangerous for the cell. It is assumed that bacteriorhodopsin, a simple and very stable light-driven H+ pump which still exists in halophilic and thermophilic Archaea, was the primary system utilizing visible light. The delta mu-H+ formed was used to reverse the H(+) ATPase, which began to function as H(+)-ATP-synthase. Later, bacteriorhodopsin photosynthesis was substituted by a more efficient chlorophyll photosynthesis, producing not only ATP, but also carbohydrates. O2, a side product of this process, was consumed by the H(+)-motive respiratory chain to form delta mu-H+ in the dark. At the next stage of evolution, a parallel energy-transducing mechanism appeared which employed Na+ instead of H+ as the coupling ion (the Na+ cycle).(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7832587 TI - Structure and evolution of cytochrome oxidase. AB - The structural features of cytochrome oxidases are reviewed in light of their evolution. The substrate specificity (quinol vs. cytochrome c) is reflected in the presence of a unique copper centre (CuA) in cytochrome c oxidases. In several lines of evolution, quinol oxidases have independently lost this copper. Also, the most primitive cytochrome c oxidases do not contain this copper, and electron entry takes place via c-type haems. These enzymes, exemplified by the rhizobial FixN complex, probably remind the first oxidases. They are related to the denitrification enzyme nitric oxide reductase. PMID- 7832589 TI - Protein structure, electron transfer and evolution of prokaryotic photosynthetic reaction centers. AB - Photosynthetic reaction centers from a variety of organisms have been isolated and characterized. The groups of prokaryotic photosynthetic organisms include the purple bacteria, the filamentous green bacteria, the green sulfur bacteria and the heliobacteria as anoxygenic representatives as well as the cyanobacteria and prochlorophytes as oxygenic representatives. This review focuses on structural and functional comparisons of the various groups of photosynthetic reaction centers and considers possible evolutionary scenarios to explain the diversity of existing photosynthetic organisms. PMID- 7832590 TI - Photobiology of bacteria. AB - The field of photobiology is concerned with the interactions between light and living matter. For Bacteria this interaction serves three recognisable physiological functions: provision of energy, protection against excess radiation and signalling (for motility and gene expression). The chemical structure of the primary light-absorbing components in biology (the chromophores of photoactive proteins) is surprisingly simple: tetrapyrroles, polyenes and derivatised aromats are the most abundant ones. The same is true for the photochemistry that is catalysed by these chromophores: this is limited to light-induced exciton- or electron-transfer and photoisomerization. The apoproteins surrounding the chromophores provide them with the required specificity to function in various aspects of photosynthesis, photorepair, photoprotection and photosignalling. Particularly in photosynthesis several of these processes have been resolved in great detail, for others at best only a physiological description can be given. In this contribution we discuss selected examples from various parts of the field of photobiology of Bacteria. Most examples have been taken from the purple bacteria and the cyanobacteria, with special emphasis on recently characterised signalling photoreceptors in Ectothiorhodospira halophila and in Fremyella diplosiphon. PMID- 7832588 TI - Oxygen reactions with bacterial oxidases and globins: binding, reduction and regulation. AB - Oxygen is favoured as terminal electron acceptor in aerobic and facultative microorganisms because of its appropriate physical state, satisfactory solubility and its desirable combinations of kinetic and thermodynamic properties. Oxygen is generally reduced by four electrons to yield oxygen, but there are important biological consequences of, and roles for, the partial reduction to superoxide and peroxide. Complex and multiple regulatory networks ensure (i) the utilization of oxygen in preference to other oxidants, (ii) the synthesis of oxygen-consuming enzymes with appropriate properties (particularly affinity for the ligand), and (iii) appropriate cellular protection in the event of oxidative stress. This contribution reviews the terminal respiratory oxidases of selected Gram-negative bacteria and microbial haemoglobin-like proteins. Recent studies of the cytochrome bd-type oxidases of Escherichia coli and Azotobacter vinelandii suggest that, despite probable similarity at the amino acid level, the reactivities of these oxidases with oxygen are strikingly different. The respiratory protection afforded to nitrogenase in the obligately aerobic diazotroph A. vinelandii by the cytochrome bd complex appears to be accompanied by, and may be the result of, a low affinity for oxygen and a high Vmax. The poorly characterized cytochrome o-containing oxidase in this bacterium is not required for respiratory protection. In E. coli, the cytochrome bd-type oxidase has a remarkably high affinity for oxygen, consistent with the view that this is an oxygen-scavenging oxidase utilized under microaerobic conditions. The demonstration of substrate (i.e. oxygen) inhibition in this complex suggests a mechanism whereby wasteful electron flux through a non-proton-pumping oxidase is avoided at higher dissolved oxygen tensions. The demonstration of two ligand binding sites (haems d and b595) in oxidases of this type suggests plausible mechanisms for this phenomenon. In E. coli, assembly of the cytochrome bd-type oxidase (and of periplasmic cytochromes b and c) requires the presence of an ABC transporter, which may serve to export haem or some "assembly factor" to the periplasm. There is at least one additional oxygen-consuming protein in E. coli the flavohaemoglobin encoded by the hmp gene. Globin-like proteins are also widely distributed in other bacteria, fungi and protozoa, but most have unknown functions. The function of HMP and the related chimaeric flavohaemoglobins in other bacteria and yeast is unknown; one of several possibilities for HMP is that its relatively low affinity for oxygen during turnover with NADH as substrate could enable it to function as a sensor of failing (or rising) cytoplasmic oxygen concentrations. PMID- 7832591 TI - Dissection of discrete kinetic events in the binding of antibiotics and substrates to the galactose-H+ symport protein, GalP, of Escherichia coli. AB - GalP is the membrane protein responsible for H(+)-driven uptake of galactose into Escherichia coli. It is suggested to be the bacterial equivalent of the mammalian glucose transporter, GLUT1, since these proteins share sequence homology, recognise and transport similar substrates and are both inhibited by cytochalasin B and forskolin. The successful over-production of GalP to 35-55% of the total inner membrane protein of E. coli has allowed direct physical measurements on isolated membrane preparations. The binding of the antibiotics cytochalasin B and forskolin could be monitored from changes in the inherent fluorescence of GalP, enabling derivation of a kinetic mechanism describing the interaction between the ligands and GalP. The binding of sugars to GalP produces little or no change in the inherent fluorescence of the transporter. However, the binding of transported sugars to GalP produces a large increase in the fluorescence of 8-anilino-1 naphthalene sulphonate (ANS) excited via tryptophan residues. This has allowed a binding step, in addition to two putative translocation steps, to be measured. From all these studies a basic kinetic mechanism for the transport cycle under non-energised conditions has been derived. The case of genetical manipulation of the galP gene in E. coli has been exploited to mutate individual amino acid residues that are predicted to play a critical role in transport activity and/or the recognition of substrates and antibiotics. Investigation of these mutant proteins using the fluorescence measurements should elucidate the role of individual residues in the transport cycle as well as refine the current model. PMID- 7832592 TI - A functional chimeric membrane subunit of an ion-translocating ATPase. AB - A chimeric transport protein was made by expression of a fusion of the arsB genes from Escherichia coli plasmid R773 and Staphylococcus aureus plasmid pI258. The two genes were fused to encode a functional protein with first eight membrane spanning alpha-helices of the S. aureus and the last four helices of the E. coli protein. The hybrid protein provided arsenite resistance and transport. When an arsA gene was expressed in trans with the ArsB proteins encoded by the R773, pI258 and fusion genes, arsenite efflux was dependent on chemical but not electrochemical energy. The Ars system is hypothesized to be a novel transport system that functions as a primary ATP-driven pump or a secondary carrier, depending on the subunit composition of the complex. PMID- 7832593 TI - Solute transport and energy transduction in bacteria. AB - In bacteria two forms of metabolic energy are usually present, i.e. ATP and transmembrane ion-gradients, that can be used to drive the various endergonic reactions associated with cellular growth. ATP can be formed directly in substrate level phosphorylation reactions whereas primary transport processes can generate the ion-gradients across the cytoplasmic membrane. The two forms of metabolic energy can be interconverted by the action of ion-translocating ATPases. For fermentative organisms it has long been thought that ion-gradients could only be generated at the expense of ATP hydrolysis by the F0F1-ATPase. In the present article, an overview is given of the various secondary transport processes that form ion-gradients at the expense of precursor (substrate) and/or end-product concentration gradients. The metabolic energy formed by these chemiosmotic circuits contributes to the 'energy status' of the bacterial cell which is particularly important for anaerobic/fermentative organisms. PMID- 7832595 TI - Antioxidants and the prevention of coronary heart disease. AB - Oxygen-free radical reactions have been implicated in many chronic disease processes, including atherosclerotic cardiovascular disease. Recent studies of lipid metabolism have suggested that oxidative modification of low-density lipoprotein accelerates atherogenesis. Micronutrient antioxidants, including alpha-tocopherol and beta-carotene, however, can neutralize oxygen-free radicals and inhibit low-density lipoprotein oxidation. This review examines (1) the role of oxidized low-density lipoprotein in atherogenesis, (2) the association between nutritional antioxidant intake and atherosclerosis, and (3) observational and clinical trial data on the effect of antioxidants in reducing the risk of coronary heart disease. While evidence suggests that antioxidant supplements protect against coronary heart disease, definitive recommendations await results from ongoing randomized trials of primary and secondary prevention. PMID- 7832594 TI - Bacterial sodium ion-coupled energetics. AB - For many bacteria Na+ bioenergetics is important as a link between exergonic and endergonic reactions in the membrane. This article focusses on two primary Na+ pumps in bacteria, the Na(+)-translocating oxaloacetate decarboxylase of Klebsiella pneumoniae and the Na(+)-translocating F1Fo ATPase of Propionigenium modestum. Oxaloacetate decarboxylase is an essential enzyme of the citrate fermentation pathway and has the additional function to conserve the free energy of decarboxylation by conversion into a Na+ gradient. Oxaloacetate decarboxylase is composed of three different subunits and the related methylmalonyl-CoA decarboxylase consists of five different subunits. The genes encoding these enzymes have been cloned and sequenced. Remarkable are large areas of complete sequence identity in the integral membrane-bound beta-subunits including two conserved aspartates that may be important for Na+ translocation. The coupling ratio of the decarboxylase Na+ pumps depended on delta muNa+ and decreased from two to zero Na+ uptake per decarboxylation event as delta mu Na+ increased from zero to the steady state level. In P. modestum, delta mu Na+ is generated in the course of succinate fermentation to propionate and CO2. This delta mu Na+ is used by a unique Na(+)-translocating F1Fo ATPase for ATP synthesis. The enzyme is related to H(+)-translocating F1Fo ATPases. The Fo part is entirely responsible for the coupling of ion specificity. A hybrid ATPase formed by in vivo complementation of an Escherichia coli deletion mutant was completely functional as a Na(+)-ATP synthase conferring the E. coli strain the ability of Na(+) dependent growth on succinate. The hybrid consisted of subunits a, c, b, delta and part of alpha from P. modestum and of the remaining subunits from E. coli. Studies on Na+ translocation through the Fo part of the P. modestum ATPase revealed typical transporter-like properties. Sodium ions specifically protected the ATPase from the modification of glutamate-65 in subunit c by dicyclohexylcarbodiimide in a pH-dependent manner indicating that the Na+ binding site is at this highly conserved acidic amino acid residue of subunit c within the middle of the membrane. PMID- 7832596 TI - Management of the behavioral manifestations of dementia. AB - Dementia affects 5% of persons over age 65 years and 20% of those over 80 years of age and is expected to increase further in the primary care setting as the population ages. The constellation of neuropsychiatric disorders includes dementia, organic personality disorder, and organic psychotic disorder. Dementia is the most prevalent disorder, accounting for approximately 70% of the neuropsychiatric disease of institutionalized patients. PMID- 7832597 TI - Unexplained illnesses among Desert Storm veterans. A search for causes, treatment, and cooperation. Persian Gulf Veterans Coordinating Board. AB - Between August 1990 and March 1991, the United States deployed 697,000 troops to the Persian Gulf to liberate Kuwait from Iraqi occupation. Since the Gulf War, most veterans seeking medical care at Departments of Veterans Affairs and Defense medical facilities have had diagnosable conditions, but the symptoms of several thousand veterans have not been readily explained. The most commonly reported, unexplained complaints have been chronic fatigue, rash, headache, arthralgias/myalgias, difficulty concentrating, forgetfulness, and irritability. These symptoms have not been localized to any one organ system, and there has been no consistent physical sign or laboratory abnormality that indicates a single specific disease. Because of the unexplained illnesses being experienced by some Gulf War troops, a comprehensive clinical and research effort has been organized by the Departments of Veterans Affairs, Defense, and Health and Human Services to provide care for veterans and to evaluate their medical problems. To determine the causes and most effective treatments of illnesses among Gulf War veterans, a thorough understanding of all potential health risks associated with service in the Persian Gulf is necessary. These risks are reviewed in this article and include possible reactions to prophylactic drugs and vaccines, infectious diseases, and exposures to chemicals, radiation, and smoke from oil fires. PMID- 7832598 TI - Lack of effectiveness of magnesium in chronic stable asthma. A prospective, randomized, double-blind, placebo-controlled, crossover trial in normal subjects and in patients with chronic stable asthma. AB - BACKGROUND: Magnesium sulfate has been helpful in the treatment of acute exacerbations of asthma. We hypothesized that magnesium would also be an effective bronchodilator in patients with chronic stable asthma. METHODS: We performed a prospective, randomized, double-blind, placebo-controlled, crossover trial in 15 patients with chronic, stable asthma and 10 nonasthmatics. On study day 1, spirometry and albuterol challenge were used to confirm the presence of asthma according to American Thoracic Society criteria. On study day 2, subjects received intravenous magnesium sulfate (2 g) or placebo (saline). On study day 3, subjects were crossed over to receive the other drug. Spirometry was performed before, during, and after drug or placebo administration. Circulating ionized magnesium concentrations were determined before and after intravenous magnesium or placebo administration. RESULTS: Magnesium infusion caused no statistically significant changes in forced expiratory volume in 1 second (mean +/- SEM, 1.92 +/- 0.13 L before, 1.98 +/- 0.12 L during, and 2.01 +/- 0.14 L after magnesium administration), forced vital capacity (mean +/- SEM, 3.44 +/- 0.25 L before, 3.60 +/- 0.26 L during, and 3.59 +/- 0.25 L after magnesium administration), or maximum forced expiratory flow rate (mean +/- SEM, 5.42 +/- 0.44 L/second before, 5.46 +/- 0.46 L/second during, and 5.57 +/- 0.49 L/second after magnesium administration). Placebo caused no changes in these three physiologic variables. CONCLUSION: Magnesium is not effective as a bronchodilator in chronic, stable asthmatics or in normal non-asthmatic adults. PMID- 7832599 TI - Physician attitudes about anticoagulation for nonvalvular atrial fibrillation in the elderly. AB - BACKGROUND: Our goal was to determine whether patient age affects a physician's reported likelihood of using anticoagulant therapy or the intensity of anticoagulant therapy for patients with nonvalvular atrial fibrillation. METHODS: We surveyed a nationwide sample of 1189 randomly selected office-based practitioners in three strata: primary care (geriatrics, internal medicine, family practice, and general practice), cardiology, and neurology. A vignette based questionnaire was used to measure attitudes and beliefs regarding anticoagulation risks and effectiveness, barriers to anticoagulation in clinical practice, and likelihood of using anticoagulation and target intensity of anticoagulation at three patient ages (55, 65, and 75 years) for four clinical scenarios (chronic non-valvular atrial fibrillation with mild left atrial enlargement, intermittent or paroxysmal atrial fibrillation, recent-onset atrial fibrillation, and atrial fibrillation with recent [3 months] embolic stroke). RESULTS: The overall response rate was 38%. The mean likelihoods of using anticoagulation for the three ages were unequal (P < .0001) for each scenario. Most physicians were "very" or "somewhat" likely to use anticoagulant therapy for a 65-year-old with left atrial enlargement (71%), intermittent or paryoxysmal atrial fibrillation (68%), recent-onset atrial fibrillation (86%), or embolic stroke (96%). Fewer physicians were likely to use anticoagulant therapy for a 75 year-old with left atrial enlargement (63%), intermittent or paroxysmal atrial fibrillation (56%), recent-onset atrial fibrillation (80%), or embolic stroke (93%). Among physicians equally likely to use anticoagulation for 65- and 75-year old patients, intensity of anticoagulant therapy (target international normalized ratio or prothrombin time ratio) was lower (P < .04) for the 75-year-old. CONCLUSION: Anticoagulant therapy may be less often and less intensively used for elderly patients with nonvalvular atrial fibrillation. PMID- 7832600 TI - Withdrawal or withholding of treatment at the end of life. Results of a nationwide study. AB - BACKGROUND: Decisions to withhold or withdraw treatment (nontreatment decisions) become increasingly important because they have to be made more frequently and more explicitly. This nationwide study provides information on the occurrence and background of these nontreatment decisions. METHODS: Three studies were undertaken: interviews with 405 physicians, 5197 answered questionnaires concerning deceased persons, and information about 2257 deaths collected by a prospective study. RESULTS: Of all deaths, 30% appeared to be sudden and unexpected. In 39% of all nonsudden deaths, a nontreatment decision was made. This percentage varied by specialty (28% to 55%). Nontreatment decisions were made more often in older female patients. The decisions were made at the explicit request of the patient (19%), after discussion with the patient or after a previous wish (22%), or without any involvement of the patient (59%). Of this last group, 87% of patients were not competent at the time of the decision. In 24% of cases of nontreatment, life was shortened by at least a week. Of all physicians interviewed, 56% had changed their attitude since the beginning of their practice, most of them toward more nontreatment decisions at the end of life. CONCLUSIONS: Nontreatment decisions are made frequently in medical practice. Most often the physician has to weigh medical and nonmedical burdens and benefits. For this to be done properly, the patient should be involved whenever possible. Other requirements are optimal palliative treatment, better prognostic knowledge, consultation of other specialists, and the absence of defensive motives. PMID- 7832601 TI - Is postmenopausal estrogen therapy associated with neuromuscular function or falling in elderly women? Study of Osteoporotic Fractures Research Group. AB - BACKGROUND: Muscle strength declines with advancing age; the causes of this are uncertain. In women, strength begins to decline around the time of menopause, suggesting that hormonal changes might influence strength. To determine the effect of postmenopausal estrogen use on muscle strength, neuromuscular function, and the risk of falling, we examined 9704 participants aged 65 years or more enrolled in the Study of Osteoporotic Fractures. METHODS: We measured hip abductor, triceps extensor, and hand-grip muscle strength, balance, gait speed, and self-reported functional disability. Falls during the first year of follow-up were determined from postcards that participants mailed every 4 months indicating whether they had fallen in the previous 4 months (> 99% complete follow-up). RESULTS: After adjusting for age, medications, medical history, and personal habits, current estrogen users did not differ in a clinically meaningful way from those who had never used estrogen on tests of hip abductor strength (mean difference, 0.15 kg; 95% confidence interval, -0.05 to 0.34 kg), triceps extensor strength (0.005 kg; -0.17 to 0.18 kg), or grip strength (0.30 kg; 0.00 to 0.59 kg). Gait speed, time to stand five times from a chair, balance, self-reported disability, and incidence of falls (odds ratio, 1.12; 95% confidence interval, 0.87 to 1.44) also did not differ between current users and never users. In addition, current users were similar to past users on all measures. CONCLUSION: We found no evidence that postmenopausal estrogen use has beneficial effects on muscle strength or neuromuscular function or that it reduces the risk of falling. PMID- 7832602 TI - Detecting delirium among hospitalized older patients. AB - BACKGROUND: Delirium occurs commonly among older hospitalized patients and is frequently not recognized. In an effort to identify tools useful to clinicians in the diagnosis of delirium, test characteristics of four screening instruments were compared. METHODS: Patients 65 years of age or older who were admitted to one of four medical and surgical wards of a university teaching hospital were followed up prospectively. Potential subjects were excluded if unavailable for interviews or discharged within 48 hours of admission, or if judged too impaired to participate in the daily interviews. Research assistants administered four instruments used to detect delirium: Digit Span Test, Vigilance 'A' Test, Clinical Assessment of Confusion, and Confusion Assessment Method. Abnormal scores on these tests or suspicion of acute confusion prompted a referral to the clinician-investigators who then assessed the patient daily for delirium based on the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition criteria. RESULTS: Delirium occurred in 64 (14.8%) of 432 subjects. The positive likelihood ratios for all of the instruments were significantly more than 1. The instruments remained useful when applied to selected subgroups: subjects in whom acute mental status changes were documented, subjects on surgical services, and subjects with impaired cognitive status on admission. Combinations of any two instruments did not perform substantially better than the instrument with the best test characteristics: the Clinical Assessment of Confusion. All instruments were more useful at confirming delirium than in excluding it. CONCLUSION: The four instruments studied, which are suitable for use at the bedside, can aid the clinician in identifying patients likely to be suffering from delirium. PMID- 7832603 TI - Physicians' assessment of functional health status and well-being. The patient's perspective. AB - BACKGROUND: Ascribing quality to medical care rests in part on the expectation of physician behavior and the content of care. The adoption of functional outcomes of care as legitimate measures of quality will require greater attention to patient-provided assessments of health and add new dimensions to medical practice and quality assessment. METHODS: We conducted a cross-sectional, national population survey of adults to obtain estimates of the frequency with which physicians reportedly inquire about patients' functional health status and emotional well-being, patients' attitudes about such assessments, and the perceived use of data thus obtained in the therapeutic process. RESULTS: The majority of physicians rarely or never ask about the extent to which patients' health limits their ability to perform everyday activities (64.7% to 78.7%); neither do they inquire about limitations imposed by emotional problems (71.4% to 84.4%). Physicians are more likely to make such inquiries in the presence of chronic illness or diminished health status, or with older patients, although such assessments remain the exception to usual practice and a large portion of functional impairment is undiscovered. More than 60% of respondents want their physicians to assess their functional health status and well-being. CONCLUSIONS: While individuals want their physicians to assess their functional performance and emotional well-being as a part of medical care, by their reports this occurs infrequently. The content of care may be less comprehensive than physicians believe to be the case. PMID- 7832604 TI - Race and sex differences in rates of invasive cardiac procedures in US hospitals. Data from the National Hospital Discharge Survey. AB - BACKGROUND: Lower rates of invasive cardiac procedures have been reported for blacks and women than for white men. However, few studies have adjusted for differences in the type of hospital of admission, insurance status, and disease severity. SETTING, DESIGN, AND PARTICIPANTS: Data from the National Hospital Discharge Survey were used to investigate race and sex differences in rates of cardiac catheterization, percutaneous transluminal coronary angioplasty, and coronary artery bypass surgery among 10,348 persons hospitalized for acute myocardial infarction. RESULTS: White men consistently had the highest procedure rates, followed by white women, black men, and black women. After matching for the hospital of admission and adjusting for age, in-hospital mortality, health insurance, and hospital transfer rates (with white men as the referent), the odds ratios for cardiac catheterization were 0.67 (95% confidence interval [CI], 0.51 to 0.87) for black men, 0.72 (95% CI, 0.63 to 0.83) for white women, and 0.50 (95% CI, 0.37 to 0.68) for black women. Similar race-sex differences were noted for percutaneous transluminal coronary angioplasty and coronary artery bypass surgery. CONCLUSIONS: Race and sex differentials in the rates of invasive cardiac procedures remained despite matching for the hospital of admission and controlling for other factors that influence procedure rates, suggesting that the race and sex of the patient influence the use of these procedures. PMID- 7832605 TI - Dissolution of intracardiac mass lesions in the primary antiphospholipid antibody syndrome. AB - The antiphospholipid antibody syndrome has numerous cardiac manifestations, including valvular thickening, insufficiency, and mass lesions. The mass lesions may be confused with atrial myxomas and other vegetations, sometimes necessitating a surgical diagnosis. There are no prospective studies on treatment or follow-up of intracardiac lesions in antiphospholipid antibody syndrome. We prospectively followed up three patients with antiphospholipid antibody syndrome for intracardiac lesions (one atrial and two mitral valve masses) complicated by systemic embolization. Anticoagulation led to complete resolution of the masses in 6 weeks to 3 months. We propose that initial treatment of an intracardiac lesion in patients with antiphospholipid antibody syndrome should be a trial of systemic anticoagulation before surgical intervention. PMID- 7832606 TI - Community hospital forbids the use of limited code orders. PMID- 7832607 TI - Treatment of Helicobacter pylori infection. PMID- 7832608 TI - Does 'aggressive approach' equal higher cost? PMID- 7832609 TI - Provider assessments of compliance with zidovudine. PMID- 7832610 TI - Generalists' prudence may lead to better outcomes. PMID- 7832611 TI - [Suicidal carbon monoxide poisoning in an electric car. An unusual case report]. AB - The authors report a case of a man who committed suicide by poisoning with carbon monoxide in his electric vehicle. He applied a small motor generator with no exhaust normally used for charging the vehicle's batteries at home, that was found on the loading space behind the seat. This demonstrates the value of a thorough scene investigation. PMID- 7832612 TI - [Analysis of combined phenothiazine-opiate poisoning]. AB - Report about 2 death cases due to an overdosage of phenothiacine derivates. The EMIT-test showed positive results concerning opiates for both cases. But morphine only was detected in one case by a fluorimetric method. The EMIT-test for opiates can show positive results in error, if there exist phenothiacines in the specimen at the same time. PMID- 7832613 TI - [Does a bone gunshot wound leave pure lead bullet metal residues?]. AB - The objective of the study was to give a survey on the possibilities and limits of reconstruction in cases of gunshot injuries of the vertebral bodies. X-ray examinations of the vertebral column hit by lead bullets of .22 rimfire ammunition regularly revealed small fragments of lead from the missile deposited along the wound track through the bone. PMID- 7832614 TI - ["Crows' feet wrinkles" in high voltage electric accident--a sign of survival?]. AB - A "crowsfoot-like" pattern is considered as being a sign of vitality in fatalities due to the effects of smoke, fire or high voltage (active or reflex contraction of mimic muscles). Introducing the autopsy results of a high voltage accident (66,600 V) it is discussed, whether this phenomenon and the underlying contraction of the facial muscles could also be caused by electrical current in the agony or supravital period. It seems possible that this mechanism of direct muscle contraction anticipates a nerval indirect stimulation of muscle fibres by innervating motoneurones--active or on the basis of a polysynaptic extraneous reflex. If the electrophysiological course discussed should be right, a "crowsfoot-like" pattern in equivalent cases could be interpreted as a vital sign only with great reserve. PMID- 7832615 TI - [How dangerous are "mouse trap projectile traps"?]. AB - The authors research by experiments to define the potency of wounding of a special mouse trap which belongs to the spring-guns. Besides the regular assigned 9 mm blank cartridge also the 9 x 17 mm "green" cattle stunning cartridge is tested. Shots were made on soap, cotton and skin on different conditions. As result the authors found that by close range shots (up to 1 cm) by the blank cartridge badly healing wounds are caused. The 600 Joule cattle stunning cartridge is able to mutilate the hand by contact shots. PMID- 7832616 TI - [An unusual case of extensive cadaver ingestion by a domestic dog]. AB - There are only a few reports on cases in which the body of a human who died unnoticed in a house was destructed by a dog. The presented case seems to be unusual in that the extent of destruction was severe and the distribution of injuries was different from that reported in the literature. A 59-year-old man was found dead naked in a room, the cause of death being ischemic heart disease. The lower part of the body was lying in a so-called kotatsu. Wounds were confined to the upper part of the body. The head was skeletonized. The anterior thorax was missing. What was different in our case from previous ones was that the genitals were spared from destruction; the kotatsu frame may have prevented the dog from approaching this region. The extensive destruction within the short period of about 3 days may be explained by the fact that the victim was naked when he died. PMID- 7832617 TI - [Normal blood pressure profiles during exercise according to age, sex and protocols]. AB - Systolic and diastolic blood pressure profiles of 2,808 healthy subjects are reported according to age, sex and exercise protocols. The rates of increase of systolic pressures are expressed with respect to the heart rate and decrease with age. For a given sub-maximal effort the systolic blood pressure is lower in males and in the younger age groups: the diastolic blood pressure only increases significantly on exercise after 50 years of age. These variations according to age and sex were confirmed on treadmill exercise but the peak pressure values were lower. These quantitative results differ from those of previously reported studies and suggest that the diagnostic criteria of hypertension of effort should be redefined. PMID- 7832618 TI - [Sudden coronary death outside of hospital; an comparative autopsy study of subjects with and without previous cardiovascular diseases]. AB - Autopsy studies of the heart of 221 subjects who suffered pre-hospital coronary sudden death were performed at the Paris Medico-Legal Institute over a period of 3 years to compare the lesions observed in subjects without known cardiovascular disease (Group A: n = 160; 72.4%) with those of subjects with known cardiovascular disease (Group B: n = 61). The proportion of men was greater in Group B (77%) that in Group A (62.5%). The average age of sudden death was the same in both groups: 65 years for men and 77 years for women. Sudden death usually occurred in the home (83%) at rest and, in one third of the cases, during sleep. Sudden death occurred in a context of severe coronary artery disease in both groups: significant triple vessel stenosis (> 75%) in 60% of subjects in both groups but thrombosis was found in only 13% of cases in Group A and 15% of cases in Group B. The mean weight of the heart was significantly greater than normal in both groups and in both sexes. In addition, the mean weight of the heart of subjects in Group B was significantly greater than that of subjects in Group A (p < 0.05). This autopsy study showed that prehospital coronary sudden death was the first sign of coronary disease in 70% of cases. Irrespective of whether the subject had known cardiovascular disease or not, sudden death occurred under similar circumstances and, in both cases, in the context of severe coronary artery disease. PMID- 7832619 TI - [Sorin-Pericarbon pericardial bioprosthesis. A 4-year follow-up study]. AB - Between January 1986 and December 1986, 106 Sorin-Pericarbon (new prostheses made of bobine pericardium) valves were implanted by our group: the object of this paper is to report the medium-term results of this new bioprosthesis. The probability of degeneration-free function at 4 years was 96.5 +/- 3.7% in patients with aortic valve replacement; the probability of reoperation-free survival for all patients was 95.2 +/- 3.3% and 96.5 +/- 3.7% for patients with aortic valve replacement with this prosthesis. The results of this new Sorin Pericarbon bioprosthesis at medium-term are satisfactory and need to be confirmed at long-term by further follow-up. PMID- 7832620 TI - [Quantification of mitral valve insufficiency by Doppler echocardiography. Correlation with cine-angiography in 60 patients]. AB - Non-invasive quantification of mitral regurgitation remains a clinical problem. The aim of this study was to assess a new methodology of Doppler echocardiographic assessment of the mitral regurgitant fraction. The study included 60 patients (average age 61 years) in sinus rhythm with mitral regurgitation. The cardiac output was measured by Doppler echocardiography at four sites: the aortic, pulmonary and mitral rings and at the tips of the mitral leaflets by a method previously validated and published. Using the average of the aortic and pulmonary cardiac outputs on the hand and the mitral cardiac output on the other, it was possible to calculate the regurgitant fraction: (mean mitral flow-mean aortic/pulmonary flow)/mean mitral flow. This was correlated with the Sellers angiographic grades of regurgitation. The results confirm this validated procedure: the correlation of aortic and pulmonary flows was good: r = 0.94. This also held true for mitral flow at the two sites: r = 0.96. The correlation between the Doppler echocardiographic regurgitant fraction and the angiographic estimation of the severity of mitral regurgitation was good: r = 0.89. There was a statistically significant difference between the Doppler echocardiographic regurgitant fractions corresponding to Sellers Grades I, II and III mitral regurgitation (p = 0.0001). This study shows that Doppler echocardiographic measurements of blood flow at different orifices of the heart applied to the quantification of mitral regurgitation is a reliable method, the use of which, with strict methodological criteria, may be proposed in everyday clinical practice. PMID- 7832621 TI - [Late ventricular potentials and mitral valve prolapse]. AB - In order to determine the predictive value for ventricular arrhythmias of ventricular late potentials (LP) in mitral valve prolapse (MVP) the authors performed high amplification signal-averaging ECG (SA) and 24 hours ambulatory ECG (Holter) monitoring in 68 consecutive patients (34 men, 34 women, average age 48 +/- 17.7 years) with echocardiographically diagnosed MVP. Patients with bundle branch block or associated cardiac disease were excluded. Echocardiography showed 26 patients to have floppy mitral valves (38.2%), 50 patients to have posterior deplacement > or = 5 mm of the mitral valves in systole (73.5%) and 35 patients to have mitral regurgitation (51.4%). Holter monitoring showed 17 patients without ventricular extrasystoles (VES), 15 had Lown Grade I, 6 had Lown Grade II, 3 had Lown Grade III, 15 had Lown Grade IV A and 12 had Lown Grade IV B ventricular arrhythmias. Therefore, 30 patients had complex ventricular arrhythmias (> or = Lown Grade III) and 13 patients had spontaneous non-sustained ventricular tachycardia (NSVT) (one patient had NSVT on resting ECG but not on Holter monitoring). Eighteen patients had LP (26.5%). The incidence of complex ventricular arrhythmias was higher in patients with mitral regurgitation (62.8% versus 27.7%; p < 0.005) whereas the incidence of NSVT was not significantly different (25.7% versus 17.1%; p = 0.15). On the other hand, the frequency of complex ventricular arrhythmias was not significantly different in the presence or absence of LP (61.1% versus 40%: NS) whereas the incidence of NSVT was higher in patients with LP (44.4% versus 10%; p < 0.005).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7832622 TI - [Conservative surgery in the treatment of infectious mitral valve insufficiency]. AB - In order to analyse the results of conservative mitral valve surgery in the treatment of mitral regurgitation due to infective endocarditis, the authors reviewed the cases of 48 patients operated between 1974 and April 1993 (36 operations having been performed after 1989, a period during which only 3 patients underwent mitral valve replacement for the same indication). Thirty-four patients were operated after sterilisation of the infective endocarditis, and 14 patients were treated during the active phase. There were 32 men and 16 women with an average age of 45 +/- 13 years. In two thirds of the cases, the causative organism was a streptococcus. Half of the patients were operated during the acute stage because of their poor haemodynamic status, 5 because of residual bacterial vegetations after one or more embolic events and two because of the infection itself. On the other hand, patients were operated after the infective phase because of severe mitral regurgitation, responsible for severe symptoms (NYHA Class III) in 16 cases. From the anatomical point of view, the peroperative finding of 14 patients operated in the acute phase included dilatation of the annulus (N = 9), ruptured chordae (N = 9), perforation (N = 8) or vegetations (N = 8); in the patients operated later, the incidence of perforation and vegetations was much lower (20%) whereas dilatation of the annulus was almost constant (91%).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7832623 TI - [Implantation of Strecker's endocoronary prosthesis. Apropos of 21 cases]. AB - The aim of this study was to assess the safety and efficacy of implantation of Strecker coronary stents. The implantation was performed in 21 patients during elective angioplasty (N = 18) or in emergency situations (N = 3). The indications were acute occlusion after angioplasty (N = 3), restenosis (N = 12), incomplete balloon angioplasty results (N = 4) and implantation of first intent (N = 2). The site of implantation was a venous bypass graft in 9 cases, the left anterior descending artery in 5 cases, the right coronary artery in 4 cases and the left circumflex in 3 cases. The average length of the lesions was 8.4 +/- 4.1 mm, including 15 short (< 10 mm) and 6 long (> 10 mm) lesions. Four lesions were located at an acute angle (> 45 degrees) and 4 at the site of origin of a side branch. The diameter of the normal segment of the treated artery was < 3 mm in 12 cases and > 3 mm in 9 cases. Seven 3 mm, five 3.5 mm, six 4 mm and three 4.5 mm diameter stents were implanted. There were no failures to position or implant the stents. After the implantation, the minimal lernen diameter of the artery at the angioplasty site was greater than that obtained with balloon (2.87 +/- 0.67 mm versus 1.83 +/- 1.11 mm, p < 0.001). There was no early restenosis at control angiography at 24 hours (2.78 +/- 0.20 mm versus 2.87 +/- 0.67 mm NS).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7832624 TI - [Evaluation of coronary vasomotricity by intracoronary ultrasonography]. AB - Coronary vasomotion dependent on the endothelium and on the smooth muscle has been intensively studied by quantitative angiography and intracoronary Doppler. Intracoronary ultrasound is a new imaging technique which allows precise measurement of the section of the coronary artery. This study was undertaken to assess the value of intracoronary ultrasound in the investigation of epicardial coronary artery vasomotion. Twenty hypercholesterolaemic patients with irregularity of the arterial lumen on angiography and 6 normo-cholesterolaemic subjects with normal coronary angiogram (control group) were included. An intracoronary ultrasonic catheter with a rotating mirror (4.3 French, CVIS) emitting at 30 MHz was positioned in the proximal segment of a coronary artery. Endothelial function was studied during sympathetic stimulation by a cold pressor test and during increased coronary flow by local injection of papaverine. The intima of the coronary arteries of the patient group was significantly thicker than that of the control group. The cold test induced significant paradoxical vasoconstriction of the atheromatous coronary arteries and a significant vasodilatation of the coronary arteries of the control group. The increased coronary flow tended to constrict the ateromatous arteries but significantly dilated the normal arteries. Administration of Linsidomine (SIN-1) induced vasodilatation by direct relaxation of the smooth muscle in both groups. No correlation was observed between the thickness of the intima measured by intracoronary ultrasound and the abnormal vasomotor response to the vasomotion different stimuli. The results of this study concord with those of studies of coronary by quantitative angiography. Intracoronary ultrasound provides an accurate method of studying coronary endothelial function and the vasomotor tone of the epicardial coronary arteries. PMID- 7832625 TI - [Percutaneous transluminal angioplasty of subclavian, axillary and brachiocephalic trunk arteries. Apropos of 18 patients]. AB - The authors report the immediate and mid term results of percutaneous transluminal angioplasty of stenosis of the subclavian (16 cases), brachiocephalic (1 case) and axillary arteries (1 case) in a series of 18 patients. These lesions were responsible for isolated ischaemia of the arm in 6 cases, vertebrobasilar insufficiency in 6 cases and an association of the two presentations in 2 cases; in 4 asymptomatic patients, the procedure was undertaken to maintain cerebral perfusion. A technical success was obtained in all cases, with one femoral haematoma and one episode of transient visual disturbance, which were spontaneously regressive, as the only complications. The good results were sustained clinically at the end of follow-up (4 to 40 months, average 17.7 months) in 13 of the 14 patients who were followed up. The symptoms recurred after 26 months in the final case which led to the diagnosis of restenosis which was successfully redilated. PMID- 7832626 TI - [Perioperative ischemia in coronary surgery caused by coronary spasm of an angiographically normal coronary artery]. AB - Spasm of healthy native coronary arteries is rare but a serious cause of perioperative ischaemia after coronary bypass surgery. The authors report five characteristic cases. In each case, the spasm presented with giant ST elevation and haemodynamic changes. In one case, further coronary bypass surgery was required. In three cases, symptomatic treatment of the hypotension associated with diltiazem completely cured the problem. One case was complicated by a small myocardial infarction. There were no fatalities. Previously reported cases often describe very heavy therapeutic protocols, justified by the high risks of this condition. Due to the fact that it is not possible to identify a target population, simple prophylactic treatment with diltiazem seems to be justified in patients undergoing coronary artery bypass surgery. PMID- 7832627 TI - [Left-sided His bundle ablation after failure of right-sided approach: technique and initial results]. AB - Although interruption of atrioventricular conduction has been widely used over the last decade in patients with supraventricular arrhythmias and rapid conduction resistant to antiarrhythmic therapy, the incidence of atrioventricular block obtained by delivering the energy at the tricuspid ring ranges from 45 to 92%. Failure of this technique is usually related to the inhability to record endocavitary electrogrammes compatible with probable success by the right-sided approach. The authors report four cases of interruption of atrioventricular conduction in 4 men (average age 61.5 +/- 10 years) by the retrograde arterial catheterisation after one or more (1 to 3) failures by the right-sided approach. After arterial puncture, the ablation catheter is positioned against the interventricular septum below the aortic cusps to record the His bundle electrogram. His bundle ablation was obtained after an average of 2 radio frequency energy applications (range 1 to 3). At the time of effective application, the average amplitude of the endocavitary electrogram was as follows: auriculogram 0.09 mV (range 0.05 to 0.2 mV), His bundle electrogram 0.19 mV (0.15-0.22 mV), ventriculogram 1.36 mV (1.0 to 1.7 mV). No complications were observed. After an average follow-up of 4 months, the 4 patients were still in complete atrioventricular block. This preliminary series shows that left-sided interruption of atrioventricular conduction is effective and safe. It may be proposed after failure of a right-sided attempt. PMID- 7832628 TI - [False pseudoaneurysm of the left ventricle after myocardial infarction. Recognition by transesophageal echocardiography]. AB - Left ventricular pseudo-false aneurysm is caused by a discrete rupture of the myocardial wall which remains circumscribed within the wall itself, realising a cavity joined to the left ventricle by a narrow neck. It is an extremely rare complication of myocardial infarction. Two cases diagnosed in vivo by left ventriculography are reported. Their diagnosis and precise locations were confirmed by transoesophageal echocardiography. In the first case, the pseudo false aneurysm was situated in the interventricular septum and, in the second, in the antero-lateral wall. The natural history of asymptomatic pseudo-false aneurysms is unknown. The advanced age of the patients and the possibility of regular follow-up by transoesophageal echocardiography were the main reasons for surgical abstention in these particular cases. PMID- 7832629 TI - [Angiosarcoma of the pericardium. Apropos of a case]. AB - Malignant primary cardio-pericardial tumours are rare and difficult to diagnose because of the diversity of their clinical expression. The authors report a case of pericardial angiosarcoma and review the literature, underlining the value of new non-invasive imaging techniques in the diagnosis and surgical approach to obtaining histological confirmation. Magnetic resonance imaging is a valuable tool in this context as it allows scanning of the tumoral extension in all spatial planes and the visualisation of the haemorrhagic signs of malignancy the pericardial effusion related to this pathology. PMID- 7832630 TI - [Percutaneous venoplasty for the implantation of a dual-chamber cardiac pacemaker]. AB - During reoperation for pacemaker implantation, venous catheterisation of the homolateral subclavian vein encountered obstruction at the brachiocephalic vein. Balloon angioplasty of the severe brachiocephalic stenosis was performed via the femoral vein. After repeat subclavian venous catheterisation two new pacing wires could be introduced without difficulty followed by active fixation in the atrium and passive fixation in the ventricular apex. The initial ventricular pacing wire was isolated and respected. The femoral vein approach gave simple and direct access to the site of dilatation at a distance to the operative field which was shielded from an infectious risk. The technique and results of percutaneous venous recanalisation have not been extensively analysed during reoperation for cardiac pacing. In chronic cardiac pacing, the success of homolateral operation despite venous occlusion or stenosis, ensures preservation of the venous capital. PMID- 7832631 TI - [Hydatid cyst of the interventricular septum. Apropos of a case]. AB - A cardiac tumour of the interventricular septum was detected in a young woman presenting with an ejectional systolic murmur. Surgical ablation was carried out before a precise diagnosis was made. Histopathological analysis of the surgical specimen confirmed a hydatid cyst. The main complication was complete atrioventricular block. This case underlines the difficulty of making the diagnosis of intracardiac hydatid disease in a non-specific context, because of the long period of clinical latency, despite the considerable aid of echocardiography and other medical imaging techniques (CT scan and magnetic resonance imaging. PMID- 7832632 TI - Analysis of virus-cell binding characteristics on the determination of Japanese encephalitis virus susceptibility. AB - The susceptibility of fourteen established cell lines to infection with Japanese encephalitis virus (JEV) was assayed using an indirect fluorescent antibody technique. In kinetic studies, the degree of binding and internalization of JEV allowed the identification of high susceptibility and low-susceptibility cells. Scatchard analysis showed that JEV specifically bound to high-susceptibility Vero cells with greater affinity than to low-susceptibility NRK cells. Microinjection of viral genomic RNA into NRK cells induced highly efficient production of viral antigen and infectious virions. A hemagglutinin-inhibiting monoclonal antibody against JEV (MAb 301) inhibited the binding of JEV to the Vero and NRK cells. JEV was found to bind to a 74K molecule present in the membrane fraction of Vero cells and this binding was inhibited by MAb 301. Importantly, the 74K molecule was not detected in the membrane faction of NRK cells. These results suggest that early events in the JEV-cell interaction influence the susceptibility of cells to infection, and in particular suggests that the 74K molecule may be a possible candidate or component of the cellular receptor for JEV. PMID- 7832633 TI - Identification of an N-linked glycan in the V1-loop of HIV-1 gp120 influencing neutralization by anti-V3 antibodies and soluble CD4. AB - Glycosylation is necessary for HIV-1 gp120 to attain a functional conformation, and individual N-linked glycans of gp120 are important, but not essential, for replication of HIV-1 in cell culture. We have constructed a mutant HIV-1 infectious clone lacking a signal for N-linked glycosylation in the V1-loop of HIV-1 gp120. Lack of an N-linked glycan was verified by a mobility enhancement of mutant gp120 in SDS-gel electrophoresis. The mutated virus showed no differences in either gp120 content per infectious unit or infectivity, indicating that the N linked glycan was neither essential nor affecting viral infectivity in cell culture. We found that the mutated virus lacking an N-linked glycan in the V1 loop of gp120 was more resistant to neutralization by monoclonal antibodies to the V3-loop and neutralization by soluble recombinant CD4 (sCD4). Both viruses were equally well neutralized by ConA and a conformation dependent human antibody IAM-2G12. This suggests that the N-linked glycan in the V1-loop modulates the three-dimensional conformation of gp120, without changing the overall functional integrity of the molecule. PMID- 7832634 TI - Antibody to HIV-1 Tat protein inhibits the replication of virus in culture. AB - The HIV-1 transactivator protein Tat is essential for viral replication. Tat is released from infected cells and can be taken up and transactivate HIV-LTR in LTR CAT transfected cell lines. The present study shows that the addition of monoclonal antibody to Tat in IIIB and MN-infected cultures reduces the HIV antigen production in a concentration dependent manner. These data suggest that external Tat might be important in the replication of HIV, exerting the effect in a paracrine fashion. Using 1 microgram/ml of anti-Tat antibody resulted in a decline of HIV antigen production to 33% and 45% of controls in IIIB and MN infected H9 cells, respectively. A time course experiment showed progressively increased inhibition of replication during 7 days of exposure to anti-Tat antibody, which could be due to increasing Tat concentration. The inhibitory effect of anti-Tat antibodies on the replication of HIV could play an important regulatory role during infection in vivo. PMID- 7832635 TI - The role of IgG subclass of mouse monoclonal antibodies in antibody-dependent enhancement of feline infectious peritonitis virus infection of feline macrophages. AB - Antibody-dependent enhancement (ADE) of feline infectious peritonitis virus (FIPV) infection was studied in feline alveolar macrophages and human monocyte cell line U937 using mouse neutralizing monoclonal antibodies (MAbs) directed to the spike protein of FIPV. Even among the MAbs that have been shown to recognize the same antigenic site, IgG 2a MAbs enhanced FIPV infection strongly, whereas IgG 1 MAbs did not. These IgG 2a MAbs enhanced the infection even when macrophages pretreated with the MAb were washed and then inoculated with the virus. Immunofluorescence flow cytometric analysis of the macrophages treated with each of the MAbs showed that the IgG 2a MAbs but not the IgG 1 MAbs bound to feline alveolar macrophages. Treatment of the IgG 2a MAb with protein A decreased the binding to the macrophages and, in parallel, diminished the ADE activity. Although no infection was observed by inoculation of FIPV to human monocyte cell line U937 cells, FIPV complexed with either the IgG 2a MAb or the IgG 1 MAb caused infection in U937 cells which are shown to express Fc gamma receptor (Fc gamma R) I and II that can bind mouse IgG 2a and IgG 1, respectively. These results suggest that the enhancing activity of MAb is closely correlated with IgG subclass and that the correlation is involved in binding of MAb to Fc gamma R on feline macrophage. PMID- 7832636 TI - The nucleotide sequence of the 5'non-coding and capsid coding genome regions of two bovine enterovirus strains. AB - The sequence of cDNA clones representing the 5' non-coding regions (NCR) and capsid regions of two bovine enteroviruses (strains PS-87 and RM-2; serotype two viruses) have been determined and compared with that obtained from a serotype one strain (VG-5-27). All three strains showed a longer 5' NCR compared to human enteroviruses and rhinoviruses due in part to a hundred residue insertion approximately at a hundred residues in from the 5' end. However, another domain occurring at nucleotide 187-222 in poliovirus is absent in each bovine enterovirus. Comparisons of the predicted structural protein amino acid sequences indicate that PS-87 shares most sequence identity with RM-2 and then with VG-5-27 in that order. The VP1 protein of PS-87 and RM-2 are shorter than the equivalent VP1 of VG-5-27 due in part to a truncation at their C-terminii. VP3 is only slightly smaller than VP2 in each virus. PMID- 7832637 TI - Concentration and distribution of infectivity and PrPSc following partial denaturation of a mouse-adapted and a hamster-adapted scrapie strain. AB - PrPSc is a specific protein marker for slow infectious diseases known as the transmissible subacute spongiform encephalopathies. Although PrPSc is closely associated with infectivity, it is not known if it is the infectious agent itself, a component of the agent or merely adventitiously associated with infectivity. In the present study we demonstrate that the resistance of PrPSc to partial denaturation and of infectivity to inactivation differs markedly for two scrapie strains. Proteinase K treatment or electrophoretic analysis of partially denatured PrPSc preparations reveal a dissociation between infectivity and demonstrable PrPSc. Our findings support other evidence that not all PrPSc is required for infectivity. Our studies combined with previous biological analyses suggest that PrPSc cannot be the sole component associated with the infectious agent. PMID- 7832638 TI - Decontamination studies with the agents of bovine spongiform encephalopathy and scrapie. AB - Macerates of bovine brain infected with bovine spongiform encephalopathy (BSE) agent, and rodent brain infected with the 263K or ME7 strains of scrapie agent, were subjected to porous-load autoclaving at temperatures between 134 and 138 degrees C for < or = 60 min. Bioassay in rodents showed that none of the regimens produced complete inactivation. Homogenates of BSE-infected bovine brain were exposed for < or = 120 min to solutions of sodium hypochlorite or sodium dichloroisocyanurate containing < or = 16,500 ppm available chlorine. There was no detectable survival of infectivity after the hypochlorite treatments but none of the dichloroisocyanurate solutions produced complete inactivation. Homogenates of BSE-infected bovine brain, and rodent brain infected with the 263K and ME7 strains of scrapie agent, were exposed for < or = 120 min to 1M or 2M sodium hydroxide but no procedure produced complete inactivation of all agents tested. PMID- 7832639 TI - The complete nucleotide sequences of the coat protein cistron and the 3' non coding region of a newly-identified potyvirus infecting sweetpotato, as compared to those of sweetpotato feathery mottle virus. AB - Complementary DNA representing 728 nucleotides of the 3' end of the genomic RNA of sweetpotato virus G (SPV-G) a newly-identified potyvirus infecting sweetpotato, was cloned and sequenced. This sequence was combined with that previously determined for the 5' terminal part of the coat protein cistron of the virus. The whole sequence contained a single open reading frame (ORF) of 1065 nucleotide, with the capacity to encode a coat protein of 355 amino acids, significantly larger than that of other potyviruses. The ORF was followed by an untranslated region of 222 nucleotides and a poly (A) tail. The coat protein of SPV-G was only distantly related to that of known potyviruses, with the exception of sweetpotato feathery mottle virus (SPFMV). Indeed, sequence identity in the C terminal three quarters of the coat protein (more than 80%) and in the 3' untranslated region (more than 70%) indicate that SPV-G should be considered as closely related to, though distinct from SPFMV. This subset relationship is similar to that previously reported for members of the bean yellow mosaic virus subgroup or the bean common mosaic virus subgroup. PMID- 7832640 TI - Isolation and characterization of a novel mutant mouse cell line resistant to Newcastle disease virus: constitutive interferon production and enhanced interferon sensitivity. AB - In our attempt to isolate mutant cell lines resistant to Newcastle disease virus (NDV) we developed an improved procedure for enrichment of NDV-resistant cells from mouse FM3A cells and isolated a novel NDV-resistant mutant cell line, Had-2, with characteristics different from Had-1, a previously reported NDV-receptor deficient mutant strain. Had-2 cells adsorbed NDV normally but the accumulation of viral mRNAs and proteins was inhibited. Had-2 cells had to be grown at higher cell densities in order to be NDV-resistant, and it was revealed that they did not exhibit NDV-resistance when grown at lower cell densities. A conditioned medium prepared from a culture of Had-2 cells grown at high cell density was able to make a low-density culture NDV-resistant. The activity of the conditioned medium to induce NDV-resistance was completely neutralized by addition of both anti interferon (IFN)-alpha and anti IFN-beta antibodies, indicating that Had-2 cells were constitutively releasing IFNs, though their levels were rather low. Had-2 cells were also characterized by an increased sensitivity to IFNs as compared with the parental FM3A cells, since the conditioned medium containing IFNs did not render FM3A cells resistant to NDV. PMID- 7832641 TI - Characterization of three different transgenic mouse lines that carry human poliovirus receptor gene--influence of the transgene expression on pathogenesis. AB - Three transgenic mouse lines, ICR-PVRTg1, ICR-PVRTg5, and ICR-PVRTg21, which are susceptible to poliovirus, have been established by introducing the human gene for poliovirus receptor (PVR) into the genome of mouse strain ICR. Genetic characterizations of the PVR gene were carried out on these mouse lines to define the approximate copy number, insertion site, and expression of the transgene in the central nervous system (CNS). The transgene was integrated in the chromosome 4, 12, and 13 of ICR-PVRTg1, ICR-PVRTg5 and ICR-PVRTg21 mice, respectively, and was stably transmitted to progeny mice. ICR-PVRTg1 appeared to have the most abundant copy numbers of the transgene and showed the highest level of PVR mRNA and membrane associated PVR protein in the CNS among the three mouse lines. Those in ICR-PVRTg21 and ICR-PVRTg5 were at intermediate and lowest levels, respectively. In the CNS, PVR mRNA was detected at high levels only in neurons of the spinal cord and brain stem where poliovirus can replicate, suggesting that the PVR mRNA expression confers cell specificity to poliovirus in the CNS. ICR PVRTg1 and ICR-PVRTg5 showed the highest and the lowest sensitivity to poliovirus, respectively, whereas ICR-PVRTg21 was in-between. These results may suggest that poliovirus sensitivity of the mice is attributed to relative levels of PVR expression. PMID- 7832642 TI - Expression kinetics and subcellular localization of HIV-1 regulatory proteins Nef, Tat and Rev in acutely and chronically infected lymphoid cell lines. AB - Information concerning the expression kinetics and subcellular localization of HIV regulatory proteins is of importance in understanding the viral pathogenesis and may be relevant for drug and vaccine development, as well. We have used combined immunocytochemistry and in situ hybridization to study firstly, the order of expression of regulatory HIV-1 proteins Nef, Rev and Tat in relation to non-spliced and spliced mRNA expression and secondly, the subcellular localization of these proteins in acutely and chronically infected human T-cell lines. We used monoclonal antibodies against HIV-1 Nef, Tat, Rev and gp160, and RNA probes reacting either with all mRNAs (nef) or only with the full-length mRNA (gag-pol). In acutely infected MT-4 and H9 cells, four distinct phases of infection could be defined. In the first phase lasting from 0 to 6 h post infection, only incoming virus could be demonstrated by gp160 immunocytochemistry. During the second, regulatory phase (6-9 h), abundant cytoplasmic expression of Nef, Rev and Tat proteins and a positive in situ RNA hybridization with the nef probe was seen, while the in situ hybridization with full-length mRNA probe and immunohistochemistry for gp160 were still negative. The productive phase (12-48 h) was characterized by abundant expression of full length mRNA and gp160, and by the nuclear localization of Nef and Tat proteins. In contrast, an antibody that recognized the RRE binding region of the Rev protein localized Rev in the cytoplasm both during the regulatory and productive phase. During the fourth, cytopathic phase, the expression of mRNA or viral proteins decreased and the regulatory proteins studied were again mainly localized in the cytoplasm. Based on the results, we speculate that HIV Nef may function as a nuclear factor, and that Tat is possibly bound by cellular proteins before its transport to the nucleus. PMID- 7832643 TI - Hepatitis C virus (HCV) genotype distribution in German isolates: studies on the sequence variability in the E2 and NS5 region. AB - We report on molecular characterization of hepatitis C virus (HCV) isolates in intravenous drug abusers, as compared to non-drug using patients with posttransfusion hepatitis or sporadic hepatitis of unknown origin. Virus typing was performed by RFLP analysis of PCR products in the 5' NCR. Subtyping was done by hybridization with subtype specific probes or by sequencing in the NS4 and NS5 region, respectively. HCV subtype 1b was found most commonly among all the isolates. However, the subtype 3a had a high prevalence (about 46%) in the group of drug addicts. In these subtype 3a isolates the N-terminal part of the E2 protein was highly variable. This confirms the presence of a hypervariable region (HVR1) in this envelope protein found in all hepatitis C viruses. Each subtype 3a isolate examined had a characteristic unique hypervariable region in the E2 protein. It is noteworthy that there are four amino acids in this region which were highly conserved between all HCV sequences published. It can be assumed that such conserved amino acids are significant for structure and function of this viral protein. In our HCV subtype 3a isolates the NS5 sequences were highly conserved. PMID- 7832644 TI - Unusual splice sites in the E1A-E1B cotranscripts synthesized in adenovirus type 40-infected A549 cells. AB - The adenovirus E1 DNA region consists of two transcription units, E1A and E1B. In this paper we report that the E1A-E1B cotranscripts containing sequences of both the E1A and E1B regions are synthesized during adenovirus type 40 (Ad40) infection of A549 cells. Cytoplasmic RNA was isolated from Ad40-infected A549 cells at 24, 72, and 100 h post infection (p.i.). The complementary (c) DNA was synthesized by reverse transcription using an oligo-dT primer and then amplified by the polymerase chain reaction (PCR) using primers derived from the E1A and E1B regions. The cDNAs thus amplified were sequenced either directly or after cloning into bacteriophage M13 vectors. Analysis of cDNA indicated that the E1A-E1B cotranscripts are synthesized at 72 h p.i., but not at 24 or 100 h p.i. Nucleotide sequences of three cDNAs of the E1A-E1B cotranscripts indicated that the cotranscripts originate from the E1A promoter and lack sequences for both the E1A poly(A) site and E1B cap site. The splices create open reading frames for E1A E1B fused polypeptides around the E1A-E1B junctions in these mRNAs. Most interestingly, the sequence analysis showed that the 5' and 3' splice junctions in the two E1A-E1B cotranscripts do not conform to the splice consensus GT-AG rule. Our results thus suggest that factor(s) which lead to unusual splicing in the E1 mRNAs are present in Ad40-infected A549 cells. PMID- 7832645 TI - Sequence variability in the genome-3'-terminal region of BYDV for 10 geographically distinct PAV-like isolates of barley yellow dwarf virus: analysis of the ORF6 variation. AB - Nucleotide sequence of the genome terminal region 3' to the capsid-readthrough cistron were compared for 10 PAV-like isolates of barley yellow dwarf virus (BYDV) from three continents. The sequenced region varied in length from 853 to 864 nucleotides and the extent of sequence homology among the isolates ranged from 84 to 99%. Sequence variations occur mainly in two locations, one in the ORF6 coding region and the other near the genome 3' terminus. Sequence homology grouping reveals three genetically distinct clusters of PAV isolates (A, B and C). Cluster A consists of the Australian isolates, cluster B of one Canadian and three French isolates, and cluster C of the French isolate, RG. Dissimilarities with the corresponding genome-3'- terminal region of the BYDV-MAV serotype were greater than those observed between the PAV isolates alone. Comparison with the sequence of the 3' untranslated region of soybean dwarf virus revealed two stretches of nucleotide similarity, suggesting a common ancestor. Study of the coding ability revealed that the ORF6 is present in all the sequenced PAV isolates but differs in size and deduced amino acids composition. However, the fact that the majority of nucleotide changes are restricted to the third base position of the ORF6-codons suggests that ORF6 codes for a functional protein. PMID- 7832646 TI - A genetic analysis of macrophage activation and specific antibodies in relation to the resistance of heterogeneous mouse populations to MHV3 infection. AB - The genetically selected high antibody responder mice (HIII) are susceptible and the low antibody responder mice (LIII) are resistant to the experimental infection with Mouse Hepatitis Virus 3 (MHV3). The mortality rates of the F1 hybrids and of the F2 segregants showed the codominance of the susceptible and resistant characters. The direct individual intrapopulation correlation between the induction of antiviral state in macrophages activated by IFN gamma and the resistance to the virus infection, showed that an antiviral state could be induced in resistant mouse macrophages, whereas in susceptible mouse macrophages no restriction of virus replication could be observed. A direct inter- and intrapopulation correlation of pre-existing antibody titres against MHV3 with the mortality and a direct interpopulation correlation of those titres with the mean survival time of susceptible animals was shown. The data indicate, among the mechanisms of resistance against the virus infection, a role of IFN gamma macrophage-activation and of antibodies against MHV3 which may delay the mean survival time in susceptible animals. PMID- 7832647 TI - L cell clone developing plaques upon infection with measles virus (Edmonston strain). AB - An L cell clone developing cytopathic plaques upon infection with measles virus (Edmonston strain) was obtained. The sensitivity as measured by the newly devised UV-Vero assay was not significantly different between plaque-forming and non plaque-forming L cell clones. Cytopathogenicity and sensitivity to the virus infection appear to be under different host cell regulations. PMID- 7832648 TI - Mycoplasma stimulates HIV-1 expression from acutely- and dormantly-infected promonocyte/monoblastoid cell lines. AB - Treatment of a myelo-monocyte cell line, J22HL-60, dormantly infected with human immunodeficiency virus type 1 (HIV-1) with heat-inactivated extracts of Acholeplasma (A) laidlawii (250 micrograms/ml) enhanced virus production more than 45-fold as assessed by p24 viral core antigen assay. When treated with a suboptimal dose of TPA or TNF-alpha, Acholeplasma extracts further augmented virus production in J22HL-60 cells. H7, an inhibitor of protein kinase C(PKC), almost completely abrogated HIV-1-inducing ability of Acholeplasma extracts in the cells. A. laidlawii and several other mycoplasmas also enhanced acute infection of U937 cells as shown by increased virus-positive cells and augmentation of HIV-1 production in the culture supernatant independent of their pathogenicity to humans. PMID- 7832650 TI - Do breast implants really produce negative impacts to recipients? PMID- 7832649 TI - Rapid detection of influenza A neuraminidase subtypes by cDNA amplification coupled to a simple DNA enzyme immunoassay. AB - A newly developed colorimetric method, DNA enzyme immunoassay (DEIA), was applied to the detection of neuraminidase subtypes N1 and N2 of influenza A viruses. Reverse transcription and polymerase chain reaction with universal primers were used for genomic amplification of H1N1, H2N2, and H3N2 strains. Following amplification, an aliquot of the PCR product was hybridized to biotinylated DNA sequences (N1/N2 probes) immobilized on microtiter wells. The hybridization event was revealed by monoclonal antibodies to double stranded DNA in a standard ELISA reaction. The assay described here was able to distinguish accurately between the two neuraminidase subtypes of human influenza A viruses. It is a simple and rapid method facilitating the handling of a large number of samples and therefore seems to be easily applicable to diagnostic laboratories. PMID- 7832651 TI - Hastings lecture, December 10, 1993, Rockville, Maryland, U.S.A. PMID- 7832653 TI - The decline in serum albumin after conversion to high flux, high efficiency dialysis. AB - Hypoalbuminemia among chronic hemodialysis patients is recognized as a poor prognostic sign. We observed that many of our chronic patients had a progressive decrease in their plasma albumin concentrations after they were converted to high flux, high efficiency dialysis from conventional dialysis mode. This change occurred in the absence of changes in the KT/V and protein catabolic rate (pcr) normalized to body mass. When nitrogen losses were measured, we found no difference in the dialysate concentrations of urea, alpha amino nitrogen, uric acid, or total nitrogen when high flux polysulfone was compared with high efficiency Cuprophan. While urea was the predominant nitrogen solute in all dialysate samples, there were some with a large gap between total and urea nitrogen. Alpha amino nitrogen losses, expressed as leucine equivalents, were substantial, ranging from 8.4 to 9.8 g/3.5 h dialysis treatment. We believe that the increased losses of nitrogen experienced by patients after their conversion to a more efficient method of dialysis and not compensated for by a spontaneous increased intake of protein led to the observed fall in plasma albumin. Both urea and amino acid nitrogen losses need to be accounted for when achievement of higher KT/V dialysis is pursued. PMID- 7832652 TI - Adsorption of human recombinant erythropoietin on dialysis membranes in vitro. AB - The adsorptive characteristics of 5 dialysis membranes for recombinant human erythropoietin (EPO) were studied in vitro in a closed circuit system. For 120 min, EPO added with bovine serum was significantly adsorbed by polymethylmethacrylate (PMMA) and polyacrylonitrile (PAN) membranes but not by Cuprophan, ethylene vinyl alcohol (EVAL), or polysulfone (PS) membranes. In addition the EPO adsorptive rate, as well as that of beta 2-microglobulin (beta 2 MG), was greater with a PMMA membrane than with a PAN membrane. EPO was not detected in the ultrafiltrate at 15 min with 5 membranes. These results indicate that EPO was eliminated by membrane adsorption only with some dialysis membranes. PMID- 7832654 TI - In vitro and in vivo evaluation of protamine-heparin membrane for microencapsulation of rat Langerhans islets. AB - Rat pancreatic islets were microencapsulated with multilayer protamine-heparin (PH) membrane. Basal and stimulatory insulin secretion of microencapsulated islets was similar to the controlled free islets in vitro. During the long-term culture (up to 2 weeks) mean insulin release of encapsulated islets did not significantly differ from the mean of free ones (the ratio of mentioned means was 54-167%). Empty PH microcapsules transplanted into Wistar rats intraperitoneally and under the kidney capsule were generally harmless up to 4 months. In only a few cases traces of fibrotic tissue around capsules entrapped in the omentum were found. No damage of microcapsules structure was observed. The worst results were obtained in the instance of retroperitoneal transplantation. We conclude, therefore, that PH membrane was proved to be highly biocompatible, nontoxic for islets, and did not impair viability and glucose-dependent insulin secretion of Langerhans islets in in vitro culture. PMID- 7832655 TI - Preliminary study on the effect of substrate size on cellular immunomodulations. AB - It is well known that the adsorption behavior of lymphocytes on fiber materials is related to the fiber size. In our previous study, murine lymphocytes cultured on various sizes of fibers showed different interleukin 2 (IL-2) activity, and ultrafine fibers of 1.5 microns showed the highest value. Based upon those results and to further evaluate the effects of fibers of different sizes on the modulation of lymphocyte functions, Concanavalin A (Con A) was immobilized on the surface of fibers having different diameters, and murine lymphocytes were cultured on these fibers. Fiber size effects on the lymphocytes were evaluated in terms of IL-2 production and adhesion morphology. The Con A immobilized fibers could stimulate lymphocytes to levels as high as 70-80% of the maximal value induced by the Con A solution. Statistical differences in IL-2 production were not observed among the fiber sizes although as fibers decreased in size, the contact area of the lymphocytes with fibers became smaller. The results suggest that smaller diameter fibers with less contact to adherent lymphocytes can affect lymphocyte function to similar extents on larger diameter fibers and that ultrafine fibers might be useful substrates for immobilizing immunomodulators. PMID- 7832656 TI - Comparative study of five types of IABP balloons in terms of incidence of balloon rupture and other complications: a multi-institutional study. AB - The Multi-Institutional IABP Balloon Study Group in Japan (14 institutions) conducted a retrospective nonrandomized study to elucidate the incidence and type of IABP balloon-related complications relative to design and durability of five different clinically available balloons: TMP (n = 960), Kontron (n = 943). Datascope (n = 485), Mansfield (n = 226), and Aries (n = 189) balloons. A total of 2,803 patients (1,973 males, 830 females, mean age 62.1 years) spent a total of 243,856 h on the pump. Forty-nine balloons (1.7%) ruptured as recognized by the appearance of blood in the catheter (39 cases) or console alarm (4 cases). Ten patients required surgical removal of the balloon due to entrapment. Other IABP balloon-related complications requiring surgical intervention or with a lethal outcome occurred in 89 patients (3.2%). They included lower limb ischemia (61 cases), hematoma (11 cases), extensive dissection (6 cases), perforation (5 cases), entrapment without balloon rupture (3 cases), and mesenteric infarction (3 cases). The incidence of rupture, other major complications, and total complications, respectively, for each balloon was 0, 2.7, and 2.7 for TMP, 1.6, 4.3, and 5.9% for Kontron, 4.1, 1.9, and 6.0% for Datascope, 1.3, 2.7, and 4.0% for Mansfield, and 5.8, 3.7, and 9.5% for Aries. In conclusion, the TMP balloon demonstrates a significantly lower rate of rupture while the incidence of other complications for the 5 balloons is not significantly different. PMID- 7832657 TI - Prevention of calcification of tissue valves. AB - In this study an attempt was made to find an optimum method of chemical treatment to prevent the calcification of bioprosthetic heart valves. Bovine pericardium was washed in a 5% sodium chloride solution followed by trypsin (Tr) treatment and was kept in 0.1% glutaraldehyde (GA) with a gradual increase in concentration up to 0.25% GA and finally posttreated with a 4% chitosan (Ch) solution. Fresh, 0.2% GA, 0.625% GA, and sodium chloride-Tr-GA treated pericardial samples were taken for comparative study. Tensile testing showed comparable strength and elongation at the breaking point for all groups. The thermal shrinkage studies indicated merit of the proposed treatment (5% sodium chloride-trypsin glutaraldehyde treated pericardia with chitosan and without chitosan posttreatment). Collagenase assay showed that all differently treated (GA) materials were equally resistant to collagenase. All samples were implanted subcutaneously in rats for 2, 4, 8, or 12 weeks for calcification study. Morphological and mineral analyses showed complete prevention of calcification in sodium chloride-trypsin-GA-chitosan treated pericardium (Ca was 1.1 +/- 0.27 mg/g, von Kossa 0) at the 12th week of implantation. PMID- 7832658 TI - Cavitation dynamics of mechanical heart valve prostheses. AB - Nine different mechanical mitral heart valves were chosen in order to study cavitation dynamics in detail in an in vitro flow system simulating a single event of mitral valve closure. The transvalvular pressure (ventricular minus atrial pressure) rise rate averaged during the valve closing period was used as an index of the loading rate. A series of photographs in the vicinity of the inflow surface of the valve were attempted during the bubble appearance period using a stroboscopic visualization technique. The in vitro study revealed three sources of cavitation initiation in the design of the mechanical heart valves tested: stop (seat stop or seating lip), inflow strut, and clearance (gap formed between the occluder and the housing or between the two occluders in the closed position). Among these, the occluder stop design was the most critical to cavitation since all valves having the stop at the edge of the major orifice area showed a higher intensity of cavitation and threshold loading rates below the estimated normal physiological value. The analysis of bubble locations and dynamics led us to propose that the fluid squeezing effect between the occluder and the stop in the housing and the streamline contraction effect along the clearance are factors responsible for cavitation incipience. PMID- 7832659 TI - Extraction of serum proteins adsorbed on the surface of dialysis membranes. AB - Extraction of adsorbed proteins from dialysis membranes that had been used during actual hemodialysis procedures was performed. The condition of extraction with SDS plus 2-mercaptoethanol at 95 degrees C is more efficient than with only PBS or with SDS solution without 2-mercaptoethanol at 37 degrees C. PMID- 7832660 TI - Use of hemoperfusion in experimental intoxication with nerve agents. AB - The aim of this study was to evaluate the efficiency of hemoperfusion (HP) through coated resin adsorbent Synachrom E-5 in animal intoxications with organophosphate inhibitors of cholinesterases type of nerve agents. Five anesthetized dogs were intoxicated with 2 to 6 LD50 of VX substance and another 4 with 2 to 3 LD50 sarine. Both nerve agents were given i.m. after starting 5 h HP. The clinical and laboratory tests were monitored during each HP. HP therapy prevented the development of serious signs of intoxication provided that the administered quantity of both sarine and the VX substance was only 2 doses of LD50. Specific antidote therapy was necessary to prevent cardiorespiratory failure in animals intoxicated with a higher dose of poison. The results obtained show that HP through Synachrom E-5 in intoxication with nerve agents sarine and the VX type is only partially successful. PMID- 7832661 TI - The effect of stimulating voltage on time characteristics of contraction in cardiomyoplasty. AB - In cardiomyoplasty (CMP), the strength of a skeletal muscle increases as the stimulating voltage increases. On the other hand, timing of stimulation in CMP is a problem not yet solved. This experiment assessed the relationship between stimulating voltage and time characteristics in the contraction of skeletal muscles. In acute experiments using rabbits, the time required to reach maximal muscle contraction did not change significantly with voltage. In conclusion, stimulation voltage does not affect time characteristics. Thus, the best timing of stimulation in CMP can be assessed independently of voltage. PMID- 7832662 TI - Fluctuations of the sympathetic nerve discharges in animals without natural heartbeat. AB - To assess the effect of artificial circulation on the circulatory regulatory system, rhythmical fluctuations in the cardiovascular system and autonomic nerve discharges were analyzed in animal experiments using adult mongrel dogs. Two pneumatically actuated ventricular assist devices were implanted as total biventricular bypass (BVB) under general anesthesia; then, the natural heart was electrically fibrillated to constitute the BVB part of the complete prosthetic circulation model. All hemodynamic data and sympathetic nerve discharges were recorded and calculated in the computer system by the use of spectral analyzing methods. In the power spectrum of the arterial blood pressure waveform during prosthetic circulation, the Mayer wave peak was significantly decreased though the respiratory wave peak was not significantly changed. However, the Mayer wave peak in sympathetic nerve discharges was significantly increased though the respiratory wave peak was not significantly changed. These results suggest that rhythmical fluctuations are a necessary response of the circulatory regulatory system including the autonomic nervous system. However, sympathetic nerve discharges respond to the artificial heart without rhythmical fluctuations. PMID- 7832663 TI - The present status of assisted reproductive technology in Asia-Oceania. AB - This is a survey on the present status of assisted reproductive technology in the Asia-Oceanic region. The survey formats were sent to the 19-member societies of AOFOG. By the end of August 1991, 11 countries responded: Australia, Egypt, Hong Kong, Israel, Japan, Malaysia, New Zealand, Philippines, Republic of China, Singapore and Thailand. This report is a summary of data from 12 countries including Korea. It comprised of 14 headings: IVF, GIFT, AIH, AID, donor sperm in ART, donor eggs in ART, preembryos from IVF for donation, cryopreservation of eggs, cryopreservation of fertilized eggs and preembryos, research of preembryos, surrogate mothers, additional procedures, quality assurance in reproductive technology and formation of policy for emerging reproductive technology. Each heading is composed of status of regulations, cost and coverage and the results and management of program. PMID- 7832664 TI - Breast metastasis from primary cervical cancer. AB - Metastasis to the breast from primary cervical cancer is rare. A 52-year-old woman developed breast metastasis 6 months after the diagnosis of primary cervical cancer. The mammography showed discrete well defined nodules without microcalcification. Fine needle aspiration cytology confirmed the diagnosis. Treatment with cis-platinum chemotherapy and local radiotherapy resulted in complete response. The patient continues to be alive and disease-free 18 months since the diagnosis of breast metastasis. PMID- 7832665 TI - Fetal bladder outlet obstruction diagnosed at 13-weeks' gestation. AB - An ultrasonographic examination revealed increased fetal bladder size as well as fetal bilateral hydronephrosis at 13-weeks' gestation. Diagnosis of the fetal urethral obstruction was made. Repeated ultrasonography was undertaken from the 13th to through 16th weeks of gestation. Percutaneous puncture with aspiration and laboratory analysis of fetal urine was performed at 15-weeks' gestation. The fetal renal function seemed not to be damaged by use of these antenatal procedures. Following induced abortion at 16-weeks' gestation, an autopsy showed that the fetal urethral obstruction was caused by a posterior valve, with no histological evidence of fetal renal dysplasia. PMID- 7832666 TI - Management of an infected urachal cyst during pregnancy. AB - An infected urachal cyst complicating a pregnancy is extremely rare, but is considered to present a high risk to both the mother and the fetus. We treated a patient with an infected urachal cyst diagnosed at 29 weeks of gestation. A healthy infant was delivered by cesarean section at 37 weeks of gestation. The patient underwent excision of the unruptured cyst 37 days later. This is the first reported case of an infected urachal cyst complicating a pregnancy, that was diagnosed before rupture and was managed without serious sequelae for either the mother or the fetus. The diagnosis and management of the infected urachal cyst complicating the pregnancy is discussed. PMID- 7832667 TI - Hepatitis-B vaccination in pregnancy: safety and immunogenic response in mothers and antibody transfer to neonates. AB - Hepatitis B infection during pregnancy causes increased, maternal morbidity and perinatal mortality. No specific therapy is available, hence neonatal immunoprophylaxis is recommended by WHO. However, the advantages of maternal immunization are manifold. Therefore, 15 pregnant HBsAg negative women were studied after 3 dozes of hepatitis B specific vaccine. No untoward effects of vaccine were observed and a good immunogenic response with very high antibody titres 178 IU/l and 184 IU/l at delivery and 3 months post delivery respectively were noted. Passive transfer of antibodies to the neonates was 100% at birth but these levels declined rapidly. Hence hepatitis B specific vaccine is safe and immunogenic in pregnant women and protects their babies in the immediate neonatal period. PMID- 7832668 TI - Choriocarcinoma in a term placenta with pulmonary metastasis. AB - This is a case report of choriocarcinoma in the placenta of a patient who had a term delivery at the 38th week of pregnancy. The pregnant woman had hemoptysis at the 26th week of pregnancy, and a chest X-ray revealed a tumor in the left lung. She had suffered from a hydatidiform mole in a previous pregnancy in 1989. The patient's serum level of beta-human chorionic gonadotropin (hCG) had been below the normal level before the present pregnancy. Choriocarcinoma was histologically found at 3 sites in the placenta. Her urine hCG levels decreased rapidly after delivery. A partial lobectomy was performed after 2 courses of chemotherapy, and no choriocarcinoma was recognized histologically, because the lesions were hemorrhagic and necrotic. At present, the mother is free of disease, and the baby is growing normally. The placenta should be examined in a detail in post-molar pregnancy. PMID- 7832669 TI - Development of an effective and simple insemination method for the in vitro fertilization of patients with male-factor infertility. AB - An insemination method involving mechanical removal of the cumulus and multiple oocytes per dish (MRC-MOPD) was applied to achieve in vitro fertilization (IVF) of patients with male-factor infertility, and the prognosis of IVF and embryo transfer was evaluated. Although the fertilization rate of patients with male factor infertility was only 41.4% (12/29) using standard insemination methods, a 73.0% (27/37) fertilization rate was achieved with the MRC-MOPD method. Moreover, 10 patients with male-factor infertility who were treated with the MRC-COPD method achieved clinical pregnancy. A comparison of the results in the 10 patients who were treated with both methods in common reveals that the MRC-MOPD method also increased the fertilization rate per oocyte. The rate of occurrence of polyploid fertilization did not increase, although large numbers of sperm were inseminated via the MRC-MOPD method. These results indicate that the MRC-MOPD method is an effective and simple insemination technique to achieve successful IVF of patients with male-factor infertility. PMID- 7832670 TI - Pregnancy outcome and mitral valve prolapse. AB - Mitral valve prolapse (MVP) comprises a large proportion of obstetric cardiac problems and has a general prevalence of 4%. We examined the obstetric outcome of patients with MVP delivered between 1988-1991 at the National University Hospital, Singapore. During this interval, deliveries totalled 16,755 of which 85 (0.51%) had maternal cardiac disease. Of these, 28 (32.9%) had echocardiographic evidence of non-myxomatous MVP. Ten patients (37.5%) had demonstrable mitral regurgitation and 4 (14.3%) had benign ventricular ectopics. All patients remained well throughout pregnancy. Gestation at delivery and use of analgesia did not differ significantly from non-cardiac patients. However, the labour induction rate was twice the department average at 17.9%. Twenty-four (85.7%) patients achieved vaginal delivery and 4 (14.3%) patients were delivered abdominally. All babies were liveborn. Eight patients (28.6%) did not receive antibiotic prophylaxis during labour and postpartum period and remained afebrile. The role of antibiotics in this category of patients is discussed. Patients with MVP without myxomatous valve changes may expect excellent pregnancy outcome. PMID- 7832671 TI - The predictive value of extremes of birth weight, mother's height and ethnic origin on the likelihood of emergency caesarean section. AB - We reviewed the deliveries in a teaching hospital in a multiracial community over the period of one year (1988), and investigated the relationship between maternal height, ethnic origin, and the extremes of birth weight with the likelihood of emergency lower segment caesarean section (LSCS). After excluding patients with obvious indications for LSCS, 5,050 patients were entered in the study. Chi square analysis showed that the risk of emergency LSCS is significantly higher in the Indians compared to Chinese and Malays, but does not differ significantly between the latter two groups. Logistic regression analysis showed that birth weight of less than 2,500 g or greater than 3,500 g is the most significant association with emergency LSCS rate. Conditional logistic regression showed that, provided the individuals conformed to the characteristics of the cohort in this study, risk of emergency LSCS for a 150 cm (25th centile) tall Indian pregnant lady is almost twice that of a 158 cm (75th centile) tall non-Indian). PMID- 7832672 TI - Determinants of birth weight in Vietnamese detainees in Hong Kong. AB - Five hundred and fifty singleton pregnancies amongst Vietnamese Boat People delivering between January and December 1993 were studied post-natally. Multiple regression analysis showed no direct effect of ethnic origin on birth weight. When analyses were repeated on the two main ethnic subgroups we found that, amongst Anamese patients, both gestation at delivery and birth weight independently increased with longer duration of stay in Hong Kong. This relationship was not seen in Vietnamese patients of Chinese ethnic origin. Possible reasons for these different relationships are discussed. PMID- 7832673 TI - The value of a single sensitive urine pregnancy test in prediction of pregnancy outcome. AB - A simple and reliable indicator for pregnancy outcome will be valuable clinically for patient management and for counselling women whose pregnancies are results of subfertility treatment. This study aimed at evaluating the ICON II test, a simple semiquantitative sensitive urine pregnancy test, in predicting pregnancy outcome in women who conceived after various forms of subfertility treatment. The ICON II test was performed on day 20 after the ovulating dose of hCG administration or spontaneous LH surge. One hundred and forty-five consecutive pregnancies were studied, 99 being viable and 46 nonviable which included subclinical abortion, clinical abortion and ectopic pregnancies. There was a significant difference in the luteal serum progesterone and hCG levels between viable and nonviable pregnancies. There was also a significant difference in the ICON II test result, i.e. either weakly positive (hCG of 25-50 IU/l) and positive (hCG > 50 IU/l) and the pregnancy outcome (p < 0.0001). The specificity of a weakly positive ICON II test in predicting poor pregnancy outcome was 98.8% whereas the sensitivity was 28.6%. In conclusion, a weakly positive ICON II test is useful in predicting poor pregnancy outcome. PMID- 7832674 TI - Trial of vaginal birth following cesarean section for arrest disorders of labor: analysis of patients with well-documented medical records. AB - We elucidated several controversial problems surrounding the vaginal trial in patients with prior abdominal delivery under the diagnosis of failure to progress or cephalopelvic disproportion, by conducting a prospective 6-year survey on the basis of patients who underwent prior operation for arrest disorders of labor (ADL). Of 45 full-term women who were defined as patients of prior ADL following a review of their past medical records, 28 patients underwent trial of labor and 75% (21/28) were successfully delivered of their infants vaginally. The seemingly critical determinants as to whether or not a vaginal birth is successful are the difference in neonatal weights between prior and current pregnancies as well as the difference between maternal obstetric conjugate and fetal biparietal diameter. These data suggest that patients who underwent prior cesarean section for indications of ADL have a high chance of safely succeeding if given a trial of labor under certain exclusionary criteria. PMID- 7832675 TI - Causes and factors affecting perinatal mortality at Princess Basma Teaching Hospital in North Jordan. AB - This is the first study about the perinatal mortality in North Jordan. Between 1st June 1991 and 31st May 1992, 8,146 deliveries took place at Princess Basma Teaching Hospital. There were 250 perinatal deaths comprised of 124 stillbirths and 126 early neonatal deaths. The perinatal mortality rate was 30.6 per 1,000. The factors which might have affected this rate were mainly prematurity, low birth weight, unexplained intrauterine fetal death, and congenital malformations. The possible ways of improving the results are discussed. PMID- 7832676 TI - Activities of phospholipase A2, cyclooxygenase, and PGI2 synthase of umbilical venous endothelial cells in preeclamptic women. AB - To elucidate the cause of low prostacyclin (PGI2) production in severe preeclampsia (PE), we studied the activities of phospholipase A2, cyclooxygenase, and PGI2 synthase in umbilical venous endothelial cells obtained from healthy pregnant women and from patients with mild or severe PE. Umbilical venous endothelial cells homogenized in a buffer solution were analysed by calculating the apparent Vmax (mean +/- SEM: p mol/min mg protein) and Km (mean +/- SEM: microM) values for phospholipase A2 activity by the release of arachidonic acid from phosphatidylcholine, for the activity of a complex of cyclooxygenase and PGI2 synthase by the conversion of arachidonic acid to PGI2, and the activity of PGI2 synthase by conversion of PGH2 to PGI2. The phospholipase A2 activity of normal-pregnancy cells (Vmax: 17.0 +/- 2.7 Km: 0.26 +/- 0.04) (n = 10) significantly exceeded that of cells from women with either mild PE (5.8 +/- 0.5, 0.12 +/- 0.02) (n = 4) or severe PE (6.3 +/- 2.0, 0.08 +/- 0.03) (n = 5). The apparent combined activity of cyclooxygenase and PGI2 synthase in mild PE (552 +/ 142, 0.29 +/- 0.07) (n = 8) significantly exceeded that of a normal pregnancy (176 +/- 42, 0.76 +/- 0.25) (n = 7), whereas that in severe PE (326 +/- 36, 3.26 +/- 0.78) (n = 3) was significantly lower than that of a normal pregnancy. PGI2 synthase activity in mild PE (305 +/- 50, 0.12 +/- 0.07) (n = 4) exceeded that of a normal pregnancy (220 +/- 45, 0.13 +/- 0.06) (n = 5), whereas that in severe PE (55 +/- 12, 0.16 +/- 0.04) (n = 3) was lower than that of a normal pregnancy. The phospholipase A2 activity in cells of normal pregnant women exceeded that of cells of women with mild or severe PE. The combined activity of cyclooxygenase and PGI2 synthase in a normal pregnancy was lower than in mild PE, but higher than in severe PE. Similar results were found for PGI2 synthase activity; in normal pregnancy the activity was less than in mild PE, but higher than in severe PE.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7832677 TI - Macrophage activation factors and cytokines in peritoneal fluid from patients with endometriosis. AB - Endometriosis is often associated with infertility, which might be a consequence of intraperitoneal macrophage activation and various immunological events related to it. To determine what triggers macrophage activation and what immunologic conditions occur in the peritoneal cavity of a patient with endometriosis, we measured the amounts of phospholipase A2, cholesterol fractions (HDL, LDL, and VLDL), interleukins (IL)-1 and 6, granulocyte-macrophage-colony stimulating factor (GM-CSF), and phosphatidylserine in peritoneal fluid. Peritoneal-fluid samples were collected during laparoscopy or laparotomy from 14 patients with endometriosis and from 11 patients with other diseases (5 with myoma uteri, 5 with benign ovarian cysts and 1 with a double uterus) as controls. With regard to phospholipase A2, there were no significant differences between the endometriosis group and the control group. LDL was significantly lower in the endometriosis group than in the control (p < 0.05). The levels of IL-1 and GM-CSF were similar in both groups; IL-6, however, was higher in 7 endometriosis patients with associated infertility than in the 9 non-endometriosis fertile patients. These findings suggest that inflammatory tissues are not related to the activation of intraperitoneal macrophages in endometriosis patients. Cholesterol fractions (HDL or LDL) might participate in macrophage activation in these patients, but this remains to be clarified. The high IL-6 levels observed in infertile endometriosis suggest that some immunological events that prevent patients from becoming pregnant take place in women with endometriosis-associated infertility. PMID- 7832678 TI - Suppression of plasma glutathione peroxidase activity by ifosfamide. AB - Plasma glutathione peroxidase (GPx) is synthesized predominantly in the kidneys. Plasma-GPx activities were measured in 12 patients with gynecological malignancies before and after chemotherapy. The patients were treated with cisplatin alone (P); with VP16 and cisplatin (EP); with cyclophosphamide, doxorubicin, and cisplatin (CAP); or with ifosfamide, doxorubicin, and cisplatin (IAP). The protein levels of the enzyme were semi-quantitatively determined by immuno-blot analysis. Plasma GPx activity was decreased by an average of 61% (p < 0.01) in patients treated with IAP, while no significant decreases were observed in patients treated with any drug combinations without ifosfamide. Immuno-blot analysis of plasma samples from a patient treated with IAP revealed no differences in the protein levels of plasma GPx either before or after IAP administration, although the plasma GPx activity decreased 83%, from 0.173 to 0.029 units/ml. The results indicate that the decrease in plasma GPx activity was not due to impaired production of the enzyme in the kidneys, and that ifosfamide is responsible for inhibition of the enzyme activity. Since GPx is an enzyme of major importance in detoxification of lipid peroxides in the brain, CNS toxicity induced by ifosfamide might be related to severe suppression of plasma GPx activity. PMID- 7832679 TI - Observations in Australia of the use of glass ionomer cement restorative material. AB - The aim of this study was to evaluate, with the aid of a questionnaire distributed to selected groups of dentists, the use of glass ionomer cement in different types of proximal restorations and further to evaluate any complications observed with the use of GIC. Few dentists responded in the 'Often' category regarding the observation of secondary caries or gingival inflammation in association with GIC fillings compared with about three-quarters of the dentists who reported on posterior composite resin restorations. Tunnel cavities had been prepared and restored by 54 per cent of the dentists, simple proximal restorations in primary molars by 89 per cent and 'sandwich' restorations by 69 per cent. Few dentists with at least two years experience with tunnel restorations observed biological complications, but fracture of the marginal ridge was reported in the 'Often' category by 12 per cent. Among the dentists with at least five years experience with proximal restorations in primary molars 59 per cent of the operators mentioned more complications with these than with amalgam restorations. Biological complications were not a great problem with glass ionomer/composite laminates but wear or dissolution of the proximal GIC surface was recorded in the 'Often' section by 14 per cent of those placing them. PMID- 7832680 TI - Clinical behaviour over three years of GS-80 and Lojic+ amalgam alloys. AB - The clinical performance of GS-80 and Lojic+amalgam alloys was compared with that of Dispersalloy, Valiant PhD, Lojic N and Permite C amalgam alloys over periods of up to three years. The 1114 restorations were placed by one dentist in 23 canine, 418 premolar and 673 molar permanent teeth of 301 adult patients treated in a private practice. Direct and indirect clinical assessments were made of the restorations for failures (there were no true failures), and for the deterioration of four clinical factors. All restorations were rated as being either 'good' (A) or 'adequate' (B) for each of the four factors which, apart from surface texture, showed some slight but statistically-significant clinical deterioration with time. Lojic+ and Permite C showed clinically slight but statistically more surface roughness and marginal fracture, while Lojic+ and GS 80 showed more surface tarnishing, than did the other alloys. There were no statistically significant differences between the alloys for marginal staining. PMID- 7832681 TI - The effect of investment type on the fit of cast titanium crowns. AB - In order to determine the best laboratory procedure for titanium crown casting, a set of thermal expansion measurements and casting experiments were carried out using a casting machine (argon arc, pressure difference type) and three different investments, two conventional SiO2 based investments and a new Al2O3/MgO based investment. The thermal expansion measurements involved a cycle of heating and cooling. The relatively low mould temperatures recommended (200 degrees C) or chosen (350 degrees C) for the conventional investments provided zero or negative mould expansion for the compensation of metal shrinkage. Crowns made from these investments exhibited heavy reaction with the mould, and the common cleaning method of sand blasting appeared to be essential. This cleaning process, however, was not adequate for the assessment of casting accuracy as the short sand blasting time (15 s) rapidly altered the fit of the crowns. The metal reacted little with the new investment and the best compensation (0.15 mm discrepancy) for the metal shrinkage, as assessed 'as cast', was achieved when the investment was heated to 950 degrees C and then cooled to the recommended mould temperature (600 degrees C). PMID- 7832682 TI - Low level laser therapy for dentinal tooth hypersensitivity. AB - A comparative double blind study testing low level laser therapy (Gallium/Aluminium/Arsenide laser [GaAlAs]) against placebo was carried out in the management of dentinal tooth hypersensitivity. Subjects demonstrating dentinal hypersensitivity and complying with strict selection criteria were randomly assigned to an active and placebo group. Low level laser therapy was applied for one minute to both the apex and cervical area of the tooth; and reapplied at one week, two-week and eight-week intervals. Dentinal hypersensitivity was rated at each visit. There were 28 subjects in the placebo group and 22 and 21 subjects, respectively, in the tactile sensitivity and thermal sensitivity groups. Comparisons between the groups were conducted using independent groups t-test. In both the tactile and thermal sensitivity groups differences between the active and placebo groups were significant from the first week and increased further in the second and eighth weeks. The mean value of thermal sensitivity decreased 67 per cent (p < 0.001) compared with placebo (17 per cent) and tactile sensitivity decreased 65 per cent (p = .002) compared with placebo (21 per cent) at eight weeks. Results demonstrate that the GaAlAs laser is an effective method for the treatment of both thermal and tactile dentinal hypersensitivity. There were no reported adverse reactions or instances of oral irritation. PMID- 7832683 TI - Social impact of oral conditions among older adults. AB - Oral symptoms and their effects on well-being provide an indication of the social impact of oral disease and can be used to document the burden of illness within populations. This report presents findings about the social impact of oral disease among a random sample of 1217 non-institutionalized persons aged 60 years and over living in Adelaide and Mt Gambier. They completed a questionnaire containing 49 questions about the effect of oral conditions on dysfunction, discomfort and disability. Over 5 per cent of dentate persons and over 10 per cent of edentulous persons reported impacts such as difficulty in chewing, discomfort during eating and avoidance of foods 'fairly often' or 'very often' during the previous 12 months. Impacts on social roles and interpersonal relationships were reported by up to 5 per cent of persons. Edentulous persons reported social impact more frequently, particularly in areas related to chewing and eating. Older age was associated with significantly greater amounts of impact among dentate persons, while edentulous males reported significantly more impact than edentulous females. There were larger variations among dentate persons according to their dental utilization patterns, with the highest levels of impact reported by individuals who usually attended for dental problems and who had attended the previous year. The high frequency of social impact reported in this study no doubt reflects extensive levels of disease experience, including high rates of missing teeth and edentulism, among older adults. PMID- 7832684 TI - Perceptions of denture aesthetics: a two-centre study of denture wearers and denture providers. AB - A study into perceptions of complete dentures was carried out in two dental schools, one in Australia and the other in England. Two-hundred participants were asked to assess photographs of five sets of dentures for age, gender and personality. Results were subjected to a multi-rater kappa statistic. Although no centre was determined to be better than the other, it was highly significant that Australian teachers were confident enough to state that they were unable to determine age or gender from the information supplied. PMID- 7832685 TI - Lingual mandibular bone defect. Case report and review of the literature. AB - An unusual case of lingual mandibular bone defect (Stafne's bone cavity) is presented in which the lesion extended to above the inferior dental canal and caused expansion of the buccal cortical plate. The literature is reviewed with regard to the incidence, plausible aetiologic factors and methods of investigation of such lesions. PMID- 7832686 TI - Mouthguard protection in sports injury. Case report. PMID- 7832687 TI - Nursing caries: literature review and report of a case managed under local anaesthesia. AB - Although the prevalence of dental caries in children has fallen in recent years, significant numbers of children are still treated for nursing caries. This form of rampant caries affects the primary dentition and causes rapid destruction of normally resistant surfaces. The treatment of nursing caries is multifactorial, involving the child, parents, dental team and other health care providers to ensure the restorative dental treatment is supported by parental education in caries prevention, oral hygiene and infant nutrition. This paper presents a literature review on the condition, followed by a case report of a child with nursing caries treated in the clinic under local anaesthesia. PMID- 7832688 TI - Development of the Diploma in Clinical Dentistry (Conscious Sedation and Pain Control) Faculty of Dentistry, University of Sydney. AB - The Diploma in Clinical Dentistry (Conscious Sedation and Pain Control) of the Faculty of Dentistry, University of Sydney, is the first dedicated programme devoted to this field in Australia. Its development followed a decision by the Dental Board of New South Wales to require a formal qualification from the University of Sydney before dental practitioners could offer sedation and pain management in practice. The programme is conducted at Westmead Hospital in conjunction with the Department of Anaesthetics, and satisfies the guidelines developed by the Royal Australasian College of Dental Surgeons and the Royal Australasian College of Surgeons. The course is conducted either over one or two years, with block sessions requiring attendance at Westmead Hospital, together with assignments which are completed outside the block sessions. In this way, a dental practitioner enrolled in the programme is able to continue practice. The block sessions need not be completed over one year, but must be completed within two years. PMID- 7832689 TI - Charity begins at home--or does it? PMID- 7832690 TI - Why is dentistry not appreciated? PMID- 7832691 TI - Altered colonizing ability for the ceca of broiler chicks by lipopolysaccharide deficient mutants of Salmonella typhimurium. AB - Salmonella typhimurium strain 3333/O was used to assess the role of bacterial lipopolysaccharide (LPS) in intestinal colonization of broiler chicks by salmonellae. LPS-defective TnPhoA mutants of this strain were isolated. The sensitivities of the mutants to smooth and rough phages and LPS banding patterns in sodium dodecyl sulfate-polyacrylamide gel electrophoresis indicated a defect in the polysaccharide side chain of the LPS molecule. Colonization was determined by orally administering 10(8) cells each of the wild-type and/or the mutant strains per chick and counting the colony-forming units (CFU) from the ceca 1 to 3 weeks after gavage. CFU of chicks given the LPS-deficient strains either were not detected or were significantly lower than the CFU from chicks given the wild type strain. The incidence of the wild-type strain in spleens was higher than incidence of the mutant strains. In vitro binding studies with LPS-deficient mutants derived in this study and from S. typhimurium LT2 suggest that LPS side chain components may shield the bacterial cell from entrapment in the chicken mucus. The LPS layer appears to enhance persistence of Salmonella in the avian intestinal tract. PMID- 7832693 TI - Inhibition of the in vitro development of Eimeria tenella in chick kidney cells by immune chicken splenocytes. AB - An in vitro microbicidal assay was used to study the immune response of chickens to Eimeria tenella by measuring the effect of splenocytes from immunized chickens on intracellular development of E. tenella. Splenocytes were prepared from specific-pathogen-free chickens [strain P2a(B19B19) or N2a(B21B21)], immunized one, two, or three times with non-lethal doses of E. tenella. Twelve hours following infection of chick kidney cells (CKCs) with E. tenella sporozoites, splenocytes were added to infected CKCs for 4, 8, or 36 hours. Intracellular E. tenella development was allowed to continue until 72 hours after sporozoite infection, when intracellular development was quantitated by counting merzoites. Immune splenocytes significantly inhibited E. tenella intracellular development after one, two, or three immunizations. Significant inhibition occurred with 4, 8, or 36 hours of coculture and was no greater with longer co-culture times. Immune P2a splenocytes significantly reduced merozoite development in both syngeneic P2a and allogeneic N2a infected CKCs, whereas immune N2a splenocytes had little effect on E. tenella development in either N2a or P2a infected CKCs. These results suggest that immune splenocytes are induced and act relatively rapidly and are not apparently restricted by the major histocompatibility complex, consistent with natural killer cell activity. PMID- 7832692 TI - Transfer of maternal anti-rotavirus IgG to the mucosal surfaces and bile of turkey poults. AB - Turkey poults from hens vaccinated against avian group A rotavirus were examined to study the transfer of maternally derived anti-rotavirus IgG (rIgG) to the mucosal surfaces (intestinal and tracheal), serum, yolk, and bile. During the first week of life, maternal rIgG titers in intestinal mucosal washings were 200 to-500-fold less than rIgG titers in the circulation, as determined by enzyme linked immunosorbent assay (ELISA). The intestinal titers in 10- and 13-day-old poults were negligible. A moderate linear correlation (r = 0.6) was present between rIgG titer in the blood circulation and the intestines, with a serum cutoff level of 10,000 ELISA units. Maternal rIgG was detected in tracheal washings only during the first 3 days of life. Biliary rIgG titers were fourfold higher than intestinal titers at day of hatch but had declined considerably in 1 day-old poults. Yolk had relatively high rIgG titers at hatching. Maternal rIgG titer in the small intestine was determined after in situ ligation of the individual segments; it was highest in the duodenum, followed by the ileum and jejunum. There was evidence that rIgG in the intestine was transferred from the blood and not directly from the yolk sac. Bidirectional movement of rIgG between circulation and intestine was also detected. Maternal rIgG was not detected in the intestinal washings of progeny from hens naturally infected with rotavirus. PMID- 7832694 TI - Diurnal rhythms of plasma corticosterone concentrations in racing pigeons (Columba livia domestica) exposed to different light regimens, and the influence of frequent blood sampling. AB - The effects of two different light regimens and the frequency of blood sampling on the diurnal plasma corticosterone concentrations in racing pigeons (Columba livia domestica) were investigated. The daily light regimens tested were a period of light during the day (DL; lights on 0515-2215) and shifting of the light period by 12 hours (SL; lights on 1715-1015). In the first experiment, the influence of the frequency of blood sampling was investigated by comparing plasma corticosterone concentrations at 28-hr intervals for several days and at 4-hr intervals during one day. Sampling at 4-hr intervals resulted in significantly higher corticosterone concentrations in plasma than sampling at 28-hr intervals. Within both groups, the plasma corticosterone concentrations at the first and last sampling times did not differ significantly. Concentrations of plasma corticosterone were always highest during the dark period, and the corticosterone rhythm in the SL experiment was strictly in phase with the altered light/dark schedule. PMID- 7832695 TI - Sensitivity of the hypothalamic-pituitary-adrenal system of pigeons (Columba livia domestica) to suppression by dexamethasone, cortisol, and prednisolone. AB - The sensitivity of the hypothalamic-pituitary-adrenal system in pigeons (Columba livia domestica) to glucocorticoid feedback was studied after single intravenous administration of dexamethasone (500, 100, 50, 10, 5, 1, 0.5, and 0.1 micrograms/kg), cortisol (15,000, 3000, 1500, 300, 150, 30, 15, and 3 micrograms/kg), and prednisolone (3500, 700, 350, 70, 35, 7, 3.5, 0.7, and 0.35 micrograms/kg). Dose responses, the threshold doses, and the onset of maximum suppression were determined by measuring plasma corticosterone concentrations around the expected peak of plasma corticosterone in pigeons kept on a shifted light regimen. At 52 hr following the highest dose of dexamethasone, and at 48 hr following the highest doses of cortisol and prednisolone, plasma corticosterone concentrations were similar to the initial values and to the control values. Following the minimum doses that resulted in suppression of the normal diurnal variation in plasma corticosterone concentration (0.5 microgram dexamethasone/kg, 15 micrograms cortisol/kg, and 0.7 microgram prednisolone/kg), plasma corticosterone concentrations were similar to values of the control group and to initial values within 24 hr. The onset of suppression of plasma corticosterone concentrations was between 30 and 60 min following 1 microgram dexamethasone/kg, 7 micrograms prednisolone/kg, or 30 micrograms cortisol/kg. Suppression was greatest at 60 min following prednisolone and cortisol administration, and at 90 min following dexamethasone administration. It is concluded that the hypothalamic pituitary-adrenal system of pigeons reacts to exogenous glucocorticoids by early delayed feedback, is more sensitive to suppression by glucocorticoids than that of mammals, and is suppressed for the longest time by dexamethasone. These observations indicate that some of the side effects of glucocorticoid therapy are likely to be at least as frequent and as severe in birds as in mammals. PMID- 7832696 TI - Identification and localization of glycoprotein B expression in lymphoid tissues of chickens infected with turkey herpesvirus. AB - One-day-old chickens were inoculated with turkey herpesvirus (HVT). Using an indirect immunofluorescence assay with a monoclonal antibody against HVT glycoprotein B (gB), we determined the course of productive HVT infection in peripheral blood mononuclear cells (PBMCs), spleen, thymus, and bursa. PBMCs were examined from days 4 through 35 postinfection (PI). The spleen, thymus, and bursa were examined from 21 through 70 days PI. Although productive infection in PBMCs was detected at 4 to 12 days PI, it ended by 14 days PI. Splenic cells expressed gB at 21, 28, 35, and 70 days PI, whereas the thymus was positive for gB expression at 21 and 35 days PI. The bursa was never positive for gB expression. At 21, 28, 35, and 70 days PI, plaque formation after co-cultivation of PBMCs with chicken embryo fibroblasts indicated the presence of HVT in infected chickens by co-cultivation assays. On the basis of indirect immunofluorescence assay, gB expression in the spleen and thymus indicates a productive HVT infection in chickens. PMID- 7832697 TI - Fumonisin mycotoxicosis in broilers. Weights and serum chemistry modifications. AB - The effects of fumonisin B1 (FB1) intoxication in chickens was evaluated in three experiments. Two-day-old broiler chicks were fed a diet containing 10 mg pure FB1/kg feed for 6 days; some chicks were necropsied at this time, and others were allowed to recover for 5 weeks before necropsy. In two other experiments, 2-day old chicks were fed a broiler starter ration prepared with Fusarium moniliforme culture material containing FB1; one group received 30 mg/kg for 2 weeks, and another received 300 mg FB1/kg for 8 days. Compared with controls, intoxicated chicks exhibited diarrhea; decreases in body weight and in liver, spleen, and bursa absolute weights; a hepatic relative weight increase; and spleen relative weight decrease. Triglycerides, uric acid levels, and alkaline phosphatase activity decreased, and gamma glutamyl transferase, aspartate aminotransferase, lactic dehydrogenase, creatine kinase, and cholesterol increased. The results indicate that low doses of pure FB1 (10 mg/kg) and FB1 from Fusarium moniliforme culture material (30 mg/kg) are toxic to young chicks. PMID- 7832698 TI - Predictive value of multiple drag-swab sampling for the detection of Salmonella from occupied or vacant poultry houses. AB - The results of four independent complete drag-swab samplings of a 31-farm broiler production complex are described. Samplings of vacant poultry farms (i.e., between flocks) and occupied farms (i.e., containing chickens) were completed in four 3-day intervals beginning in July 1992 and ending in May 1993. During the first two sampling periods, two drag-swab assemblies were dragged through each individual house and pooled into one sample to evaluate overall incidence of Salmonella detection among vacant and occupied houses. During the second two sampling periods, four drag-swab assemblies were dragged through houses to evaluate frequency of Salmonella detection on individual assemblies within each house. Over the four sampling periods, mean isolation frequencies were 42.2% for vacant poultry farms and 76.2% for occupied poultry farms. When four assemblies were dragged in vacant houses and cultured separately, the probability of detecting salmonellae contamination increased with increasing numbers of assemblies, indicating that multiple drag-swab assemblies should be used for sampling either vacant or occupied broiler houses for the presence of Salmonella. On vacant farms, 89.5% of the total isolations occurred in only one house of two house farms; the remaining 10.5% of farms were positive in both houses. Salmonella isolation from occupied farms occurred in 54.2% of the samplings in only one house, whereas 45.8% of occupied farms were positive in both houses. These data show a higher frequency of Salmonella isolation on multiple swabs in occupied poultry houses, possibly indicating a quantitatively greater presence of Salmonella in these houses. PMID- 7832699 TI - Development and evaluation of a non-isotopically labeled DNA probe for the diagnosis of infectious laryngotracheitis. AB - A digoxigenin-labeled cloned infectious laryngotracheitis virus (ILTV) DNA fragment was evaluated as a nonradioactive alternative probe in the diagnosis of infectious laryngotracheitis. The dot-blot hybridization protocol was optimized and was capable of detecting 40 pg of purified ILTV DNA and as few as 50 ILTV infected chicken embryo liver cells. The utility of this approach for diagnostic use was evaluated through four ILTV inoculation trials using a mild field isolate, a virulent challenge strain, a tissue-culture-origin vaccine, and an egg origin vaccine. Birds were examined for clinical signs of ILT, and conjunctival and pharyngeal swabs from inoculated and sentinel birds were tested for ILTV by the digoxigenin-labeled probe and by virus isolation. In general, higher numbers of ILTV-positive samples were detected by both assays from conjunctival swabs. For the non-vaccine strains, detection by dot-blot hybridization was equivalent to that for virus isolation. However, for the two vaccine strains, there was some lack of correlation between the dot-blot results and the virus-isolation results. The kappa values between virus-isolation results and dot-blot results for the tissue-culture-origin vaccine, egg-origin vaccine, Ont 1598 field isolate, and virulent strain were 0.00, 0.16, 0.39, and 0.24, respectively, for pharyngeal samples and 0.19, 0.29, 0.58, and 0.48, respectively, for conjunctival samples. PMID- 7832700 TI - Analysis and characterization of Mycoplasma gallisepticum isolates from Pennsylvania. AB - Because Mycoplasma gallisepticum F strain vaccine can be pathogenic in chickens and is pathogenic in turkeys, we monitored the spread of MG F strain into unvaccinated flocks by screening field and experimental isolates. Thirteen MG isolates obtained from various sources in Pennsylvania were screened using several techniques capable of differentiating between MG strains. DNA restriction enzyme analysis (REA), Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) protein profiles, non-isotopic DNA probes, and a monoclonal antibody specific for F strain were used to characterize each of the 13 isolates. Three of the 13 isolates were identical to F strain; two of these were obtained from challenge studies, and one was a field isolate from a multiple-age commercial egg farm where the F strain vaccine had been used in the past. The remaining 10 isolates were different from MG F strain but were quite similar if not identical to each other according to REA; SDS-PAGE protein profiles show similarities between the 10 isolates. The results suggested that F strain vaccine is not a major cause of field outbreaks of MG in Pennsylvania. PMID- 7832701 TI - Sensitivity of avian Eimeria spp. to seven chemical and five ionophore anticoccidials in five Belgian integrated broiler operations. AB - Coccidia were isolated from 122 Belgian broiler farms without clinical coccidiosis. Shuttle programs including robenidin or nicarbazine in the starter (7-14 days) followed by an ionophore or diclazuril in the grower ration were most commonly used. Out of 215 coccidiosis-positive groups, 146 Eimeria acervulina, 65 E. maxima, and 88 E. tenella isolates were tested without further laboratory propagation in 17 sensitivity profiles. For each profile, oocytes were pooled from 9 +/- 4 farms (mean +/- SD) that used the same anticoccidial program and that belonged to the same integrated broiler operation. Each suspension contained an equal number of isolates and oocyst numbers from each farm tested. Each profile included an unmedicated uninfected group, an unmedicated infected group, and 11 medicated infected groups, consisting each of three replicates of three Ross chicks. Medication started at 8 days of age, and each inoculated bird received 50,000 sporulated oocysts at 10 days. Results were related to the anticoccidial program that had been in use. Chemical drugs showed the highest activity against Eimeria, whereas ionophores were less efficacious. Of the latter, monensin (110 ppm) was least active; narasin (70 ppm), salinomycin (60 ppm), and maduramicin (5 ppm) took an intermediate position, and lasalocid (90 ppm) was most active. A 50% improvement in weight gain was obtained in 7 to 10 out of 17 profiles with 100 + 8.35 ppm clopidol/methylbenzoquate (10), 125 ppm nicarbazin (9), 3 ppm halofuginone (8), and 1 ppm diclazuril (7). A 50% improvement in feed conversion was obtained in 7 to 11 profiles with nicarbazin (11), halofuginone (10), diclazuril (9), 33 ppm robenidine (9), clopidol/methylbenzoquate (7), and lasalocid (7). Based on relative oocyst output, the highest activity against E. acervulina was obtained with clopidol/methylbenzoquate (8/16); the highest activity against E. maxima was obtained with lasalocid (6/6), diclazuril (5/6), and halofuginone (5/6); and the highest activity against E. tenella was obtained with diclazuril (8/8), amprolium/ethopabate (5/8), halofuginone (4/8), maduramicin (4/8), and nicarbazin (4/8). PMID- 7832702 TI - Effect of bentonite incorporated in a feed ration with tilmicosin in the prevention of induced Mycoplasma gallisepticum airsacculitis in broiler chickens. AB - A factorial arrangement of tilmicosin and bentonite was evaluated for efficacy in broiler chickens infected with Mycoplasma gallisepticum and correlated to tilmicosin recovery in a feed assay method. Tilmicosin at 300-500 g/ton prevented development of airsacculitis. The addition of 2% bentonite to the ration caused tilmicosin at 300 g/ton to be ineffective in controlling air-sac lesions, whereas 400 and 500 g/ton were moderately effective. Six percent bentonite rendered tilmicosin completely ineffective at all dose levels. There was a direct correlation between the percentage of bentonite in the feed rations, the percentage of the tilmicosin recovered in the assay procedure, and the increased incidence of air-sac lesions. PMID- 7832703 TI - Passive cross-protection provided by antisera directed against in-vivo-expressed antigens of Pasteurella multocida. AB - Chicken antisera produced against the detergent-insoluble fraction of in vivo grown P-1059 (serotype 3) Pasteurella multocida passively protected against heterologous X-73 (serotype 1) challenge. Likewise, antisera from chickens that survived infection by live P-1059 provided passive heterologous protection. The two antisera, which contained cross-protection antibodies, were adsorbed with the detergent-insoluble fraction of in vitro-grown P-1059 and still passively cross protected against heterologous serotype challenge. The proteins of in vivo-grown P-1059 that had molecular weights of 204,000, 192,000, 179,000, and 153,000, which were recognized by the adsorbed antisera on immunoblots, may be responsible for cross-protection. PMID- 7832704 TI - Ultrastructural examination and cell count determinations of avian glomeruli from grossly normal and grossly swollen kidneys of broilers at slaughter. AB - Kidneys from broiler chickens at slaughter (6 to 7 weeks of age and mixed sex) were collected by U.S. Department of Agriculture personnel. Forty kidneys were collected from grossly normal birds with grossly normal kidneys (Group D). Grossly swollen kidneys were collected from birds that were otherwise grossly normal (Group A), that had gross lesions of Marek's disease (Group B), or that had gross lesions of squamous cell carcinoma (Group C). These kidneys were fixed in Carson's 10% buffered formalin, embedded in plastic, sectioned at 2 microns, and then stained with periodic acid-Schiff-hematoxylin for glomerular cell counting. Tissue was also processed for electron microscopy from six Group D birds and from six birds total from Groups A, B, and C that had the most severe histologic glomerular lesions. Glomerular tuft cell counts and visceral epithelial cell counts were performed by light microscopy at a magnification of 100x (oil immersion). Total tuft cell counts of all abnormal groups (A, B, and C) were significantly higher (P < 0.05) than those of Group D. Reptilian glomerular tuft cell counts for all abnormal groups were significantly higher (P < 0.05) than the reptilian glomerular tuft counts for Group D. Mammalian glomerular tuft cell counts for Groups A and B were significantly higher than those of the control group (Group D). Electron microscopic examination of the glomeruli from selected birds revealed no dense deposits in the basement membrane and no effacement of epithelial podocyte foot processes. No essential ultrastructural differences were noted between the control group and the abnormal groups. PMID- 7832705 TI - Response of specific-pathogen-free turkeys to vaccines derived from marble spleen disease virus and hemorrhagic enteritis virus. AB - Tissue-culture-propagated marble spleen disease virus (MSDV-TC) and two preparations of spleen homogenate (MSDV-SH and MSDV-SH-TC) were compared as anti hemorrhagic enteritis virus (HEV) vaccines in specific-pathogen-free turkeys. Both types of vaccines spread horizontally among turkeys, induced anti-HEV antibodies, and protected turkeys against challenge with virulent HEV. Antibody development and horizontal spread of virus occurred earlier in turkeys given MSDV SH or MSDV-SH-TC than in those given MSDV-TC. Virulent HEV was serially passed in MDTC-RP19 cells. The 30th passage virus (HEV-P30) was nonpathogenic for turkeys but was immunogenic. Turkeys exposed to HEV-P30 had viral antigen in the spleen, developed neutralizing antibodies, and resisted virulent HEV. The principal difference between MSDV-TC and HEV-P30 vaccines was that MSDV-TC caused well defined splenomegaly in turkeys, whereas HEV-P30 protected turkeys without causing spleen enlargement. PMID- 7832706 TI - Infectious bursal disease viruses: molecular differentiation of antigenic subtypes among serotype 1 viruses. AB - Published nucleotide sequence data for IBDV variant viruses (A and 1048E) and classic viruses (STC, 52-70, PBG98, Cu-1, and 002-73) were used to identify restriction enzyme sites that could potentially be used to differentiate these strains of IBDV. To test this hypothesis, the genomes of IBDV strains STC, MD, NC, and OH were converted to cDNA using reverse transcriptase (RT) and then amplified using the polymerase chain reaction (PCR). The PCR primers were selected from relatively conserved sequence regions in the VP2 gene, and they were used to amplify a 394-base-pair fragment. The restriction enzymes (RE) DraI, EcoRII, SacI, Sau3AI, StyI, and TaqI were tested for their ability to digest the RT/PCR products. The STC classic virus was SacI-, StyI-, and EcoRII-positive and DraI-, Sau3AI-, and TaqI-negative. The MD, NC, and OH viruses were DraI-, Sau3AI , and TaqI-positive and SacI-, StyI-, and EcoRII-negative. The classic STC strain could be differentiated from the variant MD strain using the RT/PCR-RE assay. Based on these results and the presence or absence of other restriction sites that were predicted by published nucleotide sequence data, the RT/PCR-RE assay has the potential to differentiate IBDV isolates MD, A, and 1048E. Published nucleotide sequence data and the RT/PCR-RE results obtained using STC and MD indicated that variant viruses MD, A, and 1048E could be differentiated from classic viruses STC, 52-70, PBG98, Cu-1, 002-73, and NC. PMID- 7832707 TI - Differentiation of two strains of Mycoplasma gallisepticum with monoclonal antibodies and flow cytometry. AB - Identification of infecting Mycoplasma spp. is difficult and not routine for strain. This paper describes a procedure for the rapid identification of the strain of M. gallisepticum. Monoclonal antibodies were prepared against M. gallisepticum F and M. gallisepticum S6. Aliquots of 24-hour broth cultures of these organisms were incubated briefly with either of the monoclonal antibodies. A second incubation was made with anti-mouse immunoglobulin conjugated to fluorescein isothiocyanate. Fluorescent intensity associated with the organisms was measured with a flow cytometer. The criterion for identification was a comparative increase in fluorescent intensity when the strain and monoclonal antibody were homologous. The procedure correctly differentiated the F and S6 strains of M. gallisepticum in a blind study. PMID- 7832708 TI - The pathogenesis of quail bronchitis. AB - To determine the fate of virus and characterize the development of lesions, 1 week-old bobwhite quails (Colinus virginianus) were inoculated intratracheally with 10(6) mean tissue-culture-infective doses of quail bronchitis virus. Quails were killed and necropsied sequentially at 2, 4, 8, 16, and 24 hours postinoculation (PI) and on days 2-10 PI. Virus was first isolated from the lung as early as 2 hours PI, from cecal tonsils and bursa of Fabricius 4 hours PI, and from spleen and liver 8 hours PI. Tissue virus titers were highest on days 4 to 6 PI, corresponding with the severity of histologic lesions. Viral inclusions were present in tracheal mucosal epithelium by day 2 PI. On day 3 PI, tracheal epithelium was deciliated, formed an irregular luminal border, and had more frequent inclusions. On days 4 and 5 PI, tracheal epithelium was partially desquamated, but there were minimal leukocytic infiltrates. Bronchiolar epithelium underwent similar changes, but the leukocytic infiltration was more intense and included lymphocytes and heterophils. There was extension of leukocytic infiltrates into surrounding lung that was most extensive on day 3 PI. Hyperplasia of splenic macrophages was first identified on day 2 PI and peaked by day 5 PI. PMID- 7832709 TI - Histological study of tibial dyschondroplasia-like lesion from light-type chicks fed cysteine-supplemented diets. AB - Tibial dyschondroplasia (TD)-like lesions were induced in New Hampshire x Single Comb White Leghorn cross chicks (NH x SCWL) by feeding excess levels of cysteine. The chicks fed a corn/soybean-meal-based diet had no spontaneous TD. The chicks fed the basal diet supplemented with 1.5% or 3.0% cysteine showed more than 50% TD-like lesions at 10 days of age; in another experiment, 1.6% cysteine induced TD (15%) at 3 weeks of age. A low incidence of rachitic-like lesions was found in Expt. 2 but was not associated with the dietary treatments. The TD-like lesion had a normal upper growth plate and a large mass of cartilage extending into the metaphysis; in contrast, the rachitic-like lesion had a widened upper growth plate. Microscopic examinations of the growth plates showed a widened prehypertrophic zone for the TD-like lesion and a widened proliferative zone for the rachitic-like lesion compared with the normal growth plate. PMID- 7832710 TI - Decreased egg production in turkeys experimentally infected with eastern equine encephalitis virus or Highlands J virus. AB - Turkey breeder hens were experimentally infected with strains of eastern equine encephalitis (EEE) virus or Highlands J (HJ) virus previously isolated from turkey hens experiencing decreased egg production. Depression and inappetance were observed on day 1 postexposure (PE) in hens inoculated with either EEE virus or HJ virus, and egg production fell in each virus-inoculated group from approximately 75% to less than 20% within 2-3 days PE. Egg production remained depressed (less than 20%) for 15 days in EEE-virus-inoculated hens and for 7 days in HJ-virus-inoculated hens. EEE virus and HJ virus were recovered from various tissues on days 1-5 PE, and virus was detected in eggs laid on days 2-5 PE. The findings of this study confirm that EEE virus and HJ virus are potential causes of decreased egg production in turkey breeder hens. PMID- 7832711 TI - Experimental infection of young broiler chickens with eastern equine encephalitis virus and Highlands J virus. AB - Two-week-old broiler chickens were experimentally infected with either eastern equine encephalitis (EEE) virus or Highland J (HJ) virus. Mortality rates were 24/30 (80%) in EEE-virus-inoculated chickens and 2/30 (7%) in HJ-virus-inoculated chickens. Chickens inoculated with EEE virus exhibited severe depression and somnolence on days 1-6 postexposure (PE), with 17/30 birds dying during this period. After day 6 PE, EEE-virus-inoculated chickens exhibited abdominal distention, depression, and growth retardation, and an additional seven chickens died. Pathologic changes in EE-virus-inoculated chickens dying on days 1-6 PE consisted of multifocal necrosis in the heart and liver, as well as lymphoid depletion and necrosis in the thymus, spleen, and bursa of Fabricius. Ascites, pericardial effusion, and right ventricular dilatation of the heart were the predominant lesions in chickens dying after day 6 PE. No clinical signs were observed in sham-inoculated controls or in most HJ-virus-inoculated chickens. Ascites, pericardial effusion, and multifocal myocardial necrosis were observed in 2/30 HJ-virus-inoculated chickens that died or were euthanatized after development of clinical signs. These findings indicate that both EEE virus and HJ virus are pathogenic for young chickens. PMID- 7832712 TI - Transmission of Salmonella typhimurium during hatching of broiler chicks. AB - Horizontal spread of Salmonella during hatching of broiler chicks was studied in three experiments. In each experiment, 120 unincubated, fertile hatching eggs were inoculated by immersion for 15 min in a 16 C physiological saline solution containing 1 x 10(8) colony-forming units per ml of a nalidixic-acid-resistant strain of S. typhimurium. When inoculated eggs were transferred to hatchers after 17 to 18 days of incubation, control eggs at the same stage of incubation were added to the same tray and to trays above and below the tray containing inoculated eggs. Fertile inoculated eggs hatched at a rate of 86%, despite the high level of Salmonella contamination, indicating that chicks in eggs contaminated with salmonellae are likely to hatch and may contaminate other chicks in the same hatcher cabinet. Air samples showed a sharp increase in contamination in the hatcher at 20 days of incubation. Approximately 58% of mouth swabs and 90% of chick rinses were Salmonella-positive, in both inoculated and control eggs. In samples from inoculated eggs, Salmonella was detected in the digestive tract of 8% of embryos at transfer from incubator to hatcher and in 55% of chicks at hatch. From control eggs, 44% of digestive tracts of hatched chicks were positive, indicating that Salmonella in a contaminated hatcher can reach the gut of chicks hatching from Salmonella-free eggs before they are removed from the hatcher. PMID- 7832713 TI - In vivo evaluation of the pathogenicity of field isolates of infectious bronchitis virus. AB - The pathogenicity of 13 field isolates of infectious bronchitis virus (IBV) isolated from Georgia broiler farms from 1989 to 1992 was evaluated using the IBV and Escherichia coli mixed-infection model. Based on the clinical signs, mortality, and lesions, the isolates were classified as high, intermediate, and low in pathogenicity. The in vivo classification was compared with the serotype classification results obtained by reverse transcriptase-polymerase chain reaction-restriction fragment length polymorphism analysis. The high pathogenicity group was composed of five isolates representing three serotypes: Arkansas, Georgia variant (GAV), and Massachusetts. Isolates in the intermediate- and low-pathogenicity groups were all representatives of the Connecticut serotype, except for one isolate, which belonged to the Massachusetts serotype. PMID- 7832715 TI - Splenic granulomas in broiler chickens produced experimentally by inoculation with Eubacterium tortuosum. AB - Eubacterium tortuosum, a gram-positive anaerobic filamentous bacillus, was isolated from splenic and hepatic granulomas of a 56-day-old slaughtered chicken. This isolate was injected intravenously into two groups of 2-week-old broiler chickens, which were necropsied 19 days later. Five of 15 chickens injected with 5 x 10(6) colony-forming units of a 48-hour culture of E. tortuosum developed splenic granulomas typical of those seen in chickens at slaughter. No lesions were observed in chickens given 5 x 10(5) colony-forming units of E. tortuosum or in control chickens receiving phosphate-buffered saline solution. Attempts to reisolate E. tortuosum from experimentally infected chickens were unsuccessful; however, typical filamentous organisms were observed in splenic granulomas of all five affected chickens. PMID- 7832714 TI - A rapid method for screening for Salmonella typhimurium in a chicken cecal microbial consortium using gene amplification. AB - A rapid sample processing method has been developed to detect low numbers of Salmonella typhimurium in a chicken cecal microbial consortium. Using phoP specific primers under stringent amplification conditions and gene probe analysis, fewer than 100 colony-forming units (CFUs) were detectable when pure cultures were employed. When the polymerase chain reaction assay was run on cecal contents from birds infected with S. typhimurium, only positive cecal samples containing as few as 700 CFUs reacted to the assay, and the negative bird samples reacted only when the samples were spiked with S. typhimurium cells. The method employed for sample processing is simple and provides a sensitive means of detecting S. typhimurium-specific sequences in trace amounts in the presence of mixed chicken cecal microbial populations. PMID- 7832716 TI - The leukocyte response of Japanese quail to Rous sarcoma virus-induced tumors. AB - In male Japanese quail, different circulating leukocyte responses were observed for progressors (birds developing a massive tumor that persisted throughout the experiment) and regressors (birds developing a tumor that gradually disappeared) after initial challenge with Rous sarcoma virus (RSV). Blood was sampled before and at weekly intervals postinoculation. Blood smears were prepared and stained with Diff Quik, and a light microscope (1000 x) was used in a direct count of 50 fields. Leukocytes were classified as heterophils, lymphocytes, monocytes, or eosinophils. The significant increase (P < 0.05) in total leukocytes at 14 days in regressors and progressors was consistent with the increase in tumor growth. The regressors' individual percentage of leukocytes did not deviate from control values, whereas the progressors' percentages of heterophils and monocytes were significantly higher (P < 0.05) and of lymphocytes significantly lower (P < 0.05) than those of controls by 14 days postinoculation. Indicative of this was the progressors' heterophil to lymphocyte ratio, which was significantly higher (P < 0.05) than that of controls 14 days post RSV challenge and remained elevated throughout the experiment. These findings suggest that the progressors' immune response is suppressed by proliferation of malignant cells. Therefore, the heterophil to lymphocyte ratio may be used in addition to tumor size to identify those birds that will regress RSV-induced tumors. PMID- 7832718 TI - A serosurvey using enzyme-linked immunosorbent assay for antibodies against poultry pathogens in ostriches (Struthio camelus) from Zimbabwe. AB - Horseradish peroxidase-conjugated goat anti-ostrich IgG was raised and used in commercial enzyme-linked immunosorbent assay kits to detect antibodies reactive with 11 poultry pathogens in sera from 149 ostriches from nine farms around Zimbabwe. Antibodies were detected to turkey rhinotracheitis virus (99%), Newcastle disease virus (23%), avian reovirus (19%), infectious bursal disease virus (15%), avian encephalomyelitis virus (15%), Mycoplasma gallisepticum and/or M. synoviae (11%), reticuloendotheliosis virus (10%), Salmonella enteritidis (8%), avian leukosis virus (3%), infectious bronchitis virus (2%), and Pasteurella multocida (< 1%). Although evidence of prior infection with turkey rhinotracheitis and newcastle disease virus was present on all farms tested, there was marked variation between farms in the prevalence of exposure to other poultry pathogens. PMID- 7832717 TI - Isolation and characterization of serum immunoglobulin classes of the ostrich (Struthio camelus). AB - Immunoglobulins were separated from ostrich sera by ammonium sulfate precipitation and ion-exchange chromatography. Two classes of immunoglobulin could be identified, corresponding to IgG and IgM of other species, based on elution profiles from ion-exchange columns and molecular mass estimation on gel filtration chromatography and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). On SDS-PAGE, the heavy chains of IgG and IgM were shown to have molecular masses of 67.5 kDa and 65 kDa, respectively, and the light chains common to both were shown to have a molecular mass of 27 kDa. The ostrich immunoglobulins were not recognized by monoclonal and polyclonal antibodies against immunoglobulins of many species of animals tested, nor by antibodies against chicken immunoglobulins. PMID- 7832719 TI - Diseases and management of backyard chicken flocks in Chitungwiza, Zimbabwe. AB - To gather information on backyard chicken flocks in Chitungwiza, an urban center in Zimbabwe, 85 flock owners were interviewed. The mean flock size was 53 birds (range 1-650), and most birds were kept for meat, for either domestic consumption or local sale. Mean age at slaughter was 12.4 weeks (range 8-24). None of the owners vaccinated their birds, and reported mortality rates were high (mean 25%), most commonly being associated with diseases causing eye and respiratory problems. Most owners complained of a lack of technical and veterinary advice. Commercial enzyme-linked immunosorbent assays on sera from 460 birds in 52 flocks showed that the birds had been exposed to avian reovirus (3%), avian leukosis virus (9%), avian encephalomyelitis virus (11%), Newcastle disease virus (27%), Mycoplasma gallisepticum and M. synoviae (33%), Pasteurella multocida (52%), infectious bursal disease virus (55%), reticuloendotheliosis virus (65%), and infectious bronchitis virus (86%). Parasite infections were detected only rarely. PMID- 7832720 TI - Proventriculitis and ventriculitis associated with zygomycosis in ostrich chicks. AB - This report describes eight cases of proventriculitis and ventriculitis in ostrich chicks less than 2 months old. Clinical signs included acute onset of lethargy and anorexia in three cases, and chronic weight loss with lethargy and anorexia in four cases; no history was available in one case. There was limited antibiotic therapy in two cases; a third case was treated for giardiasis. Concurrent bacterial, yeast, and viral infections were common. Lymphoid depletion and/or necrosis of bursa, thymus, and spleen suggested severe immune challenge or immunosuppression in many cases. Histologically, there was severe ulcerative proventriculitis and ventriculitis with intralesional fungal hyphae. In two chicks with granulomatous pneumonia, similar fungal hyphae were also observed in the lung. Fungal hyphae were rarely septate, with irregular, non-parallel walls, and ranged in diameter from 7 to 20 microns. Occasional globoid distentions of the hyphae were present. Fungi were identified morphologically as species in the Zygomycetes class; in one case a Mucor sp. was cultured. Zygomycetes appear to be potentially serious opportunistic pathogens of ostrich chicks. PMID- 7832721 TI - Particles resembling circovirus in the bursa of Fabricius of pigeons. AB - Histological examination of the bursae from 12 pigeons under 4 months old revealed basophilic globular inclusion bodies, 5 to 25 microns in diameter, in the cytoplasm and the nuclei of the various bursal follicular cells. Electron microscopy of these inclusions revealed large electron-dense areas containing non enveloped icosahedral viral particles, 14-19 nm in diameter, either loosely arranged or in paracrystalline array. Similar basophilic globular inclusion bodies were seen in the spleen and cecal tonsils of a few pigeons and in the duodenum of one pigeon. There were various degrees of lymphoid depletion in the bursa, spleen, and bone marrow. The morphology of the inclusions in the bursa and size of the viral particles are most consistent with circovirus. Preliminary studies on the bursae of two pigeons were negative for psittacine beak and feather disease (PBFD) viral antigen and nucleic acid by immunoperoxidase staining, DNA in situ hybridization, and polymerase chain reaction techniques, suggesting that this virus differs from PBFD virus. Most of the pigeons had concurrent infections such as paramyxovirus-1, salmonellosis, herpesvirus, and hepatic and cerebral trichomoniasis associated with adenovirus. PMID- 7832722 TI - Isolation of an adenovirus from an ostrich (Struthio camelus) causing pancreatitis in experimentally infected guinea fowl (Numida meleagris). AB - An adenovirus was isolated from the pancreas, kidney, and lung of a dead 4-month old ostrich (Struthio camelus). Experimental infection of week-old guinea fowl (Numida meleagris) was carried out in order to study transmission. Of the infected keets, six out of 15 died; these exhibited pancreatitis, presence of a hemorrhagic liquid in the abdominal cavity, kidney degeneration, and pulmonary lesions. The remaining birds, euthanatized on day 21 postinoculation, showed chronic pancreatitis. The virus was reisolated from the pancreas, lung, and kidney of the infected keets. PMID- 7832723 TI - Hemorrhagic enteritis by adenovirus-like particles in turkeys: a possible pathogenic mechanism. AB - This paper describes an outbreak of hemorrhagic enteritis due to adenovirus in turkeys in Spain. Diagnosis of the disease was confirmed by histopathological examination and the observation of adenovirus in spleen mononuclear cells and intestinal infiltrate. Evidence was also found of intravascular coagulation, which may give rise to the bleeding considered characteristic of this disease. PMID- 7832724 TI - Nutritional encephalomalacia in turkeys: diagnosis and growth performance. AB - An outbreak of neurological disease in 2 1/2-to-3 1/2-week-old male turkey poults was diagnosed morphologically as nutritional encephalomalacia. About 20 to 30% of the flock of 6360 showed clinical signs, which included going down with legs extended or hock-sitting and inability to get up, incoordination, weakness, staggering, trembling, torticollis, and opisthotonus. The most important gross postmortem changes were found in the brain, which consisted of an enlarged and swollen cerebellum with focal and/or diffuse hemorrhages. Major histopathological alterations included congestion, hemorrhages, necrosis, and malacia associated with hyaline capillary thrombi affecting the cerebellar cortex and adjacent white matter. Except for a slightly higher mortality, flock performance compared favorably with performance of other flocks grown in the same farm as well as with the national average for market tom turkeys. PMID- 7832725 TI - Aspergillus fumigatus keratitis with intraocular invasion in 15-day-old chicks. AB - Eye infections were initially observed in single-comb white leghorn breeder chicks at 5 days of age, and morbidity increased from 0.05% to 1.5% after debeaking at 7 days of age. All chicks necropsied at 15 days of age had cheesy yellow exudate within the conjunctival sac of one eye and small (1 mm diameter) white nodular lesions in lungs and on thoracic air-sac membranes. Histopathologic examination of the eyes revealed septate fungal hyphae and inflammatory cells in the anterior chamber, cornea, and conjunctival sac. Similar fungal hyphae were present within lung granulomas. Aspergillus fumigatus was isolated from the eyes. Eye infections were the only health problem reported for several consecutive flocks on this farm. Elimination of moldy feed from the diet and environment and proper management of sawdust litter have prevented fungal ophthalmitis in subsequent flocks. PMID- 7832726 TI - Chlamydiosis in commercial rheas (Rhea americana). AB - Mild to marked splenomegaly was observed in three of four rheas that died acutely in three unrelated commercial ratite facilities in Southeastern Louisiana. Mortalities occurred within a 5-week period in birds ranging from 2 months to 3 years of age. Multifocal hepatic and splenic necrosis with mononuclear cell infiltrates, typical of chlamydiosis in other avian species, was present on histopathologic sections. The diagnoses were confirmed by demonstration of inclusion bodies in splenic impression smears and fluorescent-antibody testing performed on Vero cell cultures. PMID- 7832727 TI - Complicated infectious coryza outbreaks in Argentina. AB - Seventeen complicated outbreaks of infectious coryza in layer, broiler-breeder, and broiler flocks were studied. In the layer flock outbreaks, drops in egg production of up to 35% were seen. In the broiler flocks and several of the layer flocks, losses due to persistent mortality and/or culling varied between 2 and 5%. Signs of infectious coryza in both layers and broiler-breeders were typical; in broilers, however, swollen head-like syndrome was seen. Except in one flock, no viral diseases were clinically or serologically detected. Excluding broiler breeders, birds from most other flocks were serologically positive for Mycoplasma gallisepticum, and some were also positive for M. synoviae. Haemophilus paragallinarum was isolated from all of the outbreaks, but only as a pure culture in three outbreaks. Isolation of H. paragallinarum from sites such as liver, kidney, and particularly tarsal arthritis and ocular globes appears to be reported for the first time. Serovar A was isolated in eight outbreaks, serovar B in six, serovar C in one, and untypable serovars in two. The severity of these infectious coryza outbreaks may have been increased by concurrent salmonellosis, pasteurellosis, and mycoplasmosis, although under certain conditions H. paragallinarum is able to cause septicemia. Ten of the outbreaks occurred in birds vaccinated against infectious coryza; this may be due to the use of vaccines that do not provide protection against the types of H. paragallinarum that affect poultry in the region. PMID- 7832729 TI - Performance during mild acute hypoxia. AB - The controversy regarding the effects of mild hypoxia on learning performance needs to be resolved, since this may be affecting flight operations and safety. This study examined the ability to learn new tasks at low altitudes. Naive subjects (n = 144) performed spatial orientation (Manikin), serial choice reaction time (SCRT) and logical reasoning (Baddeley) tasks at ground level and at altitudes of 1,524 m (5,000 ft), 2,438 m (8,000 ft), 3,048 m (10,000 ft), and 3,658 m (12,000 ft), at rest or during exercise (VO2 = 600 ml O2.min-1) in a hypobaric chamber. Each task was performed over four serial repetitions (blocks) and presented at ground level or one of the four test altitudes in a first session, and in the reverse order in a second session. Performance for the Manikin and SCRT tasks improved significantly (p < 0.0001) over the 4 blocks. No significant difference was found between the corresponding 4 blocks of the first session in resting and exercising subjects tested at ground level before altitude compared to altitude before ground level. In general, RT for the 3 tasks were faster in resting than in exercising subjects. These results indicate that the ability to learn new tasks is not impaired by mild hypoxia at altitudes of up to 3,658 m. We detected a biphasic response to altitude in LRT and SCRT performance, but not for Manikin performance. PMID- 7832728 TI - Hepatic hemosiderosis and Klebsiella bacteremia in a green aracari (Pteroglossus viridis). AB - A green aracari (Pteroglossus viridis) was presented for necropsy after being found dead; no previous clinical signs had been noted. Microscopic examination revealed multifocal necrosis of the liver, spleen, and lung compatible with an acute bacteremia. Klebsiella pneumoniae was isolated from the liver, kidney, and intestine. Histopathological and toxicological findings also reflected a concurrent hepatopathy due to excess iron accumulation. Hepatic hemosiderosis has been reported in mynahs, birds of paradise, and quetzals but has not previously been reported in the green aracari. PMID- 7832730 TI - An overview of international issues in astronaut psychological selection. AB - The NASA Johnson Space Center Medical Sciences Division convened an In-House Working Group on Psychiatric and Psychological Selection of Astronauts in 1988. Working with the European Space Agency (ESA) and the National Space Development Agency (NASDA) of Japan, psychiatrists and psychologists experienced in selecting individuals for training as astronauts or analogous duties studied the development of appropriate criteria. Psychiatric criteria generally concern the detection of pathological conditions, and thus "select-out" applicants by disqualification. Psychological criteria may be used to identify specific affirmative criteria that make an individual particularly well-qualified for such duties, and thus concern "select-in" processes for operational crews. As space missions grow longer, and as crews become larger and more demographically diversified, the long-ignored questions, "What sort of healthy individuals should be selected for such missions," and "How do we know this?" will become more critical to the success of space exploration. The papers included in this Panel concern the results of these investigations, and represent long-needed quantification of these two selection processes, select-out and select-in, in several cultures. PMID- 7832731 TI - Predicting astronaut effectiveness: a multivariate approach. AB - In this study, measures of astronaut effectiveness were administered to volunteers from the astronaut corps in order to validate psychological "select in" criteria for long-duration space missions. Using a peer nomination format, astronauts rated their peers with whom they had either flown or trained. Factor analysis revealed two latent performance dimensions: job competence and group living. The job competence dimension measured the instrumental aspects relating to job knowledge and job performance. The group living dimension measured the interpersonal aspects relating to teamwork and desirability as a colleague on Space Station. Analyses revealed that the personality variables could explain a significant proportion of the variance in the group living performance dimension, but not the job competence performance dimension. The findings are not surprising since astronauts are highly screened on the basis of past attainment, but are not as highly screened on aspects relating to teamwork and interpersonal concerns. PMID- 7832733 TI - Astronaut psychiatric selection procedures: a Japanese experience. AB - This paper presents the results of the first application of a structured NASA psychiatric interview for Japanese astronaut selection. We undertook a semi structured, diagnostic, clinical psychiatric interview with 45 Japanese astronaut applicants for the position of mission specialist-astronaut, and performed "select-out" psychiatric evaluations according to DSM-III-R psychiatric diagnostic criteria. Two applicants (4.4%) who met Axis I or Axis II disorder criteria in DSM-III-R were evaluated as "Disqualified." There were 13 applicants "Qualified with Reservation"; the majority of their diagnoses were "hypomania." Those applicants "Qualified with Reservation" and "Disqualified" were not finally selected to be astronauts. This structured interview was not only useful for "select-out" psychiatric screening of Japanese astronauts, but also made clear the Japanese characteristics of this selection procedure. PMID- 7832732 TI - Psychological predictors of astronaut effectiveness. AB - Are the personality characteristics of astronauts related to their professional effectiveness? In order to answer this question, effectiveness and personality data were collected from 65 NASA astronauts. Several findings emerged from these data. Five personality subscales were related to effectiveness in one form or another. They were: high Negative Expressivity and Negative Communion (subordinate and gullible), low Impatience and Irritability, low Openness (to new ideas and experiences), low Negative Instrumentality (egoism) and high Agreeableness. Examining the graphs of these relationships indicated that they were not linear. This examination indicated that high levels on these undesirable personality characteristics (e.g., Impatience/Irritability) were distributed across all levels of effectiveness. Low levels of the undesirable personality characteristics were found only among the most effective astronauts. We concluded that these other-directed personality qualities will assume increasing importance in long-term spaceflight, and consequently, should be the focus of greater attention in future astronaut selection and training. PMID- 7832734 TI - Psychological evaluation of Japanese astronaut applicants. AB - In 1991, a new psychological selection procedure was employed during the selection of Japanese Space Station astronauts. It was based on international selection criteria developed by an international psychological/psychiatric working group. A total of 372 individuals--fewer than expected--submitted applications for Space Station astronaut in Japan. Of the applicants, 233 were given several psychological written tests [Anxiety Scale, Performance Test, General Aptitude Test Battery, and Environmental Adjustment Test Battery (EATB)] in Phase I of the selection. Forty-five applicants went on to take the General Aptitude Test Battery (GATB), Human Assessment Method (a group test), a semi structured psychological interview and an intelligence test in Phase II of the selection. All applicants were found to be highly intelligent. Interestingly, an unexpectedly large number of candidates were disqualified by the newly developed EATB. Assessment of individual functioning in a group (the Human Assessment Method) resulted in no applicant being ranked in either the "qualified with reservation" (QR) or "disqualified" (DQ) category. Much has been learned from this initial application of psychological "select-in" testing, but further efforts are needed to improve both psychological criteria and evaluation methods and to determine their reliability and validity. PMID- 7832735 TI - Psychological evaluation of European astronaut applications: results of the 1991 selection campaign. AB - In the summer of 1991, the European Space Agency (ESA) performed its second selection campaign since 1977 in order to find 10 astronaut candidates (laboratory specialists and space plane specialists). An integral part of this selection process was the psychological evaluation, according to the principles laid down in the study report "Definition of Psychological Testing of Astronaut Candidates." After national preselection, 59 applicants underwent the psychological evaluation, which consisted of the assessment of operational aptitudes (basic cognitive and psychomotor functions) and personality traits (motivation, social capability, stress resistance). The test program included a diverse number of tests, questionnaires, behavioral ratings, biographical data, and semi-structured interviews. About 50 scores were available for each subject. A comparison of the test scores with the original normative data, culture fairness of the psychological selection, and discriminant functions analyzing the assessment decisions will be presented and discussed. PMID- 7832736 TI - Economy class syndrome: rheology, fluid balance, and lower leg edema during a simulated 12-hour long distance flight. AB - In order to study pathological changes that might lead to deep vein thrombosis and pulmonary embolism in long-distance air travel passengers, 12 healthy volunteers were investigated during 4 simulated 12-h flights (day and night). The influence of repeated leg exercise was compared with constant sitting. Plasma viscosity, hematocrit, albumin, fluid balance, and lower leg swelling were measured. Rheological studies showed only circadian rhythm alterations. An average of 1150 ml fluid was retained, which correlated with an increase in body weight. The lower leg volume increase was significant, but not pathological. Periodic leg exercising showed no measurable preventive effects. These changes in healthy human volunteers are within physiological variations and are not sufficient to provide a definitive cause of venous thrombosis in healthy passengers. They do, however, suggest alterations produced by long-distance air travel that could intensify the risk of developing deep venous thrombosis in passengers with predisposing risk factors. PMID- 7832737 TI - Blood flow velocity in common carotid artery in humans during breath-holding and face immersion. AB - Blood flow velocity was measured in the common carotid artery of humans during breath-holding (BH) in the supine and upright positions, and during breath-hold face immersion (FIBH) in cold (20 degrees C) and warm (35 degrees C) water in the upright position with 90 degrees flexion of the upper body, to test the influences of the body position, facial immersion and temperature on changes in cerebral blood flow. Simultaneously, the heart rate (HR) and blood pressure (BP) under the same conditions, and the end-tidal PO2 and PCO2 (PETO2 and PETCO2) during supine BH, were also measured. Results showed that posture had no significant effect on the apneic HR. Bradycardia developed during cold FIBH, but not warm FIBH. The BP increased during BH in both positions, and during both cold and warm FIBH. The PETO2 decreased and the PETCO2 increased significantly at the end of BH. The blood velocity decreased transiently at the beginning of upright BH, but increased time-dependently during both supine and upright BH. Moreover, the velocity increased more during warm FIBH than during BH's, and even more during cold than warm FIBH. When bradycardia occurred during cold FIBH, the velocity integral per minute tended to decrease. These results suggest that the cerebral blood flow increases in these conditions of BH. This increase can be explained by the increase in PETCO2 and decrease in PETO2, possibly with a slight contribution from the increase in the BP.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7832738 TI - Pilot-related factors in aircraft crashes: a review of epidemiologic studies. AB - The epidemiologic studies of pilot-related factors in aircraft crashes are reviewed with regard to: 1) study design and methods; 2) major findings; and 3) data and methodological issues. In the last 60 years, numerous studies have been conducted to examine the relationships of pilot characteristics to the risk of aircraft crashes. Much attention has been paid to pilots' medical condition, age, flight experience, and alcohol use. Most studies were based on crash analysis, using case reports and case series. Few studies have applied a formal, rigorous epidemiologic design. Planned case-control and cohort studies are extremely rare. In some cases, the deficiencies in study design and data analysis have resulted in controversial findings. More epidemiologic studies using state-of-the-art methodology are needed to identify various risk factors of aircraft crashes, to better understand the interrelationships among pilot, aircraft, and environment, and to develop and assess safety policies and other intervention programs. PMID- 7832739 TI - Suicide by use of aircraft in the United States, 1979-1989. AB - Intentional aircraft crashes are a dramatic cause of death. The entire set of fatalities due to this cause of death in the United States has not been described. Mortality data from aircraft crashes determined as being due to suicide were obtained from National Center for Health Statistics (NCHS) and National Transportation Safety Board (NTSB) data sources. The NCHS reported that, between 1979 and 1989, ten persons committed suicide by aircraft crashes. Twenty aircraft crash fatalities were also reported during the period in which the intent of death could not be determined as either suicide, homicide, or accidental. White middle-aged males accounted for the majority of deaths. The NTSB reported, for the years 1979-89, that nine fatal aircraft accidents were suicide. All fatalities were male pilots operating small fixed wing aircraft. NTSB investigations identified evidence for important adverse psychologic factors in most pilots. PMID- 7832740 TI - Economy class syndrome. AB - A recent case of the "Economy Class Syndrome" is presented, emphasizing the syndrome's aeromedical implications and prevention. The clinical presentation, current modes of prophylaxis and therapy, plus a brief but pertinent historical background, are described. The syndrome is potentially fatal, and the authors stress that the condition needs to be recognized as a preventable hazard of air travel. Adoption of the preventive measures described herein can assist in promoting healthy air travel. PMID- 7832741 TI - The first "operation babylift" flight. PMID- 7832742 TI - HIV-encephalopathy: should we await a catastrophe before screening? PMID- 7832743 TI - Aviation medicine. PMID- 7832744 TI - Chemical nucleases as probes for studying DNA-protein interactions. PMID- 7832745 TI - Expression and DNA binding of the human 52 kDa Ro/SSA autoantigen. AB - The 52 kDa Ro/SSA protein is an intracellular autoantigen that is frequently recognized by antibodies in sera of patients with systemic lupus erythematosus or Sjogren's syndrome. While the function of this molecule is not known, zinc finger and leucine zipper motifs have been identified in its predicted amino acid sequence which suggest that it may interact with nucleic acids. To test this hypothesis, the human gene which encodes this protein was cloned in a baculovirus and expressed in Spodoptera frugipoda cells. Extracts from these infected insect cells were used as a source of protein for this study. The protein is similar in size and antigenicity to that expressed in human cells. This protein binds to DNA at physiological temperature and is eluted with high concentrations of sodium chloride. Striking similarities were found between the sequence in, and adjacent to, the nucleic acid-binding motifs of 52 kDa Ro/SSA and a growing family of zinc finger proteins which have been shown to bind to DNA or regulate gene expression. The findings presented here place this protein structurally and functionally in this family and demonstrate a biochemical assay which can be used to study its function. PMID- 7832746 TI - Partial sequence of the purified protein confirms the identity of cDNA coding for human lysosomal alpha-mannosidase B. AB - Human lysosomal alpha-mannosidase has been purified by a simple and rapid method in sufficient quantities for the analysis of its subunit composition and partial protein sequencing. Analysis of the N-terminal residues of the 30 kDa polypeptide has enabled us to confirm the identity of the recently cloned cDNA that was tentatively identified as that of lysosomal alpha-mannosidase [Nebes and Schmidt (1994) Biochem. Biophys. Res. Commun. 200, 239-245] and to locate the position of this polypeptide within the total deduced amino acid sequence. This finding will therefore provide a firm foundation for the characterization of alpha mannosidosis mutations. PMID- 7832747 TI - Comparative studies on bile flow and biliary lipid excretion after bile-acid loading in normal and partially hepatectomized rats. AB - This study was performed to investigate sequential changes in bile secretion and biliary lipids after taurocholic acid (TCA) loading of regenerating rat liver. TCA was administered intravenously at stepwise-increasing doses to groups of non operated control and partially hepatectomized rats, 24, 72 and 168 h after surgery. Bile flow, bile-acid output (BAO) and phospholipid output (PLO) (expressed per gram of liver) in partially hepatectomized rats increased more than in the controls. Using an isolated perfusion rat-liver system, TCA infusion was also carried out on groups of non-operated control and hepatectomized rats 72 h after operation. Again bile flow, BAO and PLO (expressed per gram of liver) were significantly higher in the partial hepatectomy case, mirroring the results obtained in vivo. When horseradish peroxidase (HRP) was pulse-loaded in isolated perfusion preparations, the second peak of biliary HRP secretion in hepatectomized rats was significantly higher than in controls. We conclude that increased bile-acid flow in partially hepatectomized rats is dependent upon acceleration of vesicular transport accompanying or following proliferation in regenerating livers. PMID- 7832748 TI - Tissue-specific and developmentally regulated alternative splicing in mouse skeletal muscle ryanodine receptor mRNA. AB - The ryanodine receptor is a channel for Ca2+ release from intracellular stores. By PCR analysis, we identified two alternatively spliced regions in mRNA of the mouse skeletal muscle ryanodine receptor (sRyR). The splice variants were characterized by the presence or absence of 15 bp (ASI) and 18 bp (ASII) exons. The exclusion of these exons results in the absence of the regions corresponding to Ala3481-Gln3485 and Val3865-Asn3870, respectively, of rabbit sRyR; these amino acid sequences exist in the modulatory region, where sites for phosphorylation and binding of Ca2+, calmodulin and ATP are postulated to be. We also detected sRyR in brain and heart as well as in skeletal muscle, and the splicing patterns were found to be tissue-specific. Only the ASII-lacking isoform was detected in heart, whereas in other tissues the ASII-containing isoform was predominant. The splicing patterns were also found to change during development. In skeletal muscle, the ASI-containing isoform increased gradually from embryo to adult. The ASII-lacking isoform abruptly increased upon birth, but the ASII-containing isoform increased steadily afterwards. In cerebrum, the ratio of the ASII containing isoform to the ASII-lacking one increased abruptly during embryonic days 14 and 18. These findings suggest that the alternative splicing of ASI and ASII, by affecting the modulatory region, generates functionally different sRyR isoforms in a tissue-specific and developmentally regulated manner. PMID- 7832749 TI - Inactivation during denaturation of ribonuclease A by guanidinium chloride is accompanied by unfolding at the active site. AB - Inactivation of pancreatic RNAase A occurs in guanidinium chloride (GdmCl) at low concentrations before the unfolding of the molecule as a whole can be detected [Liu and Tsou (1987) Biochim. Biophys. Acta 916, 455-464]. We have now shown that the rate of digestion of the RNAase molecule by either trypsin or proteinase K increases significantly at low concentrations of GdmCl where the enzyme is largely inactivated, but fluorescence and absorption measurements reveal no conformational changes. N-Terminal sequence analysis of the peptide fragments generated shows that proteolysis occurs primarily at or near the active site. The decrease in activity of RNAase at low concentrations of GdmCl is therefore due to partial unfolding of the molecule, particularly at the active site and not to an inhibition by the denaturant. PMID- 7832750 TI - Non-enzymic glycation of fibrous collagen: reaction products of glucose and ribose. AB - Non-enzymic glycation of collagen involves a series of complex reactions ultimately leading to the formation of intermolecular cross-links resulting in changes in its physical properties. During analysis for the fluorescent cross link pentosidine we identified the presence of an additional component (Cmpd K) in both glucose and ribose incubations. Cmpd K was formed more quickly than pentosidine in glucose incubations and more slowly than pentosidine in ribose incubations. Cmpd K represented 45% of the total fluorescence compared with 15% for pentosidine in glucose incubations and 25% of the total fluorescence compared with 30% for pentosidine in the ribose incubations. Cmpd K is not an artefact of in vitro incubations, as it was shown to be present in dermal tissue from diabetic patients. Subsequent high-resolution h.p.l.c. analysis of glucose incubated collagen revealed Cmpd K comprise two components (K1 and K2). Further, a similar analysis of Cmpd K from the ribose incubations revealed two different components (K3 and K4). These differences indicate alternative mechanisms for the reactions of glucose and ribose with collagen. The amounts of these fluorescent components and the pentosidine cross-link determined for both glucose and ribose glycation were found to be far too low (about one pentosidine molecules per 200 collagen molecules after 6 months incubation with glucose) to account for the extensive cross-linking responsible for the changes in physical properties, suggesting that a further additional series of cross-links are formed. We have analysed the non-fluorescent high-molecular-mass components and identified a new component that increases with time of in vitro incubation and is present in the skin of diabetic patients. This component is present in sufficient quantities (estimated at one cross-link per two collagen molecules) to account for the changes in physical properties occurring in vitro. PMID- 7832751 TI - Effect of retinoic acid on protein synthesis by foetal bovine chondrocytes in high-density culture: down-regulation of the glucose-regulated protein, GRP-78, and type II collagen. AB - The effect of 0.1-10 microM retinoic acid (RA) on foetal bovine chondrocytes was investigated in high-density cultures (0.6 x 10(6) cells/cm2). After 5 days of culture in ascorbate-free medium, control chondrocytes presented a typical rounded shape and synthesized type II, IX, XI and III collagens. After RA treatment on days 2-5 of culture, the cells exhibited a fibroblast-like shape and decreased synthesis of total protein (48%) and pepsinresistant proteins (60%) as determined by [35S]methionine labelling. Addition of RA was not followed by the expression of type I collagen, but induced quantitative changes in the synthesis of cartilage-specific collagens (II, IX and XI) as measured by direct autoradiography of the corresponding bands after SDS/PAGE. The main change was in type II collagen synthesis, with a 80% decrease in the cell-layer fraction and a 89% decrease in culture-medium fraction; inhibition of type IX and XI collagen synthesis was limited to 25 and 31% respectively. Modifications to intracellular proteins induced by RA were determined by using two-dimensional electrophoresis associated with a computerized imaging system. Synthesis of one of the more abundant proteins (pI 4.8; 78 kDa) was decreased by 75% after RA treatment. This protein was characterized by micro-sequencing as the glucose-regulated protein 78 (GRP 78). It was reported previously to bind denatured collagen and mutated type I procollagen molecule and to function as a molecular chaperone for collagen molecules. It remains to demonstrate whether the parallel down-regulation of GRP 78 and type II collagen observed here corresponds to a co-ordinate regulation of these two proteins. PMID- 7832752 TI - Identification of candidate residues for interaction of protein S with C4b binding protein and activated protein C. AB - Protein S is a plasma factor essential for prevention of thrombosis, partly due to its activity as a cofactor for the plasma anticoagulant protease-activated protein C. To expand knowledge about structure-function relationships in homologous protein S molecules, studies of protein S from different species have been performed. Protein S anti-coagulant activity in human, monkey, bovine, and porcine plasma has been inactivated by purified human C4b binding protein (C4BP) with dose-dependence, suggesting that each protein S can bind human C4BP and that only the free form of each is anti-coagulantly active. Purified porcine protein S has a 10-fold higher Kd for human C4BP than has human protein S. Protein S residues 420-434 provide an essential binding site for the negative regulator C4BP. cDNA sequences show that protein S residues 420-434 are highly conserved in all four species with the notable exception of Lys-429-Ile in porcine protein S. Differences between porcine and human protein S, e.g. Lys-429-Ile, Lys-43-Ala, Ser-197-Leu, Ser 199-Phe, Glu-463-Gly, Lys-571-Glu, Asn-602-Ile, Gln-607-Pro, may contribute to the decreased affinity of porcine protein S for human C4BP. Moreover, the species specificity of cofactor activities of various species of protein S is determined for human versus bovine-activated protein C, and these results, combined with sequence comparisons, agree with previous evidence that the thrombin-sensitive region and the first epidermal growth factor domain of protein S, i.e. residues 47-116, are responsible for recognition of activated protein C. PMID- 7832753 TI - Kinetics of the cooperative binding of glucose to dimeric yeast hexokinase P-I. AB - Kinetic studies of the cooperative binding of glucose to yeast hexokinase P-I at pH 6.5 have been carried out using the fluorescence temperature-jump technique. Three relaxation effects were observed: a fast low-amplitude effect which could only be resolved at low glucose concentrations (tau 1(-1) = 500-800 s-1), an intermediate effect (tau 2) which showed a linear dependence of reciprocal relaxation time on concentration, and a slow effect (tau 3) which showed a curved dependence on glucose concentration, increasing from approximately 28 s-1 at low concentrations to 250 s-1 at high levels. The findings are interpreted in terms of the concerted Monod-Wyman-Changeux mechanism, the two faster relaxations being assigned to binding to the R and T states, and the slow relaxation to isomerization between the states. Quantitative fitting of the kinetic data to the mechanism has been carried out using independent estimates of the equilibrium parameters of the model; these have been derived from equilibrium dialysis data and by determining the enhancement of the intrinsic ATPase activity of the enzyme by the non-phosphorylatable sugar lyxose, which switches the conformation of the enzyme to the active R state. PMID- 7832754 TI - Tissue distribution of the receptor for plasma retinol-binding protein. AB - The tissue distribution of the retinol-binding-protein receptor has been studied by using a cell-free binding assay. High binding activity was found in placenta, retina pigment epithelial cells, bone marrow and kidneys. Specific binding activity was also found in the small intestines, spleen and liver, and to a lesser extent in lung. Scatchard analysis revealed that the difference in binding activity was due to variations in receptor level and not affinity changes. When the kidneys were separated into cortex and medulla we found that almost all the specific binding activity present in kidneys was recovered in the cortex. The choroid plexus, an important site in the delivery of nutrients to the cerebrospinal fluid, expressed very high binding activity. The pineal gland, which has been shown to store vitamin A, also showed high binding activity. Testes from immature animals showed higher binding activity than testes from mature rabbits. Cultured undifferentiated kidney keratinocytes showed about 40 times higher binding activity than differentiated cells. Skin fibroblasts demonstrated no binding activity. In conclusion, the data presented in this report show that the level of the retinol-binding-protein receptor varies considerably between cell types. The observed tissue distribution of the receptor agrees well with the present knowledge on retinol function and metabolism by various cells. PMID- 7832755 TI - Role of protein kinase C activation in synthesis of complement components C2 and factor B in interferon-gamma-stimulated human fibroblasts, glioblastoma cell line A172 and monocytes. AB - The synthesis of C2 and factor B, the key components of complement system, is performed by various kinds of cells and is also up-regulated by interferon-gamma (IFN-gamma). By using human fibroblasts, human glioblastoma cell line A172 and monocytes, we investigated the signal-transduction mechanism for IFN-gamma induced synthesis of C2 and factor B. The C2 and factor B synthesis induced by IFN-gamma in all three cell types was inhibited by a protein kinase C (PKC) inhibitor, 1-(5-isoquinolinyl-sulphonyl)-2-methylpiperazine (H-7). The depletion of PKC in these cell types after treatment with phorbol 12-myristate 13-acetate (PMA) resulted in inhibition of IFN-gamma-induced C2 production. In addition, IFN gamma treatment elicited a decrease in cytoplasmic PKC in A172 cells, indicating that PKC is activated by IFN-gamma. These results suggest that PKC is crucial for IFN-gamma-induced C2 and factor B synthesis. Northern-blot analysis showed that the effects at H-7 were at least partly mediated by modulation of C2 and factor B mRNA abundance in A172 cells. Since treatment of fibroblasts and A172 cells with IFN-gamma had no effect on intracellular Ca2+ concentration, and since neither EGTA nor nifedipine inhibited C2 or factor B synthesis induced by IFN-gamma, we concluded that intracellular Ca2+ mobilization was not involved in the effect of IFN-gamma. In addition, genistein, herbimycin A and N-(6-aminohexyl)-5-chloro-1 naphthalene-sulphonamide (W-7) had no inhibitory effect on IFN-gamma-mediated action in any of the three cell types, which suggests that IFN-gamma acts independently of tyrosine kinases and calmodulin-dependent protein kinases. PMID- 7832756 TI - Role of tyrosine kinase and protein kinase C in the steroidogenic actions of angiotensin II, alpha-melanocyte-stimulating hormone and corticotropin in the rat adrenal cortex. AB - The role of protein kinases in the steroidogenic actions of alpha-melanocyte stimulating hormone (alpha-MSH), angiotensin II (AngII) and corticotropin (ACTH) in the rat adrenal zona glomerulosa was examined. Ro31-8220, a potent selective inhibitor of protein kinase C (PKC), inhibited both AngII- and alpha-MSH stimulated aldosterone secretion but had no effect on aldosterone secretion in response to ACTH. The effect of Ro31-8220 on PKC activity was measured in subcellular fractions. Basal PKC activity was higher in cytosol than in membrane or nuclear fractions. Incubation of the zona glomerulosa with either alpha-MSH or AngII resulted in significant increases in PKC activity in the nuclear and cytosolic fractions and decreases in the membrane fraction. These effects were all inhibited by Ro31-8220. ACTH caused a significant increase in nuclear PKC activity only, and this was inhibited by Ro31-8220 without any significant effect on the steroidogenic response to ACTH, suggesting that PKC translocation in response to ACTH may be involved in another aspect of adrenal cellular function. Tyrosine phosphorylation has not previously been considered to be an important component of the response of adrenocortical cells to peptide hormones. Both AngII and alpha-MSH were found to activate tyrosine kinase, but ACTH had no effect, observations that have not been previously reported. Tyrphostin 23, a specific antagonist of tyrosine kinases, inhibited aldosterone secretion in response to AngII and alpha-MSH, but not ACTH. These data confirm the importance of PKC in the adrenocortical response to AngII and alpha-MSH, and, furthermore, indicate that tyrosine kinase may play a critical role in the steroidogenic actions of AngII and alpha-MSH in the rat adrenal zona glomerulosa. PMID- 7832757 TI - Cloning, sequencing and heterologous expression of a cDNA encoding pigeon liver carnitine acetyltransferase. AB - Two overlapping cDNA clones encoding pigeon liver carnitine acetyltransferase (EC 2.3.1.7) (CAT) were isolated from a pigeon liver lambda gt11 cDNA library by gene amplification using oligonucleotide primers based on the N-terminal amino acid sequence of the enzyme. The two clones, which represent the 5' and 3' ends of the gene, were spliced together to form a single cDNA construct containing the entire coding sequence for CAT, with an in-frame TGA stop codon 42 bases before the first ATG start site and a 3'-untranslated segment of 1057 bases. The largest open reading frame of 1942 nucleotides predicted a polypeptide of 627 amino acids and a molecular mass of 71.1 kDa. The N-terminus and four internal peptides from the amino acid sequence of pigeon breast muscle CAT were identified in the predicted sequence of the liver cDNA clone. The identity of the CAT cDNA was confirmed by heterologous expression of active recombinant CAT (rCAT) in insect cells using the baculovirus expression system. Western blots of rCAT from infected insect cell lysates and immunodetection with a rabbit anti-CAT polyclonal serum showed an immunoreactive protein band similar in size to native CAT from pigeon breast muscle. Like the native enzyme, rCAT was capable of acylating carnitine with a preference for small-chain acyl-CoAs of carbon chain lengths C2-C4. PMID- 7832758 TI - Caldesmon mRNA splicing and isoform expression in mammalian smooth-muscle and non muscle tissues. AB - The recent determination of the genomic sequence of human caldesmon indicates that eight caldesmon mRNA species could be generated by selection of exon 1 or 1', exon 3a or 3ab and/or exon 4. We used reverse transcriptase PCR to determine which transcripts were produced in human, rabbit and sheep artery, vein, lung, intestine, kidney and liver. In all tissues the same three transcripts were present: exons 1'-2-3a-5-6...13, exons 1'-2-3a3b-5-6-...13 and exons 1'-2-3a3b-4 5-6...13. Exon 1 was not present and exon 4 was only present when exon 3b was also present. Three protein isoforms of caldesmon can be distinguished by electrophoresis on high-porosity 6% polyacrylamide gel: 130 kDa, 120 kDa and 70 kDa. The 70 kDa isoform lacks the sequence encoded by exon 3b. We investigated whether the two high-molecular-mass isoforms correspond to the presence and absence of exon 4 using an antiserum specific to the sequence encoded by exon 4. Western-blotting and immunoprecipitation experiments showed that both the 130 kDa and the 120 kDa isoforms were expressed with and without the exon 4 sequence. We therefore propose that the molecular-mass heterogeneity arises from additional first exons, possibly with separate promoter regions, which have not yet been characterized in the genomic sequence. PMID- 7832759 TI - Post-transcriptional regulation of the content of spermidine/spermine N1 acetyltransferase by N1N12-bis(ethyl)spermine. AB - Spermidine/spermine N1-acetyltransferase (SSAT) is the rate-limiting enzyme for the degradation and excretion of polyamines in mammalian cells, and its activity is known to be increased enormously on exposure to polyamines and polyamine analogues. The mechanism by which such an analogue, BESM [N1N12 bis(ethyl)spermine], increases the content of SSAT was investigated by transfecting COS-7 cells with plasmids containing SSAT cDNA in the pEUK expression vector. Despite a large increase in mRNA production, there was only a very small increase in SSAT activity in the transfected cells. When BESM was added at 36 h after transfection, there was a large and very rapid increase in SSAT protein amounting to 380-fold in 12 h without any increase in the mRNA. SSAT protein turned over very rapidly, with a half-life of about 20 min. In the presence of BESM, this turnover was greatly reduced, and the half-life increased to more than 13 h. However, this increase was not sufficient to account for all of the increase in SSAT protein, suggesting that there is also regulation of the translation of the mRNA by BESM. Further evidence for such translation regulation was obtained by studying the polysomal distribution of the SSAT mRNA. In the absence of BESM, most of the mRNA was present in fractions which sedimented more slowly than the monoribosome peak. In BESM-treated cells, a significant proportion of the SSAT mRNA was moved into the small-polysome region of the gradient. The expression of SSAT and the effects of BESM on the polysomal distribution of SSAT mRNA were not affected by the 5'- or 3'-untranslated regions of the mRNA, since constructs which lacked all of these regions gave similar results to constructs containing the entire mRNA sequence. These results show that the increased transcription of the SSAT gene that occurs in the presence of polyamine analogues such as BESM is not sufficient for SSAT expression and that post-transcriptional regulation is critical for the control of SSAT content. PMID- 7832760 TI - Evidence for a free N-acetylneuraminic acid-hydroxylating enzyme in pig mandibular gland soluble fraction. AB - The activity of a free N-acetylneuraminic acid (Neu5Ac)-hydroxylating enzyme which converted Neu5Ac into N-glycolyl-neuraminic acid (Neu5Gc) was demonstrated in the soluble fraction of pig mandibular gland. The hydroxylation was possible only with NADPH as the electron donor. The apparent Km was 4.5 mM Neu5Ac. At 0.5 mM monovalent cations had no effect on the hydroxylation of Neu5Ac whereas bivalent cations gave varied inhibition capacities ranging from 14 to 75%. EDTA gave a time-dependent enhancement of activity. It was concluded that the enzyme does not require an exogenously added inorganic cofactor. Results from salt fractionation of the soluble fraction and the use of inhibitors such as mercurials suggested that the hydroxylation of Neu5Ac to Neu5Gc may involve other, as yet unknown, component(s) and the possibility of electrons donated by NADPH being transferred to activated molecular oxygen (second substrate). We propose to name this enzyme N-acetyl-neuraminic acid hydroxylase. PMID- 7832761 TI - Glucose-transporter (GLUT4) protein content in oxidative and glycolytic skeletal muscles from calf and goat. AB - It is well accepted that skeletal muscle is a major glucose-utilizing tissue and that insulin is able to stimulate in vivo glucose utilization in ruminants as in monogastrics. In order to determine precisely how glucose uptake is controlled in various ruminant muscles, particularly by insulin, this study was designed to investigate in vitro glucose transport and insulin-regulatable glucose transporter protein (GLUT4) in muscle from calf and goat. Our data demonstrate that glucose transport is the rate-limiting step for glucose uptake in bovine fibre strips, as in rat muscle. Insulin increases the rate of in vitro glucose transport in bovine muscle, but to a lower extent than in rat muscle. A GLUT4 like protein was detected by immunoblot assay in all insulin-responsive tissues from calf and goat (heart, skeletal muscle, adipose tissue) but not in liver, brain, erythrocytes and intestine. Unlike the rat, bovine and goat GLUT4 content is higher in glycolytic and oxido-glycolytic muscles than in oxidative muscles. In conclusion, using both a functional test (insulin stimulation of glucose transport) and an immunological approach, this study demonstrates that ruminant muscles express GLUT4 protein. Our data also suggest that, in ruminants, glucose is the main energy-yielding substrate for glycolytic but not for oxidative muscles, and that insulin responsiveness may be lower in oxidative than in other skeletal muscles. PMID- 7832762 TI - Ultraviolet radiation stimulates a biphasic pattern of 1,2-diacylglycerol formation in cultured human melanocytes and keratinocytes by activation of phospholipases C and D. AB - Ultraviolet radiation (UVR) induces melanin synthesis by human epidermal melanocytes, and phospholipid-derived 1,2-diacylglycerols (DAGs) have been implicated in mediating this response. In previous experiments, addition of the synthetic DAG 1-oleoyl-2-acetylglycerol to cultured pigment cells stimulated melanogenesis. The purpose of the present study was to analyse the effects of UVR on the endogenous generation of DAGs. It was found that in a number of cultured cell types, including human melanocytes and B16 mouse melanoma cells, but also human keratinocytes and Swiss 3T3 fibroblasts, exposure to a single dose of UVR stimulated a biphasic increase in endogenous DAG formation. An early transient rise, over seconds, was followed by a more sustained delayed rise over minutes. The early rise in DAG levels was accompanied by a transient rise in inositol trisphosphate formation, indicating activation of phosphatidylinositol-specific phospholipase C. The delayed rise was accompanied by activation of phospholipase D. This endogenous DAG formation by pigment cells is further evidence for the involvement of DAGs in UVR-induced epidermal melanin synthesis. Since DAG formation is also seen in other cells types, it is possible that DAGs may be involved in an array of UVR-induced responses. PMID- 7832763 TI - Expression and selective inhibition of the constitutive and inducible forms of human cyclo-oxygenase. AB - The enzyme cyclo-oxygenase catalyses the oxygenation of arachidonic acid, leading to the formation of prostaglandins. Recently two forms of cyclo-oxygenase have been described: a constitutive (COX-1) enzyme present in most cells and tissues, and an inducible (COX-2) isoenzyme observed in many cells in response to pro inflammatory cytokines. Constitutive and inducible forms of human cyclo-oxygenase (hCOX-1 and hCOX-2) were cloned and expressed in insect cells, utilizing a baculovirus expression system. hCOX-1 had a specific activity of 18.8 mumol of O2/mg with a Km of 13.8 microM for arachidonate and Vmax. of 1500 nmol of O2/nmol of enzyme, whereas hCOX-2 had a specific activity of 12.2 mumol of O2/mg with a Km of 8.7 microM for arachidonate and a Vmax. of 1090 nmol of O2/nmol of enzyme. Indomethacin inhibited both hCOX-1 and hCOX-2, whereas NS-398 and Dup-697 selectively inhibited hCOX-2. Both NS-398 and Dup-697 exhibited time-dependent inactivation of hCOX-2, as did indomethacin on both enzymes. The competitive inhibitor of hCOX-1, mefenamic acid, also displayed competitive inhibition of hCOX-2. These results demonstrate the ability to generate selective non-steroidal anti-inflammatory drugs (NSAIDs), which could provide useful improvement therapeutically in the treatment of chronic inflammatory disease. PMID- 7832764 TI - Regulation of membrane-associated tyrosine phosphatases in UMR 106.06 osteoblast like cells. AB - Protein tyrosine phosphatases play an important role in cell metabolism. Three distinct protein tyrosine phosphatase activities have been identified in an osteoblast-like cell line, UMR 106.06. These activities comprised two membrane associated phosphatases and one cytosolic phosphatase of apparent molecular mass > 153 kDa, 80 kDa and 40 kDa respectively, estimated by gel filtration. On the basis of differences in apparent molecular mass, proteolytic-digestion profiles, substrate specificities and responses to a range of extracellular influences and inhibitor molecules, the two membrane-associated tyrosine phosphatases are distinct proteins. Tyrosine phosphatase activity in UMR 106.06 cells was sensitive to cell density. Cells at confluence contained membrane protein tyrosine phosphatase with specific activity 9-fold higher than cells at medium or low cell density. This elevation in membrane tyrosine phosphatase activity was due specifically to an increase in the high-molecular-mass enzyme. This phosphatase was also responsive to extracellular matrix components. This activity was elevated in cells grown on a collagen type-I matrix independently of cell density. Membrane and cytosolic protein tyrosine phosphatases were differentially regulated by a variety of agents including phorbol 12-myristate 13-acetate, parathyroid hormone, epidermal growth factor, okadaic acid and transforming growth factor beta. These observations suggest that regulatory influences control tyrosine phosphorylation in UMR 106.06 cells including cell-cell contact, cell matrix contact and signal transduction involving tyrosine and serine/threonine phosphorylation events. PMID- 7832765 TI - Comparison of the activities of a multiple inositol polyphosphate phosphatase obtained from several sources: a search for heterogeneity in this enzyme. AB - A multiple inositol polyphosphate phosphatase (formerly known as inositol 1,3,4,5 tetrakisphosphate 3-phosphatase) was purified approx. 22,000-fold from rat liver. The final preparation migrated on SDS/PAGE as a doublet with a mean apparent molecular mass of 47 kDa. Upon size-exclusion chromatography, the enzyme was eluted with an apparent molecular mass of 36 kDa. This enzyme was approximately evenly distributed between the 'rough' and 'smooth' subfractions of endoplasmic reticulum. There was a 20-fold range of specific activities of this phosphatase in CHAPS-solubilized particulate fractions prepared from the following rat tissues: liver, heart, kidney, testis and brain. However, each of these extracts contained different amounts of endogenous inhibitors of enzyme activity. After removal of these inhibitors by MonoQ anion-exchange chromatography, there was only a 2.5-fold range of specific activities; kidney contained the most and brain contained the least. We prepared and characterized polyclonal antiserum to the hepatic phosphatase, which immunoprecipitated 85-100% of both particulate and soluble phosphatase activities. The antiserum also immunoprecipitated, with equivalent efficacy, CHAPS-solubilized phosphatase activities from heart, kidney, testis, brain and erythrocytes (all prepared from rat). Our data strengthen the case that the function of the mammalian phosphatase is unrelated to the metabolism of Ca(2+)-mobilizing cellular signals. The CHAPS-solubilized phosphatase from turkey erythrocytes was not immunoprecipitated by the polyclonal antiserum, and is therefore an isoform that is structurally distinct, and possibly functionally unique. PMID- 7832766 TI - A novel receptor-type protein tyrosine phosphatase with a single catalytic domain is specifically expressed in mouse brain. AB - Protein tyrosine phosphatases (PTPases) are important regulatory proteins that, together with protein tyrosine kinases, determine the phosphotyrosine levels in cell signalling proteins. By PCR amplification of mouse brain cDNA fragments encoding the catalytic domains of these enzymes, we identified three novel members of the PTPase gene family. Northern-blot analysis showed that two of these novel clones represent brain-specific PTPases, whereas the third originates from a large-sized mRNA that is more ubiquitously expressed. A full-length cDNA encoding one of the brain-specific PTPases, PTP-SL, was isolated. Sequence analysis revealed a transmembrane PTPase containing a single catalytic phosphatase domain that has 45% homology to a rat cytoplasmic brain-specific PTPase named STEP. This suggests a role for PTP-SL in cell-cell signalling processes in the brain. PMID- 7832767 TI - Suppression of sterol 27-hydroxylase mRNA and transcriptional activity by bile acids in cultured rat hepatocytes. AB - In previous work we have demonstrated suppression of cholesterol 7 alpha hydroxylase by bile acids at the level of mRNA and transcription, resulting in a similar decline in bile acid synthesis in cultured rat hepatocytes [Twisk, Lehmann and Princen (1993) Biochem. J. 290, 685-691]. In view of the substantial contribution of the 'alternative' or '27-hydroxylase' route to total bile acid synthesis, as demonstrated in cultured rat hepatocytes and in vivo in humans, we here evaluate the effects of various bile acids commonly found in bile of rats on the regulation of sterol 27-hydroxylase in cultured rat hepatocytes. Addition of taurocholic acid, the predominant bile acid in rat bile, to the culture medium of rat hepatocytes resulted in a 72% inhibition of sterol 27-hydroxylase activity. The effect was exerted at the level of sterol 27-hydroxylase mRNA, showing a time and dose-dependent decline with a maximal suppression (-75%) at 50 microM taurocholic acid after 24 h of culture. The decline in mRNA followed first-order kinetics with an apparent half-life of 13 h. Under these conditions cholesterol 7 alpha-hydroxylase mRNA (-91%) and bile acid synthesis (i.e. chenodeoxycholic and beta-muricholic acid, -81%) were also maximally suppressed. In contrast, no change was found in the level of lithocholic acid 6 beta-hydroxylase mRNA. Assessment of the transcriptional activity of a number of genes involved in routing of cholesterol towards bile acids showed similar suppressive effects of taurocholate on expression of the sterol 27-hydroxylase and cholesterol 7 alpha hydroxylase genes (-43% and -42% respectively), whereas expression of the lithocholic 6 beta-hydroxylase gene was not affected. Taurocholic acid and unconjugated cholic acid were equally as effective in suppressing sterol 27 hydroxylase mRNA. The more hydrophobic bile acids, chenodeoxycholic acid and deoxycholic acid, also produced a strong inhibition of 57% and 76% respectively, whereas the hydrophilic beta-muricholic acid was not active. We conclude that (1) a number of bile acids, at physiological concentrations, suppress sterol 27 hydroxylase by down-regulation of sterol 27-hydroxylase mRNA and transcriptional activity and (2) co-ordinated suppression of both sterol 27-hydroxylase and cholesterol 7 alpha-hydroxylase results in inhibition of bile acid synthesis in cultured rat hepatocytes. PMID- 7832768 TI - Determination of the structure of two novel echistatin variants and comparison of the ability of echistatin variants to inhibit aggregation of platelets from different species. AB - Two new variants of short disintegrins were purified from the venom of Echis carinatus leakeyi and named echistatin beta and gamma. These proteins were found to be about 85% similar in amino acid sequence to echistatin alpha which has been well studied. The disulphide pattern of echistatin gamma appeared to be identical with that of echistatin alpha. They all contain the adhesive recognition sequence Arg-Gly-Asp (RGD) but inhibit the aggregation of platelets from human and other mammals with different potencies. Echistatin beta and alpha are far more effective on platelets from humans and guinea pigs than those from rabbits and rats whereas echistatin gamma is less discriminating of the platelets of the species tested. This species-dependent platelet sensitivity to echistatin beta and gamma could be attributed to the variations in residues 15, 21, 22 and 27, which are close to or within the RGD loop, rather than to the C-terminal variations after residue 46. Taking advantage of the presence of methionine residues flanking both sides of the ARGDDM motif in echistatin gamma, we deleted this hexapeptide by CNBr cleavage to produce des-(23-28)-echistatin gamma. The modified protein showed c.d. and fluorescent spectra grossly similar to the intact echistatin but its antiplatelet potency decreased more than 200-fold. We thus propose that a favourable conformation of the RGD region is responsible mainly for the high-affinity binding of echistatin to the platelet glycoprotein IIb-IIIa as shown previously for the binding of medium-size disintegrin. PMID- 7832769 TI - Escherichia coli dihydrodipicolinate synthase: characterization of the imine intermediate and the product of bromopyruvate treatment by electrospray mass spectrometry. AB - Simplified procedures for assaying and purifying dihydrodipicolinate synthase (EC 4.2.1.52), the first enzyme of the lysine biosynthetic pathway, have been developed and electrospray ionization m.s. has been used to observe the imine intermediate with pyruvate and to investigate the reaction of the enzyme with bromopyruvate and fluoropyruvate. PMID- 7832770 TI - Thapsigargin inhibits Ca2+ entry into human neutrophil granulocytes. AB - The mechanism of Ca2+ entry after ligand binding to receptors on the surface of non-excitable cells is a current focus of interest. Considerable attention has been given to Ca2+ influx induced by emptying of intracellular pools. Thapsigargin, an inhibitor of microsomal Ca(2+)-ATPase, is an important tool in inducing store-regulated Ca2+ influx. In the present paper we show that, at concentrations above 500 nM, thapsigargin also has an opposite effect: it inhibits store-regulated Ca2+ influx into Fura-2-loaded human neutrophil granulocytes. As thapsigargin has been frequently applied at concentrations up to 2 microM, its inhibitory action on plasma-membrane Ca2+ fluxes deserves consideration. PMID- 7832771 TI - Streptolysin-O induces release of glycosylphosphatidylinositol-anchored alkaline phosphatase from ROS cells by vesiculation independently of phospholipase action. AB - Streptolysin-O (SLO), a cholesterol-binding agent, was used for studies on the release of glycosylphosphatidylinositol (GPI)-anchored alkaline phosphatase (AP) from ROS cells. Treatment of cells with SLO resulted in a time- and concentration dependent release of AP into the extracellular medium. This release was potentiated by Ca2+ and bovine serum, but not by GPI-specific phospholipase D (GPI-PLD) purified from bovine serum. The released AP distributed to the detergent phase after Triton X-114 phase separation. This result suggested that the released AP contained an intact GPI anchor, and thus both proteolysis and anchor degradation by anchor-specific hydrolases, including GPI-PLD, as the potential mechanisms for SLO-mediated AP release were ruled out. The released AP sedimented at 100,000 g. A substantial amount of lipids was detected in the 100,000 g pellet. Cholesterol and sphingomyelin were enriched in SLO-released material, compared with intact cells. These results were consistent with vesiculation as the mechanism for SLO induction of AP release. Two other cholesterol-binding agents, saponin and digitonin, were also able to release AP, possibly by a similar vesiculation mechanism, whereas others, including nystatin, filipin and beta-escin, failed to elicit any AP release. Eight GPI-anchored proteins were identified in ROS cells, and all were substantially enriched in the vesicles released by SLO. Taken together, these results do not provide any support for the hypothesis that the clustering of GPI-anchored proteins in the plasma membrane is responsible for their resistance to GPI-PLD cleavage. PMID- 7832772 TI - Catalytic-rate improvement of a thermostable malate dehydrogenase by a subtle alteration in cofactor binding. AB - The nucleotide-binding fold of many NAD(+)-dependent dehydrogenases contains a conserved acidic amino acid residue which hydrogen-bonds with the 2'- and 3' hydroxy groups of the adenine-ribose of the cofactor. This residue is highly conserved as aspartate in malate dehydrogenases, except in the thermophilic enzyme from Thermus aquaticus B (TaqMDH), which has glutamic acid-41 in the equivalent position. The catalytic mechanism was dissected to investigate the functional significance of this difference in TaqMDH with respect to a mutant enzyme where glutamic acid-41 was replaced by aspartic acid. The mutant enzyme was found to retain a high degree of protein structural stability to both thermal and chemical denaturation. When compared with the wild-type enzyme the mutant had a higher Km and Kd for both reduced and oxidized cofactors (NADH and NAD+) and a 2-3-fold increase in steady-state kcat in both assay directions. The rate determining step for the reduction of oxaloacetate by wild-type TaqMDH was shown to be the rate of NAD+ release, which was about 2.5-fold higher for the mutant enzyme. This correlates well with the 1.8-fold higher steady-state kcat of the mutant enzyme and represents an improvement in the steady-state kcat of a thermophilic enzyme at moderate temperature by a conservative amino acid substitution which increases the rate of product release. PMID- 7832773 TI - Trypanosomatid cysteine protease activity may be enhanced by a kininogen-like moiety from host serum. AB - African trypanosomes contain cysteine proteases (trypanopains) the activity of which can be measured by in vitro digestion of fibrinogen, after electrophoresis in fibrinogen-containing SDS/polyacrylamide gels. When assessed by this procedure, trypanopain from Trypanosoma brucei (trypanopain-Tb) is estimated to have a molecular mass of 28 kDa. However, two additional bands of trypanopain activity (87 kDa and 105 kDa) are observed if serum is added to the trypanopain before electrophoresis. Formation of the 87 and 105 kDa bands is frequently accompanied by a reduction in the intensity of the 28 kDa activity which suggests that the extra bands are complexes of the 28 kDa trypanopain-Tb and a molecule from rat serum called rat trypanopain moledulator (rTM). The rTM-induced activation of cysteine proteases is not restricted to T. brucei as it is also observed with proteases from other protozoan parasites such as bloodstream forms of Trypanosoma congolense and the mammalian-infective in vitro-derived promastigote forms of Leishmania donovani and Leishmania major. The physical properties of rTM resemble those of the kininogen family of cysteine protease inhibitors. rTM is an acidic (pI 4.7) heat-stable 68 kDa glycoprotein with 15 kDa protease-susceptible domains. This resemblance between rTM and kininogens was confirmed by the positive, albeit weak, immunoreactivity between anti-(human low molecular-mass kininogen) antibody and rTM as well as anti-rTM antibody and human low-molecular-mass kininogen. Furthermore, commercial preparations of human-low molecular-mass kininogen and chicken egg white cystatin mimicked rTM by forming extra bands of proteolytic activity in the presence of trypanopain-Tb. In some instances, low-molecular-mass kininogen was also observed to increase the rate of hydrolysis of 7-(benzyloxycarbonyl-phenylalanyl-arginyl-amido)-4- methylcoumarin by live T. brucei. Although this effect was rather erratic, in no instance was significant inhibition observed when this putative cysteine protease inhibitor was used under these conditions. The activation of parasite cysteine proteases by commonly accepted cysteine protease inhibitors is unexpected and may have important pathological repercussions. PMID- 7832774 TI - Effects of aluminium on the hepatic inositol polyphosphate phosphatase. AB - There is speculation that some of the toxic effects of Al3+ may originate from it perturbing inositol phosphate/Ca2+ signalling. For example, in permeabilized L1210 mouse lymphoma cells, 10-50 microM Al3+ activated Ins(1,3,4,5)P4-dependent Ca2+ mobilization and Ins(1,3,4,5)P4 3-phosphatase activity [Loomis-Husselbee, Cullen, Irvine and Dawson (1991) Biochem. J. 277, 883-885]. Ins(1,3,4,5)P4 3 phosphatase activity is performed by a multiple inositol polyphosphate phosphatase (MIPP) that also attacks Ins(1,3,4,5,6)P5 and InsP6 [Craxton, Ali and Shears (1995) Biochem. J. 305, 491-498]: 5-50 microM Al3+ increased MIPP activity towards both Ins(1,3,4,5)P4 (by 30%) and Ins(1,3,4,5,6)P5 (by up to 500%), without affecting metabolism of InsP6. Higher concentrations of Al3+ inhibited metabolism of all three substrates, and in the case of InsP6, Al3+ altered the pattern of accumulating products. When 1-50 microM Al3+ was present, InsP6 became a less effective inhibitor of Ins(1,3,4,5)P4 3-phosphatase activity; this effect did not depend on the presence of cellular membranes, contrary to a previous proposal. The latter phenomenon largely explains how, in a cell-free system where Ins(1,3,4,5)P4 3-phosphatase is inhibited by endogenous InsP6, the addition of Al3+ can apparently increase the enzyme activity. However, there was no effect of either 10 or 25 microM Al3+ (in either the presence or absence of apotransferrin) on inositol phosphate profiles in either Jurkat E6-1 lymphoma cells or AR4-2J pancreatoma cells. PMID- 7832775 TI - The site of action of Ca2+ in the activation of steroidogenesis: studies in Ca(2+)-clamped bovine adrenal zona-glomerulosa cells. AB - The Ca(2+)-messenger system plays a crucial role in the regulation of steroid production in adrenal zona-glomerulosa cells, as it is known to mediate the action of both angiotensin II and K+. In the present study we used intact isolated glomerulosa cells in which the cytosolic free Ca2+ concentration ([Ca2+]c) was clamped at various levels with the Ca2+ ionophore ionomycin in order to locate the site(s) of action of Ca2+. By measuring in parallel steroid synthesis and [Ca2+]c, we show that Ca2+ levels (50-860 nM) regulate the production of both pregnenolone (up to 669 +/- 71.1% of the basal production) and aldosterone (up to 301 +/- 42.2%; EC50 = 303 nM). By contrast, Ca2+ did not stimulate the conversion of 11-deoxycorticosterone into aldosterone. Ca2+ modulation did not affect the formation of pregnenolone from freely diffusible analogues of cholesterol, indicating that Ca2+ acts at a step upstream of cholesterol side-chain cleavage. Moreover cycloheximide, an inhibitor of protein translation and of adrenocorticotropin-induced facilitation of intramitochondrial cholesterol transport, the rate-limiting step in steroidogenesis, also blocked Ca(2+)-triggered pregnenolone formation. This is consistent with a model in which Ca2+ promotes cholesterol transfer between mitochondrial membranes. In addition, agents using the cyclic AMP pathway as well as angiotensin II potentiated the steroidogenic response to increases in [Ca2+]c by augmenting both the efficacy and the potency of Ca2+. This effect of angiotensin II did not involve protein kinase C. These results establish a direct link between agonist-induced [Ca2+]c rises and a specific step of the steroidogenic pathway. PMID- 7832776 TI - Mu-opioids activate phospholipase C in SH-SY5Y human neuroblastoma cells via calcium-channel opening. AB - We have recently reported that, in SH-SY5Y cells, mu-opioid receptor occupancy activates phospholipase C via a pertussis toxin-sensitive G-protein. In the present study we have further characterized the mechanisms involved in this process. Fentanyl (0.1 microM) caused a monophasic increase in inositol 1,4,5 trisphosphate mass formation, with a peak (20.5 +/- 3.6 pmol/mg of protein) at 15 s. Incubation in Ca(2+)-free buffer abolished this response, while Ca2+ replacement 1 min later restored the stimulation of inositol 1,4,5-trisphosphate formation (20.1 +/- 0.6 pmol/mg of protein). In addition, nifedipine (1 nM-0.1 mM), an L-type Ca(2+)-channel antagonist, caused a dose-dependent inhibition of inositol 1,4,5-trisphosphate formation, with an IC50 of 60.3 +/- 1.1 nM. Elevation of endogenous beta/gamma subunits by selective activation of delta opioid and alpha 2 adrenoceptors failed to stimulate phospholipase C. Fentanyl also caused a dose-dependent (EC50 of 16.2 +/- 1.0 nM), additive enhancement of carbachol-induced inositol 1,4,5-trisphosphate formation. In summary, we have demonstrated that in SH-SY5Y cells activation of the mu-opioid receptor allows Ca2+ influx to activate phospholipase C. However, the possible role of this mechanism in the process of analgesia remains to be elucidated. PMID- 7832777 TI - Dinucleotide repeats in the human surfactant protein-B gene and respiratory distress syndrome. AB - Pulmonary surfactant, a lipoprotein complex, is essential for normal lung function, and deficiency of surfactant can result in respiratory-distress syndrome (RDS) in the prematurely born infant. Some studies have pointed towards a genetic contribution to the aetiology of RDS. Because the surfactant protein B (SP-B) is important for optimal surfactant function and because it is involved in the pathogenesis of pulmonary disease, we investigated the genetic variability of the SP-B gene in individuals with and without RDS. We identified a 2.5 kb BamHI polymorphism and studied its location, nature and frequency. We localized this polymorphism in the first half of intron 4 and found that it is derived by gain or loss in the number of copies of a motif that consists of two elements, a 20 bp conserved sequence and a variable number of CA dinucleotides. Variability in the number of motifs resulting from either deletion (in 55.3% of the cases with the variation) or insertion (44.7%) of motifs was observed in genomic DNAs from unrelated individuals. Analysis of 219 genomic DNAs from infants with (n = 82) and without (n = 137) RDS showed that this insertion/deletion appears with significantly higher frequency in the RDS population (29.3 as against 16.8%, P < 0.05). PMID- 7832778 TI - Effects of tetradecylthiopropionic acid and tetradecylthioacrylic acid on rat liver lipid metabolism. AB - Studies of effects of 4-thia-substituted fatty acid analogues on rat liver lipid metabolism are described. With isolated hepatocytes tetradecylthiopropionate was shown to divert [1-14C]oleate from beta-oxidation into esterification, the total amount of [1-14C]oleate metabolized remaining unchanged. Tetradecylthiopropionyl CoA was a good substrate for mitochondrial carnitine palmitoyltransferases I and II (EC 2.3.1.21), acyl-CoA oxidase (EC 1.3.3.6), for the microsomal (but not mitochondrial) glycerophosphate acyltransferase (EC 2.3.1.15), and for long-chain acyl-CoA dehydrogenase (EC 1.3.99.3). In isolated hepatocytes, its 4-thia-trans-2 enoic derivative, tetradecylthioacrylate, inhibits both beta-oxidation of, and incorporation of, [1-14C]oleate into lipids. In rat liver mitochondria tetradecylthiocrylate inhibited beta-oxidation. The degree of inhibition was not markedly increased by preincubation with tetradecylthioacrylate. Tetradecylthioacrylyl-CoA was a poor substrate for carnitine palmitoyltransferase I, and inhibited carnitine palmitoyltransferase II, microsomal glycerophosphate acyltransferase and acyl-CoA oxidase. It is concluded that the inhibitory effects of tetradecylthiopropionyl-CoA are expressed intramitochondrially, whereas primary sites of inhibition by tetradecylthioacrylyl-CoA are extramitochondrial. PMID- 7832779 TI - An extracellular domain of the beta subunit is essential for processing, transport and kinase activity of insulin receptor. AB - The extracellular portion of the insulin receptor (IR) beta-subunit has four cysteine and four asparagine residues which are potentially involved in disulphide bond formation between the alpha- and beta-subunits and N-linked glycosylation respectively. However, the function of this portion is not fully understood. In order to investigate the role of the extracellular domain of beta subunit, we created a deletion mutant of IR cDNA which lacked 47 amino acid residues encoded by 141 bp corresponding to exon 13 of the IR gene. Insulin binding and surface labelling of COS 7 cells transiently expressing the mutant insulin receptors (IR delta Ex13) showed that the mutated receptors were not expressed on the cell surface. However, immunoblot analysis showed that uncleaved form (190 kDa) of the mutant receptors were intracellularly expressed. Deglycosylation with endoglycosidase H showed that the mutant receptors had mainly high-mannose oligosaccharide chains. The mutant IRs bound with high affinity to lentil lectin but with low affinity to wheat germ agglutinin. Therefore, it is suggested that misfolding of the mutant receptors inhibits transport to the Golgi apparatus where processing of oligosaccharide chains, as well as proteolytic cleavage into subunits, takes place. The binding affinity of the mutant receptors for insulin was 50% of normal. Furthermore, insulin stimulated autophosphorylation of IR delta Ex13 was markedly impaired. These data provide the evidence for a critical role of the extracellular domain of IR beta subunit for processing and transport as well as the intramolecular signal transduction to activate IR tyrosine kinase. PMID- 7832781 TI - Phorbol ester stimulates choline uptake in Swiss 3T3 fibroblasts following introduction of the gene encoding protein kinase C alpha. AB - Phorbol 12-myristate 13-acetate (PMA) stimulated radiolabelled choline uptake and incorporation into phosphatidylcholine (PtdCho) in a time- and concentration dependent manner in wild-type NIH 3T3 fibroblasts. The accumulation of labelled choline induced by PMA was paralled by an increase in choline mass. The results implicate protein kinase C (PKC) in the regulation of choline uptake. In order to address the PKC-subtype specificity of this response, a study was undertaken in Swiss 3T3 fibroblast cells, which normally express very low levels of PKC alpha. A retroviral expression system was used to introduce the genes for PKC alpha and neomycin resistance (used for selection) into the cells. Two resulting lines expressed PKC alpha at levels that were 20-fold higher than those found in the control (neomycin-resistant) line, or in the wild-type cells. In control Swiss 3T3 fibroblasts, 1 microM PMA elevated choline levels by only 30%, whereas, in Swiss 3T3 cell lines that stably over-expressed PKC alpha, PMA caused a 5-fold enhancement in [14C]choline accumulation. This concentration of PMA significantly increased [14C]PtdCho levels in both control and PKC alpha-over-expressing lines, although the effect in the latter was significantly greater. The effects of PMA were inhibited by the PKC antagonist sphingosine. These results implicate PKC alpha in the regulation of choline accumulation and phospholipid synthesis in fibroblasts. Although additional PKC subtypes appear to participate in the control of PtdCho synthesis in these cells, PMA-stimulated choline uptake in Swiss 3T3 fibroblasts is almost entirely dependent on the presence of PKC alpha. PMID- 7832780 TI - Receptor-mediated activation of recombinant Trpl expressed in Sf9 insect cells. AB - The Drosophila proteins, Trp and Trpl, are suggested to be cation channels responsible for depolarization of the receptor potential associated with stimulation of insect photoreceptor cells by light. Consistent with this hypothesis, we recently showed that recombinant Trpl forms Ca(2+)- and Ba(2+) permeable non-selective cation channels when expressed in Sf9 cells using the baculovirus expression vector. As Trpl may be activated in the photoreceptor cell after stimulation of phospholipase C, we hypothesized that a similar regulation of recombinant Trpl may be observed in the Sf9 cell after activation of heterologous membrane receptors linked to Ca(2+)-signal-transduction pathways. To test this hypothesis, Ca2+ signalling was examined in Fura-2-loaded Sf9 cells infected with baculovirus containing cDNA for the M5 muscarinic receptor alone (M5 cells) or in cells co-infected with both M5 and Trpl-containing baculoviruses (M5-Trpl cells). Addition of carbachol (100 microM) to M5 cells produced an increase in cytosolic free Ca2+ concentration ([Ca2+]i) (mean +/- S.D.; n = 17) from 101 +/- 20 to 762 +/- 178 nM which declined to a sustained elevated level of 384 +/- 102 nM after 3 min. The sustained component was eliminated by removal of extracellular Ca2+ or by addition of La3+ or Gd3+ (10 microM). In M5-Trpl cells, basal [Ca2+]i increased as a function of time after infection. To evaluate the contribution of Ca2+ influx to the overall profile observed, Ba2+, a Ca2+ surrogate that is not a substrate for the Ca2+ pump, was used. The increase in basal [Ca2+]i seen in M5-Trpl cells was associated with an increase in basal Ba2+ influx. Addition of carbachol to M5-Trpl cells at 30-36 h after infection produced a large increase in [Ca2+]i to a sustained value of 677 +/- 143 nM. This change in [Ca2+]i was (1) blocked by atropine, (2) attenuated in the absence of extracellular Ca2+, and (3) relatively insensitive to La3+, but blocked by Gd3+ in the 0.1-1 mM range. In the presence of 10 microM Gd3+ to block the endogenous receptor-mediated Ca(2+)-influx in M5-Trpl cells. In sharp contrast increase in Ba2+ influx in M5-Trpl cells. In sharp contrast, neither Ca2+ nor Ba2+ influx through Trpl was affected by thapsigargin, a selective inhibitor of the endoplasmic reticulum Ca(2+)-ATPase pump.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7832782 TI - Role of phosphodiesterase isoenzymes in regulating intracellular cyclic AMP in adenosine-stimulated smooth muscle cells. AB - Three phosphodiesterase (PDE) isoenzymes were separated by Mono Q h.p.l.c. column chromatography from the soluble fraction of a homogenate of pig aortic smooth muscle cells. The first peak of PDE activity was stimulated by calmodulin in the presence of calcium. The second broad peak contained at least two activities, which were sensitive to inhibition by CI-930 or rolipram respectively. The distribution of total cellular enzyme activity in different subcellular fractions was also determined. The majority (78%) of the total activity was present in the cytosolic fraction, 18% of activity was in a membrane-bound form and 4% of activity was associated with the cytoskeleton. Rolipram-sensitive PDE was present predominantly in the cytosolic fraction, whereas cyclic GMP-inhibited, CI-930 sensitive PDE was evenly distributed between the cytosolic and particulate fractions. All of the calmodulin-dependent PDE activity was found in the soluble fraction. CI-930 and rolipram enhanced, by 2-fold and 3-4-fold respectively, the adenosine-stimulated rise in cellular cyclic AMP level. The increase in cyclic AMP levels due to CI-930 or rolipram was dose-dependent. Removal of adenosine once cyclic AMP had risen resulted in a rapid fall in cyclic AMP levels even in the presence of rolipram and CI-930. M&B 22,948, the calmodulin-dependent PDE inhibitor, caused less than a 25% increase of the adenosine-stimulated cyclic AMP levels by itself, but it contributed substantially to controlling the cyclic AMP levels after the removal of adenosine when used together with CI-930 and rolipram. These phenomena suggested that all three PDE isoenzymes participated in modulating cellular cyclic AMP levels after adenosine stimulation, and that differential importance of the individual isoenzymes depends on cellular cyclic AMP levels. PMID- 7832783 TI - Thrombin interaction with a recombinant N-terminal extracellular domain of the thrombin receptor in an acellular system. AB - The cDNA of the human endothelial cell thrombin receptor has been cloned and a chimeric fusion protein consisting of glutathione-S-transferase (GST) and the portion 25-97 corresponding to the N-terminal first extracellular domain of the thrombin receptor (TRE) has been expressed in Escherichia coli. Introduction of a factor Xa cleavage site in the fusion protein allowed purification of TRE after removal from the GST carrier protein. Purified GST-TRE or TRE have been tested in solution for their ability to interact with thrombin. alpha-Thrombin cleaved the fusion protein at position Arg-41-Ser-42 of TRE in a time- and concentration dependent manner and GST-TRE competed with the tripeptidic substrate S-2238 for hydrolysis by thrombin (Ki = 0.5 microM). gamma-Thrombin that lacks the anion binding exosite was 100-fold less potent than alpha-thrombin at cleaving GST-TRE. TRE competed with polymerizing fibrin monomers for binding to thrombin (Ki = 7.5 microM). The cleavage of GST-TRE by alpha-thrombin was inhibited by several alpha thrombin exosite ligands such as the C-terminal peptide of hirudin, thrombomodulin and fibrin(ogen) fragment E. In contrast, platelet glycocalicin did not inhibit GST-TRE cleavage. In conclusion, the use of purified soluble GST TRE allowed us to derive an affinity constant for thrombin interaction with the N terminal domain of the receptor and to confirm the location of the cleavage site at Arg41-Ser-42 of the receptor. The importance of the thrombin anion-binding exosite for thrombin receptor recognition is highlighted by the low reactivity of gamma-thrombin for GST-TRE and by competition experiments, which in addition indicate that binding sites for fibrin(ogen), thrombomodulin and GST-TRE are overlapping. In contrast, binding of thrombin to GST-TRE and glycocalicin are not mutually exclusive, indicating that glycocalicin and TRE interact with discrete subsites within the large groove that constitutes the anion-binding exosite. PMID- 7832784 TI - Protein hydroperoxides can give rise to reactive free radicals. AB - Proteins damaged by free-radical-generating systems in the presence of oxygen yield relatively long-lived protein hydroperoxides. These hydroperoxides have been shown by e.p.r. spectroscopy to be readily degraded to reactive free radicals on reaction with iron(II) complexes. Comparison of the observed spectra with those obtained with free amino acid hydroperoxides had allowed identification of some of the protein-derived radical species (including a number of carbon-centred radicals, alkoxyl radicals and a species believed to be the CO2 radical anion) and the elucidation of novel fragmentation and rearrangement processes involving amino acid side chains. In particular, degradation of hydroperoxide functions on the side chain of glutamic acid is shown to result in decarboxylation at the side-chain carboxy group via the formation of the CO2 radical anion; the generation of an identical radical from hydroperoxide groups on proteins suggests that a similar process occurs with these molecules. In a number of cases these fragmentation and rearrangement reactions give rise to further reactive free radicals (R., O2-./HO2., CO2-.) which may act as chain carrying species in protein oxidations. These studies suggest that protein hydroperoxides are capable of initiating further radical chain reactions both intra- and inter-molecularly, and provide information on some of the fundamental mechanisms of protein alteration and side-chain fragmentation. PMID- 7832785 TI - Human plasma phospholipid transfer protein accelerates exchange/transfer of alpha tocopherol between lipoproteins and cells. AB - alpha-Tocopherol (alpha-T), an important anti-oxidant of plasma lipoproteins and cell membranes, is secreted from liver together with very-low-density lipoproteins into the blood stream. Other serum lipoprotein classes gain alpha-T by exchange and transfer processes. We show here that the lipoprotein-free d > 1.22 g/ml fraction of human or pig serum increases the exchange rate of alpha-T by a factor of 2-4 as compared with spontaneous exchange/transfer. The alpha-T exchange/transfer (alpha-TET) activity was purified by multiple-step column chromatography. It gave a single band in PAGE with an apparent molecular mass of 75 kDa, and was found to be identical with the phospholipid transfer protein (PLTP). PLTP catalysed alpha-T exchange between different lipoprotein classes, as well as the transfer of alpha-T from artificial liposomes to high-density lipoproteins. The alpha-TET activity measured with a newly developed assay in ten healthy people was 2.45 +/- 0.88 nmol.ml-1.h-1.alpha-TET activity was negatively correlated with plasma low-density lipoprotein-cholesterol (r = -0.75; P < 0.01). It is concluded that human PLTP catalyses exchange/transfer processes of alpha-T between lipid compartments. This factor may be of relevance in atherogenesis and tumour initiation and growth. PMID- 7832786 TI - Perinatal maturation of rat kidney mitochondria. AB - In the rat kidney, NaK-ATPase activity increased between days 19 and 20 of gestation (+50%) and between 1 and 24 h after birth (+20%), requiring an increased energy supply. In order to determine whether mitochondrial changes were involved, renal mitochondrial development was investigated from day 19 of gestation to 1 day after birth. Slot-blot analyses of mitochondrial-DNA/nuclear DNA ratio and determination of citrate synthase activity showed a doubling in the mitochondrial pool between days 19 and 20 of gestation. In isolated mitochondria, oxygen consumption remained unchanged between days 19 and 20 of gestation, and then it was enhanced between days 20 and 21 of gestation (+70%) and between 1 and 24 h after birth (+50%). We also focused on one of the respiratory-chain complexes, ATP synthase, and measured its activity and content during the perinatal period. We demonstrated increases in both activity and content of ATP synthase between days 20 and 21 of gestation and between 1 and 24 h after birth, thus suggesting that changes in ATP synthase activity are ascribed to an increase in the mitochondrial density of ATP synthase complexes. Moreover, the mitochondrial ATP/ADP ratio only increased between 1 and 24 h (+90%), indicating a critical step in the renal respiratory-chain maturation at that time. We therefore conclude that the postnatal enhancement of renal mitochondrial oxidative capacity might depend on protein synthesis de novo and on changes in the adenine nucleotide concentrations. PMID- 7832787 TI - A novel isoenzyme of aldehyde dehydrogenase specifically involved in the biosynthesis of 9-cis and all-trans retinoic acid. AB - The pleiotropic effects of retinoids are mediated by two families of nuclear receptors: RAR (retinoic acid receptors) and RXR (retinoid X receptors). 9-cis Retinoic acid is a specific ligand for RXR receptors, whereas either 9-cis- or all-trans-retinoic acid activates the RAR receptor family. The existence of RXRs suggests a new role for isomerization in the biology of retinoic acid. We report here the identification of an aldehyde dehydrogenase in the rat kidney that catalysed the oxidation of 9-cis- and all-trans-retinal to corresponding retinoic acids with high efficiency, 9-cis-retinal being 2-fold more active than all-trans retinal. Based on several criteria, such as amino acid sequence, pH optimum, and inhibition by chloral hydrate, this enzyme was found to be a novel isoenzyme of aldehyde dehydrogenase. 9-cis-Retinol, the precursor for the biosynthesis of 9 cis-retinal was identified in the rat kidney. The occurrence of endogenous 9-cis retinol and the existence of specific dehydrogenase which participates in the catalysis of 9-cis-retinal suggest that all-trans-retinoi(d) isomerization to 9 cis-retinoi(d) occurs at the retinol level, analogous to all-trans-retinol isomerization to 11-cis-retinol in the visual cycle. PMID- 7832788 TI - Characteristic differences in the primary structure allow discrimination of cyclodextrin glucanotransferases from alpha-amylases. PMID- 7832789 TI - Possible involvement of retinoid-like cofactor in serum in hemin/protoporphyrin IX-induced differentiation of human leukemia K562 cells. AB - Serum is generally added to media used for mammalian cell culture and for investigation of in vitro cell differentiation induction. Erythroid differentiation of human leukemia cell line K562 is induced by hemin or protoporphyrin IX in the presence of fetal bovine serum (FBS). Addition to the medium of retinoids enhanced the differentiation, and addition of retinoid antagonists suppressed the differentiation. Making the added FBS retinoid-free, i.e., treatment of the serum with charcoal, also reduced the efficiency of the cell differentiation induced by hemin or protoporphyrin IX. These facts suggest that retinoids or retinoid-like cofactor(s) in serum are necessary for hemin/protoporphyrin-IX-induced erythroid differentiation of K562 cells. PMID- 7832790 TI - Neuronal specificity of subtype SQSC1 of squid putative sodium channel. AB - The distribution of SQSC1 mRNA in tissues of squid Loligo bleekeri was studied by the blot hybridization method. The complete cDNA for the coding region of SQSC1, the invertebrate putative sodium channel, was prepared from squid optic lobe (Sato and Matsumoto, Biochem. Biophys. Res. Comm. 186, 61-68, 1992). Transcriptional products of the SQSC1 gene were found to consist of two main different lengths (12 and 9 kb). The transcriptional products were detected in all the nervous tissues examined: optic lobes, cerebral ganglia and giant stellate ganglia. However, it was not detected in the muscle, suggesting the SQSC1 gene is specific for sodium channels of squid nerve cells. SQSC1 appears more widely distributed in the nervous system than GFLN1 which they reported as expressed specifically in stellate ganglion of the squid (Rosenthal and Gilly, Proc. Natl. Acad. Sci. USA 90, 10026-10030, 1993). PMID- 7832791 TI - Neurohumoral factors during transition from left ventricular hypertrophy to failure in Dahl salt-sensitive rats. AB - The relationship between the reduction in the positive inotropic effects (PIE) of beta-adrenergic stimulation and the level of systemic and tissue neurohumoral factors during the course from left ventricular (LV) hypertrophy to congestive heart failure (CHF) was studied in Dahl salt-sensitive rat (DS) CHF model. Control studies were performed in age-matched Dahl salt-resistant (DR) rats. In DS rats at CHF stage, plasma atrial natriuretic peptide (ANP) and norepinephrine (NE) levels were elevated markedly and myocardial NE level was decreased compared with those in the age-matched DR rats. On the other hand, at the hypertrophy stage, we observed no significant differences in plasma ANP or NE level between the two strains in spite of decrease in myocardial NE concentration. The PIE induced by isoproterenol was reduced at the stage of compensatory LV hypertrophy, which was followed by further reduction of PIE at CHF stage. The results distinctively indicate that beta-adrenergic desensitization in the myocardium which was accompanied with the abnormalities in local sympathoneuronal regulation begins during mechanically compensated LV hypertrophy and precedes systemic augmentation of sympathomimetic hormones. PMID- 7832792 TI - c-jun inhibited the alternative splicing of neuron-specific amyloid precursor protein, but stimulated the non-neuron type one in P19 EC cells. AB - Three alternative splicing products of amyloid precursor protein (APP), APP770, 751 and 695, were detected in mouse embryonal carcinoma (EC) P19 cells by reverse transcriptase RNA polymerase chain reaction (RT-PCR). Alternative splicing of APP pre-mRNA in P19EC cells was remarkably changed by c-jun transformation. The relative ratio of APP770 encoding exons 7 and 8, non-neuron type, was increased by c-jun transformation, while that of APP 695 not encoding exons 7 and 8, neuron specific one, was decreased. These results suggested that skipping of exons 7 and 8 was specifically blocked in c-jun transformed cells. APP 695, which increases in P19 EC cells under the culture conditions that induce the neuronal differentiation, did not increase in C2C5 cells under the same conditions, suggesting that c-jun transformed cells were not in the neuronal cell lineage and lost the ability to differentiate into neurons. PMID- 7832793 TI - Low-frequency EPR study of chromium(V) formation from chromium(VI) in living plants. AB - The reduction of Cr(VI) by green algae and higher plants was investigated using a low-frequency EPR spectrometer equipped with an extended loop gap resonator. Incubation of algae (Spirogyra and Mougeotia) with Cr(VI) generated both Cr(V) and Cr(III). The maximum Cr(V) signal was observed in about 10 minutes. Incubation of Cr(VI) with oat, soybean, and garlic generated Cr(V). The maximum Cr(V) peak appeared after more than 10 hours of incubation, and Cr(V) was located predominantly in the roots. The Cr(V) peak exhibited hyperfine splittings of about 0.79 gauss, typical of the Cr(V) complexes with diol-containing molecules. The results suggest that the reduction of Cr(VI) to lower oxidation states by living plants may provide a detoxification pathway for Cr(VI) in ecological systems. The results also indicate that low-frequency EPR may be used to investigate the metabolism of paramagnetic metal ions in intact plants. PMID- 7832794 TI - Lipid accumulation and foam cell formation in Chinese hamster ovary cells overexpressing very low density lipoprotein receptor. AB - The rabbit very low density lipoprotein receptor gene was introduced into LDL receptor-negative Chinese hamster ovary cells (ldl-A7). Incubation of the transfected cells with rabbit beta-VLDL (5 to 8 micrograms protein/ml), for 6 days, induced foam cell formation. The cells accumulated lipid droplets visualized by oil red-O staining; the cellular cholesteryl ester and triglyceride content increased two- to threefold. [3H]Oleate incorporation into cholesteryl [3H]oleate was stimulated threefold by incubation of cells with beta-VLDL (20 micrograms protein/ml). Northern blot analysis revealed the presence of VLDL receptor mRNA in rabbit resident alveolar macrophages. Incubation of the macrophages with beta-VLDL (20 micrograms protein/ml) for 24 hours induced foam cell formation but had virtually no effect on VLDL receptor mRNA abundance. These results suggest that the VLDL receptor on macrophages may play an important role in foam cell formation. PMID- 7832795 TI - GTP gamma S-induced pepsinogen secretion from gastric chief cells does not require carboxyl methylation or translocation of low molecular weight (LMW) GTP binding proteins. AB - We identified at least four LMW GTP-binding proteins in membrane and cytosolic fractions from dispersed gastric chief cells. Extraction of membrane-bound GTP binding proteins with various agents revealed that these proteins are intimately associated with chief cell membranes. Upon extraction with Triton X-114, the majority of GTP-binding proteins partitioned into the detergent phase, indicative of their hydrophobic nature. Although carboxyl methylation of LMW GTP-binding proteins has been shown to regulate their localization and function, inhibitors of carboxyl methylation had no effect on GTP gamma S-induced pepsinogen secretion. Moreover, pre-permeabilization of chief cells for up to 20 min did not alter GTP gamma S-induced secretion, suggesting that the guanine nucleotide analogue interacts with membrane-bound GTP-binding proteins to elicit a secretory response. PMID- 7832796 TI - Biochemical and genetic characterization of a replication protein A dependent DNA helicase from the yeast, Saccharomyces cerevisiae. AB - We have purified a DNA dependent ATPase/DNA helicase, DNA helicase B, from S. cerevisiae. Helicase B was a 129-kDa polypeptide. The ATPase activity of helicase B was strongly DNA dependent. The DNA helicase activity was stimulated by yeast replication protein A, indicating a probable function in DNA replication. Helicase B showed a 5'-->3' polarity of movement. Protein sequencing indicated that helicase B was identical to a hypothetical 127-kDa polypeptide encoded by yORF61, located 5' upstream of the BMH1 locus in chromosome V. The protein sequence contained a "type I ATP/GTP binding motif" and other helicase-like motifs and the expressed protein exhibited helicase activity. Thus, we concluded that yORF61 is the gene for helicase B and will be referred to as HCSB. PMID- 7832797 TI - Tunicamycin inhibits the expression of functional thrombin receptors on human T lymphoblastoid cells. AB - N-linked glycosylation plays an important role in intracellular trafficking and the surface expression of many membrane-associated proteins. In the present report we investigated the effect of tunicamycin, a specific inhibitor of N linked glycosylation, on the expression and function of the thrombin receptor on human T-lymphoblastoid cells. We found that tunicamycin selectively inhibited thrombin-induced Ca2+ mobilization in a dose-dependent manner while the same response triggered by anti-CD3 antibody was unchanged in these cells. Surface expression of the thrombin receptor, as assessed by immunofluorescence staining using two different antibodies, was strongly decreased in the presence of tunicamycin. These findings indicate a role for N-linked glycosylation in the surface expression of the thrombin receptor in T lymphoid cells. PMID- 7832798 TI - Susceptibility of human T-lymphotropic virus type I infected cell line MT-2 to hepatitis C virus infection. AB - To obtain a hepatitis C virus (HCV) proliferation system, we examined the susceptibility of various cultured cell lines to HCV infection. We found that a human T-lymphotropic virus type I infected cell line MT-2 was fairly sensitive to HCV infection. Using the polymerase chain reaction, intracellular positive stranded HCV RNA was detected until at least 15 days postinoculation (p.i.). Intracellular negative-stranded HCV RNA was also detected at 10 days p.i., although not at 7 days p.i., suggesting that HCV is replicating in MT-2 cells 10 days p.i. Sequence analysis of hypervariable region 1 (HVR1) revealed that HVR1 sequences from cells 10 days p.i. had become homogeneous, although HVR1 sequences from the inoculum showed the typical quasi-species. We also found a lack of anti HVR1 antibody against the HVR1 species which became homogeneous at 10 days p.i., although we easily detected antibody against the other HVR1 species obtained from the inoculum. These findings suggest that MT-2 cells are susceptible to HCV infection and are capable of supporting HCV replication. PMID- 7832799 TI - Selectivity in inositol phosphate production following pancreatic acinar cell desensitization. AB - The effects of pancreatic acinar cell desensitization by carbamylcholine (Cch), caerulein (Cae) and the phorbol ester TPA on the production of inositol tris and tetrakisphosphates were studied. In control acini, Cch and Cae caused comparable increases in Ins (1,4,5) P3, Ins (1,3,4,5) P4 and Ins (1,3,4) P3 after 15 sec stimulation. Desensitization by Cch totally inhibited the subsequent production of all three inositol phosphates in response to Cch. Desensitization by Cae allowed a subsequent production of all three inositol phosphates in response to Cae, but with a significant reduction. Desensitization by TPA reduced the production of Ins (1,4,5) P3 in response to Cch and Cae and totally inhibited that of the two other inositides. These data point to phospholipase C as a prime target for the altered production of inositol phosphates. PMID- 7832800 TI - Identification of a specific transport system for L-arginine in human platelets. AB - The present study demonstrates that human platelets possess a specific L-arginine transport system able to provide adequate amounts of L-arginine for endogenous nitric oxide production. L-arginine uptake takes place through a saturable high affinity carrier-mediated Na(+)-independent process which is significantly inhibited by L-ornithine, L-lysine and N omega-methyl-L-arginine. The high affinity of the transport process and the pattern of inhibition are consistent with mediation of L-arginine transport via the Na(+)-independent y+ system. The data on the kinetic parameters of the transporter suggest a possible role for arginine plasma levels in the regulation of platelet nitric oxide production. PMID- 7832801 TI - A novel promoting action of fullerene C60 on the chondrogenesis in rat embryonic limb bud cell culture system. AB - Fullerene C60 was solubilized with polyvinylpyrrolidone (PVP) in water, and the aqueous solution was applied to the rat limb bud cell differentiation system. By the incubation with various concentrations of C60 with poly(vinylpyrrolidone), cell differentiation was extremely promoted, up to the levels of a 3.2-fold increase of the controls. Although poly(vinylpyrrolidone) alone inhibited the cell differentiation in proportion to the concentration, the observed promoting action by C60 surpassed the action of poly(vinylpyrrolidone). This specific promoting action on the chondrogenesis is the novel significant activity of C60. PMID- 7832802 TI - Regulation of sex-hormone-binding globulin production by endogenous estrogens in vitro. AB - The effect of endogenous estrogens on sex-hormone-binding globulin (SHBG) production was studied in HepG2 cells. 17 beta-estradiol, estrone, and estrogens from both 2- and 16 alpha-hydroxylative pathways stimulated SHBG production, but not in parallel with their binding affinities for the estrogen receptor. Thus, the underlying mechanism may be other than a pure interaction with the estrogen receptor. PMID- 7832803 TI - Characterization of recombinant human aldolase B and purification by metal chelate chromatography. AB - Recombinant human aldolase B and the native enzyme purified from human liver were found to be identical in size, charge, structure, Km constants for fructose-1,6 bis(phosphate) and fructose-1-phosphate, and the activity ratio of the two substrates. Thus recombinant aldolase B is a valid model for the native enzyme and can be used to study mutations that cause hereditary fructose intolerance or others designed in the active site. Addition of six histidine residues to the amino-terminus of the recombinant enzyme did not alter its structural or functional characteristics and allowed for purification by immobilized metal affinity chromatography. This purification protocol does not require a stable or active enzyme and will facilitate the study of mutant aldolase B enzymes that would otherwise be difficult to purify. PMID- 7832804 TI - Radioimmunoassay of the APC gene product using antibodies against its middle and carboxyl regions. AB - A radioimmunoassay (RIA) has been developed for the adenomatous polyposis coli protein (APC). High-avidity rabbit polyclonal antibodies were produced against synthetic peptides corresponding to amino acids 1865-1881 (APC-1) and to amino acids 1336-1350 (APC-2) in APC's 2844 amino acid sequence. Both antibodies were utilized in RIA to evaluate full-length APC that is present in the insoluble particulate fraction of cell lysates. High salt extraction, often employed for coiled-coil type protein preparations, was found to be useful for extraction of APC from lysates of normal colonic epithelium. Proteolytic digestion of high salt extracts increased antibody reactivity toward both epitopes, suggesting that APC 1 and APC-2 antigenic sites are partially concealed due to APC's involvement in multiprotein complexes. Thus, RIA using our antibodies will provide a valuable tool for APC protein purification and in studies for elucidating APC's biologic function. PMID- 7832805 TI - Identification of novel cellular genes transcriptionally suppressed by v-src. AB - Our aim is to identify cellular genes whose transcriptional suppression by the v src oncogene contributes directly and specifically to the transformed and tumorigenic phenotype. We used a modified PCR-based subtractive hybridization technique to isolate 9 cDNAs whose abundance in NIH3T3 fibroblasts is decreased 3 15-fold following transformation by the activated oncogene, v-src. Sequence analysis reveals that 3 cDNAs are unlike those in GenBank. The remaining 6 cDNAs are indentical or highly similar to rat helix-destabilizing protein gene (hnRNP A1), mouse CTLA-2 alpha cysteine protease, rat cytochrome c oxidase (COX) VIc subunit, mouse Type I collagen, human gravin and a partial human cDNA (clone A7C09) isolated by random automated sequencing. Northern blot analysis indicates that the basal level of transcripts in untransformed NIH3T3 of all the genes except mouse Type I collagen was at least 10-fold lower than that of HMG Co-A Reductase, which is abundantly transcribed. These data suggest that the down regulation of some or all of these genes contributes to v-src-induced changes in mitogenic control or cell morphology. PMID- 7832806 TI - Down-regulation of interleukin-8 gene expression in HL60 cell line by human Kunitz-type trypsin inhibitor. AB - Urinary trypsin inhibitor (UTI) is one of the Kunitz-type protease inhibitors in human. Little is known about its anti-inflammatory functions other than protease inhibition. We studied the effect of UTI on gene expression of interleukin-8 (IL 8), an inflammatory cytokine. UTI inhibited IL-8 gene expression induced by lipopolysaccharide (LPS) in HL60 cells. The IL-8 concentrations in the cells and medium after LPS stimulation increased time-dependently in the absence of UTI, but did not increase in the presence of UTI. On the other hand, UTI did not inhibit either the synthesis or the release of IL-8 induced by the calcium ionophore A23187. UTI inhibited increase of cytosolic Ca2+ stimulated by LPS but not by A23187. Our results suggest that the inhibition by UTI is due to its effect on the cell membrane involved in regulating Ca2+ influx. PMID- 7832807 TI - Characterization of the proximal promoter region of the rat somatostatin receptor gene, SSTR4. AB - In the present study, the putative promoter region of rSSTR4 gene has been cloned and characterized. Primer extension and RNAase protection analysis reveals the existence of multiple transcriptional initiation sites, the five major ones mapping between -126 and -18 relative to the ATG initiation codon. Sequence analysis reveals that the region lacks TATA and CCAAT promoter elements, possesses a high GC content and contains a number of potential SP1 binding sites. In addition, potential AP-2, GCF, and PuF binding sites and an octimer motif were also identified. Thus, the promoter of rSSTR4 shows similar features to promoters of highly regulated growth factor receptors and oncogenes. The potential role these transcriptional binding sites play in regulating rSSTR4 expression is currently being investigated. PMID- 7832808 TI - Transformation of microorganisms with the plasmid vector with the replicon from pAC1 from Acetobacter pasteurianus. AB - A number of gram-negative and gram-positive bacteria species was screened for the expression of the gram-negative plasmid pACK5 and pACT72 with replicon of pAC1 plasmid from Acetobacter pasteurianus. As was described previously, both plasmids were expressed in Escherichia coli, Acetobacter pasteurianus, Acetobacter aceti, Shigella spp. and Citrobacter spp. Expressions of plasmids were successful in twelve species tested, Comamonas terrigena, Salmonella typhimurium, Serratia marcescens, Bacillus cereus, Bacillus megatericum, Bacillus subtilis, Lactobacillus helveticus, Micrococcus luteus, Sarcina lutea, Staphylococcus aureus, Staphylococcus epidermidis, Streptoccocus feacalis, and the stability of plasmid DNA was tested after cultivation in non-selective conditions. PMID- 7832809 TI - p53 controls proliferation of early B lineage cells by a p21 (WAF1/Cip1) independent pathway. AB - We examined a role of p53 in early B cell development using fetal liver (FL) cells from p53 deficient (-/-) mice. Expression of p53 was detected in early B lineage (pre-B) cells developed in the stromal cell-dependent FL cell culture. Proliferation of the pre-B cells from the p53(-/-) mice was augmented, suggesting that p53 negatively regulates proliferation of pre-B cells. Although p21 (WAF1/Cip1) is a downstream effector of p53 and mediates growth arrest by inhibiting the action of cyclin-dependent kinases, expression of p21 was also induced in the pre-B cells from p53(-/-) mice. These results indicate that expression of the p21 in pre-B cells is independent of p53 and that the regulatory effect of p53 on proliferation of pre-B cells is mediated by a p21 independent pathway. PMID- 7832810 TI - Full active baculovirus-expressed human monocyte chemoattractant protein 1 with the intact N-terminus. AB - The Sf-9 insect cells infected with a recombinant baculovirus integrated with a cDNA encoding human monocyte chemoattractant protein-1 (MCP-1) produced three different MCP-1s, which were isolated by reverse-phase HPLC as 13kDa, 14kDa, and 15kDa bands on SDS-PAGE. The heterogeneity between these MCP-1s was ascribed to the different degree of O-glycosylation with Gal beta 1-3GalNAc beta 1-Ser/Thr, while the 13kDa was regarded as carbohydrate-free. The integrity of the N-termius was confirmed by the amino acid sequence analysis. Each MCP-1 isolated showed equipotent monocyte chemotactic activity, which was rather higher than that of the E. coli-derived one. PMID- 7832811 TI - EGF stimulates polyamine uptake in Caco-2 cells. AB - We investigated the effects of epidermal growth factor (EGF) on polyamine uptake in Caco-2 cell monolayers. Cells were grown until confluence (day 7) or until differentiation (day 14). Polyamine uptake into Caco-2 cells was stimulated by EGF in a dose-dependent manner. Both basal and EGF-stimulated uptake rates were higher in 7- than in 14-day-old Caco-2 cells. Stimulation with EGF resulted in a significant increase in Vmax and an increased affinity for putrescine and spermine. Polyamine uptake was not inhibited when protein synthesis was blocked by cycloheximide, implying that no additional protein synthesis occured for stimulatory effect of EGF on polyamine uptake. The tyrosine kinase inhibitor, genistein, completely inhibited EGF-stimulated polyamine uptake, indicating that tyrosine phosphorylation plays a role in EGF-stimulated polyamine uptake in Caco 2 cells. The effect of EGF on polyamine uptake into Caco-2 cells, therefore, could be due to translocation of intracellular proteins which were not previously incorporated into the membrane, or direct alteration of polyamine transporter. PMID- 7832812 TI - Fibronectin activates murine peritoneal macrophages for tumor cell destruction in the presence of IFN-gamma. AB - Increasing evidence indicates that interaction of cells with fibronectin (Fn) affects many aspects of cellular responses including growth, morphology, differentiation, and activation. However, it is not known whether Fn could activate macrophages for the tumor cell killing. Here we report that Fn provides a signal for murine macrophage activation to tumoricidal activity. Tumoricidal activity was determined by the release of 51Cr from prelabeled P815 mastocytoma target cells. Fn alone had no effect, whereas recombinant interferon-gamma (rIFN gamma) weakly induced C57BL/6 murine macrophages to kill P815 mastocytoma cells. However, combination of Fn with rIFN-gamma synergized to activate macrophages to lyse tumor cells in a dose dependent manner. Secretion of nitric oxide (NO) correlated with tumor cell killing, and the activated macrophages failed to kill tumor cell targets in the presence of NG-monomethyl-L-arginine (NGMMA), a competitive inhibitor of NO synthase (NOS). Fn, unlike lipopolysaccharide (LPS), alone had no effect on NO synthesis by itself and did not induce bioactive tumor necrosis factor-alpha (TNF-alpha) secretion from murine peritoneal macrophages. The data illustrate the potential for Fn to activate macrophage-mediated antitumor mechanisms in addition to its better characterized role as a cell adhesion molecule. PMID- 7832813 TI - Musk xylene induces and inhibits mouse hepatic cytochrome P-450 2B enzymes. AB - The purpose of this work was to characterize the effects of musk xylene on mouse hepatic microsomal enzyme activities. Male B6C3F1 mice were dosed for 7 days at 0 or 200 mg musk xylene/kg after which microsomes were prepared. Musk xylene treatment increased liver weight by 40%, caused hepatocellular hypertrophy and increased total cytochrome P-450 2-fold over control. Microsomes from musk xylene treated mice showed increased activity for the dealkylation of ethoxy- and methoxyresorufin, results consistent with increased CYP1A1 and 1A2 protein levels determined by Western blotting. No increase in pentoxyresorufin-O-dealkylation activity was seen, but musk xylene treatment markedly increased CYP2B protein levels. Preliminary in vitro studies showed that musk xylene inhibited mouse CYP2B enzymes (IC50 approximately 1 microM), but did not affect the activities of CYP1A1 or 1A2. This inhibition was not NADPH-dependent. These results indicate that, in mice, musk xylene causes generalized hepatic changes similar to classical CYP2B inducers. However, musk xylene is also a potent inhibitor of the CYP2B enzymes. PMID- 7832814 TI - Synthesis and conformational investigation of tandem repeat sequence in RNA polymerase II. AB - The largest subunit of RNA polymerase II has a very interesting sequence in the C terminus; that is, a tandem repeat sequence of Ser-Pro-Thr-Ser-Pro-Ser-Tyr consisted of proline residues and three kinds of residues having side-chain hydroxyl groups. Although lack of this tandem repeat is a lethal event in vivo, its functional role is unclear. The sequential polypeptide corresponding to this tandem repeat, poly(Ser-Pro-Thr-Ser-Pro-Ser-Tyr), was synthesized and its conformation was investigated by circular dichroism comparing to the monomeric heptapeptide. In addition, the theoretical conformational analysis based on the molecular mechanics was tried for the heptapeptide in the repeating unit and the periodic polyheptapeptide corresponding to the tandem repeat sequence. These results suggested the possibility that the tandem repeat contains a kind of super conformation composed of the repetitive turn structure in the native state. The characteristic repetitive turn structure would be the key of its function mechanism. PMID- 7832815 TI - Flow stimulates ICAM-1 expression time and shear stress dependently in cultured human endothelial cells. AB - Human umbilical vein endothelial cells were subjected to controlled levels of shear stress in a flow-loading apparatus, and changes in the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) were measured by flow cytometry. Application of shear stress (15 dynes/cm2) increased the cell surface expression of ICAM-1 2.7 times the control level 4 hr after the onset of flow, while it caused no change in VCAM-1 expression. The increase of ICAM-1 expression by shear stress was time- and force dependent and reversible. Flow loading using perfusates with different viscosity revealed that the increase in ICAM-1 was shear-stress- rather than shear-rate dependent. Reverse transcriptase/polymerase chain reaction analysis showed upregulation of ICAM-1 mRNA levels by shear stress, whose time course closely paralleled that of the cell surface protein. These results suggest that shear stress generated by blood flow acts as a regulator of cell adhesion molecule expression on vascular endothelial cells. PMID- 7832816 TI - Different effects of base analog substitutions in BamHI restriction site on recognition by BamHI endonuclease and BamHI methylase. AB - BamHI endonuclease and BamHI methylase were used to investigate their specific interaction with the common recognition sequence, GGATCC. Five derivatives of the oligonucleotide, GACGGATCCGTC, containing a variety of single-base analog substitutions within the hexameric recognition core were synthesized. Steady state kinetics for the reaction of the endonuclease and the methylase showed that both enzymes recognize the sequences by contacting with functional groups exposed in both major and minor grooves of the site but in different ways. Removal or substitution of the 5-methyl group in thymidine blocked the endonuclease reaction completely but still allowed the methylase reaction with less efficiency. The data also showed that the methylase made a critical minor groove contact with the 2-amino group of the first G but the endonuclease did with that of the second G. PMID- 7832817 TI - Risk evaluation of CVS. PMID- 7832818 TI - Prozone phenomenon in secondary syphilis. Has its time arrived? AB - We present three patients with syphilis in which the prozone phenomenon was present--a very high antibody titer, leading to a false-negative test in undiluted specimens. One of our three patients was positive for human immunodeficiency virus (HIV), another was at risk for HIV infection, and had some clinical findings compatible with HIV infection (this patient was seen before HIV serologic tests were available). We propose that HIV infection, by its B-cell dysregulation, may lead to higher nontreponemal serologic titers, raising the possibility that the prozone phenomenon may be more prevalent in HIV-positive individuals with syphilis than in luetic patients who are negative for HIV. PMID- 7832819 TI - Differences in abuse reported by female and male Canadian medical students. AB - OBJECTIVE: To assess differences between male and female medical students concerning their experiences of abuse during training in a large Canadian medical school. DESIGN: Voluntary, anonymous cross-sectional survey of first- and fourth year medical students during February 1991. SETTING: University of Toronto School of Medicine. PARTICIPANTS: Of 396 first- and fourth-year students surveyed after one of their regular classes, 347 (117 women, 230 men) completed the questionnaire. INTERVENTION: A 165-item, multiple-choice questionnaire concerning experiences of verbal or emotional abuse, sexual harassment and physical abuse, completed within 30 minutes. MAIN OUTCOME MEASURES: Differences between male and female respondents in abuse experiences before and during medical training, the relation between abuse before and during training, and the psychologic and behavioural effects of abuse during training. RESULTS: The experiences of the male and female respondents differed mainly in regard to sexual harassment: 42% (49/117) of the women and 11% (25/230) of the men reported sexual harassment before entering medical school (p < 0.0001); 46% (54/117) and 19% (43/230) respectively reported sexual harassment during medical training (p < 0.0001); and women who reported sexual harassment were the only respondents for whom a significant relation was found between abuse before and during training (p < 0.043). The women were more distressed than the men by all forms of abuse. A significant relation was shown between male students who reported experiencing abuse during medical training and mistreating patients (p < 0.0001). CONCLUSION: Female students' experiences of sexual harassment differed from those of their male counterparts. As well, the female students' reactions to and ways of coping with all types of abuse differed from those of the male students. PMID- 7832820 TI - Timing of extubation after oesophagectomy. AB - Ventilatory support for 24 h after surgery is standard practice in many units after oesophagectomy, especially for patients in whom respiratory problems are anticipated. Weaning difficulties may occur, however, and there is increasing evidence that mechanical ventilation is associated with alveolar trauma. A deliberate change in policy was instituted in the authors' unit in January 1990 to make early extubation mandatory in all patients undergoing elective oesophagectomy, apart from those in whom serious perioperative problems were encountered. The present study compared two sets of patients: group 1 (n = 36) underwent oesophagectomy in the year before the policy change and group 2 (n = 45) oesophagectomy in the year after. The two groups were similar in age, sex and respiratory risk factors. Early extubation was carried out in 38 patients in group 2 compared with eight in group 1 (P < 0.001). Only two patients in group 2 required prolonged ventilation compared with ten in group 1 (P < 0.005). No patient in group 2 required reventilation compared with seven in group 1 (P < 0.005), and no patient in group 2 who had undergone early extubation required delayed ventilation. The mean ventilation time and length of stay in the intensive care unit were significantly reduced following the policy change. Early extubation after elective oesophagectomy is an attainable goal and results in a significant reduction in both the morbidity rate and cost of surgery. PMID- 7832821 TI - Forensic nurse specialists. Working with perpetrators and hostage negotiation teams. AB - 1. A felony defendant's behavior and thinking prior to and during the commission of the crime are the primary focus of the relationship between the client and the psychiatric forensic nurse. 2. Psychiatric forensic nurses provide competency therapy, and train the defendants in courtroom behavior and how to assist their attorney. Therapy includes mock court-room activities, review of the contents of the police reports, and discussion of plea options. 3. Because the dimensions of practice identified overlap into criminal justice and law enforcement, psychiatric forensic nurses are a valuable resource to hostage negotiation teams. PMID- 7832822 TI - Hypertonic saline prehydration in patients undergoing transurethral resection of the prostate under spinal anaesthesia. AB - Thirty-three patients undergoing elective transurethral resection of the prostate were allocated randomly to receive either 0.9% isotonic saline 7 ml kg-1 (16 patients), or 3% hypertonic saline 7 ml kg-1 (17 patients) as a preload before spinal anaesthesia. After spinal anaesthesia, the incidence of systolic arterial pressure < 75% of control value was greater in the normal saline group than in the hypertonic saline group. Also, the mean dose of phenylephrine required to maintain arterial pressure > 75% of the baseline value was significantly greater in the normal saline group than in the hypertonic saline group. PMID- 7832823 TI - Medical skills and knowledge. How necessary are they for psychiatric nurses? AB - 1. Today's psychiatric population presents with a higher acuity and complexity of problems. Concomitant medical diagnoses may add to the psychiatric nurse's uneasiness with medical-surgical skills and knowledge. 2. A needs assessment survey of nurses' medical-surgical skills and knowledge was conducted at a private psychiatric facility. Of the 163 surveys distributed, 55 were returned (response rate = 33.74%). The greatest number of skill requests (30.56%) were for assessment skills, mainly general physical assessment. 3. To survive as a specialty, psychiatric nursing must include physical as well as psychologic assessments; psychiatric nurses must reintegrate a medical knowledge base while maintaining a balance with the psychodynamic aspects of care. PMID- 7832824 TI - Magnetic orotracheal intubation: a new technique. AB - We sought to determine the effectiveness of a magnet placed over the thyroid cartilage in the neck to guide an endotracheal tube into the trachea. Forty patients aged 18 to 60 yr with normal airway anatomy (ASA grade I) who required general anesthesia with an endotracheal tube and paralysis for their surgery were chosen and informed consents were obtained. The tip of the epiglottis was exposed with a No. 3 MacIntosh laryngoscope, and a magnet was held over the thyroid cartilage. A catheter with stylet was placed behind the epiglottis allowing the magnet to pull the stylet and catheter close to the glottic opening. The catheter was advanced into the trachea over the stylet and its position was confirmed by auscultating the lungs and by capnography. An extension tube was connected to the catheter, and the endotracheal tube was guided into the trachea over the catheter. The tracheas of 37 patients were intubated on the first attempt with the magnet. The tracheas of the remaining three patients could not be intubated on the first attempt but were successfully intubated without complications on the second attempt. An additional five patients with an anterior larynx whose tracheas could not be intubated with direct laryngoscopy also had tracheal intubation with a magnet. This magnet-guided technique can be used when it is difficult to expose a patient's larynx. It is noninvasive, simple, and can be used without any delay when expensive flexible fiberoptic endoscopes are not readily available. The procedure takes an average of 1 to 2 min. PMID- 7832825 TI - Roles of N-type and Q-type Ca2+ channels in supporting hippocampal synaptic transmission. AB - Several types of calcium channels found in the central nervous system are possible participants in triggering neurotransmitter release. Synaptic transmission between hippocampal CA3 and CA1 neurons was mediated by N-type calcium channels, together with calcium channels whose pharmacology differs from that of L- and P-type channels but resembles that of the Q-type channel encoded by the alpha 1A subunit gene. Blockade of either population of channels strongly increased enhancement of synaptic transmission with repetitive stimuli. Even after complete blockade of N-type channels, transmission was strongly modulated by stimulation of neurotransmitter receptors or protein kinase C. These findings suggest a role for alpha 1A subunits in synaptic transmission and support the idea that neurotransmitter release may depend on multiple types of calcium channels under physiological conditions. PMID- 7832826 TI - A set of anti-crystallin monoclonal antibodies for detecting lens specificities: beta-crystallin as a specific marker for detecting lentoidogenesis in cultures of chicken lens epithelial cells. AB - Seven hybridoma lines which produced monoclonal antibodies against lens crystallins were established. They could detect alpha A-, alpha B-, gamma-, delta , and several beta-crystallins of different species of animals with high avidities. Although immunohistological analysis of chicken and mouse lenses showed the typical distributions of each crystallin as have been reported so far, the ectopic expression of alpha B or delta-crystallin was observed in the brain or the kidney of chicken, respectively. Subsequently, crystallin production during the process of lentoidogenesis in cultures of chicken lens epithelial cells was examined with these antibodies. Western blot analysis revealed that beta-crystallins were not detected in cultured cells before lentoidogenesis, although all other crystallins were detected throughout the culture period. Immunostaining of cultures indicated clearly that expression of beta-crystallins was restricted to lentoid bodies. These data confirmed the lens fiber specificity of beta-crystallins as previously reported in the messenger RNA level. In addition, we found that small-size delta-crystallin (48 kDa) accumulated before the onset of lentoidogenesis. These results strongly suggest that the differentiated state of lens cells in vitro could be classified by examination of the expression pattern of crystallins. In addition, the anti-crystallin monoclonal antibodies produced in this study could be useful for detecting lens specificities. PMID- 7832827 TI - CNS germinomas: curable tumours in two adolescents. AB - Two cases of central nervous system germinoma are described which highlight the various presentations of this tumour in different anatomical locations. The first case is that of a 15 year old boy with a suprasellar germinoma who presented with the classical triad of diabetes insipidus, visual disturbance and hypopituitarism. The need for full hormonal evaluation and replacement therapy is stressed. In the second case a 14 year old boy with pineal germinoma presented with features of raised intracranial pressure, Parinaud's syndrome and normal anterior pituitary function. Both cases were treated with corticospinal irradiation which resulted in regression of the tumours. Follow up has now been for over 4 years with no sign of recurrence. PMID- 7832828 TI - Laboratory blunders revisited. AB - Blunders which occurred over a 1 year period in the clinical chemistry departments of two health districts were recorded and categorized according to type and detection stage. A blunder was defined as an incident leading to an incorrect result/set of results either being reported or detected at the final checking-out stage in the laboratory. Of the total of 120 blunders--which is a blunder rate of less than 0.1% of requests--53 (44%) were detected at the final checking-out stage. Blunders detected after the report had left the laboratory were divided into those subsequently picked up by laboratory personnel (23); those detected by clinicians (19); and those by external quality assessment schemes (21). The types of blunder were fairly equally distributed between the booking-in (36), analysis (38), and reporting (35) stages of the laboratory process. A formal review of blunders detected in laboratories is a valuable aid to overall performance. PMID- 7832829 TI - Fever: blessing or curse? A unifying hypothesis. AB - Considerable data indicate that fever and its mediators have the capacity both to potentiate and to inhibit resistance to infection. It is difficult to reconcile these apparently contradictory observations if they are viewed solely from the standpoint of the individual. However, when viewed from the perspective of the species, both fever's salutary effects on mild to moderately severe infections and its pernicious influence on fulminating infections become teleologically plausible. If one accepts preservation of the species, rather than survival of the individual, as the essence of evolution, fever and its mediators might have evolved as mechanisms both for accelerating recovery of individuals from localized or mild to moderately severe systemic infections in the interest of continued propagation of the species and for hastening the elimination of fulminantly infected individuals who pose a threat of epidemic disease to the species. PMID- 7832830 TI - Mitochondrial biogenesis in striated muscle. AB - Mitochondrial biogenesis (synthesis) has been observed to occur in skeletal muscle in response to chronic use. It also occurs in cardiac muscle during growth and hypertrophy, and it may be impaired during the aging process. This review summarizes the literature on the processes of mitochondrial biogenesis at the biochemical and molecular levels, with particular reference to striated muscles. Mitochondrial biogenesis involves the expression of nuclear and mitochondrial genes and the coordination of these two genomes, the synthesis of proteins and phospholipids and their import into the organelle, and the incorporation of these lipids and proteins into their appropriate locations within the matrix, inner or outer membranes. The emphasis is on the regulation of these events, with information derived in part from other cellular systems. Although descriptions of mitochondrial content changes in heart and skeletal muscle during altered physiological states are plentiful, much work is needed at the molecular level to investigate the regulatory processes involved. A knowledge of biochemical and molecular biology techniques is essential for continued progress in the field. This is a promising area, and potential new avenues for future research are suggested. PMID- 7832831 TI - Functioning ectopic supradiaphragmatic pituitary adenomas. AB - Pituitary adenomas arising far from the pituitary gland occur rarely as a result of defects in embryological migration. Likewise, there have been reports of isolated suprasellar adenomas (clinically nonfunctioning), presumably derived from cells of the pars tuberalis. In this report, we present four cases of functional pituitary adenomas (three adrenocorticotrophic hormone, one prolactin) confined to the supradiaphragmatic region. In each case, the tumors were initially treated unsuccessfully by operations via the transsphenoidal route because of expected intrasellar processes with suprasellar extension. PMID- 7832832 TI - The neurologic basis of fever. PMID- 7832833 TI - Glucocorticoids and the genesis of depressive illness. A psychobiological model. AB - Abnormalities in the hypothalamic-pituitary-adrenal axis (HPA) have been the most consistently demonstrated biological markers in depressive illness. Numerous other neuroendocrine disturbances have also been described, including blunted clonidine-induced growth hormone release and blunted fenfluramine-induced prolactin release. These disturbances are generally interpreted in terms of monoaminergic receptor dysfunction. The theory presented here suggests that chronic stress which activates the HPA will in certain susceptible people produce changes in central monoamines. The high level of glucocorticoid receptors on such central neurons is postulated as mediating the alterations. Thus monoamine abnormalities, rather than being a core aetiological feature of depression, are seen as secondary to HPA overdrive. PMID- 7832834 TI - New regulations hurting radiology. PMID- 7832835 TI - Reduced coronary vasodilator function in infarcted and normal myocardium after myocardial infarction. AB - BACKGROUND: The ability of the coronary vascular bed to dilate and thus increase blood flow to the myocardium may be impaired in coronary artery disease, even in regions of myocardium supplied by an angiographically normal coronary artery. If this kind of vasomotor dysfunction was present or accentuated after acute myocardial infarction, it might influence the extent of ischemia and necrosis in areas not directly injured by the infarction. METHODS: We studied 13 patients (mean [+/- SD] age, 62 +/- 11 years) with single-vessel coronary artery disease after they had received thrombolytic therapy for myocardial infarction. Using positron-emission tomography (PET) with oxygen-15-labeled water, we measured regional myocardial blood flow under basal conditions and after the intravenous administration of dipyridamole (0.5 mg per kg of body weight over a period of four minutes) 8 +/- 3 days after infarction in all 13 patients (1-week study) and 6 +/- 2 months after infarction in 9 of the 13 (6-month study). On both occasions we measured blood flow both in the infarcted region and in a region of myocardium that was remote from the infarcted region and supplied by a normal artery. RESULTS: At the one-week PET study, the coronary vasodilator response (the ratio of the myocardial blood flow after the administration of dipyridamole to basal blood flow) was 1.12 +/- 0.50 in the infarct-related artery and 1.53 +/- 0.36 in the remote region (P = 0.015). At the six-month study, the coronary vasodilator response was 1.42 +/- 0.37 in the infarcted region and 2.19 +/- 0.69 in the remote region (P = 0.004 for the comparison with the infarcted region; P = 0.011 for the comparison with the remote region at the one-week study). The value in remote myocardium remained lower than that in similar regions in 10 control patients, who had single-vessel coronary artery disease but no evidence of myocardial infarction (3.17 +/- 0.72; P = 0.009). CONCLUSIONS: After acute myocardial infarction, there is a severe vasodilator abnormality involving not only resistance vessels in infarcted myocardium, but also those in myocardium perfused by normal coronary vessels. This dysfunction may affect the extent of myocardial ischemia and necrosis after coronary occlusion. PMID- 7832836 TI - Are some occupational therapists in physical disability practice settings hastening the extinction of mental health practice? PMID- 7832837 TI - The Royal Flying Doctor Service of Australia. Its foundation and early development. AB - In 1994 the Royal Flying Doctor Service of Australia celebrates its 66th year of service to rural Australians. From an experiment in Cloncurry, Queensland, in 1928, the organisation has grown to become a national aerial health service operating 37 aircraft over approximately 80 per cent of the Australian continent. The development of the RFDS and its current work is woven into the fabric of past and contemporary life in outback Australia. PMID- 7832838 TI - Clinical problem-solving. An anatomy lesson. PMID- 7832839 TI - Renal transplantation. PMID- 7832840 TI - Distribution of NHS funds between fundholding and non-fundholding practices. AB - OBJECTIVES: To estimate the amount spent on specific hospital care by health agencies in 1993-4 and compare it with the resources allocated to patients registered with fundholding practices for the same type of care. To investigate whether fundholding practices and health agencies pay different amounts for inpatient care. DESIGN: Examination of hospital episode statistics, 1991 census data, and family health services authority and health agency records. SETTING: Health agencies and fundholding practices in the former North West Thames Regional Health Authority. MAIN OUTCOME MEASURES: Amount per capita allocated to inpatient and outpatient care for patients registered with fundholding and non fundholding practices. Average specialty cost per finished consultant episode for health agencies and fundholding practices. RESULTS: The ratio of per capita funding for patients in non-fundholding practices to those in fundholding practices ranged from 59% to 87% for inpatient and day case care and from 36% to 106% for outpatient care. Average specialty costs per episode were similar for fundholding practices and health agencies. CONCLUSIONS: Fundholding practices seem to have been funded more generously than non-fundholding practices in North West Thames. PMID- 7832841 TI - American science in crisis: the need to revise the NIH funding policy. PMID- 7832842 TI - Prescribing selective serotonin reuptake inhibitors as strategy for prevention of suicide. AB - OBJECTIVE: To evaluate a policy to reduce the incidence of suicide by means of changing the prescribing of antidepressants from the older tricyclic antidepressants to the routine first line use of selective serotonin reuptake inhibitors or newer tricyclic and related antidepressants. DESIGN: Cost effectiveness analysis with sensitivity analyses using observational data on costs, volume of prescribing, deaths, and toxicity. SETTING: United Kingdom primary care. INTERVENTIONS: Selective serotonin reuptake inhibitors or newer tricyclic and related antidepressants compared with the use of older tricyclics. MAIN OUTCOME MEASURES: Cost per life saved and cost per life year saved. RESULTS: The potential number of lives which may be saved from a switch to the routine first line use of selective serotonin reuptake inhibitors is between 300 and 450 each year. The cost per life year gained ranges from 19,000 pounds to 173,000 pounds, depending on the assumptions used. The cost per life year gained through the use of the newer tricyclic and related antidepressants is considerably lower. CONCLUSIONS: The cost per life year gained through avoiding suicides by the routine first line use of serotonin reuptake inhibitors is likely to be high. The new tricyclics and related drugs are of similar toxicity to the serotonin reuptake inhibitors but are considerably cheaper and so are most cost effective for this purpose. Further research is required on such prescribing. Because of the great uncertainties the shift to considerably more expensive options must be further investigated. PMID- 7832843 TI - Surgical pearl: ear piercing facilitated by magnetic earrings. PMID- 7832844 TI - Risk assessments of low-level exposures. PMID- 7832845 TI - The Hippocratic oath. PMID- 7832846 TI - [Immunotherapy of drug poisoning]. AB - Immunotherapy of drug intoxications is based on intravenous administration of antibodies or antibody Fab fragments specific to a drug. Mechanism of action involves toxin complexation in the antibody distribution space resulting in a gradient efflux of the toxin from its binding site by dissociation of toxin receptor to the vascular space. Reversal of toxic effects by specific Fab fragments has been demonstrated experimentally for digitalis, colchicine and tricyclic antidepressants. The intravenous administration of antibodies or Fab fragments alters toxin pharmacokinetics including tissular depletion, plasma redistribution and decrease of systemic clearance. Benefit of this therapy in clinical toxicology has been clearly shown for cardiac glycosides but has to be confirmed for colchicine and tricyclic antidepressants. Safety and efficacy of specific Fab fragments should permit an extension of this antidotal procedure towards other toxins. PMID- 7832847 TI - Correlation between p53 mutations and antibody staining in breast carcinoma. PMID- 7832848 TI - Taurine supplementation for cats. PMID- 7832849 TI - Breast implants and connective-tissue diseases. PMID- 7832851 TI - Computer-assisted diagnosis in Europe. PMID- 7832850 TI - Breast implants and connective-tissue diseases. PMID- 7832852 TI - The neurologic basis of fever. PMID- 7832853 TI - HIV vaccines get the green light for Third World trials. PMID- 7832854 TI - Injury, death, and cholesterol. PMID- 7832855 TI - Persistently perplexing purpuras: thrombotic thrombocytopenic purpura and immune thrombocytopenic purpura. PMID- 7832856 TI - CO2 in the environment of sleeping infants. PMID- 7832857 TI - Vasectomy and testicular cancer. PMID- 7832858 TI - Auto-PEEP, high frequency jet ventilation. PMID- 7832859 TI - Predicting complete cytogenetic response in chronic myelogenous leukemia patients treated with recombinant interferon alpha. PMID- 7832860 TI - Comment: evening primrose oil in the treatment of rheumatoid arthritis--proper application of statistical analysis. PMID- 7832861 TI - Stereological considerations concerning the measurement of individual osteoid seams and resorption cavities. PMID- 7832862 TI - Increase in incidence of invasive cervical cancer. PMID- 7832863 TI - NHS funds for fundholders and non-fundholders. Non-fundholders are disadvantaged. PMID- 7832864 TI - Ethnicity in epidemiological research. Ethnicity revolves around culture. PMID- 7832865 TI - Selective serotonin reuptake inhibitors. Total profile of drug should be considered. PMID- 7832866 TI - Natural history of childhood asthma. Other studies have been ignored. PMID- 7832867 TI - Aerosol deposition in mechanically ventilated patients. PMID- 7832868 TI - Darier's disease cosegregating with affective disorder. PMID- 7832869 TI - ICD-10: a neuropsychiatrist's nightmare? PMID- 7832870 TI - A study on client selection criteria and services for home health care--C.V.A., head and spinal cord injury in patients. AB - This study was done to clarify the types of health care that should be offered. It focus on developing client selection criteria based on the needs of inpatients with cerebral vascular diseases, head injuries and spinal cord injuries. Two research methods were adopted. One was a methodological approach for developing client selection criteria and the other was analytical approach to clarify the types of services to be offered. From the research findings, the following summarized conclusions have been drawn. 1. The problem and item criteria used to select patients requiring home health care, namely, a prototype evaluation tool, consisted of 12 items in four areas; physiological status, functional status, psychological status and environmental status. After assessing each item at three levels, the categorization was done according to the classification criteria. The item internal consistency of the completed tool was .8358, .8390, the interrater reliability was in the range of 84 percent-98 percent and the classification consistency was 92 percent. As external criteria, the relationship of the prototype tool to the Health Status Scale, the Barthel Index of Functional Status Assessing Devices and the number of health problems of the patient was examined and all were found to be statistically significant, verifying the validity of the tool. 2. Using the tool to classify the inpatients according to the established client selection criteria, 84.2 percent were classified as patients requiring home health care, 8.8 percent were assessed as suitable for outpatient care and 7.0 percent were assessed as patients needing to be hospitalized. 3. Clients assessed as requiring home health care had 72 different kinds of health problems, which could be classified into four categories; 54 types of physiological status problems, 8, psychological, 6, functional and 4, environmental status problems. For each problem, the percentage of patients who suffered from the disorders ranged from 2.1 percent-66 percent. More than half of the subjects had problems related to urination, paralysis, contracture or locomotion. For the physiological category, many of the health problems were due to disorders of muscles and bone, whereas skin and breathing disorders were relatively low. The mean number of health problems in this category as 11.1. 4. Reviewing the literature, it was found that home health care consisted of 10 activity areas, namely, sanitation, nutrition, breathing, skin, body temperature maintenance, medication, assessment and observation, education and counselling.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7832871 TI - [The effects of programmed jogging on metabolism and cardio-pulmonary function of type II diabetic patients]. AB - This study was done for the purpose of testing effects of programmed jogging as one of the self care activities on glucose and lipid metabolism and cardio pulmonary function in type II diabetic patients. Research design was a repeated measure as non-equivalent control group pre-post test quasi-experimental design. Thirty type II diabetic patients who received follow-up care regularly at the out patient department of internal medicine in two general hospitals which had diabetic clinic were studied. Fourteen were assigned to the experimental group and sixteen to the control group. The experimental group participated in the programmed jogging 3 times per week for 4 weeks and the control group didn't have the programmed jogging. The programmed was developed from a review of the literature done by the researcher. Data were analyzed by X2-test, t-test, paired t-test and MANOVA using SPSS/PC The results are summarized as follows; 1. There were no significant difference between the experimental group and the control group for general characteristics and the pre-test of metabolism and cardiopulmonary function. 2. Hypothesis 1) that type II diabetic patients who participate in the programmed jogging will have a higher level of glucose metabolism than type II diabetic patients who don't do programmed jogging was partly supported(FBS; between groups F = 9.57, p < .05, time within the experimental group F = 24.28, p < .001, .05, HbA1C; between groups t = 1.09, p > .05, time within the experimental group t = 2.32, p < .05). 3. Hypothesis 2) that type II diabetic patients who participate in the programmed jogging will have a higher level of lipid metabolism than type II diabetic patients who don't do programmed jogging was rejected(triglyceride; between groups F = .85, p > .05, time within the experimental group F = 7.87, p < .05, total cholesterol; between groups F = 4.07, p > .05, time within the experimental group F = .02, p > .05, HDL cholesterol; between groups F = 2.72, p. > 05, time within the experimental group F = 9.81, p < .05, body weight; between groups F = 2.72, p > .05, time within the experimental group F = 15.38, p < .001).(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7832872 TI - Career-selection regulations hurting anesthesia. PMID- 7832873 TI - Quis custodeit custodes ipsos? PMID- 7832875 TI - Doing the right thing: stop worrying about cholesterol. PMID- 7832874 TI - Is intake of trans-fatty acids and saturated fat causal in coronary heart disease? PMID- 7832876 TI - Neurodevelopmental implications of septal dysgenesis. PMID- 7832877 TI - Anal sphincter physiology. PMID- 7832878 TI - Epidemiology and health care reform. PMID- 7832879 TI - Radionuclide migration through the genital tract in infertile women with endometriosis. PMID- 7832880 TI - Nonvenereal treponematosis. PMID- 7832881 TI - Oral cancer. PMID- 7832882 TI - Solution-oriented therapy. PMID- 7832883 TI - In response to article by Bone et al. PMID- 7832884 TI - Re: Possible mechanism for seeding of tumor during radical prostatectomy. PMID- 7832885 TI - Emergency medical services: factors associated with poor survival. PMID- 7832886 TI - HIV testing, counseling, and prophylaxis after sexual assault. PMID- 7832887 TI - An evaluation of the article by Delistraty D.A., Reisman E.J., and Snipes M. "A physiological and nutritional profile of young female figure skaters". PMID- 7832888 TI - Human herpesvirus 6 DNA in skin biopsy tissue from marrow graft recipients with severe combined immunodeficiency. PMID- 7832889 TI - Effects of interleukin-2 on hepatitis B vaccination in uraemic patients. PMID- 7832890 TI - Cervical assessment and preterm delivery. PMID- 7832891 TI - Sumatriptan-induced chest pain. PMID- 7832892 TI - Treatment of chronic leg ulcers. PMID- 7832893 TI - The meaning of overseas specialist training. PMID- 7832894 TI - Economic implications of assisted reproductive technology. PMID- 7832895 TI - Clinical problem-solving: an anatomy lesson. PMID- 7832896 TI - Second trimester abortion. PMID- 7832897 TI - Management of septic abortion. PMID- 7832898 TI - Renal transplantation. PMID- 7832899 TI - Transgenic-mouse model of amyotrophic lateral sclerosis. PMID- 7832900 TI - Modern human origins. PMID- 7832901 TI - Polymerase patent problems. PMID- 7832902 TI - Functioning ectopic supradiaphragmatic pituitary adenomas. PMID- 7832903 TI - Pure motor hemiparesis. PMID- 7832904 TI - Paroxysmal hemicrania. PMID- 7832905 TI - Use of statistics for comparing two measurement methods. PMID- 7832906 TI - Dispute sparks final comments. PMID- 7832907 TI - Risk from low-dose exposures. PMID- 7832908 TI - Prognostic significance of intraoperative rupture of ovarian cancer. PMID- 7832909 TI - Emergency medicine in South Africa. PMID- 7832910 TI - Proper film reading with proper filming. PMID- 7832911 TI - Immunoassays for tropical parasitic infections: how sensitive and specific. PMID- 7832912 TI - Fatal syndrome in lambs. PMID- 7832913 TI - The sine qua non of breast cancer. PMID- 7832914 TI - Alteration in red blood cell sodium and potassium concentrations and increased lipid peroxidation in patients with chronic renal failure on maintenance hemodialysis: a hypothesis. PMID- 7832915 TI - Spinal anesthesia after failed epidural anesthesia. PMID- 7832916 TI - A piezoelectric neuromuscular monitor. PMID- 7832917 TI - Fever: blessing or curse? PMID- 7832918 TI - Coelenterate sting. PMID- 7832919 TI - Vertical muscle-sparing thoracotomy. PMID- 7832920 TI - Predictors of conduction disturbances after coronary bypass grafting. PMID- 7832921 TI - Current tonometer disinfection may be inadequate for hepatitis B virus. PMID- 7832922 TI - Choroid plexus cysts in the fetal brain. PMID- 7832923 TI - Non-progression in HIV infection. PMID- 7832924 TI - [Late endocrine and growth sequelae after cancer treatment in children]. AB - Growth and endocrinological disturbances are possible late side-effects of cancer treatment in childhood. These side-effects can be treated, thus their discovery is important. The side-effects particularly appear in the years following treatment with irradiation and/or alkylating chemotherapy. After irradiation of the brain or the neck the function of the thyroid and the parathyroid glands should be tested every third month the first year, and later on annually. Two years after the end of treatment, the patient should be examined for growth hormone deficiency. This examination should be carried out annually. One should be alert to symptoms of pubertas praecox the years prior to puberty. At the age when puberty is expected and thereafter one should look for signs of secondary hypogonadism. Primary hypogonadism may follow radiotherapy below the diaphragm and/or treatment with alkylating chemotherapeutics; further, reduced fertility in men and early menopause in women may follow these treatments. The bone structure of the face and the teeth may be damaged by radiation and chemotherapy, so therefore yearly examination by a dentist with specialty in this subject is recommended. Surgery in order to improve function may be a possibility. PMID- 7832925 TI - Telephone helpline unit in Athens: differences between women and men suicidal callers. PMID- 7832926 TI - Adult first generalized seizure: etiology, biological tests, EEG, CT scan, in an ED. AB - The purpose of this study was to evaluate adult first seizures in an emergency department by analyzing etiologic and epidemiological data and studying the usefulness of biological screening, electroencephalogram (EEG), and cerebral computed tomography (CT) scan. This was a retrospective study of a 3-year period during which 247 patients were admitted to an emergency department for a first generalized seizure. A CT scan had been performed in 247 patients and an EEG in 209. Etiologies were found to be (1) unknown, (2) alcohol abuse, (3) stroke, and (4) tumor. Early recurrence rate was 18.5%. EEG was of low interest in emergency. The rate of cerebral focal lesions on CT scan was significantly lower when both examination results and EEG were normal. The rate of metabolic abnormalities was 4.9%. It was concluded that (1) a short hospitalization is advisable because of recurrences, (2) recurrence rate does not increase significantly in patients with focal cerebral lesion, (3) metabolic screening is necessary, and (4) CT scan will be an outpatient procedure for most patients. PMID- 7832927 TI - Retrograde intubation difficulty in an 18-year-old muscular dystrophy patient. PMID- 7832928 TI - Delayed traumatic cervical cord transection. PMID- 7832929 TI - Utilization of a regional poison center by primary care and emergency physicians. PMID- 7832930 TI - Cardiac contusion as a primary clinical entity. PMID- 7832931 TI - Acute incarcerated inguinal hernia attributed to sexual intercourse. PMID- 7832932 TI - Value of serum tricyclic antidepressant levels with massive nortriptyline overdose and persistent hypotension. PMID- 7832933 TI - Spontaneous retroperitoneal hemorrhage presenting as asystolic arrest. PMID- 7832934 TI - Mobile satellite EMS communications. PMID- 7832935 TI - Estimated charges for ED lacerations. PMID- 7832936 TI - Laryngeal mask airway for emergency medicine. PMID- 7832937 TI - Bowel obstruction and radiopaque vitamin B12 "pseudobezoar". PMID- 7832938 TI - Spontaneous bowel perforation in drug abusers. PMID- 7832939 TI - Ketoconazole and zidovudine overdose. PMID- 7832940 TI - Acute hyponatremia in ultra-endurance athletes. PMID- 7832941 TI - Misdiagnosis of anticholinergic delerium as schizophrenic psychosis. PMID- 7832942 TI - How long will it take? How much will it cost?: multiple regression and neural network programs at ED triage. PMID- 7832943 TI - Treatment of heatstroke. PMID- 7832944 TI - Efficient, safe right subclavian vein puncture. PMID- 7832945 TI - Evaluation of subcutaneous injection of local anesthetic agents as a method of tick removal. AB - The usefulness of subcutaneous injection of three local anesthetic agents to stimulate tick detachment in an animal model was evaluated. American dog ticks (Dermacentor variabilis) were placed on three New Zealand white rabbits and allowed to attach for 24 hours. Dead and unattached ticks were manually removed. Three local anesthetic agents were studied: 1% lidocaine (group A); 1% lidocaine with epinephrine 1:200,000 (group B); and 1% chloroprocaine (group C). For each group, a total of 0.25 mL of anesthetic agent was injected subcutaneously under the attached portion of each tick, resulting in formation of a 5- to 6-mm wheal. For all three anesthetic agents studied (group A, 34 ticks; group B, 28 ticks; group C, 31 ticks), none of the ticks spontaneously detached within 1 hour after injection. Subcutaneous injection of 1% lidocaine, 1% lidocaine with epinephrine, and 1% chloroprocaine are not effective methods for rapid tick removal in the animal model. PMID- 7832946 TI - Lidocaine via iontophoresis in laceration repair: a preliminary safety study. AB - Iontophoresis is a painless technique for topical anesthesia that uses an electric field to drive charged ions across an epithelial surface. The safety of this technique for laceration repair has never been demonstrated. The purpose of this study was to investigate the effect of iontophoretic fields on rapidly proliferating cells involved in laceration wound healing. The study was a prospective single-blinded animal study using a guinea pig model. Twelve guinea pigs each received four induced, uncontaminated lacerations. Each guinea pig was randomly assigned to 1 of 3 groups (4 guinea pigs in each group). One group received lidocaine via iontophoresis, one group received injected lidocaine, and one group received half iontophoresis and half injected lidocaine. After anesthetic treatment, wounds were then repaired in a standard fashion. The wounds were examined grossly on a daily basis and on day 10 the incised skin containing the laceration was examined by a pathologist blinded to the treatment group. A total of 48 wounds were assessed for wound healing, 24 of which received lidocaine via iontophoresis and 24 lidocaine via injection. The power of the study to determine a 40% difference between the two groups was 0.8. There was significantly more granuloma and granulation tissue formation in the iontophoresis group than in the injected lidocaine control group (P = .0004, Fisher's exact test).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7832947 TI - High-dose MDI salbutamol treatment of asthma in the ED. AB - Beta-adrenergics have long been under special scrutiny because of their potential for cardiotoxicity. To assess the safety of high doses of salbutamol delivered by metered dose inhaler (MDI) with spacer in the emergency department (ED) setting, 11 patients (mean age 33 +/- 12.2 years) with severe acute asthma were studied. All patients were treated with 400 micrograms of salbutamol at 10-minute intervals for 3 hours (1,200 micrograms each 30 minutes or 7,200 micrograms at 180 minutes. There were dose-related significant increases in forced expiratory volume in the first second (FEV1) and peak expiratory flow (PEF) (P < .01), with a net mean increase of 90.4% and 80.1%, respectively. A significant (P < .01) reduction of heart rate was observed with treatment. At the end of protocol, reductions ranged from 7 beats/min to 35 beats/min (mean decrease 10.6 +/- 10.5 beats/min). There was no prolongation in the QTc interval. Mean baseline serum potassium was 4.23 +/- 0.53 mmol/L and decreased nonsignificantly after treatment to 3.99 +/- 0.62 mmol/L. Only 4 patients showed net decreases. There were no significant changes in oxygen saturation and plasma glucose. The mean end treatment salbutamol level was 10.0 +/- 1.67 ng/mL. These data support the notion that treatment of acute asthma patients in the ED with 2.4 mg salbutamol per hour delivered by MDI and spacer produce satisfactory bronchodilation, low serum concentration, and minimal extrapulmonary effects. PMID- 7832948 TI - Exacerbation of verapamil-induced hyperglycemia with glucagon. AB - To evaluate the effects of verapamil intoxication and glucagon treatment on blood glucose levels in an intact canine model, 15 mg/kg verapamil was administered intravenously over a 30-minute period to mongrel dogs under pentobarbital anesthesia. Animals in the experimental group subsequently were administered 2.5 mg glucagon followed by an infusion of 2.5 mg per hour; control group animals were administered an equal volume of saline. Blood glucose was assessed before verapamil administration (baseline), and at 10 minutes (time 10) and 60 minutes (time 60) after completion of the verapamil infusion. Glucose values were compared between control and experimental groups using Dunnett's method (P = .05). At baseline, no animals were hyperglycemic and there was no difference in glucose levels. Animals in both groups became hyperglycemic after verapamil infusion. At time 10, the experimental group had significantly higher glucose levels (265 +/- 17.1 mg/dL) than the control group (209 +/- 18.3 mg/dL). By time 60, there was no significant difference between glucose values in the control (262 +/- 31.4) and experimental (246 +/- 24.8) groups. It was concluded that verapamil intoxication consistently resulted in hyperglycemia in this model. Glucagon therapy was associated with an early but nonsustained exacerbation of verapamil-induced hyperglycemia. PMID- 7832949 TI - Comparison of pediatric end-tidal CO2 measured with nasal/oral cannula circuit and capillary PCO2. AB - This study was designed to determine whether end-tidal carbon dioxide (ETCO2) values obtained by noninvasive oral/nasal cannula circuit with side-stream capnometry correlate reliably with capillary PCO2 (CapCO2) in a pediatric population without cardiopulmonary problems. Each patient was monitored until a reliable 5-minute ETCO2 waveform was obtained. A capillary blood gas sample was drawn while, simultaneously, ETCO2 was recorded. The difference between CapCO2 and ETCO2 levels was tested with a paired t-test at P < .001. The limits of agreement were established with a 95% confidence level. The stability of the measured difference across the range of mean scores (CapCO2 + ETCO2/2), age, and respiratory rate was tested using simple linear regression. Fifty-eight children (23 girls and 35 boys) had mean ETCO2 readings of 33.96 mm Hg (SD 4.26), and mean CapCO2 readings of 35.93 (SD 4.04). A relative average bias of 1.96 with ETCO2 lower than CapCO2 was established with 95% limits of agreement of +/- 5.2 mm Hg (t = 5.71). Variability of difference scores was not related to range of mean scores (r = .08), age (r = .09), or respiratory rate (r = .25). End-tidal CO2 measured by an oral/nasal cannula capnometry circuit is a noninvasive method of assessing indirect measurements of PCO2 in a normal pediatric population. PMID- 7832950 TI - Transcription services in the ED. AB - This study's objectives were to determine the cost-effectiveness of introducing a transcription service into an emergency department (ED) and to determine the capacity of such a service to improve physician satisfaction. A prospective study of full-time emergency physicians was conducted in the ED of a community hospital in which a transcription service was introduced during peak periods of demand. Measurement was defined from a time-and-motion study consisting of direct observation by an industrial engineer who measured documentation time required for written and dictated charts. Surveys examined satisfaction with each record type among the emergency and non-emergency medical staff. It was found that dictation of the medical record was notably faster than writing (155 seconds compared with 220 seconds per record, P = .0002) for all physicians examined. Total productivity of the department improved by 3.8% (from 2.20 patients per physician-hour to 2.28 patients per physician-hour), calculated from patient volumes of 7,355 and 7,075 with the same staff (P < .05). When the records were transcribed, the mean subjective scores for satisfaction with the medical record improved from 2.1 to 3.6 (P = .0025) on a scale of 1 to 4. Surveys of nonemergency staff physicians documented that legibility score improved from 2.6 to 3.1 (P = .0056) and completeness improved from 2.6 to 3.0 (P = .0157), both on a scale of 1 to 4. It was concluded that dictating and transcribing ED medical records decreases the time required for documentation, improves record legibility and quality, allows more patients to be seen per physician-hour, and improves the satisfaction of emergency and nonemergency physicians. PMID- 7832951 TI - Direct evidence for the occurrence of superoxide radicals in the small intestine of the burned rat. AB - To determine if superoxide radicals (O2-) and related metabolites are generated in extradermal tissues of burned animals, 2-methyl-6-[p-methoxyphenyl]-3,7 dihydroimidazol [1,2-a]pyrazin-3-one (MCLA) was infused intravenously into rats, and change in the chemiluminescence (CL) intensity of the small intestine was determined by using a sensitive photodetector. When animals were challenged with burn stress of 40% total body surface area (TBSA), the CL intensity of the intestine gradually increased, reaching a maximum within 1 hour and remaining elevated for up to 3 hours. Pretreatment of animals with a long-acting superoxide dismutase (SOD) derivative (SM-SOD) significantly inhibited the increase in CL intensity. Administration of SM-SOD immediately after inducing burn injury also significantly inhibited the increase in CL. These results suggest that superoxide radicals are generated in extradermal tissues, such as the small intestine, in the early stage after burn injury. PMID- 7832952 TI - Central cord syndrome presenting as unilateral weakness. AB - Central cord syndrome is the most common incomplete traumatic spinal cord lesion. It is characterized by disproportionately greater upper-extremity motor impairment than lower-extremity motor impairment, bladder dysfunction, and variable degree of sensory loss below the level of the injury. This article reports the case of a patient who presented with unilateral weakness after a fall and later developed the typical central cord syndrome. The variability of central cord syndrome has been discussed by other authors, but this is the first case of a patient that initially presented as unilateral weakness. PMID- 7832953 TI - Response of headaches to nonnarcotic analgesics resulting in missed intracranial hemorrhage. AB - The differential diagnosis of headache is broad, ranging from immediately life threatening to benign etiologies. Currently, headaches can be treated successfully with various nonnarcotic analgesics. Three cases are presented in which patients with headaches were treated in an emergency department with nonnarcotic analgesics which relieved their headaches; subsequently, these patients returned to be diagnosed with intracranial hemorrhage. Some nonnarcotic analgesics may relieve symptoms of intracranial hemorrhage through their recognized mechanisms of action. Avoiding such occurrences requires that the diagnosis of headache be made with careful consideration of the patient's history. A patient presenting with a new onset of severe headache or a headache that is different from those experienced in the past deserves a thorough diagnostic work-up including a computed tomography scan followed by lumbar puncture if indicated. Diagnostic decisions regarding headache should not be based on a patient's response to any analgesic, nonnarcotic or narcotic. PMID- 7832954 TI - Myxomatous embolization resulting in unilateral amaurosis. AB - A patient with sudden, painless monocular blindness is an uncommon emergency department presentation. Despite often futile attempts to treat the blindness, most clinicians search for a source of possible embolization. A patient is presented that developed monocular blindness without a clinically apparent source. Advanced diagnostic imaging showed a previously undetected atrial myxoma. The salient clinical features, diagnostic techniques, and therapeutic interventions for this uncommon cardiac tumor are discussed. PMID- 7832955 TI - Retrograde intubation training using a mannequin. AB - The purpose of this study was to determine the efficacy of a mannequin for training emergency caregivers in the technique of retrograde intubation. This was a descriptive study using duration of time needed for completion of intubation as a measure of success. A cohort of 88 Emergency Medical Service (EMS) personnel included prehospital caregivers, registered nurses, and respiratory care practitioners. Participants were trained in retrograde intubation by modeling. Students practiced before they were tested. Every subject successfully completed intubation on the first timed effort. Subjects performed retrograde intubation in a mean time of 71 seconds (95% confidence interval +/- 4 seconds), with a range of 42 to 129 seconds. It was concluded that retrograde intubation can be taught easily with a mannequin and that this skill can be learned by emergency caregivers by modeling. Bag-valve-mask ventilation can be performed at any time without the need to restart or interrupt the procedure. Retrograde intubation can be introduced as an intubation technique for the difficult airway encountered by EMS personnel. PMID- 7832956 TI - Manual external (fist) pacing during high-degree atrioventricular block: a lifesaving intervention. PMID- 7832957 TI - Using JPEG image compression to facilitate telemedicine. AB - Economical applications of teleradiology and telemedicine are limited to the existing telephone network infrastructure, which greatly limits the speed of digital information transfer. Telephone lines are inherently slow, requiring image transmission times to be unacceptably long for large, complex, or numerous images. JPEG (Joint Photographic Experts Group) image transmission has been shown to compress images to 10% of the original file size without a noticeable change in the quality of the image. This study was carried out to assess the quality of medical diagnostic images after JPEG compression and decompression. X-rays, computed tomography scans, and ultrasound samples were compressed and decompressed using JPEG. The compressed JPEG images were indistinguishable from the original images. The JPEG images were approximately 10% of the original file size. This would reduce image transmission times by 90% (eg, an unacceptable time of 50 minutes would be reduced to an acceptable time of 5 minutes). JPEG can be used to optimize teleradiology and telemedicine. PMID- 7832958 TI - Staffing and equipping emergency medical services systems: rapid identification and treatment of acute myocardial infarction. National Heart Attack Alert Program Coordinating Committee Access to Care Subcommittee. AB - Each year, about 1,250,000 people in the United States experience an acute myocardial infarction (AMI). Emergency medical services (EMS) systems play a key part in the prehospital care and transportation of AMI patients. Rapid, state-of the-art treatment by EMS personnel is essential for improving AMI survival and outcomes, as dramatized by the patient who is the victim of out-of-hospital cardiac arrest. In order to improve the prehospital care provided to AMI patients, this article by the Access to Care Subcommittee of the National Heart Attack Alert Program Coordinating Committee makes a number of recommendations regarding the staffing and equipping of EMS systems. The recommendations cover the "chain of survival" concept, universal and enhanced 9-1-1, emergency medical dispatching, ground ambulance specifications, automated external defibrillators, advanced life support coverage, medical direction, 12-lead electrocardiograms, and prehospital thrombolysis. PMID- 7832959 TI - Infrared emission detection tympanic thermometry may be useful in diagnosing acute otitis media. AB - To determine the utility of infrared emission detection (IRED) tympanic thermometry in diagnosing acute suppurative otitis media (ASOM), a prospective, nonblinded sampling of ear temperatures was performed. Children between the ages of 6 months and 6 years presenting to an urban emergency department were included in the study. Tympanic temperatures were determined in all subjects. Clinical data, tympanic audiometry, and telephone follow-up were used to define ASOM. Temperature differences were determined for children with unilateral ASOM and those without ear infection. Data from 48 patients were analyzed. The mean temperature difference in the control group, 0.23 degrees +/- 0.15 degrees C (95% confidence interval [CI], 0.17 degree to 0.29 degree C) differed from those with ASOM: 0.39 degree +/- 0.29 degree C (95% CI, 0.25 degree to 0.53 degree C, P = .047). Logistic regression was used to describe the predictive relationship between temperature difference and probability of ASOM. We conclude that IRED tympanic thermometry may be useful in diagnosing ASOM when used with other clinical data. PMID- 7832960 TI - Emergency medical dispatching: rapid identification and treatment of acute myocardial infarction. National Heart Attack Alert Program Coordinating Committee Access to Care Subcommittee. AB - Emergency medical telephone calls (ie, those made to 9-1-1 or 7-digit emergency numbers) are directed to emergency medical dispatchers (EMDs) who are responsible for quickly obtaining critical pieces of information from the caller, then activating an appropriate level of emergency medical services (EMS) response and providing the caller with patient care instructions until medical help arrives. The impact of well-trained, medically managed EMDs on the early care of potential acute myocardial infarction (AMI) patients is believed to be beneficial. However, standards for emergency medical dispatching vary widely across the nation. To improve emergency medical dispatching for AMI patients in the United States, this article by the Access to Care Subcommittee on behalf of the National Heart Attack Alert Program makes a number of recommendations regarding the use of medical dispatch protocols, provision of dispatch life support, EMD training, EMD certification, and emergency medical dispatch quality control and improvement processes. PMID- 7832961 TI - Hidden trauma: the mostly missed diagnosis of domestic violence. AB - Domestic violence is an epidemic that rages throughout our society. Despite its overwhelming incidence and prevalence, this abuse goes unrecognized and unaddressed in the majority of health care settings. Nonetheless, battered women expect health care providers to initiate discussions about abuse. Improved awareness through education at all levels and protocols will help interrupt the cycle of intergenerational learned violence. Without intervention, domestic violence is perpetuated and escalates. PMID- 7832962 TI - Cost analysis of stapling versus suturing for skin closure. AB - A randomized, prospective study was performed to test the null hypothesis that there is no difference between the cost of stapling and suturing for skin closure of selected linear lacerations. Appropriate wounds were randomly assigned to be closed by staples or sutures. Wound lengths, skin closure times, and the number of staples or the number and types of sutures used were recorded. Costs for materials and labor were calculated. The average total cost per case was $17.69 (with suture kit) and $7.84 (without suture kit) for the staple Group compared with $21.58 for the suture Group (P = .0001 for each). It is concluded that stapling is less costly than suturing and that the advantage appears to increase as laceration length increases. PMID- 7832963 TI - Blunt gastrointestinal injury in trauma patients. AB - The evaluation, management, and final outcome of 34 patients with blunt gastrointestinal injury (BGI) were reviewed. Initial absence of symptoms and signs led to two delayed diagnoses. Sonography provided 80% (12/15) positive predictive value, and three false-negative patients were subsequently detected by diagnostic peritoneal lavage (DPL). Besides repeated clinical surveillance, screening by sonography complemented with DPL provided early detection of blunt bowel injury in trauma patients. In the outcome analysis, BGI patients with high injury-severity scores, intraoperative hypotension, or accompanying major medical diseases were associated significantly with increased risk of infectious complications (P < .05). PMID- 7832964 TI - Raising the decontamination level for thyroid hormone ingestions. AB - Ninety-two pediatric cases (age < or = 6 years) of acute thyroid hormone ingestions that were reported over a 20-month period to one American Association of Poison Control Centers (AAPCC)-certified regional poison center were reviewed to determine whether significant toxicity in pediatric patients is associated with acute ingestions of < or = 5 mg levothyroxine (T4) equivalent of thyroid hormone and the highest-tolerated milligram-per-kilogram dose. Parameters evaluated included patient weight, amount ingested, drug preparation, treatment type, outcome, management site, and relevant comments. Eight patients had mild symptoms requiring no specific medical intervention and there was no correlation between the amount ingested and symptoms observed. The maximum T4 dose ingested without gastrointestinal decontamination was 0.13 mg/kg (2 mg). A literature review was also conducted. Only one case of moderate toxicity with a dose of less than 5 mg T4 equivalent was found in the literature review. Significant toxicity is not expected with ingestions of less than or equal to 5 mg T4 equivalent of thyroid hormone. PMID- 7832965 TI - Do not resuscitate, but do not forget comfort. PMID- 7832966 TI - Inhaled beta agonists and acute asthma. PMID- 7832967 TI - Successful treatment of reflex sympathetic dystrophy with gabapentin. PMID- 7832968 TI - Psychiatric illness masking the signs and symptoms of perforated viscus. PMID- 7832969 TI - Fever response to acetaminophen. PMID- 7832970 TI - Synthesis and biotransformation of 3-hydrazinopyridazine drugs. AB - Several derivatives of 3-hydrazinopyridazine are reported to possess interesting biological properties as chemotherapeutics, anti-inflammatory agents, CNS depressants and stimulants and anti-hypertensives. In particular, variously substituted 3-hydrazinopyridazines raised considerable interest as peripheral vasodilators with improved potency and safety compared to hydralazine and dihydralazine. More recently, some compounds bearing substituents which may also account for beta-adrenoceptor blocking properties were prepared and studied in approaches aimed at combining in single molecules both the vasodilating and the beta-adrenoceptor blocking activity in an appropriate balance. When substituents are alkylic or arylic, the pyridazine nucleus is synthesized through the appropriate 4-oxoacid, otherwise 3,6-dichloropyridazine is generally used as starting compound. In the latter case, while the nucleophilic substitution of the first chlorine atom is easily obtained, the reactivity of the second chlorine is considerably reduced when the first group introduced has electro-donating properties (alkoxy or alkylamino groups) and an excess of hydrazine is required under forcing conditions. Since 3-chloro-6-hydrazinopyridazine is practically unreactive, it was found to be convenient to convert it to 3-chloro-6 (triphenylmethylazo)pyridazine, whose halogen atom is activated towards nucleophiles, and to restore the hydrazino group after the substitution. 3 Hydrazinopyridazines are extensively metabolized, mainly by acetylation of the free hydrazino group, followed by cyclization, or by reaction with endogenous carbonyl compounds and, to a lower extent, by hydrolysis or oxidation. When the hydrazino group is protected, biotransformation is generally less extensive, giving rise to an active metabolite which in turn follows the metabolic pathways outlined above. Interestingly, pharmacokinetic studies on cadralazine (a 3 hydrazinopyridazine protected as ethoxycarbonyl derivative) support the attractive hypothesis that the pro-drug is biotransformed topically to the active metabolite in the endothelium of arterial vessels, close to the site at which smooth muscle relaxation is required. PMID- 7832971 TI - Choleretic activity of 3-[ring substituted benzotriazol-1(2)-yl]alkanoic and alkenoic acids. AB - In order to investigate the influence of structural modifications on the high choleretic activity of 3-(benzotriazol-1-yl)butanoic acid, a set of new benzotriazolyl alkanoic and alkenoic acids was prepared and, together with some other acids previously described, tested in rats by i.v. administration at the dose of 0.5 mmol/kg. Most of the tested compounds exhibited a good choleretic activity comparable with or higher than that of the model acid and of dehydrocholic acid (+56% mean increase of bile volume during 4 hours). Influence of nature and position of substituents was shown in some cases: a moderate decrease of activity was observed for methoxy derivatives and for the introduction of a methyl group in position 6, while a trifluoromethyl group in the same position enhanced the activity (10). Activity was maintained after the introduction of unsaturation in the chain (17,18), but was completely suppressed when unsaturation was associated with a shortening of the alkenoic chain (16). Moving the butanoic chain from position 1 to position 2 in the case of the nitroderivative (15) produced a striking increase of activity (from +42 to +118 mean variation of bile volume during 4 hours), while the same change in the unsubstituted acid 1 abolished the activity. PMID- 7832972 TI - Synthesis and free radical scavenging properties of the enantiomers of erdosteine. AB - The synthesis of enantiomers R and S of erdosteine, a derivative of homocysteine gamma-thiolactone, and the NMR studies for the determination of the enantiomeric excess with chiral shift reagent on the more soluble ethyl esters, are described. Pharmacological data relative to the free radical scavenging properties of the R and S enantiomers are reported. In particular, it has been documented that the S isomer is more effective than R isomer in protecting mice against lethal doses of paraquat (substance able to form free radicals when administered by i.p. route). PMID- 7832973 TI - Biological effects of hesperidin, a citrus flavonoid. (Note I): antiinflammatory and analgesic activity. AB - The present study was undertaken to define in vivo the antiinflammatory and analgesic activities of hesperidin, an important flavanone of Citrus sp.. We used hesperidin obtained from the solid residue of orange peel after an acidic pretreatment. Our results showed that hesperidin possesses significative antiinflammatory and analgesic effects. PMID- 7832974 TI - Biological studies on 2,1-benzisothiazole derivatives. II. Evaluation of antimicrobial and genotoxic properties of bz-nitro-, 3-ethylacetate-, 3-amino- and 3-substituted amino 2,1-benzisothiazoles. AB - The in vitro antimicrobial activity of bz-nitro-, 3-ethylacetate-, 3-amino- and 3 substitutedamino 2,1-benzisothiazoles was evaluated. The compounds studied were found to display a very low activity against bacteria and fungi, with the exception of compound 61, which exhibited a relatively high activity against Bacillus subtilis, Escherichia coli and Saccharomyces cerevisiae. As for genotoxic properties, compounds 1-3, 5 and 6 showed DNA-damaging activity in the Bacillus subtilis rec-assay. The Salmonella-microsome assay confirmed the genotoxicity of these compounds and also revealed the mutagenicity of compounds 4, 7-12, 23, 24, 31, 33-35, 38, 39, 44, 49, 51, 53, 57-63. Structure-activity relationships showed all the compounds containing an aromatic nitro group or an unsubstituted amino group to possess genotoxic properties. Whereas most of the 3 acylamino-, 3-acylalkylamino- and 3-azomethynderivatives showed mutagenic activity, none of the 3-alkylamino-2,1-benzisothiazoles was active. None of the 1,2-isomers studied showed genotoxic properties. PMID- 7832975 TI - Modified chemotactic peptides: synthesis and biological activity of HCO-Met-delta ZLeu-delta ZPhe-OMe. AB - For-Met-delta ZLeu-delta ZPhe-OMe (3) has been synthesized as a new analogue of the prototypical chemotactic agent For-Met-Leu-Phe-OMe (fMLP-OMe). Compound 3 is characterized by presence of two consecutive alpha,beta-didehydro amino acid residues [delta ZLeu = (Z)-alpha,beta-didehydroleucine; delta ZPhe = (Z) alpha,beta- didehydrophenylalanine] located at the central and C-terminal position, respectively. When tested on human neutrophils the N-formyltripeptide 3, although less active than the parent, is able to induce chemotaxis, superoxide anion production and lysozyme release. The activity of 3 has been compared to that of related fMLP-OMe analogues containing a single delta ZPhe residue located at the C-terminal position. PMID- 7832976 TI - Synthesis of 2'-heptylcarbamoyloxy-2-methyl-6,7-benzomorphan: a new analogue of heptylphysostigmine (MF 201). AB - The synthesis of 2'-heptylcarbamoyloxy-2-methyl-6,7-benzomorphan is described. The compound is structurally related to the cholinesterase inhibitor heptylphysostigmine (MF 201) because the angular methyl group of the esoroline nucleus has been changed into a bridging carbon and the anilinic nitrogen has been replaced by a methylene group. This compound proved to be a potent cholinesterase in vitro inhibitor. PMID- 7832977 TI - Fungicidal activity of O-esters of benzophenone oximes. AB - Some acyl- and aroyl derivatives of benzophenone oximes variously benzene substituted were prepared and tested in vitro and in vivo against fungal plant pathogens of different taxonomic classes. The tested compounds showed remarkable activity, especially some O-acetyl derivatives. PMID- 7832978 TI - Synthesis of some 2-[(benzazole-2-yl)thoiacetyl]phenol derivatives and preliminary investigation on their vasodilatory activity. AB - Some 2-[(benzazol-2-yl)thioacetyl]phenol derivatives were synthesized and their structures were elucidated by IR, NMR and microanalyses. The vasodilatory activity of the obtained compounds was investigated. PMID- 7832979 TI - The complete primary structure of late lactation protein from quokka (Setonix brachyurus). AB - The complete primary structure of the late lactation protein from the milk of quokka (Setonix brachyurus) is presented. The amino acid sequence was established by N-terminal sequence analysis of high-performance liquid chromatography purified intact protein and peptides isolated from chemical and enzymatic digests of the protein. The protein contains 158 residues including four cysteines. The sequence comparison with the tamar wallaby (Macropus eugenii) late lactation protein shows only five differences. The protein is identified as a new member of a novel late lactation protein family present in the milk of marsupials. PMID- 7832980 TI - Autophosphorylation-dependent protein kinase phosphorylates Ser25, Ser38, Ser65, Ser71, and Ser411 in vimentin and thereby inhibits cytoskeletal intermediate filament assembly. AB - The autophosphorylation-dependent protein kinase has been identified as a potent vimentin kinase that incorporates 2 mol of phosphates per mol of protein and generates five major phosphorylation sites in vimentin. Tryptic phosphopeptide mapping by high-performance liquid chromatography followed by sequential manual Edman degradation and direct peptide sequence analysis revealed that Ser-25, Ser 38, Ser-65, and Ser-71 in the amino-terminal domain and Ser-411 in the carboxyl terminal domain are the phosphorylation sites in vimentin phosphorylated by this kinase, indicating that autophosphorylation-dependent protein kinase is a potent and unique vimentin kinase. Functional study further revealed that phosphorylation of vimentin by autophosphorylation-dependent protein kinase can completely inhibit polymerization and assembly of the cytoskeletal intermediate filament as demonstrated by electron microscopic analysis. Taken together, the results provide initial evidence that the autophosphorylation-dependent protein kinase may function as a vimentin kinase involved in the structure-function regulation of the cytoskeletal system. The results also support the notion that this cyclic nucleotide- and calcium-independent protein kinase may function as a multisubstrate/multifunctional protein kinase involved in the regulation of diverse cell functions. PMID- 7832981 TI - Reductive methylation and pKa determination of the lysine side chains in calbindin D9k. AB - The Lys residues in the 75-residue Ca(2+)-binding protein calbindin D9k were reductively methylated with 13C-enriched formaldehyde. The possible structural effects resulting from the chemical modification were critically investigated by comparing two-dimensional NMR spectra and the exchange rates of some of the amide protons of the native and the modified protein. Our results show that the protein retains its structure even though 10 Lys out of a total of 75 amino acid residues were modified. In the Ca(2+)- and apo-forms of the protein, the 13C-methylated Lys residues can be detected with high sensitivity and resolution using two dimensional (1H, 13C)-heteronuclear multiple quantum coherence (HMQC) NMR spectroscopy. The pKa values of the individual Lys residues in Ca(2+)-calbindin D9k and apo-calbindin D9k were obtained by combining pH titration experiments and (1H, 13C)-HMQC NMR spectroscopy. Each Lys residue in the Ca(2+)- and apo-forms of calbindin D9k has a unique pKa value. The Lys pKa values in the calcium protein range from 9.3 to 10.9, while those in the apo-protein vary between 9.7 and 10.7. Although apo-calbindin D9k has a very similar structure compared to Ca(2+) calbindin D9k, the removal of two Ca2+ ions from the protein leads to an increase of the pKa values of the Lys residues. PMID- 7832983 TI - Isolation and properties of a T-kininogenase from bovine erythrocyte membranes. AB - A kininogenase from bovine erythrocyte membranes has been purified 140-fold by affinity chromatography on pepstatin A-Agarose followed by ion exchange chromatography on CM Cellulose. The purified enzyme showed an apparent molecular weight of 31,000 daltons as measured by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Its pH optimum is 7.5, and it was totally inhibited by soybean trypsin inhibitor, phenylmethyl-sulfonylfluoride, aprotinin, pepstatin, and dithiotreitol, suggesting the presence of a disulfide bond(s) whose integrity is(are) essential for maintaining the native three-dimensional structure. The referred enzyme was able to release kinin from a substrate partially purified from rat plasma. The kininogenase was activated by Zn2+, Ca2+, and cysteine-HCl. PMID- 7832982 TI - Spontaneous methylation of hemoglobin by S-adenosyl-methionine by a specific and saturable mechanism. AB - The methyl group from S-adenosylmethionine (AdoMet) is transferred into hemoglobin without any evident involvement of an enzyme. There are multiple sites for incorporation of the methyl group into hemoglobin, since both alpha and beta chains are methylated. The methyl linkages formed in hemoglobin are stable at both alkaline and acidic pH, and the reaction occurs optimally at slightly below neutral pH. Only a small fraction (approximately 2%) of hemoglobin tetramers are methylated under the conditions tested. Acid hydrolysis of [3H-methyl]-labeled hemoglobin and determination of phenylisothiocynate derivatives yields N epsilon methyl lysine, which accounts for about one-half of the incorporated [3H-methyl] radioactivity. Other amino acids are methylated as well, with much of the remaining radioactivity being distributed among one or more of the side chains of histidine, cysteine, and arginine. Methyl group transfer to hemoglobin from AdoMet is slow and inefficient (kcat/Km approximately 5 x 10(-2), but the reaction velocity tends toward a plateau with increasing AdoMet concentration in a manner suggesting that saturable binding of AdoMet onto hemoglobin is involved in methyl transfer. The velocity of hemoglobin methylation is inhibited by S adenosylhomocysteine, the known end-product inhibitor of methyltransferases, a further indication that methyl group transfer involves binding and catalysis by a specific site (or sites) in the hemoglobin molecule. These observations may help to explain the known existence of methylated hemoglobins in erythrocyte. PMID- 7832984 TI - Incorporation of two 18O atoms into a peptide during isoaspartyl repair reveals repeated passage through a succinimide intermediate. AB - To study the mechanism of protein carboxyl methyltransferase-driven repair of age damaged sites in polypeptides, a model L-isoaspartyl peptide, L-isotetragastrin, was enzymatically repaired to normal L-tetragastrin in the presence of 18O enriched water. By this design, the enrichment of 18O atoms in the peptide would reflect the number of passages through a hydrolyzable succinimide intermediate during formation of the repaired product. Mass determinations by FAB mass spectrometry revealed repaired peptide with two 18O atoms incorporated, demonstrating that more than a single cycle of methylation and demethylation is necessary to ensure stoichiometric repair. PMID- 7832985 TI - Monitoring the effect of subunit assembly on the structural flexibility of human alpha apohemoglobin by steady-state fluorescence. AB - A single energy transfer distance, between the sole intrinsic tryptophanyl donor [14(A12)] and a nonfluorescent sulfhydryl acceptor probe (4 phenylazophenylmaleimide, PAPM) attached to the only cysteine [104(G11)], has been employed to examine the effect of subunit assembly on the structure of the heme-free human alpha-hemoglobin. Efficiencies of energy transfer were measured in 0.05 M potassium phosphate buffer, pH 7.0, at 5 degrees C, and the structural flexibility of alpha-apohemoglobin, in the absence and presence of human beta heme-containing chains, was examined by a steady-state solute quenching technique. The quenched efficiencies (EQ) and Forster distances (R0Q) were analyzed by least-squares to determine the goodness of fit (chi R2) for the assumed distribution parameters: average distance r and half-width hw. Data for alpha-apohemoglobin in the absence and presence of beta h chains yielded values for r of 18 and 22 A and hw of 20 and 8.5 A, respectively. Although the increase in r for alpha-apohemoglobin in the presence of beta h chains was presumably a consequence of additional quenching from the heme moiety, the change in the half width strongly indicated a decrease in the flexibility of the alpha-apohemoglobin chain within the assembled protein. A transition in structural flexibility similar to that demonstrated here may be an important aspect of human hemoglobin assembly. PMID- 7832987 TI - The role of magnetic resonance imaging in the diagnosis of soft tissue lesions. AB - Over the last decade MR imaging has gained widespread acceptance as the modality of choice for initial evaluation of a soft tissue mass. Although MR imaging generally does not predict the histologic nature of a mass, significant data are accumulating on MR imaging features useful in the diagnosis of several benign conditions and a few malignant ones. Soft tissue masses that do not demonstrate tumor-specific features on MR imaging should be considered indeterminate and possibly malignant and a biopsy should be obtained. This article reviews the literature and elaborates on soft tissue conditions where MR imaging features can suggest an accurate diagnosis of a soft tissue mass. The article also reviews other important applications of MR imaging as well as recent developments in pulsing sequences and MR spectroscopy. The major series studying the diagnostic value of MR imaging in soft tissue masses is discussed and compared. PMID- 7832986 TI - Models of the three-dimensional structures of echidna, horse, and pigeon lysozymes: calcium-binding lysozymes and their relationship with alpha lactalbumins. AB - Similarities in amino acid sequences, three-dimensional structures, and the exon intron patterns of their genes have indicated that c-type lysozymes and alpha lactalbumins are homologous proteins, i.e., descended by divergent evolution from a common ancestor. Like the alpha-lactalbumins, echidna milk, horse milk, and pigeon eggwhite lysozymes all bind Ca(II). Models of their three-dimensional structures, based on their amino acid sequences and the known crystal structures of domestic hen eggwhite and human lysozymes and baboon and human alpha lactalbumins, have been built. The several structures have been compared and their relationships discussed. PMID- 7832988 TI - Human polymorphism in drug metabolism: mutation in the dihydropyrimidine dehydrogenase gene results in exon skipping and thymine uracilurea. AB - A condition called thymine uracilurea has been described that is due to a lack of dihydropyrimidine dehydrogenase (DPD) activity. Cancer patients experiencing acute 5-fluorouracil toxicity also have lower-than-normal DPD activities. However, to date, the molecular basis of this disorder has not been addressed. In this study, the phenotype and genotype of a family that presents a patient showing no DPD activity was determined. Fibroblast mRNAs from the patient and four family members were subjected to reverse transcriptase polymerase chain reaction (RT-PCR) using primers generated from the human DPD cDNA sequence. DPD mRNA from the patient was found to lack a segment of 165 nucleotides that results from exon skipping. DPD mRNA from the parents and a sibling were found to be heterozygous for the deleted and the normal mRNA, while a brother had two normal transcripts. DPD activities and levels of DPD protein correlated with genotype; the deficient patient had no detectable DPD protein. PCR analysis of the genomic DNA from this family revealed that the defective mRNA is not due to a deletion of a portion of the gene that contains the exon, thus implying that the mutation is the result of an as yet nonidentified point mutation that causes faulty splicing. PMID- 7832989 TI - Intrinsic activity of human immunodeficiency virus type 1 protease heterologous fusion proteins in mammalian cells. AB - We have generated various mammalian expression constructs that produce fusion proteins of human immunodeficiency virus type 1 (HIV-1) protease (PR) with the HIV-1 Nef protein. The expression of these proteins is inducible by the HIV-1 Tat protein. High-level expression of proteolytically active PR was produced from PR imbedded into Nef coding sequences, flanked by PR cleavage sites. The fusion protein was cleaved nearly to completion and did not exhibit the regulated processing that is seen with the virally encoded PR. No cytotoxic effect of PR expression was detected. The self-cleavage of PR could be inhibited by a specific inhibitor of HIV-1 PR (U75875). Elimination of the aminoterminal PR cleavage site did not have a measurable effect on cleavage of the precursor fusion protein. The cleaved fusion proteins appeared to be extremely unstable in the transfected cells. These findings demonstrate the intrinsic activity of HIV-1 PR in mammalian cells, in the context of a heterologous fusion protein. PMID- 7832990 TI - Isolation of three novel human genes encoding G protein-coupled receptors. AB - We have cloned and mapped the chromosomal location of three novel human genes encoding G protein-coupled receptors that we have named GPR6, GPR5, and GPR4. The entire coding region for each of these genes was contained on single exons. Gene GPR6 encoded a receptor that shared closest identity (71% in the transmembrane regions) with the human orphan receptor GPR3 and was localized to chromosome 6 (q21-q22.1). Northern blot analysis revealed that GPR6 transcripts were abundant in the human putamen and to a lesser extent in the frontal cortex, hippocampus, and hypothalamus. Gene GPR5 encoded a receptor that most closely resembled the orphan receptor RBS11 (48% in the transmembrane regions) and the MIP 1 alpha/RANTES receptor (45% in the transmembrane regions) and was localized to chromosome 3 (p21.3-p21.1). Gene GPR4 shared identity (40% in the transmembrane regions) with the human platelet-activating factor receptor and was localized to chromosome 19 (q13.2-q13.3). PMID- 7832991 TI - Structural organization of the mouse DNA repair gene, N-methylpurine-DNA glycosylase. AB - N-Methylpurine-DNA glycosylase (MPG), a ubiquitous DNA repair enzyme, removes N alkylpurines and other purine lesions induced in DNA by simple alkylating carcinogens. A mouse MPG cDNA clone was isolated from a lambda recombinant phage library of BALB/c mouse lung cell and characterized. Using the mouse MPG cDNA as a probe, the complete mouse MPG gene was isolated in two overlapping lambda recombinant genomic clones. The 6-kb gene has four exons containing 1,002 bp of coding sequence. The transcription start site was identified in the genomic sequence by primer extension of MPG mRNA from a mouse lung fibroblast cell line. The location of this transcription start site was confirmed by in vitro transcription with the promoter-containing plasmid template. Promoter function of the sequence 5' upstream of the transcription initiation site was shown by transient expression of the firefly luciferase reporter gene under the control of this sequence in transfected human and mouse cells. The mouse MPG promoter contains no TATA box, but has a CAAT element and is G.C-rich with putative AP2 elements and SP1-complementary sequences. PMID- 7832992 TI - Amplification of the murine mdr2 gene and a reconsideration of the structure of the murine mdr gene locus. AB - A common feature of cells selected in vitro for the multidrug resistance (MDR) phenotype is the amplification and concomitant overexpression of the mdr genes. In murine macrophage-like J774.2-derived MDR cell lines, there is a good correlation between levels of amplification and expression for the mdr1b gene, but not for the other two gene family members, mdr1a and mdr2. To understand this phenomenon better, a study of the amplification and expression of the mdr2 gene was undertaken. Southern blotting of genomic DNAs from a series of six MDR cell lines revealed that five of these lines had 5'-end amplification of mdr2, whereas only three contained 3'-end amplification. The analysis also suggested the involvement of a recombination hot-spot in this phenomenon. Despite the observation that the ratio between the number of copies of the 5' and 3' ends of the gene differs among cell lines, the ratio of 5' to 3' end transcription of mdr2 was approximately 1 in all cell lines. An analysis of promoter methylation in MDR cell lines demonstrated that this mechanism may play a role in regulating the transcription of mdr2, but not of mdr1b. Long-range mapping of the mdr locus in parental and amplified cell lines suggested that the three mdr genes are oriented in the same direction, and also revealed the presence of a number of rearrangement events. Models for the murine mdr gene locus in wild-type cells and in a cell line containing a rearrangement are presented. PMID- 7832993 TI - Gene evolution of epoxide hydrolases and recommended nomenclature. AB - We have analyzed amino acid sequence relationships among soluble and microsomal epoxide hydrolases, haloacid dehalogenases, and a haloalkane dehalogenase. The amino-terminal residues (1-229) of mammalian soluble epoxide hydrolase are homologous to a haloacid dehalogenase. The carboxy-terminal residues (230-554) of mammalian soluble epoxide hydrolase are homologous to haloalkane dehalogenase, to plant soluble epoxide hydrolase, and to microsomal epoxide hydrolase. The shared identity between the haloacid and haloalkane dehalogenases does not indicate relatedness between these two types of dehalogenases. The amino-terminal and carboxy-terminal homologies of mammalian soluble epoxide hydrolase to the respective dehalogenases suggests that this epoxide hydrolase, but not the soluble epoxide hydrolase of plant or the microsomal epoxide hydrolase, derives from a gene fusion. The homology of microsomal to soluble epoxide hydrolase suggests they derive from a gene duplication, probably of an ancestral bacterial (epoxide) hydrolase gene. Based on homology to haloalkane dehalogenase, the catalytic residues for the soluble and microsomal epoxide hydrolases are predicted. A nomenclature system based on divergent molecular evolution is proposed for these epoxide hydrolases. PMID- 7832994 TI - A cluster of cytochrome P450 genes of the CYP6 family in the house fly. AB - A cluster of genes of the CYP6 family was found in a series of overlapping lambda DASH clones from a genomic library of the house fly, Musca domestica. Four complete genes, CYP6A3, CYP6A4, CYP6A5, and CYP6C1, and fragments of two other genes, CYP6A6 and CYP6C2, were closely linked on a 24-kb segment of DNA. Restriction fragment length polymorphism (RFLP) analysis of PCR-amplified segments of two of the genes showed that the cluster is localized on chromosome V of the house fly. Each gene contained a short intron of 57 to 125 bp interrupting a conserved Glu codon, as in the previously described CYP6A1 gene. The gene fragment CYP6A6 consisted only of the coding region downstream from this intron, i.e., about one-third of the complete P450. The gene fragment CYP6C2 was missing a short amino-terminal part of the coding region, and may represent the two last exons of a larger gene. Gene duplication and chromosomal inversion events may explain the origin of this cluster. The P450 proteins deduced from the nucleotide sequences shared 39-71% amino acid identity with each other. This low identity and the lack of evidence of recent gene conversion events suggested that this cluster may be evolutionarily ancient and that homologous clusters may be found in other holometabolous insects. Evidence for transcription of the genes and for correct splicing of the introns was obtained by northern blotting and reverse transcription polymerase chain reaction (RT-PCR) experiments. No overexpression was observed in any of three insecticide-resistant house fly strains. RT-PCR and sequencing also revealed the existence of other genes or alleles closely related to the members of this cluster. PMID- 7832995 TI - A binary model of repetitive DNA sequence in Caenorhabditis elegans. AB - A great amount of genomic DNA in multicellular eukaryotic organisms is regarded as junk because it has no real function in protein coding. However, there is growing evidence that noncoding DNA can play a vital role in the regulation of gene expression during development (Lee et al., 1993). This indicates that the so called junk DNA may have essential functions that are yet to be found (Nowak, 1994). A novel binary model of noncoding repetitive DNA sequence is proposed to illustrate its possible structure and implications in genome organization and development. PMID- 7832996 TI - A sensitive method for detection of mutations--a PCR-based RNase protection assay. AB - Several techniques are currently available for detecting point mutations in DNA. The most widely used methods either use hazardous chemicals (chemical mismatch cleavage) or can detect mutations only in short (200- to 500-bp) fragments (single-stranded conformational polymorphism and denaturing gradient gel electrophoresis). In an effort to develop a sensitive and reliable method for the detection of mutations in large segments of DNA, a novel RNase protection assay using RNase I was developed. In this method, the desired portion of the gene is amplified by the polymerase chain reaction (PCR) using specific oligonucleotides and hybridized to a 32P-labeled RNA probe containing the wild-type sequence. The RNA/DNA hybrid is subsequently digested with RNase I, which cleaves the RNA at the mismatch sites. The protected RNA fragments are separated on a denaturing polyacrylamide-urea gel and detected by autoradiography. Four different RNA probes from two protein tyrosine phosphatases (PTP1C and PTP2C) were assayed using this procedure. Several mutants of the two enzymes were tested using wild type RNA probes. Single-base changes involving all four bases at the mismatch site could be detected efficiently. The ability of this method to detect insertions and single-base deletions was also demonstrated. Using a PCR-based RNase protection assay, a single-base deletion in PTP1C in the motheaten mutation in mice could be detected. Using fragments amplified from genomic DNA, mice that were heterozygous for the motheaten mutation could be distinguished from wild type and homozygotes for this mutation.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7832997 TI - Lipase catalyzed esterification in AOT reverse micelles: a structural study. AB - AOT reverse micelles are used to cosolubilize hydrophilic and hydrophobic reactants of lipase catalysed esterification. Depending on the nature of the alcohol, a drastic change of the initial rate of the esterification is observed. A structural study of the micellar system with and without reactant is undertaken to explain the change in the activity with the various alcohols. PMID- 7832998 TI - Positron annihilation spectroscopy and micellar systems. AB - Positron annihilation spectroscopy (PAS) has emerged as a powerful technique for investigating structural changes, phase transitions and microenvironmental transformations in a variety of systems. The process of molecular aggregation in micellar systems is known to be cooperative and size limited; it shows features similar to that of a classical phase transition. Similarly, the changes in the concentration of surfactant and the solubilizate bring about several microstructural and conformational transformations in these systems. High sensitivity of positron annihilation parameters to such changes makes it a potential candidate for investigating micellar and microemulsion systems. This paper deals with this aspect of positron annihilation spectroscopy. Applications of this technique to investigate conformational, structural and microenvironmental transformations in micellar and microemulsion systems are discussed. Its superiority over the conventional techniques in such investigations is demonstrated. It is shown that this technique reveals finer details of otherwise considered to be single phase regions in a phase diagram. Its usefulness in delineating phase boundaries and hence in mapping of phase diagrams is also discussed. PMID- 7832999 TI - The surface properties of phospholipid liposome systems and their characterisation. AB - The field of liposome (vesicle) research has expanded considerably over the last 30 years. In physical chemical terms liposomes have many of the characteristics of colloidal particles and their stability is determined in part by the classical surface forces. It is now possible to engineer a wide range of liposomes varying in size, phospholipid composition and surface characteristics. The surfaces of liposomes can be modified by the choice of bilayer lipid as well as by the incorporation and covalent linkage of proteins (e.g. antibodies and sugar binding proteins [lectins]), glycoproteins and synthetic polymers. Much of the impetus for liposome design has come from their potential value as drug delivery systems. The development of technologies for the production of such a range of liposome systems has presented interesting problems in the characterisation of their properties. The review addresses the progress that has been made in characterising the surfaces of different types of liposomes with specific reference to their electrophoretic properties and their interpretation and the physical interactions between liposomal bilayers. PMID- 7833000 TI - Bacterial interference in vitro. Comparison between a quantitative kinetic and a cocultivation blood agar test method. AB - The aim of the present study was to compare two methods for estimation of bacterial growth interference between various bacteria using a Bioscreen robot analyzer, allowing kinetic documentation, and a cocultivation test on blood agar plates. Six laboratory strains with different virulence and growth requirements were used: Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis, Fusobacterium nucleatum, Streptococcus mitis, Staphylococcus aureus, and Staphylococcus epidermidis. The interference activity was correlated with a reference system of Streptococcus sanguis (strain alpha 89) and Streptococcus pyogenes (group A streptococci, GAS serotypes T 9 and T 22). The methods used and results obtained were as follows: 1. Estimation of synergistic and antagonistic bacterial interferences using a Bioscreen robot analyzer. Suspensions of viable bacteria were added to microtiter plates with different concentrations of UV light-killed bacteria in liquid media. The Bioscreen analyzer monitored bacterial growth every 10 min for 24 h giving kinetic data during the growth period. Synergisms as well as antagonisms were demonstrated between the tested bacterial strains which have not earlier been reported in the literature. However, the antagonistic effect observed between the six strains was less than that induced by the S. sanguis strain on the two strains of S. pyogenes. 2. Cocultivation of bacterial strains on blood agar surface with precultivated or simultaneously stamped interfering bacteria indicated no detectable interference between the six tested bacterial strains, while the S. sanguis strain inhibited the growth of S. pyogenes strains as well as the hemolysis around the colonies. The Bioscreen method was found more sensitive for testing bacterial interference compared to the commonly used blood agar test. PMID- 7833001 TI - Isolation and identification of Encephalitozoon hellem from an Italian AIDS patient with disseminated microsporidiosis. AB - Microsporidia are primitive mitochondria-lacking spore-forming eukaryotic protozoa that infect a wide variety of animals and also humans. Of the five genera (Encephalitozoon, Enterocytozoon, Septata, Nosema and Pleistophora) that cause infections in humans, Enterocytozoon bieneusi, Septata intestinalis, and Encephalitozoon hellem are being increasingly identified in patients with acquired immunodeficiency syndrome (AIDS). E. bieneusi causes gastrointestinal disease, S. intestinalis causes gastrointestinal and disseminated disease, and E. hellem causes ocular as well as disseminated disease. We have established in continuous culture a strain of microsporidia isolated from the urine and throat washings of an Italian AIDS patient and identified it as Encephalitozoon hellem, based on its ultrastructural morphology, antigenic pattern, and polymerase chain reaction-amplified small subunit ribosomal RNA. We believe that this is the first time that a strain of microsporidia has been isolated from the throat washings of a patient with microsporidiosis. PMID- 7833002 TI - The high-affinity folate receptor of normal and malignant human colonic mucosa. AB - The hypothesis that folate depletion is a risk factor for development of colonic neoplasia prompted us to study the presence of a putative folate receptor in human colon mucosa. Binding of 3H-folate to normal and malignant mucosa studied by equilibrium dialysis was of high-affinity type (K = 10(10) L/mol) and displayed apparent positive cooperativity. Radioligand dissociation was slow at pH 7.4, but rapid at pH 3.5. As compared to methotrexate, 5 formyltetrahydrofolate was a potent inhibitor of binding. Gel filtration revealed a 25 kDa and a 100 kDa peak of folate-binding activity. Immunoreactivity studies were performed with rabbit antibodies against human 25 kDa milk folate-binding protein. Immunoblotting showed a single band at 65 kDa, and tissue sections exhibited immunostaining of mucosal areas. The present folate receptor with characteristics similar to those of other high-affinity folate-binding proteins may serve as a regulator of intracellular folate concentration in colon mucosa. PMID- 7833003 TI - Peritoneal interleukin-6, interleukin-8 and granulocyte elastase activity after elective abdominal surgery. AB - In this study we investigated the interleukin-8 concentration (IL-8) and granulocyte elastase activity (GE) after elective abdominal surgery. Postoperative interleukin-6 (IL-6), IL-8 concentrations and GE in the peritoneal fluid were examined in 27 patients who underwent various types of elective abdominal surgery. We compared these results with clinical parameters of surgical stress, operating time (OT) and blood loss during the operation (BL). P-IL-6 and P-IL-8 were significantly correlated with OT (P-IL-6; r = 0.67, P < 0.001: P-IL 8; r = 0.59, P < 0.001) and BL (P-IL-6; r = 0.61, P < 0.001: P-IL-8: r = 0.48, P < 0.01). P-IL-8 was significantly correlated with P-IL-6 (r = 0.68, P < 0.001) and there was a positive correlation between GE and P-IL-8 (r = 0.37, P < 0.05). These findings indicate that IL-8 might activate granulocytes in the peritoneal cavity after elective abdominal surgery and that assaying P-IL-6 and P-IL-8 is useful in assessing the host's response to surgical stress. PMID- 7833005 TI - Immunoglobulin-containing cells in the colonic mucosa in patients with human intestinal spirochaetosis. AB - The relative proportions of cells containing the various classes of immunoglobulins in the colonic mucosa were determined in eight patients with human intestinal spirochaetosis (HIS) and in eight controls. All specimens were taken from colonic resections performed because of adenocarcinoma. None of the cases with HIS showed an inflammatory reaction in the mucosa as judged subjectively by light microscopy. Cases with HIS had smaller proportions of IgD- and IgE-positive cells and a larger proportion of IgA cells as compared with the controls, whereas the proportions of IgG and IgM cells were similar in the two groups. Taking into account the large individual variations in the proportions of immunoglobulins in both groups, our findings must be interpreted with caution. However, our results do not support the previous demonstration of increased percentages of IgE-positive cells in patients with HIS. PMID- 7833004 TI - Preoperative histological and cytological diagnosis and DNA ploidy assessment of localized prostatic cancer. A comparison between findings in biopsies and total prostatectomy specimens. AB - The preoperative biopsy specimens of 49 men who underwent radical prostatectomy were compared with serially step-sectioned operative specimens, in order to evaluate diagnostic accuracy as regards the presence of cancer, its grade and its DNA ploidy. Both the FNAB and TRUS-GCB undergraded the cancer by one WHO grade in about 35-40% of cases. In cases where both biopsy types were available, the degree of undergrading was the same. Determination of DNA ploidy by the single cell technique from FNAB had a sensitivity for detecting non-diploid DNA patterns of 59% whereas flow cytometric measurement of core biopsies had a sensitivity of 44.4% as regards non-diploid DNA, when compared with operative specimens. A comparison of ploidy in core biopsies versus ploidy in fine-needle aspirates revealed that more non-diploid DNA patterns were diagnosed in the fine-needle aspirates. These aneuploid patterns were not all confirmed by flow cytometric evaluation of the operative specimens, in which, however, more aneuploid patterns were diagnosed compared with the single-cell technique from FNAB. We conclude that the standard technique with 1-3 fine-needle aspirates or 1-3 TRUS-GCB has a pronounced tendency by both biopsy methods to underestimate the tumour grade. DNA ploidy analysis by FNAB and the single-cell cytometric method reveals aneuploid cell lines not found in the flow cytometric evaluation. In order to determine whether this reflects a methodological problem or a true discrimination between the ability of the two methods to find non-diploid cell lines further studies are needed. However, for a more correct preoperative assessment of tumour grade and DNA ploidy, more extensive sampling is required. PMID- 7833006 TI - Comparison of genotypic and phenotypic methods for species identification of coagulase-negative staphylococcal isolates from blood cultures. AB - Coagulase-negative staphylococci are often isolated from blood cultures. Simple methods are needed for correct identification of those species most frequently found. In this study, PCR methods were developed for the identification of S. epidermidis and S. haemolyticus, based on DNA sequences in their 16S rDNA. The results obtained by these methods were compared with those obtained using a number of phenotypic methods, including two commercial kits API Staph and Staphzyme. Fifteen type collection strains and 133 blood culture isolates were tested. The sensitivity of the PCR for identification of S. epidermidis was 99% compared with API Staph, but the specificity was lower, 94%, because of positive results also for S. capitis. The results by the PCR for identification of S. haemolyticus correlated closely with the Staphzyme results, 13 isolates being identified by Staphzyme and 16 by the PCR. API Staph, however, identified only four clinical isolates as S. haemolyticus, probably too few. Among the individual phenotypic tests performed, a trehalose-mannitol agar method and a desferrioxamine disc diffusion test for the identification of S. epidermidis were found to be very accurate. Anaerobic growth after overnight incubation could be used to distinguish S. epidermidis from S. hominis. The conclusion is that a majority of all Gram-positive, catalase-positive and coagulase-negative blood culture isolates can be typed as regards species level using only a few genotypic and/or phenotypic tests. PMID- 7833007 TI - DNA content and expression of PCNA and p53 in Hodgkin's disease and Hodgkin's like B-cell lymphoma. AB - DNA ploidy (by image cytometry) and expression of proliferating cell nuclear antigen (PCNA) and p53 tumor suppressor gene product (by immunohistochemistry) were investigated in 15 cases of Hodgkin's disease (HD) and 12 cases of HD-like B cell lymphoma (HD-like NHL). Reed-Sternberg (RS) cells and their variants were DNA aneuploid in all cases. However, the fraction of hyperoctaploid tumor cells was higher in HD than in HD-like NHL. PCNA expression was high in neoplastic cells (> 50%) and variable (5-40%) in reactive lymphocytes in both HD and HD-like NHL. p53 positivity was found in RS cells and their variants in 64% of HD cases, but only in 25% of cases of HD-like NHL. Our results support the suggestion that HD-like B-cell lymphomas should be considered as highly malignant non-Hodgkin's lymphomas rather than Hodgkin's disease. PMID- 7833008 TI - The first fatal case of Vibrio vulnificus infection in Denmark. AB - Vibrio vulnificus can cause severe infections in humans and persons with preexisting liver disorders are especially at risk. In this paper we report what is to our knowledge the first fatal case of V. vulnificus infection in Denmark. The patient was a 68-year-old man with a history of chronic lymphatic leukemia and hepatic cirrhosis. Physicians should be aware of the clinical manifestations of this disease and should be especially attentive to patients at risk of acquiring the infection if there has been possible exposure to V. vulnificus by contact with seawater or contaminated material such as eels. PMID- 7833009 TI - Detection of respiratory syncytial virus in children in the 1993-94 winter season in Izmir, Turkey, by two diagnostic methods. AB - Respiratory syncytial virus (RSV) infection was searched for in 65 children between 2 months and 2 years of age hospitalized with the presumptive diagnosis of acute bronchiolitis, and in 35 children aged 6 months to 8 years with upper respiratory tract symptoms, by direct fluorescent antibody (DFA) test and cell culture. RSV infection was detected in 29.2% of the first and in 11.4% of the second group. The overall positivity rate was 23%. The sensitivity and the specificity of the commercially available DFA test in comparison with cell culture were 81.8% and 92.5%, respectively. PMID- 7833010 TI - Hybridization of multiply loaded microsatellites does not require nested primers. PMID- 7833011 TI - Reducing background interference on Southern blots probed with nonradioactive chemiluminescent probes. PMID- 7833012 TI - Use of magnesium ions to increase the stability and decrease the aggregation of nuclear preparations of HL-60 cells. PMID- 7833013 TI - Ultrafast DNA recovery from agarose by centrifugation through a paper slurry. PMID- 7833014 TI - Hydrolysis of ribosomes by electrophoretically blotted ribotoxin. PMID- 7833015 TI - A procedure to construct partial genomic libraries for gene cloning from fungi. PMID- 7833016 TI - Simultaneous purification of multiple, large DNA fragments from agarose gels. PMID- 7833018 TI - Characterization of persistent artifacts resulting from RT-PCR of alternatively spliced mRNAs. PMID- 7833017 TI - Fluorescent primers allow direct confirmation of restriction enzyme cleavage of PCR products. PMID- 7833019 TI - Thin-layer chromatography assay for the incorporation of digoxygenin into nucleic acids. PMID- 7833020 TI - An efficient site-directed mutagenesis method based on PCR. PMID- 7833021 TI - Detection enhancement of computer images of bands from western blots using a grayscale scanner. PMID- 7833022 TI - Isolation of genomic DNA from avian whole blood. PMID- 7833023 TI - Improved protocol for directional multimerization of a DNA fragment. PMID- 7833024 TI - Enrichment-mediated PCR amplification of an unknown DNA fragment flanking a known sequence. PMID- 7833025 TI - BSA treatment of plasticware reduces TGF beta binding. PMID- 7833026 TI - Use of low-melt agarose for the efficient isolation of large DNA fragments. PMID- 7833027 TI - A low-cost and efficient procedure for harvesting DNA-labeled cells using a dot blot apparatus. PMID- 7833028 TI - Stripping of hybridization membranes. PMID- 7833029 TI - A versatile and general prokaryotic expression vector, pLACT7. AB - We have previously reported the constitutive over-expression of the tRNA-guanine transglycosylase (TGT) from plasmid pTGT1 in Escherichia coli. To obtain a controllable expression system for TGT, we have subsequently cloned the tgt gene into pET21b. Though the overexpression of TGT is inducible in pET21b, the plasmid has a low copy number, a poor yield of single-stranded DNA and relies on an E. coli strain that produces T7 RNA polymerase for protein expression. We have combined the features of pTZ18U and pET21b and have constructed a versatile plasmid pLACT7 that has a high copy number, a high yield of single-stranded DNA and both the T7 and lac promoters for protein expression in a wide variety of E. coli strains. PMID- 7833030 TI - Isolation of mRNA and genomic DNA from epithelial cells in human milk and amplification by PCR. AB - Studies on the regulation of human milk protein genes and suitable cell culture systems have been limited due to restricted availability of tissue samples from lactating women. Although mammary gland tissue has been available from mammary reduction surgery, studies on tissue-specific expression of milk protein genes require samples obtained during specific stages of expression in the tissue, i.e., lactation. We have therefore developed a technique to isolate mRNA and genomic DNA directly from epithelial cells isolated from human milk and used PCR methodology to specifically amplify the cDNA and genomic DNA for human beta casein. When comparing fresh human milk with milk that has been stored for five hours at 37 degrees C or frozen and thawed, we found that the amount of mRNA isolated was considerably higher from fresh milk. However, in spite of this, we could still isolate intact mRNA from frozen milk. The described methodology should be useful in studies on milk protein gene expression during lactation and studies on variants of milk protein genes. PMID- 7833031 TI - Automated blot hybridization and washing apparatus. AB - An apparatus that automates the hybridization and washing of blots is described. With this apparatus, blots are hybridized and washed inside of open-ended tubes that rotate within stationary bottles. The blots are washed in the bottles by the automatic addition and removal of solutions eliminating contact between researchers and contaminated solutions. The apparatus has been routinely used for blot hybridizations of soybean genomic DNA using single-copy DNA clones as probes. The quality of the autoradiograms from these hybridizations was similar to that obtained with a rotisserie-style hybridization system currently used in many labs. PMID- 7833032 TI - Nonradioactive northwestern analysis using biotinylated riboprobes. AB - A nonradioactive modification of the Northwestern assay is described and applied to the detection of RNA-binding proteins. The nonradioactive assay is based on the use of biotinylated riboprobes, which are stable and easy to handle. Chemiluminescence is generated with streptavidin-conjugated peroxidase and provides even better sensitivity than the radioactive detection method to assay RNA binding to proteins bound to nitrocellulose. PMID- 7833033 TI - Microsatellite genome screening: rapid non-denaturing, non-isotopic dinucleotide repeat analysis. AB - The study of reverse genetics has made it possible for scientists to isolate and identify the genes responsible for such human diseases as cystic fibrosis and Duchenne- and Becker-type muscular dystrophy. The expensive and time-consuming process of detecting restriction fragment length polymorphisms by Southern blotting was the only method available to localize these genes. With the discovery of polymorphic microsatellite sequences in the human genome, the speed and ease of which a genome screening can be performed has increased dramatically. This paper reports on advanced methods for detection of microsatellite-repeated sequences making the task of mapping human genes simpler, safer and more economical. PMID- 7833034 TI - A vector, pHisGal, allowing bacterial production of proteins fused to a hexahistidine-tagged Gal4 DNA-binding domain. AB - A vector, pHisGal, was constructted that allows isopropyl-beta-D thiogalactopyranoside (IPTG)-inducible expression of the DNA-binding domain of the yeast transcription factor Gal4 in Escherichia coli. Protein sequences to be tested for transcription regulatory potential in conjunction with the Gal4 DNA binding domain can be inserted in-frame into a multiple cloning site at the C terminus of Gal4. A hexahistidine sequence fused to the N terminus of Gal4 allows efficient purification of the bacterially produced protein by affinity chromatography on nickel nitrilotriacetic acid (Ni-NTA) columns. Purified Gal4 fusion proteins produced in E. coli showed DNA-binding activity in electrophoretic nobility shift assays and were highly active in cell-free transcription assays from higher eukaryotic cells. PMID- 7833035 TI - An oligonucleotide-directed, in vitro mutagenesis method using ssDNA and preferential DNA amplification of the mutated strand. AB - The sequential addition of primers in a PCR enables one to preferentially amplify one of the two strands of a heteroduplex DNA template. This serves as the basis for a novel site-directed mutagenesis technique involving a heteroduplex DNA template that has been generated from a single-stranded, wild-type template and one or more mutagenic oligonucleotides. This preferential PCR method yields a mutation efficiency greater than 90% (consistent with the theoretical estimate for the method). The ability to generate multiple mutants also enables the screening of potential mutants by restriction endonuclease digestion. PMID- 7833036 TI - Direct PCR of whole blood and hair shafts by microwave treatment. AB - We report a simple and rapid method for DNA preparation suitable for PCR by microwave irradiation. When mouse whole blood and hair shafts were directly irradiated and subjected to PCR, a unique gene such as the retinoblastoma susceptibility gene was reproducibly amplified. This method was useful for screening a transgene sequence in transgenic mice. PMID- 7833037 TI - Optimized chemiluminescent detection of DNA amplified in the exponential phase of PCR. AB - We describe a procedure for quantitative detection of nucleic acids by coupling PCR with improved chemiluminescent detection techniques. After performing PCR in the exponential phase in the presence of a trace amount of digoxigenin-11-dUTP, the amplified products are transferred to a positively charged nylon membrane. The membrane is cleaned with a modified method involving sodium dodecyl sulfate and ethanol washing steps to ensure low backgrounds in chemiluminescent detection. The membrane is exposed to two stacked x-ray films to increase the dynamic response in a film exposure. This sensitive and quantitative procedure is useful for molecular biology studies. PMID- 7833038 TI - Determination of changes in specific gene expression by reverse transcription PCR using interspecies mRNAs as internal standards. AB - A method is described for the determination of changes in gene expression by reverse transcription of the target mRNA followed by PCR amplification of the resulting cDNA (RT-PCR), using the lipoprotein lipase gene as the model system. Known proportions of human and rat adipose tissue homogenates are mixed and are processed together throughout the RT-PCR procedure so that the rat tissue serves as an internal standard for the measurement of human adipose tissue lipoprotein lipase (LPL) in all steps including RNA extraction, reverse transcription and PCR amplification. Taking advantage of the highly conserved sequence of the LPL gene across species, selected homologous regions of the human and rat genes are amplified using the same primer pair and resulting in the same lengths of amplified DNA fragments. The two amplified products are then separated from each other by making use of differences in the position of a restriction site in the two amplified DNA fragments. The method is simple, precise and reproducible and avoids construction of tailored nucleic acids for use as internal standards. PMID- 7833039 TI - Detection of mutations and polymorphisms using fluorescence-based dideoxy fingerprinting (F-ddF). AB - We have adapted the dideoxy finger-printing (ddF) technique for detecting DNA sequence variants to fluorescence detection (F-ddF) using an Applied Biosystems Model 373A DNA Sequencer equipped with GENESCAN 672 software and an external temperature control device. The fingerprints can be precisely aligned using an internal standard run in the same lanes. This facilitates location and characterization of mobility changes resulting from sequence variants. As compared to fluorescence detected single-strand conformation polymorphism analysis (F-SSCP), F-ddF is equally efficient for detection of sequence variants, and it offers additional advantages. These include information regarding location of the sequence variation, greater reliability for distinguishing one sequence variant from another and the capacity to generate large PCR fragments and analyze them in smaller subsegments. Read length and overall quality of data from F-ddF are sequence-dependent when Taq DNA polymerase is used, but reducing terminator concentration can extend read length. The strengths and weakness of F-ddF and F SSCP are different. Thus F-ddF may work better in a given situation than F-SSCP and vice versa. A strategy for using F-ddF to circumvent limitations of F-SSCP is described. PMID- 7833040 TI - Two large insert vectors, lambda PS and lambda KO, facilitate rapid mapping and targeted disruption of mammalian genes. AB - The construction and the testing of two lambda phage vectors are described that greatly simplify the tasks of mapping genomic DNA and making replacement-type gene-targeting vectors for mammalian cells from a library of isogenic genomic DNA. The first vector, lambda PS, accommodates up to 20 kb and allows inserts to be automatically subcloned in plasmid form because of the presence of loxP sites flanking the insert. The second vector, lambda KO, accommodates up to 16.7 kb and allows inserts to be automatically subcloned as plasmids containing HSVtk genes that are positioned flanking the inserted genomic DNA. We have prepared highly redundant libraries from genomic DNA of 129/Sv-strain mice for the construction of targeting vectors. In our scheme, the locus of interest is characterized using a library made in lambda PS. For instance, suitable flanking probes can be derived to determine targeting events. The final targeting construct with flanking HSVtk genes is obtained using the lambda KO cloning vector. The entire procedure is exemplified by successful targeting of the X-linked mouse hprt locus. PMID- 7833041 TI - A semiquantitative rosetting assay for detection of cell-surface class I major histocompatibility complex molecules. AB - A method for detection of cell-surface antigens, referred to as cell-bead immunoassay (CBIA), has been developed by cross-linking monoclonal antibodies specific for cell-surface antigens to protein G-agarose beads. In this case, the antibodies were specific for different murine class I major histocompatibility complex (MHC) antigens and murine beta 2 microglobulin. The antibody-conjugated beads were incubated with cells expressing the relevant MHC molecule and observed microscopically for rosette formation. The number of cells bound per bead correlated with the amount of class I MHC expressed per cell, as measured by fluorescence activated cell sorting (FACS) analysis. In addition, changes in the amount of surface antigen expressed after induction could be followed by CBIA. The advantages of CBIA over other commonly used techniques, such as FACS and immunofluorescence, are that it requires only a few minutes incubation after beads are prepared, and no further manipulations are needed after the cells and beads are mixed together. Although CBIA is primarily a qualitative technique, it can also be used semiquantitatively by determining the number of cells bound per bead. PMID- 7833042 TI - Fully-automated, nonradioactive solid-phase sequencing of genomic DNA obtained from PCR. AB - Nonradioactive sequencing in combination with solid-phase template purification is a powerful method for sequence analysis, especially of PCR-generated fragments. To perform DNA sequencing under optimal conditions, it is necessary to obtain a well-purified and single-stranded (ss) DNA template. The disadvantage of ssDNA sequencing is that additional steps are required to generate ssDNA templates before any sequencing reactions can be carried out and is thus more time-consuming. Here we describe an automated solid-phase system for direct sequencing of ssPCR products that incorporates magnetic beads coated with streptavidin as solid support and a computer-controlled device (PolySeq) with heating, magnetic and mixing functions, all of which are integrated into a robotic workstation (Biomek 1000). This solid-phase method is extremely useful for rapid template purification and strand separation of DNA obtained from PCR as well as for high-quality dideoxyribonucleotide chain termination sequencing with fluorescently labeled primers. The system allows the complete automation of the sequencing procedure starting with PCR amplicons. DNA sequencing results obtained with this system were reproducible and gave an excellent length of readable sequences with low background and an analysis capacity of 30,000-40,000 bp per week. PMID- 7833043 TI - "Checkerboard" DNA-DNA hybridization. AB - A method is introduced for hybridizing large numbers of DNA samples against large numbers of DNA probes on a single support membrane. Denatured DNA from up to 43 samples was fixed in separate lanes on a single membrane mounted in a Miniblotter 45. The membrane was then rotated 90 degrees in the same device, which enabled simultaneous hybridization with 43 different DNA probes. Hybridizations were also performed on lysates of bacterial cells blotted to membranes. A MiniSlot device allowed lysates loaded in parallel channels to be aspirated through the membrane, depositing horizontal lanes on the membrane surface. Hybridizations were performed in vertical lanes with either digoxigenin-labeled whole genomic probes or 16S rRNA-based oligonucleotide probes directly conjugated to alkaline phosphatase. The method permits the simultaneous determination of the presence of multiple bacterial species in single or multiple dental plaque samples, thus suggesting its usefulness for a range of clinical or environmental samples. PMID- 7833044 TI - Cell-to-cell contact and extracellular matrix. PMID- 7833045 TI - Fibronectin structure and assembly. AB - Significant progress has been made recently in the determination of the structure and assembly of the important matrix protein fibronectin, a molecule mainly constructed from three modular units denoted Fn1, Fn2 and Fn3. Atomic resolution structures are now available for all three single modules, for Fn1 and Fn3 module pairs, and for the disulphide-linked join between fibronectin monomers. Combined with results from new binding and mutation studies, the new structural information is leading to a clearer view of structure/function relationships in intact fibronectin. PMID- 7833046 TI - Integrin-ligand interactions: a year in review. AB - Many cell-cell and cell-matrix interactions depend upon the engagement of specific ligands by members of the integrin family of cell-adhesion receptors. In concert with the identification of new integrins, the number of integrin ligands continues to expand dramatically. The diversity of the integrin ligands bridges many areas of cell and molecular biology. Ligand recognition by integrins requires not only the presence of the cognate primary sequence within an appropriate secondary structure, but also the correct tertiary and quaternary structure of the ligand. Presentation of an 'activated' ligand sequence to specific contact sites within the integrin under specified divalent-cation conditions is necessary for a productive and high-affinity interaction. PMID- 7833047 TI - Basal lamina assembly. AB - From studies of the 'classical' components, models for the assembly and structure of an idealized basal lamina have been developed. In particular, the evidence supports the concept of enmeshed collagen and laminin polymers, in which nidogen/entactin acts as a bridge between these molecules and provides anchorage for diverse matrix components. Different basement membranes, however, possess different members of the basic basal lamina families, such as the newly described alpha 6 (IV) collagen, alpha 2 (merosin) laminin, and beta 3 laminin (in kalinin/nicein) chains. Even though these members share homologous domains and sequences, and are likely to share certain functions, they also possess unique characteristics that are expected to provide for basal lamina heterogeneity. A combination of genetic, recombinant and biochemical approaches are now being applied to elucidate the special roles of both old and new components. PMID- 7833048 TI - Desmosomal cadherins: another growing multigene family of adhesion molecules. AB - The formation of supracellular structures, i.e. tissues and organs, is dependent on the spatially and temporally regulated formation of semistable cell-cell contacts. In recent years, the molecular components of such cell junctions, especially those occurring in epithelial cells, have been studied extensively, and the main proteins and glycoproteins of the 'adhering junctions' such as the desmosomes and the zonula adherens of polar epithelial cells have been characterized. We are now beginning to understand the complex protein-protein interactions that contribute to the assembly and disassembly of these structures and their roles in the attachment of specific filaments of the cytoskeleton. PMID- 7833049 TI - The plant extracellular matrix: in a new expansive mood. AB - Plant cell expansion requires the integration of local wall loosening and the controlled deposition of new wall materials. Although we still know little of the latter process, two new classes of proteins have been discovered that may function in the former. Evidence is increasing that the plant extracellular matrix can exert a regulatory effect over cell behaviour. New approaches, in particular a molecular genetic analysis of cell wall mutants, are likely to speed up our understanding of wall biosynthesis, structure and function. PMID- 7833050 TI - Focal adhesion kinase and associated proteins. AB - Focal adhesion kinase (pp125FAK), a protein tyrosine kinase, has recently been suggested to regulate aspects of signalling induced by integrins and by certain growth factor and hormone receptors. New studies indicate that the domains of pp125FAK regulate its interactions with integrin subunits, other protein tyrosine kinases, and the focal adhesion associated protein paxillin. Through these interactions, pp125FAK may regulate signalling via different extracellular ligands. PMID- 7833051 TI - Tumor-suppressor gene products in cell contacts: the cadherin-APC-armadillo connection. AB - Various structural components of intercellular junctions have recently been found to represent (or be related to) products of tumor-suppressor genes. The tumor suppressor gene product adenomatous polyposis coli (APC) binds to beta 2-catenin (homologous to the product of Drosophila armadillo), which is cytoplasmically associated with the cell adhesion molecule E-cadherin. PMID- 7833052 TI - Drosophila integrins and their ligands. AB - The major advance during the past year was the identification of ligands for two of the previously known position-specific integrins in Drosophila. At the same time, two new Drosophila integrin subunits (one alpha and one beta) were discovered, and significant progress was made on developmental genetic analyses of integrin functions, shedding light on the roles of integrins in Drosophila development. PMID- 7833053 TI - Cadherins and catenins: interactions and functions in embryonic development. AB - During the past year, the family of cadherin cell-adhesion molecules has increased in number and diversity. Recent studies have also emphasized how cadherin activity can be regulated by the dynamic association with intracellular components, the catenins, and with extracellular molecules that are linked to different cell-signaling pathways. Finally, the initial steps have been taken towards identifying the function of cadherins in vivo, including their potential roles in early embryonic development. PMID- 7833056 TI - Cell-to-cell contact and extracellular matrix. PMID- 7833055 TI - Microbial adhesins recognizing extracellular matrix macromolecules. AB - Microorganisms express a family of cell-surface adhesins that specifically recognize and bind components of the extracellular matrix. Adhesion of microorganisms to host tissues represents a critical phase in the development of many types of infections. Recent studies have focused on the mechanisms of microbial attachment at a molecular level, including the identification of ligand binding domains in several cell-surface adhesins from Gram-positive bacteria and the construction of adhesin-deficient isogenic mutants. PMID- 7833054 TI - Adhesion and matrix in vertebrate development. AB - The extracellular matrix supports the adhesion and migration of cells during morphogenesis and influences cell differentiation. Cell interactions with the extracellular matrix are mediated in large part by members of the integrin family of cell-surface receptors. Recent progress in this area has resulted in the identification of multiple integrins, many of which are expressed in position specific patterns during vertebrate development. The contributions of these receptors to specific developmental events are now being investigated in a variety of systems using a combination of genetic, molecular and immunological approaches. PMID- 7833057 TI - The anion-binding exosite is critical for the high affinity binding of thrombin to the human thrombin receptor. AB - The thrombin receptor has been shown to be a novel member of the family of G protein coupled receptors (Vu, T.-K. H., Hung, D.T., Wheaton, V.I., and Coughlin, S.R. (1991) Cell 64, 1057-1068). This receptor appears to be activated through a thrombin-mediated proteolytic mechanism which exposes a "tethered ligand" responsible for receptor activation. In order to investigate the initial interactions of thrombin with this receptor, we have constructed cell lines which express high levels of the human thrombin receptor and studied the binding of various forms of thrombin to the cell surface. Analysis of transfected cells with thrombin receptor monoclonal antibodies identified a particular cell line (clone #5-18) which displayed > 150,000 thrombin receptors per cell. Clone #5-18 appeared to express functional receptors since treatment with thrombin resulted in both a 15-20 fold increase of cytoplasmic phosphoinositide levels and a comparable shift in the EC50 of thrombin-mediated calcium mobilization when compared to non-transfected CHO cells. Binding of 125I-alpha-thrombin to clone #5 18 did not reach equilibrium at 37 degrees C. However, direct binding studies of 125I-alpha-, 125I-diisopropylphospho (DIP)-alpha-, and 125I-beta-thrombin to clone #5-18 demonstrated that binding at 4 degrees C was saturable and reversible for each ligand. Analysis of the binding data revealed Kd's of 0.8 nM, 0.7 nM and 9.7 nM for 125I-alpha-, 125I-DIP-alpha- and 125I-beta-thrombin respectively. Association of 125I-alpha-, DIP-alpha, and beta-thrombin could be competed by unlabelled alpha- and DIP-alpha-thrombin. Unlabelled beta-thrombin, which has a modified anion-binding exosite, was a poor competitor for 125I-alpha- and 125I DIP-alpha-thrombin, but did compete for 125I-beta-thrombin. In addition, the hirudin54-65 peptide competed at submicromolar concentrations for the binding of alpha- and DIP-alpha-thrombin, but not for beta-thrombin. This peptide binds specifically at the anion-binding exosite of alpha-thrombin and has been shown to have a lower affinity for beta-thrombin. These results demonstrate directly a high affinity interaction between thrombin and its receptor, and suggest that an important component is the high affinity association of the thrombin receptor with the anion-binding exosite of thrombin. PMID- 7833058 TI - Transforming growth factor-beta: antisense RNA-mediated inhibition affects anchorage-independent growth, tumorigenicity and tumor-infiltrating T-cells in malignant mesothelioma. AB - Transforming growth factor-beta (TGF-beta) is produced by a number of tumor cell types including human malignant mesothelioma (MM), but its role as a direct or indirect factor in tumorigenesis is incompletely understood. We have investigated the expression of TGF-beta isoforms by human and murine MM cells and have analysed the effects of inducible antisense RNA-mediated inhibition of TGF-beta expression on murine MM in vitro and in vivo. The results showed that (a) TGF beta 1 and -beta 2 were produced by both human and mouse MM cells, (b) antisense RNA against either TGF-beta 1 or -beta 2 cross-inhibited both TGF-beta 1 and beta 2 expression, (c) inhibition of TGF-beta expression reduced the anchorage independent growth of MM cells in vitro and the tumorigenicity of MM cells in vivo, and (d) inhibition of TGF-beta expression led to increased T lymphocyte infiltration into tumors. The data suggest that TGF-beta has multiple tumor enhancing effects in MM. PMID- 7833059 TI - Bone morphogenetic proteins inhibit proliferation, induce reversible differentiation and prevent cell death in astrocyte lineage cells. AB - Bone Morphogenetic Proteins (BMPs) induce the differentiation of Serum-free Mouse Embryo (SFME) cells into astrocytes (D'Alessandro et al., 1994) as demonstrated by change in morphology, increase in Glial Fibrillary Acidic Protein (GFAP) content and classification as both type 1 and 2 astrocytes. Further analyses showed that in the presence of BMP, cells which had differentiated into astrocytes were inhibited from proliferation. Moreover, removal of BMP resulted in a resumption of proliferation accompanied by a loss of GFAP expression over time, indicating that under these in vitro conditions the differentiation was reversible. Since EGF is absolutely required for the survival of SFME cells, we examined the effect of its removal in the presence of BMP. Cell survival was > 80% in the presence of BMP-2, 7 or 2/7 and < 10% in the presence of TGF-beta 1. These data demonstrate that BMPs have effects on the proliferation, differentiation and survival of cells in the astrocyte lineage. PMID- 7833060 TI - The international standard for basic fibroblast growth factor (FGF-2); comparison of candidate preparations by in vitro bioassays and immunoassays. AB - Three preparations of recombinant basic fibroblast growth factor (bFGF, FGF-2) were evaluated, using a variety of in vitro bioassays and immunoassays, by 11 laboratories in six countries for their suitability to serve as international standards (IS) for bFGF. Two preparations of human sequence bFGF showed broadly similar behavior in different assays, but the relative activity of the third preparation, a modification of the human sequence, showed more variability. All three preparations were predicted to be sufficiently stable to serve as an IS. On the basis of the results reported here, the World Health Organization (WHO) established one of the preparations (coded 90/712) as the international standard for basic fibroblast growth factor, and assigned it a content of 1600 International Units (IU) per ampoule. The IS may be obtained for use in the calibration of local standards by writing to NIBSC, PO Box 1193, Potters Bar, EN6 3QH, UK. PMID- 7833061 TI - [Hypertensive cardiopathy: will a diastolic functional study be clinically relevant?]. PMID- 7833062 TI - [Does the modified Bruce protocol induce physiological stress equal to that of the Bruce protocol?]. AB - OBJECTIVE: To determine if the physiological stress induced by the modification of Bruce protocol used in our hospital is equivalent to the original protocol. DESIGN: Retrospective analysis of clinical history, physical examination and stress test of apparently healthy individuals submitted to cardiac check up. SETTING: Outpatient private cardiological clinical. PARTICIPANTS: Sequential sampling of 80 individuals apparently healthy, submitted to cardiac check-up between April 1988 and September 1992. MATERIAL AND METHODS: Comparison of heart rate, blood pressure and double product progression, as well as time of exercise of individuals studied by the Bruce protocol (group A: n = 51) with the same data of individuals tested by the modified Bruce protocol (group B: n = 29). MEASUREMENTS AND MAIN RESULTS: The first stage of group A protocol provokes a superior physiologic stress than group B protocol, since there are bigger increments on heart rate (28.8 +/- 9.9 vs. 20.2 +/- 11.2 bpm; p < 0.01), blood pressure (27.0 +/- 11.3 vs. 14.3 +/- 11.4 mmHg; p < 0.0001) and, consequently, higher double products. In submaximal stages with the same speed and grade on the treadmill the hemodynamical stress is similar in both groups. At peak exercise, group A attains higher values on systolic blood pressure (197.1 +/- 9.5 vs. 188.8 +/- 10.4 mmHg; p < 0.001), double product (34330.4 +/- 2191.8 vs. 33060.9 +/- 2049.8; p = 0.01) and corrected exercise time also higher than estimated (929 +/- 91 vs. 818 +/- 94 sec; p = 0.02). It could be found that more individuals on group A (76% vs. 48%; p = 0.02) could complete the stage of 6.8 Km/h x 16% (stage IV on Bruce protocol and V on modified Bruce protocol. CONCLUSIONS: Modified Bruce protocol has a lighter initial increment, but decreases moderately the capacity of peak exercise due to peripheral fatigue secondary to the first stage of low intensity. Bruce protocol has a higher initial increment but permits to attain higher peak exercise intensities. Bruce protocol seems more adequate to individuals with good physical capacity and the modified Bruce protocol to individuals moderately limited in their functional capacity due to bad physical fitness or illness. PMID- 7833063 TI - [The repercussions of pulmonary congestion on ventilatory volumes, capacities and flows]. AB - OBJECTIVES: To evaluate the effects of pulmonary congestion on pulmonary function. STUDY DESIGN: Prospective study performed in patients with left ventricular failure or mitral stenosis. MATERIAL AND METHODS: Forty-eight hospitalized patients were included suffering from pulmonary congestion either from left ventricular failure or mitral stenosis. While in hospital all patients were submitted to right heart catheterization by the Swan-Ganz method and also to an echocardiographic examination. Within 48 hours after the patients were submitted to the following lung function studies: lung volumes and capacities by the multi-breath helium dilution method and airway flows by pneumotachography. Respiratory symptoms were evaluated by the Medical Research Council Questionnaire and the functional class classified according to the NYHA. Correlations were made between the functional and clinical data. RESULTS: Regarding the cardiac evaluation patients presented with a mean pulmonary wedge pressure of 19.9 +/- 8.6 mmHg, a cardiac index of 2.5 +/- 0.8 l/min/m2, an end diastolic dimension of the left ventricle of 65.9 +/- 10.1 mm, and end systolic dimension of 51.2 +/- 12.2 mm, with a shortening fraction of 21.8 +/- 9.5%. The pulmonary evaluation showed a restrictive syndrome with a reduction in the mean values of the following parameters: total pulmonary capacity 71 +/- 14.4% of the predicted value (pv), forced vital capacity (FVC) 69.8 +/- 20.5% pv, and forced expiratory volume (FEV1) of 64 +/- 21.8% vp. The index FEV1/FVC was within the normal value of 72.7 +/- 9.7%. These lung function results did not correlate significantly with either the clinical, the hemodynamic or echocardiographic findings. CONCLUSION: In these group of patients pulmonary congestion led to the development of a restrictive syndrome which failed to correlate in severity with the duration of the disease, the pulmonary wedge pressure and the left ventricular function. PMID- 7833064 TI - [Refractory heart failure in a 26-year-old woman with idiopathic hemochromatosis]. AB - Idiopathic hemochromatosis, the most frequent inherited disease in Caucasians, is frequently undiagnosed. In this disorder, characterized by a continued inappropriated absorption of dietary iron, the clinical manifestations result from damage to those organ systems in which iron has been pathologically deposited, namely, the heart and the liver. Typically, hemochromatosis becomes clinically manifest in later life and in men more frequently than in women. This has been attributed to the extra loss of iron in women through menstruation and pregnancies. Removal of the excess iron by phlebotomy will prevent all of the complications of hemochromatosis of when begun early. In this paper, we report a case of a young woman with a eight years evolution of amenorrhea, cardiac failure, diabetes mellitus and increased pigmentation of the skin, associated with biochemical markers of iron overload. It is emphasized that hemochromatosis most be excluded in all patients with a unexplained cardiac failure. PMID- 7833065 TI - [The ambulatory recording of the long-term electrocardiogram]. AB - In the past 5 years, a new approach was developed to evaluate the patient with sporadic symptoms as is the patient with syncope--the long-term ambulatory loop electrocardiogram monitoring. This method allow to assure the heart rate and rhythm at the moment of the symptoms hardly to be able with the other diagnostic tools disposable. The long-term ambulatory loop electrocardiogram monitoring was not to replace the actual tools, but complement them. Newer devices are smaller and too light, and have the ability of registry some minutes before and after the symptom. In the near future, the devices will be able to detected and store arrhythmias and to possess an easy and accessible management. With continued and profitable work that has been done in this area, a large proportion of patients with the diagnosis of "syncope of unknown etiology" can have a diagnostic and specify therapeutic and we will be able to assert with more strictness if the symptoms related by the patient are or not of cardiovascular origin. PMID- 7833066 TI - [Monuments to Sousa Martins]. PMID- 7833067 TI - Comparison of neonatal outcomes. PMID- 7833068 TI - Sudden cardiac death in childhood and adolescence. PMID- 7833069 TI - Haemophilus influenzae type b. PMID- 7833070 TI - Childhood asthma appears to be increasing: but how good is the evidence? PMID- 7833071 TI - Outcome of neonates transported between Level III centres depends upon centre of care. AB - This study aimed to clarify whether the adverse outcomes seen in babies transported between New Zealand Level III intensive care nurseries were due to the transport itself or to possible differences in care in different centres. The outcomes of 34 infants inborn at National Women's Hospital, Auckland but transported to other centres were compared with those of 68 matched controls inborn at the receiving centres and with 68 controls inborn and cared for at National Women's Hospital. Transport was associated with a transient (non significant) deterioration in respiratory status but no increase in chronic lung disease. However, infants cared for elsewhere, whether transported or control, had more periventricular hemorrhage than Auckland babies (23% and 29% vs 15%, P = 0.03) and worse neurodevelopmental outcome (70% and 66% vs 88% of those whose outcomes were known were normal at follow up, P = 0.002). We conclude that differences in care between centres may be more important than the transport itself in determining the long-term outcome of transported neonates. PMID- 7833072 TI - Sequelae of Haemophilus influenzae type b meningitis in aboriginal and non aboriginal children under 5 years of age. AB - Between 1984 and 1990, 257 cases of Haemophilus influenzae type b (Hib) meningitis occurred in children under five years of age in Western Australia. We obtained information on possible sequelae in 131 cases (all non-Aboriginal) by medical record review and parental interview, and in a further 116 cases (60 non Aboriginal, 56 Aboriginal) by medical record review only; no follow-up information was available for ten children (nine non-Aboriginal, 1 Aboriginal). The incidence of Hib meningitis in children under five years of age was 26.3 per 100,000 for non-Aboriginal and 152.2 per 100,000 for Aboriginal children. The case fatality rate was 3.5% for non-Aboriginal children and 14.0% for Aboriginal children. Sequelae were recorded for 17.1% of non-Aboriginal and 22.4% of Aboriginal children who survived Hib meningitis. Surviving Aboriginal children experienced severe sequelae following Hib meningitis almost three times more frequently than surviving non-Aboriginal children (10.5% vs 3.6%), although mild and moderate sequelae were not more common in Aboriginal children. The information on incidence and severity of sequelae in this study was obtained by chart review and parental interview, and hence may be subject to error or bias, particularly for mild and moderate disabilities. Outcomes like death and severe sequelae, such as cerebral palsy and profound intellectual and physical disability, are less subject to bias. Of Aboriginal children who contracted Hib meningitis in Western Australia over the study period, 22.8% either died or had severe sequelae, while only 7.0% of non-Aboriginal children experienced these severe outcomes. PMID- 7833073 TI - Prevalence, severity and medical management of asthma in European school children in 1985 and 1991. AB - This present study, conducted in 1991, examined trends in the prevalence, severity and medical management of asthma in European school children by repeating the protocol of a study performed in 1985, using the same schools and questionnaire. One thousand, nine hundred and one children in 1991 were compared with 1084 children in 1985. The prevalence of respiratory symptoms increased significantly by approximately one-third, although the increase in the diagnostic label 'asthma' did not increase significantly. Asthma severity indices (> 12 asthma attacks in the last 12 months and symptoms in the last month) were not significantly increased, except for night cough in the last month (1985 7.0%, 1991 9.9%, P = 0.008). In 1991, children with wheeze in the last 12 months were more likely to be diagnosed as having asthma and treated with bronchodilators and prophylactic drugs than in 1985. We conclude that the prevalence of asthma symptoms has increased from 1985 to 1991, but the two indices of severity of asthma are mostly unchanged. Diagnosis of asthma in children with symptoms has improved but asthma still appears underrecognized. Drug treatment of asthma has increased. PMID- 7833074 TI - Two hour seminar improves knowledge about childhood asthma in school staff. AB - Teachers and support staff are often called upon to manage asthma at school but may have little knowledge and understanding of the condition. The aim of this study was to determine whether a short seminar would improve knowledge in non health professionals. Seventy school staff attended one of five 2 h seminars presented by an asthma educator. Participants completed the Newcastle Asthma Knowledge Questionnaire (AKQ) before, and 2 months after, the seminar. The mean initial score (maximum possible 31) was 16.4 (range 4-26), increasing to 23 (range 13-29, P = 0.0001). There was a large increase in knowledge about symptoms, pathophysiology, preventive medications and side effects of medications. Initially almost all of the participants had deficiencies in knowledge about reliever medications and the management of exercise-induced asthma. After the seminar, knowledge in these areas was still poor, with only one third of the participants answering them correctly. The results have been used to modify the content of the 2 h seminar with increased emphasis on those areas in which deficiencies in knowledge were demonstrated. No data are available yet as to whether this improved knowledge has improved management. PMID- 7833075 TI - A blinded comparison of clinical and echocardiographic evaluation of the preterm infant for patent ductus arteriosus. AB - The accuracy of the characteristic physical signs of a patent ductus arteriosus (PDA), that is, a systolic murmur, increased volume of pulses and increased praecordial activity, in diagnosing a haemodynamically significant PDA in ventilated premature infants was prospectively evaluated. Fifty-five ventilated preterm infants (birthweight < 1500 g) had daily echocardiographic and clinical evaluation for a PDA for the first 7 days of life. The examiners were blinded to each other's findings. Probability analysis was performed for the accuracy of each clinical sign in detecting a haemodynamically significant PDA as defined by echocardiographic criteria. Clinical signs were poor at detecting a significant PDA in the first 4 days of life. On day 1, none of the 10 infants with a significant PDA had a murmur. By day 4, clinical signs were better at detecting a significant PDA, but specificity remained poor with many false positive signs. Six infants had murmurs with a closed duct. The development of echocardiographic haemodynamic significance preceded the development of physical signs by a mean of 1.8 days. Significant ductal shunts often occurred silently, but the development of a murmur often marked an increase in the velocity of the flow through the duct rather than an increase in the size of a shunt. This study confirms that echocardiography is required for the reliable early diagnosis of a PDA in ventilated preterm infants. PMID- 7833076 TI - Inguinal hernia in extremely preterm infants. AB - The prevalence of inguinal hernia during primary hospitalization was determined in 250 infants with gestational age 24-29 weeks. Fourteen per cent developed hernia, with prevalence significantly higher in boys than girls. Infants with respiratory distress syndrome and those requiring prolonged mechanical ventilation were significantly predisposed to the development of hernia. Male infants, especially those who required prolonged ventilatory assistance, were at greatest risk. This information may be used when counselling parents regarding complications of very preterm infants. PMID- 7833077 TI - Congenital heart disease: a 10 year cohort. AB - In order to describe the epidemiology of congenital heart disease in Western Australia, a retrospective, population-based cohort study was conducted using data collected from multiple sources of ascertainment by the Western Australian Birth Defects Registry. The prevalence of congenital heart disease was 7.65 per 1000 total births. Nine per cent of all cases had a chromosomal disorder, another 17% had extracardiac defects in addition to congenital heart disease, and 75% had isolated congenital heart disease. Congenital heart disease was more common in Aboriginal compared with non-Aboriginal infants, and in multiple births compared with singletons. Compared with infants weighing 3000 to 3499 g, infants of lower birthweight were more likely to have congenital heart disease, and infants in the heaviest category (> or = 3500 g) were less likely to have congenital heart disease. Three per cent of all stillbirths were known to have a cardiac defect, as were 15.2% of neonatal deaths and 10.8% of post-neonatal deaths. PMID- 7833078 TI - Death in neonatal intensive care. AB - The aim of this study was to review the frequency of decisions to withdraw treatment from neonates who had died in a large neonatal intensive care unit, the reasons for these decisions, and the procedures followed. A 12 month retrospective review of medical and nursing records was undertaken. There were 67 deaths; treatment was withdrawn from 52 infants who were dead or dying, from 9 infants on the basis of a severe congenital abnormality, and from 6 infants with severe acquired brain damage. The decision-making process and the management of treatment withdrawal are reviewed. It is concluded that withdrawal of treatment resulting in death occurs frequently in the neonatal intensive care service of National Women's Hospital, Auckland, New Zealand, but is usually a recognition of the inevitable. Truly elective withdrawal of treatment is uncommon in the immature infant, but does occur in the context of multiple abnormalities or severe birth asphyxia, where it follows a formal procedure. PMID- 7833079 TI - Age-related changes in oxygen saturation over the first year of life: a longitudinal study. AB - Stability of oxygen saturation depends on maturation and function of individual components of the respiratory system. The aim of this study was to record and analyse comprehensive oxygen saturation data in a longitudinal study over the first year of life. Detailed sleep studies were performed on 15 normal infants eight times in the first year of life. The accrued oxygen saturation data were analysed on a computerized oximetry data analysis system. Results show the mean sleep saturation levels trending upwards and stabilizing by 185 days. There was an inverse curvilinear relationship between mean age and median desaturation time and the median number of desaturations at < or = 95, < or = 92 and < or = 90% saturation. The mean cumulative desaturation time < or = 90% in the first 4 months was 11.08 min (range 2.5-36.57 min). This study demonstrates monotonic patterns of increasing saturation and decreasing number and time of desaturations < or = 95% and < or = 90% but a random pattern of desaturations < or = 85% occurs across the first 6 months of life. Cumulative desaturation times over the first 4 months of life were high and could be important to the development of maturity of the respiratory system. After 6 months, all indices of saturation and desaturation point to a stable and mature respiratory system. PMID- 7833080 TI - The effect of halothane on neonatal ciliary beat frequency. AB - The effect of a commonly used anaesthetic agent, halothane, on neonatal cilial function was determined. A nasal cilial sample was taken from 13 healthy, term, newborn infants. For 1 h, half of each sample was exposed to halothane and half to air. Cilial function was assessed by measuring beat frequency with a modified light transmission method. Cilial beat frequency was significantly slower in the cilia exposed to halothane, 9(s.d. 2.5)Hz, than to air, 12.9(s.d. 1.5)Hz. Decreased mucociliary clearance following halothane anaesthesia is due, at least in part, to a directly depressant effect of halothane on ciliated cells. PMID- 7833081 TI - Vitamin A status in preterm neonates with and without chronic lung disease. AB - It has been proposed that there is an association between vitamin A (VA) deficiency and the development of chronic lung disease (CLD) in preterm infants. This study was designed to measure the VA status in preterm infants and to compare the results in the group of babies who developed CLD with the group who did not. Vitamin A status was assessed by measuring plasma VA, retinol binding protein (RBP) and the plasma VA:RBP molar ratio in 25 infants of less than 31 weeks gestation during the first 28 days of life. Eleven babies developed CLD and 14 did not. There was no significant difference in plasma VA levels between the CLD and non CLD groups during the first 28 days. The majority of infants had adequate VA status, with a subgroup being deficient. PMID- 7833082 TI - A comparative study of the growth of South-East Asian children in south-west Sydney born in Australia and overseas. AB - The height and weight of two groups of South-East Asian children between the ages of 1 and 10 years living in south-west Sydney were compared to determine the effects of environment on growth and development. One group of these children was born overseas and the other in Australia. The children who were born in Australia were found to be significantly taller (1-2%) and heavier (10%) than those born overseas. This would suggest that ecological factors including health and nutrition contribute to these differences. PMID- 7833083 TI - Ventricular septal defect and sudden death in early childhood. AB - A 2 1/2 year old boy collapsed at home and was taken immediately to the local hospital in cardiorespiratory arrest where attempted resuscitation was unsuccessful. At autopsy, massive cardiomegaly was found associated with a large membranous ventricular septal defect. There was also an early acute bronchopneumonia. Although growth parameters indicated failure to thrive, no specific health problems had been noted by the family apart from an apparent mild 'upper respiratory infection' prior to death. While the occurrence of sudden and unexpected death in cases of undiagnosed isolated ventricular septal defect has not been emphasized in the literature, this case demonstrates that sudden death may be a problem in early childhood. This is particularly so in cases of untreated large defects with cardiomegaly when additional stresses such as acute infection occur. PMID- 7833084 TI - Primary hyperparathyroidism in a 14 year old girl presenting with bone deformities. AB - A 14 year old girl with bilateral genu valgum of 6 years duration was brought for evaluation of primary hyperparathyroidism. She had clinical features of rickets such as frontal bossing, rachitic rosary, lumbar lordosis and fixed adduction deformity of the left leg. She had undergone osteotomy earlier for correction of these deformities without benefit. Laboratory investigations showed hypercalcaemia and hypophosphataemia, with elevated alkaline phosphatase and parathyroid hormone levels. A skeletal survey showed generalized decreased density of bone and brown tumours and, coincidentally, a right renal calculus. A computerized tomography scan of the neck and thallium-technetium subtraction scan delineated an adenoma of the left superior parathyroid gland, which was surgically removed. Parathyroid adenoma manifesting with bone deformities, especially genu valgum, is very rare in children. Early diagnosis and prompt treatment is essential to prevent such deformities. PMID- 7833085 TI - Oral calcium treatment in vitamin D-dependent rickets type II. AB - Vitamin D-dependent rickets type II is a rare hereditary disease that results from target organ resistance to the action of 1,25-dihydroxyvitamin D3. There is a great heterogeneity in the clinical presentation of this condition. The affected patients usually present early in childhood with clinical and biochemical evidence of rickets. Physiological replacement dosage of 1,25 dihydroxyvitamin D3 has no therapeutic effect. Responses to pharmacological doses of vitamin D metabolites or long-term calcium infusion have been variable. A case is reported here of an 8 year old girl, of consanguineous parents with vitamin D dependent rickets, type II, in whom treatment with high dose oral calcium resulted in marked biochemical and radiological improvement. It is concluded that high dose oral calcium treatment is an effective treatment option for patients with vitamin D-dependent rickets type II. PMID- 7833086 TI - Breast feeding in neonatal alloimmune thrombocytopenia. AB - Infants with neonatal alloimmune thrombocytopenia are at risk of severe intracranial haemorrhage. Placental transfer of maternal immunoglobulin G (IgG) directed against fetal platelet antigens is known to be the underlying mechanism. Since breast milk contains IgG it is theoretically possible that breast feeding of these infants could cause thrombocytopenia. The following case report shows that an infant with neonatal alloimmune thrombocytopenia may be safely breast fed, even when the breast milk contains the platelet specific antibody (HPA-1a). PMID- 7833087 TI - Hydrocephalus ex vacuo and clasp thumb deformity due to congenital cytomegalovirus infection. AB - A case of congenital hydrocephalus in a male infant with flexion deformity of the thumbs and great toes is reported. A maternal uncle had undefined intellectual impairment and X-linked hydrocephalus was considered among the differential diagnoses. However, this diagnosis was considered unlikely as the pyramids were preserved at autopsy. In addition, postmortem histopathology and viral culture established cytomegalovirus (CMV) infection as the underlying cause of the hydrocephalus. Although CMV infection is a well recognized cause of congenital hydrocephalus, the associated flexion deformities of the thumbs and great toes have not been previously described and may reflect injury to the corticospinal tracts. PMID- 7833088 TI - Two dose MMR vaccine schedule. PMID- 7833089 TI - Childhood poisoning in Hong Kong: experience of the Drug and Poisons Information Bureau from 1988 to 1992. PMID- 7833090 TI - Survival of low birthweight infants in central Queensland. PMID- 7833091 TI - In vitro growth behaviour of acute myeloid leukaemic cells. PMID- 7833092 TI - Predictive value of thymidylate synthase and dihydropyrimidine dehydrogenase. PMID- 7833093 TI - Lonidamine: in vitro/in vivo correlations. PMID- 7833094 TI - Consistency of histopathological reporting of breast lesions detected by screening: findings of the U.K. National External Quality Assessment (EQA) Scheme. U. K. National Coordinating Group for Breast Screening Pathology. AB - The aim of the scheme was to determine consistency of histopathological reporting in the United Kingdom National Breast Screening Programme. This external quality assessment scheme involved 51 sets of 12 slides which were circulated to 186-251 pathologists at intervals of 6 months for 3 years. Participants recorded their diagnoses on standard reporting forms, which were submitted to the U.K. National Cancer Screening Evaluation Unit for analysis. A high level of consistency was achieved in diagnosing major categories of breast disease including invasive carcinoma and the important borderline lesions, radial scar and ductal carcinoma in situ (DCIS), the latter exceeding a national target set prior to the onset of the scheme. Atypical hyperplasia (AH) was reported with much less consistency although, where it was the majority opinion, over 86% of diagnoses were of benign disorders and only 14% were of DCIS. Inconsistency was encountered in subtyping and measuring DCIS, the former apparently due to current uncertainties about classification and the latter to poor circumscription, variation in size in different sections and merging with zones of AH. Reporting prognostic features of invasive carcinomas was variable. Measurement of size was achieved with adequate consistency except in a small number of very poorly circumscribed tumours. Grading and subtyping were inconsistent although the latter was not specifically tested and will be the subject of future study. Members of the National Coordinating Group achieved greater uniformity than the remainder of the participants in all diagnostic categories, but both groups experienced similar types of problem. Our findings suggest that participation in the scheme improves diagnostic consistency. In conclusion, consistency in diagnosing invasive carcinoma and radial scar is excellent, and good in DCIS, but improvements are desirable in diagnosing atypical hyperplasia, classifying DCIS and reporting certain prognostic features of invasive tumours. Such improvements will require further research, the development of improved diagnostic criteria and the dissemination of clearer guidelines. PMID- 7833095 TI - Elevated doses of carmustine and mitomycin C, with lonidamine enhancement and autologous bone marrow transplantation in the treatment of advanced colorectal cancer: results from a pilot study. AB - 10 patients with advanced colorectal cancer were treated with elevated doses of carmustine and mitomycin C. The regimen was potentiated by lonidamine and supported by autologous bone marrow transplantation. The results of this pilot study were encouraging, with a response rate of 50% and a significantly better survival for responders versus non-responders. No appreciable toxicity of the therapy was observed. This aspect, together with the simplicity of the procedure, calls for further investigations to confirm the good therapeutic index of the treatment. PMID- 7833096 TI - A randomised trial of MACC chemotherapy with or without lonidamine in advanced non-small cell lung cancer. Cuneo Lung Cancer Study Group (CuLCaSG) AB - Combination chemotherapy with anti-proliferative agents is the usual treatment for patients with advanced non-small cell lung cancer (NSCLC), good performance status and no major clinical contraindications. Lonidamine (LND), a new drug with an innovative mechanism of action, might potentiate anti-cancer activity of conventional cytotoxic drugs, with no increase of specific toxicity. Following a pilot study of feasibility, we now report the results of a randomised trial evaluating MACC chemotherapy, as originally described, versus the same regimen+LND. 151 patients with advanced NSCLC were assigned at random to the two treatment arms. LND 150 mg was given orally three times daily. Treatment was continued until progression of disease, unacceptable toxicity or refusal by the patient (median number of cycles of MACC, three for both arms; median duration of LND administration, 8 weeks in the arm concerned). Actual dose intensities (DI) of MACC and LND were, respectively, 100 and 83% of those intended (median values). There was a negative correlation between duration of chemotherapy and the DI of MACC reached in each patient, but no correlation between the duration of treatment with LND and its DI. DIs of LND and MACC were not correlated with each other. In all, 15 objective responses (one complete and four partial responses in the MACC group, 10 partial responses in patients on MACC+LND) were observed. Median progression-free survivals were 20 weeks (confidence interval, CI 14-22) for the group on LND and 17 weeks (CI 12-17) for the control group (non significant difference). Median overall survivals were, respectively, 30 weeks (CI 23-40) and 27 weeks (CI 22-34), P = non-significant. Toxicity was as expected by the use of MACC, and similar in both arms, except for more severe anaemia and gastric toxicity in the group on MACC+LND. Other uncommon side-effects, seen only in this latter group, were mild to moderate and reversible and included myalgia, asthenia, testicle pain, headache, visual troubles, incubi and dizziness. Subjective tolerance to the treatment, and perception of physical and psychological well-being were rated similarly by patients of both groups. MACC plus LND is a moderately active regimen in advanced NSCLC, with a foreseeable and reversible toxicity of low-medium grade. Potential enhancements of anti-tumour efficacy of chemotherapy, and possible host survival benefits derived from the use of LND are not substantiated by the results of this trial. PMID- 7833097 TI - Epidoxorubicin and lonidamine in refractory or recurrent epithelial ovarian cancer. AB - Lonidamine (150 mg x 3 day orally, days 1-5) plus high dose epidoxorubicin (120 mg/m2 intravenously, day 3) was tested in 26 patients with refractory or recurrent epithelial ovarian cancer, to assess the anti-tumour activity and the toxicity of this combination of drugs. All patients were evaluable for toxicity and 24 for tumour response. Two complete responses (8.3%) and six partial responses (25.0%) were recorded for a total response rate of 33.3%. 6 of 8 responding patients were pretreated with anthracyclines. Stable disease was obtained in 7 patients (29.2%). Toxicity was acceptable; only 1 (3.8%) patient stopped chemotherapy because of a left ventricular ejection rate reduction > 20%. The most relevant side-effect was leucopenia (grade 3-4, 34.6%). In conclusion, the association of lonidamine and high-dose epidoxorubicin has promising activity as second-line treatment in patients with refractory or recurrent epithelial ovarian cancer. PMID- 7833099 TI - How relevant is secondary leukaemia for initial treatment selection in Hodgkin's disease? AB - Specific tools of decision analysis, a set of mathematical rules for simplifying complex decisions, were applied to evaluate the impact of secondary leukaemia on the selection of initial treatment in Hodgkin's disease (HD). For this purpose, a combined 'expected utility' considering survival, relapse free survival, and secondary leukaemia was determined for different treatment strategies. Our analysis revealed that considerations of secondary leukaemia for initial therapy should include the a priori estimation of all possible events which may occur after initial treatment, e.g. the probabilities of recurrence and success of salvage therapy. In early and intermediate stage HD, for example, the minimal risk of leukaemia after successful radiotherapy (RT) must be weighed against the increased risk after treatment failure and subsequent salvage therapy. Thus, the difference of expected risk of leukaemia between RT and combined modality treatment (CMT) is within 4% for HD, stage II B and near to 0% in stage III A. In advanced stage HD, the addition of RT to chemotherapy has no adverse effect on the expected utility of initial treatment. These conclusions are only marginally affected by reported differences in rates of recurrence, salvage success, and secondary leukaemia. Subjective quality of life considerations, such as the latency period between treatment and leukaemia and patients' attitudes towards the occurrence of leukaemia, did not significantly affect expected utilities. In summary, our results strongly suggest that presently there is no sound basis for reducing the intensity of initial treatment in HD to avoid secondary leukaemia. PMID- 7833098 TI - Safety, tolerability, efficacy and plasma concentrations of tropisetron after administration at five dose levels to children receiving cancer chemotherapy. AB - In a double-blind, placebo-controlled, escalating dose study, 44 children receiving cancer chemotherapy of various degrees of emetogenicity were randomly allocated to once-daily treatment with tropisetron 0.05 mg/kg (6 patients), 0.10 mg/kg (5 patients), 0.20 mg/kg (6 patients), 0.33 mg/kg (6 patients), 0.50 mg/kg (6 patients) or placebo (15 patients). All doses of tropisetron were well tolerated; no tropisetron recipient discontinued treatment because of intolerance and no adverse effect could be plausibly correlated to tropisetron administration. Therapeutic plasma concentrations of tropisetron (> 3 ng/ml) were present for 9 h after administration of doses of 0.10 mg/kg or more. Tropisetron at doses of at least 0.20 mg/kg was significantly more effective in preventing vomiting than lower tropisetron doses or placebo, both in terms of treatment failure (> four vomits) (P = 0.015) and patient and investigator efficacy ratings (P = 0.04 for investigator rating; P = 0.035 for patient rating). Further comparative studies of the efficacy of tropisetron in chemotherapy-induced emesis in children are warranted. PMID- 7833100 TI - Scalp cooling has no place in the prevention of alopecia in adjuvant chemotherapy for breast cancer. AB - 35 patients were studied to determine the effectiveness of scalp hypothermia in the prevention of alopecia caused by adjuvant chemotherapy for breast cancer. Scalp hypothermia was induced by the newly developed Theracool cooling machine. The chemotherapeutic regimen consisted of one perioperative course of doxorubicin 50 mg/m2, cyclophosphamide 600 mg/m2 and 5-fluorouracil 600 mg/m2 (EORTC protocol 10854). Only 4 (11%) patients showed acceptable hair preservation (no or minor alopecia). 12 patients (34%) had moderate alopecia, all requiring a wig. 19 patients (54%) had complete alopecia. No scalp metastases were observed after scalp cooling. These results and a review of the literature suggest that scalp hypothermia to prevent alopecia may only be effective in a cytotoxic regimen containing an anthracycline as the sole alopecia-inducing agent. With current adjuvant chemotherapy for breast cancer, in which a combination of cyclophosphamide and an anthracycline is often used, there is no place for scalp hypothermia. PMID- 7833102 TI - Limb-sparing therapy of extremity soft tissue sarcomas: treatment outcome and long-term functional results. AB - The purpose of this study is to assess the long-term success rate and functional results of limb-sparing therapy in a group of 156 patients with soft tissue sarcomas of the extremities in the Netherlands Cancer Institute, treated according to a standard protocol of surgery and radiotherapy, if indicated. The patients (79 females and 77 males) were treated between 1977 and 1983 by an intended wide local excision with a margin of at least 2 cm. Postoperative radiotherapy was applied in 117 patients; 26 patients had surgery only, including 13 patients who had to be treated by amputation. The total dose was 60 Gy, with 40 Gy to a large volume and a boost of 20 Gy to the tumour bed at 2 Gy per fraction, five fractions per week. Most sarcomas were located in the proximal part of the lower extremity (51%). The group comprised 50 liposarcomas, 47 malignant fibrous hystiocystoma (MFH) and 59 other histologies; 69 (44%) had high grade tumours. Three treatment groups with limb-sparing treatment were defined: group I (n = 26) patients who had a complete excision receiving no further treatment, group II (n = 64) with narrow surgical margins and radiotherapy and group III (n = 53) with incomplete resection and radiotherapy. The 10-year actuarial overall survival and local control rate for all patients was 63 and 81%, respectively. Multivariate analysis showed that histological grade (P < 0.0001), age (P = 0.0005) and location deep to the fascia (P = 0.0008) were independent prognostic factors for survival, while local control was predicted by grade (P = 0.0014) and treatment group (p = 0.028). Patients with surgery only (group I) had 81% 5-year local control as compared to 92% with radiotherapy after narrow surgery (group II) and 74% with incomplete surgery and radiotherapy (group III). Limb preservation when attempted was achieved in 90% of the patients. After limb-sparing treatment, 7% had severe impairment of mobility, 3% had lymph oedema and 16% marked fibrosis. Fractures in the irradiated bone occurred in 6% of the patients. The combination of limited surgery followed by radiotherapy resulted in a high local control rate with good functional results. Ultimately limb sparing treatment was successful in 83% of all patients with extremity sarcomas. PMID- 7833101 TI - Endocrine changes with the aromatase inhibitor fadrozole hydrochloride in breast cancer. AB - Fadrozole hydrochloride is a potent aromatase inhibitor with proven clinical effectiveness. However, its optimal dose and its effects on serum aldosterone levels/electrolyte balance have been disputed. To resolve these issues, a double blind randomised endocrine study of three doses of fadrozole hydrochloride [0.5 mg twice daily (bd); 1.0 mg bd; 2.0 mg bd] was conducted in 80 (68 evaluable) postmenopausal patients with advanced breast cancer over a period of 3 months. There were substantial falls in the serum levels of oestradiol, oestrone and oestrone sulphate. For oestrone only, there was a significant effect of dose (on treatment means: 0.5 mg, 38.0 pmol/l; 1.0 mg, 25.0 pmol/l; 2.0 mg, 23.9 pmol/l). All oestrogens showed a similar pattern in relation to time, with the 3-month mean being higher than those at 1 and 2 months, and this was significant for oestradiol (P = 0.012). There was an indication that complete suppression of oestradiol and oestrone was not maintained throughout the 12-h dosing period, but the data and its interpretation are complicated by a minor diurnal rhythm in these parameters. There were significant increases in 17-hydroxyprogesterone and androstenedione which may be due to a block of 11 beta-hydroxylase. There was a statistically non-significant fall in aldosterone levels (P = 0.06) during treatment (median pretreatment, 446 pmol/l; median decrease, 125 pmol/l). However, the concurrent significant fall in the plasma sodium: potassium ratio indicated that changes in aldosterone secretion did occur. None of these effects on adrenal pathways was of a degree which is likely to have clinically relevant consequences. It is concluded that fadrozole hydrochloride achieves near maximal suppression of oestrogens at 1 mg bd, and that its effects on aldosterone synthesis are unlikely to be of clinical significance. PMID- 7833103 TI - Multiple defects of T helper cell function in newly diagnosed patients with Hodgkin's disease. AB - T helper cell (TH) function, as assessed by interleukin-2 (IL-2) production and [3H]thymidine incorporation, was studied in 47 newly diagnosed untreated patients with Hodgkin's disease (HD) and 34 healthy controls. Three different stimuli were used to stimulate in vitro peripheral blood mononuclear cells (PBMC): influenza A vaccine (FLU), HLA alloantigens (ALLO) and phytohaemagglutinin (PHA). Four different patterns of TH function were observed in HD patients: (1) IL-2 production in response to all of the stimuli (40%); (2) IL-2 production in response to ALLO and PHA but not to FLU (26%); (3) IL-2 production in response to PHA alone (19%); and (4) failure to respond by IL-2 production to any of the three of the stimuli (15%). Thus, defective in vitro TH function was detected in the majority of these patients (60%). Defective TH function was observed in none of the 34 controls. Severely compromised TH function (patterns 3 and 4) tended to be associated with more advanced clinical presentation and more compromised haematological parameters (P < 0.05). The IL-2 production assay was more sensitive than the proliferative assay as only 30% of the HD patients failed to proliferate in response to FLU, and none failed to proliferate in response to either ALLO or PHA; this assay can detect subtle, multiple patterns of immune dysregulation in untreated HD patients. Our results suggest that HD is associated with a fundamental dysregulation in TH function, illustrate the complexity of such dysregulation, and raise the possibility that HD progression will be associated with a type-1-type-2 switch in immunoregulatory cytokine production. PMID- 7833104 TI - A randomised study of cisplatin versus thiotepa as induction chemotherapy in advanced ovarian carcinoma. AB - Between 1980 and 1984, a total of 171 patients with advanced epithelial ovarian carcinoma and residual tumour after surgery were randomly assigned to treatment groups receiving either cisplatin or thiotepa. The objective of the study was to evaluate the regimes with regard to response and survival. The two groups were well balanced with respect to age, FIGO stage, histology, grade and residual tumour after surgery. In the cisplatin group, 66% responsed to treatment compared to 38% in the thiotepa group (P < 0.00005). The median progression-free survival was 10.5 months and 6.3 months, respectively. The corrected survival was somewhat, but non-significantly, higher in the cisplatin group than in the thiotepa group, with an 8-year corrected survival of 10.6 and 7.4%, respectively. In a multivariate analysis, based on progression-free survival with FIGO stage, residual tumour after surgery, histological type and grade as covariables, treatment with thiotepa had a relative risk of 1.64 compared to cisplatin (95% confidence interval 1.17-2.30, P = 0.004). PMID- 7833105 TI - Cisplatin and etoposide versus cyclophosphamide, epirubicin and vincristine in small cell lung cancer: a randomised study. AB - From September 1986 until December 1991, 139 patients with histologically-proven small cell lung cancer, age < 75 years, performance status > 40, absence of brain metastases and no previous treatment, were randomised to receive either CEV cyclophosphamide 1000 mg/m2 intravenous (i.v.), epirubicin 70 mg/m2 i.v., vincristine 1.2 mg/m2 i.v., every 3 weeks or PE (cisplatin 20 mg/m2 i.v. and etoposide 75 mg/m2 i.v. for 5 consecutive days, every 3 weeks) for six cycles. After three cycles, responding patients received radiotherapy to the chest (45 Gy/15 sessions) and to the brain (30 Gy/10 sessions--only in patients with limited disease achieving complete remission). 3 patients were ineligible. Patient characteristics included (CEV/PE) total number 66/70, median age 60/61 years, median performance status 80/80, extended disease 33/48 cases (P = 0.04). In evaluable patients, 42/62 (67.7%) responded to CEV while 42/58 (72.4%) responded to PE (P = non-significant); respective complete response rates were 16.1 and 29.3% (P = non-significant) and respective complete response rates in patients with extended disease were 9.4 and 28.9% (P = 0.03). Median survival was 10.5 months, without significant differences in the two treatment arms, even after adjustment for stage. PE was less well tolerated than CEV. Although PE is more active than CEV in certain subsets of patients, its apparent inability to improve survival in this and in other studies questions its routine use in small cell lung cancer. PMID- 7833106 TI - Metastatic medulloblastoma: the experience of the French Cooperative M7 Group. AB - A retrospective analysis was performed to determine the outcome of children with metastatic medulloblastoma given a standardised treatment programme. Of 68 consecutive patients treated in the French M7 protocol for medulloblastoma, 23 presented with metastatic disease. They were uniformly treated with surgery, and the same protocol of chemotherapy and craniospinal radiotherapy. The 7-year relapse-free survival rate is 43% for metastatic patients compared to 68% for patients with localised disease. Survival did not correlate with age, sex, location of metastases, extent of initial surgery and the dose of radiation therapy on the posterior fossa. Survival did correlate with the dose to the cranial field with a threshold dose of 30 Gy. Patients with metastatic disease have a worse prognosis and require more aggressive therapies at initial presentation. The prognostic impact of the different sites of metastatic disease requires further evaluation in cooperative studies. PMID- 7833107 TI - Immunoscintigraphy of bone sarcomas--results in 5 patients. AB - The feasibility of using the murine monoclonal antibody, TP-1, for clinical immunoscintigraphy was examined in a pilot study involving 5 patients with bone sarcomas. 131I-labelled F(ab')2 antibody fragments were injected in doses of 0.8 1.0 mg (90-130 MBq), and the accumulation of radioactivity was examined by scintigraphy, and assessed by direct measurements on biopsied tumour and normal tissue. One osteosarcoma patient had a primary tumour in the femur, whereas the other 4 had single lung metastases detected by other diagnostic methods. Immunoscintigraphy of the femoral primary was optimally visualised after 22 h. In 2 patients, the method failed to detect lung metastasis, in 1 of the cases possibly related to less than optimal methodological conditions. In 2 other patients, increased accumulation of radioactivity indicated one and three lung tumours, in addition to the single metastasis observed by X-ray and CT scanning, tumours that were later confirmed and removed surgically. The concentration of radioactivity in tumour and normal tissues 44-72 h after antibody injection could be measured in 4 patients. The tumour to blood ratios were in the range of 1.2 4.2, compared to 0.1-0.8 for various normal tissues. The results indicate that immunoscintigraphy with TP-1 antibody fragments have a potential for early detection of lung metastases in patients with bone sarcoma. PMID- 7833108 TI - Patterns and temporal trends in the incidence of malignant disease in children: I. Leukaemia and lymphoma. AB - Patterns and trends in incidence of leukaemia and lymphoma in children aged under 15 years and resident in the North Western Regional Health Authority area of England at diagnosis, over the 35-year time period 1954-1988, were analysed. The study included 1407 cases registered with the Manchester Children's Tumour Registry, 100% of which had a histologically or cytologically verified diagnosis. Log-linear modelling identified significant linear increases in acute lymphocytic leukaemia (ALL) (average quinquennial increase 4%) and Hodgkin's disease (HD) (10%), but not in acute non-lymphocytic leukaemia nor non-Hodgkin's lymphoma. Additionally, the chi 2 test for trend identified a significant increase in the incidence of chronic myeloid leukaemia. The possibility that the increases seen in ALL and HD are linked to increases in prevalence of unknown infectious agents is discussed. PMID- 7833109 TI - Patterns and temporal trends in the incidence of malignant disease in children: II. Solid tumours of childhood. AB - Incidence patterns and trends, in children, of individual types of non-reticulo endothelial solid tumours and of all cancers combined (including leukaemia and lymphoma) were analysed. The study included 3360 cases diagnosed in residents under 15 years of age of the North Western Regional Health Authority area of England during 1954-1988. Log-linear modelling identified significant increases of juvenile astrocytoma (average quinquennial increase 15%) in males, of medulloblastoma (19%) and neuroblastoma (17%) in females, and of non-skin epithelial tumours (18%) overall, and a significant decrease of unspecified malignant neoplasms around 1974 by approximately 80%. The chi 2 trend test identified significant increases in gonadal germ cell tumours and skin cancers, and borderline significant increases in craniopharyngioma and hepatoblastoma. The incidence of all cancers combined increased significantly in those aged under 1 year (8%), 1-4 years (5%) and 10-14 years (8%). Age-sex patterns were similar to those in other Caucasian populations. Studies of incidence trends can provide the basis for investigations of the aetiology of childhood cancers. PMID- 7833110 TI - Parallel studies of clonogenic leukaemia cells and the leukaemia cell population as a whole in acute myelogenous leukaemia. AB - The clonogenic cells in patients with acute myelogenous leukaemia (AML) were evaluated with respect to the relationship between primary and secondary cloning capacity and the proliferative and molecular biological characteristics of the leukaemia cell population as a whole. Secondary cloning capacity was correlated with primary cloning efficiency, and with the ability of the clonogenic cells to produce large sized clones. The cloning capacity of AML cells was unrelated to the cell cycle characteristics of the leukaemia cell population in vivo or to the level of myc, myb, fms, or interleukin (IL)1 beta expression. The sensitivities of the clonogenic cells to cytosine arabinoside and daunorubicin were inversely correlated with the ability of the leukaemia cells to produce large sized clones in vitro. This latter observation may explain the reported relationships between the clonogenic capacity of AML cells and response to chemotherapy. PMID- 7833111 TI - A role for dihydropyrimidine dehydrogenase and thymidylate synthase in tumour sensitivity to fluorouracil. AB - Despite being one of the oldest anti-cancer drugs, fluorouracil (FU) is still being increasingly used in cancer chemotherapy. The source of variability for FU sensitivity in patients may be complex, although an overproduction of thymidylate synthase (TS) was the only mechanism of resistance identified in tumours from FU resistant patients. Dihydropyrimidine dehydrogenase (DPD) is the first and rate limiting enzyme of FU catabolism. Thus, DPD activity may be a potential factor for controlling FU responsiveness. A panel of 19 human tumour cell lines, including digestive tract, breast and head and neck cancer cells, were investigated. Both TS and DPD activities were measured in parallel to FU responsiveness. None of the cell lines had been previously exposed to FU, and thus expressed a spontaneous sensitivity to FU. Sensitivity between cell lines showed marked differences, with IC50 values ranging from 45 ng/ml (colon cell line) to 5063 ng/ml (head and neck cell line). TS activity was measurable in all cell lines and varied within a 46-fold range. DPD activity was detected in all but four cell lines, showing a 100-fold range of variation. Cell lines most sensitive to FU exhibited the lowest DPD and TS activities and vice versa. Simple linear regression analysis showed that both TS (r2 = 0.22, P = 0.042) and DPD (r2 = 0.27, P = 0.022) activities were significantly correlated to FU effectiveness (log 10 IC50): the greater the enzyme activities, the higher the FU IC50. TS and DPD were demonstrated to be independent variables. A multiple regression analysis showed that the combination of TS and DPD activities explained 36% of the variability in FU IC50 (r2 = 0.36, P = 0.01). Two groups of cell lines could be identified, one group with both low TS and low DPD activities (G1), and the other with either high TS and/or high DPD activities (G2). Mean FU IC50 values were 193 and 930 ng/ml in G1 and G2, respectively, and this difference in FU sensitivity was highly significant (P = 0.009). The present study shows, for the first time, that DPD activity in tumour cells is an independent factor significantly related to FU sensitivity. These results should encourage DPD and TS coupled measurements in tumours of patients before FU treatment in order to establish their prognostic relevance. DPD and TS measurements could also be used during the treatment course to determine the implication of these enzymes in the development of tumour resistance to FU. PMID- 7833112 TI - Wide range for optimal concentration of folinic acid in fluorouracil modulation- experimental data on human tumour cell lines. AB - The clinical use of the fluorouracil (FU)-folinic acid (FA) combination is hampered by the still open choice of the optimal schedule, with marked controversy as concerns the optimal FA dose. This in vitro study on FU-FA combinations in 17 human cancer cell lines, representative of tumour types responding to FU-FA treatment, reassesses the notion of the optimal FA concentration. Cells were exposed for 5 days to various FU-FA concentrations (0.07-77 microM, 14 concentrations, for FU; and 0.0025-100 microM for FA). The growth inhibition was assessed by the MTT test. The investigated cell lines exhibited FU IC50 ranging from 0.4 to 38.9 microM (median 3.7 microM). In six out of 17 cell lines investigated, the addition of FA did not result in a substantial enhancement of FU cytotoxicity (group 1). For the remaining 11 cell lines responding to FA supplementation (group 2), the maximal enhancement factor ranged from 3 to 8, meaning that in the presence of optimal FA concentration, the efficient FU concentration (IC50) was reduced by between 3 and 8 as compared to the efficient FU concentration without FA supplementation. For cell lines responding to FA supplementation, the optimal FA concentrations ranged from 10( 7) to 4 x 10(-4) M (4000-fold range) with a median value at 9.6 x 10(-7) M. Distribution of cell doubling time was not significantly different between group 1 and group 2. In contrast, the FU IC50 were significantly different (P = 0.02) between group 1 (median 7.4 microM) and group 2 (median 2.2 microM), thus indicating that cell lines with the greatest FU cytotoxicity enhancement by FA were those intrinsically sensitive to FU and vice versa. PMID- 7833113 TI - p53 protein and vimentin in invasive ductal NOS breast carcinoma--relationship with survival and sites of metastases. AB - p53 protein and vimentin status were available from immunocytochemical studies of 253 formalin-fixed paraffin-embedded invasive ductal not otherwise specified (NOS) carcinomas from patients for whom follow-up data was also on file. For the 127 node-negative patients, multivariate analysis showed a highly significant correlation between p53 and vimentin (P < 0.001), a strong correlation between vimentin and probability of survival to 90 months but only a weak association between p53 and survival to 90 months. p53 also never entered trees of prognostic indicators derived using stepwise regression with Kaplan-Meier statistics for node-negative and node-positive subgroups, while vimentin status dominated the node-negative trunk. In addition, p53 and vimentin status were analysed versus the site of the first distant metastasis for node-negative and node-positive patients. Analysis by p53 status showed no significant effect on visceral metastases. In contrast, vimentin-positive primaries metastasised twice (and in node-negative patients, 3.5 times) as often to lung, liver and brain as did the vimentin-negative primaries. Both p53-positive and vimentin-positive tumours showed a significantly lower tendency to metastasise to the bone than did their negative counterparts. PMID- 7833114 TI - In vitro effect of lonidamine on the cytotoxicity of mitomycin C and BCNU in human colon adenocarcinoma cells. AB - The ability of lonidamine (LND), an energolytic derivative of indazole carboxylic acid, to modulate the cytotoxic activity of mitomycin C (MMC) and 1,3,bis(2 chloroethyl)-1-nitrosourea (BCNU) was investigated in two human adenocarcinoma cell lines (LoVo and HT29) expressing different sensitivity profiles to the drugs. After a 1-h treatment with MMC or BCNU, cells were postincubated for 24 h with 150-225 microM LND. In the LoVo cells, a synergistic interaction between LND and MMC or BCNU was observed at both LND concentrations. In HT29 cells, only additive effects of the drugs given in sequence were seen. Flow cytometric analysis indicated that LND was generally able to stabilise the cell cycle perturbations induced by MMC and BCNU in the two cell lines. The ability of LND to potentiate anticancer drug activity, and the consideration that LND causes side-effects different from those of conventional antitumour drugs, make this compound an attractive candidate for multidrug combination therapy in colon cancer. PMID- 7833115 TI - Point mutations in the mdr1 promoter of human osteosarcomas are associated with in vitro responsiveness to multidrug resistance relevant drugs. AB - Among human sarcomas, osteosarcomas usually display high intrinsic mdr1 expression while malignant fibrous histiocytomas (MFH) do not. A comparative polymerase chain reaction (PCR)-based sequence analysis of the mdr1 promoter revealed point mutations in seven out of nine osteosarcomas at nucleotides +103 (2 cases T-->C) and +137 (5 cases G-->T). No changes were seen in eight MFHs. When COS cells transfected with CAT constructs containing the T-->C chloramphenicol acetyltransferase mutant mdr1 promoters were treated with vincristine or doxorubicin, expression of the CAT gene was enhanced to a higher extent than with constructs containing wild-type or G-->T-mutant mdr1 promoters. We suggest that there is a correlation between the type of mdr1 promoter mutation and responsiveness to MDR relevant drugs. PMID- 7833116 TI - The synergistic and antagonistic effects of cytotoxic and biological agents on the in vitro antitumour effects of suramin. AB - Suramin has shown antitumour activity in vitro and in vivo. At plasma levels higher than 200 microM there is, however, excessive toxicity. We have, therefore, attempted to improve the antitumour effects of suramin in vitro by combining it with several other antitumour agents. The MCF-7 mammary carcinoma and PC3 prostate cancer cell lines were exposed continuously to suramin and the other agents for 6 days. The sulphorhodamine B (SRB) assay was used for the assessment of growth inhibition. The dose-response interactions were evaluated using the median-effect analysis with the Chou and Talalay computer programme. In the MCF-7 cell line, the combination of suramin plus doxorubicin (DXR), cisplatin (CDDP), 5 fluorouracil (5-FU) or tumour necrosis factor (TNF) resulted in synergistic growth inhibition, whilst its combination with miltefosine (HPC) was antagonistic. In the PC-3 cell line, suramin plus CDDP or TNF was synergistic, whilst its combination with DXR, 5-FU and HPC was antagonistic. All tested combinations with interferon-alpha (IFN-alpha), interferon-gamma (IFN-gamma) and with the combination of both IFN-alpha+IFN-gamma were not synergistic. The synergistic effect of suramin with DXR was schedule dependent. Pretreatment (addition of DXR on day 1 and suramin on days 2-5) was additive at the IC50 level, in both cell lines. Addition of DXR at day 5 was more effective than simultaneous exposure. We found a synergistic effect for the combination of suramin with CDDP and TNF in both cell lines. In addition the combination with DXR and 5-FU was synergistic in MCF-7. Sequential administration of DXR-suramin or suramin-DXR increased the growth inhibition. PMID- 7833117 TI - Intron splice acceptor site sequence variation in the hereditary non-polyposis colorectal cancer gene hMSH2. AB - Common but weakly penetrant mutations of certain genes may confer an increased susceptibility to colorectal cancer and account for a proportion of 'sporadic' cases. We analysed DNA from 111 colorectal cancer cases and 114 controls for a specific candidate sequence variation in the hereditary non-polyposis colorectal cancer gene hMSH2. The variant sequence was found in a quarter of individuals, and there was no difference between cancer cases and controls, according to age of development of cancer or presence of family history. It thus appears that this particular sequence variation is a polymorphism rather than a mutation which increases cancer susceptibility. PMID- 7833118 TI - Tissue-specific expression of neural cell adhesion molecule (NCAM) may allow differential diagnosis of neuroblastoma from embryonal rhabdomyosarcoma. AB - The MSD1 region of neural cell adhesion molecule (NCAM) was originally described as being spliced into the 120-kDa isoform of NCAM isolated from muscle. The 105 bp region is inserted between exons 12 and 13 and actually consists of three separate exons, MSD1a, MSD1b and MSD1c of 15, 48, 42 bp, respectively. In addition, a further exons consisting of a single triplet has been designated MSD1d, making the full insert size 108 bp. As the MSD1 region was originally described as being selectively expressed in muscle tissue, we have investigated whether it is also present on tumours of rhabdoid origins and whether its presence can be used as the diagnostic marker to distinguish other small round cell tumours of childhood, such as neuroblastoma. Using a variety of human tumour cell lines, we demonstrated the presence of the MSD1 region on all rhabdomyosarcomas investigated. However, neuroblastoma cell lines only expressed subcompartments of the MSD1 region. The MSD1c exon was not spliced into the NCAM molecules isolated from any of the neuroblastoma cell lines investigated. On the basis of this finding, it appears that neuroblastoma and rhabdomyosarcoma can be distinguished by the expression of MSD1c mini-exon. Further studies are underway to attempt to define a monoclonal antibody that recognises the region, using mice immunised with synthetic peptides, and to confirm the finding using fresh biopsy material. PMID- 7833119 TI - Oestradiol stimulates growth of oestrogen receptor-negative MDA-MB-231 breast cancer cells in immunodeficient mice by reducing cell loss. AB - Growth stimulation by oestrogens in immunodeficient mice is characteristically restricted to tumours expressing oestrogen receptors (ER). We now describe oestrogen-stimulated growth of the ER-negative human breast cancer cell line MDA MB-231, subclone 10A. Cell culture experiments confirmed that 10A cells are unresponsive to a wide concentration range of oestradiol (E2) in vitro. Analysis of growth curves in vivo revealed significantly longer tumour volume doubling times for the control group than for the E2-treated group. Cell cycle studies using in vivo labelling with bromodeoxyuridine (BrdU) and flow cytometric analysis showed essentially equal potential doubling times for controls and E2 treated animals. These results suggest that E2 reduces cell loss, rather than stimulating proliferation. E2-stimulated growth was seen in both natural killer (NK) cell producing athymic (nude) mice and congenitally NK cell deficient beige nude mice. We conclude that E2-induced natural killer cell suppression is an unlikely mechanism of action. PMID- 7833120 TI - A novel microculture kinetic assay (MiCK assay) for malignant cell growth and chemosensitivity. AB - The THERMOmax microplate reader was adapted for monitoring the growth kinetics of human leukaemic OCI/AML-2 and mouse tumour J-774.1 cell lines in continuous culture. Fluid evaporation from wells, CO2 escape and contamination were prevented by hermetic sealing of the microcultures in wells of a 96-well microplate, thus enabling the cells to grow exponentially for 72 h under the conditions of the incubated microplate reader. For both OCI/AML-2 cells, which grow in suspension, and adherent J-774.1 cells, a linear correlation was demonstrated between the number of unstained cells seeded in a given microplate well and the optical density (OD) of that well. Therefore, the OD/time curve of the culture could be deemed to be its growth curve. By the use of the linear fit equation, the actual number of the cells in the wells was computable at any time point of the assay. In the chemosensitivity test, an inhibitory effect of ARA-C on the growth of the cells could be estimated by viewing of the growth curves plotted on the screen. The maximum kinetic rates (Vmax) of the curves in the control and the ARA-C-treated wells were compared, yielding a growth inhibition index (GII). Comparison of results of the kinetic chemosensitivity assay with those of a [3H]thymidine incorporation assay revealed that the novel assay is suitable for precise quantitation of the cell chemosensitivity, is more informative and has the added technical advantage of performance without recourse to radioactive or chemically hazardous substances. PMID- 7833121 TI - The S-100-related calcium-binding protein, p9Ka, and metastasis in rodent and human mammary cells. PMID- 7833122 TI - Prospects for proton-beam radiotherapy. AB - Proton beams are already being employed for radiation therapy in 15 centres worldwide and over a dozen more are planned. Good clinical results have been reported in uveal melanomas and in sarcomas of the skull base. Calculated dose distributions for the treatment of brain, lung, head and neck and pelvic tumours predict an improvement relative to multiple-field or conformal photon radiotherapy. Protons may well provide high-precision radiotherapy that will lead to improved treatment of certain tumours in specific anatomical locations. PMID- 7833123 TI - Oestrogens, proteases and breast cancer. From cell lines to clinical applications. AB - Human breast cancer is characterised by its high frequency of metastasis and its oestrogen responsiveness, allowing specific anti-oestrogen therapy. Oestrogens are promoting agents that stimulate early steps of mammary carcinogenesis. The availability of several oestrogen receptor (ER)-positive and ER-negative human breast cancer metastatic cell lines has allowed characterisation of several hormone-regulated genes, some of which are involved in growth and metastasis. Moreover, these models have allowed examination of the mechanisms by which hormone antagonists (anti-oestrogens and anti-progestins) act on their respective receptors to inhibit tumour growth. By contrast, no convenient in vitro models are available to investigate the mode of action of oestrogens and anti-oestrogens on non-malignant mammary cells. Among the oestrogen-regulated genes, some are also regulated by growth factors, such as the cathepsin D gene, whose overexpression in primary breast cancers has been associated with relapse and metastasis in several retrospective clinical studies. The mechanism and consequences of cathepsin D overexpression on metastasis are reviewed. From these studies on cell lines, new immunological and genetic probes have been raised that can be applied to breast cancer tissue to titrate in patients expression of different genes involved in the control of mammary tumour growth and invasion. These tissue markers should help to stratify primary breast cancers according to their ability to metastasise and respond to therapies and consequently to choose the best therapy. Over the next decade, these studies should lead to new therapeutical approaches of breast cancers which resist classical systemic therapies. PMID- 7833124 TI - Treatment of the carcinoid syndrome with a depot formulation of the somatostatin analogue lanreotide. PMID- 7833125 TI - Hepatitis C virus infection and B-cell lymphomas. PMID- 7833126 TI - Mitoxantrone and 5-fluorouracil modulated by the pure (6S) stereoisomer of leucovorin as second-line chemotherapy for advanced breast cancer. PMID- 7833127 TI - A rapidly progressing leiomyosarcoma expressing drug-resistance markers failed to respond to cyclosporin A-associated chemotherapy. PMID- 7833128 TI - A pilot study of early hospital discharge in adult patients with fever and neutropenia. PMID- 7833129 TI - Pre-operative radiotherapy for rectal cancer: what benefit? Which technical parameters? PMID- 7833130 TI - Post-mastectomy radiotherapy: is it cure after all? PMID- 7833131 TI - Double modulation of 5-fluorouracil in advanced colorectal cancer with low-dose interferon-alpha 2b and folinic acid. The "GISCAD" experience. Italian Group for the Study of Digestive Tract Cancer. AB - In advanced colorectal cancer the addition of folinic acid (FA) has been shown to lead to increased activity, at least in terms of response rate, in comparison with 5-fluorouracil (5FU) alone. Similarly, interferon-alpha (IFN) is able to potentiate 5FU, although high doses cause heavy toxicity. Given the different mechanisms of action of the two agents, the double modulation of 5FU deserves clinical evaluation. In a multicenter study (involving both primary care and referral institutions) 63 patients with advanced colorectal cancer, previously untreated with chemotherapy, received, in an outpatient setting, FA (200 mg/m2 i.v. bolus) + 5FU (400 mg/m2 i.v. in 15 min) for 5 consecutive days every 4 weeks + IFN 3 x 10(6) U on alternate days, starting 1 week before chemotherapy. During the 5 days of 5FU + FA, IFN was administered daily. The antitumour activity, the impact on response duration and survival and toxicity of the combination were evaluated according to WHO criteria. Of the 63 enrolled patients, 56 were evaluable: there were 2 complete responses (3%) and 13 partial responses (21%), giving an objective response rate of 24% (95% confidence interval 13-35%); no change was observed in 17 cases and progressive disease in 24. Median duration of response was 9 months and median survival (all patients) 13 months. Toxicity was acceptable, even though 4 patients presented reversible grade 4 side-effects (2 mucositis and 2 diarrhoea). With this schedule and these doses, addition of IFN did not lead to any increase in the activity of 5FU + FA. In colorectal cancer, further clinical studies with these drugs should be based on a deeper experimental knowledge of their mechanisms of interaction. PMID- 7833132 TI - Inter-relationships between single carbon units' metabolism and resting energy expenditure in weight-losing patients with small cell lung cancer. Effects of methionine supply and chemotherapy. AB - The one-carbon unit metabolism was investigated in 8 weight-losing patients with small cell carcinoma of the lung (SCLC). At diagnosis, 6 of the 8 patients had elevated formiminoglutamic acid (FIGLU) excretion after a histidine load, suggesting a lack of one-carbon units. In accordance, a significant decrease of FIGLU excretion was observed in the patients after oral administration of DL methionine for 4 days. The elevated FIGLU excretion was positively correlated to weight loss prior to diagnosis and negatively correlated to serum albumin at time of diagnosis. After 3 months of combination chemotherapy, FIGLU excretion was reduced in all patients except 1, who had progressive disease. Despite the elevated FIGLU excretions, all patients had normal blood folate levels. The resting energy expenditure (REE) was recorded in 7 patients, and a significant, positive correlation was observed between pretreatment FIGLU excretion and REE, although the REE measured in this group of patients was within the normal range. These data demonstrate an increased demand of "active" one-carbon units in energy consumption in a group of weight-losing cancer patients. The one-carbon unit deficit was reconditioned by oral administration of the one-carbon unit donor DL methionine. PMID- 7833133 TI - Dysplasia in normal-looking urothelium increases the risk of tumour progression in primary superficial bladder cancer. AB - Random urothelium biopsies were taken at initial endoscopic surgery from 1001 patients with primary superficial bladder cancer. The clinical course of all the patients was assessed prospectively. Actuarial risks of recurrence and disease progression were determined for prognostic characteristics and comparisons were made using log-rank tests. The independent prognostic significance of concomitant intra-aurothelial dysplastic changes was examined with Cox's regression analyses. The 3-year risk of recurrence in patients with dysplasia and carcinoma in situ (CIS) in macroscopically normal-looking urothelium was only slightly higher than the risk in patients without dysplastic changes (56, 58 and 51%, respectively; P = 0.25). Concomitant dysplasia or CIS significantly increased the 3-year risk of disease progression (17 and 31%, respectively, versus 7%; P < 0.001). After adjustment for the effects of age, tumour stage, grade, size and multicentricity, the result of random biopsies had no prognostic significance regarding the risk of recurrence, but the detection of dysplasia or CIS increased the risk of progression by approximately 80%. This result suggests that random urothelium biopsies may be useful as an additional guide in defining therapy in primary superficial bladder cancer. PMID- 7833134 TI - Management of bowel obstruction in patients with advanced ovarian cancer. AB - In a retrospective study, 58 patients with bowel obstruction due to advanced ovarian cancer were analysed. In a forward stepwise proportional hazard regression analysis, we looked for factors influencing bowel obstruction-free survival. Patients who presented with bowel obstruction as the first sign of ovarian cancer and those with a longer interval between last cancer treatment and bowel obstruction did better. Patients with ascites did worse. No other independent factors were found. Based on these data, we classified patients into a favourable prognosis group (no previous treatment or interval since last treatment exceeding 6 months; no ascites) and a poor prognosis group (interval since last treatment shorter than 6 months; ascites). Patients from the favourable prognosis group had a median bowel obstruction-free survival of 8 months, compared to 1 month for the poor prognosis group (P < 0.001). Surgery had a marginally significant positive effect on bowel obstruction-free survival when compared to medical treatment in the favourable prognosis group (P = 0.052). Surgery had no effect at all in the poor prognosis patients. PMID- 7833135 TI - Testosterone levels as a marker of prognosis to goserelin treatment in metastatic breast cancer. AB - Testosterone levels were measured in blood and urine of 35 premenopausal metastatic breast cancer patients before starting therapy with the gonadotrophin releasing hormone (GnRH) analogue, goserelin. The aim of the study was to verify the reliability of testosterone measurement as a marker of prognosis. The time interval between starting therapy and progressive disease (time to progression) was chosen to assess prognosis. Univariate and multivariate analysis showed that only urinary testosterone levels were significantly associated with time to progression (Wald test 6.66, P = 0.01 for univariate and Wald test 7.93, P = 0.0049 for multivariate analysis), whereas no association was found for testosterone in blood. A statistical model is proposed to evaluate probability of progressive disease in relation to testosterone values in urine at different times. According to the model, the probability of progression decreases with increasing urinary testosterone values. PMID- 7833136 TI - Local recurrences of soft tissue sarcomas in adults: a retrospective analysis of prognostic factors in 102 cases after surgery and radiation therapy. AB - Between 1974 and 1990, 102 adult patients (age 18-86 years) with the diagnosis of a soft tissue sarcoma (STS) were treated with photons and/or electrons in combination with surgery. The total doses in the initial treatment volume (second order target volume) was 40-50 Gy. For the coning down volume (first order target volume) the median total dose was 59 Gy (range 45-72 Gy). A total of 18% (18/102) local failures was observed. In multivariate analysis, prognostic factors for the occurrence of a local failure were identified as follows: treatment of a primary or recurrent STS (P = 0.02), total dose (P = 0.025) and tumour grade (P = 0.05). Mode of surgery, tumour size (trunk versus extremity), pre- or postoperative radiotherapy, combined chemotherapy and tumour size (T1 versus T2) had no significant impact on the local relapse-free survival. These data give further evidence that combined surgery and radiotherapy is an effective modality in treatment of soft tissue sarcomas. PMID- 7833137 TI - Sudden tumour regression with enhanced natural killer cell accumulation in a patient with stage IV breast cancer. AB - Spontaneous regression of advanced breast cancer is a rare phenomenon. Efforts have been made in order to explain it by means of immunological mechanisms. Corticosteroids have demonstrated important efficacy in the treatment of breast cancer. We present a patient with stage IV breast cancer in whom large tumour masses dramatically regressed during treatment with dexamethasone alone. In this patient, histological and hormonal findings, with results of analyses on surface and intracellular blood cells markers demonstrated significant redistribution of lymphocytes and accumulation of natural killer cells in tumour masses. It seems that dexamethasone has acted through the hypophyse against cancer. PMID- 7833138 TI - At what age do sunburn episodes play a crucial role for the development of malignant melanoma. AB - The age relationship between sunburns and malignant melanoma was investigated in a population-based, matched, case-control study from the South Swedish Health Care Region (the highest risk area for melanoma in Sweden). Between 1988 and 1990, a total of 400 patients with a first diagnosis of malignant melanoma and 640 healthy controls aged 15-75 years answered a comprehensive questionnaire including questions regarding ultraviolet radiation exposure. In addition, a literature review was performed. The average number of episodes of sunburn per year was significantly associated with malignant melanoma (relative risk, RR = 1.9 for > or = three episodes per year versus never). Outdoor employment during the summer was associated with a decreased risk for the development of malignant melanoma (RR = 0.8). Data from case-control studies and migration studies concerning age relationship between sunburns and melanoma are inconsistent. From our own data, we did not find a higher risk of melanoma developed in individuals who had experienced severe sunburns in childhood. Instead, a significantly increased risk was associated with sunburns after age 19 years, RR = 2.2 for a history of more than five times versus never. Even if the hypothesis is biologically plausible, that episodes of sunburn early in life are associated with a higher risk of melanoma, so far epidemiological evidence is scarce. There is a need for better prospective epidemiological studies addressing this issue. PMID- 7833139 TI - Immunohistochemical localisation of hydroxysteroid sulphotransferase in human breast carcinoma tissue: a preliminary study. AB - Understanding the function and regulation of the metabolism of steroid hormones by breast tumours will be instrumental to the development of novel treatments for this widespread disease. We have examined the expression of hydroxysteroid sulphotransferase, an enzyme which inactivates many steroids, in particular androgens, in normal breast tissue and in six ductal-type mammary carcinomas using immunohistochemistry. The enzyme is not expressed in the epithelial cells which line the normal breast duct, but is present in significant amounts in neoplastic cells, suggesting that the gene encoding this protein is activated at some stage of the neoplastic transformation. The implications of this finding for the role of steroid metabolism in breast cancer are discussed. PMID- 7833140 TI - Estimating completeness of cancer registration in Saarland/Germany with capture recapture methods. AB - Completeness of population-based cancer registration has been most commonly quantified by indirect measures, such as the death certificate only index or the mortality/incidence ratio. A major disadvantage of these measures is their strong dependence on the case fatality rate. Capture-recapture methodology offers an approach to estimate completeness directly which does not share this limitation. In this paper, a three-sources modelling approach is employed to derive estimates of completeness for the population-based cancer registry of Saarland. Overall, completeness is found to be high: estimates for all types of cancer range from 95.5 to 96.9% for calendar years 1970, 1975, 1980 and 1985. There is some variation with age (consistently high levels above age 30 years, a minimum of 87.7% in age group 15-29 years) and between cancer sites. Among the most common cancer sites, estimates of completeness are highest for gastrointestinal cancers (97.2%) and breast cancer (97.1%), while lower estimates of completeness are derived for cancers of the female genital organs (92.5%), the urinary tract (91.8%) and the prostate (91.0%). Although capture-recapture estimates are sensitive to the underlying assumptions about dependence between sources, careful application is encouraged to supplement traditional methods for evaluating completeness of cancer registration. PMID- 7833141 TI - Modulation of Bcl-2 and Ki-67 expression in oestrogen receptor-positive human breast cancer by tamoxifen. AB - The expression of the bcl-2 proto-oncogene, which is associated with prolonged cell survival and prevention of programmed cell death, was investigated in human primary breast carcinomas prior to and following endocrine therapy with the anti oestrogen, tamoxifen. Using the BCL-2-100 antibody, a 26-kD protein was detected by western immunoblot in the cytosols of oestrogen receptor (ER)+ve human breast cancers. In a cross-sectional study, the immunohistochemical expression of Bcl-2 was observed in 32% of invasive breast cancers, but in 65% of tumours treated with tamoxifen (P = 0.009). There was a significant association of Bcl-2 with ER status, with 64% of untreated and 88% of tamoxifen-treated Bcl-2-positive tumours being ER+ve. A significantly lower Ki-67 score was found in tamoxifen-treated tumours which were Bcl-2-positive compared with Bcl-2-negative (9.3 versus 24.6%, P = 0.01). In a separate series of sequential Trucut biopsies from 18 patients, the frequency of Bcl-2 expression was increased in ER+ve tumours from 3/12 to 8/11 following tamoxifen (P = 0.04). This was also associated with a significant reduction in mean Ki-67 score from 32 to 12% (P = 0.0004). The observations from this study clearly indicate that Bcl-2 in human breast cancer is associated with ER status, and that expression is enhanced in ER+ve tumours following tamoxifen, in association with reduced cell proliferation. PMID- 7833142 TI - In vitro sequence-dependent synergistic effect of suramin and camptothecin. AB - Suramin, a hexasulphonated naphthylurea with activity in prostatic cancer, possesses a wide variety of antitumour mechanisms of action, one of which is the inhibition of topoisomerase II. In this in vitro study, suramin was combined with the topoisomerase I inhibitor, camptothecin. Several suramin concentrations (0.2 3000 microM) were combined with camptothecin (0.4 pM-20 microM) in MCF-7 and PC3 human cancer cell line cultures. In addition, we studied the topoisomerase II and I gene expression by northern blot analysis, and the cell cycle distribution by flow cytometry, after exposure to suramin. While there was only an additive effect when suramin and camptothecin were added simultaneously, a remarkable synergism was obtained when camptothecin was added after a 3-day exposure to suramin. Topoisomerase II and I gene expression and the number of cells in S phase were significantly reduced after exposure to suramin. In conclusion, interaction of suramin with camptothecin is schedule-dependent and can be synergistic. These findings might help in identifying optimal combinations of suramin or other topoisomerase II inhibitors, with topoisomerase I inhibitors. PMID- 7833143 TI - Growth-inhibitory effects of the natural phyto-oestrogen genistein in MCF-7 human breast cancer cells. AB - Genistein, a natural isoflavonoid phyto-oestrogen, inhibits the tyrosine kinase activity of growth factor receptors and oncogene products, as well as the in vitro growth of some tumour cell lines. The low incidence of breast cancer in countries with a flavonoid-rich soy-based diet and the protection afforded by soy derived products against experimental mammary tumours in rats suggest that genistein and other isoflavonoid compounds may exert an anti-tumour activity. We analysed the effects of genistein on cell number and cell cycle progression (flow cytometric analysis of propidium iodide-stained nuclei) of human breast cancer cells (MCF-7) in vitro. Genistein produced a significant, dose-dependent inhibition of MCF-7 cell growth with an ID50 of approximately 40 microM after 72 h of incubation. Cell cycle analysis showed a reversible G2/M arrest in cell cycle progression at 10 microM genistein concentrations, whilst a marked fall in S-phase cell percentage associated with a persistent arrest in G2/M phase was observed in cultures treated with genistein doses equal to or greater than 50 microM. These effects were significant at 24 h of incubation; flow cytometric analysis at later times (48 and 72 h) revealed a population of cells with decreased DNA content and nuclear fragmentation characteristic of apoptosis. Thus, the growth inhibitory activity of genistein in MCF-7 cells results from the sum of cytostatic and apoptotic effects. Since the mitogenic action of insulin and insulin-like growth factor (IGF)-I in MCF-7 cells is a tyrosine kinase dependent phenomenon, we analysed the genistein impact on S-phase entry produced by insulin in cultures partially synchronised in G0/G1 phase by serum deprivation. Insulin addition after a 36-h culture period in serum-free medium produced a strong increase in the percentage of S-phase cells (from 18.4 +/- 2.3 to 46.2 +/- 4.1 after 24 h) which was almost completely blocked by 100 microM genistein (20.1 +/- 3.1). Immunofluorescence analysis with a fluoresceine isothiocyanate (FITC)-conjugated anti-phosphotyrosine antibody revealed a strong increase in MCF-7 cell staining after insulin stimulation, but not when genistein was added with insulin. In conclusion, the dietary phyto-oestrogen genistein inhibits in vitro growth of MCF-7 human breast cancer cells through blocks in the "critical checkpoints" of cell cycle control and induction of apoptosis. These effects are likely to depend on impairment in the signal transduction pathway from tyrosine kinase receptor(s). PMID- 7833144 TI - Somatostatin receptor expression in lung cancer. AB - Experimental evidence suggests that somatostatin analogues may have a role to play in the management of lung tumours. We evaluated membrane preparations of nine small cell lung cancer (SCLC) cell lines and of tumour samples from 3 patients with non-small cell lung cancer (NSCLC), 1 patient with an atypical carcinoid and another with a bronchial carcinoid for the presence of specific binding sites for RC-160, a potent growth inhibitory octapeptide analogue of somatostatin. Specific binding was noted on six of nine SCLC lines. Radio receptor assay on the cell line NCI H 69 showed evidence of two specific binding sites for RC-160, one with high affinity and the other with low affinity. Binding sites were also found on all five tumour samples. Scatchard analysis indicated the presence of a single class of receptors with high affinity in each case. Histological assessment of the resected specimens before binding assay showed them to be comprised of tumour cells and necrotic tissue, stroma and/or inflammatory cells. Therefore, the specific binding of RC-160 may be to tissues other than the tumour cells. In 3 patients, from whom the tumour samples were obtained, radiolabelled somatostatin analogue scintigraphy using [111In] pentetreotide was performed prior to surgery. In all cases, the radiolabel localised the disease. This study demonstrates the presence of specific binding sites for RC-160 in SCLC. Furthermore, the detection of specific binding in vitro and in vivo in NSCLC and intrapulmonary carcinoids demonstrates that these tumours contain cells which express specific binding sites for somatostatin. These results suggest that RC-160 may have a role to play as a therapeutic agent in lung cancer. PMID- 7833145 TI - Effects of the microtubule-disturbing agents docetaxel (Taxotere), vinblastine and vincristine on epidermal growth factor-receptor binding of human breast cancer cell lines in vitro. AB - Epidermal growth factor (EGF) is a mitogenic peptide that binds to surface membrane receptors (EGFR) of breast cancer cells. After binding, secondary transmitter molecules are activated by tyrosine phosphorylation of the intracellular receptor domaine. The activity of the EGF/EGFR system can be modulated by a variety of chemically unrelated compounds including cytostatic agents. The purpose of our present study was to determine the effects of mitotic inhibitors on EGF receptor binding on human breast cancer cells. We found that MDA-231 and MDA-468 cells bind substantially more [125I]EGF after preincubation with docetaxel, vinblastine and vincristine. This effect was concentration- and time-dependent, reaching a maximum at 3000 ng/ml and 48 h incubation for docetaxel, and 100 ng/ml and 48 h incubation for vinca alcaloids. Subsequent experiments showed an increase in the rate of EGF binding as well as maximal binding capacity. Scatchard analysis of binding experiments under equilibrium conditions indicated that this was due to an increase in the number of apparent EGF binding sites. Modulation of EGF receptor binding by docetaxel, vinblastine, and vincristine was not detectable when isolated membranes were used, indicating that intact cytoplasmatic mechanisms are required for the upregulation of EGF receptors. PMID- 7833146 TI - Relationships between tamoxifen binding proteins in primary breast cancer biopsies. AB - Using high-resolution isoelectric focusing gel electrophoresis (IEF), two tamoxifen binding sites (TBS) with isoelectric point (pI) values of 4.5 and 4.3 were identified, with different affinities for tamoxifen. The form at pI 4.3 (HTBS) displayed high affinity for the ligand (kD approximately 5 nM), while the protein at pI 4.5 (LTBS) had lower affinity (kD approximately 50 nM). LTBS was found in the microsomal fraction and HTBS in the cytosol. Of a total of 319 tumours studied, 257 were oestrogen receptor (ER) positive and 106 HTBS positive. In this combined group, thus able to bind tamoxifen either through the presence of ER or HTBS (or both), ER and PR were both negatively correlated with HTBS (P < 0.0001). The oestrogen-induced protein pS2 was assayed in 92 of the 319 tumours, and was also negatively (P < 0.0001) correlated with HTBS. The levels of HTBS were similar between infiltrating ductal carcinomas without special features (NOS) and non-NOS forms. However, HTBS concentrations were significantly higher in poorly differentiated grade 3 carcinomas than grade 2 (P < 0.05) and grade 1 (P < 0.01) forms. Conversely, ER concentration was lower in grade 3 than grade 1 forms (P < 0.05). Both the relationship between high affinity TBS and ER and the high concentration of HTBS in ER-poor grade 3 carcinomas may have a bearing on the known variability of tumour response to endocrine therapy and prognosis. PMID- 7833147 TI - P53 mutation in a series of epithelial ovarian cancers from the U.K., and its prognostic significance. AB - In an initial study of 20 fresh ovarian tumour samples, we compared the immunohistochemical positivity of staining of the p53 protein with the presence of missense mutations of the p53 gene. This revealed a prevalence of 50% with a perfect correlation between mutation and immunohistochemical staining. Detection of the p53 protein by immunohistochemistry was, therefore, used as a reliable indicator for the presence of P53 mutation, and was applied to a study of an archival series of 93 ovarian tumours. Positive immunostaining of the p53 protein was observed in 47% of this series. Cox regression was used to assess whether various clinical variables and P53 mutation were related to survival. As a result, it was found that positive staining of the p53 protein was independent of age, tumour differentiation, tumour type, though possibly not stage. There was some evidence that p53 positivity was associated with reduced survival after adjusting for other variables, but the result was not statistically significant. PMID- 7833148 TI - Expression of the multidrug resistance-associated protein (MRP) gene in human lung tumours and normal tissue as determined by in situ hybridisation. AB - In a number of cell lines with a multidrug resistant phenotype, there is no overexpression of the putative efflux pump, P-glycoprotein. Some such lines do, however, overexpress the MRP gene which encodes a protein bearing considerable amino acid homology to P-glycoprotein. We have used in situ hybridisation to study expression of the MRP gene in human cell lines, lung tumours (representing all the major histologies) and normal lung tissue. Considerable heterogeneity of expression was seen in parental cell line COR-L23/P whereas relatively uniform high-level expression was seen in the resistant line COR-L23/R. Normal bronchial epithelium was strongly positive, but the major epithelial component of all eight lung tumours studied showed only a negative to weak signal. However, the leading edge of the tumours consistently produced a more intense signal similar to that in normal epithelium. Areas of lymphocytic infiltrate were more strongly positive than the tumour epithelium. These results suggest that expression of the MRP gene may be a significant factor determining response of lung tumours to chemotherapy, but that considerable caution is needed in the interpretation of expression studies carried out on homogenised tissue biopsies. PMID- 7833149 TI - Mutational analysis of the first 14 exons of the adenomatous polyposis coli (APC) gene. AB - In the present study, the polymerase chain reaction single strand conformation polymorphism (PCR-SSCP) technique has been applied to the mutation analysis of the adenomatous polyposis coli (APC) gene. We examined the first 14 exons of the APC gene in 46 polyposis coli patients. Five germline mutations were observed, including a single-nucleotide substitution and small (1-4 bp) deletions leading, in 4 cases, to a stop codon. A missense mutation in exon 3 and a 1 bp deletion in exon 4 of the APC gene were observed in patients presenting with the attenuated form of FAP. PMID- 7833150 TI - Should clinicians be concerned about the carcinogenic potential of tamoxifen? PMID- 7833151 TI - Control of oncogene expression by antisense nucleic acids. PMID- 7833152 TI - Salivary glands enlargement in association with cytosine arabinoside application in patients with acute myeloid leukaemia. PMID- 7833153 TI - Low-dose BCG in superficial bladder cancer with strain Connaught Canada--as effective as strain Pasteur Paris? PMID- 7833154 TI - Human leucocyte interferon-alpha therapy can induce a second response in treatment of thrombocytosis in patients with neutralising antibodies to recombinant interferon-alfa 2a. PMID- 7833156 TI - L-myc allele polymorphism and prognosis for metastases in Russian gastric cancer patients. PMID- 7833155 TI - Recombinant interferon-gamma in a patient with multiple myeloma. PMID- 7833157 TI - Male breast cancer: incidence, mortality and survival rates from an Italian population-based series. PMID- 7833158 TI - FLEP (5-fluorouracil, leucovorin, etoposide, cisplatin) in advanced gastric cancer. PMID- 7833159 TI - Discovertebral junction of the spine--a cadaveric study by spin-echo MR imaging. AB - To evaluate the MR appearance of the discovertebral junction (DVJ) of the spine, we examined 161 DVJs in 27 cadaveric spines using superconductive MR imaging. T1 , proton density-, and T2-weighted spin-echo imaging were used. With a small surface coil, higher resolution and more sharply defined contours of the DVJ were obtained than when using a head coil. Cortical bone had very low signal intensity in all sequences. Cartilaginous end-plate (CP) was of low to intermediate signal intensity on T1-weighted images, and of low signal intensity on proton density- and T2-weighted images. MR images were able to reveal the gross CP appearances, Schmorl's nodules, and adjacent bone marrow pathology. We conclude that MR imaging is valuable for assessing abnormalities of the DVJ. PMID- 7833160 TI - A new technique for nonsurgical repair of peripheral pseudoaneurysm. AB - Peripheral vascular lesions may be inaccessible to treatment using catheter techniques. Ultrasound imaging in combination with Doppler may identify such lesions and provide possibilities for image-guided compression, injection of embolizing material by direct puncture, or both. PMID- 7833161 TI - Correlation between chondroitin sulfate iron colloid-enhanced MR imaging and the histological grade of hepatocellular carcinoma. AB - The association between contrast enhancement by chondroitin sulfate iron colloid (CSIC) and the histological grade of hepatocellular carcinoma (HCC) was evaluated in 24 patients diagnosed by histological examination of surgical specimens (26 nodules: 11 well-differentiated and 15 poorly-moderately-differentiated nodules). In the well-differentiated HCC nodules, the tumor-liver contrast to noise ratio (CNR) was not significantly increased after i.v. CSIC injection on both T1 weighted and T2-weighted images. In the moderately-poorly-differentiated HCC, CNR was significantly increased after CSIC administration on both T1-weighted and T2 weighted images (p < 0.01). MR imaging using CSIC may be useful for diagnosing the degree of HCC differentiation. PMID- 7833162 TI - Radiation burden in high-resolution CT of the lungs. PMID- 7833163 TI - Low-field MR imaging (0.1 T) in patients with clinically suspected acute spinal block. AB - The diagnostic usefulness of a 0.1 T MR unit in patients with clinical suspicion of acute spinal block was studied in 59 patients who were referred to acute MR investigation. The records were reviewed retrospectively 1 month after the MR for assessing the clinical impact of the examination. Ninety-eight per cent had a true-positive examination confirmed by surgery (21%) or observation (77%). In 60% of the patients the MR imaging had a therapeutic consequence. In only one patient did the level of visualised pathology at the MR examination not correlate with the clinical findings; the patient subsequently refused surgical treatment. We conclude that a low-field MR unit is excellent for acute examination of patients clinically suspected of acute spinal block. PMID- 7833164 TI - Ultrasonography in arthritis of the knee. A comparison with MR imaging. AB - Ultrasonography (US) of the knee in gonarthritis was evaluated with gadolinium DTPA-enhanced MR imaging as a reference. The study included 13 patients with gonarthritis, 2 patients with osteoarthritis and 5 healthy controls. Compared to MR, US identified 100% (12/12) of joint effusions, 100% (5/5) of Baker's cysts, 57% (8/14) of the synovial membranes of the suprapatellar recess and 38% (3/8) of bone erosions. No MR or clinical findings characterized the patients with ultrasonographically identifiable synovial membranes. Quantitative MR- and US estimates of effusion, synovial membrane and cartilage thicknesses were correlated. The Spearman correlation coefficients were 0.87, 0.86 and 0.82, respectively. US reliably demonstrated joint effusions and Baker's cysts but showed lack of sensitivity for demonstration of the synovial membrane and bone erosions. When the synovial membrane was identifiable, the measurements of synovial thickness by US appeared precise. Cartilage evaluation by US seemed dependable. The clinical value was limited, because the weight-bearing areas were inaccessible. PMID- 7833166 TI - Experiences with a teleradiology system in pulmonary diseases. AB - Chest radiographs of 43 patients were digitized and sent from Paimio Hospital to Turku University Central Hospital. Fifteen of the patients had a pneumothorax, 12 had interstitial lung disease and 16 were controls. The images were interpreted by 5 radiologists during their duty shift. The first reading session consisted of images with 1,024 x 1,024 pixel resolution and the second of images with 2,048 x 2,048 matrix followed by the original chest radiographs. ROC studies were performed from the answers based on a 5-point confidence scale. In the pneumothorax group the average area under the individual ROC curve was 0.928 with the 1,024 x 1,024 matrix and 0.983 with the 2,048 x 2,048 matrix. In the fibrosis group the average area under the individual ROC curve was 0.877 with the 1,024 x 1,024 matrix and 0.831 with the 2,048 x 2,048 matrix. The results suggest that the 1,024 x 1,024 matrix is adequate in the detection of pneumothoraces and fibrosis. PMID- 7833165 TI - Static, dynamic and first-pass MR imaging of musculoskeletal lesions using gadodiamide injection. AB - Forty-five patients with known or suspected musculoskeletal tumors were examined with static and dynamic MR imaging to evaluate the safety, tolerability and diagnostic utility of gadodiamide injection and to assess the diagnostic value of dynamic MR imaging and parametric "first-pass" (FP) images. The proportion of patients presenting more diagnostic information on the contrast-enhanced compared to the precontrast spin-echo examinations was determined. The dynamic enhancement characteristics were evaluated with time-intensity curves and parametric images of the FP enhancement rate. The tolerance of gadodiamide injection was good. Contrast enhancement was useful for delineating tumor from muscle, and differentiating viable from necrotic tissue and cystic from solid lesions. Malignant tumors showed a significantly higher slope value, earlier onset of enhancement, and higher maximum enhancement than benign lesions. However, slope values could not be used to predict the malignant potential of a lesion, due to overlap between highly vascular benign and low vascular malignant lesions. By displaying highly vascular areas, parametric FP images provided useful information on the most active part in a tumor before biopsy and for assessing the incorporation of bone-chip allografts. Static, dynamic and FP MR imaging using gadodiamide injection appears safe and provides useful information for diagnosis, biopsy and follow-up of musculoskeletal lesions. PMID- 7833167 TI - Combination of gadolinium and dysprosium chelates as a cellular integrity marker in MR imaging. AB - A combination of gadolinium (Gd) and dysprosium (Dy) chelates was investigated as a potential marker of cell-membrane integrity by means of a double-contrast effect in MR imaging. Blood samples with varying hematocrit (Hct) levels containing intact or lysed cells were used as model systems. With intact cells, the agents were assumed to be distributed solely extracellularly and the highest Hct studied (69%) was assumed to mimic the ratio of extracellular to intracellular water in tissue. The combined effect on image intensity of Gd (in a concentration corresponding to 0.2 mmol/kg b.w. in humans) and Dy (0.6 mmol/kg b.w.) applied simultaneously was a marked difference in signal intensity between samples with intact and lysed cells in both the T1- and T2-weighted spin-echo images with a corresponding increase in the contrast-to-noise ratio. This was the result of a T1 reduction caused by Gd with a negligible Dy susceptibility effect in areas with lysed cells. On the other hand, the Dy susceptibility effect (i.e. reduced apparent T2) dominated in areas with intact cells. Thus, the combination of Gd and Dy may serve as a marker of cell-membrane integrity in MR examinations. PMID- 7833168 TI - Cardiac effects of adding electrolytes and oxygen to iohexol in a dog model of contrast media-induced ventricular fibrillation. AB - We investigated whether addition of a balanced electrolyte supplement and oxygen to the nonionic contrast medium iohexol reduces the risk of ventricular fibrillation (VF), and studied regional electrophysiology prior to the VF event. Twenty ml of each test solution were infused at a rate of 0.5 ml/s into the left anterior descending coronary artery (LAD) in 8 anesthetized dogs. LAD was externally occluded during infusion, to simulate a wedged catheter situation. ECG, hemodynamics, regional epicardial monophasic action potential duration (MAPD) and ventricular activation times (VAT) were calculated. All infusions with iohexol caused VF within 27 s. Five of 12 infusions with iohexol + 30 mmol NaCl, 3 of 11 infusions with iohexol+electrolytes (IPE) NaCl, KCl, CaCl2 and MgCl2) and 4 of 11 infusions with IPE with oxygen addition (IPE+O2) caused VF after 45 s. Iohexol did not change MAPD prior to the VF event. Iohexol + 30 mmol NaCl and the IPE solutions lengthened MAPD initially, but at the time of the VF event MAPD were normalized or shortened. We conclude that electrolyte supplement to iohexol may prevent VF, probably by lengthening MAPD. PMID- 7833169 TI - Coronary angioplasty using a low osmolar nonionic contrast medium. A retrospective angiographic and clinical evaluation. AB - This study was performed to investigate the occurrence of acute angiographic and clinical complications following PTCA using a low osmolar nonionic contrast medium. Five hundred consecutive PTCA procedures were analyzed retrospectively. The incidence of acute in laboratory complications during PTCA as well as complications occurring during the hospital stay 24 to 48 hours after the procedure were recorded. Occlusion of the dilated artery or a side branch was observed in 19 (3.8%) of the procedures, major dissection in 34 (6.8%), and thrombus in 14 (2.8%). One patient died, 6 (1.2%) required emergency coronary artery bypass grafting (CABG), 4 (0.8%) required an emergency PTCA, and 7 (1.4%) suffered myocardial infarction (MI). Our results show that angiographic findings of thrombus, major dissection and occlusion were serious conditions that related to the clinical complications MI, emergency CABG and re-PTCA. Patients with unstable angina were risk patients for both angiographic and clinical complications. Low rates of intraarterial thrombus formation and coronary artery occlusion indicate good angiographic technique and anticoagulant and antiplatelet medication. PMID- 7833170 TI - Experimental studies comparing iohexol and 51Cr-EDTA for glomerular filtration rate measurements. AB - The total plasma clearance as well as the renal clearance of iohexol were evaluated for determination of the glomerular filtration rate (GFR) in 16 anesthetized pigs. The iohexol levels in urine and plasma were measured by X-ray fluorescence. The total plasma clearance of 1 and 4 ml/kg b.w. of iohexol 300 mg I/ml was compared to the simultaneously as well as nonsimultaneously calculated total plasma clearance of 51Cr-EDTA. The total plasma clearance of 51Cr-EDTA and of iohexol turned out to be equal and independent of the injected dose of iohexol. The injected dose did not have any effect on the renal clearance of iohexol either. It is concluded that iohexol and 51Cr-EDTA are similar as marker substances for determination of the GFR. PMID- 7833171 TI - Effect of iopentol on renal function and its use for calculation of glomerular filtration rate in children. AB - Nineteen children received 99mTc-DTPA for renography. The next day they received a simultaneous injection of the non-ionic contrast medium iopentol for urography and another injection of 99mTc-DTPA. The glomerular filtration rate (GFR) was estimated from the plasma elimination of 99mTc-DTPA as well as iopentol. Serum concentrations of creatinine and beta 2-microglobulin, and urine concentrations of creatinine, beta 2-microglobulin, alkaline phosphatase, N-acetyl glucosaminidase, and albumin were determined. A significant reduction (12 +/- 3%) of GFR was observed after the injection of iopentol, without a subsequent rise in serum creatinine or beta 2-microglobulin. The urinary excretion of albumin and beta 2-microglobulin remained unchanged, while the excretion of alkaline phosphatase and N-acetyl-glucosaminidase was significantly increased after the urography, indicating some tubular effects of iopentol. Iopentol caused few and mild adverse events, the diagnostic yield was high, and the small changes in the renal tubular function parameters are presumed to be without clinical importance. The observed depressive effect on the GFR demands further investigations before iopentol can be recommended as a GFR-marker in children. PMID- 7833172 TI - Cerebral thromboembolic complications associated with the use of a nonionic contrast medium in coronary angiography. AB - Cerebrovascular complications were registered in 11 patients (0.21%) of 5,339, consecutively submitted to coronary angiography with the nonionic contrast medium iohexol (Omnipaque). Six of the patients had diseases predisposing them to thromboembolic complications, 3 of whom earlier had symptoms of cerebral stroke. Excluding these 6, the incidence of cerebral thromboembolic events was 0.10% in patients with no predisposing diseases. Precise catheterization technique and some anticoagulation and antiplatelet activity therapy are definite precautions against these complications, while the role of the contrast medium is still debated. PMID- 7833173 TI - Acute and late adverse reactions to low-osmolal contrast media. AB - A prospective study of acute and late reactions to low-osmolal contrast media was conducted in 4,875 patients. The contrast medium was injected intravenously in 4,417 patients and intraarterially in 458 for CT, urography or angiography. In the i.v. group only nonionic contrast media, iohexol or iopamidol, were used and in the intraarterial group both ionic and nonionic contrast media, ioxaglate and iohexol, were used. The patients completed 2-phase questionnaires, the rate of reply being 88%. In the i.v. group the incidence of acute reactions was 1.2% and that of late reactions was 4.7%. In the intraarterial group the incidence of acute reactions was 7.4% and the incidence of late reactions was 4.8%. Women and patients from under 40 to 60 years of age were the most susceptible to late reactions. The risk factors for late reactions are allergy, medicine allergy, previous adverse reaction to contrast medium and other diseases including diabetes mellitus, heart-, liver- and kidney diseases. PMID- 7833174 TI - Intracranial iotrolan distribution following cervical myelography. Postmyelographic registration of adverse effects, psychometric assessment and electroencephalographic recording. AB - Following iotrolan cervical myelography 14 consecutive patients were evaluated with respect to intracranial contrast distribution and elimination, side effects, EEG-changes and psychometric assessments. The contrast medium is distributed in the subarachnoid space, in the ventricles and finally extracellularly in the cortex. Headache was the most prevalent side effect, occurring in half of the patients, 43% of "severe" grade. Eight patients showed mild nonspecific EEG changes and all patients showed neuropsychologic disturbances. PMID- 7833175 TI - Iodide mumps after intravascular administration of a nonionic contrast medium. Case report and review of the literature. AB - Swelling of the submandibular, sublingual and/or parotid glands ("iodide mumps") is an uncommon complication to intravascular administration of contrast material. The etiology remains unclear, but the reaction seems to be idiosyncratic or related to toxic accumulation of iodide in the ductal systems of the salivary glands. The introduction of nonionic contrast media has not eliminated the risk of developing iodide mumps. The first reported case of iodide mumps after intravascular administration of iopromide (Ultravist 300) is presented. PMID- 7833176 TI - Deuterium MR spectroscopy at 4.7 T. Quantification of tumour and subcutaneous tissue blood flow in animal models. AB - Deuterium MR spectroscopy was used for the determination of tissue blood flow (TBF). The tracer D2O was injected into the tissue of interest, and tracer washout was followed using a 4.7 T spectroscopy/imaging unit. Normal subcutaneous tissue in rats was studied, as well as tissue influenced by vasoactive agents (papaverine and adrenaline). The vasoactive agents introduced changes of 40% in TBF, compared with normal tissue. Normal tissue measurements were repeated using various D2O injection volumes (5-400 microliters). The injection volume 5 microliters gave TBF 11.7 +/- 2.0 ml/100 g.min (mean +/- 1 SD). This value was 40% higher than corresponding values observed at larger injection volumes (200 400 microliters). This injection volume effect is probably partly due to a capillary dilution caused by tracer administration, and partly related to the non physiological deuterium signal decrease observed in dead rats. Blood flow measurements in human colon tumours implanted in nude mice showed a rather poor reproducibility, not improved by the use of a multiple site injection technique. PMID- 7833177 TI - MR imaging of multiple myeloma in tumour mass measurement at diagnosis and during treatment. AB - The bone marrow of the spine, pelvis and proximal femora was examined with MR imaging at diagnosis in 30 cases of multiple myeloma (MM), and during treatment on 69 occasions. The MR pattern was normal, focal or diffuse and correlated to stage. A tumour mass index (TMI) was calculated by estimating the total myeloma mass visualised at MR imaging. The TMI correlated significantly with stage, lytic bone lesions, serum calcium, serum beta-2-microglobulin and survival. No abnormalities were seen at MR investigation in 4 of 6 patients classified as stage II because of osteoporosis only. Therapy efficacy evaluation with MR imaging corresponded to clinical evaluation on 54 of the 69 occasions. MR examination of bone marrow in MM patients can be used for tumour mass assessment, both at diagnosis and during follow-up. Valuable information can be obtained when the tumour mass is difficult to estimate using clinical criteria, e.g. in non secretory MM or when osteoporosis is the only variable indicating an increase in the tumour mass. PMID- 7833178 TI - Artifacts in MR imaging caused by small quantities of powdered iron. AB - The MR image artifacts caused by minute metallic particles were investigated by imaging small powdered iron quantities from 0.01 mg to 1.7 mg in water phantoms. Images with T1-weighted GRE 3-D and T2-weighted SE 2-D sequences were reconstructed with 5 MR imagers: at 0.04 T, 0.1 T (2 scanners), 1.0 T and 1.5 T. In GRE 3-D images the artifacts were round, clearly demarcated black areas, whereas in SE 2-D images artifact areas were elliptic and surrounded by a bright irregular rim with ghost veils in the direction of frequency encoding. The area of the artifact increased slightly up to 0.1 mg of iron, but grew clearly with larger samples. It appeared to behave independently on the MR imager system for all iron samples. This study shows that even microscopic magnetic particles cause a notable distortion in the MR image independently of the MR equipment used. PMID- 7833179 TI - Association of rectal diverticula and scleroderma. AB - Barium enema examinations of 7,200 patients were analyzed to determine the presence of rectal diverticula. Five patients with rectal diverticula, a prevalence of 0.07%, were found. Their diameters varied from 10 to 80 mm. Each of the patients had a single rectal diverticulum. Two patients had scleroderma with no other diverticula in the large bowel. None of our patients had symptoms referable to the rectal diverticula. PMID- 7833180 TI - A prescription for success: integrating 12 inpatient and 17 outpatient programs. PMID- 7833181 TI - How to support a hospital-based model for nursing research. PMID- 7833182 TI - The critical pathway to outcomes research. PMID- 7833183 TI - The manipulative manager: interventions for the nurse executive--Part 2. PMID- 7833184 TI - Gene therapy for cardiovascular disease. PMID- 7833185 TI - Why the controversy about electron beam computed tomographic screening for coronary atherosclerosis? PMID- 7833186 TI - Cardiac remodelling. PMID- 7833187 TI - Trends in the age and sex of patients undergoing coronary revascularisation in the United Kingdom 1987-93. AB - OBJECTIVES: To describe how coronary revascularisation rates in the United Kingdom (in the public and private sectors) vary by age and sex; how these relations have changed between 1987 and 1993; whether significant differences exist between geographical areas, public and private sectors, and hospitals; and to make comparisons with trends in North America. DESIGNS: Secondary analysis of data on the age, sex, procedure, NHS/private, and health district of residence of patients. SETTING: Resident population of South East Thames, East Anglian, and North Western health regions and Greater Glasgow, Lanarkshire, and Ayr/Arran health boards (11.6 million; 20% United Kingdom population). PATIENTS: All 19,665 residents who underwent either coronary artery bypass grafting or percutaneous coronary angioplasty without any concomitant procedure during 1987-8, 1989-90, 1991-2 and 1992-3 in either NHS or independent hospitals. MAIN MEASURES: Population based rates of revascularisation by age, sex, area of residence, and NHS/private treatment. Secular trends in the age (mean, standard deviation, range), and sex ratio (male to female) of patients. RESULTS: Revascularisation rates in men were about four times higher than in women (1992-3: 1340 v 362/10(6) aged 25 years or more). The highest rates were in those aged 55-64 years (for men) and 55-64 and 65-74 years (for women). In 1992-3 the mean age of female patients was three years older than that for men (61.2 v 58.3) and that for coronary artery grafting was over two years older than for angioplasty (59.4 v 56.9). Between 1987-8 and 1992-3 the male to female ratio decreased (4.2:1 to 3.55:1) and the mean age of patients increased steadily by about six months each year. Intervention rates for the older groups increased faster than those for the younger, particularly in high rate regions. The age and sex mix of patients varied between regions and districts/boards. The mean age of patients varied by nine years and the sex ratio varied twofold between NHS hospitals. The male to female ratio was higher in private than NHS patients (1992-3: 5.5:1 v 3.6:1), suggesting greater access to care for men than women in the private sector. The trends observed in the United Kingdom are similar to those that have occurred in North America, with the exception of a decrease in the male to female ratio, which has not previously been reported. CONCLUSION: The increase in the revascularisation rate has been accompanied by an increasing proportion of women and older people. The extent of these changes varies between geographical areas. The change in the sex ratio has occurred despite an increasing contribution by the private sector, to which women have less access than men. PMID- 7833188 TI - A comparison of early mortality and morbidity after single and bilateral internal mammary artery grafting with the free right internal mammary artery. AB - OBJECTIVE: To compare differences in early mortality and morbidity in patients receiving a single internal mammary artery graft (SIMA) with those receiving bilateral internal mammary artery grafts (BIMA) with a free right internal mammary artery (RIMA). DESIGN: Retrospective analysis of 150 patients undergoing BIMA grafting between 1989-1992 who were carefully matched with 150 patients undergoing SIMA grafting between 1987-1992 for known cardiovascular risk factors, extent of coronary disease, left ventricular function, and number of coronary grafts. Operative variables noted included aortic cross clamp time and bypass time. Postoperative cardiac, respiratory, and wound complications were also noted. RESULTS: Operative mortality was 2% in the SIMA group and 1.3% in the BIMA group (NS). Other than the prevalence of ventricular arrhythmias (P = 0.025), which were more common in the BIMA group, there were no significant differences between the two groups in terms of postoperative morbidity. At median (interquartile range) follow up of 27.94(0.86) and 23.94(0.74) months for the SIMA and BIMA groups respectively there were no deaths. 87% of the SIMA group and 91% of the BIMA group were free of symptoms at follow up. CONCLUSIONS: The earlier fears regarding increased early mortality and morbidity after BIMA surgery were not confirmed by this study. All patients receiving both mammary arteries had a free rather than pedicle right internal mammary graft. The early mortality and morbidity reported here compares favourably with previous reports on the use of a pedicle graft. PMID- 7833189 TI - Pericardial effusion after cardiac surgery: incidence, site, size, and haemodynamic consequences. AB - OBJECTIVE: To evaluate the incidence, characteristics, and haemodynamic consequences of pericardial effusion after cardiac surgery. DESIGN: Clinical, echocardiographic, and Doppler evaluations before and 8 days after cardiac surgery; with echocardiographic and Doppler follow up of patients with moderate or large pericardial effusion after operation. SETTING: Patients undergoing cardiac surgery at a tertiary centre. PATIENTS: 803 consecutive patients who had coronary artery bypass grafting (430), valve replacement (330), and other types of surgery (43). 23 were excluded because of early reoperation. MAIN OUTCOME MEASURES: Size and site of pericardial effusion evaluated by cross sectional echocardiography and signs of cardiac tamponade detected by ultrasound (right atrial and ventricular diastolic collapse, left ventricular diastolic collapse, distension of the inferior vena cava), and Doppler echocardiography (inspiratory decrease of aortic and mitral flow velocities). RESULTS: Pericardial effusion was detected in 498 (64%) of 780 patients and was more often associated with coronary artery bypass grafting than with valve replacement or other types of surgery; it was small in 68.4%, moderate in 29.8%, and large in 1.6%. Loculated effusions (57.8%) were more frequent than diffuse ones (42.2%). The size and site of effusion were related to the type of surgery. None of the small pericardial effusions increased in size; the amount of fluid decreased within a month in most patients with moderate effusion and in a few (7 patients) developed into a large effusion and cardiac tamponade. 15 individuals (1.9%) had cardiac tamponade; this event was significantly more common after valve replacement (12 patients) than after coronary artery bypass grafting (2 patients) or other types of surgery (1 patient after pulmonary embolectomy). In patients with cardiac tamponade aortic and mitral flow velocities invariably decreased during inspiration; the echocardiographic signs were less reliable. CONCLUSIONS: Pericardial effusion after cardiac surgery is common and its size and site are related to the type of surgery. Cardiac tamponade is rare and is more common in patients receiving oral anticoagulants. Echo-Doppler imaging is useful for the evaluation of pericardial fluid accumulations after cardiac surgery. It can identify effusions that herald cardiac tamponade. PMID- 7833190 TI - Regional myocardial velocity imaged by magnetic resonance in patients with ischaemic heart disease. AB - OBJECTIVE: To assess the pattern of global and regional left ventricular long axis motion during early diastole in patients with ischaemic heart disease with and without myocardial infarction using magnetic resonance velocity mapping. DESIGN: Prospective study of 26 patients with a history of myocardial infarction (age 29-78, mean 55 years) and 21 patients with coronary artery disease without infarction (age range 39-71, mean 58 years). Values were compared with a control group (19 controls, age 35-76, mean 52 years) with a low likelihood of cardiovascular disease. RESULTS: Regional long axis velocity varied with time and position around the ventricle. All measurements were taken at the time of maximum early diastolic long axis velocity. Patients with coronary artery disease without infarction had lower values for maximum (mean (SD)) (99 (30) v 125 (33) mm/s, P < 0.05) and mean peak early diastolic wall motion (63 (13) v 82 (22) mm/s, P < 0.05) than controls. The coefficient of variation showed greater inhomogeneity of relaxation in patients than in controls (38 (18)% v 27 (10)%). All values were lower in patients with previous infarction than in patients with coronary artery disease without infarction and normal subjects. In patients with previous myocardial infarction the maximum (mean (SD)) early diastolic velocity was 80 (22) mm/s (P < 0.01 compared with controls and P < 0.05 compared with patients without infarction) and the mean (SD) velocity was 47 (18) mm/s (P < 0.01 compared with controls). The coefficient of variation was greater (52 (33)%) than for controls (P < 0.05) and patients with coronary artery disease without infarction. 18 of 26 patients with previous myocardial infarction and 13 of 21 patients with coronary artery disease without infarction had regional abnormalities corresponding to areas of fixed or reversible ischaemia on exercise electrocardiography or thallium myocardial perfusion tomography. CONCLUSIONS: Magnetic resonance velocity mapping can be used to assess regional long axis myocardial velocity. Ischaemic heart disease causes alterations in the patterns of left ventricular long axis velocity during early diastole. PMID- 7833191 TI - Antibiotic prophylaxis in permanent pacemaker implantation: a prospective randomised trial. AB - BACKGROUND: Pacemaker pocket infection is a potentially serious problem after permanent pacemaker implantation. Antibiotic prophylaxis is commonly prescribed to reduce the incidence of this complication, but current trial evidence of its efficacy is conflicting. A large prospective randomised trial was therefore performed of antibiotic prophylaxis in permanent pacemaker implantation. The intention was firstly to determine whether antibiotic prophylaxis is efficacious in these patients and secondly to identify which patients are at the highest risk of infection. METHODS: A prospective randomised open trial of flucloxacillin (clindamycin if the patient was allergic to penicillin) v no antibiotic was performed in a cohort of patients undergoing first implantation of a permanent pacing system over a 17 month period. Intravenous antibiotics were started at the time of implantation and continued for 48 hours. The trial endpoint was a repeat operation for an infective complication. RESULTS: 473 patients were entered into a randomised trial. 224 received antibiotic prophylaxis and 249 received no antibiotics. A further 183 patients were not randomised but were treated according to the operator's preference (64 antibiotics, 119 no antibiotics); these patients are included only in the analysis of predictors of infection. Patients were followed up for a mean (SD) of 19(5) months. Among the patients in the randomised group there were nine infections requiring a repeat operation, all in the group not receiving antibiotic (P = 0.003). In the total patient cohort there were 13 infections, all but one in the non-antibiotic group (P = 0.006). Nine of the infections presented as erosion of the pulse generator or electrode, three as septicaemia secondary to Staphylococcus aureus, and one as a pocket abscess secondary to Staphylococcus epidermidis. Infections were significantly more common when the operator was inexperienced (< or = 100 previous patients), the operation was prolonged, or after a repeat operation for non-infective complications (principally lead displacement). Infection was not significantly more common in patients identified preoperatively as being at high risk (for example patients with diabetes mellitus, patients receiving long term steroid treatment), although there was a trend in this direction. CONCLUSIONS: Antibiotic prophylaxis significantly reduced the incidence of infective complications requiring a repeat operation after permanent pacemaker implantation. It is suggested that antibiotics should be used routinely. PMID- 7833192 TI - Dilated cardiomyopathy and the dystrophin gene: an illustrated review. AB - Cardiomyopathy is often found in patients with Duchenne and Becker muscular dystrophy, which are X linked muscle diseases caused by mutations in the dystrophin gene. Dystrophin defects present in many different ways and cases of mild Becker muscular dystrophy have been described in which cardiomyopathy was severe. Female carriers of Duchenne muscular dystrophy can develop symptomatic skeletal myopathy alone or combined with dilated cardiomyopathy. They can also develop dilated cardiomyopathy alone. X linked dilated cardiomyopathy has been found in association with dystrophin defects. The relation between the molecular defects and the cardiac phenotypes has not yet been established. New mutations in the dystrophin gene are common and such mutations cause one third of the cases with Duchenne and Becker muscular dystrophy. This means that sporadic cases of cardiomyopathy caused by dystrophin defects are likely. This paper reports such a case in a boy of 14 who died of dilated cardiomyopathy. Before the cardiac investigation, which was performed one month before he died, he had not complained of muscular weakness. He had minor signs of limb girdle myopathy and slightly increased concentrations of serum creatine kinase. He was found to have an unusual deletion in the dystrophin gene. PMID- 7833193 TI - Dilated cardiomyopathy due to type II X-linked 3-methylglutaconic aciduria: successful treatment with pantothenic acid. AB - A case of dilated cardiomyopathy in a young boy secondary to type II 3 methylglutaconic aciduria is described. A metabolic cause for his dilated cardiomyopathy was suspected because of the development on the electrocardiogram of an unusual "camel's hump" shape of the T waves, and of progressive thickening with increasing echogenicity of the left ventricular wall. He initially improved on digoxin treatment, but did not maintain the response with conventional dietary treatment for this condition. Supplementation with L-carnitine was associated with rapid deterioration in cardiac state, and may be contraindicated in this condition. At a point when the patient was moribund, large doses of pantothenic acid, a precursor of coenzyme A, produced a dramatic and sustained improvement in myocardial function and in growth, neutrophil cell count, hypocholesterolaemia, and hyperuricaemia, which suggests that limitation of availability of coenzyme A is a fundamental pathological process in this condition. The clinical improvement has been maintained for 13 months, and myocardial function is now nearly normal. Oral pantothenol, unlike pantothenic acid, is not efficacious. PMID- 7833194 TI - Immunosuppressive treatment for myocarditis and borderline myocarditis in children with ventricular ectopic rhythm. AB - OBJECTIVES: To ascertain the responsiveness to immunosuppressive treatment of myocarditis and borderline myocarditis in children with ventricular ectopic rhythm (that is, all ventricular arrhythmia except benign premature ventricular contractions). To determine the impact of the diagnostic information provided by an endomyocardial biopsy specimen in these patients. BACKGROUND: The therapeutic value of performing an endomyocardial biopsy in children with ventricular ectopic rhythm is not established. In turn, the treatment of myocarditis with immunosuppressive drugs is also controversial. METHODS: The case notes and endomyocardial biopsy findings of all children with ventricular ectopic rhythm and a biopsy diagnosis of myocarditis were reviewed. RESULTS: Ten (14%) of 69 patients with ventricular ectopic rhythm and an anatomically normal heart had histological evidence of myocarditis or borderline myocarditis. Eight patients received corticosteroids and efficacy was judged by regular 24 hour Holter monitoring. Total resolution of arrhythmia was seen in four, improvement in two, and no change in two patients. At follow up (8-39 months, mean 22 months), arrhythmia recurrence was seen in the two patients who showed an improvement but not resolution during treatment. Both received azathioprine with further reduction in ectopy rates. Patients who responded to treatment were symptomatic (six of six patients) at presentation compared with those who did not respond to treatment (none of two patients) who were not symptomatic. Five patients had a repeat biopsy specimen taken which confirmed histological improvement. CONCLUSIONS: Steroid treatment seems to benefit a subset of children with ventricular ectopic rhythm and a biopsy diagnosis of myocarditis or borderline myocarditis. Because it can identify a treatable cause for the ventricular arrhythmia, endomyocardial biopsy is a valuable investigation in these patients. PMID- 7833195 TI - Role of right ventricular endomyocardial biopsy in infants and children with suspected or possible myocarditis. AB - OBJECTIVES: To assess the diagnostic yield, sampling errors, risks, and therapeutic implications of right ventricular endomyocardial biopsy in children with suspected or possible myocarditis. DESIGN: Retrospective study. SETTING: Tertiary referral centre for paediatric cardiology, cardiac surgery, heart transplantation, and mechanical circulatory support. PATIENTS AND METHODS: Review of clinical and histological findings among 63 consecutive children with possible myocarditis undergoing right ventricular endomyocardial biopsy. Review of cardiac histology at subsequent necropsy or after explantation at time of transplantation. RESULTS: From January 1980 to December 1992, 76 biopsies were performed in 63 children (2 weeks to 18 years of age). In 41 cases, the biopsy was performed for evaluation of dilated cardiomyopathy. The median interval from onset of symptoms was one month. Eight children (20%; all with a history of less than six weeks duration) had biopsy proved myocarditis. Five of the eight children made a full recovery, including four who presented in cardiogenic shock. By contrast, only three of 33 children without evidence of myocarditis showed recovery of ventricular function. The whole heart was available for histological examination in 23 patients. Myocarditis was confirmed in one patient, and no evidence of myocarditis was found in the remaining 22 (all with negative biopsies). One procedure related death occurred in a 2 week old infant with dilated cardiomyopathy. In 22 cases, biopsy was performed for the evaluation of arrhythmia. Only one biopsy showed myocarditis. CONCLUSIONS: The diagnostic yield of a biopsy is low in children with arrhythmias. In children presenting with profound ventricular dysfunction, a diagnosis of acute myocarditis may avoid premature consideration of transplantation as this group has an important potential for full recovery. In less critically ill patients and in those with a longer duration of symptoms the justification for biopsy is not as clear and the procedure is not without risk. PMID- 7833196 TI - Umbrella occlusion of persistent arterial duct in children under two years. AB - OBJECTIVE: To assess the use of trans-catheter occlusion of a persistent arterial duct in symptomatic children < 2 years of age. DESIGN: Descriptive study of selected, non-randomised infants with persistent arterial duct who underwent attempted umbrella occlusion. SETTING: Tertiary referral centre. PATIENTS: Between June 1990 and April 1993, 29 young children with a symptomatic persistent arterial duct underwent attempted transcatheter occlusion. Their age ranged from 1.5 to 23 months, with the youngest infant weighing 2.9 kg. The diagnosis was established before operation in all patients by cross sectional echocardiography. INTERVENTION: Transcatheter occlusion of a haemodynamically important persistent arterial duct was performed with the Rashkind ductal umbrella. In the past year the front loading technique has been used to place the 12 mm umbrella through a 6 F (French) sheath and the 17 mm device through a 8 F sheath so extending the indications for their use. RESULTS: Umbrellas were successfully placed in 25 (86.2%) infants and there was symptomatic improvement in all. There were no deaths or severe complications. The four failures occurred early in the series. They were caused by kinking of the 11 F sheath in two cases and embolisation into the left pulmonary artery in one case. The procedure was abandoned in the fourth case because of a large duct. Only three of the 25 patients had small residual shunts at one year follow up (all with 17 mm devices) but no stenosis or turbulence was noted in any of the patients. CONCLUSION: The transcatheter occlusion of persistent arterial duct in young children with symptoms is a safe alternative to surgery. The new front loading umbrella technique enables successful ductal closure in even smaller infants than earlier devices. PMID- 7833197 TI - Primary transcatheter umbrella closure of perimembranous ventricular septal defect. AB - OBJECTIVES: The starting hypothesis was that some perimembranous ventricular septal defects can be closed safely and effectively with a Bard Rashkind double umbrella introduced through a long transvenous sheath. DESIGN: A descriptive study of all patients who underwent attempted transcatheter umbrella closure of a perimembranous ventricular septal defect. Those patients selected for the study had symptoms of a ventricular septal defect and a perimembranous ventricular septal defect shown by transthoracic echocardiography. The morphological criteria used were a posterior perimembranous defect with a diameter of < or = 8 mm not associated with overriding of the aortic or pulmonary valve or with aortic valve prolapse. The haemodynamic criteria for inclusion in the study were a right to left ventricular systolic pressure ratio of > 0.45, a Doppler derived right ventricular systolic pressure of > 50 mm Hg, and a pulmonary to systemic flow ratio > 3:1. SETTING: A tertiary referral centre. PATIENTS: 13 infants, children, and adolescents with a perimembranous ventricular septal defect aged 3 weeks to 16 years and weighing 1.8-46 kg. INTERVENTIONS: A modified Rashkind ductal double umbrella was introduced through a long transvenous sheath and positioned on either side of the ventricular septal defect. Placement was guided by transoesophageal echocardiography. RESULTS: 10 out of 13 patients underwent successful partial or complete closure of a perimembranous ventricular septal defect. There were three placement failures. Two of these were associated with a ventricular septal defect too large for the umbrella device. In a third case the umbrella was opened in the left ventricular outflow tract necessitating surgical removal and closure of the ventricular septal defect. CONCLUSION: Transcatheter umbrella closure of a perimembranous ventricular septal defect is technically feasible and can be therapeutically successful, although the procedure is moderately difficult to perform and the mean procedure time is > 120 minutes. It is an alternative to surgery in some cases, but the overall results would not support its routine use even with the introduction of larger devices of the current design. PMID- 7833198 TI - Self expanding stents in congenital heart disease. AB - OBJECTIVES: To show potential indications for and clinical use of self expanding stents in patients with congenital heart disease. DESIGN: Descriptive study of selected, non-randomised patients with balloon expandable but persistent stenoses in whom the use of a balloon expandable stent was considered suboptimal or impossible. SETTING: A tertiary referral centre. PATIENTS: 10 patients, aged 15 days to 32 years. Six patients after atriopulmonary or cavopulmonary anastomosis, two with pulmonary atresia and multiple aortopulmonary collaterals, one with coarctation of the aorta, and one with congenital pulmonary venous stenosis. RESULTS: Successful, uncomplicated, placement of 10 stents with the desired haemodynamic results, even in tortuous vessels with many stenoses. CONCLUSIONS: Self expanding stents have a role in the treatment of patients with congenital heart disease. They should be considered when a smaller delivery system and flexibility would aid placement, or in the treatment of long or multiple sequential stenoses. PMID- 7833199 TI - Comparison of Doppler derived haemodynamic variables and simultaneous high fidelity pressure measurements in severe pulmonary hypertension. AB - OBJECTIVE: To assess relations between right ventricular pressure measured with a high fidelity transducer tipped catheter and the characteristics of tricuspid regurgitation recorded with Doppler echocardiography. DESIGN: A prospective non randomised study of patients with severe pulmonary hypertension referred for consideration of lung transplantation. SETTING: A tertiary referral centre for cardiac and pulmonary disease, with facilities for invasive and non-invasive investigation, and assessment for heart and heart-lung transplantation. PATIENTS: 10 patients with severe pulmonary hypertension being considered for lung transplantation. ENDPOINTS: Peak right ventricular, pulmonary artery, and right atrial pressures; peak positive and negative right ventricular dP/dt; peak Doppler right ventricular-right atrial pressure drop; Doppler derived peak positive and negative right ventricular dP/dt; and time intervals of Q to peak right ventricular pressure and to peak positive and negative right ventricular dP/dt. RESULTS: The mean (SD) pulmonary artery systolic pressure was 109 (29) mm Hg. The peak Doppler right ventricular-right atrial pressure drop underestimated peak right ventricular pressure by 38 (21) mm Hg, and by 21 (18) mm Hg when the Doppler value was added to the measured right atrial pressure (P values < 0.05). This discrepancy was greater for higher pulmonary artery pressures. The timing of peak right ventricular pressure differed, with the Doppler value consistently shorter (mean difference 16 ms, P < 0.05). Values of peak positive and negative right ventricular dP/dt and the time intervals Q-peak positive right ventricular dP/dt and pulmonary closure to the end of the pressure pulse differed between the two techniques in individual patients, but not in a consistent or predictable way. CONCLUSIONS: Doppler echocardiography significantly underestimates the peak right ventricular pressure and the time interval to peak right ventricular pressure in pulmonary hypertension, particularly when severe. These differences may be related to orifice geometry. Digitisation of Doppler records of tricuspid regurgitation provides useful semiquantitative estimates of absolute values and timing of peak positive and negative right ventricular dP/dt. Clinically significant differences may exist, however, and must be considered in individual patients. PMID- 7833200 TI - Adjustment of QT dispersion assessed from 12 lead electrocardiograms for different numbers of analysed electrocardiographic leads: comparison of stability of different methods. AB - OBJECTIVE: Normal electrocardiographic recordings were analysed to establish the influence of measurement of different numbers of electrocardiographic leads on the results of different formulas expressing QT dispersion and the effects of adjustment of QT dispersion obtained from a subset of an electrocardiogram to approximate to the true QT dispersion obtained from a complete electrocardiogram. SUBJECTS AND METHODS: Resting 12 lead electrocardiograms of 27 healthy people were investigated. In each lead, the QT interval was measured with a digitising board and QT dispersion was evaluated by three formulas: (A) the difference between the longest and the shortest QT interval among all leads; (B) the difference between the second longest and the second shortest QT interval; (C) SD of QT intervals in different leads. For each formula, the "true" dispersion was assessed from all measurable leads and then different combinations of leads were omitted. The mean relative differences between the QT dispersion with a given number of omitted leads and the "true" QT dispersion (mean relative errors) and the coefficients of variance of the results of QT dispersion obtained when omitting combinations of leads were compared for the different formulas. The procedure was repeated with an adjustment of each formula dividing its results by the square root of the number of measured leads. The same approach was used for the measurement of QT dispersion from the chest leads including a fourth formula (D) the SD of interlead differences weighted according to the distances between leads. For different formulas, the mean relative errors caused by omitting individual electrocardiographic leads were also assessed and the importance of individual leads for correct measurement of QT dispersion was investigated. RESULTS: The study found important differences between different formulas for assessment of QT dispersion with respect to compensation for missing measurements of QT interval. The standard max-min formula (A) performed poorly (mean relative errors of 6.1% to 18.5% for missing one to four leads) but was appropriately adjusted with the factor of 1/square root of n (n = number of measured leads). In a population of healthy people such an adjustment removed the systematic bias introduced by missing leads of the 12 lead electrocardiogram and significantly reduced the mean relative errors caused by the omission of several leads. The unadjusted SD was the optimum formula (C) for the analysis of 12 lead electrocardiograms, and the weighted standard deviation (D) was the optimum for the analysis of six lead chest electrocardiograms. The coefficients of variance of measurements of QT dispersion with different missing leads were very large (about 3 to 7 for one to four missing leads). Independently of the formula for measurement of QT dispersion, omission of different leads produced substantially different relative errors. In 12 lead electrocardiograms the largest relative errors (> 10%) were caused by omitting lead aVL or lead V1. CONCLUSIONS: Because of the large coefficients of variance, the concept of adjusting the QT dispersion for different numbers of electrocardiographic leads used in its assessment is difficult if not impossible to fulfil. Thus it is likely to be more appropriate to assess QT dispersion from standardised constant sets of electrocardiographic leads. PMID- 7833201 TI - Anomalous course of the left anterior descending coronary artery between the aorta and pulmonary trunk: a rare cause of myocardial ischaemia at rest. AB - When the left anterior descending coronary artery follows an anomalous course between the aorta and pulmonary artery it can cause myocardial ischaemia or sudden death during exercise in young people. Coronary arteriography in a 27 year old man with angina pectoris at rest showed a left anterior descending coronary artery arising from a common right trunk and running from the aorta to the pulmonary artery. Follow up after revascularisation was uneventful. PMID- 7833202 TI - Ruptured aortic dissection into the left atrium which presented as congestive heart failure and was diagnosed by transoesophageal echocardiography. AB - A 72 year old man was admitted with severe dyspnoea. Ten days before he had had intense thoracic pain with loss of consciousness that was followed by increased dyspnoea. A continuous murmur was heard in the precordial and the left infrascapular regions. Lung auscultation showed stasis over the lower half of both lungs. Transthoracic echocardiography showed a bicuspid aortic valve and a dissection of the proximal aorta, which was considerably enlarged. Transoesophageal echocardiography confirmed dissection of the proximal aorta and showed a communication from the false lumen of the aortic dissection to the left atrium; and colour flow Doppler showed a continuous shunt to the left atrium. After transoesophageal echocardiography the patient had emergency surgical repair, which was successful. He had no complications in the post-operative period. PMID- 7833203 TI - Tissue plasminogen activator (alteplase) treatment for femoral artery thrombosis after cardiac catheterisation in infants and children. PMID- 7833204 TI - Lumbar disc degeneration and segmental instability: a comparison of magnetic resonance images and plain radiographs of patients with low back pain. AB - We analyzed disc space height, angular displacement, tilting movement, and horizontal displacement in 109 patients with low back pain and/or sciatica, on plain radiographs of the lumbar spine. These parameters were compared with the grade of disc degeneration as evaluated by magnetic resonance imaging with the aim of studying lumbar segmental instability. Disc space height decreased in proportion to the grade of disc degeneration. Angular displacement was significantly less with severe disc degeneration, accompanied by a tendency to stabilization of the motion segment. Tilting movement and horizontal displacement did not correlate with the grade of disc degeneration. Lumbar segmental instability was recognized at all levels even in individuals who appeared to be normal or to have mild disc degeneration. The incidence of lumbar segmental instability at the L3-4 level was significantly higher in patients with normal discs or mild disc degeneration. At the L4-5 and L5-S levels it did not differ between different grades of disc degeneration. PMID- 7833205 TI - Joint-preserving operations for elderly patients with advanced and late-stage coxarthritis. AB - Forty-one hips in 38 elderly patients with osteoarthritis of the hips, operated on with joint preserving techniques at the age of 55 years or more, were analyzed clinically radiologically. Bilateral involvement was seen in 13 cases. Ten hips were operated on after this study, before the patients were 55 years old, or no operation has yet been done. The average age at operation was 59 years, and the average preoperative hip scores (Merle d'Aubigne) were as follows: pain 2.8; range of motion (ROM) 4.4; gait 3.4. Average preoperative hip flexion and abduction were 88 degrees and 20 degrees respectively. Mean follow-up period was 57 months, and mean final hip scores were: pain 5.1; ROM 4.6; gait 4.0. Significant improvement was seen in pain and gait scores but no improvement in ROM scores. Excellent and good scores were achieved in half of the cases. Failure was seen in four cases. Hip pain recurred in nine patients. Five out of these patients were classified as atrophic according to Bombelli's classification of osteoblastic response of osteoarthritis of the hip. The responsiveness of the femoral head influenced the clinical results of the joint-preserving operations. PMID- 7833206 TI - Surgical treatment of acromioclavicular dislocation. AB - Sixty-five patients were operated on for acromioclavicular dislocation between 1980 and 1991. Seventeen type II and 48 type III dislocations according to the criteria of Tossy et al. were treated. Three different surgical techniques were employed. (1) tension band wiring, (2) a modification of the Bosworth repair, (3) reconstruction of the ligaments with augmentation by a PDS (polydioxanon) cord. Forty-four patients could be investigated retrospectively, and an additional 12 were recorded by questionnaire. The Taft score was used, representing self assessment, clinical statements and radiological findings. Of all investigated patients 87.5% had a normal range of motion without any loss of strength, and 32% suffered an osteoarthritis of the acromioclavicular joint. The average Taft score was 9.8. With respect to the three surgical techniques, reconstruction of the ligaments augmented by a PDS cord produced the best result, an average Taft score of 10.8. PMID- 7833207 TI - Nonunion using a canine model. AB - The investigation involved a search for a model of atrophic nonunion. Fifty-two mature, adult, mongrel dogs were used to study the repair after creating a 0.5-cm bone defect in the mid-diaphysis of the radius. In addition, a 2-cm wide strip of periosteum was circumferentially resected from each osteotomy extremity. No immobilization was used thereafter. The reparative process was assessed by X rays, histology, vascular injection, and scintigraphy. The dogs we distributed into three groups according to the time of follow-up (1, 3, and 6 months). Two kinds of repair were recognized after 3 months and were well-established after 6 months: disturbed healing with much callus (54%) and disturbed healing with absent or scanty callus (46%). In the first instance, the periosteum had regenerated and produced the external callus. The bone ends were capped with fibrocartilage; the vascularization around the defect was increased and displayed a well-defined vascular picture. In the healing pattern with absent external callus (atrophic nonunion), the bone defect was enlarged and filled with fibrous tissue, but there was no deficient vascularization in and around the osteotomy. Radioactivity counting showed an increased uptake around the osteotomy site in both types of repair, which persisted over time but was higher in the 1-month group. It was concluded that the present model yields a consistent pattern of a disturbed reparative process that mimics human cases of atrophic or hypertrophic nonunion. The differences between the two kinds of repair seemed to be related to the periosteal capacity of regeneration. PMID- 7833208 TI - Optimization of cryopreservative procedures for human articular cartilage chondrocytes. AB - Procedures are being developed which use isolated articular cartilage (AC) chondrocytes to restore damaged articular surfaces. The availability of isolated human chondrocytes for transplantation may be increased by low-temperature storage (banking). At present, no single method of freezing chondrocytes has been proven to be optimal. In this project, two different freezing protocols, I and II, were compared. Protocol I used freezing rates of -1 degrees C/min down to a temperature of -40 degrees C. Protocol II used a freezing rate of -1 degree C/min down to -10 degrees C and faster rates thereafter. Cells were stored for 2 weeks at -196 degrees C. Survival and function of the cells after thawing were evaluated by histological examination and determination of 35S- and 3H-thymidine incorporation after 1 and 2 weeks of high-density monolayer culture. Cells frozen with protocol I showed better function and survival (99.75%) than cells frozen with protocol II (85%). Both groups showed slowing of metabolism and replication after freezing when compared with controls. We conclude that controlled freezing of adult human chondrocytes at rates of -1 degrees C/min improves survival. Banking of human AC chondrocytes may be feasible using protocol I, although some questions regarding the long-term behaviour of human AC chondrocytes after cryopreservation remain to be answered. PMID- 7833209 TI - Uncemented total hip replacements and thigh pain. AB - We reviewed 51 uncemented total hip replacements (THRs) in 44 patients (mean age 62 years) and average postoperative follow-up period of 4 years. The evaluation system used was based on that of D'Aubigne-Postel-Charnley, and the excellent and very good results totalled over 90%. There were no revisions or aseptic loosenings, and only one late infection and one death due to cardiac infarction. Special attention was paid to the so-called thigh pain phenomenon which, despite current views, was found to be unexpectedly low (only one case) and also gone within 2 years. We feel that the design of the prosthesis used, its kind of alloy, the anatomic shape of the stem and the low modulus of the elasticity as well as the avoidance of the press fitting technique at the distal part of the stem are important factors in avoiding the stress shielding phenomenon and thigh pain. PMID- 7833210 TI - Extensor indicis proprius transfer for loss of extensor pollicis longus function. AB - In the period 1969-1991, 46 extensor indicis proprius tendon transfers were performed for functional loss of extensor pollicis longus. The long-term function of the thumb was reviewed in 22 patients with an average follow-up of 7 years. Based on Geldmacher's evaluation scheme for assessment of the results of extensor tendon reconstruction, we report 5 excellent (23%), 4 good (18%), 12 satisfactory (55%) and 1 poor (4%) result. The mean loss of pinch strength was 8% compared with the contralateral, non-operated thumb. Subjectively, the majority of the patients (86%) described no limitations in their daily life activities. It is recommended that the transfer be tight enough to give full thumb extension and that the hand be immobilized with the thumb in this position for 4 weeks. PMID- 7833211 TI - Fracture of the tibial tray following PCA knee replacement. A report of two cases. AB - We report two cases in which fracture of the tibial metal tray was thought to be due to improper design of the tray and heavy polyethylene wear. The bone beneath the fractured portion of the tray was deficient and had been replaced by granulomatous fibrous tissue including numerous polyethylene wear particles and foreign-body giant cells. Osteolysis occurred as a tissue reaction to these particles. PMID- 7833212 TI - Collagen turnover after tibial fractures. AB - Collagen turnover after tibial fractures was examined in 16 patients with fracture of the tibial diaphysis and in 8 patients with fracture in the tibial condyle area by measuring sequential changes in serological markers of turnover of types I and III collagen for up to 26 weeks after fracture. The markers were the carboxy-terminal extension peptide of type I procollagen (PICP), the amino terminal extension peptide of type III procollagen (PIIINP), and the pyridinoline cross-linked carboxy-terminal telopeptide of type I collagen (ICTP). The latter is a new serum marker of degradation of type I collagen. A group comparison showed characteristic sequential changes in the turnover of types I and III collagen in fractures of the tibial diaphysis and tibial condyles. The turnover of type III collagen reached a maximum after 2 weeks in both groups. The synthesis of type I collagen reached a maximum after 2 weeks in the diaphyseal fractures and after 6 weeks in the condylar fractures. The degradation of type I collagen increased after 4 days and reached a maximum at 2 weeks in both groups. The interindividual variation was wide. On a group basis, the turnover of types I and III collagen had levelled of within 26 weeks, although some patients had clearly elevated parameters at the end of the observational period. We suggest that delayed healing of tibial diaphyseal fractures is accompanied by an early increase in the turnover of types I and III collagen. PMID- 7833213 TI - Quantitative assessment of fracture healing. The value of computerised sonometry in a correlative animal experiment in sheep. AB - Usually follow-up of the healing process of bone fractures is by subjective assessment of standard X-rays, based on the clinician's personal experience. It is therefore impossible to completely avoid misjudgements in the evaluation of the mechanical stability. Other authors have reported that the mechanical response of bony structures to a knock impulse allows a definitive statement about the stiffness of a fracture. The practicability of computerised sonometry in computer-aided evaluation of the mechanical vibration reaction and the acoustic transmission of sound through osseous structures for assessing stability has been proved in experimental and clinical studies. We designed an animal study that would allow a systematic correlation between the diagnostic investigations in general use. As a main goal, this study tries to correlate sonography with other quantitative techniques, even if they are not used under everyday clinical conditions. Our results show that methods based on direct assessment of the mechanical stability between fracture fragments allow a more exact evaluation of fracture healing. This study helps to classify the results of computerised sonometry together with other diagnostic procedures used for the evaluation of fracture healing, and furthermore provides a basis for clinical interpretation of the findings of a new, non-invasive technique for precise quantitative assessment of fracture healing. PMID- 7833214 TI - The skeletal radiology of the distal tibiofibular joint. AB - In bony or ligamentous injuries of the distal tibiofibular joint, inserting the fibula into the incisura fibularis tibiae can be difficult. In order to check the correct position of the fibula by means of X-ray, two radiological parameters could be distinguished in patients with surgically or conservatively treated fractures of the lateral malleolus. With the help of these easily measureable X ray parameters, incongruences in the distal tibiofibular joint can be detected. PMID- 7833215 TI - Dislocation of the shoulder with ipsilateral humeral shaft fracture. AB - Dislocation of the shoulder with ipsilateral shaft fracture is an uncommon, but serious injury. I present one case report and the guidelines used for treatment. The method employed was Hackethal's pins through open reduction. The dislocation was reduced during surgery. The fracture and dislocation healed without any problems, and there was no damage to the radial nerve. After a recent follow-up, the patient was allowed to return to work without restrictions, and he has regained normal mobility. PMID- 7833216 TI - Arterial pseudoaneurysm of the ankle after plantar flexion-inversion injury. A rare complication and its non-invasive diagnosis. AB - We report a case of arterial pseudoaneurysm over the lateral side of the ankle caused by plantar flexion-inversion injury and discuss the aetiology of this rarely seen complication. In the English orthopaedic literature, our case is the first of the very few previously reported cases with a similar aetiology which was examined and confirmed by colour Doppler ultrasound. PMID- 7833217 TI - Tear of the biceps femoris tendon. AB - The clinical and operative findings of an isolated rupture of the biceps femoris tendon are described. The immediate suture and the initial postoperative treatment with a knee brace limiting extension to 20 degrees and flexion to 70 degrees resulted in a free range of motion and full activity of the biceps femoris. PMID- 7833219 TI - Local L-NG-monomethyl-arginine attenuates the vasodilator action of bradykinin in the human forearm. AB - 1. Studies in animals indicate that bradykinin relaxes blood vessels directly through an action on smooth muscle and indirectly through the release of endothelium-derived mediators. Its precise mechanism of action in the human arterial circulation is not yet known. 2. In this study the effects of a specific inhibitor of nitric oxide synthase, L-NG-monomethyl-arginine (L-NMMA) and noradrenaline on the vasodilator responses to bradykinin were examined in the forearm arterial bed of healthy volunteers. Noradrenaline was used as a control for vasoconstriction by L-NMMA; glyceryl trinitrate (GTN) as a control vasodilator acting independently of the NO synthase enzyme. 3. L-NMMA (4 mumol min-1; 5 min) alone reduced resting forearm blood flow by 44% (P < 0.01; n = 6) confirming that nitric oxide plays an important role in regulating vascular tone. 4. Bradykinin (10 and 100 pmol min-1; 3 min each dose) and GTN (2 and 5 nmol min 1; 3 min each dose) increased forearm blood flow in a dose-dependent manner (percentage changes 171 +/- 17% and 398 +/- 35%, and 176 +/- 21% and 268 +/- 42%, respectively; n = 6). 5. The response to bradykinin, but not that to GTN, was attenuated by L-NMMA compared with noradrenaline (P < 0.05; n = 6), suggesting that bradykinin-induced vasodilatation in the forearm is mediated, at least in part, by stimulating release of nitric oxide. PMID- 7833220 TI - Inhibition of bradykinin-induced vasodilation in human forearm vasculature by icatibant, a potent B2-receptor antagonist. AB - 1. The effect of icatibant (D-Arg-[Hyp3, Thi5, D-Tic7, Oic8] bradykinin) a potent B2-kinin receptor antagonist, was studied on bradykinin-induced vasodilation in the human forearm. 2. Eight healthy normotensive men were studied in a rising dose random-placebo controlled study. Placebo and icatibant (20, 50 and 100 micrograms kg-1 i.v.) were administered double-blind. Forearm blood flow was measured by venous occlusion plethysmography during rising dose brachial artery infusions of bradykinin (10-3,000 ng min-1) 60-90 min after placebo or icatibant. 3. Plasma concentrations of icatibant fell exponentially following each of three doses, up to the final measurement. Elimination half-lives calculated from linear regression of the mean data were 25, 27 and 29 min after 20, 50 and 100 micrograms kg-1 doses respectively. 4. Icatibant inhibited the effect of bradykinin (P < 0.001 at each dose of icatibant) in a dose-dependent manner. Bradykinin (100 ng min-1) increased mean blood flow in the infused arm by 238 +/- 31% when infused following placebo, by 112 +/- 21% after icatibant 20 micrograms kg-1, by 71 +/- 14% after icatibant 50 micrograms kg-1 and by 48 +/- 9% after icatibant 100 micrograms kg-1. 5. These results demonstrate that icatibant antagonises B2-receptor mediated vasodilation in human forearm resistance vessels. The findings provide a quantitative basis for future studies of the role of bradykinin in the response to angiotensin converting enzyme inhibitors and in circulatory disease. PMID- 7833218 TI - Clinical pharmacology, physiology and pathophysiology of superficial veins--2. PMID- 7833221 TI - Effects of dideoxyinosine and dideoxycytidine on the intracellular phosphorylation of zidovudine in human mononuclear cells. AB - 1. Zidovudine (3'-azido-2',3'-dideoxythymidine; AZT; ZDV) is a dideoxynucleoside analogue active against human immunodeficiency virus (HIV). We are currently investigating the intracellular metabolism of ZDV to its putative active triphosphate form (ZDV triphosphate) in peripheral blood mononuclear cells and a lymphoblastoid cell line (h1A2v2). 2. Optimal conditions for intracellular phosphate formation in peripheral blood mononuclear cells occurred following a 72 h preincubation with the mitogen phytohaemagglutinin at a concentration of 10 micrograms ml-1. ZDV was metabolized predominantly to the monophosphate with smaller amounts of the di- and triphosphate anabolites. There was considerable inter- and intraindividual variability in phosphate formation in peripheral blood mononuclear cells. A similar pattern of phosphorylation was seen with the h1A2v2 lymphoblastoid cell line with ZDV monophosphate being the major metabolite. 3. With increasing interest in combination nucleoside analogue therapy in HIV positive patients it is important to know if an interaction occurs at the level of phosphorylation. Neither dideoxyinosine (ddI) or dideoxycytidine (ddC) significantly reduced the intracellular phosphorylation of ZDV in either peripheral blood mononuclear cells or h1A2v2 cells. In contrast thymidine always gave marked inhibition (e.g. at 2.0 microM, 89% inhibition of total phosphate formation in peripheral blood mononuclear cells and 79% in h1A2v2 cells). It is, therefore, unlikely that in vivo either ddI or ddC will perturb ZDV phosphorylation. PMID- 7833222 TI - Responses to low dose intravenous perindoprilat infusion in salt deplete/salt replete normotensive volunteers. AB - 1. Intravenous ACE inhibitor therapy appears to have a role in the treatment of acute heart failure and early after myocardial infarction. Practical experience with intravenous administration with activation of renin is limited. We report responses to perindoprilat (Pt, 0.67 mg) or placebo (P) infused over 4 h in normotensive male volunteers (n = 12, 19-28 years, 53-77 kg) with double-blind, placebo controlled salt depletion (SD) or salt repletion (SR) as a model of the activated renin system. 2. Salt depletion caused no significant fall in serum sodium (P, 139.4 +/- 2.4; Pt, 138.3 +/- 1.9) compared with salt replete preparation (P, 139.9 +/- 1.2; Pt, 139.7 +/- 0.9) but elevation of plasma renin activity 2-3-fold. Pretreatment baseline systolic blood pressure following salt depletion (P, 121 +/- 9.3/71 +/- 7.9; Pt, 121.5 +/- 9.6/69 +/- 8.1) was higher than following salt replete preparation (P, 114 +/- 9.5/61 +/- 7.2; Pt, 116.9 +/- 6.9/67 +/- 7.2). 3. Baseline corrected supine SBP fell significantly and to a similar extent following active treatment regardless of activation of the renin system (SD, -14.6 +/- 9.5/-9.4 +/- 6.4; SR, -12 +/- 14/-10.1 +/- 6.6) compared with placebo (SD, -6.1 +/- 6/-3.7 +/- 5.6; SR, -4.7 +/- 10/-1.3 +/- 6.5). Heart rate was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7833223 TI - At equipotent doses, isradipine is better tolerated than amlodipine in patients with mild-to-moderate hypertension: a double-blind, randomized, parallel-group study. AB - 1. The objective of this double-blind parallel-group study was to compare the tolerability of isradipine and amlodipine, specifically, the side-effects known to be related to the use of dihydropyridine calcium antagonists. 2. A total of 205 patients with mild-to-moderate essential hypertension were randomized to receive either the sustained-release (SRO) formulation of isradipine (n = 103) or amlodipine (n = 102), both at dosages of 5 mg once daily. Blood pressure measurements were taken at the end of the dosing interval to assess the antihypertensive efficacy of the two drugs. 3. Adverse reactions were assessed in two ways: a) spontaneously reported adverse events were recorded and investigated in depth for severity, duration, relation to the study drug, and outcome; b) a questionnaire was used to elicit specific adverse reactions known to be related to the use of dihydropyridine calcium antagonists which were evaluated for severity, duration, relation to the study drug, and outcome. 4. After 6 weeks of active treatment, both isradipine and amlodipine reduced mean sitting systolic/diastolic blood pressure: from 165.1/100.1 to 145.2/89.7 mm Hg with isradipine; and from 164.1/100.6 to 145.7/90.5 mm Hg with amlodipine. There was no difference in antihypertensive effect between isradipine and amlodipine (95% CI: -3.73 to 4.73 and -1.89 to 3.49 for differences in systolic and diastolic blood pressure, respectively). 5. The number of patients spontaneously reporting adverse events was significantly higher (P = 0.02; 95% CI: 3.1 to 26.7%) with amlodipine (33.3%) than with isradipine (18.4%).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7833224 TI - Clinical response to non-steroidal anti-inflammatory drugs in urate-crystal induced inflammation: a simultaneous study of intersubject and intrasubject variability. AB - 1. It is well known that an individual subject often responds preferentially to a particular nonsteroidal anti-inflammatory drug (NSAID) and clinical response to these drugs is characterised by considerable variability between individuals. Variability in response has often been attributed to the episodic nature of musculoskeletal disease. Few studies have studied intrasubject variability in response to these drugs using a multiple crossover design. A major difficulty has been the lack of objective, validated measures of inflammation sensitive to NSAIDs. The primary aim of the present study was to test the utility of urate crystal induced inflammation as a tool to predict NSAID response in humans. 2. An inflammatory reaction was established in twenty-five healthy subjects with intradermal injection of urate crystals on four separate occasions separated by 1 week. Each subject was randomly assigned to receive either ibuprofen on two of these occasions (800 mg four times over 36 h) or matched placebo on the other two occasions using a double-blind, cross-over design. Decrease in the area under the wheal size-time curve was used to indicate anti-inflammatory response. 3. Peak inflammatory response was observed at about 32 h and had dissipated by 56 h post urate injection. The logarithmic mean wheal area was significantly lower after ibuprofen (mean +/- s.e. mean; 6.74 +/- 0.09) compared with placebo (6.96 +/- 0.07 mm h); a difference of 20% (95% confidence interval for difference: 1 to 35%; P < 0.05). 4. There was marked intra- and intersubject variability in response to ibuprofen over the four treatment periods.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7833225 TI - Disappearance kinetics of solutes from synovial fluid after intra-articular injection. AB - 1. Five rheumatoid patients with a knee joint effusion participated in the study. An aqueous solution (0.1 to 0.2 ml) containing paracetamol, salicylate, diclofenac and [125I]-albumin was injected into a given joint to yield target concentrations of approximately 20 micrograms ml-1 for diclofenac, salicylate and paracetamol and 10(8) counts ml-1 for [125I]-albumin. 2. Paracetamol, salicylate and diclofenac were analysed in synovial fluid by h.p.l.c. [125I]-albumin was analysed using gamma counting. 3. The clearances (+/- s.d.) obtained for the solutes were [125I]-albumin (0.0053 +/- 0.0019 l h-1), diclofenac (0.0096 +/- 0.0061 l h-1), salicylate (0.024 +/- 0.022 l h-1) and paracetamol (0.055 +/- 0.041 l h-1). The corresponding fractions unbound of these solutes in synovial fluid were 0.0, < or = 0.01, 0.34 +/- 0.09 and 0.85 +/- 0.10, respectively. 4. Diffusion of unbound solute through the synovium is estimated to account for (+/- s.d.) 0.52 +/- 0.08, 0.87 +/- 0.06 and 0.99 +/- 0.01 of the total clearance of diclofenac, salicylate and paracetamol from the joint space, respectively. The remaining proportion of clearance is accounted for by efflux of solute bound to albumin. 5. An expression for the ratio of synovial fluid to total plasma concentrations after systemic administration was developed to include both diffusion of unbound solute and albumin flux. Most solutes appear to satisfy the conditions in which this expression reduces to the limiting case where the unbound concentration of the solute is identical in the synovial fluid and plasma under steady state conditions. PMID- 7833226 TI - Adenosine modulation of neurotransmission in penile erection. AB - 1. Adenosine inhibited the noradrenaline-induced contraction of rabbit corpus cavernosum in a dose-dependent manner. The effect of adenosine was greater in intact corpus cavernosa than in endothelium-denuded preparations. This finding indicates that the relaxing effect of adenosine is partially endothelium dependent and involved in the release of endothelium-derived relaxing factors. 2. Adenosine and its analogues relaxed the noradrenaline-induced contractile response as well as inhibited the transmural nerve induced contraction with the potency order: NECA > R-PIA > adenosine. These data indicate that adenosine can modulate both the non-adrenergic non-cholinergic and adrenergic neurotransmission. DMPX, an adenosine antagonist selective for the A2 receptors, abolished the electrically elicited relaxation. However, CGS 21680, selective for A2a receptor, had no effect on relaxation. Therefore, adenosine receptors involved in the modulation of neurotransmission in rabbit corpus cavernosum appear to be A2b subtype. 3. Adenosine also induced an increase in human cavernosal arterial velocity and resistive index measured by colour duplex sonography. The combination of adenosine and 10 micrograms prostaglandin E1 was more effective in resistive index and erection grade than 20 micrograms prostaglandin E1 alone. Our results suggest that adenosine seems to be an important neuromodulator for penile erection and can be an effective and alternative combination in the treatment of impotence. PMID- 7833227 TI - The effect of erythromycin on the pharmacokinetics and pharmacodynamics of zopiclone. AB - 1. The effect of erythromycin on the pharmacokinetics and pharmacodynamics of oral zopiclone, a non-benzodiazepine hypnotic, was investigated in a double blind, cross-over study. 2. Ten healthy volunteers were given placebo or 500 mg erythromycin orally three times a day for 6 days followed by an oral dose of 7.5 mg zopiclone. 3. Erythromycin increased plasma zopiclone concentration by 4-fold at 0.5 h (P < 0.05) and by 2-fold at 1 h (P < 0.05). There were increases of 3- and 2-fold in the AUC(0,1 h) and AUC(0,2 h) values (P < 0.05). The total AUC of zopiclone increased by 80% (P < 0.05) but the peak concentration by only 40% (P < 0.05). The peak time of zopiclone concentration was reduced from 2 to 1 h (P < 0.001). 4. Significant pharmacodynamic differences between the treatments were observed from 0.5 h to 2 h with respect to saccadic latency and digit symbol substitution tests. 5. The interaction between erythromycin and zopiclone resulted mainly in accelerated absorption which may lead to a faster hypnotic effect in patients. PMID- 7833228 TI - Pharmacokinetics and effects on intracranial pressure of sufentanil in head trauma patients. AB - Ten patients with head trauma received an intravenous bolus of sufentanil (2 micrograms kg-1) followed at 30 min by infusion of sufentanil (median 150 micrograms h-1) and midazolam (median 9.0 mg h-1) over 48 h. Median (range) values of pharmacokinetic parameters for sufentanil were: t1/2,z = 16 (7-49) h; CL = 1215 (519-2550) ml min-1; CLR = 7 (2-38) ml min-1; Vss = 10.0 (6.8-24.2) 1 kg-1. Decreases in intracranial pressure (ICP) (from 16.1 +/- 1.7 to 10.8 +/- 1.3 mm Hg; P < 0.05) and mean arterial blood pressure (MAP) (from 85.5 +/- 3.9 to 80.2 +/- 4.9 mm Hg; P < 0.05) were observed within 15 min of the bolus injection of sufentanil and remained unchanged thereafter. Thus, cerebral perfusion pressure (CPP = MAP-ICP) was stable. PMID- 7833229 TI - Stereoselective disposition of ibuprofen enantiomers in infants. AB - The pharmacokinetics of the enantiomers of ibuprofen were investigated after oral administration of a single 7.6 +/- 0.3 mg kg-1 dose of the racemate in 11 infants. Mean (+/- s.d.) half-lives were 1.6 +/- 0.5 h for S(+) and 1.5 +/- 0.5 h for R(-) and mean (+/- s.d.) AUC values were 31.5 +/- 14.3 mg l-1 h for S(+) and 36.6 +/- 13.8 mg l-1 h for R(-). Since plasma concentrations of the active S(+) isomer were lower than those reported in adults, a higher dosage might be required in infants. PMID- 7833231 TI - Expanded programme on immunization. Diphtheria outbreak. PMID- 7833230 TI - Lansoprazole does not affect the bioavailability of oral contraceptives. AB - The effects of the proton pump inhibitor lansoprazole on the bioavailability of a low-dose oral contraceptive (OC), containing 0.03 mg ethinyloestradiol (EE) and 0.15 mg levonorgestrel (LNG), were investigated. Twenty-four healthy females (aged 19-35 years; weight 60.6 +/- 7.1 kg) participated in a multiple-dose, placebo-controlled, randomized two-way cross-over study. All subjects received the OC over 2 full menstrual cycles from day 1 to day 21 separated by a drug-free interval of 7 days. Lansoprazole (60 mg day-1) or placebo was coadministered for 3 weeks each. Plasma concentrations of EE and LNG were determined by GC-MS. The 90% confidence intervals for ratios of Cmax and AUC after log transformation of both EE and LNG ranged between 91 and 111%, indicating that lansoprazole did not affect the bioavailability of EE and LNG. PMID- 7833232 TI - CDR and GPV technical briefings at WHO headquarters. PMID- 7833233 TI - Expanded programme on immunization. Progress towards poliomyelitis eradication, 1990-1994. PMID- 7833234 TI - Right to nurse. Culture transplant. PMID- 7833236 TI - Changing the culture for carers. PMID- 7833235 TI - Right to nurse. Gagged and bound. PMID- 7833237 TI - World AIDS day. Fighting for families. PMID- 7833238 TI - Patients' views of rehabilitation. AB - Patients and nurses may not appreciate the differences between acute care settings and rehabilitation units. The relative informality and 'hands-off' approach of nurses in the latter can lead to confusion and misunderstanding for people whose exclusive experience of nursing is in the acute sector. At the behest of concerned nurses on a rehabilitation unit, the author conducted interviews with discharged patients to try to establish what their perceptions of the unit were, and how these influenced their progress. The results suggested that the patients' misconceptions may have been hindering their rehabilitation potential. The nurses subsequently devised an action plan to improve understanding of the unit's aims and practices. Follow-up interviews after the plan's implementation showed that it had been successful in improving patients' understanding and engagement with the rehabilitation process. PMID- 7833239 TI - Avoiding disturbed sleep in hospitals. AB - The second article in our series on patients' sleep and night nursing explores the reasons why patients may have difficulty in sleeping in hospital. The author looks at the various definitions and classification of insomnia and identifies the most likely causes of a disturbed night's sleep in hospital. PMID- 7833241 TI - Communication: stand by your lying down devices. PMID- 7833240 TI - Women's health: breast screaming. PMID- 7833242 TI - Cerebral palsy (continuing education credit). PMID- 7833243 TI - Cardiology update. Radio frequency catheter ablation. PMID- 7833244 TI - Cardiology update. Antiarrhythmic drugs. PMID- 7833245 TI - Cardiology update. ACE inhibitors. PMID- 7833246 TI - Cardiology update. Beta blockers in cardiology. PMID- 7833247 TI - Cardiology update. Is it VT? PMID- 7833248 TI - IL-3 increases surface proteoglycan synthesis in haemopoietic progenitors and their adhesiveness to the heparin-binding domain of fibronectin. AB - Haemopoietic progenitor cells (HPC) synthesize and accumulate a single type of membrane-associated chondroitin sulphate proteoglycan (MA-PG), which participates in HPC adhesiveness to fibronectin by interacting with its heparin-binding domain. Shortly after incubating cells with IL-3, we observed an increase in MA PG synthesis in the multipotent (FDCP-mix) but not in the bipotent (FDCP-1) progenitor cell line. The charge density, hydrodynamic size, nature of the glycosaminoglycan (GAG) chains and stability of MA-PG from IL-3-treated and non treated FDCP-mix cells were the same, suggesting that IL-3 affects the amount of MA-PG. The latter was evaluated by flow cytometry using monoclonal antibodies to the core protein and GAG residues. In all cases the mean fluorescence intensities were higher for IL-3-treated than for untreated cells. Cell adhesion studies to dishes coated with the fibronectin 40 kD fragment, containing the heparin-binding domain, demonstrated that adhesiveness of IL-3-treated cells was higher than that of untreated cells. These results suggest that in multipotent haemopoietic cells IL-3 regulates the amount of membrane-associated proteoglycans, which in turn modify the adhesive interactions of cells with the heparin-binding domain of fibronectin. PMID- 7833249 TI - Idiotype-specific T cells in multiple myeloma stage I: an evaluation by four different functional tests. AB - Idiotype-specific T cells were characterized in patients with multiple myeloma stage I by analysing idiotype-induced DNA synthesis (3H-thymidine incorporation), IL-2 and IFN-gamma production at the single cell level (ELISPOT) (in vitro tests) and delayed type hypersensitivity (DTH) skin reaction (in vivo test). In seven out of eight patients at least one of the four tests was positive. In five patients three or more tests were positive. One patient was negative in all four tests. Six patients had both IL-2 and IFN-gamma-secreting cells and three of them also a DTH response. Furthermore, those three patients with a proliferative response also had IL-2 and IFN-gamma-secreting cells induced by the idiotype. The data indicate that part of the idiotype-specific T cell fraction belongs to the CD4 Th1 cell population. Whether CD8-specific T cells also were present could not be ruled out. The present study provides further support for the existence of idiotype-specific T cells in multiple myeloma. Such cells might be an important target for an immune-mediated therapeutic approach. PMID- 7833250 TI - Rapid detection of hereditary and acquired platelet storage pool deficiency by flow cytometry. AB - Platelet aggregation is commonly used to investigate patients with possible dense granule storage pool deficiency (delta SPD), but recent studies have shown that this investigation is not specific or sensitive for this disorder. We describe a simple one-step technique to detect mepacrine loaded platelets by flow cytometry and found a good correlation (r = 0.83) between this method and the enumeration of platelet dense granules by conventional fluorescent microscopy. Seven patients with congenital delta SPD had significantly (P < 0.001) reduced mepacrine labelling detected by flow cytometry (mean 15%; range 5-23%) compared to normal controls (mean 48%; normal range 32-64%). Six patients with other hereditary platelet disorders had normal mepacrine labelling (mean 49%; range 34-66%) and were clearly distinguished from patients with delta SPD despite similar platelet aggregation patterns. Acquired delta SPD is frequently associated with the platelet function defect described in the myeloproliferative and myelodysplastic disorders (MPD/MDS) and we compared platelet aggregation and mepacrine labelling in 15 of these patients. The results confirm that delta SPD occurs commonly in MPD/MDS with 7/15 patients having reduced mepacrine staining but, like the findings in hereditary delta SPD, 3/7 patients with normal platelet aggregation had delta SPD. Similarly abnormal platelet aggregation was not diagnostic of delta SPD as 4/8 of these patients had normal mepacrine levels. These results may contribute to the known lack of correlation between the limited assessment of platelet function and bleeding events in MPD/MDS. We found mepacrine labelling of platelets detected by flow cytometry to be a useful, simple and inexpensive method to detect hereditary and acquired delta SPD which will improve the definition of the platelet defect in these disorders in the clinical laboratory. PMID- 7833251 TI - Altered platelet phospholipid-dependent thrombin generation in thrombocytopenia and thrombocytosis. AB - Platelet phospholipid dependent thrombin generation was determined in 20 patients with thrombocytosis, 18 with thrombocytopenia, and 25 normal controls, using a quantitative chromogenic assay. Platelets from patients with myeloproliferative disorders displayed normal lag times to 20 nM thrombin concentration but increased thrombin potentials, even when corrected for platelet size. Platelets from patients with reactive thrombocytosis supported normal thrombin generation. ITP platelets were large, with a proportionate increase in thrombin potentials, but very short lag times to 20 nM thrombin concentration. Following marrow ablation there was a progressive loss of activation-induced enhancement of thrombin generation. Platelets from patients with idiopathic aplastic anaemia supported normal thrombin generation. These findings indicate that platelet phospholipid-dependent thrombin generation is altered in many patients with a variety of quantitative platelet disorders, and this may be an important determinant of the clinical expression of these disorders. PMID- 7833252 TI - High prevalence of platelet autoantibodies in patients with systemic lupus erythematosus. AB - The aim of this study was to determine the prevalence of platelet autoantibodies (PAA) in patients with systemic lupus erythematosus (SLE) and its correlation with clinical and other laboratory manifestations of the disease, as well as to evaluate the influence of platelet count and disease activity on the result of the test for PAA. Ninety SLE patients, 29 with thrombocytopenia, were evaluated. The presence of PAA was determined using the direct and indirect platelet suspension immunofluorescence test. A total of 166 PAA determinations were performed in the 90 patients upon entry into the study. Fifty-six of the 90 patients (62%) with SLE were positive for PAA. There were no statistically significant correlations between the presence of PAA and the different disease manifestations except for thrombocytopenia (P = 0.0005). The presence of PAA in the same patient was significantly associated with current thrombocytopenia and disease activity. It was concluded that the prevalence of PAA in SLE patients is high. All SLE patients with thrombocytopenia had PAA, although some patients with PAA had a normal platelet count. The presence of PAA in SLE patients is not synonymous with thrombocytopenia but should instead be regarded as one of the multiple serological abnormalities which may develop in these patients. PMID- 7833253 TI - Plasma concentrations of fibrinogen and factor VII in adult life and their relation to intra-uterine growth. AB - To examine the relation between fetal development and plasma concentrations of fibrinogen and factor VII in adult life we followed up 202 men and women, now aged around 50 years, who had been measured in detail at birth. Plasma concentrations of fibrinogen were related to weight and abdominal circumference at birth. In men, after adjustment for cigarette smoking and current obesity, plasma concentrations of fibrinogen fell by 0.12 g/l (95% CI 0.05-0.19) for each pound increase in birthweight and by 0.10 g/l (95% CI 0.03-0.17) for each inch increase in abdominal circumference. In contrast, analysis of the data for women showed no statistically significant relation between plasma fibrinogen concentration and weight or abdominal circumference at birth. No relation was seen between concentrations of factor VII and measurements made at birth in either sex. These findings suggest that, in men, reduced growth of the liver in fetal life has a long-term influence on fibrinogen metabolism. PMID- 7833254 TI - Factor VIII:C increases after desmopressin in a subgroup of patients with autosomal recessive severe von Willebrand disease. AB - Patients with severe von Willebrand disease (vWD) usually show no increase of factor VIII/von Willebrand factor (VIII/vWF) after desmopressin (DDAVP) infusion and the bleeding time (BT) remains markedly prolonged. We have tested the biological responsiveness to DDAVP in six patients, belonging to six different families, with phenotypic evidence for severe vWD. Baseline VIII:C ranged from 12 to 32IU/dl, ristocetin cofactor activity (RiCof) was unmeasurable in all the patients, vWF antigen (vWF:Ag) ranged from 0.5 to 3.5 IU/dl, and in all patients the BT was longer than 30 min. No measurable vWF was present in patient's platelets, and plasma and platelet vWF multimers were virtually absent. An autosomal recessive pattern of inheritance was evident in all the propositi. After DDAVP infusion, there was no BT shortening. In four patients, VIII:C increased post-infusion and in three patients levels greater than 50 IU/dl were attained. RiCof reached a maximum of 11 IU/dl and vWF:Ag 9 IU/dl. In one of these four patients, DDAVP allowed a safe dental extraction, without resorting to blood products. In the remaining two patients no VIII/vWF changes were observed after DDAVP. In conclusion, a subgroup of patients with severe vWD shows an increase of VIII:C after DDAVP. A test infusion with this agent is advisable in patients with severe vWD before considering treatment with VIII/vWF concentrates. PMID- 7833255 TI - Rapid genotype analysis in type 2B von Willebrand's disease using a universal heteroduplex generator. AB - A new diagnostic technique based on DNA heteroduplex analysis has been used to identify specific point mutations in the von Willebrand's factor (vWF) gene of patients with von Willebrand's disease type 2B. Molecular analysis in these patients has shown previously that their mutations are clustered in a short region of sequence in exon 28 of the vWF gene. The principle of the method involves heteroduplex formation between amplified genomic sequence containing the defect and an exon 28 vWF gene universal heteroduplex generator (UHG). The UHG is a synthetic vWF gene exon 28 homologue which contains a number of sequence mismatches designed to generate allele specific heteroduplexes for each type 2B mutation. Individual mutant genotypes are identified by characteristic banding patterns following polyacrylamide minigel electrophoresis. The technique is rapid, simple, inexpensive, and is ideally suited for adoption by non-specialist haematology laboratories for screening purposes. PMID- 7833256 TI - Cleaved antithrombin (ATc): a new marker for thrombin generation and activation of the coagulation system. AB - A modified form of antithrombin (AT) cleaved at the active site by thrombin (ATc) has been shown to be generated in vivo, corresponding to 1-4% of the circulating AT. An enzyme immunoassay has been developed for measuring ATc following plasma treatment with ammonium sulphate and heat denaturation of native AT. ATc plasma levels were found to be significantly higher (P = 0.003) in patients developing venous thromboembolism when compared to patients without such events or healthy controls (age and sex matched). In addition, ATc levels correlated with thrombin generation markers: thrombin-AT complex (r2 = 0.66, P = 0.005) and prothrombin fragment 1 + 2 (r2 = 0.58, P = 0.018), but, in contrast to both these markers, elevated ATc levels were detected for at least 2 weeks after the thromboembolic event. In conclusion, ATc appears to be a new marker for thrombin generation and overall activation of the coagulation system, having the advantage of being detected in the circulation for a longer period than other thrombin generation markers. PMID- 7833257 TI - The use of anti-D to improve post-transfusion platelet response: a randomized trial. AB - Patients undergoing induction chemotherapy for acute leukaemia often become refractory to platelet transfusions. Increased clearance of transfused platelets due to alloimmune destruction has been identified as one of the primary mechanisms contributing to this refractory state. We performed a double-blind randomized trial to determine whether the administration of anti-D to Rh-positive individuals could prevent the refractory state and improve post-transfusion platelet response. Rh-positive patients with acute leukaemia undergoing induction chemotherapy and requiring platelet transfusions were allocated to weekly intravenous anti-D (20 micrograms/kg) or placebo. Platelets and red cell concentrates were administered according to standardized transfusion guidelines. Outcome measures included platelet transfusion utilization, red cell utilization, platelet recovery 18-24 h post-infusion, and the percentage of patients refractory to platelet transfusion. There were 43 patients studied: 21 received anti-D and 22 saline placebo. The mean number of platelet concentrates required per day of observation was 0.59 (SD 0.22) in the anti-D group and 0.61 (SD 0.22) in the placebo group, P = 0.86. No difference was detected between groups in terms of platelet recovery post-infusion, refractoriness to platelet transfusion or frequency of infection (P = 0.97). Red cell concentrate utilization was significantly increased in the anti-D group compared to the placebo group, 0.58 units per day versus 0.37 units per day respectively, P = 0.005. We conclude that the use of anti-D did not improve post-transfusion platelet response in Rh positive patients with acute leukaemia, but did result in an increased need for red cell transfusion. PMID- 7833258 TI - Genomic RFLP typing of human platelet alloantigens Zw(PlA), Ko, Bak and Br (HPA 1, 2, 3, 5). AB - The diallelic human platelet alloantigen systems 1-5 have been found to result from single base pair substitutions in the encoding genes of platelet membrane glycoproteins IIIa, Ib, IIb and Ia. This is the basis of DNA methods for determination of platelet alloantigens. In this study, 98 blood donors were typed in the HPA-1, 2, 3 systems and, for the first time, in the HPA-5 system. Serologically obtained data (MAIPA and platelet agglutination) were compared with results from analysis of restriction fragment length polymorphisms (RFLP). Discordances were found in the HPA-2 and 3 systems and can be ascribed to false typing results in both the serological and genomic methods. In the HPA-1, 2 and 5 systems, all samples were typed correctly with RFLP analysis. Serologically, two donors were falsely typed positive with anti-HPA-2b in platelet agglutination and one donor with anti-HPA-3a in MAIPA assay. In the HPA-3 system, another four donors were misinterpreted to be HPA-3a negative in RFLP analysis. Possible technical problems in PCR-RFLP-typing are discussed and another strategy of HPA-1 typing using the restriction enzyme Scr FI is evaluated. PMID- 7833260 TI - Plasma clearance of transferrin in control and hypotransferrinaemic mice: implications for regulation of transferrin turnover. AB - Kinetic studies were performed to determine the clearance of iodinated transferrin in hypotransferrinaemic mice, as compared to normal animals. Clearance of i.v. (and i.p.) administered radiolabelled protein in homozygous (hpx/hpx) mice was significantly faster than in heterozygous (hpx/+) and wild type control (+/+) groups. A comparable t1/2 value for transferrin clearance in hpx/hpx mice was derived from a study in which immunoassay was performed on serum samples obtained at various times post-injection with normal mouse serum, indicating that the clearance of 125I reflected true clearance of transferrin protein. The clearance rate in the hpx/+ group was significantly slower than in +/+ mice. Calculation of transferrin synthesis rates in these two groups suggested that transferrin levels do not regulate transferrin synthesis rates, but may affect degradation; this observation is consistent with the fact that transferrin levels in hpx/+ mice are > 50% of the values in +/+ mice, and indicates a partial compensation for reduced synthesis. The rapid clearance in hpx/hpx mice is an additional factor in determining the low levels of circulating transferrin in these synthesis-impaired mutants. PMID- 7833259 TI - Quantitative assessment of erythropoiesis in haemodialysis patients demonstrates gradual expansion of erythroblasts during constant treatment with recombinant human erythropoietin. AB - Recombinant human erythropoietin (rHuEpo) has been shown to be effective in correcting the anaemia of chronic renal failure. It has been reported that reticulocytes as well as erythroid progenitors increase within 1-2 weeks, with no further elevation beyond this time interval. However, the erythroblast pool is quantitatively the most important compartment of erythropoiesis, and the rate, extent and duration of the expansion of erythropoietic activity in response to rHuEpo is not known. Treatment with rHuEpo was given to 64 patients i.v. thrice weekly after haemodialysis. The effect of rHuEpo was obvious from the early elevation of reticulocyte counts, but much of this increase was due to a rapid output of shift reticulocytes which levelled off after a few weeks. Serum transferrin receptor (TfR), a quantitative measure of erythropoiesis, increased progressively over 6 weeks to reach a plateau phase at about twice baseline values. The Hct increased progressively and continued to rise steadily after the TfR plateau was reached. The speed and extent of the expansion of erythropoietic activity correlated with the later haematological response to rHuEpo. When rHuEpo was discontinued, erythropoietic activity returned progressively to baseline values, to rise again gradually when treatment was resumed. Part of the Hct increase was also due to haemoconcentration. The results indicate that changes in the various erythroid compartments vary considerably in intensity and speed, and that the erythroblast compartment in particular is slow to respond to modifications in the erythropoietin stimulus. PMID- 7833261 TI - Iron chelators induce apoptosis in proliferating cells. AB - The iron chelators 1,2-dimethyl-3-hydroxypyrid-4-one (L1) and desferrioxamine (DFO) were found to induce apoptosis of proliferating activated T-lymphocytes and of the promyelocytic cell line HL60, but not of resting peripheral blood lymphocytes or granulocytes. The induction of apoptosis was quantified by propidium iodide staining of apoptotic/dead cells and flow cytometry. In activated T-lymphocytes incubated with the chelators at equivalent iron-binding concentrations (300 microM L1 or 100 microM DFO) for 24 h, L1 caused a 54% increase in cell death and DFO a 57% increase. In HL60 cells L1 caused a 50% increase in cell death and DFO a 40% increase. DNA cytofluorometry of HL60 cells treated with either chelator showed an increase in the percentage of cells with hypodiploid DNA content. Presaturation of the chelators with ferric chloride abrogated these effects. L1 and DFO did not induce apoptosis in resting peripheral blood lymphocytes or granulocytes, even after 48 h of incubation. PMID- 7833262 TI - Human recombinant granulocyte-macrophage colony stimulating factor (hrGM-CSF) improves double hemibody irradiation (DHBI) tolerance in patients with stage III multiple myeloma: a pilot study. AB - Double hemibody irradiation (DHBI) is an alternative treatment of stage III multiple myeloma (MM) in patients aged over 55 years. Toxic side-effects such as myelosuppression are a severe limiting factor to its use. We performed DHBI associated with human recombinant granulocyte-macrophage colony stimulating factor (hrGM-CSF) as support therapy in 10 patients with stage III MM to improve the tolerance to this treatment. Ten patients received subcutaneously 5 micrograms/kg/d of hrGM-CSF during 2 weeks after each course of hemibody irradiation. All these patients had stage III MM: eight previously received chemotherapy, six of them were regarded as patients with refractory MM and two with relapse. Two patients received DHBI as first-line treatment. hrGM-CSF increased safety and tolerance of DHBI. GM-CSF support reduced the mean time between upper body irradiation (UBI) and lower body irradiation (LBI): 41 v 108 d in a cohort of 32 patients previously treated without growth factor support. Overall there was no lethal infection with hrGM-CSF or granulocytopenia (5.0 x 10(9)/l v 0.4 x 10(9)/l at day 15 in patients without growth factor). hrGM-CSF also reduced stomatitis grading and thrombocytopenia (90 x 10(9)/l v 45 x 10(9)/l at day 15). Furthermore, hrGM-CSF increased blood colony forming unit-granulocyte macrophage (CFU-GM) and was well tolerated in all but one patient. hrGM-CSF reduces toxic side-effects of DHBI, thus providing an effective treatment in patients with advanced and resistant MM. PMID- 7833263 TI - Cytomegalovirus-induced T-cell proliferation and the development of progressive multifocal leucoencephalopathy following bone marrow transplantation. AB - Progressive multifocal leucoencephalopathy (PML) is a rare disorder characterized by progressive demyelination within the brain. It is usually fatal and occurs when there are defects in cell-mediated immunity. We report a case of PML which developed following allogeneic bone marrow transplantation. It was preceded by the development of a persistent polyclonal expansion of large granular lymphocytes (LGLs) which appeared to rise as a consequence of cytomegalovirus infection. PMID- 7833264 TI - Plasma nitrate concentrations in neutropenic and non-neutropenic patients with suspected septicaemia. AB - Nitric oxide (NO) is an important physiological mediator of vascular tone and is thought to be involved in the pathogenesis of septic shock. Plasma nitrate is the stable end product of NO oxidation and in part reflects endogenous NO production. We measured plasma nitrate levels in 47 episodes of suspected septicaemia in 43 in-patients (16 male and 27 female, age 15-63 years). Nitrate concentrations were significantly higher (P < 0.01) compared to healthy controls. Further analysis revealed that significantly elevated levels occurred only in the septic patients who had normal or elevated numbers of neutrophils in the peripheral blood and were hypotensive on presentation. Failure of plasma nitrate concentrations to rise significantly in patients with neutropenia suggests that this cell type may be important in the activation of the arginine-NO system in severe sepsis in man. PMID- 7833265 TI - Family studies in an extremely large mild haemophilia A pedigree which includes 10% of Greek haemophiliacs. AB - We illustrate the usefulness of direct mutation detection for genetic counseling by showing its application to an extremely large mild haemophilia A pedigree (91 haemophiliacs) originating from the village of Aiani in Macedonia, northern Greece. The causative mutation has already been shown to be an A to T transversion in codon 280 of the FVIII gene which replaces Asn 280 (AAC) by Ile (ATC) and which creates a new Bam HI restriction site in exon 7. The latter permitted direct, rapid and reliable detection of the mutation in relevant family members. All major branches of the family were shown to share the mutation, and carrier status was diagnosed or excluded for 23 possible carriers. Other interesting characteristics of the Aiani haemophilic population are a slightly higher longevity and fecundity than that observed in the general population and a wide range of FVIII:C levels (5-25%) associated with the mutation. PMID- 7833266 TI - Characterization of blasts from a patient with eosinophilic blast crisis of chronic myelogenous leukaemia. AB - We investigated the biological characteristics of 'eosinophilic' leukaemic blasts from a patient with eosinophilic blast crisis of chronic myelogenous leukaemia (CML). Southern blot analysis of the bcr gene demonstrated the identical single rearranged band in both the leukaemic blasts and mature eosinophils. IL-3, IL-5 and GM-CSF significantly enhanced proliferation and differentiation of these leukaemic blasts, and only eosinophils were generated from in vitro cultures. Those eosinophils expressed the B3A2 chimaeric messenger RNA seen in the leukaemic blasts. These observations indicate that eosinophil progenitors may be involved in the development of eosinophilic blast crisis of CML and that IL-3, IL 5 and GM-CSF act on the leukaemic eosinophil progenitors. PMID- 7833267 TI - Myelodysplastic syndrome in two young brothers. AB - We report the youngest cases of myelodysplastic syndrome (MDS) in two brothers aged 7 and 2 years. The maternal grandfather and maternal grandmother had been exposed to radioactive fallout after the atomic bomb attack on Hiroshima in 1945. The elder brother demonstrated pancytopenia with < 1% blast cells in his peripheral blood and < 5% in his bone marrow at diagnosis. The younger brother was thrombocytopenic without increased blasts. The karyotype of bone marrow cells from the elder brother was 46,XY, -7, +der (7), t(1:7) (lqter-lq11::7q11-7pter), but the younger brother's karyotype was normal. Immature myeloid cells in the bone marrow from both brothers were morphologically abnormal. A diagnosis of refractory anaemia (RA) was made in both brothers. Atavism due to radioactive poisoning was suspected in the development of MDS in these two cases. PMID- 7833268 TI - Absence of hepatitis A virus transmission by high-purity solvent detergent treated coagulation factor concentrates in Scottish haemophiliacs. AB - Recent reports of hepatitis A virus (HAV) infection in haemophiliacs receiving high-purity solvent detergent (HP.SD) treated factor VIII concentrates have brought into question the efficacy of this virucidal method for inactivating HAV. To assess whether HAV may have been transmitted by HP.SD concentrates, we compared seroprevalence in haemophiliacs with different disease severity, sought evidence of seroconversion to HAV since introduction of HP.SD products, and directly examined concentrates for HAV RNA by PCR. Our data suggest that Scottish haemophiliacs are not being infected with HAV by HP.SD concentrates produced initially by CRTS Lille and presently by PFC Edinburgh and supplied by the Scottish National Blood Transfusion Service (SNBTS). PMID- 7833269 TI - Hypercalcaemia and increased serum interleukin-6 levels induced by all-trans retinoic acid in patients with multiple myeloma. AB - All-trans retinoic acid (ATRA) inhibits human myeloma cell growth in vitro, presumably through the down-regulation of interleukin 6 receptors (IL-6R). Based on these and other studies, we initiated a phase II clinical trial using ATRA in patients with advanced refractory multiple myeloma (MM). We report that three out of six treated patients developed severe hypercalcaemia following administration of ATRA, which was accompanied by a significant rise in serum IL-6 levels. Normal calcium levels were restored after the discontinuation of the drug and the administration of standard anti-hypercalcaemic care. We suspect that down regulation of IL-6R resulted in increased serum IL-6 levels, leading to advanced bone resorption and hypercalcaemia. We conclude that the use of ATRA in patients with advanced MM is not warranted. PMID- 7833270 TI - A novel CSF-1 binding factor in a patient in complete remission following cytotoxic therapy for lymphoma. AB - A novel colony stimulating factor-1 (CSF-1) binding factor present in the serum from a patient in remission from lymphoma is described. Radioimmunoassay (RIA) repeatedly failed to detect circulating levels of CSF-1 in the peripheral blood system of this patient. Molecular analysis showed a normal CSF-1 gene structure by Southern blot analysis and a 46,XX karyotype by cytogenetic analysis. CSF-1 mRNA expression in peripheral blood leucocytes was confirmed using reverse transcriptase polymerase chain reaction analysis. Morphological analysis of bone marrow cells was normal and peripheral blood progenitor cell colony assays showed a pattern of growth within the normal range in response to CSF-1 alone and in combination with other cytokines. Analysis of the patient's plasma and conditioned media prepared from peripheral blood mononuclear and granulocytic cell fractions for their ability to bind 125Iodine-labelled CSF-1 revealed the presence of a plasma CSF-1 binding factor. This binding factor was not present in the patient's urine, because CSF-1 was detected by RIA and production of the binding factor by the patients peripheral blood white cells could not be demonstrated in vitro. To our knowledge, this is the first reported case of a soluble CSF-1 binding factor. PMID- 7833271 TI - Detection of t(14;18) in British follicular lymphoma using cytogenetics, Southern blotting and the polymerase chain reaction. AB - Cytogenetics, Southern blotting and PCR were used to detect t(14;18) in 72 British patients with follicular lymphoma. The overall incidence of the translocation was 76%. Cytogenetics was the most successful technique, but 10-30% of translocations detected karyotypically were missed by molecular methods, presumably due to break-points falling outside the range of probes and primers used here. Reliance on molecular detection alone may considerably underestimate the incidence of t(14;18) and it is therefore essential to use the most comprehensive range of probes and primers available. PMID- 7833272 TI - Family history and inherited thrombophilia. PMID- 7833273 TI - Incidence of myelofibrosis following treatment of primary polycythaemia by venesection. PMID- 7833274 TI - Generation of human natural killer cells from pharmacologically purged bone marrow. AB - Human natural killer (NK) cells play an important role in first-line defence against primary and metastatic tumours. Their stimulation after autologous bone marrow transplantation (ABMT) may be useful to eradicate residual tumour cells. Human NK cells originate in bone marrow (BM) but little is known about their progenitors and lineage development. We studied NK cell ontogeny from BM progenitors obtained by 'purging' normal BM with 4-hydroperoxycyclophosphamide (4HC); this agent is known to destroy all but the most primitive BM progenitors. NK cells, defined by their phenotypic markers and cytolytic activity, could be generated from 4HC-treated BM cells during in vitro cultures over stromal BM feeder layers and in suspension cultures containing a mixture of soluble cytokines; Interleukine 2 appears to be essential for the full development of this population. A lag period exists before NK cells can be found in significant numbers in culture; this suggests that a delay in initiation of immunotherapy after ABMT ought to be considered, particularly when using purged marrow. PMID- 7833275 TI - Circulating megakaryocytes and their progenitors (BFU-MK and CFU-MK) in term and pre-term neonates. AB - Thrombocytopenia is a common occurrence in sick newborn babies. Despite this, platelet production in the newborn has rarely been assessed, principally because of the difficulties of obtaining bone marrow, especially on a serial basis. We have developed two miniaturized assay systems to study megakaryocyte (MK) progenitor cell differentiation, from BFU-MK and CFU-MK to mature MK, by culturing mononuclear cells purified from 0.5-1 ml of neonatal peripheral blood. BFU-MK and CFU-MK were assayed in agar, whilst total cultured MK precursors and mature MK were assessed in liquid culture. In both systems, MK lineage cells were identified morphologically and by an anti-IIb/IIIa antibody (CD61). Normal ranges for MK precursors in term neonates were established from cord blood studies of 40 healthy term babies and compared with cord blood studies in 16 non thrombocytopenic pre-term babies (gestational age range 24-36 weeks). Pre-term babies had greater numbers of all MK precursors than term babies: BFU-MK 414 +/- 61 v 151 +/- 18 colonies/ml (mean +/- SEM); CFU-MK 2444 +/- 337 v 869 +/- 64 colonies/ml; total MK precursors 213 +/- 36 v 54 +/- 6 x 10(3) cells/ml and mature MK 20 +/- 4 v 7 +/- 1 x 10(3) cells/ml. In addition, in newborn babies (n = 22), with no evidence of platelet consumption, circulating MK progenitor numbers at birth correlated with platelet numbers. These data indicate that in the newborn the measurement of circulating MK precursors provides a good indicator of megakaryocytopoiesis, and hence platelet production, and therefore is a useful and practical way of investigating neonatal thrombocytopenia. PMID- 7833276 TI - Increased levels of soluble CD8 and CD4 in patients with infectious mononucleosis. AB - Plasma levels of soluble CD8 (sCD8) and soluble CD4 (sCD4) in 44 patients with infectious mononucleosis (IM) were studied. A marked increase in sCD8 (22366 +/- 2702 U/ml; control: 219 +/- 10 U/ml; P < 0.0001) and significant increase in sCD4 (19.3 +/- 0.9; control: 8.1 +/- 0.2, P < 0.0001) strongly suggest activation of both CD8+ and CD4+ lymphocytes, which is important in restraining Epstein-Barr virus-infected B lymphocytes. Levels of sCD8 strongly correlated with the percentage and the absolute number of both CD8+ and CD8(+)-HLA-DR+ lymphocytes. In addition, we showed increased release of sCD8 from lymphocytes in vitro and increased ratio between plasma sCD8 and the number of CD8+ lymphocytes in blood, indicating that elevation of plasma sCD8 is due to expansion of CD8+ subset as well as increased sCD8 release from each CD8+ cell. Increased sCD4 release from CD4+ lymphocytes, the number of which is not increased in the blood during IM, was also seen. Patients with more severe fever had higher levels of sCD8 and sCD4. During convalescence sCD8 and sCD4 levels showed progressive decrease; however, even at 60-119 d after onset the levels of sCD8 and sCD4 remained higher than normal, suggesting prolonged lymphocyte activation. These results suggest that sCD8 and sCD4 are useful in monitoring immune activation during IM. PMID- 7833277 TI - Mutations in the p53 gene are not limited to classic 'hot spots' and are not predictive of p53 protein expression in high-grade non-Hodgkin's lymphoma. AB - We have investigated the relationship between the p53 genotype and phenotype in a series of 22 high-grade non-Hodgkin's lymphomas (NHLs) in which we sequenced the p53 gene open reading frame (exons 2-11). Immunostaining for p53 was already available for these cases. Mutations were found in 10/22 cases (45%) and 3/10 were in exons 4 or 10 outside the classic 'hot spot' regions (exons 5-8). Comparison with immunostaining indicated that, besides cases with the 'expected' patterns (in which gene mutation and protein detection were either both present or both absent) there were also cases in which p53 protein was detected in the absence of any mutation and those with a mutant gene in which the protein was undetectable. These data show that: (1) in high-grade NHLs mutations frequently occur outside the classic hot spot regions and (2) staining for p53 is not predictive of the status of the gene, i.e. whether or not a mutation is present. Therefore in order to document p53 involvement in lymphoid tumours it is necessary both to sequence at least the whole translated open reading frame of the gene and to show evidence of protein expression by immunostaining. PMID- 7833278 TI - p53 mutation in the myelodysplastic syndromes. AB - We have studied point mutations in exons 5-8 of the p53 gene in the myelodysplastic syndromes (MDS) by using polymerase chain reaction (PCR) single strand conformation polymorphism (SSCP) analysis and direct nucleotide sequencing. The subtypes examined were: refractory anaemia (RA), refractory anaemia with ring sideroblasts (RARS), chronic myelomonocytic leukaemia (CMML), refractory anaemia with excess blasts (RAEB), refractory anaemia with excess blasts in transformation (RAEBt), and acute myeloid leukaemia (AML) which had evolved from MDS. 26 cases of MDS were studied. 12 of these were sequentially sampled but none changed its p53 status during the time of the study (18 months). Four mutations (one nonsense and three missense) were identified. Each case with a mutation was of an advanced MDS subtype, suggesting that p53 mutation in these diseases is a terminal genetic event in the process of leukaemogenesis. The nonsense mutation inserted a premature stop codon in a case of AML which had evolved from RAEB; this mutation has been reported before in both chronic myeloid leukaemia (CML) and Burkitt's lymphoma. The three missense mutations have not previously been reported in haematological malignancies. PMID- 7833279 TI - Efficacy of erythropoietin in the myelodysplastic syndromes: a meta-analysis of 205 patients from 17 studies. AB - Erythropoietin (epo) can be used to improve the anaemia of patients with myelodysplastic syndromes (MDS), but the efficacy is relatively low and the treatment is expensive. So far, no individual clinical trial has been sufficiently extensive to provide a basis for a decision model for the use of epo in MDS. This meta-analysis included 17 original articles with a total of 205 patients with MDS who had been treated with epo. 33 patients (16%) showed a significant response to treatment. Patients with refractory anaemia with ring sideroblasts (RAS) showed a lower response rate than all other patients (7.5% v 21%, P = 0.010). The difference in response rate between patients with and without transfusion need was also highly significant (10% v 44%, P < 0.001). The serum level of epo was significantly lower in the responding patients, but this parameter on its own could not be used to identify patients with a favourable response. FAB group (RAS versus others), transfusion need and s-epo (>/< 200 U/l) were combined in a model to provide information about the probability of response in different groups of patients. Patients with no transfusion requirement and MDS other than RAS showed a response rate of > or = 50%, irrespective of their serum level of epo. In patients with RAS and s-epo > 200 U/l, no response was observed. In the remaining groups the response rates varied between 9% and 33%. This meta analysis shows that the efficacy of epo in MDS in general was low, but that groups of patients with an acceptable response rate could be identified. PMID- 7833280 TI - The effect of cyclosporine on haematological parameters in patients with paroxysmal nocturnal haemoglobinuria. AB - Four patients with paroxysmal nocturnal haemoglobinuria (PNH) were treated with cyclosporine. The treatment with cyclosporine was based on the hypothesis that immune-mediated bone-marrow damage is the common pathogenetic mechanism of aplasia and PNH, with lack of GPI-linked ligands for an immune attack (i.e. LFA 3, CD58) rendering PNH cells a growth advantage over other bone marrow cells. In the first patient, presenting with a mixed AA/PNH syndrome, a gradual recovery from aplasia was seen after prolonged treatment with cyclosporine. In a second patient, with a mixed AA/PNH syndrome, no haematological improvement was noted during cyclosporine administration, but this patient became transfusion independent with increasing neutrophil and platelet counts after a course of ATG in combination with androgen therapy. Both these patients showed an increment in the proportion of neutrophils with normal expression of GPI-linked proteins concurrently with the improvement of haematological characteristics. In the two other patients, presenting with typical PNH, cyclosporine treatment did not result in any change in haematological characteristics, nor in PNH parameters. No significant change in haemolytic parameters was seen in any of the patients. It is concluded that immunosuppressive therapy may be of benefit in patients with a mixed AA/PNH syndrome. This effect became apparent after prolonged treatment with cyclosporine in one patient, and after a subsequent course of ATG with concomitant androgen therapy in another. PMID- 7833281 TI - The response of cord blood megakaryocyte progenitors to IL-3, IL-6 and aplastic canine serum varies with gestational age. AB - Fetal cord blood (CB) is rich in haemopoietic stem cells and progenitors. We studied the clonogenic, proliferative and maturational responses of megakaryocyte (MK) progenitors in CB, from different gestational ages, to various cytokines: IL 3, IL-6, IL-3 + IL-6, and aplastic canine serum (PICS-J), and compared their responses to those of progenitors in adult peripheral blood (PB) or bone marrow (BM). We found that 34-week gestation CB produced some spontaneous colonies 28 +/ 4.7 CFU-MK in the absence of exogenous cytokines, and produced more CFU-MK and BFU-MK in response to IL-3, IL-6 and IL-3 + IL-6 than the other samples tested. Proliferation of CFU-MK was maximal at 34 weeks and decreased gradually toward term. When compared to adult BM or PB, the CB-derived CFU-MK had increased cellularity and contained significantly more cells undergoing fragmentation into platelet-like particles after stimulation with IL-3 or IL-6. Post-irradiation aplastic canine serum (PICS-J) was a highly potent stimulator of MK progenitors at all developmental stages. Our results indicate that CB MK progenitors are exquisitely sensitive to exogenous cytokines and that the magnitude of their proliferative and maturational responses to cytokines is related to developmental age. PMID- 7833282 TI - Transfusion-associated graft-versus-host disease in a patient treated with Cladribine (2-chlorodeoxyadenosine): demonstration of exogenous DNA in various tissue extracts by PCR analysis. AB - Transfusion-associated graft-versus-host disease can occur in both immunocompetent and immunocompromised hosts. Cladribine is a synthetic analogue of adenine used in the treatment of lymphoid malignancies, commonly associated with a decrease in T lymphocytes. Cladribine was given for a low-grade non Hodgkin's lymphoma with thrombocytopenia as the main side-effect. Six units of pooled non-irradiated platelets were transfused from six unrelated donors; 10 d later a clinical picture typical of graft-versus-host disease resulted. Polymerase chain reaction of the highly polymorphic DNA minisatellites and HLA-DR oligotyping were used to demonstrate the exogenous DNA. In the patient's blood and tissues, only the pattern of donor 5 was found. The patient (DRB1*0301/1101; DRB3*0101/02) and this donor (DRB1*0301/1104; DRB3*02) by chance shared a partial common haplotype. This complication highlights the sensitivity of DNA minisatellite analysis. It further raises the question of transfusion and of prophylactic irradiation of all blood products in immunosuppressed patients and those treated with cladribine. This case represents a previously unreported situation where an immunosuppressed patient was able to eliminate cells from five totally HLA-DR dissimilar donors but not from one heterozygous donor with strong HLA-DR similarity. PMID- 7833283 TI - Post-transplant lymphoproliferative disorders with genetic abnormalities commonly found in malignant tumours. AB - Post-transplant lymphoproliferative disorders (PTLD) are potentially fatal complications of organ transplants. Impairment of the immune system by immunosuppressive drugs is the assumed cause of PTLD. The Epstein-Barr virus (EBV) is detected in most of the PTLD studied and is considered as the main aetiological agent. The clinical course of PTLD patients remains unpredictable, some lymphoproliferations regress after discontinuation of the immunosuppressive treatment, others behave as true malignant tumours. The mechanism by which a viro induced lymphoproliferation evolves to an autonomous tumour remains unclear, and little is known about the genetic changes that occur during this process. We report two cases of fatal EBV-associated PTLD in heart transplant recipients. Both tumours were monoclonal and carried numerous chromosomal abnormalities, including a classic t(8;14)(q24;q32) with rearrangement of the MYC proto oncogene. One tumour demonstrated an amplification of the proto-oncogene N-MYC. The EBNA2 gene was not expressed in tumoral cells, suggesting that the chromosomal abnormalities contributed the function of EBNA2 in these cells. The morphology of the tumours indicated that the cases presented here were not Burkitt's lymphomas. These findings provide some clues with regard to the genetic changes which lead to a B-cell malignancy in some transplant patients. PMID- 7833284 TI - Early identification of Epstein-Barr virus-associated post-transplantation lymphoproliferative disease. AB - Epstein-Barr virus-associated lymphoproliferative disease (EBV-LPD) is a common, usually fatal, complication developing after transplantation of bone marrow from HLA-mismatched or HLA-matched unrelated donors. Prompted by recent reports of successful treatment of EBV-LPD, we investigated methods which could result in early identification of patients at high risk for this disorder, thus improving the likelihood of successful therapeutic interventions. Both the outgrowth of transformed B lymphocytes ex vivo (100% correlation) and the detection of EBV DNA by a PCR method (80% correlation) showed statistically significant association with the histopathological diagnosis of EBV-LPD. Because these abnormalities can be detected prior to the onset of clinical disease. It should now be possible to use a combination of the methods described here to identify patients at high risk of developing EBV-LPD, thus enabling early therapeutic intervention. PMID- 7833285 TI - spitz, a Drosophila homolog of transforming growth factor-alpha, is required in the founding photoreceptor cells of the compound eye facets. AB - Cell type specification and differentiation in the developing Drosophila compound eye begins in the morphogenetic furrow. In the furrow, cells are organized into evenly spaced preclusters and there is a synchronized arrest of the cells' mitotic cycle in G1. We report that recessive spitz loss-of-function mutations affect compound eye development. Spitz is homologous to the human transforming growth factor-alpha. In mosaic clones, spitz function is required in the first photoreceptor cells to differentiate for normal ommatidial development. spitz loss-of-function mutations are dominant suppressors of EgfrE gain-of-function mutations of the epidermal growth factor-receptor gene. These data suggest that the spitz product is a precluster promoting factor. spitz transcription increases abruptly in the morphogenetic furrow, the obverse of Egfr expression. We present a model for the expression of, and cellular requirement for, this growth factor homolog. PMID- 7833286 TI - The spitz gene is required for photoreceptor determination in the Drosophila eye where it interacts with the EGF receptor. AB - Little is known about the mechanisms by which photoreceptors other than R7 are determined during Drosophila eye development. By looking for mutations that modify the phenotype caused by ectopic expression of the rhomboid gene in the eye, I have discovered that the spitz gene is required for photoreceptor determination. Mosaic analysis suggests that spitz, which encodes a TGF alpha homologue, produces a diffusible signal during ommatidial development. Other members of the spitz group and the EGF receptor also interact with sev-rho, in a pattern that suggests a model in which rhomboid can act as a mediator of a ligand receptor interaction between spitz and Egfr in the developing eye. These data suggest that photoreceptors other than R7 use a Ras1 signalling pathway activated by the spitz/Egfr interaction, in a manner analogous to the Ras1 pathway activated by boss/sevenless in photoreceptor R7. PMID- 7833287 TI - Towards a genetic basis for kidney development. AB - Although it is not easy to investigate the regulatory basis of developmental processes in most mammalian tissues, the mouse kidney has several distinct advantages as a model system. Its development involves a wide variety of developmental processes that include induction, stem-cell regulation, a mesenchyme-to-epithelium transition, epithelial morphogenesis and pattern formation. Further, there are several genetic disorders associated with its development, much of nephrogenesis will take place in vitro and a significant start has been made in elucidating the regulatory molecules involved in its ontogeny. Here, we summarise current knowledge on how the various aspects of kidney development are controlled at the genetic level. For this, we have compiled a table showing when and where the more than forty regulatory genes thus far identified are expressed during nephrogenesis (this table being a subset of a database also containing information on structural and functional proteins expressed during nephrogenesis). The data on the regulatory genes demonstrate, in particular, the importance of the Wilms' tumour gene, WT1, in nephrogenesis, the growth-stimulating interaction between the hepatocyte growth factor and its receptor, c-met, and the differences between uninduced and induced metanephric mesenchyme. In an attempt to highlight those stable developmental pathways which underpin the formation of the kidney and to facilitate future work, we have identified possible checkpoints occurring during nephrogenesis (stages at which a positive signal is needed for development to continue). The data to hand suggest that such checkpoints occur when metanephric mesenchyme is established in the intermediate mesoderm, when induction takes place, when stem cells are activated and before mesenchyme aggregates to form nephrogenic condensations.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7833288 TI - The C-terminus of the homeodomain is required for functional specificity of the Drosophila rough gene. AB - In contrast to most Drosophila homeobox genes, which are required during embryogenesis, the rough gene is involved in photoreceptor cell specification in the compound eye. Taking advantage of the viability of null rough alleles and the small size of the rough gene, we have combined in vivo and in vitro mutagenesis to define important functional domains in the rough protein. All missense mutations found to disrupt rough function mapped to highly conserved amino acids in the homeodomain (HD), suggesting that the nature of few, if any, single amino acids outside the HD is critical for rough activity. The analysis of chimeric proteins, in which the whole HD or parts of it were swapped between the rough and Antennapedia (Antp) proteins, revealed that the C-terminus of the rough HD is important for rough activity in vivo. This C-terminal region was also found to be required for the recognition of rough binding sites in vitro. Our data suggest that amino acids located in the C-terminus of the homeodomain may play important roles in selective binding site recognition. PMID- 7833289 TI - Two tightly-linked Drosophila male accessory gland transcripts with the same developmental expression derive from independent transcription units. AB - Acp26Aa and Acp26Ab are Drosophila male accessory gland transcripts that are tightly linked and transcribed from the same DNA strand. Despite their being separated by 20 base pairs, the transcripts show identical responses to several developmental signals. These observations make it important to determine whether the 26A region contains two separable genes with the same developmental expression or a single developmentally regulated transcription unit whose product is processed to yield Acp26Aa and Acp26Ab. We show that Acp26Aa and Acp26Ab are separate mRNAs using a reverse transcription-polymerase chain reaction assay and reporter gene fusions. We also show that the regulatory elements for Acp26Ab lie within a fragment containing the intergenic region and transcribed sequences of Acp26Aa and Acp26Ab. PMID- 7833291 TI - Neuroprotective actions of excitatory amino acid receptor antagonists. PMID- 7833290 TI - An oncogenic form of human raf can specify terminal body pattern in Drosophila. AB - Terminal portions of the Drosophila body pattern are specified by an extracellular ligand generated at each end of the early syncytial embryo. This ligand triggers the localized transcription of two gap segmentation genes, tailles (tll) and huckebein (hkb) through a signal transduction cascade involving the receptor tyrosine kinase torso (tor) and homologues of ras, raf, and mek (map kinae kinase). In contrast to the ligand, these signal transducing components are expressed ubiquitously. Here, we show that a constitutively active form of human raf1 protein can trigger tll and hkb transcription in Drosophila embryos and specify elements of the terminal body pattern. This result indicates a strong functional conservation between Drosophila and mammalian raf proteins and argues that the localized activity of Drosophila raf (D-raf) normally carries spatial information specifying the end portions of the body. PMID- 7833292 TI - Pharmacologic management of shock-induced renal dysfunction. PMID- 7833293 TI - Autoantibodies against cytochromes P450: role in human diseases. PMID- 7833294 TI - Therapy of cancer metastasis by systemic activation of macrophages. PMID- 7833295 TI - 5-Hydroxytryptamine receptor subtypes: molecular and functional diversity. PMID- 7833296 TI - Pharmacologic therapy of obsessive compulsive disorder. AB - OCD is an anxiety disorder that was once viewed as rare and very difficult to treat. Although the first evidence that a serotonergic drug, clomipramine, might be effective in treating symptoms of OCD was published by Fernandez-Cordoba and Lopez-Ibor Alino in 1967, controlled trials demonstrating the efficacy of pharmacologic treatments in OCD did not appear until the 1980s. The availability of potentially effective treatments, combined with the awareness of prevalence rates for the disorder that are higher than previously believed, led to considerable interest in OCD. Numerous studies have been undertaken to investigate the biology of OCD. The observation that drugs that act by inhibiting serotonin uptake, such as clomipramine, fluvoxamine, sertraline, and fluoxetine, are effective in treating symptoms of OCD has resulted in intense interest in the relationship between serotonin and this disorder. Several lines of investigation support a serotonergic hypothesis for the pathophysiology and treatment of this disorder. Clomipramine, a tricyclic antidepressant that is a potent serotonin uptake inhibitor, was the first pharmacologic treatment for OCD to be studied in large multicenter trials. The successful outcome of these studies resulted in marketing approval by the United States Food and Drug Administration in 1989. Subsequently, similar multicenter trials have been undertaken with the selective serotonin uptake inhibitors fluvoxamine, sertraline, and fluoxetine. Results from these multicenter trials indicate that all these drugs are more effective than placebo in treating OCD. However, meta-analytic techniques applied to the data from controlled trials of these drugs suggest that the effect size for clomipramine is somewhat larger than that of the selective serotonin uptake inhibitors. A number of other drugs that affect serotonin through mechanisms other than uptake inhibition have been tried as treatments for OCD. Because of the small size of many of these studies, it is difficult to evaluate them in the context of the multicenter trials that studied hundreds of patients. Nevertheless, there may be a role for other serotonergic drugs in the treatment of OCD, particularly as adjunctive treatments used to enhance the effect of the serotonin uptake inhibitors. The data supporting the use of adjunctive treatment are limited and cannot be considered to demonstrate definitively the value of augmentation strategies with adjunctive treatment. Nevertheless, the serotonin uptake inhibitors, although effective in a large number of patients, do not appear to provide adequate symptom relief for some patients. Furthermore, among the patients who do respond to serotonin uptake inhibitors, complete remission in uncommon, which leaves a need for improvement of therapies.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7833297 TI - Mechanism of action of antibiotics in chronic pulmonary pseudomonas infection. PMID- 7833298 TI - Quinolinic acid in neurological disease: opportunities for novel drug discovery. PMID- 7833299 TI - Discrimination of geometric angle in the fronto-parallel plane. AB - This study determines the sensitivity of human observers to 2D fronto-parallel angles. Angle discrimination thresholds vary as a function of base angle and stimulus configuration orientation. However, these variations can all be understood from the well-known meridional anisotropy for orientation discrimination of the orientations that define the angle. Specifically, observers do not show any special sensitivity to angles of 90 degrees and 180 degrees (straightness). Instead it is claimed that observers measure geometric angle by comparing the visual orientations that define the angle, although it is shown that they are not fully efficient in this comparison operation. An explicit visual reference angle does not improve discrimination thresholds (that is, observers can perfectly well supply one from memory), nor do observers need an explicit visual reference orientation in an orientation discrimination task. PMID- 7833300 TI - Stimulus manipulations that reduce the square-wave illusion. AB - When observers view a triangle-wave luminance profile, they often report a square wave illusion with a depth component. Alternate bars appear to be in different depth planes and the surface appears corrugated; illuminated from either the right or the left. These perspectives alternate with continuous viewing. One explanation for this illusion stems from a local energy model of feature detection proposed by Morrone and Burr (Proc. Roy. Soc. Lond. B235, 221-245, 1988). This model assumes two phase-sensitive mechanisms that process lines and edges in the visual image. It is suggested that the square-wave illusion derives from rivalry between these two mechanisms. In experiment 1, the aim was to determine whether phase alternation of the triangle wave would lead to differences in the duration and number of perceptual reversals of the illusion. The results indicate a decline in illusion duration and frequency of reversal rate with increased alternation rate. With the addition of some assumptions about the temporal resolution of the line and edge detectors, the results support the proposed explanation. In Experiment 2, the effects of high spatial-frequency contrast increments and decrements were explored. Increments did not lead to significant increases in the duration of the square-wave illusion or reversal rate, but decrements resulted in a substantial reduction in the illusion duration and reversal rate. The results indicate that manipulations which alter the phase relationships of the triangle wave decrease the illusion, but manipulations which maintain them do not. PMID- 7833301 TI - A model for the early stages of motion processing based on spatial and temporal edge detection by X-cells. AB - A model for the early stages of motion processing in the visual cortex is presented. The 'building block' for this model is the 'rebound response', which is the neuronal response evoked when a sufficient inhibitory stimulus is turned off. This response enables detection of temporal changes when the stimulus involves spatial changes. The model suggests that adjacent subunits in primary cortical cells have different weight functions for rebound responses, and thus a synergistic type of response is evoked in the preferred direction, which is predicted for both light and dark stimuli. Predictions of the model for different stimuli and receptive field structures are discussed. It appears to be more economical than previous motion models. PMID- 7833302 TI - Rotating stripes provide a simultaneous display of sustained and transient channels. AB - A slowly rotating striped pattern provides an instantaneous display of the temporal response characteristics of the visual system. The effect seen is that of a central column of clearly resolved stripes. The distribution of contrast across the width of the band displays the temporal frequency response; the spatial phase of the resolved stripes shows the temporal phase response of the mechanisms involved; and the orientation of the band indicates the transport delay. This band consists of two distinct regions, which suggests that there are at least two independent channels involved. At low temporal frequencies, a linear channel capable of carrying colour information mediates the appearance; at higher temporal frequencies, a nonlinear, achromatic channel predominates. The chromatic response to the pattern suggests that there is some interaction between channels. Computer simulation of a sustained and a transient channel produces an output similar to that perceived, thereby reinforcing the notion that this simple device enables one to display simultaneously the properties of the sustained and transient channels. PMID- 7833303 TI - Local research ethics committees: hindrance or help? PMID- 7833304 TI - The effect of maternal posture on fetal cerebral oxygenation during labour. AB - OBJECTIVE: To measure the effect of changes in maternal posture on fetal cerebral oxygenation during normal labour. DESIGN: A prospective study comparing changes in the fetal cerebral concentrations of oxyhaemoglobin, deoxyhaemoglobin and cerebral blood volume, measured by near infrared spectroscopy, in women with effective epidural analgesia when moved from the left lateral to the supine position during labour. SETTING: A London teaching hospital obstetric unit. SUBJECTS: Fourteen women during uncomplicated labour at term. RESULTS: When compared with the left lateral position, the supine position was associated with a significant decrease in the mean concentration of fetal cerebral oxyhaemoglobin of 1.12 (SD 1.0, 95% CI 0.49 to 1.75) mumol. 100 g-1 (P < 0.01) without any significant change in the mean concentration of deoxyhaemoglobin and cerebral blood volume. These changes were associated with a significant decrease in the mean cerebral oxygen saturation of 8.3 (SD 8.8, 95% CI 1.5 to 15.1)% (P < 0.05, n = 9). CONCLUSION: Changes in maternal posture during labour, in women with effective epidural analgesia, are associated with a significant decrease in fetal cerebral oxygenation. PMID- 7833305 TI - The management of severe ovarian hyperstimulation syndrome. PMID- 7833306 TI - Interleukin-6, tumour necrosis factor and soluble tumour necrosis factor receptors in women with pre-eclampsia. AB - OBJECTIVES: Generalised maternal endothelial cell dysfunction appears to be an underlying problem in pre-eclampsia presumed to be caused, directly or indirectly, by one or more circulating factors derived from the placenta. Recently it has been suggested that tumour necrosis factor (TNF) may play an important role in pre-eclampsia and contribute to endothelial activation. This study was designed to investigate this proposal. DESIGN: Plasma TNF-alpha, IL-6 and both forms of soluble TNF receptors (p55 and p75 TNF-R) have been measured by ELISA in 31 pre-eclamptic patients and 31 pregnant controls matched for age, parity and gestational age. RESULTS: Levels of IL-6, TNF-alpha and soluble TNF-R (p55 and p75) were significantly higher in pre-eclamptic patients, compared with age and gestation matched controls with a wide variation in levels between pre eclamptic individuals. There was a correlation between levels of IL-6 and TNF or TNF-R and between TNF and TNF-R levels. However, when the pre-eclamptic patients were subdivided on the basis of the severity of their disease, the median values of plasma concentrations of IL-6, TNF-alpha and TNF-R were all higher in the group with lower platelet counts. CONCLUSIONS: These new findings are consistent with the concept that the maternal syndrome of pre-eclampsia is associated with endothelial dysfunction and provide evidence that at least part of this dysfunction could arise from excessive release of TNF-alpha into the circulation. PMID- 7833307 TI - Expectant management of twin pregnancy with single fetal death. AB - OBJECTIVE: To evaluate the course and outcome of expectantly managed twin pregnancies with single fetal death in the second half of gestation. DESIGN: Case controlled study of 29 consecutive pregnancies from 1973 to 1993, with sonographic evidence of a twin at 20 weeks gestation with antenatal demise later in pregnancy, matched for maternal parity with 58 twin pregnancies without fetal death and delivered in the same year as the index case. Outcome measures included the incidence of complications of pregnancy, gestational age and mode of delivery, placentation, and perinatal outcome. SETTING: University Hospital Rotterdam. RESULTS: The frequency and severity of pregnancy-induced hypertensive disorders was significantly higher in the study group than in controls. We found no differences between the study group and controls with regard to median gestational age at delivery (33 weeks versus 34 weeks) and median birthweight of liveborn infants (1880 g versus 2160 g). No consumptive coagulopathy was apparent in our 29 patients. The main cause of neonatal death was prematurity; multicystic encephalomalacia was not observed. CONCLUSIONS: Our results support expectant management in twin pregnancies complicated by single fetal death. PMID- 7833308 TI - Measurement of fetal liver, brain and placental volumes with echo-planar magnetic resonance imaging. AB - OBJECTIVE: To quantify accurately in utero fetal liver, brain and placental volumes using echo planar imaging, and to assess whether the technique has the potential to enhance intrauterine fetal assessment. DESIGN: Thirty-two singleton, complicated pregnancies were scanned using echo planar imaging, a form of magnetic resonance imaging. Pregnancies were subdivided on the basis of whether the fetus was found subsequently to have an individualised birthweight ratio above (n = 21) or below (n = 11) the 10th centile. Comparisons of the organ volumes of these two groups were made. RESULTS: The first quantitative in utero measurement of fetal liver volume showed a linear relation between liver volume and gestational age in fetuses where the individualised birthweight ratio was above the 10th centile (the normal growth group). Ten of the 11 liver volume measurements of fetuses subsequently found to have an individualised birthweight ratio below the 10th centile fell on or outside the 95% confidence limits established for the normal growth group. In contrast, no such differences were demonstrated when the brain and placental volumes were considered, with 10 of the 11 brain measurements and all of the 11 placental measurements falling within the 95% confidence limits of the normal growth group. CONCLUSIONS: A single measurement of fetal liver volume using echo planar imaging enabled accurate identification of fetuses subsequently found to have individualised birthweight ratios below the 10th centile. If these findings are repeated in larger, more representative studies, this suggests that the technique has the potential to contribute to intrauterine fetal assessment. PMID- 7833309 TI - The effects of maternal betamethasone administration on the fetus. AB - OBJECTIVE: To examine prospectively the effects of maternal betamethasone administration on fetal heart rate variation, body, breathing and eye movements and the rest-activity cycle. DESIGN: Thirty-one women on 38 occasions were at risk of premature delivery and received two doses of betamethasone 24 h apart. Gestational age ranged between 26 and 32 weeks. Fetal heart rate was monitored on each of five successive days (0-4) and fetal body, breathing and eye movements were recorded on days 0, 2 and 4. RESULTS: Compared with the control day before steroid administration (day 0), both long term and short term fetal heart rate variation were reduced on days 2 and 3 (P < 0.01). In one-third of the cases, fetal heart rate variation fell transiently below the lower normal range for gestational age. Body movements were reduced on day 2 by 50% (P < 0.01) due to prolonged periods of inactivity (P < 0.01). Breathing movements were largely absent on day 2 (P < 0.01), but the occurrence of eye movements remained unchanged after betamethasone administration. All values returned to baseline on day 4, indicating that no fetal deterioration had occurred during the course of the study period. Similar responses to betamethasone were observed in five fetuses when studied at re-presentation two weeks later. CONCLUSIONS: Maternal betamethasone administration causes a considerable but transient reduction in fetal body movements and activity periods, breathing and heart rate variation, without affecting fetal eye movements. Knowledge of this phenomenon is important when assessing the fetal condition. The effect may be due to a glucocorticoid receptor mediated process in the fetal brain. PMID- 7833310 TI - Vaginal ultrasound studies of bladder neck mobility. AB - OBJECTIVE: To introduce a simple, well-standardised vaginal ultrasound technique and to compare the position and mobility of the bladder neck in continent and stress incontinent women using this technique. DESIGN: A single-centre prospective case-control study. SETTING: Ikazia Hospital, Rotterdam, The Netherlands. SUBJECTS: One hundred and sixty women; sixty randomly chosen women referred to our outpatient department who volunteered for the study to develop a standardised technique, fifty stress-incontinent women and fifty controls who volunteered for the study for comparison using the standardised technique. MAIN OUTCOME MEASURES: Standardisation with regard to bladder volume, horizontal axis and Valsalva force. The position of the bladder neck at rest, during straining and during squeezing. RESULTS: The probe we use does not alter bladder neck mobility. A standardised bladder volume of 250 ml was used rather than maximum bladder capacity. A Foley catheter introduced into the bladder, with the balloon half-filled with soapy water and half with air gives an easily recognisable fluid level, which is parallel to the horizontal axis of the patient. A standardised Valsalva force of 30 cm H2O can exclude differences in bladder neck mobility due to spontaneous and uncontrolled abdominal force. Measurements by two independently working investigators showed good conformity. The position of the bladder neck in the stress incontinent women was significantly lower and significantly more posterior at rest, during straining and during squeezing. At the same time in stress incontinent women there was significantly more descent during straining and less elevation during squeezing. However, there was a considerable overlap between the two groups for all parameters. CONCLUSIONS: This standardised vaginal ultrasound technique is a feasible, acceptable and reproducible technique for the study of female bladder neck mobility. The position and mobility of the bladder neck is significantly different in stress incontinent women as compared to continent controls. The great overlap between the two groups still limits the clinical relevance. PMID- 7833311 TI - Mortality after gynaecologic operations in Finland, 1986-1991. AB - OBJECTIVE: To study the current in-hospital, 30-day and 42-day mortality after conventional gynaecologic procedures in Finland, with special reference to hysterectomy. DESIGN: Nationwide six-year annual study. SETTING: Data were from the Finnish Population Register Centre, the Finnish Cause-of-Death and Hospital Discharge Register, and the Register for Legal Abortions and Sterilisations. SUBJECTS: Gynaecologic operations (n = 299,257) performed between January 1986 and December 1991. MAIN OUTCOME MEASURES: The overall and age-adjusted mortality rates during the initial hospitalisation, as well as 30 and 42 days after the operations. Age-adjusted probability of dying within 42 days after hysterectomy compared with the overall probability of age-matched Finnish female control population. RESULTS: Overall mortality rates per 10,000 hysterectomies increased gradually from 6.0 during initial hospitalisation to 9.1 and 12.9 when calculated 30 and 42 days post-operatively. The overall 42-day mortality rates of radical hysterectomy, curettage and laparoscopy (other than sterilisation) exceeded the post-hysterectomy mortality rate, while the rates after caesarean section, legal abortion and laparoscopic sterilisation did not. No deaths occurred after laparoscopic sterilisation (n = 40,346). The patients who died after radical hysterectomy, curettage and for other laparoscopy than sterilisation were old, and the great majority of them died of cancer. CONCLUSIONS: The mortality rates after gynaecologic procedures in Finland are currently very low and have clearly decreased in recent decades. Patients may be reassured that conventional gynaecologic operations are safe. PMID- 7833312 TI - The incidence of cervical intraepithelial neoplasia among women with renal transplant in relation to cyclosporine. AB - OBJECTIVE: To evaluate the policy of an annual smear to screen renal transplant recipients for cervical intraepithelial neoplasia and invasive carcinoma and to determine the incidence of abnormal smears and CIN before and after the introduction of cyclosporine (1983). DESIGN: A retrospective study over the period 1971 to 1992. SUBJECTS: Postmenarchial women who received renal transplants and who were on immunosuppressive treatment for at least one month. MEAN OUTCOME MEASURES: Cytology and histology results. RESULTS: A total of 144 women who received renal transplantation were eligible for our study. Observation time varied from 1 to 227 months (median 59 months) with a mean for the group transplanted before 1983 (Group A) of 103 months, and for the group transplanted after 1983 (Group B) of 46 months. Of these women, 25 had an abnormal smear. Of these, 14 were confirmed by histology and repeated smears of the other 11 patients were negative. Within the 60 women in Group A with an abnormal smear, six had CIN I or CIN II, three had CIN III and one showed adenocarcinoma of the endometrium. Among the 84 women in Group B, four had CIN I or CIN II and none had CIN III. The overall incidence of abnormal cytology was 17.3%, with no invasive cervical carcinoma in this group. CONCLUSIONS: Our policy of screening is adequate. With the introduction of cyclosporine the incidence of abnormal cytology and histology has a tendency to decrease. However, the duration of risk is not comparable yet. PMID- 7833313 TI - Nausea and vomiting in pregnancy: a review of the problem with particular regard to psychological and social aspects. PMID- 7833314 TI - The use of a tissue expander as a vaginal stent in vaginal reconstruction. PMID- 7833315 TI - Autologous blood transfusion in patients undergoing radical hysterectomy. PMID- 7833316 TI - c-erbB-2 oncogene expression in Stage I epithelial ovarian cancer. PMID- 7833317 TI - Intraventricular haemorrhage and maternal brain death associated with antepartum cocaine abuse. PMID- 7833318 TI - Postpartum haemolytic uraemic syndrome treated with plasma infusion. PMID- 7833319 TI - Prenatal diagnosis of microbial invasion of the amniotic cavity with Campylobacter coli in preterm labour. PMID- 7833320 TI - Conserving the cervix at hysterectomy. PMID- 7833321 TI - Conserving the cervix at hysterectomy. PMID- 7833322 TI - Conserving the cervix at hysterectomy. PMID- 7833323 TI - Conserving the cervix at hysterectomy. PMID- 7833324 TI - Phenytoin prophylaxis in severe pre-eclampsia and eclampsia. PMID- 7833325 TI - Fetal immunological and haematological changes in intrauterine infection. PMID- 7833326 TI - Induction of labour confers benefits in prolonged pregnancy. PMID- 7833327 TI - Surgery for genuine stress incontinence. PMID- 7833328 TI - Birth under water: sink or swim. PMID- 7833330 TI - Hydralazine boluses for the treatment of severe hypertension in pre-eclampsia. PMID- 7833329 TI - The role of the gynaecologist in the diagnosis and management of child sexual abuse. PMID- 7833331 TI - Expression of transforming growth factor-alpha in the normal cervix and in the benign and malignant lesions of the uterine cervix. PMID- 7833332 TI - Late fetal heart decelerations and changes in cerebral oxygenation during the first stage of labour. AB - OBJECTIVE: To test the hypothesis that late fetal heart rate decelerations are associated with a decrease in cerebral oxygenation. DESIGN: Changes in fetal cerebral concentrations of oxyhaemoglobin and deoxyhaemoglobin were measured by near infrared spectroscopy, before, during and after contractions with late fetal heart rate decelerations and compared with changes during contractions with no alteration of heart rate. SETTING: Teaching hospital obstetric unit. SUBJECTS: Ten women in labour at term. RESULTS: The changes in fetal cerebral oxyhaemoglobin and deoxyhaemoglobin concentrations that occurred during contractions were quantitatively similar, irrespective of the fetal heart rate changes. However, late fetal heart rate decelerations were associated with a significantly greater fall, after the uterine contraction, in the mean concentration of fetal cerebral oxyhaemoglobin of 0.52 mumol/100 g (SD 0.25) (P < 0.001) and a significantly greater rise in the mean concentration of deoxyhaemoglobin of 0.36 mumol/100 g (SD 0.35) (P < 0.01). CONCLUSION: Late fetal heart rate decelerations are associated with a significant decrease in cerebral oxygenation. PMID- 7833333 TI - Anterior cranial base morphology in mice with midfacial retrusion. AB - The role of the anterior cranial base in the morphogenesis of class III malocclusions remains uncertain. This study was conducted to determine whether morphologic deficiencies occur in the anterior cranial base in the Brachyrrhine (Br) mouse mutant showing severe midfacial retrusion, which is characteristic of a class III malocclusion. Crania from three groups of C3H/Hej, 3H1 Br/+, and 3H1+/+ mice, each consisting of 15 animals, were collected at 1, 3, and 5 days of age (total = 135). The anterior cranial base from each specimen was subjected to computerized reconstruction and ten landmarks were digitized from each model. The landmark configurations were compared using Procrustes analysis. Significant differences between models were determined at each age. In order to localize differences between forms, average landmark configurations derived from Procrustes analysis were subjected to finite-element analysis. Size-change values for the 3H1 Br/+ animals showed magnitudes that increased in an anteroposterior direction when compared to the 3H1 +/+ and C3H/Hej animals at all ages. The largest values were located posteriorly along the ossifying front of the presphenoid. In five of six comparisons, the size-change values separated into two distinct clusters. The posterior region of the anterior cranial base was divisible into two subclusters, one located superiorly and the other inferiorly. These data suggest that midfacial retrusion in the Br mouse may be caused, in part, by growth deficiencies in the posterior region of the anterior cranial base, particularly the presphenoidal and sphenoethmoidal regions. PMID- 7833334 TI - Effects of visible and invisible orofacial defects on self-perception and adjustment across developmental eras and gender. AB - Self-ratings of satisfaction with appearance and accomplishment of psychosocial tasks were examined by age and gender among school aged children with visible defects (cleft lip and/or palate, n = 272), or invisible defects (cleft palate only, n = 159), and dental patients (n = 128) without clefts. Using weighted least squares ANOVA and logistic regressions, the results revealed that subjects with visible defects expressed greater dissatisfaction with their appearance than those subjects with invisible defects (p < .001). Subjects with invisible defects consistently expressed lower problem solving ability than subjects with visible defects (p < .001) and dental patients with no defects (p < .05). Both groups with clefts expressed less social independence (p < .001); and subjects with clefts reported having more friends than other children (p < .01). Implications for clinicians and further research are discussed. PMID- 7833335 TI - Treatment effects on facial development in patients with unilateral cleft lip and palate. AB - Retrospective studies into the effects of some aspects of treatment on facial development were based on x-ray films obtained in 58 men with unilateral cleft lip and palate operated on by palatal pushback. Because of mandibular retroposition, individuals subjected to systematic orthodontic treatment had better sagittal jaw relations and occlusion of incisors than insufficiently treated patients. The retroposition was attained with orthodontic proclination of upper incisors leading to a positive overjet and retraining the anterior development of the mandible. In patients with complete clefts operated on at about 6 years of age, sagittal jaw relations were more favorable than in those who had surgical repair at 4 years of age. The superior results in the group operated at a later age were due, in part, to the slighter retrusion of the maxilla. These differences were not apparent in incomplete clefts nor in patients with isolated cleft palate reported earlier. On the basis of these observations, a differentiated approach was proposed for determining the most convenient age for palatoplasty, according to individual types of clefts and their extent. The findings provided evidence of the essential role of orthodontic therapy for the configuration of the lower face in clefts. PMID- 7833336 TI - Phonetic features by babies with unilateral cleft lip and palate. AB - Twenty-three babies with nonsyndromic unilateral cleft lip and palate were audiotaped at regular intervals from 5 to 35 months of age. Narrow phonetic transcription of their comfort-state vocalizations and word approximations was accomplished to describe phonetic development over time and according to the nonrandomized age of palatoplasty. The babies that had earlier palatal repair produced significantly higher percentages of oral stops after 12 months of age than babies with similar clefts that had later palatal repair. No significant differences are evident, however, according to age of palatoplasty, for mean frequency use of oral fricatives up to 3 years of age. For all 23 babies, regardless of the age of palatoplasty intervention, time is an even stronger variable than age of palatoplasty for development of palatal, alveolar and velar place features, oral stops, and oral fricatives. PMID- 7833337 TI - Comparison of velopharyngeal growth patterns between cleft lip and/or palate patients requiring or not requiring pharyngeal flap surgery. AB - This investigation compares the patterns of velopharyngeal growth in cleft lip and/or palate patients. Those who had velopharyngeal competence and acceptable speech are compared with those who presented with velopharyngeal incompetence requiring pharyngeal flap surgery or prosthesis later. Lateral cephalograms of 30 cleft palate only (CPO), 35 unilateral cleft lip and palate (UCLP), and 20 bilateral cleft lip and palate (BCLP) children of the Lancaster Cleft Palate Clinic were studied. These records were taken at 6 month intervals during the first 2 postnatal years and annually thereafter up to 6 years of age. Soft tissue landmark points in the velopharyngeal region were digitized. Length and thickness of the soft palate and height and depth of the nasopharynx were measured. Evaluation of the growth curves of these four cephalometric variables indicated only two significant differences between children who later required pharyngeal flap surgery and those who did not. These differences were found in the growth in length of the soft palate of the CPO group and in the growth in depth of the nasopharynx of the BCLP group. Based on the present cephalometric data, it is impossible to predict at an early age those cleft lip and/or palate patients who will later require pharyngeal flaps. PMID- 7833338 TI - Facial left-right dominance in cleft lip and palate: three-dimension evaluation. AB - Studies on facial left-right dominance in individuals without craniofacial anomalies have demonstrated controversial results. This is probably due to the frequent use of two-dimensional methods, yet left-right dominance consists of transverse, vertical, and sagittal components. The aim of the present study was to describe three-dimensionally facial left-right dominance in individuals with an operated complete unilateral cleft lip and palate on the left side (LUCLP), on the right side (RUCLP), and in individuals without craniofacial anomalies (controls). Using stereophotogrammetry, three-dimensional coordinates for 16 bilateral and 10 midsagittal facial landmarks were determined for the LUCLP group (N = 32), the RUCLP group (N = 17), and the control group (N = 80). Left-right dominance was measured in three directions. Individuals without craniofacial anomalies showed a facial left sided dominance in the transverse direction, a facial right sided dominance in the sagittal direction, and no particular dominated side in the vertical direction. Individuals with a unilateral cleft lip and palate demonstrated a facial dominance of the nonaffected side in the vertical direction as well as in the sagittal direction, with no particular side dominant in the transverse direction. Generally, there was more variation in left right dominance within the face in the vertical and sagittal directions. PMID- 7833339 TI - Medieval example of cleft lip and palate from St. Gregory's Priory, Canterbury. AB - An archaeologically retrieved skeleton from medieval Canterbury possibly of the late eleventh or twelfth century, displays clear evidence of cleft lip and palate. A case of cleft palate dating from the seventh century, is known from an Anglo-Saxon cemetery at Burwell. This is the first evidence for both cleft lip and palate in British archaeological material. The individual had survived into adulthood. Apart from an odontome, there was no osseous evidence of any other abnormalities. Artistic evidence of cleft lip dates to the fourth century B.C. and surgical intervention (A.D. 390) is known from China. PMID- 7833340 TI - Experimental and clinical experience with distraction osteogenesis. AB - G.A. Ilizarov's clinical insights and experimental biology have developed into what is known today as distraction osteogenesis. Initially used for the treatment of fractures and nonunions, his methods have proven successful for limb lengthening and bone transportation. A brief history of the development of distraction osteogenesis, definition of terms, methods, and monitoring techniques are described. The primary mechanism, intramembranous ossification, is direct bone formation in uniform gradients of mineralization from a central fibrous interzone. New bone is produced from the local host surfaces and quickly remodels to the equivalent macro and microstructure. Blood supply at the focus of distraction, dependency on a latency period, different rates, and rhythms of distraction are all tested and discussed. Data from experimental tibial lengthening in more than 125 animals (dogs, rabbits, and rats) show that distraction osteogenesis provides unlimited new bone formation that remodels at daily rates ranging from 200 to 400 microns. In over 100 clinical cases, patients ranging in age from 18 months to 49 years have regenerated bone at an average rate of 213 microns in adults and 385 microns in children. Approximately 10% of these cases required supplemental bone grafts. The article proposes that distraction osteogenesis might be successfully applied in craniofacial surgery. PMID- 7833341 TI - Oblique facial cleft, cleft palate, and supernumerary teeth secondary to amniotic bands. AB - A case of oblique facial cleft with supernumerary deciduous molars, probably caused by amniotic bands is reported. Besides facial cleft, and cleft palate and lip, there are sulci on the left side of the face and on the left posterior alveolar ridge. The sulci may be impressions of amniotic bands at a late gestational age and supernumerary teeth may also be related to these amniotic bands. PMID- 7833342 TI - Phenotypic variation in acrocephalosyndactyly syndromes: unusual findings in patient with features of Apert and Saethre-Chotzen syndromes. AB - The acrocephalosyndactyly syndromes have presented diagnostic challenges because of overlap in their clinical manifestations. We present a patient with features most suggestive of Apert syndrome, but with a pattern of syndactyly not previously described. In contrast to the complex syndactyly reported as a universal feature of this syndrome, this patient shows close to total simple syndactyly of the index through ring fingers of each hand. Differential diagnoses are discussed. Because the features are reminiscent of Apert syndrome, we suggest that a new classification of hand morphology should be added to include the pattern described here. PMID- 7833343 TI - Presurgical orthopedic premaxillary alignment in cleft lip and palate reconstruction. AB - Premaxillary malposition is a difficult problem in cleft lip and palate repair. Orthopedic palatal devices are excellent in positioning the premaxilla, though they are somewhat cumbersome and require complex techniques in adjusting precisely the position of the premaxilla prior to repair. A new technique has been developed for premaxillary repositioning in conjunction with palatal shelf expansion and obturation. The procedure implements microplate fixation anterior to the premaxillary segment and linked to a palatal splint by adjustable elastics. The microplate is inserted through a nasal floor incision and secured by a tight submucosal tunnel through minimal dissection between the prolabium and premaxilla. The last hole of each microplate protrudes through the mucosa and is attached to a pin-retained palatal splint by an elastic chain. Differential tension is applied to the chains to allow gradual repositioning of the protruding maxilla while the splint expands and maintains positioning of the lateral palatal segments. These elastic retractors can be adjusted by staff in the outpatient office. During the past 2 years, this technique has been used successfully in 21 consecutive patients with unilateral or bilateral cleft lip and palate. Its technical ease and design allows simple adjustments to control premaxillary positioning and growth before definitive surgical closure. PMID- 7833345 TI - Regulation of phospholipase D activity by neutral lipids in egg-yolk phosphatidylcholine small unilamellar vesicles and by calcium ion in aqueous medium. AB - Hydrolysis activity of phospholipase D from Streptomyces chromofuscus (PLD) was studied in small unilamellar vesicles (SUV) of egg yolk phosphatidylcholine (PC). The enzyme was associated with PC-SUV in a Ca(2+)-dependent manner. Both apparent maximum velocity, Vmax(app), and reciprocal of apparent Michaelis constant, i.e., apparent binding constant, 1/Km(app), increased with Ca2+ concentration, and the maximum values of these kinetic parameters were obtained at about 20 microM Ca2+. Incorporation of 1,2-diacylglycerol (DAG), cholesterol (Chol) or alpha-tocopherol (Toc) into PC-SUV induced shift of the antisymmetric PO2- stretching band of PC to lower frequency. The neutral lipids in SUV brought about increase of the Vmax(app) value (Yamamoto et al. (1993) Biochim. Biophys. Acta 1145, 293-297). On the basis of these findings we discussed the regulation of PLD activity in terms of the Ca(2+)-dependent complex formation of PLD with SUV, and the enhancement of susceptibility of the P-O bond in PC molecule by neutral lipids. PMID- 7833344 TI - Photoaffinity labelling of the ATP-binding sites of two Ca2+,Mg-ATPase isoforms in pancreatic endoplasmic reticulum. AB - Pancreatic rough ER ATP-binding proteins, including two isoforms of SERCA-2b Ca2+,Mg-ATPase, were identified using specific photoaffinity labelling with 8 azido-ATP. 8-Azido-ATP irreversibly inhibited Ca2+,Mg-ATPase activity only after UV irradiation and the inhibition was prevented by inclusion of 5 mM ATP in the labelling reaction. Rough ER proteins of apparent molecular masses 141, 111, 100, 84, 69, 55 and 47 kDa were detected following photoaffinity-labelling with 8 azido-[alpha-32P]ATP. The two bands at 111 kDa and 100 kDa corresponded in molecular mass to the two SERCA-2b Ca2+,Mg-ATPase isoforms previously demonstrated immunologically [1]. Immunoprecipitation of rough ER proteins by a SERCA-2b-specific antibody showed that the two ATPase bands were photoaffinity labelled. Photoaffinity labelling of the 111 and 100 kDa proteins was: (a) abolished when Ca2+,Mg-ATPase activity was inactivated by EDTA-treatment of rough ER membranes; (b) inhibited by the Ca2+,Mg-ATPase inhibitor vanadate; (c) not affected by thapsigargin. The data demonstrate that pancreatic rough ER contains two isoforms of the SERCA-2b Ca2+,Mg-ATPase whose ATP-binding properties are susceptible to inhibition by vanadate but not thapsigargin. PMID- 7833346 TI - P-glycoprotein of blood brain barrier: cross-reactivity of Mab C219 with a 190 kDa protein in bovine and rat isolated brain capillaries. AB - P-glycoprotein (P-gp), an active efflux pump of antitumor drugs, is strongly expressed in endothelial cells of the blood brain barrier (BBB). Two proteins (155 and 190 kDa) were detected by Western blot analysis of beef and rat capillaries with the monoclonal antibody (MAb) C219. In order to characterize the nature of these proteins, their profile of solubilization by different detergents was established and compared with that of P-gp from the CHRC5 tumoral cell line. The 155 kDa protein (p155) of capillaries and the P-gp of CHRC5 cells were well solubilized by deoxycholate and Elugent, whereas the 190 kDa kDa protein (p190) was only solubilized by sodium dodecylsulfate (SDS). Both proteins have different patterns of extraction by Triton X-114, p155 partitioning as a membrane protein, while p190 was insoluble. Deglycosylation of capillary proteins resulted in a 27 28 kDa decrease in the apparent molecular weight of p155, similar to that observed for the P-gp of CHRC5 cells, but a decrease of only 7-8 for p190. Only p155 was immunoprecipitated by MAb C219. These results suggest that only p155 is the P-gp in BBB and that MAb C219 cross-reacts with a 190 kDa MDR-unrelated glycosylated protein. Consequently, the use of this antibody, which is frequently used to detect P-gp in tumors, could be a pitfall of immunohistochemistry screening for cancer tissues and lead to false positive in the diagnosis of MDR. PMID- 7833347 TI - An unexpected effect of ATP on the ratio between activity and phosphoenzyme level of Na+/K(+)-ATPase in steady state. AB - According to the Albers-Post model the hydrolysis of ATP catalyzed by the Na+/K(+)-ATPase requires the sequential formation of at least two conformers of a phosphoenzyme (E1P and E2P), followed by the K(+)-stimulated hydrolysis of E2P. In this paper we show that this model is a particular case of a more general class of models in all of which the ratio between ATPase activity (v) and total phosphoenzyme level (EP) in steady state is determined solely by the rate constants of interconversion between phosphoconformers and of dephosphorylation. Since these are thought to be unaffected by ATP, the substrate curves for ATPase activity and EP should be identical in shape so that the ratio v/EP ought to be independent of the concentration of ATP. We tested this prediction by parallel measurements of v and EP as a function of [ATP] in the absence or presence of non limiting concentrations of K+, Rb+ or NH+4. In the absence of K+ or its congeners, both curves followed Michaelis-Menten kinetics, with almost identical Km values (0.16 microM) so that v/EP remained independent of [ATP]. In the presence of either K+, Rb+ or NH+4, v and EP increased with [ATP] along the sum of two Michaelis-Menten equations. The biphasic response of v is well known but, to the best of our knowledge, our results are the first demonstration that the response of EP to [ATP] is also biphasic. Under these conditions, the ratio v/EP increased with [ATP] from 19.8 to 40.1 s-1 along a hyperbola that was half maximal at 9.5 microM. To preserve the validity of the current model it seems necessary to assume that ATP acts on the E1P <--> E2P transition and/or on the rate of hydrolysis of E2P. The latter possibility was ruled out. We also found that to fit the Albers-Post model to our data, the rate constant for K+ deocclussion from E2 has to be about 10-times higher than that reported from measurements of partial reactions. The results indicate that the Albers-Post model quantitatively predicts the experimental behavior of the Na(+)-ATPase activity but is unable to do this for the Na+/K(+)-ATPase activity, unless additional and yet unproved hypothesis are included. PMID- 7833348 TI - Regulation by phorbol esters of the glycine transporter (GLYT1) in glioblastoma cells. AB - The high-affinity glycine transporter in neurons and glial cells is the primary means of inactivating synaptic glycine. The effects of 12-O-tetradecanoylphorbol ester (TPA), a potent activator of protein kinase C (PKC), on the high-affinity Na(+)-dependent glycine transport were investigated in C6 cells, a cell line of glial origin. Incubation of C6 cells with TPA led to concentration- and time dependent decrease in the glycine transport that could be completely suppressed by the addition of the PKC inhibitor staurosporine. The TPA effect could be mimicked by oleoylacetylglycerol and exogenous phospholipase C. Northern and Western blot analysis indicate that C6 cells express the GLYT1 glycine transporter. Incubation of COS cells transiently transfected with a full-length clone of the GLYT1 transporter in the presence of TPA, produces a decrease in glycine uptake. PMID- 7833349 TI - Wheat germ agglutinin stabilization of erythrocyte shape: role of bilayer balance and the membrane skeleton. AB - The effects of wheat germ agglutinin (WGA), Limulus lectin, and concanavalin A on cell shape changes were examined in human erythrocytes. These agents inhibited echinocytosis in cells having elevated cytosolic Ca2+ or incorporated foreign phosphatidylcholine, but had no effect on cell stomatocytosis in response to incorporated phosphatidylserine. The role of the membrane skeleton in this selective membrane fixation was examined. WGA inhibited echinocytosis in cells previously depleted of polyphosphoinositides to reduce membrane skeleton binding to transmembrane proteins, treated with phorbol ester to enhance protein 4.1 phosphorylation, heat-treated to denature spectrin, alkylated with p chloromercuribenzoate to dissociate glycophorin from the membrane skeleton, or subjected to elevated cell 2,3-diphosphoglycerate to alter organization of the spectrin-actin-protein 4.1 complex. Limulus lectin and increased concentrations of WGA also stabilized discoid shape in pronase-digested cells containing no detectable intact glycophorin. In contrast, cell digestion with sialidase abolished the shape-stabilizing effect of WGA. The results suggest that the membrane skeleton is not involved in WGA shape stabilization. Rather, they suggest that glycoproteins and glycolipids interact with the lectin to stabilize cell surface molecular associations, forming a superficial calyx that inhibits outward, but not inward, membrane bending. PMID- 7833350 TI - Characteristics of specific 125I-omega-conotoxin GVIA binding and 125I-omega conotoxin GVIA labeling using bifunctional crosslinkers in crude membranes from chick whole brain. AB - Characteristics of specific 125I-omega-conotoxin GVIA (125I-omega-CgTX) binding and 125I-omega-CgTX labeling using bifunctional crosslinkers were systematically investigated in crude membranes from chick whole brain. Aminoglycosides and dynorphine A (1-13) inhibited the specific binding of 125I-omega-CgTX, but not that of the L-type calcium ion channel antagonist [3H](+)PN200-110. It seems likely that the inhibitory effect of dynorphine A (1-13) does not involve kappa opiate receptors, based on results with the opiate receptor antagonist naloxone and the kappa-opiate receptor agonist U50488H. Spider venom, Cd2+ and La3+ inhibited the specific binding of 125I-omega-CgTX, as well as that of [3H](+)PN200-110. Various L-type Ca2+ channel antagonists did not affect the specific binding of 125I-omega-CgTX. 125I-omega-CgTX specifically labeled 135 kDa and 215 kDa bands in crude membranes under reduced and non-reduced conditions, respectively. The crosslinker disuccinimidyl suberate (DSS) yielded better 125I omega-CgTX labeling than the other two crosslinkers tested. We investigated the effect of various Ca2+ channel antagonists on 125I-omega-CgTX labeling with DSS in detail, and found that there is a strong correlation between the effects of Ca2+ channel antagonists on 125I-omega-CgTX labeling of the 135 kDa band and specific 125I-omega-CgTX binding. These results suggest that aminoglycosides and dynorphine A (1-13) are specific inhibitors of specific 125I-omega-CgTX binding, and that labeling of the 135 kDa band with 125I-omega-CgTX using DSS involves the specific binding sites of 125I-omega-CgTX, perhaps including one of the neuronal N-type Ca2+ channel subunits in the crude membranes. PMID- 7833351 TI - Real-time X-ray diffraction study at different scan rates of phase transitions for dipalmitoylphosphatidylcholine in KSCN. AB - Multibilayer arrays of dipalmitoylphosphatidylcholine (DPPC) in 1 M KSCN were characterized using real-time X-ray diffraction and differential scanning calorimetry. A phase transition sequence was observed as a function of increasing temperature which involved changes from the interdigitated subgel (Lc(inter)) to interdigitated gel (L beta(inter)) to disordered (L alpha) bilayer states. The phase transition mechanisms were unambiguously determined by comparison of results from fast and slow scans. The Lc(inter)-->L beta(inter) phase transition was shown to involve a continuous change in acyl chain spacing between the rectangular subgel acyl chain unit cell into an hexagonal gel acyl chain unit cell. The mechanism is similar to that for subgel to gel state transitions involving non-interdigitated DPPC bilayers. PMID- 7833352 TI - Use of thermal analysis to distinguish magnesium and calcium stimulated ATPase activity in isolated transverse tubules from skeletal muscle. AB - The presence of calcium stimulated adenosine triphosphatase (Ca2+,Mg(2+)-ATPase) activity in isolated transverse tubule (t-tubule) membranes is distinguished from magnesium adenosine triphosphatase (Mg(2+)-ATPase) activity on the basis of differing thermal stabilities. The Mg(2+)-ATPase is the major protein component of the t-tubule membrane, and it can be difficult to discriminate between the low levels of Ca2+ stimulated ATPase activity found in isolates of t-tubules compared to the much higher Mg(2+)-ATPase activity. Thermal analysis reveals different inactivation temperatures (Ti) for the proteins responsible for ATP dependent calcium transport (Ti = 49 degrees C) and Mg(2+)-ATPase activity (Ti = 57 degrees C) in isolated t-tubule membranes. The differential scanning calorimetry profile of t-tubule membranes consists of three major components with transition temperatures (Tm) of 51 degrees C, 57 degrees C and 63 degrees C. Denaturation of the component with Tm = 57 degrees C correlates with inactivation of Mg(2+) ATPase activity, and denaturation of the Tm = 51 degrees C component correlates with the inactivation of Ca2+,Mg(2+)-ATPase activity and calcium transport. The functions of the t-tubule membrane component or components that denature with Tm = 63 degrees C have yet to be identified. The lack of stimulation of calcium transport in isolated t-tubules by oxalate, the impermeability of isolated t tubules to oxalate, and experiments performed on t-tubules with defined amounts of sarcoplasmic reticulum (SR) added suggest that contamination of the isolated t tubules by SR is unlikely to account for the level of Ca2+,Mg(2+)-ATPase activity detected. The presence of a Ca2+,Mg(2+)-ATPase in the t-tubule membrane would provide a mechanism that may be involved in the partial removal of calcium that is accumulated in the junctional space during muscle relaxation or calcium that is released from the terminal cisternae of sarcoplasmic reticulum during excitation-contraction coupling. PMID- 7833353 TI - Sterols stabilize the ripple phase structure in dihexadecylphosphatidylcholine. AB - The presence of various sterols in mixtures with dihexadecylphosphatidylcholine (DHPC) was studied using static X-ray diffraction of temperature equilibrated samples, and real-time X-ray diffraction of samples undergoing temperature scans. It was found that these sterols eliminate the interdigitation of the alkyl chains in the DHPC sub-gel and gel-state bilayers while stabilizing the ripple gel-state at the expense of the gel-state bilayer phase. The ripple-ripple phase transition previously observed for dipalmitoylphosphatidylcholine in the presence of low molar concentrations of sterols (Wolfe et al. (1992) Phys. Rev. Lett. 68, 1085 1088) was also observed for similar DHPC-sterol mixtures. In addition, we show the first evidence that the presence of 5 alpha-cholestane-3 beta,5,6 beta-triol will cause the lipid mixtures to continue to adopt a ripple mesophase structure even after the DHPC alkyl chain becomes disordered. PMID- 7833354 TI - Young gay men and HIV: running the risk? AB - HIV research often depicts 'adolescents' and 'youth' as having 'unique' qualities which predispose them to sexual risk. Yet, the evidence points to unsafe sexual behaviour as not being socially uniform. At a time when the idea of 'risk groups' for HIV is being subjected to increasing public scrutiny, researchers also need to question assumptions about youth 'risk'. This study examines whether young gay men are at greater risk for unsafe sexual behaviour than older gay men. A questionnaire was administered to 284 predominately gay identified men in Melbourne, Australia, recruited from gay groups, health clinics, gay pubs and nightclubs, sex on premises venues, and the social networks of these men. The results show that, while there was no difference in the level of recent unprotected anal intercourse between age groups, young men (under 25 years) from gay commercial venues or who did not belong to a gay organization(s) had a significantly higher level of recent unprotected anal sex than other young gay men. These results suggest that sexual safety may be more appropriately explained as a social process, rather than a youthful characteristic, and that researchers should include cohort effects into their analyses. PMID- 7833355 TI - Identifying helpful and unhelpful behaviours of loved ones: the PWA's perspective. AB - Twenty-five gay men with AIDS were interviewed about their social support networks and asked to describe specific interpersonal exchanges with network members which they perceived to be helpful and unhelpful. Content-analysis of responses revealed 12 main categories of helpful behaviours (providing encouragement, companionship, information, practical assistance, material aid, philosophical perspective, support for other network members, expressing concern, sharing feelings, acting as role model, allowing reciprocity, interacting naturally) and 11 categories of unhelpful behaviours (pessimism, physical avoidance, criticizing one's response to AIDS or medical treatment, making unreasonable demands, patronizing attitude, rude comments, insincerity, breaking confidentiality, acting judgmental or ashamed). The perceived helpfulness of particular behaviours varied depending on which network member performed them and the timing of the support attempt. Implications for increasing the effectiveness of support attempts by network members are discussed. PMID- 7833356 TI - Individual differences associated with high-risk sexual behaviour: implications for intervention programmes. AB - Simpson & Gangestad's (1991) sociosexual orientation inventory measures people's willingness to engage in uncommitted sexual relations. People with unrestricted sociosexual orientations report more casual sex encounters, and multiple and concurrent sexual partners, factors known to increase the risk for exposure to human immunodeficiency virus (HIV). This study investigated the relationship of sociosexuality to an 'impulsive' personality profile characterized by impulsivity in decision-making, general risk-taking tendencies, and greater responsiveness to situational cues. It was found that an unrestricted sociosexual orientation was associated with greater impulsivity in decision-making on Tellegen's (1982) multidimensional personality questionnaire (MPQ) Control subscale, greater risk taking tendencies on Tellegen's (1982) MPQ Harm-Avoidance subscale, and a greater responsiveness to situational cues as measured on Snyder's (1974) self-monitoring scale. Although unrestricted individuals had more knowledge about safe sex behavioural practices, they were more likely to engage in unprotected sexual intercourse (i.e. no condom use). Implications for HIV risk reduction educational programs targeting this population are discussed. PMID- 7833357 TI - When patients first suspect and find out they are infected with the human immunodeficiency virus: implications for prevention. AB - To evaluate how individuals infected with the human immunodeficiency virus (HIV) became aware of their infection, when they first suspected they were infected with HIV and factors associated with suspecting HIV infection, we surveyed 227 patients at an urban outpatient HIV clinic. Though nearly all patients acknowledged risk factors for HIV, 60% reported that they did not suspect that they were infected until they received a positive HIV antibody test result. Non white patients were less likely to suspect HIV infection prior to testing than white subjects (p < 0.03). Subjects not suspecting infection more often received HIV testing through a screening program or during a medical encounter (p = 0.02) and were less likely to be told by others that they might be infected (p = 0.001) than patients suspecting infection prior to testing. Forty-eight percent of subjects who suspected HIV infection prior to testing waited one year or more before obtaining their HIV antibody test. Interventions to reduce faulty personal HIV risk perception are needed to promote earlier HIV diagnosis. PMID- 7833358 TI - The Mental Adjustment to HIV scale: measurement and dimensions of response to AIDS/HIV disease. AB - Attitudes of people with HIV disease towards HIV have seldom been measured. However, a well-established scale to measure attitudes toward cancer in those with the disease, the 38-item Mental Adjustment to Cancer (MAC) scale was modified to assess adjustment to HIV disease. We administered the scale to 107 Australian men with HIV infection, of whom 36 had an AIDS-defining condition, who were patients at an ambulatory care facility and in a research study. The data were factor analyzed using a method identical to that used in the development of the MAC scale to determine the latent dimensions of attitudes toward HIV/AIDS. The Mental Adjustment to HIV scale (MAH) factor analysis revealed five factors: Helplessness-Hopelessness, Fighting Spirit, and Denial-Avoidance as in the original MAC scale, plus a Fatalism subscale which also measured Preoccupation, and a new subscale, which measured Belief in Influencing the Course of the Disease. Together, these five factors accounted for half of the variance. These data suggest that while there are similarities between mental attitude to cancer and mental attitude to HIV in the latent dimensions of the questionnaire items, there are also some differences. Most significant is the belief in people with HIV disease in being able to personally influence the course of the illness, and the combination of Preoccupation with Fatalism. The five subscales of the MAH scale had Cronbach's alpha reliabilities between 0.80 and 0.55. The MAH appears to be a useful way to measure total attitudes and subscale scores of people with HIV infection, including AIDS, to their disease. PMID- 7833359 TI - Changes in public knowledge and attitudes to HIV/AIDS in Wales, 1987 to 1992. AB - This paper presents information on changes in public knowledge and attitudes to HIV/AIDS in Wales between 1987 and 1992. The results indicate that throughout this period the majority of adults in Wales were aware of the high risk of infection from sexual intercourse and sharing needles with, and coming into contact with the blood of, someone with HIV. Nevertheless, the proportion who said that sexual intercourse with someone with HIV carries a high risk declined, and in 1992 confusion still remained about the nature of HIV infection amongst a substantial minority of respondents. More than one in ten of the adults in the most recent survey were of the opinion that kissing or being near someone with HIV who is coughing or sneezing carries a high risk of infection. The data also indicate that attitudes to those with HIV remained uneven in 1992. Whilst a greater proportion in 1992 than in 1987 held the view that people with HIV should be able to live normally in the community, attitudes appear to have hardened towards those perceived to be practising high risk behaviours, such as injecting drug users and homosexuals. The data also suggest that attitudes appear to be closely related to levels of knowledge. Given the apparent confusion and prejudice highlighted by the surveys, it is suggested that there is a continuing need for general campaigns to maintain public awareness of HIV-related issues, although this must also be complemented by more in-depth targeted education programmes. PMID- 7833360 TI - 'We just want to be a normal family...'. Paediatric HIV/AIDS services at an inner London teaching hospital. AB - The nature of the HIV epidemic in the UK is changing with the increasing number of infected women and children. This recent onset means that there are few data about the specific problems of HIV in families. This study examines current issues in service provision to HIV infected children and their families at an inner-London teaching hospital. A sample of ten families were interviewed, from a caseload of approximately 100 HIV-positive children. Of the ten children, seven were under the age of 5 years. All the children were vertical transmissions and six of the mothers were from Sub-Saharan Africa. Only three of the ten children were identified antenatally. In terms of service provision, families were very satisfied with the care provided by the study hospital's paediatric HIV team but felt that the hospital's paediatric and adult HIV services were poorly co ordinated and impractically located over different sites. Families did not have confidence in GP and community services, preferring to use hospital services which they felt to have more expertise in paediatric HIV. Future policy developments will have to confront the hospital-centred nature of paediatric HIV services and develop primary and community care services. PMID- 7833361 TI - Perceived risk of becoming infected with HIV by donating blood and changes in reported blood donation practice among the Scottish general public 1989-1992. AB - A total of 17,537 respondents aged 18-60 and resident in Edinburgh and Glasgow were interviewed between January 1989 and May 1992 as part of a large scale continuous monitoring survey of lifestyles and health. A computer assisted telephone interview (CATI) system was used. Respondents were chosen randomly from households with telephones. The objective was to see whether concern about the risks of becoming infected with HIV by donating blood led to a change in the blood donating habits of existing blood donors. Results showed no change in the percentage of donors, ex-donors and non-donors between 1989 and 1992, but a recent decrease in the percentage of respondents who thought that you could become infected with HIV by donating blood was observed. The percentage of new donors and ex-donors balanced each other out, but in all years respondents reporting a decreased frequency of donation outweighed those reporting an increased frequency. The belief that you can become infected with HIV by donating blood was most prevalent among non-donors followed by ex-, current and new-donors in that order. There was some evidence that the belief that you can become infected with HIV by donating blood was adversely affecting blood donation habits. PMID- 7833362 TI - HIV-1 infection at two public psychiatric hospitals in New York City. AB - Seroprevalence for HIV-1 was anonymously evaluated between November 1989 and July 1991 among severely mentally ill patients at two public psychiatric hospitals in New York City. The study population consisted of new admissions and long-stay patients aged 18-59. Of 1116 eligible patients, usable samples were obtained from routine blood drawings on 971 (87%). Seroprevalence was comparable among men (5.2%) and women (5.3%). Age did not predict seropositivity. Men with a recorded history of homosexual behaviour or injection drug use were, respectively, 1.8 and 2.0 times more likely to be seropositive than men without these histories. Women with a recorded history of injection drug use were 4.0 times more likely to be seropositive than women without such a history. Ethnicity was not predictive for men, but Black women were 2.4 times more likely to be HIV-1 positive than non Black women. Severely mentally ill inpatients had a substantial rate of HIV-1 seropositivity, indicating a need for additional testing, education and counselling efforts for this population. PMID- 7833363 TI - A method for determining rates of sexual activity in schoolchildren. AB - This report details a novel methodology for determining rates of sexual activity in schoolchildren. The method has been found to be acceptable to schools, parents and students, it receives a high level of co-operation, a low (1%) parental withdrawal, and a low number (3%) of inadequate responses. A marked advantage of this method is the absence of direct questioning about first intercourse which is often considered inappropriate within schools. Validation conducted by interview at the time of the questionnaire and one year postal questionnaire follow-up indicates that this method gives a good estimate of sexual activity for school populations. PMID- 7833364 TI - STD knowledge and behaviours among clients of female sex workers in Bali, Indonesia. AB - This study investigated knowledge, beliefs, and practices related to STDs and AIDS among clients of low price sex workers in Bali, Indonesia. These men are at high risk of STD and HIV transmission. They have poor knowledge of the basic concepts of STD and HIV transmission and prevention, and they practice a variety of ineffective prevention strategies including partner selection and the prophylactic use of antibiotics. They report a mean of 1.9 paid sexual partners in the previous week and very low frequencies of condom use. Over 25% had experienced an STD symptom in the previous 6 months, with self treatment with antibiotics reported by a third. Recent experience of an STD was related to the number of sex worker partners in the previous month and to ever having used a condom with a sex worker. The implications of the study findings for the development of comprehensive STD control programs including educational campaigns, condom promotion, and the strengthening of STD case management by health care providers are discussed. PMID- 7833365 TI - World Health Organization Global AIDS Statistics. PMID- 7833366 TI - Genes, genes, and more genes. PMID- 7833367 TI - Development and characterization of recombinant adenoviruses encoding human p53 for gene therapy of cancer. AB - We have constructed recombinant human adenoviruses that express wild-type human p53 under the control of either the Ad 2 major late promoter (MLP) or the human cytomegalovirus (CMV) immediate early gene promoter. Each construct replaces the Ad 5 E1a and E1b coding sequences necessary for viral replication with the p53 cDNA and MLP or CMV promoter. These p53/Ad recombinants are able to express p53 protein in a dose-dependent manner in infected human cancer cells. Tumor suppressor activity of the expressed p53 protein was assayed by several methods. [3H]Thymidine incorporation assays showed that the recombinant adenoviruses were capable of inhibiting DNA synthesis in a p53-specific, dose-dependent fashion. Ex vivo treatment of Saos-2 tumor cells, followed by injection of the treated cells into nude mice, led to complete tumor suppression using the MLP/p53 recombinant. Following a single injection of CMV/p53 recombinant adenovirus into the peritumoral space surrounding an in vivo established tumor derived from a human small cell lung carcinoma cell line (NIH-H69), we were able to detect p53 mRNA in the tumors at 2 and 7 days post-injection. Continued treatment of established H69 tumors with MLP/p53 recombinant led to reduced tumor growth and increased survival time compared to control treated animals. These results indicate that recombinant adenoviruses expressing wild-type p53 may be useful vectors for gene therapy of human cancer. PMID- 7833368 TI - Safety and toxicity of catheter gene delivery to the pulmonary vasculature in a patient with metastatic melanoma. AB - One approach to gene therapy for human cancer is transcatheter injection of DNA liposomes into tumor masses. To determine the feasibility of selective delivery of recombinant genes by a catheter to the pulmonary vasculature in humans, a patient with melanoma received two treatments of HLA-B7 plasmid DNA complexed to cationic liposomes into a right posterior basal pulmonary artery associated with a mass lesion. The treatments were well tolerated. No adverse respiratory, cardiac, immunologic, or other organ toxicities were detected. The delivery of recombinant genes by catheter may be a useful modality to treat human malignancy and other diseases. PMID- 7833369 TI - Overexpression of human methylmalonyl CoA mutase in mice after in vivo gene transfer with asialoglycoprotein/polylysine/DNA complexes. AB - Methylmalonic acidemia resulting from genetic deficiency of methylmalonyl CoA mutase (MCM) is an often fatal metabolic disease. Somatic gene therapy for this disorder may require gene replacement in the liver. We describe overexpression of MCM in the liver of mice after in vivo gene delivery using asialoglycoprotein/polylysine/DNA (ASO/PL/DNA) targeted delivery to the liver of plasmids expressing recombinant MCM. After intravenous administration of the ASO/PL/DNA complex, the vector sequences are cleared from the blood with t1/2 = 2.5 min and > 95% of the vector is taken up by the liver. Vector sequences are cleared from the liver with t1/2 = 1.0-1.3 hr. MCM enzyme activity in the liver increases to levels 30-40% over baseline 6-24 hr after injection. No acute or chronic toxicity was observed. This net level of expression is likely to be therapeutic for MCM if the complex could be administered repetitively to treat acute episodes of life-threatening acidosis or establish a steady-state level of MCM activity. Repetitive administration of the ASO/PL/DNA complexes in mice was associated with formation of antibodies against asialo-orosomucoid and the asialo orosomucoid complex but not against DNA. PMID- 7833370 TI - Evaluation of the respiratory epithelium of normals and individuals with cystic fibrosis for the presence of adenovirus E1a sequences relevant to the use of E1a- adenovirus vectors for gene therapy for the respiratory manifestations of cystic fibrosis. AB - Lung disease associated with disorders such as cystic fibrosis (CF) may be amenable to somatic gene therapy in which there is delivery of the normal gene directly to the respiratory epithelium using E1a- adenovirus (Ad) type 2- or 5 based vectors. For safety reasons, the Ad vectors are rendered replication deficient by deletion of the E1a region. Because there is the theoretical possibility of an E1a- replication-deficient vector replicating as a result of recombination or complementation with Ad 2/5 E1a sequences present in the target cell, this study is directed toward evaluating respiratory epithelium of normals and individuals with CF for the presence of E1a sequences. Using Ad 2/5 E1a specific primers and the polymerase chain reaction to evaluate DNA recovered from freshly isolated nasal and bronchial epithelium recovered by brushing, E1a sequences were detected in respiratory epithelium of 19 of 91 normals (21%). In the E1a-positive samples, the average of E1a copy number was 55 +/- 18/10(3) recovered cells. In CF individuals, 7 of 52 (13%) had detectable E1a sequences in the respiratory epithelium, with E1a copy number in the positive samples of 80 +/ 21/10(3) recovered cells. These results demonstrate that there are detectable Ad 2/5 E1a sequences in the respiratory epithelium of a small percentage of normals and individuals with CF. Because of the theoretical potential of such sequences supporting replication of E1a- Ad vectors, human gene therapy protocols for CF utilizing such vectors should consider evaluating study individuals for the presence of Ad 2/5 E1a sequences in the respiratory epithelium. PMID- 7833371 TI - Transfer of an anti-HIV-1 ribozyme gene into primary human lymphocytes. AB - We reported previously that human CD4+ T cell lines stably expressing a hairpin ribozyme targeted to the human immunodeficiency virus type 1 (HIV-1) U5 leader sequence were resistant to challenge with diverse HIV-1 viral clones and clinical isolates (Yamada et al., 1994). To simulate more closely the in vivo infection process for investigations of anti-HIV-1 ribozyme gene therapy, we developed a system to transfer this ribozyme gene into freshly isolated human peripheral blood lymphocytes (PBLs) using a murine retrovirus vector. Following transduction and G418 selection, human PBLs from multiple donors expressed the ribozyme and resisted challenge by HIV-1 viral clones and clinical isolates, while control vector-transduced PBLs remained fully permissive for HIV-1 infection. No inhibition of an HIV-2 clone lacking the target was seen in ribozyme-expressing PBLs. Ribozyme expression had no effect on viability or proliferation kinetics of the primary lymphocytes. This study is the first demonstration in primary human T cells of resistance to HIV-1 infection conferred by gene transfer. A human clinical trial is in development to test further the safety and efficacy of this ribozyme in PBLs of HIV-1-infected patients in vivo. PMID- 7833372 TI - Interleukin-2 gene-transduced human melanoma cells efficiently stimulate MHC unrestricted and MHC-restricted autologous lymphocytes. AB - Two human melanoma lines were transduced by a retroviral vector with the gene of the human interleukin-2 (IL-2) and characterized for their immunological properties in comparison with the parental lines. Transduction resulted in the production of biologically active IL-2 in the average amounts of 2,282 and 2,336 pg/ml per 10(5) cells per 24 hr over 3 and 2 months by the Me14932/IL-2 and the Me1B6/IL-2 lines, respectively. Melanoma-transduced cells lost their tumorigenicity in nude mice. No major changes in the phenotype were observed in IL-2 gene-transduced lines. In fact, more than 90% of cells expressed class I and II(DR) HLA, adhesion molecules, integrins, and melanoma-associated antigens. Irradiation with 100-400 Gy, while inhibiting tumor cell growth in vitro, allowed the release of IL-2 by the transduced cells for at least 5 weeks. The two melanoma lines also maintained susceptibility to lysis by lymphokine-activated killer (LAK) cells and by a HLA-A2-restricted melanoma-specific cytotoxic T lymphocyte (CTL) clone recognizing the melanoma antigen (Melan-A). In a limiting dilution assay, transduced, but not parental melanoma lines unless added with an amount of IL-2 comparable to that released by the transduced cells, were able to expand both nonspecific and melanoma-specific CTL precursors from autologous peripheral blood lymphocytes (PBL). In mixed lymphocytes-tumor cultures, IL-2 gene-transduced melanoma cells stimulated the expansion of major histocompatibility complex (MHC)-unrestricted effectors from autologous PBL, and of CD3+ CD8+ MHC-restricted CTL from tumor-invaded lymph nodes. These results indicate that IL-2 gene transduction does not alter significantly the expression of the immunologically relevant molecules of human melanoma lines while increasing their ability to stimulate both specific and nonspecific lymphocyte responses. These lines will be of value in the vaccination of melanoma patients. PMID- 7833373 TI - Human MDR gene transfer in patients with advanced cancer. PMID- 7833374 TI - [Enteral nutrition and fiber in intensive care]. AB - As in other fields of Medicine and Nutrition, the study of Alimentary Fiber or Dietary Fiber is becoming particularly intensive: its use in Intensive Care patients has however scarcely been explored. For comparison, its utility in diarrhea is assumed as main indication. This has not however been demonstrated. The scant research studies have not proven that diarrhea is controlled, particularly taking account of its complexity and multifactorial etiology. However, its utility has been shown in glucose-intolerance which is so common in Intensive Care Units, as in Diabetes. Current research is examining its bacterial fermentation products, short-chain fat acids (acetate, propionate and butyrate) and their importance as an energy source both of the intestinal and systemic mucosa. Short-chain fat acids are the preferred fuel of the colonic mucosa and an additional calorie contribution ought not to be ignored. PMID- 7833375 TI - [The role of multiparameter indices in preoperative nutritional assessment]. AB - The consequence of malnutrition in surgical patients is an increase in post operative complications. Detection of alteration in the nutritional state is a target in surgery theatres, using a variety of methods, notably anthropometry, analytic protein calculation, and delayed hypersensitivity cutaneous trials, which provide and objective assessment of the different body behaviors. A drawback is the large number of calculations required per patient, so that there is a limited number of patients with all the normal tests. To improve results in predicting complications in surgical patients based on nutritional parameters, the use is proposed of Multiparametric Nutritional Indices, obtained from the joint valuation of those parameters, by using multivariable statistical calculation techniques. The main indices in the literature are described. Multiparametric Indices are useful and easily calculated for the nutritional screening of surgical populations. PMID- 7833376 TI - [Bacterial translocation: the effect of supplements with dietary fiber in enteral diets in an experimental model of methotrexate-induced enterocolitis]. AB - Bacterial translocation, described by 1979 by Berg and Garlington as the movement of viable bacteria through anatomically intact intestinal mucosa to the mesenteric ganglia, is suspected of playing an important role in the development of sepsis with no apparent focus, fundamentally in polytraumatized and sever surgical patients: even now, with the wide range of antibiotic and chemotherapy agents available for treatment, this sepsis represents a high rate of hospital morbid-mortality. To assess the function as barrier of the intestinal mucosa and the influence of dietary fiber thereon, we studied bacterial translocation measured as positive cultures of the mesenteric lymphatic ganglia in an experiment model of enterocolitis induced by the intraperitoneal injection of 20 mg/kg of Methotrexate (MTX), using 72 male S-D rats, half of which were used as control group. These animals were sub-divided into four series according to the diet they were to receive. In addition to bacterial translocation, we examined the intestinal mucous parameters (mucosa weight, protein and DNA content, and number of mitoses) to quantify the potential trophic effect of dietary fiber on the intestinal mucosa. In the group subject to enterocolitis, there were no significant differences in the bacterial translocation with the series fed with defined-formula diets supplemented or otherwise with dietary fiber. Only the series receiving standard feed showed a significant reduction of bacterial translocation. pectin improved all mucous parameters when compared with the other diets studied. In the control group, the bacterial translocation rate was zero in all dietary series. PMID- 7833378 TI - [Quality control of total parenteral nutrition in the 1991-1992 biennium]. AB - OBJECTIVE: To assess the degree of compliance with standards defined for Total Parenteral Nutrition (TPN) quality control in our hospital in the two-year period 1991-1992. MATERIAL AND METHODS: All available information was assessed concerning 52 patients (32 men and 17 women) for whom a TPN course was prescribed in relation with certain pre-set indications. These patients received a total of 1140 TPN units with the TPN lasting an average of 21.9 days (range, 1-73 days). Monitoring was done by the Nutrition and Diet Section. The degree of compliance was assessed with the standards model proposed by the Providence Medical Center, Portland (USA) (PMCP) with 24 parameters (PM): indications, initiation in the first 24 hours, nutritional assessment in the first 24 hours, period of the TPN, metabolic complications (14 PM), septic complications (3 PM), nutritional consequences (2 PM) and TPN losses. All parameters were appraised and admitted, except for urea, which was corrected to standard values of our Laboratory (< 44 mg/dl), with Transferrin evaluation instead of iron binding capacity (TIBC), taking as compliance standard a figure of > 190 mg/dl. All analytical calculations were carried out in our Central Laboratory Service. RESULTS: Of all the parameters, the following were discarded, not being calculated on a routine basis: total CO2, serous magnesium, urinary uric nitrogen, nitrogen balance, positive hemocultures, catheters and TPN losses. Levels of compliance varied between 31.9% and 100%, with 8 parameters within the standards (Initiation, 100%; evaluation in first 24 hours, 100%; extent, 100%; creatinine, 100%; total bilirubin, 92.2%; cholesterol, 99.5%; transferrin, 35.9%). Seven parameters fell short (Na, 88.1%; K, 92.9%; Cl, 89.3%; Urea, 54.4%; Glucose, 96.4%; P, 94.1%; Triglycerides, 71.9%). CONCLUSIONS: We infer from our study that there is a need to make use of a large part of the indicators described in the literature as indicators for quality guarantee of a TPN program, and the use of new parameters must be assessed in normal monitoring. PMID- 7833377 TI - [The relation of the adhesion phenomenon and the experimental resistance of colonic anastomoses. The effect of epiploplasty]. AB - INTRODUCTION: We made an experimental study of the influence of the peritoneal adherence process on the strength of colic anastomosis. METHOD: 60 rats, in three groups of 20. Group I, colic anastomosis; Group II, colic anastomosis with epipoplasty; Group III, colic anastomosis covered with plastic material. They were slaughtered on the fourth post-operative day and we assessed the adherence parameters, removing the segment with anastomosis and measuring its breakage strength. Laplace's Law was applied to calculate Wall Breakage Stress (WBS). RESULTS: Group I: The statistically most significant influence on WBS was that of adherences to the anastomotic line (p = 0.005). WBS measured in anastomosis with adherence on 100% of the circumference was greater than in those where some part remained to be covered (p = 0.006). Group II: mean WBS was higher than in Group I as a whole (p = 0.005) and similar to that of the anastomosis in this group 100% covered by adherences (p = 0.017). Group III: mean WBS was lower than that of Group I (p = 0.009) and Group II (p = 0.000). CONCLUSIONS: The beneficial effect was demonstrated of adherences to the anastomotic line on the strength of colic anastomosis so that this process should not, wherever possible, be obstructed. During an epiploplasty, 100% coverage must be ensured: this technique must therefore be considered to belong to the group of high-risk colic anastomoses. PMID- 7833379 TI - [Our experience in the nutritional treatment of anorexia nervosa (1989-1991)]. AB - The purpose of this study was to assess the evolution in the nutritional situation of patients diagnosed with anorexia nervosa in the Clinical Nutrition Service between January 1 1989 and December 31 1991. Twenty-eight admitted patients (4 men and 24 women) and 38 outpatients (3 men and 35 women) were monitored, with an age of 22.4 +/- 6.4 years and average evolution time of the illness of 3.8 +/- 5 years. Nutritional state was evaluated with anthropometric, biochemical and immunological parameters. Following nutritional therapy, malnutrition and BMI (Body Mass Index) improved significantly over the initial evaluation in all patients, whether admitted or outpatients. All anthropometric parameters improved significantly during the period of treatment of admitted patients, but AMC (arm muscle circumference) rose only in outpatients. An unrestricted diet plus nutritional counselling was the most-used therapeutic procedure in outpatients while most of the admitted patients required dietary supplements. Calorie malnutrition is very common in patients diagnosed with anorexia nervosa: vitamin or trace element deficiencies are very infrequent. Nutritional therapy, suitably coordinated with psychotherapeutic treatment, is effective, enhancing both the nutritional state and anomalous dietary habits. PMID- 7833380 TI - [The prediction of postoperative septic complications by means of nutritional parameters. II. The verification of the predictive formula]. AB - An assessment was made of the predictive capacity of the following predictive formulation named Nutritional Sepsis Risk: NSR = 14.26 - 1.76 (albumin) - 1.47 (risk area) This was done in a sample of 65 surgery patients with digestive pathology who were candidates for selective surgery. All had undergone a pre operative nutritional evaluation program, based on anthropometric and analytical data and Retarded Hypersensitivity Cutaneous Tests (RHCT). NSR was calculated pre operatively. Infections were assessed qualitatively and quantitatively using Elebeute and Stoner's sepsis index. There were a total of five post-operative infections (7.69%). The NSR intersection point was calculated with an ROC curve, situated in a score of 3. The NSR detected the five infections, so is 100% sensitive, with 70% specificity and, in the detection of the septic risk population, surpassed the other nutritional parameters, whether anthropometric or analytical, and the RHCTs, when they were studied individually. PMID- 7833381 TI - [An updated list of SENPE members, 1994. Sociedad Espanola de Nutricion Parenteral y Enteral]. PMID- 7833382 TI - Cell proliferation kinetics of normal and tumour tissue in vitro: quiescent reproductive cells and the cycling reproductive fraction. AB - Current methods for measuring the cell kinetics of human tumours are made and interpreted within the context of a simplistic two compartment model for cell proliferation, consisting of cells that are cycling and those that are not. It is now recognized that the non-cycling compartment of many tumours is heterogeneous, composed of non-reproductive end-stage cells and reproductive cells that are dormant/quiescent. We have developed an in vitro analysis that distinguishes for the first time quiescent reproductive cells from non-reproductive end-stage cells and have integrated this analysis with monolayer clonogenic and suicide assays to simultaneously quantitate the duration of the cell cycle and reproductive cells that are: cycling, quiescent, clonogenic, and non-reproductive end-stage cells. We have defined a new parameter, the Cycling Reproductive Fraction (CRF), which is the cycling cell population referenced specifically to the reproductive cell population. Measurements of CRF from 72 tumour biopsies and from 5 normal foreskins showed that CRF approached 100% in some tumours; however, CRF showed near normal values (< 1%) in others suggesting that cell cycle control may be maintained in some tumours. Because of CRF's improved specificity, we believe that CRF may enhance classification, prognostication, and the optimization and prediction of response to chemotherapy. PMID- 7833383 TI - A mathematical model of glioma growth: the effect of chemotherapy on spatio temporal growth. AB - During the past two decades computerized tomography (CT) and magnetic resonance imaging (MRI) have permitted the detection of tumours at much earlier stages in their development than was previously possible. In spite of this earlier diagnosis the effects of earlier and more extensive treatments have been difficult to document. This failure has led to an increasing awareness of the importance of infiltration of glioma cells into surrounding grossly normal brain tissue such that recurrence still occurs. In this paper a simple mathematical model for the proliferation and infiltration of such tumours is introduced, based in part on quantitative image analysis of histological sections of a human brain glioma and especially on cross-sectional area/volume measurements of serial CT images while the patient was undergoing chemotherapy. The model parameters were estimated using optimization techniques to give the best fit of the simulated tumour area to the CT scan data. Numerical solution of the model on a two dimensional domain, which took into account the geometry of the brain and its natural barriers to diffusion, was used to determine the effect of chemotherapy on the spatio-temporal growth of the tumour. PMID- 7833384 TI - Existence of a commitment program for mitosis in early G1 in tumour cells. AB - The proliferation of normal non-tumourigenic mouse fibroblasts is stringently controlled by regulatory mechanisms located in the postmitotic stage of G1 (which we have designated G1pm). Upon exposure to growth factor depletion or a lowered de novo protein synthesis, the normal cells leave the cell cycle from G1pm and enter G0. The G1 pm phase is characterized by a remarkably constant length (the duration of which is 3 h in Swiss 3T3 cells), whereas the intercellular variability of intermitotic time is mainly ascribable to late G1 or pre S phase (G1ps) (Zetterberg & Larsson (1985) Proc. Natl. Acad. Sci. USA 82, 5365). As shown in the present study two tumour-transformed derivatives of mouse fibroblasts, i.e. BPA31 and SVA31, did not respond at all, or only responded partially, respectively, to serum depletion and inhibition of protein synthesis. If the tumour cells instead were subjected to 25-hydroxycholesterol (an inhibitor of 3-hydroxy-3 methyglutaryl coenzyme A reductase activity), their growth was blocked as measured by growth curves and [3H]-thymidine uptake. Time-lapse analysis revealed that the cells were blocked specifically in early G1 (3-4 h after mitosis), and DNA cytometry confirmed that the arrested cells contained a G1 amount of DNA. Closer kinetic analysis revealed that the duration of the postmitotic phase containing cells responsive to 25-hydroxycholesterol was constant. These data suggest that transformed 3T3 cells also contain a 'G1pm program', which has to be completed before commitment to mitosis. By repeating the experiments on a large number of tumour-transformed cells, including human carcinoma cells and glioma cells, it was demonstrated that all of them possessed a G1pm-like stage. Our conclusion is that G1pm is a general phenomenon in mammalian cells, independent of whether the cells are normal or neoplastic. PMID- 7833387 TI - Unlimited possibilities in the information age. PMID- 7833386 TI - Preparing and using life care plans. PMID- 7833385 TI - Relationship between epidermal growth factor receptor levels, autophosphorylation and mitogenic-responsiveness in normal mouse mammary epithelial cells in vitro. AB - Mammary epithelial cells were isolated from mid-pregnant BALB/c mice, grown within collagen gels and maintained on DME/F12 (1:1) media containing 10% bovine calf serum and 10 micrograms/ml insulin. Initial time-course and dose-response studies showed that epidermal growth factor (EGF)-induced autophosphorylation of the EGF-receptor (EGF-R) in these cells was maximal 5 min after exposure to 75 ng/ml EGF. Mammary epithelial cells displaying little or no growth during their first 2 days in primary culture cells were found to contain low levels of EGF-R. However, EGF-induced autophosphorylation of the EGF-R in these cells was extremely intense. Subsequent studies demonstrated that during the proliferative and plateau phases of growth, EGF-R levels progressively increased, while conversely EGF-induced autophosphorylation of the EGF-R decreased over time in primary culture. These results demonstrate that EGF-R levels and autophosphorylation do not show a direct correlation with mammary epithelial cell mitogen-responsiveness. Intense EGF-R autophosphorylation appears to be required for initiating growth, but sustained mammary epithelial cell proliferation occurs when EGF-R autophosphorylation is low. This inverse relationship between EGF-R levels and autophosphorylation may reflect changes in receptor affinity and function during the various phases of mammary epithelial cell growth in primary culture. PMID- 7833388 TI - Contracts with your attorney-clients. PMID- 7833389 TI - What gives your firm the cutting edge? PMID- 7833390 TI - International craniofacial bibliography. PMID- 7833391 TI - The fourth generation in bone repair. PMID- 7833392 TI - Facilitating diagnosis, prognosis, and management: distinguishing isolated and syndromic anomalies. AB - Birth defects comprise a significant percentage of craniofacial abnormalities, particularly in infants and children. A patient in whom these anomalies represent part of a larger syndrome may have features, such as a congenital heart defect and a urogenital malformation, which complicate pre- and post-operative management. Distinguishing isolated anomalies from syndromic anomalies is important. Appropriate diagnosis, referral, and prognosis is facilitated by examining specific parts of the body. The embryonic face develops coincident with the limbs, so their malformations can often be found concurrently. Two common considerations in dysmorphologic diagnosis are: 1) malformations of midline structures (brain, palate, heart, genitalia) tend to occur together; and 2) an underlying diagnosis may be present in a patient with two major or three minor anomalies. Presented herein are definitions of major and minor anomalies, and some of the syndromes in which they can be found. It is suggested that children with a craniofacial anomaly, isolated or syndromic, should be evaluated by a geneticist, and that patients with two or more major anomalies should have a chromosome analysis performed. PMID- 7833393 TI - Use of coral granules in the craniofacial skeleton. AB - Solid coral blocks have been used as a bone graft substitute in clinical orthopedics for more than 12 years. In this study, 36 patients with 54 craniofacial osseous contour defects received subperiosteal augmentations with natural coral granules made chiefly of calcium carbonate. The patients were followed for 12 to 36 months. The postoperative results were satisfactory; there were only 5 sites of clinically evident resorption. There were 2 incidences of wound irritation and 1 instance of overt infection. Technical aspects of the procedure are discussed. PMID- 7833394 TI - Noncraniofacial manifestations of Crouzon's disease. AB - Although most interest centers on the craniofacial region in Crouzon's disease, noncraniofacial manifestations are important because they may complicate both diagnosis and management. A population of 59 patients with Crouzon's disease was reviewed to determine the frequency of these deformities. Stylohyoid ligament calcification (50%) and cervical spine (40%) and elbow (18%) abnormalities were the most common. Minor hand deformities (10%), other musculoskeletal deformities (7%), and visceral anomalies (7%) were also seen. Acanthosis nigricans was not present in this population. Recommendations are made for the assessment and management of Crouzon's disease with reference to these areas. PMID- 7833395 TI - Temporal contour deformity after coronal flap elevation: an anatomical study. AB - Temporal contour deformity is defined as a concavity or depression in the temporal region located superior to the zygomatic arch and immediately posterior to the lateral orbital rim. The deformity can present as a consequence of extended coronal flap elevation for exposure of the lateral craniofacial skeleton. This study describes the anatomical and pathological features of the deformity and identifies causative factors. The series consists of unilateral temporal contour deformities after coronal flap elevation in 6 patients. A standardized data sheet was used in documenting details of the initial temporal dissection, clinical findings, and radiological features. Elevation of the temporal soft tissues was based on a qualitative analysis of coronal magnetic resonance imaging (MRI) scans comparing the affected and the unaffected temporal regions. The MRI studies demonstrated normal volume of the temporalis muscle in all cases, with no evidence of atrophy or disinsertion of the muscle. Diminution in the volume of the superficial temporal fat pad was identified in 4 patients, whereas inferior displacement or prolapse of the superficial temporal fat pad was noted in 2 patients. PMID- 7833396 TI - Surgical correction of severe scaphocephalic deformities. AB - Sagittal synostosis may result in severe skull deformities. Characteristic components of the deformity include extreme elongation, frontal and occipital bossing, temporal pinching, and angulatory apical skull deformation. Conventional strip craniectomy often fails to correct these complex problems completely in severe early or late cases of sagittal synostosis. Techniques for total calvarial vault reconstruction have previously been reported, but a single large series has not been presented. Eighteen consecutive patients ranging in age from 3 months to 5 years (mean = 12 months) with severe early and late scaphocephalic skull deformities underwent total calvarial vault reshaping. All children required transfusions ranging from 250 to 1,100 mL. Operative times averaged 6 hours, and hospital stay ranged from 4 to 7 days. There was no perioperative mortality. Two patients experienced transient syndrome of inappropriate secretion of antidiuretic hormone, which responded to fluid restriction. One patient was noted to have a 2-cm parietal craniectomy defect 9 months after operation. Microscrews, which were used in all 18 patients, had to be removed in 2 patients when they became palpable. Excellent aesthetic results were noted in all 18 patients up to 36 months of follow-up. PMID- 7833397 TI - Long-term results of vascularized cranial bone grafts. AB - The clinical and radiographic results of 9 consecutive vascularized full thickness cranial bone grafts to the midface are examined for a period of 3 to 8 years. Satisfactory contour was maintained throughout the follow-up in 5 patients with severe congenital facial deformities. Axial computerized tomography revealed complete survival of a trilaminar bone graft in each case. The complications were limited to a small area of alopecia in the midportion of one temporal scar. This relatively tedious harvest of bone is indicated for severe congenital malar and maxillary midface hypoplasia beginning at 4 years of age. PMID- 7833398 TI - Repair of experimental calvarial defects with Bio-Oss particles and collagen sponges in a rabbit model. AB - Various materials have been used for reconstruction of both acquired and congenital calvarial defects. Unfortunately, each has its limitations. Autologous bone grafts have irregular rates of resorption that may require secondary corrective surgery, and individual harvest sites have limited stores that can necessitate additional donor locations. Alloplastic materials have unlimited quantities and volume stability but they may not become incorporated and are associated with a higher incidence of infection. The optimal bone substitute should stimulate new bone formation and permanently supplant the temporary space filler, thereby reconstituting the surgical defect. We evaluated 2 newly available bone substitutes, resorbable natural bone mineral (Bio-Oss particles) and a combination of collagen and natural bone mineral collagen combination (Bio Oss sponges), to repair calvarial defects in an adult, male, New Zealand white rabbit model. We found that the particulate Bio-Oss material resorbed and then underwent the normal physiological stages of bone remodeling. The collagen and Bio-Oss combination was replaced by new bone ingrowth. These materials may have potential for use in the reconstruction of skull defects. PMID- 7833399 TI - Bacterial exposure required to induce rabbit calvarial bone graft infection by superficial contamination. AB - Little is known about the minimum bacterial dose required to induce infections by superficial contamination alone (i.e., not direct inoculation). This study quantified superficial rabbit calvarial bone graft contamination by exposing parietal bone grafts to Staphylococcus aureus. Two 5 x 5-mm full-thickness calvarial bone grafts were harvested from 40 rabbits and contaminated with different concentrations (range = 10(7)-10(11) colony-forming units [CFUs]/mL) of S. aureus by immersion. One graft from each rabbit was cultured immediately, and the other was inset into a calvarial donor site, fixed in place with wire, and observed for evidence of infection. At harvest (28 days postoperatively), a bacterial exposure of greater than 10(8) CFUs/mL of S. aureus was required to induce infections in the rabbit calvarial grafts (p < 0.001, Student's t-test), transmitting an infectious dose of approximately more than 10(4) CFUs per graft. These results validate the previously known dogma regarding the number of organisms needed to manifest infection [1,2] and highlight a multifold increment in bacterial count needed to transmit this infectious dose by superficial contamination alone. Such a model may be useful in investigating the efficacy of various treatment modalities of contaminated bone. PMID- 7833400 TI - Craniofacial treatment of giant-cell tumors of the sphenoid bone. AB - We report a craniofacial approach for resection of a giant-cell tumor of the sphenoid bone. Complementary radiotherapy was performed because of the incomplete tumor remotion. Four-year follow-up is presented. PMID- 7833401 TI - Duplication of the midface. AB - Facial duplication is one of the rarest forms of craniofacial anomalies. Only a few cases have been reported and described in the literature. We describe here two cases of midfacial duplication, one in a male and the other in a female. Both were examined clinically and radiologically including computed tomographic scanning, with three-dimensional computer reconstruction in the second patient. A histopathological examination was also carried out in both patients for the removed abnormal masses. The embryology of the face, together with the morphopathogenesis and the surgical management and outcome of the two patients, is discussed in detail. PMID- 7833402 TI - Facial cleft no. 30. AB - Midline clefts of the lower lip, mandible, tongue, and neck are rare congenital deformities and are classified as facial cleft no. 30 by Tessier. This is a report of a patient who presented with congenital fibrotic neck cord but no lower lip cleft, which has been the most frequently observed pathognomonic sign of this anomaly. The patient was treated initially for thyroglossal remnant. In the patients who present with a fibrotic cord located at the cervical midline without a lower lip cleft, the diagnosis of facial cleft no. 30 should be kept in mind. PMID- 7833403 TI - Rigid mesh fixation for alloplastic cranioplasty. AB - The evolution of cranioplasty techniques is described. A cranioplasty technique is presented that incorporates metallic mesh within acrylic and utilizes the principle of rigid fixation to avoid micromotion at the alloplastic-bone interface. Six procedures have been completed without complications. PMID- 7833404 TI - Bone graft of the zygoma in a patient with Treacher-Collins Syndrome. PMID- 7833405 TI - Prevention of "temporal hollowing" after fronto-orbital advancement for craniosynostosis. AB - Depression of profile in the temporal region is commonly seen after orbital rim advancement procedures. A newly developed temporalis musculoosseous flap has been designed with the intent to prevent this postoperative occurrence. PMID- 7833407 TI - International craniofacial bibliography. PMID- 7833406 TI - Immediate bone reconstruction after tumor resection around the orbit. AB - Cranial bone graft was used to reconstruct an orbital defect after resection. The repair was done so that the patient did not experience any deformity after the orbital resection. PMID- 7833408 TI - Bone grafting in the future: induction or distraction? PMID- 7833409 TI - Value of three-dimensional computed tomography in craniomaxillofacial surgery. AB - Three-dimensional (3-D) computed tomographic (CT) scans of 72 adult patients were evaluated by two observers in a blinded fashion by comparing the 3-D images with the two-dimensional (axial and coronal) CT scans. With 3-D CT, the observers found improved visualization of facial anatomy in certain patients (i.e., asymmetries of the whole face and skull, large defects of the midface and skull vault, and fractures with major dislocation). In these defects, the information can be assimilated more rapidly. The documentation of effects of cranial surgery on craniofacial growth and resorption after reconstruction with autologous material can also be evaluated more accurately. Because higher levels of radiation are used, 3-D CT protocols are less indicated in patients with minor dislocation of fractures, tumors, and inflammations. Three-dimensional CT images in these patients are of little help and can mislead the surgeon. Further improvements in hardware and software will allow more accurate surgical planning by performing interactive surgery or by producing precise models. PMID- 7833410 TI - Mandibular vascular malformations: treatment and long-term results. AB - Two cases of intraosseous vascular anomalies of the mandible--including surgical treatment and 10-year follow-up--are reported. Early aggressive resection not only resulted in resolution of symptoms and restoration of facial symmetry but also exhibited significant osseous regeneration without grafting. PMID- 7833411 TI - Le Fort type III osteotomy for midface deficiency in selected cleft palate patients. AB - The comprehensive treatment of cleft lip and palate continues to evolve as understanding of the pathogenesis of this malformation and refinement of surgical techniques for its treatment have improved. The malformation, although varying in severity from individual to individual, is now considered an abnormality of the entire maxilla. Our experience indicates that a finite minority of cleft patients exists with significant malar and midfacial projection deficiency in addition to class III malocclusion who will benefit from a more extensive midfacial advancement. We have treated 10 patients with a diagnosis of cleft lip and palate as well as malar and midfacial retrusion with a Le Fort type III advancement. In this group of patients, there were two early postoperative complications. Two patients (20%) experienced late occlusal changes; 4 patients underwent orthodontic correction; and the other required a Le Fort type I osteotomy. Three patients (30%) experienced predicted velopharyngeal insufficiency requiring a pharyngeal flap for correction. All patients demonstrated both subjective and objective improvement in facial aesthetics and Angle's class I occlusion after surgery. In patients with cleft lip and palate who also have midfacial retrusion, the Le Fort type III advancement provides a more complete correction of the facial deformity as well as the malocclusion. This approach should be integrated into the comprehensive management of this deformity by individuals trained in craniofacial techniques. PMID- 7833412 TI - Mandibular distraction lengthening in the severely hypoplastic mandible: a problematic case with tongue aplasia. AB - Distraction lengthening is a technique that was initially developed for correction of lower limb length discrepancies. It has recently been adapted to maxillofacial problems and has gained increasing popularity in this application. This report illustrates the principles involved in mandibular distraction lengthening and offers possible solutions to potentially limiting clinical problems. First, conventional technique dictates that a distinct periosteal sleeve is necessary for distraction osteogenesis to occur. However, in this case, distraction was performed through an area of scar tissue in which the native periosteum was destroyed. The ability to extend the use of the technique of distraction successfully to suboptimal clinical situations may broaden the indications for its use. Second, fixator instability is a potentially common problem in these cases because of the forces involved in distraction osteogenesis and the duration of the process. However, mechanical rigidity is essential consolidation (typically requiring twice as long as the distraction phase). Fixator instability can be successfully salvaged during the mineralization phase of bony healing through the use of an onlay corticocancellous bone "plate," which resorbs as the distraction gap gains strength. This report highlights one of the main advantages of the distraction process: the expansion of the soft-tissue matrix of the face. PMID- 7833413 TI - Lengthening of the mandible by distraction osteogenesis: experimental work in rabbits. AB - The purpose of this experimental work was to lengthen the mandible in rabbits by means of distraction osteogenesis. The excellent results on the lengthening of the extremities with the Ilizarov technique and the unpredictable results in the mobilization of the facial bones by means of osteotomies and grafts are reasons for the application of the gradual distraction method in mandibular lengthening. Bone lengthening was first performed in 1905; but Ilizarov rekindled interest in 1951 when he induced bone neoformation in the extremities by the distraction technique using multiplanar wires and external circular fixators. We lengthened the mandible in 12 New Zealand adult rabbits using different mountings of the Ilizarov apparatus by means of two fixation techniques: transfixion and nontransfixion. In the transfixion group (6 rabbits), the two wires were passed through both mandibular rami. In this group, a 2-cm lengthening was obtained. In the nontransfixion group (6 rabbits), only one mandibular ramus was included with the transfixion wires. In this group, 1-cm lengthening was achieved. Unilateral lengthening was obtained with the nontransfixion technique and the lengthening of both rami with the transfixion technique. The results were evaluated by clinical periodic postoperative radiographs and histological studies of newly formed bone and surrounding soft tissues (masticatory muscles, arteries, and so on). The results demonstrated that lengthening of the mandible is obtained by means of a mature and normal new bone that is produced in the osteotomized area. PMID- 7833414 TI - Internal calvarial bone distraction in rabbits with experimental coronal suture immobilization. AB - Correction of craniosynostosis involves removal of the coronal suture to allow for expansion of the developing brain and normal craniofacial growth. Frequently, however, the site reossifies, restricts growth, and requires additional surgery. The present study was designed to assess the effects of an internal, subperiosteal calvarial distractor on suturectomy site patency and compensatory craniofacial growth changes in an experimental rabbit model of coronal suture synostosis. In the present study, 43 1 1/2-week-old rabbits were used. Amalgam markers were placed across the frontonasal, coronal, and anterior lambdoidal sutures in all animals. Twenty-nine rabbits underwent bilateral coronal suture immobilization using methyl methacrylate. Fourteen rabbits were left untreated and served as sham controls. At 6 weeks of age, the immobilized rabbits were divided into three groups: (1) immobilized (controls), (2) suturectomy, and (3) suturectomy and distraction. The distractors were activated percutaneously at an average of 0.6 mm/week for 5 weeks (3 mm total). Lateral head radiographs were taken at 1 1/2, 6, 12, and 18 weeks of age. Results revealed that, by 6 weeks of age, animals with coronal suture immobilization exhibited significantly (p < 0.01) reduced growth across the coronal suture, resulting in shorter and inferiorly rotated cranial vaults compared with sham controls. By 12 weeks of age, rabbits with distraction returned to normal (sham control) coronal suture marker separation, whereas rabbits with immobilized sutures and suturectomy only showed significantly reduced marker distances. Rabbits with distraction also exhibited greater anterior cranial base lengths compared with the other experimental groups.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7833415 TI - In the absence of periosteum, transplanted fetal and neonatal rat coronal sutures resist osseous obliteration. AB - Normal craniofacial development depends on expansion of the cranial vault by growth at the sutures. Inappropriate development of the sutures leads to global disruption of patterns of craniofacial growth. Tissue interactions between dura mater and suture matrix play a critical role in the phenotypic maintenance of cranial sutures. However, the function of the periosteum in this process remains under-reported and controversial. To examine the contribution of periosteum in maintaining the patency of coronal sutures, fetal and neonatal rat coronal sutures were transplanted to surgically created defects in adult rat host parietal bones. These sutures were examined for their ability to persist in the host milieu in the presence and absence of both donor and host periosteum. This study established that removal of both host and transplant periosteum, unlike removal of dura mater, did not lead to obliteration of either fetal or neonatal sutures. Thus, periosteum and dura mater are nonequivalent tissues with respect to influence on suture patency. PMID- 7833416 TI - Median mandibular cleft. AB - We report on a patient with median cleft of mandible and lower lip and its associated corrective treatment, and we review the literature. PMID- 7833418 TI - Reconstruction of the anterior cranial floor with bone grafts. PMID- 7833417 TI - Surgical management of the acromegalic face. AB - We describe the planning and one-stage surgical correction of acromegalic facies. Patients with this condition may benefit from a relatively short treatment to solve both their aspect and their buccal functional problems. The aggressiveness of the surgical treatment, along with the characteristics of the disease, may make the permeability of the airway during the postoperative period problematic; therefore, we believe that temporary tracheostomy is indicated. PMID- 7833419 TI - Technique for costochondral graft placement. AB - The use of costochondral grafts in the acute trauma setting is controversial. This new technique has recently been utilized in two patients with severe condylar head fractures using a newly designed Synthes AO mesh plate with microscrews (0.8 mm) and 1.5-mm fixation. The technique provides superb rigid fixation. This fixation technique is multifaceted and can be used in all settings of acute and chronic costochondral graft replacement. PMID- 7833420 TI - New bone formation by biological rhythmic distraction. AB - Bone regeneration by distraction has become an accepted method for correction of congenital and acquired deformities. Unifocal bone generation is discussed as a technical note to demonstrate its feasibility in craniofacial surgery. The technique is simplified by the reorientation of the apparatus used, and the distraction is performed over a period of time to achieve a balance in the facial skeleton. Orthodontic elastics are used to balance the occlusion. PMID- 7833421 TI - Sleep EEG features of adolescents with major depression. AB - A substantial body of research in adults has established that certain sleep polysomnographic abnormalities are commonly found in depressed patients, including sleep continuity disturbances, reduced slow-wave sleep, shortened rapid eye movement (REM) latency and increased REM density. To date the findings in depressed adolescents are equivocal. Three consecutive nights of polysomnographic recordings were obtained in 31 hospitalized depressed adolescents and 17 age matched normal controls. The depressed adolescents had a shorter REM latency, shorter sleep latency, more REM sleep, and less stage 3 nonREM (NREM) sleep. There was a trend for melancholic and suicidal patients to have a shorter REM latency. PMID- 7833422 TI - Growth hormone responses to pyridostigmine in schizophrenia: evidence for cholinergic dysfunction. AB - The hypothesis that increased central cholinergic neurotransmitter function may be present in schizophrenic illness and may underlie negative symptoms was tested using a neuroendocrine challenge approach. The cholinergic challenge used was the anticholinesterase pyridostigmine, thought to cause the release of growth hormone (GH) from the anterior pituitary by diminishing inhibitory somatostatin tone. Eleven patients, six neuroleptic-naive and five neuroleptic-free, satisfying DSM III-R criteria for schizophrenia and 11 matched controls took part. Subjects received pyridostigmine (120 mg orally) and blood was sampled at 0, 60, 90, 120, and 180 min for GH estimation. Peak GH responses were significantly increased in the schizophrenic group compared to controls. There was no relationship between individual peak GH values and negative symptom ratings (Scale for the Assessment of Negative Symptoms). Neither could a relationship be established between other aspects of psychopathology or dyskinesias and GH responses. An increased pyridostigmine/GH response is also found in affective disorders and could be related to nonspecific symptoms common to all these diagnostic groups. This study suggests that schizophrenia may be associated with increased cholinergic neurotransmitter function but the relationship between this cholinergic dysfunction and schizophrenia may involve psychopathology not specific to schizophrenia. PMID- 7833423 TI - No evidence of linkage or allelic association of schizophrenia with DNA markers at pericentric region of chromosome 9. AB - Based on our previous study suggesting the pericentric region of chromosome 9 as of potential importance in schizophrenia, we have carried out a linkage study between the schizophrenia phenotype and the dinucleotide repeat polymorphisms D9S55, D9S15, and D9S202 in three pedigrees multiply affected with schizophrenia. In addition, we have conducted allelic association studies using 60 patients with schizophrenia and 60 controls with polymorphisms at D9S55 and D9S15 markers. No evidence for linkage or association was found. The results indicate that susceptibility genes for schizophrenia are less likely to be located at the pericentric region of chromosome 9, assuming genetic homogeneity of the pedigrees. PMID- 7833424 TI - The development of a method to measure [3H] dopamine uptake by washed platelets provides no evidence for circulating inhibitors of platelet dopamine uptake in schizophrenia. AB - Altered [3H] dopamine uptake by platelet-rich plasma (PRP) has been reported in some subjects with schizophrenia (Rotman et al 1980; Dean et al 1990). As platelet dopamine uptake was measured using PRP, it was not possible to determine if the changes in schizophrenia were intrinsic to the platelet or due to plasma factors. Furthermore, the constraints of plasma as a medium for platelet suspension has hindered the study of the physiological requirements of platelet dopamine uptake. A method is now reported that allows platelets to be suspended in a controlled medium while preserving the dopamine uptake mechanism of the platelet. Dopamine uptake by platelets in a controlled medium was dependent on temperature, energy, sodium, and chloride. Furthermore, plasma from subjects with schizophrenia and schizophreniform disorder did not significantly alter [3H] dopamine uptake by platelets compared to the effect of plasma from control subjects. Hence, these data provide no evidence for a circulating inhibitor of platelet [3H] dopamine uptake in plasma from subjects with schizophrenia. PMID- 7833425 TI - Subclinical impairment of lung airways in patients with panic disorder. AB - Lung function was assessed in 17 panic patients and 20 healthy controls. Panic patients had abnormal values for some dynamic lung volumes, namely Peak Expiratory Flow Rate (PEFR), Expiratory Flow at 75% of Vital Capacity (FEF75) and Maximum Mid-Expiratory Flow Rate (MMEF). Such functional abnormalities might indicate subclinical obstruction of lung airways, possibly relevant to the mechanisms related to panic disorder (PD). PMID- 7833426 TI - Plasma pyridoxal phosphate in anxiety disorders. AB - One hundred and eighty-nine subjects with either generalized anxiety disorder, panic disorder, or obsessive-compulsive disorder were evaluated for plasma pyridoxal phosphate (PLP) levels and compared with normal controls. There was no difference in plasma PLP levels between the anxiety disorder groups and normal controls. Low levels of plasma PLP were found in 42% of the controls. Our results suggest that previous reports of low PLP levels in psychiatric patients are unlikely to be significant in the etiology of the psychiatric disorders. PMID- 7833427 TI - Opioid tonus and luteinizing hormone secretion in anorexia nervosa: priming effect with serotonin precursor L-5-hydroxytryptophan during pulsatile gonadotropin-releasing hormone administration. AB - In anorexia nervosa (AN) luteinizing hormone (LH) release is often impaired during opioid blockade. We investigated whether a restoration of the endogenous sex steroid milieu, together with a rise in central serotonergic tone, could increase LH responsiveness to Naloxone (NAL) in seven young women affected by AN. The spontaneous pulsatility of gonadotropins and their response to gonadotropin releasing hormone (GnRH) and NAL challenges were tested before and after 13 days of pulsatile GnRH treatment and oral administration of L-5-hydroxytryptophan. Low and unpulsatile gonadotropin levels, responsive to GnRH, but not to NAL, were found before treatment. Pulsatile GnRH brought about a quasi-normal secretory pattern and 17 beta-estradiol increased to preovulatory levels in six of seven patients. On day 13 the lack of response to NAL administration was still present, however. A neuroendocrine disorder seems to be present in AN, which appears more complex than in other forms of hypothalamic amenorrhea. PMID- 7833428 TI - Acute and delayed effects of corticotropin-releasing hormone on dopamine activity in man. AB - Interactions between the hypothalamic-pituitary-adrenal (HPA) axis and central dopamine systems have been hypothesized to play a role in the pathophysiology of psychosis, but the normal physiology of HPA axis-dopamine interactions has not been fully defined. We report results from two uncontrolled pilot studies which explored the effects of ovine corticotropin-releasing hormone (CRH) on dopamine activity in healthy human subjects. Administration of CRH did not produce changes in plasma levels of homovanillic acid (HVA), the major dopamine metabolite, over the subsequent 3.5 hours. However, when the effects of CRH were followed over a longer period in a small subgroup, we found that CRH administration produced a two-fold rise in plasma HVA levels 20 hours later, without affecting plasma levels of 3-methoxy-4-hydroxyphenylglycol (MHPG), a major metabolite of norepinephrine. Thus, the findings of these pilot studies suggest that CRH may exert delayed but not acute effects on dopamine activity in man. PMID- 7833429 TI - Free-running period of circadian rhythms is shorter in rats with a genetically upregulated central cholinergic system. AB - The free-running circadian rhythm of drinking activity was monitored in constant darkness in a genetic line of rats, the Flinders Sensitive Line (FSL), which show increased muscarinic receptors in several brain regions. Compared to control rats, the Flinders Resistant Line (FRL), that do not show increased muscarinic receptors, the free-running period of drinking activity was shorter in the FSL rats (FSL period = 24.02 +/- 0.01 vs FRL period = 24.12 +/- 0.02; p < .001). In an attempt to determine whether other rhythms were similarly affected, we simultaneously monitored drinking activity, gross motor activity, and core temperature in free-running constant darkness conditions. The results from three FSL and FRL rats showed that the circadian periods of all three rhythms were shorter in FSL rats. These findings indicate that an animal model with an upregulated central cholinergic system demonstrates an accelerated circadian pacemaker. PMID- 7833430 TI - Striatal D2-dopamine receptor occupancy during treatment with typical and atypical neuroleptics. PMID- 7833431 TI - Metoclopramide and tardive dyskinesia. PMID- 7833432 TI - Methylphenidate increases rat cerebral cortex levels of N-acetyl-aspartic acid and N-acetyl-aspartyl-glutamic acid. PMID- 7833433 TI - Polymerization kinetics, glass transition temperature and creep of acrylic bone cements. AB - Sulfix-6 and Zimmer LVC 60/30 bone cements were selected and the polymerization kinetics and resulting glass transition temperature Tg; creep behaviour in the dry or water-saturated state; and sorption and diffusion of water were studied. The calculation of conversion was based on a comparison of the residual polymerization heat measured by differential scanning calorimetry and the corresponding theoretical value. The conversion reached 99% after 90 min of quasi adiabatic polymerization starting at 23 degrees C or after 10 min of isothermal polymerization at 37 degrees C. The Tgs of the cements prepared in the former way were about 82 and 100 degrees C, respectively. Creep rate of the bone cements at 37 degrees C decreased with the time of creeping. Sorbed water enhanced the compliance, but reduced the creep rate for long times so that water sorption during the service time may not have detrimental effects on the creep resistance of the cements. Both types of cements contained about 1% of low molar mass substances extractable by water. Measurements of the sorption kinetics of water showed that the diffusion coefficient is 0.14 x 10(-11) and 0.22 x 10(-11) m2/s and 1 yr sorption achieves 2.11% and 2.89% for Sulfix and Zimmer, respectively. PMID- 7833434 TI - Aluminium release from glass ionomer cements during early water exposure in vitro. AB - Aluminium is a major constituent of glass ionomer cements. During mixing and setting aluminium is released from the glass into the polyalkeonic acid solution. Part of this aluminium may not combine with the polyalkeonic acid, but may be released from the cement. The aluminium release from auto-cured and light-cured glass ionomer cements during early water exposure was studied. The former cements released more aluminium than the latter. Scanning electron microscopy (SEM) showed extensive loss of polymer matrix for the cements with the highest aluminium release. Insufficient curing of light-cured cements also resulted in loss of matrix. It is suggested that the considerable release of aluminium from glass ionomer cements during early water exposure may explain the reported lack of mineralization of predentin in the pulp beneath glass ionomer cements. This would correspond to the inhibiting effect of aluminium on bone mineralization. PMID- 7833435 TI - Cessation of strain facilitates bone formation in the micromotion chamber implanted in the rabbit tibia. AB - Short, daily periods of externally-applied strain have been shown previously to affect the differentiation of mesenchymal tissue. In this study, we examine the effects of discontinuing a strain protocol known to produce primarily fibrous tissue rather than bone in the micromotion chamber (MC). Five MCs were inserted into the proximal tibial metaphysis of mature male New Zealand white rabbits. The MC has a 1 x 1 x 5 mm pore for tissue ingrowth. After osseointegration of the fixed outer cylinder of the chamber, the inner movable core was manipulated for 40 cycles per day delivered at a rate of 1 Hertz ('40'). This provided motion at the interface between the cylinder and the core. The tissue in the pore was harvested after 3 wks. The MCs were then manipulated at 40 cycles per day for 3 wks and then the manipulations were discontinued for 3 additional wks ('40 + 0'); the contents of the chamber were harvested after 6 wks. Finally, the chambers were left without manipulation ('0') and harvested after 3 wks. Histological sections from unmoved chambers ('0') contained extensive trabecular bone, embedded in a fibrovascular stroma. The '40' specimens were composed primarily of longitudinally orientated fibrous tissue. The '40 + 0' specimens were similar histologically to the '0' specimens. The amount of bone ingrowth expressed as a percentage of the area of the section averaged 37 +/- 6 (mean +/- standard error of the mean) for the '0' specimens, 20 +/- 2 for the '40' specimens and 37 +/- 7 for the '40 + 0' specimens.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7833436 TI - Surface modification of titanium alloy implants. AB - Hip replacement stems manufactured from Ti6Al4V titanium alloy were surface treated in one of four ways and tested for dissolution resistance in bovine serum. Those stems treated thermally were found to have significantly lower metal ion release compared with those receiving standard commercial treatments. The improved dissolution behaviour is associated with a change in the surface oxide structure from mixed titanium oxides to a more stable rutile structure. PMID- 7833437 TI - Preparation and characterization of lectin-latex conjugates for specific bioadhesion. AB - This paper reports on the preparation and characterization of certain bioadhesive model drug deliver systems formed by a carrier (e.g. modified nanoparticles of polystyrene) and a ligand (e.g. tomato lectin, asparagus pea lectin, Mycoplasma gallisepticum lectin or albumin). Three different manufacturing methods (carbodiimide and glutaraldehyde coupling and physical adsorption) were studied. The activity of the lectin-latex conjugates and albumin-latex conjugate (control) were tested with gastric pig mucin. The manufacturing method had an insignificant effect on the activity, but all lectin-latex conjugates interacted two or three times more with mucin than with the control. PMID- 7833438 TI - Solubility behaviour of synthetic hydroxyapatites in aqueous solution: influence of amorphous constituents on pH value. AB - Some hydroxyapatites show a considerable increase of pH in aqueous solution. Rinsing experiments were performed on two commercial samples, and the pH value was plotted as a function of time. The plots lead to the conclusion that a soluble amorphous phase is responsible for the increase in pH. This investigation was supported by X-ray diffraction, microscopy and chemical analyses. PMID- 7833439 TI - Influence of plasma modification on biological properties of poly(ethylene terephthalate). AB - Poly(ethylene terephthalate) film was modified with argon or perfluorohexane plasma to obtain hydrophilic or hydrophobic surfaces, respectively. Various biological experiments in vitro and in vivo were chosen in order to evaluate the influence of such treatment on biocompatibility. Plasma modification does not cause toxic effects and does not influence disadvantageously the tested polyester biocompatibility. The huge changes in surface energy cause only minor changes in the biological behaviour of the samples. PMID- 7833440 TI - Adsorption of bovine serum albumin onto acrylamide-maleic acid hydrogels. AB - In this study, acrylamide-maleic acid hydrogels containing different amounts of maleic acid have been prepared by irradiating with gamma radiation. They have been used in experiments on bovine serum albumin (BSA) adsorption. Acrylamide maleic acid hydrogel containing 60 mg of maleic acid and irradiated at 5.20 kGy has been used for swelling and diffusion studies in water, solutions of NaCl and BSA. For this hydrogel, maximum and minimum swellings have been observed with water (1680%) and the solution of BSA (1085%), respectively. Diffusions of water, NaCl and BSA within hydrogels have been found as non-Fickian types of diffusion. In the experiments of BSA adsorption, Langmuir type adsorption has been found. The hydrogel prepared with 60 mg maleic acid and having been irradiated at 2.00 kGy has been found to be the best adsorption system for BSA. The adsorption capacity of acrylamide hydrogel has been increased by the addition of maleic acid almost 1.5-3-fold. PMID- 7833441 TI - Molecular weight dependence of calcification of polyethylene glycol hydrogels. AB - In vivo calcification of polyethylene glycol diacrylate (PEG DA) hydrogels of molecular weight (MW) 400, 1000, 4000, 6000 and 10,000 and polyethylene glycol tetraacrylate (PEG TA) of MW 18,500 was investigated using a rat subcutaneous model. This study was performed in 4-wk-old rats for durations of 1, 3, 6 and 8 wk. The results indicate a strong dependence of calcification upon the MW of the PEG precursor or the MW between crosslinks. Results for gels implanted for 6 wk show that calcification was maximal at a PEG MW of 1000 (224 mg/g +/- 12.8, n = 4) (mean +/- SEM) with less at MW = 400 (23.0 mg/g +/- 9.30, n = 4) and considerably less at higher MWs, e.g. for MW = 10,000 (0.23 mg/g +/- 0.01, n = 4). Results for other time periods indicate a similar calcification trend. The extent of calcification of gels from PEG TA (MW = 18,500) was intermediate (1.09 mg/g +/- 0.43, n = 3) between PEG DA (MW = 6000) (1.39 mg/g +/- 0.42, n = 6) and PEG DA (MW = 10,000) at 6 wk, i.e. calcification depended upon the PEG MW between crosslinks. When composite gels were implanted, such that a highly calcifying gel (MW = 400 or 1000) was encapsulated within a gel of low calcification (MW = 4000), the gel inside calcified to at least the same extent as if it had not been encapsulated. Thus, direct contact with tissues is apparently not necessary for calcification to occur. Energy dispersive X-ray spectroscopy was performed on the mineral deposits in the gels and a P:Ca ratio of 0.67 +/- 0.04 (95% confidence interval) for MW 1000 gels and 0.60 +/- 0.07 for MW 400 gels was found to be consistent with deposition of Ca3(PO4)2. PMID- 7833442 TI - Histomorphometry of hydroxyapatite coated and uncoated porous titanium bone implants. AB - Two different groups of hydroxyapatite (HA) coated and uncoated porous titanium implants, 250-350 microns and 500-700 microns diameter beads, were press-fitted into femoral canine cancellous bone. After 12 wks, the dogs were killed and histomorphometric backscattered electron microscopy studies were carried out. Comparing HA coated versus uncoated implants in the 250-350 microns bead diameter group, the percentage of bone (P = 0.01) and bone index (P = 0.01) were higher in the HA coated implants. Comparing HA coated versus uncoated implants in the 500 700 microns bead diameter group, bone ingrowth (P = 0.01) and bone depth penetration (P = 0.008) were higher in HA coated samples. It can be concluded that the HA coating was an effective method for improving bone formation and ingrowth in the porous implants. PMID- 7833443 TI - Biodegradable microspheres: a new delivery system for growth hormone. AB - A drug delivery system for biologically active agents targeted to specific cells could be used to improve tissue repair in orthopaedics. The system should be controllable and capable of drug release over an extended period of time. Biodegradable, membrane-moderated, monolithic microspheres for the controlled release of growth hormone (GH) were developed and the release of GH was monitored in vitro. Cross-linked gelatin microspheres were used as the vehicle, with the drug dispersed within the gelatin. The amount of GH released from the microspheres was increased following ultrasonication. The release of growth hormone was monitored in phosphate buffered saline and horse serum. Interestingly, a higher level of GH was detected in the phosphate buffered saline than in serum. In addition, both pH and enzyme-induced degradation had an effect on the swelling kinetics of the gelatin microspheres. The release of GH from the microspheres was diffusion controlled, during the time period studied. PMID- 7833444 TI - Radiation grafting of hydrophilic monomers onto poly[bis(trifluoroethoxy)phosphazene]. AB - The hydrophilic monomers dimethylacrylamide (DMAA) and acrylamide (AAm) were radiation grafted onto poly[bis-(trifluoroethoxy)phosphazene] (PTFP) for biocompatibility enhancement through direct irradiation of the polymer films immersed in monomer-solvent mixtures, and the progress of grafting was followed up to a large monomer depletion. The water absorption of the samples was found to increase as the amount of the grafted chains increased. The grafted chains, mainly confined in the film surface at high dose rates, progressively extend to the interior of the sample as the dose rate decreases. In the grafted samples the ultimate mechanical properties epsilon r and sigma r were essentially preserved. The in vivo tests indicated an enhancement of surface biocompatibility in the PTFP-g-AAm samples and not in the PTFP-g-DMAA samples. PMID- 7833445 TI - Cultural technique for in vitro modelling of prolonged bioadhesion. AB - This paper describes the development of a culture system for bioadhesion testing of gels over prolonged periods. Hamster cheek pouch mucosa was placed on collagen gels or steel mesh supports and submerged in growth medium for periods up to 7 d. Mucosal integrity and morphology were well maintained on mesh supports, but necrosis quickly occurred on collagen gels. Pilot studies with Orabase adhering to the tissue showed no detrimental effects, with the adhesive remaining in place for 4-6 h. It is concluded that the system shows promise for the investigation of prolonged bioadhesion. PMID- 7833446 TI - Analysis of cardiorespiratory signals--methodology and applications in infants. AB - Heart rate variability and thoracal respiratory movements were examined in two babies aged six months during eight hour polysomnographic recordings. Computer assisted analysis in the time and frequency domain were performed to investigate the mechanisms underlying cardiorespiratory control. Coherence and phase relation between cardiac cycles and respiration were investigated in detail. Both methods demonstrated that during quiet sleep (stage 3/4), the cardiorespiratory coupling was significantly increased as compared to active sleep (REM sleep). PMID- 7833447 TI - [High-performance biosignal amplifier for electrophysiologic studies for special safety requirements]. AB - For the recording of minute bioelectric signal voltages in the fields of medical research and diagnostic applications, a high-performance amplifier is needed to provide the signal levels necessary for a significant analysis. Irrespective of the concrete application, the major parameters required for a comparative evaluation of such systems are sensitivity, bandwidth and noise. Some applications also make special demands on electrical safety measures. With the aim of using an amplifier with a particularly powerful magnetic stimulator, and in view of the special requirements for brain voltage recording in a fully conscious patient, a universally applicable amplifier system has been developed that incorporates safety measures that ensure virtually risk-free application. The stimulation artefact can be suppressed completely by means of automatic offset regulation of the preamplifier. The circuit elements in electrical contact with the organism are separated from the rest of the measuring system by a high voltage insulation barrier. The main innovation and central subject of this article is an active protective system with an extremely short response time, which reliably cuts off the relevant amplifier circuits as soon as the ceiling signal level is exceeded. In accordance with relevant regulations, the user is warned of any first failure by a program-controlled self-test run by the protective unit and done automatically when the amplifier is activated. Exhaustive tests with a prototype have confirmed, among other things, that the integration of the new protective device does not reduce the amplifier output to any measurable extent. PMID- 7833448 TI - [Device availability to successful applications--a definition of terms]. AB - The operation of technical equipment is increasingly considered an important part of quality. But the terms related with "operation" are seldom clearly used. A terminology is hardly ever seen. Nevertheless, a generally accepted and uniformly used definition of terms is essential for scientific work. In this paper, the path from the availability of a device to the successful application is inquired. The terms used are defined. The central term "operation" is examined for significance and requirements. The differences between the man and the machine aspects are stressed. The wish to optimize operation leads to the psychological factors, their significance and a survey of the potential for further optimization of operation using biomedical devices as an example. PMID- 7833449 TI - [Numerical treatment of bone as anisotropic material]. AB - A three-dimensional finite element model of the femur shaft taking account of its microscopic structure has been developed. In the first instance, the material properties of a homogenised material replacing the inhomogeneous structure of compact bone were determined with the aid of a two-dimensional finite element model containing information on the bone structure and the mechanical behaviour of osteons. The bone structure with its irregular hole pattern (Haversian canals of the osteons) was idealised by assuming the bone to be a homogeneous plate with the holes arranged in a hexagonal or square pattern. The regular structure considered allowed on to compute the stresses and deformations of a modelled characteristic segment under given boundary conditions and loads. With these values new material constants (Young's and shear moduli, Poisson's ratios) of the continuum substitute were calculated. These constants were the material properties of the three-dimensional finite element model of the femur shaft, which was then used for stress calculations under the load components of the one legged stance. PMID- 7833450 TI - An amazing distortion in DNA induced by a methyltransferase. PMID- 7833451 TI - Transferrin binding capacity as a marker of differentiation and maturation of rat erythroid cells fractionated by counter current distribution in aqueous polymer two-phase systems. AB - Rat bone marrow cell populations, containing different proportions of erythroid cells, have been fractionated by counter-current distribution in the non-charge sensitive dextran/polyethyleneglycol two-phase systems on the basis of hydrophobic cell surface properties. Cell fractions with a low distribution coefficient, which contain non-erythroid cells and early erythoblasts, showed a low transferrin binding capacity and a low haemoglobin/cell ratio whereas cell fractions with a high distribution coefficient, which contain intermediate-late erythroblasts and mature red cells, showed an elevated transferrin binding capacity and the highest haemoglobin/cell ratio. These results support transferrin binding capacity as a good marker parameter for the erythroid bone marrow cell differentiation and maturation processes. PMID- 7833453 TI - The imidazoline derivative calmidazolium inhibits voltage-gated Ca(2+)-channels and insulin release but has no effect on the phospholipase C system in insulin producing RINm5F-cells. AB - The present study shows that the calmodulin antagonist calmidazolium inhibited influx of Ca2+ through voltage-gated Ca(2+)-channels in clonal insulin producing RINm5F-cells. The mechanism of inhibition may involve both Ca(2+)-calmodulin dependent protein kinases and direct binding of calmidazolium to the Ca(2+) channel. Calmidazolium did not affect uptake of Ca2+ into intracellular Ca(2+) pools, inositol 1,4,5-trisphosphate (InsP3) formation or action on intracellular Ca(2+)-pools. The calmodulin inhibitor also did not affect glucose utilization or oxidation in RINm5F-cells, speaking against an unspecific toxic effect of the compound. KCl-and ATP-stimulated insulin release from RINm5F-cells was attenuated by calmidazolium, whereas basal hormone secretion was unaffected. PMID- 7833452 TI - Chlorpromazine and other psychoactive drug induced alterations of a membrane bound enzyme in rat brain. AB - Psychoactive drugs like chlorpromazine (CPZ), imipramine, lithium and amphetamine in one way or another affect behaviour. The drug responses are presumably mediated by inducing a change in the activity of membrane bound enzymes. CPZ is very potent in inhibiting the alkaline phosphatase activity in rat brain. The combined effect of CPZ with other drugs shows that CPZ and imipramine together inhibit the enzyme activity significantly greater than the individual inhibition either by CPZ or by imipramine alone. Effective inhibition of the alkaline phosphatase activity with a single drug or combined drugs may lead to a change in neuronal permeability through glucocorticoids thereby affecting mood. PMID- 7833454 TI - Effects of oscillating air flow on the rheological properties and clearability of mucous gel simulants. AB - This in vitro study addressed the question of clearance-related changes in the physical properties of mucous gel simulants (MGS) subjected to oscillating air flow. Delineating some of the possible mechanisms of action for the reported beneficial effects of high-frequency chest compression (HFCC) therapy constituted the rationale. The rheological variables measured were spinnability by filancemeter and viscoelasticity (mechanical impedance, G*, and loss tangent, tan delta) by magnetic microrheometry. Two derivative parameters, mucociliary clearability index (MCI) and cough clearability index (CCI), were computed from the rheological variables, based on relationships established from model studies of clearance. Two ranges of air flow oscillation frequencies used previously in animal and clinical studies, i.e., 12-13 Hz or 22-23 Hz, were applied. The measurements were made after application of oscillating air flow for 15, 30 and 60 minutes, and compared with those at baseline and negative control. A significant decrease in log G* with administration of oscillations was observed (p = 0.06 at 30 minutes, p < 0.01 at 60 minutes, for G* measured at 1 rad/s). Spinnability also decreased by 19.3% and 30.7% after 15 minutes; 32.9% and 41.1% after 30 minutes; 36.4% and 50.5% after 60 minutes, for 12 Hz and 22 Hz, respectively (all significantly different from baseline). There was a positive correlation between viscoelasticity and spinnability, and a negative correlation between spinnability and CCI, but no correlation between spinnability and MCI. Oscillating air flow seemed to act as a physical "mucolytic" that affected mostly the cough clearability of the mucus simulant. PMID- 7833455 TI - Clot growth under periodically fluctuating shear rate. AB - To control the morphology of a clot formed on an artificial flow path in pulsatile blood flow, the hydrodynamic effect of periodically fluctuating shear rate on clot growth has been quantitatively investigated in vitro. Uniform shear rates were applied to a sample of beagle blood in the concave-convex cones system. These shear rates were sinusoidally fluctuated between a maximum and a minimum in one direction at frequencies between 0.1 and 0.6 Hz. Evaluation of clot growth was derived from a clot ratio, which was experimentally determined from the rate of increase of frictional torque between the two cones. The results show that clot growth is controlled so as not to occupy a large space when the minimum shear rate is higher than 100 s-1, or when the time of application of lower (< 100 s-1) shear rates is modified by the intermittent application of higher (> 500 s-1) shear rates as long as the frequency is less than 0.6 Hz. PMID- 7833456 TI - Lateral deformation and movement effects on flow through distensible tube models of blood vessels. AB - The fluid flow through a tube with an oscillating elliptical cross-section was analyzed in order to understand better the effects of lateral deformation and movement on flow patterns in large and medium-sized blood vessels. Time-dependent elliptical deformation may be caused by external forces, as is the case for the large vessels near the heart, or by lateral movement of the entire compliant vessel, as in the coronary arteries. An analytic, perturbation-type solution was found for the case of fully developed flow in a tube where the cross-section oscillated periodically from an ellipse to a circle. Analytic expressions were found for all three components of the velocity vector. The effects of the deformation on the axial velocity profile included near-wall fluctuations in velocity that depended on the local wall motion. At higher values of the Womersley parameter, these effects were more pronounced. Secondary flow patterns were established that swirled fluid from the center of the vessel to the walls, then back to the center. It was concluded that these phenomena could be important to flow in the largest vessels, but may not be so important in determining flow patterns in the coronary arteries. PMID- 7833457 TI - On the transport of a suspended particle in flow through the entrance region of a tube. AB - The motion of a single, spherical particle, released at different radial positions at the inlet of the entrance region of a straight circular laminar flow tube (Re = 260), was studied theoretically. Radial migration of the particle, either toward the tube center or toward the tube wall, was predicted. Based on the hypothesis that the particle experienced a lift force which was produced by the vorticity in the boundary layer and a velocity difference between the center of the suspended particle and the fluid medium, an inertia-vorticity fluid dynamic model was formulated to analyze the particle radial motions. Computational flow dynamics (CFD) solutions obtained from a 9.8 mm diameter tube model included the resulting particle loci for three particle radii (a = 0.1 cm, 0.085 cm, 0.050 cm), with the particle entry at various radial positions. The computation also covered a range of different particle entry speeds. The results showed that the particle migrates toward the tube center if it lags behind the medium in the core region; otherwise, it migrates toward the tube wall. Additional flow experiments were conducted in a circular (2R = 10.2 mm), 300 mm long straight tube. A small polystyrene sphere (2a = 1.72 mm, density rho p = 1.014 g.cm-3) was released at the inlet (X = 0, eta/R = 0.48) with two dimesionless release velocities (omega p = 0, and omega p > 1.0). The recorded particle traces agree well with the computational model. PMID- 7833458 TI - Simulation of non-Newtonian blood flow in an end-to-side anastomosis. AB - In order to quantify the importance of non-Newtonian blood rheology on anastomotic flow patterns, the characteristics of Newtonian and non-Newtonian blood flows were compared in a 2-D, 45 degree end-to-side anastomosis model under both steady and unsteady flow conditions. All flows were assumed to be two dimensional, and were simulated numerically using parameters consistent with blood flow in the femoral artery. A novel, purely viscous constitutive relation, based on a generalized form of the power law relation, was developed to model the non-Newtonian rheology of blood. The resulting wall shear stress patterns indicate that for the parameter values under consideration, non-Newtonian blood rheology has a significant effect on steady flow wall shear stresses, but no significant effect on unsteady flow wall shear stresses. Based on these and other simulations, a parameter is formulated that gives an indication of the importance of non-Newtonian blood rheology under a given set of flow conditions. In addition, an argument is presented for allowing the conclusions from this two dimensional study to be extended to three-dimensional blood flow. PMID- 7833459 TI - Simultaneous determination of hematocrit, aggregate size and sedimentation velocity by He-Ne laser scattering. AB - A method has been developed to study erythrocyte aggregation parameters based on He-Ne laser light scattering. Laser light is passed through a well mixed sample of blood and the forward scattered light intensity is recorded continuously. The orientation of erythrocytes, formation of aggregates and their sedimentation under the gravitational field produces a variation in scattered light intensity. The amplitude and frequency of light signal fluctuations depend on the size of aggregates and their sedimentation velocity. From the recorded light signal, the different erythrocyte aggregation parameters of interest are simultaneously obtained. PMID- 7833460 TI - Clinical issues in the prevention of dental-induced endocarditis and prosthetic joint infection. AB - No issue in medicine or dentistry is the subject of more misunderstanding than the prevention of infective endocarditis and late prosthetic joint infections. To resolve some of the confusion, national medical groups have published guidelines for the prevention of these infections, including the use of antibiotic prophylaxis for certain dental procedures and certain at-risk patients. While these guidelines are helpful, there still are clinicians who either do not recommend antibiotics when indicated or recommend antibiotics without indication. An understanding of these issues helps to prevent not only the infections but also the adverse antibiotic effects and associated legal problems. The learning objective of this article is to to educate clinicians on the prevention of dental induced endocarditis and prosthetic joint infections. PMID- 7833461 TI - Effect of a silica-containing etchant on shear bond strength to dentin. AB - The viscosity of phosphoric acid etchants for enamel and dentin may be increased by the addition of silica. This in vitro study investigated the effect of a silica-containing 10% phosphoric acid gel on the bond strength of composite resin to dentin as compared to a 10% phosphoric acid gel without silica, using 20 extracted human molars. The results indicated that the etchant containing submicron silica provided higher bond strengths than the etchant without a silica constituent. The learning objective of this article is to provide the findings of the study for the clinicians. PMID- 7833462 TI - Use of the CO2 laser in soft tissue and periodontal surgery. AB - The use of laser energy is by now established in some areas of the medical and dental professions. This article reviews the history of the carbon dioxide laser and discusses the advantages, indications, and contraindications of laser in soft tissue and periodontal surgery. Four clinical cases are presented to illustrate laser techniques in excisional biopsy, gingivectomy, coagulation of graft donor site, and a frenectomy procedure. The learning objective of this article is to familiarize the reader with this relatively new addition to oral surgical procedures. PMID- 7833463 TI - Oral leukoplakia and erythroplakia: a review and update. AB - Soft tissue health in the oral cavity is essential for overall dental and medical health and a successful maintenance of any restoration. This article reviews the clinical, etiologic, and prognostic features of oral leukoplakia, the most common of all chronic mucosal lesions, affecting 3% of all adults. The newest definitions for leukoplakia, erythroplakia, and smokeless tobacco keratosis are offered, along with a rationale for predicting malignant transformation and for treatment planning of these most important precancers. The learning objective of this article is to update the information for the clinician for early diagnosis and treatment of these lesions. PMID- 7833464 TI - The leukodepletion of cellular blood products in the prevention of HLA alloimmunization and refractoriness to allogeneic platelet transfusions. PMID- 7833465 TI - Inherited thrombophilia: resistance to activated protein C as a pathogenic factor of venous thromboembolism. PMID- 7833466 TI - The coding sequence of Duffy blood group gene in humans and simians: restriction fragment length polymorphism, antibody and malarial parasite specificities, and expression in nonerythroid tissues in Duffy-negative individuals. AB - The coding and untranslated flanking sequences of Duffy gene (FY) in humans and simians are in a single exon. The difference between the two codominant alleles, FY*A and FY*B, is a single change at nucleotide 306: guanidine is in FY*A and adenine is in FY*B. This produces a codon change that subsequently modifies the amino acid at position 43 of gpFy, the major subunit of the Duffy blood group protein complex. The glycine at this position in antigen Fya exchanges with aspartic acid in antigen Fyb. The guanidine at nucleotide 306 creates an additional Ban I restriction site in FY*A. Ban I digestion of DNA-PCR amplified products of FY*B and FY*A yields three and four fragments, respectively. Restriction fragment length polymorphism (RFLP) studies show that Fy(a+b-) and Fy(a-b+) whites are FY homozygous, that most Fy(a-b-) blacks have FY*B, and most Fy(a+b-) blacks are FY*A/FY*B heterozygous. In the black population a silent FY*B is very common, but a silent FY*A has not been found yet. On RNA blot analysis, the gpFy cDNA clone detected mRNA in the lung, spleen, and colon but not in the bone marrow of Duffy-negative individuals. Therefore, there is no null phenotype in Fy(a-b-) blacks. The gpFy homology between human and chimpanzee is 99% with a single residue change at position 116 (valine to isoleucine), whereas a 94% homology is found in squirrel and rhesus monkeys, and there is a 93% homology in aotus monkey when compared with humans. The N-terminal exocellular domain of simian gpFy helps to identify a set of amino acids critical for antibody and malarial parasite specificities. PMID- 7833467 TI - Genomic organization of the glycoprotein D gene: Duffy blood group Fya/Fyb alloantigen system is associated with a polymorphism at the 44-amino acid residue. AB - The Duffy blood group antigen has been characterized by its roles on red blood cells: as a receptor for the malarial parasites and as a promiscuous receptor for chemokine superfamily. Recently, the Duffy blood group associated glycoprotein D (gpFy) cDNA has been cloned (Chaudhuri et al: Proc Natl Acad Sci USA 90:10793, 1993). In this report we describe the organization of genomic DNA coding for the gpFy and elucidate the molecular nature of Fya/b polymorphisms. By a Southern blotting analysis probed with gpFy cDNA, gpFy gene was shown to be composed of three DNA fragments; 1.1-kb Sac I, 1.9-kb EcoRI, and their intervening 47-bp fragments. We cloned the 1.1-kb Sac I and 1.9-kb EcoRI fragments by inverted polymerase chain reaction (IPCR) procedure. The promoter region of the gpFy gene was cloned by IPCR of 1.1-kb Sac I fragment and the 3' flanking sequence was cloned by IPCR of 1.9 kb EcoRI fragment. The both IPCR products contained on both side the known gpFy cDNA sequence without introns, as expected. Although no TATA or CCAAT boxes are present in the promoter sequence, several transcription factor binding site motifs are contained, including AP-1, HNF-5, TCF-1, ApoE B2, W element, H-APF-1, and Sp-1. The 3' flanking region has two additional polyadenylation signals, other than that used in the cDNA, and also has an indirect and a direct repeat sequence clustered with the 5' flanking region. These facts indicate a possibility that the gpFy gene has been evolved by multiple retrotransposition events. By comparing the coding area of the gpFy gene in 28 Duffy-positive individuals, we elucidated that one base change that results in an amino acid substitution [GA-T(Asp44)-->GGT(Gly)] is in accordance with the Fya/Fyb polymorphism. This fact proves that the gpFy cDNA and its gene described in this report encode the Duffy blood group system. PMID- 7833468 TI - A novel gene, AF1q, fused to MLL in t(1;11) (q21;q23), is specifically expressed in leukemic and immature hematopoietic cells. AB - Translocations involving chromosomal band 11q23 are associated with leukemias. These translocations fuse the MLL, a gene with sequence homology to the Drosophila trithorax, to genes from a number of other chromosomal loci. We have characterized two t(1;11)(q21;q23) translocations that fuse the MLL gene to a novel gene, AF1q on chromosomal band 1q21, in two infants with acute myelomonocytic leukemia (AMMOL). In one of these patients, der(11) represents an inframe fusion of the N-terminal portion of MLL gene to the complete AF1q open reading frame, whereas der(1) does not give rise to an open reading frame. This observation suggests that the N-terminal portion of MLL gene is critical for leukemogenesis in translocations involving band 11q23. The predicted wild-type AF 1q product is a 9-kD protein with no similarity to any other protein in the data banks. The AF1q mRNA is highly expressed in the thymus but not in peripheral lymphoid tissues. In contrast to its restricted distribution in normal hematopoietic tissue, AF1q was expressed in all leukemic cell lines tested. PMID- 7833469 TI - p16 gene homozygous deletions in acute lymphoblastic leukemia. AB - The p16 protein is a cyclin inhibitor encoded by a gene located in 9p21, which may have antioncogenic properties, and is inactivated by homozygous p16 gene deletion or, less often, point mutation in several types of solid tumors often associated to cytogenetic evidence of 9p21 deletion. We looked for homozygous deletion and point mutation of the p16 gene in acute lymphoblastic leukemia (ALL), where 9p21 deletion or rearrangement are also nonrandom cytogenetic findings. Other hematologic malignancies including acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), chronic lymphocytic leukemia (CLL), and myeloma were also studied. Homozygous deletion of the p16 gene was seen in 9 of the 63 (14%) ALL analyzed, including 6/39 precursor B-ALL, 3/12 T-ALL, and 0/12 Burkitt's ALL. Three of the 7 ALL with 9p rearrangement (including 3 of the 5 patients where this rearrangement was clearly associated to 9p21 monosomy) had homozygous deletion compared to 5 of the 55 patients with normal 9p (the last patient with homozygous deletion was not successfully karyotyped). Single stranded conformation polymorphism analysis of exons 1 and 2 of the p16 gene was performed in 88 cases of ALL, including the 63 patients analyzed by Southern blot. Twenty-six of the cases had 9p rearrangement, associated to 9p21 monosomy in at least 12 cases. A missense point mutation, at codon 49 (nucleotide 164), was seen in only 1 of the 88 patients. No homozygous deletion and no point mutation of the p16 gene was seen in AML, MDS, CLL, and myeloma. Homozygous deletion of interferon alpha genes (situated close to p16 gene in 9p21) was seen in only 3 of the 9 ALL patients with p16 gene homozygous deletion, and none of the ALL without p16 gene homozygous deletion. Our findings suggest that homozygous deletion of the p16 gene is seen in about 15% of ALL cases, is not restricted to cases with cytogenetically detectable 9p deletion, and could have a pathogenetic role in this malignancy. On the other hand, p16 point mutations are very rare in ALL, and we found no p16 homozygous deletions or mutations in the other hematologic malignancies studied. PMID- 7833470 TI - Small noncleaved cell lymphoma and leukemia in adults. A retrospective study of 65 adults treated with the LMB pediatric protocols. AB - In France, more than 80% of children with Burkitt's lymphoma or Burkitt's leukemia (ALL3) are now cured with the LMB (B-cell non-Hodgkin's lymphoma and B ALL) protocols of the Societe Francaise d'Oncologie Pediatrique, but so far, poor results have been obtained in the few adult studies available. We have analyzed the experience with LMB protocols in adult patients. This retrospective study involved 65 adult patients with small noncleaved cell lymphoma or ALL3 treated with the LMB protocols. They were 17 to 65 years old and not previously treated. Human immunodeficiency virus-infected patients were excluded. The diagnoses were made between September 1984 and August 1991. According to the Murphy classification, 12 patients (18%) had stage I or II disease, 25 (38%), stage III disease; 4 (6%), stage IV disease; and 24 (37%), ALL3 (> or = 25% blasts). According to the Ann Arbor classification, 9 patients had stage I disease; 8 patients, stage II; 5 patients, stage III; 21 patients, stage IV disease; and 22 patients, ALL (> or = 30% blasts). Twelve patients had central nervous system (CNS) involvement before treatment. Thirty-nine patients were treated according to the LMB 84 protocol scheme; 14 according to the LMB 86 protocol, and 12 patients received the LMB 84 induction courses followed by the LMB 86 consolidation courses. Three patients underwent bone marrow transplantation (BMT) while in second complete remission (CR) and 3 others had refractory disease. There were some protocol violations caused by empirical medical decisions: local irradiation was performed in 4 patients, 2 patients received prophylactic radiation to the brain that was not specified in the protocol, 13 patients underwent BMT in first CR, and methotrexate doses were modified in 10 patients. Fifty-eight patients (89%) achieved a CR. There were four (6%) primary induction treatment failures, and three (4%) early treatment-related deaths. Eight patients relapsed between 2 and 30 months after CR (median, 4.7 months). Forty-seven patients are alive in CR (45 first CR, 2 second CR) with a median follow-up of 57 months (24 to 93 months). There were five toxicity-related deaths among patients in CR including four BMT-related deaths and five deaths caused by refractory relapses. One patient died in CR at 62 months of rectal cancer. The 3-year overall survival rate is 74% (SE = 5). According to the stages in the Murphy classification, the 3-year survival rates are stages I and II, 100%; stage III, 80% (SE = 7); and stage IV and ALL, 57% (SE = 8). Seven of 12 patients with initial CNS disease are alive with a median survival of 56 months.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7833471 TI - Expression of TAL-1 proteins in human tissues. AB - Rearrangement of the tal-1 gene (also known as SCL or TCL-5) occurs in at least 25% of T-cell acute lymphoblastic leukemias (T-ALLs) and results in the aberrant expression of tal-1 mRNA in the neoplastic cells. Also, tal-1 mRNA is constitutively expressed in erythroid precursors and megakaryocytes. This report describes a direct immunocytochemical study of the distribution and localization of TAL-1 protein in normal human tissues and cell lines using four monoclonal antibodies raised against recombinant TAL-1 proteins. One of these reagents recognizes a protein of 41 kD molecular weight in in vitro-translated TAL-1 proteins, two others recognize proteins of 39 and 41 kD molecular weight, and the fourth antibody also recognizes a TAL-1 protein of 22 kD in addition to the 39- and 41-kD proteins. These anti-TAL-1 antibodies label the nuclei of erythroid precursor cells and megakaryocytes in fetal liver and adult bone marrow. The punctate pattern of nuclear labeling suggests that TAL-1 may comprise part of a novel nuclear structure, similar to that recently found for the PML protein. The nuclei of T cell lines known to express mRNA encoding the full-length TAL-1 protein (eg, CCRF-CEM, RPMI 8402, and Jurkat) are also labeled. A study of normal human tissues (including thymus) showed labeling of smooth muscle, some tissue macrophages, and endothelial cells. TAL-1 protein is undetectable in other cell types. These reagents may play an important role in the diagnosis of T-ALL and could also be used in the context of lymphoma diagnosis on routinely fixed material. PMID- 7833472 TI - Secretion of cytokines (interleukins-1 alpha, -3, and -6 and granulocyte macrophage colony-stimulating factor) by normal human bone marrow megakaryocytes. AB - The effects of cytokine stimulation [recombinant human interleukin (rhIL)-1 alpha, rhIL-3, rhIL-6, rhIL-11, and rh granulocyte-macrophage colony-stimulating factor (GM-CSF)] on the secretory activity of normal human megakaryocytes were studied by means of the reverse hemolytic plaque assay (RHPA) in enriched cell preparations. This test facilitates an extremely sensitive determination of cytokine secretion at the single-cell level, together with the clear-cut identification of each immunostained (CD61) secretory active megakaryocyte. Moreover, the reverse transcriptase-polymerase chain reaction (RT-PCR) was used to investigate the expression of IL-6, IL-6 receptor (IL-6R), IL-9, IL-10, IL-12, and IL-13 mRNA in highly concentrated megakaryocyte preparations. In comparison with the spontaneous secretion rate, stimulation with rhIL-1 alpha, rhIL-6, and rhGM-CSF failed to induce a significant increase in the release of cytokines by CD61+ cells. On the other hand, both rhIL-3 and, in a less pronounced way, rhIL 11 exerted a marked effect on IL-6 secretion. Additionally, after stimulation with rhIL-3, a significant enhancement of the secretion of IL-3 and GM-CSF, but not of IL-1 alpha, could be observed. Using the RT-PCR, a significant induction of IL-6 expression could be appreciated in the enriched megakaryocyte population (60% to 80%) stimulated with rhIL-3. The results of this study provide persuasive evidence that a number of cytokines are synthesized and secreted by human megakaryocytes and not only by hematopoietic stroma cells. These data suggest the existence of autocrine and paracrine mechanisms that may influence maturation and differentiation of megakaryocytes as well as act on various stroma cells to sustain an appropriate hematopoietic micro-environment. PMID- 7833473 TI - Release of Fc gamma RIIa2 by activated platelets and inhibition of anti-CD9 mediated platelet aggregation by recombinant Fc gamma RIIa2. AB - Thrombin-activated human platelets and megakaryocyte cell lines release soluble Fc gamma RII (Fc gamma RIIa2) containing the extracellular and intracellular regions of Fc gamma RIIa1, but lacking the transmembrane domain. Use of polyclonal antibodies directed either against the entire intracytoplasmic tail, or against a peptide located near the C-terminal part of the intracellular region of Fc gamma RIIa2, showed the presence of both a complete form of Fc gamma RIIa2 and a C-terminal truncated form in supernatants of platelets after release of their alpha granule contents and in culture supernatants of megakaryocyte cell lines. Furthermore, recombinant Fc gamma RIIa2 inhibited in a dose-dependent manner Fc-dependent anti-CD9 antibody-induced platelet aggregation. Thus, release of Fc gamma RIIa2 by activated platelets could play an important role in the regulation of platelet activation by immune complexes. PMID- 7833474 TI - Calin from Hirudo medicinalis, an inhibitor of von Willebrand factor binding to collagen under static and flow conditions. AB - Calin from the saliva of the medicinal leech, Hirudo medicinalis, is a potent inhibitor of collagen mediated platelet adhesion and activation. In addition to inhibition of the direct platelet-collagen interaction, we presently demonstrate that binding of von Willebrand to coated collagen can be prevented by Calin, both under static and flow conditions in agreement with the occurrence of binding of Calin to collagen, confirmed by Biospecific Interaction Analysis. To define whether Calin acted by inhibiting the platelet-collagen or the platelet-von Willebrand factor (vWF)-collagen-mediated thrombus formation, platelet adhesion to different types of collagens was studied in a parallel-plate flow chamber perfused with whole blood at different shear rates. Calin dose-dependently prevented platelet adhesion to the different collagens tested both at high- and low-shear stress. The concentration of Calin needed to cause 50% inhibition of platelet adhesion at high-shear stress was some fivefold lower than that needed for inhibition of vWF-binding under similar conditions, implying that at high shear stress, the effect of Calin on the direct platelet-collagen interactions, suffices to prevent thrombus formation. Platelet adhesion to extracellular matrix (ECM) of cultured human umbilical vein endothelial cells was only partially prevented by Calin, and even less so at a high-shear rather than a low-shear rate, whereas the platelet binding to coated vWF and fibrinogen were minimally affected at both shear rates. Thus, Calin interferes with both the direct platelet-collagen interaction and the vWF-collagen binding. Both effects may contribute to the inhibition of platelet adhesion in flowing conditions, although the former seems to predominate. PMID- 7833475 TI - Calin from Hirudo medicinalis, an inhibitor of platelet adhesion to collagen, prevents platelet-rich thrombosis in hamsters. AB - Interaction between exposed collagen and platelets and/or von Willebrand factor is believed to be one of the initiating events for thrombus formation at sites of damaged endothelium. Interference with this mechanism may provide an anti thrombotic potential. Calin, a product from the saliva of the leech Hirudo medicinalis, was tested in vitro and for its in vivo activity in a thrombosis model in hamsters. Calin specifically and dose dependently (IC50:6.5 to 13 micrograms/mL) inhibited human platelet aggregation induced by collagen. In addition, specific platelet adhesion onto microtiter wells coated with collagen and detected with a monoclonal antiglycoprotein IIb/IIIa antibody-conjugated with horseradish peroxidase, could be completely prevented with Calin (IC50:22 micrograms/mL). A dose-response curve was constructed in groups of six hamsters in whom a standardized trauma was induced on the femoral vein. Thrombus formation was followed continuously using video recording and processing of the image obtained upon transillumination of the vessel. Intravenous Calin dose-dependently inhibited platelet-rich thrombus formation in this model with an ED50 of 0.07 mg/kg and complete inhibition with 0.2 mg/kg. No effects were seen on coagulation tests or bleeding times, whereas ex vivo aggregation induced by collagen was inhibited dose dependently. Local application of leech saliva, Calin, hirudin, or the combination of the latter two into the bleeding time wound of hamsters resulted in a mild prolongation of the bleeding time (twofold to threefold). A similar experiment in baboons did not cause any prolongation of the bleeding time. This is in sharp contrast with the long-lasting bleeding after a leech bite itself in both species. Calin from the leech Hirudo medicinalis is able, by binding to collagen, to effectively interfere with platelet-collagen interaction, which results in an antithrombotic effect observed in a platelet-rich thrombosis model in hamsters. PMID- 7833476 TI - Fibrinogen inhibits the heparin cofactor II-mediated antithrombin activity of dermatan sulfate. AB - Dermatan sulfate is a naturally occurring antithrombotic glycosaminoglycan. The antithrombin activity of several dermatan sulfate preparations has been measured in whole human plasma and found to be -55% of that in purified systems. Kinetic studies under pseudo-first-order conditions indicated that the reduction in antithrombin activity of dermatan sulfate in plasma compared with that in buffer was due to noncompetitive inhibition with respect to dermatan sulfate. Analysis of the protein profile bound to immobilized dermatan sulphate showed that on a molar basis, histidine-rich glycoprotein and apolipoprotein E were the most abundant proteins specifically bound, together with significant amounts of fibrinogen and vitronectin. Addition of these proteins to the purified system showed that only fibrinogen inhibited the antithrombin activity of dermatan sulfate and that it did so in a concentration-dependent manner over the physiologic range of plasma fibrinogen levels. These results indicate that the anticoagulant activity of dermatan sulfate may be modulated in human plasma by fibrinogen. PMID- 7833477 TI - Substitution of Val for Met at residue 239 of platelet glycoprotein Ib alpha in Japanese patients with platelet-type von Willebrand disease. AB - Genomic DNA was studied from four patients with platelet-type von Willebrand disease (vWD) from two Japanese families previously reported. The entire coding region of platelet glycoprotein (GP) Ib alpha, a component of the platelet receptor for von Willebrand factor (vWF), was examined by polymerase chain reaction (PCR) followed by direct DNA sequence analysis. A single point mutation was found in all patients resulting in substitution of Val (GTG) for Met (ATG) at residue 239 of GPIb alpha. All patients were heterozygous for the mutation, whereas none of the unaffected family members had an amino acid substitution at residue 239. Because the nucleotide substitution destroys an NIa III restriction site on GPIb alpha, PCR products were subjected to digestion with this enzyme; DNA fragments from both normal and mutant alleles were detected in all affected individuals. In allele-specific PCR, DNA was amplified from patients' genomic DNA using either adenine- or guanine-containing primers, whereas only adenine containing primer successfully amplified DNA from normal individuals. Cloning of amplified DNA into bacteriophage M13mp19 and subsequent DNA sequence analysis confirmed the mutation in these families. The absence of the amino acid substitution at residue 239 of GPIb alpha in the normal individuals tested, together with the linkage of this substitution to the phenotypic expression of disease in these two families and in a family recently described suggest that this amino acid change is a molecular basis for platelet-type vWD, and the substitution may produce a quite similar phenotype to the one reported previously (Gly to Val at residue 233 of GPIb alpha). PMID- 7833478 TI - Favorable prognosis of hyperdiploid common acute lymphoblastic leukemia may be explained by sensitivity to antimetabolites and other drugs: results of an in vitro study. AB - DNA hyperdiploidy is a favorable prognostic factor in childhood acute lymphoblastic leukemia (ALL). The explanation for this prognostic significance is largely unknown. We have studied whether DNA ploidy was related to cellular resistance to 12 drugs, assessed with the methyl-thiazol-tetrazolium assay, in samples of 74 children with common (CD10+ precursor B-cell) ALL. Sixteen patients had hyperdiploid ALL cells and 58 patients had nonhyperdiploid ALL cells. Hyperdiploid ALL cells were more sensitive to mercaptopurine (median, 9.0-fold; P = .000003), to thioguanine (1.4-fold; P = .023), to cytarabine (1.8-fold; P = .016), and to I-asparaginase (19.5-fold; P = .022) than were nonhyperdiploid ALL cells. In contrast, these two ploidy groups did not differ significantly in resistance to prednisolone, dexamethasone, vincristine, vindesine, daunorubicin, doxorubicin, mitoxantrone, and teniposide. The percentage of S-phase cells was higher (P = .05) in the hyperdiploid ALL samples (median, 8.5%) than in the nonhyperdiploid ALL samples (median, 5.7%). However, the percentage of cells in S phase was not significantly related to in vitro drug resistance. We conclude that the favorable prognosis associated with DNA hyperdiploidy in childhood common ALL may be explained by a relative sensitivity of hyperdiploid common ALL cells to antimetabolites, especially to mercaptopurine and to I-asparaginase. PMID- 7833479 TI - Molecular characterization of 16p deletions associated with inversion 16 defines the critical fusion for leukemogenesis. AB - The inversion of chromosome 16 [inv(16)] in acute myeloid leukemia (AML) is associated with a p-arm deletion in a subset of patients. The inversion results in two fusion genes: 5'-CBFB/MYH11-3' on 16p and 5'-MYH11/CBFB-3' on 16q. We have studied cells from 42 patients with inv(16) (38 patients) or t(16;16) (four patients) to define the frequency and characteristics of the deletion further. Using fluorescence in situ hybridization (FISH) with probes from cosmids, cosmid contigs, and yeast artificial chromosomes (YACs), we found that six patients with inv(16) had a deletion of between 150 and 350 kb centromeric to the p-arm inversion breakpoint cluster region (p-ibc). This region was shown to contain the 5' portion of the myosin heavy chain (MYH11) gene. YACs containing the p-ibc, which had been useful as FISH probes in the diagnosis of inv(16), detected the inversion in deletion as well as nondeletion patient cells. Thus, the deleted region identified in patients is entirely contained within the human genomic content of the YACs. Southern blot experiments using probes flanking the p-ibc indicated that the deletion removes segments within 10 kb centromeric of the p ibc. Reverse transcription-polymerase chain reaction (RT-PCR) using primers from the 5' region of CBFB and the 3' region of MYH11 (distal to the p-ibc) produced the 5'-CBFB/MYH11-3' chimeric transcript in inv(16)/del patients. These data confirm that the 5'-CBFB/MYH11-3' chimeric transcript, rather than the reciprocal 5'-MYH11/CBFB-3', is the critical product for chromosome 16-related leukemogenesis. PMID- 7833480 TI - Function of wild-type or mutant Rac2 and Rap1a GTPases in differentiated HL60 cell NADPH oxidase activation. AB - Studies of neutrophil nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation in a cell-free system showed that the low molecular-weight guanosine triphosphatase (GTPase) Rac was required, and that Rap1a may participate in activation of the catalytic complex. Full-length posttranslationally modified Rac2 was active, whereas only the 1-166 truncated form of Rap1a was functional in the cell-free system, and thus, clarification of the function of Rap1a and Rac2 in intact human phagocytes is needed to provide further insight into their roles as signal transducers from plasma membrane receptors. In the present studies, oligonucleotide-directed mutagenesis was used to introduce a series of mutations into human rap1a or rac2 in the mammalian expression vector pSR alpha neo. HL60 cells transfected with wild-type or mutated rac2 or rap1a cDNA constructs and control HL60 cells transfected with the pSR alpha neo vector containing no inserted cDNA were selected in G418-containing media, then subclones were isolated. Compared with the parent HL60 cells, each of the stable transfected cell lines differentiated similarly into neutrophil-like cells and expressed comparable levels of NADPH oxidase components p47-phox, p67-phox and gp91-phox. The differentiated vector control cell line produced O2. in response to receptor stimulation at rates that were not significantly different from parent HL60 cells. O2-. production by differentiated cell lines expressing mutated N17 Rap1a or N17 Rac2 dominant-negative proteins was inhibited, whereas O2-. production by the subline overexpressing wild-type Rap1a was increased by fourfold. O2-. production by the differentiated cell line expressing GTPase-defective V12 Rap1a was also significantly inhibited, a finding that is consistent with a requirement for cycling between guanosine diphosphate- and GTP-bound forms of Rap1a for continuous NADPH oxidase activation in intact neutrophils. A model is proposed in which Rac2 mediates assembly of the p47 and p67 oxidase components on the cytosolic face of the plasma membrane via cytoskeletal reorganization, whereas Rap1a functions downstream as the final activation switch involving direct physical interaction with the transmembrane flavocytochrome component of the NADPH oxidase. PMID- 7833481 TI - Biosynthesis of granule proteins in normal human bone marrow cells. Gelatinase is a marker of terminal neutrophil differentiation. AB - Differentiation and maturation of myeloid cells is characterized by the sequential acquisition of two distinct cytoplasmic granule subsets, azurophil granules and specific granules. We recently showed the existence of a third granule subset, gelatinase granules. To investigate whether appearance of gelatinase granules marks a further step in maturation of myeloid cells beyond the appearance of specific granules, we sorted normal human bone marrow cells into one of three groups according to maturity by centrifugation on Percoll density gradients. The biosynthesis of myeloperoxidase (MPO) (an azurophil granule marker), lactoferrin and neutrophil gelatinase-associated lipocalin NGAL (specific granules markers) and gelatinase was then studied in each of these groups. We found that gelatinase was synthesized mainly in the group containing band cells and segmented cells. This contrasted with lactoferrin and NGAL, which were synthesized almost exclusively in the group containing myelocytes and metamyelocytes, and with MPO, which was mainly synthesized in the group containing myeloblasts and promyelocytes. Immunocytochemistry was in full agreement with the biosynthesis data, and showed that gelatinase appears in band cells, whereas NGAL and lactoferrin both appear in myelocytes. Thus, acquisition of gelatinase granules marks a step in neutrophil differentiation beyond the appearance of specific granules. PMID- 7833482 TI - Simultaneous measurement of reticulocyte and red blood cell indices in healthy subjects and patients with microcytic and macrocytic anemia. AB - Using the new Bayer H*3 hematology analyzer (Leverkusen, Germany), we have determined red blood cell and reticulocyte indices in 64 healthy subjects, in patients with microcytosis due to iron deficiency (58 patients) and heterozygous beta-thalassemia (40 patients), and in patients with macrocytosis (28 patients). We found in all cases that reticulocytes were larger than mature red cells by 24% to 35%, with a hemoglobin concentration 16% to 25% lower and a similar hemoglobin content. The correlation between red cell and reticulocyte indices was strikingly tight (r = .928 for volume, r = .929 for hemoglobin concentration, r = .972 for hemoglobin content) in all four groups, regardless of red blood cell size. The ratio of reticulocyte to red blood cell mean corpuscolar volume (MCV ratio) was constantly above 1. Inversion of the MCV ratio was observed only in four patients. It was always abrupt and transitory and was associated with erythropoietic changes leading to the production of red blood cells of a different volume (treatment of megaloblastic anemia, functional iron deficiency, bone marrow transplantation). In two cases of marrow transplantation, reticulocyte volume fell during the aplastic phase after conditioning chemotherapy and then rapidly increased up to values higher than before; this production of macroreticulocytes was the earliest sign of engraftment. PMID- 7833483 TI - Leukocyte depletion of random single-donor platelet transfusions does not prevent secondary human leukocyte antigen-alloimmunization and refractoriness: a randomized prospective study. AB - We studied the value of leukocyte depletion of platelet transfusions for the prevention of secondary human leukocyte antigen (HLA)-alloimmunization in patients with a high-risk of prior immunization induced by pregnancies. Seventy five female patients with hematologic malignancies (mostly acute leukemia) and a history of pregnancy were randomized to receive either standard random single donor platelet transfusions (mean leukocytes, 430 x 10(6) per transfusion) or leukocyte-depleted random single-donor platelet transfusions. Leukocyte depletion to less than 5 x 10(6) leukocytes per platelet transfusion (mean leukocytes, 2 x 10(6) per transfusion) was achieved by filtration. Of the 62 evaluable patients, refractoriness to random donor platelets occurred in 41% (14 of 34) of the patients in the standard group and in 29% (8 of 28) of the patients in the filtered group (P = .52); anti-HLA antibodies developed in 43% (9 of 21) of individuals in the standard group and 44% (11 of 25) of cases in the filtered group. The time toward refractoriness and development of anti-HLA antibodies was similar for both groups. We conclude that leukocyte depletion of random single donor platelet products to less than 5 x 10(6) per transfusion does not reduce the incidence of refractoriness to random donor platelet transfusion because of boostering of anti-HLA antibodies. PMID- 7833484 TI - Rh E/e genotyping by allele-specific primer amplification. AB - It has been shown that the Rhesus (Rh) blood group antigens are encoded by two homologous genes: the Rh D gene and the Rh CcEe gene. The Rh CcEe gene encodes different peptides: the Rh C, c, E, and e polypeptides. Only one nucleotide difference has been found between the alleles encoding the Rh E and the Rh e antigen polypeptides. It is a C-->G transition at nucleotide position 676, which leads to an amino acid substitution from proline to alanine in the Rh e-carrying polypeptide. Here we present an allele-specific primer amplification (ASPA) method to determine the Rh E and Rh e genotypes. In one polymerase chain reaction, the sense primer had a 3'-end nucleotide specific for the cytosine at position 676 of the Rh E allele. In another reaction, a sense primer was used with a 3'-end nucleotide specific for the guanine at position 676 of the Rh e allele and the Rh D gene, whereas the antisense primer had a 3'-end nucleotide specific for the adenine at position 787 of the Rh CcEe gene. We tested DNA samples from 158 normal donors (including non-Caucasian donors and donors with rare Rh phenotypes) in these assays. There was full concordance with the results of serologic Rh E/e phenotyping. Thus, we may conclude that the ASPA approach leads to a simple and reliable method to determine the Rh E/e genotype. This can be useful in Rh E/e genotyping of fetuses and/or in cases in which no red blood cells are available for serotyping. Moreover, our results confirm the proposed association between the cytosine/guanine polymorphism at position 676 and the Rh E/e phenotype. PMID- 7833485 TI - Adult bone marrow-derived pluripotent hematopoietic stem cells are engraftable when transferred in utero into moderately anemic fetal recipients. AB - We have used W41/W41 (C57BL/6-Ly 5.1, Gpi-1b) anemic mice and a newly developed double congenic donor strain (C57BL/6-Ly 5.2, Gpi-1a) to determine if adult bone marrow (BM) injected in utero could provide stem cell engraftment. Of 38 fetuses injected intraperitoneally on day 13/14 of gestation with donor BM cells, 17 (47%) were live-born. On day 6, 12% had erythroid engraftment. On day 59, in 50% (8/16) of mice, 50% to 75% of erythroid cells, 42% of T cells, 5% of B cells, and 26% of granulocytes in the peripheral blood (PB) were derived from the in utero injected donor BM. At 141 days, thymic, splenic, lymph node, BM, and PB chimerism studies showed that 57% to 80% of T cells, 10% to 15% of B cells, and 27% to 43% of granulocytes were of donor origin. At this time, BM was injected into irradiated secondary recipients. On day 104 posttransfer, a mean 23% of T cells, 8% of B cells, and 40% of granulocytes were derived from the in utero donor BM. These data indicate that adult BM has hierarchical engraftment capabilities in W41/W41 mice and prove that stem cells are engraftable in utero. PMID- 7833486 TI - Interleukin-10 administration decreases survival in murine recipients of major histocompatibility complex disparate donor bone marrow grafts. AB - Studies in mice and humans have indicated that the predominance of interleukin-4 (IL-4)- and IL-10-producing T-helper type 2 (Th2) cells may serve to downregulate acute graft-versus-host disease (GVHD) reactions, whereas IL-2-producing Th1 cells have been implicated in facilitating acute GVHD. We explored the possibility that the in vivo infusion of IL-10 would inhibit acute GVHD induced by fully allogeneic donor grafts. Unexpectedly, IL-10 infusions resulted in a dose-dependent increase in GVHD-induced mortality. The acceleration of lethal GVHD by IL-10 occurred in irradiated recipients of T-cell-depleted bone marrow (BM) plus 5, 15, or 25 x 10(6) splenocytes but did not influence the post-BM transplantation (post-BMT) survival rate of recipients of BM without splenocytes, suggesting that the IL-10 effects were not due to toxicity. Antimurine IL-10 neutralizing monoclonal antibody injections, administered to diminish endogenous IL-10, reduced GVHD-associated mortality and improved the clinical appearance of the recipients. For BM graft rejection studies, IL-10 was infused into sublethally irradiated recipients of anti-Thy 1.2 + C' T-cell-depleted, fully allogeneic BM grafts. In a short-term (day 7) in vivo assay, IL-10 infusions significantly inhibited allogeneic (but not syngeneic) BM proliferation in vivo, indicative of increased graft rejection. In long-term chimerism experiments, IL 10 infusions caused a significant increase in early post-BMT mortality caused by a profound anemia typically associated with graft rejection and aplasia. A slightly higher irradiation dose (650 cGy v 600 cGy) eliminated the anemia but did not reverse the graft rejection process associated with IL-10 administration. We conclude that the in vivo infusion of exogenous IL-10 in recipients of fully allogeneic donor grafts results in accelerated GVHD and graft rejection in the strain combinations tested to date. PMID- 7833487 TI - Lack of alterations in the cytoplasmic domains of the granulocyte colony stimulating factor receptors in eight cases of severe congenital neutropenia. PMID- 7833488 TI - Allogeneic bone marrow transplantation for CD3+/TCR gamma delta+ large granular lymphocyte proliferation. PMID- 7833489 TI - Homozygous MTS1 (p16INK4A) deletion in primary tumor cells of 163 leukemic patients. PMID- 7833490 TI - Simultaneous detection of type A and type B PML/retinoic acid receptor alpha fusion transcripts in acute promyelocytic leukemia. PMID- 7833491 TI - Molecular analysis of the Mono Mac 6 cell line: detection of an MLL-AF9 fusion transcript. PMID- 7833492 TI - Lymphoma classification proposal: clarification. PMID- 7833493 TI - Risk factors for the development of diabetic complications. PMID- 7833494 TI - Comparison of efficacy, secondary failure rate, and complications of sulfonylureas. AB - The data from three clinical trials are presented, comparing the efficacy of different sulfonylureas in the treatment of type II diabetes. In a multicenter study, gliclazide improved control in 49% of patients who had failed on other drugs. When five groups of type II diabetic patients were treated concurrently with five randomly allocated different sulfonylureas over 1 year, the percentage of patients achieving normal HbA1 levels was best with gliclazide (80%) and glibenclamide (74%), when compared with chlorpropamide (17%), glipizide (40%), and gliquidone (40%). Secondary failure rate over 5 years was assessed in 248 type II diabetic patients randomly allocated to three different sulfonylureas and found to be lowest with gliclazide (7%) compared with glibenclamide (17.9%): p < 0.1) and glipizide (25.6%: p < 0.005). The incidence of hypoglycemia was significantly higher with glibenclamide than with gliclazide (p < 0.05). The differences in efficacy and secondary failure rate between sulfonylureas may be related to the mechanism of insulin release from the beta-cell and the more physiological action of gliclazide could partly explain this. These trials suggest that gliclazide is a potent sulfonylurea with a low rate of secondary failure and a low incidence of side effects and may be a better choice in long term sulfonylurea therapy. PMID- 7833495 TI - Glucose modulates the amount, but not the kinetics, of insulin released by sulfonylureas. AB - This study compares the insulin-secretory profiles induced by therapeutical concentrations of four different sulfonylureas--tolbutamide, gliquidone, gliclazide, and glibenclamide--and the amount of hormone released by each under different ambient glucose concentrations, using the isolated perfused rat pancreas model. All four sulfonylureas stimulated B-cell function, but the kinetics varied. Tolbutamide, gliquidone, and gliclazide produced a quick, biphasic release, whereas glibenclamide stimulated a delayed monophasic insulin secretion. Dramatic falls in insulin release were observed when ambient glucose concentrations were lowered. Glucagon release was not influenced by any of the sulfonylureas whatever the metabolic condition, neither directly nor indirectly, via an insulin-mediated paracrine inhibition of A-cell activity. PMID- 7833496 TI - Impaired glycogen synthesis of skeletal muscle in patients with insulin-resistant diabetes mellitus. PMID- 7833497 TI - Effect of sulfonylurea agents on pyruvate dehydrogenase activity in circulating lymphocytes from patients with non-insulin-dependent diabetes mellitus (NIDDM). AB - In circulating lymphocytes from patients with non-insulin-dependent diabetes mellitus (NIDDM) subnormal pyruvate dehydrogenase (PDH) activity returns to normal following patient treatment with sulfonylurea (gliclazide, 80 mg twice daily/5 weeks). Moreover, in vitro in cells from diabetic patients exposed to insulin at 50 microU/mL PDH activation also occurs; in cells of controls the same happens for insulin at 5 microU/mL, whereas at 50 microU/mL inhibition takes place. Therefore, the low PDH activity in cells of NIDDM patients might be caused by defective insulin control on the enzyme and its recovery in gliclazide-treated patients by drug-mediated removal of the defect. The validity of the hypothesis was verified in this study where cells of NIDDM patients before and after gliclazide treatment were exposed, in vitro, to insulin at 5 and 50 microU/mL and then tested for PDH activity. In such conditions, the profile of PDH behavior in treated patients was no longer comparable to that in untreated patients but closer to that in euglycemic controls, thus supporting the view that the recovery of PDH activity in NIDDM patients following gliclazide treatment might be the expression of an additional effect that the drug would have in these patients, aimed to renew cell responsiveness to insulin. PMID- 7833499 TI - Effects of gliclazide on fibrin network. AB - Fibrin network structure is altered by diabetes, peripheral vascular disease, and by some drugs. The antidiabetic drug, gliclazide, increases fibrin fiber thickness but reduces whole network permeability. The networks are, however, more lysable. These effects are further examined in this study using electron microscopy. Changes were observed in protein concentrations in fibrin fibers, in fibrin fiber alignment and in fiber porosity. These results show that gliclazide modifies fibrin monomer polymerization so that the fibrin network is rendered more susceptible to fibrinolysis. This pharmacological action of gliclazide may be useful in the treatment of thromboembolism. PMID- 7833498 TI - From hemobiology to vascular disease: a review of the potential of gliclazide to influence the pathogenesis of diabetic vascular disease. AB - Patients with type II diabetes commonly die from thrombotic vascular disease. Large vessel occlusion due to thrombosis or atherosclerotic stenosis is a process accelerated by diabetes and results in premature death. Diabetic small vessel disease, with its unique microangiopathic process, underlies many of the large vessel changes as well as causing retinopathy and nephropathy. The microangiopathic changes produce a prothrombotic tendency that has been widely reported in type II diabetes. There is reduced endothelial cell production of prostacyclin and the activators of fibrinolysis, together with increased platelet reactivity. In addition, there is increased lipid peroxidation and oxidative stress due to excess free-radical activity and impaired antioxidant defenses particularly in the presence of microvascular disease. The development of many of these abnormalities is associated with poor long-term glycemic control. However, the changes are also seen in atherosclerosis in nondiabetic patients where the progression of the disease can be modified by antiplatelet agents and antioxidants. The process of vascular damage is accelerated by diabetes, often due to co-existing disease and aging, although it is not clear that improvement in long-term glycemic control by lowering blood glucose levels to near to the nondiabetic state reduces the development of small and large vessel disease. Although the biochemical mechanism underlying this observation remains uncertain, protein glycosylation and increased platelet reactivity are implicated and interrelated. Increased oxidative stress due to excess free-radical activity may be central to diabetic vascular disease as endothelial cell damage, lipoprotein oxidation, modification of both platelet reactivity and arachidonic acid cascade are all properties of free radicals and their reaction products lipid peroxides.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7833500 TI - Hemobiological properties of gliclazide. AB - Non-insulin-dependent diabetes mellitus (NIDDM) is associated with an increased risk of macro- and microvascular degenerative complications. Gliclazide is a second generation sulfonylurea that is widely used in the treatment of type II diabetes mellitus. Its hypoglycemic activity is well documented. In addition to its metabolic effects, gliclazide has beneficial effects on the hemobiological abnormalities of NIDDM. These effects are mediated by the azabicyclo-octyl ring grafted on to its aulfonylurea core. Numerous studies have demonstrated that gliclazide reduces platelet hyperadhesion and platelet hyperaggregability. These actions have been extensively confirmed in diabetic patients over periods of up to 3 years. With regard to platelet functions, several groups have demonstrated a significant reduction in serum and intraplatelet beta thromboglobulin and thromboxane B2. In animal models, in-vitro and in-vivo gliclazide stimulates endothelial prostacyclin synthesis. The beneficial effects of the compound on thromboxane/prostacyclin balance have been recently confirmed in type II diabetic patients after a 3-month treatment period. Concerning fibrinolysis, gliclazide restores low plasminogen activity to normal in NIDDM patients previously treated with first-generation sulfonyl-ureas. Gliclazide increases fibrinolytic potential by increasing endothelial cell tissue plasminogen activator and pre-kallikrein activity. More recent studies suggest that gliclazide may have effects on fibrin network structure, rendering the fibrin more amenable to fibrinolysis. Finally, it has been shown that gliclazide has a potent free-radical-scavenging activity in vitro. This property has been recently confirmed in vivo in type II diabetic patients and may suggest that platelet reactivity and oxidative stress are related in these patients.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7833501 TI - In vitro assessment of adrenocortical toxicity. PMID- 7833502 TI - In vitro methods to study hypertrophy of cardiac cells. PMID- 7833503 TI - Analysis of malaria pigment from Plasmodium falciparum. AB - The biochemical pathway for the production of malaria pigment (haemozoin) forms a fundamental difference between host and parasite and is likely to be an important drug target. A simple method for the isolation of malaria pigment is described. The resultant product retained the in vivo crystalline appearance of pigment as judged by polarizing microscopy. Conditions were found for the disaggregation and separation of pigment. As malaria pigment can adsorb drugs, haem, and iron, such separation techniques are useful tools for studies on the impairment of haemoglobin digestion and pigment formation by antimalarials. PMID- 7833504 TI - Inhibitory effects of solvent and solid-phase extraction residues on mixed lymphocyte cultures. AB - Residues from eight solvents/solvent mixtures before and after their passage through C18- bonded phase columns were assayed for cytostatic activity using mixed lymphocyte cultures (MLC). All residues, except those from acetonitrile, exhibited cytostatic activity (15%-35% MLC inhibition as measured by 3H-thymidine incorporation). Passage of solvents through bonded phase columns contributed an additional and significant cytostatic effect (19%-69% MLC inhibition). Pretreatment of columns with methanol led to further increases in the release of cytostatic residues from the columns, only when followed by less polar solvents (hexane, ethylacetate, etc.). It is concluded that residues from solid-phase extraction columns may interfere with subsequent cell culture-based assays for proliferative/antiproliferative activity. PMID- 7833505 TI - Characterization of a method for the detection of drugs with free radical scavenging activity using porcine leukocytes. AB - The effects of a range of free-radical scavenging drugs on luminol-enhanced chemiluminescence (CL) generated by porcine leukocytes, following activation by two nonreceptor-mediated stimulants, phorbol myristate acetate (PMA; a protein kinase activator) and ionomycin (a cation ionophore), and by xanthine plus xanthine oxidase (X-XO), have been examined. Superoxide dismutase (0.1 units/mL) and catalase (50 units/mL) inhibited X-XO, but they were ineffective in leukocyte suspensions except at concentrations 500 times and 20 times higher. Sodium azide (10(-5) to 10(-3) M) caused a marked inhibition in CL production in activated leukocytes, but not of X-XO CL. The antioxidants, glutathione (10(-3) M) and L ascorbic acid (10(-3) M) were ineffective in activated leukocytes, but caused total inhibition of X-XO-induced CL. Mannitol (100 mM) had no effect on chemiluminescence in either system. Captopril (10(-3) M) produced an inhibition of CL in both systems and this inhibition was significantly modified by pH. Thus, the present study has established a standard screening procedure for the assessment of free-radical scavenging activity using activated porcine leukocytes and xanthine-xanthine oxidase. PMID- 7833506 TI - Assessment of blood flow changes at multiple sites in rabbit skin using a 133Xenon clearance technique. AB - 133Xenon clearance represents a clinically useful method of measuring local circulatory function in a variety of different tissues. The method detailed in this article describes how the 133Xenon clearance technique can be adapted to simultaneously measure cutaneous blood flow, over a 15-min period, at a large number of skin sites within the same animal. Blood flow changes are measured in response to intradermally injected vasoactive test agents. The multisite injection plan which forms part of the method removes bias due to site variations and generates data that can be analysed statistically. Results are expressed as the percent change in 133Xenon clearance at test agent-injected sites as compared to control, saline-injected sites. The method provides an accurate and time efficient measure of skin blood flow. In the present study, the technique is used to assess the receptor-mediated mechanism of action of the vasodilator calcitonin gene-related peptide (CGRP) and the possibility that the vasoconstrictor endothelin-1 acts to stimulate the release of vasodilator quantities of endogenous CGRP. PMID- 7833507 TI - Image analysis quantification of the Miles assay. AB - The Miles assay for vascular permeability has high intra- and interassay coefficients of variation (CVs). Quantification, usually by dye extraction and spectrophotometry, is time consuming. In this study, quantification by this means was compared with image analysis using the Olympus CUE-2 Image Analyzer (version 4). The test substance was recombinant human vascular permeability factor (rhVPF). The quantification process took approximately 10 min with image analysis. Formamide extraction and spectrophotometry required 1 hr of preparation, 4-6 days of incubation, and 1 hr for filtration and spectrophotometry. Between assay CVs ranged from 0 to 30% for spectrophotometry, but were all < 10% for image analysis. The sensitivity (2SD above the negative control mean) of the image analysis approach was 64 +/- 25 ng/mL, whereas for spectrophotometry it was 65 +/- 29 ng/mL. Interanimal CVs for rhVPF at 200 and 1000 ng/mL were 15% and 26% when assessed by spectrophotometry and 7% and 22%, respectively, by image analysis. The R2 value for the correlation of image analysis with spectrophotometry was 81.4%. Test substances injected close to the spine evoked a greater permeability response than those injected laterally: at 200 ng/mL p = 0.005, at 1000 ng/mL p = 0.1 (unpaired t tests). PMID- 7833508 TI - Prostaglandin and tumor necrosis factor secretion by peritoneal macrophages isolated from normal and arthritic rats treated with liposomal methotrexate. AB - The effect of a novel liposomal preparation containing a phospholipid conjugate of methotrexate (MTX-LIPO) upon macrophage mediator release was investigated in normal and arthritic rats ex vivo. Peritoneal macrophages isolated from MTX-LIPO treated arthritic rats and stimulated with lipopolysaccharide produced significantly less tumor necrosis factor (TNF) and prostaglandin (PGE2) than did macrophages isolated from saline-treated controls. In the same experimental system, free methotrexate only inhibited prostaglandin release, but it was more potent than MTX-LIPO in this respect. Additional studies are presently underway to investigate the effect of MTX-LIPO and MTX treatment upon the lipopolysaccharide-induced rise in plasma levels of various proinflammatory mediators in vivo. Haematopoietic toxicity was demonstrated in blood isolated from rats treated with free MTX, and this was as characterized by a significant reduction in reticulocyte count compared with MTX-LIPO and saline-treated rats. PMID- 7833509 TI - Lethal effect of latex gloves on Xenopus laevis tadpoles. PMID- 7833510 TI - Physiologic and pharmacologic factors that affect myocardial relaxation. AB - Evaluation of the myocardial relaxation has become important in the last years. An impaired relaxation may precede contractile dysfunctions and even cause heart failure. To treat this impaired lusitropism it is necessary to properly assess the lusitropic state of the heart and understand how drugs affect the cellular mechanisms underlying myocardial relaxation (sarcoplasmic reticulum function, Ca2+ fluxes through the sarcolemma and myofilament Ca2+ sensitivity). Current information regarding these issues is provided in this review. The relative usefulness of the mechanical parameters used to evaluate the lusitropic state of the heart in experimental models applied in pharmacology will also be discussed. PMID- 7833512 TI - Videothoracoscopy in trauma: early experience. AB - We present a series in which videothoracoscopy was used to evaluate and manage patients after thoracic trauma. We used this technique in 11 patients with thoracic injuries. We describe 5 representative cases. It was used successfully in 10 of 11 patients. Indications included evaluation of ongoing hemothorax, evacuation of clotted hemothorax and empyema, and decortication for persistent airleak. Etiologies included blunt trauma, stab wounds, and gunshot wounds. PMID- 7833511 TI - Laparoscopic cholecystectomy in a freestanding outpatient surgery center. AB - Laparoscopic cholecystectomy in a freestanding outpatient surgery center was evaluated. Fifty-five patients undergoing laparoscopic cholecystectomy during a 10-month period from December 1992 to October 1993 were included in this study. There were 10 males and 45 females, with a mean age of 42 years. All patients had a history consistent with biliary colic. Forty-nine patients had documentation of cholelithiasis by ultrasonography, 3 had documentation of cholelithiasis by other diagnostic procedures, and 3 had a diagnosis of biliary dyskinesia. The mean surgery time was 75 min, with a range of 43-145 min. Fifty-four intraoperative cholangiography attempts were made, and 81% were successful. In 19%, intraoperative cholangiography was unsuccessful secondary to a small cystic duct. Fifty of the patients (90%) in this study were discharged from the surgery center without significant sequelae. Four patients were admitted to the hospital postoperatively, 1 for bradycardia, 1 for nausea, 1 for i.v. antibiotics secondary to purulent cholecystitis, and 1 for inability to maintain an adequate oxygen saturation. Another patient was admitted 1 week postoperatively for right upper quadrant pain. After a negative hepatobiliary scan, this patient was discharged without sequelae. The average facility charge of laparoscopic cholecystectomy in this series was $2300, compared with the average charge of $6500 in our community hospital. We conclude that laparoscopic cholecystectomy can be performed safely and cost effectively in a freestanding outpatient surgery center with proper patient selection. PMID- 7833513 TI - Extraperitoneal endoscopic inguinal herniorrhaphy performed without carbon dioxide insufflation. AB - Laparoscopic extraperitoneal herniorrhaphy is an alternative to the standard open inguinal herniorrhaphy. The procedure is usually done with general or epidural anesthesia and carbon dioxide (CO2) insufflation. Previously, if the peritoneum was perforated in a patient on whom epidural anesthesia was used, conversion to general anesthesia was required because of the resulting pneumoperitoneum. Eliminating CO2 insufflation from the procedure would obviate this problem. The following is a description of the first 5 reported cases of extraperitoneal endoscopic herniorrhaphy done without the need for CO2 insufflation. PMID- 7833514 TI - Laparoscopic cholecystectomy in acute cholecystitis. AB - Between January 1991 and December 1992, 220 patients underwent laparoscopic cholecystectomy and were monitored prospectively. Twenty-seven patients (12.3%) had acute cholecystitis, according to strict clinical and pathologic criteria. Their average age was 60.4 years. The average operative time was 121 min. Two of the 27 patients (7.4%) required conversion to open laparotomy. The postoperative morbidity rate was 11%. The average hospital stay was 1.9 days. This series provides further evidence that laparoscopic cholecystectomy can be used safely and effectively to treat acute cholecystitis when performed by experienced surgeons. PMID- 7833516 TI - A laparoscopic-assisted extraperitoneal bladder neck suspension: an initial experience. AB - A new procedure is described for the correction of stress urinary incontinence caused by hypermobility of the urethrovesical junction using an extraperitoneal laparoscopic approach with the use of a new needle. There has been no previous publication of this approach. The initial study shows that this procedure offers technical advantages over the existing procedures and requires short hospitalization, less use of postoperative pain medication, and early recovery. We hope to report a long-term follow-up in the future. PMID- 7833515 TI - Metabolic responses to cholecystectomy: open vs. laparoscopic approach. AB - Laparoscopic cholecystectomy is considered a minor surgical procedure. In a prospective, randomized study, we compared the metabolic responses to surgery in two groups of patients submitted to open or laparoscopic cholecystectomy. The aim of the study was to verify if the latter caused less metabolic changes. Blood samples were drawn before the operation (basal), 1 h and 2 h after skin incision, and on the first and second postoperative days. The following parameters were studied: cortisol, renin, and leukocytes, including subpopulations. The mean values for age, weight, height, basal neutrophil and lymphocyte counts, basal values of cortisol and renin of patients, and sex distribution of group 1 patients (open, n = 20) matched with those for group 2 (laparoscopic, n = 20), with the exception of age (p < 0.05). No differences were detected between the two groups in terms of cortisol and renin values. However, the neutrophil count 1 h after skin incision was statistically significantly higher with the laparoscopic approach (p < 0.05). The lymphocyte count on the second postoperative day was also statistically significantly higher in group 2 (p < 0.05). We conclude that when a cholecystectomy is performed, the laparoscopic approach has no advantage over the open approach from the standpoint of the metabolic responses we studied. It appears that leukocytes have a more rapid return to normal values after laparoscopic cholecystectomy. Although pneumoperitoneum is known to be responsible for important cardiorespiratory changes, no worse response was found in the laparoscopic group than in the open group. PMID- 7833517 TI - Measurement of gastric and small bowel electrical activity at laparoscopy. AB - Recordings of gastric electrical activity can be employed in the diagnosis of certain gastric motility disorders. Since the best recordings are obtained from electrodes implanted at laparotomy, the scope of application of this technique is limited. The current study details a method of measuring gastric electrical activity at laparoscopy. The patients were 3 Caucasian women whose age range was 16 to 30 years. Their pertinent history included symptoms of nausea, vomiting, constipation, and abdominal pain. Gastric and small bowel electrical activity was measured with stainless steel electrodes implanted into the serosa of the stomach and small bowel at laparoscopy. Laparoscopy was performed for small bowel biopsy, bowel resection, or feeding tube placement. The recorded signals were evaluated by manual analysis. Good quality gastric and small bowel electrical activities were obtained. Amplitude, frequency, rhythmicity, and direction of propagation information were readily obtained by visual inspection. Laparoscopic measurement of gastric electrical activity produces excellent quality recordings comparable with recordings from electrodes implanted at laparostomy. The technique combines the advantage of laparoscopy with the usefulness of serosal measurement of gastrointestinal electrical activity. PMID- 7833518 TI - The use of absorbable clips in laparoscopic cholecystectomy. AB - A prospective randomized controlled study was conducted to evaluate the use of absorbable clips in elective laparoscopic cholecystectomy. Fifty consecutive patients, 36 females and 14 males, were randomized into two groups. Group 1 patients had metal clips, and group 2 patients had absorbable clips applied on the cystic duct and cystic artery. These patients were followed for 3 months postoperatively. There was no difference between the two groups with regard to operative time, hospital stay, and postoperative complications. The absorbable clips were as effective as the metal clips in providing hemostasis and securing on the cystic duct stump. PMID- 7833519 TI - Extracorporeal knot tying using an atraumatic Babcock clamp. AB - Extracorporeal knot tying is a method of avoiding the difficult and time consuming skill of intracorporeal knot tying and can be equally effective. An endoscopic Babcock clamp can be used instead of the usual knot-pusher devices so that the suture material does not become dislodged. The Babcock clamp lays the knot flat and applies equal traction on each end of the suture. PMID- 7833520 TI - Laparoscopic-assisted bipedicle omental flap mobilization for reconstruction of a chest wall defect. PMID- 7833521 TI - Laparoscopic management of a splenic cyst. AB - Laparoscopic management of a splenic cyst in a 17-year-old patient is discussed. Indications and technical aspects of the procedure are presented. The etiology of splenic cysts and treatment alternatives are discussed. A cyst-peritoneum window was performed successfully using minimally invasive techniques, with a short hospital stay and preservation of the spleen. Minimally invasive surgery provides an alternative to conventional surgical procedures on selected patients with splenic cysts. PMID- 7833522 TI - Endoscopic treatment of vesicoileal anastomotic stricture. AB - A 26-year-old man with anastomotic stricture at the junction of an ileal ureter and the bladder was managed successfully by endoureterotomy. Follow-up at 18 months indicated the absence of recurrent stricture. To our knowledge, endourologic management of an ileovesical anastomotic stricture has not been reported previously. PMID- 7833523 TI - Planned laparoscopic repair of a spigelian hernia using a composite prosthesis. AB - A planned elective repair, via the laparoscope, of a spigelian hernia is described. The repair was performed using a composite mesh prosthesis consisting of a sandwich of polyester fiber mesh and polyglactin 910 mesh, sutured together with polyglactin 910 suture at the operating table before introduction. The technique is applicable to other hernias of the anterior abdominal wall. PMID- 7833524 TI - Laparoscopic ventral hernia repair. AB - Laparoscopic repair of ventral hernia can be done with advanced training. We present a case report with intraoperative photographs and description of the surgical technique. PMID- 7833525 TI - Laparoscopic management of appendiceal intussusception associated with villous adenocarcinoma. AB - The authors present a case of appendiceal intussusception, a rare finding that can be associated with appendiceal neoplasms. A 74-year-old woman with right lower quadrant abdominal pain was found to have an appendiceal intussusception associated with a villous adenocarcinoma and was managed with a laparoscopic assisted right hemicolectomy. This case is presented along with a review of the symptoms, diagnosis, classification, and appropriate management of this entity via laparoscopy. PMID- 7833526 TI - The XXIInd National Conference of Immunology. Autoimmune manifestations in some rheumatic diseases: pathogenetic and therapeutic aspects. Bucharest, 20-22 September 1993. Proceedings and abstracts. PMID- 7833527 TI - Tissue injury induced by immune complexes--the most important pathogenical mechanism of collagen and rheumatic diseases. PMID- 7833528 TI - Modern techniques of immunomodulation in rheumatoid arthritis. PMID- 7833529 TI - The role of cytokines in the pathogenesis of autoimmune processes in some rheumatic diseases. PMID- 7833530 TI - Immune intervention in autoimmune diseases--MHC blockade. PMID- 7833531 TI - On the size of Hassall's corpuscles in human fetuses. AB - The areas of prevailingly solid (SHC) and prevailingly cystic (CHC) Hassall's corpuscles in the thymuses of both male and female fetuses 16-39 weeks old were established. The results show that the mean areas of the Hassall's corpuscles increase with fetal age, with the greatest difference between the 16-19 week and 20-23 week age groups. The data indicate that the thymus represent an organ showing a developmental pattern similar to other organs like the spleen's relative growth in human fetus, whose functions are different during the fetal period, being necessary to study its growth in distinct short periods to determinate differentials growth coefficients. PMID- 7833532 TI - Quantitative study of the lysosomes of epithelial cells from human mammary glands and fibroadenoma during proliferative and secretory phase of the menstrual cycle. AB - The cyclic lysosome number variation in fibroadenoma and normal breast epithelial cells in 13 women, using light microscopy and Gomory acid phosphatase method, was studied. The menstrual cycle phase was determined by the last menstrual period, plasmatic progesterone level and endometrium biopsy. Seven lumps were extirpated in the proliferative phase and other 7 in the secretory period. The lysosomes were counted in the fibroadenoma and the normal breast epithelia. The statistical analysis of the findings showed that both fibroadenoma and normal breast epithelia present a number of lysosomes statistically higher in proliferative than in the secretory phase. It was also noted that the number of lysosomes in fibroadenomas is always greater than in the normal breast, independently of the phase of the menstrual cycle. PMID- 7833533 TI - Oxytocin-immunoreactive nerve cells in the supraoptic nucleus of the hypothalamus after treatment with histamine. AB - Immunohistochemical, morphometric and statistical methods were used to study oxytocin immunoreactive elements in the supraoptic nucleus (SON) of the hypothalamus of 180 male rats. Untreated rats, rats that were given either an intraperitoneal (ip) or intracerebroventricular (icv) injection of histamine (HA) (n = 40 each group) and control animals that received ip or icv injections of saline were included in our study. Oxytocin immunoreactive neurons and oxytocin labelled nerve tracts were found in the SON of untreated animals. Treatment with saline either intracerebroventricular or intraperitoneally did not modify the oxytocin immunoreaction described for untreated animals. I.c.v. treatment with HA increased the numbers of oxytocin labelled elements. On the contrary, oxytocin immunoreaction after intraperitoneal treatment with HA was similar to that described for control and untreated animals. The morphometric and statistical studies confirmed these findings. The importance and signification of these results are discussed in this paper. PMID- 7833534 TI - [Relative growth of the pancreas in the human fetus]. AB - The relative growth of the pancreas was studied in 30 human fresh fetuses of known age (ranging from 2nd to 3rd trimesters) by using of the allometric method (Y = a X b). The weight of the pancreas (in grams) was correlated to the fetal parameters of maturity: age (in weeks), crown-rump length (in millimeters) and fetus weight (in grams). The growth of the weight of the pancreas presented positive allometry relative to gestational age and C-R length (b = 4.16 and 3.90 respectively), and light positive allometry relative to the weight of the fetuses (b = 1.15). These data are important today because non invasive methods like ultrasonography make possible to investigate the normal prenatal growth of several organs. PMID- 7833535 TI - Volumetric and histochemical characteristics of the glomerular zone of the rat adrenal gland 90 days after exposure to detergents. AB - Using the methods of volumetry and histochemistry of the cells, we investigated the morphophysiological characteristics of the glomerular zone of the adrenal gland in rats which, after a 1-month exposure to the effects of detergents in a factory, lived through another 90 days under laboratory conditions. At the same time, control rats lived under normal conditions. The changes found in lipids and nucleic acids were manifested by different reaction of the cells in comparison with the controls. The volumetry of the cell nuclei in the glomerular zone showed statistically significant differences in the correlation of the experimental and the control animals from the aspect of the functional state of this part of the adrenal cortex. This was corroborated by the findings obtained using the methods of histochemistry. PMID- 7833536 TI - Synaptophysin expression during in vitro neuronal differentiation. An immunocytochemical and a confocal laser microscopic study. AB - Primary neuronal cultures from mammalian fetal brains are widely used for morphological, biochemical and pharmacotoxicological studies. The usefulness of relatively pure neuronal cultures are now demonstrated for such studies. We have compared the neuronal survival and differentiation, the synaptophysin expression and the glial cell percentage in primary neuronal cultures using two different media: a M1 medium containing 10 % fetal calf serum and a M2 medium supplemented with hormones, ions and chemicals. Our study demonstrates that the M2 medium (a serum-free defined medium) is associated with an increased survival at 14 days of culture, an earlier neuronal differentiation and synaptophysin expression in cell bodies and neurites as it was confirmed by immunocytochemical and confocal laser microscopic studies. PMID- 7833537 TI - [The corrosion casting technique for the study of the temporal bone and its contents]. AB - The study, learning and teaching of the temporal bone complexity requires different methods. One of them, it's the corrosion cast technique (repletion corrosion). Using soft masses in its final solid state permits to obtain casts of a big discriminating power. This methodology permits to study size, extension and relations of the temporal bone contents, working on with the classic methods of studying this bone. PMID- 7833538 TI - Carotid artery disease and myocardial revascularization. PMID- 7833539 TI - Risk factors for renal dysfunction after coronary surgery: the role of cardiopulmonary bypass technique. AB - We studied 316 patients undergoing cardiopulmonary bypass for coronary artery surgery in order to determine perioperative risk factors for postoperative renal dysfunction. A preliminary univariate analysis was performed by chi 2 analysis for categorical data and Mann-Whitney U-test for continuous variables to detect significant correlations between each risk factor and the occurrence of moderate or severe renal dysfunction. Subsequently, a multiple logistic regression was applied to the three risk factors identified as predictive for severe renal dysfunction. Low cardiac output syndrome and need for banked blood transfusions combined with a low haematocrit value during cardiopulmonary bypass increase the probability of severe renal dysfunction in the postoperative course. PMID- 7833540 TI - Selective heparinization of the extracorporeal membrane oxygenation circuit using continuous infusions of protamine and heparin in a short-term pig model. AB - Systemic heparinization is required for both neonatal and paediatric extracorporeal membrane oxygenation (ECMO). However, it places the patient at risk of serious haemorrhage. We report an alternative: 'selective' heparinization of the ECMO circuit using a continuous infusion of heparin near the venous catheter as blood enters the circuit, and a simultaneous protamine infusion near the arterial catheter as blood enters the patient. Theoretically, the circuit remains heparinized while the patient maintains near-normal clotting activity. Three healthy piglets were placed on venoarterial ECMO in standard fashion. When the animal and its extracorporeal circuit flow were stable, a protamine infusion was begun: 1 mg of protamine to neutralize each 100 units of infused heparin. No haemodynamic instability was noted during the five hours of each study. Mean activated clotting times (ACT) were significantly lower in all three piglets than in their respective circuits (p < 0.001). We conclude that 'selective' heparinization of the ECMO circuit is possible using continuous infusions of protamine and heparin in a short-term piglet model. PMID- 7833541 TI - Rethinking the AAMI/ISO 'International Standard' for oxygen transfer performance of artificial lungs. AB - We believe we have fulfilled the five objectives outlined in the introductory section to this text. Unquestionably, the clinical perfusionist will be confronted with a set of conditions that do not match the very specific values proposed for our in vitro performance testing. The in vitro results for a particular brand of oxygenator can serve as a 'performance baseline', predicting oxygen transfer performance under standard conditions. It is encumbant upon the clinical perfusionist to assess the impact that each variable (i.e. Hb, blood flow and SvO2) will have on the overall oxygen transfer performance. Table 5 illustrates how increases or decreases in each of these three variables can influence the resulting VO2/minute. The clinical perfusionist must manipulate these variables in order to satisfy the oxygen transfer demand created by the patient on CPB. In order for the in vitro performance testing to be helpful in the clinical environment, the perfusionist must: (1) be familiar with the results and the conditions under which they were achieved; and (2) be able to assess and interpret how their current set of conditions on cardiopulmonary bypass will impact on the oxygenator's performance. Example Brand Y membrane oxygenator is being used clinically on a patient weighing 115 kg and consuming 320 ml O2/minute. According to Table 4, this VO2/minute exceeds the 277.2 ml O2/minute achieved during its in vitro performance test.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7833542 TI - Determination and comparison of heat exchange efficiency of four commercially available blood cardioplegia sets. AB - An in vitro comparison of the heat exchange properties of the Electromedics D1081A, Sarns MP-4 'Conducer Coil' 165720, Bentley HE-100 and the Shiley BCD Plus 4: 1 blood cardioplegia sets was performed. The efficiency was calculated for each heat exchanger and post-heat exchange blood path temperatures were compared. The calculated efficiency for each heat exchanger is as follows: Electromedics D1081A at 18 l/minute coil water flow (0.95); Sarns MP-4 165720 at 9 l/minute coil water flow (0.93); Bentley HE-100 at 10 l/minute coil water flow (0.91); Shiley BCD Plus at 15 l/minute coil water flow (0.90). Blood path, precoil temperatures for each unit were compared statistically with no differences found (p > 0.05). Blood side, postcoil temperatures were then compared. The average postcoil blood path temperature of the Electromedics D1081A was 1.6 degrees +/- 0.1 degree C, of the Sarns MP-4 165720 it was 2.1 degrees +/- 0.1 degree C, of the Bentley HE-100 it was 2.7 degrees +/- 0.3 degree C, and the Shiley BCD Plus 3.0 degrees +/- 0.4 degree C. The results of this experiment indicate that the average postcoil temperature of the Electromedics D1081A was lower than the Sarns MP-4 165720 (p < 0.05) which was lower than that of the Bentley HE-100 (p < 0.05) and Shiley BCD Plus (p < 0.05). No statistical difference was found between the average postcoil temperature of the Bentley HE-100 and the Shiley BDC Plus. PMID- 7833543 TI - D-901 neonatal oxygenator: a new perspective. AB - Five infants with congenital heart disease were perfused with the D-901 neonatal oxygenator at the time of their cardiac surgery. The ability to reduce the prime volume below the blood volume as well as the blood handling and gas transfer characteristics were studied. In all cases the prime volume was less than or equal to the blood volume of the patient. This resulted in a reduction in the use of homologous blood products. Due to the concept of the D-901 it was possible to adapt the tubing in such a way that a complete prime of 220 ml was obtained. The device had a maximum oxygen transfer of 45 ml/min. The maximum carbon dioxide removal was 50 ml/min at a blood gas ratio of one. The mean platelet count post bypass decreased to 91% of the baseline value. Mean free haemoglobin levels increased to 86 mg/100 ml at 120 minutes of bypass. We conclude that the D-901 oxygenator opens new perspectives for perfusion in small babies in terms of priming volume and use of homologous blood products while maintaining good gas transfer characteristics. However, larger series are necessary to expand our experience with this device and its limitations. No specific problems related to the device were encountered and all infants had an uneventful postoperative course. PMID- 7833544 TI - Air handling characteristics of five membrane oxygenators. AB - This project looked at the potential of five different membrane oxygenators to allow passage of catastrophic quantities of air in a clinically simulated environment. All the oxygenators were set up in an identical circuit using heparinized human blood as the perfusate. The study was carried out at flow rates ranging from 1.0 to 6.0 l/min. The clinical situation of obstructed venous drainage was simulated by clamping the venous return line at each respective flow rate, while the initial level of blood in the open system hard shell venous reservoir was maintained at 600 ml. The time interval between the application of the clamp on the venous line and the first appearance of macroscopic air in the arterial line was recorded at each level of flow rate. A graph of time versus flow rate was plotted for each oxygenator type. At a flow rate of 6 l/min, the Safe II oxygenator took 20 seconds to allow passage of air after the venous line was clamped, while it took the Bentley Univox Oxygenator only 10 seconds. The Dideco oxygenator, which has a valve incorporated in its reservoir, did not, however, allow any air to be pumped forward at all. At low rates, some of the oxygenators offered protection against passage of air into the arterial line. Thus the Cobe oxygenator offered protection at flow rates of less than 2 l/min, the Safe II oxygenator at flow rates of up to 2.5 l/min and the Bard oxygenator at flow rates up to 3 l/min.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7833545 TI - Clinical evaluation of the Medtronic Maxima Plus membrane oxygenator. AB - The purpose of this study was to clinically evaluate the degree of improvement, if any, in the oxygen transfer performance of the recently released Medtronic Maxima Plus membrane oxygenator. The outside diameter of the hollow fibres was reduced, increasing the membrane surface area from 2.0 m2 to 2.3 m2 without altering the polycarbonate housing. Maximum extrapolated oxygen transfer of the Maxima Plus (444 ml O2/minute) was increased 23.68% when compared to the Maxima (359 ml O2/minute). When expressed per metre squared of membrane surface area, the Maxima Plus had an increase of 13.5 ml O2/m2/minute (7.24%) over the Maxima. Pressure drop across the Maxima Plus was within 3.5 mmHg of the Maxima over the range of clinical blood flows indicating that the fibre bundle packing density was not significantly altered. Oxygen transfer consistency, expressed as a function of the standard deviation of oxygenator performance index values, was not significantly different for the two oxygenators. We concluded that the improvement in total oxygen transfer was due to an increase in membrane surface area as well as enhanced transfer efficiency per metre squared. We believe that the improved oxygen transfer performance was accomplished without impacting significantly upon the other attributes of the oxygenator (e.g., pressure drop, consistency, priming volume). PMID- 7833546 TI - Clinical evaluation of the CDI System 400 blood gas monitor. PMID- 7833547 TI - International Symposium on HIV Infection in Children. Valencia, Spain. PMID- 7833548 TI - The global HIV pandemic. AB - The paper reviews the distribution, transmission patterns, and likely impacts of the HIV pandemic at the beginning of 1993. As of early 1993, a cumulative total of 611,589 cases of AIDS were reported to the World Health Organization (WHO); however, because of less than complete diagnosis and reporting, the WHO estimates that a total of 2.5 million cases of AIDS had actually occurred. As of early 1993, the WHO estimates that there have been approximately 13 million infections, of which about 1 million have been in children. By the year 2000 the WHO predicts that there will be 30-40 million cumulative infections in the world, of which 90% will be in developing countries and almost half will be among women. The epidemic of HIV infection in the decade of the 1980s will result in an epidemic of AIDS in the 1990s, which will place great social and economic strains on many countries, particularly those in many areas of the developing world. PMID- 7833549 TI - Mass media and HIV epidemia in the United States. PMID- 7833550 TI - The role of UNESCO in school-based education for the prevention of AIDS. PMID- 7833551 TI - Maternal and pediatric AIDS in the United States: the current situation and future research directions. AB - The epidemic of HIV infection and disease in women, adolescents and children represents a complexly intertwined biological and social challenge to health care workers and researchers alike. When considering various issues in confronting this epidemic, women must be viewed as individuals important in their own right, as the primary caretaker of their family members (both infected and uninfected), and as the sexual partners of men who may or may not be infected. Of the myriad of compelling biological questions facing AIDS researchers today, two of the most interesting involve the timing and determinants of vertical transmission and the natural history of HIV infection and disease in women. Scientifically, confronting this epidemic involves research into pathogenesis, epidemiology, natural history, treatment, and prevention of HIV infection. Primary emphasis in the research arena in HIV/AIDS in the United States is focused on therapeutic and prophylactic research. Other research issues are very important, including studies of early diagnostic techniques, behavioral research concerning reproductive choices, the role of breastfeeding in HIV transmission, HIV-specific adolescent issues, and surrogate markers of disease progression. PMID- 7833552 TI - Epidemiology of HIV infection in children in Italy. The Italian Register for HIV Infection in Children. AB - As of April 1992, 2337 children born to HIV-1-positive mothers were recorded by our multicentre study. Another 131 children were infected by contaminated blood products, while in 5 cases the risk factor remained unknown, as their personal history was lacking. The number of perinatally exposed children increased exponentially from 1981 to 1986, then stabilized. Of these, at last visit 624 were infected (531 P-2, 93 P-1), 463 were P-O and 1195 had seroreverted. Drug addiction continues to be the most frequent maternal risk factor, although infection acquired through sexual contact gradually increased up to 26.5% in 1991. Of the 762 first children identified at birth and older than 15 months of age, 132 (17.3%) acquired infection and seroconverted to HIV. A similar transmission rate was observed in 43 second-born children. PMID- 7833553 TI - Epidemiological and serological studies in HIV-infected Ethiopian immigrants to Israel. AB - In the last 10 years, Ethiopian Jews have immigrated to Israel in large numbers. Up to 1990 they came directly from their remote villages in northern Ethiopia and no HIV infection was detected in the several thousands that came. In contrast, 1.74% of approximately 14,000 new immigrant Ethiopians who arrived in 1991-92, after spending more than a year in Addis Ababa, were HIV positive. Several infants born in Israel following the latter immigration were found to be infected, whereas more than 2500 children born in Ethiopia were negative. Sexual transmission during their stay in Addis Ababa is thought to be the only route of infection, and therefore this is a newly infected population. Immunological studies revealed very low CD4 count in HIV-infected people. HIV-negative Ethiopian immigrants to Israel also have a lower CD4 count than the general Israeli population. Further studies are currently under way to look at the natural history of this particular HIV-infected group. PMID- 7833554 TI - Prevention program of HIV infection in Ethiopian new immigrants to Israel. AB - In 1991, more than 15,000 Ethiopian Jews immigrated to Israel after spending more than a year in Addis Ababa. They came from remote villages and had had no contact with modern medicine for centuries. About 2% of these new immigrants were found to be HIV positive. Their completely different background forced the Israeli government to develop a special educational program explaining about the modes of HIV infection and prevention measures. The staff participating in the program were mainly Ethiopian Jews who immigrated to Israel before 1990 and were employed as nurses or social workers. The goal of the study was to prevent the spread of the virus; thus the target population was those who were infected with HIV. As most of them were illiterate, posters with pictures were used to explain risk factors, and lectures were given explaining what a virus is and, especially, the "carrier state". Using this program the spread of HIV inside the Ethiopian community seems to have diminished. PMID- 7833555 TI - Mother-to-child HIV-1 transmission: quantitative assessment of viral burden as a diagnostic tool and prognostic parameter in HIV-1-infected children. AB - Polymerase chain reaction was performed in 251 infants born to HIV-1-seropositive mothers to diagnose HIV-1 infection. Assay specificity was invariably > 95%, regardless of age at testing, while sensitivity ranged from 15% in neonates (within 48 h of birth) to > 95% in infants over 1 month of age. Evaluation of viral burden in 43 infected infants by means of quantitative DNA-PCR disclosed that the number of HIV-1 proviruses ranged from 5 to 947 per 100,000 peripheral blood mononuclear cells. Clinical follow-up demonstrated that a high viral burden was associated significantly with disease onset. PMID- 7833556 TI - Application of the polymerase chain reaction for the detection of HIV in specimens from newborn screening programs. AB - The use of the polymerase chain reaction (PCR) permits detection of HIV proviral DNA in the universally collected "dried blood spot specimens" of newborn screening programs. Detection of HIV proviral DNA among the annual cohorts of seropositive specimens from ongoing anonymous newborn HIV seroprevalence studies can provide a laboratory-based estimate of maternal-infant transmission rates. Preliminary data suggest that maternal-infant transmission rates may be higher in areas where the newborn seroprevalence rates are highest. PMID- 7833557 TI - Autoimmune phenomena in children with human immunodeficiency virus infection and acquired immunodeficiency syndrome. AB - We have studied sera from 44 children with Human Immunodeficiency Virus infection and Acquired Immunodeficiency Syndrome using immunoblotting, radioimmunoassay, enzymoimmunoassay and indirect immunofluorescence. We have detected a low incidence of antinuclear (2.9%), anti-reticulin (2.9%) and anti-smooth muscle (14.7%) antibodies by indirect immunofluorescence. By enzymoimmunoassay we have detected anti-dsDNA (20.5%) and anti-ENA [anti-nRNP (61.3%), anti-Sm (29.5%), anti-Ro (47.7%) and anti-La (18.1%)] antibodies. Tests for anti-dsDNA by radioimmunoassay were negative, suggesting the presence of low-avidity anti-DNA antibodies. By immunoblotting we have detected anti-C (nRNP) (33.3%), anti-BB' (Sm) (33.3%), anti-Ro (60 KD) (4.5%) and anti-La (11.3%) antibodies. The presence of anti-Ro antibodies was associated with progressive neurological disease. Long term follow-up studies with larger numbers of patients are necessary to evaluate the clinical significance of the presence of anti-dsDNA and anti-ENA antibodies in children infected with Human Immunodeficiency Virus. PMID- 7833558 TI - Evolution of immunological abnormalities in HIV infection by vertical transmission. AB - Forty-four children infected through vertical transmission, from a total of 146 born to HIV-positive mothers, were studied. Immunological data were analysed and compared with those of the noninfected children. Two transmission patterns emerge from the clinical and immunological characteristics: (i) infants infected during pregnancy with severe immunodeficiency and clinical manifestations before the age of 1 year, and (ii) children probably infected perinatally, who have better clinical outcome. Immunological data are important for prognosis and early therapeutic protocols to be established. PMID- 7833559 TI - HIV mass screening of infants and mothers: historical, technical, and practical issues. AB - Screening groups of anonymous infants for HIV antibody, as an index of maternal infection rates, has been a widely used seroepidemiological method since being introduced in 1986 in Massachusetts (USA). One shortcoming has been the applicability only to parturient women, thus necessitating corrections for fertility rates in extrapolation to all women. A second disadvantage has been controversy and confusion about the distinction between anonymous seroprevalence studies and linked testing. However, there have been major advantages such as the "leading indicator" nature of the data obtained. Experience with screening nearly a half million Massachusetts newborns through December 1992 has shown seroprevalence rates stabilizing at 2.4 per 1000, and with consistent 10-fold differences between groups of birth hospitals serving different socio economically defined populations. In addition to predicting the future of the AIDS epidemic in children, the information provides a reference point for comparing the completeness of targeted identifications of HIV infection in mothers and infants. PMID- 7833560 TI - Vertical transmission of HIV infection. AB - Transmission of HIV infection from mother to child may occur before, during or after delivery. Estimates of the rate of vertical transmission range from 15-20% in Europe to 25-35% in Africa. Mother-to-child transmission is associated with progression of disease in the mother, severe prematurity and breastfeeding. The association with mode of delivery needs further investigation. Attention is now being given to intervention to reduce mother-to-child transmission of HIV infection. PMID- 7833561 TI - The opportunistic and bacterial infections associated with pediatric human immunodeficiency virus disease. AB - Opportunistic and bacterial infections remain the leading causes of death of Human Immunodeficiency Virus-infected children, despite recent advances in the diagnosis of HIV infection during early infancy; antiretroviral therapies; advances in the treatment of some infections; an improved understanding of the cellular immune systems during early childhood; and new strategies for the prevention of some infections. However, these advances appear to be changing the natural history of pediatric HIV infection, resulting in an improved and longer life for infected children. This article briefly reviews the epidemiology, predictors, and treatments of the most common infections associated with pediatric HIV disease, including Pneumocystis carinii pneumonia, recurrent bacterial infections, candidiasis, herpes group viruses, mycobacterial disease and cryptosporidiosis. PMID- 7833562 TI - Epidemiology of pediatric human immunodeficiency virus infection in the United States. AB - Human Immunodeficiency Virus (HIV) infection is a growing problem for children worldwide. As of 31 December 1992, 4249 children with Acquired Immunodeficiency Syndrome (AIDS) under 13 years of age had been reported to the US Centers for Disease Control and Prevention (CDC). HIV is transmitted to children predominantly from their mothers. Nearly all cases of HIV infection acquired from blood transfusions in the United States occurred before donor-screening practices were implemented in March 1985. In 1991, approximately 7000 HIV-infected women gave birth to a liveborn infant in the United States, for a prevalence of 1.7 per 1000 women. Despite recent advances in prophylactic therapy for opportunistic infections, Pneumocystis carinii pneumonia remains the most common AIDS-defining illness in children in the United States. If these cases are to be prevented, children born to HIV-infected mothers will need to be identified early and monitored appropriately for CD4+ cell counts to determine the need for prophylaxis. PMID- 7833563 TI - Human immunodeficiency virus type 1 infection and breast milk. The Italian Register for HIV Infection in Children. AB - Major questions are whether mothers infected with the Human Immunodeficiency Virus type 1 (HIV-1) transmit the virus through breast milk and the magnitude of the additional transmission risk. The demonstration of a dose-response effect is an epidemiological method to demonstrate causality. Thus, a study was carried out by the Italian Register for HIV Infection in Children on 961 children of known infection status. Duration of breast-feeding was considered as the level of exposure in 168 ever breast-fed children. Results showed that duration of practice significantly increased the risk of transmission. The adjusted infection odds ratio for one day of breast- versus exclusive formula-feeding was 1.19 with narrow confidence limits (1.10-1.28). In a second study by the Register on 556 children of known infection status and derived prospectively, an infection odds ratio of 2.55 (confidence interval: 1.03-6.37) was calculated in breast- versus exclusively formula-fed children. Several lines of evidence, including the above mentioned data from the Italian Register for HIV Infection in Children, showed a contribution of breast-feeding to mother-to-child HIV-1 transmission. Thus, this practice is now discouraged in HIV-1 infected mothers living in industrialized societies where formula feeding is practical and attainable. Mode of feeding was known in 2183 children enrolled in the Register and born to HIV-1 infected mothers since 1981. It could be observed that feeding habits of at-risk infants changed in Italy in the middle 1980s, when a large majority of subjects was identified at birth.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7833564 TI - Pediatric HIV infection: neurologic and neuropsychologic findings. AB - Neurologic and neuropsychologic findings are early and important prognostic indicators of symptomatic HIV disease among infants and young children. The most common presentations include progressive encephalopathy, loss of motor milestones, and corticospinal tract abnormalities. It is hypothesized that, in some instances, the more severe neurologic manifestations of HIV noted in infancy may reflect the consequences of in utero HIV infection, or the increased vulnerability of infants to HIV infection during a time of rapid brain growth. Current research suggests that infants with basal ganglia calcification and those with plummeting or low CD4+ counts are at particular risk of severe central nervous disease progression. In contrast to infants and toddlers, older children and adolescents appear to demonstrate only subtle neurologic dysfunction until very late in their illness. Findings seen include attentional difficulties, fine motor tremors, visual sequencing problems, and depressive affect. One of the challenges for the 1990s will be rapidly to identify those infants who are at high risk of central nervous system disease progression, and to institute effective treatments that can halt the devastating effects of HIV on the developing brain. In addition to early identification of the high-risk infants, neuropsychologic, neuroimaging and laboratory measures need to be identified that will allow effective monitoring of responses to therapy. PMID- 7833565 TI - Antiretroviral therapy for children. AB - Advances in the development of antiviral drugs have been rapid and dramatic. Since the recognition of HIV-1 as the cause of AIDS in 1984, and improved understanding of retroviral replication and pathogenesis, three antiviral drugs, Zidovudine, Didanosine, and Zalcitabine, have been developed to the point of routine use in humans. There is substantial experience with the former two in children. Despite being unable to cure HIV-1 infection, the benefits of antiretroviral therapy, including extended survival and reductions in opportunistic infections in adults, and improved weight gain and well-being in children, are strong arguments for routine treatment of symptomatic disease. Because these agents may also interfere with human cellular processes and have toxicities including anemia, neutropenia, pancreatitis, and neuropathy, their routine use for the treatment of asymptomatic children requires further controlled study. There are multiple candidate agents being developed for entry into clinical trials. An additional potentially effective strategy is the use of combinations of drugs at the same time or in sequence to maximize the viral targets being attacked, while minimizing toxicity, and to prevent the emergence of a drug-resistant virus. PMID- 7833566 TI - The use of antibiotics in the treatment and prevention of infection in HIV infected children. AB - Children with HIV infection have an unusual susceptibility to bacterial infection, related to several immune abnormalities. Selection of initial antibiotic therapy must be individualized in these children. Patients with community-acquired disease are most likely to have infection by polysaccharide encapsulated bacterial organism, most commonly Streptococcus pneumoniae and less frequently by Haemophilus influenzae type b. If it is possible to treat the patients at home, the use of amoxicillin-clavulanic acid might be appropriate. Other authors propose management with parenteral ceftriaxone because of the better compliance and the malabsorption. In hospitalized patients, concern for Gram-negative enteric pathogens other than polysaccharide-encapsulated organisms requires initial therapy with a third-generation cephalosporine in combination with an aminoglycoside. Trimethoprim-sulfamethizole is the most common drug used in HIV-infected children because it is recommended for the initial therapy and for prophylaxis of pneumocystis carinii pneumonia, which occurs in as many as 42% of these children. PMID- 7833567 TI - HIV vaccine development and clinical trials. AB - The magnitude of HIV pandemic has made the development of HIV vaccines an urgent biomedical research priority. Although the biologic problems in designing a vaccine for a chronic viral infection like HIV are formidable, there has been encouraging progress. More than a dozen first generation prophylactic HIV vaccine candidates have completed phase I human trials that have established the safety and immunogenicity of these products in adults. A phase II trial of two HIV subunit envelope vaccines in adults at high risk of HIV infection is underway in the United States, and preparations for phase III efficacy trials have begun. Preliminary studies are under way to evaluate the potential application of active and passive immunization for preventing vertical transmission of HIV. Because of the higher rate of HIV transmission and a more abbreviated time course to disease, it may be more efficient to evaluate the efficacy of HIV vaccines in HIV infected pregnant women and their offspring than in adults who are exposed sexually to HIV. PMID- 7833568 TI - Longitudinal follow-up studies. AB - A longitudinal study should be undertaken only when there is a clear reason to justify this and a reasonable chance of achieving the objectives. A multidisciplinary approach is often required, and continuity of staff and long term collaboration with colleagues are important for their success. A longitudinal approach is required to estimate the prevalence of an infection in pregnancy and the rate of vertical transmission and to clarify the natural history in infected children. An example of cytomegalovirus infection is given; the parallels with HIV are obvious. PMID- 7833569 TI - Epidemiology of HIV infection in children in Europe. AB - In Europe the Human Immunodeficiency Virus (HIV) epidemic in children is an important public health problem. Reliable epidemiological information varies widely among countries, and there is no standard method to document the pandemia. By September 1992, a total of 81,849 AIDS cases were identified. France had 21,487, Spain 15,678 and Italy 14,784 (63% of all cases). The highest rate per 100,000 inhabitants occurred in Spain (88.9), France had 70.6 and Italy 63.5. The numbers of HIV+ newborns (NB) in Spain were 4673, in Italy 2,693, in Belgium 368, in Scotland 79 and in Holland 11. The highest rate of HIV+ NBs per 100,000 inhabitants occurred in Spain (120.1), the lowest in Holland (0.73). In Western Europe, 82% of all cases were due to vertical transmission. Mothers' venous drug use was the most common form of HIV transmission. PMID- 7833570 TI - Behavioral risks for HIV in adolescents. AB - A psychosocial perspective on adolescent risk behavior is used to highlight aspects of psychological development and social environment that are relevant to sexual activity and substance use. Differences in behavior are also related to factors such as age and gender that have biological, developmental, and demographic implications. Sexual activity and substance use increase during adolescence, and are often interrelated. In the USA in 1992, 69% of 8th graders and 88% of 12th graders had drunk alcohol. In 1990, 54% of high school students had had sexual intercourse. Age of sexual initiation has decreased in recent cohorts, but condom use by adolescents has increased, with 35% of 15-19-year-old women reporting using condoms. Interventions that successfully change adolescent risk behavior take account of the teen's level of development and social context. PMID- 7833571 TI - Adolescents and HIV infection: a clinician's perspective. AB - Increasing concern in the United States has centered on HIV infection in adolescents. While less than 0.4% of all reported cases of AIDS are reported in adolescents 13-19 years of age, it is speculated that upwards of 20% of all AIDS cases have acquired their infection as teenagers. Most cases are now reported to occur among minority youth and most are now related to sexual or drug use behavior. The natural history of HIV infection in adolescents has yet to be defined. Many adolescents have progressed to clinically significant low CD4+ cells by the time their infection is discovered. While traditional risk factors are also risk factors for adolescents, number of sexual partners and noninjection drug use appear to be related to an increased risk of HIV infection in this age group. Prevention efforts must target both techniques as well as one-on-one counselling. Health care providers have a unique role to play in both patient and community education. PMID- 7833572 TI - Policy, ethics, and reproductive choice: pregnancy and childbearing among HIV infected women. AB - As the numbers of women infected with HIV continue to increase, there are more calls for women who are HIV-infected not to have children, or for policies to be created that limit or try to influence the reproductive choices of HIV-infected women. Although motivated by legitimate concerns, such potential policies may be problematic in terms of their threats to the autonomy of women and considerations of justice. An alternative counseling approach is proposed that advocates encouraging HIV-infected women to make reasoned and considered decisions concerning childbearing. Such an approach would require providers to discuss with women not only the medical facts relevant to vertical transmission, but also many of the psychosocial issues relevant to the woman's interest in bearing a child. Moreover, the encounter would be contextualized to include discussion of issues unique to the woman's situation and other family considerations. PMID- 7833573 TI - Paediatric AIDS: a new child abuse. AB - In relation to youth rights, a new view has been created in recent decades that is included in the fundamental law of the child: the recognition of the right to education and the chance to develop a mature personality capable of creativity and liberty. Because of HIV infection it is very important to pay particular attention to the rights of the seropositive child and children born to seropositive mothers, which may be hampered not only in developing countries but also in the industrial world. HIV-affected children and their families are becoming abused and at high risk of becoming abused and this encroaches upon youth rights. As a consequence, in 1991 the Italian Society of Paediatrics issued a "Charter for the rights of seropositive children", which became an important document for all health care and social workers who deal with HIV-affected children. In this paper, we also consider the impact of HIV infection on the three main rights of children: the right to live, the rights of security and the rights of socialization. PMID- 7833574 TI - Myofascial pain, fibromyalgia and chronic fatigue. PMID- 7833575 TI - Treatment of recurrent tension headache: a meta-analytic review. AB - The primary aim of this study was to investigate which treatment, patient, and study characteristics are related to treatment outcome in tension headache. Literature on the subject was obtained by searching for articles published in English through CD-rom Compact Cambridge and PSYCHLIT (1970/1993) on the subjects of headache and tension or muscle contraction in combination with therapy or treatment. Inclusion criteria were prospective design, tension headache, > or = five subjects per condition; pre- and posttreatment scores available, subjects older than 16 years. Each article was independently reviewed and its data encoded by the two authors. Finally, 78 articles with 175 treated and nontreated conditions (total of 2,866 patients) were selected for this study. Meta-analysis revealed that cognitive therapy, relaxation, or electromyelographic (EMG) biofeedback alone or in combination with relaxation were superior to no treatment and to pseudo/placebo therapy. Pharmacological and other therapies were better than no treatment. However, restricting the analyses to studies using a headache diary, the results of pharmacological therapy were comparable to those of placebo therapy. Moreover, a better treatment outcome was found in studies with a relatively short duration of headache complaints (r = -0.31) and with a relatively younger patient sample (r = -0.22). The year of publication was negatively related with improvement (r = -0.36). No relationship between treatment outcome and other treatment characteristics (duration, transfer of treatment), patient characteristics (gender, method of patient recruitment), and study characteristics (internal validity of the study, criteria for diagnosing tension headache, number of patients, drop-outs) was found. These findings suggest that treatment outcome may be affected more by patient characteristics than by treatment characteristics. Finally, some practical and research implications of these findings are discussed. PMID- 7833576 TI - Function and the patient with chronic low back pain. AB - OBJECTIVE: To undertake a comparative examination of the reliability and validity of two frequently used self-report measures of functional disability, the Pain Disability Index (PDI) and the Oswestry Low Back Pain Disability Questionnaire (OLBPDQ). DESIGN: A descriptive ex-post facto design was used in the study. SETTING: Pain clinics and neurosurgical units at three metropolitan hospitals. SUBJECTS: One hundred patients with chronic low back pain of noncancer origin were administered the two questionnaires as part of a larger questionnaire battery. RESULTS: Acceptable internal consistency values of 0.76 for the PDI and 0.71 for the OLBPDQ were obtained. A correlation of r = 0.63 was found between the PDI and the OLBPDQ, supporting the concurrent validity of the two scales. Both the scales were found to be correlated to the Beck Depression Inventory scores (PDI, r = 0.42; OLBPDQ, r = 0.39), with higher disability associated with greater depression. Only the total PDI score was found to be sensitive to functional status differences within the patient sample. CONCLUSIONS: These findings support other recent work in favor of the PDI. The PDI had a slightly higher internal consistency and was more sensitive than the OLBPDQ. PMID- 7833577 TI - Relationship of the Pain Disability Index (PDI) and the Oswestry Disability Questionnaire (ODQ) with three dynamic physical tests in a group of patients with chronic low-back and leg pain. AB - OBJECTIVE: To determine the relationship between overall disability in daily activities, assessed with the Pain Disability Index (PDI) and the Oswestry Disability Questionnaire (ODQ), and impaired performance on three physical tests in patients with chronic low-back pain. DESIGN AND SUBJECTS: The PDI and ODQ were administered in a cross-sectional study, before beginning a back rehabilitation program, to 45 patients with low-back pain of > or = 3 months' duration, with or without radiation to the legs. All patients also performed repetitive sit-up, arch-up, and squatting tests. SETTING: Tertiary care center. RESULTS: Modestly significant (p < 0.05) or significant (p < 0.01) inverse correlations (Pearson's r = 0.30-0.41) were noted between the PDI and the ODQ and all three physical performance tests. When normative data were used, the correlation (Spearman's rs = -0.45) between PDI and the squatting test remained significant (p < 0.01), whereas it was modestly significant (rs = -0.33, p < 0.05) between the ODQ and squatting test and between the PDI and arch-up test (rs = -0.35, p < 0.05). Compared with patients presently working, those on sick leave had significantly higher scores on the PDI and ODQ (Wilcoxon's two-sample test: p < 0.001) and also significantly worse performance on all physical tests (p < 0.001). CONCLUSIONS: The PDI and ODQ, as measures of self-perceived disability, and impaired performance on repetitive squatting, arch-up, and sit-up tests, as measures of physical capability, show some overlap in low-back-pain patients. Both types of disability measures are clearly influenced by the patient's work status. PMID- 7833578 TI - Perception of pain and exertion during exercise on a cycle ergometer in chronic pain patients. AB - HYPOTHESIS: Chronic pain patients (CPP) are generally thought to present with reduced fitness in relation with pain enhancement during exercise. A distortion of exertion perception may coexist, which could lead CPP to reduce physical activities. DESIGN: Case-control study, with a nonrandomized consecutive sample that was age matched. SETTING: A Chronic Pain Unit in a Multidisciplinary Pain Center of a university hospital in a city of > 1,000,000 inhabitants. SUBJECTS: 42 CPP referred for evaluation and 34 controls (staff members and relatives). OUTCOME MEASURES: Fitness index and exertion perception index was obtained by a cycle ergometer test. Trend analysis was performed on pain scores reported on a visual analogue scale during exertion. RESULTS: Male CPP mean fitness index was found to be significantly reduced. No difference in exertion perception was found between groups. Trend analysis of reported pain revealed that 49% of CPP showed a positive trend, 5% a negative trend, and 46% showed no significant trend as exercise intensity increased. There was no significant relation between type of trend and fitness nor exertion perception index. CONCLUSIONS: Only male CPP have a reduced work capacity. Exertion perception seems normal among CPP. The possible distortion of exertion perception as a causal factor in the reduced fitness of CPP has to be rejected. Lack of significant correlation between type of trend of pain while exercising on a cycle ergometer and fitness index shows that one should be careful in proposing that reduced fitness is only related to pain enhancement during exercise in CPP. PMID- 7833579 TI - Profile of Caucasian women with possible genetic predisposition to reflex sympathetic dystrophy: a pilot study. AB - OBJECTIVES: To test possible human lymphocyte antigen (HLA) associations in subjects with reflex sympathetic dystrophy (RSD), and to determine correlation of HLA associations to treatment outcomes. DESIGN: Identification of class I (HLA-A, B, C) and class II (HLA-DR and DQ) (MHC) antigens by well-defined reagents in patients with RSD. SETTING AND PATIENTS: The HLA analysis was performed on 15 Caucasian women attending a university pain clinic and diagnosed with RSD on the basis of strict inclusion and exclusion criteria. OUTCOME MEASURES: Resistance to treatment was defined on the basis of lack of response to conservative management, failure to experience long-term symptom relief after sympathetic blocks, recurrence of pain after sympathectomy, need for palliative treatment, and degree of residual disability at the end of all treatments. RESULTS: A twofold increase of A3, B7, and DR2(15) MHC antigens was observed in the study population compared to control frequencies. Eighty (five of six) of DR2(15) positive patients proved to be resistant to treatment. CONCLUSIONS: The results of this pilot study are the first to suggest a possible genetic diathesis in RSD patients with poor treatment outcome. If this finding can be confirmed in larger studies, strictly defined RSD could constitute the third neuroimmune disorder (besides multiple sclerosis and narcolepsy) associated with DR2(15). Gene(s) conferring susceptibility to RSD may be present within or near the MHC region of the short arm of chromosome 6. Due to the small size of our study group it is imperative that larger studies be done in RSD patients employing strict diagnostic criteria to confirm or refute our original observations. PMID- 7833580 TI - Psychological problems in chronic prostatitis patients with pain. AB - OBJECTIVE: Men with chronic prostatitis are frequently seen in urological practice and are difficult to treat with standard antimicrobial medications. This pilot study was designed to take a different perspective in assessing chronic prostatitis patients with pain by evaluating them using a standard chronic pain clinic psychological approach. DESIGN: Twenty men, 27% of the referred group of patients with chronic prostatitis and pain, completed the MMPI and a structured psychological interview. Their findings were compared to age- and education matched men seeking treatment for chronic low back pain. SETTING: Data were collected at the Pain Clinic within the Department of Anesthesiology at the University of Washington Medical Center. PATIENTS: Patients were 20 men referred from a urology-based Prostatitis Clinic and 20 men referred to the Pain Clinic for chronic low back pain. RESULTS AND CONCLUSIONS: The two groups differed in the impact of their pain problem on their lives. Prostatitis patients were employed but reported that their symptoms greatly interfered with their sexual/romantic relationships. Back pain patients reported that their pain interfered primarily with work; most of these patients had long-term marital relationships, whereas few prostatitis patients did. Half of the prostatitis patients met criteria for major depression, but back pain patients were more somatically focused, depressed, and anxious. The constellation of relationship problems, disruptions in sexual functioning, levels of depression, along with failure of multiple previous medical treatments in men with chronic prostatitis indicates that continued antimicrobial therapy is unlikely to provide the "cure" these patients seek. Psychological evaluation, couples' counseling, individual counseling, and medications for depression all may play a role in a comprehensive approach to these patients. These results must be considered as preliminary and as representative of a possibly skewed sample of prostatitis patients since only those men who accepted the referral to a pain clinic psychologist for an evaluation were assessed. Clearly, they are likely to be among the patients who are most psychologically and sexually impaired by the chronic prostatitis and associated pain. A further study with less self-selection is indicated. PMID- 7833581 TI - Factors associated with failure of trigger point injections. AB - OBJECTIVE: The purpose of this study was to investigate factors that may influence the outcome of trigger point injections for myofascial pain syndrome. No prior studies have correlated preexisting factors with treatment outcome or assessed the magnitude of risk of treatment failure associated with such factors. DESIGN AND PATIENTS: Thirty-one factors derived from patient evaluation and physical examination were selected according to prior studies of mixed pain groups focusing on clinical importance and ease of assessment in a typical clinic setting. Included in the analysis were 193 patients who received trigger point injections and who completed baseline questionnaires. Factors were analyzed via univariate and logistic regression analyses both for independent association with short-term treatment outcome and for magnitude of risk of failure associated with each factor following adjustment for other factors. RESULTS: In univariate analysis an increased risk of treatment failure was associated with unemployment due to pain at the start of treatment, no relief from analgesic medication, constant pain, high levels of pain-at-its-worst and pain-at-its least, prolonged duration of pain, change in social activity, and lower levels of coping ability. Alcohol use was associated with a decreased risk of treatment failure. In logistic regression analysis, only lack of employment, prolonged duration, and change in social activity were independently associated with treatment outcome. Constant-versus-intermittent pain was included in the logistic model because there was an increase in risk that may be clinically important and because it influenced the effect of change in social activity. These results were not affected by the number or type of additional treatments the patients had. CONCLUSIONS: These results suggest that several factors should be considered in treating myofascial pain patients with trigger point injections, and this study supports the belief that pain is a multidimensional problem and that a variety of factors may influence treatment outcome. PMID- 7833582 TI - Laboratory findings in reflex sympathetic dystrophy: a preliminary report. AB - OBJECTIVE: The purpose of our study was to compare sudomotor and vasomotor indices in patients with clinical reflex sympathetic dystrophy. DESIGN: Vasomotor tone was determined by measuring skin blood flow with laser Doppler flowmeters and skin temperature by infrared thermometry. Resting and evoked sweat output was measured with the quantitative sudomotor axon reflex test. Control values were determined from studies on 223 normal subjects. SETTING: The setting was a tertiary/academic medical center. PATIENTS: There were 12 patients with clinical reflex sympathetic dystrophy in an extremity. MAIN OUTCOME MEASURES: These were skin vasomotor tone and evoked sweat output. RESULTS: Resting sweat output asymmetry was seen in 67% of patients, quantitative sudomotor axon reflex test asymmetry was seen in 75%, and vasomotor changes in 80%. When sudomotor and vasomotor indices were combined, abnormalities were seen in all patients. CONCLUSIONS: Laboratory quantitation of autonomic indices enhances the clinical evaluation of patients with reflex sympathetic dystrophy. PMID- 7833583 TI - Successful treatment of postherpetic neuralgia with oral ketamine. AB - OBJECTIVE: To demonstrate the possibilities of the use of oral ketamine in the treatment of postherpetic neuralgia. SETTING: A pain clinic in a university hospital. PATIENT: A patient with postherpetic neuralgia of the ophthalmic nerve. INTERVENTION: Subcutaneous and later oral ketamine after classical treatment had failed. RESULTS: A complete recovery was accomplished without any sign of side effects. CONCLUSIONS: Oral ketamine may provide an alternative in the treatment of postherpetic neuralgia. The possible mechanism of action by its N-methyl-D aspartate (NMDA) blocking properties is discussed. PMID- 7833584 TI - Referred pain of peripheral nerve origin: an alternative to the "myofascial pain" construct. AB - The theory of myofascial pain syndrome (MPS) has been constructed around the trigger point (TrP), a region within a muscle from which local and remote pain can be evoked by palpation. Although their pathophysiology is obscure, TrPs have been regarded as the cause of myofascial pain. Spread and chronicity of pain are attributed to the activation of latent, secondary, and satellite TrPs. Although it lacks internal validity, this tautological concept has given rise to a system of empirical treatment that has been uncritically accepted by many. However, not only does the anatomical distribution of pain referred from TrPs bear a close relationship to the course of peripheral nerves, but the pain of MPS is also similar to nerve trunk pain, which is an example of somatic referred pain. Pain of peripheral nerve origin can be present without neurological deficit and with normal findings on conventional electrodiagnostic examination. In contrast to the theory of MPS, which considers the TrPs to be sites of primary hyperalgesia, this article argues that all MPS phenomena are better explained as secondary hyperalgesia of peripheral neural origin. PMID- 7833585 TI - Should folate supplementation be routinely recommended for older patients receiving methotrexate? PMID- 7833586 TI - Optimal treatment of venous (stasis) ulcers in elderly patients. AB - In elderly patients, even those with a typical venous (stasis) ulcer, coexisting conditions like peripheral arterial insufficiency and diabetes are very common. Therefore, all elderly patients with leg ulcers should have a complete medical assessment. The mainstay of treatment for venous ulcers is compression therapy, exercise and leg elevation at rest. Long term treatment with double bandages (zinc paste bandages and elastic compression), changed once weekly, is the recommended standard treatment in the elderly. Hydrocolloid dressings are also suitable for long term treatment in clean ulcers, and should be changed once or twice weekly and combined with compression. Sloughy, exudating ulcers might need redressing daily with a desloughing agent for a short period of time. The risk of sensitising patients with chronic leg ulcers is high and few topical preparations, with low antigenicity, should be used. Infection and ulcerated skin cancers should be ruled out in nonhealing ulcers if the patient complies with compression therapy. After healing, the patient should be advised to continue compression therapy with stockings to prevent recurrences. New noninvasive techniques for investigation of venous insufficiency can select patients suitable for venous surgery, but many elderly patients are not interested in surgery or have other ailments that prevent surgery. PMID- 7833587 TI - Anxiety in elderly patients. A comparison of azapirones and benzodiazepines. AB - The onset of primary generalised anxiety or other anxiety disorders during old age is unusual. However, these disorders are often chronic and may persist into old age, so that their occurrence in the elderly population is not rare. Secondary anxiety is also very common and may be related to endogenous stimuli, such as concomitant medical illness, or exogenous events such as loss of friends, change in life status or financial concerns. As the elderly constitute the most rapidly growing segment of the population of many developed nations, this is a problem of significant proportion. Anxiety disorders cause considerable morbidity and dysfunction and have even been shown to increase mortality rates. Nonetheless, the disorders are readily diagnosable if symptoms are properly interpreted. Failure to do so, dramatically and unnecessarily inflates healthcare costs. Certain presentations are more typical in the elderly. For example, somatisation and generalised anxiety are more common, and panic disorder is seen less often, in elderly than in younger patients. Once diagnosed, both nondrug and drug interventions may be effective. Benzodiazepines, although well recognised as useful, have been excessively criticised in terms of general use in the past. Extreme caution is warranted when these agents are used in geriatric patients as they may exacerbate cognitive impairment and cause psychomotor effects that may lead to adverse events and outcomes. Newer agents, such as the azapirones, have a lag-time to onset of action and require patient education for efficient use. They are, however, very effective in elderly patients and have been shown to be remarkably free of dangerous adverse effects. They have a very favourable risk to benefit profile in the elderly. Proper selection of therapeutic intervention allows clinicians to relieve symptoms with minimal risk of adverse effects in elderly patients. PMID- 7833588 TI - Diseases of periodontal tissues in the elderly. Description, epidemiology, aetiology and drug therapy. AB - Periodontal diseases are among the most prevalent conditions in adults, and afflict many individuals of all ages. They refer to a cluster of inflammatory conditions of the periodontium, the tissues that surround the teeth. Ultimately, periodontal diseases cause the loss of alveolar bone support and may lead to tooth loss. The clinical presentation of periodontal diseases is primarily independent of the age of a person, and successful diagnosis and treatment can be achieved in both young and old individuals. These diseases primarily include gingivitis, periodontitis and oral vesiculobullous diseases of the gingival tissues. Multiple oral, systemic and behavioural factors contribute to the occurrence and progression of these conditions. Appropriate treatment requires accurate diagnosis and the use of oral nonsurgical and surgical techniques, topical and systemic medications and an emphasis on self-applied oral hygiene practices. PMID- 7833589 TI - The role of interleukin-6 in certain age-related diseases. AB - Interleukin-6 (IL-6) is a pro-inflammatory cytokine with a wide range of functions. Perhaps the most important physiologically is its role as a mediator of the acute phase inflammatory response. Normally, there is little measurable IL 6 in the circulation, but levels increase abruptly to nanogram amounts during an inflammatory process. During aging, it has been proposed that the tight regulation of IL-6 gene expression becomes less effective and levels are measurable even when there is no evidence for inflammation. Several investigators have identified this cytokine as being involved in the pathogenesis of various disease processes and we have suggested that certain age-associated diseases are directly related. Among these are late-life lymphoma and myeloma, osteoporosis and possibly Alzheimer's disease. PMID- 7833592 TI - Mathematical modeling of corneal epithelial wound healing. AB - We propose a reaction-diffusion model of the mechanisms involved in the healing of corneal surface wounds. The model focuses on the stimulus for increased mitotic and migratory activity, specifically the role of epidermal growth factor. Analysis of the model equations elucidates the interaction and roles of the model parameters in determining the speed of healing and the shape of the traveling wave solutions which correspond to the migration of cells into the wound during the initial phase of healing. We determine an analytic approximation for the speed of traveling wave solutions of the model in terms of the parameters and verify the results numerically. By comparing the predicted speed with experimentally measured healing rates, we conclude that serum-derived factors can alone account for the overall features of the healing process, but that the supply of growth factors by the tear film in the absence of serum-derived factors is not sufficient to give the observed healing rate. Numerical solutions of the model equations also confirm the importance of both migration and mitosis for effective would healing. By modifying the model we obtain an analytic prediction for the healing rate of corneal surface wounds when epidermal growth factor is applied topically to the wound. PMID- 7833593 TI - Modeling protein cores with Markov random fields. AB - A mathematical formalism is introduced that has general applicability to many protein structure models used in the various approaches to the "inverse protein folding problem." The inverse nature of the problem arises from the fact that one begins with a set of assumed tertiary structures and searches for those most compatible with a new sequence, rather than attempting to predict the structure directly from the new sequence. The formalism is based on the well-known theory of Markov random fields (MRFs). Our MRF formulation provides explicit representations for the relevant amino acid position environments and the physical topologies of the structural contacts. In particular, MRF models can readily be constructed for the secondary structure packing topologies found in protein domain cores, or other structural motifs, that are anticipated to be common among large sets of both homologous and nonhomologous proteins. MRF models are probabilistic and can exploit the statistical data from the limited number of proteins having known domain structures. The MRF approach leads to a new scoring function for comparing different threadings (placements) of a sequence through different structure models. The scoring function is very important, because comparing alternative structure models with each other is a key step in the inverse folding problem. Unlike previously published scoring functions, the one derived in this paper is based on a comprehensive probabilistic formulation of the threading problem. PMID- 7833591 TI - Changes in the renin-angiotensin-aldosterone axis in later life. AB - The renin-angiotensin-aldosterone system (RAAS) is one of the main systems involved in the regulation of blood pressure and sodium homeostasis. In animal experiments and in humans, the plasma renin activity and aldosterone levels are reduced with aging. The age-related differences in plasma renin activity and aldosterone are more pronounced in stimulated conditions (when sitting in an upright position, when salt intake is restricted and when plasma volume is depleted) than under basal conditions. Age-related alterations of the kidney (glomerulosclerosis, decreased number of functional nephrons) might account for the age-related differences in the active to inactive plasma renin ratio. In the same way, a diminished synthesis of angiotensinogen by the liver could contribute to the decrease in the activity of the RAAS in aging. This is partially compensated for by increases in the density of angiotensin II receptors reported in elderly patients. Furthermore, aging is associated with a reduced adrenal responsiveness to angiotensin II, contributing to lower production of aldosterone and alterations of sodium homeostasis. Estradiol and progesterone help stimulate the secretion of renin. Reduced levels of these hormones at menopause also lead to reduced plasma renin activity. In relation to these findings, several studies have shown that reductions in blood pressure, induced by short or long term treatment with angiotensin converting enzyme (ACE) inhibitors, were more pronounced in old than young hypertensive patients. An insertion/deletion polymorphism in the ACE gene has been described; the genotype deletion/deletion of this gene has been reported to be closely associated with longevity. This result was unexpected since the same deletion polymorphism was also shown to represent a potent risk factor for myocardial infarction. PMID- 7833594 TI - The basic reproduction ratio R0 for a sexually transmitted disease in a pair formation model with two types of pairs. AB - We study a model for pair formation and separation with two types of pairs which differ in average duration. A fraction f of all newly formed pairs have a long duration (denoted by "steady"), the remaining fraction 1-f have a short duration ("casual"). This distinction is motivated by data about the survival times of partnerships in a sociological survey. In this population we consider a sexually transmitted disease, which can have different transmission rates in steady and in causal partnerships. We investigate under which conditions an epidemic can occur after introduction of the disease into a population where the process of pair formation and separation is at equilibrium. If there is no recovery we can compute an explicit expression for the basic reproduction ratio R0; if we take recovery into account we can derive a condition for the stability of the disease free equilibrium which is equivalent to R0 < 1. We discuss how R0 depends on various model parameters. PMID- 7833595 TI - Multichannel evoked potentials as voltage space trajectories. AB - Multichannel brain evoked potentials can be represented as trajectories V(t) in n dimensional voltage space, analogous to three-channel Lissajous trajectories (3 CLT). Equations of motion are developed based on an arbitrary number of dipole generators at arbitrary locations within the brain, and the properties of 3-CLT are generalized to the higher dimensional case. The trajectory is shown to be limited to k < n dimensions, and k channels are found to be sufficient for predicting the potential difference between any two points on the head, provided that an empirically determined set of linear functionals is known. A method for choosing the "best" m-channel montage (m < or = k) is described, by associating with each montage an alternating m-tensor on Rk. Planar analysis of the voltage trajectories is generalized to the k-dimensional case, in which m-planes are compared using a mapping between the Grassman manifold and real projective space. PMID- 7833590 TI - Age-related changes in signal transduction. Implications for neuronal transmission and potential for drug intervention. AB - Problems associated with aging will become one of the leading health dilemmas of the next century. Age-associated diseases, including those affecting the neuronal system, are increasing in frequency. Age-related deficiencies in the brain result in impaired motor functions, sleep, behaviour and cognitive functions. Good functioning of the brain is based on the communication between neurons, by means of signal sending and processing. Neuronal transmission is a very complex phenomenon which involves neuromediator receptors, ion channels and various signal transduction systems. Aging is associated with modification of many brain neurotransmitter and second messenger systems directly involved in signal transduction. Thus, signal transduction events that are deficient in the aged include calcium mobilisation, phosphatidylinositol breakdown, cyclic nucleotides formation, accumulation of proto-oncogene transcripts and synthesis of new proteins, such as certain neurotransmitters. Other events in signal transduction, such as protein tyrosine kinase activity, G-protein structure and function and receptor-G-protein coupling, have not been studied in great detail as yet. Alterations in these various intracellular signalling events may fundamentally influence the functional activity of neurons, and, in consequence, play an important role in the age-dependent alterations of brain functions. Future studies are needed to better understand the molecular basis and the importance of signal transduction changes with aging. Such knowledge will certainly lead to design of better drugs for the prevention or treatment of age-related deficiencies or diseases, such as Parkinson's disease or Alzheimer's disease. PMID- 7833596 TI - Reconstruction of the seasonally varying contact rate for measles. AB - With the extended Kalman filter the time dependent contact rate for measles in the SEIR-model is reconstructed from data of the incidence of this infectious disease in the city of New York. It is concluded that although these data show through the years an irregular change in the number of infected children the contact rate is definitely periodic and follows the season. The analysis gives improved values of the parameters in the SEIR-model for this special problem. PMID- 7833598 TI - Optimization of the mouse bioassay for deoxynivalenol as an alternative to large animal studies. PMID- 7833597 TI - Follow-up study of intrauterine growth of transplacental Yu-Cheng babies in Taiwan. PMID- 7833599 TI - Inhibitory effect of captan in the small intestine absorption capacity of the mouse. PMID- 7833600 TI - Alteration in the tranquilizing potency of chlorpromazine in rats exposed chronically to the insecticide, endosulfan. PMID- 7833601 TI - Effect of subchronic oral treatment with terbium on gastrointestinal uptake of calcium and phosphorus. PMID- 7833602 TI - Mutagenic effect of extracts from particulate matter collected with sediment traps in the archipelago of Stockholm and the open northern Baltic. PMID- 7833603 TI - Distribution of mercury in the soft tissues of the blue tilapia Oreochromis aureus (Steindachner) after acute exposure to mercury (II) chloride. PMID- 7833604 TI - Mercury accumulation profiles and their modification by interaction with cadmium and lead in the soft tissues of the cichlid Oreochromis aureus during chronic exposure. PMID- 7833605 TI - Alterations in the tissue lipid profiles of Lamellidens marginalis under ambient ammonia stress. PMID- 7833606 TI - Observations on fungal infection of the ovary of laboratory-cultured Daphnia magna. PMID- 7833607 TI - Lipid peroxidation in the gill and hepatopancreas of Oziotelphusa senex senex fabricius during cadmium and copper exposure. PMID- 7833608 TI - Influence of protective agents in the toxicity of cadmium to a freshwater fish (Channa punctatus). PMID- 7833609 TI - Trace metals in gills of fish from the Arabian Gulf. PMID- 7833610 TI - Involvement of metallothionein in cadmium accumulation and elimination in the clam Ruditapes decussata. PMID- 7833611 TI - Sediment trace metal concentrations from the mudflats of Kuala Juru and Kuala Muda of Malaysia. PMID- 7833612 TI - Formation of benzene by hardeners containing benzoyl peroxide and phthalates. PMID- 7833613 TI - Toxicity of heavy metals to bacteria in sediments. PMID- 7833614 TI - Organochlorine contaminants in common tern (Sterna hirundo) eggs and young from the river Rhine area (France). PMID- 7833615 TI - Respiratory metabolism of millipedes after poisoning with cypermethrin. PMID- 7833616 TI - Interactions between subsurface microbial assemblages and mixed organic and inorganic contaminant systems. PMID- 7833618 TI - The flatworm nervous system: pattern and phylogeny. AB - The flatworms occupy a position at the base of the metazoan phylogenetic tree; they have a bilateral symmetric nervous system and an archaic brain. The following aspects, brought into focus by the use of new methods, will be dealt with in the present paper. 1. The high degree of diversity on all levels of the flatworm nervous system (NS). 2. The concept of main nerve cords is defined and the use of this concept in avoiding confusions in the terminology of nerve cords is stressed. 3. The archaic nature of the stomatogastric NS is reviewed. 4. The new data about neuronal celltypes implying advanced features at this low phylogenetic level. 5. The ultrastructural studies of neuronal cells indicating (A) that a common secretory cell type containing dense-core vesicles is archaic and a likely progenitor cell type for conventional neurons of advanced flatworms and (B) that an independent evolution of synaptic structures and glial cells has occurred inside the flatworm taxon. 6. The multitude of neuroactive substances demonstrated by light microscopic histofluorescence, immunocytochemistry, liquid chromatography, and HPLC. The cholinergic, aminergic, and peptidergic substances often occur in different neuronal compartments. PMID- 7833617 TI - Effects of mercury (II) species on cell suspension cultures of Catharanthus roseus. PMID- 7833619 TI - Comparative aspects of peptidergic signaling pathways in the nervous systems of arthropods. AB - Comparative aspects of arthropod peptidergic systems--in principle--can be studied on the level of precursor sequences (genes, preprohormones), peptide sequences (peptide families), and peptide expression patterns within the nervous system. The number of known arthropod neuropeptide precursor sequences is as yet far too small to provide a reasonably large basis for extended comparative studies. Comparative studies of peptide sequences have shown that many peptides belong to families with homologous members in both invertebrates and vertebrates. Comparative research on peptide expression has to find out whether phylogenetic necessities lead to "hard wired" neurochemical identities, i.e., a more or less fixed "Bauplan" that not only determines the lineage and morphology of a neuron but also its transmitter(s), or whether these necessities demand greater flexibility (plasticity), and hence cause great variability that would complicate comparative studies. As will be shown here, both possibilities appear to exist. On the one hand, peptidergic neurons may exist in comparable form in different groups of arthropods. On the other hand, the neurochemical identity of cells may vary in segmented organisms when comparing serially homologous sets of nerve cells in different segments. As a further complication, identical or similar peptides may serve different functions, even in closely related species. In view of these functional aspects in particular, it appears that peptidergic signalling pathways represent rapidly evolving systems. This conclusion, although very interesting in itself, reduces the use of such systems for general comparisons. However, arthropod nervous systems represent excellent model systems for the study of homology. At least for morphological and ontogenetic aspects arthropods provide numerous opportunities to study homology on the level of the individually identified peptidergic nerve cell. PMID- 7833620 TI - Repeating patterns of motoneurons in nematodes: the origin of segmentation? AB - Evolutionarily diverse groups of animals share numerous similarities as individual neurons are assembled into functional neural circuits. One example is the hierarchical sequence of events that individual nerve cells follow during morphological development. In the initial step a presumptive neuron is generated and positioned appropriately. Second, the undifferentiated cell elaborates a growth cone capable of interacting with extrinsic cues and leading the presumptive axonal process as it is guided into areas where potential synaptic targets reside. Finally, the differentiating nerve cell selects among appropriate and inappropriate target cells as it completes the process of selective synaptogenesis. The extracellular matrix molecule laminin provides a second example, this time at the molecular level. Biochemical and genetic studies have shown that this molecule directs process guidance of neurons in vertebrates, annelids, and nematodes. In both examples an interest in neural development has provided a window through which evolutionarily processes have been revealed. The free-living soil nematode Caenorhabditis elegans possesses several features that collectively place it in a rather unique position among metazoans and has allowed genetic and cellular studies to be integrated at the level of identified neurons and neural circuits. This review will focus on developmental studies of C. elegans locomotory neural circuits. General issues that will be addressed are the similarities and differences among different taxa regarding: the relationship between cell lineage and cell fate determination in generating reiterative neural patterns; pioneer cells and the molecular basis for process guidance and finally genetic epigenetic events involved in sculpting highly specific synaptic patterns. PMID- 7833621 TI - The nervous systems of cnidarians. AB - Cnidarians have simple nervous systems and it was probably within this group or a closely-related ancestor that nervous systems first evolved. The basic plan of the cnidarian nervous system is that of a nerve net which, at some locations, has condensed to form nerve plexuses, or circular or longitudinal nerve tracts which may be syncytia. At the ultrastructural level, many cnidarian neurons have the combined characteristics of sensory, motor, inter- and neurosecretory neurons and thus appear to be multifunctional. We propose that these multifunctional neurons resemble the ancestors of the more specialized neurons that we find in higher animals today. The primitive nervous system of cnidarians is strongly peptidergic: from a single sea anemone species Anthopleura elegantissima, we have now isolated 16 different novel neuropeptides. These peptides are biologically active and cause inhibitions or contractions in muscle preparations or isolated muscle cells from sea anemones. The various peptides are located in at least six distinct sets of neurons showing that sea anemone neurons have already specialized with respect to their peptide content. Using immuno electronmicroscopy, we have found that the peptides are located in neuronal dense cored vesicles associated with both synaptic and non-synaptic release sites. All these data indicate that evolutionarily "old" nervous systems use peptides as transmitters. We have also investigated the biosynthesis of the cnidarian neuropeptides. These neuropeptides are made as large precursor proteins which contain multiple (up to 36) copies of immature neuropeptides. Thus, the biosynthesis of neuropeptides in cnidarians is very efficient and comparable to that of higher invertebrates, such as molluscs and insects, and vertebrates. PMID- 7833622 TI - Genesis of segmental identity in the leech nervous system. AB - The Antennapedia-class homeobox genes are likely to play a role in the specification of neuronal identities in invertebrates. The leech Hirudo medicinalis, a species well-suited for the analysis of these genes at the level of identified neurons, contains homologs of many Antennapedia-class and related genes. The expression pattern in the central nervous system of four leech homebox genes was examined in detail. Lox1 is expressed during early gangliogenesis in one pair of transient neurons present in every segment and, at later stages, in 15-20 pairs of neurons per segment. Lox2 is expressed in 25-30 pairs of neurons repeated in the posterior two-thirds of the midbody. Lox4 is present in 20-30 pairs of iterated neurons in the posterior half of the midbody, and in smaller subset of them in more anterior ganglia. Lox6 is expressed in 15-20 pairs of neurons of the third subesophageal neuromere and in fewer cells of more posterior ganglia. The subsets of neurons that express these homeobox genes are different but overlapping. Combinations of Lox genes could in theory generate enough variability to specify all central neurons in a leech ganglion. PMID- 7833623 TI - Antiviral activity of NK 1.1+ natural killer cells in C57BL/6 scid mice infected with murine cytomegalovirus. AB - The activation, proliferation, and antiviral effects of natural killer (NK) cells were examined in a newly developed stock of mice, C57BL/6JSz mice homozygous for the severe combined immunodeficiency (scid) mutation. These mice lack functional T and B cells and express the NK 1.1 alloantigen. Such NK 1.1 expression facilitates the analysis of NK cells and their depletion in vivo with a monoclonal anti-NK 1.1 antibody. These mice, therefore, provide an excellent model to examine unambiguously the interactions between viral infections and NK cells in a system devoid of adaptive immune response mechanisms. Here we show that murine cytomegalovirus (MCMV) and lymphocytic choriomeningitis virus (LCMV) infections resulted in profound levels of NK cell activation. NK cells also proliferated greatly in response to LCMV but generally to a lesser degree in response to MCMV. Depletion of the NK cell activity in vivo caused substantial increases in MCMV synthesis and MCMV-induced pathology. These results further support the concept that NK cells are major regulators of MCMV pathogenesis. PMID- 7833624 TI - Changes in tumor-associated NK 1.1+ large granular lymphocyte precursors after cyclophosphamide injection: in vitro characterization and potential therapeutic application. AB - Large granular lymphocytes (LGLs) could be generated in vitro from tumor associated cells (TACs) derived from the rhabdomyosarcoma, 76-9, but only after treatment of the tumor bearers with cyclophosphamide (CY). The ability to generate LGLs in vitro was dependent on the presence of high concentrations of recombinant interleukin (rIL)-2 and related to the phase of tumor regression induced by CY. Maximum yields of LGLs were obtained when TACs were derived on days 7 or 8 after CY injection. TACs derived on day 8 and grown in rIL-2 for 5 days were shown to express NK 1.1, B220, IL-2 receptor (IL-2R), Thy-1.2 and a late NK cell differentiation antigen identified by monoclonal antibody, 4H12. They did not express MAC-1, CD3, alpha/beta T cell receptor, CD4 or an early NK cell differentiation antigen identified by monoclonal antibody, 3C2. The expression of NK 1.1, B220, IL-2R, Thy-1.2 and 4H12 by TACs growing in rIL-2 was relatively stable over a 12-day period. IL-2-activated TACs were shown to lyse YAC-1 cells, the wild-type 76-9 tumor cells and two clones of the 76-9 tumor, as well as cells from an independently derived sarcoma, 77-23. Intratumor injection of IL-2-activated TACs or rIL-2 after CY injection induced a significant delay in the recurrence of tumor growth. The data suggest that the increase of IL-2 reactive cells after CY injection and their intratumor disposition may indicate a potential for in situ antitumor effects. PMID- 7833625 TI - Natural killer cell suppression of IgM production. AB - The mechanisms by which natural killer (NK) cells regulate B cell function are not well understood. In this paper, the suppressive effects of NK cells on IgM production by lipopolysaccharide (LPS)-stimulated B cells were studied. We found that interleukin (IL)-2-activated NK (NKa) cells, but not unstimulated NK cells, suppressed IgM production by B cells stimulated with LPS. Suppression of antibody production required direct NKa-B cell contact, as demonstrated in cultures utilizing semiporous membranes for cell separation, and was the consequence of a reduction in the number of IgM-producing cells, as determined by enzyme-linked immunospot assays. Suppression could not be accounted for by cytotoxic mechanisms since the NKa cells caused neither cytolysis of 51Cr-labelled B cells or B cell apoptosis. While NKa-B cell contact was necessary for suppression, cell contact alone was not sufficient. Rather, both NKa-B cell contact and NKa production of interferon (IFN)-gamma were necessary. Since only IL-2-activated, but not unstimulated, NK cells suppressed IgM production, we investigated the potential for IL-4, which has been reported to downregulate IL-2-induced NK cell proliferation, to prevent NKa cell suppressive activity. While IL-4 antagonized IL-2-induced NK cell proliferation, it was completely ineffective in antagonizing NKa cell suppression of IgM production. The requirement for IL-2 activation of NK cells for suppression of IgM production suggests that NK cells may be part of a physiologic negative feedback mechanism to downregulate antibody production. PMID- 7833626 TI - Expression and functional role of dipeptidyl peptidase IV (CD26) on human natural killer cells. AB - The expression and functional role of dipeptidyl peptidase IV (DP IV, CD26, EC 3.4.14.5) was studied on human natural killer (NK) cells. Here we show that freshly isolated NK cells do express only low amounts of DP IV. However, after IL 2 stimulation of NK cells (70% purity) surface DP IV expression was significantly increased in a subpopulation (30%) of these cells. Specific DP IV inhibitors (Lys [Z-(NO2)]-piperidide, Lys-[Z(NO2)]-thiazolidide) and polyclonal antibodies directed against the ectopeptidase suppressed DNA synthesis and cell cycle progression of NK cells. The natural cytotoxic activity of DP IV+ CD56+ cells was found unchanged in comparison to those of DP IV- CD56+ cells. DP IV inhibitors had no effect on the natural cytotoxicity of mononuclear cells. From these data we conclude that DP IV is involved in the regulation of proliferation of NK cells, whereas natural cytotoxicity seems to be regulated independently. PMID- 7833628 TI - Strengthening the global network. PMID- 7833627 TI - Effects of N-(4-hydroxyphenyl)-retinamide on the number and cytotoxicity of natural killer cells in vitamin-A-sufficient and -deficient rats. AB - N-(4-hydroxyphenyl)retinamide (4-HPR), a synthetic retinoid with anticarcinogenic activity, has been shown to lower the plasma retinol level rapidly and significantly. We reported previously that vitamin A-deficient rats (plasma retinol < 0.175 mumol/l) have a low number of natural killer (NK) cells in peripheral blood. To investigate the effects of 4-HPR on NK cell number and activity, two studies were conducted. In study 1, vitamin-A-sufficient rats were fed a 'therapeutic' dose of 4-HPR (2 mmol/kg of diet) for 30 days. Despite a low plasma retinol concentration (approximately 0.1 mumol/l), the number of NK cells was not reduced. Moreover, the NK cytolytic activity per cell was significantly elevated. White blood cell and differential counts were normal. In study 2, the biological activity of 4-HPR was examined in vitamin-A-deficient rats. Rats depleted of vitamin A were fed a diet containing 4-HPR (54.7 micrograms/g of diet) for 11 days. Vitamin-A-dependent processes including growth, hematocrit, lymphocyte count and the number of NK cells were restored. For comparison, another group of vitamin-A-deficient rats were repleted with retinoic acid (RA; 4.2 micrograms/g diet); this treatment also effectively restored these vitamin-A dependent processes. Therefore, despite the plasma-retinol-lowering property of 4 HPR, treatment with this retinoid did not impair NK cell number or function. Indeed, 4-HPR showed vitamin A activity similar to RA, and may stimulate NK cell cytotoxicity. PMID- 7833629 TI - Problems following discharge after intensive care. AB - Intensive care units (ICUs) are now present in most acute care hospitals. While long-term studies on patients admitted to these units have been performed to identify mortality, functional outcome and quality of life, there is little information on the recovery period in the weeks immediately following discharge. The aim of this study was to identify and describe the sequelae found in patients at 3 months after leaving the ICU. The study was conducted over a 6-month period during 1991, in a university teaching hospital in Sydney, Australia. 54 patients with a length stay (LOS) of greater than 48 hours in the ICU were included. Each patient was interviewed in an outpatient clinic attached to the ICU. Information collected included pre-admission details, reason for admission, treatments provided and complications encountered. General health state, social and employment details, functional status, referral patterns since discharge and recollection of ICU stay were studied. The major findings indicated that many of the patients interviewed were returning towards near normal general health, but were suffering mild to moderate physical and psychosocial sequelae. In the majority of cases the problems were not incapacitating. The predominant complaints were minor to severe pain, sleeping difficulties, tiredness and breathlessness. Financial problems were reported by a small number of patients. Depression, irritability or a feeling of loneliness were present in over one third of the group. More than half the patients required referral for further assessment. 34% of patients had no recollection of their ICU stay. 16 patients (29.6%) reported unpleasant memories including nightmares and hallucinations.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7833630 TI - Intestinal barrier failure and the development of the systemic inflammatory response syndrome. AB - At the present time, terms used to describe the clinical entity of sepsis are used inappropriately and interchangeably. The source and foci of infection are often unidentified, yet it is clear that some form of inflammatory episode is occurring. The following paper seeks to clarify the terminology used to describe 'sepsis' and link this with a non-bacteraemic source of this inflammatory response--the small intestine. The importance of accurately reflecting oxygen extraction and oxygen consumption by cells is addressed and a movement from the current emphasis on haemodynamic measurement to variables which reflect metabolic rate and lactic acidosis is discussed. Issues which are the concern of nurses working in intensive care are examined, in terms of primary prevention and secondary management. PMID- 7833631 TI - Bereavement care: relationships between the intensive care unit and the general practitioner. AB - This study examines relationships between an intensive care unit and the general practitioners within a local health authority in respect of bereavement care. A questionnaire to all 113 local general practitioners generated a response from 67 (59.3%). While about two-fifths of respondents reported at least one of their patients dying on the intensive care unit, half said that they were often first informed by relatives. Although four-fifths of inner city general practitioners offered some form of bereavement service, it ranked lowest in terms of priority on time, and a further one-seventh provided no service at all. Half the respondents thought that hospital staff could do more to help. The implications for practice are discussed. PMID- 7833632 TI - Learning from the experience of loss: people bereaved during intensive care. AB - In Hartlepool Intensive Therapy Unit (ITU) nurses have recently addressed the needs of relatives while they are visiting the department and afterwards during their bereavement. However in order to determine how best to improve nurses' service we decided to ask those people bereaved their opinions about their experience in order to meet their requirements in the most appropriate way. 16 recently bereaved relatives were interviewed concerning a variety of areas, including information they received in the ITU, support they were given by nurses, how they coped after their loss, and suggestions for improvements. Although this was a small study important areas for improvement were highlighted, and we have now been able to address these further in nursing service and make plans for future developments. PMID- 7833633 TI - Developing an information booklet to meet the needs of intensive care patients and relatives. AB - Changes in the economic climate and the delivery of health care require that preoperative information programmes are effective and efficiently implemented. In order to be effective the pre-operative programme must meet the information needs of intensive care unit (ICU) patients and their relatives. Efficiency can be achieved through a structured pre-operative programme which provides a framework for teaching. The need to develop an ICU information booklet in a large teaching hospital in Northern Ireland has become essential to provide relevant information and improve the quality of service for patients and relatives, as set out in the White Paper, 'Working for Patients', (DoH, 1989). The first step in establishing a patient education programme was to ascertain patients' and relatives' informational needs. A 'needs assessment' identified the pre-operative information needs of ICU patients and their relatives (McGaughey, 1994) and the findings were used to plan and publish an information booklet. The ICU booklet provides a structure for preoperative visits to ensure that patients and relatives information needs are met. PMID- 7833634 TI - A right to die? AB - Often nurses within the critical care setting face moral dilemmas when confronted with issues surrounding resuscitation and withdrawal of treatment. In this article the nurses' role and the patients' rights regarding resuscitative measures and withdrawal of basic and advanced forms of life support are discussed. Cases that have improved decision-making have been used to illustrate the dilemmas involved. It is hoped that critical care nurses will become more aware of their vital role when these decisions are being made. PMID- 7833635 TI - Children visiting members of their family receiving treatment in ICUs: a literature review. AB - Occasionally people ask if children can visit members of their family who are patients in our intensive care unit (ICU). To allow us to devise a unit policy based on research, the author felt it necessary to review literature concerning child visitors to ICUs, more specifically the reasons why they should or should not be allowed to visit. Unfortunately very little has been written about the effects of visits to ICU on children; so it was felt that it would be beneficial to review the literature concerning child visitors to wards other than ICUs, as well, and also review the reasons behind hospital visiting policies for adults. The literature reviewed suggested that no reasons have been found not to allow children to visit but that advice should be given to the parents allowing them to come to the final decision. If the parents then decide to allow the child to visit, further support for all the family should be given. PMID- 7833636 TI - The care and rehabilitation of cardiac patients and their families: a report of a study tour of the USA. AB - I visited four centres of clinical cardiac care and rehabilitation to examine, compare and discuss the development of nursing research and practice and the application of this knowledge to patients and their families after a heart attack or cardiac surgery. The key areas examined were the organisation of services, specific interventions, and outcome and evaluation criteria. American care and rehabilitation services generally appear to be more directed towards the family and involve a wide range of health professionals from different disciplines. The systems, when compared to their British counterparts, are more structured in terms of organisation, coordination and evaluation, and are more geared towards cost-containment, effectiveness and efficiency. However, although British systems are increasingly emulating the American ones, they are in many respects more innovative, flexible and tailored to individual needs. PMID- 7833637 TI - Karyometric study of basal cell carcinoma. PMID- 7833638 TI - An audit of CO2 laser surgery in the mouth. AB - The use of the carbon dioxide laser to perform surgical procedures in the oral cavity has been described the last few years. This study involved the clinical audit of 83 patients who had undergone laser surgery in the oral cavity during 1985 to 1990 in Birmingham, England. The diagnosis of the 83 lesions treated were benign, premalignant or malignant. The most common sites of the lesions were the floor of the mouth/ventral surface of the tongue and other parts of the tongue, followed by upper alveolus and/or palate, angle of the mouth and/or cheeks, lower alveolus, and lips. The results showed that the use of the carbon dioxide laser in treating oral soft-tissue pathology presented advantages over conventional techniques. Although trismus, numbness and early signs of infection were observed after surgery, local discomfort and pain were the most common complaints after laser surgery. The carbon dioxide laser does not offer any enhanced cure-rate for oral pathology, but rather it is a precise means of removing soft tissue lesions in selected patients with little upset afterwards. PMID- 7833639 TI - Streptococci of the mutans group: confirmation of intrafamilial transmission by mutacin typing. PMID- 7833641 TI - Influence of time of calcium hydroxide iodoform paste replacement in the treatment of root perforations. PMID- 7833640 TI - Healing process of the gingival mucosa and dental alveolus following tooth extraction and suture with polyglycolic acid and polyglactin 910 threads. Comparative histomorphologic study in rats. PMID- 7833642 TI - Human papilloma virus--its association with epithelial proliferative lesions. AB - The Papillomaviruses are DNA viruses which belong to the Papova family, having a great affinity for epithelial tissue. They can produce proliferative lesions either in the skin or mucosa, in man and other animals. Various kinds of lesions, mainly benign, are caused by numerous types of HPV involving the well-known verruca vulgaris, oral papilloma, condiloma acuminatum and the focal epithelial hyperplasia, as well as a possible association with other alterations and lesions. PMID- 7833643 TI - Adhesion of calcium hydroxide-containing root canal sealers. PMID- 7833644 TI - Apical leakage using various sealers and root canal filling techniques. PMID- 7833645 TI - Evaluation of chelating action of EDTA in association with Dakin's solution. PMID- 7833646 TI - The oro-facial-digital syndrome--manifestations in the oral cavity--case report. PMID- 7833647 TI - Gingival hyperplasia due to a removable partial prosthesis--case report. PMID- 7833648 TI - Hans-Lukas Teuber: a tribute. AB - Hans-Lukas Teuber (1916-1977) was one of the most influential neuropsychologists of his generation. In the first part of his career he headed the Psychophysiology Laboratory at the New York University--Bellevue Medical Center. There he and his associates played a major role in establishing human neuropsychology as a rigorous experimental science closely linked to contemporary neurophysiology and experimental psychology. In the second part of his career he founded the Department of Psychology at the Massachusetts Institute of Technology. This rapidly became a world center of the neuro- and cognitive sciences and a model for the establishment of new neuroscience centers that brought together neuroanatomy, neurophysiology, neuropsychology, and cognitive psychology into an interacting community. Teuber's contributions extended far beyond the institutions he founded and the many important experimental and theoretical papers he wrote. He was a consummate organizer, synthesizer, and sponsor of research on the brain, as well as the mentor of many of today's leading brain researchers. This special issue on object recognition and the temporal lobes is dedicated to his memory. PMID- 7833649 TI - How inferior temporal cortex became a visual area. AB - The origins of contemporary work on the temporal cortex and object recognition are traced from their roots in phrenology through the search for a cortical visual area to the discovery of the Kluver-Bucy syndrome and its fractionation, finally ending with early single-neuron recording studies. PMID- 7833650 TI - Development of inferior temporal cortex in the monkey. AB - Inferior temporal (IT) cortex is critical for visual pattern recognition in adult primates. However, the functional development of IT cortex appears to be incomplete until late in the first year of life in monkeys and probably beyond. Responses of neurons in IT are substantially weaker, of longer latency, and more susceptible to anesthesia within at least the first half year of life. In addition, refinement of connections of IT, particularly those with regions in the opposite hemisphere and with regions related to memory and attention, continues for at least several months after birth. Moreover, many of the pattern recognition functions that IT supports in adulthood themselves show a very protracted period of development, and damage to IT cortex in infancy appears to have relatively little effect on pattern recognition abilities, despite the pronounced effects of comparable damage in adulthood. These findings all suggest that IT undergoes an extended period of postnatal development, during which both visual experience and the maturation of other brain structures may contribute to the emergence of mechanisms of pattern recognition within IT. In other respects, fundamental characteristics of IT emerge quite early. For example, despite their weaker responses, IT neurons have adult-like patterns of responsiveness- including pronounced form selectivity and large bilateral receptive fields--as early as we were able to test (approximately 6 weeks). Thus, IT cortex appears to be prewired with (or predisposed to develop rapidly) neural circuitry sufficient to produce basic properties remarkably similar to those found in the adult animal. Future studies of IT cortex will need to address the development of signals related to perceptual constancies and to formation and retrieval of visual object memories, the development of interactions with other regions involved in visual recognition (particularly frontal cortex), and the specific mechanisms underlying various types of plasticity present in IT cortex in both developing and mature primates. PMID- 7833651 TI - Processing of contrast polarity of visual images in inferotemporal cortex of the macaque monkey. AB - Cells in the anterior part of the inferotemporal cortex (anterior IT) respond to moderately complex stimulus features of object images. To study dependency of their responses on contrast polarity of stimulus images, we selected cells with optimal stimuli that were defined only by shape and not related to texture or color, and examined effects of reversing the contrast of the image or removing it except for edges between dark and bright parts of the image ("outlining"). The contrast reversal produced a reduction of the response to the optimal stimulus by > 50% in 60% of tested cells; the outlining, in 70%. When the two transformations were considered together, 94% of the cells showed a reduction by > 50%. Effects of the transformations on shape selectivity were also studied by comparing responses to several different shapes each of whose contours were expressed in different ways. Statistically significant changes in relative effectiveness of the different shapes as a function of contour expression were observed in more than half of the cells. These results suggest that responses of individual cells in anterior IT carry information about contrast polarity as well as about shape. PMID- 7833652 TI - Recognition of objects and their component parts: responses of single units in the temporal cortex of the macaque. AB - We investigated the role that different component parts play in the neural encoding of the visual appearance of one complex object in the temporal cortex. Cells responsive to the sight of the entire human body (but no to control stimuli) were tested with two subregions (head alone with the body occluded from sight and the body alone with the head occluded). Forty-two percent (22 of 53) of cells responded to the whole body and to one of the two body regions tested separately: 72% (17 of 22) responding to the head and 28% (5 of 22) to the rest of the body. Forty-two percent (22 of 53) of cells responded independently to both regions of the body when tested in isolation. The remaining cells (17%, 9 of 53) were selective for the entire body and unresponsive to component parts. The majority of cells tested (90%, 35 of 39) were selective for perspective view (e.g., some cells respond optimally to the side view of the body, others to the back view). Comparable levels of view sensitivity were found for responses to the whole body and its parts. Results indicate (1) separate neuronal analysis of body parts and (2) extensive integration of information from different parts. Contrary to influential models of object recognition (Marr and Nishihara, 1978; Biederman, 1987), the results indicate view-specific processing both for the appearance of separate object components and for integration of information across components. PMID- 7833653 TI - Inferior temporal mechanisms for invariant object recognition. AB - The specific size and retinal location of an object are readily perceived, yet recognition of an object's identity is hardly affected by transformations of its size or location. To explore how such stimulus transformations are treated by known mechanisms for visual short-term memory in inferior temporal (IT) cortex, IT cells were recorded in monkeys performing a delayed matching-to-sample task. The stimuli were pictures of complex objects, and the monkeys ignored differences in size and retinal location when matching the test items to the sample held in memory. The sensory information communicated by cells was assessed in their responses to the sample stimuli, and mnemonic information was assessed in their responses to the test stimuli. In the sensory domain, the ordering of relative stimulus preferences for nearly all cells was invariant over changes in size or location; however, some cells nonetheless preferred stimuli of a given size or location. In the mnemonic domain, the responses of many cells were modulated according to whether the test stimulus matched the sample held in memory, and these memory effects were invariant over the relative sizes and locations of the stimuli. Thus, IT neuronal populations may mediate not only the recognition and memory of object identity, which are invariant over size and location, but also the perception of the transformations themselves. PMID- 7833654 TI - Properties of simulated neurons from a model of primate inferior temporal cortex. AB - The physiological properties of neurons in inferior temporal (IT) cortex of the macaque monkey suggest that this cortical area plays a major role in visual pattern recognition. Based on the properties of IT, and one of its major sources of input, V4, a model is proposed that can account for some of the shape recognition properties of IT neurons including selectivity for complex visual stimuli and tolerance to the size and location of the stimuli. The model is composed of three components. First, stimulus location tolerance is modeled after the complex-cell-like properties observed in some V4 neurons. The second component of the model is an attentionally controlled scaling mechanism that facilitates size-invariant shape recognition. The transition from edge orientation-selective neurons in V4 to neurons with more complicated stimulus preference in IT is explained by the third component of the model, a competitive learning mechanism. Single-unit analysis of receptive field properties, stimulus selectivity, and stimulus size and position tolerance was performed on "neurons" from the simulation. Comparison of results from the simulation and a study of actual IT neurons shows that the set of mechanisms incorporated into the simulation is sufficient to emulate the physiological data. PMID- 7833655 TI - Human extrastriate visual cortex and the perception of faces, words, numbers, and colors. AB - Electrophysiological correlates of the processing of visual information were studied in epileptic patients with electrodes chronically implanted on the surface of striate and extrastriate cortex. In separate experiments patients viewed faces, letter strings (words and non-words), numbers, and control stimuli. A negative potential, N200, was evoked by faces, letter strings, and numbers, but not by the control stimuli. N200 was recorded bilaterally from discrete regions of the fusiform and inferior temporal gyri. These category-specific face, letter string, and number "modules" vary in location. In most cases there was no overlap in the location of face and letter-string modules, suggesting a mosaic of functionally discrete regions. In some cases letter-string and number N200s were recorded from the same location, suggesting that these modules may be less spatially and functionally discrete. Face N200-like potentials can be recorded from temporal scalp, allowing the possibility of studying early face processing in normal subjects. Longer-latency face-specific potentials were recorded from the inferior surface of the anterior temporal lobe. Potentials evoked by colored checkerboards were recorded from a region of the fusiform gyrus posterior to the fusiform region from which category-specific N200s were recorded. These results suggest that there are several processing streams in inferior extrastriate cortex. In addition to object recognition systems previously proposed for faces and words, our preliminary results suggest a separate system dealing with numbers. Postulated systems dealing with larger manipulable objects and animals have not been detected. PMID- 7833656 TI - Functional segregation of color and motion processing in the human visual cortex: clinical evidence. AB - Anatomical and physiological investigations indicate two major distinct functional streams within the extrastriate visual cortex of the macaque monkey, and behavioral observations suggest that the ventral (occipitotemporal) pathway is the cornerstone for object recognition whereas the dorsal (occipitoparietal) pathway is primarily involved in visuospatial perception and visuomotor performance. In the context of this dichotomy we conducted a psychophysical and neuropsychological study of visual perceptual abilities in two stroke patients, each with lesions involving several extrastriate areas. Magnetic resonance imaging demonstrated bilateral lesions; in one patient (E.W.) the lesion involves the ventral medial portions of the occipital and temporal lobes, and in the other (A.F.) the lesion involves dorsally the occipital-parietal area, including the region of the temporal-parietal-occipital junction. E.W. suffers from achromatopsia of central origin, prosopagnosia, visual agnosia, and alexia without agraphia. His depth and motion perception, including recognition of moving objects, are normal. He has superior visual field loss bilaterally, and slightly impaired acuity, and complains that the world appears in a deep twilight even on a sunny day. In contrast, A.F. shows specific deficits of stereopsis, spatial localization, and several aspects of motion perception. He is also impaired at recognizing objects presented from unconventional views, but recognition of prototypical views of objects, and color and form discrimination are normal, as is his ability to recognize faces. The anatomical characteristics of the lesions of these two patients permit a direct experimental comparison of the effects of lesions confined to the parietal or temporal pathways. E.W.'s and A.F.'s performance on the psychophysical and neuropsychological tasks discussed here supports the functional distinction between a dorsal and a ventral extrastriate system but additionally suggests the existence of a pathway involved in identification-from-motion that is separate from both the dorsal early motion/spatial analysis pathway and the ventral color/static-form pathway. PMID- 7833657 TI - Effect of postoperative 131I treatment on thyroglobulin measurements in the follow-up of patients with thyroid cancer. AB - Correlation of serum thyroglobulin (Tg) levels with recurrent cancer was performed in 200 patients who had undergone a subtotal thyroidectomy for well differentiated thyroid carcinoma. Patients were divided into three groups: (1) those not treated postoperatively with radioactive iodine, (2) those treated with low dose (30 mCi) radioactive iodine, and (3) those treated with high dose (50 250 mCi) radioactive iodine. Tg levels proved to be reliable in detecting recurrent thyroid cancer regardless of the dose of radioactive iodine given postoperatively. These results reinforce the recommendation of using the Tg assay as the primary method of following these patients postoperatively, even when there was less than a total thyroidectomy and ablation with radioactive iodine. PMID- 7833658 TI - Hurthle cell neoplasms of the thyroid gland: reassessment of functional capacity. AB - We treated a hyperthyroid man and a euthyroid woman who had autonomously functioning Hurthle cell adenomas and demonstrated uptake of radioactive 131I in a woman with recurrent Hurthle cell carcinoma. Since these tumors are thought to be inactive, we reassessed the functional capacity of Hurthle cell neoplasms by reviewing the medical records of all patients operated upon for these tumors at our medical center from 1950 through November, 1993. We also reviewed series of Hurthle cell neoplasms identified from a MEDLINE search of papers published from 1960 to November, 1993. We identified 92 patients with Hurthle cell neoplasms. Thyroid scintigraphy was performed in 28 of 72 patients with benign adenomas and six of 20 patients with Hurthle cell carcinomas. In addition to the two index cases, four euthyroid patients had hot nodules that partially suppressed the extranodular tissue; seven patients had warm nodules. Thyroid scans performed in patients with Hurthle cell carcinomas revealed five cold nodules and one warm nodule. Our index patient with carcinoma displayed elevated serum thyroglobulin levels when the cancer recurred. This patient and another had uptake of 131I by recurrent or metastatic cancer that allowed for treatment with this nuclide. Of 539 patients identified in a literature survey, 489 had benign Hurthle cell adenomas and 50 had Hurthle cell carcinoma. Thyroid scans performed in 282 patients revealed 247 cold nodules, 20 warm nodules, and 8 hot nodules. Our results, added to those published in case series of Hurthle cell neoplasms, indicated that 4.4% of thyroid scans were hot and 8.9% were warm.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7833659 TI - Resistance to thyroid hormone in subjects from two unrelated families is associated with a point mutation in the thyroid hormone receptor beta gene resulting in the replacement of the normal proline 453 with serine. AB - Resistance to thyroid hormone (RTH) is a condition of impaired tissue responsiveness to thyroid hormone characterized by elevated free thyroid hormone levels in serum accompanied by nonsuppressed TSH. RTH has been associated with mutations in the thyroid hormone receptor (TR) beta gene. We report studies carried out in 9 members of a family (F94) of Jewish ethnic origin and a single subject of Mexican origin. All subjects fulfilling the criteria of RTH (6 of family F94 and one of family F27) had the same point mutation in the T3-binding domain on one of the two alleles of the TR beta gene. This mutation resulted in the replacement of the normal proline-453 with serine (P453S). Nevertheless, the clinical characteristics of affected members of each of the two families differed as did the severity of hormonal resistance in terms of responses to the administration of L-T3. Genetic studies indicate that the same mutation occurred independently in each of the two families. PMID- 7833660 TI - Sequence analysis of the thyrotropin (TSH) receptor gene in congenital primary hypothyroidism associated with TSH unresponsiveness. AB - Congenital primary hypothyroidism due to thyrotropin (TSH) unresponsiveness is a very rare disorder and only a few cases have been documented previously. To elucidate whether structural abnormalities in the TSH receptor (TSHR) could be a primary underlying mechanism of this disorder, we analyzed nucleotide sequence of the entire coding region of the TSHR gene in three patients diagnosed with congenital primary hypothyroidism associated with TSH unresponsiveness. Diagnosis of TSH unresponsiveness was largely made based on the following criteria: (a) congenital primary hypothyroidism with autosomal recessive inheritance, (b) a nongoitrous thyroid gland in a normal position with low thyroidal radioactive iodine uptake, (c) normal in vitro TSH bioactivity or absent in vivo response to exogenous TSH, and (d) absence of thyroid autoantibodies. The TSHR cDNA was successfully obtained from RNA of peripheral mononuclear leukocytes with reverse transcription and polymerase chain reaction, and was sequenced directly. Comparison of these nucleotide sequences with the normal TSHR sequence revealed no difference in the predicted amino acid sequence with a heterozygous polymorphism in codon 601 in one patient, indicating absence of TSHR structural abnormalities in these patients. Our results indicate that congenital primary hypothyroidism associated with TSH unresponsiveness is unlikely to be due to mutations in the TSHR-structure gene. PMID- 7833661 TI - Thyroid hormone binding to isolated human apolipoproteins A-II, C-I, C-II, and C III: homology in thyroxine binding sites. AB - Thyroid hormone binding to lipid-free apolipoprotein (apo) A-II, C-I, C-II, and C III isolated from human plasma was investigated by photoaffinity labeling with [125I]T4 and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Both the monomeric and polymeric forms were specifically labeled. Inhibition by 10 microM unlabeled L-T4 was > or = 50%, suggesting affinity constants in the nM to microM range; the least inhibition was seen with apoA-II. Unlabeled D-T4 and reverse T3 (rT3) gave the same inhibition as unlabeled L-T4. Inhibitors of thyroid hormone binding to plasma proteins showed a different inhibitor potency with each apolipoprotein and a pattern different from that seen with T4 binding globulin (TBG) and transthyretin (TTR). Also in contrast to TBG, where only unsaturated nonesterified fatty acids (NEFA) are effective inhibitors, both unsaturated and saturated NEFA as well as other lipids inhibited T4 labeling. The flavonoid EMD 21388 was ineffective, confirming that it is a selective inhibitor of T4 binding to TTR. T4 binding to the apoCs was confirmed by the quenching of tryptophan fluorescence by unlabeled L-T4. (ApoA-II was not studied since it lacks tryptophan). Since the self-association of apolipoproteins involves interaction between amphipathic alpha-helices, and since the polymeric forms show specific T4 binding properties as in the parent monomer, the T4-binding domain appears to be outside the alpha-helical domain, as previously seen with apoA-I.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7833663 TI - Differentiation of postpartum thyrotoxicosis by serum thyroglobulin: usefulness of a new multisite immunoradiometric assay. AB - Destruction-induced thyrotoxicosis and Graves' thyrotoxicosis must be differentiated, since they are treated differently. To find a useful marker, we examined serial changes in serum thyroglobulin (Tg) concentrations in 20 patients with postpartum thyroid disease (9, euthyroid Hashimoto's disease; 11, Graves' disease in remission in early pregnancy). Serum Tg was measured by a new multisite immunoradiometric assay that allows little influence of anti-Tg autoantibodies. Eight women developed destruction-induced thyrotoxicosis 1 to 4 months postpartum, 6 had relapse of Graves' thyrotoxicosis 2 to 4 months postpartum, and 6 remained euthyroid. In destruction-induced thyrotoxicosis, serum Tg 2 months before the onset was 13.3 +/- 11.4 micrograms/L, then clearly increased 1 month before (34.5 +/- 31.9 micrograms/L) and was even higher at the onset of thyrotoxicosis (116.5 +/- 137.1 micrograms/L). In contrast, serum Tg increased only at the onset in Graves' thyrotoxicosis (from 25.9 +/- 25.2 micrograms/L 1 month before to 76.1 +/- 75.3 micrograms/L at the onset, p < 0.05). There was no difference in serum Tg level at the onset between the two disorders. However, when data were expressed as the percent increase from the level one month before, and the cut-off value were taken at 150%, all 7 patients above the cut-off developed destruction-induced thyrotoxicosis, and 6 of 7 below had recurrent Graves' thyrotoxicosis. Thus, serial measurement of serum Tg is useful for the differentiation of destruction-induced thyrotoxicosis from Graves' thyrotoxicosis after delivery. PMID- 7833662 TI - Seroreactivity to bacterial antigens is not a unique phenomenon in patients with autoimmune thyroid diseases in Canada. AB - It has been suggested elsewhere that the enteric pathogen Yersinia enterocolitica (Y.e.) might be implicated etiologically in autoimmune thyroid disease (AITD). To reevaluate this hypothesis in the Canadian population, where the prevalence of anti-Y.e. antibodies in the general population is very low (< 1%), we have studied the occurrence of antibacterial reactivity (against Y.e. 0:3 and 0:9, Escherichia coli and Staphylococcus aureus) in the sera of patients with Hashimoto's thyroiditis (HT), Graves' disease (GD), nontoxic nodular goiter (NTG), and autoimmune rheumatic diseases (ARD) as well as normal controls (C). Using the tube agglutination method, no single positive sample was detected in these subjects. No differences in the mean levels of anti-Y.e. 0:3 or 0:9 by ELISA were observed between various groups of patients. Immunoreactivity in the course of medical therapy during 5-12 months did not show significant changes in any of 12 ARD and AITD patients. Some serological reactivity to the plasmid containing strain of Y.e. 0:3 was demonstrated in all subjects by the Western blotting technique. However, weaker signals and fewer bands were noticed in these sera compared to sera from patients with acute yersiniosis. Analysis of the pattern of reactivity did not show any difference in reactivity to any protein between the groups of subjects. The immunodominant antigen in Y.e. 0:3 to which IgG reacted in almost all subjects was the plasmid encoded 240-kDa protein. Our study favors the view that there is a merely coincidental incidence of seroreactivity to bacterial antigens, which appears to be irrespective of diagnosis. PMID- 7833664 TI - Clinical and molecular genetics studies in Pendred's syndrome. AB - A large and highly inbred kindred including patients with incomplete and complete forms of Pendred's syndrome was studied. Blood samples were collected from 42 individuals (23 affected and 19 normal), and serum thyroid hormones, TSH, Tg, and anti-TPO autoantibodies were assayed. Thyroid function studies have indicated euthyroidism in all 42 individuals. The affected subjects, however, had significantly elevated serum Tg levels (19.4 +/- 6.8 ng/dL) as compared with normals (9.6 +/- 2.9 ng/dL). Nineteen subjects had clinical and or ultrasonographic evidence of a multinodular goiter. In addition, 13 individuals had impaired hearing with or without goiter. Computer axial tomography scan studies in six patients confirmed the presence of a defective cochlea (Mondini's cochlear defect) in three of these subjects. It has been suggested that thyroperoxidase (TPO) in patients with Pendred's syndrome might be defective for coupling but could be partially effective for iodide organification. We have investigated possible abnormalities in the TPO gene by Southern blot analysis. Genomic DNA was obtained from peripheral blood leukocytes of 40 subjects (22 affected and 18 normal). DNA samples were digested with five restriction enzymes and hybridized with the pM5 probe (831 bp). Polymorphic fragment patterns obtained with three of the five enzymes employed were equally distributed in normal and affected subjects of this kindred. Lod score analysis did not disclose any linkage of TPO gene polymorphisms with the phenotypic characteristics observed in this family. Our findings may be explained in two different ways. First one might have hitherto undetected mutations in the TPO gene, and, second, the pathology may in fact be due to a genetic defect lying elsewhere. PMID- 7833665 TI - Multicompartmental analysis of triiodothyronine kinetics in hypothyroid patients treated orally or intravenously with triiodothyronine. AB - Kinetic studies were performed with i.v. 125I T3 in four athyreotic women on two occasions each, once while they were taking oral T3 (30 micrograms T3 every 12 h) and again while on i.v. T3 replacement (same dosage schedule). The kinetic data were analyzed by a 7-compartment model, representing the plasma volume, the fast and slow peripheral exchange compartments, the iodide pool (as a delay compartment prior to appearance in the urine), the intestine (as a delay compartment before appearance in the feces), and the urine and feces. Modeling was done by the SAAM methodology. All data sets, and also the mean data treated as though they were data from a single subject, were fitted for the two limit solutions in which all metabolism was assumed to be in one or the other of the exchange compartments. The mean data set was also fitted to a solution in which limits were imposed on the excretion parameters and the partition of metabolism between the 2 peripheral exchange compartments was estimated. We found that steady-state parameters for removal of T3 from the circulation (the MCRs and DRs) were increased during the i.v. T3 replacement period compared with the oral replacement period, especially in the fast exchange compartment. Measured serum stable T3 levels (RIA) were lower in the i.v. than in the oral study, both at 8 and at 12 h after the most recent T3 dose. These values corresponded to similar differences in the circulating T3 levels projected from the model, although the T3 values projected from the model were greater than the measured T3 levels for unknown reasons.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7833666 TI - Secondary malignancy of the thyroid gland: a case report and review of the literature. AB - Metastatic cancer to the thyroid gland is uncommon. In this report we describe a patient with a malignant fibrous histiocytoma that metastasized to the thyroid, possibly to a preexisting thyroid nodule. A review of the literature reveals that breast and lung carcinoma are the most frequently identified sources of secondary thyroid carcinoma found at autopsy, while renal carcinoma comprises over 50% of secondary thyroid malignancies discovered clinically. A number of authors suggest that preexisting thyroid disease (i.e., multinodular goiter and thyroid nodules) may provide a nidus for metastases to the thyroid gland. PMID- 7833667 TI - Choriocarcinoma metastasis in the thyroid gland. AB - We report a 34-year-old woman with intrathyroid metastasis of choriocarcinoma associated with pulmonary and brain metastasis. The patient presented with a solitary thyroid nodule. Needle biopsy showed anaplastic malignant cells. Pathologic evaluation after thyroidectomy showed choriocarcinoma in the thyroid gland and the patient subsequently underwent combined chemotherapy and radiotherapy with satisfactory response. This is only the third reported case of metastatic choriocarcinoma in the thyroid gland and emphasizes this rare clinical presentation of choriocarcinoma. PMID- 7833668 TI - The appearance, distribution, and longevity of receptor-[125I]T3 complexes within the nuclei of isolated rat hepatocytes. AB - The nuclei of isolated rat hepatocytes were separable into three receptor compartments based upon their differential salt extractabilities: nucleoplasmic receptors (NP) extractable with 0.15 M KCl, high-salt extractable receptors (HSE) extractable with 0.4 M KCl, and salt-resistant receptors (SR) extractable with 0.4 M KCl/5 mM dithiothreitol. The receptor distribution among the three compartments was approximately NP, 45%; HSE, 30%; SR, 25%. The mean percent occupancy with endogenous T3 of the SR receptors (86%) was higher than the occupancies of the NP receptors (68%) and the HSE receptors (63%). When hepatocytes were pulsed with 3 nM [125I]T3 at 37 degrees C for brief intervals, receptor-[125I]T3 complexes were detectable in all three nuclear compartments within 15 sec. With increasing pulse intervals up to 120 sec, the receptor content of each nuclear compartment increased progressively and without evidence of preferential accumulation in any of the three compartments. To determine the life span and intercompartmental "migration" pattern of nuclear receptors, hepatocytes were pulsed with 3 nM [125I]T3 at 37 degrees C for 2.5 min or 5 min, followed by a chase with a 500-fold excess of nonlabeled T3. The population of receptor-[125I]T3 complexes generated during the pulse was serially recovered at increasing intervals after the chase. The complexes of each compartment dissociated with a half-life of approximately 3 min and manifested no predilection to accumulate in any of the compartments. Exposure of isolated hepatocytes to 3 nM T3 for 5 min or 10 min at 37 degrees C induced no change in the gross intercompartmental distribution of receptors compared to control hepatocytes incubated without T3.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7833669 TI - Ted Astwood's intellectual legacy: some personal viewpoints. PMID- 7833670 TI - Hyperthyroidism, thyroid hormone therapy, and bone. AB - Clinically symptomatic osteoporosis and fractures from thyrotoxicosis have been rare since the availability of antithyroid drugs and radioiodine for the treatment of hyperthyroidism. However, the widespread use of bone density measurements and sensitive TSH assays in the past decade has demonstrated that women taking levothyroxine with subclinical hyperthyroidism have reduced bone density. Cortical bone is affected more than trabecular bone, and postmenopausal women are at a greater risk than premenopausal women. However, it is uncertain whether subclinical hyperthyroidism is associated with an increased risk of fracture. Hypothyroidism is associated with an increase in cortical bone width. The initiation of levothyroxine treatment in hypothyroid women results in a reduction in cortical bone width to levels seen in euthyroid controls after 6-12 months. There is no reduction in bone density when women with subclinical hypothyroidism are treated with levothyroxine for a year. A single study showing reduced bone density in patients receiving chronic levothyroxine replacement therapy requires confirmation and raises an important question: Does levothyroxine replacement therapy, which results in higher serum thyroxine concentrations than those seen in euthyroid controls, accurately mimic physiology? PMID- 7833671 TI - Cigarette smoking and the thyroid. AB - Relevant English language articles published from 1970 through 1993 regarding the possible influence of cigarette smoking on the thyroid were identified through a MEDLINE search and manual searches of identified articles. Thiocyanate in tobacco smoke influences the thyroid by a competitive inhibition of iodine uptake and organification in the gland. Also the stimulation of the sympathetic nervous system by cigarette smoke and benzpyrene, another constituent of tobacco, is thought to influence thyroid gland function. The thyroid hormones and TSH receptor autoantibodies are not affected by smoking, but serum TSH levels have been found to be slightly reduced. Smokers have a higher frequency of goiter and increased serum thyroglobulin levels, especially in iodine-deficient areas. Graves' ophthalmopathy is strongly associated with cigarette smoking; the more severe the eye disease the stronger the association. Graves' disease without ophthalmopathy is also associated with smoking, though this association is weaker. Thiocyanate level in cord blood equilibrates completely with the level in the mother, and a reverse correlation has been demonstrated between birth weight and thiocyanate level in cord blood. Cigarette smoking induces similar changes in thyroid function in the adult and the fetus. No separate study has elucidated the effects of cessation of smoking, but there seems to be longstanding effects induced by smoking, some probably irreversible. PMID- 7833672 TI - The pathology of autoimmune thyroid disease: a review. AB - Lymphocytic infiltration of the thyroid gland is the pathologic hallmark of autoimmune thyroid disease. Lymphoid cells are seen in the stroma of glands affected by Graves' disease. However, large lymphoid infiltrates are characteristic of that spectrum of diseases conveniently termed chronic lymphocytic thyroiditis. In this review, the pathology of the various subtypes of chronic thyroiditis is enumerated, including recently defined lesions, i.e., painless thyroiditis, thyroiditis associated with interleukin chemotherapy, and peritumor thyroiditis are reviewed. The unifying morphologic characteristics seen in these conditions are discussed. PMID- 7833673 TI - Urticaria due to blue dye in synthroid tablets. PMID- 7833674 TI - Resistance to thyroid hormone: an historical overview. AB - Resistance to thyroid hormone (RTH) is an inherited syndrome characterized by reduced tissue responsiveness to thyroid hormone. Subjects have elevated serum thyroid hormone levels in association with a nonsuppressed TSH. Goiter and thyroid test abnormalities have most often led to further investigation, underscoring the paucity of specific clinical manifestations of RTH. Hypothyroidism has been considered when growth or mental retardation was the presenting symptom and thyrotoxicosis when dealing with attention deficit or hyperactivity. Failure to recognize the inappropriate persistence of TSH secretion, in spite of elevated thyroid hormone levels, has commonly resulted in erroneous diagnosis leading to treatment aimed to normalize the thyroid hormone level. More than 400 subjects with this syndrome have been identified. The mode of inheritance appears to be autosomal dominant in the majority of families. It has long been suspected that RTH is most likely caused by an abnormal thyroid hormone receptor (TR), but this hypothesis could not be directly tested until the isolation of two TR genes, TR alpha and TR beta, located in chromosomes 17 and 3, respectively. TR beta gene mutations have been recently identified in 68 families with RTH. All mutations are located in the T3-binding domain, straddling the putative TR-dimerization region. Mutant TRs exhibit hormone-binding impairment, the degree of which does not correlate with the severity of clinical manifestations. This finding, and the fact that heterozygous subjects with complete TR deletion are not affected, while those with point mutations are, indicated that interactions of the mutant TRs with normal TRs and with other factors, are responsible for the dominant inheritance of RTH and its clinical heterogeneity.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7833675 TI - Iodine and the thyroid: 33 years of study. PMID- 7833676 TI - Type I iodothyronine deiodinase: unexpected complexities in a simple deiodination reaction. PMID- 7833677 TI - Thyroid dysfunction in the recently pregnant: postpartum thyroiditis. PMID- 7833678 TI - Fetal thyroid metabolism: a pluralistic system. PMID- 7833679 TI - Immunoregulation in autoimmune thyroid disease. AB - We have postulated over many years that autoimmune thyroid diseases (AITD) are disorders of immunoregulation due to antigen specific defect(s) in suppressor (regulatory) T (Ts) lymphocyte function. Despite earlier skepticism, there is recent increased evidence to support this view. Several investigators working with animal models have demonstrated T lymphocyte subsets that are regulatory, i.e., will prevent AITD; conversely, depletion of these cells precipitates the lesion in the experimental models. These cells have been shown to be inadequately activated by specific antigen. In human AITD, recent studies have demonstrated that CD8+ (suppressor/cytotoxic) and CD8+CD11b+ ("pure suppressor") cells are activated by irrelevant antigen normally, but are significantly less well activated in response to thyroglobulin or thyroperoxidase. In further similar studies, CD8+ cells from patients with Graves' disease (GD) are induced normally in response to glutamic acid decarboxylase-65 (GAD-65), the putative beta cell antigen important in insulin-dependent diabetes mellitus (IDDM), but significantly less to synthetic TSH receptor (TSHR). Conversely, CD8+ cells from patients with IDDM are activated normally in response to TSHR, but significantly less to GAD-65. While these reductions in activation are partial only, and other additive factors playing on the immune system may be necessary to precipitate AITD, this disorder in the activation of Ts cells may be fundamental to the development of these disorders. This in turn may be due to molecular disturbances in MHC-related genes that dictate the mechanisms of presentation of specific antigen. PMID- 7833680 TI - Pathogenesis of Graves' ophthalmopathy. PMID- 7833681 TI - Approaches to the treatment of high-risk thyroid cancer. PMID- 7833686 TI - Nurse alert! The real facts behind investigation. PMID- 7833682 TI - Molecular mechanisms of thyroid hormone action. AB - This brief review deals with the key trans- and cis-elements that are currently believed to participate in TH action at the transcriptional level. The reader is also referred to other recent reviews (53,54). In sum, there are multiple levels of complexity that make an understanding of the fundamental mechanisms of TH action difficult. However, the interactions of multiple TRs and TRAPS along with putative coactivators and ligands provide the cell with a wide range of biological responses. An appreciation of these phenomena will ensure insight into regulated gene expression in general, and the mode of action of TH in particular. While the field has progressed greatly since Jack Oppenheimer first described the nuclear binding of TH, there are "many more miles to go" for all of us, including Jack. We trust the journey will continue to be captivating. PMID- 7833687 TI - Primary health care and education needs: an update from the nursing education coalition. PMID- 7833688 TI - Architecture and health care: Saskatchewan leads the way in information technology. PMID- 7833689 TI - Complementary health care workshop: putting the wellness model to work. PMID- 7833690 TI - Reduction of P3b in patients with temporo-parietal lesions. AB - By recording event-related EEG potentials from patients with frontal, parietal, or temporo-parietal lesions, we wanted to determine the cortical area that is relevant to the P3b component, replicating the approach used by Knight and associates who found reduced P3bs in patients with temporo-parietal lesions. They used auditory and somatosensory stimuli. We wanted to replicate their findings in auditory and visual oddball tasks and analysed potentials evoked by targets and by standard stimuli. Temporo-parietal patients' P3bs were reduced with auditory targets and lacked a distinct Pz maximum with visual targets. Further, auditory N1 was reduced both with targets and standards, P3 to visual standards and P2 to auditory standards were reduced. Parietal patients' P3bs differed only slightly from the control group, being somewhat reduced over the lesioned hemisphere with visual stimuli. Their P3 to visual standards was, however, reduced to the same extent as was the temporo-parietal patients'. Frontal patients did not differ from the control group both in their P3b and in their P3 to standards but had a number of conspicuous features in modality-specific components. In sum, our results on P3b (as well as on N1) replicate Knight's findings, confirming his conclusion that integrity of the temporo-parietal junction is critical for P3b. Implications for hypotheses on P3 are discussed. PMID- 7833691 TI - Auditory selective attention is impaired in Parkinson's disease--event-related evidence from EEG potentials. AB - Selective attention refers to the ability to focus on one channel of information in the presence of distracting other channels. For the visual modality, results on impairments of selective attention have been conflicting in patients with idiopathic Parkinson's disease (PD). Independent of possible interferences from visual or movement disturbances selective attention can be measured as the so called 'processing negativity' (PN) using auditory evoked potentials. Therefore, auditory selective attention with the PN was measured in 14 patients with PD and 16 control subjects. Subjects had to attend to tones presented to one ear (i.e. to press a button to occasionally presented longer tones) and ignore tones presented to the other ear. Tones were presented at a rate of 1/s ('slow') or 2/s ('fast'). PN was measured as the difference of the potentials evoked by attended minus ignored standard tones. PN was significantly smaller in the PD patients than in the controls with slow presentation. There was no difference between both groups with fast presentation. PN remained unchanged when patients had a 12-h withdrawal of their usual anti-Parkinsonian drug therapy. PD patients and controls did not differ in their P3 component evoked in the usual 'oddball' task nor in the mismatch negativity evoked by the occasionally longer tones in the PN task. The results provide evidence for an impairment of auditory selective attention that is specific for patients with PD (i.e. independent of the P3 component). PMID- 7833692 TI - Movement-related slow potentials during motor imagery and motor suppression in humans. AB - Electro-encephalograms (EEGs) associated with motor imagery and motor suppression were recorded from motor-related frontal regions in humans. A negative potential was observed both during motor imagery and during NO-GO responses, as well as in movement trials. The negative potentials observed in the motor imagery trials had a similar pattern to those observed in the movement trials, although the potentials were different from those during NO-GO responses. The peak amplitude of the negative potential recorded at FCz was significantly larger than those recorded at F3, F4, C3 and C4 in the imagery task. The peak amplitude of the negative component in movement trials was larger than that in the imagery trials of all recording positions. By contrast, during the GO/NO-GO task, the peak amplitude during NO-GO responses was larger than that during the GO responses at every position. It appears, therefore, that motor imagery and motor suppression are associated with their own specific internal processes which are reflected by specific EEG patterns in motor-related frontal areas. PMID- 7833693 TI - Movement-related potentials associated with motor inhibition as determined by use of a stop signal paradigm in humans. AB - The motor inhibition process was examined in humans by monitoring reaction times, electromyograms, and movement-related potentials. Four subjects performed a simple visual Stop Signal Paradigm. The results were as follows. (1) The EEG waveform pattern was remarkably consistent among subjects. NO-GO-specific negative-positive potentials were observed under all experimental conditions. (2) The timing of the onset and the peak latency of the negative potential relative to the second stimulus, S2, were constant (about 200-210 ms and 250-260 ms for each) regardless of changes in the S2 delay. The time interval between the initial onset of the negative potential and its peak latency was constant (about 50 ms). (3) By contrast, the peak-to-peak time between the negative potential and the positive potential became smaller as the S2 delay was increased. It is suggested, therefore, that the motor inhibition process might consist of different sub-processes and that some part of the inhibition process might be of constant and specific duration. PMID- 7833694 TI - Neurophysiological differences between perception and imagery. AB - The present study was designed to examine brain activity underlying mental imagery is conceptualized as behavior guided by internal representation only, the activity of the prefrontal lobes was assumed to be a measure of differentiation of imagery from perception. Twenty-one subjects were requested to observe and imagine a swinging pendulum and to touch and imagine a coshball in separate trials. The EEG was recorded from 15 standard electrode sites and analyzed with (1) traditional alpha power and (2) an estimation of dimensional complexity (a measure derived from nonlinear dynamics). Both EEG measures revealed expected object-related differences during perception as well as during imagery. The visual pendulum showed relative to the tactile coshball increased dimensional complexity and less alpha power at parietal and frontal sites. However, only the EEG dimension supported the main hypothesis: Imagery resulted in increased prefrontal dimensional complexity in comparison to perception independent of the modality of the image. In contrast, for alpha power the difference between imagery and perception was due to stimulus modality. PMID- 7833695 TI - Moving potential field of frontal midline theta activity during a mental task. AB - The movement of potential field (potential flow) of frontal midline theta activity (Fm theta) was examined by using optical flow detection techniques in image processing in 6 normal subjects. Electroencephalograms (EEGs) over the fronto-central region were recorded from 13 electrodes around Fz. The potential flow of Fm theta was estimated on a frame which consisted of a square grid of 19 x 19 points in which each of the 13 electrodes was positioned with Fz at the center of grid. The peak-to-trough amplitude distribution was rounded or oval with a maximum just anterior to Fz. In each hemisphere, potential field moved medially in a region anterior to Fz, posteriorly near or at the midline and laterally in a region posterior to Fz. In the temporal sequence of potential field, at each point velocity directions tended to change progressively clockwise or counterclockwise. In the whole frame, a rotary movement of potential flow was found with a center at the middle on each side. Our findings suggested that a potential maximum at the midline may be due to overlapping of fields of opposite direction over the frontal scalp, arising from sources of similar orientation in both hemispheres. It can be assumed that Fm theta propagates in a clockwise direction in the left hemisphere and in a counterclockwise direction in the right hemisphere. PMID- 7833696 TI - Astrocytes implicated in the energizing of intermediate memory processes in neonate chicks. AB - Day-old chicks trained in a single trial passive avoidance task develop three sequentially dependent stages of discrimination memory. The second intermediate stage is made up of two phases: the initial A phase being susceptible to inhibition of oxidative metabolism in the tricarboxcylic acid (TCA) system with 2,4-dinitrophenol (DNP), and a second DNP-insensitive B phase. The studies reported in this paper found that doses of the metabolic toxins fluoroacetate (0.2 mM) and fluorocitrate (0.1 mM) previously reported to disrupt the astrocytic TCA cycle only, also disrupt the A (but not the B) phase of intermediate memory, suggesting an interaction between the astrocytic and neuronal oxidative systems may be required to meet the metabolic demands of this earlier phase. The B phase, on the other hand, was not expressed in the presence of the glycolytic inhibitor iodoacetate (1 mM), suggesting that glycolysis (known to be more efficient in astrocytes) and glycogenolysis (which may be exclusive to astrocytes) may support this second phase of intermediate memory. In this regard, the rise in forebrain noradrenaline levels previously reported to occur before the appearance of the B phase is particularly relevant. Given that noradrenaline has been shown to be capable of enhancing glycogenolysis in astrocyte-enriched cell cultures, it is conceivable that noradrenaline exerts an effect on memory by stimulating the glycolytic system in astrocytes, thereby providing energy or metabolites (e.g. pyruvate) needed to sustain the cellular processes operating during the B phase of intermediate memory. PMID- 7833697 TI - How many general practitioners for 1433 patients? PMID- 7833698 TI - Guidelines, enthusiasms, uncertainty, and the limits to purchasing. AB - Recently government ministers have set out their vision of the future of purchasing. Ineffective treatments will be discarded and purchasing will be based on guidelines or protocols rather than activity. But have the advocates of this approach considered all the issues? This paper examines the challenges of balancing the desire for protocol based uniformity with the needs of individual patients, explores the extent to which existing purchasing structures can support this process, and questions whether such moves will actually lead to reduced costs. In each case it is concluded that oversimplistic analyses are likely to be misleading and that much of the current debate fails to recognise the complexity of health care. PMID- 7833699 TI - Conflict, power, negotiation. PMID- 7833700 TI - Acyclovir for childhood chickenpox. Cost is unjustified. PMID- 7833701 TI - Acyclovir for childhood chickenpox. No reason not to treat. PMID- 7833702 TI - WHO fellowships--what do they achieve? AB - Training health professionals is one of WHO's major strategies for improving health care in the developing world. The aim, to strengthen a country's own capacity rather than injecting expertise from outside, is in the best tradition of sustainable development. But how effective is this so called "capacity building in human resources"? Since it accounted for $43m of WHO's budget in 1992 3 and is considered by WHO to be a major contribution to health in individual countries, it deserves detailed examination. PMID- 7833703 TI - Clinical gastroenterology. PMID- 7833704 TI - Voluntary agreement on tobacco advertising. PMID- 7833705 TI - Molecular cancer epidemiology can predict risk. PMID- 7833706 TI - Randomised controlled trials and health services research. PMID- 7833707 TI - Pressure sores. Carers should provide informed, cohesive approach. PMID- 7833708 TI - Pressure sores. Clinical trials best way of assessing different matresses. PMID- 7833709 TI - Assessing risk of suicide. Samaritans' scoring system helps develop judgment. PMID- 7833710 TI - Antidepressants and suicide. PMID- 7833711 TI - Patient confidentiality in New Zealand. PMID- 7833712 TI - Misoprostol and birth defects. PMID- 7833713 TI - Training in laparoscopic surgery. PMID- 7833714 TI - Vascular surgical services. PMID- 7833715 TI - Enalapril and beta blockers in chronic renal failure. PMID- 7833716 TI - Seasonal variations in fatal pulmonary embolism. Several mechanisms contribute. PMID- 7833717 TI - Seasonal variations in fatal pulmonary embolism. Malignant phase hypertension does not vary by season. PMID- 7833718 TI - Failure of consultant expansion. PMID- 7833719 TI - Histopathology and medical laboratory scientific officers. PMID- 7833720 TI - Human rights in Iraq. PMID- 7833721 TI - Evidence based policymaking. PMID- 7833722 TI - Acute dissection of the thoracic aorta. PMID- 7833723 TI - GPs, patients, and the distance between them. PMID- 7833724 TI - Clonality in Langerhans' cell histiocytosis. PMID- 7833725 TI - Gulf war syndrome needs coordinated study. PMID- 7833726 TI - The Netherlands lags behind in heart operations. PMID- 7833727 TI - Premature baby in US provokes ethical dilemma. PMID- 7833728 TI - South Africa plans more rural clinics. PMID- 7833729 TI - Dutch hospitals face up to living wills. PMID- 7833730 TI - Food and Drug Administration under assault. PMID- 7833731 TI - United Kingdom Prospective Diabetes Study (UKPDS). 13: Relative efficacy of randomly allocated diet, sulphonylurea, insulin, or metformin in patients with newly diagnosed non-insulin dependent diabetes followed for three years. AB - OBJECTIVE: To assess the relative efficacy of treatments for non-insulin dependent diabetes over three years from diagnosis. DESIGN: Multicentre, randomised, controlled trial allocating patients to treatment with diet alone or additional chlorpropamide, glibenclamide, insulin, or metformin (if obese) to achieve fasting plasma glucose concentrations < or = 6 mmol/l. SETTING: Outpatient diabetic clinics in 15 British hospitals. SUBJECTS: 2520 subjects who, after a three month dietary run in period, had fasting plasma glucose concentrations of 6.1-14.9 mmol/l but no hyperglycaemic symptoms. MAIN OUTCOME MEASURES: Fasting plasma glucose, glycated haemoglobin, and fasting plasma insulin concentrations; body weight; compliance; and hypoglycaemia. RESULTS: Median fasting plasma glucose concentrations were significantly lower at three years in patients allocated to chlorpropamide, glibenclamide, or insulin rather than diet alone (7.0, 7.6, 7.4, and 9.0 mmol/l respectively; P < 0.001) with lower mean glycated haemoglobin values (6.8%, 6.9%, 7.0%, and 7.6%, respectively; P < 0.001). Mean body weight increased significantly with chlorpropamide, glibenclamide, and insulin but not diet (by 3.5, 4.8, 4.8, and 1.7 kg; P < 0.001). A similar pattern was seen for mean fasting plasma insulin concentration (by 0.9, 1.2, 2.4, and -0.1 mU/l; P < 0.001). In obese subjects metformin was as effective as the other drugs with no change in mean body weight and significant reduction in mean fasting plasma insulin concentration (-2.5 mU/l; P < 0.001). More hypoglycaemic episodes occurred with sulphonylurea or insulin than with diet or metformin. CONCLUSION: The drugs had similar glucose lowering efficacy, although most patients remained hyperglycaemic. Long term follow up is required to determine the risk-benefit ratio of the glycaemic improvement, side effects, changes in body weight, and plasma insulin concentration. PMID- 7833732 TI - Bottle feeding and the sudden infant death syndrome. AB - OBJECTIVE: To determine whether the risk of the sudden infant death syndrome is increased in bottle fed babies. DESIGN: Population based case-control study matching for age and time. SUBJECTS: All babies aged 1 week to 1 year dying of sudden infant death syndrome during November 1987 to April 1989 or February 1990 to June 1991 and two live controls. SETTING: Avon and north Somerset. MAIN OUTCOME MEASURES: Breast or bottle feeding, sleeping position, maternal smoking, parental employment, and length of gestation. RESULTS: Compared with being fully breast fed, the crude odds ratio for sudden infant death in fully bottle fed babies was 3.1 and for mixed breast and bottle fed babies 1.5. These odds ratios fell to 1.8 (95% confidence interval 0.7 to 4.8) and 1.2 (0.5 to 2.7) respectively after maternal smoking, parental employment, preterm gestation, and sleeping position had been adjusted for. Sleeping position partly masked the effect of being bottle fed on sudden infant death as breast fed babies were more likely to have slept prone than bottle fed babies. CONCLUSIONS: Bottle feeding is not a significant independent risk factor for the sudden infant death syndrome. Patterns of maternal smoking, preterm gestation, and parental employment status account for most of the apparent association with bottle feeding. PMID- 7833733 TI - Effect of environmental factors on risk of injury of child pedestrians by motor vehicles: a case-control study. AB - OBJECTIVE: To identify and assess contribution of environmental risk factors for injury of child pedestrians by motor vehicles. DESIGN: Community based case control study. Environmental characteristics of sites of child pedestrian injury were compared with the environmental characteristics of selected comparison sites. Each comparison site was the same distance and direction from home of control child as was the injury site from home or relevant case child. Two control sites were selected for each injury site. SETTING: Auckland region of New Zealand. SUBJECTS: Cases were 190 child pedestrians aged < 15 who were killed or hospitalised after collision with a motor vehicle on a public road during two years and two months. Controls were 380 children randomly sampled from population and frequency matched for age and sex. MAIN OUTCOME MEASURE: Traffic volume and speed and level of parking on curbs at injury sites and comparison sites. RESULTS: Risk of injury of child pedestrians was strongly associated with traffic volume: risk of injury at sites with highest traffic volumes was 14 times greater than that at least busy sites (odds ratio 14.30; 95% confidence interval 6.98 to 29.20), and risk increased with increasing traffic volume. High density of curb parking was also associated with increased risk (odds ratio 8.12; 3.32 to 19.90). Risk was increased at sites with mean speeds over 40 km/h (odds ratio 2.68; 1.26 to 5.69), although risk did not increase further with increasing speed. CONCLUSION: Reducing traffic volume in urban areas could significantly reduce rates of child pedestrian injury. Restricting curb parking may also be effective. PMID- 7833734 TI - Predictive value of human papillomavirus type for histological diagnosis of women with cervical cytological abnormalities. PMID- 7833735 TI - Long term effects of guar gum on lipid metabolism after carotid endarterectomy. PMID- 7833736 TI - Appropriate prescribing in asthma and its related cost in east London. AB - OBJECTIVES: To determine the patterns of preventive to reactive prescribing for asthma among general practices in the City and East London Family Health Services Authority area and their relation to prescribing cost. DESIGN: Descriptive study of asthma prescribing during April 1992 to March 1993. Prescribing data were linked with general practice and population data on one database. SETTING: City and East London Family Health Services Authority area, including all general practices in contract with the authority, which covers the inner city London Boroughs of Hackney, Tower Hamlets, and Newham and the Corporation of the City of London. SUBJECTS: All 163 general practices as at 1 June 1993. MAIN OUTCOME MEASURES: Ratios of prescribed inhaled corticosteroids plus cromoglycates (prophylactic treatment) to bronchodilators; distribution of the cost of asthma prescribing; distribution of overall generic prescribing; proportion of asthma generic prescribing; distribution of cost of overall drugs prescribed per prescribing unit. RESULTS: Practices approved for band 3 health promotion or asthma surveillance and those with a general practitioner trainer had on average higher ratios of prophylactic to bronchodilator treatment and significantly higher asthma drug costs than other practices. Those practices with high levels of overall generic prescribing had significantly higher prophylactic to bronchodilator ratios than those with lower levels of generic prescribing. Practices with higher levels of asthma drug generic prescribing also had significantly higher prophylactic prescribing. However, the proportion of generically prescribed asthma drugs was lower than overall generic prescribing. There was no correlation between the ratio of prophylactic to bronchodilator asthma prescribing and the proportion of overall drugs expenditure, but high spending practices spent significantly more on asthma drugs. CONCLUSIONS: Pressure to reduce the cost of asthma prescribing may lead to a lowering of the ratio of prophylactic to bronchodilator treatments. However, reducing prophylactic prescribing would run contrary to the British Thoracic Society guidelines and might worsen the quality of asthma care. PMID- 7833737 TI - Acute viral encephalitis in childhood. PMID- 7833738 TI - Perinatal and infant postmortem examination. PMID- 7833739 TI - Shared care in diabetes. PMID- 7833740 TI - Primary orthostatic tremor. PMID- 7833742 TI - Research shows how HIV exhausts the body. PMID- 7833743 TI - Mental health law obsolete, says inquiry. PMID- 7833741 TI - Assessing the consequences of changing childbirth. PMID- 7833744 TI - Hunt begins for patients suspected of having hepatitis C. PMID- 7833745 TI - Making Europe's blood safer. PMID- 7833746 TI - Report criticises London ambulance service. PMID- 7833747 TI - China fights fall in IQ due to iodine deficiency. PMID- 7833749 TI - Britain does too many x rays, says Audit Commission. PMID- 7833748 TI - Study supports screening for the fragile X syndrome. PMID- 7833750 TI - Britain will unite doctors' training grades. PMID- 7833751 TI - Ambulances and management. PMID- 7833752 TI - Randomised controlled trial for evaluation of fitness programme for patients with chronic low back pain. AB - OBJECTIVE: To evaluate a progressive fitness programme for patients with chronic low back pain. DESIGN: Single blind randomised controlled trial. Assessments were carried out before and after treatment by an observer blinded to the study and included a battery of validated measures. All patients were followed up by postal questionnaire six months after treatment. SETTING: Physiotherapy department of orthopaedic hospital. SUBJECTS: 81 patients with chronic low back pain referred from orthopaedic consultants for physiotherapy. The patients were randomly allocated to a fitness programme or control group. INTERVENTION: Both groups were taught specific exercises to carry out at home and referred to a back-school for education in back care. Patients allocated to the fitness class attended eight exercise classes over four weeks in addition to the home programme and backschool. RESULTS: Significant differences between the groups were shown in the changes before and after treatment in scores on the Oswestry low back pain disability index (P < 0.005), pain reports (sensory P < 0.05 and affective P < 0.005), self efficacy reports (P < 0.05), and walking distance (P < 0.005). No significant differences between the groups were found by the general health questionnaire or questionnaire on pain locus of control. A benefit of about 6 percentage points on the disability index was maintained by patients in the fitness group at six months. CONCLUSION: There is a role for supervised fitness programmes in the management of moderately disabled patients with chronic low back pain. Further clinical trials, however, need to be established in other centres to confirm these findings. PMID- 7833753 TI - Value and quality of perinatal and infant postmortem examinations: cohort analysis of 400 consecutive deaths. AB - OBJECTIVES: To evaluate the contribution that perinatal and infant necropsy makes to clinical practice and to see how this might be influenced by the quality of the investigation. DESIGN: Cohort analysis, with data from the all Wales perinatal survey, of perinatal and infant deaths during 1993 of babies born to mothers usually resident in Wales. The clinicopathological classification of death based on clinical details was compared with the classification after necropsy. Similarly, cases in which necropsy yielded new information were identified. The quality of the necropsy was assessed by scoring six aspects of the examination. SUBJECTS: 400 consecutive deaths at 20 weeks of gestation to 1 year of age. MAIN OUTCOME MEASURES: Necropsy rate, effect of necropsy on clinicopathological classification, new information disclosed by necropsy, quality of necropsies, and the link between new information and quality of the necropsy. RESULTS: Necropsy was performed in 232 cases (58%). The clinicopathological classification was altered by necropsy in 29 cases (13%). New information was obtained in 60 cases (26%), and in 42 (18%) it disclosed the cause of death. The quality of necropsy was substantially higher when the main cause of death was detected than when nothing new was found. CONCLUSION: Necropsy is underused. Clinicians should be more positive about necropsies and realise how much clinically relevant information can be obtained from a good quality examination. PMID- 7833754 TI - Sexual health education interventions for young people: a methodological review. AB - OBJECTIVES: To locate reports of sexual health education interventions for young people, assess the methodological quality of evaluations, identify the subgroup with a methodologically sound design, and assess the evidence with respect to the effectiveness of different approaches to promoting young people's sexual health. DESIGN: Survey of reports in English by means of electronic databases and hand searches for relevant studies conducted in the developed world since 1982. Papers were reviewed for eight methodological qualities. The evidence on effectiveness generated by studies meeting four core criteria was assessed. Judgments on effectiveness by reviewers and authors were compared. PAPERS: 270 papers reporting sexual health interventions. MAIN OUTCOME MEASURE: The methodological quality of evaluations. RESULTS: 73 reports of evaluations of sexual health interventions examining the effectiveness of these interventions in changing knowledge, attitudes, or behavioural outcomes were identified, of which 65 were separate outcome evaluations. Of these studies, 45 (69%) lacked random control groups, 44 (68%) failed to present preintervention and 38 (59%) postintervention data, and 26 (40%) omitted to discuss the relevance of loss of data caused by drop outs. Only 12 (18%) of the 65 outcome evaluations were judged to be methodologically sound. Academic reviewers were more likely than authors to judge studies as unclear because of design faults. Only two of the sound evaluations recorded interventions which were effective in showing an impact on young people's sexual behaviour. CONCLUSIONS: The design of evaluations in sexual health intervention needs to be improved so that reliable evidence of the effectiveness of different approaches to promoting young people's sexual health may be generated. PMID- 7833755 TI - Diuretic effect of frusemide in patients with nephrotic syndrome: is it potentiated by intravenous albumin? PMID- 7833756 TI - Parents in the recovery room: survey of parental and staff attitudes. PMID- 7833757 TI - Why patients choose paracetamol for self poisoning and their knowledge of its dangers. PMID- 7833759 TI - Multiple significance tests: the Bonferroni method. PMID- 7833758 TI - Low income scheme index: a new deprivation scale based on prescribing in general practice. AB - OBJECTIVES: To describe and validate a new deprivation index, based on the percentage of prescribed items exempt from the prescription charge under the low income scheme, at both family health services authority and practice level. DESIGN: Comparison of the index with three other deprivation indices and correlation of index values with the use of drugs given for conditions with known social class gradients. SETTING: All 90 family health services authorities and 7619/9289 practices in England. RESULTS: The ranking of family health services authorities on the new index correlated highly with rankings on the other indices. Values in relation to the use of drugs given for conditions with known social class gradients were in the predicted direction at both family health services authority level and practice level; correlation was highly significant at the authority level, but less significant at practice level. CONCLUSIONS: The new index provides a good measure of deprivation at family health services authority level, and at practice level the results are sufficiently encouraging to warrant further research. It provides the best available instrument for relating deprivation to the use of drugs in any population that can be defined by prescribing data, but an attempt to use it in determining allocation of resources would at this stage be premature. PMID- 7833760 TI - Do anticonvulsants alter the natural course of epilepsy? Treatment should be started as early as possible. PMID- 7833761 TI - Do anticonvulsants alter the natural course of epilepsy? Case for early treatment is not established. PMID- 7833762 TI - WHO's special programmes: undermining from above. AB - Despite the World Health Organisation's spoken commitment to developing integrated primary health care, its most visible and successful activities are not integrated within countries; they are its disease specific intervention programmes, such as the Global Programme on AIDS and the programmes for the control of diarrhoeal and acute respiratory diseases. The 10 or so special programmes, all but one of which (the onchocerciasis control programme) are based in Geneva, have found increasing favour among donors, but critics say that they undermine WHO's attempts to integrate its activities at country level and discourage countries from developing their own capacity. PMID- 7833764 TI - Secrecy in the NHS. Wide public consultation in Cambridge and Huntingdon. PMID- 7833763 TI - Secrecy in the NHS. Threat of action for libel. PMID- 7833765 TI - Secrecy in the NHS. Dismissal means denial of right to practice. PMID- 7833766 TI - Secrecy in the NHS. Clinicians should not restrict access to basic information. PMID- 7833767 TI - Secrecy in the NHS. Cordial relationships restored. PMID- 7833768 TI - Secrecy in the NHS. Doctors were previously the leading practitioners of secrecy. PMID- 7833769 TI - Secrecy in the NHS. Royal Devon and Exeter Hospital has policy of openness. PMID- 7833770 TI - Secrecy in the NHS. Advocacy for public health will continue. PMID- 7833771 TI - Secrecy in the NHS. Defend the principles of our calling together. PMID- 7833772 TI - Secrecy in the NHS. Public health advocacy will remain. PMID- 7833773 TI - Secrecy in the NHS. PHLS reports on food poisoning should be published routinely. PMID- 7833774 TI - Measles campaign. Little importance placed on infants aged under 15 months. PMID- 7833775 TI - Measles campaign. Rubella component of vaccine was ignored. PMID- 7833776 TI - Clinical scores in the differential diagnosis of acute stroke. PMID- 7833777 TI - Ethnic variation in epidemiology of hip fracture. PMID- 7833778 TI - Stroke units. PMID- 7833779 TI - Intercultural consultations. Language is not the only barrier. PMID- 7833780 TI - Intercultural consultations. Multilingual literature is useful. PMID- 7833781 TI - Prescribing exercise in general practice. PMID- 7833782 TI - Auditing absence due to sickness. PMID- 7833783 TI - Biological washing powders as allergens. PMID- 7833784 TI - Resuscitation skills of MRCP candidates: one year on. PMID- 7833785 TI - Visual evoked potential measurement by adaptive filtering. AB - The method of ensemble averaging (EA), commonly used to improve signal-to-noise ratio (SNR) in evoked potential measurements, loses potentially useful information regarding response variability across trials. Due to the usually low SNR, it is difficult to extract the response from individual trials. The present paper describes an adaptive signal enhancer (ASE) that is capable of tracking the variation of visual evoked potential (VEP) from trial to trial as well as improving SNR. This ASE requires two inputs: a primary input, which is the raw noise-corrupted response, and a reference input, which is designed for an optional performance of ASE. We used moving ensemble averaging (MEA) to form the dynamic reference input. Experimental results in humans show a satisfactory performance of the ASE in determining VEP to single stimulus and in tracking the temporal changes of the signal. PMID- 7833786 TI - A review of pulse propagation in viscoelastic arteries with distributed flow leakage. AB - Current mathematical models for describing pulse propagation in arteries are summarized. These models include the effects of viscoelasticity, frequency dependent friction, and other factors. One factor that has not been previously considered is the effect of distributed flow leakage. This leakage is known to have a significant effect on pulse propagation in rigid tubes and it has been assumed to have a similar effect in compliant tubes. These effects are described here, along with the results of a recent study by these authors on the effects of the distributed flow leakage in compliant tubes. PMID- 7833787 TI - Experimental development of a chitosan-bonded beta-tricalcium phosphate bone filling paste. AB - Bone filling substances are needed to meet several requirements including nontoxicity, setting time, changes in pH values, and amount of dissolved elements as well as mechanical properties. In this study, the bone-generating composites were prepared by employing the in vivo absorbable beta-tricalcium phosphate as a parent matrix kneaded with CaO, MgO, and ZnO as bone mineral additives with different compositions. The setting time, pH values, compressive strength were investigated as a function of the amount of these bone mineral additives. It was found that the setting time was shortened by increasing CaO, MgO, and ZnO contents. Increasing ZnO contents resulted in the pH value lower, while the pH values increased by increasing CaO and MgO contents. Increasing ZnO contents caused the compressive strength stronger, on the other hand, the compressive strength was weakened by increasing MgO contents. Furthermore, calcium appears to be selectively released from the hardened composite sample. PMID- 7833788 TI - Effect of shock wave treatment on femoral prosthesis and cement removal. AB - The present study has examined the efficacy of shock wave treatment to aid in the removal of bone cement in human cadaver femora after femoral prosthesis implantation. The shock waves were applied to the specimens at four points, in the circumference 90 degrees apart, at three levels. Four hundred shocks were applied at each point with intensity level of 25 kV. Extraction time of the bone cement was significantly (p < 0.002) faster in the treated versus untreated control groups. The average extraction time was decreased by 32%. Shock wave treatment also reduced the amount of residual cement inside the bone surface by an average of 55% (p < 0.006). The number of shocks needed to remove the prosthesis from bone cement also decreased significantly (p < 0.001) after shock wave treatment. PMID- 7833789 TI - Excitotoxic mechanisms in the pathogenesis of dementia. AB - Alzheimer disease and related dementias, in common with most major neurological diseases, are characterized by localized brain damage. An abundance of senile plaques and neurofibrillary tangles in certain brain areas is pathognomic of the disease: of the two, the density of tangles may correlate more closely with disease severity ante mortem. Clinical manifestation of the disease also results from a locally severe loss of neurones. This might be caused by over-stimulation by excitant amino acid transmitters such as glutamate, which would promote cell death. Mechanisms which might give rise to the localization of Alzheimer pathogenesis include hypersensitivity to damage because a cell carries a particular sub-set of post-synaptic receptors; local variations in the efficiency of excitatory amino acid transport; and, possibly, local exacerbation of toxicity by substances such as beta-amyloid. Elucidation of such mechanisms could lead to new pharmacotherapies of dementia. PMID- 7833790 TI - [3H]adenosine transport in rat dorsal brain stem using a crude synaptosomal preparation. AB - The neuromodulator adenosine, has been shown to have the highest density of central uptake sites in the nucleus tractus solitarius in the dorsal brain stem. The nucleus tractus solitarius is involved in the central regulation of reflex cardiovascular activity suggesting that adenosine may also be involved in central cardiovascular control. Thus, the present study has characterized the transport of [3H]adenosine into rat dorsal brain stem synaptosomes. The process was found to be saturable and highly dependent on temperature. Furthermore, [3H]adenosine transport in rat dorsal brain stem synaptosomes was far more sensitive to the removal of sodium ions than has been previously reported for rat cortical synaptosomes. In addition transport was rapid, being linear for at least 30 s at 37 degrees C, reaching equilibrium within 1 min and had an apparent Km value of 2.7 +/- 0.2 microM (n = 4) and a Vmax value of 135.5 +/- 17.8 pmol/mg protein/min (n = 4). These kinetic parameters are within an order of magnitude of adenosine uptake processes found in rat cerebral cortical synaptosomes. Transport of [3H]adenosine was significantly inhibited by an excess of unlabelled adenosine (1 mM) and the adenosine uptake inhibitor S(4-nitrobenzyl)-6-thioinosine (100 microM) while morphine (150 microM) and flurazepam (150 microM) were largely ineffective as inhibitors of the process, in contrast with previous findings in rat cortical synaptosomes. The present findings demonstrate the presence of a high affinity transport system for adenosine in the rat dorsal brain stem which appears to differ in some properties to uptake processes found in rat cortex. PMID- 7833791 TI - Phagocytic microglia release cytokines and cytotoxins that regulate the survival of astrocytes and neurons in culture. AB - Numerous studies have now shown that microglia secrete factors which may influence the growth and survival of cells in the CNS. We employed glia-neuron co cultures to investigate the net effect of soluble products from secretory microglia upon astroglia and neurons following microglial activation by a phagocytic signal. Stimulation of microglia produced soluble factors that both increase the number of astroglia and decrease the number of neurons. The astroglial proliferating activity was blocked when incubated with an interleukin 1 (IL-1) receptor antagonist while the neurotoxic effect was inhibited by a N methyl-D-aspartate (NMDA) receptor antagonist. Recombinant IL-1 served as a potent mitogen for cultured astroglia and promoted neuron survival by indirect actions upon astrocytes. These observations suggest that reactive microglia mediate both astrogliosis and neuronal injury through the simultaneous release of cell growth factors and poisons. The net effect of secretion products from phagocytic microglia is to diminish neuronal survival. PMID- 7833792 TI - Changes in muscarinic (M1 and M2 subtypes) and phencyclidine receptor density in the rat brain following trimethyltin intoxication. AB - The main purpose of this study was to determine whether one or both of the muscarinic receptor subtypes (M1 and M2) contributed to the total cholinergic receptor loss found in trimethyltin (TMT) treated rats and to assess the effect of TMT on phencyclidine (PCP) receptor density in several regions of the rat brain. The distribution and changes in muscarinic (M1 and M2) receptor and PCP receptor sites were analysed by means of quantitative autoradiography using [3H]quinuclidinyl benzilate (QNB) and [3H] N-(1-(2-thienyl) cyclohexyl) 3,4 piperidine (TCP) respectively. The results demonstrate a TMT induced decrease in [3H]QNB binding in a large number of brain regions particularly the hippocampal formation, for both M1 and M2 muscarinic receptor subtypes. There is also a decrease in [3H]TCP binding in several brain regions. The effects of TMT on PCP receptors suggest that TMT induced damage is not restricted to the cholinergic system and that N-methyl-D-aspartate (NMDA) receptors are also affected. PMID- 7833793 TI - Changes of pharmacological properties of (1S,3R)-ACPD-sensitive glutamate binding sites in developing mouse cerebellum. AB - Autoradiography of [3H]glutamate binding to mouse cerebellar sections was used to study the distribution of (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid ((1S,3R)-ACPD) sensitive [3H]glutamate binding sites and the sensitivity of these sites to drugs preferentially acting on one or few types of the metabotropic receptor family. The inhibitory effect of (1S,3R)-ACPD on [3H]glutamate binding and its estimated inhibition constant showed the presence of a different global metabotropic receptor population according to the region considered. During ontogeny, the (1S,3R)-ACPD binding site density increased in the molecular layer (ML), in contrast it decreased in the internal granular layer (IGL) and the deep cerebellar nuclei (DCN). In addition, different sensitivities to (RS)-alpha methyl-4-carboxyphenylglycine (MCPG), (S)-4-carboxyphenylglycine (4-CPG), (2S,3S,4S)-alpha-(carboxycyclopropyl)glycine (L-CCG-I) and L-2-amino-4 phosphonobutyric acid (L-AP4) were demonstrated according to the region and the age. In the DCN, the high (1S,3R)-ACPD binding site density at PND 10 seems to be also sensitive to L-CCG-I but not to MCPG, 4-CPG or L-AP4. In the ML, the MCPG-, the 4-CPG- and the L-AP4-sensitive [3H]glutamate binding sites appeared during ontogeny and the L-CCG-I-sensitive [3H]glutamate binding sites were already present at PND 10. In the IGL, L-CCG-I-sensitive binding sites disappeared in contrast to the L-AP4-sensitive binding sites which appeared during development even if the total (1S,3R)-ACPD binding site density was relatively weak in the adults. These results all reflected the multiplicity of the receptor subtypes included in the cerebellar metabotropic component. PMID- 7833794 TI - Rapid and selective enhancement of DNA binding activity of the transcription factor AP1 by systemic administration of N-methyl-D-aspartate in murine hippocampus. AB - Brain nuclear extracts of ddY mice contained 3 different transcription factors with leucine-zipper domains, including activator protein-1 (AP1), cyclic AMP responsive element binding protein (CREB) and Myc. An intraperitoneal injection of N-methyl-D-aspartate (NMDA) was effective in selectively inducing 6-fold enhancement of DNA binding activity of AP1 in the hippocampus 2 h after the administration. Furthermore, NMDA induced less than 2-fold potentiation of the AP1 binding in the striatum, hypothalamus, medulla-pons and cerebral cortex in a rank order of decreasing magnitude. However, the AP1 binding was not significantly affected by the systemic injection of NMDA in the midbrain and cerebellum. In contrast, NMDA virtually did not alter DNA binding activities of both CREB and Myc in discrete structures of murine brain under similar experimental conditions. These results suggest that the systemic administration of NMDA may induce rapid and selective enhancement of DNA binding activity of AP1 in murine hippocampus. PMID- 7833795 TI - Possible dysfunction of ionotropic glutamate receptors in cerebellum of epileptic E1 mouse brain. AB - Binding of [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten- 5,10-imine (MK-801) to an ion channel domain on the N-methyl-D-aspartate (NMDA)-sensitive subclass of brain glutamate (Glu) receptors was highest in the hippocampus of the hereditary epileptogenic mutant El as well as its parent ddY strain mice, when determined before and at equilibrium in the presence of 3 different agonists at the respective domains on the NMDA receptor complex, including Glu, glycine (Gly) and spermidine (SPD). Cerebellar [3H]MK-801 binding before equilibrium was significantly lower in El mice than in ddY mice, while the binding was not significantly different from each other in other brain structures of both strains of mice. Kinetic analysis revealed that the association rate was significantly lower with [3H]MK-801 binding in the cerebellum of El mice than of ddY mice. In contrast to ddY mice, furthermore, Gly failed to potentiate cerebellar [3H]MK-801 binding before equilibrium in El mice, with SPD being active in significantly inhibiting the binding. However, saturation analysis revealed that the affinity and density of cerebellar [3H]MK-801 binding at equilibrium in El mice were not significantly different from those in ddY mice. In addition, epileptogenic El mice had significantly higher levels of [3H]SPD binding in all brain structures examined than ddY mice, whereas [3H]DL-alpha-amino-3-hydroxy-5- methylisoxazole-4 propionate binding was significantly lower in the cerebellum of El mice than of ddY mice. These results suggest that dysfunction of cerebellar Glu receptors may be at least in part responsible for a variety of abnormal symptoms observed in epileptic El mice. PMID- 7833796 TI - Differential subcellular localization of two populations of glutamate/AMPA receptors in the rat telencephalon. AB - The distribution of glutamate AMPA receptors in the synaptosomal and microsomal fractions of neonatal and adult rat telencephalon was studied by determining the saturation kinetics at equilibrium of 3H-AMPA and 3H-CNQX binding. At both ages, synaptosomal preparations exhibited two populations of 3H-AMPA binding sites with a small number of high affinity sites and a large number of low affinity sites. 3H-AMPA binding to microsomal preparations from both neonatal and adult rat telencephalon exhibited a much higher proportion of high affinity relative to low affinity sites. 3H-CNQX binding to the same fractions did not parallel 3H-AMPA binding, but was correlated with the low affinity 3H-AMPA binding and with a marker of plasma membranes. The results suggest that nonsynaptic glutamate/AMPA receptors have a high affinity for agonist and become low affinity when inserted into postsynaptic membranes and that 3H-CNQX binds synaptic but not nonsynaptic glutamate/AMPA receptors with high affinity. PMID- 7833797 TI - Content and fatty acid composition of cardiolipin in the brain of patients with Alzheimer's disease. AB - The frontal, temporal and occipital cortex from human brains affected by Alzheimer's disease were analyzed for their contents and fatty acid compositions of cardiolipin. Phospholipids were purified using an HPLC system and cardiolipin was found to be present in the same amount (on a protein basis) as in age-matched controls. One-third of the total fatty acyl moieties of this phospholipid were saturated, one-third monounsaturated and one-third polyunsaturated. In affected brain regions the levels of certain polyunsaturated fatty acids displayed moderate decreases, not exceeding 10-15%. However, the total amount of polyunsaturated fatty acids decreased by only 9%. These results demonstrate that the amount and structure of brain cardiolipin are not modified to any great extent in connection with Alzheimer's disease. PMID- 7833798 TI - Structure and functions of arrestins. AB - Transmembrane signal transductions in a variety of cell types that mediate signals as diverse as those carried by neurotransmitters, hormones, and sensory signals share basic biochemical mechanisms that include: (1) an extracellular perturbation (neurotransmitter, hormone, odor, light); (2) specific receptors; (3) coupling proteins, such as G proteins; and (4) effector enzymes or ion channels. Parallel to these amplification reactions, receptors are precisely inactivated by mechanisms that involve protein kinases and regulatory proteins called arrestins. The structure and functions of arrestins are the focus of this review. PMID- 7833799 TI - Interactions between human defensins and lipid bilayers: evidence for formation of multimeric pores. AB - Defensins comprise a family of broad-spectrum antimicrobial peptides that are stored in the cytoplasmic granules of mammalian neutrophils and Paneth cells of the small intestine. Neutrophil defensins are known to permeabilize cell membranes of susceptible microorganisms, but the mechanism of permeabilization is uncertain. We report here the results of an investigation of the mechanism by which HNP-2, one of 4 human neutrophil defensins, permeabilizes large unilamellar vesicles formed from the anionic lipid palmitoyloleoylphosphatidylglycerol (POPG). As observed by others, we find that HNP-2 (net charge = +3) cannot bind to vesicles formed from neutral lipids. The binding of HNP-2 to vesicles containing varying amounts of POPG and neutral (zwitterionic) palmitoyloleoylphosphatidylcholine (POPC) demonstrates that binding is initiated through electrostatic interactions. Because vesicle aggregation and fusion can confound studies of the interaction of HNP-2 with vesicles, those processes were explored systematically by varying the concentrations of vesicles and HNP-2, and the POPG:POPC ratio. Vesicles (300 microM POPG) readily aggregated at HNP-2 concentrations above 1 microM, but no mixing of vesicle contents could be detected for concentrations as high as 2 microM despite the fact that intervesicular lipid mixing could be demonstrated. This indicates that if fusion of vesicles occurs, it is hemi-fusion, in which only the outer monolayers mix at bilayer contact sites. Under conditions of limited aggregation and intervesicular lipid mixing, the fractional leakage of small solutes is a sigmoidal function of peptide concentration. For 300 microM POPG vesicles, 50% of entrapped solute is released by 0.7 microM HNP-2. We introduce a simple method for determining whether leakage from vesicles is graded or all-or-none. We show by means of this fluorescence "requenching" method that native HNP-2 induces vesicle leakage in an all-or-none manner, whereas reduced HNP-2 induces partial, or graded, leakage of vesicle contents. At HNP-2 concentrations that release 100% of small (approximately 400 Da) markers, a fluorescent dextran of 4,400 Da is partially retained in the vesicles, and a 18,900-Da dextran is mostly retained. These results suggest that HNP-2 can form pores that have a maximum diameter of approximately 25 A. A speculative multimeric model of the pore is presented based on these results and on the crystal structure of a human defensin. PMID- 7833800 TI - Subunit interface mutants of rabbit muscle aldolase form active dimers. AB - We report the construction of subunit interface mutants of rabbit muscle aldolase A with altered quaternary structure. A mutation has been described that causes nonspherocytic hemolytic anemia and produces a thermolabile aldolase (Kishi H et al., 1987, Proc Natl Acad Sci USA 84:8623-8627). The disease arises from substitution of Gly for Asp-128, a residue at the subunit interface of human aldolase A. To elucidate the role of this residue in the highly homologous rabbit aldolase A, site-directed mutagenesis is used to replace Asp-128 with Gly, Ala, Asn, Gln, or Val. Rabbit aldolase D128G purified from Escherichia coli is found to be similar to human D128G by kinetic analysis, CD, and thermal inactivation assays. All of the mutant rabbit aldolases are similar to the wild-type rabbit enzyme in secondary structure and kinetic properties. In contrast, whereas the wild-type enzyme is a tetramer, chemical crosslinking and gel filtration indicate that a new dimeric species exists for the mutants. In sedimentation velocity experiments, the mutant enzymes as mixtures of dimer and tetramer at 4 degrees C. Sedimentation at 20 degrees C shows that the mutant enzymes are > 99.5% dimeric and, in the presence of substrate, that the dimeric species is active. Differential scanning calorimetry demonstrates that Tm values of the mutant enzymes are decreased by 12 degrees C compared to wild-type enzyme. The results indicate that Asp-128 is important for interface stability and suggest that 1 role of the quaternary structure of aldolase is to provide thermostability. PMID- 7833801 TI - Dimerization of beta B2-crystallin: the role of the linker peptide and the N- and C-terminal extensions. AB - beta B2- and gamma B-crystallins of vertebrate eye lens are 2-domain proteins in which each domain consists of 2 Greek key motifs connected by a linker peptide. Although the folding topologies of beta B2- and gamma B-domains are very similar, gamma B-crystallin is always monomeric, whereas beta B2-crystallin associates to homodimers. It has been suggested that the linker or the protruding N- and C terminal arms of beta B2-crystallin (not present in gamma B) are a necessary requirement for this association. In order to investigate the role of these segments for dimerization, we constructed two beta B2 mutants. In the first mutant, the linker peptide was replaced with the one from gamma B (beta B2 gamma L). In the second mutant, the N- and C-terminal arms of 15- and 12-residues length were deleted (beta B2 delta NC). The beta B2 gamma L mutant is monomeric, whereas the beta B2 delta NC mutant forms dimers and tetramers that cannot be interconverted without denaturation. The spectral properties of the beta B2 mutants, as well as their stabilities against denaturants, resemble those of wild type beta B2-crystallin, thus indicating that the overall peptide fold of the subunits is not changed significantly. We conclude that the peptide linker in beta B2-crystallin is necessary for dimerization, whereas the N- and C-terminal arms appear to be involved in preventing the formation of higher homo-oligomers. PMID- 7833802 TI - Equilibrium unfolding of Escherichia coli ribonuclease H: characterization of a partially folded state. AB - We have examined the equilibrium unfolding of Escherichia coli ribonuclease HI (RNase H), a member of a family of enzymes that cleaves RNA from RNA:DNA hybrids. A completely synthetic gene was constructed that expresses a variant of the wild type sequence with all 3 cysteines replaced with alanine. The resulting recombinant protein is active and folds reversibly. Denaturation studies monitored by circular dichroism and tryptophan fluorescence yield coincident curves that suggest the equilibrium unfolding reaction is a 2-state process. Acid denaturation, however, reveals a cooperative transition at approximately pH 1.8 to a partially folded state. This acid state can be further denatured in a reversible manner by the addition of heat or urea as monitored by either CD or tryptophan fluorescence. Analytical ultracentrifugation studies indicate that the acid state of RNase H is both compact and monomeric. Although compact, the acid state does not resemble the native protein: the acid state displays a near-UV CD spectrum similar to the unfolded state and binds to and enhances the fluorescence of the dye 1-anilinonaphthalene, 8-sulfonate much more than either the native or unfolded states. Therefore, the acid state of E. coli RNase H has the characteristics of a molten globule: it retains a high degree of secondary structure, remains compact, yet does not appear to contain a tightly packed core. PMID- 7833803 TI - Quantitative analysis of the kinetics of denaturation and renaturation of barstar in the folding transition zone. AB - The fluorescence-monitored kinetics of folding and unfolding of barstar by guanidine hydrochloride (GdnHCl) in the folding transition zone, at pH 7, 25 degrees C, have been quantitatively analyzed using a 3-state mechanism: U(S)<- >UF<-->N. U(S) and UF are slow-refolding and fast-refolding unfolded forms of barstar, and N is the native protein. U(S) and UF probably differ in possessing trans and cis conformations, respectively, of the Tyr 47-Pro 48 bond. The 3-state model could be used because the kinetics of folding and unfolding of barstar show 2 phases, a fast phase and a slow phase, and because the relative amplitudes of the 2 phases depend only on the final refolding conditions and not on the initial conditions. Analysis of the observed kinetics according to the 3-state model yields the values of the 4 microscopic rate constants that describe the transitions between the 3 states at different concentrations of GdnHCl. The value of the equilibrium unfolded ratio U(S):UF (K21) and the values of the rate constants of the U(S)-->UF and UF-->U(S) reactions, k12 and k21, respectively, are shown to be independent of the concentration of GdnHCl. K21 has a value of 2.1 +/- 0.1, and k12 and k21 have values of 5.3 x 10(-3) s-1 and 11.2 x 10(-3) s 1, respectively. Double-jump experiments that monitor reactions that are silent to fluorescence monitoring were used to confirm the values of K21, k12, and k21 obtained from the 3-state analysis and thereby the validity of the 3-state model.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7833804 TI - Thermal unfolding of tetrameric melittin: comparison with the molten globule state of cytochrome c. AB - Whereas melittin at micromolar concentrations is unfolded under conditions of low salt at neutral pH, it transforms to a tetrameric alpha-helical structure under several conditions, such as high peptide concentration, high anion concentration, or alkaline pH. The anion- and pH-dependent stabilization of the tetrameric structure is similar to that of the molten globule state of several acid denatured proteins, suggesting that tetrameric melittin might be a state similar to the molten globule state. To test this possibility, we studied the thermal unfolding of tetrameric melittin using far-UV CD and differential scanning calorimetry. The latter technique revealed a broad but distinct heat absorption peak. The heat absorption curves were consistent with the unfolding transition observed by CD and were explainable by a 2-state transition mechanism between the tetrameric alpha-helical state and the monomeric unfolded state. From the peptide or salt-concentration dependence of unfolding, the heat capacity change upon unfolding was estimated to be 5 kJ (mol of tetramer)-1 K-1 at 30 degrees C and decreased with increasing temperature. The observed change in heat capacity was much smaller than that predicted from the crystallographic structure (9.2 kJ (mol of tetramer)-1 K-1), suggesting that the hydrophobic residues of tetrameric melittin in solution are exposed in comparison with the crystallographic structure. However, the results also indicate that the structure is more ordered than that of a typical molten globule state. We consider that the conformation is intermediate between the molten globule state and the native state of globular proteins. PMID- 7833805 TI - Stabilization of myoglobin by multiple alanine substitutions in helical positions. AB - We have carried out a series of multiple Xaa-->Ala changes at nonadjacent surface positions in the sequence of sperm whale myoglobin. Although the corresponding single substitutions do not increase the thermal stability of the protein, multiple substitutions enhance the stability of the resulting myoglobins. The effect observed is an increase in the observed Tm (midpoint unfolding temperature) relative to that predicted from assuming additivity of the free energy changes corresponding to single mutations. The stabilization occurs in the presence of urea, as measured by the dependence of the unfolding temperature on urea concentration. The sites that have been altered occur in different helices and are not close in sequence or in the native structure of myoglobin. The observed effect is consistent with a role of multiple alanines in residual interactions in the unfolded state of the mutant proteins. PMID- 7833806 TI - The chaperonin from the archaeon Sulfolobus solfataricus promotes correct refolding and prevents thermal denaturation in vitro. AB - We have isolated a chaperonin from the hyperthermophilic archaeon Sulfolobus solfataricus based on its ability to inhibit the spontaneous refolding at 50 degrees C of dimeric S. solfataricus malic enzyme. The chaperonin, a 920-kDa oligomer of 57-kDa subunits, displays a potassium-dependent ATPase activity with an optimum temperature at 80 degrees C. S. solfataricus chaperonin promotes correct refoldings of several guanidine hydrochloride-denatured enzymes from thermophilic and mesophilic sources. At a molar ratio of chaperonin oligomer to single polypeptide chain of 1:1, S. solfataricus chaperonin completely inhibits spontaneous refoldings and suppresses aggregation upon dilution of the denaturant; refoldings resume upon ATP hydrolysis, with yields of active molecules and rates of folding notably higher than in spontaneous processes. S. solfataricus chaperonin prevents the irreversible inactivations at 90 degrees C of several thermophilic enzymes by the binding of the denaturation intermediate; the time-courses of inactivations are unaffected and most activity is regained upon hydrolysis of ATP. S. solfataricus chaperonin completely prevents the formation of aggregates during thermal inactivation of chicken egg white lysozyme at 70 degrees C, without affecting the rate of activity loss; ATP hydrolysis results in the recovery of most lytic activity. Tryptophan fluorescence measurements provide evidence that S. solfataricus chaperonin undergoes a dramatic conformational rearrangement in the presence of ATP/Mg, and that the hydrolysis of ATP is not required for the conformational change. The ATP/Mg induced conformation of the chaperonin is fully unable to bind the protein substrates, probably due to disappearance or modification of the substrate binding sites. This is the first archaeal chaperonin whose involvement in protein folding has been demonstrated. PMID- 7833807 TI - Refined structure of dimeric diphtheria toxin at 2.0 A resolution. AB - The refined structure of dimeric diphtheria toxin (DT) at 2.0 A resolution, based on 37,727 unique reflections (F > 1 sigma (F)), yields a final R factor of 19.5% with a model obeying standard geometry. The refined model consists of 523 amino acid residues, 1 molecule of the bound dinucleotide inhibitor adenylyl 3'-5' uridine 3' monophosphate (ApUp), and 405 well-ordered water molecules. The 2.0-A refined model reveals that the binding motif for ApUp includes residues in the catalytic and receptor-binding domains and is different from the Rossmann dinucleotide-binding fold. ApUp is bound in part by a long loop (residues 34-52) that crosses the active site. Several residues in the active site were previously identified as NAD-binding residues. Glu 148, previously identified as playing a catalytic role in ADP-ribosylation of elongation factor 2 by DT, is about 5 A from uracil in ApUp. The trigger for insertion of the transmembrane domain of DT into the endosomal membrane at low pH may involve 3 intradomain and 4 interdomain salt bridges that will be weakened at low pH by protonation of their acidic residues. The refined model also reveals that each molecule in dimeric DT has an "open" structure unlike most globular proteins, which we call an open monomer. Two open monomers interact by "domain swapping" to form a compact, globular dimeric DT structure. The possibility that the open monomer resembles a membrane insertion intermediate is discussed. PMID- 7833808 TI - Refined structure of monomeric diphtheria toxin at 2.3 A resolution. AB - The structure of toxic monomeric diphtheria toxin (DT) was determined at 2.3 A resolution by molecular replacement based on the domain structures in dimeric DT and refined to an R factor of 20.7%. The model consists of 2 monomers in the asymmetric unit (1,046 amino acid residues), including 2 bound adenylyl 3'-5' uridine 3' monophosphate molecules and 396 water molecules. The structures of the 3 domains are virtually identical in monomeric and dimeric DT; however, monomeric DT is compact and globular as compared to the "open" monomer within dimeric DT (Bennett MJ, Choe S, Eisenberg D, 1994b, Protein Sci 3:0000-0000). Detailed differences between monomeric and dimeric DT are described, particularly (1) changes in main-chain conformations of 8 residues acting as a hinge to "open" or "close" the receptor-binding (R) domain, and (2) a possible receptor-docking site, a beta-hairpin loop protruding from the R domain containing residues that bind the cell-surface DT receptor. Based on the monomeric and dimeric DT crystal structures we have determined and the solution studies of others, we present a 5 step structure-based mechanism of intoxication: (1) proteolysis of a disulfide linked surface loop (residues 186-201) between the catalytic (C) and transmembrane (T) domains; (2) binding of a beta-hairpin loop protruding from the R domain to the DT receptor, leading to receptor-mediated endocytosis; (3) low pH triggered open monomer formation and exposure of apolar surfaces in the T domain, which insert into the endosomal membrane; (4) translocation of the C domain into the cytosol; and (5) catalysis by the C domain of ADP-ribosylation of elongation factor 2. PMID- 7833809 TI - Computer modeling of substrate binding to lipases from Rhizomucor miehei, Humicola lanuginosa, and Candida rugosa. AB - The substrate-binding sites of the triacyl glyceride lipases from Rhizomucor miehei, Humicola lanuginosa, and Candida rugosa were studied by means of computer modeling methods. The space around the active site was mapped by different probes. These calculations suggested 2 separate regions within the binding site. One region showed high affinity for aliphatic groups, whereas the other region was hydrophilic. The aliphatic site should be a binding cavity for fatty acid chains. Water molecules are required for the hydrolysis of the acyl enzyme, but are probably not readily accessible in the hydrophobic interface, in which lipases are acting. Therefore, the hydrophilic site should be important for the hydrolytic activity of the enzyme. Lipases from R. miehei and H. lanuginosa are excellent catalysts for enantioselective resolutions of many secondary alcohols. We used molecular mechanics and dynamics calculations of enzyme-substrate transition-state complexes, which provided information about molecular interactions important for the enantioselectivities of these reactions. PMID- 7833810 TI - Anatomy of an engineered NAD-binding site. AB - The coenzyme specificity of Escherichia coli glutathione reductase was switched from NADP to NAD by modifying the environment of the 2'-phosphate binding site through a set of point mutations: A179G, A183G, V197E, R198M, K199F, H200D, and R204P (Scrutton NS, Berry A, Perham RN, 1990, Nature 343:38-43). In order to analyze the structural changes involved, we have determined 4 high-resolution crystal structures, i.e., the structures of the wild-type enzyme (1.86 A resolution, R-factor of 16.8%), of the wild-type enzyme ligated with NADP (2.0 A, 20.8%), of the NAD-dependent mutant (1.74 A, 16.8%), and of the NAD-dependent mutant ligated with NAD (2.2 A, 16.9%). A comparison of these structures reveals subtle differences that explain details of the specificity change. In particular, a peptide rotation occurs close to the adenosine ribose, with a concomitant change of the ribose pucker. The mutations cause a contraction of the local chain fold. Furthermore, the engineered NAD-binding site assumes a less rigid structure than the NADP site of the wild-type enzyme. A superposition of the ligated structures shows a displacement of NAD versus NADP such that the electron pathway from the nicotinamide ring to FAD is elongated, which may explain the lower catalytic efficiency of the mutant. Because the nicotinamide is as much as 15 A from the sites of the mutations, this observation reminds us that mutations may have important long-range consequences that are difficult to anticipate. PMID- 7833811 TI - The NMR solution structure of the pheromone Er-2 from the ciliated protozoan Euplotes raikovi. AB - The NMR structure of the pheromone Er-2 from the ciliated protozoan Euplotes raikovi has been determined in aqueous solution. The structure of this 40-residue protein was calculated with the distance geometry program DIANA from 621 distance constraints and 89 dihedral angle constraints; the program OPAL was employed for the energy minimization. For a group of 20 conformers used to characterize the solution structure, the average pairwise RMS deviation from the mean structure calculated for the backbone heavy atoms N, C alpha, and C' of residues 3-37 was 0.31 A. The molecular architecture is dominated by an up-down-up bundle of 3 short helices of residues 5-11, 14-20, and 23-33, which is similar to the structures of the homologous pheromones Er-1 and Er-10. Novel structural features include a well-defined N-cap on the first helix, a 1-residue deletion in the second helix resulting in the formation of a 3(10)-helix rather than an alpha helix as found in Er-1 and Er-10, and the simultaneous presence of 2 different conformations for the C-terminal tetrapeptide segment, i.e., a major conformation with the Leu 39-Pro 40 peptide bond in the trans form and a minor conformation with this peptide bond in the cis form. PMID- 7833812 TI - The NMR solution structure of the pheromone Er-1 from the ciliated protozoan Euplotes raikovi. AB - The 3-dimensional structure of the pheromone Er-1 isolated from the ciliated protozoan Euplotes raikovi has been determined in aqueous solution by 1H NMR spectroscopy. The structure of this 40-residue protein was calculated with the distance geometry program DIANA on the basis of 503 upper distance constraints derived from nuclear Overhauser effects and 77 dihedral angle constraints derived from spin-spin coupling constants, and refined by restrained energy minimization with the program OPAL. The Er-1 solution structure is represented by a group of 20 conformers with an average RMS deviation relative to the mean structure of 0.55 A for the backbone atoms N, C alpha, and C', and 0.93 A for all heavy atoms of the complete polypeptide chain, residues 1-40. The molecular architecture is dominated by an up-down-up bundle of 3 alpha-helices formed by residues 2-9, 12 19, and 24-33. Although this core part coincides closely with the previously determined structure of the homologous pheromone Er-10, the C-terminal peptide segment adopts a novel conformation. This is of interest in view of previous suggestions, based on sequence comparisons, that this molecular region may be important for the different specificity of receptor recognition by different pheromones. PMID- 7833813 TI - Structure comparison of the pheromones Er-1, Er-10, and Er-2 from Euplotes raikovi. AB - The NMR structures of the homologous pheromones Er-1, Er-10, and Er-2 from the ciliated protozoan Euplotes raikovi are compared. For all 3 proteins the molecular architecture is made up of an antiparallel 3-helix bundle. The preservation of the core part of the structure is directly manifested by similar patterns of slowed backbone amide proton exchange rates, hydrogen bond formation, and relative solvent accessibility. To align the 6 half-cystine residues in the individual sequences within the preserved 3-dimensional core structure, several deletions and insertions had to be introduced that differ from those previously proposed on the basis of the primary structures. Of special interest is a deletion in the second helix of Er-2, which is accommodated by a transition from an alpha-helix in Er-1 and Er-10 to a 3(10)-helix in Er-2. The most significant structural differences are located in the C-terminal part of the proteins, which may have an important role in specific receptor recognition. PMID- 7833814 TI - Facile transition between 3(10)- and alpha-helix: structures of 8-, 9-, and 10 residue peptides containing the -(Leu-Aib-Ala)2-Phe-Aib- fragment. AB - A structural transition from a 3(10)-helix to an alpha-helix has been characterized at high resolution for an octapeptide segment located in 3 different sequences. Three synthetic peptides, decapeptide (A) Boc-Aib-Trp-(Leu Aib-Ala)2-Phe-Aib-OMe, nonapeptide (B) Boc-Trp-(Leu-Aib-Ala)2-Phe-Aib-OMe, and octapeptide (C) Boc-(Leu-Aib-Ala)2-Phe-Aib-OMe, are completely helical in their respective crystals. At 0.9 A resolution, R factors for A, B, and C are 8.3%, 5.4%, and 7.3%, respectively. The octapeptide and nonapeptide form ideal 3(10) helices with average torsional angles phi(N-C alpha) and psi(C alpha-C') of -57 degrees, -26 degrees C and -60 degrees, -27 degrees for B. The 10-residue peptide (A) begins as a 3(10)-helix and abruptly changes to an alpha-helix at carbonyl O(3), which is the acceptor for both a 4-->1 hydrogen bond with N(6)H and a 5-->1 hydrogen with N(7)H, even though the last 8 residues have the same sequence in all 3 peptides. The average phi, psi angles in the decapeptide are -58 degrees, 28 degrees for residues 1-3 and -63 degrees, -41 degrees for residues 4-10. The packing of helices in the crystals does not provide any obvious reason for the transition in helix type. Fourier transform infrared studies in the solid state also provide evidence for a 3(10)- to alpha-helix transition with the amide I band appearing at 1,656-1,657 cm-1 in the 9- and 10-residue peptides, whereas in shorter sequences the band is observed at 1,667 cm-1. PMID- 7833815 TI - Optimization of the electrostatic interactions in proteins of different functional and folding type. AB - The 3-dimensional optimization of the electrostatic interactions between the charged amino acid residues was studied by Monte Carlo simulations on an extended representative set of 141 protein structures with known atomic coordinates. The proteins were classified by different functional and structural criteria, and the optimization of the electrostatic interactions was analyzed. The optimization parameters were obtained by comparison of the contribution of charge-charge interactions to the free energy of the native protein structures and for a large number of randomly distributed charge constellations obtained by the Monte Carlo technique. On the basis of the results obtained, one can conclude that the charge charge interactions are better optimized in the enzymes than in the proteins without enzymatic functions. Proteins that belong to the mixed alpha beta folding type are electrostatically better optimized than pure alpha-helical or beta strand structures. Proteins that are stabilized by disulfide bonds show a lower degree of electrostatic optimization. The electrostatic interactions in a native protein are effectively optimized by rejection of the conformers that lead to repulsive charge-charge interactions. Particularly, the rejection of the repulsive contacts seems to be a major goal in the protein folding process. The dependence of the optimization parameters on the choice of the potential function was tested. The majority of the potential functions gave practically identical results. PMID- 7833816 TI - Pseudodihedrals: simplified protein backbone representation with knowledge-based energy. AB - Pairwise contact energies do not explicitly take protein secondary structure into account, and so provide an incomplete description of conformational energy. In order to construct a Hamiltonian that specifically relates to protein backbone conformations, a simplified backbone angle is used. The pseudodihedral angle (the torsion angle between planes defined by 4 consecutive alpha-carbon atoms) provides a simplified backbone representation and continues to manifest information about secondary-structure elements: the pseudo-Ramachandran plot contains helical and sheetlike regions. The distribution of pseudodihedral angles is highly sensitive to the identity of the central pair of amino acids. Therefore, a sequence-dependent, knowledge-based potential energy was found according to a quasichemical approximation. These functions form complementary additions to the contact potentials currently in use. This pseudodihedral potential greatly enhances the ability to design sequences that are specific to a given conformation and also improves the ability to discriminate a native conformation from many other conformations. PMID- 7833817 TI - Derivation of rules for comparative protein modeling from a database of protein structure alignments. AB - We describe a database of protein structure alignments as well as methods and tools that use this database to improve comparative protein modeling. The current version of the database contains 105 alignments of similar proteins or protein segments. The database comprises 416 entries, 78,495 residues, 1,233 equivalent entry pairs, and 230,396 pairs of equivalent alignment positions. At present, the main application of the database is to improve comparative modeling by satisfaction of spatial restraints implemented in the program MODELLER (Sali A, Blundell TL, 1993, J Mol Biol 234:779-815). To illustrate the usefulness of the database, the restraints on the conformation of a disulfide bridge provided by an equivalent disulfide bridge in a related structure are derived from the alignments; the prediction success of the disulfide dihedral angle classes is increased to approximately 80%, compared to approximately 55% for modeling that relies on the stereochemistry of disulfide bridges alone. The second example of the use of the database is the derivation of the probability density function for comparative modeling of the cis/trans isomerism of the proline residues; the prediction success is increased from 0% to 82.9% for cis-proline and from 93.3% to 96.2% for trans-proline. The database is available via electronic mail. PMID- 7833818 TI - A neural network model for the prediction of membrane-spanning amino acid sequences. AB - The architecture and weights of an artificial neural network model that predicts putative transmembrane sequences have been developed and optimized by the algorithm of structure evolution. The resulting filter is able to classify membrane/nonmembrane transition regions in sequences of integral human membrane proteins with high accuracy. Similar results have been obtained for both training and test set data, indicating that the network has focused on general features of transmembrane sequences rather than specializing on the training data. Seven physicochemical amino acid properties have been used for sequence encoding. The predictions are compared to hydrophobicity plots. PMID- 7833819 TI - Looking at enzymes in action in the 1950s. PMID- 7833820 TI - Degradation of bacteriophage lambda deoxyribonucleic acid in vitro by sulfur mustard. AB - The degradation of bacteriophage lambda (lambda) deoxyribonucleic acid (DNA) by interaction with 0.1, 0.5 and 1 mM concentrations of sulfur mustard (SM) was investigated using agarose gel electrophoresis. Alkaline agarose gel electrophoresis also revealed single strand breaks at 0.5 and 0.1 mM concentrations of SM. The presence of magnesium ions in the reaction mixture prevented DNA degradation. It is proposed that the degradation of lambda DNA by its interaction with an excess of SM may be caused by the breakage of phosphodiester backbone of DNA via the formation of an intermediate phosphotriester bond. PMID- 7833821 TI - A new type of RNA editing. 5S ribosomal DNA transcripts are edited to mature 5S rRNA. AB - The primary structure of the 5S rRNA from Arabidopsis thaliana was determined. A comparison of this nucleotide sequence with that of 5S rRNA gene showed two differences. Furthermore, we compared all plant 5S rRNA and 5S rDNA sequences known to date and found that lack of colinearity is widespread among higher plant 5S rRNAs and occurred mainly in the double stranded regions. To explain this, we suggest a mechanism which converts putative products of pseudogene ("cryptogene") to mature 5S rRNA molecule. This kind of editing mechanism functions primarily in stems of 5S rRNA in order, to correct mispairing and thereby restoring the Watson Crick base pairs. This idea could explain why so many different 5S rRNA genes or gene like sequences and only one 5S rRNA species exist in the plant cell. The editing can serve as a new mechanism of regulation of 5S rRNA synthesis in addition to transcription of 5S rRNA gene. PMID- 7833822 TI - The role of delta-6- and delta-9-desaturase in the fatty acid metabolism of hepatomas with different growth rate. AB - The fatty acid composition of microsomal membranes from Morris hepatomas 9618A, slow growing, and 3924A, fast growing, confirm the higher content in oleic acid and the loss of PUFAs of the tumours with respect to controls. The specific activities of delta-9-desaturase indicate alternative metabolic pathways for the increased production of oleic acid in the two hepatomas. The delta-6-desaturase activity is much lower in tumours than in controls. However the loss of PUFAs found in tumours seems to be mostly due to a low content in linoleic acid. PMID- 7833823 TI - Transitions of hepatic purine metabolism of Ehrlich ascites tumor bearing mice in different phases of tumor growth. AB - The concentrations of purine nucleotides, nucleosides and nucleobases in hepatocytes taken from healthy control mice and from Ehrlich ascites tumor bearing mice have been measured. The level of adenine nucleotides in the hepatocytes was higher during the proliferating phase in comparison with the resting phase of tumor growth and with control mice hepatocytes. The tracerkinetic studies on purine catabolism have been carried out on liver cells at different periods of tumor growth. The dynamics of radioactive tracers was mathematically modelled by a system of differential equations for both the concentrations and the specific radioactivities of the metabolites. Large differences in metabolic flux rates between control hepatocytes and hepatocytes in different phases of tumor growth were observed. The final purine degradation of hepatocytes was found to be accelerated in the resting phase but not in the proliferating phase of tumor growth. This result is in accordance with increased ATP concentration of liver itself in the proliferating phase of tumor growth. A conclusion is possible that the liver does not supply nucleosides and nucleobases for the Ehrlich ascites tumor cells during the proliferating phase of tumor growth. PMID- 7833824 TI - Immunological crossreactivity of G-protein beta subunit and receptors for activated C-kinase. AB - Selective antisera against: 1) RACKs, 2) a putative common PKC-binding domain (peptide I), and 3) G-protein subunits, were used for immunoblot analysis with recombinant purified beta 1 gamma 2 subunits and a crude preparation of RACKs. Antipeptide I recognized not only RACKs but also the G-protein beta subunit. In addition, two RACK-specific antisera immunoreacted with the G-protein beta subunit. Similarly, anti-G beta comm and S-217 (beta gamma-specific antiserum) crossreacted with RACKs. Using an overlay assay, it was observed that proteins immunoprecipitated with anti-RACKs or with anti-G beta antisera bound activated PKC. PMID- 7833825 TI - Specific recognition sites for oligosaccharides in avian liver nuclei. AB - The presence of glycoproteins and sugar-binding sites in the nucleus is well ascertained. In order to verify the existence of specific nuclear protein carbohydrate interactions, oligosaccharides were released from nuclear or non nuclear glycoproteins by Peptide-N-glycosidase F, labeled by reduction with NaB3H4 and added to whole chicken liver nuclei and to subnuclear insoluble fractions (nucleoli, nuclear matrix and nuclear envelope). The analysis of the binding of the oligosaccharides to the nuclear fractions, performed in the presence or absence of competitor sugars, suggest that some rare oligosaccharides species, present only among the nuclear carbohydrates, are specifically recognized by the nuclear matrix. PMID- 7833826 TI - Modulation of cytochrome P450 activities by 7,8-benzoflavone and its metabolites. AB - 7,8-Benzoflavone(ANF) is a potent in vitro inhibitor of CYP1A2 but is an in vitro activator of CYP3A4. We have investigated the inhibition of caffeine 3 demethylation by metabolites of ANF as well as ANF by human liver microsomes. ANF was the most potent among all the compounds tested. Metabolites of ANF with dihydrodiol substitution at positions 5,6 or 7,8 showed less inhibitory activity. These results suggest that ANF lies in the most appropriate orientation to the active site of CYP1A2. The activation of CYP3A4 enzyme activities by ANF and its metabolites was also investigated. Testosterone 6 beta-hydroxylation mediated by CYP3A4 was stimulated by ANF and metabolites with substitutions at positions 5,6 or 7,8. Hydroxy ANF metabolites, however, decreased the testosterone 6 beta hydroxylation. PMID- 7833827 TI - Some properties of the malonyl-CoA sensitive carnitine long/medium chain acyltransferase activities of peroxisomes and microsomes of rat liver. AB - 1. An increase in the ionic strength of the assay medium markedly increased the basal activity of the malonyl-CoA-sensitive carnitine medium/long chain acyltransferases in peroxisomes and microsomes and decreased the malonyl-CoA inhibition. 2. ATP-Mg largely reversed the salt mediated stimulation of both the peroxisomal and the microsomal activities. 3. The octylglucoside solubilization of the peroxisomes and microsomes caused only marginal losses of their catalytic activity but the malonyl-CoA inhibition was nearly fully abolished. 4. Starvation increased the above activity of peroxisomes and microsomes and decreased their sensitivity to malonyl-CoA inhibition. Tritiated etomoxir labeled a approximately 47 kDa peptide in these organelles, the intensity of which was decreased on starvation. Collectively these findings strengthen the notion that the malonyl CoA sensitive carnitine acyltransferases in mitochondria, microsomes, and peroxisomes are distinct proteins. PMID- 7833828 TI - Effect of temperature on molecular structure of cyclosporin A. AB - By reversed-phase HPLC and NMR spectroscopy, cyclosporin A (CsA) was found to have several molecular structures in polar solvents. In addition, temperature change was found to cause the structural alteration in the polypeptide chain of CsA. Although CD spectrum of CsA in ethanol/water was indicative of the beta-turn structure rather than the beta-sheet structure of the polypeptide chain, the temperature-dependent structural changes were undetectable by CD spectroscopy. The inhibitory effect of CsA on peptidyl prolyl cis-trans isomerase activity was suppressed with elevation in temperature. These results indicate that the alteration in the tertiary structure of CsA plays an important role for the binding capability to its receptor and the immunosuppressive activity. PMID- 7833829 TI - Stimulation of erythrocyte membrane Mg(2+)-ATPase activity by dinitrophenol and other membrane-disturbing agents. AB - Erythrocyte membrane Mg(2+)-ATPase activity was stimulated by echinocytogenic agents (2,4-dinitrophenol and salicylate), a stomatocytogenic agent Triton X-100 and other membrane-disturbing agents including hydrophobic organic anions, alcohols and detergents. Various possible mechanisms of the stimulation are possible but apparently most probable one consists in induction of membrane phospholipid scrambling by the compounds studied (as demonstrated for DNP) and of aminophospholipid translocase (flippase) activity. PMID- 7833830 TI - Nitecapone: a nitric oxide radical scavenger. AB - Nitecapone [3-(3,4-dihydroxy-5-nitrobenzylidene)-2,4-pentanedione], is a scavenger of nitric oxide produced in vitro. It reduced the rate of methemoglobin formation from oxyhemoglobin exposed to nitric oxide generated from the reaction of hydroxylamine with Complex I of catalase and it decreased the amount of nitrite formed in the reaction of oxygen with nitric oxide generated from sodium nitroprusside. Nitecapone also affected the L-arginine dependent accumulation of nitrite in a suspension of peritoneal rat neutrophils. The related compounds entacapone [2-cyano-N, N-diethyl-3-(3,4 dihydroxy-5-nitrobenzyl)-propenamide] and OR 1246 [3-(3,4-dihydroxy-5-nitrobenzyl)-2,4-pentanedione] were also able to scavenge nitric oxide. The action of nitecapone on nitric oxide expands the role of nitecapone as a scavenger of reactive oxygen species, and suggests nitecapone, entacapone and OR 1246 as potential therapeutic agents for the treatment of diseases connected with increased production of nitric oxide. PMID- 7833831 TI - Ribosomal protein S1 in archaea. AB - Cell extracts and ribosomes of thermoacidophilic and halophilic archaebacteria were analysed by immunoblotting to detect ribosomal protein S1 homologues. Antisera to E. coli S1, the N-terminal ribosome binding domain (F2a) and the central and COOH-terminal nucleic acid binding domain (S1F1) of the protein were used. The results show that the thermoacidophilic archaebacterium sulfolobus acidocaldarius contains a protein with molecular weight of 66,000 that cross reacts with anti-S1F1. However, the halophilic archaebacteria Halobacterium halobium, H. cutirubrum and H. salinarum contain a protein of molecular weight of about 100,000 that cross-reacts only with anti-F2a. The results indicate a differential conservation of the structural and functional domains of protein S1 in archaebacteria. PMID- 7833832 TI - Phosphorylation of endogenous substrates of yeast protein kinase C regulated by lipid-triton micelles. AB - In the DE-52 fraction 19 of the crude cytosolic extract of Saccharomyces cerevisiae, the 31-kDa endogenous substrate(s) of protein kinase C were detected by SDS-polyacrylamide gel electrophoresis and autoradiography. Phosphorylation of the substrate(s) depended on Ca2+, phosphatidylserine and diacylglycerol. It was also enhanced by phosphatidylinositol, phosphatidylethanolamine and phosphatidylglycerol (dioleoyl), but inhibited by arachidonic acid and sphingosine. PMID- 7833833 TI - Sodium-22 uptake in erythrocytes can differentiate between the essential and the secondary hypertensive patient. AB - To determine the Na+/K+ ATPase independent 22Na+ influx into erythrocytes (E) from normal subjects (N), from essential hypertensive patients (EH), and from renal failure patients with secondary hypertension (SH), these studies involved two assay conditions. The erythrocyte suspensions were incubated for 30 minutes at 37 degrees C under two assay conditions: (i) with assay buffers containing 5mEq/L KC1 and varying amounts of NaCl (5 to 100 mEq/L) and (ii) with assay buffers with a range of KC1 (5 to 100 mEq/L) and a constant amount of 5 mEq/L NaCl. The ouabain insensitive percent uptake of 22Na+ in 2 x 10(9) E/mL from N, EH, and SH were 2.77 +/- 0.34, 4.37 +/- 0.83, and 3.72 +/- 0.60, respectively, when the assay media contained equimolar amounts of NaCl and KC1 (5 mEq/L each). The 22Na+ uptake was decreased gradually by progressive increasing concentrations of NaCl or of KC1 in the assay media. When erythrocytes were incubated in assay buffers containing either 50mEq/L NaCl with 5 mEq/L KC1 and 50 mEq/L KC1 with 5 mEq/L NaCl, the relative percentages of 22Na+ uptake in erythrocytes became significantly increased [65% increases in EH, 17% increases in SH over that in N subjects, 41% increases in EH over that of SH subjects; and, 49% increases in EH, 23% increases in SH other than in N subjects, 21% increases in EH over that of SH subjects, respectively]. None of the other assay media showed such differences in the 22Na+ uptake values.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7833834 TI - Study of the succinate dehydrogenase activation in permeabilized mitochondria through the Ca(2+)-stimulated phospholipase A2. AB - The development of a mitochondrial membrane permeability triggered by the Ca(2+) stimulation of PLA2 (phospholipase A2; EC 3.1.1.4.) and based on swelling, polyunsaturated fatty acids release and calcium influx, induced the activation of SDH (succinate dehydrogenase; EC 1.3.9.9.) without damaging mitochondria structures. The activity of SDH increased within the length of permeabilization treatment before reaching a plateau. The study of Km and Vm showed that the affinity of SDH for succinate and the maximal velocity were increased. Based on these results, the change of SDH activity triggered under these conditions could be explained by a substrate activation of SDH taking account that the succinate content was significantly enhanced. PMID- 7833835 TI - Organization of the gene for the alpha-subunit of mouse beta-N acetylhexosaminidase (HEXa). AB - Genomic clones spanning the mouse HEXa gene were isolated and the exon-intron organization determined. The locations of all exon-intron junctions were identical to those of the human HEXa gene but the large intron 1 was shorter in the mouse (14Kb) than in the human gene (18Kb). PMID- 7833836 TI - Monoclonal antibodies against the Fc fragment of IgA alpha-chain: preparation and clinical application. AB - Fragments of the heavy alpha-chain of IgA (IgA Fc alpha) were prepared and purified from the serum of patients with heavy chain disease. It was used to immunize BALB/c mice. The immunized mouse spleen cells were then fused with myeloma cells Sp2/O. Through successive recloning of the hybridoma cell lines by the limiting dilution method, four subclonal hybridoma cells (D2, E4, F5 and G10) capable of screening IgA Fc alpha were found. Intraperitoneal transplantation of these cells induced ascites in the BALB/c mice, from which four types of monoclonal antibodies (McAb-IgA Fc alpha) were obtained. The highest McAb titer was as high as 1:16348 by the hemagglutination inhibition (HAI) test. These McAb's reacted specifically with IgA Fc alpha, but not with IgG, IgM, IgD, kappa or lambda. Serum samples from 92 normal subjects and 73 patients with various diseases were tested for Ig genetic markers by means of HAI. The family trees of three positive cases were surveyed. Results showed that the McAb-IgA Fc alpha may be used to determine the genetic marker of IgA allotypes. PMID- 7833837 TI - An immunodetection method for the quantitation of human acyl CoA:glycine N acyltransferase in biological samples. AB - An immunochemical method for quantitation of human acyl CoA:glycine N acyltransferase (ACGNAT) has been developed. A 33 kD ovine ACGNAT was purified to homogeneity and was used to raise polyclonal antibodies in rabbits. These antibodies were then employed for developing a sensitive immunodiagnostic method as they cross-reacted with human ACGNAT. Using this methodology, a linear correlation was seen between specific activity and ACGNAT concentration in an ammonium sulphate precipitation fraction (40-60%) of hepatic tissues of children and adults of 4 h age to 11 year old (r = 0.99, n = 6). PMID- 7833838 TI - Effects of transforming growth factor-beta 1, interleukin-1 alpha and interleukin 6 on rat Sertoli cell proteoglycan synthesis. AB - In the testis, growth factors and cytokines are synthesized by Sertoli cells and peritubular cells. In different cell types, these mediators are known to regulate the metabolism of extracellular matrix molecules, such as proteoglycans. In this study, we have tested the action of three of these mediators (IL-1 alpha, IL-6 and TGF-beta 1) on the proteoglycan synthesis of rat Sertoli cells. The proteoglycan synthesis was unchanged by IL-1 alpha, nor by IL-6 up to 20 ng/ml, during any maturation stage (14, 21 and 35 days). By contrast, Transforming Growth Factor-beta 1 (TGF-beta 1) enhanced Sertoli cell proteoglycan production from 21 day-old rats, with an optimal response at 1 ng/ml. Kinetic studies showed that the effect of TGF-beta 1 (1ng/ml) was higher after 24 hours of incubation. In presence or in absence of TGF-beta 1, a proteoglycan accumulation was observed in the extracellular compartment between 12 and 48 hours, but this factor did not modify the proteoglycan distribution between cell layer and medium. Furthermore, TGF-beta 1 increased proteoglycan anabolism at all Sertoli cell maturation stages studied but this stimulation was greater for the early maturation stages (14 and 21 days). On the other hand, proteoglycan catabolism was not modified by TGF-beta 1. In conclusion, TGF-beta 1 secreted by rat Sertoli and peritubular cells could modulate, in an autocrine/paracrine way the synthesis of one of the main extracellular matrix components. PMID- 7833839 TI - Purification and characterization of rice sucrose synthase isozymes. AB - From an extract of milk-ripe stage rice grains, four sucrose synthase activities could be separated by a FPLC Mono Q column. They are considered isozymes because they show different electrophoretic mobilities in a non-denaturing gel. However, the migration rates of their subunits in SDS-PAGE were indistinguishable and had a molecular mass of 94 kDa. The native forms had identical molecular mass of 440 kDa, thus they were considered to be tetrameric but carrying different ionic charges. Ouchterlony assay indicates that they have the same epitopes. All isozymes use UDP as the best nucleoside diphosphate substrate. When characterized by the ratio of catalytic rates of sucrose synthesizing and cleaving reactions, the isozyme that had the slowest migration rate in PAGE had the smallest value. PMID- 7833840 TI - Expression of a biologically active human granulocyte-macrophage colony stimulating factor fusion protein in Escherichia coli. AB - A gene encoding human granulocyte-macrophage colony stimulating factor(GM-CSF), was cloned into plasmid pEZZ318 and fused to a DNA segment coding for the signal peptide of staphylococcal protein A and a synthetic gene coding for a protein with ability to bind immunoglobulin G(IgG). The fusion protein was expressed in Escherichia coli and biologically actively secreted into the growth medium. Approximately all of the total activity was secreted into the culture medium, where levels of activity approached 1.96 x 10(8) units/liter. Purification of the fusion protein was performed in a single step by affinity chromatography with immobilized IgG to a specific activity of 1.2 x 10(8) units/mg. PMID- 7833841 TI - Expression of proto-oncogenes, genes for muscle specific isoforms and heat shock protein (HSP) -70 gene in hypertrophied cardiac muscles from patients with atrial septal defect or tetralogy of Fallot. AB - Studies on the expression of proto-oncogenes and muscle specific genes in hypertrophied human hearts have shown that proto-oncogenes such as c-myc, c-fos and c-ras are activated in both atrial and ventricular tissues of patients with atrial septal defect (ASD) and tetralogy of Fallot (TOF). Although the expression of muscle specific genes such as MLC2 and skeletal alpha-actin are induced the expression of tissue specific cardiac actin remained the same in both the control and diseased tissues. Further, an increased synthesis of messengers of heat shock protein gene-HSP70 was observed in the ventricular tissues of TOF patients, with out much of a change in atrial tissues of patients with ASD. PMID- 7833842 TI - Oxygen regulation of TGF-beta 1 mRNA in human hepatoma (Hep G2) cells. AB - Solid tumours comprise populations of cells whose behaviour is thought to be influenced by growth factors and the local oxygen environment. We investigated the effect of oxygen on steady state levels of transforming growth factor-beta 1 mRNA in cultured human hepatoma cells. Northern blot analysis demonstrated that hypoxia mediated an early and sustained induction of TGF-beta 1 mRNA above that seen at higher oxygen tensions. The data suggests that modulation of TGF-beta 1 expression by the local oxygen environment may be important in tumour development and progression. PMID- 7833843 TI - Central immune system, the self and autoimmunity. AB - We model how auto-reactive B cells are kept under control by an idiotypic network. Autoimmunity occurs when the control is broken by an infection or not achieved through an abnormal ontogenetic evolution. We describe the idiotypic network, viz., the central immune system, by idiotype-anti-idiotype pairs which are coupled to a set of highly connected clones, which interact with each clone of the network. Some clones of the central immune system recognize self-antigen. We find a huge variety of fixed points which can be classified as tolerant, autoimmune, and neutral states according to the concentration of the auto reactive antibody. Most significant are auto-reactive clones which are a member of an idiotype-anti-idiotype pair. In a healthy individual, an autoimmune disease is induced by an antigen infection which triggers a transition from a tolerant to an autoimmune state. Autoimmunity is induced more readily by an antigen coupling to the anti-idiotype than by one interacting with the auto-reactive clone itself. We indicate a possible therapy which simply reverses the processes that have lead to the autoimmune disease. In the early development of the central immune system its highly connected, core part serves to draw the more specific clones of idiotype-anti-idiotype pairs into the network. In order to avoid autoimmunity in ontogenetic evolution the anti-idiotype of an auto-reactive clone must be formed in advance by a sufficiently long period of time. Thus, a well ordered succession of the appearance of the more specific clones is required. PMID- 7833844 TI - Stochastic model of chemoattractant receptor dynamics in leukocyte chemosensory movement. AB - Mammalian white blood cells are known to bias the direction of their movement along concentration gradients of specific chemical stimuli, a phenomenon called chemotaxis. Chemotaxis of leukocyte cells is central to the acute inflammatory response in living organisms and other critical physiological functions. On a molecular level, these cells sense the stimuli termed chemotactic factor (CF) through specific cell surface receptors that bind CF molecules. This triggers a complex signal transduction process involving intracellular biochemical pathways and biophysical events, eventually leading to the observable chemotactic response. Several investigators have shown theoretically that statistical fluctuations in receptor binding lead to "noisy" intracellular signals, which may explain the observed imperfect chemotactic response to a CF gradient. The most recent dynamic model (Tranquillo and Lauffenburger, J. Math. Biol. 25, 229-262. 1987) couples a scheme for intracellular signal transduction and cell motility response with fluctuations in receptor binding. However, this model employs several assumptions regarding receptor dynamics that are now known to be oversimplifications. We extend the earlier model by accounting for several known and speculated chemotactic receptor dynamics, namely, transient G-protein signaling, cytoskeletal association, and receptor internalization and recycling, including statistical fluctuations in the numbers of receptors among the various states. Published studies are used to estimate associated constants and ensure the predicted receptor distribution is accurate. Model analysis indicates that directional persistence in uniform CF concentrations is enhanced by increasing rate constants for receptor cytoskeletal inactivation, ternary complex dissociation, and binary complex dissociation, and by decreasing rate constants for receptor internalization and recycling. For most rate constants, we have detected an optimal range that maximizes orientation bias in CF gradients. We have also examined different desensitization and receptor recycling mechanisms that yield experimentally documented orientation behavior. These yield novel insights into the relationship between receptor dynamics and leukocyte chemosensory movement behavior. PMID- 7833846 TI - Intrinsic time scaling in survival analysis: application to biological populations. AB - A method of dimensionless time-scaling based on extrinsic expectation of life at birth but intrinsic to a system generating a survival distribution is introduced. Such scaling allows the survival fraction function and its associated mortality function to serve as Green's functions for their generalized equivalents, i.e., a "population" function and a "death" function. The analytical mechanics of utilizing these concepts are formulated, applied to the classical Gompertz and Weibull survival models, and discussed with respect to biological relevance. PMID- 7833845 TI - The magnitude and significance of Ca2+ domains for release of neurotransmitter. AB - It is now widely accepted that localized high concentrations of Ca2+ (Ca2+ domains) play a major role in controlling the time course of neurotransmitter release. In the present work we calculate the magnitude and the time course of Ca2+ domains that evolve in the vicinity of a Ca2+ channel and an adjacent release site. In the calculations we consider a accurately dimensioned Ca2+ channel. Moreover, the Ca2+ current is continuously adjusted with regard to the accumulated intracellular Ca2+ and, in addition, endogenous buffers are considered. The calculations, carried out by the software FIDAP, based on finite element method, show that the Ca2+ concentrations achieved near the release sites are significantly lower than claimed by other investigators. Furthermore, we present arguments indicating that the Ca2+ domains, regardless of their magnitude, do not play a role in controlling the time course of release of neurotransmitter. PMID- 7833847 TI - Pattern matching between two non-aligned random sequences. AB - Given two independent sequences of letters, we seek the probability distribution of the length of the longest matching word. This word can be in different positions in the two sequences and we consider both perfect and nearly perfect matching. We derive bounds and approximations for the probability and compare them with other bounds and approximations. The results can be applied to DNA sequences in molecular biology and generalized matching between two independent random sequences. PMID- 7833848 TI - Hypnosis modelling in neural networks. AB - In the framework of the neural network theory effects similar to hypnotic displays are constructed. They are based on the associative paradigm involving non-linear interaction of excitatory and inhibitory channels with synaptic memory. The non-linearity of long-term memorizing processes may cause effects exhibited by blind spots, which are interpreted as the first stage of hypnosis. More complicated phenomena are discussed in terms of a two-layer network. PMID- 7833849 TI - Memory capacity in large idiotypic networks. AB - Many models of immune networks have been proposed since the original work of Jerne [1974, Ann. Immun. (Inst. Pasteur)125C, 373-389]. Recently, a limited class of models (Weisbuch et al., 1990, J. theor. Biol 146, 483-499) have been shown to maintain immunological memory by idiotypic network interactions. We examine generalizations of these models when the networks are both large and highly connected to study their memory capacity, i.e., their ability to account for immunization to a large number of random antigens. Our calculations show that in these minimal models, random connectivities with continuously distributed affinities reduce the memory capacity to essentially nil. PMID- 7833850 TI - A kinetic model of coronary reactive hyperemic response to transient ischemia. AB - A kinetic model is proposed to delineate the factors that determine the coronary reactive hyperemic response (RHR) to transient ischemia. The model comprises of myocardial-interstitial (M) and vascular (V) compartments. Vasodilator metabolites (VM) are produced in the M compartment during the interval of coronary occlusion. The rate of VM production is dependent on the flow rate during the ischemic period, the ratio of excess flow above the control level (R) to the loss of flow during occlusion period (D), the amount of oxygen stored and the degree of vasodilation in the V compartment prior to occlusion. Following a complete release of occlusion, VM are transported from the M to V compartment and are washed out or degraded with time. The time course of RHR is determined by the coronary patency which is proportional to VM concentration in the V compartment. Based on a set of numerical constants, the model is tested by simulating RHR to the various occlusion manoeuvres: a pair of 10 sec occlusions separated by brief release, a 15 sec release followed by a second brief occlusion, a brief release of an occlusion followed by restricted inflow and a period of restricted inflow after occlusion. The simulated results fit the experimental R/D and RH durations data of canine hearts. Factors that determine the impairment of RH capacity in coronary stenosis are suggested in terms of the model scheme. PMID- 7833851 TI - Kinetic study of an enzyme-catalysed reaction in the presence of novel irreversible-type inhibitors that react with the product of enzymatic catalysis. AB - In the present paper a kinetic study is made of the behaviour of a Michaelis Menten enzyme-catalysed reaction in the presence of irreversible inhibitors rendered unstable in the medium by their reaction with the product of enzymatic catalysis. A general mechanism involving competitive, non-competitive, uncompetitive and mixed irreversible inhibition with one or two steps has been analysed. The differential equation that describes the kinetics of the reaction is non-linear and computer simulations of its dynamic behaviour are presented. The results obtained show that the systems studied here present kinetic co operativity for a target enzyme that follows the simple Michaelis-Menten mechanism in its action on the substrate, except in the case of an uncompetitive type inhibitor. PMID- 7833852 TI - Bifurcation and stability analysis of a temperature-dependent mite predator-prey interaction model incorporating a prey refuge. AB - The non-linear behavior of a differential equations-based predator-prey model, incorporating a spatial refuge protecting a constant proportion of prey and wit temperature-dependent parameters chosen appropriately for a mite interaction on fruit trees, is examined using the numerical bifurcation code AUTO 86. The most significant result of this analysis is the existence of a temperature interval in which increasing the amount of refuge dynamically destabilizes the system; and on part of this interval the interaction is less likely to persist in that predator and prey minimum population densities are lower than when no refuge is available. It is also shown that increasing the amount of refuge can lead to population outbreaks due to the presence of multiple stable states. The ecological implications of a refuge are discussed with respect to the biological control of mite pests. PMID- 7833853 TI - Ion induced deformation of soft tissue. AB - In this paper the effects of changing the ion concentration in and around a sample of soft tissue are investigated. The triphasic theory developed by Lai et al. (1990, Biomechanics of Diarthrodial Joints, Vol. 1, Berlin, Springer-Verlag) is reduced to two coupled partial differential equations involving fluid ion concentration and tissue solid deformation. These equations are given in general form for Cartesian, cylindrical and spherical geometries. After solving the two equations quantities such as fluid velocity, fluid pressure, chemical potentials and chemical expansion stress may be easily calculated. In the Cartesian geometry comparison is made with the experimental and theoretical work of Myers et al. (1984, ASME J. biomech. Engng, 106, 151-158). This dealt with changing the ion concentration of a salt shower on a strip of bovine articular cartilage. Results were obtained in both free swelling and isometric tension states, using an empirical formula to account for ion induced deformation. The present theory predicts lower ion concentrations inside the tissue than this earlier work. A spherical sample of tissue subjected to a change in salt bath ion concentration is also considered. Numerical results are obtained for both hypertonic and hypotonic bathing solutions. Of particular interest is the finding that tissue may contract internally before reaching a final swollen equilibrium state or swell internally before finally contracting. By considering the relative magnitude, and also variation throughout the time course of terms in the governing equations, an even simpler system is deduced. As well as being linear the concentration equation in the new system is uncoupled. Results obtained from the linear system compare well with those from the spherical section. Thus, biological swelling situations may be modelled by a simple system of equations with the possibility of approximate analytic solutions in certain cases. PMID- 7833854 TI - Hox genes and the identity of motor neurons in the hindbrain. AB - The Hox genes comprise a gene family of thirty-eight members in vertebrates. The genes are organized in four gene clusters and activated during gastrulation. Analysis of embryonic expression patterns has indicated that morphological segments along the body axis are characterized by different combinations of expressed Hox genes, the 'Hox codes'. Hox codes can be influenced by exposing embryos to retinoic acid, concomitantly with perturbation of segmental identities. In the murine hindbrain this can be clearly demonstrated for the preotic region containing the trigeminal and facial motor nuclei. The correlation between normal or perturbed segment morphology and the Hox codes is reviewed and discussed. PMID- 7833855 TI - Genetic mechanisms of early neurogenesis in Drosophila melanogaster. AB - The neuroectoderm of insects contains an initially indifferent population of cells which during later development will give rise to the progenitor cells of the neural and epidermal lineages. Experimental evidence indicates that cellular interactions determine which cells will adopt each one of these fates. The invoked cell interactions are assumed to be mediated by the products of several genes forming a complex, not yet well understood network of interrelationships. Elements of this network are the proteins encoded by Delta and Notch, which appear to convey the regulatory signals between the cells; the proteins encoded by the achaete-scute gene complex, which regulate neural development, and the proteins encoded by the Enhancer of split gene complex, which give neuroectodermal cells access to epidermal development. The proneural genes appear to be the key elements in the regulation of the cellular decision. PMID- 7833856 TI - Synaptogenesis in Drosophila: coupling genetics and electrophysiology. AB - Drosophila is one of the most fully described eukaryotic organisms and, as a system, offers the most advanced genetic and molecular techniques. In particular, Drosophila embryonic development has been subject to intensive genetic and molecular examination. Drosophila is also one of the few genetically malleable organisms to permit electrophysiological investigation and so allow detailed physiological characterization of specific molecular lesions. These two fields, the developmental and electrophysiological, are being coupled for the first time to examine a key aspect of neural development, synaptogenesis. Here, I describe synaptogenesis in the Drosophila embryo at the identified neuromuscular junction. I focus particular attention on the use of known genetic mutations to dissect the mechanisms of synapse formation. This simple, well-characterized synapse is already proving valuable in describing the defects of mutations in genes essential for synaptic development and function. In the long term, this system will allow us to systematically mutate the Drosophila genome to identify and describe the genetic and molecular pathways directing the construction of a synapse. PMID- 7833857 TI - The neuron as a mosaic of proteins. PMID- 7833858 TI - The unique and shared properties of neuronal growth cones that enable navigation and specific pathfinding. AB - The neuronal growth cone has as one of its primary functions the role of guiding the elongating neurite to its appropriate target. The events during pathfinding require that the neuronal growth cone responds to particular molecules in the environment by making appropriate changes in the behavior of the growth cone. This paper discusses the role of intracellular calcium as a signalling system mediating these responses. The specific roles of the growth cone filopodia in acting as antennae in advance of the motile growth cone are discussed in the context of calcium mediated pathfinding events. PMID- 7833859 TI - Evolution of the IL-6/class IB cytokine receptor family in the immune and nervous systems. AB - It has been suggested that the cytokine receptor has a structure similar to immunoglobulin and this structural similarity has raised the possibility that they have evolved from a common ancestral molecule. In the early 1970s, it was discovered that developing sympathetic neurons could switch from an adrenergic to cholinergic phenotype. The search for a diffusible factor responsible for this eventually led to the identification of leukemia inhibitory factor (LIF). Cholinergic differentiation factor (CDF)/LIF has turned out to belong to the IL 6/class IB cytokine family. In this article we further speculate on a plausible molecular pathway for the IL6/class IB receptor family in the immune and nervous systems. We think that the evolution of the IL-6/class IB receptor family may have occurred in at least two major steps. Firstly, binding subunits of an IL-6 receptor and for a CDF/LIF receptor evolved and secondly, a third binding subunit of a CNTF receptor evolved. Our evolutional consideration predicts that the binding subunits generally determine the specificity of the receptors and it is possible that novel members of the cytokine family and their receptors exist in the nervous system. PMID- 7833861 TI - Who's been nibbling on my PSD: is it LTD? PMID- 7833860 TI - The inactivation behaviour of voltage-gated K-channels may be determined by association of alpha- and beta-subunits. AB - Voltage-gated K-channels of the Shaker related subfamily have two subunits, membrane integrated alpha- and peripheral beta-subunits. alpha-Subunits may assemble as tetramers and form in in vitro expression systems functional K channels. beta-Subunits cannot from channels by themselves. Like for alpha subunits, the rat nervous system apparently expresses a family of beta-subunit proteins. We have demonstrated that one rat K-channel beta-subunit, Kv beta 1, contains an inactivating domain. Upon association of alpha- and Kv beta 1 subunits, delayed-rectifier type K-channels are converted to rapidly inactivating A-type K-channels. The beta-subunit inactivation domain acts via a ball and chain type mechanism previously proposed for N-type inactivation of alpha-subunits. The association of alpha- and beta-subunits endows the nervous system with an unprecedented flexibility and diversity of K-channels which may play an important role in the regulation of nervous excitability. PMID- 7833862 TI - Bcl-2 and neuronal selection during development of the nervous system. PMID- 7833863 TI - [HLA molecules in rheumatoid arthritis. It's time for changing the model]. PMID- 7833864 TI - [Chondrocyte cultures: contribution and prospects in rheumatic practice]. PMID- 7833865 TI - [Respiratory involvement in ankylosing spondylarthritis: relations to alpha-1 antitrypsin phenotypes and tobacco consumption]. AB - The distribution of alpha-1-antitrypsin phenotypes was similar in 555 controls and 98 patients with ankylosing spondylitis: the MM phenotype (including "main" MM subtypes, i.e., M2M2 and M3M3, and "secondary" MM subtypes) was found in 86% of subjects and "rare" phenotypes combining M, F, S, and Z in 14%. Six per cent of the controls and none of the ankylosing spondylitis patients had the M4M4 phenotype (p < 0.01). Respiratory function tests were performed in 49 patients with axial ankylosing spondylitis and 30 controls matched on sex, age, body mass index, smoking status, nonsteroidal antiinflammatory drug use and distribution of "main" and "secondary" phenotypes (no subjects in this study had "rare" phenotypes); the significant reduction in chest expansion seen in the ankylosing spondylitis group (5.6 +/- 2.7 cm versus 8.7 +/- 1.2; p < 0.001) was correlated with total capacity (p < 0.04) and vital capacity (p < 0.001). Restrictive ventilatory dysfunction was seen in four ankylosing spondylitis patients versus no controls (p < 0.02). Proximal airway obstruction, pulmonary distension and decreases in the diffusing capacity for carbon monoxide were seen in similar proportions of ankylosing spondylitis patients and controls. In the ankylosing spondylitis group, evidence of pulmonary distension included increases in mean residual functional capacity and mean residual volume (105.6 +/- 21.2% versus 94.8 +/- 17.4, p < 0.03, and 100.3 +/- 22.8% versus 88.6 +/- 17.9, p < 0.04, respectively) and bullous emphysema in the lung bases in two patients (versus no controls). In the small subgroup of ankylosing spondylitis patients with lung distension or a decreased diffusing capacity for carbon monoxide, smokers and nonsmokers were evenly balanced but subjects with "secondary" phenotypes outnumbered those with "main" phenotypes (p < 0.02); in contrast, our data suggested that smoking may play the central role in the proximal airway obstruction. Our findings suggest that in addition to previously established causes of pulmonary involvement in ankylosing spondylitis a "secondary" MM phenotype (i.e., neither M2M2 nor M3M3) may be a risk factor for lung distension and impaired diffusing capacity for carbon monoxide. PMID- 7833866 TI - [Osteoarthritis with rice bodies rich in calcium microcrystals. 4 cases with ultrastructural study]. AB - Rice bodies are often found in inflammatory joint fluid specimens, especially from rheumatoid arthritis patients, but have rarely been reported in osteoarthritis. We found rice bodies in knee joint fluid specimens from four of 88 patients with osteoarthritis. There were three males and one female. Age ranged from 61 to 86 years. Three patients had slowly progressive knee osteoarthritis and one had rapidly destructive disease. Abundant, recurrent effusions occurred in all four patients despite one to five local corticosteroid injections per patient and radiation synovectomy in two patients. The joint fluid specimens contained 120 to 320 cells/mm3 and large numbers of rice bodies that stained with alizarin red S. Transmission electron microscopy studies showed that the rice bodies were composed of fibrin and contained numerous intra- and extra cellular calcium crystals composed of apatite alone in two cases and of a combination of apatite and calcium pyrophosphate dihydrate in the two others. Collagen fibers and fragments of bone and cartilage were present in a few rice bodies. Phagocytic cells, type C synoviocytes, chondrocytes and a few inflammatory cells were also seen. These rice bodies composed mainly of fibrin and apatite may have played a role in the pathogenesis of the recurrent joint effusions in our patients. PMID- 7833867 TI - [Correlations between measurements of the sense of knee position and the severity of joint lesions in knee osteoarthritis]. AB - The primary purpose of this study was to analyse the relationship between 4 different methods of measuring the knee position sense of persons diagnosed as having osteoarthritis of the knee and position sense deficit with their disease severity. To this end, the active position sense of 8 patients was assessed in sitting using a potentiometer known to measure knee angles precisely. Also administered was a validated subjective questionnaire, the Lequesne algofunctional index. The measurements of position sense included: total reproduction error; mean absolute reproduction error; variability in algebraic error or variable error; and the average constant error of 5 angle reproduction tests. The total error, mean absolute error and constant error measurements were significantly correlated with the handicap scores on the questionnaire (p < 0.01). These results plus the further finding of a bias towards target underestimation in this group strongly suggests that impaired proprioception might be an important pathogenetic factor in determining the severity of this disabling disease. PMID- 7833868 TI - [Osteocalcin and smoking]. AB - Smoking is a risk factor for osteoporosis. Nicotine and nonnicotine tobacco smoke components have been shown to depress osteoblast activity in a number of in vitro and animal studies. To determine whether smoking is associated with depressed osteoblast activity in humans, we measured serum osteocalcin levels (using a radioimmunological method based on an antibody to human osteocalcin) in 24 male or female smokers and 24 matched nonsmokers. Overall, osteocalcin levels were significantly lower in smokers (15 +/- 6.95 ng/ml) than in nonsmokers (21.27 +/- 8.34 ng/ml) (p = 0.007). The difference between smokers and nonsmokers was significant in males (15.3 +/- 4.5 vs 23.27 +/- 9.7; p = 0.02) but not in females (16.27 +/- 8.9 vs 19.45 +/- 6.7; p = 0.2). These data suggest that smoking may induce osteoblast depression, either directly or via hormonal changes. PMID- 7833869 TI - [Bone mineral density of the femoral neck, a cross-sectional study of normal values in 827 French women aged 36 to 86 years]. AB - The need for determining country-specific reference bone mineral density values has been emphasized. The effects of age and time since menopause on femoral neck bone mineral density in healthy women are still insufficiently documented. The goal of this study was to determine age-specific femoral neck bone mineral density values and postmenopausal bone loss rates in French women. Dual-energy X ray absorptiometry was used to measure lumbar spine, femoral neck, and Ward's triangle bone mineral densities in 827 women aged 36 to 86 years. Inclusion criteria included a negative history for established or suspected osteoporosis. A cross-sectional, retrospective design was used. Lumbar spine bone mineral densities were similar to reference values reported previously in healthy subjects from other countries. Consequently, we considered that the femoral neck values that we obtained were those of a healthy population. Results were as follows: 1) The annual rate of bone loss at the femur increased within one or two years after menopause (to 1.5% and 2% at the femoral neck and Ward's triangle, respectively), remained high for 12-13 years, then declined (0.8% and 1.2%, respectively). 2) Femoral bone loss was slow before the age of 55 years (0.2% and 0.5% per year) and continued at a faster rate thereafter (1.3% and 1.7% per year). Our study provides normal reference femoral bone mineral density values for French women. Our data confirm that age and time since the menopause have a substantial influence on bone mineral density, not only at the lumbar spine, but also at the femoral neck. PMID- 7833870 TI - [Macrophage activation syndrome in rheumatic diseases in children]. PMID- 7833871 TI - [Bone metastases in epidural invasion of gastrinoma]. AB - Malignant gastrinoma is a nonbeta islet cell tumor which rarely disseminates to the bone. However, in the case reported herein, diffuse metastatic bone disease with symptomatic epidural spread developed. Somatostatin and 99mTc-HDP bone scans demonstrated hot spots in the same sites, establishing that the bone lesions contained somatostatin receptor. Irradiation was effective in relieving pain. PMID- 7833872 TI - [Rheumatoid arthritis and recurrent rheumatism associated with sclerosing cholangitis]. AB - The authors report two cases presenting to a rheumatologist, one with palindromic rheumatism and previously undiagnosed ulcerative colitis, and one with rheumatoid arthritis. Both were subsequently found to have early sclerosing cholangitis with some response treatment. PMID- 7833873 TI - [Coxitis after surgical excision of intracapsular osteoid osteoma of the femur neck]. AB - A case of destructive arthropathy of the hip with onset two years after surgical removal of an intracapsular osteoid osteoma of the femoral neck is reported. Coincidental occurrence in the same joint of an osteoid osteoma and a destructive arthropathy of unknown etiology cannot be ruled out. However, another hypothesis which deserves discussion is that self-perpetuating synovitis was triggered by the release of mediators of inflammation due to presence of the osteoid osteoma. PMID- 7833874 TI - [2 unusual cases of avascular necrosis of the scaphoid]. AB - The authors report two cases of histologically-proven avascular necrosis of the carpal scaphoid. Both were treated surgically. The cause was a congenital defect in one of the patients and repetitive microtrauma in the other. PMID- 7833875 TI - [Treatment of Takayasu's disease with low-dose methotrexate. Apropos of a case]. AB - Persistent evidence of inflammation at the occlusive phase of Takayasu's arteritis is of adverse prognostic significance. Low-dose weekly methotrexate therapy given in combination with a corticosteroid may be effective in such patients. We report a personal case which supports the data obtained by Fauci and coworkers, as well as the conclusions of the other two similar case-reports in the literature. PMID- 7833876 TI - [Inflammatory myositis disclosing Horton disease]. PMID- 7833877 TI - [Bone metastases of uterine leiomyosarcoma. Apropos of a case]. PMID- 7833878 TI - [Paget disease of bone in black Africa. Apropos of a case in Congo]. PMID- 7833880 TI - [L4 and L5 double nerve root pain following percutaneous nucleotomy at the L4-L5 level]. PMID- 7833879 TI - [Osteoarticular pain and osteocondensation disclosing acute leukemia in adults]. PMID- 7833881 TI - [Can the outcome of rheumatoid arthritis be predicted at the onset of the disease?]. PMID- 7833882 TI - [Primary camptocormia is a para-vertebral myopathy]. PMID- 7833883 TI - [Treatment of Horton disease. Value of synthetic antimalarials. Apropos of a retrospective study of 36 patients]. AB - Thirty-six patients with giant cells arteritis were studied retrospectively. Histological examination of the temporal artery or another artery was positive in 95% of cases. Mean follow-up was five years. A synthetic antimalarial was used in every case. Two groups were differentiated. One (Group I) was composed of 21 patients who were given the antimalarial drug as part of the first-line therapy, either with a corticosteroid in a mean dose of 36 mg/d (18 patients) or with a nonsteroidal antiinflammatory agent. The other group (Group II) included 15 patients in whom the antimalarial was used after a period of corticosteroid therapy, because of steroid-dependency (n = 5) or adverse effects (n = 9), or as part of a routinely used protocol (n = 1). Withdrawal of the corticosteroid was achieved in 81% of cases, after a mean interval of 15 months. Many patients discontinued the corticosteroid after less than one year. The 18 Group I patients who were given a corticosteroid were all able to discontinue this drug. The overall recovery rate was 58%; mean time to recovery was 33 months with a mean follow-up of 52 months. There were no recurrences at discontinuation of the treatment. Adverse effects of antimalarial therapy were recorded in 30.5% of patients and required discontinuation of the drug in 19%. The most often used regimen was hydroxychloroquine (40 mg/d) for at least two years and prednisone 20 to 30 mg/d for two months, in the absence of vascular complications.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7833884 TI - [Search of papillomavirus genome in synovial membranes and rheumatoid nodules]. AB - IgG antibodies to rat esophagus stratum corneum are highly specific for rheumatoid arthritis and have been recently shown to be directed against human (pro)filaggrin. Although the mechanisms underlying the loss of tolerance of B lymphocytes for filaggrin remain unelucidated, a role of infection with the human papillomavirus has been suggested on the basis of the following facts: 1) the protein exhibiting the greatest molecular homology with filaggrin is papillomavirus-encoded; 2) human papillomavirus proteins bind to cytoskeletal proteins; 3) human papillomavirus replication is enhanced by friction and rheumatoid lesions predominantly develop in areas subjected to friction, as shown by the distribution of rheumatoid nodules; 4) the rheumatoid pannus resembles a benign tumor. The objectives of this study were to look for the human papillomavirus genome in six synovial membrane specimens and two rheumatoid nodule specimens from rheumatoid arthritis patients with disease durations of more than ten years and in 20 synovial membrane specimens collected during surgical procedures in osteoarthritis patients. The methods used were polymerase chain reaction with papillomavirus-specific primers. The papillomavirus genome was not detected in any of the 28 specimens. A role for the human papillomavirus in the pathogenesis of rheumatoid arthritis cannot be ruled out on the basis of these findings because filaggrin is expressed in other tissues, including the thymic medulla epithelium. In addition, the primers used in this study may have been inappropriate. PMID- 7833885 TI - [Rheumatic manifestations of chronic hepatitis C and response to the treatment with interferon alpha-2b]. AB - Chronic hepatitis C can be responsible for a broad range of autoimmune manifestations, including cryoglobulinemia and Sjogren's syndrome. We report our experience with six patients (five women and one man; mean age 55.6 years) in whom hepatitis C was diagnosed during evaluation of joint symptoms. Polyarthralgia was the main symptom and was often accompanied with myalgia; a polyalgic syndrome was seen in some patients. Isolated cytolysis was consistently found, although, in some instances, liver enzyme elevations were moderate and postdated the onset of the clinical symptoms. The diagnosis of hepatitis C was confirmed by recombinant immunoblot assay (RIBA) in every case. The polymerase chain reaction (PCR) detected hepatitis C virus RNA in five of the six patients. Histological findings were characteristic of chronic hepatitis. All six patients had immunological test abnormalities, which included presence of rheumatoid factors (2 of 6), positive antinuclear antibodies without anti-DNA antibodies (3 of 6) and low serum complement levels (3 of 6). A cryoprecipitate was found in four of the six patients. Four patients reported symptoms of sicca syndrome and two had Chisholm grade III lesions upon examination of salivary gland biopsy specimens. Four patients were given a six-month course of interferon alpha. In three of these four patients, evaluation at the end of the treatment showed abatement or resolution of symptoms, normal liver function tests, unchanged or diminished antinuclear antibody titers, and normal serum complement levels. In the remaining patient, no changes in symptoms or transaminase levels occurred during interferon alpha treatment. In conclusion, rheumatic symptoms can be the most prominent manifestation of chronic hepatitis C.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7833886 TI - [Diagnostic value of spinal puncture-biopsy in non-infectious spinal diseases. Apropos of 41 cases]. AB - To evaluate the diagnostic value of percutaneous vertebral biopsy in noninfectious diseases of the spine, we retrospectively studied 41 cases seen between 1985 and 1992. The level of the lesion was lumbar in 29 cases, thoracic in 11, and cervical in one. There were 19 crush fractures, 11 lytic lesions, six sclerotic lesions, and three mixed lesions. The biopsy was done because of an abnormal magnetic resonance imaging signal in one patient and because of epiduritis in another. The thoracic and lumbar biopsies were done under x-ray guidance using the technique developed by Laredo and Bard. Computed tomography guidance was used for the cervical biopsy. There were no adverse events. The final histological diagnosis was metastatic disease in 17 cases (41.5%), myeloma or plasmacytoma in six cases (14.7%), primary vertebral neoplasia in two cases (4.8%), lymphoma in one case (2.4%), osteoporosis in nine cases (22%), Paget's disease in three cases (7.4%), amyloidosis in one case (2.4%), aseptic osteitis in one case (2.4%), and vertebral necrosis in one case (2.4%). A second biopsy procedure was done in three patients (surgically in two cases and percutaneously in one) because of discrepancies between histological findings and other data. The final diagnosis was metastatic disease in all three patients. Overall, the diagnostic yield of percutaneous vertebral biopsy was 92.6% and varied little with initial roentgenographic or computed tomographic findings. However, yield was only 56% for the diagnosis of tumorous lesions, with variations according to roentgenographic and computed tomographic changes, 90.1% for osteolytic lesions, 66.6% for mixed lesions, 47.4% for crush fractures, and 16.6% for sclerotic lesions.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7833887 TI - [Outcome of osteoporosis in Cushing disease. Presentation of a severe form in adults treated with nandrolone. Very favorable course with a 32-years follow-up]. PMID- 7833888 TI - [T-lymphocyte receptor genes: genome organization and genetic mechanisms of repertoire diversity]. AB - The T-cell receptor (TCR) is fundamental to the immune process in both health and disease. Reviewed here is the genetic organisation of the gene complexes which encode the TCR polypeptide chains alpha, beta, gamma, and delta. The TCR is by necessity a diverse structure and we consider the genetic mechanisms responsible for this. These include multiple variable gene segment isotypes, somatic recombination of gene segments, imprecisions in the recombination process and allelic variations in gene segments structure and regulation. PMID- 7833889 TI - [Idiotypic T-lymphocyte receptor in animal and human autoimmune diseases]. AB - Animal models have demonstrated that the T-cell repertoire is restricted when the response to defined autoantigens is studied. Anti-V beta specific monoclonal antibodies or specific V beta-derived peptides can be used to manipulate autoreactive T-cells to either prevent or treat established experimental disease in animals. In some animal models of arthritis, inherited differences in the TCR repertoire can protect against the development of experimental autoimmune disease. Human studies have generally given conflicting results with regard to the role of the TCR complexes as susceptibility loci for disease. This may be due to the heterogeneity present in the human population and/or in the diseases studied. In some diseases, where there is convincing evidence for putative autoantigens (multiple sclerosis) or distinct immunodysfunctional pathology (hypergammaglobulinaemic primary Sjogren's syndrome), restricted TCR repertoires and germline TCR susceptibility loci can be discerned. Recent evidence suggests that autoimmune disease may eventually be mapped to regulatory regions of the TCR V genes rather than the allelic differences in coding region structure. This may have implications for the future therapy of autoimmune rheumatic disease. PMID- 7833891 TI - [Severe laryngeal involvement in rheumatoid arthritis requiring permanent tracheostomy]. AB - A 72-year-old woman with severe rheumatoid arthritis developed atlantoaxial subluxation requiring surgery. Tracheal intubation was performed during the procedure. Gradually worsening dysphonia and dyspnea developed postoperatively. Laryngoscopy showed palsy of both vocal cords and coalescence of the arytenoid cartilages. Despite surgical treatment, permanent tracheostomy was required. There is evidence that laryngeal involvement is common but usually subclinical or mild in rheumatoid arthritis patients. Tracheal intubation can cause the laryngeal lesions to flare. Clinical manifestations are nonspecific and sometimes misleading (e.g., cough or pharyngeal and laryngeal pain). Direct laryngoscopy and computed tomography of the larynx allow evaluation of the lesions of the different components of the larynx. The case reported herein demonstrates that rheumatoid arthritis patients should be screened for laryngeal involvement by history and ENT examination and that any laryngeal abnormalities should be reported to the anesthesiologist if tracheal intubation is planned. PMID- 7833892 TI - [Value of cytological analysis of the synovial fluid in multicentric reticulohistiocytosis. A case]. AB - The authors report the case of a patient who had both multicentric reticulohistiocytosis--a systemic disease characterized by symmetric polyarthritis and papulonodular skin lesions--and an ovarian adenocarcinoma. Synovial fluid analysis found histiocytes with a ground-glass cytoplasm, binucleate giant cells, and undifferentiated cells undergoing mitosis. PAS positive, diastase-resistant cells similar to the synovial fluid histiocytes were seen in the synovial and cutaneous biopsy specimens. These findings established the diagnosis of multicentric reticulohistiocytosis and suggested an underlying malignancy. Whether or not multicentric reticulohistiocytosis is a paraneoplastic syndrome remains unsettled. However, our report provides evidence that synovial fluid analysis can be helpful not only for the early diagnosis of multicentric reticulohistiocytosis but also for suggesting the presence of an underlying tumor, especially when arthritis is the presenting symptom. PMID- 7833890 TI - [Hemiplegia and contralateral multiple aseptic osteonecrosis]. AB - A patient who received treatment for acute myelogenous leukemia (chemotherapy, irradiation, corticosteroid therapy) developed cerebral radionecrosis with hemiplegia (treated by corticosteroids) then multiple foci of osteonecrosis on the nonparalyzed side. The mechanisms which may have prevented osteonecrosis from occurring on the side of the hemiplegia are discussed. PMID- 7833893 TI - [Suspected gold-induced pneumonitis complicating polyarthritis in human immunodeficiency virus infection]. PMID- 7833894 TI - [Stress fracture of the sternum. Apropos of a case]. PMID- 7833895 TI - [Primary myelofibrosis and osteolytic lesions]. PMID- 7833896 TI - [Pitfalls in imaging (MRI and scintigraphy) of femoral osteoid osteoma]. PMID- 7833897 TI - [Moraxella nonliquefaciens spondylodiscitis]. PMID- 7833898 TI - [A new case of polymyositis caused by tiopronin in rheumatoid arthritis, confirmed by histology]. PMID- 7833899 TI - [Poncet's tuberculous rheumatism: a sterile controversy?]. PMID- 7833900 TI - [True recurrent and locally migratory forms of algodystrophy]. PMID- 7833901 TI - Perinatal morbidity and mortality in substance using families: effects and intervention strategies. AB - The epidemic of drug abuse has overwhelmed men, women and children and caused incalculable damage to an honoured structure in human civilization--the family. Moreover, during the past decade, increasing numbers of pregnant drug-dependent women have been presenting themselves to medical facilities, some to receive ongoing prenatal care, but others only to deliver their babies without the benefit of any medical services. The present chapter reviews the current literature, as well as the experiences of the author, with regard to the sociomedical characteristics of pregnant, drug-dependent women. The effects of substances of abuse on pregnancy, the foetus and the newborn with respect to morbidity and mortality are presented. Recommendations for management of both the pregnant drug-dependent women and her child, on the basis of clinical research, are also outlined. Although overall medical advances have escalated during the past three decades, there is still much to learn with regard to the effects of drugs of abuse upon families. Moreover, methods of prevention and treatment still need considerable study. By re-evaluating the areas of strength and weakness in the body of available knowledge, future research will be able to enhance the ability to help those unfortunate families that are effected by substance abuse. PMID- 7833902 TI - The dynamic interaction between family and substance dependence: an international perspective. AB - The purpose of this article is to highlight the complex interrelationship between the family and psychoactive substance dependence and the important role of the family in the prevention, treatment, rehabilitation and social reintegration of substance-dependent persons. In addition, illustrations of the influence of the family on substance dependence and the effect of substance-dependent members on the family are analysed on the basis of data from countries in Africa, the Americas, Asia and Europe. PMID- 7833903 TI - The family in Thailand and drug demand reduction: problems of urban Thai society in transition. AB - Thailand is undergoing ever-accelerating socio-economic transformation which exercises tremendous strains on its basic social institution, the Thai family. The family has traditionally exercised firm control over its members, thus ensuring cohesion and conformity to social norms. Progressive destabilization and disorientation of urban society resulting in a weakening of its foundations and gradual erosion of core functions has led to a deterioration of the family's role and importance. The deterioration of the role of the family is even more critical in the Thai context because, traditionally, the Thai family provided the strongest and most dependable bulwark against social evils of any kind, not the least of which has become drug abuse. The grave state of the country's drug (heroin) abuse problems has recently been further aggravated with the emergent HIV/AIDS epidemic. That epidemic has affected substantial portions of intravenous heroin drug users, posing threats for families all over the country. Evidently, affected families have not been able to protect vulnerable members from becoming drug users; worse still, families have frequently contributed to creating or compounding the problem. Measures need be taken to effectively check this detrimental trend and avert further erosion. The Thai family needs reorientation, parenting and family skills. That would help reinforce the role of the family in preventing drug abuse as well as in rehabilitating former users. To back up the Thai family, still other social groups need to be recruited which can assume some of its stabilizing functions. PMID- 7833904 TI - Culture, drug abuse and some reflections on the family. AB - The authors recently completed a set of monographs on culture and drug use and abuse in a tribal district in Gujarat in western India where changes have occurred in alcohol consumption, two districts in Karnataka in south India where widespread use of cannabis is prevalent, six districts of Gujarat where extensive opium drinking is common, and also on the drug abuse situation in Goa, Delhi and Bombay. On the basis of those studies, the authors call for decentralized planning and a review of the Single Convention on Narcotic Drugs of 1961, and they critique some of the dominant practices in contemporary prevention and rehabilitation of addicts. The role of the family is examined as a socialization institution for transmittal of culture. The limits posed by patriarchy on the extent to which the family can be an agent of primary or secondary prevention of drug use and abuse are indicated. PMID- 7833905 TI - The family and substance abuse in the United Republic of Tanzania. AB - The family in the United Republic of Tanzania has traditionally been a paramount institution invested with important functions of socialization. It provided spiritual guidance, emotional and social support systems, security and education, and defined the moral and ethical system in which the community was intricately bound together. The institution is weakening under the impact of modernization at a pace that far exceeds the pace at which newer institutions are emerging to assume those responsibilities. Drug abuse is becoming an unwelcome guest under those circumstances. It is proposed that active measures should be taken at the community and national policy level to strengthen and employ the family for the purpose of promoting a drug-free lifestyle. PMID- 7833906 TI - Separation anxiety: the etiology of nondisjunction in flies and people. AB - Two new studies examine the recombinational history of human chromosomes that nondisjoin at the first meiotic division in females. Our analysis of these studies suggests two possible etiologies of nondisjunction in terms of well understood properties of chromosome mechanics. For both the X chromosome and for chromosome 21, 60-70% of nondisjoined chromosomes are derived from chiasmate bivalents, many of which display unusual patterns of exchange. The patterns of exchange and nondisjunction observed for human chromosome 21 parallel those exhibited by a mutation in Drosophila that impairs spindle assembly and function. Based on these similarities, we propose that nondisjunction of chromosome 21 in human females results from an age-dependent loss of spindle-forming ability. The recombinational histories of nondisjoining human X chromosomes are quite different from those of chromosome 21, but rather parallel those obtained for spontaneous nondisjunction in Drosophila females. The data for X chromosome disjunction in both species can be explained by a model in which nondisjunction is the consequence of the age-dependent movement of transposable elements. According to this model, nondisjunction is explained as the consequence of the repair of transposon-induced breaks in the DNA. Both models provide reasonable alternatives to biologically implausible explanations such as the 'production line hypothesis'. PMID- 7833907 TI - Non-disjunction of chromosome 21 in maternal meiosis I: evidence for a maternal age-dependent mechanism involving reduced recombination. AB - Over 300 cases of trisomy 21 were analyzed to characterize the causes of maternal non-disjunction and to evaluate the basis for maternal age-dependent trisomy 21. We confirmed the observation that recombination along 21q is reduced among non disjoined chromosomes 21 and further demonstrated that the alterations in recombination are restricted to meiosis I origin. Analysis of the crossover distribution indicates that reduction in recombination is not due simply to failure of pairing and/or absence of recombination in a proportion of cases. Instead, we observed an increase in both zero- and one-exchange events among trisomy 21-generating meioses suggesting that an overall reduction in recombination may be the underlying cause of non-disjunction. Lastly, we observed an age-related reduction in recombination among the meiosis I cases, with older women having less recombination along 21q than younger women. Thus, reduced genetic recombination may be responsible, at least in part, for the association between advancing maternal age and trisomy 21. PMID- 7833908 TI - p53 tagged sites from human genomic DNA. AB - The product of the tumor suppressor gene p53 binds to DNA and activates transcription from promoters containing its consensus binding site. This activity has been hypothesized to be responsible for its biological effects. However, the total number and nature of human genomic sites with which p53 can functionally interact is unknown. In this paper, we have used a Saccharomyces cerevisiae-based screen to identify human genomic sequences that activate transcription from an adjacent reporter gene in a p53-dependent manner (p53-tagged sites, PTS). Fifty seven different PTS were identified, and the total number of such sites in the human genome was predicted to be between 200 and 300. Almost all contained two adjacent copies of the previously defined consensus 5'-PuPuPuC(A/T)(T/A)GPyPyPy 3'. Spacing between the copies was found to be critical for sequence-specific transcriptional activation in vivo. These results further refine the nature of the genomic sequences likely to be most important for p53-mediated tumor suppression. PMID- 7833909 TI - Sequence analysis of the fragile X trinucleotide repeat: implications for the origin of the fragile X mutation. AB - This study addresses mechanism of instability of the FMR-1 (CGG)n-repeat, and investigates features which may distinguish between normal stable and fragile X unstable repeats. To achieve this, we have sequenced 178 alleles to analyze patterns of AGG interruptions within the CGG repeat, and have typed the (CA)n repeat at DXS548 for 204 chromosomes. Overall, our data is consistent with the idea that the length of uninterrupted CGG repeats determines instability. We predict that certain sequence configurations [no AGG, and (CGG)9-11AGG(CGG) > or = 20] present in the general population, are predisposed towards replication slippage. Association between these proposed predisposing repeats and DXS548 alleles may explain the previously reported frequencies of fragile X mutations and large-size normal repeats on specific haplotype backgrounds. We propose that predisposing alleles arise in the general population by as yet undefined mechanism(s) which introduce a relatively long stretch of pure CGG repeat at the 3'-end (relative to the direction of transcription) of the FMR-1 repeat region. The 3' pure repeat may then be susceptible to further expansion by replication slippage. Slippage on these predisposing chromosomes could accumulate over many generations until a threshold size is reached, at which point the repeat is susceptible to greater instability (i.e. premutation stage). Thus, results suggest that evolution of fragile X full mutations could involve 4 definable stages: 1) ancestral events leading to the formation of predisposing alleles which have large total repeat length (e.g. between 35 to 50) but no AGG or 1 AGG; 2) gradual slippage of these predisposing alleles to small premutations (S alleles); 3) conversion from S alleles to larger premutations (Z); 4) massive expansion from a Z allele to a full mutation (L). PMID- 7833910 TI - Precursor arrays for triplet repeat expansion at the fragile X locus. AB - To determine factors governing triplet repeat expansion at FMR1, we need to understand the basis of normal variation. We have sequenced the FMR1 repeat from 102 normal X chromosomes and show that most are interrupted with a regularly spaced AGG trinucleotide giving an ordered structure to the array. Five types of arrays were identified consisting of varying numbers of a core unit with consensus [AGG(CGG)9]. Additional variation in the length of the (CGG)n portion within each unit generates the continuum of lengths seen on normal chromosomes. Ten per cent contain long, uninterrupted tracts of (CGG)n, and their lengths suggest they have arisen by the loss of AGG triplets from longer interrupted arrays. Haplotype analysis of arrays carrying long, uninterrupted (CGG)n tracts suggests that they occur more frequently on genetic backgrounds which are more highly represented on fragile X chromosomes. These arrays may well be precursors from which the larger fragile X associated arrays have arisen by further expansion. PMID- 7833911 TI - A Stickler syndrome gene is linked to chromosome 6 near the COL11A2 gene. AB - Stickler syndrome (hereditary arthro-ophthalmopathy) is caused by mutations in the structural gene for collagen type II (COL2A1) in approximately 50% of cases. In the other families with this syndrome, the genetic defect is unknown. We have performed linkage analysis in a large Dutch kindred with a Stickler syndrome phenotype that was unlinked to COL2A1. As an initial strategy, we tested polymorphisms that are within or near genes encoding other cartilage collagens. Close linkage was demonstrated with polymorphic markers from 6p22 to 6p21.3. The highest lod score was 4.36 without recombination with D6S276. Since COL11A2 has also been localized to this chromosome region, a mutation in this collagen gene is an attractive explanation for the Stickler syndrome phenotype in this family. These data support the hypothesis that abnormalities of type XI collagen may be involved in inherited osteochondrodysplasias, such as Stickler syndrome. PMID- 7833912 TI - Monoallelic expression of normal mRNA in the PIT1 mutation heterozygotes with normal phenotype and biallelic expression in the abnormal phenotype. AB - The combined deficiency of thyrotropin, growth hormone and prolactin, caused by PIT1 abnormality manifests in the homozygous or heterozygous state. We studied a patient having an allele with Arg271Trp mutation, which produces clinical symptoms in heterozygotes by a dominant-negative effect. However, in the family, her father, grandmother and aunts had the same mutation without clinical symptoms, although the proband had typical phenotypic expression. We analyzed the PIT1 transcript in peripheral lymphocytes by reverse transcription-polymerase chain reaction and found monoallelic expression of normal allele in the father and grandmother and skewed pattern of biallelic expression in the proband. The phenotypic expression of PIT1 abnormality may depend on different transcription of the PIT1 gene. PMID- 7833913 TI - Linkage of a new locus for autosomal dominant familial spastic paraplegia to chromosome 2p. AB - Autosomal dominant familial spastic paraplegia (AD-FSP) is a genetically heterogeneous neurodegenerative disorder characterized by a spasticity of the lower limbs. A locus causing AD-FSP (FSP1) has been previously mapped to chromosome 14q. We now report linkage of a second AD-FSP locus (FSP2) to chromosome 2p21-p24 in five of seven French families and one large Dutch pedigree. The analysis of recombination events and multipoint linkage place FSP2 within a 4 cM interval flanked by loci D2S400 and D2S367. PMID- 7833914 TI - MIC2R: a transcribed MIC2-related sequence associated with a CpG island in the human pseudoautosomal region. AB - Sequences related to exons 1, 4 and 5 of the human pseudoautosomal gene MIC2 have been detected on the X and Y chromosomes of humans and other primate species. Isolation of these sequences has defined a new transcribed locus, MIC2R (MIC2 related) which is associated with the second most proximal CpG-rich island in the human pseudoautosomal region. Genomic sequences from the MIC2R locus show that it is composed of a single sequence related to exon 1 and at least four tandem copies of sequences related to exons 4 and 5 of MIC2. Comparison of the four exon 4- and 5-related sequences suggest that they are the result of sequential duplication of a 2.8 kb region during evolution. Transcripts from the MIC2R locus have been detected in all tissues analysed and a number of different transcripts appear to be generated by alternative RNA splicing. However, as none of the transcripts analysed to date contain a significant open reading frame, the function of the MIC2R locus remains unknown. PMID- 7833915 TI - Assignment of a locus for dominantly inherited venous malformations to chromosome 9p. AB - Venous malformation is the most common type of vascular anomaly. Depending upon size and location, these slow-flow anomalies may cause pain, anatomic distortion, or threaten life. Most venous malformations occur sporadically and present as solitary lesions. They also occur in several syndromes, some of which demonstrate Mendelian inheritance. We have mapped the locus for an autosomal dominant disorder in a three generation family that manifests as multiple cutaneous and mucosal venous malformations. This locus lies within a 24 cM interval on chromosome 9p, defined by the markers D9S157 and D9S163. The alpha and beta interferon gene cluster and the putative tumor suppressor genes MTS1 and MTS2 are also in this region. Characterization of the gene responsible for this disorder should yield insights into the precise pathogenic mechanisms for venous malformations. PMID- 7833916 TI - Dystroglycan: brain localisation and chromosome mapping in the mouse. AB - Duchenne muscular dystrophy (DMD) is accompanied by varying degrees of mental retardation. The molecular basis for this is unknown, although at least four dystrophin transcripts regulated by specific promoters and undergoing elaborate splicing control are present in brain areas associated with cognitive function. In muscle the absence of dystrophin causes instability of a dystrophin-associated protein complex (DAPC) linking the cytoskeleton to the extracellular matrix; this disruption is accompanied by muscle necrosis. The laminin-binding component of DAPC, dystroglycan, in contrast to other components of DAPC, has been found in brain homogenates. This suggests that the link between the membrane cytoskeleton and extracellular matrix mediated by dystrophin-dystroglycan may play a functional role in brain. We have cloned a mouse dystroglycan partial cDNA and have mapped this gene in the mouse to chromosome 9. Further, in situ hybridisation to mouse brain sections shows that the dystroglycan gene is expressed in relatively few structures and co-localises with dystrophin mRNA in hippocampus, dentate gyrus, olfactory bulb and Purkinje neurons but, surprisingly, not in the cortex. Dystroglycan is also expressed in those brain areas where the dystrophin-related protein (utrophin) is present. Our results provide a basis for a future characterisation of the role of dystrophin dystroglycan association in the brain. PMID- 7833918 TI - A histidine to tyrosine replacement in lysosomal acid lipase causes cholesteryl ester storage disease. AB - The genetic defect causing cholesteryl ester storage disease (CESD) has been investigated in an 11 year old patient. Lysosomal acid lipase (LAL) activity in cultured skin fibroblasts and peripheral lymphocytes was reduced to approximately 3% and approximately 4% of controls, respectively. The parents had low acid lipase activity in white blood cells. Using the polymerase chain reaction followed by ribonuclease protection assay, we examined the LAL mRNA from the liver of the affected patient to identify small deletion, abnormal splicing or missense mutation. Using this technique we identified a LAL mRNA cytosine to thymidine transition in position 923, predicting a missense substitution of tyrosine for histidine in codon 274. By differential oligonucleotide hybridization on an amplified white blood cell mRNA, the cytosine to thymidine transition was investigated in the family members and in the population. No normal mRNA coding for cytosine in position 923 was detectable in the propositus and mRNA from the phenotypically normal parents coded for both cytosine and thymidine. This can only be accounted for by assuming that the propositus is homozygote for the mutation. The mutation, segregated in the family with levels of acid lipase activity in white blood cells, was not detected in mRNA from 60 normal subjects. These data provide evidence that the cytosine to thymidine transition in position 923 in LAL mRNA causes the clinical expression of CESD in this patient. The predicted substitution of tyrosine for histidine in codon 274 suggests that this amino acid is involved in the structure-function of the lysosomal acid lipase enzyme. PMID- 7833917 TI - Pathophysiology of sodium channelopathies: correlation of normal/mutant mRNA ratios with clinical phenotype in dominantly inherited periodic paralysis. AB - It is often suggested that polygenic or environmental factors are responsible for clinical variability between patients with identical mutations. However, most dominant diseases are caused by a change-of-function alteration in the mutant allele's protein product. All patients are heterozygous and presumably express both mutant and normal proteins from the corresponding genes. Thus, a possible molecular mechanism for clinical variability could be the difference in relative levels of mutant vs. normal mRNA in different patients with the same mutation. To investigate this hypothesis, it is necessary to have access to a series of tissue biopsies from many patients with the same mutation causing a clinically variable dominant disease. Human hyperkalemic periodic paralysis (HyperPP) has been shown to be a clinically variable disorder caused by change-of-function mutations of the skeletal muscle sodium channel protein. We recently identified a large (> 50,000) pedigree of affected Quarter Horses sharing the same causative amino acid alteration of the muscle sodium channel protein. The horses like humans show substantial clinical variability. In this report, we developed a fluorescent reverse transcription-polymerase chain reaction assay which quantifies the relative levels of normal and mutant mRNA expression of the horse adult skeletal muscle sodium channel gene in affected Quarter Horses. We found that asymptomatic horses showed more normal sodium channel mRNA, while moderately affected horses showed more mutant mRNA. The ratios of mutant/normal mRNA between these two groups are statistically different, suggesting that severity of HyperPP Quarter Horses may indeed be correlated to the ratio of mutant and normal sodium channel gene expression in skeletal muscle. PMID- 7833919 TI - A family with Ehlers-Danlos syndrome type III/articular hypermobility syndrome has a glycine 637 to serine substitution in type III collagen. AB - Ehlers-Danlos syndrome (EDS) is a heterogeneous group of heritable disorders of connective tissue. The type III variety is characterized by joint hypermobility and minor hyperextensibility and softness of the skin. While collagen fibril structure has been shown to be abnormal in such patients, the underlying molecular defect(s) has not been determined. Here we characterize the first mutation found in a family with EDS III. Analysis of cultured fibroblasts from the affected family revealed intracellular retention of type III collagen. This is usually a biochemical characteristic of EDS IV, caused by mutations of COL3A1. Analysis of the cDNA sequence in this EDS III family revealed a glycine to serine mutation at amino acid residue 637 of the type III collagen molecule. This was confirmed by allele-specific oligonucleotide hybridization against amplified genomic DNA. Thus mutations of type III collagen can cause either EDS IV or EDS III. Two affected family members had virtually normal skin and so more closely resembled the phenotype of articular hypermobility syndrome. PMID- 7833920 TI - Localization of a gene for autosomal dominant amelogenesis imperfecta (ADAI) to chromosome 4q. AB - Amelogenesis imperfecta (AI), is an inherited odontological disease which affects the formation of enamel. We report a linkage analysis study performed on three Swedish families, where the affected members had an autosomal dominant variant of AI (ADAI) clinically characterized as local hypoplastic. Significant linkage to microsatellite markers on chromosome 4q were obtained. Recombinations localized the ADAI locus to a chromosome region which contains both a locus for the dental disorder dentinogenesis imperfecta and the albumin gene. Serum albumin has been suggested to play a role in enamel formation, and the albumin gene is therefore a candidate gene for this genetic disease. PMID- 7833921 TI - Molecular basis of essential fructosuria: molecular cloning and mutational analysis of human ketohexokinase (fructokinase). AB - Essential fructosuria is one of the oldest known inborn errors of metabolism. It is a benign condition which is believed to result from deficiency of hepatic fructokinase (ketohexokinase, KHK, E.C.2.7.1.3). This enzyme catalyses the first step of metabolism of dietary fructose, conversion of fructose to fructose-1 phosphate. Despite the early recognition of this disorder, the primary structure of human KHK and the molecular basis of essential fructosuria have not been previously defined. In this report, the isolation and sequencing of full-length cDNA clones encoding human ketohexokinase are described. Alternative mRNA species and alternative KHK isozymes are produced by alternative polyadenylation and splicing of the KHK gene. The KHK proteins show a high level of sequence conservation relative to rat KHK. Direct evidence that mutation of the KHK structural gene is the cause of essential fructosuria was also obtained. In a well-characterized family, in which three of eight siblings have fructosuria, all affected individuals are compound heterozygotes for two mutations Gly40Arg and Ala43Thr. Both mutations result from G-->A transitions, and each alters the same conserved region of the KHK protein. Neither mutation was seen in a sample of 52 unrelated control individuals. An additional conservative amino acid change (Val49IIe) was present on the KHK allele bearing Ala43Thr. PMID- 7833922 TI - The Wilms tumour (WT1) gene is mutated in a secondary leukaemia in a WAGR patient. AB - The Wilms tumour (WT1) gene was first localized through its deletion in individuals with the WAGR syndrome (Wilms tumour, aniridia, genitourinary abnormalities and mental retardation). Such individuals have a 30-50% lifetime risk of developing Wilms tumour and carry constitutional interstitial deletions of chromosome 11p13, including the WT1 gene. Second primary tumours occurring in such individuals might also be related to their genetic predisposition to cancer, as shown for hereditary retinoblastoma. We have found a mutation in the zinc finger region of the remaining WT1 allele in a case of acute myeloid leukaemia developing in a Wilms tumour survivor with the WAGR syndrome. This mutation would be predicted to disrupt DNA binding by this developmentally regulated transcription factor. This finding implicates the WT1 gene in the regulation of myelopoiesis and suggests that WT1 mutations may be found in some sporadic leukaemias. PMID- 7833923 TI - Functional characterization of the novel L108W and P186L mutations detected in the type II 3 beta-hydroxysteroid dehydrogenase gene of a male pseudohermaphrodite with congenital adrenal hyperplasia. AB - Two isoenzymes are responsible for 3 beta-hydroxysteroid dehydrogenase/delta 5 delta 4-isomerase (3 beta-HSD) activity in humans. We analyzed the structure of types I and II 3 beta-HSD genes in a male pseudohermaphrodite suffering from a severe salt-losing form of congenital adrenal hyperplasia. We did not detect any mutation in the type I 3 beta-HSD gene, but we found two different missense mutations in exon IV of the type II 3 beta-HSD gene of the patient; a conversion of codon Leu108 into a Trp (L108W) inherited from his mother and a conversion of codon Pro186 into a Leu (P186L) inherited from his father. We assessed the effect of the L108W and P186L mutations on 3 beta-HSD activity by in vitro analysis of mutant enzymes expressed in heterologous COS-1 cells. Using homogenates from transfected cells, the Km values for PREG were 7 +/- 2 and 8 +/- 2 microM for the recombinant L108W and P186L enzymes, respectively, compared with 2.2 +/- 0.2 microM for the normal type II 3 beta-HSD enzyme. Moreover, Km values for NAD+ were much higher for the L108W and P186L proteins, being 678 +/- 166 and 920 +/- 351 microM, respectively, compared with 24 +/- 3 microM for the normal type II 3 beta-HSD enzyme. Vmax values for PREG and NAD+ were lower for both mutant enzymes; thus, the in vitro overall efficiency, relative to the normal enzyme, is approximate as 0.3% and 0.2% for the L108W and P186L enzymes, respectively.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7833925 TI - Localization of merosin-negative congenital muscular dystrophy to chromosome 6q2 by homozygosity mapping. AB - Congenital muscular dystrophies (CMD) are autosomal recessive, heterogeneous disorders. The commonest forms are the Fukuyama CMD (FCMD), associated with mental retardation and structural brain anomalies, and classical (occidental) CMD, with pure muscle expression. FCMD has been localized to chromosome 9q31-q33. Following the discovery of merosin deficiency in some CMD cases, we have localized, by homozygosity mapping and linkage analysis (Zmax = 5.6; theta = 0.0 for marker AFM127xb2) in four merosin-negative families a CMD gene in a 16 cM region of chromosome 6q2 in the region of the laminin M chain gene. In three consanguineous, merosin-positive, CMD families there was no linkage to either chromosome 6q2 or 9q31-q33. PMID- 7833924 TI - Characterization of the Wilson disease gene encoding a P-type copper transporting ATPase: genomic organization, alternative splicing, and structure/function predictions. AB - Wilson disease is an autosomal recessive disorder of copper transport. Disease symptoms develop from the toxic build-up of copper primarily in the liver, and subsequently in the brain, kidney, cornea and other tissues. A candidate gene for WD (ATP7B) has recently been identified based upon apparent disease-specific mutations and a striking amino acid homology to the gene (ATP7A) responsible for another human copper transport disorder, X-linked Menkes disease (MNK). The cloning of WD and MNK genes provides the first opportunity to study copper homeostasis in humans. A preliminary analysis of the WD gene is presented which includes: isolation and characterization of the 5'-end of the gene; construction of a genomic restriction map; identification of all 21 exon/intron boundaries; characterization of extensive alternative splicing in brain; prediction of structure/function features of the WD and MNK proteins which are unique to the subset of heavy metal-transporting P-type ATPases; and comparative analysis of the six metal-binding domains. The analysis indicates that WD and MNK proteins belong to a subset of transporting ATPases with several unique features presumably reflecting their specific regulation and function. It appears that the mechanism of alternative splicing serves to regulate the amount of functional WD protein produced in brain, kidney, placenta, and possibly in liver. PMID- 7833927 TI - Evidence for origin, by recurrent mutation, of the phenylalanine hydroxylase R408W mutation on two haplotypes in European and Quebec populations. AB - The R408W mutation in the phenylalanine hydroxylase gene (PAH) of phenylketonuria patients occurs on haplotypes 2.3 and 1.8 in Europeans. The mutation involves a CpG dinucleotide; nonetheless, a single recombination event might also explain the two haplotype associations. By analysis of an STR in the PAH gene 5' to the 408 codon and of the VNTR system in the 3' UTR, we identified unique features of the haplotype 1.8 chromosome harbouring the R408W mutation which are not accounted for by recombination. We conclude that recurrent mutation is the origin of R408W on different PAH haplotypes in Europeans. PMID- 7833926 TI - Selection of cDNAs using chromosome-specific genomic clones: application to human chromosome 13. AB - We have developed a general method for en masse isolation of cDNAs present in a normalized library by hybridization to arrayed chromosome-specific phage lambda clones; we have used this approach to initiate exon-mapping of human chromosome 13. An advantage of the simultaneous isolation of cDNA/lambda pairs is that it allows cytogenetic assignment of a bona fide genomic clone by in situ hybridization, which also verifies that the corresponding cDNA or a homologous expressed sequence resides on chromosome 13. This information is enriched by partial sequencing of a selected cDNA from both ends. The sequence of the 3' noncoding region provides an 'identifier' that is used to develop STSs, while the sequence from the 5' end, often corresponding to a coding region, is used for homology searches in databases that occasionally reveal gene functions. PMID- 7833928 TI - The gene for hereditary breast-ovarian cancer, BRCA1, maps distal to EDH17B2 in chromosome region 17q12-q21. AB - A gene for hereditary breast and ovarian cancer, BRCA1, has been mapped to chromosome 17q12-q21. This gene is responsible for cancer susceptibility in the majority of families with multiple cases of ovarian cancer and early-onset breast cancer. We report linkage results of a family with 10 cases of breast cancer and a single case of ovarian cancer. A recombinant event in this family places BRCA1 distal (telomeric) to the locus EDH17B2, which codes for the enzyme estradiol 17 beta-dehydrogenase II. This recombinant is based on the appearance of breast cancer in a 45 year old woman. Under our genetic model, we estimate the probability that this woman carries a BRCA1 mutation to be 94%. These data further reduce the region of assignment of BRCA1 on chromosome 17q12-q21 and should expedite positional cloning of this important gene. PMID- 7833929 TI - Novel missense and frameshift mutations in the tissue-nonspecific alkaline phosphatase gene in a Japanese patient with hypophosphatasia. PMID- 7833930 TI - Mutations in the vasopressin V2-receptor gene in three families of Italian descent with nephrogenic diabetes insipidus. PMID- 7833931 TI - Four novel mutations of the APC (adenomatous polyposis coli) gene in FAP patients. PMID- 7833932 TI - Detection of a novel mutation (stop 468) in exon 10 of the low-density lipoprotein receptor gene causing familial hypercholesterolemia among French Canadians. PMID- 7833933 TI - A novel homozygous point mutation in the collagen VII gene (COL7A1) in two cousins with recessive dystrophic epidermolysis bullosa. PMID- 7833934 TI - Deletion of the ferrochelatase gene in a patient with protoporphyria. PMID- 7833935 TI - X-linked dominant Charcot-Marie-Tooth neuropathy: valine-38-methionine substitution of connexin32. PMID- 7833936 TI - Eleven novel germline mutations in the adenomatous polyposis coli (APC) gene. PMID- 7833937 TI - Twelve simple repeat sequence polymorphisms on chromosomes 4, 11, 16 and 21. PMID- 7833938 TI - A locus of the candidate gene family for azoospermia factor (YRRM2) is polymorphic with a null allele in Japanese males. PMID- 7833939 TI - Dinucleotide repeat polymorphism in the human IL1A gene. PMID- 7833940 TI - SSC polymorphisms in interleukin genes. PMID- 7833941 TI - Amino acid polymorphism (Gly209Ser) in the ACADS gene. PMID- 7833942 TI - HindIII RFLP in the human CD53 gene on 1p13. PMID- 7833943 TI - Dinucleotide repeat polymorphism at D14S542. PMID- 7833944 TI - G/T polymorphism in CRYA2 gene. PMID- 7833945 TI - A dinucleotide repeat polymorphism at the D9S749 locus. PMID- 7833946 TI - Microsatellite repeat polymorphism at the D16S366 locus. PMID- 7833947 TI - Genetic heterogeneity of apolipoprotein E and its influence on plasma lipid and lipoprotein levels. AB - Apolipoprotein E (apoE) is one of the major protein constituents of chylomicron and very-low-density lipoprotein (VLDL) remnants and plays a central role as a ligand in the receptor-mediated uptake of these particles by the liver. Including the most common variant, apoE3, 30 apoE variants have been characterized. At present, 14 apoE variants have been found to be associated with familial dysbetalipoproteinemia, a genetic lipid disorder characterized by elevated plasma cholesterol and triglyceride levels and an increased risk for atherosclerosis. Seven apoE variants were found to be associated with other forms of hyperlipoproteinemia. This report presents an overview of all currently known apoE variants and their effects on lipoprotein metabolism. PMID- 7833948 TI - Deletion spanning the 5' ends of both the COL4A5 and COL4A6 genes in a patient with Alport's syndrome and leiomyomatosis. AB - Alport's syndrome is characterized clinically by a nonimmune glomerulopathy, often accompanied by sensorineural hearing loss and lens abnormalities, frequently due to mutations in the COL4A5 gene. The association of AS with diffuse leiomyomatosis, a benign proliferation of smooth muscle that occurs most often in the esophagus, trachea, and female genitalia, has been reported. Recently, a deletion involving both the COL4A5 and COL4A6 genes has been reported in four unrelated families. We report an additional case with Alport's syndrome associated with leiomyomatosis carrying a deletion of both COL4A5 and COL4A6 genes. A detailed characterization of the genomic region involved in the deletion event has been performed. Our results demonstrate that the deletion removed exon 1 of COL4A5 and exons 1 and 2 of COL4A6. PMID- 7833950 TI - Homologous loci DXYS156X and DXYS156Y contain a polymorphic pentanucleotide repeat (TAAAA)n and map to human X and Y chromosomes. AB - We report the isolation and characterization of a polymorphic pentanucleotide repeat (TAAAA)n, which was mapped to human chromosomes X and Y (loci DXYS156X and DXYS156Y) by PCR amplification of DNA from a monochromosomal somatic cell hybrid panel (NIGMS panel 2). The (TAAAA)n repeat of loci DXYS156 occurs within a human LINE element at a position where the consensus sequence contains a single TAAAA motif. In 72 unrelated CEPH individuals seven alleles were detected which ranged in size from 125 to 165 bp in 5 bp intervals. The two largest alleles (160 and 165 bp) were observed only in males, which suggests that they were amplified from the Y chromosome DXYS156Y locus. The other 5 alleles were present in two copies in females and in a single copy in males, which suggests that they were amplified from the X chromosome DXYS156X locus. Locus DXYS156X was polymorphic in CEPH families with an observed heterozygosity in females of 46% (27 of 59). Linkage analysis with DNA markers on the X chromosome revealed significant lod scores for a location of DXYS156X close to markers DXS1002 (theta = 0.000; zeta = 8.43), DXYS1X (theta = 0.015; zeta = 17.3), DXS3, and PGK1 in the region of chromosome Xq13. The sequence of DXYS156Y derived from the 165 bp allele has been deposited in Genbank with accession number X71600. PMID- 7833949 TI - Metachromatic leukodystrophy in the Navajo Indian population: a splice site mutation in intron 4 of the arylsulfatase A gene. AB - Metachromatic leukodystrophy (MLD) is an autosomal recessive disorder of myelin metabolism, resulting from the inability to properly degrade 3 sulfogalactosylceramide (sulfatide). This metabolic block is often due to defective functioning of the lysosomal enzyme arylsulfatase A (ARSA). Unmetabolized sulfatide accumulates in the white matter of the CNS and in the peripheral nerves, leading to progressive demyelination and death. Late infantile, juvenile and adult clinical variants of MLD have been described. A Navajo Indian child was diagnosed with late infantile MLD (LIMLD), and his ARSA gene was amplified in three overlapping regions by the PCR and sequenced. A single mutation was found: a G-->A transition in the first nucleotide of intron 4 (IVS4nt1), which abolishes the 5' splice site consensus sequence. Negligible amounts of ARSA mRNA were observed in Northern blots. However, PCR amplification and sequencing of the ARSA cDNA showed that all of the mRNA species from the patient have exon 4 deleted. A new reading frame is thus established which results in a premature stop codon within exon 5. A minority of transcripts had additional splicing errors. Both parents carry this mutation, and the father also carries the pseudodeficiency (PD) allele. Three additional unrelated Navajo LIMLD patients were found to be homozygous for the same MLD-causing mutation by allele specific oligonucleotide (ASO) hybridization. This method could be used for carrier and patient identification in this population. PMID- 7833951 TI - Erroneous assignment of Gaucher disease genotype as a consequence of a complete gene deletion. AB - Two sisters with moderately severe Gaucher disease were diagnosed as having the usually relatively benign 1226G/1226G genotype by examination of DNA amplified from exon 9, where this mutation is located. Because of the discrepancy between the apparent genotype and the phenotype, we suspected that one of the alleles had not amplified. Therefore, the DNA of both parents was examined. The father was heterozygous for the 1226G mutation but the mother did not have this abnormality. It was shown that the mother and both daughters had a deletion of the glucocerebrosidase gene: only about one-half of the polymerase chain reaction (PCR) amplification product of the glucocerebrosidase gene in this region was found, compared to internal controls consisting of the glucocerebrosidase pseudogene and of the adjacent liver pyruvate kinase (PKLR) gene. The appearance of Southern blots developed with full length glucocerebrosidase cDNA probes showed that the band unique to the functional glucocerebrosidase gene had reduced intensity, and no abnormal bands were present after digestion with any restriction endonuclease, indicating that the entire coding region was deleted. PMID- 7833952 TI - Screening for mutations in the exon 26 of the apolipoprotein B gene in hypercholesterolemic Finnish families by the single-strand conformation polymorphism method. AB - To date, the only known apolipoprotein B (apo B) mutation causing hypercholesterolemia is the apo B 3500 Arg-->Gln or the familial defective apo B (FDB) mutation. This mutation has not been detected in the Finnish population. We have set up a systematic single-strand conformation polymorphism (SSCP) analysis based screening method to search for other mutations in the exon 26 of the apo B gene in 21 Finnish hypercholesterolemic probands. The 7572-bp exon 26 covers half of the coding region of the gene including the DNA sequence coding for the putative low-density lipoprotein (LDL) receptor binding site on the apo B protein. Exon 26 was amplified as six 1190- to 1435-bp fragments, each of which was further split into three smaller 213- to 579-bp segments by restriction enzymes. These digestion products were run on nondenaturing polyacrylamide gels using at least three different electrophoretic conditions and autoradiographed. All previously known genetic variants in the exon 26 were detected by the SSCP method. A C-->T change at nucleotide 7064, in complete association with the XbaI site, was characterized by direct sequencing. This variant did not affect the amino acid sequence of the apo B protein. The SSCP-based procedure appears suitable for systematic screening for DNA sequence changes in large coding regions. PMID- 7833953 TI - A single base pair substitution within the paired box of PAX3 in an individual with Waardenburg syndrome type 1 (WS1). PMID- 7833954 TI - Five novel missense mutations of the phenylalanine hydroxylase gene in phenylketonuria. PMID- 7833955 TI - Redefining the psychosomatic family: family process of 26 eating disorder families. AB - This paper reports part of the data from a comparative trial of two forms of family intervention for the management of eating disorders in adolescents. Measures of family process at the beginning of treatment included Expressed Emotion (EE) and the Family Adaptability and Cohesion Evaluation Scales (FACES). EE in the families of both anorexic and bulimic patients were, on the whole, at low levels. The low levels of parental Critical Comments might be taken to represent the conflict avoiding character of the families of psychosomatic patients. However, the families showed low levels of Emotional Overinvolvement, which contradicts the clinical descriptions. The FACES scores revealed patterns that were superficially contradictory to the accepted clinical descriptions in that the patients appeared to have perceived their families as not close and as highly structured. The parents experienced their family structure as more similar to the clinical descriptions, scoring their families as more flexible and cohesive than do the patients. The FACES ideals for family organization scored by patients and parents more nearly equate with the clinical descriptions of enmeshment and lack of boundary structure. The relationship between the research findings and the clinical evaluation will be discussed. PMID- 7833956 TI - Pursuit of thinness and onset of eating disorder symptoms in a community sample of adolescent girls: a three-year prospective analysis. AB - Community-based prospective studies are needed to shed light on mechanisms that may influence development of eating disorders and identify variables that could serve as potential targets for prevention efforts. In this paper we examine level of weight preoccupation and other variables prospectively associated with age of onset of eating disorder symptoms over a 3-year interval in a community sample (N = 939) of young adolescent girls. 3.6% (32/887) experienced onset of symptoms over the interval. Only one factor, a measure of Weight Concerns, was significantly associated with onset (p < .001). Girls scoring in the highest quartile on the measure of Weight Concerns had the shortest survival time (12% incidence by age 14.5) and those scoring in the lowest quartile had the highest survival time (2% incidence by age 14.5; p < .001). This finding is consistent with both theoretical and clinical perspectives and represents one of the first prospective demonstrations of a linkage between weight and body shape concerns and later onset of eating disorder symptoms. An understanding of the independent variables that predispose girls to development of symptoms is a useful step towards the establishment of a rational basis for the choice of a prevention intervention target. PMID- 7833957 TI - Binge eating antecedents in normal-weight nonpurging females: is there consistency? AB - We examined the situational antecedents of binge eating episodes and tested for consistency in the antecedents. We evaluated the antecedents of two successive binges via structured interviews with 50 normal-weight nonpurging females who regularly binge. Cluster analysis yielded two categories of binge-promoting situations: solitary negative affect situations and social eating situations. When this empirically derived classification of binge situations was used, the two successively occurring binges did not systematically fall into the same cluster. Consistency on other measures was also modest. Implications of these findings for conceptual models of binge eating and treatment, including the prospect of individually tailored interventions, are discussed. PMID- 7833958 TI - Defense style in women with eating disorders. AB - A relatively new instrument, the Defense Style Questionnaire (DSQ), represents an efficient method by which to quantify an individual's psychological defense style. We administered the DSQ to 66 women hospitalized for anorexia nervosa, bulimia nervosa, or concurrent anorexia and bulimia nervosa. Contrary to our expectations, there were no consistent patterns of identifiable defense styles specific to these groups in qualitative, univariate, and multivariate analyses. The failure of the DSQ to demonstrate specificity across eating disorder subgroups suggests it is not informative in regard to the pathogenesis of these specific syndromes. In contrast, in a previous study, we found temperamental measures to be informative. PMID- 7833959 TI - Melatonin disturbances in anorexia nervosa and bulimia nervosa. AB - The pineal gland releases melatonin into the blood stream in response to sympathetic noradrenergic stimulation of pinealocytes. This process is inhibited by light via the retino-hypothalamic-pineal pathway. Hence melatonin is predominantly released in darkness. Because serotonin is a precursor of melatonin, the intake of dietary tryptophan may also influence melatonin levels. Although the exact physiological role of melatonin in humans is unclear, it appears to be implicated in reproductive physiology, especially in terms of the onset of menarche. Low levels of melatonin also occur in depression. In this review, studies of melatonin in patients with anorexia nervosa and bulimia nervosa are considered in relation to potential abnormalities of noradrenergic function and circadian rhythm. The influence of weight loss, binging and purging, and depression on melatonin is discussed. Other studies involving the assessment of melatonin in relation to menstrual function are required. PMID- 7833960 TI - Body image changes over the menstrual cycle in normal women. AB - Changes in body image across the menstrual cycle and the relationship between these changes and menstrual distress were investigated in an effort to identify determinants of body dissatisfaction. Twenty-six normally cycling women between 18-40 years of age and 90-115% of ideal body weight, with no history of an eating disorder, completed a series of body image measures and a measure of menstrual distress during three menstrual cycle phases: perimenstrual, follicular, and luteal. These phases were identified with serum levels of ovarian hormones and basal body temperature. Results indicated that body dissatisfaction as measured by the number of body-related negative thoughts and anxiety about appearance was significantly highest during the perimenstrual phase. In contrast, measures of body size perception remained stable. Several somatosensory and psychological symptoms of menstrual distress were significantly associated with body dissatisfaction during the perimenstrual phase including, water retention, autonomic reactivity, control, negative affect, and impaired concentration. This association of body dissatisfaction and menstrual distress strongly suggests that menstrual cycle changes play a significant role in body image. PMID- 7833961 TI - Psychometric properties of the Children's Eating Attitudes Test. AB - As interest in eating disorders has grown, there has been an increased need for psychometrically sound measures of young children's eating attitudes and behaviors. The present report examines one promising measure, the children's version of the Eating Attitudes Test (ChEAT; (Maloney, McGuire, & Daniels. [1988]. Journal of the American Academy of Child and Adolescent Psychiatry, 5, 541-543; Maloney, McGuire, Daniels & Specker. [1989]. Pediatrics, 84, 482-489). Like the EAT-26, (Garfinkel & Garner. [1982]. Anorexia nervosa: A multidimensional perspective. New York: Brunner/Mazel), this is a 26-item self report questionnaire. As part of a larger study, the ChEAT was administered to 308 middle school girls. Analyses indicated that the 26-item version had adequate internal reliability, both for the entire sample and for each of the three grades. However, a 23-item version had even better internal reliability. Concurrent validity was demonstrated for the 26-item version in that correlations between the ChEAT and independent measures of weight management and body dissatisfaction were significant. Again, the concurrent validity was slightly better for the 23-item version. Factor analysis of the ChEAT-26 yielded factors quite similar to those of the EAT-26. However, an additional ChEAT factor emerged that tapped restricting and purging behaviors. On the whole, the ChEAT emerged as a promising instrument for measuring disturbed eating attitudes and behaviors in middle school girls. PMID- 7833962 TI - Ideal female body shape: role of body weight and waist-to-hip ratio. AB - Interrelationships of female body fat distribution as measured by the waist-to hip ratio (WHR), overall body size, perceived attractiveness, youthfulness, health, and need to lose weight were investigated. Drawings showing thin females with high WHRs and heavier females with low WHRs were presented to college-age women with low and high scores on the Restrained Eating Scale (Herman & Polivy. [1980]. Obesity [pp. 208-225]. Philadelphia: Saunders) and men who ranked figures for various attributes. Female subjects, regardless of their eating style, as well as male subjects, judged heavier female target figures with low WHRs as more attractive and healthier than thinner figures with higher WHRs. The rankings for youthfulness and need to lose weight were not systematically affected by the size of the WHR. Female subjects perceived heavier female target figures with low WHR to represent ideal female figures. Female subjects with a restrained eating style felt their own body was not similar to idealized female figures and expressed unhappiness with their body shape; this was not true of unrestrained eaters. It is proposed that female attractiveness and ideal female shape may be more influenced by WHR than overall body size. PMID- 7833963 TI - Body fat distribution and perception of desirable female body shape by young black men and women. AB - The relation between body fat distribution as measured by waist-to-hip ratio (WHR) and perception of desirable female body shape was investigated in college age black men and women. Subjects judged attractiveness, various personal qualities, and desirability for long-term relationships of 12 line drawings of female figures that represented three body weight categories (normal, underweight, and overweight) and four levels of WHRs (0.7, 0.8, 0.9, and 1.0). Judgments of attractiveness and desirability for long-term relationships were affected by body weight and the size of the WHR. Both male and female subjects ranked normal weight figures with 0.7 and 0.8 WHR as more attractive and desirable for long-term relationships; neither underweight nor overweight figures, irrespective of WHR size, were assigned high ranking for these variables. These findings do not support the notion that black young men and women find overweight female figures as desirable and attractive. PMID- 7833964 TI - Seasonal fluctuations in mood and eating behavior in bulimia nervosa. AB - Thirty-five bulimia nervosa (BN) patients with high seasonality scores on a modified version of the Seasonal Pattern Assessment Questionnaire (SPAQ) were administered semistructured clinical interviews to further assess their seasonal symptom patterns. A diversity of patterns were identified, consistent with a multidimensional model of seasonality in the BN population. Overall, the results suggest that seasonality may be an important dimension to consider in patients with BN. PMID- 7833965 TI - Preliminary study of eating disorders among French female adolescents and young adults. AB - We have performed an exploratory study of eating disorders among female adolescents (N = 38) and young adult (N = 38) students living in Paris, France. A high percentage of the subjects in the adolescent (68.4%) and young adult (50%) groups displayed one or more atypical eating behaviors with grazing being prominent (60.5% and 42.1%, respectively) in both groups. Bulimia nervosa (DSM III-R) was found only in the older group (3/38 vs. 0/38). Binge eating was significantly more frequent among the older subjects (12/38 vs. 1/38). Nicotine dependence and daily grazing with a history of grazing during childhood were reported in all subjects with bulimia nervosa (DSM-III-R). These data, while requiring replication in larger samples, indicate that atypical eating behaviors are common in the populations sampled. Furthermore, daily grazing (especially with a history of grazing during childhood) and nicotine dependence may be strongly associated with the development of bulimia nervosa. PMID- 7833966 TI - Body size estimation and body dissatisfaction in eating disorder patients and normal controls. AB - In this study comparing 41 eating disorder patients and 34 female controls, the video distortion technique was used to test the accuracy of body size estimation and to assess the ideal body image. No difference was found in the estimation of actual body sizes, although the accuracy of estimation was quite variable in both bulimics and anorexics. With regard to the ideal body image, significant differences were found: All bulimics and 92.6% of the controls wished to be thinner versus 42.9% of the anorexics (23.8% wished to be larger). Looking at subjective body experience, as measured with a self-report questionnaire (Body Attitudes Test), body dissatisfaction appeared to be negatively correlated with the ideal body image but not with the estimation of actual body sizes. PMID- 7833967 TI - Factor analysis of multiple measures of body image disturbance: are we all measuring the same construct? AB - Two studies were conducted to determine the overlap among multiple measures of subjective body image disturbance. Study 1 was conducted on 219 adolescent females (ages 14-18 years) who completed seven widely used indices of self reported body image disturbance. Study 2 involved 162 college females (ages 17-35 years) and six measures of disturbance, five of which were identical with those instruments used in Study 1. Factor analyses indicated the existence of two factors in the adolescent sample, however, one factor was quite strong and accounted for most of the variance. Analyses on the adult subjects revealed the existence of a single body image factor. It was concluded that the measures under investigation largely reflect an underlying single factor of body image, despite their common usage in the literature as indicators of multiple aspects of body image disturbance. PMID- 7833968 TI - Pelvic fascia strength in women with stress urinary incontinence in comparison with those who are continent. AB - Biophysical properties of the anterior vaginal wall as well as the rectus fascia were evaluated in vivo by penetrating the Stamey needle into these tissues of 26 female patients with stress incontinence in comparison with those of 21 continent subjects. The results demonstrated that shear strength of the anterior vaginal wall was lower in incontinent patients than in continent subjects (P < 0.01). Shear strength of the rectus fascia in the patients, which was not supposed to be related to urinary incontinence and should have had the same strength as the control subjects, was also found to be lower than the control (P < 0.01). Shear strength of the vaginal wall was not correlated with age irrespective of their continence status (P > 0.05). Based on our findings it is concluded that some women suffering from stress incontinence may have a hereditary disorder of biophysical properties of the tissues. PMID- 7833970 TI - Basis of severity grade in detrusor hyperreflexia. AB - For both treatment and research it is useful to classify detrusor hyperreflexia/instability according to degree of severity, because it relates to symptomatic impact. However, there has been no systematic evaluation of criteria for severity assignment. This report compares patient classification by urodynamic data according to 3 methods: arbitrary criteria, a severity index, and an empirical cluster analysis. Within the primary urodynamic data there were no natural groupings as a basis for division into discrete patient groups. By all three methods, however, severity level did relate to symptoms. PMID- 7833969 TI - Abnormal sensitivity to intravesical potassium in interstitial cystitis and radiation cystitis. AB - The urgency-frequency syndrome (UFS) (non-bacterial cystitis, interstitial cystitis) may well represent a heterogenous group with several etiologies. This study was based on the hypothesis that one subset of UFS patients has a leaky (to solutes) epithelium and cations such as potassium could thereby diffuse subepithelially and provoke symptoms. It was also hypothesized that normal impermeable transitional epithelium would not allow cations to diffuse across the cells during the K+ provocation test and no symptoms would be experienced. If the epithelium was permeable ("leaky"), diffusion would occur and provoke symptoms. Water or 0.4 M KCl was placed intravesically into normal volunteers and interstitial cystitis (IC) patients. Water did not provoke symptoms in either group but KCl provoked 4.5% of normals and 70% of IC patients. Differences were significant (P < 0.0001). This test provides a valuable diagnostic tool for UFS and a valuable research tool to separate epithelial permeability problems from other subsets of patients. A third group, consisting of 11 IC patients in remission on heparinoid therapy, was also tested and only 18% were provoked by KCl. Four patients with radiation cystitis were also examined and all four (100%) were provoked by the potassium. PMID- 7833971 TI - Functional obstruction of the female urethra: relevance to refractory bed wetting and recurrent urinary tract infection. AB - A 20-year-old woman and 3 girls were referred to our urodynamic unit because of refractory bed wetting, recurrent urinary tract infection, and/or weak stream. All patients required extremely high detrusor pressure to evacuate urine, a mean of 116 cm of water. Urethral configuration was either a ballooning or a spinning top shape. Organic stenosis of the urethra was not detected by bougie a boule. Urodynamically, functional obstruction at the distal urethra was found to be an etiology of these symptoms. When the urethra was dilated with the Otis urethrotome, all patients were greatly benefitted both symptomatically and urodynamically without an adverse effect of urinary incontinence. We stress clinical importance of pressure flow study and fluoroscopic monitoring of the bladder and urethra when one encounters female patients with long histories of above symptoms. PMID- 7833972 TI - Detrusor-myoplasty, innervated rectus muscle transposition study, and functional effect on the spinal cord injury rat model. AB - The purpose of this investigation was to determine the feasibility of striated muscular augmentation of the urinary bladder (detrusor-myoplasty, DMP). Initial studies, transposition, and bladder wrap using several distinct muscle groups was attempted in laboratory rats, goats, and fresh human cadavers. The rectus abdominus muscle was found to be best suited to completely encompass the bladder with an intact neural and vascular supply. The technique was then applied in a rat model of spinal cord injury (SCI). Modified Tarlov ratings were employed to assess neurologic function 30 days after SCI. The median final neurological score of SCI rats with and without DMP was 4 and 5, respectively. Sham-operated SCI (control) rats, with and without DMP, both had normal final Tarlov scores of 12 (P < 0.05). Muscle blood flow values for the flap and the contralateral undissected rectus muscles were not significantly different (97 +/- 34 and 105 +/ 40 ml/100 g tissue/min, respectively, P = 0.47). Postoperatively, no bowel or abdominal wall functional deficits were apparent. The rotated muscular flap remained innervated and vascularized. Analysis of 24 hr micturition patterns demonstrated no differences in oral fluid intake/24hr, voided volume/24hr, and ratio of number of micturitions during the night vs. day among the four groups: (1) control (neither SCI nor DMP), (2) DMP only, (3) SCI only, and (4) SCI with DMP. Spinal cord injured rats with and without detrusor-myoplasty demonstrated a significant decrease in the number of micturitions/24hr, an increased volume per micturition, and greater largest and smallest micturition volumes (P < 0.05) when compared to controls. The micturition patterns among SCI rats with and without DMP were similar, as were non-SCI animals with and without DMP. This is the first report of the principle and technique of detrusor-myoplasty. Dissection of rats, goats, and human cadavers revealed that a vascularized and innervated rectus muscle flap can be rotated into the pelvis and wrapped around the bladder without tension. Significant loss of bladder capacity did not occur with skeletal muscle adaptation. Detrusor-myoplasty may be applicable for patients with an areflexic detrusor and non-intact sacral motor roots who are not candidates for sacral anterior root neurostimulation. PMID- 7833974 TI - Contractility of the guinea pig bladder measured in situ and in vitro. AB - To study the relative importance of neurogenic factors in detrusor contractility and to relate a total bladder in vitro contractility model to a previously described bladder wall strip model, active intravesical pressure values were compared in situ and in vitro in eight male guinea pigs. In situ, the active pressure was measured in spontaneous isometric and non-isometric micturition contractions. In vitro, the active pressure was measured in isometric contractions of the same bladders, developed in response to optimal electrical stimulation. The volume dependence of the active pressure generated by the bladder was measured in vitro in order to relate bladder capacity to the volume where the generated force is maximal and to determine the optimal volume at which to study detrusor contractility. The results indicated that in normal micturition the detrusor muscle was not fully stimulated: active pressure in isometric contractions in vivo was about 60% of the pressure values attained in vitro at the same bladder volume. Most micturitions occurred at a volume where the active pressure generated in vitro was about 80% of the maximal pressure. The active pressure-bladder volume relationship complied with the sliding filament-cross bridge theory. In whole bladder preparations active stress was about twice as high as in strips. PMID- 7833973 TI - Ultrasound diagnosis of bladder outlet obstruction in rabbits. AB - One of the primary characteristics of partial outlet obstruction secondary to BPH is an increase in bladder mass commonly referred to as bladder hypertrophy. This condition has been simulated in rabbits by the partial ligation of the catheterized urethra. Ultrasonography has been utilized in both adult and pediatric urology to visualize the bladder and diagnose specific bladder disorders. The aim of the present study is to determine if ultrasonography can visualize bladder wall hypertrophy induced by obstruction. Partial outlet obstructions were created in NZW rabbits using standard methodologies, and then 5 to 7 days later, sonography was performed. The films were read by both the principal investigator and blinded investigators instructed to determine bladder wall thickness and from this predict the bladder weight. Then results were correlated with cystometrograms (CMGs) and whole bladder weights. Both the principal investigator and the blinded investigators were consistently able to distinguish obstructed from control bladders based solely on sonographic depictions of relative bladder wall thickness. In addition, the investigators were able to distinguish between low (control), medium, and high bladder weights based on sonography. The accuracy of predicting the bladder weights increased when cystosonograms were correlated with CMG studies. Thus, the degree of bladder hypertrophy can be accurately estimated by the combination of cmg and ultrasonography. PMID- 7833975 TI - Elastic wall properties and collagen content in the ureter: an experimental study in pigs. AB - We used an impedance planimetric method to look at elastic wall properties of ureter in ten anaesthetized pigs. A balloon was stepwise inflated and deflated in the ureteropelvine junction, in the mid-ureter, and in the intramural part of the ureter at the ureterovesical junction with pressures up to 70 cmH2O, while the pressure and balloon cross-sectional area (Bcsa) were measured simultaneously. The elastic wall parameters were calculated from these measurements. At sacrifice, tissue samples were collected for analysis of collagen content of the ureteral wall. A non-linear clockwise relation (hysteresis loops) between Bcsa and balloon pressure was demonstrated. At maximal inflation of the balloon, the Bcsa, wall tension, and compliance were 35.28 +/- 3.52, 38.44 +/- 3.23, and 61.36 +/- 8.09 mm2, 230.71 +/- 12.82, 242.38 +/- 10.49, and 302.17 +/- 20.03 cmH2O x m, and 0.167 +/- 0.047, 0.124 +/- 0.002, and 0.182 +/- 0.040 mm2 x cmH2O-1 in the intramural part of the ureter, middle part, and ureteropelvine junction, respectively. The collagen content was 0.3249 +/- 0.0077, 0.3301 +/- 0.0066, and 0.3457 +/- 0.0060 mg x mg-1 dry defatted weight in the intramural part, in the middle, and in the ureteropelvine junction, respectively. The collagen content of the ureteropelvine junction was significantly higher than that of the middle of ureter (P < 0.02) and than that of the intramural part (P < 0.05). No significant correlations were found between the elastic parameters at maximal inflation of the balloon and the collagen content (P < 0.10). In conclusion the elastic wall properties were significantly different in the three ureteral segments and the collagen content of the ureteropelvine junction differed from that of the two distal locations. However, no relationship between the wall properties and the collagen content was found. PMID- 7833976 TI - Comparative studies on intracellular calcium and NADH Fluorescence of the rabbit corpus cavernosum. AB - Erectile function (erection and detumescence) involves the complex interaction of direct neuronal stimulation of corporal smooth muscle, neurohumoral release of specific endothelial contractile and relaxant factors, and secondary modulation by a variety of putative neuropeptides and vasoactive modulators. Using surface spectrofluorometry, we have correlated spontaneous contractile activity and the contractile response to field and pharmacological agents with intracellular calcium and NADH metabolism. The results demonstrate that the corpus cavernosal tissue has very unusual properties. Spontaneous contractile activity is correlated with a phasic increase in intracellular calcium. However, spontaneous contractile activity is most often correlated with a bi-phasic effect on the ratio of NADH/NAD. At the start of the spontaneous contraction, there is a sharp phasic increase in NADH/NAD; peak contractile force occurs simultaneous with a phasic decrease in this ratio showing that at peak force generation, there is a decrease in the level of intracellular energy. Phenylephrine stimulation results in an increase in intracellular calcium in proportion to the increase in tension; however, phenylephrine stimulation at low concentrations results in a net increase in the NADH/NAD ratio whereas high concentrations of phenylephrine result in a net decrease in the NADH/NAD ratio. In general, field stimulation results in a decrease in tension at low frequencies, a biphasic response at midfrequencies, and a contraction at high frequencies. These contractile responses are directly directly related to alterations in the intracellular concentration of calcium. That is, a decrease in tension is preceded by a decrease in intracellular calcium while an increase in tension is preceded by an increase in intracellular free calcium. Field stimulation results in a rapid and phasic alteration in the NADH/NAD ratio; however, the NADH/NAD response can be either an increase, decrease, or biphasic response. There does not appear to be a consistent relationship between the contractile/relaxant response to field stimulation and altered NADH/NAD ratio. Finally, ATP, bethanechol, and nitroprusside induce a decrease in the basal tension of the corpus cavernosal strips which corresponds with a decrease in the NADH/NAD ratio. However, whereas nitroprusside relaxation is correlated with a decreased intracellular calcium level, both ATP and bethanechol stimulate an increase in intracellular free calcium. These studies indicate that the response of the corpus cavernosal tissue to both field stimulation and pharmacological agents is complex and may involve both direct and indirect actions of a variety of cellular mediators on the corporal smooth muscle. PMID- 7833977 TI - Information technology in tomorrow's health care. PMID- 7833978 TI - Development of a clinical engineering knowledge-based system to facilitate departmental decision making. PMID- 7833979 TI - Patient-focused care: one hospital's implementation. PMID- 7833980 TI - Justifying and tracking BMET training. AB - We have outlined the importance of BMET training and how it is a crucial investment for not only the health care facility but also clinical engineering and individual BMETs. Training methods and funding mechanisms are also important aspects of the continuing education process. Being aware of the alternatives helps to achieve the goals of the clinical engineering program. We have also demonstrated management techniques of acquiring training, evaluating courses, and keeping statistics. Courstat manages statistics of training intensity among BMETs. This kind of tool provides managers with an overall picture of departmental expertise. PMID- 7833982 TI - Reduction of antigenic protein levels in latex gloves after gamma irradiation. AB - Gamma irradiation is currently the method most commonly used to sterilize surgical gloves. In this study, the effect of gamma irradiation on antigenic proteins in latex gloves was examined. Protein extraction and quantitation were carried out using latex gloves before and after sterilization. Antigenic protein levels were determined by an ELISA assay specific for latex proteins (LEAP). LEAP analysis revealed a significant decrease after gamma-irradiation sterilization. This observation may partially explain the lower levels of extractable antigenic proteins found in sterile surgical gloves compared with nonsterile examination gloves. However, gamma irradiation was less effective than autoclave sterilization in reducing protein levels. PMID- 7833981 TI - Vibration in metal and non-metal incubators. AB - The purpose of this study was to determine the amount of vibration transmitted to the surface of an incubator mattress. Empty incubators with metal (n = 12) and non-metal (n = 12) bases were monitored for vibration levels when the incubators were turned "off" and when they were turned "on." High levels of low-frequency vibration were detected in both types of incubators in both conditions. The metal incubators transmitted significantly less vibration to the mattress than did the non-metal incubators at several frequencies in the "off," the "on," and the "adjusted" conditions. These results suggest that infants experience significant whole-body vibration while lying in incubators. PMID- 7833984 TI - Critical care help for Estonia and Ukraine. PMID- 7833983 TI - A simple portable ocular light device for phototherapy of seasonal affective disorder. AB - The authors report the development and a safety and acceptability study of a portable ocular light device, the SADlite. The study was conducted in 15 adult patients who had seasonal affective disorder (SAD). Each patient was given three two-week "on" phototherapy periods alternating with three two-week "off" periods. The SADlite provides 8,000 lux. Thirteen (13) of the 15 patients were completers and, as a group, achieved impressive clinical and statistically significant improvement (p < 0.0001) on three standard outcome measures. The SADlite was well tolerated, produced no adverse visual effect, and was preferred by patients previously exposed to stationary phototherapy devices. PMID- 7833985 TI - [Use of Cefuroxime as antibiotic prophylaxis in the surgical management of scoliosis]. AB - Cefuroxim treatment as antibiotic prophylaxis was used in the operative treatment of the scoliosis. It was found that this antibiotic was an effective drug. There was't any postoperative suppuration and no side effect of the Cefuroxim was registered. PMID- 7833986 TI - [Perioperative antibiotic prophylaxis in orthopedics]. AB - This study outlines the special connection between hip endoprosthesis implantation and the dangers of surgical infections. It surveys in detail the theoretical and practical aspects of perioperative antibiotic prophylaxis. On the basis of 85 cement hip prosthesis the author summarize the characteristics of the second generation Cephalosporins and give an account of their favourable results achieved by the use of Zinacef injection. PMID- 7833987 TI - [Prophylactic use of Zinacef in orthopedics]. AB - Authors give a brief summary on necessity of antibiotic prophylaxis in orthopaedics, pointing out the hip, knee arthroplasty and the spinal fusion with Steffee plate. They introduce the applied antibiotic, called Zinacef and it's antibacterial spectrum and the way in prophylaxis is discussed. No any septic complication was observed out of one thousand surgical interventions. PMID- 7833988 TI - [Antibiotic prophylaxis in orthopedic surgery]. AB - In orthopaedics where a great number of implants are in use, the chance for infection is high. To keep up the aseptic condition and giving antibiotic in the perioperative time is necessary. According to the effect on postoperative bleeding authors did compare two second generation cephalosporin, the cefamandol and the cefuroxim, which are mainly used in antibiotic prophylaxis. The gamma carboxylation of glutaminic acid is inhibited by cefamandol in the liver, which is necessary in the prothrombin synthesis. The cefuroxim is without any effect on prothrombin synthesis. The postoperative bleeding was significantly higher following cefamandol administration. According to the authors in orthopaedics, where the blood loss could be high, that type of antibiotic prophylaxis is recommended, which has no effect on bleeding. PMID- 7833989 TI - [Management of Achilles tendon injuries in our department]. AB - Authors introduce the different methods in the treatment of Achilles tendon injury, including the "ordinary" surgical technique and the new method, using Tissucol. They point out the importance of indication and proper rehabilitation. Concerning the results and the complications they give evaluation of 98 patients. PMID- 7833990 TI - [Preliminary experience with gamma nails]. AB - Good fixation, ability for full weight-bearing in most of the cases, closed surgical technique-these are the advantages of lately developed intramedular osteosynthesis for instabil pertrochanteric and subtrochanteric fractures, called gamma nailing. These advantages do make the general and local complications less and do help the fast rehabilitation. Authors give report on 28 patients, were operated on with gamma nailing within the last 1.5 year. Local complication, infection, loosening, breakage, pseudoarthrosis was not observed. The healing was complete in all evaluated cases. 2/3 of the patients had full weight-bearing following surgery. According to the authors the results are very good in the cases of instabil subtrochanteric and pertrochanteric fractures, therefore the method is highly recommended in similar cases. PMID- 7833991 TI - [Possibilities of autologous bone transplantation]. AB - The classical autologous bone transplantation is introduced by the author. Summary is given on the advantages, disadvantages of this method and on the personal experience. The personal experience based on 55 cases from 49 patients. Concerning the clinical result, 3.5 months average healing time was observed, followed by autologous bone transplantation. The final outcome was not affected by the amount of transplanted bone. The message of this publication is to introduce the disadvantages and the limitation of using this classical method. The most frequent complication was the donor site pain. The publication is summarizing the advantages and the disadvantages of this method in Hungary for the first time. PMID- 7833992 TI - [Experience with the surgical correction of restricted movement of the knee joint]. AB - Authors treated 34 patients from 1989 to 1992 with restricted knee movements in the Department of Sport Medicine. The average age of the patients was 32 years, the youngest was 16 and the eldest was 54 years old, and the female male ratio was 14/20. 71% of the patients had some kind of ligament surgery in the past. Arthrolysis was performed in 24 cases. 13 cases out of 24 was performed arthroscopically and the rest was done following arthrotomy. Manipulation under anaesthesia was satisfactory in 5 cases, 4 patients had combined treatment and 1 had extraarticular intervention only. The range of motion was 0-11-81 degrees to start with, and it has improved up to 0-2-124 degrees in average 13 month time following the arthrolysis. There was correlation between the restriction and between the time of primary ligament reconstruction, the sex and the age of the patients. To perform the arthrolysis in time is important and the physiotherapist and the constant passive motion is inevitable. PMID- 7833993 TI - [Prognostic evaluation of the classification of distal radius fractures]. AB - Authors give historical review of different classifications in the cases of distal radial fractures. They give analysis on advantage and disadvantage of three different classifications, based on 633 cases, according to the practical applicability, to the expected outcome and to the way of treatment. According to the analysis the Older classification gives good prognosis, but the Frykman classification is without any practical importance. The AO classification is prognostically more or less satisfactory. PMID- 7833994 TI - [Early experience with total shoulder arthroplasty]. AB - The author gives a report on the indication, on the surgical technique and on the results of shoulder arthroplasty, following 30 porous coated, unconstrained, BIO MODULAR total endoprothesis were implanted. The pain, which was uncurable with any other methods, was relieved by implanting the total shoulder prosthesis. The functional result is determined by the condition of rotator cuff and by the way of reconstruction, rehabilitation and cooperation of the patients. The experience in soft tissue surgery is absolute necessary to be successful. PMID- 7833995 TI - [Complex bilateral breast reconstruction using a bipedicled flap under intraoperative angiographic control]. AB - The authors report cases of complex bilateral autologous breast reconstruction performed at one sitting after bilateral ablation as a result of non-malignant disease. During planning, as well as execution of the operations, up-to-date pre- and intraoperative examinations were employed in order to enhance to safety of the procedures. PMID- 7833996 TI - [The lateral supramalleolar fasciocutaneous flap and its modification]. AB - The author gives a report on the lateral supramalleolar fasciocutan flap, supplied by the a. peronea perforans, according to Maquelet and the Valenti's modification is introduced as well. The indications are discussed on the experience of two cases, treating calcaneal skin defect. PMID- 7833997 TI - [Idiopathic heterotopic ossification]. AB - Three cases of localized, benign heterotopic ossification, occurred in the hip joint region, are presented. The aspects of the pathogenesis, differential diagnosis and prognosis are briefly discussed. PMID- 7833998 TI - [Callus luxurians in osteogenesis imperfecta]. AB - A case is introduced with osteogenesis imperfecta, suffered from left femoral fracture and a consecutive hypertrophic callus formation, with extreme swelling on the thigh. Concerning the laboratory tests the only significant difference was the elevation in alkaline phosphatase activity and a moderate elevation in ESR. The case is reported because of it's accidental appearance. PMID- 7833999 TI - To know what we do. PMID- 7834000 TI - Sexual harassment of critical care nurses: a costly workplace issue. AB - BACKGROUND: Sexual harassment in the workplace is a prevalent form of impermissible sex discrimination in employment. The high profile of this issue in the media, together with laws prohibiting sexual harassment, have not prevented this problem for working nurses. OBJECTIVES: To describe and determine the extent of sexual harassment incidents experienced by nurses working in critical care areas, and to determine attitudes about, and presence of policies regarding, sexual harassment in hospitals. METHODS: For this descriptive study the federal government's definition of sexual harassment and a list of sexually harassing behaviors was mailed with a survey to 188 critical care nurses. RESULTS: Findings indicated that 46% of the respondents had been harassed. Offensive sexual remarks (56%), unwanted physical contact (53%), unwanted nonverbal attention (27%), requests for dates (16%), and sexual propositions (9%) were types of sexual harassment experienced. Sexual assault was experienced by one woman. Harassers were physicians (82%), coworkers (20%), or immediate supervisors (7%). A majority of the incidents (69%) were not reported. Most nurses (80%) had not received training, nor were there policies and procedures to follow in most cases for reporting harassment. CONCLUSIONS: These results suggest that many critical care nurses are harassed and that relatively few hospitals have sexual harassment policies known to employees. They also indicate that sexual harassment training, policies, and procedures are needed to provide a safe, healthy work environment for critical care nurses. PMID- 7834001 TI - Weaning from mechanical ventilation: concept development. AB - This article, the first in a series, is written to clarify the process of weaning from mechanical ventilation and to promote the development of a common language for understanding the complex weaning process. The Third National Study Group on Weaning From Mechanical Ventilation proposes a conceptual model and definitions that will provide a framework for future research on this important topic. This conceptual framework describes the preweaning phase, the weaning process, and the outcome phase of mechanical ventilation. Potential outcomes are completion of weaning, lack of completion, and terminal weaning. The weaning decision continuum incorporates: (1) when and how to begin the weaning process, (2) how to select therapies to assist with difficult weaning and chart progress during weaning, and (3) when to stop weaning if progress is no longer being made. An inherent assumption of this model is that each patient will display unique responses to the weaning process. The proposed conceptual framework and definitions provide a foundation for developing clinical practice guidelines and for guiding future ventilator weaning research. PMID- 7834002 TI - Weaning from short-term mechanical ventilation: a review. AB - The purposes of this article are to: identify gaps in the research literature on weaning adult patients from short-term mechanical ventilation, highlight the scientific base for practice guidelines, and suggest future research directions. Data bases from 1989 through June 1993 were reviewed, and relevant research articles were extracted, analyzed, and synthesized within the AACN Third National Study Group framework. Seminal work and other supportive literature also were used in this review. Despite considerable research on predictors and patient responses to weaning from short-term mechanical ventilation, few of the findings can be applied to clinical practice at this time. Less research is available on weaning modes and therapies that facilitate weaning from short-term mechanical ventilation; fruitful research in these areas depends in part on a better understanding of patient responses and accurate weaning predictors. PMID- 7834003 TI - Endotracheal saline and suction catheters: sources of lower airway contamination. AB - BACKGROUND: Normal saline instillation prior to endotracheal suctioning is a critical care ritual that persists despite a lack of demonstrated benefit. Saline instillation may dislodge viable bacteria from a colonized endotracheal tube into the lower airway, overwhelming the defense mechanism of immunocompromised patients. OBJECTIVE: To determine the extent to which normal saline irrigation and suction catheter insertion dislodge viable bacteria from endotracheal tubes. METHODS: Endotracheal tubes from 10 critical care patients intubated for at least 48 hours were obtained immediately after extubation. Each tube was used in random order for both saline instillation and suction catheter insertion. Dislodged material was cultured for quantitative analysis. RESULTS: Suction catheter insertion dislodged up to 60,000 viable bacterial colonies. A 5-mL saline instillation dislodged up to 310,000 viable bacterial colonies. CONCLUSIONS: The potential for infection caused by dislodging bacteria into the lower airway is additional evidence that routine use of saline during suctioning procedures should be abandoned. PMID- 7834004 TI - Defining unnecessary disinfection procedures for single-dose and multiple-dose vials. AB - BACKGROUND: Recommendations in the literature conflict on the necessity of disinfecting single-use vials prior to aspiration of fluid. Interventions to disinfect the stopper surface on multiple-dose vials vary considerably. OBJECTIVES: To determine the necessity of alcohol disinfection of the stopper on single-dose vials and to compare povidone-iodine and alcohol versus alcohol-only disinfection of the stopper prior to each needle penetration on multiple-dose vials. METHODS: The rubber stopper surfaces of 100 single-dose vials were cultured for the presence of bacteria. To determine the efficacy of two procedures for disinfection of multiple-dose vials, 87 stopper surfaces routinely disinfected with both povidone-iodine and alcohol were cultured for bacteria. After a change in practice, 100 multiple-dose vials routinely disinfected with alcohol only were cultured for the presence of bacteria. RESULTS: Of the cultures done on single-dose vial stoppers, 99% were sterile. A comparison of the two disinfection techniques for multiple-dose vials revealed that 83 (95%) of the 87 vials prepped with both povidone-iodine and alcohol were sterile, compared with all stoppers disinfected with alcohol only. CONCLUSIONS: This study shows the lack of necessity of any disinfection procedure on the rubber stopper of single dose vials and the efficacy of alcohol only for disinfecting the stopper of multiple-dose vials. PMID- 7834005 TI - Use of extracorporeal photochemotherapy in heart transplant recipients during acute rejection: a case study. AB - Despite the growing availability of improved immunosuppressive agents, acute and chronic rejection episodes remain a major complication in heart transplant recipients. The rejection of allografts is a normal part of the body's response to foreign antigens. The key to controlling this response is to administer a regimen of multiple immunosuppressive drugs. Evidence indicates that by adding extracorporeal photochemotherapy to a standard immunomodulatory regimen, the rejection process can be reversed without significantly increasing patient risk. In this case study we examine extracorporeal photochemotherapy and the care of patients receiving this therapy. PMID- 7834006 TI - Tachycardia-induced cardiomyopathy: a case study. PMID- 7834007 TI - Severe insulin resistance treated with plasmapheresis: case report and discussion. PMID- 7834008 TI - Oxazepam overdose associated with ethanol ingestion: treatment with a benzodiazepine antagonist. PMID- 7834009 TI - Effect of do-not-resuscitate orders on the nursing care of critically ill patients. AB - BACKGROUND: The effect of a do-not-resuscitate order on the standard of care of critically ill patients is of concern to practitioners, patients, and their families. Because "do not resuscitate" may be misconstrued to include more than "no cardiopulmonary resuscitation," it may influence the aggressiveness with which some patients are managed. Nurses play a central role in determining standards of care. Hence, confusion on their part as to the meaning of this term can have a significant impact on patient care. OBJECTIVES: To compare nurses' attitudes about standards of care for critically ill patients with and without a do-not-resuscitate order. METHOD: A quasi-experimental design using simulation measurement was used for this study. RESULTS: Nurses reported that they would be significantly less likely to perform a variety of physiologic monitoring modalities and interventions for patients with a do-not-resuscitate order than for patients without such an order. Patients with a do-not-resuscitate order were more likely to receive psychosocial interventions including assessment of their spiritual needs and more flexible visiting practices. CONCLUSIONS: Our findings suggest that "do-not-resuscitate" may be misinterpreted to include more than "no cardiopulmonary resuscitation" even if the patient is receiving aggressive medical management. Misinterpretation of orders not to resuscitate may be related to a variety of factors including lack of understanding about hospital policy and ethical and moral values of the staff. We suggest replacing orders such as "Do not resuscitate" with clearly defined resuscitation plans that are jointly determined by the multidisciplinary team, patient, and family. PMID- 7834010 TI - Organ donation and the rural critical care nurse. AB - BACKGROUND: Less than 20% of people who meet the criteria for organ donors are estimated to donate organs. OBJECTIVE: To examine the knowledge and attitudes of rural critical care nurses regarding organ donation. METHODS: Forty-six critical care nurses from a southwestern medical center provided data for this study. Self reported knowledge and attitudes were measured using the Organ Donor Attitude Questionnaire and compared with respondents' demographic characteristics. RESULTS: Knowledge scores were found to be average (74% correct). Attitude scores reflected a strongly positive attitude toward organ donation. Increased knowledge of organ donation was not found to be related to a positive attitude. However, both attitude and knowledge were found to be positively correlated with previous experience in caring for either organ donors or recipients. Results were compared with data collected in an urban setting and found to be similar. CONCLUSIONS: Results of this study indicate that exposure to patients affected by organ procurement increased knowledge and improved attitudes of the nurses who provided care. Increased knowledge and positive attitude are important when providing support to families and caring for potential donors. These factors could increase the supply of donors for transplants, which is a goal of the organ procurement process. PMID- 7834011 TI - Heart rate variability: prognostic implications. AB - HRV offers information about sympathetic and parasympathetic autonomic function and thus can serve as a measure of risk stratification for serious cardiac arrhythmias and sudden cardiac death. HRV appears to be altered in patients with acute myocardial infarction or diabetic neuropathy and is affected by other physiologic and pathophysiologic processes. Use of HRV measurements requires continued investigation to determine optimal methods and tools by which HRV indices and its variables are analyzed. Long-term studies are required to help correct for differences in values pertaining to age and disease process. Also, studies are needed to determine how patient management strategies will be affected by knowledge gained through HRV analysis and to determine which patient populations should be monitored for HRV analysis and to identify those at risk for sudden cardiac death. PMID- 7834012 TI - Localization of metallothionein in the mammalian central nervous system. AB - This review concerns the immunohistochemical localization of metallothionein (MT), a metal-binding protein, in the mammalian central nervous system (CNS). Expression of MT in the mammalian CNS is abundant. In the mouse brain, MT expression is found in some glial cells, whereas in the adult rat brain immunoreactivity varies from no expression at all to abundant reactivity throughout the whole brain. In primates and humans, MT expression is mainly found in astrocytes. Thus, MT expression in the mammalian CNS is found in the pia arachnoid, ependymal cells and astrocytes. Cells expressing MTs can, in this way, supply essential metals to neurons and may protect neurons against toxic ions. PMID- 7834013 TI - Metallothionein in developing human brain. AB - Localization of metallothionein (MT) in the developing human brain was investigated by immunohistochemical techniques. Fetal brain at 21 weeks showed no MT expression. In 35-week-old fetuses, glial cells in the gray matter showed MT expression in the nucleus and perinuclear cytoplasm, but glial cells in the white matter showed MT not only in the nucleus and perinuclear cytoplasm but also in glial processes. At 40 weeks, glial cells in gray and white matter expressed immunoreactive MT in the nucleus, cytoplasm and glial processes. Blood vessels were positive for MT. In the infant brain, there were clear differences in glial cells between protoplasmic and fibrous astrocytes; their nuclei, cytoplasm and processes were positive for MT, but the MT-positive glial processes of protoplasmic astrocytes were fine. In the child, typical protoplasmic astrocytes in gray matter and fibrous astrocytes in white matter were observed and their nuclei, cytoplasm and glial processes were positive for MT. Pia mater and blood vessels expressed MT in infants and children. PMID- 7834015 TI - Brain metallothionein in stress. AB - Brain metallothionein (MT) levels have been measured in the rat brain in basal and stress situations with polyclonal antibodies which do not cross-react significantly with the brain-specific MT isoform growth inhibitory factor (MT III). Acute immobilization stress increases MT levels in most but not all brain areas. In contrast, chronic immobilization stress has no effect on MT levels. Although glucocorticoids and monoamines appear to have a role in brain MT regulation in control rats, they do not appear to have a vital role in stressed rats. Experiments with primary cultures enriched in neurons or astrocytes indicate that MT is present in both cell types and that responds to the well known MT inducers zinc, copper and glucocorticoids. PMID- 7834014 TI - Metallothionein in amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by loss of motor neurons in the spinal cord, brainstem and motor cortex. Ten percent of the cases are familial and these have been linked to point mutations in the gene coding for cytosolic copper, zinc superoxide dismutase. The etiology of sporadic ALS is unknown. To further investigate the possible role of metals in causing the disease, we investigated metallothionein (MT) levels in ALS organs and serum. We previously reported significantly increased MT levels in ALS liver and kidney. These are not reflected in serum MT levels, which are normal in ALS. In ALS spinal cord, MT is expressed in gray matter protoplasmic astrocytes. Induction of MT synthesis in ALS may denote increased metal exposure or may result from increased oxidative stress, as in familial ALS. PMID- 7834016 TI - Growth-inhibitory factor, metallothionein-like protein, and neurodegenerative diseases. AB - Growth-inhibitory factor (GIF), which is deficient in the Alzheimer's disease brain, is a 68-amino-acid metallothionein-like protein. GIF is expressed in the central nervous system but not in peripheral tissues including dorsal root ganglion. GIF is immunocytochemically distributed in Bergmann's glia in the cerebellum and astrocytes in the neocortex, hippocampus, striatum, brain stem, and spinal cord. Strong GIF immunoreactivity is localized in astrocyte cell bodies and fine long processes, which are closely associated with neural perikarya and dendrites, such as layers 2-6 of cerebral gray matter, the molecular layer of the dentate gyrus, the pyramidal layer of the hippocampus and spinal gray matter. GIF is induced in reactive astrocytes in the cerebral cortex in cases of meningitis and Creutzfeldt-Jakob disease or in reactive astrocytes surrounding old cerebral infarcts. On the other hand, GIF is reduced in the subset of reactive astrocytes in lesioned areas of degenerative diseases such as Alzheimer's disease, multiple-system atrophy, Parkinson's disease, progressive supranuclear palsy and amyotrophic lateral sclerosis. Reduction of GIF is correlated with neuronal loss. Thus, perturbation in normal neuroglial interaction in degenerative diseases may lead to a reduction of GIF in reactive astrocytes. PMID- 7834017 TI - Frozen shoulder. PMID- 7834018 TI - Knee meniscal transplantation. PMID- 7834019 TI - The effect of exercise on immune function. PMID- 7834020 TI - [Research and practice in family care. Intelligence and heart]. PMID- 7834021 TI - [Learning with the families]. PMID- 7834022 TI - [Inducing the change: understanding the nature of the problem]. PMID- 7834023 TI - [A tool which can also help mothers]. PMID- 7834024 TI - [Health and marriage: what do elderly couples think of it?]. PMID- 7834025 TI - [When the aged take care of themselves]. PMID- 7834026 TI - [The consumption of psychotropic drugs by the aged]. PMID- 7834027 TI - [Evaluation of a validation group on communication of elderly patients with irreversible cognitive deficiencies]. PMID- 7834028 TI - [Claudette Seyer: tightly woven family ties. Interview by Claire Chabot]. PMID- 7834029 TI - [Health care and spiritual care; an holistic approach written into the law]. PMID- 7834030 TI - [The new baccalaureate of the University of Quebec at Chicoutimi is taking off]. PMID- 7834031 TI - [Removing the premature from the incubator. From the traditional method to the kangaroo method]. PMID- 7834032 TI - [My little Amelie, in my arms at last!]. PMID- 7834033 TI - Searching for identity on the front lines (telephone lines, that is) PMID- 7834034 TI - [Schizophrenia. Increasing the means of nursing interventions]. PMID- 7834035 TI - [The CII and geronto-geriatric research]. PMID- 7834036 TI - [Short and mid-term outcome of a cohort of 1157 newborn infants with respiratory distress syndrome]. AB - BACKGROUND: Data concerning neonates with acute respiratory distress syndrome (RDS) are still scarce. The characteristics and follow-up of a French cohort which has participated in an international trial concerning the efficacy of artificial surfactant have been studied. POPULATION AND METHODS: One thousand one hundred and fifty-seven neonates admitted from October 1990 to December 1991 in 27 French intensive care units because of RDS due to hyaline membrane disease were included in the study, whatever their birthweight and gestational age (GA). RESULTS: Three hundred and sixteen neonates (27.3%) were born from twin or multiple pregnancies. Fourty-five (5.5%) of the mothers had been given corticosteroids for the week preceding delivery. 55.5% were delivered by cesarean section. Mean GA was 31.0 +/- 2.9 weeks and mean birth-weight was 1,603 +/- 625 g. Two hundred and sixty-six neonates (23%) were small for GA. Two hundred and twenty-three died after a mean survival of 4.2 days (63% before the end of the first week and 80% before the end of the third week). Fifty percent of these deaths were due to respiratory distress, 28% to severe brain disorders and 9% to infections. The bronchopulmonary dysplasia rate was 21.7%. Early ultrasound scan of the brain showed major injuries in 19.5% of cases; the second scan performed in 822 infants was normal in 84.3%. CONCLUSIONS: Taking into account GA, mortality and morbidity rates were similar to those of the other non-French participating centres. PMID- 7834037 TI - [Small intestine ulcers 12 years after ileosigmoid anastomosis for neonatal necrotizing enterocolitis]. AB - BACKGROUND: Ileal ulcers can be seen several years after surgery for neonatal necrotizing enterocolitis. They may be due to chronic bacterial colonisation of the intestine. CASE REPORT: A 12 year-old boy admitted suffering from chronic severe anemia (hemoglobin 6.5 g/dl), hypochromic and microcytic. Digestive bleeding was negative and the patient was successfully given iron for 6 months. Anemia was found again several months after cessation of treatment. Rectosigmoidoscopy showed several ulcers with inflammatory mucosa, near anastomosis secondary to an extensive bowel resection due to necrotizing enterocolitis. Ulcers of the distal small bowel persisted despite mesalazine and iron therapy and required resection of the intestine on both sides of the anastomosis. A few months later, recurrence of both ulcers and anemia led to the search for bacterial overgrowth which was confirmed by breath hydrogen testing. The patient was then given metronidazole plus amoxicillin by alternate courses and is well one year later. CONCLUSIONS: Chronic bacterial colonization can be responsible for ileal ulcers several years after intestinal resection, requiring a prolonged controlled follow-up. PMID- 7834038 TI - [Use of tissue plasminogen activator in the treatment of aortic thrombosis in newborn infants]. AB - BACKGROUND--Aortic thrombosis is more frequent since the use of umbilical artery catheters in neonatal intensive care units. Some drugs or surgery are proposed to prevent complications; experience with tissue plasminogen activator (tPA) is still limited. CASE REPORT NO 1--A neonate, weighing 2400 g, developed respiratory distress requiring insertion of a catheter into her umbilical artery at H12. Ultrasonography on day 3 showed aortic thrombosis extending to the right renal artery which was confirmed by angiography. tPA 0.1 mg/kg was administered through the catheter, followed by 0.3 mg/kg/h for 3 hours and heparin, 100 IU/kg/hour for 54 hours. Angiography, performed 18 hours later, showed complete disappearance of the thrombosis. CASE REPORT NO 2--A neonate, weighing 2520 g suffered at 12 hours of life from seizures, apnea and bradycardia which required insertion of a catheter into her umbilical artery. Cyanosis of the right leg with weakening of femoral pulsations, 14 hours later, lead to the diagnosis of aortic thrombosis which was confirmed by aortography. The patient was given tPA 0.1 mg/kg followed by 0.3 mg/kg/h for 3 hours and heparin 100 IU/kg/hour for 6 hours. Amplitude of femoral pulsations strikingly increased within 6 hours with the disappearance of cyanosis. CONCLUSION--These results suggest that tPA can be useful in neonates presenting with aortic thrombosis. PMID- 7834039 TI - [Laparoschisis: a familial form]. AB - BACKGROUND--Familial cases of gastroschisis are exceptional. CASE REPORT NO. 1--A boy was admitted at birth suffering from gastroschisis. Surgical repair was done but the patient died on day 24 with septicemia. CASE REPORT NO 2--Fifteen years later, gastroschisis was discovered by ultrasonography in a male fetus (GA = 26 weeks). Successful surgical repair was done just after the birth at a normal term. Mothers of both cases were sisters. CONCLUSIONS--The rare familial cases of gastroschisis have been seen in sibships. This is the first familial case seen in first cousins. PMID- 7834040 TI - [Sulfite oxidase deficiency presenting as Leigh syndrome]. AB - BACKGROUND: An enzyme deficiency can be demonstrated in 15 to 20% of cases of Leigh syndrome. A case of isolated sulphite oxidase deficiency is reported in a girl presenting with Leigh syndrome. CASE REPORT: An 8 month-old girl was admitted suffering from hypotonia and slow increase of head circumference (-1 SD). Examination showed spastic quadriplegia, dyskinesia, axial hypotonia and difficulties in swallowing. The patient had a coarse face, broad nasal bridge, long philtrum and ectopia lentis. Brain CT scan showed bilateral hypodensity of lenticular nuclei and moderate cortical atrophy. Amino acid chromatography showed accumulation of S sulfocysteine and low levels of cysteine. The sulphite test was positive. Sulphite oxidase activity in fibroblasts and liver was undetectable contrasting with a normal activity of xanthine oxidase. Progressive brain damage led to death at 1 year of age. Prenatal diagnosis of sulphite oxidase deficiency was made in two further pregnancies. CONCLUSIONS: The search for sulphite oxidase deficiency must be included in discussing the etiology of Leigh syndrome; the sulphite test is a simple method of screening such cases. PMID- 7834041 TI - [Late declaration of pregnancy: an indicator of psychosocial vulnerability of the family]. AB - Social, economical and family characteristics were studied in 90 women who notified their pregnancy beyond the French legal recommended limit of 3 months (LNP). The development of the children born from these pregnancies was also studied. A group of women notifying their pregnancy within the legal limit of 3 months served as a control. The data were collected at home by nurses from the Service de Protection Maternelle et Infantile visiting the family at the time of notification of the pregnancy and at ages 4, 12 and 36 months. The results showed frequent psychological, economical and social disabilities of women with LNP, presenting high rates of unemployment, low income, unusual ages of pregnancy (44% before 20 years and after 35 years), absence of father, consideration of voluntary interruption of pregnancy. Their offspring had a frequent unfavourable family environment, but their development did not show significant differences at 3 years of age as compared with children of the control group: however they presented signs suggesting a greater vulnerability, and especially frequent language and behaviour disturbances. From these data LNP appears as an indicator of psycho-social vulnerability of the family. Therefore LNP should lead to a systematic visit of the family at home by a social worker in order to assess its degree of psycho-social vulnerability and to provide, when necessary, preventive action directed towards the protection of the child development. PMID- 7834042 TI - [Radiological case of the month. Synovial osteochondromatosis]. PMID- 7834043 TI - [Dental caries after repeated administration of pediatric syrups]. PMID- 7834044 TI - [Leukemoid reaction and typhoid fever]. PMID- 7834045 TI - [Multifactorial heredity and common diseases]. PMID- 7834046 TI - [What glycemic control can be achieved in young diabetics without residual secretion of endogenous insulin? What is the frequency of severe hypoglycemia and subclinical complications?]. AB - BACKGROUND: Successful therapeutic management of the child and adolescent with diabetes mellitus requires insulin administration, dietary management, physical activity and physical fitness, and emotional support. The ultimate aim is to avoid long-term microvascular, renal and neurologic complications by maintaining blood glucose concentrations close to the normal range. We determined the mean annual glycosylated hemoglobin levels (HbA1c) that can be achieved in young diabetic patients without residual insulin secretion. POPULATION AND METHODS: One hundred and twenty-nine patients aged 17.7 +/- 6.4 yr (m +/- SD) were followed sequentially for 1 year by the same pediatric diebetologist. They had a diabetes duration from 2 to 27 yr (mean: 9.7). Mean age at onset of diabetes was 8.1 +/- 3.7 yr. C-peptide was undetectable in all patients. Subclinical retinopathy, neuropathy and nephropathy were looked for in all patients. HbA1c was measured by an HPLC method (normal range: 4.4-6.0%) at each visit (6.6 +/- 1.9 visits/yr/patient). RESULTS: Mean (SD) annual HbA1c levels were 6.9 +/- 1.5%, ie 115% of normal values. The frequency of monthly home blood glucose monitoring (HBGM) was between 0 and 250 measurements (77 +/- 49). HbA1c was not related to sex, ethnicity, age, and duration of diabetes. There was no difference between the 84 patients on only two or three daily insulin injections (aged 15.1 +/- 5.6 yr with a diabetes duration of 7.5 +/- 5.2 yr), and the 45 patients on four injections using the basal bolus regimen (aged 22.5 +/- 5.2 yr with a diabetes duration of 13.7 +/- 5.5 yr). The regression analysis showed a weak but significant inverse correlation between HbA1c and frequency of HBGM as well as frequency of outpatient clinic attendance. The yearly incidence rates of severe hypoglycemia were 0.10 in the two injection group and 0.31 in the four injection group without relationship to HbA1c levels. Frequency of subclinical complications was 15% for nephropathy, 31% for neuropathy and 39% for retinopathy. The minimum age at which incipient complications appear was 13 yr for one complication, 17 yr for the association of two complications, 23 yr for the association of three, after a diabetes duration of 3, 7, 15 yr, respectively. CONCLUSIONS: In 30% of young diabetic patients without residual insulin secretion, it is possible to obtain mean annual HbA1c levels within the normal range. Increased frequency of HBGM and of clinic attendance help to reduce HbA1c levels. In contrast, multiple insulin injection therapy, allowing more freedom for diet, does not necessarily improve metabolic control and is associated with a higher incidence of severe hypoglycemic episodes. Incipient complications have to be looked for by sensitive methods from puberty. PMID- 7834047 TI - [Health and factors associated with glycemic control in 165 children with insulin dependent diabetes, aged 7-23 year]. AB - BACKGROUND: A multicenter cross-sectional study was the first step of a project aimed at performing an educational diagnosis for IDDM children in France. POPULATION AND METHODS: Inclusion criteria were age 7 to 13 years, IDDM duration > 6 months and to be followed in a university pediatric department. One hundred and seventy-three children, followed in six centers, were eligible. One hundred and sixty-five of them (age 10.2 +/- 1.9 years and IDDM duration 3.1 +/- 2.7 years) agreed to participate. Standardized questionnaires were completed by the parents and children. Clinical examination was performed and a medical questionnaire was completed by the usual diabetologist of children. HbA1c was measured using a single HPLC method (normal levels +/- 2 sd = 4.5 to 5.7%). RESULTS: Mean HbA1c was 8.3 +/- 1.6% (range 5-13.2%) and values were distributed as follows: < or = 7% for 24.5%, < or = 8% for 46.6% and > 10% for 14% of the children. Age (r = 0.33, P < 0.001), duration of diabetes (r = 0.29, P < 0.001), number of biochemical hypoglycemias (r = -0.21, P < 0.01) and cholesterol level (r = 0.31, P < 0.001) were correlated with HbA1c levels and accounted for 30% of the variance in predicting HbA1c. The difference of HbA1c levels between prepubertal and pubertal children was significant (P < 0.02). Other usual clinical parameters as well as indexes for diabetes monitoring were not significantly correlated with HbA1c. In addition, four subgroups were associated with a significant deterioration (delta > or = 1%) in mean HbA1c levels: 1) age > 10 years (n = 82, P < 0.01); 2) pubertal stage in girls (Tanner stages III vs I, P < 0.05); 3) IDDM duration > or = 2 years (n = 106, P < 0.001); 4) a non French native mother (n = 27, P < 0.001). CONCLUSIONS: Only 50% of this group under specialized care had an acceptable level of glycemic control (HbA1c < or = 8%). Factors related to glycemic control were identified, as well as subgroups of children at particular risk for bad glycemic control which requires specifically targeted interventions. The analyse of sociodemographic, psychological, familial and cognitive factors is currently being conducted in this population, in order to find other explicative variables of glycemic control and to develop specifically targeted educational programs. PMID- 7834048 TI - [Persistent mullerian duct syndrome (males with uterus): a pediatric problem]. AB - BACKGROUND: The persistent mullerian duct syndrome (PMDS) is characterized by the persistence of the uterus and Fallopian tubes in otherwise normally virilized boys. Its diagnosis is usually made during a surgical procedure for inguinal hernia or cryptorchidism. We report six recent cases of PMDS, in which we have studied anti-Mullerian hormone (AMH) serum levels. CASE REPORTS AND METHODS: Six boys including three brothers were operated on for cryptorchidism or inguinal hernia. Surgical exploration showed persistence of the uterus and Fallopian tubes in patients having normal 46, XY karyotype and male gonads. The AMH serum levels were measured by Elisa and the AMH gene by single strand conformation polymorphism of PCR products. RESULTS: The three brothers showed a mutation in the AMH gene which leads to the replacement of leucine by proline at position 70 and to a defect in AMH production. In two other patients, serum AMH values were normal, no mutation on the AMH gene was found, and end-organ insensitivity was suggested to explain the persistence of mullerian derivatives. In the last patient, although AMH serum levels were very low due to a progressive degeneration of testicular tissue, molecular analysis of the AMH gene suggested that end-organ resistance might be the cause of the persistence of mullerian ducts. CONCLUSION: PMDS is not extremely rare. Many diagnostic mistakes are made which could be prevented by performing pelvic or inguinal ultrasonography before surgical treatment of bilateral cryptorchidism or irreducible inguinal hernia. Prognosis depends upon the integrity of the testicular tissue, sometimes compromised for yet unexplained reasons, and upon the successful correction of cryptorchidism, which is complicated by the close anatomical relationship between the vasa deferentia and the Mullerian derivatives. PMID- 7834049 TI - [Ultrasonographic survey of the effect of umbilical arterial catheterization in newborn infants]. AB - BACKGROUND: Incidence of aortic thromboses in the neonatal period is significantly increased after umbilicar artery catheterization. POPULATION AND METHODS: Fourty neonates (GA: 34.7 +/- 7.2 wks and birth weight: 2377 +/- 786 g) were prospectively studied in order to assess frequency and natural history of aortic thromboses due to umbilical artery catheterization. Investigation was based on serial real-time ultrasonography (2.3 times/week). Presence of aortic thrombus was correlated with the existence of clinical complications and the results of biological findings (prothrombin and fibrinogen levels; hematocrit) and platelet number. RESULTS: Aortic thrombosis was found in six patients (15%); it was clinically asymptomatic in two (5%). A vascular wall-fixed catheter was shown in ten infants (25%); this finding was associated with thrombosis in five cases and preceded thrombosis in one other. The presence of thrombus and/or abnormal position of the catheter was not correlated with gestational age, birth weight, duration of catheterization, blood hemostasis and results of bacteriological cultures of the tip of the catheter. CONCLUSIONS: Ultrasonographic control must be repeated after umbilical artery catheterization. It permits evaluation of renal flux and can lead to removal of catheter and/or peculiar therapeutic measures. PMID- 7834050 TI - Salicylate trapping of .OH as a tool for studying post-ischemic oxidative injury in the isolated rat heart. AB - The use of salicylate as a chemical trap for .OH represents a simple and convenient alternative to the use of spin trapping techniques to study oxidative injury in isolated perfused organs. In these systems, salicylate is included in the perfusion buffer at concentrations ranging from 0.1 to 2 mM depending on the detection apparatus employed. In our studies, we have used a coulometric detector, which has a theoretical efficiency of 100% as compared to 1-5% for the standard glassy carbon electrode. We have been able to generate reproducible results by inclusion of only 100 microM salicylate, a concentration demonstrated not to affect pre- or post-ischemic cardiac function. In initial studies, we observed an increase in perfusate 2,5-dihydroxybenzoic acid consistent with an early post-ischemic burst of .OH, not unlike that reported using spin trapping techniques. Since then we and others have used this technique to examine possible relationships between .OH formation and treatments that alter post-ischemic cardiac functional recovery. For example, preischemic loading of hearts with copper results in increases in post-ischemic dysfunction and LDH release that were associated with an increase in 2,5-dihydroxybenzoate and by inference, .OH formation. Alternatively, we have reported that the nitroxide spin label, TEMPO, reputed to be a superoxide dismutase mimetic, decreased post-ischemic arrhythmias and 2,5-dihydroxybenzoate formation. Most recently, we have observed that preischemic loading of hearts with zinc-bis-histidinate results in improved post ischemic cardiac function and decreased LDH release; changes that were associated with decreased 2,5-dihydroxybenzoate formation. These studies indicate that under certain conditions, salicylate is a valuable alternative to spin trapping techniques to probe the role of .OH in cardiac oxidative injury, particularly when applied to the isolated perfused heart preparation. PMID- 7834051 TI - Inhibitory effect of bifemelane on superoxide generation by activated neutrophils measured using a simple chemiluminescence method. AB - We evaluated the effect of 4-(2-benzylphenoxy)-N-methylbutylamine hydrochloride (bifemelane hydrochloride) on superoxide production by human neutrophils using an MCLA-dependent chemiluminescence assay. Bifemelane hydrochloride dose-dependently inhibited superoxide production by neutrophils stimulated with phorbol myristate acetate, opsonized zymosan, or N-formyl-methionyl-leucyl-phenylalanine, while it had no effect on superoxide production by a hypoxanthine-xanthine oxidase system. These results indicate that bifemelane hydrochloride does not have a scavenging effect, but has an inhibitory effect on superoxide generation by neutrophils. Although this drug is commonly used for treating chronic cerebral infarction, it may also have a protective effect on acute ischemia/reperfusion injury. PMID- 7834052 TI - Sequential oxidative damage, and changes in iron-binding and iron-oxidising plasma antioxidants during cardiopulmonary bypass surgery. AB - Cardiopulmonary bypass patients undergoing heart valve replacement surgery appear to be under oxidative stress, when compared with normal healthy controls, by showing increased levels of protein and lipid damage. During bypass surgery two further episodes of oxidative stress occur. The first is seen when patients are placed on extracorporeal blood circulation and oxygenation which results in a rise in lipid peroxides and thiobarbituric acid-reactive substances. The second phase of oxidative stress occurs during reperfusion of the myocardium following removal of the aortic cross clamp. Coincident with evidence of increased oxidative damage to lipids during these latter phases of oxidative stress were decreases in plasma iron-binding and iron-oxidising antioxidant activities. PMID- 7834053 TI - Free radical inactivation of rabbit muscle creatinine kinase: catalysis by physiological and hydrolyzed ICRF-187 (ICRF-198) iron chelates. AB - Creatine kinase is a sulfhydryl containing enzyme that is particularly susceptible to oxidative inactivation. This enzyme is potentially vulnerable to inactivation under conditions when it would be used as a diagnostic marker of tissue damage such as during cardiac ischemia/reperfusion or other oxidative tissue injury. Oxidative stress in tissues can induce the release of iron from its storage proteins, making it an available catalyst for free radical reactions. Although creatinine kinase inactivation in a heart reperfusion model has been documented, the mechanism has not been fully described, particularly with regard to the role of iron. We have investigated the inactivation of rabbit muscle creatine kinase by hydrogen peroxide and by xanthine oxidase generated superoxide or Adriamycin radicals in the presence of iron catalysts. As shown previously, creatine kinase was inactivated by hydrogen peroxide. Ferrous iron enhanced the inactivation. In addition, micromolar levels of iron and iron chelates that were reduced and recycled by superoxide or Adriamycin radicals were effective catalysts of creatinine kinase inactivation. Of the physiological iron chelates studied, Fe(ATP) was an especially effective catalyst of inactivation by what appeared to be a site-localized reaction. Fe(ICRF-198), a non-physiological chelate of interest because of its putative role in alleviating Adriamycin induced cardiotoxicity, also catalyzed the inactivation. Scavenger studies implicated hydroxyl radical as the oxidant involved in iron-dependent creatine kinase inactivation. Loss of protein thiols accompanied loss of creatine kinase activity. Reduced glutathione (GSH) provided marked protection from oxidative inactivation, suggesting that enzyme inactivation under physiological conditions would occur only after GSH depletion. PMID- 7834054 TI - Enhancement of nitrogen dioxide-induced lipid peroxidation and DNA strand breaking by cysteine and glutathione. AB - Nitrogen dioxide less than 100 ppm in air induced lipid peroxidation of liposome composed of 1-palmitoyl-2-arachidonylphosphatidylcholine as assessed by thiobarbituric acid reactivity. The nitrogen dioxide-induced lipid peroxidation was enhanced by cysteine, glutathione and bovine serum albumin. While the activity of nitrogen dioxide in air to induce single strand breaks of supercoiled plasmid DNA was low, the breaking was remarkably enhanced by cysteine, glutathione and bovine serum albumin. ESR spin trapping using 5,5-dimethyl-1 pyrroline N-oxide showed that certain strong oxidant(s) were generated by interaction of nitrogen dioxide and cysteine. The spin trapping using 3,5-dibromo 4-nitrosobenzene-sulfonate suggested that sulfur-containing radicals were generated by interaction of nitrogen dioxide and cysteine or glutathione. Hence, certain sulfur-containing radicals generated by the interaction which could effectively induce lipid peroxidation and DNA strand breaks. PMID- 7834055 TI - Antioxidant properties of plastoquinol and other biological prenylquinols in liposomes and solution. AB - Oxidation of biological prenylquinols, like plastoquinol-9 (PQH2-9), ubiquinol-10 (UQH2-10), reduced vitamins K1 (VK1H2) and K2 (VK2H2), alpha-tocopherol quinol (alpha-TQH2) and alpha-tocopherol (alpha-T) was followed by their fluorescence during sonication of egg yolk lecithin/prenylquinol liposomes. The order of magnitude of oxidation of the prenylquinols by free radicals generated during sonication was UQH2-10 > VK2H2 > VK1H2 > alpha-TQH2 > PQH2-9 > alpha-T. It was shown that egg yolk lecithin undergoes degradation even when sonicated briefly under atmosphere of nitrogen and at 0 degree C. A kinetic study of free radical scavenging action of the prenylquinols in solvents of different polarity was performed. The pseudo-first-order rate constants, k, for the reaction of the prenylquinols with 1,1-diphenyl-2-picrylhydrazyl (DPPH) in hexane showed that their scavenging activity changes in the order VK2H2 > VK1H2 > alpha-TQH2 > PQH2 9 > alpha-T > UQH2-10, being the highest in hexane and methanol, whereas in acetone and ethyl acetate the scavenging activity appeared much lower. The reaction rate constants, k, were apparently not dependent on the solvent polarity. The antioxidant activity of the prenylquinols in natural membranes is discussed. PMID- 7834056 TI - Antioxidant activity of saliva and periodontal disease. AB - The antioxidant activity of saliva has been investigated in 28 apparently healthy individuals and seven dental patients with periodontal disease. The results show that the major aqueous antioxidant component of whole saliva is uric acid, with lesser contributions from ascorbic acid and albumin. All are present at lower concentrations than those found in the plasma water. The total antioxidant activity (TAA) of saliva correlates (r2 = 0.972) with the concentration of uric acid, which contributes more than 70% of the TAA. Stimulation of salivary flow is associated with increased production of antioxidants. The antioxidant potential of saliva does not appear to be compromised in patients with periodontal disease but this may relate to the antioxidant flow from the gingival crevicular fluid. PMID- 7834058 TI - Jones transfer to the lesser rays in metatarsalgia: technique and long-term follow-up. AB - Thirty-three feet in 29 patients with metatarsalgia were reviewed after Jones transfer to the lesser rays to evaluate the long-term results and the indications for these procedures. Transfer of the long extensor tendons to their respective metatarsal necks and fusion of the interphalangeal joints with shortening of the toe were performed. The procedures were performed in patients with symptoms of metatarsalgia, secondary to anterior pes cavus deformity (clawfeet, 16 patients), and in patients with mild or severe spreadfoot deformity with fall of the central metatarsals (12 patients). In all of our patients, the striking clinical sign was the long toes. Rating of the results was based on (1) the presence of pain or calluses and (2) residual deformity of the forefoot and toes. Symptoms of metatarsalgia were relieved in 25 feet, occasionally present in 6 feet, and unchanged in 2 patients. Complete correction of the deformity was achieved in 26 patients, 6 patients had slight residual deformities, and in the 1 poor result, overcorrection was present after the procedure. This operation is believed to be an excellent choice for patients with metatarsalgia due to (simple) pes cavus deformity and in patients with clawing and metatarsalgia secondary to excessively long toes. PMID- 7834057 TI - Prevention of carbon tetrachloride-induced lipid peroxidation in liver microsomes from dehydroepiandrosterone-pretreated rats. AB - Dehydroepiandrosterone (DHEA), a lipid soluble steroid, administered to rats (100 mg/kg b.wt) by a single intraperitoneal injection, increases to twice its normal level in the liver microsomes. Microsomes so enriched become resistant to lipid peroxidation induced by incubation with carbon tetrachloride in the presence of a NADPH-regenerating system: also the lipid peroxidation-dependent inactivation of glucose-6-phosphatase and gamma-glutamyl transpetidase due to the haloalkane are prevented. Noteworthy, the liver microsomal drug-metabolizing enzymes and in particular the catalytic activity of cytochrome P450IIE1, responsible for the CCl4-activation, are not impaired by the supplementation with the steroid. Consistently, in DHEA-pretreated microsomes the protein covalent binding of the trichloromethyl radical (CCl3 degrees), is similar to that of not supplemented microsomes treated with CCl4. It thus seems likely that DHEA protects liver microsomes from oxidative damage induced by carbon tetrachloride through its own antioxidant properties rather than inhibiting the metabolism of the toxin. PMID- 7834059 TI - Painful heel syndrome: results of nonoperative treatment. AB - One hundred five patients (70% female and 30% male; average age, 48 years) with 132 symptomatic heels were treated according to a standard nonoperative protocol and then reviewed at an average follow-up of 29 months. The treatment protocol consisted of nonsteroidal anti-inflammatory medications, relative rest, viscoelastic polymer heel cushions, Achilles tendon stretching exercises, and, occasionally, injections. Obesity, lifestyle (athletic versus sedentary), sex, and presence or size of heel spur did not influence the treatment outcome. Ninety four patients (89.5%) had resolution of heel pain within 10.9 months. Six patients (5.7%) continued to have significant pain, but did not elect to have operative treatment, and five patients (4.8%) elected to have surgical intervention. Despite attention to the outcome of surgical treatment for heel pain in the current literature, initial treatment for heel pain is nonoperative. The treatment protocol used in this study was successful for 89.5% of the patients. PMID- 7834060 TI - Heel cord advancement in children with spastic equinus deformity. AB - Heel cord advancement has been advocated for treatment of spastic equinus deformity. Transferring the gastrosoleus anteriorly weakens it by changing the lever arm rather than the resting length. A retrospective review of 90 children with 122 limbs undergoing heel cord advancement revealed 11% excellent, 53% good, and 35% poor results (average follow-up 9.7 years). The results were statistically better in diplegics and community walkers. The better results in previous studies may be due to procedure modifications and shorter follow-up. Since we obtain comparable results with simpler heel cord lengthenings, we no longer do heel cord advancement. PMID- 7834061 TI - Validity and reliability of the first distal metatarsal articular angle. AB - A laboratory study was undertaken to quantify the validity, the intra- and interobserver reliability, and the effect of first metatarsal orientation on the distal metatarsal articular angle (DMAA). First metatarsals from six cadavers were isolated by sharp dissection and attached to a custom-made triplanar protractor. This allowed controlled positioning of the first metatarsal in the three cardinal planes. Each specimen was moved through a stepwise sequence of first metatarsal orientation changes. Radiographs were taken at each position. The distal (metatarsophalangeal) articular surface of the first metatarsal was then circumscribed with metallic paint and the radiographic series was repeated. DMAA measurements were made on each radiograph multiple times by two measurers blinded to the parameters of variation. The difference between the standard (clinical) radiographic technique for estimating the DMAA and the metallic paint DMAA averaged -0.9 degrees (SD = 2.4 degrees). Longitudinal rotation (P < .0001) and varus deviation (P < .02 at 10 degrees) of the first metatarsal had a significant effect on the radiographic determination of the DMAA. Although intraobserver reliability for DMAA measurement was high, interobserver reliability for the clinical technique of measurement was poor (pooled intraclass correlation coefficient = 0.14). PMID- 7834062 TI - Long-term results of triple arthrodesis: 42 cases followed for 25 years. AB - We reviewed 42 patients who had had triple arthrodesis 25 years after surgery. The patients' age averaged 20 years. All patients had deformities due to poliomyelitis. They were satisfied with the operation, except for one patient. Good results were noted in 13, fair in 26, and poor in 3 cases. There was delayed wound healing in 8, superficial infection in 4, and avascular necrosis of the talus in 2 cases. There was no case of delayed union or nonunion. We found degenerative joint changes in 12 ankles and in 9 feet; fourteen patients experienced pain. In spite of these long-term changes, which appear acceptable, triple arthrodesis is a useful procedure for many deformities of the foot and can solve patients' problems for many years. PMID- 7834063 TI - Treatment of delayed unions and nonunions of the proximal fifth metatarsal with pulsed electromagnetic fields. AB - Nine delayed unions and nonunion of the proximal fifth metatarsal were treated with pulsed electromagnetic fields (PEMF). All fractures healed in a mean time of 4 months (range 2-8 months). Those fractures treated with both pulsed electromagnetic fields and a nonweightbearing cast healed in a mean time of 3 months (range 2-4 months). The average duration of follow-up was 39 months (range 24-60 months). There were no refractures. When compared with reported healing times and morbidity for conventional casting, medullary curettage with inlay bone, and closed axial intramedullary screw fixation, pulsed electromagnetic fields provided an effective alternative for the treatment of delayed unions and nonunion of the proximal fifth metatarsal. PMID- 7834064 TI - Material properties of the plantar aponeurosis. AB - Material properties of the plantar aponeurosis were determined by a two dimensional video tracking method to simultaneously measure the aponeurosis deformation. Failure loads averaged 1189 +/- 244 N and were higher in men. Average stiffness of the intact fascia was 203.7 +/- 50.5 N/mm at a loading rate of 11.12 N/sec and it did not vary significantly for the loading rates of 11.12 to 1112 N/sec. The high tensile loads required for failure were consistent with clinical and biomechanical studies and indicated the importance of the aponeurosis in foot function and arch stability. PMID- 7834065 TI - Effect of metatarsal pads and their positioning: a quantitative assessment. AB - Many conditions of the foot have been related to pressure maldistribution. Alteration of plantar pressure through improvements of shoe fit, orthoses, and surgery are presumed to correct pressure maldistribution. We evaluated 10 volunteers with normal, asymptomatic feet. With the use of an ultrathin in-shoe sensor, plantar pressures were measured within the shoe at the shoe/foot interface. Test conditions included three pad types: large foam, large felt, and small felt. They were evaluated in three positions: normal (at the metatarsal head base) and 5 mm proximal and 5 mm distal to the normal position. When compared with the control condition without the pad, each pad type and position caused a variable effect upon plantar pressure. On average, the small felt pad caused the greatest and most consistent decrease in pressure at the metatarsal heads (19.15%). Distal positioning tended to cause the greatest decreases in pressure for all pad types. A pad type and position was found to decrease metatarsal pad pressure in each subject. Metatarsal pads can effectively decrease plantar pressures within the shoe. PMID- 7834066 TI - Acute rupture of the peroneal longus tendon in a runner: a case report and review of the literature. AB - Traumatic rupture of the peroneal longus tendon is rare and the diagnosis may be difficult. Swelling and tenderness about the lateral aspect of the ankle, increased hindfoot varus, and pain with active eversion are helpful clinical signs. Magnetic resonance imaging may be helpful in making the diagnosis. We present the case of a patient who sustained an acute rupture of the peroneal longus tendon. The tendon was repaired primarily and the patient was able to return to running. A high index of suspicion is required to prevent a delay in the diagnosis and further disability. PMID- 7834067 TI - Osteoid osteoma of the lateral cuneiform bone. AB - An unusual case of osteoid osteoma is reported emphasizing the necessity of a careful history and physical examination combined with an adequate imaging supply. Treatment was surgical with an en bloc excision of the lesion. PMID- 7834068 TI - The last rights. PMID- 7834069 TI - Study opportunities in the health sciences: a registered nurse's guide. PMID- 7834070 TI - Putting the squeeze on media watch. PMID- 7834071 TI - Nurses and medication. Part 4. Prescribing power: panacea or punishment? PMID- 7834072 TI - Nursing and the law. Documentation and 'usual practice'. PMID- 7834073 TI - Skin cancer: helping those who need it most. PMID- 7834074 TI - Enhancement of lipid phagocytosis by cloned cells derived from rat malignant fibrous histiocytoma under hyperlipemic conditions. AB - The histogenesis of malignant fibrous histiocytoma (MFH) was studied by observing the influence of hyperlipemic (HL) conditions on the behavior of cloned MT-8 cells with an undifferentiated mesenchymal character and MT-9 cells with histiocytic and fibroblastic features, both derived from a spontaneous rat MFH. The cells were grown in medium containing 10% normal rat serum (CSM) or 10% HL rat serum (HSM) for 1, 3, 8 and 24 h. The cells grown in HSM showed a time dependent, significant increase in numbers of cytoplasmic lipid droplets per cell and cells positive for acid phosphatase (ACP) and non-specific esterase (NSE) compared with cells grown in CSM. The number of cells positive for two different anti-rat monocyte/macrophage monoclonal antibodies (ED-1 and ED-2) also increased significantly in HSM. This histiocytic nature was confirmed by electron microscopy. Tumors were induced by inoculating MT-8 and MT-9 cells into rats on a standard diet and rats on a HL diet. MT-8 and MT-9 tumor cells in HL rats phagocytized lipid droplets and showed stronger positive reactions for ACP and NSE compared with tumors in control rats. These results imply that xanthomatous cells in MFH may be a phenotype of MFH cells expressing an enhanced histiocytic nature. MFH cells seem to alter their behavior depending on cultural or microenvironmental conditions. PMID- 7834075 TI - Three-dimensional analysis of human carotid atherosclerotic ulcer associated with recent thrombotic occlusion. AB - To clarify the mechanism of ulcer formation of atherosclerotic plaques in human carotid arteries, autopsy investigations were performed on eight patients who had died of cerebral infarction due to recent carotid thrombosis. Eleven control patients who had carotid atherosclerosis without thrombosis were also investigated. Histological changes of the arteries in serial sections were reconstructed three-dimensionally. Each artery with occlusive thrombosis was found to have an intimal ulcer at the head of the thrombus on the proximal slope near the base of the thickened atheromatous plaque at the carotid sinus. Most ulcers formed obliquely or longitudinally, were parallel to the vessel axis, had a fusiform shape, and measured 7 +/- 2 x 3 +/- 1 mm (mean +/- s.d.). The ulcers arose by marginal separation of the innermost layer from the underlying layer of the stratified intima. An underlying atheroma developed along the borders of these intimal layers reaching the subendothelium, with thinning of the intimal cap to less than 150 microns. The process of ulceration may be generated by vessel injury induced by hemodynamic forces, such as tensile forces and shear stress. The ulcer may extend along the fragile region where the wall may exhibit uneven compliance due to differences in the tissue structures of each intimal layer. Furthermore, macrophages may play a key role in ulcer formation. PMID- 7834076 TI - Pathology of the spleen in primary biliary cirrhosis: an autopsy study. AB - Pathologic changes of the spleen in primary biliary cirrhosis (PBC) were studied using autopsy cases. By analysis of the data complied in the Annual Registry of Autopsies of Japan (1977-92), it was found that the splenic weight of 184 cases of PBC (450 +/- 224 g) was significantly heavier than that of 41 control autopsy cases of non-biliary liver cirrhosis from the School of Medicine, Kanazawa University (341 +/- 189 g), and also of 210 control cases filed in the Annual Registry of Autopsies of Japan (1982; 334 +/- 174 g). Among the cases of PBC, the splenic weight was positively correlated with the liver weight. There was no significant difference in the splenic weight between the cases belonging to histologic stages 1-3 and those of stage 4. Fibrosis extending from the splenic trabecula, proliferation and dilatation of the splenic sinus, and congestion in the red pulp, all being compatible with chronic splenic congestion, were similarly observed in the spleen in PBC as well as in other non-biliary cirrhotic cases. The present study indicates that the PBC patients present splenomegaly in the non-cirrhotic histologic stage and splenomegaly persists thereafter. However, the histopathologic changes of the spleen peculiar to PBC were not specified in this autopsy study. Prolonged portal hypertension and other mechanisms, possibly related to immune disarrangement, may be responsible for the prominent splenomegaly in PBC. PMID- 7834077 TI - Heat-induced antigen retrieval of proliferating cell nuclear antigen and p53 protein in formalin-fixed, paraffin-embedded sections. AB - Immunohistochemical demonstration of proliferating cell nuclear antigen (PCNA) and p53 protein is important, particularly for the surgical diagnosis of neoplastic disorders. An effective, simple and reproducible method was established for observing the expression of these intranuclear antigens in routinely processed, formalin-fixed paraffin-embedded sections. Dramatic improvement of the antigenicity was obtained when the deparaffinized sections were heated in a hot water bath at 90 degrees C for 120 min in 0.01 mol/L citrate buffer, pH 6.0, for PCNA and in 0.01 mol/L phosphate-buffered saline, pH 7.2, for p53 protein. These reliable pretreatments are useful for the detailed comparative analysis of the expression of PCNA and p53 protein and fine histologic architecture and for retrospective study using a large number of archival specimens. PMID- 7834078 TI - Immunohistochemical demonstration of p53 protein in colorectal adenomas and adenocarcinomas. Reliable application of the heat-induced antigen retrieval method to formalin-fixed, paraffin-embedded material. AB - Ninety-nine polypoid neoplasms and eight advanced adenocarcinomas of the colon were studied immunohistochemically for p53 protein expression. For reproducible antigen retrieval, formalin-fixed, paraffin-embedded archival sections were heated at 90 degrees C for 120 min in 0.01 mol/L phosphate-buffered saline, pH 7.2, prior to immunostaining. Proliferating cell nuclear antigen served as a positive control marker for effective antigen retrieval. The 99 polyps were categorized into 24 high-grade adenomas, 60 non-invasive cancer-in-adenomas (CIA), and 15 CIA with stromal invasion. All the polyps contained portions of low grade adenoma. Positive nuclear staining of p53 protein was observed in none of the non-neoplastic mucosa, nine (9%) of 99 low-grade adenomas, 17 (71%) of 24 high-grade adenomas, 46 (77%) of 60 non-invasive CIA, 10 (67%) of 15 invasive CIA, and five (63%) of eight advanced carcinomas. When the antigen retrieval treatment was omitted, the positivity rates were 0, 2, 17, 35, 40, and 63%, respectively. When the antigen-retrieved staining pattern was classified into (i) 'sparse' (< 25% of the nuclei of neoplastic glands labeled), 'scattered' (25-75%) and 'dense' (> 75%); or (ii) 'focal' (the positively labeled glands occupying < 25% of the tumor area), 'intermediate' (25-75%) and 'diffuse' (> 75%), the sparse and focal patterns predominated in high-grade adenomas and non-invasive CIA with low-grade atypia, while the dense and diffuse patterns predominated in invasive CIA and all the advanced carcinomas revealed the dense and diffuse patterns. Non invasive CIA with high-grade atypia belonged to an intermediate type between the two groups.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7834079 TI - Clinicopathological and immunophenotypic studies on 12 cases with B cell chronic lymphocytic leukemia. AB - To clarify the histogenesis of B cell chronic lymphocytic leukemia (BCLL), clinicopathological and immunophenotypic studies were performed using a large panel of monoclonal antibodies on 12 cases with BCLL including three cases with prolymphocytic/chronic lymphocytic leukemia (CLL/PL). Immunophenotypically, CD19 and CD20 were positive for all cases of this series and CD5, CD21, CD22, CD23, CD25, CD38, Leu-8, KB-61, and bcl-2 protein were expressed in variable proportion from case to case. CD10, however, did not react. No alkaline phosphatase (ALP) positive cases were found. The phenotype of BCLL was similar to that of B cells of the mantle zone (MZ) of secondary follicle in the lymph node. It is therefore postulated that the neoplastic cells of BCLL in these cases might be derived from B cells of the MZ. Moreover, the cells possibly originated from the lymphocytes located in the inner layer of the MZ, since ALP+ B cells are usually observed in the outer layer of the MZ. The pseudofollicular (PF) pattern was observed in four biopsied lymph nodes among five cases tested, but no such a pattern in an aspiration clot of bone marrow. These four cases consisted of three cases with CLL and a case with CLL/PL. The immunohistochemical study showed that there were many proliferating cells showing Ki-67+ in the PF area of the lymph nodes. In these cases, leukemic cells might have developed from the PF area of the lymph node. PMID- 7834080 TI - An autopsy case of malignant mesothelioma associated with asbestosis. AB - An autopsy case of malignant mesothelioma with asbestosis caused by asbestos exposure for 17 years is reported. Autopsy revealed that mesothelioma spread extensively in all serosal tissues including pleura, pericardium, diaphragm, peritoneum and tunica vaginalis testis. Histopathologically, most of the tumor showed an epithelial form, but sarcomatous and microcystic patterns were also observed. The tumor cells had abundant glycogen and hyaluronic acid and, immunohistochemically, they were positive for cytokeratin, vimentin and epithelial membrane antigen (EMA). Long, slender microvilli were characteristically observed in these tumor cells. All of these data were compatible with malignant mesothelioma. Procollagen type I (procol.l) immunostaining was performed to reveal the mesenchymal character of mesothelioma. Both epithelial-type cells and sarcomatous-type cells showed positive staining for procol.l, although the latter showed stronger immunoreactivity. Immunostaining for procol.l was found to be one of the useful tools for distinguishing mesothelioma from adenocarcinoma. Using an extraction method for asbestos fibers, asbestos bodies were found in many tissues including lymph nodes, liver, small intestine, spleen, kidney, testis and pleura, in addition to lung parenchyma. Although multiple tumor metastases from an undetermined primary site is not ruled out, 'multifocal tumorigenesis' is suspected from the widespread deposit of asbestos fibers. PMID- 7834081 TI - A case of low-grade fibromyxoid sarcoma of the thigh. AB - A case of low-grade fibromyxoid sarcoma in the thigh of a 21 year old female is described. The patient had a fist-sized well-defined mass in her left thigh that enlarged over a 6 month period. Histologically, the neoplasm showed contrasting fibrous and myxoid areas with a swirling growth pattern. Cellularity was low to moderate, and the stromal cells were benign looking without mitoses or nuclear pleomorphism. The tissue was not noticeably vascular. Some stromal cells were aggregated around the blood vessels. The stromal cells were immunoreactive to vimentin, but were negative to keratin, desmin, alpha-smooth muscle actin, actin HHF35, S-100 protein, neuron-specific enolase, and epithelial membrane antigen. Ultrastructural examinations of the stromal cells revealed well-developed rough endoplasmic reticulum, mitochondria, pinocytotic vesicles, and numerous intermediate-sized filaments in the cytoplasm. These findings seem to indicate that the stromal cells were fibroblastic in origin. The occurrence of the tumor in a young adult, its location and its large, well defined borders together with the characteristics revealed through histological investigation, indicated that it was in fact what has been termed by Evans as a low-grade fibromyxoid sarcoma. PMID- 7834082 TI - Giant symptomatic myelolipoma of the adrenal gland. AB - A case of giant symptomatic myelolipoma is described in which clinical differentiation was difficult. It was considered to be an extremely rare case of giant myelolipoma arising in the adrenal gland. Histologically the present case contained more lipomatous elements than others reported to data. This is a case of giant adrenal myelolipoma with a few foci of myeloid elements and it is suggested that this case has a true neoplastic nature rather than a hyperplastic or metaplastic one. PMID- 7834083 TI - A case of retroperitoneal malignant mesenchymoma. AB - A rare case is reported of malignant mesenchymoma of a retroperitoneal lesion involving the kidney and composed of leiomyosarcoma and liposarcoma. The tumor, measuring 13 x 12 x 11 cm and weighing 1910 g, arising from the soft tissue of the retroperitoneum or renal capsule, was completely removed surgically. Thirteen months after surgical operation, multiple metastasis was observed. Immunohistochemical and electron microscopical examination showed two different mesenchymal elements. Magnetic resonance imaging findings were compatible with the pathological findings. This case appears to be the second in the world literature. PMID- 7834084 TI - Mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach progressing to overt B cell malignancy. AB - A 70 year old man, who underwent subtotal gastrectomy under the diagnosis of reactive lymphoid hyperplasia 6 years earlier, suffered from diffuse large-cell type B cell lymphoma in the remnant stomach. Retrospectively reviewed, the initial lesion was consistent with mucosa-associated lymphoid tissue (MALT) lymphoma, a low-grade B cell malignancy, based upon histologic, cytologic and immunohistochemical features. Both the initial and recurrent tumors revealed the phenotypes of mantle zone cells, DBA44-positive. It is noteworthy that the overt lymphoma cells retained the capacity for inducing germinal center-like nodules consisting of LN1 and DNA7-positive cells even in the invading site. The diagnosis of reactive lymphoid hyperplasia of the stomach should be made after careful exclusion of the possibility of MALT lymphoma. PMID- 7834086 TI - Colors of the spectrum. Radiation oncology nursing. PMID- 7834085 TI - Non-isotopic single strand conformation polymorphism (PCR-SSCP) with subsequent direct sequencing after silver staining. PMID- 7834087 TI - The sixth Tuesday of the Month. PMID- 7834088 TI - Cancer pain guidelines: no small comfort. PMID- 7834089 TI - Management perspectives. Nursing department's shared governance experience. PMID- 7834090 TI - Breast cancer: two nurses share their personal stories. Interview by Kyle Louise Jossi. PMID- 7834091 TI - Autologous bone marrow transplant unit offers hope. PMID- 7834092 TI - From manager to leader, controller to facilitator: a changing role for the nurse manager. PMID- 7834093 TI - Colors of the spectrum. Perioperative nursing. PMID- 7834094 TI - "Are you a male nurse?". PMID- 7834095 TI - Management perspectives. Nurse managers. PMID- 7834096 TI - From homelessness to nursing school. PMID- 7834097 TI - A nursing adventure in the rain forest. PMID- 7834098 TI - The Clinical Center Nursing Department at the National Institutes of Health (NIH) Bethesda, MD. PMID- 7834099 TI - From DC to Russia: crossing cultures. PMID- 7834100 TI - [The use of an indirect immunoenzyme method in the diagnosis of leptospirosis]. AB - Sensitivity and specificity of indirect immunoenzyme method for determining antileptospirosis antibodies have been studied. Supersound antigenic preparations are used as antigens. Determination of genus-specific antibodies and antibodies of more narrow specificity including serogroup specific ones is possible in the elaborated test. A spectrum of revealed serogroup specific antibodies expends in patients with leptospirosis when using polyvalent antigenic preparations. PMID- 7834101 TI - [The diagnosis of mycotoxin hepatitis in swine]. AB - Mycotoxin hepatitis which develops in pigs when they eat fodder contaminated by mycotoxin (sterigmatocystin) is registered at large pig breeding farms of Ukraine. Diagnostics of mycotoxin hepatitis of pigs induced by sterigmatocystin is based on clinical-epizootiological studies and mycotoxin analysis of the fodder including detection of fungi, producers of sterigmatocystin and determination of the content of mycotoxin itself. The authors have suggested a method based on extraction of mycotoxin from the fodder by means of the mixture of chloroform and 4% water solution of potassium chloride, on concentration of the chloroform residue, its separation in a thin layer of silicagel, and UV examination of chromatograms. The method sensitivity is 30 micrograms per 1 kg of the product. This method will permit diagnosis of mycotoxin hepatitis in animals and will promote timely prophylactic measures. The method is easy to be applied in veterinary laboratories. PMID- 7834102 TI - [The growth characteristics of Enterococcus faecium under batch cultivation conditions]. AB - Growth peculiarities of the strain of homoenzymic lactic acid bacteria Enterococcus faecium under periodic cultivation have been studied. The effect of carbohydrates source on the level of biomass accumulation and efficiency of its use by the strain is shown. Glucose concentration in the medium being increased from 1.0 to 3.5%, the economic effect decreases from 16.0 to 10.6%. It is established that only at the beginning of cultivation the specific growth rate of the strain is determined by the concentration of lactic acid. This dependence can be described by Ierusalimsky's equation. The obtained values of micronm and Kp are 1.5 h(-1) and 6.5 g/l, respectively. Biomass concentration being above 0.3 g ACB/l, the strain growth depends on two factors: inhibition of lactic acid and limitation of the sources of nitrogen nutrition. Interaction of these two factors results in considerable decrease of specific rate of bacterial growth. PMID- 7834103 TI - [The lectins of Mollicutes]. AB - Lectine-carbohydrate interactions take the fundamental part in the intercellular relations as well as in microbes pathogenicity. Pathogenic Mollicutes are characterized by the firm adhesion to the cells of the affected organs of people, animals, insects and plants. Proteins which are localized on the external side of the mollicute membrane and interact with carbohydrate residues on the surface of mucous membranes of the damaged organs and vice versa take part in the adhesion. High degree of specificity of protein-carbohydrate interactions determines the pathogenic specializations to the cells of one or another organ of the host. Since proteins which take part in the mollicutes adhesion are rich in proline and hydrophobic fields it is not excluded that the adhesion processes are combined with hydrophobic interrelations between the cells of the pathogen and host. Substances from the cells of Mollicutes which completely correspond to the definition "lectin", i.e., are in a pure form, the carbohydrate-binding proteins specific to certain carbohydrate residues are not still isolated. Thus the mollicute lectines should be called lectine-like substances rather than lectines. Mollicutes form a lot of such substances and they may be separated into the extracellular (soluble) substances which are found outside the cell of the nutritious medium; intermediate (half-soluble) substances detected in the nutritious medium and in the state integrate into the microorganism membrane, and membrane-related (insoluble) substances which occur only in the state rigidly adhered to the membrane. Carbohydrate composition of lectine-like substances in different mollicutes is different which is the reflection of heterogenicity of the Mollicutes class representatives. PMID- 7834104 TI - [The epidemiological characteristics of the immunological response in campylobacteriosis]. AB - An analytical survey of literature on the problem of immunological aspects of campylobacteriosis is presented. Antigenic nature of various components of a bacterial cell of these agents is described. Schemes of serotyping of campylobacteria on the basis of thermolabile and thermostable antigens are analyzed. It is shown expedient to use serotyping for determination of an infection source in the epidemiological practice. Proceeding from the published data presented, a conclusion is made that it is necessary to develop the home schemes of serotyping. At the same time a problem on development of new proximate methods promoting immunological indication of campylobacteriosis antigens in various ecological niches is not less urgent and is to be taken into account when planning antiepidemiological measures against the campylobacteriosis infection. PMID- 7834105 TI - [The serine proteinases of thermophilic bacilli]. AB - The method of affinity chromatography using bacitracine as a specific ligand was applied to isolate and purify serine proteinases of 8 strains of thermophilic bacilli, including 4 strains of the species Bacillus subtilis, 2 strains of the species B. licheniformis and 2 strains of the species B. circulans. Study of physicochemical and catalytic properties of the enzymes of thermophiles has shown their complete identity with subtilysines as to molecular weight, optimal action conditions, sensitivity to inhibitors and specificity of the action both in respect to natural and in respect to artificial substrates of subtilysines. Four of eight studied enzymes (two of B. licheniformis, two of B. subtilis) were serologically relative to subtilysines of the type of Karlsberg; the rest of the enzymes did not produce the precipitation lines in the reaction of double immunodiffusion in gel with antiserum to subtilysine of the Karlsberg type. All the studied enzymes differed from commercial preparations of subtilysines (producers: B. licheniformis and B. subtilis) in the higher thermal stability: time of half-inactivation at 60 degrees C was 4.5-6 h for the enzymes from different strains of thermophiles; at 80 degrees C this value was 8-13 min. A capacity to lyse the living cells of some gram-negative bacteria and yeast is the most characteristic feature of the studied proteinases of thermophiles as against analogous enzymes of mesophilic strains of bacilli and enzymes of the animal origin. PMID- 7834106 TI - Phylogeny of mitochondrial DNA clones in tassel-eared squirrels Sciurus aberti. AB - The tassel-eared squirrel, Sciurus aberti, includes six subspecies which occupy restrictive and apparently identical habitats in Ponderosa pine forests in the south-western United States and Mexico; the strict habitat requirement of this species is based on dietary requirements which are only fulfilled in these forests. To examine evolutionary relationships among certain subspecies of S. aberti, we obtained estimates of nucleotide diversity within subspecies as well as nucleotide divergence between subspecies using mitochondrial DNA (mtDNA) analysis. Restriction site polymorphisms were identified in samples of the four US subspecies: S. a. aberti (Abert), S. a. kaibabensis (Kaibab), S. a. ferreus (Ferreus), and S. a. chuscensis (Chuska) Fourteen mtDNA clones were resolved that were, with one exception, uniquely subspecific. Dendrograms constructed by neighbour-joining and maximum parsimony methods revealed two major assemblages: (1) an Abert/Kaibab group; and (2) a Ferreus/Chuska group. The Abert vs. Ferreus clones exhibited the greatest net nucleotide divergence, with a lineage separation estimate approximating 572,000 years ago assuming a nucleotide substitution rate of 7.15 x 10(-9)/year/site. Five out of ten Chuska squirrels shared a clone with one Abert sample; the relative sizes of these two populations and their respective ranges as well as their close proximity support the proposal for relatively recent intermixing of Abert and Chuska populations resulting in what appears to be Abert-->Chuska migration. Nucleotide diversity within subspecies ranked as Kaibab < Ferreus < Abert < Chuska; the relatively high diversity for the Chuska sample is based on the apparent introgression of Abert mtDNA. The relative diversity exhibited by Kaibab, Ferreus and Aberti samples corresponds to the range size of the respective subspecies. PMID- 7834107 TI - The establishment of a hybrid zone between red and sika deer (genus Cervus). AB - Japanese sika deer (Cervus nippon nippon) were introduced to Scotland around 80 years (20 generations) ago. The sika phenotype is expanding its range and hybridizing extensively with native red deer (Cervus elaphus) leading to the establishment of a hybrid zone. This zone is currently moving and cannot be considered to be at equilibrium. Cervid genotypes and mitochondrial haplotypes were mapped across the sika phenotype range, using diagnostic protein isozymes, microsatellite nuclear DNA markers and RFLPs in mtDNA. These were analysed to estimate heterozygote deficits and nuclear linkage disequilibria and cytonuclear disequilibria in relation to gene frequencies and time since contact. Introgression was found in both taxa and strong linkage disequilibria and heterozygote deficits characterize the populations longest exposed to hybridization. Populations further from the introduction site, where hybridization is facilitated by the dispersal of sika-like stages, show low values for linkage disequilibria and heterozygote deficit. The observed patterns in genotype are explained in terms of assortative mating and a selective advantage of the sika genotype. The genetic integrity of the Scottish mainland red deer is shown to be at risk from the invasion of sika. PMID- 7834108 TI - Population differentiation in randomly amplified polymorphic DNA of red-cockaded woodpeckers Picoides borealis. AB - Random amplified polymorphic DNA (RAPD) phenotypes generated by 13 primers were scored for 101 individuals in 14 populations of the endangered red-cockaded woodpecker Picoides borealis. Although no population-specific markers were found, the frequencies of several markers differed significantly among populations. Application of the recently developed AMOVA method (analysis of molecular variance; Excoffier, Smouse & Quattro 1992) showed that more than 90% of phenotypic variance occurred among individuals within populations; of the remaining variance, half was attributed among groups of geographically adjacent populations and half among populations within those groups. The statistical significance of these patterns was supported by Monte Carolo sampling simulations and permutation tests. Estimation of allele frequencies from phenotypes provided somewhat weaker evidence for population structure, although among-population variance in allele frequencies was detectable (Fst = 0.19; chi 2(169) = 509.3, P < 0.0001). UPGMA cluster analyses based on Rogers' (1972) genetic distance revealed grouping of some geographically proximate populations. A Mantel test indicated a positive (r = 0.16), although not significant, correlation between geographic and genetic distances. We compared a subset of our RAPD data with data from a previous study that used allozymes (Stangel, Lennartz & Smith 1992). RAPD (n = 75) and allozyme (n = 245) results based on samples from the same ten populations showed similar patterns. Our study indicates that RAPDs can be helpful in differentiating populations at the phenotypic level even when small sample sizes, estimation bias, and inability to test for Hardy-Weinberg equilibrium complicate the genotypic interpretation. Lack of large differences among populations of red-cockaded woodpeckers may allow flexibility in interpopulation translocations, provided factors such as habitat preference, latitudinal direction of translocation, and status of donor populations are considered. PMID- 7834109 TI - Reproductive isolation and the period gene of Drosophila. AB - The identification of genes of large effect on ecologically important traits is an important aim of molecular ecology. The period gene of Drosophila is a candidate for a gene with a large influence on premating isolation between Drosophila species, as it determines species specific aspects of courtship behaviour. Strains of D. melanogaster are available which have been genetically transformed with the period gene of either D. melanogaster or D. simulans. Here we show that D. melanogaster females do not discriminate between two such strains. This suggests that period may only make a small contribution to total premating isolation between these species. We discuss the use of genetically transformed strains in assessing the influence of single genes on complex traits. PMID- 7834110 TI - Colorectal tumourigenesis. AB - Colorectal cancer is significant because of its lethality and high incidence in the Western world. Furthermore, it is a particularly suitable model for studying the events involved in the progression from normal tissue to invasive cancer. There is a great deal of epidemiological and histopathologic evidence to implicate the adenomatous polyp as the precursor to colorectal cancer. Moreover in recent years investigators have uncovered some of the molecular genetic events that underlie the progression from normal epithelium to polyp to cancer. It is hoped that an increased understanding of the molecular changes will afford opportunities for new diagnostic, prognostic and therapeutic strategies in the management of this disease. PMID- 7834111 TI - Villous adenoma of the main pancreatic duct: a clue to the pathogenesis of pancreatic malignancy. AB - We describe the case of a 78 year old woman with a severely dysplastic villous adenoma of the duct of Wirsung presenting with abdominal pain, emesis, weight loss, and hyperamylasemia. Abdominal ultrasound, computed tomography, and endoscopic retrograde cholangiopancreatography suggested an intraductal lesion in the head of the pancreas with a dilated distal duct. The patient underwent uncomplicated pancreaticoduodenectomy and has done well. A review of the literature on benign and malignant neoplasms of the main pancreatic duct allows formulation of the typical clinical syndrome, appropriate diagnostic work-up, treatment, and prognosis of patients with these rare lesions. The pancreatic ductal epithelium can present the full spectrum of lesions along the pathogenetic route to malignancy. This is evidence for the presence of an adenoma-to-carcinoma sequence in the pancreas analogous to that which exists in the colon. PMID- 7834112 TI - Natural immunity in breast cancer patients during neoadjuvant chemotherapy and after surgery. AB - Breast cancer is the most common cancer in women. Surgery, and more recently neoadjuvant chemotherapy, are being utilized as the initial treatment for breast cancer; however little is known about their effects on the natural immune system. The natural immune system (natural killer [NK] cells) is thought to be important in immune surveillance, including protection from metastasis during the intravascular tumour seeding that occurs during surgery. To investigate the effects of surgery on the natural immune system, we studied the pre-operative and post-operative peripheral blood lymphocytes (PBL) of 10 patients with stage I or II breast cancer: there was a 71.6 +/- 25.3% post-operative reduction in NK cell function (P < 0.005, Student's paired t-test). To investigate the effects of neoadjuvant chemotherapy and surgery, we examined PBL from five patients with stage III breast cancer: NK cell function dropped 95.7 +/- 1.9% after neoadjuvant chemotherapy, and there was a further 51.0 +/- 23.4% decrease after surgery (P < 0.05, Student's paired t-test). Neither group of patients had decreased numbers of NK cells, changes in the percentage of T helper or suppressor cells, or alterations in the production of cytotoxic factor by NK cells. These findings suggest that the impairment in NK cell function reflects a defect in the ability of NK cells to recognize and/or bind to tumour target cells. We conclude that the initial treatment of breast cancer patients, whether it involves surgery alone or with neoadjuvant chemotherapy, profoundly impairs their natural immune system and could increase the risk of metastasis. Further studies are needed to delineate the mechanism of this derangement in natural immunity and possibly alter its course. PMID- 7834113 TI - Prognostic significance of signet ring cell carcinoma of the stomach. AB - A retrospective analysis of 3,702 gastric cancer patients operated on between 1981 and 1991 was carried out to compare the clinicopathological features of signet ring cell (SRC) gastric cancer with other cell types. Four hundred and fifty patients (12.2%) had signet ring cell gastric carcinoma. There was a tendency for patients with the signet ring cell gastric cancer to be younger and female, and of the middle-third part of stomach to be involved. The proportion of early gastric cancers in signet ring cell gastric cancers was 43%, which was significantly higher than in the other histological types [33% in well differentiated (WD) type, 23% in moderately differentiated (MD) type, and 13% in poorly differentiated (PD) type]. Early stage signet ring cell gastric carcinomas were less invasive in depth and had less lymph node metastasis. However, signet ring cell gastric cancers in advanced stage were more invasive and had more lymph node metastasis than other cell types. There was no significant difference in five year survival rates (5YSR) among patients with different histological cell types in early stage gastric cancers. But, in advanced gastric cancers, the prognosis for patients with the signet ring cell type was significantly worse than for the other types (SRC, 31.9% 5YSR; WD, 45.1% 5YSR; MD, 38.4% 5YSR; PD, 34.5% 5YSR) (P < 0.05), which can be explained by the finding that advanced gastric cancers with signet ring cell type have a larger tumour size, more lymph node metastasis, a deeper invasive depth and more Borrmann type 4 lesions than other histological types. This study suggests that signet ring cell gastric cancer may have a different biological behaviour. PMID- 7834114 TI - Cytocidal effect of high energy shock wave on tumour cells enhanced with larger dose and multiple exposures. AB - Cultured LLC-WRC256 (Walker rat carcinoma) cells were exposed to different doses of high energy shock waves (HESW). The immediate viabilities were 98% in the control cells, and 74%, 53% and 18% following 400, 800, and 1500 HESW treatment, respectively. Surviving cells in the 400 and 800-treated HESW demonstrated delayed upward growth rate curves, and the 1500 HESW-treated a downward curve. Agar clonogenic efficiencies for surviving cells were 36% (control), 20% (400 HESW), 15% (800 HESW) and 3% (1500 HESW). LLC-WRC256 tumours in Wistar rats were treated once every other day with 1500 HESW on a total of three occasions. Tumours treated with HESW grew more slowly (4.9 cm3) than those in the control (13.5 cm3). HESW fragmented cells and destroyed cell membranes and intracellular organelles. A histological examination of tumours treated with HESW demonstrated local haemorrhage with necrosis in the HESW focus area. Damage to the surrounding skin and soft tissue was slight and transient. These findings suggest that the growth of tumour cells can be suppressed in vitro and in vivo by treatment with HESW. PMID- 7834115 TI - Primary lymphoma of the appendix. Case report and review of the literature. AB - Malignant lymphomas comprise 1-4% of the malignant neoplasms of the gastrointestinal tract, but appendiceal lymphomas are exceedingly rare. Herein is presented a case of a well differentiated lymphocytic lymphoma of the appendix found incidentally at hernia repair. Forty-six cases of appendiceal lymphoma have been reported since 1898 with a mean patient age of 25.7 years. Thirty-one patients presented with right lower quadrant pain, and a mass was an incidental finding in five. Of the 46 cases, follow-up was possible in 28. There were four deaths within 30 days of the operation and five deaths within 1 year. Although extensive follow-up is limited, there have been only two reported deaths secondary to primary appendiceal lymphoma since 1945 and these two cases are discussed in detail. Based on this extensive review, appropriate recommendations are made. PMID- 7834116 TI - Influence of biological response modifiers: measurement of tumor blood flow and temperature. AB - Human recombinant interferon-alpha-2b (IFN) is known to inhibit growth of both normal and tumor cells and to stimulate immune effector cell function. We have previously shown that IFN and other biological response modifiers augment accumulation of radiolabeled antibodies in tumors. This investigation demonstrates that 30 min post i.m. administration of IFN significantly (p < 0.01) enhances tumor perfusion in tumor-bearing mice and persists for a much longer time than in normal tissue, which, in part, may contribute to the enhanced tumor uptake of radiolabeled monoclonal antibodies within 1.5 h of their administration. Histological examinations of tumors obtained from animals receiving IFN 72 h previously did not show changes in inflammatory cells. Our investigation shows that laser Doppler flowmetry and color Doppler imaging can provide an excellent means of measuring tumor perfusion changes in small living animals where radioactive tracers cannot be used. PMID- 7834117 TI - Hyperthermia enhances the cytotoxicity of National Institutes of Health 3T3 cells transfected with a noncleavable transmembrane pro-tumor necrosis factor deletion mutant. AB - Hyperthermia has been shown to potentiate the cytotoxicity of exogenously added tumor necrosis factor (TNF) against tumor cell targets. The mechanism for that interaction is not known, but among the possibilities are that heat enhances internalization of ligand-bound TNF or enhances processing of internalized TNF. In this study, we found that NIH 3T3 cells transfected with an expression vector containing the full-length human pro-TNF secreted TNF and that hyperthermic treatment of chromium-labeled L929 target cells at 43 degrees C for 1 h potentiated the cytotoxicity of these transfectants against the L929 cells in clonogenic survival and chromium-release assays. On the other hand, transfectants expressing a transmembrane, nonsecretable pro-TNF mutant that kills L929 cells by cell-to-cell contact without internalization also exhibited enhanced cytotoxicity against heated L929 cell targets. Thus, potentiation of the cytotoxicity of TNF by hyperthermia is not strictly dependent on enhanced internalization of ligand bound TNF or enhanced processing of internalized TNF. PMID- 7834118 TI - Potential to involve multiple effector cells with human recombinant interleukin-2 and antiganglioside monoclonal antibodies in a canine malignant melanoma immunotherapy model. AB - Human tumors originating from neuroectodermal cells such as malignant melanoma and neuroblastoma express high levels of disialogangliosides GD2 and GD3, making these antigens ideal for targeting by monoclonal antibodies (Mabs). The purpose of this study was to investigate expression and targeting of gangliosides on canine melanoma. Using immunohistochemical methods, we analyzed the expression of disialogangliosides GD2 and GD3 on canine oral malignant melanomas with murine Mabs 14.G2a and R24 that recognize GD2 and GD3 disialogangliosides, respectively, on human tumors. We also assessed the ability of Mab 14.G2a (and its mouse-human chimera, ch 14.18) to mediate antibody-dependent cellular cytotoxicity (ADCC) in vitro against a canine malignant melanoma cell line with human recombinant interleukin-2 (IL-2) activated canine peripheral blood lymphocytes (PBL), or canine neutrophil effector cells. Our data show that Mabs 14.G2a and R24 recognized fresh frozen canine oral melanoma. Mabs 14.G2a or ch 14.18, or IL-2, potentiated lysis of the canine malignant melanoma cell line by canine PBL. The killing effect observed using the combination of either Mab with IL-2 was additive. Mab 14.G2a mediated potent ADCC of canine melanoma by canine neutrophils. These studies indicate that disialogangliosides are expressed on fresh canine melanoma cells. Mabs reactive with these antigens can target and trigger tumor killing by multiple canine effector populations and IL-2 can potentiate these effects by canine lymphocytes. Thus, canine oral malignant melanoma, a spontaneously occurring, metastatic cancer in the dog, may be a relevant animal model to investigate combination immunotherapy using antitumor Mab and IL-2. PMID- 7834119 TI - Intraperitoneal adoptive immunotherapy of ovarian carcinoma with tumor infiltrating lymphocytes and low-dose recombinant interleukin-2: a pilot trial. AB - A pilot study was conducted in patients who had advanced epithelial ovarian carcinoma, and who were refractory to platinum-based chemotherapy, to determine the feasibility and clinical effects of a schedule of intraperitoneal (IP) tumor infiltrating lymphocytes (TIL) expanded in recombinant interleukin-2 (rIL-2), and low-dose rIL-2 IP. TIL were expanded from solid metastases or malignant effusions in serum-free AIM V medium supplemented with low concentrations (600 IU/ml) or rIL-2 using a four-step method of expansion that included a hollow fiber bioreactor (artificial capillary culture system). Patients received IP TIL suspended in dextrose 5% in sodium chloride 0.2% containing 0.1% human albumin and 6 x 10(5) IU rIL-2 on day 1, followed by 6 x 10(5) IU rIL-2/m2 body surface area, administered daily by bolus IP injection, on days 2-4, 8-11, and 15-18. In the absence of disease progression, two additional 4-day cycles of IP rIL-2 were administered. Patients (n = 3) whose TIL failed to grow in vitro received IP IL-2 alone. Eight patients received rIL-2 expanded TIL (10(10)-10(11) range) plus rIL 2 followed by several cycles of rIL-2 alone. One of these patients was treated twice with TIL plus rIL-2. Expanded TIL were primarily CD3+CD4+TCR alpha beta+ (eight TIL-derived T-cell lines). One TIL-derived T-cell line was comprised mostly of CD3+CD8+TCR alpha beta+ cells. Eleven patients (eight treated with TIL plus rIL-2 and three patients treated with rIL-2 alone) received a total of 38 cycles of rIL-2 without TIL. Grade 3 clinical toxicity (peritonitis) occurred in 1 of 9 cycles of TIL plus rIL-2 and 1 of 38 cycles of rIL-2 alone. Each cycle was 4 days long. Grade 3 anemia occurred in 1 of 9 TIL plus rIL-2 cycles and 3 of 38 cycles of rIL-2 alone. There were no measurable responses; however, four of eight patients treated with IP TIL plus rIL-2 had some indication of clinical activity: ascites regression (two patients), tumor and CA-125 reduction (one patient), and surgically confirmed stable tumor and CA-125 values (one patient). The schedule of IP TIL plus low-dose rIL-2 shows manageable toxicity and is worthy of further evaluation in patients with epithelial ovarian cancer who have less tumor burden. PMID- 7834120 TI - Phase II trial of recombinant interleukin-1 beta in patients with metastatic renal cell carcinoma. AB - Interleukin-1 (IL-1) plays a central role in the immune system, partly by stimulating the production of interleukin-2 (IL-2) and other cytokines by lymphocytes. In preclinical studies, recombinant interleukin-1 (rIL-1 beta) has shown antitumor activity. We conducted a phase II trial to evaluate the efficacy of rIL-1 in metastatic renal cell carcinoma (RCC). rIL-1 beta was given at a dose of 50 ng/kg i.v. daily for 5 days on a 28-day schedule. Nineteen patients were registered; 16 completed two cycles and were evaluable for response. There were no complete or partial responses to treatment. Toxicity was generally mild and typically involved grades I and II fever, rigors, hypotension, and weight gain. Severe neurologic toxicity was seen in two patients, grade IV seizures were seen in one, and grade III somnolence was seen in another. Analysis of soluble IL-2 receptor (sIL-2r) levels revealed an increase from a mean pretreatment level of 4,567 pg/ml to a mean of 6,124 pg/ml posttreatment (p < 0.001). The mean pretreatment IL-6 level was 51 pg/ml, increased to 84 pg/ml posttreatment (p < 0.05). Patients with bulky disease had higher sIL-2r levels, and patients with tumor fevers had higher IL-6 and sIL-2r levels than patients without fever did. A neutrophilic leukocytosis and a mild thrombocytosis were observed in response to rIL-1 beta administration. We conclude that rIL-1 beta in this dose and schedule is inactive in metastatic RCC. PMID- 7834121 TI - Phase II trials of high-dose interleukin-2 and lymphokine-activated killer cells in advanced breast carcinoma and carcinoma of the lung, ovary, and pancreas and other tumors. AB - Treatment with interleukin-2 (IL-2) used alone or in combination with lymphokine activated killer (LAK) cells is known to be an active therapy for patients with advanced renal cell carcinoma and melanoma. To further explore the activity of IL 2/LAK cell therapy in patients with advanced cancer of various primary sites, the Extramural IL-2/LAK Working Group (ILWG) initiated two phase II trials of high dose IL-2/LAK therapy: one in patients with advanced breast carcinoma, and one in patients with advanced cancer arising in other sites. Patients with advanced renal cell carcinoma, melanoma, colorectal carcinoma, and lymphoma (Hodgkin's and B-cell non-Hodgkin's) were not eligible for the latter trial, but were treated on other ILWG trials that have been reported previously. Sixty-nine patients received high-dose IL-2 (600,000 IU/kg administered by a 15-min intravenous infusion every 8 h) on days 1-5 and days 11-15. Leukapheresis was performed for collection and ex vivo expansion of LAK cells on days 7-10, and the LAK cells were reinfused on days 11, 12, and 14. The studies were designed to determine whether treatment with IL-2/LAK resulted in at least a 40% response rate, a level of activity that was believed to be sufficient to justify the toxicity and cost of IL-2/LAK therapy. An adequate number of patients with carcinoma of the breast (N = 12), pancreas (N = 8), ovary (N = 7), and lung (non-small cell; N = 6) were accrued to assess response; most of these patients had prior chemotherapy that had failed.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7834122 TI - Phase II trial of recombinant human macrophage colony-stimulating factor in metastatic soft tissue sarcoma. AB - This Phase II study was undertaken to access the activity of recombinant human macrophage colony stimulating factor (M-CSF) in metastatic soft tissue sarcoma based on the observation of a partial response in a patient with leiomyosarcoma during an earlier Phase I trial. Fifteen patients with metastatic soft tissue sarcoma (seven males and eight females) were entered on the trial between October 1990 and March 1991. Seven of these patients had leiomyosarcoma. One mg/M2 of M CSF was administered by rapid intravenous infusion every 8 h on days 1-5 and 15 19. Treatment cycles were repeated at 35-day intervals. Patients were evaluated initially for response after the first cycle, and then following alternate cycles. One partial response was observed in a patient with metastatic small bowel leiomyosarcoma (response rate 7%, 95% confidence interval, 0-33%). Two additional patients had stable disease for 10-15 months on study. Four patients had clinically significant bleeding from tumor sites during M-CSF therapy. No evidence of toxicity directly attributable to M-CSF was observed in any patient. Mean monocyte counts increased in patients during the first 20 days of treatment (p = 0.013). At this dose and schedule, meaningful activity of M-CSF in previously treated patients with soft tissue sarcoma could not be demonstrated. However, the activity observed in patients with leiomyosarcoma in this trial and in the previous Phase I study are intriguing. Further studies of M-CSF in previously untreated patients with leiomyosarcoma may be warranted. PMID- 7834123 TI - Bilateral adrenal hemorrhage and adrenal insufficiency in a patient with lymphomatous adrenal infiltration following administration of a fusion toxin (DAB486 interleukin-2). AB - DAB486IL-2 is a novel fusion toxin in which the ADP-ribosyltransferase and membrane-translocating domains of diphtheria toxin have been combined with the interleukin-2 (IL-2) gene, creating a recombinant protein capable of selectively intoxicating cells bearing the high-affinity IL-2 receptor. Clinical activity has been documented in Hodgkin disease and the non-Hodgkin lymphomas; toxicities have been minimal and include mild hepatic transaminitis, proteinuria, and hypersensitivity reactions. In this report, a patient with tumor-stage cutaneous T-cell lymphoma developed clinical adrenal failure with bilateral adrenal hemorrhage and necrosis 7 weeks after completing a 5-day course of treatment with DAB486IL-2. The relationship of fusion toxin therapy to the development of this unusual toxicity is discussed. PMID- 7834124 TI - Early Childhood Asthma: what are the questions? Proceedings of a workshop. Salem, Massachusetts, May 18-20, 1994. PMID- 7834125 TI - Working in partnership with patients. PMID- 7834126 TI - Experience of supervising discharges. PMID- 7834127 TI - On the receiving end of breast cancer. PMID- 7834128 TI - The asthma experience: altered body image and non-compliance. AB - Asthma remains a frustrating and underestimated threat to health. Non-compliance with medication is a frequent problem, especially when asthma attacks are difficult to predict, and amongst children and young adults. Non-compliance has been attributed to shortfalls in patient education. There may, however, be an attitudinal-altered image dimension to the problem. PMID- 7834129 TI - Powerlessness of caregivers in home care. AB - Patients are not the only ones who suffer when they have a chronic illness; significant others and family members can also suffer. Reaction to chronically ill family members and the problems in their care varies among significant others. As the number of elderly individuals is increasing the number of chronically ill people needing care is also increasing. Not only do patients feel powerless but personal factors, factors in the environment, and factors related to the illness itself can also provide a conceptual framework for organizing factors that affect feelings of powerlessness among family members and significant others. PMID- 7834130 TI - Nursing treatment of patients with chronic leg ulcers in the community. AB - A descriptive survey of current reported practice by 146 community nurses for their nursing treatment of leg ulcers was undertaken. Sixty-four per cent of nurses reported they would apply compression bandages to only venous ulcers; in only 23% of cases could the products described achieve an adequate level of compression. A variety of modern wound dressings were used by the nurses; 89% of nurses reported using a combination of different products layered over the ulcer. There is no evidence that this has any beneficial effect and could therefore be a potential waste of money, as well as contributing to allergic skin reactions. It would be useful if primary-health-care teams and Family Health Service Authority information pharmacists formulated protocols based upon effective treatments for patients with chronic leg ulcers. PMID- 7834131 TI - Occupational stress amongst care staff working in nursing homes: an empirical investigation. AB - A questionnaire survey of care staff in nursing homes examined staff stress. Staff completed questionnaires covering Type A behaviour, job satisfaction, psychological well-being, relaxation behaviour, coping skills and demographic details. A specific measure of nursing home stress was developed following a pilot study. From a total sample of 375, 112 (30%) responses were obtained. On the stress questionnaire the major stressors were found to be 'unsatisfactory wages', 'shortage of essential resources', 'not enough staff per shift', 'feeling undervalued by management', 'lifting heavy patients' and 'working with colleagues who are happy to let others do the work'. Factor analysis of stress questionnaire responses identified five major stress groupings. These were, 'differing expectations about patient care', 'management factors', 'lack of support from other staff', 'feeling inadequately trained to deal with job demands' and 'home work conflicts'. Examination of stress outcomes showed that many staff were under pressure, with high levels of smoking and alcohol intake. Given the increasing importance of nursing home care for the elderly the present study is timely. The implications of the findings for further research, and for the training of staff in nursing homes are considered. PMID- 7834132 TI - An exploratory study of the alternative theoretical frameworks of student nurses. AB - Alternative theoretical frameworks are the tacit assumptions and logical structures of practical action. Student nurses have alternative theories in which ethical and technical knowledge are combined to form high-level heuristics which assist with understanding and responding to client problems. The alternative theories of student nurses can be observed to guide care giving and therefore the theory-practice gap may not be as wide as is often assumed. The values and beliefs about nursing held by student nurses are broadly similar to those advocated for the profession as a whole. PMID- 7834133 TI - Nurses' attitudes to the teaching and training of cardio-pulmonary resuscitation. PMID- 7834134 TI - Nursing makes a difference. PMID- 7834135 TI - A penny for your thoughts. PMID- 7834136 TI - Monitoring diabetic control. AB - Recent research from America has confirmed that the quality of metabolic control achieved by people with insulin-dependent diabetes does influence the onset and progression of diabetic complications. More than ever before diabetic individuals now have good reasons for striving to attain as good a standard of diabetic control as is possible. Regular monitoring of diabetic status is essential if good control is to be achieved. This article will focus upon the concept of control and consider aspects of diabetic monitoring which may be undertaken either by patients or through professional services. Both direct and indirect monitoring methods will be discussed and strengths and weaknesses considered. PMID- 7834137 TI - Reading research critically. II. An introduction to appraisal: assessing the evidence. AB - This is the second of two articles providing an introduction to the critical appraisal of research reports. In this paper guidelines for evaluating the quality of evidence and the validity of conclusions are suggested, and a check list of evaluation points is presented. PMID- 7834138 TI - A further critical description of the therapeutic community. AB - A review of the literature pertaining to therapeutic communities in Britain is presented. An outline of the historical origins and development of communities is provided. Overall, the review is set within a somewhat sceptical context. Mention is made of the inherent confusion of descriptions resulting from the proliferation of competing terminologies in the field. Problems of research are also itemized as are problems of ideological interference with both theory and practice. A tentative conclusion suggests that outcome measures might assist the process of describing these communities more accurately. PMID- 7834140 TI - Community psychiatric nurses for the elderly: well tolerated, few side-effects and effective in the treatment of depression. AB - Depression in elderly people is a common yet treatable psychiatric problem. The Gospel Oak depression study researched this much overlooked group and has shown that a community psychiatric nurse (CPN) was able significantly to improve the mental state of depressed elderly people. A multifaceted package of care was co ordinated and delivered by one CPN over a study period of 3 months. A detailed account is given of those interventions implemented, highlighting those which were of most benefit for the patient. Outcome was assessed independently and it was found that those patients allocated to CPN care improved significantly compared to the non-intervention control group. Ways in which nurses can enhance care given to patients in the community are discussed. PMID- 7834139 TI - Identifying feelings engendered during triage assessment in the accident and emergency department: the use of visual analogue scales. AB - Feelings engendered during 585 triage nursing assessments made by a total of 10 nurses were studied. Marked differences in nurses' feelings were demonstrated towards patients attending the accident and emergency (A&E) department with 'primary care' needs compared with those assessed as having 'A&E' needs. In particular, nurses demonstrated more negative feelings, in the form of less sympathy, more irritation and less motivation to help, towards patients with 'primary care' needs. Nurses' feelings were adversely affected by delays in patient presentation following the occurrence of illness or injury. Nurses perceived patients' attendance as illegitimate when it had deviated from expected norms of health-care-seeking behaviour. These findings were elicited using visual analogue scales completed immediately following the triage assessment of the patients. This work is part of a larger study into developing the primary care role of accident and emergency nurses. The culture of the A&E department is discussed, and the need to challenge and change this culture to ensure it becomes more responsive to individual patients' needs is advocated. This paper calls for development of triage training and education and further investigation into the effects of nurses' attitudes on patient assessment. PMID- 7834141 TI - The ethics of smoke-free zones: an exploration of the implications and effectiveness of a non-smoking policy as a health-promotion strategy in the context of an orthopaedic trauma ward. AB - Pressure to reduce the incidence of smoking is increasing and widespread, coming from health professionals, independent research groups and Government policy objectives. Moves to introduce non-smoking policies within health-service premises are gaining acceptance, and form an element of the Government's overall health plan. This paper considers the background to smoking prohibition in hospitals, its merits and drawbacks as a health-promotion strategy, and some of the health and ethical issues that may arise. In particular, the paper explores the application of non-smoking policies in the speciality of orthopaedic trauma, the benefits and conflicts that may occur, and the scope for nurses in this area to resolve problems resulting from these policies. PMID- 7834142 TI - Nursing diagnoses: a Dutch perspective. AB - In this article, the authors adopt a position with respect to the definition of 'nursing diagnosis'. Two central functions of a classification system for nursing diagnoses are distinguished: domain and communication. Seven issues related to the development of such a classification system are discussed. These issues are of a methodological, philosophical and practical nature. A proposal is made for further study and development of a Dutch classification system for nursing diagnoses, preferably in collaboration with NANDA. PMID- 7834143 TI - [The health structure legislation 1993--is it really the salvation of our health care system?]. PMID- 7834144 TI - [Basis and state of quality assurance in nursing]. PMID- 7834145 TI - [Portrait of a reader: Ursula Stienecker. "For years I lifted the wrong way"Interview by Elisabeth von Samson]. PMID- 7834146 TI - [Introducing Gertrud Stocker, a teacher of nursing professions at the switchplate of power]. PMID- 7834148 TI - ["Surgery in the basement ought to be prohibited". Nurses demand standards of quality for surgery]. PMID- 7834147 TI - [Students demand practical instruction in the functional services]. PMID- 7834149 TI - ["Nursing is not a glutted profession". Interview by Eyke Gerster]. PMID- 7834150 TI - [Changing of the guard in pediatric nursing. Andreas Kray from Neuss is the successor of Elisabeth Oltrogge from Hannover]. PMID- 7834151 TI - [Human support is the supreme commandment. Analysis of problems of older tumor patients regarding therapy and care]. PMID- 7834152 TI - [What the dying need from the caring. Accompaniment requires respect for the patient]. PMID- 7834153 TI - [Diabetes mellitus: one of the most frequent disorders in our focus]. PMID- 7834154 TI - [A diabetic pregnancy is always a risk pregnancy. In spite of this diabetic women have a good chance of having a healthy baby]. PMID- 7834155 TI - [We would not think of striking. Nursing and unions can not yet find each other]. PMID- 7834156 TI - [A plea for the use of mentors. A student poll shows up deficiencies in teaching]. PMID- 7834157 TI - [Less work, lower costs, better quality of life. Experiences with the use of a special air mattresses for the prevention of decubitus ulcers]. PMID- 7834158 TI - [Lumbar pain and exhaustion--are they unavoidable? The simplest aids are often lacking in home care]. PMID- 7834159 TI - NSAID-related adverse drug interactions with clinical relevance. An update. AB - The prevalence and incidence of adverse drug interactions involving NSAIDs remain unknown. To identify those proposed drug interactions of greatest clinical significance, it is appropriate to focus on interactions between commonly used and/or commonly coprescribed drugs, interactions for which there are numerous well documented case reports in reputable journals, interactions validated by well designed in vivo human studies and interactions affecting high-risk drugs and/or high-risk patients. While most interactions between NSAIDs and other drugs are pharmacokinetic, NSAID-related pharmacodynamic interactions may be considerably more important in the clinical context. However, prescriber ignorance is likely to be a major determinant of many adverse drug interactions. Adverse drug interactions involving NSAIDs may be restricted by rational prescribing and by careful monitoring, particularly high-risk patients, drugs and therapy periods. Prescribing NSAIDs is relatively contra-indicative for patients on oral anticoagulants due to hemorrhage and for patients taking high dose methotrexate due to bone marrow toxicity, renal failure and hepatic dysfunction. Combination NSAID therapy cannot be justified since toxicity may be increased without any improvement in efficacy. Where lithium or antihypertensives are coprescribed with NSAIDs, aspirin or sulindac are preferred and close monitoring is mandatory for lithium toxicity and hypertension respectively. Phenytoin or oral hypoglycemic agents may be administered with NSAIDs other than pyrazoles and salicylates, provided, the patients are monitored carefully at the initiation and cessation of NSAID treatment. Digoxin, aminoglycosides and probenecid may be coprescribed with NSAIDs but close monitoring is required, particularly for high risk patients such as the elderly. Indomethacin and triamterine should be avoided due to the risk of renal failure, high dose aspirin should be replaced by naproxen in patients on sodium valproate and care is required when corticosteroids are administered to patients taking salicylates long term in high dosage. Interactions between NSAIDs and antacids or cholestyramine are generally avoidable by administering these drugs at different times. PMID- 7834160 TI - Oxygen release kinetics in healthy subjects and diabetic patients. I: The role of 2,3-diphosphoglycerate. AB - Glycosylated hemoglobin (HbA1c), found in higher concentration in diabetic patients (average 9% versus 5% in healthy subjects), has an approximately ten fold higher oxygen affinity than non-glycosylated hemoglobin (HbA0). But the oxygen affinity in blood from diabetic patients does not differ from that in healthy subjects. Thus, it was concluded that 2,3-DPG, which lowers the oxygen affinity of hemoglobin by stabilizing deoxyhemoglobin and which is increased in diabetic patients, compensates for the effect of HbA1c. Therefore, oxygen release kinetics of hemoglobin in diabetic patients (HbA1c = 9.3 +/- 0.3%) and healthy subjects (HbA1c = 5.2 +/- 0.3%) were compared and the influence of 2,3-DPG determined using the stopped flow technique. The oxygen dissociation rate constant (k) of hemoglobin from the two groups did not differ (diabetic patients, 64.4 +/- 3.1 s-1 and healthy subjects, 65.1 +/- 2.3 s-1). Addition of supraphysiological concentrations of 2,3-DPG produced physiologically insignificant changes in this parameter. It is concluded that 2,3-DPG may not be the major factor compensating for the effect for HbA1c on oxygen release in diabetic patients. PMID- 7834161 TI - Effects of caffeine or ethanol on treadmill performance and metabolic responses of well-trained men. AB - The effects of caffeine and ethanol on treadmill performance and metabolic responses to exercise were determined in four trained runners. Caffeine (2.5 mg.kg-1 body weight) or ethanol (25 ml) in 150 ml of grapefruit juice (total volume) or grapefruit juice (placebo) was randomly administered 10 minutes prior to and at 30 minutes of a 60 minutes treadmill run. The speed and grade of the treadmill was adjusted to elicit an average oxygen consumption of 80-85% of the subject's maximal oxygen consumption. All subjects completed the treadmill run for the caffeine and placebo conditions. Three of the four subjects could not complete the treadmill run following the second administration of ethanol. Exercise heart rate was significantly greater for the ethanol condition than for the placebo condition. Exercise oxygen consumption was greater following ethanol administration than for placebo, but the differences were not significant. Blood glucose rose significantly between 0 and 30 minutes of treadmill running for all three conditions. Between 30 minutes of treadmill running and either 60 minutes or the time of termination of the exercise, blood glucose decreased significantly by 24% following the second ethanol treatment. Plasma fatty acid, triglyceride, creatine phosphokinase, and renin contents followed expected exercise changes with a blunting of the rise of plasma fatty acids at 30 minutes of exercise for the ethanol condition. It was concluded that the administration of ethanol adversely influenced treadmill exercise performance by eliciting a hypoglycemic effect between 30 minutes and the termination of the exercise. PMID- 7834162 TI - Hemodynamic effects of the calcium channel blocker pranidipine on exercise induced angina. AB - Hemodynamic effects of a newly developed calcium channel blocker, pranidipine, on dynamic exercise-induced angina were investigated. Ten patients with stable effort angina pectoris underwent symptom-limited bicycle ergometer exercise testings before and after a single oral administration of pranidipine, and effects of pranidipine on systemic, cardiac and coronary hemo-dynamics induced by dynamic exercise were evaluated invasively. Pranidipine administration reduced systemic vascular resistance (from 1,764 +/- 109 to 1,115 +/- 60 dynes.sec/cm5; p < 0.01 at test, and from 1,120 +/- 102 to 795 +/- 62 dynes.sec/cm5; p < 0.05 at peak exercise) and mean arterial pressure (from 93 +/- 5 to 76 +/- 3 mmHg; p < 0.01 at test, and from 85 +/- 7 to 72 +/- 6 mmHg; p < 0.05 at peak exercise) with the increase in heart rate and cardiac index throughout exercise. Pranidipine also decreased coronary vascular resistance from 1.29 +/- 0.21 to 0.89 +/- 0.17 mmHg/ml/min (p < 0.05) at resting condition. At peak exercise, rate-pressure product and myocardial oxygen consumption decreased (from 237 +/- 21 to 215 +/- 18 x 10(2); p < 0.05, and from 31.3 +/- 7.5 to 21.7 +/- 3.9 ml/min; p < 0.05, respectively), while coronary vascular resistance did not change significantly. Furthermore, pranidipine mitigated ST-segment depression and elevation of pulmonary artery wedge pressure at peak exercise (from 0.20 +/- 0.03 to 0.13 +/- 0.02 mV; p < 0.01, and from 25 +/- 3 to 11 +/- 2 mmHg; p < 0.01, respectively). These results suggest that the major therapeutic effects of pranidipine for dynamic exercise-induced angina would be to reduce myocardial oxygen demand by improving peripheral circulation and reducing preload and afterload.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7834163 TI - Effect of urinary pH on the pharmacokinetics of salicylic acid, with its glycine and glucuronide conjugates in human. AB - We studied the effects of urinary pH on the kinetics of salicylic acid (SA) with its metabolites and assessed the contribution of alkaline hydrolysis of salicylic acid acyl glucuronide to the renal clearance of salicylic acid. Hydrolysis of SAAG in alkaline urine contributes marginally to the high renal clearance and excretion of salicylic acid, validating alkalinization of a patient with SA overdose. Under acidic urine conditions, salicylic acid (SA) had a terminal plasma t1/2 value of 3.29 +/- 0.52 hours while under alkaline urine conditions this t1/2 was significantly reduced to 2.50 +/- 0.41 hours (p = 0.0156). The total oral body clearance of salicylic acid under acidic conditions (1.38 +/- 0.43 l/h) is significantly lower than under alkaline urine conditions (2.27 +/- 0.83 l/h; p = 0.0410). The Km and Vmax values of SA, and its conjugates salicylic acid phenolic glucuronide (SAPG), salicyluric acid (SU) and salicyluric acid phenolic glucuronide (SUPG) did not differ statistically under acidic and alkaline urine conditions. The protein binding of SA was 93.8 +/- 1.0% and that of SU was 89.7 +/- 2.2% in vivo and in vitro. SUPG had a protein binding of 84.8 +/- 1.8%, while SAPG showed no protein binding at all. The renal excretion of salicylic acid depends strongly on the urinary pH. The percentage of the dose excreted unchanged increased from 2.3 +/- 1.5% under acidic conditions to 30.5 +/ 9.1% under alkaline conditions (p = 0.0006). Alkaline urine lowered by 50% the percentage of the dose excreted as SU (p = 0.0028), SAAG (p = 0.0013), and SUPG (p = 0.0296), while SAPG is only marginally lowered (p = 0.0589).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7834164 TI - Biopharmaceutic approach in designing a controlled release tablet of sodium monofluoro phosphate. Characterization of absorption sites and evaluation of modified dosage form. AB - Based on the results from in vivo study in dogs, it was decided to characterize the absorption sites of sodium monofluoro phosphate (NaMFP). It was hypothesized that bioavailability upon p.o. administration can be improved for controlled release dosage forms if the drug release is confined to segments of gastrointestinal tract responsible for absorption. To characterize the principal sites of absorption of NaMFP, in situ segmental absorption studies were carried out in rats. It was found that NaMFP is predominantly absorbed from the small intestine. The larger surface area and presence of alkaline phosphatase enzymes, are attributed to the higher absorption from the small intestine. Based on these results the delivery time was limited to 6 h to restrict the release of the drug within the principal sites of absorption. The dose was adjusted to 160 mg of NaMFP. After studying in vitro release profiles, the drug to polymer ratio was adjusted to 1: 1.1. The modified dosage form was finally subjected to bioavailability studies in humans. An immediate release dosage form was used to compare the efficacy in a two-period crossover study. The extent of bioavailability was 99% and the dosage form was effective in reducing the fluctuations. PMID- 7834165 TI - Endogenous digoxin-like substance in liver failure. AB - Digoxin-like immunoreactive substance (DLIS) has been detected in several patient populations that were not receiving digoxin. We therefore studied the sensitivity of EMIT Convenience Pack Digoxin immunoassay to interference by DLIS in patients with liver failure. Serum digoxin was measured in cirrhotic patients with moderate to severe liver failure (Child-Pugh B or C grade), patients with mild liver disease (chronic hepatitis) and matched control patients without liver disease. Excluded were patients taking or who had ever received any cardiac glycoside in the past. Blood samples were obtained by venipuncture and assayed in duplicate. Twenty-two out of 30 cirrhotic patients (73%) showed false-positive results, vs. one of 6 patients (16.7%) with mild liver disease, and 1 of 10 (10%) controls. The serum DLIS level was negatively correlated with prothrombin activity (r = -0.55, p < 0.00011). Digoxin levels must be interpreted carefully in patients with moderate to severe liver failure. PMID- 7834166 TI - Risk of atherosclerosis in women six years after uterine leiomyoma surgery as compared with healthy women. AB - 44 women at the age between 40 and 60, who underwent uterine leiomyoma surgery six years previously and 45 healthy women were examined for total cholesterol (TC), HDL-cholesterol (HDL-C), LDL-cholesterol (LDL-C), triglycerides (TG) and 17 beta-estradiol (E2). The value of the atherogenic coefficient [sequence: see text] and [sequence: see text] were determined. The clinical condition of the women was also evaluated. It was shown that independently on the extent of surgery, significantly (p < 0.01 and p < 0.001) higher values of LDL-C and lower values (p < 0.05) of atherogenic coefficients of [sequence: see text] were recorded, which is evidence of risk atherosclerosis and coronary heart disease (CHD) in all groups of women. A greater intensity of atherosclerotic changes in women with bilateral oophorectomy (group B'beta) may be connected both with older age and a higher body weight inducing these processes and is evidence of pathogenetic disorders caused by laparotomy. We confirmed that oophorectomy in women with leiomyoma during the perimenopausal period does not result in atherosclerosis and CHD risk when preserving the ovaries during laparotomy. PMID- 7834167 TI - [Comparison of the results of conventional ultrasonography and color doppler analysis in the evaluation of the nature of adnexal tumors. II. Color duplex doppler ultrasonography]. AB - The author evaluates the possibilities of coloured Doppler vaginosonography for prebioptic evaluation of the nature of ovarian tumours. He investigated the site of vascularization of tumours and qualitatively the blood flow by assessing the vascular resistance (PI, RI) and character of the flow velocity curve. The results revealed a statistically significant (p < or = 0.05) trend of central vascularization of malignant tumours. A new parameter with a 100% sensitivity and 89% specificity proved to be the notch at the beginning of the diastolic part of the velocity curve which was not observed in any carcinomas but was present in 89% of benign lesions. The vascular resistance was significantly lower in malignant tumours. The cut off value of malignity of the pulsatility index PI = 0.7 had a 86% sensitivity and 100% specificity. The cut off value of the resistance index RI is 0.6 with a 100% sensitivity and 75% specificity. Comparison of the predictive values of malignity of conventional and coloured duplex ultrasonography revealed that for evaluation of the nature of ovarian tumours coloured duplex sonography with several parameters is more suitable. PI and RI alone can be considered rather as indicators of active growth. PMID- 7834168 TI - [Factors affecting the results of in vitro fertilization. II. The effect of andrologic factors]. AB - We studied 297 couples in our IVF and ET programme and male factor was present in 113 cases (38%). The parameters of standard spermiograms cannot predict the fertilization potential of the specimen in vitro. However, we could demonstrate that the number of the sperm cells after the swim-up procedure correlates very well with the fertilization rate in vitro and pregnancy rate (fertilization rate 63.6% vs. 27.7% in couples with less than 1 million spermcells/ml after swim-up, pregnancy rate 20.2% vs. 5.0%). In these cases the use of the more sophisticated laboratory methods is indicated. PMID- 7834169 TI - [Sexual function in women with breast carcinoma in relation to the time interval after mastectomy]. AB - Within the framework of more extensive research in a group of women after treatment of breast cancer the authors paid attention also to changes of sexual function in relation to the time which elapsed after ablation (modified radical mastectomy). 151 patients replied to the question pertaining to changes of the general status of sexual intercourse after treatment of carcinoma, as compared with the year preceding establishment of the diagnosis. With regard to their replies the probands were divided into four sub-groups: A-paradoxical improvement of sexual life (n = 12, 7.9% of the group, mean age 42.3 years), B-sexual life unaltered (n = 82, 54.3%, mean age 45.1 years), C-slight sexual dysfunction (n = 32, 21.2%, mean age 46.0 years), and D-severe sexual dysfunction (n = 25, 16.6% of the group, mean age 48.3 years). Attention was focused on the time intervals: under one year, 1-2 years and more than 2 years after operation. In addition to an analysis of changes in sexual function the authors compared also the neuroticism of different subgroups assessed by means of a N5 questionnaire. Rather surprisingly the authors proved a significantly more frequent deterioration of sexual function in patients after a prolonged interval following operation. This relationship applies even when the age factor of probands is eliminated. The significantly highest ratio of women with a marked neurotic symptomatology was found in patients with slight sexual dysfunction (subgroup C). PMID- 7834170 TI - [Antibiotic prophylaxis in cesarean section]. AB - Childbirth by Caesarean section is associated with 7-10x more complications than spontaneous childbirth [28] whereby the second place is held by infection. One of the possible ways how to prevent these infectious complications is antibiotic prophylaxis. Views on the latter still differ as regards selection of the antibiotic, its effectiveness, onset of administration, dosage, period of administration etc. Prophylaxis should meet the following demands; it should be aimed, of short-term character, bactericide and non-toxic-these demands are met by cephalosporins of the second generation [11]. The objective of the present work was to evaluate the contribution of the prophylactic administration of antibiotics, i.e. a cephalosporin of the second generation-Zinacef (Cefuroxime). The group was formed by 23 women to whom a dose of Zinacef was administered after childbirth by Caesarean section and subsequently twice after 8-hour intervals (1.5-0.75-0.75 i.m.). The control group (23 women) did not have this prophylaxis. In both groups the authors compared the indication of s.c., time of loss of amniotic fluid before s.c., results of cultivations from the cervix, vagina, amniotic fluid, lochiae and sutures. The authors evaluated the postoperative course where they were interested in infectious complications, the temperature curve, period of hospitalization, the necessity to administer another antibiotic or to proceed with the antibiotic therapy after the prophylactic dose. The results are clearly in favour of the prophylactic administration of antibiotics to the risk group of patients delivering by Caesarean section. PMID- 7834171 TI - [Evaluation of the radical extent of surgery in cancer of the uterine cervix]. PMID- 7834172 TI - [The cesarean section scar and subsequent labor. II. Criteria for subsequent vaginal delivery; risk factors for uterine rupture]. PMID- 7834173 TI - [New findings on the mechanism of sexual maturation]. PMID- 7834174 TI - [Ethical problems in assisted reproduction--gamete donors]. PMID- 7834175 TI - [Discussion of the article by I. Huvar, et al: "Hysteroscopic resection of myomas"]. PMID- 7834176 TI - [Ethical problems in genetic counseling in the area of prenatal diagnosis]. PMID- 7834177 TI - [Case no. 4--nonutilization of CTG monitoring capabilities]. PMID- 7834178 TI - Mutations in transmembrane segment VII of the AT1 receptor differentiate between closely related insurmountable and competitive angiotensin antagonists. AB - Chimeric constructs between the human and the Xenopus laevis AT1 receptor have demonstrated, that the binding of non-peptide angiotensin antagonists is dependent on non-conserved residues located deep in transmembrane segment VII of the AT1 receptor. Here we have studied four pairs of closely related antagonists each consisting of a competitive and an insurmountable compound differentiated by one out of three different types of minor chemical modifications. None of the antagonists bound to the Xenopus receptor and the binding of all of the compounds to the human receptor was severely impaired by the introduction of non-conserved residues from transmembrane segment VII of the Xenopus receptor. In all four pairs of antagonists the competitive compound was affected more by these substitutions than the corresponding insurmountable one (209 vs. 22, 281 vs. 29, 290 vs. 29 and 992 vs. 325-fold increase in Ki values). A similar pattern was observed in response to substitution of a single non-conserved residue in transmembrane segment VII, Asn295 to Ser. These results indicate that a common molecular mechanism distinguishes the interaction of insurmountable and competitive antagonists with the AT1 receptor. PMID- 7834179 TI - Parallel tolerance between platelet cyclic GMP and preload effects of nitroglycerin in anaesthetized mini-pigs. AB - The effects of acute intravenous nitroglycerin (NTG) administration on platelet cyclic GMP in relation to changes in indices of preload (end-diastolic volume) and afterload (effective arterial elastance) were evaluated in the anaesthetized mini-pig, using pressure-volume analysis. NTG (1-30 micrograms kg-1 min-1, i.v.) elicited a dose-dependent fall in preload and afterload, and an increase in arterial blood platelet cyclic GMP. Repeated doses of NTG (30 micrograms kg-1 min 1) resulted in tolerance to the preload but not afterload effects. The increases in platelet cyclic GMP were also attenuated, being highly correlated with the preload changes. Therefore, platelet cyclic GMP appears to reflect NTG-induced venous tolerance, rather than arterial responsiveness. The measurement of platelet cyclic GMP may represent a simple approach for monitoring the degree of venous tolerance to NTG in animals or patients, facilitating further mechanistic investigations. PMID- 7834180 TI - Synergistic inhibition by BQ-123 and BQ-788 of endothelin-1-induced contractions of the rabbit pulmonary artery. AB - In the rabbit isolated pulmonary artery, neither the ETA receptor antagonist, BQ 123 (10 microM), nor the ETB receptor antagonist, BQ-788 (10 microM), inhibited the contractions induced by 1 nM endothelin-1 (ET-1). However, the combination of BQ-123 and BQ-788 completely inhibited the ET-1-induced contraction. In contrast, the ETB-selective agonist, sarafotoxin S6c (1 nM)-induced contraction was completely inhibited by BQ-788 but not by BQ-123. In receptor binding assays, [125I]-ET-1 specific binding to pulmonary arterial membranes was inhibited by BQ 123 (1 microM) by approximately 20% and additive treatment with BQ-788 (1 microM) completely inhibited the BQ-123-resistant component of [125I]-ET-1 specific binding. The present study demonstrates synergistic inhibition by BQ-123 and BQ 788 of ET-1-induced contraction of the rabbit pulmonary artery and the coexistence of ETA and ETB receptors, suggesting that the activation of either only ETA or only ETB receptors may be sufficient to cause complete vasoconstriction. Therefore, blockade of both receptor subtypes would be necessary for the inhibition of some ETA/ETB composite types of responses. PMID- 7834181 TI - Sustained prejunctional facilitation of noradrenergic neurotransmission by adrenaline as a co-transmitter in the portal vein of freely moving rats. AB - 1. The duration of the facilitatory effect of adrenaline on the electrically evoked overflow of noradrenaline was studied in the portal vein of permanently adreno-demedullated freely moving rats. 2. Rats were infused with adrenaline (20 or 100 ng min-1) for 2 h. After an interval of 1 h, when plasma adrenaline had returned to undetectable levels, electrical stimulation resulted in an enhanced catecholamine overflow amounting to 219% (noradrenaline) and 241% (noradrenaline plus adrenaline) of control (saline infusion), respectively. 3. When stimulation was applied again, in the same animal, at 24, 48 and 72 h after the first stimulation episode, the evoked noradrenaline overflow was 150, 111 and 102% (after 20 ng ml-1 adrenaline) and 158, 134 and 105% (after 100 ng min-1 adrenaline) of control. 4. The beta 2-adrenoceptor antagonist, ICI 118,551 (0.3 mg kg-1), blocked the facilitatory effect obtained after the 100 ng min-1 adrenaline infusion on all days. 5. The results show that adrenaline, after being taken up by and released from sympathetic nerve terminals, is able to facilitate the evoked noradrenaline overflow through activation of prejunctional beta 2 adrenoceptors for at least 48 h after administration. PMID- 7834182 TI - Blockade of P2X-purinoceptors by trypan blue in rat vas deferens. AB - 1. The possibility of an antagonist effect of trypan blue at P2X-purinoceptors was studied in rat vas deferens. 2. Trypan blue (3.2-320 microM) shifted the concentration-contraction response curve of alpha,beta-methylene ATP (alpha,beta MeATP) to the right and simultaneously increased the maximum of the curve by up to 40%. The Schild plot had a slope not significantly different from unity and yielded a pA2 value of 5.3 (KB 4.9 microM). 3. Suramin (32 microM) also shifted the concentration-response curve of alpha,beta-MeATP to the right, KB 2.6 microM, and increased the maximum by 31%. In the presence of suramin (32 microM), trypan blue (32 microM) did not change the concentration-response curve of alpha,beta MeATP. 4. 1-Amino-8-naphthol-3, 6-disulphonate (H-acid) 10 mM, the sulphonic acid carrying moiety of trypan blue, shifted the concentration-response curve of alpha,beta-MeATP to the right, KB 1.4 mM, and increased the maximum by 33%. 5. Trypan blue did not change contractions elicited by high K+ and noradrenaline. 6. Trypan blue attenuated the purinergic component of neurogenic contractions, IC50 44.9 microM, but did not change the adrenergic component. 7. It is concluded that trypan blue blocks P2X-purinoceptors in rat vas deferens. The increase of the maximum of the alpha,beta-MeATP concentration-response curve is similar in mechanism to the increase produced by suramin. PMID- 7834183 TI - Characterization of the binding of the first selective radiolabelled histamine H3 receptor antagonist, [125I]-iodophenpropit, to rat brain. AB - 1. The binding of the first selective radiolabelled histamine H3-receptor antagonist [125I]-iodophenpropit to rat cerebral cortex membranes was characterized. 2. [125I]-iodophenpropit, radiolabelled to a high specific activity of 1900 Ci mmol-1, saturably bound to a single class of sites with a KD of 0.57 +/- 0.16 nM (n = 4) and Bmax of 268 +/- 119 fmol mg-1 protein. 3. Specific binding at a concentration below 1 nM represented 50 to 60% of total binding. 4. Binding of [125I]-iodophenpropit to rat cerebral cortex membranes was readily displaced by histamine H3-agonists and antagonists. In contrast, the inhibitory potencies of selective histamine H1- and H2-receptor ligands were very low. 5. [125I]-iodophenpropit was biphasically displaced by the histamine H3 receptor antagonists, burimamide and dimaprit, which may indicate the existence of histamine H3-receptor subtypes. Other histamine H3-receptor antagonists showed a monophasic displacement. 6. Competition binding curves of H3-agonists were biphasic and showed a rightward shift upon the addition of the nonhydrolysable GTP analogue, guanosine 5'-o-(3-thio) triphosphate (GTP gamma S; 100 microM) which implicates the interaction of histamine H3-receptors with G-proteins. The affinities of the H3-receptor antagonists iodophenpropit, thioperamide and burimamide were not altered by GTP gamma S. 7. Histamine competition binding curves were shifted to the right by different nucleotides (100 microM) with a rank order of potency GTP gamma S > Gpp(NH)p, GTP. 8 In vitro autoradiographic studies revealed a heterogeneous distribution of [125I]-iodophenpropitbinding sites in rat brain, with highest densities observed in specific cerebral cortical areas and layers,the caudate-putamen complex, the olfactory tubercles, the hippocampal formation, the amygdala complex, the hypothalamic area and the mammillary bodies.9 It is concluded that the histamine H3-receptor antagonist, [125I]-iodophenpropit, meets the criteria fo ra suitable radioligand for histamine H3-receptor binding studies in rat brain. PMID- 7834184 TI - Sympathetic neurotransmission in the tail artery of aging rats. AB - 1. Age-related changes in noradrenergic neurotransmission in the tail arteries of three rat strains: outbred Wistar (WI/Ico), inbred Wistar (WAG/Rij) and inbred Fischer (F344) have been compared in the present study. 2. The arterial noradrenaline content varied from 5 to 10 ng mg-1 wet weight amongst young (3 to 6-month old) representatives of each strain, but did not change with age. As protein content increased in senescent rats (24-month old) by 30-40%, arterial tissue growth would not appear to receive a concomitant increase in sympathetic growth leading to relative, age-related, structural sympathectomy in all strains. 3. The vasoconstrictor response to transmural electrical stimulation was diminished in adult and senescent rats of all strains. 4. As far as could be judged from the increase in noradrenaline release following perfusion with the alpha-adrenoceptor antagonist, phentolamine (1 microM), the presynaptic alpha 2 adrenoceptor-mediated inhibition of noradrenaline release was intact in old representatives of all strains. 5. With blockade of the two main systems which control noradrenaline release in the rat tail artery, viz, neuronal reuptake with cocaine (4 microM) and presynaptic alpha 2-adrenoceptors with phentolamine (1 microM), stimulation-evoked release of noradrenaline was similar at all ages and in all strains. This suggests that in the rat tail artery the basic mechanism of neuronal release of noradrenaline is not functionally modified by aging. 6 We conclude that as sympathetic nerve terminals are apparently intact in all three strains of senescent rats used, the age-associated deficit of alpha-adrenergic control of vascular function is postsynaptic in nature. PMID- 7834185 TI - Potent contractile actions of prostanoid EP3-receptor agonists on human isolated pulmonary artery. AB - 1. In 13 of 15 experiments, prostaglandin E2 (PGE2) and sulprostone (a prostanoid EP1/EP3-receptor agonist) contracted isolated rings of human pulmonary artery at low concentrations (> or = 5 and > or = 0.5 nM respectively). Tissue was obtained from patients undergoing surgery mainly for carcinoma of the lung. Characterization of the receptors involved was complicated by loss of sensitivity to the contractile PGE action over the experimental period. In contrast, contractile responses to KCl, phenylephrine and the specific thromboxane (TP-) receptor agonist, U-46619, did not decrease with time. 2. The relative contractile potencies for seven PGE analogues, measured during the first few hours after setting up the preparations, were as follows: sulprostone > misoprostol = gemeprost > or = PGE2 > or = GR 63799X > 17-phenyl-omega-trinor PGE2 > or = 11-deoxy PGE1. This ranking indicates that an EP3-receptor is involved. 3. The contractile action of sulprostone was not blocked by the TP receptor antagonists, EP 169 and GR 32191, and the EP1-receptor antagonist, AH 6809. 4. In two experiments, PGE2 (50 nM) reduced basal tone and sulprostone was a weak contractile agent. Phenylephrine-induced tone was also inhibited by PGE2 (EC50 = 5-20 nM), 11-deoxy PGE1 and butaprost (a selective EP2-receptor agonist); the latter prostanoids were about 2 and 4 times less potent than PGE2 respectively. Interactions with phenylephrine were different in experiments where PGE2 alone was contractile: PGE2 induced contraction superimposed on the phenylephrine response and 11-deoxy PGE1 induced either further contraction or had no effect. Butaprost produced relaxation at high concentrations;this may not be an EP2 action since preparations were highly sensitive to relaxant actions of prostacyclin (IP-) receptor agonists (cicaprost and TEI-9063).5 The study has shown that in the majority of experiments on the human isolated pulmonary artery,the contractile EP3 system outweighed the relaxant EP2 system. However, in two experiments the reverse was true. It is not clear to what extent these differences are due to disease processes affecting the tissues.The findings are discussed in relation to the adverse cardiovascular responses occasionally encountered during treatment of postpartum haemorrhage with sulprostone, and more generally to the clinical use of EP-receptor agonists in man. PMID- 7834186 TI - Decrease in calcium currents induced by aminoglycoside antibiotics in frog motor nerve endings. AB - 1. The effects of the aminoglycoside antibiotics, streptomycin, neomycin and gentamicin were examined on perineural currents and evoked acetylcholine (ACh) release at frog motor nerve endings. 2. In the standard solutions used previously to measure Ca2+ currents, streptomycin reduced the peak amplitude of the Ca2+ component of the perineural current. 3. In a solution in which changes in both Ca2+ currents and evoked ACh release can be recorded simultaneously, both Ca2+ currents and evoked ACh release were reduced by aminoglycosides in the potency order neomycin > streptomycin > gentamicin. This potency sequence is similar to that reported previously for these agents as inhibitors of neurally-evoked contractions of mammalian skeletal muscle. 4. These data suggest that the presynaptic inhibitory effects of aminoglycoside antibiotics at the neuromuscular junction occur as a consequence of a reduction in Ca2+ currents in the motor nerve terminal. PMID- 7834187 TI - Differential inhibition of neuronal calcium entry and [3H]-D-aspartate release by the quaternary derivatives of verapamil and emopamil. AB - 1. Verapamil and emopamil are structurally related phenylalkylamine calcium channel/5-HT2 receptor antagonists that differ in their anti-ischaemic properties in experimental studies. The quaternary ammonium derivatives of these compounds were prepared and tested in assays of neuronal voltage-sensitive calcium channel (VSCC) function to determine whether the compounds act at intra- or extracellular sites. 2. The compounds were tested in K(+)-evoked: (1) rat brain synaptosomal 45Ca2+ influx, (2) release of [3H]-D-aspartate from rat hippocampal brain slices and (3) increase of intracellular calcium in rat cortical neurones in primary culture. 3. Verapamil, emopamil and the emopamil quaternary derivative caused concentration-dependent and comparable (IC50 values approximately 30 microM) inhibition of synaptosomal 45Ca2+ influx and [3H]-D-aspartate release. The verapamil quaternary derivative was considerably less active in these assays (IC50 > 300 microM). 4. The evoked increase of intracellular calcium in cortical neurones was inhibited with the following rank order of potency (IC50 value, microM): emopamil (3.6) > verapamil (17) > emopamil quaternary derivative (38) > verapamil quaternary derivative (200). 5. The results suggest that verapamil and emopamil inhibit nerve terminal VSCC function (synaptosomal 45Ca2+ influx and [3H]-D-aspartate release) by acting at distinct intracellular and extracellular sites, respectively. Verapamil and emopamil may inhibit cell body VSCC function (evoked increase of intracellular calcium in neocortical neurones) by acting at both intracellular and extracellular sites. 6. The different 'sidedness' of action of emopamil and verapamil on nerve terminal VSCC function and/or the preferential inhibition of cell body VSCC function by emopamil may at least partially explain the relatively greater neuroprotective efficacy of emopamil in experimental models of ischaemia. PMID- 7834188 TI - Antiplatelet activities of FK409, a new spontaneous NO releaser. AB - 1. We reported that (+/-)-(E)-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexeneamide (FK409) released nitric oxide (NO) spontaneously with a chemiluminescence analyzer. The aim of this study was to compare antiplatelet activities of FK409, a new NO releaser, with those of isosorbide dinitrate (ISDN) in vivo and in vitro. In order to elucidate the differences in antiplatelet activities between FK409 and ISDN, we compared their modes of action. 2. In in vitro experiments, FK409 had a more potent inhibitory effect on rat platelet aggregation induced by adenosine 5'-diphosphate (2.0 microM) than ISDN (IC50 = 4.32 +/- 0.95 microM and > 100 microM respectively). 3. In the rat extracorporeal shunt model (in vivo experiments), FK409 suppressed thrombus formation dose-dependently from 0.32 mg kg-1, p.o. and showed the maximum inhibition (52% inhibition vs. vehicle treatment) at 10 mg kg-1, p.o., while ISDN showed no inhibition at 10 mg kg-1 and only 17% inhibition at 32 mg kg-1, p.o. 4. FK409 could generate nitrite, which is an oxidative product of NO, much faster than ISDN in phosphate buffer solution and rat plasma during 60-min incubation at 37 degrees C. 5. These data show that FK409 has more potent antiplatelet effects than ISDN, by acting through spontaneously released NO. PMID- 7834189 TI - Up-regulation of [3H]-des-Arg10-kallidin binding to the bradykinin B1 receptor by interleukin-1 beta in isolated smooth muscle cells: correlation with B1 agonist induced PGI2 production. AB - 1. Binding of the specific bradykinin B1 receptor agonist, [3H]-des-Arg10 kallidin (-KD) was investigated in smooth muscle cells (SMC) isolated from rabbit mesenteric arteries (RMA). 2. [3H]-des-Arg10-KD specifically bound to interleukin 1 (IL-1)-treated RMA-SMC in a saturable fashion with an equilibrium dissociation constant (KD) of 0.3-0.5 nM. The number of binding sites per cell was 20,000 35,000. Kinins inhibited [3H]-des-Arg10-KD binding to RMA-SMC with an order of potency very similar to that observed in typical B1 specific bioassays: des-Arg9 bradykinin (BK) approximately KD >> BK. Furthermore, the B1 receptor antagonist [Leu8]des-Arg9-BK inhibited [3H]-des-Arg10-KD binding with an IC50 of 43 nM as expected for its effect at B1 receptors. The B2 receptor antagonists, NPC 567 and Hoe 140 only affected [3H]-des-Arg10-KD binding at very high concentrations (IC50 = 0.8 microM and IC50 > 10 microM, respectively). 3. Des-Arg9-BK (B1 agonist) and [Hyp3]Tyr(Me)8-BK (B2 agonist) did not induce prostacyclin (PGI2) production by RMA-SMC. Lipopolysaccharide (LPS) treatment of the cells did not affect the B1 agonist response whereas IL-1 beta treatment produced a 7 fold increase in des Arg9-BK-stimulated PGI2 production. IL-1 beta also stimulated the response to B2 agonists. 4. Des-Arg9-BK-induced PGI2 secretion in IL-1-primed RMA-SMC was mediated by B1 receptors since it was inhibited by [Leu8]des-Arg9-BK (IC50 = 56 73 nM) but not by Hoe 140. High concentrations of NPC 567 (IC5o = 2.4 micro M) were required to inhibit PGI2 production induced by B1 agonists.5. IL- 1-treated RMA-SMC displayed a 5 fold increase in the number of B1 receptors without modification of the affinity constant, thus establishing a possible relationship between the receptor density and the IL-i-primed B1 response.6. LPS treatment of the cells induced a 4 fold increase in B1 receptor number without modifying PGI2 secretion. This observation suggests that IL-1 but not LPS, in addition to increase in the number of receptors, signals the cell to permit the coupling of B1 receptors to the PLA2/cyclo-oxygenase pathway. PMID- 7834190 TI - Effects of the calcium channel blockers, diltiazem and Ro 40-5967, on systemic haemodynamics and plasma noradrenaline levels in conscious dogs with pacing induced heart failure. AB - 1. Calcium channel blockers increase cardiovascular morbidity and mortality in patients with left ventricular dysfunction. These adverse effects are probably related to the negative inotropic effect of calcium channel blockers and/or a neurohormonal activation. 2. The present study was designed to examine, in conscious dogs, the acute haemodynamic and sympathetic effects of diltiazem and Ro 40-5967 (a novel calcium channel blocker) in the control state and in heart failure. 3. Thirteen dogs were instrumented with a micromanometer and an aortic catheter. After completion of experiments in the control state, heart failure was induced by right ventricular pacing (250 beats min-1, 3 weeks). Diltiazem and Ro 40-5967 were given intravenously (0.8 mg kg-1 and 1.0 mg kg-1 respectively). Cardiac output was measured by a thermodilution technique. 4. In the control state, both agents decreased similarly mean aortic pressure with significant increases in heart rate, cardiac output (both +1.0 l min-1 and P < 0.001) and plasma noradrenaline (both +55%) without changes in left ventricular dP/dtmax. In heart failure, for matched decreases in mean aortic pressure, neither diltiazem nor Ro 40-5967 changed heart rate significantly; diltiazem decreased cardiac output (-0.3 l min-1, P < 0.02) and dP/dtmax (-14%, P < 0.001) while Ro 40-5967 still increased cardiac output (+0.3 l min-1, P < 0.02) although the increased amount was smaller than in the control state. Plasma noradrenaline level was increased more during diltiazem infusion (+120%) than during Ro 40-5967 infusion (+38%, P < 0.001). 5. Diltiazem and Ro 40-5967 have similar haemodynamic and sympathetic effects in the control state.Heart failure alters haemodynamic and sympathetic responses to both calcium channel blockers but the magnitude of the alteration appears to be different. Diltiazem exerts a depressant effect on cardiac function which cannot be overcome by its vasodilator effect and sympathetic stimulation, while Ro 40-5967 has little effect on cardiac function. These data suggest that novel calcium channel blockers with less depressant effect may not be detrimental in heart failure. PMID- 7834191 TI - Relaxation of human isolated mesenteric arteries by vasopressin and desmopressin. AB - 1. The effects of vasopressin and deamino-8-D-arginine vasopressin (DDAVP, desmopressin) were studied in artery rings (0.8-1 mm in external diameter) obtained from portions of human omentum during the course of abdominal operations (27 patients). 2. In arterial rings under resting tension, vasopressin produced concentration-dependent, endothelium-independent contractions with an EC50 of 0.59 +/- 0.12 nM. The V1 antagonist d(CH2)5Tyr(Me)AVP (1 microM) and the mixed V1 V2 antagonist desGly-d(CH2)5D-Tyr(Et)ValAVP (0.01 microM) displaced the control curve to vasopressin to the right in a parallel manner without differences in the maximal responses. In the presence of indomethacin (1 microM) the contractile response to vasopressin was significantly increased (P < 0.01). 3. In precontracted arterial rings, previously treated with the V1 antagonist, d(CH2)5Tyr(Me)AVP (1 microM), vasopressin produced endothelium-dependent relaxation. This relaxation was reduced significantly (P < 0.05) by indomethacin (1 microM) and unaffected by the V1-V2 receptor antagonist desGly-d(CH2)5D Tyr(Et)ValAVP (1 microM) or by NG-nitro-L-arginine methyl ester (L-NAME, 0.1 mM). 4. The selective V2 receptor agonist, DDAVP, caused endothelium-independent, concentration-dependent relaxations in precontracted arterial rings that were inhibited by the mixed V1-V2 receptor antagonist, but not by the V1 receptor antagonist or by pretreatment with indomethacin or L-NAME. 5. Results from this study suggest that vasopressin is primarily a constrictor of human mesenteric arteries by V1 receptor stimulation; vasopressin causes dilatation only during V1 receptor blockade. The relaxation appears to be mediated by the release of vasodilator prostaglandins from the endothelial cell layer and is independent of V2 receptor stimulation or release of nitric oxide. In contrast, the relaxation induced by DDAVP is largely dependent on stimulation of V2 receptors. PMID- 7834192 TI - Effects of intrinsic prostaglandins on the spontaneous contractile and electrical activity of the proximal renal pelvis of the guinea-pig. AB - 1. The effects of blocking prostaglandin biosynthesis with indomethacin on the spontaneous electrical and contractile activity recorded in smooth muscle strips of the guinea-pig renal pelvis were examined using standard tension and membrane potential recording techniques. 2. Circumferentially cut strips of proximal renal pelvis contracted more frequently (4.5 +/- 0.2 min-1) than strips cut from the mid region (1.3 +/- 0.2; P < 0.05, n = 5) of the renal pelvis. 3. Indomethacin (1 nM-10 microM) reduced the amplitude and frequency of the contractions of the renal pelvis in a concentration- and time-dependent manner. Contractions were completely abolished in the presence of 30 microM indomethacin. 4. After indomethacin blockade, activation of prostaglandin F2 alpha (PGF2 alpha) receptors with dinoprost (1-100 nM) restored the amplitude and frequency of the spontaneous contractions of renal pelvis. Higher concentrations of dinoprost (> 100 nM-3 microM) increased the contraction amplitude of the proximal and mid renal pelvis 1.9 and 1.6 times respectively. The contraction frequency of the mid renal pelvis, but not the proximal pelvis, was also raised above its pre indomethacin frequency. 5. The spontaneous electrical activity recorded in proximal strips of the renal pelvis was designated to come from three cell types: (i), pacemaker cells (10% of cells recorded), with simple action potentials comprising relatively slow rising and repolarizing phases triggered on top of a slowly-developing pre-potential; (ii), driven cells (75% of cells), with complex action potentials comprising a rapid initial spike, followed by a period of membrane oscillation and a plateau of 0.2-2 s duration; and (iii), intermediate cells (15%) which fired action potentials with an initial rapid and a long plateau phase. 6. Indomethacin (10-30 micro M) decreased the amplitude and frequency of the action potentials recorded in driven and intermediate cells. The membrane potential of these cells also depolarized 5mV to-51.2 +/-2.6mV (n=5).7. Dinoprost (300 nM-1.5 micro M) increased the rate of action potential discharge, without affecting the membrane potential of driven cells previously exposed to indomethacin (30 micro M).8. These data suggest that the endogenous release of prostaglandins is necessary for the in vitro spontaneous contractile activity recorded in the guinea-pig renal pelvis. Blockade of the synthesis of these prostaglandins appears either to modify the ability of the driven regions of the renal pelvis to fire action potentials or to reduce the coupling of these driven regions to their pacemaker cells. PMID- 7834193 TI - Inhibition of glucocorticoid-induced epidermal and dermal atrophy with KH 1060--a potent 20-epi analogue of 1,25-dihydroxyvitamin D3. AB - 1. The possibility of preventing and treating glucocorticoid-induced skin atrophy with KH 1060 (the potent 20-epi-22-oxa-24a-homo-26,27-dimethyl analogue of 1,25 dihydroxyvitamin D3) was examined in a hairless mouse model. 2. KH 1060 (0.625 6.25 pmol cm-2 of skin) applied topically for 7 days together with 2.5 nmol cm-2 betamethasone-17-valerate prevented, in a concentration-dependent manner, the development of epidermal, dermal and total skin thinning caused by the glucocorticoid. The effect of KH 1060 on the epidermis occurred at a lower dose than on the dermis, and at doses above 1.25 pmol cm-2 KH 1060 caused epidermal hyperplasia. 3. KH 1060 (2.5 pmol cm-2) prevented the development of betamethasone-associated skin atrophy in mice during a long-term (4 weeks) treatment, and reversed established cutaneous glucocorticoid atrophy. 4. Radiolabelling experiments with [35S]-sulphate and [3H]-proline in vivo revealed that KH 1060 stimulated the synthesis of sulphated glycosaminoglycans and hydroxyproline in skin treated with betamethasone. 5. These findings strongly suggest that KH 1060 prevents and reverses glucocorticoid-induced skin atrophy by stimulating epidermal proliferation and enhancing synthesis of extracellular matrix in the dermis. PMID- 7834194 TI - Role of phosphodiesterases III and IV in the modulation of vascular cyclic AMP content by the NO/cyclic GMP pathway. AB - 1. The effect on cyclic nucleotide contents of selective inhibitors of cyclic nucleotide phosphodiesterase (PDE) isoforms III and IV (respectively SK&F 94120 and rolipram) and their interactions with endothelium and NO have been studied in rat aorta in the presence of indomethacin (10 microM). The participation of NO was assessed by using either NG-nitro-L-arginine methyl ester (L-NAME) (NO synthase inhibitor: 30 microM) or 3-morpholinosydnonimine (SIN-1, NO donor: 10 microM with SOD 100 units ml-1). 2. The presence of endothelium significantly increased both adenosine 3':5'-cyclic monophosphate (cyclic AMP, 1.7 fold) and guanosine 3':5'-cyclic monophosphate (cyclic GMP, 2.2 fold) contents. Cyclic GMP was largely affected by L-NAME or SIN-1 treatment, this was not the case for cyclic AMP suggesting that the presence of endothelium modified cyclic AMP content in aorta independently of the NO production. 3. In the presence or absence of endothelium, neither SK&F 94120 nor rolipram, alone or combined, significantly modified cyclic GMP content. 4. The PDE III inhibitor significantly affected cyclic AMP content only in non treated aorta without endothelium. In contrast, the PDE IV inhibitor increased cyclic AMP in all conditions. These increases were generally about 2 fold but markedly higher in aorta treated with SIN-1 and superoxide dismutase (SOD, 6 fold). Association of a low concentration of the PDE III inhibitor (5 microM) with the PDE IV inhibitor (30 microM) potentiated the effect of the PDE IV inhibitor on cyclic AMP content, except for aorta without endothelium treated with SIN-1 plus SOD. 5. These data indicate that the presence of the endothelium could increase cyclic AMP content independently of NO and prostacyclin (PGI2) production. Furthermore, an increase in cyclic GMP content (modulated by NO production) could enhance the cyclic AMP accumulation induced by the PDE IV inhibitor. This result supports the hypothesis that PDE III inhibition by endogenous cyclic GMP may potentiate the effect of PDE IV inhibition on cyclic AMP content. Taken together with our previous studies on relaxation, these results suggest that the NO/cyclic GMP pathway could induce PDE IV-dependent regulation of cyclic AMP via PDE III inhibition. PMID- 7834195 TI - Differential potentiation by depolarization of the effects of calcium antagonists on contraction and Ca2+ current in guinea-pig heart. AB - 1. The effects of elevation of extracellular K+ concentration ([K+]o) on the negative inotropic potencies of three representative calcium antagonists, diltiazem, verapamil and nifedipine, were investigated in guinea-pig papillary muscle preparations. 2. The negative inotropic effect of diltiazem was potentiated 110 fold when [K+]o was raised from 2.7 mM to 12.7 mM. The effect of verapamil was also potentiated to a lesser extent, but that of nifedipine was not affected. 3. Resting membrane potentials in ventricular muscles were about -80 mV and -60 mV in 2.7 mM K+ and 12.7 mM K+, respectively. 4. To clarify the mechanism responsible for the differential potentiation of the negative inotropic effects, the blocking actions of the three calcium antagonists on the L-type Ca2+ channel current (ICa(L)) were compared at the holding potentials of -80 mV and -60 mV by the whole-cell patch-clamp technique. 5. The use-dependent blocking effect of diltiazem on ICa(L) was enhanced markedly by the change in the holding potential from -80 mV to -60 mV. The effect of verapamil was also enhanced to a lesser extent but that of nifedipine was not affected in this range of depolarization. 6. The differential effects of the [K+]o elevation on the negative inotropic potencies of the three calcium antagonists are explained by the differences in voltage-dependency of their use-dependent blocking effects on ICa(L). 7. The properties of diltiazem and verapamil observed in this study may contribute to their protective effects on the ischaemic myocardium, without affecting the normal myocardium. PMID- 7834196 TI - Release of Ca2+ from intracellular store in smooth muscle cells of rat portal vein by ATP-induced Ca2+ entry. AB - 1. The action of adenosine 5'-triphosphate (ATP, 10 microM) was studied in single patch-clamped smooth muscle cells of rat portal vein where the free internal Ca2+ concentration in the cell (Cai) was estimated by the emission from the dye indo 1. 2. In the presence of 20 microM gallopamil (D600), a blocker of voltage dependent Ca2+ channels, ATP applied to cells held at a holding potential of -60 mV evoked a transient inward current and an increase in Cai. 3. The rise in Cai evoked by ATP was completely suppressed in the absence of external Ca2+ although a transient inward current was still observed. 4. ATP-induced responses were not modified by the addition of the inositol 1,4,5-trisphosphate receptor antagonist, heparin (1 mM) in the pipette solution. 5. In the presence of caffeine (5 mM) or ryanodine (100 microM) in the pipette solution, which deplete the intracellular Ca2+ store, the ATP-induced Cai rise was greatly reduced. 6. Our results suggest that in single cells from rat portal vein, ATP releases Ca2+ from intracellular stores without involving InsP3, but via a Ca2+ release mechanism activated by Ca2+ influx through ATP-gated channels. PMID- 7834197 TI - Effects of divalent cations on the potency of ATP and related agonists in the rat isolated vagus nerve: implications for P2 purinoceptor classification. AB - 1. By use of a 'grease-gap' technique, the depolarizing effects of adenosine 5' triphosphate (ATP) and ATP analogues on the rat isolated vagus nerve were determined in normal and in Ca2+/Mg(2+)-free (+ 1 x 10(-3) M ethylenediamine tetraacetic acid) physiological salt solution (PSS). 2. In normal PSS, ATP produced concentration-dependent depolarization responses but the concentration effect curve to ATP was incomplete and a maximum effect was not achieved. The threshold concentration for depolarization was 1 x 10(-5) M and at the highest concentration tested (1 x 10(-3) M) the peak amplitude of the response to ATP only amounted to 71% of the depolarization produced by a near maximal response to 5-hydroxytryptamine (5-HT, 1 x 10(-5) M). 3. In Ca2+/Mg(2+)-free PSS, ATP produced depolarization responses at much lower concentrations and of markedly larger amplitude. Under these conditions, the threshold concentration for depolarization was 1-3 x 10(-7) M and the maximal response to ATP amounted to 526% of the response to 5-HT (1 x 10(-5) M) in normal PSS. The concentration effect curve to ATP was sigmoid, with a defined maximum effect and a mean EC50 value of 1.2 x 10(-6) M. 4. In contrast to the effects on responses to ATP, the absence of divalent cations in the PSS did not modify the effective concentrations of either alpha, beta-methylene ATP or 5-HT. However, the maximum responses to both alpha, beta-methylene ATP and 5-HT were significantly increased in Ca2+/Mg(2+)-free PSS. 5. The depolarizing effects of several analogues of ATP were determined in Ca2+/Mg2+-free PSS.ATP-gamma-S and 2-methylthioATP were of similar potency to ATP (respective equi-effective molar ratios(EMRs) of 1.9 and 1.3, where ATP = 1) and similar maximum responses were obtained. Alpha, beta MethyleneATP, beta, gamma-methylene ATP and ,beta, gamma-imido ATP were considerably less potent than ATP, analysis yielding mean EMRs of 48.9, 85.0 and 60.0, respectively. Maximum responses to these latter three agonists were not obtained at the highest concentrations tested (1 x 10-4-3 X 10- M). Benzoyl ATP, adenosine 5'-0-(2-thiodiphosphate) and adenosine diphosphate produced only small depolarizing responses at high concentrations (>1 x 10-4 M). Adenosine monophosphate, adenosine and uridine S'-triphosphate each had little or no depolarizing effect in Ca2+/Mg2+-free PSS.6. These data demonstrate that in the absence of divalent cations the excitatory actions of some, but not all, purine nucleotides in the rat vagus nerve are markedly potentiated. In Ca2+/Mg2+-free PSS, the rank order of agonist potencies was ATP = 2-methylthioATP = ATP-gamma S>> alpha,beta-methylene ATP = beta, gamma imido ATP = P,y-methylene ATP. These findings are in stark contrast to our previous observations in normal PSS where the rank order of agonist potencies for these nucleotides was alpha,beta methyleneATP> ATP-gamma-S > beta,gamma-imido ATP = beta,gamma-methylene ATP> 2 methylthioATP> ATP.7. We suggest that the two different rank orders of potency can be explained by differential metabolism involving Ca2+/Mg2+-dependent ectonucleotidases. If so, these data indicate that ATP and 2-methylthioATP are inherently more potent than alpha,beta-methylene ATP as agonists at neuronal P2X purinoceptors in the rat vagus nerve. The possible implications of these findings to the present system for subclassifying P2 purinoceptors are profound. PMID- 7834199 TI - Modulation by neuropeptide Y of parasympathetic nerve-evoked nasal vasodilatation via Y2 prejunctional receptor. AB - 1. In pentobarbitone anaesthetized dogs, preganglionic stimulation of the superior cervical sympathetic nerve (15V, 1 ms, 10 Hz) induced marked reduction of nasal arterial blood flow, whereas parasympathetic nerve stimulation (5 V, 1 ms, 10-30 Hz) evoked frequency-dependent vasodilatation. 2. Sympathetic nerve stimulation for 3 min at 10 Hz evoked significant (P < 0.05) and prolonged attenuation of the vasodilator response to subsequent parasympathetic stimulation. Pretreatment with phentolamine (0.5 mg kg-1 h-1), propranolol (1 mg kg-1) and atropine (0.5 mg kg-1) reduced the vasoconstrictor effect of sympathetic stimulation by 35 +/- 4% whereas the parasympathetic nerve-evoked vasodilatation was not significantly modified. Atropine-resistant parasympathetic vasodilatation remained significantly attenuated for more than 30 min after non adrenergic sympathetic nerve-evoked vasoconstriction. 3. Vasodilator effects of exogenous vasoactive intestinal polypeptide and peptide histidine isoleucine and vasoconstrictor effects of exogenous neuropeptide Y (NPY) and the NPY analogue [Leu31, Pro34] NPY (Y1-receptor agonist, 8 nmol kg-1), were not altered by adrenoceptor antagonists and atropine f1p4eas the effects of exogenous noradrenaline and acetylcholine were virtually abolished. Attenuation of parasympathetic-evoked vasodilatation could be mimicked by exogenous NPY (8 nmol kg-1) and the NPY analogue, N-acetyl [Leu28, Leu31] NPY 24-36 (Y2-receptor agonist, 20 nmol kg-1) but not by exogenous Y1-receptor agonist. The Y2-receptor agonist did not show significant vasoconstrictor action. 4. It is concluded that sympathetic nerve stimulation attenuates parasympathetic vasodilatation via NPY release acting on prejunctional Y2 receptors. PMID- 7834198 TI - Inhibitory effect of strychnine on acetylcholine receptor activation in bovine adrenal medullary chromaffin cells. AB - 1. Strychnine, which is known as a potent and selective antagonist of the inhibitory glycine receptor in the central nervous system, inhibits the nicotinic stimulation of catecholamine release from bovine cultured adrenal chromaffin cells in a concentration-dependent (1-100 microM) manner. At 10 microM nicotine, the IC50 value for strychnine is approximately 30 microM. Strychnine also inhibits the nicotine-induced membrane depolarization and increase in intracellular Ca2+ concentration. 2. The inhibitory action of strychnine is reversible and is selective for nicotinic stimulation, with no effect observed on secretion elicited by a high external K+ concentration, histamine or angiotensin II. 3. Strychnine competes with nicotine in its effect, but not modify the apparent positive cooperatively of the nicotine binding sites. In the absence of nicotine, strychnine has no effect on catecholamine release. Glycine does not affect catecholamine release nor the inhibitory action of strychnine on this release. 4. These results suggest that strychnine interacts with the agonist binding site of the nicotinic acetylcholine receptor in chromaffin cells, thus exerting a pharmacological effect independently of the glycine receptor. PMID- 7834200 TI - Modulation of 5-HT release in the guinea-pig brain following long-term administration of antidepressant drugs. AB - 1. The aims of the present study were to determine whether long-term 5 hydroxytryptamine (5-HT) reuptake blockade and inhibition of type-A monoamine oxidase (MAO-A) lead to an enhancement of the electrically evoked release of tritum from guinea-pig brain slices preloaded with [3H]-5-HT, and to assess the sensitivity of the terminal 5-HT1D autoreceptor, the alpha 2-adrenoceptor also located on 5-HT terminals, and the 5-HT3 receptor that modulates 5-HT release following these two types of antidepressant treatments. 2. The electrically evoked release of tritium was significantly enhanced following a 21-day treatment with the 5-HT reuptake blocker, paroxetine and the reversible MAO-A inhibitor, befloxatone, in preloaded slices of the hypothalamus, hippocampus and frontal cortex 48 h after removal of the osmotic minipumps used to deliver the drugs. 3. The inhibitory effect of the terminal 5-HT autoreceptor agonist, 5 methoxytryptamine, on the evoked release of tritium was attenuated in slices of the hypothalamus, hippocampus, but not frontal cortex, following the paroxetine treatment. In the befloxatone group, the effectiveness of 5-methoxytryptamine was unaltered in the same brain structures. 4. The sensitivity of the alpha 2 adrenoceptor on 5-HT terminals, assessed using UK 14.304, was attenuated in hypothalamus, hippocampus, but not frontal cortex slices prepared from befloxatone-treated guinea-pigs and preloaded with [3H]-5-HT. The paroxetine treatment did not alter the sensitivity of this alpha 2-adrenoceptor in the hypothalamus. 5. The sensitivity of the alpha 2-adrenoceptor on noradrenaline terminals, also assessed using UK 14.304, was not altered in hippocampus and hypothalamus slices preloaded with [3H]-noradrenaline following the long-term befloxatone treatment. 6. In frontal cortex slices, [3H]-5-HT uptake was no longer significantly attenuated after a 21-day treatment with paroxetine, whereas it was still markedly inhibited in hypothalamus slices. The enhancing effect of paroxetine on the evoked release of [3H]-5-HT in the superfusion medium was no longer evident in frontal cortex slices of the paroxetine group. These data indicate that long-term 5-HT reuptake blockade desensitized the 5-HT transporter in the frontal cortex. 7. The capacity of the 5-HT3 receptor agonist, 2 methyl-5 HT, to enhance the electrically evoked release of tritium was not altered in hypothalamus, hippocampus, and frontal cortex slices prepared from befloxatone treated guinea-pigs, but was significantly attenuated in the paroxetine group also treated for 21 days. Following a 2-day paroxetine treatment, the enhancing effect of 2-methyl-5-HT on tritium release was unaltered in frontal cortex slices. PMID- 7834201 TI - Blockade by ifenprodil of high voltage-activated Ca2+ channels in rat and mouse cultured hippocampal pyramidal neurones: comparison with N-methyl-D-aspartate receptor antagonist actions. AB - 1. The block by ifenprodil of voltage-activated Ca2+ channels was investigated in intracellular free calcium concentration ([Ca2+]i) evoked by 50 mM K+ (high [K+]o) in Fura-2-loaded rat hippocampal pyramidal neurones in culture and on currents carried by Ba2+ ions (IBa) through Ca2+ channels in mouse cultured hippocampal neurones under whole-cell voltage-clamp. The effects of ifenprodil on voltage-activated Ca2+ channels were compared with its antagonist actions on N methyl-D-aspartate- (NMDA) evoked responses in the same neuronal preparations. 2. Rises in [Ca2+]i evoked by transient exposure to high-[K+]o in our preparation of rat cultured hippocampal pyramidal neurones are mediated predominantly by Ca2+ flux through nifedipine-sensitive Ca2+ channels, with smaller contributions from nifedipine-resistant, omega-conotoxin GVIA-sensitive Ca2+ channels and Ca2+ channels sensitive to crude funnel-web spider venom (Church et al., 1994). Ifenprodil (0.1-200 microM) reversibly attenuated high-[K+]o-evoked rises in [Ca2+]i with an IC50 value of 17 +/- 3 microM, compared with an IC50 value of 0.7 +/- 0.1 microM for the reduction of rises in [Ca2+]i evoked by 20 microM NMDA. Tested in the presence of nifedipine 10 microM, ifenprodil (1-50 microM) produced a concentration-dependent reduction of the dihydropyridine-resistant high-[K+]o evoked rise in [Ca2+]i with an IC50 value of 13 +/- 4 microM. The results suggest that ifenprodil blocks Ca2+ flux through multiple subtypes of high voltage activated Ca2+ channels. 3. Application of the polyamine, spermine (0.25-5 mM), produced a concentration-dependent reduction of rises in [Ca2+]i evoked by high [K+]o. The antagonist effects of ifenprodil 20 micro M on high-[K+]0-evoked rises in [Ca2+]. were attenuated by spermine 0.25 mM but not by putrescine 1 or 5 mM. In contrast,spermine 0.1 mM increased rises in [Ca2+]i evoked by NMDA and enhanced the ifenprodil (5 micro M) block of NMDA-evoked rises in [Ca2+]i.4. Similar results were obtained in mouse cultured hippocampal pyramidal neurones under whole-cell voltage-clamp. Ifenprodil attenuated both the peak and delayed whole-cell IB. with an IC% value of 18 +/- 2 micro M, whilst it attenuated steady state NMDA-evoked currents with an IC50 of 0.8 +/- 0.2 micro M. Block of IBa by ifenprodil 10 JaM was rapid in onset, fully reversible and occurred without change in thecurrent-voltage characteristics of Ba. The ifenprodil block of IBa was enhanced on membrane depolarization and was weakly dependent on the frequency of current activation. Spermine 0.1 mM potentiated control NMDA-evoked currents but attenuated IB,. In agreement with the microspectrofluorimetric studies, co application of spermine produced a small enhancement of the inhibitory effect of ifenprodil 10 micro M on NMDA-evoked responses whereas the reduction of I4 by ifenprodil 10 micro M in the presence of spermine was less than expected if the inhibitory effects of ifenprodil and spermine on IBa were simply additive.5. The results indicate that ifenprodil blocks high voltage-activated Ca2+ channels in rat and mouse cultured hippocampal pyramidal neurones. Although the Ca2+ channel blocking actions of ifenprodil are observed at higher concentrations than those associated with NMDA antagonist activity, Ca2+ channel blockade may contribute, at least in part, to the established neuroprotective and anticonvulsant properties of the compound. PMID- 7834202 TI - Role of kinins in anaphylactic-induced bronchoconstriction mediated by tachykinins in guinea-pigs. AB - 1. In the present study, we have investigated the role of kinins in allergen induced bronchoconstriction. 2. Anaesthetized guinea-pigs were sensitized to ovalbumin, ventilated artificially, pretreated with atropine (1.4 mumol kg-1, i.v.) and total pulmonary resistance (RL) measured. In preliminary studies in the presence of the neutral endopeptidase inhibitor, phosphoramidon (4.5 mumol kg-1, i.v.), the bradykinin B2 receptor antagonist Hoe 140 (0.1 mumol kg-1, i.v.) completely abolished the increase in RL following aerosolized bradykinin (1 mM, 40 breaths), but had no effect on the increase in RL following aerosolized neurokinin A (NKA, 10 microM, 40 breaths). On the other hand, a combination of the NK1 (CP-96,345, 2 mumol kg-1, i.v.) and NK2 (SR 48968, 0.3 mumol kg-1, i.v.) tachykinin receptor antagonists abolished completely the increase in RL produced by NKA and partially inhibited the increase in RL produced by bradykinin. These results confirm previous studies that suggest that bradykinin induces the release of tachykinins from sensory nerves in guinea-pig airways. 3. Aerosolized ovalbumin (0.5%, 5 breaths) increased RL in sensitized guinea-pigs pretreated with atropine (1.4 mmol kg-1, i.v.), an effect that began within 2 min and reached a maximum within 5 min; RL remained above baseline at 20 min. Pretreatment with the bradykinin B2 receptor antagonist, Hoe 140, decreased the bronchoconstrictor effect of ovalbumin markedly at 10 to 20 min. In the presence of phosphoramidon (4.5 mumol kg-1, i.v.) the inhibition induced by Hoe 140 was apparent earlier and remained over the 20 min period of study. 4. Pretreatment with a combination of NK1 (CP-96,345) and NK2 (SR 48968) tachykinin receptor antagonists also markedly inhibited ovalbumin-induced bronchoconstriction; addition of the bradykinin B2 receptor antagonist to the NK1 and NK2 tachykinin receptor antagonists had no additional inhibitory effect on antigen-induced bronchoconstriction.5. These findings confirm that activation of sensory nerves to release tachykinins in guinea-pig airways contribute to antigen-induced bronchoconstriction, and provide evidence that tachykinin release is due to kinins generated during the allergic response. PMID- 7834203 TI - Differential effects of the PAF receptor antagonist UK-74,505 on neutrophil and eosinophil accumulation in guinea-pig skin. AB - 1. The effect of the dihydropyridine, platelet activating factor (PAF) receptor antagonist, UK-74,505, on leucocyte accumulation and oedema formation in guinea pig skin was investigated. The inflammatory reactions studied were elicited by exogenous mediators, a passive cutaneous anaphylactic (PCA) reaction and zymosan particles. 2. Leucocyte accumulation and oedema formation were measured as the local accumulation of i.v. administered 111In-labelled neutrophils or eosinophils together with 125I-labelled albumin. UK-74,505 was either administered i.v. or used to pretreat the radiolabelled leucocytes in vitro prior to their last wash and injection into recipient animals. 3. In vitro, UK-74,505 inhibited PAF induced elevations in cytoplasmic levels of Ca2+ ([Ca2+]i) in fura-2-loaded guinea-pig neutrophils and eosinophils with IC50 values of 10(-9) M and 7 x 10( 9) M respectively. Neutrophils and eosinophils pretreated with 10(-7) M and 10( 6) M UK-74,505 respectively, and maintained at 37 degrees C, were unresponsive to PAF for the 4 h period investigated. 4. In vivo, using 2 h test periods, i.v. UK 74,505 (0.5 and 2.5 mg kg-1) inhibited the accumulation of 111In-neutrophils, 111In-eosinophils and oedema formation induced by intradermal PAF, but had no effect on responses elicited by leukotriene B4 (LTB4) and zymosan-activated plasma (ZAP, used as a source of C5a des Arg). UK-74,505 (2.5 mg kg-1) was also without an effect on response induced by a PCA reaction but significantly suppressed the 111In-eosinophil accumulation following the intradermal administration of zymosan particles. The 111In-neutrophil accumulation induced by zymosan particles was not, however, affected by UK-74,505. 5. In a second series of in vivo experiments, "'In-leucocytes were pretreated in vitro with UK-74,505 prior to their last wash and injection into recipient animals. Radiolabelled neutrophils, and eosinophils were pretreated with 10-7 M and 10-6 M UK-74,505 respectively, concentrations previously shown to block the leucocyte responses to PAF in vitro for up to 4 h. The in vitro pretreatment of the cells with the PAF antagonist, whilst not affecting the responses to intradermally-injected PAF, suppressed the"'In-eosinophil accumulation response induced by zymosan particles.6. The results of this study indicate that PAF is not involved in neutrophil accumulation, eosinophil accumulation and oedema formation induced by LTB4, ZAP and a PCA reaction. Endogenous PAF does, however, appear to have a role in zymosan-induced eosinophil accumulation but not neutrophil accumulation, suggesting the existence of different inflammatory pathways in the induction of neutrophil and eosinophil accumulation in vivo. Furthermore, while leucocyte accumulation induced by exogenous PAF does not appear to involve leucocyte PAF receptors, the mechanism by which endogenous PAF mediates the zymosan-induced eosinophil accumulation appears dependent on the expression of PAF receptors on eosinophils. PMID- 7834204 TI - Block of the delayed rectifier current (IK) by the 5-HT3 antagonists ondansetron and granisetron in feline ventricular myocytes. AB - 1. We investigated the effects of two 5-HT3 antagonists, ondansetron and granisetron, on the action potential duration (APD) and the delayed rectifier current (IK) of feline isolated ventricular myocytes. Whole-cell current and action potential recordings were performed at 37 degrees C with the patch clamp technique. 2. Ondansetron and granisetron blocked IK with a KD of 1.7 +/- 1.0 and 4.3 +/- 1.7 microM, respectively. At a higher concentration (30 microM), both drugs blocked the inward rectifier (IKl). 3. The block of IK was dependent on channel activation. Both drugs slowed the decay of IK tail currents and produced a crossover with the pre-drug current trace. These results are consistent with block and unblock from the open state of the channel. 4. Granisetron showed an intrinsic voltage-dependence as the block increased with depolarization. The equivalent voltage-dependency of block (delta) was 0.10 +/- 0.04, suggesting that granisetron blocks from the intracellular side at a binding site located 10% across the transmembrane electrical field. 5. Ondansetron (1 microM) and granisetron (3 microM) prolonged APD by about 30% at 0.5 Hz. The prolongation of APD by ondansetron was abolished at faster frequencies (3 Hz) showing reverse rate dependence. 6. In conclusion, the 5-HT3 antagonists, ondansetron and granisetron, are open state blockers of the ventricular delayed rectifier and show a clear class III action. PMID- 7834205 TI - Inhibition of the glutamate transporter and glial enzymes in rat striatum by the gliotoxin, alpha aminoadipate. AB - 1. The effect of the gliotoxic analogue of glutamate, alpha aminoadipate, on the high affinity transport of D-[3H]-aspartate into a crude striatal P2 preparation, and on the activity of two enzymes of which glutamate is the substrate has been examined. 2. The L-isomer of alpha aminoadipate competitively inhibited the transport protein, with a Ki value of 192 microM, whereas the D-isomer of alpha aminoadipate was ineffective. The potent convulsant, L-methionine-S-sulphoximine, was also without effect on the activity of the glutamate transport protein. 3. L alpha Aminoadipate was a competitive inhibitor of both glutamine synthetase, and gamma-glutamylcysteine synthetase, with Ki values of 209 microM and 7 mM respectively. Once again, the D-isomer of alpha aminoadipate was a far weaker inhibitor of either enzyme. 4. The results are discussed in terms of the mechanism of action of alpha aminoadipate in causing toxicity of glial cells. PMID- 7834206 TI - Peptide histidine isoleucine-like immunoreactivity release from the rat gastric fundus. AB - 1. Longitudinal muscle strips from the rat gastric fundus were subjected to in vitro electrical field stimulation (EFS) under non-adrenergic non-cholinergic (NANC) conditions to study the release of peptide histidine isoleucine-like immunoreactivity (PHI-LI) and the correlation between PHI-LI release and NANC relaxation. 2. Different radioimmunoassay (RIA) systems employing C-terminal- and N-terminal-specific anti-PHI sera were used to determine the relative contributions of PHI and its C-terminally extended forms, peptide histidine glycine (PHI-Gly) and peptide histidine valine [PHV(1-42)], to the PHI-LI released by the rat gastric fundus. 3. In the presence of atropine (1 microM) and guanethidine (5 microM), EFS (120 mA, 1 ms, 0.25-32.0 Hz, trains of 2 min) induced frequency-dependent relaxations of 5-hydroxytryptamine (3 microM) pre contracted strips. 4. EFS at frequencies of 8-32 Hz evoked significant increases in PHI-LI outflow. The increases in PHI-LI outflow evoked by 16-Hz EFS were abolished by tetrodotoxin (3 microM) and by a calcium-free medium, indicating an active release process from intramural nerves. 5. The EFS-induced release of PHI LI measured with the N-terminal-specific antiserum was significantly greater than that detected with the C-terminal-specific antisera. 6. Sephadex G-25 gel permeation chromatographic analysis was performed on the PHI-LI release in response to 32-Hz EFS. A C-terminal-specific antiserum revealed one peak co eluting with the rat PHI standard. When PHI-LI was measured with the N-terminal specific antiserum, two peaks were found that co-eluted with the rat PHV(1-42) and rat PHI-Gly/PHI standards, respectively. 7. The present data suggest that the extended forms of PHI are the primary components of the PHI-LI released by NANC inhibitory neurones in the rat gastric fundus and support a NANC inhibitory neurotransmitter role for PHI and its extended forms in this tissue. PMID- 7834207 TI - Cooling effects on nitric oxide production by rabbit ear and femoral arteries during cholinergic stimulation. AB - 1. Ear (cutaneous) and femoral (deep) arteries from rabbit were perfused at 37 degrees C and 24 degrees C (cooling) and the production of nitrite, as an index of nitric oxide production, was measured under basal conditions and cholinergic stimulation. 2. In both types of arteries under control conditions, the basal production of nitrite was similar at 24 degrees C and 37 degrees C. Compared with the control conditions, the basal production of nitrite was significantly lower in ear and femoral arteries without endothelium or treated with NG-nitro-L arginine methyl ester (L-NAME, 10(-4) M) but it was similar in those treated with atropine (10(-6) M). 3. At 37 degrees C, methacholine (10(-7)-10(-5) M) increased the production of nitrite in ear and femoral arteries; this increase persisted during 30-60 min and was practically abolished by L-NAME (10(-4) M), atropine (10(-6) M), or removal of the endothelium. In ear arteries the total nitrite production to activation with methacholine was higher at 24 degrees C than at 37 degrees C due to this production persisted increased for a longer period (> 150 min), whereas in femoral arteries it was lower at 24 degrees C than at 37 degrees C. 4. It is suggested that: (a) the endothelium of rabbit ear and femoral arteries produce nitric oxide under basal conditions, which is increased by cholinergic stimulation, and (b) cooling potentiates endothelial nitric oxide production to cholinergic stimulation in cutaneous arteries, whereas it inhibits this production in deep arteries. PMID- 7834208 TI - Trichloroethanol potentiation of gamma-aminobutyric acid-activated chloride current in mouse hippocampal neurones. AB - 1. The action of 2,2,2-trichloroethanol on gamma-aminobutyric acid (GABA) activated Cl- current was studied in mouse hippocampal neurones in tissue culture by use of whole-cell patch-clamp recording. 2. Trichloroethanol increased the amplitude of currents activated by 1 microM GABA or 0.1 microM muscimol. Trichloroethanol, 1-25 mM, potentiated current activated by 1 microM GABA in a concentration-dependent manner with an EC50 of 3.0 +/- 1.4 mM and a maximal response (Emax) of 576 +/- 72% of control. 3. Trichloroethanol potentiated currents activated by GABA concentrations < 10 microM, but did not increase the amplitude of currents activated by concentrations of GABA > or = 10 microM. Despite marked potentiation of currents activated by low concentrations of GABA, trichloroethanol did not significantly alter the EC50, slope, or Emax of the GABA concentration-response curve. 4. Trichloroethanol, 5 mM, potentiated GABA activated current in neurones in which ethanol, 10-500 mM, did not. The effect of trichloroethanol was not altered by the putative ethanol antagonist, Ro 15-4513. Trichloroethanol did not potentiate currents activated by pentobarbitone. 5. In the absence of exogenous GABA, trichloroethanol at concentrations > or = 2.5 mM activated a current that appeared to be carried by Cl- as its reversal potential changed with changes in the Cl- gradient and as it was inhibited by the GABAA antagonists, bicuculline methiodide and picrotoxin. 6. Since trichloroethanol is thought to be the active metabolite of chloral hydrate and other chloral derivative anaesthetics, potentiation of the GABA-activated current in central nervous system neurones by trichloroethanol may contribute to the sedative/hypnotic effects of these agents. PMID- 7834209 TI - Developmental changes in ANP-stimulated guanylyl cyclase activity enhanced by ATP in rat lung membrane fractions. AB - 1. ANP (atrial natriuretic peptides)- or ANP/ATP-stimulated guanylyl cyclase activities were compared in adult (2 month old) and neonatal (5-7 day old) rat lung membrane fractions. 2. The enzyme activities of both membranes depended on the incubation time and ATP concentration: although the activities of both membranes were similar after a short incubation time (4 min), those in adult membranes were lower than those of neonatal membranes after longer incubation times (10 and 30 min) or at lower concentrations of ATP. 3. ANP/ATP gamma S stimulated guanylyl cyclase activities, which were much higher than ANP/ATP stimulated activities, were similar in both membranes. 4. ATPase activity of adult membranes was higher than that of neonatal membranes, suggesting that hydrolysis of ATP leads to a decrease of ANP/ATP-guanylyl cyclase activity in adult membranes. Triton X-100 enhanced and diminished ANP/ATP-stimulated guanylyl cyclase activities of adult and neonatal membranes, respectively, and thereby abolished the adult/neonatal difference in the membrane response to ATP. 5. ANP stimulated activities of both membranes were much more activated by pre incubation with ATP gamma S than those induced by simultaneous addition of ATP gamma S. The former activities were decreased to levels of the latter by Triton X 100. The latter activities were not affected by Triton X-100. 6. The present results suggested that conformation of lung plasma membranes is related to activation of the ANP receptor/guanylyl cyclase system. PMID- 7834210 TI - The effects of aldose reductase inhibition with ponalrestat on changes in vascular function in streptozotocin diabetic rats. AB - 1. The responses of rat isolated aortae to vasoconstrictor and vasodilator agents have been studied in 14-day streptozotocin-diabetic rats. The effects of treatment with the aldose reductase inhibitor, ponalrestat, on these responses have also been investigated. 2. Maximum contractile responses and aortic sensitivity to phenylephrine were significantly enhanced in 14-day diabetic aortae. 3. In contrast, endothelium-dependent relaxations to carbachol were depressed in diabetic rats, whilst endothelium-independent relaxations to forskolin and sodium nitroprusside were unchanged. 4. Pretreatment with ponalrestat (25 mg kg-1, daily) prevented both the enhanced maximum contractile responses to phenylephrine and the depressed endothelium-dependent relaxations to carbachol in aortae from 14-day diabetic rats. Ponalrestat however, had no effect on the reduced phenylephrine EC50 values observed in tissues from diabetic animals. 5. It is concluded that ponalrestat prevents the depression of endothelium-dependent aortic relaxations induced by diabetes of 14 days duration, suggesting that the polyol pathway is involved in these vascular changes. Ponalrestat does not prevent the increase in aortic sensitivity to alpha 1 adrenoceptor agonists. PMID- 7834211 TI - Characterization of prostanoid receptors on rat neutrophils. AB - 1. The effects of various prostanoid agonists have been compared on the increase in intracellular free calcium ([Ca2+]i) and the aggregation reaction of rat peritoneal neutrophils induced by N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP). 2. Prostaglandin E2 (PGE2) and the specific IP-receptor agonist, cicaprost, both inhibited the FMLP-induced increase in [Ca2+]i (IC50 33 nM and 18 nM respectively) and the FMLP-induced aggregation reaction (IC50 5.6 nM and 7.9 nM respectively). PGD2, PGF2 alpha, and the TP-receptor agonist, U 46619, were inactive at the highest concentration tested (1 microM). 3. The EP1-receptor agonist, 17-phenyl-omega-trinor PGE2, and the EP3-receptor agonists, GR 63799X and sulprostone, had no inhibitory effect on FMLP-stimulated rat neutrophils. 4. PGE1 (EP/IP-receptor agonist) and iloprost (IP-receptor agonist) inhibited the FMLP-induced increase in [Ca2+]i with IC50 values of 34 nM and 38 nM respectively. The EP2-receptor agonists, butaprost and misoprostol (1 microM), inhibited both FMLP-stimulated [Ca2+]i and aggregation. However another EP2 receptor agonist, AH 13205, was inactive in both assays. 5. Prostanoid receptors present on rat neutrophils were further characterized by measuring [3H]-adenosine 3':5'-cyclic monophosphate ([3H]-cyclic AMP) accumulation. Only those agonists capable of stimulating [3H]-cyclic AMP accumulation were able to inhibit both FMLP-stimulated [Ca2+]i and aggregation. 6. These results indicate that rat neutrophils possess inhibitory IP and EP-receptors; the relative potencies of PGE2, misoprostol and butaprost are those expected for the EP2-receptor subtype. No evidence for DP, FP, TP or EP1 and EP3-receptors was obtained. PMID- 7834212 TI - Inhibitory transmitter action of calcitonin gene-related peptide in guinea-pig ureter via activation of glibenclamide-sensitive K channels. AB - 1. In single sucrose gap, electrical field stimulation (EFS, 1-5 Hz) produced graded hyperpolarization of the membrane of the guinea-pig ureter smooth muscle, which was blocked by tetrodotoxin (0.3 microM) or in vitro capsaicin desensitization (3 microM for 15 min). Capsaicin itself produced a transient hyperpolarization of the membrane on its first application. 2. Superfusion with human alpha calcitonin gene-related peptide (CGRP, 30-300 mM) likewise produced a transient hyperpolarization of the membrane, mimicking the neurogenic inhibitory junction potential (i.j.p.). The hyperpolarization by CGRP was unaffected by tetrodotoxin, indicating a postjunctional site of action. 3. Both the EFS-evoked i.j.p. and the CGRP-induced hyperpolarization were inhibited by the CGRP receptor antagonist, CGRP(8-37) (0.3-3 microM) which did not affect the hyperpolarization produced by the KATP channel opener, cromakalim (0.3 microM). 4. The KATP channel blocker, glibenclamide (1 microM) blocked both the EFS-evoked i.j.p. and the CGRP induced hyperpolarization. 5. When evoked in a low K medium (1.2 mM, KCl being replaced by an equimolar amount of NaCl), the EFS-evoked i.j.p. and the CGRP induced hyperpolarization were both markedly enhanced, consistent with the idea that opening of K channels underlies both responses. 6. The present findings provide direct electrophysiological evidence for a neurotransmitter role of CGRP, released from the peripheral endings of capsaicin-sensitive primary afferent neurones, in the guinea-pig ureter. The action of both exogenous and endogenous CGRP involves the activation of glibenclamide-sensitive (KATP) potassium channels. PMID- 7834213 TI - Block of human voltage-sensitive Na+ currents in differentiated SH-SY5Y cells by lifarizine. AB - 1. The ability of lifarizine (RS-87476) to block human voltage-sensitive Na+ channel currents was studied by use of whole cell patch clamp recording from differentiated neuroblastoma cells (SH-SY5Y). 2. The Na+ conductance in differentiated SH-SY5Y cells (24.0 +/- 2.4 nS, n = 11) was half-maximally activated by 10 ms depolarizations to -37 +/- 2 mV and was half-maximally inactivated by predepolarizing pulses of 200 ms duration to -86 +/- 3 mV (n = 11). 3. At low stimulus frequencies (0.1 to 0.33 Hz) voltage-dependent sodium currents were completely blocked, in a concentration-dependent manner, by extracellular application of either tetrodotoxin (EC50 = 4 +/- 1 nM, n = 12) or by lifarizine (EC50 = 783 +/- 67 nM, n = 9). The onset of block by lifarizine (tau = 91 +/- 14 s at 10 microM) was considerably slower than that of tetrodotoxin (tau = 16 +/- 3 s at 100 nM). 4. Lifarizine (1 microM) reduced the peak sodium conductance in each cell (from 26.4 +/- 2.0 nS to 15.1 +/- 2.7 nS, n = 4) without changing the macroscopic kinetics of sodium current activation or inactivation (V1/2 = -35 1 mV and -87 +/- 4 mV respectively, n = 4). Similarly, lifarizine (1 microM) did not affect the reversal potential of the macroscopic sodium current (+14 +/- 5 mV in control and +16 +/- 2 mV in 1 microM lifarizine; n = 4) or reactivation time-constant (tau = 14.0 +/- 4.4 ms). 5. Block of the sodium channel open state by tetrodotoxin (30 nM) did not prevent the inhibition caused by a subsequent application of lifarizine (3 micro M). In contrast the depression caused by lifarizinewas readily reversible after pretreatment of cells with the local anaesthetic, lignocaine (1O mM).6. These data demonstrate that lifarizine is a use- and voltage-dependent antagonist of human voltage sensitive sodium currents. The slow kinetics and pharmacology of the block by lifarizine indicate that access of this drug to the channel is more restricted than that of tetrodotoxin and may involve an allosteric site or state of the channel that is also regulated by local anaesthetics. PMID- 7834214 TI - Bradykinin B2 receptors and coupling mechanisms in the smooth muscle of the guinea-pig taenia caeci. AB - 1. In the smooth muscle of the guinea-pig taenia caeci, bradykinin produces a relaxation followed by a contraction. In the presence of hexamethonium and guanethidine, both these phases of the response were insensitive to tetrodotoxin (100 nM), omega-conotoxin GVIA (100 nM) and ibuprofen (1 microM), suggesting that they are due to a direct action on the smooth muscle. 2. The B1 receptor selective agonist, [des-Arg9]-BK (1-100 microM), was inactive in the taenia caeci, and the B1 receptor-selective antagonist, [Leu8,des-Arg9]-BK (1-10 microM), did not inhibit either phase of the bradykinin-induced response. The B2 receptor-selective antagonist, D-Arg-[Hyp3,Thi5,D-Tic7,Oic8]-BK (Hoe 140) (30-300 nM), inhibited both the bradykinin-induced relaxation and contraction with a similar affinity (apparent pKB estimates of 8.5 +/- 0.1 and 8.4 +/- 0.1 respectively). 3. In a depolarizing high-K(+)-solution, bradykinin produced concentration-related contractions, though of diminished magnitude; but no relaxation was observed in such media. In Krebs solution, the Ca(2+)-activated K(+)-channel blocker, apamin (10 nM), abolished relaxant responses. These observations suggest that contraction results both from membrane potential dependent, and membrane potential-independent, mechanisms; whereas relaxant responses result entirely from membrane potential-dependent mechanisms. Contractile responses obtained in the high K(+)-solution were inhibited by D-Arg [Hyp3,Thi5,D-Tic7,Oic8]-BK with an apparent pKB value of 8.4 +/- 0.1. 4. In a Ca(2+)-free, EGTA-containing medium, relatively high concentrations of bradykinin (> 100 nM) produced transient contractions, suggesting that a component of the contractile response results from release of Ca2+ from an intracellular store. This intracellular Ca2+ store could be refilled in the presence of extracellular Ca2+. The B, receptor antagonist, [Leu8,des-Argj-BK (10 micro M), did not inhibit this bradykinin-induced contraction, whereas the B2 receptor antagonist, D-Arg [Hyp3,Thi5,D-Tic7,Oic8]-BK(100 nM) markedly attenuated it (P<0.001; n = 6).5. Bradykinin (10 nM- 100 micro M) significantly elevated tissue levels of total [3H]-inositol phosphates in the presence of Li?, after incubation with myo-[3H] inositol. The B, receptor-selective agonist, [des-Argl-BK(100IM) did not stimulate [3H]-inositol phosphate formation, and the B, receptor-selective antagonist,[Leu8,des-Argl-BK, did not inhibit the formation of [3H]-inositol phosphates in response to a submaximal concentration of bradykinin (1I0 1M; P> 0.05). Two B2 receptor antagonists, D-Arg-[Hyp3,DPhe7]-BK and D-Arg-[Hyp3,Thi5,D Tic7,Oic8]-BK, inhibited bradykinin-induced accumulation of total[3H]-inositol phosphates with apparent pKB estimates of 5.4 +/0 0.3 and 8.4 +/- 0.1, respectively.6. These data suggest that in the guinea-pig taenia caeci, the five aspects of the action of bradykinin studied (the relaxant and the contractile elements of the biphasic mechanical response, the contractile response in a depolarizing high-K' solution medium and zero-Ca2+ media, and stimulation of phosphatidylinositol turnover), all result from activation of B2 receptors. A possible causal relationship is suggested between these B2 receptor-mediated membrane potential-dependent, and -independent events,and their roles in excitation contraction coupling. PMID- 7834215 TI - Differential effects of P2-purinoceptor antagonists on phospholipase C- and adenylyl cyclase-coupled P2Y-purinoceptors. AB - 1. Stimulation of P2Y-purinoceptors on turkey erythrocytes and many other cell types results in activation of phospholipase C. In contrast, we have observed recently that P2Y-purinoceptors on C6 rat glioma cells are not coupled to phospholipase C, but rather, inhibit adenylyl cyclase. 2. In this study we investigated the pharmacological selectivity of the P2-purinoceptor antagonists, suramin, reactive blue 2, and pyridoxal phosphate 6-azophenyl 2',4'-disulphonic acid (PPADS) for phospholipase C- and adenylyl cyclase-coupled P2Y-purinoceptors. 3. In C6 glioma cells, suramin and reactive blue 2 competitively antagonized the inhibitory effect of 2MeSATP on adenylyl cyclase (pKB = 5.4 +/- 0.2 and 7.6 +/- 0.1, respectively), whereas PPADS at concentrations up to 100 microM had no effect. 4. In contrast, in the turkey erythrocyte preparation, PPADS at concentrations up to 30 microM was a competitive antagonist of P2Y-purinoceptor stimulated phospholipase C activity (pKB = 5.9 +/- 0.1). Suramin and reactive blue 2 produced both a shift to the right of the concentration-effect of 2MeSATP for the activation of phospholipase C and a significant decrease in the maximal inositol phosphate response. 5. Turkey erythrocytes also express a phospholipase C-coupled beta-adrenoceptor. Concentrations of PPADS that competitively inhibited the P2Y-purinoceptor-mediated response had only minimal effects on the activation of phospholipase C by beta-adrenoceptors. In contrast, suramin and reactive blue 2 produced a non-competitive inhibition, characterized by decreases in the maximal response to isoprenaline with no change in the potency of this beta adrenoceptor agonist. 6. The differential effect of PPADS on P2Y-purinoceptors of C6 glioma cells and turkey erythrocytes adds further support to the idea that different P2Y-purinoceptor subtypes mediate coupling to adenylylcyclic and phospholipase C. PMID- 7834216 TI - Muscarinic (M1) receptor-mediated inhibition of K(+)-evoked [3H]-noradrenaline release from human neuroblastoma (SH-SY5Y) cells via inhibition of L- and N-type Ca2+ channels. AB - 1. Human neuroblastoma (SH-SY5Y) cells were preincubated with [3H]-noradrenaline ([3H]-NA) in the presence of 0.2 mM pargyline to examine the modulation of K(+) evoked [3H]-NA release by muscarinic agonists. 2. Release of [3H]-NA evoked by 4 min exposure to 100 mM K+ could be partially inhibited by 5 microM nifedipine and partially inhibited by 100 nM omega-conotoxin GVIA (omega-CgTx). When nifedipine and omega-CgTx were added together, evoked release was inhibited by approximately 93%. 3. K(+)-evoked [3H]-NA release was inhibited by > 90% by pretreatment of cells for 2 min with muscarine, carbachol or oxotremorine methiodide (each at 300 microM). For muscarine, inhibition of evoked release was both time- and concentration-dependent and was reversible. Muscarine also inhibited [3H]-NA release evoked by veratridine (28 microM) and replacement of extracellular Ca2+ with Ba2+, but not that evoked by the Ca2+ ionophore, A23187 (19 microM). 4. Residual K(+)-evoked [3H]-NA release measured in the presence of either nifedipine (5 microM) or omega-CgTx (100 nM) was inhibited by muscarine with a similar potency as release evoked in the absence of either Ca2+ channel blocker. Pretreatment of cells for 16-24 h with pertussis toxin (200 ng ml-1) did not affect K(+)-evoked release per se or the ability of muscarine to inhibit such release. 5. Muscarinic inhibition of K(+)-evoked [3H]-NA release was potently antagonized by pirenzepine (pA2 8.14) and by hexahydrosiladiphenidol (pA2 9.03), suggesting the involvement of an M1 receptor. 6. Our results demonstrate that 100 mM K+-evoked release of [3H]-NA from the human neuroblastoma is mediated by activation of both L- and N-type Ca2+ channels. Activation of muscarinic Ml receptors can inhibit release via a pertussis toxin-insensitive mechanism which involves non-selective inhibition of L- and N-type Ca2+ channels. PMID- 7834217 TI - Mediation by SRIF1 receptors of the contractile action of somatostatin in rat isolated distal colon; studies using some novel SRIF analogues. AB - 1. The motor effects of somatostatin-14 (SRIF), and several SRIF peptide analogues were investigated on the rat isolated distal colon. The objective of these studies was to characterize the receptor mediating the contractile action of SRIF by comparing the relative agonist potencies of a range of SRIF analogues. 2. SRIF (1 nM-1 microM) produced concentration-dependent contractions with an EC50 value of approximately 10 nM. Contractile responses induced by SRIF were insensitive to atropine (1 microM) or naloxone (1 microM) but abolished by tetrodotoxin (1 microM). Somatostatin-28 (SRIF28), also induced concentration dependent contractions and was equipotent with SRIF. Phosphoramidon (1 microM) and amastatin (10 microM) did not increase the potency of either SRIF or SRIF28. 3. The SRIF peptide analogues, octreotide, SRIF25, seglitide, angiopeptin and CGP23996 (1 nM-1 microM) produced contractile responses in the rat distal colon, each having similar potency and maximal activity relative to SRIF. The SSTR2 receptor-selective hexapeptide, BIM23027 (0.1 nM-1 microM), and the SRIF stereoisomer, D-Trp8-SRIF (0.1 nM-1 microM), were the most potent agonists examined being approximately 12 and 7 times more potent than SRIF, respectively. In contrast, the SSTR5 receptor-selective analogue, L362,855, was approximately 120 times weaker than SRIF, whilst the SSTR3 receptor-selective analogue, BIM23056, was inactive at concentrations up to 3 microM. 4. The putative SRIF receptor antagonist, (cyclo(7-aminoheptanoyl Phe-D-Trp-Lys-Thr[Bzl]))(CPP) (1 microM), had no agonist activity and had no effect on contractions induced by SRIF. 5. The contractile actions of BIM23027 and seglitide were subject to pronounced desensitization. Desensitization of preparations by BIM23027 (0.3 JIM) abolished the contractile action of SRIF andSRIF28 but had no effect on contractions produced by acetylcholine (0.1 nM-I1M), suggesting thatBIM23027, SRIF and SRIF28 act via a common receptor mechanism.6. In conclusion, the rat isolated distal colon contracts in response to SRIF and a number of SRIF analogues. Seglitide and octreotide exhibited similar potency and maximal activity relative to SRIF,suggesting that in the rat colon the receptor mediating contraction belongs to the SRIF,-receptor group,of which the recombinant SSTR2, SSTR3 and SSTR5 receptors appear to be subtypes. The high potency of BIM23027, the weak agonist activity of L362,855 and the lack of activity exhibited by BIM23056suggests that the SRIF receptor mediating contraction in the rat distal colon is similar to there combinant SSTR2 receptor. PMID- 7834219 TI - Physical and genetic mapping of human chromosome 3 loci containing microsatellite repeats. AB - One hundred and six microsatellite repeat-containing loci, including 59 CA containing repeats from the CEPH/Genethon collection, were regionally assigned on human chromosome 3 using a somatic cell hybrid mapping panel, diving the chromosome into 14 intervals. The others were dinucleotide and tetranucleotide repeat-containing loci newly developed for human chromosome 3, of which 26 were also localized by means of genetic linkage analysis against selected CEPH microsatellites. The regional assignment of these two marker sets in a common mapping panel facilitates their integration. Incorporation of these highly polymorphic loci into the developing physical and genetic maps should provide useful information for studies of various diseases involving chromosome 3. PMID- 7834218 TI - In vitro potency and mode of action of ANQ9040: a novel fast acting muscle relaxant. AB - 1. The in vitro potency and mode of action of the novel, rapid-onset steroidal relaxant ANQ9040 were characterized in the rat isolated phrenic nerve hemidiaphragm. 2. At 32 degrees C, ANQ9040 antagonized neurally evoked contractures with EC50s of 21.5 microM for unitary twitches; 14.4 microM for 2 Hz 'trains of four'; and 7.5 microM for 50 Hz (2 s) tetanic stimulus trains. 3. (+) Tubocurarine was 22-24 times more potent than ANQ9040 in comparative organ bath experiments. 4. Intracellular recording from endplates revealed that ANQ9040 (0.53-10.0 microM) dose-dependently and reversibly decreased the amplitude of miniature-endplate potentials (IC50 of circa 0.95 microM) without changing transmembrane potential. 5. Surmountable antagonism of subthreshold responses to exogenous (ionophoretic) acetylcholine provided evidence for a non-depolarizing and competitive blockade of post-junctional nicotinic receptors. 6. Sucrose gap recordings of phrenic nerve action potentials revealed that, at concentrations up to 32 microM, ANQ9040 produced no tonic or frequency-dependent antagonism of axonic Na+ channels. 7. We conclude that ANQ9040 is a relatively low-affinity, non-depolarizing, nicotinic antagonist. The in vitro results are discussed in relation to factors impinging on relaxant kinetics and current models for frequency-dependent fade. PMID- 7834220 TI - Condensation behaviour of the human X chromosome in male germ cells and Sertoli cells examined by fluorescence in situ hybridization. AB - The chromatin condensation behaviour of the human X chromosome has been studied by fluorescence in situ hybridization (FISH) analysis in germ cells and Sertoli cells of the adult testis, and comparisons are made with previous findings for the human Y chromosome and for chromosome 7. In meiotic prophase, the X chromosome can be seen to extend greatly at zygotene and to contract through pachytene into the sex vesicle. Such extension, which has also been noted for the human Y chromosome at this stage of meiosis, could be a prerequisite for XY pairing and crossing-over. By in situ hybridization analysis, the sex chromosomes of patients with 'Sertoli-cell-only' syndrome appear extremely contracted compared with the normally extended state of those in adult Sertoli cells of fertile men. By contrast, the state of expansion for chromosome 7 in Sertoli cells appears identical for sterile and fertile testes. This could suggest an association between gene-controlled germ cell losses and failure of expansion of the sex chromosome axes. The variable patterns of extension and contraction for the X and Y chromosome axes in germ cells and Sertoli cells might provide underlying clues to patterns of expression noted for sex-linked genes in the human testis. PMID- 7834221 TI - XY chromosome behaviour in the germ-line of the human male: a FISH analysis of spatial orientation, chromatin condensation and pairing. AB - We have used multicolour fluorescence in situ hybridization to study the behaviour of the X and Y chromosomes in relation to a representative autosome, chromosome 1, on air-dried testicular preparations from normal fertile human males. In a proportion of Sertoli cells at interphase as well as spermatogonial metaphases there is an apparent selective undercondensation of the heterochromatic block of the long arm of the Y, which may be of functional significance with respect to Y-specific gene activity, initiating and maintaining spermatogenesis; we suggest that this may involve a mechanism similar to heterochromatin position-effect variegation in Drosophila. In the supporting Sertoli as well as pre-meiotic and leptotene cells the X and Y occupy relatively restricted domains at opposite poles of the nuclear membrane, while the chromosome 1 centromere regions are located interstitially and appear prealigned. The XY pairing and 'sex vesicle' formation comprises a complex series of spatial movement and differential condensation patterns. On the basis of these observations we propose that: the XIST/Xist gene, known to be involved in somatic X inactivation, imposes a chromatin reorganization leading to bending at the X inactivation centre both at first meiotic prophase in males and in the soma in females; and the differential X and Y segments are protected from potentially deleterious meiotic exchanges by their separate spatial orientation. In addition, there is an indication that the timing of pairing and first meiotic segregation of the sex chromosomes is different, and precocious in comparison to the pairing and segregation of the autosomes, which may explain the high incidence of sex chromosome aneuploidy in sperm. PMID- 7834222 TI - Functional cloning of centromere protein B (CENP-B) box-enriched alphoid DNA repeats utilizing the sequence-specific DNA binding activity of human CENP-B in vitro. AB - The centromere is a distinctive portion of the chromosome consisting of 'centromere DNA' and 'centromere proteins'. Recently, a direct molecular interaction was discovered between human centromere protein B (CENP-B) and human centromeric alphoid repeats. This enabled us to isolate the CENP-B-targeted centromeric DNA sequences by positively utilizing the biologic activity of CENP-B in vitro. In the previous model experiment, we found that oligonucleotides covering the CENP-B binding sequences were enriched by the DNA immunoprecipitation procedure. Here we apply the same technique to the direct isolation of a functional part of human centromeric DNA from a genomic DNA library. Restriction digestion of two isolated clones showed the typical repeating pattern of an alphoid family that is known to localize at the centromeric region of all human chromosomes. Sequence analysis showed that these two clones frequently contain the authentic CENP-B binding motif, CTTCGTTGGAAACGGGA, or a new one with one base replaced, CTTCGTTGGAAACGGGT. The frequent distribution of these motifs suggests that the isolated sequences are directly involved in the organization of centromeric heterochromatin at the primary constriction in conjunction with CENP-B. PMID- 7834223 TI - The arrangement and transcription of telomere DNA sequences at the ends of lampbrush chromosomes of birds. AB - The arrangement of loops and chromomeres at the ends of lampbrush chromosomes in four species of bird is described with reference to chromomeres, loops and transcription units. Unlike the situation described in lampbrush chromosomes of amphibians, the lampbrush chromosomes of birds end in a terminal chromosome with conspicuous loops emerging from it. The fine-scale morphology of the ribonuclear protein matrix of these terminal loops is different from that of the majority of loops elsewhere on the chromosomes. In many cases the loops associated with the terminal chromomere are open ended, emerging from the chromomere but not returning to it at the other end. The distal ends of terminal open-ended loops therefore represent the true ends of the chromatids that make up a lampbrush half bivalent. The pattern of binding of three telomeric DNA sequence probes to the terminal regions of bird lampbrush chromosomes, under conditions of DNA/DNA and DNA/RNA transcript in situ hybridization has been investigated by fluorescence in situ hybridization. All three probes gave the same results. With DNA/DNA and DNA/RNA transcript hybridization, three classes of structure were labelled: the terminal chromomere, a small number of interstitial chromomeres and the terminal transcription unit on telomere loops. Labelling of telomere loops, but not of terminal or interstitial chromomeres, was eliminated by ribonuclease treatment before in situ hybridization. The labelled regions of telomere loops were spaced away from the labelled terminal chromomere by an unlabelled sub telomeric transcription unit. After DNA/DNA in situ hybridization, no labelled loops were seen. DNA/RNA transcript in situ hybridization with single-stranded hexamers of each strand of telomeric DNA showed that the terminal transcription unit on telomere loops represents transcription exclusively from the C-rich strand of the repeat outwards towards the end of the chromosome. It is concluded that transcription specifically of the C-rich strand of strictly terminal clusters of telomere repeats is an obligatory event on the lampbrush chromosomes of birds and is unlikely to represent indiscriminate readthrough from proximally located gene elements. PMID- 7834224 TI - Human corticotropin-releasing hormone receptor gene (CRHR) is located on the long arm of chromosome 17 (17q12-qter). AB - Using polymerase chain reaction amplification of commercially available DNA templates, we have mapped the human corticotropin-c releasing hormone receptor gene (CRHR) to the long arm of chromosome 17 (17q12-qter). PMID- 7834225 TI - [The evaluation of the working conditions and the characteristics of the prevalence of vibration-induced disease among miners in the Far North]. AB - The article covers the data of physiologic and hygienic evaluation of vibration disease prevalence among miners of Far North and evaluation of their work conditions. The authors compare effects of local vibration on miners in the mines with negative ambient temperatures during the year and in those with the low positive temperatures. The negative temperatures and local vibration appeared to disorder formation of specific physiologic response to the stated factors. The data presented cover prevalence and progressing of vibration disease among the miners in Far North. PMID- 7834226 TI - [The effect of exposure to radiation and other industrial factors on the morbidity of the personnel in enterprises in the mining and processing of rare earth metal ores]. AB - Multivariate regression analysis proved that radiation of allowable level had no unfavorable influence on morbidity with transitory disablement. Increased from 0.15 to 2.0 microGy/hr dose rate of gamma radiation at the workplaces resulted in slightly lower morbidity. Unfavorable influence on morbidity was caused by physical factors (noise, vibration, microclimate, work hardness), irritating and neurotoxic chemicals in amounts which seldom exceeded the allowable norms, hostile climate and geographic conditions. PMID- 7834227 TI - [The assessment of combined exposure to radiation and chemical factors based on the study of the morbidity of personnel in radiation-chemical manufacture]. AB - The study analyzed the work conditions of personnel engaged into production of plastic modified by radiation. The analysis revealed that the staffers exposed to combined action of radiation and chemical factors face 6 times more intensive harm from radiation resulting in more cardiovascular diseases. All that should be considered in setting the norms for annual radiation doses at workplaces. Real production demands maximal allowable dose to equal 1 rem/year, if the personnel is exposed to chemicals (ozone, nitrogen oxides, ethylene, formaldehyde, acrolein). The scientist elaborated a method to evaluate combined action of chemicals and radiation, which is based on dependence of morbidity on personnel's age. During the further calculation of summarized factor all previous parameters are added, given their enhance. PMID- 7834228 TI - [Erythrocyte structure and function in iron-deficiency states in painters]. AB - The studies of lipid peroxidation, antioxidant defence, structure and functions of erythrocytes in iron deficiency of painters revealed severe changes in the cells' chemiluminescence, sulfhydryl and catalase activities, levels of free cholesterol, lipoproteins, hystidine and glucose-6-phosphate dehydrogenase, saponin resistance and viscosity of erythrocytes. The changes appeared to depend on duration of exposure to the toxic chemicals. The data presents additional markers of toxic influence on erythrocytes in developing iron deficiency of painters. PMID- 7834229 TI - [The modelling of the composition of the thermal oxidative breakdown products of aviation oils determined in the cabin air of aircraft]. AB - The authors suggested a method to obtain a mixture of chemicals from splitting thermo-oxidation of aviation oil. The qualitative and quantitative aspects of the mixture correspond to the concentration of the chemicals in the air of aircraft cabins. The possibility to obtain such mixtures helps to assess in hygienic laboratory conditions a level of air pollution with aviation oil in aircraft cabins. PMID- 7834230 TI - [An analysis of the chromosome aberrations in the peripheral blood lymphocytes of workers in the manufacture of pyromellitic dianhydride]. AB - The report covers results of cytogenetic screening of workers engaged into pyromellitic dianhydride production. Occurrence of chromosomal aberrations in peripheral lymphocytes was studied in 42 workers and 35 donors. The group of the workers exposed to pyromellitic dianhydride demonstrated reliably increased occurrence of aberrant metaphases (4.47%) in comparison with the value in the reference group (2.29%). The principles showing formation of chromosomal aberrations were studied, and their dependences on sex, age, length of service and smoking were revealed. The data obtained prove potential mutagenic danger of the stated production. Revealed stabilization of genetic disorders, depending on longer length of service, could be connected with peculiarities of vital cycle of the lymphocyte units studied. PMID- 7834232 TI - [An academic program and plan for a postgraduate course on the current problems of occupational medicine and human ecology (teaching experience)]. PMID- 7834231 TI - [Occupational factors, socioeconomic status and cancer of the female reproductive organs (a review of the literature)]. PMID- 7834233 TI - [The skin autologous microflora index as a test for predicting acute morbidity in mass medical examinations of workers]. AB - Basing on assessment of skin microflora in 3186 apparently health able-bodied individuals and on subsequent study of acute morbidity, the authors revealed direct dependence between these parameters: only 3.4% of people with normal level of microflora became ill during 1 month after the examination, the value of those with higher level was 15.5%. Therefore the skin microflora test could serve for prognosis. PMID- 7834234 TI - [The classification of human thermal states during overheating]. AB - A classification of human heat states is based on mechanisms of changes in human temperature status. Quantitative integral criteria (factors F1, F2, F3) elaborated earlier are the main principles of classification, which reflect the mechanisms of temperature changes in various regions of human body exposed to overheating. The classification comprises 4 classes. The first two represent different levels of optimum state, the third one is upper allowable level of overheating, the fourth one--maximal level of overheating. The classification usable for diagnosis of human heat states varying from comfortable one to critical overheating. PMID- 7834235 TI - [Cooling of the hands as a factor aggravating the unfavorable effect of local vibration]. PMID- 7834236 TI - [The specific and nonspecific mechanisms of the formation of adaptive compensatory reactions during extreme exposure to heat]. AB - A total of 250 white male rats were subjected to 48 hours experiment in order to study specific (functional state of thermoregulation, heart muscle, brain cortex) and nonspecific (ration of free radical oxidation activity to antioxidant system activity) mechanisms of adaptational and compensatory reactions, those of alteration and restoration after single critical heating (temperature 41.5 +/- 0.5 degrees C) during 1 hour. The animals appeared to develop no adaptation to the studied heating level, that was demonstrated by assessment of specific regulatory systems and by studies of free radical oxidation and antioxidant system activities. PMID- 7834237 TI - [Intestinal parasite and Clonorchis sinensis infection among the inhabitants in the upper stream of Taechong Dam, Kumgang (River)]. AB - The prevalence of intestinal parasites and Clonorchis sinensis infection was observed among inhabitants in the upper stream of Kumgang (River) from January to October 1991. A total of 743 fecal specimens was examined by cellophane thick smear and formalin-ether concentration technique. The parasite positive rate including helminth eggs and protozoan cysts was 40.8%, the positive rates for every species were: Clonorchis sinensis 30.8%, Metagonimus spp. 14.5%, Fasciola spp. 0.7%, Taenia spp. 1.5%, Ascaris lumbricoides 0.4%, Enterobius vermicularis 0.1%, Hookworm 0.1%, Trichuris trichiura 1.6%, Entamoeba coli 0.7%, E. histolytica 0.3%, Endolimax nana 0.3%, Giardia lamblia 0.3% and Iodamoeba buetschlii 0.1%, respectively. The cumulative positive rate in Okchon-gun showed 51.1%, in the Kumsan-gun 50.8% and in the Muju-gun 28.6%. Through this survey, it was concluded that the soil transmitted intestinal parasites including helminthseggs and protozoan cysts have been decreased remarkably among the inhabitants along the upper stream of Taechong Dam, Kum-gang (River), on the other side, Clonorchis sinensis, Metagonimus spp. and Taenia spp. are still morderate prevalent. PMID- 7834238 TI - [Chronological observation on intestinal histopathology and intraepithelial lymphocytes in the intestine of rats infected with Metagonimus yokogawai]. AB - The relationship between the intestinal histopathology and number and position of intraepithelial lymphocytes (IEL) was observed chronologically in the small intestine of rats experimentally infected with Metagonimus yokogawai. Fifteen Sprague-Dawley rats were orally infected each with 3,000 metacecariae, and 3 were kept uninfected for controls. Three rats each were sacrificed on the day 5, 10, 15, 24 and 70 post-infection (PI) and samples of the small intestine, 5 cm, 10 cm, 20 cm and 70 cm posterior to the pylorus were taken. The samples were processed routinely and stained with Giemsa. The intestinal histopathology was severe during the day 5-15 PI and characterized by villous atrophy, crypt hyperplasia, and decrease of villus/crypt height ratio. After the day 24 PI, the intestinal lesions showed some tendency of recovery. The number of IEL increased at the early stage of infection, but decreased thereafter to a lower level than that of controls, with progression of the pathological changes. Then, the IEL number began to increase again after the day 24 PI. In control rats, the great majority of the IEL were located at the basal region of the epithelium. During the early stage of infection, however, a considerable proportion of IEL was found to have moved to the intermediate or apical region of the epithelium. From the above results, it is suggested that the change of IEL number and position during the course of M. yokogawai infection should be closely related to the progression and recovery of the intestinal histopathology. PMID- 7834240 TI - Characterization of a cysteine proteinase from adult worms of Paragonimus westermani. AB - Paragonimus westermani, the lung fluke, is known to migrate to the pulmonary tissue of mammalian hosts and causes pathological changes in the lungs. An acidic thiol-dependent proteinase with a molecular weight of approximately 20,000 daltons was purified to homogeneity using ion-exchange chromatography and gel filtration chromatography. On SDS-PAGE, the molecular weight of the enzyme was 17,500 daltons. Isoelectric point was 6.45. The enzyme was similar to the acidic cysteine proteinase of vertebrates in the properties of pH 5.5 for at least two days when stored at 4 degrees C. The cysteine proteinase was capable of degrading collagen and hemoglobin. Sera of patients with paragonimiasis and mice infected with P. westermani reacted in immunoblots with the partially purified proteinase. This result suggested that the cysteine proteinase of P. westermani may play a role in migration in tissues, and in acquisition of nutrients by parasites from the host. It is also potentially an antigen for the serodiagnosis of paragonimiasis. PMID- 7834239 TI - Correlation of sonographic findings with histopathological changes of the bile ducts in rabbits infected with Clonorchis sinensis. AB - Clonorchiasis is an important parasitic disease of humans in Korea. The present study intended to compare sonographic findings with histopathological changes in experimental clonorchiasis. Eighteen New Zealand white rabbits were infected with metacercariae of Clonorchis sinensis, and examined 4, 10, and 22 weeks post infection (PI). Four infected rabbits were treated with praziquantel 10 weeks PI and were examined 12 weeks after treatment. Sonography revealed mild to severe dilatation of the intrahepatic ducts (IHDD) and slightly increased periductal echoes in 12 out of 14 rabbits at 4 weeks PI, and all of the animals after 10 and 22 weeks PI and 12 weeks after treatment. The histopathological lesions were duct dilatation, mucosal hyperplasia, and periductal fibrosis, which progressed from 4 weeks to 22 weeks PI and even in treated rabbits. The dilated intrahepatic ducts over 1 mm diameter were detected by sonography. The present results indicate that sonographic findings are well correlated with histopathological lesions in rabbit clonorchiasis except for early phase of light burden of infection. The sonography has a limitation in discriminating residual sequelae of the ducts after praziquantel treatment. PMID- 7834241 TI - Identification of surface antigen of Trichomonas vaginalis. AB - Plasma membrane proteins of a Korean isolate of Trichomonas vaginalis HY-1 were fractionated for antigen analysis. Homogenates of T. vaginalis were fractionated by the differential centrifugation using sucrose step-gradient method. The interface layer from the 25%/45% sucrose was collected as a plasma membrane fraction and its purity was examined by transmission electron microscopy. The antigenicity of plasma membrane fraction was analysed by enzyme-linked immunoelectrotransfer blot technique with immune rabbit serum and compared with surface antigen labelled with N-hydroxysuccinimide-biotin. The fluffy fraction of 25%/45% sucrose interface was homogeneous and membrane particles were present as extended sheet and concentric vesicles showing typical trilamellar appearance under transmission electron microscope. Seven fractions at 40, 50, 60, 110, 130, 140 and 150 kDa were identified as the antigenic membrane proteins in EITB with anti HY-1 rabbit serum. The common band at 60 kDa was detected both in antigenic fractions of plasma membrane and surface protein labelled with NHS-biotin. This result indicates that this protein is considered as a major surface antigen of T. vaginalis. The role of this surface antigen at 60 kDa should be studied further. PMID- 7834242 TI - [Antigen analysis of Toxoplasma gondii lysate and excretory-secretory materials by enzyme-linked immunoelectrotransfer blot (EITB)]. AB - Recently, the importance of toxoplasmosis is raised as a complication in immunosuppressed or AIDS patients. Our study focused on the identification of a variety of Toxoplasma antigens by immunoblotting. Rabbits and BALB/c mice were immunized with Toxoplasma lysate (RH strain), frozen tachyzoites (RH strain) or cysts (Beverly and Fukaya strain). Blood were collected from ear vein, heart or orbital plexus for detecting the serum antibody levels. For excretory-secretory (E.S) antigens, T. gondii (RH) tachyzoite were cultured in CHL (Chinese hamster lung) cells with MEM containing of 5% FCS. After 72 hrs, culture supernatant was collected. BALB/c mice were inoculated with RH tachyzoite intraperitoneally and peritoneal fluids were extracted three days later. E.S antigens were detected in culture supernatant and infected mouse peritoneal fluid by EITB. Serum IgG levels in rabbit were 1:512 of 10 days after primary immunization, 1:2,048 of 10 days after secondary immunization, 1:1,024 of 20 days after secondary immunization by IFAT, respectively. Serum IgG levels of immunized mice were 1:128 after 7 weeks. Tachyzoite antigens of the RH strain were detected 25 protein bands ranging 10 kDa-220 kDa of molecular weights with Coomassie blue stain. Toxoplasma major antigens corresponding to MW of 24 kDa, 27 kDa, 30 kDa, 35 kDa, 38 kDa were recognized by IgG and IgM antibodies. Excretory-secretory antigens present in culture supernatant with M. W. of 20, 30 kDa and in infected mouse peritoneal fluid with M.W. of 33 (P30), 45 kDa. When RH tachyzoite antigen was probed with different mice sera immunized with 2 strains of T. gondii, the IgG antibody band of Fukaya and Beverly strain (8 week-serum) is identical to those of RH strain. It is considered that the 30 kDa polypeptide detected in excretory-secretory materials and lysate was important major antigen of T. gondii (RH). PMID- 7834243 TI - [The effect of silica on the development of experimental Acanthamoeba meningoencephalitis with reference to the macrophage role in mice]. AB - The role of macrophages was observed in intranasally infected C3H/HeJ mice with trophozoites (3 x 10(5)) of Acanthamoeba culbertsoni which was a kind of free living amoebae inducing meningoencephalitis in human and experimental animals. The mortality was 60% in the group of intraperitoneally injected mice with silica (0.5 mg/0.5 ml). It was much higher than that of 10% in the group of amoeba infected mice without silica administration. The phagocytic index of peritoneal macrophages co-cultured with Toxoplasma gondii was estimated daily. In contrast to the control and amoeba infected group which didn't show significant fluctuation of the phagocytic indices, the silica administrated group revealed under 3% until day 3, and gradual increase up to 24.7% in day 5 which was same level of amoeba infected group without silica administration. The level of interleukin-1b (IL-1b) measured by ELISA was the highest in the amoeba infected group without silica injection and the lowest in the amoeba infected group with silica administration. In the test of the amoebicidal activity of mice peritoneal macrophages in vitro, silica administration revealed reducing effect on amoebicidal activity of macrophages. In conclusion, macrophages were proven to play a significant role in defense mechanism against the development of experimentally induced Acanthamoeba meningoencephalitis. PMID- 7834244 TI - Clonorchiasis and metagonimiasis in the inhabitants along Talchongang (River), Chungwon-gun. AB - To evaluate the status of clonorchiasis and metagonimiasis of the inhabitants near Talchongang (River) in Chungwon-gun, Chungchongbuk-do, the stools of 67 inhabitants were examined by formalin-ether sedimentation method from August to September, 1993. Also freshwater fish caught in Talchongang were examined by slide compression method. The egg positive cases of Clonorchis sinensis and Metagonimus sp. were 22 (32.8%), and 14 (20.9%), respectively. Of 17 species of examined fish. 14 species were infected with C. sinensis and 13 species with Metagonimus sp. The adult worm collected from 2 patients after treatment with praziquantel was Metagonimus Miyata type. Also the adult worm obtained from the experimental mice infected with metacercariae from Zacco platypus was Metagonimus Miyata type. We found the highly endemic area of clonorchiasis and metagonimiasis along Talchongang. PMID- 7834245 TI - Egg positive rates of Clonorchis sinensis and intestinal helminths among residents in Kagye-ri, Saengbiryang-myon, Sanchong-gun, Kyongsangnam-do. AB - Stools of the residents in a village in Saengbiryang-myon, Sanchong-gun, Kyongsangnam-do were examined for the eggs of intestinal helminths. In 1987, infection rate of 76 residents by Clonorchis sinensis was 80.3% with mean eggs per gram of feces (EPG) 27,781. C. sinensis-infected persons were treated once with praziquantel 60 mg/kg, q.i.d. Seventeen persons (22.4%) infected by Metagonimus yokogawai was coinfected with C. sinensis. In 1993, C. sinensis egg positive rate was 48.4% with mean EPG 5,929. Reinfection rate of follow-up cases by C. sinensis was 55.2% during 5 years and 5 months. Infection rate by M. yokogawai was 3.2%. This village was an endemic focus of clonorchiasis occurring reinfection high. PMID- 7834246 TI - Infestation rate of lice in patients in a mental hospital, Seoul, Korea. AB - We examined the infestation rate of head and/or body lice in patients in a mental hospital, Seoul, Korea on June 27-28, 1988. Of 438 women, 146 (33.3%) were positive with nits or worms of louse. Of 143 men, 22 (15.4%) were positive with those of louse. Regular control programs were necessary to this hospital. PMID- 7834247 TI - Infectivity of Paragonimus westermani developing in a final host to another final host. AB - In the definitive hosts, metacercariae of Paragonimus westermani excyst in host duodenum, penetrate intestinal wall, migrate peritoneal and thoracic cavities, and develop to sexual maturity in 8 weeks. This study was undertaken to examine the age of the maturing P. westermani when their infectivity to the other definitive hosts was retained. On 3, 7, 10, 14, 21 and 28 days after feeding the metacercariae to cats through a gastric tube, the developing worms were harvested. The juveniles of different age were fed again to other experimental cats. One to 12 weeks after the oral-transfer infections, the experimental cats were examined for establishment of infections. In the cats to which 3-day and 7 day old juveniles (grown up to 1.4 mm long) were fed, 31.4% and 22.6% of the transferred worms were found infected. The worms of 10-28 days old were not infective. Early maturing stages grown up to 7 days maintained their infectivity to the other definitive hosts. PMID- 7834248 TI - Two vivax malaria cases detected in Korea. AB - On June and July 1994, two cases of vivax malaria were consecutively diagnosed at the Yongsan Hospital, Chung-Ang University in Seoul. The first patient was a soldier serving in western parts of the demilitarized zone (DMZ) while the second case was a resident of a village near DMZ. Neither patients had history of being abroad. Republic of Korea (ROK) has been free of malaria since the mid-1970s except for imported cases. The two vivax malaria cases, together with an additional patient detected in 1993, occurred in relatively small areas near DMZ. This necessitated an epidemiologic surveillance. When medical records and blood smears in the areas were examined, no other cases were found. Of 7,723 mosquitoes collected by a black light trap for two nights in June, 7,066 (91.5%) were Anopheles sinensis. In order to evaluate a significance of the recent malaria occurrence, a surveillance system should be operated in the areas. PMID- 7834249 TI - Swallowing disorders in the elderly. PMID- 7834250 TI - Peptic ulcer disease in the elderly. PMID- 7834251 TI - Constipation and fecal incontinence in the elderly. PMID- 7834252 TI - Pancreatic disease in the elderly. PMID- 7834253 TI - Liver disease in the elderly. PMID- 7834254 TI - Maintenance ECT, again... PMID- 7834255 TI - Continuation ECT: relapse prevention in affective disorders. AB - Relapse rates after the acute treatment of affective disorders with drugs or electroconvulsive therapy (ECT) are high (often 50-95%), despite preventive pharmacotherapy. In practice, some patients receive continuation and maintenance ECT after successful treatment of the index episode with ECT. We reviewed the charts of patients with affective illnesses who received continuation ECT (C-ECT) in our inpatient service from 1985 to 1991. In 33 courses of C-ECT, mean intertreatment interval was 10.1 days and the average duration of treatment was 10 weeks. One-year follow-up was available for 21 patients. Seven (33%) patients relapsed and needed re-admission within 1 year. The relapse rate for the patients with delusional depression was 42%, lower than the 95% reported for patients with delusional depression maintained on continuation pharmacotherapy before the C-ECT program started in our facility. No single factor examined was a significant predictor of relapse except C-ECT, which exhibited a sustained prophylactic effect for the year after the index episode. PMID- 7834256 TI - Maintenance ECT in intractable manic-depressive disorders. AB - Twenty-two patients suffering from intractable recurrent unipolar or bipolar mood disorders were enrolled in a maintenance-ECT protocol (ECT-M) for more than 18 months, with a treatment at approximately monthly intervals. Eleven have continued treatment for > 2 years. Whereas 44% of the year had been spent in the hospital with at least three episodes a year prior to ECT-M, only 7% of the year was spent in the hospital during ECT-M with only one relapse every 16 months requiring admission (p < 0.001). Forty-five percent of the patients were in full remission and 27% in partial remission according to DSM-III-R criteria. ECT-M responsiveness of rapid-cyclers and delusional depressed patients usually drug refractory has been very encouraging with full or partial remission for 100% of rapid-cyclers and 80% of delusional depressed patients. PMID- 7834257 TI - Relationship between rate of administration of electroconvulsive shocks and rate of learning in rats: implications for the practice of ECT. AB - Number of electroconvulsive therapy (ECT) treatments administered and severity of psychopathology confound the interpretation of clinical studies that address the relationship between the rate of administration of ECT and cognitive morbidity occasioned by the treatment. A preclinical study was therefore conducted to address the issue. Three groups (n = 8/group) of adult male Sprague-Dawley rats received six electroconvulsive shocks (ECS) in daily ECS, 3 ECS/week, and 2 ECS/week schedules; a fourth group (control; n = 8) received only sham ECS. From days 2 to 7 after the conclusion of the ECS/sham ECS course, the rats were monitored for learning on the Hebb-Williams complex maze. The control, 2 ECS/week, and 3 ECS/week groups showed significant learning by days 3, 5, and 7, respectively, while the daily ECS group showed no significant learning during the assessment period. This indicates that even when the cumulative effect of ECS on learning is controlled for, more frequent ECS is associated with slower learning. Extrapolating to clinical settings, it is suggested that wider spacing of ECT may lessen ECT-induced cognitive morbidity. PMID- 7834259 TI - EEG monitoring during ECT research. AB - The current practice of monitoring brain electrical activity with single channel recordings during ECT induced seizures does not meet contemporary EEG standards. Multichannel recordings are essential for artifact identification, determination of seizure endpoint, and assessment of electrophysiological features in different brain regions. Careful attention to technical aspects and detailed descriptions are important for interpretation and for scientific communication. Standardized procedures for EEG monitoring during ECT should be developed for general clinical use and for research and training applications. PMID- 7834258 TI - Efficacy of electroconvulsive therapy after propofol and methohexital anesthesia. AB - Fifty-eight patients with major depression were randomly assigned to receive a hypnotic dose of either propofol or methohexital for their complete treatment series of electroconvulsive therapy (ECT). As expected, seizure duration was significantly shorter with propofol than with methohexital anesthesia. Both groups recovered from their depression at the same rate. There was a significant improvement in the Hamilton Rating Scale for Depression scores between the first and last ECT session. However, this was independent of the choice of propofol or methohexital as the anesthetic. This study supports previous reports that seizure duration does not influence recovery from depression. PMID- 7834260 TI - Visually determined high-frequency seizure activity. AB - The duration of high-frequency electroconvulsive therapy (ECT) seizure activity, the "spike seizure duration," was rated by two experienced clinicians from the paper EEG recording, along with total EEG seizure duration. The spike seizure duration, taken together with other seizure duration measurements, has shown differences between ECT methods of apparently different efficacy, such as unilateral and bilateral ECT. Close correspondence between the raters demonstrated high reliability for the determination of spike seizure duration, with interrater reliability kappa of 0.92 (p < 10(-6), although the raters employed different rules for selecting the end point. PMID- 7834261 TI - Supraventricular tachycardia in a patient receiving ECT, clozapine, and caffeine. AB - A patient receiving electroconvulsive therapy (ECT), clozapine, and intravenous caffeine sodium benzoate developed supraventricular tachycardia. This was rapidly treated with intravenous verapamil. Subsequent maintenance ECT given without caffeine was well tolerated. We believe the combination of clozapine and caffeine at the time of ECT was responsible for the arrhythmia. PMID- 7834262 TI - HIV-induced stupor treated with ECT. AB - A 27-year-old man positive for human immunodeficiency virus (HIV) presented with severe depressive stupor, peripheral neuropathy, and myelopathy. The onset of psychiatric symptoms, closely followed by neurological symptoms, without other possible somatic etiology suggests that HIV itself might precipitate psychosis. The patient was treated successfully with electroconvulsive therapy. The advantages and risks are discussed. PMID- 7834263 TI - Diazepam or lorazepam for prolonged seizures? PMID- 7834264 TI - Citations of recent literature in convulsive therapy. PMID- 7834265 TI - The efficacy of the neo-liberal individual choice model for encouraging post disaster change: developments in the East Cape region of New Zealand following Cyclone Bola (March 1988). AB - The government of New Zealand instituted a new policy of disaster response in an attempt to bring about change and development in the relatively remote agricultural region which was struck by a severe cyclone in March 1988. The new policy involved a change from payment for restoration to compensation for loss. This new policy was based on the neo-liberal position that individual choice should prevail in decision making and that significant change will result from this adherence to an individual decision making approach. The new policy did not accomplish any significant degree of change in the intended areas of land ownership and land use. Most of the farmers used the compensation funds to carry out on-farm restoration work which facilitated the resumption of pre-cyclone farming activities. It is argued that the efficacy of a neo-liberal individual choice model for accomplishing post-disaster change and development is limited and that a more institutionally and organisationally based approach would be much more effective and efficient. PMID- 7834266 TI - An examination of the 1990-91 famine in Sudan. AB - Shortly before and during the harvest of 1990, a series of warnings were issued by concerned international and UN agencies that Sudan would experience a very poor harvest followed by an acute food shortage over the period 1990-91. The 1990 harvest was estimated to be similar to that obtained in 1984. After the very poor harvest in 1984, Sudan experienced a major famine during which deaths may have numbered in the hundreds of thousands. There were fears that this experience might be repeated in 1990-91. By the time of the subsequent 1991 harvest, it was clear to all that a severe food crisis had been experienced. There were severe shortages of water and food and very high malnutrition rates of children were noted by UNICEF across a wide range of areas. Despite these adverse indications, starvation deaths were probably numbered in thousands, rather than hundreds of thousands. Famine mortality, which may include deaths from famine associated disease, was similarly low. The initial predictions, it now seems, may have over estimated famine mortality almost one hundred times. Several potential explanations of the over-estimate are examined. These include prediction errors, government and donor responses to the drought such as food aid and immunization, and traditional community and household level coping strategies in times of food shortage. PMID- 7834267 TI - Monitoring local food security and coping strategies: lessons from information collection and analysis in Mopti, Mali. AB - Save the Children Fund (UK) established a local food security monitoring project in the Mopti region of Mali, which was operational between 1987 and 1993. This article describes some of the lessons learnt from this experience of monitoring food security and coping strategies. It illustrates how coping strategies can be an important element in tracking vulnerability in the Sahel, but that interpretation is complex and there are limitations to their use. Secondly, consideration must be given to the institutional context in which information systems are set up. Information providers must be linked institutionally to response mechanisms, to ensure that data are fed systematically into the design, implementation and monitoring of appropriate response. PMID- 7834268 TI - Strategy and organizational disaster preparedness. AB - Strategy is introduced as a predictor of disaster preparedness. Tests with multiple regression show that strategy, disaster experience and capacity for disaster response are the strongest predictors of preparedness. We conclude that the measure of strategy warrants further refinement and that the study of preparedness must move from idiosyncratic, disconnected studies to a more theoretically organized set of studies that verify useful guidelines for monitoring and enhancing disaster preparedness. PMID- 7834269 TI - Recommended methods for the disposal of sanitary wastes from temporary field medical facilities. AB - Emergency field medical facilities constructed after a disaster are frequently managed by medical staff even though many of the day-to-day problems of hospital management are unrelated to medicine. In this paper we discuss the short-term management of one of these problems, namely the control and disposal of sanitary wastes. It is aimed at persons in the medical profession who may find themselves responsible for a temporary hospital and have little or no previous experience of managing such situations. The wastes commonly generated are excreta, sullage and refuse. In addition, surface water must also be considered because its inadequate disposal is a potential health hazard. The paper concentrates on short-term measures appropriate for the first six months of the hospital or clinic's existence. Facilities expected to last longer are recommended to install conventional waste management systems appropriate to the local community and conditions. In most situations, wastes should be disposed of underground either by burial (for solids) or infiltration (for liquids). The design, construction and management of appropriate disposal systems are described. PMID- 7834271 TI - International Seminar on Society and Disaster Prevention, Universidad Nacional Autonoma de Mexico, 23-25 February 1994. PMID- 7834270 TI - Observations on the Yokohama World Conference on Natural Disaster Reduction, 23 27 May 1994. PMID- 7834272 TI - World Conference on Natural Disaster Reduction, Yokohama, 23-27 May 1994. PMID- 7834273 TI - Hunting the hemochromatosis gene: progress and problems. AB - Hereditary hemochromatosis (HFE) is an inherited recessive disorder which causes progressive iron overload. Homozygotes for the affected gene develop symptoms of parenchymal organ damage and especially liver cirrhosis in midlife. Early diagnosis is important in order to prevent symptoms. The protein responsible for the increased iron absorption is unknown. The tight association of the disease gene with HLA-A has been known for nearly 20 years, but its precise localization remains uncertain. Linkage and linkage disequilibrium analyses in different populations have focussed on two possible locations of the gene either very close to HLA-A, or at the telomeric site of 6p in the vicinity of the D6S105 marker. PMID- 7834274 TI - Further localization of the gene for hereditary paragangliomas and evidence for linkage in unrelated families. AB - Paragangliomas of the head and neck are slow-growing tumors that rarely show malignant progression. Familial transmission has been described, consistent with an autosomal dominant gene that is maternally imprinted. Clinical manifestations of hereditary paraganglioma are determined by the sex of the transmitting parent. All affected individuals have inherited the disease gene from their father, expression of the phenotype is not observed in the offspring of an affected female or female gene carrier until subsequent transmittance of the gene through a male gene carrier. Recently, we assigned the gene responsible for paragangliomas (PGL) to chromosome 11q23-qter by linkage in a single large Dutch kindred. We now report confirmation of this localization in five unrelated Dutch families with hereditary paragangliomas. On the basis of segregation of haplotypes in the available family material, we localize the PGL locus between markers STMY and CD3D on chromosome 11q22.3-q23. PMID- 7834275 TI - Transforming growth factor alpha: a modifying locus for nonsyndromic cleft lip with or without cleft palate? AB - Most (but not all) studies have found weak but significant association between restriction fragment length polymorphisms at the transforming growth factor alpha (TGFA) locus on chromosome 2p13 and nonsyndromic cleft lip with or without cleft palate (CL +/- P). However, all attempts to demonstrate genetic linkage between TGFA and CL +/- P in families have produced consistently negative lod scores which provide evidence against linkage. We typed a 3-allele single-strand conformation polymorphism at TGFA in 14 extended families with multiple CL +/- P members from West Bengal, India. No significant TGFA differences were observed between the entire sample of 34 affected people and a sample of 38 unaffected people unrelated to each other (p = 0.39). However, affected individuals with CL only showed significant differences from unaffected individuals (p = 0.008). More interestingly, the CL only and CL+P groups of individuals differed strongly from each other in their TGFA frequencies (p = 0.0002). Using an autosomal dominant model with reduced penetrance for the inheritance of a major CL +/- P locus (suggested by our prior segregation analyses), a non-significant maximum lod score of 0.13 at a recombination frequency of 20% was obtained. We suggest that the TGFA locus only modifies expression (severity) of the CL +/- P trait, which is controlled by a major (necessary) locus elsewhere; this could explain the difficulty in obtaining positive linkage results. PMID- 7834276 TI - Analysis of the molecular variance at the phenylalanine hydroxylase (PAH) locus. AB - The frequencies of the different haplotypes identified at the phenylalanine hydroxylase (PAH) locus were analyzed for both phenylketonuria (PKU) and normal haplotypes of various European, Asiatic, Polynesian and Black American populations. These molecular variants were studied by applying a specific model of multivariate analysis of variance, allowing an estimation of components of variance at different levels of hierarchical subdivisions (intrapopulation, among different geographical groups of populations, and between PKU and normal haplotypes within populations). The results indicate that the PAH polymorphism could be appropriate to study divergence between African, European and Asiatic population groups, but is not sufficient to explain the diversity among European populations. However, the differences in PAH haplotype frequencies between PKU and normal haplotypes are statistically significant over all European populations. PMID- 7834277 TI - Improved risk assessment for insulin-dependent diabetes mellitus by analysis of amino acids in HLA-DQ and DRB1 loci. AB - Polymorphisms in HLA class II genes have been shown to contribute to susceptibility or protection against insulin-dependent diabetes mellitus (IDDM). In the present study the role of HLA class II haplotypes and the role of DQ alpha Arg52, DQ beta Asp57 and of polymorphic amino acids, located in the antigen binding groove and the CD4-binding domain of the DR beta 1 chain, were studied in 210 unrelated Caucasian IDDM patients and 205 controls. The results showed that the genotype homozygous for DR beta 1Lys71+, which is in linkage disequilibrium with DQ alpha 1Arg52+ provided a major risk (relative risk, RR = 15.46) for IDDM and that combination of DR beta 1Lys71+/+ with homozygosity for DQ beta qAsp57-/- of the DQ beta 1 chain significantly increased the RR for developing IDDM (RR = 20.41). The DQ alpha 1Arg52(-)-DQ beta 1Asp57+ haplotype in cis or trans position conferred the highest protection against IDDM (RR = 0.08). Our findings confirm that protection against IDDM is provided by HLA-DQ loci but that susceptibility for IDDM is provided by both HLA-DRB1 and DQB1 loci. Our results also provide a new and more specific approach to determine the risk of any random Caucasian individual to develop IDDM. Indeed, increased susceptibility or protection against IDDM can be determined by the rapid and simple typing of DR beta 1Lys71, DQ alpha 1Arg52 and DQ beta 1Asp57 in a random person. PMID- 7834278 TI - Mapping of microsatellite markers in the Alagille region and screening of microdeletions by genotyping 23 patients. AB - Alagille syndrome (AGS) has been assigned to 20p11.23-20p12.2 according to minimum overlap between deletions observed on the chromosome 20 short arm of 9 patients. We report here the localisation of 5 microsatellite markers (D20S41, D20S48, D20S50, D20S56, and D20S58) within the deletion of one AGS patient. This study allows an estimation of the genetic extent of this deletion as being between 30 and 36 cM, and demonstrates its paternal origin. The search for submicroscopic deletions in 23 AGS patients, by typing these 5 markers, failed to reveal allelic loss. However, these results lead to the proposition that the AGS locus lies in one of the seven intervals defined by the six microsatellite markers in the region flanked by D20S5 and D20S18. PMID- 7834279 TI - A European research conference on the inherited disorders and their genes in different European populations. PMID- 7834280 TI - European Gene Mapping Project (EUROGEM): genetic maps based on the CEPH reference families. PMID- 7834281 TI - The EUROGEM map of human chromosome 1. PMID- 7834282 TI - The EUROGEM map of human chromosome 2. PMID- 7834283 TI - The EUROGEM map of human chromosome 3. PMID- 7834284 TI - The EUROGEM map of human chromosome 4. PMID- 7834285 TI - The EUROGEM map of human chromosome 5. PMID- 7834286 TI - The EUROGEM map of human chromosome 6. PMID- 7834287 TI - The EUROGEM map of human chromosome 7. PMID- 7834288 TI - The EUROGEM map of human chromosome 8. PMID- 7834289 TI - The EUROGEM map of human chromosome 9. PMID- 7834290 TI - The EUROGEM map of human chromosome 10. PMID- 7834291 TI - The EUROGEM map of human chromosome 11. PMID- 7834292 TI - The EUROGEM map of human chromosome 12. PMID- 7834293 TI - The EUROGEM map of human chromosome 13. PMID- 7834294 TI - The EUROGEM map of human chromosome 14. PMID- 7834295 TI - The EUROGEM map of human chromosome 15. PMID- 7834296 TI - The EUROGEM map of human chromosome 16. PMID- 7834297 TI - The EUROGEM map of human chromosome 17. PMID- 7834298 TI - The EUROGEM map of human chromosome 18. PMID- 7834299 TI - The EUROGEM map of human chromosome 19. PMID- 7834300 TI - The EUROGEM map of human chromosome 20. PMID- 7834301 TI - The EUROGEM map of human chromosome 21. PMID- 7834302 TI - The EUROGEM map of human chromosome 22. PMID- 7834303 TI - The EUROGEM map of human chromosome X. PMID- 7834304 TI - Spectral editing in MAS NMR of aprotic solids. 31P-113Cd cross-polarization and heteronuclear double-quantum filtering studies in II-IV-V2 semiconductor alloys. AB - Magic-angle-spinning NMR spectra of aprotic solids, ceramics and glasses frequently suffer from poor site resolution due to wide chemical shift distribution effects. In such cases, cross-polarization and heteronuclear double quantum filtering experiments involving nuclei other than 1H offer unique spectral editing capabilities. The utility of such assignment techniques for examining site populations in semiconductor alloys is demonstrated for the chalcopyrite systems CdGeAs2-xPx, CdSiAs2-xPx and ZnxCd1-xGeP2. The results permit a distinction between local and non-local effects on experimental chemical shift trends and reveal that compositional dependences observed in these alloys are dominated by non-local chemical shift contributions. PMID- 7834305 TI - A method for detection of spectral spin diffusion from minor peaks, and its application to 19F MAS NMR of antimony(III)-doped fluorapatite. AB - A new technique for detecting spectral spin diffusion in solids under MAS NMR conditions that is particularly well suited for accurately measuring cross relaxation from minor spectral components is presented. The pulse sequence, SINK (Saturation Inter-Nuclear Kinetics), selectively saturates the magnetization of a minor spectral component with a series of rotor-synchronized DANTE pulse trains and monitors spin diffusion to other peaks with a non-selective 90 degrees pulse. We have used SINK with 19F MAS NMR on samples of calcium fluorapatite doped with Sb3+ to measure spin diffusion between a weak peak at 68.6 ppm due to fluoride ions associated with Sb3+ and other peaks in the spectrum. The SINK experiment clearly demonstrates that spin diffusion from the former peak to the main resonance of fluorapatite at 64.0 ppm is faster than spin diffusion to a second antimony-related peak at 65.6 ppm. These results strengthen our previous conclusion that antimony(III) occupies a phosphate site in the apatite lattice, with an SbO3(3-) group replacing a PO4(3-) group. The SINK experiment also enables the detection of a "hidden" peak at approximately 62.9 ppm that is otherwise obscured by the intense main peak at 64.0 ppm. PMID- 7834306 TI - Local monitoring of proton spin diffusion in static and rotating samples via spy detection. AB - A method is described for investigating local proton "spin diffusion" by means of a 13C spin probe. The procedure does not require spectral resolution of proton resonance lines and can be applied in the laboratory frame of reference as well as in the rotating frame. Experimental results are presented for a static single crystal of ferrocene and for a powder sample under magic-angle spinning. The spin diffusion rate constant is found to be proportional to the spinning speed in the range from 1 to 8 kHz. PMID- 7834307 TI - Corrections to the cross-polarization dynamics in solids. The effect of nonsecular terms of heteronuclear dipolar interaction on cross-relaxation. AB - The dynamic theory of cross-polarization in solids is modified by considering the contribution of the nonsecular terms of the heteronuclear dipolar interaction Hamiltonian in the laboratory frame to cross-relaxation. This contribution is evaluated numerically and confirmed experimentally. It is shown that these nonsecular terms may play a considerable role in cross-relaxation in many systems, especially in those with fast internal molecular motion. The complication in the cross-polarization process is further revealed. PMID- 7834308 TI - Deuteron NMR spectra of ND4ClO4 single crystal at low temperatures. AB - 2H NMR spectra of ND4ClO4 single crystal were obtained at v0 = 44 MHz. Orientation and temperature (1.9-75 K) dependences were measured. Fitting the spectra gives the effective quadrupole coupling constants for all deuterons and the ground torsional level structure. The isotope reduction of the (A-T) and (A E) tunnelling splittings, i.e., the ratios of the respective splittings for NH4+ and ND4+, were found to be different. The splittings at T = 24 K are about 60% of the helium temperature values. The spectrum undergoes intermediate narrowing by reorientations between 26 and 34 K and tunnelling related features in the spectra are eradicated. After reaching the extreme narrowing limit, a doublet with gradually decreasing separation was observed, what was attributed to averaging by torsional oscillations of increasing amplitude. At high temperatures (T > 75 K), the narrow spectrum reflects fast multiaxial reorientation of the ammonium ion. PMID- 7834309 TI - A simple theoretical treatment of quadrupolar effects on magic-angle-spinning solid-state NMR spectra of spin-1/2 nuclei in the limit of large quadrupole coupling constants. AB - A simple approach is discussed for studying the effect of quadrupolar nuclei on the magic-angle-spinning solid-state NMR lines of spin-1/2 nuclei in the limit of large quadrupole coupling constants. Equations are derived both for the isotropic shifts and the Pake-like powder patterns for any quadrupolar spin and for arbitrary orientations of the internuclear vector with respect to the unique axis of an axially symmetric quadrupole tensor. First-order effects due to a small Zeeman perturbation on these lines are explored, as well as deviations from axial symmetry in the electric field gradient when S = 3/2 quadrupolar nuclei are involved. Spectral parameters likely to be observed in the case of coupling between 31P and 201Hg are also discussed. PMID- 7834310 TI - Correlations between 27Al magic-angle spinning nuclear magnetic resonance spectra and the coordination geometry of framework aluminates. AB - A range of aluminate sodalites of general formula M8(AlO2)12.X2, where M and X are a divalent cation and anion, respectively, has been synthesised. The structures of these materials, which contain a single aluminum environment, have been refined from powder X-ray or neutron diffraction data and the compounds further characterised using 27Al magic-angle spinning nuclear magnetic resonance (MAS NMR). Correlations between (i) the Al-O-Al bond angles and the 27Al chemical shift and (ii) the quadrupolar coupling constant and the distorted AlO4 tetrahedral geometry have been determined. PMID- 7834311 TI - The first solid-state 171Yb nuclear magnetic resonance spectra. AB - The first powder and magic-angle spinning (MAS) experiments on 171Yb are reported. The divalent ytterbium compound RbYbI3 was studied by solid-state 171Yb nuclear magnetic resonance (NMR) and a powder spectrum of axial symmetry was obtained. The principal components of the chemical shielding tensor were determined as sigma 11 = sigma 22 = -62 ppm and sigma 33 = 124 ppm. An inversion recovery experiment showed an anisotropic relaxation behavior with the parallel component relaxing faster than the perpendicular component (T1 perpendicular = 426 ms, T1 parallel = 298 ma). The natural line width of 800 Hz, which corresponds to an effective T2 of 0.4 ms, was obtained from the MAS spectrum. PMID- 7834312 TI - 29Si and 27Al magic-angle spinning nuclear magnetic resonance of sialon X-phase. AB - The 29Si isotropic chemical shift of sialon X-phase (Si3Al6O12N2) is reported unequivocally for the first time. The implications of the 29Si and 27Al magic angle spinning (MAS) nuclear magnetic resonance (NMR) spectra for atomic ordering within X-phase are discussed. PMID- 7834313 TI - Structural characterisation of Na2ZrO3. AB - A combination of X-ray and electron diffraction, electron microscopy and solid state nuclear magnetic resonance (NMR) has been used to elucidate the structure and the ordering of Na2ZrO3. The diffraction data confirm a monoclinic crystal structure. A sample prepared by a conventional solid-state reaction of the components is shown by both X-ray diffraction and electron microscope imaging to have an extremely high concentration of planar defects associated with stacking disorder of the planes along the c-axis. The incidence of these defects is significantly reduced in a sample recrystallised from a bismuth oxide flux. NMR indicates that the local coordinations are well defined in both samples but with some sharpening of the spectra from the recrystallised sample indicative of the increase of long-range order. The 23Na magic angle spinning (MAS) NMR spectra clearly show three distinct sites with widely differing quadrupolar interaction parameters that can be related to the known site symmetries. Two distinct oxygen resonances are observed in the MAS NMR spectrum from an 17O-enriched sample while the static 91Zr NMR spectrum can be simulated with one set of interaction parameters. PMID- 7834314 TI - Application of nuclear magnetic resonance magic sandwich echo imaging to solid polymers. AB - A solid-state 1H nuclear magnetic resonance (NMR) imaging technique based on magic sandwich echoes (MSE) is described for obtaining spatial projections of solid polymer samples. The modification of MSE multiple echo detection is combined with short gradient pulses applied during the sandwich windows. This allows proton homonuclear decoupling in solids with dipolar couplings up to 50 kHz. For a rapid gating of the gradients a fast gradient pulse driver was constructed with switching times between 550 and 910 ns giving a maximum gradient strength of 330 mT/m. With our detection technique the spectral width can be doubled. One-dimensional projections and spatially resolved spectra of rigid polymer phantoms are presented. For contrast enhancement the use of the T1 relaxation time and the number of the magic sandwiches functioning as an adjustable magnetization filter discriminating between different strengths of the dipolar coupling is demonstrated. PMID- 7834315 TI - Cross-polarization dynamics in 2,6-dimethylbicyclo[3.3.1]nonane-exo-2-exo-6-diol inclusion compounds as studied by 13C magic-angle spinning nuclear magnetic resonance spectroscopy. AB - Solid-state 13C nuclear magnetic resonance (NMR) spectra of a number of inclusion compounds of 2,6-dimethyl-bicyclo[3.3.1]nonane-exo-2-exo-6-diol (host) with small organic small molecules (guests) have been studied. With 3,4-dichloro-1,2,5 thiadiazole and tetrachloroethylene as guests, line splittings of the host resonances were observed due to the location of the guest in the host lattice. The cross-polarization (CP) dynamics of these inclusion compounds have been studied and shown to be indicative of weakly coupled systems. As expected, the proton spin lattice relaxation times in the rotating frame (T1pH) of the host are increased by the presence of rapidly moving guest because the efficiency of homonuclear dipolar relaxation in the rotating frame is reduced. However, strong transient oscillations were also observed for the guest molecules during the Hartmann-Hahn transfer of magnetisation from the more abundant 1H spins to the 13C spins during spin lattice rotating frame relaxation. These oscillations were found to be greatest for carbons with largest chemical shift anisotropies. PMID- 7834316 TI - Determination of 51V quadrupole and chemical shift tensor orientations in V2O5 by analysis of magic-angle spinning nuclear magnetic resonance spectra. AB - Magic-angle spinning (MAS) 51V nuclear magnetic resonance (NMR) spectra of V2O5 have been recorded at various fields to evidence the relative effects of the quadrupole interaction and electronic shielding at the nucleus. A refinement of the spectra using theoretical simulations has been performed assuming a simultaneous existence of these two anisotropic interactions. The relative orientation of the principal axes for both tensors has been obtained. The results agree with previous single-crystal studies. Reliability of the results is discussed. A fundamental indetermination of the actual relative tensor orientations remains, owing to the powder nature of the sample. PMID- 7834317 TI - Magic-angle spinning nuclear magnetic resonance of half-integer quadrupole nuclei: effect of spin-locking efficiency on powder lineshapes. AB - 23Na spin-lock magic-angle spinning (MAS) and cross-polarization (CP) MAS nuclear magnetic resonance (NMR) spectra have been traced for sodium-containing compounds such as Na2SnO3.3H2O, Na2TeO4.2H2O, Na2SiO3.9H2O and NaBO2.2H2O whose asymmetric factors in quadrupole interaction are 0.00, 0.37, 0.63 and 0.80, respectively. The lineshapes in the spin-lock/MAS and CP/MAS NMR spectra are different from those in the spectra measured with the single-pulse sequence (SP) combined with 1H dipolar decoupling (DD). In other words, the former lineshapes are distorted from the theoretical ones broadened by the second-order quadrupole interaction. The lineshapes are distorted during the spin-locking period, since the spin locking efficiency depends on the crystallite orientation in a powder sample. We have discussed the distortion on theoretical bases and simulated the observed spectra. PMID- 7834318 TI - Measurement of 13C chemical shift tensor principal values with a magic-angle turning experiment. AB - The magic-angle turning (MAT) experiment introduced by Gan is developed into a powerful and routine method for measuring the principal values of 13C chemical shift tensors in powdered solids. A large-volume MAT probe with stable rotation frequencies down to 22 Hz is described. A triple-echo MAT pulse sequence is introduced to improve the quality of the two-dimensional baseplane. It is shown that measurements of the principal values of chemical shift tensors in complex compounds can be enhanced by using either short contact times or dipolar dephasing pulse sequences to isolate the powder patterns from protonated or non protonated carbons, respectively. A model compound, 1,2,3-trimethoxybenzene, is used to demonstrate these techniques, and the 13C principal values in 2,3 dimethylnaphthalene and Pocahontas coal are reported as typical examples. PMID- 7834319 TI - Residual interactions of a quadrupolar nucleus subject to high magnetic field and magic-angle spinning. AB - This is a theoretical study of nuclear magnetic resonance (NMR) spectra to be obtained from a powder specimen spinning in the magnetic field. The nuclear system is assumed to be magnetically dilute and to exhibit a combination of electric quadrupole interaction, magnetic shielding anisotropy and heteronuclear spin coupling. Formulas are given for the line positions and centreband linewidths of all transitions of the quadrupolar nucleus, in terms of scalar products of local interaction tensors. A number of unusual effects are predicted. PMID- 7834320 TI - Structural analysis of highly oriented poly(p-phenylene-terephthalamide) by 15N solid-state nuclear magnetic resonance. AB - The structure of an aromatic polyamide, poly(p-phenylene-terephthalamide) (PPTA), was studied in the solid state using 15N nuclear magnetic resonance (NMR) spectroscopy. Spectra of uniaxially aligned molecules placed with the axis of alignment both parallel with and perpendicular to the applied magnetic field were analyzed to yield the orientations of specific molecular bonds with respect to the fiber axis. The 15N chemical shift tensor was characterized by simulating powder pattern spectra of both PPTA and a model compound, benzanilide. Chemical shift and dipolar coupled chemical shift line shapes were calculated through Euler angle transformations from the principal axis system (PAS) reference frame to the fiber axis system (FAS) frame. The orientations of NH and NC' bonds in PPTA are determined as well as the orientational distribution of the PPTA fiber axis. The structural parameters determined for PPTA are compared with those obtained by X-ray diffraction. PMID- 7834321 TI - Interpreting nuclear magnetic resonance spectra of disordered materials: direct inversion of powder patterns. AB - The nuclear magnetic resonance (NMR) spectra of disordered materials are often interpreted by assuming distributions of the interaction parameters and fitting the spectra under these assumptions. Here we illustrate methods to extract the distributions directly from the spectra, making no such prior assumptions. The inhomogeneously broadened powder pattern observed in the NMR spectrum of a disordered solid is expressed as an integral over the powder patterns for individual sites weighted by the population distribution of the different sites. The resulting integral equation is solved for the underlying probability distribution of sites, both by singular value decomposition and by a regularization method. Results are shown for model and real one-dimensional and two-dimensional NMR experiments, with and without noise. PMID- 7834322 TI - Application of one-dimensional nutation nuclear magnetic resonance to 51V in ferroelastic BiVO4. AB - The central line intensity of a spin I = 7/2, excited by a radio frequency (rf) pulse, is calculated by taking into account the first-order quadrupolar interaction during excitation. Thus, the result is valid for any ratio of quadrupolar coupling to pulse amplitude. The quadrupolar coupling of the nuclei vanadium 51V in a single crystal of ferroelastic BiVO4 is determined using this one-dimensional (1D) mutation method. PMID- 7834323 TI - Two-dimensional one-pulse rotational echo spectra. AB - Recently a two-dimensional representation of one-dimensional spinning sideband magic-angle spinning (MAS) spectra has been published with applications to deuteron MAS nuclear magnetic resonance (NMR). The introduction of a new time axis, based on the rotor period, allows the separation of isotropic and anisotropic chemical shifts. It is shown here that, in addition to untangling spinning sideband spectra, data-processing steps can be incorporated which enabled applications of the method to signals from nuclei with anisotropies smaller than those of the quadrupole coupling of deuterons. This is achieved by linear prediction of the rotary echo signals. Advantages and limitations of the algorithm are discussed and demonstrated with experimental results of 13C cross polarization (CP) MAS spectra of glycine. PMID- 7834324 TI - [Loratadine versus terfenadine in perennial allergic rhinitis: ability to inhibit skin response]. AB - We studied 104 medical student from the UANL, with symptoms of perenneal allergic rhinitis, including only 30 patients for this study; seven patients with loratadin 10 mg, eight with loratadine 20 mg and 15 with terfenadine 120 mg/day/21 days, 20 mg of loratadine and 120 mg of terfenadine demonstrated significant decrease of the symptoms (P). Two patients had collateral effects with terfenadine, but terfenadine were more effective than the loratadine in the reduction of the skin reactivity. PMID- 7834325 TI - [Asthma induced by aspirin and arachidonic acid metabolites. II. The role of leukotrienes (part four)]. AB - Although the mechanism of aspirin-induced asthma is unknown, it has be suggested that adverse nasal and bronchial reactions are caused by an increased production of lipoxygenase products. We have measured the release of urinary LTE4, TXB2 and 11-dehydro-TXB2 of aspirin induced asthmatics and controls by radioimmunoassay and HPLC methods during aspirin challenge and after desensitization. The overproduction demonstration of urinary LTE4 during aspirin challenge and the decrease after desensitization in inversal direct proportion manner with TXB2 suggest a "shunting" of the arachidonic acid metabolites of the target cells. Whichever theory is to be pursued further, it must also accommodate the clinical effect of aspirin densitization. PMID- 7834326 TI - [Potentially fatal anaphylaxis. Report of 3 cases]. AB - Near fatal anaphylactic reactions to food are rarely reported, we identified three such cases in the Allergy Clinic at Children's Hospital Federico Gomez in Mexico. All had known food allergies, they received familiar training for identification and recognition of anaphylactic reaction and how to administer adrenaline rapidly. Our results are similar to those found in the literature. PMID- 7834327 TI - [Smoking. Changes produced by urethane on macrophage receptors and the complement system]. AB - The present of communication result of the analysis action urethane, that is yield of burning tobacco, provoked alterations on macrophages, complement system and red blood cells. Our data show that urethane high concentration kill macrophages and red blood cells and severely inhibits complement activity. These findings suggest that urethane high concentrations injury to macrophage's receptors, complement system and red blood cells and these are associated with pathologic process related with passively and actively smoking individuals. PMID- 7834328 TI - [The use of methotrexate in cortico-resistant asthma]. AB - Methotrexate represents a new therapeutic modality in patients with corticoresistant asthma. Its mechanism of action is the competitive inhibition of the folate reducing enzyme, converting folic acid in tetrahydrofolate during the S phase of the cell cycle. It is 50% fixed to albumin and excreted by glomerular filtration and proximal tubule secretion. PMID- 7834329 TI - Effect of gamma-aminobutyric acid on synaptic transmission and long-term potentiation in rat superior cervical ganglion. AB - The effect of gamma-aminobutyric acid (GABA) on synaptic transmission in rat superior cervical ganglion (SCG) was assessed in vitro by extracellular recording. Postganglionic compound action potentials (CAPs) triggered by preganglionic stimulation were blocked in a reversible and concentration dependent fashion by short, 60 s long, superfusion with GABA (IC50 = 39.3 microM), with the GABAA agonist muscimol (IC50 = 8.7 microM) or with the GABAB agonist baclofen (IC50 = 145 microM). Responses to GABA and muscimol, but not to baclofen, exhibited desensitization after 5 min long superfusions with the drugs. In a long-term potentiation (LTP) paradigm, the degree of potentiation found 30 min after a tetanic train of stimuli (20 Hz for 20 s) was strongly inhibited by GABA (100-250 microM), when superfused at the time of tetanic stimulus or shortly thereafter. The effect of GABA on SCG LTP was mimicked by muscimol but not by baclofen. The results are compatible with the view that GABA exerts overall inhibitory effects in rat SCG, including transmission blockade of single impulses (through activation of GABAA and GABAB receptors) and impairment of activity dependent potentiation of nicotinic transmission (through activation of GABAA receptors). PMID- 7834330 TI - Regulation of tyrosine hydroxylase in olfactory bulb cultures: selective inhibition of depolarization-induced increase by endogenous opioids. AB - Regulation of tyrosine hydroxylase (TH) by second messenger pathway activators was examined in rat olfactory bulb cell cultures. The number of TH-immunoreactive neurons was increased 2-3-fold by 36 h treatments with forskolin (Fsk, 10(-6) M) or phorbol myristate acetate (PMA, 10(-7) M), but was not significantly increased by a depolarizing concentration of KCl (45 mM). In contrast, KCl increased media [Met5]enkephalin (ME) immunoreactivity 2-fold in these cultures, equivalent to stimulation with Fsk or PMA. The possibility was examined that ME or another opioid produced by the cultures selectively inhibited the TH response to KCl. Pretreatment with the opioid receptor antagonist naloxone (10(-6) M) greatly increased the number of TH-immunoreactive neurons observed in response to KCl treatment, but had no effect on basal or Fsk-stimulated TH immunostaining, nor on basal or stimulated ME release. The increase in TH-immunoreactivity observed with combined KCl plus naloxone treatment was prevented by pretreating the cultures with the calcium channel blocker nimodipine (10(-6) M), which had no effect on Fsk stimulation or basal TH immunostaining. These data suggest that endogenous opioids selectively inhibit KCl-stimulated Ca2+ entry and thus TH induction in olfactory bulb cell cultures. These cultures offer a simple model system for further study of TH regulation in dopaminergic neurons. PMID- 7834331 TI - Limbic system fos expression associated with paternal behavior. AB - Axon-sparing lesions of the medial nucleus of the amygdala (MeA) decrease male parental behavior in the highly social prairie vole. To assess further the role of the amygdala in paternal behavior, male and female prairie voles were exposed to a pup or a non-social olfactory stimulus for 3 hours, and cells expressing Fos peptide were labelled using immunocytochemistry. Compared to controls, males exposed to a pup showed an increase in Fos expression in the MeA, as well as in several areas with connections to it: the accessory olfactory bulb, lateral septum, medial preoptic area, medial bed nucleus of the stria terminalis, nucleus reuniens and paraventricular nucleus of the thalamus. There was no increase in Fos immunoreactivity in the paraventricular nucleus of the hypothalamus or piriform cortex. The same pattern of Fos expression was found in female voles, with the exception of the thalamic paraventricular nucleus, where there was an increase in the pup-exposed group that was not statistically significant (P = 0.11). In addition, the magnitude of induction in females was markedly less than that in males in the medial preoptic area. These results provide further evidence that the MeA is involved in paternal behavior, and suggest certain other areas previously implicated in meternal behavior may also be involved in the control of paternal behavior in this species. PMID- 7834332 TI - Picrotoxin-induced epileptic activity in hippocampal and neocortical slices (guinea pig): suppression by organic calcium channel blockers. AB - Epileptic activity induced by the GABAA receptor antagonist bicuculline is known to be blocked by organic calcium antagonists. To further analyse the mechanism underlying convulsant activity induced by substances reducing GABA-mediated synaptic transmission, the effect of organic calcium channel blockers on epileptic activity induced by the GABAA channel blocker picrotoxin in hippocampal and neocortical slices of guinea pigs were investigated. Verapamil and flunarizine suppressed paroxysmal depolarization shifts (PDS) of single neurons and accompanying epileptic field potentials (EFP). As a measure of drug action the repetition rate of epileptic events were used. The depression down to 10% the initial value (90% depression) is indicated. In the hippocampus verapamil suppressed PDS/EFP within 70 +/- 16 min (40 mumol/l) and within 39 +/- 5 min (60 mumol/l). This suppression was reversible with washout of verapamil. Flunarizine irreversibly blocked EFP/PDS within 108 +/- 14 min (18 mumol/l). In the neocortex verapamil reversibly suppressed EFP within 146 +/- 6 min (40 mumol/l) and 127 +/- 26 min (60 mumol/l). Flunarizine irreversibly blocked EFP within 181 +/- 30 min (3 mumol/l) and 109 +/- 13 min (18 mumol/l). The results suggest that voltage dependent calcium channels are essentially involved in picrotoxin-induced epileptic activity. PMID- 7834333 TI - Thymectomy-induced deterioration of learning and memory in mice. AB - Male ddY mice were thymectomized 4 weeks after birth. Learning behaviors, tested in passive and active avoidance performances and in a spatial memory task, were significantly impaired in thymectomized mice at 10 months after thymectomy, in addition to the reduced immune response. Contents of hypothalamic norepinephrine and hypothalamic choline acetyltransferase activity were significantly increased in thymectomized mice. These results suggested that thymectomy at young adult life in mice not only impaired the immune response, but also deteriorated the learning and memory ability. PMID- 7834334 TI - Brain temperature- and behavior-related changes in the dentate gyrus field potential during sleep, cold water immersion, radiant heating, and urethane anesthesia. AB - The field potential evoked in the dentate gyrus (DG) by stimulation of the perforant path (PP) is known to vary with ongoing behavior and with brain temperature. To further study these phenomena chronic stimulating and recording electrodes were implanted into the PP and DG of rats, and a thermistor was implanted into the contralateral homotopic DG. Field potentials and brain temperature records were made during (1) slow wave sleep (SWS), (2) radiant heating, (3) immersion in cool water, (4) a control session during which no manipulations were made, and (5) under urethane anesthesia. In another group of rats field potentials were recorded during (1) baseline immobile wakefulness, (2) SWS, (3) before SWS or after gentle awakening from SWS (eyes open and presence of intermittent slow waves in the EEG), (4) immobile wakefulness, and (5) 24 h later. Findings were that field EPSP slope decreased and population spike (PS) amplitude increased by up to 60% of baseline values during conditions in which brain temperature was reduced (SWS, immersion in cool water, urethane anesthesia). Conversely, EPSP slope increased and PS amplitude decreased by up to 100% of baseline values during conditions in which brain temperature increased (awakening from SWS, radiant heating, and warming after immersion in cool water or urethane anesthesia). Product moment correlations between brain temperature and field potential measures confirmed the statistical reliability of these findings and accounted for up to 77% of the variance. These findings confirm the robust effect on hippocampal field potentials of brain temperature changes due to exogenous heating and cooling, and extend this effect to anesthetic- and sleep induced brain temperature changes. They also identify a state that behaviorally resembles quiet wakefulness but resembles SWS in terms of neocortical EEG, brain temperature, and hippocampal field potential measures. The findings indicate the need to control for brain temperature-mediated changes in hippocampal research that uses the dentate gyrus field potential as a dependent measure. PMID- 7834336 TI - Lack of fever suppression or central AVP release in 1K1C hypertensive rats. AB - Previous studies from our laboratory showed a transient suppression of the febrile response to intracerebroventricular (i.c.v.) PGE1 in the one-kidney, one clip (1K1C) model of hypertension. This may have been due to an enhanced vasopressinergic transmission since arginine vasopressin (AVP), acting within the central nervous system (CNS), is thought to mediate endogenous antipyresis. These initial experiments utilized a protocol for the induction of 1K1C hypertension which produced an initial rapid rise in blood pressure, evident by day 4 following surgery, with a corresponding inhibition of the febrile response. The present experiments utilized a more slowly developing 1K1C hypertension (evident by day 12 following surgery) to firstly attempt to determine if inhibition of the febrile response is due to the actual change in blood pressure or to neural signals arising from the clipped kidney, and secondly to determine if the concentration of AVP in push-pull perfusates of the ventral septal area (VSA) of pyrogen-treated sham-operated and 1K1C rats were altered. In urethane anaesthetized rats, i.c.v. PGE2 evoked brisk monophasic fevers in both 1K1C and sham-operated animals, with no significant difference between fever heights. Consistent with this, we found no increase in immunoreactive AVP from perfusates of the VSA of 1K1C rats. These results suggest that there is no inhibition of the febrile response to PGE2 when a slower developing hypertension is induced, nor is there an elevated release of AVP into the VSA under our conditions. We conclude that a rapid increase in blood pressure, and not high blood pressure per se, is required to produce an inhibition of the febrile response. PMID- 7834335 TI - Early L-dopa treatment initially retards but later enhances dopamine receptor supersensitivity following unilateral dopamine denervation. AB - Rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of nigrostriatal dopamine neurons were administered 25 mg/kg L-DOPA methyl ester/2 mg/kg carbidopa once or twice per day or saline in separate treatment groups for 13 days. Treatment was initiated within 18-20 h postoperative, well-before the onset of denervation supersensitivity. Contralateral rotation emerged as a response to L-DOPA on day 7 postoperative first in the L-DOPA once/day group and then on day 9 for the L-DOPA twice/day group. Thus, early postoperative L-DOPA treatment retarded but did not prevent the development of dopamine receptor supersensitivity. Following a 14-day withdrawal period, these same L-DOPA treated groups exhibited substantially higher rates of contralateral rotation to an L-DOPA challenge as compared to a drug-naive group with comparable 6-OHDA lesions. HPLC-EC measurements of L-DOPA in striatal and cortical tissue samples showed no differences in concentration across the L-DOPA treatment groups. There were several differences, however, in the neurochemical impact of L-DOPA on frontal cortex vs. striatum. In the striatum but not the cortex, L-DOPA concentrations were higher in the 6-OHDA than the intact hemisphere and, L-DOPA increased dopamine concentrations in cortex but not in the striatum. Behaviorally, L-DOPA exerted two diametrically opposite effects linked to the state of dopamine receptors. Prior to the onset of dopamine receptor supersensitivity L-DOPA suppressed locomotor behavior and delayed the emergence of denervation supersensitivity. Once denervation supersensitivity developed, however, the L-DOPA engaged sensitization mechanisms and enhanced locomotor behavior and dopamine receptor supersensitivity. These findings suggest that the initiation of antiparkinsonian treatment prior to the onset of denervated dopamine receptor supersensitivity in the 6-OHDA model is a valuable strategy to determine if a drug treatment retards or facilitates the development of dopamine receptor supersensitivity. PMID- 7834337 TI - Immunocytochemical localization of the alpha-, beta I-, beta II- and gamma subspecies of protein kinase C in the monkey visual pathway. AB - We examined the distribution of alpha-, beta I-, beta II- and gamma-subspecies of protein kinase C (PKC) in the monkey visual pathway, including the retina, the lateral geniculate nucleus (LGN) and the visual cortex (area 17). In the retina, alpha-PKC immunoreactivity was found in cone photoreceptor and in bipolar cells. beta I-PKC immunoreactivity was present in the ganglion cell layer and the optic nerve fibers. The beta II- and gamma-PKCs were not found in the retina. In the LGN, intense gamma-PKC immunoreactivity was found in a part of magno and parvo cells. The LGN was negative for the alpha-, beta I- and beta II-PKC. All four PKC subspecies were present in the visual cortex but the distribution was distinct. The beta I-PKC immunoreactive cells were scattered in all layers, while the alpha PKC immunoreactive cells were prominent in layers II, III, IVb, IVc and VI, and the beta II-PKC immunoreactive cells were found in layers II, III, IVb and VI. The intense gamma-PKC immunoreactivity was present in the neuropils in layers I, IVa, IVc and VI and also in soma and dendrites in layers II and VI. It thus seems likely that each subspecies plays a specific role in neuronal transmission in the visual pathway. PMID- 7834338 TI - Immunohistochemistry with an antibody to human liver carboxylesterase in human brain tissues. AB - Human liver carboxylesterase (CE) is an enzyme capable of metabolizing drugs, and may also function as a regulator of lipid metabolism. We examined one isoform of CE by immunohistochemistry in the brains of neurologically normal, Alzheimer disease (AD), amyotrophic lateral sclerosis (ALS) and cerebral infarction cases. In all but the infarcted brains, the anti-CE antibody stained only capillary endothelial cells in the brain and spinal cord tissues. In infarct brain areas, intense immunoreactivity of the macrophages was seen. In contrast, the macrophages in the ALS lateral columns and the reactive microglia located in the center of classical senile plaques in AD, as well as other reactive microglial cells in the grey matter, showed no immunoreactivity. In the central nervous system, CE may function as a protective factor against foreign chemicals in capillary endothelial cells, and the antibody to CE may serve as a marker for invading macrophages from the systemic circulation. PMID- 7834339 TI - An N-methyl-D-aspartate receptor antagonist does not prevent eye-specific segregation in the ferret retinogeniculate pathway. AB - Recent studies have shown that electrical activity, particularly that mediated by NMDA receptors, has a profound effect on the development of specific neuronal connections. Blocking NMDA receptors in the ferret's lateral geniculate nucleus prevents the segregation of retinal afferents into ON and OFF sublaminae. We have now examined the involvement of NMDA receptors in the separation of afferents from the two eyes that occurs in the lateral geniculate nucleus several weeks earlier in development. Blockade of NMDA receptor activity does not appear to interfere with this eye-specific segregation. PMID- 7834340 TI - Cerebral microvascular responses to endothelins: the role of ETA receptors. AB - The regulatory role of endothelins in cerebral microvessels was investigated in a recently developed model system which allows the study of small cerebral vessels in their normal microenvironment. Using brain slices of the rat neocortex, it was shown that the isopeptide endothelin-3 (ET-3) had no effect on cerebral microvessels, while the isopeptide endothelin-1 (ET-1) produced a potent, dose dependent vasoconstriction. When a recently developed antagonist of ETA receptors (cyclo-[D-Asp-L-Pro-D-Val-L-Leu-D-Trp]; ETant) was administered prior to treatment with ET-1, the vasoconstrictor response to ET-1 was inhibited in a dose dependent manner. When ETant was administered after the establishment of a constriction by ET-1, the constrictor response to ET-1 was partially reversed, and this effect was weaker than that seen in the pre-treatment paradigm. These findings indicate that constrictor responses to ET-1 in cerebral microvessels are mediated by ETA receptors. Inasmuch as endothelins have been implicated in pathological forms of vasoconstriction in the CNS, the present findings also suggest that endothelin antagonists may be useful in the treatment of cerebral ischemia. PMID- 7834341 TI - Short-term but not long-term adrenalectomy modulates amplitude and frequency of the CRH41 episodic release in push-pull cannulated median eminence of free-moving rats. AB - CRH 41 release in push-pull cannulated median eminence (ME) was measured in unanesthetized male rats, 3 and 7 days after adrenalectomy (ADX) and in sham lesioned controls. Perfusion started at 13.30 h and perfusate samples were collected at 5 min intervals for 3 h to estimate the mean release rate of CRH41. The major parameters of the neurohormone's episodic release pattern were analyzed using the Ultra algorithm. In a parallel study, 3 groups of similarly treated rats were used to measure plasma ACTH and hypothalamic CRH41. Three days after ADX, the plasma ACTH titers had risen 14-fold, the hypothalamic CRH41 content had decreased by 40%, while the CRH41 release in the ME had doubled as a result of a significant increase in most variables of the pulsatile release pattern: pulse frequency (+34%; P < 0.01), mean amplitude (+36%; P < 0.05), mean peak levels (+67%; P < 0.01) and mean pulse nadirs (x2.5; P < 0.01). Seven days after ADX, even though plasma ACTH had further increased to 30-times control levels, hypothalamic CRH41 content and CRH41 release in the ME had returned to almost control levels. The possible mechanisms of the discrepancy between the CRH and ACTH response time-courses following ADX are discussed. PMID- 7834342 TI - Marked regional disturbances in brain metabolism of monoaminergic neurotransmitters in the genetically dystonic hamster. AB - The genetically dystonic hamster is an animal model of idiopathic (torsion) dystonia that displays sustained abnormal movements and postures either spontaneously or in response to mild environmental stimuli. Since dystonic attacks occur in the absence of any lesion which can be defined by standard histopathological techniques in the central nervous system, the presumption is that dystonia in mutant hamsters is due to some biochemical disturbance activity in brain regions involved in motor functions. In the present study we determined the monoamine neurotransmitters dopamine, noradrenaline, adrenaline and serotonin (5-HT) as well as the dopamine metabolites homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC) and the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA) in 14 brain regions of male and female dystonic hamsters and age matched non-dystonic controls. All determinations were done at age of maximum susceptibility for induction of dystonic attacks. Since both genders of dystonic hamsters exhibit the same characteristic age-dependent time-course of dystonia, it was assumed that only those biochemical alterations are critically involved in dystonia that occur in both female and male animals. The neurochemical data show that except for a significant decrease of dopamine and HVA in the olfactory bulb, no consistent changes in dopamine metabolism are present across brain regions, including the basal ganglia, of dystonic hamsters. In contrast, marked increases in noradrenaline and 5-HT or 5-HIAA were found in several brain areas of both genders, indicating an enhanced activity of central noradrenergic and serotonergic nuclei in the brainstem. The present results suggest the involvement of noradrenergic and serotonergic neural systems in the pathophysiology of dystonia. Based on these data and recent theoretical suggestions from clinical findings, drugs which reduce noradrenergic and serotonergic neurotransmission may be a useful therapeutic approach to dystonia. PMID- 7834343 TI - The distribution of excitatory amino acid receptors in the normal human midbrain and basal ganglia with implications for Parkinson's disease: a quantitative autoradiographic study using [3H]MK-801, [3H]glycine, [3H]CNQX and [3H]kainate. AB - Quantitative receptor autoradiography using [3H]MK-801, [3H]glycine, [3H]CNQX and [3H]kainate was employed to determine the distribution and density of excitatory amino acid (EAA) binding sites in the midbrain and basal ganglia of the normal human nervous system. Detailed knowledge of the anatomy and subtype specificity of glutamate receptors is important both in understanding the normal physiology of basal ganglia neurotransmission and the pathophysiological changes occurring in diseases affecting the basal ganglia such as Parkinson's disease (PD). In PD, glutamate receptor activation may contribute to cell death of dopaminergic neurones in the substantia nigra. In addition, perturbation of glutamate neurotransmission resulting from dopamine depletion in the basal ganglia is likely to contribute to the clinical manifestations of motor dysfunction. The distribution and density of ligand binding representing N-methyl-D-aspartate (NMDA), AMPA (2-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) and kainate receptors has a heterogeneous distribution in the human midbrain and basal ganglia. In the substantia nigra relatively high densities of [3H]MK-801 and strychnine-insensitive [3H]glycine binding sites representing NMDA receptors were present, whereas only moderate densities of [3H]CNQX and [3H]kainate binding sites were present, compared to other regions. In both the medial globus pallidus and subthalamic nucleus, binding sites representing NMDA, AMPA and kainate receptors were all present at low density. These findings suggest that the clinical usefulness of modifying glutamatergic neurotransmission in these basal ganglia nuclei may be limited by the relatively low density of EAA binding sites present. PMID- 7834344 TI - Differential effect of amygdaloid lesions on CRF-41, ACTH and corticosterone responses following neural stimuli. AB - The effect of amygdaloid (AMG) lesions on changes in median eminence (ME) CRF-41 and serum ACTH and corticosterone (CS) levels following neural stimuli were investigated in rats. In intact animals photic or acoustic stimuli caused CRF-41 depletion from the ME and a rise in serum ACTH and CS levels. In rats with medial or central AMG nuclei lesions, these responses were blocked. Basal AMG lesions were not effective. Also, all groups of animals responded normally to ether stress. These results indicate a differential effect of AMG nuclei on the hypothalamo-pituitary-adrenocortical (HPA) axis and demonstrate that the facilitatory effect of the AMG nuclei on the HPA axis responses involves the release of ME CRF-41, which stimulates ACTH and consequently CS secretion. PMID- 7834345 TI - Nerve growth factor released by transgenic astrocytes enhances the function of adrenal chromaffin cell grafts in a rat model of Parkinson's disease. AB - Previous studies have demonstrated that astrocytes genetically modified to express recombinant nerve growth factor (NGF) support the survival and neuronal transdifferentiation of intrastriatal adrenal chromaffin cell grafts at 2 weeks post-transplantation [15]. The present study was performed to determine whether these effects would be maintained at longer times post-transplantation and, if so, whether the co-grafts would reduce rotational behavior in the unilateral 6 hydroxydopamine-lesioned rat. In the present study, we have demonstrated that primary type I rat astrocytes infected with a replication-defective retrovirus conferring expression of a mouse beta-NGF cDNA sequence secrete NGF at a rate that is approximately 40-fold higher than that of controls (i.e., 8.0 vs. 0.2 pg NGF/h/10(5) cells, respectively). The genetically modified astrocytes were also found to express recombinant NGF following intrastriatal transplantation, as indicated by a 23% increase in striatal NGF content compared with controls, measured at 4 weeks post-transplantation. When NGF-producing astrocytes and adrenal chromaffin cells were co-grafted into the dopamine-denervated striatum of the unilateral 6-hydroxydopamine-lesioned rat, the chromaffin cells displayed extensive neurite outgrowth and a 5-12-fold increase in survival compared to controls at 10 weeks post-grafting. These effects were paralleled by a 60% reduction of apomorphine-induced rotational behavior, suggesting a partial normalization of striatal function. These results suggest that genetically modified astrocytes promote the prolonged survival and function of adrenal chromaffin cell grafts in a rat model of Parkinson's disease. PMID- 7834346 TI - Cholecystokinin blockade of emotional stress- and CRF-induced colonic motor alterations in rats: role of the amygdala. AB - Intracerebroventricular (i.c.v.) injection of corticotropin-releasing factor (CRF) and emotional stress (ES) induce stimulation of colonic motility in rats, an effect blocked by i.c.v. injection of CCK-8s. This study examined in rats the contribution of the central nucleus of the amygdala (CA) in the blocking effect of CCK-8s on ES and CRF-induced colonic hypermotility. CRF (500 ng/kg, i.c.v.) induced a 73.5% increase in colonic spike burst frequency. Bilateral infusions of 1, 5, 10 and 20 ng/kg of CCK-8s in the CA region 10 min prior to CRF i.c.v. injection reduced, in a dose related manner, the CRF-induced stimulation of colonic motility. A 109% increase in colonic spike burst frequency was observed in rats placed in a test cage in which they had previously received electric footshocks (ES). CCK-8s and A-71623, a selective CCK-A receptor agonist, (10, 25 and 50 ng/kg) infused bilaterally into the CA, 30 min before ES, significantly reduced this stimulatory effect, while CCK-4 and A-63387, a selective CCK-B receptor agonist (10, 25 and 50 ng/kg), had no effect on such a response. CA lesions by ibotenic acid did not affect ES-induced increase in colonic spike activity. However, CCK-8s (50 ng/kg) microinfused into CA lesioned rats was unable to block the ES-induced stimulation of colonic motility, while CCK-8s i.c.v. injected (100 ng/kg) is still active on the colonic response to ES. These results suggest that CA is a site of interaction of CCK-8s with CRF to block the colonic response to stress and that these effects involve the CCK-A receptor subtype.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7834347 TI - Effects of muscarine on K(+)-channel currents in the C-cells of bullfrog sympathetic ganglion. AB - The effects of muscarine on small, putative C-cells and large, putative B-cells dissociated from bullfrog paravertebral sympathetic ganglia were studied by whole cell and single channel recording techniques. The dominant action of muscarine was to activate an inwardly-rectifying K+ current (IK(G)) in C-cells and to suppress M-current (IM) in B-cells. However, both IM and IK(G) were affected by muscarine in 5 out of 78 putative C-cells and in 8 others only IM was affected. By contrast, IK(G) was only activated in 1 out of 105 B-cells. This predicts that the muscarinic slow IPSP, which can be evoked by preganglionic stimulation, occurs exclusively in C-cells. 6% of these cells could, however, generate a muscarinic slow EPSP in addition to a slow IPSP and 10% could generate a slow EPSP without a slow IPSP. The rectification associated with IK(G) was neither a direct consequence of the direction of movement of K+ ions nor a simple consequence of channel block by intracellular Mg2+ or Na+ ions. The fit of the activation curve by a Boltzmann equation suggests that the conductance underlying IK(G) is controlled by a voltage-dependent gating charge (valency approximately 2). Muscarine activated no new channels in outside-out or cell-attached patches but increased the opening probability of two types of K+ channels (unitary conductances approximately 20 pS and approximately 55 pS). The possible role of these channels in the generation of IK(G) is discussed. PMID- 7834348 TI - Localization in rat brain of the trace metals, zinc and manganese, after intracerebroventricular injection. AB - Autoradiographic studies of rat brain, after 65ZnCl2 or 54MnCl2 injection into the lateral ventricle, revealed that 65Zn and 54Mn were transferred freely through the cerebrospinal and extracellular fluid compartments; both tracers appeared in all the ventricles 1 h after injection. At 6 days after injection, 65Zn was concentrated in the hippocampal formation and hypothalamic nuclei but not in the cerebral cortex and superior colliculus of the ipsilateral hemisphere, with a lower uptake into contralateral hemisphere except for the hypothalamic nuclei. 54Mn was concentrated in some brainstem nuclei, such as the red and pontine reticular nuclei, to about the same extent in both hemispheres. These results suggest that both metals were taken up gradually into brain mainly via the cerebrospinal fluid. Relatively high uptake of 65Zn into the cerebral cortex and superior colliculus after intravenous injection suggests uptake in those regions is through two blood/brain barriers. PMID- 7834349 TI - Effect of p-chloroamphetamine administration on monoamine metabolism in the rat nucleus accumbens and locomotor activity: studies with intracerebral dialysis in freely moving rats. AB - Changes in the level of dopamine (DA) and its metabolites [3,4 dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA)] and serotonin (5 HT) and its metabolite [5-hydroxyindoleacetic acid (5-HIAA)] were determined sequentially in freely moving rats by using a brain dialysis method. The purpose of the study was to find the relationship between changes in the monoamine metabolism in the nucleus accumbens and locomotor activities following PCA administration. Subsequently it was found that locomotor activity significantly increased 1 and 2 h after PCA administration (2 mg/kg, i.p.) while the DA content in the dialysis fluid rose significantly after 1 and 2 h. On the other hand, the 5-HT level did not show significant changes. The DOPAC, HVA, and 5-HIAA levels were significantly reduced 1 to 6 h after PCA administration. It was suggested that the increase in locomotor activity caused by PCA administration is an expression of abnormal behavior caused by DA release from the nucleus accumbens. PMID- 7834350 TI - Inhibition of corticosterone synthesis by Metyrapone decreases cocaine-induced locomotion and relapse of cocaine self-administration. AB - Several studies have recently shown that basal and stress-induced secretion of corticosterone may enhance vulnerability to drugs of abuse. In this report, we studied the effects of metyrapone, an inhibitor of the synthesis of corticosterone, on cocaine-induced locomotion and on the relapse of cocaine self administration. Locomotor response to cocaine was studied because psychomotor effects of drugs have been shown to be related to their reinforcing properties. Self-administration was studied in the relapse phase since blockade of relapse is central to the therapy of addiction. Before these behavioral tests, rats in different experimental groups were injected subcutaneously with either metyrapone (100 mg/kg) or vehicle, twice a day for 8 days. Metyrapone treatment reduced cocaine-induced locomotor activity and relapse of cocaine self-administration, without inducing a nonspecific disruption of motor or food-directed behaviors. Under these experimental conditions, the metyrapone treatment totally blocked stress-induced corticosterone secretion but did not modify basal corticosterone levels. These results confirm the involvement of glucocorticoids in the pathophysiological mechanisms underlying vulnerability to drug abuse, and may have implications for the development of new therapeutic strategies of drug addiction. PMID- 7834351 TI - Expression of a novel non-angiotensin II [125I]CGP 42112 binding site in healing wounds of the rat brain. AB - We characterized a novel non-angiotensin II binding site that is recognized by the angiotensin II AT2 receptor ligand [125I]CGP 42112, in healing brain wounds of adult rats. The binding, which was highest at 3 days after injury, appears to be localized to activated microglia surrounding the wound. The novel CGP 42112 binding site may have a role in the function of microglia and in mechanisms of tissue repair in the brain. PMID- 7834352 TI - Regional alteration of cholinergic function in central neurons of trisomy 16 mouse fetuses, an animal model of human trisomy 21 (Down syndrome). AB - The trisomy-16 (TS16) mouse is considered to be a model of human trisomy 21 (Down syndrome) because of genetic homology between mouse chromosome 16 and human chromosome 21. We examined cholinergic function of brain and spinal cord tissue and in cultured neurons from TS16 mouse compared with that of age matched controls. Mean acetylcholinesterase activity in both tissue types did not differ between trisomic and control conditions. Acetylcholine (ACh) synthesis, measured as choline O-acetyltratransferase (acetyl-CoA) activity, was reduced to 67% of control in TS16 brain but not in TS16 spinal cord. Steady-state accumulation of ACh precursor, [3H]choline, was measured in primary cell cultures. Steady-state choline uptake was reduced to 35% and to 61% in neurons of TS16 brain and spinal cord, respectively, when compared with controls. Kinetics experiments in TS16 brain cells showed a 50% reduction of the maximal velocity of choline uptake when compared to controls. Further, the ACh release induced by KCl depolarization in TS16 spinal cord neurons did not differ from control neurons but was reduced in TS16 brain neurons. This effect cannot be explained solely by a reduction in ACh synthesis. The results indicate that the TS16 condition in mice significantly modified the cholinergic function in brain, and to a lesser degree in spinal cord, suggesting that the higher gene dosage inherent to the trisomic condition affects cholinergic neurons in different regions of the central nervous system in a differential fashion. PMID- 7834354 TI - Hemorrhage-induced vasopressin release in the paraventricular nucleus measured by in vivo microdialysis. AB - Experiments were carried out, using the technique of in vivo microdialysis in conscious rats, to determine whether hemorrhage, a potent stimulus for the release of vasopressin from the posterior pituitary into the circulation, would also result in a local release of vasopressin from the paraventricular nucleus (PVN), and whether this release is affected by gender. Male and non-estrous female rats were prepared with a microdialysis probe adjacent to the PVN and femoral arterial and venous catheters the day before the experiment. On the day of the experiment, rats was bled either 20% or 30% of blood volume. The concentration of vasopressin in the dialysate increased significantly in the males following both hemorrhages and in the females following the 30% hemorrhage. There were no statistically significant differences in the post-hemorrhage dialysate vasopressin concentration with respect to either gender or magnitude of the hemorrhage. The plasma vasopressin concentration increased markedly in response to the hemorrhage and this response was greater in females following the 30% hemorrhage. There were no gender differences in the reduction in arterial pressure following either hemorrhage. It is concluded that physiological stimuli for the release of vasopressin into the circulation also result in intrahypothalamic release of this hormone. PMID- 7834353 TI - Endogenous adenosine exerts inhibitory effects upon the development of spreading depression and glutamate release induced by microdialysis with high K+ in rat hippocampus. AB - Spreading depression (SD) is known to be involved in the N-methyl-D-aspartate receptor-mediated neuronal damage. In urethane-anesthetized rats, we examined the release of adenosine and glutamate during SD induced by microdialysis of high K+ perfusate through the hippocampal CA1 area. The effects of endogenous adenosine upon SD were studied by applying an adenosine antagonist, theophylline (1 mM) and by a simultaneous application of adenosine uptake blockers, dipyridamole (DPR) (100 microM) and nitrobenzylthioinosine (NBI) (50 microM). The dialysates were sampled every 5 or 10 min and analyzed by HPLC. SD was identified by flattening of background EEg and disappearance of population spikes recorded from the pyramidal cell layer of CA1 area by a glass microelectrode. Adenosine and glutamate release was enhanced significantly in association with the occurrence of SD. Theophylline increased the release of glutamate and the incidence of SD and decreased the latency of the SD occurrence. DPR+NBI decreased the release of glutamate and the occurrence of SD, but increased extracellular adenosine concentration. The effects of DPR+NBI were blocked by application of a selective antagonist of adenosine A1 receptor, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 0.1 microM). These findings suggest that endogenous adenosine exerts inhibitory influences upon the development of SD and the glutamate release through the A1 receptor in rat hippocampus. PMID- 7834355 TI - Localization and gene expression of serotonin 1A (5HT1A) receptors in human brain postmortem. AB - We investigated the binding parameters, i.e. the maximum binding capacity (Bmax) and the dissociation constant (Kd), of [3H]8-hydroxy-2-(di-N-propylamino)tetralin ([3H]8-OH-DPAT) labeling the serotonin receptor of the 1A type (5HT1A), and the distribution of the mRNA encoding it in some human brain areas obtained from autoptic samples. The results showed that the Bmax was significantly higher in the hippocampus than in the prefrontal cortex and the striatum, while the Kd had the inverse, although not significant, pattern. The expression study revealed that 5HT1A mRNA distribution in the hippocampus and prefrontal cortex was consistent with the data of the [3H]8-OH-DPAT binding. A different result was obtained in the striatum where no 5HT1A mRNA expression was detected, despite the measurement of specific [3H]8-OH-DPAT binding. These findings underline the different nature of [3H]8-OH-DPAT binding sites in different brain areas and the need for further studies on 5HT receptor gene expression in human brain. PMID- 7834356 TI - Culture of arterial chemoreceptor cells from adult cats in defined medium. AB - Recently patch clamp techniques and optical fluorometric techniques have been applied to freshly dissociated or cultured carotid body. However, very few studies have shown the effects of the dissociation and/or culture conditions on the health and function of the cells. The purpose of this study was to develop a culture method which support healthy and functioning carotid body cells from adult cats. Carotid bodies were dissociated with 0.1-0.2% collagenase and gentle trituration. The cells were plated on glass wells coated with poly-D-lysin and Matrigel, and cultured in chemically defined medium. Culture was maintained for up to 37 days without overgrowth of fibroblasts. Glomus cells extended their processes within and from clusters. Single glomus cells acquired the shape of neurons. Glomus cells synthesized dopamine and its secretion increased during exposure of the cells to hypoxia. Tyrosine hydroxylase was expressed throughout the culture period. These results indicate that glomus cells cultured under conditions described here are healthy and function in a manner similar to that in vivo. PMID- 7834357 TI - Cortical areas are revealed by distribution patterns of proteoglycan components and parvalbumin in the Mongolian gerbil and rat. AB - Cortical areas in rodents have been basically characterized by its cytoarchitecture, connectivity or by physiological parameters. In this study we show that they are revealed by distribution patterns of proteoglycans and parvalbumin-immunoreactivity. Brains of young adult Mongolian gerbils (Meriones unguiculatus) and Wistar rats were cut into series of transversal sections. Proteoglycan components were detected using the N-acetylgalactosamine binding Wisteria floribunda agglutinin (WFA) and antibodies against chondroitin sulphate proteoglycan (CSPG). Differences between cortical areas were found to exist with regard to the occurrence and the density of perineuronal nets, but were also expressed in varying staining intensities for WFA and CSPG of the neuropil. Primary neocortical areas (somatosensory, auditory, visual cortex) were characterized by an intense neuropil staining in layer IV and the upper part of layer VI. Using the same methods strong labelling was also typical of the neuropil in the retrosplenial cortex, of layer Ia in the prepiriform cortex and the hippocampal CA3 field. In tangential sections cut from gerbil cortical hemispheres, some of the heavily lectin-stained cortical areas were sharply delineated from adjacent faintly labelled regions, others showed more diffuse borders. In the rat, the area-specific staining for WFA was less clearly expressed than in the gerbil. Immunocytochemistry of the calcium-binding protein parvalbumin in alternate sections showed labelling patterns of neuropil which resembled those of WFA-binding and CSPG-immunoreactivity in the entire neocortex and hippocampus. From these results it can be concluded that functional peculiarities of cortical fields may not only be determined by neuronal network parameters but also by the spatial arrangement of extracellular matrix proteoglycans. PMID- 7834358 TI - A dopaminergic-glutamatergic basis for the action of amphetamine and cocaine. AB - The behavioral effects of amphetamine and cocaine are generally considered to be the result of their indirect dopaminergic activity. Recent reports, however, suggest that the activity of the psychomotor stimulants involves not only the dopaminergic but also the glutamatergic system. In the present study the role of the glutamate system in the action of the stimulants was investigated in mice with the use of glutamatergic agonists and antagonists administered either intraperitoneally or intracranially into the striatum. CPP, an NMDA-type glutamate antagonist, given systemically or intrastriatally, blocked stereotypy induced by either amphetamine or cocaine. These results represent pharmacological evidence that the glutamate system is an essential component in the expression of the stereotypic effect of the psychomotor stimulants, and that a locus of this action of glutamate is in the striatum. These conclusions were supported further by the observation that NMDLA administered focally into the striatum caused stereotypy which was indistinguishable from that produced by either amphetamine or dopamine. Stereotypy induced by amphetamine injected into the striatum was blocked by CPP or sulpiride administered either systemically or directly into the striatum; in contrast, stereotypy induced by NMDLA given into the striatum was blocked by CPP but not by sulpiride, regardless of whether the antagonists were presented systemically or into the striatum. The data suggest that stereotypy induced by amphetamine or cocaine is mediated by a dopaminergic activation of a glutamatergic system within the striatum. PMID- 7834359 TI - Reduced choline acetyltransferase activity and muscarinic M1 receptor levels in aged Fisher 344 rat brains did not parallel their respective mRNA levels. AB - Differences in the acetylcholine (ACh)-mediated neuronal system of the brain between aged and young rats were studied by measuring choline acetyltransferase (ChAT) activity, muscarinic M1 receptor (M1-R) and their respective mRNA levels. In aged rats, ChAT activity and the M1-R level were significantly reduced in the cerebral cortex, hippocampus and striatum compared with that in young rats. On the other hand, there was no difference in the ChAT mRNA level in the striatum and the basal forebrain, or the M1-R mRNA level in the cerebral cortex, hippocampus and striatum between aged and young rats. The effects of chronic administration of bifemelane (4-(2-benzylphenoxy)-N-methylbutylamine hydrochloride), which is used for the treatment of sequelae of cerebrovascular diseases, were also evaluated. In aged rats chronically administered bifemelane, the ChAT activity recovered to the level in the young rats in the cerebral cortex and hippocampus, and the M1-R level recovered completely in the cerebral cortex, hippocampus and striatum. However, the ChAT mRNA level and the M1-R mRNA level were not affected by bifemelane administration. Thus, the decreases and recoveries in ChAT activity and M1-R level did not parallel the changes in their respective mRNAs. These results suggest that the age-related impairments in ACh mediated neuronal system are considered to be caused primarily by disorders of post-transcriptional events. PMID- 7834360 TI - Purkinje cell loss from alternating sagittal zones in the cerebellum of leaner mutant mice. AB - The cerebellum and inferior olive of adult homozygous leaner mutant mice (tgIa/tgIa) were examined using anti-vitamin D-dependent calcium binding protein immunohistochemistry, and Nissl staining. The immunohistochemical staining revealed that cerebellar Purkinje cell loss in leaner is restricted to alternating saggital compartments of the cerebellar cortex. The absence of Purkinje cells from specific sagittal zones of the cerebellar cortex apparently results in a loss of immunochemical staining of Purkinje cell axons and terminals from specific regions of the leaner cerebellar nuclear complex. A specific pattern of atrophy was also observed in the leaner inferior olive. PMID- 7834361 TI - Ionic dependence of adenosine uptake into cultured astrocytes. AB - Adenosine uptake in cultured astrocytes is dependent on various ions and energy metabolism. The Na(+)-gradient plays an important role, since nigericin, ouabain, amiloride and substitution of Na+ with choline inhibited adenosine uptake. The proton-gradient was of importance, since carbonylcyanide m-chlorophenylhydrozone (CCCP) and omeprazole also inhibited adenosine uptake. Furthermore, adenosine uptake was dependent on Cl- anion. Substitution of Cl- with isethionate, as well as DIDS or furosemide inhibited adenosine uptake. Adenosine uptake was also sensitive to Ca2+ gradient, removal of extracellular Ca2+ and calcimycin inhibited adenosine uptake. Adenosine uptake was not dependent on extracellular K+ and was not affected by valinomycin. Although, K(+)-channel openers (BRL 34195 and nicorandil) as well as the K(+)-channel antagonist, glyburide, inhibited adenosine uptake, the inhibitory effect of BRL 34915 was not antagonized by glyburide. Rotenone and 2,4-dinitrophenol also inhibited adenosine uptake. Ionic dependence and metabolic energy dependence of adenosine uptake suggest that uptake is primarily an active process. PMID- 7834362 TI - Immunologic localization and kinetic characterization of a Na+/Ca2+ exchanger in neuronal and non-neuronal cells. AB - The plasma membrane Na+/Ca2+ exchanger is believed to play a role in the regulation of Ca2+ fluxes in neurons, though the lack of specific inhibitors has limited the delineation of its precise contribution. We recently reported the development of antibodies against a 36-kDa brain synaptic membrane protein which immunoprecipitated exchanger activity from solubilized membranes. In the present study we examined the kinetics of the Na+/Ca2+ exchanger in primary neurons in culture, in a neuronal hybrid cell line (NCB-20), and in a fibroblast-like cell line (CV-1) to see whether the level of exchanger activity correlated with the degree of immunostaining produced by our antibodies. The Vmax was determined for each cell type and found to be highest in primary neurons. Exchanger activity increased in primary neurons between days 1 and 6 in culture, but no such time dependent change occurred in either of the cell lines. Immunoblot analysis of the three cell types probed with the anti-36-kDa protein antibodies revealed significantly greater immunostaining in the primary neurons compared with the other two cell types. Intensity of staining of neurons also increased significantly between days 1 and 6 in culture. Immunocytochemistry showed significant labelling of the primary neurons on the neuritic processes and points of contact between cells. The NCB-20 and CV-1 cells showed considerably lower levels of immunoreactivity. The antibodies immunoextracted approximately 90% of the exchanger activity in the primary neurons and approximately 70 and 50% of the activity in NCB-20 and CV-1 cells respectively.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7834363 TI - Characterization of basic fibroblast growth factor-mediated acceleration of axonal branching in cultured rat hippocampal neurons. AB - We analyzed in more detail the effect of basic fibroblast growth factor (bFGF) on morphogenesis of rat hippocampal neurons in dissociated cell culture. As a result, we found that bFGF selectively promoted the bifurcation and growth of axonal branches without affecting the elongation rate of primary axons. The dendritic outgrowth was rather inhibited by bFGF. These effects of bFGF resulted in increased complexity of axonal trees. The effect of bFGF was concentration dependent (0.1-10 ng/ml) and was abolished by the presence of anti-bFGF neutralizing antibody. The accelerated axonal branch formation in the presence of bFGF was restored to the basal rate following removal of bFGF, suggesting that the action of bFGF is reversible and that the continuous presence is required for bFGF to accelerate the branch formation. bFGF probably works as a progression signal rather than as a triggering signal. The bFGF-mediated acceleration of axonal branch formation was blocked by treatment with heparitinase and by tyrosine inhibitors, herbimycin A and lavendustin A, indicating the importance of heparan sulfate and tyrosine kinase in bFGF signal transduction. Treatment with a protein kinase C activator phorbol-12-myristate-13-acetate did not significantly affect the neurite branching, and the action of bFGF was not blocked by a protein kinase C inhibitor staurosporine. Protein kinase C is unlikely to play a role in branch formation. The novel action of bFGF as a regulator of axonal branching must be a particularly useful model for the study of neuritogenesis and synaptogenesis of brain neurons. PMID- 7834364 TI - The protective effects of stress control may be mediated by increased brain levels of benzodiazepine receptor agonists. AB - Control over stress protects against many of the deleterious effects of stress exposure, but the endogenous mediators responsible for these prophylactic effects have remained elusive. Using behavioral pharmacology, in vitro radioligand binding and neurochemical analyses, we demonstrate that exposure to escapable stress results in brain and behavior changes reminiscent of benzodiazepine administration. The stress control group shows significant protection against picrotoxinin-induced seizures, reductions in [35S]t-butylbicyclophosphorothionate (TBPS) binding and a 3-fold increase of benzodiazepine-like substances in brain in comparison to both yoked-inescapable shock and non-shock controls. These observations suggest that coping behavior leads to the release of endogenous benzodiazepine-like compounds in brain which protect the organism from stress pathology. PMID- 7834365 TI - Ultrastructural analysis of beta-amyloid-induced apoptosis in cultured hippocampal neurons. AB - Following treatment with the beta-amyloid (A beta) 25-35 analog, scanning and transmission electron microscopy were used to investigate the morphological changes in cultured hippocampal neurons during the course of degeneration. Ultrastructural analysis revealed focal cell surface blebbing and rapid condensation of nuclear chromatin. Changes in cytoplasmic morphology included prominent vacuole formation, dispersal of polyribosome rosettes and the disappearance of the golgi complex, smooth endoplasmic reticulum and microtubules with increased cytoplasmic electron density. Mitochondria and limited rough endoplasmic reticulum remained intact throughout the process of cell death. These results provide additional evidence suggesting A beta-induced cell death in vitro occurs via an apoptotic mechanism. PMID- 7834366 TI - The evolution of a rat model of chronic spontaneous limbic seizures. AB - The evolution of untreated partial epilepsy is unknown. This study uses a newly developed model of chronic limbic epilepsy to determine whether seizures inexorably worsen in duration, frequency and behavioral accompaniment. The seizures begin following an episode of limbic status epilepticus induced by continuous electrical stimulation of the hippocampus, and they persist for more than a year (longest duration followed). We monitored 10 rats continuously with combined EEG and closed circuit television for 24 weeks following the first recorded spontaneous seizure. Seizure duration, behavioral accompaniment and frequency all intensified during the early stages, but the last 12-16 weeks of the study were characterized by a plateau for all measures. The results showed significant increases that occurred over the first 12 weeks only (P < 0.01 for duration and behavioral accompaniment, P < 0.05 for seizure frequency). These findings suggest that untreated epilepsy will undergo an early maturation process, but that once the seizures mature they remain stable over a prolonged period. It was also noted that 67% (P < 0.00001) of the seizures occurred during the day, suggesting that the sleep-wake cycle has a strong influence on the occurrence of seizures in this model of limbic epilepsy. PMID- 7834367 TI - Effects of acoustic prepulses on the startle reflex in rats: a parametric analysis. AB - Small changes in the sensory environment, called prepulses, prior to a startle eliciting stimulus can either inhibit or facilitate the startle reaction. To investigate this apparent discrepancy, a number of characteristics of the acoustic prepulse were varied and the effects on the startle reaction were studied. The results showed that increasing the intensity of the prepulse (81-85 dB) resulted in an increased inhibition and could even turn facilitation into inhibition (at 3-13 ms prepulse-startle interval). Varying prepulse lengths (1-45 ms) did not change the observed startle modification. Only when the prepulse offset was close to the startle onset, changes could be observed. Confronting the animal with the same test session for several days resulted in increased inhibition and a change from facilitation to inhibition (at 3-13 ms prepulse startle interval). The results demonstrate that the characteristics of the prepulse determine its effect on the startle reaction. An hypothetical model is proposed which might explain the observed data. PMID- 7834368 TI - Loss of calbindin-immunoreactivity in CA1 hippocampal stratum radiatum and stratum lacunosum-moleculare interneurons in the aged rat. AB - Alterations in hippocampal circuitry may underly age-related learning and memory impairment. We showed in a previous study that the GABAB-mediated slow inhibitory postsynaptic potential (IPSP) induced in CA1 pyramidal neurons by electrical stimulation of stratum radiatum, is depressed in the hippocampus of the aged rat. This could be due to alterations in GABAergic interneuron functions. We report in this study that the number of hippocampal calbindin-immunoreactive (CaBP-IR) GABAergic interneurons is decreased in the aged rat. The mean number of CaBP-IR interneurons per slice decreases by 50% in the aged rat. The most severe loss was observed in the stratum radiatum of CA1 (78%), with a less consistent loss of immunoreactivity in CA3 (35%). In contrast, the mean number of interneurons containing parvalbumin (PV), was not significantly decreased in the aged rat. Our results show a loss of CaBP immunoreactivity in a population of GABAergic interneurons, which might be related to an altered function of these interneurons and consequently of GABAergic synaptic transmission in the aged rat. In contrast, PV immunoreactivity in interneurons located close to the pyramidal layer does not decrease in the hippocampus of the aged rat. PMID- 7834369 TI - Opposing activities of brain opioid receptors in the regulation of humoral and cell-mediated immune responses in the rat. AB - The role of brain delta- and kappa-opioid receptors in the regulation of PFC response, Arthus hypersensitivity reactions and delayed hypersensitivity reactions was studied following intracerebroventricular (i.c.v.) administration of opioid receptor agonists and antagonists. Eight-week-old male Wistar rats, with polyethylene cannulae inserted into the lateral brain ventricles, were i.c.v. treated with different doses of delta-opioid receptor agonist methionine enkephalin (Met-Enk), delta-opioid receptor antagonist ICI 174864, kappa-opioid receptor agonist MR 2034, and kappa-opioid receptor antagonist MR 2266. In rats sensitized for plaque-forming cell (PFC) assay, the first drug injection was given 1 h prior to immunization, and then every 24 h until day 4. One h after the last treatment, rats were sacrificed and (PFC) assay performed. In rats immunized for hypersensitivity skin reactions, the first drug injection was given 1 h before immunization, and then every 48 h until day 14. Skin reactions were elicited one h after the last drug administration. Opioid receptor agonists Met Enk and MR 2034 stimulated and suppressed PFC response, Arthus and delayed skin reactions respectively. ICI 174864 decreased the number of PFC and intensity of hypersensitivity skin reactions whereas MR 2266 increased the number of PFC, but did not affect to a greater extent hypersensitivity reactions. Stimulation of PFC produced by 1 microgram/kg of Met-Enk was completely blocked with 10 and 50 micrograms/kg of ICI 174864. MR 2034-induced suppression was partially and completely antagonized with 10 and 50 micrograms/kg of MR 2266 respectively. The present results suggest that brain opioid receptors differentially affect humoral and cell-mediated immune responses. PMID- 7834370 TI - Brain cholecystokinin and beta-endorphin systems may antagonistically interact to regulate tissue DNA synthesis in rat pups. AB - Previously, we have shown that intracisternal (i.c.) administration of beta endorphin suppresses brain and liver DNA synthesis in rat pups. This finding is consistent with the view that endogenous CNS beta-endorphin plays an important role in controlling postnatal growth. Recent evidence suggests that brain CCK8, the sulfated carboxyterminal octapeptide fragment of cholecystokinin, may function physiologically as an endogenous opioid antagonist. We now report that CCK8 injected i.c. together with beta-endorphin effectively prevented beta endorphin from inhibiting brain and liver DNA synthesis in 10-day-old rats. CCK8 blocked the liver DNA effect of beta-endorphin via actions within the brain, as subcutaneous administration of CCK8 was ineffective. In contrast to CCK8, i.c. administration of CCK8U (the unsulfated form of CCK8) together with beta endorphin did not prevent beta-endorphin from inhibiting liver DNA synthesis, and only slightly reversed the brain DNA effect. The results obtained support a role for endogenous brain CCK8 in the modulation of tissue DNA responses to CNS beta endorphin and possibly to other endogenous opioids. If so, interference with brain CCK function could disrupt tissue growth. Thus, normal mammalian development may require a close functional interaction between the cholecystokinin and beta-endorphin systems in the brain. PMID- 7834371 TI - Expression of CDK5 (PSSALRE kinase), a neural cdc2-related protein kinase, in the mature and developing mouse central and peripheral nervous systems. AB - CDK5 is a cdc2-related protein kinase that is known to be highly expressed in mature brain. In this study, we obtained a mouse CDK5 cDNA by screening an adult mouse cDNA library. Northern blot analysis demonstrated that the mouse CDK5 mRNA was expressed especially highly in brain, and moderately in kidney, testis and ovary. In brain the expression of CDK5 is already seen at embryonal 12.5 days (E12.5), and it gradually increases through the embryonal stage. After birth, the expression is maintained at a high level to adulthood. In situ hybridization demonstrated that the expression of CDK5 mRNA was distributed in neurons throughout the brain, spinal cord and peripheral ganglia, especially in the hippocampal pyramidal cells, cerebellar Purkinje cells, cortical neurons, olfactory mitral cells, mesencephalic and motor trigeminal nuclei and trigeminal ganglion. In any portion, no apparent expression was observed in glia. During development, the expression of CDK5 was already seen at E12.5 intensely in trigeminal and dorsal root ganglia, and moderately and diffusely in the central nervous system. The expression pattern of CDK5 is quite in contrast with that of CDC2. The fact that CDK5 is expressed in terminally differentiated non-dividing neurons predicts an alternative function(s) in addition to controlling the cell cycle. PMID- 7834372 TI - The development of cutaneous afferent pathways in fetal sheep: a structural and functional study. AB - In this study we have examined the functional and structural development of cutaneous afferent pathways in the fetal sheep hindlimb from 67 to 143 days of gestation. The earliest age at which extracellular discharges could be evoked in dorsal root ganglia and in dorsal horn cells by natural cutaneous stimulation was 75 days. The majority of cells responded to light stroking or indentation of the skin (low threshold) although some cells responded to intense squeezing (high threshold). With increasing gestational age, the majority of cells continued to respond to low threshold stimuli with cells responding to intense mechanical stimuli being recorded less frequently. Dorsal root ganglion cells responding to the cutaneous application of noxious heat (> 45 degrees C) were first observed at 107 days. We have also shown that fibres projecting from dorsal horn cells and presumably entering the spinothalamic tract carry signals at least as far as the mid thoracic spinal cord by 104 days. Ultrastructural studies of the skin revealed bundles of unmyelinated axons located to blood vessels throughout the dermis at 68 days. Innervation of the skin was first observed by silver staining at 75 days when fibres could be seen running along blood vessels in the dermis. With increasing gestational age fibres were seen traversing the dermis to innervate the epidermis as free nerve endings. Wool/hair follicle innervation was first evident at about 100-106 days with only a few follicles being innervated at this age. By 115 days, nerve endings had begun to form circumferential wrappings around follicles and by 134 days lanceolate terminals were observed around the base of the follicles. Biocytin-labelled afferent fibres entered the dorsal horn at 56 days. This initial innervation was sparse but by 76 days there was a marked increase in both the number of afferent fibres entering the dorsal horn and in the extent of their arborisation. Ultrastructural studies revealed that terminals immunoreactive for calcitonin gene-related peptide were present in lamina I as early as 61 days. The period of maximal synaptogenesis and synaptic maturation of this group of terminals appeared to occur between 87-128 days. Therefore the commencement of activation of dorsal horn cells by natural cutaneous stimulation occurs by mid gestation (75 days) in the fetal sheep. This is at the same time or just after peripheral nerves first innervate the skin and about 2 weeks after primary afferent terminals can be identified in the dorsal horn. PMID- 7834373 TI - Tachykinin-related neuropeptides in the central nervous system of the snail Helix pomatia: an immunocytochemical study. AB - The distribution of neurons reacting with an antibody raised against an insect neuropeptide, locustatachykinin I, was investigated in the CNS of the snail Helix pomatia. The localization of the neurons was compared with that of the substance P-like immunoreactive (SPLI) neurons in the different ganglia. Altogether, there are approximately 800-1000 locustatachykinin-like immunoreactive (LomTKLI) neurons in the Helix CNS, occurring with an overwhelming dominancy (83.5%) in the cerebral ganglia. Within the cerebral ganglia, the majority of LomTKLI neurons were localized in the procerebrum. The number of SPLI neurons was high; approximately 2000 SPLI nerve cells were found in the Helix CNS. The majority (44.5%) of SPLI neurons was also found in the cerebral ganglia and they were also concentrated in the procerebrum. The neuropils of all ganglia were densely innervated by both LomTKLI and SPLI fibers except the medullary mass of the procerebrum where only SPLI elements form an extremely dense innervation. In addition to the neutrophil processes, LomTKLI neurons sent axon processes to the peripheral nerves. SPLI fibers also formed a dense network of varicose fibers in the connective tissue sheath around the ganglia where they innervated the blood vessel walls too. Immunolabeling on alternating cryostat sections revealed that LomTKLI and SPLI neurons are localized near each other in most cases; co localization of the two immunoreactive materials could be seen in a very small number of neurons of the pedal and pleural ganglia. The present results show that the Helix CNS possesses distinct neuronal populations using different tachykinin related peptides. It is suggested that the differential distribution of these neuropeptides also implies a diversity in their central and peripheral functions. PMID- 7834374 TI - GABAergic system inducing hyperthermia in the rat preoptic area: its independence of prostaglandin E2 system. AB - Brain temperature of conscious freely moving rats was recorded during perfusion of the preoptic area (POA) with neuroactive compounds using the microdialysis technique. Unilateral perfusion of the POA with the sodium channel blocking agent, tetrodotoxin (1 microM), induced a pronounced hyperthermia. Of the neuroactive compounds examined, the greatest thermogenic response to local perfusion of the POA was elicited by the GABAergic agonist, muscimol. Muscimol (10, 20 and 100 microM) exhibited a dose-dependent and reversible hyperthermia. This hyperthermia was attenuated by co-perfusion with the GABAergic antagonist, bicuculline (10 microM). Muscimol-induced hyperthermia was independent of prostaglandin biosynthesis, and additive with prostaglandin E2 (10 microM) induced hyperthermia. Prostaglandin E2-induced hyperthermia was not affected by co-perfusion with bicuculline. These data suggest the existence of two independent neurochemical systems for genesis of hyperthermia colocalized within the POA. PMID- 7834375 TI - Behavioral effects of basal forebrain grafts after dorsal septo-hippocampal pathway lesions. AB - There are many reports that basal forebrain grafts ameliorate behavioral impairments produced by dorsal septo-hippocampal pathway lesions, but several studies have either found that this recovery may be unrelated to concomitant restitution of cholinergic markers, may be modest and depend on certain experimental conditions or instead that grafts may actually exacerbate lesion induced impairments. In this study, rats received one of three lesions of the dorsal septo-hippocampal pathways or a sham lesion, at 32 days of age, and intrahippocampal basal forebrain grafts or the vehicle control 10 days later. In grafted rats with total aspirative lesion of the fimbria-fornix, there was a substantial AChE-positive hippocampal reinnervation but no improvement of the severe lesion-induced spatial learning deficits, either reference memory or working memory, whether tested at 1 or 5 months post-grafting. In rats with bilateral medial fimbria lesions, grafts were successful, normal in appearance and produced substantial hippocampal cholinergic reinnervation; relative to non grafted counterparts, however, grafted medial fimbria rats showed an early reference memory impairment and a persistent exacerbation of a working memory deficit. Exacerbation of learning impairments was also apparent in grafted rats with partial hippocampal denervation due to lesion of the cingulate and adjacent cortex above the fimbria-fornix. Nonetheless, basal forebrain grafts normalised general activity in these lesion groups, irrespective of whether the lesion induced change was an increase or a decrease relative to controls. Graft-derived lesion groups, irrespective of whether the lesion-induced change was an increase or a decrease relative to controls. Graft-derived AChE-positive innervation was more marked than expected in both grafted cingulate-lesioned rats and grafted sham-lesioned rats, while control grafts of fetal cortex (above the septum) produced little or no AChE-positive innervation. Size of basal forebrain grafts, originally 3 microliters at two dorsal sites per hippocampus, increased markedly from rostral to caudal dorsal hippocampus in all groups but did not differ significantly across grafted groups, even with respect to non-lesioned rats. This study adds further evidence that basal forebrain grafts, successful with respect to cholinergic reinnervation, do not always enhance cognitive functions in rat hippocampal lesion models, and confirms that these grafts may have adverse effects after partial septo-hippocampal system lesions. It is important to attend to both the potential negative and positive effects of neural grafts. PMID- 7834376 TI - Sex differences in hippocampal long-term potentiation (LTP) and Pavlovian fear conditioning in rats: positive correlation between LTP and contextual learning. AB - Three experiments investigated sex differences in hippocampal long-term potentiation (LTP) and Pavlovian fear conditioning in rats. Experiment 1 revealed a robust sex difference in the magnitude of LTP induced at perforant path synapses in the dentate gyrus of pentobarbital-anesthetized rats. This sex difference in LTP was evident in rats of 35 and 60 days of age and was not the result of pre-LTP sex differences in perforant path synaptic transmission; 20-day old rats did not show LTP. An analysis of field potentials evoked during LTP induction revealed a sex difference in the magnitude of N-methyl-D-aspartate (NMDA) receptor activation that was highly correlated with the magnitude of LTP. Experiment 2 showed that males condition more fear, measured as freezing, to the contextual conditional stimuli (CSs) of a conditioning chamber compared to their female counterparts. This sex difference in conditional freezing was apparent with both low and high unconditional stimulus (US, footshock) intensities. Experiment 3 revealed that the enhanced fear conditioning in males was specific to contextual CSs, and consisted of a more rapid rate of conditioning. Together, these experiments reveal a positive correlation between the magnitude of hippocampal LTP and a form of learning that depends on the hippocampus. Furthermore, they suggest a neural basis for sex differences in hippocampus dependent learning tasks. PMID- 7834377 TI - 1,3-Dipropyl-8-cyclopentylxanthine attenuates the NMDA response to hypoxia in the rat hippocampus. AB - Excitatory amino acids may cause neuronal damage and death in cerebral hypoxia and ischemia, through the activation of different subtypes of glutamate receptors, in particular of the N-methyl-D-aspartate (NMDA) receptor. In the present work, the effect of hypoxia on the component of the field excitatory postsynaptic potential (fepsp) mediated by the NMDA receptor was studied in the hippocampal CA1 area of the rat. A period of 15 min of hypoxia induced virtual abolition of the NMDA receptor-mediated fepsp and a 94.8 +/- 0.7% maximal decrease in the fepsp. A period of 3 min of hypoxia induced a 89.3 +/- 12.3% maximal decrease in the NMDA receptor-mediated component of the fepsp and only a 50.8 +/- 11.5% maximal decrease in the fepsp. Both periods of hypoxia thus induced a more pronounced depression of the NMDA receptor-mediated component of the fepsp than of the fepsp. We found that 48.5 +/- 9.1% decrease (about half of the total decrease) in the NMDA receptor-mediated fepsp, and 51.6 +/- 19.6% decrease (approximately all decrease) in the fepsp induced by hypoxia (3 min) were reversed in the presence of the selective adenosine A1 receptor antagonist, 1,3-dipropyl-8- cyclopentylxanthine (DPCPX) (50 nM), and thus likely to be mediated by endogenous adenosine, through the activation of adenosine A1 receptors.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7834378 TI - Vasopressin-induced calcium signaling in cultured hippocampal neurons. AB - We recently demonstrated that the neural peptide vasopressin (AVP) can act as a neurotrophic factor for hippocampal nerve cells in culture. Because the neurotrophic effect of vasopressin is mediated by the V1 receptor, we investigated AVP activation of calcium signaling pathways in cultured hippocampal neurons. Results of this investigation demonstrate that exposure of cultured hippocampal neurons prelabeled with [3H]myo-inositol to vasopressin induced a significant accumulation of [3H]inositol-1-phosphate ([3H]IP1). The selective V1 vasopressin receptor agonist, [Phe2, Orn2]vasotocin, induced a significant accumulation of [3H]IP1 whereas a selective V2 vasopressin receptor agonist, [deamino1, D-Arg8]-vasopressin, did not. Moreover, V1 agonist-induced accumulation of [3H]IP1 was blocked by the selective V1 vasopressin receptor antagonist d(CH2)5[Tyr(Me)2]-vasopressin. V1 agonist-induced accumulation of [3H]IP1 was concentration dependent and exhibited a steep inverted U-shaped curve that included both stimulation and inhibition of [3H]IP1 accumulation. Time course analysis of V1 agonist-induced accumulation of [3H]IP1 revealed significant increase by 20 min which continued to be significantly elevated for 60 min. Investigation of the effect of closely related peptides on [3H]IP1 accumulation indicated that the vasopressin metabolite peptide AVP4-9 and oxytocin significantly increased [3H]IP1 accumulation whereas the vasopressin metabolite peptide AVP4-8 did not. AVP4-9 and oxytocin induced [3H]IP1 accumulation were blocked by the V1 vasopressin receptor antagonist d(CH2)5[Tyr(Me)2]-vasopressin. V1 receptor activation was associated with a pronounced rise in intracellular calcium. Results of calcium fluorometry studies indicated that V1 agonist exposure induced a marked and sustained rise in intracellular calcium that exhibited oscillations.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7834379 TI - A modulatory role of central cholinergic transmission in control of the 10-Hz rhythm in sympathetic nerve discharge. AB - In 43 urethane-anesthetized or decerebrate, baroreceptor-denervated cats, spectral analysis showed that most of the power in sympathetic nerve discharge (SND) was at frequencies < 6 Hz. In 18 of these cats, physostigmine (100 micrograms/kg i.v.) induced a 10-Hz rhythm in inferior cardiac SND that was eliminated by atropine sulfate (0.25 mg/kg i.v.; n = 6). In contrast, the naturally occurring 10-Hz rhythm that appeared in SND in other experiments was atropine-insensitive (n = 6). The data indicate that central muscarinic cholinergic transmission is not essential for the naturally occurring 10-Hz rhythm. Nonetheless, facilitation of cholinergic transmission can induce a 10-Hz rhythm. PMID- 7834380 TI - Depletion and recovery of the calcium-binding proteins calbindin and parvalbumin in the pigeon optic tectum following retinal lesions. AB - Retinal lesions in pigeons produced a marked depletion of somata and neuropil staining for both calbindin-D28k and parvalbumin immunoreactivities in the contralateral optic tectum. Calbindin-like immunoreactivity reappeared in some tectal layers by 6 weeks postlesion, whereas paravalbumin-like immunoreactivity recovered almost completely after 5 weeks. These data indicate that the retinal input may control the expression of calbindin and parvalbumin in the pigeon optic tectum. PMID- 7834381 TI - Ionic properties of IK,n in outer hair cells of guinea pig cochlea. AB - The ionic properties of voltage-dependent K+ current activated at the resting membrane potential (IK,n) of outer hair cells (OHC) isolated from the guinea pig cochlea were studied using a patch-clamp technique in a whole-cell recording mode. The reversal potential of IK,n indicated a high selectivity for K+, and the relative permeability ratios for various monovalent cations were K+:Rb+:NH4+ = 1:1.21:0.13. Decrease in extracellular Cl- inhibited the IK,n. IK,n was blocked by Cs+ and Ba2+, although the inhibitory manner of Cs+ and Ba2+ were voltage dependent and voltage-independent, respectively. By the use of puff-application method, the local application of Ba2+ to basolateral surface of OHC shifted the holding current level in an inward direction, whereas the application to apex and hair showed little change. Indicating that the IK,n channels preferentially locate at the basolateral region of cell membrane. PMID- 7834382 TI - Degenerative changes in epinephrine tonic vasomotor neurons in Alzheimer's disease. AB - The C-1 region in the rostral ventral lateral medulla contains mainly epinephrine (Epi) neurons. These neurons are the tonic vasomotor center of the brain. We previously demonstrated changes in the enzymatic activity of phenylethanolamine N methyltransferase (PNMT) in axon terminals and cell bodies of Epi neurons from the medulla of Alzheimer's disease (AD) brains. In this study, we investigated the perikarya of C-1 neurons for the morphometric, immunohistochemical and histochemical changes that are seen in severely affected regions of Alzheimer brain. The mean areas and size distributions of C-1 neurons from 6 AD and 6 neurologically normal patients were compared using the Wilcoxon rank sum test and Kolmogorov-Smirnov z tests respectively. Additional brain sections from the C-1 region of AD and control individuals were stained with cresyl violet or immunostained with antibodies to the lysosomal hydrolase cathepsin D, Tau-2, Alz 50 and beta-amyloid protein. The average area of C-1 neurons in AD brains was decreased 18.3% (P < 0.001) compared to the areas of the same cell population in age-matched control brains. A shift toward smaller sized C-1 neurons was seen in the AD cases. Nissl stain demonstrated a central chromatolytic appearance in 3.7% of AD neurons sampled. No beta-amyloid deposits were detected histologically or immunocytochemically in the C-1 region of AD brains. Both Tau-2 and Alz-50 immunoreactivity was observed in occasional (1%) C-1 neurons from AD brains but not in controls. A small proportion (30%) of the C-1 neurons showing atrophy displayed increased cathepsin D immunoreactivity.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7834383 TI - Calcium-activated proteolysis in rat neocortex induced by transient focal ischemia. AB - Ischemia-induced elevation of intracellular calcium triggers a cascade of events which is considered to play a major role in neuronal death. One candidate to participate in this process is the calcium-sensitive protease, calpain. This protease is activated by calcium, and is capable of degrading critical cytoskeletal and regulatory proteins. In order to further elucidate the role of calpain in focal ischemic damage, the present study investigated the proteolysis of spectrin, a preferred substrate for calpain, in response to transient focal ischemia. Ischemia was induced by occluding reversibly both carotid arteries and the left middle cerebral artery for three hours in Sprague-Dawley rats. Western blotting techniques were used to identify and quantify the amounts of spectrin breakdown products (BDPs) in neocortical samples from the area destined for infarction, the peri-infarct area, and the contralateral hemisphere. Substantial increases in spectrin proteolysis were observed within the first few hours of ischemia in the areas that will undergo infarction. The increase in spectrin BDPs in these areas reached a plateau around the end of the 3 h ischemic period. In the peri-infarct zone, the levels of spectrin BDPs increased in a biphasic manner. A small to moderate increase was observed by the second hour of ischemia, followed by a larger increase between the 6th and 24th hours post-ischemia. The contralateral neocortex showed a significant increase in BDPs at 2 h after the initiation of ischemia. A smaller increase in BDPs was observed thereafter.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7834384 TI - 1-Methyl-4-phenylpyridinum kills differentiated PC12 cells with a concomitant change in protein phosphorylation. AB - 1-Methyl-4-phenylpyridinum (MPP+), a selective neurotoxin, destroys the dopaminergic nigrostriatal pathway and results in a parkinsonian syndrome. Exposure of differentiated PC12 cells with nerve growth factor for 5 days to MPP+ (100 microM) for 4 h induced DNA fragmentation which is typical for the programmed cell death. MPP+ treatment (100 microM) concomitantly stimulates S6 kinase activity and resultant phosphorylation of S6 protein of 40S ribosomal subunits in the cells. Cycloheximide treatment prevents the MPP(+)-induced DNA fragmentation and enhancement of the phosphorylation of S6 protein. The present data demonstrate that neurotoxin, MPP+, kills differentiated PC12 cells by the apparent involvement of apoptotic process. Furthermore, the data strongly suggest that a change in protein phosphorylation might be involved in the signal transduction of MPP+ neurotoxicity and/or the protection from its toxicity. PMID- 7834385 TI - Ciliary neurotrophic factor (CNTF) enhances the effects of nerve growth factor on PC12 cells. AB - The rat pheochromocytoma cell line PC12 responds readily to nerve growth factor (NGF) but poorly to ciliary neurotrophic factor (CNTF). However, in a selected line derived from PC12 that normally responded weakly to NGF, CNTF potentiated the effect of NGF with respect to inhibition of proliferation, neurite outgrowth, and choline acetyltransferase (ChAT) induction. ChAT activity was assayed enzymatically, and an increase in the mRNA of ChAT was also detected by means of reverse transcription-polymerase chain reaction (RT-PCR). The PCR product was verified by sequencing and by Southern hybridization using a specific oligonucleotide probe. The presence of CNTF receptor in PC12 cells was confirmed by RT-PCR for its mRNA. The results indicate that PC12 responds to CNTF mainly when used in combination with NGF, and suggest an interaction between the two growth factors. PMID- 7834386 TI - N-methyl-D-aspartate receptors mediate post-traumatic increases of protein kinase C in rat brain. AB - Male Sprague-Dawley rats were subjected to traumatic brain injury (TBI) using a lateral fluid percussion-induced injury model. Effects of varying severities of TBI (mild = 1.1 +/- 0.1 atm; moderate = 2.2 +/- 0.2 atm; severe = 2.9 +/- 0.1 atm) on the levels of protein kinase C in rat cerebral cortex and hippocampus were investigated by quantitative autoradiography using [3H]phorboldibutyrate ester ([3H]PDBu) binding as a marker. Binding of [3H]PDBu in the cerebral cortex and hippocampus was increased bilaterally following TBI, with changes related to injury severity. Significant increases were observed in hippocampus of injured animals, as compared to sham-operated controls, at 1 h after trauma. Maximum levels of binding in both cerebral cortex and hippocampus were reached by 3 h, with a return to control levels at 6 h and 72 h, respectively. Treatment with MK 801 (1 mg/kg, i.v.) administered 15 min before trauma prevented the injury induced increase of [3H]PDBu binding in hippocampus and cerebral cortex. These results demonstrate that TBI induces bilateral, time-dependent increases of protein kinase C in the hippocampus and cerebral cortex that are related to injury severity. Changes are mediated by actions at NMDA receptors, probably reflecting post-traumatic release of glutamate. PMID- 7834387 TI - Caudal brain stem plays a role in metabolic control of estrous cycles in Syrian hamsters. AB - In Syrian hamsters, a critical factor necessary for the occurrence of normal estrous cycles appears to be the cellular availability of oxidizable glucose. For example, estrous cycles are inhibited by food deprivation or treatment with 2 deoxy-D-glucose (2DG), a drug that inhibits cellular glucose utilization. Several lines of evidence suggest that these effects require the participation of neurons in part of the caudal brain stem, the area postrema (AP) and adjacent, reciprocally-innervated nucleus of the solitary tract (NTS). This study was designed to examine the role of the AP in 2DG-induced anestrus. Hamsters received either aspiration lesions directed at the AP or sham operations. Between 12 and 16 days after surgery, both sham-operated and lesioned hamsters showed two consecutive 4-day estrous cycles, as measured by estrous behavior and vaginal discharge. Subsequently, both groups were treated with doses of 2DG known to inhibit the estrous cycle (1750 mg/kg every 6 h on days 1 and 2 of the cycle). Hamsters were tested for measures of estrous cyclicity daily after treatment. Only 9% of the sham-operated hamsters showed estrous cycles within 5 days after the start of 2DG treatment. In contrast, all of the hamsters with confirmed lesions of the AP showed estrous cycles within 5 days of the start of 2DG treatment. Histology showed that most lesions removed the AP plus part of the medial NTS, while two lesions removed part of the AP only.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7834388 TI - Cholinotoxic effects on acetylcholinesterase gene expression are associated with brain-region specific alterations in G,C-rich transcripts. AB - To study the mechanisms underlying cholinotoxic brain damage, we examined ethylcholine aziridinium (AF64A) effects on cholinesterase genes. In vitro, AF64A hardly affected cholinesterase activities yet inhibited transcription of the G,C rich AChE DNA encoding acetylcholinesterase (AChE) more than the A,T-rich butyrylcholinesterase (BChE) DNA. In vivo, intracerebroventricular injection of 2 nmol of AF64A decreased AChE mRNA in striatum and septum by 3- and 25-fold by day 7, with no change in BChE mRNA or AChE activity. In contrast, hippocampal AChE mRNA increased 10-fold by day 7 and BChE mRNA and AChE activity decreased 2-fold. By day 60 post-treatment, both AChE mRNA and AChE levels returned to normal in all regions except hippocampus, where AChE activity and BChE mRNA were decreased by 2-fold. Moreover, differential PCR displays revealed persistent induction, specific to the hippocampus of treated rats, of several unidentified G,C-rich transcripts, suggesting particular responsiveness of hippocampal G,C-rich genes to cholinotoxicity. PMID- 7834389 TI - The actions of 5-HT1 agonists and antagonists on nociceptive processing in the rat spinal cord: results from behavioural and electrophysiological studies. AB - We have developed a technique which allows drugs to be microinjected intrathecally intrathecally in anaesthetised rats whilst single unit recordings are made from dorsal horn neurones. Using this technique together with recordings of tail flick latency (TFL) elicited from lightly anaesthetised rats we have found that the specific 5-HT1a agonist 8-OH DPAT (15, 150, 300 nmol) increases nociceptive responses recorded from single dorsal horn neurones and decreases TFL. The non-specific 5-HT1b agonist TFMPP (300 nmol) and the general 5-HT1 agonist 5-CT (0.3, 3.0, 30 nmol) both decreased nociceptive responses and has inconsistent effects on TFL. Intrathecally applied 5-HT (130, 260 nmol) generally reduced nociceptive neuronal responses and increased TFL. In a minority of experiments, however, 5-HT increased nociceptive responses and it is suggested that this effect is associated with activation of 5-HT1a receptors. Activity at 5 HT1b receptors has the effect of suppressing or reducing responsiveness. The increased responsiveness of dorsal horn neurones to noxious stimulation associated with activity at 5-HT1a receptors may be associated either with increases in receptive field size, promotion of spinal nocifensive reflexes or the facilitation of the rostral transmission to specific brainstem sites. PMID- 7834390 TI - Neuropeptide K enhances glucocorticoid release by acting directly on the rat adrenal gland: the possible involvement of zona medullaris. AB - Neuropeptide K (NPK), a member of the kassinin-like tachykinin family, is contained in the rat hypothalamus and is known to stimulate pituitary ACTH release. The intraperitoneal bolus administration of NPK dose-dependently enhanced corticosterone blood level not only in intact rats, but also in hypophysectomized/ACTH replaced animals. NPK did not affect corticosterone secretion of dispersed rat adrenocortical cells; however, it concentration dependently raised basal corticosterone production by decapsulated adrenal quarters (including both cortical and medullary tissues). Minimal and maximal effective concentrations were 10(-9) and 10(-8) M, respectively. 10(-8) M NPK potentiated corticosterone response of adrenal quarters elicited by 10(-12) M ACTH, but not that evoked by higher concentrations of ACTH. The direct corticosterone secretagogue effect of 10(-8) M NPK is annulled by 10(-6) M alpha helical-CRH or corticotropin-inhibiting peptide, competitive inhibitors of CRH and ACTH, respectively. In light of these findings, the hypothesis is advanced that NPK exerts a direct stimulatory action on adrenocortical secretion and that the mechanism underlying this effect of NPK may involve the activation of the intra-medullary CRH/ACTH system. PMID- 7834391 TI - Posttraining infusion of lidocaine into the amygdala basolateral complex impairs retention of inhibitory avoidance training. AB - The present experiment examined the role of the central nucleus and basolateral complex in the retention of inhibitory avoidance training by reversibly inactivating these regions with lidocaine immediately following training. Male Sprague-Dawley rats were surgically implanted bilaterally with cannulae aimed at the central nucleus or the basolateral complex. One week later, they received one trial inhibitory avoidance training (0.45 mA; 1 s), followed immediately by infusions of lidocaine hydrochloride or buffer (10 micrograms/0.25 microliters). Retention was tested 2 days after training. Immediate posttraining infusions of lidocaine into the central nucleus did not affect retention performance; in contrast, immediate posttraining infusions of lidocaine into the basolateral complex significantly impaired retention performance. In addition, the effect of posttraining infusions of lidocaine into the basolateral complex was time dependent: infusions administered 6 h after training also impaired memory, but infusions administered 24 h after training had no effect. Immediate posttraining infusions of lidocaine also impaired the retention performance of rats trained with a more intense footshock (0.75 mA). However, at the higher footshock intensity, administration of lidocaine 6 h after training had no effect on retention performance. The time- and footshock-dependent retrograde impairment of memory produced by posttraining reversible inactivation of the basolateral complex suggests that this region of the amygdala is involved in the consolidation of memory for inhibitory avoidance training. PMID- 7834392 TI - Not everyone with AIDS gets timely health services. PMID- 7834393 TI - Reflections of Desert Storm. PMID- 7834394 TI - L-2-oxothiazolidine-4-carboxylic acid (procysteine) inhibits expression of the human immunodeficiency virus and expression of the interleukin-2 receptor alpha chain. AB - These studies were undertaken to examine the in vitro effects of the cysteine pro drug L-2-oxothiazolidine-4-carboxylic acid (Procysteine) on human immunodeficiency virus expression. Procysteine inhibited HIV expression in human peripheral blood mononuclear cells as detected by measurement of supernatant core antigen. In transient transfection assays, Procysteine inhibited gene expression controlled by the HIV-1 promoter in activated Jurkat cells but not in resting Jurkat cells. Gel-shift assays showed that Procysteine inhibited NF-kappa B DNA binding activity in nuclear extracts. Procysteine did not affect the production of interleukin-2 by peripheral blood mononuclear cells of healthy HIV seronegative subjects, as measured by bioassay but it decreased the density of cell-surface interleukin-2 receptors detected by flow cytometry after stimulation with phytohemagglutinin (PHA). Thus, Procysteine inhibits HIV expression, HIV promoter activity, and NF-kappa B binding activity in vitro. Procysteine does not affect interleukin-2 production but inhibits interleukin-2 receptor expression in PHA-stimulated peripheral blood mononuclear cells. PMID- 7834395 TI - Pathologic and serologic responses of isogeneic twin lambs to phenotypically distinct lentiviruses. AB - Viral strain differences in the degree of lymphoid interstitial pneumonia (LIP) and in antibody responses to ovine lentivirus (OvLV) infection have been described in experimentally inoculated neonatal lambs. To rule out the possibility that these differences were due to differences in host genetic factors, one lamb from each of three sets of artificially produced identical twins was inoculated with a lytic strain of OvLV (85/34), and the corresponding twin was inoculated with a persistent strain (84/28). One lamb of a fourth set of twins was inoculated with the lytic strain of OvLV, and the corresponding twin was inoculated with a cell culture supernatant. The degree of LIP, as determined by histologic analysis of the lung sections collected at necropsy, was independent of the virus strain used for inoculation. The amount of OvLV proviral DNA in alveolar macrophages correlated with the degree of LIP. However, differences in the antibody response of genetically identical lambs to OvLV structural proteins indicated that the two strains have different in vivo immunogenic properties. The lack of difference in the degree of LIP between lambs with identical genetic backgrounds suggests that host genetic factors may be important in determining the degree of inflammatory response by the lung. PMID- 7834396 TI - Biological and genetic changes in ovine lentivirus strains following passage in isogeneic twin lambs. AB - Ovine lentivirus (OvLV) strains vary in cytopathogenicity, but the correlation, if any, between viral cytophenotypes and in vivo pathogenicity is poorly understood. To examine this issue and to evaluate changes in OvLV strains following passage in vivo, biological and genetic characteristics of OvLV isolates following in vivo passage were compared with those of the parent strain used for inoculation of two sets of isogeneic twin lambs. Plaque-purified OvLV strains with "slow/low" (84/28) and "rapid/high" (85/34) cell culture phenotypes were used for inoculation of the lambs. The phenotypes of the parent OvLV strains were compared with virus isolates from the four lambs by assaying virus replication and cytopathogenicity in goat synovial membrane cells. Viral population genetic differences in the env region were compared by polymerase chain reaction (PCR) amplification and denaturing gradient gel electrophoresis (DGGE) of the fragments. Virus isolates recovered from rapid/high virus-infected sheep were more lytic and developed syncytia earlier than viruses reisolated from sheep inoculated with the slow/low strain. Isolates from lambs infected with 84/28 were more cytopathic in all assays than was their parent strain. Isolates from animals infected with 85/34 were more lytic and syncytiogenic than the parent strain, but responded similarly in replication assays. Although there were no consistent phenotypic differences between virus isolates recovered from sets of twins with markedly different degrees of lymphoid interstitial pneumonia (LIP), the DGGE band patterns of PCR amplified env fragments of the virus isolates from the twin lamb set with severe LIP, but not the set with slight LIP, were distinctly different from those of the parental viruses. PMID- 7834397 TI - Toxicity of sulfonamide-reactive metabolites in HIV-infected, HTLV-infected, and noninfected cells. AB - It has been suggested that the high rates of adverse reactions to sulfonamides among patients with AIDS may be related to an increased sensitivity to reactive drug metabolites among HIV-infected cells. To study this hypothesis, we investigated the toxicity of the hydroxylamine of sulfamethoxazole in HIV infected and noninfected MOLT-3 cultured human T-lymphoblasts. Toxicity was assessed by trypan blue dye exclusion. The hydroxylamine of sulfamethoxazole produced concentration-dependent toxicity in HIV-infected cells, with marked toxicity seen when HIV-infected cells were incubated with 400 microM of the hydroxylamine (82 +/- 8%); this was significantly greater than the toxicity seen among noninfected cells (p < 0.01). There was no concentration-dependent toxicity seen among noninfected cells or in cells infected with HTLV-I, suggesting that the concentration-dependent toxicity seen was specifically related to HIV infection. HIV-infected cells had significantly lower glutathione concentration than did noninfected cells (p < 0.05). Incubation with the hydroxylamine of sulfamethoxazole produced a concentration-dependent decline in glutathione content that was similar in infected and non-infected cells. Co-incubation with glutathione or N-acetylcysteine significantly reduced the toxicity of hydroxylamine of sulfamethoxazole in HIV-infected cells (p < 0.05). Our data supports the role of reactive sulfonamide metabolites in the pathogenesis of adverse reactions to sulfonamides among patients with AIDS. PMID- 7834398 TI - Combination therapy with recombinant human soluble CD4-immunoglobulin G and zidovudine in patients with HIV infection: a phase I study. AB - To determine the effect of zidovudine (ZDV) on the pharmacokinetic disposition of recombinant soluble CD4 immunoglobulin G (rCD4-IgG) and to evaluate the safety and preliminary activity of concurrent administration of ZDV with rCD4-IgG, we undertook an open-label, dose-escalating, 12-week study. The regimens of intravenous rCD4-IgG and oral ZDV we used were (a) 300 micrograms/kg rCD4-IgG twice per week and 300 mg ZDV per day, (b) 300 micrograms/kg rCD4-IgG twice per week and 600 mg ZDV per day, (c) 1,000 micrograms/kg rCD4-IgG twice per week and 300 mg ZDV per day, (d) 1,000 micrograms/kg rCD4-IgG twice per week and 600 mg ZDV per day, and (e) 3,000 micrograms/kg rCD4-IgG twice per week and 300 mg ZDV per day. Subjects were recruited from three AIDS clinical trials units. Forty-one patients with HIV infection who had CD4 cell counts < or = 500 cells/mm3 and < 120 days of previous ZDV therapy participated. Pharmacokinetic interactions were assessed with the second regimen. Mean calculated peak serum rCD4-IgG concentrations were 5.47 micrograms/ml with ZDV and 8.28 micrograms/ml without ZDV, with serum half-lives of 34.2 and 32.0 h, respectively. Antibodies to rCD4 IgG were not detected. Seven episodes of severe adverse events occurred in five patients: one episode each of severe nausea, fever, or abnormal liver function tests and four episodes of severe neutropenia. Mean hemoglobin and neutrophil counts decreased, and mean platelet counts increased in all regimens, but there were no significant differences among regimens, rCD4-IgG dose, or ZDV dose.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7834399 TI - The duration of breastfeeding by HIV-1-infected mothers in developing countries: balancing benefits and risks. AB - How best to advise mothers infected with human immunodeficiency virus type 1 (HIV 1) in developing countries regarding breastfeeding is an important issue that has generated considerable debate. Previous studies have addressed this problem by means of mathematical models, but without considering the issue of the duration of breastfeeding. A mathematical model was developed to compare the age-specific risks of mother-to-child HIV transmission versus the excess mortality due to not breastfeeding. In this model it is assumed that both the risk of mother-to-child transmission of HIV through breast milk and the relative risk of not breastfeeding do not vary with age. The model indicates that, in HIV-1 seropositive mothers, the decrease in child mortality afforded by breastfeeding may exceed the risk of mother-to-child HIV-1 transmission only during the first 3 7 months of life. Thereafter the risk of HIV-1 transmission probably exceeds the mortality benefit of breastfeeding. Experimental studies of counselling HIV-1 infected mothers to limit their duration of breastfeeding should be considered in the setting of developing countries. PMID- 7834400 TI - Predictive markers for mother-to-child transmission of HIV-1 in Dar es Salaam, Tanzania. AB - The aim of this study was to determine immunological factors associated with increased risk of mother-to-child transmission of HIV-1 that could be used as predictive markers in Tanzanian women. One hundred and thirty-eight HIV-1 seropositive and 117-seronegative mothers and their newborns were recruited at delivery and followed up at Muhimbili Medical Centre in Dar es Salaam, Tanzania. Blood specimens from the mothers were analyzed for HIV-1 p24 antigen, beta 2 microglobulin (B2M), T-lymphocyte subsets, and presence of viral DNA in blood mononuclear cells by the polymerase chain reaction (PCR). Among 138 seropositive mothers, 30 (21.7%) had transmitted HIV-1 to their children, as shown by a positive PCR in the child. The vertical transmission rate was significantly higher in women with a percentage of CD4 lymphocytes < or = 20 (eight of 24, 33%) or a level of B2M > or = 2 mg/L (21 of 62, 34%) than in women with a higher percentage of CD4 lymphocytes (10 of 73, 14%) or a lower level of B2M (eight of 57, 14%) (p = 0.034 and 0.018, respectively). In eight of 18 (44%) transmitting mothers the percentage of CD4 lymphocytes was < or = 20, and in 21 of 29 (72%) transmitting mothers the B2M level was > or = 2 mg/L. In women with both a low percentage of CD4 lymphocytes (< or = 20) and a high level of B2M (> or = 2 mg/L), the vertical transmission rate was 54%.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7834401 TI - Maternal factors associated with perinatal HIV-1 transmission: the French Cohort Study: 7 years of follow-up observation. The French Pediatric HIV Infection Study Group. AB - A nationwide, longitudinal study of infants born to human immunodeficiency virus seropositive mothers has been under way in France since 1986. After 7 years of follow-up observations, we will update our assessment of the transmission rate in France and analyze, on a larger number of mother-infant pairs, the influence of maternal factors. Among the 848 pairs included in this analysis, the transmission rate was 20.2 +/- 2.7%. The transmission rate has remained stable with time and was not influenced by the mode of delivery, the mode of maternal infection, or the mother's ethnic origin. It was twice as high among the breast-fed infants as among the bottle-fed infants (40 vs. 19%, p < 0.04). Two factors were identified in a multivariate analysis (that did not include lymphocyte subset counts and the mode of feeding) as being associated with an increased risk of maternofetal transmission: p24 antigenemia (odds ratio = 3.1, confidence interval, = 1.5-6.2; p < 0.003) and elevated maternal age (p < 0.05). In the subgroup of 277 women whose absolute CD4+ lymphocyte counts at the time of delivery were available, the risk of transmission increased gradually from 15% of counts of > 600 CD4+ cells to 43% at counts of < 200. The risk of transmission was also related to the percentage of CD8+ cells, but each of the two factors seemed to play an independent role: the risk was lowest (12%) when the CD4+ cell count was > 500 and the proportion of CD8+ cells was < or = 40%, and was highest (50%) for values < 200 and > 40%.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7834402 TI - Disseminated Mycobacterium avium infection among HIV-infected patients in Kenya. AB - Previous studies from Africa have been unable to identify disseminated Mycobacterium avium complex (MAC) infection in patients with advanced human immunodeficiency virus (HIV) infection. We performed mycobacterial blood cultures and CD4 counts on 48 symptomatic adults with advanced HIV infection admitted to the hospital in Nairobi, Kenya over 4 weeks in 1992. Fourteen patients had mycobacteremia; these patients had significantly lower CD4 counts than the patients with negative cultures (14/mm3 vs. 85/mm3; p < 0.01). Three patients (6%) were bacteremic with M. avium (mean CD4 count, 10/mm3) and 11 (23%) were bacteremic with Mycobacterium tuberculosis complex (MTB) (mean CD4 count, 15/mm3). Thus, M. avium bacteremia was detected significantly less frequently in the study population than MTB bacteremia (p = 0.04). The minimum rate for HIV associated disseminated M. avium infection in patients admitted to the hospital in Nairobi was estimated to be approximately 1%. Patients with mycobacteremia died or were discharged home sick before the diagnosis was made. Disseminated M. avium does occur in adults with advanced HIV infection in sub-Saharan Africa, but is less common than disseminated MTB. PMID- 7834403 TI - Vitamin A deficiency in non-vitamin-supplemented patients with AIDS: a cross sectional study. AB - The prevalence of vitamin A deficiency and its association with dietary retinol intake in patients with AIDS was assessed in a cross-sectional study. Sixty eligible patients with AIDS provided serum samples that were analyzed for retinol content. Exclusion criteria included current use of vitamin supplements (57% of the 140 willing to participate) and pregnancy (none). Past dietary intake was determined using a standardized food intake frequency questionnaire. The prevalence of hyporetinemia was 22%. This was a 241-fold greater prevalence than that of a representative sample of the U.S. population, after adjusting for age and sex. There was a positive association between serum retinol status and dietary intake, but 27% of those with adequate intake had serum retinol levels below the normal range. These findings suggest that regardless of intake, patients with AIDS may represent a population at considerable risk of vitamin A deficiency. PMID- 7834404 TI - Illness stage, concurrent medications, and other correlates of low testosterone in men with HIV illness. AB - Our objective was to assess whether illness stage, markers of illness progression, and use of medications believed to lower testosterone are associated with low serum testosterone in HIV+ men. Data were available for 234 HIV+ men screened for eligibility for a study of testosterone replacement therapy and/or an antidepressant trial. A screening interview was used to elicit demographic and medical information. Blood was drawn to measure markers of immunodeficiency and serum testosterone. Thirty-eight percent of the sample had testosterone levels below the normal range. Low testosterone was associated with lower CD4 cell count, later stage of illness, use of megestrol, and older age. Regression analysis showed that only age and use of such medications as megestrol were significant predictors of low testosterone. Given the prevalence of low testosterone in HIV+ men and its link to sexual dysfunction, more research is needed on treatments aimed at correcting or compensating for this hormonal deficiency as well as the study of the impact of such medications as megestrol on testosterone levels in older men. PMID- 7834405 TI - HIV prevalence and sexual behavior in a cohort of New York City gay men (aged 18 24). AB - An ethnically diverse cohort (n = 174) of New York City gay men (aged 18-24) was studied to determine human immunodeficiency virus (HIV) prevalence and to document sexual behavior patterns. Blood tests of 87 men showed an HIV prevalence of 9%, but only 3% of the previously tested men (n = 77) reported knowledge of a positive test result at baseline interview. An annual HIV seroconversion rate of 2% was observed. Ethnic minority men were more likely to test HIV positive. In addition, the median number of both sexual episodes and sex partners, and the proportion of men who engaged in anal intercourse, increased significantly from 1990 to 1991. During this 2-year period, 91% of the men engaged in unprotected receptive oral intercourse, and 37% engaged in unprotected receptive anal intercourse. PMID- 7834406 TI - Increased tumor necrosis factor-alpha serum levels in patients with HIV wasting syndrome and euthyroid sick syndrome. PMID- 7834407 TI - Association of HIV and STDs in Haiti: implications for blood banks and HIV vaccine trials. PMID- 7834408 TI - Rising HIV-1 prevalence in STD clinic attenders in Jamaica; traumatic sex and genital ulcers as risk factors. PMID- 7834409 TI - HIV care: a changing health care system. PMID- 7834410 TI - HIV and Managed Care, Henry J. Kaiser Foundation Forum. Menlo Park, California, March 3-4, 1994. PMID- 7834411 TI - HIV disease and managed care: an overview. PMID- 7834412 TI - The impact of physician financial incentives on high-risk populations in managed care. AB - The challenge of managed care is to design a system in which rules and incentives together create a system of checks and balances that ensure both efficient and high-quality care. Incentives need to be administered so that physicians--both primary care providers and specialists--are not forced to choose between personal and/or organizational financial viability and patients' care. To accomplish this goal, payment needs to be linked both to quality and productivity and appropriately risk-adjusted. Quality assurance programs must ensure that both efficient and high-quality care is being provided and must maintain the satisfaction of both physicians and members. AIDS patients may be harmed by a system in which the more services a physician performs, the more he or she is paid--the traditional way in which American health care has been delivered heretofore. Managed care may undermine the care of high-risk patients if it arbitrarily reduces the high volume of care they require. However, a managed care system with effective checks and balances on financial incentives and quality of care can ensure that an efficient and high standard of care is being met--across all populations, including both healthy and high-risk patients. PMID- 7834413 TI - Quality of care and HIV infection: theory and practice. AB - The first section of this article provides a brief, conceptually oriented overview of the "state of the art" in quality assessment. The second section examines what we know about quality assessment in HIV disease. The third section attempts to synthesize this information and make some practical recommendations. These recommendations are starting points on a road to understanding quality assessment in HIV disease, not a destination. Scant empiric data underpin these recommendations, and it is my expectation and hope that they will evoke discussion and debate. Although this article touches only briefly on quality improvement, decisions about what to do with the information gathered may be just as important as decisions about what to measure. The concepts described in the continuous quality improvement literature, even though they are only beginning to be applied to health care, may be an important guidepost on the road to improved quality. PMID- 7834414 TI - Welcoming presentation to the Henry J. Kaiser Family Foundation Forum on AIDS and Managed Care. PMID- 7834415 TI - Developing quality review criteria from standards of care for HIV disease: a framework. PMID- 7834416 TI - HIV risk adjustment: issues and proposed approaches. PMID- 7834417 TI - AIDS, risk adjustment, and health care financing in New York State. PMID- 7834418 TI - Managed care, AIDS, and the politics of risk. PMID- 7834419 TI - HIV care: a capitated alternative. AB - Given sufficient and participatory planning, a cluster of excellence for HIV/AIDS could be designed that could yield benefits to payers, providers, and patients. Such a cluster of excellence would be at risk for all care provided to an enrollment population made up of PWAs and would be globally capitated based upon the average cost of providing care to this population in the current, unmanaged health care environment. The cluster would be freed from conventional use constraints and be free to manage the care of their enrollment population with minimal payer interference. But it would be at risk for managing the cost of care to the enrollees within the global capitation rate. PMID- 7834420 TI - Consumer protections for people living with HIV within systems of managed care. PMID- 7834422 TI - Immediate versus delayed free-tissue transfer salvage of the lower extremity in soft tissue sarcoma patients. AB - BACKGROUND: Free tissue transfer (FTT) can extend the limits of limb salvage in patients with soft tissue sarcoma (STS), but few data exist on the efficacy and morbidity in this patient population. METHODS: We prospectively examined 19 patients who underwent resection of STS and an immediate or a delayed FTT reconstruction between November 1989 and May 1992. RESULTS: There were 11 immediate and eight delayed FTT reconstructions (mean age 52 years). All delayed patients presented with complications resulting from previous STS treatment. Defects involved the leg (n = 7), knee (n = 2), and thigh (n = 10) and had a mean size of 129 cm2, 154 cm2, and 283 cm2, respectively. Preoperative radiatiotherapy had been administered to 74% of patients in the series (mean dose 53 Gy). FTT success rate was 95% (one failure in the delayed group). Limb salvage and postreconstruction ambulatory rates were both 95%. The overall complication rate was 47%, with the trend of a higher rate (63%) in the delayed group compared with the immediate group (36%). The immediate reconstruction group required no additional operative procedures before FTT and had a shorter hospital stay (13 days) compared with that of the delayed reconstruction group (40.6 days). Mean follow-up was 11.9 months (range 2-30). CONCLUSIONS: FTT is a reliable and versatile adjunctive treatment for lower extremity salvage of patients with STS. Immediate reconstruction appears to carry a lower complication rate and a faster rehabilitation for the patient. PMID- 7834424 TI - What is a surgical oncologist? PMID- 7834423 TI - Expression of growth factor receptors, the focal adhesion kinase, and other tyrosine kinases in human soft tissue tumors. AB - BACKGROUND: The tyrosine kinases are a family of genes that includes many growth factor receptors and protooncogenes. They appear to have a role in many cancers, but have not been systematically studied in the pathogenesis and progression of human sarcomas. METHODS: To characterize the protein tyrosine kinases that are expressed in human sarcomas, we used a polymerase chain reaction (PCR)-based method to construct kinase-specific cDNA libraries from low-grade and high-grade primary tumors. Thereafter, individual tyrosine kinase gene expression was assessed in a panel of sarcoma cell lines and primary tumors using Northern blotting and PCR. RESULTS: We identified 19 species of tyrosine kinase genes, including many growth factor receptors, the human homolog of the focal adhesion kinase (FAK) gene, and a novel trk-related kinase designated HGK2. Messenger RNA expression analyses showed relative overexpression of the two forms of the platelet-derived growth factor receptors (PDGFRs) with expression of the alpha form restricted to a subgroup of high-grad and metastatic sarcomas. We were unable to demonstrate coexpression of the PDGF isoforms in primary tumors that overexpressed the receptors, suggesting that a PDGF/PDGFR autocrine pathway may not be a central mechanism in the malignant transformation of sarcomas in vivo. FAK expression was observed in a variety of sarcomas, with increased levels in several high-grade and metastatic leiomyosarcomas. CONCLUSIONS: When grouped together by histologic cell type and grade, the expression data of the 19 kinases in primary tumors described a greater degree of heterogeneity than is generally appreciated by clinicopathologic classification schemes. This diversity suggests that sarcomas, even those that appear to be clinically similar, arise through a variety of molecular pathways involving tyrosine kinases. PMID- 7834425 TI - Intrapleural photodynamic therapy: results of a phase I trial. AB - BACKGROUND: The management of pleural neoplasms, specifically mesothelioma, remains difficult. We performed a phase I trial in 54 patients with isolated hemithorax pleural malignancy to determine (a) the feasibility of intraoperative, intrapleural photodynamic therapy after debulking surgery; (b) the influence of light dose/sensitizer interval on postoperative morbidity in order to define the photodynamic therapy (PDT) maximal tolerated dose (MTD); and (c) whether first order dosimetry could be applied to this complex geometry. METHODS: Cohorts of three patients were given escalating intraoperative light doses of 15-35 J/cm2 48 h after i.v. delivery of 2.0 mg/kg Photofrin II (Quadra Logic Technologies, Vancouver, British Columbia, Canada), and then escalating light doses of 30-32.5 J/cm2 after a 24-h sensitizer/operation interval. Twelve patients could not be debulked to the prerequisite 5 mm residual tumor thickness. The remaining 42 patients underwent 19 modified pleuropneumonectomies, five lobectomy pleurectomies, and 18 pleurectomies. Intrapleural PDT was delivered using 630 nm light from two argon pump-dye lasers, and real-time and cumulative light doses were monitored using seven uniquely designed, computer-interfaced photodiodes. RESULTS: There was one 30-day mortality from intraoperative hemorrhage. In the 48 h sensitizer/operation group (n = 33), possible PDT-related complications included an empyema with late hemorrhage in one of three patients at 17.5 J/cm2 and a bronchopleural fistula at 35 J/cm2. At each of these light doses, three additional patients were treated without complication. Two patients subjected to 24-h sensitizer dosing and 32.5 J/cm2 developed esophageal perforations after pleuropneumonectomy at identical sites. The MTD was declared as 30 J/cm2 light with a 24-h dosing interval when none of the six patients (three original, three repeat) at that level developed toxicity. CONCLUSIONS: These data demonstrate that resection and intrapleural PDT can be performed safely with currently available sensitizers and lasers. Phase II and III trials are now warranted at this MTD in a homogeneous population of patients with pleural malignancies. PMID- 7834426 TI - Prognostic evaluation of intracranial metastasis in malignant melanoma. AB - BACKGROUND: Malignant melanoma (MM) is often reported as the third most common cause of intracranial metastasis (IM) after carcinoma of the breast and lung. Most patients with advanced MM will have widespread extracranial disease, but the majority will die from intracerebral spread. METHODS: A retrospective review of 117 patients with documented IM from MM over the past 25 years was undertaken. Various factors (including age, race, sex distribution, primary lesions with Clark's level, Breslow's thickness, primary sites and staging at initial presentation, diagnosis of IM and its various treatment methods, survival data, and autopsy findings) were analyzed. Prognostic indicators were clarified from this analysis as a predictor of central nervous system (CNS) metastasis. An ideal treatment plan was also analyzed in order to predict a better survival. RESULTS: Fifty-eight percent of patients were male; 42% were female. Seventy-one percent of the primary lesions were of Clark's level IV and V, with mean Breslow's thickness of 3.5 mm. Median time interval between the initial diagnosis and development of IM was 3.5 years. Complete surgical resection of the intracranial lesion in the brain resulted in the longest mean survival of 10.3 months, whereas mean survival for the group with no treatment was only 3 weeks. Patients with primary lesions of the head and neck had the lowest mean survival of 3.3 months, whereas those whose primary sites were unknown had the longest mean survival of 7.5 months. One- and 2-year survival were 9% and 3%, respectively. All but one of the 30 patients at autopsy were found to have visceral metastasis, namely of the lung, liver, and bone. CONCLUSION: An aggressive search for metastasis should be undertaken in patients at high risk of developing CNS metastasis, e.g., male, head and neck primary, Clark's level IV and V, Breslow's thickness of > 3 mm, and presence of visceral metastases, mainly lung. A complete surgical resection should be attempted whenever possible, with adjunctive use of whole-brain irradiation, along with systemic chemotherapy for further control of recurrence and to prolong survival. PMID- 7834427 TI - Age-related differences in breast cancer treatment. AB - BACKGROUND: More than half of the cases of breast cancer treated in the United States occur in women over age 65. This study investigates age-related differences in breast cancer therapy. METHODS: A retrospective review of all women with primary operable invasive breast cancer treated at the University of Michigan Breast Care Center over a 30-month period showed a total of 77 older patients aged > or = 65 years (median, 71; oldest patient, 92) for whom full information was available regarding comorbidity, tumor stage and histology, and details of surgery, radiation, and chemohormonal therapy and complications. Fifty one similar younger patients aged 55-64 years (median, 59) were identified for comparison. Patients were classified as either having received standard treatment or non-standard treatment. Standard therapy was prospectively defined as follows: local/regional--lumpectomy and axillary lymph node dissection plus radiation therapy or modified radical mastectomy; systemic--chemotherapy and/or tamoxifen for stage II disease. A comorbidity score calculated for each patient assigned one point each for nursing home residence, nonambulatory status, recent surgery, and each medical problem requiring drug therapy. RESULTS: When overall treatment (local/regional plus systemic) was assessed, proportionately fewer older patients (55 of 77 versus 47 of 51; p < 0.01) received standard treatment. Fewer older than younger patients (62 of 77 versus 50 of 51; p < 0.01) received surgical therapy that included an axillary dissection. A smaller proportion of older patients received radiation therapy following lumpectomy and axillary lymph node dissection (26 of 29 versus 19 of 19; N.S.). Overall, only 59 of 77 older patients versus 50 of 51 younger patients (p < 0.001) received standard local/regional care. Similar proportions of younger and older patients (19 of 22 and 24 of 30, respectively) received standard systemic therapy for stage II breast cancer, but older patients were less likely to receive chemotherapy than younger patients (7% versus 50%; p < 0.001). Treatment-related complications were not age-related but were more frequent in patients receiving standard treatment than in patients receiving nonstandard treatment (45 of 102 versus two of 26; p < 0.001). Comorbidity score correlated with the use of nonstandard therapy but not with age. The scores for both older and younger patients receiving overall standard treatment were 0.8 versus 1.5 and 1.4, respectively, in patients receiving nonstandard treatment. Interestingly, explanations for decisions to deviate from standard treatment guidelines were often not identified. Comorbidity was explicitly noted in only one of four younger patients who received nonstandard treatment therapy. In 22 older patients who received nonstandard treatment, comorbidity was cited in eight cases, patient age was cited in six cases, and patient choice was cited in four cases. Follow-up (median, 34 months) did not show that disease-free or overall survival differences were related to age or to treatment (standard versus nonstandard). CONCLUSIONS: These data demonstrate age-related variations in breast cancer treatment in a multidisciplinary breast care unit. Lower complication rates and equivalent short term outcomes in women who received nonstandard therapy suggest good clinical judgment may have played a role in these differences. Although age-related patient preferences and comorbidity are relevant, the age-related attitudes of caregivers must also be taken into account to fully explain these variations. PMID- 7834428 TI - Preoperative high-dose radiation and chemotherapy in adenocarcinoma of the esophagus and esophagogastric junction. AB - BACKGROUND: Esophageal adenocarcinoma (EA) incidence is rising. Defining optimal management is essential because median survival after surgery alone is only approximately 12 months. High-dose radiation (> 5000 cGy) and chemotherapy (HDRCT) preoperatively for patients with EA has not been fully investigated. We evaluated tumor response, resectability, and survival following HDRCT in patients with localized EA. METHODS: Thirty patients with American Joint Committee on Cancer (AJCC) clinical stage I or II EA were prospectively treated with HDRCT. The treatment consisted of 60 Gy radiation at 2 Gy per fraction with concurrent infusional 5-fluorouracil (5-FU) and a bolus of mitomycin C followed by esophagogastrectomy. The range of follow-up was 7 to 69 months, with a median of 31 months. RESULTS: Twenty of 30 patients (67%) received full-course HDRCT. Severe esophagitis precluded full-dose radiation in 10 patients. Three patients developed neutropenia and fever requiring admission to a hospital. Two patients died preoperatively of treatment-related complications. Nine patients were not explored. Eighteen patients were resected with curative intent; the remaining three had metastatic disease at laparotomy. Seven of 18 resected patients (39%), or 7/30 (23%) of all patients treated, had a pathologic complete response. There was one operative death. Overall local control was seen in 25/30 patients (83%). Median overall survivals for resected and for all patients were 23 and 13 months, respectively. CONCLUSIONS: Preoperative HDRCT in patients with EA results in encouraging local tumor response and local control. Overall survival, however, may not be improved, and the treatment-related mortality of 10% is higher than reported with surgery alone or with preoperative chemotherapy. PMID- 7834429 TI - Ability of low-dose cyclophosphamide to overcome metastasis-induced immunosuppression. AB - BACKGROUND: Lymphocytes obtained from tumor-draining lymph nodes (DLN) can have potent in vivo antitumor activity after in vitro activation with bryostatin 1 and ionomycin. However, the presence of visceral metastases in the donor can inhibit the effectiveness of such lymphocytes. In the present study, we tested the ability of low-dose cyclophosphamide to overcome metastasis-induced immunosuppression in a murine model. METHODS: Mice were injected with MCA-105 sarcoma cells in the footpad alone or in the footpad and the tail vein to establish lung metastases. Cyclophosphamide was given i.p. 1 day before harvesting the draining popliteal lymph nodes. For all donor groups, DLN cells were activated with 5 nM bryostatin 1 and 1 microM ionomycin and cultured for 7 days in 20 U/ml IL-2. Activated DLN cells were then adoptively transferred to syngeneic mice with 3-day lung metastases. RESULTS: The adoptive transfer of DLN cells from mice with footpad tumors only significantly reduced the number of lung metastases compared to untreated mice. However, activated DLN cells obtained from mice with both footpad and lung tumors were significantly less effective. Treatment of similar donor mice with 10 mg/kg cyclophosphamide significantly improved the anti-tumor activity of adoptively transferred cells. This dose of cyclophosphamide did not reduce the number of cells obtained from each lymph node or the expansion of cell numbers in vitro. CONCLUSIONS: These results suggest that the administration of low-dose cyclophosphamide prior to harvesting DLN cells may improve the success of adoptive immunotherapy in cancer patients. PMID- 7834430 TI - Recent experience with Wilms' tumor: 1978-1991. AB - BACKGROUND: The treatment of Wilms' tumor has undergone major advances in the past four decades. Current therapy is based on both the stage and pathology of the tumor. We have reviewed our recent experience with this tumor to assess the results of treatment on protocols that generally avoid the use of doxorubicin. METHODS: Between January 1978 and December 1991 we treated 114 children with renal tumors. Ninety-one (80%) had favorable histology Wilms' tumor and 23 (20%), unfavorable histology tumors (13 anaplastic Wilms' tumors, four clear cell tumors of the kidney, and six sarcomatous tumors with rhabdoid elements). Chemotherapy was divided into two eras: 1978-1982 (vincristine and actinomycin-D) and 1983 1991 [vincristine and actinomycin-D for all patients, and cyclophosphamide for those with favorable histology and metastatic disease (n = 13) and all patients with anaplastic histology (n = 13)]. Four patients with clear cell or rhabdoid/sarcomatous tumor, three of whom are disease-free, were treated with a five-drug regimen (vincristine, doxorubin, cyclophosphamide, platinum, and VP 16). Approximately two thirds of the patients received megavoltage radiotherapy to the tumor bed. Mean abdominal radiation doses from 1978 to 1982 were slightly higher than those used from 1983 to 1991 (2,597 +/- 782 cGy vs. 2,039 +/- 524 cGy, respectively). RESULTS: No isolated local failures were observed in any favorable histology patient who received radiotherapy. Among the 91 patients with favorable histology, there was no statistically significant difference in event free survival irrespective of stage. Outcome for patients with anaplastic or clear cell variants was not different from that for those patients with favorable histology, but there were only small numbers in these groups for comparison. Only children with a rhabdoid/sarcomatous variant demonstrated survival that was different from all others (p = 0.00). Our previously reported patients with stage I tumors (< 550 g) (n = 11) who were treated by nephrectomy only continue to have an excellent outcome (survival 100%). CONCLUSIONS: Wilms' tumors remain highly curable. Some unfavorable histology tumors require intensive therapy. Others such as our stage I tumors may be best observed without adjuvant therapy to avoid the toxicity of treatment. PMID- 7834431 TI - Post-treatment sarcoma in breast cancer patients. AB - BACKGROUND: Many patients treated for breast cancer with radiotherapy will survive their disease and be at risk for treatment-related sarcoma for many years. METHODS: In order to identify patients with post-treatment sarcoma and define this disease, we examined the records of 99 patients treated for sarcoma with a history of antecedent breast carcinoma. Of these patients, 51 were felt to have a sarcoma unrelated to breast cancer treatment and 48 were felt to have a treatment-related sarcoma (secondary to lymphedema and/or radiation). RESULTS: Lymphangiosarcoma of the extremity was the most common histologic subtype of post treatment sarcoma, accounting for 22 of 48 cases (46%). Twenty-six patients (54%) developed nonlymphangiosarcoma post-treatment sarcoma; all of these were radiation-associated sarcomas. The median latency interval between the diagnosis of breast cancer and the development of sarcoma was 11 years (range 4-44) and was not different between the two groups. However, patients with nonlymphangiosarcoma were significantly younger when diagnosed with breast cancer than were those with lymphangiosarcoma of the extremity (median 43 vs. 51 years, p < 0.001). The survival of all 48 patients was poor: 5-year survival was 29%. Five-year survival of patients with other types of post-treatment sarcoma was just as poor as those with lymphangiosarcoma of the extremity (30% vs. 28%, p = 0.98). CONCLUSIONS: Patients who develop sarcoma after treatment for breast cancer have a poor prognosis whether it occurs as Stewart-Treves syndrome or other types of post treatment sarcoma. Younger patients may be at higher risk than are older patients for the development of nonlymphangiosarcoma post-treatment sarcoma. PMID- 7834432 TI - Primary adenocarcinoma of the duodenum: management and survival in 67 patients. AB - BACKGROUND: Because of the rarity of primary adenocarcinoma of the duodenum, accumulation of natural history data has been difficult. As a result, debate continues over important treatment issues. METHODS: We did a retrospective review of 67 patients with nonampullary adenocarcinoma of the duodenum treated at the University of Texas M.D. Anderson Cancer Center between 1967 and 1991. Presenting symptoms and signs, diagnostic studies, operation performed, surgical pathology, and survival were analyzed. RESULTS: A primary duodenal tumor was demonstrated by upper gastrointestinal radiographs (UGI) in 37 of 42 patients (88%), esophagogastroduodenoscopy (EGD) in 49 of 55 (89%), and computerized tomograms (CT) in 21 of 42 (50%). A curative resection was performed in 36 of the 59 patients who underwent operation (61%); 27 had pancreaticoduodenectomies and nine had wide local excisions. Overall 5-year survival was 29%. The 5-year survival difference between resected and unresected patients was 54% versus 0%, respectively (p < 0.0001). No survival difference was noted between patients who underwent pancreaticoduodenectomy rather than wide local excision. Lymph node metastases were significantly related to the occurrence of distant metastases (p = 0.0034). The 5-year survival for patients with stage I or II tumors was 100% and 52%, respectively, compared to 45% and 0% for stage III and IV (p < 0.0001). CONCLUSIONS: Our data suggest that UGI and EGD are effective for diagnosing duodenal carcinoma. Survival is improved by curative resection and is not compromised by a wide local excision instead of a pancreaticoduodenectomy for lesions of the third and fourth portion. We recommend that adjuvant chemotherapy be considered for stage III disease, because distant failure is the predominant pattern of failure in this group. PMID- 7834434 TI - Salvage abdominoperineal resection following combined chemotherapy and radiotherapy for epidermoid carcinoma of the anus. AB - BACKGROUND: Up to one-third of patients with anal epidermoid cancer will fail initial chemoradiotherapy (CT-RT) or have local recurrence after treatment. This study evaluates the Memorial Sloan-Kettering Cancer Center (MSKCC) experience with salvage abdominoperineal resection (APR) in these patients. METHODS: Thirty eight patients who underwent salvage APR following 5-fluorouracil (5-FU), mitomycin C, and radiotherapy over the past 12 years were analyzed by retrospective review. Survival was calculated by the Kaplan-Meier method and comparisons by log-rank analysis. RESULTS: The indications for APR were recurrent disease after CT-RT in 14 patients and persistent disease in 24 patients. Median follow-up time and survival were 47 and 41 months, respectively. The actuarial 5 year survival was 44%. Twenty-three patients had recurrent disease after APR. Inguinal lymphadenopathy at initial presentation (p < 0.05), fixation of tumor to the pelvic sidewall (p < 0.01), and pathologic involvement of the perirectal fat (p < 0.01) adversely affected survival. Age, gender, initial response to CT-RT, initial stage of the primary tumor, histologic levator muscle involvement, status of perirectal lymph nodes, and extent of lymphadenectomy did not affect survival. CONCLUSIONS: Salvage APR can be expected to yield a moderate number of long-term survivors, but the high rate of disseminated failure suggests the need for additional postoperative treatment. PMID- 7834433 TI - Modulation of oncogene and tumor-suppressor gene expression: a novel strategy for cancer prevention and treatment. AB - BACKGROUND: Advances in our understanding of the molecular biology of cancer have the potential for translation into clinical cancer prevention and treatment strategies. Oncogenes and tumor suppressor genes have been implicated in the development of human cancers Mutations in gene families occur in both premalignant lesions and invasive tumors. CONCLUSION: Recombinant DNA constructs can be made that eliminate expression of a mutant oncogene protein or provide a normal copy of a tumor suppressor gene to the cancer cell. Reversal of a single genetic lesion is sufficient to inhibit cancer cell proliferation and tumorigenicity. Viral vectors are now being evaluated for direct delivery of these constructs to human tumors. PMID- 7834435 TI - Patterns of residual disease after preoperative chemoradiation in ultrasound T3 rectal carcinoma. AB - BACKGROUND: Rectal carcinoma tends to recur locally, with invasion of adjacent organs and significant pelvic pain. Both radiation therapy alone and combined chemoradiation have been used in an attempt to decrease the local recurrence rate and thereby improve survival. Although preoperative chemoradiation can clinically downstage rectal tumors, the pathologic extent of the residual disease has not been studied. METHODS: Thirty-seven patients with T3 rectal cancer diagnosed by transrectal ultrasonography (uT3) received 45 Gy with continuous infusion 5 fluorouracil (300 mg/m2/day). Proctoscopy with mucosal/submucosal biopsy was performed in patients (16 of 37) posttreatment and before definitive surgery. RESULTS: Microscopic evaluation of the 37 resected specimens showed a 30% (11 patients) pathologic complete remission rate. The pattern of residual disease in the remaining 26 patients showed that nine (25%) had microscopic residual tumor without evidence of mucosal involvement. Of the 14 patients with a negative proctoscopic evaluation and biopsy only, five (36%) had no residual tumor on final pathology. CONCLUSIONS: After chemoradiation, the pathologic presentation of rectal cancer may be altered, making endoscopic procedures and mucosal/submucosal biopsies unreliable in detection of residual disease. Despite the relatively good pathologic complete remission rate noted in this study, all patients undergoing chemoradiation for uT3 rectal carcinomas need definitive surgical resection to confirm a complete clinical remission. PMID- 7834436 TI - Mediastinal tumors in children: experience with 196 cases. AB - BACKGROUND: Mediastinal masses are relatively common in infants and children. These lesions are often neoplastic in origin and have a high risk of malignancy. METHODS: This report concerns 196 infants and children with mediastinal tumors. Fifty-five cases (28%) were benign, and 141 (72%) were malignant. Diagnosis included Hodgkin's disease (47), neuroblastoma (46), non-Hodgkin's lymphoma (37), teratoma (18), ganglioneuroma (14), cystic hygroma (11), Schwannoma (five), germ cell tumors (three), lipoma (three), thymic tumor (three), malignant histiocytosis (two), neurofibroma (two), mesenchymal sarcoma (one), rhabdomyosarcoma (one), peripheral neuroectodermal tumor (one), hamartoma (one), and hemangioma (one). Diagnoses were usually made by assessing the patient's age, radiologic evidence of tumor location, the presence of calcium in the tumor, and the presence of tumor markers (alpha-fetoprotein, vanillmandelic acid, human chorionic gonadotropin). Diagnoses were verified by histologic evaluation. Resection was the only treatment for benign tumors. Biopsy and chemotherapy (and/or radiation) were employed for lymphoid tumors, and resection and adjuvant therapy were used for other solid malignancies. RESULTS: Survival was achieved in 53 of 55 (96.3%) patients with benign tumors and 105 of 141 (74.4%) patients with malignant tumors. CONCLUSIONS: Seventy-two percent of mediastinal tumors in this study were malignant. Early diagnosis followed by biopsy and chemotherapy for lymphoid tumors or resection of nonlymphoid tumors along with aggressive adjuvant therapy result in high survival rates (74.4%). Children with benign tumors almost always survive (96.3%) after resection. PMID- 7834437 TI - Iodine 131 thyroid ablation in female children and adolescents: long-term risk of infertility and birth defects. AB - BACKGROUND: The use of radioactive iodine, or iodine 131 (131I), for remnant thyroid ablation and the treatment of cervical and distant metastatic disease in patients with thyroid cancer is well accepted. 131I concentrates in the bladder, and irradiation to the ovaries has been theorized to increase the risk of infertility and birth defects in subsequent offspring. METHODS: We conducted a retrospective review of the charts of 154 children and adolescents treated at our institution for thyroid cancer between 1951 and 1991. Review of these charts identified 68 females diagnosed with thyroid cancer, < or = 20 years of age, who received 131I as part of their therapy at our institution. Charts were reviewed and patients recontacted, and initial tumor, date of diagnosis, and 131I administration, including doses, were recorded. Complete pregnancy histories including current health status of the children were also recorded. RESULTS: Twenty-two patients who never attempted pregnancy were excluded from analysis. Eleven patients could not be contacted and were considered lost to follow-up and thus excluded from the study. In the remaining 35 patients, mean age at 131I administration was 18.3 years (range 14.1-20.8), mean follow-up, 16.8 years (range 5.6-39.8), and mean 131I dose, 148.53 mCi (range 77.2-250). Three patients were diagnosed infertile after extensive workup (8.6%). The remaining 32 patients had 69 pregnancies resulting in 60 term and four premature deliveries. There were two elective abortions for nonmedical reasons and three spontaneous abortions. Only two children were conceived within 1 year of 131I therapy. Both were born with birth defects that proved fatal within 8 months. No other children were born with birth defects. One other child born with an estimated gestational age of 27 weeks died due to complications related to his prematurity. No anomalies were noted at autopsy. Of the 61 children alive for follow-up, no major health problems were identified other than asthma in two children. CONCLUSIONS: 131I, used in doses up to 250 mCi, is not associated with any long-term risk of infertility. The risks of infertility or birth defects are not different from those of the general population. Because the two children with birth defects were born to mothers treated either during pregnancy or 6 months before conception, it might be wise to suggest avoiding pregnancy for up to 1 year after 131I treatment. PMID- 7834438 TI - Positron emission tomography and breast masses: comparison with clinical, mammographic, and pathological findings. AB - BACKGROUND: Positron emission tomography (PET) is a means of imaging tissue based upon its metabolic activity. Initial studies in the field of oncology suggest that PET may be useful for diagnosis, staging, and treatment of various tumors. METHODS: Twenty-eight patients with 37 breast lesions were studied with PET using [fluorine-18] 2-deoxy-2-fluoro-D-glucose (FDG) to assess which clinicopathological characteristics relate to FDG accumulation by the primary tumor. RESULTS: PET-FDG was found to successfully discriminate malignant from benign breast lesions (p = 0.02) and identify axillary lymph node metastases. FDG uptake by the primary tumor was found to be independent of age, menopausal status, race, tumor size, laterality, histologic differentiation, ploidy, DNA index, estrogen or progesterone receptor value, pathologic stage, and serum glucose. Higher tumor nuclear grade and S-phase were associated with more FDG accumulation by the primary tumor compared with normal breast tissue. PET-FDG correctly identified five malignant lesions that were indeterminant for cancer both on clinical breast examination and mammography and identified one occult cancer that was neither palpable nor apparent mammographically. PET-FDG correctly identified clinical occult axillary metastatic cancer in five patients. CONCLUSIONS: This study shows that PET-FDG imaging can distinguish malignant from benign breast lesions among a diverse group of patients and suggests that PET-FDG may not only allow for preoperative staging of patients but also provide information about prognosis. This study provides impetus for continued research into PET-FDG imaging of breast lesions, which could have a major impact on the treatment of breast cancer. PMID- 7834439 TI - Lobular carcinoma in situ: observation without surgery as an appropriate therapy. AB - BACKGROUND: The finding of lobular carcinoma in situ (LCIS) in the breast has generally prompted treatment with unilateral or bilateral mastectomy. Most experts now feel that LCIS simply identifies a woman who is at high risk to develop future breast cancer and requires only close clinical and mammographic follow-up. This approach has been recommended at our institution for > 15 years. This study defines the natural history of a population of women with LCIS who were treated by observation alone. METHODS: Women with a pathologic diagnosis of LCIS were identified by tumor registry search. Records and pathology were reviewed. Radiographic-pathologic correlation was performed on women who had undergone mammographic-localized breast biopsies. One hundred forty-nine women with LCIS were identified. Eighty four were excluded from analysis because of synchronous invasive cancer or ductal carcinoma in situ (DCIS). The remaining 65 women formed the basis of this report. RESULTS: Sixty-five women with LCIS were treated from 1963 through 1990. Median follow-up was 83 months. No women were lost to follow-up. Median age at diagnosis was 48 years (range 37-81), and 32% had a family history of breast cancer. Clinical findings leading to biopsy were breast mass in 43, nipple discharge in three, and mammographic abnormality in 19. Mammographic-pathologic correlation showed that the focus of LCIS in these 19 women was not associated with the mammographic abnormality. Fourteen of 65 women underwent mastectomy after diagnosis of LCIS (nine ipsilateral, five bilateral). Fifty-one of 65 women elected observation alone. In the observation group, 13 of 51 women (25%) underwent a second breast biopsy for a clinical or mammographic abnormality during the follow-up period. The median interval to biopsy was 50 months. Pathology was benign in two, LCIS in seven, DCIS in one, and invasive cancer in three. All seven women with LCIS on subsequent biopsy continued with observation and none developed breast cancer. All four cancers were detected by mammography without an associated palpable mass. Three of four cancer masses were < 1 cm in diameter. The woman with DCIS was 47 years of age and developed DCIS 106 months after LCIS diagnosis. She was treated by total mastectomy and is disease free 108 months later. The three women with invasive cancer developed this at 41, 53, and 69 months after diagnosis of LCIS. All were < 50 years of age. All three cancers were in the same breast as the previous LCIS. Two women were treated by modified radical mastectomy, and the third had wide excision/axillary dissection followed by radiation therapy. They are alive and disease-free at 16, 82, and 116 months. CONCLUSIONS: Four of 51 women treated with observation alone after diagnosis of LCIS developed breast cancer. All were detected by screening at an early stage. LCIS appeared to be an incidental finding on biopsy of mammographic abnormalities. The policy of observation alone for the finding of LCIS spares women mastectomy. Furthermore, cancers that develop in follow-up are likely to be detected at an early stage and be amenable to curative therapy. Observation alone is appropriate treatment for women with LCIS. PMID- 7834440 TI - Accelerated hepatic arginine transport in the tumor-bearing rat. AB - BACKGROUND: Arginine plays a pivotal role in regulating ureagenesis, polyamine biosynthesis, and nitric oxide production, metabolic pathways that may be stimulated in the liver of the tumor-bearing host. Normally, plasma arginine is excluded from the hepatocyte intracellular space by the low basal activity of its membrane transporter. We hypothesized that progressive malignant disease is associated with an increase in carrier-mediated arginine transport across the hepatocyte plasma membrane. METHODS: Twenty-four adult Fischer 344 rats were implanted subcutaneously with fibrosarcomas (TBR) and were studied when the tumors were small [10 +/- 1% of body weight (BW)], medium-sized (15 +/- 1% of BW), and large (25 +/- 1% of BW). Groups of control rats (n = 24) were pair-fed to match carcass weights of the three TBR groups. Livers were excised, and hepatocyte plasma membrane vesicles (HPMVs) were prepared by Percoll density gradient centrifugation. Arginine transport by HPMVs was assayed by a rapid mixing/filtration technique. Vesicle purity and functionality were assessed by membrane enzyme marker enrichments and transportability into an osmotically active space. RESULTS: Arginine uptake by HPMVs was mediated by both saturable carrier-mediated (System y+) and nonsaturable (diffusion) components. The time course of arginine uptake in HPMVs in the three groups showed similar equilibrium transport rates, indicating similar vesicle sizes. The presence of the growing tumor resulted in a 40-120% increase in System y(+)-mediated arginine transport in HPMVs. This response was dependent on tumor size and was due to a stimulation of carrier Vmax, suggesting an increase in the number of functional System y+ carriers in the hepatocyte plasma membrane. The Na(+)-dependent transport of the System A analog MeAIB was also increased, but only in rats with large tumors. CONCLUSIONS: Tumor growth results in a progressive increase in hepatic arginine transport, a response mediated primarily by an increase in the activity of System y+. This accelerated transport may amplify the availability of arginine to support key arginine-dependent metabolic pathways in the hepatocyte. PMID- 7834441 TI - Prevention of chronic radiation enteropathy by dietary glutamine. AB - BACKGROUND: Nearly 50% of all cancer patients receive therapeutic radiation during the course of their disease. The risk of late complications is the main dose-limiting factor in the delivery of radiation therapy. The small intestine, the major site of chronic radiation enteropathy, is also the principal organ of glutamine consumption. We therefore hypothesized that the provision of supplemental glutamine may have a protective effect on the development of chronic radiation enteropathy. METHODS: This study evaluated the effects of supplemental oral glutamine on the development of chronic radiation (XRT) enteropathy. After scrotalization of a loop of small intestine, rats were randomized to receive 1 g/kg/day glutamine (GLN) or glycine (GLY) by gavage. After 2 days of prefeeding, rats were randomized to 1 of 4 groups: GLN + XRT (n = 10), GLY + XRT (n = 10), GLN only (n = 10), GLY only (n = 10). Twenty Gy was delivered to the scrotalized bowel in the GLN + XRT and GLY + XRT groups via a collimated beam. Gavage was continued for 10 days. Animals were then pair-fed chow. Rats were killed at 2 months postirradiation. Chronic radiation injury was assessed microscopically. RESULTS: Injury scores in GLN + XRT were similar to those of unirradiated bowel and significantly different from GLY + XRT (1.89 +/- 0.48 in XRT + GLN vs. 6.42 +/- 1.55 in the XRT + GLY, p < 0.01). Elevated Injury Scores in the XRT + GLY group correlated with gross thickening and fibrosis, a 10-fold decrease in gut GLN extraction (1.40 +/- 4.3% in GLY + XRT vs. 16.0 +/- 5.1% in GLN + XRT, p < 0.05), and a 30% decrease in glutathione content (2.46 +/- 0.19 and GLY + XRT vs. 3.17 +/- 0.17 GLN + XRT, p < 0.05). CONCLUSIONS: Provision of GLN during abdominal/pelvic XRT may prevent XRT injury and decrease the long-term complications of radiation enteropathy. PMID- 7834442 TI - Perineal reconstruction after surgical extirpation of pelvic malignancies using the transpelvic transverse rectus abdominal myocutaneous flap. AB - BACKGROUND: The nonhealing perineal wound is often a catastrophic complication after aggressive surgical extirpation of pelvic malignancies. METHODS: Eleven patients underwent perineal reconstruction using an inferiorly based transpelvic transverse rectus abdominal myocutaneous (TRAM) flap for large nonhealing postsurgical perineal wounds. After debridement of the perineum, the rectus muscles and their skin islands were mobilized, preserving their inferior epigastric blood supply. The flap was then taken through the midline abdominal incision transpelvically into the perineal defect. The study population was composed of three men and eight women ranging in age from 43 to 76 years (mean 59). The primary diagnosis was recurrent carcinoma of the rectum or anus (n = 5), recurrent squamous cell carcinoma of the vulva or cervix (n = 4), and recurrent sacral chordoma (n = 2). All patients had received adjuvant radiation therapy and all patients had undergone one to four previous attempts at perineal closure. The perineal defect ranged in size from 72 cm2 to 1,250 cm2 (mean 337). RESULTS: There were no perioperative deaths. Ten of the 11 patients (91%) had primary wound healing of the TRAM flap, perineal wound, and donor site. One patient with recurrent chordoma developed recurrent tumor at the suture line 4 months postoperatively. CONCLUSIONS: The inferiorly based transpelvic TRAM flap is a safe and effective reconstructive technique for recalcitrant nonhealing perineal wounds after extirpation of pelvic malignancies. PMID- 7834443 TI - Management of metastatic brain tumors. AB - BACKGROUND: Brain metastases are the most common neurological complication of systemic cancer. They represent a serious cause of morbidity and mortality and a significant challenge for neurosurgeons. They outnumber all other intracranial tumors combined and, with advances in technology and treatment of systemic cancer, are on the increase as cancer patients live longer. METHODS: We have reviewed the major factors that influence the occurrences of metastases in the central nervous system: primary cancer, patient age and sex, clinical aspects of presentation, basic diagnostic modalities, diagnostic imaging (computed tomography and magnetic resonance imaging), and treatment considerations. In discussing these different aspects, we emphasize the efficacy of different treatment options, including recent information regarding multiple metastases that broadens the scope of surgical implications. The criteria we present are directed toward considerations made by general surgeons, as well as those made by neurosurgeons. CONCLUSIONS: Although radiotherapy remains the main therapeutic modality, surgical excision has increasingly shown advantages in certain settings, as has stereotactic radiosurgery. Chemotherapy is less effective, but its advantages are reviewed, as are the implications of recurrent metastases. PMID- 7834444 TI - In favor of video-assisted thoracic surgery and a eulogy for thoracoscopy. PMID- 7834445 TI - Measurement of rectal cancer. PMID- 7834446 TI - Contribution of videothoracoscopy to the management of the cancer patient. AB - BACKGROUND: Videothoracoscopy has rapidly become a popular procedure, but its technical feasibility has been emphasized without critically evaluating its role in the management of thoracic disease. To assess the value of videothoracoscopy in the diagnosis and staging of the cancer patient and to determine if it has added to our previous standard approach of thoracoscopy performed with a mediastinoscope without video, we established a prospective database when we initiated videothoracoscopy in January 1992. METHODS: Patients were offered videothoracoscopy as an alternative to thoracotomy only if other standard approaches (e.g., needle biopsy, mediastinoscopy) were inadequate to diagnose or stage cancer or to restage patients after therapy. Parameters entered and analyzed in a prospective database were patient name; age; sex; past history; indications for videothoracoscopy; procedure type; surgical technique; whether conversion to thoracotomy was necessary, and if so, why; complications; and pathology. A complete case list of thoracoscopies performed in 1991 before videothoracoscopy was available provided historical comparison. RESULTS: From January 1 to December 31, 1991, 82 patients underwent thoracoscopy using a mediastinoscope for diagnosis and therapy of pleural disease. From January 1 to July 31, 1992, 160 patients (male:female = 81:79; mean age 56 years) had videothoracoscopy; 72 of 160 patients (44%) had procedures that previously would have required thoracotomy: 69 lung wedge resections, one pericardial window, one pleurectomy, one mediastinal node sampling. No major resectional procedures (e.g., lobectomy, esophagectomy) were performed by videothoracoscopy. Twenty-two percent of all patients (35 of 160), and 23% of wedge resection patients (16 of 69) required conversion to thoracotomy because videothoracoscopy was inadequate for diagnosis or staging. Reasons for conversion (multiple reasons in five patients) included further resection required in 23 patients; inability to evaluate lesion in 11; adhesions in five; and inability to tolerate one lung ventilation in two. The chest tube was in place postoperatively for a mean of 2.3 days. Thirty-day postoperative complications included ventilation for > 48 h in one patient; prolonged air leak in one; pneumonia in one; arrhythmia in one; and death from progressive disease in two. CONCLUSIONS: Although the role of videothoracoscopy in the treatment of primary thoracic malignancies and pulmonary metastases is still undefined, this early experience indicates that videothoracoscopy often enhances the ability to diagnose and stage patients by obviating thoracotomy. PMID- 7834447 TI - Variables related to risk of recurrence in rectal cancer without lymph node metastasis. AB - BACKGROUND: There has been recent interest in the use of local excision for rectal cancer under consideration of patient's quality of life. However, local excision of the primary tumor does not remove the areas of lymphatic spread. Therefore, the decision to use this procedure must be considered carefully. METHODS: The authors retrospectively analyzed 142 patients who underwent radical resection of rectal cancer without lymph node metastasis in order to define the risk factors for recurrence. The macroscopic and microscopic pathological characteristics, immunohistochemical staining for p53, and DNA ploidy pattern of the primary tumor were examined as potential predictors of recurrence. RESULTS: The rates for 5-year disease-free survival, local control, freedom from distant metastasis, and overall survival in these 142 patients were 87%, 93%, 93%, and 91%, respectively. Factors related to recurrence and prognosis included the depth of tumor invasion, vascular/lymphatic involvement, tumor differentiation, and tumor size. However, p53 staining and DNA ploidy pattern were not useful indicators. CONCLUSIONS: Our findings suggest that adjunctive radiotherapy and chemotherapy should be considered for patients who have rectal cancer without lymph node metastasis in the following situations: tumor invasion of the serosa, vascular/lymphatic involvement, moderately differentiated adenocarcinoma, and lesions > 2 cm in diameter. Local excision should not be used in these situations, even if there are no lymph node metastases. PMID- 7834448 TI - Laparoscopic colectomy for cancer: some cause for pause. PMID- 7834450 TI - Primary gastrointestinal sarcomas: analysis of prognostic variables. AB - BACKGROUND: Primary gastrointestinal sarcomas are uncommon, and the clinicopathological determinants of survival remain unclear. In order to correlate clinical presentation, pathological assessment, and treatment with outcome, we have analyzed our institution's recent experience with these tumors. METHODS: Records of adult patients admitted to our institution between July 1982 and December 1991 were reviewed. RESULTS: During this period, 38 adult patients (> 16 years of age) were admitted to our institution with a primary gastrointestinal sarcoma. They accounted for 2% of all adult sarcoma admissions during that period. The study population was composed of 26 men and 12 women. Ages ranged from 29 to 82 years (mean 59). Disease was localized to the primary site in 30 patients (81%). The stomach was the most frequent site of disease (20 cases). The small bowel was affected in nine cases (five duodenum, four jejunum) and the large bowel in nine cases (two colon, seven rectum). Ninety-two percent of patients were symptomatic at presentation. A complete resection was performed in 27 cases, incomplete resection in seven cases, and biopsy only in the remaining three patients. Nine patients received doxorubicin-based chemotherapy. Leiomyosarcoma (n = 35) was the predominant histological diagnosis. Twenty-six tumors were classified as high grade (68%) and 12 as low grade (32%). Overall actuarial 5-year survival was 28% (median follow-up 26 months). Weight loss (p = 0.02) and pain at presentation (p = 0.05) were adverse prognostic factors. Histological grade (p = 0.0002), completeness/extent of surgical resection (p = 0.005), or small bowel primary site were significant determinants of overall survival. The resection of contiguous organs did not affect survival if the primary tumor was completely excised (p = 0.422). Age, race, sex, presentation (prior surgery), tumor size, or adjuvant therapy were not significant prognostic factors. Recurrence was noted in 44% after complete resection, and mean time to recurrence was 9 months (median 7, range < 1-37). Hepatic metastases (42%) and local recurrence (42%) were the predominant sites of initial failure. For patients with a complete resection, grade was the major prognostic determinant (5 year survival: high grade/complete resection 18% vs. low grade/complete resection 72%, p = 0.002). CONCLUSION: The prognosis of gastrointestinal sarcomas is poor. Complete surgical excision is the optimal therapy. However, our results suggest that surgery alone is inadequate for high-grade tumors. We believe that these patients should be considered candidates for investigational adjuvant therapies. PMID- 7834451 TI - Laparoscopic colectomy for cancer: a favorable opinion. PMID- 7834452 TI - Internal mammary node status: a major prognosticator in axillary node-negative breast cancer. AB - BACKGROUND: The internal mammary lymph nodes (IMN) have received little attention in recent years, yet are a well-documented site of metastasis and a major prognostic factor in early-stage breast cancer. METHODS/RESULTS: Ten-year follow up of the final 195 patients treated by extended radical mastectomy (ERM) in this practice (selected largely on the basis of medial tumor location, and comprising 15% of all patients treated from 1965 to 1978) found IMN+ in 24% of all cases: 36% of AX+ versus 18% of AX- patients (p = 0.0023). In a multivariate analysis, the disease-free survival impact of IMN+ (p = 0.004) was second only to axillary node involvement (p < 0.0005), and surpassed tumor size (p = 0.077). IMN+ was equally frequent for tumors less than, or greater than, 2 cm (24%), and was not significantly related to patient age. Among AX- patients, there was a twofold greater risk of recurrence or death at 10 years for IMN+ than for IMN-. Among T1N0 patients, 19.6% were IMN+. CONCLUSIONS: Failure to consider IMN status in the steadily enlarging cohort of T1N0 breast cancers may result in the undertreatment of a significant proportion of stage I patients. Systemic adjuvant therapy should be considered for T1N0 patients with central or medial tumors. PMID- 7834449 TI - Impact of the human genome project on medical practice. AB - BACKGROUND: The Human Genome Project is a coordinated effort to define the human genetic blueprint. The goals include construction of a variety of maps of the human genome, including the identification and localization of all genes. The discovery of genes responsible for human diseases has had a significant impact on the practice of medicine. METHODS: Methods for defining the human genome include cytogenetic, physical, and genetic mapping techniques. A variety of strategies have been used to identify human genes, especially those genes that are responsible for disease. Once a disease gene has been identified, this information can be used to develop new diagnostic and therapeutic procedures. RESULTS: A number of disease genes have already been identified, leading to improved diagnosis and novel approaches to therapy. A new type of mutation, trinucleotide repeat expansion, has been found to be responsible for at least seven diseases with an unusual inheritance pattern. CONCLUSIONS: Materials and technology generated by the Human Genome Project and related research have provided important tools for the diagnosis and treatment of patients afflicted with genetic diseases. PMID- 7834453 TI - Raf-1 protein expression in human breast cancer cells. AB - BACKGROUND: The Raf-1 kinase, a 72-kDa cytoplasmic serine-threonine kinase, plays a central role as a second messenger in signal transduction. After ligand binding to a variety of transmembrane tyrosine kinase growth factor receptors including epidermal growth factor (EGF) receptor, the 72-kDa kinase is activated through phosphorylation to a 74-kDa phosphoprotein. The Raf-1 kinase is constitutively activated in many transformed cells either directly, by mutations within its amino-terminus regulatory region, or indirectly, due to overstimulation by autocrine growth factors or activated proximal oncogenes. The role of Raf-1 kinase in breast cancer has not been studied. METHODS: To investigate the role of Raf-1 kinase expression and its activation in breast cancer, we studied three human breast cancer cell lines expressing varying amounts of EGF receptor to determine the level of Raf-1 protein and the proportion expressed in the higher molecular weight form. Effects of serum starvation and stimulation with EGF on the Raf-1 protein were studied in T47D, BT474, and MDA-MB231 cells by precipitation of cell lysates with an anti-Raf-1 antibody followed by immunoblotting. [3H]Thymidine incorporation by these cells after EGF stimulation was also determined as a measure of DNA synthesis. RESULTS: In all three breast cancer cell lines studied, the Raf-1 protein was identified in a 70- and a 74-kDa form. The level of Raf-1 was similar in all three cell lines and appeared unrelated to EGF receptor expression on the cell surface. The majority of the protein was found in the 74-kDa form even after serum starvation. A minor shift from the lower to higher molecular weight form of Raf-1 was apparent in cells treated with EGF, and increased [3H] thymidine incorporation could be demonstrated in two of the cell lines after EGF stimulation. CONCLUSION: Baseline expression of the 74-kDa or activated form of the Raf-1 kinase appeared to be elevated in the breast cancer cells studied, indicating constitutive activation. Further investigation into the role of Raf-1 protein in the pathogenesis of breast cancer is indicated. PMID- 7834454 TI - Needle-localized thoracoscopic resection of indeterminate pulmonary nodules: impact on management of patients with malignant disease. AB - BACKGROUND: The efficacy and therapeutic impact of needle-localized thoracoscopic resection (NLTR) was examined in patients with cancer who present with small indeterminate pulmonary nodules (IPNs). METHODS: Between December 1991 and August 1992, 30 patients underwent needle localization of 33 IPNs under computed tomography (CT) guidance followed by thoracoscopic resection. All previous attempts to characterize these small pulmonary nodules (mean size 7.9 +/- 4.9 mm) had failed. Twenty patients had an established diagnosis of cancer 1 month to 20 years before detection of the lung abnormality, whereas the remaining patients had no prior history of cancer. RESULTS: Histology of NLTR specimens in patients with a previous diagnosis of malignancy included 13 malignant and seven benign lesions. In all patients with cancer, therapeutic decisions were influenced by NLTR results. Thoracoscopic related complications were noted in two patients. Average length of hospital stay for NLTR was 6.7 +/- 3.9 days. CONCLUSION: NLTR in this series has proven to be a safe, well-tolerated, and accurate method for diagnosing and influencing the management of recently identified IPN. NLTR appears warranted for small pulmonary nodules not amenable to less invasive diagnostic modalities. PMID- 7834455 TI - Complications of thyroid surgery. AB - BACKGROUND: The morbidity of thyroid surgery is low. Despite this, some authors advocate a subtotal thyroidectomy instead of a total thyroidectomy, to avoid the higher morbidity associated with a total thyroidectomy. METHODS: We retrospectively evaluated the complications of thyroid surgery in Leiden between January 1, 1982 and October 1, 1990. Three hundred forty-one patients--261 women and 80 men--had 356 operations; 15 patients were operated on twice; there were 152 total hemithyroidectomies, 3 subtotal hemithyroidectomies, 33 total thyroidectomies, 122 bilateral subtotal hemithyroidectomies, 12 combinations of total and subtotal hemithyroidectomies, and 34 other operations. RESULTS: Calculated for the nerves at risk (n = 489), the percentage of permanent recurrent nerve lesions was 3.1 (in the 5 most recent years it was 1.2%). There was no significant difference between total or subtotal (hemi)thyroidectomies. Initial symptomatic hypocalcemia necessitating supplementation was encountered 42 times (12.5%). The occurrence of permanent symptomatic hypocalcemia (6%) was not significantly different between total and subtotal (hemi)thyroidectomies (p = 0.06). The duration of surgery was 137.8 min for bilateral subtotal thyroidectomies and 182.9 min for bilateral total thyroidectomies (p < 0.0001). There was no difference in blood loss between total and subtotal (hemi)thyroidectomies. CONCLUSIONS: Because total thyroidectomy carries a risk of complications similar to that for subtotal thyroidectomy, it is not logical to avoid total resections. If the number of total resections were increased, it is anticipated that fewer reoperations, which involve a relatively high morbidity rate, would have to be performed. PMID- 7834456 TI - Use of laparoscopic techniques in oncologic right colectomy in a canine model. AB - BACKGROUND: The purpose of this study was to evaluate the feasibility of laparoscopic oncologic righ colectomy (RC) with intraperitoneal ileocolic anastomosis (ICA) in a canine model. METHODS: In 21 dogs a laparoscopic RC with transection of the main right colic artery and removal of adjacent lymph nodes (LN) was carried out using an Nd:YAG contact laser and endoscopic stapler. Two weeks after surgery, all animals were killed. The number of remaining right colon mesenteric LN, length of remaining right colic artery, bursting pressure (BP) of ICA, and postoperative morbidity were evaluated. RESULTS: No major intraoperative complications were recorded. One dog died of pneumonia and heartworms. There were no postoperative septic or anastomotic complications. All dogs passed feces within the first 24 h postoperatively. Median operative time was 135 min (range 105-180 min). Length of remaining right colic artery after oncologic resection was 4.5 mm (range 3-7 mm), the number of remaining LN was 0, and the median anastomotic BP was 232 mm Hg (range 132-312 mm Hg). CONCLUSION: Oncologic resection of the right colon with high vascular ligation, wide mesenteric clearance of LN, and intraperitoneal anastomosis is feasible and safe in a canine model. PMID- 7834457 TI - Isolation perfusion in extracorporeal circulation with interleukin-2 and lymphokine-activated killer cells in the treatment of in-transit metastases from limb cutaneous melanoma. AB - BACKGROUND: Therapies of advanced melanoma patients with interleukin-2 (IL-2) and cytotoxic lymphocytes have produced interesting results, but a larger diffusion of these treatments is limited by the severe side effects due to IL-2 systemic infusion. A strictly regional administration of IL-2 and cells by an isolation perfusion (IP) in extracorporeal circulation (ECC) for the treatment of regional melanoma metastases could improve tolerability and efficacy of this specific modality of immunotherapy. METHODS: Ten patients were submitted to adoptive immunotherapy with IL-2 and lymphokine-activated killer (LAK) cells by IP in ECC. The schedule of treatment included the first course of a 5-day systemic administration of IL-2 (Proleukin, EuroCetus 9-12 x 10(6) IU/m2/day continuous infusion); autologous LAK cells were obtained via leukapheresis and after in vitro activation were given (range 8-28 x 10(9)) along with IL-2 (120-2,400 IU/ml of perfusion priming) to the affected limb by IP; IL-2 (9-12 x 10(6) IU/m2/day) was also administered by systemic continuous infusion for 5 days starting on the day after IP. RESULTS: All patients concluded the treatment without any major local or systemic toxicities. Clinical responses included one complete and six partial remissions; three patients had stable disease. All patients are alive. Follow-up after IP ranged from 12 to 35 months (median: 22). The analysis of circulating lymphocytes revealed the rapid disappearance of LAK cells, suggesting their extravasation and/or endothelial adhesion in perfused tissues. CONCLUSIONS: IP with IL-2 and LAK cells is a new approach for the treatment of in-transit metastases due to cutaneous melanoma. The treatment appears to be feasible and reliable. Further biological and immunological studies should permit amelioration of the present modality of treatment. PMID- 7834458 TI - Advances in the treatment of early- to late-stage colorectal cancer: 20 years of progress. AB - BACKGROUND: Numerous scientific and clinical advances have made significant changes in our understanding of the etiology of colorectal cancer and in the diagnosis and treatment of patients with large bowel malignancy or its precursor lesions. METHODS: A personal view of 20 years of progress was presented at the Commission on Cancer lecture during the 1993 Clinical Convocation of the American College of Surgeons. RESULTS AND CONCLUSIONS: Improvement in the diagnosis and treatment of early bowel cancers, significant benefit from multimodality therapy of more advanced resectable bowel cancers, and better articulated selection criteria in patients with recurrent colorectal cancers are reviewed. Most importantly, both physical and emotional consequences of our therapies are shown to have diminished without sacrificing the ability to cure. Perhaps the next major challenge is for the general surgeon to assume responsibility as the primary medical manager of any patient with gastrointestinal cancer from the time of diagnosis onward. PMID- 7834459 TI - Replacement level fertility and future population growth. AB - 'Replacement level fertility' is a technical term which seems almost self explanatory. However there are some important qualifications which make it a more difficult concept than might be supposed. Also, the relationship between replacement level fertility and zero population growth is complicated. The article explains why this is so and thus why, although the United Kingdom's current level of fertility is below replacement level, population is projected to grow for the next thirty years. PMID- 7834461 TI - 1991 Census of Great Britain: summary of results. AB - All the scheduled Topic Statistics Population Statistics reports from the 1991 Census are now published. This article illustrates the Census range of statistics contained in these reports, making some comparisons with results from the 1981 Census for those topics where there are comparable figures. PMID- 7834460 TI - Spatial variations in ethnic minority group populations in Great Britain. AB - This article is concerned with contrasts in the geographical distribution of people from the white and ethnic minority groups within Great Britain. It begins by describing regional variations in ethnic composition and maps the distribution of ethnic minority groups at the local authority district scale. The article then demonstrates that most people from the white ethnic group live in wards with very small populations from ethnic minority groups, while people from ethnic minority groups tend to be found where the share of minorities in the resident population is relatively high. The focus then switches to the neighbourhood (enumeration district) scale, at which a very marked degree of spatial segregation in the distribution of ethnic groups is revealed. The local authority districts in which the degree of segregation of people from ethnic minority groups relative to the rest of the population is greatest are listed. PMID- 7834462 TI - Asthma, the changing scene? AB - This short article looks at the changes in the rate of asthma episodes reported to the Birmingham Research Unit of the Royal College of General Practitioners. The general perception is that the incidence of asthma is on the increase and is worse in summer than previously thought. The data do not support such a view. The reported incidence of asthma is increasing, there is a peak in summer, but that has been so for several years, and the June peak of 1994 was not as high as that of 1992. PMID- 7834463 TI - Estimated numbers of one-parent families and their prevalence in Great Britain in 1991. AB - This article gives the final estimate of the number of one-parent families in Great Britain in 1991--1.3 million--and a provisional estimate--of 1.4 million- for 1992. It also estimates that there were 2.2 million dependent children living in one-parent families in 1991, and provides a provisional estimate for 1992 of 2.3 million. Overall, in 1992, about one in five families with dependent children was a one-parent family and about one in five of all dependent children lived in a one-parent family. The article also examines the family sizes of one-parent families; the profiles by marital status of both lone mothers and lone fathers; the ages of lone parents and of their dependent children, and the geographical variation in the prevalence of lone parenthood within Great Britain in 1991. Finally, census data on the family composition of households are examined to investigate the extent to which lone parent families live in multi-family households, and the relationship between the lone parent and the head of the other main family in the household. PMID- 7834465 TI - Organ and functional preservation in the management of genitourinary cancer: bladder, prostate, and penis. PMID- 7834464 TI - Efficacy of postoperative 5-FU, high-dose leucovorin, and sequential radiation therapy for clinically resectable rectal cancer. AB - We report the local control and survival in a previously reported phase I dose escalation trial of combined postoperative 5-FU, high dose leucovorin (LV), and sequential radiation therapy followed by maintenance LV/5-FU for the treatment of patients with clinically resectable rectal cancer. Following surgery for stages T3-4N0-2M0 primary (21) or recurrent (4) rectal cancer, 25 patients received 5 FU/LV x 1 cycle. Radiation therapy (5040 cGy) began on day 8. A second cycle of 5 FU/LV was given concurrent with the fourth week of radiation. Patients received an additional 10 cycles of LV/5-FU. The median follow-up was 40 months (range 18 52). The incidence of grade 3+ acute toxicity in the 9 patients who received the recommended dose of 5-FU was 44%. The local failure rate was 28%. Abdominal and distant failure rates were 24%. The 3-year actuarial disease-free survival was 74% and the overall survival was 80%. Our preliminary data reveal reasonable local control and survival rates. However, further follow-up is needed to assess our results at 5 years. Postoperative combined modality therapy with high-dose LV may be an option for the adjuvant treatment of patients with resectable rectal cancer. PMID- 7834466 TI - Preservation of function in genitourinary cancers: psychosexual and psychosocial issues. AB - GU cancers are commonly associated with treatment-related sexual dysfunction, varying from mild to severe. For the clinical oncologist, it is important to be aware that sexual problems or sexual dysfunction may occur as a result of any aspect of cancer and cancer treatment. Sexual function is sensitive to the effects of trauma, both physical and emotional. This is particularly the case for patients whose cancer affects their genitals. Despite some commonalities of psychosocial and psychosexual issues in GU patients across diagnostic categories, GU patients do not present as one distinct, homogeneous group. GU neoplasms, with the exception of bladder cancer, affect mostly men. Men and women tend to differ in their ways of dealing with emotional distress and physical illness. While the man may typically do well using denial as a defense and may not want to discuss his feelings about his diagnosis and treatment, his partner may suffer if her way of coping is oriented toward communicating thoughts and feelings about the situation. Another important difference in this population is related to age and developmental differences. Testicular cancer typically is diagnosed in young men between the ages of 15 and 34 (46). The patients often still live with their parents or have just formed families of their own. In contrast, prostate cancer is diagnosed in older men, who are at a completely different stage in their lives when they have to deal with this challenge. Developmental stage at the time of diagnosis and treatment is an important variable in adaptation to cancer (47). Since GU malignancies and their treatments directly or indirectly affect sexual organs and sexual functioning, issues of sexual body image and identity as men or women are frequent concerns for GU patients. This is most obviously the case for men facing penectomy or orchiectomy. Similarly, women undergoing cystectomy with its simultaneous removal of uterus, ovaries, and parts of the vaginal wall face issues regarding their femininity as well as doubts about future sexual functioning. However, body image concerns are not limited to these two groups but may affect any cancer patient. The experience of having lost all hair due to chemotherapy, bearing of surgical scars, lost or altered functioning, and just the realization of having had cancer may change the way a patient feels about his/her body permanently.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7834467 TI - On neoadjuvant hormonal downsizing of localized carcinoma of the prostate: effects on the volume of normal tissue irradiation. PMID- 7834468 TI - Chemotherapy in locally advanced, squamous cell head and neck cancer: limitations, lessons learned, and evolving standards of care. PMID- 7834469 TI - Soft tissue sarcomas of the extremities: continuing challenges for a multidisciplinary team. PMID- 7834470 TI - Symptomatic acute mucositis can be minimized or prophylaxed by the combination of sucralfate and fluconazole. AB - Mucositis is a common and often serious acute morbidity when radiation is delivered to portals encompassing the oral cavity, pharynx, or esophagus. In an effort to minimize this side effect, the combination of sucralfate and fluconazole was prescribed to 40 patients. Half were given sucralfate, 1 g in suspension q.i.d. from the first week to the completion of radiation with fluconazole 100 mg., q.d. for 14 days initiated during the fourth week. The remaining individuals were placed on the same dosages of the two drugs dispensed simultaneously after symptoms appeared. For both cohorts the combination of sucralfate and fluconazole was effective in diminishing oral discomfort and pain associated with radiation and chemotherapy. When medication was delivered from the first week of therapy, all patients could achieve the prescribed radiation dose without treatment interruption and be maintained on a regular diet. The combination of drugs was also effective in minimizing symptoms once they appeared. PMID- 7834471 TI - Congruence of SQM1 protein expression with methotrexate sensitivity and transport. AB - Expression of SQM1 protein, a membrane protein, was shown to be reduced in human squamous carcinoma of the head and neck (SqCHN) cell lines made less sensitive to methotrexate (MTX). High correlation of SQM1 protein expression with MTX transport (r = .94) and MTX sensitivity (r = .94) was found in MTX-resistant sublines developed from a clonally drived SqCHN cell line, SCC 15S1. Unlike SQM1 protein, there was no significant difference in amount or molecular weight of reduced-folate binding protein found in the membrane of a MTX-resistant subline, SCC15R1-3 and SCC15S1. Furthermore, MTX surface membrane binding was not significantly altered in SCC15R1-3. Compared to SCC15S1 parent cell line, SCC15R1 3 subline with similar DHFR enzyme level and MTX polyglutamylation showed a marked reduction in MTX uptake due to a decrease in Vmax without a significant change in Kt. These findings suggest the existence of membrane molecules like SQM1 protein that may indirectly affect MTX transport. PMID- 7834472 TI - A phase II study of continuous infusion of trimetrexate in patients with refractory acute leukemia. AB - Trimetrexate, a second-generation folate antagonist, is a potent inhibitor of dihydrofolate reductase with a broader spectrum of activity and different mechanism of entry and intracellular accumulation than methotrexate. Six patients with refractory or relapsed acute leukemia were treated with a 5-day continuous infusion of trimetrexate of 8 mg/m2/day after an initial loading dose of 4 mg/m2 to achieve a target plasma concentration of 0.2-0.5 microM. In 4 patients with peripheral blasts at study entry, transient decrease or disappearance of blasts was observed, although no decrease of bone marrow blasts occurred. Mucositis was dose-limiting and severe in 4 patients. Neutrophil and platelet nadirs occurred on day 5-12 postinfusion. Because of dose-limiting mucositis, this dose schedule of trimetrexate is not recommended for further studies in refractory acute leukemia. However, other dose schedules (24- to 72-hr infusions) and its use as a modulating agent with thiopurines or leucovorin in patients that are resistant to methotrexate should be explored. PMID- 7834473 TI - Head and neck cancer: present status and future prospects of adjuvant chemotherapy. AB - For more than 15 years, active clinical research and continuing efforts in the field of CT in head and neck cancer have produced a modest but definite progress and achievements in this disease. We are a long way away from producing more definitive and acceptable results and higher cure rates in this disease. The achievements of systemic CT in patients with head and neck cancers are summarized in this review. Continuing efforts and investigation are needed to study the efficacy of systemic CT in patients with resectable head and neck cancer. We are continuing to investigate the best timing and sequence of CT as part of CMT and then the efficacy of such treatment in patients with resectable cancer. Efforts are underway to improve on the results in patients with NPC and patients with unresectable disease with the use of chemotherapy as part of CMT. Efforts are also underway to consolidate and improve on the results obtained with systemic CT to preserve laryngeal function. We strongly believe that with continuation of these serious efforts further achievement and impact can be obtained with systemic CT as part of other modalities in these patients. PMID- 7834474 TI - Preservation of organ and function in the treatment of laryngeal cancer. PMID- 7834475 TI - Organ and functional preservation in the management of cancers of the eye and eyelid. PMID- 7834476 TI - Organ and functional preservation in the management of breast cancer. AB - Breast conservation surgery combined with radiation therapy has established itself as a good alternative to mastectomy for patients with stage I and II breast cancer. This method can also be used to treat patients with DCIS. Careful clinical, mammographic, and pathological evaluations are essential for appropriate selection of patients for breast conservation treatment. Particular attention must be paid to the application of skillful surgical and radiotherapeutic techniques in order to achieve satisfactory long-term control, survival, and cosmetic results. Adjuvant chemotherapy may be used when indicated. The integration of chemotherapy with radiation therapy may be sequential or concurrent, but the optimal method of integration has not yet been determined. PMID- 7834477 TI - Neoadjuvant hormonal downsizing of localized carcinoma of the prostate: effects on the volume of normal tissue irradiation. AB - A prospective evaluation of neoadjuvant hormonal downsizing in patients with localized carcinoma of the prostate was undertaken to assess its effect on normal tissue irradiation. Twenty patients with stage T1 or T2 (A, B) carcinoma of the prostate received 3 months of Lupron prior to definitive radiotherapy. The volumes of the prostate, seminal vesicles, bladder, and rectum from both the pre- and posthormone treatment planning CT were entered onto a 3-D treatment-planning system. The treatment planning parameters were standardized to facilitate comparison of the pre- and posthormonal volumes. Following the three monthly injections of Lupron, the average volume of the prostate was reduced by 37%. As a consequence, the volume of the bladder receiving at least 40, 52, and 64 Gy was reduced by an average of 15, 18, and 20%, respectively. In addition, the volume of the rectum receiving at least 40, 52, and 64 Gy was reduced by an average of 13, 20, and 34%, respectively. In conclusion, in patients with localized prostate cancer, downsizing of the prostate resulted in a reduction in the volume of bladder and rectum receiving high radiation doses. This approach may result in an improvement in the therapeutic ratio by reducing the morbidity of treatment. PMID- 7834478 TI - Combined surgery and radiation therapy for limb preservation in soft tissue sarcoma of the extremity: the Massachusetts General Hospital experience. AB - The results presented here indicate that excellent local control rates can be achieved using radiation in combination with limb-sparing surgery. At least three challenges remain and need to be addressed in future prospective trials. One is the need to reduce wound complications. In this regard, the influence of chemotherapy on the healing of the irradiated wound needs to be better defined as well as the role of recombinant growth factors and cytokines in tissue repair. Second is the need to better assess functional and psychological outcome in patients who are long-term survivors as well as in patients who succumb to distant disease. Despite the limited information on this end-point, it appears that strategies that reduce wound morbidity ultimately have a beneficial outcome with regard to functional and psychological status. Third, our greatest challenge is to improve the rates of distant disease control. Despite excellent local control rates following limb-sparing procedures, greater than 50% of patients will ultimately die of their disease. New systemic therapies must be developed to control systemic dissemination. The ultimate goal of combined surgery, radiation, and chemotherapy will be to preserve limb function in patients who are cured of their disease. PMID- 7834479 TI - Organ and functional preservation in the management of anorectal cancers. PMID- 7834480 TI - The radiologic report: a realistic approach. AB - The radiologic report records all of the important steps taken in the practice of radiology and should be evaluated with special interest. The literature reflects the subjectivity inherent to a field left to personal interpretation, and few prospective studies of radiologic reporting are available. To determine the characteristics of the ideal radiologic report, the authors held workshops with two groups of radiologists and residents in radiology. The following items (in order of priority) were considered of prime importance by the participants and are discussed here: expression of an opinion and presentation of a workable differential diagnosis; an answer to the referring physician's question; a list of the limitations of the examination, if any; open-ended recommendations to the referring physician; integration of the findings with the clinical context; a synthesis of the findings obtained with various imaging modalities, when pertinent; and a complete description of the findings. The radiologic report has been compared to a scientific paper, and this comparison suggests the format for bringing these items together. The resulting realistic blueprint for the ideal radiologic report can be tailored to fit every imaging situation. Moreover, it can be a useful tool for evaluating the whole imaging process. PMID- 7834481 TI - Thoracic manifestations of ovarian hyperstimulation syndrome. AB - OBJECTIVE: To determine the thoracic manifestations of severe ovarian hyperstimulation syndrome, the major serious complication of induction of superovulation with exogenous gonadotropins. PATIENTS AND METHOD: The authors reviewed the medical records and available images for 771 patients who had received gonadotropins to induce superovulation for in-vitro fertilization and embryo transfer or intrauterine insemination of concentrated sperm. The patients, ranging in age from 28 to 43 years, had been treated between October 1990 and July 1992. RESULTS: In 22 patients (3%) severe hyperstimulation syndrome was diagnosed clinically and confirmed with ultrasonography. Pleural effusion occurred in five of these (23%), one of whom required thoracentesis. Atelectasis, associated with adult respiratory distress syndrome (ARDS) and internal jugular vein thrombosis, developed in one patient, and ventilation-perfusion mismatch of uncertain cause occurred in another. CONCLUSIONS: Respiratory distress in patients with ovarian hyperstimulation syndrome is most likely due to lung restriction caused by ascites, the large cystic ovaries, or pleural or pericardial effusion. Pulmonary embolism and ARDS may rarely occur. Pulmonary manifestations, not previously well recognized, form an important part of this syndrome, and radiologic input with regard to assessment, monitoring and management are needed. PMID- 7834482 TI - Reducing the concentration of contrast medium in dynamic computed tomography of the neck: consequences for image quality, side effects and cost. AB - OBJECTIVE: To determine the efficacy of two concentrations of nonionic contrast medium (320 and 240 mg iodine/mL; Optiray [ioversol], Mallinckrodt Medical) for enhanced dynamic computed tomography (CT) of the neck. PATIENTS AND METHODS: Between March 1992 and August 1993, 50 patients undergoing dynamic CT of the neck were assigned randomly to receive either the higher-strength or the lower strength contrast agent. The amount of opacification was measured objectively, and the quality of the scans was assessed subjectively by two radiologists without knowledge of which contrast agent had been administered. Both immediate and delayed side effects were recorded. RESULTS: The higher-strength contrast medium gave greater opacification (p = 0.0006, t-test), but both concentrations yielded images of excellent quality (p = 0.125, chi 2 test). The number of patients affected by immediate minor complications was lower with Optiray 240 (11 [44%]) than with Optiray 320 (23 [92%]) (p < 0.001, chi 2 test). The number of patients affected by delayed side effects was similar in the two groups (7 [28%] with Optiray 240 and 9 [36%] with Optiray 320; p > 0.70, chi 2 test). No predictive relation between immediate and delayed complications was observed. CONCLUSIONS: Because adequate contrast can be obtained with the lower-strength contrast medium, it can be used in dynamic CT of the neck as a means of reducing the cost and the side effects associated with such imaging. PMID- 7834483 TI - Insertion of subcutaneous central venous infusion ports by interventional radiologists. AB - OBJECTIVE: To evaluate the safety and efficacy of radiologic implantation of subcutaneous chest wall infusion ports by interventional radiologists, rather than surgeons, at a tertiary care hospital. PATIENTS AND METHODS: Review of radiology department and hospital records for 38 patients (ranging in age from 21 to 70 years), in whom a total of 41 infusion ports had been inserted between January 1992 and January 1994. RESULTS: All of the implantations were successful. The only acute complication was pneumothorax, which occurred in one patient; insertion of a chest tube was required. There were no cases of hematoma, air embolism or arterial puncture. The infusion ports remained in place for 12 to 492 days (for a mean of 167 catheter days per patient). Total follow-up was 6863 catheter days. The overall incidence of catheter-related infection was 1.3/1000 catheter days; removal of the port was necessary in eight cases. Occlusion of the catheter occurred in two cases, one after 21 days and the other after 308 days. Neither migration nor fracture of the catheter tip occurred. Overall, removal of the port was required because of catheter-related complications in nine cases (22%); in these cases the port was removed after a mean of 181 (range 21 to 420) days. CONCLUSIONS: Because the success and complication rates observed here were similar to those reported for insertions performed in the operating room, the authors conclude that central venous infusion ports can be safely and efficiently implanted by interventional radiologists. PMID- 7834484 TI - Magnetic resonance imaging of paraganglioma of the cauda equina. AB - The authors describe atypical magnetic resonance imaging (MRI) findings for pathologically proven paraganglioma of the filum terminale in a 27-year-old man. MRI showed an intradural tumour, which enhanced after administration of gadolinium and which showed evidence of cystic areas. Hemosiderin rings and vessels were not observed. PMID- 7834485 TI - Intracranial mycotic aneurysm in a patient with endocarditis caused by Cardiobacterium hominis. AB - An intracranial mycotic aneurysm developed in a 35-year-old woman with endocarditis, caused by Cardiobacterium hominis, around a prosthetic valve. This type of aneurysm is a rare, life-threatening entity, and C. hominis is extremely uncommon as the causative agent. The pathogenesis and monitoring of intracranial mycotic aneurysm are discussed. PMID- 7834486 TI - Breast abscess as a late complication of plombage. AB - The authors describe a patient who had undergone plombage as a treatment for tuberculosis approximately 40 years previously and who presented with a breast abscess secondary to migration of the plombage material. This complication of plombage, which has not previously been reported, was demonstrated by computed tomography. PMID- 7834487 TI - Small-cell carcinoma of the esophagus with regression after combination chemotherapy and radiation therapy. AB - The authors present an unusual case of small-cell carcinoma of the esophagus, which manifested on double-contrast esophagography as an ulcerated submucosal mass. The lesion underwent dramatic regression after combination chemotherapy and radiation therapy, which has occasionally been used as an alternative to surgery in patients with this rare but aggressive esophageal neoplasm. PMID- 7834488 TI - Multiple pulmonary nodules as a manifestation of cat-scratch disease. AB - Cat-scratch disease is an unusual bacterial illness that only rarely shows pulmonary involvement. The authors describe a 19-year-old woman with chronic renal failure who presented with multiple pulmonary nodules, a previously undescribed manifestation of cat-scratch disease. PMID- 7834489 TI - Osteogenic sarcoma metastatic to the kidney: spontaneous subcapsular hemorrhage with renal artery thrombosis. AB - The authors describe an occult metastatic deposit in the kidney of a 22-year-old woman; such lesions are not usually detected until autopsy. They postulate that after the development of acute subcapsular hematoma, a "renal compartmental syndrome" occurred, leading to renal artery thrombosis. Primary vascular involvement by the metastatic osteosarcoma, which was remote from the renal hilus, was not identified pathologically. PMID- 7834490 TI - Primary renal artery dissection. AB - A typical case of primary renal artery dissection, an unusual entity causing renal infarction, is described. This abnormality, masquerading as renal colic, affects otherwise-healthy middle-aged men. Angiography, which will confirm the diagnosis, should precede nephrectomy, because vascular repair may be feasible. PMID- 7834491 TI - Gastrointestinal perforation or vascular injury? A diagnostic dilemma for computed tomography in blunt abdominal trauma. AB - The authors describe an unconscious 20-year-old woman with Crohn's disease who was examined after a motor vehicle accident. During dynamic computed tomography after intravenous and oral administration of contrast material, contrast agent was observed in the peritoneal cavity. The source of the free contrast material was active bleeding, but it was initially mistaken for extravasation from the bowel. Exploratory laparotomy revealed transection of the superior mesenteric vein. PMID- 7834492 TI - Residents' corner. Answer to case of the month #29. Atherosclerotic aneurysm of the left subclavian artery. PMID- 7834493 TI - Tendon injuries: application of magnetic resonance imaging. AB - More people of all ages are now spending more time participating in sports, both competitive and recreational. This increase in participation has been accompanied by an increase in the number of tendon injuries. Tendons can also be injured during trauma, as part of degenerative disease and with chronic overuse. Magnetic resonance imaging (MRI) has greatly improved the ability to detect and characterize these injuries. The MRI appearance of several important tendons, in both the normal state and after injury of various types, is described and depicted in this review. PMID- 7834494 TI - [Mechanism of sorting of secretory proteins and formation of secretory granules in neuroendocrine cells]. AB - We have investigated the mechanism by which constitutive and regulated secretory proteins are sorted in the trans Golgi network (TGN). Although this mechanism is believed to involved the selective aggregation of regulated secretory proteins, the factors responsible for the formation of these aggregates, which can be detected by electron microscopy as electron dense material in the lumen of the TGN, were unknown. The mechanism involved in the sorting of these aggregates to secretory granules is also poorly understood. Concerning the first point, the study of the aggregation of two regulated secretory proteins, chromogranin B and secretogranin II (granins) in the neuroendocrine cell line PC12 showed that a decrease in pH and an increase in calcium concentration in the TGN as compared to the more proximal compartments of the secretory pathway are sufficient to trigger the selective aggregation of the granins in this compartment. Results on the aggregation of the granins in the TGN of the pituitary GH4C1 cells in which the level of synthesis of regulated secretory proteins can be manipulated also suggested a role of protein concentration in the aggregation process. Finally, since granins aggregates in the TGN of PC12 cells largely excluded glycosaminoglycan chains which served as constitutively secreted bulk flow markers, we concluded that the selective aggregation of regulated secretory proteins, triggered by the specific luminal milieu of the TGN, is a crucial step in their segregation from constitutive secretory proteins. Concerning the second point, we studied the role of the single, highly conserved disulfide bond in chromogranin B on its sorting to secretory granules. We showed that reduction of this disulfide bond by incubation of intact PC12 cells with the membrane permeable thiol reducing agent dithiothreitol (DTT) causes the missorting of chromogranin B to the constitutive secretory pathway. This treatment only slightly decreased the intracellular storage of secretogranin II, which lacks cysteine, into secretory granules. We found that the effect of DTT on chromogranin B, which was already known to prevent disulfide bond formation in the endoplasmic reticulum, occurred in the TGN. We concluded that the sorting, in the TGN, of chromogranin B to secretory granules is dependent upon the integrity of its disulfide bond and that DTT treatment in vivo is as valuable tool to study the post-endoplasmic reticulum traffic of disulfide bond containing proteins. PMID- 7834495 TI - [Calcium-dependent regulated secretion is controlled by GTPase Rab3 in neuroendocrine cells]. AB - Changes in intracellular free calcium concentration ([Ca2+]i) play a fundamental role in the regulation of hormone secretion by endocrine and neuronal cells. The increase in [Ca2+]i is one of the principle events in stimulus-secretion coupling. Secretory phenomena are subjected to modulation via a large number of intracellular factors which can act on vesicular transport, exocytosis or endocytosis. Among these factors are proteins able to bind and hydrolyse the nucleotide GTP belonging to the ras superfamily of small GTPases (or superfamily of small G proteins). GTPases of the Sec4/Ypt1/Rab family have been implicated in the regulation of intracellular vesicle traffic. A role for Rab3 in regulating secretion was initially proposed because of its specific expression in the nervous and endocrine systems, and its association with secretory vesicles. The function of Rab3 has been studied in two types of neuroendocrine cells: the anterior pituitary lactotroph cells and the adrenal medulla chromaffin cells. Two techniques were combined: intracellular injection of antisense oligonucleotides and recombinant proteins, followed by membrane capacitance measurements. The inhibition of Rab3b synthesis in lactotroph cells by antisense oligonucleotides provokes an inhibition of exocytosis. On the other hand, injection of antisense oligonucleotides directed against rab3a into chromaffin cells led to a stimulation of the secretory response to successive depolarizations of the cell membrane. These results indicate that Rab3 proteins control the calcium-dependent secretory process in neuroendocrine cells. In lactotroph cells Rab3b seems to play a stimulatory role, whereas Rab3a acts as a negative regulator of catecholamine release in chromaffin cells. PMID- 7834496 TI - [Parotid gland in rats, a model for the study of regulated exocrine secretion]. AB - In rat parotid glands protein secretion studied in vitro is weakly stimulated by carbachol (which induces Phospholipase C activation) and strongly by isoprenaline (which activates the adenylate cyclase system). We show in this work that the simultaneous activation of the two types of receptors induces a potentiation of protein secretion. This is not due to an enhanced IP3 or cAMP accumulation nor any modification on calcium movements. Potentiation of protein secretion is also mimicked by analogues of second messengers suggesting that this phenomenon is a post-receptor event which takes place at a distal step from messenger production. Furthermore we also showed that the activation of beta-adrenergic receptor led to two parallel events: cAMP accumulation and calcium movements. These two events were required to obtain maximal secretion. We also show that cholinergic induced secretion is also the result of a synergism between calcium and protein kinase C activation. At a physiological level, the synergism between two different transduction pathways must play an important role. This surely allows the cells to give maximal response, without any desensitization phenomena. PMID- 7834497 TI - [In vitro study of clastogenic properties of nitrites and nitrates]. AB - In vitro culture of peripheral blood lymphocytes has been used to evaluate the ability of nitrates (NaNO3) and nitrites (NaNO2) to produce chromosome aberrations in mammalian cells. Whereas treatment with NaNO3 did not increase the spontaneous yield of aberrations, exposure to high doses of NaNO2 resulted in an low increase of micronucleated cells and of chromatid gaps. PMID- 7834498 TI - [Expression of cytokine messenger RNA in murine placenta]. AB - The expression of the cytokine genes in normal placenta was studied using RT-PCR method capable of detecting low levels of mRNA. Total RNA was prepared from placenta of specific pathogen-free BALB/c mice at the 16th day of gestation by acid guanidinium thiocyanate-phenol-chloroform (AGPC) method. cDNA was synthesized by M-MLV reverse transcriptase, and amplified using the specific oligonucleotide primers for IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, TNF-alpha, IFN alpha, IFN-beta and IFN-gamma by PCR method. IL-1 beta, IL-6, TNF-alpha, IFN alpha, IFN-beta and IFN-gamma mRNA were detected in all the placentas tested. On the other hand, the expressions of IL-2, IL-3, IL-4, and IL-5 mRNA were not detected at all. These results suggest that these cytokines may play a role in the evolution of pregnancy. PMID- 7834499 TI - [Possible existence of non-identified anti-leukemic factor in the crude sampling of natural human interferon gamma]. AB - Human natural interferon gamma (IFN-gamma) exerts differentiating and cytocidal effects in vitro on the human myeloblastic leukemia cell line ML-2. The anti leukemic effects of the crude preparation of IFN-gamma are more intensive than those of the mixture of purified IFN-gamma, IFN-alpha, tumor necrosis factor alpha and lipopolysaccharide, suggesting existence of an unknown anti-leukemic factor in the crude IFN-gamma sample. PMID- 7834500 TI - [Influence of brain grafts on growth restoration of snail (Helix aspersa) deprived of the midbrain]. AB - Microsurgical removal of the mesocerebrum from the brain of juvenile snails stopped their growth whereas intracerebral implantation of desheathed cerebral ganglia (CG) re-established it. When the animals were grafted with CG from very young snails growth was much more stimulated than with CG from donors of the same age or from adults. Furthermore, young CG of juvenile fast growing specimens of the large species (Helix aspersa maxima) induced a higher growth rate than the CG of the ordinary small garden snails (Helix aspersa aspersa). Labelling of the neural grafts with the vital fluorescent dye fast blue enabled us to follow the repopulation of the lesioned area of the brain of the host during the functional integration of the implanted neurons into the circuits that control growth in snails. PMID- 7834501 TI - [Increase of 5'-nucleotidase activity in liver plasma membranes during fasting in the rat]. AB - The effect of fasting on 5'-nucleotidase activity was assessed in microsomes and purified plasma membranes from rat liver. The microsomal 5'-nucleotidase activity (mean value: 0.062 mumol/min/mg protein at 37 degrees C in the fed rat) is increased about twice in the fasted rat (mean values: 0.11, 0.125 and 0.11 mumol/min/mg protein after 24, 48 and 72 hours of fasting, respectively). This result was further confirmed after separation of plasma membranes from the bulk of microsomial membranes by sucrose gradient centrifugation. The results are discussed with respect to the phosphatidylinositol glycan-mediated anchoring of the ectoenzyme to the cell membrane and to the putative biological effect of extracellular adenosine on the liver metabolism. PMID- 7834502 TI - [Paul Rossignol (1923-1994)]. PMID- 7834503 TI - [A model of phenotypic plasticity: the hypothalamo-posthypophyseal neurons]. AB - In neurons, which are post-mitotic cells, a structural and biochemical plasticity occurs, namely for the mediators. The magnocellular hypothalamic neurons innervating the neural lobe are a favourable model for the study of the dynamic aspects of neuropeptides expression. In fact, they synthetize these peptides in large amounts, as a function of the physiological or experimental conditions. In addition to the major neuropeptides, oxytocin (OT) and vasopressin (VP) which are contained in control rats within different neuronal populations, immunocytochemistry and in situ hybridization used alone or in combination in the same preparations have revealed other neuropeptides and corresponding mRNAs respectively. These multiple labellings demonstrate that after osmotic stimulation or during lactation some neurons are able to synthetize OT and VP simultaneously, together with galanin and even tyrosine hydroxylase (but not catecholamines). Similarly, hypophysectomy or transection of the pituitary stalk differentially modify the contents in mRNA coding for VP, OT and galanin. These results have also been described in other neuronal types such as spinal ganglia sensory neurons, suggesting possible mechanisms at different levels of genetic expression: transcription, translation, post-translational events and possibly interneuronal exchanges of mRNA. The in vivo regulation of this neurochemical plasticity probably involves the innervation of these neurons and perhaps the colocalized peptides themselves. In fact, galanin selectively inhibits the expression of VP but not that of OT. Functional implications of the neuronal phenotypic plasticity in the adaptation of the nervous system to the changing physiological conditions are discussed, together with its possible implications in pathology and therapeutics. PMID- 7834504 TI - [Cutaneous immune system]. AB - The skin is not only a physico-mechanical barrier between the environment and the body, but it also functions as an immune organ. The immunological function of epidermis is principally linked to the presence in this tissue of a distinct subpopulation of dendritic cells: the Langerhans cells (LC). LC constitute 2-4% of epidermal cell population and within epidermis they are the only cells which express MHC class II antigens constitutively. LC play a key role in the initiation of T cell responses to cutaneous antigens by picking up the antigen and migrating to the draining lymph node where they trigger specific T cell activation. There is also evidence that keratinocytes participate in immune responses in the skin since these cells produce a wide variety of cytokines that can modulate T cell responses. Dendritic cells comprise a system of highly efficient antigen-presenting cells which initiate immune responses such as the sensitization of T cells restricted by major histocompatibility complex molecules, the rejection of organ transplants and the formation of T-cell dependent antibodies. Dendritic cells are found in many non-lymphoid tissues, such as skin and mucosa (Langerhans cells), and they migrate after antigen capture through the afferent lymph or the bloodstream to lymphoid organs, where they efficiently present antigen to T cells. Dendritic cells are difficult to isolate and, although they originate from bone marrow their growth and differentiation are still poorly characterized. Granulocyte macrophage-colony stimulating factor (GM-CSF) favours the out-growth of dendritic cells from mouse peripheral blood. The cooperation between GM-CSF and tumour necrosis factor-alpha (TNF-alpha) is crucial for the generation of human dendritic/Langerhans cells from CD34+ haematopoietic progenitors. The availability of large numbers of these cells should now facilitate the understanding of their role in immunological regulation and disorder. Recent studies reported that after 2-3 days in vitro incubation, both murine and human LC undergo profound phenotypic changes, as an enhancement in the expression of MHC class I and II antigens, LFA-3 and ICAM-1 molecules, a concomitant decrease of CD1a antigens and a loss of Fc gamma RII. Furthermore, cultured LC (cLC) lose or markedly reduce their specific cytoplasmic organelles: the Birbeck granules. Therefore, after a 2-3 days in vitro incubation, LC seem to acquire most of the features of lymphoid dendritic cells.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7834505 TI - [Molecular approach of hair biology]. AB - The pilo-sebaceous unit is the site of numerous cell interactions, involving epithelial cells--hair follicle and sebaceous gland--, fibroblasts--dermal papilla--, nerve fibres, melanocytes, endothelial cells, and the immune system- Langerhans cells and lymphocytes--. From these timely and spacely regulated interactions results a complex process, namely the hair cycle comprising three main phases: anagen, catagen and telogen. Anagen is the growing phase of the follicle, catagen is a phase of involution, and telogen is a resting phase. Although the structure and the histology of the follicle is well known today, the molecular events controlling the hair cycle, namely the anagen-catagen and telogen-anagen transitions, remain obscure. The development of in vitro and in vivo models, however, has given some insights on the role growth factors such as IGF-1, TGF alpha, HGF, and EGF, as well as androgens such as the 5 alpha dihydrotestosterone, cytokines such as IL-1 and potassium channel openers such as minoxidil. Many other mediators are likely to be discovered in the next future, the toughest task being to understand the integration of the diverse signals resulting in the harmonious development of the hair follicle. PMID- 7834506 TI - Reconstruction of human skin in culture. AB - The possibility of cultivating cells in vitro has been one of the most important technical breakthroughs of the last decades and is the basis of much of the progress in cell biology. The first aim of cell biologists was to find how to stimulate cell growth using more and more sophisticated culture conditions. The success of Rheinwald and Green for long term subcultivation of keratinocytes is a brilliant example of the importance of this approach. When achieving technical conditions which make possible long term subcultivation of normal cells, biologists have looked to chemically defined medium, making possible analytical study of the effect of peptides or drugs on cells growth and differentiation. When comparing cellular response in monolayer culture in vitro, with cells in vivo, it became clear that most of the cell responses observed on dedifferentiated cells in monolayer culture are not at all predictive for the response of the same cells in vivo. These differences seem to be due to cell-cell and cell-matrix interactions existing in vivo which are responsible for cell differentiation and pharmacological responses. In order to develop in vitro cell culture systems predictive for the in vivo cell response, and to make possible alternative model systems for animal drug testing, new sophisticated systems have been developed. These systems attempt to reproduce in vitro the cell to cell and cell-matrix interactions responsible for cell differentiation, with the hope of realizing, step by step, a real organogenesis in vitro. The first human organ for which this concept has been developed, is the skin. We would like to review the most recent development of this technique, making possible the realization in vitro of a living skin equivalent. The work of our Laboratory has been mainly concerned by the investigation of two questions: Are the cells, in the living skin equivalent, in a functional and differentiated state close to the in vivo one? Is it possible, using the skin equivalent system, to obtain, in vitro, cell responses predictive for the in vivo ones? PMID- 7834507 TI - [Regeneration of transplanted human liver: gene expression at the time of graft implantation]. AB - The liver tissue mRNA expression of protooncogenes c-fos, c-myc, c-Ha-ras, c-met and c-erb B1, and TGF alpha and TGF beta genes is sequentially and temporarily increased in the early stages after partial hepatectomy, ischaemia or other mitogenic stimuli. These gene expressions were studied in 38 samples of liver tissue from 24 patients who underwent orthotopic liver transplantation, at different evolution stages. Eleven samples were obtained from surgical liver biopsies before graft implantation at day 0 (Group A), 14 samples from percutaneous liver biopsies during the post-operative period from day 9 to day 48 (Group B) and 13 samples in the long-term follow-up period from day 102 to day 1,382 (Group C). Gene expression was studied using 32P-labeled cDNA and oligonucleotidic probe hybridization in slot blots. A GAPD gene was used as a control gene. All expression values of protooncogenes were related to those of the GAPD gene. After cold ischaema, the relative gene expression (quantity of specific mRNA/quantity of GAPD mRNA ratio) tended to diminish in most cases. The relative expressions of c-fos, c-myc, c-Ha-ras, c-met and TGF alpha gene were correlated at day 0. During and after the liver transplantation, an overexpression of c-fos, c-myc, c-Ha-ras, c-met and TGF alpha was observed in different pathological conditions such as cold ischaemia and conservation injury, acute rejection, and cytomegalovirus infection. In three cases the relative expression values of c-fos, c-myc and c-Ha-ras increased over long-term follow-up without any associated acute pathology. These results suggest the necessity of an intercellular mediation--by means of graft reperfusion--in induction of hepatocyte proliferation and regeneration of the transplanted liver. PMID- 7834509 TI - [Expression of cytokine messenger RNA in human spleen]. AB - The expression of the cytokine genes in human spleen was studied using reverse transcriptase-polymerase chain reaction (RT-PCR) method capable of detecting low levels of mRNA. Total RNA was prepared from human spleen by acid guanidinium thiocyanate-phenol-chloroform (AGPC) method. cDNA was synthesized by M-MLV RTase using oligo (dT)16 primer, and amplified using the oligonucleotide primers specific for IL-1 alpha, IL-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL 9, TNF-alpha, IFN-alpha, IFN-beta and IFN-gamma by PCR method. Although IL-1 beta, IL-4, IL-5, IL-6, IL-7, IL-8, TNF-alpha, IFN-alpha and IFN-gamma mRNA were detected in all the samples tested, IL-3 and IFN-beta mRNA was not detected at all. These results suggest that many kinds of cytokines may be produced constitutionally in human spleen, and its pattern of cytokine production was similar to that in mice. PMID- 7834508 TI - [Utilization of linoleate and alpha-linolenate in peritubular cells and Sertoli cells in culture]. AB - The capacity of cultured peritubular cells to synthesize long-chain polyunsaturated fatty acids (PUFA) from the essential fatty acid (EFA) precursors 18:2n-6 and 18:3n-3 was tested, and compared to the PUFA biosynthesis in Sertoli cells. The concentrations of each EFA required to obtain maximal incorporation into membrane lipids were determined. The two EFA were added to the culture medium as free fatty acids complexed to albumin in a molar ratio of 12:1. When the substrates were added individually, the maximal levels of biosynthesis in peritubular cells were obtained with 0.70 microgram/ml of 18:2n-6 or 18:3n-3 in culture medium. With Sertoli cells, the concentration of 0.70 micrograms/ml linoleate or of 2.00 micrograms/ml alpha-linolenate in culture medium appeared to correspond to levels required for maximal incorporation and utilization of the n 6 PUFA or n-3 PUFA. Incorporation and metabolic utilization were always more important in cultured Sertoli cells than in cultured peritubular cells. The peritubular cell appeared to incorporate linoleate les efficiently than alpha linolenate at identical concentrations. In agreement with observations in other cell systems (15), we found a preferential utilization of 18:3n-3 over 18:2n-6 by the delta 6 desaturase in the peritubular cell and in the Sertoli cell. PMID- 7834510 TI - Societe Francaise de Recherche sur les Radicaux libres. Reunion d'ete du vendredi 1er juillet 1994. [Society for Free Radical Research. Summer meeting of Friday, 1 July 1994]. PMID- 7834511 TI - A religious conflict. PMID- 7834513 TI - BRN spells out legal limits on use of UAPs. PMID- 7834512 TI - Congress recommends using ANA dues to fight restructuring. PMID- 7834514 TI - California Board of Registered Nursing unlicensed assistive personnel guidelines. PMID- 7834515 TI - Nursing practice program promotes advocacy and activism. PMID- 7834516 TI - [Experimental study of mechanism of survival of venous flaps]. AB - The mechanism of survival of venous flaps was studied by observations employed in the study of microcirculation and blood vessel perfusion in rabbits. Initially, the flap was nourished by venous blood (within 72 hours): venous blood flowed slowly from the principal vein to its tributary veins, and then through the venous anastomoses (including small venous anastomoses, venular anastomoses and terminal venule anastomoses), reaching other tributary veins. No backflow from venules into capillaries was seen. The second stage was arterial nourishing and vessel reconstructive period (72 hours to 6 weeks): new vessels began to grow into the flaps at 72 hours postoperatively. 4 days postoperation, arterial flow with low velocity appeared in the primary flap arteries and the backflow of venous blood disappeared. 7 days postoperation, the abnormal, flow in 'unphysiologic' channels was replaced by the normal flow in 'physiologic' channels completely. 6 weeks postoperation, the vessel structure of venous flaps was the same as that of normal skin. These results suggested that rich venous network in venous flaps and early invasion of new blood vessels are the mainstay of venous flaps survival. PMID- 7834517 TI - [The causes of necrosis of arteriovenous flap and its modification]. AB - Arteriovenous flaps have been developed for more than ten years, however the cause of necrosis of the flap remains obscure. We observed the changes in the microcirculation of the flap, and it was revealed that most of capillaries were occluded in the early arterialized stage, and the capillary patency was only 10% 20%. The latter was increased to 80%-90% three days later. All these changes were due to the damage of endothelial cells by arterial blood, because of high pressure and oxygen tension, resulting if cell swelling, fissuring, exfoliation and finally thrombosis. As a consequence, the effective microcirculation volume became decreased. As venous endothelial cells required time to adapt arterial blood, and expansion of skin could increase tissue capillaries in number, the arteriovenous flap was modified by skin expansion before arterialization. This method improved the survival rate remarkably. PMID- 7834518 TI - [Total nose reconstruction by expanded forehead flap]. PMID- 7834519 TI - [A study of method of repair of defects of nasal tip and ala]. AB - Since 1957, the authors repaired 119 cases of nasal tip and alar defects using four kinds of method: (1) 27 cases by full-thickness skin graft; (2) 36 cases by free auricular composite graft; (3) 12 cases by local skin flap; (4) 44 cases by upper arm tube flap. The operation method was selected according to the size of nasal defect, available quantity of the remnant nasal tip and ala, and the soft tissue around the defect. The following problems were discussed in detail: (1) the principles of the selection of repairing method; (2) operative procedure; (3) the key points for the repair of nasal defects. PMID- 7834520 TI - [Carcinoma arising from postburn scars (report of 5 cases)]. AB - Carcinoma arising from postburn scars is rare. We have encountered 5 patients suffering from this late complication of scars, accounting for 0.32% of 1563 admissions for late surgery after burn injuries. They were all males, with a mean age of 56 years. The mean latent period was 43.2 years, and it was apparently longer when the acute burn injury occurred earlier in life. The site of predilection was the lower extremity, and multiple biopsies of various sites of the lesion remained to be the measure of confirmation. Pathologically, they were all squamoon cell carcinoma, grade I in 4 cases and grade II in 1. Immunohistochemical staining with anti-proliferation cell nuclear antigen (PCNA) showed that PCNA positive nuclei of squamous cell carcinoma were more numerous, as compared with that in the neighboring pseudo -epitheliomatous hyperplasia (PEH) and in normal skin, denoting markedly augmented assimilation of DNA in malignant degeneration. On the contrary, the number of Langerhan's cells were smallest in cancer area, as compared with PEH and normal skin. The diagnosis, treatment and prevention of such malignant degeneration in postburn scars have been discussed. PMID- 7834522 TI - [Vascularized outer-table calvarial bone flaps to repair depressed disfigurement of face]. AB - Utilizing the superficial temporal artery as the pedical, seven vascularized outer-table calvarial bone flaps have been raised for the reconstruction of a variety of craniofacial deformities. Satisfactory results were obtained. The advantages of the flap include: 1. proximity to the operative field; 2. it is a membranous bone similar to that of the facial bone; 3. it is more or less malleable, so that it can be formed into different shapes, in different sizes and thickness; 4. donor-site scar is inconspicuous; 5. no postoperative pain; 6. no resorption. PMID- 7834521 TI - [Study on urine ALb, serum and urine beta 2-m, IgG, and THP]. AB - The urine ALb, serum and urine beta 2-m, IgG, and THP were serially determined with radioimmunoassay to assess the renal functions during various stages of burn in 52 patients with TBSA over 30% (mean +/- s 58.4% +/- 18.88%). It was found that the urine levels of ALb, IgG, and THP and the serum and urine levels of beta 2-m were remarkably increased and that the serum levels of IgG were decreased after burns. Our study suggested that the measurements of urine ALb, serum and urine beta 2-m, IgG, and THP using radioimmunoassay were sensitive in assessing renal glomerular permeability and tubular functions after burn. It is presumed that such methods might be used to help identify the location, the extent, and the severity of the renal abnormalities and provide valuable information about the differential diagnosis and the prognosis of the renal damage in patients with extensive burns. PMID- 7834523 TI - [Mapping of face and extremity skin cleavage lines in Chinese adult cadavers]. AB - On fresh Chinese adult cadavers, which were obtained within 6 hours of sudden death, multiple skin holes of 1 cm apart were made with a conical steel punch of a diameter of 5 mm. Chinese ink was dipped into the wounds, which presently appeared to be rhomboid slits. Mapping of the directions of these rhomboid slits gave rise to cleavage lines of that area. This paper presents the skin cleavage lines of the face and extremities in Chinese adult cadavers. PMID- 7834524 TI - [The protection of gut mucosa with early enteral feeding in burned rabbits]. AB - The mechanisms of the protection of gut mucosa with early enteral feeding in burns were investigated. A 25% TBSA burn rabbit model, in which a gastrostomy, and a blind segment of the jejunum were formed before the thermal injury. 39 rabbits were randomly divided into three groups: A. burn and feeding with the nutritional fluid within 30 minutes postburn through gastrostomy. B. same as A except feeding with cold water instead of nutritional fluid; and C. no burn and fed freely. The results showed that burn injury caused an increase in mucosal oxygen consumption, intestinal uric acid formation and MDA (malondialdehyde) production, and decrease in submucosal blood flow. However, these were significantly improved by early enteral feeding after burn injury. The changes in the mucosa of the jejunal blind segment were similar to that of the rest of jejunum. It indicated that the effect of enteral feeding might be a systemic as well as a local one. It is concluded that the early enteral feeding can maintain the mucosal function and structure of the gut, as evidenced by a decrease in the mucosal hypermetabolism, improvement in submucosal blood flow and reduction in gut injuries as a result of reperfusion. PMID- 7834525 TI - [Effects of Chinese herb decoction sizunzituang on metabolism and nutrition in burnt guinea pigs]. AB - Sizunzituang is a decoction prepared by boiling water extraction of codonopsis pilosulae, Acractylodes, poria and glycyrrhiza. Male burnt (30% TBSA) guinea pigs weighing 380-420 grams with a pre-formed gastrostomy were studied. The animals were divided into two groups, both of them were fed with pellet chow. One received sizunzituang, while the other group served as controls. The treated group was found to eat more food, with better nitrogen balance, higher body and ileum mucosal weights, and higher nitrogen contents of the liver and ileum mucosa than control group. However, the body and carcase weights as well as gastrocnemius muscle nitrogen contents in the treated group were reduced significantly as compared with those in the control group. In addition, Sizunzituang can also regulate the secretion of hormones and visceral water contents. The above findings indicate that the decoction may be beneficial in improving the metabolism, nutrition, and visceral organ functions after a burn injury. PMID- 7834526 TI - [Experimental study of radiated pig skin incorporated with norfloxacin and silver]. AB - This paper presents the preparation and experimental use of radiated pigskin incorporated with norfloxacin and silver (RPSNS). The results show that tensile strength, tissue adherence and water-vaporu permeability of RPSNS are not significantly different from that of pigskin without radiation. The histological structure of RPSNS is essentially normal. However, some of the epidermal cells present vesicles. No positive culture is found in RPSNS and radiated pigskin, while the rate of positive bacterial culture of pigskin sterilized by Bromogeramin is 10%. RPSNS can effectively inhibit Staphy. aureus, Ps aeruginosa, E. coli, Proteus and Klebsiella. The results indicate that RPSNS is a kind of sterile biological dressing with strong anti-bacterial effect. PMID- 7834527 TI - [An experimental model of electric injury by high voltage]. AB - A standardized 10,000-volt, 2 + 0.15-A, 5-s electric burn rabbit model was established. Microscopic examination revealed that there was patchy cellular necrosis intermingled with viable cells in the muscle in the burn area. Grossly, there was a distinct interface between viable and nonviable tissues. The resulted injury correlated well with clinical features of electric burn. PMID- 7834528 TI - [Changes in lymphocyte membrane fluidity after burn and its significance]. AB - In the present experiment, the change in lymphocyte membrane fluidity after burn was observed by measurement of fluorescent depolarization with DPH as a probe. 11%-12% TBSA of full-thickness skin burn was made in Balb/c mice. Six days later the animals were killed and their spleen were obtained. Then membrane fluidity and IL-2 production of splenic lymphocytes were measured, and lipid peroxide level of the spleen was assayed. The results showed that the fluidity decreased significantly with suppression of lymphocyte proliferation and IL-2 production, and that the lipid peroxide level increased. There was a negative correlation between the decrease in membrane fluidity and the suppression of lymphocyte functions. The same correlation also existed between the changes in membrane fluidity and the lipid peroxide level. The data indicated that the decreased membrane fluidity might be one of the causes for lymphocyte dysfunction and related to the enhancement of lipid peroxidation after burn. PMID- 7834529 TI - [Study of bronchoalveolar lavage fluid harvested from the dogs with steam inhalation injury]. AB - The significances of analyzing bronchoalveolar lavage fluid (BALF) were studied using a steam inhalation injury model. Bronchoalveolar lavage was carried out at 1 and 5 h after steam inhalation injury. The parameters investigated included cellular analysis, the total protein content, malondialdehyde (MDA) content, the activity of superoxide dismutase (SOD), and the angiotensin converting enzyme (ACE) in the BALF, and pathologic examination of lungs. The study indicated that some informations of the pathophysiological changes in the lungs after inhalation injury could be acquired by the BALF analysis. PMID- 7834530 TI - [The relationship between opportune administration of antibiotics and infection after burn injury: an experimental study]. AB - 45 male rabbits with 15% III degree burn were infected with Pseudomonas aeruginosa. They were divided into three groups: the prevention group, in which cpz (cefoperazone) was immediately administered after the scald at the dose of 25 mg/kg with an interval of 1/12 h for a total of 4 doses; the treatment group, in which cpz was administered 48 th after the scald with the dosage same as above; control group in which cpz was not administered. The findings were as follows: In the prevention group, gross observation showed dessication and crustation of the surface of the wound within 1 week after the scald. By employing immunofluorescent antibody it was found that P. A existed only in the superficial layer. However, ulceration and exudation were found in the control and treatment group within 3 or 4 days after the scald, and P. A was shown to have invaded the deep muscular tissue to cause intermuscular septal abscess. The positive rate of blood culture of bacteria in the prevention group (10/81) was significantly lower than that of the treatment (15/57) and the control groups (21/76, P < 0.05). The death rate of the prevention group (2/15) was significantly lower than that of the treatment (10/15) and the control groups (9/15, P < 0.05). The above finding showed that antibiotics specific to the infectious organism of the wound in extensive burn patients should be given in the early exudation stage in order to ward off invasive infection. PMID- 7834531 TI - [Effect of crystal no. 4 of polygonum cuspidatum on the viability of island flaps with venous stasis: an experimental study]. AB - The effects of crystal No. 4 of Polygonum cuspidatum on microcirculatory changes of island flaps in rats following resumption of blood flow after venous occlusion of six hours were observed with a special TV set with magnification of 500X. The pathological events and survival rate of flaps were recorded as well. The results showed that the survival rate, amount of open capillaries, amount of blood flow, and velocity of blood flow of flaps treated by crystal No. 4 of polygonum cuspidatum were much higher than those of untreated control flaps. The white thrombosis and endothelial damage of dermal vessels were alleviated by administration of crystal No. 4 of polygonum cuspsidatum. The experiment also showed that there were no differences between flaps treated with crystal No. 4 of polygonum cuspidatum preoperatively and flaps treated with it postoperatively. PMID- 7834532 TI - [Effects of cytokines on post-traumatic metabolism]. PMID- 7834533 TI - [Heel reconstruction by the composite island flap of the lower leg]. AB - From 1987, 6 to 1992, 6 cases of heel defect were repaired successfully by reverse transfer of the composite island flap from the lateral lower leg. The flap, pedicled with peroneal vessels, consisted of skin, subcutaneous tissue, fibula and adjacent muscles. The contour and function were satisfactory. PMID- 7834534 TI - [Reverse fasciocutaneous flap of medial aspect of leg for the repair of dorsum of foot]. PMID- 7834535 TI - [Island fasciocutaneous flap with lateral cutaneous branch of popliteal artery for the repair of soft tissue defect of lower extremity]. PMID- 7834536 TI - [Application of the thoraco-umbilical flap in emergent repair of large defect of limbs]. AB - We have repaired larger detect of limbs after emergent debridement using the thoraco-umbilical flap on 13 cases, 6 of which were vascular island flaps, 7 were free flaps. The size of the flaps was 10 cm x 26 cm to 12 cm x 42 cm. All the flaps survived completely. The advantages of the flap are: (1) the pedicle of the flap is long and has a large diameter, (2) the flap can be made quite long so as to cover the whole ulna or tibia, (3) the flap can be used to repair bony defect by carrying a rib as an osteocutaneous flap. PMID- 7834537 TI - [Clinical use of the thoraco-umbilical flap]. PMID- 7834538 TI - [Experimental study of carbohydrate metabolism of venous flaps]. AB - In this experimental study, three sorts of grafts (venous flap, composite graft and axial flap) were created. According to the results of relative contents of LD1, and LD5 in these grafts, the conclusion was drawn: Oxyhemoglobin remaining in the grafts maintained normal carbohydrate metabolism within 24 hours postoperatively. 48 hours later, aerobic oxidation of carbohydrate abated but kept in a considerable level in venous flaps due to the existence of venous blood. 72 hours after the operation, aerobic oxidation of carbohydrate in venous flaps reached its lowest point. At this point, the venous flaps would necrose gradually unless a new nourishing source be obtained. From the 4th postoperative day, aerobic oxidation of carbohydrate of venous flaps began to increase. By the 7th day, aerobic oxidation of carbohydrate of venous flabs returned to normal. PMID- 7834539 TI - [Mandibular advancement for the treatment of micrognathia with obstructive sleep apnea]. AB - Fifteen patients with micrognathia and obstructive sleep apnea syndrome (OSAS) are presented. All patients were evaluated before and after surgery by physical examinations, cephalometric, fibroptic pharyngoscopy and oxygen saturation (SaO2). A method that allows isolated advancement of the genial tubercle and genioglossus muscle is described. The operation could enlarge the pharyngeal airway space at the base of the tongue (P < 0.05), increase SaO2 and decrease MP H (P < 0.05) so that the symptoms of OSAS improved or disappeared. The facial symmetry and chin prominence also improved significantly. This method is simple and effective for the treatment of OSAS due to micrognathia and obviates the need for intermaxillary fixation. But it is not indicated for patients with severe malocclusion or airway obstruction on more than one sites. PMID- 7834540 TI - [Congenital lower lip sinuses]. AB - Congenital lower sinuses are rare and are found often in association with cleft lip and/or palate, named Van der Woude syndrome. Although the condition per se does not always require surgical attention, its genetic character is interesting. Four cases of congenital sinuses are described and recent literature is reviewed. PMID- 7834541 TI - [Application of the island skin flap to repair facial soft tissue defects]. AB - We have applied the island skin flap for facial reconstruction and repair in 45 cases with very satisfactory results. The advantages of the island flap are: (1) having relatively long and flexible pedicle for transfer, (2) having good blood supply, (3) with well-matched color and texture and (4) avoiding the second operation. The characteristics and technical problems are discussed in the paper. PMID- 7834542 TI - [Vaginoplasty with sigmoid colon, a report of 91 cases]. PMID- 7834543 TI - [A study of computer aided simulation system for orthognathic surgery]. AB - How easily to stimulate the orthognathic surgery with high accuracy and good reliability and visually explain the prediction of surgery to the patient with maxillomandibular deformities remains a key focus in oral and maxillofacial surgery. A Computer Aided Simulation System for Orthognathic Surgery (CASSOS) was developed by means of the technique of digital image processing, with which a detailed analysis could automatically be performed, including 71 measurements of distance, degree and ratio for frontal cephalograms and 68 measurements for lateral one with a computer aided diagnosis. A quantitatively surgical simulation for prediction of operation could satisfactorily be done for the clinical use. All data and images were printed by laserjet and color video printer. All procedures were finished in 20 minutes. PMID- 7834544 TI - [The role tumor necrosis factor in multiple organ dysfunction caused by bowel ischemia and reperfusion]. AB - To explore the role of tumor necrosis factor (TNF) in the pathogenesis of multiple organ dysfunction following bowel ischemia and reperfusion, 98 rats were subjected to occlusion of the superior mesenteric artery for 45 minutes. It was found that the plasma TNF level increased rapidly after release of the clamp, peaking to 27.59 +/- 11.13 ng/ml 2 hours after reperfusion. Its changes in quantity was directly related to endotoxin in the portal circulation. Furthermore, the results showed that pretreatment with monoclonal antibody to TNF alpha could significantly lowered the plasma TNF content and notably improved the functions of various organs. This study demonstrated that release of TNF might result in systemic hypotension and remarkable damage to liver, kidneys and lungs, which contributed to the development of sepsis and multiple system organ failure following severe ischemia-reperfusion injury of the intestine. PMID- 7834545 TI - [The prognostic implication of determination of activation of leucocyte in severe burns]. AB - Using NBT test, the relationship between the percentage change of activated neutrophils with the survival time of animals after severe burns was observed. The results showed that the NBT positive rate of neutrophils increased markedly after burn, and the NBT positive rate at 5 h postburn was negatively related to the survival time of burned animals. Continuous monitoring of neutrophil indicated that if the NBT positive rate after burn remained in the normal range, or increased initially to high level and then decreased to lower than normal, the survival time was longer. However, if the NBT positive rate increased continuously after burn, the survival time was shorter. Therefore, continuous assay of neutrophil activation with NBT is an important index for the prognosis of severe burns. Lowering of NBT positive rate was observed in rats treated with polygonum cuspidatum, and these rats lived much longer than those without the treatment. PMID- 7834546 TI - [Experimental study of the evaluation of efficacy of fluid replacement based on Parkland formula for burn shock]. AB - In order to investigate the effect of fluid resuscitation of burn shock according to Parkland formula and to find out whether it leaves any damage due to hypoxia, 22 male mongrel dogs with 50% III degrees burn were divided randomly into two groups. Group 1 (14 dogs) received no fluid replacement, whereas in group 2 (8 dogs) Ringer's lactate solution was given according to Parkland formula after the injury. Swan-Ganz catheter was inserted to the pulmonary artery before burn. FAP, CVP, PAP, cardiac output and blood gas analysis were measured preburn and at 2, 6, 12, 18, 24, 36 and 48 hours postburn. The results demonstrated that group 1 dogs all died within 12 hours postburn and group 2 dogs all survived over the shock period. However, even in these survived dogs, markedly decreased cardiac output and oxygen consumption were observed over the first 18 hours postburn. This indicated that fluid replacement according to Parkland formula can not completely correct the inadequacy of tissue perfusion, and it may leave certain damage of oxygen deficiency. Therefore, further improvement in fluid resuscitation and combined treatment for early burn shock to raise cardiac output and improve tissue oxygen delivery may be needed. PMID- 7834547 TI - [Changes in the contents of plasma SOD and MDA in 50% III degree burn dogs after delayed fluid replacement]. AB - The plasma SOD and MDA content were determined in 50% III degree burn dogs with delayed fluid replacement. The results showed that the activity of plasma total SOD and CuZn-SOD rapidly declined and were obviously lower during the first 5 days postburn than preburn values, while the content of Mn-SOD did not show significant change. The plasma MDA was evidently elevated in 24 hour but returned to the normal level in 48-72 hours after burn, however it distinctly rose again after 72 hours post-burn. The results suggest that delayed fluid replacement induced generation of free radicals after burn injury, with the result of the occurrence of lipid peroxidation. PMID- 7834548 TI - [Biochemical analysis of protein homogenates in skin stored at different temperatures]. AB - The amount and constitution of protein, its ultraviolet photo-absorption ability, and the amount of esterase of homogenates of cadaver, guinea pig and mouse skin, which were stored under various temperatures of 4 degree C, -20 degree C, -80 degree C and -196 degree C, were assayed by using ultraviolet spectrophotometer and polyacrylamide gel electrophoresis. The results show that there are changes in various degree in biochemical components of skin protein and esterase after being stored at different temperatures as compared with fresh skin. PMID- 7834549 TI - [A 5-year retrospective investigation of occupation-related burns in Zhenjiang area]. AB - During the 5 years from June 1986 to June 1991, 221 patients were admitted to our department of burn surgery because of occupation-related burns. The average age was 31.2 years, and 83.4 per cent was male. Most of the patients (79.6 per cent) were referred to our hospital within 24 h of their injury. The most common etiology was flame (33.0 per cent). The mean body surface area of all 221 cases was 17.1 per cent, with a mean full-thickness component of 8.1 per cent. COMPLICATIONS: inhalation injury 18 cases (8.1 per cent); sepsis 5 cases (2.3 per cent) confirmed by positive blood cultures at an average time of 10.2 days postburn, and the commonest organism was pseudomonas aeruginosa; pneumonia 5 cases (2.3 per cent). The mortality of these 221 cases was 1.8 per cent. The average time of stay in our hospital was 34.3 days. The total expenditure was about 740,000 Yuan. First aid on the spot and early correct treatment are stressed. It is essential to put prevention first, and the measures to lower the incidence of occupation-related burns were discussed to serve as a reference for labor protection department and occupation-related burns institute. PMID- 7834550 TI - [Significance of superficial-musculoaponeurotic system and facial retaining ligaments in rhytidectomy]. PMID- 7834551 TI - The elevation of plasma DNA in patients with systemic lupus erythematosus is attributable to increased DNA release and defective DNA binding of mononuclear cells. AB - BACKGROUND: Although immunoprecipitable DNA has been found in a subgroup of patients with systemic lupus erythematosus (SLE) exhibiting systemic vasculitis and/or central nervous system involvement, the mechanism for elevated plasma DNA in these patients is poorly understood. METHODS: The plasma DNA concentrations and reactivity of serum and lymphocytes to six species of double-stranded DNA from calf thymus, human placenta, Escherichia coli, Micrococcus lysodeikticus, Clostridium perfringens and poly (dG.dC). poly (dG.dC) were measured in twenty seven patients with active SLE. To understand the mechanism of increased plasma DNA in SLE, the DNA binding and release of the mononuclear cells were examined. RESULTS: Compared with the controls, the incidence of the presence of plasma DNA was markedly increased in SLE (59.3% in SLE vs. 7.4% in controls) as detected by counterimmunoelectrophoresis. Except for DNA from Clostridium perfringens, the reactivity of lupus sera to various DNA samples was significantly higher than that of the controls. The reactivity of lymphocytes to 6 species of DNA (as defined by 3H-thymidine incorporation of the cells) was also higher in SLE patients. In DNA binding and releasing experiments, patients with SLE were found to have decreased 3H-DNA binding activity (0.169 +/- 0.018 micrograms/2 x 10(6) cells in SLE vs. 0.283 +/- 0.02 micrograms/2 x 10(6) cells in controls, p = 0.001) but to have increased spontaneous release of DNA (1,465 +/- 412 cpm in SLE vs. 630 +/- 179 cpm in controls, p = 0.0173) in mononuclear cells. CONCLUSIONS: The results suggest that some subsets of lymphocytes can be sensitized by different DNA samples in vivo to increase endogenous DNA release from mononuclear cells, which in addition to decreased DNA clearance as has been previously reported, may be responsible for the elevation of plasma DNA in patients with SLE. PMID- 7834552 TI - Serological evaluation for tuberculosis by antigen 60 IgG ELISA test. AB - BACKGROUND: Tuberculosis remains a significant global health problem, especially among developing countries. It unfortunately results in high morbidity and mortality rates. This disease is also prevalent to a large extent in Taiwan. The traditional tuberculous tests, including the acid-fast smear and culture, have a limited activity in regard to extrapulmonary or smear-negative tuberculosis. A new testing is necessary to improve diagnosis of this disease. METHODS: An enzyme linked immunosorbent assay (ELISA) test for detection of serum IgG antibodies, based on Antigen 60, was applied to 146 subjects including 68 non-tuberculous cases and 78 tuberculous cases. A titer of less than 200 serounits was considered negative, and one of 200 or more serounits was thought positive. RESULTS: In the healthy group, which included 5 newborns, 5 children and 20 healthy adults, 6.1% (2/30) showed positive results. Of the 15 hospital attendants, 60% (9/15) also displayed positive results. Nine of 17 cases (52.9%) with non-tuberculous pulmonary diseases had positive results. Among 6 cases with other diseases, the results were all negative. The false positive rate in non-tuberculous group was 29.4% (20/68). In 10 cases with inactive pulmonary tuberculosis, 30% (3/10) showed positive results. In 50 with active pulmonary tuberculosis, 88% (44/50) generated positive results. Effectual results were obtained in 66.7% (8/12) of the cases with extrapulmonary tuberculosis. Including 6 cases with mixed pulmonary and extrapulmonary tuberculosis, 83.3% (5/6) proved positive results. The positive rate in active tuberculous group was 83.8% (57/68). CONCLUSIONS: The ELISA test, for detection of IgG antibody with Antigen 60, is helpful in improving the diagnosis of tuberculosis, especially in extrapulmonary tuberculosis. PMID- 7834553 TI - Enterococcal bacteremia in a medical center. AB - BACKGROUND: The enterococci have become important nosocomial pathogens. They can cause multiple site infections and enterococcal bacteremia becomes more frequently associated with a high mortality rate. Previous studies of enterococcal bacteremia showed a variety of results. To establish the significance and importance of enterococci as nosocomial pathogens in this hospital, to characterize their clinical pictures and to search for the risk factors for mortality, this retrospective study was performed. METHODS: There were 208 cases of enterococcal bacteremia which occurred from 1988 to 1992. Twenty-seven cases had no medical charts, dismissing possibility of evaluation. Finally, 181 cases of enterococcal bacteremia were analysed. RESULTS: One hundred and eighteen episodes were nosocomial infections. Polymicrobial bacteremia occurred in 68.5% of the patients and the most common co-isolate was Pseudomonas aeruginosa. Those patients (78.5%) with underlying diseases and malignancies were the most common underlying problems. The portal of entry could be found in 69.6 percent of patients, with the gastrointestinal tract the most common sources. Antimicrobial susceptibility testing showed high gentamicin resistance rate (89.5%), and ampicillin still had about 80 percent sensitivity rate. The group who received specific antibiotic therapy for enterococcus showed lower mortality (36.4% versus 47.6%). Only one case had infective endocarditis. Forty-nine patients suffered from septic shock, the cause of 30 deaths. Totally 75 patients died during hospitalization. Besides sepsis, another major cause of death was their underlying diseases itself. CONCLUSIONS: Enterococci have no doubt become important nosocomial pathogens and enterococcal bacteremia were associated with high mortality, especially in elderly patients with underlying diseases such as malignancy or diabetes. When clinically dealing with sepsis from the gastrointestinal or biliary tract, especially when previous cephalosporins therapy showed no response, the possibility of enterococcal bacteremia should always be considered. PMID- 7834554 TI - Sclerotherapy on liver cirrhosis with esophageal variceal bleeding: eight years of experience. AB - BACKGROUND: Patients with liver cirrhosis usually die of hepatic failure and variceal bleeding. Successful treatment of the latter can reduce mortality. Sclerotherapy is one method often used. This study compared (a) the successful rate of acute bleeding control; (b) short- and long-term survival rate between those with and without treatment with sclerotherapy to evaluate the clinical benefit of sclerotherapy for liver cirrhosis patients with esophageal variceal bleeding. METHODS: Between August 1983 and December 1991, 183 cirrhotic patients with esophageal variceal bleeding receiving endoscopic injection sclerotherapy (EIS) was compared with 123 patients without sclerotherapy treatment retrospectively. The severity of underlying liver disease was classified using a modified Child's classification. Sclerotherapy was done within 48 hours after active bleeding in the sclerotherapy-treated group, while the medical treatment group received Sengstaken-Blakemore (SB) tube or pitressin infusion only. RESULTS: Successful rate of acute bleeding control was 81.63% (120/147) in the EIS group and 59.35% (73/123) in the medical treatment group. The worse the hepatic function of the patients, the lower the success of acute bleeding control in both groups. Fifty subjects (74.63%) had varices eradicated in 67 sclerotherapy treatment patients with regular follow-up. Patients receiving EIS had a better long-term survival than those without treatment. Benefit of EIS on long-term survival was more significant in Child B patients and less in Child C and Child A patients. Death from variceal bleeding was lower in the EIS group than in the medical treatment group (32% vs 62.6%). Complications of EIS were rare. Eight patients died of aspiration pneumonia, spontaneous bacterial peritonitis or acute renal failure after sclerotherapy, and most were Child B and C patients. Sixteen patients had esophageal stricture. Four needed dilatation treatment. CONCLUSIONS: The sclerotherapy-treated group had a higher control rate of acute bleeding and lower mortality rate from esophageal variceal bleeding compared with the medical-treated group. The procedure prolonged long-term survival in Child B patients but did so less frequently in Child A and Child C patients. The incidence of complications was low. As a whole, EIS is a safe and efficient method for control of esophageal variceal bleeding. PMID- 7834555 TI - Primary malignant cardiac tumor: an analysis of seven cases. AB - BACKGROUND: Primary malignant cardiac tumor is a rare disorder which has a myriad of clinical manifestations. It dominates about one-fourth of all cardiac tumors, exhibiting typically malignant histological characteristics and invasive behavior. METHODS: Seven cases of primary malignant cardiac tumor were collected over eight years (1985-1993) in this hospital. Each case had different manifestations. All cases were diagnosed by physical examination, echocardiogram and were subsequently proved by tissue pathology. RESULTS: The majority of these seven cases of primary malignant cardiac tumor had clinical symptoms of chest distress, shortness of breath and paroxysmal nocturnal dyspnea. The relatively young ages of the patients ranged from 11 to 62 years. One case of angiosarcoma, one case of fibrosarcoma, one case of leiomyosarcoma and three cases of lymphoma had the characteristics of cardiac hemodynamic obstruction which was induced by location and size of the tumors in the heart. Five cases of those primary malignant cardiac tumor were mortal; the average life span was nine months following surgical resection and chemotherapy. CONCLUSIONS: From a clinical viewpoint, primary malignant cardiac tumor characteristically displays a rapid downhill course. Death most often occurs from a few weeks to two years after the onset of symptoms. Because these tumors are rare and have a poor clinical outcome, early diagnosis and treatment are vital. PMID- 7834556 TI - Ultrasound-guided biopsy of thoracic masses. AB - BACKGROUND: Fine needle aspiration cytologic examination may be sufficient for managing patients with primary lung cancer. However, the procedure is not reliable for benign lesions and metastatic lung cancers. An attempt was made to find the influence of cell type on the results of fine needle aspiration and cutting biopsy. METHODS: One hundred and sixteen patients with thoracic nodules or masses underwent chest ultrasound examination and percutaneous ultrasound guided needle biopsy. All patients underwent ultrasound-guided fine needle aspiration biopsy (UGAB) and thirty-eight of them also underwent ultrasound guided cutting biopsy (UGCB). Thoracic lesions were divided into seven groups. RESULTS: Using UGAB alone, the diagnostic rate varied from 56% (mediastinal tumor) to 91% (lung mass). When both methods of UGAB and UGCB were evaluated, the diagnostic rate varied from 67% (pulmonary nodule) to 100% (collapsed lung with mass and pancoast tumor). When thoracic lesions were divided into carcinomatous neoplasms (n = 88) and noncarcinomatous lesions (n = 21), a higher diagnostic rate was found in the carcinomatous group than in the noncarcinomatous group (92% versus 53%, p < 0.001). Correct histologic results between both groups had no statistical significance (64% versus 56%, p > 0.05). CONCLUSIONS: Ultrasound guided needle biopsy has a high diagnostic yield of thoracic tumors, and carcinomatous masses can be easily diagnosed by UGCB. Noncarcinomatous masses and benign tumors frequently need UGAB to obtain a histologic diagnosis. PMID- 7834557 TI - Percutaneous biliary stone removal under fluoroscopy. AB - BACKGROUND: Bile duct stone is a common biliary tract disease in Taiwan. Surgery and choledochoscopy are the current methods of treatment. This is a retrospective review of 65 cases who were admitted with postoperative biliary residual stones, or cholangitis secondary to the biliary stones. Percutaneous biliary stone removals under fluoroscopy were attempted. METHODS: Either a T-tube tract or percutaneous transhepatic cholangial drainage tract or both were used for stone removal. Angiographic superselective catheterization technique was applied for superselective cholangiography to identify the location of stones and to deliver basket and electrohydraulic lithotripsy probe to the site of the stones. Balloon dilation was applied for biliary stricture. RESULTS: Most of the cases needed multiple sessions (four, on an average) to remove all stones. There were 52% of the cases who needed balloon dilation for associated biliary strictures, and 7.7% of the cases had residual stones at the end of the procedure, because of technical difficulties. Chills and fever, pancreatitis, hepatic arterial injury and perforation of the common bile duct were procedure-related complications. In follow-up studies, 15% of the cases had recurrent biliary stones and 4.6% of the patients expired from malignant biliary tumors. CONCLUSIONS: Percutaneous biliary stone removal under fluoroscopy is beneficial for direct visualization of the location and number of the stones, and the architectural changes of the bile ducts. Superselective catheterization and balloon dilation were responsible for the high success rate (92.5%) here. PMID- 7834558 TI - Insulin-dependent diabetes mellitus in twins: a case report. AB - Dizygotic twin babies with a gestational age of 35 weeks were born with birth weights of 1800 gm and 1200 gm respectively. One infant had gangrene of her right foot at the age of eleven days. The other contracted urinary tract infections twice, at the ages of one month and two months. The blood sugar levels of both infants were high (> 450 mg/dl) during admission at three months old. During that admission, one twin suffered from diabetic ketoacidosis and the other had acute diarrhea. Both infants began treatment with insulin and were followed up until they were four years old. The HLA typing of both patients showed no relation to DR3 or DR4. PMID- 7834559 TI - Insulin autoimmune syndrome in a patient with methimazole and carbimazole-treated Graves' disease: a case report. AB - Insulin autoimmune syndrome (IAS) includes fasting or reactive hypoglycemia, hyperinsulinemia and the presence of insulin-binding antibodies in patients who have never been exposed to exogenous insulin. The report concerns a 34-year-old male patient with Graves' disease who had history of having taken methimazole for two months, without any consequence, 4 years previously. However, when methimazole was again administered for three weeks followed by a week of carbimazole, the patient suffered hypoglycemia 4 times during the next 4 weeks. He denied history of diabetes mellitus (DM), of taking any oral hypoglycemic agent or of having received insulin injection. Laboratory data showed total serum insulin level > 320 microU/mL, free insulin 55 microU/mL and insulin antibody 88.3%. Oral glucose tolerance test (OGTT) revealed DM pattern. Since the patient had history of allergy to anti-thyroid drugs before this event, so he was treated with radioiodine (131I). There was no episode of hypoglycemic attack during 15 months of follow-up. PMID- 7834560 TI - Positive antinuclear antibody in peripheral T cell lymphoma: a case report. AB - The association of malignant lymphoma with positive antinuclear antibody is uncommon, and their relationship is not clear. Here a 35-year-old man is presented who initially had a high titer of antinuclear antibody; later, peripheral T cell lymphoma was found. It is suggested than an unexplained high antinuclear antibody titer may warrant searching for a malignancy. PMID- 7834561 TI - Survival of paraquat intoxication complicated with mediastinal emphysema: a case report. AB - Paraquat intoxication is a common medical problem in this country. The mortality is high, particularly in the cases of high dose ingestion. Mediastinal emphysema observed in paraquat intoxication always means mortality, however, we experienced a survivor. A 29 y/o female ingested about 10-15 c.c. of 24% (2.4-3.6 gm) paraquat to attempt suicide. Nausea and protracted vomiting occurred shortly after. During hospitalization, mediastinal emphysema developed on the 7th day and subsided 10 days later. Serum paraquat level determination revealed 185 ng/ml in 20 hours after ingestion and 34 ng/ml on the 6th day. She received general supportive treatments with the augmentation of sodium thiosulfate. Hypokalemia had been observed for 11 days and was intractable until hypomagnesemia was identified and corrected. So far, she had returned back to her work for more than 1 year, although the chest x-ray revealed slight pulmonary fibrosis. The high ingested dose, oral ulcers, high serum level and mediastinal emphysema of this patient all implicate a poor prognosis of paraquat intoxication; however, these contradict the observed survival of our patient. In conclusion, mediastinal emphysema observed in paraquat intoxication is not related to the serum level of paraquat. It does not absolutely lead to death and may simply come from the esophageal rupture after vigorous vomiting in paraquat intoxication. PMID- 7834562 TI - Fabry's disease: clinical, pathologic and biochemical manifestations in two Chinese males. AB - Fabry's disease is a rare hereditary disease transmitted as an X-linked recessive trait with the primary metabolic defect of an enzyme alpha-galactosidase A, resulting in deposition of glycolipids (ceramide trihexoside) in various tissues, including the kidneys. Two sibling cases of Chinese adult male patients in a family with Fabry's disease were completely evaluated including the clinical, pathologic and biochemical studies. Both of the patients had the similar clinical manifestations such as telangiectases, proteinuria, acral pains, corneal opacities, tortuous renal vessels and recurrent fever. Chronic renal insufficiency was noted in Case 1, whereas Case 2 had normal renal function. Microscopic hematuria was noted in Case 1. In renal biopsy, LM showed foamy vacuolation of the glomerular visceral epithelial cells and EM showed widespread myelin bodies (Zebra bodies) in kidney tissues, most numerous in visceral epithelia in both cases. Those findings are diagnostic for Fabry's disease. The plasma activity of alpha-galactosidase of Case 1 was 0.8 and that of Case 2 was 1.0 (normal reference range: 8.5-18.5 nmol/hr/min). The plasma activity of alpha galactosidase A of Case 1 was 0.4 and that of Case 2 was 0.8 (normal reference range: 7.9-16.9 nmol/hr/min). All the enzyme activities in both cases were much lower than those of normal subjects. In addition to clinical presentations, pathologic study and biochemical study with assays of plasma or serum activities of alpha-galactosidase and alpha-galactosidase A are important steps in the diagnosis of Fabry's disease.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7834563 TI - Pneumoperitoneum caused by spontaneous bacterial peritonitis: a case report. AB - Spontaneous bacterial peritonitis (SBP) rarely presents as pneumoperitoneum. Only four such cases have been reported in the English literature. This report concerns a 65 year-old male patient with SBP and pneumoperitoneum. He has had a history of peptic ulcer. However, upon examination, no associated diseases or compromised immunity was detected. He presented with acute abdominal pain and subphrenic free air. An emergency laparotomy was performed, under the impression of a perforated peptic ulcer. Yet, no intraabdominal pathology except 200 ml of purulent ascites was found. The ascites culture yielded E. coli, B. fragilis, and P. aeruginosa confirming the diagnosis of SBP. Antibiotics which are sensitive to gas-forming bacteria should be prescribed before the result of the ascites culture is known. PMID- 7834564 TI - Depot drug delivery system for 5-fluorouracil after filtration surgery in the rabbit. AB - We investigated the potential value of 50:50 poly (DL glycolic acid-lactic acid) (PGLA) copolymer as a degradable depot delivery system for 5-fluorouracil (5-FU) after filtration surgery. Analysis of retrieved discs after implantation in 22 eyes of 22 pigmented rabbits showed a dual drug release profile and polymer mass loss characteristics. In a second group of pigmented rabbits implantation of PGLA discs impregnated with 5-FU (22 eyes) significantly lengthened the survival time of filtration fistulae compared with discs without 5-FU (18 eyes) or no disc (10 eyes) (p < 0.0001). Use of PGLA copolymer impregnated with 5-FU could prove valuable for patients undergoing glaucoma filtering surgery. PMID- 7834565 TI - Ocular toxicity of mitomycin C and 5-fluorouracil in the rabbit. AB - We studied the histotoxic effects of mitomycin C and 5-fluorouracil (5-FU) in the eyes of New Zealand white rabbits using light microscopy. Twenty-four eyes of 24 rabbits received subconjunctival injections of mitomycin C (0.025, 0.05, 0.10, 0.20, 0.40 or 0.80 mg/mL) or 5-FU (10.0 mg/mL), either alone (0.25 mL) or in combination with anterior chamber injections (0.05 mL), once daily for 4 consecutive days. Two eyes of two rabbits received subconjunctival and anterior chamber injections of unpreserved sterile saline. The eyes were examined regularly for external signs of toxicity and were enucleated 4 weeks after the last injection. Mitomycin C produced considerable tissue damage in the anterior segment, the severity being related to both the concentration and the route of administration. Eyes that received both subconjunctival and anterior chamber injections showed more damage than those that received subconjunctival injections alone. At the highest concentration of mitomycin C the cornea was inflamed, with stromal necrosis and marked endothelial loss. Hemorrhagic iris necrosis was also seen. In contrast, the 5-FU-treated eyes showed no microscopic evidence of toxicity. We conclude that there is greater risk of toxic anterior segment effects when mitomycin C is used as adjunctive therapy following filtration or pterygium surgery. PMID- 7834566 TI - Duchenne muscular dystrophy: negative scotopic bright-flash electroretinogram but not congenital stationary night blindness. AB - Patients with Duchenne muscular dystrophy (DMD) have recently been reported to have an abnormal scotopic electroretinogram (ERG) showing weak rod-related responses along with a negative configuration of the bright-flash response, which has been described as being similar to the one in congenital stationary night blindness (CSNB). We compared qualitatively and quantitatively the ERGs of 6 subjects with DMD, 10 subjects with the complete form of CSNB (cCSNB), 13 subjects with the incomplete form of CSNB (iCSNB) and 1 subject with complex glycerol kinase deficiency (CGKD). The rod-related activity and the bright-flash responses were abnormal and similar in all four groups. The cone-related activity, however, was within normal limits only in the DMD group; the b-wave was subnormal in CGKD, truncated in cCSNB and nearly absent in iCSNB. The electrophysiologic signature in DMD clearly distinguishes the retinal function of these patients from any other retinal condition so far described. PMID- 7834567 TI - Duchenne muscular dystrophy: negative scotopic bright-flash electroretinogram and normal dark adaptation. AB - Recent reports indicate that most subjects with Duchenne muscular dystrophy (DMD) have a negative scotopic bright-flash electroretinogram (ERG). We performed dark adaptometry in seven patients with the DMD phenotype. Three patients had the negative bright-flash response combined with severely reduced rod-related activity; their mean psychophysical dark-adapted threshold was -5.5 +/- 0.3 (normally -5.4 +/- 0.3) cd.m-2. Two of the three patients were able to sit through the complete test: the profile of their dark adaptation curve was normal. The four other patients had a normal scotopic ERG, and their mean psychophysical dark-adapted threshold was -5.3 +/- 0.3 cd.m-2. One of the four was able to complete the entire procedure, and a normal profile was found. In patients with DMD the dark adaptation measurements are normal despite abnormalities in rod related ERG activity. PMID- 7834568 TI - Anterior transposition of the inferior oblique for dissociated vertical deviation with inferior oblique overaction. AB - We reviewed the charts of 17 children (27 eyes) who underwent anterior transposition of the inferior oblique muscle for dissociated vertical deviation coexistent with inferior oblique overaction. All the eyes showed an improvement in the inferior oblique overaction. Twenty-one eyes had reduction in the dissociated vertical deviation, five eyes showed no change in the degree of dissociated vertical deviation, and in one case the hyperdeviation increased after surgery. No intraoperative or late postoperative complications were noted. Anterior transposition is an effective procedure for weakening inferior oblique overaction coexistent with dissociated vertical deviation. PMID- 7834569 TI - Sebaceous carcinoma and hyperplasia of the caruncle. A clinicopathological report. PMID- 7834570 TI - Cysticercosis of the orbit. PMID- 7834571 TI - Effect of cyclopiazonic acid on contractile responses in slow and fast bundles of cremaster skeletal muscle from the ferret. AB - The effects of cyclopiazonic acid (CPA) on twitch force, calcium (Ca2+) uptake and release by the sarcoplasmic reticulum (SR), and Ca2+ sensitivity of contractile apparatus were studied using intact and chemically skinned cremaster fibers and compared with those on the extensor digitorum longus and soleus. In cremaster muscles treated with CPA (0.5-5 microM) a potentiation of the twitch was observed, associated with an increase in time to peak and in time of relaxation. In Triton-skinned fibers, CPA, at concentrations less than 10 microM, exerted no significant effect on the contractile apparatus of either slow- or fast-twitch fibers. In slow-twitch fibers, a dose-dependent increase in Ca2+ sensitivity was associated with a decrease in maximal tension, at CPA concentrations > 10 microM. In saponin-skinned fibers, during the uptake phase, CPA at > 10 microM induced a dose-dependent decrease in caffeine contracture. The possibility of an action on the SR Ca2+ release channel was excluded by testing the effect of CPA during the releasing phase. The enhancing effect of CPA (0.5-5 microM) on mechanical activity could be explained by an inhibition of the SR Ca2+ ATPase in skeletal muscle cells without an effect on the contractile proteins. Our results strongly suggest that CPA (< 10 microM) has a highly specific effect on the SR Ca2+ pump in the fast- and slow-twitch fibers and therefore could be a good tool to study the mechanisms of Ca2+ regulation in skeletal muscles.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7834572 TI - Effects of essential amino acids on food and water intake of rats. AB - This study examined the effects of selected groups of essential amino acids (EAAs), given by gavage, on short-term food and water intake. Amino acid groups were selected on the basis of their common physiologic functions in relation to current hypotheses on the role of amino acids in food intake control, and the quantities given were based on the proportions in 1.5 g of the EAA content of albumin. The complete EAA mixture (1.5 g) suppressed food intake by an average of 60 and 37% during the 1st and 2nd h of feeding, respectively, but had no influence on feeding in the subsequent 12 h. Total daily (14 h) intake was decreased by 9%. With the exception of the aromatic amino acid (Phe + Tyr + Trp, 0.34 g) group, all groups significantly decreased food intake by a comparable magnitude (32%) during the 1st h. In this time period, rats given the EAAs, Arg + Met + Val (0.38 g), and Arg + His + Lys (0.44 g) mixtures increased their water intake, whereas intake by rats given the Phe + Tyr + Trp + Thr (0.46 g) and Ile + Leu + Val (0.45 g) mixtures was unchanged. Thus, the food intake suppression caused by EAAs was not accounted for by an equal effect of its component amino acid groups. As well, food intake suppression by amino acid groups was not explained by increased water consumption, nor was it simply related to the quantity of nitrogen provided by the treatment. PMID- 7834573 TI - Effects of Buthus martensii Karsch scorpion venom on the release of noradrenaline from in vitro and in vivo rat preparations. AB - The aim of this study was to test the neuronal effects of the Chinese Buthus martensii Karsch (BMK) scorpion venom in vivo and in vitro in order to understand the mechanism involved in the cardiovascular pressor effect of this venom. In conscious unrestrained rats, administration of 100 micrograms/kg i.v. BMK venom induced an increase in blood pressure, which was associated with a significant increase in plasma noradrenaline. In isolated atria, BMK also induced an increase in the stimulation-induced release of [3H]noradrenaline in a dose-dependent manner. The modulatory effect of agents acting at sympathetic prejunctional adrenoceptors on [3H]noradrenaline release was not altered by BMK venom administration. Finally, it was observed that 100 micrograms/mL BMK venom increased the intracellular calcium concentration in acutely dissociated sympathetic neurons from adult rat superior cervical ganglion. This action appeared to be mainly due to an influx of extracellular calcium. BMK venom induced a small rise in intracellular calcium in the absence of external calcium, indicating that it may also mobilize calcium from intracellular stores. The results observed in this study suggest that BMK venom may induce pressor responses by releasing noradrenaline from the sympathetic nerve terminals and that activation of neuronal calcium channels may be involved in that process. PMID- 7834574 TI - Alpha 1-adrenoceptor subtypes mediating contraction of the femoral artery in spontaneously hypertensive rats. AB - alpha 1-Adrenoceptors (ARs) were divided into alpha 1H and alpha 1L subtypes by their different affinities for bunazosin or prazosin. alpha 1H-ARs were further subdivided into alpha 1A, alpha 1B, and alpha 1C subtypes. Therefore, this study was undertaken to determine which alpha 1-AR subtypes were involved in the activation of femoral artery preparations by alpha 1-AR agonists in spontaneously hypertensive rats (SHR). For comparison, aortic strips were also incorporated in the present study. In the presence of propranolol, deoxycorticosterone, and desipramine, norepinephrine (NE) contracted the vascular strips in a dose dependent manner. Negative log EC50 values and maximum responses of NE-induced contraction of the SHR femoral artery were unchanged and increased, respectively, compared with those of Sprague-Dawley and Wistar-Kyoto rats (WKY). Contractile responses of the SHR aortae to NE were similar to those of the normotensive tissues. Schild plot data for alpha 1-AR antagonists indicated that alpha 1-AR subtypes mediating contraction of the aorta were homogeneous and had high affinities for bunazosin (pA2 9.4, alpha 1H subtype) and WB 4101 (pA2 9.3) and a low affinity for 5-methylurapidil (pA2 7.7). In the femoral artery, because Schild plots for bunazosin had slopes of less than 1.0, there were alpha 1H and alpha 1L subtypes. Bunazosin, at 10(-9) M, which could mask the alpha 1H subtype, yielded a Schild plot for bunazosin with a slope not different from unity and decreased the pA2 value for bunazosin (pA2 9.4 vs. 8.5).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7834575 TI - Effects of some naturally occurring prostanoids and some cyclooxygenase inhibitors on the contractility of the human lower uterine segment in vitro. AB - The contractility of strips of human lower segment myometrium obtained from elective cesarean section performed at term of pregnancy was studied in vitro. The effects of indomethacin and tiaprofen upon spontaneous contractile activity were examined. Concentration-effect curves for PGD2, PGE2, PGF2 alpha, 6-keto PGE1, and 6-keto-PGF1 alpha were constructed in the presence of indomethacin. Neither indomethacin nor tiaprofen in concentrations up to 100 mumol/L had any effect upon spontaneous activity. Contractions were induced by the prostanoids with the following mean EC50 values: PGE2, 13 nM; PGF2 alpha, 250 nM; PGD2, 790 nM; both 6-keto-PGF1 alpha and 6-keto-PGE1 were without effect in concentrations up to 30 mumol/L. In some tissues PGE2 inhibited spontaneous activity with a mean IC50 of 100 nM. No other prostanoid tested caused inhibition under any circumstance. The marked potency differences between the natural prostanoids is an important parameter to consider when assessing their relative contributions to the process of parturition and the design of new therapeutic agents for the management of preterm labour. PMID- 7834576 TI - Beta-adrenergic receptor desensitization in the early stage of hereditary cardiomyopathy in hamsters. AB - The beta-adrenergic receptor (beta AR)/adenylyl cyclase signalling pathway was examined in cardiac membranes from cardiomyopathic Syrian hamsters. Three stages were examined during the progression of this hereditary cardiomyopathy (30 days old, prenecrotic phase; 60 days old, necrotic phase; and 120 days old, compensatory phase). Isoproterenol-stimulated adenylyl cyclase activity was decreased by 32 +/- 16% in 30-day-old cardiomyopathic hamsters, compared with age matched controls. This was not accompanied by any change in the fluoride- or forskolin-stimulated activities, suggesting that the decrease reflects a perturbation of the receptor-mediated stimulation. Neither the density nor the subcellular distribution of the beta AR, as assessed by [125I]iodocyanopindolol binding assays, was affected in these animals. However, the agonist binding properties of the beta AR were significantly affected. Indeed, the effect of guanyl nucleotides on isoproterenol binding was decreased in 30-day-old cardiomyopathic hamsters. Given that guanyl nucleotide sensitivity is correlated with the ability of the beta AR to productively interact with Gs protein, these results suggest that the decreased beta-adrenergic-stimulated adenylyl cyclase activity results from a functional uncoupling of the beta AR with no change in receptor density. The desensitization of the beta-adrenergic-stimulated adenylyl cyclase was transient, since no change in isoproterenol-stimulated adenylyl cyclase was detected in 60- and 120-day-old hamsters, compared with age-matched controls. Similarly, the receptor number and distribution were not affected at those ages.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7834577 TI - Pharmacological but not physiological modulation of cortical acetylcholine release by cholinergic mechanisms in the nucleus basalis magnocellularis. AB - The role of muscarinic transmission in the activation of cholinergic neurons ascending to the neocortex from the nucleus basalis magnocellularis (NBM) was investigated. The release of acetylcholine (ACh) from the neocortex of urethane anesthetized rats was measured using microdialysis, and a second microdialysis probe was inserted into the NBM to apply drugs to the NBM and to measure ACh release from this area. Cholinergic neurons in the NBM were activated synaptically by stimulating the pedunculopontine tegmentum (PPT). Systemically administered scopolamine greatly increased the PPT stimulation evoked cortical release of ACh when the cortical probe was perfused with the cholinesterase inhibitor neostigmine. PPT stimulation evoked release was also high when the cortical probe was perfused with atropine plus neostigmine, but it was not increased any further by systemic scopolamine or by scopolamine perfused through the NBM probe. When neostigmine was perfused through the NBM probe, PPT stimulation evoked cortical ACh release was halved, but the release was restored when the NBM solution also contained scopolamine. The resting release of ACh within the NBM was increased by local neostigmine, but evoked release in the NBM was large only in the presence of local scopolamine. Both of these increases were blocked by perfusion of the NBM with tetrodotoxin. These results suggest that muscarinic transmission within the NBM does not control the activation of cholinergic neurons under physiological conditions, when the diffusion of ACh is limited by its hydrolysis. However, when ACh is allowed to diffuse to a wider area, it may inhibit the release of an excitatory transmitter, probably glutamate, via presynaptic muscarinic receptors. PMID- 7834578 TI - Hyperthyroidism stimulates mitochondrial proton leak and ATP turnover in rat hepatocytes but does not change the overall kinetics of substrate oxidation reactions. AB - Thyroid hormones have well-known effects on oxidative phosphorylation, but there is little quantitative information on their important sites of action. We have used top-down elasticity analysis, an extension of metabolic control analysis, to identify the sites of action of thyroid hormones on oxidative phosphorylation in rat hepatocytes. We divided the oxidative phosphorylation system into three blocks of reactions: the substrate oxidation subsystem, the phosphorylating subsystem, and the mitochondrial proton leak subsystem and have identified those blocks of reactions whose kinetics are significantly changed by hyperthyroidism. Our results show significant effects on the kinetics of the proton leak and the phosphorylating subsystems. Quantitative analyses revealed that 43% of the increase in resting respiration rate in hyperthyroid hepatocytes compared with euthyroid hepatocytes was due to differences in the proton leak and 59% was due to differences in the activity of the phosphorylating subsystem. There were no significant effects on the substrate oxidation subsystem. Changes in nonmitochondrial oxygen consumption accounted for -2% of the change in respiration rate. Top-down control analysis revealed that the distribution of control over the rates of mitochondrial oxygen consumption, ATP synthesis and consumption, and proton leak and over mitochondrial membrane potential (delta psi m) was similar in hepatocytes from hyperthyroid and littermate-paired euthyroid controls. The results of this study include the first complete top-down elasticity and control analyses of oxidative phosphorylation in hepatocytes from hyperthyroid rats. PMID- 7834579 TI - Excitability of human motor cortex during hyperventilation and hypercapnia. AB - We tested the hypothesis that the excitability of corticospinal neurons was altered by changes in PCO2. Magnetic stimulation was used to excite the neurons in the human motor cortex that give rise to the fast-conducting corticospinal pathway. The characteristics of the composite excitatory postsynaptic potentials (EPSPs) produced in individual spinal motoneurons by cortical stimulation were derived from changes in the firing probability of voluntarily activated motor units. The amplitudes of these composite EPSPs in response to a constant cortical stimulus were assumed to reflect the excitability of cortical neurons. In 10 healthy subjects, we found no statistically significant changes in the excitability of the cortical neurons during normocapnic conditions (mean end tidal PCO2 5.1 kPa), during hyperventilation-induced hypocapnia (mean end-tidal PCO2 2.9 kPa), and during hyperoxic hypercapnia induced by a rebreathing technique (mean end-tidal PCO2 6.9 kPa). We conclude that the excitability of corticospinal neurons activated by magnetic stimulation is not significantly affected by changes in PCO2. PMID- 7834581 TI - Dietary calcium, defective cellular Ca2+ handling, and arterial pressure control. AB - The association between dietary calcium intake, calcium metabolism, and blood pressure form the basis of this review. Epidemiologic data consistently show an inverse relationship between dietary calcium and blood pressure. Clinical trials of calcium supplementation have not been as consistent in outcome. Approximately two-thirds of the supplementation studies have found a beneficial effect of calcium on blood pressure. The lack of consistency in outcome from the clinical trials relative to the epidemiological literature may be related to calcium intake. The epidemiological literature indicates an inverse relationship between calcium intake and blood pressure, with those individuals with the lowest calcium intake (< 700 mg/day) having the highest blood pressure. Clinical studies utilizing patients with high baseline calcium levels (> 700 mg/day) may not see an effect of calcium supplementation on blood pressure because of a ceiling effect. Supplemental calcium appears to correct a defect in calcium handling characterized by a renal calcium leak, increased circulating parathroid hormone, and increased intracellular calcium levels. In part, the deficit in cellular calcium homeostasis may be a consequence of abnormal calmodulin activity. Specifically, it appears that calmodulin activity is diminished in experimental hypertension and that increasing dietary calcium may improve calmodulin activity in the spontaneously hypertensive rat. The deficit in calmodulin activity has the potential to interfere with a number of cellular processes crucial to the regulation of cell function and maintenance of appropriate vascular tone. It is concluded that additional research should be directed toward understanding the ramifications of altered calmodulin activity in hypertension and the influence that dietary calcium can have on the activity of calmodulin. PMID- 7834580 TI - Regulation of vascular smooth muscle tone. AB - Vascular smooth muscle tone is regulated primarily by the sarcoplasmic free Ca2+ concentration, which determines the level of myosin phosphorylation. Stimulation of the muscle results in an increase in free [Ca2+], whereupon Ca2+ binds to calmodulin, inducing a conformational change enabling calmodulin to interact with and activate myosin light chain kinase. The active Ca2+.calmodulin.myosin light chain kinase complex catalyses the phosphorylation of serine-19 of the two 20-kDa light chains of myosin; this triggers cross-bridge cycling and the development of force. Relaxation follows restoration of free [Ca2+] to the resting level, whereupon calmodulin dissociates from myosin light chain kinase, which is thereby inactivated, and myosin is dephosphorylated by myosin light chain phosphatase and remains detached from actin. Overwhelming evidence now exists in favour of the central role of myosin phosphorylation-dephosphorylation in smooth muscle contraction-relaxation. However, considerable evidence supports the existence of additional, secondary mechanisms that can modulate the contractile state of smooth muscle either by altering the Ca2+ sensitivity of the contractile response or otherwise modulating one of the molecular events occurring downstream of the Ca2+ signal, e.g., the interaction of phosphorylated myosin heads with actin. The interplay of several regulatory elements confers on the contractile response of vascular smooth muscle the high degree of flexibility and adaptability required for the effective regulation of blood pressure. PMID- 7834582 TI - Fish oil, essential fatty acids, and hypertension. AB - A proper balance between the n-3 and n-6 series of essential fatty acids (EFAs) is essential for homeostasis and normal growth in humans. Dietary supplement with fish oil and related n-3 EFAs has been used to study their antihypertensive property in animals and humans with borderline and essential hypertension. In the animal models, chronic treatment of young animals generally only attenuated the development of hypertension. In animals with hypercholesterolemia, n-3 EFA supplement increased the incidence of atherosclerosis. In humans, chronic treatment with fish oil only produced a small reduction in blood pressure. The concerns are that the high dose of fish oil may interfere with the control of blood glucose in diabetic patients, and may cause prolonged bleeding in surgical patients. Studies on the animal models of hypertension showed that n-6 EFAs are more effective than n-3 EFAs in lowering and normalizing the blood pressure of these animals, probably through the production of tissue prostaglandins, which favour vasodilation. The antihypertensive effect of the n-6 EFAs in humans is not well known, because there are only a few studies, usually involving a very small number of patients. A possible side effects of n-6 EFAs for concern is that they might stimulate tumour development. A careful examination of these risk factors is needed before any recommendation can be made concerning the use of EFAs for the control of hypertension for humans. PMID- 7834583 TI - Intracellular signal transduction for vasoactive peptides in hypertension. AB - Increased peripheral resistance is the hallmark of hypertension. It may result in part from exaggerated vascular reactivity of resistance arteries. Some changes in density of surface receptors for different vasoconstrictors and vasorelaxants have been described that could play a role in physiological findings in hypertension. Smooth muscle cells of resistance arteries have increased cytosolic free calcium concentration in some models of experimental hypertension, which may contribute to enhance vascular responses. Exaggerated response of the inositol phosphate-calcium pathway has been demonstrated after stimulation with some vasoconstrictor agents such as norepinephrine, angiotension II, and vasopressin. In contrast, responses to the potent vasoconstrictor peptide endothelin-1 are either normal (in spontaneously hypertensive rats) or blunted (in deoxycorticosterone-salt hypertension). In the latter case, endothelin receptor density, inositol phosphate and diacylglycerol generation, and cytosolic calcium responses agree with blunted response of blood vessels. Increased basal cytosolic calcium and exaggerated sensitivity of myosin light chain to calcium may be mechanisms underlying increases in sensitivity of signal transduction in smooth muscle in some models of hypertension. However, in general, signal transduction of receptors for vasoconstrictors appears to be blunted rather than exaggerated, except for responses to angiotensin II. Altered structure of resistance arteries (remodeling) may be a mechanism that, even in presence of blunted intracellular signal transduction, may result in enhanced pressor responsiveness of blood vessels in hypertension. PMID- 7834584 TI - Limb salvage surgery: an advance in surgical technique. AB - "Surgery is the primary and oldest treatment for malignant musculoskeletal tumors. Until the 1970's amputation was the accepted surgical procedure for patients with malignant tumors of the extremities. Recent advances in adjuvant treatment modalities such as chemotherapy and radiotherapy, bioengineering designs of internal prosthetic devices, radiographic workups, and bone and tissue transfers provide some individuals with the option of limb-preservation" (Lewis, 1992, p. 477-478). One limb salvaging technique uses a metallic implant to replace resected tumors of the bone. It is this surgical orthopaedic advancement that is currently being used in the resection of primary malignant bone tumors of the lower extremities at Mount Sinai Hospital, Toronto, Ontario. The objectives of this paper are to review the management of musculoskeletal tumors in "skeletally mature patients", and to review a system currently being utilized at Mount Sinai Hospital which provides a surgical option for resection and reconstruction of malignant bone tumors. The role the perioperative nurse plays in providing care to patients having limb salvage surgery will also be described. All three objectives will provide insight into the challenges facing orthopaedic oncology patients who are living with cancer. PMID- 7834585 TI - Fluid replacement therapy and perioperative management. AB - Fluid management is a vital component of the perioperative management of every patient. The operating room nurse should be familiar with the dynamics of body fluids and its clinical significance. Having an understanding of fluid therapy and the individual patient's needs will enhance and assist in building the teamwork approach of care with the anesthetist. PMID- 7834586 TI - Event related outdating: a fairy tale comes true. AB - Traditionally ORs and CSRs have outdated reusable sterile goods at predetermined times. Professional standards (ORNAC, AORN, CSA) support event related outdating meaning that sterile goods remain sterile indefinitely unless package integrity is compromised. Significant savings in supply and labour costs can be realized without compromising patient care. The article outlines a model for the implementation of event related outdating. PMID- 7834587 TI - Difficult intubation: are you prepared for it? AB - The endotracheal intubation of a patient for surgery requires an anaesthetist who is aided by a skilled and experienced helper. This paper explores reasons why some patients are difficult to intubate. Some are predictable on pre-operative assessment and others are not. Suggestions are given on how the helper is useful to the anaesthetist in this potentially critical situation. PMID- 7834588 TI - Into the land of Nod: drugs used during anesthesia in day surgery. AB - This paper lists and describes some of the drugs used during anesthesia in a Day Surgery Operating Room. The classification, action and implications of these drugs are addressed. The discussion is presented under the drug classes as Narcotic Analgesics/Opioids Antagonists, Opiate Antagonists, Induction Agents, Muscle Relaxants/Neuromuscular Blocking Agents, Inhalation Anesthetics, Cholinesterase Inhibitors Anticholinesterases/Parasymphathomimetics, Anticholinergics/Antimuscarinics/Parasympatholytics, and Antiemitics. PMID- 7834589 TI - Neural networks and schizophrenia. PMID- 7834590 TI - Psychiatrists' ratings of expressed emotion. AB - The purpose of this study was to determine the extent to which psychiatrists are familiar with the concept of expressed emotion and to determine the extent of its use in their day-to-day practices. We also wished to test the ability of psychiatrists to estimate the expressed emotion status of the relatives of their patients. Following the assessment of expressed emotion in 96 relatives using the Camberwell Family Interview, the psychiatrists treating the schizophrenic patients were surveyed about their knowledge of expressed emotion and were asked to estimate the expressed emotion of their relatives. Thirty-five percent of the respondents use the expressed emotion concept daily in their practice. When the Camberwell Family Interview ratings of expressed emotion were compared with those from the psychiatrists, the agreement rate was no better than chance (45.7%). Without formal training in the use of the Camberwell Family Interview, practitioners are cautioned against ascribing an expressed emotion status to the relatives of their patients. PMID- 7834591 TI - A neural network model of cortical information processing in schizophrenia. I: Interaction between biological and social factors in symptom formation. AB - Exploiting the biological and psychological plausibility of parallel distributed processing, a neural network model of cortical processing is proposed in order to provide a framework for understanding pathological processes in schizophrenia. Major psychosocial and neurobiological factors are assigned to appropriate parameters in the model. Behaviour of the network is explored through simulation, in particular interaction between the temperature and memory loading parameters is studied. The emergent network behaviour provides a model for complex interaction between dopaminergic activity, cortical and hippocampal pathology, and psychosocial factors in the production of psychotic symptoms. This integrative model provides an account of a wide range of observations in schizophrenia. It also produces testable predictions concerning cognitive performance and the course of schizophrenia. PMID- 7834592 TI - The psychometric properties of the Competency Interview Schedule. AB - One of the most contentious issues in medical and legal practice is how to reliably assess the mental competence of individuals who consent or refuse psychiatric treatment. Current legislation does not provide clear definitions of what constitutes competence or incompetence to make a treatment decision. As a preliminary attempt to operationalize the concept of competency, we have developed a 15 item questionnaire. The present study reports on the psychometric properties of the instrument. Test-retest and interrater reliability results were good. The instrument was internally consistent and discriminated between individuals found competent and incompetent by the treating physician. PMID- 7834593 TI - The treatment of avoidant personality disorder by social skills training in the clinic or in real-life settings. AB - Twenty-eight outpatients who met DSM-III diagnostic criteria for avoidant personality disorder completed 14 one and a half hour sessions of social skills training in the clinic only or a combination of four sessions in the clinic, four sessions in real-life and six follow-up sessions in the clinic. Subjects were assessed before treatment began, after four sessions, at the end of treatment and at three month follow-up points. Training in real-life did not enhance social skills training; no significant difference between the groups at any assessment points was found. In both groups improvement in time was significant and clinically worthwhile. The treatment effects were maintained up to the three month follow-up, where available. Social skills training appears to be a useful and promising intervention for avoidant personality disorder but its long term impact remains to be investigated. PMID- 7834594 TI - [Prediction of somatization disorders in pre-pubertal girls]. AB - Several studies of female adult populations suggest that somatization problems appear during adolescence and that they are related to behavioural problems during childhood. This study uses Cloninger's personality model to verify the link between personality traits and the beginning of somatization problems in elementary school girls. This model is based on the interaction of three dimensions: novelty seeking, harm avoidance and social reward dependence. Subjects were part of a longitudinal study of the social adjustment of children from Montreal and Val d'Or families. Evaluations of the girls' behaviour in kindergarten were used to establish personality types according to Cloninger's model. The somatization problems were assessed at age ten following interviews with mothers and girls, and ratings by mothers and teachers. The results showed that somatization problems at age ten were more likely when novelty seeking and harm avoidance were high in kindergarten. The kindergarten girls with 'passive aggressive' or 'explosive-schizoid' personality profiles were more at risk of higher levels of somatization problems at age ten. However, Cloninger's hypothesized link between high levels of somatization problems and the 'histrionic' personality profile was not confirmed. PMID- 7834595 TI - The epidemiology of parasuicide in Edmonton. AB - The objective of this study was to examine some of the characteristics of parasuicides in Edmonton and to calculate rates of parasuicide. The method involved examining all records of parasuicides attending the University of Alberta Hospitals for a six month period (20% of all parasuicides in Edmonton are treated at the University of Alberta Hospitals). The results indicated that 58% of 275 subjects were single. The most frequent method (88.6%) of parasuicide was overdose. The peak age group was 25 to 29 years of age. The age range was 12 to 80 years (six percent < 15 years), mean age 30.2. The female to male ratio (cases) was 1.6:1; 30.2% were admitted; 46.5% received psychiatric emergency consultation; 41% had made a previous parasuicide. Calculated rates of parasuicide in Edmonton were at 448/100,000/year for those 15 years and older (men 357, women 534). The overall rate is higher than that found in any centre in the WHO/EURO investigation. The conclusion is that parasuicide presents a significant public health problem, and a cost burden on the health care system. PMID- 7834596 TI - A five year review of youth suicide in Manitoba. AB - Suicide is the second leading cause of death in adolescents. The suicide rate in the 15 to 24 year old age group has increased at a faster rate than in any other age group. This study is a descriptive and retrospective investigation of 204 files from the Chief Medical Examiner's office of all youths aged 24 years and less in the province of Manitoba who committed suicide between 1984 and 1988. The study found a high male to female ratio, a large number of younger adolescents and a suicide rate in the Native population which was ten times that of non Natives. The method of suicide varied by gender and race. Males more often used hanging and guns; females were more likely to overdose. Natives tended to hang themselves more than non-Natives, while non-Natives more often used guns. The highest percentage of Native suicides occurred in urban areas. Depression and substance abuse were identified as risk factors. A number of recommendations regarding information gathering post-suicide, as well as prevention and intervention programs are proposed. PMID- 7834597 TI - [Psychoimmunology and AIDS: a review of the literature]. AB - In recent years, several studies have been carried out concerning the effect of psychosocial factors on the course of infection due to the human immunodeficiency virus (HIV). After summarizing the current status of general knowledge in the field of psychoimmunology, this article reviews the results of studies conducted in regard to HIV. Two conclusions are reached. The first is that current research has not shown psychosocial factors to have any impact on either the immunity status of seropositive patients or the medical complications inherent to AIDS. The second conclusion is that several types of intervention, in particular psychoeducational approaches, stress management programs, and the strengthening of social and family support, give good results where the psychosocial well-being of patients is concerned and should motivate various health professionals to improve the focus of their interventions. Furthermore, significant methodological weaknesses in several indexed studies are noted, and these should be rectified to enable future studies to confirm or correct the present observations. PMID- 7834598 TI - Fitness to stand trial. PMID- 7834599 TI - Infectious diseases associated with molluscan shellfish consumption. AB - A history of shellfish-vectored illnesses (i.e., those associated with consumption of clams, oysters, mussels, and scallops) occurring in the past nine decades is presented. Typhoid fever was a significant public health problem among consumers of raw molluscan shellfish earlier in this century. The development of more effective sewage treatment procedures and the institution of a national program following these outbreaks led to a series of measures which eventually eliminated shellfish-associated typhoid fever. Present-day problems associated with this food source still involve some wastewaterborne bacterial illnesses. However, the principal public health concerns are with wastewater-derived viral pathogens and with bacterial agents of an environmental origin. The nature, occurrence, and magnitude of these public health problems are described. PMID- 7834600 TI - Human microsporidial infections. AB - Microsporidia are obligate intracellular spore-forming protozoal parasites belonging to the phylum Microspora. Their host range is extensive, including most invertebrates and all classes of vertebrates. More than 100 microsporidial genera and almost 1,000 species have now been identified. Five genera (Enterocytozoon spp., Encephalitozoon spp., Septata spp., Pleistophora sp., and Nosema spp.) and unclassified microsporidia (referred to by the collective term Microsporidium) have been associated with human disease, which appears to manifest primarily in immunocompromised persons. The clinical manifestations of microsporidiosis are diverse and include intestinal, pulmonary, ocular, muscular, and renal disease. Among persons not infected with human immunodeficiency virus, ten cases of microsporidiosis have been documented. In human immunodeficiency virus-infected patients, on the other hand, over 400 cases of microsporidiosis have been identified, the majority attributed to Enterocytozoon bieneusi, an important cause of chronic diarrhea and wasting. Diagnosis of microsporidiosis currently depends on morphological demonstration of the organisms themselves. Initial detection of microsporidia by light microscopic examination of tissue sections and of more readily obtainable specimens such as stool, duodenal aspirates, urine, sputum, nasal discharge, bronchoalveolar lavage fluid, and conjunctival smears is now becoming routine practice. Definitive species identification is made by using the specific fluorescein-tagged antibody (immunofluorescence) technique or electron microscopy. Treatment options are limited, but symptomatic improvement of Enterocytozoon bieneusi infection may be achieved with the anthelmintic-antiprotozoal drug albendazole. Preliminary observations suggest that Septata intestinalis and Encephalitozoon infections may be cured with albendazole. Progress is being made with respect to in vitro propagation of microsporidia, which is crucial for developing antimicrosporidial drugs. Furthermore, molecular techniques are being developed for diagnostic purposes, taxonomic classification, and analysis of phylogenetic relationships of microsporidia. PMID- 7834601 TI - Virulence of enterococci. AB - Enterococci are commensal organisms well suited to survival in intestinal and vaginal tracts and the oral cavity. However, as for most bacteria described as causing human disease, enterococci also possess properties that can be ascribed roles in pathogenesis. The natural ability of enterococci to readily acquire, accumulate, and share extrachromosomal elements encoding virulence traits or antibiotic resistance genes lends advantages to their survival under unusual environmental stresses and in part explains their increasing importance as nosocomial pathogens. This review discusses the current understanding of enterococcal virulence relating to (i) adherence to host tissues, (ii) invasion and abscess formation, (iii) factors potentially relevant to modulation of host inflammatory responses, and (iv) potentially toxic secreted products. Aggregation substance, surface carbohydrates, or fibronectin-binding moieties may facilitate adherence to host tissues. Enterococcus faecalis appears to have the capacity to translocate across intact intestinal mucosa in models of antibiotic-induced superinfection. Extracellular toxins such as cytolysin can induce tissue damage as shown in an endophthalmitis model, increase mortality in combination with aggregation substance in an endocarditis model, and cause systemic toxicity in a murine peritonitis model. Finally, lipoteichoic acid, superoxide production, or pheromones and corresponding peptide inhibitors each may modulate local inflammatory reactions. PMID- 7834602 TI - Taxonomy, biology, and clinical aspects of Fusarium species. AB - There are several taxonomic systems available for identifying Fusarium species. The philosophy used in each taxonomic system is discussed as well as problems encountered in working with Fusarium species in culture. Fusarium species are toxigenic, and the mycotoxins produced by these organisms are often associated with animal and human diseases. The implications for the association of the carcinogens, fumonisins, produced by Fusarium moniliforme and other Fusarium species with human diseases are discussed. Foreign-body-associated fusarial infection such as keratitis in contact lens wearers, onychomycosis, skin infections, and disseminated multiorgan infections are discussed. Disseminated fusarial hyalohyphomycosis has emerged as a significant, usually fatal infection in the immunocompromised host. Successful outcome is determined by the degree of immunosuppression, the extent of the infection, and the presence of a removable focus such as an indwelling central venous catheter. These infections may be clinically suspected on the basis of a constellation of clinical and laboratory findings, which should lead to prompt therapy, probably with one of the newer antifungal agents. Perhaps the use of such agents or the use of colony stimulating factors may improve the outcome of this devastating infection. However, until new approaches for treatment develop, effective preventive measures are urgently needed. PMID- 7834606 TI - Sequential coexpression of the multidrug resistance genes MRP and mdr1 and their products in VP-16 (etoposide)-selected H69 small cell lung cancer cells. AB - Resistance to drugs included in the multidrug-resistance phenotype has been attributed to overexpression of either mdr1 or MRP genes and their products in numerous cell lines, while coexpression, to our knowledge, has not previously been reported in the same cells. Human small cell lung cancer H69/VP cells were developed by continuous incubation in increasing doses of VP-16. In reverse transcription-PCR assays we found over-expression of both mdr1 and multidrug resistance protein (MRP) genes, and immunoblots showed both elevated P glycoprotein and MRP in H69/VP cells. Double immunocytochemical staining demonstrated the expression of both MRP and P-glycoprotein in the same cells, indicating that the observations do not result from the selection of two independent clones. Examination of early passages of H69/VP cells showed that overexpression of MRP mRNA occurred prior to mdr1. Thus, cell lines and clinical samples in the future should be tested for both mdr1/P-glycoprotein and MRP since a positive result for one of the phenotypes does not preclude the existence of the other. PMID- 7834607 TI - Cytotoxic T cells overcome BCR-ABL-mediated resistance to apoptosis. AB - Chronic myeloid leukemia is a disease marked by expanded clonal hematopoiesis; it is incurable by chemotherapy or radiation but is cured in a majority of patients receiving bone marrow transplantation from nonidentical sibling donors, an outcome generally attributed to a T cell-mediated graft-versus-leukemia effect. In this report, we examine the effect of the P210BCR-ABL fusion protein of the BCR-ABL oncogene, the molecular hallmark of chronic myelogenous leukemia, on the sensitivity of mouse cell lines to apoptosis induced by chemotherapy, radiation, or activated cytotoxic T lymphocytes (CTLs). We find that, although cells expressing P210BCR-ABL by gene transfer are more resistant than their normal counterparts to apoptosis induced by chemotherapy or radiation, they are equally susceptible to apoptosis induced by alloreactive CTLs. These results show that CTLs overcome BCR-ABL-mediated resistance to apoptosis and, therefore, provide a biological correlation for the success of allogeneic bone marrow transplantation in chronic myelogenous leukemia. PMID- 7834608 TI - Identical allelic loss on chromosome 11q13 in microdissected in situ and invasive human breast cancer. AB - Human breast carcinoma is thought to develop through progressive stages from atypical hyperplasias to in situ carcinoma and finally to invasive and metastatic cancer. In situ breast carcinoma consists of small, isolated neoplastic foci which cannot be selectively studied by conventional methods. In this study, we used tissue microdissection to examine the loss of heterozygosity (LOH) of chromosome 11q13 in both in situ and invasive lesions of the breast, as compared to normal breast epithelium from the same patients. Forty-one cases of sporadic breast cancer were analyzed. Tissue microdissection allows for procurement and PCR-based analysis of small lesions using either frozen or formalin-fixed, paraffin-embedded tissue sections. LOH on chromosome 11q13 was found in 24 of 36 (67%) of the informative invasive breast cancer cases using two polymorphic DNA markers specific for this region (INT2 and PYGM). Twenty-one of the cases which demonstrated LOH in the invasive tumor also contained in situ carcinoma in the same tissue section. Seventy-one % (15 of 21) of the microdissected in situ lesions showed LOH of chromosome 11q13. Every case (15 of 15) of in situ tumor with LOH showed loss of the same allele in the corresponding invasive tumor cells. The results of this study suggest that a tumor suppressor gene located on chromosome 11q13 may play an important role in the early stages of development of sporadic human breast cancer. This finding provides molecular genetic support for the hypothesis that invasive breast cancer arises from in situ lesions. PMID- 7834604 TI - Bronchoscopic diagnosis of pneumonia. AB - Lower respiratory tract infections are characterized by significant morbidity and mortality but also by a relative inability to establish a specific etiologic agent on clinical grounds alone. With the recognized shortcomings of expectorated or aspirated secretions toward establishing an etiologic diagnosis, clinicians have increasingly used bronchoscopy to obtain diagnostic samples. A variety of specimen types may be obtained, including bronchial washes or brushes, protected specimen brushings, bronchoalveolar lavage, and transbronchial biopsies. Bronchoscopy has been applied in three primary clinical settings, including the immunocompromised host, especially human immunodeficiency virus-infected and organ transplant patients; ventilator-associated pneumonia; and severe, nonresolving community- or hospital-acquired pneumonia in nonventilated patients. In each clinical setting, and for each specimen type, specific laboratory protocols are required to provide maximal information. These protocols should provide for the use of a variety of rapid microscopic and quantitative culture techniques and the use of a variety of specific stains and selective culture to detect unusual organism groups. PMID- 7834609 TI - A specific African-American CYP1A1 polymorphism is associated with adenocarcinoma of the lung. AB - A case-control study on lung cancer in African-Americans has been conducted to assess whether a novel African-American-specific polymorphism in the CYP1A1 gene increases the susceptibility to tobacco-related lung cancer. The prevalence of the AA RFLP was 17.1% in the DNA extracted from archived tissue blocks from 76 incident cases of lung cancer, and was 16.3% in peripheral blood lymphocyte DNA of 123 healthy African-American volunteers recruited from a community in the eastern United States. The analysis by histological type showed an association between adenocarcinoma (AC) of the lung and the AA RFLP (odds ratio, 2.6; 95% confidence interval, 1.1-6.3). One homozygous variant subject was present among the AC cases. The risk of AC in subjects who both smoke and carry the AA RFLP was more than double, in comparison to subjects who only smoke (relative interaction magnitude under the additive model, 24%). The mean value of pack-year in AC with the polymorphism was 5.0 +/- 2.5 and in AC without the polymorphism was 37.2 +/- 6.5 (P < 0.05). Our data suggest that a selective association exists between the AA polymorphism and adenocarcinoma of the lung and that a lower dose of tobacco is sufficient to exert carcinogenic effects on the adenomatous tissue of subjects carrying the AA polymorphism. PMID- 7834605 TI - Current status of meningococcal group B vaccine candidates: capsular or noncapsular? AB - Meningococcal meningitis is a severe, life-threatening infection for which no adequate vaccine exists. Current vaccines, based on the group-specific capsular polysaccharides, provide short-term protection in adults against serogroups A and C but are ineffective in infants and do not induce protection against group B strains, the predominant cause of infection in western countries, because the purified serogroup B polysaccharide fails to elicit human bactericidal antibodies. Because of the poor immunogenicity of group B capsular polysaccharide, different noncapsular antigens have been considered for inclusion in a vaccine against this serogroup: outer membrane proteins, lipooligosaccharides, iron-regulated proteins, Lip, pili, CtrA, and the immunoglobulin A proteases. Alternatively, attempts to increase the immunogenicity of the capsular polysaccharide have been made by using noncovalent complexes with outer membrane proteins, chemical modifications, and structural analogs. Here, we review the strategies employed for the development of a vaccine for Neisseria meningitidis serogroup B; the difficulties associated with the different approaches are discussed. PMID- 7834610 TI - Metallothionein localization and cisplatin resistance in human hormone independent prostatic tumor cell lines. AB - Metallothioneins (MT) are major cysteine-rich proteins with poorly characterized functions. We have examined the MT amount, isotype expression, and subcellular distribution in 4 human hormone-independent prostatic carcinoma cell lines. Both PC-3 and DU-145 cells were thiol-rich cells with similar MT and glutathione levels, while HPC36M and PC-3 MA2 were thiol-poor cells with lower MT and glutathione levels. All 4 prostatic cell lines expressed the MTIIA isoform at a basal level; DU-145 cells also constitutively expressed MTIE mRNA. Using antibodies for both total MT and MTIIA, we defined MT to cytoplasmic and nuclear domains in PC-3 cells, to perinuclear and nuclear domains in HPC36M cells, and to prominent nonnucleolar nuclear domains in DU-145 and PC-3 MA2 cells. These results indicate that the subcellular distribution is cell type specific and not reflective of the total MT content or MT isoform. Resistance to cadmium in all 4 cell lines was correlated with total MT levels, while resistance to the anticancer agent cisplatin correlated best with nuclear MT content. We suggest that the subcellular localization of MT is functionally important in cellular protection against the anticancer agent cisplatin in human prostatic cancer cells. PMID- 7834612 TI - Pharmacokinetics of 9-cis-retinoic acid in the rhesus monkey. AB - 9-cis-Retinoic acid is a naturally occurring biologically active retinoid capable of binding and transactivating both the retinoic acid receptors and the retinoid X receptors. A study was performed to characterize the pharmacokinetics 9-cis retinoic acid following i.v. bolus administration in the nonhuman primate. Groups of three animals received i.v. bolus doses of 9-cis-retinoic acid of either 50 or 100 mg/m2. Blood and cerebrospinal fluid samples for determination of 9-cis retinoic acid concentration were obtained prior to and 5, 10, 15, 30, 45, 60, 75, 90, 120, 150, 180, 240, 360, and 480 min following drug administration. The plasma drug concentration profile of 9-cis-retinoic acid was consistent with a first-order elimination process, with a harmonic mean half-life of 31 min, and a mean clearance of 97 ml/min/m2. The pharmacokinetics of 9-cis-retinoic acid were linear over the dose range studied. Plasma concentrations of all-trans-retinoic acid following 9-cis-retinoic acid administration were less than the limit of quantitation (0.1 microM), suggesting that isomerization to all-trans-retinoic acid is not a major metabolic pathway. In contrast to all-trans-retinoic acid, the elimination of 9-cis-retinoic acid did not appear to be capacity limited (saturable). Previous studies in the Rhesus monkey have shown that repeated dosing with all-trans-retinoic acid leads to a reduction of this saturable component of elimination and results in reduced exposure to drug. These studies, in an animal model highly predictive of humans, suggest that declines in plasma concentrations of 9-cis-retinoic acid as a result of its repeat administration at doses up to 100 mg/m2 will not occur. PMID- 7834611 TI - Methotrexate-alpha-phenylalanine: optimization of methotrexate prodrug for activation by carboxypeptidase A-monoclonal antibody conjugate. AB - Methotrexate-alpha-phenylalanine (MTX-Phe), a second-generation prodrug in the MTX alpha-peptide series designed for activation to MTX by carboxypeptidase-mAb conjugates, was synthesized by reaction of the p-nitrophenyl ester of 4-amino-4 deoxy-10-methylpteroic acid with L-glutamyl-alpha-L-phenylalanine. Production of MTX from MTX-Phe, catalyzed by bovine pancreas carboxypeptidase A (CPA), was 250 fold faster than the corresponding reaction involving methotrexate-alpha-alanine, previously the best MTX peptide substrate for the enzyme. The amount of CPA required to make MTX-Phe equitoxic with MTX, when tested against UCLA-P3 human lung adenocarcinoma cells in vitro, was more than 10-fold lower than that required to achieve the same result with MTX-alpha-alanine. When the lung tumor cells were treated with CPA conjugated to KS1/4 (a mAb targeted to these cells) and excess conjugate removed by extensive washing, the ID50 for MTX-Phe improved from 2.2 x 10(-6) M (no enzyme present) to 6.3 x 10(-8) M; the latter value was comparable to that of the parent drug MTX (4.5 x 10(-8) M). [3H]MTX-Phe was synthesized and used to investigate the mechanism by which the prodrug exerts its cytotoxic effect in the presence and absence of CPA. The present results demonstrate that, for use in conjunction with CPA-mAb conjugates, the alpha phenylalanine derivative is the optimal prodrug form of MTX (and probably other antifols that contain the glutamate moiety). PMID- 7834603 TI - Hepatitis C: progress and problems. AB - The hepatitis C virus (HCV), a single-stranded RNA virus, is the major cause of posttransfusion hepatitis. HCV isolates differ in nucleotide and amino acid sequences. Nucleotide changes are concentrated in hypervariable regions and may be related to immune selection. In most immunocompetent persons, HCV infection is diagnosed serologically, using antigens from conserved regions. Amplification of RNA may be necessary to detect infection in immunosuppressed patients. Transmission by known parenteral routes is frequent; other means of spread are less common and may represent inapparent, percutaneous dissemination. Infection can lead to classical acute hepatitis, but most infected persons have no history of acute disease. Once infected, most individuals apparently remain carriers of the virus, with varying degrees of hepatocyte damage and fibrosis ensuing. Chronic hepatitis may lead to cirrhosis and hepatocellular carcinoma. However, disease progression varies widely, from less than 2 years to cirrhosis in some patients to more than 30 years with only chronic hepatitis in others. Determinants important in deciding outcome are unknown. Alpha interferon, which results in sustained remission in selected patients, is the only available therapy. Long-term benefits from such therapy have not been demonstrated. Prevention of HCV infection by vaccination is likely to be challenging if ongoing viral mutation results in escape from neutralization and clearance. PMID- 7834613 TI - Apoptin, a protein derived from chicken anemia virus, induces p53-independent apoptosis in human osteosarcoma cells. AB - Previously, we have shown that the chicken anemia virus-derived VP3 ("apoptin") protein induces apoptosis in chicken mononuclear cells. Here, we report that apoptin also induces apoptosis in human osteosarcoma cells, regardless of whether they expressed wild-type, mutant p53, or no p53 at all. Moreover, the nuclear location of apoptin appears to be important for its optimal induction of apoptosis. The fact that apoptin can induce p53-independent apoptosis in human tumor cells makes apoptin a potential candidate for treatment of frequently occurring types of cancer cells that do not contain functional p53. PMID- 7834614 TI - Evidence for a multifocal origin of papillary serous carcinoma of the peritoneum. AB - Histopathological evidence suggests that papillary serous carcinoma of the peritoneum (PSCP) may be multifocal in origin. Utilizing a PCR based method to detect tandem repeat polymorphisms in formalin fixed tissue, loss of heterozygosity at eight loci on chromosomes 1, 3, 4, and 17 was studied in six cases of PSCP. Loss of heterozygosity was assessed at between 5 and 11 tumor sites/patient. Allelic losses at 4 loci (1q32-qter, 3p14.3-21.1, 17q12, 17q21.3 23) were noted. Three cases demonstrated a different pattern of allelic loss at various anatomic sites within the same patient. In an additional case, a mutation of the p53 gene, detected by quantitative PCR followed by single-strand conformation polymorphism analysis, was detected in only 2 of 5 tumor sites. The pattern of allelic loss and the mutational pattern of the p53 gene varied at tumor sites within the same patient in 4 of 6 cases of PSCP. These findings are consistent with histopathological evidence that PSCP is multifocal in origin. PMID- 7834615 TI - Increased p16 levels correlate with pRb alterations in human urothelial cells. AB - The CDKN2 (MTS1) gene is located at 9p21; its product, p16, inhibits the cyclin D/CDK4 complex that phosphorylates pRb, thus negatively regulating cell cycle progression [M. Serrano et al., Nature (Lond.), 366: 704, 1994; A. Kamb et al., Science (Washington DC), 264: 436, 1994; T. Nobori et al., Nature (Lond.), 368: 753, 1994]. CDKN2 mutations are more common in cultured human uroepithelial cells (HUC) than in uncultured bladder cancers. We examined the status of CDKN2/p16 in early and late passage (P) cultures of HUC. HUC immortalization was not accompanied by p16 loss, even in cells with a hemizygous 9p21-pter deletion, but late passage cultures with a p16 loss showed decreased generation time. Thus, the data do not indicate that CDKN2 is a candidate for a chromosome 9 senescence gene but suggest that p16 loss may confer a growth advantage in vitro. Significant differences in p16 levels were observed among HUC cell lines, but no CDKN2 mutations were detected. However, an inverse correlation between elevated p16 and loss of pRb function was observed (P < 10(-4)). Ten samples with normal pRb showed low or undetectable p16 levels, while seven samples with known pRb alterations showed abundant p16 but nevertheless grew vigorously in culture. These results support the hypothesis that p16 mediated cell cycle inhibition, as well as p16 regulation, occurs via pRb dependent pathway(s). PMID- 7834616 TI - Variant estrogen receptor messenger RNA species detected in human primary hepatocellular carcinoma. AB - The development of hepatocellular carcinoma (HCC) in addition to cirrhosis affects males in a significantly higher proportion than females. Liver estrogen receptors increase when HCC develops in males; however, these tumors usually respond poorly to antiestrogens. We have, therefore, hypothesized that, similar to breast cancer, estrogen receptors in males with HCC may be mutated. Variant estrogen receptor transcripts (lacking exon 5 of the hormone binding domain) were investigated by reverse transcription-PCR in 14 patients (7 males and 7 females) with HCC. While females mostly displayed the wild-type transcript (both in peritumoral and in tumor liver tissue), males showed both transcripts in the cirrhotic tissue and almost only the variant in the tumor. As the variant ER transcripts when translated could give rise to truncated receptors still able to constitutively activate transcription, they may be key factors in favoring deregulated proliferation in the male liver. PMID- 7834617 TI - Acceleration of apoptosis in transforming growth factor beta 1-treated M1 cells ectopically expressing B-myb. AB - Inappropriate expression of genes involved in cell proliferation can result in altered regulation of apoptosis, a process of programmed cell death. Since B-myb has recently been implicated in the cell cycle progression we wanted to examine its role in the apoptotic process. For this purpose we used transforming growth factor beta 1 (TGF-beta 1)-treated M1 myeloid leukemia cell lines that continuously express murine B-myb. It was found that in cells overexpressing B myb, TGF-beta 1-induced apoptosis was accelerated as assessed by cell viability and DNA fragmentation into nucleosomal fragments. A DNA ladder was detected after 24 h of TGF-beta 1 treatment in these cells, whereas it was not detected until after 36 h in the parental M1 cells. It was further determined by Northern blot analysis that this higher sensitivity of B-myb overexpressing clones was not due to a change in the expression of TGF-beta receptor type I or in the kinetics of the regulation of c-myc, c-myb, bcl-2, and/or bax. PMID- 7834618 TI - Reciprocal Rb inactivation and p16INK4 expression in primary lung cancers and cell lines. AB - cdk4-mediated phosphorylation of the retinoblastoma susceptibility protein (Rb) is stimulated by cyclin D1, an oncogene, and inhibited by p16, a candidate tumor suppressor. We examined these proteins in non-small cell lung cancer (NSCLC), which is predominantly Rb positive, and small cell lung cancer (SCLC), which is Rb negative. Most NSCLC and SCLC resection specimens and cell lines overexpress cyclin D1 (indicating that cyclin D1 overexpression and Rb inactivation can coexist in SCLC). However, 9 of 9 Rb-positive NSCLC cell lines have absent or low p16, while an Rb-negative NSCLC line and 5 of 5 SCLC cell lines have high levels of p16. In primary resection specimens, p16 was undetectable in 18 of 27 NSCLC samples and abundant in 4 of 5 SCLC samples. Our data confirm the predicted reciprocity between Rb inactivation and p16 expression in a common human malignancy and define differential p16 expression as a fundamental distinction between NSCLC and SCLC. PMID- 7834619 TI - In vivo occurrence of p16 (MTS1) and p15 (MTS2) alterations preferentially in non small cell lung cancers. AB - Frequent homozygous deletions of the p16 (MTS1) gene encoding a cyclin-dependent kinase inhibitor were recently reported in various tumor cell lines including examples derived from lung cancers, but direct evidence for their occurrence in lung cancer patients has not been reported thus far. In the present study, alterations of p16 and/or p15, a p16-related cyclin-dependent kinase, were observed not only in lung cancer cell lines but also in the corresponding tumor specimens in vivo, excluding the possibility of in vitro artifacts. Interestingly, a clear specificity was also noted in terms of the affected histological subtype; i.e., only non-small cell lung cancers carried alterations (6 of 20 as compared to 0 of 20 small cell lung cancer cell lines). PMID- 7834620 TI - Translocation and activation of protein kinase C by the plasma cell tumor promoting alkane pristane. AB - Pristane (2,6,10,14-tetramethylpentadecane) is a C19-isoalkane that promotes the development of plasmacytomas in genetically susceptible BALB/c mice. Similarities between the effects of pristane and protein kinase C (PKC)-activating phorbol esters suggested that the tumor promoting activity of pristane might involve the activation of PKC. Here we show that up to 5 mol% of pristane can be homogeneously incorporated into phosphatidylcholine/phosphatidylserine bilayers. Membrane-incorporated pristane partially activated PKC and increased phorbol ester binding to the bilayer by more than 50%. Pristane (50 microM) delivered as an inclusion complex with beta-cyclodextrin to promyelocytic HL-60 leukemia cells induced a partial long-term translocation of PKC to the cell membrane. This was accompanied by differentiation of HL-60 cells into macrophage-like cells. It is concluded that activation of PKC may comprise an important aspect of the tumor promoting potential of pristane. PMID- 7834621 TI - Metabolic activation of N-hydroxy arylamines and N-hydroxy heterocyclic amines by human sulfotransferase(s). AB - Several N-hydroxy metabolites of carcinogenic arylamines and heterocyclic amines were examined as substrates for bioactivation by human liver sulfotransferases (STs). Among the N-hydroxy derivatives studied, N-hydroxy-2-acetylaminofluorene, N-hydroxy-2-aminofluorene, N-hydroxy-4,4'-methylene-bis(2-chloroaniline), N hydroxy-2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, and N-hydroxy-2-amino-6 methyldipyrido[1,2-a:3',2'-d]imidazole were each metabolically activated by 3' phosphoadenosine-5'-phosphosulfate-dependent human liver STs. No ST-mediated DNA binding of N-hydroxy-2-amino-3-methylimidazo[4,5-f]quinoline or N-hydroxy-2-amino 3,8-dimethylimidazo[4,5-f]quinoxaline was detected under our assay conditions. In the 12 human hepatic cytosols studied, the extent of 3'-phosphoadenosine-5' phosphosulfate-dependent DNA binding of the N-hydroxy derivatives were all significantly correlated with levels of thermostable phenol ST (TS-PST) activity but not with thermolabile phenol ST or dehydroepiandrosterone ST activities. The propensity of these N-hydroxy arylamines and N-hydroxy heterocyclic amines to serve as selective substrates for human TS-PST was further confirmed by inhibition with 2,6-dichloro-4-nitrophenol and by thermostability studies. N hydroxy-2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and N-hydroxy-4,4' methylene-bis(2-chloroaniline) were also used as substrates to study ST-dependent metabolic activation in other human tissue preparations. 3'-phosphoadenosine-5' phosphosulfate-dependent DNA binding activity was detected in human liver and colon cytosols but not in pancreas, larynx, or urinary bladder epithelial cytosols. Since the TS-PST appears to be expressed polymorphically in human populations, the finding that human TS-PST is capable of metabolically activating N-hydroxy metabolites of several carcinogenic arylamines and heterocyclic amines suggests that TS-PST may have an important role in determining interindividual susceptibility to these environmental and dietary carcinogens. PMID- 7834622 TI - Evaluation of chemopreventive agents in different mechanistic classes using a rat tracheal epithelial cell culture transformation assay. AB - The rat tracheal epithelial (RTE) cell focus inhibition assay was used to identify potential chemopreventive agents. Ninety-nine agents were evaluated for their ability to inhibit benzo[a]pyrene-induced transformation of RTE cells. Freshly isolated RTE cells were exposed to benzo[a]pyrene alone or in combination with a chemopreventive agent. After 30 days in culture, transformed foci were scored and inhibition was quantitated. In these studies, foci formation was inhibited mainly by agents which modulate the initiation of carcinogenesis by altering drug-metabolizing enzymes, inhibiting the binding of benzo[a]pyrene to DNA, enhancing detoxification of activated carcinogens, or by inducing epithelial cell differentiation. Such agents include antioxidants, free radical scavengers, glutathione S-transferase enhancers, vitamins, retinoids, and sulfhydryl compounds. Agents which inhibit ornithine decarboxylase and arachidonic acid metabolism were not as effective. The RTE assay provides important data for agent selection prior to whole animal-screening assays in the development of chemoprevention drugs. PMID- 7834623 TI - Tamoxifen induces short-term cumulative DNA damage and liver tumors in rats: promotion by phenobarbital. AB - Tamoxifen administered in the diet (420 ppm) to Wistar rats (TOX:P) for only 3 months caused cumulative hepatic DNA damage as assessed by 32P-postlabeling, consistent with the proposal that tamoxifen is a genotoxic carcinogen in this species. Promotion of tumor development with phenobarbital after discontinuation of dietary tamoxifen resulted in the formation of liver carcinomas after 9 months. At 12 and 20 months in this study, the majority of these rats had liver carcinomas. Rats treated with tamoxifen for 3 months but not promoted with phenobarbital also developed liver tumors over a longer period of time. These tumors were predominantly adenomas, with one carcinoma, and occurred at a lower incidence than the tumors produced by promotion with phenobarbital. Rats treated with phenobarbital alone did not develop tumors after 20 months. Tamoxifen induced DNA adducts were relatively persistent, with only a 38% decrease 3 months after tamoxifen treatment had been discontinued. This demonstrates that, in a susceptible species (the rat), tamoxifen can cause initiation of liver cancer after only 3 months exposure. It is proposed that the persistence of such DNA adducts may account for the ability of phenobarbital to promote a high incidence of liver carcinoma, even after discontinuation of tamoxifen treatment. These data are relevant to the concern for women given prophylactic tamoxifen for long periods in that even if there is a relatively small amount of cumulative tamoxifen-induced liver DNA damage, liver tumors could be promoted by other agents, even after the cessation of tamoxifen treatment. PMID- 7834624 TI - Modulator inhibits nuclear translocation of the glucocorticoid receptor and inhibits glucocorticoid-induced apoptosis in the human leukemic cell line CEM C 7. AB - Modulator is an endogenous low-molecular-weight regulator of both glucocorticoid and mineralocorticoid receptors as well as protein kinase C. Structural analysis of modulator purified to apparent homogeneity suggests that it is a novel ether aminophosphoglyceride. In this report, we show that modulator inhibits cytosolic human glucocorticoid receptor (GR) complex activation as measured by DNA cellulose binding. In addition, modulator blocks glucocorticoid-induced nuclear translocation of the GR in intact human leukemic (CEM C-7) cells, as illustrated by immunocytochemical localization. Furthermore, we demonstrate that modulator, by blocking the activation and subsequent translocation of GR, inhibits glucocorticoid-mediated apoptosis, characterized by chromatin condensation, internucleosomal DNA fragmentation, and cell death in glucocorticoid-sensitive CEM C-7 cells. Modulator inhibits glucocorticoid-induced c-myc gene repression and glucocorticoid receptor gene up-regulation. These data suggest that modulator functions to regulate the GR in intact cells as well as in cytosolic preparations. In addition, the inhibition of glucocorticoid-induced programmed cell death by modulator sheds light on the cellular function of modulator as well as on the mechanism by which apoptosis occurs in CEM C-7 cells. PMID- 7834625 TI - Age at establishment of Helicobacter pylori infection and gastric carcinoma, gastric ulcer, and duodenal ulcer risk. AB - Helicobacter pylori is an important risk factor for gastric cancer, gastric ulcer, and duodenal ulcer, yet most infected persons do not develop disease. We examined two correlates of acquisition age, sibship size and birth order, to evaluate the hypothesis that early life acquisition of H. pylori is a risk factor for the development of these illnesses. In earlier nested case-control studies of a cohort of Japanese American men in Hawaii, evidence of H. pylori infection was associated with the development of gastric cancer or gastric or duodenal ulceration during the subsequent period, 1968-1989. The present analysis included 102, 147, and 64 men who developed adenocarcinoma of the distal stomach, gastric ulcer, and duodenal ulcer, respectively, and a matched control for each. Sibship size and birth order data were analyzed as risk factors for development of these diseases. H. pylori-infected but not H. pylori-uninfected men from larger sibships (odds ratio, 2.06) and of higher birth order (odds ratio, 1.67) were at increased risk for developing gastric cancer. H. pylori- infected men but not uninfected men at higher birth order had increased risk of gastric (odds ratio, 1.64) but not duodenal ulcers. These data are consistent with the hypothesis that early life acquisition of H. pylori increases the risk of developing both gastric cancer and gastric ulcer but not duodenal ulcer. PMID- 7834626 TI - Multifactorial resistance to 5,10-dideazatetrahydrofolic acid in cell lines derived from human lymphoblastic leukemia CCRF-CEM. AB - 5,10-dideaza-5,6,7,8-terrahydrofolic acid (DDATHF) is a potent antiproliferative agent in cell culture systems and in vivo in a number of murine and human xenograft tumors. In contrast to classical antifolates, which are dihydrofolate reductase inhibitors, DDATHF primarily inhibits GAR transformylase, the first folate-dependent enzyme along the pathway of de novo purine biosynthesis. The (6R) diastereomer of DDATHF (Lometrexol), currently undergoing clinical investigation, was used to develop CCRF-CEM human leukemia sublines resistant to increasing concentrations of the drug. Three cell lines were selected for ability to grow in medium containing 0.1 microM, 1.0 microM, and 10 microM of (6R)DDATHF, respectively. Impaired polyglutamylation was identified as a common mechanism of resistance in all three cell lines. A progressive decrease in the level of polyglutamylation was associated with diminished folylpolyglutamate synthetase activity and paralleled increasing levels of resistance to the drug. However, the expression of folylpolyglutamate synthetase RNA was not altered in the resistant cell lines compared to the parent cells. The most resistant cell subline also displayed an increased activity of gamma-glutamyl hydrolase. The sublines were scrutinized for other possible mechanisms of resistance. No alterations in drug transport or in purine economy were found. Modest increases were found in the activity of methylene tetrahydrofolate dehydrogenase but no alterations of other folate-dependent enzymes were observed. Increases in accumulation and conversion of folic acid to reduced forms, particularly 10-formyltetrahydrofolate, was also seen. The resistant cell lines were sensitive to dihydrofolate reductase inhibitors, methotrexate and trimetrexate, for a 72-h exposure period but showed cross-resistance to methotrexate for 4 and 24 h exposures. Cross-resistance was also shown toward other deazafolate analogues for both short- and long-term exposures. PMID- 7834627 TI - N-[2-(2-methyl-5-nitroimidazolyl)ethyl]-4-(2-nitroimidazolyl)butanamide (NSC 639862), a bisnitroimidazole with enhanced selectivity as a bioreductive drug. AB - Compounds containing two redox centers, both of which must be reduced for full expression of cytotoxicity by oxygen-inhibitable pathways (bis-bioreductive drugs), have potential as cytotoxins with high selectivity for hypoxic tumor cells. The bisnitroimidazole N-[2-(2-methyl-5-nitroimidazolyl)ethyl]-4-(2 nitroimidazolyl)butanamide (NNB, NSC 639862), in which a 2-nitroimidazole and 5 nitroimidazole moiety are joined via a carboxamide linker, is highly selective for hypoxic AA8 Chinese hamster cells (200-fold by 8 h) relative to mononitroimidazoles (5-25-fold). A bis-bioreductive mechanism is consistent with the marked increase in hypoxic potency and selectivity of NNB with time and the apparent requirement that the two nitro groups be present in the same molecule. NNB differed from mononitroimidazoles in inducing fewer DNA single strand breaks at equivalent toxicity, suggesting that a duplex DNA lesion (locally doubly damaged site) may be responsible for cell killing. Alkaline elution studies and the lack of hypersensitivity of the repair-defective UV4 cell line indicate that the cytotoxic lesion is not a DNA interstrand cross-link. NNB shows greater hypoxic selectivity than the alkylating 2-nitroimidazole RB 6145 against AA8 cells and is active in combination with radiation when administered in multiple doses against the MDAH-MCa-4 mouse mammary carcinoma. PMID- 7834628 TI - Intratumoral activation and enhanced chemotherapeutic effect of oxazaphosphorines following cytochrome P-450 gene transfer: development of a combined chemotherapy/cancer gene therapy strategy. AB - Cyclophosphamide and its isomer ifosfamide are cell cycle-nonspecific alkylating agents that undergo bioactivation catalyzed by liver cytochrome P-450 enzymes. The therapeutic efficacy of these oxazaphosphorine anticancer drugs is limited by host toxicity resulting from the systemic distribution of activated drug metabolites formed in the liver. Since tumor cells ordinarily do not have the capacity to activate oxazaphosphorines, we examined whether introduction into tumor cells of a cDNA encoding CYP2B1, a major catalyst of oxazaphosphorine activation, sensitizes the cells to the cytotoxic effects of cyclophosphamide and ifosfamide. Here we show that 9L gliosarcoma cells stably transfected with a cDNA encoding rat CYP2B1 are highly sensitive to cyclophosphamide and ifosfamide cytotoxicity as compared to parental 9L cells or 9L cells transfected with an Escherichia coli beta-galactosidase gene. The CYP2B1 enzyme inhibitor metyrapone protects the CYP2B1-expressing 9L cells from oxazaphosphorine cytotoxicity, demonstrating that the chemosensitivity of these cells is a direct consequence of intracellular prodrug activation. Moreover, CYP2B1-expressing 9L cells potentiate the cytotoxic effects of cyclophosphamide and ifosfamide toward cocultured CYP2B1 negative 9L tumor cells. This "bystander effect" does not require cell-cell contact, and therefore may have the therapeutic advantage of distributing cytotoxic drug metabolites to a wide area within a solid tumor mass. In vivo experiments using Fischer 344 rats implanted s.c. with CYP2B1-expressing 9L tumor cells demonstrated that intratumoral expression of the CYP2B1 gene provides a substantial therapeutic advantage over that provided by liver cytochrome P-450 dependent drug activation alone; cyclophosphamide treatment resulted in complete growth inhibition of CYP2B1-positive tumors, whereas only a modest growth delay effect was obtained with CYP2B1-negative tumors. These studies establish that drug-activating CYP genes may be useful for the development of novel combined chemotherapy/gene therapy strategies for cancer treatment utilizing established cancer chemotherapeutic agents. PMID- 7834629 TI - Sensitization of human renal cell carcinoma cells to cis diamminedichloroplatinum(II) by anti-interleukin 6 monoclonal antibody or anti interleukin 6 receptor monoclonal antibody. AB - Cytotoxic chemotherapy has shown little antitumor activity against renal cell carcinoma (RCC). It has been demonstrated that RCC cells secrete interleukin 6 (IL-6) and express IL-6 receptors (IL-6Rs). IL-6 inhibits apoptosis and enhances manganese superoxide dismutase expression. Several anticancer chemotherapeutic agents exert their cytotoxic activity in part through the induction of apoptosis and the production of free radicals. Thus, the resistance of RCC cells to the anticancer agents might correlate with IL-6 expression. The present study tested this hypothesis by examining the effect of anti-IL-6 mAb and anti-IL-6R mAb on the sensitivity of human RCC cells to anticancer chemotherapeutic agents. Treatment of Caki-1 cells with anti-IL-6 mAb or anti-IL-6R mAb in combination with cis-diamminedichloroplatinum(II) (CDDP) or mitomycin C overcame their resistance to CDDP or mitomycin C. However, treatment of Caki-1 cells with anti IL-6 mAb or anti-IL-6R mAb in combination with Adriamycin, vinblastine or 5 fluorouracil did not overcome their resistance to these anticancer agents. Treatment of CDDP-resistant Caki-1 cells (Caki-1/DDP), two other RCC cell lines (ACHN and A704), and three freshly derived RCC cells with CDDP in combination with anti-IL-6 mAb or anti-IL-6R mAb reversed the resistance to CDDP in all these tumors. We then studied the effectiveness of other platinum derivatives. Treatment of Caki-1 cells with anti-IL-6 mAb or anti-IL-6R mAb enhanced their sensitivity to carboplatin, but not to trans-diamminedichloroplatinum(II). Several experiments investigated the mechanism of the antibody-mediated sensitization of RCC cells to CDDP. Incubation of Caki-1 cells with anti-IL-6 mAb or anti-IL-6R mAb did not change the intracellular accumulation of CDDP. The expressions of the multidrug resistant phenotype (gp170) and c-myc oncogene were not affected by the antibody-mediated sensitization. Treatment of Caki-1 cells with the anti-IL-6 mAb or anti-IL-6R mAb down-regulated the expression of glutathione S-transferase pi mRNA. This study demonstrates that treatment of RCC cells with CDDP in combination with anti-IL-6 mAb or anti-IL-6R mAb can overcome their CDDP-resistance and that the down-regulation of glutathione S-transferase pi expression by anti-IL-6 mAb or anti-IL-6R mAb might play a role in the enhanced cytotoxicity obtained.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7834630 TI - In vivo enhanced antitumor activity of carmustine [N,N'-bis(2-chloroethyl)-N nitrosourea] by simvastatin. AB - The effects of a combination of simvastatin, a cholesterol-lowering agent, and carmustine (BCNU; N,N'-bis(2-chloroethyl)-N-nitrosourea) on experimental C6 glioma were studied in vitro and in vivo. In vitro simvastatin and BCNU alone inhibited cell proliferation in a dose-dependent fashion. A subliminal concentration of simvastatin (0.1 microM) markedly and synergistically increased the BCNU toxicity to C6 glioma cells. The cytofluorimetric analysis of DNA from simvastatin-treated C6 glioma cells showed, besides the already described arrest in G1, an arrest/retardation in G2-M. Mitotic index from C6 cells incubated with simvastatin (10 microM) decreased by about 90%, indicating a specific C6 arrest/retardation in G2. The drug effects could be completely reversed by simvastatin withdrawal or mevalonate addition to the cultured cells. The combination of simvastatin and BCNU resulted predominantly from the profound retardation of cells in the G2-M compartment of the cell cycle. In vivo simvastatin (administered daily mixed with food) and BCNU (single i.p. injection), when given separately, caused a dose-dependent inhibition of labeling index in C6 glioma homografts (ID50, 61 mg/kg/day and 8.7 mg/kg, respectively). The combination of the lowest doses tested (simvastatin, 25 mg/kg/day and BCNU 0.3 mg/kg) resulted in a significant growth delay (compared to either drug alone) in C6 glioma (P < 0.05). There was no significant increase in toxicity as assessed by myelosuppression (WBC counts and bone marrow labeling index) and body weight. The results provide in vivo support for the combined use of simvastatin, a cholesterol-lowering agent, and BCNU in brain tumor treatment. PMID- 7834631 TI - In vivo antitumor activity of two new seven-substituted water-soluble camptothecin analogues. AB - The development of camptothecin-like compounds as inhibitors of topoisomerase I for the treatment of resistant tumors has generated clinical excitement in this new class of drugs. We have developed two novel water-soluble camptothecin analogues which are specific inhibitors of topoisomerase I and are potent cytotoxins with significant antitumor activity. We added water-solubilizing groups off position 7 in the B ring of either 10,11-ethylenedioxy- or 10,11 methylenedioxy-20(S)-camptothecin. These water-soluble camptothecin analogues were demonstrated to be nanamolar inhibitors of the topoisomerase I enzyme in the cleavable complex assay. The compounds, GI147211 [7-(4-methylpiperazinomethylene) 10,11-ethylenedioxy-20(S)-camp tot hecin], and GI149893 [7-(4 methylpiperazinomethylene)-10,11-methylenedioxy-20(S)-cam pto thecin], were compared to topotecan, a known water-soluble inhibitor of topoisomerase I. Both GI compounds were found to be slightly more potent than topotecan as inhibitors of topoisomerase I in the cleavable complex assay and were 1.5-2 times more soluble. Tumor cell cytotoxicity assays using 5 separate cell lines demonstrated that both GI compounds were 5-10 times more potent than topotecan, although by comparison all three topoisomerase I inhibitors were unaffected by the multidrug resistance P-glycoprotein. The antitumor activity of all three topoisomerase I inhibitors was compared concomitantly in two human colon xenograft models. In both models, GI147211 and GI149893 were able to induce regression of established HT-29 and SW-48 colon tumors by as much as 60%. The antitumor activity of both compounds were also demonstrated in the MX-1 and PC-3 xenografts. Microscopic examination of selected tissues indicated that drug-induced toxicity was primarily limited to the gastrointestinal tract and was comparable among the three compounds. Further clinical development of this class of compounds is ongoing. PMID- 7834632 TI - Anti-CD54 (ICAM-1) has antitumor activity in SCID mice with human myeloma cells. AB - Recent studies have suggested that ICAM-1 (CD54) is involved in the pathogenesis of human multiple myeloma. A monoclonal antihuman CD54 antibody has been generated by immunizing BALB/c mice with human myeloma cell lines. SCID mice injected with human ARH-77 myeloma cells develop disseminated myeloma which is similar in several respects to multiple myeloma in humans. The mice have monoclonal gammopathy and succumb to hind leg paralysis caused by infiltration of tumor cells into the thoracolumbar vertebrae, resulting in compression of the spinal cord. In the absence of treatment, the mean paralysis time of the SCID/ARH 77 mice is 29 days. When the SCID/ARH-77 mice received four consecutive daily i.v. injections of anti-CD54 mAb commencing 1 day after tumor inoculation, they survived for 150 days, at which time the experiment was terminated. Histopathological analyses indicated that prior to death all control SCID/ARH-77 mice had myeloma cells in the vertebrae and skull. At this time, the anti-CD54 treated mice had no evidence of tumor. High levels of human immunoglobulin were detected in the sera of control, but not treated mice. F(ab')2 fragments of the anti-CD54 antibody also had similar, albeit, slightly less antitumor activity in vivo, suggesting that antibody effector function may account for some, but not all the antitumor activity of anti-CD54. In vitro studies indicate that anti-CD54 does not inhibit homotypic adhesion, the binding of myeloma cells to murine bone marrow stromal cells, or cell proliferation. By exclusion, we propose that the CD54-mediated homing of these ARH-77 cells to certain anatomical sites is crucial for their growth in vivo. PMID- 7834633 TI - Role of natural killer cells in psychosocial stressor-induced changes in mouse mammary tumor growth. AB - We have shown that social housing conditions affect the growth rate of the androgen-responsive Shionogi mouse mammary tumor (SC115) and differentially stimulate splenic natural killer (NK) cell activity. Mice reared in a social group and then singly housed (GI) following tumor cell injection have increased tumor growth rates and increased NK cell activity, whereas mice reared individually and then group housed following tumor cell injection have decreased tumor growth rates and decreased NK cell activity compared to that in mice remaining in their rearing group. The present study was undertaken to determine whether NK cells are involved in mediating the effects of social housing conditions on SC115 tumor growth rates. We demonstrate that the presence of the SC115 tumor significantly stimulates the activity of NK cells at the tumor site in the first 7 days after tumor cell injection, and that, consistent with the data on splenic NK cells, mice of the GI group (largest tumors) have significantly greater levels of NK cell activity than mice reared individually and then group housed (smallest tumors). We further demonstrate that in mice of the GI group, in vivo stimulation of NK cell activity by polyinosinic:polyCMP correlates with a corresponding increase in tumor growth rate. These findings suggest that NK cell activity may play a role in mediating the increased tumor growth rate observed in mice of the GI housing condition. PMID- 7834634 TI - Negative growth control of HeLa cells by connexin genes: connexin species specificity. AB - In order to examine whether different connexin gene species exert different degrees of tumor-suppressing activity, we characterized growth characteristics of a gap junction-deficient human cancer cell line, HeLa cells, before and after transfection with cDNA for three different connexins, connexin (cx) 26, cx 40, and cx 43. All transfected cell lines (3 clones transfected with the cx 26 gene, 2 clones with cx 40, and 1 with cx 43) showed establishment of gap junctional intercellular communication (GJIC). Two of the cx 26-transfected clones showed significantly slower growth compared with the parental HeLa cells. When transfectants were grown in soft agar, the three cx 26-transfected clones grew much less than the other transfectants and parent HeLa cells. When injected into nude mice, the two cx 26 clones which exhibited the highest amount of cx 26 transcript induced almost no tumors, whereas other transfectants, including the cx 26 clone which exhibited the lowest amount of cx 26 transcript, were tumorigenic. Among transfectants of various connexin genes, there was no good inverse correlation between their GJIC and tumorigenicity. GJIC levels were significantly higher in tumors induced in nude mice by clone cx 26 A and E transfectants. These results suggest that all of the connexin genes examined could induce recovery of GJIC of HeLa cells, but only the cx 26 gene exerts strong negative growth control on HeLa cells; thus, this connexin gene may have different functions from other connexin genes. PMID- 7834635 TI - Detection of chromosomal breakage in the 1cen-1q12 region of interphase human lymphocytes using multicolor fluorescence in situ hybridization with tandem DNA probes. AB - A novel multicolor fluorescence in situ hybridization approach, using an alpha satellite probe which labels the centromeric region on chromosome 1 and a classical satellite probe which targets an adjacent breakage-prone region (1q12), has been used to detect both hyperdiploidy and chromosome breakage in interphase human cells. With the use of this technique significant increases in chromosomal breakage were observed in interphase and metaphase lymphocytes irradiated in vitro. Metaphase analysis indicated that a significant proportion of these breakage events represented potentially stable aberrations such as translocations and inversions. A comparison of frequencies using a single classical satellite probe and the adjacent alpha and classical satellite probes indicated that this tandem label procedure allowed chromosomal breakage to be detected and distinguished from hyperdiploidy in untreated interphase lymphocytes, indicating the potential of this procedure for human biomonitoring. To determine whether this hybridization approach could detect alterations in humans, peripheral blood lymphocytes were obtained from a group of pesticide applicators and mixers and compared with a nonexposed control group. Significant increases in both hyperdiploidy and chromosomal breakage affecting the labeled region on chromosome 1 were observed in the pesticide-exposed group. These results indicate that this hybridization strategy allows hyperdiploidy and chromosomal breakage to be detected rapidly in interphase human cells and may facilitate the detection of chromosomal alterations in human populations exposed to carcinogenic and genotoxic agents using tissues which have not been previously amenable for cytogenetic analysis. PMID- 7834636 TI - Mutations of the p53 gene and p53 protein overexpression are associated with sarcomatoid transformation in renal cell carcinomas. AB - Renal cell carcinomas sometimes show sarcomatoid transformation, thus comprising both sarcomatous and carcinomatous components. Such sarcomatoid renal cell carcinomas are highly malignant with pronounced proliferative activity. The present investigation was conducted to assess the mutational status of the p53 and H-ras genes independently in carcinomatous and sarcomatous portions of individual tumors, applying PCR, subcloning, and sequencing to 14 cases. Sarcomatoid portions showed an extremely high mutation rate for the 53 gene (11 of 14, 78.6%) with two mutational hot spots at codons 278 (8 of 14, 57.1%) and 244 (6 of 14, 42.9%). Five cases showed double mutations, four cases had mutations at codons 278 and 244, and one case had mutations at codons 278 and 248. In contrast, the carcinomatous portions demonstrated a low mutation rate for the p53 gene (2 of 14, 14.3%) and no double mutations were detected. Ten cases showed genetic heterogeneity in the p53 gene between the two tumor components. Furthermore, p53 overexpression was immunohistochemically observed only in those components with p53 mutations, mainly in the sarcomatoid portions. No H-ras mutations were observed. The findings strongly suggest that p53 mutations leading to overexpression of p53 protein are closely associated with sarcomatoid transformation in renal cell carcinomas. PMID- 7834637 TI - Effect of a mutation at tyrosine 950 of the insulin-like growth factor I receptor on the growth and transformation of cells. AB - Recent evidence has shown that the insulin-like growth factor I (IGF-I) receptor plays a major role in the establishment and maintenance of transformation. To identify domains in the IGF-I receptor that are necessary for transformation, the tyrosine at residue 950 of the human IGF-I receptor cDNA was mutated to phenylalanine, and the plasmid expressing the mutant receptor was stably transfected into R- cells, which are mouse embryo fibroblasts with a targeted disruption of the type 1 receptor for the insulin-like growth factors. At variance with the wild-type receptor, the Y950 mutant receptor has lost its ability to transmit an IGF-I-mediated mitogenic signal or to transform R- cells. These experiments show, for the first time, that tyrosine 950 of the IGF-I receptor is necessary for its mitogenic and transforming activities. PMID- 7834639 TI - High rates of thioredoxin secretion correlate with growth arrest in hepatoma cells. AB - Thioredoxin (TRX), a disulfide-reducing intracellular dithiol enzyme, is synthesized by both normal liver cells and the hepatocarcinoma cell line HepG2. Only the former, however, secrete abundant TRX extracellularly. When cultured in mild reducing conditions, HepG2 cells but not normal hepatocytes increase the rate of TRX secretion and undergo growth inhibition accompanied by morphological changes. Also, recombinant TRX inhibits proliferation of HepG2 cells. In contrast, exogenous thiols and TRX stimulate proliferation of a B-cell lymphoma line, indicating that different cell types respond differently to variations in the extracellular redox potential. PMID- 7834638 TI - p53-independent induction of WAF1/CIP1 in human leukemia cells is correlated with growth arrest accompanying monocyte/macrophage differentiation. AB - The p53 tumor suppressor gene plays a role in controlling a G1 phase checkpoint. The WAF1/CIP1 gene with encodes p21WAF1/CIP1 protein, an inhibitor of cyclin dependent kinases, is a downstream mediator of p53 function. We examined expression of the WAF1/CIP1 gene and its relationship to growth arrest and differentiation in p53-null human leukemic cell lines. We show that p53 independent induction of WAF1/CIP1 occurs in human leukemia cells treated with 12 O-tetradecanoylphorbol-13-acetate, okadaic acid, or IFN-gamma but not with retinoic acid, vitamin D3, or DMSO. Furthermore, WAF1/CIP1 induction correlates with growth arrest associated with monocyte-macrophage differentiation. The present studies support the idea that WAF1/CIP1 gene expression can be regulated through multiple mechanisms, suggesting that strategies may be designed to restore the G1 checkpoint controls in p53-null cells by targeting these p53 independent mechanisms of WAF1/CIP1 induction. PMID- 7834640 TI - Host organ specifically determines cancer progression. AB - In order to further understand the role of the host organ in tumor progression, we have transplanted into nude mice histologically intact human colon cancer tissue on the serosal layers of the stomach (heterotopic site) and the serosal layers of the colon (orthotopic site). Xenograft lines Co-3, which is well differentiated, and poorly differentiated COL-3-JCK were used for transplantation. After orthotopic transplantation of the human colon tumors on the nude mouse colon, the growing colon tumor resulted in macroscopically extensive invasive local growth in 4 of 10 mice, serosal spreading in 9 of 10 mice, musclaris propria invasion in 1 of 10 mice, submucosal invasion in 3 of 10 mice, mucosal invasion in 3 of 10 mice, lymphatic duct invasion in 4 of 10 mice, regional lymph node metastasis in 4 of 10 mice, and liver metastasis in 1 of 10 mice. In striking contrast, after heterotopic transplantation of the human colon tumor on the nude mouse stomach, a large growing tumor resulted but with only limited invasive growth and without serosal spreading, lymphatic duct invasion, or regional lymph node metastasis. It has become clear from these studies that the orthotopic site, in particular the serosal and subserosal transplant surface, is critical to the growth, spread, and invasive and metastatic capability of the implanted colon tumor in nude mice. These studies suggest that the original host organ plays the same critical role in tumor progression. PMID- 7834641 TI - In vivo local expansion of clonal T cell subpopulations in renal cell carcinoma. AB - Renal cell carcinoma (RCC) is one human tumor to which the immune response may control the growth of tumor cells. These tumors are infiltrated by a large mononuclear infiltrate mainly composed of T lymphocytes. To characterize the lymphocytes infiltrating RCC, we analyzed the molecular structure of the T cell receptor (TCR) alpha and beta chains in tumor and paired peripheral blood lymphocytes from a series of 6 untreated patients. We first determined V alpha and V beta gene segment usage by PCR using a panel of V specific oligonucleotide primers (V alpha 1-w29 and V beta 1-w24). A highly diverse usage of TCR V alpha and V beta gene usage was observed in 5 of 6 tumors. In addition, the few tumor overexpressed V beta specificities detected by reverse transcription-PCR were shown to contain minor T cell expansions. Strikingly, 1 of the 6 tumor studied displayed a skewed TCR repertoire with V beta 4 transcript representing 25% of the TCR signals. Clonality of the tumor overexpressed V beta transcripts was analyzed by CDR3 size distribution analysis. In the particular tumor displaying a biased repertoire large expansions of T cell subpopulations were detected (particularly in V beta 4) specifically at the tumor site. Such T cells may be expanded locally in response to tumor antigens. PMID- 7834642 TI - Induction of apoptosis by sphingosine in human leukemic HL-60 cells: a possible endogenous modulator of apoptotic DNA fragmentation occurring during phorbol ester-induced differentiation. AB - The present studies were undertaken to characterize the potential role of sphingosine in the regulation of apoptosis in HL-60 promyelocytic leukemia cells. A 6-h exposure of HL-60 cells to sphingosine or its methylated derivative, N,N dimethylsphingosine, caused internucleosomal DNA fragmentation and stereotypical morphological changes characteristic of apoptosis (i.e., cell shrinkage, nuclear condensation, and the formation of apoptotic bodies), as well as that to pharmacological inhibitors of protein kinase C such as 1-(5-isoquinolinesulfonyl) 2-methylpiperazine and staurosporine. Apoptosis by sphingosine and N,N dimethylsphingosine was measured using a flow cytometric method. The percentages of apoptotic cells in cultures treated with sphingosine (10 microM) and N,N dimethylsphingosine (10 microM) for 6 h were 55.6 +/- 7.8% and 84.2 +/- 11.6%, respectively. HL-60 cells were induced to differentiate toward macrophages by treatment with 5 nM 4 beta-phorbol 12-myristate 13-acetate (PMA). Internucleosomal DNA fragmentation, which was a hallmark of apoptosis, was first detected after 10-h exposure to PMA and increased with longer treatment. Sphingosine concentrations in the cells increased concomitantly with the increasing proportion of apoptotic cells during cell differentiation. Sphingosine level in HL-60 cells differentiated by treatment with PMA for 48 h was about 3.3 fold greater than that in untreated cells. Differentiated HL-60 cells exhibited a markedly increased conversion of exogenously added [3H]ceramide to [3H]sphingosine, indicating elevation of ceramidase activity. Moreover, exposure to sphingosine resulted in down-regulation of c-myc mRNA. These observations suggest the possible role of sphingosine in induction of apoptotic DNA fragmentation during PMA-induced differentiation in myeloid leukemia cells. Sphingosine may function as an endogenous modulator mediating the apoptotic signal. PMID- 7834643 TI - Solid tumor cells express functional "tethered ligand" thrombin receptor. AB - Previous work demonstrated that alpha-thrombin promoted tumor cell adhesion to endothelium and extracellular matrix as well as enhanced the metastatic capacity of tumor cells. This study was initiated to investigate whether the thrombin effect on tumor cells is mediated through the "tethered ligand" thrombin receptor. RT-PCR analysis using primers based on the human thrombin receptors detected mRNA in human colon adenocarcinoma cells (clone A), whose authenticity was confirmed by Southern hybridization. The presence of thrombin receptor mRNA in rat (W256 carcinosarcoma) and mouse (melanoma) tumor cells was demonstrated by RT-PCR/Southern blotting using species-specific PCR primers. Sequencing of the PCR fragment of clone A cells revealed complete homology with the reported human cDNA sequence. Subsequently, tumor cells derived from three species, i.e., human, rat, and mouse, were found to express the thrombin receptor protein as revealed by immunoblotting using ligand peptide-derived mAb ATAP138, whose reactivity towards the M(r) approximately 66,000, potential thrombin receptor was blocked by preincubating the antibody with the immunogen peptide SFLLRNPNDKYEPF (TRP 14). Finally, peptides TRP 14 and TRP 7 (SFLLRNP), but not TRP 5 (FLLRN), were found to mimic alpha-thrombin in stimulating tumor cell adhesion to fibronectin, suggesting that the thrombin receptors expressed on solid tumor cells are biologically functional. PMID- 7834644 TI - Fifth Heidelberger Conference on Targets for Cancer Research: prevention, differentiation, and selective therapy. PMID- 7834645 TI - Genetic polymorphism and cancer susceptibility: fourteenth Sapporo Cancer Seminar. PMID- 7834646 TI - An electrochemical synthesis of methyl alpha-isomaltoside. AB - A novel approach has been developed for the synthesis of methyl alpha isomaltoside (10), comprising, as the first step, electrochemical conversion of the hydroxyl groups of methyl alpha-D-glucopyranoside into the corresponding anions. The anions subsequently react with tetra-O-acetyl-alpha-D-glucopyranosyl bromide to give methyl 2',3',4',6'-tetra-O-acetyl-alpha-isomaltoside (8) as the main product, O-deacetylation of which affords 10. The glycosidation proceeds under complete stereochemical control. PMID- 7834647 TI - Structural studies of the enterotoxigenic Escherichia coli (ETEC) O153 O antigenic polysaccharide. AB - The O-specific side-chain of the lipopolysaccharide from Escherichia coli O153 has been investigated using methylation analysis, Smith degradation, partial hydrolysis, FABMS, and NMR spectroscopy as the principal methods. It is concluded that the polysaccharide is composed of pentasaccharide repeating-units having the following structure. PMID- 7834648 TI - Structural studies of the Shigella boydii type 5 O-antigen polysaccharide. AB - The structure of the Shigella boydii type 5 O-antigen polysaccharide has been investigated by sugar and methylation analyses, and specific degradations. It is proposed that it is composed of hexasaccharide repeating units with the following structure. The repeating unit also contains an O-acetyl group, linked to one of the primary positions. [formula: see text] PMID- 7834649 TI - Synthesis of cyclohexakis- and cycloheptakis-(1-->4)-(7-amino-6,7- dideoxy-alpha D-gluco-heptopyranosyl), homoanalogues of 6-amino-6-deoxy cyclomaltooligosaccharides. PMID- 7834650 TI - Synthesis of acylphosphonyl analogues of phosphatidyl-myo-inositol as inhibitors of phosphatidylinositol-specific phospholipase C. PMID- 7834651 TI - A conformational study of the Smith degradation product of the Klebsiella K40 capsular polysaccharide by 1D NOESY and molecular mechanics calculations. PMID- 7834652 TI - Polymer-supported enzymic synthesis on a preparative scale. PMID- 7834653 TI - Differential chemical modification of substrate binding areas in porcine pancreatic alpha-amylase by three regioisomeric photolabile ligands. AB - Three regioisomeric radiolabelled spacer-modified oligosaccharides: methyl 4'-O [4-S-(3-azi-4-alpha-D-glucopyranosyloxy-1-[3H]butyl)-6- deoxy- 4-thio-alpha-D xylo-hex-5-enopyranosyl]-alpha-maltoside (12a, G1-G3*), methyl 4-O-[4-S-(3-azi-4 alpha-maltosyloxy-1-[3H]butyl)-6-deoxy-4-t hio- alpha-D-xylo-hex-5-enopyranosyl] alpha-D-glucopyranoside (15a, G2-G2*) and methyl 4-S-(3-azi-4-alpha maltotriosyloxy-1-[3H]butyl)-6-deoxy-4-th io-alpha- D-xylo-hex-5-enopyranoside (16a, G3-G1*) were synthesised and used as photoaffinity probes for the chemical modification of porcine-pancreatic alpha-amylase (PPA). Incorporation of covalently attached radioactivity amounted to 25-38% of the stoichiometric value. Tryptic digestion of the three labelled protein preparations PPA-G1-G3*, PPA-G2 G2*, and PPA-G3-G1* and the purification of the labelled peptides by fractional HPLC yielded altogether six pure components. On the basis of the published three dimensional structure peptides G1-G3-II, G2-G2-II, and G2-G2-III were part of the catalytic site. G1-G3-I and G2-G2-I were part of the surface binding site. The major component derived from PPA, labelled by G3-G1*, corresponded to an area that is neither close to the active site nor to the surface starch-binding domain, which clearly indicates the presence of a third, hitherto undetected, substrate-binding site. PMID- 7834654 TI - Di-D-fructose dianhydrides from the pyrolysis of inulin. AB - Inulin was pyrolyzed in air to produce di-D-fructose dianhydrides (DFDAs) in approximately 26% yield, three of which were identified by MS, NMR, and comparison with literature data. The mass spectra of the per-O-trimethylsilyl derivatives of the DFDAs are discussed. A mechanism is proposed for the formation of DFDAs from inulin during pyrolysis. PMID- 7834655 TI - Structural determination of the capsular antigen of Escherichia coli O8:K25:H9. AB - The primary structure of the acidic capsular antigen of Escherichia coli O8:K25:H9 was shown by monosaccharide analysis, methylation analysis, and by 1D and 2D 1H and 13C NMR spectroscopy to be composed of linear tetrasaccharide repeating units having the structure: PMID- 7834656 TI - A novel mono-sulfated pentaglycosylceramide with the isoglobo-series core structure in rat kidney. AB - A five-sugar sulfated glycosphingolipid containing an isoglobo-series carbohydrate core was isolated from rat kidney and its structure characterized by compositional analysis, FTIR spectroscopy, methylation analysis and 1H NMR spectroscopy of the intact glycolipid and its limited degradation products, and negative liquid secondary ion mass spectrometry (LSIMS). The two dimensional chemical shift correlated spectroscopy and NOE spectroscopy provided information on the sugar sequence and linkage as well as anomeric configurations, so as to establish the presence of a 3-O-sulfated galactose and a Gal alpha 1-3Gal structure within the molecule. Negative LSIMS with collision-induced dissociation defined the sugar sequence and ceramide composition, allowing to confirm the presence, and indicating the position, of the sulfate group. The glycosphingolipid was found to be a mono-sulfated derivative of the isoglobo series core, with the following structure: HSO3(-)-3Gal beta 1-3GalNAc beta 1 3Gal alpha 1-3Gal beta 1-4Glc beta 1-1Cer (iGb5Cer V3-sulfate). PMID- 7834657 TI - NMR assignment and conformational analysis of the antigenic capsular polysaccharide from Streptococcus pneumoniae type 9N in aqueous solution. AB - Complete 1H and 13C NMR assignments, determined by one- and two-dimensional homo- and hetero-nuclear experiments, are reported for the antigenic capsular polysaccharide (CPS) from Streptococcus pneumoniae serotype 9N (S9 in American nomenclature). Distance constraints derived from 1D NOE difference experiments were combined with energy minimisation (simulated annealing) and molecular dynamics (MD) calculations to determine the most favoured conformation of S9 in aqueous solution at 70 degrees C. NOE values simulated for several static conformational models using the NOEMOL program did not correlate well with experimental values, whereas time averaged interproton distances calculated from 500 ps of restrained MD (using the Tropp formalism to account for rapid internal mobility) were in close agreement with experimentally derived distance estimates. PMID- 7834658 TI - Molecular recognition of antigenic polysaccharides: a conformational comparison of capsules from Streptococcus pneumoniae serogroup 9. AB - Aqueous solution conformations of three antigenic bacterial capsular polysaccharides (CPS) from S. pneumoniae serogroup 9 were determined using a combination of NMR data (NOE build-up rates and conformation-dependent chemical shifts), simulated annealing, and molecular dynamics simulations. Each polymer adopts a flexible extended ribbon conformation in solution. Conformations of structural elements shared by each PS are indistinguishable. Differences in conformations are minor and localised at the sites of structural variations; there is no evidence of long-range stabilisation of a secondary structure. It is likely that antigenic specificity of Group 9 PS is dominated by local structural variation rather than by conformational differences. PMID- 7834659 TI - After health care reform legislation: now what? PMID- 7834660 TI - Whose conflict is it anyway? Advantages of mediation in health care setting. PMID- 7834661 TI - New opportunities for registered nurses in health care demand management. PMID- 7834662 TI - Colorado's peer health assistance diversion program for nurses ... an overview. PMID- 7834663 TI - Mountain/rural nurses on the move! PMID- 7834664 TI - Disaster volunteer. PMID- 7834665 TI - Putting prevention into practice. PMID- 7834666 TI - Nursing practice implications of Supreme Court decision on nurses as supervisors. PMID- 7834667 TI - Alternative dispute resolution--who cares?--you care! PMID- 7834668 TI - [Diagnosis and therapy of disseminated intravascular coagulation]. AB - The syndrome of disseminated intravascular coagulation (DIC) is an acquired coagulation disorder which is characterized by a significant activation of haemostasis and the formation of intravascular microthrombi, the consumption of coagulation factors and activation of fibrinolysis. DIC has similar clinical stages and a similar laboratory picture, regardless of the causal factor. The diagnosis of DIC should be based on anamnestic, clinical and laboratory data. The laboratory diagnosis of DIC is possible by using relatively simple tests, which have the character of statim examinations. DIC treatment is based on the principle of treatment of the cause, discontinued consumption of haemostatic material, substitution of lacking factors and restoration of the microcirculation. The possible development of DIC must be taken into account in a number of acute conditions, in particular the development of shock syndrome. The presented article summarizes some views on causes, diagnosis and possible treatment of DIC. PMID- 7834669 TI - [Autotransfusion in cardiosurgery procedures]. AB - BACKGROUND: The use of autotransfusions for planned surgery is becoming quite common. The objective of the present work was to find out whether autotransfusions are safe for cardiosurgery and what is their value. METHODS AND RESULTS: On average 2.3 transfusion units (T.U.) of blood were taken from 62 patients (52 men and 10 women, age 53.7 +/- 10 years) with a planned revascularization of the heart muscle (54x) or valvular operations (8x). During 129 blood collections a drop of systolic pressure occurred (141 +/- before and 134 +/- 21 mm Hg after blood sampling, p < 0.02). The diastolic BP and pulse rate did not change. In nine instances (7%) the authors recorded minor side-effects. After an initial drop of haemoglobin (p < 0.001) during subsequent sampling no further drop was recorded (139.4 +/- 11.8, 130.6 +/- 9.8, 129 +/- 10.5, 130.3 +/- 11.8 g/l). The iron levels, binding capacity and ferritin were within a normal range. During operation 26% of the patients, i.e. 16 (15 men and one woman) did not need a transfusion of homologous blood. The patients were younger (44.7 +/- 8.6 years) and the extracorporeal circulation was shorter (65 +/- 29 min.) than patients with transfusions of homologous blood (37 men, 9 women, 56.8 +/- 8.6 years, 91 +/- 24 min., p < 0.001). CONCLUSIONS: When contraindications are respected autotransfusions before cardiosurgery are safe. In some patients they can replace homologous blood. PMID- 7834670 TI - [Monitoring plasma levels of vitamin D metabolites in simvastatin (Zocor) therapy in patients with familial hypercholesterolemia]. AB - BACKGROUND: Simvastatin is a hypolipidaemic agent, a statin which inhibits cellular cholesterol synthesis by blocking 3HMG CoA reductase. The authors present a report on levels of plasma metabolites of vitamin D after treatment with 10 and 20 mg simvastatin daily in 13 patients, heterozygotes with hypercholesterolaemia during a five-week period. METHODS AND RESULTS: During simvastatin treatment in all patients plasma levels, of the sum of hydroxylated vitamin D metabolites and 1,25-dihydroxyvitamin D after five weeks of treatment with 10 and 20 mg hypolipidaemic drug were examined. For assessment of vitamin D metabolites radioassay was used which assesses the sum of hydroxylated vitamin D metabolites, and radioimmunoanalysis for assessing the 1,25-dihydroxyvitamin D plasma level. For statistical evaluation the non-parametric Friedman test and simultaneous testing was used. CONCLUSIONS: Simvastatin raises the plasma levels of the sum of hydroxylated vitamin D metabolites and 1,25-dihydroxyvitamin D in a dose-dependent ratio. The authors recommend to monitor the plasma levels of vitamin D metabolites over a longer time period. PMID- 7834671 TI - [Determination of peritoneal permeability in chronic peritoneal dialysis using the peritoneal equilibration test]. AB - BACKGROUND: The success of chronic peritoneal dialysis depends among others on the extent of its function as a semipermeable membrane. This so-called functional characteristic can be assessed by several procedures, e.g. by using the so-called peritoneal equilibration test. The objective of the author's investigation was to assemble experience with the method, and based on the results, elaborate an individual therapeutic plan. METHODS AND RESULTS: In 17 patients (8 men, 9 women, mean age when chronic peritoneal dialysis was started 58.4 +/- 11.8 years) the functional capacity of the peritoneum was evaluated using the peritoneal equilibration test (PET). The principle of the test is assessment of the D/P ratio for creatinine and D/Do for glucose (D = concentration of the substance in the dialysate, p = blood concentration of the substance, Do = glucose concentration in the dialysis solution at the time of onset of the test) during four-hour dialysis with 2000 ml solution with a glucose concentration of 2.27% (127 mmol/l). The standardized procedure of the peritoneal equilibration test (12) was modified as regards the calculation of the D/Do ratio: this change simplifies the manipulation with the outlet dialysate and does not affect the result of the test. A total of 22 examinations were made. Based on the results, four patients were included in category H (high peritoneal permeability), 11 into category HA (high average peritoneal permeability) and 2 into category LA (low average permeability). The patients with a higher peritoneal permeability had a lower serum protein concentration (r = -0.63, p < 0.001), and the proteinaemia correlated indirectly with protein losses into the dialysate (r = -0.54, p < 0.01). Intermittent treatment which was prescribed to patients with a high average peritoneal permeability could reduce the total protein losses into the dialysate. CONCLUSIONS: The peritoneal equilibration test is an available method which makes it possible to evaluate the functional properties of the peritoneum. PMID- 7834672 TI - [The fluorescence flow cytometry technique in the diagnosis of hereditary platelet disorders--a case of Glanzmann's thrombasthenia]. AB - The authors describe a method for the diagnosis of heredital platelet membranopathies by means of monoclonal antibodies against the main membrane glycoproteins of thrombocytes, glycoprotein Ib and IIIa. The platelets are differentiated in the flow fluorocytometer from other blood cells by the typical optic profile caused by their size and granular character. Monoclonal antibodies are bound to the appropriate membrane glycoprotein and their amount is then detected by means of a secondary antibody labelled with fluorescein. The intensity of fluorescence of individual platelets is proportional to the number of molecules of the appropriate glycoprotein on their surface. By the above technique a case of Glanzmann's thrombasthenia was diagnosed, a rare hereditary haemorrhagic disease, characterized by the absence or abnormal function of glycoprotein complex IIb/IIIa the platelet receptor for fibrinogen. PMID- 7834674 TI - [General and medical terminology]. PMID- 7834673 TI - [The structure of ethics committees in American hospitals]. PMID- 7834675 TI - [J.E. Purkinje and gastroenterology]. PMID- 7834676 TI - [Modern methods of mitochondrial genome analysis]. AB - DNA diagnosis uses for identification of disorders of the mitochondrial genome currently used methods of restrictive analysis by selective proliferation of selected sections of the mtDNA by polymerase chain reaction (PCR) and sequence. With regard to the considerable natural variability it is essential to evaluate very carefully the assembled results and provide evidence of a causal relationship of changes found in mtDNA and morphological, biochemical and clinical symptoms. PMID- 7834677 TI - [Comparison of the effects of omega-3 polyunsaturated fatty acids and Olbetam (Acipimox) in the treatment of hypertriglyceridemia]. AB - BACKGROUND: Hypertriglyceridaemia associated with low HDL-concentrations is considered an independent risk factor of ischaemic heart disease. The drug of choice in this disorder is nicotinic acid. The aim of the presented work was to compare the hypolipidaemic effect of fish oils rich in omega-3 fatty acids (Activepa 30-TGR, Hydromartens, Norway) with a nicotinic acid derivative, acipimox (Olbetam, Farmitalia Carlo Erba, Italy). METHODS AND RESULTS: The preparations were administered for a three-week period to two groups of patients with hypertriglyceridaemia and low HDL cholesterol levels. The groups had comparable body weights and baseline parameters of lipid metabolism. In the group treated with Olbetam (750 mg/day), 17x hyperlipoproteinaemia type IV and 6x IIB) after treatment significant changes of the following parameters were recorded: triglycerides (-18%; P < 0.001), HDL cholesterol (+19%; P < 0.01), HDL2 and HDL3 cholesterol (+33%; +14%; P < 0.001, P < 0.01), apo B (+25%; P < 0.01), apo A-I (+7%; P < 0.01), ratio of apoB/A-I (+17%; P < 0.01). Furthermore, there was s drop of the atherogenic index (total cholesterol/HDL cholesterol) by 22% (P < 0.001). In the group of subjects (17x type IV and 8x type IIB) whose diet was enriched with omega-3 fatty acids (3.5 g/day), the following parameters changed significantly: triglycerides (-44%; P < 0.001), the atherogenic index (-23%; P < 0.001), HDL cholesterol (+11%, P < 0.01), HDL2 and HDL3 cholesterol (+13%, +17%; P < 0.01, P < 0.05). Changes of apo B, apo A-I concentrations and their ratios were not significant. Comparison of the effect of the two preparations on the investigated parameters revealed a more marked rise of the HDL cholesterol (P < 0.05), apo B (P < 0.01) concentrations and the apo B/-A-I ratio (P < 0.05) during Olbetam treatment. As to the action of the two preparations on further investigated parameters (total and LDL-cholesterol), no significant differences found. CONCLUSIONS: The assembled results indicate that enrichment of the diet with fish oil rich in omega-3 fatty acids has a hypolipidaemic effect comparable to acipimox. It is thus feasible to use fish oils as a drug of first choice in the treatment of hypertriglyceridaemia associated with a reduction of HDL cholesterol concentration. PMID- 7834678 TI - [Anorexia nervosa--the views of the internist]. AB - BACKGROUND: From the metabolic aspect anorexia nervosa is long-term incomplete starvation, sometimes interrupted by bulimic periods. Biochemical investigations reveal a differentiated protein catabolism, a decrease of protein carriers, enzymes, hormones, changes of minerals and their reserves, metabolic acidosis, a reduced plasma protein formation and other changes. As to psychic changes, behavioural abnormalities are found as well as altered attitudes and possibly also a more marked psychiatric symptomatology. The objective of the investigation was to test the extent and depth of metabolic changes and their possible improvement during intense metabolic care; permanent care of a clinical psychologist formed part of the treatment. METHODS AND RESULTS: In five patients, age 17-44 years, height 155-170 cm, body weight on admission 29-42 kg with the clinical diagnosis of anorexia nervosa the following most marked metabolic changes were revealed: a low basal energy expenditure (range 4367-5468 kJ) calculated for fasting (3057-3828 kJ), reduced energy reserves of sugars, fats and protein, reduced total protein values (48-68 g/l), serum albumin (25-39 g/l); prealbumin (0.13-0.29 g/l), transferrin (1.2-2.59 g/l) and total cholesterol (five of six values were either at the lower borderline of normal values or reduced). The urinary N output per 24 hours was increased. After complete parenteral nutrition for 3-9 days (energy load increased from 150-190 kJ/kg body weight, amino acids from 30 to 60 g/day, and 50-100 ml 20% Nutralipid/day) and possible supplements the weight increment was 1.5-1.7 kg after 18-57 days in hospital. Throughout the hospital stay the patients were looked after by a psychologist. After returning home two patients developed a relapse. CONCLUSIONS: Complete parenteral nutrition is an effective way of realimentation in anorexia nervosa. Psychological support is essential but it cannot prevent a relapse. PMID- 7834679 TI - [Dialysis therapy in the Czech Republic in 1993]. AB - 1. The number of haemodialyzation centres increased in 1993 to 6.6/1 million population and thus also the number of dialyzation beds increased to 47.1/1 million population. 2. The extended and free dialyzation capacity made it possible to cover a record number of new patients (96/1 million population as compared with the European average of 61/1 million population). However, the number of older age groups and diabetics increased (in the group above 50 years of age to 17%). The number of patients admitted "from the street" did not decline -it still accounts for one third! 3. In the course of 1993 277 patients/1 million population were dialyzed which is more than in all states of the former eastern bloc. To the date of Dec. 31, 1993 215 patients/1 million population survived. The mortality rate was 13.2%. 4. Hepatitis still remains a major problem--the number of HbsAg positive patients during the last three years did not change, similarly as the prevalence of hepatitis. 5. The dialyzed population is steadily getting older which is not favourable for its prosperity (62% of the patients are older than 50 years). 6. Technical equipment for dialyzation treatment is not yet optimal--21% of the apparatus was amortized, bicarbonate dialysis in all patients was used only in half the centres. 7. The favourable trend in the development of peritoneal dialysis (CAPD) continued, a threefold number of patients was treated as compared with 1992. PMID- 7834680 TI - [Construction of recombinant vaccinia viruses]. AB - Expression system based on vaccinia virus (VV) is used both for recombinant protein production in vitro and as an alive vaccine. The article summarizes various strategies for recombinant VV construction, and describes preparation of recombinants expressing various forms of S and C genes of hepatitis B virus (HBV). It is shown, that the CV-1 cells infected with these recombinants synthesized the MS (middle) and the LS (large) polypeptides of the surface antigen (HBsAg) and the nucleocapsid antigen (HBcAg) polypeptide and the polypeptide HBeAg. Posttranslation modification of all expressed proteins was the same as at HBV infection. PMID- 7834681 TI - [Ethics and health care reform]. PMID- 7834682 TI - [The fate of physicians at the 2nd Internal Medicine Clinic of the General Medical Hospital in Prague during the German Occupation. A reverent remembrance attended by Vaclav Havel, President of the Czech Republic]. PMID- 7834683 TI - [The role of the university professor and the university student]. PMID- 7834684 TI - [Successful endoscopic treatment of choledocholithiasis in our facility]. PMID- 7834685 TI - [Etiologic study on the relationship between HBV, HCV and HCC]. AB - A total of 110 HCC patients were sampled randomly in 20 townships of Qidong county (a higher incidence area of HCC in China) from Mar. to Sept. 1989. Each patient was paired with two healthy persons as control. The results showed that the prevalences of HBV and HCV in 110 patients were 85.45% and 17.27% respectively, and were significantly higher that in control (50.45% and 4.09%). Using Conditional Logistic Regression Model. we found that the main risk factors of HCC in Qidong were HBsAg and Pre-S2 for HBV and anti-HCV for HCV. The OR value were 10.22, 2.96 and 2.63, respectively. Drinking tea was the only protective factor (OR = 0.36). Among 110 HCC patients. 13.64% were positive for both HBV and HCV. The OR value was the highest (6.48). 88.18% patients were either HBV or HCV positive. The OR values were similar (3.90 and 3.89). It suggests that the most important risk factor of HCC in Qidong was HBV infection because it had a higher prevalence among the population while the HCV infection having an equal OR value was also a risk factor. PMID- 7834686 TI - [An epidemiologic study on an outbreak of measles in a particular group of infants]. AB - An outbreak of measles broke out and prevailed in the Beijing Children Welfare House from March 23rd to April 27th, 1992. The 18 victims accounted for 4.8% of the whole infant population in the Welfare House, 11 of them being babies of less than 8 months. One third of the attacked babies were in bad condition and were hospitalized in the observation room. The clinical manifestations indicated that severe symptoms, more complications but favourable prognosis were characteristic of the infant patients. Based on the epidemiologic study and serological test, it was found that the outbreak and spread of the measles originated from outside the Welfare House. It was also found that the vaccinated handicapped infants exposed to natural measles were highly protected. This investigation leads to the conclusion that the cause of this measles outbreak was laid to the vacancy of planning immunization and the existence of a large number of non-protected babies. PMID- 7834687 TI - [Preliminary investigation on acute flaccid paralysis (AFP) cases in Jinan area]. AB - Eighty AFP cases under 12 years old from 6 hospitals in Jinan were investigated. Among them, there were 17 (21.25%) cases with poliomyelitis (POLIO), 40 (50.00%) cases with Guillian-Barre syndrome (GBS) and 23 (28.75%) cases with other AFP diseases. Most AFP cases occurred from May to October and no significant seasonal difference was found for each kind of AFP cases (P > 0.05), but the average age for POLIO cases (1.55 +/- 1.24) was significantly lower than that for non-POLIO AFP cases (3.76 +/- 2.58) (P < 0.01). The reporting rate from hospitals to each level of epidemic prevention station (EPS) for POLIO, GBS and other AFP cases were 100%, 12.50% and 43.75%, respectively (P < 0.01). Sixty-five AFP cases occurred in 6 prefectures around Jinan city. The average incidence rate (per 100,000) for total AFP, non-POLIO AFP and GBS cases among children under 12 years old were 1.11, 0.89 and 0.53, respectively. The results are helpful to estimate the incidence of AFP cases among children in north provinces of China and also indicate that the POLIO surveillance system in Shandong Province at the present is not sensitive enough, so the AFP cases reporting work of hospitals and the surveillance at each level of EPS should be enhanced. PMID- 7834688 TI - [A surveillance on acute respiratory infection]. AB - History prospective methods were employed in this surveillance on acute respiratory infection (ARI) in four villages in Ping Yi and Gao Mi counties. One thousand-one hundred-and sixty four households, 4,379 individuals with 4365.92 person-years were followed up for ARI. The incidence of ARI was 0.4542 episodes/person-year and the household incidence rate was 68.99%. No death case of ARI occurred during the surveillance period. Of all the 18 ARI diseases under surveillance the three diseases with highest incidence were common cold, upper respiratory tract infection and bronchitis. These three diseases all showed obvious family clustering tendency. The incidence of ARI was highest in children under 1 year of age (1.3403 episodes/person year), followed by 2-6 year age group. The lowest was in 20-29 year age-group (0.2885 episodes/person-year). There was no significant difference between sexes. The ARI incidence in spring (0.18024 episodes/person-season) was higher than in other seasons, with the peak between March and April. The hospital attending rate was 90.07%. Among the patients, 80.05% received antibiotics, 13.06% received hormone, 2.10% received intravenous rehydration. ARI accounted for 24.83% of all the out-patients in township hospitals, 19.05%, of which were preschool children. For these children, 70.78% were using antibiotics, 23.31% using hormone, 10.06% using intravenous rehydration. Of the patients, the risk factors of ARI included low birth weight, difficult labour, malnutrition, illiteracy, low income, poor ventilation and lighting of the living room, poor living condition and cigarette smoking. The results presented will be of great significance to policy-making of ARI control in Shandong Province. PMID- 7834689 TI - [The effect of medical treatment on hypertension community control--a follow-up study of more than one thousand hypertensives in East City Proper, Beijing]. AB - Hypertension exerts a great threat on human health. Although most of countries promote the management of hypertension in communities, the role of treatment of hypertension is still controversial, it directly influences the strategy of hypertension community control. This study was based on the survey of essential and borderline hypertension in Gu-lou District of East City Proper, Beijing in 1981, and the management of 1339 hypertensives in the follow-up from 1982 to 1985, and the mortality registration in the district by Disease Surveillance System. By observing the prognosis within one year among different treatment groups (nonusers, less than 9 months and more than 9 months within one year), 1289 patients were followed up for a total of 4283 person-years. Crude analyses, stratified and logistic analyses with multi-variables adjustment of age, sex, blood pressure, with or without end-organ damage, etc. could not find that treatments had obvious effects on the reduction of incidence and mortality of stroke, mortality of CVD and all-cause in hypertensives except severe cases. The stratified analyses dy smoking also showed that smoking had a disadvantageous effects for treated hypertensives. Based on our results, we suggest that health education should be a major part of hypertension management program in community; treatments of hypertension should consider the flexible situation of patients and may not be a priority in hypertension community control program. PMID- 7834690 TI - [The surveillance on the present situation of immune levels of 1044 children vaccinated with seven kinds of vaccines in Dali Prefecture]. AB - A total of 1044 children selected in age groups of 4, 8 and 12 years old from 12 countries (cities) with stratified random sampling method were monitored on the present situation of immune levels according to the programme on immunization in 1991. The results showed that the positive rates and the geometric mean titers of antibodies to measles were 87.16% +/- 3.14%, 5.83 +/- 0.41 (56.90%, < 1:8), respectively; to pertussis were 78.13% +/- 9.19% 218.10 +/- 23.39 (41.62%, > or = 1:320); to DAT were 74.4% +/- 11.04%, 0.098 +/- 0.025; to TAT were 75.86% +/- 11.09%, 0.136 +/- 0.03; to poliomyelitis (ELISA) were type I 89.99%, 220.51, type II 83.38%, 201.27, type III 86.09%, 275.08, 3 types 79.48%, 255.91 (27.23%, > or = 1:400); to Japanese B encephalitis (HI) were 67.47% +/- 3.34%, 39.44 +/- 1.48. The conversion of OT was 24.73%. It showed significant difference among these counties and among 3 age groups (P < 0.01). In 4-year age group, the vaccinated rate and the result of immune surveillance were the same. The antibody level and the incidence of measles showed negative correlation. PMID- 7834691 TI - [Evaluation on efficacy of plasma-derived hepatitis B vaccine and persistence of protective level after vaccination]. AB - From October 1990 to May 1993, 300 students aged 18 to 20 years in Xian were studied to evaluate the efficacy of plasma-derived hepatitis B vaccine made in five factories. AntiHBs titer in 5 vaccinated groups reach the highest at the twelfth month after the first injection and decreased afterwards. The positive rate of anti-HBs decreased slowly, but the titer of anti-HBs fell sharply. Compared with the control group, the differences were all significant. The results showed that the efficacies of hepatitis B vaccine made in five factories were similar. The protection rate of hepatitis B vaccine against HBV infection was 79.22%. PMID- 7834692 TI - [A longitudinal study on maternal-fetal transfer of antibody against poliomyelitis]. AB - A study on antibody distribution and titer against poliovirus in 67 mothers and their 60-day-old new-born babies was carried out in Shi-yan, Hubei Province. The positive rates and the geometric mean titers of antibodies against Types I-II poliovirus in mothers were 98.58%, 1:32.67; 95.5%, 1:30.07; 92.5%, 1:14.58, respectively. In their 60-day-old babies, the antibody positive rates and geometric mean titers fell obviously: they were 34.3%, 1:2.45; 34.3%, 1:2.22; and 14.9%, 1:1.34, respectively. The authors suggest to immune those neonates (OPV zero), or to immune those mothers beginning from 28 weeks of pregnancy in order to raise the antibody titer and protect their babies during the early days. PMID- 7834693 TI - [Using ELISA to evaluate the serologic and epidemiologic effect following rabies vaccination]. AB - After vaccinating the people bitten by animals against rabies, we have examined their serum antibodies by using ELISA. One year later, we sent a mail to everyone of them inquiring if he had contracted rabies. The response rate was 85%. The case fatality rate of the positive antibody group was 0.24% (1/415). The case fatality rate of the negative antibody group was 3.16 (3/95). It showed that there was significant difference in the case fatality rate of rabies between the two groups, (P = 0.022). The dead person of the positive antibody group was bitten on his cheek by a rabid dog. He had not cleaned his wound. He had received 6 injections of rabies vaccines. His incubation period was 28 days. The P/N of serum antibody on the 28th day was 3.27. PMID- 7834695 TI - [The supplementary effect of consulting vaccination in expanded program on immunization (EPI)]. AB - This study was carried out in 420 of children aged 12-24 months in two counties of Gansu Province, China. The result showed that general consulting rate was 30.24% in county or township hospital. The average consulting time was 2.14. A formula was designed K = R x C (1-V) for detecting the effect of consulting vaccination in EPI. The maximum supplementary coefficients of initial immunization of outpatient children for the vaccines were as follows: BCG 0.3024, TOPV-3 0.0953, DPT-3 0.0929, MV 0.0643. And once immunization were BCG 0.3024, TOPV 0.2643, DPT 0.2381, MV 0.0643. The study also explores the supplementary effect of consulting vaccination in different vaccination times and immunization coverages. PMID- 7834696 TI - [Detection of antibodies against Legionella pneumophila from pleural effusion--a case report of Legionnaire's pneumonia with pleural effusion]. AB - Using TAT and ELISA, 50 samples of pleural effusion and sera from patients infected with non-Legionella pneumophila were detected for antibodies against Legionella pneumophila serogroups 1 and 6, respectively. The average titre and upper limit value (99%, mean + 2.326S) calculated. In addition, a pleural effusion and a serum from a patient with Legionnaire's pneumonia were also detected by TAT and ELISA. The result showed that the titre of this antibody in his pleural effusion was not only over the upper limit, but also higher than that in his serum. PMID- 7834694 TI - [Investigation on HBV-M among hospital workers and observation on the efficacy of vaccination against type B hepatitis]. AB - An epidemiological study on HBV infection among 315 staff of PUMC Hospital was carried out with detection of HBsAg, anti-HBs and anti-HBc by ELISA. The results showed that 138 persons had one or more markers of HBV infection and an overall HBV prevalence rate 43.8%. The positive rates of HBsAg anti-HBs, anti-HBc were 6.3%, 28.9% and 8.6%, respectively. This indicates that HBV infection is a risk factor for medical staff, but there was no significant difference among medical, surgical and other members. In 1992, 177 workers whose HBV markers were negative received 3 doses of HB vaccine at 0, 1 and 6 months, respectively. 91.3 percent of them showed an anti-HBs response one month after the last inoculation. The result shows that our national made HB vaccine is safe and immunogenic. PMID- 7834697 TI - [The use of finite population sampling and lot quality assurance sampling in estimating "immunization coverage rate" in villages (towns)]. AB - We have used Finite Population Sampling and Lot Quality Assurance Sampling (LQAS) in a field survey of "immunization coverage rate" for EPI in three villages (towns) in Lanxi Zhejiang Province. The results showed that there was no significant difference (P > 0.05) between the rates of two samplings and between the rate of sampling and population. These results indicated that both Finite population Sampling and LQAS are cheap and simple, and can represent the immunization coverage level of population. PMID- 7834698 TI - [The investigation on drug resistance to N. gonorrhoeae in Benxi district]. AB - The sensitivity of 95 strains of N. gonorrhoeae to antibiotics was determined. In 1990, among 18 strains of N. gonorrhoeae, 7 (38.90%) were resistant to Penicillin G, 3 (16.66%) to Gentamicin, 8 (44.44%) Kanamycin, 8 (44.44%) Midecamycin. In 1992, among 77 strains of N. gonorrhoeae, 61 (79.22%) were resistant to Penicillin G, 38 (49.35%) to Gentamicin, 62 (80.52%) to Kanamycin, 54 (70.13%) to Midecamycin, 56 (72.72%) to Ampicillin 60 (77.92%) to Erythromycin, 22 (28.57%) to Cefazolin, 18 (23.37%) to Cefotaxime. The results showed that Cefazolin and Cefotaxime were the most effective antibiotics, Gentamicin was the next. PMID- 7834699 TI - [Advance in the study of Chlamydia pneumoniae]. PMID- 7834700 TI - [An analysis of the uneven prevalence of tuberculosis in various areas and regions in China]. AB - This article analyzed the uneven prevalence of tuberculosis in various areas and regions and its trend in China nowadays based on the data of the nationwide epidemiological sampling survey of tuberculosis in 1979 and 1990. The highest prevalence was 25-30 times higher than the lowest among provinces, municipalities and regions. The prevalence in remote areas and regions was significantly higher than that in coastal areas and municipalities. The ratios of the prevalence of pulmonary tuberculosis between cities and countryside were 1:2.4-2.8. Most of the investigation points which had a higher prevalence was located in remote and inland areas. Some minority areas which had higher prevalence resided in the northwest and southwest remote areas. The uneven tuberculosis prevalence in various areas and regions indicated that tuberculosis is still an important public health problem in China at present. PMID- 7834701 TI - [A prospective study on the relationship between body mass index and mortality from all causes in 15,827 middle aged and elderly citizens]. AB - The association between Body Mass Index (BMI) and mortality from all causes was investigated in a cohort study of 15827 citizens (aged 35 and over) in Shanghai. During about 3-year follow up the person-year mortality for men and women were 1311.78/100000 and 1036.87/100000, respectively. Cox regression analysis was conducted in a lower and an upper range of BMI, respectively. The inverse association between BMI and mortality in the lower range was statistically significant for men and women. The positive association between BMI and mortality in the upper range was highly statistically significant for women but not for men. Logistic regression analysis conducted over the entire range of BMI showed that BMI and all-cause mortality association was significantly "L"-shaped distribution for men and women. The mortality or relative hazard curve can be fit with quadratic model (Y = a-bX + cX2) in different sex. PMID- 7834702 TI - [Measles surveillance in a rural area: assessment of a passive reporting system]. AB - Comparison of the data provided by the passive epidemic reporting system (PERS) with those of epidemicologic investigation during the outbreak of measles in a rural area, Rongshui County, from November 26, 1992 to May 10, 1993 indicated that the PERS delayed the report one month during the outbreak, failed to describe the time, place and age distributions correctly. The main drawbacks of the PERS were tediousness and delay. The reformed active surveillance system with diagnostic recipe made the reporting precedures much simpler and well acceptable by the physicians. PMID- 7834703 TI - [Epidemiologic study on the risk factors of postpartum hemorrhage]. AB - The 1:2 matched case-control retrospective study of postpartum hemorrhage (PPH) was undertaken in Suizhou, Hubei Province from 1 January 1990 to 31 December 1991. The subjects consisted of 109 women who had a PPH (blood loss equal to or more than 500 ml) and 218 women whose blood loss at delivery was less than 200 ml. The results showed that multiparity, age younger than 20 or older than 36, long second and third stages of labour, abortion, low income, lack of obstetric care, etc, were identified as risk factors statistically. PMID- 7834704 TI - [Analysis on clinical epidemiology of acute bacterial pneumonia in children]. AB - Results of quantitative culture of pathogenic bacteria in nasopharyngeal secretions of 154 cases of hospitalized children with bacterial pneumonia demonstrated that the highest culture rates were Haemophilus influenzae (39.0%) and streptococcus pneumoniae (20.8%). Recovery rate of H. influenzae and Str. pneumoniae among children of various age groups demonstrated that the smaller the age, the higher the recovery rate. The recovery rates of these two bacteria were highest in December and in November, respectively. PMID- 7834705 TI - [Epidemiologic investigations on genetic character of congenital preauricular fistala]. PMID- 7834706 TI - [Molecular epidemiological characteristics of Salmonella typhi strains isolated in China. I. Analysis of Salmonella typhi strains isolated in China by multilocus enzyme electrophoresis]. AB - Multilocus enzyme analysis by polyacrylamide gel electrophoresis (PAGE) was used to analyse 335 isolates of S. typhi from several provinces where high morbidity of typhoid fever was observed in recent years. We analysed 7 metabolic enzymes encoded by chromosome. The results showed that all the enzyme loci were polymorphic. The average alleles per locus was 7.4 (2-19): the mean genetic diversity per locus was 0.498 (0.198 0.883). There were 147 distinctive electrophoretic types (ETs) in 335 isolates. With cluster analysis by the average linkage method, we found that there were 22 subclones, 12 clones among all isolates studied. Most isolates in 1988 from both Jiangsu and Zhejiang provinces belonged to one clone; the isolates from Guangxi Province in 1990 and parts of Hubei isolates belonged to one clone; the isolates from Hunan and Guizhou provinces during several-year period were homogeneous. However, the isolates from Xinjiang Autonomous Region were remarkebly different from other provinces, belonging to a particular clone. We also observed that the isolates from an outbreak or epidemic were from a one subclone. PMID- 7834707 TI - [Studies on the early serodiagnosis of leptospirosis by dot-ELISA]. AB - Thirty serum samples of patients with early leptospirosis from whom cultures of leptospira were positive were tested by dot-enzyme linked immunosorbent assay (dot-ELISA) and microscopical agglutination test (MAT). The results showed that the positive rate of dot-ELISA (40%) was higher than that of MAT (13.3%). One hundred and ninety-eight serum samples from patients with clinical diagnosis of early leptospirosis were tested by dot-ELISA, MAT and blood culture. The results showed that the positive rate of dot-ELISA (64.6%) was higher than that of blood culture (15.2%) and MAT (14.1%). The longer the time of the illness, the lower the positive rate of the blood culture. However, the positive rate of dot-ELISA was stable in different stages of the illness. PMID- 7834708 TI - [The study on ELISA methods for detection of specific antibodies against hemorrhagic fever with renal syndrome virus in rat sera]. AB - Three ELISA methods were developed to detect specific antibodies against hemorrhagic fever with renal syndrome virus (HFRSV) in rats sera. It was shown that all three kinds of McAb-ELISA were specific, sensitive and simple for the detection of HFRSV antibodies in rat sera. PMID- 7834709 TI - [Advances in the study of eperythrozoonosis]. PMID- 7834710 TI - [Is Helicobacter pylori infection the etiology of duodenal ulcer?]. PMID- 7834711 TI - [Relative risk regression models]. PMID- 7834712 TI - Teenage obstetric and gynaecological problems in an African city. AB - OBJECTIVE: To measure the prevalence of sexually transmitted diseases (STD), pelvic inflammatory disease (PID), cervical cancer, pregnancy and use of contraception in teenagers, and to determine socioeconomic factors associated with these conditions to aid planners of medical services and promotion of sexual health. SUBJECTS: 181 Ethiopian teenagers and 1,845 women aged 20 to 45 years for comparison. SETTING: Gynaecological outpatient department, antenatal, postnatal and family planning clinics, in two teaching hospitals and a mother and child heath centre in Addis Ababa, Ethiopia. METHODS: Results of serologic tests for STD, clinical evidence of PID, and cervical cytology were analysed against socio economic factors. RESULTS: In teenagers early age at first marriage/coitus, more common in those of rural origin, was associated with poverty, a greater number of lifetime sexual partners, and prostitution: 40 pc were first sexually active before the menarche. Prevalence of seropositivity to specific STD pathogens was; Treponema pallidum (TPHA) 21 pc, Neisseria gonorrhoeae (gonococcal antibody test: GAT) 40 pc, genital chlamydiae 51 pc, hepatitis B virus 36 pc, herpes simplex virus (HSV-2) 32 pc, and Haemophilus ducreyi 16 pc: 92 pc of teenagers were seropositive to one or more STD's. STD seroprevalence was higher in those with more than one sexual partner, those sexually active by age 15 (very high in those sexually active by age 12), those involved in prostitution and those attending the family planning clinic. Forty three pc had clinical evidence of PID; one married at age 10 had invasive cervical cancer by age 18; 40 pc of teenagers were pregnant compared with 25 pc of those aged 20 to 45; 21 pc attended for family planning; of regular FPC attenders 81 pc were GAT seropositive. CONCLUSION: Despite legislation early age of sexual debut is common, STD and PID are widely prevalent, the pregnancy rate in adolescents is high and contributes to the national population growth rate. Action is required at family, medical and governmental level to encourage cultural acceptance that marriage and sexual activity should not occur before the age of 16 years, with education appropriate to culture to prevent STD. Similar studies are recommended in other countries to establish a baseline for informed strategy regarding prevention of STD and health education. PMID- 7834713 TI - Sexual behaviour and HIV knowledge among adolescent boys in Zimbabwe. AB - A study on sexual behaviour and knowledge of HIV risk was undertaken amongst 511 male students in Zimbabwe. The study was conducted amongst pupils aged 11 to 19 years drawn from urban and rural secondary schools using a self-administered questionnaire. Thirty seven pc of the students reported that they had experienced sexual intercourse, with up to 63 pc reporting having had more than one partner. Twenty one pc of boys aged 12 years reported having had intercourse and the proportion increased with age. Knowledge about AIDS was high (93 pc) with up to 75 pc of the boys reporting that they received the information through the media and only 31 pc got it from their teachers. Logistic regression used to analyse reasons for variation in HIV/AIDS knowledge and of modes of its transmission determined that educational level, actual school attended, access to information from magazines and educational aspirations were significant predictors (p values = 0,005) of knowledge. Individual risk assessment was higher amongst students who reported sexual experience (p = 0,0001). Sixty pc of the sexually experienced boys reported having used condoms. Six pc of the boys reported having intercourse with a commercial sex worker and of these, 85 pc used condoms. Compared with previous studies there appeared to be a reduction in high risk behaviours amongst male secondary school students. However, there is need for increased HIV preventive information through school educational programmes, as increase and variation in HIV information and modes of transmission was seen depending on access to information. PMID- 7834715 TI - Carcinoma of the breast at Ga-Rankuwa Hospital histopathology laboratory (South Africa). AB - Four hundred and twenty five breast carcinomas diagnosed in female Black patients constitute the material of this study. Most tumours were seen between the ages of 40 and 49 years with another peak seen in the seventh decade. The commonest histological tumour type was an infiltrating ductal carcinoma (NOS), constituting 90.4 pc of all the tumours. Twenty five tumours (5.9 pc) had mucinous histological appearance. There were only four (0.9 pc), intraductal carcinomas. Fifty three pc of all the tumours had a high grade histology (grade III). PMID- 7834714 TI - Comparison of arm circumference against standard anthropometric indices using data from a high density town near Harare, Zimbabwe. AB - In a limited controlled sample, the performance of the middle upper arm circumference (MUAC) was compared to those of standard indices (weight for age, height for age and weight for height), using 90 children aged one to four years living in a high density town near Harare, Zimbabwe. Using a cut off point of 15,5 cm, the MUAC performed best in relation to the weight for age (sensitivity 66,7 pc (95 pc confidence interval (CI) 53,3-80,0 pc), specificity 76,2 pc (95 pc CI 61,7-80,5 pc)) than to any other standard index. Nevertheless, this performance was unsatisfactory because about 30 in every 100 (28,9 pc) children would have been inaccurately identified as healthy or diseased. Although we do not have evidence from the present study to recommend the use of the MUAC in identifying children who are malnourished and living in similar high density areas, the MUAC may be applicable to children living in areas of higher prevalence of malnutrition. PMID- 7834716 TI - Persistent fever in severe malaria in children. AB - Plasmodium falciparum species with reduced susceptibility to chloroquine have emerged in West Africa since the mid 1980s. Local strains, however, remain sensitive to amodiaquine with peripheral parasite clearance achieved within seven days in the majority. Blood cultures from 33 children (aged two to 12 years), who remained pyrexial after clearance of their parasitaemia, isolated causative organisms in 19 (57.6 pc) samples, with Salmonella species the commonest (68.4 pc) of all isolates. Complicating septicaemia needs consideration and early institution of treatment with antibiotics in children with severe malaria. Persistent pyrexia in malaria is not always due to resistance to antimalarials in areas with recent emergence of chloroquine resistant strains. A combination of amodiaquine and cotrimoxazole is suggested as a useful initial treatment. PMID- 7834717 TI - The grumbling appendix in urban Zimbabwe--what are we treating? AB - The concept of chronic appendicitis has not been accepted by pathologists. However, quite a number of patients with chronic Right Iliac Fosa (RIF) pain are subjected to appendicectomy. Most of them are found to have fibrosed appendices indicating previous inflammation. A number are found normal. A number of urban people with Right Iliac Fosa (RIF) pain have established parasitic conditions which can be found if they are thoroughly investigated. Some of these may be responsible for the grumbling appendix syndrome. PMID- 7834718 TI - Typhoid fever associated with severe hepatitis. AB - While typhoid is quite common in our environment, presentation in association with severe hepatitis and hepatic encephalopathy is uncommon. The case of a 14 year old male with typhoid who presented with jaundice and severe hepatitis with encephalopathy is presented. The first symptoms occurred one week before presentation. The clinical features and laboratory investigations confirmed typhoid fever. The associated severe hepatitis could have been related to a direct liver involvement by Salmonella typhi, drug toxicity or hepatitis B infection from previous indiscriminate parenteral drugs. The specific cause of the hepatitis could not be confirmed. The patient is presented to illustrate a rare association and possible complication of typhoid fever, inappropriate self and other medication in the place of proper hospital presentation and assessment and the diagnostic difficulties confronting many centres in the developing environment. PMID- 7834719 TI - Utility of AgNOR technique in distinguishing reactive mesothelial hyperplasia, malignant mesothelioma and pulmonary adenocarcinoma. PMID- 7834720 TI - Proximal left anterior descending artery stenosis: dangerous or not? PMID- 7834721 TI - Percutaneous transluminal coronary angioplasty of the left main coronary artery in patients with rest angina. AB - Left main coronary angioplasty may be a therapeutic revascularization procedure for a subset of patients with symptomatic coronary artery disease. The purpose of this study is to report procedural outcomes and long-term clinical follow-up of 15 patients who underwent either protected or unprotected left main angioplasty for rest angina. These patients represent a cohort of unstable angina patients who were considered high risk for coronary artery bypass surgery. Ten of 15 patients had Canadian Heart Class IV angina, and three patients were hemodynamically unstable. Balloon angioplasty was successful in 4 patients, and one patient was treated with directional atherectomy. Initial angiographic success was achieved in 14 of 15 patients (93%). Major complications (myocardial infarction, emergent coronary artery bypass graft, death) occurred in one patient (6%); 73% of the patients were asymptomatic or had stable exertional angina at 6 months follow-up. One year survival was 87% (13 of 15). During the follow-up period six patients had repeat catheterization for recurrent angina. Four of these patients had left main restenosis and underwent successful repeat left main angioplasty. No patient had coronary bypass surgery during follow-up. This report suggests that left main angioplasty can be a safe and effective revascularization procedure for critically ill patients with unstable angina who are at high risk for coronary bypass surgery. PMID- 7834723 TI - Coronary artery ectasia: local pathology or diffuse disease? AB - It is not known whether general or local factors influence the pathogenesis of coronary ectasia. We analyzed prospectively coronary angiograms from 2,186 consecutive patients with 32 patients (1.5%), identified as having coronary artery ectasia. Sixteen subjects had coronary ectasia in more than one segment of the same or a different artery. In 20 of 72 (28%) ectatic segments there was a proximal, related stenosis. In these cases ectasia was more often saccular than fusiform (16 vs. 4) compared to ectasia without a proximal, related stenosis (21 vs. 31, P = 0.003), and the mean length of the ectatic segment was shorter (8.0 vs. 15.1 mm, P = 0.013). Subjects with ectasia after a stenosis often had other ectatic segments unrelated to stenoses. The high incidence of multisegment involvement suggests that coronary ectasia results from a diffuse abnormality of the vessel wall. In predisposed individuals localized ectasia may follow a stenosis, suggesting poststenotic dilatation. PMID- 7834722 TI - Peripheral arterial angioplasty balloons as adjuncts to percutaneous coronary revascularization. AB - Although PTCA balloon technology has improved dramatically since the first catheters were introduced over a decade ago, some limitations remain. The largest conventional balloon size available is 4.0 mm diameter. Larger size balloons are sometimes necessary for saphenous vein graft dilatation or in very large native coronary arteries. Also, adjunctive balloon angioplasty is used frequently after atherectomy and other coronary device therapy. Current generation balloons are not always necessary in this setting, since a large lumen has already been established. Thus, it has become useful in our laboratory to use peripheral arterial angioplasty balloons for both large coronary vessel dilatation, and also for adjunctive dilatation after device use. We describe our initial experience with peripheral arterial angioplasty balloons as adjuncts to percutaneous coronary revascularization. PMID- 7834724 TI - A simple balloon-sizing method in Inoue-balloon percutaneous transvenous mitral commissurotomy. AB - This study was carried out to examine whether the previously determined balloon sizing method based on patient height was valid for percutaneous transvenous mitral commissurotomy using the current second-generation Inoue balloon catheter. The study consisted of 70 patients with pliable noncalcified mitral valves (group 1) and 85 patients with calcified mitral valves and/or severe subvalvular lesions (group 2). The mitral valve area was increased more in group 1 than in group 2 (1.0 +/- 0.3 to 1.9 +/- 0.5 cm2 versus 1.0 +/- 0.3 to 1.6 +/- 0.5 cm2, P = 0.002). Using the stepwise dilatation technique, none of the group 1 patients developed severe mitral regurgitation. Severe mitral regurgitation occurred in 4 patients (4.7%) in group 2. In conclusion, a simple balloon sizing method based on body height for selection of an appropriate-sized balloon catheter, as well as an initial inflated balloon diameter for the stepwise dilatation technique is useful for optimal acute outcomes in mitral commissurotomy. PMID- 7834725 TI - Reopening of an arterial duct after total occlusion with Rashkind's double umbrella device. AB - Reopening of a previously totally occluded ductus arteriosus with the Rashkind umbrella device occurred in a 5-yr-old girl, a previously unreported occurrence. Total occlusion using a second device was successful. This report emphasizes the need for regular follow-up with color flow Doppler echocardiography to diagnose and exclude a residual ductus even when apparent early closure has occurred. PMID- 7834726 TI - Diffuse spasm of a free gastroepiploic artery graft during percutaneous balloon angioplasty. AB - Percutaneous transluminal balloon dilation of an 8-month-old free graft of the gastroepiploic artery was followed by diffuse and profound graft spasm. Because free arterial grafts are more prone to spasm, suitable precautions, such as administration of calcium channel antagonists, should be taken before attempting any interventions on these vessels. PMID- 7834727 TI - Approach to total occlusion of an aorto-ostial "Y" saphenous vein graft with anterior descending graft limb stenosis by serial balloon angioplasty and elective stent deployment. AB - Coronary revascularization using balloon angioplasty and stent placement for unstable angina was performed in a 74-year-old woman with an aorto-ostial occlusion of a "Y-type" saphenous vein graft and a severe stenosis in the body of a 14-year-old left anterior descending saphenous vein graft. Multiple prior coronary bypass graft surgeries, location of branch graft lesions, and length of the ostial stenosis must be considered in selecting the approach to revascularization. PMID- 7834728 TI - Role of side holes in guide catheters: observations on coronary pressure and flow. AB - When performing coronary angioplasty, guide catheter intubation of the ostium often leads to a damping of the pressure tracing. In contrast, when a guide catheter with side holes is used, the pressure tracing is most often superimposable to the pressure wave recorded through the side arm of a femoral artery sheath introducer. This pressure wave gives the reassuring impression of normal hemodynamics in the coronary artery. To illustrate the role of guide catheter side holes and that guide catheter pressure does not necessarily equal the actual coronary artery perfusion pressure, we report observations on trans ostial pressure gradients at rest and during increased coronary flow rates. An abbreviated in vivo study of side holes on the maximal achievable blood flow, employing timed blood flow collections in 7F and 8F side hole guide catheters, was made in 10 patients. At high mean aortic pressure levels, the blood flow through the side holes did not exceed 80 and 60 mL/min for 8 and 7F guide catheters, respectively. These observations suggest that, under some conditions, the guide catheter may produce a resting or hyperemic trans-ostial gradient and that the flow provided only by the side holes of guide catheter is limited. Guide catheter interference with normal flow should be considered in interventional procedures even when arterial pressure appears normal. PMID- 7834729 TI - Catheter sizes for quantitative coronary arteriography. AB - In quantitative coronary arteriography (QCA), the outer diameter of the contrast catheter is used almost exclusively as the calibration device. Since the true outer diameter of these catheters are smaller than the French sizes listed by the manufacturer, it has been advocated to measure the actual sizes with a precision micrometer. However, this represents a significant effort in the organizations of the QCA Angiographic Core Laboratories and of the participating cardiac catheterization laboratories. In the Dutch REGRESS trial on regression/progression of coronary artery disease, we have measured a total of 2,104 catheters from four different manufacturers. In 2,048 of the 2,104 catheters the variabilities in the measurements were 0.02-0.03 mm, which represents an error of only 1% of the average catheter sizes. In the remaining 56 catheter measurements, the variability was 0.04 mm. From these data we may conclude that from now on the stated mean values can be used for calibration purposes. This has important practical consequences for running clinical trials and QCA Core Laboratory operations. PMID- 7834730 TI - Extension of a spontaneous coronary artery dissection due to thrombolytic therapy. AB - We describe a case of spontaneous coronary artery dissection in a 38-year-old woman presenting with anterior myocardial infarction who was initially treated with thrombolysis. During the administration of thrombolytics the clinical symptoms and the electrocardiogram (ECG) deteriorated. Coronary angiography revealed a major dissection in the proximal left descending coronary artery. A spontaneous dissection was hypothesized to have extended by thrombolytic-induced bleeding into the dissected vessel wall. Therefore, we advocate that, especially in young female patients presenting with an acute myocardial infarction and without cardiac risk factors, direct coronary angiography be considered, rather than thrombolytic therapy, in order to decide for the optimal therapeutic strategy. PMID- 7834731 TI - Gianturco-Roubin stent placement for variant angina refractory to medical treatment. AB - A 43-yr-old man with mild, fixed obstruction of the left anterior descending (LAD) coronary artery and severe, uncontrolled variant angina underwent placement of an endovascular stent to preserve patency of the artery. The decision for stent placement was based on several factors, including refractoriness to medical treatment and standard balloon angioplasty, documented spasm localized to the proximal LAD lesion, and the morbidity, mortality, and costs associated with the surgical approach in this type of patient. At follow-up, there was moderate restenosis of the stented coronary segment; the vasospastic angina syndrome had totally resolved. PMID- 7834732 TI - Modified multipurpose catheter enhances clinical utility for cardiac catheterizations. AB - The Multipurpose technique for coronary arteriography employs a single catheter. The benefits are a reduction in the cost of the procedure and a shorter procedural time by experienced operators. To enhance the performance of these catheters, a modification was made in the materials and tip design, and these modifications were clinically evaluated in a small study. Compared to the control group of patients (n = 41), patients catheterized with the Multipurpose-SM (n = 43) were shown to have a shorter procedural time as measured by a reduced fluoroscopy time (7.08 min vs. 9.52 min, P = .007). This difference is statistically significant at a 95% confidence level and resulted in less radiation exposure to the operator and cath lab staff. The procedural time was significantly reduced by fewer catheter exchanges (19% study vs. 46% control; P = .006), which were needed to successfully complete the procedure. The new Multipurpose-SM catheter also demonstrated enhanced flexibility for cannulating coronary arteries with superior or anterior takeoffs. This study concludes that the utilization of a modified Multipurpose-SM catheter is safe and effective in cannulating both the left and right coronary arteries, bypass grafts, and performing left ventriculography. The primary benefits of using this modified catheter are reduced fluoroscopy time and the need for fewer catheter exchanges. PMID- 7834733 TI - Restenosis following subclavian artery angioplasty for treatment of coronary subclavian steal syndrome: definitive treatment with Palmaz-stent placement. AB - We report a case of progressive angina pectoris 4 years post coronary bypass surgery, in which the left internal mammary artery (LIMA) was grafted to the native left anterior descending coronary artery. The coronary-subclavian steal phenomenon was proven angiographically with retrograde reflux through the LIMA graft into the distal subclavian vessel, downstream from a critical stenosis at the origin of the subclavian artery. After initially successful angioplasty of the ostial subclavian lesion, restenosis and return of angina prompted repeat dilatation and placement of a Palmaz 154-M stent. Follow-up catheterization has demonstrated persistent patency at the stented site and absence of coronary steal. PMID- 7834734 TI - Endoluminal stenting of a subclavian artery stenosis to treat ischemia in the distribution of a patent left internal mammary graft. AB - Subclavian artery stenosis is a rare cause of recurrent myocardial ischemia in patients who have undergone left internal mammary-coronary artery bypass grafting. A patient with this syndrome was successfully treated by placement of Palmaz biliary stents in the left subclavian artery. Angiographic and hemodynamic evidence of restricted subclavian flow resolved following stenting, as did the patient's unstable angina syndrome. Endoluminal stenting of the proximal subclavian artery for the treatment of coronary-subclavian steal can be performed safely and provides an alternative to other forms of surgical or percutaneous (PTCA, directional atherectomy) revascularization for treatment of this disorder. PMID- 7834735 TI - Transesophageal echocardiography assisted retrieval of embolized inferior vena cava stent. AB - A 32-year-old male with Budd-Chiari syndrome and stenosis of the inferior vena cava presented to the hospital with severe abdominal pain. Two contiguous, 14 mm, overlapping (joined) Palmaz stents were placed across the area of stenosis in the inferior vena cava. The stents later embolized to the left pulmonary artery and were retrieved non-surgically over a Grollman balloon catheter with transesophageal echocardiographic assistance. This case report highlights the advantages and limitations of transesophageal echocardiographic assistance in such a procedure. PMID- 7834736 TI - Treatment of intracoronary thrombus with local urokinase infusion using a new, site-specific drug delivery system: the Dispatch catheter. AB - BACKGROUND: The presence of intracoronary thrombus significantly increases the risk of conventional balloon angioplasty because of a high incidence of abrupt closure, distal embolization, and no-reflow phenomenon. The purpose of this study was to assess a new technique for treating intracoronary thrombus consisting of the local delivery of urokinase directly to the angioplasty site with a novel, catheter-based, drug delivery system. METHODS: The Dispatch catheter is a new local, drug-delivery device that allows for the prolonged infusion of therapeutic agents at an angioplasty site while still maintaining distal coronary perfusion. Six patients with angiographic or clinical evidence of intracoronary thrombus were treated with 150,000 units of urokinase over a 30-min period using this device prior to or following conventional balloon angioplasty and/or directional atherectomy. RESULTS: Successful delivery of urokinase directly to the angioplasty site was achieved in all 6 patients without hemodynamic or electrocardiographic compromise. In all six cases, local urokinase therapy resulted in complete dissolution of angiographic intracoronary thrombus and/or reduction of the coronary stenosis. Limited ischemia due to side-branch occlusion by the catheter's coils was noted in one patient. Distal embolization or no reflow phenomenon were not observed in any case. CONCLUSION: The local drug delivery catheter used in this study was able to successfully and rapidly achieve intracoronary thrombolysis by delivering limited quantities of urokinase directly to the angioplasty site, while still maintaining distal coronary perfusion. This technique of local, thrombolytic drug delivery may be useful in the percutaneous treatment of intracoronary thrombus and thrombus-containing stenoses. PMID- 7834737 TI - In vitro study of a radiofrequency guidewire aimed at recanalization of totally occluded peripheral arteries. AB - A novel radiofrequency ablative system (40 msec-train pulses with twenty 200 msec pulses at the carrier frequency of 750 KHz and 1 Hz repetition rate) aimed at recanalizing totally occluded peripheral arteries was investigated by means of in vitro tissue ablation from human postmortem arterial wall samples. The samples were submitted to irradiation with a guidewire 150 cm long, maximum diameter of ceramic tip 0.033 inch positioned perpendicular to the tissue surface in saline, contrast medium or blood using varying generator power. Ablation efficacy was determined as the depth of vaporization per pulse delivered. Electrical current for the train duration was measured as voltage at the 1 ohm-resistor. In saline, the ablation efficacy increased from 8 to 65 microns/pulse with generator power increasing from 11 W to 27.5 W. There was no significant difference in the ablation efficacy between saline and blood. In contrast medium, the ablation efficacy was significantly lower. For the same generator power, the electrical current varied during the ablation procedure from 1.3 +/- 0.2 A at the beginning of the procedure to 1.1 +/- 0.2 A after the first pulses and to 2.0 A before artery wall perforation occurred. Neither tissue ablation nor current variations were observed when radiofrequency energy was emitted on calcified tissue. The diameter of craters was 0.89 +/- 0.1 mm (range: 0.85-0.96 mm). No major thermal injury such as carbonization or charring was observed.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7834738 TI - Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. AB - A number of different intracellular signaling pathways have been shown to be activated by receptor tyrosine kinases. These activation events include the phosphoinositide 3-kinase, 70 kDa S6 kinase, mitogen-activated protein kinase (MAPK), phospholipase C-gamma, and the Jak/STAT pathways. The precise role of each of these pathways in cell signaling remains to be resolved, but studies on the differentiation of mammalian PC12 cells in tissue culture and the genetics of cell fate determination in Drosophila and Caenorhabditis suggest that the extracellular signal-regulated kinase (ERK-regulated) MAPK pathway may be sufficient for these cellular responses. Experiments with PC12 cells also suggest that the duration of ERK activation is critical for cell signaling decisions. PMID- 7834739 TI - MAP kinase pathways in yeast: for mating and more. PMID- 7834740 TI - Transcriptional regulation by extracellular signals: mechanisms and specificity. PMID- 7834741 TI - Dimerization of cell surface receptors in signal transduction. PMID- 7834742 TI - Protein kinases and phosphatases: the yin and yang of protein phosphorylation and signaling. PMID- 7834743 TI - Modular binding domains in signal transduction proteins. PMID- 7834744 TI - Heterotrimeric G proteins: organizers of transmembrane signals. PMID- 7834745 TI - Calcium signaling. PMID- 7834746 TI - Phospholipid signaling. PMID- 7834747 TI - Cloning and functional analysis of BAG-1: a novel Bcl-2-binding protein with anti cell death activity. AB - Using a protein interaction cloning technique, we identified cDNAs that encode a novel Bcl-2-binding protein, termed BAG-1. The BAG-1 protein shares no significant homology with Bcl-2 or other Bcl-2 family proteins, which can form homo- and heterodimers. In gene transfer experiments using a human lymphoid cell line, Jurkat, coexpression of BAG-1 and Bcl-2 provided markedly increased protection from cell death induced by several stimuli, including staurosporine, anti-Fas antibody, and cytolytic T cells, relative to cells that contained gene transfer-mediated elevations in either BAG-1 or Bcl-2 protein alone. BAG transfected 3T3 fibroblasts also exhibited prolonged cell survival in response to an apoptotic stimulus. The findings indicate that bag-1 represents a new type of anti-cell death gene and suggest that some routes of apoptosis induction previously ascribed to Bcl-2-independent pathways may instead reflect a need for the combination of Bcl-2 and BAG-1. PMID- 7834748 TI - Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death. AB - To extend the mammalian cell death pathway, we screened for further Bcl-2 interacting proteins. Both yeast two-hybrid screening and lambda expression cloning identified a novel interacting protein, Bad, whose homology to Bcl-2 is limited to the BH1 and BH2 domains. Bad selectively dimerized with Bcl-xL as well as Bcl-2, but not with Bax, Bcl-xs, Mcl-1, A1, or itself. Bad binds more strongly to Bcl-xL than Bcl-2 in mammalian cells, and it reversed the death repressor activity of Bcl-xL, but not that of Bcl-2. When Bad dimerized with Bcl-xL, Bax was displaced and apoptosis was restored. When approximately half of Bax was heterodimerized, death was inhibited. The susceptibility of a cell to a death signal is determined by these competing dimerizations in which levels of Bad influence the effectiveness of Bcl-2 versus Bcl-xL in repressing death. PMID- 7834749 TI - Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. AB - The bax gene promoter region contains four motifs with homology to consensus p53 binding sites. In cotransfection assays using p53-deficient tumor cell lines, wild-type but not mutant p53 expression plasmids transactivated a reporter gene plasmid that utilized the bax gene promoter to drive transcription of chloramphenicol acetyltransferase. In addition, wild-type p53 transactivated reporter gene constructs containing a heterologous minimal promoter and a 39-bp region from the bax gene promoter in which the p53-binding site consensus sequences reside. Introduction of mutations into the consensus p53-binding site sequences abolished p53 responsiveness of reporter gene plasmids. Wild-type but not mutant p53 protein bound to oligonucleotides corresponding to this region of the bax promoter, based on gel retardation assays. Taken together, the results suggest that bax is a p53 primary-response gene, presumably involved in a p53 regulated pathway for induction of apoptosis. PMID- 7834750 TI - Ubiquitin is attached to membranes of baculovirus particles by a novel type of phospholipid anchor. AB - Purified budded virions of Autographa californica nuclear polyhedrosis virus (AcNPV) contain abundant amounts of free ubiquitin, which has an altered electrophoretic mobility on SDS gels as compared with standard ubiquitin. Phase extraction of virion proteins with Triton X-114 indicated that the modified form of ubiquitin behaved as an integral membrane protein. The membrane-bound form of ubiquitin was labeled with both phosphate and palmitate, and its electrophoretic mobility was altered by treatment with phospholipase A2 and a phosphatidylcholine specific phospholipase D. Mild trypsin digestion indicated that the acyl group was not linked to the C-terminus of the protein. Acylated ubiquitin could not be radiolabeled with a membrane-impermeable Bolton-Hunter reagent unless virus was pretreated with detergent. Together, these experiments suggest that ubiquitin is attached to the inner face of the viral membrane by a novel type of phospholipid anchor. PMID- 7834751 TI - Genetic and electrophysiological studies of Drosophila syntaxin-1A demonstrate its role in nonneuronal secretion and neurotransmission. AB - Cloning and characterization of the Drosophila syntaxin-1A gene, syx-1A, reveal that it is present in several tissues but is predominantly expressed in the nervous system, where it is localized to axons and synapses. We have generated an allelic series of loss-of-function mutations that result in embryonic lethality with associated morphological and secretory defects dependent on the severity of the mutant allele. Electrophysiological recordings from partial loss-of-function mutants indicate absence of endogenous synaptic transmission at the neuromuscular junction and an 80% reduction of evoked transmission. Complete absence of syx-1A causes subtle morphological defects in the peripheral and central nervous systems, affects nonneural secretory events, and entirely abolishes neurotransmitter release. These data demonstrate that syntaxin plays a key role in nonneuronal secretion and is absolutely required for evoked neurotransmission. PMID- 7834752 TI - Targeted disruption of the p50 subunit of NF-kappa B leads to multifocal defects in immune responses. AB - NF-kappa B, a heterodimeric transcription factor composed of p50 and p65 subunits, can be activated in many cell types and is thought to regulate a wide variety of genes involved in immune function and development. Mice lacking the p50 subunit of NF-kappa B show no developmental abnormalities, but exhibit multifocal defects in immune responses involving B lymphocytes and nonspecific responses to infection. B cells do not proliferate in response to bacterial lipopolysaccharide and are defective in basal and specific antibody production. Mice lacking p50 are unable effectively to clear L. monocytogenes and are more susceptible to infection with S. pneumoniae, but are more resistant to infection with murine encephalomyocarditis virus. These data support the role of NF-kappa B as a vital transcription factor for both specific and nonspecific immune responses, but do not indicate a developmental role for the factor. PMID- 7834753 TI - Multiorgan inflammation and hematopoietic abnormalities in mice with a targeted disruption of RelB, a member of the NF-kappa B/Rel family. AB - RelB, a member of the NF-kappa B/Rel family of transcription factors, has been implicated in the constitutive expression of kappa B-regulated genes in lymphoid tissues. We have generated mice carrying a germline mutation of the relB gene, resulting in the absence of RelB protein and a dramatic reduction of constitutive kappa B-binding activity in thymus and spleen. Mice homozygous for the disrupted relB locus had phenotypic abnormalities including multifocal, mixed inflammatory cell infiltration in several organs, myeloid hyperplasia, splenomegaly due to extramedullary hematopoiesis, and a reduced population of thymic dendritic cells. RelB-deficient animals also had an impaired cellular immunity, as observed in contact sensitivity experiments. Thus, RelB plays a decisive role in the hematopoietic system, and its absence cannot be functionally compensated by any other member of the NF-kappa B/Rel family. PMID- 7834755 TI - A conversation with Walter F. Lamacki, candidate for the office of American Dental Association president-elect. PMID- 7834756 TI - Sexual harassment in the dental office: an assessment. PMID- 7834754 TI - Dendritic cell progenitor is transformed by a conditional v-Rel estrogen receptor fusion protein v-RelER. AB - A conditional v-Rel estrogen receptor fusion protein, v-RelER, causes estrogen dependent but otherwise unaltered v-rel-specific transformation of chicken bone marrow cells. Here, we demonstrate that such v-relER-transformed cells exhibit B lymphoid determinants in line with earlier studies on v-rel-transformed cells. However, following inactivation of v-RelER oncoprotein activity by administration of an estrogen antagonist, cells differentiate into antigen-presenting dendritic cells as judged by several morphological and functional criteria. Additionally, under yet different culture conditions, v-relER cells differentiate into cells resembling polymorphonuclear neutrophils. Our studies therefore suggest that the conditional v-RelER, and probably also the authentic v-Rel, transform a common progenitor for neutrophils and dendritic cells. PMID- 7834758 TI - Donald J. Provenzale, Chicago Dental Society President, 1994-1995. PMID- 7834757 TI - Sexual contact between dentist and patient: is dating ethical? PMID- 7834759 TI - The downside of infection-control recommendations, guidelines and requirements: legal exposure. PMID- 7834760 TI - Healthcare reform: the Chicago point of view. PMID- 7834761 TI - International investing is inviting. PMID- 7834762 TI - Infection control: it doesn't cost, it pays. PMID- 7834763 TI - Is there an RPZ valve in your future? PMID- 7834764 TI - An implant fixed bridge as replacement for a removable partial denture. AB - This case report documents the replacement of a mandibular partial denture with an implant bridge. With this alternative, the specialist and general dentist can combine their expertise in surgical, restorative and maintenance therapies to develop and maintain a high level of patient comfort and confidence. PMID- 7834765 TI - Fears for patient safety grow as profit-driven restructuring continues. Inappropriate use of assistive personnel jeopardizes patient care. PMID- 7834766 TI - Every patient deserves a nurse. Nurses improve quality of care in hospitals. PMID- 7834767 TI - [The advances in the research on the effects of nitric oxide on pulmonary hypertension]. PMID- 7834768 TI - [Effects of hypoxia-induced endothelin release on the proliferation of pulmonary artery smooth muscle cells]. AB - On the Co-culture model of pulmonary arterial endothelial cells (PECs) and smooth muscle cells (PSMCs), we studied the effects of hypoxia on the release of endothelin in cultured PECs and whether or not these effects could trigger the proliferation in PSMCs. Increase of the transcription of ET gene in cultured pulmonary arterial endothelial cells was shown when endothelial cells were exposed to hypoxia for 24h (95% N2 + 5% CO2, PO2 40-45mmHg in media), was showed to increase the transcription of ET gene in cultured pulmonary arterial endothelial cells by using situ hybridization method. The secretion of ET-1 from those cells into media by ET-1 radioimmunologic detection while 3HTdr incorporation in cultured PMCs was higher compared with normoxia, and administration of ETAb significantly reduced the increase of the incorporation in those compared with hypoxia alone. These results showed that exposure to hypoxia can promote ET-1 gene expression in PECs as well as release of ET from those cells, which of ET can stimulate DNA synthesis in cultured PMCs. It is suggested that enhanced ET release from PECs under hypoxia could stimulate PSMCs' proliferation which may induce pulmonary vessel remodeling--which may involve in the development of hypoxic pulmonary hypertension. PMID- 7834769 TI - [Inhibition of endogenous nitric oxide synthesis enhances acute hypoxic pulmonary vasoconstriction]. AB - The objective of this study was to observe the role of endogenous nitric oxide, formed from L-arginine, in the regulation of acute hypoxic pulmonary vasoconstriction by inhibiting its synthesis with the false substrate NG-nitro-L arginine methyl ester (L-NAME) in anesthetized dogs. L-NAME (1 mg/kg, 5 mg/kg, 15 mg/kg) significantly increased the mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR) during hypoxic ventilation (FiO2 = 0.10) and its action lasted for 90-180 minutes. The maximum increase value (MIV) of hypoxic mPAP in three groups (4 dogs each group) is 1.1 +/- 0.2, 1.5 +/- 0.3, 1.6 +/- 0.4 kPa (1 kPa = 7.5 mmHg), respectively, while that of hypoxic PVR is 58.4 +/- 15.6, 99.3 +/- 28.8, 78 +/- 4.0 kPa.s/L (all P < 0.05 vs hypoxic control before the injection). The increase percent of hypoxic mPAP and PVR induced by L-NAME (15 mg/kg) was 45.23 +/- 5.78% and 133.2 +/- 35.22% 30 minutes after the injection, which was more remarkable than that of mPAP and PVR (18.83 +/- 5.63%, 84.13 +/- 22.67%, respectively) by L-NAME (1 mg/kg). L-arginine (0.5 g/kg) reversed the effect of L-NAME (5 mg/kg) on mPAP and PVR at hypoxic ventilation within one hour. L-NAME also markedly increased hypoxic mean arterial blood pressure at the dose of 15 mg/kg (MIV 2.7 +/- 0.7 kPa) and systemic vascular resistance at the three separate doses (MIV 354.4 +/- 99.7, 456.2 +/- 105, 361.5 +/- 70 kPa x s/L, respectively), meanwhile it remarkably decreased cardiac output and heart rate during hypoxia.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7834770 TI - [Alternations of collagen content and collagen gene expression in rat vascular structural remodeling of pulmonary artery induced by hypoxia]. AB - The change of collagen content and procollagen alpha 1 (I), alpha 1 (III) mRNA expression in rat vascular structural remodeling of extrapulmonary artery (EPA) induced by hypoxia were investigated. 72 wistar male rats weighing 200-300g were used and divided into 2 groups: air-breathing group (N group, 39 rats) and hypoxic group (H group, 33 rats exposed to 5000m hypobaric hypoxia for 7 days). Results showed that mPAp, Rv/(Lv+s), the wet, dry weights and hypoxyproline (HP) content in EPA of H group were increased from 2.83 +/- 0.09kPa (mean +/- smean), 0.23 +/- 0.01, 5.2 +/- 0.2mg, 1.7 +/- 0.1mg and 22.3 +/- 1.0 micrograms)/100g BW (body weight) to 4.77 +/- 0.12kPa, 0.43 +/- 0.01, 10.5 +/- 0.5mg, 4.1 +/- 0.2mg and 58.4 +/- 3.4 micrograms/100g BW (body weight) to 4.77 +/- 0.12kPa, 0.43 +/- 0.02, 10.5 +/- 0.5mg, 4.1 +/- 0.2mg and 58.4 +/- 3.4 micrograms/100g (all P < 0.01). Dot Blot and Northern Blot hybridization analyses showed that in EPA of H group procollagen alpha 1(I) and alpha 1(III) mRNAs were increased 154% and 177% (all P < 0.05). Histological study (HE) showed that hypoxia could induce an increase in the wall thickness of EPA, particularly in adventitial thickness of the pulmonary arterial trunk. Electron microscopy revealed the hypertrophied medial smooth muscle cells containing a significant increase in rough endoplasmic reticulum (RER), in extracellular ground, collagen fibers and elastin were increased. In adventitia, the fibroblasts showed both hypertrophy and hyperplasia and surrounding collagen fibers were increased. These studies suggested that fibroblast might play important role in the remodeling of EPA during the early hypoxic pulmonary hypertension and the increase of collagen gene expression might be involved in the mechanism of collagen content and remodeling of EPA induced by hypoxia. PMID- 7834771 TI - [Protective effect of putrescine on oleic acid-induced respiratory distress syndrome (RDS)]. AB - The effect of putrescine on oleic acid-induced RDS were studied in rat, it was found that preadministration of putrescine to rat with RDS significantly improved its hypoxemia, pulmonary edema and histologic injury; inhibited the leakage of protein from plasma; lowered increase of pulmonary lipid peroxidation products (malondialdehde, MDA). The result suggests that putrescine could have significant potential for clinical treatment of acute pulmonary injury. PMID- 7834772 TI - [Infection of acid-fast bacterial L-forms]. AB - One hundred and fifty five cases which pathological diagnosis were chronic lymphadenitis were studied in order to detect infection of acid-fast bacterial L forms by Ziehl-Neelsen (ZN), intensified kinyoun (IK) and immunohistochemical staining (PAP). The results showed that the expression of M-tuberculosis antibody was positive in 106 cases (68.4%). Among them, 94 cases (60.6%) were positive in IK staining. The positive rate of acid-fast bacillus was 0.6% (1 case), of L forms was 60% (93 cases). L-forms are higher pleomorphic, spherical bodies, giant bodies or long filaments were shown. The L-forms mostly localised within macrophages, only a few distributed sporadically. The possible causes of misdiagnosis physician and pathologist were discussed. The prognostic value was also suggested. PMID- 7834773 TI - [The diagnostic value of anti-BB-antibody estimation in sarcoidosis]. AB - Anti-BB-antibody estimation was carried out in 100 cases of sarcoidosis, 40 cases of suspected sarcoidosis, 45 cases of pulmonary tuberculosis, 39 cases of pulmonary infections, 17 cases of bronchogenic carcinoma and 60 healthy persons as control. The result showed, that the patients suffering from sarcoidosis had the highest positive rate of anti-BB-antibody levels, whereas the positive rate of anti-BB-antibody levels in patients suffering from suspected sarcoidosis, pulmonary infections and tuberculosis was lower than that in patients suffering from sarcoidosis. Patients suffering from bronchogenic carcinoma and healthy controls had the lowest levels of anti-BB-antibody. It was suggested that sarcoidosis may have some relationship with infection. PMID- 7834774 TI - [Tumor infiltrating lymphocytes inhibit spontaneous lung metastasis of LA795 adenocarcinoma in mice]. AB - Tumor Infiltrating Lymphocytes (TILs) isolated from LA795 lung adenocarcinoma in mice have a remarkable antitumor activity, by using T739 syngeneic mice. TILs cytolytic activity in vitro is higher than that of LAK cells. TILs significantly inhibit spontaneous lung metastasis in vivo. The results in experiment I showed the following: TILs injection in tail vein, the inhibitory rate is 73.3%; TILs injection at tumor, 79.9%. The results in experiment II are similar to these in experiment I, and TILs antitumor activity in vivo is as three times as that of LAK cells. PMID- 7834775 TI - [Radiologic findings of calcification of small round shadow in silicosis]. AB - A follow-up radiologic observation was carried out on 12 cases of calcification of small round shadows in silicosis of sandstone masons. The main radiologic features of this disorder were presented. The incidence and the affecting factors were discussed with a brief review of literature. PMID- 7834776 TI - [The use of color Doppler flow imaging in diagnosis and differential diagnosis of some pulmonary masses]. AB - The status of blood supply was examined in twenty-nine patients with pulmonary masses with color doppler flow imaging. The results showed that there are no significant blood signals in 5 benign masses. One patient with pulmonary arterio venous fistula can be diagnosed. Pulmonary inflammatory pseudotumor and 20 lung cancers have rich blood supply. The peak forward velocity and resistance index between them have obvious difference statistically (P < 0.05, P < 0.01). It is concluded that color doppler can be regarded as an useful and noninvasive method before operation in diagnosing some pulmonary masses. PMID- 7834777 TI - [The clinical significance of detection of anti-BCG-A60 antibody by ELISA in diagnosis of tuberculosis]. AB - In order to find out the clinical significance of detection of BCG-A60 antibody by ELISA in diagnosis of tuberculosis, 734 cases of non-tuberculosis patients and 560 cases of tuberculosis has been examined. The result of A60-ELISA test for IgG as diagnosilic criteria of tuberculosis, sensitivity is 84.5%, specificity is 89.3%, It shows satisfactory effect, so it can be used as an helpful method in clinical diagnosis of tuberculosis. IgG, IgA and IgM are measured at same time, and find that a combined use of the IgG and IgM ELISA studies considerably increases the significance of the test. PMID- 7834778 TI - [Bronchial hyperreactivity in bronchial asthma]. PMID- 7834779 TI - [The problems of beta 2 adrenergic agonist in the treatment of asthma]. PMID- 7834781 TI - [Cellular adhesion molecules and asthma]. PMID- 7834780 TI - [A preliminary study of potassium channel activator and its anti-asthma action]. PMID- 7834782 TI - [Eosinophilic airway inflammation and airway hyperresponsiveness]. AB - In order to investigate the effects of accumulation and activation of eosinophils on the airway responsiveness we developed an animal model of eosinophilic airway inflammation by administration of polymyxin B. Bronchoalveolar lavage confirmed the presence of significantly increased numbers of eosinophils in polymyxin B treated guinea pigs compared with that in saline-treated guinea pigs. Contrary to our expectation, no significant increase in airway responsiveness was obtained in polymyxin B-treated group. The results also showed that both intratracheal instillation and inhalation of FMLP to polymyxin B-treated guinea pigs enhance the airway responsiveness to intravenous 5-HT. The indice of eosinophil activation, EPO activity after the FMLP administration in polymyxin B-treated guinea pigs was significant increased. It suggested that accumulated eosinophils be highly activated. The results indicate that eosinophil accumulation does not necessarily cause AHR and accumulated eosinophil activation plays an important role in the development of AHR. Accumulated eosinophil activation would be one of the trigger for asthma attack. PMID- 7834783 TI - [Changes in glucocorticoid receptor and phospholipase A2 in guinea pig asthma models]. AB - In this study we determined the glucocorticoid receptor (GR) level (using 3H dexamethasone as a ligand) and phospholipase A2 (PLA2) activity of lung tissue in guinea pig asthma models at 1st, 3rd, 7th and 14th day of asthma attacks. The results showed that the GR maximal binding capacity (Bmax, fmol/mg pro.) were 54.36 +/- 26.57, 30.99 +/- 10.01, 19.40 +/- 10.06, and 29.16 +/- 11.35; GR dissociation constant (Kd, nmol/L) were 12.73 +/- 4.06, 8.28 +/- 3.23, 5.70 +/- 2.91, and 6.40 +/- 2.64 respectively; and PLA2 actisis (U) were 181.58 +/- 41.50, 239.80 +/- 61.15, 243.08 +/- 31.35, and 235.71 +/- 86.13 respectively. The GR Bmax, Kd and PLA2 of actisis control group were 61.48 +/- 27.60 (fmol/mg pro.), 13.11 +/- 2.88 (nmol/L), 81.06 +/- 15.97 (U). The GR Bmax and Kd of asthmatic animals decreased significantly since the 3rd day, but the PLA2 activity increased significantly since the 1st day as compared to the control group (P < 0.01). The changes of GR Bmax had significant negative correlation with those of the PLA2 activity (r = -0.9023, P < 0.05). The mechanism of the GR and PLA2 actisis changes of asthma animal models were discussed. PMID- 7834784 TI - [Comparative analysis of PD25-V50 and PD20-FEV1 as a judgement of bronchial provocation test]. AB - PD25-V50 as a judgement of bronchial provocation test was compared with PD20 FEV1. Both PD25-V50 and PD20-FEV1 showed linear correlation, but PD25-V50 was more sensitive than PD20-FEV1 for the diagnosis of bronchial asthma, and had higher specificity and sensitivity, and lower false-negative and false positiverate. Moreover PD25-V50 provided the advantages of shorter period of histamine provocation and lower dose of inhaled histamine, so that avoided the side effects of higher dose of histamine. PMID- 7834785 TI - [Airway epithelium affects relaxing effect of verapamil]. AB - The characteristic features of airway hyperreactivity disease are non-specific hyperresponsiveness, insensitive to spasmolysant and damage of epithelium. In our experiment, we measured the tension change of isolated trachea smooth muscle of guinea pig in reacting to acetylcholine and verapamil. It confirmed that (1) the removal of epithelium increases the reactivity of preparations to acetylcholine and reduces the effect of verapamil, (2) in above process the epithelium-derived relaxing factor (EpDRF) had participated in airway hyperreactivity and (3) EpDRF was not derived from metabolism of cyclooxygenase. PMID- 7834786 TI - [Application of radionuclide gastroesophageal reflux imaging in patients with chronic bronchitis and asthma]. AB - To determine the relationship between gastroesophageal reflux (GER) and pulmonary diseases, we studied 29 chronic bronchitis, 32 asthmatic patients, and 9 control subjects. GER was diagnosed by esophageal endoscopy and gastroesophageal scintiscanning. Evidence of GER in the chronic bronchitic patients was 51.74%; in the asthmatics it was 37.5%; and no GER was confirmed in the control subjects. Gastroesophageal scintiscan had 100% sensitivity, but only 68.42% specificity. The mechanism whereby reflux triggers pulmonary problems was investigated by using the scintiscan for pulmonary aspiration, but no pulmonary aspiration was detected in all subjects. Pulmonary function tests did not show any differences between patients with or without reflux (P > 0.05). Thus, our results show that GER is common in chronic bronchitics and asthmatics, which indicates that there is some relationship between GER and chronic bronchitis as well as asthma. PMID- 7834787 TI - [Familial cervical lung hernia: a report of 4 cases in a family]. AB - In this study 4 members of three generations in one family suffered cervical lung hernia was reported. In this 4 cases, there were 2 males, and 2 females, and 3 cases found on the right side, 1 on the left side of neck. Their ages were 55, 32, 5 and 6, respectively. X-ray examinations and CT scan showed typical characteristics. Chromosome examination analysis with high resolution G band was done for 2 of them, no abnormal changes were found. From pedigree analysis we think this type of disease is an autosomal dominant hereditary disease. This familial abnormality has not been found in medical literature, and so we suggest a namelity "Familial cervical lung hernia". PMID- 7834788 TI - [Case report of pulmonary histoplasmosis]. AB - A case of pulmonary histoplasmosis in Beijing was reported Patient's CT scan showed naly patchy consolidation partly with small cavitations and hilar silhouette enlarged in both lungs. On pathologic examination, Histoplasma Capsutatums were found in the lung tissures by percutaneous lung biopsy. Skin rash had developed in the course. After treated by fluconaxole, most of the lung lesions and skin rash disappeared. PMID- 7834789 TI - [Correlation between bronchoalveolar lavage fluid angiotensin converting enzyme levels and T cell subsets in patients with sarcoidosis]. AB - BALF ACE levels were assayed in patients with sarcoidosis, and their correlation with lymphocyte percentage and TH/Ts ratio in BALF were analysed. The results showed a positive correlation (r = 0.4453, P < 0.05; r = 0.7085, P < 0.01). BALF ACE level was decreased as patients with active sarcoidosis improved clinically, indicating that BALF ACE level may be a sensitive biological parameter in the diagnosis and disease activity assessment of sarcoidosis. PMID- 7834790 TI - [Specific detection of Mycobacterium tuberculosis in clinical material by PCR and Southern blot]. AB - An amplified fragment of 245 base pairs from IS-986 sequence hybridized specifically with DNA of M. tuberculosis complex strains. The fragment was labelled with digoxigenin. After amplification by PCR and southern blot hybridization with the dig-labelled probe, the limit of detection of purified genomic M. tuberculosis DNA amounted to 1 fg. We detected sputum, pleural and synovial fluid with active tuberculosis by PCR and southern blot, and the sensitivities were 81.0%, 64.2% and 57.7%, respectively. From the result of the experiment, it is a very useful method for diagnosis of tuberculosis by combining PCR with Southern blot. PMID- 7834791 TI - 32P-HPLC suitable for characterization of DNA adducts formed in vitro by polycyclic aromatic hydrocarbons and derivatives. AB - Analysis of DNA adducts demands both high sensitivity and good resolution. A high performance liquid chromatography method for 32P-postlabeled DNA adducts (32P HPLC) was used to investigate DNA adduct formation from 38 polycyclic hydrocarbons and biphenyls in vitro. The 32P-HPLC method proved to be useful for separation, detection and characterization of DNA adducts from most of the substances. The in vitro method used to form the DNA adducts, with calf thymus DNA, nucleotide 3'-phosphates and metabolic activation through S-9 liver homogenate, gave poor quantitative reproducibility. However, the results showed that the 32P-HPLC method was suitable for characterizing DNA adducts from many substances. From 35 of the tested substances 365 DNA and nucleotide 3'-phosphate adducts were detected and characterized concerning retention times. Of the adducts, 171 were detected in DNA and 39 of them from five substances were characterized concerning target nucleotides. The retention time library built can be used in future analyses of DNA with complex patterns of DNA adducts. PMID- 7834792 TI - Cell proliferation and advancement of hepatocarcinogenesis in the rat are associated with a decrease in connexin 32 expression. AB - The expression of connexin 32 (Cx32), a major liver gap junction protein, after partial hepatectomy (PH) and during development and progression of hepatocarcinogenesis was studied in the rat. Cx32 was quantitatively analyzed by counting immunohistochemically demonstrated protein spots on the membranes of hepatocytes. Livers were sequentially examined after PH to assess the correlation with cell proliferation. For the analysis of different stages in carcinogenesis, Cx32 was assayed in N-ethyl-N-hydroxyethylnitrosamine-induced enzyme altered foci (EAF), hyperplastic nodules (HN), hepatocellular carcinomas (HCC), pulmonary metastatic HCC and transplanted HCC in relation to their degree of altered enzyme expression. Cx32 showed: (i) a rapid decrease after PH to its lowest levels during and 12 h after the S phase of cell proliferation when 5-bromo-2' deoxyuridine (BrdU) labeling indices were examined; (ii) a progressive decrease from early preneoplasia EAF to HN and HCC, values for pulmonary metastatic and transplanted HCC being 0; (iii) clearly inverse correlations with increased BrdU index and degree of altered enzyme expression in HN, indicating that these, with the lowest Cx32 count, are closest to HCC. Therefore, the observed decrease appears linked to cell proliferation and progression of hepatocarcinogenesis, providing a reflection of cellular independence and growth advantage. PMID- 7834793 TI - Lack of an effect of novel inhibitors with high specificity for protein kinase C on the action of the phorbol ester 12-O-tetradecanoylphorbol-13-acetate on mouse skin in vivo. AB - The inhibitory effects of three novel staurosporine-derived compounds were tested with five different types of protein kinases, including protein kinase C (PKC). IC50 values of two of these compounds were found to be 300 to > 5000 times lower for PKC alpha beta gamma (a mixture of the PKC isoenzymes alpha, beta and gamma) than for any of the other protein kinases. The inhibitory action of the most selective inhibitor was tested also with the Ca(2+)-unresponsive PKC isoenzyme delta and was found to suppress PKC alpha beta gamma and PKC delta differentially. The highly specific PKC inhibitors are active both in cell culture and in vivo. They inhibit the PKC-catalyzed phosphorylation of the specific PKC substrate MARCKS in Swiss-3T3 fibroblasts and the okadaic acid induced edema of the mouse ear. However, the more complex biological processes triggered by the phorbol ester 12-O-tetradecanoylphorbol-13-acetate in mouse skin, such as inflammation, stimulation of cellular hyperproliferation and tumor promotion, remain largely unaffected upon topical application of these compounds. PMID- 7834795 TI - Analysis of UV-induced DNA photoproducts by 32P-postlabelling. AB - UV-induced cyclobutane dimers and 6-4 photoproducts, containing an unmodified nucleotide at the 5'-position were released from DNA by means of digestion with DNase I, snake venom phosphodiesterase and prostatic acid phosphatase. The enzymes were deactivated by proteinase K followed by ethanol precipitation. The products were phosphorylated by polynucleotide kinase and [gamma-32P]ATP. The TLC system used for the analysis enables separation of the different photoproducts and detection at a fmol level. T4 endonuclease treatment was applied to confirm the positions of cyclobutane dimers. PMID- 7834794 TI - Microsomal and peroxidase activation of 4-hydroxy-tamoxifen to form DNA adducts: comparison with DNA adducts formed in Sprague-Dawley rats treated with tamoxifen. AB - Using rat liver microsomal preparations and peroxidase enzymes, we have investigated the formation of DNA adducts by the antiestrogen compound tamoxifen (TAM) and its metabolite 4-hydroxy-tamoxifen (4-OH-TAM). When reduced nicotinamide-adenine dinucleotide phosphate (NADPH) was used as a cofactor in microsomal activation of either 4-OH-TAM or TAM, one DNA adduct and relative DNA adduct levels of 4.6 and 3.1 x 10(-8), respectively were detected by 32P postlabeling. The DNA adduct produced by microsomal activation of 4-OH-TAM and TAM was the same. With cumene hydroperoxide (CuOOH) as the cofactor for the microsomal activation of either 4-OH-TAM or TAM, three to six DNA adducts were produced; the relative adduct levels were 8.0 and 20.6 x 10(-8), respectively. Comparison of the DNA adduct patterns produced by 4-OH-TAM and TAM showed that they were distinct. However one of the DNA adducts (a) produced by microsomal activation of 4-OH-TAM using CuOOH was the same as adduct a produced by microsomal activation of 4-OH-TAM with NADPH. Activation of 4-OH-TAM with horseradish peroxidase resulted in the formation of a single DNA adduct and a relative adduct level of 20.7 x 10(-8). Rechromatography analysis of this DNA adduct showed that it was identical to that produced by microsomal activation of 4-OH-TAM with NADPH and one of the adducts produced using CuOOH as the cofactor. Ten DNA adducts and a relative adduct level of 15.3 x 10(-8) were detected in the liver of female Sprague-Dawley rats treated daily with 20 mg/kg of TAM for 7 days. The DNA adduct pattern in the liver of the treated animals was similar to that produced by microsomal activation of TAM using CuOOH as the co-factor. The principal DNA adduct (no. 6) formed in the livers of rats treated with TAM was the same as the principal DNA adduct formed following microsomal activation of TAM using CuOOH as a cofactor. The DNA adduct formed following microsomal activation of either TAM or 4-OH-TAM using NADPH was also present as one of the adducts (1) formed in vivo following TAM treatment. These studies demonstrate that 4-OH-TAM can be activated to form DNA adducts and that it contributes to the formation of DNA adducts in the liver of rats treated with TAM. PMID- 7834796 TI - A histopathological study on alterations in DMBA-induced mammary carcinogenesis in rats with 50 Hz, 100 muT magnetic field exposure. AB - Several epidemiological studies have indicated that residential or occupational exposure to 50 or 60 Hz magnetic fields (MF) may increase the risk of breast cancer, possibly by suppression of pineal production of the oncostatic hormone melatonin. In view of the methodological problems of epidemiological studies on MF exposure and cancer risk, laboratory studies are needed to determine whether 50/60 Hz exposure can initiate, promote or copromote mammary cancer. In the present study, 216 female Sprague-Dawley rats were divided into four groups. Two of the groups (with 99 animals each) received oral applications of 7,12 dimethylbenz[a]anthracene (DMBA) and were either sham-exposed or exposed in a 50 Hz, 100 muT MF for 24 h/day 7 days/week for a period of 91 days. The other two groups (nine animals each) were either sham-exposed or MF-exposed without DMBA treatment. The exposure chambers and all other environmental factors were identical for MF-exposed and sham-exposed animals. At the end of the 3 month period of MF exposure, all rats were used for histopathological diagnosis of lesions. At the time of necropsy, significantly more MF-exposed DMBA-treated rats exhibited macroscopically visible mammary tumours than DMBA-treated controls. Furthermore, the size of mammary tumours was significantly larger in MF-exposed rats. Histopathological examination of the mammary gland showed that the number of neoplastic and non-neoplastic lesions did not significantly differ between groups, indicating that MF exposure had not altered the incidence of mammary lesions but had only accelerated tumour growth, consistent with a co-promoting effect. In the MF-exposed group, significantly more rats exhibited malignant mammary tumours than in controls, indicating that MF exposure had affected the progression of DMBA-induced lesions. The number of metastases of mammary tumours or of primary lesions in other organs in response to DMBA was not affected by MF exposure. In rats without DMBA application, no non-neoplastic or neoplastic lesions were determined. The data demonstrate that long-term exposure of DMBA treated female rats promotes the growth and progression of mammary tumours, while tumour incidence is not affected, at least under the experimental conditions of the present study. The data thus add to the accumulating evidence that MF exposure exerts tumour co-promoting effects. PMID- 7834797 TI - Effect of beta-carotene and wheat bran fiber on colonic aberrant crypt and tumor formation in rats exposed to azoxymethane and high dietary fat. AB - The typical high-fat, low-fiber American diet promotes colon cancer. An alternative to radical changes in dietary habits is to reinforce the diet with cancer protectors. Experiments to evaluate the effects of beta-carotene in the presence of high fat and low and high dietary levels of wheat bran fiber were designed using the Fischer-344 rat colon cancer model. Rats (20/group), were given either high fat (20% w/w), low wheat bran, fiber (1% w/w) diets, or high fat (20% w/w) high wheat bran fiber (8% w/w) diets, with different levels of beta carotene. After 2 weeks of adaptation, half were given two weekly s.c. injections of azoxymethane (AOM, 15 mg/kg body wt); and half two weekly s.c. injections of saline. Six weeks later, five rats from each dietary group were killed to evaluate the comparative effect of different dietary regimens on the induction of colon aberrant crypt foci (ACF). The remaining rats were maintained on their respective diets for an additional 20 weeks to examine the effect on colon tumor incidence. The total number of ACF/rat in the low-fiber groups declined from 44.0 +/- 4.18 to 12.8 +/- 1.95 in response to increasing amounts of beta-carotene from 1 to 20 mg/kg diet. A similar progressive reduction in total ACF/rat was also seen in the high-fiber groups (20.8 +/- 2.92 to 9.2 +/- 0.58). ACF did not develop in the saline-exposed groups. Similarly colon tumor incidence declined from 73% to 20% in high-fiber groups and from 27% to 13% in low-fiber groups in response to increasing amounts beta-carotene from 1 to 20 mg/kg diet. The results showed that beta-carotene and wheat bran, individually and when combined, protected the colon in rats consuming high-fat, western-style diets from ACF and benign or malignant tumor formation. PMID- 7834798 TI - Exposure of mammalian cell cultures to benzo[a]pyrene and light results in oxidative DNA damage as measured by 8-hydroxydeoxyguanosine formation. AB - Carcinogenic polycyclic aromatic hydrocarbons induce DNA damage through direct covalent interactions with nucleotides of the DNA in cells in which they are activated to 'ultimate carcinogenic metabolites'. To determine whether they also induce oxidative damage to DNA under the same circumstances, early passage Syrian hamster embryo and human mammary carcinoma cell line MCF-7 cultures were treated for 24 h with 0-5 micrograms/ml benzo[a]pyrene (BaP) or for 1 h with 0-100 microM methylene blue (as a positive control for oxidative damage). The cells were then exposed to fluorescent light for 1 or 4 h or retained in darkness. After cell harvest, DNA isolation and enzymatic digestion of the DNA to deoxyribonucleosides, the amounts of 8-hydroxy-2'deoxyguanosine (8-OH-dGuo) and unmodified deoxyguanosine present were determined by reverse-phase HPLC with electrochemical and UV detection respectively. Cultures treated with methylene blue for 1 h followed by light exposure for 1 h contained 5-fold (10 microM) and 8- to 28-fold (100 microM) higher 8-OH-dGuo levels than cells treated with methylene blue not exposed to light or untreated cells with methylene blue not exposed to light or untreated cells exposed to light. There was no significant change in 8-OH-dGuo levels in cultures treated with 1-5 micrograms/ml BaP for 24 h in the absence of light. However, both the human and hamster cell cultures treated with BaP and then exposed to fluorescent light for 4 h contained 3-fold (1 micrograms/ml) and 8- to 10-fold (5 micrograms/ml) higher 8-OH-dGuo levels than those not exposed to light or not treated with BaP. These results indicate that BaP treatment does not cause 8-OH-dGuo formation in DNA of cells maintained in darkness. Exposure of BaP-treated cells to fluorescent light causes formation of significant amounts of oxidative DNA damage as measured by 8-OH-dGuo formation. These findings suggest that oxidative damage of DNA could be involved in tumor induction by BaP in tissues, such as skin, in which exposure to BaP can occur in the presence of light. PMID- 7834799 TI - Transplantation of normal hepatocytes modulates the development of chronic liver lesions induced by a pyrrolizidine alkaloid, lasiocarpine. AB - Lasiocarpine (LC), a pyrrolizidine alkaloid, is able to induce a series of chronic and progressive lesions in rat liver, including a long-lasting block in the cell cycle, the appearance of enlarged hepatocytes (megalocytosis), fibrosis, cirrhosis and malignant neoplasma. In this study the effect of transplantation of normal hepatocytes on the development of LC-induced chronic lesions in rat liver was examined. Two-month-old male Fischer 344 rats were given a single dose of LC (80 mumol/kg i.p.). Four weeks later all animals were subjected to 2/3 partial hepatectomy (PH). In addition, at the time of PH one group of rats were transplanted with normal hepatocytes isolated from a syngeneic donor (10(6) cells/rats via the portal vein), while the other group received only the culture medium. All rats were killed 14 weeks after the operation. Grossly, the liver of rats exposed to LC followed by PH with no transplantation of normal hepatocytes was small in size (% liver wt/body wt 1.66 +/- 0.08) and exhibited a few whitish nodules. Histologically, approximately 88% of the liver section was occupied by enlarged hepatocytes and hepatocyte nodules composed of smaller hepatocytes developed in every animal in this group. In addition, extensive bile ductular proliferation was present. However, the liver of rats that were similarly treated but received normal hepatocytes were significantly larger in size (% liver wt/body wt 2.16 +/- 0.07) and were almost completely free of megalocytosis, bile ductular proliferation and hepatocyte nodules. These findings indicate that transplantation of normal hepatocytes is able to modulate the development of chronic liver lesions induced by LC and may be relevant to the pathogenesis of progressive liver diseases such as neoplasia and cirrhosis. PMID- 7834800 TI - The DNA binding activity of the liver transcription factors LFB1 (HNF1) and HNF4 varies coordinately in rat hepatocellular carcinoma. AB - As renal cell carcinomas are characterized by the disappearance of the transcription factor LFB1, which is known to be primarily involved in gene regulation in the liver, we have measured the presence of LFB1 in rat hepatocellular carcinomas induced by diethylnitrosamine. The level of LFB1 binding activity in adenoid-cystic as well as trabecular tumours shows some variation and may either be lower or higher than in the non-tumorous tissue. The amount of LFB1 binding activity correlates with the binding activity of HNF4, a transcription factor reported to stimulate LFB1 expression. As the levels of LFB1 and HNF4 binding activity differ extensively in various hepatocellular carcinomas, it is unlikely that these transcription factors play a general role in hepatocarcinogenesis. This is in contrast to renal carcinogenesis where a dramatic loss of LFB1 is a consistent feature. PMID- 7834801 TI - Loss of expression of basement membrane proteins reflects anomalies of chromosomes 3 and 12 in the rat 4-nitroquinoline-N-oxide model of oral carcinogenesis. AB - This study examined the cytogenetic characteristics of keratinocyte cell lines derived from rat oral tissues treated in vivo with the carcinogen 4 nitroquinoline-N-oxide. A parent tumour with a spectrum of differentiation was used to establish clonal subpopulations that formed differentiated (squamous cell carcinomas; SCCs) and undifferentiated (spindle cell phenotype) tumours following transplantation to athymic mice. By contrast to spindle cell tumours, SCCs elaborated basement membrane proteins (laminin and collagen IV). Both diploid and tetraploid subpopulations formed either SCCs or spindle cell tumours. An unbalanced 10q+ translocation was common to all cell lines. Anomalies of chromosomes 3 and 12 (gain, loss, deletions, translocations) were present only in cell lines that formed spindle cell tumours and were absent in keratinocytes forming SCCs. The results suggest that proto-oncogenes and/or tumour suppression genes located to rat chromosomes 3 and 12 may control tumour cell differentiation. PMID- 7834802 TI - Aflatoxin B1-induced immortalization of cultured skin fibroblasts from a patient with Li-Fraumeni syndrome. AB - To examine the mechanisms of immortalization in human cells, normal human diploid fibroblasts (WHE-7) and skin fibroblasts from a patient with Li-Fraumeni syndrome (MDAH 087) and a mutant p53 allele were treated with aflatoxin B1 (AFB1). Exogenous metabolic activation of AFB1 with rat liver post-mitochondrial supernatant (PMS) was used and the optimal treatment conditions needed were determined by the inducibility of unscheduled DNA synthesis. The same degree of cytotoxicity was observed with MDAH 087 cells and normal WHE-7 cells treated with AFB1 at 0.1, 0.3 or 1 microgram/ml for 2 h with a 2% PMS mixture. All WHE-7 cell cultures (AFB1-treated and controls) failed to escape from senescence, whereas three out of nine AFB1-treated cultures of MDAH 087 cells escaped senescence. MDAH 087 cells treated with 0.1 microgram/ml of AFB1 two or three times initially decreased in growth approximately 40 days [10 population doublings (PD)] after the first treatment. However, the cells recovered with faster growth rates after approximately 100 additional days and grew continuously. Both cultures were immortal, defined as continuous growth for over 300 PD. Cells treated once with 0.3 microgram/ml of AFB1 also escaped senescence, although they had about a 230 day time lag before restoration of cell growth. The three AFB1-treated cell lines exhibited altered morphologies, chromosome aberrations (numerical and structural aberrations) and loss of the wild-type p53 allele. Although immortal, the cells were non-tumorigenic in nude mice. Spontaneous immortalization of untreated MDAH 087 was not observed in this study. The results indicate that AFB1 treatment of cells from a Li-Fraumeni patient, but not cells from normal individuals, can induce immortalization. This model may be useful for studying mechanisms of chemically induced immortalization. PMID- 7834803 TI - Cancer chemoprevention by aliphatic selenocyanates: effect of chain length on inhibition of mammary tumors and DMBA adducts. AB - The objective of this study was to examine the anticarcinogenic activity of a series of aliphatic selenocyanates with increasing length of the carbon side chain, CH3-(CH2)n-SeCN, in which n = 0, 2, 4 or 6. Their ability to prevent mammary cancer was evaluated during the initiation phase using the rat 7,12 dimethyl-benz[a]anthracene (DMBA) model. Each compound was added to the diet at a final concentration of 2 p.p.m. Se and was given from 2 weeks before to 1 week after DMBA administration. Analysis of the tumor data suggested the following order of chemopreventive potency for this series of aliphatic selenocyanates: heptyl approximately pentyl > propyl > methyl. Thus it appears that the length of the carbon side chain is a determinant in modulating the efficacy of these selenium homologs. In vivo results of total DMBA binding and adduct formation in the mammary cells showed a similar trend of progressive reductions following treatment by selenocyanates with increasing length of the alkyl side chain. These studies strongly indicate that aliphatic selenocyanates are effective blocking agents in the DMBA model and are capable of modulating events in the initiation phase of mammary carcinogenesis. PMID- 7834804 TI - Cancer risk of heterocyclic amines in cooked foods: an analysis and implications for research. AB - Heterocyclic amines (HAs) are formed as pyrolysis products during the cooking of meats/fish. These substances are potent mutagens in the Ames/Salmonella assay and are also carcinogens in laboratory animals. In order to assess the magnitude of the cancer risk posed by their presence in the US diet, we estimated the average intakes of HAs, based on analyses of the concentrations of HAs in cooked foods and data from a dietary survey of the US population and quantified the cancer potencies of the individual compounds using dose-response data from animal bioassays. Measured concentrations of HAs in cooked foods were taken from a major review of the open literature. Only those concentrations that were associated with normal cooking conditions were chosen for use in estimating dietary intakes. The average consumption of HA-bearing foods was determined by analyzing statistically the intakes of 3563 individuals who provided 3 day dietary records in a USDA sponsored random survey of the US population during 1989. Dietary intakes of the five principal HAs in descending order were 2-amino-1-methyl-6 phenylimidazo [4,5-b]pyridine (PhIP) > 2-amino-9H-pyrido[2,3-b]indole (A alpha C) > 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) > 2-amino-3,4,8 trimethylimidazo[4,5-f]quinoxaline (DiMeIQx) > 2-amino-3-methylimidazo[4,5 f]quinoline (IQ). The carcinogenic potencies, in contrast, were almost the reverse order: IQ > DiMeIQx > MeIQx > PhIP > A alpha C. An upper-bound estimate of the incremental cancer risk is 1.1 x 10(-4), using cancer potencies based on a body surface area basis. Nearly half (46%) of the incremental risk was due to ingestion of PhIP. Consumption of meat and fish products contributed the most (approximately 80%) to total risk. PMID- 7834805 TI - Carcinoma formation in NMRI mouse skin painting studies is a process suggesting greater than two stages. AB - The two-stage model of carcinogenesis, which incorporates clonal growth of intermediate cells, has gained increasing attention in recent years. It was formulated to match tumor incidence data and expanded to encompass observations made in initiation-promotion carcinogenicity experiments. Mouse skin experiments are perceived as supporting this model, with papillomas representing the intermediate cells and carcinomas representing the malignant cells. In this manuscript, the two-stage model is applied to data concerning papilloma and carcinoma formation from an initiation-promotion NMRI mouse skin painting experiment which included stop-promotion. It is shown that the model is not compatible with these data if all papillomas are considered premalignant lesions. The model was modified to allow for a heterogeneous population of papillomas. In this case, unless one assumes that premalignant and terminally benign papillomas are morphologically different in the sense that both types of papillomas at detection limit contain distinct numbers of actively dividing initiated cells, the model predicts larger numbers of papillomas at the end of the experiment than were actually observed. The best explanation is that the model is not in accordance with these data and that the data indicate the need for stages between initiated and malignant cells. PMID- 7834807 TI - N-acetylation and N-formylation of carcinogenic arylamines and related compounds in dogs. AB - When sulfanilamide, p-aminobenzoic acid, 4-amino-biphenyl, 2-aminofluorene or 1 aminopyrene was given orally to dogs, the corresponding N-acetyl and N-formyl derivates were isolated from urine or feces. These metabolites were identified unequivocally by comparison with an authentic sample by UV and mass spectrometry and their behaviour in TLC and HPLC. Dog intestinal flora and several bacterial strains exhibited both N-acetylating and N-formylating activities, in varying degrees, toward all of the arylamines tested. The metabolites formed by the intestinal bacteria were also isolated and identified unequivocally. The results suggest that the intestinal microflora plays an important role in the formation of N-acyl derivatives from arylamines in dogs. PMID- 7834806 TI - Malignant progression of papillomas induced by the initiation--promotion protocol in NMRI mouse skin. AB - Recording of individual responses to initiation-promotion was used to study the relationship between papilloma and carcinoma formation in NMRI mouse skin. This type of analysis is without precedent in that it allows a statistical evaluation of the data which was impossible with previously published analyses based upon cumulative tumor response data evaluated in other mouse strains. Initiation with DMBA and promotion with TPA yielded papillomas consisting of two sub-populations, reversible and persistent papillomas. The ratio of persisting to reversible papillomas was independent of the duration of promotion, indicating comparable growth rates for both types of papillomas. Fifty percent of the persistent and 4% of all papillomas progressed into carcinomas. Promotion for > 20 weeks increased neither the total number of papillomas nor the number of carcinomas. Both the maximum number of persistent and the maximum number of reversible papillomas correlated with the risk of malignant progression, excluding persistent papillomas as being the exclusive precursor lesions for malignant progression. PMID- 7834808 TI - Frequent T:A-->G:C transversions in X-irradiated mouse cells. AB - Ionizing radiation is a known carcinogen and teratogen. However, the point mutations produced by ionizing radiation in mammalian cells have not been fully characterized. Determination of a characteristic spectrum of X-ray-induced mutations in mammalian cells could provide clues to cellular repair processes and could serve as a marker of individual exposure to radiation. Mouse fibroblasts containing in their genome multiple copies of a recoverable lambda phage shuttle vector were used to detect and analyze radiation-induced point mutations in the supF mutation reporter gene. Following fractionated doses of ionizing radiation, a unique mutational spectrum notable for a high proportion of T:A-->G:C transversions (57%) was found. This pattern was distinct from the spectra of UV induced and spontaneous mutations detected in the same mouse cell assay system (mainly C:G-->T:A transitions). The predominance of T:A-->G:C transversions and the pattern of mutation hot-spots are consistent with a possible role for polymerase beta in the repair of X-ray-damaged DNA. These results may also help to define a distinctive mutational signature of X-ray exposure in mammalian cells. PMID- 7834809 TI - Endogenous formation of N-nitrosomorpholine in mice from 15NO2 by inhalation and morpholine by gavage. AB - Male CD-1 mice were exposed to an nominal concentration of 20 p.p.m. of 15N nitrogen dioxide (15NO2) for 6 h/day for 4 days and for 2 h on the day 5, and to 1 g morpholine/kg body wt by gavage daily for five consecutive days. N Nitrosomorpholine (NMOR) was found in whole mice, stomachs, skins with hair, and remains. The sum of individual tissue concentrations measured separately was 3421 ng/tissue, where the average skin weighed 4.3 g, the average stomach weighed 1.0 g and the average remains weighed 22.2 g. The average whole mouse weighed 27.7 g and contained a total of 3903 ng of NMOR. The concentration of NMOR was highest in the skin, next highest in the stomach, and lowest in the remains. However, the total quantity of NMOR per tissue, while highest in the skin (83%), was next highest in the remains (14.8%) and lowest in the stomach (2.2%). GC-MS analysis served to distinguish between the NMOR of 15NO2 origin and that of other origin. All of the NMOR in the whole mouse homogenates was identified as 15NMOR. In the stomach 73% was identified as 14NMOR, representing 1.6% of the total NMOR in the mouse, and 27% as 15NMOR, representing 0.6% of the total NMOR in the mouse. N Nitrosamine formation in vivo is discussed as a possibly ongoing mammalian process. PMID- 7834810 TI - Induction of mutations by replication of malondialdehyde-modified M13 DNA in Escherichia coli: determination of the extent of DNA modification, genetic requirements for mutagenesis, and types of mutations induced. AB - The mutagenicity of the lipid peroxidation product, malondialdehyde (MDA), was measured in the lacZ alpha forward mutation assay using a recombinant M13 phage, M13MB102. Single-stranded M13MB102 DNA was reacted with MDA at neutral pH and the modified DNA was transformed into strains of Escherichia coli induced for the SOS response. Increasing concentrations of MDA led to an increase in lacZ alpha mutations coincident with an increase in the level of the major MDA deoxyguanosine adduct. Spontaneous and MDA-induced M13MB102 mutants were collected and the lacZ alpha target region was subjected to automated DNA sequence analysis. The most common sequence changes induced by MDA were base-pair substitutions (76%). Of these, 43% (29/68) were transversions, most of which were G-->T (24/29). Transitions account for 57% of the base-pair substitutions (39/68) and were comprised exclusively of C-->T (22/39) and A-->G (17/39). Frameshift mutations were identified in 16% of the induced mutants and were comprised of mainly single base additions occurring in runs of reiterated bases (11/14). The diversity of base-pair substitution and frameshift mutations induced by MDA at low levels of adduction suggests it may be an important contributor to endogenous mutagenesis and carcinogenesis in aerobic organisms. PMID- 7834811 TI - Mitochondrial pyruvate metabolism in liver and kidney during acidosis. AB - Pyruvate transport and carboxylation have been determined in mitochondria from liver and kidney cortex isolated from Wistar rats with acidosis produced by three different treatments: fasting, exercise and ingestion of ammonium chloride. Fasting for 48 h or swimming for 2 h resulted in an increased rate of CO2 fixation by mitochondria from both organs incubated with pyruvate. This increase was accompanied by a rise in the rate of pyruvate transport in all cases except in mitochondria derived from the kidney of the fasted animals. Acute acidosis produced by the ingestion of ammonium chloride resulted in increases in pyruvate transport and carboxylation in kidney mitochondria, but a drop in pyruvate carboxylation was observed in mitochondria from the liver. The results are discussed in terms of the differential regulation of the mitochondria steps for gluconeogenesis from three carbon precursors in liver and kidney, taking into consideration the hormonal status of the animals and the prevailing available substrates in each condition. PMID- 7834812 TI - Uric acid synthesis by rat liver supernatants from purine bases, nucleosides and nucleotides. Effect of allopurinol. AB - The synthesis of uric acid from purine bases, nucleosides and nucleotides has been measured in reaction mixtures containing rat liver supernatant and each one of the following compounds at 1 mM concentration (except xanthine, 0.5 mM and guanosine and guanine, 0.1 mM). The rates of the reaction, expressed as nanomoles of uric acid synthesized g-1 of wet liver min-1 were: ATP, 10; ADP, 37; AMP, 62; adenosine, 108; adenine 6; adenylosuccinate, 9; IMP 32; inosine, 112; hypoxanthine, 50; GTP, 19; GDP, 19; GMP, 27; guanosine, 34; guanine, 72; XMP, 10; xanthosine, 24; xanthine, 144. These figures divided by 55 correspond to nanomoles of uric acid synthesized min-1 per mg-1 of protein. The rate of synthesis of uric acid obtained with each one of those compounds at 0.1 and 0.05 mM concentrations was also determined. ATP (1 mM) strongly inhibited uric acid synthesis from 0.05 mM AMP (91 per cent) and from 0.05 mM ADP (88 per cent), but not from adenosine. CTP or UTP (1 mM) also inhibited (by more than 90 per cent) the synthesis of uric acid from 0.05 mM AMP. Xanthine oxidase was inhibited by concentrations of hypoxanthine higher than 0.012 mM. The results favour the view that the level of uric acid in plasma may be an index of the energetic state of the organism. Allopurinol, besides inhibiting uric acid synthesis, reduced the rate of degradation of AMP. The ability of crude extracts to catabolize purine nucleotides to uric acid is an important factor to be considered when some enzymes related to purine nucleotide metabolism, particularly CTP synthase, are measured in crude liver extracts. PMID- 7834813 TI - Glucocorticoid-induced changes in liver: effect of dexamethasone administration on DNA topoisomerase I and II activities and distribution of histone H1 subtypes. AB - The activities of DNA topoisomerase I and II and the relative proportions of the histone H1 subtypes were investigated in rat liver which was undergoing hypertrophy and exhibiting increased transcriptional activity following the administration of dexamethasone. There was a rise in the level of activity of DNA topoisomerase I and a slight fall in that of DNA topoisomerase II. The relative proportions of the H1 subtypes were altered due to a preferential increase in H1.1. The results are discussed in relation to the effect of glucocorticoids on the transcription and replication of hepatic DNA. PMID- 7834814 TI - Characterization of gamma-glutamyltranspeptidase in the liver of the frog: 2. Response to season, temperature and thyroid hormone in Rana pipiens. AB - The impact of season and temperature on frog liver gamma-glutamyltranspeptidase was assessed by measuring the activity of this enzyme in plasma membranes isolated from the livers of Rana pipiens obtained as summer and winter frogs; subjected to short-term (3 weeks) temperature acclimation; and subjected to multiple-temperature shifts. Plasma levels of T3 were determined. gamma Glutamyltranspeptidase was found to be 2.2-fold higher in the summer frog relative to the winter frog; decreased by 44 percent in the summer frog by cold acclimation and increased by 1.7-fold in the winter frog by warm acclimation; and increased by 1.9-fold in the summer frog and 2.8-fold in the winter frog subjected to multiple-temperature shifts. Plasma T3 levels were found to be 42 fold higher in the summer frog relative to the winter frog; decreased by 42 percent by cold acclimation and increased by 2.9-fold by warm acclimation; and decreased by 39 percent and 38 percent in the summer and winter frogs subjected to multiple temperature shifts. T3 replacement during the last phase of the multiple-temperature shift protocol, restored the plasma T3 levels to 75 percent of the control levels and prevented the increase evoked by the multiple temperature shifts in gamma-glutamyltranspeptidase activity. Indeed, enzyme activity in the T3 replaced state was 19 percent lower than in the control state. The involvement of thyroid hormone as a negative regulator of enzyme activity is discussed. PMID- 7834815 TI - Time-dependent irreversible inhibition of bovine kidney alkaline phosphatase by oxidized adenosine. Use of this compound as a site-directed inhibitor for studying uncompetitive inhibition. AB - The L/B/K type of mammalian alkaline phosphatase (ALP) is inhibited uncompetitively by nucleotides. A combination of adenosine and nicotinamide is more effective than either adenosine or nicotinamide alone, probably because a dinucleotide structure is necessary to trigger a conformational change accompanying binding of structures such as NADH. It has been suggested that a loop region containing residue 429 in the ALP polypeptide is important in the interaction of uncompetitive inhibitors with the enzyme. In the L/B/K isoenzyme, residue 429 is a histidine and is a potential target for modification. In an attempt to learn more about the molecular events accompanying inhibition of ALP by uncompetitive inhibitors, bovine kidney ALP was reacted with oxidized adenosine in the presence of nicotinamide to see if site-directed modification occurs. Kidney ALP was irreversibly inactivated by oxidized adenosine but the reaction was slow. The site modified is likely to be close to the region of binding. Sequence data for the kidney enzyme shows that in the region of residue 429 there are no residues except His429 itself that is likely to react with oxidized adenosine. PMID- 7834816 TI - Differences in the G/total actin ratio and microfilament stability between normal and malignant human keratinocytes. AB - The state of polymerization of actin and the organization of actin filaments is widely believed to be related to cellular transformation. Since the intracellular monomer (G) and filamentous (F) actin content reflects the state of microfilament polymerization, we measured the G/total actin ratio in primary cultures of normal and malignant human keratinocytes. In normal keratinocytes the mean value of this ratio was 0.30 +/- 0.03 (mean +/- SE, n = 15), while in basal cell carcinoma (BCC) keratinocytes it was 0.49 +/- 0.03 (n = 8) and in squamous cell carcinoma keratinocytes (SCC) 0.5 +/- 0.07 (n = 4), indicating a 1.7-fold increase of the G/total actin ratio in malignant cells. These results imply that the proportion of polymerized actin is decreased markedly in malignant keratinocytes, suggesting alterations of microfilament structures which probably occur during the transformation process. This was supported by the morphological changes of microfilament structures as assessed by fluorescence microscopy. A different distribution of actin filaments in normal and malignant cells became evident; stress-fibres were converging in patches at several points in SCC cells, when compared to normal keratinocytes. Furthermore, incubation of normal and malignant keratinocytes with cytochalasin B indicated differences in the resistance of their microfilament networks. After 1 h exposure to 10(-6) and 10(-5) M cytochalasin B, microfilaments in normal cells appeared to be less affected than their counterparts in neoplastic cells. Even in a high excess of cytochalasin B (10(-4) M), normal keratinocytes preserved their shape, while both basal cell and SCC were totally disrupted.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7834817 TI - Activation of phosphoinositide-specific phospholipase C of rat neutrophils by the chemotactic aldehydes 4-hydroxy-2,3-trans-nonenal and 4-hydroxy-2,3-trans octenal. AB - A comparison has been made between the effects of 4-hydroxy-2,3-trans-nonenal (HNE) and 4-hydroxy-2,3-trans-octenal (HOE), two lipid peroxidation products, on the basal and GTPgammaS-stimulated activities of phosphoinositide-specific phospholipase C (PL-C) of rat polymorphonuclear leukocytes. PL-C activity was determined in vitro by measuring the hydrolysis of [3H] phosphatidylinositol-4,5 bis- phosphate (PtdIns-P2) added as exogenous substrate to neutrophil plasma membranes. PL-C was activated by concentrations of HNE ranging from 10(-8) to 10( 6) M both in the presence and in the absence of 2 x 10(-5) M GTPgammaS; HOE stimulated the enzymatic activity between 10(-11) and 10(-8) M; maximal stimulation was given by 10(-11) M HOE plus GTPgammaS. The aldehyde concentrations able to accelerate PtdIns-P2 breakdown displayed a good correspondence with those which have been reported to stimulate the oriented migration of rat neutrophils. Pretreatment of neutrophils with pertussis toxin prevented the stimulation of PL-C by 10(-11) M HOE and by HOE plus GTPgammaS. Our results suggest that the chemotactic action of HNE and HOE might depend on the activation of PL-C; furthermore a regulatory G protein appears to be involved in the acceleration of PtdIns-P2 turnover by HOE. PMID- 7834818 TI - Hyaluronan-mediated protective effect against cell damage caused by enzymatically produced hydroxyl (OH.) radicals is dependent on hyaluronan molecular mass. AB - Hyaluronan (HA) protected tendon fibroblasts against cell damage mediated by hydroxyl radicals (OH.) as demonstrated by release of 51Cr from labelled cells. Protection afforded by high molecular mass (M(r)) HA (1218 kDa) was much more effective than that provided by lower (176 kDa and 668 kDa) M(r) HA. OH. was generated by coupling H2O2 produced by glucose oxidase:glucose to [Fe(2+)-EDTA] chelate in a Fenton-type system. The flux of OH. was measured by a spectrofluorimetric assay of salicylate produced by the reaction of benzoate with OH.. Cell damage caused by the OH. generating system was prevented in the presence of catalase, which destroyed H2O2. Damage caused in a standard incubation time increased with increased amounts of glucose oxidase. Protection against OH.-mediated cell damage increased with increasing concentration of HA. The presence of HA did not interfere with the enzyme-Fenton system, as monitored by production of gluconate. On the other hand, HA scavenged OH. produced by the enzyme-Fenton system, as shown by competition with benzoate, which produced less salicylate in the spectrofluorimetric assay in the presence of HA. The reaction of OH. with HA was measured directly by a pulse radiolysis technique in which a hydrated electron (eaq-) produced OH. by the reaction with nitrous oxide. Second order rate constants obtained in distilled H2O or in phosphate buffer showed no dependence on HA M(r). Similarly, fluorimetric assay of the flux of in the enzyme Fenton system confirmed that HA competed with benzoate, thus lowering salicylate production, and the flux was also independent of the molecular mass of HA.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7834819 TI - Sperm phospholipid methyltransferase activity during preparation for exocytosis. AB - The present report describes experiments to evaluate phospholipid methyltransferase activity in golden hamster spermatozoa incubated under different conditions. Washed cauda epididymal sperm were incubated with taurine, in the presence or absence of epinephrine. At various times, the sperm were separated, and phospholipid methyltransferase activity measured. Also, at each time, aliquots of the sperm suspension were assayed for motility, and acrosome reactions. Some sperm incubated in the presence of taurine and epinephrine were capacitated by 3.5 h, because about 40 per cent of them can undergo the acrosome reaction 10 min after addition of the fusogen lysophosphatidylcholine. In epinephrine-free incubations the fusogen failed to stimulate acrosome reactions. On the other hand, epinephrine stimulated by twofold phospholipid methyltransferase activity from '0 time' incubated sperm, in comparison to that observed in taurine-treated cells. Enzyme activities from both taurine or epinephrine plus taurine-treated cells decreased as the incubation time of the sperm suspension increased. Kinetic properties of the sperm phospholipid methyltransferase activity were modified by the presence of taurine and epinephrine when S-adenosylmethionine was used as the substrate. These results suggest that refined molecular events occur in the sperm cell during the acquisition of fertilizing ability. PMID- 7834820 TI - Effect of pentoxifylline and somatostatin on tumour necrosis factor production by human pulmonary macrophages. AB - Cytokines seem to act predominantly in a paracrine manner when producing their deleterious effects during sepsis. Therefore, local TNF alpha release by pulmonary macrophages would have a central role in the pathogenesis of the adult respiratory distress syndrome (ARDS). By contrast, pentoxiphylline (PTXF) can reduce lung damage in septic animal models, and somatostatin (SS-14) has been shown to down-regulate TNF alpha-receptor expression in monocytes, suggesting an immunomodulatory action for this hormone. The aim of this work was to study the effect of PTXF and SS-14 on lipopolysaccharide (LPS)-induced TNF alpha release by human pulmonary macrophages. Macrophages were obtained from multiple organ donor lungs. Donors with either a recent history of tobacco smoking, more than 72 hr of mechanical ventilation, or any radiological pulmonary infiltrate were not included in this study. After 1 hr of culture, LPS stimulated TNF alpha release in a dose-dependent manner (2.34 +/- 0.20 and 11.32 +/- 1.38 pg/microgram protein, P < 0.01, in response to 2.5 and 10 micrograms/ml LPS, respectively). This response was significantly inhibited by both PTXF, 100 micrograms/ml (0.24 +/- 0.07 vs. 2.43 +/- 0.20, P < 0.01, and 1.30 +/- 0.08 vs. 11.32 +/- 1.38, P < 0.01, pg/micrograms protein, 2.5 and 10 micrograms/ml LPS, respectively) and SS 14, 0.4 ng/ml (0.26 +/- 0.07 vs. 2.43 +/- 0.20, P < 0.01, and 0.60 +/- 0.19 vs. 11.32 +/- 1.38, P < 0.01, pg/micrograms protein, 2.5 and 10 micrograms/ml LPS, respectively).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7834821 TI - Lactate monitoring with subcutaneous microdialysis in patients with shock: a pilot study. AB - We describe the use of subcutaneous microdialysis for continuous sampling of lactate to monitor the plasma lactate concentration in eight patients with shock. The dialysate lactate concentrations were significantly correlated with the plasma lactate concentrations (r = 0.8229), but the linear regression lines varied between patients. Therefore, we used the individual regression line of each patient for calibration to calculate estimated plasma values from the dialysate concentrations. While the estimated values were linearly correlated to the plasma lactate values (r = 0.912), the 95% confidence interval of the estimated values was +/- 2.8 mmol/L. Thus, subcutaneous microdialysis does not allow accurate estimation of the plasma lactate concentration. In 3 of the 8 patients, there was a significant negative correlation between the dialysate/plasma lactate ratio and the plasma lactate concentration. This suggests that besides plasma lactate, other factors such as subcutaneous adipose tissue metabolism and blood flow, may influence subcutaneous sampling and dialysate lactate concentration as well. While microdialysis can be used for on line sampling and continuous monitoring of the concentration of extracellular substances, for the purpose of plasma lactate monitoring, sampling probes should be designed that permit intravascular placement. PMID- 7834822 TI - Beneficial effects of extracellular glutathione against endotoxin-induced liver injury during ischemia and reperfusion. AB - The potential beneficial effect of hepatocellular glutathione against inflammatory liver damage was investigated in a model of endotoxin-enhanced ischemia-reperfusion injury. Animals were subjected to 20 min of hepatic ischemia, followed by 4 hr of reperfusion. The injection of 0.5 mg/kg Salmonella enteritidis endotoxin potentiated liver injury and the postischemic oxidant stress, as indicated by increased plasma levels of glutathione disulfide. Depletion of hepatic glutathione levels by > 90% with phorone and inhibition of glutathione synthesis with buthionine sulfoximine further increased liver injury in this model, as indicated by enhancement of plasma alanine aminotransferase activities from 2,234 +/- 122 U/L to 4,024 +/- 282 U/L. Continuous infusion of a glutathione (GSH) solution in GSH-depleted animals (22 mumol/kg/hr) attenuated reperfusion injury by 55%. In vitro experiments demonstrated the capability of GSH to react rapidly with reactive oxygen species, such as hydrogen peroxide (H2O2) and hypochlorous acid (HOCl). Only H2O2 oxidized GSH quantitatively to its disulfide; HOCl oxidized GSH to higher oxidation states. These data support the hypothesis that the enhanced release of hepatocellular GSH functions as a defense mechanism against reactive oxygen species generated by inflammatory cells during endotoxemia and reperfusion. This internal defense system of the liver may be of general importance in preventing, or at least limiting, liver damage by reactive oxygen generated in particular by Kupffer cells during their physiological function to remove gut-derived endotoxin and bacteria. PMID- 7834823 TI - Effects of free radical scavengers, methylprednisolone, and ulinastatin on acute xanthine and xanthine oxidase-induced lung injury in rats. AB - We investigated the role of free radicals, especially from activated neutrophils, in acute xanthine and xanthine oxidase-induced lung injury in rats. We evaluated the effects of intravenously administered intracellular and extracellular free radical scavengers (for O2-., H2O2, and .OH), methylprednisolone (MP), and Ulinastatin (UST, a protease inhibitor), on this animal model of lung injury. At 5 min prior to the intrabronchial injection of a mixture of xanthine (X, 100 nmol) and xanthine oxidase (XO, 1 unit) used to induce unilateral lung damage, rats were pretreated intravenously with superoxide dismutase (SOD, 40 mg/kg), SOD (40 mg/kg) plus catalase (CAT, 30 mg/kg), dimethylthiourea (DMTU, 500 mg/kg), N-2 mercaptopropionyl glycine (MPG, 20 mg/kg), MP, 30 mg/kg, and UST, 50,000 units/kg. Each scavenger was infused intravenously at one-half the initial dose for 20 min after intrabronchial injection; 3 hr later, we examined the wet/dry lung weight ratios and the levels of thiobarbituric acid-reactive substances (TBARS) in lung tissue. Intrabronchial injection of the X/XO mixture markedly increased wet/dry lung weight ratios and lung tissue content of TBARS. Histopathologic changes were observed in the injected lung as well. Pretreatment with SOD + CAT, DMTU, and UST significantly reduced the increases in wet/dry lung weight ratios and lung tissue content of TBARS induced by the intrabronchial injection of the X/XO mixture. Our data suggest indirectly that free radicals (H2O2, .OH) and proteases from activated neutrophils may contribute, in part, to the lung damage induced by the O2-.-generating system of xanthine and xanthine oxidase. PMID- 7834824 TI - Role of oxyradicals in cardiovascular depression and cellular injury in hemorrhagic shock and reinfusion: effect of SOD and catalase. AB - We investigated the effects of hemorrhagic shock and reinfusion on the cardiac function and contractility, plasma CK and CK-MB activity and lactate concentration, oxyradical-producing activity of polymorphonuclear leukocytes (PMNL-CL), cardiac chemiluminescence (LV-CL), antioxidant enzymatic activity [superoxide dismutase (SOD), catalase, glutathione peroxidase (GSH-Px)], and malondialdehyde (MDA) concentration in anesthetized dogs, to determine the role of oxyradicals in cardiac depression and cellular injury in hemorrhagic shock and reinfusion. The dogs were assigned to four groups: group I (sham), 4 hrs duration; group II, 4 hr of shock; group III, 2 hr of shock, followed by reinfusion for 2 hr; and group IV, as in group III, but pretreated with SOD and catalase. Hemorrhagic shock was produced by withdrawing blood to maintain the mean arterial pressure at 50 +/- 5 mm Hg. Cardiac function and contractility were depressed during hemorrhagic shock. Plasma CK; CK-MB and lactate; and cardiac MDA, Mn-SOD, and CuZn-SOD increased, while catalase activity decreased during shock. Following reinfusion after 2 hr of shock, hemodynamic parameters and plasma lactate tended to return toward control values. Plasma CK and CK-MB, PMNL CL and cardiac MDA, total SOD, Mn- and CuZn-SOD increased further, while LV-CL and GSH-Px decreased. In spite of the increased antioxidant reserve, oxidative damage was noted. Pretreatment with SOD and catalase attenuated the deleterious effects of shock and reinfusion on the cardiovascular function, plasma CK, CK-MB, and lactate, PMNL-CL, cardiac MDA and SOD, and LV-CL. Protection was incomplete for cardiovascular function and plasma CK and CK-MB. These results suggest that oxyradicals (O2-, H2O2) may be partly involved in the deterioration of cardiovascular function and cellular injury during hemorrhagic shock and reinfusion. PMID- 7834825 TI - Intrinsic pumping of mesenteric lymphatics is increased after hemorrhage in awake sheep. AB - Lymphatic vessels have the ability to contract and transport liquid and protein from tissue spaces to the intravascular space. The purpose of this investigation was to test whether this lymph pump is stimulated following a fixed volume hemorrhage in awake sheep. To quantitate lymphatic pumping in vivo, a mesenteric lymphatic was isolated from all lymph input and provided with Krebs solution at a fixed transmural pressure. A branch of the mesenteric duct was cannulated to provide a measure of lymph flow rate. Each animal was either bled 25% of blood volume over 5 min or was observed. Systemic arterial blood pressure declined in all bled sheep (P < 0.05). Hemorrhage had no effect on lymph flow from mesenteric ducts. However, hemorrhage significantly enhanced lymphatic pumping, approximately 200% of control values 3 hr after hemorrhage (P < 0.01). Increased lymphatic pumping after hemorrhage may play an important role in blood volume and protein restitution. PMID- 7834826 TI - Apoptosis (programmed cell death) in arteries of the neonatal lamb. AB - We have examined whether cell death contributes to postnatal remodeling of arteries in lambs. First, abdominal aortic smooth muscle cell proliferation rates fell from 2.87 +/- 0.08% per day at 3 days of age to 1.75 +/- 0.15% per day at 21 days. These proliferation rates would yield a 50% increase in DNA content in the absence of cell death. No increase in DNA content was observed (P < .05 for predicted versus measured accumulation); therefore, significant cell death was inferred. The same analysis did not indicate high cell-death rates in the carotid, renal, or iliac arteries; however, cell death was detected in situ by end-labeling partially degraded DNA with terminal deoxynucleotidyl transferase or by nuclear labeling with propidium iodide, a fluorescent dye that permeates only nonviable cells. Nuclei were labeled in all arteries, although labeling was most frequent in the abdominal aorta, a vessel that regresses substantially after birth. Cell death was apoptotic because DNA extracted from arteries and end labeled with [32P]dCTP produced a series of low molecular weight bands (DNA ladder) on an agarose gel, a hallmark of apoptosis. The ladder was strong for neonatal abdominal aorta but weak for other arteries. Only weak laddering was observed for fetal abdominal aortas in late gestation, confirming that high apoptosis rates in this vessel were initiated after birth. Intense DNA ladders and frequent in situ labeling indicated high rates of apoptosis in the postnatal intra-abdominal umbilical artery, another vessel that regresses after birth. We conclude that apoptosis contributes to postpartum arterial remodeling. This contribution is greatest in arteries that regress after birth. PMID- 7834827 TI - c-myc in vasculoproliferative disease. AB - Antisense oligonucleotides to genes central to cellular proliferation have suppressed smooth muscle cell growth in vitro and in vivo. We now report that although the response of cultured smooth muscle cells to antisense oligonucleotides to c-myc and c-myb is identical, the response of the injured arterial wall to these oligomers depends on the kinetics of gene expression and oligonucleotide delivery. Two different antisense oligonucleotides to each oncogene were administered to the perivascular aspect of injured rat carotid arteries via polymer-based delivery systems. The acute release of antisense oligonucleotides from the Pluronic gels reduced in vitro cell growth 54.8% with c myc and 56.9% with c-myb. The more sustained release from ethylene vinyl acetate copolymer (EVAc) matrices was slightly less efficient, inhibiting proliferation 47.3% and 43.3%, respectively. However, although both EVAc and Pluronic release of c-myb antisense oligonucleotide sequences inhibited intimal hyperplasia 2 weeks after injury, only the more prolonged EVAc matrix release of antisense oligonucleotide to c-myc was effective. The failure of the short course of c-myc oligomer release from Pluronic gels stemmed from early successful suppression with late loss of regulation and not from inactivation of the antisense oligonucleotide within the polymeric gel. Within 24 hours of injury, Pluronic based release of c-myc antisense oligomers reduced mRNA levels in the tunica media 2.5-fold and immunocytochemical identification of c-myc expression by 98.8%. As a result, the number of proliferating cells was decreased 6.5-fold 3 days after injury.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7834828 TI - Activation of mitogen-activated protein kinase in porcine carotid arteries. AB - The thin-filament protein h-caldesmon (the high molecular weight isoform of caldesmon) is phosphorylated in resting and contracted porcine carotid arteries. Phosphorylation of h-caldesmon in intact tissue occurs at sites that are covalently modified by mitogen-activated protein kinase (MAPK) in vitro. In this study, we have evaluated MAPK activation in arteries in response to mechanical load and pharmacological stimulation. MAPK was extracted from resting and stimulated porcine carotid arteries and then partially purified by anion-exchange fast-performance liquid chromatography. MAPK activity was separated into two peaks corresponding to the tyrosine-phosphorylated 42- and 44-kD isoforms of MAPK (p42MAPK and p44MAPK, respectively). Of the total MAPK activity, 42% was associated with p42MAPK, and 58% was associated with p44MAPK, this percentage was not altered by stimulation of the muscles with either KCl (110 mmol/L) or phorbol 12,13-dibutyrate (PDBu, 1 mumol/L). Both p42MAPK and p44MAPK, purified from porcine carotid arteries, phosphorylated h-caldesmon at the same sites and to levels approaching or > 1 mol phosphate per mole protein. In unloaded muscle strips, MAPK activity was 39 pmol.min-1.mg protein-1 when assayed with the peptide substrate APRTPG-GRR. MAPK activity increased in response to incremental mechanical loading to a maximum of 99 pmol.min-1.mg protein-1 at 16 x 10(3) N/m2. MAPK activity could be further increased in loaded muscles by pharmacological stimulation. With KCl stimulation, MAPK activities rose to a peak of 205 pmol.min 1.mg protein-1 at 10 minutes and then declined to basal values at 30 and 60 minutes.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7834829 TI - Coexpression of P2Y and P2U receptors on aortic endothelial cells. Comparison of cell localization and signaling pathways. AB - Depending on the vascular bed considered, the actions of ATP on the endothelium are mediated by either P2Y or P2U receptors. The two types of receptors seem to coexist on bovine aortic endothelial cells, where they are both coupled to phospholipase C. In this study, we have investigated whether they are truly coexpressed on the same cells and whether their signaling pathways diverge beyond phospholipase C activation. Measurements of [Ca2+]i in single cells showed that almost all bovine aortic endothelial cells are responsive to both 2-methylthio ATP (2MeSATP), an agonist of P2Y receptors, and UTP, an agonist of P2U receptors. UTP stimulated the release of prostacyclin from freshly isolated bovine aortic endothelial cells, even when they were exposed to cycloheximide at the time of their collection: this indicates that P2U receptors must already be expressed on endothelial cells in situ and do not appear during cell culture. The time course of inositol phosphate (InsP) accumulation and the relative proportion of Ins(1,4,5)P3, Ins(1,3,4,5)P4, and Ins(1,3,4)P3 were similar in cells stimulated by 2MeSATP or UTP. UTP and 2MeSATP both stimulated the hydrolysis of phosphatidylcholine by phospholipase D, as reflected by the release of [3H]choline from prelabeled cells. The responses to both agents were blocked after downregulation of protein kinase C, resulting from a prolonged exposure to phorbol 12-myristate 13-acetate: this blockade occurred at a step distal to phospholipase C activation. A single difference between the two pathways has been identified: the effect of 2MeSATP on InsP3 was significantly more inhibited after a short exposure to phorbol 12-myristate 13-acetate than that of UTP.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7834830 TI - cGMP and nitric oxide modulate thrombin-induced endothelial permeability. Regulation via different pathways in human aortic and umbilical vein endothelial cells. AB - Previous studies have demonstrated that cGMP and cAMP reduce the endothelial permeability for fluids and macromolecules when the endothelial permeability is increased by thrombin. In this study, we have investigated the mechanism by which cGMP improves the endothelial barrier function and examined whether nitric oxide (NO) can serve as an endogenous modulator of endothelial barrier function. Thrombin increased the passage of macromolecules through human umbilical vein and human aortic endothelial cell monolayers and concomitantly increased [Ca]2+ in vitro. Inhibition of these increases by the intracellular Ca2+ chelator BAPTA indicated that cytoplasmic Ca2+ elevation contributes to the thrombin-induced increase in endothelial permeability. The cGMP-dependent protein kinase activators 8-bromo-cGMP (8-Br-cGMP) and 8-(4-chlorophenylthio)cGMP (8-PCPT-cGMP) decreased the thrombin-induced passage of macromolecules. Two pathways accounted for this observation. Activation of cGMP-dependent protein kinase by 8-PCPT-cGMP decreased the accumulation of cytoplasmic Ca2+ in aortic endothelial cells and hence reduced the thrombin-induced increase in permeability. On the other hand, in umbilical vein endothelial cells, cGMP-inhibited phosphodiesterase (PDE III) activity was mainly responsible for the cGMP-dependent reduction of endothelial permeability. The PDE III inhibitors Indolidan (LY195115) and SKF94120 decreased the thrombin-induced increase in permeability by 50% in these cells. Thrombin treatment increased cGMP formation in the majority of, but not all, cell cultures. Inhibition of NO production by NG-nitro-L-arginine methyl ester (L NAME) enhanced the thrombin-induced increase in permeability, which was restricted to those cell cultures that displayed an increased cGMP formation after addition of thrombin. Simultaneous elevation of the endothelial cGMP concentration by atrial natriuretic factor, sodium nitroprusside, or 8-Br-cGMP prevented the additional increase in permeability induced by L-NAME. These data indicate that cGMP reduces thrombin-induced endothelial permeability by inhibition of the thrombin-induced Ca2+ accumulation and/or by inhibition of cAMP degradation by PDE III. The relative contribution of these mechanisms differs in aortic and umbilical vein endothelial cells. NO can act in vitro as an endogenous permeability-counteracting agent by raising cGMP in endothelial cells of large vessels. PMID- 7834831 TI - Integrin-mediated collagen matrix reorganization by cultured human vascular smooth muscle cells. AB - Vascular smooth muscle cells perform the important function of modulation of vascular extracellular matrix. Because integrins mediate many cell-matrix interactions, the role of integrins in reorganization of collagen by cultured human vascular smooth muscle cells was studied. Immunoprecipitation demonstrated that human vascular smooth muscle cells express multiple beta 1 integrins. Monoclonal antibody A2-IIE10 (a blocking anti-alpha 2 antibody) inhibited adhesion of smooth muscle cells to collagen by 31%. The blocking anti-alpha 1 antibody 1B3.1 inhibited adhesion by 40%, whereas a blocking anti-alpha 3 antibody had no effect on adhesion. When 1B3.1 and A2-IIE10 were both used, a 79% reduction in adhesion was observed, indicating that active alpha 1 and alpha 2 integrins cooperatively mediate adhesion. The blocking anti-beta 1 antibody Mab13 abolished smooth muscle cell-mediated gel contraction, and the alpha 2-blocking antibody A2-IIE10 had a dose-dependent partial inhibitory effect (37%). In contrast, blocking antibodies to alpha 1 and alpha 3 had no effect. When anti alpha 1 (1B3.1) and anti-alpha 2 (A2-IIE10) monoclonal antibodies were combined, no synergistic effect on inhibition of gel contraction was observed. Surprisingly, collagen gel contraction was inhibited by 46% by an anti-beta 1 antibody (TS2/16) known for its stimulatory effect on cell adhesion. Thus, whereas alpha 1 beta 1 and alpha 2 beta 1 integrins both participate in adhesion of vascular smooth muscle cells to collagen, only alpha 2 beta 1 integrins mediate collagen reorganization. In addition, collagen reorganization appears to be a dynamic process, adversely affected by excessive adhesion strengthening. PMID- 7834832 TI - Continuous nitric oxide inhalation reduces pulmonary arterial structural changes, right ventricular hypertrophy, and growth retardation in the hypoxic newborn rat. AB - Breathing low oxygen levels for several weeks produces progressive pulmonary artery hypertension and smooth muscle hypertrophy and hyperplasia in many species. Because nitric oxide (NO) is an important regulator of pulmonary vascular tone, we examined whether the continuous inhalation of low levels of NO gas would attenuate pulmonary arterial structural changes in hypoxic rat pups. Nine-day-old rat pups and their mothers continuously breathed at FIO2 0.21 or 0.10 with or without adding 20 ppm (by volume) NO for 2 weeks. Lung tissue was obtained for vascular morphometric analysis, and the hearts were dissected to measure right ventricular weight and levels of mRNA encoding rat atrial natriuretic factor (rANF). In addition, femur and skull length were radiographically determined. Breathing at FIO2 0.10 for 14 days increased pulmonary arterial wall thickness and the proportion of muscular arteries in the lung periphery. Right ventricular weight and right ventricular rANF gene expression increased, whereas body weight and skeletal growth were reduced (all P < .05). Continuous inhalation of 20 ppm NO at FIO2 0.10 for 2 weeks decreased hypoxic pulmonary vascular structural changes and somatic growth retardation and prevented the increase of right ventricular weight and right ventricular rANF mRNA levels. These observations suggest that chronically breathing NO attenuates pulmonary vascular smooth muscle hypertrophy and/or hyperplasia and extension into distal arterial walls, right ventricular hypertrophy, and growth retardation of newborns breathing at a low oxygen level. PMID- 7834833 TI - Propafenone preferentially blocks the rapidly activating component of delayed rectifier K+ current in guinea pig ventricular myocytes. Voltage-independent and time-dependent block of the slowly activating component. AB - The effects of propafenone on the delayed rectifier K+ current were studied in guinea pig ventricular myocytes by using the patch-clamp technique. In these myocytes, this current consists of at least two components: a La(3+)-sensitive component activating rapidly with moderate depolarizations and a La(3+)-resistant current slowly activating at more positive potentials. In the absence of La3+ (when both components are present), propafenone inhibited the delayed outward current, its effects being more marked after weak than after strong depolarizations. Propafenone-induced block of the tail currents elicited on return to -30 mV was more marked after short than after long depolarizing pulses. In the presence of 1 mumol/L propafenone, the envelope-of-tails test was satisfied, thus indicating that at this concentration propafenone completely blocks the rapidly activating component. In the presence of La3+ (when only the slow component is present), the steady state inhibition induced by 5 mumol/L propafenone on both the maximum activated and the tail currents was independent of the test pulse voltage. Development of propafenone-induced block on the slowly activating component was very fast and linked to channel opening. In addition, the blockade appeared to be use dependent, with the rate constant of the onset kinetics at 2 Hz being 0.44 +/- 0.1 pulse-1. The recovery process from propafenone-induced block exhibited a time constant of 2.5 +/- 0.4 s. These results indicated that propafenone preferentially inhibits the rapidly activating component of the delayed rectifier and that it blocks in a voltage-independent and time-dependent manner the slow component of this current. PMID- 7834834 TI - Partial inhibition of Ca2+ current by methoxyverapamil (D600) reveals spatial nonuniformities in [Ca2+]i during excitation-contraction coupling in cardiac myocytes. AB - The laser scanning confocal microscope was used in conjunction with the Ca2+ indicator fluo 3 to examine the spatiotemporal properties of free Ca2+ ([Ca2+]i) transients in isolated rat cardiac myocytes. We show that localized increases in [Ca2+]i (Ca2+ sparks) can be triggered by membrane depolarization in cardiac myocytes when the sarcolemmal Ca2+ current amplitude is reduced by methoxyverapamil (D600). These depolarization-evoked Ca2+ sparks are similar in amplitude and spatiotemporal properties to spontaneous Ca2+ sparks previously observed at rest. These observations support the idea that Ca2+ sparks are the result of the activation of functional elementary units of sarcoplasmic reticulum (SR) Ca2+ release. The synchronous activation of a large number of Ca2+ sparks can explain the increased amplitude and slower time course of the electrically evoked [Ca2+]i transient as well as the presence of spatial nonuniformities in [Ca2+]i during its rise. The data shown here suggest a model for excitation contraction coupling in which the amplitude of the [Ca2+]i transient is regulated by variations in the probability of recruitment of elementary SR Ca2+ release units as well as the amount of Ca2+ released by each unit. Since the activation of each release unit will depend on the local amplitude of the Ca2+ current, this model can explain the regulation of the amplitude of the [Ca2+]i transient by the Ca2+ current. In addition, these data indicate that caution should be applied to the interpretation of signals obtained with nonlinear Ca2+ indicators during the rising phase of the [Ca2+]i transient, when the nonuniformities in [Ca2+]i are largest. PMID- 7834835 TI - Adenosine A2a and A2b receptors in cultured fetal chick heart cells. High- and low-affinity coupling to stimulation of myocyte contractility and cAMP accumulation. AB - Adenosine exerts pronounced biological effects in the heart cell. The role of multiple adenosine receptor subtypes in regulating the heart cell function is not known. Ventricular cells cultured from chick embryos 14 days in ovo were used to study a novel feature of heart cell regulation by the stimulatory adenosine receptors. The inhibitory adenosine A1 receptor pathway was first inactivated by pertussis toxin treatment of the cultures, and the effects of adenosine agonists and antagonists on the heart cell contractile amplitude, measured via an opticovideo motion detection system, and on the modulation of cAMP level were determined. Adenosine and N-ethyladenosine-5'-uronic acid (NECA), capable of activating both the adenosine A2a and A2b receptors, caused a greater increase in the contractile amplitude than did the A2a-selective agonist 2-[4-(2 carboxythyl)phenylethylamino]-5'-N-ethylcarboxamidoa denosine (CGS21680). NECA caused a biphasic increase in cAMP, which became monophasic in the presence of the A2a receptor-selective antagonist 8-(3-chlorostyryl)caffeine, whereas the CGS21680-induced cAMP response was monophasic. Blocking with 8-(3 chlorostyryl)caffeine abolished most of the CGS21680-elicited contractile or cAMP response while attenuating only part of the adenosine- or NECA-stimulated responses. Blocking with the A2b-selective antagonists 1,3-diethyl-8 phenylxanthine or alloxazine caused a more pronounced inhibititon of the contractile or cAMP response by adenosine or NECA than by CGS21680. Affinity of the A2a receptor was 60-fold higher than that of the A2b receptor. These data demonstrate that a functional A2b receptor is expressed on the heart cell and is capable of mediating augmentation of cardiac myocyte contractility and that adenosine A2a and A2b receptors, with greatly different affinity, coexist and are coupled to the same functional responses. Taken together, the data suggest a novel feature of heart cell regulation, where the high-affinity A2a receptor can play an important modulatory role in the presence of a low level of adenosine, whereas the low-affinity A2b receptor becomes functionally important when the adenosine level is high. PMID- 7834836 TI - Inositol phosphate release and metabolism in rat left atria. AB - The phosphatidylinositol (PtdIns) turnover pathway in intact heart tissue differs from that in most cell types in that products of the inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] kinase pathway are not detected in 3H-labeling studies. In contrast, Ins(1,4,5)P3 kinase products are detected in isolated neonatal cardiomyocytes. To understand the basis for the observed properties of the cardiac pathway, a detailed study of inositol phosphate (InsP) release has been undertaken by using isolated adult rat left atria. Addition of norepinephrine to 3H-labeled atria caused a slow increase in 3H-labeled Ins(1,4,5)P3 and a more rapid increase in 3H-labeled Ins(1,4)P2, its immediate dephosphorylation product. The mass of Ins(1,4,5)P3 was high in unstimulated atria (13.5 +/- 1.1 pmol/mg tissue, mean +/- SEM, n = 4) and did not change with stimulation. Measurements of the specific activities of Ins(1,4,5)P3 and PtdIns(4,5)P2 provided an estimate of the turnover rate of Ins(1,4,5)P3 that was 20- to 40-fold lower than the rate of accumulation of 3H label in InsP1 and InsP2. In agreement with this, specific activities of InsP1 and InsP2 were higher than the specific activity of InsP3 in both control and stimulated atria. Neomycin (5 mmol/L) did not inhibit the accumulation of 3H-labeled InsP1 and InsP2 in left atria, even though it reduced the accumulation of 3H label in Ins(1,4,5)P3, providing evidence that InsP1 and InsP2 do not derive primarily from Ins(1,4,5)P3. Stimulation with norepinephrine for 20 minutes resulted in a parallel decrease in 3H-labeled Ins(1,4,5)P3 and in Ins(1,4,5)P3 mass, demonstrating that atria do not contain two different pools of Ins(1,4,5)P3.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7834837 TI - Inositol phosphate release and metabolism during myocardial ischemia and reperfusion in rat heart. AB - A detailed study of the effects of global myocardial ischemia and reperfusion on inositol phosphate release and metabolism has been undertaken by using isolated perfused rat hearts. Ischemia for longer than 5 minutes caused a cessation of inositol phosphate production, with inositol phosphates initially present accumulating as isomers of inositol monophosphate. This inhibition was independent of norepinephrine. In contrast, 2-minute reperfusion following 20 minute ischemia produced a rapid and transient release of inositol phosphates that was dependent on the release of norepinephrine and mediated by alpha 1 adrenergic receptors. By a number of criteria, this reperfusion response was different from the norepinephrine response in normoxic tissue. First, total release of inositol phosphates was greater (466 +/- 37 compared with 345 +/- 29 cpm/mg protein, P < .05). Second, inositol 1,4,5-trisphosphate was released with postischemic reperfusion (103 +/- 18 to 207 +/- 11 pmol/mg protein), whereas release was not detected in normoxic myocardium. In agreement with this, neomycin (0.5 and 5 mmol/L) inhibited inositol phosphate release only under reperfusion conditions. Third, the reperfusion response, unlike the response in nonischemic tissue, required extracellular Ca2+. Longer periods of reperfusion resulted in a return to a pattern of inositol phosphate release that was not different from that seen in normoxic tissue. The rapid and transient release of inositol 1,4,5 trisphosphate at 2-minute postischemic reperfusion provides an explanation for the enhanced role of alpha 1-adrenergic receptors under these conditions and suggests an important role for this compound in initiating reperfusion-induced pathological events. PMID- 7834838 TI - Role of extracellular and intracellular acidosis for hypercapnia-induced inhibition of tension of isolated rat cerebral arteries. AB - The importance of smooth muscle cell pHi and pHo for the hypercapnic vasodilation of rat cerebral arteries was evaluated in vitro. Vessel segments were mounted in a myograph for isometric tension recording; pHi was measured by loading the smooth muscle cells with the fluorescent dye BCECF, and pHo was measured with a glass electrode. In all studies, Ca(2+)-dependent basal tension (in the absence of any agonist) and tension in the presence of arginine vasopressin were investigated. Control solution was physiological saline bubbled with 5% CO2 and containing 25 mmol/L HCO3- (pH 7.45 to 7.50). Induction of hypercapnic acidosis (10% CO2) or normocapnic acidosis (15 mmol/L HCO3-) caused significant inhibition of smooth muscle tension, and both conditions reduced pHi as well as pHo. N-Nitro L-arginine significantly inhibited the relaxation to hypercapnic acidosis but had no significant effect on relaxation to normocapnic acidosis. Predominant extracellular acidosis, induced by reducing [HCO3-] from 25 to 9 mmol/L and CO2 from 5% to 2.5%, also caused inhibition of tension in steady state. By contrast, predominant intracellular acidosis, induced by increasing [HCO3-] from 25 to 65 mmol/L and CO2 from 5% to 15%, induced a small increase of basal tension and a small decrease of tension in the presence of arginine vasopressin. The responses to predominant intracellular or extracellular acidosis were qualitatively similar in the presence and absence of endothelium and in the presence and absence of N nitro-L-arginine. It is concluded that the extracellular acidosis and not smooth muscle intracellular acidosis is responsible for the relaxation to hypercapnic acidosis. PMID- 7834839 TI - Circulating leukocyte counts, activation, and degranulation in Dahl hypertensive rats. AB - Previous evidence has shown that rats with spontaneous hypertension have on average about twice as many circulating leukocytes in comparison with their normotensive counterparts, the Wistar-Kyoto rats. Since such high levels of leukocytes may increase the risk for vascular complications for hypertensive animals, it is useful to ascertain whether a comparable derangement is present in other forms of hypertension. The present study deals with the properties of the circulating leukocytes in rats exhibiting another form of experimental hypertension; Dahl salt-sensitive (Dahl-S) hypertensive rats were compared with Dahl salt-resistant (Dahl-R) control rats. Measurements were performed to determine the following: circulating hematocrit levels, leukocyte counts, differential counts, number of activated leukocytes (by means of nitro blue tetrazolium [NBT] reduction), leukocyte adhesion in vitro and neutrophil CD-18 expression, alkaline phosphatase activity in individual neutrophils and in the plasma, and myeloperoxidase activity in neutrophils. The experimental cohort consisted of Dahl-S and Dahl-R rats maintained for a 6-week period on a 6% NaCl diet. The results show a highly significant elevation in the number of total leukocytes, neutrophil and monocyte counts, and NBT-positive neutrophils and monocytes in Dahl-S but not Dahl-R rats. There was a significant loss of alkaline phosphatase and myeloperoxidase activity in the neutrophils of the salt-treated Dahl-S rats but not in the neutrophils of the untreated Dahl-S or Dahl-R rats. No significant differences were found in neutrophil adhesion under in vitro test conditions between the two strains maintained on the salt diet.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7834840 TI - Negative chronotropic effect of endothelin 1 mediated through ETA receptors in guinea pig atria. AB - Endothelins exert potent excitatory cardiac effects by acting on specific receptors on myocytes. In this study, we have examined the signal transduction mechanism for the chronotropic effect of endothelins in guinea pig atria. A competition binding of [125I]endothelin 1 ([125I]ET-1) using the recently developed ETA receptor-selective antagonist BQ123 showed the presence of almost equal populations of ETA (44%) and ETB (56%) receptors in the guinea pig right atria. In a concentration-response study, endothelin 3 (ET-3), an agonist with higher affinity to ETB receptors than to ETA receptors, and sarafotoxin S6c (STXS6c), an ETB receptor-selective agonist, increased the rate of spontaneous beating at all concentrations tested (10 pmol/L to 100 nmol/L). In contrast, ET 1, a nonselective agonist, increased the heart rate at lower concentrations (10 pmol/L to 10 nmol/L) but decreased it at higher concentrations (30 to 100 nmol/L). When ET-1 (100 nmol/L) was applied in a single amount, heart rate was strongly increased; however, this increase was followed by a rapid decline in the response. ET-1 (100 nmol/L) but not ET-3 or STXS6c significantly reduced the heart rate when it was raised by isoproterenol (ISO, 300 nmol/L) either in the absence or presence of a phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX). Correspondingly, ET-1 significantly reduced the ISO-induced elevation of cAMP accumulation (19.1 +/- 1.7 pmol/mg protein [n = 8] and 12.6 +/- 1.2 pmol/mg protein [n = 7] in the absence and presence of ET-1, respectively; P < .01), which was also observed even in the presence of IBMX.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7834841 TI - Electrophysiological effects of 4-hydroxynonenal, an aldehydic product of lipid peroxidation, on isolated rat ventricular myocytes. AB - Aldehydic products of lipid peroxidation, such as 4-hydroxynonenal (4-HNE), have been implicated in the etiology of pathological changes under oxidative stress. To identify the mechanism by which 4-HNE alters cellular excitability, its effects on isolated rat ventricular myocytes were studied. Superfusion with 100 to 880 mumol/L 4-HNE led to a time- and concentration-dependent rigor shortening of myocytes. A reduction in [Ca2+]o and inhibition of transsarcolemmal Ca2+ transport by 1 mmol/L La3+ did not affect either the magnitude or the time course of 4-HNE-induced myocyte rigor. Superfusion of myocytes with 400 mumol/L 4-HNE led to an increase in the action potential duration, progressive depolarization of the resting membrane potential, and an increase in the input resistance (Rin) of the myocyte (phase I), followed by a loss of electrical excitability. Continued superfusion with 4-HNE resulted in membrane hyperpolarization and a prominent decrease in the Rin (phase II). The decrease in Rin coincided with myocyte rigor. In whole-cell voltage-clamp experiments, superfusion with 4-HNE inhibited current through the inward rectifier K+ channel (IK1). 4-HNE had no effect on either the magnitude or the rate of "rundown" of L-type Ca2+ currents. Exposure to 4-HNE led to an increase in the magnitude of the fast inward Na+ current (INa). The voltage dependence of the steady state parameters for activation and inactivation of INa shifted to more positive potentials, with a resultant increase in the window current. 4-HNE-induced myocyte rigor was accompanied by a large increase in time-independent currents that displayed linear dependence on the membrane potential and were inhibited by glibenclamide, suggesting activation of the ATP-sensitive K+ channel. Steady state currents recorded in Cs(+)-containing Ringer's solution with La3+ and tetrodotoxin and Cs(+)-containing internal solution (leak currents) were not affected by 4-HNE. Superfusion with 4-HNE resulted in a significant decrease in the cellular concentration of nonprotein thiols and a severe decrease in [ATP]i. The energy charge of the myocytes fell from 0.9 to 0.3. These observations indicate that 4 HNE-induced membrane depolarization may be due to an inhibition of IK1. Changes in voltage dependence of INa, inhibition of IK1, and membrane depolarization appear to contribute to the prolongation of the action potential, observed during phase I. Depletion of [ATP]i may be responsible for changes observed during phase II, ie, activation of the ATP-sensitive K+ channels, membrane hyperpolarization, decrease in Rin, and rigor shortening of the myocytes. These results suggest that stable products of lipid peroxidation, such as 4-HNE, are proarrhythmic and may contribute to the cytotoxic effects of oxidative stress. PMID- 7834842 TI - Nitric oxide-generating compounds inhibit total protein and collagen synthesis in cultured vascular smooth muscle cells. AB - Nitric oxide (NO) participates in the regulation of vascular tone and smooth muscle cell proliferation, but little is known of its effect on total protein and matrix synthesis in smooth muscle. We studied the effects of the NO-generating compounds S-nitroso-N-acetylpenicillamine (SNAP, 0.4 to 1.2 mmol/L) and sodium nitroprusside (SNP, 0.1 to 0.5 mmol/L) on total protein (using [3H]leucine) and collagen (using [3H]proline) synthesis in cultured rabbit aortic smooth muscle cells. Both agents caused dose-dependent inhibition of the relative rate of protein (maximum reduction of 87% [SNAP] and 80% [SNP]) and collagen synthesis, as measured by trichloroacetic acid-precipitated label. The magnitudes of percent inhibition of total protein and collagen synthesis were approximately equal. Inhibition of protein synthesis by SNAP and SNP was prevented by hemoglobin (10 mumol/L), suggesting that the protein synthesis inhibition was due to NO release. Inhibition of protein synthesis was reversible after removal of SNAP and SNP and was not caused by damage to the cells. These results suggest that NO may function as a modulator of vascular smooth muscle cell protein synthesis and production of extracellular matrix components. PMID- 7834843 TI - Inhibition of vascular smooth muscle cell K+ currents by tyrosine kinase inhibitors genistein and ST 638. AB - The whole-cell patch-clamp technique was used to characterize the effects of several tyrosine kinase inhibitors on the voltage-gated K+ current (IK) in rat and rabbit pulmonary artery cells. IK was blocked in a dose-dependent manner by genistein (20 to 100 mumol/L) and ST 638 (0.5 to 40 mumol/L) but not by the inactive genistein analogue diadzein (100 mumol/L). This inhibition was not significantly altered when ATP was excluded from the patch pipette or when it was replaced by the poor tyrosine kinase substrate ATP-gamma-S. The inhibition was also unaffected by inclusion of the tyrosine phosphatase inhibitor orthovanadate in either the bath (0.5 mmol/L) or pipette (0.2 mmol/L) solutions. In the rat, IK ordinarily inactivated negligibly over 300 ms. In the presence of 10 mumol/L ST 638, however, IK reached a peak approximately 5 ms after depolarization (to +60 mV) and then decayed markedly. In the rabbit, IK demonstrated a prominent rapidly decaying initial component that was only slightly inhibited by ST 638, which preferentially blocked the sustained current; genistein showed the opposite selectivity. These observations indicated that IK blockade by genistein and ST 638 was not mediated by an inhibition of tyrosine kinase activity and further suggested that in both types of cells genistein and ST 638 preferentially blocked rapidly and slowly inactivating components of IK, respectively. PMID- 7834845 TI - [Iontophoretic atropine attenuates the inhibitory effect of stimulating SmI on nociceptive responses of pf neurons]. AB - Using the techniques of multimicropipette and iontophoresis, we observed whether ACh was involved in the cortical descending modulation of Pf neurons in rats. It was shown that the inhibition elicited by stimulation of the sensorimotor area (SmI) was attenuated after microiontophoretic atropine and that the nociceptive responses of Pf neurons were obviously reduced by microiontophoretic ACh. Therefore, it suggests that ACh may be considered as one of the neurotransmitters involved in the descending modulation of pain. PMID- 7834844 TI - [Involvement of glutamate in corticofugal modulation of intralaminar nuclei from SII via motor cortex in acupuncture analgesia]. AB - The present experiments were designed to study the effect of glutamate on cortical somatosensory area II (S II) producing descending modulation of intralaminar nuclei (ILN) via the motor cortex (MCtx) in acupuncture analgesia. The glutamate antagonist glutamate diethylester (GDEE) or saline was topically applied at MCtx in 17 cats. Single unit activities of ILN neurons were extracellularly recorded. The results were as follows: 1. The nociceptive responses of ILN neurons were attenuated by stimulating S II after topical administration of saline at MCtx. However, the inhibitory effect of stimulating S II in the same neurons was reduced after application of GDEE. There was a significant difference at 0'-1' after the stimulation between the two groups (n = 10, P < 0.05). 2. The inhibitory effect of electroacupuncture (EA) on nociceptive responses was reduced after topical application of GDEE, while marked inhibition was shown at 0'-10' after cessation of EA in the saline control group (n = 11, P < 0.05). The results, together with the finding that the majority of S II neurons could be activated by EA, showed that glutamate released from S II to MCtx might be involved in corticofugal modulation of ILN from S II via MCtx in acupuncture analgesia. PMID- 7834846 TI - [Changes of norepinephrine release in rat's nucleus reticularis paragigantocellularis lateralis in acupuncture analgesia]. AB - Norepinephrine (NE) of the nucleus reticularis paragigantocellularis lateralis (RPGL) plays an important role in acupuncture analgesia (AA). The aim of this experiment was to investigate the role of NE in RPGL during AA at presynaptic level by using push-pull perfusion, high performance liquid chromatography with electrochemical detection (HPLC-ECD) techniques. The results indicated that pain threshold increased significantly after 20 min of EA, while the content of NE and its metabolite MHPG in the perfusate from the RPGL was markedly decreased. A negative correlation existed between the changes of pain threshold and the release of NE and MHPG. It is indicated that electroacupuncture (EA) is able to inhibit the release of NE from the RPGL during AA. PMID- 7834847 TI - [The study of mechanisms and effects of prophylaxis and cure of electroacupuncture against ischemia injury in brain]. AB - In order to observe the influence of electroacupuncturing (EA) "Ren Zhong" point on acute ischemia injury in brain, an experimental model of acute ischemia injury in brain was produced by antidromically blocking double common carotid arteries in 18 rabbits. The basic arteries' pressure will be increased by EA, RA and the contents of AI, A II increased and the content of LA reduced obviously in brain. An experimental evidence was given for the safety of EA anesthesia and the curative effect of EA on ischemia in brain. PMID- 7834848 TI - [Effects of electro-acupuncture on EEG during transient global ischemia and reperfusion in gerbils]. AB - In the model of gerbil of acute global ischemia and reperfusion, we studied the effects of electro-acupuncture (EA) on total power of EEG at different periods of global ischemia and reperfusion. The "Fengfu" (GV 16) and "Jinsuo" (GV 8) points were stimulated by electrical pulse with frequency 7 Hz and intensity of 5-6 mA for 30 min. Recording was made before ischemia and 0 min, 15 min, 30 min, 60 min, 120 min and 240 min after reperfusion respectively. The results were as follows: 1. In the control group, after 10 min of ischemia, the amplitude of EEG was severely inhibited, even became flatten, and the total power of EEG was significantly decreased to 1.41 + 1.29%. After reperfusion, the recovery of total power was very slow. The peak level of recovery occurred at 120 min following reperfusion was 27.39 + 11.31%. 2. In comparison with the control group, the EA remarkably improved the recovery of EEG after ischemia and reperfusion. The recovery of total power was 71.45 + 16.46% (P < 0.01), and 75.27 + 18.43% (P < 0.01) at 120 min and 240 min after reperfusion respectively. These results strongly indicate that EA could reduce the EEG inhibition during global ischemia and improve the recovery after reperfusion. PMID- 7834849 TI - [Influence of acupuncture at zusanli point on function of 5-HT and M receptor in rat's brain and spleen]. AB - 5-HT and muscarine (M) receptors total binding capacities (Rt) in different brain areas and spleen were determined using receptor radioligand binding assay (RLBA) after needling zusanli of rats. And the rats without needling and needling Taichong point were used as control. These results showed that 5-HT and M receptors Rt were decreased obviously than control group in rat's cerebral cortex, hippocampus, striatum, spinal cord and spleen when needling zusanli can produce obvious acupuncture analgesia. 5-HT Rt in brain stem and medulla oblongata was obviously decreased and not changed in thalamus. M receptor Rt value was not changed clearly in brain stem and medulla oblongata as well, but it was obviously decreased in thalamus. These results showed that effects of acupoints on Various meridians are different, thus the results of acupuncture at Zusanli are distinct from taichong. PMID- 7834850 TI - [Influence of electroacupuncture of neiguan (PC 6) on ami-induced changes in electrical activity of dorsal horn neurons]. AB - The electrical activity of the dorsal horn (DH) neurons was recorded extracellularly by glass micro-pipettes in urethane-chloralose anesthetized rabbits to analyze the role of the thoracic segments (T2-T3) of the spinal cord in the integration of information from electroacupuncture (EA) at Neiguan (PC 6) and acute myocardial ischemia (AMI). Results were: 1) after AMI, of 83 DH neurons, 18 displayed a significant excitatory response, 14 an obvious inhibitory reaction and 51 no apparent change; 2) after EA at Neiguan (PC 6), of 10 neurons with AMI-induced excitatory response, the electrical activity of 9 neurons was suppressed and the other 1 still maintained its excitatory state; of 8 neurons with AMI-induced inhibitory response, 7 were relieved from the suppressed state, the other 1 had no change following EA; and 3) the receptive field and the responsive types to somatic stimulation were examined in 83 DH neurons. Results showed that signals from EA at Neiguan (PC 6) and AMI could converge to the DH neurons of T2-T3. It suggests that DH participates in the integrative course of information from EA and AMI and thus it is one of the connective links between Neiguan (PC 6) and the heart. PMID- 7834851 TI - [The lesion of somatosensory area II of cerebral cortex reducing the effects of electroacupuncture of "zusanli" on nucleus raphe magnus in rats]. AB - This work was to study the influence of lesion of Sm II on effects of electroacupuncture (EA) upon nucleus raphe magnus (NRM). The experiments were performed on rats. The unit discharges of NRM neurons and their responses to noxious stimulation on tail tip were recorded extracellularly with glass microelectrode. The excitatory neurons of NRM were chosen and divided into two groups, one of them (n = 10) was control before lesion of bilateral Sm II and another (n = 17) after lesion, two neurons of this group were also observed before lesion. It was found that the neurons in the control group before lesion of sm II could be activated by EA of "Zusanli", the increase of spontaneous diacharges in 0-10 minutes and the 20th minute, and the decrease of their nociceptive responses in 0-25 minutes were statistically significant (P < 0.05 0.001). But in the group after lesion the neurons were not obviously activated by EA of "Zusanli". The difference of the spontaneous discharges between the two group was statistically significant in 0-10 minutes (P < 0.05-0.001), the nociceptive responses in 0-10 minutes and at the 20th minute (P < 0.05-0.001). The results show that integrity of Sm II is important to acupuncture analgesia, and further suggest that information from EA of "Zusanli" could arrive at Sm II at least partially, and then activate NRM inducing analgesia. PMID- 7834852 TI - [The influence of acupuncture at zusanli on cyclic nucleotide contents of plasma, different brain regions and spleen in rats]. AB - We observed cyclic nucleotide content of plasma, brain and Spleen tissues when analgesia was produced by acupuncture at the Zusanli. The restrained group without acupuncture was as blank control and acupuncture at Taichong as acupuncture control. We found that after acupuncture at Zusanli the concentration of cyclic nucleotide in plasma was increased significantly (P < 0.05) and the cAMP concentration of spleen had a tendency of enhancement, but the content of cAMP in the cortex had a tendency of decrease. The concentration of cAMP, cGMP and its ratio cAMP/cGMP was different in cortex and spinal cord between acupuncture at Zusanli and Taichong groups. These results showed that acupuncture at Zusanli and Taichong could induce different changes of concentration of cAMP and cGMP. PMID- 7834853 TI - [The effects of electroacupuncture treatment on nucleolar organizer regions of adrenal cortex in ovariectomized rats]. AB - The present paper reports the morphometric analysis of nucleolar organizer regions (NORs) of the adrenal cortex in ovariectomized rats following electroacupuncture (EA) using argyrephil (Ag-NOR) method for NORs. Animals were divided into four groups, the control group (CT group, n = 4), the EA group (n = 3), the ovariectomized group (OV group, n = 4) and the ovariectomized electroacupuncture group, (OV+EA group, n = 7). The number of AgNORs of 100 cells from zona fasciculata of the adrenal cortex in each case of all groups was counted at random and the mean +/- SE (number/cell) in each group was calculated as follows: OV+EA group 2.71 +/- 0.26, OV group 1.62 +/- 0.15, EA group 1.21 +/- 0.04 and CT group 1.48 +/- 0.03. The mean of AgNORs in OV+EA group differed highly significantly from the other three groups (P < 0.01) tested by ANOVA and LSD method, No significant distinction was found among the OV group, EA group and CT group. Gross specimen examination showed that adrenal glands in OV+EA were significantly heavier than those in the other three groups (P < 0.01). Vaginal smears showed that a response like that of estrogen-induced with exfoliative cells appeared in the OV+EA group rats following EA. EA had no influence on the change of exfoliative cells in EA group. The results suggest that EA may promote the synthesis and secretion of the adrenal steroid hormones, the androgen of which will then be transformed into estrogen in other tissues, thus compensating the deficiency of estrogen induced by ovariectomy. PMID- 7834854 TI - [Effects of electroacupuncture on central and peripheral monoamine neurotransmitter in the course of protecting rat stress peptic ulcer]. AB - The experimental Wistar rats were divided into two groups, the acupuncture group and the control group. Stress-induced gastric ulcer models were established by immersion of restrained rats in water. The results are as follows: 1. Stress induced peptic ulceration was able to be protected with electroacupuncture. 2. Synthesis and decomposition of central and peripheral 5-HT in the electroacupunctured tats was inhibited. 3. The NE levels in the three brain regions (cortex, hypothalamus, brainstem) and blood were seen in the electroacupuncture group more than that in the control group, but the NE levels was smaller in the gastric tissue. 4. The higher levels of DA in the gastric tissue and blood were seen in the electroacupuncture group than in the control group. The results indicated that protecting rat stress ulceration with electroacupuncture was connected with monoamine neurotransmitter of centre and periphery. PMID- 7834855 TI - [Effect of some drugs on electroacupuncture analgesia and cytosolic free Ca2+ concentration of mice brain]. AB - In this paper, the effects of some analgesic drugs such as corydalis yanhusuo, Angelica dahurica and Analginum on electroacupuncture analgesic function were studied. In the meantime, the concentrations of cytosolic free Ca2+ ([Ca2+]i) in mice hypothalamus (HT) and periaqueductual grey (PAG) were determined by use of the fluorescence dye Fura-2/AM and AR-CM cation measurement system. The results showed that Corydalis yanhusuo obviously strengthened the analgesic function produced by electroacupuncture. Besides, the [Ca2+]i in the two brain regions of mice in these analgesic experiments with electroacupuncture and Corydalis yanhusuo were all decreased (compared with saline control group, P < 0.01), In the same experimental condition, the [Ca2+]i in Angelica dahurica group and Analginum group has no significant difference compared with the control group, the analgesic mechanisms may be different from that of electroacupuncture and Corydalis yanhusuo. PMID- 7834856 TI - [Involvement of purines in analgesia produced by weak electro-acupuncture]. AB - In the present investigation the intensity of stimulated electro-acupuncture (EA) was measured by electrophysiological collision technique. In the behavioral experiments, by applying the weak electro-acupuncture pulses (50 Hz, 1-1.5mA), not enough to activated A delta afferent fibers, to Yanglingquan and Xuanzhong points, the latency of nociceptive hind limb withdrawal reflex, but not tail flick latency was prolonged. Administered intraperitoneally, both theophylline and caffeine, P1-purinergic (adenosine) receptor antagonists, could block the electroacupuncture-induced elevation of the nociceptive thresholds in a dose effect related manner, whereas dipyridamole, an inhibitor of adenosine release, could shorten the after of electro-acupuncture in a dose dependent way. These results suggest that weak electro-acupuncture may induce analgesia and purines appear to be involved in this process. PMID- 7834857 TI - [Regulation on beta-END in tumor-bearing mice by moxibustion on Guanyuan point]. AB - The experimental results demonstrated that moxibustion on Guanyuan point could promote the hyperplasia of the pituitary and the adrenal gland which showed atrophy in control group. Also, the moxibustion treatment stimulated the secretion of beta-END from the pituitary and the adrenal gland, increased the level of serum beta-END significantly and kept the high level for quite a long time, that was advantageous for beta-END to carry out the immunomodulation. The data further suggested that moxibustion treatment do not cause the instant release but probably constant release of the beta-END. PMID- 7834858 TI - [Potentiation of electroacupuncture analgesia on visceral pain by metoclopramide and its mechanism]. AB - The present study was to investigate the effect of metoclopramide (MCP) on electroacupuncture analgesia (EAA) and its mechanism on a rabbit visceral pain model. The results showed that MCP 8mg/kg i.v. could potentiate EAA and prolong the analgesic duration. The potentiation effect could be attenuated by icv apomorphine (APO) (a mixed D1/D2 agonist). The analgesic duration was shortened by icv SKF38393 (a selective D1 agonist) or LY171555 (a selective D2 agonist). Using HPLC-ECD, we also found that the HVA content in CSF significantly increased at 20 min. after electroacupuncture (EA) or MCP 8mg/kg i.v. (P < 0.05), but the change of HVA content was not significant when EA and MCP 8mg/kg i.v. were used together. All these observations indicate that MCP have effects of potentiating EAA and prolonging analgesic duration. These effects are related to the blockade of the central DA receptor. The activations of D1 or D2 receptor is unfavourable to the expression of EA after effect. PMID- 7834859 TI - [Regulating effect of electro-acupuncture on dysrythmia of gastro-colonic electric activity induced by erythromycine in rabbits]. AB - The myoelectric activity of gastro-colon was recorded in 20 rabbits. The model of gastro-colonic disorder was produced by vena injection of erythromycine (EM) (7 mg/kg). We investigated regulating effect of electro-acupuncture (EA) on the disorder of gastrocolonic electric activity (GEA). After the vagotomy the effect of EA was observed. In fasting and anaesthetic rabbits, the frequency and amplitude of GEA were 4.47 +/- 1.23 cmp, 1.90 +/- 0.27 mV at antrum, 8.33 +/- 2.61 cpm, 0.51 +/- 0.12 mV at ascending colon, 6.74 +/- 2.68 cpm, 0.35 +/- 0.10 mV at descending colon. After injection of EM, the frequency and amplitude of GEA were increased, the latency and duration of EM effect were 36.5 +/- 4.5 min and 3.8 +/- 1.4 min, the great contraction wave was showed. EA could shorten the duration and latency, decrease the frequency, amplitude and variation coefficient of GEA. After vagotomy the effect of EA disappeared. These results indicate that vagus nerve plays an important role in regulating effect of EA on gastro-colonic disorder. PMID- 7834861 TI - [Effects of electrical stimulation of S II and electroacupuncture on contents of some free amino acids in the precruciate cortex]. AB - Effects of electrical stimulation of the somatosensory area II (S II) of the cerebral cortex and electroacupuncture (EA) on contents of r-aminobutyric acid (GABA), glutamic acid (Glu), aspartic acid (Asp) and alanine (Ala) in the precruciate cortex (PreCtx) were investigated in order to probe if the free amino acids in the preCtx are involved in the S II descending modulation and acupuncture analgesia. Adult cats were randomly divided into four groups: control, EA, electrical stimulation of S II and stimulation of S II plus EA. EA was applied at right Huantiao and Yanglingquan acupoints for 30 min and electrical stimulation was given on the S II surface. Amino acids were separated by paper chromatography and determined with spectrophotometry. Results showed that the stimulation of S II or/and EA had no significant effects on the contents of GABA, Glu, Asp and Ala in the PreCtx, indicating that the four amino acids are probably not involved in regulatory effects of EA and the stimulation of S II on the PreCtx. PMID- 7834860 TI - [The experimental study of prevention and treatment of the side-effects of chemotherapy with acupuncture (comparison among the effect of acupuncture at different acupoint)]. AB - After an intraperitoneal injection of cyclophosphamide in rats, there was pathologic changes in hemopoietic, immune and visceral function. Acupuncture respectively at Zusanli, Dazhui and Shenshu points could decrease the above mentioned harms in the rats, the effect of acupuncture on hemopoietic function: Dazhui more than or equal to Zusanli, Zusanli more than Shenshu; the effect of acupuncture on immune function: Zusanli more than Dazhui, Dazhui more than or equal to Shenshu; the effect of acupuncture on the function of the liver and the kidney: Shenshu more than or equal to Zusanli, Zusanli more than Dazhui. The effect of acupuncture at all three points, i.e. Zusanli. Dazhui and Shenshu was more than that at any single point due to their coordination. There was no obvious effect when acupuncture at non-acupoints on tail. PMID- 7834862 TI - Cystic fibrosis and phosphatidylcholine biosynthesis. AB - The cystic fibrosis (CF) gene defect may be associated with a defect in membrane recycling. We have investigated the metabolism of the main constituent of plasma membrane, phosphatidylcholine (PC). In this study of platelets and fibroblasts, we show an increased uptake of choline into PC of CF cells as compared with normal cells. No accumulation of PC was seen. Other patients with respiratory disease (not CF) showed normal rates of incorporation of choline into platelet PC. Platelets from heterozygote individuals showed intermediate turnover rates of choline incorporation into PC. The increase in choline incorporation into PC in CF platelets was not due to modified or increased sensitivity to either cAMP or prostaglandin E2. The total amount and the proportions of the major phospholipids in platelets of control and CF individuals were identical. These findings indicate an increased turnover rate of this phospholipid in CF cells rather than an increased net synthesis. PMID- 7834863 TI - Serum neurone-specific enolase concentrations in patients with neurological disorders. AB - A radioimmunoassay (RIA) has been developed for neurone-specific enolase (NSE) and used to measure serum levels in patients with a range of neurological disorders. Serum NSE levels were within the normal range in 21 patients with multiple sclerosis and 4 patients with Guillain-Barre syndrome. Normal serum NSE levels were also recorded in patients with motor neurone disease, anterior spinal thrombosis, multi-infarct disease, benign intracranial hypertension and peripheral neuropathy. However, two patients in coma, one as a result of encephalitis, the other due to subarachnoid haemorrhage (SAH) had elevated serum NSE. In the former, serum NSE levels appeared to predict a deterioration in clinical state, levels later returning to normal before an improvement in clinical condition. In the patient with SAH, levels were elevated on admission and remained elevated until death. Serum NSE levels may be of use in predicting outcome in patients with acute neurological disease. PMID- 7834864 TI - Radioimmunoassay of vasopressin during pregnancy. Use and removal of cystylaminopeptidase inhibitors. AB - This paper describes a radioimmunoassay (RIA) for arginine-vasopressin in which o phenanthroline effectively inhibits cystyl-amino-peptidase activity in whole blood and plasma from pregnant women but in which o-phenanthroline is removed during the extraction of vasopressin from plasma to prevent disturbance of the RIA. Cystyl-amino-peptidase causes immediate degradation of vasopressin unless cystyl-amino-peptidase enzyme inhibitors such as o-phenanthroline are applied. However, o-phenanthroline interferes with RIA. We report an extraction procedure over octadecasyl silica-packed Sep-Pak C18 columns, by which cystyl-amino peptidase as well as most of the cystyl-amino-peptidase inhibitor is removed from plasma with chloroform. The average o-phenanthroline concentration (0.25 mmol/l) found in the assay medium after extraction appeared not to interfere with the RIA. Polyacrylamide gel isoelectric focusing of extracts of platelet-rich and platelet-poor plasma from pregnant women revealed a single vasopressin immunoreactive peak in the RIA. Recovery and between-assay coefficients of variation of 3.2 ng/l vasopressin from pregnancy whole blood were comparable with non-pregnant controls (57%/8% and 59%/13%, respectively). Results with this assay compare well with those of another assay using inhibitors in pregnant subjects and with results in non-pregnant subjects. PMID- 7834865 TI - Binding of aluminium to plasma proteins: comparative effect of desferrioxamine and deferiprone (L1). AB - Ultramicrofiltration techniques were used to study both the binding of aluminium to high molecular weight proteins in the presence of different concentrations of desferrioxamine and deferiprone (L1) and the kinetics of aluminium release from human serum proteins. Human serum from healthy volunteers was used in all studies. The serum was spiked with aluminium (100 micrograms/l) and different concentrations of chelators. Ultramicrofiltration was performed with Amicon YMT membranes which had a nominal cut-off of 30,000 Da. Aluminium was measured by graphite furnace atomic absorption spectrometry in total serum and ultrafiltered fluid. Deferiprone shows a higher capability to displace aluminium from serum proteins (80%) than desferrioxamine (60%) at equivalent concentrations of the chelators. The kinetics of the release were also faster for deferiprone, taking 20 min to achieve its maximum effect, whereas, desferrioxamine achieved only 80% of its maximum effect after 2 h. Thus, deferiprone could be an attractive alternative to desferrioxamine, as an aluminium chelator agent. PMID- 7834866 TI - Longitudinal changes in serum zinc concentration and distribution after acute myocardial infarction. AB - The authors studied the changes in serum zinc concentration and distribution during the 15 days following acute myocardial infarction in 21 patients. The method is based on ultrafiltration and electrothermal atomic absorption spectrometry. It is rapid and needs only 2.5 ml of serum. Serum and erythrocyte copper and zinc, serum zinc-binding ligands and serum enzyme activities were also determined. Serum zinc (P < 0.00001) and exchangeable zinc (mainly albumin-bound zinc, P = 0.01) declined within the first 3 days and then returned gradually to reference ranges. Exchangeable zinc was correlated with transthyretin (P = 0.00001) and total serum zinc (P < 0.00001). Exchangeable zinc accounted for virtually all of the differences in total serum zinc concentration after myocardial infarction. This result could be related to an increase of zinc uptake by tissues. Therefore, studies are needed to evaluate whether zinc supplementation in the early stages of acute myocardial infarction might improve prognosis. PMID- 7834867 TI - Naftidrofuryl inhibits the release of 5-hydroxytryptamine and platelet-derived growth factor from human platelets. AB - Angioplasty and bypass-grafting are associated with restenosis which limits their efficacy. Platelet-rich thrombus formation is the predominant cause of acute occlusion whereas platelet release products with proliferating properties, e.g. 5 hydroxytryptamine (5-HT) and platelet-derived growth factor (PDGF), may contribute to late restenosis. Naftidrofuryl (NAF), a drug for the treatment of peripheral vascular disease, was shown previously to inhibit platelet shape change and aggregation. This study establishes whether NAF inhibits the release of 5-HT and PDGF from platelets obtained from healthy subjects. Platelets stimulated with agonists aggregated less and released less 5-HT/PDGF when pre incubated with NAF. Indomethacin (INDO), a cyclooxygenase inhibitor, alone inhibited aggregation and PDGF/5-HT release; NAF enhanced the inhibitory effects of INDO. The effect of NAF, on its own or in combination with a cyclooxygenase inhibitor, may therefore confer protection against graft occlusion. PMID- 7834868 TI - Development and evaluation of a spectrophotometric assay for complex III in isolated mitochondria, tissues and fibroblasts from rats and humans. AB - A spectrophotometric method to assay the activity of complex III in isolated mitochondria, tissues and fibroblasts from patients and rats has been developed and validated. Decylubiquinol was shown to be a suitable substrate with a saturating concentration between 100 and 200 mumol/l. The optimal pH was found to range from 7.4 to 8.0. The enzyme reaction was linear for incubations containing up to 15 micrograms/ml mitochondrial protein, 250 micrograms/ml liver tissue, 375 micrograms/ml skeletal muscle or 100 micrograms/ml fibroblast protein. Intraday and interday variability of the assay for different enzyme sources was below 15% and 10%, respectively. Assessment of complex III activity in liver and fibroblasts from patients with signs of mitochondrial dysfunction revealed the usefulness of the newly developed assay in the diagnosis of complex III deficiency. PMID- 7834869 TI - Heightened free radical activity in blacks with chronic pancreatitis at Johannesburg, South Africa. AB - Four indices of free radical activity were measured in fasting serum/plasma samples from 14 consecutive blacks with clinically quiescent chronic pancreatitis and 15 outwardly healthy hospital personnel at Soweto, the township near Johannesburg in South Africa. The patients had higher serum levels than did controls of lipid isomerisation (P < 0.002) and peroxidation (P < 0.05) markers, with lower plasma levels of glutathione (P < 0.0001) and bioactive fraction of vitamin C (P < 0.002). Lipid peroxide and non-bioavailable vitamin C concentrations in Sowetan patients were significantly higher than in their counterparts from Manchester, UK (P < 0.0001, P < 0.0005, respectively). These differences mirrored those in controls in that outwardly healthy Sowetans had much higher serum lipid peroxide levels than Manchester controls (P < 0.001) and much lower plasma concentration of vitamin C (P < 0.001) and hence of the bioavailable fraction ascorbate (P < 0.0002). Heightened free radical activity is thus a common denominator in chronic pancreatitis irrespective of geography, or putative aetiological factors whether alcoholism or idiopathic, since that ratio was approximately 95:5 at Johannesburg and 50:50 at Manchester. The further finding of subclinical oxidative stress in Sowetan controls and the endemic nature of chronic pancreatitis in that area supports the hypothesis that oxidative stress may be involved in its pathogenesis. PMID- 7834870 TI - A microassay for urinary phenol using capillary gas chromatography and optimised enzymic hydrolysis. AB - An improved capillary gas chromatography method is described for the assay of urinary phenol for the assessment of benzene exposure. Enzymatic hydrolysis with an extract of Helix pomatia is used to liberate phenol from its glucuronide and sulphate conjugates in urine and has the advantage in that complete hydrolysis occurs and clean chromatograms are produced. Furthermore, an internal standard (2,4-xylenol) has been incorporated in the method enabling rapid and single step extraction of phenol. The microassay can be used to measure phenol concentrations as low as 1 mg/l in urine thus making it a suitable method for monitoring benzene exposure. PMID- 7834871 TI - Is there a need for creatinine adjustment of urinary steroid hormone levels in studies of early fetal loss? PMID- 7834872 TI - Separation of lipoprotein fractions by ultracentrifugation: investigation of analytical recovery with sequential flotation and density gradient procedures. PMID- 7834873 TI - Sulfadiazine/N4-acetylsulfadiazine crystalluria in a patient with the acquired immune deficiency syndrome (AIDS) PMID- 7834874 TI - The collegium oto-rhino-laryngologicum amicitiae sacrum (CORLAS). An anachronistic club or a selected group of scientifically orientated individuals? PMID- 7834875 TI - Tinnitus and temporomandibular pain-dysfunction disorder. PMID- 7834876 TI - E-cadherin as a functional marker of the differentiation and invasiveness of squamous cell carcinoma of the head and neck. AB - The cell-cell-adhesion molecule E-cadherin is necessary for the maintenance of the epithelial cellular structure. We were able to show a correlation between decreasing E-cadherin expression, dedifferentiation and increased invasiveness in a cell line model. We studied 73 squamous cell carcinomas from the upper aerodigestive tract using the immunofluorescent method to demonstrate expression of E-cadherin. Decreased E-cadherin expression correlated with a decreased grade of differentiation and an increased lymph node metastatic rate. This confirms the significance of E-cadherin as a marker for differentiation and invasiveness of squamous cell carcinoma of the pharynx and larynx. PMID- 7834877 TI - Predictive factors for the resolution of childhood otitis media with effusion following initial surgical treatment. AB - A prospective study of outcome after treatment for glue ear was performed in a sample of 143 children aged between 1 and 11 years. The resolution or recurrence of effusion following initial surgery was analysed in relation to six potentially relevant factors. Multivariate analysis showed that resolution of effusion was statistically more frequent in ears found to have a dry tap at surgery, children with a history of atopy, those who underwent adenoidectomy and it was related to the age of the child at operation. Older children had a better prognosis. Univariate analysis suggested that girls have a significantly better outcome than boys, but this was not confirmed in multivariate analysis. The results suggest that there should be a longer period of observation in atopic individuals and older children. Furthermore, the study showed that ears with dry taps should not be treated with ventilation tubes. PMID- 7834878 TI - Informed consent: questionnaire survey of British otolaryngologists. AB - This postal questionnaire of British otolaryngologists has shown that most strive to obtain true informed consent when recommending surgery. The consent form is usually signed on the ward or at a pre-admission clinic and witnessed by a house officer. One-third of house officers received no instructions about what to discuss at this time, however, most consultants keep some record of what was discussed. A quarter of surgeons use information sheets, those not using them are more likely to anticipate problems with their use. An assessment of which complications are usually discussed is given. Comparison with a similar study shows increased disclosure of complications, perhaps a more defensive approach in surgical practice is developing. PMID- 7834879 TI - Soft tissue cervical metastases of squamous carcinoma of the head and neck. AB - Some 497 of 3085 patients with squamous cell carcinoma of the head and neck treated between 1963 and 1990 had a later radical neck dissection at some time after initial treatment. The histological slides were all reviewed, firstly to confirm the presence of squamous cell carcinoma within the neck, and secondly to ascertain whether the metastasis was to soft tissue, to a lymph node or to both. The presence of extracapsular rupture in lymph node deposits was also assessed. Of the 497 patients, 138 had soft tissue deposits only, and 359 had nodal deposits only. Of the patients with nodal deposits 165 had extracapsular rupture and 194 did not. The 5-year survival of the 138 patients with soft tissue metastases was 27% compared with 33% for patients with extracapsular rupture and 50% for patients with no extracapsular rupture. Weighted logistic regression showed that soft tissue deposits were significantly more common in patients in poor general condition, plus poorly differentiated squamous cell carcinoma plus T4 tumours (P < 0.005), and in patients with poorly differentiated squamous cell carcinoma plus T4 tumours (P < 0.025). Cox's multivariate analysis with backward elimination showed that gender, histological differentiation, site of primary tumour and age of patient had no statistically significant effect on survival. The number of nodes (P < 0.0001), the presence of extracapsular rupture (P < 0.0001) and the presence of soft tissue free metastases (P < 0.001) were all highly significant. The N-status at recurrence also reached statistical significance (P < 0.0001). PMID- 7834880 TI - Nasal congestion during the menstrual cycle. AB - Oestrogens have been considered to cause nasal congestion during the menstrual cycle and during pregnancy. The aim of the present study was to evaluate the degree of nasal congestion during the menstrual cycle in healthy women. Nasal peak expiratory flow (nPEF) was measured and subjective nasal stuffiness was scored morning and evening by 27 women for 3 months and by 14 women for 6 months. During the menstrual days, when the serum oestrogen level is lowest, the morning nPEFs were significantly lower compared with the rest of the cycle (P = 0.0012). The difference was most pronounced for the second day of the cycle (P = 0.00034). The correlation between nPEFs and the subjective scores was high (R = 0.98), while the coefficient of variation within the series of three nPEF recordings was low (6.4%). It is concluded that the nasal obstruction experienced during menstruation cannot be explained by increased serum levels of oestrogen. PMID- 7834881 TI - Matutinal vertigo--a chronobiological phenomenon. AB - Matutinal vertigo, characterized by vertiginous attacks occurring in the morning, has been noted in a significant percentage of patients with vestibular disorders and is considered to be precipitated by the patient's movements preparatory to arising from bed. Chronobiological studies of the variations of positional nystagmus in 10 patients with acute vertigo revealed rhythms of circadian periodicities in eight. The acrophases (i.e. computed peak hour), of nearly 40% of the circadian rhythms were found between 02.00 and 07.00 hours. Chronobiological characteristics of the vestibular system are postulated to play a part in the development of this clinical phenomenon. PMID- 7834882 TI - An in vitro model for measuring tryptase release from nasal mucosa in response to allergen challenge. AB - A simple in vitro nasal mucosal culture model has been developed to measure release of the mast cell specific enzyme tryptase in response to allergen challenge. Patients who were undergoing inferior turbinectomy were skin-tested for commonly inhaled allergens. The mucosa from the inferior turbinates was kept viable using Minimal Essential Medium. Tryptase release into the medium was measured using the Pharmacia Riact Assay. There was a significant increase in tryptase release in response to allergen challenge from the mucosa harvested from skin-test positive patients. Mucosa from skin-test negative patients failed to demonstrate an increase in tryptase release. This could prove to be a useful research model for the study of nasal type I hypersensitivity and drugs that affect it. PMID- 7834883 TI - Validity of a patient-administered questionnaire for routine otolaryngology admissions. AB - In this study the accuracy of a questionnaire filled in by 109 parents of children admitted for routine ENT surgery was compared with the well recognized verbal clerking. A major problem in communication between doctors and parents was highlighted, as just 44% of the parents were able to state the operation their children were admitted for. The study also showed that it is impossible to rely on parents to give the information required in the form of replies to questionnaires as the sensitivity of the questions designed to recognize risk factors was poor. PMID- 7834884 TI - Complications in ENT--a nationwide audit carried out in November 1992. AB - We report a prospective audit of complications following ENT surgery during November 1992 from 42 consultants across the United Kingdom. Complications were reported as codes, and results were analysed at the Royal College of Surgeons Comparative Audit Unit. A total of 174 complications were reported, giving an annualized complication rate per consultant of 5.7-7.0% (depending on whether only the most severe complication per patient is counted or all complications). This compares with an annual complication rate of 1.49% reported retrospectively for the year of 1991 by the same consultants. PMID- 7834885 TI - Vocal rehabilitation after pharyngo-laryngectomy--the Provox valve. AB - We describe our experience using the Provox voice prosthesis in patients undergoing free jejunal loop transfer following total pharyngo-laryngectomy. From our series and the few reports in the literature, the use of a voice prosthesis appears to be an effective method of speech rehabilitation in this group of patients. PMID- 7834886 TI - Laser debulking of obstructing laryngeal tumours. AB - A consecutive series of 11 patients presenting with obstructing laryngeal neoplasms over an 8-month period have been treated by laser debulking of the tumour in order to avoid a tracheotomy. Providing that all members of the team are experienced in microlaryngeal laser surgery, this technique can be safely and effectively used in the management of obstructing laryngeal neoplasms. PMID- 7834887 TI - Relevance of function tests in the diagnosis of vestibular disorders. AB - The diagnostic value or relevance of a vestibular function test is dependent on the whole clinical and functional context of each particular case. It is not the ability to show 'abnormality' in a high number of patients complaining of whatever kind of vertigo, that indicates the relevance of a function test. Neither is relevance of a test based upon the possibility that this test can re categorize some patients in the same way as has been done by other tests. Each test evaluates some particular functional aspect and this is very different from one test to another. A test is more relevant, i.e. indicates more abnormality when the type of vertigo caused by the dysfunction is also considered. These statements are confirmed by experience in peripheral vestibular disorders, especially benign paroxysmal positional vertigo (BPPV). A paroxysmal positional nystagmus (ppn) (nystagmus and vertigo elicited by movements and manoeuvres) is linked to the problem of provoked vertigo and gives a confirmation of this vertigo by reproducing it in some manoeuvres. Some inconstancy in the reproduction of this ppn may cause difficulties in diagnosis. Caloric tests are the clue for diagnosis of sudden unilateral loss (so-called neuronitis), whereas they give only complementary information for patients with BPPV. Posturography adds information in all categories concerning the standing position and can be interesting in the scope of rehabilitation treatment. The findings of a retrospective study in patients with BPPV (n = 95), compared with patients with Meniere's disease (n = 89) and others with sudden unilateral loss syndrome (n = 48), illustrate these concepts. PMID- 7834888 TI - Acute epiglottitis--aetiology, epidemiology and outcome in a population before large-scale Haemophilus influenzae type b vaccination. AB - Over a period of 18 years 219 consecutive cases of acute epiglottitis were diagnosed and subsequently investigated in order to elucidate the aetiology, epidemiology and outcome of this disease in a well-defined population in Sweden before general vaccination against Haemophilus influenzae type b infection was introduced. Compared with the results from other parts of the industrialized world, high incidence rates were found in both children (14/100,000/year) and adults (2.3/100,000/year). The annual trend showed a significant decline in incidence among children, whereas in adults it remained unchanged. In cases where the aetiological agent could be determined, infection with H. influenzae type b was the main cause of disease in all age groups. However, in adults 27% (6/22) had a disease caused by micro-organisms other than H. influenzae type b that were verified with a blood culture. Sixty-eight per cent had a negative blood culture. The mortality rate was 0.5% (1/219) and 6% (13/219) developed a significant complication of the disease. PMID- 7834889 TI - Revision surgery in otosclerosis--operative findings in 186 patients. AB - Over a 14-year-period 186 revision operations for otosclerosis were performed. In 90% of the patients the indication for revision was too large an air-bone-gap. A number of different surgical techniques had been used at the primary operation. The purpose of the investigation was to describe the middle ear abnormality at the revision operation. Most often adhesions, acentric prosthesis, reobliteration and necrosis of the long process of the incus were found. The middle ear abnormality found at revision operation was correlated to the primary surgical technique used and the information obtained can be of value, when a revision operation is considered. The surgical technique used at revision operation was determined by the operative findings. The best hearing improvement was obtained when a small-fenestration-technique was used primarily or as the method for revision. In revision stapes surgery, the experience of the surgeon is important and centralization of this type of operation is recommended. PMID- 7834890 TI - Acoustic rhinometry compared with anterior rhinomanometry in the assessment of the response to nasal allergen challenge. AB - Acoustic rhinometry was used to assess nasal airway patency objectively and was compared with the more established method of anterior rhinomanometry. Ten patients with allergic rhinitis underwent 15 nasal challenges with allergen to which they showed positive skin-prick tests. Responses were assessed by measuring the minimum nasal cross-sectional area (Amin.) using acoustic rhinometry and by measuring nasal airway resistance (NAR) using anterior rhinomanometry. The measurements of Amin. and NAR showed a significant negative correlation. Acoustic rhinometry appears to be superior to anterior rhinomanometry in quantifying the response to nasal allergen challenge and may be particularly useful in patients with initial nasal blockage. PMID- 7834891 TI - Associations of genotypes at the apolipoprotein AI-CIII-AIV, apolipoprotein B and lipoprotein lipase gene loci with coronary atherosclerosis and high density lipoprotein subclasses. AB - Association studies were carried out in a sample of 86 patients from Sweden who had survived a myocardial infarction (MI) at a young age and 93 age-matched healthy individuals, to compare the impact of polymorphisms at the apolipoprotein (apo) AI-CIII-AIV gene cluster on among-individual differences in plasma lipid and lipoprotein traits, the five high density lipoprotein (HDL) subclasses (2b to 3c), lipoprotein lipase (LPL) activity and presence and progression of atherosclerosis. Individuals were genotyped for four polymorphisms; 5'apoAI (G/A 75), 3'apoAI (PstI; P +/-), apoCIII (C/T1100) and apoCIII (PvuII; V +/-), using PCR-based techniques. Allele frequencies were similar in healthy individuals and patients (frequencies of alleles in combined population: 5'apoAI-A-75 = 0.14, 3'apoAI-P- = 0.05, apoCIII-T1100 = 0.27 and apoCIII-V- = 0.18). In the healthy individuals, levels of low density lipoprotein (LDL) triglycerides were significantly associated with genotypes of the apoCIII-PvuII polymorphism (p = 0.02), but no other associations were found between lipids or HDL subclasses and single polymorphisms in the apoAI-CIII-AIV gene cluster. Levels of triglycerides and very low density lipoprotein (VLDL) triglycerides were significantly higher in the presence of the haplotype defined by the presence of apoCIII-T1100 and common alleles of the other three polymorphisms, explaining 5.8% and 7.8% (p = 0.03 and 0.01), respectively, of sample variance. In the patients, no associations were found between lipids or HDL subclasses and variation at the apoAI-CIII-AIV gene cluster. Associations were also examined between levels of HDL subclasses and variation at the apoE (common isoforms), apoB (signal peptide and XbaI polymorphisms) and lipoprotein lipase (PvuII, HindIII and Serine447/Stop polymorphisms) gene loci. In the patient group only, levels of protein in HDL2b, HDL2a and HDL3b subclasses were significantly associated with genotypes of the LPL-HindIII polymorphism (22.1, 19.3 and 11.4%, respectively, of sample variance; p < 0.05). Finally, associations were examined between genotypes at the apoAI CIII-AIV gene cluster and the extent of coronary atherosclerosis. Global severity of atherosclerosis at the first angiography was weakly associated with genotypes of the apoCIII-C/T1100 polymorphism, presence of the T1100 allele being associated with 53% lower median score (1.6 vs 0.75; p = 0.09).(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7834892 TI - The KBG syndrome: follow-up data on three affected brothers. AB - In this report we present follow-up data on a family in which several members were found to have short stature, craniofacial anomalies and dento-skeletal abnormalities (KBG-syndrome). As adults, the three affected brothers of the original report are moderately to severely mentally retarded. Their phenotype with a distinct craniofacial appearance did not change much from that seen during childhood and adolescence. Adult height is far below the third centile, with arm spans exceeding stature by at least 9 cm. PMID- 7834894 TI - X;1 translocation in a female Menkes patient: characterization by fluorescence in situ hybridization. AB - Menkes disease is an X-linked recessive disorder of copper metabolism, characterized by progressive neurological degeneration, abnormal hair and connective tissue manifestations. We present a female Menkes patient, with classical Menkes features, carrying a de novo balanced translocation 46,X,t(X;1)(q13;q12). The breakpoint on the X chromosome was narrowed down to Xq13.3 within a 1 Mb YAC contig containing the Menkes gene, using fluorescence in situ hybridization. The translocated X chromosome was of paternal origin and non randomly active leading to the expression of the disease. This was additional evidence for paternal origin of de novo chromosome rearrangements, including all the X; autosomal translocations examined so far. PMID- 7834893 TI - Charcot-Marie-Tooth disease type 1A: the parental origin of a de novo 17p11.2-p12 duplication. AB - Charcot-Marie-Tooth disease type 1A (CMT1A) is an autosomal dominant peripheral neuropathy associated with a DNA duplication on chromosome 17p11.2-p12 in the majority of cases. Most of the sporadic cases are due to a de novo duplication. We have screened for this duplication in 11 Danish patients with CMT type 1, using four different techniques, and identified a de novo duplication in a sporadic case. Analysis of the fully informative pVAW409R3a alleles in this family showed the duplication to be of paternal origin. PMID- 7834895 TI - Familial translocation t(10;14) (q26.1;q32.3): report of three offspring with 10q deletion and 14q duplication. AB - We describe two brothers and a cousin with common clinical features, including mild mental retardation, motor delays, hypotonia with truncal ataxia, esotropia, and mild facial and hand dysmorphia. The initial routine chromosome study failed to detect any abnormality in the proband. Based on a high index of clinical suspicion, high-resolution chromosome studies were performed on the proband's parents. A small reciprocal translocation t(10;14) (q26.1;q32.3) was detected in the father. The breakpoint on the derivative chromosome 14 was further placed telomeric to the immunoglobulin heavy-chain gene cluster at the band q32.33 by fluorescence in situ hybridization. Studies of the proband and two affected paternal cousins revealed that each had inherited the same derivative chromosome 10 from their carrier parents. This unbalanced karyotype resulted from an adjacent-1 segregation of the 10;14 translocation. PMID- 7834896 TI - Mild phenotype and normal gonadal function in females with 4p trisomy due to unbalanced t(X;4)(p22.1;p14). AB - In this report we describe the mild phenotypic manifestations and normal gonadal function in a 50-year-old mother and her 17-year-old daughter with 4p trisomy resulting from an unbalanced t(X;4)(p22.1;p14) mat. Late replication of the der(X) was demonstrated by BrdU incorporation with spreading of the late replication to the 4p portion as an explanation of the reduced effect of the trisomy 4p/monosomy Xp on the physical and secondary sexual development in both patients. PMID- 7834897 TI - HLA-A, B and DR antigens in patients with gonadal dysgenesis. AB - HLA (human leukocyte antigens) antigens A, B, and DR were determined in a series of 50 patients with gonadal dysgenesis (GD), separated into different groups according to karyotype. There were no significant differences in frequency of HLA antigen types between GD patients and the population control. When frequencies of the HLA antigens in the various GD patient groups by karyotype were compared, only one significant difference was found: HLA-A3 was more common among GD patients with isochromosome X than among GD patients with karyotype 45,X (p < 0.001, corr. p < 0.008). Although GD patients have a higher expectancy for development of autoimmune disorders, and in our 50 patients thyroglobulin and/or microsomal antibodies were detected in 20 (i.e., 40%), we failed to find any increased frequency of specific HLA antigen types known to be associated with juvenile autoimmune thyroiditis. PMID- 7834898 TI - Mixed gonadal dysgenesis and cell line differentiation. Case presentation and literature review. AB - A male patient with mixed gonadal dysgenesis, involving a streak gonad on the right and a histologically normal testis in the left, was found to have a 45,X/46,X,dic(Yp) chromosome constitution on peripheral blood cultures. Fibroblasts grown from both gonads showed the "normal" testicular tissue to have e 45,X/46,X,dic(Yp), whereas the cells from the streak gonad were all 45,X. The structure of the dic(Yp) chromosome was confirmed using non-isotopic in situ hybridization with Y centromere and Yp specific probes. On hormonal stimulation, testosterone levels rose by 50%. The "normal" testis was left in situ, but close follow up will be required in view of the malignant potential. PMID- 7834899 TI - Oligodontia, short stature and small head circumference with normal intelligence. AB - Complete absence of third molars and mandibular permanent second molars is reported in a 19-year-old female, with occipito-frontal head circumference and height at the 3rd centile. The patient's intelligence, appearance and physical examination were normal. Direct count of the patient's sweat pores in different areas of the palms and digits was normal. Microcephaly, short stature and normal intelligence have been reported in two families as a distinct autosomal dominant syndrome. To the best of our knowledge, oligodontia, in addition to these findings, has not been previously reported. PMID- 7834900 TI - Marfan and cri du chat syndromes in an 18-month-old child: evidence of phenotype interaction. AB - We report on an 18-month-old girl who has both the cri du chat and Marfan syndromes. She was born at term to a 29-year-old woman with the clinical diagnosis of Marfan syndrome. An evaluation for developmental delay at 2 months of age showed a karyotype of 46,XX,del(5)(15.1), consistent with cri du chat syndrome. At age 18 months she was tall (90 cm, > 95th centile), with an decreased upper segment:lower segment ratio (1.0), and microcephalic (OFC 42.5 cm, < 5th centile). Facial features were typical of cri du chat syndrome. The palm, middle finger and foot lengths were at or above the 95th centile for age. She was hypotonic, and her developmental level was approximately 8-10 months. Echocardiography showed redundant mitral valve tissue, mild mitral insufficiency, dilated aortic sinuses, and a small muscular VSD. We would have anticipated that a patient with an autosomal deletion who also had Marfan syndrome would have had growth failure. However, in this patient the skeletal features of Marfan syndrome (increased body length, decreased upper segment:lower segment ratio, and increased palm, finger, and foot length) predominate. PMID- 7834901 TI - Down syndrome associated with systemic lupus erythematosus: a mere coincidence or a significant association? AB - An 8-year-old male, who had Down syndrome associated with systemic lupus erythematosus (SLE), is described. He also had a partial complement 4 deficiency. This case is a reminder that the physician should be aware of the possibility of an immune defect in a male presenting with SLE at a young age. The question of whether the association of Down syndrome with SLE is coincidental or whether there is a predilection for autoimmune disorders in Down syndrome is discussed. PMID- 7834902 TI - Down syndrome and male fertility: PCR-derived fingerprinting, serological and andrological investigations. AB - Down syndrome, the most common birth defect causing mental retardation, is characterized by a specific phenotype including subfertility or sterility and hypogonadism in males. In contrast, several females with Down syndrome have borne offspring. Here, a male with trisomy 21 fathering an infant is described. This observation is verified by serological markers, DNA fingerprinting using different DNA micro- or minisatellites and andrological investigations. PMID- 7834903 TI - Epigenetics: an overview. PMID- 7834904 TI - Epigenetic effects in eukaryotic gene expression. AB - In the broadest terms, epigenetic phenomena in eukaryotes depend on the interaction of alleles or repeated sequences or on the mitotic inheritance of chromatin states or methylation patterns. One of the most exciting aspects of the study of epigenetic phenomena is the insight that can be gained into the structure and assembly of higher-order chromatin structures, an important subject that has proved refractory to current biochemical methodologies. Rapid progress in the study of gene inactivation in fungi, plants, and invertebrates will provide new hypotheses to be tested in mammals. PMID- 7834905 TI - Inheritance of chromatin states. AB - The packaging of regulatory DNA within the eukaryotic chromosome has considerable potential not only for modulating the transcriptional activity of genes, but also for propagating states that are permissive or restrictive for transcription. Sequence-specific transcription factors, histones and their modifications, chromodomain proteins and enzymes that modify histones, DNA methylation and proteins that recognize methylated DNA could all play independent or interrelated roles in regulating gene activity. They all also have the potential of propagating their interactions with nascent DNA following replication. However, observations on the phenomenon of X chromosome inactivation suggest that the formation and stability of specific histone-DNA interactions through replication may be central to the inheritance of chromatin states, and that other molecular mechanisms have supporting roles. The future offers the exciting prospect of reconstructing the propagation of stable active or repressed chromatin states in vitro, and consequently understanding the events occurring at the replication fork in molecular detail. PMID- 7834906 TI - Epigenetics and the maintenance of gene activity states in Caenorhabditis elegans. AB - The nematode Caenorhabditis elegans has been the subject of many detailed investigations in developmental biology. Molecular analyses have failed to detect covalent alterations to DNA, such as methylation or rearrangement, during development of C. elegans. Genetic experiments indicate that imprinting of gamete genomes does not occur to any significant extent. The maintenance of gene activity states in this organism may depend predominantly on regulatory gene circuitry. Some possible examples of maintenance circuits are discussed. PMID- 7834907 TI - Spreading the silence: epigenetic transcriptional regulation during Drosophila development. AB - In early Drosophila development a complex cascade of diffusible transcription factors generates an intricate expression pattern of developmental regulators such as the homeotic genes. The mechanism which subsequently maintains the pattern during the rest of development is mainly using epigenetic features for its function. Evidence comes from the analysis of the Polycomb-group (Pc-G), a class of genes which is responsible for maintaining the inactive state of expression. The Pc-G was found to share many parallels to genes involved in heterochromatin formation. Different members of the Pc-G interact in large multiprotein complexes, which apparently can cover and inactivate large chromosomal domains. Specific DNA elements have been identified that are used by the Pc-G proteins to nucleate these specialized domains of silent chromatin. Thus, the Pc-G proteins appear to permanently inactivate genes by generating heterochromatin-like structures which could then be inherited by the daughter cells in an epigenetic manner. Heritable gene silencing is an important but little understood mechanism in pattern formation. Phenomenologically related effects have been observed in many organisms. These range from the transcriptional silencing of the inactive mating type loci in yeast to parental imprinting phenomena and X-chromosome inactivation in mammals. Analysis of these functions in Drosophila provides an excellent model system for studying the molecular basis of such epigenetic mechanisms that use higher order chromatin structures for transcriptional repression. PMID- 7834908 TI - Positional information and pattern formation in development. AB - A widely used mechanism for pattern formation is based on positional information: cells acquire positional identities as in a coordinate system and then interpret this information according to their genetic constitution and developmental history. In Drosophila maternal factors establish the axes and set up a maternal system of positional information on which further patterning is built. There is a cascade of gene activity which leads both to the development of periodic structures, the segments, and to their acquiring a unique identity. This involves the binding of transcription factors to regulatory regions of genes to produce sharp thresholds. Many of the genes involved in these processes, particularly the Hox complex, are also involved in specifying the body axis and limbs of vertebrates. There are striking similarities in the mechanisms for specifying and recording positional identity in Drosophila and vertebrates. PMID- 7834909 TI - Expression of an X-linked HMG-lacZ transgene in mouse embryos: implication of chromosomal imprinting and lineage-specific X-chromosome activity. AB - X-chromosome activity in female mouse embryos was studied at the cellular level using an X-linked lacZ transgene which encodes beta-galactosidase (beta-Gal). Translation of maternal RNA in oocytes is seen as beta-Gal activity that persists into early cleavage-stages. Zygotic transcription of the transgene from the maternal X chromosome (Xm) is first found at about the 8-cell stage. By contrast, expression of the lacZ transgene on the paternal X chromosome (Xp) is not seen until later at the 16-32-cell stage. Preferential inactivation of Xp occurs in the mural trophectoderm, the primitive endoderm, and derivatives of the polar trophectoderm, but a small number of cells in these lineages may still retain an active paternal X chromosome. X inactivation begins at 3.5 days in the inner cell mass but contrary to previous findings the process is not completed in the embryonic ectoderm by 5.5 to 6.0 days. Regional variation in beta-Gal activity is also observed in the embryonic ectoderm during gastrulation which may be related to the specification of cell fates. Random inactivation of Xp and Xm ensues in all somatic tissues but the process is completed at different times in different tissues. The slower progression of X inactivation in tissues such as the notochord, the heart, and the embryonic gut is primarily due to the persistent maintenance of two active X chromosomes in a significant fraction of cells in these tissues. Recent findings on the methylation of endogenous X-linked genes suggest that the prolonged expression of beta-Gal might also be due to the different rate of spreading of inactivation along the X chromosome to the lacZ transgene locus in different tissues. PMID- 7834910 TI - Experimental embryological analysis of genetic imprinting in mouse development. PMID- 7834911 TI - Preparing reformers for nursing's future. PMID- 7834912 TI - Evaluation in patients with Alport syndrome of knowledge of the disease and attitudes toward prenatal diagnosis. AB - Cloning of the COL4A5 gene has now made possible prenatal testing for Alport syndrome with X-linked dominant inheritance. We interviewed 27 females and 24 males with Alport syndrome to evaluate their knowledge of the disease and its transmission, and their attitudes to prenatal testing. Twenty-two males and 8 females were on renal replacement therapy. In all cases transmission was compatible with X-linked disease. Only 59% of the interviewees (74% of women, 42% of men) knew that gender was the major determinant in progression of the disease. Knowledge of the mode of inheritance was adequate in only 25%, in both sexes. Seventy percent of the participants (78% of women, 63% of men) would use prenatal testing. Of the women in favor of prenatal diagnosis, 67% and 39% would terminate pregnancy in the case of an affected male or female fetus, respectively. Of the men in favor of prenatal diagnosis, 53% would consider termination of an affected fetus. In summary, a majority would use prenatal testing, but only one or two thirds of them wished to use selective abortion. As in other inherited disorders, there is a discrepancy between the demand for prenatal diagnosis and the decision to terminate pregnancy. Most of the participants who would terminate a pregnancy had, however, little knowledge of the clinical and genetic aspects of Alport syndrome on which to base such a decision. An important aspect of genetic counselling is to assist consultants in reaching a decision regarding future reproductive behaviour which is appropriate to their situation. This study underlines the need to improve education and counselling to assure appropriate use of prenatal testing. PMID- 7834913 TI - Thin glomerular basement membrane in diabetic patients with urinary abnormalities. AB - To clarify the clinical and pathological significance of thin glomerular basement membranes (Thin-GBM) appearing in evident diabetics, we examined the renal biopsies from 179 diabetes mellitus (DM) patients with urinary abnormalities in which the number of non insulin dependent diabetes mellitus cases was 140 cases while the remaining 39 cases had insulin dependent diabetes mellitus. In addition, 17 of these cases were found to have either segmental or diffuse Thin GBM by electron microscopy. The clinical and morphological parameters between the diabetics with Thin-GBM (DM-Thin-GBM) and the diabetics without Thin-GBM (the controls) were significantly different regarding DM duration (DM-Thin-GBM vs control: 5.3 +/- 5.5 vs 9.8 +/- 6.5 years, p < 0.01), Ccr (67.0 +/- 25.5 ml/min vs 45.6 +/- 24.4 ml/min, p < 0.01), the incidence of hematuria (52.9% vs 24.5%, p < 0.05) and hypertension (13.3% vs 51.3%, p < 0.05). The severity of glomerular damage was mild in the DM-Thin-GBM group as compared to the control. The renal survival rate from the onset of urinary abnormalities was higher in the DM-Thin GBM group than in the control (p < 0.01). In the case of DM-Thin-GBM, the grade of proteinuria correlated with the mean width of the thickened GBM (p < 0.01) and the spread of the thickened GBM which was more than 500 nm in width (p < 0.001). The severity of microscopic hematuria correlated with the spread of the Thin-GBM (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7834914 TI - The changing pattern of children's dialysis and transplantation over 20 years. AB - The changing treatment and outcome for children with chronic renal failure (CRF) requiring renal replacement therapy (RRT) was assessed in children referred to the only paediatric unit in the North West Region of England between 1968 and 1988. There were 108 children. Referrals in consecutive 5-year time periods increased from 9 to 41 over the 20 years with the overall incidence of new referrals less than 15 years old reaching 8.5 per million childhood population in 1983-87, whilst the proportion of children under 5-years increased from 0% to 22%. The survival rate was better in those commencing RRT in the later years: 5 year survival 56% for the 1968-72 cohort vs 88% for 1978-82. The increasing number of referrals particularly among young children, coupled with improved survival rates have considerable implications when determining the provision of care for children with ESRD. PMID- 7834915 TI - Renal transplantation in patients over sixty years of age. AB - The aim of this study was to analyze whether old age affects the outcome of renal transplantation. Data were presented on all 337 renal allografts performed from January 1, 1987 to November 30, 1992 in the department of Nephrology and Urology, University Hospital of Nancy. Of these, 32 (9.5%) were performed in patients over 60 years old at the time of transplantation (mean duration of follow-up 22.3 +/- 17.1 months). No significant difference was noted in patient and graft survivals between the two groups at 36 months (respectively 83.8% and 76.1% in elderly patients; 96% and 82.8% in younger recipients). In the older group, all grafts were lost due to death (2/5) or nephrectomy (3/5) with a functional transplant (3/5) whereas chronic rejection accounted for the majority of graft loss in the younger group (23/43, p < 0.05). Episodes of acute rejection occurred with a very low incidence in elderly patients (15.6%). Infections were infrequent in this group and did not represent serious complications. Functional rehabilitation and quality of life were as good in elderly as in younger recipients. These results suggest that renal transplantation is an acceptable form of treatment for patients older than 60 years with end-stage renal disease in the absence of obvious contraindication. PMID- 7834916 TI - Nutritional status, muscle composition and plasma and muscle free amino acids in renal transplant patients. AB - To investigate the effects of renal transplantation (Rtx) on the nutritional status, muscle composition and the plasma and muscle free amino acid (AA) pattern, three groups of altogether 30 renal transplant patients (group I n = 10; 46 +/- 14 [SD] days after Trx), (group II n = 10; 13 +/- 2 months after Rtx) and (group III n = 10; 9 +/- 2 years after Rtx) underwent anthropometric measurements, blood sampling and percutaneous muscle biopsy. The immunosuppressive therapy consisted of prednisolone, azathioprine and cyclosporine-A. The results were compared with data from age-matched healthy subjects. Renal function was impaired in groups I, II and III. Serum albumin was decreased in groups I and II. The patients of group II had an increased percentage of body fat, triceps and subscapular skin folds and total sum of skinfolds. In group I the ratio alkaline-soluble protein (ASP) to DNA, which is a sensitive index of protein depletion on the cellular level, was decreased. Muscle magnesium content was decreased whereas the muscle DNA, sodium and chloride contents were increased. The mean plasma concentration of most essential AA (EAA) was essentially normal except phenylalanine which was increased in groups I and II.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7834917 TI - Immunologic disturbances and levels of parathyroid hormone in uremic patients in replacement dialysis therapy. AB - We studied the changes in cellular immunity in patients in replacement dialysis therapy (RDT) and examined the relationship between T-lymphocyte function and plasma levels of parathyroid hormone (PTH). In a preliminary study we found that increased plasma levels of PTH were associated with a decrease of T-lymphocytes and CD4, an increase in CD8 and a reduction in the ratio of CD4 to CD8. In the present study we examined the relationship between plasma levels of PTH, interleukin 2 receptors (IL-2R) and soluble human CD8 (S-CD8). We studied 54 patients divided into two groups: 26 patients with normal levels of PTH and 28 patients with increased levels of PTH. We found a significant reduction in total T-lymphocytes in both groups as compared to controls, with an inverse correlation between total T-lymphocytes and plasma PTH in the second group (R = -0.52). There was an increase in IL-2R in the group II as compared to the controls and also in the total population of uremic patients with a linear correlation between levels of IL-2R and PTH (R = 0.6). The levels of S-CD8 showed a significant increase in both groups with a linear correlation between levels of SC-D8 and PTH (R = 0.63). No specific differences were seen between patients treated with and without 1,25 dihydroxyvitamin D3. The elevated levels of PTH affect the lymphocyte function and are associated with change in cellular immunity with reduction in total number of T cells, and increases in levels of CD8, S-CD8 and IL-2R. PMID- 7834918 TI - Uremic encephalopathy. AB - The neurologic manifestations of renal failure are variable, nonspecific and most likely result from multiple metabolic derangements. Commonly used neurodiagnostic tests may be abnormal but are generally nondiagnostic. The EEG, although nonspecific, correlates with clinical symptoms and may be of diagnostic value if serial studies are performed. The pathophysiology of uremic encephalopathy is not well understood and multiple potential "uremic toxins" have been evaluated. Of these, parathyroid hormone is the only substance to be clearly linked to clinical findings. It is likely that other, even unidentified toxins, may play a role in the complex pathogenesis of neurologic disease associated with renal failure. PMID- 7834919 TI - Which bicarbonate concentration is adequate to lactate-buffered substitution fluids in maintenance hemofiltration? AB - We investigated the metabolic and hemodynamic effects of a lactate- and a bicarbonate-buffered (bicarbonate concentration 31.4 mmol/l, type I) hemofiltration substitution fluid in a prospective crossover study of 3 weeks each in 11 patients on maintenance hemofiltration. The lactate-buffered hemofiltration (lactate concentration 34-44.5 mmol/l) lead to hyperlactatemia in all patients without signs of overt lactic acidosis but showed a better control of acid-base balance (pH, base excess, standard bicarbonate) than the type I bicarbonate-buffered fluid (p < 0.01). In 6 patients a higher concentration of bicarbonate- (39.7 mmol/l, type II) buffered fluid was tested. The parameters of acid-base balance showed a better control during type II than during type I bicarbonate hemofiltration and were similar to the lactate-buffered phase. Plasma lactate levels between type I and type II bicarbonate hemofiltration were not different. Also in the steady state phase of the treatment (days 7-9 [week 3]) parameters of acid-base balance rose more to normal values during type II than during lactate-buffered hemofiltration. Hemodynamic parameters showed no differences between the three types of buffers used. Furthermore, also the type II bicarbonate fluid was well tolerated. Bicarbonate in a higher concentration (39.7 mmol/l) proved to be a safe and practical alternative to lactate-buffered hemofiltration. PMID- 7834920 TI - Crescentic fibrillary glomerulonephritis associated with intermittent rifampin therapy for pulmonary tuberculosis. AB - This case study reveals an unusual finding of rapidly proliferative crescentic glomerulonephritis in a patient treated with rifampin who had no other identifiable causes for developing this disease. This patient underwent a 10 month regimen of rifampin and isoniazid for pulmonary tuberculosis and was discovered to have developed signs of severe renal failure five weeks after completion of therapy. Renal biopsy revealed severe glomerulonephritis with crescents, electron dense fibrillar deposits and moderate lymphocytic interstitial infiltrate. Other possible causes of rapidly progressive glomerulonephritis were investigated and ruled out. This report documents the unusual occurrence of rapidly progressive glomerulonephritis with crescents and fibrillar glomerulonephritis in a patient treated with rifampin. PMID- 7834921 TI - Unusual presentation of glomerulocystic kidney disease in an adult patient. AB - A 38-year-old Latin-American man developed uremic syndrome without any evidence of previous kidney diseases or any other health problems. Ultrasound and CT scan confirmed normal size of the kidneys without evidence of urinary tract obstruction or renal parenchymal cysts. Kidney biopsy showed cystic dilatation of Bowman's space (glomerulocystic kidney disease). The patient was started on hemodialysis. Severe renal dysfunction and uremic symptoms are a rare initial manifestation of glomerulocystic kidney disease. This pathology should be considered in the differential diagnosis of patients with normal size kidney and chronic renal failure. PMID- 7834922 TI - Concurrence of de novo membranous glomerulonephritis and recurrent IgA nephropathy in a renal allograft. AB - Recurrent IgA nephropathy is commonly reported in renal transplant. De novo membranous glomerulonephritis is the most frequent type of glomerulonephritis seen in renal transplant. Nevertheless, to the best of our knowledge, the association of these two conditions in a single patient has never been documented. We wish to report one such case. PMID- 7834923 TI - Reduced nocturnal blood pressure fall is similar in continuous ambulatory peritoneal dialysis to that in hemodialysis and undialysed end-stage renal disease. PMID- 7834924 TI - Thrombolytic therapy of renal vein thrombi and follow-up. PMID- 7834925 TI - Association of familial nephritis without deafness and multiple sclerosis. PMID- 7834926 TI - Hemodialysis with cuprophane membranes is associated with a reduction in peripheral blood mononuclear cells expressing VLA-4 cell adhesion molecule. PMID- 7834927 TI - Neurologic side-effects of ganciclovir. PMID- 7834928 TI - Acute interstitial nephritis, omeprazole and antineutrophil cytoplasmic antibodies. PMID- 7834929 TI - Acronyms for heart failure trials. PMID- 7834930 TI - Prognosis of coronary artery spasm patients. PMID- 7834931 TI - Congenital heart disease and pregnancy. AB - In Europe and North America, a dramatic fall in the incidence of rheumatic fever and rheumatic heart disease has coincided with advances in medical and surgical management of congenital heart disease and has resulted in a shift in the relative incidence of these two categories of cardiac disorders in women of child bearing age. This review deals with pregnancy and congenital heart disease- unoperated and operated. Central to this topic is the intricate interplay between maternal circulatory and respiratory physiology and maternal congenital heart disease, and the effects of this interplay upon the fetus which is exposed to risks that threaten its intrauterine viability and to risks that subsequently express themselves as developmental defects or transmitted congenital malformations of the heart or circulation. PMID- 7834932 TI - The severity of residual coronary stenosis immediately after thrombolytic therapy does not influence the size of later left ventricular asynergic area. AB - To determine whether the severity of residual coronary artery stenosis immediately after thrombolytic therapy influences the size of later left ventricular (LV) asynergic area, we reviewed coronary angiograms (CAGs) and left ventriculograms (LVGs) of 31 patients with acute myocardial infarction (AMI). All patients received intracoronary urokinase therapy within 6 h after onset of AMI due to total occlusion of the proximal left anterior descending coronary artery (LAD). A dose of 960,000 IU urokinase was infused into the ostium of the left coronary artery over 40 min. Patients in whom antegrade blood flow without delayed distal filling was restored received rigorous anticoagulation. The patients were divided into three groups according to the severity of the coronary lesion immediately after urokinase therapy: 9 patients with complete occlusion in Group 1, 15 with > 90% stenosis in Group 2, and 7 with < 90% stenosis in Group 3. There were no significant differences in the baseline clinical characteristics among the patients in the three groups. The LADs in Group 1 were also totally occluded 1 month after urokinase therapy, the treated vessels in both Groups 2 and 3 were still patent, and patients in Group 2 showed a further reduction in residual stenosis. When LV asynergic area, regional wall motion, and global ejection fraction (EF) were compared among the three groups, no significant differences were demonstrated. In comparison with the data immediately after urokinase therapy, all parameters 1 month after therapy were significantly improved in both Groups 2 and 3.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7834933 TI - Directional coronary atherectomy in women compared with men. AB - The influence of gender on the procedural outcome of directional coronary atherectomy (DCA) is controversial. This study of 373 consecutive patients (418 lesions) undergoing DCA demonstrates that the procedural success rate of DCA is significantly lower in women compared with men (72.7 vs. 82.9%, p = 0.011). Women have significantly smaller coronary arteries than men (2.5 mm vs. 2.7 mm, p = 0.028) and were older than men (66 vs. 61 years, p = 0.0001). Multivariate analysis identifies small coronary vessel size rather than female gender per se as an independent predictor of poor procedural outcome. Procedural success rates in women with coronary vessel size > or = 2.5 mm is significantly higher (92.2%) than in women with coronary vessel size < 2.5 mm (73.1%), and parallels that in men with vessel size > or = 2.5 mm (89.3%). Inability to engage the ostium of the coronary artery adequately with the guiding catheter and to cross the lesion with the atherectomy device is significantly more common in women compared with men. Major ischemic complication rates are similar in women and men (8.5 vs. 8.7%). Groin complications are significantly more common in women compared with men (13.5 vs. 2.9%). We conclude that procedural success rates in women may be improved by careful patient selection, with particular attention to small vessel size. DCA is best performed in vessels > 2.5 mm in diameter. PMID- 7834934 TI - Neuroendocrine activation in relation to left ventricular function in chronic severe congestive heart failure: a subgroup analysis from the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). AB - Left ventricular (LV) function and plasma levels of cardiovascular hormones were examined in patients with severe chronic congestive heart failure (CHF), randomized to placebo or enalapril, in addition to conventional therapy. M-mode echocardiography and plasma hormone concentrations were available at baseline and after 6 weeks of treatment. There was a significant relationship between LV systolic function and levels of angiotensin-II and norepinephrine. Enalapril increased LV fractional shortening (FS%) (13.3 +/- 5.6 to 15.4 +/- 5.8, p < 0.05) and decreased the systolic time interval index (0.58 +/- 0.14 to 0.48 +/- 0.15, p < 0.05) concurrent with a significant decrease in angiotensin-converting enzyme activity and in aldosterone, angiotensin-II, and norepinephrine concentrations after 6 weeks. No changes were found in the placebo group. However, there was no direct relationship between the amount of change in neurohormones and improvement in LV function after 6 weeks. These findings indicate that in patients with severe chronic CHF, severe LV systolic dysfunction is associated with high plasma levels of angiotensin-II and norepinephrine, which can be favorably modified by enalapril. This may be of importance for prolonging life in severe heart failure. The lack of relationship between changes in individual hormones and systolic function suggests complex dynamic interaction. It is, therefore, not sufficient to predict changes in LV function by measuring changes in only one hormone. PMID- 7834935 TI - Artificial intelligence versus logistic regression statistical modelling to predict cardiac complications after noncardiac surgery. AB - The traditional approach to developing models predictive of cardiac events has been to perform logistic regression (LR) analysis on a variety of potential predictors. An alternative to use an artificial intelligence system called a neural network (NN) which simulates biological intelligence. To evaluate the potential applicability of the latter method, we compared the ability of LR and NN techniques to predict cardiac events after noncardiac surgery. A total of 200 patients (training group) underwent cardiac risk assessment before major noncardiac surgery using 17 clinical parameters and 7 quantitative indices based on dipyridamole-thallium imaging. There were 21 post-operative myocardial infarctions and/or cardiac deaths. Data from the training group were used to develop two predictive models: one based on backward stepwise LR multivariate statistical analysis and the other one using a neural network. Both models were then validated on a second group of 160 consecutive patients also referred for preoperative risk stratification (validation group). The NN consisted of 14 input, 29 hidden, and 1 output neurons and used a back-propagation algorithm (learning rate 0.2, training tolerance 0.5, sigmoid transfer function). The sensitivity, specificity, positive and negative predictive accuracies for the prediction of postoperative events in the validation group of 160 patients were, respectively, 67% (6/9), 82% (124/151), 18% (6/33), and 98% (124/127) for LR, and 67% (6/9), 96% (145/151), 50% (6/12), and 98% (145/148) for the NN, with a difference in specificity which attained statistical significance (p < 0.01). Artificial intelligence may provide a useful alternative to conventional LR statistical analysis for the purpose of preoperative cardiac risk assessment. PMID- 7834936 TI - Regression of left ventricular hypertrophy with long-term treatment of nifedipine in systemic hypertension. AB - We investigated the regression of left ventricular (LV) hypertrophy with long term treatment of nifedipine in patients with systemic hypertension. Echocardiograms of the LV were obtained in nine patients before and at a mean of 50 months (13-105 months) after nifedipine monotherapy (30-60 mg/day). Nifedipine significantly reduced both systolic and diastolic blood pressures (BP) by a mean of -46 mmHg and -21 mmHg, respectively. With systemic BP reduction, LV mass was significantly reduced by a mean of -15%, associated with a decrease in LV posterior wall thickness and end-diastolic dimension. There was no significant change in LV fractional shortening. We conclude that nifedipine may cause regression of LV hypertrophy in systemic hypertension, and that reversal of the increase in LV mass could be maintained during long-term nifedipine treatment. PMID- 7834937 TI - Amyloid disease of the heart. AB - A 70-year-old woman with a history of hypertension had been well until 3 years before when she developed atrial fibrillation and subsequently congestive heart failure. The heart failure became worse and she had three fainting spells. Low voltage on electrocardiogram and global hypokinesis on echocardiography were suggestive of cardiac amyloidosis. The patient died suddenly of intractable ventricular fibrillation. Autopsy confirmed heavy infiltration of the myocardium by amyloid. PMID- 7834938 TI - Clustered lipid droplets in the endomyocardial biopsies from a patient with neuroleptic malignant syndrome. AB - Neuroleptic malignant syndrome is caused by serious adverse effects of antipsychotic agents and occurs only rarely. Endomyocardial biopsies documented unique clustered lipid droplets in a Japanese man with this disease. After administration of haloperidol, he had symptoms of high fever, respiratory dysfunction, and cardiogenic shock, and subsequently suffered from multiple organ failure. Fortunately, he was completely cured with intensive therapy. In the convulsant stage, left ventricular endomyocardial biopsies were performed that yielded the interesting discovery of unique clustered lipid droplets among the myofibrils. It was suggested that although the pathomechanism of neuroleptic malignant syndrome is unknown, this disease may be characterized by a lipid metabolic disorder of the cardiac muscle cell. PMID- 7834939 TI - Refractory hypoxemia in inferior myocardial infarction from right-to-left shunting through a patent foramen ovale: a case report and review of the literature. AB - Right ventricular (RV) infarction is a well-recognized complication of some acute inferior myocardial infarctions. Recently, there have been numerous case reports of RV infarctions complicated by severe refractory hypoxemia secondary to right to-left shunting through a patent foramen ovale. An additional case missed by transthoracic echocardiography and cardiac catheterization is reported and the English literature on the subject is reviewed. PMID- 7834940 TI - Bilateral renal artery occlusion: an unusual presentation of atrial fibrillation and hypertrophic cardiomyopathy. AB - Hypertrophic cardiomyopathy predisposes patients to atrial fibrillation and the development of systemic embolization. We describe a rare case of bilateral renal artery thrombosis which presented as acute renal failure requiring dialysis. The patient was successfully treated with a selective, continuous infusion of urokinase which resulted in the return of adequate renal function. PMID- 7834941 TI - Edward Jenner. PMID- 7834942 TI - [An autopsied case of Fabry's disease presenting with parkinsonism and cardiomegaly as a cardinal clinical manifestation]. AB - A 68-year-old male had been followed up under a clinical diagnosis of parkinsonism for 5 years. He was admitted to the Kanto Teishin Hospital with a chief complaint of difficulty in swallowing. Physical findings were almost normal. Neurological examination showed parkinsonism including mask-like face, positive Myerson's sign, mild rigidity, marche a petit pas, and retropulsion, and pyramidal signs including mild right hemiparesis, generalized hyperreflexia and positive Babinski's sign on both sides. Routine blood analysis was normal, except for elevated LDH level. He was found to have cardiac enlargement (CTR 58.7%) in chest roentogenogram, left ventricular hypertrophy (LVH), right bundle branch block and myocardial ischemia in electrocardiogram, as well as LVH, asymmetrical septal hypertrophy, mild MR and AR in echocardiogram. A T2 weighted brain MRI disclosed multiple high signal intensities in the basal ganglia and deep white matter regions which suggest parkinsonism resulting from multiple cerebral infarctions. An upper gastrointestinal endoscopic examination revealed esophageal and gastric carcinomas. He died of ventricular fibrillation 14 days after an operation of these carcinomas. Autopsy showed severe cardiomegaly (800 g) and vacuolar change of myocardium with lamellar body on electron microscopic examination. A definite biochemical diagnosis of Fabry's disease was made by demonstration of deposition of a large amount of trihexosylceramide in the myocardium, kidney, and liver. This case presented parkinsonism and cardiomegaly without typical signs of Fabry's disease. Therefore, Fabry's disease should be considered as one of possible underlying diseases, when a patient has cardiomegaly or ischemic cerebrovascular disease without risk factors, even if he has no typical signs of Fabry's disease. PMID- 7834943 TI - [A case of isolated oculomotor nerve palsy due to cavernous dural arteriovenous malformation (AVM)]. AB - A 44-year-old man developed left-sided blepharoptosis and diplopia. Clinical examination showed left-sided blepharoptosis, a 2.5 mm dilated but reactive left pupil and an impaired left-eye adduction. There was no proptosis, bruit or conjunctival injection. Computed tomographic scan (CT) and magnetic resonance image (MRI) of the orbits, cavernous sinus region and brainstem were normal. Carotid angiography demonstrated a dural arteriovenous malformation of the left cavernous sinus supplied by the meningohypophyseal artery of the internal carotid artery and the middle meningeal artery of the extrenal carotid artery, with drainage into the inferior petrosal sinus. Magnetic resonance angiography (MRA; 3D-time of flight method) showed a slight vascular blush at the cavernous sinus region, but not enough to yield a diagnosis. The oculomotor nerve palsy resolved over the following 7 months. PMID- 7834944 TI - [A case of progressive supranuclear palsy showing improvement of rigidity, nuchal dystonia and autonomic failure with trazodone]. AB - A 63-year-old man was admitted to the hospital with a 1,5-year history of progressive dementia, supranuclear ophthalmoplegia, pseudobulbar palsy, rigidity and dystonia in the neck and the upper trunk. Magnetic resonance imagings showed severe atrophy of the frontal lobe and the brainstem. He was diagnosed as having progressive supranuclear palsy (PSP). Rigidity, nuchal dystonia, frequent micturition, and profuse sweating ameliorated after trazodone administration. Furthermore, additional administration of L-dopa and droxidopa improved his pseudobulbar palsy, akinesia, and lack of initiative. Single photon emission tomography using IMP after medication showed increased IMP-uptake in the frontal areas and the basal ganglia compared with that before medication. This patient illustrates a substantial role of impairments in the serotonin system in the production of some PSP symptoms. PMID- 7834945 TI - [A case of painful involuntary contraction of the left latissimus dorsi muscle, successfully treated with left thoracodorsal nerve resection]. AB - A 66-year-old Japanese man underwent the resection of the upper lobe of the left lung for primary lung cancer. One year later, his back muscles neighboring the operation scar gradually began to twitch upwards intermittently. The involuntary muscle twitch was accompanied with severe local pain, and intensity of the pain and contraction slowly increased. The abnormal muscle contractions were confined to the left latissimus dorsi muscle on needle EMG. The pain and movement ceased by blocking of either thoracodorsal nerve or brachial plexus, and disappeared finally by resection of the nerve. The impulses causing involuntary, painful contractions were thought to originate in the damaged thoracodorsal nerve, transmitted to CNS and re-transmitted to the thoracodorsal nerve. PMID- 7834946 TI - [Isolated oculomotor nerve palsy caused by mesencephalic hemorrhage]. AB - A 62-year-old man with a history of diabetes mellitus, hypertension and liver damage has sudden diplopia on Nov. 4, 1992. Ocular movements of this right eye were normal, but his left eyelid was completely ptotic, and left pupil was dilated and nonreactive to light. In primary position, his left eye deviated outward, and could not move to any direction. He was diagnosed as having total oculomotor nerve palsy of the left side without any other neurological signs or symptoms; his consciousness level was alert and mental state was normal. The present case showed normal facial sensation, no facial palsy and no tongue deviation. Deep tendon reflexes were hypoactive bilaterally. Pyramidal tract sign, cerebellar sign, and gait disturbance were not observed. Superficial sensation of the extremity was normal. Brain CT scan revealed a small mesencephalic hemorrhage extending to the tegmentusm ventral to the cerebral aqueduct of the left side. Brain magnetic resonance imaging demonstrated a high intensity area in the left oculomotor nucleus and its fascicles in the midbrain on T1- and T2-weighted image. The oculomotor nerve palsy of the left eye gradually improved, but mydriasis, adduction impairment and downward gaze palsy continued, and oculomotor nerve palsy of the left eye was compatible with so called inferior branch palsy of the oculomotor nerve. Moreover, contralateral eye movements were normal except for mild upward gaze palsy. Oculomotor nerve palsy of this type was consistent with the syndrome of oculomotor nucleus described by Pierrot-Deseillingny in 1981. It was presumed that the superior rectus muscle is innervated by the contralateral oculomotor nerve nucleus in man as well as in animals. PMID- 7834947 TI - [Hypoxic encephalopathy with quadriplegia and cortical blindness]. AB - We report a 63-year-old woman with quadriplegia and cortical blindness due to hypoxic encephalopathy. She was hospitalized with a fever of 40 degrees C. After injection of an antipyretic drug, she suddenly entered a state of shock. Artificial breathing was induced, but she did not regain consciousness. She was admitted to this hospital in a state of coma. One month later, she regained consciousness, and her quadriplegia and decreased visual acuity became apparent. Neurological examination revealed cortical blindness (initially with Anton sign), geotropic ocular deviation, forced weeping, flaccid quadriplegia, and bilateral pyramidal tract signs (generalized hyperreflexia, positive bilateral Babinski sign). Magnetic resonance imaging of the brain, on a T2 weighted image, showed high-intensity areas in the bilateral precentral gyri and bilateral calcarine cortex. In this case, artificial breathing was induced immediately after shock, and respiratory arrest occurred for a very short time, suggesting that the cause of this hypoxia may be due to mild hyproperfusion. Among previously reported cases, there are 5 cases with relative selective lesions in the bilateral precentral gyri and bilateral calcarine cortex. Findings in all cases were by autopsy, revealing oligemic hypoxia. The onsets of these cases were cardiogenic or peripheral shock from cardiac arrest or arrhythmia, etc., during surgery. Two cases died in a coma state. The other 3 cases regained consciousness with quadriplegia. Among these 3 cases, the case reported by Murayama had quadriplegia and cortical blindness, as in this case.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7834948 TI - [Pure anterograde amnesia due to bilateral fornix lesions]. AB - The patient was a right-handed 59-year-old female technician who was admitted to our hospital with a complaint of memory loss. Clinical examination revealed pure anterograde amnesia regarding episodic memory, while semantic and procedural memory was intact. Radiological procedures (CT scan and MRI) revealed a tumor of the septum pellucidum, which localized from the lower part of the corpus callosum to the anterior parts of the bilateral fornices. Transcallosal total removal was performed (pathological examination revealed that it was astrocytoma). Radiological and operative findings showed that the thalamus, the mammillary bodies, the hippocampus, and the basal forebrain, which are closely related to memory, were spared. After the operation, she reported no further memory disturbance. Preoperative neuropsychological tests revealed anterograde amnesia for verbal and visual stimuli, but postoperatively the former disappeared and the latter improved. Pre- and postoperatively, she was nonaphasic, and her immediate memory, intelligence, and frontal functions were intact. Cases of amnesia due only to fornix lesions are rare, and have not been reported yet in Japan. Our case is valuable in terms of showing that only the fornix lesion was responsible for memory disturbance. The main symptom resulting from fornix lesion is thought to be anterograde amnesia. PMID- 7834949 TI - [A case of pontine hemorrhage presenting with abnormal vertical ocular movements]. AB - A 52-year-old woman was admitted to hospital because of sudden loss of consciousness. Neurological examination on admission revealed a comatose consciousness level, horizontal and upward palsies of both eyes and quadriparesis. The diagnosis of pontine hemorrhage was confirmed based on a brain CT scan, which showed a high density area involving the bilateral pontine tegmentum and right midbrain tegmentum at the inferior collicular level. The left eye moved downward below its primary position, and the movements usually comprised rapid downward and slow upward excursions and, on occasion, slow downward and rapid upward excursions, and were arrhythmical with irregular amplitudes. Oculocephalic maneuver did not modify the ocular movements. No horizontal movements were seen with ice-cold water irrigation into the ear canal on either side. Sixty days after hemorrhage onset, her right eye began to assume the same abnormal vertical movements as the left one, and 90 days after their onset, the ocular movements became oscillations. The abnormal vertical ocular movements in our patient were characterized by irregularities of phase, rhythm and amplitude. Accordingly, they were easily differentiated from ocular bobbing and ocular dipping. As these abnormal ocular movements resembled those of a float pulled by a fish, we propose they be termed ocular floating. The paramedian pontine reticular formation (PPRF) is believed to excite the burst neurons of the rosral interstitial nucleus of medial longitudinal fasciculus (riMLF) responsible for upward gaze and inhibit those for downward gaze. This role was suggested by the clinical observation that a pontine tegmental lesion causes upward gaze palsy.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7834950 TI - [Acute relapsing ataxic polyradiculoneuritis following respiratory tract infections]. AB - We report a patient with a relapsing form of acute ataxic polyradiculoneuritis. The patient developed marked sensory ataxia with mild limb weakness following a respiratory tract infection. Five similar relapses occurred over 18 years. The symptoms reached their maximum in 2 weeks, followed by subsequent gradual improvement over 1-2 months. Sural nerve biopsy showed mild loss of large myelinated fibers. PMID- 7834951 TI - [Mobius syndrome with crossed total hemiatrophy--a case report]. AB - The patient was a 26-year-old male who was noted to have asymmetry on the face, upper limbs, and trunk, and who showed no pursuit eye movements and no changes in the facial expression from birth. The patient developed transient global amnesia and was hospitalized. Neurological examination established atrophy of the right face, and left trunk involving the upper limb, and bilateral oculomotor and abducens nerve palsy. In auditory brainstem response, waves III to V were bilaterally obscured, and the blink reflex disclosed disturbances of peripheral facial nerve and the brainstem, suggesting developmental abnormalities of the facial motor nucleus. Contralateral R1 was also recorded in the blink reflex, and crossed trigeminofacial pathway was suspected. Mobius syndrome is associated with various muscle and skeletal abnormalities, but the coexistence of crossed total hemiatrophy has not been reported. We think that our case might be the first case of Mobius syndrome with total hemiatrophy. PMID- 7834952 TI - [A case of MELAS associated with prosopagnosia, topographical disorientation and PLED]. AB - We report a case of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) associated with prosopagnosia, topographical disorientation, and periodic lateralized epileptiform discharge (PLED) on electroencephalography (EEG) in a 23-year-old right-handed man. The first MELAS attack occurred on March 1, 1991, while the patient was drinking. Magnetic resonance imaging (MRI) revealed a lesion of abnormal intensity in the left occipital lobe. The second attack occurred on October 1, 1991. This time, the major symptoms were visual loss of acute onset, nausea, and vomiting. EEG examination showed transient PLED. MRI revealed a new area of abnormal intensity in the right occipital lobe, lingual gyrus, fusiform gyrus and the posterior part of the parahippocampal gyrus. During the clinical course of the patient, prosopagnosia and topographical disorientation appeared. There have been few reports of MELAS associated with prosopagnosia, topographical disorientation, and PLED. However, MELAS attacks tend to occur in the cortex of the occipital lobe. We therefore believe that these neuropsychological symptoms and PLED are likely to be associated with MELAS. PMID- 7834953 TI - [A case of unilateral gustatory disturbance produced by the contralateral midbrain lesion]. AB - We reported a case of unilateral gustatory disturbance produced by a lesion in the contralateral midbrain. A 37-year-old man first noticed dysesthesia in the left side of his face. Later, the patient developed dysesthesia of the left part of the lip, muscular weakness on the left lower extremity and gustatory disturbance on the left side. MR scan disclosed a lesion in the tegmentum of the right midbrain, which showed low intensity on a T1-weighted image and high intensity on a T2-weighted image. This lesion could be due to multiple sclerosis. This case suggests that the unilateral gustatory information ascends via the contralateral pathway at the midbrain level. It is suggested that the central gustatory pathways above the ipsilateral pontine taste are ascend via the contralateral projections to the thalamic taste area (parvicellular portion of the ventral posteromedial thalamic nucleus, VPMpc). PMID- 7834954 TI - [A case of progressive hemifacial atrophy associated with immunological abnormalities]. AB - We reported a case of progressive hemifacial atrophy associated with immunological abnormalities. This patient, a 35-year-old woman, had a history of high fever of unknown etiology associated with anemia and leukocytopenia at the age of 19. Eight months later, right hemifacial atrophy, alopecia and partial lipodystrophy of the right upper arm were developed. And the progression had stopped in the latter twenties. At the age of 35, she visited our hospital because of the hemifacial atrophy. Physical examination revealed right hemifacial atrophy, large alopecia at parietal and right temporal region, and partial lipodystrophy of the right upper arm. CT, MRI and ultrasound tomography of the head and the arm showed skin and scalp atrophy, temporal muscle atrophy and decrease of subcutaneous soft tissues. There was no autonomic dysfunction. Serum IgG was increased, and RA factor, anti-nuclear antibody, anti-DNA antibody and LE cell were positive. In this case, immunological abnormalities were considered to be related to the pathogenesis of hemifacial atrophy. PMID- 7834955 TI - [A patient of late-onset nemaline myopathy with mononuclear cell infiltration]. AB - We described a 50-year-old woman with late-onset nemaline myopathy with focal mononuclear cell infiltrates in her muscle biopsy. She developed difficulty in climbing stairs, and elevating her arms for 5 months after the onset of the disease. On admission, neurological examination revealed moderate weakness and atrophy in the proximal limb and neck muscles. Laboratory studies were within normal limits except mildly elevated serum CK and aldolase levels. Electromyography showed myopathic changes in the right triceps and quadriceps muscles examined. A biopsy from the left biceps brachii muscle revealed increased variation in fiber size, with numerous basophilic atrophic fibers. There were some foci of mild mononuclear cell infiltration. Most of basophilic fibers contained nemaline bodies on modified trichrome stain. On electron microscopy numerous nemaline bodies were present in fibers with marked myofibrillar degeneration. Azathioprine and prednisolone administration was not effective to improve her condition. As mononuclear cell infiltration has been occasionally described in the previously reported patients of adult-onset nemaline myopathy, inflammatory process may have some roles in formation of nemaline bodies on the way of acute myofibrillar degeneration. PMID- 7834956 TI - [The relation between Bickerstaff's encephalitis and anti-GQ1b antibody]. PMID- 7834957 TI - [Autonomic nervous function in progressive supranuclear palsy--comparison with Parkinson's disease and healthy controls]. AB - This study evaluated the autonomic nervous function in 6 patients with progressive supranuclear palsy (PSP). The autonomic nervous functions in PSP patients were compared with those in 17 patients of Parkinson's disease (PD) and 9 age-matched healthy control subjects. Results were that all PSP patients and 59% of PD patients had sympathetic skin response (SSR) abnormalities. Significant abnormalities in cardiovascular response observed in PD patients suggested the presence of sympathetic and parasympathetic disturbances. There were no significant differences between PSP patients and control subjects in cardiovascular responses. But some of PSP patients showed abnormal cardiovascular responses compared with the results from the control subjects. In PSP patients mild disturbances in cardiovascular responses and sudomotor dysfunction were suggested. We consider that the high incidence of SSR abnormality is at least partially related to the presence of disturbances in the frontal lobes. PMID- 7834958 TI - [Anti-voltage-gated calcium channel antibodies in the Lambert-Eaton myasthenic syndrome]. AB - We have tested 29 patients with the Lambert-Eaton myasthenic syndrome (LEMS) for serum antibodies to voltage-gated calcium channels (VGCC) using an immunoprecipitation assay in which [125]-omega-conotoxin GVIA is used to label calcium channels extracted from IMR-32, a human neuroblastoma cell line. Fifty five percent of these patients had significant levels of antibody [31.6 (26.5, 48.2) (med., Q1, Q3) pmol/L, n = 29], compared with healthy controls [21.5 +/- 3.4 (mean +/- SD) pmol/L, n = 30] and other neurological disorders [25.2 +/- 4.2 (mean +/- SD) pmol/L, n = 10]. These antibodies were found in 43% of the patients with small cell lung carcinoma (SCLC) without signs and symptoms of LEMS [32.2 +/ 7.2 (mean +/- SD) pmol/L n = 30] and 7% of the myasthenic patients [21.4 +/- 6.8 (mean +/- SD) pmol/L n = 14]. Anti-VGCC antibody titers did not correlate with presence of SCLC, disease duration, or an electromyographic index of disease severity. Our results suggest that the antibodies detected in this assay are specific to some patients with LEMS, but not all. This assay is a useful aid in diagnosing LEMS but has much room for improvement. PMID- 7834959 TI - [The effect of droxidopa on the monoamine metabolsim in the human brain]. AB - Droxidopa (L-threo-3,4-dihydroxyphenylserine) is an artificial amino acid, which is used to supplement noradrenaline (NA) in neurodegenerative disorders. Droxidopa is decarboxylated into NA by aromatic L-amino acid decarboxylase in the brain, but its effects on other monoamine neurotransmitters, such as dopamine (DA) and serotonin (5-HT) have not been systematically examined. The monoamine metabolism has been suggested to interact with each other in the brain, and by analysis of the cerebrospinal fluid, L-DOPA, a precursor amino acid used for supplement of DA, was found to inhibit serotonin synthesis in the brain. To examine the effects of droxidopa on the monoamine metabolism, the intraventricular fluid of the patients administered with droxidopa and L-DOPA was analyzed. The levels of monoamines, their precursor amino acids, and their metabolites were compared between the patients administered with L-DOPA. In the patients administered by droxidopa and L-DOPA, droxidopa was shown to increase the concentrations of monoamines (NA, DA and 5-HT), but the difference was not statistically significant by comparison with those treated by L-DOPA alone. The metbolites of DA and 5-HT by monoamine oxidase, 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindoleacetic acid (5-HIAA) were also found to increase by droxidopa administration. On the other hand, the metabolites of NA and DA by catechol-O-methyltransferase (COMT), normetanephrine (NMN) and 3-methoxytyramine (3-MT), decreased in the patients treated with droxidopa and L-DOPA compared with the patients administered with L-DOPA alone and control patients.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7834960 TI - [Study on the metabolism of droxidopa in humans]. AB - Supplement of the deficient neurotransmitters is one of the most effective therapies for neurodegenerative disorders. For the treatment of Parkinson's disease, L-DOPA therapy has been applied to replace dopamine, and droxidopa (L threo-3,4-dihydroxyphenylserine) therapy to supply noradrenaline (NA). Droxidopa, an artificial amino acid, is decarboxylated by aromatic L-amino acid decarboxylase (AADC) into NA. By application for Parkinson's disease, it alleviated neurological symptoms such as freezing phenomenon, which are refractory to L-DOPA. However, as a precursor of a monoamine, droxidopa was found to be not so effective as L-DOPA; and the clinical efficiency of droxidopa is variable among patients. The metabolic pathway of droxidopa in the brain was examined using human materials. The intraventricular fluid of patients treated with droxidopa, and of control was analyzed by high-performance liquid chromatography with multi-eletrochemical detection (Neurochem). In the intraventricular fluid of the patients treated, free NA concentration increased to be 5.67 +/- 3.40 nM from non-detectable level in the control patients. The patients with higher free NA levels clinically responded better to droxidopa. However, free NA levels varied among patients; and the mechanism of the individual variance should be clarified. In the intraventricular fluid, in addition to NA, a large amount of a metabolite of droxidopa by catechol-O methyltransferase (COMT), 3-O-methoxy-droxidopa (3OMD), was detected, followed by the metabolites by DOPS-aldolase (DOPS-ALD), protocatechualdehyde and protocatechuic acid. It indicates that considerable parts of administered droxidopa are catabolized by COMT and DOPS-ALD, but not by AADC.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7834961 TI - [Pathomechanism of juvenile muscular atrophy of unilateral upper extremity (Hirayama's disease)--extensibility and asymmetry of the cervical posterior dural wall]. AB - We performed myelography in chin-up position during neck flexion in 20 patients with juvenile muscular atrophy of unilateral upper extremity, and we also performed CT-myelography in rotational position during neck flexion in 15 of them. In this disease, in which posterior lower cervical dural wall shifts anteriorly and compresses the spinal cord during neck flexion, we found that the anterior dural shift and cord compression became lessened by making chin-up without changing the position of neck flexion. By measuring the posterior dural length from foramen magnum to C6 vertebra on the profile of myelogram in neutral and neck flexion posture, we found that the posterior lower cervical dural wall of this disease was less extensible during neck flexion than that of control cases. On CT-myelogram the spinal cord compression of muscularly atrophic side increased by the neck rotation to the non-atrophic side during neck flexion, which is the position of maximum extension of posterior dural wall. The spinal cord compression decreased by the rotation to the atrophic side. We think that the low extensibility and asymmetry of posterior lower cervical dural wall may be the cause of this disease and its laterality may be relevant to unilaterality of this disease. These findings could also explain the efficacy of cervical immobilization by using cervical coller. PMID- 7834962 TI - Chirality in new drug development. Clinical pharmacokinetic considerations. PMID- 7834963 TI - Clinical pharmacokinetics of paclitaxel. AB - Paclitaxel is a new anticancer agent showing significant promise as therapy for solid tumours and leukaemia, given alone or in combination with other chemotherapeutic agents. Paclitaxel concentrations in biological specimens can be measured using high performance liquid chromatography, or more recently by immunoassay. Pharmacokinetic studies in which adults have been administered pacliaxel intravenously over 1 to 96 hours have demonstrated the following pharmacokinetic characteristics: extensive tissue distribution; high plasma protein binding (approximately 90 to 95%); variable systemic clearance, with average clearances ranging from 87 to 503 ml/min/m2 (5.2 to 30.2 L/h/m2); and minimal renal excretion of parent drug (< 10%). In vitro and in vivo studies have demonstrated that paclitaxel is extensively metabolised by the liver to 3 primary metabolites. Cytochrome P450 enzymes of the CYP3A and CYP2C subfamilies appear to be involved in hepatic metabolism of paclitaxel. Although early reports suggested that paclitaxel has first-order pharmacokinetics, some recent trials in children and adults suggest that its elimination is saturable. The clinical importance of saturable elimination would be greatest when large dosages are administered and/or the drug is infused over a shorter period of time. In these situations, achievable plasma concentrations are likely to exceed the affinity constant for elimination (Km). Thus, small changes in dosage or infusion duration may result in disproportionately large alterations in paclitaxel systemic exposure, potentially influencing patient response. A pharmacokinetic analysis of the combination of cisplatin and paclitaxel has demonstrated that paclitaxel clearance is apparently sequence dependent. Patients administered cisplatin prior to paclitaxel had lower clearances and greater clinical toxicity than patients receiving paclitaxel before cisplatin. Additional pharmacodynamic analyses have shown nonhaematological and haematological toxicity to correlate better with parameters of paclitaxel exposure (e.g. area under the plasma concentration-time curve, duration of plasma concentrations exceeding 0.1 mumol/L) than with the administered dosage. PMID- 7834964 TI - Excretion of psychoactive drugs into breast milk. Pharmacokinetic principles and recommendations. AB - The postpartum period is a time of great physical and emotional changes. The incidence of psychiatric illness is higher in this period than at any other time in a women's life. Therefore, the question of whether women receiving psychotropic drugs should continue breast feeding is an important one. Drug excretion in breast milk depends mostly on passive diffusion of the unionised unbound drug. Passive diffusion is affected mainly by the drug disposition in lactating mothers, by the physicochemical properties of the molecule and by the protein and lipid contents of breast milk. Indeed, breast milk can be considered as a compartment with bidirectional transfer rather than a reservoir into which drug accumulates. Benzodiazepines are the most prescribed psychotropic drugs. Generally there does not seem to be any contraindication to breast feeding after a single dose, provided the dose administered is relatively low. If higher doses are to be used or long term administration is required, then breast feeding should probably be discontinued, particularly with drugs with a long elimination half-life. On the basis of the average concentration of phenobarbital (phenobarbitone) in milk, breast feeding is not recommended. For glutethimide, breast feeding would appear to be safe for the infant when a single dose is taken occasionally. Zopiclone may also be prescribed on a short term basis to breast feeding mothers. Due to limited available data or to the large amount transferred to milk, administration of phenothiazines and nonphenothiazine tricyclic, butyrophenone, and benzamide antipsychotics to breast feeding mothers cannot be recommended. Breast feeding is not always considered an absolute contraindication to lithium therapy, but the mother should watch for signs of toxicity in her baby. Whether clomipramine should be contraindicated during breast feeding depends on the concentration of active metabolites in breast milk, and this has not yet been determined. It is probably safe for mothers to breast feed while receiving amitriptyline, but before more conclusive recommendations are made more infants should be studied. The available data suggest that the amount of doxepin and its metabolite in breast milk is small. However, the metabolite of doxepin may accumulate in the infant with risk of sedation and respiratory depression: therefore, an alternative antidepressant should be selected for breast feeding mothers.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7834965 TI - Polymer conjugates. Pharmacokinetic considerations for design and development. AB - Soluble polymer conjugates have only recently been introduced into clinical practice. They can be subdivided into 2 main categories: polymer-protein conjugates, so far the most widely studied; and polymer-drug conjugates, particularly those containing conventional antitumour agents, that are still at an early stage of development. Polymer conjugation can be used to alter the biodistribution, elimination and rate of metabolism of covalently bound drugs. In the case of protein adducts, polymer conjugation prolongs the protein plasma elimination half-life (5- to 500-fold increases in elimination half-life have been reported), reduces proteolytic degradation and has the added benefit of reducing immunogenicity. Cellular uptake of low molecular weight drugs convalently bound to polymeric carriers is restricted to the endocytic route. Thus, the organ and subcellular distribution of the drug can be modified. Cellular uptake has been used to facilitate drug targeting and decreased toxicity. In this review, the theoretical rationale for polymer conjugation is described, as is the limited clinical pharmacokinetic experience with polymer conjugates. As an alteration of the pharmacokinetic profile of a drug was one of the underlying arguments for creation of polymeric conjugates, more clinical pharmacokinetic studies are urgently needed to permit the validation of appropriate pharmacokinetic models that can be used in the future to assist in the optimisation of clinical protocols, and improved conjugate design. PMID- 7834967 TI - Magnetic resonance imaging: spinal cord imaging with the turbo-fluid attenuated inversion recovery (FLAIR) pulse sequence. AB - Twelve patients with suspected or proven spinal cord disease were studied with a fluid attenuated repeated echo sequence employing a fast spin-echo data acquisition (Turbo-FLAIR) and the results were compared with those obtained with conventional T1- and T2-weighted spin-echo sequences. The Turbo-FLAIR sequence utilized an unselected 180 degrees pulse to reduce the signal from CSF followed by a spin-echo sequence based on the Rapid Acquisition with Relaxation Enhancement (RARE) pulse sequence for data acquisition. Three and four echo versions were used. Four low signal intensity lesions (cysts or syrinxes) were seen of which three were better seen with the Turbo-FLAIR sequence than with the other sequences. The remaining lesion was equally well seen. Of the seven high signal lesions found, six were better seen with the Turbo-FLAIR sequence and one was equally well seen. The Turbo-FLAIR sequence is more rapid than the T2 weighted spin-echo sequence and compares favourably with the combined results of both the T1- and T2-weighted spin-echo sequences for lesion conspicuity. PMID- 7834968 TI - Ultrasound-guided pigtail catheter drainage of malignant pericardial effusions. AB - Anterior pericardiocentesis was performed under ultrasound guidance using indwelling pigtail catheters in nine patients with malignant pericardial effusions and cardiac tamponade. Symptoms were alleviated in all cases and there were no deaths attributable to the procedure. Catheters remained in place for a median of 24 h (range 8-168 h). Complications were minor: asymptomatic left-sided or bilateral pleural effusions (n = 3), atrial fibrillation (n = 2), transient pericardial pain (n = 1) and erratic drainage (n = 1). Recurrence of the pericardial effusion was limited to a single case and occurred after 5 months of effective palliation. The procedure was successfully repeated with no further recurrence. One patient who went on to surgical fenestration 11 days after pericardiocentesis died 24 h post-operatively. The remaining patients died of the underlying malignant disease without further cardiac complication. Survival following the procedure ranged from 3 to 8 months. Ultrasound-guided pigtail catheter drainage is a minimally invasive, safe and effective method for the palliation of cardiac tamponade in patients with malignant pericardial disease. PMID- 7834969 TI - A comparison of colour duplex ultrasound with venography and varicography in the assessment of varicose veins. AB - Ninety-three legs in 68 consecutive patients presenting for preoperative assessment of varicose veins were examined by a combination of ascending venography with varicography and also by colour duplex ultrasound. Ninety-one to ninety-two per cent of incompetent sapheno-femoral and sapheno-popliteal communications were demonstrated by ascending venography/varicography and 92-95% by ultrasound. Ascending venography/varicography demonstrated 83-90% of incompetent perforators whilst ultrasound demonstrated only 40-63%. We conclude that ultrasound is an accurate method of assessing primary and recurrent sapheno femoral and sapheno-popliteal incompetence but is of limited value in assessing perforator incompetence. This is a significant limitation of ultrasound in view of the importance of perforator disease, and it is likely that this technique can only be used in combination with other venographic methods. PMID- 7834970 TI - Does pre-scan oxygen improve ultrasonic imaging of the pancreas? AB - Ultrasonic imaging of the pancreas is often impaired by overlying bowel gas. Oxygen therapy has, in the past, been shown to be effective in reducing the gas in the cysts of pneumatosis coli. Using the same hypothesis, a randomized, single blind study comparing ultrasonic imaging of the pancreas with and without prior oxygen therapy was carried out. Fifty-eight consecutive patients with acute abdominal complaints were randomized to two groups: Group 1, control - no oxygen (n = 30, 14 male, 16 female, mean age 61.9 +/- 17.8 years); Group 2, treatment (n = 28, 14 male, 14 female, mean age 61.4 +/- 14.5 years) received oxygen therapy (100% humidified at 101/min for 8-10 h prior to the ultrasound). Pancreatic visualization was graded good, moderate or poor. Mean paO2 in Group 1 was 10.9 +/ 1kP and in Group 2 was 36 +/- 10.5kP (P < 0.001 unpaired t-test). Pancreatic visualization was: GOOD-Group 1, 8; Group 2, 19; MODERATE - Group 1, 8; Group 2, 4; POOR - Group 1, 14; Group 2, 5. Oxygen therapy is a safe, cheap, non-invasive method of improving pancreatic visualization and may act by reducing overlying bowel gas. PMID- 7834971 TI - Radiological appearances of implantable defibrillator systems. AB - Implantable defibrillator systems have been used in over 20,000 patients worldwide. Such systems use a variety of different electrodes and the identification of these and the recognition of associated problems with them presents a challenge to the radiologist. The appearance of currently available implantable defibrillation systems and the use of radiological examination in patient follow-up and system troubleshooting is discussed based on our experience with a large population of patients receiving these devices. Radiological examination is excellent for demonstrating displacement of distortion of defibrillation electrodes, but in our experience is ineffective for the identification of lead conductor fractures. PMID- 7834966 TI - Pharmacokinetic optimisation of therapy with newer antidepressants. AB - Since the early 1950s, when imipramine was first introduced, a whole series of antidepressants with differences in structures, neurochemical effects and pharmacokinetics have been developed. Structurally or functionally, they have been classified as tricyclic antidepressants (TCAs), tetracyclic antidepressants, monoamine oxidase inhibitors (MAOIs), or selective serotonin (5 hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs). In addition, there is a series of antidepressants with unique structures. Many of the newer TCAs appear to have shorter half-lives than the standard TCAs (e.g. imipramine), allowing for the possibility of a more rapid response, but requiring the drugs to be given in multiple daily doses, which may reduce patient compliance. The short time to peak plasma concentration (tmax) can also lead to rapid onset of adverse effects. The tetracyclic antidepressants have longer elimination half-lives (t1/2) than the TCAs, but there is only very minimal evidence for a relationship between drug concentrations in the blood and clinical response. The triazolopyridines, like the newer TCAs, show pharmacokinetic evidence for rapid onset of adverse effects and the need for multiple daily doses due to short tmax and t1/2. The newer MAOIs are a significant addition to therapy, as the rapid binding action of these medications increases their safety margin with regard to tyramine interactions. Further information in this area is required. In addition, moclobemide has pharmacokinetic features that are clinically beneficial (e.g. aging and renal dysfunction have little effect on the elimination of the drug), but also features that are not beneficial (e.g. nonlinear pharmacokinetics). Among the SSRIs, there are a range of t1/2 values for the parent drugs, from relatively short t1/2 values of less than 24 hours (paroxetine, fluvoxamine) to among the longest found (e.g. 2 days for fluoxetine). Only 2 of the agents (sertraline and citalopram) have linear pharmacokinetics, and 1 drug has nonlinear pharmacokinetics within the usual therapeutic range (fluvoxamine). Once a therapeutic blood concentration is established, linearity is helpful in avoiding the small dose changes and repeated rechecking of concentrations of medications that would be required for those agents with nonlinear pharmacokinetics. Sertraline stands out as having the best effects on behaviour among all antidepressants. However, fluoxetine and fluvoxamine are least likely to penetrate into breast milk. All 3 of the structurally unique newer antidepressants [amfebutamone (bupropion), viloxazine venlafaxine] have relatively short tmax values (1 to 2 hours), which may relate to the early onset of adverse effects. Amfebutamone has the benefits of linear pharmacokinetics with potential for defined therapeutic blood concentrations, lack of effect of liver enzymes on metabolism of the drug, and lack of significant effects of either aging or hepatic dysfunction on elimination of the drug. Thus, the antidepressants best suited for pharmacokinetic optimisation of therapy are the following: desipramine, sertraline, fluvoxamine, citalopram and amfebutamone. PMID- 7834972 TI - Intraperitoneal fluid collections following liver transplantation in a paediatric population. AB - Reduced-size liver transplant techniques are now widely used in paediatric liver transplantation programmes. An argument against their use is the potential for an increased incidence of post-operative fluid collections arising from the cut surface of the liver. The distribution and management of fluid collections after 70 paediatric liver transplants (18 whole and 52 reduced), performed over a 3 year period is reported. Fluid collections occurred in seven of the whole liver transplant (WLT) group and in 23 of the reduced-size liver transplant (RLT) group. The incidence of fluid collections in the two groups was therefore similar (39% and 44%). Intervention was required in 20 collections: in the RLT group, seven of these were due to biliary anastomosis leaks or bowel perforation, the incidence of the remaining collections requiring intervention was similar in the two groups. In conclusion the overall incidence of fluid collections was not increased by the use of reduced-size liver transplants, and the increased rate of intervention in the RLT group was not related to the cut surface. PMID- 7834973 TI - Iohexol in patients undergoing urography: a comparison of polypropylene containers (Unique Soft Pack) and glass vials. AB - The purpose of the present phase IV multicentre trial was to evaluate general patient tolerance to Omnipaque 350 mgI/ml (iohexol) supplied in polypropylene containers compared to that of the same product supplied in routinely used glass vials, with emphasis on allergy-like adverse events. Polypropylene is a pure plastic material with practically no additives, and has been tested in vitro as a contrast medium packaging material for several years. Handling of these containers is easier and safer than handling of glass vials. Iohexol was administered to 1481 patients undergoing urography (741 patients in the glass vial group, 740 in the polypropylene container group), all of whom successfully participated in the trial. Six centres, representing four European countries, participated. Patients were randomized to receive iohexol from either polypropylene containers or traditional glass vials according to a double blind, parallel design. Pre-established inclusion and pre-admission exclusion criteria were followed, as well as routine procedures for preparation of the patients and conduct of the urography examinations at each hospital. Patient tolerance was assessed by recording all adverse events experienced over a period of up to 1 h after the procedure. Allergy-like events were defined as coughing, sneezing, nausea, vomiting, urticaria or itching. No adverse events were experienced by 56.5% of the patients in the glass vial group, nor by 58.0% of those in the polypropylene group. Discomfort (mainly a sensation of warmth) was reported by 39.4% and 38.6% of the patients, and adverse events other than discomfort by 7.4% and 5.9% of the patients, respectively. There seemed to be a correlation between the speed of injection and the frequency of discomfort (an increase with increasing speed), both of which varied a lot between centres. There was no significant difference in the incidence of allergy-like events between the two groups. Such reactions were seen in 2.0% of patients in the glass vial group and 1.9% of those in the polypropylene container group. There was no significant difference between the patients' tolerance to iohexol supplied in traditional glass vials or in polypropylene containers. Therefore, the new polypropylene container can be recommended as a container for Iohexol. PMID- 7834974 TI - Testicular infarction mimicking tumour on scrotal ultrasound--a potential pitfall. AB - We present two cases of spontaneous testicular infarction. Although the clinical presentation indicated an acute pathology, the ultrasound examination demonstrated focal, hyporeflective intra-testicular lesions that could not be discriminated from tumour. As a result of the ultrasound examinations, radical orchidectomies were performed and diagnoses of spontaneous testicular infarction proven histologically. PMID- 7834975 TI - Domiciliary radiography: an important service? AB - General practitioners' (GP) perceptions, comparative costs and potential influence on patient management of a domiciliary radiography service were reviewed. A postal questionnaire was sent to 159 local GPs, 130 of whom responded. Seventy-one per cent of respondents had requested domiciliary radiography in the previous year and 79% felt loss of the service could potentially be detrimental. Although 98% recognized that a chest X-ray was a suitable domiciliary radiography examination, 6% thought that a barium swallow could be adequately carried out with domiciliary equipment. Forty-nine per cent perceived a need for a domiciliary ultrasound service. Sixty-three per cent believed that domiciliary radiography was cheaper than return ambulance transport with departmental examination, although estimates showed a domiciliary visit to cost 82 pounds versus 60 pounds for a departmental visit. A retrospective review of 50 consecutive domiciliary radiography examinations showed that elderly and immobile patients were imaged most frequently. Malignancy was diagnosed in 14%, infection in 26% and a fracture in 14%. Overall there was an anticipated management change in 50% of patients. PMID- 7834976 TI - Technical report: radiological evaluation of patellar malalignment using a new frame for axial imaging of the patellae. AB - Axial radiographs were performed on 59 children and adolescent patients with patellar malalignment using the method described by Laurin. A special frame was used to keep the knees in 20 degrees flexion and to maintain standard conditions. Radiological indices were measured before realignment surgery. A statistically significant difference (P < 0.0001) in the lateral patellofemoral angle was observed comparing malaligned and control patellae. Laurin's technique using a special frame provides a method of obtaining standard radiological measurements of patellar malalignment for use in surgical planning. PMID- 7834977 TI - Case report: central venous catheter fracture due to compression between the clavicle and first rib. AB - A central venous catheter inserted via the subclavian route may be compressed by the clavicle and adjacent first rib. This appearance on a radiograph has been previously described as the 'pinch-off sign' and indicates the need to remove the catheter, due to a significant risk of subsequent fracture. A case and its management are presented, followed by discussion of the radiographic appearances and their cause. PMID- 7834978 TI - Contrast-enhanced MR imaging of intrahepatic cholangiocarcinoma. AB - The unenhanced spin-echo T1-weighted images, contrast-enhanced (dynamic and conventional) T1-weighted images and spin-echo T2-weighted images of 19 patients with histologically proven intrahepatic cholangiocarcinoma were reviewed. The results showed that typical intrahepatic cholangiocarcinoma presented as a large mass of low signal intensity on T1-weighted images. On T2-weighted images tumours generally presented as high signal intensity masses. In five patients the tumours exhibited varying degrees of central hypointensity on T2-weighted images. On contrast-enhanced images, large tumours (diameter larger than 4 cm, n = 14) typically showed peripheral enhancement with delayed or incomplete central filling. This pattern was seen most commonly. Smaller tumours (diam. 2-4 cm, n = 5) typically exhibited homogenous enhancement. On dynamic studies, enhancement of the tumours showed a centripetal pattern. Complete enhancement was observed in the small tumours. Among the larger lesions central sparing of the tumours was seen. It is concluded that contrast-enhanced MR imaging is useful in the diagnosis of intrahepatic cholangiocarcinoma. The characteristic enhancing pattern of intrahepatic cholangiocarcinoma was seen less commonly in smaller tumours. Definite differentiation from other liver masses in this case could be less certain. PMID- 7834979 TI - Case report: enlargement of a mediastinal mass during treatment for Hodgkin's disease may be due to accumulation of fluid within thymic cysts. AB - A patient with Hodgkin's Disease (HD) is described as one in whom a mediastinal mass showed progressive enlargement during the first two cycles of chemotherapy owing to accumulation of fluid within thymic cysts. This phenomenon was identified by computed tomography. Dependence on plain radiography would have led to an erroneous diagnosis of progressive HD. We suggest that in all cases of mediastinal HD, apparent failure to respond to treatment must be further investigated by computed tomography or magnetic resonance imaging. Such a policy should avoid unnecessary changes in therapy when enlargement of thymic cysts causing mediastinal widening is mistakenly interpreted as being due to progressive disease. PMID- 7834980 TI - Case report: multiple myeloma--a rare presentation. AB - An unusual case of multiple myeloma is reported in a 61-year-old man presenting with hepatomegaly and multiple hypoechoic lesions in the liver seen on ultrasound. Following cytotoxic chemotherapy the size and number of the lesions within the liver had significantly reduced. PMID- 7834981 TI - Case report: soap--another artefact that can mimic intramammary calcifications. PMID- 7834982 TI - The efficacy of double reading mammograms in breast screening. PMID- 7834983 TI - The efficacy of double reading mammograms in breast screening. PMID- 7834984 TI - Small bowel follow-through. PMID- 7834985 TI - Percutaneous antegrade ureteric stent insertion in malignant disease. PMID- 7834986 TI - Turbo-flash MRI for delineating vascular anatomy. PMID- 7834987 TI - Estimation of kinetic constants in ion transport studies: regression analysis and Monte-Carlo simulation. PMID- 7834988 TI - Atrial natriuretic peptide inhibits cyclosporin A-induced endothelin production and calcium accumulation in rat vascular smooth muscle cells. AB - 1. As we have previously shown, cyclosporin A enhances the vasoconstrictor induced rise in intracellular free calcium in vascular smooth muscle cells. This effect may contribute to important side-effects in cyclosporin therapy, such as hypertension and nephrotoxicity. Atrial natriuretic peptide has been shown to inhibit this effect as well as the cyclosporin-stimulated transmembrane calcium influx in smooth muscle cells. 2. The present study, therefore, was designed to examine the effect of cyclosporin and atrial natriuretic peptide on total cellular calcium content in the rat. Furthermore, since cyclosporin was recently shown to induce endothelin production in smooth muscle cells, we investigated the effect of atrial natriuretic peptide on this potentially adverse cellular effect of cyclosporin therapy. 3. Total cell calcium was measured by atomic absorption, and cellular endothelin production was estimated by radioimmunoassay. 4. Preincubation of the cells with cyclosporin (10 micrograms/ml) for 30 min increased total cell calcium from 2.6 +/- 0.5 to 6.9 +/- 0.3 nmol/mg of protein (P < 0.01). Within 24 h endothelin production was significantly enhanced in the presence of cyclosporin (52.2 +/- 2.5 versus 65.9 +/- 2.7 fmol/mg of protein, P < 0.05). Therefore, the cyclosporin-induced rise in total cell calcium in smooth muscle cells is associated with enhanced production of endothelin. Thus, it is tempting to speculate that the cyclosporin-induced changes in calcium kinetics may be mediated by endothelin. 5. In the presence of atrial natriuretic peptide (10(-8) mol/l), the cyclosporin-induced rise in total cell calcium was significantly reduced (6.9 +/- 0.3 versus 5.1 +/- 0.2 nmol/mg of protein, P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7834989 TI - Vascular responses to vasopressin antagonists in man and rat. AB - 1. The effects of the non-peptide arginine vasopressin V1 receptor antagonist (OPC-21268) and the non-peptide V2 receptor antagonist (OPC-31260) on vasopressin induced contraction of human internal mammary arteries and rat mesenteric resistance arteries were investigated. 2. In human internal mammary arteries, the non-peptide V1 receptor antagonist, OPC-21268, failed to antagonize vasopressin induced contraction at low concentrations and potentiated the contraction at higher concentrations (300 nmol/l, P < 0.05). A peptide selective V1 receptor antagonist ([d(CH2)5, sarcosine7]arginine vasopressin) potently inhibited the vasopressin-induced contraction, indicating the presence of functionally constrictor V1 receptors in human internal mammary arteries. Both peptide (desGly NH29[d(CH2)5, D-Ile2, Ile4]arginine vasopressin) and non-peptide 'selective' V2 receptor antagonists (OPC-31260, 3 mumol/l) significantly antagonized vasopressin induced contraction (P < 0.01), indicating partial V1 receptor antagonist activity. 3. The vasopressin-induced contraction in human internal mammary arteries was reversed by high concentrations of the non-peptide V2 receptor antagonist, OPC-31260, but not by the non-peptide V1 receptor antagonist, OPC 21268. 4. The effects of OPC-21268 and OPC-31260 were specific to vascular vasopressin receptors as neither compound influenced endothelin- or noradrenaline induced contraction in human internal mammary arteries. 5. In rat mesenteric resistance arteries, both OPC-21268 (10 nmol/l) and OPC-31260 (1 mumol/l) antagonized vasopressin-induced contraction (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7834990 TI - Effects of angiotensin II and aldosterone on diastolic function in vivo in normal man. AB - 1. Doppler echocardiographic indices of diastolic function and systemic haemodynamics were studied in response to infusions of angiotensin II (1, 2, 5 and 10 ng min-1 kg-1), D-aldosterone (2, 4, 10 and 20 ng min-1 kg-1) and placebo [0.9% (w/v) NaCl] in ten normal male subjects. 2. Dose-related increases in systolic and diastolic blood pressure were observed with angiotensin II infusion at rates of 2 ng min-1 kg-1 and above, whereas no changes in blood pressure occurred with D-aldosterone. No changes in aortic stroke distance or heart rate were seen with either angiotensin II or aldosterone infusion. 3. Compared with placebo, angiotensin II infusion produced a dose-related prolongation of the isovolumic relaxation time [mean and 95% confidence intervals 12.0 (8.2-15.8) ms, P < 0.001] at 10 ng min-1 kg-1, and a significant reduction in the ratio between early and late transmitral flow velocity integrals at 2 ng min-1 kg-1, [-0.84 ( 1.63 to -0.05), P < 0.05] and 5 ng min-1 kg-1 [-0.76 (-1.47 to -0.05), P < 0.05]. No changes in Doppler echocardiographic indices of diastolic function were observed with D-aldosterone infusion. 4. These data suggest that angiotensin II, even at a sub-pressor concentration, produces an impairment of left ventricular diastolic filling, which occurs independently of its effect on aldosterone release. PMID- 7834992 TI - Insulin sensitivity in post-obese women. AB - 1. Both increased and decreased sensitivity to insulin has been proposed to precede the development of obesity. Therefore, insulin sensitivity was measured during a 2 h hyperinsulinaemia (100 m-units min-1 m-2) euglycaemic (4.5 mmol/l) glucose clamp combined with indirect calorimetry in nine weight-stable post-obese women and in nine matched control women preceded by 12 h fasting after 48 h on a standardized diet. 2. Both glucose disposal rate (post-obese women, 9.5 +/- 2.2 mg min-1 kg-1, control women, 11.2 +/- 1.4 mg min-1 kg-1, not significant) and glucose oxidation (3.6 +/- 0.5 mg min-1 kg-1 versus 4.0 +/- 0.7 mg min-1 kg-1, not significant) were similar in the two groups during the last 30 min of the clamp. Lipid oxidation also decreased similarly during the clamp in the post obese women (from 30.4 +/- 12 to 2.0 +/- 7 J min-1 kg-1) and in the control women (from 33.6 +/- 11 to 5.4 +/- 8 J min-1 kg-1, not significant). Basal plasma concentrations of free fatty acids were similar, but at the end of the clamp free fatty acids were lower in the post-obese women than in the control women (139 +/- 19 and 276 +/- 48 mumol/l, P = 0.02). 3. We conclude that the insulin sensitivity of glucose metabolism is unaltered in the post-obese state. The study, however, points to an increased antilipolytic insulin action in post-obese subjects, which may favour fat storage and lower lipid oxidation rate postprandially.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7834993 TI - Recovery of 13C in breath from infused NaH13CO3 increases during euglycaemic hyperinsulinaemia. AB - 1. The effect of euglycaemic hyperinsulinaemia on the recovery of 13C in expired CO2 has been assessed in six normal subjects. Each was studied on three occasions: once with a 6 h primed constant infusion of NaH13CO3 combined with a euglycaemic hyperinsulinaemic clamp for the last 3 h (study 1), once with a 6 h primed constant infusion of NaH13CO3 alone (study 2) and once with a 6 h infusion of normal saline combined with a hyperinsulinaemic clamp for the last 3 h (study 3). Measurements of 13C enrichment of expired CO2 were made in the third and sixth hour of each infusion. 2. There was no significant increase in enrichment during study 3 (3 h 0.00047 +/- 0.00016 versus 6 h 0.00069 +/- 0.00028 atom per cent excess) with potato-starch-derived D-glucose used to maintain euglycaemia. 13C recovery increased in the sixth hour of both study 1 and 2 (study 1: 3 h 74.4 +/- 2.0 versus 6 h 85.5 +/- 2.6%, P < 0.01; study 2: 3 h 72.1 +/- 2.4 versus 6 h 81.7 +/- 1.4%, P < 0.01). There was no significant difference in recovery between studies 1 and 2. 3. These results suggest that increased recovery during a sequential euglycaemic clamp is predominantly time-dependent. Studies which use this technique to examine the effect of insulin on substrate oxidation should take this into account. PMID- 7834991 TI - Metabolic abnormalities in skeletal muscle after myocardial infarction in the rat. AB - 1. The effect of experimental myocardial infarction on exercise and recovery of rat skeletal muscle was studied using 31P n.m.r. 4 weeks post-operatively. 2. Myocardial infarction (12 +/- 3% of left ventricular volume), insufficient to produce haemodynamic manifestations of heart failure, was without significant effect on exercise bioenergetics of skeletal muscle. 3. Citrate synthase activity was reduced by 17% in the infarcted animals and there was a marked slowing of the rate of phosphocreatine recovery after infarction (half-time 0.7 +/- 0.1 min to 1.6 +/- 0.2 min) in the absence of evidence of left ventricular failure or hypertrophy. 4. The study of recovery bioenergetics could provide a more sensitive measure of mitochondrial function than exercise, where no bioenergetic abnormality was detected. 5. Myocardial infarction can produce evidence of mitochondrial abnormality in skeletal muscle in the absence of haemodynamic compromise. PMID- 7834994 TI - Glomerular charge selectivity in primary glomerulopathies. AB - 1. Glomerular charge selectivity was assessed using the ratio of the clearance of pancreatic isoamylase to the clearance of the more anionic salivary isoamylase (CPAm/CSAm) in 53 patients with primary glomerulopathies (minimal change nephropathy, idiopathic membranous nephropathy, IgA nephropathy) and a wide range of albumin excretion rates and in 31 healthy subjects. Fractional clearances of pancreatic and salivary isoamylases (FCPAm, FCSAm) and of albumin (FCAlb) were also measured. 2. CPAm/CSAm and FCPAm were negatively correlated with FCAlb for the whole patient group (rs = -0.56 and rs = -0.65, respectively, P < 0.0001 for both), but there was no correlation of FCSAm with FCAlb. 3. For patients with near-normal albumin excretion rates (< 100 mg/24 h), there was no difference in CPAm/CSAm between the three types of glomerulopathy or between patients and healthy subjects. 4. These data suggest that glomerular charge selectivity at the size of amylase (which is smaller than albumin) is progressively lost as albuminuria increases from normal to the nephrotic range. Size restriction progressively increases until albuminuria is very heavy. When the albumin excretion rate is near normal, charge selectivity is also normal in the three main forms of primary glomerulopathy. PMID- 7834996 TI - Restoration by corticosteroids of the hyperaldosteronism in hyponatraemic rats with panhypopituitarism. AB - 1. In the syndrome of inappropriate secretion of antidiuretic hormone, hyponatraemia is associated with a normal bicarbonate concentration despite dilution. This normal bicarbonate concentration is related to the development of a hyperaldosteronism, which is attributed to a direct stimulation of the zona glomerulosa by the hyponatraemic state. Some workers have suggested that, to develop this hyperaldosteronism requires the presence of a pituitary factor. To determine whether the pituitary gland plays a role in this hyponatraemia-induced hyperaldosteronism, water intoxication was performed for 24 h in normal and in panhypopituitaric rats. 2. In normal rats, hyponatraemia (108 mmol/l), induced by the administration of 1-desamino-8-D-arginine vasopressin and 2.5% D-glucose 0.45% NaCl by gavage (15% body weight) was associated with a mild increase in bicarbonate concentration, and blood acid-base equilibrium showed a mixed metabolic and respiratory alkalosis (pH 7.57, partial pressure of CO2 29 mmHg, base excess +5.5 mmol/l), and aldosterone concentration was increased 3-fold as compared with the control value. When hyponatraemia (110 mmol/l) was induced in a similar manner in panhypopituitaric rats, we observed a very low aldosterone concentration (< 50 pg/ml) and a compensated respiratory alkalosis (pH 7.45, partial pressure of CO2 30 mmHg, base excess -2.6 mmol/l). The restoration of a hyperaldosteronaemic state in this group of rats was related essentially to corticosteroid intake. 3. These data suggest that corticosteroids play a critical role in the development of hyponatraemia-related hyperaldosteronism, a phenomenon not necessarily dependent on a pituitary factor. PMID- 7834995 TI - Role for endothelin in the renal responses to radiocontrast media in the rat. AB - 1. The involvement of endothelin in the renal responses to radiocontrast media was examined in the rat in vitro and in vivo using BQ123, a selective endothelin (ETA) receptor antagonist, and phosphoramidon, an endothelin-converting enzyme inhibitor. 2. For experiments in vitro, an isolated perfused rat kidney was employed perfusing in closed circuit with an albumin-based Krebs-Henseleit solution. The effects of BQ123 and phosphoramidon on the renal responses to iotrolan (iso-osmolar radiocontrast media) and diatrizoate (high-osmolar radiocontrast media) were examined. In vivo, renal conductance was measured using a Doppler flow probe in the anaesthetized rat pretreated with indomethacin, and the effects of BQ123 and phosphoramidon on the renal response to intravenous diatrizoate were examined. 3. In vitro, iotrolan and diatrizoate both produced a biphasic effect on the glomerular filtration rate, characterized by a transient increase followed by a sustained fall. Pretreatment with BQ123 (10 mumol/l), but not phosphoramidon (1 mmol/l), prevented both the increase and the sustained fall in glomerular filtration rate induced by radiocontrast media. 4. In vitro, iotrolan and diatrizoate both produced a sustained fall in renal perfusate flow. An initial increase in renal perfusate flow was only observed with diatrizoate. Pretreatment with BQ123 (10 mumol/l), but not with phosphoramidon (1 mmol/l), markedly inhibited the sustained fall in renal perfusate flow produced by both iotrolan and diatrizoate. BQ123 (10 mumol/l), however, markedly potentiated the renal vasodilatation produced by diatrizoate.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7834997 TI - Fatty acid synthesis by rat liver after chronic ethanol feeding with a low-fat diet. AB - 1. Chronic alcohol feeding with a low-fat diet (4.4% total calories) produced a two- to three-fold increase in hepatic triacylglycerol and esterified cholesterol compared with pair-fed low-fat diet controls. Plasma lipids were similar in both groups. 2. Hepatic fatty acid synthesis rates measured in vivo with 3H2O were significantly lower in the alcohol-fed animals than in controls. Activities of hepatic fatty acid synthase (EC 2.3.1.85) and acetyl-CoA carboxylase (EC 6.4.1.2) were reduced in the alcohol-fed rats. 3. These results indicate that enhanced hepatic fatty acid synthesis does not occur in rats fed alcohol and a low-fat diet for 4 weeks, and is thus not implicated in the pathogenesis of alcohol induced fatty liver. PMID- 7834998 TI - Plasma endogenous digoxin-like substance levels are dependent on blood O2 in man. AB - 1. Recently, we have demonstrated that hypoxic breathing is followed by an increase in plasma digoxin-like substance in normal men. 2. This study was undertaken in order to evaluate whether or not a low arterial O2 partial pressure is combined with an increase in plasma digoxin-like substance in chronic pathological conditions also. 3. Sixteen male patients (mean age 53.1 +/- 3.7 years) affected by chronic obstructive pulmonary disease of a mild stage were studied. They were further subdivided according to their arterial O2 partial pressure into 'mild hypoxic' (n = 8, mean age 52.5 +/- 2.7 years), with an arterial O2 partial pressure between 66 and 75 mmHg, and 'severe hypoxic' (n = 8, mean age 54.3 +/- 5.1 years), with an arterial O2 partial pressure < or = 65 mmHg, groups. Seven healthy men (mean age 48.5 +/- 4.8 years) voluntarily participated as the control group. 4. Plasma digoxin-like substance levels were significantly higher in 'severe hypoxic' patients (203.5 +/- 9.9 pg/ml) than in both 'mild hypoxic' patients (169.5 +/- 31.4 pg/ml, P < 0.02) and normal subjects (158.9 +/- 12.4 pg/ml, P < 0.0001) and were directly correlated with urinary Na+ excretion (severe hypoxic group, r = 0.756, P < 0.007; mild hypoxic group, r = 0.789, P < 0.02). Considering the two hypoxic groups together, plasma digoxin like substance levels were negatively correlated with arterial O2 partial pressure (r = -0.740, P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7834999 TI - Intraluminal colonic release of immunoreactive tumour necrosis factor in chronic ulcerative colitis. AB - 1. Tumour necrosis factor is a proinflammatory macrophage-derived polypeptide cytokine. Its participation in disease processes has been usually inferred from data obtained from experiments in vitro or from measurements of its plasma circulating levels. To investigate its role in chronic ulcerative colitis, we have quantified in vivo the steady-state release of tumour necrosis factor into the colonic lumen. 2. We studied 19 patients with untreated active ulcerative colitis and seven patients with irritable bowel syndrome as controls. A group of seven patients with active ulcerative colitis were studied before and after 4 weeks on treatment with oral 5-aminosalicylic acid. By means of an intracolonic double-lumen perfusion tube, an isotonic solution was continuously infused 50 cm from the anal verge at a rate of 5 ml/min, and was recovered 30 cm distally by siphonage. Effluents were assayed for tumour necrosis factor by a specific e.l.i.s.a. and for prostaglandin E2 and leukotriene B4 by specific r.i.a.s. 3. The intracolonic release of tumour necrosis factor was undetectable in patients with irritable bowel syndrome, whereas measurable release occurred in 15 out of 19 patients with active ulcerative colitis (P < 0.01). Prostaglandin E2 and leukotriene B4 release were also increased in active ulcerative colitis by comparison with irritable bowel syndrome (P < 0.01). Five out of seven patients with colitis improved with 5-aminosalicylic acid treatment, and tumour necrosis factor release became undetectable or decreased markedly (P < 0.05 compared with before treatment). However, tumour necrosis factor release remained high in the non-responder patients. 4. These findings indicate that intracolonic immunoreactive tumour necrosis factor release is enhanced in active chronic ulcerative colitis, becoming undetectable when mucosal lesions are healed. These results suggest that the luminal release of tumour necrosis factor may serve as an objective index of inflammatory activity in patients with chronic ulcerative colitis. PMID- 7835000 TI - Model for whole body production of tumour necrosis factor-alpha in experimental endotoxaemia in healthy subjects. AB - 1. Tumour necrosis factor-alpha is considered an important mediator in the pathophysiology of several diseases. Although much information is available about the serum concentrations of this cytokine in these illnesses, little is known about the production of tumour necrosis factor-alpha in disease in vivo. 2. In the present study we aimed to estimate the extent and the kinetics of whole body tumour necrosis factor-alpha synthesis in experimental endotoxaemia in six healthy humans. For this purpose we first examined the pharmacokinetic behaviour of an intravenously injected bolus of recombinant human tumour necrosis factor alpha (50 micrograms/m2) in another group of six normal subjects. We then calculated the total amount of tumour necrosis factor-alpha produced after intravenous injection of endotoxin (2 ng/kg) as the product of the systemic clearance of recombinant human tumour necrosis factor-alpha (9.5 +/- 5.0 ml min-1 kg-1) and the area under the tumour necrosis factor-alpha concentration-time curves in the endotoxaemic subjects. 3. Recombinant human tumour necrosis factor alpha showed evident two-compartment kinetics with an initial rapid disappearance (t1/2 5.1 +/- 2.2 min) and a terminal slower elimination (t1/2 49 +/- 5 min). Tumour necrosis factor-alpha synthesis after endotoxin varied markedly between individuals, ranging from 11.8 to 114.1 micrograms (52.7 +/- 34.7 micrograms). The changes in time of the serum concentrations of tumour necrosis factor-alpha after administration of endotoxin could be accurately described with an adapted two-compartment open model that incorporated both rapid tumour necrosis factor alpha production (74% of the total amount) and slow tumour necrosis factor-alpha production (26%).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7835001 TI - Colorado's female smokers have more underweight babies. PMID- 7835002 TI - Corporate practice of medicine. No longer "When?" but "How?". PMID- 7835003 TI - IME rules: interference or insurance? PMID- 7835004 TI - Clinical correlation of anticentromere antibodies. AB - A retrospective survey of all patients with a positive anticentromere antibody (ACA) determination was undertaken over a 3-years period of time in a university hospital. Forty-five patients were positive for anticentromere antibodies. The analysis of the clinical characteristics and diagnoses of the patients with anticentromere antibodies were correlated and showed a diverse array of symptoms. Only 4.4% had CREST syndrome, 6.7% had limited scleroderma, 17.8% had diffuse scleroderma, 20% had other connective tissue diseases, 20% had other miscellaneous rheumatic conditions, 11.1% had tumours and 20% other nonrheumatic diseases. The study shows that the presence of ACA, as detected during routine ANA-testing, does not strongly suggest a diagnosis of CREST at that time. The presence of a scleroderma-variant in almost 50% of the patients and the occurrence of Raynaud's phenomenon in 62% underscores, however, an association of ACA with (early) scleroderma-like disorders. PMID- 7835005 TI - Reduced sulphoxidation capacity in D-penicillamine induced myasthenia gravis. AB - Myasthenia gravis may be observed due to treatment with penicillamine (D-PA). The sulphoxidation capacity was measured in nine Swedish patients with rheumatoid arthritis (RA) who had developed myasthenia gravis toward D-PA. The results show that in eight of nine patients tested, this parameter was markedly reduced. A patient with poor sulphoxidation capacity has a twelve-fold greater risk of developing this rare side effect. The significance of this is discussed. PMID- 7835006 TI - Sjogren's syndrome in Israel: primary versus secondary disease. AB - Sixty Israeli patients, 30 with primary Sjogren's syndrome (SS) and 30 with rheumatoid arthritis (RA) and secondary SS, were evaluated. The Schirmer-1 test and a positive labial salivary gland biopsy were found to be the most helpful tools in assessing the diagnosis of SS. Extraglandular features such as Raynaud's phenomenon, lymphadenopathy and CNS involvement as well as parotid gland enlargement (p < 0.05) were more common in primary SS. Antinuclear antibodies, especially anti-Ro (SSA) and anti-La (SSB) were also more common in primary SS (p < 0.05). Our results are in accord with those of many European centers, despite the different genetic background. PMID- 7835007 TI - Cold-induced vasospasm in patients with fibromyalgia and chronic low back pain in comparison to healthy subjects. AB - Using capillary videomicroscopy of the nail fold, the frequency of cold-induced vasospasm and capillary hemodynamic parameters were studied after application of cold in 50 patients with primary fibromyalgia, 50 patients with chronic low back pain, and 50 healthy controls. Cold-induced vasospasm was detected in 38% of the patients with fibromyalgia. In this group it was significantly more frequent than in the patients with chronic low back pain (20%, p < 0.05) and healthy subjects (8%, p < 0.001). In the fibromyalgia group, the magnitude of vasospasm as measured by the capillary blood flow deceleration after cold application correlated negatively with the pain intensity as measured by pain score (r = 0.3839, p < 0.01). No differences in clinical appearance were found between patients with and without cold-induced vasospasm in both the fibromyalgia and low back pain group. PMID- 7835008 TI - Additive two DMARD therapy of the patients with rheumatoid arthritis. AB - From the beginning of 1987 to the end of 1989, 72 rheumatoid arthritis patients (RA) whose disease could not be controlled by a single disease modifying antirheumatic drug (DMARD) were selected for the trial treatment. They continued the DMARD treatment used initially at its regular dose, and then started another DMARD regimen at 1/3 to 1/2 of the regular dose as an additive DMARD treatment, which we have designated as Additive Two DMARD Therapy (ATDT). The patients were followed until the end of 1992. In the 3 months of ATDT, the effectiveness of ATDT was obtained in 42 (58.3%) patients who showed more than a 30% decrease in the initial Lansbury's activity index (AI). The rate of side effects at 3 months were 5.6%. Tiopronin, bucillamine or salazopirine added to gold sodium thiomalate or tiopronin were suggested as the recommended DMARD combinations for ATDT. The suppressive effects on AI, ESR, CRP and rheumatoid factor continued for as long as 18 to 24 months. The mean period of ATDT was 21.7 months and that at which ATDT proved useful was 31.9 months. A discontinuation of the first DMARD treatment without any following disease aggravation was obtained in 10 of 15 patients whose disease activity had been sufficiently suppressed for longer than a year. In conclusion, ATDT was suggested to be a useful way of treating RA patients whose disease activity could not be controlled by a single DMARD treatment, as well as a way of evaluating the next DMARD while the ongoing DMARD was observed to gradually lose its initial drug effect. PMID- 7835009 TI - Clinical experience with etidronate in osteoporosis. AB - Clinical experience with cyclical etidronate for the treatment of osteoporosis was reviewed in 69 consecutive patients. Six patients stopped treatment either due to adverse effects (5) or the decision to take hormone replacement therapy (HRT) (1). Bone mineral density (BMD) measurements using dual energy X-ray absorptiometry (DXA) were obtained in 63 patients (33 with spinal osteoporotic fractures and 30 with osteopenia) before and 1 year after treatment. BMD increased by an average of 4.50% (p < 0.001) in the lumbar spine (range +14% to 12%) and 5.5% (p < 0.01) at Ward's triangle (range +31% to -13%) while there was no significant change at the femoral neck (range +11% to -12%) and greater trochanter (range +12% to -15%). Significant rises in BMD were found at the lumbar spine and Ward's triangle in both osteoporotic and osteopenic groups. Of patients analysed after 1 year, 83% had an increased bone mass at the lumbar spine and 55% at the femoral neck. We conclude that there is a wide variation in the bone mass response to cyclical etidronate therapy, and in a minority of patients bone mass does not increase. For the majority of osteoporotic patients, however, we confirm the efficacy and tolerability of cyclical etidronate for the preservation of bone mass over 1 year in a clinical setting. PMID- 7835010 TI - Involvement of atlanto-axial joint in rheumatoid arthritis: rare or frequent? AB - The authors studied the incidence of atlanto-axial joint involvement by conventional radiography and CT in 183 patients with classical or definite rheumatoid arthritis (RA). In determining lesions the significance of factors such as age, sex, duration and severity of the disease was evaluated. Atlanto axial subluxations turned out to be quite frequent (30%) in the series of patients examined and were directly correlated with age, duration and stage of the disease, and extraarticular manifestations. Clinical symptoms were evident in only 70.9% of cases, confirming the correlation reported by other authors between clinical manifestations and radiologically observed lesions. Traditional radiography performed in the dynamic position revealed a prevalence of anterior subluxation, whereas CT gave a precise indication of the entity and type of atlanto-axial lesion. In conclusion, the authors confirm the importance of such investigations in all patients with RA, even those without evident clinical manifestations. They also emphasize the necessity of periodic monitoring in view of the possible risk of mortality in these patients. PMID- 7835011 TI - Lymphoedema of the limbs in rheumatoid arthritis. AB - The lymphoedema of the extremities is a rare complication of rheumatoid arthritis (RA); it does not appear to be correlated with positivity for rheumatoid factor nor with the clinical activity of the disease. The authors describe 6 cases of lymphoedema in patients affected by RA; in 3 of them the lymphoedema was localized in the upper and in the remaining cases in the lower limbs. Four patients, (one of whom has been subjected to a lymphoangiography which demonstrates an obstruction of the deep lymphatics), presented an increase of the plasma fibrinogen degradation products (FDP). This could confirm the hypothesis according to which the lymphoedema could be attributable to an obstruction of the lymphatics caused by fibrin and other degradation products of the coagulation system. In one case the authors underscore the therapeutic effectiveness of lymphodrainage associated with administration of diuretics. PMID- 7835012 TI - Tender points or tender patients? The value of the psychiatric in-depth interview for assessing and understanding psychopathological aspects of fibromyalgia. AB - Although the aetiology of fibromyalgia is still unexplained, evidence favouring the role of psychopathology is accumulating, at least in a subgroup of patients; however, the exact aetiological significance of psychopathology in this syndrome is difficult to assess. Various assessment strategies have both strengths and weaknesses. Two case reports are presented which illustrate the value of the psychiatric in-depth interview (including psychodynamic-biographical history taking) for assessing and understanding psychological/psychiatric aspects of fibromyalgia. PMID- 7835013 TI - Vegetarian diet for patients with rheumatoid arthritis--status: two years after introduction of the diet. AB - We have previously reported that a significant improvement can be obtained in rheumatoid arthritis patients by fasting followed by an individually adjusted vegetarian diet for one year. The patients who changed their diet could be divided into diet responders and diet nonresponders. After the clinical trial the patients were free to change diet or medication and after approximately one year they were asked to attend a new clinical examination. We compared the change from baseline (i.e. at the time of study entry) to the time of the follow-up examination for diet responders, diet nonresponders and controls who ate an omnivorous diet. The following variables favoured diet responders: pain score, duration of morning stiffness, Stanford Health Assessment Questionnaire index, number of tender joints, Ritchie's articular index, number of swollen joints, ESR and platelet count [corrected]. The difference between the three groups were significant for all the clinical variables, except for grip strength. There was no significant difference between the groups with regard to laboratory or anthropometric variables. At the time of the follow-up examination all diet responders but only half of the diet nonresponders still followed a diet. Our findings indicate that a group of patients with rheumatoid arthritis benefit from dietary manipulations and that the improvement can be sustained through a two year period. PMID- 7835014 TI - Rheumatoid arthritis is not associated with prior tonsillectomy or appendectomy. AB - To re-evaluate a reported association of rheumatoid arthritis (RA) with antecendent tonsillectomy or appendectomy, questionnaires were sent by post to 3673 patients who had been diagnosed as having either RA or osteoarthrosis (OA). Of those who responded 1524 were RA and 1194 OA patients. No significant differences were found between these groups with regard to the frequency of prior lymphoid surgery. This was also the case when the RA group was replaced by its rheumatoid factor (Rf) positive or Rf negative subgroup. A separate analysis of a subgroup consisting of 671 Rf positive RA patients for whom OA control subjects matched for sex and year of birth were available again showed no statistical differences in frequencies of tonsillectomy and appendectomy. Neither did partitioning the group according to the age at which lymphoid surgery was performed bring any association with an increased occurrence of RA to light. We therefore reject the hypothesis that RA is associated with antecedent tonsillectomy or appendectomy. PMID- 7835015 TI - Prediction of radiographic damage in hands and feet in rheumatoid arthritis by clinical evaluation. AB - Radiography of hands and feet is a standard measure of outcome in rheumatoid arthritis. We hypothesised that this radiological information can be reproduced by clinical evaluation. A rheumatologist examined 78 patients with rheumatoid arthritis and tried to predict the radiological Larsen score, for the proximal interphalangeal (PIP), metacarpophalangeal (MCP), wrist, ankle, and metatarsophalangeal (MTP) joints. Spearman correlation between clinical Larsen and X-ray Larsen was 0.79 for hands and 0.66 for feet. There was no significant difference in scores for PIP, MCP, wrists, or ankles, but MTP joints were underscored by clinical Larsen relative to X-ray Larsen (median of 20 vs 22 respectively, p = 0.04). Categorical data for index finger MCP joints showed significant proportional agreement of 37% (Kappa 0.24, p < 0.0001). In conclusion, the Larsen X-ray score can be predicted by clinical examination with surprising accuracy in the small hand joints but less so in the feet. Although the favourable agreement shown in this study does not make X-rays redundant, we suggest that clinical examination of the hands should be further refined and standardised as a measure of outcome. PMID- 7835016 TI - A method for classification of the posterior atlanto-axial subluxation. AB - Atlanto-axial subluxation and dislocation in rheumatoid arthritis is a multidirectional abnormality. The most common subluxations take place anteriorly, vertically or laterally. Posterior atlanto-axial subluxations are rare. The distance between a line tangential to the anterior aspect of the axis (C2) and the most posterior aspect of the anterior arch of the atlas (C1) could be used to measure the displacement in posterior atlanto-axial subluxation. Routine measurement of this distance could give us a better idea of the frequency of this type of affection in rheumatoid arthritis of the cervical spine. Serial measurements might be used to estimate the progression of the disease. PMID- 7835017 TI - Evaluation of the 1st EULAR Pan-European postgraduate course rheumatology Leuven 12-18 September 1993. PMID- 7835018 TI - Klinefelter's syndrome and rheumatoid arthritis. Report of a case and review of the literature. AB - Our case report describes a patient with Klinefelter's syndrome (KFS) associated with rheumatoid arthritis (RA). He had active RA in 1985 but his arthritis almost subsided in 1993 without intensive treatments for RA as well as KFS. Recently, the lower levels of testosterone in male RA patients, especially at the active phase has been reported. However, it is still questionable whether hypogonadism is a predisposing factor or just a consequence of disease. Since our case had a mild clinical course, and since the incidence of RA associated with KFS is very rare in comparison with other rheumatic diseases, may suggest that the low levels of testosterone are not a predisposing factor to the activity of RA. PMID- 7835019 TI - Bilateral pleural effusion in a patient with urticarial vasculitis. AB - A 32-year-old woman with a 6-year history of urticaria, acute anterior uveitis and mesangial glomerulonephritis developed bilateral pleural effusion. A thorough laboratory workup during repeated attacks of concomitant urticaria and bilateral pleural effusion together with the histopathological finding of the skin biopsy revealed normocomplementemic leukocytoclastic vasculitis. Bilateral pleural effusion should be included in the clinical spectrum of urticarial vasculitis syndrome. PMID- 7835020 TI - Sternoclavicular septic arthritis: a rare but serious complication of subclavian venous catheterization. AB - Sternoclavicular septic arthritis is a rare complication of subclavian venous catheterization. We estimate that septic involvement of this joint may be as common as one in 500 catheterizations. We report two patients with insidious onset of shoulder pain, chest discomfort, low-grade fever and slight but painful swelling of a sternoclavicular joint four weeks following subclavian venous catheterization. Positive blood cultures in the presence of abnormal bone scan and abnormal conventional X-ray examination or computed tomography of the sternoclavicular joint led to the diagnosis of septic arthritis. Both patients responded well to antibiotic treatment. Based on our observations and that reported in the literature, the earliest changes of sternoclavicular septic arthritis may be detected by bone scan while plain X-ray studies and CT become abnormal during advanced stages of this type of arthritis. We would like to alert physicians to this cause of fever and joint pain in patients who previously underwent subclavian venous catheterization. PMID- 7835021 TI - Percutaneous vertebroplasty with acrylic cement in the treatment of a Langerhans cell vertebral histiocytosis. AB - A 25-year-old man developed multiple eosinophilic granuloma of bone including vertebral and sacral localization. Radiotherapy was initially administered. One year later, a relapse occurred in another vertebrae which was previously irradiated. Percutaneous vertebroplasty was, for the first time to our knowledge performed, in this indication, with a good clinical result with follow-up now for one year. We emphasize that such treatment is permissible only in symptomatic, progressive lesions, with threatened decompensation of spinal stability. This technique should be used only on an adult. PMID- 7835022 TI - Combination therapy for rheumatoid arthritis and drug-induced systemic lupus erythematosus. AB - Development of drug-induced systemic lupus erythematosus (SLE) is an uncommon complication of the use of D-penicillamine and sulphasalazine. We report two cases of patients with rheumatoid arthritis (RA) who developed symptoms and signs of SLE and suggest that increasing use of these two agents as combination therapy in RA may cause an additive risk to the occurrence of this complication. PMID- 7835023 TI - Pulmonary amyloidosis and unusual lung involvement in SLE. AB - The association of systemic lupus erythematosus (SLE) with amyloidosis is exceptional. We present a 37-year-old patient who was diagnosed five months earlier for SLE. She developed an acute episode of chest pain, cough and dyspnoea. Hypoxemia and obstructive changes in respiratory tests were present. The chest X-ray was repeatedly normal. Open lung biopsy revealed lupus pneumonitis with positive stain for immunoglobulins and complement, bronchiolitis obliterans, and pulmonary amyloidosis. PMID- 7835024 TI - Eosinophilic hepatitis: a new feature of the clinical spectrum of the eosinophilia-myalgia syndrome. AB - The eosinophilia-myalgia syndrome associated with L-tryptophan-containing products is highlighted by eosinophilia, incapacitating myalgias, and diverse multisystemic manifestations. In addition to involvement of the skin, skeletal muscle, and peripheral nerves, visceral damage has been quite prominent, particularly affecting the lungs, the heart, and the liver. Hepatic involvement has been manifested by altered liver tests but is clinically silent. We report the unique case of a woman with this syndrome who developed abdominal pain, a clinical picture of hepatitis and chronically abnormal liver tests. Histologic examination of the liver disclosed eosinophilic hepatitis with piecemeal necrosis. The occurrence of clinically overt hepatic involvement has not been reported previously. Potential mechanisms of liver damage in eosinophilia-myalgia syndromes are discussed. PMID- 7835025 TI - Coexistence of spinal arteriovenous malformation and ankylosing spondylitis--are they related? AB - A 50-year-old man with long standing ankylosing spondylitis developed cauda equina syndrome, which was found to be coexistent with a spinal arterio-venous malformation. Paraplegia ensured following an acute exacerbation of back pain along with an attack of uveitis. Vasculitis changes were found on resected abnormal vessels. PMID- 7835026 TI - The benign long-term effect of cholesterol crystal synovial cysts. AB - Synovial effusions containing cholesterol crystals are uncommon. Most of the few reported cases have been found in patients with seropositive rheumatoid arthritis. In vitro studies, as well as an animal model, have suggested that cholesterol crystals could have a role in inflammation of the joints. In this report we present a case of seronegative arthritis, complicated by large carpal synovial cysts which contained numerous cholesterol crystals. The long-term presence of the cysts, without evidence of joint destruction, suggests that cholesterol crystal formation is probably a rare epiphenomenon, rather than a harbinger of inflammation. PMID- 7835027 TI - Breast granuloma and C.R.S.T. syndrome. AB - One case of CRST syndrome with breast granuloma is presented. The presumed diagnosis were infectious or neoplastic diseases. High doses of corticosteroids led to improvement in breast nodules. PMID- 7835028 TI - Syndrome of limited joint mobility (SLJM) in diabetic patients. PMID- 7835029 TI - The Hong Kong adult health survey, 1991. PMID- 7835030 TI - The Hong Kong adult oral health survey--1991: background, study population, and methods. AB - This second adult oral health survey was conducted with the following main aims: 1) to describe the oral health conditions and to analyse the oral health care needs and demands of 65-74-yr-olds in Hong Kong, and to propose appropriate strategies for meeting their needs in the light of societal obligations; 2) to describe the oral health conditions and to analyse the oral health care needs and demands of 35-44-yr-olds in Hong Kong with special emphasis on assessment of changes in this age group since 1984 (when the first adult oral health survey was conducted); 3) to assess the impact of sociodemographic and dental care system factors on the oral health status of selected adult age groups: and 4) to utilize survey data to refine curriculum development and research strategies in the Faculty of Dentistry, as well as in the proposal of appropriate action to governmental committees on dental health policy. For enhanced comparability with the previous study, the 35-44-yr-olds were selected from the same geographic areas of Hong Kong Island. Multistage cluster sampling was used to recruit the study population, defined geographic units and addresses being used as the starting-point. A sample of 398 subjects was selected, of whom 93% were both interviewed and clinically examined. The 65-74-yr-olds were recruited from housing estates in all principal areas of Hong Kong, yielding a sample of 559 subjects, of whom 96% were both interviewed and clinically examined.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7835031 TI - Dental health knowledge and attitudes among the middle-aged and the elderly in Hong Kong. AB - Previous studies on adult Hong Kong Chinese have indicated that their level of knowledge of and attitudes toward dental health might be a potential barrier to effective oral preventive efforts. The knowledge and attitudes of elderly Chinese have not previously been studied. The objectives of this study were to describe Hong Kong adults' knowledge of the causes of the two main oral diseases, caries and periodontal disease, and possible preventive measures, and to analyse possible relationships between knowledge and attitudes and selected sociodemographic and utilization variables. Two populations aged 35-44 yr (n = 398) and 65-74 yr (n = 559) were selected for the study, which was conducted as structured interviews. A knowledge score was constructed from questions on caries and periodontal disease development and prevention. Attitudes were measured in the younger group by beliefs and evaluations of those beliefs according to the theory of reasoned action (the higher the score, the more positive the attitude). Knowledge scores were almost normally distributed in the younger respondents, but were heavily skewed toward 0 in the older group. In both age groups, increased level of education and regularity or recency of dental visits were strongly associated with dental knowledge. Women, regular dental care users, and prevention-oriented respondents had higher attitude scores. There was no correlation between knowledge and attitudes. Some improvement in knowledge seems to have taken place, especially on the cause of caries, with fewer 35-44-yr-old respondents claiming lack of knowledge of the causes of caries and gum disease than in a previous study.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7835032 TI - Chinese health beliefs and oral health practices among the middle-aged and the elderly in Hong Kong. AB - The purpose of this paper was to study possible relationships between traditional Chinese health beliefs and health practices in adult Chinese in a modernized society. The study populations comprised 398 35-44-yr-old and 559 65-74-yr-old Hong Kong Chinese. The respondents were categorized into three groups with weak, moderate, or strong Chinese beliefs on the basis of interview questions on the causes of gum disease. Chinese preventive practices and Chinese pain practices were defined according to respondents' reported use of recommended traditional cures. Questions on generally accepted oral practices were phrased in terms of frequency of daily brushing of teeth, use of toothpicks the previous day, and whether or not teeth were flossed the previous day. Around one-third of the respondents had weak, almost one-half had moderate, and around one-quarter expressed strong Chinese health beliefs. No significant differences in Chinese health beliefs were found between men and women in either age group, or between the age groups. In the 35-44 age group, more of those with a higher education were in the "weak" Chinese health belief category, whereas, conversely, more of those with a lower education expressed stronger Chinese health beliefs (P < 0.05). Women in both age groups reported significantly more frequent brushing. Toothpicks were used by around three-quarters of both age groups, but flossing was extremely rare.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7835033 TI - Attitudes toward dentists and the dental care system among the middle-aged and the elderly in Hong Kong. AB - A sample of 398 35-44-yr-old and 559 65-74-yr-old Hong Kong Chinese were interviewed by trained interviewers using a structured questionnaire in an oral health survey conducted in 1991. The present analysis aimed to describe the dental-care-seeking behaviour and attitudes of these subjects. It was found that 43% of the younger and 23% of the older age group had visited a dentist within the past year. More than half of the elderly and a quarter of the adults had not been to a dentist for 3 yr or more, and the main reason given by these subjects was that they felt that nothing was wrong. The vast majority of the subjects consulted a dentist only when they had toothache or other dental problems. Less than 20% of the 35-44-yr-olds visited a dentist for a check-up or teeth cleaning, and these subjects were described as having a prevention-oriented attitude toward oral care. The result of a logistic regression analysis showed that there was a higher chance for subjects to have this attitude if they had dental programme coverage, perceived their teeth to be good, had better dental health knowledge, had a more positive dental attitude, and were less anxious about dental care. However, the influence of these factors was quite weak, because the overall percentage of correct classification of the model was 83.7% and the sensitivity was only 23.3%. PMID- 7835034 TI - Use of dental services by the middle-aged and the elderly in Hong Kong. AB - The objectives of this analysis were to describe the dental service use pattern of the 35-44- and 65-74-yr-old age groups and to determine to what extent this pattern could be explained by selected sociodemographic and attitudinal variables. The study populations comprised 398 35-44-yr-old and 559 65-74-yr-old Hong Kong Chinese. Use of dental services was determined on the basis of the respondents' own perception of the regularity of their dental visits and by the time since the last dental visit. The younger groups was categorized into regular users, irregular users, and nonusers, and the older group was categorized into three groups according to last dental visit (within 2 yr, 2-5-yr, 5 yr or more). A modification of the Andersen and Newman model for individual determinants of health care use was used as the framework for a logistic regression analysis. Predisposing variables were sex, education, occupation, attitudes, knowledge, preventive orientation, and dental anxiety; enabling variables were Family Possession Index, income, family support and access to a dental programme; need variables were perceived conditions of teeth, dental problems, dental pain, need for treatment, normative need for treatment, and denture wearing. In general, use of dental services was low. For the 35-44-yr-olds, the best regression model (sensitivity: 62%, specificity: 95%, overall correct classification: 88%) indicated that there was an increased probability of having a regular dental care pattern if respondents were prevention oriented, had access to a dental benefit programme, had not experienced pain, had a higher income, perceived their teeth as fair or poor, and perceived a need of treatment.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7835035 TI - Tooth and root conditions in the middle-aged and the elderly in Hong Kong. AB - In an oral health survey of Hong Kong Chinese conducted in 1991, a sample of 372 35-44-yr-olds and 537 noninstitutionalized 65-74-yr-olds were interviewed and clinically examined. The examination procedures, instruments, and diagnostic criteria used to detect coronal caries followed those recommended by the World Health Organization (1987). The diagnostic criteria used to assess root-surface caries were based on those used in a national oral health survey of US employed adults (National Institute of Dental Research, 1987). Calibration of examiners was conducted before the survey and the interexaminer reliability was found to be very high; the kappa statistics were 0.93 and 0.91 for the younger and older age groups, respectively. None of the 35-44-yr-olds were edentulous and 96% had 21 teeth or more. The prevalence of edentulousness among the elderly was 12%. The DMFT indices of the younger and older age groups were 8.7 and 18.9, respectively. In both age groups, MT was the major component of the DMFT index, and female subjects had a slightly higher score. The prevalences of decayed/filled roots were 7% and 26% for the 35-44- and 65-74-yr-olds, respectively. As compared with previous surveys conducted in Hong Kong, there has been a 40% reduction in the DMFT index of the 35-44-yr-olds since 1968, but little change in the tooth and root conditions was noted between 1984 and 1991. PMID- 7835036 TI - Tooth spaces in and prosthetic treatment received by the middle-aged and the elderly in Hong Kong. AB - The purpose of this study was to describe the state of the dentition of middle aged and elderly Chinese in Hong Kong in terms of teeth present, tooth spaces, and prosthetic treatment received. In an oral health survey conducted in 1991 in Hong Kong, a sample of 372 35-44-yr-olds and 537 noninstitutionalized 65-74-yr olds was interviewed and clinically examined. In all dentate subjects, each tooth was scored for the presence/absence of that tooth, a tooth space of 5.5 mm which had not been treated, or the presence of a denture or pontic replacing that tooth. Each denture was assessed according to a set of criteria. None of the 35 44-yr-olds were edentulous and the mean number of teeth present was 27.5. About 40% of the third molars and about 35% of the mandibular first molars were missing. For only 1% of the missing teeth had space closure resulted in missing teeth not being recorded as tooth spaces or treated tooth spaces. Overall, 72% of the 35-44-yr-olds had no prosthesis, 17% had a bridge or bridges, 12% had a denture or dentures, and 1% had both. Of the 65-74-yr-olds, 12% were edentulous, and the dentate subjects had a mean number of 17 teeth present. About 70% of the molars were missing. Overall, only 29% of the elderly had no prosthesis, 52% had a denture or dentures, 33% had a bridge or bridges, and 13% had both. Only 35% and 28%, respectively, of the middle-aged and elderly denture wearers had no complaint about their dentures.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7835037 TI - Oral mucosal lesions in 65-74-year-old Hong Kong Chinese. AB - There have been no reported surveys of oral mucosal lesions among the elderly in Asian countries. Therefore, the purpose of this study was to determine the prevalence of oral mucosal lesions among 65-74-yr-old, community-dwelling elderly Chinese in Hong Kong and to determine the prevalence of lesions in denture wearers, tobacco smokers, and alcohol drinkers. A total of 537 noninstitutionalized 65-74-yr-olds were interviewed and clinically examined in an oral health survey conducted in 1991. In the survey, the elderly underwent a systematic examination of their oral mucosa by one of the three examiners with the aid of an overhead light. The examiners were trained and calibrated before and during the survey, and a specially prepared colour atlas of oral mucosal lesions was used for lesion recognition. No mucosal lesions were detected in 64% of the elderly. In the 193 elderly subjects with lesions, 80% exhibited only one lesion. There was no difference in prevalence between men and women. The more common lesions, each being found in 5-7% of the elderly, were lingual varicosities, frictional keratosis on the buccal mucosa, denture stomatitis on the palatal mucosa, and denture-induced hyperplasia in the maxillary and mandibular buccal sulcus. Denture wearers had a higher prevalence of lesions (40%) than nonwearers (32%). There was no difference in the prevalence or number of oral mucosal lesions between those defined as users of tobacco and alcohol and those defined as nonusers in this study. No confirmed oral malignancies were found. PMID- 7835038 TI - Periodontal conditions among the middle-aged and the elderly in Hong Kong. AB - The aim of this study was to describe the periodontal conditions in 372 35-44-yr old and 537 noninstitutionalized 65-74-yr-old Hong Kong Chinese who were examined clinically for loss of attachment, recession, probing depth, calculus, and bleeding after probing. Community Periodontal Index (CPI) data and treatment need indications were compiled from index teeth or their substitutes. The prevalence of loss of attachment varied considerably in both cohorts according to the definition of the threshold (> or = 6, > or = 9, and > or = 12 mm, respectively). The mean numbers of teeth with loss of attachment at the > or = 6-mm threshold and at higher thresholds were small. In both age cohorts, about one-fifth of subjects had probing depths > or = 6-mm, while at the > or = 9-mm threshold only 2-3% were so affected. Although recession was an important component of loss of attachment in the younger cohort, in the older cohort the prevalence and extent of recession were greater than for probing depths at thresholds > or = 4 mm. All subjects had one or more teeth with calculus, bleeding, or both, most teeth being so affected. Eighty-four of the 537 65-74-yr-old subjects were excluded either because of edentulousness or because extractions indicated for the remaining teeth would have rendered the subjects edentulous. The distribution of subjects according to their highest CPI score was remarkably similar for the two cohorts. No subjects in either age group were assessed as "healthy" (CPI code 0) or had "bleeding only" (code 1) as their highest score. While most subjects scored CPI code 2 or 3 as their highest score, only 17% of the younger and 15% of the older cohort scored Community Periodontal Index of Treatment Needs (CPITN) code 4.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7835039 TI - Oral health care needs among the middle-aged and the elderly in Hong Kong. AB - A sample of 372 35-44-yr-olds and 537 noninstitutionalized 65-74-yr-olds were clinically examined in an oral health survey of Hong Kong Chinese conducted in 1991. The examination procedures and diagnostic criteria for assessing restorative and extraction treatment need followed those recommended by the World Health Organization. The Community Periodontal Index-based periodontal treatment needs involving index teeth or their replacements were computed from separate clinic scores for maximum probing depth, presence of calculus, and bleeding after probing. A set of criteria for assessing prosthodontic treatment need was specially laid down for this survey. Examiners were calibrated before the survey, and the interexaminer reliability was found to be generally good. Besides reporting the various individual normative treatment need items in the traditional way, the present analysis used some holistic treatment-need categories which may have manpower-requirement implications for the classification of subjects. All dentate subjects surveyed required some treatment. Only 6% of the elderly, all edentulous, required denture work only. Of the 35-44-yr-olds, 42% needed scaling and oral hygiene instruction only, which could be provided by dental hygienists. The treatment needs of the vast majority of the middle-aged and the elderly (mainly scaling; simple fillings; and extractions, dentures, or both) could be easily handled by general dentists. Only about one-fifth of the subjects in both age groups required some complex care such as endodontics, crowns, and advanced periodontal treatment, which could be delivered by senior dentists or dentists with specialist training. PMID- 7835040 TI - Use of Medicaid for mental health care by clients of community support programs. AB - The use of Medicaid for mental health services by the severely mentally ill is examined using paid Medicaid claims for clients of Community Support Programs in Wisconsin. The extent to which clients participate in Medicaid, the types and amounts of mental health services, and the costs of services are discussed. A narrow majority of CSP clients use Medicaid, which provides a substantial amount of case management service for program participants. Psychotropic medications are also used by a large percentage of clients. Other relatively common services covered by Medicaid are medication checks and psychotherapy. Average annual Medicaid payments for mental health services (including medications) are $2438. PMID- 7835041 TI - HIV risk factors for persons with serious mental illness. AB - HIV risk factors were assessed among 120 persons in treatment for serious mental illness. Although subjects had good general knowledge regarding HIV, many engaged in high risk behaviors. Condom use was infrequent among those who had multiple sexual partners, and sharing needles was common for those who used i.v. drugs. Clearly, factual knowledge about HIV was not sufficient to prevent risky behavior. Nearly half of the sample was categorized as at medium to high risk, and almost half of the participants, especially those at medium risk, underestimated their own level of risk. The results suggest that education and intervention strategies should focus on increasing the accuracy of the individual's risk assessment as well as changing attitudes towards condoms and improving skills in using condoms. Assessing personal risk and adopting risk reduction strategies are the keys to successful AIDS prevention for persons with serious mental illness. PMID- 7835042 TI - Assessments of community mental health support systems: a key informant approach. AB - This article describes the development of a 'key informant survey' to assess the performance of local systems of care for persons with a chronic mental illness. The measure yields ratings of: (1) the extent to which clients experience service delivery problems in 11 community support system elements, (2) overall performance of the community support system, and (3) the performance of local mental health authorities. Following pre-testing, the survey was administered to 699 respondents in nine U.S. cities. Internal consistency coefficients were found to be within acceptable ranges for all of the scales across all nine cities. Analyses comparing mean values for performance ratings showed that the nine sites could be arranged into three groups representing high, medium and low system performance. These findings support observations from site visits conducted over several years and suggest that the survey is a valid instrument for assessing local systems of care. PMID- 7835043 TI - Identifying the mental health needs of children living in families with AIDS or HIV infection. AB - The present article highlights the mental health needs of children living with loved ones who have AIDS or HIV infection. In addition the article describes an intervention program which is being developed to meet the needs of the children and their families. Children who live in families affected by AIDS and HIV infection, like children who live with other life-threatening illnesses, are vulnerable to psychological distress. They experience numerous separations from parents, changes in the nature and predictability of emotional nurturing, concerns about loss, disruptions in routine and contact with peers, and economic hardship. AIDS and HIV infection present the additional stressors that stem from discrimination, stereotyping, and social ostracism. Finally, many families living with AIDS or HIV infection are disenfranchised, living under the pall of poverty and substance abuse. The intervention program described is being implemented in an urban community mental health clinic to meet the diverse mental health needs of the children living in these families. Preliminary implications of the program are discussed so as to begin a dialogue with other agencies who are challenged to meet the needs of this heterogeneous population. PMID- 7835044 TI - The effectiveness of community support programs for persistently mentally ill in rural areas. AB - The purpose of this study was to determine the effectiveness of a rural community support program by a comparison of the number of days hospitalized for an equal amount of time before and after participation in the program. It was found that participation resulted in a significant reduction in the number of days hospitalized. PMID- 7835046 TI - Consumers as service providers: the promise and challenge. AB - The importance of consumers in planning, providing and evaluating mental health services has received increasing recognition. Consumer participation as staff members on professional multidisciplinary teams describes one model of consumer involvement in providing services. This report gives the perspective of the professional leadership of such a team which employs two full-time "consumer advocates" (CAs). CAs have made significant and valuable contributions to the clinical work of the team by virtue of their street smarts, engagement skills, peer support, positive role modeling, fighting stigma, and education of co workers. However, the CA/professional collaboration presented a number of challenging questions for ongoing discussion, including: 1) What is the role of the CA? 2) What are the boundaries between CAs and patients and the implications of these boundaries for the potential effectiveness of CAs? 3) What supervision should the CA have and with whom? 4) What is the impact of the CA's individual experience with mental illness on their work? Examples are presented of both the clinical contribution of CAs and how the importance of addressing the above questions became evident in the work of the team. We found that CAs were extremely important team members; however, an ongoing dialogue between consumers and professionals is essential to operationalize this important collaboration. PMID- 7835045 TI - Not all homeless women are alike: effects of motherhood and the presence of children. AB - Previous work suggests that the population of homeless women is a heterogeneous group, and that motherhood and the presence or absence of children define sub groups that may be distinct. The current study is a systematic study of 300 homeless women (90% of whom were mothers) according to these suggested sub groupings. Mothers whose children were with them, compared to other women, were younger and often unemployed and welfare dependent. Mothers without their children had higher rates of nonsubstance Axis I disorders (48%) and alcoholism (33%), and 72% had a lifetime psychiatric diagnosis. Homeless mothers whose children are not with them represent a deviant subgroup with more personal (and fewer social) vulnerabilities to homelessness and may represent a target population for focus of psychiatric treatment efforts. Mothers with their children may benefit more from increased attention to social services. PMID- 7835047 TI - Isolated free fluid on abdominal computerized tomographic scan: an indication for surgery in blunt trauma patients? AB - A retrospective study of 792 patients who sustained blunt traumatic injury and underwent abdominopelvic computerized tomographic scan (CT) evaluation was performed. Patients who had free intraperitoneal fluid without evidence of solid visceral organ damage served as the study population. Sixty-six (8.3%) of patients were identified as having free fluid without evidence of solid organ injury. Pelvic fractures occurred in 14 of the 66 (21.2%) patients. Splenic injuries requiring laparotomy were not diagnosed initially on CT scan of the abdomen in four (6%) patients. Mesenteric or small bowel injuries occurred in six (9%) patients. Nine (13.6%) of the patients expired. Thirty-five patients (53%) had no sequelae of intra-abdominal injuries and required no surgical intervention. If patients with pelvic fractures are excluded, 10 (19.2%) of the patients required operative intervention for their injuries. It is our conclusion that free fluid as the only significant finding on CT scan in blunt trauma patients may be a harbinger of significant intra-abdominal injury, and that these patients need to be closely observed to decrease morbidity associated with these potential injuries. PMID- 7835050 TI - An open letter to insurors/payors. PMID- 7835048 TI - The pectoralis major myocutaneous flap in reconstructive head and neck surgery revisited: a recent experience. AB - Although the pectoralis major myocutaneous flap (PMMF) has proved to be a reliable method of reconstruction for the head and neck surgeon, the current emphasis in tissue replacement has shifted to microvascular free-tissue transfer. This has prompted us to review retrospectively all PMMFs performed for reconstruction following head and neck cancer resection at the University of Connecticut Health Center over a recent four-year period. A total of 24 flaps were utilized consecutively in 23 patients, following a variety of ablative procedures. Postoperative complications occurred in 14 of the 24 flaps (59%), and 11 of the 14 patients who experienced postoperative complications had received previous radiation therapy. Seven of the complications were felt to be major because they prolonged hospital stay, or they required secondary reconstructive procedures (four of seven cases). There were no instances of total flap failure. In our experience, the PMMF has proved to be reliable and useful in a variety of head and neck reconstructive procedures. We conclude that the PMMF remains an excellent option for repair of defects resulting from head and neck cancer resection. PMID- 7835049 TI - Problem-based learning: a better way? PMID- 7835051 TI - Human corneal studies with a vitrification solution containing dimethyl sulfoxide, formamide, and 1,2-propanediol. AB - We tested the tolerance of human corneas to a vitrification solution, modified VS41A, containing 3.1 M dimethyl sulfoxide, 3.1 M formamide, and 2.2 M 1,2 propanediol in a carrier solution consisting of the corneal storage medium CPTES with 2.5% w/v chondroitin sulfate. Seven human corneas were exposed for 10 min each to graded concentrations of the solution at 0 degree C, remaining in the full-strength solution for 10 min. The corneas had significantly more endothelial cell damage (P < 0.05) than seven mated control corneas, but it was minimal (4.3% cell loss). Attempts at vitrification and rewarming of three corneas exposed to the solution by this protocol, however, resulted in ice formation in the peripheral corneal stroma and severe endothelial damage. Presumably, equilibration with the cryoprotectant in the thicker periphery of the human cornea had not occurred. Ice did not form on the center of one cornea, and substantial numbers of central endothelial cells survived after vitrification in this case. Immersion of the human corneas for 25 min in each of the four graded solutions at 0 degree C was required for sufficient penetration of the cryoprotectant to allow total corneal vitrification and rewarming without ice formation. This prolonged exposure to modified VS41A caused unacceptable damage to the corneal endothelium, however. Successful vitrification of human corneas with this solution will require a safe method for obtaining corneal equilibration with the cryoprotectant. PMID- 7835052 TI - Do trehalose and dimethyl sulfoxide affect intermembrane forces? AB - The sugar trehalose is produced in some organisms that survive dehydration and desiccation, and it preserves the integrity of membranes in model systems exposed to dehydration and freezing. Dimethyl sulfoxide, a solute which permeates membranes, is added to cell suspensions in many protocols for cryopreservation. Using a surface forces apparatus, we measured the very large, short-range repulsion between phosphatidylcholine bilayers in water and in solutions of trehalose, sorbitol, and dimethyl-sulfoxide. To the resolution of the technique, the force-distance curves between bilayers are unchanged by the addition of trehalose or sorbitol in concentrations exceeding 1 kmol.m-3. A relatively small increase in adhesion in the presence of trehalose and sorbitol solutions may be explained by their osmotic effects. The partitioning of trehalose between aqueous solutions and lamellar phases of dioleylphosphatidylcholine was measured gravimetrically. The amount of trehalose that preferentially adsorbs near membrane surfaces is at most small. The presence of dimethyl sulfoxide in water (1:2 by volume) makes very little difference to the short-range interaction between deposited bilayers, but it sometimes perturbs them in ways that vary among experiments: free bilayers and/or fusion of the deposited bilayers were each observed in about one-third of the experiments. PMID- 7835053 TI - Potassium uptake and water content in hepatocytes isolated from rat livers preserved in Euro-Collins and UW solutions and after transplantation. AB - Isolated hepatocytes from the rat were used to assess the maintenance of liver cell function in relation to the composition of the preservation medium. After separation by collagenase, they were incubated in Krebs-Ringer-Bicarbonate medium (KRB), Euro-Collins (EC), or University of Wisconsin (UW) solutions. Potassium influx, cell volume, and transaminase release were measured in cells freshly separated from control livers or from livers preserved in vitro up to 12 h in these media or having undergone orthotopic liver transplantation (OLT). While ion exchange levels were retained in all media, cells shrank significantly in UW but were able to restore their volume after 3 h of liver preservation. With regard to in vivo conditions, UW appears to be the best medium to prevent edema and to maintain more stable potassium exchange and enzyme production. These results are of value for liver transplantation in humans. PMID- 7835054 TI - Design of a cryogenic videocamera-recorder and image processing system and calculation of volumes of red cells. AB - Since Rowe reported that the storage technique for red cells at very low temperatures had been realized successfully, many experts who work in the fields of cryobiology and medicine have turned their attention to this storage technique for tissues and organs. Since the first quantitative cryomicroscope was made successfully about 20 years ago, it has been possible to observe changes in shape and phase. Particularly the image processing technique has laid the foundation for quantitative analysis of the relationship between changes in shape and damage from freezing of cells and cooling rate and storage temperature. In this work, we constructed a system consisting of a cryomicroscope, a videocamera-recorder, and an image processor. We carried out many experiments with red cells in cold storage and have established a model for calculating the volumes of red cells. In our experiments we also dynamically traced the shape changes of cells with various experimental parameters. PMID- 7835055 TI - Current status of calcium channel blockers. PMID- 7835056 TI - A dermatologic diary. Portrait of a practice. PMID- 7835057 TI - Nevus flammeus. PMID- 7835058 TI - Postoperative alopecia: a case report and literature review. AB - Postoperative alopecia is the temporary or permanent loss of hair that occurs following prolonged immobilization during general anesthesia and intubation. The clinical and histopathologic aspects of a typical case are described and the literature reviewed. Localized pressure-induced ischemia is the likely cause. Patients at highest risk for permanent hair loss include those subject to cardiac or gynecologic surgical procedures where the combined intraoperative and postoperative intubation time exceeds twenty-four hours. Frequent intraoperative and postoperative head repositioning provides excellent prophylaxis. PMID- 7835059 TI - Shedding oral mucosa. AB - Four patients presented with asymptomatic gray-white oral mucosal tissues that sloughed and peeled away leaving a normal tissue base. This peeling phenomenon appeared unlike any known oral mucosal disease, although it somewhat resembled leukoedema and chemically irritated oral mucosa due to certain dentifrices and mouthwashes. Examination of biopsy tissue from three of the four cases along with stripped tissue from the fourth case revealed an intraepithelial cleft near the surface of each specimen. The linear cleft ran parallel to the epithelial surface. Foci of adjacent cells displayed intracellular edema, a feature commonly noted in leukoedema. There was evidence of neither acantholysis nor inflammation. The microscopic pattern was unlike the mucosal entities pemphigus vulgaris, mucosal pemphigoid, lichen planus, candidiasis, and mucosal biting. Although the authors questioned the patients in detail regarding all forms of mechanical and chemical trauma, including those from certain dentifrices and mouthwashes, they could not detect causative factors for these lesions. PMID- 7835060 TI - Melkersson-Rosenthal syndrome. AB - Four patients with recurrent upper lip and facial swelling and lingua plicata together with peripheral facial nerve palsy involvement were diagnosed as having Melkersson-Rosenthal syndrome. Because of the rarity of this syndrome in children, we present the results of follow-up evaluations of our patients and review the literature. PMID- 7835061 TI - Koebner reaction in psoriasis due to secondary syphilis. AB - A patient with a two-year history of psoriasis showed a widespread eruption that was clinically and histologically similar to psoriasis. Results of blood tests revealed syphilitic infection, appearing to be secondary syphilis. The flare-up of guttate psoriasis was considered to represent a Koebner phenomenon due to secondary syphilis. PMID- 7835062 TI - Petechial glove and sock syndrome caused by parvovirus B19. AB - The petechial glove and sock syndrome is a recently described febrile dermatosis characterized by acral edema, petechiae in a characteristic distribution, and enanthem, which has been associated in several cases with parvovirus B19 seroconversion. We report an additional case of petechial glove and sock syndrome that further corroborates the role of parvovirus B19 as a causative agent of this syndrome in adults. PMID- 7835063 TI - Perianal streptococcal dermatitis: two familial cases. AB - Two familial cases of perianal streptococcal dermatitis in a 3-year-old girl and her 5-1/2-year-old brother are reported. The clinical features of well-demarcated perianal erythema variably associated with itching, painful defecation with subsequent constipation, rectal bleeding, and proctitis are reviewed, together with suggestions for the best therapy. PMID- 7835064 TI - Review of the morphological variations in cutaneous cryptococcosis with a new case resembling varicella. AB - A 26-year-old black man with acquired immune deficiency syndrome and disseminated cryptococcosis presented with multiple small white vesiculopustular skin lesions on the face, trunk, and upper extremities mimicking varicella. To our knowledge, this is a novel presentation of cutaneous cryptococcal infection. A review of the morphologic variations seen in cutaneous Cryptococcus infections in patients with and without acquired immune deficiency syndrome is also presented. PMID- 7835065 TI - Cutaneous metastases from carcinoma of the ovary. AB - Cutaneous metastases from ovarian carcinoma are very uncommon. Two cases are presented that demonstrate the typical clinical features of this rare complication of advanced ovarian cancer. Through recognition of the characteristic appearance and distribution of the lesion, the physician may suspect the diagnosis based on clinical examinations. PMID- 7835066 TI - Seborrheic keratosis with trichilemmomas masquerading as melanoma. AB - Seborrheic keratoses are benign lesions and, generally, are easily diagnosed based on clinical criteria. However, several types of benign as well as malignant lesions have been found associated with seborrheic keratoses, thus confusing the clinical picture. Presented is the first reported case of trichilemmomas occurring within seborrheic keratosis and masquerading as melanoma with regression. Biopsy of unusual seborrheic keratoses is recommended. PMID- 7835067 TI - The art of cryosurgery. AB - Cryosurgery is an art as well as a science. Of course just as a sculptor or painter must learn about stone, wood, canvas, paper, chisels, rasps, paint brushes, and other materials, the cryosurgeon must understand the science underlying cryosurgery. He or she must learn the properties of the various cryogens, the apparatus for applying them, the three-dimensional extent of the lesions to be treated, and the tissue content of these lesions. He or she should also know the susceptibility of various portions of the target lesion and surrounding tissues to varying insults with cold. PMID- 7835068 TI - Dermal lymphoplasmacytic/lymphoplasmacytoid lymphoma (immunocytoma) in a 40-year old man. AB - The skin may be the site of origin of a lymphomatous process or it may be secondarily involved as a systemic manifestation of a lymphoma arising in an extradermal (extracutaneous) site. Dermal lymphomas are difficult to recognize and differentiate from non-specific chronic dermatitis. Several histologic features have been proposed to help in differentiating between benign and malignant lymphoid dermal infiltrates. However, this distinction has been difficult to reproduce consistently. With use of immunologic techniques applied to fresh or paraffin-embedded material, the differentiation between a benign or malignant dermal cell process has been dramatically improved. PMID- 7835069 TI - Quantitative cytophotometric and autoradiographic analysis of the cell cycle kinetics during growth and development of the plasmodium in the myxomycete Didymium iridis. AB - Nuclear changes in basic protein, RNA, and DNA in plasmodia of Didymium iridia at 4, 8, and 12 days during their progression through the growth cycle prior to sporulation were analysed. Relative determinations of basic protein and RNA were made using naphthol yellow-S/azure B in conjunction with absorption microspectrophotometry. DNA was quantified by quantitative cytophotometric measurements of Feulgen-stained nuclei. Autoradiographic techniques provided information on periods of DNA synthesis. A net decrease in protein and RNA to a point of stabilization was shown which correlated with increased age of the organism and decreased nutrient supply in the plasmodia. The 4C DNA content of the 4 day plasmodia indicated rapid growth and high metabolic activity while in the 8 day plasmodia a 2C DNA was observed consistent with the presence of a G1 period of some duration. PMID- 7835070 TI - Effects of TRH and TRH-like peptides on anterior pituitary cell proliferation in rats. AB - Although the effect of TRH on the mitotic activity of anterior pituitary gland has been described, its involvement in the control of pituitary cell growth is still considered controversial: The present paper deals with the effect of a single dose (100 micrograms/kg body wt) of TRH or of TRH-like tripeptides pGlu His-Gly (colon mitosis inhibitor, CMI) and pGlu-His-Gly-NH2 (CMI-NH2) on anterior pituitary cell proliferation in adult male rats. The incorporation of bromodeoxyuridine (BUdR) into cell nuclei was used as the index of cell proliferation. It was found that TRH and (CMI-NH2) but not CMI increased the BUdR labelling of the anterior pituitary cell nuclei 12 h after peptide administration. These findings support the hypothesis of the positive control of anterior pituitary cell proliferation by TRH, and, possibly, by some other TRH like peptides. PMID- 7835071 TI - Effect of iturin A, a lipopeptide from Bacillus subtilis on morphology and ultrastructure of human erythrocytes. AB - Iturin A, a lipopeptide from Bacillus subtilis, induced morphological modifications of human erythrocytes and a concomitant release of exovesicles. The modifications depended on the lipopeptide concentration and on the incubation time. Crenation of cells occurred while invaginations appeared when the incubation time was increased. This suggested that iturin A was gradually translocated from the outer layer into the inner half of the bilayer. For one lipopeptide concentration, heterogeneity in the form of the erythrocytes was observed which could result from heterogeneity in the self-association of iturin A. The lipid composition of exovesicles was markedly different from that of the native erythrocytes; they were enriched in cholesterol, sphingomyelin and phosphatidylcholine. Freeze-fracture showed that the ultrastructure of the protoplasmic face of the membrane was not modified by iturin A but, when erythrocytes were prefixed with glutaraldehyde prior to iturin A treatment, irregular smooth protuberances appeared with a decrease of intramembranous particles density. These protuberances which covered the complete area of the cell may have been complex associations of iturin A, phospholipids and cholesterol. PMID- 7835072 TI - Vitamin A ameliorates the genotoxicity in mice of aflatoxin B1-containing Aspergillus flavus infested food. AB - Young weaning Swiss albino mice were orally administered crude aflatoxin B1 in a dose mimicking human exposure condition, i.e. at 0.05 micrograms/kg body weight/day for 14 weeks. Vitamin A (retinol) was orally administered along with the toxin in double (132 IU/kg body wt/day) the human equivalent therapeutic dose. The results suggested that vitamin A minimised the frequency of toxin induced clastogeny in both mitotic and meiotic chromosomes. The decreases in sperm count as well as increases in abnormality in the gross morphology of the sperm-head, as observed upon toxin treatment, was ameliorated by the vitamin A. PMID- 7835073 TI - Activity of neural cell adhesion molecule (N-CAM) components: a review. AB - The neural cell adhesion molecule, N-CAM, is a well-characterized component of nervous system morphogenesis and histogenesis. It mediates aggregation of neurons by binding homophilically to N-CAM on apposing cells. Different forms are generated through alternative splicing of one gene and varied amounts of carbohydrate determine binding strength. This review summarizes results of contemporary studies which link N-CAM components with activity involving the maintenance and reorganization of the brain following injury. Current studies which suggest mechanisms of function are also included. PMID- 7835074 TI - Combined Q-banding and fluorescence in situ hybridization for the identification of bovine chromosomes 1 to 7. AB - Eleven probes were assigned to bovine chromosomes 1 to 7 by fluorescence in situ hybridization (FISH). The identification of chromosomes was based on QFQ-banding prior to in situ hybridization and comparison with the Reading Conference (1976) and ISCNDA (1989) standards. The probes used for FISH can now be utilized as identification and discrimination features for bovine chromosomes 1 to 7 and particularly for chromosomes 4 and 6, which are difficult to distinguish. Comparison of our mapping data with previous assignments and of the standard chromosome banding patterns prompt us to propose a change in the ISCNDA nomenclature: ISCNDA chromosome 4 should be named chromosome 6 and vice versa. Chromosome 4 is marked by the ribosomal RNA cluster RNR3, and chromosome 6 is characterized by the casein gene cluster and an anonymous satellite (D6Z1). PMID- 7835075 TI - Description of a 700-kb yeast artificial chromosome contig containing the BCL1 translocation breakpoint region at 11q13. AB - We screened two human yeast artificial chromosome (YAC) libraries by polymerase chain reaction (PCR) with oligonucleotides specific to the BCL1 major translocation breakpoint cluster region at 11q13. Five YACs were isolated. Two of them were chimeric. One of these and remaining three YACs were characterized by hybridization with various known 11q13 probes, Alu-PCR fingerprinting, in situ hybridization, and isolation of YAC ends. A map of this ca 700-kb YAC contig was obtained. This map was consistent with maps established from total human genomic DNA. Every YAC in this region was found unstable and gave rise to reproducibly deleted lineages. Analysis in detail of these deletions over many generations showed that more than a single sequence might be involved. The availability of cloned material will facilitate the search for the still elusive genetic elements responsible for amplifications, deletions and translocations observed at 11q13 in malignancies. PMID- 7835076 TI - Confirmation of 9q34 as the chromosomal site of the human lipocalin LCN1 gene. AB - The gene encoding the lipocalin LCN1 was previously assigned to human chromosome 8q24 by fluorescence in situ hybridization of a genomic DNA fragment and to 9q34 by in situ hybridization of a radiolabeled cDNA fragment of LCN1. To resolve this discrepancy, we used hamster x human hybrid cells for polymerase chain reaction experiments. These investigations confirmed the localization of LCN1 on chromosome 9. PMID- 7835077 TI - Chromosomal localization of the human and rat genes (PDE4D and PDE4B) encoding the cAMP-specific phosphodiesterases 3 and 4. AB - Through the use of somatic cell hybrids segregating either human or rat chromosomes, we determined the chromosome localizations of two genes encoding cAMP-specific phosphodiesterases (cAMP-PDEs). PDE4D, the gene encoding the cAMP PDE isoform 3 (IVd), was assigned to human chromosome 5 and rat chromosome 2, and PDE4B, the gene encoding the cAMP-PDE isoform 4 (IVb), was assigned to human chromosome 1 and rat chromosome 5. These localizations extend the homology between rat chromosome 2 and human chromosome 5, on the one hand, and between rat chromosome 5 and human chromosome 1, on the other hand. PMID- 7835078 TI - 32nd Annual American Cytogenetics Conference. Virginia, April 23-26, 1994. Abstracts. PMID- 7835079 TI - Assignment of the human skeletal muscle alpha-tropomyosin gene (TPM1) to band 15q22 by fluorescence in situ hybridization. AB - A sequence-tagged site (STS) was developed for the human skeletal muscle alpha tropomyosin gene (TPM1) and used to isolate a genomic clone, lambda TPM1.1, containing part of the TPM1 gene. Fluorescence in situ hybridization of this clone to metaphase chromosome spreads localised TPM1 to chromosome band 15q22. This localisation in humans is consistent with that recently described for the mouse. PMID- 7835080 TI - Chromosome banding in Amphibia. XXI. Inversion polymorphism and multiple nucleolus organizer regions in Agalychnis callidryas (Anura, Hylidae). AB - Cytogenetic analyses were performed on several populations of the Central American tree frog Agalychnis callidryas, using conventional methods and banding techniques. The karyotype of this species is distinguished by an inversion polymorphism in chromosome 9, which is either submetacentric or telocentric. The populations examined are in Hardy-Weinberg equilibrium with respect to the two alternative morphs of chromosome 9. This is the first report of the occurrence of an intrapopulational chromosomal inversion polymorphism in the order Anura. In male meiosis, the two chromosomes 9 form a bivalent exhibiting a ring-like pairing configuration with terminal chiasmata in both arms, regardless of whether the paired homologs are heteromorphic or homomorphic. Furthermore, individual specimens of A. callidryas exhibit one or two unexpected 18S + 28S ribosomal RNA gene clusters, in addition to the standard nucleolus organizers. The chromosomal localization of these extra nucleolus organizers is identical in all metaphases from the same specimen and shows a specific intraindividual pattern. The karyotype evolution in the phyllomedusine hylids, the structure of the various classes of heterochromatin, and the occurrence and possible origin of the rare inversion polymorphisms and multiple nucleolus organizers in A. callidryas and a few other amphibian species are discussed. PMID- 7835081 TI - Mapping of an ordered set of 14 cosmids to human chromosome 12p by two-color in situ hybridization. AB - To map human chromosome 12p aberrations by fluorescence in situ hybridization (FISH), cosmids were isolated or obtained for 14 known 12p loci (D12S119, D12S158, D12S178, D12S370, D12S380E, A2M, CACNL1A1, FGF6, GAPD, KRAS2, PRB1, PZP, TPI1, and VWF). Using two-color FISH with three labeled probes to interphase nuclei, and to prometaphase chromosomes where possible, the order of these loci was sequentially determined to be pter-D12S158-D12S380E-CACNL1A1-FGF6- D12S370 VWF-GAPD-TPI1-A2M-PZP-PRB1-D12S 178-D12S119-KRAS2-cen. Two cell lines were analyzed with this set of cosmids. The EBV-transformed cell line TA carries a der(12) with a deletion of bands 12p13.1-->p11.2.D12S178, D12S119, and KRAS2 were absent in the der(12), whereas the other loci were present. The second cell line, GM01203A, exhibits a balanced t(4;12)(4q25; 12p13.3) with a breakpoint between FGF6 and D12S370. PMID- 7835082 TI - X-linked juvenile retinoschisis (RS) maps between DXS987 and DXS443. AB - X-linked juvenile retinoschisis (RS) has previously been localized to a 7-8 cM interval between markers at (DXS43, DXS207) and (DXS274, DXS41). Our analysis of more than 300 meioses in two multigeneration RS families identified eight recombinant RS chromosomes and narrowed the RS locus to an interval between DXS987 and DXS443. Our data suggest the following order of loci: Xpter-DXS207 DXS987-([DXS418-DXS999], RS)-DXS443-DXS365-DXS274-Xcen. PMID- 7835083 TI - Assignment of CD38, the gene encoding human leukocyte antigen CD38 (ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase), to chromosome 4p15. AB - CD38 has been used as a phenotype marker of lymphocyte differentiation. Recently, we have demonstrated that cyclic ADP-ribose can be synthesized and hydrolyzed by CD38 and acts as a second messenger in insulin secretion from pancreatic beta cells. We have mapped the CD38 gene to human chromosome 4p15 by fluorescence in situ hybridization. PMID- 7835084 TI - Chromosomal assignment of the heparin-binding cytokine genes MDK and PTN in mouse and man. AB - MDK and PTN are two members of a family of heparin-binding cytokines thought to be involved in a number of developmental processes. The locations for these genes were determined in man and mouse using somatic cell hybrid analysis and interspecific backcross analysis. Human MDK was mapped to 11p13-->p11. MDK in the mouse (Mdk) was mapped to a syntenic region of mouse Chromosome 2. A pseudogene of Mdk was mapped to mouse Chromosome 11. The closely related human gene PTN was mapped to a separate location on human chromosome region 7q22-->qter. PMID- 7835085 TI - Cytogenetics and karyosystematics of Oryzomys albigularis (Rodentia, Cricetidae) from Venezuela. AB - Several authors have proposed that Oryzomys albigularis constitutes a supraspecific complex and that chromosomal pericentromeric inversions have played a fundamental role in the diversifying process. With the purpose of clarifying the unclear taxonomic situation of the nominal forms of O. albigularis living in Venezuela, a cytogenetic study was carried out on individuals from five different localities along the Andean range and the Cordillera de la Costa. All of the individuals examined showed a diploid number (2n) of 66 chromosomes, but there were differences in the number of autosomal arms (FN = 90, 92, and 104) and in the morphology of the X chromosome (metacentric or acrocentric). The C-banding pattern was similar in all populations, autosomal heterochromatin was restricted to the centromere, and the Y chromosome was the only one that had completely heterochromatic arms. G-banding was useful in making arm-to-arm comparison between the FN = 90 and FN = 104 karyomorphs; 23 shared pairs were found, 7 pairs differed due to pericentric inversions, and 3 pairs had no correspondence. We postulate that these karyomorphs probably correspond to allospecies, and that the specific denominations must correspond to two previously recognized populations of sigmodontine rodents: O. caracolus Thomas 1914 (2n = 66, FN = 90), for the populations from the Cordillera de la Costa, and O. meridensis Thomas 1894 (2n = 66, FN = 104), for the populations distributed between the middle and extreme north of the Andean range. The specific denomination for the populations of animals from the southern portion of the Andean range (Oryzomys sp., 2n = 66, FN = 92) is still to be determined. PMID- 7835086 TI - Chromosomal localization of the BLV receptor candidate gene in cattle, sheep, and goat. AB - The BLV receptor candidate gene has been localized precisely on cattle, goat, and sheep chromosomes using nonradioactive in situ hybridization and simultaneous fluorescent R-banding. The probe, a whole plasmid containing a 2.3-kb bovine cDNA fragment encoding part of this gene, was nick-translated in the presence of biotin-11-dUTP. It hybridized on band q15 of cattle chromosome 7, goat chromosome 7, and sheep chromosome 5, thus confirming the homoeology based on banding patterns among the chromosomes of these three species. PMID- 7835088 TI - Genetic linkage mapping of HSD3B1 and HSD3B2 encoding human types I and II 3 beta hydroxysteroid dehydrogenase/delta 5-delta 4-isomerase close to D1S514 and the centromeric D1Z5 locus. AB - The enzyme 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4-isomerase (3 beta HSD) catalyses an essential step in the biosynthesis of all steroid hormones. Consequently, classical 3 beta-HSD deficiency is responsible for a severe form of congenital adrenal hyperplasia. The HSD3B1 and HSD3B2 genes encoding the types I and II 3 beta-HSD isoenzymes, respectively, have been previously assigned by in situ hybridization to the chromosome 1p13.1 region. To determine the physical distance between these two genes, NotI and SacII digests of genomic DNA were resolved by pulse-field gel electrophoresis and hybridized with type I and type II 3 beta-HSD cDNAs used as probes. The detection of a single band under low stringency conditions indicates that HSD3B1 and HSD3B2 are located within an approximately 0.29 megabase SacII DNA fragment. We constructed a high resolution genetic map of the region flanking the polymorphic HSD3B1 and HSD3B2 genes including ten Genethon markers and the two NIH/CEPH markers AMY2B and D1Z5. The HSD3B1A and HSD3B2A markers were mapped relative to other reference markers through eight CEPH reference families. The order of polymorphic genes and markers is: pter-[AMY2B-D1S239]-D1S457-D1S502-D1S250-+ ++D1S252-[HSD3B1A -HSD3B2A-D1S514] [D1Z5-D1S442]-D1S305-D 1S303-D1S484-qter. The D1S514 marker was thus closely linked to HSD3B1A (theta < 0.001; lod = 14.13) and HSD3B2 (theta = 0.008; lod = 35.36). The HSD3B loci are located 1-2 cM of the centromeric marker D1Z5. PMID- 7835087 TI - Cloning and regional assignment of the human myosin heavy chain 12 (MYH12) gene to chromosome band 15q21. AB - Sequences encoding 1,235 bp of the human myosin heavy chain 12 (MYH12) gene have been cloned from a human brain cDNA library by PCR amplification. The human sequence is 95.8% identical to the mouse sequence at the amino acid level, indicating that the MYH12 gene has been evolutionarily well conserved. Somatic cell hybrid analysis and in situ hybridization place the MYH12 gene on human chromosome 15, at band q21, and extend distally the known region of chromosome 15 linkage homology on mouse chromosome 9. PMID- 7835089 TI - Construction and analysis of microcell hybrids containing dual selectable tagged human chromosomes. AB - We have constructed a panel of human x murine microcell hybrids containing individual human chromosomes tagged with a dual selectable marker conferring hygromycin B resistance and ganciclovir sensitivity. Over 500 independent microcell hybrids (B78MC) were generated and more than 200 individually isolated. We have identified the human chromosome content of several B78MC hybrids and verified that the majority are responsive to positive and negative selection. Once fully characterized, this panel will be useful in the study of dominant regulators of gene activity, such as tissue specific regulators and tumor suppressor genes. PMID- 7835090 TI - Male sterility and double heterozygosity for chromosomal inversion. AB - A meiotic analysis has been carried out on male mice heterozygous for one of two inversions in Chromosome 2, In(2)5Rk and In(2)2H, as well as on double heterozygotes for these two overlapping inversions. Electron microscopic observation of synaptonemal complexes revealed that heterosynapsis had occurred in a large number of spermatocytes, producing a small number of cells with an inversion loop. Heterozygous carriers of a single inversion loop reproduced quite normally, whereas doubly heterozygous carriers of a double loop showed a reduction in spermatogenesis. These data shed new light on the role of inversions in speciation. PMID- 7835091 TI - Fine deletion mapping of the p22 region of the human X chromosome using a radiation-induced hybrid panel. AB - Radiation-induced somatic cell hybrids containing fragments of the human X chromosome were constructed. A panel of 17 hybrids was selected with the help of known markers in the Xp22 region. These hybrids identified 11 different breakpoints between Xp22.2 and Xp21.3. Eight markers were located in eight of the nine corresponding intervals, resulting in the following physical map: tel...DXS89-DXS278-DXS85-(DXS1224, DXS16)-(GLRA2, DXS987)-DXS207-(DXS-197, DXS1053)-(DXS43, DXS1195)-(DXS1229, DXS-999)-(DXS1052, DXS92, DXS274)-(DXS41, DXS1226)-DXS1198-DXS28...cen. PMID- 7835092 TI - Expression and chromosomal localization of cDNA clones from an enriched human retinal pigment epithelial (RPE) cell line library: identification of two RPE specific genes. AB - We have previously constructed an enriched cDNA library from a human retinal pigment epithelium (RPE) cell line and generated expressed sequence tags (ESTs) from novel clones. Here, we report the analysis of expression of 14 cDNAs and identify two clones, AA1 and AA28, that appear to be specifically expressed in RPE but not in any other tissue tested. We have also localized 15 novel cDNAs (including the two RPE-specific cDNAs) to human chromosomes using in situ hybridization or in conjunction with somatic cell hybrid analysis. The cDNAs were mapped to the following chromosomal regions: 1p35-->p33, 1q41-->q42 (two clones), 3q11.2-->q13.1, 3q24-->q25, 4q13-->q21, 6q22-->q23, 7q34-->q36, 10q23-->q24, 11q23-->q24, 15q25-->q26, 19p13.3, 20p13, 21q11.2-->q21, and 21q22.2-->q22.3. The genetic and functional analysis of the two RPE-specific genes should contribute to a better understanding of RPE function. Chromosomal localization of RPE cDNAs will be valuable in identifying candidate genes for inherited diseases involving RPE dysfunction and aid in establishing the expression map of the human genome. PMID- 7835093 TI - Genetic characterization of general transcription factors TFIIF and TFIIB of Homo sapiens sapiens. AB - Analysis of loci GTF2F1 and GTF2B, encoding Rap 74 (a subunit of TFIIF) and TFIIB, respectively, showed that they are present in a single copy in the human genome and are localized at 19p13.3 and 1p22, respectively. By using as probe a cDNA for Rap 30 (the other subunit of TFIIF), we localized the GTF2F2 locus to 13q14; the same probe also detected a cross-hybridizing sequence at 4q31 whose functional importance remains to be elucidated. These data and those previously published by our group demonstrate that genes coding for class II general transcription factors with reported sequence similarity to bacterial sigma proteins are scattered in different regions of the human genome, with no evidence of clustering. This dispersion and the identification of homologs of both TBP and TFIIB in Archaea suggest an early evolutionary origin of the general transcription apparatus of contemporary eukaryotes. PMID- 7835094 TI - Eigenanalysis of DAPI-stained chromosomes: tools and strategies toward computer assisted analysis of FISH experiments. AB - The fluorescent dye 4',6-diamidino-2-phenylindole (DAPI) is widely used as a chromosome counterstain in fluorescence in situ hybridization (FISH) studies. It produces a Q-banding pattern that allows for both chromosome identification and the assignment of molecular probes to specific chromosome bands. Using a statistical procedure based on eigenanalysis, we have extracted features from digital images of DAPI-stained chromosomes and constructed prototypes of each of the 24 human chromosomes. The features of these prototypes are directly proportional, in intensity profile and band location, to those of real chromosomes. The prototype's intensity profile can be translated into cytogenetic bands to provide a computer-based strategy for chromosome mapping and analysis amenable to automation. Data presented here were obtained using images from the 24 human chromosomes and mouse X chromosome. Moreover, the same procedure is general and can be used for the analysis of chromosomes from other species, as well as with banding techniques other than those using DAPI. PMID- 7835095 TI - Absence of terminal telomeric FISH signals in chromosomes from immortal Chinese hamster cells. AB - In contrast to normal Chinese hamster cells, terminal telomeric signals were not detectable by fluorescence in situ hybridization (FISH) in their immortalized counterparts, even when a sensitive cooled CCD camera was used for acquiring FISH images. Since the telomeres were detectable by FISH in immortal human cells, this suggests that hamster and human cells might have different mechanisms of telomere processing. PMID- 7835097 TI - Assignment of Tp53 and Tk1 to chromosome 13 in Peromyscus by fluorescence in situ hybridization. AB - Mus domesticus DNA probes for the tumor suppressor protein-53 (Tp53) and thymidine kinase-1 (Tk1) genetic loci were used to identify clones representing these loci in a Peromyscus leucopus (white-footed mouse) cosmid library. The cosmid-derived homologous probes were biotinylated and hybridized to P. maniculatus (deer mouse) chromosomes. Probes for both genes hybridized to the chromosome 13 pair identified by prior G-banding. Deer mouse chromosome 13 shares a region of homology with mouse chromosome 11, rat chromosome 10 and human chromosome 17. PMID- 7835096 TI - Trisomy 7 in nonneoplastic epithelial kidney cells. AB - Trisomy 7 has been found as the sole clonal chromosome aberration in a number of tumor types, including renal cell carcinomas (RCC), and also in non-neoplastic kidney tissue. It has recently been proposed that the cells harboring trisomy 7 in RCC and in the surrounding tissue may be tumor infiltrating T-helper lymphocytes. We performed cytogenetic analysis of metaphase cells and FISH of interphase nuclei in uncultured and cultured non-neoplastic kidney tissues from 13 patients with renal or urothelial carcinomas, and 4 patients with inflammatory kidney diseases. FISH analysis showed that the frequency of +7 varied between 1.0 8.9% (mean 3.3%) in uncultured cells and between 0.4-8.6% (mean 4.4%) after one week of cell culture. The frequency of +7 after one week of culture was 1.0-19.0% (mean 6.1%) as determined by cytogenetic analysis. Immunoenzymatic staining of both uncultured and cultured cells with the alkaline phosphatase reaction and monoclonal antibodies for CD3 showed that the frequency of T-cells in uncultured cells and in primary cultures varied between 2.9-10%. The number of T-cells decreased with time and number of in vitro passages to less than 1% after 7-8 weeks, but the frequency of +7 remained fairly constant. Combination of FISH with immunostaining using CD3 for T-lymphocytes and cytokeratins for epithelial cells showed that the cells with +7 were mainly epithelial cells whereas only 0-5% were T-lymphocytes. The results have obvious implications for the interpretation of the significance of trisomy 7 in neoplasia. PMID- 7835098 TI - Introduction of the special section dedicated to bone marrow transplantation. PMID- 7835099 TI - Enhanced immunogenicity in mice with hepatitis B vaccine complexed to human hepatitis B immunoglobulin. AB - Purified human hepatitis B immunoglobulin (HBIG) was complexed to plasma derived hepatitis B vaccine (HBVac) at different concentrations and used to immunize Balb/c mice. An enhanced humoral immune response was observed when HBVac was complexed to HBIG in excess of antigen, compared to that immunized with the vaccine alone. Proliferation of splenic lymphocytes was detected when mice were immunized with HBIG complexed to HBVac (0.2-1 microgram), whereas in mice immunized only with HBVac at one microgram, no lymphocyte proliferation was observed. The enhanced immunogenicity of HBIG: HBVac is T cell dependent. The importance of using critical ratio of HBIG and HBVac is indicated, and future application of this complex for vaccination of low- or nonresponders to the present HBVac, as well as for treatment of chronic hepatitis B patients is discussed. PMID- 7835100 TI - Involvement of nitric oxide in the vasodilator and depressor effect of calcitonin gene-related peptide. AB - In present study, we examined the effects of NG-nitro-L-arginine (LNNA), an inhibitor of nitric oxide synthase (NOS), and/or methylene blue (MB), a blocker of guanylate cyclase on the vasodilator response of isolated rat arteries including aorta and mesenteric artery to calcitonin gene-related peptide (CGRP) by in vitro vasoconstriction experiment, and the effect of LNNA on the depressor action of CGRP by in vivo hemodynamic experiment. Furthermore, the effect of CGRP on NOS activity and cyclic guanylate monophosphate (cGMP) content were also examined by NOS activity assay and radioimmunoassay (RIA), respectively. The results showed that LNNA and/or MB significantly decreased, but not abolished, the vasodilator response of isolated rat aorta and mesenteric artery to CGRP. The depressor effect of CGRP on LNNA-induced hypertensive rats (LHR) was obviously weaker than that on spontaneously hypertensive rats (SHR), renal hypertensive rats (RHR) and normotensive rats (NWR). In addition, CGRP (0.5 nmol/kg) increased the NOS activity of rat aorta tissue by 1.3 times (P < 0.05) and resulted in an increase of cGMP content of aorta (1.27 times, P < 0.05) and myocardium (1.38 times, P < 0.05). The results suggested that NO is involved in the action of CGRP. PMID- 7835101 TI - Assessment of autopsic samples of carotid atherosclerosis in the aged by intravascular ultrasound. AB - To assess the value of intravascular ultrasound in detecting carotid atherosclerosis, we compared the ultrasound images of 48 carotid artery segments from autopsies with their histological findings. The results showed that by intravascular ultrasonography one could distinguish between elastic and muscular tissues of arteries, determine the lesions of fibroelastosis and calcified plaques on arterial wall, and precisely measure the wall thickness, inner and outer diameter, luminal area and cross-sectional area of arteries with a high correlation between the data measured from ultrasonography and histological study (r values were 0.98, 0.97, 0.97, 0.96 and 0.96, respectively). This study suggests that intravascular ultrasound might be effectively used for morphological study and detection of atherosclerotic lesions in vivo. PMID- 7835102 TI - Study of the external counterpulsation (ECP) therapy for senile dementia of the Alzheimer's type (SDAT). AB - Ten patients with SDAT received the ECP therapy. The examination of Hasegawa's Dementia Scale (HDS), single photor emission computed tomography (SPECT) brain imaging, and some biochemical parameters in blood and CSF were selected to evaluate the effect of ECP for SDAT. After ECP treatment, the average HDS score of the patients increased, the value of P was close to 0.05; and the cortical cerebellar ratios of SPECT brain scan, the superoxide dismutase (SOD) activity and the concentrations of somatostatin-like immunoreactivity (SLI), dynorphin AL 13 (Dyn Al-13) in blood and/or CSF were significantly elevated. The results indicated that ECP could not only improve cerebral blood flow, but also make a notable impact on biological active substances in blood and CSF. It is suggested that ECP is beneficial to SDAT patients. PMID- 7835103 TI - Experimental study on hepatic vascular exclusion with atrioportacaval shunt in dogs. AB - The main effects of hepatic vascular exclusion (HVE) on the body are hemodynamic changes and metabolic disorders. We developed a new technique--atrioportacaval shunt (APCS) both to increase the blood--return volume and to decompress the portal system and the inferior vena cava below the occlusion during HVE in canine. Experimental results showed that HVE-APCS is characteristic of simplicity and safety. During HVE-APCS central venous pressure (CVP), mean arterial pressure (MAP), mean pulmonary arterial pressure (MPAP), pulmonary capillary wedged pressure (PCWP) and pulmonary vascular resistance (PVR) remained almost stable while cardiac output (CO) decreased by 34.5-45.6% and systemic vascular resistance (SVR) increased by 46.8-65.7%. The recirculation injury to ischemic liver was mild owing to concomitant decompression of the portal system. It may be concluded that HVE-APCS is an ideal method to control the bleeding from the major hepatic veins and retrohepatic vena cava. PMID- 7835104 TI - Bone remodelling after internal fixation with different stiffness plates: ultrastructural investigation. AB - Forty adult New Zealand rabbits were used in this experiment. Four rabbits served as control and the rest 36 being divided into 3 groups, each of which was fixed respectively with methylmethacrylate, titanium alloy and stainless steel plate on the left intact tibiae. The cortical bone beneath the plate was harvested at 2, 4, 8 and 12 weeks after operation and observed by means of using transmission electron microscope. The major ultrastructural changes after internal fixation with different stiffness plates were alteration of osteocyte life cycle, perilacunar matrix and disorder of osteoblast and osteoblast coupling. The greater the stiffness of the plate, the greater the ultrastructural change. PMID- 7835105 TI - Electron microscopic observations of tegumental damage in adult Schistosoma japonicum after in vivo treatment with levo-praziquantel. AB - The in vivo effects of a single dose of levo-praziquantel, 75 mg/kg in PEG 400, on the tegumental surface of adult S. japonicum were compared with the effects of a single dose (150 mg/kg) of the mixed isomer preparation, using scanning and transmission electron microscope. Worms were recovered from mice at 10 min, 30 min, 1 hr, 4 hr, 12 hr, 24 hr and 48 hr after treatment. After 10 min exposure to either compound, the tegumental folds and sensory organelles were swollen and the tegument vacuolated. After 12-24 hr, the surface was eroded and exfoliated with exposure of intrategumental and/or subtegumental tissues and attachment of leukocytes to the denuded areas. Vehicle controls were normal throughout the time period examined. These studies demonstrate that the levo isomer of praziquantel causes acute structural damage to the tegument similar to that seen with the mixed isomer preparation. PMID- 7835106 TI - Differential ultrasonic diagnoses of pulmonary benign and malignant space occupied lesions of the peripheral type. AB - 87 patients with pulmonary space-occupied lesions of the peripheral type which were either adhesive or close to pleura were examined using ultrasonography. Of them, 64 cases of lung cancers and 23 of benign lesions were then confirmed by histopathology. Five sonographic features, including configuration, echogenicity patterns, bronchial air phase in foci, margin, and pleural involvement, were significantly different between malignant and benign diseases (P < 0.01). The differential ultrasonography used in this series showed a sensitivity of 61% (14/23), a specificity of 95% (61/64), and an accuracy of 86% (75/87). The results of the study demonstrate that the ultrasonography is helpful in differentiating malignant and benign peripheral lung lesions near the plerua. PMID- 7835107 TI - An immunocytochemical study on the distribution of calcitonin gene-related peptidergic nerve fibers in rat nasal mucosa. AB - The distribution of calcitonin gene-related peptidergic (CGRP) nerve endings in rat nasal mucosa was investigated with immunocytochemical technique (ABC method). The results showed that CGRP endings had a robust localization along the walls of arterioles, venules and around the acini of glands, with the endings near the wall of arterioles being most strongly stained. The typical morphology of CGRP endings could be recognized as multistage-branched terminals with rosary varicosities. CGRP immunoreactive neurons were also found in the trigeminal ganglion (TG). Supported by morphological evidence, we suggest that CGRP endings in rat nasal mucosa are the peripheral fibers originating from the ganglion cells in TG. These fibers may be involved in the perception of mucosal stimuli and the propagation of nerve impulse to the central terminals and will thus release CGRP in the brain stem. There is also possibility that CGRP may be peripherally released following local stimulation in the nasal mucosa and exert influences on the mucosal functions. PMID- 7835108 TI - Pathological changes of oxytalan fibers in the human gingiva of chronic periodontitis. AB - The gingiva samples were obtained from 40 patients with chronic periodontitis after flap operation and 20 cases having healthy gingiva after ectopic wisdom tooth extraction. We investigated the oxytalan fibers by light microscopy (LM), transmission electron microscopy (TEM), and scanning electron microscopy (SEM). The results demonstrated that under normal conditions numerous oxytalan fibers were widely and evenly distributed throughout the periodontal tissues. There was marked degeneration of the oxytalan fibers in chronic peridontitis. The predominant features were disintegration, fragmentation or disappearance of the oxytalan fibers under the basement membrane. Around the blood vessels, the oxytalan fibers decreased in density with fragmentation of the fibers and sometimes they disappeared almost completely. These results indicated that degeneration and destruction of the oxytalan fibers were closely correlated with the chronic periodontitis process, leading to reduced function occlusion of teeth. PMID- 7835109 TI - Hysteroscopic tubal catheterization and hydrotubation for treatment of infertile women with tubal obstruction. AB - We reported the efficacy of interval hysteroscopic tubal catherization and hydrotubation for three months in 54 infertile women with tubal obstruction (102 fallopian tubes). By comparison of HSGs before and after treatment, 86 of 102 tubes (84%) showed the improvement of tubal patency (P < 0.01). 56 tubes were patent (54.9%). This method is effective for partially patent tubes (87.5%), intramural tubal obstruction (62.5%), and the obstruction at the distal portion of the fallopian tube (13.3). One -12 month follow-up after treatment, 12 of 35 women whose tubes became completely patent achieved intrauterine pregnancies. PMID- 7835110 TI - Unruptured aneurysm of the left coronary sinus of valsalva associated with aneurysm of the interventricular septum. PMID- 7835111 TI - [The rational use of cesarean section]. PMID- 7835112 TI - [Relation between cesarean section rate and perinatal mortality rate]. AB - In order to evaluate the effect of cesarean section on reduction of perinatal mortality rate (PMR). All cases delivered in Beijing Obstetrics and Gynecology Hospital from Jan. 1, 1980 to Dec. 31, 1992 were analysed. The total number of delivery in study period was 74,199. Number of cesarean section delivery was 18,557. The cesarean section rate was 25.0%. The total number of perinatal baby was 74,914. The number of perinatal death was 1,140. PMR was 15.2%. The 13 years were divided into three periods to compare the cesarean section rate and PMR. The 1st period was from 1980 to 1984. The 2nd period was from 1985 to 1988. Years from 1989 to 1992 were 3rd period. The cesarean section rate was increasing year by year. It was significant since 1985. On the other hand, the PMR was marked decreasing since 1983. But there was no continually decrease in 2nd period. In 3rd period trend of decreasing PMR was shown. There was no significant difference in PMR especially in neonatal mortality rate (NMR) between cesarean section group and vaginal delivery group in 1st period. In 2nd period the PMR and NMR of cesarean section group was higher than that of vaginal delivery group (P < 0.01). In 3rd period it was lower in cesarean section group (P < 0.05). Main causes of neonatal deaths in cesarean section group were congenital abnormalities and respiratory diseases. In 2nd period pulmonary hemorrhage, hyaline membrane disease were marked higher in cesarean section group. It was related to more premature and low birth weight babies in this group.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7835113 TI - [Trial vaginal delivery for women with previous cesarean section]. AB - A retrospective analysis was made on 85 cases of trial labor after previous cesarean section (CS) and compared with 100 primiparous vaginal deliveries (as control) during the last 10 years. Oxytocin infusion has been used in 61 trial cases to induce and/or to accelerate labor, and valium, procaine and atropine administered during the labor process in 23 of them. 65 of the 85 cases (76.5%) successfully delivered through the vagina (VD group), while 20 cases (23.5%) had repeat CS following failure in trial labor (CS group), and 3 women had reatened uterine rupture. There was 1 neonatal death in the VD trial labor group. No obvious difference in the Apgar scores of newborns was found between the CS group and the controls, and the duration of the labor process was much shorter in the VD trial group than that in the primiparae (7.51 +/- 2.44 hrs vs. 9.10 +/- 3.75 hrs) (P < 0.01). This study indicated that following a previous uneventful transverse lower segment cesarean section, trial labor should be encouraged under supervision. PMID- 7835114 TI - [Detection of uterine scar defect during pregnancy by ultrasonics]. AB - B type ultrasonography was used to observe the formation of lower uterine segment in 71 primigravide and the status of lower uterine segment scar in 31 multiparae with previous cesarean section (CS), from the 33 to 41 gestational week. Results showed that the lower uterine segments was formed in all 102 cases after the 33rd week. Compared with the primigravide, the lower uterine segment in the CS group was longer, thinner and not as wide after the 37th gestational week. Defective scars of the lower uterine segment were found in 7 cases of the CS group and 2 of them were diagnosed as threatened dehiscence owing to the fetal sac protruding from the scar site. Condition of all these cases were confirmed during operation. The present study suggested that B ultrasonic scar can be a helpful and noninvasive method for detecting scar defect in the lower uterine segment following CS. PMID- 7835115 TI - [Clinical analysis of 36 repeat cesarean sections performed extraperitoneally]. AB - Extraperitoneal repeat cesarean section (CS) performed in 36 women with previous intraperitoneal CS (group A) was compared with another 36 cases of intraperitoneal repeat CS (group B). The average blood loss was 146ml in group A and 230ml in group B (P < 0.01). Operation time in group A lasted 40 minutes including 9 cases of tubal ligation coincidentally and 66 minutes in B with 12 tubal ligation (P < 0.05). There were 2 cases of peritoneal damage and 1 transient hematuria in group A. Postoperative morbidity in group A was 16.7% and 38.9% in group B (P < 0.01). The average time for bowel function recurrence was 26.2 hours in A and 52.6 in B respectively. No evident complication occurred in either group. It indicated that extraperitoneal route might be superior to intraperitoneal one for repeat cesarean section. PMID- 7835116 TI - [Low-dose of processed rhubarb in preventing pregnancy induced hypertension]. AB - A prospective randomized double blind study with processed rhubarb (low dose of 0.75g/day) was carried out in pregnant women at risk of pregnancy induced hypertension (PIH). Rhubarb (140 cases) or placebo (125 cases) was given to women at risk of PIH consecutively from the 28th week of gestation till delivery, and another 68 pregnant women as control. Results showed that 5.7% of rhubarb treated women developed PIH, a rate substantially lower than the 20.8% of the placebo group (P < 0.01). After 9-10 weeks of treatment, the plasma fibronectin (Fn) level and Plasminogen activator inhibiter (PAI) value were found significantly lower (P < 0.05) in the rhubarb treated group than in the placebo. Antithrombin III (ATIII) level also decreased significantly less in the rhubarb group as compared with the placebo (P < 0.05). It indicated that low dose of processed rhubarb has a good prophylactic effect on PIH. The mechanism may be related with the inhibition of PAI activity, reduced Fn synthesis and decreased damage to vascular endothelium. PMID- 7835117 TI - [Effect of early suckling and emptying the breasts after nursing on exclusive breastfeeding]. AB - A prospective study was carried out in 239 pairs of mothers and their newborns to determine the effect of early suckling and emptying the breasts after nursing on exclusive breastfeeding during four months after birth. The results showed that the early suckling could help the newborns to latch on the breast more readily and correctly than the newborns in control group and enhance the mothers' confidence on exclusive breast feeding. Emptying the breasts after nursing tended to increase the volume of breastmilk; thereby facilitating the exclusive breastfeeding rate during four months after birth. Besides the technique of expressing the breast would enable the mother to continue exclusively breast feed her baby after a temporary separation. Early suckling and emptying the breasts after nursing are to be recommended as important measures in supporting breastfeeding. PMID- 7835118 TI - [The effect of co-administration of low dosage growth hormone and gonadotropin for ovarian hyperstimulation in vitro fertilization and embryo transfer]. AB - The co-administration of low dosage growth hormone (GH) and gonadotropin (Gn) to women with suboptimal response to GnRH-a/hMG/hCG hyperstimulation regimen during previous cycles in in vitro fertilization-embryo transfer (IVF-ET) might be beneficial by promoting the maturation of oocytes, improving the fertilization rate and increasing the number of embryos replaced. Our results showed the pregnancy rate increased significantly. However, this protocol neither enhanced ovarian response to Gn, nor reduced Gn dosage required for follicular recruitment. The levels of insulin-like growth factor I (IGF-I) in the co treatment group increased from 150 +/- 44 micrograms/L to 222 +/- 46 micrograms/L (P < 0.01) during the administration of GH. These increased significantly as compared with the control group. The present study showed that the administration of GH in low doses is effective. PMID- 7835119 TI - [Urinary gonadotropin fragment measurement in the monitoring of trophoblastic disease]. AB - Urinary gonadotropin fragment (UGF) is a small peptide which is present in the urine of pregnant women and of women with trophoblastic diseases as well as with certain nontrophoblastic malignancies. 275 samples each of urine and blood from 46 patients with trophoblastic diseases were taken for UGF and hCG measurements and compared. 24 samples from 12 healthy, nonpregnant women were taken as control. Cut-off values of UGF and hCG used for measuring the sensitivity of trophoblastic diseases were respectively > 0.2 microgram/L and above 20 micrograms/L. It was found that 64.0% of the urine samples gave UGF values > 0.2 microgram/L and 66.5% of the blood samples showed hCG levels above 20 micrograms/L (P > 0.1). No false-positive rate was observed in the control group. However, among patients who were found to have low or negative hCG values, 57.6% showed positive UGF levels. These findings suggest that in patients with positive levels of both UGF and hCG, the UGF measurement may not be necessary. But for patients with low or negative blood hCG values, certain percentage of urine UGF could still be detected. PMID- 7835120 TI - [Soluble interleukin-2 receptor level in the sera and ascitic fluids in patients with ovarian cancer]. AB - In 31 patients with ovarian cancer, the sIL-2R level of the sera and ascitic fluids were measured by ELISA, to investigate the inhibitive effect of sIL-2R purified from ascitic fluids on normal lymphocyte transformation, stimulated with phytohemagglutinin (PHA). The results showed that the sera sIL-2R levels in the patients were much higher than those in the normal controls (857 +/- 428kU/L vs 235 +/- 90kU/L, P < 0.001). The sera sIL-2R levels in mucinous cancer were significantly higher than those in serous cancer (988 +/- 539kU/L vs 488 +/- 233kU/L P < 0.01). But no obvious correlation was observed with the histopathological grading, nor with metastasis. Higher levels of sIL-2R were also observed in the ascitic. The normal lymphocyte transformation stimulated with PHA was significantly inhibited by high sIL-2R purified from the ascitic fluids. PMID- 7835121 TI - [Multiload Cu250 intrauterine devices and VCu200 intrauterine devices for women with previous failure of stainless steel ring intrauterine devices: a 5-year randomized clinical trial]. AB - Two hundred rural women with history of stainless steel ring (SSR) intrauterine devices (IUD) failure (i.e. expulsion or pregnancy with IUD-in-situ) were randomly allocated into Multiload Cu250 (MLCu250) or VCu200 group. The follow up rate was 97.5% at the end of 5-year. The 5-year gross cumulative continuation rates per 100 women for MLCu250 and VCu200 were 80.0 and 81.7 respectively. The 5 year cumulative expulsion rate was significantly lower in MLCu250 group (1.0) than that in VCu200 group (8.1) (P < 0.05), while the pregnancy rate was higher in MLCu group (12.0 vs. 4.1) but no statistical significant difference existed between the 2 groups. The removal for bleeding and (or) pain were similar (6.0 and 6.1). There was one ectopic pregnancy in each group and no removal for medical or personal reasons. The expulsion and pregnancy cases in the present study were not associated with their previous failures. It was concluded that both types of copper IUD were effective for women with previous failure of SSR. The study also showed that MLCu250 might be used as long as 5 years. Should surface area of copper be increased, further decreased pregnancy rate would be expected. PMID- 7835122 TI - [Indicatin and complications of cesarean section]. PMID- 7835123 TI - [Synchronous primary cancers of endometrium and ovary]. PMID- 7835124 TI - [Analysis of national maternal death surveillance: 1989-1991]. AB - An analysis of maternal mortality in 247 cities, districts and countries of 30 provinces, municipalities and autonomous regionscovering a population of 100,000,000 in China in 1989-1991 was reported. The total number of live births was 4,201,457 in the pilot area, and the number of maternal deaths was 3,274 giving an average maternal mortality rate (MMR) of 80.0/100,000. After correction, the average MMR was 87.8/100,000. The MMR per annum was in decreasing trends and in different regions were different from one another. The first 6 leading causes of maternal deaths in 3,274 cases, in decreasing order of importance, were: obstetric hemorrhage, pregnancy induced hypertension, cardiac diseases, puerperal infection, amniotic fluid embolism, and hepatic diseases. The result of audit on maternal deaths was as follow: 89.0% of the maternal deaths were avoidable, and 11.0% were unavoidable. Three aspects of the maternal deaths in China were formulated form this study. PMID- 7835125 TI - [Serum level of soluble interleukin-2 receptor and T-lymphocyte subpopulations in normal pregnancy]. AB - Serum soluble interleukin-2 receptor (sIL-2R) levels and T lymphocyte subpopulations were measured in 87 cases of normal pregnancy and 109 normal non pregnant women as control group. It was found that sIL-2R level and CD8 T subpopulation increased as compared with control group (214,600 +/- 70,400 U/L vs 162,100 +/- 84,100 U/L, P < 0.01; 37.6% +/- 5.3% vs 31.3% +/- 7.0%, P < 0.01), but the ratio of CD4/CD8 was lower than that of control group (1.2 +/- 0.2 vs 1.5 +/- 0.5, P < 0.01). No significant difference was found between CD3, CD4 subpopulations of pregnancy and that of control group (64.1% +/- 7.3% vs 66.0% +/ 9.9%, P > 0.05; 44.1% +/- 5.8% vs 43.8% +/- 9.0%, P > 0.05). And no significant relation was found between sIL-2R level and CD3, CD4, CD8 subpopulations, CD4/CD8 (r = 0.203 2, 0.207 7, 0.103 7, 0.121 4 respectly, P > 0.05). These results suggested that the changes of T lymphocytes and sIL-2R may play an important role in maintaining normal pregnancy and sIL-2R may be one of factors improving fetal survival. PMID- 7835126 TI - [Measurement of plasma fibronectin concentrations in normal pregnancy and pregnancy induced hypertension and its clinical significance]. AB - Plasma fibronectin (Fn) concentrations were measured in 472 cases of normal pregnancy and pregnancy induced hypertension (PIH), and 50 cases of normal individuals using radioimmune turbidity method. The results showed that the mean value of Fn in 390 cases of normal pregnancy with various weeks of gestation was 445 +/- 159 mg/L significantly higher than the average of 299 +/- 76 mg/L in 50 cases of normal individuals and 250 +/- 89 mg/L in 22 cases of normal women. As pregnancy progressed, the plasma Fn value increased slightly. The 82 cases of PIH had an average plasma Fn level of 783 +/- 168 mg/L, which was significantly higher than that in normal pregnancy. If plasma Fn concentrition of 600 mg/L was used as cut-off point for the diagnosis of PIH, the sensitivity reached to 83%. Plasma Fn level increased as the disease of PIH progressed. Therefore, plasma Fn concentrition could be used as a reliable indicator to the severity of PIH. PMID- 7835127 TI - [Tumor necrosis factor in peritoneal fluid of infertile women with endometriosis and its relation to sperm motility]. AB - Tumor necrosis factor (TNF) of 16 infertile women with endometriosis was measured in their peritoneal fluid (PF) with double monoclonal antibody ELISA method, and its effect on sperm motility and membrane integrity was evaluated by semen analysis and hypoosmotic swelling test (HOS). Comparing with that of infertile women without endometriosis (n = 11) and normal fertile women (n = 7), the level of PF-TNF was significantly higher in women with endometriosis (P < 0.01), in accord with the stage of the disease. In the PF of these patients after incubation with the donor sperms, the percentages of forward movement, total motility and hypoosmotic swelling of the donor sperms were significantly decreased (P < 0.01), showing a negative correlation to TNF levels. These results indicate that the elevation of PF-TNF in endometriosis has detrimental effect on sperm function. PMID- 7835128 TI - [Glucose and lipid metabolism in patients with polycystic ovary syndrome]. AB - Glucose and lipid metabolism were studied in 30 patients with polycystic ovary syndrome (PCOS), divided into obese (n = 17) and non-obese (n = 13) groups according to BMI > 27 or < 24. Another 30 healthy controls were also divided into obese (n = 14) and nonobese (n = 16) normal groups on the same index. Cubital venous blood was drawn from each participant for oral glucose tolerance test (OGTT), insulin and lipid profile determination, for PCOS groups at the end of 3 months amenorrhea and control groups within the first 10 days of the menstrual cycle. The results showed: (1) the PCOS groups had much higher insulin level before and after OGTT than the normal groups. There was a significant positive correlation between fasting insulin level and testosterone concentration; (2) in lipid profile, the triglyceride levels in both obese groups were significantly higher than that in the non-obese groups, in whom a strong positive correlation between triglyceride and BMI was found. It is concluded that the obese and non obese PCOS were correlated with insulin alteration, and the changed serum lipid in obese PCOS patients might be the effect of obesity but not PCOS. PMID- 7835129 TI - [A controlled study of chemiluminescent enzyme immunoassay for the measurement of estrogen receptor in tissue of gynecological neoplasms]. AB - In this study, chemiluminescent enzyme immunoassay (CLEIA) has been developed for the measurement of estrogen receptor (ER) in 34 gynecological oncological tissues from 15 cases of endometrial carcinoma, 15 cases of ovarian tumors and 4 cases of other gynecological tumors. The accuracy, specificity and sensitivity of CLEIA for ER were compared with that of dextran-coated charcoal (DCC) and enzyme immunoassay (EIA). RESULTS: (1) the standard curve of ER-CLEIA showed a significant linear correlation between the luminosity and ER concentration (r = 0.9786, P < 0.001); (2) The results of CLEIA and that of the other two methods were compared; the correlation coefficients were > 0.8 and their corresponding rates were > 90%; (3) the positive rate of ER determined by these three methods showed no significant differences, however, the mean value of ER-CLEIA was the highest among them. It is concluded that the CLEIA has a higher sensitivity than that of the other two methods for the measurement of ER. PMID- 7835130 TI - [The characteristic of lymphokine-activated killer cells induced from tumor draining lymph-node cell]. AB - A short time lymphocyte culture for lymphokine activated killer (LAK) cells was presented, the lymphocytes being collected from the tumor draining regional lymph nodes in seven patients with gynecologic malignant tumors. The results showed different cytotoxic activities of LAK cells against Lewis pulmonary cancer cells, CAOV, cells and the new separated ovarian cancer cells. And the cytotoxic activity of the LAK cells increased with the rise of the effecter cell-target cell ratio and maintained at a certain level when the rise of the latter's increase reached a certain extent. The cytotoxic activity of the LAK cells against autologous tumor cells (as from ovarian cancer) were shown to be much stronger than against the others. As the culture days lengthened, the cytotoxicities of the LAK cells from interleukin-2/OKT 3 culture became stronger than from interloukin-2 alone. Large quantities of lymphocytes could be collected from tumor-draining lymphe nodes. This is a preliminary investigation on the inducing of LAK cells from lymphocytes of the draining regional lymph nodes of malignant gynecologic tumors. The quantitative increase of LAK cells and the effect of their cytotoxic activities are to be further explored. PMID- 7835131 TI - [Quantitative analysis of the cellular DNA and RNA contents of hydatidiform mole and its clinical significance]. AB - The cellular DNA and RNA contents of 152 patients with hydatidiform moles (69 benign and 83 malignant) were analysed by flow cytometry (FCM), and strict follow up was implemented. The chorionic villi of twelve cases in early pregnancy were used as normal control and another 12 cases of choriocarcinoma as positive control. Retrospective as well as prospective studies were conducted. The results showed that the accuracy rates of diagnosis of DNA aneuploid and RNA were respectively 66.7% and 82.6% in benign moles, 68.7% and 81.9% in invasive moles. Statistically the RNA parameter was significantly more sensitive the DNA parameter (P < 0.05). Analysis with both RNA and DNA parameters in predicting malignancy, the accuracy rate was 94.0%. Our study suggests that both the aneuploidy DNA and RNA contents may be important indicators for forecasting malignant change. The RNA parameter is more sensitive than the DNA parameter, and the use of both parameters is more accurate than either one alone. In addition, the concept of "standard DNA index" is raised. PMID- 7835132 TI - [Operative treatment for vulvar cancer by different methods]. AB - A retrospective analysis of 88 patients with vulvar cancer treated by radical vulvectomy and groin lymphadenectomy from July, 1958 to December, 1990 is presented. 88 cases are divided into two groups based on different operative methods: the enbloc group (25 cases) and the non-enbloc group (63 cases). No significant statistic differences are found in the 5-year survival rates (76.0% vs 79.8%) and the complications (erysipelas, lower extremity edema) between the two groups. The wound healing time is 14.4 days shorter in the non-enbloc group than enbloc group. Factors such as clinical staging, metastasis to the inguinal lymph nodes and histopathological classification are also investigated for correlation with the prognosis. PMID- 7835133 TI - [Long-term clinical observation on VCu200 intrauterine devices]. AB - A comparative study was carried out in 350 women using VCu200 intrauterine devices (IUD) and 350 women using stainless steel ring (SSR) IUD for 5-18 years. The endometrial changes and shapes of IUD were studied. The results showed that the pregnancy rate was significantly lower in VCu200 group after 5 years of insertion. In spite of the oxidation, erosion or breakage of the copper wire, calcium deposit of even deformation of the IUD, they were not associated with an increased incidence of endometrial carcinoma and pelvic inflammatory disease. It is suggested that VCu200 IUD need not to be removed if the IUD keeps normal shape and the copper wire remains intact by X ray examination. PMID- 7835134 TI - [Advances in the study of oncogenes and tumor suppressor genes in endometrial carcinoma]. PMID- 7835135 TI - [To accelerate the research on cytokine]. PMID- 7835136 TI - [To improve the accuracy of the pathological diagnosis of lymphadenopathy]. PMID- 7835137 TI - [The effects of recombinant human transforming growth factor beta on inducing differentiation of fresh leukemia cells in acute monocytic leukemia M5]. AB - By using fresh leukemia cells from 5 cases of acute monocytic leukemia M5 as in vitro model, we investigated the effects of recombinant human transforming growth factor beta 1 (rhTGF-beta 1) on differentiation induction of fresh leukemia cells. The results indicated that after 6 days of induction with TGF-beta 1 in a concentration of 10 ng/ml, leukemia cells in 5 AML-M5 patients differentiated obviously to maturation. The proportion of monoblasts and premonocytes was reduced, while that of mature mononuclear cells elevated. Following administration of TGF-beta 1, alpha-nonspecific esterase (alpha-NSE), whose expression could be inhibited by sodium fluoride, remained positive and peroxidase (POX) was shown to be weakly positive. These results demonstrated that TGF-beta 1 may induce in vitro differentiation of fresh leukaemia cells, but the reactions to TGF-beta 1 may vary in different cases. PMID- 7835138 TI - [Effect of recombinant human growth factors: recombinant human interleukin-6, recombinant human granulocyte-macrophage colony-stimulating-factor and recombinant human erythropoietin on normal human hematopoietic progenitor cells]. AB - The effect of recombinant human growth factors: rhIL-6, rhGM-CSF and rhEPO on normal human hematopoietic progenitor cells was studied by using liquid and semisolid culture systems. The results showed that the expanding folds of progenitor cells after culturing with the three growth factors were 4.3 +/- 0.6, 9.4 +/- 0.9 and 13.7 +/- 1.0 respectively, being markedly higher than those of control (2.4 +/- 0.7, P < 0.01. In the presence of IL-6 alone, no CFU-E colony was observed and only CFU-GM colonies were formed in the semisolid culture. When IL-6 was added with EPO, the number of CFU-E colonies was significantly higher than that of EPO alone (P < 0.01). In the presence of IL-6 plus GM-CSF or IL-6 plus GM-CSF and EPO, CFU-Mix colonies were observed. Moreover, the total number of colonies was significantly higher than that of IL-6 or GM-CSF alone (P < 0.01). It is suggested that IL-6 is an important hematopoietic regulator. IL-6 may act on hematopoietic progenitor cells to enhance their proliferation. The target cells of IL-6 are the same as those of GM-CSF. IL-6 has synergistic action with EPO and GM-CSF, to enhance erythropoiesis with EPO and proliferation of multipotential progenitor cells with rhGM-CSF and EPO. However, the mechanism of the synergism between IL-6 and other growth factors is still unknown. PMID- 7835139 TI - [Inhibition of proto-oncogene c-myc expression with recombinant human tumor necrosis factor-alpha and interferon-gamma in HL-60 cell lines and acute myelocytic leukemic fresh cells]. AB - HL-60 cell lines and AML fresh bone marrow cells were incubated with rhTNF-alpha and rhIFN-gamma in suspension culture system. Then total RNA was prepared for dot blot with 32P nick-translated c-myc DNA probe. The expression changes of c-myc oncogene when the HL-60 cell lines were treated with rhTNF-alpha and IFN-gamma and the AML fresh bone marrow cells treated with rhTNF-alpha alone were observed. The results showed that when the HL-60 cells were treated with 100U/ml or 500U/ml IFN-gamma and 50U/ml rhTNF-alpha for 8 hours, the expression of c-myc oncogene can be inhibited remarkably. The combination of rhIFN-gamma and rhTNF-alpha shows synergistic effect on inhibition of c-myc expression. High expression of c-myc was found in 8 patients with AML; c-myc mRNA level decreased remarkably after treatment of fresh bone marrow cells with 50U/ml rhTNF-alpha for 12 hours in 6 cases, while the remaining 2 cases showed minimal changes. The results demonstrate that rhTNF-alpha have inhibitive effect on c-myc expression in HL-60 cells and AML fresh leukemic cells. It also indicates the possibility of treating AML with low-dose rhTNF-alpha. PMID- 7835140 TI - [Intravenous placental immunoglobulin for treatment of chronic graft versus host disease]. AB - Intravenous placental immunoglobulin (IV Pt IG) was used for the treatment of chronic graft versus host disease (CGVHD) in 30 patients who are refractory to steroid and cyclosporinic A. 15 (50%) patients showed excellent response and 11 (36.66%) good response. The total response rate is 86.66%. The dosage of IV Pt IG was 4 gm/day in adults by intravenous infusion. Effectiveness of IV PtIG was discerned within 2 weeks. The plasma levels of IgG, IgA and IgM were tested before and after IV PtIG treatment. There was no significant statistical difference between the plasma IgG, IgA, IgM levels in pre- and post-treatment period. The efficacy of IV PtIG against CGVHD is therefore ascribed to its pharmacological effect. PMID- 7835141 TI - [Changes in soluble interleukin-2 receptor and its significance in nephrotic syndrome]. AB - Serum and urine soluble interleukin-2 receptor (SIL-2R) levels were determined with ELISA method in 36 cases of nephrotic syndrome in order to investigate the significance of the change of SIL-2R level. The results showed the values in nephrotic stage group (n = 22) exceeded those in nephrotic stage remission group (n = 14, P < 0.01) and those in healthy controls (n = 20, P < 0.01). However, there was no difference of SIL-2R values either in serum or urine between nephrotic stage remission group and healthy controls (P > 0.05). Serum SIL-2R values were correlated with those of serum creatinine (r = 0.44, P < 0.01) and urine SIL-2R values were correlated with those of urine protein excretion (r = 0.48, P < 0.01). The study suggests that increased concentration of SIL-2R can serve as an indicator of nephrotic syndrome activation and/or exacerbation of renal dysfunction. PMID- 7835142 TI - [An animal model of peptic ulcer induced by destruction of dopaminergic neurons]. AB - An animal ulcer model resembling human peptic ulcer elicited with neurotoxin 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by different routes of administration, i.e., intracerebroventricular (i.c.v.), subcutaneous (s.c.) or intraperitoneal (i.p.) injections was newly established. MPTP given in multiple daily doses by either i.c.v., s.c. or i.p. produced 50%-100%, 75% and 100% gastric or duodenal ulcers respectively with low mortality and was indicative of a better animal model in elucidating the correlation between neurotransmitters and ulcer diseases. This compound decreased total gastric acid output, increased the combined mucus secretion and serum gastrin, but had little effect on secretion of free gastric acid. Thus these results showed that MPTP-induced gastroduodenal ulcers are possibly associated with impaired defensive ability of mucosa, especially of mucus bicarbonate barrier instead of gastric acid. However, further study is needed to demonstrate why administration of the drug in different routes produced different ulcers. PMID- 7835143 TI - [Changes in the clinical features of infective endocarditis in recent decade]. AB - In order to know whether there are changes of the clinical features of infective endocarditis (IE) in recent decades, 66 cases of IE diagnosed from 1983 to 1992 were included in this study and compared with the IE patients of Beijing area from 1948 to 1963. The results showed the following changes in the recent decade: 1. Rheumatic heart diseases accounted for less and congenital heart diseases more of the proportion of IE cases when compared with materials of previous decades. Idiopathic mitral valve prolapse and valvular degeneration were found in some of the patients. 2. Cardiac operation and catheterization induced IE became more common, whereas oral infection incited IE less. 3. Skin lesion got much less so that the clinical manifestations of IE were atypical. 4. Hospital mortality decreased markedly. PMID- 7835144 TI - [Analysis of patients of psoriasis coexisting with chylothorax]. AB - Six patients diagnosed as Psoriasis with complication of chylothorax (3 of chylothorax, 3 of both chylothorax and chyloperitoneum, age from 21 to 50, male 4, female 2) were reported. All patients have a history of taking a chinese medicine named "complex Wulong powder" for treating psoriasis. All patients have not the history of trauma, operation, and the history of living in epidemic focus of filariasis. Their X-ray exam and CT exam of chest did not show lung lesion but pleural effusion. Chylothorax coexisting with psoriasis was not found in literature. This result suggests that using complex WuLong powder might be the cause of chylothorax. The mechanism was unknown. PMID- 7835145 TI - [A study on the relation between cerebral lesion and cognitive defect in multi infarct patients]. AB - 240 cases of multi-infarct patients with more than two cerebral infarct lesions in CT findings were collected successively from 1991 to 1992. 42.92% of them were shown to have cognitive defect with a series of neuropsychological tests. Correlation of the occurrence of cognitive defect with the CT findings such as the location and extent of focal lesions as well as the presence of cerebral atrophy or subcortical degeneration were carried out. According to the results by multiple regression and factor analysis, the location and extent of the focal infarct lesions were not the primary determining factor for the occurrence of cognitive defect. It is, therefore, suggested that the term of ischemic or vascular dementia be used clinically instead of the so-called multi-infarct dementia. PMID- 7835146 TI - [The relation between lithium and glucose metabolism]. PMID- 7835147 TI - Symposium on Germline Development. London, 20-22 July 1993. PMID- 7835148 TI - Embryonic germ cell lines and their derivation from mouse primordial germ cells. AB - When primordial germ cells of the mouse are cultured on feeder layers with the addition of the polypeptide signalling molecules leukaemia inhibitory factor, Steel factor and basic fibroblast growth factor they give rise to cells that resemble undifferentiated blastocyst-derived embryonic stem cells. These primordial germ cell-derived embryonic germ cells (EG cells) can be induced to differentiate extensively in culture and also form teratocarcinomas when injected into nude mice. Additionally, they contribute to chimeras when injected into host blastocysts. We have derived multiple EG cell lines from 8.5 days post coitum (dpc) embryos of C57BL/6 inbred mice. Four independent EG cell lines with normal male karyotypes have formed chimeras (up to 70% coat colour chimerism) when injected into BALB/c host blastocysts. Chimeric mice from all four cell lines are fertile, but only those from one line have transmitted coat colour markers through the germline. Studies have also been carried out to determine whether gonadal primordial germ cells can give rise to pluripotent EG cells. Germ cells from gonads of 15.5 dpc C57BL/6 embryos and newborn mice failed to produce EG cell lines. EG cell lines capable of forming teratocarcinomas and coat colour chimeras have been established from primordial germ cells of 12.5 dpc genital ridges. We are currently testing the genomic imprinting status of the insulin like growth factor type 2 receptor gene (Igf2r) in our different EG cell lines. PMID- 7835149 TI - Control of germ cell differentiation in Caenorhabditis elegans. AB - The germline of Caenorhabditis elegans is organized in a linear fashion--the most distal germ cells remain in mitosis, those in the middle enter meiosis and proximal cells differentiate as sperm or oocytes. Two signal transduction pathways control germ cell fates. The glp-1 gene mediates a signal that promotes mitosis and the genes of the sex determination pathway mediate a signal that determines if germ cells will develop as sperm or oocytes. Information from these pathways acts through terminal regulators to specify cell fate. For example, fog 1 and fog-3 are required to initiate spermatogenesis and gld-1 appears to be required to initiate oogenesis. Study of these terminal regulators suggests that the decisions about sexual identity and mitosis are linked in germ cells. We propose a tripartite interaction that forces germ cells to adopt one of only three fates--mitosis, spermatogenesis or oogenesis. PMID- 7835150 TI - Sex determination of germ cells in Drosophila. AB - Many lines of evidence indicate that in Drosophila the mechanism for establishing the sex of the female germline is different from that acting in somatic cells. In the soma Sxl has an embryonic determinative role and is required throughout the life of female flies; in germ cells its expression begins only in the larval ovary. Both the mechanism for activating Sxl and the genes controlled by Sxl are different in the germline. A number of genes have been identified that are essential either for survival (e.g. ovo, otu) or differentiation (snf, Sxl, fl(2)d, bgcn) of female germ cells. ovo is required during embryogenesis for survival of pole cells. Genetic interactions with dominant alleles of ovo and/or Sxl indicate that otu, Sxl, snf and fl(2)d act in the same pathway as does ovo. bgcn differs in that neither ovo nor SxlD mutations affect the bgcn phenotype even though XX bgcn germ cells enter the male pathway. bgcn causes sterility in both sexes. Although the germline defect is cell autonomous in mosaic gonads, bgcn is also required in the somatic tissue for maintaining oogenesis of wild type germ cells. Several dominant suppressors of bgcn have been identified and some have properties similar to Suppressors of variegation, suggesting that chromatin structure is critical for proper germ cell sex determination. PMID- 7835151 TI - Germ cell specification in Volvox carteri. AB - Volvox carteri illustrates with diagrammatic clarity Weismann's concept of an immortal germline that produces a mortal soma that will carry it for a time, but then perish. Each V. carteri adult consists of about 16 asexual reproductive cells (gonidia) in the interior of a sphere that consists at its surface of about 2000 biflagellate somatic cells. When mature, each gonidium divides to form a juvenile with this same cellular composition. Half-way through their maturation, juveniles hatch out of the parenteral spheroid, whereupon parental somatic cells undergo programmed death while juvenile gonidia prepare for a new round of reproduction. The first visible step in V. carteri germ-soma differentiation is asymmetric cleavage, which sets apart large gonidial initials from small somatic initials. Experimental analysis indicates that it is a difference in size, not any difference in cytoplasmic quality, that determines whether a cell will become germinal or somatic. Mutational and molecular studies lead to the following model for the genetic control of the germ-soma dichotomy: first, the gls locus acts to cause asymmetric division; then large cells activate a set of lag loci that suppress expression of somatic genes, while small cells activate the regA locus that suppresses gonidial genes. PMID- 7835152 TI - Molecular genetics of the early stages of germ cell differentiation during Drosophila oogenesis. AB - Germ cells frequently develop in syncytial clusters. We are using molecular genetic approaches to the formation of these clusters in Drosophila as a paradigm for cellular differentiation. The genes described in this paper act during an initial step of cluster formation (bag-of-marbles gene [bam]) and near the end of syncytial divisions (orb gene). The results presented suggest that the bam gene product is required for the four incomplete cytokineses that characterize the initial stages of cluster formation. The orb gene, previously identified as an ovarian-specific cDNA which predicts a new member of the RNA-recognition motif family of RNA-binding proteins, is required for both early and late stages of oogenesis. Strong orb alleles arrest egg development at the time of nurse cell oocyte cyst formation; weak alleles disrupt formation of the anteroposterior and dorsoventral axes within the oocyte during late oogenesis. We postulate that Orb is a constituent of cytoplasmic multiprotein complexes which deliver RNA molecules to specific addresses within the oocyte. PMID- 7835153 TI - Egalitarian and the choice of cell fates in Drosophila melanogaster oogenesis. AB - Oogenesis in Drosophila females begins with the formation of a cyst of 16 interconnected sister cells, one of which eventually becomes the definitive oocyte. The other 15 become nurse cells, performing nutritive roles for the oocyte. There are four alternative developmental pathways in each cyst: winning pro-oocyte, losing pro-oocyte and cells with three ring canals, all of which enter meiosis, and the twelve obligate pro-nurse cells, which do not. In flies homozygous for the female-sterile mutation egalitarian (egl) all 16 cells follow the same intermediate pathway. All nuclei enter meiosis (shown by their attainment of synaptonemal complex of at least mid-zygotene levels and by their attainment of pachytene numbers and locations of recombination nodules), then all exit it and become morphologically indistinguishable from nurse cells in wild type flies. The wild-type allele of egl therefore performs two active but opposite roles in cell fate choice. Early on it is necessary for inhibition of meiotic entry in the 'obligate' pro-nurse cells; later it is necessary for meiotic maintenance in the 'winning' pro-oocyte. One can account for both roles from a single function by invoking gradients through the early cyst; the egl+ function appears to be required for the normal function of these gradients. PMID- 7835154 TI - The onset of spermatogenesis in fish. AB - Under cultivation conditions, male Japanese eels (Anguilla japonica) have immature testes containing only spermatogonia together with inactive testicular somatic cells, Leydig cells and Sertoli cells. Using a recently developed organ culture system for eel testes, we have shown that hormonal induction of spermatogenesis in eel testes involves gonadotropin stimulation of Leydig cells to produce 11-ketotestosterone, a potent androgen in fish. In turn, 11 ketotestosterone activates Sertoli cells to stimulate premitotic spermatogonia to complete spermatogenesis. Our current research focuses on the isolation and characterization of genes that show altered expression in eel testes during gonadotropin-induced spermatogenesis. One up-regulated and three down-regulated genes have been isolated. Northern blot analysis and in situ hybridization reveal that mRNA for activin B is absent in testes before gonadotropin injection and is abundant in Sertoli cells in testes injected with gonadotropin for one to six days after injection. This stimulation of activin B mRNA is accompanied by spermatogonial proliferation. Gonadotropin treatment also causes a rapid rise in the testicular concentrations of mRNA for 3 beta-hydroxysteroid dehydrogenase, the rate-limiting enzyme for gonadotropin-induced 11-ketotestosterone production. We have also obtained three down-regulated cDNAs which are abundant in testes before gonadotropin treatment and disappear almost completely in testes one day after gonadotropin injection. PMID- 7835155 TI - Somatic cell-germ cell relationships in mammalian testes during development and spermatogenesis. AB - In the mammalian testis, somatic cells under hormonal regulation greatly influence the different stages of spermatogenesis, both in intermittent breeders and in animals which produce sperm continuously. In turn, specific populations of germinal cells modulate the function of Sertoli cells, the chief somatic cells within mammalian seminiferous tubules. Tubule formation can take place in the absence of germinal cells. Unlike homologous granulosa cells in the ovary, Sertoli cells retain many of their usual functions in germ cell-free animals. Some of the properties of Sertoli cells and their responses to stimulation by androgens or follicle-stimulating hormone are dependent upon information transmitted from neighbouring germinal cells at specific stages of the cycle of the seminiferous epithelium. We review the roles of some of the growth factors and paracrine agents synthesized and secreted by different classes of testicular cells. The potential roles of some of the known factors secreted by Sertoli cells (e.g. activin, inhibin, anti-Mullerian hormones, TGF-beta and somatomedin C) are considered in relation to the control of tubule formation, spermatogonial proliferation and cytodifferentiation, meiosis and the subsequent stages of spermatogenesis. We stress the importance of the unique tubule cytoarchitecture within which cell interactions take place and the changing nature of this cytoarchitecture at different stages of gonadal maturation. PMID- 7835156 TI - Specification and development of the germline in Caenorhabditis elegans. AB - Maternal-effect sterile (mes) genes encode maternal components that are required for establishment and development of the germline. Five such genes have been identified in the nematode Caenorhabditis elegans. Mutations in one of the genes result in defects in the asymmetric division and cytoplasmic partitioning that generate the primordial germ cell P4 at the 16-24-cell stage of embryogenesis. As a result of these defects, the P4 cell is transformed into a muscle progenitor and mutant embryos develop into sterile adults with extra body muscles. Mutations in the other four mes genes do not affect formation of the germline during embryogenesis, but result in drastically reduced proliferation of the germline during post-embryonic stages and in an absence of gametes in adults. The failure to form gametes may reflect a defect in germline specification or may be a consequence of reduced germline proliferation. We are currently testing these two possibilities. In addition to the mes gene products, wild-type function of the zygotic gene glp-4 is required for normal post-embryonic proliferation of the germline. Germ cells in glp-4 mutant worms are arrested in prophase of the mitotic cell cycle and are unable to enter meiosis and form gametes. Thus, following establishment of the germ lineage in the early embryo, both maternal and zygotic gene products work in concert to promote the extensive proliferation of the germline and to enable germ cells to generate functional gametes. PMID- 7835157 TI - Primordial germ cell formation in birds. AB - At the early somite stage, chicken embryo primordial germ cells comprise a population of about 200 dispersed, morphologically distinct cells, located in the extraembryonic germinal crescent. Tracing the origin of primordial germ cells at earlier stages is at present not possible by either cytological or immunohistochemical techniques. To resolve this difficulty we have microdissected embryos at early embryonic stages, isolated fragments from various positions and incubated them to the somite stage, when the primordial germ cells can be visualized accurately. From these studies a distinct developmental pattern has emerged. (1) At the uterine stage, when the area pellucida starts to thin out, there is already a defined area, confined to the most central part of the blastodisc, which constitutes the sole source of the future primordial germ cells. (2) As development proceeds, the area that gives rise to the primordial germ cells expands peripherally. (3) Primordial germ cells thereafter migrate as isolated cells, descending to the lower layer, the hypoblast. (4) This gradual process starts at the onset of blastulation and terminates towards the end of gastrulation. (5) The hypoblast, destined to become the yolk sac endoderm, is pushed anteriorly during gastrulation by morphogenetic movements to be replaced by the endoderm proper; the primordial germ cells are carried forwards with it and occupy an extraembryonic location. PMID- 7835158 TI - Clonal analysis of the origin of primordial germ cells in the mouse. AB - Qualitative and quantitative clonal analysis has been used to answer three basic questions about the establishment of the germ cell lineage in the mouse. Where do primordial germ cells originate? What is the size of the founding population at the time of lineage restriction? When and where does lineage restriction occur? Single epiblast cells of 6.0 dpc and 6.5 dpc mouse embryos were injected with a short-term lineage label (lysinated rhodamine dextran, LRDX) and their descendants traced after 40 h embryo culture at neural plate and early somite stages, respectively. An objective matching technique was used to detect the lineage marker in primordial germ cells identified by their characteristic alkaline phosphatase staining. Precursors of the primordial germ cells were found in the proximal epiblast close to the extraembryonic ectoderm in both pregastrulation and early-streak stage embryos. They form part of the presumptive extraembryonic mesoderm and are not lineage restricted while in the epiblast. Quantitative analysis gives a best fit to a model of a founding population of 45 at the time of lineage restriction. The data indicate that the generation time lengthens at the time of allocation. Calculation of clonal histories gives a best fit of 16 h generation time after allocation compared with < 7 h before allocation, with lineage restriction occurring at the early midstreak stage, presumably in the region posterior to the streak in which primordial germ cells are first identifiable. Therefore primordial germ cells are probably allocated early during gastrulation in a group of > 40 cells already segregated in the extraembryonic mesoderm. PMID- 7835159 TI - Evolutionary aspects of primordial germ cell formation. AB - Animal embryos can be classified into three types depending on the time when the adult body form is specified--after metamorphosis, progressively by addition of posterior segments, or as a single event early in development. Segregation of germ cells correlates with specification of adult body form. When the adult body form is specified late in development, e.g. after metamorphosis (molluscs, echinoderms, cirripedes, hemichordates, cephalochordates and ascidians), germ cells appear in the early adult and at the site where the gonads will develop. When the adult body form is specified progressively during development by the sequential addition of posterior segments (annelids, onychophorans and most arthropods) germ cells are segregated either before or during addition of segments, in close association with the growth zone. In nematodes, chaetognaths, collembolans, higher holometabolous insects and vertebrates, the adult body form is specified early in development and germ cells are typically segregated correspondingly early and in extraembryonic regions. Therefore, as a general conclusion, germ cells appear to be segregated in locations and/or at times that exclude them from the process of specification of adult body form. Germ plasm is restricted to embryos in which exclusion of germ cells is difficult because the embryo is small or the signal specifying adult body form is pervasive. A possible role for germ plasm is thus as additional protection for the cells from the processes specifying adult body form. PMID- 7835160 TI - The Macro Flow Planktometer: a new device for volume and fluorescence analysis of macro plankton including triggered video imaging in flow. AB - A newly developed macro flow planktometer is described for measuring plankton organisms with a size of 100-2,000 microns by the flow principle in time-saving and noncontact fashion. Based on the method of changes in electric resistance (Coulter principle), the device allows determination of the body volume of living organisms in their natural medium (fresh or seawater) at a measuring rate of up to 50 organisms per second. Simultaneous, laser-excited fluorescence measurement permits quantitative detection of fluorescent substances within the organisms. Controlled by the multiparametric measurement, video images of organisms of particular interest can be taken in the flow chamber using a stroboscopic imaging system. Valuable morphological information on the material under test is thus available in addition to the analytical measurement. Data acquisition and imaging, the total system control, and the fast data evaluation are performed with an IBM-AT compatible computer using an extensive software package. The easy to-handle desktop unit can be used both in land laboratories and on ships. The modular structure of the system permits any desired combination of individual components to adapt it to various requirements. The operability of this new measuring system is demonstrated by several applications. PMID- 7835161 TI - Scoring of radiation-induced micronuclei in cytokinesis-blocked human lymphocytes by automated image analysis. AB - The micronucleus assay in human lymphocytes is, at present, frequently used to assess chromosomal damage caused by ionizing radiation or mutagens. Manual scoring of micronuclei (MN) by trained personnel is very time-consuming, tiring work, and the results depend on subjective interpretation of scoring criteria. More objective scoring can be accomplished only if the test can be automated. Furthermore, an automated system allows scoring of large numbers of cells, thereby increasing the statistical significance of the results. This is of special importance for screening programs for low doses of chromosome-damaging agents. In this paper, the first results of our effort to automate the micronucleus assay with an image-analysis system are represented. The method we used is described in detail, and the results are compared to those of other groups. Our system is able to detect 88% of the binucleated lymphocytes on the slides. The procedure consists of a fully automated localization of binucleated cells and counting of the MN within these cells, followed by a simple and fast manual operation in which the false positives are removed. Preliminary measurements for blood samples irradiated with a dose of 1 Gy X-rays indicate that the automated system can find 89% +/- 12% of the micronuclei within the binucleated cells compared to a manual screening. PMID- 7835162 TI - A disposable-chamber temperature-regulation system for the study of intracellular calcium levels in single live T cells using fluorescence digital-imaging microscopy. AB - Utilizing flow cytometry, we previously demonstrated that the potassium channel blocker margatoxin (MgTX) inhibits the [Ca2+]i transient involved in T-cell activation. We wished to extend these studies to single-cell transients using florescence digital-imaging microscopy (DIM). However, the most currently available temperature-regulation chambers reuse part or all of the apparatus and introduce compounds via perfusion. Thus, these apparatuses are not suitable for studies involving compounds that are particularly sticky. We have designed a dual temperature regulation system that will maintain Nunc, eight-well, coverglass bottom, disposable chambers, and three disposable addition pipets at 37 degrees C for physiological studies on an inverted digital-imaging microscope. We have demonstrated that calcium transients of human T lymphocytes can be initiated and monitored reproducibly during the addition of three distinct chemical species. The DIM results correlate with flow cytometry measurements in the number of responding cells and the heterogeneity of the response in both control and MgTX inhibited cultures. Additionally, DIM revealed that the [Ca2+]i transient is more rapid than the flow-cytometric measurement indicated. The correlation between flow cytometry and DIM permits the amalgamation of these results in the interpretation of studies on the regulation of T-cell activation. PMID- 7835163 TI - Improved sensitivity in flow cytometric intracellular ionized calcium measurement using fluo-3/Fura Red fluorescence ratios. AB - Measurement of changes in intracellular ionized calcium concentrations ([Ca2+]i) has proved to be of wide use in the study of cellular responses to activating stimuli. The fluorescent dye Indo-1 has successfully been used in flow cytometry for this purpose, and when used as a ratiometric indicator it provides optimum sensitivity and accuracy. Unfortunately, this dye requires ultraviolet (UV) excitation which is often not available. We show here that similar results can be obtained using a ratio of green to red fluorescence from the simultaneous loading of the dyes Fura Red and fluo-3. Both Fura Red and fluo-3 are excited using the commonly available blue 488 nm laser line. With appropriate concentrations of the two dyes, the magnitude of response with the fluo-3/Fura Red ratio is greater than that achieved with indo-1, while the intercellular variation in measurement is similar to that seen with indo-1. Analyses can be simultaneously combined with immunofluorescent detection of PE-labeled antibodies to enable [Ca2+]i measurement within cell subsets. PMID- 7835164 TI - Evaluation of a method for quantitative immunohistochemical analysis of cisplatin DNA adducts in tissues from nude mice. AB - The reproducibility of an immunohistochemical method for visualization and quantitation of the cytotoxic drug cisplatin (CDDP) in its active position, bound to nuclear DNA, was investigated in tissues from CDDP-treated nude mice. Kidney, liver, and tumor sections were stained with a PAP technique using an antiserum elicited against CDDP-DNA adducts. The resulting brown nuclear precipitate was quantitated using a CAS 200 image analyzer. The variance components of the errors in the staining procedure and in the image analysis were estimated. The method was found to be feasible for comparisons between slides of the same type of tissue, stained in the same batch, and measured by one observer on one occasion. The method should be a valuable tool for studies of CDDP pharmacodynamics, sensitivity prediction, and the effects of interactions between CDDP and other drugs and chemomodulators. PMID- 7835165 TI - Factors underlying the variability of lipid droplet fluorescence in MA-10 Leydig tumor cells. AB - Neutral lipids accumulate in cellular lipid droplets. These droplets vary remarkably in number and amount between cells. In the present studies, the variability in lipid content was quantified by comparing the coefficient of variation of fluorescence histograms of nile red lipid-stained cells to the variability of cell size or cell protein distributions. This measure of lipid droplet variability persisted through a wide range of cell lipid content and averaged 4.4-fold more variability than cell size and 2.6-fold more variability than cell protein content. While looking for possible explanations for this variability, it was determined that cell to cell variability could not be explained by multiple clonal populations of cells or the confluence of the cell monolayer. Analysis of lipid variability using a more droplet-specific fluorescent dye, bodipy, reduced variability by about 44%. Cell cycle analysis revealed that G2 + M cells contained more lipid than S-phase cells, which in turn contained more lipid than G0 + G1 cells, but that variability was equally large throughout the cell cycle. The cholesteryl ester hydrolase inhibitor, diethylumbelliferyl phosphate, inhibited hydrolysis of both cholesteryl esters and triglycerides. Lipid content of diethylumbelliferyl phosphate-treated cells increased while the variability in lipid staining decreased by an average of 72%. Thus, the excess lipid fluorescence variability compared to cell size or protein fluorescence could in part be explained by variability in cellular hydrolysis of triglyceride and cholesteryl ester. Excess lipid fluorescent variability could be reduced by an average of 44% when a more lipid droplet-specific stain was used instead of nile red. PMID- 7835166 TI - Classification of red blood cells as normal, sickle, or other abnormal, using a single image analysis feature. AB - Sickle cell anemia is a disease for which there is currently no effective treatment. One method of evaluating clinical status is the counting of cell types based on morphology. There is a need for a rapid, reproducible method, superior to human inspection, for classification of these cells. Quantitative digital image analysis is being applied to this need. Blood from 24 patients with sickle cell anemia (SS) and SC disease and ten hematologically normal volunteers (AA) was stressed by bubbling with nitrogen. One hundred fifty cells were analyzed from each sickle specimen, and 100 were analyzed from each nonsickle specimen. Expert observers classified each cell as normal (N), sickle (S), or other abnormal (A). Cells were analyzed with a custom, high-resolution image-analysis instrument. A total of 42 features including metric, optical density-derived, and textural features were extracted. The metric feature Form Factor (4 pi Area/Perimeter2) was selected by recursive partitioning analysis as the sole feature needed for segregating cells into the classes of N, A, and S. The agreement of automated classification (using cutpoints determined by recursive partitioning analysis) with a human expert for specimens from individuals with sickle cell anemia was 89% for N-, 73% for A-, and 92% for S-classified cells. For specimens from AA individuals, the agreement was 92% for N and 76% for A. For specimens from individuals with sickle cell anemia, rates of agreement between two human experts were compared and found to be 86% for N, 84% for A, and 80% for S. For specimens from AA individuals, the agreement was 90% for N and 87% for A. PMID- 7835167 TI - Textural differences between AA and SS blood specimens as detected by image analysis. AB - High-resolution image analysis was employed in the analysis of round (discoid) erythrocytes from hematologically normal (AA) individuals, AA individuals with nonspecific anemia, individuals with sickle cell trait (AS), individuals with SC disease (SC), and individuals with sickle cell anemia (SS). The shape feature Form Factor (4 pi Area/Perimeter2) was used to select round cells and to exclude sickle and other abnormal cells. Textural features extracted from round cells of SS and SC patients were found to differ from those derived from cells of normal andanemic AA individuals. Two textural features, Standard Deviation of Run Length Matrix Counts and Rotation Moment of the Cooccurrence Matrix, discriminated between patients mean values from AA samples and those from SS samples. The ability of textural features to separate round cells into classes based on genotype suggests that high resolution image analysis may be an effective tool in the study and monitoring of sickle cell disease. PMID- 7835168 TI - Flow cytometry distinction between adherent and phagocytized yeast particles. AB - Our laboratory recently developed a light microscopy staining technique that provides a mean to distinguish between yeast that are simply bound to the surface of macrophages and yeast that have actually been phagocytized by macrophages (7). We adapted this technique by using fluorescent probes in order to test phagocytic activity by flow cytometry. Thus we are able to distinguish unambiguously extracellular from intracellular yeast during phagocytosis with the fast rate of flow cytometry (approximately 200 cells/s). The fluorescence quenching induced by a 1% tannic acid solution (w/v) can be applied to any FITC-labeled, heat-killed yeast cell or bacteria. The yeast cells already engulfed in the macrophage remain with their native fluorescence (internal and external pH equilibrated by 50 microM monensin 30 min/4 degrees C) protected from the action of tannic acid, a nonmembrane permeable molecule. The results presented here validate this new technique. An application is presented showing the inhibition of endocytosis by cytochalasin-B. PMID- 7835169 TI - Quantitative determination of particle concentrations in experimental and marine environmental samples. AB - As the application of flow cytometry increases across the environmental sciences, there is a need to expand instrument flexibility. In particular, some of the major applications within aquatic research demand an ability to quantify the particles under investigation, expressing them as numbers per unit of sample volume. Two of the principal areas of flow cytometric investigations are the characterisation of naturally occurring particulate assemblages in the oceans and investigations into the feeding behaviour of "filter feeding" organisms on the mixtures of such particles. In both cases some of the most useful data derived from flow cytometry require that analyses be determined in terms of particle concentrations. Therefore, a simple and practical modification is described, which allows known sample volumes to be analysed on flow cytometers. The method has a high degree of flexibility in sample volume and is cost effective and reliable. It involves introducing a standard chromatography "loop injection valve" into the sample-handling fluidics system. Use of fluorescent beads shows that a range of particle sizes and concentrations can be used with this system. Tests, also using fluorescent beads and an algal culture, show that replicate 100 microliter sample volumes can be analysed and counted with a coefficient of variation of less than 3%. PMID- 7835170 TI - The relationship of vascular changes to metabolic factors in diabetes mellitus and their role in the development of peripheral nerve complications. PMID- 7835171 TI - Insulin and lipoprotein metabolism with special reference to the diabetic state. PMID- 7835172 TI - Effects of insulin on whole-body and regional amino acid metabolism. PMID- 7835173 TI - Vascular defects in the aetiology of peripheral insulin resistance in diabetes. A critical review of hypotheses and facts. PMID- 7835175 TI - Vitreous surgery in children. AB - This study examines the results of research on the surgical treatment of children with various vitreous diseases. Vitrectomy was performed on 44 eyes in children, from four months to fifteen years of age, suffering from the following diseases: lensectomy complications as vitreocorneal adhesions or immersion of lens mass into the vitreous; persistent hyperplastic primary vitreous (PHPV), trauma consequences, uveitis and eyeball subatrophy. Preoperational examination included measurement of visual acuity, biomicroscopy, direct and indirect ophthalmoscopy, tonography, ultrasonography and electrophysiological examinations. Vitreotome 'ocutome' was used to perform the operations. A transcyliar approach was used in all but 14 cases, for which the operations were performed by limbal incision. Improvement of visual functions was noted in 28 eyes (63.3%), and relatively good visual function was achieved in 7 eyes (16.9%). Visual acuity remained unchanged in 6 eyes (13.6%) because of severe amblyopia, although the transparency of optic zone was restored and the fundus did become visible. IN 10 (22.7%) of the children visual acuity could not be measured because of too young an age. One day after surgery a cellular suspension in the vitreous was observed in many eyes. This however, resolved within 3 days. Intraocular pressure usually returned during the first week after surgery. Hypotonia remained for 1-2 months after subtotal vitrectomy. The transcyliar extraction of pathological vitreous in children is generally a less traumatic and more convenient means of intravitreal manipulation, but 2 cases of intraoperational hemophthalmia suggested that iridiocyclitis is a contraindication for transcyliar approach. Transcorneal extraction is a less traumatic surgical method in such cases. PMID- 7835176 TI - Effect of bendazac lysine on lens and retina in diabetics. AB - The possible beneficial effects on the lens and retina which Bendazac Lysine may have in the treatment of adult diabetic patients were investigated. Twenty patients, ranging in age from 54.80 +/- 5.86 years old, were studied. The average duration of the diabetes was 11.32 +/- 4.10 years. Thirteen patients had background retinopathy. The metabolic controls carried out during the study were satisfactory (HbA1 < 11%). Bendazac Lysine (500 mg three times a day) was administered for 6 months. Blood-retinal barrier permeability (VPR and VPRt) and lens transmittance (t) were evaluated prior to and 6 months after treatment by fluorophotometry. No statistically significant differences between the pre- and post-treatment values of the retina permeability were observed, however, there was a statistically significant improvement (p < 0.05) (initial value: t = 0.813 +/- 0.040 and final value: t = 0.823 +/- 0.037) in the lens transmittance. The authors conclude that Bendazac Lysine has a beneficial effect on the lens in the diabetic adult although no improvement in the permeability of the blood-retinal barrier has been observed. PMID- 7835174 TI - Clinical and laboratory investigations of the relationship of accommodation and convergence function with refractive error. A literature review. AB - Studies of the relationship of clinical and laboratory measures of accommodation and convergence function with refractive error are reviewed. There are inconsistencies in results from study to study presumably due, in part, to methodological differences. However, some basic trends can be outlined. In studies in young adults, accommodation in darkness (dark focus), optical reflex accommodation, and proximally induced accommodation are less in myopes than in emmetropes and hyperopes. It also appears that nearpoint esophoria is associated with higher rates of myopia progression in children. Implications for myopia etiology are discussed. PMID- 7835177 TI - Orbicular synkinesis after facial paralysis: treatment with botulinum toxin. AB - Involuntary lid closure not rarely accompanies aberrant regeneration of nerve fibers after different types of facial paralysis. 23 patients with such synkinesis were treated with botulinum toxin injections into the orbicularis oculi muscle. After periocular injections all patients showed much improvement: a period of, on the average, 13 symptom-free weeks was followed by a period of minimal symptoms. There were only minor complications. Whenever repeated treatment is necessary, botulinum toxin proves to be an effective therapy for involuntary lid closure after defective healing following facial paralysis. PMID- 7835178 TI - Bilateral optic neuritis with branch retinal artery occlusion associated with vaccination. AB - A case of a 40-year old marine with bilateral optic neuritis and a branch retinal artery occlusion after vaccination is presented. Blood investigations showed no abnormalities. Cerebrospinal fluid studies revealed a lymphocytic pleocytosis and IgG antibodies against hepatitis A and rabies. Computerized tomography and magnetic resonance imaging of the brain were negative. A diagnosis of vaccine induced auto-immune demyelinative optic neuritis was made. The clinical picture improved after systemic corticosteroid treatment. PMID- 7835179 TI - Prognostic factors and postoperative course following single-plate Molteno implantation. AB - We evaluated potential preoperative and early postoperative prognostic indicators for chronic intraocular pressure control in 38 consecutive glaucoma patients undergoing single-plate Molteno implantation. Six months following surgery 22 patients had an intraocular pressure < or = 18 mm Hg and were considered successes. Twelve patients had an intraocular pressure > 18 mm Hg and were considered failures. Factors such as age, race, sex, type of glaucoma, phakic status, eye treated, intraocular pressure, bleb elevation, or number of glaucoma medicines were not significantly related to postoperative intraocular pressure control (p > 0.05). Postoperatively a significant difference in intraocular pressure was not observed between success and failure groups until three (13.8 +/ 5.4 versus 20.8 +/- 6.4 mm Hg, p = 0.010) and six (11.2 +/- 3.3 mm Hg versus 21.2 +/- 1.2 mm Hg, p < 0.001) months. Approximately 50% of patients who had an intraocular pressure > 20 mm Hg and 75% of those who measured < 20 mm Hg at any given examination in the early postoperative period were controlled six months postoperatively. Patients controlled at six months maintained control for as long as 43 months postoperatively. This study indicates that in the early postoperative period after a single-plate Molteno implant some patients have an ocular hypertensive phase but may ultimately be controlled, whereas most patients with an intraocular pressure within the normal range maintain control long-term. PMID- 7835181 TI - Understanding hydrodelineation: the term and the procedure. PMID- 7835182 TI - Iris chafing in pseudophakia. AB - Iris defects occur in pseudophakic patients with posterior chamber intraocular lens in sulcus. Prevalence of pigmentary dispersion syndrome and pigmentary glaucoma has been evaluated in 920 pseudophakic patients (920 eyes). 16.08% of patients showed pigment dispersion syndrome, while 1.96% developed pigmentary glaucoma. Diabetic patients had a statistically significant greater prevalence of these complications than non-diabetic ones (p < 0.05). The authors suggest the preventive use of alpha-blockers in presence of pigment dispersion syndrome or diabetes mellitus, even in absence of ocular hypertension. PMID- 7835180 TI - Megalocornea. Clinical and genetic aspects. PMID- 7835183 TI - Tear mucus ferning in patients with Sjogren's syndrome. AB - The purpose of this study is to evaluate the possibility of using the mucus ferning phenomenon of the tears as a diagnostic test for Keratoconjunctivitis sicca in patients with Sjogren's syndrome. Using a polarising light microscope dried samples were tested for ferning phenomenon collected from (1) 36 healthy controls, (2) 21 patients with primary Sjogren's syndrome, and (3) 15 patients with secondary Sjogren's syndrome. Patients with Sjogren's had xerostomia, abnormal salivary gland biopsy and at least two positive tests for Kerato conjunctivitis sicca. Patterns of mucus crystallization were classified into 5 types according to uniformity, branch spreading and integrity (types I, II normal, types III, IV, V abnormal). Abnormal ferning was found in tear samples of 8 out of 72 normal control eyes, 38 out of 42 with primary Sjogren's syndrome and 25 out of 30 with secondary Sjogren's syndrome. The differences between both primary and secondary Sjogren's syndrome, in comparison to healthy controls, were significant (p < 0.001). The sensitivity of the method was found 90% for primary Sjogren's syndrome and 80% for secondary Sjogren's syndrome. According to our data, tear mucus ferning test is a simple, sensitive and specific test to estimate Keratoconjunctivitis sicca in patients with Sjogren's syndrome. PMID- 7835184 TI - Endophthalmitis after lens extraction. AB - This article describes most features of endophthalmitis after lens extraction: symptomatology, differential diagnosis, prognosis, treatment and prevention. Literature findings are compared to the author's proper extensive experience with endophthalmitis. Cultures have been positive in 153 cases. A hundred and fifteen of them were seen after previous ocular surgery. Amongst these cases 104 were seen after cataract surgery. PMID- 7835185 TI - Ocular manifestations of relapsing polychondritis. Three case histories. AB - Relapsing polychondritis is a rare, presumably inflammatory autoimmune disorder affecting cartilagenous structures throughout the body. The ears, nose, joints, eyes and the respiratory tract are most frequently involved. The main ocular manifestations are episcleritis and scleritis, conjunctivitis, iridocyclitis and chorioretinitis, cataract and corneal infiltrates and melting. Extraocular signs and symptoms often are indicative of the diagnosis. Therapy includes systemic steroids, immunosuppressive drugs and dapsone. Three case histories are reported and the literature of ocular manifestations of relapsing polychondritis is reviewed. PMID- 7835186 TI - Evoked otoacoustic emissions behaviour in retinitis pigmentosa. AB - The hearing function was studied in 26 patients affected by retinitis pigmentosa (RP) and in their relatives. Sixteen patients showed bilateral normal hearing when examined with traditional audiometric methods. In these normoacusic patients evoked otoacoustic emissions (EOE) have been studied. The EOE offer a unique opportunity to measure objectively the function of outer hair cells: they record the amplitude of the energy produced by the outer hair cells of the coclea following an acoustic stimulation. The data have been statistically compared, using the Student's t-test, with those obtained in a homogeneous control-group of normal subjects. In normoacusic subjects with RP the average values of EOE intensity are statistically lower than those of normal subjects in 64 of the 127 frequency bands examined. Moreover, the distribution of the EOE in patients with retinitis pigmentosa proved to be more discontinous than that observed in the normal subjects. The EOE recorded in 14 normoacusic relatives show in some cases small anomalies but the data, on account of the limited sample group, cannot be statistically evaluated. Therefore a subclinical alteration of the Organ of Corti is found in 100% of the patients affected by RP, although they appear to be normoacusic to usual audiometric tests. PMID- 7835187 TI - Clostridium perfringens endophthalmitis. AB - Our report describes a 35 year-old male who sustained a penetrating injury with an intraocular foreign body and developed endophthalmitis. Gram stain showed Gram positive bacilli and culture grew Clostridium perfringens. The patient was managed successfully by therapeutic vitrectomy and intravitreal and systemic antibiotic therapy. Early vitrectomy and intravitreal antibiotics should be considered in patients who develop severe endophthalmitis following penetrating injury. PMID- 7835188 TI - No-stitch combined glaucoma cataract-surgery. AB - A new method of small incision cataract surgery is presented which allows sutureless wound closure with a fistulating aperature for regulating IOP. After in-the-bag pcIOL implantation, a triangular opening is made into the posterior scleral valve and combined with a peripheral iridectomy. Sufficient regularization of the IOP and good visual results could be observed in the majority of all 61 eyes operated on using this method. PMID- 7835189 TI - Identification of the preferential gaze position through elevation of visual fatigue in a selected group of VDU operators. A preliminary study. AB - A selected group of VDU workers were tested in an attempt to achieve objective evidence of visual fatigue and to identify a preferential monitor/gaze position during a particular work setting. Each subject was scored in a two-phase test. The highest mean scores were achieved when the monitor was lowered with respect to the primary/gaze position; the scores obtained with the monitor in primary or upward gaze position were significantly lower (p < 0.001). The downward gaze position should be considered more comfortable for both innervational and anatomical factors, as stated in previous studies of ocular mobility. A reduction of vertical saccades could also play a role in lessening visual fatigue in this gaze position. PMID- 7835190 TI - Tilt and decentration of bag-fixated intraocular lenses: a comparative study between capsulorhexis and envelope techniques. AB - Malposition of an intraocular lens (IOL) may cause symptoms such as glare, halos, and other visual aberrations. The purpose of this study is to determine the effect of two different anterior capsulotomy techniques on IOL tilt and decentration. Bag-fixated IOL implantation after uncomplicated extracapsular cataract extraction was performed using both envelope (65 eyes) and continuous circular capsulorhexis (CCC) technique (42 eyes). Eyes were followed-up at least 6 months postoperatively. While the mean IOL decentration after envelope technique was found to be 0.65 mm, this was 0.15 mm after CCC technique. On the other hand, the mean actual tilting angle of IOL after envelope technique was 5.66 degrees, whereas this was 1.13 degrees after CCC technique. The aforementioned differences were statistically significant (p < 0.01, and p < 0.01). Furthermore, in 17 eyes (26.1%) where envelope technique and in 29 (69.0%) eyes where CCC technique was used demonstrated no IOL tilt and decentration. This study shows that the CCC technique may result in less optical problems due to IOL malposition compared to the envelope technique. PMID- 7835191 TI - Ocular manifestations of Hansen's disease. AB - A detailed ophthalmic evaluation including slitlamp biomicroscopy, measurement of corneal sensitivity using Cochet and Bonnet aesthesiometer, Schirmer's test and Goldmann applanation tonometry was carried out in 89 patients of Hansen's disease attending the leprosy clinic with or without ocular symptoms and willing to undergo eye evaluation. Thirty-one patients had lepromatous leprosy (8 with erythema nodosum leprosum), 56 patients had borderline disease (13 with reversal reactions) and 2 had tuberculoid disease. In addition to the well documented changes of lagophthalmos (6.7%), uveitis (7.3%) and cataracts (19%), we noted prominent corneal nerves in 133 eyes (74.7%), beaded corneal nerves in 19 eyes (10.7%), corneal scarring in 10 eyes (5.6%), corneal hypoaesthesia in 51 eyes (28%) and dry eye in 18 eyes (13%). Beaded corneal nerves and/or stomal infiltrates occurred mainly in the lepromatous group (75%). Ocular hypotony (IOP less than 12 mm Hg) was not seen more frequently in Hansen's as compared to age and sex matched controls with refractive errors or cataracts (33.7%, vs. 37.8%, p = 0.33). Our study highlights the primary corneal involvement with corneal neuropathy as the predominant feature of Hansen's disease. PMID- 7835192 TI - Long-term results of vitreous surgery for proliferative diabetic retinopathy. AB - In order to study long-term anatomical and functional results the authors evaluated the data from 260 patients who underwent pars plana vitrectomy for proliferative diabetic retinopathy. Indications for surgery were: vitreous hemorrhage, 68 eyes (26.2%); vitreous hemorrhage & tractional retinal detachment, 84 eyes (32.3%); tractional retinal detachment, 82 eyes (31.5%); and combined tractional-rhegmatogenous retinal detachment, 26 eyes (10%). In 118 eyes vitreoretinal surgery was combined with silicone-oil tamponade. The retina was completely attached posterior to a scleral buckle in 251 eyes (96%) at the time of the last examination. After a follow-up period of at least 12 months in a group of patients with vitreous hemorrhage, visual acuity improved in 88% of the eyes. Visual acuity was better than 0.5 in 31% of eyes. In group of eyes with nonresorbing vitreous hemorrhage & tractional retinal detachment visual acuity improved in 52% of eyes. Visual acuity improved in 76% of eyes with tractional retinal detachment and in 81% of eyes with combined tractional & rhegmatogenous retinal detachment. When comparing the latest postoperative visual acuity to visual acuity after three months postoperatively, visual acuity was unchanged in 88%, in 10% it became worse and in 3 cases (1%) became better. In the postoperative period, recurrent vitreous hemorrhage occurred in 33 (13%) eyes, reproliferation in 12 eyes. Cataract developed in 45 of 168 phakic eyes. If postoperative visual acuity before cataract formation was good, extracapsular cataract extraction with posterior chamber intraocular lens implantation was performed. Otherwise simple intra or extracapsular cataract extraction was performed. In 19 cases cataract operation was performed together with silicone oil extraction. Neovascular glaucoma developed postoperatively in 15 eyes (6%). Retinal detachment occurred postoperatively in 21 eyes (8%). In 15 eyes the retina was successfully reattached after additional operations. PMID- 7835193 TI - The importance of fluorescein angiography in diagnosing pattern dystrophies of the retinal pigment epithelium. AB - We describe three different types of pattern dystrophies in the retinal pigment epithelium: annular dystrophy, butterfly-shaped dystrophy with features of cone dystrophy, and butterfly dystrophy. In all the cases, fluorescein angiography was a good method to evaluate the morphology and range of macular changes. The butterfly-shaped lesions were not always easily visible with the ophthalmoscope, therefore, the fluorescein angiography was diagnostic. We also examined 17 relatives of these patients to discover the mode of inheritance in these diseases. The annular dystrophy seemed to be recessively inherited or a possible sporadic case, as was the unusual pattern dystrophy with features of cone dystrophy. The dominant heredity was found in the typical cases of butterfly pattern dystrophy. PMID- 7835194 TI - Detection sensitivity to light offsets is abnormal in glaucomatous visual field. AB - The detection thresholds in the central visual fields of glaucomatous (n = 21), ocular hypertensive (n = 21) and normal (n = 13) individuals were tested with both light decrements (offsets = dark spots) on a cathode ray tube (CRT) and light increments (onsets = bright spots) on a bowl projection perimeter. Both types of stimuli were of equal surface area (Goldmann size IV = 16 mm2) and duration (200 milliseconds) on a 10 cd/m2 background intensity. Computerized threshold testing with light offsets on CRT could document the glaucomatous visual field loss with high accuracy and might indicate early glaucomatous visual field loss missed by the conventional light onset stimuli. PMID- 7835195 TI - The antiproliferative effect of fractionized radiation therapy: optimization of dosage. AB - Fractionized radiation therapy with high-energy electrons have proven to reduce retinal detachment rate from 85% to 5% in the fibroblast model using a dosage of 3000 rad, starting from the first postoperative day. The purpose of this study is to gain more information about the therapeutic range of fractionized radiation therapy in experimental PVR. We therefore investigated the efficacy of this therapy when the total dose is reduced to 2000 rad. Irradiation treatment started on the first postoperative day. Eight weeks after cell implantation 5 of 14 eyes (35%) in the irradiated group and 15 of 16 eyes of the control group (93%) showed traction detachment. The statistically significant result proves a broad therapeutic range of fractionized radiation therapy in experimental PVR. We believe that a combination with antiinflammatory drugs could lead to a dose reduction in both therapies in patients. PMID- 7835196 TI - Levocabastine eye drops in the treatment of vernal conjunctivitis. AB - The efficacy and tolerability of levocabastine eye drops in vernal conjunctivitis (VC) were evaluated in a double-blind, placebo-controlled trial involving 46 patients over a period of 4 weeks. After 1 week of treatment, therapeutic efficacy was considered to be excellent or good for 70% of the levocabastine treated patients compared with only 33% of patients in the placebo group (p < 0.009). Levocabastine patients experienced significantly greater relief of their individually severest symptom than placebo-treated patients both after 1 week and at the end of the trial (p < 0.04). The reduction in symptom severity was significantly greater in the levocabastine group than in the control group for photophobia (p < 0.003) after 1 week, and for photophobia (p < 0.008), irritation (p = 0.05) and itchy eyes (p = 0.05) at the end of the trial. The percentage of days on which patients were completely symptom-free was significantly higher in the levocabastine group than in the placebo group (28% versus 4%; p < 0.02). Eight placebo-treated patients withdrew from the trial due to treatment inefficacy compared with only four levocabastine-treated patients (p = 0.013). Two of the three levocabastine, and all five placebo patients who elected to continue on open-label levocabastine had an excellent or good overall response after 1 to 3 weeks of treatment. All reported adverse reactions were mild and their incidence was equal in the two treatment groups. Levocabastine eye drops are effective and well tolerated in the treatment of VC. PMID- 7835198 TI - From the president: the strategy of synergy. PMID- 7835197 TI - Normalisation of asymmetric astigmatism after intralesional steroid injection for upper eye lid hemangioma in childhood. AB - Infantile hemangiomas affect about 5% (3%-8%) of the population, showing a predilection for the face. After a phase of rapid enlargement between the 3rd and the 9th month of life, 70% regress by the age of six after a period of stability. 43%-60% of the children with eye lid hemangiomas develop strabismic, anisometropic, or deprivation amblyopia. Previous studies found the majority of cases resulting from anisometropia (especially asymmetric astigmatism) rather than strabism or occlusion of the visual axis. Several methods of treatment- surgical excision, irradiation, sclerosing agents, systemic steroids, ligation, cryotherapy--have been used but all with a risk of local or systemic complications. Local injections of steroids are a simple method of therapy with a high rate of resolution of hemangiomas, but still with a high degree of bad visual output because of persistent astigmatism. In four children with asymmetric astigmatism (axis of astigmatism towards the hemangioma) in which the injection was given at the beginning of the phase of enlargement, amblyopia could be avoided by preventing corneal steepening from becoming permanent. PMID- 7835199 TI - AADE position statement: medical nutrition therapy for people with diabetes mellitus. PMID- 7835200 TI - Practical mineral recommendations: translation to clinical practice. PMID- 7835201 TI - Games and activities to teach children about diabetes and nutrition. PMID- 7835202 TI - The experience of living with insulin-dependent diabetes: lessons for the diabetes educator. AB - The purpose of this grounded theory study was to investigate the experience of living with insulin-dependent diabetes mellitus. Data were collected from interviews with four participants, and from their diabetes papers and journals. This article summarizes the results of the data collection and presents implications for diabetes educators. The results challenge the traditional compliance/adherence paradigm within which current diabetes education programs operate and provide evidence of the need to move to a new integration paradigm. The new paradigm would replace adherence relationships with collaborative alliances between clients and educators and encourage educators to practice empathy as a way of knowing. PMID- 7835203 TI - Self-efficacy and confidence in outcomes as determinants of self-care practices in inner-city, African-American women with non-insulin-dependent diabetes. AB - The purpose of this study was to examine the extent to which perceived self efficacy and confidence in outcomes, selected demographic variables, and disease characteristics (age, duration of diabetes, presence of documented complications) affect an individual's adherence over time to a diabetes regimen of home glucose testing, medication/insulin administration, diet, and exercise. A convenience sample of 118 inner-city, African-American women with type II, non-insulin dependent diabetes mellitus receiving outpatient care at a large urban hospital were asked to complete measures of each of the psychosocial variables on two occasions, separated by an interval of 4 to 5 months, and coinciding with their next scheduled clinic visit. Bivariate and multivariate analyses at Times 1 and 2 demonstrated the ability of self-efficacy alone to explain diet, exercise, and home-testing behaviors while suggesting variability within individuals in sense of self-efficacy over time. PMID- 7835204 TI - Foot care assessment in patients with diabetes: a screening algorithm for patient education and referral. AB - The foot care behaviors of patients with diabetes were assessed by medical history, and their feet were examined for peripheral neuropathy, peripheral vascular disease, foot ulcers, and deformities. The sample consisted of 136 patients (14 with insulin-dependent diabetes and 122 with non-insulin-dependent diabetes). Mean age was 61 years and mean duration of diabetes was 13 years. Peripheral vascular disease was found in 25% of the patients, peripheral neuropathy in 33%, and 13% had both peripheral vascular disease and peripheral neuropathy. Potentially unsafe nail and foot care practices were identified, suggesting that routine diabetes care may not provide sufficient foot care education and follow-up for all patients. A screening algorithm was developed to provide guidelines for individualizing foot care education and referral of patients with diabetic foot disease. The recommendations included annual diabetes foot care assessments and education for those at low risk for foot amputation, intensive foot care education and more frequent follow-up for individuals with peripheral neuropathy or peripheral vascular disease, and referral to a foot care specialty clinic for individuals with peripheral neuropathy and peripheral vascular disease, or foot ulcers. PMID- 7835205 TI - Assessment of sulfonylurea adherence and metabolic control. AB - This study was designed to compare sulfonylurea adherence assessment by providers, patients' self-report, pill counts, and a medication event monitoring system (MEMS-3) device, and correlate the estimates of metabolic control by provider, patient, and laboratory. Forty-seven outpatient veterans with fair to poor metabolic control of non-insulin-dependent diabetes mellitus were enrolled and received monthly refills of sulfonylurea in vials with a cap containing an electronic medication monitoring microprocessor. Pill counts and fasting plasma glucoses were measured monthly, and glycohemoglobin and a 24-hour diet recall were obtained at 0 and 60 days. Investigators then asked providers and patients to assess adherence and metabolic control. Forty-seven percent were nonadherent to medication using MEMS-3, 29% using pill counts, 29% using provider assessment, and 31% using self-report. Thirty-one percent of providers and 53% of patients assessed metabolic control differently than laboratory values. Assessment of medication adherence by provider, patient, and pill counts did not explain metabolic control as closely as assessment by MEMS-3. PMID- 7835206 TI - Young-adult perspectives of insulin-dependent diabetes. AB - The purpose of this study was to document the self-care behaviors of patients with type I diabetes, identify their concerns about having diabetes, and measure their level of control (HbA1c). A 20-point questionnaire was mailed to 105 young adults with type I diabetes. Fifty-nine (56%) returned the questionnaire (33 males, mean age 23.2 years; 26 females, mean age 22.7 years). Duration of diabetes was 5 months to 25 years (mean = 11.28 years). HbA1c range was 5% to 13.9% (mean = 7.85%, normal < 6.6%). Sixty-eight percent performed at least one blood glucose test per day and 12% reported not testing at all. The number of insulin injections per day ranged from 2 to 5, and 83% regularly adjusted their insulin dose. Confidence in adjusting insulin was not related to duration of diabetes, age, or sex. Insulin manipulation to control weight was reported by 38% (24 females, 2 males). The long-term complications they were concerned about were eye disease (35%), pregnancy and childbirth (27%), hypoglycemia (13%), and loss of independence (5%). Hypoglycemia was always recognized by 35%, although 50% sometimes confused it with stress, tiredness, and high blood glucose. All subjects reported that hypoglycemia affected their lifestyle. PMID- 7835207 TI - Effect of glycemic control on vitamin B12 metabolism in diabetes mellitus. AB - To determine the effect of glycemic control on vitamin B12 (B12) metabolism in diabetes mellitus, we studied B12 metabolism in 19 diabetic patients with poor glycemic control and 15 normal individuals. The diabetic patients had significantly higher total B12 binding capacity (3303 +/- 963 pg/ml), higher serum B12 levels (1173 +/- 503 pg/ml) and unsaturated B12 binding capacity (2131 +/- 902 pg/ml) when compared with the normal controls, but there was no difference in R-binder levels and the B12 binding ratio between the two groups. During a 2-week admission to establish glycemic control, the fructosamine levels in the diabetic patients decreased from 556 to 428 mumol/l and the total B12 binding capacity as well as unsaturated B12 binding capacity were significantly improved to the normal range (P < 0.01), but serum B12 levels, R-binder levels and the B12 binding ratio were not changed. There was a significant association between serum fructosamine levels and the total B12 binding capacity in poorly controlled diabetic patients and the decrease of fructosamine was correlated significantly with the change of total B12 binding capacity and serum B12 levels in diabetic patients. These results indicate the effects of glycemic control on B12 metabolism in diabetes mellitus. PMID- 7835208 TI - Diabetes mellitus in patients with liver cirrhosis. AB - In spite of the high prevalence of diabetes mellitus (DM) in patients with liver cirrhosis (LC) few studies have focused on the clinical implications of this association. We investigated the clinical and pancreatic-endocrine features of 34 patients who developed DM after LC (Group I). Results were compared with 34 carefully matched patients with only Type II DM (Group II). A standard meal test was performed in 26 patients with normal renal function from each group to assess beta-cell function. Group I patients, less frequently had retinopathy (14.7% vs. 45.5%, P < 0.05) and a family history of diabetes (23.5% vs. 58.8%, P < 0.01). Group I patients also showed signs of enhanced insulin resistance, reflected by higher insulin dose requirements in insulin-treated patients (0.87 +/- 0.10 vs. 0.62 +/- 0.05 IU/kg/day, P < 0.01) and increased basal C-peptide values (0.88 +/- 0.06 vs. 0.68 +/- 0.07 pmol/l, P < 0.05, respectively) than those in Group II. These results suggest that several clinical features, probably related to the hepatopathy, define DM occurring in patients with LC. PMID- 7835209 TI - Correlation of peripheral nerve fatigue following vibratory stimulation with hyperglycemia in diabetic patients. AB - To determine whether the vibratory perception threshold (VPT) was altered in patients with diabetes, we measured this parameter after 5 min of conditioning vibration in 59 patients with non-insulin-dependent diabetes mellitus (NIDDM), with (n = 36) and without clinical neuropathy (n = 23). Thirty-seven healthy volunteers served as controls. VPT in the diabetic patients was significantly correlated with fasting plasma glucose (FPG) level, but not with age. Although VPT increased in all three groups, the increase disappeared completely within 5 min in controls, but was sustained for over 5 min in the diabetic groups. delta VPT, the difference between VPT 10 s after activation and the baseline VPT, was significantly larger in the diabetic groups than in the control group, and in diabetic patients, was closely correlated with FPG, but not baseline VPT or age. These findings indicate that VPT is markedly increased in diabetic patients following repetitive vibratory cutaneous stimulation and does not recover easily, perhaps as a result of defects in peripheral nerve excitability linked to glycemic control. PMID- 7835210 TI - Effect of aging on plasma 1,5-anhydroglucitol levels in humans and rats. AB - Since normal reference values change with age in some clinical parameters, we measured the plasma levels of 1,5-anhydroglucitol (AG), a new marker of glycemic control in diabetes mellitus, in healthy subjects and in rats. Our results showed a significantly negative correlation of the marker with age in humans and that the plasma AG levels of older rats were markedly lower than those of younger counterparts. This remarkable reduction of AG in the older rat group can be partially explained by our finding that aged animals excreted AG more rapidly in the urine than younger ones, besides a decrease in food intake. We therefore suggest that normal clinical reference values for plasma AG levels should be modified according to age. PMID- 7835211 TI - Glucagon-like peptide-1 (GLP-1) molecular forms in human pancreatic endocrine tumors resemble those in intestine rather than pancreas. AB - Different glucagon-like peptide-1 (GLP-1) molecular forms are produced in the pancreas and the small intestine by differential processing of proglucagon. In this report, molecular forms of GLP-1 in two human pancreatic endocrine tumors were studied and compared with those in the pancreas and small intestine. A predominant GLP-1 immunoreactive form in the pancreas was eluted at the position of GLP-1(1-36) amide, whereas a predominant immunoreactive form in the ileal mucosa was eluted at the position of GLP-1(7-36) amide. In a glucagonoma, GLP-1 immunoreactive forms corresponding to GLP-1(7-36) amide and GLP-1(7-37) were predominant and immunoreactive forms at the position of GLP-1(1-36) amide and GLP 1(1-37) were minor. In another tumor, an insulinoma, immunoreactive forms were detected at the positions of GLP-1(7-36) amide, GLP-1(7-37), GLP-1(1-36) amide and GLP-1(1-37). Thus, the pattern of GLP-1 molecules in pancreatic tumors was not a pancreatic pattern and mimicked that found in the small intestine or consisted of both the patterns found in the small intestine and the pancreas. These data suggest that neoplastic transformation of the islet cells is associated with a switching in processing phenotype from islet (A) cells to intestinal (L) cells. PMID- 7835212 TI - HLA, ESD, GLOI, C3 and HP polymorphisms and juvenile insulin dependent diabetes mellitus in Tamil Nadu (south India). AB - Fifty juvenile insulin dependent diabetes mellitus (JIDDM) patients of Tamil Nadu (South India) were typed for HLA-A, -B, -C, -DR, and -DQ, ESD, GLOI, C3 and HP polymorphisms. The frequencies of B8, DR3, DR4, DR53 and DQ2 antigens of the HLA system were significantly higher in the patients than in controls (relative risk, RR = 4.81; 5.14; 3.98; 3.36 and 2.53, respectively). However HLA-DR2, -DR5 and DQ1, observed less frequently in the patient group, appear to play a role of protection against the disease (RR = 0.32; 0.30 and 0.20 respectively). HLA haplotype analysis demonstrated very high relative risk associated with two hitherto unreported haplotypes namely A3,DR1 and Cw3,DR4 (RR = 27.30 and 20.00, respectively) and also scanty distribution of the haplotypes A1,B17 and DR2,DQ1 (RR = 0.39 and 0.36, respectively) in the patient group. Among other genetic markers tested, GLOI is informative with its phenotype GLOI 2-1 showing positive association with JIDDM (RR = 4.06). PMID- 7835213 TI - Vascular complications in non-insulin dependent diabetics in Thailand. Thai Multicenter Research Group on Diabetes Mellitus. AB - Ten hospitals participated in a cross-sectional study to determine the prevalence of vascular complications in non-insulin dependent diabetes mellitus (NIDDM). The patients were 1433 females and 627 males, aged 24-88 years (mean +/- S.D. = 58.0 +/- 9.9). Duration of diabetes varied from newly diagnosed to 42 years (mean +/- S.D. = 8.2 +/- 6.5). Obesity was noted in 16.9% of males and 27.4% of females. The prevalence of hypertension, myocardial infarction (MI), hemiplegia, absent dorsalis pedis pulse, gangrene and amputation were 38.4, 2.8, 3.7, 5.8, 0.3 and 1.3%, respectively. Diabetic retinopathy (DR) was found in 32.1% of the patients. Proteinuria of > or = 2+ was observed in 18.7% of the patients. Stepwise multiple logistic regression analysis revealed that hypertension was significantly and independently correlated with MI, hemiplegia and DR but not with proteinuria or absent dorsalis pedis pulse. DR and proteinuria had a strong correlation with each other. Age of the patients weakly correlated with macrovascular diseases. Diabetic control and duration showed a weak correlation with microvascular complications. This study showed that DR was frequently found in Thai NIDDM. Hypertension was not only the commonest disorder but it also showed an independent association with other vascular complications. Early detection and intervention for both need to be emphasized and re-enforced in clinical practice. PMID- 7835214 TI - Prevalence of diabetes in pregnant women--a study from southern India. AB - This study was carried out to assess the prevalence of diabetes in southern Indian women during pregnancy. Nine hundred and fifty women having > or = 24 weeks of gestation, attending two general gynaecology centres for antenatal check ups were screened. Initially, the screening test with 1-h plasma glucose sampling following 50 g glucose load was done and those with glucose values > or = 140 mg/dl were subjected to a 3-h oral glucose tolerance test (OGTT) with 100 g glucose load. Among the 950 women, 6 were known diabetic subjects. Of the other 944, 89 were positive on screening test and 67 of them reported for OGTT. Four were detected to have gestational diabetes mellitus (GDM) (O'Sullivan and Mahan's criteria). Therefore the prevalences of total diabetes and GDM were 1.19% and 0.56%, respectively. PMID- 7835215 TI - Role of cytochrome P450 2E1 in the metabolism of 1,1,2,3,3,3-hexafluoropropyl methyl ether. AB - 1,1,2,3,3,3-Hexafluoropropyl methyl ether is developed as an alternative to replace ozone-depleting chlorofluorocarbons. The metabolism of 1,1,2,3,3,3 hexafluoropropyl methyl ether was studied in rat and human liver microsomes and in rats in vivo. Rat and human liver microsomes metabolized 1,1,2,3,3,3 hexafluoropropyl methyl ether to inorganic fluoride and formaldehyde in a ratio of 2:1. 2,3,3,3-Tetrafluoropropionic acid was also identified as a metabolite by GC/MS and 19F-NMR. In rat liver microsomes, formation of inorganic fluoride and formaldehyde from 1,1,2,3,3,3-hexafluoropropyl methyl ether was dependent on the presence of NADPH, time, substrate concentration and protein concentration, and was linear for up to 35 min. Microsomes from unpretreated rats oxidized 1,1,2,3,3,3-hexafluoropropyl methyl ether at low rates (3.56 nmol fluoride.20 min 1.mg-1). Pretreatment of rats with pyridine and ethanol, inducers of cytochrome P450 2E1, increased the rate of fluoride formation. The rates of fluoride formation from 1,1,2,3,3,3-hexafluoropropyl methyl ether correlated well with the relative amount of cytochrome P450 2E1 in the microsomes as quantified by immunoblotting. Coincubation of 1,1,2,3,3,3-hexafluoropropyl methyl ether with microsomes and diethyldithiocarbamate (100 microM), an inhibitor of cytochrome P450 2E1, reduced fluoride production by > 80%. In different samples of human liver microsomes, rates of fluoride formation were higher than observed in liver microsomes from unpretreated rats and correlated well to the content of cytochrome P450 2E1 protein as determined by immunoblotting and chlorzoxazone 6 hydroxylation.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7835216 TI - 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) modulates rat liver microsomal cyclophosphamide and ifosphamide activation by suppressing cytochrome P450 2C11 messenger RNA levels. AB - The alkylating anticancer drug 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU; lomustine) is frequently administered to cancer patients as part of a combination chemotherapy regimen. Previous studies have indicated that CCNU treatment of adult male rats leads to prolonged decreases in liver cytochrome P450 (CYP)-mediated enzyme activities. Because the alkylating agent prodrugs cyclophosphamide and ifosphamide are known to be activated by liver cytochrome P450 enzymes, the potential for interaction between CCNU and these oxazaphosphorines was examined. Treatment of adult male rats with a single dose of CCNU (30 mg/kg i.p.) resulted in a progressive loss of liver microsomal cyclophosphamide and ifosphamide hydroxylation activities in vitro (30-60% decrease after 7-27 days). The individual liver P450 forms modulated by CCNU were then identified using P450 form-specific microsomal testosterone hydroxylase assays. CCNU treatment was found to decrease substantially CYP2C11-dependent testosterone 2 alpha-hydroxylase activity (80-90% decrease after 14 or 27 days), but it did not affect CYP3A2-dependent testosterone 6 beta-hydroxylase activity. It only modestly decreased CYP2A2-mediated testosterone 15 alpha-hydroxylase activity. The reduction in CYP2C11 activity was not associated with a decline in liver microsomal NADPH-cytochrome P450 reductase activity, but rather was caused by a complete suppression of CYP2C11 mRNA levels. In contrast to other alkylating agents, such as cisplatin, which is known to feminize the overall expression profile of gender-specific liver enzymes, CCNU did not increase levels of the female-predominant liver enzymes steroid 5 alpha-reductase and CYP2C7, nor did it deplete circulating testosterone levels.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7835217 TI - Role of Kupffer cells in storage and metabolism of benzo(a)pyrene in the liver. AB - This study investigates the possible role of Kupffer cells in storage and metabolism of benzo(a)pyrene in the liver. In perfused liver, benzo(a)pyrene (4 120 microM) in 0.3% albumin increased fluorescence (366-->405 mm) on the liver surface in a dose-dependent manner, suggesting that it accumulated in liver tissue. The maximal increase of benzo(a)pyrene fluorescence was diminished by 60% when Kupffer cells were destroyed by gadolinium chloride treatment (10 mg/kg iv). Gadolinium chloride also decreased the yield of isolated nonparenchymal cells by 65%. In frozen sections of livers perfused with 4 microM benzo(a)pyrene for 1 hr, fluorescence was approximately 5 times greater in cells lining the sinusoids than in parenchymal cells. Moreover, yellow-green fluorescent particles were detected in cultured Kupffer cells, but were barely visible in parenchymal and Ito cells, indicating that Kupffer cells actively accumulated benzo(a)pyrene. In contrast to the cell specificity for benzo(a)pyrene accumulation, rates of monooxygenation of benzo(a)pyrene were up to 20-fold higher in isolated parenchymal than in Kupffer cells. In nonparenchymal cells, basal rates of production of benzo(a)pyrene phenols were approximately 50 pmol/10(6) cells/hr. In contrast, rates were approximately 335 pmol/10(6) cells/hr in parenchymal cells. Further, total [3H]benzo(a)pyrene metabolism was approximately 8-fold higher in parenchymal than in nonparenchymal cells. Albumin increased production of benzo(a)pyrene phenols by 3-fold in parenchymal cells, but was without effect in nonparenchymal cells. Pretreatment of rats with gadolinium chloride increased the production of benzo(a)pyrene phenols in perfused liver by > 50%.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7835218 TI - cDNA-directed expression of human cytochrome P450 CYP3A4 using baculovirus. AB - A recombinant baculovirus containing the human CYP3A4 cDNA was constructed and used to express CYP3A4 in SF9 insect cells (0.46 +/- 0.13 nmol/mg protein, 103 +/ 29 nmol/liter, N = 15). The enzyme represented approximately 2-3% of total cellular protein and could be purified by a two-column procedure to a specific content of 12.7 nmol/mg protein. Catalytic activity of the purified enzyme after reconstitution was optimum using molar ratios of CYP3A4 to cytochrome b5 to NADPH P450 oxidoreductase of 1:3:20, respectively. The enzyme metabolized cortisol, erythromycin, testosterone, and (R)-warfarin. Recombinant baculovirus expresses the highest amounts of all expression systems published to date of catalytically intact CYP3A4. This system is an excellent alternative for the isolation and characterization of P450 forms from human liver. PMID- 7835219 TI - Physiological disposition of L-663,581, a partial agonist of the benzodiazepine receptor, in laboratory animals. AB - L-663,581, 7-chloro-4,5-dihydro-5-methyl-3-(5-(1-methylethyl)-1,2,4-oxadiazol -3 yl)6H-imidazo(1,5-A)(1,4)benzodiazepin-6-one, is an investigational partial agonist for benzodiazepine receptors. This study was designed to characterize the absorption and disposition of the drug and its active metabolites in rats, dogs, and rhesus monkeys. Following intravenous administration (5 mg/kg), L-663,581 was cleared rapidly in all species. The plasma clearance was approximately 95, 40, and 48 ml/min/kg for rats, dogs, and monkeys, respectively. Comparison of urinary recoveries of radioactivity after oral and intravenous dosing indicated that approximately 80-90% of the dose was absorbed in rats and dogs, and 50% in monkeys. The bioavailability was approximately 45% in dogs, 23% in rats, and very low in monkeys after oral administration (5 mg/kg), suggesting an extensive first pass metabolism in all species. HPLC radiohistograms of urine from all species after intravenous administration revealed that only a trace amount of intact drug was present, indicating that the drug was mainly eliminated by biotransformation. NMR and mass spectral analyses showed that hydroxylation is a major biotransformation pathway. Two active metabolites have been identified as mono- and bis-hydroxy analogs. In addition, the disposition of the monohydroxylated metabolite was also studied in these species. Elimination of the metabolite from plasma was much slower than that of the parent drug in all species. Systemic conversion of L-663,581 to the monohydroxylated metabolite was approximately 43% in rats, 52% in dogs, and only 11% in monkeys. PMID- 7835220 TI - Oxidation of R(+)- and S(-)-carvedilol by rat liver microsomes. Evidence for stereoselective oxidation and characterization of the cytochrome P450 isozymes involved. AB - Incubation of R(+)- and S(-)-carvedilol with rat liver microsomes showed the formation of four oxidative metabolites: 1-hydroxycarvedilol (1-OHC), 8 hydroxycarvedilol (8-OHC), 4'-hydroxycarvedilol (4'-OHC), and O desmethylcarvedilol (DesC). The structures of these metabolites were confirmed by cochromatography with the authentic metabolites and by thermospray ms. As expected from in vivo metabolism studies, 1-OHC and 8-OHC were the major products for both enantioners used as a substrate. The S/R enantiomeric ratios for intrinsic clearance (Vmax/KM) of 1-OHC, 8-OHC, DesC, and 4'-OHC were 0.40, 1.99, 0.77, and 2.71, respectively, showing that stereoselective oxidation occurs in this species. These findings strongly suggest that the stereoselective biliary excretion of the two major carbazole ring-hydroxylated glucuronides, 1 hydroxycarvedilol O-glucuronide, and 8-hydroxycarvedilol O-glucuronide observed previously in rats can be explained by stereoselective hydroxylation in liver. The cause of the difference in intrinsic clearance for 1-OHC and 8-OHC between the two enantiomers was based on the difference in affinity to the catalyzing enzyme. The main enzyme concerned in the 1- and 8-hydroxylation of both enantiomers is considered to be CYP2D1 from the following observation: the marked strain differences between Sprague-Dawley and Dark Agouti rats and competitive inhibition by quinine. In the O-demethylation of both enantiomers, CYP2C11 is probably the major catalyzing enzyme, because sex differences, but no strain difference, were observed in both Sprague-Dawley and Dark Agouti rats, and also anti-CYP2C11 strongly inhibited this demethylation. PMID- 7835221 TI - Pharmacokinetics of HIV protease inhibitor DMP 323 in rats and dogs. AB - DMP 323 is a symmetrically substituted cyclic urea compound with demonstrated activity against human immunodeficiency virus (HIV) in vitro. DMP 323 has been measured in rat and dog plasma via liquid-liquid extraction and HPLC. The limit of quantitation is 10 ng/ml using 0.5 ml plasma. Following an intravenous dose of 5 mg/kg to rats, DMP 323 exhibited an apparent volume of distribution at steady state of 6.36 liters/kg and clearance of 7.12 liters/hr/kg. The same dose administered intravenously to dogs resulted in apparent volume of distribution at steady-state and clearance values of 2.28 liters/kg and 1.48 liters/hr/kg, respectively. Elimination half-lives were 0.95 hr in rats and 1.80 hr in dogs. DMP 323 was rapidly absorbed from oral solution doses in rats (3, 5, and 10 mg/kg) and dogs (5 and 10 mg/kg), achieving maximum plasma concentrations in 1 hr or less in both species. Absolute bioavailability of DMP 323 from oral doses ranged from 15 to 27% in rats and from 37 to 38% in dogs. Pharmacokinetics were unchanged in rats and dogs over 8-day t.i.d. and 5-day b.i.d. multiple oral dose regimens, respectively. Oral doses administered to fed animals resulted in lower plasma concentrations of DMP 323 than the same doses administered to fasted animals. Because of its in vitro high potency and acceptable pharmacokinetics, DMP 323 seems to be a worthy candidate for further study in the effort to develop an inhibitor of HIV protease for use in the therapy of AIDS. PMID- 7835222 TI - Studies on the glucuronidation of dopamine D-1 receptor antagonists, SCH 39166 and SCH 23390, by human liver microsomes. AB - Dopamine D-1 receptor antagonists are currently under investigation for use as antipsychotic agents. Two potent and selective D-1 receptor antagonists, SCH 39166 and SCH 23390, have been studied extensively in various experimental animal models. SCH 39166 has a more prolonged duration of action in primates in vivo and a lower rate of in vitro glucuronidation by microsomes from squirrel monkey liver. Because the rate of glucuronidation seems to govern the duration of action and may limit the use of these agents in humans, the glucuronidation of SCH 39166 and SCH 23390 by microsomes isolated from human liver was studied. The rates of glucuronide formation (Vmax) for SCH 39166 were much lower than those of SCH 23390, yet the KM values were similar. Therefore, the average efficiency (Vmax/KM) of SCH 39166 glucuronidation was only 14% that of SCH 23390. These results agree with previous studies in hepatic microsomes from squirrel monkeys. Marked inhibition of SCH 39166 glucuronidation by SCH 23390 and its pharmacologically inactive stereoisomer, SCH 23388, was observed. The inactive stereoisomer of SCH 39166, SCH 39165, was a weak inhibitor. In contrast, substrates for morphine UDP-glucuronosyltransferase (UGT), and p-nitrophenol, an alternative substrate for numerous human hepatic UGTs, did not inhibit SCH 39166 glucuronidation. Further separation of human hepatic UGTs activities using chromatofocusing chromatography indicated that SCH 39166 UGT activity was distinct from human hepatic UGT2B15 and human hepatic pI 6.2 UGT activity. Thus, a unique human hepatic UGT may be involved in SCH 39166 glucuronidation.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7835223 TI - Stereoselective hydroxylation of tacrine in rats and humans. AB - An enantiospecific method was developed for assessing the stereochemistry of tacrine (9-amino-1,2,3,4-tetrahydroacridine monohydrochloride monohydrate; THA) metabolism to 1-hydroxytacrine (1-OH-THA) in humans and rats. In addition, limited metabolic studies with human liver microsomal preparations were conducted, and the stereochemistry of rac-1-OH-THA disposition was also examined. The analytical method incorporates an achiral normal phase separation and isolation of 1-OH-THA, followed by a chromatographic step using chiral normal phase chromatography to resolve the enantiomers of 1-OH-THA. The achiral method was applied to quantitation of total 1-OH-THA in human urine specimens collected for 24 hr following administration of a single 40 mg oral dose of tacrine to 15 healthy elderly volunteers. Total 1-OH-THA accounted for approximately 5% of the administered dose. THA and 2-OH-THA were also quantitated and found to comprise < 1% and approximately 2% of the administered dose, respectively. 4-OH-THA was not detectable. The dextrorotatory (+)-isomer comprised approximately 94% of the 1-OH THA recovered in urine. In vitro studies utilizing human liver microsomes found enantioselective formation of the (+)-isomer (approximately 90%), whereas incubations with rac-1-OH-THA showed residual substrate to be racemic. The method was also applied to determination of the enantiomeric composition of 1-OH-THA in the urine of rats given a single oral 16 mg/kg dose of THA. The percentage of 1 OH-THA excreted in urine as the (+)-isomer was 94%.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7835224 TI - Sulfation of acetaminophen and acetaminophen-induced alterations in sulfate and 3'-phosphoadenosine 5'-phosphosulfate homeostasis in rats with deficient dietary intake of sulfur. AB - Sulfation of drugs depends on the availability of 3'-phosphoadenosine 5' phosphosulfate (PAPS), which requires inorganic sulfate for its synthesis. Therefore, decreased alimentary intake of inorganic sulfate or its precursor, cysteine, may compromise sulfation of xenobiotics. To test this hypothesis, separate groups of rats were maintained for 5 days on synthetic diets, which lacked sulfate, or cysteine, or both sulfate and cysteine. These dietary restrictions did not cause growth retardation or depletion of glutathione in liver. Under anesthesia, the animals were injected with acetaminophen (0.5 mmol/kg, i.v.) and elimination of acetaminophen from blood and excretion of acetaminophen metabolites in urine and bile was simultaneously quantified. Deficient intake of inorganic sulfate or cysteine alone did not significantly change elimination and biotransformation of acetaminophen. Combined nutritional deficiency of sulfate and cysteine, however, resulted in a 40% reduction in the excretion of acetaminophen-sulfate, quantitatively the most significant metabolite. Concomitantly, these animals eliminated acetaminophen from blood at a slower rate and converted more acetaminophen to its toxic intermediate, as indicated by increased excretion of acetaminophen-thioether conjugates. Serum and tissue sulfate concentrations were decreased to significantly lower levels in rats on sulfate and cysteine deficient diets, than in rats with a sufficient sulfur supply. Thus, reduced sulfation is apparently caused by diminished availability of inorganic sulfate for PAPS synthesis, even though hepatic and renal PAPS levels were not depleted more by acetaminophen in rats with deficient dietary supply of sulfate and cysteine than in rats with adequate sulfur intake.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7835225 TI - Detoxication of the 2',3'-epoxide metabolites of allylbenzene and estragole. Conjugation with glutathione. AB - The enzymatic detoxication in vitro of the 2',3'-epoxide derivatives of allylbenzene and estragole was examined, and the relative rates of enzymatic glutathione conjugation and epoxide hydrolysis were compared with those for styrene 1',2'-oxide. HPLC was used to determine the amounts of dihydrodiol and glutathione conjugate metabolites formed by cell extracts from several sources. Although some differences among species were observed, in general, the rates of epoxide inactivation by both pathways are similar. We conclude that one explanation for the apparent lack of genotoxicity of these allylic epoxides in vivo may be their rapid metabolic inactivation by both glutathione S-transferases and epoxide hydrolases, which occur to approximately equal degrees in vitro. PMID- 7835227 TI - Formation of toxic metabolites from thiabendazole and other thiazoles in mice. Identification of thioamides as ring cleavage products. AB - The metabolism of three nephro- or hepatotoxic thiazoles--2-(thiazol-4 yl)benzimidazole (thiabendazole) (1a), 4-tert-butyl-2-methyl-thiazole (1b), and 2 (p-methoxyphenyl)-4-methylthiazole (1c)--was examined in mice with special regard to the formation of ring cleavage products. By GC/MS analyses of derivatized metabolites and comparison with authentic samples, thioformamide and benzimidazol 2-ylglyoxal as the accompanying fragment were identified as urinary metabolites in mice dosed with 1a. Similarly, 1b produced thioacetamide and tert butylglyoxal, and 1c produced p-methoxy-thiobenzamide (and its S-oxide) and methylglyoxal. These results could be explained by the postulated metabolic pathways where thiazoles would undergo microsomal epoxidation of the C = C double bond and, after being hydrolyzed, the resulting epoxide would then be decomposed to form the corresponding thioamides and alpha-dicarbonyl fragments. PMID- 7835226 TI - Novel carbamate metabolites of mofegiline, a primary amine monoamine oxidase B inhibitor, in dogs and humans. AB - Mofegiline or MDL 72,974A ((E)-4-fluoro-beta-fluoromethylene benzene butanamine hydrochloride) is a selective enzyme-activated irreversible inhibitor of monoamine oxidase B, which is under development for use in the treatment of Parkinson's disease. Male beagle dogs were given single p.o. (20 mg/kg) and i.v. (5 mg/kg) doses of [14C]-Mofegiline. Total radioactivity excreted in urine and feces over 96 hr was, respectively, 75.5 +/- 3.8 and 6.3 +/- 3.4% of the dose after p.o. and 67.9 +/- 0.5 and 3.9 +/- 2.4% after i.v. administration. Unchanged drug in urine represented 3% of the dose after po and less than 1% after i.v. administration. Mofegiline was thus extensively metabolized in dogs, and urinary excretion was the major route of elimination of metabolites. HPLC, with on-line radioactivity detection, showed the presence of four major peaks (M1, M2, M3, and M4), representing respectively 50, 9, 5, and 0.5% of the administered dose excreted in 0-24 hr urine. TSP-LC-MS, FAB-MS, and NMR spectra of the purified metabolites were obtained. M1, the major metabolite in dogs, was shown to have undergone defluorination of the beta-fluoromethylene moiety, and one carbon addition. Its structure was confirmed to be a cyclic carbamate. M2 was a N carbamoyl O-beta-D-glucuronide conjugate of parent drug. The formation of M1 and M2 is likely to involve initial reversible addition of CO2 to the primary amine function. M3 was a N-succinyl conjugate of the parent drug. M4 had also undergone defluorination to yield a urea adduct of an unsaturated alpha, beta aldehyde. Structures of M1 and M3 were further confirmed by comparing their MS and NMR spectra with those of authentic reference compounds. TSP-LC-MS ion chromatograms of human urine, obtained from two male volunteers after p.o. administration of 24 mg of drug, showed selected molecular ion peaks with the same retention time as the metabolites identified in dogs. In humans, these common metabolites represented a similar percentage of the administered dose to that in dogs. The present study demonstrates that NMR, TSP-LC-MS are complementary analytical techniques, which allow structural identification of unhydrolyzed drug conjugates. The formation of carbamates of amine-containing drugs may be more common than previously reported. PMID- 7835228 TI - Metabolism of methoxyphenamine in vitro by a CYP2D6 microsomal preparation. AB - Metabolism of methoxyphenamine (MP) was conducted in vitro using commercially available microsomes prepared from human AHH-1 TK+/-cells in which CYP2D6 had been expressed. This study has confirmed the involvement of CYP2D6 in the metabolism of MP to O-desmethylmethoxyphenamine (ODMP) and 5 hydroxymethoxyphenamine (5HMP), but not to N-desmethylmethoxyphenamine. It has also revealed that CYP2D6 catalyzes the formation of another, hitherto unknown, ring-hydroxylated metabolite of MP, isomeric with 5HMP. The analytical procedure used to identify and quantify MP metabolites involved an acetylation procedure that had distinct advantages. MP and its basic and amphoteric metabolites were all converted to neutral products that were efficiently extracted into organic solvent. The acetylated products also had good chromatographic properties and provided mass spectra that were readily interpretable. MP metabolism studies were also conducted with CYP2D6 microsomes in the presence of quinidine and quinine. The former was the more potent inhibitor of CYP2D6-catalyzed oxidations of MP. Its inclusion resulted in complete inhibition of metabolism of MP to ODMP, 5HMP, and its novel isomer. This study shows that the in vitro use of human cytochrome P450 isozyme preparations in drug metabolism studies can aid in the identification of possible in vivo metabolites of these drugs in humans and can provide information on putative drug-drug interactions. PMID- 7835229 TI - Inter-individual differences of 4-[4-(4-methylphenyl)-phenylmethoxy-1 piperidinyl]butyric acid disposition in rats: possible involvement of genetic polymorphism. AB - Inter-individual differences of drug plasma concentration were recognized in outbred rats after an oral or intravenous administration of (+)-4-[4-(4 methylphenyl)phenylmethoxy-1-piperidinyl]butyric acid hydrochloride ((+)-MPPB). Rats could be divided into two phenotypes, the rapid metabolizing (RM) group and the slow metabolizing (SM) group. The hepatic clearance of RM-phenotyped Sprague Dawley rats was about 10 times larger than that of the SM group. Outbred male and female Sprague-Dawley rats and male Wistar rats were mixtures of the RM and SM groups. On the other hand, all inbred male Lewis rats were RM, and all inbred male F344 and ACI rats were SM. This study was undertaken to investigate the inter-individual differences of (-)-MPPB and the metabolic pathways of (+)- and ( )-MPPB. When (-)-MPPB was orally administered to male Sprague-Dawley rats, similar inter-individual differences of plasma concentration were recognized. RM phenotyped Sprague-Dawley rat liver microsomes metabolized (+)-MPPB to 4 hydroxymethylphenyl-MPPB (M1), and (-)-MPPB to M1 and 4'-hydroxyphenyl-MPPB (M2). The formation of these metabolites was less with SM-phenotyped than with RM phenotyped Sprague-Dawley rat liver microsomes. The kinetic parameters of M1 formation from (+)-MPPB by RM-phenotyped rat liver microsomes were characteristic of a two-enzyme system with a 100-fold difference in their affinities (KM values). On the other hand, SM-phenotyped rats have only the low-affinity enzyme system. An inhibition study demonstrated that both enzymes were cytochrome P450.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7835230 TI - Pharmacokinetics of dapsone and amino acid prodrugs of dapsone. AB - Amino acid amides of dapsone (DDS), a primary aromatic amine, have been synthesized as water-soluble, chemically stable prodrugs that target peptidase enzymes for cleavage to the parent drug in vivo. The pharmacokinetics of DDS, monoacetyldapsone (MADDS; a known metabolite), and various L- and D-amino acid derivatives of DDS were investigated in New Zealand white rabbits after intravenous administration. DDS and MADDS exhibit reversible kinetics and establish a pseudoequilibrium in vivo. In this study, the analytical procedure assayed for both DDS and MADDS, with formation of MADDS accounting for approximately 25% of the clearance of DDS. The L-amino acid derivatives of DDS were rapidly (t1/2 < 2 min) and quantitatively converted to DDS after intravenous administration to rabbits. Data are consistent with conversion of the L-amino acid amides to DDS by the action of stereospecific aminopeptidase enzymes and suggest that they would be good prodrug candidates. The corresponding D-amino acid derivatives were also quantitatively converted to DDS, but the half-lives ranged from 30 to 60 min. The specific mechanism for conversion of the D-amino acid amides to DDS is unknown. PMID- 7835231 TI - Effects of diltiazem on the disposition and metabolism of the enantiomers of propranolol in the dog during multiple oral dosing. AB - The intravenous and oral dose kinetics and metabolism of the enantiomers of propranolol were investigated in five dogs during steady-state oral racemic propranolol dosing (5 mg/kg, every 8 hr for 3 days). These results were compared with those obtained during concomitant administration of oral diltiazem (2.5 mg/kg, every 8 hr for 3 days) in the same animals. The oral and intravenous propranolol test doses consisted of a pseudoracemic mixture of equal amounts of hexadeuterated-(R-(+))- and dideuterated-(S-(-))-propranolol. Propranolol metabolism in the urine was evaluated by coadministering 150 muCi of [4' 3H]racemic propranolol HCl, along with the deuterium-labeled compounds. Plasma concentrations of the deuterated enantiomers were measured by HPLC-thermospray MS, using undecadeuterated racemic propranolol as the internal standard. Diltiazem coadministration had no significant effects on either the systemic clearance, renal clearance, the apparent volume of distribution, or the elimination half-lives of either enantiomer. On the other hand, concomitant diltiazem treatment significantly reduced the oral clearance of S-(-)- and R-(+) propranolol by 58 and 61%, respectively. These reductions resulted in an increase in their respective apparent steady-state oral availabilities of 129 and 106%. The S/R enantiomeric ratio of the oral availability of propranolol was not significantly changed from control. The urinary propranolol metabolites were isolated and purified by solvent extraction and HPLC and quantitated by radioactivity. Twelve metabolites, including propranolol, were isolated and quantitated in the urine. A significant reduction in the percentage of ring oxidation products and a significant increase in the percentage of naphthoxylactic acid and propranolol glucuronide excreted in the urine occurred in the diltiazem-treated animals. The S/R enantiomeric ratios of urinary excreted propranolol, propranolol glucuronide, 4'-hydroxypropranolol glucuronide, and its sulfate were not altered by diltiazem. These results suggest that the decreased oral clearances of the enantiomers of propranolol by diltiazem is caused by a selective decrease in the formation of ring-oxidized products. PMID- 7835232 TI - Stable expression of a human liver UDP-glucuronosyltransferase (UGT2B15) with activity toward steroid and xenobiotic substrates. AB - A full-length cDNA clone (HE8a) for a human hepatic UDP-glucuronosyltransferase was isolated from a human liver cDNA library and stably expressed in human embryonic kidney 293 (HK293) cells. Sequence analysis of the cDNA revealed that it was identical to UDPGTh-3 isolated by Chen et al. (Biochemistry 32, 10648 10657, 1993). HE8a is a member of the UGT2B gene family, and it has been designated UGT2B15. Over 100 compounds were tested for their reactivity with the expressed protein. UGT2B15 stably expressed in HK293 cells displayed glucuronidation activity toward several classes of xenobiotic substrates, including simple phenolic compounds, 7-hydroxylated coumarins, flavonoids, anthraquinones, and certain drugs and their hydroxylated metabolites. In addition, the expressed enzyme also catalyzed the glucuronidation of endogenous estrogens and androgens. Apparent KM and enzyme efficiency values for certain food-derived substrates (e.g., naringenin and eugenol) for expressed UGT2B15 were similar to those determined for endobiotic substrates, suggesting that some naturally occurring substances are good substrates for this enzyme and that glucuronidation of endogenous compounds could be affected by xenobiotics derived from dietary sources. PMID- 7835234 TI - Carbonyl reduction of 6-tert-butyl-2,3-epoxy-1,4-benzoquinone, a metabolite of 3 tert-butyl-4-hydroxyanisole, by rat liver microsomes and cytosol. PMID- 7835233 TI - Inhibition of p-nitrophenol hydroxylase in rat liver microsomes by small aromatic and heterocyclic molecules. AB - The cytochrome P450 isoenzyme P4502E1 is constitutively expressed in human liver and catalyzes the oxidation of many known or suspected carcinogens of low molecular weight. In this structure-metabolism study, the role that heteroatoms in heterocyclic compounds play in determining their affinity for P4502E1 was investigated. The ability of 16 six-membered and 10 five-membered compounds to inhibit the hydroxylation of p-nitrophenol, which is specifically catalyzed by P4502E1, was studied in suspensions of microsomes from rat livers in which P4502E1 had been induced by inclusion of acetone in the drinking water. Apparent Ki values were extrapolated from kinetic models of Dixon or Cornish-Bowden plots for enzyme inhibition. Enzyme inhibition was generally of the non-or uncompetitive type. Pyridine was the most potent and benzene one of the least potent inhibitors, with Ki values of 0.4 microM and 8,400 microM, respectively. Pyridazine was less inhibitory than 1,3,5-triazine, which inhibited P4502E1 to a lesser degree than pyrazine and pyrimidine. Among the unsubstituted unsaturated five-membered ring molecules, pyrrole was a better inhibitor than furan or thiophene. 4-Methylimidazole was a much stronger inhibitor than imidazole or 1 and 2-methylimidazole. The ability of compounds to inhibit P4502E1 seems to depend in the main on the presence of a nitrogen atom in the molecule and on the ability of the nitrogen lone pair of electrons to ligand to the heme. PMID- 7835235 TI - [Current status of antithrombotic therapy]. PMID- 7835236 TI - [Budesonide]. PMID- 7835237 TI - [Gene therapy in oncology. A model of change in pharmacology?]. PMID- 7835238 TI - [Usefulness of therapy for ascites in liver cirrhosis]. PMID- 7835239 TI - [Diagnosis of immune defects]. PMID- 7835240 TI - [The first early summer meningoencephalitis in the Saarland]. PMID- 7835241 TI - [Somatostatin receptor scintigraphy and endoscopic ultrasound for the diagnosis of insulinoma and gastrinoma]. AB - In a prospective study of 13 patients (three males and 10 females; mean age 53 [8 82] years) the value of somatostatin receptor scintigraphy (SRS) and endoscopic ultrasonography (EUS) was compared with transabdominal ultrasound (US), computed tomography (CT) and magnetic resonance imaging (MRI) in the diagnosis of insulinoma (six patients) or gastrinoma (seven patients). There were ten separate primary lesions of each tumour type, proven histologically. For insulinoma the sensitivity of EUS was 90%, SRS 10% and CT, US and MRI together 20%. For gastrinoma the sensitivity of EUS was 90%, SRS 100%, and 30% for the other three methods together. Thus EUS had a high diagnostic localizing sensitivity for both tumours, while SRS was highly sensitive only in the diagnosis of gastrinoma, not insulinoma. The value of CT, MRI and conventional ultrasonography lies in their ability to visualize distant metastases. PMID- 7835242 TI - [Pulmonary mucormycosis in an HIV-infected patient]. AB - A 51-year-old man, known to have chronic-aggressive hepatitis B, HIV infection and exertional dyspnoea, was hospitalized because of acute physical deterioration, cough with whitish exudate and dyspnoea at rest. Despite a CD4/CD8 ratio of 0.16 no prophylactic measures against Pneumocystis carinii had been taken. On examination the lungs were unremarkable, but the liver was enlarged and there were petechiae over all parts of the body. Laboratory tests showed impaired liver functions and a rise in lactate dehydrogenase activity (538 U/l). Chest radiogram demonstrated small to very small infiltrates in the lung. As Pneumocystis carinii pneumonia was suspected but bronchoscopy was too risky, he was at first treated with trimethoprim/sulphamethoxazole (four times 320/1600 mg/24 h intravenously). When this failed, he received pentamidine (4 mg/kg, after 4 days 2 mg/kg intravenously), and finally cefotiam (twice 2 g daily), tobramycin (three times 40 mg daily) and corticoids (100 mg). Despite this treatment he died after 10 days from respiratory failure. Autopsy revealed interstitial pneumonia throughout the lung as well as focal mucor infiltrations in the wall of middle calibre lung veins. Mucor is a ubiquitous, facultatively pathogenic mold fungus. PMID- 7835243 TI - [Catheter ablation as an emergency treatment in Wolff-Parkinson-White syndrome with signs of acute infarct]. AB - A 53-year-old man known to have Wolff-Parkinson-White syndrome suffered an acute posterior-wall myocardial infarction. Despite successful thrombolysis treatment with streptokinase he continued to have attacks of supraventricular tachycardia with angina. The ECG showed a short P-R interval and pre-excitation with positive delta waves in leads V1-6, as well as signs of re-infarction. The tachycardias could not be satisfactorily suppressed by drug treatment. Coronary angiography revealed triple vessel disease. During this investigation ventricular extrasystoles occurred which initiated orthodromic supraventricular tachycardia and angina, as well as monophasic S-T elevations in leads II, III and aVF. This provided the indication for immediate high-frequency catheter ablation left laterally at the mitral anulus after a left-lateral accessory conduction pathway had been identified. Three days later the stenoses of the circumflex and anterior interventricular branches were dilated. The patient has been free of symptoms for 3 months and can exercise up to 150 W. The tachycardias have not recurred. PMID- 7835244 TI - Glial hyaluronate-binding protein expression in aggregating brain cell cultures. AB - We analyzed the expression of glial hyaluronate-binding protein (GHAP), an integral component of the extracellular matrix, in aggregating brain cell cultures of fetal rat telencephalon using immunofluorescence. GHAP immunoreactivity appeared after 1 week in culture, simultaneous with the first deposits of myelin basic protein, and showed a development-dependent increase. Comparison of glia-enriched and neuron-enriched cultures showed that only glial cells express GHAP. Three peptide growth factors, epidermal growth factor, fibroblast growth factor and platelet-derived growth factor, which are known to stimulate the differentiation of glial cells, modulated the deposit of GHAP immunoreactivity. The 3-dimensional structure of aggregate cultures promoted GHAP deposition, suggesting that cell-cell interactions are required for extracellular matrix formation. Furthermore GHAP production seemed to depend on the developmental stage of the glial cells. PMID- 7835245 TI - Prenatal human lateral geniculate nucleus: a quantitative light microscopic study. AB - Using morphometric methods, a quantitative study has been carried out on the lateral geniculate nucleus (LGN) of human fetuses ranging in gestational age from 13 to 38 weeks. The volume of the nucleus as well as the neuronal, glial and dead cell populations have been studied in Nissl preparations. While the volume of the LGN shows a progressive increase throughout the period of study, the age period of 15-20 weeks is identified as a period of spurt in volumetric growth. Neuronal density and total neuronal number fall continuously while glial density and total glial population show a steady increase with advancing gestational age. Pyknotic dead cells are seen throughout the period of study with a peak die off between 14 and 18 weeks. The study, for the first time, outlines the critical period for volumetric spurt and neuronal death in the developing human LGN. PMID- 7835246 TI - Ca2+/calmodulin protein kinase and protein kinase C expression during development of rat hippocampus. AB - The expression of the genes encoding the alpha subunit of type-II calcium/calmodulin-dependent protein kinase (CAM-KII alpha) and the gamma subspecies of protein kinase C (PKC gamma) was examined throughout postnatal rat brain development by in situ hybridization histochemistry. CAM-KII alpha was found to be expressed sequentially over the different hippocampal subregions, beginning with expression in the pyramidal cells of CA3 at birth, followed by expression in the external blade of the dentate gyrus and in CA1 on postnatal day (PND) 5 and, finally, on PND 8 in the internal blade of the dentate gyrus. PKC gamma expression, in contrast, rose simultaneously in the hippocampal subregions CA1 and CA3, with little expression over the dentate gyrus. This fashion of expression corresponds to the similar maturational state of the pyramidal cells in CA1 and CA3, whereas CAM-KII alpha expression during development of the rat hippocampus follows the time table of afferent lamination, which is delayed in CA1 compared to CA3. Furthermore, we found a temporal overexpression of CAM-KII alpha in the hippocampal subfields CA1 and CA3 at the end of the second postnatal week which coincides with the development of N-methyl-D-aspartate receptor binding. PMID- 7835247 TI - Neurotoxic effects of tumor necrosis factor alpha in primary human neuronal cultures are mediated by activation of the glutamate AMPA receptor subtype: implications for AIDS neuropathogenesis. AB - Human immunodeficiency virus type 1 (HIV) infection of the central nervous system is characterized by neuronal loss in discrete areas of the central nervous system. We have previously demonstrated that HIV-infected monocytes in culture with astroglial cells produce high levels (> or = 200 pg/ml) of the cytokine tumor necrosis factor-alpha (TNF alpha). We now demonstrate that TNF alpha (> or = 200 pg/ml) is neurotoxic to cultured primary human fetal cortical neurons at both light and electron microscopic levels. Subtoxic doses of TNF alpha (50 pg/ml) are neurotoxic in combination with the glutamate (+/-)-alpha-amino-3 hydroxy-5-methylisoxazole-4-proprionic acid (AMPA) subtype receptor agonist AMPA (100 microM). The neurotoxic effects of TNF alpha (200 pg/ml) are blocked in part by the AMPA receptor antagonist, 6-cyano-7-nitroquinoxaline-2, 3-dione (10 microM). This suggests that TNF alpha may exert neurotoxic effects on human neurons by indirect activation of AMPA receptors, which may be important in the pathogenesis and treatment of HIV-mediated encephalopathy. PMID- 7835248 TI - In vivo model of HIV infection of the human brain. AB - Approximately one quarter of the AIDS patients have severe HIV encephalitis with diffuse neuronal damage that may be mediated by immune factors secreted by CNS macrophages. Based on an in vitro brain microsphere model, we developed an in vivo system in which human embryonic brain tissue survives for several months in the interscapular fat pad of SCID mice. Coculture of human brain tissue with macrophages prior to transplantation resulted in infiltration of the microspheres by activated macrophages. When the macrophages were infected in vitro with a neurotropic HIV strain, viral particles were detected in vivo up to 3 months after transplantation. HIV-infected transplants contained multinucleated giant cells similar to those seen in HIV encephalitis. However, the neuroglial component degenerated in the fat pad of SCID mice. The absence of synaptogenesis in the human transplants suggests that the murine fat pad lacks adequate stimuli or support for human neuronal differentiation. To study neurologic damage associated with HIV infection, sites of implantation that stimulate synaptogenesis (e.g. murine CNS) will need to be explored. Based on these findings we conclude that transplantation of brain microspheres with HIV-infected macrophages into SCID mice may be an achievable model of HIV encephalitis. PMID- 7835249 TI - Trauma. PMID- 7835250 TI - Injuries in Africa: a review. AB - Injuries--unintentional and intentional--include a wide range of conditions such as road traffic injuries, falls, burns, poisonings, and assaults. Worldwide, unintentional injury is the fifth most common cause of death, responsible for 5.2% of the total mortality. Rates are declining in industrialized countries, for example, in the US from 72/100,000/year around 1900 to 40 in 1982 and 30 in 1988. African injury data are mainly based on hospital records, and few population based incidence estimates have been made. This review concludes that in sub Saharan Africa, injuries rank third behind diarrhoea and malaria at 40,000 episodes and 100 deaths per 100,000 population per year. Incidences are higher in males than in females, and the most common cause is fall, followed by road traffic injury, assault, burn and poisoning. Substantial reductions are possible through prevention programmes. PMID- 7835251 TI - Fatal non-transport injuries in Nairobi, Kenya. AB - Records from the office of the Registrar of Births and Deaths in Nairobi, Kenya, were studied with the aim of determining the magnitude of fatalities due to injuries sustained in the living environment. This information covered the period between 1986 and 1990. Data were collected over a one month period from 3rd July 1991 to 9th August 1991. The information which was collected from the death certificates included type of injury resulting in death, age and sex of the victim. The results from a total of 944 records revealed that males suffered more deaths than females (M:F ratio was 2.67:1). The most commonly occurring type of injury resulting in death was burns (22.5%). This was followed by drowning (18.1%), head injuries (18%) and suicide by hanging (12%). Stab wounds and poisoning (excluding food poisoning) each accounted for 6% of the total deaths, inhalation of vomit (5.2%) and crush injuries due to falling from a height (3.8%). Bullet wounds, asphyxia due to choking, abortion and electrocution each contributed less than 3% of total deaths. The age bracket with the highest number of deaths was between 20 years to 39 year's (51.4%) while infants and children 0 4 years alone contributed 16% of the total deaths. Since non-transport fatalities are common in all age groups, health education programmes must target both children and the adult population. PMID- 7835252 TI - Accidents involving adults in the home environment in Nairobi, Kenya. AB - Hospital records covering the period between 1986 and 1990 obtained from 10 major city hospitals and 12 City Council Health clinics were reviewed and information on age, sex, occupation, type and cause of injury and its management was extracted. Also extracted was information on outcome of treatment. This paper deals only with information related to persons aged 18 years and above. The results show that out of 9648 hospital records reviewed, 48% were adult cases, with a male to female ratio of 1.5:1. Age group 18-35 years constituted more than 70% of all the cases, declining markedly with increasing age. The slums and low income group residential areas contributed 63% of the cases. The main types of injuries attended to were open wounds (34%), burns (13%), swellings (7%), lacerations and bruises (6%), bites and limb injuries (5%), respectively. The results show that there is a clear case for a community operational research project with a strong accident prevention component. PMID- 7835253 TI - Fractures in childhood in Khartoum. AB - A prospective study of fractures in 231 children received at Khartoum North Teaching Hospital(KNTH) was carried out for a period of six months. The incidence of child fracture rated as one per day, then it increased from the age of 5 years onwards in boys and between 6 and 8 years in girls. Most injuries were sustained during the day time, especially between late afternoon and sunset. 82% of injured children presented to a medical facility, while 18% were taken to native healers first. Non-road traffic accidents accounted for 84% of the fractures mainly due to sports, domestic injuries and falls; whereas road traffic accidents were 16% and occurred mainly in pedestrians. Forty three percent of the fractures needed only first aid and splintage while 42% needed closed reduction. Thirty one percent of all patients were treated as inpatients. The long bones were affected in 91% of all fractures, the commonest site being the distal end of the forearm (26%), followed by supracondylar fracture of the humerus (15.6%). In the upper limb, left-sided fractures predominated. The epiphyseal injuries were 3.5% of all fractures, mainly at the distal radial epiphysis. Boys were commonly affected between 13-15 years of age. Open fractures constituted 9.8% of the series and were mainly due to traffic accidents in town dwellers, the most vulnerable bones were those of the leg and foot. Pathological fractures accounted for 2.2% and were due to bone cysts and osteogenesis imperfecta. The problem of child safety and the preventive measures need to be more stressed. PMID- 7835254 TI - Factors affecting the morbidity of vitamin D deficiency rickets and primary protection. AB - Rickets was investigated in 860 children in the 3 to 36 month age group in 21 villages attached to Sinik Health Centre, in northeastern Turkey. The blood calcium, phosphorus and alkaline phosphatase levels of suspect cases were determined following examination and wrist x-rays taken. The prevalence of cross sectional rickets was determined, in the cohort group formed by removing the rickets cases (to the first group, advice was not given; to the second, 400 IU of vitamin D) and its incidence determined. The prevalence of rickets was calculated as 9.8% with no distinction observed between males and females (P > 0.05). It is higher in children in the 3-6 month group (23.97%) (P < 0.05); exposed rarely to the sun (P < 0.001); without fish in diet (P < 0.01); born to mother under 18 years old (P < 0.001); with a mother not using contraception (P < 0.01). The prevalence of acute respiratory infections (ARI) was calculated as 47.62% and 35.70% (P < 0.05) in children with and without rickets, respectively. The prevalence of enteritis was calculated as 29.76% and 18.43% (P < 0.05) in children with rickets and without rickets, respectively. Rickets was not seen where 400 IU of vitamin D was administered, while incidence for the twelve-month period was calculated as 3.8% in the other group. Combatting rickets is important in developing countries where deaths under five years are largely due to ARI and enteritis. PMID- 7835255 TI - Diagnoses and prescriptions for patients managed during a free health care day in Eldoret, Kenya. AB - Diagnoses and prescriptions for 2,218 patients seen during a "Free Health Care Day" in a semi-urban African town were reviewed. There was a marked tendency to over-prescription, coupled with a failure to use available laboratory tests to diagnose conditions such as malaria and intestinal parasites. Only 37 of 413 patients with malaria had a diagnostic blood smear (17 positive, 20 negative) done. Nevertheless, many patients without any clear diagnosis received multiple drugs. The mean number of drugs prescribed was two; and three or more drugs were prescribed for 677 (33%) patients. The adverse pharmacological and financial aspects of excessive drug prescription are stressed in this communication. PMID- 7835256 TI - Knowledge and attitude of health workers towards leprosy in north-western Botswana. AB - The knowledge and attitude of health workers in north-western Botswana towards leprosy was determined by interviewing ninety nine health workers from various health institutions. Knowledge on causation of leprosy was generally lacking. Although majority of respondents knew that the disease is curable, less than half knew the correct duration of treatment. The attitude of service providers was influenced by poor knowledge, and more than a third claimed that patients should be isolated. The pattern of health seeking behaviour, initially traditional or religious healers and then modern health facilities, was a significant finding. In order to ensure early case detection and prevent deformities, it is vital that education of community, patients and health workers is provided to an extent that health seeking behaviour is altered. Traditional and religious leaders must also be included in such training sessions. PMID- 7835257 TI - Susceptibility pattern of Neisseria gonorrhoeae isolated at the Komfo, Anokye Teaching Hospital, Ghana to commonly prescribed antimicrobial agents. AB - This study which aimed to determine the susceptibility patterns of seven often prescribed antimicrobial agents for treatment of gonorrhoea in Kumasi, Ghana, over a study period of 3 years (1991 through 1993), examined a total of 1187 specimens (high vaginal, cervical and urethral). Identification of N. gonorrhoeae was by colonial morphology, oxidase test, sugar fermentation test and the Gram stain. The Intra-lactam strip method was used to determine which Neisseria gonorrhoeae isolates were beta lactamase producers (PPNG). Of the 1115 PPNG strains encountered, 300 were selected for MIC determination against seven (penicillin, cotrimoxazole, tetracycline erythromycin, spectinomycin, norfloxacin and ceftriaxone) antimicrobial agents in current usage in Kumasi, Ghana. Based on our results it was concluded, that PPNG strains are rampant/endemic in Kumasi, Ghana and that most exhibited multiple antimicrobial resistance. This situation requires, therefore, a serious review of the current Ghana Ministry of Health gonorrhoea treatment regimen. Suggestions to this end have been made. PMID- 7835258 TI - Clinical and immunological markers in Kenyan pulmonary tuberculosis patients with and without HIV-1. AB - Amongst newly diagnosed pulmonary tuberculosis patients, 44% were co-infected with human immunodeficiency virus (HIV). Pulmonary tuberculosis patients with HIV 1 presented more frequently with lymphadenopathy and diarrhoea than those without HIV-1. Peripheral blood CD4+ counts were significantly lower in patients with pulmonary tuberculosis with HIV-1 than those with pulmonary tuberculosis alone, P = 0.0292. CD4+ lymphocyte counts, lymphadenopathy and BCG scar could serve as indicators of HIV-1 infection in pulmonary tuberculosis (PTB) patients. PMID- 7835259 TI - Cryptosporidiosis among medical patients with the acquired immunodeficiency syndrome in Tikur Anbessa Teaching Hospital, Ethiopia. AB - Fresh stool specimens, collected at random from 63 medical in-patients with acquired immunodeficiency syndrome (AIDS), were studied prospectively for Cryptosporidium oocyst. The diagnosis of AIDS was made according to the clinical case definition of the Bangui criteria. These patients presented with profuse watery diarrhoea, significant weight loss and other associated symptoms and signs of clinical manifestations of symptomatic human immunodeficiency virus (HIV) infection. Using the modified Kinyoun acid fast staining technique, 25(39.7%) of the stool specimens were positive for Cryptosporidium oocyst. This study showed that the protozoan, Cryptosporidium parvum, may be responsible for a significant proportion of cases of chronic diarrhoea among AIDS patients in Ethiopia. PMID- 7835260 TI - Gut parasites in HIV-seropositive Zambian adults with diarrhoea. AB - We undertook a nine month study to define the frequency of parasitic infections in adults with diarrhoea presenting at the medical filter clinic and the Dermatovenereology clinic of the University Teaching Hospital in Lusaka, Zambia. A total of 287 patients with diarrhoea were enrolled in the study; 130 from the adult medicine filter clinic recruitment consulting room and 157 patients from the Dermatovenereology clinic. Of 130 patients from the adult filter clinic, 85 (65%) were HIV-seropositive and 45 (35%) were seronegative for HIV. Out of 85 HIV seropositive patients, 58 (68.2%) had acute diarrhoea and 27 (31.8%) had chronic diarrhoea. Of the 45 HIV-seronegative patients, 35 (77%) had acute diarrhoea and 10 (23%) had chronic diarrhoea. All of the 157 patients recruited from the Dermatovenereology clinic were HIV-seropositive. Of these, 97 (62%) had chronic diarrhoea; 7 (4%) had acute diarrhoea, and 53 (34%) patients had no diarrhoea. The common parasites detected were Ascaris lumbricoides, hookworm, Entamoeba coli, and Cryptosporidium spp. Isospora belli and Cryptosporidium spp were seen only in the HIV-seropositive group. In the Dermatovenereology clinic there was a statistically significant difference between parasite detection rate of Isospora belli and Cryptosporidium spp in HIV-seropositive patients with chronic diarrhoea compared to asymptomatic HIV-seropositive individuals P < 0.01 and p = 0.05, respectively). A significant difference in detection rates of Entamoeba coli was seen between the HIV-seropositive group in the Dermatovenereology clinic [17 (10.8%) out of 157] compared to 1 (1.5%) out of 85 in the adult medicine filter clinic.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7835261 TI - Risk factors for the development of diarrhoea in the neonatal ward of Ethio Swedish Children's Hospital. AB - A retrospective case control study was made to determine the risk factors for development of diarrhoea in a neonatal ward of Ethio-Swedish Children's Hospital over a period of 12 months. A total of 803 neonates' record was screened for the presence of diarrhoea during their hospital stay. There were 79 cases with an attack rate of 9.84%. The identified risk factors are gestational age less than 37 weeks, birth weight of less than 2500 gms, formula feeding and hospital stay of more than 10 days. Prophylactic usage of antibiotics have proven to be non beneficial in reducing the acquisition of diarrhoea. Anticipation of the problem in those that are at risk and persistent surveillance to detect cases would be of paramount importance in reducing the overall morbidity. PMID- 7835262 TI - Clinical analysis of mortality in hospitalized Zambian children with sickle cell anaemia. AB - The hospital records of 62 Zambian children with sickle cell anaemia (SCA) who died during a 3 year period (January 1987 to December 1989) at the Paediatric Wing of the University Teaching Hospital, Lusaka, Zambia, were reviewed retrospectively. The SCA patients accounted for 2.92 percent of the total admissions and the average case fatality was 6.61 percent of the total SCA admissions. The case fatality rate has reduced considerably as compared to the one observed in 1970 in Zambia, although the major causes of death remain the same. The maximum mortality was noted in the age group of one to five years (54.84%). The common causes of death were infections (29.54%), vasoocclusive crises (22.72%) and splenic sequestration crises (20.45%). The problems of sub Saharan Africa, like malaria, malnutrition and now the HIV infection also adde to the mortality (15.90%). PMID- 7835263 TI - The efficacy and safety of ketoconazole in visceral leishmaniasis. AB - This study was an open evaluation of the efficacy and safety of Ketoconazole, 15 mg/kg/day orally for 3 weeks in 7 evaluable patients with Visceral Leishmaniasis in Kenya. Of all the seven patients who received ketoconazole, none had appreciable clearance of parasites from the splenic aspirate smears that were microscopically examined. All the splenic aspirate cultures done on these patients in the three weeks remained positive for leishmania parasites. Splenic sizes of these patients generally remained unchanged throughout the study period. The mean haemoglobin at the start of treatment was not different from that at the end of treatment. Liver function tests throughout treatment remained unchanged, i.e. within normal limits. It is concluded that Ketoconazole, 15 mg/kg/day orally given to these patients was not effective as an antileishmania drug although there was a one log drop in the parasite load. However, no serious side effect were noted in all of the patients during treatment. PMID- 7835264 TI - Umbilical vein injection for retained placenta: clinical feasibility study of a new technique. AB - Intraumbilical oxytocin infusion for retained placenta is a relatively new and promising technique. We have tested the clinical feasibility of different infusion techniques in this study. Nine patients had intraumbilical infusions through a mucus aspiration catheter and 12 by an 18 gauge needle. Infusion was successful in 7(77.7%) of 9 cases following catheterisation and in 7(58.3%) of 12 cases following direct injection. Both techniques were clinically feasible, but direct injection was somewhat easier than catheterisation. The importance of non operative management of retained placenta, particularly in areas with limited medical facilities, is discussed and an approach to the management of retained placenta proposed. PMID- 7835265 TI - Crossed testicular ectopia with fused bilateral duplication of the vasa deferential: an unusual finding in cryptochidism. AB - A case of a one year and ten month old boy with crossed testicular ectopia, fused vasa deferentia, and common processus vaginalis containing both testes is reported. This is the first case of transverse testicular ectopia we have come across since 1978. Diagnosis was made on the operation table as the child came for repair of right inguinal hernia. Right testis was palpable in the groin; the left testis was not palpable anywhere along the pathway of descent. Because of ductal fusion, both testes were brought down on the right side to avoid damage during separation and placed in either hemiscrotum through transceptal window. PMID- 7835266 TI - Pneumatosis cystoid intestinalis: a case report. AB - A case of pneumatosis cystoid intestinalis associated with duodenal ulcer and pyloric stenosis is reported. Review of literature revealed that, this is the first reported case in the Sudan and in Africa at large. The clinical presentation of this patient was confusing and it seems reasonable to consider pneumatosis in the differential diagnosis of pneumoperitonium associated with duodenal ulcer to avoid unnecessary laparotomy. PMID- 7835267 TI - Growth hormone binding protein--errant receptor or active player? PMID- 7835268 TI - Measurement of growth hormone-binding protein in the rat by a ligand immunofunctional assay. AB - We have developed a ligand immunofunctional assay (LIFA) for quantifying the circulating functional GH-binding protein (GHBP) in the rat. This two-site solid phase assay uses a capture monoclonal antibody (4.3) specific to the hydrophilic C-terminal segment of rat GHBP (rGHBP), saturation of binding with human GH, and a detection system of rabbit antihuman GH polyclonal antibody and peroxidase conjugated antirabbit immunoglobulin G antibody. Results were compared with Scatchard estimates derived by immuno-precipitation with monoclonal antibody 4.3. This assay was used to determine the GHBP levels in male and female rats and to investigate the diurnal properties and dynamics of GH and GHBP interaction in 15 min blood sampling over a 6-h period. The dynamic range of the rLIFA was 0.15 20.0 nM recombinant rGHBP, with intraassay and interassay coefficients of variation of 10.5% (n = 20) and 12.9% (n = 12), respectively. Serum GHBP levels determined by the rLIFA and those derived from Scatchard estimates were strongly correlated (n = 8; beta = 0.55; r2 = 0.89; P = 0.0005). Male rats had lower GHBP levels (6.5 +/- 0.7 nM; mean +/- SE; n = 14) than female rats (35.4 +/- 2.7 nM; n = 15; P = 0.0001). In the diurnal study, male rats had higher GH peaks (312.5 +/- 121.6 ng/ml; n = 7) than female rats (96.5 +/- 15.4 ng/ml; n = 9; P < 0.0001). In contrast to the pulsatile secretion of GH, GHBP levels in both sexes remained stable and showed no relationship to secretory pulses of GH. However, the GH bursts significantly altered the distribution of the GH-GHBP complex in male rats. By saturation and mass analysis, the greater GH pulsatile secretion in male rats resulted in occupancy of GHBP from less than 5% at nadir to about 80% at secretory peaks, in contrast to the less than 5-15% range of GHBP occupancy in female rats. In male rats, greater than 80% of GH at secretory peaks existed in the free form, whereas in female rats, 16-23% of GH existed in the free form during pulsatile secretion. In summary, the rLIFA shows good correlation to Scatchard analysis using an identical antibody. We conclude that this assay provides a rapid, sensitive, and accurate measurement of the circulating functional GHBP in the rat, and that it facilitates the study of GH and GHBP dynamics under a range of physiological conditions. PMID- 7835269 TI - Expression and distribution of messenger ribonucleic acids for growth hormone (GH) receptor and GH-binding protein in mice during pregnancy. AB - The GH-binding protein (GHBP) in rodents consists of a ligand-binding domain, which is identical to the extracellular portion of the GH receptor (GHR), and a hydrophilic carboxyl-terminal domain, in place of the transmembrane and intracellular domains of the GHR. The two proteins are encoded by separate messenger RNAs (mRNAs), which are believed to be derived from a single gene by alternative splicing. In the present study, we report the gestational profiles of mouse GHR (mGHR) and mGHBP mRNAs in adipose tissue, brain, heart, kidney, liver, lung, mammary gland, muscle, ovary, and pituitary and describe the ontogeny of both messages in the liver of late gestational fetuses and newborns. A ribonuclease protection assay was used to simultaneously detect the two transcripts with an antisense RNA probe complementary to the extracellular domain and hydrophilic tail-encoding regions of the mRNAs. Levels of hepatic GHR and GHBP mRNAs increased with fetal age. In the maternal liver, the abundance of both messages increased during pregnancy, with GHR mRNA levels rising less than GHBP mRNA. Also, the ratio between the two messages in this tissue increased during pregnancy in favor of mGHBP mRNA. In maternal mammary tissue, however, expression levels of both transcripts decreased gradually throughout pregnancy starting on day 8 of gestation and declining further during lactation, reaching a minimum 7 fold reduction on day 6 of lactation relative to nonpregnant values. Although there were no pregnancy-related changes in the remaining tissues we examined, the ratio of the abundance of GHR mRNA to that of GHBP mRNA varied tissue specifically. In the maternal brain, heart, liver, and mammary gland, mGHBP mRNA levels were higher than mGHR mRNA levels. In the maternal muscle and adipose tissue, the abundance of the two mRNA species was comparable. These observations indicate a gestational, developmental, and tissue-specific regulation of the expression of mGHR and mGHBP species. PMID- 7835270 TI - Dehydroepiandrosterone functions as more than an antiglucocorticoid in preserving immunocompetence after thermal injury. AB - Reduced cellular immune responses and altered cytokine production by cells from mice exposed to thermal injury are minimized if dehydroepiandrosterone (DHEA) is administered after experimental burn injury in mice. An analysis of similar tests of immune function developed by mice given the antiglucocorticoid, 17 beta hydroxy-11 beta-[4-dimethylaminophenyl]17 alpha-propynyl-estra-4,5-diene-3-one (RU486), after the burn revealed no difference in immune function between the RU486-treated mice and the untreated burn group. At the levels of drug used, both DHEA and RU486 were able to completely block the effects of glucocorticoid treatment on immune function in mice, establishing a direct antiglucocorticoid activity of each steroid. Because thermal injury-mediated changes in immunity could be overcome by the administration of DHEA, but not RU486, the data suggest that the elevations in adrenal output of glucocorticoids are not responsible for the alterations in immune function after experimental thermal injury of mice. The results of this study have provided further insight into the mechanism of action of DHEA in this experimental model. The ability of DHEA to preserve immune function in severely thermally injured mice appears to extend beyond an antiglucocorticoid activity. PMID- 7835272 TI - Retinoid-X receptor (RXR) differentially augments thyroid hormone response in cell lines as a function of the response element and endogenous RXR content. AB - Retinoid-X receptor (RXR) forms heterodimers with thyroid hormone receptor (TR) and significantly enhances binding to thyroid hormone response elements (TREs). Expression of RXR in a transient transfection assay augments the T3 response, but the influences of the specific cell line and TRE used have not been systematically studied. We determined RXR alpha and -beta augmentation of the TR alpha-mediated T3 response in transient transfection assays of COS, JEG, and mouse embryonic stem (ES) cell lines for a series of eight wild-type thyroid hormone (T3) and retinoic acid response elements (previously shown to bind TR). RXR augmented T3-induced expression in COS and ES cells (1.5- to 4-fold greater expression with added RXR compared to TR alone), but had minimal effect on augmentation of response in JEG cells. For most elements studied there was a proportional augmentation of basal and T3-stimulated expression. TREs from rat GH and laminin-B1, however, had relatively higher levels of T3-induced expression as a result of RXR cotransfection (T3 induction ratios increased 2-fold or greater). Previous characterization of these elements demonstrates that they contain more than two hexameric binding domains, all of which can simultaneously bind TR. The influence of endogenous RXR expression in a cell line on RXR augmentation of the T3 response was determined. RXR alpha and -beta messenger RNA (mRNA) expression was quantitated by Northern blot in each cell line. COS and JEG cells expressed almost exclusively RXR alpha mRNA, although expression was almost 2-fold higher in JEG compared to COS cells (12 +/- 2.5 vs. 6.8 +/- 0.5 density units relative to actin; mean +/- SE; P < 0.05). ES cells expressed only RXR beta mRNA, but at a very low level (0.4 +/- 0.1). Nuclear extracts prepared from JEG and COS cells augmented TR binding proportional to the endogenous RXR mRNA expression, and the heterodimer band was supershifted by the addition of antibody to RXR alpha. Nuclear extracts from ES cells had no detectable TR heterodimer binding to a range of response elements. RXR augmentation of the T3 response differs among cell lines and is greater in those with reduced endogenous RXR. Furthermore, the functional augmentation of the T3 response ratio by RXR is likely to require additional sequences contained in only a subset of elements in which RXR augments TR binding. PMID- 7835271 TI - Action of metformin on glucose transport and glucose transporter GLUT1 and GLUT4 in heart muscle cells from healthy and diabetic rats. AB - The effects of the antidiabetic drug metformin on glucose transport were investigated in freshly isolated heart muscle cells from healthy and streptozotocin-diabetic rats. In vivo treatment of diabetic rats with metformin failed to affect the basal and insulin-stimulated rate of glucose transport measured in isolated cells. In vitro exposure to therapeutic concentrations (< or = 10(-4) M) of metformin did not influence glucose transport, even upon incubation times up to 5 h or in the presence of high glucose (20 nM). In contrast, higher metformin concentrations produced an 8- to 12-fold increase in glucose uptake (with a lag of 90 min, and a maximum at 180 min and approximately 5 mM). In the presence of submaximal insulin concentrations (< or = 3.10(-10) M), the effects of metformin (5 mM) and of insulin were more than additive, whereas, at saturating insulin concentrations (10(-8) M), partial additivity was observed. Like insulin, metformin caused an approximately 1.6-fold increase in the content of both glucose transporter isoforms GLUT1 and GLUT4 in the plasma membrane of cardiac myocytes, with a corresponding decrease in an intracellular membrane fraction. cAMP-elevating treatments depressed the metformin-, but not the insulin dependent glucose uptake, by 20-30%. In myocytes from diabetic rats, the rate of metformin-activated glucose transport was similar to that of cells from control animals, whereas basal and insulin-stimulated transport were substantially diminished. Finally, metformin (5 mM) induced a slight depression of oxygen consumption and energy metabolism of myocytes (as determined by measuring their level of energy-rich phosphates) comparable to the effects of hypoxia in rat hearts. In conclusion, these data do not provide evidence in favor of the hypothesis that glucose uptake by muscle tissue represents the site of metformin's therapeutic action in vivo. On the other hand, the large, insulin independent effect of metformin at high concentrations (approximately mM) in vitro may be related to the action of hypoxia and occurs through a redistribution of glucose carriers from an intracellular locus to the plasma membrane. The mechanism (or signal) involved in metformin's action is likely to differ from that triggered by insulin and is not impaired in the diabetic state. PMID- 7835274 TI - Steroid hormone receptors selectively affect transcriptional activation but not basal repression by thyroid hormone receptors. AB - Thyroid hormone receptors (TRs) and steroid hormone receptors belong to a large superfamily of nuclear hormone receptors. The interactions between these receptor subfamilies are poorly understood. In this study, cotransfection assays were used to examine the effects of estrogen and glucocorticoid receptors on TR-mediated repression of basal transcription by unliganded TR and transcriptional activation by liganded TR with two different thyroid hormone response element-containing reporter plasmids. Surprisingly, it was found that steroid hormone receptors blocked T3-mediated transcriptional activation with little or no effect on basal repression by unliganded TR. The mechanism for blocking TR-mediated transcriptional activation does not require steroid hormone receptor binding to the thyroid hormone response element but, rather, may involve titration of a critical coactivator(s) required for T3-mediated transcriptional activation. These studies strongly suggest divergent pathways for transcriptional activation and basal repression by TRs. Additionally, these studies raise the potential for nuclear hormone receptors to modulate TR-mediated transcriptional activation in steroid hormone-responsive tissues. PMID- 7835273 TI - Epidermal growth factor (EGF) receptor carboxy-terminal domains are required for EGF-induced glucose transport in transgenic 3T3-L1 adipocytes. AB - Insulin-stimulated glucose transport in adipocytes is mediated by the insulin receptor. To ascertain whether a related receptor could also trigger this response, the epidermal growth factor (EGF) receptor (EGFR) was introduced into adipocytes. 3T3-L1 fibroblasts were infected by a retroviral construct encoding either the full-length (WT) or a carboxy-terminal truncated (c'973) human EGFR; truncation of the amino acids distal to 973 removes all autophosphorylation motifs. After selection and conversion to adipocytes, the level of EGFR expression was retained in infectant adipocytes (150,000 and 250,000/cell, respectively), but not in the parental 3T3-L1 adipocytes (< 5000/cell). WT and c'973 EGFR exhibited ligand-dependent tyrosine kinase activity and stimulated mitogen-activated protein kinase activity equivalently; neither phosphorylated insulin receptor substrate-1. WT EGFR, but not c'973 EGFR, underwent ligand induced autophosphorylation. EGF did not stimulate tyrosine phosphorylation of the insulin receptor or insulin receptor substrate-1. EGF had a minimal effect on glucose transport by parental 3T3-L1 adipocytes. Glucose transport in the WT EGFR adipocytes was stimulated equivalently by insulin and EGF; exposure to insulin and EGF in combination did not result in augmented transport. Glucose transport in the c'973 EGFR adipocytes was stimulated by insulin, but not by EGF. GLUT4 was translocated to the plasma membrane to a similar extent in response to insulin or EGF in the WT EGFR adipocytes; only insulin caused a significant GLUT4 translocation in the parental or c'973 EGFR adipocytes. These data suggest that the insulin and EGF signaling pathways that lead to glucose transport converge in these adipocytes down-stream of the insulin receptor, and that activation of this pathway requires signaling motifs in the carboxy-terminus of the EGFR. This model system represents a novel approach with which to dissect signal transduction pathways in terminally differentiated adipocytes. PMID- 7835275 TI - Expression of insulin-like growth factor I in normally and abnormally developing coho salmon (Oncorhynchus kisutch). AB - Changes in levels of insulin-like growth factor-I (IGF-I) messenger RNA (mRNA) in tissues of normally and abnormally growing (stunted) juvenile coho salmon in seawater were studied. Profiles of hepatic IGF-I mRNA levels were compared with changes in growth and plasma concentrations of GH and insulin. In normally growing fish, IGF-I mRNA levels, as measured by solution hybridization-RNase protection assay, showed that hepatic IGF-I mRNA levels of yearling salmon were highest in May and June. Increased hepatic IGF-I mRNA levels followed increases in both plasma GH and insulin. Levels of hepatic IGF-I mRNA decreased in July, after a sharp decline in plasma GH in June, and remained low until the following spring. The growth rate for normal fish also decreased during fall and winter. After increases in plasma GH and insulin, which peaked in late February, hepatic IGF-I mRNA levels increased rapidly and reached a second peak in April. Increases in plasma GH and hepatic IGF-I mRNA observed in the second year were smaller and occurred earlier than in the first spring in seawater. Growth retardation (stunting) resulted from the premature transfer of cultured fish to seawater. Compared with normally growing fish, these stunted salmon had significantly higher levels of plasma GH but lower levels of plasma insulin. Hepatic IGF-I mRNA levels in stunted salmon were significantly lower, despite elevated plasma GH levels. These results indicate that hepatic levels of IGF-I mRNA in juvenile coho salmon increase in springtime, after an increase in plasma GH and insulin. These seasonal increases in GH and IGF-I precede the rapid growth period coinciding with the springtime increases in temperature and photoperiod and may therefore be associated with these environmental cues. The elevated plasma GH and reduced hepatic IGF-I mRNA levels observed in growth-retarded salmon suggested that stunted salmon may be GH resistant. Hepatic GH resistance and diminished IGF-I production may be the central endocrine defects leading to growth retardation in stunted salmon. PMID- 7835276 TI - Expression of parathyroid hormone-related peptide and its receptor messenger ribonucleic acids during fetal development of rats. AB - PTH-related peptide (PTHrP) is a causative agent of hypercalcemia associated with malignancy. PTHrP binds to and activates the same receptor as does PTH. Because PTHrP has been suggested to regulate the growth and differentiation of cells as a paracrine/autocrine factor, we examined the expression of both PTHrP and its receptor genes during fetal development of rats (15-20 days gestation) by in situ hybridization with riboprobes. Both PTHrP and its receptor messenger RNAs (mRNAs) were expressed not only in the skeleton, but also in many fetal extraskeletal tissues, such as choroid plexus, ears, lungs, tooth buds, heart, and skin. In these extraskeletal tissues PTHrP mRNA was expressed mainly in surface-lining cells, whereas its receptor mRNA was expressed mainly in adjacent mesenchyma cells. In endochondral bones, these two genes were expressed in largely discrete, but mostly neighboring, areas, although the localizations of these two mRNAs changed over developmental stages. The expression patterns of PTHrP and its receptor mRNAs during fetal development suggest PTHrP's roles as a paracrine factor and its involvement in epithelial-mesenchymal(-like) interactions. PMID- 7835277 TI - Effects of membrane-permeant and -impermeant thiol reagents on Ca2+ and K+ channel currents of mouse pancreatic B cells. AB - The membrane permeant thiol reagent diazene dicarboxylic acid bis-(N' methylpiperazide) (DIP) has been shown to inhibit insulin secretion and Ca2+ uptake in pancreatic B cells in the presence of a stimulating glucose concentration (20 mM), whereas the nonpenetrating analog of DIP (bis-N' methyliodide; DIP + 2) stimulates insulin release and Ca2+ uptake at a low glucose concentration (3 mM). The effects of DIP and DIP + 2 were tested on currents through ATP-sensitive K+ (K+ATP) channels and voltage-dependent Ca2+ channels (with Ba2+ as the charge carrier) in mouse pancreatic B cells in the whole-cell mode of the patch-clamp technique. DIP (0.1 mM) almost completely inhibited both the K+ATP and Ca2+ channel currents. In contrast, DIP + 2 (0.1 mM) did not affect the Ca2+ channel current but reduced the whole-cell K+ATP current by about 40%. The data strongly suggest that the suppression of insulin secretion previously observed with DIP is due to a reduction of the current through voltage dependent Ca2+ channels, whereas the stimulation of hormone release induced by DIP + 2 is caused by the partial inhibition of K+ATP channel current. PMID- 7835278 TI - Impaired protein kinase C activation is associated with decreased hepatic alpha 1 adrenoreceptor responsiveness in adrenalectomized rats. AB - The present work aimed to study the influence of corticosteroids on the alpha 1 adrenoreceptor-induced activation of hepatic metabolic functions. The experiments were performed in a nonrecirculating liver perfusion system featuring continuous monitoring of pO2, pCa2+, Ca2+, pH, and portal pressure. The alpha 1-adrenergic induced stimulation of respiration, H+ and Ca2+ release, glycogen breakdown, and gluconeogenesis, were diminished in livers from adrenalectomized animals. The normal liver responsiveness was restored on administration of exogenous corticosteroids but not mineralocorticoids. The following observations support the conclusion that corticosteroids control a hepatocyte-specific early postreceptor step in the alpha 1-adrenergic signaling pathway: 1) the alpha 1 adrenergic stimulation of vascular smooth muscle contraction was not impaired by corticosteroid deficiency; 2) the alpha 1-adrenoreceptor ligand-binding affinity does not seem to be altered by adrenalectomy; 3) the alpha 1-adrenergic-induced intracellular alkalosis, protein kinase C activation, and Ca2+ mobilization were diminished in hepatocytes from adrenalectomized rats, indicating that both Ca(2+) dependent and -independent processes were altered; and 4) non-receptor-mediated homeostatic mechanisms of metabolic or intracellular pH control were not impaired by adrenalectomy. PMID- 7835279 TI - Activation of protein kinase C stimulates the tyrosine phosphorylation and guanosine triphosphatase-activating protein association of p60 in rat hepatoma cells. AB - In the present studies, insulin was found to stimulate in a rat hepatoma cell line (called FAO cells) the tyrosine phosphorylation of the 60-kilodalton p21ras GTPase-activating protein (GAP)-associated protein called p60. Surprisingly, the tyrosine phosphorylation of this protein was also almost equally stimulated by an activator of protein kinase C (PKC), the phorbol ester phorbol 12-myristate 13 acetate (PMA). The tyrosine phosphorylation of p60 induced by either agent correlated with the formation of the GAP-p60 complex in situ and an increase in the ability of p60 to directly bind to the SH2 domain of GAP in vitro. Several lines of evidence indicated that the PMA-induced tyrosine phosphorylation of p60 occurred through a different mechanism than that induced by insulin. First, the stimulation of tyrosine phosphorylation of p60 by maximal concentrations of the two agents was almost additive. Second, down-regulation of PKC or pretreatment with a specific inhibitor of PKC abolished the ability of PMA to stimulate tyrosine phosphorylation of p60 but had no effect on the insulin stimulation. And third, long-term pretreatment with insulin abolished the insulin response but did not affect the response to PMA. The PMA effect did seem to be mediated via a tyrosine kinase, since it was blocked by quercetin, an inhibitor of tyrosine kinases. These results indicate that both PMA and insulin can equally stimulate in FAO cells the tyrosine phosphorylation of p60 and its association with GAP, although these two agents seem to act via different signaling systems. PMID- 7835280 TI - Inhibition of cardiac myocyte maturation by 1,25-dihydroxyvitamin D3. AB - The signals that regulate cardiac myocyte maturation in the neonatal heart are not completely understood. In our study we examined the effects of 1,25 dihydroxyvitamin D3 [1,25-(OH)2D3] on primary cultures of ventricular myocytes isolated from neonatal rat hearts. Our data show that 1,25-(OH)2D3 inhibited an increase in both the muscle-specific form of creatine kinase and V1 myosin isoenzyme levels in myocytes induced to mature by serum withdrawal. Thus, in contrast to other cell types studied to date, in the heart, 1,25-(OH)2D3 blocks cell maturation. Treating cultures with phorbol 12-myristate 13-acetate induced a decrease in the muscle-specific isoenzyme of creatine kinase similar to the effects of 1,25-(OH)2D3. Interestingly, we found that staurosporine, a protein kinase-C inhibitor, blunts the effects of 1,25-(OH)2D3 and has the opposite effect of phorbol 12-myristate 13-acetate on cultured myocytes induced to mature by serum withdrawal. Thus, our data identify a novel role for 1,25-(OH)2D3 in the regulation of myocardial development and suggest that 1,25-(OH)2D3 may be acting through a protein kinase-dependent mechanism to maintain cardiac myocytes in an immature state. PMID- 7835281 TI - Cytokine and hormonal stimulation of human osteosarcoma interleukin-11 production. AB - Osteoclast-mediated bone resorption plays a crucial role in osseous remodeling. Osteoblasts are important regulators of this activity, in part through their ability to produce osteoclast-regulating soluble factors such as interleukin-6 (IL-6). IL-11 is a newly appreciated pleotropic cytokine whose spectrum of biological activities overlaps with that of IL-6. As a result, we hypothesized that osteoblasts are an important skeletal source of this cytokine. To test this hypothesis, we characterized the IL-11 production of unstimulated and stimulated SaOS-2 human osteosarcoma cells. Unstimulated cells produced modest amounts of IL 11. The osteotropic agents recombinant IL-1 (0.25-5 ng/ml), transforming growth factor-beta 1 (0.1-10 ng/ml), PTH (10(-8)-10(-11) M), and PTH-related peptide ((10(-8)-10-11 M) further increased SaOS-2 cell IL-11 protein production and messenger RNA accumulation. These stimulatory effects were dose and time dependent, and the IL-11 that was produced was bioactive, as demonstrated by its ability to stimulate the proliferation of T10D plasmacytoma cells. The protein kinase-C activator, 12-O-Tetra-decanoylphorbol 13-acetate, and a variety of cAMP agonists [forskolin, prostaglandin E1, prostaglandin E2, and (Bu)2AMP] also stimulated osteoblast IL-11 protein production and messenger RNA accumulation. In contrast, recombinant IL-4, recombinant interferon-gamma, and endotoxin did not stimulate SaOS-2 cells in a similar fashion. Importantly, the ability to produce IL-11 was not a unique property of SaOS-2 cells, because primary human trabecular bone osteoblasts also produced significant amounts of bioactive IL-11 when stimulated with transforming growth factor-beta 1. These studies demonstrate that appropriately stimulated human osteoblasts and osteoblast-like cells are potent producers of IL-11 and suggest that osteoblast-derived IL-11 may be an important component of the cytokine network mediating osteoblast-osteoclast communication in normal and pathological bone remodeling. PMID- 7835282 TI - Calcium receptor messenger ribonucleic acid levels in the parathyroid glands and kidney of vitamin D-deficient rats are not regulated by plasma calcium or 1,25 dihydroxyvitamin D3. AB - The level of extracellular ionized calcium ([Ca2+]o) is the primary physiological regulator of PTH secretion. Complementary DNAs encoding the calcium receptor (CaR) protein that mediates this response have been cloned from bovine and human parathyroid glands. This protein is a seven-transmembrane, G-protein-coupled receptor linked to the mobilization of intracellular Ca2+ in response to increases in [Ca2+]o. More recently, a rat kidney CaR has been cloned and shown to be 92% identical at the amino acid level to the bovine parathyroid CaR. Homologous or heterologous regulation of the expression and/or function of a variety of G-protein-coupled receptors has been documented in numerous cell types. Therefore, we determined whether [Ca2+]o and 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3], major regulators of PTH synthesis and secretion, affect CaR gene expression in parathyroid gland and kidney in rats. CaR messenger RNA (mRNA) levels were quantified in pairs of parathyroid glands and single kidneys from individual animals using a solution hybridization assay. The effects of Ca2+ and 1,25-(OH)2D3 on CaR gene expression were assessed independently in vitamin D deficient (-D) rats. A wide range of plasma Ca2+ levels (0.7-1.9 mM) was produced by supplementing -D diets with varying amounts of calcium and by infusing CaCl2 i.v. for 7 days using osmotic minipumps. There was no correlation between plasma Ca2+ levels and steady state CaR mRNA levels in parathyroid gland (r = -0.18) or kidney (r = 0.25). In another group of -D rats, 1,25-(OH)2D3 was infused sc at 25 and 275 ng/kg.day for 10-12 days. Dietary calcium was adjusted to maintain normocalcemia in some of the groups. No effect of 1,25-(OH)2D3 administration on CaR mRNA levels occurred in parathyroid glands or kidney regardless of the resultant plasma Ca2+ or 1,25-(OH)2D3 levels. In conclusion, neither parathyroid gland nor kidney CaR mRNA levels are regulated by plasma Ca2+ and 1,25-(OH)2D3 levels in the experimental models examined here. PMID- 7835283 TI - Enhanced sensitivity of pancreatic islets from preobese 2-week-old ob/ob mice to neurohormonal stimulation of insulin secretion. AB - Insulin secretion from perifused islets of preobese, 2-week-old, genetically obese (ob/ob) mice and their lean littermates was examined to identify early onset abnormalities in regulation of insulin secretion by ob/ob mice. The ob/ob mice were slightly hyperinsulinemic (+20%) and hypoglycemic (-12%) at 2 weeks of age. Pancreatic islet size, DNA content, and insulin content were similar in ob/ob and lean mice. The responsiveness of islets to glucose, as determined by 20 mM glucose-induced insulin secretion, and the sensitivity of islets to glucose, as determined by the glucose threshold for insulin secretion, were unaffected by phenotype, but two insulin secretagogues that potentiate glucose-induced insulin secretion via activation of the phospholipase-C signal transduction pathway (i.e. acetylcholine, and cholecystokinin) were more effective in stimulating insulin secretion from islets of ob/ob mice than from islets of lean mice. Both responsiveness and sensitivity to acetylcholine and cholecystokinin potentiation of glucose-induced insulin secretion were enhanced in islets from ob/ob mice. Further, glucose-dependent insulinotropic polypeptide, which stimulates glucose induced insulin secretion via activation of adenylate cyclase, interacted with acetylcholine to further augment differences in insulin secretion between islets from ob/ob and lean mice. The signal transduction pathway common to acetylcholine and cholecystokinin, and cross-talk between this pathway and the glucose dependent insulinotropic polypeptide signal transduction pathway are loci for early-onset defects in control of insulin secretion from islets of ob/ob mice. PMID- 7835284 TI - The hypothalamic-pituitary-adrenal axis in rat pregnancy and lactation: circadian variation and interrelationship of plasma adrenocorticotropin and corticosterone. AB - The circadian variation in immunoreactive (I-) ACTH and corticosterone was studied at several stages throughout rat pregnancy and compared with those before pregnancy and during lactation. Serial blood samples were obtained from chronically cannulated, conscious rats at 2- to 3-h intervals beginning at 0800 h at diestrus of the cycle; on days 2, 6, 10, 14, 18, and 22 of pregnancy (term = day 23); and on day 4 of lactation. Plasma I-ACTH and corticosterone were determined in all samples, and indices of their circadian variation (acrophase, mesor, and amplitude) were derived by cosinor analyses within each rat. A circadian variation in corticosterone was clearly evident in all groups, with individual cosinor r2 values being consistently high. Plasma I-ACTH also exhibited distinct circadian variation up to day 14 of pregnancy, but the cosinor r2 value then fell (P < 0.05, by analysis of variance) and remained low during lactation. Mesor levels (midpoint of the derived circadian range) of I-ACTH fell (P < 0.05) by 34% to 20.6 +/- 2.4 pg/ml by day 2 of pregnancy; corticosterone also fell (P < 0.05) by 34% to 141 +/- 27 ng/ml, and both changes were due primarily to reductions in peak levels. I-ACTH mesors then remained effectively unchanged for the remainder of pregnancy, but mesor corticosterone increased progressively after day 10 to reach a maximum of 286 +/- 28 ng/ml by day 22, and this rise was due to elevations in both trough and peak corticosterone levels. Further changes occurred after parturition, with mesor I-ACTH increasing more than 2-fold between day 22 of pregnancy and day 4 of lactation, whereas mesor corticosterone declined by more than half over the same period. Plasma corticosterone and I-ACTH were positively associated within rats in all groups (P < 0.01), but the common slope of this association increased considerably after midgestation, indicative of higher corticosterone levels for a given concentration of I-ACTH. In summary, this study identifies marked changes in the hypothalamic-pituitary-adrenal axis during rat pregnancy and lactation. Although a circadian variation in corticosterone was observed throughout, that in plasma I ACTH was evident early in pregnancy but declined after midgestation. Absolute concentrations of plasma I-ACTH and corticosterone fell in parallel early in pregnancy, but corticosterone subsequently increased without any change in I ACTH.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7835285 TI - Differential positive and negative transcriptional regulation by tamoxifen. AB - Tamoxifen, a nonsteroidal antiestrogen and breast cancer chemotherapeutic, exhibits both estrogen agonist and antagonist properties. Rat GC3 cells grown under estrogen-free conditions were analyzed for the expression of model luciferase reporter genes, either positively or negatively regulated by estrogens. Expression assays adding tamoxifen alone or in combination with 17 beta-estradiol were performed to determine agonist or antagonist activities. In rat GC3 cells, tamoxifen acts as an estrogen antagonist for gene activation, but as an agonist for repression. Regulation by tamoxifen is mediated by estrogen receptor (ER), not via nonreceptor tamoxifen effects. Evaluation of human ER shows that although the wild-type receptor behaves similarly to the rat receptor, the Gly400 to Val400 mutant receptor does not. Tamoxifen, an effective agonist for gene repression with rat and wild-type receptor, shows no agonist activity using this mutated Val400 receptor. Yet, 17 beta-estradiol and clomiphene, another mixed agonist/antagonist, are effective agonists for gene repression with all three receptors. In this model system, tamoxifen functions as antagonist or agonist, depending on whether the ER acts to activate or repress its gene target. In other systems regulated by estrogens, functional analyses of ER action might also serve to predict the agonist or antagonist activity of tamoxifen. PMID- 7835287 TI - Cloning and molecular characterization of complementary deoxyribonucleic acid corresponding to a novel form of pituitary adenylate cyclase-activating polypeptide messenger ribonucleic acid in the rat testis. AB - Pituitary adenylate cyclase-activating polypeptide (PACAP), a neuropeptide that greatly stimulates adenylyl cyclase activity in cultured anterior pituitary cells, was isolated from ovine hypothalamus in 1989. Investigation of the distribution of PACAP messenger RNA (mRNA) in rat tissues by Northern blot analysis revealed an anomalous signal in the testis. In this study we have isolated and characterized this unusual mRNA, which is approximately 800 bases long (approximately 1.5 kilobases shorter than that reported in the rat hypothalamus). Cloning and sequencing of the complementary DNA corresponding to this message revealed that the sequences are identical except for 126 bases at the 5'-end of the 5'-untranslated region of the smaller transcript. This region has no homology to either the published hypothalamic sequence or any other known sequence. Northern blot analysis of total RNA from various species showed that a smaller form of PACAP mRNA is also present in human, murine, and bovine testis, although in these species the message is slightly smaller. In addition, Northern blot analysis of these tissues using a probe directed to the 126-base 5'-region, revealed conservation of this sequence between species. Although the structure of the rat PACAP gene is unknown, preliminary investigations into the origins of the two mRNA species by PCR of genomic DNA suggests that they are transcribed from separate genes and not the product of alternate splicing. PMID- 7835286 TI - Regulation of thyroid-stimulating hormone beta-subunit and growth hormone messenger ribonucleic acid levels in the rat: effect of vitamin A status. AB - T3 inhibits transcription of the rat TSH beta gene, and two T3 response elements have been identified that bind T3 receptors and that share sequence homology with the consensus sequence that is also recognized by retinoic acid receptors (RARs). We, therefore, asked whether RA was a regulator of TSH beta gene expression in vivo. Using RNase protection analysis, we found that vitamin A deficiency led to a 2-fold increase in rat pituitary TSH beta messenger RNA (mRNA) levels, which returned to normal 18 h after treatment with RA (20 micrograms/rat). Vitamin A deficiency had no effect on TSH beta mRNA levels in hypothyroid rats. Coadministration of RA and T3 (10 micrograms/100g body wt) to either vitamin A deficient or vitamin A-deficient, hypothyroid animals caused decreases in TSH beta mRNA content that were indistinguishable from those seen with T3 alone. Surprisingly, vitamin A deficiency had no significant effect on GH mRNA levels in euthyroid or hypothyroid rats. Furthermore, treatment of vitamin A-deficient, hypothyroid animals with RA for either 18 or 72 h had no effect on GH mRNA levels, whereas T3 caused 11-fold and 18-fold increases in GH mRNA, respectively, at these times. We also used transient transfection to test for direct, retinoid receptor-mediated regulation of TSH beta gene transcription by RA. A plasmid TSH beta luciferase, containing 0.8 kilobases of rat TSH beta gene 5'-flanking sequences, exon 1, and 150 base pairs of intron 1, was transfected into CV-1 cells. Cotransfection with RAR alpha and retinoid X receptor-beta induced TSH beta expression by 3.5-fold, and treatment with RA suppressed this induction by 46%. These results show that vitamin A levels play a significant role in regulating the expression of the TSH beta gene, but not the GH gene, in vivo and suggest that RA may suppress TSH beta gene transcription directly by an RAR retinoid X receptor heterodimer-mediated mechanism. PMID- 7835288 TI - Insulin receptor-related receptor messenger ribonucleic acid in the stomach is focally expressed in the enterochromaffin-like cells. AB - The insulin receptor-related receptor (IRR) is a member of the insulin receptor family. In contrast to the widespread expression of insulin receptor and insulin like growth factor-I receptor messenger RNA (mRNA), the expression of IRR mRNA is highly restricted to the kidney and stomach. IRR mRNA in the kidney is focally expressed in the renal distal tubule cells. However, the cellular localization of IRR mRNA in the stomach remains to be elucidated. Here, we examined the cellular localization of IRR mRNA in the rat stomach by in situ hybridization. IRR mRNA in the stomach was abundantly localized in the basal third of the oxyntic glands of the fundic stomach. IRR mRNA in the stomach was colocalized with mRNA for histidine decarboxylase, a marker for the enterochromaffin-like (ECL) cells, indicating that the expression was restricted to ECL cells. ECL cells actively produce and store histamine, which is an important physiological stimulant of acid secretion from the parietal cells. The preferential localization of IRR mRNA in ECL cells suggests that the IRR plays an important role in the function of these cells. PMID- 7835289 TI - Characterization of deoxyribonucleic acid-protein interactions at a growth hormone-inducible nuclease hypersensitive site in the rat insulin-like growth factor-I gene. AB - Many of the growth-promoting effects of GH are mediated by insulin-like growth factor-I (IGF-I), a highly conserved, 70-residue basic peptide. Previous studies have demonstrated that GH rapidly stimulates IGF-I expression in vivo, and our laboratory has identified a GH-regulated alteration in chromatin configuration, manifested as a hormonally induced deoxyribonuclease-I (DNase-I)-hypersensitive site in the second IGF-I intron. In the current study, we have used in vivo DNase I footprinting to map this hormonally responsive chromatin domain to an approximately 350-nucleotide region and have identified DNA-protein interactions within the hypersensitive site by in vitro gel mobility shift experiments and DNase-I footprinting studies. DNA-protein binding was localized to two adjacent segments of 32 and 48 nucleotides. In 1 of these regions, protein-DNA contacts were also detected in vivo on guanine residues by dimethylsulfate footprinting. DNA-binding activity was present in GH-deficient rats, but was not modified by hormone treatment. Our results define a rapid and reversible genomic alteration in response to GH in a GH-regulated gene and delineate a target within chromatin for GH action. PMID- 7835290 TI - Expression of messenger ribonucleic acid encoding tissue inhibitor of metalloproteinases-2 within ovine follicles and corpora lutea. AB - Metalloproteinase inhibitors, such as tissue inhibitors of metalloproteinases 1 and 2 (TIMP-1 and -2), play a key role in the regulation of metalloproteinases that modify extracellular matrix composition. Although expression of TIMP-1 within ovarian tissues has been well characterized, little information is available regarding expression of TIMP-2. The objective of the present studies was to characterize the ontogeny and localization of TIMP-2 messenger RNA (mRNA) within ovine preovulatory follicles and luteal tissue. Total cellular RNA was isolated from preovulatory follicles collected before (presurge; n = 3), or 12-14 h after (post surge; n = 4) an LHRH-induced gonadotropin surge, and from luteal tissue collected on days 3, 7, 10, 13, and 16 post estrus (n = 5, 5, 4, 5, and 5, respectively). TIMP-2 mRNA was expressed by both presurge and postsurge follicles, and expression did not increase after the gonadotropin surge (P = 0.44). In situ hybridization localized TIMP-2 mRNA primarily to the thecal layer of post-surge follicles (n = 3). TIMP-2 mRNA was also localized in a heterogeneous distribution within corpora lutea collected on days 3 and 10 post estrus (n = 3 each). Concentrations of TIMP-2 mRNA (picograms per microgram tissue DNA) were greater in corpora lutea collected during the early luteal phase (days 3 and 7) than the late luteal phase (day 16; P < 0.05). TIMP-2 mRNA was detected in purified populations of both small (n = 4) and large (n = 3) luteal cells, and mRNA concentrations (picograms per microgram DNA) were greater in the large luteal cells (P < or = 0.0002). In addition, immunoreactive TIMP-2 (approximately 21,000 M(r)) was detected by Western blot analysis of ovine luteal cell secreted proteins. We conclude that 1) TIMP-2 mRNA is expressed by the thecal layer of ovine preovulatory follicles and expression is not increased by the preovulatory gonadotropin surge; 2) expression of TIMP-2 mRNA is maximal during the early luteal phase; and 3) expression of TIMP-2 mRNA is greatest in large luteal cells. PMID- 7835291 TI - Metabolic activation of Ca(2+)-independent phosphoinositide hydrolysis in beta cells and its role in the control of insulin secretion. AB - Recent studies have led to the proposal that the oxidative metabolism of glucose leads to the generation of messengers, in addition to ATP, that are important in the ability of changes in extracellular glucose concentration to stimulate insulin secretion from pancreatic beta-cells. In particular, there is now evidence that glucose induces both a Ca(2+)-dependent and Ca(2+)-independent increase in phosphoinositide (PI) hydrolysis. To explore the relationship between oxidative metabolism and PI hydrolysis, we examined the effect of low concentrations (2.5 mM) of alpha-ketoisocaproate (KIC) and monomethylsuccinate (MMSucc) either alone or in combination on insulin secretion and PI hydrolysis in isolated rat pancreatic islets incubated with either no glucose, 5 mM glucose, or 20 mM glucose. A combination of KIC and MMSucc leads to a marked increase in largely (80%) Ca(2+)-independent PI hydrolysis in either the absence or presence of 5 mM glucose. When glucose is absent, this combination of substrates induces a very small and transient first phase of insulin secretion but no significant second phase of secretion. In the presence of 5 mM glucose, either KIC or MMSucc alone induces a first phase of insulin secretion with a peak secretory rate 10 fold greater than the basal rate but only a small second phase of secretion approximately 5-fold above control. However, in the presence of 5 mM glucose, the combination of KIC plus MMSucc induces a large biphasic increase in insulin secretion: peak first-phase secretion is increased 30-fold, and second-phase 40 fold. These response are comparable to those induced by 20 mM glucose and are completely inhibited by 0.5 microM nitrendipine. In contrast, KIC plus MMSucc do not enhance the insulin secretory response induced by 20 mM glucose. Previous data showed that when 20 mM glucose acts, the resulting increase in PI hydrolysis is only partially Ca2+ dependent. A reanalysis of these data shows that raising the glucose concentration from 5 to 7 mM causes a 2-fold increase in Ca(2+) independent PI hydrolysis, and a further increase to 20 mM leads to a further 2 fold increase in Ca(2+)-dependent PI hydrolysis. These data show that these two pathways are regulated by different ranges of glucose concentration. They raise the interesting possibility that these distinct pathways have different signaling functions. In particular, raising the glucose concentration from 5 to 7 mM is known to alter the responsiveness of beta-cells to a variety of neurohumoral agonists and to tolbutamide.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7835292 TI - Mutual antagonistic interactions between the thyrotropin (adenosine 3',5' monophosphate) and protein kinase C/epidermal growth factor (tyrosine kinase) pathways in cell proliferation and differentiation of cultured human thyroid follicles. AB - Our aim has been to delineate the role of the major signal transduction pathways believed implicated in the control of thyroid function and growth: the cAMP-, epidermal growth factor (EGF) (tyrosine kinase)-, and protein kinase C (PKC) mediated mechanisms. The experimental model used was our system of thyroid follicles of human origin cultured in suspension under serum-free conditions in which the follicular three-dimensional structure is retained. The phorbol ester 12-O tetradecanoylphorbol 13-acetate (TPA) time and dose dependently (10(-11)-10( 7) M) inhibited TSH-stimulated thyroid functions (cAMP formation, iodide uptake and organification, and T3 secretion). TPA also inhibited such forskolin- and 8 BrcAMP-stimulated effects, suggesting that the attenuation of the cAMP-dependent pathway occurs at steps both pre- and post-cAMP formation. The effects of TPA were mimicked by another PKC activator, phorbol 12,13-dibutyrate, but not by a phorbol ester that fails to activate PKC, 4 alpha-phorbol 12,13-didecanoate, and were reversed by staurosporine, a PKC inhibitor. The TPA actions seem, therefore, to be PKC-mediated. EGF exhibited a time- and dose-dependent (0.02-8 nM) restraining influence on the above TSH-stimulated differentiated functions, except for cAMP, which was enhanced. EGF also blunted such forskolin- and 8 BrcAMP-induced response parameters, suggesting inhibition at a post-cAMP locus. Regarding cell proliferation, during the initial stages of culture (day 2), TPA dose dependently (10(-11)-10(-7) M) attenuated cell proliferation, but subsequently (day 7 of culture) the same doses of TPA stimulated cell multiplication. The TPA-mitogenic and antimitogenic effects could not be mimicked by 4 alpha-phorbol-12,13-didecanoate and were reversed by staurosporine, thus indicating a PKC-mediated pathway for such TPA actions. EGF, on the other hand, only enhanced cell proliferation at a late stage (coincident with the TPA mitogenic effect). TSH (0.5 U/liter) inhibited both the mitogenic and antimitogenic actions of TPA as well as the cell-proliferative influence of EGF. In conclusion, the data demonstrate mutual antagonistic interactions between the signal transduction pathways: the PKC and EGF (tyrosine kinase) pathways seem to inhibit TSH (cAMP)-mediated human thyroid cell differentiation, whereas TSH attenuates PKC-mediated thyroid cell mitogenesis and antimitogenesis as well as EGF-mediated cell proliferation. PMID- 7835293 TI - D1 receptors mediate dopamine stimulation of immunoreactive atrial natriuretic factor (ANF) release and pro-ANF messenger ribonucleic acid expression of rat hypothalamic neurons in culture. AB - Atrial natriuretic factor (ANF) and its smaller congeners are produced and released from rat brains to regulate the cardiovascular system, drinking behavior, and neurohormone release at the central level. In the hypothalamus, the adenylyl cyclase-cAMP system plays an important role in modulating the function of ANF neurons in the paraventricular nuclei and the periventricular regions that receive rich dopaminergic inputs. We report here a novel observation of a dopamine (DA) D1 agonist, SKF-38393, modulating immunoreactive (ir) ANF and pro ANF messenger RNA (mRNA) expression in rat hypothalamic neurons. In long term primary cultures of neonatal rat hypothalamic cells, treatment with SKF-38393 increased irANF secretion in a time-related and dose-dependent manner, with an ED50 of approximately 10(-7) M and a concentration producing maximum effect of 10(-5) M. This stimulating effect of SKF-38393 was mimicked by 10(-5) M DA, a physiological ligand for D1 receptors. Furthermore, both of the stimulatory effects were abolished by SCH-23390, a D1 antagonist. These immunoassay findings were accompanied by corresponding changes in the abundance of pro-ANF mRNA in the cultures, as examined by colorimetric Northern blot analysis. By combining the techniques of in situ hybridization and immunocytochemistry, the mRNA of D1 receptor was colocalized in approximately 90% of the irANF-positive cells in the cultures. In addition, cholera toxin, an irreversible activator of adenylyl cyclases, markedly increased irANF secretion and cAMP production in a dose dependent manner. This effect mimicked that of D1 agonist-stimulated ANF release, in that the latter also concurrently enhanced cAMP production in the hypothalamic cultures. Furthermore, the stimulatory effect of D1 agonist on irANF release was markedly suppressed by rp-cAMPS, a cAMP antagonist. We, thus, conclude that the release and gene expression of ANF in rat hypothalamic neurons are directly stimulated by DA acting through its D1 receptors on ANF neurons; this effect may operate at the genomic level and is mediated at least in part through activation of the cAMP-dependent kinase-A pathway. PMID- 7835294 TI - Localization and characterization of interleukin-1 receptors in the islets of Langerhans from control and nonobese diabetic mice. AB - Numerous in vivo and in vitro studies have shown the effects of interleukin-1 (IL 1) on insulin and glucagon secretion. To understand the mechanism of these effects, we performed localization and characterization of IL-1 receptors (IL-1R) in pancreas using a quantitative autoradiography method and recombinant human (rh) [125I]IL-1 alpha as a ligand. Frozen sections of pancreas were studied in control (C3H/He) and nonobese diabetic (NOD) mice (a model of autoimmune type I diabetes). Compared to splenic IL-1R, a very high density of specific IL-1R (> 4 fold that in spleen) was found on the islets of Langerhans in both strains. In C3H/He mice, competition experiments demonstrated the presence of one high affinity binding site (Ki = 3.4 and 3.2 x 10(-10) M; binding capacity, 137 and 122 fmol/mg protein for rhIL-1 alpha and rhIL-1 beta, respectively), comparable to type I IL-1R described on T-lymphocytes. In prediabetic NOD mice, these IL-1R were expressed with the same density, affinity, and specificity as in the control strain. Before the onset of diabetes, the expression of IL-1R protein on the islet cells appears to be entirely normal. In contrast, in diabetic NOD mice, IL 1R are sharply decreased, correlating with the intensity of islet destruction. In conclusion, the localization and high density of IL-1R on the mouse islets of Langerhans complement previous studies showing the presence of messenger RNA for type I IL-1R on the islets of Langerhans. These results support a direct physiological effect of IL-1 on pancreatic hormones, such as insulin and glucagon, and a potential role of IL-1R in the pathogenesis of type I diabetes. PMID- 7835295 TI - Dopamine D2 receptors regulate in vitro melanotrope L-type Ca2+ channel activity via c-fos. AB - Dopamine D2 receptor stimulation of cultured primary melanotropes was found to depress L-type calcium channel activity, whereas D2 receptor antagonist application increased it. When tested on culture days 10, 16, and 20, control cells displayed increasing rises of intracellular Ca2+ in response to K+ depolarization, indicating an increase in channel activity in the absence of dopaminergic regulation. When treated with 1 microM bromocriptine from culture day 1, cells showed minimal increase in channel activity. When bromocriptine was added on day 16, intracellular Ca2+ response to high K+ declined by day 20; removal of the agonist on day 16 resulted in the reappearance of increased responsiveness. Thus, in vitro inhibitions could be initiated or reversed with application or withdrawal of dopamine D2 receptor agonist. Cultured melanotropes were treated with antisense oligodeoxynucleotides directed against the start sequences of the D2 receptor and c-fos messenger RNA. D2 receptor antisense nucleotide prevented the depressive effect on channel activity induced by D2 agonist treatment. c-fos antisense oligodeoxynucleotide blocked the rise in channel activity. The dopamine D2 receptor antagonist haloperidol, which increased channel activity, could not reverse the c-fos antisense deoxynucleotide block. These results strongly support the idea that the chronic suppression of secretion-related activities by dopaminergic stimulation seen in the intermediate lobe in vivo is effected by chronic suppression of c-fos by D2 receptors. PMID- 7835296 TI - Apparent seasonal rhythms in hypothalamic neuropeptides in rats without photoperiod changes. AB - An apparent seasonal or circannual rhythm in the hypothalamic content of CRF, TRH, neurotensin, and neuromedin N has been observed in 12 separate monthly coherts (n = 10@ or 130 total) adult, male Sprague-Dawley rats obtained at the same time each month from a single commercial supplier and held under constant (12:12) photoperiod conditions since birth. Both annual and 4-month (terannual) harmonics can be statistically discerned in these apparent rhythms, which exhibit cycles containing concentration changes up to 3-fold the lowest levels across the year (CRF increases 390%, TRH increases 173%, neurotensin increases 136%, and neuromedin N increases 150%). Hypothalamic somatostatin did not exhibit these statistically significant robust rhythms nor did any peptide in regions outside the hypothalamus. These data indicate that a mechanism allowing enhanced or diminished physiological availability of these regulatory neuropeptides at different times of the year may exist and may display distinct cycles even in the absence of normal photoperiod cues. Possible regulatory responses of pituitary receptor populations for these hypothalamic peptides must be considered. As certain of these neuropeptides also appear to be altered in the cerebrospinal fluid of patients with major depression or schizophrenia, similar hypothalamic cyclic changes may underly psychiatric symptoms with seasonal periodicity. PMID- 7835297 TI - The effect of thyroid hormone treatment on the gene expression and enzyme activity of rat liver sodium-potassium dependent adenosine triphosphatase. AB - The effects of thyroid hormone (T3) treatment on liver Na,K-adenosine triphosphatase (Na,K-ATPase) at the levels of subunit messenger RNA (mRNA), enzymatic activity, and enzyme content were studied in euthyroid rats injected for 5 consecutive days with T3. Northern and slot blot analyses of polyadenylated mRNA revealed that T3 treatment coordinately increases the level of mRNA encoding the alpha 1- and beta 1-subunits, approximately 4- and 3-fold, respectively, above basal levels. To determine whether this increase in the subunit mRNA consequently results in an increase in the synthesis of the enzyme, a modified liver cell fractionation procedure was developed, and the subcellular fractions from control and T3-treated livers were examined biochemically. Western blot analysis and Na,K-ATPase assay demonstrated that T3 treatment resulted in a 2 fold increase in both the amount and activity of the enzyme. Furthermore, the Western blot analysis of endoglycosidase-H-treated membrane fractions revealed an increase in the amount of the precursor beta-subunit in the T3-treated liver rough microsomal fraction, suggesting that an increase in subunit synthesis contributes at least partially to the increase in the rat liver Na,K-ATPase by T3 treatment. PMID- 7835299 TI - Control of growth hormone (GH) binding protein release from human hepatoma cells expressing full-length GH receptor. AB - In humans and rabbits, the circulating GH binding protein (GHBP) is released from the GH receptor by cleavage at a site proximal to the cell surface. There is evidence that GHBP status is predictive of GH responsiveness, presumably because it reflects GH receptor status. This assumes that GHBP release is not a regulated step. Here we report a model for study of GHBP release that provides some insight into this question. Human HepG2 cells were stably transfected with rabbit GH receptor and shown to be responsive to nonprimate (bovine) GH, indicating functionality of the transfected receptor. These cells released GHBP of the expected size, and this release could be increased by incubation with a phorbol ester, which stimulated receptor synthesis through the cytomegalovirus promoter. We surveyed a wide range of protease inhibitors both with and without streptolysin-O permeabilization, with the intention of defining the endogenous protease. Of 16 inhibitors, only benzamidine proved an effective inhibitor of release, indicating the existence of a novel protease. We could increase GHBP release with a membrane impermeable thiol blocker, suggesting activation of a membrane protease. We examined the ability of IGF-1, insulin, dexamethasone, sex steroids, and T4 to influence GHBP release. Although these agents are known to be effective in the parent hepatoma line, none were effective in modulating GHBP release, although GH itself decreased release by around 30% as assessed with a ligand immunofunctional assay. We conclude that GHBP release appears to be constitutive in this model and driven by receptor availability. This is consistent with an in vivo situation where circulating GHBP provides an index of hepatic receptor expression. PMID- 7835298 TI - The expression, characterization, and crystallization of wild-type and selenomethionyl human chorionic gonadotropin. AB - Although the glycoprotein hormone hCG was crystallized over 4 yr ago, it is only now that three-dimensional structural information is available. This manuscript reports the method for successful production of modified expressed hormone, the characteristics of the crystallized protein, and unexpected observations during the crystallization process. Two different routes of solution to the structure of hCG were followed. The first was based on the traditional method of heavy atom isomorphous replacement, and the second was the more novel method of expressing the protein with selenomethionine substituting for methionine and applying multiwavelength anomalous diffraction analysis. Selenomethionyl hCG was employed to successfully grow the crystals used for the solution of the structure of hCG after partial deglycosylation by hydrogen fluoride (HF) treatment. The selenomethionyl hCG proved to be more hydrophobic than the expressed form of native hCG. Furthermore, expressed forms of hCG that were deglycosylated by HF proved to be more intact and less susceptible to peptide bond cleavages during the crystallization process than the urinary form of HF-treated hCG studied previously. It was found that addition of reducing agent during the crystallization period was necessary for the growth of crystals of HF-treated selenomethionyl hCG suitable for diffraction studies. Growth of crystals of HF treated expressed hCG were accelerated by the addition of dithiothreitol, but would successfully grow without reductant. HPLC analysis of the HF-treated hormones before and during the crystallization process was used to identify alterations in the molecules, including oxidation and aggregation, both of which may affect the growth of crystals. PMID- 7835300 TI - Effects of streptozotocin treatment in growth hormone (GH) and GH antagonist transgenic mice. AB - To investigate GH's role in diabetic end organ damage, experimental diabetes was induced with streptozotocin (STZ) in bovine GH (bGH) or bGH antagonist transgenic mice and in their nontransgenic (NTG) litter mates. Body growth, blood glucose, serum insulin-like growth factor-I levels, liver GH receptor (GHR) binding, and kidney histology of these animals were evaluated. After administration of multiple low doses of STZ, 90% of the mice developed hyperglycemia. The diabetic animals, especially those expressing GH and GH antagonist transgenes, demonstrated retarded body growth and reduced insulin-like growth factor-I levels when compared with their nondiabetic litter mates. Kidney histology revealed severe glomerulosclerosis in diabetic and nondiabetic bGH transgenic mice. Diabetic NTG mice exhibited moderate kidney lesions. Diabetic bGH antagonist transgenic mice possessed normal glomeruli indistinguishable from those seen in nondiabetic NTG mice. GHR-binding assays revealed that liver GHR-binding sites were significantly reduced in diabetic NTG mice and transgenic dwarf mice when compared with their nondiabetic controls. Conversely, liver GHR-binding ability was significantly increased in bGH transgenic mice as compared with their NTG littermates and remained high during diabetes. It is concluded that transgenic mice that express a GH antagonist are protected from diabetes and or GH-induced nephropathy. PMID- 7835301 TI - Type 1 astrocytes influence luteinizing hormone-releasing hormone release from the hypothalamic cell line GT1-1: is transforming growth factor-beta the principle involved? AB - The possible existence of a humoral communication between glial cells and LHRH secreting neurons has been studied using the LHRH-secreting GT1-1 cell line and type 1 astrocytes. Two different designs have been adopted: 1) GT1-1 cells were coincubated with purified cultures of type 1 rat astrocytes, and 2) GT1-1 cells were exposed to the conditioned medium (CM) in which type 1 rat astrocytes had been grown for 24 h. LHRH was measured by RIA in the medium of the GT1-1 cell cultures at different time intervals. The data show that short periods (1, 3, and 6 h) of either coculture or exposure to previously frozen CM significantly increase the release of LHRH from the GT1-1 cells. However, more prolonged times of coculture (e.g. 2 and 5 days) or exposure to CM (e.g. 48 h) induce a significant decrease in the amount of LHRH in the medium. The stimulatory effect on LHRH release appears to be specific for type 1 astrocytes (either cortical or hypothalamic), because neither the CM of oligodendrocytes nor the CM of LNCaP cells (a cell line derived from a human prostatic cancer) possess stimulating activities. Heating the type 1 astrocyte-CM to 100 C for 10 min does not eliminate the ability of the CM to significantly increase the release of LHRH from GT1-1 cells at 1, 3, and 6 h. Because of the opposite effects encountered in the short and long term experiments, it was hypothesized that the CM might contain, in addition to LHRH-releasing principle(s), LHRH-degrading properties. Known amounts of standard LHRH were then added to type 1 astrocyte-CM, either untreated or submitted to heating at 100 C for 10 min. The amount of LHRH added to untreated CM decreases progressively; on the contrary, the amount of LHRH added to heated CM remains unchanged. These results confirm that one or more heat sensitive enzymes able to degrade LHRH may be present in the type 1 astrocyte-CM. As previously mentioned, the experiments reported so far were performed using type 1 astrocyte-CM that had been kept frozen for various periods of time, before being tested for its LHRH-releasing activity. Surprisingly, fresh CM proves to be inactive, whereas heated CM is effective; this suggests that the factor involved might be activated by the two opposite experimental procedures.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7835302 TI - Stage and cell-specific expression of the adenosine 3',5' monophosphate phosphodiesterase genes in the rat seminiferous epithelium. AB - Four genes (ratPDE1/IVc, ratPDE2/IVa, ratPDE3/IVd, and ratPDE4/IVb) encoding different isoforms of phosphodiesterase that specifically hydrolyze the second messenger cAMP (cAMP-PDEs) are present in the rat. Previous data from our laboratory indicated that these genes are differentially expressed in the somatic and germ cells of the seminiferous epithelium of the testis. To further characterize their spatial and temporal expression in the seminiferous tubules, in situ hybridization was used to monitor the expression of the four cAMP-PDE messenger RNAs (mRNAs). The signals corresponding to ratPDE1/IVc and ratPDE2IVa mRNAs were localized in two restricted layers of the seminiferous epithelium. The ratPDE1/IVc mRNA was present in a region of the epithelium corresponding to the location of middle-late pachytene spermatocytes. Conversely, the ratPDE2/IVa signal was confined to a more adluminal area corresponding to the location of maturing round spermatids. The ratPDE3/IVd and ratPDE4/IVb mRNAs were distributed throughout the span of the seminiferous epithelium, indicating a localization in the Sertoli cell cytoplasm. Although the intensity of the signal corresponding to ratPDE4/IVb was similar in all seminiferous tubule stages, the ratPDE3/IVd signal varied in intensity in tubules at different stages of the seminiferous cycle. Maximal expression was present in tubules at stages I-V and XI-XIII of the cycle and minimal at stages VIII-IX of the cycle. The expression of the ratPDE3/IVd mRNA positively correlated with the ability of specific inhibitors of the cAMP PDEs to potentiate the FSH-dependent cAMP accumulation in tubules at different stages of the seminiferous cycle, with maximal potentiation observed at stages II VI of the cycle. These data demonstrate that different cAMP-PDE genes are active in different cells of the seminiferous tubules and that the ratPDE3/IVd gene is expressed in the Sertoli cell in a cyclical fashion during the seminiferous cycle. PMID- 7835303 TI - Regulation of 1,25-dihydroxyvitamin D3 receptors by parathyroid hormone in osteoblastic cells: role of second messenger pathways. AB - The regulation of vitamin D receptor (VDR) abundance in MC3T3-E1 mouse osteoblasts and UMR 106-01 rat osteosarcoma cells by rat PTH 1-34, human PTH related protein 1-34, and agents that activate specific signal transduction pathways was studied. Treatment of these cells with forskolin (FSK) caused up regulation of VDR, whereas treatment with phorbol esters suppressed VDR levels. PTH or PTH-related protein treatment induced a 2- to 3-fold increase in VDR, which was equivalent to that elicited by FSK in UMR 106-01 cells but less than the FSK-induced increase (approximately 8-fold) in MC3T3-E1 cells. PTH treatment of MC3T3-E1 cells resulted in an approximately 3-fold increase in VDR levels with maximum stimulation occurring at 10(-9) M PTH after 4 h of treatment. In UMR 4-7 cells, a subclone of UMR 106-01 cells that express cAMP resistance due to regulated expression of a mutant form of the type 1 regulatory subunit of the cAMP-dependent protein kinase A (PKA), the up-regulation of VDR abundance due to FSK and PTH treatment was mostly prevented. Pretreatment of MC3T3-E1 cells with staurosporine, an inhibitor of PKC, resulted in an approximately 3-fold increase in basal VDR levels but did not enhance the PTH-mediated up-regulation of VDR. Collectively, these data suggest that the increase in VDR abundance observed in these target cells is mainly due to the activation of the PKA signal transduction pathway. Treatment of UMR 106-01 cells with PTH for 4 h before exposure of the cells to 1,25-dihydroxyvitamin D3 resulted in a 2-fold increase in the induction of 25-hydroxyvitamin D3-24 hydroxylase messenger RNA. Thus, exposure of target cells to PTH augments their response to 1,25-dihydroxyvitamin D3 due to up regulation of VDR abundance. PMID- 7835304 TI - The effect of medroxyprogesterone acetate on bone metabolism in the oophorectomized, tamoxifen-treated rat. AB - Tamoxifen (TAM) is used primarily in the management of breast cancer, and it also has bone-sparing effects similar to estrogen. In breast cancer patients TAM may have a potential role in the prevention and management of osteoporosis. TAM therapy is associated with uterine hyperplasia, and medroxyprogesterone acetate (MPA) added to the regimen provides protection against this. Due to the potential combined use of MPA and TAM in the clinical setting, this study was conducted to assess whether MPA acted synergistically, dampened, or enhanced the TAM effect on bone. Seventy-five female rats (60 oophorectomized; Ox), were randomized into five groups and received either TAM (0.1 mg/kg.day) and/or MPA (0.3 mg/kg.day) therapy over 28 days as follows: 1) sham; 2) Ox; 3) Ox plus TAM; 4) Ox plus MPA; and 5) Ox plus TAM plus MPA. Blood was sampled on days 0, 14, and 28 for measurement of ionized calcium, PTH, 1,25-dihydroxyvitamin D, osteocalcin, and insulin-like growth factor 1. TAM-treated rats showed a reduction in body weight serum osteocalcin, PTH, and insulin-like growth factor 1. Histomorphometric analysis of the proximal tibia showed less cancellous bone volume in Ox rats, and the effect was attenuated by TAM. MPA alone had no significant effect on cancellous bone volume. All the bone formation parameters evaluated (bone formation rate, mineral apposition rate, percent calcein-labeled surface, and number of osteoblasts) were higher in Ox rats compared with sham-operated rats and were lower in TAM-treated rats compared with Ox rats. These parameters were not changed by MPA, alone or in combination with TAM. The number of osteoclasts was higher in Ox rats compared with sham-operated rats and was reduced by TAM. MPA therapy alone or in combination with TAM did not affect number of osteoclasts. These results suggest that MPA neither dampened nor enhanced the effect of TAM on bone. PMID- 7835305 TI - Gonadal steroids regulate rat anterior pituitary levels of TSH-releasing hormone- and pyroglutamyl-glutamyl-proline amide-like immunoreactivity. AB - The novel peptide, pyroglutamylglutamylprolineamide (pGlu-Glu-ProNH2, EEP), which has structural and immunological similarities to TRH (pGlu-His-ProNH2) has recently been shown to contribute to total TRH-like immunoreactivity (t-TRH-LI) detected in the rabbit prostate and rat and porcine anterior pituitary. This study was undertaken to determine the effects of gonadal steroids on t-TRH-LI and its components in the rat hypothalamus and pituitary. EEP-like immunoreactivity (EEP-LI) was separated from TRH-LI by ion exchange chromatography and detected by TRH RIA. Although male and female posterior pituitary and hypothalamic t-TRH-LI levels were similar, the mean t-TRH-LI in female anterior pituitaries was significantly lower than that in males, 10.3 +/- 2.9 pmol/g vs. 24.4 +/- 2.5 pmol/g (P < 0.01). Anion exchange analysis of control anterior pituitary samples distinguished two peaks of t-TRH-LI, corresponding to [125I]-TRH marker and [3H] EEP markers. In control female anterior pituitaries EEP-LI accounted for 26.0 +/- 2.4% of t-TRH-LI, whereas in males it accounted for 43.3 +/- 5.3% of the total. Hypothalamic and posterior pituitary samples only contained t-TRH-LI corresponding to [125I]-TRH markers. There was no significant change in hypothalamic and posterior pituitary levels of t-TRH-LI after ovariectomy or orchidectomy. Anterior pituitary levels of t-TRH-LI, however, were increased by an estimated 6-fold after ovariectomy and 2-fold after orchidectomy. After ovariectomy, the proportions of t-TRH-LI accounted for by TRH-LI and EEP-LI were reversed in the female. EEP-LI now accounted for the majority of t-TRH-LI, constituting an increase of approximately 21-fold in pituitary EEP-LI levels. The changes in the levels of pituitary TRH-LI and EEP-LI induced by ovariectomy were reversed by 17-beta-estradiol. As in the ovariectomized samples EEP-LI was increased (2-fold) by orchidectomy. Both TRH-LI, which increased 1.6-fold, and EEP-LI were restored to control values after testosterone replacement. These findings confirm the hypothesis that pituitary TRH-LI and EEP-LI are regulated by gonadal status. The fact that these changes were not observed in the hypothalamus and posterior pituitary suggests that TRH-LI and EEP-LI have specific functional significance in the pituitary gland. PMID- 7835306 TI - Evidence for atrophy and apoptosis in the ventral prostate of rats given the 5 alpha-reductase inhibitor finasteride. AB - Castration causes cell loss in the rat ventral prostate through a process called apoptosis. Although 5 alpha-reductase inhibition also causes prostate cell loss, the mechanisms involved have been debated. To investigate this question further, we have evaluated the histological responses of the rat ventral prostate to both castration and 5 alpha-reductase inhibition. Rats were left intact, castrated, or given the selective 5 alpha-reductase inhibitor finasteride. After 4, 9, 14, and 21 days the prostates were excised, the androgen and DNA content determined, and the tissue was subjected to histological and histomorphometric analysis. Finasteride and castration decreased prostate weight at day 21 by 65% and 93%, respectively. Castration decreased DNA content (micrograms per prostate) by a maximum of 88% at 14 days. Finasteride had no significant effect on DNA content after 4 days and decreased DNA content by a maximum of 52% at 14 days. When castrate prostate sections were stained for tissue transglutaminase, a marker of apoptotic cell death, a maximum of 23% of epithelial cells were stained by day 14 with a return to control levels by day 21. Finasteride caused a less intense increase in staining in which 16% of epithelial cells stained for tissue transglutaminase on day 9 with a return to baseline by day 14. When prostate sections were stained for DNA breaks, another marker of cell death, castration, caused a peak of staining on day 4 with 6% of epithelial cells staining and a return to near control levels by day 21. Finasteride-induced staining was less intense with peak staining at day 4 (0.7% of epithelial cells) and a return to control values by day 9. Morphometrics were used to assess the effect of castration and finasteride on prostate duct size and epithelial cell mass. After 4 days of finasteride treatment, the mean ductal mass decreased by 47%, with no significant change thereafter. The mean epithelial cell mass decreased by 15% on day 4 and 60% on day 9, with no further decrease thereafter. Castration caused a more rapid and greater decrease in both morphometric parameters with a 95% reduction in the mass of prostate ducts and a 93% decrease in epithelial cell mass by day 9. We conclude that castration induces a more profound involution of the rat ventral prostate than does 5 alpha-reductase inhibition. Cell loss occurs in both groups, but the degree of cell loss is less with finasteride.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7835307 TI - One class of growth hormone (GH) receptor and binding protein messenger ribonucleic acid in rat liver, GHR1, is sexually dimorphic and regulated by GH. AB - In the rat, alternatively spliced messenger RNA (mRNA) species encode GH receptor (GHR) and GH-binding protein (GHBP). Additionally, these mRNAs are alternatively spliced in the 5'-untranslated region, resulting in at least two classes of GHR and GHBP mRNA with distinct first exons and identical coding regions. These alternative first exons define two unique classes of GHR and GHBP mRNA (called GHR1 and GHR2). The GHR1 class of RNA is expressed only in the liver, is far more abundant in females than males, and is particularly abundant during pregnancy. GHR1 RNA is induced later in development than is GHR2. Additional classes of GHR and GHBP RNA may also exist. The genomic structure of the GHR1 first exon reveals a putative promotor region with no TATA box, CAAT box, or other sequence elements suggesting specific responses. An in vivo approach was used to investigate the regulation of GHR1 expression. In female rats, gonadectomy was found to reduce the percentage of steady state GHR1 RNA levels in the liver, whereas male castration resulted in an induction of GHR1 RNA. However, short-term treatment with estrogen or testosterone had little effect, suggesting that direct regulation of GHR1 expression may occur through effector(s) other than gonadal steroids. Hypophysectomy abolished GHR1 RNA in females. Treatment of hypophysectomized females and castrated males with GH by single injection did not significantly induce GHR1 RNA, but treatment by continuous infusion of GH did. Little change in non-GHR1 RNA levels was observed for each of these treatments. The results suggest that: 1) the sexual dimorphism observed in total GHR and GHBP RNA in rat liver is attributable to the sexually dimorphic expression of the GHR1 class of RNA; 2) the sexually dimorphic pattern of GH release in rats regulates the GHR1 class of RNA; 3) changes in GHR and GHBP expression observed on gonadectomy, hypophysectomy, GH treatment, and pregnancy are best attributed to GHR1 regulation; and 4) since GHR1 is liver specific, the observed increases in serum GHBP concentration in response to sex steroids, GH pattern, and pregnancy are likely to originate from the liver. PMID- 7835308 TI - In vivo presence of the high affinity nerve growth factor receptor Trk-A in the rat pancreas: differential localization during pancreatic development. AB - It is now established that the pancreatic islet cells derive from precursors present in the pancreatic ducts. These precursor cells as well as the factors that influence their differentiation to mature insulin-secreting beta-islet cells are nevertheless not elucidated yet. However, the large number of similarities existing between beta-cells and neuronal cells led to the suggestion that these two different cell types may be sensitive to the same growth and differentiation factors, for example, nerve growth factor (NGF), which is important for the differentiation and survival of several neurons. It was previously demonstrated that the high affinity NGF receptor, Trk-A, which is sufficient for NGF signal transduction, is expressed in different beta-cell lines and in normal rat islet cells in primary culture. The aim of this study was therefore to examine whether the Trk-A receptor is present in vivo in the rat pancreas during development and in adult life. By double immunofluorescence analysis using anti-Trk-A/antiinsulin or anti-Trk-A/antiglucagon antibodies on pancreatic sections of adult rats, it is demonstrated that the Trk-A protein is present in the beta- and not in the alpha islet cells of adult rat pancreas. No Trk-A immunostaining was observed in the exocrine pancreas or in the pancreatic ducts of adult pancreas. Interestingly, the pattern of Trk-A immunolocalization in the pancreas is different during fetal life, when Trk-A immunostaining is observed in the pancreatic ductular cells and undetectable in both beta- and alpha-islet cells. During late prenatal and early postnatal life, Trk-A immunostaining is present in the islet cells, although weaker than in adult rats, and progressively decreases in the pancreatic ducts, as pancreatic maturation progresses. The intensity and localization of the Trk-A immunostaining in the rat pancreas are therefore developmentally regulated. PMID- 7835309 TI - Cooperation of thyrotropin, but not basic fibroblast growth factor, with an adenosine receptor agonist in Ca2+ mobilization from thapsigargin-sensitive pools in single FRTL-5 thyroid cells. AB - TSH-induced intracellular Ca2+ concentration ([Ca2+]i) changes in single FRTL-5 thyroid cells were analyzed by digital video imaging of fura-2-loaded cells. More than 80% of the cells responded to as little as 30 nM TSH, resulting in a [Ca2+]i rise in the presence and absence of extracellular Ca2+. One micromolar concentration of N6-(L-2-phenylisopropyl)adenosine (PIA) caused no appreciable [Ca2+]i increase in more than 300 cells examined, but induced the [Ca2+]i elevation in more than 90% of the cells that had previously been treated with TSH. Pertussis toxin treatment abolished the PIA, but not the TSH, action, whereas thapsigargin-induced Ca2+ depletion of the inositol 1,4,5-trisphosphate sensitive pool inhibited the actions of both TSH and PIA. The time courses of Ca2+ response considerably differentiated among single cells, but showed similarity among different areas in each cell. These results suggest that PIA induces Ca2+ release from the same thapsigargin-sensitive pool as that targeted by TSH. The lack of PIA stimulation of basic fibroblast growth factor-induced phospholipase-C gamma activation as well as the rise in [Ca2+]i suggests that the cooperative PIA action occurs specifically on phospholipase-C beta. PMID- 7835310 TI - Progesterone-induced secretion of dipeptidyl peptidase-IV (cluster differentiation antigen-26) by the uterine endometrium of the ewe and cow that costimulates lymphocyte proliferation. AB - Dipeptidyl peptidase-IV (DPPIV) is a serine proteinase widely distributed in mammalian tissues, including lymphocytes, where it is identical to the T-cell activation antigen, cluster differentiation antigen-26. In the present study, DPPIV enzymatic activity was found in uterine secretions of unilaterally pregnant ewes in increasing amounts as gestation progressed. Progesterone increased DPPIV in uterine secretions from ovariectomized ewes and cows. DPPIV was enriched from ovine uterine secretions by a combination of cation exchange, gel filtration, lectin, and Gly-Pro-NH2 affinity chromatographies. The mol wt was 107 kilodaltons, as indicated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis under reducing conditions, and 140 kilodaltons by gel filtration. The pI was estimated to be 6.8. Enzymatic activity had a pH optimum of 8.3 and a Km of 0.32 mM. The sequence of the 34 N-terminal amino acids was 77-87% homologous to an internal region of human cluster differentiation antigen-26 and rat liver DPPIV. Thus, uterine DPPIV appears to be missing the signal sequence that allows integration into the cytoplasmic membrane. DPPIV was localized immunohistochemically to lumenal and glandular endometrial epithelial cells and, in some pregnant ewes, discrete endometrial stromal cells. Highly enriched sheep uterine DPPIV costimulated proliferation of mitogen-treated sheep lymphocytes. Stimulation occurred in the presence of the uterine milk proteins, a pair of progesterone-induced endometrial secretory proteins with well characterized lymphocyte inhibitory activity. However, uterine milk proteins did not inhibit the costimulatory effect of DPPIV on phytohemagglutinin-L stimulated-lymphocyte proliferation. In conclusion, the uterine endometrium synthesizes a biologically active form of DPPIV under the influence of progesterone that is capable of enhancing mitogen-stimulated T-lymphocyte proliferation. PMID- 7835311 TI - Endogenous calcitonin attenuates parathyroid hormone-induced cancellous bone loss in the rat. AB - Although calcitonin (CT) treatment has been shown to prevent bone loss in estrogen-deficient states, the function of endogenous CT in bone metabolism is not clearly established. To test the hypothesis that endogenous CT has a role in bone conservation, we compared the bone-resorbing effect of exogenous PTH between CT-deficient [thyroparathyroidectomized (TPTX)] and CT-sufficient [parathyroidectomized (PTX)] rats. Studies were carried out with two doses (30 and 40 pmol/h) of bovine PTH-(1-34) to examine dose responsiveness and with or without T4 replacement in TPTX rats to exclude the influence of thyroid function on the results. Sham-operated control rats received vehicle. At comparable hypercalcemia (mean +/- SEM, 13.6 +/- 0.8 vs. 12.7 +/- 1.0 mg/dl) after 3 days of sc infusion of 30 pmol/h PTH, serum CT levels were significantly (P < 0.05) higher in PTX rats (66.0 +/- 8.0 pg/ml) than in TPTX rats (17.7 +/- 4.3). CT deficient TPTX rats showed a significant cancellous bone loss in the proximal tibia [bone volume (BV/TV), 4.2 +/- 1.0%] compared with control rats 10.4 +/- 1.2%) In contrast, there was no bone loss in CT-sufficient PTX rats (BV/TV, 10.9 +/- 0.5%). A similar difference in the serum CT level and more marked difference in BV/TV (0.9 +/- 0.3% vs. 8.1 +/- 1.3%) were observed between TPTX and PTX rats infused with 40 pmol/h PTH. The magnitude of bone loss in TPTX rats was not different between T4-supplemented and nonsupplemented groups. Unlike cancellous bone, the PTH-induced decrease in the cortical thickness of the tibia was comparable in TPTX and PTX rats. The extent of increase in serum osteocalcin after PTH infusion was not different between TPTX and PTX groups. These results indicate that in the rat, endogenous CT has a protective effect against PTH stimulated cancellous bone loss, but not cortical bone loss. PMID- 7835312 TI - Cloning of a complementary deoxyribonucleic acid encoding the murine homolog of the very low density lipoprotein/apolipoprotein-E receptor: expression pattern and assignment of the gene to mouse chromosome 19". PMID- 7835313 TI - Induction of glucocorticoid receptor expression in hypothalamic magnocellular vasopressin neurons during chronic hypoosmolality. AB - The site of action for the modulation of hypothalamo-neurohypophyseal function by adrenal steroids is not known. Glucocorticoid receptors (GR) are an obvious potential site of action, but there have been conflicting reports of GR localization in magnocellular neurons. We confirm studies finding undetectable levels of GR in vasopressin or oxytocin neurons, but now report that chronic hypoosmolality induces the expression of GR in magnocellular vasopressin neurons, but not oxytocin neurons. These data support the hypothesis that the vasopressin gene can be directly inhibited by glucocorticoids, and that the induction of GR expression in magnocellular neurons may be part of a redundant set of mechanisms to suppress the expression of AVP during periods of prolonged hypoosmolality. This mechanism represents a novel form of steroid feedback control in brain. PMID- 7835314 TI - Macrophage colony-stimulating factor and interleukin-1 alpha maintain the survival of osteoclast-like cells. AB - When mouse bone marrow cells were co-cultured with a stromal cell line. ST2, numerous osteoclast-like multinucleated cells (MNCs) were formed. To enrich the MNCs which were tartrate-resistant acid phosphatase (TRAP)-positive, we treated the cultures with dispase. Enriched TRAP-positive MNCs adhering to the bottom of the dish were cultured for a further 24h with medium containing 15% fetal calf serum. More than 80% of TRAP-positive MNCs were detached from the dish during the culture. However, when ST2 cells were included during the culture period, survival of TRAP-positive MNCs were significantly increased. Moreover, among various factors examined for the survival of TRAP-positive MNCs, only M-CSF and IL-1 alpha were effective in prolonging viability of TRAP-positive MNCs. PMID- 7835315 TI - Antiestrogens inhibit in vitro bone resorption stimulated by 1,25 dihydroxyvitamin D3 and the vitamin D3 analogs EB1089 and KH1060. AB - 1,25-Dihydroxyvitamin D3 (1,25-(OH)2D3) has been shown to inhibit breast cancer cell growth both in vitro and in vivo. A major drawback is that high doses of 1,25-(OH)2D3 are needed which may result in undesirable side effects like the development of hypercalcemia and an increased risk of bone metastases due to the stimulation of bone resorption by 1,25-(OH)2D3. Several newly developed 1,25 (OH)2D3 analogs have a reduced calcemic activity, but their direct effects on bone resorption have not yet been examined. Presently, the antiestrogen tamoxifen is the most important endocrine therapy for breast cancer. Recent studies have demonstrated the benefit of the combination tamoxifen and 1,25-(OH)2D3/analogs for the inhibition of breast cancer cell growth. Besides inhibition of breast cancer growth tamoxifen appeared to have beneficial effects on bone. The purpose of the present study was to investigate the effect of tamoxifen on 1,25-(OH)2D3- and analogs (EB1089 and KH1060)-stimulated bone resorption in an in vitro model. Bone resorption was stimulated by 1,25-(OH)2D3 and analogs in a dose-dependent manner with KH1060 and EB1089 being more potent and 1,25-(OH)2D3. Tamoxifen caused a strong dose-dependent inhibition (70% at 10 microM) of 1,25-(OH)2D3- and EB1089-stimulated bone resorption. KH1060-stimulated bone resorption was also inhibited by tamoxifen but to a lesser extent (36%). Also the pure antiestrogen ICI164,384 but not 17 beta-estradiol inhibited 1,25-(OH)2D3-stimulated bone resorption. Together, this study demonstrates that tamoxifen considerably reduces 1,25-(OH)2D3/analogs-stimulated bone resorption and therefore may be useful to reduce the risk of bone metastases. This together with the observed beneficial effects on breast cancer cell growth indicates that tamoxifen together with 1,25 (OH)2D3/analogs is an interesting combination for the treatment of breast cancer. The mechanism of the bone resorption inhibitory action is not yet known but seems to be independent of the estrogen pathway. PMID- 7835316 TI - Valid measurements of total IGF concentrations in biological fluids. Recommendations from the 3rd International Symposium on Insulin-like Growth Factors. PMID- 7835317 TI - Hydrodynamics of segmentally flexible macromolecules. AB - Segmentally flexible macromolecules are composed of a few rigid subunits linked by joints which are more or less flexible. The dynamics in solution of this type of macromolecule present special aspects that are reviewed here. Three alternative approaches are described. One is the rigid-body treatment, which is shown to be valid for overall dynamic properties such as translational diffusion and intrinsic viscosity. Another approach is the Harvey-Wegener treatment, which is particularly suited for rotational diffusion. The simplest version of this treatment, which ignores hydrodynamic interaction (HI) effects, is found to be quite accurate when compared to a more rigorous version including HI. A third approach is the Brownian dynamics simulation that, albeit at some computational cost, might describe rigorously cases of arbitrary complexity. This technique has been used to test the approximations in the rigid-body and Harvey-Wegener treatments, thus allowing a better understanding of their validity. Brownian trajectories of simplified models such as the trumbbell and the broken rod have been simulated. The comparison of the decay rates of some correlation functions with the predictions of the two treatments leads to a general conclusion: the Harvey-Wegener treatment determines the initial rate, while the long-time behavior is dominated by the rigid-body relaxation time. As an example of application to a specific biological macromolecule, we present a simulation of an immunoglobulin molecule, showing how Brownian Dynamics can be used to predict rotational and internal dynamics. Another typical example is myosin. Literature data of hydrodynamic properties of whole myosin and the myosin rod are compared with predictions from the Harvey-Wegener and rigid-body treatments. The present situation of the problem on myosin flexibility is analyzed, and some indications are given for future experimental and simulation work. PMID- 7835318 TI - Thermal broadening of the Soret band in heme complexes and in heme-proteins: role of iron dynamics. AB - We report the thermal broadening of the Soret band in heme-CO, heme-OH and protoporphyrin IX in the temperature range 300-20 K. For protoporphyrin IX the temperature dependent Gaussian line broadening follows the behavior predicted by the harmonic approximation in the entire temperature range investigated. In contrast, for heme-CO and heme-OH the harmonic behavior is obeyed only up to about 180 K and an anomalous line broadening increase is observed at higher temperatures. This effect is attributed to the onset of anharmonic motions of the iron atom with respect to the porphyrin plane. Comparison with previously reported analogous data for heme proteins enables us to suggest that the onset of substrate interconversions in these latter systems can be reflected in motions of the iron atom with respect to the porphyrin plane. PMID- 7835319 TI - Semiempirical calculations of the oxygen equilibrium isotope effect on binding of oxamate to lactate dehydrogenase. AB - Semiempirical methods have been used in an attempt to predict theoretically the experimentally observed value of 0.9840 for the oxygen isotope effect on binding of oxamate to lactate dehydrogenase. The overall strategy involved vibrational analysis of oxamate in two different environments; that of the active site residues and in aqueous solution. The comparison of calculated values with the experimentally determined isotope effect proved the AM1 Hamiltonian to be superior to the PM3 Hamiltonian in this modelling. While most tested methods of accounting for solvent effects on the vibrational frequencies of the solute yielded similar results it turned out that what was crucial for the purpose of determination of the isotope effect was the model of oxamate in the active site of the enzyme. In particular, the major factor responsible for the inverse value of this isotope effect can be ascribed to the formation of an ordered, bifurcated hydrogen bond between the oxamate carboxylate and the guanidinium group of the active site histidine. PMID- 7835320 TI - Intermediate states in ligand photodissociation of carboxymyoglobin studies by dispersive X-ray absorption. AB - The ligand photodissociation of sperm whale carboxymyoglobin (MbCO) at low temperature (15K-100K) under extended illumination has been studied by X-ray Absorption Near Edge Structure (XANES) spectroscopy using the dispersive technique. XANES simulations through the multiple scattering (MS) approach allow one to interpret the spectroscopic data in structural terms, and to investigate the Fe site structure configurations of the states that follow the CO photodissociation as a function of temperature. The Fe site in the photoproduct is unbound, with an overall structure similar to the deoxy-form (Mb) of the protein. The Fe site structure changes from T < 30K(Mb*) to T > 50K (Mb**), revealing the existence of a slower unbound state Mb**. A model is proposed which includes the faster state (Mb*) as a planar porphyrin ring with a displacement of Fe from the heme plane of less than 0.3 A, and the slower state (Mb**) with a domed heme. PMID- 7835321 TI - A fluorescence depolarization study of the orientational distribution of crossbridges in muscle fibres. AB - A fluorescence depolarization study of the orientational distribution of crossbridges in dye-labelled muscle fibres is presented. The characterization of this distribution is important since the rotation of crossbridges is a key element in the theory of muscle contraction. In this study we exploited the advantages of angle-resolved experiments to characterize the principal features of the orientational distribution of the crossbridges in the muscle fibre. The directions of the transition dipole moments in the frame of the dye and the orientation and motion of the dye relative to the crossbridge determined previously were explicitly incorporated into the analysis of the experimental data. This afforded the unequivocal determination of all the second and fourth rank order parameters. Moreover, this additional information provided discrimination between different models for the orientational behaviour of the crossbridges. Our results indicate that no change of orientation takes place upon a transition from rigor to relaxation. The experiments, however, do no rule out a conformational change of the myosin S1 during the transition. PMID- 7835322 TI - Activation and deactivation properties of rat brain K+ channels of the Shaker related subfamily. AB - We studied the activation properties of members of the Shaker-related subfamily of voltage-gated K+ channels cloned from rat brain and expressed in Xenopus oocytes. We find that Kv1.1, Kv1.4, Kv1.5, and Kv1.6 have similar activation and deactivation kinetics. The k+ currents produced by step depolarisations increase with a sigmoidal time course that can be described by a delay and by the derivative of the current at the inflection point. The delay tends to zero and the logarithmic derivative seems to approach a finite value at large positive voltages, but these asymptotic values are not yet reached at +80 mV. Deactivation of the currents upon stepping to negative membrane potentials below -60 mV is fairly well described by a single exponential. The decrease of the deactivation time constant at increasingly negative voltages tends to become less steep, indicating that this parameter also has a finite limiting value, which is not yet reached, however, at -160 mV. The various clones studied have very similar voltage dependencies of activation with half-activation voltages ranging between 50 and -11 mV and maximum steepness yielding and e-fold change for voltage increments between 3.8 and 7.0 mV. The shallower activation curve of Kv1.4 is likely to be due to coupling with the fast inactivation process present in this clone. PMID- 7835323 TI - New parenteral substrates in clinical nutrition. Part II. New substrates in lipid nutrition. PMID- 7835324 TI - Intestinal transport and fermentation of resistant starch evaluated by the hydrogen breath test. AB - OBJECTIVE: To study fermentability of different samples of resistant starch (RS), compared to one another and to lactulose, and to study the effect on gastric emptying of addition of RS to test meal. Finally to study if adaptation to RS results in a measurable change in fermentation pattern, (H2/CH4 production). Sources of RS: Raw potato starch (RPS), 58% RS; corn flakes (CF), 5% RS; hylon VII high amylomaize starch, extrusion cooked and cooled (HAS) 30% RS; highly retrograded hylon VII high amylomaize starch (HRA) 89% RS. DESIGN: (1) Fermentation: seven healthy volunteers ingested in randomized order 50 g RPS, 100 g CF, 75 g HAS, 25 g HRA. End-expiratory H2/CH4 was measured every 30 min for 12 to 22 hours post-ingestion as a measure of fermentation. A dose-response study of RPS, 5, 10, 25, 50, 75 and 100 g was performed. (2) Adaptation: In five 3-week periods seven volunteers added daily to their usual diet 50 g of either RPS, HAS, oat bran, wheat bran or common maize starch. The polysaccharides were administered in randomized order. The test periods were separated by 1 week's wash out. Basic end-expiratory H2/CH4 was measured once a week prior to and during the test periods. (3) Gastric emptying: The rate of increase in blood glucose was measured after test meals consisting of 50 and 100 g of RPS, 50 g HAS and 50 g glucose dissolved in a gel, alone, and mixed with 25 g of RPS. As controls we chose wheat bran and oat bran. RESULTS: (1) We found that RPS is fermentable, although the cumulated excessive H2 production after 50 g RPS corresponding to 29 g RS was clearly less than after 10 g lactulose. The time from ingestion of RPS to a sustained increase in end-expiratory H2 (apparent transit time; 5-11 h) was longer than lactulose (1-4 h), indicating either a slow passage through the small intestine or a slow fermentation rate. 100 g of corn flakes (4.6 g RS) resulted in a measurable increase in H2 production, equivalent to 10-20 g RPS, whereas neither of the two samples of hylon VII high amylomaize resulted in any significant increase in H2 production. The dose-response study with RPS showed that even 5 g of RPS resulted in a measurable increase in end expiratory H2, and increasing doses from 5 g to 100 g resulted in a seemingly exponential increase in H2 production. (2) 3 weeks' daily administration of HAS resulted in a slightly elevated increase in basic end-expiratory H2, although the increase did not reach statistical significance. RPS resulted in a sustained increase in basic end-expiratory H2. Both RS samples increased measurable end expiratory CH4 in volunteers with measurable CH4 production after a lactulose load, but 3 weeks' daily challenge with these slowly fermentable substrates did not increase measurable CH4 in volunteers, who prior to the study only produced CH4 intermittently. (3) The rate of increase in blood sugar was unaffected by addition of RS or non-starch-polysaccharides to the test meal, indicating that addition of the polysaccharides does not affect gastric emptying. CONCLUSIONS: A fraction of RPS is resistant to digestion in the small intestine, and it is fermentable by the colonic microbial flora. RS from CF, HAS and RPS give very different H2 responses, either due to differences in digestion patterns or fermentation patterns. Short-term adaptation (3 weeks) to HAS or RPS does not change the H2/CH4 response. RS does not affect gastric emptying of a test meal consisting of glucose dissolved in a gel. PMID- 7835325 TI - Changing prevalence of xerophthalmia in Indonesia, 1977-1992. AB - OBJECTIVE: The primary objective of this analysis was to determine if the prevalence of xerophthalmia in Indonesia has changed over the period 1977-78 to 1992. DESIGN: The design was two cross-sectional prevalence surveys conducted in the same rural sample locations 14 years apart. SETTING: The studies were conducted in 15 provinces of Indonesia using a stratified random selection of villages. SUBJECTS: All persons in selected villages < 6 years of age were eligible for participation. Children were recruited during a door-to-door census of villages and invited to present for an eye examination at a central point in the village. A total of 19,032 subjects were included in the 1977-78 and 18,508 children in the 1992 survey. RESULTS: Overall, the prevalence of active xerophthalmia among preschool children declined by 75% (1.33% in 1977-78 to 0.34% in 1992). Active corneal disease declined by 95% (1/1000 in 1977-78 to 0.05/1000 in 1992). While the overall declines were dramatic and highly significant (P < 0.0001), selected provinces continued to show rates higher than the WHO criteria for a problem of public health significance. CONCLUSIONS: The prevalence of xerophthalmia has declined significantly over the past 14 years in Indonesia. The specific reasons for this decline cannot be ascribed to any particular intervention due to the multitude of health and social changes that have occurred during this period. PMID- 7835326 TI - Exercise-induced suppression of appetite: effects on food intake and implications for energy balance. AB - OBJECTIVE: To examine the effects of exercise on short term energy intake and to investigate the existence of exercise-induced anorexia. DESIGN: Two studies were conducted, both with three treatment conditions and employing a repeated measures design. SETTING: The Human Appetite Research Unit at Leeds University Psychology department. SUBJECTS: Twenty three healthy, lean male subjects (n = 11 and n = 12 respectively) were recruited from the student/staff population of Leeds University. INTERVENTIONS: Subjects were randomly assigned to a control, low intensity and high intensity exercise treatment in the first study and to a control, short duration and long duration exercise treatment (high intensity) in the second. Motivation to eat was measured by visual analogue rating scales and by the length of the time between the end of exercise and the volitional onset of eating. Energy and macronutrient intakes were measured by means of a free selection test meal and by recorded intakes for the next 2 days. RESULTS: Subjective feelings of hunger were significantly suppressed during and after intense exercise sessions (P 0.01), but the suppression was short-lived. Exercise sessions had no significant effect on the total amount of food consumed in the test meal but intense exercise delayed the start of eating (P < 0.05). When energy intake was assessed relative to the energy expended during the exercise or control periods, only the long duration, high intensity session created a significant short-term negative energy balance (P < 0.001). CONCLUSIONS: These studies indicate that exercise-induced anorexia can be characterized by a brief suppression of hunger, accompanied by a delay to the onset of eating. The temporal aspects of exercise-induced anorexia may best be measured by the resistance to begin eating rather than the amount of food consumed. PMID- 7835327 TI - Validation of the food frequency questionnaire with the 4-day record method and analysis of 24-h urinary nitrogen. AB - OBJECTIVE: To validate a semi-quantitative food frequency questionnaire (FFQ). DESIGN: FFQ was evaluated by a 4-day food record (FR), four consecutive 24-h urinary collections, and study-specific cut-off limits for ratio between energy intake (EI) and basal metabolic rate (BMR). SETTING: Department of geriatric medicine, Goteborg University, Vasa Hospital, Gothenburg, Sweden. SUBJECTS: 76 consecutive 70-year-olds from representative population studies. RESULTS: FFQ provided consistently higher intakes of energy and nutrients than FR (1.18-2.51 of the FR values). For energy 95% CI estimates were 7167-8083 KJ and 9333-10579 KJ, by FR and FFQ methods, respectively. The correlation coefficients varied between 0.35 (total sugar) and 0.60 (energy and fat). The proportions and distribution of macronutrients were in good agreement between FFQ and FR. 95% CIs for the ratio between protein intake estimated by dietary methods and urinary protein were 1.14-1.36 and 1.00-1.13 for the FFQ and FR methods, respectively. However, the EI/BMR ratio for FR (1.27) was not in conformity with habitual energy expenditure compared to cut-off limits. CONCLUSION: This validity study showed that the agreement regarding distribution of energy from macronutrients between dietary methods and the reasonable ratio of FFQ-EI/BMR allow the conclusion that the FFQ method well reflects habitual intake of elderly Swedes. PMID- 7835328 TI - Socio-demographic correlates of dietary habits in mid to late adolescence. AB - OBJECTIVE: To examine socio-demographic correlates of dietary habits at 15 and 18 years. DESIGN: First and second sweeps of a longitudinal survey, based on a two stage stratified clustered random sample. SETTING: Central Clydeside Conurbation, in the West of Scotland. SUBJECTS: A random sample of 1682 households containing 15-year-olds was approached by Strathclyde Regional Council, 70% of whom agreed to have their names passed on to the MRC. 1009 (86%) of this target sample were interviewed at baseline. 908 (90%) were re-interviewed at age 18. Analyses are restricted to respondents who took part in both data collection sweeps. MEASURES: Questions on meal patterns and food choices were included in the interviews: self complete questionnaires included a dietary inventory. Social class was measured by reference to the head of household at baseline: information on own labour market position and place of residence was obtained at 18. RESULTS: At 18 there was clear differentiation in food choices and meal patterns according to sex and both parental social class and own current labour market position. Controlling for class, dietary habits at 15 were independently related to future labour market position. Overall changes in eating habits between 15 and 18 were slight, though females were more likely to have increased consumption of foods consistent with current recommendations, while the un/non-employed reduced their consumption of a midday meal. CONCLUSIONS: Dietary habits are established in mid-teens and closely associated with lifestyle, facts which need to be taken into consideration in designing effective nutrition education programmes. PMID- 7835329 TI - Replacing starch with sucrose in a high glycaemic index breakfast cereal lowers glycaemic and insulin responses. AB - OBJECTIVE: To test the hypothesis that replacing starch with sugar in a processed breakfast cereal that has a high glycaemic index could significantly decrease glycaemic and insulin responses. DESIGN: Subjects consumed in random order three equi-carbohydrate meals based on a popular puffed rice cereal containing three levels of sucrose (0, 21 and 43 g). Postprandial glucose and insulin responses were compared using the incremental area under the curve (AUC). SUBJECTS: Twelve healthy volunteers (5 males and 7 females) with normal glucose tolerance drawn from the university community, mean age 23 years (range: 20 to 27 year), mean body mass index 22.6 kg/m2 (range: 18.6 to 31.2 kg/m2). RESULTS: Glycaemia was significantly lower after the meal containing the highest amount of sugar (glucose AUC 101.7 +/- 14.0 mmol/l.120 min) compared with the non-sweetened cereal (155.5 +/- 18.0 mmol/l.120 min, P < 0.01). There was a significant inverse correlation between the amount of sucrose incorporated and the degree of glycaemia (analysis of covariance coefficient = -1.25, P = 0.00). Similarly, the plasma insulin response was significantly lower after the highest sugar meal (insulin AUC 2267 +/- 346 microU/ml.120 min) compared with the meal without sugar (3505 +/- 365 microU/ml.120 min, P < 0.01). CONCLUSIONS: We found a significant reduction in glycaemic and insulin responses when sugar replaced the rapidly digested starch in a processed breakfast cereal, i.e. the opposite of what is commonly believed. Thus sweetened breakfast cereals may not compromise glycaemic control more so than the unsweetened counterpart. PMID- 7835330 TI - Effects of low-dose iron supplementation in women with low serum ferritin concentration. AB - We studied effects of dose and treatment duration during low-dose iron supplementation in premenopausal, non-pregnant women, with initial serum ferritin and haemoglobin concentrations < 20 micrograms x l-1 and > or = 120 g x l-1, respectively. The study was randomized, double-blind and placebo-controlled. Three groups completed a 6-month study: placebo (n = 27), FE-9 (9 mg iron x day 1, n = 18) and FE-27 group (27 mg iron x day-1, n = 19). The supplement consisted of 11% heme and 89% inorganic iron. In FE-27, serum ferritin increased from (mean, 95% confidence interval) 11.8 (9.7; 14.4) to 25.3 (18.6; 34.4) micrograms x l-1 in 1 month, and remained stable after that (ANOVA: group effect, P = 0.0003). In both FE-9 and FE-27, blood haemoglobin levels increased from 136 (132; 140) to 142 (139; 145) g x l-1 in 1 month, remaining constant after that (group effect, P = 0.001). Hence, the 27 mg daily dose of organic/inorganic iron corrected both mild anaemia and storage iron depletion, whereas the 9 mg dose did not affect iron stores. Elongation of treatment duration above 1 month brought about only minor changes. PMID- 7835331 TI - Genesis of the novel epidemic Vibrio cholerae O139 strain: evidence for horizontal transfer of genes involved in polysaccharide synthesis. AB - Only Vibrio cholerae strains of serotype O1 are known to cause epidemics, while non-O1 strains are associated with sporadic cases of cholera. It was therefore unexpected that the recent cholera epidemic in Asia was caused by a non-O1 strain with the serotype O139. We provide evidence that O139 arose from a strain closely related to the causative agent of the present cholera pandemic, V. cholerae O1 El Tor, by acquisition of novel DNA which was inserted into, and replaced part of, the O antigen gene cluster of the recipient strain. Part of the novel DNA was sequenced and two open reading frames (otnA and otnB) were observed, the products of which showed homology to proteins involved in capsule and O antigen synthesis, respectively. This suggests that the otnAB DNA determines the distinct antigenic properties of the O139 cell surface. The otnAB DNA was not detected in O1 strains, but was present in two non-O1 V. cholerae strains with serotypes O69 and O141. In the O69 and O139 strains the otnAB genes were located proximate to the putative insertion sequence (IS) element rfbQRS, which is associated with O antigen synthesis genes in O1 strains, and may have played a role in the insertion of the otnAB DNA in the recipient chromosome. Our results suggest that the O139 strain arose by horizontal gene transfer between a non-O1 and an O1 strain. The acquired DNA has altered the antigenic properties of the recipient O1 strain, providing a selective advantage in a region where a large part of the population is immune to O1 strains.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7835332 TI - Transport route for synaptobrevin via a novel pathway of insertion into the endoplasmic reticulum membrane. AB - Synaptobrevin/vesicle-associated membrane protein is one of the soluble N ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins. It is proposed to provide specificity for the targeting and fusion of vesicles with the plasma membrane. It belongs to a class of membrane proteins which lack a signal sequence and contain a single hydrophobic segment close to their C terminus, leaving most of the polypeptide chain in the cytoplasm (tail-anchored). We show that in neuroendocrine PC12 cells, synaptobrevin is not directly incorporated into the target organelle, synaptic-like vesicles. Rather, it is first inserted into the endoplasmic reticulum (ER) membrane and is then transported via the Golgi apparatus. Its insertion into the ER membrane in vitro occurs post-translationally, is dependent on ATP and results in a trans-membrane orientation of the hydrophobic tail. Membrane integration requires ER protein(s) different from the translocation components needed for proteins with signal sequences, thus suggesting a novel mechanism of insertion. PMID- 7835333 TI - Synaptobrevin binding to synaptophysin: a potential mechanism for controlling the exocytotic fusion machine. AB - The synaptic vesicle protein synaptobrevin (VAMP) has recently been implicated as one of the key proteins involved in exocytotic membrane fusion. It interacts with the synaptic membrane proteins syntaxin I and synaptosome-associated protein (SNAP)-25 to form a complex which precedes exocytosis [Sollner et al. (1993b) Cell, 75, 409-418]. Here we demonstrate that the majority of synaptobrevin is bound to the vesicle protein synaptophysin in detergent extracts. No syntaxin I was found in this complex when synaptophysin-specific antibodies were used for immunoprecipitation. Conversely, no synaptophysin was associated with the synaptobrevin-syntaxin I complex when syntaxin-specific antibodies were used for immunoprecipitation. Thus, the synaptobrevin pool bound to synaptophysin is not available for binding to syntaxin I and SNAP-25, and vice versa. Synaptobrevin synaptophysin binding was also demonstrated by chemical cross-linking in isolated nerve terminals. Furthermore, recombinant synaptobrevin II efficiently bound synaptophysin and its isoform synaptoporin, but not the more distantly related synaptic vesicle protein p29. Recombinant synaptobrevin I bound with similar efficiency, whereas the non-neuronal isoform cellubrevin displayed a lower affinity towards synaptophysin. Treatment with high NaCl concentrations resulted in a dissociation of the synaptobrevin-synaptophysin complex. In addition, the interaction of synaptobrevin with synaptophysin was irreversibly abolished by low amounts of SDS, while the interaction with syntaxin I was enhanced. We conclude that synaptophysin selectively interacts with synaptobrevin in a complex which excludes the t-SNAP receptors syntaxin I and SNAP-25, suggesting a role for synaptophysin in the control of exocytosis. PMID- 7835334 TI - A role for soluble NSF attachment proteins (SNAPs) in regulated exocytosis in adrenal chromaffin cells. AB - Digitonin-permeabilized chromaffin cells secrete catecholamines by exocytosis in response to micromolar Ca2+ concentrations, but lose the ability to secrete in response to Ca2+ as the cells lose soluble proteins through the plasma membrane pores. Such secretory run-down can be retarded by cytosolic fractions, thus providing an assay for proteins potentially involved in the exocytotic process. We have used this assay to investigate the role of N-ethylmaleimide-sensitive fusion protein (NSF) and soluble NSF attachment proteins (SNAPs) in regulated exocytosis. Recombinant alpha- and gamma-SNAP stimulated Ca(2+)-dependent exocytosis, although recombinant NSF was ineffective, despite the fact that NSF and alpha-SNAP leak from the permeabilized cells with similar time courses. However, around one third of cellular NSF was found to be present in a non cytosolic form and so it is possible that this is sufficient for exocytosis and that exogenous SNAPs stimulate the exocytotic mechanism by acting on the leakage insensitive NSF. The stimulatory effect of alpha-SNAP displayed a biphasic dose response curve and was maximal at 20 micrograms/ml. The effect of alpha-SNAP was Ca(2+)- and MgATP-dependent and was inhibited by N-ethylmaleimide and botulinum A neurotoxin, indicating a bona fide action on the exocytotic mechanism. Furthermore, Ca2+ concentrations which trigger catecholamine secretion acted to prevent the leakage of NSF and alpha-SNAP from permeabilized cells. These findings provide functional evidence for a role of SNAPs in regulated exocytosis in chromaffin cells. PMID- 7835335 TI - Electron microscopy of antibody complexes of influenza virus haemagglutinin in the fusion pH conformation. AB - Activation of the membrane fusion potential of influenza haemagglutinin (HA) at endosomal pH requires changes in its structure. X-ray analysis of TBHA2, a proteolytic fragment of HA in the fusion pH conformation, indicates that at the pH of fusion the 'fusion peptide' is displaced by > 10 nm from its location in the native structure to the tip of an 11 nm triple-stranded coiled coil, and that the formation of this structure involves extensive re-folding or reorganization of HA. Here we examine the structure of TBHA2 with the electron microscope and compare it with the fusion pH structure of HA2 in virosomes, HA2 in aggregates formed at fusion pH by the soluble, bromelain-released ectodomain BHA and HA2 in liposomes with which BHA associates at fusion pH. We have oriented each HA2 preparation for comparison, using site-specific monoclonal antibodies. We conclude that the structural changes in membrane-anchored and soluble HA preparations at the pH of fusion appear to be the same; that in the absence of a target membrane, the 'fusion peptide' of HA in virosomes associates with the virosome membrane so that HA2 is membrane bound at both N- and C-termini, which implies that inversion of the re-folded HA can occur; and that the structural changes observed by X-ray analysis do not result from the proteolytic digestions used in the preparation of TBHA2. PMID- 7835336 TI - Novel transmembrane topology of the hepatitis B virus envelope proteins. AB - The small (S), middle (M) and large (L) envelope proteins of the hepatitis B virus (HBV) are initially synthesized as multispanning membrane proteins of the endoplasmic reticulum membrane. We now demonstrate that all envelope proteins synthesized in transfected cells or in a cell-free system adopt more than one transmembrane orientation. The L protein disposes its N-terminal preS domain both to the cytoplasmic and the luminal side of the membrane. This unusual topology does not depend on interaction with the viral nucleocapsid, but is preserved in secreted empty envelope particles. Pulse-chase analysis suggests a novel process of post-translational translocation leading to the non-uniform topology. Analysis of L deletion mutants indicates that the block to co-translational translocation can be attributed to a specific sequence within preS, suggesting that translocation of L may be regulated. Additional topological heterogeneity is displayed in the S region of the envelope proteins and in the S protein itself, as assayed in a cell-free system. S proteins integrated into microsomal membranes exhibit both a luminal and a cytoplasmic orientation of the internal hydrophilic region carrying the major antigenic determinants. This may explain the unusual partial glycosylation of the HBV envelope proteins. PMID- 7835337 TI - Suppression of apoptotic death in hematopoietic cells by signalling through the IL-3/GM-CSF receptors. AB - Interleukin 3 (IL-3) and granulocyte-macrophage colony stimulating factor (GM CSF) exert their biological functions through acting on a specific receptor which consists of a ligand-specific alpha subunit and the shared common beta subunit. Inhibition by genistein of a subset of IL-3/GM-CSF-mediated signals, including c myc induction, resulted in the abrogation of DNA synthesis, however, IL-3 still protected cells from apoptotic cell death. Conversely, a C-terminal truncated form of the GM-CSF receptor, which is missing a critical cytoplasmic region required for activation of the Ras/Raf-1/MAP kinase pathway, induced DNA synthesis, but failed to prevent cell death in response to GM-CSF. Consequently, cells died by apoptosis in the presence of GM-CSF, despite displaying a transient mitogenic response. However, expression of activated Ras protein complemented defective signalling through the mutant receptor and supported long-term proliferation in concert with GM-CSF. These results indicate that IL-3 and GM-CSF prevent apoptosis of hematopoietic cells by activating a signalling pathway distinct from the induction of DNA synthesis and that long-term cell proliferation requires the activation of both pathways. PMID- 7835338 TI - Involvement of p21ras distinguishes positive and negative selection in thymocytes. AB - Small molecular weight GTP binding proteins of the ras family have been implicated in signal transduction from the T cell antigen receptor (TCR). To test the importance of p21ras in the control of thymocyte development, we generated mice expressing a dominant-negative p21ras protein (H-rasN17) in T lineage cells under the control of the lck proximal promoter. Proliferation of thymocytes from lck-H-rasN17 mice in response to TCR stimulation was nearly completely blocked, confirming the importance of p21ras in mediating TCR-derived signals in mature CD4+8- or CD8+4- thymocytes. In contrast, some TCR-derived signals proceeded unimpaired in the CD4+8+ thymocytes of mice expressing dominant-negative p21ras. Analysis of thymocyte development in mice made doubly transgenic for the H-Y specific TCR and lck-H-rasN17 demonstrated that antigen-specific negative selection occurs normally in the presence of p21H-rasN17. Superantigen-induced negative selection in vivo also proceeded unhindered in H-rasN17 thymocytes. In contrast, positive selection of thymocytes in the H-Y mice was severely compromised by the presence of p21H-rasN17. These observations demonstrate that positive and negative selection, two conceptually antithetical consequences of TCR stimulation, are biochemically distinguishable. PMID- 7835339 TI - A dual functional signal mediator showing RhoGAP and phospholipase C-delta stimulating activities. AB - We have cloned a novel regulator protein, p122, in the PLC-delta signalling pathway by screening a rat brain expression library with antiserum raised against purified phospholipase C-delta 1 (PLC-delta 1). This novel p122-RhoGAP binds to PLC-delta 1 and activates the phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolyzing activity of PLC-delta 1. As suggested by the deduced amino acid sequence, this regulator protein shows a similarity to the GTPase activating protein (GAP) homology region of Bcr and possesses GAP activity for RhoA, but not for Rac1; no guanine nucleotide exchange activity for RhoA and Rac1 was detected. These findings suggest that this novel RhoGAP is involved in the Rho signalling pathway, probably downstream of Rho activation, and mediates the stimulation of PLC-delta, which leads to actin-related cytoskeletal changes through the hydrolysis of PIP2, which binds to actin binding proteins such as gelsolin and profilin. PMID- 7835340 TI - Characterization of rho GTPase family homologues in Drosophila melanogaster: overexpressing Rho1 in retinal cells causes a late developmental defect. AB - The rho family of GTPases has been implicated in regulating changes in cell morphology in response to extracellular signals. We have cloned three widely expressed members of this family from Drosophila melanogaster; a rho homologue (Rho1) and two rac homologues (Rac1 and Rac2). Flies harbouring a Rho1 transgene that is specifically expressed in the eye exhibit a dramatic dose dependent disruption of normal eye development. Flies bearing at least two copies of the transgene display a severe rough eye phenotype characterized by missing secondary and tertiary pigment cells, a substantial reduction in the number of photoreceptor cells and a grossly abnormal morphology of the rhabdomeres. Cell fate determination in the imaginal disc occurs normally and abnormalities become manifest late in pupariation, coincident with the phase when the cells undergo major morphological changes. This phenotype is modified by mutations at several other loci that have been implicated in signal transduction, but not by mutations in ras pathway components. PMID- 7835341 TI - Ubiquitination of the G1 cyclin Cln2p by a Cdc34p-dependent pathway. AB - Recombinant G1 cyclin Cln2p can bind to and stimulate the protein kinase activity of p34CDC28 (Cdc28p) in an extract derived from cyclin-depleted and G1-arrested Saccharomyces cerevisiae cells. Upon activating Cdc28p, Cln2p is extensively phosphorylated and conjugated with multiubiquitin chains. Ubiquitination of Cln2p in vitro requires the Cdc34p ubiquitin-conjugating enzyme, Cdc28p, protein phosphorylation and unidentified factors in yeast extract. Ubiquitination of Cln2p by Cdc34p contributes to the instability of Cln2p in vivo, as the rate of Cln2p degradation is reduced in cdc34ts cells. These results provide a molecular framework for G1 cyclin instability and suggest that a multicomponent, regulated pathway specifies the selective ubiquitination of G1 cyclins. PMID- 7835342 TI - Heme binds to a short sequence that serves a regulatory function in diverse proteins. AB - Heme is a prosthetic group for numerous enzymes, cytochromes and globins, and it binds tightly, sometimes covalently, to these proteins. Interestingly, heme also potentiates binding of the yeast transcriptional activator HAP1 to DNA and inhibits mitochondrial import of the mammalian delta-aminolevulinate synthase (ALAS) and the catalytic activity of the reticulocyte kinase, HRI. All three of these proteins contain a short sequence, the heme regulatory motif (HRM), that occurs six times adjacent to the HAP1 DNA binding domain, twice in the leader targeting sequence of ALAS and twice near the catalytic domain of the HRI kinase. Here we show that a 10 amino acid peptide containing the HRM consensus binds to heme in the micromolar range, and shifts the heme absorption spectrum to a longer wavelength, a direction opposite to the change caused by cytochromes or globins. Further, we show that a single HRM regulates the acidic activation domains of HAP1 and GAL4 independently of regulation of DNA binding of the transcription factors. These findings thus establish a novel heme binding sequence which is structurally distinct from sequences in globins or cytochromes and which has a regulatory function. PMID- 7835343 TI - Novel mechanism and factor for regulation by HIV-1 Tat. AB - Tat regulation of human immunodeficiency virus (HIV) transcription is unique because of its specificity for an RNA target, TAR, and its ability to increase the efficiency of elongation by polymerase. A reconstituted reaction that is Tat specific and TAR-dependent for activation of HIV transcription has been used to identify and partially purify a cellular activity that is required for trans activation by Tat, but not by other activators. In the reaction, Tat stimulates the efficiency of elongation by polymerase, whereas Sp1 and other DNA sequence specific transcription factors activate the rate of initiation. Furthermore, while TATA binding protein (TBP)-associated factors (TAFs) in the TFIID complex are required for activation by transcription factors, they are dispensable for Tat function. Thus, Tat acts through a novel mechanism, which is mediated by a specific host cellular factor, to stimulate HIV-1 gene expression. PMID- 7835344 TI - The bovine papillomavirus 1 E2 protein contains two activation domains: one that interacts with TBP and another that functions after TBP binding. AB - The E2 transactivator of bovine papillomavirus type-1 is unable to activate minimal promoters in vivo that contain only E2 binding sites and a TATA box. This block can be overcome by over-expression of human TATA binding protein (TBP) or by the addition of either SP1 binding sites or an initiator element to the promoter, suggesting that the binding of TFIID may normally be a rate-limiting step for activation by E2. Surprisingly, purified E2 and TBP bind co-operatively to DNA in vitro when the sites are closely spaced. E2 does not affect the on rate of association but reduces the off rate. The E2 region responsible for this effect is located in the hinge region that links the classic transactivation and DNA binding domains. We demonstrate that the TBP stabilizing domain contributes in vivo to co-operativity with co-expressed TBP and to activation of the major late minimal promoter (MLP) containing E2 sites. In contrast, promoters with SP1 sites are activated to wild-type levels by such a mutant. This promoter specificity is also evident in vitro. A truncated E2 mutant, lacking the classic transactivation domain but containing the TBP stabilizing domain, stimulates transcription of the MLP in vitro, but does not activate promoters with SP1 sites. In conclusion, our results show that the E2 transactivation domain has a modular structure. We have identified one domain which probably acts at an early step in the assembly of the pre-initiation complex and which is involved in reducing the dissociation rate of bound TBP in vitro. The classic N-terminal activation domain of E2 might affect one or several step(s) in the assembly of the preinitiation complex occurring after the binding of TFIID. PMID- 7835345 TI - A mutation in the C31 subunit of Saccharomyces cerevisiae RNA polymerase III affects transcription initiation. AB - The C31 subunit belongs to a complex of three subunits (C31, C34 and C82) specific to RNA polymerase (pol) III that have no counterparts in other RNA polymerases. This complex is thought to play a role in transcription initiation since it interacts with the general initiation factor TFIIIB via subunit C34. We have obtained a conditional mutation of pol III by partially deleting the acidic C-terminus of the C31 subunit. A Saccharomyces cerevisiae strain carrying this truncated C31 subunit is impaired in in vivo transcription of tRNAs and failed to grow at 37 degrees C. This conditional growth phenotype was suppressed by overexpression of the gene coding for the largest subunit of pol III (C160), suggesting an interaction between C160 and C31. The mutant pol III enzyme transcribed non-specific templates at wild-type rates in vitro, but was impaired in its capacity to transcribe tRNA genes in the presence of general initiation factors. Transcription initiation, but not termination or recycling of the enzyme, was affected in the mutant, suggesting that it could be altered on interaction with initiation factors or on the formation of the open complex. Interestingly, the C-terminal deletion was also suppressed by a high gene dosage of the DED1 gene encoding a putative helicase. PMID- 7835346 TI - Transcription-coupled repair removes both cyclobutane pyrimidine dimers and 6-4 photoproducts with equal efficiency and in a sequential way from transcribed DNA in xeroderma pigmentosum group C fibroblasts. AB - We investigated the contribution of the global and the transcription-coupled nucleotide excision repair pathway to the removal of structurally different DNA lesions. The repair kinetics of UV-induced cyclobutane pyrimidine dimers (CPDs) and pyrimidine (6-4) pyrimidone photoproducts (6-4PPs) were determined in an active and inactive gene in normal human fibroblasts and in xeroderma pigmentosum group C (XP-C) fibroblasts. Previously we have shown that in normal human cells exposed to a UV dose of 10 J/m2 repair of CPDs takes place via two pathways: global repair and transcription-coupled repair, the latter being responsible for accelerated repair of CPDs in the transcribed strand of active genes. So far, no clear evidence for transcription-coupled repair of 6-4PPs has been presented. Here we demonstrate that 6-4PPs really form a target for transcription-coupled repair. In XP-C cells, exposed to 30 J/m2 and only capable of performing transcription-coupled repair, CPDs as well as 6-4PPs are removed selectively and with similar kinetics from the transcribed strand of the adenosine deaminase (ADA) gene. The non-transcribed strand of the ADA gene and the inactive 754 gene are hardly repaired. In contrast to XP-C cells, normal cells exposed to 30 J/m2 lack strand-specific repair of both 6-4PPs and CPDs, suggesting that transcription-coupled repair is overruled by global repair, probably due to severe inhibition of transcription at this high UV dose. The much more rapid repair of 6-4PPs compared with CPDs in normal cells may be related to higher affinity of the global repair system for the former lesion. In XP-C cells the similarity of the rate of repair of both 6-4PPs and CPDs in the transcribed strand at 30 J/m2 indicates that transcription-coupled repair of photolesions takes place in a sequential way. Our results strongly suggest that the significance of transcription-coupled repair for removal of lesions depends on the type of lesion and on the dose employed. PMID- 7835347 TI - Efficient trans-cleavage of a stem-loop RNA substrate by a ribozyme derived from neurospora VS RNA. AB - We have constructed a ribozyme containing 144 nucleotides of Neurospora VS RNA that can catalyze the cleavage of a separate RNA in a true enzymatic manner (Km approximately 0.13 microM, kcat approximately 0.7/min). Comparison of the rates of cis- and trans-cleavage, as well as the lack of effect of pH on the rate of cleavage, suggest that a rate-limiting step, possibly a conformational change, occurs prior to cleavage. The minimum contiguous substrate sequence required for cleavage consists of one nucleotide upstream and 19 nucleotides downstream of the cleavage site. Unlike most other ribozymes which interact with long single stranded regions of their substrates, the minimal substrate for the VS ribozyme consists mostly of a stable stem-loop, which would appear to preclude its recognition simply via extensive Watson-Crick base pairing. PMID- 7835348 TI - Effects of secondary structure on pre-mRNA splicing: hairpins sequestering the 5' but not the 3' splice site inhibit intron processing in Nicotiana plumbaginifolia. AB - We have performed a systematic study of the effect of artificial hairpins on pre mRNA splicing in protoplasts of a dicot plant, Nicotiana plumbaginifolia. Hairpins with a potential to form 18 or 24 bp stems strongly inhibit splicing when they sequester the 5' splice site or are placed in the middle of short introns. However, similar 24 bp hairpins sequestering the 3' splice site do not prevent this site from being used as an acceptor. Utilization of the stem-located 3' site requires that the base of the stem is separated from the upstream 5' splice site by a minimum of approximately 45 nucleotides and that another 'helper' 3' splice site is present downstream of the stem. The results indicate that the spliceosome or factors associated with it may have a potential to unfold secondary structure present in the downstream portion of the intron, prior to or at the step of the 3' splice site selection. The finding that the helper 3' site is required for utilization of the stem-located acceptor confirms and extends previous observations, obtained with HeLa cell in vitro splicing systems, indicating that the 3' splice site may be recognized at least twice during spliceosome assembly. PMID- 7835350 TI - Inhibition of spoilage and food-borne pathogens by lactic acid bacteria isolated from fermenting tef (Eragrostis tef) dough. AB - A study was carried out at the Department of Biology, Addis Abeba University, in 1991 to determine the inhibitory potential of fermenting tef and the lactic acid bacteria isolated from fermenting tef dough on Salmonella spp., Pseudomonas aeruginosa, Klebsiella spp., Bacillus cereus and Staphylococcus aureus. The test bacteria grew in the fermenting tef uptill 30 hr or till the pH dropped to 4.7. Thereafter, growth was inhibited and decreases in population were apparent. The results showed that the spent media from all of the four lactic acid bacterial isolates, namely, Lactobacillus spp., Pediococcus spp., Leuconostoc spp. and Streptococcus spp. inhibited the test bacteria. Acidity on its own was not responsible for the inhibition of the test bacteria. The spent medium from Streptococcus spp. showed the best inhibitory activity amongst the lactic acid bacteria. PMID- 7835349 TI - The Holliday junction intermediates of lambda integrative and excisive recombination respond differently to the bending proteins integration host factor and excisionase. AB - In lambda site-specific recombination, the integrative and excisive reactions proceed via two different Holliday junction intermediates, both of which are generated and resolved by a pair of sequentially ordered single strand exchanges. Factors affecting the directionality and efficiency of the second pair of strand exchanges were examined using artificial Holliday junctions (chi-forms). The integrative and excisive recombination intermediates respond differently to the accessory DNA bending proteins integration host factor and excisionase (Xis). These differences between the two recombination intermediates result from a different interaction pattern between proteins binding to the left (P arm) and right (P' arm) of the crossover region. The effect of Xis protein on the directionality of resolution, i.e. the choice of which strands are exchanged, is consistent with a role in promoting the second strand exchange during excision. Proteins binding to the left of the crossover region (P arm) primarily influence the directionality of resolution, while proteins binding to the right (P' arm) have a greater effect on the overall efficiency of resolution. Together, the effect of proteins binding to sites in the P and P' arms is to greatly enhance resolution of the two different Holliday intermediates and to favor resolution in the 'forward' direction for both integrative and excisive recombination. PMID- 7835351 TI - Renal and ureteral stones, a review based on 104 operated cases from Tikur Anbessa Hospital. AB - One-hundred-four cases of stones in the upper urinary tract treated by open surgery during 1979 to 1982 at the Tikur Anbessa Hospital have been retrospectively reviewed. Among the patients, 76.5% were between the age of 20 and 40 years and there was a predominance of men with a male to female ratio of 3.7:1. More than 50% of patients presented with a history of illness from one to five years and most of the presenting symptoms and signs were the same as reported by others. Fourteen of the 73 patients tested (19%) had positive urine culture. Conservative operations of pyelolithotomy and ureterolithtomy were made in 71.2% of the patients. Nephrolithotomy was made in 14.3%, partial nephrectomy in 3.8% and nephrectomy in 8.7%. Of the patients 92.3% had an uneventful postoperative course. Mortality was 1.9% and occurred in patients with stone anuria. Chemical analysis of stones from 25 patients showed calciumoxalate in 21, and calciumoxalate with additional phosphate in three patients. One patient had pure uric acid stone. PMID- 7835352 TI - The relation of early nutrition, infections and socio-economic factors to the development of childhood diabetes. AB - The relationship of development of diabetes from birth up to 15 years of age to the type of feeding in infancy, childhood infections and vaccination was studied in 55 patients attending Endocrinology Clinics of the Ethio-Swedish Children's and Tikur Anbessa Hospitals over a period of two years (January 1990 to December 1991). Seventy-four unaffected siblings and 107 unrelated controls were interviewed for comparison. No significant difference was found in relation to type of feeding up to the ages of three, six and 12 months or older between patients and unaffected siblings. Histories of measles, chicken pox and whooping cough were equally distributed between the two groups. However, introduction of bottle-feeding was significantly more frequent among unrelated controls at three months of age (9/39 diabetics versus 41/83 controls) and six months of age (26/39 diabetics vs 72/83 controls) chi 2 = 6.6, (p < 0.01) and chi 2 = 5.6 (p < 0.05) respectively. The odds ratios between diabetics and unrelated controls for introduction of bottle-feeding at three months and six months of age were 0.32 (confidence intervals 0.14-0.74) and 0.31 (confidence intervals 0.13-0.77) respectively. The use of cow's milk and other formulas in bottle-feeding showed a significant negative association with the development of diabetes chi 2 = 5.8 (p < 0.025), chi 2 = 3.8 (p < 0.05) respectively. A history of vaccination against tuberculosis, measles, diphtheria, pertussis, tetanus (DPT) and polio was significantly more common among unrelated controls than diabetics, chi 2 from 4.6 to 11.4 (p < 0.05 to p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7835353 TI - The status of Schistosoma mansoni and snail hosts in Tigray and northern Wello regions, northern Ethiopia. AB - A survey of Schistosoma mansoni infection and snail hosts was carried out in 1992 in six accessible schools and 11 water bodies respectively. Five to ten per cent of the students were randomly selected for stool examination by the Ritichie's method. In Adwa town, however, stools of 100 students out of the 199 selected were re-examined by Kato's method to assess intensity of infection. Results of stools examined by Ritichie's method showed that S. mansoni positive patients were present in four out of six (66.7%) schools, the prevalence for school ranging from 1% in Maychew to 61.8% in Adwa. In all the localities, there was significant male preponderance in the prevalence of infection (p < 0.05). Among those whose stools were examined by the Kato's method in Adwa town, both prevalence and geometric mean egg count per gram of faeces (EPG) were highest in the 10 to 14 years age group reaching 68% and 597 followed by 64% and 591 respectively in the 15 to 19 years of age. Of the S. mansoni positive students in Adwa, 86% excreted 200 or more EPG, 84% of those in the 10 to 14 years of age excreted as high as 1,600 EPG. Sexwise, no significant difference was observed in EPG (p > 0.05). Biomphalaria pfeifferi, the principal snail host of S. mansoni in Ethiopia, were collected from five out of the 11 waterbodies and were found shedding human schistosome cercariae in two of them, their infection rate reaching 0.7%. The ecological characteristics observed were found suitable for snail propagation.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7835354 TI - A two year retrospective study of birth weight in Sidamo Regional Hospital. AB - This is a two year retrospective analysis of 1,260 live single births at Sidamo Regional Hospital during 1989-1990. The mean birth weight was 3,243 g (SD +/- 625). There were 678(53.8%) boys and 582(46.2%) girls. The mean birth weight for boys and girls were 3,324 g (SD +/- 622) and 3147 g (SD +/- 611), respectively (t = 5.05; p < 0.001). There were significant correlations between birth weight and the age of the mother (r = 0.20; p < 0.001) as well as with parity (r = 0.15; p < 0.001). Eight per cent of the babies had birth weight less than 2,500 g. Five per cent of boys and 11% of girls had low birth weights (chi 2 = 8.8; p < 0.002). Higher proportion of low birth weight was also found among the young and primiparous mothers. A multiple linear regression analysis showed a significant and independent effect of maternal age and sex of the baby on birth weight. The findings are in general agreement with previous studies from Ethiopia and other developing countries. However, as this study is based on hospital data, community based studies are needed to examine the true pattern of birth weights as hospital data may be biased. PMID- 7835355 TI - Meningioma resembling an epidermoid tumor. AB - A case of retro-orbital meningioma who presented to the Department of Surgery, Neuro-surgery Unit of Tikur Anbessa Hospital in June 1993 with a progressive right eye proptosis is described. Exploration through a right frontal craniotomy showed a well circumscribed and encapsulated thickened bony tumor that had a cavity containing a cheesy-yellowish oily material. The lesion was successfully shelled-out. The preoperative diagnosis was meningioma. However, based on its intraoperative macroscopic appearance, mode of presentation, and location of the lesion an impression of an epidermoid tumor (cholesteatoma) was made. The result of histologic examination turned out to be meningioma (psammomatous type). Literature review on both conditions, the pathologic characteristics and clinical features are discussed briefly. PMID- 7835356 TI - Adult pneumococcal meningitis with no inflammatory cells in the CSF. AB - An 18 year old male patient was admitted to the Medical Intensive Care Unit of the Tikur Anbessa Hospital in October 1988. He was in deep coma and had findings consistent with a left lobar pneumonia. Lumbar puncture revealed a turbid CSF. Gram stain on both centrifuged and uncentrifuged specimens revealed plenty of gram positive diplococci with no single inflammatory cell. CSF culture proved the organism to be Streptococcus pneumoniae. The patient was put on combination of high doses of intravenous sodium-penicillin and chloramphenicol with all appropriate supportive management. However, the patient died only after three hours of stay in the hospital. The condition of diminished to absent inflammatory response in the CSF associated with pneumococcal meningitis in adults is discussed with a review of the literature. PMID- 7835357 TI - The 20th Kellersberger Memorial Lecture, 1994. Leprosy and tuberculosis combined programmes: an uneasy partnership? AB - One of the purposes of this memorial lecture is to relate progress and difficulties in the field of leprosy to work in other fields. Tuberculosis is a disease closely related to leprosy and in 1982 the Kellersberger lecture was given by Dr. Styblo, someone whose name is synonymous with the development of effective Tuberculosis Control Programme in Africa. His title was "Tuberculosis and its control: lessons to be learned from past experience, and implications for leprosy control programme" (1). Many countries in Africa, including Ethiopia, have adopted the strategy of a combined leprosy and TB control programme. In this lecture then, I will examine more closely the strategy of combining the two programmes. I want to look at some of the problems that may arise and then draw out the ways in which each side of the partnership can contribute to the other, so that the combination can be more effective than either programme could hope to be on its own. This lecture will focus mainly on management issues, which are currently the most important barriers to effective control of both diseases, but the socio-economic aspects of disease, so much a part of Dr. Kellersberger's working life, will also be prominent. PMID- 7835358 TI - Rate adaptive pacing in sick sinus syndrome: effects of pacing modes and intrinsic conduction on physiological responses, arrhythmias, symptomatology and quality of life. AB - An atrial-based pacing mode is superior to ventricular constant rate demand pacing (VVI) mode in patients with sick sinus syndrome (SSS) by providing both rate adaptation and atrioventricular (AV) synchrony. The use of a non-atrial sensor to overcome chronotropic incompetence and preserve normal intrinsic AV conduction in pacemaker therapy for SSS was investigated in 15 consecutive patients (mean age 66 +/- 2 years). All had intact AV conduction (antegrade conduction capacity > 100 beats.min-1 and an atrial paced to intrinsic R interval of < or = 220 ms). DDDR pacemakers capable of being programmed into atrial rate adaptive (AAIR), dual chamber rate adaptive (DDDR) and ventricular rate adaptive (VVIR) modes were used. Beginning with an acute study, arterial pressure was invasively assessed in each pacing mode during physiological stresses and low level exercise. In the ambulatory phase, the incidence of ventricular pacing and arrhythmias (Holter recording), diurnal blood pressure changes (ambulatory blood pressure recording), and symptom and quality of life level (questionnaires and interviews) were compared. Despite similar heart rate changes during acute physiological stresses, a higher blood pressure was recorded during AAIR or DDDR pacing compared with VVIR pacing. Systolic blood pressure over 24 h was lower in the VVIR mode (122 +/- 5 mmHg) than AAIR/DDDR pacing (129 +/- 6/128 +/- 6 mmHg, P < 0.05). VVIR pacing was associated with a higher frequency of atrial and ventricular ectopics, with two patients developing paroxysmal atrial fibrillation. Ventricular pacing was used in a higher percentage in the DDDR compared with the VVIR mode (64 +/- 11 and 39 +/- 7%, P < 0.03). VVIR pacing was associated with more palpitations, a lower level of general well being and depression. Despite the use of a sensor to overcome chronotropic incompetence, VVIR pacing is a less satisfactory pacing mode for SSS. Although AAIR/DDDR pacing may achieve similar haemodynamic and clinical status, in patients with intact AV conduction, AAIR pacing may be preferable by avoiding an abnormal ventricular activation pattern. PMID- 7835359 TI - The use of Gianturco-Roubin flexible metallic coronary stents in old saphenous vein grafts: in-hospital outcome and 7 day angiographic patency. AB - After placement of a Gianturco-Roubin metallic, coiled coronary stent(s) following balloon angioplasty (PTCA), a pre-discharge (7 day) angiogram determined the patency of the old coronary bypass vein graft(s) (SVG) (> or = 5 years remote from their last surgery, mean age: 8.5 +/- 1.8 years). Metallic, coiled stents were successfully deployed in 95/96 (99%) patients within 100/101 (99%) SVGs. The indications for deployment were threatened [81 patients (84%)] or acute [15 patients (16%)] vein graft closure following PTCA. Intragraft urokinase infusion was performed in 17 patients (17%) [6 patients with baseline occlusions; 11 with abrupt closure post PTCA]. Complications encountered included three (3%) in-hospital deaths (two procedure related) two (2%) Q wave myocardial infarctions, six (6%) non-Q wave myocardial infarctions, and 22 (22%) bleeding problems. These included, not mutually exclusively, 21 (22%) requiring transfusions, six (6%) cases of gastrointestinal bleeding, six (6%) pseudoaneurysms, five (5%) retroperitoneal haemorrhages and two (2%) cerebrovascular accidents. All patients received dipyridamole, aspirin, dextran, and anticoagulation (heparin 10-20,000 U intra-procedurally); a heparin infusion was continued for 5 +/- 1 days, despite warfarin administration which attained a therapeutic prothrombin time (PT) (1.5-2 times control) by 3 +/- 1 days. Out of the 95 successfully treated patients, six with eight stented grafts were ineligible for pre-discharge angiography. Of the six, three died in hospital (four SVGs), one had an intracerebral haemorrhage (one SVG), and two were asymptomatic patients with chronic renal failure (three SVGs).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7835360 TI - Cardiovascular neural regulation during and after prolonged high altitude exposure. AB - Eight young healthy male subjects, members of a Himalayan expedition, underwent 24 h Holter monitoring before departure, after 1 and 4 weeks at high altitude (5000 m) and after return to sea level. At high altitude, the circadian reciprocal changes in low and high frequency (LF, HF) were absent, with no significant reduction in the LF to HF ratio over the 24 h; moreover, the proportion of adjacent R-R intervals that differed by more than 50 ms (pNN50) decreased significantly and remained lower after return to sea level. Urine catecholamines increased at high altitude, but only norepinephrine, after 1 week of exposure, rose significantly. Upon return to sea level the density, but not the affinity, of [alpha]2-adrenergic receptors on platelets decreased significantly compared to pre-expedition values. At high altitude increased sympathetic activity was indicated by elevation of urine norepinephrine and by the loss of circadian rhythm in spectral components. The simultaneous reduction of HF and pNN50 demonstrated decreased vagal tone. The persistence of increased sympathetic activity could explain the downregulation of adrenergic receptors after prolonged high altitude exposure. PMID- 7835361 TI - Ultrastructural analysis of skeletal muscle. Microvascular dimensions and basement membrane thickness in chronic heart failure. AB - Chronic heart failure (CHF) is characterized by increased systemic vascular resistance and diminished blood flow to exercising skeletal muscle. The pathogenesis of the increased resistance is not known, and may be due to muscle atrophy, functional abnormalities of resistance vessels or to structural changes in the microcirculation such as endothelial cell swelling. We have compared the ultrastructure of the microvasculature in needle biopsies of the quadriceps muscle from seven control subjects with normal left ventricular function to 10 patients with moderate or severe heart failure, optimally treated and without evidence of fluid overload. Samples were processed for ultrathin sectioning using ruthenium red as a specific basement membrane (BM) stain. Electron micrographs were taken of 10 transversely cut capillaries from each specimen. The total cross sectional area of the vessels and the area of the endothelium was determined, and the short axis diameter was measured as an index of vessel diameter. The BM thickness was calculated from the mean of six readings around the periphery of the vessel. The short axis diameter in the two groups was not significantly different (controls 3.37 +/- 0.21 microns, CHF 3.56 +/- 0.37 microns, mean +/- 1SD). No difference in total cross-sectional area (controls 11.64 +/- 1.86 microns 2, CHF 13.56 +/- 2.78 microns 2) or area of the endothelium (controls 4.90 +/- 1.18 microns 2, CHF 6.00 +/- 1.58 microns 2) was observed. The thickness of the BM was marginally increased in subjects with CHF when compared to control subjects (0.31 +/- 0.077 microns vs 0.246 +/- 0.047 microns, P = 0.05).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7835362 TI - Effect of beta-blockade on baroreflex sensitivity and cardiovascular autonomic function tests in patients with coronary artery disease. AB - We wished to assess the effects of beta-blockade on baroreflex sensitivity and standard tests of integrity of autonomic nervous function in patients with coronary artery disease, and to determine whether the effects of lipophilic (metoprolol) and hydrophilic (atenolol) beta-blockers differ. Beta-blocking drugs increase spontaneous heart rate variability in healthy subjects and in patients with coronary heart disease, but little is known about their effects on baroreflex sensitivity and heart-rate based tests of autonomic integrity. In a randomly allocated double-blind crossover study with three 2-week treatment periods, metoprolol CR 200 mg once a day, or atenolol 100 mg once a day, or placebo once a day, were administered to 18 male patients with stable coronary artery disease. Baroreflex sensitivity was determined from the natural baroreflex challenge of Valsalva strain. Heart rate reactions to standard stimuli were measured. No significant differences were found between the effects of atenolol and metoprolol. Beta-blockade did not significantly affect the baroreflex sensitivity, but it diminished the Valsalva ratio significantly (P < 0.001). The difference between maximum and minimum heart rate during hyperventilation was also significantly lower during beta-blockade. The heart rate response to standing up and the ratio of maximum to minimum heart rate during deep breathing were not influenced by beta-blockade. Discontinuation of beta-blockade seems to be unnecessary for reliable determination of baroreflex sensitivity in patients with coronary artery disease, when the natural pressure challenge of Valsalva strain is sued. Both hydrophilic and lipophilic bet-blockers interfere with certain diagnostic tests of autonomic nervous function.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7835364 TI - The significance of anticardiolipin antibodies and anti-heart muscle antibodies for the diagnosis of postpericardiotomy syndrome. AB - Postpericardiotomy syndrome (PPS) is a frequent complication after cardiac surgery. In a recent study, elevated anticardiolipin antibody (ACLA) titres were observed in patients with PPS. The value of anti-heart muscle antibodies (AHA) for the diagnosis of PPS remains controversial. Therefore, a prospective double blind study was performed to test the sensitivity and specificity of ACLA and AHA for the diagnosis of PPS. ACLA titres (ELISA) and AHA, elevated by immunofluorescence, the clinical course and routine laboratory parameters were assessed in 57 patients before and after elective cardiac surgery. ACLA increased and AHA first appeared after surgery in patients both with and without PPS. The sensitivities of a > or = 1.5-fold increase in IgM-ACLA titres, of a > or = 2 fold increase in IgG-ACLA titres and of the occurrence of AHA > or = 2+ for the diagnosis of PPS were 60%, 20% and 20%. The respective specificities were 43%, 79% and 85%. Thus, after cardiac surgery, increased ACLA titres and the occurrence of AHA, as assessed by immunofluorescence, may only contribute to the diagnosis of PPS to a limited extent. PMID- 7835363 TI - Endothelium-dependent and endothelium-independent vasomotion in large coronary arteries and in the microcirculation after cardiac transplantation. AB - Endothelium-dependent and endothelium-independent vasodilation of the epicardial conduit vessels and the microcirculatory coronary vessels was investigated with cumulative doses of acetylcholine (ACh 50 micrograms and 100 micrograms i.c.), nitroglycerin (0.3 mg i.c.) and dipyridamole (0.56 mg.kg-1 i.v.) in 17 patients (3 female/14 male; age: 47 +/- 3.6 years) with angiographically normal coronary arteries 40 +/- 5.1 months after cardiac transplantation. The effect of ACh on large conduit arteries was evaluated angiographically. Coronary blood flow velocity changes were measured utilizing an 8F Judkins style 20 MHz Doppler catheter positioned in the left main coronary artery. A coronary flow index was calculated from the mean Doppler flow velocity and the computed cross-sectional vascular area. After 50 micrograms of ACh the diameter of proximal, middle and distal segments of the left anterior descending coronary artery decreased significantly by 7.6 +/- 2.06% (P < 0.05), 10.6 +/- 3.5% (P < 0.01) and 12.6 +/- 3.29% (P < 0.01) and after 100 micrograms ACh by 10.5 +/- 2.4% (P < 0.05), 13.0 +/- 3.7% (P < 0.01) and 15.3 +/- 3.9% (P < 0.01). The endothelium-independent vasodilator nitroglycerin (0.3 mg i.c.) induced an increase in vascular diameter of 14.4 +/- 3.1% (P < 0.01), 18.6 +/- 4.1% (P < 0.01) and 20.8 +/- 2.9% (P < 0.01) in proximal, mid and distal segments of the left anterior descending coronary artery.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7835365 TI - Observations of the relationship between left ventricular aneurysm and ST segment elevation in patients with a first acute anterior Q wave myocardial infarction. AB - Seventy-eight consecutive survivors of a first acute anterior Q wave myocardial infarction (AMI) underwent two-dimensional echocardiography (2D echo), colour Doppler echo and radionuclide angiography (RNA) for the diagnosis of left ventricular (LV) anteroapical aneurysm, in order to study the relationship of this complication to precordial ST segment elevation in these patients. The ST elevation (mm) in lead V2, the maximum ST elevation in V1-V6 and the sum of ST elevation in V1 to V6 were calculated. LV aneurysm was present in 19 patients by 2D echo, of whom 12 had a paradoxical systolic flow pattern (red and outward towards the transducer) at the apex. There was no difference between the mean ST elevation in V2 or the maximum ST elevation in V1-V6 in patients with and without an aneurysm, although the sum of ST elevations in V1 to V6 was higher in the former group (P < 0.01). ST elevation of patients with and without paradoxical systolic flow also did not differ significantly. Wall motion abnormality (akinesis and dyskinesis) by 2D echo in the anterior wall was seen in 74% of patients with and 36% of patients without an aneurysm (P < 0.005), and in the septal region in 63% and 47% of respective patients (P-NS). There was no difference between the magnitude of ST elevation in subgroups of patients with ejection fraction (EF) < or = 30% to > or = 40%, but the mean EF of patients with (23 +/- 2.1%) and without a LV aneurysm (34 +/- 1.3%) differed (P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7835366 TI - Vessel wall changes in the proximal non-treated segment after PTCA. An in vivo intracoronary ultrasound study. AB - Intimal disruption is known to induce prolonged intimal functional disturbance and is thought to be one of the mechanisms contributing to restenosis after PTCA. Although such damage can be induced by minimal trauma, the inevitable far greater disruption caused by passage of the PTCA apparatus through the stenosis does not appear to induce significant angiographically documented intimal proliferation. Pathological studies, however, have suggested that such a process might occur. Intravascular ultrasound allows in vivo study of vessel wall shape and constitution and is a far more sensitive detector of coronary atheroma than angiography. In this study we sought to determine the frequency of such functional disturbances and to assess their significance with respect to restenosis. The study group comprised 18 patients who underwent IVUS examination immediately after PTCA and at 6-months follow-up. They were analysed for luminal dimensions and vessel wall changes at the site of PTCA and at the level of the proximal non-treated segment. Seven patients (38%) had restenosed at follow-up IVUS examination; two patients had angiographically demonstrated luminal narrowing proximal to the PTCA site whereas seven had new intimal thickening in the proximal non-treated segment demonstrated by IVUS. Six patients had no intimal changes in either PTCA treated or untreated segments. Proximal intimal thickening was seen more frequently in those in whom increased intimal thickening at the PTCA site was noted. A trend (P < 0.1) was found towards an increased rate of new proximal vessel disease in those patients who had angiographically restenosed. IVUS demonstrates new intimal thickening in proximal non-treated segments in a considerable number of or patients undergoing PTCA.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7835367 TI - Baroreflex sensitivity in men with recent myocardial infarction; impact of age. AB - We investigated the effect of age on baroreflex sensitivity (BRS) in 39 male patients, who had survived their first myocardial infarction (MI) and in 15 age matched controls. BRS was inversely related to age in both MI patients (r = 0.632, P < 0.0001) and controls (r = -0.706, P < 0.0001). The relationship between BRS and age, however, was significantly different in MI patients as compared with healthy controls: BRS was markedly higher and the BRS-age regression slope was significantly steeper in controls than in MI patients. As a consequence, the decrease in BRS caused by MI (delta BRS = age-specific expected BRS--measured BRS) was related inversely to age (r = -0.66, P < 0.05) i.e. delta BRS was greatest among young MI patients. However, the relative BRS (BRS% = measured BRS divided by the age-specific expected BRS) did not correlate with age. The average BRS% of MI patients was 37% lower than that of controls. MI size and left ventricular (LV) systolic function did not correlate with BRS. BRS correlated with variables related to cardiac diastolic function (peak late LV filling rate r = -0.43, P < 0.05), exercise capacity (r = 0.31, P < 0.05) and the extent of ST-depression during exercise (r = -0.40, P < 0.05), but all these correlations lost their significance after the adjustment for age. In conclusion, age is a factor that should be taken into consideration when evaluating the mechanisms of BRS impairment associated with different diseases.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7835368 TI - Aorta and aortic valve morphologies predisposing to aortic dissection. An in vivo assessment with transoesophageal echocardiography. AB - Predisposing factors for aortic dissection are well known from necropsy series. To evaluate the frequency of aortic and aortic valve disease in aortic dissection in vivo, 139 patients with acute aortic dissection (96 men, 43 women, mean age 60.5 +/- 15.7 years) were studied by transoesophageal echocardiography (TEE) using 3.5 and 5.0 MHz transducers. Left ventricular hypertrophy by TEE, defined as an end-diastolic wall thickness of the left ventricular septal wall over 1.5 cm, was found in 42 (67.7%) of 62 patients with type I, in 10 (58.8%) of 17 patients with type II and in 46 (76.7%) of 60 patients with type III dissection. The mean value for the aortic root diameter was 3.2 +/- 1.3 cm.m-2 in type I dissection and 2.8 +/- 0.9 cm.m-2(ns) in type II dissection. In the patient group with type III dissection this diameter was significantly smaller (1.8 +/- 0.9 cm.m-2; P < 0.001). Thickening of aortic valve leaflets was demonstrated in six (9.7%) of 62 patients with aortic dissection type I (two of them with mild aortic stenosis), in two (11.8%) of 17 patients with aortic dissection type II and in 15 (25.0%) of 60 patients with aortic dissection type III. A bicuspid aortic valve was diagnosed in five (6.3%) of 79 patients with aortic dissection types I and II and in one (1.7%) of 60 patients with type III dissection. By colour coded Doppler echocardiography, aortic regurgitation was found in 46 (74.2%) of 62 patients with type I, 13 (76.5%) of 17 patients with type II and 23 (38.3%) of 60 patients with type III dissection.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7835369 TI - Insulin resistance in chronic heart failure. AB - The objective of this study was to investigate the existence of abnormalities of insulin sensitivity in patients with chronic heart failure. Glucose metabolism and insulin resistance were assessed in 10 male patients with severe, chronic heart failure and in 10 matched control subjects. Glucose, insulin and C-peptide concentration profiles were measured following a 0.5 g.kg-1 intravenous glucose tolerance test. Insulin sensitivity (inversely related to insulin resistance) was estimated by minimal modelling analysis of the glucose and insulin profiles. Heart failure patients had similar mean fasting plasma glucose concentration to controls but a significantly greater mean fasting plasma insulin concentration (P = 0.002) and C-peptide concentration (P = 0.02). Plasma glucose response profile was similar in the two groups but the incremental plasma insulin response profile of the heart failure group was significantly greater (P = 0.004). Mean insulin sensitivity was 73% lower in the heart failure patients (P = 0.003). These findings show that patients with severe chronic heart failure are hyperinsulinaemic and insulin resistant compared with a matched health group. This insulin resistance and hyperinsulinaemia may contribute to the progressive deterioration in myocardial function and associated clinical features of fatigue and reduced exercise tolerance seen in heart failure. Interventions designed to overcome or reduce insulin resistance warrant further investigation. PMID- 7835370 TI - Transthoracic echo/Doppler in the identification of patients with chronic non valvular atrial fibrillation at risk for thromboembolic events. AB - Left atrial spontaneous echo contrast, detected by transoesophageal echocardiography in patients with non-valvular atrial fibrillation reflects slow blood flow and is associated with an increased risk of cardio-embolism. The purpose of this study was to find echo/Doppler predictors of left atrial spontaneous echo contrast by transthoracic examination. In a retrospective case control study, 17 patients with chronic non-valvular atrial fibrillation who had suffered a recent cerebral ischaemic event (group A) and 17 patients with chronic non-valvular atrial fibrillation who had not suffered such an event (group B) were studied. Both groups were matched for age and sex. All patients underwent standard transthoracic echocardiography with transmitral Doppler as well as transoesophageal echocardiography. Left atrial spontaneous echo contrast was demonstrated by transoesophageal echocardiography in nine group A patients and in two group B patients (P = 0.028); left atrial spontaneous echo contrast was not detected by transthoracic echocardiography in these patients. All patients with left atrial spontaneous echo contrast (11 patients) had a left atrial size, corrected for base index, exceeding 24 mm and a transmitral time velocity integral < 10 cm (sensitivity 100%). Left atrial spontaneous echo contrast was absent in six patients with both characteristics (specificity 74%). CONCLUSION: transthoracic echo/Doppler aids in the prediction of the presence of left atrial spontaneous echo contrast and the identification of patients with non-valvular atrial fibrillation with increased cardioembolic risk, thus avoiding transoesophageal echocardiography. PMID- 7835371 TI - Patterns of neuroendocrine activation at rest and during exercise following acute myocardial infarction. AB - Previous studies of neurohumoral activation following myocardial infarction have concentrated on the within-hospital phase and have only made measurements at rest. The objectives of this study were to measure neuroendocrine activity in the early convalescent phase of myocardial infarction at rest and during symptom limited maximal exercise and to study the effects of early drug therapy. We studied 75 patients, mean age 57 (range 37-74) without evidence of overt heart failure, following Q-wave myocardial infarction. Patients were studied a mean of 17 days following myocardial infarction and compared with 11 age-matched control subjects. Plasma noradrenaline, adrenaline, atrial natriuretic peptide and plasma renin activity were measured at rest, at submaximal and symptom-limited maximal treadmill exercise. At the time of study 40 patients were taking beta-blockers, 19 diuretics and 16 no treatment. Atrial natriuretic peptide levels were higher at rest (P = 0.0001) and at symptom-limited exercise (P = 0.002) in the patient group than in the control subjects. Although there were no significant resting differences between the patient subgroups, at symptom-limited exercise plasma atrial natriuretic peptide levels were significantly higher in the patients taking beta-blockers than in the other patient groups (P = 0.001). Plasma renin activity was no different between the patients and the control subjects at rest or during exercise. Those patients taking diuretics had higher values at rest (P = 0.001) and during exercise (P = 0.005) compared with the remaining patients. There were no significant differences in resting or maximal exercise levels of plasma noradrenaline and adrenaline between the patients and the control subjects (all P > 0.1).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7835372 TI - Emergency room prediction of mortality and severe complications in patients with suspected acute myocardial infarction. AB - This study aims at describing the in-hospital prognosis of patients admitted with suspected acute myocardial infarction, focusing on the possibility of emergency room prediction of the risk for death and severe complications. From 7157 consecutive patients with chest pain or other symptoms suggestive of acute myocardial infarction in the emergency room, 4690 were hospitalized. Of these, 246 (5%) died in hospital, with a mortality rate among the 921 patients who developed myocardial infarction of 14%, and among those without infarction of 3%. From the clinical history, examination and electrocardiogram in the emergency room, independent predictors of death and death or any severe complication were determined by logistic regression analysis. These included age, initial degree of suspicion of infarction, electrocardiographic pattern, history of diabetes mellitus, history of congestive heart failure and on admission arrhythmias, loss of consciousness, acute congestive heart failure, or unspecific symptoms. From these analyses the probability of death or death or any severe complication can be calculated. Thus, 18% of patients hospitalized due to suspected acute myocardial infarction suffered a severe complication or died in hospital. From a statistical model it is possible to predict the in-hospital prognosis of every such patient. PMID- 7835373 TI - Cardiorespiratory and symptomatic variables during maximal and submaximal exercise in men with stable effort angina: a comparison of atenolol and celiprolol. AB - Celiprolol is a novel beta 1 selective adrenoreceptor blocker with partial beta 2 agonism and direct vasodilator activity. These ancillary properties may reduce symptomatic breathlessness and fatigue and modify respiration during exercise. To test this hypothesis 20 men with stable effort angina were enrolled in a double blind crossover study to investigate the effects of atenolol 100 mg once daily (A) and celiprolol 400 mg once daily (C) on cardiorespiratory and symptomatic variables during maximal and submaximal exercise. Total exercise time on a modified Bruce protocol was similar on both treatments: C12.5 min, A 13.1 min. During steady state submaximal exercise at 60-75% (mean 68%) of maximum work capacity, minute ventilation (C33.81 min-1, A 33.51 min-1), oxygen uptake (C14.6 ml.kg-1.min-1, A15.1 ml.kg-1.min-1), respiratory exchange ratio (C 0.89, A 0.87), ratio of VE/VCO2 (C 33.6, A 33.4), ratio of VE/VO2 (C 2.34, A 2.72), Borg perceived exertion score (C 11.2, A 10.9) and visual analogue scores for breathlessness (C 29.5, A 25.9) and muscle fatigue (C 28.9, A 26.0) were all similar on both treatments. At maximal exercise capacity on the modified Bruce protocol, minute ventilation (C 58.31 min-1, A 60.41 min-1), oxygen uptake (C 21.3 ml.kg-1.min-1, A 21.7 ml.kg-1.min-1), respiratory exchange ratio (C 1.02, A.1.05), ratio VE/VCO2 (C 34.8, A 35.9), and ratio VE/VO2 (C 2.80, A 2.83) were also similar on both drugs. Over a 10 day period anginal attacks (C 10.1 +/- 10.4, A 5.4 +/- 5.9) and sublingual GTN use (C 5.9 +/- 10.3, A 4.4 +/- 9.8) were both more frequent on celiprolol).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7835374 TI - Coronary heart disease risk factors in women. AB - Coronary heart disease is the leading cause of death among women. Reported risk factors for women are smoking, use of oral contraceptives, diabetes, elevated blood pressure, elevated blood lipids, low socio-economic status, low educational attainment, Type A behaviour and chronic troubling emotions. Via an on-line literature search (Medline and Psychlit) all case-control and prospective studies of coronary heart disease risk factors in women have been collected from 1978 to 1993. Smoking remains the most prominent risk factor for myocardial infarction in young women, the risk increasing significantly with the amount of cigarettes smoked. Use of modern low-dose oral contraceptives in healthy, non-smoking women does not increase the risk. Oestrogen replacement therapy seems to protect against coronary heart disease, although the reduction in risk may have been over estimated. Elevated cholesterol and elevated blood pressure are major risk factors, and diabetes seems to have a stronger impact on risk in women than in men. Low socio-economic class is a stronger risk factor for women than for men and the double loads of career and family seem to increase risk for women. PMID- 7835375 TI - Some observations on the mechanism of pressure related atrial fibrillation. AB - In order to investigate the effect of atrial pressure on the propensity of the atria to fibrillate and the mechanism of this association, the right atrial pressure was changed acutely by transfusion-bleeding in 12 anaesthetized open chest dogs. Under various atrial pressures the conduction time was measured between two pairs of hook electrodes positioned on the two atrial appendages respectively. The effective refractory period was measured by continuous pacing of the right atrium at a 250 ms cycle length at double threshold intensity and interpolating a progressively earlier stimulus after each eighth paced beat. The propensity of fibrillation was studied by rapid (450 min-1) pacing of the atria at double threshold intensity for 10 s at different atrial pressures. At a high (> or = 14 mmHg) atrial pressure the conduction time (45.7 +/- 14.2 ms) was significantly (P < 0.01) longer, the effective refractory period (157.9 +/- 15.2 ms) significantly (P < 0.01) longer and the atrial fibrillation (11/19 or 57.9%) significantly (chi 2 = 9.95, P < 0.001) more common than at a low (< or = 10 mmHg) pressure (35.2 +/- 11.6, 146.2 +/- 12.4, 3/24 or 12.5%, respectively). Analysis of variance showed that the probability of atrial fibrillation was significantly affected by the atrial pressure but not by either the conduction time or the effective refractory period. The findings suggest that an increase in right atrial pressure by acute volume overload prolongs the inter-atrial conduction time and right atrial refractoriness and increases the propensity of the atria to fibrillate by rapid atrial stimulation.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7835376 TI - Are dysplastic intramyocardial artery-like structures in hypertrophic cardiomyopathy really coronary vessels? PMID- 7835377 TI - The economic and social impact of migraine. AB - Migraine is an episodic disorder which is often disabling both during and between attacks. While pain intensity is the most important symptom to individual sufferers, headache-related disability is the major determinant of the economic impact of illness. Because migraine is underdiagnosed and under-treated, cost effective healthcare interventions could serve to reduce the burden of illness on individual sufferers and society. Measures which assess both pain intensity and disability might serve to capture the essential elements of migraine and provide the basis for effective healthcare interventions. PMID- 7835379 TI - The diagnosis and treatment of migraine: a clinician's view. AB - The introduction of the International Headache Society (IHS) diagnostic criteria has made migraine a 'positive' diagnosis, not one of exclusion. Studies in Canada have shown that many sufferers do not consult their physician about their migraine, and that the use of over-the-counter and prescription analgesics is common. Treatment should comprise a physician-patient partnership based on a correct and accepted diagnosis, in which both participate in a programme of education about the condition, identification and reduction of migraine triggers, and appropriate use of non-pharmacological, prophylactic and acute pharmacological treatments. The pathogenesis of chronic daily headache is uncertain, but it is frequently associated with habitual overuse of simple analgesics and ergotamines. PMID- 7835378 TI - A review of current treatments for migraine. AB - Acute drug therapy is the mainstay of treatment for migraine sufferers, with prophylaxis reserved for those with frequent or severe attacks. The majority of treatments have been in use for many years, although their value is often poorly documented due to a lack of well-controlled trials undertaken with defined diagnostic criteria and study end-points. Analgesics with anti-emetics, nonsteroidal anti-inflammatory drugs and ergot derivatives are used for acute treatment. Recently, the selective 5-HT1 receptor agonist sumatriptan has become available and been shown to have significant benefits over traditional therapies for the acute treatment of migraine. Beta-blockers, flunarizine and 5-HT2 antagonists have been used for prophylaxis, and although many patients report a reduction in attack frequency, breakthrough attacks still occur. PMID- 7835380 TI - The clinical profile of sumatriptan: efficacy in migraine. AB - The efficacy of the 5-HT1 receptor agonist sumatriptan in the acute treatment of migraine has been investigated in an extensive programme of controlled clinical trials. Sumatriptan provided rapid relief from migraine headache with onset of relief occurring within 10 min of a 6 mg subcutaneous injection and within 30 min of a 100 mg oral dose. Maximum benefit was observed by 2 h after the injection and 4 h after the oral dose. Sumatriptan also significantly decreased the incidence of associated migraine symptoms (nausea, photophobia, phonophobia) and the need for rescue medication. Sumatriptan was an effective treatment for migraine with and without aura and when used at any time during the attack. Oral sumatriptan 100 mg provided significantly greater pain relief and had a more rapid onset of action than two commonly used acute treatments for migraine. Efficacy is maintained in long-term use, with no evidence of tachyphylaxis or dependence. Sumatriptan, whether given subcutaneously or orally, is an effective long-term acute treatment for migraine. PMID- 7835381 TI - The clinical profile of sumatriptan: cluster headache. AB - Cluster headache is a rare form of severe idiopathic headache characterized by unilateral short-lasting episodes of excruciating pain in association with autonomic disturbances. Subcutaneous sumatriptan has been investigated as an acute treatment for cluster headache in two randomized, double-blind, placebo controlled, crossover trials. About 75% of patients given subcutaneous sumatriptan 6 mg reported headache relief within 15 min, in comparison with 26 35% given placebo (p < 0.001 in both studies). The need for rescue medication (100% oxygen by inhalation) at 15 min was significantly lower after sumatriptan treatment as were the severity of functional disability and incidence of non headache symptoms. Results of a long-term study indicate that the tolerability and efficacy of sumatriptan 6 mg is maintained in long-term use, and that there is no evidence of tachyphylaxis. PMID- 7835382 TI - The clinical profile of sumatriptan: safety and tolerability. AB - The safety and tolerability of sumatriptan have been extensively studied. The majority of adverse events (defined as any medical event irrespective of possible causal relationship to treatment) were mild to moderate in intensity, transient and resolved spontaneously. In short-term studies, the most frequently reported adverse events were nausea, vomiting, dizziness, vertigo, malaise, fatigue, injection-site reactions, heaviness, pressure, feelings of warmth and headache. The adverse event profile was unchanged during long-term open treatment and was unaffected by frequency of treatment with sumatriptan. In 3-5% of patients, the symptoms of pressure and warmth were experienced in the chest, but extensive investigations, including ECG monitoring, have indicated that these symptoms are not normally associated with cardiac dysfunction. PMID- 7835383 TI - The epidemiology of migraine. AB - To obtain accurate estimates of migraine prevalence, population-based studies are required. Clinic-based studies include a highly selected group of migraine sufferers. Even in population-based studies, there have been wide variations in estimates of migraine prevalence. A meta-analysis has shown that age, gender and case definition account for 70% of this variance. Recent studies using International Headache Society (IHS) diagnostic criteria have given relatively consistent estimates of migraine prevalence (about 15-18% of women and 6% of men) and indicate that migraine occurs most commonly in men and women aged 25-55 years. Migraine is a heterogeneous condition with a spectrum of severity and associated disability, and it is under-diagnosed worldwide. PMID- 7835384 TI - Important factors influencing the strength of autologous fibrin glue; the fibrin concentration and reaction time--comparison of strength with commercial fibrin glue. AB - Fibrin glue was prepared from citrated plasma of human donors by means of ethanol. The outcome was a fibrinogen concentrate with a mean concentration of 43 mg/ml. The fibrinogen was converted to fibrin by the addition of 0.3 part of thrombin solution, 150 NIH U/ml, containing 100 mM calcium chloride. In a rat model full-thickness skin grafts were sealed with the glue, and the adhesive strength was measured at different fibrin concentrations, and after a variable reaction time, and compared to commercial fibrin glue (Tisseel). The strength of ethanol-prepared glue was directly proportional to the fibrin concentration, and increased rapidly within the first minutes of the reaction time. The strength of the commercial glue could be obtained with autologous fibrin glue at the same fibrin concentration. PMID- 7835385 TI - Effect of atropine and truncal vagotomy on the exocrine pancreatic function in dogs stimulated with intraduodenal tryptophan. AB - The purpose of this experimental study was to analyze the effect of different doses of atropine and bilateral transthoracic truncal vagotomy on pancreatic secretion. We chose the dog as our experimental model and used the modified Thomas method to obtain gastric juice, removing the gastric acid with a gastric cannula. An additional duodenal cannula was used for the selective intubation of the greater pancreatic duct in order to obtain pure pancreatic juice. To stimulate pancreatic secretion the pancreas was stimulated with intravenous secretin at a constant dose and intraduodenal tryptophan at gradually increasing doses. The juice was collected at 10-min intervals and volume, output of bicarbonate and protein were determined. The results obtained show that low doses of atropine (0.65, 1.25 and 5 micrograms/kg/h) strengthen the suppressive effect of truncal vagotomy on the hydrobicarbonate secretion. Greatest suppression was found in the highest dosage of atropine in response to the intraduodenal tryptophane at gradually increasing doses. The above results suggest the possible existence of local enteropancreatic cholinergic reflexes that are readily suppressed by atropine and vagotomy. Suppression is not global though, since there is no significant reduction in the pancreatic protein secretion, which shows a dosage-effect curve in response to the gradually increasing doses of intraduodenal tryptophan released by the action of endogenous cholecystokinin. Our hypothesis is that there exists a nonvagal enteropancreatic cholinergic reflex. PMID- 7835386 TI - Influence of various fatty acids on tumour growth in total parenteral nutrition. AB - The aim of parenteral nutrition in tumour patients is to offer an alternative nutritional support to the patient without accelerating the growth of the tumour. For this purpose we fed a total of 100 rats, divided into five groups of 20 animals each (10 with and 10 without tumours), for a total period of 15 days with various nutritional regimes. Group 1 received glucose, group 2 long-chain triglycerides, group 3 medium-chain triglycerides (MCT), group 4 omega-3 fatty acids, and group 5 an oral diet. On the 10th day the Yoshida sarcoma in its ascites form was implanted into the tumour-bearing rats. In animals receiving MCT or omega-3 fatty acids tumour growth was considerably smaller than in the other groups (group 1 vs. groups 3 and 4; p < 0.05). Unfavourable effects of the administration of these fatty acids on the general condition of the animals were not observed [muscle nitrogen content (mg/kg body weight): MCT = 82.3, omega-3 fatty acids = 65.25]. The impulse cytophotometric measurements did not demonstrate any influence on the pattern of cell division (p > 0.05). We think that modulation of the immune system by feeding with MCT or omega-3 fatty acids was responsible for the reduced tumour growth in relation to the other groups. The extrapolation of these results to the clinical situation, however, may not be possible. PMID- 7835387 TI - Enlargement of the right ventricular outflow tract and the pulmonary artery with a new biodegradable patch in transannular position. AB - Absorbable, nonwoven patches made from polyhydroxybutyrate (PHB) were implanted as transannular patches into the right ventricular outflow tract and pulmonary artery in 13 weanling sheep, the test group. Six sheep, in which a transannular Dacron patch was implanted, served as control group. The test and the control patches were harvested 3-24 months later. The results were documented macroscopically, by histological examination, and by scanning electron microscopy. The 6-keto-PGF1 alpha activity was measured in the regenerated tissue and compared with that in the native pulmonary artery. No aneurysms were noted. Regeneration of a neointima and a neomedia, comparable to native arterial tissue, was observed in the test group. In the control group, a neointimal layer was present but no neomedia comparable to native arterial tissue. Scanning electron microscopy disclosed differences in the endothelial structure between the test and control groups. 6-keto-PGF1 alpha activity was present in both the test and control groups. It is concluded that absorbable, nonwoven patches of PHB can be used as a scaffold for tissue regeneration in low-pressure systems. The regenerated vessel had structural and biochemical qualities in common with the native pulmonary artery. PMID- 7835388 TI - Adenine nucleotide metabolism in relation to graft viability in rat small-bowel transplantation. AB - The relation between the level of cellular adenine nucleotides and graft viability after cold preservation and warm ischemia was studied by using a rat small-bowel transplantation model. The rat jejunum was preserved in lactated Ringer's solution at 4 degrees C for 120 min, and was then transplanted syngeneically under warm ischemia after between 60 and 180 min. The recovery levels of ATP and the energy charge at 30 min after reperfusion in the viable graft were significantly higher than those in the nonviable graft. None of the grafts were viable when the recovery level of ATP at 30 min after reperfusion was less than 2.8 mumol/g dry weight. These results suggest that the recovery level of ATP at 30 min after reperfusion is a reliable parameter for graft viability in small-bowel transplantation. PMID- 7835389 TI - Intraluminal bypass: a device for ruptured aortic aneurysm. AB - A novel device was constructed and used to bypass a ruptured aortic aneurysm internally in vitro. Three human aortas each containing an abdominal aneurysm were used for the production of transparent silicons rubber replicas. A pulsatile flow within the range of physiological parameters was employed. The aortic aneurysms were ruptured iatrogenically. After positioning the device in the aneurysm, complete control of fluid leakage through the ruptures was achieved. Normal flow through aortic abdominal branches and distal to the aneurysm was maintained. PMID- 7835390 TI - Purification and characterization of prolyl oligopeptidase from bovine lens. AB - Prolyl oligopeptidase (EC 3.4.21.26) has been purified 26,000-fold from bovine lens tissue by anion-exchange chromatography, gel filtration and isoelectric focussing, with an overall yield of 11%. The purified enzyme exhibited an isoelectric point of 4.8, a pH optimum of 7.5 and a molecular mass of 72 kDa under both native and denaturing conditions. The enzyme was inhibited by diisopropylfluorophosphate and N-ethylmaleimide, indicating the presence of an essential serine residue and an -SH group. The purified enzyme hydrolyzes the elastase substrate tboc-ala-ala-pNA an order of magnitude more rapidly than N-suc gly-pro-MCA. It also hydrolyzes other elastase substrates including N-suc-ala-ala ala-pNA, N-suc-ala-ala-pNA, N-suc-ala-ala-pro-ala-pNA and tboc-ala-ala-pro-ala pNA, but at a slower rate. While the purified preparation of the lens enzyme rapidly hydrolyses bradykinin, ile-ser-bradykinin, insulin B chain, angiotensin and val-his-leu-thr-pro-val-glu-lys at the carboxyl side of proline, it does not hydrolyse either lens crysallins or bovine serum albumin. The amino acid sequence (GMFYNAYPQQDG) of a tryptic peptide from the enzyme is identical to the porcine brain prolyl oligopeptidase sequence 184-195. A similar activity has been identified in human lenses using both tboc-ala-ala-pNA and N-suc-gly-pro-MCA as substrates. The molecular weight, substrate specificity, inhibitor susceptibility and amino acid sequence data suggest that the bovine lens prolyl oligopeptidase is similar to prolyl endopeptidase isolated from other sources. PMID- 7835391 TI - Colloid osmotic pressure of steer alpha- and beta-crystallins: possible functional roles for lens crystallin distribution and structural diversity. AB - This study addresses the general mechanisms whereby the major cytoplasmic proteins from the adult bovine lens contribute both to transparency and maintenance of the refractive index gradient across the lens. Colloid osmotic properties and quaternary structure were measured for alpha- and beta-crystallins isolated from the steer lens, including low-molecular-weight crystallins from the cortex (alpha Le and beta L) and nucleus (alpha Ln) and high-molecular-weight crystallins from the nucleus (alpha H and beta H). In electron microscopic images of rotary-shadowed preparations alpha Le appears as spherical particles 16 nm in diameter, alpha Ln appeared as individual spheres or small aggregates of spherical subunits, alpha H contained large irregular aggregates as large as 180 nm, and both beta L and beta H appeared as elliptical particles of 7-9 nm diameter. Secondary osmometry showed that for all these crystallins colloid osmotic pressure increased monotonically in a non-linear fashion with protein concentration. For the alpha-crystallins, osmotic pressure rose more steeply with concentration for alpha Le than for either alpha Ln or alpha H, so that at 0.3 g ml-1 at 0.1 M ionic strength, the colloid osmotic pressure of alpha Le, alpha Ln and alpha H were approximately 2.6 x 10(5) dyn cm-2, 1.6 x 10(5) dyn cm-2 and 1.0 x 10(5) dyn cm-2, respectively. In a similar manner, osmotic pressure rose more steeply with concentration of beta L than for beta H, so that at 0.3 g ml-1 at 0.1 M ionic strength the colloid osmotic pressures of beta L and beta H were 2.6 x 10(5) dyn cm-2 and 1.1 x 10(5) dyn cm-2, respectively. The osmotic pressure of alpha Le dropped as ionic strength was increased from 0.02 to 0.4 M. For beta L and beta H, osmotic pressure dropped as ionic strength was increased from 0.02 to 0.1 M but was nearly the same at 0.1 M and 0.4 M ionic strength. The data for steer alpha Ln and beta H were similar to previous reports for calf cortical alpha L and beta-crystallins, respectively. The osmotic pressure isotherms for alpha Le, beta L and that previously reported for steer cortical extract were nearly identical, whereas the nuclear crystallins (alpha Ln, alpha H or beta H) generated slightly higher pressures than those previously reported for steer nuclear crystallin extracts. In all cases, osmotic pressure rose more steeply with concentration for the cortical crystallins than for the nuclear crystallins.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7835392 TI - Immunohistochemical evidence for the presence of vasopressin in the rat harderian gland, retina and lacrimal gland. AB - The presence of vasopressin in the Harderian gland, the retina and the lacrimal gland of the rat, has been examined immunohistochemically. After fixation in Bouin's solution, immunostaining is accomplished with the peroxidase antiperoxidase method. In the retina, the immunoreactive vasopressin is almost exclusively restricted to the ganglion cell layer. In the Harderian gland, the immunoreactivity is localized in the epithelial cells of the excretory duct and restricted to the cytoplasm. In the lacrimal gland, the immunoreactivity is localized in the secretory cells of the acini and the intercalated ducts and the immunostaining is restricted to the cytoplasm surrounding the nucleus. The possible functions of vasopressin in these ocular structures are discussed. PMID- 7835393 TI - Isochromatics in eye lenses. PMID- 7835394 TI - A partial cDNA sequence corrects the human alpha A-crystallin primary structure. PMID- 7835395 TI - The presence of functional melatonin receptors in the iris-ciliary processes of the rabbit eye. AB - There is evidence in the literature to suggest that melatonin has a functional role in the iris-ciliary body (ICB). In this study we provide results which argue for the occurrence of melatonin receptors in this region of the eye. Autoradiography showed that specific binding of 125I-iodomelatonin is associated with the ICB although the resolution did not allow for discrimination of binding between the ciliary epithelium and the iris musculature. The binding of 125I iodomelatonin to ICB homogenates is saturable with a single population of binding sites and with KD and Bmax values of 428 pM and 170 fmol (g wet weight)-1, respectively. The order of potency of various substances to compete with the 125I iodomelatonin binding sites is chloromelatonin = melatonin > 6-OH-melatonin > N acetylserotonin > 5-methoxytryptamine > serotonin. Neither iodomelatonin nor serotonin affected basal levels of cAMP, but both decreased the forskolin elevated cAMP levels. However, the iodomelatonin effect, unlike that of serotonin, was not antagonised by propranolol. The combined data argue for the presence of melatonin receptors in the ICB of the rabbit. These receptors are negatively linked to the stimulation of cAMP and are distinguishable from serotonin receptors. PMID- 7835397 TI - Collagen type IV gene expression in human optic nerve heads with primary open angle glaucoma. AB - Previous studies have demonstrated proliferation of basement membranes in the optic nerve head in primary open angle glaucoma (POAG). We used in situ hybridization (ISH) of a radiolabeled riboprobe specific for human collagen IV, a ubiquitous component of basement membranes, to identify cells actively synthesizing basement membranes in the optic nerve head in POAG. In addition, to detect and further characterize the collagen IV mRNA transcripts, we used reverse transcriptase-polymerase chain reaction (RT-PCR) in total RNA extracted from individual optic nerve heads with POAG and from age-matched normal controls. ISH results demonstrate that, in POAG, numerous astrocytes in the prelaminar region expressed collagen IV mRNA. Lamina cribrosa cells and astrocytes in the compressed lamina cribrosa hybridized the probe. Few astrocytes and lamina cribrosa cells hybridized the probe in the optic nerve head of normal age-matched controls. RT-PCR products for collagen IV and for glyceraldehyde-3-dehydrogenase (G3PDH), a reference gene, were detected by agarose electrophoresis as single bands of the expected sizes and positively identified by Southern hybridization using specific cDNA probes in normal and POAG samples. No additional products (bands) were observed in RT-PCR experiments, indicating that there was no genomic DNA contamination in the total RNA extract. The lack of additional bands suggests that, at least in the ten samples used in this study, there were no alternatively spliced RNA products in any of the amplified sequences. Semi-quantitative analyses using densitometry showed a two-fold increase in collagen type IV PCR present in POAG samples. No differences were detected in levels of G3PDH PCR products between POAG and normal samples. This investigation provides evidence of increased biosynthesis of collagen type IV at the mRNA level in optic nerve heads with POAG. Whether this phenomenon represents a response to elevated intraocular pressure or a reparative mechanism to the loss of axons remains to be determined. PMID- 7835396 TI - Down-regulation of vasoactive intestinal peptide receptors by protein kinase C in fetal human non-pigmented ciliary epithelial cells. AB - Stimulation of cAMP formation in fetal human non-pigmented ciliary epithelial cells by 10 microM prostaglandin E1 was inhibited by 30-50% by 15 min prior exposure to 1 microM phorbol 12-myristate, 13-acetate. Evidence that this inhibition was due to activation of protein kinase C is the following. First, inhibition was also caused by 10 microM dioctanoylglycerol, a diacylglycerol analog. Second, no inhibition was observed using 4 alpha phorbol didecanoate, an ineffective activator of protein kinase C, whereas phorbol didecanoate was effective. And third, prior exposure of cells to staurosporine, an inhibitor of protein kinase C, blocked phorbol ester-induced inhibition of cAMP stimulation. Phorbol esters also inhibited stimulation of cAMP formation by 10 nM vasoactive intestinal peptide and by 1 microM isoproterenol. Stimulation of cAMP formation by either 1 microM cholera toxin or 10 microM forskolin was not inhibited by prior exposure of cells to phorbol esters. This suggests that protein kinase C acts neither at the level of GS activation of adenylyl cyclase, nor by inhibiting adenylyl cyclase directly. The possibility that protein kinase C acts on adenylyl cyclase-linked receptors was assessed by measuring the effect of phorbol esters on specific binding of [125I]vasoactive intestinal peptide to intact cells. Treatment of cells with either 1 microM phorbol 12-myristate,13-acetate or phorbol didecanoate resulted in a 25-40% reduction in the number of binding sites for [125I]vasoactive intestinal peptide, with little change in dissociation constants.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7835398 TI - DNA interstrand crosslinking agents and human ocular fibroblasts: differential sensitivity to mitomycin-C and cis-diaminedichloroplatinum(II). AB - Although clinical application of mitomycin-C (MMC) as an adjunct to glaucoma filtration and pterygium ablation surgeries is based on its inhibitory effect on the local fibroblast proliferation, the extent to which fibroblasts of Tenon's capsule and adjacent tissues (ocular fibroblasts) are susceptible to MMC still remains to be investigated. In this context, we substantially compared the sensitivity of ocular fibroblasts to MMC with normal fibroblasts of other tissue origins and with Fanconi's anemia (FA) fibroblasts known to be supersensitive to MMC due to presumable genetic susceptibility. Since MMC kills cells mainly by forming DNA interstrand crosslinks, cis-diaminedichloroplatinum (CDDP), another crosslinking agent, was also used to evaluate the cytotoxic effect of crosslinks on ocular and other fibroblasts. Following the treatment with various concentrations of MMC or CDDP for 1 hr, fibroblasts were incubated for 14 days until colonies developed. Based on the colony number reflecting the cell number which survived, the regression lines of survival rates were plotted in a semilogarithmic fashion. D0 and D10, doses which reduced survival rate to 37% and 10%, respectively, were interpolated and compared among the three cell groups. Ocular fibroblasts were about 2.5 times more sensitive than other normal fibroblasts, but 4-5 times more resistant than FA fibroblasts, to MCC, since the mean D0 of ocular, other normal, and FA fibroblasts was 0.063, 0.171 and 0.015 micrograms ml-1, respectively, and the mean D10 of these was 0.154, 0.401 and 0.029 micrograms ml-1, respectively. On the other hand, ocular fibroblasts exhibited an isosensitivity to CDDP compared with other normal fibroblasts. FA fibroblasts showed a supersensitivity to CDDP as well. DNA synthesis assay analysed by immunocytochemistry using bromodeoxyuridine (BrdU) and anti-BrdU antibody showed a similar hypersensitivity to MMC but a normosensitivity to CDDP of ocular fibroblasts. These results may indicate that intracellular activation of MMC to the reactive reduced form progresses more effectively in ocular fibroblasts than in fibroblasts originating in other tissues. The hypersensitivity to MMC of ocular fibroblasts is not attributed to genetic susceptibility because of the normosensitivity to CDDP. CDDP may be a promising agent as an alternative to MMC in the ophthalmic fields. PMID- 7835399 TI - Facilitated transport of lactate by rabbit corneal endothelium. AB - Proton coupled lactate transport across the rabbit corneal endothelium was studied using a pH-sensitive intracellular fluorescent probe. Functional indications that lactate transport is carrier-mediated and coupled to H+ at the apical endothelium (aqueous humor facing) that were found were: (1) proton influx was a saturable function of lactate concentration; (2) L-lactate produced a faster maximal H+ influx and had a higher affinity for the transporter (Vmax = 1.6 mM min-1, apparent K1/2 = 31 mM) than its optical isomer, D-Lactate (Vmax = 0.9 mM min-1, apparent K1/2 = 59 mM); (3) the lactate-induced acidification was inhibitable by apical mersalyl acid. These results are consistent with the presence of an apical lac-:H+ cotransporter. On basolateral addition of lactate to a de-epithelialized cornea, the endothelial cells transiently acidified by 0.05 units, but then alkalinized by 0.07, 0.02 units over baseline. The basolateral lactate-induced acidification was inhibited by 75% by mersalyl acid, while the net alkalinization observed under control conditions was unaffected. The alkalinization was Na(+)-dependent yet amiloride-insensitive. Alkalinization on addition of basolateral lactate could also be inhibited by apical mersalyl. These results suggest that the acidification represents lactate influx through basolateral Lac-:H+ cotransport while the net alkalinization is due to basolateral Na(+)-dependent lactate uptake and lactate efflux through apical Lac :H+ cotransport. These facilitated transport mechanisms could provide for the efficient removal of lactate from the highly glycolytic cornea. PMID- 7835400 TI - Osmoregulatory alterations in myo-inositol uptake by bovine lens epithelial cells. III. Effects of cycloheximide and colchicine on Na(+)-myo-inositol cotransporter activity under hypertonic conditions, inhibition of a plasma membrane osmotic stress protein. AB - Cultured bovine lens epithelial cells adapt to hypertonic sodium stress via an increase in Na(+)-myo-inositol cotransporter activity and accumulate myo inositol. At least 12 hr of hypertonic exposure was necessary to enhance myo inositol accumulation; and thereafter, uptake activity continued to increase throughout the duration of a 72-hr exposure period. Switching from hypertonic to isotonic medium for 24 hr reversed the otherwise elevated accumulation activity. The protein synthesis inhibitor, cycloheximide, did not affect myo-inositol uptake in isotonic medium but markedly decreased myo-inositol uptake in hypertonic medium. Cells exposed to hypertonic conditions and the microtubule disrupter, colchicine, similarly showed marked impairment of the otherwise enhanced myo-inositol uptake. These studies indicated that hypertonicity-induced elevation of Na(+)-myo-inositol cotransporter activity in cultured bovine lens epithelial cells is not solely attributed to the increased sodium gradient alone, but rather involves increased de novo synthesis of the Na(+)-myo-inositol cotransporter protein(s). PMID- 7835401 TI - Ageing of glutathione reductase in the lens. AB - The distribution of glutathione reductase activity in concentric layers from the lens has been determined as a function of age for 16 species. Primate lenses have almost ten times the level of glutathione reductase found in other species. Comparison with the activity of hexokinase revealed that this is not due to a higher overall rate of metabolism in these lenses. By contrast, the higher activity found in bird and fish lenses reflects a higher metabolic activity in these tissues. In all species, a gradient of activity was observed with the highest specific activity in the outermost cortical fibres, decreasing to virtually no activity in the inner parts of the tissue. No alterations were found in this gradient with increasing age, other than an increase in the amount of nuclear tissue essentially devoid of activity. The maximum activity in the outer cortical fibres was the same, regardless of the age of the lens. The time taken, in different species, for the specific activity to decrease by half, was estimated from the rate of protein accumulation. This time was found to vary from a few days to several years, indicating that the decrease in activity is not due to ageing but rather, it is related to the maturation of fibre cells. These observations are discussed in terms of current concepts of lens ageing and cataract formation. PMID- 7835402 TI - The incorporation and release of 12(S)-hydroxyeicosatetraenoic acid and its major metabolite, 8(S)-hydroxyhexadecatrienoic acid, from rabbit corneal lipids. AB - 12(S)-Hydroxyeicosatetraenoic acid (12(S)-HETE) is the predominant corneal lipoxygenase metabolite formed after injury. To investigate the metabolic fate of this eicosanoid in the tissue, [3H]12(S)-HETE was injected intracamerally into rabbits. Corneas were removed 1 to 18 hr after labeling. In some experiments, either entire corneas or the constituent tissues (epithelium, endothelium and stroma) were then incubated in oxygenated Ames' medium for different times. Eighteen hours after injection, the radioactivity was mainly incorporated into the membrane phospholipids, phosphatidyl choline (49%) and phosphatidyl ethanolamine (40%). Free 12(S)-HETE represented less than 1% of the total label. Analysis of the products after phospholipase A2 treatment indicated that the label was acylated in the sn-2 position. HPLC analysis of extracts from tissue and medium showed the presence of 12(S)-HETE and a more polar metabolite established as 8(S)-hydroxyhexadecatrienoic acid [8(S)-OH-16:3] by gas chromatography-mass-spectrometry. Within 1 hr of injection, 27% of the tissue label was recovered as 8(S)-OH-16:3 and at 8 hr the ratio of incorporated 8(S)-OH 16:3 to 12(S)-HETE was 2:1. 8(S)-OH-16:3 was released into the medium faster than 12(S)-HETE. Metabolism was highest on the epithelial corneal surface. The mitochondrial beta-oxidation inhibitor, 4-pentenoic acid, did not inhibit the formation of 8(S)-OH-16:3 which suggested a peroxisomal beta oxidation.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7835403 TI - Tight junctions of the human ciliary epithelium: regional morphology and implications on transepithelial resistance. AB - The tight junctions of the human ciliary epithelium have been studied using the freeze-fracture technique with particular regard to regional differences in the tight junction networks and implications on the transepithelial resistance. The tight junctions of the non-pigmented epithelium always form continuous networks and consist of from two to more than 20 superimposed strands (mean 3 to 4), suggesting that relatively tight and leaky sites of the paracellular pathway coexist within the same cell perimeter. The tight junction morphology is more complex in the anterior pars plicata than in the posterior pars plicata, but its complexity increases again towards the pars plana. The application of an electrical circuit analysis to morphometric freeze-fracture data suggests that the transepithelial resistance decreases from the anterior pars plicata (32 omega cm2) towards the posterior plicata (26 omega cm2) and becomes lowest in the pars plana (19 omega cm2) and that the transepithelial resistance of the native epithelium is lower than most reported calculations based on electrophysiological measurements. We conclude that human ciliary epithelium is a leaky layer, but that the anterior ciliary processes are less leaky than the posterior processes and the pars plana despite the occurrence of the breakdown of the blood-aqueous barrier predominantly in the anterior pars plicata. PMID- 7835404 TI - A group of novel glutathione S-transferase isozymes showing high activity towards 4-hydroxy-2-nonenal are present in bovine ocular tissues. AB - Recently, a mouse glutathione S-transferase (GST) isozyme, mGSTA4-4, which belongs to a distinct group of GSTs has been characterized in our laboratory. During the present studies, Western blot analyses of bovine ocular tissues using the antibodies raised against the recombinant mGSTA4-4 obtained by expression in Escherichia coli revealed that the orthologs of mGSTA4-4 were present in cornea, retina, iris-ciliary body and sclera, but absent in lens. These novel GST isozymes of bovine ocular tissues were purified by immunoaffinity chromatography using the antibodies against rec-mGSTA4-4 and were designated as bGST 5.8 (their pI value being 5.8). Amino acid sequences of CNBr fragments of bGST 5.8 from cornea, sclera, retina and iris-ciliary body showed high degree of primary structure homologies with the corresponding regions of mGSTA4-4 indicating these bovine GST isozymes were distinct from the alpha. mu and pi group GSTs and were the newest members of the group of GSTs to which mGSTA4-4 belongs. There were significant differences among the amino acid sequences of bGST 5.8 of cornea and iris-ciliary body and retina suggesting presence of at least two closely related genes at bGST 5.8 locus. bGST 5.8 isozymes showed high activity toward 4-HNE (four-to-five-fold higher than that towards 1-chloro-2,4-dinitrobenzene), expressed GSH-peroxidase activity towards fatty acid hydroperoxides and phospholipid hydroperoxides, and showed GSH-conjugating activity towards fatty acid epoxides suggesting that these isozymes may play an important role in protection mechanism against the endogenous toxicants formed during lipid peroxidation. PMID- 7835405 TI - Exchange of retinol between IRBP and CRBP. AB - During a bleach, all-trans-retinol passes from the photoreceptor outer segments to the retinal pigment epithelium (RPE), where retinol is found associated with cellular retinol-binding protein (CRBP). Interphotoreceptor retinoid-binding protein (IRBP) is thought to facilitate this exchange, but the transfer of retinol between IRBP and CRBP has not been explored. In this study we used a mixture of purified IRBP and CRBP as a model system to measure the amount and rate of retinol transfer between the two proteins. When retinol is transferred from IRBP to CRBP, its absorbance maximum shifts from 330 to 350 nm. By monitoring the increase in absorbance at 350 nm after mixing CRBP with IRBP-bound retinol, we measured the amount and time course of retinol transfer from IRBP to CRBP. To complement the absorbance measurements, the IRBP and CRBP in these mixtures were subsequently separated by size-exclusion HPLC and individually analysed for retinol content by scanning the effluent with a multiple-diode-array detector. As determined by measuring the change in absorbance at 350 nm, the mean percentage of IRBP-bound retinol transferred to CRBP was 103 +/- 11% (n = 9). The mean half-time of the transfer was 4.2 +/- 1.3 sec; time to reach equilibrium was 30-60 sec. IRBP that was separated from the mixture by HPLC contained little or no retinol, while the isolated CRBP was nearly saturated with retinol. No detectable transfer from CRBP to IRBP was observed. The distribution of retinol between these two proteins was consistent with the nearly 100-fold higher affinity of CRBP for retinol compared with IRBP. Both the degree and time-course of transfer support the idea that this difference in affinity contributes to the flow of retinol to the RPE during a bleach in vivo and, therefore, may play a role in the physiological regeneration of rhodopsin. PMID- 7835406 TI - Levels of expression of the genes for glutathione reductase, glutathione peroxidase, catalase and CuZn-superoxide dismutase in rat lens and liver. AB - Oxidative mechanisms are thought to play a major role in several biological phenomena, including cataract formation. In the following studies we determined the relative levels of expression of the genes for the mRNAs for glutathione peroxidase (GPx), glutathione reductase (GR), CuZn-superoxide dismutase (CuZn SOD) and catalase, in both the rat lens and liver. Northern blot hybridization methods were used to determine the mRNA size. The RNase protection method was used to determine levels of expression for these mRNAs plus levels of expression for alpha A-crystallin and gamma-crystallin mRNAs in the lens, and gamma-actin mRNAs in both the lens and the liver; using [32P]-labeled specific cRNA probes transcribed from the various cDNA clones for the mRNAs being studied. The data was normalized relative to the level of expression of alpha A-crystallin and gamma-actin mRNAs in the lens, and to gamma-actin mRNA in the liver. We find the levels of the mRNAs in the lens fall in the following descending order: GPx > GR > CuZn-SOD > catalase, in the same order as has been reported for the activities of the enzymes in the lens. In the liver, levels of these mRNAs were as follows: GPx > CuZn-SOD > GR > catalase. In the liver, CuZn-SOD mRNA was expressed at about four times the level found in the lens, GPx at three times, catalase at three times and GR at about the same level.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7835407 TI - The redox active components H2O2 and N-acetyl-L-cysteine regulate expression of c jun and c-fos in lens systems. AB - Hydrogen peroxide (H2O2) is implicated in human cataract development. At the molecular level H2O2 has been observed to cause damage to DNA, protein and lipid. It is now demonstrated, for the first time in a lens system, that H2O2 at concentrations found in cataract patients induces expression of both c-jun and c fos. At optimal concentrations of H2O2, mRNA accumulation of c-jun and c-fos in the rat lenses is induced 20- and 18-fold above normal levels respectively, but with distinct kinetics. This induction occurs at the transcriptional level. H2O2 also induces transactivation by activating protein-1 (AP-1) in rabbit lens epithelial cells. The antioxidant N-acetyl-cysteine (NAC) has a dual effect on the induction of c-jun and c-fos. Preincubation of rat lenses with 5 mM NAC inhibits the induction by H2O2, while 30 mM and 50 mM NAC induce expression of these genes and mask the H2O2 effect. H7 (50 microM), genistein (2 microM) and okadaic acid (20 nM), all block the induction of c-jun and c-fos mRNA accumulation in the H2O2-treated rat lenses. These results suggest that H2O2 activates protein kinase and phosphatase dependent signal transduction pathways to induce c-jun and c-fos expression which may regulate lens crystallin genes and other genes containing AP-1 binding sites. PMID- 7835409 TI - Persistent increases in scotopic B-wave amplitudes after lead exposure in monkeys. AB - The electroretinogram (ERG) of rhesus monkeys was re-examined more than 2 years after termination of lead exposure when mean blood lead levels had declined to values below 10 micrograms dl-1. Amplitude of the b-wave was increased by lead exposure at scotopic conditions, while there were no changes in photopic signals. The lead-induced effects were similar to alterations detected during the treatment phase and, thus, are not dependent on current exposure. Taking into account, that dopamine antagonists cause similar changes in the ERG, it is suggested that the observed effects may be mediated by a permanent change of dopaminergic processes since immunoreactivity also revealed adverse effects on the dopaminergic system in the retinae of these monkeys. PMID- 7835408 TI - Agonist-induced rise in intracellular calcium of lens epithelial cells: effects on the actin cytoskeleton. AB - Primary cultures of rabbit and skate lens epithelia were used to investigate the effect of calcium release from intracellular stores upon the actin cytoskeleton. Primary cultures were loaded with fura-2 AM and intracellular calcium, i.e. (Ca2+)i, quantitated using a Hamamatsu Photonics digital imaging system. Agonists used were bombesin, inositol-1,4,5-trisphosphate (IP3), thapsigargin (Tg), neuropeptide Y (NPY) and calcium chloride. Recordings were typically made on seven cells in each case. We found that IP3 caused a 6-8-fold immediate release of (Ca2+)i in rabbit cells, but skate cells showed no response unless permeabilized with saponin, whereupon an increase of about 50% occurred. Tg induced release from internal stores in rabbit cells, but had no effect on skate cells. Bombesin caused a large increase in (Ca2+)i release in both, while NPY had no effect in either. Skate cells incubated in calcium-free EGTA-Ringer's solution responded rapidly to addition of 5 mM CaCl2, whereas only three of 35 rabbit cells responded, and in gradual fashion. After calcium imaging, the cells were fixed and stained with rhodamine phalloidin or with an antibody against IP3 receptor (IP3R) conjugated to FITC. Fluorescence microscopy revealed that the actin cytoskeleton had reorganized from the normal stress fiber pattern into polygonal networks. Tg caused the same structures to form in rabbit cells, but bombesin had no effect. IP3 receptor was located intracellularly, presumably on endoplasmic reticulum, and was not associated with plasma membranes. The rapid response of rabbit cells may have been caused by the DMSO in which fura-2 was dissolved. We have found an interesting difference in agonist-induced calcium release between rabbit and skate cells. The latter may utilize either a Ca-Na exchanger or capacitative calcium entry, which could reflect a difference in lens accommodative mechanisms. This seems relevant in view of the fact that the rabbit lens accommodates through change in shape, whereas the skate lens does so through translation of position. PMID- 7835410 TI - A 1H NMR spectroscopic comparison of gamma S- and gamma B-crystallins. AB - Two-dimensional 1H NMR spectroscopic studies are presented on bovine gamma S- and gamma B-crystallin. In gamma S-crystallin, the four N-terminal residues have great flexibility compared with the rest of the molecule and assume a random coil conformation. NMR spectroscopy and electrospray mass spectrometry show that the N terminal residue is acetylated. Thus, gamma S-crystallin is similar to the acidic beta-crystallins in having a flexible N-terminal extension and an N-terminus that is blocked with an acetyl group but no C-terminal extension. In addition to the short N-terminal extension in gamma S-crystallin, other unassigned resonances are also observed in the NMR spectra. In gamma B-crystallin, however, cross-peaks in the NH to alpha-CH region of the spectrum are essentially restricted to the last three residues of the C-terminal domain. The NMR data imply that gamma S crystallin has a more flexible structure than gamma B-crystallin. Sedimentation equilibrium studies on gamma S-crystallin are consistent with this proposal. Resonances from the N-terminal extension of gamma S-crystallin are not affected by the presence of alpha-crystallin implying that this region is not involved in interactions between the two molecules. It is concluded that gamma S-crystallin shares structural properties which are intermediate between the beta- and gamma crystallins. PMID- 7835412 TI - A possible chaperone-like quaternary structure for alpha-crystallin. PMID- 7835411 TI - Synthesis of insulin and its effects in Y79 human retinoblastoma cells. AB - This paper demonstrates that Y79 human retinoblastoma cells contain immunoreactive insulin (IRI) and release it in the medium. Cells cultured either in suspension or in monolayer showed a similar content of IRI. Moreover, in both conditions, IRI concentration was higher in cells cultured in serum-supplemented medium rather than in serum-free medium. Retinoblastoma cells are capable of synthesizing insulin. This was demonstrated by incubating Y79 cells with [3H]leucine. The synthesized radioactive insulin was separated and assayed by means of a HPLC procedure described in this paper. Both cell growth and [3H]thymidine and [3H]uridine incorporation into acid-insoluble fraction was reduced (-75%) in Y79 cells cultured without serum with respect to those cultured in the presence of serum. The addition of insulin to the serum-free medium stimulated both cell division and DNA and RNA labeling, with values approaching those obtained with serum supplemented cultures. Insulin-like growth factor I exerted similar effects, but at a much lower concentration than insulin. We suggest that both insulin and IGF-I may represent mitogenic signals for these cells which might be mediated through insulin-like growth factor I receptors. PMID- 7835413 TI - Sequence of rho small GTP-binding protein cDNAs from human retina and identification of novel 5' end cloning artifacts. PMID- 7835414 TI - Release of alpha-A sequence 158-173 correlates with a decrease in the molecular chaperone properties of native alpha-crystallin. PMID- 7835415 TI - Effect of 'hypoxia' on the proliferation of microvascular cells in vitro. PMID- 7835416 TI - Formate binding to ferric wild type and mutant myoglobins thermodynamic and X-ray crystallographic study. AB - The X-ray crystal structure of the formate derivative of ferric loggerhead sea turtle (Caretta caretta) Mb has been determined at 2.0 A resolution (R = 0.164) by difference Fourier techniques. Formate, sitting in the central part of the heme distal site, is coordinated to the heme iron as unidentate ligand, through the O1 oxygen atom, and is hydrogen bonded to the distal His64(E7) NE2 atom through O2. Thermodynamics for formate binding to ferric loggerhead sea turtle Mb, sperm whale Mb, Aplysia limacina Mb, as well as to the VR and VRS mutants of sperm whale Mb were obtained between pH 4.5 and 8.5, at 20.0 degrees C. These results, representing the first structure of a ferric hemoprotein:formate complex solved by X-ray crystallography, outline the role of amino acid residues at positions E7, F8 and E10 in modulating ligand binding properties of oxygen carrying proteins. PMID- 7835417 TI - Calcium-dependent translocation of sorcin to membranes: functional relevance in contractile tissue. AB - Sorcin, a 22 kDa calcium binding protein present in abundance in cardiac tissue and in multi-drug resistant cells and previously described as a soluble protein, is now shown to undergo a calcium-dependent translocation process from the cytosol to cellular membranes in both systems. The translocation process takes place also in E. coli BL21 cells that express recombinant sorcin, r-sorcin, and can be exploited in the purification of the protein. Calcium binding to purified r-sorcin occurs at micromolar concentrations of the metal and is accompanied by a conformational change that renders the protein soluble in the non-ionic detergent Triton X-114. This finding suggests that lipids are the target of sorcin on cellular membranes. The possible significance of the calcium-dependent translocation of sorcin in the specialized functions of sorcin-expressing cells is discussed. PMID- 7835418 TI - Structure of microcin C51, a new antibiotic with a broad spectrum of activity. AB - The structure of microcin C51, a new antibiotic produced by E. coli, has been determined. This antibiotic was shown to be a 1.18 kDa nucleotide peptide. It consists of a heptapeptide with formylmethionine as the N-terminus and a C terminal asparagine linked with nebularin-5'-monophosphate through the three methylene bridge. The OH-group of threonine is substituted. The peptide chain of microcin C51 synthesized on ribosomes is the longest among the known biologically active nucleotide peptides. PMID- 7835419 TI - Dynamic hole burning within special pair absorption band of Rhodobacter sphaeroides (R-26) reaction center at room temperature. AB - The absorbance spectrum of reaction centers of Rhodobacter sphaeroides at room temperature consists of relatively narrow spectral components which are moving in the femtosecond time scale and can be bleached by femtosecond laser pulses in the short wavelength region with a subsequent broadening and red shift of the bleaching (time constant approximately 250 fs). These data are discussed in terms of the population of the vibronic wave packets in the ground state by the interaction with phonons at 293K. The motion of these packets is probably responsible for the absorbance spectrum of the primary electron donor P at 293K with enhanced short wavelength components and with suppressed Stokes components. PMID- 7835420 TI - A pre-existing protease is a common effector of thymocyte apoptosis mediated by diverse stimuli. AB - Data from a number of model systems support a role for proteolysis in apoptotic cell death. Using immature rat thymocytes, we demonstrate that the inhibitors N tosyl-L-lysyl chloromethylketone (TLCK) and N-tosyl-L-phenylalanyl chloromethylketone (TPCK) have very different effects on apoptosis. TLCK inhibits apoptosis induced by diverse stimuli at an early stage prior to both DNA fragmentation and cytoplasmic changes. We show that the TLCK-sensitive target is pre-existing and not synthesized in response to apoptotic stimuli. The contrasting effects of TLCK and TPCK support the hypothesis that the TLCK target is a trypsin-like protease which is a common effector of thymocyte apoptosis. PMID- 7835421 TI - Angiography contrast agents interact with serine proteinases. The molecular structure of the model system elastase/iohexol. AB - Pancreatic elastase was co-crystallised with iohexol, a tri-iodo benzenic contrast agent used in angiography analyses. The X-ray analysis of the complex reveals the presence of three molecules of iohexol associated with the proteinase with low occupancy factors. Two iohexol molecules are located in and near the active site of the enzyme and provide a model for explaining the inhibition of the hemostatic system, one of the major and inconvenient side effect associated with these chemicals. PMID- 7835422 TI - Epidermal growth factor induces serine phosphorylation of actin. AB - Stimulation of cells by epidermal growth factor induces a rapid polymerisation of actin in the cortical skeleton. Activation of the EGF-receptor leads to autophosphorylation and to phosphorylation of specific intracellular substrates. Here we show that actin is phosphorylated in vitro and in vivo upon EGF stimulation. Two-dimensional phospho-amino acid analysis shows that phosphorylation occurs on serine, not on tyrosine residues. PMID- 7835423 TI - Cloning and expression of human neutrophil lipocalin cDNA derived from bone marrow and ovarian cancer cells. AB - Human neutrophil lipocalin (HNL) cDNA was amplified by PCR technology in combination with deoxyinosine containing oligonucleotides for cloning, sequencing and production of the recombinant protein in E. coli. The primers were targeted to the corresponding DNA backtranslate of the mature protein resulting in a PCR amplified 534 bp cDNA from different reverse transcripts of ovarian cancer cell line and bone marrow cell mRNAs. Sequence analysis revealed that two different cDNAs from ovarian cancer and bone marrow cells could be obtained. Cloning and expression of HNL cDNAs were performed in E. coli strain HMS 174 [DE3] using the pET system yielding in two recombinant proteins with a molecular weight of 21 kDa which is consistent with an 178 amino acid residues containing sequence of the mature HNL protein. N-terminal amino acid sequence analysis of the expression products showed an identical polypeptide sequence missing the E. coli processed starting methionine. PMID- 7835424 TI - Existence of a new protein component with the same function as the LukF component of leukocidin or gamma-hemolysin and its gene in Staphylococcus aureus P83. AB - Staphylococcal toxins, leukocidin and gamma-hemolysin, consist of two protein components, i.e. LukF and LukS for leukocodin and H gamma I and H gamma II for gamma-hemolysin. From a culture fluid of Staphylococcus aureus strain P83, a new protein component of leukocidin or gamma-hemolysin which was designated as LukM was isolated. This component showed the same biological activity as that of LukF component for leukocidin or H gamma I component of gamma-hemolysin in combination with LukS or H gamma II. However, the LukM component cross-reacted with the anti LukS antibodies but not with the anti-LukF antibodies. On the basis of chemical analysis of the LukM component and the cloning and nucleotide sequencing of the lukM gene of S. aureus P83, we have demonstrated that LukM is an entirely new protein component of leukocidin or gamma-hemolysin. The deduced amino acid sequence of LukM from the lukM gene showed 66.7% and 67% identity to that of LukS and H gamma II, respectively. However, the amino acid sequence of LukM and LukF showed only 29% homology. PMID- 7835426 TI - Cleavage of recombinant and cell derived human immunodeficiency virus 1 (HIV-1) Nef protein by HIV-1 protease. AB - Recombinant purified Nef protein of HIV-1, as well as Nef protein derived from extracts of permanently HIV-1 infected glioblastoma cells and monocytes, are specifically cleaved by the HIV-1 protease. Nef cleavage products in cellular extracts treated with protease showed identical molecular weights as those obtained by digestion of purified Nef with recombinant HIV-1 protease. Since cellular extracts were prepared by detergent and mechanical lysis it cannot be excluded that physiological cytoplasmic conditions were altered. The lack of Nef cleavage by endogenous HIV-1 protease in infected cells might be due to low concentrations of viral protease and the presence of Gag precursor molecules as natural substrate. Using a panel of monoclonal antibodies two cleavage fragments of 19 kDa and 8 kDa were defined. The cleavage site was located by microsequencing between amino acid 57 and 58 (AW*LEAQEEEEVGF). The conserved cleavage motif within HIV-1 Nef suggests a potential biological function of Nef processing. PMID- 7835425 TI - Characterization of a null mutation in ace-1, the gene encoding class A acetylcholinesterase in the nematode Caenorhabditis elegans. AB - Two genes (ace-1 and ace-2) encode two major classes (A and B) of acetylcholinesterase (AChE) in the nematode Caenorhabditis elegans. A null mutation in ace-1 (allele p1000) suppresses all acetylcholinesterase activity of class A. We have identified an opal mutation TGG (W99)-->TGA (Stop) as the only alteration in the mutated gene. This leads to a truncated protein (98 instead of 620 amino acids) with no enzymatic activity. The mutation also reduces the level of ace-1 transcripts to only 10% of that in wild-type animals. This most likely results from a destabilization of mRNA containing the nonsense message. In contrast, compensation of class B by class A AChE in the null mutant strain ace-2 takes place with unchanged ace-1 mRNA level and enzymatic activity similar to class A AChE. PMID- 7835427 TI - Ha-Ras stimulates uptake and phosphorylation of ethanolamine: inhibition by wortmannin. AB - Transformation of NIH 3T3 fibroblasts by Ha-Ras resulted in large increases in the phosphorylation of both [14C]ethanolamine (Etn) and [14C]choline (Cho) when these precursors were added to the medium. Wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI3K), preferentially decreased phosphorylation of externally added Etn in the Ha-Ras transformed, but not in the untransformed, fibroblasts. However, wortmannin had no effect on the phosphorylation of Etn formed endogenously by phorbol ester-stimulated hydrolysis of phosphatidylethanolamine. Data suggest that interaction of mutated Ras with PI3K leads to specific stimulation of Etn uptake, followed by nearly quantitative phosphorylation of Etn by a Ras-activated Cho/Etn kinase. PMID- 7835428 TI - The NssBF element, a sequence of the Drosophila melanogaster retrotransposon 1731 potentially implicated in transcriptional repression and replication. AB - The nuclear single-stranded DNA binding factor (NssBF) has been characterized as a nuclear protein that binds to a 26 nucleotides sequence in the long terminal repeat (LTR) of the Drosophila melanogaster 1731 retrotransposon. This sequence, called NssBF element, was analysed by gel retardation experiments using wild-type and mutated oligonucleotides. In vitro transcription experiments were performed and suggest that NssBF element binding protein(s) represses transcription through the 1731 promoter. Furthermore, computer assisted sequence comparisons put forward a possible role of this element and/or its associated DNA binding proteins in replication. PMID- 7835429 TI - Protein synthesis in collagen lattice-cultured fibroblasts is controlled at the ribosomal level. AB - Fibroblasts cultivated in three-dimensional lattices exhibit a large decrease of protein synthesis, mainly through transcriptional control. However, no previous work was devoted to a potential ribosomal regulation. We evaluated ribosomal ribonucleic acid (RNA) in monolayer- and collagen lattice-cultured fibroblasts. After one week of culture, total RNA was 60% lower in lattice-cultured fibroblasts than in monolayer-cultured cells. The decrease was identical for 18 S and 28 S rRNA subfractions. The half-life of RNA was much shorter in collagen lattice-cultured fibroblasts than in monolayers. These results suggest that protein synthesis in lattice-cultured fibroblasts is partly regulated at the ribosomal level. PMID- 7835430 TI - Regulation of the MAP kinase cascade in PC12 cells: B-Raf activates MEK-1 (MAP kinase or ERK kinase) and is inhibited by cAMP. AB - In PC12 cells, cAMP stimulates the MAP kinase pathway by an unknown mechanism. Firstly, we examined the role of calcium ion mobilization and of protein kinase C in cAMP-stimulated MAP kinase activation. We show that cAMP stimulates p44mapk independently of these events. Secondly, we studied the role of B-Raf in this process. We observed that NGF, PMA and cAMP induce the phosphorylation of B-Raf as well as an upward shift in its electrophoretic mobility. We show that B-Raf is activated following NGF and PMA treatment of PC12 cells, and that it can phosphorylate and activate MEK-1. However, cAMP inhibits B-Raf autokinase activity as well as its ability to phosphorylate and activate MEK-1. This inhibition is likely to be due to a direct effect since we found that PKA phosphorylates B-Raf in vitro. Further, we show that B-Raf binds to p21ras, but more important, this binding to p21ras is virtually abolished with B-Raf from PC12 cells treated with CPT-cAMP. Hence, these data indicate that the PKA mediated phosphorylation of B-Raf hampers its interaction with p21ras, which is responsible for the PKA-mediated decrease in B-Raf activity. Finally, our work suggests that in PC12 cells, cAMP stimulates MAP kinase through the activation of an unidentified MEK kinase and/or the inhibition of a MEK phosphatase. PMID- 7835431 TI - The N- and C-termini of the tricarboxylate carrier are exposed to the cytoplasmic side of the inner mitochondrial membrane. AB - Polyclonal antibodies were raised in rabbits against two synthetic peptides corresponding to the N- and C-terminal regions of the rat-liver mitochondrial tricarboxylate carrier. ELISA tests performed with intact and permeabilized rat liver mitoplasts showed that both anti-N-terminal and anti-C-terminal antibodies bind only to the cytoplasmic surface of the inner membrane, indicating that both termini of the membrane-bound tricarboxylate carrier are exposed to the mitochondrial intermembrane space. Furthermore, tryptic digestion of intact mitoplasts markedly decreased the binding of anti-N-terminal and anti-C-terminal antibodies to the tricarboxylate carrier. These results are consistent with an arrangement of the tricarboxylate carrier monomer into an even number of transmembrane segments, with the N- and C-termini protruding toward the cytosol. PMID- 7835432 TI - Quarternary structure amplification of protein folding differences observed in 'native' platelet factor-4. AB - Platelet factor 4 (PF4), a protein of 70 residues, exists in solution as a distribution of monomer, dimer and tetramer (M-D-T) states in slow exchange on a 600 MHz 1H-NMR chemical shift time scale. Well-resolved Y60 ring proton resonances in each aggregate state allow derivation of M-D-T populations. Under the same set of solution conditions, M-D-T aggregate state distributions vary from prep to prep or with repeated freeze-drying or raising/lowering the solution pH. These variations are not the result of chemical modifications and reflect differences in the strength of subunit associations and therefore folding. Variations are greatest at pH values at or below the pKas of carboxylate groups, supporting the idea that electrostatic interactions modulate PF4 subunit interactions. Treating these distributions as true equilibria results in free energy differences of about 0.5 kcal/mol subunit. Quarternary structure amplifies free energy differences among various folded states of monomer PF4. PMID- 7835433 TI - Two resident ER-proteins, CaBP1 and CaBP2, with thioredoxin domains, are substrates for thioredoxin reductase: comparison with protein disulfide isomerase. AB - Protein disulfide-isomerase (PDI) is the best known representative of a growing family of enzymes with thioredoxin domains. Two such proteins with thioredoxin (Trx) domains, CaBP1 and CaBP2 (ERp72), have previously been isolated from rat liver microsomes. Here we report that they, like PDI are substrates for thioredoxin reductase and will catalyze NADPH-dependent insulin disulfide reduction. The activity of CaBP1 and CaBP2 in this assay was higher than that of PDI but lower than that of E. coli Trx. Furthermore, as isolated the thioredoxin domains of CaBP1 and CaBP2 were in disulfide form as judged by stoichiometric oxidation of 2 and 3 mol of NADPH in CaBP1 and CaBP2, respectively. The redox potential of the active site disulfide/dithiol was estimated from the equilibrium with a mutant E. coli Trx, P34H Trx, with a known redox potential (-235 mV). This showed that CaBP1 and CaBP2, like PDI, have a much higher redox potential than wild type thioredoxin (-270 mV) in agreement with a role in formation of protein disulfide bonds. In conclusion, in vitro CaBP1 and CaBP2 share catalytic properties in thiol disulfide-interchange reactions with PDI. Thus, the well known activity of PDI is not unique in the endoplasmic reticulum and CaBP1 and CaBP2 may be regarded as functional equivalents. PMID- 7835434 TI - Interaction of cysteine proteinases with recombinant kininogen domain 2, expressed in Escherichia coli. AB - The calpain-binding domain 2 of the kininogens, the major plasma inhibitors of cysteine proteinases, was expressed in Escherichia coli. Expression of soluble protein was optimal at 15 degrees C and was augmented by growing the bacteria in sorbitol and betaine. The recombinant domain showed high affinity (Ki 0.3-1 nM) for cathepsin L and papain, and a somewhat lower affinity (Ki approximately 15 nM) for calpain. The binding to cathepsin H was substantially weaker, and no inhibition of actinidin and cathepsin B was detected. The affinity for cathepsin L was comparable to that reported for the domain isolated from plasma L kininogen, whereas the affinities for papain and calpain were about tenfold lower. The latter difference may be due to the recombinant domain being nonglycosylated. PMID- 7835435 TI - Kinetic studies on the formation of acridine-linked DNA triple helices. AB - We have used DNase I footprinting to measure the rate of intermolecular triple helix formation at the target sites A6G6.C6T6 and G6A6.T6C6 with the acridine linked oligonucleotides Acr-T5C5 and Acr-C5T5, respectively. Under pseudo first order reaction conditions we find that the reactions are slow, with half-lives of several minutes. The rates are dependent on the concentration of the third strand oligonucleotide and yield bimolecular association rate constants of 300 M-1.s-1 for Acr-T5C5 binding to A6G6.C6T6 and 2000 M-1.s-1 for the interaction of Acr C5T5 with G6A6.T6C6. PMID- 7835436 TI - Secondary structure in solution of two anti-HIV-1 hammerhead ribozymes as investigated by two-dimensional 1H 500 MHz NMR spectroscopy in water. AB - Two hammerhead chimeric RNA/DNA ribozymes (HRz) were synthesized in pure form. Both were 30 nucleotides long, and the sequences were such that they could be targeted to cleave the HIV-1 gag RNA. Named HRz-W and HRz-M, the former had its invariable core region conserved, the latter had a uridine in the invariable region replaced by a guanine. Their secodary structures were determined by 2D NOESY 1H 500 MHz NMR spectroscopy in 90% water and 10% D2(0), following the imino protons. The data show that both HRz-M and HRz-W form identical secondary structures with stem regions consisting of continuous stacks of AT and GT pairs. An energy minimized computer model of this stem region is provided. The results suggest that the loss of catalytic activity that is known to result when an invariant core residue is replaced is not related to the secondary structure of the ribozymes in the absence of substrate. PMID- 7835437 TI - [Alveolar bone replacement by implantation of Ossynth and Ossnativ hydroxy apatite ceramics]. AB - Natural and synthetic HA-granulate (made by SZIKKTI Budapest) were implanted to 91 patients by the authors with the aim of bone replacement. Follow up controls proved that the biomaterial has been incorporated without clinical symptoms and complaints in 87 percent. Biopsies taken from replacement site showed that the HAK isolated from natural substance could be incorporated into the calcified tissue and it is also able to help the formation of the new bone. PMID- 7835438 TI - [Inspection of surgical rubber gloves used during dental procedures]. AB - The resistance and durability of operating rubber gloves (PALMA) during different types of dental treatment were investigated. Six percent of the rubber gloves were found to be defective. One pair of gloves could be used 2.15 times on average. The vulnerability of the gloves increased after repeated sterilizations. The results suggest that the use of disposable gloves should be preferred in the daily dental practice. PMID- 7835439 TI - Ocular malformations and the fruits of developmental genetics. PMID- 7835440 TI - The molecular biology of Norrie's disease. AB - The Norrie's disease gene has been accurately located on the short arm of the X chromosome. The methodology underlying this achievement and the structure of the three-exon gene is described in this review article. The clinical implications of these recent advances are discussed. Allelic variants of Norrie's disease and the phenomenon of females affected by X-linked disease are also discussed. PMID- 7835441 TI - Extraocular muscle problems in thyroid eye disease. AB - In this paper methods of visualisation of the extraocular muscle changes in thyroid eye disease are discussed. The histopathology of extraocular muscle biopsies has been studied by both light and electron microscopy to show the type of cellular infiltration and the amorphous material in the extracellular matrix. A series of questions to which answers have not yet been found concerning thyroid eye disease are posed which may help to direct new research projects. Finally, in the last part of the paper, the surgical results in a series of 41 patients having ocular muscle surgery for diplopia and/or compensatory head postures due to thyroid eye disease are described. The conclusions drawn from these results are that one should maintain the patient euthyroid, establish by orthoptic measurements that the ocular movements have been stable for at least 6 months, treat by recessing tight muscles using adjustable sutures, and aim to undercorrect the vertical deviation at the time of adjustment. PMID- 7835442 TI - The STIR sequence MRI in the assessment of extraocular muscles in thyroid eye disease. AB - Nineteen patients with thyroid eye disease were examined with magnetic resonance imaging using the Short Tau Inversion Recovery (STIR) sequence and compared with normal controls. The Signal Intensity Ratio (SIR) of each of the four recti was obtained by comparison with the signal intensity of the adjacent temporalis muscle. The SIR was compared with disease activity assessed using Werner's grading system, a clinical inflammatory score, and the range of extraocular movements. Results show that a high SIR is associated with a high index of disease activity. This technique is likely to prove useful in assessing disease activity and planning the management of thyroid eye disease, particularly with respect to immunosuppression. PMID- 7835443 TI - Persisting hypotropias following protective ptosis induced by botulinum neurotoxin. AB - Botulinum toxin A induced ptosis (BTXAP) has become an established method for producing a temporary ptosis for corneal protection. Adams et al1 reported from an initial series of 15 patients and observed that the ptosis lasted for a mean period of 2.5 weeks and that full recovery was achieved after a mean of 8.1 weeks. They noted that in 80% of cases there was a temporary superior rectus weakness which lasted for a mean of 6 weeks. We present three cases in which the superior rectus weakness was permanent and required corrective strabismus surgery. We believe that these are the first cases reported. We propose two possible mechanisms which may be acting together: firstly that a prolonged period of occlusion may have led to a breakdown of fusion, and secondly that following botulinum toxin induced superior rectus weakness there was contracture of the ipsilateral antagonist muscle further disrupting fusional mechanisms. PMID- 7835444 TI - Electrophysiology and psychophysics in ocular hypertension and glaucoma: evidence for different pathomechanisms in early glaucoma. AB - It is not clear whether glaucomatous optic nerve damage is the end result of one pathological process or whether there are several mechanisms by which the final disease is manifest. The use of electrophysiological and psychophysical tests which measure the function of specific subdivisions of the visual pathways have been shown to be of use in the early diagnosis of glaucoma. In addition these results may help to elucidate the mechanisms of loss of visual function in patients with early glaucoma. One hundred and ninety-three patients with ocular hypertension (intraocular pressure > 24 mmHg, with normal visual fields and optic discs), 30 with glaucoma and 35 controls underwent pattern electroretinogram (PERG), peripheral colour contrast thresholds, motion detection thresholds (MDT) and Humphrey automated visual fields at the same visit. For each test there was a significant proportion of patients with abnormal results as has been found in previous studies of these techniques. However, there was a significant lack of correlation between the groups with only a small number of patients having abnormalities on more than one test. Of the patients demonstrating abnormal PERGs, 36% had abnormal colour contrast and 32% abnormal MDT, but only 15% were abnormal on both tests. Early glaucomatous damage may be focal or diffuse in nature. Similarly there may be preferential damage to ganglion cells subserving different visual functions or damage at different retinal layers. The results lend support to these hypotheses and give further evidence that more than one pathomechanism may be involved early in the glaucomatous process. PMID- 7835445 TI - Diurnal intraocular pressure variation in low-tension glaucoma. AB - A retrospective analysis of diurnal variation in intraocular pressure (IOP) in 101 untreated low-tension glaucoma (LTG) patients was carried out to ascertain the role of IOP as a causative factor in the aetiology of optic nerve damage in LTG. The diagnosis of LTG was made only after IOP monitoring as an inpatient, which involved 2 hourly consecutive measurements by Goldmann applanation tonometry from 08:00 to 22:00 hours inclusive. The highest IOP during the diurnal curve was 17.4 mmHg (SD 3.00) at 10:00 and the lowest value was 15.0 mmHg (SD 2.7) at 22:00. Seventy-seven per cent of patients had a peak IOP value recorded between 08:00 and 12:00 hours inclusive. The mean peak IOP was 18.3 mmHg (SD 2.6) and the mean trough was 13.1 mmHg (SD 2.2). Thus the mean diurnal range in IOP of 5.2 mmHg (SD 2.2) was similar to that reported by other workers in normals. Neither the diurnal pattern nor the range of IOP values seen in this study supports the view that abnormal IOP levels are a significant risk factor in the pathogenesis of optic nerve damage in all patients with LTG. PMID- 7835446 TI - Spatial distribution of back scattering in the nuclear area of the non cataractous human lens. AB - The spatial distribution of back scattering from a vertical cross-section of the nuclear area in non-cataractous human lens was investigated. The cross-section was centred on the pupil. There is no significant difference in average nuclear back scattering between sides. The distribution of back scattering along an axis perpendicular to the anatomical axis can be modelled as a second-order polynomial. It is believed that the increase of back scattering in the central region corresponds to the peak protein concentration in the centre of the nucleus. This information was obtained by imaging back scattering with Scheimpflug photography. The back scattering was measured photometrically in a 3 x 10 matrix of measuring areas within the lens nucleus. Each measuring area was 0.20 x 0.20 mm in size. It is anticipated that the established model will allow detection of nuclear cataract with high sensitivity, especially in early stages. PMID- 7835447 TI - The role of light scatter in the degradation of visual performance before and after Nd:YAG capsulotomy. AB - The aim of this study was to determine whether capsulotomy size influences visual performance. Snellen visual acuity and forward light scatter (light scattered towards the patient's retina, but out of the focussed retinal image) measurements using simple computer graphics based on van den Berg's technique were used to measure visual performance. Twelve patients were studied: 4 had small central capsulotomies through undilated pupils and 8 had wide capsulotomies through dilated pupils. The two groups were matched for age and pre-laser Snellen acuity. Following treatment, both groups had equal improvements in Snellen acuity. There was only a significant (p < 0.001) improvement in forward light scatter readings in the group who received wide capsulotomies. Measurements of forward light scatter are more sensitive than Snellen acuity testing in demonstrating loss of visual performance in patients with media opacities. It is recommended that pupils are dilated prior to Nd:YAG capsulotomy if forward light scatter from capsule remnants and the consequent glare disability are to be minimised. PMID- 7835448 TI - Posterior capsule opacification following diabetic extracapsular cataract extraction. AB - Review was performed of extracapsular cataract extraction with posterior chamber lens implantation in 90 diabetic patients and 263 non-diabetic patients. There was a higher incidence of posterior capsular opacification as judged by the requirement for Nd:YAG posterior capsulotomy in patients with non-proliferative (12/35, 34%) or quiescent proliferative diabetic retinopathy (8/18, 44%) than in non-diabetic patients (48/263, 18%) (Mantel-Haenszel p = 0.04). Although subgroup analysis showed a higher incidence of posterior capsule opacification in diabetics with non-proliferative or quiescent proliferative retinopathy than in diabetics without retinopathy, this was not statistically significant (Mantel Haenszel p = 0.19 and p = 0.07, respectively). Following cataract surgery in diabetics with retinopathy, frequent review and prompt management of posterior capsular opacification is recommended, to maintain adequate fundus visualisation at a time when deterioration of retinopathy is likely. PMID- 7835449 TI - A prospective, controlled study of a 9/0 elastic polypropylene suture for cataract surgery: refractive results and complications. AB - A prospective, randomised study was performed on 52 patients undergoing routine limbal extracapsular cataract surgery to compare the effect of 10/0 nylon and 9/0 elastic polypropylene sutures on post-operative astigmatism. Both the magnitude and the axis of the astigmatism were measured by keratometry and refraction pre operatively and at regular intervals for 3 months post-operatively. Both groups showed an increase in the magnitude of astigmatism immediately post-operatively. The polypropylene group showed a more rapid decrease in astigmatism over the first 7 days and subsequent stabilisation, although the only significant (p < 0.05) difference in astigmatism between the two groups was at 1 week post operatively. Both groups showed 'with-the-rule' astigmatism immediately post operatively, although more of the polypropylene group developed 'against-the rule' astigmatism by the end of the study. Despite an early reduction in post operative astigmatism in the polypropylene group, early spectacle prescribing would not be recommended because of the shift in the axis of astigmatism. In addition, the polypropylene group had a 4 times greater incidence of iris prolapse compared with the nylon group. PMID- 7835450 TI - Persistent binocular diplopia following cataract surgery: aetiology and management. AB - We studied all patients referred to the orthoptic department with binocular diplopia following cataract surgery between January 1991 and June 1993. Persistence of diplopia for a minimum of 3 months after cataract surgery was required for inclusion in the study. Eighty-one patients (2% of all patients who underwent cataract surgery during this time) satisfied the entry criteria. The patients fell into two groups: non-traumatic and traumatic cataracts. Horizontal deviations were seen in 24 patients. Vertical deviations were seen in 8 patients and a combined horizontal and vertical deviation was seen in 49 patients. Fresnel prisms were used to manage the diplopia in 58 patients. Of these, 48 patients in the non-traumatic group regained binocular single vision with this prism while 10 in the traumatic group benefited. Mechanical and sensory causes are discussed. PMID- 7835451 TI - The adherence of silicone oil to standard and heparin-coated PMMA intraocular lenses. AB - During combined cataract extraction and intraocular lens insertion in eyes undergoing removal of silicone oil, we noted that oil became adherent to the implant. This adhesion persisted post-operatively. Although patients seemed not to be symptomatic as a result of this effect, the oil interferes with the fundal examination. Since heparin-coated intraocular lenses are more hydrophilic than unmodified lenses, oil should spread less well on these lenses and therefore be less adherent. This study was conducted to test this hypothesis. Heparin-surface modified and unmodified polymethylmethacrylate (PMMA) lenses were immersed in 1000 centistoke neat silicone oil and in an emulsion of silicone oil taken from a patient. The lenses were washed with saline solution in an attempt to remove adherent oil. The lenses were photographed for examination and qualitative comparison. It was found that both neat and emulsified silicone oil was strongly adherent to both surface-modified and unmodified lenses, and could not easily be washed off. The heparin-coated lenses showed a tendency for adherence of emulsified oil. It is concluded that heparin coating of intraocular lenses does not prevent, though may reduce, oil adherence. We recommend that care be taken to avoid contact between oil and implant during combined oil removal and cataract extraction. PMID- 7835452 TI - A comparative trial between diclofenac-gentamicin and betamethasone-neomycin drops in patients undergoing cataract extraction. AB - Eighty patients were randomised in a single-masked parallel-group study to receive topically either the test drug, a diclofenac and gentamicin combination, or a betamethasone and neomycin combination after routine cataract extraction and intraocular lens implantation. Each group was assessed over a 6 week period for post-operative inflammation. The two drug combinations were equally effective in suppressing inflammation in the early post-operative stages and the diclofenac gentamicin combination was slightly more effective in the later stages. The test drug was well tolerated and showed no adverse effects. We feel it is an effective and relatively safe drug which has a role as an anti-inflammatory agent after cataract extraction and has potential advantages in certain circumstances. PMID- 7835453 TI - Drug resistance and Acanthamoeba keratitis: the quest for alternative antiprotozoal chemotherapy. AB - Trophozoites and cysts of 20 isolates of Acanthamoeba from the cornea and five from related samples were tested in vitro for sensitivity to ten drugs (three aromatic diamidines, two aminoglycosides, two macrolides, a polyene macrolide antibiotic, an organoarsenical and an antimetabolite) and two cationic antiseptics (chlorhexidine and polyhexamethylene biguanide, PHMB). Only chlorhexidine and PHMB showed uniform amoebacidal activity. Aromatic diamidines (pentamidine isethionate, propamidine isethionate and diminazene aceturate) generally proved effective against both forms of the amoeba; only pentamidine gave synergy with the biguanide while propamidine gave an additive effect. Other drugs tested proved erratic or ineffective against different isolates. Chlorhexidine alone, or together with propamidine, was subsequently used in two patients with proven Acanthamoeba keratitis; the causative isolates were sensitive to the individual compounds and to the combination in vitro. The treatment provided resolution of the clinical disease; amoebae were shown to be nonviable by histology and culture. The combination of chlorhexidine and propamidine is recommended for treatment of proven Acanthamoeba keratitis. PMID- 7835454 TI - Is genetic predisposition an important risk factor in age-related macular degeneration? AB - Age-related macular degeneration (ARMD) is the most common cause of visual morbidity in the aged in the Western world. The aetiology of ARMD is unknown. Although clinicians have noted that ARMD demonstrates a familial tendency, the question regarding the role of hereditary factors in ARMD remains unanswered. The aims of this study were to assess the level of genetic input into ARMD and to assess the mode of inheritance of the disease. Fifty affected patients and 50 age and sex-matched controls and their immediate families were invited to take part in the study. Thirty-six patients, controls and their families were studied. Eighty-one siblings of affected patients and 78 control siblings were available. Twenty of the 81 affected siblings were found to suffer from ARMD. In contrast only 1 of 78 control siblings had ARMD. This was statistically significant. The results confirm that hereditary factors are important in the aetiology of ARMD. PMID- 7835455 TI - The 'baseball' orbital implant: a prospective study. AB - The 'baseball' orbital implant was described by Frueh and Felker in 1976. Although this implant was originally described for use as a secondary implant, it has also been widely used as a primary implant at the time of enucleation. This prospective study evaluated the effectiveness of this implant used both primarily and secondarily. Forty-four patients were implanted between April 1990 and May 1991, 19 of the implants being primary and 25 secondary. A standardised operative and post-operative protocol was followed. The mean follow-up time was 31 months (range 24-36 months). The patients were evaluated for the degree of volume replacement, implant and associated prosthesis motility, secondary eyelid and socket problems, patient satisfaction, the need for further surgery and post operative complications. The overall results achieved by primary implantation were superior to those of secondary implantation. Our results suggest that this implant provides a satisfactory functional and cosmetic rehabilitation of the anophthalmic patient with few complications. PMID- 7835456 TI - Orbital disease in herpes zoster ophthalmicus. AB - Three cases of orbital inflammatory disease caused by herpes zoster are described. This extremely rare complication occurred between 5 days and 14 days following the skin eruption and slowly resolved with or without treatment. Biopsy of a chronic inflammatory lesion on the cheek of one patient demonstrated a sterile vasculitis and granulomatous liponecrosis, a process which may underlie the orbital disease in these patients. PMID- 7835457 TI - Bilateral orbital metastases from transitional cell carcinoma of the bladder. AB - A case of bilateral orbital metastases arising from a primary transitional cell carcinoma of the bladder is presented, with simultaneous presentation of both primary and metastatic disease. The literature is reviewed. PMID- 7835458 TI - Lacrimal surgery in patients with congenital cranial or facial anomalies. AB - A series of 26 patients with lacrimal dysfunction due to congenital cranial or facial anomalies are reviewed. The underlying anatomical abnormalities responsible for symptoms and their influence on surgical management and outcome are discussed and illustrated with representative cases. It is shown that by adaptation of standard surgical techniques a high success rate can be achieved. PMID- 7835459 TI - Primary sebaceous carcinoma of lacrimal gland: a previously unreported primary neoplasm. AB - We describe a patient who presented with a rapidly growing neoplasm of the lacrimal gland which histologically was a sebaceous gland carcinoma. The eyelid was entirely normal on examination under anaesthesia. Sebaceous differentiation has been described on only three previous occasions, arising within pre-existing tumours of the lacrimal gland such as pleomorphic adenoma. In this case there is a single tumour cell line within normal lacrimal gland, and the eyelid is normal. This points to a previously unreported diagnosis of primary sebaceous carcinoma of the lacrimal gland. PMID- 7835460 TI - Intraocular caterpillar hairs (setae): clinical course and management. AB - Ophthalmia nodosa is a well-documented condition. We present a case in which a live caterpillar was rubbed into a patient's eye and, after relentless penetration of the hairs into the globe, vitrectomy was required. We discuss the differing clinical features of these injuries, the mode of penetration and the treatment options. PMID- 7835461 TI - Tachycardia and myocardial ischaemia following subconjunctival injection of Mydricaine No. 2. PMID- 7835462 TI - Retinal necrosis as a complication of cryotherapy. PMID- 7835463 TI - 'Balloon sign' in allergic conjunctivitis. PMID- 7835464 TI - Uveitis and skin tattoos. PMID- 7835465 TI - Coexistent optic disc pit and ocular hypertension misdiagnosed as glaucoma. PMID- 7835466 TI - Primary orbital lymphoma presenting as epiphora. PMID- 7835467 TI - Scleral explant mimicking malignant melanoma. PMID- 7835468 TI - Reaction of sorbic acid in millet and sorghum doughs: reaction with thiols. AB - The fate of sorbic acid in pearl millet and sorghum doughs on cooking and storage is reported. A solution of sorbic acid added to the cereal flours gave a dough, which was cooked to give the product 'fura'. A significant amount (40%) of the sorbic acid was not recovered from the dough and fura on extraction with methanol. The use of acidified methanol leads to a quantitative recovery of that proportion of the preservative which otherwise becomes unavailable during the cooking of the dough and evidence is presented to suggest that sorbic acid-thiol adducts are formed at that stage. PMID- 7835470 TI - Determination of bromate in bread by capillary gas chromatography with a mass detector (GC/MS). AB - A sensitive method was developed for the determination of bromate in bread by capillary gas chromatography with a mass detector (GC/MS). Bromate was extracted with water from bread samples. After centrifugation, the supernatant was filtered and Cl- was removed by an OnGuard-Ag cartridge column. The mixture was absorbed on a DEA solid phase extraction column and washed with water. Bromate was then eluted with 3 M potassium chloride solution. Two ml of 4 x 10(-3) M styrene monomer solution (washed with 1% sodium hydroxide solution before use), 1 ml 0.01 M potassium bromide solution and 1 ml sulphuric acid were added to the eluent and shaken vigorously. The styrene bromo derivative (alpha-bromomethyl benzenemethanol[2-bromo-1-phenylethanol]) was extracted with 2 ml n-hexane, and determined by GC/MS. Recoveries of bromate from breads were in the range 91.3 98.1% (0.03-0.50 micrograms/g), and the limit of detection was 0.03 microgram/g. Pullman and open top types of white bread, produced by a sponge and dough method and a short process method respectively, were prepared in our laboratory for measurement of residual bromate. When 30 micrograms/g or less bromate as HBrO3 (pullman type), and 75 micrograms/g bromate or less as KBrO3 (open top type), was added to flour, no residual bromate was detected in either type of bread. PMID- 7835469 TI - Antimicrobial action of some GRAS compounds against Vibrio vulnificus. AB - Vibrio vulnificus is a bacterium indigenous to estuarine waters and is known to be a significant human pathogen. Infections are generally associated with the consumption of raw oyster. In an attempt to identify possible antimicrobial agents against this organism that might be used in foods, ten compounds that are generally recognized as safe (GRAS) by the FDA were tested against both the opaque and translucent morphotypes of V. vulnificus. Eight of those compounds had a lethal effect for both morphotypes of this bacterium. Diacetyl had the lowest lethal concentration (50 ppm) of the GRAS compounds tested within 24 h. Lactic acid and butylated hydroxyanisole possessed lethal activities at 300 ppm and 400 ppm, respectively, within 3 h. The mode of action of lactic acid against V. vulnificus appears to be an effect primarily of pH, while the antimicrobial activities of diacetyl and BHA appeared not to be affected by pH. No significant differences were found for opaque to translucent, or from translucent to opaque switching, in examining the possible effects of the GRAS compounds on colonial morphology. PMID- 7835471 TI - Polyethylene terephthalate bottles (PRBs): a health and safety assessment. AB - As part of a multi-client project, the potential public health risks of the reuse of polyethylene terephthalate (PET) refillable bottles (PRBs) following possible misuse has been investigated. Participants in the project provided data and information from previous studies conducted independently at contract laboratories. These studies were sponsored by the clients in order to provide further research data on PET containers and their safety. In this report, the results of five of these studies along with the results of a recent study carried out at TNO are compiled and reported. PET refillable bottles were exposed to 62 contaminants, including pesticides, that a consumer could potentially store in bottles. After storage with a contaminant under well defined conditions, the bottles were washed, filled with a simulated beverage, and stored for various lengths of time. The beverage and in some cases the bottle wall were then analysed for the presence of the contaminants. Toxicological evaluation of the analytical results from these tests on contaminant residue remigration showed that even under exaggerated exposure conditions, there was no public health concern. Only one compound, parathion, remigrated to a level that required a more in-depth risk evaluation, and under the most conservative assumptions, it too presented no real health hazard. Additionally, current detection systems employed to ensure product quality detect a wide variety of contaminants, including commercial formulations of parathion. Data developed in this paper are consistent with the finding that PRBs can be safely reused. For preventing negative effects on product quality (e.g. taste), however, good manufacturing procedures including visual and electronic inspection systems are required to eliminate abused bottles. PMID- 7835472 TI - Migration of mineral hydrocarbons into foods. 6. Press lubricants used in food and beverage cans. AB - Unused food and beverage cans were supplied by manufacturers together with two typical samples of press lubricants used to facilitate stamping of can ends. The lubricants were based on mineral hydrocarbon fractions. The cans were of aluminium two-piece construction (two sizes) and tin-plate steel three-piece construction (two sizes) and of four representative types. Gas chromatographic analysis was used to distinguish the two press lubricants from one another by their n-alkane profiles. Analysis of solvent extracts of the cans indicated that one of the two press lubricants had been used in the manufacture of the three piece cans and the other lubricant for the two-piece cans. Residual levels of hydrocarbons were between 0.05 and 1.1 mg per can. Based on the capacity of the cans and assuming all the mineral hydrocarbon transferred to the contents, maximum levels in foods and beverages could be between 0.1 and 4.4 mg/kg. A limited number of retail products were also analysed. For the 35 samples covering 18 retail brands of canned foods and beverages, press lubricants were considered to be present in 50% of the products at levels ranging from 0.05 to 1.0 mg per can, equivalent to 0.1 to 3.6 mg/kg of food. Additionally mineral oil of unknown origin was detected in 10 of the retail products at levels of 0.1 to 4.7 mg/kg. Analysis of a sparkling apple juice packed in a glass bottle showed mineral oil at 0.3 mg/kg compared with 0.7 mg/kg for the same canned product, indicating that although mineral oils may be used in can manufacture they may also be derived from other parts of the food processing chain. PMID- 7835473 TI - Determination of benzene residues in recycled polyethylene terephthalate (PETE) by dynamic headspace-gas chromatography. AB - A dynamic headspace-gas chromatography (HS/GC) method was developed to quantitate benzene in recycled PETE material derived from 21 PETE beverage bottles. The analytical system consisted of a purge-and-trap apparatus which was interfaced directly with a gas chromatograph/flame ionization detector. Cryofocusing and non cryofocusing GC systems were used. The technique was applied to spiked PETE test samples which were prepared at various benzene concentrations ranging from 100 ppb to 117 ppm. The initial spiked benzene concentration in the PETE test samples was determined gravimetrically. The HS/GC technique was limited by the slow desorption rate of benzene from the PETE matrix; as a result, multipurges were performed at 60 degrees C. Regression analysis was done on the multipurge data to develop a desorption model which would predict the total amount of benzene in the PETE. The calculated results agreed with the experimental recoveries within +/- 10%. Recovery depended on the initial benzene level in the PETE and ranged from 70 to 90% after the first five purges. PMID- 7835474 TI - Analysis of pesticide residues in hops and their extraction by liquid CO2 during the production of hop extracts. AB - A method has been developed for analysing pesticide residues in whole hops, hop pellets and hop extracts by GC-MS. Five batches of hop pellets containing nine different pesticides (triadimefon, dicofol, mephosfolan, bupirimate, cyhalothrin, tetradifon, endosulfan, pyrazophos and total bisdithiocarbamates) were extracted with liquid CO2. Pesticide concentrations in the original hop pellets and the extracts were determined. The pesticides were concentrated by the extraction process (concentration factor 1.3-8.3), except for the bisdithiocarbamates, which were not extracted. When the same amount of bitterness was added into the brewing process using liquid CO2 extract as opposed to hop pellets, for most of the pesticides proportionately less pesticide was added. However, for two pesticides (dicofol and triadimefon) corrected residue levels were similar to, or in some cases slightly higher than, those in hop pellets. PMID- 7835475 TI - Lead and cadmium contents in Finnish breads. AB - A total of 647 breads from nine bakeries were pooled into 48 representative samples. After wet digestion in concentrated HNO3, the contents of lead and cadmium were determined using electrothermal atomic absorption spectrometry with Zeeman effect background correction and (NH4)H2PO4 matrix modification. The mean lead and cadmium contents found in the various types of bread were: rye bread 16 and 14, coffee bread 19 and 23, French bread 8 and 27, whole wheat bread 8 and 30, mixed bread group I 17 and 27, and mixed bread group II 14 and 28 micrograms/kg. The mean and median lead contents of all breads were 14 and 8 micrograms/kg. The samples showed a very high variation in their lead contents. In the present study, the lead content found in Finnish breads was much lower than that in the late 1970s. The mean and median cadmium contents in all of the bread samples analysed were 24 and 25 micrograms/kg. The cadmium content of rye breads was clearly lower than that of the other bread types studied. The content of cadmium in the different types of bread was at about the same level as that reported in Finnish breads in the late 1970s. PMID- 7835476 TI - Health care system reform--a call to action. PMID- 7835477 TI - Reflections on World War II. Part II. PMID- 7835478 TI - Covering your butt. PMID- 7835479 TI - The mammography report: communication problems. PMID- 7835480 TI - The Medical Center of Delaware. The HIV community program. PMID- 7835481 TI - Abundance and creating wealth. PMID- 7835482 TI - Periodontics with a garden view. PMID- 7835483 TI - Hygienist- and staff-compensation plans. PMID- 7835484 TI - Serving dentists the best choices. PMID- 7835485 TI - Can you afford not to be computerized? PMID- 7835486 TI - Acceptance for cosmetic dentistry. PMID- 7835487 TI - The economics of in-house casting. PMID- 7835488 TI - Dental infection control--can we call the changes progress? PMID- 7835489 TI - Cutting out the 'middle man'--one of dentistry's concerns. PMID- 7835490 TI - A place of serenity in New York City. PMID- 7835491 TI - Serving the homebound. PMID- 7835492 TI - "I never saw a tooth walk into my office." The L.D. Pankey Institute is teaching dentists to see their patients in a new light. PMID- 7835494 TI - Tough strategies for tough times. PMID- 7835493 TI - How to maximize your time at a dental meeting. PMID- 7835495 TI - Infection control in a new office. PMID- 7835496 TI - Maximize capital gains on a practice sale. PMID- 7835497 TI - Customized, light-cured chairside staining. PMID- 7835498 TI - Predictable root-coverage grafting: the subepithelial connective-tissue graft. PMID- 7835499 TI - Bleaching and the new dentistry. PMID- 7835500 TI - Condylar hyperplasia: correlation of histological and scintigraphic features. AB - Scintigaphy using 99mTc-MDP is widely advocated as a method of diagnosis and presurgical assessment of patients with condylar hyperplasia. A previous study has demonstrated that hyperplasia of the mandibular condyle is characterized histologically by the presence of an uninterrupted layer of undiffentiated germinative mesenchyme cells, a layer of hypertrophic cartilage and the presence of islands of chondrocytes in the subchondral trabecular bone. This study was undertaken to determine whether there was any association between the degree of 99mTc-MDP uptake and the histological features of condylar hyperplasia. The parameters examined were trabecular bone volume, depth of cartilage islands and the presence of forming and resorbing surfaces. The images were analyzed by three experienced observers, who ranked the images according to degree of asymmetry between sides and the degree of uptake on the affected side. There was a significant correlation between the proportions of resorbing and osteoid covered bone surfaces and scintigraphic appearances. The rank correlations were rs = 0.55 (P = 0.3) between the resorptive surfaces and degree of symmetry and rs = 0.53 (P = 0.04) between the osteoid surfaces and absolute uptake. The correlation was higher for both methods (rs = 0.64 in each case) when the osteoid surface and resorptive surface measurements were combined. The results indicate that visual examination of radioisotope bone scans by experienced observers is a valid form of assessment of bone activity in condylar hyperplasia. PMID- 7835502 TI - Advanced imaging in evaluation of a central mandibular haemangioma. AB - We present a case of histologically-verified central cavernous haemangioma. The conventional radiological films as well as the computed tomographic (CT) and magnetic resonance imaging (MRI) features of this lesion are described. Plain films showed many of the typical radiological signs of haemangioma, whereas CT was primarily useful for illustrating the bony components of the tumour as well as delineating soft tissue extensions and bony defects not normally visible with plain film examination. MRI proved particularly useful, demonstrating the vascular nature and flow voids representative of feeder vessels and delineating the true extent of the lesion. The literature pertaining to the imaging features of central haemangioma is reviewed and the complementary use of plain films, CT and MRI described. To our knowledge, this is the first report detailing the MRI characteristics of a central mandibular haemangioma. PMID- 7835501 TI - Coronoid process enlargement. AB - A case is reported of unilateral process enlargement in a 22-year-old man causing limitation of mandibular movements. The radiographic features suggested an osteochondroma. Following coronoidectomy, a definitive diagnosis of coronoid hyperplasia was made. PMID- 7835503 TI - Registration techniques for digital subtraction radiography. PMID- 7835504 TI - Towards improving third molar extraction decisions. PMID- 7835505 TI - Radiographic caries diagnosis and monitoring. AB - Radiography is still the best diagnostic technique which is widely available to dentists. Digital radiography offers improved imaging through lower dose and lack of chemical processing. However, monitoring of incipient caries progression requires imaging systems which are as good as film with testing at the D1 level (WHO). Care is required in constructing valid caries models. Work is required to define the necessary digital image quality as measurement accuracy for monitoring caries progression may be as high as 0.15 mm. A case has been made for using the highest sensitivity possible, since caries is a disease where a 'wait and see' policy should produce no unnecessary treatment from increased false positives. Individual site monitoring should be performed on both low and high caries risk patients. High-risk subjects still need to be monitored since DMFS is not a valid site level predictor. PMID- 7835506 TI - Quantitative assessment of image quality using niobium filtration for cephalometric radiography. AB - The effect of added niobium filtration on image quality in cephalometric radiography was quantitatively evaluated using the Modulation Transfer Function (MTF). A conventional full-wave cephalometric X-ray generator (Quint Sectograph) and a constant potential, high frequency X-ray generator (Orthophos CD) were compared with respect to the effects on the MTF of the added filtration. There was a slight reduction in image quality with both machines when adding niobium filtration. PMID- 7835507 TI - Factors determining the diagnostic accuracy of digitized conventional intraoral radiographs. AB - A number of factors may determine the diagnostic accuracy of digitized intraoral radiographs. Conventional film radiographs were digitized with three different digitizers, a laser-scanner, a drum-scanner and a TV camera. Digital images, varying in pixel size, grey level and image processing, were displayed on three different video-monitors and assessed by 10 dentists. The detectability of incipient proximal surface caries was used as an index of the diagnostic accuracy and the effect of the different factors compared by means of receiver operating characteristic (ROC) analysis. Images digitized by the drum-scanner were found to have the best diagnostic accuracy. Sufficient diagnostic accuracy could be attained on the low-cost video monitor of a personal computer. Digital images with a pixel size of 100 microns and 32 grey levels were found to be acceptable for intraoral radiographs for diagnostic purposes. These results provide a practical guide for establishing a digital image acquiring system for any intraoral radiographs, reducing demands on data storage to a minimum. PMID- 7835508 TI - Effects of contrast equalization on energy imparted to the patient: a comparison of two dental generators and two types of intraoral film. AB - Technical evolution in maxillofacial radiology has in the last decade provided faster films and the constant potential generator. The consequences of these innovations for radiographic contrast and energy imparted to the patient are analysed. On the basis of physical measurements a test model has been developed for correcting exposure parameters in order to maintain or restore image contrast. These measurements are expressed in and developed from basic radiological concepts and physical formulas presented in an earlier paper (Helmrot E. et al., Dentomaxillofac. Radiol. 1991; 20: 135-46). The test model can also be used to demonstrate the balance between contrast and energy imparted to the patient in the radiographic process. Changing to constant potential generators and faster film may each result in a degradation in contrast, which is possible to restore by a controlled adjustment of the kV-setting. Maintenance of constant image quality results in a slight reduction in the net gain in energy imparted, due to the generator and/or film shift. When, for example, a conventional single-pulse generator operated at 65kVp tube potential was replaced by a modern constant potential unit, the kV-setting had to be decreased by 5 to 8 kV to maintain the same radiographic contrast. This correction could be done without increasing energy imparted to the patient, taking into account the fact that the spectral characters of the photon energy are not identical. If, in addition, faster intraoral film with lower film contrast was introduced, together with the constant potential unit, the kV-setting had to be further decreased to maintain the radiographic contrast.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7835509 TI - Direct digital radiography for the detection of defects in a standard aluminium test object through composite resin restorative materials. AB - While the RVG 32000 (Trophy Radiologie, Vincennes, France) is in wide use for direct digital intraoral radiography in dentistry, there is a dearth of information in the literature concerning the system's sensitivity to small changes in radiographic density consistent with initial and recurrent dental caries. A standardized 7 mm aluminium test block was used as a phantom for perceptibility testing of density changes, both with and without the superimposition of composite resin sheets of various thicknesses. Defects in the block were randomly positioned and varied from 0.1 to 1.5 mm. Thermal prints were used for evaluation. Standard linear images, with no enhancement, were compared with three enhanced modes, standard mode with gradient enhancement (enhanced standard), standard X-function and zoom high resolution (ZHR). Sensitivity improved in the following sequence: standard 0.58 < enhanced standard 0.75 < X function 0.94 < ZHR 0.95. Accuracy improved in the following sequence: standard 0.45 < enhanced standard 0.58 < X-function 0.73 < ZHR 0.74. Specificity was 1.0 both for X-function and for ZHR. These two modes both proved significantly better (P < 0.05) for the detection of 0.1 mm defects than the other two modes tested. No significant difference was found between X-function and ZHR. As ZHR requires four times the radiation exposure as standard exposures with the X-function, the latter is preferred for the task described in this study. PMID- 7835510 TI - Comparison of periapical and detailed narrow-beam radiography for diagnosis of periodontal pathology. AB - The diagnostic performance of the detailed narrow-beam (DNB) technique of the Scanora multimodal X-ray system was compared with periapical radiography for detecting periodontal pathology. In total, 253 sites in 133 patients were examined. Receiver operating characteristics (ROC) of both imaging modalities were analyzed in relation to the ratings of five observers for the whole dentition, three dental regions and five types of periodontal lesion. ROC analysis demonstrated that the overall diagnostic performance of DNB radiography was better (P < 0.05) than that of periapical radiography. DNB radiography was significantly superior (P < 0.01) for detecting marginal widening of periodontal membrane space, but there was no significant difference between the two techniques for crestal erosion, vertical bone loss, furcation involvement or calculus. The regional differences found in overall diagnostic performance of the two imaging modalities were not significant. The sensitivity for periapical radiography was 71% and for DNB radiography 85%, and the specificities 82% and 81% respectively. It is concluded that DNB radiography is a good radiographic examination for periodontal disease, and an acceptable alternative to periapical radiography. PMID- 7835511 TI - Effective dose and risk assessment from film tomography used for dental implant diagnostics. AB - There are no data relating complex film tomography with effective dose that may be used to estimate the relative risk associated with dental implant diagnostics. The purpose of this study was to calculate the effective dose and estimate risk from the use of the Scanora multimodal imaging system. With the use of a tissue equivalent human phantom and thermoluminescent dosimetry, panoramic radiography was found to result in an effective dose of 26 microSv, while complex film tomography resulted in an effective dose of < 1 microSv to 30 microSv depending on the anatomical location of the imaging plane and the collimation option. An effective dose of this magnitude for panoramic radiography was estimated to represent a probability for stochastic effects on the order of 1.9 x 10(-6). Similarly, the effective dose associated with film tomography may be estimated to be equal to a probability for stochastic effects in the range of << 1 x 10(-6) to 2.2 x 10(-6). PMID- 7835512 TI - Bitewing-based alveolar bone densitometry: digital imaging resolution requirements. AB - The resolution requirements were determined for detection of incremental alveolar bone loss from digitized Ektaspeed radiographs. Ten clinical radiographs were examined with a calibrated optical microscope to measure the smallest feature of interest discernible for alveolar bone. Images of trabeculae > 100 microns in diameter could be identified, but smaller ones could not be resolved. The Nyquist Criterion requires sampling with 50 microns (or smaller) pixels to measure such features. Numerous 25 microns Ag aggregates were present. Fifty microns resolution is a practical compromise between noise level and feature resolution. In another example of 10 bitewings digitized at 8 bit grey scale, about half the available range was used for alveolar bone, resulting in uncertainty, over a range of 2 optical density (OD) units, of about 1.42% at the average OD for alveolar bone (1.1). With the same radiographs digitized at 12 bit resolution, over 2000 of 4096 grey scales were used with a corresponding uncertainty of about 0.09%. Twelve-bit precision was also able to resolve smaller increments in an aluminium stepwedge than was 8 bit precision. Twelve-bit grey scale and 50 microns spatial resolution are recommended for alveolar bone densitometry performed with Ektaspeed radiographs. PMID- 7835513 TI - Direct digital imaging with and without niobium filtration for detection of density differences beneath steel orthodontic bands. AB - An in vitro investigation was carried out to determine the efficacy of the RVG 32000 (Trophy Radiologie, Vincennes, France) in detecting subtle density variations in a standard aluminum test object through steel orthodontic bands. The density variations were of the same magnitude as those found when dental caries develops beneath bands during orthodontic therapy. The procedure was carried out with both standard aluminum filtration and added niobium filtration. This study revealed the imaging system to have a wide recording latitude with no significant differences in the diagnostic decisions being made between with entrance doses ranging from 189-517 microGy without niobium, and 169-267 microGy with added niobium. No significant difference was found between the diagnostic yield of images made with and without added niobium filtration. The accuracy was 89% with added niobium and 90% without added niobium. Specificity was 99% for both filtration conditions. It was generally possible to detect defects as small as 0.2-0.3 mm in 7 mm of aluminum through 0.26 mm steel orthodontic band material. It is concluded that the RVG 32000 has a wide recording latitude which permits detection of small density changes beneath orthodontic band material. The addition of niobium filtration did not interfere with this diagnostic task. PMID- 7835514 TI - Radiographic detectability of bone loss in the bifurcation of mandibular molars: an experimental study. AB - The aim of this study was to evaluate observer performance in the diagnosis of bone loss in the bifurcation of mandibular molars on conventional radiographs. Standardized radiographs were obtained of the first and second molars in 10 dry hemimandibles at baseline and after preparation of bony defects corresponding to degree I and degree II buccal furcation involvements. The radiographs were randomly presented to 12 observers who were asked to determine the presence or absence of bone loss. Receiver operating characteristic (ROC) curve analysis was used for evaluation. The mean AZ-value of all observers was 81% for the first molar and 80% for the second. As the degree of furcation involvement increased, the mean AZ-value of the observers also improved from 68% (furcation involvement degree I) to 86% (degree II). Multiple regression analysis revealed that lesion depth was the factor which most strongly influenced the observers' diagnostic performance. PMID- 7835515 TI - Limitations of panoramic radiography in the detection of bone defects in the posterior wall of the maxillary sinus: an experimental study. AB - Some lesions in the maxillary sinus may be adequately detected by panoramic radiography. The present study was designed to evaluate the ability of panoramic radiography in detecting experimental bony defects in the posterior wall of the maxillary sinus by comparison with Waters' projection and CT. Bony defects in the mediosuperior and medioinferior regions of the posterior wall were readily detected by panoramic radiography, but those in the laterosuperior or centre were not. It is concluded that there are limitations to the detection of bony defects in the posterior wall of the maxillary sinus by panoramic radiography alone. It is recommended that this technique should not be used for the detection of small osteolytic lesions in the maxillary sinus. PMID- 7835516 TI - Quantitative analysis of masticatory muscles using computed tomography. AB - Quantitative information on the normal size range of the masticatory muscles needed for successful treatment of facial asymmetry is sparse. Our purpose in this study was to define morphological indicators for the volume of the masticatory muscles on CT. Cross-sectional areas and volumes of the masseter and medial pterygoid muscles were measured from CT scans of 65 patients. The muscles were scanned from origin to insertion and the maximum cross-sectional area (MCSA) and its location together with the total volume were determined. The mandibular foramen was used as a landmark to determine the location of MCSA. The location of MCSA of masseter muscle was centred 8 mm above the mandibular foramen, and that of medial pterygoid muscle at the foramen. The MCSA of both muscles was highly correlated with volume suggesting that this parameter might serve as an indicator of their volume. Knowledge of the location of the MCSA would facilitate its measurement and so reduce radiation exposure. There was a positive correlation between the two muscles for both volume and MCSA. This finding could be relevant for future studies of the relationship between the morphology, biomechanics and pathology of the masticatory muscles. PMID- 7835517 TI - Cephalometric changes after gradual lengthening of the mandible: an experimental study in sheep. AB - Gradual distraction after osteotomy has been used both clinically and experimentally to lengthen the mandible. In this experimental study in sheep, the changes in dimensions after osteotomy and gradual distraction were analysed by means of cephalometry. There was a strong correlation between the amount and duration of distraction and the increase in length of the mandible. The difference in length between the operated and control sides persisted for up to 1 year. It was concluded that new bone was deposited and that the increase in length of the mandible was real and permanent. PMID- 7835518 TI - Age changes in the volume of the human maxillary sinus: a study using computed tomography. AB - An understanding of the age-related changes in the volume of the normal maxillary sinus will help to identify sinus abnormalities. Normal maxillary sinus volume was measured on axial CT scans in 115 cases, and analysed in relation to age, the presence of premolar and molar teeth, size of the midfacial skeleton and body height and weight. The volume ranged from 4.56-35.21 cm3 (mean: 14.71 +/- s.d. 6.33 cm3) in patients aged over 20 years. There was no significant sex difference and a close correlation between the two sides was found. The volume increased up to the age of 20 years, but then decreased. There was no significant difference in patients with and without maxillary premolars and molars between the ages of 50 and 79 years. The difference in right and left dentitions had no influence on the maxillary sinus volume over the age of 20 years. Adult maxillary sinus volume correlated with the interzygomatic buttress distance. In adult females, there was a significant correlation between the volume and the zygomatic-occipital distance. In adult males, the volume correlated with body height and weight. It appears that volume changes with age might be related to skeletal size and physique. PMID- 7835519 TI - Sexual dimorphism in mesiodistal dentin and enamel thickness. AB - This study evaluates sexual dimorphism in mesiodistal diameter, enamel thickness and dentin thickness of the permanent posterior mandibular dentition in order to gain a better understanding of variation in mesiodistal tooth size. The results relate to a sample of 59 males and 39 females, 20-35 years of age. Bitewing radiographs of the right permanent mandibular premolars and molars were illuminated and transferred at a fixed magnification to a computer via a video camera. Enamel and dentin landmarks were identified and digitized on the plane representing the maximum mesiodistal diameter of each tooth. The results showed significant sex differences (p < 0.01) in mesiodistal diameter favouring males over females. Dimorphism was more pronounced for the molars than for the premolars. Enamel thickness, which is 0.4-0.7 mm greater for the molars than premolars, shows no significant sex differences. Dentin is significantly thicker in males than females, and is 3.5-4.0 mm thicker in molars than premolars. It is concluded that sexual dimorphism in mesiodistal tooth sizes is due to differences in dentin thickness and not enamel thickness. PMID- 7835520 TI - Pneumocele of the maxillary sinus: a case report and literature review. AB - A panoramic radiograph of a 27-year-old female who had sustained midfacial trauma incidentally revealed a greatly expanded, hyperlucent right maxillary sinus. Further radiological exploration, including tomography, demonstrated that the expansion was mainly localized to the inferomedial part of the antrum with encroachment on the nasal and oral cavities. ENT examination was unremarkable. The lesion was diagnosed as a pneumocele. No treatment was rendered. Repeated tomography nine years later showed no changes. Today, 23 years later, the patient is still asymptomatic. A literature review reveals only nine previous cases of pneumocele of the maxillary sinus. PMID- 7835521 TI - Some considerations in the evaluation of diagnostic tests in dentistry. PMID- 7835522 TI - When will excellent radiographic images be available to the general dental office? AB - Dental radiography is a highly regarded diagnostic practice. More than 25% of all radiographs are taken for dental purposes, so their improvement will benefit many patients. Although recent advances in materials and processing have contributed to incremental improvements in film-based diagnoses, computer-based enhancement of digitized conventional radiographic images is likely to yield more significant benefits. However, until cost-effective digitizing systems have been developed for the general dental office, the benefits derived from precise radiographic diagnoses and associated improvements in the standards of care will continue to elude both dentist and public. PMID- 7835523 TI - Observer performance in locating the bifurcation in mandibular molars on periapical radiographs. AB - The ability to identify radiographically the bifurcation in mandibular molars and the influence of morphological factors on the observers' decisions were investigated in 10 dry mandibles. Standardized periapical radiographs were obtained with and without lead markers in the bifurcation. Then 23 observers marked the bifurcation on tracing paper placed on the radiographs. The distance between the 'true' bifurcation (the lead indicators) and the observers' markings was assessed. On average, it was identified at a point 0.26 mm (s.d. 0.5) apical to its 'true' location on the first molar, and 0.65 mm (s.d. 1.15) coronal on the second molar. Interobserver variation for first and second molars was 0.5 mm and 1.06 mm respectively. Corresponding intraobserver variation was 0.47 mm and 1.14 mm. Of the four morphological characteristics analysed, the mesiodistal width of the bifurcation was found to have the strongest influence on the accuracy. It was concluded that the wide discrepancy in the ability of the observers to locate the bifurcation could be largely attributed to intraindividual variation. PMID- 7835524 TI - Radiological and histological analysis of the structural changes in the rat parotid gland following release of Stensen's duct obstruction. AB - Sialography is the preferred method for diagnosis and treatment planning in obstructive sialadenitis. Although many experimental studies have reported changes following duct obstruction, those following release of obstruction have not been examined. The present study was undertaken to clarify: (1) the relationship between sialographic and histological changes; (2) the effects of duration and pressure of obstruction on gland recovery; (3) the possibility of establishing those sialographic features which indicate the prognosis for gland recovery. Stensen's ducts of rat parotid glands were obstructed for two different periods and at three different pressures in order to induce varying degrees of degenerative changes in the gland. The structural alterations resulting from release of obstruction were investigated by means of qualitative and quantitative microsialography and histology. Gland structure was assessed visually from the latter and classified into six groups: normal, recovery, and slight, moderate and severe degeneration and fibrous. Microsialograms were evaluated based on these groups. Qualitatively, microsialograms of the operated glands had a stricture in the obstructed region and dilation of the major ducts. Histological differences between recovery and degeneration glands were reflected in the morphology of peripheral ducts. The former showed a branch-like morphology similar to that of the normal group, and the latter contained small granule-like structures. Quantitatively, dilation of major ducts in the recovery group decreased compared with the other operated groups. There were no distinct sialographic features in the degeneration and fibrous groups which correlated with the degree of degeneration observed histologically. Duration and pressure of obstruction were highly predictive for prognosis for recovery.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7835525 TI - The effect of cathode ray tube display format on observer performance in dental digitized radiography: comparison with plain films. AB - Studies of observer performance with non-manipulated digital images are almost lacking; nor has the effect of cathode ray tube (CRT) display formats been evaluated. The present study compared the diagnostic accuracy of observers with and without clinical experience in evaluating intra-oral dental films and the corresponding non-manipulated digitized images. Three different-sized (5", 9", 17") monitors were used to study the effect of CRT display format. Artificial radiolucent and radiopaque lesions in dry human mandibles were examined. ROC curve areas were averaged and cross-tabulated according to viewing method and observer experience. For the total group, the non-manipulated digital images resulted in smaller ROC curve areas than the plain films for all CRT formats, with a significantly inferior result for the 17" images (p = 0.036). The increase in diagnostic accuracy of the digital images with decreasing CRT size was not significant (p > 0.05). There was some difference in the mean ROC curve areas between teachers and students, but the effect of the viewing methods was not significant. In terms of observer performance, the experienced observers demonstrated a reduced, and the inexperienced an increased, variability with the digital images compared with conventional film. PMID- 7835526 TI - B-mode ultrasound scanning of the tongue during swallowing. AB - The aim of the present study was to evaluate the ability of video-based dynamic B mode ultrasound in differentiating normal from abnormal swallowing. Tongue position at rest and during the oral phase of swallowing was examined with a 5 MHz transducer placed under the chin in 60 subjects aged between 6 and 33 years. 40 patients with abnormal tongue movement or swallowing were compared with a control group of 20 adults with Angle Class I occlusion without any signs of dysfunctional tongue activity. The ultrasound sequences were videotaped and the movement of the tongue in swallowing a 2 ml water bolus analysed qualitatively. An abnormal swallowing pattern was demonstrated in 19 patients. Those with an Angle Class III malocclusion had the highest rate of abnormal swallowing. Video based ultrasound scanning in the sagittal plane seems to be a useful screening method for the diagnosis of poor tongue coordination during swallowing, especially for the imaging of tongue thrust in children. PMID- 7835527 TI - Radiological findings in jaws and skull of neurofibromatosis type 1 patients. AB - Maxillary and mandibular lesions in neurofibromatosis Type 1 (NF1) in patients are described. Radiographic manifestations include radiolucent lesions with well defined, poorly-defined or irregular diffuse borders. Mandibular lesions were not associated with the inferior alveolar nerve as it coursed within the mandible. In three patients the lesions extended considerably into the cranial bones. The necessity for routine radiographic and CT evaluation of NF1 patients is emphasized. PMID- 7835528 TI - Physiology of oral swallowing studied by ultrasonography. AB - The aim of the study was to identify a number of sonographic landmarks in the evaluation of the oral phase of swallowing. Forty non-dysphagic adults (average age 38 years) and 20 normal bottle-fed newborns (average age 13 days) were submitted to videorecorded sonographic examination using two types of transducers (5 and 7.5 MHz). The adults were asked to swallow a 20 ml bolus of water and the newborns were examined while sucking from a bottle containing milk. Preliminary transverse scans of the neck were obtained to evaluate laryngeal movements during swallowing. The mouth was examined through the submental window using sagittal and coronal scans. In the newborn, additional transbuccal scans were employed. In both adults and newborns highly significant and reproducible images of single element motor events involved in swallowing were obtained. Normal sonographic images of the oral stage of deglutition form the baseline from which abnormal patterns may then be recognized. PMID- 7835529 TI - Odontogenic keratocyst involving the maxillary sinus: report of two cases. AB - The occurrence of odontogenic keratocysts in the maxilla is relatively rare, and invasion of the maxillary sinus unusual. Such cysts are normally small and unilocular. Two large keratocysts with different clinical features and radiological appearances, which had invaded the sinus, are discussed in the case reports presented here. It is suggested that if clinical signs and symptoms are absent, the radiological appearance on both conventional and panoramic radiography may be misinterpreted. PMID- 7835530 TI - Biostereometric measurement of oral tumour growth. Description of the technique and case report. AB - Following radiotherapy, it may be difficult to determine clinically whether tumour regression, stabilization or growth has occurred. Traditional diagnostic imaging may not be possible due to the small size of the tumour and the proximity of metallic restorations. A case of squamous cell carcinoma of the mandibular alveolar process in which these problems arose is presented. A computer-assisted biostereometric technique was used to identify volumetric change of the tumour. Polyvinylsiloxane impressions were obtained to record the anatomy of the tumour site. From these, stone models were made at four and eight weeks following radiotherapy. Using optical mapping techniques, tumour growth was demonstrated which was not evident on follow-up examinations. The methodolgy of biostereometry is presented and its advantages and potential applications are discussed. PMID- 7835531 TI - Lingual cortical defect of the mandible: an unusual presentation and tomographic diagnosis. AB - A well-defined, bilocular radiolucency was found in the angle of the lower left mandibular ramus. The patient was asymptomatic. Serial cross-sectional tomography of the lesion revealed a lingual concavity in the mandibular cortical bone. A diagnosis of atypical Stafne's bone cavity was made. PMID- 7835532 TI - Pharmacology and toxicology of chronically infused epidural clonidine.HCl in dogs. AB - To evaluate the physiological effects and toxicity of epidural clonidine.HCl, male Beagle dogs were prepared with chronic lumbar epidural catheters and administered constant infusions of either saline (N = 10), or 80 micrograms/hr (N = 6), 200 micrograms/hr (N = 6), or 320 micrograms/hr (N = 12) clonidine.HCl at a rate of 4 ml/24 hr for 28 days. Saline infusion had no effect upon any behavioral measure. Epidural clonidine produced a dose-dependent increase in thermal skin twitch response latency (antinociception), lowering of respiration rate, heart rate, and blood pressure, and increased sedation. The effects were maximum from approximately Day 1 to Day 3 when, with the exception of respiration which remained depressed, a progressive adaptation was observed over the course of the study. There were no negative effects on body weight, body temperature, motor function, bowel or bladder function, or clinical pathology values. After 28 days of continuous infusion, the dogs were deeply anesthetized and terminated. Cisternal cerebrospinal fluid taken at termination displayed no clinically significant differences in protein or glucose concentration. All groups, including control, had dogs which had a chronic inflammatory response in the epidural space, as represented by fibrosis, foreign body giant cells, and lymphocytes, but no spinal cord pathology. Both the steady-state plasma and CSF concentrations of clonidine were proportional to the dose; the ratio of CSF to plasma concentration was approximately 0.5. The failure to see any change in CSF composition, significant spinal cord pathology, or signs of tissue or organ toxicity emphasizes the safety of epidurally administered clonidine at infusion rates up to 320 micrograms/hr and at infusate concentrations up to 2 mg/ml. PMID- 7835533 TI - Polycyclic aromatic hydrocarbons decrease intracellular glutathione levels in the A20.1 murine B cell lymphoma. AB - Previous studies in this laboratory have shown that polycyclic aromatic hydrocarbons (PAHs) inhibit lymphocyte activation and alter intracellular Ca2+ homeostasis. Other investigators have demonstrated that intracellular Ca2+ may increase in lymphocytes following exposure to chemical oxidants or ionizing radiation. Cellular oxidants produce both a rise in intracellular Ca2+ and a decrease in intracellular levels of glutathione (GSH) in numerous cells and tissues. Therefore, the purpose of the present study was to determine whether PAHs alter intracellular levels of glutathione in lymphocytes. Using different, well-established glutathione assays, it was demonstrated in the A20.1 murine B lymphoma that PAHs induce a transient decrease in intracellular glutathione. A 10 25% decrease in reduced GSH was produced by benzo(a)pyrene, 7,12 dimethylbenz(a)anthracene, benz(a)anthracene, and anthracene within 2-4 hr of exposure. Benzo(e)pyrene did not alter intracellular levels of glutathione in A20.1 cells. We conclude that glutathione depletion may contribute to cell injury in lymphocytes exposed to PAHs. PMID- 7835534 TI - Erythrocyte and plasma cholinesterase activity in male and female rhesus monkeys before and after exposure to sarin. AB - The rhesus monkey (Macaca mulatta) has a menstrual cycle similar to the human. Differences in hormone levels have been demonstrated between the sexes and in females during the menstrual cycle but these differences in terms of organophosphorus toxicity have not been explored. Plasma cholinesterase (ChE/BuChE) and erythrocyte (RBC) acetylcholinesterase (AChE) activity were measured before and after exposure to the organophosphorus compound sarin (11 micrograms/kg, i.v.; 0.75 LD50) in six male and six female rhesus monkeys. After baseline measurements were obtained, sarin was administered to atropinized monkeys to determine in vivo differences between the sexes in their response to sarin. With the baseline values, the intraanimal and intragroup BuChE/AChE variations were found to be minimal. Following sarin intoxication and 2-PAM treatment no significant differences were seen between the sexes in the rate of reactivation of BuChE or AChE by 2-PAM. The rate of aging of sarin phosphonylated RBC AChE between the sexes was also similar. De novo regeneration of RBC AChE and plasma BuChE after sarin intoxication was different between the male and female monkeys. The female plasma BuChE recovery rate was 48% slower than the male recovery rate, while the early (first 63 days) RBC AChE recovery rate was 24.5% faster in the females. In conclusion, there probably are not any clinically significant differences between male and female rhesus monkeys acutely intoxicated with sarin. However, on subsequent exposure clinical differences may be observed due to substantial differences in the rate of de novo synthesis of both plasma BuChE and RBC AChE. PMID- 7835535 TI - Histopathology and cell replication responses in the respiratory tract of rats and mice exposed by inhalation to glutaraldehyde for up to 13 weeks. AB - In addition to being a respiratory tract irritant and cross-linking agent, glutaraldehyde has a number of properties in common with the rodent nasal carcinogen, formaldehyde. The acute and subchronic responses to glutaraldehyde in the respiratory tract of rats and mice were characterized using histopathology and epithelial cell labeling index as end points. Male and female F344 rats and B6C3F1 mice were whole-body exposed for 1 day, 4 days, 6 weeks, or 13 weeks to 0, 62.5, 125, 250, 500, or 1000 ppb glutaraldehyde using a recycling inhalation chamber. The respiratory tract, with special reference to the nose, was examined by light microscopy and histoautoradiography. Unit length labeling index (ULLI) was determined by nuclear thymidine labeling for selected sites, chosen on the basis of histopathology. A small number of animals exposed to 1000 ppb (rats and mice) or 500 ppb (mice) died before the 6-week time point; these deaths were attributed to glutaraldehyde exposure-associated occlusion of the external nares. Treatment-induced lesions, including epithelial erosions, inflammation, and squamous metaplasia, were confined to the anterior third of the nose and were present in both sexes and species. No histopathological evidence of glutaraldehyde-induced responses was observed in the trachea, central airways, or lungs, while the larynx showed minimal changes. There were clear increases in ULLI in association with acute and subacute cytotoxic responses, with similar concentration-response relationships. Neutrophilic infiltration of the squamous epithelium of the nasal vestibule, present in both rats and mice, became progressively more severe with increasing exposure time and was associated with increased ULLI. The latter responses were generally most severe at the higher glutaraldehyde exposure concentrations, while in female mice they were present at all concentrations of glutaraldehyde studied. Lesions induced by glutaraldehyde were more anterior in the nose than those reported for formaldehyde, they differed in character, and no evidence of "pre-neoplastic" lesions or karyomegaly, reported for formaldehyde, was observed with glutaraldehyde. PMID- 7835536 TI - Relationship of carcinogenicity and cellular proliferation induced by mutagenic noncarcinogens vs carcinogens. III. Organophosphate pesticides vs tris(2,3 dibromopropyl)phosphate. AB - Our laboratory has been examining the mechanisms whereby chemicals produce mutagenicity in short-term in vitro assays yet fail to produce carcinogenesis in 2-year rodent bioassays. Previous studies indicated that some mutagenic hepatocarcinogens increased cell proliferation in the target organ, the liver, while other structurally related mutagens that were noncarcinogenic failed to do so. We demonstrate in this report that another mutagenic carcinogen, tris(2,3 dibromopropyl phosphate), increased cell proliferation that was localized in the outer medulla of the kidney. This was also the target site for carcinogenesis in a 2-year bioassay and is another example of the association between chemically induced cell proliferation and carcinogenesis. This study also reports the absence of increased cell proliferation in the liver or kidney after exposure in the diet to the mutagenic organophosphate insecticides dimethoate, dioxathion, and dichlorvos following dietary exposure for 2 weeks at the same dose levels and routes of exposure that did not increase the tumor incidence in either organ in 2 year carcinogenesis assays. The present studies support the tenet that chemically induced cell proliferation may be a necessary prerequisite for chemical carcinogenesis, since in rat liver and kidney there was neither cell proliferation after 2 weeks nor tumor development after 2 years dietary exposure to the mutagenic organophosphate insecticides dimethoate, dioxathion, and dichlorvos. PMID- 7835537 TI - Reproductive and developmental toxicity studies of silicone gel Q7-2159A in rats and rabbits. AB - Studies reported here assessed the potential adverse effects of silicone gel, Dow Corning Q7-2159A, on general reproduction and fetal development in male and female Charles River CD rats and New Zealand white rabbits. Two control and three treatment groups of 30 male and 30 female rats and 25 female rabbits per group were used in the one-generation reproduction and developmental toxicity studies, respectively. The silicone gel was implanted subcutaneously in two flank sites at dosage levels of 3, 10, and 30 ml/kg. The highest dose was selected on the basis of likely human body burden. Control groups received either sterile saline or carboxymethylcellulose solution in two flank implantation sites. The control and test articles were implanted in male and female rats 61 and 47 days, respectively, prior to mating (in the rat reproduction study) and approximately 42 days prior to insemination of female rabbits (in the rabbit developmental toxicity study). There were no treatment-related effects on F0 parental general conditions and reproductive performance, F1 neonatal viability, or growth in the rat reproduction study. No maternal nor developmental effects, including teratogenicity, were observed in rabbits in the groups implanted with Q7-2159A gel in the developmental toxicity study. PMID- 7835538 TI - Reproductive and developmental toxicity studies of silicone elastomer Q7-2423/Q7 2551 in rats and rabbits. AB - The purpose of these studies was to assess the potential adverse effects of silicone breast implant envelope elastomer on general reproduction and fetal development in rats and rabbits. One control and one treatment group of 30 male and 30 female Charles River CD rats and 25 inseminated New Zealand white rabbits per group were used in the one-generation reproductive and developmental toxicity studies, respectively. Two 1.2-cm discs of silicone elastomer were subcutaneously implanted in one site in the left flank and one site in the right-flank of the treated group of rats, while four 2.5-cm discs were implanted in two sites in the left flank and two sites in the right flank of the treated group of rabbits. The size of the elastomer implants was chosen to approximate the expected body burden of women with breast implants. The control animals in both studies received subcutaneous implantation of either 1.2- or 2.5-cm discs of polyethylene of the same number in the same locations. The control and test articles were implanted in the male and female rats at 61 and 47 days, respectively, prior to mating (in the rat reproduction study) and approximately 42 days prior to insemination of female rabbits (in the rabbit developmental toxicity study). Subcutaneously implanted discs of silicone breast implant envelope elastomer did not induce maternal or developmental toxicity before or during pregnancy or during lactation, did not cause any adverse effects on the parents or neonates, and did not impair reproductive performance in the rat reproduction study. No maternal toxicity or adverse developmental effects, including teratogenicity, were observed in the treated groups in the rabbit developmental toxicity study. PMID- 7835539 TI - Inhalation toxicity of aerosolized pentamidine isethionate in rats and dogs. AB - The toxicity of inhaled aerosolized pentamidine isethionate solutions in rats and dogs was evaluated. Nose-only exposure equipment and a mass mean aerodynamic particle size of < or = 2 microns were employed. Rats received either a single inhaled dose estimated at 0, 1.4, 2.1, or 6.0 mg/kg/exposure day or 4 inhaled doses evenly spaced over 13 weeks estimated at 0, 0.35, 0.7, or 1.4 mg/kg/exposure day. Dogs were administered a single inhaled dose estimated at 0, 1.1, 3.4, or 5.0 mg/kg/exposure day. Rats administered a single inhaled dose of 6.0 mg/kg/exposure day exhibited respiratory distress. The lung-with-trachea weights of these animals were elevated relative to controls. The histopathology of acutely exposed rats consisted of dose-related neutrophil infiltration in the turbinates, larynx, and bronchi; erosion of epithelium in the turbinates and larynx; thickening of the alveoli walls with alveolar accumulation of mononuclear cells and neutrophils; and rhinitis. Rats in the highest dose group in the subchronic evaluation exhibited decreased body weight gains and reduced lung-with trachea-to-body weight ratios relative to controls. Hematology, clinical chemistry, and urinalysis values were within normal ranges. Microscopic pulmonary tissue changes were similar to those found in acute exposure with certain lesions (e.g., mucous cell hyperplasia) suggestive of a more chronic process. In addition, lung fibrosis was seen at the highest dose. In dogs, pentamidine isethionate did not cause a change in the respiratory minute volume (not measured in rats). Elevated lung-with-trachea weights were noted in the high- dose females. Hematology, clinical chemistry, and urinalysis values were within normal ranges.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7835540 TI - Measurement of nuclear DNA modification by 32P-postlabeling in the kidneys of male and female Fischer 344 rats after multiple gavage doses of hydroquinone. AB - Oral administration of hydroquinone (HQ) to male Fischer 344 (F344) rats results in dose-related kidney toxicity beginning with mild enzymuria by 1 week, significant cell proliferation by 6 weeks, and nephropathy and an increase in the incidence of renal tubule adenomas after 2 years. Female F344 rats, B6C3F1 mice, Sprague-Dawley rats, dogs, and humans are resistant to the renal toxicity of HQ associated with repeated exposure. To determine the potential of HQ to induce covalent DNA adducts in the kidney, male and female F344 rats were given 0, 2.5, 25, or 50 mg/kg HQ by gavage for 6 weeks, and nuclear DNA isolated from kidneys was analyzed by the 32P-postlabeling assay. At 50 mg/kg, males, but not females, showed an increase in the rate of excretion of N-acetyl-beta-D-glucosaminidase, indicative of proximal tubular damage. Analysis of nuclear DNA preparations by the postlabeling assay showed that HQ does not produce covalent DNA adducts in the kidneys of male and female rats. The assay's lower limit of detection is 1 adduct in 10(9) to 10(10) DNA nucleotides. No treatment-related increases in background radioactivity levels on the chromatograms were seen at locations corresponding to the major in vitro adducts of HQ and p-benzoquinone. HQ treatment, however, resulted in the reduction of the levels of certain endogenous adducts (I-compounds), the biological significance of which is unknown.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7835541 TI - Measurement of cell proliferation in the kidneys of Fischer 344 and Sprague Dawley rats after gavage administration of hydroquinone. AB - Oral administration of hydroquinone (HQ) over 2 years to male Fischer 344 (F344) rats results in a dose-related nephropathy and an increase in the incidence of renal tubule adenomas. Female F344 rats, B6C3F1 mice, and Sprague-Dawley (SD) rats are resistant to the chronic renal toxicity of HQ, and nephrotoxicity was not seen in dogs or humans following subchronic exposure. To better characterize the early development of renal toxicity in rats, cell proliferation was quantitated within the proximal (P1, P2, and P3) and distal tubule segments of the kidney in rats given 0, 2.5, 25, or 50 mg/kg HQ by gavage. Male and female F344 rats were treated for 1, 3, or 6 weeks, and male SD rats were treated for 6 weeks. Cell proliferation was quantitated by incorporation of bromodeoxyuridine, detected immunohistochemically, into newly synthesized DNA. At 6 weeks, renal cell proliferation was increased over vehicle-controls in male F344 rats dosed at 50 mg/kg. Significant elevations (p < 0.001) occurred in the P1 segments (87%) and in the P2 segments (50%) but the elevation in the P3 segment (34%) was not statistically significant. Urinalyses revealed increases in the rate of excretion of enzymes indicative of proximal tubular damage. Histopathologic evaluation of the kidneys was consistent with a dose-related tubular degeneration in the male F344 rat. No chemical-related effects were observed in the kidneys of female F344 and male SD rats. These data parallel the findings of sex- and strain-specific kidney adenomas in the 2-year bioassays, and suggest that chemically induced cell proliferation secondary to toxicity may be important in the pathogenesis of benign renal tumors in male F344 rats treated with HQ. PMID- 7835542 TI - Disposition and pharmacokinetics of isopropanol in F-344 rats and B6C3F1 mice. AB - The absorption, metabolism, disposition, and excretion of isopropanol (IPA) were studied in male and female rats and mice. Animals were exposed by i.v. (300 mg/kg) and inhalation (500 and 5000 ppm for 6 hr) routes; additionally, IPA was given by gavage to rats only in single and multiple 300 and 3000 mg/kg doses. In the rat approximately 81-89% of the administered dose was exhaled (as acetone, CO2, and unmetabolized IPA); approximately 76% of the dose in mice was exhaled after i.v. bolus but 92% was exhaled following inhalation. Approximately 3-8% of the administered dose was excreted in urine as IPA, acetone, and a metabolite tentatively identified as isopropyl glucuronic acid. Small amounts of radiolabel were found in feces and in the carcass. There were no major differences in the rates or routes of excretion observed either between sexes or between routes of administration. Additionally, repeated exposure had no effect on excretion. However, both the route of administration and the exposure or dose level influenced the form in which material was exhaled. Following exposure to 5000 ppm, a greater percentage of unmetabolized IPA was recovered in the expired air than following exposure to 500 ppm, implying saturation of metabolism. PMID- 7835543 TI - Isopropanol 13-week vapor inhalation study in rats and mice with neurotoxicity evaluation in rats. AB - This study was conducted to evaluate the possible subchronic toxicity as well as neurobehavioral effects of isopropanol, a widely used industrial and commercial solvent. Five groups, each containing 10 Fischer 344 rats/sex and 10 CD-1 mice/sex, were exposed for 6 hr/day, 5 days/week, for 13 weeks to isopropanol vapor at concentrations of 0 (control), 100, 500, 1500, or 5000 ppm. An additional 15 rats/sex were assigned to the 0, 500, 1500, and 5000 ppm groups for assessment of neurobehavioral function. No exposure-related mortalities occurred during the study. The narcotic effects of isopropanol were noted only during exposures at 1500 and 5000 ppm. These signs, noted during exposures, were typically absent following exposures. The only clinical signs observed following exposures included swollen periocular tissue, perinasal encrustation, and ataxia for rats of the 5000 ppm group. Neurobehavioral evaluations indicated no changes in any of the parameters of the functional observational battery; however, increased motor activity for female rats in the 5000 ppm group was noted at Weeks 9 and 13. Decreases in body weight and body weight gain were observed for rats of the 5000 ppm group at the end of the first week of exposure. During the remaining weeks, increases in body weight and/or body weight gain were observed for rats of the 1500 and 5000 ppm groups. No exposure-related effects on body weight were noted for male mice; however, increased body weight and body weight gain were observed for female mice of the 5000 ppm group.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7835544 TI - Metabolism and testicular toxicity of 1,3-dinitrobenzene in rats of different ages. AB - Susceptibility to 1,3-dinitrobenzene (1,3-DNB)-induced testicular damage is known to increase with age. The present study investigated the possibility that age dependent differences in metabolism and disposition could account for differences in toxicity. [14C]1,3-DNB (25 mg/kg, ip) was administered to Sprague-Dawley rats which were 31, 75, or 120 days of age. Levels of 1,3-DNB and 1,3-DNB metabolites were determined in blood and urine. As animal age increased, peak blood concentrations of 1,3-DNB were lower and declined more slowly indicating an age dependent decrease in rate of metabolism and a possible increase in volume of distribution. In younger animals, faster elimination rates were associated with higher blood levels of metabolites. Urinary metabolites were generally similar for all age groups with the exception of the diacetamidobenzene metabolite which was significantly lower in the urine of 31 days old rats. There were clear differences in the toxicokinetic profile for 1,3-DNB between the 31 day old rats and the other two age groups. However, differences between the 75 and 120 day old animals were less marked. Testicular damage induced by 1,3-DNB (25 mg/kg, ip) was hardly detectable in the youngest animals, while the intermediate age group showed a moderate lesion particularly in later stages of spermatogenesis. For the oldest animals, testicular damage was more severe, particularly in the earlier stages of spermatogenesis. Overall, the rapid elimination rate could account for the lack of 1,3-DNB toxicity in very young animals. However, simple metabolic differences were less likely to adequately explain the increase in testicular damage found as animal age increased from 75 to 120 days. PMID- 7835545 TI - Developmental neurotoxicity: evaluation of testing procedures with methylazoxymethanol and methylmercury. AB - Testing procedures for identification of potential developmental neurotoxicants were evaluated using two prototypical developmental neurotoxicants, methylazoxymethanol (MAM) and methylmercury (MeHg). Evaluation of offspring of Long-Evans rats incorporated assessments of developmental toxicity, neurochemistry, histology, and behavior, with most testing being completed near weaning. A number of endpoints in the testing strategy were sensitive to the effects of prenatal exposure to MAM [30 mg/kg on Gestation Day (GD) 15]: (1) MAM caused reduced neonatal body weights but did not effect viability or postnatal survivorship; (2) measurement of total and regional brain weight and histological analysis showed that a number of regions, the cortex and hippocampus in particular, were affected by MAM exposure; (3) an assay for glial fibrillary acidic protein (GFAP) showed that the concentration of this protein was significantly increased in the cortex and hippocampus of treated offspring; (4) a T-maze delayed-alternation procedure indicated that MAM-treated pups were slower in the acquisition phase of the task relative to control pups; (5) motor activity testing revealed hyperactivity in treated offspring that persisted into adulthood; and (6) acoustic startle procedures revealed reduced startle amplitudes in preweanlings. Few endpoints were significantly affected by prenatal MeHg exposure (1, 2, or 4 mg/kg on GD 6-15). High fetal and neonatal mortality and lower neonatal body weights were detected at the highest dose of MeHg. Although minimal effects of MeHg may reflect a relative insensitivity of the test species and/or the test methods, the combined results from both chemicals suggest that some procedures not currently required in the developmental neurotoxicity guideline may be useful in hazard identification, and further evaluation with other chemicals, species, strains, and/or exposure paradigms may be warranted. PMID- 7835546 TI - Accumulation of polychlorinated dibenzo-p-dioxins and dibenzofurans in liver of control laboratory rats. AB - Polychlorinated dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs), and biphenyls belong to a class of compounds, the polyhalogenated aromatic hydrocarbons (PHAHs), which are ubiquitous environmental contaminants. Due to the existence of a common mechanism of action, i.e., binding to the Ah receptor, the activity of members of this class of compounds is generally expressed relative to the prototypical 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as toxic equivalency factors (TEFs). In the present studies we examined the presence of liver of untreated PCDFs in standard laboratory feed and in the liver of untreated rats at three different ages (60, 140, and 200 days) in terms of concentration and in toxic equivalents (TEQs, TEF x concentration). Feed was shown to contain trace amounts of PCDDs and PCDFs and control rat liver was shown to contain several PCDD and PCDF congeners in terms of concentration of congener and concentration of TEQs contributed by that congener. The total concentration of TEQs increased with increasing age in rat liver, going from 20 ppt TEQ at 60 days to 78 ppt TEQ at 200 days of age. This accumulation in dioxin-like activity was due primarily to PCDFs. In particular the congener 2,3,4,7,8-pentachlorodibenzofuran accrued in untreated rat liver accounting for approximately 80% of the total TEQ at 200 days of age. These studies affirm the pervasive presence of PHAHs and suggest prudence in evaluating chronic rat studies in which interference from background levels of PCDDs and PCDFs may be a factor. PMID- 7835547 TI - Nongenotoxic effects of polycyclic aromatic hydrocarbons and their oxygenation by products on the intercellular communication of rat liver epithelial cells. AB - Since polycyclic aromatic hydrocarbons (PAHs) are known to have epigenetic effects, we evaluated the effect of the parent chemical and the ozonated products on in vitro cell to cell communication bioassays which measures a nongenotoxic event. The scrape loading/dye transfer (SL/DT) technique was used to determine the effect of the following PAHs on gap-junction intercellular communication (GJIC): fluorene, 1-methyl-fluorene, fluoranthene, anthracene, 9-methyl anthracene, phenanthrene, pyrene, benzo(a)pyrene, and benzo(e)pyrene. The methylated PAHs were more inhibitory to GJIC than the unmethylated counterparts. Fluoranthene, which has an additional ring added to fluorene, was more effective in inhibiting GJIC than fluorene. The three-ringed PAHs were also more inhibitory than the four- and five-ringed PAHs. A time-course study of fluoranthene and of pyrene resulted in maximal inhibition occurring within 30 min of incubation with the cells. The cells recovered from the inhibition within 1 hr after fluoranthene and pyrene were removed from the cell culture medium. Pyene, vbenzo(a)pyrene, fluorene, and fluoranthene were ozonated until the parent compound was completely eliminated as determined by reverse-phase high-pressure liquid chromatography (RP HPLC). An increased level of inhibition of GJIC was observed for the ozonated mixtures of by-products of pyrene, fluoranthene, and benzo(a)pyrene, but not for fluorene, as monitored with the SL/DT technique. The products of the ozonated pyrene mixture were fractionated and collected by RP-HPLC. Each fraction was found to be inhibitory to GJIC as monitored by fluorescence recovery after photobleaching. In conclusion, current treatment technologies, such as ozonation or biologically based oxidations and methylations, do not necessarily eliminate toxicity.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7835548 TI - [Reuse of single-use catheters: a dilemma to be clarified]. AB - This paper proposes a cost benefit approach in evaluating reuse of single-use catheters, introducing cost of disposal and the concept of financial risk. An estimation of relevant variable and fixed costs is discussed, according to conditions and prices presently existing in Northern Italy. A formal model is developed to compare alternative reuse and no-reuse strategies. Use of internal versus external (Service centers) sterilization is also briefly scrutinized. A short review of literature concerning reuse is aimed to place the issue in the proper framework, listing critical problems as far as safety, risks of rupture, identification and control procedures, legal responsibility, informed consent by the patient. The conclusion is proposed that reuse of Medium-to-High cost catheters is highly profitable from the economic standpoint, subject to the condition that stringent quality procedures and controls are implemented to assess reasonable safety on behalf of the patient. Further, size of potential savings and gain in number of procedures performed are likely to request at least some institutional attention. Last, pooling relevant risks among several institutions is a plausible way to lower costs and make reuse possible also to smaller centers. The model may be used for self-assessment purposes concerning reuse introduction; the actual estimate of risk is critical in evaluating results. PMID- 7835549 TI - [Dynamic transthoracic and transesophageal tridimensional echocardiography using rotational technique. A new perspective in echocardiography]. AB - BACKGROUND: For many years, there has been a long-standing interest in developing three-dimensional echocardiography and several approaches have been followed. However, the main interest has been centered on reconstruction of left ventricular cavity. So far, dynamic three-dimensional representation of cardiac structures has been rather disappointing. OBJECTIVES: In this study, we describe the clinical application of dynamic three-dimensional echocardiography with a rotational imaging acquisition. METHODS: Three-dimensional echocardiography was performed in 50 patients referred to the Echocardiographic Laboratory at the Thoraxcenter for routine standard two-dimensional echocardiography (multiplane transesophageal = 30 patients; transthoracic = 20 patients) for different reasons. For transthoracic echocardiography, patients with good quality images were selected. We used prototype ultrasound probes connected to commercially available echocardiographic equipments interfaced to the Echo-Scan system. The steering logic of the system controlled the image acquisition in a given plane, at a predetermined moment in the respiratory and heart cycles (respiratory and ECG gating). Ninety rotational (2 degree interval) sector images of the heart were collected. The images were digitized, reformatted and interpolated, yielding a three-dimensional data set. From this data set, any desired cross-section of the heart could be computed, volume rendered and displayed in motion. Different algorithms were applied and mixed to produce a shaded dynamic three-dimensional display of cardiac anatomy. RESULTS: Acquisition of images and three-dimensional reconstructions were possible in all the patients. Both conventional and unusual projections were displayed. Thus, we were able to represent the cardiac structures from cutting planes which could not be visualized from standard transthoracic or transesophageal approaches. In particular, in patients with mitral valve prolapse and mitral stenosis the left atrial "surgical" view on the valve provided additional information on both site and extent of leaflets pathology. The presence and the degree of systolic anterior movement were seen in all the patients with hypertrophic cardiomyopathy and outflow obstruction, and the site of the leaflet involved identified. CONCLUSIONS: Dynamic three dimensional echocardiography is clinically feasible and has the potential to offer information unavailable with conventional two-dimensional echocardiography. Rotational scanning is the logical extension of multiplane transesophageal probe, and circumvents the limitations due to the small acoustic windows during precordial acquisition. PMID- 7835550 TI - [High-resolution ultrasonographic study of atherosclerotic lesions of the carotid arteries in borderline essential arterial hypertension]. AB - BACKGROUND: High resolution echotomographic study of the carotid arteries allows the examination of the arterial wall and the resulting alterations from different factors. Aim of the present study is to evaluate the atherosclerotic lesions of the extracranial carotid arteries wall in subjects with essential borderline arterial hypertension, pharmacologically untreated. The selection of the patients was made, at first, by means of sphigmomanometric measurement of blood pressure and successively by means of 24-hour blood pressure monitoring. METHODS: We studied: 59 subjects with borderline essential hypertension with casual systolic arterial pressure between 140 and 160 mm Hg and/or diastolic between 90 and 95 mm Hg and increased ambulatorial pressure; 11 subjects with white coat hypertension with casual systolic pressure between 140 and 160 mm Hg and/or diastolic between 90 and 95 mm Hg with normal ambulatorial pressure; 30 normotensive subjects with casual blood pressure < 140/90 mm Hg and normal ambulatorial pressure. Borderline hypertensive subjects were divided in two groups: Group 1 with sensible fall of blood pressure values, from day to night, more than 10% (14.3% systolic and 14.5% diastolic), and Group 2 with reduced nocturnal blood pressure fall, lesser than 10% (3.8% systolic, 2.7% diastolic). All the patients underwent high-resolution B mode echotomography of both carotid arteries, which consented the evaluation of the myointimal thickening, of the atherosclerotic plaques with their echogenic characteristics and seat. A thickness > or = 0.95 mm Hg was considered as myointimal thickening, while a thickness > or = 2 mm was considered as plaque. RESULTS: In 59 borderline hypertensive subjects, compared with normotensive subjects, it was more frequent the detection either of myointimal thickening (p < 0.01) or subjects with plaques (p < 0.05), or subjects with more than one plaque (p < 0.05). In those subjects with white coat hypertension, it was detected a prevalence of myointimal thickening and plaques identical to that of normotensive subjects and lesser compared with borderline hypertensive subjects, not statistically meaningful. In those hypertensive subjects with reduced nocturnal blood pressure fall (Group 2), compared with Group 1, it was significatively more frequent the detection of myointimal thickening (p < 0.01), of subjects with plaques (p < 0.01) and subjects with more than one plaque (p < 0.05). There were no meaningful differences either among hypertensive and normotensive subjects or between those two sub-groups of hypertensive subjects for what concerns seat and echogenic characteristics of the plaques: the more frequent localization was at level of the common carotid artery and bifurcation, and less frequently at level of internal and external carotid artery. More frequently "hard" plaques and less frequently "fibrous", "mixed" and "soft" plaques were found. CONCLUSIONS: In conclusion, the results of our investigation document the role of the increase of the blood pressure, even of mild entity like in borderline essential hypertension, in determining atherosclerotic lesions of the carotid arterial wall, and the usefulness of both the echotomographic study, that shows such lesions, and of the ambulatory monitoring, that allows a better selection of hypertensive patients, to study and identify hypertensive subjects at minor or major risk. PMID- 7835552 TI - [Spontaneous closure of coronary fistulas: a possible prognostic role of the site of drainage]. AB - The case of a 34 month-old infant with cardiac murmur and echocardiographic signs of coronary artery fistula is presented. Cardiac catheterization was performed, revealing a right coronary artery-to-right ventricle fistula, and a significant left-to-right shunt. At 4.0 years of age she underwent a repeated catheterization, showing complete spontaneous closure of the fistula. Review of the literature shows that fistulas draining into the right ventricle have some chance to close spontaneously. Accordingly, clinical approach should therefore be considered. PMID- 7835551 TI - [Usefulness of ultrasonographic techniques in catheterization of the internal jugular vein in patients with chronic heart failure]. AB - BACKGROUND: The right internal jugular vein as a route for right heart catheterization and continuous infusion of drugs is increasingly used in patients with heart failure. Although this approach has several advantages, a small but definite number of unsuccessful vein punctures and/or of complications have been reported. This prospective study was designed to evaluate the usefulness of ultrasound techniques for cannulating internal jugular vein in a series of 310 consecutive patients with chronic heart failure. METHODS: In all patients a duplex scanning of internal jugular veins was performed before the cannulation. A subgroup of 62 patients was selected for having a "difficult" cannulation according to the following criteria: previous failure of cannulating the vein (3 unsuccessful needle advances); neck abnormalities; severe emphysema and respiratory insufficiency. In these patients a Doppler-guidance system, which consisted of a miniature ultrasound Doppler transducer inserted in a standard 19 gauge needle, was used. The needle was advanced under the skin following the maximal audio signal of the venous flow. The following variables were considered: success rate, number of needle advances to cannulate the vein, time elapsed from local anesthesia and the insertion of the catheter, minor and major complications. RESULTS: Duplex scanning showed that in 14 patients (4.5%) the right internal jugular vein was occluded or severely narrowed. In all patients the left internal jugular vein, which showed a compensatory dilatation, was successfully cannulated. In 294 of the remaining 296 patients the position of the vein was anterior to the carotid artery at a depth of 4-27 mm below the skin. With respect of the triangle formed by the two heads of the sternocleidomastoid muscle, the vein was central in 35%, medial in 15% and lateral in 60% of cases. Based on duplex scanning ultrasound data, 285 patients underwent internal jugular vein cannulation, which was achieved at the first attempt in 74% and within 3 attempts in 87% of cases. Minor and major complications occurred in 4 (1.4%) and in 1 (0.3%) respectively. By the Doppler guidance system, the cannulation was successfully achieved in 79% of patients at the first attempt and in 98% of patients (61/62) within 3 attempts. In one patient an uneventful puncture of the carotid artery occurred. The time to perform the cannulation was not significantly different using the two approaches (conventional approach: 4.4 +/- 3 minutes; Doppler guidance system: 4.2 +/- 2). Overall the internal jugular vein was successfully cannulated in 307/310 patients (99%). CONCLUSIONS: Ultrasound techniques provide useful information which facilitates the cannulation of the internal jugular vein in patients with heart failure. The Doppler guidance method allows a rapid and safe cannulation of the vein even in cases that are difficult using the conventional approach. PMID- 7835553 TI - [Syncope: an update on physiopathology, diagnosis and therapy]. PMID- 7835554 TI - [Children are not small adults]. PMID- 7835555 TI - [Autonomy and responsibility in medical action]. PMID- 7835557 TI - [Drug interactions in therapy of cardiac decompensation]. PMID- 7835556 TI - [Guide to intensive care of refractory heart decompensation]. PMID- 7835558 TI - [When to think about heart transplant?]. PMID- 7835559 TI - [Exercise test: indications and interpretation limitations in patients with heart failure]. PMID- 7835560 TI - [Endomyocardial biopsy]. PMID- 7835561 TI - [Difficult control of hyponatremia in congestive cardiac decompensation]. PMID- 7835562 TI - [Infections in patients with cardiac insufficiency]. PMID- 7835563 TI - [Should physical activity of the patient with chronic cardiac decompensation be encouraged or discouraged? Sexual activity?]. PMID- 7835564 TI - [Cardiac decompensation and syncope]. PMID- 7835565 TI - [Electrostimulation in cardiac decompensation]. PMID- 7835566 TI - [Atrial fibrillation of imprecise duration: when to think about cardioversion]. PMID- 7835567 TI - [Complex and asymptomatic hyperkinetic ventricular arrhythmias: a daily difficult decision problem]. PMID- 7835568 TI - [For which patients with cardiac decompensation is prevention of thromboembolism advisable?]. PMID- 7835569 TI - [Patients with advanced cardiac failure]. PMID- 7835570 TI - [A.N.M.C.O. Program for the biennium 1994-96]. PMID- 7835571 TI - Sensitization to painful distention and abnormal sensory perception in the esophagus. AB - BACKGROUND/AIMS: The mechanism of abnormal esophageal sensory perception in patients with unexplained chest pain is unknown. The aim of this study was to test the following two hypotheses: (1) similar to cutaneous nociceptors, esophageal stretch receptors can be sensitized by a noxious chemical stimulus, and (2) patients with esophageal chest pain have sensitized receptors. METHODS: Twenty-five patients with noncardiac chest pain underwent esophageal manometry, provocation tests, and 24-hour pH monitoring. Eleven patients had positive and 14 had negative results of esophageal provocation tests. Esophageal perception and pain thresholds for balloon stretch (in milliliters) and electrical stimulation (in milliamperes) were determined in patients and 7 healthy controls performed before and after randomized, double-blind esophageal perfusion with normal saline or 0.1N HCl. RESULTS: The basal balloon pain threshold was lower in patients with positive results of esophageal tests than in either those patients with negative results of esophageal tests or controls (P < 0.05). After acid perfusion, balloon perception and pain thresholds decreased in patients with negative results of esophageal tests (P < 0.05) and in controls (P < 0.05) but not in patients with positive results of esophageal tests. No change occurred after saline perfusion nor in electrical pain thresholds in any group after the perfusion of either fluid. CONCLUSIONS: In patients with negative results of esophageal tests and in controls, the pain threshold to balloon distention is lowered by acid. The lack of such effect in patients with positive results of esophageal tests implies that pain receptors may already be sensitized. PMID- 7835572 TI - Role of luminal ammonia in the development of gastropathy and hypergastrinemia in the rat. AB - BACKGROUND/AIMS: Chronic infection with Helicobacter pylori causes persistent elevations in gastric juice ammonia levels. Thus, we studied the effects of experimentally induced increases in gastric juice ammonia levels on gastric structure and function and gastrin homeostasis. METHODS: Rats were fed either normal chow or the diet supplemented (20 g/dL) with ammonium or sodium acetate. RESULTS: Long-term dietary ammonium loading for 2 weeks or longer resulted in a 1.5-2-fold increase in the weight and mucosal thickness of the stomach and proximal duodenum with evidence of mild gastritis and enterochromaffinlike cell hyperplasia. The ammonium-containing diet also induced a significant 2-3-fold increase in both circulating gastrin levels of fed rats and an increase in the postprandial gastrin responses over control values. Antral gastrin levels were also markedly elevated by long-term ingestion of the test diet, which was increased 3-4-fold over control values in fasted animals and less so after meal stimulation. Consistent with these findings, gastrin-specific messenger RNA was increased 2.5-3-fold in the antrum of ammonium fed rats, whereas actin-specific messenger RNA was not affected or decreased. Animals fed a diet supplemented with 20 g/dL sodium acetate sustained modest increases in mucosal thickness and serum and antral gastrin concentration, suggesting that nonspecific gastric injury and inflammation is also a factor that influences G-cell function. CONCLUSIONS: Long term exposure of the antral mucosa to elevated levels of ammonia in the gastric juice in the presence of gastritis, conditions similar to that occurring in subjects infected with H. pylori, seem to be causative factors in the development of G-cell hyperfunction. PMID- 7835573 TI - Gastric tone determines the sensitivity of the stomach to distention. AB - BACKGROUND/AIMS: Whether meal-related symptoms such as postcibal epigastric fullness and discomfort are caused by hypotonic gastric expansion or gastric hypertension is unknown. This study investigated whether symptoms in healthy individuals in response to gastric distention are produced by gastric expansion or by an increase in intragastric pressure. METHODS: Increasing gastric distentions (for 5 minutes at 5-minute intervals) at fixed pressure levels (in 2 mm Hg increments) and at fixed volume levels (in 200-mL increments) were performed in 10 healthy subjects per group; perception was measured on a 0-6 scale. Distentions were performed during intravenous infusion of saline (basal) and during gastric relaxation by intravenous administration of glucagon (4.8 micrograms/kg bolus plus 9.6 micrograms.kg-1.h-1 infusion). RESULTS: The same distending pressure tested produced 30% +/- 9% larger intragastric volumes and 80% +/- 44% higher perception scores when the stomach was relaxed by glucagon (P < 0.05 vs. basal for both). In contrast, the same distending volumes tested produced 25% +/- 7% lower intragastric pressures and 21% +/- 12% lower perception scores when the stomach was relaxed (P < 0.05 vs. basal for both). CONCLUSIONS: Epigastric symptoms in response to gastric distention are influenced by both the intragastric pressure and the intragastric volume. PMID- 7835574 TI - Long-term survival after photodynamic therapy for esophageal cancer. AB - BACKGROUND/AIMS: Photodynamic therapy (PDT) has been adapted to the endoscopic treatment of digestive cancer, but its indications and efficacy remain uncertain. The aim of this study was to assess its feasibility in the curative treatment of small esophageal tumors. METHODS: From 1983 to 1991, PDT was used to treat 123 patients with esophageal cancer who were recommended for nonsurgical treatment of squamous cell carcinoma (n = 104) and adenocarcinoma (n = 19). Endoscopic ultrasonography (EUS) was performed in 88 patients; 61 were staged uT1 and 27 were staged uT2. A hematoporphyrin derivative was injected 72 hours before laser irradiation with a 630-nm dye laser. PDT was applied alone in 56 patients and as part of a multimodal protocol in the 67 others. RESULTS: The complete response rate at 6 months was 87%. The 5-year survival rate was 25% +/- 6%, and the 5-year disease-specific survival rate was 74% +/- 5%. The complete response rate and survival rate were not different (1) between the PDT alone and the PDT multimodal treatment groups, (2) between the adenocarcinoma and squamous cell carcinoma groups, and (3) between the uT1 and uT2 EUS groups. PDT-related complications were esophageal stenosis (n = 43) and cutaneous photosensitization (n = 16). CONCLUSIONS: In patients with small esophageal tumors who pose high surgical risk, photodynamic therapy is an effective treatment. PMID- 7835575 TI - Mesalamine in the prevention of endoscopic recurrence after intestinal resection for Crohn's disease. Italian Cooperative Study Group. AB - BACKGROUND/AIMS: Recurrence of lesions of Crohn's disease of the ileum within 1 year after so-called curative resection was well documented by endoscopy in 73% 93% of cases. This study investigated the efficacy of mesalamine in reduction of endoscopic recurrence after surgery. METHODS: In a double-blind, multicenter clinical trial, 87 patients were treated with 3 g/day mesalamine (Pentasa) or with placebo within 1 month after surgery. After 12 months of treatment, severity of endoscopic lesions was recorded with a five-point score; when it was not possible to reach the anastomosis by endoscopy, a barium enema was performed. RESULTS: Seventeen clinical relapses (seven in the mesalamine group) were recorded. After 12 months, the endoscopic lesions were less frequent and less severe in the mesalamine group than were those in the placebo group (chi 2, 13.5; P < 0.008). The overall rate of severe recurrence (score of 3-4 on endoscopy or radiological documentation) was 24% in the mesalamine group and 56% in the placebo group (chi 2, 8.57; P < 0.004; difference 32%; 95% confidence interval, 22-52). The odds ratio for active treatment was 4.1. CONCLUSIONS: This study shows that mesalamine is useful in decreasing the rate and severity of endoscopic recurrences after curative surgery for ileal Crohn's disease. PMID- 7835576 TI - Hyperglycemia inhibits mechanoreceptor-mediated gastrocolonic responses and colonic peristaltic reflexes in healthy humans. AB - BACKGROUND/AIMS: The effects of hyperglycemia on colonic motor function are unknown. Therefore, colonic neuromuscular function was tested in normal volunteers as a model for constipation in diabetes. METHODS: Extended (gastrocolonic response) and local (peristaltic reflex) neural responses and colonic muscle contractility were tested under control, hyperglycemic clamp, and euglycemic, hyperinsulinemic clamp conditions with placement of barostat regulated balloons in the descending colon to measure changes in tone as differences in balloon volume. RESULTS: Hyperglycemic clamping to 274 +/- 3 mg/dL blunted increases in colon tone evoked by gastric distention (gastrocolonic response) (100-300 mL) but did not affect gastric tone. Three descending colonic balloons in series assessed the peristaltic reflex. Inflation of the middle stimulus balloon increased proximal tone, an increase that was blunted by hyperglycemia, but produced distal relaxation followed by increases in tone that were unaffected by hyperglycemia. Euglycemic, hyperinsulinemic clamping had no effect on the gastrocolonic response or peristaltic reflex. Tonic increases evoked by bethanechol (5 mg administered subcutaneously) were unaffected by hyperglycemic clamping. CONCLUSIONS: Hyperglycemia blunts mechanoreceptor mediated gastrocolonic responses and ascending contractions but not descending components of the peristaltic reflex in humans, effects not caused by hyperinsulinemia or direct muscle actions. These inhibitory effects on long and short neural reflexes that modulate colonic motility may contribute to constipation in diabetes. PMID- 7835577 TI - Quantitative endoscopy: precise computerized measurement of metaplastic epithelial surface area in Barrett's esophagus. AB - BACKGROUND/AIMS: The inability to precisely measure the area of Barrett's metaplasia has impaired the study of its natural history and response to therapy. This study used a novel computer program that creates two-dimensional maps of the esophagus allowing for calculation of the area of Barrett's metaplasia. METHODS: Endoscopic photographs of Barrett's models and patients were obtained by independent endoscopists. The program transformed the photographs into maps, and the area of Barrett's metaplasia was calculated. RESULTS: Using models, calculated areas correlated with actual areas (r = 0.96) with an overall error of 5.2%. Color, size, shape, diameter of the model, or endoscopist's experience did not affect the accuracy. Accuracy did improve by decreasing the interval between photographs from 4 cm (10.0% error) to 2 cm (4.8% error). In patients, area calculations from maps created by independent technicians correlated precisely (r = 0.99) at 1-cm (n = 22) and 2-cm (n = 40) intervals. Independent endoscopists correlated precisely in producing photographs for map construction (r = 0.99; n = 20). CONCLUSIONS: This novel computer technology produces two-dimensional maps of Barrett's metaplasia that can be used to accurately calculate area. Minimal interobserver variability in obtaining photographs is found. PMID- 7835578 TI - Scanning electron-microscopic lesions in Crohn's disease: relevance for the interpretation of postoperative recurrence. AB - BACKGROUND/AIMS: Endoscopic postoperative recurrence often occurs a few months after surgical therapy for Crohn's disease, even if the resection margins were macroscopically free of disease. Why the disease primarily recurs at the anastomotic site is not known. This study investigated resection margins in Crohn's disease in an attempt to clarify whether early lesions are relevant to the interpretation of postoperative recurrence. METHODS: Specimens of surgically resected bowel from 29 patients with Crohn's disease and tissue from 11 controls were studied with a scanning electron microscope. RESULTS: In Crohn's disease, a triad of early lesions occurring in both histopathologically unaffected and affected mucosa was revealed; the triad consisted of mucosal architectural alterations, epithelial bridge formation, and goblet-cell hyperplasia or hypertrophy or both. Seventy-three percent of patients showed early alterations within histopathologically unaffected margins in the small bowel, and 71% had such alterations in the large bowel. CONCLUSIONS: The findings provide further evidence for the concept of diffuse involvement of the whole gastrointestinal tract by the disease process. The endoscopic recurrence rate in the first year after the operative procedure is almost identical to the number of early lesions present during surgery. The term "postoperatively recurrent disease" should be used only if relevant clinical parameters change. PMID- 7835579 TI - Common occurrence of APC and K-ras gene mutations in the spectrum of colitis associated neoplasias. AB - BACKGROUND/AIMS: Chronic colitis is associated with an increased risk of colorectal neoplasia, creating a need for early diagnosis in this population. Little is yet known of the genetic changes of early lesions. Cases of colitis associated neoplasia were analyzed for APC and K-ras mutations with special emphasis given to the spectrum of noninvasive lesions. METHODS: Ten patients were studied. APC mutations were screened by an in vitro synthesized protein assay, and K-ras mutations were screened by a ligation assay. RESULTS: APC mutations were found in 5 patients, including dysplasias. K-ras mutations were present in 5 patients and in all classes of lesions, including 5 of 14 lesions indefinite for dysplasia. In only 2 patients were no mutations found. CONCLUSIONS: Mutations of APC and K-ras are common in colitis-associated neoplasia and can occur early in neoplastic progression. Serrated lesions and lesions indefinite for dysplasia may harbor genetic changes and thus are clonal, highlighting the importance of distinguishing them histologically. Assays for APC and K-ras mutations are promising as adjuncts to surveillance programs. Care will be needed in their application because the confident diagnosis of early lesions presumed to be of lesser clinical importance will raise new issues concerning prudent patient management. PMID- 7835580 TI - Incidence and recurrence rates of colorectal adenomas: a prospective study. AB - BACKGROUND/AIMS: The frequency of colorectal adenomas, the precursor lesions for most cases of colorectal carcinoma, has been generally measured as prevalence rates of adenomas at autopsy or colonoscopy. The aim of this study was to estimate the incidence rate of adenomas and compare it with the adenoma recurrence rate. METHODS: Data on colonoscopies performed in three New York City practices were collected prospectively. The cumulative rate of adenoma diagnosis on repeat colonoscopy was calculated for patients with no abnormalities on index colonoscopy ("incidence" rate) and for patients with adenomas on the index colonoscopy ("recurrence" rate). RESULTS: The cumulative incidence rate of adenomas at 36 months was 16%, and the cumulative recurrence rate at 36 months was 42% (P < 0.004). The recurrence rate was higher in patients with multiple adenomas than in those with a single adenoma on index colonoscopy, although the increase was not statistically significant. CONCLUSIONS: Although the recurrence rate has always been assumed to be elevated, this study is the first to compare the recurrence rate of adenomas with the incidence rate directly and to show that the recurrence rate is indeed elevated. PMID- 7835581 TI - Human eosinophils migrate across an intestinal epithelium in response to platelet activating factor. AB - BACKGROUND/AIMS: Transmigration of eosinophils across intestinal epithelia occurs in a variety of mucosal inflammatory disorders and results in the formation of crypt abscesses containing eosinophils. However, the conditions required to drive transepithelial migration of eosinophils are not understood. METHODS: This study investigated eosinophil migration across intestinal epithelia using purified eosinophils and confluent monolayers of the human intestinal epithelial cell line T84. RESULTS: Unactivated eosinophils (i.e., no granulocyte/macrophage colony stimulating factor [GM-CSF] preexposure) did not migrate across T84 monolayers in the presence of transepithelial gradients of C5a, n-formyl-methionyl-leucyl phenylalanine (fMLP), or platelet-activating factor (PAF). In contrast, activation of eosinophils by coincubation or pretreatment with GM-CSF enabled transepithelial migration in response to PAF but not to C5a or fMLP gradients in a time- and dose-dependent fashion. Specificity was confirmed by both the PAF receptor antagonist WEB-2086 and the PAF enantiomer 2-lyso-beta-acetyl-gamma-O hexadecyl. Finally, addition of functionally inhibitory monoclonal antibodies to CD11b but not CD11a, very late activation antigen (VLA-4), or intracellular adhesion molecule 1 inhibited eosinophil migration. CONCLUSIONS: These studies establish that physiologically directed migration of eosinophils across model epithelia occurs but that this process is governed by the state of eosinophil activation, the specific chemotactic gradient imposed, and the availability of specific surface integrins to participate in putative eosinophil-epithelial adhesion steps. PMID- 7835582 TI - Metabolic bone assessment in patients with inflammatory bowel disease. AB - BACKGROUND/AIMS: Patients with inflammatory bowel disease are at risk for osteopenia. To study the metabolic bone status of these patients, a cross sectional study was conducted. METHODS: Eighty-four patients (49 women, 35 men) with inflammatory bowel disease, 34 of whom had Crohn's disease and 50 ulcerative colitis (including 18 with prior coloproctectomy and ileoanal anastomosis), underwent clinical, dietary, and spine radiological assessments. Bone metabolism was assessed by measuring serum levels of calcium, phosphate, parathyroid hormone (1-84), 25-hydroxyvitamin D3, 1,25-dihydroxyvitamin D3, and osteocalcin. Lumbar and femoral neck bone mineral densities were measured by dual energy X-ray absorptiometry. RESULTS: Serum osteocalcin level was decreased in 29 patients (34%), 12 of whom had never undergone steroid therapy. The other biochemical markers of bone metabolism were in the normal range. Thirty-six patients (43%) had osteopenia, and 6 patients (7%) had vertebral crush fractures. Osteopenia was observed in 27 patients (52%) and 9 patients (28%) with and without corticosteroid therapy, respectively. No patient had clinical or biological signs of osteomalacia. Analysis of bone density (lumbar Z score) by a multiple regression analysis showed a statistically significant correlation with age, cumulative corticosteroid doses, sedimentation rate, and osteocalcin level (R2 = 0.76; P = 0.05). CONCLUSIONS: The results suggest that bone turnover in inflammatory bowel disease is characterized by low bone formation in the presence of normal levels of calcium-regulating hormones. PMID- 7835583 TI - Molecularly defined HLA-DR2 alleles in ulcerative colitis and an antineutrophil cytoplasmic antibody-positive subgroup. AB - BACKGROUND/AIMS: Although HLA-DR2 is associated with Japanese ulcerative colitis, data regarding an HLA-DR2 association in other populations are conflicting. A recent study suggests that HLA-DR2 is only associated with antineutrophil cytoplasmic antibody-positive ulcerative colitis. The aim of this study was to determine whether HLA-DR2 or the molecularly defined alleles within the HLA-DR2 group are associated with ulcerative colitis or a perinuclear antineutrophil cytoplasmic antibody-positive subgroup. METHODS: Unrelated white patients with a history of ulcerative colitis (n = 97) and control subjects matched to patients for Jewish ethnicity and sex (n = 149) were studied. An immunofluorescence assay was used to detect perinuclear antineutrophil cytoplasmic antibodies. A molecular, DNA-based method was used to perform HLA-DR2 typing. RESULTS: HLA DRB1*1601 was present in 11 of 149 controls and 1 of 97 patients (P = 0.031, corrected P, not significant; Fisher's Exact Test). There were no other significant differences between ulcerative colitis or ulcerative colitis stratified by perinuclear antineutrophil cytoplasmic antibody status and controls. CONCLUSIONS: The HLA-DR2 group of alleles is not associated with ulcerative colitis or a perinuclear antineutrophil cytoplasmic antibody-positive subgroup. The unexpected finding of a decreased frequency of HLA-DRB1*1601 in ulcerative colitis should be further investigated. PMID- 7835584 TI - Antineutrophil antibodies in familial inflammatory bowel disease. AB - BACKGROUND/AIMS: Antineutrophil cytoplasmic antibodies have been reported to occur more frequently in healthy first-degree relatives of patients with ulcerative colitis than in healthy controls. The aim of this study was to determine their prevalence in families in which more than one member was affected with inflammatory bowel disease. METHODS: With use of an indirect immunofluorescence method, 168 affected members and 197 unaffected first-degree relatives in 56 such families were studied. RESULTS: Antibodies were detected in 46% of patients with ulcerative colitis without a positive family history and in 44% of those within families with several affected members. There was no evidence of clustering of antibodies in particular families. Within families in which both ulcerative colitis and Crohn's disease coexisted, antibodies were detected primarily in patients with ulcerative colitis. Antibodies were seldom present (3%) in those patients with Crohn's disease, whether they were familial or nonfamilial cases. Similarly, antibodies were seldom present (3%) in controls or the unaffected first-degree relatives of patients with inflammatory bowel disease. CONCLUSIONS: Antineutrophil cytoplasmic antibodies are associated with ulcerative colitis, and their presence is not increased in the first-degree relatives of patients with ulcerative colitis. They are more likely to be a consequence of the disease than a subclinical genetic disease marker. PMID- 7835585 TI - Frequent and characteristic K-ras activation and absence of p53 protein accumulation in aberrant crypt foci of the colon. AB - BACKGROUND/AIMS: The relationship of aberrant crypt foci (ACF) to colorectal carcinogenesis is still controversial. Histological examination and analyses of K ras mutations and p53 gene expression were performed to characterize ACF. METHODS: ACF were identified microscopically in grossly normal colorectal mucosa. The ACF were separated into two pieces, one for histological and immunohistochemical examinations and the other for molecular analysis. K-ras mutations in codons 12 and 13 were analyzed by polymerase chain reaction amplification, followed by restriction fragment length polymorphism and sequencing analyses. Intranuclear p53 protein was immunostained by the avidin biotin complex method. RESULTS: Histologically, elongation and apical branching of the crypts in ACF were striking. K-ras mutations were detected in 58% of ACF (33 of 57; 46% [26 of 57] in codon 12, and 12% [7 of 57] in codon 13) and in 44% of adenocarcinomas (11 of 25; all in codon 12). In ACF, GAT mutations (12 of 26) were as frequent as GTT mutations (11 of 26) in codon 12, although GTT mutations in codon 12 were predominant in adenocarcinomas (10 of 11). No accumulation of p53 protein was detected in any ACF, although it was detected in 52% (13 of 25) of the colorectal carcinomas. CONCLUSIONS: ACF do not seem histologically to be neoplasms, although genetically they are monoclonal lesions. K-ras mutation is critical in the formation of ACF, but p53 alteration could play a causal role in tumor progression. PMID- 7835586 TI - Inhibition of resting lower esophageal sphincter pressure by pharyngeal water stimulation in humans. AB - BACKGROUND/AIMS: Normal inhibition of lower esophageal sphincter (LES) tone occurs during swallowing and belching. However, it is known that it may occur independently of these functions. The aim of this study was to characterize the effect of pharyngeal water stimulation on resting LES pressure. METHODS: The effect of rapid-pulse and slow continuous intrapharyngeal injection of minute increments of water on the resting tone of the upper and LES of 14 healthy young volunteers was evaluated by concurrent manometry, submental electromyography, and respirography. RESULTS: At a threshold volume, pharyngeal water injection induced an isolated LES relaxation in all volunteers. The threshold volume inducing LES relaxation by rapid-pulse injection, 0.16 +/- 0.01 mL, was significantly lower than that with slow continuous injection (0.5 +/- 0.05 mL) (P < 0.05). The duration and magnitude of LES relaxation were not volume dependent. The duration of LES relaxation induced by rapid-pulse injection was significantly longer than that of swallows. CONCLUSIONS: Minute amounts of liquid injected into the pharynx induce LES relaxation different from that of the normal swallow. Neither the duration nor the magnitude of this relaxation is volume dependent. Whereas the contribution of this finding to the mechanism of transient LES relaxation remains to be ascertained, it may partially explain the variability of the basal LES pressure. PMID- 7835587 TI - Regulation of terminal differentiation of zymogenic cells by transforming growth factor alpha in transgenic mice. AB - BACKGROUND/AIMS: Transforming growth factor (TGF) alpha affects the growth of gastric mucosa. Its overexpression alters the mucosa. The aim of this study was to test the possibility that it regulates differentiation of gland cells. METHODS: Transgenic mice that overexpress TGF-alpha were used to detect its effect on zymogenic (chief) cells in the stomach. To test for a general regulatory role of TGF-alpha in differentiation of zymogen-producing cells, salivary glands from transgenic mice were studied. RESULTS: In these mice, messenger RNA for pepsinogen C is present in the stomach at normal levels during the neonatal period and then decreases markedly. Zymogenic cells are present in the stomach during the neonatal period but are missing in transgenic adults. The bases of gastric glands, normally rich in zymogenic cells, are occupied by undifferentiated cells and mucous neck cells, the precursors of zymogenic cells. Zymogen granules in submandibular glands of transgenic female mice are reduced in number. Zymogen granule-containing cells in the parotid gland undergo redifferentiation to form tubular complexes, collections of ductularlike structures like those formed in the transgenic pancreas. CONCLUSIONS: TGF-alpha is a major participant in the regulation of terminal differentiation of zymogenic cells in the stomach and salivary glands. PMID- 7835588 TI - Heterogeneity of liver-kidney microsomal autoantibodies in chronic hepatitis C and D virus infection. AB - BACKGROUND/AIMS: Anti-liver-kidney microsomal (LKM) autoantibodies occur in a proportion of patients with chronic hepatitis C and D infections. Because of different immunofluorescence patterns, antibodies in hepatitis C and D were termed LKM-1 and LKM-3, respectively. The aim of the present study was to evaluate the different specificities of LKM-1 and LKM-3 antibodies. METHODS: Forty-nine samples of LKM-1 sera and 16 samples of LKM-3 sera were studied for reactivity against rat and human liver microsomal proteins by immunofluorescence, enzyme-linked immunosorbent assay, and Western blot. RESULTS: Thirty-four percent of the LKM-1 sera reacted with 50-kilodalton cytochrome P4502D6 in Western blot. In addition, a proportion of the sera recognized either a 59- or 70-kilodalton antigen, and 45% of the sera did not react in Western blot. Recently, the major LKM-3 antigen was identified as an autoepitope expressed on uridine diphosphate glucuronosyltransferases (UGT). Seven LKM-3-positive sera reacted with recombinant rabbit family one UGT. None of the anti-LKM-1-positive hepatitis C sera reacted with UGT. Antibody reactivity against liver microsomal proteins in enzyme-linked immunosorbent assay ended when antigens were pretreated with sodium dodecyl sulfate, confirming that antibodies recognize conformational epitopes. CONCLUSIONS: LKM-1 antibodies in hepatitis C are more heterogeneous and react with different antigens compared with LKM-3 antibodies in hepatitis D. PMID- 7835589 TI - Endotoxin-stimulated nitric oxide production increases injury and reduces rat liver chemiluminescence during reperfusion. AB - BACKGROUND/AIMS: Nitric oxide has many physiological functions and may play an important role in modulating tissue injury. However, the mechanism of NO action in ischemia/reperfusion injury is completely unknown. This report investigates the role of NO in hepatic reperfusion injury. METHODS: Rat liver was oxygenated for 30 minutes, followed by 30 minutes of ischemia, and then reperfused for 30 minutes. Perfusate was sampled for aspartate aminotransferase content, as an indication of hepatic injury, and for nitrite, an index of NO production. Spontaneous organ chemiluminescence was continuously monitored as a measure of oxyradical production. RESULTS: NO production by the perfused rat liver was induced in vivo by pretreatment with Escherichia coli lipopolysaccharide. This induction led to an increase in hepatic injury during reperfusion that was partially ameliorated by the NO synthase inhibitor NG-monomethyl-L-arginine. Chemiluminescence during reperfusion, a measure of superoxide production in this system, was also decreased in the lipopolysaccharide-treated animals, and this effect was blunted by NG-monomethyl-L-arginine. CONCLUSIONS: These data suggest that NO may combine with superoxide formed during reperfusion to directly cause hepatocellular injury. In vitro work shows that this chemical product is the highly toxic species peroxynitrite. PMID- 7835590 TI - Effects of extracellular Ca2+ and HCO3- on epidermal growth factor-induced DNA synthesis in cultured rat hepatocytes. AB - BACKGROUND/AIMS: The elevation of cytosolic free calcium concentration ([Ca2+]i) and intracellular pH mediate the growth factor-initiated proliferation of many cells, but it is not known if they trigger mitosis in resting hepatocytes. The maintenance of [Ca2+]i and intracellular pH depends partly on extracellular calcium concentration ([Ca2+]e) and extracellular bicarbonate concentration ([HCO3-]e). Therefore, the effects of [Ca2+]e and [HCO3-]e on hepatocyte proliferation were examined. METHODS: Epidermal growth factor induced proliferation in primary cultures of rat hepatocytes. [3H]thymidine incorporation into DNA and nuclear labeling indices were measured. RESULTS: Between 0.2 and 0.9 mmol/L of [Ca2+]e, the proliferative response to epidermal growth factor increased, and total hepatocellular Ca2+ content was increased. Increasing [HCO3 ]e also stimulated DNA synthesis in a concentration-dependent manner, maximal at 35 mmol/L. Using optimal [Ca2+]e (0.9 mmol/L) and [HCO3-]e (35 mmol/L), a synergistic stimulation of hepatocellular DNA synthesis was shown. Voltage dependent Ca2+ channel blockers failed to inhibit hepatocyte proliferation when administered in concentrations that inhibit proliferation in other cell types. CONCLUSIONS: [Ca2+]e and [HCO3-]e are both essential for hepatocyte proliferation, and their effects are synergistic. The entry of extracellular Ca2+ is critical for epidermal growth factor-induced DNA synthesis in hepatocytes, but this is not mediated by voltage-dependent Ca2+ channels. PMID- 7835591 TI - Liver resection and cyst fenestration in the treatment of severe polycystic liver disease. AB - BACKGROUND/AIMS: There is limited information on treatment options for massive, highly symptomatic polycystic liver disease. The aim of the study was to analyze the immediate and long-term outcome of combined liver resection and fenestration. METHODS: Information was abstracted from medical records. Follow-up was obtained by mailed questionnaire. Liver volume was quantified by computed tomography. RESULTS: Thirty-one patients underwent liver resection and fenestration between July 1985 and June 1993. Mean liver volume was 9357 mL before and 3567 mL after surgery. There was one death from postoperative intracerebral bleed. Eighteen patients experienced complications, usually transient pleural effusions or transient ascites. Twenty-eight of 29 surviving patients with adequate follow-up have experienced immediate and sustained relief of symptoms and improvement in quality of life. After median follow-up of 2.4 years (range, 0.2 to 7.9 years), most patients have not had clinically significant enlargement of the liver. Sequential computed tomography scans before and after surgery suggest that hepatic enlargement in the age range of the patients in the study mainly resulted from the expansion of existing cysts rather than from the development of new cysts. CONCLUSIONS: Selected patients with severe symptomatic polycystic liver disease and favorable anatomy benefit from liver resection and fenestration with acceptable morbidity and mortality. The extent of hepatic resection and fenestration is important for the long-term effectiveness of this procedure. PMID- 7835592 TI - Immunostaining for membrane attack complex of complement is related to cell necrosis in fulminant and acute hepatitis. AB - BACKGROUND/AIMS: Complement activation is one of the mechanisms involved in inflammatory lesions. Initiation of the complement terminal pathway at a cell surface leads to the formation of a cytolytic membrane attack complex. Our study assess whether a membrane attack complex-associated mechanism is involved in liver cell necrosis of fulminant and subfulminant hepatitis. METHODS: Immunostaining for membrane attack complex was compared with immunostaining for cytokeratin and complement inhibitory proteins such as membrane cofactor protein, decay-accelerating factor, and homologous restriction factor in 15 patients with fulminant hepatitis and 5 patients with nonfulminant acute hepatitis. RESULTS: In all patients, hepatocytes surrounding necrotic areas, but not those at a distance, were stained for membrane attack complex, whereas the opposite staining pattern for membrane cofactor protein was observed. In controls, no hepatocyte staining for membrane attack complex was observed, whereas membrane cofactor protein, but not decay-accelerating factor or homologous restriction factor, was detected on hepatocytes. CONCLUSIONS: Complement activation by antibody-dependent or non-antibody-dependent mechanisms might be involved in the pathogenesis of either fulminant or acute hepatitis. Modulation of membrane cofactor protein expression on hepatocytes might contribute to the sensitivity of hepatocytes to membrane attack complex and subsequent cell lysis. PMID- 7835593 TI - Genomic variations in the hepatitis B core gene: a possible factor influencing response to interferon alfa treatment. AB - BACKGROUND/AIMS: Interferon treatment causes a sustained loss of virus replication only in a proportion of patients with chronic hepatitis B. This study investigated whether genomic variations in the precore/core gene of hepatitis B virus affect the response to interferon alfa. METHODS: The precore/core region was sequenced in 46 serum samples obtained before, during, and after interferon treatment of 12 patients. RESULTS: In 23 samples from 7 responders (group A), there were 24 missense mutations, whereas in 23 samples from 5 patients who did not respond or relapsed after treatment (group B), there were 141 missense mutations (P < 0.001). All group B patients had cirrhosis, but only 2 of 7 patients in group A had cirrhosis (P = 0.026). Substitutions in amino acids 21-27 of the core protein, known to diminish HLA-A2-restricted cytotoxic T-cell function, were found in all nonresponders but in none of the responders. No significant changes occurred in the precore/core region in responders after seroconversion to antibody to hepatitis B e antigen, but multiple variations persisted in group B during treatment and new mutations appeared with the relapse of hepatitis. CONCLUSIONS: Specific mutations in the core protein that can interfere with T-cell function occur frequently in patients with advanced chronic hepatitis B and may affect the response to interferon. PMID- 7835594 TI - Fatty acid ethyl esters decrease human hepatoblastoma cell proliferation and protein synthesis. AB - BACKGROUND/AIMS: Fatty acid ethyl esters (FAEEs) are nonoxidative products of ethanol metabolism. They have been implicated as mediators of ethanol-induced organ damage because FAEE and FAEE synthase have been found specifically in the organs damaged by ethanol abuse. This study showed toxicity specifically related to FAEE or their metabolites for intact human hepatoblastoma-derived cells (HepG2). METHODS: The lipid core of human low-density lipoprotein (LDL) was extracted and the LDL particle reconstituted with either ethyl oleate or ethyl arachidonate. Cultured HepG2 cells were incubated with LDL containing FAEE. Cell proliferation was measured by [methyl-3H]thymidine incorporation. Protein synthesis was determined using L-[35S]methionine. RESULTS: Incubation of cells with 600 mumol/L ethyl oleate or 800 mumol/L ethyl arachidonate decreased [methyl 3H]thymidine incorporation into HepG2 cells by 31% and 37%, respectively. LDL reconstituted with 400 mumol/L ethyl oleate decreased protein synthesis in intact HepG2 cells by 41%. Electron microscopy revealed significant changes in cell morphology, particularly involving the cell nucleus. FAEE delivered in reconstituted LDL were rapidly hydrolyzed and the fatty acids re-esterified into phospholipids, triglycerides, and cholesterol esters, with preference for triglycerides. CONCLUSIONS: These findings provide evidence that FAEE are toxic for intact human hepatoblastoma cells and that they or their metabolites may be an important causative agent in ethanol-induced liver damage. PMID- 7835595 TI - The alpha 6-integrin receptor in pancreatic carcinoma. AB - BACKGROUND/AIMS: The alpha 6-containing integrin was suggested to be involved in the process of tumor invasion and metastasis. Therefore, the aim of the study was to investigate the expression and function of this adhesion receptor in pancreatic carcinoma. METHODS: Integrin expression was investigated in pancreatic tissue and tumor cell lines using immunohistochemistry. Radioimmunoprecipitation was used to determine the complex composition of alpha 6. To analyze the function of the alpha 6-containing integrin in pancreatic cancer, in vitro adhesion, migration, and invasion experiments were performed. RESULTS: The alpha 6 containing integrin was differentially expressed in normal pancreas and pancreatic carcinoma. Immunoprecipitation of different pancreatic carcinoma cell lines showed that alpha 6 was expressed together with the beta 4 subunit as alpha 6 beta 4 complex. However, adhesion of pancreatic cancer cells to laminin could be inhibited with anti-alpha 6 and anti-beta 1 integrin antibodies but not by anti-beta 4 integrin antibody. Migration of the cells through laminin was almost completely inhibited by anti-beta 1 antibody but not by other anti-integrin antibodies. Tumor cell invasion through a reconstituted basement membrane was only slightly inhibited by anti-alpha 6 antibody. In contrast, a marked inhibition was observed using anti-beta 1 antibodies, anti-alpha 2-anti-alpha 5 antibodies, and RGDS. CONCLUSIONS: The alpha 6-containing integrin is a laminin adhesion receptor in pancreatic carcinoma cells, possibly involved in tumor invasion through the basement membrane. PMID- 7835597 TI - Achalasia-associated squamous cell carcinoma of the esophagus: flow-cytometric and histological evaluation. AB - Although the risk of cancer is increased in patients with achalasia, biomarkers of an increased cancer risk have not been evaluated. In an esophagectomy specimen of a patient with achalasia-associated squamous cell carcinoma, normal mucosal and carcinomatous samples were systematically taken for flow cytometry and histology. The distribution of DNA aneuploidy and dysplasia was mapped within the resected specimen. Four of 10 tumor samples and 4 of 16 normal mucosal samples of the esophagus showed additional aneuploid stem lines. Gastric mucosa only showed diploid DNA histograms. S-phase fraction in normal esophageal samples (7.8% +/- 1.1%) was lower than in dysplastic and carcinomatous samples (8.8% +/- 2.4%; P = NS). Areas of mild to moderate dysplasia were detected in the esophageal mucosa adjacent to the neoplasm. This report shows the potential applicability of flow cytometry in the surveillance of patients with achalasia. However, prospective endoscopic studies with long follow-up periods are required before flow cytometric and histological parameters can be used as biomarkers of an increased cancer risk in achalasia. PMID- 7835596 TI - Failure of intravenous infusion of taurocholate to down-regulate cholesterol 7 alpha-hydroxylase in rats with biliary fistulas. AB - BACKGROUND/AIMS: The decrease in cholesterol 7 alpha-hydroxylase induced by intraduodenal infusion of taurocholate in bile fistula rats may be indirect, i.e., mediated through release or absorption of an intestinal factor in response to the presence of bile salts in the intestine. The aim of this study was to determine if negative feedback regulation of cholesterol 7 alpha-hydroxylase can be shown when equimolar concentrations of taurocholate are administered intravenously, thus bypassing the intestine. METHODS: After 96 hours of biliary diversion, taurocholate (36 mumol.h-1.100 g, rat-1) was infused into the rats either intravenously or intraduodenally for the final 24 hours. Livers were then harvested for analysis of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase specific activity, cholesterol 7 alpha-hydroxylase specific activity, messenger RNA levels, and transcriptional activity. RESULTS: Intraduodenally administered taurocholate significantly decreased HMG-CoA reductase and cholesterol 7 alpha-hydroxylase specific activity by more than 50% and cholesterol 7 alpha-hydroxylase steady-state messenger RNA levels and transcriptional activity by 50%-75%. In contrast, intravenous administration of taurocholate failed to down-regulate either cholesterol 7 alpha-hydroxylase or HMG-CoA reductase. CONCLUSIONS: Passage of taurocholate through the intestine strongly potentiates negative feedback regulation of cholesterol 7 alpha hydroxylase. A putative intestinal factor, released or absorbed in the presence of bile acids in the intestinal lumen, may play a role in the regulation of bile acid synthesis. PMID- 7835598 TI - Human papillomavirus type 16-positive esophageal papilloma at an endoscopic injection sclerotherapy site. AB - Human papillomavirus infection is important for both the development of papilloma and the progression of the papilloma-carcinoma sequence in the cervix, larynx, lung, and colon. Esophageal squamous cell papilloma is rare but important as a possible precancerous lesion. Esophageal papilloma has previously been thought to develop mainly as a result of chemical irritation by chronic gastroesophageal reflux. However, a few recent studies suggested a role for papillomavirus infection in esophageal tumorigenesis, although the exact route of transmission and invasion of the virus has not been fully elucidated. A case of esophageal squamous papilloma at the site of endoscopic injection sclerotherapy (EIS) for varices is reported. Papilloma development was followed up clinically during a 2 year period, and the papilloma was removed by endoscopic mucosal resection. Histological examination of the tissue confirmed the diagnosis of squamous cell papilloma. DNA analysis of the tumor showed integration of papillomavirus type 16 but not types 18 and 33. The surrounding normal mucosa did not contain any of the three virus types. Injury such as ulceration resulting from EIS may have provided a locus susceptible to the viral infection. The clinical course after EIS should be monitored carefully to detect papilloma formation. PMID- 7835599 TI - Plurichemical transmission and chemical coding of neurons in the digestive tract. AB - The enteric nervous system contains neurons with well-defined functions. However, when neurons of the same function are examined in different regions or species, they are found to show subtle differences in their pharmacologies of transmission and different chemical coding. Individual enteric neurons use more than one transmitter, i.e., transmission is plurichemical. For example, enteric inhibitory neurons have three or more primary transmitters, including nitric oxide, vasoactive intestinal peptide, and possibly adenosine triphosphate and pituitary adenylyl cyclase activating peptide. Primary transmitters are highly conserved, although their relative roles vary considerably between gut regions. Multiple substances, including transmitters and their synthesizing enzymes and nontransmitters (such as neurofilament proteins), provide neurons with a chemical coding through which their functions and projections can be identified. Although equivalent neurons in different regions have the same primary transmitters, other chemical markers differ substantially. Caution must be taken in extrapolating pharmacological and neurochemical observations between species or even between regions in the one species. On the other hand, careful interregion and interspecies comparisons lead to an understanding of the features of enteric neurons that are highly conserved and can be used in valid extrapolation. PMID- 7835600 TI - Epidermal growth factor-related peptides and their relevance to gastrointestinal pathophysiology. PMID- 7835601 TI - The changing relative prevalence of hepatitis C virus genotypes: evidence in hemodialyzed patients and kidney recipients. AB - BACKGROUND/AIMS: Hepatitis C virus (HCV) infection by the genotype 1b is significantly associated with a lower rate of response to interferon alfa and with severe liver disease (cirrhosis and hepatocellular carcinoma). This may reflect different intrinsic properties of this genotype 1b and/or chronological differences in the epidemiology of HCV genotypes. To address the issue of variations in genotypes prevalence, we studied in the present report the HCV genotypes of 60 hemodialyzed and kidney recipients according to the date of hemodialysis. METHODS: Anti-HCV antibodies were tested by a second-generation assay (enzyme-linked immunosorbent assay 2 and recombinant immunoblot assay 2). HCV RNA was detected by reverse-transcription polymerase chain reaction. Genotyping was performed by hybridization of type-specific probes to the amplified product from the 5' untranslated region. RESULTS: Genotype 1b accounted for more than two thirds of HCV infection in patients who underwent dialysis before 1977 but less than one third in those hemodialyzed after 1985. In contrast, other genotypes (3a, 4a, 5a) appeared in the 1980s. CONCLUSIONS: These data, obtained in an homogenous group of patients, show a changing pattern of HCV genotype prevalence over time and should be considered when discussing the potential clinical implications of HCV genetic variability. PMID- 7835602 TI - Photodynamic therapy for early esophageal cancers: light versus surgical might. PMID- 7835603 TI - HLA, antineutrophil cytoplasmic autoantibody, and heterogeneity in ulcerative colitis. PMID- 7835604 TI - Aberrant crypt foci and K-ras mutations: earliest recognized players or innocent bystanders in colon carcinogenesis? PMID- 7835605 TI - The delicate balance of nitric oxide and superoxide in liver pathology. PMID- 7835606 TI - Fatty acid ethyl esters: insight or intoxication? PMID- 7835607 TI - The reliability of noninvasive tests for celiac disease. PMID- 7835608 TI - Helicobacter pylori and gastric lymphoma. PMID- 7835609 TI - Aspirin versus colonoscopy in the reduction of carcinoma of the colon. PMID- 7835610 TI - Long-term treatment of erosive esophagitis with omeprazole: does it work? PMID- 7835611 TI - A simplified staging system for hepatocellular carcinomas. PMID- 7835612 TI - Stress--the brain and the gut. PMID- 7835613 TI - The use of gastrografin for esophageal perforation. PMID- 7835614 TI - Neurobiology of relaxation training in gastroesophageal reflux disease. PMID- 7835615 TI - Notice of duplicate publication. PMID- 7835616 TI - Characterization of the contractile responses to noradrenaline and adrenaline of aorta from normotensive and hypertensive rats. AB - 1. The effects of phenoxybenzamine treatment on the contractile responses of the aorta from WKY and SH rats to noradrenaline and adrenaline have been determined. 2. There was no change in sensitivity of the aorta to noradrenaline or adrenaline with hypertension. 3. Phenoxybenzamine treatment caused nonparallel rightward shifts of the concentration-response curves to the lower concentrations of noradrenaline and adrenaline. 4. The KA value for noradrenaline on the WKY rat aorta was 4.15 x 10(-8) M and noradrenaline produced a 95% maximum response by occupying 95% of the available alpha 1-adrenoceptors. These parameters were significantly different on the SH rat aorta; thus the KA value for noradrenaline was 76.40 x 10(-8) M and noradrenaline produced a 95% maximum response by occupying 63% of the alpha 1-adrenoceptors. 5. The KA value for adrenaline on the WKY rat aorta was 5.03 x 10(-8) M and adrenaline produced a 95% maximum response by occupying 95% of the available alpha 1-adrenoceptors. These adrenaline parameters were not significantly different on the SH rat aorta. 6. In summary this study has demonstrated that although the sensitivities of the rat aorta to noradrenaline and adrenaline do not alter, there is a change in the KA and receptor reserve for noradrenaline, but not adrenaline in hypertension. PMID- 7835617 TI - Demonstration of the "anti-stress" activity of an extract of Ginkgo biloba (EGb 761) using a discrimination learning task. AB - 1. Young (4-month-old) and old (20-month-old) rats, maintained under water restriction, were trained to discriminate to obtain a small amount of drinking water as a reward. Each animal had to learn to press a lever corresponding to a light that was randomly distributed on the left or right. 2. Introduction of an auditory perturbation ("stress") during the discriminative phase of learning modified the capacity and rate of acquisition in both young and old animals, changes that were correlated with increases in plasma concentrations of epinephrine, norepinephrine and corticosterone. 3. Stress-induced detrimental changes in both discrimination learning and plasma hormones were suppressed by 20 days of oral treatment with an extract of Ginkgo biloba leaves (EGb 761; 50 or 100 mg/kg/day) in both young and old rats, effects that became statistically significant by the third day of learning (time of maximal acquisition rate). 4. EGb 761 treatment was less effective in increasing the percentage of efficient lever presses in old than in young rats, but more effective in decreasing the number of inefficient lever presses and reaction time in the older animals. 5. These results indicate that EGb 761 can facilitate behavioral adaptation despite adverse environmental influences, a property that supports its clinical use in treating cognitive impairment, especially in elderly patients. PMID- 7835618 TI - Effect of sofalcone on tyrosylprotein sulfotransferase. AB - 1. Gastric mucus glycoproteins are actively involved in the maintenance of mucosal integrity and the impairment in their elaboration is often a prominent feature in gastric pathology. In this study, we investigated the effect of an antiulcer drug, sofalcone, on the activity of tyrosylprotein sulfotransferase enzyme involved in the secretion of proteins and glycoproteins in male 8 week old rats. 2. Using poly-Glu6, Ala3, Tyr1 (EAY) as sulfate acceptor, and 3'phosphoadenosine 5'-phosphosulfate (PAPS) as sulfate donor the optimum Golgi TPST activity was obtained at pH 6.8, in presence of 0.5% Triton X-100, 20 mM MnCl2, 50 mM NaF and 2 mM 5'-AMP. 3. Introduction of sofalcone to the reaction mixture led to the enhancement in TPST activity. The rate of stimulation was proportional to the drug concentration up to 30 micrograms, at which concentration, a 55% increase in TPST activity was attained. 4. The results attest further to the value of sofalcone as a potent mucosal strengthening agent, and suggest that the agent may promote mucin secretion via activation of tyrosine sulfation. PMID- 7835619 TI - Effect of slow and rapid cystometry on in vitro rat urinary bladder DNA synthesis. AB - 1. Partial outflow obstruction induces marked changes in detrusor contractile function and morphology. One common finding in all experimental animal models of partial outflow obstruction is a significant increase in bladder mass. 2. Previous studies have demonstrated that partial outlet obstruction induces a rapid and substantial increase in [3H]thymidine incorporation into virtually all cellular elements of the bladder. 3. The present study was designed to investigate the [3H]thymidine uptake and localization induced by exposure of the in vitro whole rat bladder model to various intravesical pressures and rates of intravesical infusion. 4. The results are as follows: (a) There were no differences in DNA concentration between control and other groups. (b) Slow infusion induced a mild increase in DNA synthesis ([3H]thymidine incorporation) at 0.5 ml and a significantly greater level of DNA synthesis at 1.6 ml. (c) [3H]thymidine incorporation was significantly increased by exposure to 7.5 cm H2O, 15 cm H2O, and 30 cm H2O. (d) Exposure to 60 cm H2O and 90 cm H2O did not initiate an increase in [3H]thymidine incorporation. (e) Autoradiography showed that all tissue elements (urothelium, connective tissue, smooth muscle) participated in the response. PMID- 7835620 TI - Anticonvulsant activity of pyrrolo[1',2':1,2]imidazo[4,5-b]pyridines, pyrrolo[2',1':2,3]imidazo[4,5-c] pyridines and pyrrolo[2,1-f]purines in DBA/2 mice. AB - 1. The behavioural and anticonvulsant effects of eight pyrroloimidazopyridines (PI1a-d and PI2a-d) and four pyrrolopurines (PP) were studied after intraperitoneal administration in DBA/2 mice, a strain genetically susceptible to sound-induced seizures. 2. The anticonvulsant effects were evaluated in DBA/2 mice on seizures evoked by means of auditory stimulation (109 dB, 12-16 kHz) in animals placed singly under a perspex dome. 3. Hypothermic activity was observed after the highest doses of the pyrroloderivatives studied. 4. Our study demonstrated that the anticonvulsant effect of pyrroloimidazopyridines (PI1 7,8,8a,9-tetrahydro-6H-pyrrolo-[1',2':1,2]imidazo[4,5-b]pyrid in-6- ones) and pyrrolopurines (PP) was generally better than corresponding pyrrolobenzimidazoles (PB) and pyrroloimidazopyridines (PI2-5,5a,6,7-tetrahydro-8H pyrrolo[2',1':2,3]imidazo[4,5-c]pyridin-8- ones) and, in some cases, comparable to that of phenytoin and desmethylclobazam. 5. The anticonvulsant potency of the derivatives studied cannot be directly related to their lipophilicity. PMID- 7835621 TI - Enhancement of gastric mucus phospholipid secretion by an antiulcer agent, ebrotidine. AB - 1. Rat gastric mucosal cells, subjected to phospholipid labeling by incubating the cell suspension in DMEM with [3H]choline, were exposed to different concentrations (0-150 microM) of H2-receptor antagonists, ebrotidine and ranitidine, and the phospholipid secretory responses were evaluated. 2. In the absence of the drugs, the secretion of choline-containing phospholipids over a 1 hr period averaged 3.97% of the total cellular labeled phospholipids. Ebrotidine caused a dose-dependent increase in the rate of phospholipid secretion which was most pronounced at 1 hr and persisted for at least 2 hr. The maximal effect was attained at 120 microM ebrotidine giving a 36% increase in phospholipid secretion. 3. The phospholipid secretory response to ebrotidine was accompanied by an increase in gastric mucosal cell cAMP level which reached a maximum value of 2.1-fold over that of controls at 1 hr. Ranitidine, in contrast, neither evoked increase in cAMP level nor caused any stimulation in phospholipid secretion. 4. The results indicate that the gastroprotective properties of ebrotidine are associated with the ability of the drug to elicit a rapid stimulation in gastric mucus phospholipid secretion, and that ranitidine does not possess such property. PMID- 7835622 TI - Effect of a reserpine-like agent on the release and metabolism of [3H]NA in cell bodies and terminals. AB - 1. The reserpine-like agent, Ro4-1284 (2-hydroxy-2ethyl-3-isobutyl-9,10-dimethoxy 1,2,3,4,6,7-hexahydro- 11b-[H] benzo (a)quinolizine) releases [3H]noradrenaline ([3H]NA) from prelabelled superior cervical ganglion (cell bodies) and nictitating membrane (nerve endings) of the cat. 2. The potency of Ro 4-1284 29.0 microM was higher in the cell bodies than in the nerve endings. 3. In both tissues, exposure to the reserpine-like agent Ro 4-1284 induced a selective increase in the spontaneous outflow of [3H]DOPEG, while the [3H]OMDA metabolites to the release induced by Ro 4-1284 was very small. 4. The desamination is the preferential way of the metabolic inactivation of the [3H]NA released by the reserpine-like agent in both parts of the noradrenergic neuron. PMID- 7835623 TI - In vitro release of [3H]noradrenaline by tyramine from the superior cervical ganglion and in the nictitating membrane of the cat. AB - 1. The release and the metabolism of [3H]noradrenaline ([3H]NA) induced by tyramine was studied in the superior cervical ganglion (cell bodies) and in the nictitating membrane (nerve endings) of the cat. 2. Exposure of the ganglia to 58.0 and 174.0 microM tyramine resulted in the release of 13.7 and 11.8% respectively of the total tissue radioactivity. In the nictitating membrane, the fractional release of radioactivity was directly proportional to the concentration of tyramine (5.8, 58.0 and 174.0 microM). 3. In ganglia [3H]DOPEG accounted for 55.8% of the radioactivity released by 58.0 microM tyramine and only 10.5% of the radioactivity was unmetabolized NA. In presence of 174.0 microM tyramine, [3H]NA increased to 28.0% of the total radioactivity and [3H]DOPEG and [3H]OMDA decreased to 45.3 and 18.9% respectively. 4. In the nerve endings, the contribution of [3H]NA, [3H]DOMA and [3H]NMN increased with the concentration of tyramine while [3H]DOPEG decreased. 5. The deamination is the first step of the metabolic inactivation of [3H]NA induced by tyramine in the cell body of the postganglionic adrenergic neuron while in the nerve endings [3H]NA is preferentially O-methylated. PMID- 7835624 TI - General properties and clinical possibilities of new selective inhibitors of catechol O-methyltransferase. AB - 1. The structure of catechol O-methyltransferase (COMT) has been recently characterized and a series of new and selective COMT inhibitors developed. 2. Entacapone, nitecapone and tolcapone are nitrocatechol-type potent COMT inhibitors in vitro (Ki in nanomolar range). They are also very selective for COMT and active in vivo even after oral administration. CGP 28014 is a pyridine derivative that is active only in vivo. 3. In animal studies, these compounds inhibit effectively the O-methylation of L-dopa, thus improving its bioavailability and brain penetration and potentiating its behavioural effects. 4. Entacapone and nitecapone have mainly a peripheral effect whereas tolcapone and CGP 28014 also inhibit O-methylation in the brain. 5. In man, entacapone, nitecapone and tolcapone all inhibit dose dependently the COMT activity in erythrocytes. These COMT inhibitors also decrease the amount of COMT dependent metabolites of adrenaline and noradrenaline in plasma. 6. In human volunteers, entacapone, tolcapone and CGP 28014 improve the bioavailability of L-dopa and inhibit the formation of 3-O-methyldopa. 7. In the first clinical studies in patients with Parkinson's disease, both entacapone and tolcapone potentiate and prolong the therapeutic effect of L-dopa. PMID- 7835625 TI - Effects of lisinopril on cardiac contractility and ionic currents. AB - 1. The effects of lisinopril, an angiotensin-converting enzyme inhibitor, were studied on cardiac contractile force, action potential characteristics and membrane ionic currents. 2. In guinea-pig atria, lisinopril (0.001-1 microM) exerted a negative inotropic effect which was accompanied by a shortening of the time to peak tension and time for total contraction. However, it did not modify atrial rate or the characteristics of the ventricular action potentials recorded either in normally polarized or in depolarized papillary muscles. 3. In isolated guinea-pig ventricular myocytes, lisinopril had no effect on the inward L-type Ca2+ (ICa,L), the inward rectifier (IK1) or the delayed rectifier K+ currents (IK), but abolished the stimulation-dependent facilitation of the ICa,L. Furthermore, it did not alter a cloned human cardiac K+ current (hKv1.5) expressed in a mouse L cell line (Ltk-). 4. The absence of negative inotropic effects in patients with congestive heart failure can be explained by the potent arterial vasodilator action of lisinopril which reduced left ventricular afterload overriding the expected direct cardiodepressant effects of the drug. PMID- 7835626 TI - Gastroprotective agents in mucosal defense against Helicobacter pylori. AB - 1. Convincing evidence now exists that infection with H. pylori plays a major role in the pathogenesis of gastric disease. Having a niche bordering two major perimeters of mucosal defenses, the bacterium apparently exerts its detrimental effect on the mucus layer as well as the gastric epithelium. Therefore, gastroprotective agents capable of counteracting these detrimental effects of H. pylori are gaining importance in the treatment of gastric disease. 2. The colonization of gastric mucosa by H. pylori involves specific glycolipid receptors bearing acidic substituents, a process inhibited by gastric sulfomucins. Two antiulcer agents bearing sulfated sugar groups have been demonstrated to possess the ability to interfere with H. pylori colonization process. These are sucralfate and sulglycotide. The two agents are also potent inhibitors of H. pylori glycosulfatase activity directed against indigenous mucosal defenses. 3. A variety of extracellular enzymes such as proteases, lipases and phospholipases, elaborated by H. pylori cause the weakening of the integrity of gastric mucus coat and render the underlying epithelium vulnerable to noxious luminal contents. Among the most potent agents capable of countering the proteolytic activity of H. pylori are nitecapone, ebrotidine and sulglycotide, while ebrotidine and sulglycotide were found to be most effective inhibitors of H. pylori lipolytic activities. 4. The gastric epithelial integrity is compromized by the H. pylori cell-wall lipopolysaccharide untoward effect on the epithelial surface receptors. The interference of the lipopolysaccharide with the laminin receptor was found to be most efficiently countered by ebrotidine, sulglycotide and sucralfate, whereas sulglycotide is the most potent in the reversal of the inhibitory effect of the lipopolysaccharide on mucin receptor binding. PMID- 7835627 TI - Stimulus-secretion coupling and Ca2+ dynamics in pancreatic acinar cells. AB - 1. Unique spatiotemporal dynamics in cytosolic Ca2+ concentration, [Ca2+]c, were characterized in various cell types. In pancreatic acinar cells, physiological concentrations of cholecystokinin octapeptide, CCK-8, (< 10 pM) induce repetitive [Ca2+]c spikes commonly termed Ca2+ oscillation, whereas relatively higher concentrations (30 pM-1 nM) evoke biphasic [Ca2+]c dynamics; a rapid transient peak followed by a sustained increase. Much higher concentrations (> 1 nM) induce a large transient followed by a steep decay. 2. These [Ca2+]c dynamics correspond to secretory responses. Repetitive [Ca2+]c change is attributable to the upstroke of the bell-shaped dose-response relationship and the biphasic change is responsible for the downstroke of the relation (so called high-dose inhibited secretion). The large transient [Ca2+]c increase is associated with morphological changes such as bleb formation. 3. Possible interrelation between dose of secretagogues, secretory responses, [Ca2+]c dynamics, IP3 production, receptor occupation and morphological change will be discussed from both pharmacological and physiological points of view. PMID- 7835628 TI - Effect of prenatal exposure to antidepressants on 5-HT-stimulated phosphoinositide hydrolysis and 5-HT2 receptors in rat brain. AB - 1. Female rats were given antidepressants, with different effects on 5-HT uptake, from day 6 of pregnancy until delivery. 2. 5-HT-stimulated inositol phosphate accumulation as well as 5-HT2 receptor density were measured at two different times in the pups. 3. Prenatal exposure to fluoxetine or iprindole reduced phosphoinositide hydrolysis in 25-day-old pups. However, chronic treatment of adult rats with fluoxetine or prenatal exposure to either desipramine or tianeptine did not modify inositol phosphate accumulation. 4. After prenatal exposure, only desipramine significantly decreased the density of [3H]ketanserin labelled 5-HT2 receptors in the pups. 5. No correlation was found between changes in inositol phosphate formation and 5-HT2 receptor number. PMID- 7835629 TI - Negative chronotropic and inotropic responses to nicotine in rat right and left atria. AB - 1. Comparison between the chronotropic and inotropic effects induced by nicotine in the right and left atrial muscles of rat was investigated. 2. Nicotine (300 microM and 1 mM) significantly produced negative chronotropic and inotropic effects in the right atrium. The effects were concentration-dependent, and reached a maximum about 30 sec after nicotine administration (1 mM). The responses were attenuated with time even during exposure to nicotine (desensitization). 3. In the left atrium, nicotine (300 microM and 1 mM) caused a negative inotropic effect. The depression was decreased with an increase in the frequencies of stimulation (1-3 Hz). The negative inotropic effect reached a maximum at approx. 60 sec later. 4. Nicotine (1 mM) caused a greater negative inotropic response in the right atrium than in the left atrium by 23% (stimulated at 3 Hz). The effects were not modified by atropine (1 microM) and hexamethonium (1 mM). 5. There was no difference between single and cumulative administrations of nicotine in both right and left atrial muscles. 6. These results suggest that the negative chronotropic and inotropic effects of nicotine may be due mainly to a direct action on the cell membrane of rat atria, accompanied with down regulation of nicotinic ACh receptors. The difference between the right and left atria could result from a different innervation of the autonomic nervous system. PMID- 7835630 TI - Effect of the sulfonylurea glyburide on glutathione and glutathione peroxidase activity in alloxan-induced diabetic rat hepatocytes. AB - 1. The effect of glyburide treatment on glutathione peroxidase activity and glutathione levels of non-insulin diabetic rats has been studied. 2. Hepatic glutathione and glutathione peroxidase concentrations were significantly reduced in diabetic animals. 3. Glyburide treatment of diabetic rats for 4 weeks corrected the changes on the glutathione levels observed in diabetic liver. 4. High blood glucose levels of untreated diabetic rats were decreased following glyburide treatment as well. 5. Administration of glyburide to diabetic rats reversed the diabetes-induced changes suggesting that glyburide may directly increase liver glutathione concentrations. PMID- 7835631 TI - Outflow of dopamine and noradrenaline originating from L-dopa and L-threo-DOPS in rat renal tissues. AB - 1. The present study has examined the formation and outflow of newly-formed dopamine (DA) and noradrenaline (NA) in slices of the renal cortex of rats given L-beta-3,4-dihydroxyphenylalanine (L-DOPA) (10, 30 or 100 mg/kg i.p.) and L-threo 3-(3,4-dihydroxyphenyl)serine (L-DOPS) (10, 30 or 100 mg/kg i.p.), respectively. The outflow of 3,4-dihydroxyphenylacetic acid (DOPAC) and 3,4 dihydroxyphenylglycol (DOPEG), the deaminated metabolites of DA and NA, respectively, was also measured. 2. The accumulation of both newly-formed DA and DOPAC in renal tissues after the administration of L-DOPA was found to be dose dependent; after 30 or 100 mg/kg L-DOPA, the levels of both DA and DOPAC were, respectively, 3- and 20-fold those observed after the administration of 10 mg/kg L-DOPA. The outflow of DA and DOPAC in kidney slices of rats treated with L-DOPA was found to progressively decline with time and reflected the DA and DOPAC tissue contents. The rate constant (k) for DOPAC efflux (k = 0.0097) was higher (P < 0.01) than that for DA efflux (k = 0.0033) and did not depend on the dose of L-DOPA. DOPAC/DA perifusate ratios were 2-fold those occurring in the tissues. 3. The levels of NA in renal tissues of rats given 30 and 100 mg/kg L-DOPS were, respectively, 3- and 6-fold those observed after the administration of 10 mg/kg L DOPS. The administration of L-DOPS was also found to be accompanied by the accumulation in renal tissues of DOPEG; this was, however, not dose dependent.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7835632 TI - Role of nitric oxide in the systemic circulation of conscious hyper- and hypothyroid rats. AB - 1. N omega-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO biosynthesis, which blocks basal NO production, caused a similar increase of mean arterial pressure (MAP) in control hyper- and hypothyroid rats at the lowest dose, however, smaller pressor effects were observed with increasing doses in hyper- and hypothyroid rats. An additional dose of L-NAME (30 mg/kg), which produced no further increase in pressure, killed 90% of the hyperthyroid rats, whereas hypothyroid and control rats survived this additional dose. 2. The systemic responses to acetylcholine (ACh), an endothelium-dependent vasodilator that stimulates NO production/release, were significantly increased in hypothyroid rats, while hyperthyroid rats showed no significant differences when compared with controls. However, 10(-8) M ACh killed hyperthyroid rats, whereas control and hypothyroid rats survived this dose. 3. The maximal hypotensive response to sodium nitroprusside (SNP), an agonist that generates NO, was similar in intact controls, hyper- and hypothyroid rats. 4. These data indicate that hyper- and hypothyroidism show a reduction in basal NO synthesis/release, this reduced systemic NO tone being essential for life in hyperthyroid rats; whereas the response to ACh is not reduced and the hypotensive response to SNP did not differ between groups, indicating that the responsiveness of the systemic circulation to NO is not altered in either thyroid disorder. PMID- 7835633 TI - Photo-induced adequate nitric oxide (PIANO)-mediated relaxation in isolated rabbit corpus cavernosum. AB - 1. We further investigated our earlier proposal that NO- and NO2-carrying molecules potentiate photorelaxation using isolated rabbit corpus cavernosum. 2. Corporal smooth muscle, in the presence or absence of endothelium, relaxed only slightly upon u.v. light (366 nm) irradiation. But, NO- and/or NO2-containing compounds such as streptozotocin and NG-nitro-L-arginine methyl ester significantly (P < 0.01) enhanced photorelaxation in this tissue. In addition, NG nitro-D-arginine methyl ester, known to lack inhibitory action on NO synthase, showed concentration-dependent potentiation of the photorelaxation. 3. Oxygen radical generating system via xanthine+xanthine oxidase and guanylate cyclase inhibitor, methylene blue, significantly (P < 0.05) inhibited the streptozotocin potentiated photorelaxation. 4. Nitrite was accumulated by photolysis of streptozotocin, NG-nitro-L-arginine methyl ester and NG-nitro-D-arginine methyl ester, in a concentration and exposure time-dependent manner. 5. These observations indicate that NO is a potent relaxant of rabbit corpus cavernosum and further support our hypothesis that NO is released by photolysis from NO- and NO2-carrying molecules. PMID- 7835635 TI - Gender and test dependence of a type of kappa mediated stress induced analgesia in mice. AB - 1. In male mice, 80 inescapable footshocks (S-80) induce analgesic responses measured by the tail flick test that are blocked by naloxone and the kappa opioid antagonist, nor-binaltorphimine. We now study the nociceptive responses, induced after this particular stress, measured by the writhing test, the tail immersion test and a high intensity tail immersion test both in male and female mice. 2. In stressed males, analgesic responses are seen in all the nociceptive tests. Naloxone (10 mg/kg) does not prevent them. 3. In stressed females, in contrast with males, no analgesia is produced in the tail flick test. The writhing test and the tail immersion test registered analgesic responses that were not prevented by naloxone (10 mg/kg). 4. We conclude that only the antinociceptive kappa opioid mediated component of the stress we study is strongly dependent on gender, in contrast to other types of analgesia triggered by the same stress. PMID- 7835634 TI - Role of nitric oxide on the endothelium-dependent vasodilation in newborn piglet cerebral arteries. AB - 1. The present study was undertaken to determine whether endothelial nitric oxide (NO) is involved in the endothelium-dependent vasodilation elicited by bradykinin (BK) in rings of newborn (1-7-day-old) piglet cerebral arteries precontracted with KCl (25 mM). 2. In these rings, BK (10(-10)-10(-6) M) induced concentration dependent relaxation. The preincubation with the precursor of NO synthesis, L arginine (10(-4) M), reduced KCl-induced contraction and increased the BK relaxation. However, preincubation with the NO synthase inhibitor, NG-nitro-L arginine-methyl ester (L-NAME; 3 x 10(-5) M), increased KCl contraction and basal tone, and inhibited BK relaxation. 3. These results suggest that the endothelium of these arteries possesses the ability to produce NO, either basal or stimulated by agents like BK. PMID- 7835636 TI - Modulation of insulin secretion and 45Ca2+ efflux by dopamine in glucose stimulated pancreatic islets. AB - 1. The effect of dopamine on calcium efflux and insulin secretion is examined in the present study. For this purpose, islets isolated from adult Wistar rats were perfused or incubated at 37 degrees C for 60 min. 2. The results obtained from perfused islets indicate that 100 microM dopamine, in the presence of 5.6 mM glucose, increases insulin secretion and causes a modest elevation of 45Ca2+ efflux. However, glucose stimuli (from 5.6 to 16.7 mM) provoked an unexpected reduction of insulin release, with no alteration in calcium efflux, when 100 microM dopamine was present in the perfusion medium. 3. Similar findings were obtained in incubated islets when the prolonged effect of dopamine was investigated. 4. The observations described above led us to conclude that bioactive amines might play an important role in the modulation of the glucose induced insulin secretion. PMID- 7835637 TI - Further evidence that the tachycardiac response to 5-hydroxytryptamine in rats is not mediated via typical 5-HT2 receptors. AB - 1. In pithed rats, the receptor type of cardiac tissue mediating the tachycardiac response to 5-hydroxytryptamine (5-HT) was analysed. 2. Ketanserin, mesulergine and methiothepin, administered in doses which antagonized the pressor response to 5-HT, slightly reduced, considerably reduced and antagonized, respectively, its tachycardiac response. 3. 8-OH DPAT and RU 24969 produced no significant tachycardia, while DOI neither mimicked nor blocked the 5-HT-induced tachycardia. 4. The tachycardia was not affected by MDL 72222, metoclopramide and cocaine. 5. The hypothesis is proposed that in rats the tachycardiac response to 5-HT is mediated via 5-HT receptors belonging to an yet unclassified subtype of 5-HT1 or 5-HT2 receptors. PMID- 7835638 TI - Interaction between dihydropyridine calcium antagonists and morphine on the brain biogenic amines. AB - 1. Nifedipine, nimodipine or nisoldipine, were i.p. administered to normal, morphine treated or morphine abstinent rats in order to study their effects on brain biogenic amines and metabolites. 2. On various brain areas, the compounds studied decreased DOPAC and/or HVA levels, but increased 5-HIAA levels, leaving unchanged DA and 5-HT contents. 3. This suggested that DA turnover was decreased, whereas 5-HT turnover was increased, by inhibition of neuronal calcium influx. 4. Calcium antagonists: (a) further enhanced the effect of morphine on 5-HT turnover, which may involve an indirect inhibition of voltage sensitive calcium channels; (b) antagonized the effects of morphine on DA turnover, which are believed to be mediated by disinhibition of dopaminergic pathways. 5. The dihydropyridine calcium antagonists showed some differences in regional specificity and in profile of effects. PMID- 7835639 TI - Effects of fencamfamine withdrawal in rats. AB - 1. The effects produced by discontinuation of long-term treatment with fencamfamine (FCF) were evaluated recording behavioral and body weight changes. 2. 48 hr after withdrawal of FCF rats showed a significant decrease in exploratory behavior when compared to saline-treated ones. 3. Discontinuation of treatment with FCF resulted in a significant increase in body weight on days of drug withdrawal. 4. These results suggest that FCF caused signs of withdrawal similar to other psychostimulant drugs. PMID- 7835640 TI - Pharmacological analysis of the inhibitory effects of KRN2391 on endothelin-1 induced contraction in isolated large coronary artery of the pig. AB - 1. The relaxant effect of KRN2391, N-cyano-N'-(2-nitroxyethyl)-3-pyridine carboximidamide-mo nomethanesulfonate (with both K+ channel opener and nitrate actions), nifedipine (Ca2+ channel blocker), nitroglycerin (nitrate) and cromakalim (K+ channel opener) were investigated in isolated porcine large coronary arteries contracted by endothelin-1. These drugs inhibited endothelin-1 induced contraction in a concentration-dependent manner. 2. The relaxation induced by KRN2391 was nearly complete at their maximum effects, but nifedipine and cromakalim could not produce complete relaxation. 3. The concentration relaxation curves for KRN2391 underwent a rightward shift in the presence of methylene blue or glibenclamide. The concentration ratios of KRN2391 calculated based on EC50 values were 2.8 and 3.7 in the presence of methylene blue and glibenclamide, respectively. 4. The concentration-relaxation curves for nitroglycerin and cromakalin underwent a rightward shift in the presence of methylene blue and glibenclamide, respectively, and the concentration ratios of nitroglycerin and cromakalim were 12.0 and 6.3. 5. These relaxant effects of KRN2391 and nitroglycerin on endothelin-1-induced contraction of porcine coronary artery were greater than those of cromakalim and nifedipine. This potent relaxant action of KRN2391 on endothelin-induced contraction is thought to be based on both a nitrate action and a K+ channel opening action. PMID- 7835641 TI - Comparative analysis of vasodilating mechanisms of Ki1769, Ki3315 and KRN2391, pyridinecarboximidamide derivatives, in porcine isolated coronary artery. AB - 1. The vasodilating mechanisms of pyridinecarboximidamide derivatives which have a nitroxyl group (KRN2391), a phenyl group (Ki1769) or a hydroxyl group (Ki3315) were studied in porcine isolated coronary artery. 2. KRN2391 (10(-6) M) increased cyclic GMP formation but did not affect intracellular cyclic AMP level. Ki1769 (10(-5) M) and Ki3315 (10(-3) M) had no effect on intracellular cyclic GMP and cyclic AMP levels. 3. Despite producing submaximal relaxation at KRN2391 (10(-6) M) and nitroglycerin (10(-6) M), the increase in cyclic GMP caused by KRN2391 was lower than that caused by nitroglycerin. 4. Methylene blue (10(-5) M) inhibited KRN2391- and nitroglycerin-induced relaxations but did not affect Ki1769- and Ki3315-induced relaxation. 5. Glibenclamide (10(-6) M) inhibited KRN2391-, Ki1769 and Ki3315-induced relaxation but did not affect nitroglycerin-induced relaxation. 6. These results suggest that the nitroxyl group of KRN239 contributes to its nitrate action and the pyridinecarboximidamide moiety plays an important role of developing a K channel opening action. PMID- 7835642 TI - Fatty acid and amino acid composition in haruan as a potential role in wound healing. AB - 1. Two species of snakehead fish are available in Sabah, i.e. Channa striatus and Channa melanosoma, and are commonly known as haruan. Haruan is consumed by many Malaysians to induce healing after a clinical operations. However, there is no scientific evidence as yet to substantiate the claim, and so it was decided to analyse the biochemical composition in haruan to determine which compounds may have a possible role or potential in wound healing. 2. Samples (midline fillet) of both species were extracted separately in hexane for the qualitative analysis of fatty acids by a gas chromatography, Hewlett-Packard 5890A, using a 10 meter superox 11 column (Alltech) at temperature between 190 and 245 degrees C. Peak areas were calculated automatically using Hewlett-Packard 3393A computing integrator. Subsequently, the amino acid composition was analysed using a precolumn derivatization reverse phase HPLC waters PICO-TAG system. 3. Haruan is found to contain unusually high arachidonic acid (AA) but almost no eicosapentaenoic acid (EPA). AA which is a precursor of prostaglandin may initiate blood clotting and be responsible for growth. Haruan also contains all the essential amino acids for wound healing, particularly glycine which is the most important component of human skin collagen. Therefore, haruan contained all the basic biochemical requirements for wound healing. PMID- 7835643 TI - Effects of atropine, pirenzepine, clonidine, and morphine on biphasic response of rat gastric fundus to field stimulation. AB - 1. Electrically evoked contractions in isolated strips of rat gastric fundus were inhibited by atropine (IC50 = 2.5 x 10(-9) M), pirenzepine (IC50 = 2.3 x 10(-8) M), clonidine (IC50 = 3.9 x 10(-8) M) and morphine (IC50 = 3.2 x 10(-7) M) in a dose-dependent manner. 2. The inhibitory effect of morphine was antagonized by naloxone (10(-6) M). The inhibitory effect of clonidine not only was not reversed by yohimbine but also was enhanced. Yohimbine per se inhibited these contractions (IC50 = 6.4 x 10(-6) M). 3. In presence of atropine (2 x 10(-6) M) and guanethidine (5 x 10(-6) M), electrical stimulation of isolated strips of rat gastric fundus produced a non-adrenergic, non-cholinergic (NANC) inhibitory response. 4. The NANC inhibitory response was decreased by morphine (10(-8)-3 x 10(-6) M). In addition, morphine decreased the tone of the muscle. These effects of morphine was antagonized by naloxone (3 x 10(-6) M). 5. Clonidine up to 10(-6) M had no influence on the NANC inhibitory response but yohimbine per se (10(-7)-3 x 10(-5) M) blocked it (IC50 = 3 x 10(-6) M). 6. These findings indicate that electrically evoked contractions in the rat gastric fundus were mediated by muscarinic receptors. In addition, the NANC inhibitory response in the isolated 5 strips of rat gastric fundus was blocked by morphine and yohimbine. PMID- 7835644 TI - Pertussis toxin prevents neomycin-induced calcium-dependent electrophysiological effects in rat hippocampal slices. AB - 1. The influence of pertussis toxin has been studied on the effects of neomycin on CA1 field potentials in rat hippocampal slices in order to determine a role played by G protein in the modulation of synaptic transmission by the drug. 2. Neomycin (500 microM), within 30 min significantly (P < 0.01) decreased the magnitude of the somatic CA1 excitatory postsynaptic potentials (EPSP) and population spike (PS) in control hippocampal slices. 3. Neomycin (500 microM), within 30 min failed to significantly affect the magnitude of the somatic CA1 EPSP and PS in slices obtained from animals treated intracerebroventricularly (ICV) with 1-2 micrograms of pertussis toxin 3 days before. 4. The results demonstrated that pertussis toxin prevents some electrophysiological effects of neomycin, suggesting a role of G protein in the modulation of the aminoglycoside antibiotic on central synaptic transmission. PMID- 7835645 TI - Cardiovascular effects of KRN2391, nitroglycerin and cromakalim in dihydroergotamine-treated pithed rats. AB - 1. The effects of KRN2391 on the cardiovascular system were compared with those of nitroglycerin and cromakalim in pithed rats treated with dihydroergotamine (DHE) in order to examine the effects of these drugs on venous blood vessels. 2. DHE (100 micrograms/kg, i.v.) produced increases in mean blood pressure (MBP), cardiac output (CO) and central venous pressure (CVP) without changes in total peripheral vascular resistance (TPR) and heart rate (HR) based on venoconstriction. The DHE-treated pithed rats, nitroglycerin (30 micrograms/kg, i.v.) decreased CO and CVP whereas cromakalim (30 micrograms/kg, i.v.) produced a slight increase in CO followed by a decrease and did not affect CVP. KRN2391 (30 micrograms/kg, i.v.) produced a decrease in CVP without affecting CO. Decreases in MBP and TPR were induced by all drugs. 3. These results suggest that nitroglycerin acts predominantly as a venodilator and KRN2391 and cromakalim showed a venodilating action in addition to an arterial dilating action in DHE treated pithed rats. However, the venodilating action of KRN2391 in this condition is more potent than that of cromakalim. PMID- 7835646 TI - Inhibition of gastric mucosal mucin receptor by Helicobacter pylori lipopolysaccharide: effect of sulglycotide. AB - 1. A receptor for mucin was isolated from the solubilized gastric epithelial cell membrane by affinity chromatography on Sepharose-bound wheat germ agglutinin. 2. The receptor protein displayed a molecular weight of 97 kDa and exhibited specific affinity towards mucin-coated surfaces. The optimum for mucin binding occurred at 60-100 micrograms/ml, while the values for the receptor were 2.0-3.1 micrograms/ml. 3. The mucin binding to the receptor was susceptible to Helicobacter pylori lipopolysaccharide which caused maximum inhibition of 91% at 30 mu/ml. This inhibitory effect of the lipopolysaccharide was abolished by a gastroprotective agent, sulglycotide. 4. The effect of sulglycotide was dose dependent and at 50 micrograms/ml produced a 94% restoration in receptor-mucin binding. Furthermore, sulglycotide was also capable of enhancing (97%) the mucin binding to its receptor in the absence of the lipopolysaccharide. 5. The results demonstrate that H. pylori through its lipopolysaccharide interferes in the interaction of mucin with gastric epithelial surfaces and that a gastroprotective agent, sulglycotide, counteracts this effect, and hence is capable of preventing the loss of mucin coat continuity occurring with H. pylori infection. PMID- 7835647 TI - In vitro and in vivo effect of the nootropic agent adafenoxate on the 5-HT1 sites in different rat brain structures. AB - 1. The effect of the nootropic agent adafenoxate (a structural analogue of meclofenoxate) on the binding parameters of 5-HT1 receptors in vitro and in vivo in rat cerebral cortex, striatum, hippocampus and hypothalamus was studied. 2. The chronic (100 mg/kg per os for 7 days) adafenoxate treatment produced a significant (24.6%) decrease in the density of 5-HT1 sites in the hippocampus. 3. In vitro adafenoxate inhibited specific [3H]5-HT binding with equal potency in all the regions studied with IC50s in the microM range. 4. It is suggested that the decrease in the density of the 5-HT1 sites in rat hippocampus might contribute to the nootropic action of adafenoxate. PMID- 7835648 TI - Biogenic monoamine uptake by rat brain synaptosomes during aging. Effects of nootropic drugs. AB - 1. In experiments on young (3-5-month-old), adult (10-11-month-old) and old (21 22-month-old) rats, it was found that significant age-related changes occurred in the high-affinity uptake of dopamine (DA), noradrenaline (NA) and serotonin (5 HT) by cortical and striatal synaptosomes. 2. Changes in DA, NA and 5-HT uptake during aging are suggested to be neurochemical correlates of cognition and memory deficits that develops in senescence. 3. The in vitro effects of the nootropic drugs piracetam, aniracetam, meclofenoxate and adafenoxate on the DA, NA and 5-HT uptake by cortical and striatal synaptosomes from young rats were studied. Administered in increasing concentrations (1 x 10(-4) to 5 x 10(-3) M) these drugs inhibited monoamine uptake. 4. Adafenoxate proved to be a more potent monoamine uptake inhibitor than the other three drugs; it inhibited the uptake in the frontal cortex and striatum without selectivity for either monoaminergic system. It is suggested that adafenoxate affects cognition through the involvement of central neurotransmission and particularly through the inhibition of monoamine uptake systems. PMID- 7835649 TI - Action of diclofenac sodium on the reparation process of the surgically perforated myometrium of pregnant albino rats: morphological and morphometrical evaluation. AB - 1. The action of a non-hormonal anti-inflammatory agent on the reparation process of the surgically-perforated myometrium of pregnant albino rats was histologically evaluated. 2. On the 14th day after perforation, the muscular layers were still interrupted. 3. The morphological study was inconclusive. A morphometrical analysis, however, demonstrated that there was a meaningful diminution in the number of leucocytes and collagen fibers and an increase in the number of fibroblasts, probably with low synthetical power, in the group treated with diclofenac sodium. All these data indicate a delay in the reparation process of the uterine musculature. PMID- 7835651 TI - Don't mask communication with patients. PMID- 7835650 TI - The action of amyl nitrite and isosorbide dinitrate on the contractility of sphincter of Oddi of guinea-pigs. AB - 1. This study was designed to investigate whether relaxation of isolated guinea pig sphincter of Oddi preparation by nitrates is mediated by guanylate cyclase activation indirectly by nitric oxide (NO), as in vascular tissues. 2. Sodium nitroprusside, isosorbide dinitrate and amyl nitrite induced dose-dependent relaxations of Oddi's sphincter precontracted by potassium chloride (150 mM). Methylene blue (5 x 10(-5) M), an inhibitor of guanylate cyclase, did not significantly inhibit the relaxations caused by nitrovasodilators. 3. Unlike potassium chloride, acetylcholine (10(-7) - 10(-3) M) induced unsustained contractions which were significantly increased by methylene blue. NG-monomethyl L-arginine (L-NMMA; 4 x 10(-4) M), an inhibitor of NO biosynthesis, also increased the contractile response to acetylcholine. 4. These results suggest that another mechanism rather than inhibition of guanylate cyclase is involved in the nitrovasodilators-induced relaxations and that acetylcholine releases a relaxing factor, possibly NO, that may modulate its own contraction in this preparation. PMID- 7835652 TI - Forensic odontology in solving crimes: dental techniques and bite-mark evidence. PMID- 7835653 TI - Unusual macrodontia. PMID- 7835654 TI - Detecting and reporting child maltreatment--dentists' obligations. PMID- 7835655 TI - Immunology in general dentistry: basics and clinical implications. PMID- 7835656 TI - Fear can mimic latex allergy in patients with dental phobia. PMID- 7835657 TI - Corrosion of dental gold restorations from inhalation of "crack" cocaine. PMID- 7835658 TI - Advanced techniques of local anesthetic injection. PMID- 7835659 TI - Basic dental-anxiety management. PMID- 7835660 TI - The right to health care: an inevitable collision. PMID- 7835661 TI - The big lip. Diagnostic and treatment considerations. PMID- 7835662 TI - Glutaraldehyde: an alternative to formocresol? PMID- 7835663 TI - Subpontic osseous hyperplasia. PMID- 7835664 TI - Radiographically detected class 1 carious lesions in clinically sound teeth. PMID- 7835666 TI - Informing patients of inadequate treatment: ethical dilemmas. PMID- 7835665 TI - Treating patients who are hard to like. PMID- 7835667 TI - Microleakage of incremental versus compression matrix bulk filling of cervical resin composite restorations. PMID- 7835669 TI - A review of methods and instrumentation for removing crowns and bridges from prepared teeth. PMID- 7835668 TI - Microleakage in heat-treated class V resin inlays cemented with five cement systems: an in vitro study. PMID- 7835670 TI - The apex: how critical is it? PMID- 7835671 TI - An alternative technique for fabricating the maxillary anterior passive appliance. PMID- 7835672 TI - The anesthetic test: a diagnostic aid for referred pain. PMID- 7835673 TI - Vasovagal syncope associated with seizure activity. PMID- 7835674 TI - Drug-induced gingival hyperplasia. PMID- 7835675 TI - Hypnotherapy for treatment of dental phobia in children. PMID- 7835676 TI - Anticipating the next oral health manpower crisis. PMID- 7835678 TI - Airborne contamination produced by electrosurgery. PMID- 7835677 TI - Patient- or physician-initiated amalgam removal for treatment of arthritis. PMID- 7835679 TI - Fluoride concentrations in bottled and filtered waters. PMID- 7835680 TI - Conductance-voltage relations in large-conductance chloride channels in proliferating L6 myoblasts. AB - Large-conductance chloride channels (maxi-Cl channels) were studied in cultured myoblasts (L6 rat muscle cell line); in excised (inside-out) and in cell attached membrane patches using a conventional patch clamp method. The incidence of maxi Cl channels was substantially higher in proliferating myoballs, then in quiescent (bottom-attached) myoblasts (90% and 50% percent of examined cells, respectively). The maxi-Cl channels in myoballs were present both in cell attached and excised patches. The channel conductance at symmetric [Cl] = 150 mmol/l was 359 +/- 42 pS (n = 74) in quiescent cells and 439 +/- 10 pS (n = 6) in proliferating myoballs respectively. The conductance of the channel in quiescent cells increased with chloride concentration in symmetric NaCl rich solutions according to Michaelis-Menten curve with the saturation limiting conductance of about 640 pS (gmax) and Km = 112 mmol/l. The shift of the reversal potential upon increasing the pipette concentration of NaCl from 150 to 250 mmol/l was consistent with PNa/PCl = 0.1. Neither the conductance nor the activation of the channel were dependent on the presence of calcium ions. The bell-shaped steady state channel conductance-voltage relationship is asymmetric and can be fitted by two Boltzmann equations with different Vh and k constants; -25.6 mV and -6.8 mV, respectively, for the negative side and +49.6 mV and +13.7 mV for the positive side in quiescent cells. The corresponding values in proliferating myoballs were as follows: -15.5 mV and -2.4 mV, respectively, for the negative side and +31.4 mV and +6.8 mV for the positive side. From the maximum slopes of the Popen versus V curves an estimate was made of the charges for the gates that close at negative (3.5) or positive (1.7) potentials, respectively, in quiescent cells. The corresponding values in myoballs were 10.6 and 3.7, respectively. The probability of one gate to be open was dependent on the state of activation of the opposite gate as determined by prepulses of the opposite polarity. The channel showed multiple (up to six) conductance levels that may develop in a step-like manner. The onset of the full-grown maxi-Cl channel is fairly abrupt; it might, however, be preceded by a small conductance unit activity. It is supposed that the differences between the quiescent myoblasts and proliferating myoballs might reflect increased expression of maxi-Cl channels in myoballs to perform as yet unknown role in the cell cycle and/or proliferation of the myoblasts. PMID- 7835681 TI - Arachidonic acid blocks large-conductance chloride channels in L6 myoblasts. AB - Modulation of high-conductance chloride channels by eicosanoids, stilbene derivatives and Zn2+ ions was studied in cultured myoblasts (L6 rat muscle cell line) in excised and cell-attached membrane patches using a conventional patch clamp method. Arachidonic acid (AA) blocked the channel at concentrations 1-50 mumol/l from the internal side of the membrane in excised (inside out) patches with a time constant of about 20 s. The block was absent when arachidonic acid was applied to the bathing solution in cell attached patches, or to the pipette solution, respectively. Arachidonic acid changed the probability of the channel being in the open state (Popen) in dependence on the applied voltage (V). The asymmetric bell-shaped Popen - V relationship showed a steeper dependence on both the negative and positive voltage, respectively, in arachidonic acid solutions. The midpoint potentials (Vh) of the Popen - V relationship were shifted towards lower membrane potential displacements from the holding potential. The recovery from the block was very slow but was found to be enhanced by application of a symmetric voltage ramp pulse. The stilbene derivative (DIDS) blocked the channel at mu molar concentrations (10-100 mumol/l) applied from the internal side of the membrane. The onset and recovery of the DIDS block showed characteristics similar to the AA block. The channel was found to be blocked reversibly by short application of Zn+ ions (1-10 mmol/l) from the internal side of the membrane. PMID- 7835682 TI - Thermal dependence of force-velocity relation of lamprey live striated muscle fibres. AB - The thermal dependence of the force-velocity relation (P - V) in thin (20-40 fibres) live twitch muscle bundles from suction apparatus of lamprey by force clamp method was investigated. The P - V relation was hyperbolic and Hill's constants were as follows: a/P0 was 0.13 +/- 0.01 and 0.08 +/- 0.01 (mean +/- S.E.M.), b was 0.46 +/- 0.02 and 0.65 +/- 0.03 at 8 degrees C and 18 degrees C, respectively. The maximal isometric tension (P0) was about 100 mN/mm2 at 8 degrees C, 18 degrees C, and 22 degrees C. After the temperature was switched from 8 degrees C to 18 degrees C, the dependence of P0 on incubation time was observed. The maximal power output determined from P - V relation using Hill's equation was 0.062 +/- 0.002 and 0.056 +/- 0.001 at 8 degrees C and 18 degrees C, respectively. The maximal velocities of shortening (V0) were 3.9 +/- 0.1 L0/s and 7.2 +/- 0.2 L0/s at 8 degrees C and 18 degrees C, respectively. Q10 for V0 in this range of temperatures was 1.86. a/P0 and power output were about 2 times lower than those reported in literature for other animals. In general, the thermal dependence of the parameters studied was similar to those reported for fish muscles and skinned lamprey muscles, P0 being relatively independent, V0 highly dependent, and a/P0 inversely dependent on temperature. PMID- 7835683 TI - Effects of mannitol hypertonicity on water and ion contents in the alga Hydrodictyon reticulatum. AB - Long-term effects of mannitol hypertonicity on the water and ion contents in the fresh-water alga Hydrodictyon reticulatum were studied. The cells did not behave as osmometers and a closer examination suggested that wall elasticity was related to the medium tonicity and that the rate of sodium extrusion from the cells depended on the wall (turgor) pressure. PMID- 7835684 TI - Voltage dependent fast calcium current in cultured skeletal myocytes of the frog Rana temporaria. AB - Voltage dependent calcium currents in cultured frog embryonic skeletal myocytes at stages of development ranging from 2 to 9 days were studied using the whole cell patch clamp technique at 19-21 degrees C. Membrane currents were recorded in the presence of 2 mmol/l Ca2+ (outside), and 60 mmol/l CsCl and 50 mmol/l TEACl (inside). In the absence of sodium current two components of inward current were observed in response to depolarization already during the early stages of myogenesis: the well-known slow dihydropyridine (DHP)-sensitive calcium current (ICa,s), and a fast-activated current. Both components persisted in the presence of 2 mumol/l tetrodotoxin. The fast-activated component was enhanced upon addition of 6 mmol/l Ca2+ or Ba2+ to the external recording solution and was decreased when the standard external solution was replaced by Ca2+ free solution. Thus, the fast component of the inward current was also carried by Ca2+ (ICa,f). Unlike ICa,s, it was not blocked with 30-150 mumol/l DHP nifedipine. During 7 s depolarization ICa,f was detected at approximately -50 mV, 20 mV more negative than the membrane potentials at which ICa,s appeared. At various test potentials t0.5 for activation of ICa,f was 8-20 ms, and the current declined during depolarization with tau in of 500-800 ms. These results indicate the existence of two types of voltage-dependent Ca2+ channels in early stages of development of frog myocytes, both known in mature frog skeletal muscle fibres. PMID- 7835685 TI - Coronary artery contractility, Na(+)-pump and oxygen radicals. AB - Oxygen radicals accumulated during ischemia and reperfusion may affect coronary contractility by endothelium dependent and independent pathways one of which may involve Na(+)-pump. Here we report a contractility assay for Na(+)-pump in pig coronary artery and use it to examine the effects of hydrogen peroxide and superoxide. Coronary artery rings contracted in a K(+)-free Krebs solution and relaxed upon subsequent exposure to K+. The relaxation approximated a single exponential decay whose rate constant depended on [K+]2. This K(+)-induced relaxation was abolished by ouabain and was attributed to Na(+)-pump. In tissues pretreated with peroxide, the rate of relaxation of the K(+)-free contracted arteries decreased with an IC50 = 1.6 +/- 0.6 mmol/l for peroxide. Another set of tissues was pretreated with the superoxide generating system containing 0.3 mmol/l xanthine + varying concentrations of xanthine oxidase (XO) and precontracted in K(+)-free Krebs solution. The rate of the K(+)-induced relaxation decreased with IC50 = 24 +/- 8 mU/ml for XO. Thus, using the relaxation assay we conclude that exposing coronary arteries to oxygen radicals can damage Na(+)-pumps. PMID- 7835686 TI - Familial aggregation of cardiovascular diseases in African-American pedigrees. AB - Familial aggregation of cardiovascular diseases and diabetes has been consistently demonstrated. However, virtually all of the evidence on the familial patterns of these diseases has come from white population samples. This study evaluates the level of familial excess risk among first degree relatives of 232 African-American pedigrees which included 1,420 individuals recruited from the Chicago, IL, area. Excess disease risk was observed among relatives (parents and offsprings) of affected probands compared to relatives of unaffected probands for coronary heart disease (odds ratio [OR] = 5.30; 95% confidence interval [CI] = 2.51-11.23); hypertension (OR = 1.98; CI = 1.41-2.80); stroke (OR = 3.24; CI = 1.08-9.70); and diabetes (OR = 2.95; CI = 1.55-5.62). The results of this study clearly show that coronary heart disease, hypertension, stroke, and diabetes aggregate in some African-American families and not others. Unaffected relatives of persons suffering from these diseases should be encouraged to have their blood pressure, lipid, and blood glucose levels measured at frequent intervals. These recommendations are particularly urgent in African-American communities because of the disproportionately high morbidity and mortality experienced from cardiovascular diseases and diabetes. PMID- 7835687 TI - Power of segregation analysis for detection of major gene effects on quantitative traits. AB - The power to detect major gene effects by rejection of the "no major gene" null hypothesis against a mixed model alternative was determined in random samples of nuclear families over a variety of conditions. Benchmarks have been developed using a varying number of families whose structure includes both parents and three children. Phenotypes were simulated assuming a Mendelian major gene under either recessive or dominant inheritance, with 0-30% residual polygenic heritability. Three trait prevalences--5, 10, and 20%--were considered in combination with increasing displacement between homozygous means, spanning a range of 14 to 36% of the phenotypic variance attributable to the major gene effect. All other assumptions of the traditional mixed model were adopted in the generating models. Segregation analysis was carried out on the simulated data sets and the proportion of samples out of 200 replications in which the null hypothesis q = 0 was rejected is reported as the power. Thus, failure to detect a major gene effect in this context is solely due to sampling variation, since no other perturbations were introduced. In general, there appears to be greater power to detect dominant major gene effects as opposed to recessive ones using otherwise comparable parameter values, and the effect of varying sibship size under dominant models appears to be greater as well. The use of joint vs. conditional likelihood calculations also was evaluated: substantial drops in power were observed when using conditional likelihoods under recessive inheritance, while the differences in power appeared to be nominal under dominant inheritance. The results of this investigation are offered as a guide to assist in the design of family studies whose aim is to detect major gene effects. PMID- 7835688 TI - Somatic allele loss in genetic linkage analysis of cancer. AB - The ability to detect or reject genetic linkage in studies of human cancer is often diminished because multiple affected relatives in a pedigree are unavailable for analysis. The observation of somatic allele loss in tumors can provide knowledge about gametic phase. Therefore, consideration of tumor genotype data could be used to obtain knowledge about gametic phase ordinarily gained from a larger sample of individuals in cancer families. The objective of the present study is to describe a method for improving the power to detect or reject genetic linkage by using knowledge about somatic genetic changes in tumor tissue. A modification to the lod score method of linkage analysis is proposed in which knowledge of gametic phase in the linkage likelihood is inferred from observations of loss of constitutional heterozygosity (LoH) in tumor tissue. This methodology was evaluated using a double backcross nuclear family with a pair of offspring. The expected lod score improved substantially when tumor genotype data were included in the analysis. For example, when the haplotype remaining in tumor tissue was identical to the inherited haplotype in constitutional tissue 99% of the time, linkage analyses without tumor genotype data would require a 2-5 times larger sample of offspring pairs to conclude linkage with an expected lod score value of 3 or greater, compared to analyses incorporating tumor genotype data. These results suggest that consideration of tumor genotype data using the proposed method can substantially improve the power of linkage analyses in cancer families. PMID- 7835689 TI - Genetic analysis combining path analysis with regressive models: the BETA path model of polygenic and familial environmental transmission. AB - We have extended the class D regressive model for the purpose of combined path and segregation analyses by incorporating the BETA path model. We have done this by expressing correlations among residuals from major genotype (RMGs) of family members under the class D regressive model as functions of path coefficients under the BETA path model. The likelihood function under the combined model was factorized into a product of conditional densities, which is dominated by bivariate normal densities. Statistical inferences under the combined model are analogous to those under the class D regressive model. PMID- 7835690 TI - Commingling analysis of memory performance in elderly men. AB - Smalley et al. [(1992) Genet Epidemiol 9:333-345] found evidence of a mixture of two distributions in memory performance among offspring of patients with dementia of the Alzheimer type (DAT), suggesting that these groups reflect genotypic subgroups of carriers and non-carriers of a putative DAT gene. One prediction of this hypothesis is that, in the general population, two distributions of memory performance are present, with a smaller proportion of subjects in the low-scoring cluster than that found among the offspring sample, but similar to the prevalence of DAT in the elderly community-at-large. Memory performance was investigated in a large sample of normal elderly males (N = 1,149; mean age = 71.4 +/- 4.7 years) to test this hypothesis. Commingling analyses of performance on the Benton visual retention test demonstrated significant negative skewness in the distribution of memory performance, requiring a transformation to fit a single normal distribution. In the absence of a transformation, two distributions fit better than one, with 6% of subjects falling into a "low"-scoring cluster. These findings are consistent with the hypothesis that memory performance may represent a premorbid or morbid difference in those who go on to develop, or currently have, DAT, possibly allowing identification of at-risk carriers of a putative single major gene for DAT. PMID- 7835691 TI - Drug allergy and protocols for management of drug allergies. PMID- 7835692 TI - Identification of new Schistosoma mansoni genes by the EST strategy using a directional cDNA library. AB - A directional size-selected cDNA library constructed from Schistosoma mansoni (Sm) adult worm RNA was used for the generation of expressed sequence tags (EST). From one or both ends of 429 distinct cDNA clones 607 EST were obtained. Of these, only 16% were previously known Sm genes. More than 22% of the clones had matches with entries for other organisms in the databases. These new Sm genes constituted a broad range of transcripts distributed among cytoplasmic structural and regulatory proteins, enzymes, membrane, nuclear and secretory proteins, and proteins with other functions. Almost 33% of the clones had no significant database matches and thus potentially represent Sm-specific genes. Among the latter, several clones, as judged by their redundancy in the library, appear to represent abundant transcripts. The data, taken as a whole, more than double the number of Sm genes identified by nucleotide sequencing and indicate the potential value of the adoption of genome sequencing strategies for the rapid increase in knowledge of complex disease-causing organisms. PMID- 7835693 TI - The Sex combs reduced gene of Drosophila melanogaster has multiple transcripts. AB - The Sex combs reduced (Scr) homeotic gene of Drosophila melanogaster specifies the development of structures within the most posterior head segment, the labium and the most anterior thoracic segment, the prothorax or T1. Here, the structure of Scr and correct sequence of the SCR protein are presented. Scr encodes a 417 amino-acid DNA-binding protein with sequence similarity to the mouse homologues, HOXA5, B5 and C5. The greatest similarity is within the DNA-binding homeodomain (hdm); shorter conserved motifs are found near the N terminus and a region N terminal to the hdm. As with most of the D. melanogaster homeotic genes, Scr has alternative exons. PMID- 7835694 TI - Expression of a putative ATPase suppresses the growth defect of a yeast potassium transport mutant: identification of a mammalian member of the Clp/HSP104 family. AB - A cDNA encoding a novel mammalian member of the Clp/HSP104 family was isolated from a mouse macrophage-like cell line (J774.1) cDNA library by suppression of the growth defect of a Saccharomyces cerevisiae trk1 trk2 double mutant. The full length version of this cDNA, termed SKD3, encodes a putative 76-kDa protein of 677 amino acids (aa). The deduced aa sequence of the SKD3 polypeptide contains four ankyrin-like repeats in the N-terminal domain and a single ATP-binding consensus site in the C-terminal domain. The 378-aa C-terminal domain of SKD3 has 57-64% similarity (30-40% identity) with members of the Clp/HSP104 family, including the ClpA regulatory subunit of the Clp protease and S. cerevisiae heat shock protein 104. Northern analysis showed that the 2.3-kb SKD3 transcript is present in a wide variety of tissues, is abundant in mouse heart, skeletal muscle and kidney, and is most abundant in testis. Members of the Clp/HSP104 family have been identified previously from bacteria, yeast and chloroplasts, and are ATPases regulating Clp protease activity and specificity, or mediating cellular responses involved in thermotolerance. SKD3 is the first member of this protein family identified in a higher eukaryote. PMID- 7835695 TI - Structure of the mouse thioredoxin-encoding gene and its processed pseudogene. AB - Thioredoxins (TXN) are small proteins with various biological functions, such as redox regulation, found in many species including bacteria, plants and animals. We previously reported the isolation of the TXN-encoding cDNAs from human and mouse. In order to elucidate the functions of the mammalian TXN system, we planned to generate Txn knockout mice, and cloned the genomic DNA fragments using the Txn cDNA as a probe. The Txn gene extends over 12 kb and consists of five exons separated by four introns. Detailed Southern analyses revealed that the mouse genome contains only one active Txn gene and one processed pseudogene (Txn ps1), in contrast to some species which have families of active TXN-encoding genes. These findings should help to understand Txn itself, and provide a basis for transgenic experiments by gene targeting. PMID- 7835696 TI - An ATF/CREB-binding site is essential for cell-specific and inducible transcription of the murine MIP-1 beta cytokine gene. AB - The murine macrophage inflammatory protein 1 beta mRNA (MIP-1 beta) is rapidly and transiently induced in macrophages by lipopolysaccharide (LPS), serum or cycloheximide. Functional studies of the MIP-1 beta proximal promoter indicate that it is cell-specific, and serum- and LPS-responsive in macrophages. A 76-bp proximal promoter sequence (-51 to -127 bp) confers cell-specific and LPS inducible activity when placed upstream from a heterologous promoter in both orientations. One essential cis-regulatory element within the enhancer-like sequence is an activating transcription factor/cAMP response element (CRE) binding protein (ATF/CREB)-binding site, although the promoter is not cAMP responsive. Electrophoretic mobility shift assays and mutational analyses suggest that the promoter site is bound by nuclear protein complexes containing cAMP independent members of the ATF/CREB family of proteins and c-Jun, and are functionally distinct from the AP1-related TPA-response element (TRE) binding activity. PMID- 7835697 TI - Structure of the genes encoding the alpha- and beta-subunits of castor pyrophosphate-dependent phosphofructokinase. AB - Full-length genomic clones encoding the alpha- and beta-subunits of the pyrophosphate-dependent phosphofructokinase (PFP) from the castor plant have been isolated and sequenced. The gene (PFP alpha) encoding PFP alpha is approx. 5.8 kb in length and contains 19 exons, which collectively encode a protein of 617 amino acids (aa) having a deduced M(r) of 67,360. PFP beta is approx. 4.6-kb long and contains 16 exons. Together, these exons encode a protein (PFP beta), of 552 aa with a deduced M(r) of 60,114. The intron-exon splice junctions in both genes contain the consensus sequences typical for plants. An alignment of intron placement in castor PFP alpha and PFP beta with introns in the 5' portion of the gene encoding the ATP-dependent phosphofructokinase (PFK) from rabbit muscle, indicates that only one intron occupies the same position in all three genes. Furthermore, within castor PFP alpha and PFP beta, only two introns are identically placed. Within the promoter regions of castor PFP alpha and PFP beta, there are short sequences having high homology to each other (up to 65%). The results demonstrate, for the first time, that there is little homology between PFP and PFK, nor are PFP alpha and PFP beta closely related. This lack of homology suggests PFP did not evolve from PFK, but rather, that PFP and PFK have probably evolved from a common ancestral gene. PMID- 7835698 TI - An altered spectrum of herpes simplex virus mutations mediated by an antimutator DNA polymerase. AB - The mutation spectrum attributable to an antimutator DNA polymerase in a eukaryotic cell was examined. Drug-resistant thymidine kinase (tk) mutants derived from both a wild-type (wt) strain, KOS and an antimutator DNA polymerase (pol) mutant, PAAr5, of herpes simplex virus (HSV), were isolated, and the mutated tk genes were characterized at the sequence level. While both transition and frameshift mutations were found in the mutated tk genes derived from the wt KOS Pol, all the PAAr5-mediated mutants analyzed were frameshift mutations. These results imply that the wt HSV Pol is less faithful than the antimutator enzyme, at least in part, because of its propensity to mediate transition mutations. PMID- 7835699 TI - Isolation and characterization of a mini-collagen gene encoding a nematocyst capsule protein from a reef-building coral, Acropora donei. AB - Genomic and cDNA clones of a mcol gene encoding mini-collagen (MCOL), a nematocyst capsule protein, have been isolated from a reef-building coral, Acropora donei (Anthozoa). The gene and its flanking regions, comprising 5382 bp and covering three exons and two introns, were sequenced. Exons 2 and 3 together have an open reading frame which can encode a MCOL of 176 amino acids (aa). The coral MCOL has all the characteristic regions present in the four hydra MCOL specified by the four mcol cDNA clones previously isolated from Hydra magnipapillata (Hydrozoa) by Kurz et al. [J. Cell Biol. 115 (1991) 1159-1169], including a central Gly-Xaa-Yaa region and flanking Pro-rich and Cys-repeat regions. This observation suggests that a mcol family is highly conserved in Anthozoa and Hydrozoa, and also that the characteristic regions present in MCOL are essential for the structure and function of these peptides. PMID- 7835700 TI - Sequence analysis and transcriptional mapping of the orf-2 gene of Autographa californica nuclear polyhedrosis virus. AB - Sequencing of the dnapol promoter region of Autographa californica nuclear polyhedrosis virus (AcNPV) revealed an overlapping open reading frame (ORF) in an antisense orientation, referred to as ORF-2. Analysis of the ORF-2 deduced amino acid sequence revealed two short regions of homology with a similar ORF from Lymantria dispar nuclear polyhedrosis virus (LdNPV). Two 3' processing signals of this gene, expressed late during infection, were shown to be located on the orf-2 stop codon and 162 nucleotides further downstream. PMID- 7835701 TI - Cloning and characterization of a developmentally regulated sea urchin cDNA encoding glutamine synthetase. AB - A 2935-bp cDNA clone encoding glutamine synthetase (GS) was isolated from a cDNA library prepared from four-blastomere Paracentrotus lividus sea urchin embryos. The sequence consists of a 75-bp 5' untranslated region (5'-UTR) followed by a 1095-bp coding region corresponding to a 365-amino-acid (aa) protein, a 1747-bp 3'-UTR and a terminal 18-bp poly(A) tail. The encoded protein shows about 66% identical residues, as compared with human and lobster class-II GS. The sequence contains the Mn(2+)-binding aa and the highly conserved aa regions observed in other GS. Northern blot analyses show that the GS mRNA is present in the sea urchin egg and is developmentally regulated in the embryo. PMID- 7835702 TI - Structures of genes encoding TATA box-binding proteins from Trimeresurus gramineus and T. flavoviridis snakes. AB - A cDNA encoding the Trimeresurus gramineus (Tg; green habu snake) TATA-box binding protein (TgTBP) was cloned and sequenced. The cDNA encodes a 33-kDa protein with an extensive sequence similarity to those derived from other organisms, except for the N-terminal domain. Genes encoding TgTBP and Trimeresurus flavoviridis (Tf; habu snake) TBP (TfTBP) were isolated using a TgTBP cDNA and their nt sequences were determined. They are the first TBP genes entirely sequenced in higher animals. Both genes span over 15 kb and are constructed from eight exons and seven introns. Comparison of the loci of introns on the aligned amino-acid sequences of TBP from six organisms (Tg, Tf, mouse, Arabidopsis thaliana, Schizosaccharomyces pombe and Acanthamoeba castellanii) indicated that there are three highly conserved loci in the C-terminal domain. PMID- 7835703 TI - Cloning of cDNA and genomic DNA encoding fibroblast growth factor receptor-4 of Xenopus laevis. AB - We have isolated and characterized the cDNA and genomic DNA encoding fibroblast growth factor receptor-4 of Xenopus laevis (XFGFR-4). The gene encompassing the total coding sequence spans about 10 kb, consists of 17 exons, and has an organization very similar to those of mammalian genes encoding FGFR-1 and -2, except that the XFGFR-4 gene does not contain an alternative exon for the third immunoglobulin-like domain nor an internal poly(A)-addition site. Thus, XFGFR-4 appears not to generate multiple forms of mRNA, as are identified for the mammalian FGFR-1, -2 and -3 genes. The amino-acid sequence of XFGFR-4 shows high homology to other vertebrate FGFR-4 species, but the similarity was significantly lower than in the cases of FGFR-1 and -2. Northern blot analysis showed the XFGFR 4 mRNA to occur throughout X. laevis early embryogenesis in a profile different from those of X. laevis FGFR-1 and -2. PMID- 7835704 TI - Structural organization, expression and chromosomal mapping of the mouse cystatin C-encoding gene (Cst3). AB - Cystatin C (CstC) is a potent cysteine-proteinase inhibitor. The structure of the mouse CstC-encoding gene (Cst3) was examined by sequencing a 6.1-kb genomic DNA containing the entire gene, as well as 0.9 kb of 5' flanking and 1.7 kb of its 3' flanking region. The sequence revealed that the overall organization of the gene is very similar to those of the genes encoding human CstC and other type-2 Cst, with two introns at positions identical to those in the human gene. The promoter area does not contain typical TATA or CAAT boxes. Two copies of a Sp1-binding motif, GGGCGG, are present in the 5' flanking region within 300 bp upstream from the initiation codon. A hexa-nucleotide, TGTTCT, which is a core sequence of the androgen-responsive element (ARE), is found in the promoter region. This region also contains a 21-nucleotide sequence, 5'-AGACTAGCAGCTGACTGAAGC, which contains two potential binding sites for the transcription factor, AP-1. The mouse Cst3 mRNA was detected in all of thirteen tissues examined by Northern blot analysis. Cst3 was mapped in the mouse to a position on distal chromosome 2. PMID- 7835705 TI - Isolation of a cDNA encoding a novel zinc-finger protein from neuroblastoma x glioma NG108-15 cells. AB - A subtraction cDNA library was constructed from control hybrid NG108-15 (mouse neuroblastoma x rat glioma) cells and NG108-15 cells which had been treated for 48 h with the delta-opioid agonist D-Ala2-D-Leu5 enkephalin (DADLE) to down regulate the delta-opioid receptor on these cells. Among the clones isolated from this library was NGD16-4, a 2768-bp clone encoding a putative 64-kDa protein containing 14 tandemly repeated zinc fingers (Zf) with high homology to the Kruppel family of Zf proteins. NGD16-4 also contains a region homologous to the A element of the Kruppel Associated Box (KRAB) domain, a domain recently linked to transcriptional repression. Southern and Northern analyses indicate that NGD16-4 is derived from the mouse genome. Northern analysis also demonstrates that expression of NGD16-4 mRNA is much higher in several mouse neuroblastoma cell lines than in mouse brain or other tissues. Although the function of NGD16-4 is unclear, the expression pattern of NGD16-4 indicates a possible association with the processes of differentiation or transformation in the mouse. PMID- 7835706 TI - A widely expressed novel C2H2 zinc-finger protein with multiple consensus phosphorylation sites is conserved in mouse and man. AB - We have cloned a murine cDNA whose deduced sequence encodes a 455-amino-acid (aa) zinc-finger protein (Zfp), PZf (penta Zf protein). Sequence analysis shows that PZf has multiple phosphorylation consensus sites for casein kinase II and protein kinase C in its N-terminal portion. This region (aa 1 to 197), which does not share significant homology to known aa sequences, has a number of charged (39 Glu, 15 Asp, 23 Lys, 22 Arg) and hydroxyl (20 Ser, 12 Thr) aa. This potentially phosphorylatable region is followed by five C2H2 Zf in the middle of the protein. The Pzf gene is transcribed as a 5-kb mRNA in all murine tissues examined. The human genome also seems to contain one or more Pzf-related genes. PMID- 7835707 TI - Cloning of BSK, a murine FRK homologue with a specific pattern of tissue distribution. AB - A novel protein tyrosine kinase (PTK) was previously identified by us from the rat insulin-producing cell line, RINm5F, by polymerase chain reaction (PCR). By using this PCR fragment to screen a cDNA library from the mouse insulin-producing cell line beta TC-1, a cDNA clone of about 2.0 kb was obtained which encodes the entire amino acid (aa) sequence of the corresponding PTK. The deduced aa sequence reveals strong homology with the members of the SRC family of intracellular PTKs. We have designated the gene as BSK (beta-cell Src-homology tyrosine kinase). Southern blot analysis after PCR with primers specific for BSK confirmed its expression in fetal and adult islets of Langerhans, in RINm5F cells and in mouse kidney. Northern blots using poly(A)+RNA from non-beta-cell tissues showed that the BSK cDNA hybridized to three mRNA transcripts (2.9, 3.1 and 5.0 kb) present in kidney, liver and lung. Extensive homology of BSK with the recently identified human gene FRK was observed. It is concluded that Bsk is a murine Frk homologue with a specific pattern of tissue expression. PMID- 7835708 TI - Cloning of a cDNA encoding murine tetranectin. AB - A full-length cDNA encoding murine tetranectin (TN) was isolated and cloned from a murine lung lambda ZAPII cDNA library. The complete nucleotide sequence was determined revealing an open reading frame encoding 202 amino acids (aa) including a signal peptide of 21 aa. An overall aa identity of 79% exists between the deduced aa sequences of human and murine TN, revealing a high evolutionary conservation of the protein. The highest expression of mouse TN was found in lung and skeletal muscle. PMID- 7835709 TI - RTR: a new member of the nuclear receptor superfamily that is highly expressed in murine testis. AB - We have identified and cloned a novel member of the nuclear receptor superfamily from murine testis, referred to as retinoid receptor-related testis-associated receptor or RTR. Degenerate PCR primers homologous to two conserved regions of the DNA-binding domain of members of this superfamily were employed to identify this gene. The amino-acid sequence of RTR is most closely related to that of the mouse RXRs with an overall identity of 32-34%; the highest similarity (61%) is observed in the DNA-binding domain. Northern blot analysis using RNA from multiple tissues showed that RTR is predominantly expressed in the testis. Northern blot analysis using RNA from different testicular cell types showed that RTR mRNA is not expressed in early germ cells or Sertoli cells but is most abundant in round spermatids. Our observations suggest that this putative transcription factor plays a role in the regulation of gene expression particularly during the post-meiotic phase of spermatogenesis. PMID- 7835710 TI - Intron-exon structure of the porcine I kappa B alpha-encoding gene. AB - Genomic clones of ECI-6 (endothelial cell inducible), the porcine I kappa B alpha gene that encodes a cytoplasmic inhibitor of the transcription factor NF-kappa B, were isolated, spanning the entire transcribed region plus 2.1 and 0.35 kb of 5'- and 3'-flanking sequences, respectively. The gene contains five introns ranging in size from 0.6 to 0.1 kb. Four of the introns are located in the coding regions for four of the five ankyrin-like repeats in the central part of the I kappa B alpha protein at similar positions. The fifth intron is located in the C-terminal region. Southern blot analysis indicates the presence of a single copy of ECI-6/I kappa B alpha in the porcine genome. PMID- 7835711 TI - Sequences of two porcine glutamic acid decarboxylases (65- and 67-kDa GAD). AB - The cDNAs encoding the porcine 65- and 67-kDa glutamic acid decarboxylases (GAD65 and GAD67, respectively) were cloned by the PCR method. The 2246-nucleotide (nt) GAD65 cDNA contained an open reading frame (ORF) coding for a protein of 585 amino acids (aa), and the 3262-nt GAD67 cDNA contained an ORF coding for a protein of 594 aa. A remarkable conservation was shown when the deduced aa sequences of porcine GAD65 and GAD67 were compared with those of other mammalian species (human, cat and rat). Porcine GAD65 is 96% identical to human and rat GAD65, and porcine GAD67 is more than 95% identical to human, cat and rat GAD67 at the aa level. PMID- 7835712 TI - Bovine Alu-like sequences mediate transposition of a new site-specific retroelement. AB - We describe a new family of 3.1-kb repetitive sequences which is present in the bovine genome. The 5' and 3' ends of the unit are flanked with sequences homologous to the 5' and 3' halves of the bovine Alu-like monomer (BM), respectively. Distribution of the 5' ends of the family members in the genome is not random. They are close to the truncated bovine Alu-like dimer (BD) which, in some cases, is followed by 40-bp repeated sequences containing block A of the RNA polymerase III promoter. The ORFs found within the unit code for peptides homologous to amino-acid sequences characteristic for reverse transcriptases (RT). The family members may be considered as mutant mobile elements whose propagation in the genomes was accomplished by means of a process including site specific recognition with BD. Because of this, we call this family the bovine dimer-driven family (BDDF). PMID- 7835713 TI - Characterization of the gene encoding carbonic anhydrase I from the pigtail macaque. AB - The structure of the gene encoding carbonic anhydrase I (CA I) was determined for the pigtail macaque Macaca nemestrina. When the deduced amino-acid sequence was compared with those of five other primates, four non-primate mammals and a turtle, seven residues were found to be unique and invariant to all of the CA I sequences. A scheme is presented for the probable evolutionary order of the six polymorphic nucleotide changes found in the coding regions of the CA I locus of pigtail macaques. PMID- 7835714 TI - An oligodeoxyribonucleotide-directed dual amber method for site-directed mutagenesis. AB - A simple procedure for in vitro site-directed mutagenesis (SDM) was developed using two oligodeoxyribonucleotide (oligo) primers, one serving as selection primer and the other for mutagenesis in the target DNA (mutagenic primer). The mutant clones can be selected by reversion mutations of dual amber (am) to dual Gln codons in the cat gene, resulting in a chloramphenicol-resistant phenotype in sup(O) host cells. Unlike previously reported procedures, the new method requires neither special chemical reagents, nor single-stranded DNA purification, nor any additional biochemical treatments such as multiple PCRs, restriction digestion and so on, but utilises one of the oligo-directed dual am (ODA) plasmids, i.e., pKF16c, pKF17c, pKF18c or pKF19c. The two amber (am) mutations located two codons apart from each other in cat (catam2) can be simultaneously reverted with a 20 nucleotide primer (CQ, pAACCAGACCGTTCAGCTGGA) during primer extension. In a model experiment using the lacZ' gene, an am mutation or a single-bp deletion (sbd) mutation was frequently co-introduced in lacZ' using a mixture of am- or sbd encoding mutagenic primer for lacZ', and the CQ primer for catam2. Applying this procedure to the human AT cDNA (encoding antithrombin), a missense mutation (Arg406-->Met) in one of the human AT variants, AT-Kyoto, involved in congenital thrombosis disease, was introduced efficiently into the wild-type cDNA (> 85%). PMID- 7835715 TI - A genome-integrated hepatitis B virus DNA in human neuroblastoma. AB - An integrated hepatitis B virus (HBV) DNA has been identified in a human neuroblastoma, cloned and sequenced. The integrated HBV DNA is not rearranged, although a 480-bp fragment is deleted. The integrated viral DNA covers the C gene fragment, the region of Pre-S and S, and the 3'-truncated X gene. PMID- 7835716 TI - Sequence of the mouse adenovirus serotype-1 DNA encoding the precursor to capsid protein VI. AB - The nucleotide sequence predicted to encode the precursor to virion structural protein VI (preVI) of mouse adenovirus (Ad) serotype-1 (MAV-1) was determined. The 237-amino-acid sequence has 45% identity and 66% similarity to the human Ad serotype-2 preVI sequence. There is a marked conservation at the C terminus, the last eleven residues of which may be necessary for activating the Ad endoproteinase, and at the N terminus, including the consensus endoproteinase cleavage site. PMID- 7835717 TI - Cloning and sequencing of the gene encoding the mouse vitamin D receptor. AB - The mouse vitamin D receptor (VDR)-encoding cDNA was cloned and the coding regions were sequenced. Comparison of the amino-acid sequence to that of humans and rats revealed high homology in the DNA- and ligand-binding domains. Divergence appeared in the internal region between the two domains. PMID- 7835718 TI - Cloning and sequencing of the murine Mxi1 cDNA. AB - The cloning and sequencing of the murine Mxi1 gene encoding Mxi1, one of Max associated proteins, is described. Murine and human sequences showed 87.9% nucleotide (nt) and 90.3% amino acid (aa) sequence homology, whereas murine and zebra fish sequences showed 67.2% nt and 67.8% aa sequence homology. PMID- 7835719 TI - ERF-2, the human homologue of the murine Tis11d early response gene. AB - A human cDNA specifying a member of the Tis11 early response gene family was cloned and sequenced. The human gene differs from its mouse homologue by encoding an additional 97 amino acids at its C-terminal end. The sequence has transactivation-like motifs, an unusual Cys-Ser-Ala-rich motif and displays sequence similarity at the extreme C-terminal end with another Tis11 family member, ERF-1. PMID- 7835720 TI - Reader says PhDs have earned the right to be called 'doctor'. PMID- 7835721 TI - Unstable angina: emphasis returns to noninvasive techniques. PMID- 7835722 TI - Tinnitus: a stepwise workup to quiet the noise within. AB - Patients with tinnitus--ringing in the ears or head--frequently present initially to their primary care physician. Tinnitus may be subjective (audible only by the patient) or objective (audible to the examiner). Subjective tinnitus is more common and may be due to peripheral or central auditory pathology, a metabolic abnormality, or anxiety/depression. Objective tinnitus is rare and is frequently due to a vascular or neuromuscular condition, intracranial or head/neck tumor, or some specific structural defect of the ear, cochlea, or retrocochlear area. The stepwise workup of tinnitus includes a comprehensive history and physical exam, audiologic evaluation, blood profile analysis, and referral when necessary. Treatments include hearing aids, masking devices, drugs, and biofeedback. PMID- 7835723 TI - DVT and pulmonary embolism: choosing the right diagnostic tests for patients at risk. AB - The diagnostic approach to venous thromboembolism depends on the clinical setting: Patients with a suspected first episode of DVT can be managed with serial US or IPG. Normal serial results exclude proximal DVT and indicate a low risk for subsequent DVT/PE. Venography is the gold standard and may be indicated if the clinical suspicion differs markedly from the US/IPG result. For patients at high risk for DVT but with no symptoms, there is no accurate noninvasive screening test, but US is superior to IPG and other methods. The diagnostic approach for suspected recurrent DVT is the same as that for a first episode of suspected DVT, providing there is a documented normal US/IPG result since the most recent DVT but prior to presentation. Venography is indicated when the US/IPG is abnormal and there is no knowledge or documentation of a previously normal result. Patients with suspected PE require a V/Q lung scan. Normal results rule out PE, and high probability scans are usually diagnostic of PE. Patients with a nonhigh probability lung scan and a low or moderate pretest probability for PE probably can be managed safely with serial US. When clinical suspicion for PE is high, we recommend venography and--if venography is normal--angiography. PMID- 7835724 TI - When your patient needs surgery: how planning can avoid complications. AB - Older patients are at high risk of perioperative morbidity due to cognitive, affective, or functional deficits. As the primary care physician, you can lower the risk of complications by taking the following steps: Eliminate medications known to cause cognitive dysfunction to help prevent postoperative confusion. Screen for postoperative delirium to identify contributing factors such as infection, whose recognition otherwise might be delayed. Assess preoperative nutritional status to identify patients with significant malnutrition, and consider nutritional repletion before elective surgery is performed. After surgery, institute timely physical therapy to prevent loss of independent ambulation or transfer in patients with borderline mobility, who are at great risk for functional decline during hospitalization. Anticipate discharge needs in collaboration with the hospital discharge planner or home health agencies. PMID- 7835725 TI - Diabetic foot: strategies to prevent and treat common problems. AB - Neuropathy, peripheral vascular disease, limited joint mobility, and reduced resistance to infection all play a role in the development of foot pathology in diabetic patients. Once established, ulcerations and infections may provoke an irreversible cascade of events, culminating in limb loss. The best cure, therefore, is prevention. Working as a team, the primary care physician and the podiatrist can prevent problems before they occur and manage problems when they do happen. Shoes for the diabetic with neuropathy should have laces or a strap, a soft wide toe-box, and ample plantar soft tissue supplementation. When ulcers do occur, the mainstays of management are weight dispersion, debridement of devitalized tissue, and use of antibiotics where appropriate. PMID- 7835726 TI - For dying patients, there is much you can do. PMID- 7835727 TI - History of otoplasty. PMID- 7835729 TI - Pre- and postoperative management in otoplasty. PMID- 7835728 TI - Embryology and surgical anatomy of the auricle. PMID- 7835730 TI - A modified anterior scoring technique. PMID- 7835731 TI - Otoplasty: Mustarde technique. PMID- 7835732 TI - Cartilage incision and excision technique. PMID- 7835733 TI - Complications in otoplastic surgery and their treatment. PMID- 7835734 TI - Revision otoplasty and special problems. PMID- 7835735 TI - [Morcellation laparoscopic hysterectomy of the CASH (Classical, Abdominal, Semm, Hysterectomy) type]. AB - A classical abdominal Semm hysterectomy (CASH) morcellation laparoscopic hysterectomy was performed without bilateral salpingo-oophorectomy in 17 patients using 4 punctures with intracorporeal and extracorporeal suturing in 13 patients and in 4 patients with stapler of 35 mm. Removal of endocervical and endometrial canal through vaginal morcellation, the advantages of this procedure are its reduced blood loss, minimum possibility of ureter or bladder injury and decreased risk of infection through vaginal contamination, as well as a fast recovery period and minimum of pain. PMID- 7835736 TI - [Hysteroscopic myomectomy. Surgical management. Presentation of a case]. AB - A case of a 34 years old woman with primary sterility secondary to multiple myomatosis, is presented. Any other sterility factor was ruled out. First, she went on laparotomy for multiple myoma resection but two of these were left. The cornual myoma couldn't be removed because the high risk of salpinx damage. The other one was a 3 cm. intracavitary tumor. After four months on leuprolide acetate therapy an hysteroscopic myomectomy was performed. The next menstrual cycle pregnancy was achieved. PMID- 7835737 TI - [Advanced gestational choriocarcinoma. A clinical-pathological study of 40 cases]. AB - Forty two cases of advanced gestational choriocarcinoma were examined, with 4 of these patients being hospitalized for less than 24 hours. Given the non specific and atypical nature of the symptomatology, it was correctly diagnosed in 20 of these cases. In the other 22 cases where the predominant clinical status was established as a result of the localized invasion of neighboring structures or through metastasis, a variety of diagnoses were given, including uterine cervical carcinoma, endometrial carcinoma, pulmonary metastasis, brain tumor, bleeding of the gastrointestinal tract. The 20 patient diagnosed with choriocarcinoma were treated in the following manner: nine were operated for hysterectomies, with one of these also receiving an omentectomy, seven more were given chemotherapy treatment based upon methotrexate, and the remaining for were simply stabilized, which produced unfavorable results in that they survived from one to twenty weeks longer, with an average on only five weeks. PMID- 7835738 TI - [Laparoscopic findings in endometriosis in women with dysmenorrhea, pelvic pain and sterility. Preliminary note]. AB - Laparoscopy was performed on patients with dysmenorrhea, sterility and pelvic pain in order to evaluate the prevalence of endometriosis in our environment therefore considering the population of female beneficiary patients of reproductive age of the ISSSTE hospital in the city of Veracruz, Ver. in Mexico. The percentages of endometriosis were similar to the reports published in the international journals with the exception of the dysmenorrhea where our results were higher. In all the cases the same variables were analyzed; age, active sexual life (V.S.A.), birth control method, menarche (men), menstrual cycle, childbirths and abortions, as well as other laparoscopic detections. Each of the endometriosis cases were classified according to the revised American Fertility Society classification of 1985 (R.A.F.S.) for endometriosis. PMID- 7835739 TI - [Endometrial aspiration biopsy]. AB - The factuality and diagnostic accuracy of aspiration endometrial biopsy with Karman's cannula, as compared with the curetted sample with Novak's cannula, were evaluated. Two hundred and thirty endometrial biopsies, were taken, as part of the study in women with fertility problems, at the Assisted Reproduction Clinic and Sterility Clinic, Instituto Nacional de Perinatologia. The samples taken with Karman's cannula, Group I (n = 115); and with Novak's cannula, Group II (n = 115), were compared: procedure's time, pain intensity, quantity and quality of samples, macro and microscopically. In 92.2% of group I, tissue adequate for diagnosis, was obtained, as compared with 84.4% in Group II; likewise, the sample was better quantitatively and qualitatively, in Group I; and required time was less than one minute in 90% in Group I, an 83% in Group II. With the use of Karman's cannula, 20% of the patients had no pain, and 0.9% with the use of Novak's cannula. So, it can be concluded that endometrial aspiration with Karman's is reasonable and reliable in the functional histological diagnosis; it permits the obtention of adequate samples, in quantity and quality, and offering as advantages less pain and more security for the patients. PMID- 7835740 TI - [Gestational herpes. Presentation of a case and review of the literature]. AB - Herpes gestationis (HG) is a rare autoimmune blistering complication of pregnancy. It is of unknown etiology and it occurs once in every 3,000 to 50,000 pregnancies. The diagnosis can strongly be suggested by the clinical picture, but it must be confirmed using immunopathological methods. The treatment of choice is local measures and systemic corticosteroids. Although the maternal prognosis is excellent, there are controversies on the perinatal outcome. A typical case of HG is presented and the literature is reviewed. PMID- 7835741 TI - [Induction of labor with misoprostol]. AB - The results obtained with the induction of labor with a synthetic analogue of prostaglandin E1: misoprostol, are presented. We reviewed 149 cases of patients admitted to this hospital (The "Policlinico Escuela Eva Peron") for induction of labor throughout a 13-month period of time since 06/01/92 until 06/30/93. All patients had a medical indication for induction of labor, a single pregnancy, cephalic - vertex presentation, no previous surgical scars on uterus, no contraindications for vaginal delivery, Bishop score below 7, gestational age over 37 weeks, and a reactive NST (Non Stress Test). Misoprostol was used intravaginally in the posterior fornix, in one dose of 100 mcg. In those patients where the spontaneous rupture of membranes was not the cause of induction itself, these were artificially ruptured at the moment of admission if possible depending on obstetric conditions, or no longer than 2 hours afterward. All patients underwent continuous fetal hart rate monitoring, during the active phase of labor. There were no failures of induction since all patients reached the active phase of labor without using oxytocin. There was an extremely high percentage of vaginal deliveries being this figure 96.6%. Only 5 patients had to undergo a cesarean section, 2 because of arrest of labor and 3 because acute fetal distress. Four cases of acute intrauterine fetal distress were registered but none of them were caused by tachysystole or hypercontractility. The mean time from the beginning of induction to delivery was 5 hours and 20 minutes (+/- 2 hs, 40') 70.5% of patients giving birth before 6 hours since admittance.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7835742 TI - [Endometrial changes caused by induction of ovarian hyperstimulation which affect the process of embryo implantation]. AB - In a natural process, the endometrium in under strict hormonal control. The protocols of multiple follicular growth produce estradiol supraphysiological concentrations (E2) that alter the progesterone/estradiol ratio (P4/E2), with concomitant diminution of endometrial receptivity; this could explain the low efficiency with assisted reproduction methods. PMID- 7835743 TI - [Evaluation of Mexican biomedical reviews. Committee on the evaluation of Mexican biomedical reviews of the Centro Nacional de Informacion y Documentacion sobre Salud]. PMID- 7835745 TI - Role of intracellular SOD in protecting human leukemic and cancer cells against superoxide and radiation. AB - Many anticancer drugs have been shown to produce superoxide anion (O2.-) and seem to involve O2.- in their mode of action. Ionizing radiation provokes the decomposition reaction of water, producing a variety of reactive oxygen species, including O2.-. The finding that cancer cells are generally low in SOD activity may offer a theoretical base for radiation therapy and chemotherapy. The purpose of this study was to examine the protective effect of intracellular SOD against cytotoxicity induced by O2.- or radiation and to investigate whether exogenous SOD can protect cells from O2.-(-) and radiation-induced cytotoxicity. For this purpose, xanthine (X) and xanthine oxidase (XOD) were employed as an O2.- ( )generating system, and a linear accelerator was used for ionizing radiation. Cytotoxicity against monolayer cancer cell lines and leukemic cell lines was estimated by measuring the release of lactate dehydrogenase from these cells. The results revealed that the resistibilites to X- and XOD-generated O2.- and radiation correlated with intracellular Cu. Zn-SOD levels and that exogenous SOD could only slightly reduce X- and XOD-induced cytotoxicity while having no influence on radiation-induced cytotoxicity. Thus, intracellular SOD may play a central role in protecting cancer cells against reactive oxygen species generated by anticancer drugs and radiation. PMID- 7835744 TI - Modulation of streptonigrin cytotoxicity by nitroxide SOD mimics. AB - Nitroxides are cell-permeable, stable radicals that react readily with paramagnetic species such as transition metals or short-lived free radicals, though not generally with diamagnetic molecules. Nitroxides can undergo one electron selective redox reactions and thereby potentially modify the activity of cytotoxic drugs. Streptonigrin (SN) toxicity requires bioreduction to yield the semiquinone radical, and the toxicity is reportedly mediated by transition metals and oxygen-derived reactive species via redox-cycling of the semiquinone intermediate. The present study shows that (1) nitroxides protected isolated DNA and also aerated or hypoxic bacterial cells from SN toxicity; (2) H2O2 potentiated the hypoxic cytotoxicity of the drug but inhibited the damage to aerated cells; (3) pretreatment of cells with H2O2 conferred some protection, but not when the drug alone was preexposed to H2O2; and (4) desferrioxamine and 2,2 dipyridyl, though neither diethylenetriamino pentaacetate, exogenous catalase, or superoxide dismutase, decreased SN-induced cell killing. The mechanisms by which nitroxides protect from SN toxicity involve both a selective radical-radical reaction with SN semiquinone and the reoxidation of reduced cellular transition metal ions. On the other hand, H2O2 appears to exert two opposing effects: (1) facilitation of cell killing by the Fenton reaction and (2) lowering the cellular level of reducing equivalents, thus inhibiting the bioreductive activation of SN. PMID- 7835747 TI - Alterations in mitochondrial membrane fluidity by lipid peroxidation products. AB - Age-related damage to the mitochondrial membrane, including decreased membrane fluidity, has been attributed to free radical reactions. Our previous studies point to lipid peroxidation as a primary cause in age-related changes in membrane fluidity. This report offers new evidence that lipid peroxidation-modulated decreases in membrane fluidity are mediated through two aldehydic lipid peroxidation products, 4-hydroxynonenal (HNE) and malondialdehyde (MDA). Hepatic mitochondria were isolated from both ad libitum fed (AL) and dietary restricted (DR) rats of different ages. Introduction of the aldehydes was found to decrease mitochondrial membrane fluidity, although the fluidity decrease induced by HNE was more pronounced than that induced by MDA. It seems likely that HNE modifies membrane fluidity by direct interaction with membrane phospholipids, as shown by the generation of a fluorescent complex between HNE and membrane phospholipids. Finally, HNE and MDA were isolated and quantitated in mitochondria. Their levels clearly differentiated between animals of different age and dietary groups. These data indicate that the reactive products of lipid peroxidation, especially HNE, may play an important role in mediating the decreased mitochondrial membrane fluidity observed in aging animals. PMID- 7835746 TI - Analysis of plasma cholesterol oxidation products using gas- and high-performance liquid chromatography/mass spectrometry. AB - The application of gas chromatography and high-pressure liquid chromatography/mass spectrometry techniques for analysis of plasma cholesterol oxidation products is described. Cholesterol oxides that are widely identified in biological samples were subjected to gas (GC) and high-pressure liquid chromatographic (HPLC) separations, and their detection and characterization by mass spectrometry (MS) were compared. Analysis of cholesterol oxides from plasma samples revealed distinct advantages for each method according to the specific cholesterol oxide in question. Whereas HPLC/MS analysis of cholesterol oxides provided less resolution and lower sensitivity as compared to GC/MS, a distinct advantage was evident for direct measurements of cholesterol-7-hydroperoxides and 7-ketocholesterol. These two cholesterol oxides are particularly sensitive to storage in solvents, derivatization procedures, and analytical conditions used for GC analysis, which are minimized or avoided using the HPLC/MS conditions described. Analysis of human and rabbit plasma samples identified cholest-5-ene-3 beta, 7 beta-diol (7 beta-hydroxycholesterol); 5,6 alpha-epoxy-5 alpha-cholestan 3 beta-ol (cholesterol-5 alpha, 6 alpha-epoxide); 5 alpha-cholestane-3 beta, 5,6 beta-triol (cholestanetriol); 3 beta-hydroxycholest-5-ene-7-one (7 ketocholesterol); and 5,6 beta-epoxy-5 beta-cholestan-3 beta-ol (cholesterol-5 beta,6 beta-epoxide) as commonly occurring components (trivial names indicated in parentheses). The latter two compounds were dramatically increased in hypercholesterolemic samples and were found in approximately equal amounts in the free cholesterol and cholesteryl ester fractions. Although most of the plasma cholesterol oxides are found in the dietary cholesterol, others are not, particularly cholesterol-5 beta,6 beta-epoxide, suggesting that at least some of these compounds are formed by in vivo oxidation of cholesterol. Despite the readily measurable levels of the above cholesterol oxides, as well as other less prominent oxides, there was no evidence of cholesterol-7-hydroperoxides associated with plasma free cholesterol. Although several of the plasma cholesterol oxides may derive from cholesterol-7-hydroperoxides, it appears that the latter are either unstable and decompose in plasma, are metabolized to other cholesterol oxidation products, or break down during their isolation. PMID- 7835748 TI - 5-methylcytosine attack by free radicals arising from bromotrichloromethane in a model system: structures of reaction products. AB - The interaction between free radicals derived from the catalytic decomposition of bromotrichloromethane and 5-methylcytosine (5MC) under different conditions were studied. The structures of the reaction products formed was established by the GC/MS analysis of their trimethylsilyl derivatives. Under anaerobic conditions, the formation of the following products was found: (1) thymine; (2) 5 hydroxymethyl uracil. Under aerobic conditions, the following reaction products were identified: (1) The same two products formed under anerobic conditions. (2) Monohydroxylated thymine. Precise location of the hydroxyl group was not established but probably corresponds to the six position isomer. (3) Two monochloro monohydroxy thymines. It is suggested that they are cis-trans isomers whose substituents are located at the 5-methyl and six positions of the base. (4) The trimethylsilyl derivative of thymine glycol. (5) Two monobromo monohydroxy adducts of thymine. One of them was detected as its underivatized form in the hydroxyl group position. (6) A partially silylated dihydroxythymine. When benzoyl peroxide was omitted from aerobic incubation mixtures, the compounds formed changed. No longer observable were: thymine; the two monochloro monohydroxy derivatives of thymine; thymine glycol, and one monohydroxythymine. On the other hand, two new reaction products were formed instead: a partially silylated monochloro-monohydroxy thymine and 5-hydroxymethyl-cytosine. If similar or equivalent reaction products were formed in DNA during CBrCl3 or CCl4 poisoning, results might be of relevance, because the 5MC content in DNA from eukaryotes is related to differentiation, gene control, and to carcinogenesis. PMID- 7835749 TI - Differential susceptibility of plasma proteins to oxidative modification: examination by western blot immunoassay. AB - Plasma proteins are exposed to oxidants in a variety of circumstances in vivo, such as during tissue injury and inflammation. In this report, the relative susceptibility of each of the major plasma proteins to oxidative modification was assessed by exposing whole plasma to a metal-catalyzed radical generating system and detecting oxidation (protein carbonyl groups) using a novel Western blot immunoassay. Proteins were derivitized with dinitrophenylhydrazine, separated by SDS-gel electrophoresis, and screened with antibodies against dinitrophenyl groups. As little as 1 pmol of protein-associated carbonyls could be detected (100 ng of a 50 kD protein containing 0.5 mol carbonyl/mol protein). Individual plasma proteins were identified by their comigration with standards, crossreactivity with specific antibodies, and by comparison of plasma to serum. Using this approach, we found that plasma fibrinogen was much more susceptible to oxidative modification compared to the other major plasma proteins, albumin, immunoglobulins, and transferrin. The results emphasize the utility of this method for studying oxidation of proteins in cell extracts and tissues and indicate that experiments on the effects of oxidation on fibrinogen function are merited. PMID- 7835750 TI - Decrease in vitamin E levels in the bone marrow of mice receiving whole-body X ray irradiation. AB - Mice were subjected to whole-body x-ray irradiation, and changes in vitamin E content and lipid peroxide levels in various tissues were examined. When mice were irradiated with 6 Gy, vitamin E content (per mg protein) in the bone marrow began to decrease 3 h later and a marked decrease to the level of 30% of that of the controls was observed on day 2. Concomitant with the decrease of vitamin E, an increase of lipid peroxide levels was also observed in the bone marrow. On day 2 after an exposure to doses ranging from 1 to 10 Gy, a dose-dependent decrease of vitamin E and an increase of lipid peroxide levels were observed in the bone marrow with a dose of 3 Gy or more. In contrast, neither a decrease of vitamin E nor an increase of lipid peroxide levels was observed in the liver, kidney, spleen, and testes even with an exposure of up to 10 Gy. After the irradiation, glutathione in the bone marrow decreased, while that in the liver increased. These results suggest that the bone marrow is more highly susceptible to oxidative damage induced by radiation than other tissues. PMID- 7835751 TI - Neuronal protection with superoxide dismutase in repetitive forebrain ischemia in gerbils. AB - The underlying mechanism for severe damage with repetitive ischemia is not fully understood. Because of prolonged periods of reperfusions between the brief insults, we speculated that the severe damage may be secondary to excessive generation of oxygen free radicals. In this study we tested the efficacy of peg superoxide dismutase (SOD) in a model of repeated ischemia in gerbils. Superoxide dismutase (SOD) or vehicle (saline) was delivered through osmotic pumps into the lateral ventricles continuously from the onset of the insult until the gerbils were sacrificed 6 days later. Three doses of SOD were used in the experiments (110, 150, and 190 units per microliter). Damage was assessed using a 0-4 point scoring system and statistical comparisons were done using the Mann-Whitney U test. There was significant protection in the hippocampus (p < 0.05), striatum (p < 0.001), and substantia nigra reticulata (p < 0.05) in the lowest dose SOD treated group (110 units per microliter). Animals treated with 150 units showed lesser (but significant) protection in the thalamus, medial geniculate nucleus, and striatum. In the animals treated with the higher dose of SOD (190 units per microliter), the extent of damage was no different than vehicle-treated controls in the cortex, striatum, and hippocampus. Compared to controls, neuronal damage was, however, significantly more severe in the medial geniculate nucleus and the thalamus in the high-dose SOD-treated animals (p < 0.05). Our experiments suggest that the SOD may have a small therapeutic window. Higher doses may either have no neuroprotective effects or may be harmful. PMID- 7835752 TI - Mechanisms of radical formation from reactions of ozone with target molecules in the lung. AB - Ozone is known to cause radicals to be formed in biological systems: for example, it initiates lipid peroxidation and vitamin E protects in vitro model systems, cells, and animals against the effects of ozone. Ozone is not itself a radical, and we have asked: With what molecules does ozone react in the lung and how are radicals produced? Ozone reacts by two quite different mechanisms to produce radicals; one involves an ozone-olefin reaction and the other a reaction with electron donors such as glutathione (GSH). The first mechanism splits an R radical out of an olefin with the structure R-CH = CH2. The R then reacts with dioxygen to become a peroxyl radical (ROO), and both carbon- and oxygen-centered radicals can be detected by the electron spin resonance spin trap method. From the effects of temperature, metal chelators, and water, it is concluded that ozone reacts by the Criegee ozonation pathway to give the classical 1,2,3 trioxolane, which then undergoes O--O bond homolysis to form a diradical. This diradical then either undergoes beta-scission to split out the R radical or forms the more usual carbonyl oxide and a carbonyl compound. (See Figure 3 in the text). The low yield of Criegee ozonide that is generally obtained probably is due in part to the reactions forming radicals from the 1,2,3-trioxolane that compete with production of the Criegee ozonide. The second mechanism for radical production involves the reaction of ozone with electron donors. If the electron donor is, for example, GSH or its ion (GS-), this reaction produces the thiyl radical GS. and 0.3-. The ozone radical anion then reacts with a proton to form the hydroxyl radical and dioxygen: O3.- + H+-->HO. and O2. Using 5,5-dimethyl-1 pyrroline-N-oxide, the spin adduct of the hydroxyl radical is detected. Similar reactions are observed with catechol. PMID- 7835753 TI - Detection of free radicals in blood by electron spin resonance in a model of respiratory failure in the rat. AB - Previous work has suggested that a free radical mechanism is involved in some types of muscle fatigue and that there can be free radicals released extracellularly. Because muscle fatigue may be an important factor in respiratory failure, the authors tested the hypothesis that increased concentrations of free radicals could be detected in the blood of animals undergoing severe resistive loading to respiratory failure. An ex vivo spin trapping technique with alpha phenyl-N-tert-butylnitrone (PBN) was used to investigate the possible formation of free radicals in systemic blood samples by electron spin resonance (ESR) spectrometry. After 2.5-3 h of severe inspiratory resistive loading with 70% supplemental inspired oxygen, free radical levels in the form of PBN-adducts were found to rise significantly over the control group breathing room air and the control group breathing 70% oxygen (p < 0.05, N = 8). There were no significant differences between control groups breathing room air and control groups breathing 70% oxygen. This study presents direct evidence that free radicals are produced ex vivo and that they can be detected in the systemic circulation due to excessive resistive loading of the respiratory muscles. PMID- 7835754 TI - Reduction of lipid-soluble nitroxides in CHO cells and macrophage tumor cells. AB - There is a need to understand the metabolism of nitroxides because of their usefulness in measurements in living cells of complex phenomena, such as biophysical properties, redox metabolism, and the concentration of oxygen at specific sites. As part of a systematic study of the metabolism of nitroxides in cells, the authors studied Chinese hamster ovary (CHO) cells and mouse macrophage tumor (M5076) cells, using a set of lipophilic nitroxides based on 5 doxyl stearate: the free acid, the methyl ester of the acid, and a phosphatidylcholine with two doxyl stearates esterified to the glycerol. The rates of metabolism of these nitroxides under anoxia differed significantly as a function of both the type of cell and the type of nitroxide. The rates of reduction of the three lipophilic nitroxides depended on their localization. The rates of reduction were first order for all three lipophilic nitroxides, and the only products detected were the respective hydroxylamines. Effects of freeze-thawing and incubation temperature differed in the two cell lines. The authors conclude that the metabolism of nitroxides in different cell lines can be quite different. This may be especially important in understanding studies using nitroxides in living cells, functional organs, and in vivo. PMID- 7835755 TI - Alterations in the bioantioxidants following thrombosis. AB - The role of free radicals in rat thrombosis has been demonstrated by studying its scavenging enzyme system. Changes in the bio-antioxidants (GSH-redox cycle, total thiol groups, vitamins E and C) that also offer protection against the free radicals, have, however, not been studied so far. This investigation was undertaken to understand the involvement of these antioxidants during thrombosis. The tissues investigated following thrombosis were blood, platelets, polymorphonuclear leukocytes (PMNLs), heart, and lung. Glutathione (GSH) content in the platelets was observed to be depleted. However, oxidized glutathione (GSSG) contents in the platelets, PMNLs, and blood remain unaltered. In addition, in the whole blood GSH levels were increased significantly, whereas there was no change in the GSSG level. Activity of glutathione reductase (GR) was decreased significantly in platelets and lungs with an increase in the total thiol groups in the lung homogenate. Activity of Glutathione peroxidase (Gpx) remained unaltered in all the tissues studied. In addition, 24% and 15% decrease in the alpha-tocopherol concentration was observed in thrombocytes and PMNLs, respectively, with no change in the ascorbate levels in these cells. Results of this investigation suggest alterations in the GSH-redox cycle in blood, platelets, and lung after thrombosis in the rat. PMID- 7835756 TI - Tamoxifen and related compounds protect against lipid peroxidation in isolated nuclei: relevance to the potential anticarcinogenic benefits of breast cancer prevention and therapy with tamoxifen? AB - Tamoxifen, 4-hydroxytamoxifen, nafoxidine, 17 beta-oestradiol and ICI 164,384 were all found to protect rat liver nuclei against Fe(III)-ascorbate dependent lipid peroxidation. The order of effectiveness of these compounds was 4 hydroxytamoxifen > 17 beta-oestradiol > nafoxidine > tamoxifen > ICI 164,384. This protection by tamoxifen against the formation of the genotoxic reactive intermediates and products of lipid peroxidation in the nuclear membrane could be important in the prevention of nuclear DNA damage and thus carcinogenesis. This possible anticarcinogenic benefit of tamoxifen treatment could be important in long-term therapy with tamoxifen (and future derivatives) and in its proposed use in the prevention of breast cancer. PMID- 7835757 TI - The old girls' network: mentorship in publishing. PMID- 7835758 TI - Spirituality, aging, and the community-dwelling caregiver and care recipient. PMID- 7835759 TI - Successful treatment using behavioral interventions of urinary incontinence in homebound older adults. PMID- 7835760 TI - Older adult care recipients' insight into their caregivers: 'beware the stone faced elephant!'. PMID- 7835761 TI - From hospital to nursing home: bridging the gaps in care. PMID- 7835762 TI - The health care rainbow. PMID- 7835763 TI - Coping with placement of a parent in a nursing home through preplacement education. PMID- 7835764 TI - Home health nursing: understanding the practice. PMID- 7835765 TI - Sugar, starch, and the diabetic diet. PMID- 7835766 TI - Reducing the risk of cardiovascular disease in older adults. PMID- 7835767 TI - Does thrombocytosis have any prognostic significance in cervical cancer? PMID- 7835768 TI - Thrombocytosis in surgically treated stage IB squamous cell cervical carcinoma (A Gynecologic Oncology Group study). AB - Thrombocytosis has previously been shown to be an unfavorable prognostic factor in cervical cancer patients treated with irradiation. We evaluated the significance of thrombocytosis (platelet count > 400 x 10(9)/liter in 623 surgically treated patients with stage IB squamous cell carcinoma of the cervix. These patients had no gross evidence of extrauterine disease at the time of exploration, and none had metastasis to the para-aortic nodes. Fifty-nine (9.5%) of these 623 patients had thrombocytosis. The 5-year survival for patients with thrombocytosis was 82% compared to 83.5% for patients with normal platelet count (P = 0.4). Pelvic node metastasis was present in 13 (22%) of 59 patients with thrombocytosis, and 77 (13.7%) of 564 patients with normal platelet count (P = 0.1). There was a significant correlation between tumor size and platelet count. Patients with thrombocytosis had a mean tumor size of 27.9 mm, while it was 20.4 mm in patients without thrombocytosis (P = 0.002). Other factors found to be associated with thrombocytosis in this population were elevated white blood cell (WBC) count (P = 0.009) and history of chronic obstructive pulmonary disease (COPD) (P = 0.02). In a multivariate analysis for thrombocytosis adjusted for COPD, WBC count, and tumor size, tumor size continued to be statistically significant (P = 0.01). These data suggest that thrombocytosis is a marker of tumor burden and not an independent prognostic factor for progression-free interval or survival. PMID- 7835769 TI - Artificial Dura Film for femoral vessel coverage after inguinofemoral lymphadenectomy. AB - Eleven patients undergoing inguinofemoral lymphadenectomy for carcinoma of the vulva had the femoral vessels covered with Dura Film (Codman, Randolph, MA); a total of 21 groins were explored. The Dura Film was sutured to the inguinal ligament, sartorius muscle fascia, and adductor longus fascia. Nine of the 21 groins became infected with 3 of these breaking down; each of these 3 required removal of the Dura Film to achieve satisfactory healing. One patient developed a unilateral inflammatory groin mass requiring surgical removal of the Dura Film. One patient developed a chronic draining sinus that required surgical intervention. Seven groins developed lymphocysts. The morbidity was high with 9 of the 11 patients experiencing complications. Coverage of the femoral vessels with Dura Film after inguinofemoral lymphadenectomy is not an effective alternative to human dura mater or sartorius muscle transplant. PMID- 7835770 TI - Lymphogenous metastasis in the primary carcinoma of the fallopian tube. AB - The bad prognosis of primary Fallopian tube carcinoma (FTC) is mostly ascribed to early lymphogenous metastasis. Yet, there is a lack of information on the tumor size at which lymph node metastasis must be expected to occur. Our study was therefore designed to correlate the anatomopathologic substratum and the histologic results with the lymph node status. Data were obtained from 21 women who received primary surgery, during which additional total pelvic and para aortic lymphadenectomy was performed as well. The "surgical" staging was compared to the final clinical staging after histologic inspection of the lymph nodes according to the FIGO classification. Lymph node metastases never occurred as long as the tumor was confined to the tube (stage I). Lymphogenous dissemination set in only after further, local expansion of the tumor, involving the ovaries, the peritoneum, or the uterus (surgical stage II); 3 of the 7 patients of surgical stage II had to be reclassified to stage III because of manifest lymph node metastases. After the onset of intra-abdominal or general metastasis (stage IV), lymph node metastases occurred significantly more often (P = 0.048). Due to the specific lymphatic drainage, lymphogenous metastasis must be expected to spread as far as to the para-aortic region even in the early stages. Highly differentiated tumors (G I) do not disseminate into the lymphatic system, not even in advanced stages, whereas anaplastic tumors (G II and III) metastasize relatively early. As soon as metastasis has occurred, prognosis of life diminishes markedly, but not significantly (49 versus 24 months, P = 0.19). Correct FTC-staging is obtained only on the basis of pelvic and para-aortic lymphadenectomy. PMID- 7835771 TI - Flow cytometric analysis of uterine sarcomas. AB - Eighty-four women with sarcoma uteri were evaluated on the basis of histopathological examination findings. In 45 of the 84 cases, a flow cytometric measure of DNA content and S-phase fraction was performed. Thirty-seven cases of the 45 were available for estimation of S-phase fraction. The histopathologic examination of paraffin-embedded tumor tissue revealed 44% leiomyosarcomas, 25% homologous mixed mullerian tumors, 17% endometrial stromacell sarcomas, 7% heterologous mixed mullerian tumors, 1% rhabdomyosarcomas, and 6% unclassified sarcomas. Eighty-six percent of the tumors were aneuploid, 14% were peridiploid, and the 5-year survivals were 20 and 60%, respectively. Clinical stage and lymphocytic reaction were found to be good prognostic parameters. Multivariate analysis of 5-year survival adjusted for age at menopause, clinical stage, mitotic frequency, lymphocytic response, and S-phase fraction did not give any further significant prognostic factors. PMID- 7835772 TI - p53 expression and genetic evidence for viral infection in intraepithelial neoplasia of the uterine cervix. AB - Infections with high-risk strains of human papillomaviruses (HPVs) and with herpes simplex virus type 2 (HSV 2), as well as inactivation of the p53 tumor suppressor gene, are important cofactors in cervical carcinogenesis. We analyzed 41 paraffin-embedded cervical intraepithelial lesions, including 25 cases of low grade cervical intraepithelia neoplasia (CIN), and 16 cases of high-grade CIN for the presence of HPV 16/18 and HSV 2 genomic sequences and for the nuclear accumulation of the p53 protein. HPV 16 DNA was detected in 24.% of low-grade CINs and in 43.7% of high-grade CINs. HPV 18 was found only in 8.% of low-grade CINs. None of the cases tested scored positive for HSV 2 DNA. Nuclear accumulation of p53 was found in 4% of low-grade CINs, and in 31.2% of high-grade CINs, including 57.1% of the lesions that were positive for HPV 16. These results indicate that HPV 16 infection was over sixfold more common than HPV 18 infection and that p53 overexpression was significantly associated with high-grade lesions. PMID- 7835773 TI - Interphase fluorescence in situ hybridization for trisomy 12 on archival ovarian sex cord-stromal tumors. AB - Trisomy 12 is a nonrandom chromosomal abnormality found in a large proportion of ovarian sex cord-stromal tumors (OSCTs), including thecoma-fibromas (TFs) and granulosa cell tumors (GCTs). The prognostic significance of trisomy 12 in these tumors, however, is unknown. A series of 16 OSCTs, obtained from patients with long-term follow-up, was analyzed for the presence of trisomy 12 by interphase fluorescence in situ hybridization on paraffin-embedded sections. Sections of the contralateral nonneoplastic ovary were available in five cases and utilized as controls. Evidence of trisomy 12 was detected in 9 of 10 TFs, and contrary to previous reports, in only one of six GCTs. One TF with trisomy 12 was a malignant variant that resulted in the death of the patient in 5 months, but the remaining TFs with trisomy 12 were cytologically and clinically benign in those with follow up available. The single GCT with trisomy 12 was a nonaggressive, stage 1 lesion without evidence of recurrence after 264 months, whereas those GCTs without trisomy 12 included one stage 2 tumor and a cytologically atypical GCT with tumor necrosis and an elevated number of mitotic figures. The evidence suggests that the great majority of OSCTs with trisomy 12 is clinically benign, but not all benign OSCTs have trisomy 12. We conclude that the presence of trisomy 12 is of limited prognostic usefulness in OSCTs. PMID- 7835774 TI - Hard choices: the gynecologic cancer patient's end-of-life preferences. AB - Few reports in gynecologic literature have addressed patient preferences about terminal care. In light of the current discussions about end-of-life decision making, a study was designed to assess the desires of patients with gynecologic cancer. A questionnaire was completed by 108 patients under treatment for gynecologic cancer at the University of Michigan Medical Center and by 39 patients from the routine gynecology clinic at the same institution. Participants were asked about their reactions to a poor prognosis, their desires for the location of terminal care, and their preferences for withdrawing or withholding life-sustaining technologies. Five percent of these cancer patients anticipated giving up the fight against their disease. Seventy-eight percent specifically expressed resolve to continue the fight against their disease. Feedback from these patients about their end-of-life preferences served to define the concept "fight." A majority preferred to receive care at home. Ninety percent of these cancer patients could envision their conditions deteriorating to the point that they would not want ventilator support. Thirty-four percent could envision refusing surgery for another life-threatening condition; 37%, a time when artificial nutrition would be refused; 22%, a time when antibiotics would be rejected. This study suggests that limiting the use of artificial respiratory support while continuing the use of artificial nutrition and hydration support would be consistent with the preferences of gynecologic cancer with end-stage disease. PMID- 7835775 TI - Prognostic indicators of survival in advanced endometrial cancer. AB - Advanced endometrial cancer represents 14% of all stages but 54% of all deaths attributed to endometrial cancer. From 1973 to 1990, the charts of 137 patients with endometrial cancer (Stage III and IV) treated by the section of Gynecologic Oncology at Rush Medical College were retrospectively reviewed. The log rank method was used for univariate analysis and Cox proportional hazards regression was used for multivariate analysis. The patients were stratified as follows: Stage III, 92 (67.2%), Stage IV, 45 (32.8%); Grade 1, 15 (10.9%), Grade 2, 47 (34.3%), Grade 3, 67 (48.9%); adenocarcinoma, 93 (67.9%), adenosquamous, 18 (13.1%), adenoacanthoma, 2 (1.5%), clear cell, 1 (0.7%), papillary serous, 23 (16.8%). Using univariate analysis, median survival was 1.71 years for Stage III versus 0.68 years for Stage IV. Median survival based on treatment was as follows: radiotherapy (RT) only (n = 16), 0.89 years, surgery only (n = 36), 0.75 years, preoperative RT+surgery (n = 7), 2.5 years, surgery+postoperative RT (n = 56), 2.63 years, and other treatments (hormonal only n = 12, chemotherapy only n = 1, and no treatment n = 9), 0.6 years. Patients with vaginal extension survived a median of 0.82 years, versus 2.49 years without this factor (P = 0.002). Patients with clinically apparent parametrial involvement survived a median of 0.70 years versus 2.65 years without this factor (P = 0.0003). Multivariate analysis was possible via a surgical database (n = 99). Age > 60 (P = 0.01), parametrial involvement (P = 0.04), and abdominal metastases (P = 0.003) were significant prognostic indicators. Papillary or clear cell histology, advanced grade, and mode of treatment were not significant. Patients with abdominal metastases or parametrial extension of tumor have a significant decrease in mean survival. PMID- 7835776 TI - Cold-knife conization versus loop excision: histopathologic and clinical results of a randomized trial. AB - Ninety patients with cervical intraepithelial neoplasia (CIN) were randomly assigned to loop excision (n = 38) or cold-knife conization (n = 52). All specimens were well evaluable at histology. The average width of the lesions at histology was 10.2 and 9.7 mm, respectively (ns). The average weight of the specimens was 2.6 and 5.6 g (P < 0.01) and the average depth was 9.2 and 15.8 mm (P < 0.01), respectively. The distance between the cervical resection margin and CIN was 14 mm after loop excision and 24 mm after cold-knife conization (P < 0.06). The margins of the specimen were not clear of disease in 8 patients after loop excision and in 12 patients after conization (ns). Two patients after loop excision and in three patients after cold-knife conization had postoperative bleeding. The results suggest that, compared with cold-knife conization, loop excision removes less healthy tissue without reducing the chances for cure. PMID- 7835777 TI - Differential response of cervical intraepithelial and cervical carcinoma cell lines to transforming growth factor-beta 1. AB - Transforming growth factor-beta 1 (TGF-beta 1) is a potent inhibitor of epithelial cell proliferation. It has been proposed that loss of sensitivity to growth inhibition by TGF-beta 1 may be an important step in the development of cervical carcinoma, but it remains unclear whether this represents an early or a late event. We compared the sensitivity to TGF-beta 1 of nontumorigenic human papillomavirus deoxyribonucleic acid (HPV DNA)-positive cell lines derived from cervical intraepithelial neoplasia (CIN), of newly established cervical carcinoma cell lines, of nontumorigenic HPV DNA-transfected cervical cell lines, and of normal ectocervical cells. There is a dose-dependent inhibition of DNA synthesis by TGF-beta 1 in the CIN cell lines and the HPV DNA-transfected cell lines. The carcinoma cell lines are resistant to the growth inhibitory effects of TGF-beta 1. The CIN cell lines are significantly more sensitive than the carcinoma cell lines (P < 0.001), but significantly less sensitive than normal cervical cells (P < 0.05). A CIN cell line which contains HPV 31b DNA is more sensitive to TGF-beta 1 at early passage than at late passage (P < 0.05). There are no differences in the sensitivity to the growth inhibitory effects of TGF-beta 1 between subclones of this cell line that have different episomal HPV DNA content, population doubling time, or differentiation characteristics. Both normal and abnormal cervical epithelial cells were able to secrete latent TGF-beta 1 or TGF-beta 2. We conclude that resistance to growth inhibition by TGF-beta 1 is likely to be a late event in the development of cervical carcinoma; it is not the mere consequence of immortalization by HPV genes acquired following transfection in vitro or infection in vivo. PMID- 7835778 TI - Detection of heterozygous XY complete hydatidiform mole by chromosome in situ hybridization. AB - Complete hydatidiform mole has a substantial risk of developing persistent gestational trophoblastic disease (PTD). Whether heterozygous complete moles, arising from dispermy, have a higher risk of such progression than their homozygous counterparts is controversial. In this study, the frequency of heterozygous XY complete mole in 93 consecutive cases of histologically proven complete moles managed in Hong Kong was assessed by the technique of chromosome in situ hybridization (CISH) using DNA probes specific for the short arm of the Y chromosome. The incidence of Y-chromosome positive complete mole in the groups of patients with spontaneous remissions and the group with PTD with or without metastasis was also compared. The presence of Y chromosome was identified in 6 of the 93 cases (6.5%), and this incidence fell within the range reported in the world literature. Of these 93 patients, 5 patients defaulted follow-up, while 10 patients developed PTD, with evidence of metastasis in 2 of them. The presence of Y chromosome was also assessed in another 15 patients with documented metastatic PTD. It was found that CISH signals for Y chromosome were identified in 5.1% (4/78) of complete moles with spontaneous remission and 8% (2/25) with PTD with or without metastasis (P > 0.05). Y chromosome was detected in 5.9% (1/17) of the complete moles that developed metastasis and in 5.8% (5/86) of the complete moles that either developed spontaneous remission or developed nonmetastatic PTD (P > 0.05). There is no correlation between the presence of Y chromosome and development of persistent gestational trophoblastic disease. PMID- 7835779 TI - Pelvic staging of advanced and recurrent gynecologic cancers: contribution of endosonography. AB - From January 1988 to December 1992, 106 patients with advanced gynecologic cancer were preoperatively explored by clinical examination (CE) and endosonography (ESG) under anesthesia and by computed tomography (CT). Sixty-one tumors were primary and 45 recurrent; the main locations were cervical (73 cases), ovarian (10 cases), and endometrial (8 cases). All the patients were operated. This prospective study compares the data from clinical and imaging examinations with the histologic findings and the surgical reports. Accuracy of the CE, ESG, cytoscopy, and CT was respectively 79, 90, 82, and 80% for vesical involvement (ESG versus CT: P < 0.05). For vesicovaginal septum extension, accuracy of ESG (92%) was statistically better than that of CE (80%) and CT (77%). Accuracy of the CE, ESG, and CT was respectively 93, 97, and 89% for rectal involvement (ESG versus CT: P < 0.02). For rectovaginal septum extension, accuracy of ESG (96%) was statistically better than that of CE (85%) and CT (85%). Endosonography is valuable in the assessment of regional staging of advanced gynecologic cancers. Since it is realized during the clinical examination under anesthesia, this low cost procedure is easily performed and provided no discomfort to the patients. PMID- 7835780 TI - Urokinase (uPA) and PAI-1 predict survival in advanced ovarian cancer patients (FIGO III) after radical surgery and platinum-based chemotherapy. AB - Fifty-one patients with advanced ovarian cancer FIGO III were studied to determine new tumor biology-oriented prognostic factors. The tumor-associated protease urokinase-type plasminogen activator (uPA) and its inhibitor PAI-1 were detected in malignant ovarian cancer tissue extracts. The concentration of both factors was significantly higher in malignant tissue compared with benign ovarian tissue specimens (P < 0.01). According to a cutoff value for uPA and PAI-1, patients could be subdivided into risk groups: patients with low uPA and PAI-1 (uPA < 0.9 ng/mg protein and PAI-1 < 13.5 ng/mg protein) had a statistically significant better prognosis than patients with high uPA and/or high PAI-1 (P = 0.01). Especially in patients without residual tumor, uPA and PAI-1 were strong prognostic parameters (P = 0.03). In multivariate analysis the residual tumor was the most powerful prognostic indicator (P = 0.013) closely followed by uPA and PAI-1 (P = 0.047). Moreover, there is a strong correlation between uPA levels and lymph node involvement (P = 0.004) and a trend to higher uPA-levels in poorly differentiated (G3 + G4) cancers (P = 0.059) and in tumors with increased ascites production (P = 0.09). A trend to higher PAI-1 levels was also noted in the above mentioned tumor situations. The differences, however, were of no statistical significance. From these data it can be concluded that the pattern of tumor spread (mainly intraabdominally versus additional extensive lymph node involvement) and tumor biological appearance (ascites production, differentiation) are reflected by the expression of the tumor-associated proteolytic factors uPA and PAI-1. Adjuvant therapy might be adjusted to uPA and PAI-1 not only in advanced ovarian cancer but also in carcinoma of low malignant potential or early-stage ovarian carcinoma. PMID- 7835781 TI - Maturation of vaginal and endometrial epithelium in postmenopausal breast cancer patients receiving long-term tamoxifen. AB - To assess the estrogenic effects of tamoxifen on vaginal and endometrial epithelium and to investigate whether these changes are associated with any pathological findings in the endometrium, 53 postmenopausal breast cancer patients receiving long-term tamoxifen and 52 control breast cancer patients without any hormonal treatment were examined. Pathological findings in the endometrium were evaluated by hysteroscopy and curettage. The main outcome measures were the maturation index in Papanicolaou (Pap) smears, estrogen-like epithelial changes in the endometrium, serum concentrations of gonadotropins, sex hormone-binding globulin (SHBG), estradiol (E2), and testosterone (T). Informative Pap smears showed estrogenic effects in 89% (41/46) of the tamoxifen group and in 49% (22/45) of the control group, and in endometrial aspiration samples in 71% (32/45) and in 41% (19/46), respectively. These changes were associated with increased concentrations of serum E2 in the control group but not in the tamoxifen group. All five patients (11%) with endometrial polyps in the control group showed estrogenic endometrial changes, whereas among 14 women with polyps in the tamoxifen group, 9 showed estrogenic changes and 5 endometrial atrophy. Endometrial adenocarcinoma was found in 3 patients in the tamoxifen group and in 2 in the control group. Pap smears showed atrophy in 2 patients in the former and in one in the latter group. These findings confirmed estrogen-like effects of tamoxifen on the vaginal and endometrial epithelium in postmenopausal breast cancer patients, but these were not closely associated with benign or malignant endometrial lesions. PMID- 7835782 TI - Steroid hormonal independence of HER-2/neu mRNA expression in four human ovarian carcinoma cell lines. AB - Overexpression of HER-2/neu, a 185-kDa tyrosine kinase growth factor receptor, in human ovarian cancers has been correlated with a poor prognosis for survival of the disease. Previous studies have demonstrated that dexamethasone (Dex) induces a dose-dependent increase in HER-2/neu mRNA levels in the ovarian cancer cell line SK-OV-3 by stabilizing the HER-2/neu message. We extended these studies to test whether estrogen (Es), progesterone (Pr), and Dex were capable of regulating HER-2/neu mRNA levels in the human ovarian cancer cell lines NIH:OVCAR-3, SW 626, OVCA 433, and Caov-3. Southern blotting demonstrated that all four cell lines contained a single copy of the 12.5-kb HER-2/neu gene. Blotting techniques demonstrated low to barely detectable levels of HER-2/neu mRNA and protein in these cell lines. To determine whether steroids regulated HER-2/neu expression, all four ovarian cancer cell lines were cultured in the presence of 1 x 10(-7) M Es, Pr, or Dex and Northern blotting was completed. Unlike SK-OV-3 cells, the cell lines tested did not respond to the steroid treatments with alterations in their HER-2/neu mRNA levels. In conclusion, neither Es, Pr, nor Dex regulates HER 2/neu mRNA levels in NIH:OVCAR-3, SW 626, OVCA 433, and Caov-3 ovarian cancer cells. Future therapeutic manipulations of HER-2/neu should not involve hormonal intervention. PMID- 7835783 TI - Small FIGO stage IB cervical cancer. AB - The International Federation of Gynecology and Obstetrics (FIGO) currently defines stage IA cervical cancer as lesions invading up to 5 mm into the stroma and with no more than 7 mm width; vascular invasion does not affect the stage assignment. The Society of Gynecologic Oncology (SGO) definition of stage IA is more restrictive with regard to depth of invasion but ignores width. We reviewed 69 patients with lesions exceeding the FIGO definition of stage IA treated between 1958 and 1991; 46 patients also exceeded the SGO criteria for stage IA. The frequency of vascular invasion showed no correlation with the depth of invasion but was correlated with the width of the lesion. Treatment consisted of conization or simple hysterectomy only (n = 27), radical abdominal hysterectomy with lymphadenectomy (n = 25), radical vaginal hysterectomy (n = 13), and conization followed by radiotherapy (n = 4). No patient developed a recurrence during a follow-up of 2-35 years. Two of the 25 patients with lymphadenectomy had one positive lymph node each. The first patient had a primary lesion with 3 mm invasion and 17 mm width, no vascular invasion, and one node metastasis 2 mm in diameter; the second had a lesion with 4 mm invasion and 10 mm width, vascular invasion, and a tumor-cell embolus in the marginal sinus of a node. These results indicate that the problems involved in treating microinvasive carcinoma of the cervix also apply to cases of small stage IB disease. It will not be possible to devise a staging system that simultaneously serves as a guideline for treatment. The current FIGO classification of stage IA2 should be expanded rather than restricted. PMID- 7835784 TI - Ultrastructural cell-to-cell interactions in hyperplastic endometrial stroma. AB - In hyperplastic endometrial stroma, cell-to-cell contacts are infrequent. Those that are present are not well developed and may appear degenerative. Significant amounts of extracellular matrix further impede contact. The cells of hyperplastic endometrial stromal are, for the most part, poorly differentiated and both apoptosis and necrosis are common. Fibroblast-like cells make up most of the increased cellularity, with few endometrial granulocytes or other cells types. PMID- 7835785 TI - Ovarian endometrioid carcinoma and endometriosis developing in a postmenopausal breast cancer patient during tamoxifen therapy: a case report and review of the literature. AB - We present the first case of ovarian endometrioid carcinoma and endometriosis in a postmenopausal patient who was treated with tamoxifen for breast cancer. The association with prolonged unopposed estrogen-like stimulation with tamoxifen as a possible factor in the development of ovarian endometrioid carcinoma is discussed. PMID- 7835786 TI - An autopsy case of serous papillary carcinoma of peritoneum with distant metastases but no peritoneal dissemination. AB - A case of a 61-year-old woman who had a serous papillary carcinoma of probable peritoneal or surface ovarian origin, which formed a single tumor mass in the pelvis but did not metastasize throughout the abdominal cavity but only to the pleura and then the hilar lymph nodes over a protracted period lasting more than 7 years, is reported. This unusually behaving tumor was well differentiated and at least partially responded to therapy, as witnessed by its histologic appearance at autopsy. This type of neoplasm usually shows diffuse peritoneal dissemination and no distant metastasis. PMID- 7835787 TI - Ovarian myxoma in a premenarchal girl. AB - A case of ovarian myxoma in a 12-year-old premenarchal girl is reported. This paper details the clinical presentation, gross and microscopic pathology, Immunocytochemical profile, and behavior of this rare tumor. The differential diagnosis and possible histogenesis is briefly discussed. PMID- 7835788 TI - Primary central nervous system recurrence after paclitaxel therapy for epithelial ovarian malignancy. AB - Paclitaxel is currently being utilized to treat neoplasms which have a significant incidence of central nervous system metastases. It is, however, unclear as to whether paclitaxel crosses the blood-brain barrier. In this report, the authors describe a patient with refractory epithelial ovarian cancer treated with paclitaxel at 135 mg/m2/24 hr every 21 days. The patient achieved a complete clinical response of all abdominal and pelvic disease, but simultaneously developed central nervous system metastases. Paclitaxel was effective against the patient's abdominal and pelvic disease but was not protective against central nervous system metastasis. PMID- 7835789 TI - Dysgerminoma in a pure 45,X Turner syndrome: report of a case and review of the literature. AB - There is a high risk of neoplasm in dysgenetic gonads. Classically, in Turner syndrome, only patients with 45, X/46, XY mosaicism karyotype or with a fragment of Y chromosome (45, X+mar) are at risk of developing gonadal tumor. A case of a dysgerminoma arisen on the dysgenetic gonad of a 45, X Turner patient in the absence of Y chromosome material at cytogenetic and molecular biology analysis is reported. Five cases of gonadal tumor with a pure 45, X chromosome constitution have been previously reported in the literature. In these cases only cytogenetic analysis was performed. This is the first case of an ovarian tumor in a 45, X Turner syndrome in which the presence of Y material can be ruled out by an extensive molecular analysis of the blood and the tumor. PMID- 7835790 TI - Metastasis from a stage IB cervical adenocarcinoma in a transposed ovary: a case report and review of the literature. AB - Adenocarcinoma originating in the endocervix may remain occult for many years. This may result in an extension to the uterine isthmus and corpus, with subsequent dissemination along the pathways of spread of uterine carcinoma, including metastasis to the ovaries. The patient described in this report had a bulky stage Ib cervical adenocarcinoma with metastasis in a transposed ovary. The metastasis was noted 6 months following postoperative external pelvic irradiation. The sequence of events strongly suggests that microscopic ovarian disease was present at the time of the original surgery. Other cases have been reported; however, the exact incidence is difficult to determine. The current literature on this subject is reviewed and recommendations are made for evaluation and treatment. PMID- 7835791 TI - A controlled clinical study on tamoxifen and the endometrium. PMID- 7835792 TI - The NIH Consensus Conference on Ovarian Cancer: screening, treatment, and follow up. PMID- 7835793 TI - Options for primary chemotherapy in advanced ovarian cancer: the European perspective. AB - Primary chemotherapy for ovarian cancer has evolved over the past 30 years from the use of single alkylating agent to several combination regimens. Treatment strategies, however, vary greatly both nationally and internationally, since no firm results can be derived from available data. Five questions can be identified: (1) Should primary chemotherapy consist of single agent or combination? (2) Should it include doxorubicin? (3) Is cisplatin or carboplatin preferred? (4) Which is the role of cisplatin dose intensity? (5) Should it include taxol? Available data from the European experience are discussed. Final considerations include: (1) Platinum combinations are more effective than single agent platinum when this drug is used at the same dose (now considered lower than current standard). (2) CAP offers a survival benefit of 7% at 6 years compared to CP. However, in most trials dose intensity was higher in CAP than in CP. (3) Cisplatin and carboplatin are equally effective. (4) There is no survival benefit when doubling the dose intensity of cisplatin over 25 mg/m2/week. (5) A confirmatory study will help define the contribution of Taxol in the first-line treatment of ovarian cancer, when administered at 175 mg/m2 over a 3-hr infusion in association with cisplatin. PMID- 7835794 TI - Options for primary chemotherapy of epithelial ovarian cancer: taxanes. AB - The taxanes, a new class of anticancer agents, act by promoting the assembly of microtubules and stabilizing formed tubules. Two taxanes, paclitaxel and docetaxel, have clinical activity in epithelial ovarian carcinomas, including tumors with platinum resistance. Toxicities associated with the taxanes include hypersensitivity, leukopenia, neurotoxicity, and alopecia. Premedication with dexamethasone, diphenhydramine, and cimetidine decreases the incidence of severe anaphylactic reactions to less than 3%. In Phase II studies, response rates to paclitaxel in patients with previously treated ovarian cancer ranged from 20 to 48%. To date, only two Phase III study using paclitaxel in the treatment of ovarian cancer have mature data. In one trial in patients with suboptimally debulked stage III and IV ovarian cancer, conducted by the Gynecologic Oncology Group, patients receiving paclitaxel/cisplatin had a significantly greater clinical response rate and surgical response rate and a significantly smaller risk of progression than those of patients receiving cisplatin/cyclophosphamide. In a Phase III study of paclitaxel in previously treated patients at two different schedules (3- and 24-hr infusions), conducted by the Canadian-European Taxol Cooperative Group, patients on the 24-hr infusion experienced significantly more grade 4 neutropenia than those receiving the 3-hr infusion. The optimal dose, schedule, and combination for paclitaxel in the treatment of patients with ovarian cancer have not yet been defined. In Phase II studies of docetaxel in patients with previously treated ovarian cancer, response rates of 33-35% were noted. Peripheral edema was noted to be a clinically significant toxicity. PMID- 7835795 TI - Second-look laparotomy in ovarian cancer. AB - The role of the second-look laparotomy has become standard management in the patients with ovarian cancer without any objective evidence that it has a major impact on survival. In patients with early-stage disease, data on second-look surgery would suggest that there is very little, if any, benefit in patients who have had optimal full surgical staging and appropriate postoperative therapy. In advanced disease, even if the second-look laparotomy is negative, one-half will develop a recurrence. The role of the second-look laparotomy as a secondary debulking procedure has been suggested by some but appears to be beneficial in only a small subset of patients--less than 10%. In patients being treated on protocol, a second-look laparotomy has become the gold standard for determining effectiveness of a specific treatment being evaluated and would tend to be justified in this group to increase our knowledge and hopefully arrive at a better postsurgical therapy. PMID- 7835796 TI - Second-look surgery in the management of epithelial ovarian carcinoma. AB - The constructs for incorporating second-look surgery (SLL) in the treatment schema for ovarian epithelial carcinoma are being challenged. Although second look surgery remains the hallmark for assessing disease status at the completion of adjuvant chemotherapy, its continued utility must demonstrate potential benefits in both the presence and absence of disease. While critics cite as unacceptable the recurrence rates (20-50%) after negative SLL, the patients so identified have demonstrated chemosensitivity and harbor optimal tumor volumes if present and possibly more biologically favorable tumors. These very characteristics should render negative SLL patients ideal candidates for consolidation therapy. Furthermore, age, histologic grade, and residual volume stratifies patients into high- and low-risk categories for recurrence after negative second look and should further facilitate consolidation therapy selection. Similarly, longevity, following positive SLL is correlated adversely to advancing age and the histologic grade and the residuum of the tumor identified at reexploration. Recognizing that age and grade are predetermined factors, aggressive secondary cytoreduction has the potential of extending longevity. The latter is supported by mathematical tumor kinetic models and several focused, large, single-institution retrospective analyses. Therefore, the value of SLL is apparent but the criteria for its continued utilization in advanced ovarian cancer should include its performance by appropriately trained surgeons and the availability of (and preferably prospective trials for) both consolidation and salvage therapy to which all patients would optimally be afforded access. PMID- 7835797 TI - Follow-up of the asymptomatic patient with ovarian cancer. AB - At present the optimal follow-up/monitoring strategy for the asymptomatic patient with advanced ovarian cancer after initial treatment remains undefined. Important considerations in the decision to take a more "passive" or "active" approach in follow-up include: (1) absence of data on the overall clinical utility of second line ("salvage") therapy in ovarian cancer; (2) costs, morbidity, and mortality of possible monitoring and treatment strategies; and (3) patient preference for a particular approach. Currently, it must be concluded that there is no evidence that intensive investigative monitoring efforts in the asymptomatic patient exert a significant positive impact on overall survival, symptom-free survival, or quality of life. However, in carefully selected patients, such a strategy may be an appropriate management option, as long as individuals followed in this manner are informed of the limited data demonstrating the value of either intensive monitoring or therapy in this clinical setting. PMID- 7835798 TI - Follow-up after primary therapy: management of the symptomatic patient-surgery. AB - The benefit of secondary surgery in patients (pts) recurring after a negative second look is still a matter of controversy. Twenty-seven patients underwent this procedure: 5 were stage I at primary surgery and 22 stage IIIC. All 5 stage I pts had a pelvic recurrence: 3 were left with no visible tumor and were then treated with cisplatin chemotherapy. Two are alive and with no evidence of disease (NED) at 45 and 62 months. In stage IIIC pts, optimal debulking (< 2 cm) was achieved in 59% (13/22), and 8 of them had no macroscopic residual tumor. All pts were then treated with cisplatin chemotherapy. Only 3 pts are still alive and NED at 56, 61, and 67 months. The most important prognostic parameters regarding secondary surgery seem to be residual tumor volume both at primary and secondary surgery, time interval between negative second-look surgery and recurrence, histology (serous) and degree of differentiation, and response to second-line chemotherapy. Finally, surgery can have a true palliative role in pts who present with bowel obstruction; in our center, most patients who had a definitive procedure did benefit from the quality of life viewpoint. PMID- 7835799 TI - Salvage chemotherapy for epithelial ovarian carcinoma. AB - Advanced epithelial ovarian cancer is a highly chemosensitive solid tumor with response rates of 70-80% to first-line chemotherapy, including a high proportion of complete responses. The majority of patients, however, eventually relapse and ultimately die of chemoresistant disease. Response rates to salvage agents are modest, and duration of response is relatively short. Important new agents have been identified in the salvage setting, however, and all patients with ovarian cancer recurring or persisting after front-line therapy should be encouraged to enroll in clinical trials. Phase II trials should include multiple adequately sized cohorts, for patients with platinum-sensitive disease and those with platinum-refractory disease. In addition, patients should be stratified by treatment-free interval. An effort should be made to report standard response endpoints, such as median duration of response, median time to progression, and median survival. Retreatment with a platinum-containing compound is appropriate in patients with platinum-sensitive disease. Trials of high-dose chemotherapy with hematologic support may be most appropriate for patients with minimal disease following first-line therapy, but are unlikely to benefit patients with platinum-resistant or bulky disease. Paclitaxel should figure prominently in consideration of salvage therapy for patients with platinum-resistant disease. Responses to other single agents or combination chemotherapy have been modest and generally of short duration. Efforts at hormonal therapy have been disappointing. Promising new agents include topoisomerase I inhibitors, such as topotecan, 9 aminocamptothecin, irinotecan (CPT-11), and pyrazoloacridine. Therapies focusing on novel molecular targets include antiangiogenesis agents, antimetastatic agents, and signal transduction inhibitors. Immunotherapy, including radioimmunotherapy, immunotoxins, and direct antitumor effects of monoclonal antibodies, may be useful. Greater understanding of the molecular pathology of ovarian cancer may help us develop more rational and effective treatment. PMID- 7835800 TI - Characteristics relating to ovarian cancer risk: implications for prevention and detection. AB - Approximately 20,000 women are diagnosed with ovarian cancer in the United States each year, and some 12,000 women die because of it. Epithelial ovarian cancer, the most common histopathologic type, is uncommon before age 40 years, after which incidence rates increase steeply until age 70-79 years and then decrease somewhat. In the United States, the lifetime risk from birth to age 85 years is about 1.5%. There is general agreement that residence in North America or northern Europe, nulliparity, and having a mother or sister with ovarian cancer are associated with an elevated risk, and that increasing number of pregnancies (whether or not full term), increasing length of oral contraceptive use, and increasing duration of lactation are protective. A history of breast or endometrial cancer appears to be associated with a slight elevation in risk. Apart from oral contraceptive use, none of these characteristics can be modified easily to reduce ovarian cancer risk. However, long-term oral contraceptive use before the menopause could prevent as much as half of all ovarian cancer. At present, the subgroup of the population at highest risk consists of women with a mother or sister with the disease; the lifetime ovarian cancer risk in these women is about 9%. A small fraction of them have families with multiple cases of ovarian cancer and early-onset breast cancer, due largely or entirely to mutated alleles of the gene BRCA1. These women, who have a lifetime risk of breast or ovarian cancer of 85-100%, need aggressive screening and possibly prophylactic surgery. PMID- 7835802 TI - Clinical and laboratory directions for ovarian cancer research. PMID- 7835801 TI - In vitro drug testing of ovarian cancer using the human tumor colony-forming assay: comparison of in vitro response and clinical outcome. AB - The purpose of this study was to assess the prognostic value of in vitro drug chemosensitivity testing using the Hamburger-Salmon human tumor colony-forming assay (HTCA) in fresh tumor samples obtained from newly diagnosed patients with stage II-IV ovarian cancer undergoing maximum cytoreductive surgery and prior to platinum-based chemotherapy. The HTCA was performed on fresh ovarian cancers obtained from 93 patients at their initial exploratory laparotomy to evaluate in vitro sensitivity to cisplatin, carboplatin, and cyclophosphamide following a 1 hr drug exposure. Prospective clinical follow-up was performed on all patients with the primary study endpoints being pathologically proven complete response at second-look surgery and disease-free and overall survival durations. In vitro drug sensitivity was strongly dose-dependent. At a concentration of 5 micrograms/ml only 23% of tumor samples were sensitive (as defined by a > or = 50% decrease in tumor colony-forming units compared to controls) to cisplatin; 13% of tumors were sensitive to carboplatin at a concentration of 50 micrograms/ml and 11% to 4-OH-cyclophosphamide at a concentration of 1 microgram/ml. At doses which were 10 times the previously stated concentrations, the sensitivity rates to cisplatin, carboplatin, and 4-OH-cyclophosphamide increased to 72, 63, and 53%, respectively. Subjects were categorized as having drug-sensitive disease if HTCA results showed in vitro drug sensitivity to at least one of the agents used in their primary chemotherapy. Multivariate analysis failed to show any advantage in clinical response rate, progression-free interval, or survival duration for patients with drug-sensitive disease compared to drug-resistant disease; however, there was evidence of a trend toward an enhanced pathologically proven complete response rate in patients who had chemosensitive tumors in vitro. Second-look surgery was performed in 28 of 55 patients with optimal surgical resections and no clinical evidence of disease at the completion of their primary chemotherapy. Fifty percent (5/10) of patients with drug-sensitive disease achieved a pathologic complete response, while only 3/18 (17%) patients with drug-resistant tumors had a documented pathologic complete response (P = 0.13). As reported in other ovarian cancer studies, patient characteristics which were found to be significantly associated with survival were stage of disease (II-III vs IV), optimal primary surgical resection (i.e., < 1 cm2 residual tumor) vs suboptimal resection, clinical measurability of disease at initiation of chemotherapy, and response to primary chemotherapy. In conclusion, in vitro drug sensitivity, as measured by the HTCA, does not appear to be an independent prognostic factor for survival in patients with stage II-IV epithelial ovarian cancer who undergo standard treatment with tumor debulking surgery and primary platinum-based chemotherapy.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7835803 TI - Research directions in epithelial ovarian cancer. AB - Major improvements in survival from ovarian cancer will likely result from a combined effort in prevention, diagnosis, screening, and treatment. Oral contraceptives can decrease the risk of ovarian cancer in women with a family history of the disease. Screening currently is not routinely recommended and awaits further refinements in tumor markers and image techniques. Surgery and chemotherapy have been the cornerstones of treatment for most patients with ovarian cancer. Paclitaxel plus a platinum compound has now become a new standard chemotherapy regimen. However, numerous clinical questions need to be explored in prospectively randomized trials to determine how best to use this agent. Basic research in ovarian cancer will likely lead to the novel therapeutic targets and completely new approaches. PMID- 7835804 TI - NIH Consensus 1994: screening. AB - Frequently, the medical and lay community has assumed that earlier diagnosis of cancer of any type automatically confers benefit and that any diagnostic test that can identify early stages of disease must therefore be useful for screening. However, there is an emerging science of screening which affords a more rigorous approach to public health recommendations in the application of new technologies to screening and early detection. A number of public health groups and agencies are using an evidence-based approach in making recommendations. Using this approach, early detection methods for ovarian cancer would meet only the weakest level of evidence to support their routine application in asymptomatic women. For this reason, the National Cancer Institute has recently launched a large randomized clinical trial to test the effectiveness of screening for ovarian cancer. PMID- 7835805 TI - Genetic, biochemical, and multimodal approaches to screening for ovarian cancer. PMID- 7835806 TI - The current status of ultrasound and color Doppler imaging in screening for ovarian cancer. AB - The lack of significant improvement in ovarian cancer survival in over 3 decades has focused interest on early disease detection as well as the development of more effective therapies. Ultrasound's ability to discern alterations in ovarian architecture and color doppler's ability to recognize malignancy-associated angiogenesis have resulted in the application of these techniques to ovarian cancer screening. Morphology scoring systems have been developed to quantitate the anatomic alterations seen on ultrasound. Prospective ovarian cancer ultrasound screening trials involving 11,283 women were evaluated: 486 participants underwent surgical exploration and 19 ovarian cancers were diagnosed. Thirteen cases were stage I where the impact of screening on disease survival is thought to be maximal; 5/13 were invasive epithelial malignancies, 7/13 were borderline tumors, and 1/13 was a granulosa cell tumor. Overall, 32 surgeries (95% CI = 20-58) were required to diagnose one stage I ovarian cancer; if only those women with a family history of ovarian cancer are included in the analysis, then 17 surgeries (95% CI = 14-41) would be required. Potential clinical implications of these results are discussed, as well as future directions for screening. PMID- 7835807 TI - Current status of screening for ovarian cancer. AB - Many women are requesting tests to screen for ovarian cancer. Extensive media coverage of this disease probably stimulates demand for these tests. Published reports from ovarian cancer screening programs have not yet demonstrated any benefit of screening. Existing programs have largely reported only the number of cancers detected during a single round of screening. Among 36,000 screened subjects reported on, 29 ovarian cancers have been detected; 12 of these were Stage I. All programs report that considerable surgery for benign disease has occurred among subjects. Follow-up, thus far, has been brief, and no control groups are included. Several new screening programs include only women with a family history of ovarian cancer. These programs also lack control groups and have little follow-up to date. A prospective, randomized trial of ovarian cancer screening to include 74,000 postmenopausal women has been initiated by NCI as part of the PLCO trial. Results from this trial should quantify the risks and benefits of screening; however, results will not be available for many years. Until there are data to show that screening reduces mortality from ovarian cancer, clinicians should not suggest these tests are beneficial, and they should avoid performing these tests outside of research protocols. PMID- 7835808 TI - The role of prophylactic oophorectomy in cancer prevention. AB - Prophylactic oophorectomy is presently the only effective method of ovarian cancer prevention. This study reviews current data on how prophylactic oophorectomy (PO) should be used in different risk groups. It is estimated that 7% of ovarian cancer patients have positive family history, of which 3-9% may end up having hereditary cancer syndromes. Women in direct genetic lineage of family cancer syndromes may have up to 50% lifetime risk of ovarian cancer. Because of such a high risk, PO is indicated for women with familial cancer syndromes after childbearing or the age of 35-40 at the latest. Most women with positive family history of ovarian cancer do not have one of the recognized hereditary cancer syndromes. However, women with one or two affected relatives do have an increased lifetime risk of ovarian cancer from a baseline of 1.6 to 5-7%. This risk is not high enough to warrant PO recommendation for a large number of women. After being properly informed and the patient still desires surgical prevention (i.e., cancer phobia), PO then becomes an indicated procedure. In women without family history of ovarian cancer, the role of PO remains controversial. The decision of PO as a concurrent procedure to other indicated gynecologic surgeries should depend on the individual patient and her ability to comply with lifelong estrogen replacement therapy. PMID- 7835809 TI - National Institutes of Health Consensus Development Conference Statement. Ovarian cancer: screening, treatment, and follow-up. AB - The National Institutes of Health Consensus Development Conference on Ovarian Cancer-Screening, Treatment, and Follow-up brought together epidemiologists; obstetrician/gynecologists; gynecologic, medical, and radiation oncologists; and the public to address the following questions: (1) What is the current status of screening and prevention in ovarian cancer? (2) What is the appropriate management of early-stage ovarian cancer? (3) What is the appropriate management of advanced epithelial ovarian cancer? (4) What is the appropriate follow-up after primary therapy? and (5) What are the directions for future research? The consensus panel concluded that there is no evidence available as yet that the current screening modalities of CA 125 and transvaginal ultrasonography can be effectively used for widespread screening to reduce mortality from ovarian cancer nor that their use will result in decreased rather than increased morbidity and mortality. They recommended that further prospective research be done to evaluate this very important issue. Women with stage IA grade 1 and most IB grade 1 ovarian cancer do not require postoperative adjuvant therapy. Many remaining stage I patients do require chemotherapy. Subsets of stage I must be fully defined and ideal treatment must be determined. Women with stages II, III, and IV epithelial ovarian cancer (other than low malignant potential tumors) should receive postoperative chemotherapy. Physicians should be encouraged to discuss clinical trial participation with women, and women should be encouraged to participate. All women should have access to accurate and complete information regarding ovarian cancer. Furthermore, there must be no barriers to women's access to qualified specialists, optimal therapy, and protocols. The full text of the consensus panel's statement follows. PMID- 7835810 TI - Management of the adnexal mass. AB - The methods for preoperative diagnosis and evaluation of the woman with a suspected ovarian neoplasm have evolved significantly with little or no impact on the surgical treatment, which remains removal of the abnormal ovary. Although most adnexal masses are benign, the primary goal of the diagnostic evaluation is the exclusion of malignancy. A complete history, physical examination, and ultrasonic imaging are vital in evaluating a suspected ovarian mass. In postmenopausal women, serum CA-125 determinations further improve sensitivity and specificity. Once the presence of an ovarian mass is established, the crucial decision is whether to observe the patient or proceed with surgical removal. If surgical removal is indicated, the proper procedure is important for staging and initiation of effective therapy. While many surgeons are now using the less invasive laparoscopic approach, the standard of care continues to be a laparotomy with either an ovarian cystectomy or oophorectomy. Future clinical research in the management of adnexal masses should focus on decreasing the number of patients undergoing a surgical procedure, and in patients who require surgery, further evaluation of laparoscopy as a safe, cost-effective means of treatment. Improved imaging techniques may allow for nonoperative management of probably benign ovarian neoplasms. PMID- 7835811 TI - Controversial issues in the management of early epithelial ovarian cancer: conservative surgery and role of adjuvant therapy. AB - The feasibility of conservative surgery and the role of postoperative adjuvant therapy are still controversial issues in the management of early ovarian cancer. Data on 99 patients below the age of 40 with stage I ovarian cancer are reported and conservative surgery was performed in 56 (56%) patients (36 stage Ia, 1 stage Ib, and 19 stage Ic). Relapse occurred in 3 stage Ia (grades 1, 2, and 3) patients, but only 1 occurrence was in the residual ovary and the patient was rescued by surgery. The other 2 patients who relapsed in distant sites died as a result of their tumors. Seventeen patients who desired to become pregnant did so for a total of 25 conceptions. These data support the possibility of some extension of the traditional conservative approach. Only two randomized studies so far have tested cisplatin as an adjuvant treatment of early disease. A Norwegian trial compared cisplatin to 32P in stage I-III ovarian cancer without residual tumor after primary surgery and found no difference in survival. An Italian study compared cisplatin to observation in stage Ia and Ib grade 2 and 3 tumors and cisplatin to 32P in stage Ic patients. While disease-free survival was statically longer in cisplatin-treated patients of both groups, no difference in survival could be detected. These results supported the design of a currently ongoing multicenter trial testing platinum-based therapy soon after surgery or at time of relapse. PMID- 7835812 TI - Management of epithelial ovarian tumors of low malignant potential. AB - The distinct pathologic and biologic nature of ovarian tumors of low malignant potential (LMP) has been officially recognized by FIGO and the World Health Organization. LMP tumors may comprise 10% of ovarian neoplasms; they occur at a mean age of 40 years. Pregnancy, breast-feeding, and the use of oral contraceptives are protective against the development of tumors of LMP. A history of infertility and use of infertility drugs appear to increase the risk of these tumors. No association with hereditary ovarian cancer syndromes has been reported. The survival associated with these tumors is 99% at mean follow-up of 7 years for patients with stage I disease, and 92% for those with stage II and II disease. Retrospectively, more patients appear to have died from complications associated with adjuvant therapy than from progressive disease. The recommended treatment is surgical, consisting of total abdominal hysterectomy, bilateral salpingo-oophorectomy, pelvic and para-aortic lymph node biopsies, peritoneal washings, and tumor debulking. In young patients with early-stage disease, conservative surgery, preserving the uterus and contralateral ovary, is acceptable. A role has not yet been established for adjuvant therapy, whether radiotherapy or chemotherapy. Laboratory investigations have not demonstrated that these tumors represent an intermediate step between benign ovarian tumors and carcinoma nor have they identified that small subset of tumors with aggressive clinical behavior. We should perhaps consider tumors of LMP in the same light as "benign" proliferative gynecologic conditions, such as endometriosis and leiomyomata. PMID- 7835813 TI - Radiotherapy in early ovarian cancer. AB - Radiation therapy is an effective curative treatment modality in early ovarian cancer. A combination of the independent prognostic factors of grade, stage, and residual disease defines an "intermediate" risk group whose probability of long term disease-free survival from abdomino-pelvic radiation therapy (APRT) is between 62 and 91%. This group in which abdomino-pelvic radiotherapy is recommended as the sole postoperative treatment is mainly constituted from patients with Stage II disease of all grades with no residuum or less than 2 cm residuum in the pelvis and selected optimal Stage III patients with low grade tumors. No therapy has been shown to benefit patients with Stage I grade 2 or 3 tumors, although relapse risks of 30% justify postoperative treatment in this group. APRT significantly reduced relapse risk in patients with Stages I and II disease, where tumors were densely adherent. The late toxicity of APRT is acceptable. When the abdominal dose is restricted to a total of 25 Gy and the pelvic dose to 45 Gy serious complications occur in less than 4% of patients. 32P, widely utilized in early-stage disease, has not been shown to be beneficial compared to cisplatin in a study of the Norwegian Radium Hospital. Its dosimetry precludes effective dosing of tumor at a depth of more than 1 to 2 mm from the peritoneal surface and of the retroperitoneal nodes. Its use should be abandoned. APRT is an effective anti-tumor modality in ovarian cancer and cannot be discarded. Further studies of this modality are justified. Its future exploitation lies in manipulations to increase the therapeutic ratio by either altered radiotherapy fractionation schemes and/or potential combination with radiation sensitizers. PMID- 7835814 TI - Preoperative evaluation of patients with suspected ovarian cancer. AB - A diagnosis of ovarian cancer should be suspected when a postmenopausal woman presents with a pelvic mass. The presence of ascites, which can be detected clinically or by ultrasound, increases the accuracy of the diagnosis. CA 125, although nonspecific in the premenopausal patient population, is very sensitive in postmenopausal patients when used in combination with clinical impression and an abnormal ultrasound. CAT scan is more sensitive than ultrasound, but may not alter surgical management. Preoperative preparation of the bowels should consist of a polyethylene glycol lavage in combination with oral and systemic antibiotics and is indicated for any woman with a mass adherent to the cul de sac. Preoperative total parenteral nutrition should be reserved for severely malnourished patients as determined by objective criteria. Early surgical intervention is a key component for the treatment of these patients, and extensive diagnostic testing should be used temperately in order to ensure expeditious treatment of these patients. In the future, the most significant impact on the survival of patients with ovarian cancer will be in the development of improved methods of screening and early detection. It is hopeful that clinical trials currently being conducted will bring us closer to that goal. PMID- 7835815 TI - Epithelial ovarian carcinoma: principles of primary surgery. AB - Surgery remains the most important facet in the initial management of epithelial ovarian cancer. Initial surgical therapy involves the establishment of the diagnosis, appropriate surgical staging, and primary cytoreductive surgery. For patients with advanced disease, surgical staging of ovarian cancer is obvious, but for apparently early disease (Stage I or II), appropriate surgical staging is extremely important and will result in the upstaging of about one-third of patients (usually to Stage III). The theoretical benefit of initial cytoreductive surgery is the removal of large necrotic tumors with a poor blood supply and the removal of large tumors that are in a slower growth phase, leaving behind tumors that are more sensitive to the effects of chemotherapy. There are multiple clinical studies indicating that "optimal" cytoreduction (removal of all tumor larger than 2 cm) results in improved complete response rates to chemotherapy, improved progression-free and overall survival, and a significant increase in the number of patients who will have a negative second-look surgical reassessment. Recent studies by the Gynecologic Oncology Group have further clarified the role of initial surgery, showing that the "biology" of the tumor is also important and that survival is directly related to residual disease within the following categories: (i) microscopic disease, (ii) optimal disease (2 cm or less in residual diameter), and (iii) suboptimal disease (greater than 2 cm diameter of residual disease). In the latter group (suboptimal disease), there may be a benefit to second attempts at surgical cytoreduction (interval cytoreductive surgery). PMID- 7835816 TI - Chemotherapy in advanced ovarian carcinoma: current standards of care based on randomized trials. AB - The mainstay of the treatment of advanced (stage III or IV) ovarian carcinoma is systemic therapy. The following review bases conclusions regarding standards of care on large, randomized trials of chemotherapy in advanced ovarian carcinoma. As of 1976, "standard" chemotherapy was single alkylating agent usually with melphalan. Studies of combination chemotherapy failed to show superiority over single alkylating agent until the introduction of cisplatin. The Gynecologic Oncology Group conducted a series of two trials in patients with large-volume disease, the first randomizing patients to either single-agent melphalan or a combination of doxorubicin and cyclophosphamide and the second to doxorubicin plus cyclophosphamide with or without cisplatin. These studies demonstrated superiority for the cisplatin-based combination in terms of overall response rate, clinical complete response rate, progression-free survival, and overall survival. Subsequent randomized trials demonstrated several important facts. First, platinum-based combinations yielded results superior to single-agent cisplatin. Second, a two-drug combination of cisplatin plus cyclophosphamide provides benefit equivalent to the three-drug combination of the same two drugs plus doxorubicin. Third, substitution of carboplatin for cisplatin yields similar results. Finally, dose escalation of chemotherapy by a factor of 2 does not offer a therapeutic advantage. The next major advance after the introduction of the platinum compounds was the demonstration of the activity of taxol, a new agent with a unique mechanism of action and apparent clinical non-cross-resistance with the platinum compounds. A recently completed GOG trial of cisplatin plus cyclophosphamide versus cisplatin plus taxol in patients with large-volume disease shows that the taxol-based combination has a superior overall response rate, clinical complete response rate, rate of achieving a state of no gross residual disease at second-look laparotomy, and progression-free survival. Survival analysis awaits maturation of the data, but the control arm has already been shown to have a median survival of 23.2 months with the median not yet reached for the taxol-based arm. These data suggest that a combination of taxol plus cisplatin should be considered the standard of care for patients with advanced ovarian carcinoma. Ongoing trials seek to define further the role of taxol in frontline chemotherapy for ovarian carcinoma. In conclusion, the standard chemotherapy for advanced ovarian carcinoma should be considered a combination of taxol plus a platinum compound. PMID- 7835817 TI - [Effect of temperature on clinical electrophysiology]. AB - Body temperature has a considerable impact on neurophysiological results. This influence of temperature is often undervalued. Abnormal findings even in healthy subjects can be caused by cold extremities only. Low surface temperature for example may lead to longer distal latencies and slower motor and sensory nerve conduction velocities. In patients with neuromuscular diseases typical results may disappear, when the examination is done beyond a standard temperature. In myasthenic patients the decrement and the jitter in single fibre electromyography decrease with temperature. In myasthenic syndrome the amplitude of the muscle compound action potentials increases and the increment at 50/s-stimulation becomes smaller at low temperature. Cold limbs lead to restoring nerve conduction in demyelinated nerve fibres; conduction block may thus disappear. Spontaneous activity becomes rare and myotonic discharges become more obvious at low temperature. In certain cases an examination at low temperatures can be helpful, e.g. for the distinction between myotonia and paramyotonia. Usually electrophysiological examinations should be done at standard temperatures. PMID- 7835818 TI - [Depression and sleep--the status of current research]. AB - Abnormalities of REM sleep, i.e. shortening of REM latency, lengthening of the duration of the first REM period and heightening of REM density, which are frequently observed in patients with a Major Depressive Disorder (MDD), have attracted considerable interest. Initial hopes that these aberrant patterns of sleep constitute specific markers for the primary/endogenous subtype of depression have not been fulfilled. The specificity of REM sleep disinhibition for depression in comparison to other psychopathological groups is also challenged. Demographic variables like age and sex exert strong influences on sleep physiology and must be controlled when searching for specific markers of depressed sleep. It is still an open question whether abnormalities of sleep are state-markers or trait-markers of depression. Beyond baseline studies, the cholinergic REM induction test (CRIT) indicated a heightened responsitivity of the REM sleep system to cholinergic challenge in depression compared with healthy controls and other psychopathological groups, with the exception of schizophrenia. A special role for REM sleep in depression is supported by the well known REM sleep suppressing effect of most antidepressants. The antidepressant effect of selective REM deprivation by awakenings stresses the importance of mechanisms involved in REM sleep regulation for the understanding of the pathophysiology of depressive disorders. The positive effect of total sleep deprivation on depressive mood which can be reversed by daytime naps, furthermore emphasizes relationships between sleep and depression. Experimental evidence as described above instigated several theories like the REM deprivation hypothesis, the 2-process model and the reciprocal interaction model of nonREM REM sleep regulation to explain the deviant sleep pattern of depression. The different models will be discussed with reference to empirical data gathered in the field. PMID- 7835819 TI - [General practice of acute inpatient treatment of mania. Retrospective comparative study of 100 patients at each of 2 psychiatric centers]. AB - We reviewed the literature regarding acute therapy of manic patients and compared these recommendations with actual practice by reviewing 399 therapies in 100 patients each from two psychiatric care centres between 1975 und 1991. Higher age, more serious disease and a higher percentage of compulsory commitments are typical of patients treated in institutions with a mandatory admission policy as compared to university clinics, which are not compelled to admit patients. The treatment methods practised in both centres deviated greatly from recommendations in the literature. In spite of widespread therapeutic recommendations, lithium and carbamazepin are seldom employed for acute treatment; neuroleptic agents were preferred for all grades of severity. Combinations of more potent antipsychotics with more sedative neuroleptics were preferred. In contrast, the chosen substances, the preferred combinations and the application form varied considerably. The state mental hospital preferred haloperidol and levomepromazin; in the university clinic clozapin and perphenazineoenanthate were important adjuncts. Both clinics remained in the low therapeutic range of dose recommendations. There were no statistically meaningful differences with regard to either the total amount of chlorpromazine equivalents applied or the duration of inpatient care. In the first one-tenth of the total treatment period, 85% of the maximal dose reached in the second tenth is already given. A continual reduction begins thereafter, until app. 40% of the peak dose in reached. Active treatment of side effects as well as more common use of depot neuroleptics in order to minimize custodial treatment, may explain the lower number of compulsory admissions in the university hospital. Extreme interindividual differences in both dosage and length of stay help in elucidating the apparently contradictory results of comparative investigations with small patient groups. Previous treatments have little or no predictive value due to large intraindividual variations. PMID- 7835820 TI - [Accelerated breakdown of membrane phospholipids in schizophrenia--implications for the hypofrontality hypothesis]. AB - Phospholipase A2 (PLA2) is a key enzyme in the metabolism of membrane phospholipids. We and other authors (Noponen et al., 1993) reported on increased PLA2 activity in serum and plasma from schizophrenic patients as compared to healthy and psychiatric controls. This increment in PLA2 activity could be inhibited by neuroleptic therapy. The breakdown of membrane phospholipids by PLA2 produces cytotoxic products such as lysophosphatidylcholine (LPC). We found in an independent series of studies increased PLA2 activity, decreased membrane phospholipids and increased LPC concentrations in platelets from schizophrenics, suggesting an accelerated breakdown of membrane phospholipids in the disease. To clarify the effects of PLA2 in the brain we investigated the effects of intracerebral PLA2 injections on dopaminergic neurotransmission in rats using Ungerstedt's model of rotational behaviour. Circing behaviour induced by DA agonists after unilateral PLA2 injections into the substantia nigra pars compacta were recorded. One, three and five weeks after intranigral PLA2 injection apomorphine induced an ipsilateral rotation, indicating a long lasting inhibition of ipsilateral nigrostriatal dopaminergic pathway by PLA2 application. Taken together, our findings indicate that a) at least a subgroup of schizophrenic patients shows increased PLA2 activity and consequently an accelerated breakdown of platelet membrane phospholipids, and b) in animal experiments the intranigral application of PLA2 inhibited the dopaminergic activity. How could these findings be related to the biology of schizophrenia? In schizophrenia a reduced dopaminergic activity in the frontal cortex has been hypothesized. Recent spectroscopy studies reported on an accelerated breakdown of membrane phospholipids in the frontal cortex from schizophrenics.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7835821 TI - Multiphasic metabolic changes in the heart of rats fed a sucrose-rich diet. AB - Long term feeding a sucrose-rich diet (SRD) to normal Wistar rats led to multiphasic changes in the activity of the pyruvate dehydrogenase complex (PDH), characterized by a significant decrease in PDHa (active form) in the short term on SRD (3 weeks) when compared to control rats fed the standard chow (STD). Although PDHa returned spontaneously to control values in the medium term (6-8 weeks) on SRD, an even more pronounced decrease was recorded when rats were kept long term on the SRD (15 weeks). Low PDHa levels recorded in the short and long term were accompanied by a two fold increase in heart acetyl-CoA concentration and the acetyl-CoA/CoASH ratio. Tissue long-chain acyl-CoA and triacylglycerol levels were also significantly higher in SRD fed rats. Spontaneous normalization of all the above metabolic parameters was observed during the medium term on SRD. Glucose-6-phosphate levels remained within control values during the short and medium term, in contrast to a two fold increase recorded in the long term on SRD. Glycogen concentrations were found moderately elevated only in the long term. Citrate concentrations were slightly increased in the short and greatly in the long term, and the fructose-2,6-bisphosphate/citrate ratio was found significantly decreased only during the long term on SRD. After 3 weeks on SRD, the protal vein Insulin/Glucagon (I/G) molar ratio was three times higher in SRD than STD rats, as opposed to an unchanged I/G ratio found in the long term.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7835822 TI - Influence of alimentary zinc deficiency on the concentration of growth hormone (GH), insulin-like growth factor I (IGF-I) and insulin in the serum of force-fed rats. AB - The study described here investigates the influence of a specific alimentary Zn deficiency on the concentration of growth hormone (GH), insulin-like growth factor I (IGF-I) and insulin in the serum of force-fed rats. For this purpose 24 male Sprague-Dawley rats with an average bodyweight of 108 g were divided into 2 groups of 12 animals each. The Zn-deficient group and the control group received for 12 days a semi-synthetic casein diet with a Zn content of 1.3 and 25 ppm respectively. In order to prevent the reduced feed intake which occurs in Zn deficiency and the associated energy and protein shortage from interfering with the experimental parameters, all animals were fed 4 times daily by gastric tube. This made it possible to supply all animals with adequate-nutrients and to synchronise the feed intake exactly. After 12 days the depleted rats were in a severe state of Zn deficiency, as demonstrated by the reduction of Zn in the serum and the femur by 62% and 44% respectively and the 70% lower serum activity of alkaline phosphatase. In the Zn-deficient rats the concentration of GH in the serum was significantly increased by 78%, while IGF-1 and insulin were significantly reduced by 28% and 25% respectively. It is thought that the growth depression observed in the Zn-deficient rats in this study despite their identical feed intake is probably due to a reduced concentration of IGF-I and insulin and that the biological activity or the binding of GH to receptors is impaired in specific alimentary Zn deficiency. PMID- 7835823 TI - Effects of Nw-nitro L-arginine methyl ester on the response to NaCl load in hyper and hypothyroid rats. AB - We assessed the effects of the inhibition of endogenous nitric oxide (NO) synthesis with Nw-nitro-L-arginine methyl ester (L-NAME) on water and sodium handling after NaCl load containing the inhibitor at 0, 0.5, 5 and 50 mg/kg in conscious control, hyper- and hypothyroid rats. L-NAME at 0.5 mg/kg caused a similar decrease in diuresis and natriuresis in control and hypothyroid rats, whereas no changes were seen in the hyperthyroid group. The saline load with 5 mg/kg of L-NAME produced no significant changes with respect to the 0 dose in any variable in control and hypothyroid rats, but increased natriuresis in the hyperthyroid group. The highest dose of L-NAME (50 mg/kg) increased the diuretic and natriuretic response in control and hyperthyroid groups, whereas in the hypothyroid group no urinary variable was significantly modified with respect to the 0 dose. These results indicate that the antidiuretic and antinatriuretic effects of L-NAME at low doses are suppressed in hyperthyroid rats, whereas the diuretic and natriuretic effects at high doses are absent in hypothyroid rats. Our findings suggest that the modulatory role of NO on sodium and water excretion is affected in both thyroid disorders. In addition, the highest dose of L-NAME killed hyperthyroid rats, indicating that NO plays an essential role for life in hyperthyroidism. PMID- 7835824 TI - Interleukin-1 beta (IL-1 beta) binds to intact porcine thyroid follicles, decreases iodide uptake but has no effect on cAMP formation or proliferation. AB - Interleukin-1 beta (IL-1 beta) is known to be involved in autoimmune thyroiditis. Since the results of different in vitro-studies on the effect of IL-1 on thyrocytes are controversial, our aim was to investigate the existence of specific binding sites for IL-1 beta and its influence on specific functions and growth of isolated porcine thyroid follicles ex vivo with a preserved iodide metabolism. For binding studies isolated thyroid follicles were incubated with 125I-IL-1 beta (213.5 nCi/ml) and with increasing concentrations of unlabelled IL 1 beta (0.06-11.5 nmol/l) for 24 h at 4 degrees C. The dissociation constant Kd was 0.85 x 10(-10) mol/l and about 800 binding sites per cell were calculated. IL 1 beta (10 U/ml) decreased basal and TSH-stimulated iodide uptake and organification after an incubation time of 45 min to 6 h without any influence on cAMP-formation. In addition, after 40 h of incubation IL-1 beta dose-dependently increased T3-secretion, followed by a decrease during simultaneous TSH stimulation, whereas there was no effect on T4-secretion. In contrast to these functional effects IL-1 beta showed no influence on the growth of thyroid follicles, so that the cytokine cannot be made responsible for goiter growth in thyroid diseases by directly influencing thyroxytes. PMID- 7835825 TI - Studies of human peripheral blood mononuclear cells (PBMC) from patients with subacute thyroiditis in severe combined immunodeficient (SCID) mice: less production of human interferon gamma than that seen for Graves' disease. AB - Human peripheral blood mononuclear cells (PBMC) from 2 patients with de Quervain's subacute thyroiditis (SAT), 2 with Graves' disease (GD), and 3 normal persons (N) were engrafted into severe combined immunodeficient (SCID) mice so as to study whether SAT PBMC would differ immunologically from GD PBMC in vivo. Human IgG was detected in all mice engrafted with PBMC from either group of patients or normal persons. Thyroid Stimulating Antibody (TSAb) was detected in the sera of mice with PBMC from SAT or GD patients, but not N. Thyroperoxidase (TPO)-antibody (Ab) and/or thyroglobulin (Tg)-Ab was detectable in the mice with GD PBMC only, but not in those with SAT or normal PBMC. The production of interferon gamma (IFN gamma) in mice engrafted with N PBMC was 8, 13 and 14 U/ml, similar to values found in sera of SCID mice with SAT PBMC (14 and 11 U/ml), i.e., much lower than that seen for GD PBMC (127 and 78 U/ml); this is consistent with the view that, compared to GD T lymphocytes, that there is probably a lower number of T lymphocytes sensitized to the thyrotrophin (TSH) receptor antigen in SAT patients. Another possibility is that the transient thyroidal antigenic release seen in the acute (hyperthyroid) phase may be insufficient for adequate T cell sensitization. Still other possibilities include the effect of more severe hyperthyroidism of GD on T cell sensitization, and CD4/CD8 cell ratios. In any event, these results are consistent with our previous view that antigenic release in SAT will not itself lead to autoimmune thyroid disease. PMID- 7835826 TI - Osteolytic activity and reversal of nephrectomy-induced hypocalcemia by a fraction other than 1,25(OH)2-vitamin D3 from Solanum malacoxylon incubated with ruminal fluid. AB - Previous studies have shown that two lipid soluble fractions (2 and 3) isolated from Solanum malacoxylon leaf extracts incubated with ruminal fluid by Sephadex LH-20 chromatography increase intestinal P absorption and blood Ca. Fraction 2 contains 1,25(OH)2-vitamin D3, vitamin D3, 25(OH)-vitamin D3 and 1,24,25(OH)3 vitamin D3. The osteolytic activity and ability to revert nephrectomy-induced hypocalcemia of fractions 2 and 3 was compared. The tibias from 19-day-old chick embryos injected with both fractions on day 15 were shorter, lighter and had a lower ash content than those from controls. Fractions 2 and 3 also decreased dry weight and ash content in frontal bones, although only the effects of fraction 3 were statistically significant. In agreement with these observations, fraction 3 was more effective than fraction 2 to increase blood Ca levels in nephrectomized rats. Extracts from rumen samples were devoid of activity. The results support the presence of a polar derivative of 1,25(OH)2D3 in ruminal fluid-treated Solanum malacoxylon. PMID- 7835827 TI - Rapid increase in lumbar spine bone density in osteopenic women by high-dose intramuscular estrogen-progestogen injections. A preliminary report. AB - This prospective pilot study has been carried out to assess the effect of high parenteral doses of estrogens and progestogens on lumbar spine bone density in osteopenic women. Thirteen osteopenic women received 40 mg estradiol valerate and 250 mg hydroxyprogesterone caproate by intramuscular injections once a week for 6 months (so called "pseudopregnancy"). One g oral calcium was added. Six out of the 13 patients (49.5 +/- 4.8 y were peri- and postmenopausal = group A. Seven patients (21.5 +/- 2.2 y) suffered from primary and secondary amenorrhea, in 4 out of them due to gonadal dysgenesis = group B. Estradiol was measured by commercial radioimmunoassay. Bone density was determined by dual-energy X-ray absorptiometry (DEXA) of the upper 4 lumbar vertebrae. Lumbar spine bone density as well as estradiol serum levels were measured before and 3 and 6 months after therapy, respectively. Estradiol increased from 34.8 +/- 7.5 pg/ml to 3226 +/- 393 pg/ml after 3 months and to 2552 +/- 254 pg/ml after 6 months, respectively, in group A. Bone density increased by 15.3 +/- 3.6% within the first 3 months to a total of 18.8 +/- 3.9% after 6 months, respectively. Two patients we have controlled for two years, maintained this increase. In group B estradiol increased from 27.8 +/- 6.5 pg/ml to 3028 +/- 728 after 3 and to 2491 +/- 684 pg/ml after 6 months. Bone density in this group increased by 11.8 +/- 1.9% within 3 and to a total of 18.2 +/- 2.8% after 6 months.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7835828 TI - Short and long-term effects of growth hormone treatment on lipid, lipoprotein, and apolipoprotein levels in short normal children. AB - Since recombinant growth hormone (GH) has been available, its use has been extended to treating not only children with growth hormone deficiency, but also short-statured children without GH deficiency. It is interesting, therefore, to determine whether GH therapy given in conventional doses causes metabolic side effects in these patients. In the present study we have examined the effect of recombinant human GH on eleven short normal children. Patients received 12 U/m2/week for 1 year. Before beginning treatment, the children had a mean annual growth velocity of 5.1 +/- 0.9 cm/yr; during the year of treatment, the therapy was effective and improved the mean growth velocity to 7.1 +/- 1.7 cm/yr, p < 0.05. We evaluated the subacute short-term effects during the first 15 days of treatment and the long-term effects for one year of GH treatment on lipid and lipoprotein levels. We found a significant increase in total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) at the 6th month. Triglycerides (TG) increased significantly at the 3rd and 6th month. Both TC and TG returned to baseline at the 12th month. In no case however did the levels of TC, LDL-C and TG go above normal nor were there any changes in the following tests: high density lipoprotein cholesterol (HDL-C), apolipoprotein (Apo) A-I, Apo B, Apo C-II, Apo C III and Apo E. In conclusion, conventional doses of GH given to short normal children are effective in ameliorating growth velocity and do not cause serious metabolic side effects. PMID- 7835829 TI - SHBG (sex hormone binding globulin) levels in insulin dependent diabetic patients according to the route of insulin administration. PMID- 7835830 TI - FSH and LH induce interleukin-6 (IL-6) release from human peripheral blood monocytes cultures in vitro. A dose-response study. PMID- 7835831 TI - Melatonin levels in psychogenic impotence. PMID- 7835833 TI - Proteolytic enzyme cathepsin D in follicular fluids and its possible role in ovulation. PMID- 7835832 TI - A novel method for detection of uterine oxytocin receptor in preparation for delivery using scraped endocervical cells. PMID- 7835834 TI - Drug-related pathological lesions of the intestinal tract. AB - Pathologists need to be more aware of the capacity of drugs, in particular non steroidal anti-inflammatory agents, to produce a wide spectrum of lesions in the intestinal tract. Whilst the histological changes brought about by drugs are generally non-specific in character, certain features such as tissue eosinophilia, the presence of apoptotic bodies in the crypts of Leiberkhun or an increase in intra-epithelial lymphocytes in the colon should always raise the suspicion of drug effects. PMID- 7835835 TI - Goseki grading in gastric cancer: comparison with existing systems of grading and its reproducibility. AB - A novel grading method which utilises intra-cellular mucin content and tubular differentiation (the Goseki grade) has been applied to 181 gastric cancers removed in potentially curative resections, and compared to conventional tumour grading (well, moderate, poor differentiation) and the Lauren, Ming and WHO classifications. The Goseki grade is significantly related to patient survival and, unlike the existing approaches, remains so after allowing for tumour stage in multivariate analyses. Potential relationships between the Goseki grade, direct tumour spread, lymph node involvement and survival have been investigated. Prognosis is particularly related to mucin content; 55% of patients with mucin rich tumours dying within 5 years compared to 29% of those with mucin-poor cancers. A smaller proportion of mucin-poor cancers show lymph node involvement (N1 and N2) than mucin-rich tumours (52% v. 73%) and a smaller proportion of cancers showing good tubular differentiation exhibit widespread lymph node involvement (N2) than tubule-poor cancers (11% v. 28%). However, these differences did not achieve statistical significance. When compared to the existing classification or grading methods, the Goseki grade was found to be highly significantly correlated with the WHO and Lauren classifications and to conventional grading, but not to the Ming classification. These inter-relations are largely dependent upon tubular differentiation. There was no relationship between Goseki grade and the lymphocytic response around the tumour margin. Inter observer agreement on the WHO type and the Lauren, Ming and Goseki grading methods was tested on 70 randomly selected cases.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7835836 TI - Observer variation in the assessment of chronic gastritis according to the Sydney system. AB - The main aims of the Sydney system for the classification of gastritis are to improve uniformity in histopathological reporting and to provide a flexible matrix of rules for grading the histological features. We sought to determine the level of interobserver agreement between pathologists in the application of the Sydney system. Three histopathologists independently examined H & E, alcian blue/PAS and modified Giemsa stained sections of two antral and two corpus gastric biopsies from 69 consecutive dyspeptic patients. After elimination of five unsuitable cases, each observer graded chronic inflammation, polymorph activity, atrophy, intestinal metaplasia and Helicobacter pylori density in the antrum and corpus on a 0-3 scale according to the Sydney system criteria. The pairwise agreement on final diagnosis and the overall and conditional agreement on histological grades were examined by kappa statistics. Agreement on the final diagnosis ranged from 83-94% with kappa values of 0.699 ('good') to 0.887 ('excellent'). Conditional probability of agreement on a diagnosis of H. pylori positive gastritis was 99%, but wider disagreements were apparent in the recognition of H. pylori negative gastritis, reactive gastritis and even normal biopsies. Overall agreement for grade ranged from 70% for antral atrophy to 94% for intestinal metaplasia in the corpus with 'moderate' or 'good' kappa values. We conclude that the diagnostic and grading criteria described in the Sydney system can be applied consistently by histopathologists. The findings underline its potential usefulness in routine practice. PMID- 7835837 TI - Monoclonal Epstein-Barr virus genomes but lack of EBV-related protein expression in different types of gastric carcinoma. AB - Thirty-nine resection specimens of gastric carcinomas have been investigated for the presence of EBV RNA sequences using a highly sensitive non-radioactive in situ hybridization technique. Transcribed EBER sequences were found in seven (18%), including four cases of undifferentiated carcinoma with prominent lymphoid infiltration and three gastric adenocarcinomas. In the positive tumours all, or nearly all, tumour nuclei were distinctly labelled. No positive signals could be detected in the non-dysplastic epithelial cells or the reactive inflammatory infiltrate. Clonality analysis using specific probes to the variable tandem repeat region of the EBV yielded single episomal bands in all four cases tested, two of which were undifferentiated carcinomas and two adenocarcinomas. By means of immunohistology, no expression of the EBV-related proteins LMP or EBNA-2 was present in tumour cells of positive cases in in situ or blotting attempts. Our results suggest that infection of gastric carcinomas by the EB virus occurs early in tumourigenesis but, in contrast to nasopharyngeal carcinomas, does not result in the expression of EBV-specific proteins. PMID- 7835838 TI - Frequent presence of latent Epstein-Barr virus infection in lymphoepithelioid cell lymphoma (Lennert's lymphoma). AB - This study deals with the investigation of the biological significance of an Epstein-Barr virus (EBV) infection in lymphoepithelioid cell lymphoma. A selection of EBV-detection techniques was applied to 15 cases, including polymerase chain reaction (PCR) for the detection of EBV-DNA, in situ hybridization (ISH) for the cellular localization of EBV-encoded small nuclear (EBER 1 and EBER 2) and immediate-early (BHLF) RNAs, and immunohistology for the detection of EBV-encoded latent membrane protein (LMP) expression. PCR and EBER ISH produced congruent results in those cases with amplifiable DNA, leading to an EBV presence in 11/15 lymphoepithelioid cell lymphoma cases (73%). EBER-ISH combined with immunohistology localized the virus predominantly in several B immunoblasts and small B lymphocytes in eight of the EBV-positive cases, five of which also contained single infected lymphocytes expressing T-cell characteristic antigens. LMP was detected using immunohistology in only a proportion of immunoblasts in four of these cases. The remaining three EBV-positive lymphoepithelioid cell lymphoma cases contained only single EBER-positive small B lymphocytes without LMP expression. No case contained BHLF-RNA expressing cells. These data imply that, although latently EBV-infected cells are frequently present in lymphoepithelioid cell lymphoma cases, the virus is probably not directly involved in the pathogenesis of this entity. PMID- 7835839 TI - Proliferating cell nuclear antigen but not p53 or human papillomavirus DNA correlates with advanced clinical stage in renal cell carcinoma. AB - In this study we investigated 56 renal cell carcinomas immunohistochemically for the expression of proliferating cell nuclear antigen (PCNA) and tumour suppressor protein p53. We also analyzed for the presence of human papilloma virus (HPV) DNA subtypes 6, 11, 16, 18, 31 and 33 by in situ hybridization. In carcinomas which showed more than 10% of PCNA positive nuclei there were significantly more cases with invasion (P = 0.032) or metastatic disease (P = 0.047). Nine out of 22 grade III-IV tumours (40.9%) but only six out of 30 grade I-II tumours (20%) showed more than 10% of PCNA positive cells (P = 0.097). Patients with 10% or more PCNA positive cells in kidney tumours had more advanced disease at the time of diagnosis than those showing less PCNA positive cells (P = 0.05). Six p53 positive cases were found among 56 tumours (11%), but only one case had more than 10% positive cell nuclei. The presence of HPV DNA was found in 29 out of 56 cases (52%). Multiple subtypes were found in 19 cases (34%). The most commonly occurring subtypes were 18 and 33. There was no association between PCNA, p53 and the presence of HPV DNA subtypes. Because of the association of PCNA with invasion and metastatic disease, it would be worth while to study PCNA further as a possible marker for aggressiveness of renal carcinomas. Both this study and those concentrated on mutational analysis suggest that p53 is generally not important for the development of renal cell carcinoma. On the other hand, the presence of HPV DNA in these tumours implicates HPV viral infection in the aetiology of renal cancer. PMID- 7835840 TI - Prognostic significance of proliferating cell nuclear antigen (PCNA) expression in gliomas. AB - The relationship between proliferating cell nuclear antigen (PCNA) expression and various clinicopathological indices (age, sex, tumour location, histological type and grade and treatment) and post-operative survival were studied in patients with central nervous system gliomas using univariate and multivariate analysis. The expression of PCNA (PC10 score) was examined immunohistochemically using the monoclonal antibody PC10 on paraffin sections from 45 cases. Univariate analysis showed that a high PC10 score as well as older age, high histological grade and the histological type (astrocytoma) were associated with reduced survival. However, multivariate analysis revealed that only PC10 score and histological type had independent prognostic significance. The most important feature influencing PC10 score was the tumour grade. Regarding the patients who relapsed, the survival from the time of original diagnosis was related to the relapse-free period, while the PC10 score of the primary tumour emerged as the only independent predictor of survival following the first recurrence. These results indicate that PCNA expression is an independent prognostic indicator in CNS gliomas. PMID- 7835841 TI - Stereological analysis of the synovial membrane in rheumatic disorders: diagnostic value of volume-weighted mean nuclear volume estimation. AB - Quantitative evaluation of nuclear size of synoviocytes was performed on 48 synovial biopsies in various rheumatic disorders: osteoarthritis (n = 10), rheumatoid arthritis (11), and chronic non-specific synovitis (14). Thirteen tissue specimens from non-inflammatory synovial membrane were included as a control group. Using the point-sampled intercepts method, unbiased stereological estimates of volume-weighted mean nuclear volume (nuclear upsilon v) were obtained. A slight increase in nuclear volume was observed in osteoarthritis in comparison with the control group with an overlap in 90% of cases. However, in rheumatoid arthritis there was a significant increase of nuclear upsilon v. Significant differences were found between rheumatoid arthritis and the control and osteoarthritis groups (P < or = 0.001). In biopsies from patients diagnosed as chronic non-specific synovitis the averaged nuclear upsilon v values were between those in osteoarthritis and rheumatoid arthritis with a wide range of data. Similar, but less significant differences were demonstrated between rheumatic disorders when using mean nuclear area. Further analysis of chronic non specific synovitis patients in combination with nuclear upsilon v estimates as a simple, unbiased, complementary tool are required to better establish the diagnostic value of nuclear stereology in the diagnosis of rheumatic disorders. PMID- 7835843 TI - Lymphocytic infiltration and destruction of parathyroid adenomas: a possible tumour-specific autoimmune reaction in two cases of primary hyperparathyroidism. AB - Two cases of primary hyperparathyroidism with underlying parathyroid adenomas were found to be associated with lymphocytic infiltration and destruction of the neoplastic tissue. There was no inflammatory infiltrate in the adjacent rim of the remnant of parathyroid gland or in the other tumour-free glands. The lymphoid cell population within the tumours was composed of both infiltrating T-cells and compact nodule-forming B-cells. In one of the tumours there was considerable fibrosis and atrophy of the adenomatous tissue. The histological picture was consistent with an autoimmune process directed against the adenomas, indicating that this reaction had, in part, been successful in reducing the abnormal cell population. PMID- 7835842 TI - Foam cell replication and smooth muscle cell apoptosis in human saphenous vein grafts. AB - Occlusion of saphenous vein grafts is a major problem after coronary artery bypass grafting. Segments of occluded and suboccluded implanted aortocoronary grafts were obtained during re-intervention bypass grafting in 47 patients yielding a total of 80 vein grafts. The grafts were studied by immunohistochemistry for smooth muscle cells (alpha-SMC actin), macrophages (HAM56), cell replication (PCNA, Ki-67) and transmission and scanning electronmicroscopy (TEM, SEM). In 81% of the examined grafts the (sub)occlusion was due to a myo-intimal thickening and an associated luminal accumulation of foam cells and mural thrombi. The foam cells were constantly found at the luminal site of the myo-intimal thickening and within the luminal part of adherent thrombi. Transmission electronmicroscopy demonstrated phagocytosis of platelets and platelet fragments by the foam cells. A significant fraction of the foam cells demonstrated nuclear immunoreactivity for Ki-67 and PCNA. The myo-intimal thickening of the vein grafts was composed of smooth muscle cells lying in a fibrous tissue matrix. The smooth muscle cells were surrounded by prominent basal lamina and showed ultrastructural features of apoptosis. Our results support the hypothesis that phagocytosis of lipid rich platelets by monocytes set up a mechanism for foam cell formation and replication in human saphenous vein grafts. The transformation of a smooth muscle cell rich myointimal thickening towards a fibrous, cell poor intimal thickening could be induced by progressive smooth muscle cell loss through apoptosis. PMID- 7835844 TI - Epithelioid sarcoma arising in a patient with neurofibromatosis type 2. PMID- 7835845 TI - Myxoid leiomyosarcoma of the uterine cervix. PMID- 7835846 TI - A poorly differentiated Sertoli-Leydig cell tumour associated with an ovarian sex cord tumour with annular tubules in a woman with Peutz-Jeghers syndrome. PMID- 7835847 TI - Invasive carcinoma with a granulomatous stromal response. PMID- 7835848 TI - Intranodal spindle cell tumour: myofibroblastoma or haemorrhagic. PMID- 7835849 TI - Gallbladder vasculitis and mixed cryoglobulinemia. PMID- 7835850 TI - Capitation versus decapitation in mental health care. PMID- 7835851 TI - What are "best practices?" Understanding the concept. PMID- 7835852 TI - Polydipsia, hyponatremia, and water intoxication among psychiatric patients. PMID- 7835853 TI - Treating the impulsive patient. PMID- 7835854 TI - Defining managed care in public-sector psychiatry. AB - Although managed care is an established force in the private sector, there is growing interest and experimentation with this concept in the public sector. This interest has been generated by the increased demand for services, the shrinking resource base due to cutbacks in state budgets, and the fragmentation of care that has accompanied the shift from a centralized, hospital-based model to a decentralized, community-based model for treating individuals with serious mental illness. But despite this interest, no consensus exists about the form or functions of managed care in the public arena. Simply importing private-sector versions of managed care is inadequate given the substantial differences in the patient population and service delivery mechanisms. The authors present a functional analysis of managed care in the public sector. Drawing on their conceptualization of managed care, they outline a functional approach to evaluating the strengths and weaknesses of treatment systems, innovations such as privatization and capitation, and recent health care reform proposals. PMID- 7835855 TI - A mental health capitation program: I. Patient outcomes. AB - OBJECTIVE: The Monroe-Livingston demonstration project's capitation payment system (CPS) was evaluated to determine whether capitated funding of mental health care, compared with fee-for-service funding, could reduce hospitalization rates and improve functioning and symptoms for severely and persistently mentally ill adults without increasing the total cost of care. METHODS: The experiment was a communitywide prerandomized clinical trial involving 422 patients. Patients who were randomized into the experimental group were eligible for enrollment in a capitated funding program administered by one of five community mental health centers. Those randomized into the control group received standard fee-based services. Follow-up interviews with patients one and two years after enrollment in the study assessed changes in symptoms and functioning. Data files of the membership corporation that coordinated community mental health services for the CPS provided measures of study patients' use of inpatient mental health services. RESULTS: During the two-year follow-up period, patients in the experimental group had significantly fewer hospital inpatient days than patients in the control group, but the two groups had no significant differences in functioning or level of symptoms. CONCLUSIONS: The CPS successfully maintained severely ill patients in the community but did not improve their functioning or level of symptoms. PMID- 7835856 TI - A mental health capitation program: II. Cost-benefit analysis. AB - OBJECTIVE: Total monetized and nonmonetized costs and benefits to society of the Monroe-Livingston demonstration project's capitated payment system (CPS) were analyzed. METHODS: Total costs and benefits of care for individuals who were prerandomized to an experimental group (of whom about 57 percent were enrolled in the CPS) were compared with those for a control group who received traditional fee-for-service care. Separate two-year results are presented for continuous patients, who were enrolled in a comprehensive CPS plan (N = 201) and for intermittent patients, who were enrolled in a partial plan (N = 155). RESULTS: All groups showed improvements on many psychosocial measures over the two years. Continuous patients in the experimental group experienced less hospitalization, more case management and transportation services, and higher levels of victimization and were more likely to live in unsupervised settings than continuous patients in the control group. Total annual per patient costs for care of continuous patients ranged from $74,000 to more than $100,000, largely reflecting differences in rates of hospitalization. Experimental subjects in the partial capitation condition differed from the control group in this plan on fewer measures; both groups reported high levels of case management and social support services and relatively lower levels of supervised housing. CONCLUSIONS: The CPS resulted in major improvements in the community's services for persons with serious mental illness and reduced the proportion of care provided in the state hospital. PMID- 7835857 TI - A multiregional study of nurses' beliefs and attitudes about work safety and patient assault. AB - OBJECTIVE: The study attempted to increase understanding of nursing staff members' beliefs and concerns about work safety and patient assault. METHODS: A study conducted at a university-affiliated psychiatric facility in California in the late 1980s was replicated in five other psychiatric settings. Data were collected using the Attitudes Toward Patient Physical Assault Questionnaire, containing 31 statements designed to elicit nurses' beliefs about safety concerns, staff performance, and legal issues related to assaults. RESULTS: A total of 557 nursing staff members at the six sites responded to the questionnaire; 84 percent were female. The majority (76 percent) had been physically assaulted at least once, but 71 percent reported feeling safe in their work environment most of the time. Compared with female staff members, males tended to believe that assaults were to be expected, that assaulted staff have personality traits that make them vulnerable to assault, and that legal action against assaultive patients might jeopardize their jobs. Recently hired staff were more confident that their facilities did not admit unmanageable patients and that the environment was adequate to prevent assaults. Staff who had been assaulted more frequently tended to believe that assaults were to be expected. CONCLUSIONS: The study highlights a nationwide concern among nursing staff about safety. Ensuring a safe working environment requires better training, more adequate staffing, and a security plan to protect staff, patients, and others. PMID- 7835858 TI - A national survey of jail diversion programs for mentally ill detainees. AB - OBJECTIVES: The authors sought information on the number, structure, and effectiveness of programs aimed at diverting mentally ill inmates from the criminal justice system into the mental health treatment system. METHODS: A working definition of a jail diversion program was developed. Mail surveys were distributed to 1,263 U.S. jails with a capacity of 50 or more detainees to ascertain the presence or absence of diversion programs. Telephone interviews with samples of respondents and nonrespondents to the mail survey yielded additional information about the programs' operation, funding, staffing, and directors' perceptions of their effectiveness. RESULTS: Information obtained from the mail and telephone surveys indicated that only 52 U.S. jails with a capacity of 50 or more detainees had formal mental health diversion programs that fit the definition developed by the authors. Programs in larger jails served fewer violent felons than did those in smaller jails. Three-fourths of the programs were located in mental health agencies. Two-thirds of program directors considered the programs to be moderately or very effective. CONCLUSIONS: Only a small number of U.S. jails have diversion programs for mentally ill detainees, and objective data on their effectiveness are lacking. Systematic evaluations are needed to determine what types of programs work best for which types of detainees. PMID- 7835859 TI - A ten-year update of administrative relationships between state hospitals and academic psychiatry departments. AB - OBJECTIVE: In a follow-up to a survey ten years earlier, the authors investigated current administrative relationships between academic departments of psychiatry and state hospitals. METHODS: A 20-item questionnaire was sent to the chairs of the 110 medical school departments of psychiatry with accredited psychiatric residencies. RESULTS: Eighty-two departments, or 75 percent, responded. Seventy one percent of the respondents reported that their department had a relationship with a state hospital; 79 percent of these relationships involved the education of psychiatric residents. Most respondents rated the quality of the relationship favorably (4 or 5 on a 5-point scale). Almost all respondents believed that residents can obtain a high-quality education in a state hospital. More than half of the departments responding to a question about the importance of a state hospital rotation rated it of major importance in their residency program. CONCLUSIONS: Many medical school departments of psychiatry remain closely involved with state hospitals and recognize the hospital as an important part of residents' education. Administrators have gained much experience about how to develop and implement mutually beneficial relationships. PMID- 7835860 TI - Psychiatric residents' attitudes toward patients with chronic mental illness. AB - OBJECTIVE: The study examined psychiatric residents' attitudes toward, knowledge about, and training in the care of patients with chronic mental illness. METHODS: The authors constructed a 41-item Residents' Attitude Toward the Chronically Mentally Ill Scale to obtain a systematic assessment of attitudes. The scale's validity was enhanced by input from 12 psychiatrists who were knowledgeable about work with and attitudes toward such patients, and a test showed the scale to have high reliability. The scale was administered to 85 psychiatric residents, along with questionnaires focused on training and knowledge and the Marlowe-Crowne Social Desirability Scale assessing defensiveness and self-deception. RESULTS: No correlation was found between residents' attitudes and years of residency training or between attitudes and knowledge about patients with chronic mental illness. Residents reported many negative attitudes toward this patient population. However, significant positive correlations were found between the residents' attitudes and their training in settings where patients were considered to receive high-quality care and supervisors were good role models. CONCLUSIONS: Constructive training experiences during residency can have a positive influence on residents' attitudes toward patients with chronic mental illness. PMID- 7835861 TI - Community psychiatry and deinstitutionalization in Jamaica. AB - Between 1960 and 1990, the population of Jamaica's single mental hospital was reduced by 58 percent, from more than 3,000 to less than 1,300. Services were reoriented from mental-hospital-based custodial care to rehabilitative, community based care with no appreciable increase in the mental health budget. Despite several changes in government over the past 30 years, continuity of public policy and fiscal support has allowed ongoing development of the island's community mental health services. The national community mental health service, which had a case-load of about 14,000 patients in 1990, relies on specially trained psychiatric nurse practitioners who provide crisis management, medication management, and supportive psychotherapy; make home visits; and carry out treatment plans developed by the community psychiatrist. Community acceptance of mentally ill persons has been enhanced by public education programs and media coverage of advances in treatment. PMID- 7835862 TI - A model for management and treatment of insanity acquittees. Psychiatric Security Review Board, State of Oregon. PMID- 7835863 TI - A profile of clients served by a mobile outreach program for homeless mentally ill persons. PMID- 7835864 TI - Expressed emotion by residential care operators and residents' symptoms and quality of life. PMID- 7835865 TI - A comparison of videocameras and official incident reports in detecting inpatient assaults. PMID- 7835866 TI - Violence against families. PMID- 7835867 TI - Outpatient suicides. PMID- 7835868 TI - Blood group polymorphisms and geography in the Sierra de Gredos, Spain. AB - The present research is designed to contribute to our knowledge of the influence of geography on the genetic population structure in the Sierra de Gredos (central Spain). This mountain range separates two distinct areas: the Tormes-Alberche valley in the north and the Tietar valley in the south. Unrelated blood donors (226), whose 4 grandparents were born in the study area, were tested for blood group markers (A1A2BO, RH, MNSs, Kell, P, and Lewis). R matrix analysis in relation to other Spanish populations agrees reasonably well with the cluster analysis of the Prevosti distance matrix using the UPGMA algorithm. Comparisons suggest a certain degree of genetic variation between the populations of these two valleys. The Sierra de Gredos can thus be considered a biological barrier limiting the gene flow between the valleys. PMID- 7835869 TI - Relationships by isonymy between persons with monophyletic and polyphyletic surnames from the Monterrey metropolitan area, Mexico. AB - Three thousand two hundred eleven males and females who resided and were interviewed in the Monterrey metropolitan area in northeastern Mexico were selected for having 1 of 10 common selected surnames as either their patronymic or matronymic name. Five of the names are considered monophyletic and five are considered polyphyletic. Because each individual has two surnames, information about the name complementary to the selected surname was analyzed using isonymy methods (1) to see the effect of immigration on the genetic composition of the population and (2) to determine the isonymy, the relationship by isonymy within and between the persons with monophyletic and polyphyletic surnames. The percentages of the most common complementary surnames, the coefficients of relationship by isonymy of surnames for a selected surname, and the coefficients of relationship between the selected surnames are higher in the monophyletic than in the polyphyletic surnames, indicating that the persons with monophyletic names still conserve some customs of the founders that possibly increase their degree of endogamy. Perhaps these indicators are inversely related to migration, indicating that the monophyletic surnames have been more stable in Monterrey since it was colonized. PMID- 7835870 TI - Sex ratio and selection by early mortality in humans: fifty-year analysis in different ethnic groups. AB - We studied the sex ratio (M/F) in representative populations of the main human ethnic groups, namely, US whites, US blacks, and Japanese. The data cover a period of over 50 years. For intra-ethnic comparison, we included analogous data on Italians. The populations studied show heterogeneous patterns: the US white and Italian populations are the most similar, with no drastic variations in live birth sex ratio throughout the period. Comparison of sex ratio data for live borns and 1-year-old infants yields a similar pattern in all groups; the differences between the two sex ratio values are constantly reducing. It can be hypothesized that in the near future the sex ratio observed at birth will be maintained up to reproductive age. If this value is stabilized by natural selection, as is likely, new relationships between the sex ratio and selection are expected to evolve in the populations of developed countries. PMID- 7835871 TI - Evidence of selection on PGM1 polymorphism in diabetic pregnancy. AB - Ninety-nine pregnant women with insulin-dependent diabetes mellitus, 83 women with gestational diabetes, and a control sample of 315 nondiabetic consecutive puerperae have been studied along with their newborn infants. Neonatal macrosomia is less frequent among diabetic mothers with phosphoglucomutase (PGM1) genotype PGM1*1/*2 than among mothers with other PGM1 genotypes. In gestational diabetes the association is more evident among younger women than among older women. Diabetic women with the PGM1*1/*2 genotype show a reduced proportion of heterozygous PGM1*1/*2 offspring. The phenomenon is much more evident among women under 28 years of age and does not depend on the quality of metabolic control. The data suggest that when both mother and fetus share the PGM1*1/*2 genotype, the deleterious effects of a diabetic environment on fetal development are more severe, leading to an early loss of zygotes. This may contribute to a decrease incidence of macromosomia among live-born infants delivered by PGM1*1/*2 mothers. PMID- 7835872 TI - Effects of maternal smoking on adverse pregnancy outcomes: examination of the criteria of causation. AB - Smoking during pregnancy has been associated with many adverse pregnancy outcomes. However, debate continues about whether smoking causes these outcomes. This review of the criteria of causation found that the relative risk of having a low-birth-weight baby is nearly doubled in women who smoke during pregnancy compared with nonsmoking women and that the relative risks of spontaneous abortion and perinatal and neonatal mortality are increased by about one-third. The magnitude of the long-term effects of maternal smoking on the physical and mental development of the offspring is small but measurable. The epidemiologic evidence associating maternal smoking with major adverse pregnancy outcomes in prospective and case-control studies displays a high degree of consistency. A dose-response gradient for smoking during pregnancy has not been clearly shown in relation to perinatal and neonatal mortality. However, there is strong support for a dose-response gradient in relation to low birth weight and spontaneous abortion and moderate support for long-term developmental effects. Although a biological causal mechanism has not been clearly delineated, considerable evidence indicates that the chemicals in tobacco smoke are capable of producing deleterious changes in the placenta and fetus. PMID- 7835873 TI - Birth weight and handedness in boys and girls. AB - The association between selected demographic variables and birth weight on the one hand and a composite hand preference score based on seven hand tasks (each performed twice) on the other was investigated in a sample of 1387 male and female schoolchildren aged 5 to 10 years old. In multiple regression models left handedness was significantly more common among boys and among children of better educated mothers and tended to decrease with age. No association was found with respect to urban or rural residence or birth order. Increased birth weight was associated with right-handedness in boys but with left-handedness in girls, and the birth weight by sex interaction term was statistically significant (p = 0.037). The demographic associations in the present study are compatible with those reported previously. The different associations of birth weight with hand preference in boys and girls indicate that the prenatal hormonal factors that affect brain lateralization and handedness are qualitatively or quantitatively different in the two sexes and may be differentially associated with birth weight. PMID- 7835874 TI - Red cell acid phosphatase types and GC polymorphisms in Merida, Oaxaca, Leon, and Saltillo, Mexico. AB - Red cell acid phosphatase types and GC polymorphisms were studied in Merida and Oaxaca, Mexico. GC polymorphisms were also investigated in Leon and Saltillo. The ACP*A, ACP*B, and ACP*C gene frequencies were 0.215, 0.770, and 0.015 respectively, in Merida and 0.205, 0.788, and 0.002, respectively, in Oaxaca. In Oaxaca the ACP*R gene had a frequency of 0.005. The results are similar to other Mestizo groups studied in Mexico; it is concluded that the ACP*C and ACP*R genes were introduced by admixture of native Amerindians with whites and blacks, respectively. The GC*1S, GC*1F, and GC*2 gene frequencies were 0.489, 0.289 and 0.222, respectively, in Leon; 0.500, 0.272, and 0.228, respectively, in Merida; 0.454, 0.337, and 0.209, respectively, in Oaxaca; and 0.505, 0.356, and 0.139, respectively, in Saltillo. These results are similar to what has been obtained in other Mestizo populations and Indian groups in Mexico, probably because the main ethnic component in both is Amerindian. PMID- 7835875 TI - mtDNA variation in 95 individuals from two populations from southwest Cameroon. PMID- 7835876 TI - mtDNA variation in the Chibcha Amerindian Huetar from Costa Rica. AB - The genetic variation in a Chibcha-speaking Amerindian tribe from lower Central America, the Huetar, was analyzed using nucleotide sequences of the hypervariable segments of the mitochondrial DNA (mtDNA) control region, the frequencies of 10 Amerindian-specific mtDNA haplotypes, and the regional distribution of private protein polymorphisms. The sequencing of 713 base pairs (bp) in the control regions of 27 individuals revealed 11 distinct lineages. These were defined by 24 variable sites and a 6-bp deletion between nucleotide pairs (np) 106 and 111. The 6-bp deletion is a new mtDNA marker that will be valuable for Amerindian taxonomic research. Control region sequences and mtDNA haplotype analyses reveal that Huetar mtDNAs are distributed in "Amerindian clusters" A, B, and D. A maximum-likelihood phylogenetic tree suggests a single origin for the 6-bp Huetar deletion in the sample. mtDNA haplotype analysis and the presence of previously characterized private protein variants (PEPA*F, TF*DCHI, and the absence of DI*A) show that the Huetar harbor polymorphisms of considerable antiquity, suggesting an early divergence from the regional founder gene pool for this population. The data also reflect a drastic constriction in population size, an evolutionary event with a proposed central effect on Huetar genetic structure. PMID- 7835877 TI - EcoRI, RsaI, and MspI RFLPs of the COL1A2 gene (type I collagen) in the Cayapa, a Native American population of Ecuador. AB - EcoRI, RsaI, and MspI RFLPs of the COL1A2 gene were analyzed, using the polymerase chain reaction technique, for the first time in a native American population: the Cayapa of Ecuador. These polymorphisms recently turned out to be good anthropological markers, both at the allele and at the haplotype frequency level. These data underline the well-known genetic affinity between the Cayapa and Asian populations. Moreover, our data on DNA polymorphisms agree with the indication of extremely low, if any, gene flow into the Cayapa gene pool from the neighboring black community, as already suggested not only by cultural data but also by protein polymorphisms. PMID- 7835878 TI - Serogenetic analysis in the study of the population structure of the eastern Adriatic (Croatia). AB - The anthropogenetic structure of six island and peninsular populations (Brac, Hvar, Korcula, Peljesac, Silba, and Olib) of the eastern Adriatic, Croatia, is analyzed on the basis of the study of four different erythrocyte antigen systems or groups (ABO, Rhesus, Kell-Celano, P) and two erythrocyte isoenzyme systems (ACP, ESD). The average sample size was 555 individuals. Allele frequencies, genetic distances, and gene diversity values were computed. The results indicate that all the populations in question have preserved their separate characteristics over the course of their (micro)evolution to the present day; this is especially noticeable for the island populations of Korcula and Olib, as these are distinguished from the other four populations by a greater degree of isolation. Today's genetic structure of the six populations can be explained through the existing historical and cultural data for the region in question, which indicate that over the course of their ethnohistory they were all influenced by significant waves of immigration and selective emigrations that must have greatly shaped their present-day population structure. PMID- 7835879 TI - Kidney and retinal defects (Krd), a transgene-induced mutation with a deletion of mouse chromosome 19 that includes the Pax2 locus. AB - The semidominant mutation Krd (kidney and retinal defects) was identified in transgenic line Tg8052. Krd/+ mice have a high incidence of kidney defects including aplastic, hypoplastic, and cystic kidneys. Retinal defects in Krd/+ mice include abnormal electroretinograms and a reduction of cell numbers that is most extreme in the inner cell and ganglion layers. Viability of Krd/+ mice is strongly influenced by genetic background, and growth retardation is observed in young animals. Homozygosity results in early embryonic lethality. Fluorescence in situ hybridization of a transgene-specific probe localized the insertion site to the distal region of mouse Chromosome 19. The sequence of the insertion site revealed transgene insertion into a LINE element with deletion of a single nucleotide from the 3' terminus of the transgene. A polymorphic microsatellite, D19Umi1, was identified in a junction clone and mapped in several large crosses. D19Umi1 is located 1.7 +/- 1.0 cM distal to Pax2, which encodes a paired type transcription factor expressed in embryonic kidney and eye. Deletion of Pax2 from the transgenic chromosome was demonstrated by Southern analysis of genomic DNA from (Krd/+ x SPRET/Ei)F1 mice. Additional genetic and molecular data are consistent with an approximately 7-cM deletion that includes the loci stearoyl CoA desaturase (Scd1), pale ear (ep), D19Mit17, D19Mit24, D19Mit27, D19Mit11, and Pax2. This deletion, Del(19)TgN8052Mm, will be useful for genetic and functional studies of this region of mouse Chromosome 19. PMID- 7835880 TI - A large duplicated area in the polycystic kidney disease 1 (PKD1) region of chromosome 16 is prone to rearrangement. AB - An area of 500 kb at the proximal end of the polycystic kidney disease 1 (PKD1) region has been mapped in detail, with 260 kb cloned in cosmids. The area cloned from normal individuals contains two homologous but divergent regions each of 75 kb, including the previously described marker 26-6. Pulsed-field gel electrophoresis identified a duplication of 75 kb of this region, referred to as the OX duplication (OXdup), in three patients with PKD1. The OXdup probably arose by an unequal exchange promoted by misalignment of partially homologous areas. Study of the OXdup in a large PKD1 family showed that it segregated with PKD1 in just one-half of the family, indicating that a recent crossover had occurred between the OXdup and PKD1 and showing that it was not a PKD1 mutation. Further analysis identified an OXdup breakpoint fragment: the OXdup was subsequently identified in 2 normal individuals of 110 assayed. The finding of the OXdup and in other individuals an 11-kb deletion (OXdel) at a similar point within this duplicated area indicates that this is an unusually unstable genomic region. PMID- 7835881 TI - A linkage map of human chromosome 14, including 13 gene loci. AB - The long arm of human chromosome 14 (14q), an acrocentric chromosome, is estimated to be approximately 93 Mb in length. Genetic maps published to date have included mostly random DNA markers. The map we present here includes 13 genes, as well as 29 random DNA segments, based on typing of the CEPH families. Our map has been placed in context with other published maps. The resulting map of 42 loci has markers on average 5 cM apart and has a total length of 163 cM. The map order differs in the telomeric region from that of other maps previously published. 14q has homology, throughout approximately half its length, with mouse chromosome 12 and has a proximal region of homology with mouse chromosome 14. PMID- 7835882 TI - Genomic organization and expressed sequences of the mouse extended H-2K region. AB - The mouse major histocompatibility complex (MHC) has long been of great interest to many biologists because of not only its critical role in the immune system, but also its association with at least three embryonic lethal genes. Here, we present an analysis of the mouse extended H-2K region using YAC technology. Six new expressed sequences were identified, demonstrating that the high gene density previously described continues. Restriction mapping of a YAC clone extending proximal of the MHC region defined a CpG-rich region located up to 320 kb away from H-2K. The absence of any CpG-rich region for a distance spanning approximately 200 kb near the YAC's proximal end suggests that the high gene density probably diminishes at a distance of 360 kb away from H-2K. The description of genomic organization of both H-2K and the extended H-2K region provides insight into the characteristics of this whole region with respect to gene diversity and density. PMID- 7835883 TI - Chromosomal localization and cDNA cloning of the human DBP and TEF genes. AB - We have isolated cDNA and genomic clones and determined the human chromosome positions of two genes encoding transcription factors expressed in the liver and the pituitary gland: albumin D-site-binding protein (DBP) and thyrotroph embryonic factor (TEF). Both proteins have been identified as members of the PAR (proline and acidic amino acid-rich) subfamily of bZIP transcription factors in the rat, but human homologues have not been characterized. Using a fluorescence in situ hybridization technique, the DBP locus was assigned to chromosome 19q13, and TEF to chromosome 22q13. Each assignment was confirmed by means of human chromosome segregation in somatic cell hybrids. Coding sequences of DBP and TEF, extending beyond the bZIP domain to the PAR region, were highly conserved in both human-human and interspecies comparisons. Conservation of the exon-intron boundaries of each bZIP domain encoding exon suggested derivation from a common ancestral gene. DBP and TEF mRNAs were expressed in all tissues and cell lines examined, including brain, lung, liver, spleen, and kidney. Knowledge of the human chromosome locations of these PAR proteins will facilitate studies to assess their involvement in carcinogenesis and other fundamental biological processes. PMID- 7835884 TI - A DNA fragment from Xq21 replaces a deleted region containing the entire FVIII gene in a severe hemophilia A patient. AB - In this paper we report the molecular characterization of a large deletion that removes the entire Factor VIII gene in a severe hemophilia A patient. Accurate DNA analysis of the breakpoint region revealed that a large DNA fragment replaced the 300-kb one, which was removed by the deletion. Pulsed-field gel electrophoresis analysis revealed that the size of the inserted fragment is about 550 kb. In situ hybridization demonstrated that part of the inserted region normally maps to Xq21 and to the tip of the short arm of the Y chromosome (Yp). In our patient this locus is present both in Xq21 and in Xq28, in addition to the Yp, being thus duplicated in the X chromosome. Sequence analysis of the 3' breakpoint suggested that an illegitimate recombination is probably the cause of this complex rearrangement. PMID- 7835885 TI - Structure and chromosomal localization of the gene (BDKRB2) encoding human bradykinin B2 receptor. AB - The bradykinin B2 receptor (BDKRB2) has high affinity for the intact kinins, which mediate a wide spectrum of biological effects, including pain, inflammation, vasodilation, and smooth muscle contraction and relaxation. In the present study, we have cloned and sequenced the gene encoding human bradykinin B2 receptor from a human genomic library. The B2 receptor gene contains three exons separated by two introns. The first and second exons are noncoding, while the third exon contains the full-length coding region, which encodes a protein of 364 amino acids forming 7 transmembrane domains. The human B2 gene shares high sequence identity with rat and mouse B2 receptor genes and significant similarity with the gene encoding the angiotensin II type I receptor in the nucleotide sequence and exon-intron arrangement. In the 5' flanking region, a consensus TATA box and several putative transcription factor-binding sites have been identified. Genomic Southern blot analysis showed that the B2 receptor is encoded by a single copy gene that was localized to chromosome 14q32 by in situ hybridization. In a Southern blot analysis following reverse transcription and polymerase chain reaction, the human B2 receptor was found to be expressed in most human tissues. PMID- 7835886 TI - Molecular cloning, sequence analysis, and chromosomal localization of the human protease inhibitor 4 (kallistatin) gene (PI4). AB - The gene encoding human protease inhibitor 4 (kallistatin; gene symbol PI4), a novel serine proteinase inhibitor (serpin), has been isolated and completely sequenced. The kallistatin gene is 9618 bp in length and contains five exons and four introns. The structure and organization of the kallistatin gene are similar to those of the genes encoding alpha 1-antichymotrypsin, protein C inhibitor, and alpha 1-antitrypsin. The kallistatin gene is also similar to the genes encoding rat and mouse kallikrein-binding proteins. The first exon of the kallistatin gene is a noncoding 89-bp fragment, as determined by primer extension. The fifth exon, which contains 308 bp of noncoding sequence, encodes the reactive center of kallistatin. In the 5'-flanking region of the kallistatin gene, 1125 bp have been sequenced and a consensus promoter segment with potential transcription regulatory sites, including CAAT and TATA boxes, an AP-2 binding site, a GC-rich region, a cAMP response element, and an AP-1 binding site, has been identified within this region. The kallistatin gene was localized by in situ hybridization to human chromosome 14q31-q32.1, close to the serpin genes encoding alpha 1 antichymotrypsin, protein C inhibitor, alpha 1-antitrypsin, and corticosteroid binding globulin. In a genomic DNA Southern blot, kallistatin-related genes were identified in monkey, mouse, rat, bovine, dog, cat, and a ground mole. The patterns of hybridization revealed clues of human serpin evolution. PMID- 7835887 TI - Chromosomal assignments of 3'-directed partial cDNA sequences representing novel genes expressed in granulocytoid cells. AB - Large scale cDNA sequencing of 3'-directed cDNA libraries allows the collection of hundreds of novel sequences (gene signatures) and understanding of their expression levels in various tissues. Granulocytoid cells were induced from the human promyelocytic leukemia cell line 60 (HL60) with dimethyl sulfoxide (DMSO), and more than 1000 gene signatures were collected from a 3'-directed cDNA library of the granulocytoid cells. By selecting appropriate sequences for primer design, we systematically assigned chromosomes of these novel gene signatures by means of the polymerase chain reaction. We used a monochromosomal hybrid cell panel DNA as the template and localized 155 gene signatures to individual chromosomes. The results showed that 125 of them were assigned to single chromosomes and 30 to more than one. Genes assigned to more than one chromosome tend to be expressed ubiquitously, and their sequences are often conserved among humans and rodents. A highly sensitive laser fluorescent analyzer and ethidium staining were used for simple and large-scale PCR mapping. PMID- 7835889 TI - Assignment of the zeta-crystallin gene (CRYZ) to human chromosome 1p22-p31 and identification of restriction fragment length polymorphisms. AB - zeta-Crystallin is a lens protein that has been associated with autosomal dominant congenital cataracts in guinea pigs and thus is a candidate for human congenital cataracts. We have assigned the zeta-crystallin gene (CRYZ) to human chromosome 1 using a Southern panel of 17 human-mouse somatic cell hybrids and regionally localized it to 1p22-p31 by fluorescence in situ hybridization. Five restriction fragment length polymorphisms were identified by analyzing the DNA from 10 unrelated, unaffected individuals. Our results will permit evaluation of its role in human cataractogenesis. PMID- 7835888 TI - Chromosomal mapping, isolation, and characterization of the mouse xanthine dehydrogenase gene. AB - Xanthine dehydrogenase (XD) is a key enzyme in the catabolism of purines. A recently isolated XD cDNA clone (Terao et al., Biochem. J. 283, 863-870, 1992) was used to analyze the genomic structure and chromosomal location of this gene. XD was found to be a single-copy gene approximately 70 kb long with 36 exons containing the transcribed sequence. The length of the mouse XD gene was much longer and the structure more complex than those of the Drosophila and Calliphora homologs. The locus encoding the XD gene (designated Xd) was mapped to the distal part of mouse chromosome 17 by haplotype analysis of 114 interspecific backcross mice. Although Xd inactivation may be responsible for xanthinuria, a rare human genetic disease, this genetic locus is not a candidate for any previously described mouse mutation. The transcription start site was defined by primer extension and RNase mapping analysis, using liver mRNA. No other transcription start sites were identified in the liver and a variety of other organs after treatment with an interferon inducer. Transient transfection analysis in NIH3T3, tEnd, and COS cells with an appropriate reporter gene demonstrated that a functional promoter is located within the first 268 bp preceding the transcriptional initiation site. PMID- 7835890 TI - Three genes in the human MHC class III region near the junction with the class II: gene for receptor of advanced glycosylation end products, PBX2 homeobox gene and a notch homolog, human counterpart of mouse mammary tumor gene int-3. AB - Cosmid walking of about 250 kb from MHC class III gene CYP21 to class II was conducted. The gene for receptor of advanced glycosylation end products of proteins (RAGE, a member of immunoglobulin superfamily molecules), the PBX2 homeobox gene designated HOX12, and the human counterpart of the mouse mammary tumor gene int-3 were found. The contiguous RAGE and HOX12 genes were completely sequenced, and the human int-3 counterpart was partially sequenced and assigned to a Notch homolog. This human Notch homolog, designated NOTCH3, showed both the intracellular portion present in the mouse int-3 sequence and the extracellular portion absent in the int-3. It thus corresponds to the intact form of a Notch type transmembrane protein. About 20 kb of dense Alu clustering was found just centromeric to the NOTCH3. PMID- 7835891 TI - Isolation and chromosomal mapping of genomic clones encoding the human fatty acid synthase gene. AB - We have isolated and sequenced 0.5- and 3.6-kb cDNA clones that cover the N terminal and carboxy-terminal regions, respectively, of the human fatty acid synthase. To localize the fatty acid synthase gene and to define its genomic structure, we have also isolated overlapping genomic clones by screening two human YAC libraries with PCR primers derived from the fatty acid synthase cDNA sequences. The DNA inserts in these human fatty acid synthase YACs hybridized with human synthase-specific cDNA probes. Using biotin-labeled Alu-PCR products of the human synthase YACs as probes for fluorescence in situ hybridization, we mapped the fatty acid synthase gene to chromosome 17q25. We also screened a chromosome 17-specific cosmid library with human synthase cDNA probes and isolated 12 cosmids, all of which had EcoRI fragments in common. DNA sequencing of an amplified PCR product from the fatty acid synthase cosmids confirmed that these genomic clones contained expressed fatty acid synthase sequences. Furthermore, the results of Southern analyses suggested that a single 40-kb cosmid clone encompasses the entire coding region of the fatty acid synthase gene. The synthase gene is located on chromosome 17 near the q25 band, which is close to the telomere and could serve as an important marker in analysis of this chromosome. PMID- 7835892 TI - AML1, AML2, and AML3, the human members of the runt domain gene-family: cDNA structure, expression, and chromosomal localization. AB - cDNAs corresponding to three human runt domain containing genes, AML1, AML2, and AML3, were isolated and characterized. In addition to homology in the highly conserved runt domain, extensive sequence similarities were also observed in other parts of the proteins. All three carried an identical, putative ATP binding site -GRSGRGKS-, and their C-terminal halves were particularly rich in proline and serine residues. While AML1 cDNAs were cloned by others, AML2 represents a new member, not previously described, of the runt domain gene family, and AML3 was identified as the human homologue of mouse PEB-P2 alpha A. The chromosomal location of AML1 to chromosome 21q22 was confirmed, while AML2 and AML3 were mapped to chromosome regions 1p36 and 6p21, respectively. Analysis of AML1 and AML2 expression in hematopoietic cell lines revealed a distinct pattern of expression. PMID- 7835893 TI - The human microsomal epoxide hydrolase gene (EPHX1): complete nucleotide sequence and structural characterization. AB - Human microsomal epoxide hydrolase (mEH) is a xenobiotic-metabolizing enzyme that detoxifies reactive epoxides to more water soluble dihydrodiol compounds. We have isolated and sequenced clones that encode the entire human mEH gene (EPHX1). The primary nuclear transcript, extending from the start of transcription to the site of poly(A) addition, is 20,271 nucleotides in length. The human mEH gene contains 9 exons, separated by 8 introns; canonical intron/exon boundary sites are observed at each junction. The introns vary in size from 335 to 6696 bp and contain numerous repetitive DNA elements, including 18 Alu sequences (each > 100 nucleotides in length) within 4 introns. Alu sequences were classified with respect to subfamily assignment. Two thousand eighteen nucleotides 5' of the transcription start and 2501 nucleotides 3' of the poly(A) addition sites were also sequenced. To evaluate the human mEH promoter, chimeric constructs were prepared linking portions of the 5' mEH flanking sequence (up to -693 bp) to a CAT reporter gene, followed by transient transfection in both COS-1. and HepG2 cells. Results from these expression experiments suggest that the human mEH gene contains a weak core promoter and that inclusion of DNA sequences 5' of the minimal promoter region negatively regulates constitutive transcription. PMID- 7835894 TI - Structure of the human gene encoding the associated microfibrillar protein (MFAP1) and localization to chromosome 15q15-q21. AB - Microfibrils with a diameter of 10-12 nm, found either in association with elastin or independently, are an important component of the extracellular matrix of many tissues. To extend our understanding of the proteins composing these microfibrils, the cDNA and gene encoding the human associated microfibril protein (MFAP1) have been cloned and characterized. The coding portion is contained in 9 exons, and the sequence is very homologous to the previously described chick cDNA, but does not appear to share homology or domain motifs with any other known protein. Interestingly, the gene has been localized to chromosome 15q15-q21 by somatic hybrid cell and chromosome in situ analyses. This is the same chromosomal region to which the fibrillin gene, FBN1, known to be defective in the Marfan syndrome, has been mapped. MFAP1 is a candidate gene for heritable diseases affecting microfibrils. PMID- 7835895 TI - Characterization of the mouse loricrin gene: linkage with profilaggrin and the flaky tail and soft coat mutant loci on chromosome 3. AB - Loricrin is the major component of a specialized structure, termed the cornified cell envelope, that is formed beneath the plasma membrane of stratified squamous epithelial cells and is coexpressed with profilaggrin in terminally differentiating epidermal keratinocytes. Full-length cDNAs for both mouse and human loricrin have been cloned and characterized, as has the human gene. Here we report the isolation and characterization of the mouse loricrin gene. The gene has a simple structure consisting of a single intron of 1091 bp within the 5' noncoding sequence and an uninterrupted open reading frame. Using PCR analyses of DNAs isolated from mouse x Chinese hamster somatic cell hybrids, we have mapped both the loricrin and the profilaggrin genes to chromosome 3. Genetic linkage analysis has shown that mouse loricin and profilaggrin lie within 1.5 +/- 1.1 centimorgans of each other. We have further shown that both genes map in the vicinity of the flaky tail (ft) and soft coat (soc) loci. These mouse mutants exhibit a number of changes in their integument, suggesting that abnormalities in these genes may contribute to the mutant phenotype. PMID- 7835896 TI - Human and mouse chromosomal mapping of the myeloid cell leukemia-1 gene: MCL1 maps to human chromosome 1q21, a region that is frequently altered in preneoplastic and neoplastic disease. AB - The MCL1 gene, recently identified in a myeloid leukemia cell line, has sequence similarity to BCL2, the gene at the t(14;18) translocation in follicular lymphoma. The chromosomal location of MCL1 has now been determined. The human locus (MCL1) was mapped to the long arm of human chromosome 1q21, using the methods of in situ hybridization and somatic cell hybrid analysis. In the mouse, MCL1-related sequences were mapped to positions on two mouse chromosomes (chromosomes 3 and 5), using haplotype analysis of an interspecific cross. The location of the locus on mouse chromosome 3 (Mcl1) was homologous to that of MCL1 on human chromosome 1; the second locus (Mcl-rs on mouse chromosome 5) may represent a pseudogene. The proximal long arm of human chromosome 1, where MCL1 is located, is duplicated and/or rearranged in a variety of preneoplastic and neoplastic diseases, including hematologic diseases and solid tumors. MCL1 is thus a candidate gene for involvement in cancer. PMID- 7835897 TI - Evidence for a locus regulating total serum IgE levels mapping to chromosome 5. AB - Genetics studies of total serum IgE levels were performed since high IgE levels correlate with clinical expression of allergy and asthma. Families ascertained through a parent with asthma were genotyped for markers on 5q where there are multiple candidate genes that may influence the control of IgE and inflammation. Evidence for linkage of the IgE phenotype to 5q was obtained by both sib-pair and lod score analysis with evidence for recessive inheritance of high IgE levels from segregation analysis. These findings represent a major step in mapping genes important in the regulation of allergic responses and the pathogenesis of asthma. PMID- 7835898 TI - Marked changes in mitochondrial DNA deletion levels in Alzheimer brains. AB - Levels of the common 4977 nucleotide pair (np) mitochondrial DNA (mtDNA) deletion (mtDNA4977) were quantitated in the cortex, putamen, and cerebellum of patients with Alzheimer disease (AD) and compared to age-matched controls. Although cerebellum deletion levels were comparably low in AD patients and controls of all ages, cortical deletion levels were clearly different. The levels of mtDNA deletions in control brains started low, but rose markedly after age 75, while those of AD patients started high and declined to low levels by age 80. Choosing age 75 to arbitrarily delineate between younger and older subjects, younger patients had 15 times more mtDNA deletions than younger controls, while older patients had one-fifth the deletion level of older controls. Younger AD patients also had fourfold more deletions than older AD patients. These results support the hypothesis that OXPHOS defects resulting from somatic mtDNA mutations may play a role in AD pathophysiology. PMID- 7835899 TI - A rapid screening method for the detection of mutations in the RET proto-oncogene in multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma families. AB - Multiple endocrine neoplasia type 2A (MEN2A) and familial medullary thyroid carcinoma (FMTC) are autosomal dominant inherited cancer syndromes with incomplete penetrance. Following the identification of mutations in the RET proto oncogene that segregate with the disease phenotype in MEN2A, MEN2B, and FMTC, genetic screening of individuals with mutations in RET may be performed. We have employed restriction endonuclease digestion of polymerase chain reaction products as an alternative to sequence analysis for rapid identification of mutant gene carriers in families in which MEN2A and FMTC are segregating. Twenty-one Australasian MEN2A and FMTC families have been screened for mutations in a cysteine-rich region of the RET proto-oncogene. Seven independent mutations were identified in key individuals in 16 of these families. We have identified a mutation in codon 620, 2053 T-->C (Cys620Arg), and two mutations in codon 634 of exon 11 of RET, 2095 T-->C (Cys634Arg) and 2096 G-->A (Cys634Tyr), all three of which were present in both MEN2A and FMTC families. PMID- 7835900 TI - Sequence of the coding region of the bovine fibrillin cDNA and localization to bovine chromosome 10. AB - We report the cDNA sequence for the bovine gene for fibrillin corresponding to the human gene, fibrillin 1 (FBN1), and the localization of the gene to bovine chromosome 10 (syntenic group U5). The identity between the human and bovine sequences is 97.8% at the amino acid level and 92% at the nucleotide level. The bovine fibrillin sequence contains the same number and type of motifs as the human FBN1 sequence, including the same number of putative calcium binding sites. All of the motifs conform to the patterns demonstrated in the human sequence, and many of the differences in identity between the sequences are conservative. PMID- 7835901 TI - Analysis of 133 meioses places the genes for nevoid basal cell carcinoma (Gorlin) syndrome and Fanconi anemia group C in a 2.6-cM interval and contributes to the fine map of 9q22.3. AB - Four disease genes (NBCCS, ESS1, XPAC, FACC) map to 9q22.3-q31. A fine map of this region was produced by linkage and haplotype analysis using 12 DNA markers. The gene for nevoid basal cell carcinoma syndrome (NBCCS, Gorlin) has an important role in congenital malformations and carcinogenesis. Phase-known recombinants in a study of 133 meioses place NBCCS between (D9S12/D9S151) and D9S176. Haplotype analysis in a two-generation family suggests that NBCCS lies in a smaller interval of 2.6 cM centromeric to D9S287. These flanking markers will be useful clinically for gene tracking. Recombinants also map FACC (Fanconi anemia, group C) to the same region, between (D9S196/D9S197) and D9S287. The recombination rate between (D9S12/D9S151) and D9S53 in males is 8.3% and 13.2% in females, giving a sex-specific male:female ratio of 1:1.6 and a sex-averaged map distance of 10.4 cM. No double recombinants were detected, in agreement with the apparently complete level of interference predicted from the male chiasmata map. PMID- 7835902 TI - Localization of the gene encoding a neutral amino acid transporter-like protein to human chromosome band 19q13.3 and characterization of a simple sequence repeat DNA polymorphism. AB - The gene encoding a human neutral amino acid transporter-like protein (SLC1A5) was mapped to chromosome band 19q13.3 by fluorescence in situ hybridization to metaphase chromosomes. A simple sequence repeat DNA polymorphism of the form (GT)n was identified in the 3'-untranslated region of SLC1A5 mRNA. Studies in the CEPH families showed significant evidence of linkage between this DNA polymorphism and markers localized to the distal long arm of chromosome 19. PMID- 7835903 TI - Organization of the region encompassing the human serum amyloid A (SAA) gene family on chromosome 11p15.1. AB - The four members of the human serum amyloid A protein (SAA) gene family are clustered on human chromosome 11p15.1. Three genes are differentially expressed and encode small apolipoproteins of M(r) 12-19 kDa: SAA1 and SAA2 encode the acute phase SAAs (A-SAAs), and SAA4 encodes the constitutively expressed SAA (C SAA). A fourth locus, SAA3, is a pseudogene. The human SAA gene family encompasses approximately 150 kb contained on a 900-kb yeast artificial chromosome contig. SAA1 and SAA2 are 15-20 kb apart and are arranged in divergent transcriptional orientations. SAA4 is 9 kb downstream of SAA2 and in the same orientation. SAA3 is 110 kb downstream of SAA4, and its relative orientation could not be determined. All genes known to be in the same human and mouse syntenic linkage group as SAA were mapped within the contig. Interphase FISH was used to orientate the region relative to the centromere: cen-LDHC-LDHA-SAA1-SAA2 SAA4-SAA3-TP H-D11S18- KCNC1-MYOD1-pter. PMID- 7835904 TI - Isolation of a human YAC contig encompassing a cluster of UGT2 genes and its regional localization to chromosome 4q13. AB - Previously we mapped the gene encoding a human bile acid UDP glucuronosyltransferase (UGT2B4) to chromosome 4. Here we report the mapping of two additional human UGT2B genes to chromosome 4 utilizing the polymerase chain reaction (PCR) and a panel of human/rodent somatic cell hybrid cell lines. A yeast artificial chromosome contig containing the UGT2B4, UGT2B9, and UGT2B15 genes was isolated, and pulsed-field gel electrophoresis and PCR revealed that several members of the human UGT2B gene subfamily are clustered within a 195-kb region of the YAC contig. These data permitted a provisional ordering of the genes as UGT2B9-UGT2B4-UGT2B15. Fluorescence in situ hybridization analysis, using the YAC DNA, permitted the regional localization of this gene cluster to chromosome 4q13. PMID- 7835905 TI - cDNA cloning of the human monocarboxylate transporter 1 and chromosomal localization of the SLC16A1 locus to 1p13.2-p12. AB - Lactate and pyruvate are transported across cell membranes by monocarboxylate transporters (MCTs). Here, we use the recently cloned cDNA for hamster MCT1 to isolate cDNA and genomic clones for human MCT1. Comparison of the human and hamster amino acid sequences revealed that the proteins are 86% identical. The gene for human MCT1 (gene symbol, SLC16A1) was localized to human chromosome bands 1p13.2-p12 by PCR analysis of panels of human x rodent cell hybrid lines and by fluorescence chromosomal in situ hybridization. PMID- 7835906 TI - Mapping the gene that encodes phosphatidylinositol-specific phospholipase C-gamma 2 in the human and the mouse. AB - We have mapped the PLCG2 gene, which encodes the enzyme phosphatidyl inositol specific phospholipase C-gamma 2. This is one of the phospholipases responsible for catalyzing the hydrolysis of phosphatidyl inositol in response to a great many mitogenic stimuli. PL C-gamma 2 is an essential component of the signal transduction pathway between tyrosine kinases and downstream events such as protein kinase C activation and intracellular calcium release. We assigned PLCG2 to human chromosome 16 by amplification within a somatic cell hybrid mapping panel. To position the locus at a much finer resolution, PLCG2 sequences were amplified from a chromosome 16-specific somatic cell hybrid panel, which placed the gene on the long arm of the chromosome in band 16q24.1, a region that has few known genes. We have hybridized a mouse Plcg2 open reading frame probe to mouse DNAs from the European Interspecific Backcross. The segregation pattern reveals the mouse Plcg2 locus maps to distal chromosome 8. PMID- 7835907 TI - Genetic mapping of the mouse prosaposin gene (Psap) to mouse chromosome 10. PMID- 7835908 TI - The retinal outer segment membrane protein-1 gene (Rom1) maps to the proximal end of mouse chromosome 19. PMID- 7835909 TI - Assignment of the endothelial-specific protein receptor tyrosine kinase gene (TEK) to human chromosome 9p21. PMID- 7835910 TI - Colonic epithelial cell lines as a source of interleukin-8: stimulation by inflammatory cytokines and bacterial lipopolysaccharide. PMID- 7835911 TI - Low-affinity receptor for IgE on human bronchial epithelial cells in asthma. AB - Bronchial epithelial cells are activated in asthma but the mechanisms underlying this activation are poorly understood. We tested the possibility that bronchial epithelial cells recovered by brushing from 15 asthmatic and 11 control subjects may be activated by an IgE-dependent mechanism. The expression of the low affinity IgE receptor (CD23) was studied by immunocytochemistry using the alkaline phosphatase anti-alkaline phosphatase technique and immunofluorescence using confocal microscopy. Four of eight allergic asthmatic patients and none of the seven non-allergic asthmatic or control subjects had a positive expression of CD23. The functional activity of CD23 was examined in the cells recovered from these subjects by stimulating them with IgE/anti-IgE. 15-HETE was not released but endothelin was released in the three or four asthmatic patients who had a positive expression of CD23. None of the other subjects released any endothelin. This study suggests that bronchial epithelial cells of asthmatic patients may be directly activated by an IgE-mediated mechanism. PMID- 7835912 TI - Regulation of synthesis of complement protein C4 in human fibroblasts: cell- and gene-specific effects of cytokines and lipopolysaccharide. AB - Synthesis and secretion of the class III major histocompatibility complex (MHC) gene product, C4, were detected in human skin fibroblasts by metabolic labelling, immunoprecipitation and SDS-PAGE analysis. Pro-C4 (approximately 185,000 MW) was present in intracellular lysates, and the mature protein was present in extracellular media, with three bands of approximately 93,000, 75,000 and 33,000 MW, corresponding to the alpha, beta and gamma chains, respectively. C4 expression was increased in a dose-dependent manner by interferon-gamma (IFN gamma), but was unaffected by interleukin-1 beta (IL-1 beta), IL-6 and tumor necrosis factor-alpha (TNF-alpha) alone, each of which augmented the expression of factor B, C3 and other complement proteins synthesized in fibroblasts. Simultaneous incubation of fibroblasts with IFN-gamma and TNF resulted in a synergistic increase in C4 synthesis. RNA blot analyses indicated that regulation of C4 synthesis by IFN-gamma and the combination of IFN-gamma and TNF was mediated primarily at a pretranslational level. Lipopolysaccharide (LPS) had no effect on C4 or HLA-DR synthesis in fibroblasts, either constitutive or IFN-gamma regulated. These results are in contrast to the effects of LPS in monocytes, where LPS decreased constitutive synthesis and counter-regulated the IFN-gamma enhanced expression of both C4 and HLA-DR. C2 expression in fibroblasts was also increased primarily by IFN-gamma. However, C2 synthesis was increased by LPS, 1L 1 and TNF, although to a lesser extent than the increase in synthesis of factor B stimulated by these mediators. These results show that up-regulation by IFN-gamma is a common feature of C2 and C4 expression in human cells that constitutively synthesize these proteins. In contrast, regulation of MHC class III and class II genes by LPS, TNF, IL-1, and IL-6 is cell- and gene-specific. PMID- 7835913 TI - Plasma clearance of the human C5a anaphylatoxin by binding to leucocyte C5a receptors. AB - The C5a anaphylatoxin is a potent complement-derived mediator of inflammation with chemotactic activity. In this study the possible role of specific high affinity binding sites for C5a on peripheral blood leucocytes for the removal of C5a from human blood plasma was investigated. The addition of purified granulocytes or mononuclear cells to complement-activated plasma resulted in the rapid and dose-dependent removal of up to 80% of plasma C5a, as determined by ELISA. The specific role of leucocyte C5a receptors (C5aR) in the plasma clearance of C5a was demonstrated by the inhibition of C5a uptake by the preincubation of cells with the C5aR-specific monoclonal antibody S5/1. Furthermore, U937 cells which had been induced by db-cAMP to express C5aR, but not undifferentiated U937 cells, were capable of removing C5a from plasma. The inhibition of C5aR internalization by monensin did not affect C5a uptake by leucocytes. The co-incubation with leucocytes had no effect on the plasma clearance of complement activation products C3a or terminal complement complex (TCC), as determined by this in vitro assay. The binding of the C5a anaphylatoxin to cellular receptors represents an effective control mechanism that protects the organism from systemic effects of this potent phlogistic mediator. PMID- 7835914 TI - Cell-surface bound complement regulatory activity is necessary for the in vivo survival of KDH-8 rat hepatoma. AB - The monoclonal antibody 5I2 recognizes and functionally inhibits a Crry-like complement regulator molecule on rat cells (corresponding to human decay accelerating factor and membrane cofactor protein activity). The inhibition of complement regulatory activity by 5I2 antibody results in complement deposition on rat cell membranes exposed to homologous complement. Two subclones of KDH-8 rat hepatoma were selected for the experiments; one expressing high (CrryH) and the second low (CrryL) amounts of Crry-like antigen. Both sublines grow in vivo in syngeneic rats, but at lower cell doses (< 10(5) cells/rat) the survival time of rats injected with CrryL cells is prolonged. Injection of tumour-bearing rats with 5I2 monoclonal antibody intraperitoneally did not influence the tumour growth. However, it resulted in 50% mortality within a few hours, accompanied by severe haemorrhage in the peritoneal cavity. Pretreatment of the tumour cells with 5I2 monoclonal antibody or its F(ab')2 fragment substantially increased the survival time of recipient rats. Even permanent survivors were found, indicating that cell membrane-associated complement regulatory activity, which provides protection against attack of homologous complement, is necessary for in vivo tumour growth. PMID- 7835915 TI - MHC class II-bound self-peptides can be effectively separated by isoelectric focusing and bind optimally to their MHC class II restriction elements around pH 5.0. AB - More than 90% of the major histocompatibility complex (MHC) class II molecules on antigen-presenting cells (APC) have in their binding site a peptide derived from an extracellular protein ingested by the APC or from a protein of the APC itself. These self-peptides can be eluted from affinity-purified MHC class II molecules by acid elution, and have been studied with a variety of techniques. We show here that the self-peptides eluted from the mouse MHC class II molecules Ad, Ed and Ek bind specifically to MHC class II molecules of the allelic type from which they were derived. The pH optimum for binding is around 5.0, i.e. the same optimum at which synthetic peptides representing sequences of foreign antigens bind to MHC class II molecules. This suggests that the physiological compartment where MHC class II molecules bind self-peptides may be very late in the endocytic pathway. The chemical properties of the eluted and labelled MHC class II peptides were studied by isoelectric focusing. This method was able to separate the peptides very efficiently, and enabled a rapid comparison of peptides eluted from different MHC molecules. The 125I-labelled peptides displayed a broad range of isoelectric points with values predominantly below neutral. This suggests that such peptides bind to MHC in a predominantly non-charged state. PMID- 7835916 TI - HLA class II molecules (HLA-DR, -DP, -DQ) on cells in the human CNS studied in situ and in vitro. AB - Human leucocyte antigen (HLA) class II molecules expressed by antigen-presenting cells (APC) are major restriction elements in the interaction between APC and T cells of the CD4+ subtype. To explore the immune accessory function of cells in the central nervous system (CNS), we studied the expression of HLA-DR, -DP, and DQ molecules on CNS cells in situ and in vitro. Reactive microglia and perivascular cells in multiple sclerosis lesions expressed all three HLA class II molecules, whereas microglia in the normal CNS expressed HLA-DR only. All three HLA class II molecules were up-regulated on cultured microglia after stimulation with interferon-gamma (IFN-gamma). Microglial stimulation of allogeneic CD4+ T cells in a mixed lymphocyte reaction (MLR) was effectively blocked using anti-HLA DR monoclonal antibodies (mAb) but not using anti-HLA-DQ mAb. HLA class II positive astrocytes and endothelial cells were not identified in normal or diseased CNS. Cultured astrocytes stimulated with IFN-gamma could, however, be induced to express HLA class II antigens of all subtypes, although great variability was observed between different donors. Our results indicate that although both microglia and astrocytes are capable of expressing all HLA class II subtypes in vitro, subtype expression differs between normal and pathological states in situ. Such selective expression may be associated with functional properties. PMID- 7835917 TI - Comparative susceptibility of peripheral blood leucocytes and related cell lines to killing by T-cell perforin. AB - The comparative susceptibility of lymphocyte subsets, monocytes and polymorphonuclear leucocytes (PMN) to killing by murine perforin was measured using physical separation techniques, cell-surface phenotyping and scatter characteristics to isolate cell types, together with propidium iodide (PI) uptake as a measure of cell death. In the majority of individuals, PMN were more resistant to perforin than other peripheral blood cells including natural killer (NK) cells and CD8+ lymphocytes. Among the lymphocytes, CD4+ cells were the most susceptible subset, followed by CD19+, CD8+ and CD56+ lymphocytes respectively. The human promyelocytic leukaemia cell line, HL-60, and the human histiocytic lymphoma cell line, U937, were readily killed by perforin. When HL-60 were differentiated to either macrophage- or neutrophil-like end cells, and U937 differentiated to macrophage-like end cells, there was no difference between differentiated and undifferentiated cells in their relative susceptibility to perforin. The relative resistance of PMN to perforin may be important in protecting them from damage in in vivo situations where both NK cells and neutrophils are localized in the same inflammatory areas. PMID- 7835918 TI - CTL recognition of west Nile virus-infected fibroblasts is cell cycle dependent and is associated with virus-induced increases in class I MHC antigen expression. AB - Confluent and non-confluent mouse embryo fibroblast (CMEF and NCMEF) monolayers were infected with West Nile virus (WNV) for 24 hr, and class I major histocompatibility complex antigen (MHC-I) concentrations measured by flow cytometry (FCM). Concentrations on CMEF increased significantly more than on NCMEF. This was not owing to differences in interferon-beta (IFN-beta)-mediated MHC induction, as the IFN-beta quantity secreted by each infected fibroblast was similar in each culture, and IFN-beta-mediated MHC-I induction on NCMEF was greater than on CMEF. Furthermore, despite neutralization of WNV-induced supernatant IFN-beta, CMEF increased MHC-I expression significantly more than NCMEF. Functionally, WNV-infected CMEF were lysed 10-fold better by WNV-specific and allospecific cytotoxic T cells, than infected NCMEF. FCM demonstrated 76% CMEF and 68% NCMEF distributed in G0/G1. This represented G0 in CMEF, and G1 in NCMEF, confirmed by ribonucleotide reductase M1 subunit labelling, where only 20% CMEF was labelled, compared to 84% NCMEF. The possible implications for antiviral immune responses are discussed. PMID- 7835919 TI - Proinflammatory cytokines and endotoxin stimulate ICAM-1 gene expression and secretion by normal human hepatocytes. AB - Hepatocytes in normal tissues express low or undetectable levels of intercellular adhesion molecule-1 (ICAM-1), as detected by immunohistochemistry. Up-regulation of ICAM-1 expression on these cells has been reported in inflammatory liver disease (hepatitis B virus infection, autoimmune liver disorders and liver allograft rejection), and the molecule has been implicated in the recruitment, retention and activation of inflammatory cells. There is, however, little information concerning the regulation of hepatocyte expression of ICAM-1. We show here, for the first time, the induction (within 30 min) of ICAM-1 gene expression in cultured normal human hepatocytes stimulated with interleukin-1 beta (IL-1 beta), tumour necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) or endotoxin. IFN-gamma was the most potent single inducer (up to fourfold at 6 hr), while further induction of ICAM-1 mRNA was achieved with cytokine combinations. Maximal mRNA expression was achieved within 10 hr. ICAM-1 could be detected readily by immunocytochemical staining on the hepatocyte surface by 12 hr, and by enzyme immunoassay in the culture medium by 24 hr. The data present clear evidence that cytokines, which have been implicated previously in inflammatory liver diseases, can up-regulate directly both ICAM-1 gene expression and protein secretion/shedding by human hepatocytes. PMID- 7835920 TI - Production of cytokines by lymphocytes from spleen, mesenteric lymph node and intestinal lamina propria of pigs. AB - Large numbers of cells can be recovered from pig intestine with phenotypes suggesting lamina propria rather than intraepithelial origin. Following activation with concanavalin A these cells produced a T-cell growth factor (TCGF) activity which was not inhibited in the presence of a monoclonal antibody recognizing pig interleukin-2 receptors (IL-2R). In contrast, the activity of recombinant human IL-2 and of supernatants from activated spleen cells was almost entirely inhibited by anti-IL-2R. The failure of anti-IL-2R to inhibit the activity of lamina propria-derived TCGF was not apparently owing to interference by soluble receptor with binding of monoclonal to target blast cells as no effect of supernatants on binding was observed. The results suggest that cells derived from the pig intestinal lamina propria fail to produce IL-2 following polyclonal activation in vitro. Consistent with this finding, IL-2 transcripts could be detected by polymerase chain reaction (PCR) following reverse transcription of mRNA derived from spleen and from mesenteric lymph node but not lamina propria lymphocytes, while IL-4 cDNA could be detected from all three sources. PMID- 7835921 TI - Neutralization of transforming growth factor-beta 1 in a mouse model of immune induced lung fibrosis. AB - We examined the contribution of the cytokine transforming growth factor beta 1 (TGF-beta 1) in the inflammatory response and fibrotic reaction in a mouse model of immune-induced lung fibrosis caused by repeated intranasal exposure to heat killed bacillus Calmette-Guerin (BCG). Mice received 200 micrograms of BCG 3 days/week for 4 weeks, and simultaneous intraperitoneal injections of a monospecific rabbit antiserum against mouse TGF-beta 1 or a preimmune serum (normal rabbit globulin). BCG instillations generated a copious release of antigenic TGF-beta 1 in the lungs at 1, 2, 3 and 4 weeks (up to 15 ng/lungs/mouse). Treatment with anti-TGF-beta 1 antiserum significantly diminished the number of free lung cells recovered by bronchoalveolar lavage (BAL), although the BAL cellular profile was not affected. Moreover, anti-TGF beta 1 treatment of challenged mice diminished very significantly the total levels of interleukin-1 beta (IL-1 beta) and tumour necrosis factor-alpha (TNF alpha) in the lungs of animals challenged with BCG. Histological examination and morphometric analysis of Masson's Trichrome-stained sections and measurements of total lung hydroxyproline levels showed a substantial decrease in lung fibrosis and granulomatous response of challenged mice given anti-TGF-beta 1. These data argue for a role for TGF-beta 1 in inducing inflammation and lung fibrosis in response to an immune stimulus. PMID- 7835922 TI - The role of TNF-alpha in T-cell-mediated inflammation depends on the Th1/Th2 cytokine balance. AB - The role of tumour necrosis factor-alpha (TNF-alpha) in tuberculosis is paradoxical because although there is much evidence for a protective role, there is also evidence that it plays a part in the tissue damage that characterizes human disease. We have shown previously that TNF-alpha frequently induces necrosis when injected into sites undergoing delayed-type hypersensitivity (DTH) responses to mycobacterial antigen. This is dependent on CD4+ T cells. However the presence of this sensitivity to TNF-alpha-induced necrosis depended on the immunization protocol. We have tested the hypothesis that sensitivity to TNF alpha depends on the cytokine profile of the induced T-cell response. All subcutaneous doses of mycobacterial immunogen used (10(7) to 10(9) organisms) primed spleen cells so that they secreted interferon-gamma (IFN-gamma) and interleukin-2 (IL-2) when cultured in vitro with soluble antigen. However priming for production of IL-4 was dose dependent as in other systems, and was produced at all times from 7 to 30 days after immunization with 10(9) organisms. Time course studies over 30 days showed that sensitivity to TNF-alpha was found in DTH sites of animals primed for IL-4 and IFN-gamma production, but not in animals primed only for the Th1 cytokines. We suggest therefore that the paradoxical role of TNF-alpha can be resolved. In 'pure' Th1 responses it may act as an additional macrophage-activating factor. In mixed Th1 + Th2 or Th0 responses it may cause tissue damage. This mixed pattern is characteristic of tuberculosis, and of the late stage of many chronic infections where elimination of the infecting organism is failing, and chronic tissue damage is seen. PMID- 7835923 TI - Infiltration of CD4+ CD8+ T cells, and expression of ICAM-1, Ia antigens, IL-1 alpha and TNF-alpha in the skin lesion of BALB/c mice undergoing repeated infestations with nymphal Ixodes ricinus ticks. AB - The skin cellular immune response of BALB/c mice was examined during three successive infestations with nymphal Ixodes ricinus ticks. An immunohistochemical analysis of skin cryostat sections 72 hr post-tick attachment revealed that CD4+ T cells outnumbered CD8+ T cells in all infestations. The CD4+:CD8+ T-cell ratio was 2.2:1 in the primary infestation, then increased to 3.2:1 and 4.7:1 in the secondary and tertiary infestations. No B lymphocytes (CD45R) were detected in the skin of control and infested mice. A positive staining of intercellular adhesion molecule-1 (ICAM-1) on vascular endothelial cells, dendritic cells and some other mononuclear cells was observed in the dermis. Also, a strong positive staining of Ia antigens on dendritic cells and infiltrated mononuclear cells was noted. The staining pattern was more intense and positive cells increased in number in the skin of re-infested mice compared to the primary infestation. In addition, cells such as epidermal keratinocytes, dermal dendritic cells and infiltrated mononuclear cells positive for the 'pro-inflammatory' cytokines interleukin-1 alpha (IL-1 alpha) and tumour necrosis factor-alpha (TNF-alpha) were localized in the skin of infested mice, as detected at the mRNA level by in situ hybridization and at protein level by immunostaining with antibodies. These results suggest that an antigen was presented to infiltrating T lymphocytes which then became activated. This event may explain the cutaneous delayed-type hypersensitivity previously described in tick-infected BALB/c mice. Importantly, this cutaneous reaction was not sufficient to protect the mouse against tick re infestation. Furthermore, ICAM-1 could mediate, at least in part, the extravasation of inflammatory cells into the skin of infested mice. PMID- 7835924 TI - The effect of dietary lipid manipulation on rat lymphocyte subsets and proliferation. AB - Polyunsaturated fatty acids (PUFA) have been shown to suppress immune cell functions in vitro. Dietary studies investigating the effects of PUFA-containing oils on lymphocyte functions have yielded contradictory findings: such studies are difficult to compare as there are many variations in protocols. The present study investigated the effects of diets containing oils rich in saturated fatty acids, monounsaturated fatty acids, n-6 PUFA or n-3 PUFA on rat lymphocyte proliferation and on receptor and surface marker expression. Rats were fed for 10 weeks on a low-fat (LF) diet (approximately 2% fat by weight) or on one of five high-fat diets, which contained 20% (by weight) hydrogenated coconut oil (HCO), olive oil (OO), safflower oil (SO), evening primrose oil (EPO) or menhaden (fish) oil (MO). Compared with feeding the LF diet, all of the high-fat diets suppressed the proliferation of lymphocytes from the spleen: although there was no significant effect of diet on the proliferation of lymphocytes from the thymus, there was a trend towards decreased proliferation with high-fat feeding. Feeding the OO, EPO or MO diets significantly suppressed proliferation of mesenteric lymph node lymphocytes compared with feeding the LF, HCO or SO diets. Dietary lipid manipulation had no effect on the proportion of T cells, B cells or monocytes/macrophages in the spleen, thymus or lymph nodes. Dietary lipid manipulation also had no significant effect on the proportions of CD4+ or CD8+ lymphocytes in spleen, thymus or lymph nodes, either in freshly prepared cells or in cells cultured in the presence of mitogen. There were no significant effects of dietary lipid manipulation on the expression of IL-2 receptors or transferrin receptors by concanavalin A (Con A)-stimulated lymphocytes. However, there was a trend towards a decrease in transferrin receptor expression by Con A-stimulated lymphocytes from the thymus and lymph nodes of the MO-fed rats and towards a decrease in the expression of IL-2 receptors by lymphocytes from the spleens and thymi of the MO-fed rats. These observations provide evidence that some dietary oils, particularly OO, EPO and MO, possess immunosuppressive properties and so may be useful in the therapy of diseases involving inappropriate lymphocyte activation. PMID- 7835925 TI - Phenotypic and functional heterogeneity of murine intestinal intraepithelial lymphocytes defined by cell density: implications for route of differentiation and responsiveness to proliferation induction. AB - The phenotype and function of murine intestinal intraepithelial lymphocytes (IEL) was studied in a Percoll-fractionated preparation that consisted of low-density cells which migrated to the 40-50% Percoll interface (IEL-40), medium-density cells which migrated to the 50-55% interface (IEL-50), and high-density cells which migrated to the 55-70% interface (IEL-55). IEL-40 and IEL-50 cells, the subsets phenotypically most similar to mature IEL, consisted of CD3+ T cells that included CD4- CD8+ and CD4+ CD8+ cells; CD4+ CD8- cells were present only in the IEL-50 fraction. T-cell receptor (TcR)alpha beta and TcR gamma delta cells were present in both IEL-40 and IEL-50 fractions. In contrast, most IEL-55 were CD3-, heat-stable antigen (HSA)+ cells that were not B cells; some IEL-55 cells were CD3lo HSA- or CD3lo HSA+ suggesting that IEL-55 are immature T cells. TcR alpha beta but not TcR gamma delta was expressed in the IEL-55 fraction. All three IEL fractions consisted of both CD8 alpha alpha and CD8 alpha beta cells. There was considerable functional heterogeneity between the three IEL fractions such that CD3-induced proliferation was greatest for IEL-50 cells and least for IEL-55 cells; that activity correlated with the proportion of Thy-1+ cells within the fractions. Both IEL-40 and IEL-50 fractions contained activated cytotoxic T lymphocytes (CTL) that were 8-16-fold more lytic than IEL-55 cells. That IEL-55 cells may be precursors of some IEL-40 and IEL-50 cells was demonstrated by a shift in cell density and by an increase in proportions of cells expressing markers of IEL-40 and IEL-50 cells following in vitro stimulation via CD3. The relevance of these findings to differences in functional activities reported for murine IEL is discussed. PMID- 7835926 TI - Locomotor phenotypes of unstimulated CD45RAhigh and CD45ROhigh CD4+ and CD8+ lymphocytes in three-dimensional collagen lattices. AB - The spontaneous locomotion of immunomagnetically isolated resting CD4+ and CD8+ lymphocytes in three-dimensional collagen gels was recorded by time-lapse videomicroscopy. Two-dimensional projections of the paths of randomly selected individual cells were digitized, plotted and quantitatively analysed. Among five different donors 46 +/- 10% of CD4+ and CD8+ lymphocytes (n = 180) showed initial spontaneous locomotion (individual speed 5-25 microns/min; mean speed CD4+ 5.2 +/ 3.6 microns, CD8+ 3.23 +/- 2.72 microns). Active CD4+ cells were constantly migrating for more than 4 hr, whereas CD8+ lymphocytes significantly slowed down after 60-90 min in the collagen gel (P < 0.003). Quantitative analysis of the paths indicated at least three migratory phenotypes: (1) spontaneously locomoting cells exhibiting high speed and low frequency of stopping; (2) a major non-motile fraction without significant displacement; and (3) a subpopulation within CD4+ and CD8+ cells with intermediate activity of speed and stopping. Further subtype analysis of immunomagnetically isolated CD45RAhigh/ROlow or CD45RAlow/ROhigh lymphocytes showed that more than 90% of CD4+ CD45RAhigh/ROlow cells were actively locomoting. In contrast, only 20% of the CD4+ CD45ROhigh/RAlow phenotype showed spontaneous motility to a limited degree. The data indicate that resting CD4+ and CD8+ lymphocytes comprise further locomotory subpopulation related to the expression of different CD45 isoforms. PMID- 7835927 TI - Intranasal administration of retinal antigens suppresses retinal antigen-induced experimental autoimmune uveoretinitis. AB - Bovine retinal extract (RE) is a heterologous mixture of highly uveitogenic proteins including S-Antigen (S-Ag), interphotoreceptor retinol binding protein (IRBP) and rhodopsin, and is a potent inducer of experimental autoimmune uveoretinitis (EAU). Intranasal inoculation of Lewis rats with RE performed daily for 10 days prior to immunization with RE suppresses both the severity and the incidence of the clinical response and histopathological changes in EAU. Significant suppression of the disease in treated animals could be achieved with a total (cumulative) intranasal inoculum of 42 micrograms of antigen. Animals which were treated with extract exhibited a normal total antibody response to S Ag, IRBP and retinal extract when compared with controls [phosphate-buffered saline (PBS) treated] animals. The antibody response in tolerized animals was predominantly anti-S-Ag IgG2a with suppression of anti-S-Ag IgM response. Treated animals had a significantly suppressed delayed-type hypersensitivity (DTH) response to retinal extract but normal response to purified protein derivative (PPD) compared to control animals. Adoptive transfer of splenocytes from treated animals also demonstrated some protection against RE-induced EAU. These results demonstrate that tolerance induction impairs the onset and severity of EAU by inhibiting the DTH response to heterologous mixture of retinal antigens. PMID- 7835928 TI - Effect of proteolytic enzymes on neutrophil Fc gamma RII activity. AB - Previous studies have demonstrated that the treatment of neutrophils with proteolytic enzymes markedly reduces the expression of receptor III for the Fc portion of IgG (Fc gamma RIII), but it does not affect the number of Fc gamma RII on the cell surface. In the present study, we analysed the effect of proteolytic enzymes on functional responses of neutrophils induced by immune complexes (IC). Our results showed that treatment with pronase or chymotrypsin markedly increased the binding of IgG-coated erythrocytes (IgG-E) to neutrophils, as well as their capability to display IgG-mediated functions such as antibody-dependent cellular cytotoxicity (ADCC) and chemiluminescence (CL) induced by IgG-E, responses that have been shown to be completely dependent on Fc gamma RII. A similar enhancing effect was observed, in all cases, after neutrophil treatment with neuroaminidase. We also studied the effect of proteolysis on neutrophil activation induced by other types of IC. It was found that pronase and chymotrypsin significantly enhanced CL responses induced by soluble IC (sIC) but did not modify the responses induced by either precipitating IC (pIC) or soluble IC prepared with cationized antibodies (catIC). On the other hand, neuroaminidase significantly enhanced CL induced by either sIC, pIC or catIC. Taken together, our data suggest that the activity of Fc gamma RII can be up-regulated by proteolysis. However, this effect appears to be strongly dependent on the characteristics of the IC employed as stimulus. PMID- 7835929 TI - Monoclonal antibodies to leucosialin (CD43) induce homotypic aggregation of the human mast cell line HMC-1: characterization of leucosialin on HMC-1 cells. AB - CD43 (leucosialin, sialophorin) is the major sialoprotein of nearly all circulating leucocytes and has important biological activities in cellular differentiation and activation. Recently, the expression of CD43 has also been demonstrated on mast cells and basophils by flow cytometry. In order to further characterize mast cell/basophil leucosialin we have investigated CD43 on the human mast cell line HMC-1, the human basophilic precursor cell line KU-812, and the human promonocytic cell line U-937. The apparent molecular weights (MW) were 123,000 (HMC-1 and KU-812) and 144,000 (U-937) by Western blot analysis. Expression of CD43 on HMC-1 was down-regulated after stimulation with phorbol myristate acetate (PMA). Three monoclonal antibodies (mAb) specific for human CD43 induced homotypic mast cell line (HMC-1) aggregation in a semi-quantitative assay, a phenomenon that has not been described before with mast cells. Monoclonal antibodies specific for seven other surface antigens and an irrelevant mAb of the same isotype had no effect. The level of aggregation was dependent on anti-CD43 mAb concentration, time and temperature. Anti-leucosialin-induced aggregation of HMC-1 cells was completely inhibited by mAb against CD11a (LFA-1) and CD18 (beta 2-chain). Monoclonal antibody to CD54 (ICAM-1) partially inhibited anti-CD43-induced homotypic aggregation, while anti-CD11b (CR3), anti-CD11c (p 150, 95) and a control mAb had no inhibitory effect. We conclude that mast cell line CD43 antigen expression is differentially regulated during cell activation, and speculate that anti-CD43-induced homotypic aggregation of HMC-1 cells is closely associated with modulation of beta 2-integrins. PMID- 7835930 TI - Characterization of liver lymphomyeloid cells in mice infected with Plasmodium yoelii sporozoites. AB - We have isolated, characterized and quantified the immunocompetent cells present in the extravascular hepatic compartment at various stages after Plasmodium yoelii malaria infection with sporozoites. Cytological analyses revealed a predominantly lymphoid population. In mice with a primary infection, the predominant cells were CD4+, CD8+ and B lymphocytes. In fully protected mice, CD3+ CD4- CD8- and polymorphonuclear cells, particularly eosinophils, were most common. The significance of changes in subpopulations is discussed in relation to antigen presentation and host-protective mechanisms. PMID- 7835931 TI - Antibody-mediated protection against Brucella abortus in BALB/c mice at successive periods after infection: variation between virulent strain 2308 and attenuated vaccine strain 19. AB - In BALB/c mice antibodies specific for the O polysaccharide (OPS) as well as T lymphocytes mediate protective immunity to Brucella abortus. We performed quantitative analyses of isotypes of OPS antibodies generated during primary infections, and tested the protective qualities of antisera at successive stages of infection against B. abortus strain 2308, representative of the wild type, and attenuated vaccine strain 19. IgM antibodies predominated during the first 3-4 weeks of infection. IgG3 antibodies increased slowly for the first 3 weeks but then rose rapidly and persisted at high levels (> 300 micrograms/ml). IgG1, IgG2a and IgG2b antibodies had increased slightly by week 4 and then remained at low to moderate levels (< 70 micrograms/ml). Week 2 serum pools (IgM high, IgG3 low or undetectable) transferred substantial protection against 2308 (> or = 1 log unit) which increased relatively little (to 1.2-1.5 log units) with later sera that were high in IgG antibodies. In contrast, week 2 sera conferred low levels of protection against 19 (< 0.6 log units), but protection was dramatically increased (to > or = 2.3 log units) with sera obtained 1 week later that had slightly increased IgG antibodies. Monoclonal IgM antibodies also provided better protection against 2308 than 19, while monoclonal IgG3 antibodies protected much better against 19. Strain 19 opsonized with antibodies taken at any stage of infection was killed within normal macrophages, whereas comparably opsonized 2308 underwent intracellular replication. Phagocytosis of 2308 was better than of 19 when brucellae were opsonized with either polyclonal IgM or IgG3 antibodies, and the difference between strains was more extreme following IgM opsonization. The data suggest an explanation for differences in the growth curves of 2308 and 19 in spleens of BALB/c mice. Higher numbers achieved by 19 at week 2 could result from extracellular replication owing to ineffectual opsonization by IgM antibodies, while the precipitous decline of 19 beginning at week 3 could be caused by the increase in more effective IgG3 opsonins that facilitate its rapid intracellular destruction. PMID- 7835932 TI - Antigen-specific human immunoglobulin production in SCID mice transplanted with human peripheral lymphocytes is dependent on CD4+ CD45RO+ T cells. AB - Severe combined immunodeficient (SCID) mice, lacking mature T and B cells and virtually devoid of endogenous serum immunoglobulins, spontaneously produce large amounts of human immunoglobulin after transplantation with human peripheral blood lymphocytes (PBL). Moreover, after immunization with antigen an active immune response resulting in a production of specific antibodies can be induced. Here we report that human T cells must be co-transplanted with B cells into the SCID mice for immunoglobulin production to occur. Resting human B cells could be activated to immunoglobulin production in the absence of human monocytes and a specific antibody response to tetanus toxoid (TT) could be induced, suggesting that the human B cells could present antigen to T cells in the SCID environment. Production of human immunoglobulins, as well as specific antibodies, was obtained only if CD4+ T cells of the memory phenotype, i.e. expressing CD45RO, were present. No human immunoglobulin, either of IgM or of IgG isotype, was found in SCID sera if mice were co-transplanted with human B cells and CD45RA expressing CD4+ T cells. However, FACS analysis revealed that the transplanted CD45RA+ cells became activated and differentiated towards CD45RO+ cells within 1-2 weeks. These cells also gained the lymphokine gene expression pattern associated with CD45RO+ cells, as demonstrated by polymerase chain reaction (PCR) analysis, and could support immunoglobulin production in SCID mice transplanted with fresh B cells. In fact, after differentiation of CD4+ CD45RA+ T cells towards expression of CD45RO, either in vivo in the SCID mouse or in vitro, these cells could interact with and activate human B cells to immunoglobulin production. Furthermore, in vitro activated and differentiated CD4+ CD45RA+ T cells from vaccinated donors were also able to support production of TT-specific antibodies provided the antigen was administered. PMID- 7835933 TI - Rapid restoration of B-cell function in XID mice by intravenous transfer of peritoneal cavity B cells. AB - The primary method employed to correct immune deficiency is bone marrow transfer. Depending upon the exact nature of the immune deficiency, however, alternative cell sources may be used to provide a more rapid reconstitution of immune function. In this report, peritoneal cavity (PerC) B cells are shown to be effective in the rapid emendation of the B-cell defect exhibited by XID mice. Restoration of normal numbers of splenic IgM antibody-secreting cells (ASC) and serum IgM levels were observed 4 and 7 days, respectively, after the i.v. transfer of 3 x 10(6) PerC. This regimen also restored responsiveness to thymus independent type 2 (TI-2) antigens in XID recipients. Transfer of 30 x 10(6) spleen (SP) cells restored these functions in XID recipients but at a considerably slower rate. The data indicate that introducing a small number of PerC B cells into systemic circulation results in the rapid restoration of serum IgM levels in unirradiated XID mice. PMID- 7835934 TI - CD4+ T cells are essential in overcoming experimental murine measles encephalitis. AB - Clinical observations and experimental animal models have stressed the importance of the cellular immune response in the recovery from measles virus infection. However, the relative contribution of different T-cell subsets to viral elimination is controversial. The aim of the present study was to define the components of the immune system which contribute to the control of measles virus infection. For this purpose the effect of in vivo depletion of CD4+ and/or CD8+ T lymphocytes in the murine model of experimental acute measles encephalitis was monitored with respect to disease manifestation, survival, neuropathological changes, virus elimination from brain, and antiviral antibody titre. In measles virus-resistant BALB/c mice removal of the CD8+ T-cell subset did not interfere with the clearance of virus from the brain. In contrast, depletion of CD4+ T cells rendered BALB/c mice susceptible to infection. Also, in measles virus susceptible C3H mice CD4+ T cells played a role in recovery from measles infection, but seemed not to be as effective as CD4+ T cells from resistant BALB/c mice. The data indicate that CD4+ T cells are essential for protection against measles virus-infection of the central nervous system. PMID- 7835935 TI - Inhibition of skin xenograft rejection by depleting T-cell receptor alpha beta bearing cells without T-cell receptor gamma delta-bearing cells or natural killer cells by monoclonal antibody. AB - We compared the effects of in vivo administration of the anti-T-cell receptor (TCR) alpha beta monoclonal antibody (mAb) (H57-597) to those of the anti-CD3 mAb (145-2C11), with or without anti-NK1.1 mAb (PK136), on xenogeneic skin graft survival in mice. In anti-TCR alpha beta mAb-treated B6 mice, F344 rat skin grafts survived for about 54 days, whereas in anti-CD3 mAb-treated B6 mice with or without anti-NK1.1 mAb treatment grafts survived about 25 days. In anti-TCR alpha beta mAb-treated B6 mice, TCR alpha beta-bearing T-lymphocyte function was completely abrogated, although TCR gamma delta-bearing T-lymphocyte function was still intact on day 9. In the anti-CD3 mAb-treated mice, the functions of both types of T lymphocytes were completely abrogated. On day 32, when most of the skin xenografts had been rejected in the anti-CD3 mAb-treated mice, the functions of both T lymphocytes had recovered considerably, and could actually respond to F344 antigens. In contrast, the function of TCR alpha beta-bearing cells had only partially recovered in the anti-TCR alpha beta mAb-treated mice. Finally, natural killer (NK) activity in the anti-TCR alpha beta mAb-treated mice was intact on day 32, when rat skin grafts still survived. In contrast, NK activity in the anti CD3 mAb plus anti-NK1.1 mAb-treated mice did not recover on day 32, when skin xenografts had already been rejected. These results suggest that TCR gamma delta bearing T cells and NK cells by themselves, at least in the absence of TCR alpha beta-bearing T cells, do not mediate xenogeneic skin graft rejection in mouse/rat combinations. PMID- 7835936 TI - Expansion of intermediate T-cell receptor cells in mice with autoimmune-like graft-versus-host disease. AB - Chronic graft-versus-host disease (GVHD) following bone marrow transplantation often gives rise to a severe autoimmune-like state. To investigate the immunopathogenesis of this diseased state, mice receiving a transplant of lymphocytes with major histocompatibility complex (MHC) class II disparity (the simplest model of chronic GVHD) were examined. (B10.Thy-1.1 x B6.C-H-2bm12) F1 mice were injected with parental B10.Thy-1.1 CD4+ splenic T cells. These mice showed intensive lymphocyte infiltration of the target organs, including the liver, salivary glands and pancreas. Indeed, the cell numbers yielded from the spleen and liver were increased, and polyclonal B-cell activation was induced by 14 days after injection. More strikingly, more than 80% of such expanding lymphocytes in the target organs became T cells with T-cell receptors (TCR) of intermediate intensity (i.e. intermediate TCR cells) that carried the properties of extrathymic origin. Despite the homogeneous expansion of intermediate TCR cells in GVHD mice, these T cells were polyclonal in terms of V beta usage. These results, in conjunction with the data using the thymectomized mice as recipients, suggested that extrathymic, intermediate TCR cells possibly of recipient origin might be intimately related to the pathogenesis of the autoimmune-like state resulting from chronic GVHD. PMID- 7835937 TI - Antibodies to human and non-human primate cellular and culture medium components in macaques vaccinated with the simian immunodeficiency virus. AB - Inactivated simian immunodeficiency virus (SIV) grown in a human T-cell line induces protection from infection by the virus in macaques. However, observations that immunization with uninfected human T cells or with SIV-1 prepared in human T cells can also induce protection, has raised the possibility that protective antigens could be of human cellular origin. Sera from animals immunized with fixed infected and uninfected human T cells, as well as from animals immunized with partially purified cell-free SIV have been examined for their ability to bind to human and macaque peripheral blood mononuclear cells (PBMC) and to components present in fetal calf serum (FCS) in which the cells were grown. Analysis by flow cytometry suggests that antibodies to human cell surface antigens can be elicited with both inactivated SIV grown in human T cells and by uninfected T cells. There was a significant association between the presence of anti-cell antibodies and protection from infection. However, anti-cell surface antibodies were not detected with macaque mononuclear cells by flow cytometry or by immunoprecipitation, unless these cells were first treated with FCS or activated by a mitogen. Immunoprecipitation of resting human PBMC with sera from immunized animals suggests the presence of antibodies to class I heavy and light chains [beta 2-microglobulin (beta 2 m)] and to bovine beta 2m, which may originate in FCS used to grow the cell line. Antibodies to CD4 were also found in sera from animals immunized with SIV grown in human T cells. We suggest that human cellular components augmented by FCS elicit anti-class I heavy chain, beta 2m, CD4 and FCS antibodies which may be responsible for protection against SIV infection in macaques. PMID- 7835938 TI - In vivo induction of IgG anti-DNA antibody by autoreactive mixed haplotype A beta z/A alpha d MHC class II molecule-specific CD4+ T-cell clones. AB - We characterized autoreactive T-cell clones derived from (NZB x NZW)F1 (B/WF1) mice. These autoreactive T-cell clones are shown to be CD4+ by immunofluorescence staining and to belong to Th2 type by cytokine release assay. Specificity analysis revealed the existence of mixed haplotype A beta z/A alpha d major histocompatibility complex (MHC) class II molecule-specific T-cell clones as well as A beta z/A alpha z- or A beta d/A alpha d-specific T-cell clones. Some but not all of the mixed haplotype A beta z/A alpha d-specific autoreactive T-cell clones showed strong activity to induce IgG anti-DNA antibody production upon transfer to young (4-month-old) B/WF1 mice, indicating that T cells with these specificities might be involved in B/WF1 autoimmunity. PMID- 7835939 TI - Mycobacteria precipitate an SLE-like syndrome in diabetes-prone NOD mice. AB - Non-obese diabetic (NOD) mice spontaneously develop organ-specific autoimmunity and are widely used as a model for diabetes. Aged NOD mice also exhibit some features of non-organ-specific autoimmune rheumatic disease such as anti-nuclear antibodies and late-onset haemolytic anaemia. Here, we report that a single dose of 2.6 x 10(7) heat-killed bacillus Calmette-Guerin (BCG) i.v. in 8-week-old NOD mice prevented diabetes but precipitated a syndrome similar to systemic lupus erythematosus (SLE). Treated mice developed haemolytic anaemia, anti-DNA and anti Sm anti-nuclear autoantibodies and an increased severity of sialadenitis. Perivascular lymphocytic infiltration in the kidneys and glomerular immune complex deposition were also found. The action of BCG appeared to be mediated by an adjuvant-like activity as treated mice showed a substantial increase in reticuloendothelial cell function and enhanced antigen presentation capacity. PMID- 7835940 TI - Lipoprotein lipase expression in natural killer cells and its role in their cytotoxic activity. AB - Lipoprotein lipase (LPL) is the key enzyme in the metabolism of triglyceride-rich lipoproteins. The patterns of LPL mRNA expression and secretion of the enzyme have not yet been established in natural killer (NK) cells. We show in the present communication that CD3- CD16+ cells (NK cells) transcribe LPL mRNA, express LPL on the surface and secrete the enzyme. In contrast, there is no LPL expression on the surface of highly purified B and T lymphocytes. Stimulation of NK cells with interleukin-2 (IL-2) reduced the expression of LPL on their surface and augmented the secretion of LPL by the cells. The addition of anti-LPL antibodies to NK cells in culture led to a complete abrogation of cytotoxicity of NK cells against the K562 tumour cell line. Furthermore, IL-2 stimulation of effector cells reversed the anti-LPL antibody-induced inhibition of cytotoxic activity. Overall, these findings suggest that LPL plays a key role in the cytotoxic activity of NK cells. PMID- 7835941 TI - A novel role for MHC class II antigens: evidence implicating a protective effect on tumour cells against cytotoxicity by NK and LAK cells. AB - There are several lines of evidence clearly demonstrating that major histocompatibility complex (MHC) class I antigens are important in protecting haemopoietic tumour cells from natural killer (NK)-mediated cell lysis. In the present studies we examined the role of MHC class II antigens in affording such protection to haemopoietic tumour cell lines. NK and lymphokine-activated killer (LAK) lysis were performed on two human B lymphoma cell lines and their mutants lacking HLA class II expression, i.e. DR, DP and DQ. Raji and T5-1 were compared to their mutants RM3 and 6.1.6, respectively. Significantly more lysis was observed with the mutants compared to the parent cell line. Effectors used included (1) peripheral blood NK effectors, (2) a human NK cell line (NK 3.3), and (3) peripheral blood LAK effectors. The increased lysis with the mutants could not be explained on the basis of (1) increased conjugate formation, (2) increased cell fragility or (3) ineffectual expression of HLA class I and other non-HLA antigens. These findings suggest that HLA class II molecules may have a novel role. They may be relevant not only in antigen presentation but may also protect tumour cells (and possibly normal activated lymphoid cells) against lysis mediated by NK and LAK cells. PMID- 7835942 TI - Influence of mouse genotype and bacterial virulence in the generation of interferon-gamma-producing cells during the early phase of Salmonella typhimurium infection. AB - Interferon-gamma (IFN-gamma) is known to play a major role in resistance to Salmonella typhimurium infection. In this study, the IFN-gamma production in spleens of mice infected with S. typhimurium was analysed at the single cell level using an ELISPOT method. The in vivo IFN-gamma production during the early phase of infection with virulent and avirulent S. typhimurium strains was examined in four mouse strains. Data show that infection with a virulent strain of S. typhimurium caused a much greater enhancement in the frequency of IFN-gamma producing cells in innately resistant (ltyr) mice (CBA and DBA/2) than in susceptible (ltys) mice (C57BL/6 and BALB/c). In contrast, infection with an avirulent strain of S. typhimurium induced a clear increase in the number of IFN gamma-producing cells in susceptible mice which was even greater than in resistant ones. These results indicate that both the host genetic background and bacterial virulence play a critical role in the regulation of IFN-gamma production during the early phase of S. typhimurium infection. PMID- 7835943 TI - The kinetics of cytokine production by draining lymph node cells following primary exposure of mice to chemical allergens. AB - Skin sensitization with chemical allergens is associated with the activation and proliferation of lymphocytes in lymph nodes draining the site of exposure. As lymphocyte activation is regulated by the action of cytokines, we have investigated the nature and kinetics of cytokine production by draining lymph node cells (LNC) from mice, following their primary exposure to chemical allergens. Both interleukin-1 (IL-1) and IL-6 were induced in a biphasic manner following primary exposure of mice to oxazolone or to dicyclohexylmethane-4,4' diisocyanate (HMDI). The initial phase of production occurred when LNC were prepared from mice 8-20 hr following exposure, while the second peak was coincident with the maximal proliferative response at 72 hr. Increased IL-4 production was observed only when LNC were prepared 96 hr following sensitization. Despite vigorous lymphocyte proliferation there was no evidence for IL-2 production by draining LNC. The ordered and transient pattern of cytokine production that occurs during the afferent phase of contact sensitization suggests that sequential cytokine signals may be involved in regulating the characteristics of the response generated within the draining lymph node. PMID- 7835944 TI - Stimulators of tumour necrosis factor production released by damaged erythrocytes. AB - We sought to characterize factors released by sonicated human erythrocytes that stimulate peripheral blood mononuclear cells (PBMC) to release tumour necrosis factor-alpha (TNF). This response is not inhibited by polymyxin B, indicating that contaminating lipopolysaccharide (LPS) is not responsible. When erythrocyte lysates are fractionated by reverse-phase chromatography using a gradient of n propanol on Sep-Pak C18 cartridges, the TNF-inducing activity elutes as a single peak. The erythrocyte-derived TNF-inducing activity is unaffected by digestion with proteases but is destroyed by mild base hydrolysis or digestion by lipases, indicating that compounds containing ester-linked acyl chains may be essential. These properties are similar to those of TNF stimulators that we have previously identified in erythrocytes infected with malaria parasites, except that the TNF inducing activity per cell is about 200 times higher in parasitized erythrocytes than in uninfected erythrocytes. Lipase-digested erythrocyte lysates inhibit the TNF-inducing factors of both normal and malaria-infected erythrocytes, suggesting that lipase digestion creates partial structures which compete with active components for macrophage receptors. Such receptors may recognize a common structure that contains an inositol monophosphate (IMP)-like component, as IMP also inhibits the TNF response to erythrocyte-derived factors and to parasite lysates whereas it does not affect the response to LPS. We conclude that lysed erythrocytes release specific cytokine-inducing factors that may contribute to the fever response to non-infectious tissue injury. PMID- 7835945 TI - Pentoxifylline in vivo down-regulates the release of IL-1 beta, IL-6, IL-8 and tumour necrosis factor-alpha by human peripheral blood mononuclear cells. AB - Pentoxifylline (PTX) is a methylxanthine compound known to inhibit the production of tumour necrosis factor-alpha (TNF-alpha), which is an important inflammatory mediator. There is also recent evidence that PTX may influence other inflammatory cytokines, such as interleukin-1 (IL-1) and IL-6. Due to the therapeutic implications, the present study addressed the in vivo effects of PTX on the release of TNF-alpha, IL-1 beta, IL-6 and IL-8 by human peripheral blood mononuclear cells (PBMC). When PBMC were obtained from healthy volunteers ingesting 5 x 400 mg PTX orally for 2 days, the ability of PBMC cultured for 24 hr to release TNF-alpha was significantly reduced, while secretion of IL-1 beta, IL-6 and IL-8 was not affected. However, when PBMC were obtained from the same individuals 5 days after PTX had been stopped, the release of all four cytokines was significantly suppressed. This effect appeared to be exerted at the transcriptional level, since Northern blot analysis revealed reduced cytokine transcripts. In order to gain more insight into the effect of PTX on cytokine release, PBMC were obtained from normal volunteers, either stimulated with lipopolysaccharide (LPS) or left unstimulated, and subsequently incubated in vitro with PTX for 48 hr. Under these conditions, only TNF-alpha was found to be reduced by PTX, while IL-1 beta and IL-8 were not affected, IL-6 was even enhanced. However, when PBMC were incubated with PTX for 24 hr, PTX removed thereafter by medium change and cells further cultured, the production not only of TNF-alpha but also of IL-1 beta, IL-6 and IL-8 was reduced, demonstrating that PTX exerts diverse (inhibitory) effects on cytokine release by PBMC. PMID- 7835946 TI - The Candida albicans phospholipomannan induces in vitro production of tumour necrosis factor-alpha from human and murine macrophages. AB - We have previously identified a Candida albicans 14,000-18,000 MW antigen reacting with anti-beta-1,2-linked oligomannosides antibodies as being a phospholipomannan (PLM). Because of the structural similarities between the C. albicans PLM and lipophosphoglycans from various microbial pathogens known to be potent tumour necrosis factor-alpha (TNF-alpha) inducers, we investigated the PLM ability to induce TNF-alpha. Incubation of human monocytic cells THP-1 with PLM led to dose-dependent production of TNF-alpha that was significantly increased by prestimulation of the cells with interferon-gamma (IFN-gamma). Production of TNF alpha by macrophages under PLM stimulation was confirmed by using macrophages elicited from the mouse peritoneal cavity. In all investigated conditions, PLM induced TNF-alpha production differed significantly in both kinetics and dose dependence from lipopolysaccharide (LPS) induction used as control. It appears, therefore, that the C. albicans PLM shares functional homologies with microbial lipophosphoglycans identified as pathogenicity factors, although prestimulation of the target cells was required for the PLM-derived opportunistic pathogen to trigger the cytokine network. PMID- 7835947 TI - Dexamethasone up-regulates granulocyte-macrophage colony-stimulating factor receptor expression on human monocytes. AB - Granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL 3) are weak inducers of major histocompatibility complex (MHC) class II expression on purified human blood monocytes. The glucocorticoid dexamethasone synergizes with GM-CSF or IL-3 for the upregulation of HLA-DR, -DP and -DQ antigen mRNA and cell-surface expression by these cells. The purpose of the present study was to address the mechanism of dexamethasone action. We demonstrate that the capacity of dexamethasone to up-regulate GM-CSF-induced MHC class II expression correlates with the capacity to up-regulate GM-CSF receptor, but not the interferon-gamma (IFN-gamma) receptor, in a highly dose-dependent manner on monocytes. Although dexamethasone induces GM-CSF receptor expression, it does not confer responsiveness to IL-5, a cytokine that shares a common chain of its heterodimeric cytokine receptor signalling molecule with IL-3 and GM-CSF. Three other steroid hormones, beta-oestradiol, vitamin D3 and dehydroepiandosterone (DHEA), were also tested for their capacity to up-regulate MHC class II expression. All three mediators failed to enhance MHC class II expression or GM-CSF receptor expression on the surface of human monocytes. These experiments suggest that dexamethasone may act to up-regulate GM-CSF-induced MHC class II antigen expression on monocytes by up-regulating cytokine receptor expression. PMID- 7835948 TI - Role of phagocytic macrophages in induction of contact hypersensitivity and tolerance by hapten applied to normal and ultraviolet B-irradiated skin. AB - Liposomes containing the drug dichloromethylene diphosphonate (Cl2MDP) can eliminate phagocytic cells, such as macrophages, when injected in vivo. In this paper we report that Cl2MDP-containing liposomes have been used experimentally to determine the extent to which cutaneous macrophages participate (1) in the induction of contact hypersensitivity (CH) when hapten is painted on normal murine skin, and (2) in the induction of CH or tolerance when hapten is painted on murine skin that has been exposed to ultraviolet B (UVB) radiation. Intradermal (i.d.) injections of Cl2MDP-containing liposomes were found to have no deleterious effects on CH induction via normal skin, whether the amount of hapten (dinitrofluorobenzene) applied to the cutaneous surface was optimal or excessive. Moreover, Cl2MDP-containing liposomes did not deplete the epidermis of Langerhans' cells. However, similar i.d. injections of Cl2MDP-containing liposomes did prevent the induction of CH when hapten was painted on UVB irradiated skin of BALB/c mice, a strain that develops CH when hapten is applied to UVB-exposed skin. These findings indicate that the antigen-presenting cell (APC) function found in skin of UVB-resistant mice following exposure to UVB radiation can be attributed to macrophages. This explains why these mice develop and display CH after UVB radiation. By contrast, i.d. injections of Cl2MDP containing liposomes failed to prevent the induction of the tolerance when hapten was applied to the surface of UVB-exposed skin of UVB-susceptible mice, such as C57BL/6. Since the dermis of UVB-exposed skin of these mice is known to contain a novel population of cells that can provide a tolerance-conferring signal, the current findings rule out macrophages as the responsible cell type. PMID- 7835949 TI - Effect of injected yeast glucan on the activity of macrophages in Atlantic salmon, Salmo salar L., as evaluated by in vitro hydrogen peroxide production and phagocytic capacity. AB - A prepared polysaccharide from the cell wall of yeast, M-Glucan, has previously been demonstrated to have immunostimulatory effects in salmonids as observed by enhanced in vivo non-specific disease resistance in Atlantic salmon, Salmo salar L., and increased in vitro bactericidal activity of rainbow trout, Oncorhynchus mykiss (Walbaum), macrophages. In the present study M-Glucan was injected intraperitoneally into Atlantic salmon and the effect on core components in the non-specific part of the immune system was observed. The hydrogen peroxide (H2O2) production of isolated head kidney macrophages from glucan-injected fish was measured 3 and 6 weeks after M-Glucan treatment and was increased at both time points upon phorbol myristate acetate-(PMA) triggering. Without PMA triggering the difference was only significant 3 weeks after glucan injection when compared to a control group injected with saline. In a phagocytic assay with macrophages and Vibrio salmonicida the initial uptake of bacteria was elevated at both 3 and 6 weeks after glucan treatment. There was no significant difference when uptake of another fish pathogenic bacteria, Renibacterium salmoninarum, was studied. Treatment of Atlantic salmon with M-Glucan also resulted in enhanced serum lysozyme activity in week 3 of the experimental period. The results indicate that M-Glucan elevates the activity of the non-specific part of the immune system and the use of M-Glucan as an immunostimulant is discussed. PMID- 7835950 TI - Differential function of dendritic cells isolated from blood and lymph nodes. AB - Dendritic cells (DC) isolated from the lymph nodes or spleens of mice and pulsed with contact sensitizers or protein antigens stimulate primary proliferative responses by syngeneic T cells and responses to alloantigens in the mixed leucocyte reaction (MLR). Using enriched human peripheral blood DC, we attempted to stimulate primary immune responses to contact sensitizers by autologous lymphocytes in vitro. No significant proliferation above background levels or CD69 expression (an early activation antigen on lymphocytes) was detected despite using a wide range of donors, chemicals, antigens and cell concentrations. Culture of DC for up to 5 days in vitro in the presence of phytohaemagglutinin (PHA)-conditioned culture supernatants, or recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) also failed to induce primary proliferative responses to contact sensitizers. Comparisons were made between blood and lymph node DC from mice to explore whether the lack of stimulation was the result of differences between mouse and human DC or between DC isolated from different tissues. DC from lymph nodes stimulated primary responses to contact sensitizers in both blood and lymph node lymphocytes whereas blood DC did not stimulate responses. Both lymph node and blood DC stimulated an allogeneic MLR, although blood DC were less efficient than those from lymph node. The data show that DC from different tissues exhibit variable functional activity. DC from blood and lymph nodes were examined to determine whether surface antigen expression is related to functional activity. Murine blood DC expressed similar levels of LFA 1, LECAM-1 and CD44 compared with lymph node DC but lower levels of MHC class II, B7 and ICAM-1. These results may therefore have important implications for antigen processing and presentation in cells from different tissue compartments. PMID- 7835951 TI - Neutrophils as effector cells of T-cell-mediated, acquired immunity in murine listeriosis. AB - The control of the infections caused by Listeria monocytogenes, considered an example of an intracellular parasite, is thought to involve co-operation between antigen-specific T cells and activated macrophages. Here we investigated the participation of polymorphonuclear leucocytes in the mechanisms of resistance during the immune phase of the antimicrobial response to L. monocytogenes infection. We found that BALB/c mice were unable to express T-cell-mediated (acquired) immunity to this pathogen in the absence of granulocytes. We propose that neutrophils should be included in the concept of cell-mediated immunity and that their antimicrobial role is not exclusively expressed during the early phases of a primary infection. PMID- 7835952 TI - Interleukin-5 mRNA levels in blood and bone marrow mononuclear cells from patients with the idiopathic hypereosinophilic syndrome. AB - High blood eosinophil counts in humans are usually due to parasitic infections, allergic processes or malignant diseases. Interleukin-5 (IL-5) is thought to be the principal eosinopoietic stimulus in most of these patients. As the causes of persistent eosinophilia in patients with the idiopathic hypereosinophilic syndrome (HES) are (by definition) unknown, a semi-quantitative assay for IL-5 mRNA in eosinophils and mononuclear cells was carried out using samples from 11 patients with HES. In three patients, unstimulated peripheral blood mononuclear cells (PBMC) and bone marrow mononuclear cells (BMMC) had markedly raised levels of IL-5 mRNA. In four of five patients studied, phorbol myristate acetate (PMA) stimulation of PBMC induced them to produce more IL-5 mRNA than four healthy subjects. In five patients, bone marrow IL-5 mRNA levels were related to blood eosinophil counts. Blood eosinophils from all six patients tested, and bone marrow granulocytes from four patients had undetectable levels of IL-5 mRNA. It was concluded that HES can be separated into two groups. One has high levels of IL-5 mRNA and/or an enhanced IL-5 mRNA response to stimulation. They may well respond to treatments which inhibit the effects of this cytokine on eosinophil progenitor cells. The second group appears to have a disease which is IL-5 independent. PMID- 7835953 TI - Expression of lacto-N-fucopentaose III (CD15)- and sialyl-Lewis X-bearing molecules and their functional properties in eosinophils from patients with the idiopathic hypereosinophilic syndrome. AB - As the carbohydrate lacto-N-fucopentaose III (CD15 antigen or X-determinant) and its sialylated derivative sialyl-Lewis X are involved in the adhesion of cells rolling along the surface of endothelial cells, experiments were done to study the presence of these molecules on human eosinophils from patients with the idiopathic hypereosinophilic syndrome. Normal-density eosinophils from some patients showed higher levels of expression for lacto-N-fucopentaose III than light-density eosinophils. In contrast, sialyl-Lewis X was highly expressed by light-density eosinophils. Activation of normal-density eosinophils with calcium ionophore A23187 resulted in increased expression of these molecules for a short time. Monoclonal antibodies to these carbohydrates stimulated eosinophils to secrete eosinophil cationic protein, but not eosinophil peroxidase, and acted as costimulatory signals for C3b-induced degranulation of eosinophil cationic protein. It was suggested that CD15 and sialyl-Lewis X might contribute to eosinophil-mediated tissue injury in patients with the idiopathic hypereosinophilic syndrome. PMID- 7835954 TI - The effect of bile acids and piroxicam on MHC antigen expression in rat colonocytes during colon cancer development. AB - The effect of bile acids and piroxicam on the expression of major histocompatibility complex (MHC) antigens in colonocytes was evaluated in rats treated with the colonic carcinogen azoxymethane (AOM). Male Fischer-344 rats were fed a basal diet (AIN-76) supplemented with 0.4% cholic acid, 0.4% ursodeoxycholic acid, 0.2% ursodeoxycholic acid plus 0.2% cholic acid, or 75 p.p.m. piroxicam. Rats were injected subcutaneously once a week for 2 weeks with AOM (15 mg/kg body weight/week) or vehicle, after being fed their respective diets for two weeks. The rats were killed at 16 weeks, while parallel identical groups of rats were killed at 28 weeks, and colon tumours were counted. None of the rats treated with AOM-vehicle developed tumours at 28 weeks, while in the AOM treated rats the frequency of colonic tumours was as follows: AOM alone 50%, cholic acid 74%, ursodeoxycholic acid 17%, piroxicam 28%, ursodeoxycholic plus cholic acid 46%. The expression of RT1A, RT1B and RT1D was determined in isolated colonocytes by immune fluocytometry. Normal rat colonocytes express all three MHC antigens strongly. Neither the bile acids nor piroxicam affected MHC antigen expression in AOM-vehicle-treated rats. AOM did not effect MHC antigen expression compared to normal controls. Cholic acid had no significant effect on the expression of MHC antigens in AOM-treated rats. Ursodeoxycholic acid alone or in combination with cholic acid increased the expression of RT1A compared to normal controls, of RT1B compared to AOM-treated rats, and of RT1D compared to controls or AOM-treated rats. Piroxicam increased the expression of all three antigens compared to either control or AOM-treated rats. These findings indicate that (1) ursodeoxycholic acid and piroxicam up-regulate colonic MHC antigen expression in the AOM model of colonic carcinogenesis; (2) the colon of rats exposed to AOM responds differently than the normal colon with respect to MHC regulation; and (3) the protective effect of ursodeoxycholic acid and piroxicam on colon tumour formation seems to be paralleled by an increase in MHC antigen expression. PMID- 7835955 TI - IL-10 enhances expression of the IL-2 receptor alpha chain on T cells. AB - Interleukin-10 (IL-10) has various immunomodulatory actions depending on the target cell type. Some of these effects have been shown to be owing to its ability to down-regulate surface expression of markers, for example HLA-DR on macrophages and CD25 (IL-2 receptor alpha chain) on B cells. In this report we show that preincubation of IL-10 for 24 hr up-regulates expression of the activation marker CD25, but not HLA-DR on cloned T cells of various phenotypes such as CD4+, CD8+, CD4- CD8- alpha beta and gamma delta T-cell receptor (TCR) expressing cells. This up-regulation of CD25 was accompanied by an increase in the T cells IL-2-dependent proliferative response in 63% of the CD4+ clones and 100% of the CD8+, CD4-, CD8- alpha beta and gamma delta TCR+ clones analysed. IL 10 was also shown to be at least partly responsible for the up-regulation of CD25 on mitogen-activated peripheral blood mononuclear cells, suggesting that IL-10 has this CD25 modulatory effect within a more physiological environment. Our data suggest that IL-10 can have a multitude of effects on human T cells, and should not be considered exclusively as an immunoinhibitory cytokine. PMID- 7835956 TI - Superantigen-induced anergy of V beta 8+ CD4+ T cells induces functional but non proliferative T cells in vivo. AB - The response profile of staphylococcal enterotoxin B (SEB)-primed murine V beta 8+ CD4+ and V beta 8+ CD8+ T cells was analysed upon rechallenge in vitro. While in vitro responses to secondary stimulation with SEB were reduced to background levels, the in vivo reactivity after rechallenge with SEB was retained, in that SEB-primed mice succumbed to lethal T-cell shock, lymphokines [interleukin-1 (IL 1), IL-2, Il-4, IL-6, IL-10, interferon-gamma (IFN-gamma), tumour necrosis factor alpha (TNF-alpha)], and lymphokine-specific mRNA accumulation could be detected in V beta 8+ CD4+ and V beta 8+ CD8+ T cells. However, V beta 8+ CD4+ T cells failed to enter the cell cycle. While the phenotype of V beta 8+ CD8+ T cells was indistinguishable from that of their counterparts from naive mice, V beta 8+ CD4+ T cells exhibited in vivo an unusual phenotype as non-proliferative but functional T cells. We conclude that in vitro-defined anergy does not disclose the functional abilities of ligand-reactive V beta 8+ T cells in vivo, and that priming with superantigen (SAg) induces in vivo a differentiation of SEB-reactive V beta 8+ CD4+ T cells into a non-proliferative but functional phenotype. PMID- 7835957 TI - Protection against tuberculosis by passive transfer with T-cell clones recognizing mycobacterial heat-shock protein 65. AB - We have previously shown that mice vaccinated by injection with J774 macrophage like tumour cells that expressed Mycobacterium leprae heat-shock protein (hsp) 65 as a transgene had acquired a remarkably high degree of protection against subsequent challenge with virulent M. tuberculosis. We show here that antigen specific T cells cloned from spleens of such vaccinated animals can transfer a high level of protection to non-vaccinated recipients. The most efficient cells were of T-cell receptor (TCR) alpha beta+ and CD4- CD8+ type and specifically lysed mycobacteria-infected macrophages. These findings are consistent with the importance for protective immunity of engaging the endogenous antigen-presenting pathway to bias the immune response towards a cytolytic action against a mycobacterial antigen that is expressed at the surface of infected macrophages. TCR gamma delta+ and TCR alpha beta+ cells interacted synergistically. PMID- 7835958 TI - gamma delta T cells play a crucial role in the expression of 65,000 MW heat-shock protein in mice immunized with Toxoplasma antigen. AB - Toxoplasma gondii is an obligate intracellular protozoan parasite and cellular immunity plays a crucial role in protection against infection with this pathogen. When mice are immunized with Toxoplasma homogenate, they readily acquire resistance against infection with a lethal dose of a low virulence Beverley strain of T. gondii. We have reported previously that expression of 65,000 MW heat-shock protein (hsp 65) in host macrophages closely correlates with protective potentials of hosts, while this protein is not expressed in Toxoplasma themselves. In this study, we examined the mechanism of expression of hsp 65 in mice immunized with Toxoplasma homogenate. Heat-shock protein was detected in peritoneal macrophages of BALB/c mice immunized 7 days previously by electroblot assay with a specific monoclonal antibody (mAb) for microbial hsp 65. Furthermore, an immunogold ultracytochemistry assay demonstrated that this protein was expressed on the cell surface of peritoneal macrophages in immune mice. This expression was not induced in those of immune athymic nude mice and SCID mice. Treatment of BALB/c mice with anti-Thy-1.2 mAb 1 day before immunization led to an almost complete loss of the expression of hsp 65. To determine the subsets of T cells responsible for induction of this protein, mice were depleted of gamma delta T cells, alpha beta T cells, CD4+ T cells or CD8+ T cells by treating with corresponding antibodies before immunization. From these experiments, gamma delta T cells were shown to be essential for the expression of hsp 65, although CD4+ alpha beta T cells also contributed to some extent. Thus, gamma delta T cells appear to play an important role in protective immunity against infection with T. gondii through mediating the expression of hsp 65 in host macrophages. PMID- 7835959 TI - A Th1 cell line (3E9.1) from resistant A/J mice inhibits induction of macrophage procoagulant activity in vitro and protects against MHV-3 mortality in vivo. AB - Induction of immune coagulants has been implicated in the pathogenesis of murine hepatitis virus strain 3 (MHV-3)-induced fulminant hepatic necrosis. Previous work from our laboratory has shown that the induction of procoagulant activity (PCA) correlates with the resistance/susceptibility to disease in inbred and recombinant inbred (RI) strains of mice. Macrophages from susceptible, but not resistant, strains of mice expressed increased levels of PCA in response to MHV-3 stimulation. T lymphocytes, however, had a marked regulatory role in the final expression of macrophage PCA. CD3+ CD4+ CD8- lymphocytes from RI H-2 compatible susceptible mice were able to instruct macrophages from susceptible mice to express significantly augmented levels of PCA, whereas CD3+ lymphocytes from RI H 2 compatible MHV-3-immunized resistant mice were able to suppress induction of PCA. In this present study, T-cell lines were derived from draining popliteal lymph nodes from resistant A/J mice, which had been immunized with MHV-3. All T cell lines showed marked proliferation to MHV-3 and MHV-JHM which was major histocompatibility complex (MHC) restricted. All cell lines were CD3+, four of these were CD4+ and one was CD8+. All of the CD4+ cell lines produced IL-2 and two produced interferon-gamma (IFN-gamma), consistent with the Th1 cytokine profile. One cell line (3E9.1) was able to inhibit the induction of macrophage PCA through production of a soluble factor although cell-to-cell contact could not be excluded. This CD4+ T-cell line conferred protection to infected and susceptible AXB8 mice. These results demonstrate that the existence of a Th1 subpopulation of cells with a regulatory effect on macrophage PCA induction in MHV-3-infected mice contributes to the resistance of the A/J strain of mice to MHV-3 infection. PMID- 7835960 TI - A role for CD4+ T cells from orally immunized rats in enhanced clearance of Pseudomonas aeruginosa from the lung. AB - The role of gut-derived CD4+ T cells in clearance of Pseudomonas aeruginosa from the lung was studied by cell transfer experiments. Mesenteric lymph node cells from unimmunized rats, or rats orally immunized with either killed P. aeruginosa or Helicobacter pylori, were transferred to naive rats which were subsequently challenged intra-tracheally with live P. aeruginosa. Recipients of unseparated mesenteric lymph node cells, purifed T cells or CD4+ T cells, from P. aeruginosa immunized donors, all exhibited enhanced bacterial clearance from the airways compared to recipients of cells from unimmunized donors. Enhanced clearance by T cells was antigen-specific as no enhanced clearance was observed by transfer of cells from donors immunized with H. pylori. PMID- 7835961 TI - The functional activity of human monocytes passively sensitized with monoclonal anti-D suggests a novel role for Fc gamma RI in the immune destruction of blood cells. AB - The role of Fc gamma RI in the immune destruction of blood cells is uncertain as serum IgG levels are sufficient to competitively inhibit interactions between this high-affinity receptor and sensitized red cells. In the current study, it is proposed that, rather than functioning as a receptor for opsonized red cells, Fc gamma RI might, under appropriate conditions, mediate the passive sensitization (or 'arming') of human macrophages with IgG antibodies resulting in the in vivo destruction of unsensitized cells expressing the corresponding antigen. To examine this hypothesis, Fc gamma RI-bearing human monocytes and U937 cells were first passively sensitized by incubation in vitro with human monoclonal anti-D, and then incubated with D-positive red cells. The uptake of monoclonal anti-D by U937 cells was rapid and, in the presence of 2.5 micrograms/ml IgG1 or IgG3 anti D, was almost complete after 5 min at 37 degrees. Subsequent incubation of passively sensitized U937 cells in an IgG-free medium for 1 hr at 37 degrees resulted in the loss from the cell surface of approximately 50% cell-bound IgG; the remaining cell-bound IgG was lost more slowly despite repeated washing. In functional assays, passively sensitized monocytes (M-IgG) mediated adherent, phagocytic and chemiluminescent (CL) responses to D-positive red cells. After incubation of M-IgG in 50% v/v fresh normal human serum (FNHS) for 2 hr, sufficient anti-D remained bound to monocytes to promote the adherence of red cells. The adherence and phagocytosis of red cells by M-IgG was enhanced by the simultaneous addition of 50% FNHS, probably owing to the binding of low levels of C3bi to red cells. In contrast, phagocytic and CL responses of unsensitized monocytes to anti-D-sensitized red cells (E-IgG) were abrogated in the presence of 0.25% v/v FNHS, presumably owing to blocking of Fc gamma RI by IgG. It is considered that in vivo, Fc gamma RI may mediate the passive sensitization of macrophages in close proximity with antibody-secreting cells in the reticular network of the splenic cords. Once 'armed' in this way, macrophages may destroy cells expressing the appropriate antigen. PMID- 7835962 TI - Peritoneal macrophages show increased cytokine gene expression following haemorrhagic shock. AB - Tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), IL-1 and transforming growth factor-beta (TGF-beta) have been recognized as important mediators of pathophysiological and immunological events associated with shock. Previous studies have indicated that although peritoneal macrophage (PM phi) antigen presentation was depressed following haemorrhage, the cytokine release capacity in response to lipopolysaccharide (LPS) was not affected in vitro. To determine the effect of haemorrhagic shock on PM phi cytokine mRNA transcription, C3H/HeN male mice were bled to and maintained at a mean arterial blood pressure of 35 mmHg for 60 min, and then adequately resuscitated. PM phi were isolated at 1 or 24 hr after haemorrhage and were incubated without or with 10 micrograms LPS/ml for 1 hr. Total RNA was then extracted followed by Northern blot analysis, as well as semi-quantitative reverse transcription and polymerase chain reaction (RT-PCR). The results of Northern blot analysis indicated that haemorrhage markedly increased LPS-induced IL-1 beta, IL-6, and TNF-alpha mRNA accumulation in PM phi at both 1 and 24 hr after haemorrhage and resuscitation. Furthermore, competitive RT-PCR demonstrated that mRNA of IL-1 beta, IL-6, TNF-alpha, as well as TGF-beta, was increased in PM phi obtained 1 hr after haemorrhage either with or without LPS stimulation. The data from Northern blot analysis and semi quantitative RT-PCR also revealed that LPS enhanced the effect of haemorrhage on PM phi cytokine gene expression. Thus, following haemorrhage, PM phi showed elevated cytokine mRNA accumulation which was not followed by an increased ability to release cytokines in response to LPS in vitro. These results, therefore, suggest that different mechanisms regulate gene expression and subsequent cytokine secretion by PM phi following haemorrhage. PMID- 7835963 TI - Anti-IL-4 monoclonal antibody and IFN-gamma administration retards development of immune dysfunction and cytokine dysregulation during murine AIDS. AB - This study was designed to determine if administration of anti-interleukin-4 (IL 4) monoclonal antibody (mAb), interferon-gamma (IFN-gamma) and their combination after LP-BM5 retrovirus infection of female C57BL/6 mice would prevent retrovirus induction of immunosuppression and cytokine dysregulation. Splenic natural killer (NK) cell activity, T- and B-cell proliferation, and T-helper type 1 (Th1) and Th2 cytokine (IL-2, IFN-gamma, IL-5 and IL-10) and monokine [IL-6 and tumour necrosis factor-alpha (TNF-alpha)] secretions were monitored, as they are usually altered dramatically after murine retrovirus infection. Administration of IFN gamma and anti-IL-4 significantly prevented retrovirus-induced suppression of splenic NK cell activity, and splenic T- and B-cell proliferation. They also significantly slowed retrovirus-induced elevation of Th2 cytokine (IL-5 and IL 10) release and monokine (IL-6 and TNF-alpha) secretion by splenocytes. They prevented the loss of Th1 cytokine (IL-2 and IFN-gamma) release by splenocytes, and alleviated splenomegaly and hypergammaglobulinemia, precursor signs of development of acquired immune deficiency syndrome (AIDS). These findings could provide insight into the roles of immunomodulator in AIDS treatment as well as the mechanisms by which retrovirus infection induces cytokine dysregulation, facilitating immunodeficiencies in AIDS. PMID- 7835964 TI - Role of IL-2 and IL-4 in exacerbations of murine antigen-induced arthritis. AB - In this study the roles of different T-cell subsets, and produced cytokines, were investigated in an animal model for acute exacerbations. Flare-up reactions are inducible in the chronic phase of a smouldering antigen-induced inflammation by injection of a small amount of an antigen into a hyper-reactive knee joint. In vivo treatment with anti-CD4 monoclonal antibodies (mAb) almost totally blocked the flare reaction, whereas anti-CD8 treatment did not exert any effect. The role of T-helper 1 (Th1) cells in delayed-type hypersensitivity-resembling diseases is generally entitled proinflammatory, whereas Th2 cells act in an anti-inflammatory manner. To investigate the role of these T-cell subsets in flare-up reactions, anti-interleukin-2 (IL-2) and anti-IL-4 mAb treatments were performed. Anti-IL-2 treatment partly blocked the flare reaction, and anti-IL-4 treatment, although the result was unexpected, blocked the flare more efficiently. Furthermore, when human recombinant IL-2 (hrIL-2) and murine recombinant IL-4 (mrIL-4) were co injected with the antigen to test their ability respectively to potentiate or down-regulate the flare reaction, both cytokines demonstrated additional pro inflammatory effects, although hrIL-2 was more potent than mrIL-4. The mere effect of hrIL-2 and mrIL-4 was studied by direct injection into a hyperreactive joint. No flare-up reaction or cell-influx could be induced, suggesting that other mediators are needed to exert pro-inflammatory effects of IL-2 or IL-4. We conclude that not only Th1 cells, but also Th2 lymphocytes (at least regarding IL 4 production) may play a pro-inflammatory role in flare-up reactions of chronic arthritis. Considering therapeutic application of Th2 cell-derived cytokines, one should be aware of the possible pro-inflammatory potential of IL-4. PMID- 7835965 TI - Recognition of a CD4+ mouse medullary thymocyte subpopulation by Amaranthus leucocarpus lectin. AB - We have used the Gal beta(1-->3)GalNAc-specific Amaranthus leucocarpus lectin to isolate a thymus cell subpopulation which is different from that sorted with Arachis hypogaea lectin. The cells recognized by A. leucocarpus lectin were predominantly CD4+, whereas a minor proportion of CD8+ cells (approximately 11%) were also identified. The A. leucocarpus-positive cells were located in the thymus medulla and the cortico-medullary junction. The cortex was negative for A. leucocarpus cells. PMID- 7835966 TI - CD4-independent signal transduction through the T-cell receptor (TCR/CD3). AB - The membrane-bound CD4 glycoprotein has been proposed to act like a co-receptor along with the T-cell antigen receptor (TCR/CD3) during ligand recognition and cell activation. Due to its association with the protein tyrosine kinase (PTK) p56lck, CD4 is believed to transduce a signal and support CD3 activation of T cells. In this study we have shown that CD3 ligation on murine T-cell hybridomas induces tyrosine phosphorylation of proteins, including phospholipase C-gamma 1 (PLC gamma 1), both in the presence as well as in the absence of CD4-linked p56lck. Furthermore, using HPB clones deficient in CD3/PTK association, it has been found that the presence of CD4/p56lck does not overcome the defect in signalling. Not even co-aggregation of CD4 with CD3 triggers tyrosine phosphorylation of proteins in these cells. Together, the present results indicate that CD3-linked PTK(s) plays a primary role in the induction of signalling through TCR/CD3, and the presence of CD4/p56lck is neither necessary nor sufficient to elicit these events. In the light of these results a possible role for CD4 in antigen presentation has been proposed. PMID- 7835967 TI - Evidence for an association of CD45 with 32,000-33,000 MW phosphoproteins on murine T and B lymphocytes. AB - In human T cells CD45 is reported to associate with both cell surface and intracellular molecules including CD2, CD4/CD8, CD5, p56lck and p59fyn. In this study the association of molecules with CD45 in murine T lymphocytes was explored using biotinylation, chemical cross-linking, immunoprecipitation and 32P labelling. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis of CD45 monoclonal antibody (mAb) (S-450-15.2) immunoprecipitates from Triton X-100 lysates of murine thymocytes that were surface biotinylated and treated with the chemical cross-linker 3,3'-dithio-bis(sulpho succinimidylpropionate) (DTSSP) showed that CD45 can be chemically linked to molecules of 25,000-32,000, 42,000 and 60,000-70,000 MW. The CD45 mAb also co precipitated a prominent 32,000 MW molecule from digitonin lysates of surface biotinylated murine thymocytes, splenocytes and D10 cells, but a weaker association was also detected on splenic B cells and on the murine B-cell lymphoma line A20. The results suggest that in these cells CD45 is associated with a 32,000 MW molecule which is exposed extracellularly. Experiments in which thymocytes were biotinylated after permeabilization with lysolecithin showed that additional molecules of 33,000, 55,000, 60,000 and 90,000 MW, presumably localized intracellularly, also co-precipitated with CD45. Labelling of murine thymocytes or D10 cells with H3(32)PO4 in vivo, and of CD45 immunoprecipitates by in vitro kinase reaction, revealed that the 32,000-33,000 MW molecules are phosphoproteins. The relationship of these molecules with the 30,000-34,000 MW molecules previously reported to associate with CD45 in human T cells is not clear as a number of differences were observed. Firstly, the molecular weight of the CD45-associated 32,000-33,000 MW molecule(s) on murine T cells and B cells is slightly lower than that observed in the human T-cell line Jurkat (34,000 MW). Secondly, phosphoamino acid analysis after in vitro kinase labelling of CD45 immunoprecipitates showed that the murine 32,000-33,000 MW molecules are phosphorylated exclusively on serines. Thirdly, although in vitro phosphorylation of the 32,000-33,000 MW molecules was inhibited by preincubation with either GTP gamma-S or GDP-beta-S, the 32,000-33,000 MW CD45-associated molecules did not bind 32P-GTP, GDP-agarose, or react with antisera to a consensus sequence of G proteins. The crucial role of CD45 for proper function of the T-cell receptor (TCR), suggests that the CD45-associated 32,000-33,000 MW molecules and kinases also may play a role in the signalling events leading to T-cell activation. PMID- 7835968 TI - The primary in vivo immune response to Mls-1 (Mtv-7 sag). Route of injection determines the immune response pattern. AB - Injection of cells expressing the retroviral superantigen Mls-1 (Mtv-7 sag) into adult Mls-1- mice induces a strong immune response including both T- and B-cell activation. This model was used for studying qualitative aspects of the immune response in normal mice with a defined antigen-presenting cell (the B cell) and without the use of adjuvant. BALB/c mice were injected locally or systemically with Mls-1-expressing spleen cells from Mls-1-congenic BALB.D2 mice. Intravenous injection led to an initially strong expansion of Mls-1-reactive V beta 6+ CD4+ cells mainly in the spleen, to a large degree explained by the trapping of reactive cells, and a rapid down-regulation of interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) production, consistent with the proposed tolerogenic property of B cells as antigen-presenting cells. However, these mice developed a slowly appearing but persistent B-cell response dominated by IgG1-producing cells, suggesting a shift in lymphokines produced rather than complete unresponsiveness. Subcutaneous injection into the hind footpad with the same number of cells led to a strong local response in the draining lymph node, characterized by a dramatic increase of V beta 6+ CD4+ T cells, local production of IL-2 and IFN-gamma and a strong but short-lived antibody response dominated by IgG2a-producing cells, characteristic of a T-helper type 1 (Th1) type of response. Both routes of injection led ultimately to deletion of reactive T cells and anergy, as defined by the inability to produce IL-2 upon in vitro stimulation with Mls-1. It is concluded that Mls-1 presented by B cells induces qualitatively different responses in vivo dependent on the route of injection. We propose that the different responses result from the migration of the injected cells to different micro-anatomical sites in the lymphoid tissue. Furthermore, these results suggest that B cells may function as professional antigen-presenting cells in vivo present in an appropriate environment. PMID- 7835969 TI - Expression of HLA class II-associated peptide transporter and proteasome genes in human placentas and trophoblast cell lines. AB - Expression of HLA class I antigens is closely controlled in the placental trophoblast cells, which interface directly with maternal cells during pregnancy. In this study, the possibility that peptide transporter (TAP-1, TAP-2) or proteasome (LMP7) genes might be involved in regulating antigen expression in these or other cells that comprise placentas was investigated. Analysis by Northern blot hybridization showed that transcripts from all three genes were present in samples of first trimester and term placental RNA. TAP-1 and TAP-2 messages were consistently more abundant in early than in late gestation placentas, whereas the reverse was observed for LMP7 mRNA. Futher experiments were done on two trophoblast cell lines. One line, Jar, is negative for HLA class I, and the second, JEG-3, expresses HLA-G as well as other HLA class I genes. Both Jar and JEG-3 cells contained TAP-1, TAP-2 and LMP7 mRNA. With the exception of LMP7 in JEG-3 cells, message from all three genes was increased by treating the trophoblast cells with interferon-gamma. While no evidence was collected to support the postulate that the HLA class I negative status of some trophoblast cell subpopulations could be related to absent or dysfunctional TAP-1, TAP-2 or LMP7 mRNA, the data are consistent with the postulate that placental cell expression of HLA class I antigens could be influenced by the availability of peptide transporters and proteasome components. PMID- 7835970 TI - Adhesion molecules involved in the binding and subsequent engulfment of thymocytes by a rat thymic epithelial cell line. AB - A rat thymic epithelial cell (TEC) line (R-TNC.1) was established from a long term TEC culture. Based on its ultrastructure, phenotype and cytokeratin profile, this line was characterized as a type of cortical TEC. R-TNC.1 cells had nursing activity which was manifested by the binding and subsequent engulfment of thymocytes. The role of adhesion molecules involved in these processes was studied extensively using a coculture of resting thymocytes and unstimulated or interferon-gamma (IFN-gamma)-stimulated R-TNC.1 cells. It was found that a number of adhesion molecules, such as CD2, CD4, CD8, LFA-1, CD18, ICAM-1 and Thy-1, was partly involved in the nursing activity. The effect of monoclonal antibodies (mAb) to these molecules depended on the incubation time and stimulation of R TNC.1 cells. The inhibitory effect of mAb to CD2, LFA-1, CD18 and ICAM-1 on thymocyte engulfment was higher than their effect on thymocyte binding to the R TNC.1 line. In addition, a LFA-1/CD18-dependent/ICAM-1-independent adhesion pathway was identified when unstimulated R-TNC.1 cells with minimal expression of ICAM-1 were used. The combination of inhibitory mAb did not completely abrogate the nursing activity of the R-TNC.1 line, suggesting the possible involvement of some other adhesion molecules. PMID- 7835971 TI - Heterogeneity of M-cell-associated B and T cells in human Peyer's patches. AB - The specialized M cells in the follicle-associated epithelium (FAE) of Peyer's patches (PP) represent an intimate interphase between luminal antigens and gut associated lymphoid tissue (GALT). M cells form pockets that contain clusters of leucocytes probably involved in the first encounter with antigens from the gut lumen. Three-colour immunofluorescence in situ phenotyping of these leucocytes in humans revealed about equal numbers of B (CD19/20+) and T(CD3+) lymphocytes, the latter mainly CD4+ (median 73%, range 40-90%), but relatively few macrophages (CD68+). Most B cells (90%) were positive for surface IgM (sIgM) and often co expressed sIgD (median 34%, range 6-60%). Occasional B cells (median 2%) did not express CD45RA (range 0-15%) and 13% virtually lacked HLA-DR (range 0-40%). Some B and T lymphocytes expressed the nuclear proliferation marker Ki-67 (range 1 10%). The M-cell pockets also contained occasional cells with cytoplasmic IgA or IgM. These sites thus contained a heterogeneous B-cell population with features of both follicular mantle (sIgD+ sIgM+) and marginal zone (sIgD- sIgM+) B lymphocytes. Adjacent T lymphocytes were generally of the memory phenotype (CD45RO+). Our findings suggest that the M-cell-associated B lymphocytes represent local extensions of B-cell follicles towards the gut lumen, developed topically to facilitate antigen presentation and diversification of mucosal immune responses. PMID- 7835972 TI - The role of macrophages and bone marrow-derived dendritic cells in the rejection of fetal thymus allografts. AB - Deoxyguanosine (dGuo)-treated fetal thymus lobes are capable of prolonged survival in histoincompatible recipients despite their expression of both class I and class II major histocompatibility complex (MHC) antigens. Although dGuo treatment has been directly shown to eliminate lymphocytes from the lobes its effect upon other marrow-derived passenger cells such as macrophages and dendritic cells is less well defined. Here we show that dGuo-treated CBA(H-2k) fetal thymus lobes allowed to develop under the renal capsule of immunoincompetent BALB/c (H-2d) mice for 3 weeks are depleted of donor-type dendritic cells in contrast to grafts of untreated lobes where donor-derived dendritic cells are still detectable at this time. Moreover, dGuo-treated thymus lobes underwent prompt allo-rejection if recolonized with donor-type dendritic cells prior to transplantation into immunocompetent recipients. Together with our observation that macrophages (or their precursors) survive dGuo treatment, these results suggest that the reduced immunogenicity of fetal thymus grafts seen following dGuo treatment is related to dendritic cell, rather than macrophage depletion. PMID- 7835973 TI - The Yaa gene-dependent B-cell deficiency worsens the generalized lymphadenopathy and autoimmunity of C57BL/6-gld male mice. AB - The BXSB mice are unique among murine models for systemic lupus erythematosus in that males are much more severely affected than females. The BXSB male disease is associated with a Y-chromosome-linked gene, which is an autoimmunity accelerator gene (Yaa). The Yaa mutation affects the B-cell subset, which becomes hyper responsive to T-cell signals. The Yaa mutation was combined to the generalized lymphadenopathy disease (gld) gene in order to know whether an additional intrinsic B-cell defect might enhance gld disease in the male mice. The B6-gld Yaa male mice were shown to display earlier and exacerbated lymphoproliferative and autoimmune features. It appeared that the milder gld syndrome observed in B6 gld male mice with a normal Y-chromosome was dependent on the mechanisms of B cell activation and that the B cells could also accelerate the lymphoproliferation and the differentiation of T cells into Thy-1+ B220+ cells. PMID- 7835974 TI - Reduced galactosyltransferase mRNA levels are associated with the agalactosyl IgG found in arthritis-prone MRL-lpr/lpr strain mice. AB - MRL-lpr/lpr strain mice have defectively glycosylated IgG. This may be related to the rheumatoid arthritis (RA)-like disease that occurs in these mice, because a similar glycosylation defect is seen in human subjects with RA. Whilst it is known that this defect is associated with reduced activity of the beta-1,4 galactosyltransferase (beta-1,4-GalTase) enzyme, the cause of this reduced activity is at present unknown. We have therefore examined the molecular genetics of beta-1,4-GalTase in MRL-lpr/lpr mice. Using 10 different restriction endonucleases we found no evidence for a polymorphic variant of the gene in glycosylation-defective mice. However, the level of mRNA for beta-1,4-GalTase was lowest in the MRL-lpr/lpr mice, the strain with the most poorly galactosylated IgG of the four strains examined. Thus, the reduced level of IgG oligosaccharide galactosylation found in MRL-lpr/lpr strain mice appears to be related to either an altered transcriptional level of, or altered mRNA stability for, beta-1,4 GalTase in lymphocytes from these mice. PMID- 7835975 TI - Characteristics of polyreactive and monospecific IgG anti-laminin autoantibodies in the rat mercury model. AB - Brown-Norway (BN) rats injected with HgCl2 produce anti-laminin antibodies responsible for an autoimmune glomerulonephritis. The properties of three IgG1 monoclonal antibodies (mAb) previously obtained in this model, and of immunoglobulins eluted from kidneys of diseased rats, were compared in the present study. Two mAb (Hg15 and Hg16) recognized laminin only, while the third one (Hg17) was polyreactive, as were some of the kidney-eluted immunoglobulins; they reacted with laminin and with several other antigens including 2,4,6 trinitrophenyl (TNP). The Hg17 mAb and kidney-eluted polyreactive antibodies were affinity purified using a TNP-bovine serum albumin (BSA) column; their affinity for TNP was high (2 x 10(-8)M, and 1 x 10(-8)M, respectively) but less than that of a TNP-specific (LO-DNP-2) mAb (2 x 10(-11) M). The Hg17 mAb and kidney-eluted antibodies reacted more effectively with TNP28-BSA than with TNP8.5-BSA, while the TNP-specific mAb reacted equally well with both conjugates. The Hg17 mAb was the most cationic (pI: 7) of the anti-laminin mAb and this was even more evident when F(ab')2 fragments were studied (pI: 8.2). The polyreactive kidney-eluted immunoglobulins that bound TNP were also more cationic (pI: 7.4-9.3) than the fraction that did not recognize TNP (pI: 5.8-8.6). The anti-laminin mAb bound in vivo to the glomerular basement membrane, but only the Hg17 mAb could be eluted with DNP alone. This study shows that polyreactive anti-laminin antibodies are produced during this autoimmune disease, and indicates that they may have pathogenic potential. PMID- 7835976 TI - IgG subclass antibody to Mycobacterium leprae 18,000 MW antigen is restricted to IgG1 and IgG3 in leprosy. AB - IgG subclass responses to Mycobacterium leprae 18,000 MW recombinant antigen (18K) were determined in sera from untreated leprosy patients using an ELISA based assay with specific monoclonal antibodies. Antibodies to M. leprae 18K were restricted to IgG1 and IgG3 antibodies with higher seropositivity in lepromatous patients (25.5% for IgG1 and 12.8% for IgG3) compared to patients with tuberculoid disease (11.5% for IgG1 and 5% for IgG3). No significant antibody response was detectable in IgG2 and IgG4 in patients with either lepromatous or tuberculoid leprosy. The selective production of antibodies in IgG1 and IgG3 subclasses could not be related to polyclonal activation in these subclasses as all IgG subclasses showed similar elevated levels at the polyclonal level. The major difference noted between lepromatous and tuberculoid leprosy patients with the IgG subclass antibody response was a strong linear correlation between IgG1 and IgG3 responses to M. leprae 18K in lepromatous patients (r = 0.703, P < 0.001) but not in tuberculoid leprosy patients (r = 0.007, P > 0.10) which may be related to immunoglobulin class switching of IgG3 to IgG1 rather than selective shifts in T-helper subsets. Our results therefore, do not support the hypothesis that activation of Th2 cells occurs in lepromatous leprosy; this issue needs further examination. PMID- 7835977 TI - Altered glycosylation and selected mutation in recombinant human complement component C9: effects on haemolytic activity. AB - Recombinant wild-type and mutated forms of human complement component C9 have been synthesized in baculovirus-infected insect cells. Wild-type recombinant C9 was indistinguishable from native C9, as judged by haemolytic activity, trypsin and alpha-thrombin digestion, reaction with antibodies to C9, enzymatic deglycosylation to the same core size and polymerization in the presence of Zn2+. Replacement of the native signal peptide with the honey-bee melittin signal peptide, and replacement of Spodoptera frugiperda (Sf9) cells with Trichoplusia ni cells produced yields of 5 micrograms C9/ml supernatant. Three C9 mutants were generated; one mutant, with four acidic residues changed to alanines in a putative calcium-binding site, had the same biological activity as recombinant C9. Another mutant, lacking 23 N-terminal amino acids, previously showing increased polymerization when produced in vitro, polymerized on secretion, rendering it inactive. It was not possible to demonstrate haemolytic activity of the third mutant, cysteines 33 and 36 mutated to alanine, as it was secreted a hundredfold less than the wild-type protein. PMID- 7835979 TI - Burnet oration. The thymus then and now. PMID- 7835978 TI - Effect of C1q on the processing of immune complexes by human neutrophils. AB - We prepared immune complexes (IC) composed of human anti-tetanus toxoid IgG and tetanus toxoid, and examined the effect of C1q on the processing of IC by human neutrophils. Treating IC with increasing amounts of C1q enhanced the binding and phagocytosis of IC by neutrophils, unless the amounts of C1q added were less than those required to saturate the C1q binding sites of IC. With the increase of unbound excess C1q, the IC processing by neutrophils decreased. Superoxide anions generated during the processing of IC-C1q were entrapped in phagosomes and were not released from neutrophils. The C1q-dependent inhibition of IC processing by neutrophils was not observed when C1q-treated neutrophils were washed and allowed to react with IC, suggesting that the inhibition by excess C1q is due to the hindrance of IC-C1q binding to neutrophils by loosely bound C1q on neutrophils. The C1q-treated, washed neutrophils still showed enhanced responses to IC, suggesting that free C1q as well as the IC-C1q complex can prime neutrophils to enhance Fc receptor (FcR)-mediated cellular responses. Thus, C1q may have two effects on the processing of IC by neutrophils; firstly, it enhances FcR-mediated cellular responses, and secondly, it prevents superoxide anion-induced tissue damage by trapping superoxide anions in phagosomes. PMID- 7835980 TI - Effects of the anti-inflammatory compounds castanospermine, mannose-6-phosphate and fucoidan on allograft rejection and elicited peritoneal exudates. AB - The glycoprotein processing inhibitor castanospermine (CS) and the monosaccharide mannose-6-phosphate (M6P), as well as some sulfated polysaccharides (SPS), have been shown to inhibit inflammation in rat models of experimental autoimmune encephalomyelitis and adjuvant-induced arthritis. Here, the anti-inflammatory effects of these agents have been further explored in murine models of allograft rejection and elicitation of peritoneal exudates. CS, M6P and the SPS, fucoidan, partially inhibited rejection of permanently accepted thyroid allografts induced by the i.p. injection of donor strain (H-2d) spleen cells with a reduction in leucocyte infiltration of 25-36%. However none of these agents reduced the more extensive leucocyte infiltration induced by the i.p. injection of P815 (H-2d) unless recipient mice were pretreated with the immunosuppressant, cyclosporin A (CsA). Elicitation of peritoneal exudates by thioglycollate was inhibited by CS, M6P and fucoidan with sustained leucopenia being induced by CS. In contrast, CS and fucoidan, but not M6P, inhibited antigen-elicited peritoneal exudates. These results suggest that CS, M6P and the SPS fucoidan exhibit subtle differences in their anti-inflammatory activity but probably inhibit inflammation at the level of leucocyte extravasation. PMID- 7835981 TI - Immunosuppression by lymphokine-activated murine killer cell line with B lymphoblast-lytic activity in vitro. AB - The in vitro immunosuppressive effect caused by a murine lymphokine-activated killer cell line with B-lymphoblast-lytic activity was studied. The cloned cells (named BC-1.10, phenotype Thy 1.2+, LFA-1+, TCR-alpha beta-, TCR-gamma delta-, Fc gamma RII-, CD2-, CD3 epsilon-, CD4-, CD8- and express mRNA of zeta chain) suppressed LPS-induced Ig synthesis by B lymphoblasts previously stimulated with LPS. Phase-contrast microscopy indicated disappearance of B lymphoblasts at 24 h after the addition of BC-1.10 cells. This suppressive effect was reduced when BC 1.10 cells were pretreated with anti-LFA-1 mAb, which inhibits cytotoxicity of this clone. These data suggest that the immunosuppressive effect of BC-1.10 is due to an elimination of B lymphoblasts, and that one of the physiological functions of lymphokine-activated killer (LAK) cells, which are induced as a consequence of immune reactions, might be immunosuppression. PMID- 7835982 TI - Changes in epidermal Langerhans cells, gamma delta T cells and CD4 T cells after intradermal infection with recombinant vaccinia virus expressing cytokine genes. AB - Langerhans cells (LC) play a critical role in cutaneous immunity, and whereas Thy 1+ dendritic epidermal cells (Thy-1+ dEC) are also present in murine epidermis, their role remains unknown. Antigens and cytokines influence the number of LC found in the epidermis. However, there has been no investigation into the effects of particular cytokines during resolution of a viral infection. In order to study this we infected mice subcutaneously with vaccinia virus (VV) constructs containing the genes encoding TNF-alpha, IL-6 or IFN-gamma and the density of LC, THY-1+ dEC and CD4+ cells was determined. In this system the cytokines were produced locally at the site of viral replication. Cell densities were examined at day 1, while the response was being initiated, and at day 5 as the infection was being resolved. Infection with VV, like exposure to other antigens, decreased the density of epidermal LC at day 1, and they remained depressed at day 5. Production of TNF-alpha during VV growth did not influence this response by LC, whereas IFN-gamma and IL-6 both increased the number of epidermal Ia+ LC at day 1 but then caused a reduction at day 5. Thy-1+ dEC were not affected by VV infection at any time-point examined, nor did any cytokine influence the density of these cells at day 1. However, by day 5 IFN-gamma and IL-6, but not TNF-alpha, decreased the number of Thy-1+ dEC.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7835983 TI - Targeting of pancreatic islets of severe combined immunodeficient mice by passive transfer of allogeneic spleen cells from non-obese diabetic mice. AB - The precise role of immune cells in beta cell killing and their manner of invasion of pancreatic islets in insulin-dependent diabetes mellitus (IDDM) are unclear. We have attempted to target pancreatic islets of severe-combined immunodeficient (SCID) mice with spleen cells from diabetic and non-diabetic female non-obese diabetic (NOD) mice given i.p. or i.v. Pancreatic, liver and kidney sections of SCID mice were assessed histologically for the presence of donor cells. The presence of raised levels of serum Ig was also used as an index of engraftment of donor cells in the periphery of SCID mice. All six SCID mice which received i.v. spleen cells from normal Swiss mice died within 2 weeks from graft versus host disease (GVHD) whereas five out of nine mice survived for 30 days after i.p. injection. No deaths were recorded after i.v. or i.p. injection of spleen cells from NOD mice. Pancreatic islets of four out of six SCID recipients of diabetic and three out of five recipients of non-diabetic spleen cells following i.p. injection showed lymphocytic infiltrates in the peri-islet and perivascular regions. All SCID mice which received i.v. spleen cells from diabetic (six SCID recipients) and non-diabetic NOD mice (seven SCID recipients) showed peri-islet and perivascular infiltrates in their pancreas. Immunohistochemical analysis showed that the islet engrafted cells were of CD4 and CD8 phenotype. Donor cells were also observed in the exocrine pancreas of some recipients. A majority of mice showed various degrees of lymphocytic aggregates in the perivascular regions of the liver but not in the kidney.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7835984 TI - Cloning, sequencing, expression and inflammatory activity in skin of ovine interleukin-8. AB - Ovine IL-8 (oIL-8) cDNA was obtained by probing a spleen cell cDNA library with human IL-8 (hIL-8) cDNA. The oIL-8 cDNA was 1434 base pairs long with a single open reading frame encoding a 101 amino acid precursor protein of relative molecular mass 11,268. The inferred amino acid sequence has 78, 82, 84 and 67% similarity with human, rabbit, porcine and guinea-pig IL-8, respectively. By analogy with the most prevalent form of hIL-8, a 72 amino acid form of oIL-8 was expressed as a fusion protein containing glutathione-S-transferase and purified by affinity chromatography on a glutathione-Sepharose column yielding 8 mg IL-8/L broth culture. The fusion protein lacked chemotactic activity for ovine neutrophils, whereas the 72 amino acid form of oIL-8 was equipotent with rhIL-8. At 6 and 24 h after intradermal injection of 10(-9) mol oIL-8, there was intense accumulation of neutrophils, and very mild accumulation of eosinophils, CD5, CD4 and T19 (a gamma delta TCR subset) cells but not CD8 cells. The availability of roIL-8 and its cDNA probes will permit the role of this important member of the IL-8 family of chemotactic cytokines to be determined in inflammatory diseases of sheep. PMID- 7835985 TI - Attenuation of adjuvant arthritis in rats by treatment with oxygen radical scavengers. AB - The contribution of reactive oxygen species (ROS), in particular hydroxyl radical (OH.), to joint inflammation was examined in rats developing adjuvant arthritis (AA) by treatment with ROS scavengers dimethylthiourea (DMTU) and DMSO. Adjuvant arthritis was induced in Sprague-Dawley (SD) rats by a single intradermal (i.d.) injection of Mycobacterium tuberculosis (MT) in oil on day 0. By day 14, all rats exhibited arthritis in the hindlimbs and the majority had involvement of the forelimbs. A marked inflammatory cell influx (75% neutrophils) was present in the synovial fluid. These cells, in vitro, spontaneously produced OH. (0.96 +/- 0.28 OH. units/h per 10(5) cells). In contrast, spontaneous OH. production by normal circulating leucocytes was absent (0.07 +/- 0.03 OH. units/h per 10(5) cells). Adjuvant-injected rats were treated with DMTU (500, 250 and 100 mg/kg), DMSO (330 and 165 mg/kg) or saline (disease control) once daily on days 8, 9 and 10 and twice daily on days 11, 12 and 13 postadjuvant injection. Both DMTU and DMSO significantly reduced the clinical evidence of arthritis (clinical scores: DMTU [500 mg/kg] = 0, P < 0.0001; DMSO [3.0 mL/kg] = 0.4 +/- 0.3, P < 0.01, compared with disease control = 2.3 +/- 0.3). Synovial fluid cell accumulation was also significantly reduced (DMTU [500 mg+kg] = 0.5 +/- 0.1 x 10(5) cells/four joints, P < 0.0001; DMSO [3.0 mL/kg] 2.75 +/- 1.9 x 10(5) cells/four joints, P < 0.01 compared with disease control = 11.76 +/- 1.7 x 10(5) cells/four joints). Neither treatment inhibited cutaneous delayed type hypersensitivity (DTH) to the disease inducing antigen.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7835986 TI - Modulation and recovery of immune response of BALB/c mice to Shigella dysenteriae antigens after cyclophosphamide treatment. AB - We have analysed the suppressive effect of cyclophosphamide, when given in vivo, on the antibody response of BALB/c mice against Shigella dysenteriae antigens using ELISA and immunoblot. Out of various protocols tried, it was found that co injection of cyclophosphamide at 150 mg/kg bodyweight, i.p., at the time of antigen administration and then after a lapse of 24 h during both primary and secondary immunizations, was the most effective in suppressing antibody response of mice. Analysis of sera by ELISA demonstrated the presence of some antibodies to S. dysenteriae antigens after secondary immunization, but immunoblot analysis using the same sera revealed complete suppression of antibody response. Animals whose antibody response was almost completely suppressed after two immunizations with co-injection of cyclophosphamide, when immunized again after the lapse of 14 days from the date of secondary immunization with Shigella antigens but without administration of cyclophosphamide, partially recovered their ability to respond to the same antigens. This protocol can now be used in mice to analyse the hierarchy of immunogenic epitopes present in a complex mixture of antigens. PMID- 7835987 TI - Putative functional domain within ORF2 on the Mycobacterium insertion sequences IS900 and IS902. AB - Repeated DNA sequences have been identified in a range of mycobacterial species and have been implicated in the increased virulence of some of these species, namely, Mycobacterium paratuberculosis and M. avium subsp. silvaticum. Here we present a case to suggest that the insertion sequences IS900 and IS902 encode a protein from a putative gene positioned on the complementary strand to their transposase genes. Based on amino acid homology analyses, this open reading frame (ORF2) could encode a transport protein. The ORF2 protein thus IS900 and IS902, may have a role in the increased pathogenicity of M. paratuberculosis and M. avium subsp. silvaticum from an M. avium background. PMID- 7835988 TI - Thymus-leukaemia antigens: the haemochromatosis gene product? AB - The gene for hereditary haemochromatosis (HFE) lies telomeric to HLA-A and is believed to be expressed in the intestinal mucosa. Its product has not been characterized, but iron overload and its pathological consequences occur only in homozygotes for this putative gene. The genes encoding the putative human counterparts of the mouse thymus-leukaemia (TL) antigens map to the area where the HFE gene lies. Here, we postulate that a human TL gene may encode a protein acting as or interacting with the transferrin (Tf) receptor in the intestinal mucosa. This hypothesis is based on the following observations: (i) hereditary haemochromatosis (HH) is due to excessive absorption of iron through the intestinal mucosa. HH has a strong association with HLA-A3, but HLA-A3 has no direct role in the pathogenesis and reflects linkage disequilibrium with a telomeric gene. (ii) An HLA-A3 homozygous genotype is associated with the highest relative risks for both early-onset leukaemia and HH. In analogy to the susceptibility locus in mice, this genotype may reflect a TL gene association in leukaemia and raise the possibility of a TL gene involvement in HH. (iii) A TL antigen-like human molecule encoded in the region telomeric to HLA-A, TCA, is expressed in leukaemia and recognized by a Tf receptor-specific monoclonal antibody. The Tf receptor is believed to have a role in the control of intestinal iron absorption. (iv) In mice, particular TL antigens are exclusively expressed in the intestinal mucosa.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7835989 TI - Comparison of cord blood and adult blood lymphocyte normal ranges: a possible explanation for decreased severity of graft versus host disease after cord blood transplantation. AB - Lymphocyte subpopulations in cord blood (CB; collected at birth from full-term babies) were compared with that of adult blood (AB) and found to contain significantly different numbers and percentages of lymphocyte subpopulations. The absolute lymphocyte count was greater in CB (4.8 +/- 1.1 x 10(9)/L) than in AB (1.69 +/- 0.38 x 10(9)/L), with CB having significantly higher absolute numbers of lymphocyte subsets even though CB percentages were significantly lower. Significant differences in percentages were found between cord and adult T cells (CB 58% vs AB 74%), NK cells (CB 19% vs AB 7%) and their subsets. CD38, a marker of activation and immaturity, was present on virtually all cord T cells and approximately half the adult T cells. CD45RA, a marker considered to define unprimed or naive cells, was expressed on 82% of cord lymphocytes as compared with 48% in AB. CD45RO was expressed on 16% of CB lymphocytes and 49% of AB lymphocytes. Cord blood contains a higher percentage and total number of immature and immunologically naive lymphocytes than AB. PMID- 7835990 TI - ORT--an adjunct for diarrhoeal diseases control. PMID- 7835991 TI - Special issue on oral rehydration therapy (ORT). PMID- 7835992 TI - Enteropathogens associated with acute diarrhoeal diseases. PMID- 7835993 TI - Vibrio cholerae O139 Bengal: the eighth pandemic strain of cholera. PMID- 7835994 TI - Prevent diarrhoea deaths advice to the mother of a child with diarrhoea. PMID- 7835995 TI - Usefulness of ORT in certain special situations of diarrhoeal diseases. PMID- 7835996 TI - Review on development and community implementation of oral rehydration therapy. AB - The review of the current status and implementation of Oral Rehydration Therapy at the community level have been presented in this communication with special emphasis on its development, ORS access rate, ORS use rate and home available fluids. The global ORS supply has gone up an increased eleven folds since 1981. Similarly the ORS access rate has also increase from 46% to 68% in 1991. However, the global ORS use rate was low (21%). The major constraints during ORT implementation which have been reported by several scientists are also discussed. PMID- 7835997 TI - Food practices during diarrhoea. AB - A study was conducted to find out the pattern of food and fluid practices during diarrhoea among 2,160 children under five. Mothers were educated to give home made fluids during diarrhoea. Their personal hygiene was studied and a positive correlation between diarrhoea and poor personal hygiene was found. After the health education programme, it was observed that mothers started giving home made fluids to the children during diarrhoea but the amount was not increased. Normal feeding was continued only in 38.2% of the episodes. PMID- 7835998 TI - Diarrhoea amongst under three children in rural Haryana. AB - A community based study was conducted to assess the magnitude of the problem of diarrhoea and factors associated with it amongst children below three years of age. Two districts in Haryana state were selected by using multistage random sampling procedure. Eight hundred eighteen children in the age group of 0-35 months belonging to scheduled caste communities were studied. All children suffering from diarrhoea at the time of survey or within last 2 weeks were included for the detailed study. The occurrence of diarrhoea was highest in age group 6-11 months (28%) and was lowest in age group 0-5 months (16%). No relationship was found between the nutritional status of children and the occurrence of diarrhoea. The percentage prevalence of diarrhoea was 42, 32 and 36 per cent amongst normally, moderately and severely malnourished children, respectively. Thirty seven percent of children suffering from diarrhoea received bottle feed. PMID- 7835999 TI - Surveillance of acute diarrhoeal diseases at village level for effective home management of diarrhoea. AB - One thousand thirtynine infants, 794 children in their second year of life and 445 children in their third year of life were followed up longitudinally from April 1984 to March 1985. Nearly 6 episodes of diarrhoea per annum, during infancy, 5.49 episodes in second and 4.19 episodes during third year of life respectively, were experienced. On an average, each episode of diarrhoea lasted for four days. 20% of infants, 6.43% of children between 1-2 years and 7.26% of children between 2-3 years, experienced weight loss of 300 gm. or more following episode of diarrhoea. Diarrhoea case fatality rate was 1.8% and 0.75% for infants and children between 1-3 years of age respectively. Home management of diarrhoeas by mothers with the advocacy of anganwadi workers and health workers yielded dividends. Sustained efforts of this kind may go a long way in management of diarrhoeas. PMID- 7836000 TI - Implementation of ORT: some problems encountered in training of health workers during an operational research programme. AB - During an operational research study on implementation of oral rehydration therapy in a block of West Bengal, India, amongst a population of 2, 16,805, a total of 171 Community Health Guides and 152 Anganwadi Workers were initially trained for one working day by lectures and slides about diarrhoea case management at the community level. The training was evaluated after two months and found to be inadequate. The workers were then retrained with modern approach using a module (prepared in local language) as suggested by World Health Organisation. The level of retention of the imparted knowledge of Health Workers for different items 2-3 months after training with lectures and slides ranged between 5-25% except preparation of ORS which was 80%. With the use of modules, 47-98% of health workers could retain the same knowledge 3 months after the training. The knowledge thus acquired were sustained even after 12 months of training to a level which was still much better than that retained 2 months after training with slides and lectures. However some of the items like indication of use of Home Available Fluids, dosage of ORS and when to refer a diarrhoea case to health facility were more difficult to recall after one year. This possibly indicates need for in-service training of grassroot level health workers at suiTable interval. PMID- 7836001 TI - Utilisation of ORT during diarrhoea in three districts of West Bengal. AB - Use of ORT is saving 1 million diarrhoeal deaths each year among children. C.S.S.M. programme aims at preventing 70% diarrhoeal deaths, through widespread use of ORT. The present study was carried out to find out the extent of the problem of diarrhoea and utilisation of ORT in three districts of West Bengal. The results showed that the utilisation of ORT was 80.8%, 70.7% and 65% in Howrah, Hooghly and 24-Parganas (South) respectively, during attacks of diarrhoea. The continuing feeding rates were 60.1%, 62.7% and 55.5% in Howrah, Hooghly and 24-Parganas (South) respectively. PMID- 7836002 TI - Maternal behaviour and feeding practices as determinants of childhood diarrhoea: some observations amongst rural Bengalee mothers. PMID- 7836003 TI - Some aspects of Diarrhoea Training and Treatment Unit in Infectious Diseases Hospital, Calcutta. PMID- 7836004 TI - Answers to questions in relation to oral rehydration therapy. PMID- 7836005 TI - 15 Years of CPITN. Workshop proceedings. Manila, Philippines, February 1994. PMID- 7836006 TI - CPITN--a WHO initiative. AB - When the WHO Global Oral Data Bank was initiated in 1969 the Periodontal Index and the Simplified Oral Hygiene Index were the two preferred methods for data accumulation. It became clear that these two indices were not wholly satisfactory and in 1977 a WHO Scientific Group meeting was convened in Moscow which produced a prototype index, the TRS 621. In 1980 a Joint Working Group was established with the FDI from which emerged the formal adoption of CPITN. As a result the CPITN has enabled the sufficient accumulation of epidemiological data to permit much progress in our knowledge of periodontal disease, as well as being developed for clinical use in screening. Those involved with the development of the CPITN may be justly proud of the subsequent achievements resulting from this initiative. PMID- 7836007 TI - Validity and relevance of the criteria of the CPITN. AB - The validity and relevance of the criteria used in the CPITN index are considered against the background of their use throughout the world in the last 15 years. Overall the CPITN criteria satisfy both measures, although some suggestions are given for further refinements. It is recommended that, in conjunction with the Periodontal Screening and Recording system, a simplification to five code numbers for both findings and treatment needs be considered. Other matters considered should include the discontinuation of the description 'shallow pocket', training in the use of a 20 g probing force and a lowering of the age at which periodontal screenings are commenced for children. PMID- 7836008 TI - CPITN--interpretations and limitations. AB - As with all indices which impose numerical scales on a biological process, there are limitations with CPITN which must be identified and recognised. The limitations are due to the index being used for purposes for which it was not originally designed and recent advances in understanding which question the underlying assumptions of the index. Whilst questioning whether these limitations are sufficient to abandon the CPITN in favour of a new index, suggestions are made for modifications to the existing system. These include, the recording of each of the clinical indicators separately, as well as including the measurement of total loss of attachment. In addition an extension of the treatment need scale from four to five points is suggested. PMID- 7836009 TI - CPITN as a basic periodontal examination in dental practice. AB - Diagnosis of a disease or condition in an individual may be defined as a conclusion which is reached following an evaluation of clinical, radiographic, laboratory and anamnestic information obtained by examination. No index designed for epidemiological purposes can be substituted for the careful process of reaching a diagnosis in an individual. However, in spite of arguments against its validity in this respect, CPITN has been suggested as a simple and quick screening tool for use in general dental practice. Several studies support this notion and that CPITN may assist in: assessing the goals for treatment, estimating the time and cost requirements, evaluating the results, and being useful in communication between dentists, specialists and auxiliary personnel. Modifications of CPITN for use with individuals have been launched in several countries which dentists and periodontists find useful and acceptable. PMID- 7836010 TI - 15 years of CPITN--a Japanese perspective. AB - In Japan CPITN has been widely applied in dentistry over the past 10 years. CPITN has been introduced for screening purposes into basic dental epidemiology, dental public health and dental clinical practice. From many surveys the periodontal needs of young, mature and elderly populations have been documented. For the purpose of promoting improved periodontal awareness and care, CPITN has been implemented in dental public health and community based activities in schools, in industry, and in health centres. This has involved periodontal screenings and appropriate health guidance. The Japanese Health Laws are being modified to include a need for periodic oral examinations which will incorporate a CPITN screening. National goals for periodontal health at different age levels, based on CPITN, have been proposed and included in the national '8020' goal for oral health. PMID- 7836011 TI - Dental public health: CPITN as a strategy towards better periodontal health. AB - The CPITN has been widely adopted in health services planning. Studies widely used for service planning indicate that deep periodontal pockets are an infrequent manifestation of the need for periodontal treatment and that a substantial amount of periodontal care can be done by dental hygienists. However, so far, CPITN data has not been helpful in placing periodontal treatment needs within the context of general health needs, partly because it is often presented in terms unfamiliar to health service planners and in categories not immediately meaningful to decision makers in the health sector. Finally, there is very limited data showing the use of CPITN for evaluating changes in periodontal status; the limited experience in evaluating change would suggest that further research is needed on the most appropriate format for data presentation and the statistical analysis of such data. PMID- 7836012 TI - Periodontal health: CPITN as a promotional strategy. AB - Community and individual involvement are essential needs in preventive programmes for periodontal health. Campaigns should be directed towards a better individual understanding of the importance of healthy gum tissues if a functional healthy dentition is to be retained over a lifetime. Effective awareness campaigns require not only participation and education of the general public, but also all levels of health care professionals. Awareness programmes need to be carefully planned and their messages clear, non-conflicting and regularly reinforced. The complete programme should be based on, and include, specific aims, goals, strategies, monitoring and evaluation. Oral health and hygiene promotion campaigns need careful coordination between the relevant agencies or institutions involved in their implementation, such as government agencies, professional associations, industry, aid groups and education organisations. PMID- 7836013 TI - Periodontal probes and probing. AB - Probing of the sensitive, soft periodontal tissues differs markedly from probing of the dental hard tissues and caries. Periodontal probing requires special skills as well as an understanding of the tissues being examined, the probing procedure and the use of an appropriately designed instrument. Periodontal probing seeks to complement the initial visual assessment of the status of the periodontal tissue. It has multiple roles: to assess the haemorrhagic response to physical pressure; to determine the presence of aetiological factors such as calculus, defective dental restorations and root erosion, and to determine the pocket dimensions. It is also essential that the periodontal tissues should not be traumatised during probing. These defined aims of probing can only be achieved by use of an instrument that is capable of performing these functions, is designed to be 'tissue friendly', suitable as a measuring instrument, and standardised to ensure reproducibility, particularly with respect to the recommended pressure of 20 g exerted during probing. In addition, the ideal probe should be suitable for use both in the clinical setting where precise data documentation is required on an individual patient basis, and for screening purposes, as in epidemiology. A probe designed to achieve these attributes PMID- 7836014 TI - Background to, and implementation of, the Periodontal Screening and Recording (PSR) procedure in the USA. AB - The background to the introduction of the CPITN based Periodontal Screening and Reporting procedure in the USA in 1992 and progress in its implementation to date is described. A description of the content of the promotion programme to dentists and the public is also presented. PMID- 7836015 TI - Summary of outcomes and recommendations of the workshop on (CPITN). PMID- 7836016 TI - An evaluation of drug injection behaviors and HIV infection. National AIDS Research Consortium. AB - This paper investigates domains of drug injection behavior and the association of derived factors to HIV serostatus. Two sets of data were randomly selected and matched from a national data set of over 40,000 drug injectors. One set was HIV seropositive and the other HIV seronegative heterosexual injectors. Samples were matched to control for the effects of race/ethnicity, gender, and age on serostatus. Factor analysis was used to investigate relationships among drug injection behaviors. Four independent factors were found. Two factors were found to be statistically related to HIV serostatus in high seroprevalence areas. None of the needle use factors was found to be significantly associated with serostatus in low seroprevalence areas. PMID- 7836017 TI - Motherhood and drug-dependency: the attributes of full-time versus part-time responsibility for child care. AB - This study examined differences between the maternal characteristics of African American drug-dependent mothers who have full-time responsibility for child care and those having part-time responsibility. The study revealed that full-time mothers have significantly higher levels of maternal adaptation than part-time mothers. For part-time mothers, the level of maternal adaptation or self-esteem did not fluctuate, regardless of whether she saw the child 4 days a week or once a month. The article identifies variables that may facilitate better maternal behaviors among drug-dependent mothers. PMID- 7836018 TI - Smoking among high school students in 10 Italian towns: patterns and covariates. AB - The associations between tobacco smoking and demographic, socioeconomic, environmental, and behavioral factors among adolescents were investigated by administering an anonymous questionnaire to 5,221 ninth (aged 14-15 years) and 4,154 thirteenth grade (aged 18-19 years) students in 10 Italian towns. Using logistic regression analysis, both current smoking and experimental smoking were statistically associated with sibling, best friend, and partner smoking, alcohol drinking, and frequency of drunkenness in both grades and sexes. Attitude of parents toward children's smoking was also found to be associated with the probability of being a current smoker, especially among ninth graders. Parental smoking was associated with current smoking among females only. Socioeconomic factors and level of knowledge of the health consequences of smoking were not associated with either experimental or regular smoking. In conclusion, this survey suggests that social environment plays a fundamental role in both first experimentation with smoking and the process of becoming a regular smoker among adolescents. Students with one or more siblings who smoke, and especially those with best friends and a partner who smoke, were much more likely to have tried smoking and to be current smokers than students without smokers in their environment. PMID- 7836019 TI - Relationship of "risk" factors to teen substance use: a comparison of abstainers, infrequent users, and frequent users. AB - This study was designed for the purpose of investigating the differences between adolescent substance abstainers, infrequent users, and frequent users on risk factors for substance use related to commitment to education, peer influence, family relationships, and intrapersonal factors. Results from analyses comparing the three groups on the risk factor variables showed that teen substance abstainers and infrequent users are more similar to each other than they are similar to frequent substance users. The study provides support for the contention that preventive efforts may be more successful if targeted at clearly identified groups of problem teen substance users. PMID- 7836020 TI - Adolescent drinking and alcohol-related problems in a nationwide general population. AB - A sample of 1,325 adolescents drawn from a nationwide multistage probability master sample of 4,290 persons were interviewed at their homes in 1984. The purpose of this study was to investigate the patterns and quantity of alcohol consumption and related problems. Moreover, mental health status of respondents and "risk" factors were explored. Alcohol use increased from the very young to the older ones and decreased between lifetime and past week frequencies. Of adolescents, 18% reported two or more alcohol-related problems including suffering from depressive symptoms. Discriminant analysis revealed 14 predictors with high discriminating power between problematic and nonproblematic drinking. PMID- 7836021 TI - Shame and depression proneness among female adult children of alcoholics. AB - Although recent clinical literature has posited that both shame and depression are important aspects in the treatment of adult children of alcoholics (ACAs), proneness to shame and depression in this group remains underexamined. This study tests the hypotheses that ACAs are more prone to shame and depression than non ACAs. The sample consisted of 60 women--30 ACAs and 30 non-ACAs--who were 22 to 55 years old during the study period and had begun treatment within the past 6 months. The dependent measures were the Depression Proneness Rating Scale and the Adapted Shame/Guilt Scale. Female ACAs were found to be more depression prone than non-ACAs (p < .05), and the difference was not explained by any of the other variables studied. Contrary to expectations, they were not found to be more shame prone. The results are discussed as they relate to alternative hypotheses, clinical implications, and future research. PMID- 7836022 TI - Access to gambling opportunities and compulsive gambling. PMID- 7836023 TI - Personality and drug preferences in normal volunteers. AB - This study examined the relationship between drug preferences as measured in a laboratory-based choice procedure and measures of personality and attitudes toward drugs. Healthy volunteers participated in laboratory-based double-blind studies measuring preference for ethanol or diazepam vs placebo. Frequency of drug choice was examined in relation to subjects' scores on personality questionnaires. Drug choice was not related to any of the personality measures examined. Personality scores were, however, related to both gender and habitual drug use. These data suggest that personality does not strongly influence responses to single doses of drugs as assessed under controlled conditions. Personality may, nevertheless, affect drug use in natural settings via other mechanisms (e.g., interacting with psychosocial variables). PMID- 7836025 TI - Pharmacokinetic study of rifaximin after oral administration in healthy volunteers. AB - Eighteen healthy male volunteers, with a mean age of 24 yrs (range 18-40), underwent an open pharmacokinetics study, aimed at detecting rifaximin concentration in blood and urine after a single oral administration of 400 mg of the antibiotic. Administration took place after a 9 hours' fast and was followed by a breakfast after 2 hours and a lunch after 5 hours. Blood samples were collected before rifaximin administration and 1, 2, 4, 8, 12, 24 and 48 hours after dosing. Urine samples were collected immediately before dosing (reference sample) and then at the end of the following intervals of time: 0-6 h, 6-12 h, 12 24 h, 24-48 h. During the whole study period, the local and general tolerance to rifaximin administration was checked. Rifaximin concentration was assessed by reversed phase high performance liquid chromatography with electrochemical detection. In almost every plasma sample, rifaximin concentration was undetectable (lower than the detection limit of the analytical method, i.e. 2 ng/ml). In urine, very small amounts of the unchanged molecule (< 0.01% of the administered dose) were found in the period 0-48 hours. These results confirm the negligible absorption by the intestinal tract of a single oral dose of rifaximin (400 mg). Local and general tolerance of the administered drug was very good. PMID- 7836024 TI - Drug-using and nonusing women: potential for child abuse, child-rearing attitudes, social support, and affection for expected baby. AB - Eighty pregnant women (25 substance using, 55 nonusing) from an American prenatal clinic serving lower-income to working-class women responded to questionnaire measures of child-rearing attitudes. The drug users' primary substance of misuse was cocaine (68%), alcohol (16%), amphetamines (12%), or sedatives (4%); polydrug use was documented for 80% of the women. The two (user and nonuser) groups were not different on demographic (age, race, marital status, education, SES, source of income) or obstetrical factors (number of pregnancies, number of children). Drug-using women scored significantly higher on a measure of child abuse potential; more than half scored in the range of clinical criterion for extreme risk. As their babies were not yet born, no actual physical abuse was documented, only a higher potential for abuse. The subgroup who were both drug users and had lower social support scored higher on child abuse potential than all other subgroups. The drug users also had lower self-esteem scores than the nonusers. The two groups did not differ on measures of overall social support, authoritarian/democratic child-rearing beliefs, or affection for the expected baby. PMID- 7836026 TI - The purine nucleotide content of lymphocytes from patients with rheumatoid arthritis. AB - A procedure has been described for the preparation of T and non-T lymphocyte populations. The purine nucleotide contents were analyzed by high-performance liquid chromatography. In healthy subjects the pattern was shown to be different in the two cell populations. In patients with rheumatoid arthritis the findings as compared with the healthy subjects were as follows; in T cells the RA patients showed a slight decrease in di- and tri-phosphates, a more significant decrease of NAD and an increase of AMP. The changes in non-T cells of the RA patients were highly significant and can be summarized as a generalized reduction of all nucleotides, except IMP which tends to increase, and GMP which remains constant. The variations observed in nucleotide content do not involve alterations of some parameters, such as the adenylates/guanylates, the ATP/ADP and GTP/GDP ratios and the energy charges for adenylates and guanylates, regarded as an index of cell energy and viability. It is possible that disturbances of purine metabolism, revealed through the determination of purine contents of lymphocytes, precede immunological events and could be useful in the study of immunologic disorders such as rheumatoid arthritis. PMID- 7836027 TI - Dynamic training and circulating neuropeptides in patients with rheumatoid arthritis: a comparative study with healthy subjects. AB - This study aimed at evaluating the effects of a dynamic physical training programme on circulating levels of corticotropin-releasing hormone (CRH), beta lipotropin (beta-LPH), and beta-endorphin (beta-EP) after high-intensity training for 6 weeks (60 min twice a week) and after low-intensity training (home training) for another 6 months in patients with rheumatoid arthritis (RA) and in healthy subjects. Additionally, differences in neuropeptide levels between the two groups were studied. A total of 30 patients with RA were randomly allocated to the study, 15 in the training group (TG) and 15 in the control group (CG). In addition, 20 healthy subjects (10 in TG; 10 in CG) participated. In addition to the biochemical analyses, the following variables were assessed for the RA group: pain and disability (Stanford health assessment questionnaire), joint tenderness (Ritchie articular index), disease activity, muscle function, aerobic capacity, sociodemographic data and attitudes. The results obtained at the start revealed significant differences (p < 0.05) between RA patients and healthy subjects concerning CRH levels, RA patients showing the lower levels (RA-group Md = 24 pmol/L, healthy group Md = 29 pmol/L). No significant differences concerning beta LPH and beta-EP were found here. After the high-intensity training period, a significant increase of the CRH levels were found for the RA-TG (pretest Md = 24 pmol/L, after 6 weeks Md = 27 pmol/L, p < 0.05). No such results were found for the healthy-TG or the control groups. Concerning beta-EP, significant differences between the RA-TG and healthy-TG were found after the training. RA patients generally showing higher levels as compared with the healthy (RA-group Md = 42 pmol/L, healthy group Md = 36 pmol/L, p < 0.05). The same pattern was found for the beta-LPH levels. In conclusion, the effects of physical training on circulating neuropeptides remain still incompletely examined, and there is no definite answer to the question whether increased beta-EP levels are good or bad. PMID- 7836028 TI - Rheumatoid nodules and cyclosporin A treatment. AB - The authors describe the appearance of rheumatoid nodules during cyclosporin A (CsA) therapy for RA. Their course was evaluated by sonography that revealed an increase in number and size of rheumatoid nodules. The relationship between CsA treatment and the onset of nodulosis is not clear and further studies are needed to assess the role of CsA treatment in the extra-articular manifestations of rheumatoid arthritis such as rheumatoid nodules. PMID- 7836029 TI - Intra-articular injection of somatostatin in knee osteoarthritis: clinical results and IGF-1 serum levels. AB - Recently somatostatin (SST) intra-articular administration has been used in the treatment of some rheumatoid diseases such as rheumatoid arthritis, psoriatic arthritis and osteoarthritis with encouraging results. The aim of this study was to evaluate the efficacy and tolerability of SST intra-articularly injected, involving 20 patients with knee osteoarthritis. Treatment consisted of 4 injections, administered weekly, each of 750 mcg SST. Additionally, in six of them we evaluated the circulating levels of the insulin-like growth factor (IGF) 1 at the base-line time and then every 7 days (immediately before each dose of SST). The results revealed an improvement in pain and in joint function after intra-articular SST, confirmed by statistical analysis. The circulating levels of IGF-1 did not show significant variations following intra-articular administration of SST. The excellent tolerability and the absence of unwanted side-effects with SST allow us to foresee that intra-articular SST could be used in cases of painful knee osteoarthritis, especially in those patients in which other drugs are not appropriate. Moreover, in the absence of modifications of serum levels of IGF-1, SST could be used in athletes. PMID- 7836030 TI - Chronic otitis media requiring ventilation tubes in tracheotomized ventilator dependent children. AB - The occurrence of sinusitis and middle ear effusions has frequently been attributed to the obstruction of the sinus ostia and/or eustachian tube. In the intensive care unit setting, edema caused by the irritation from nasogastric, nasotracheal and orotracheal tubes has been associated with this pathology and has been responsible for occult sepsis in this population. Our investigation was performed to determine the risk of chronic otitis media with effusion necessitating myringotomy with tympanostomy tubes among tracheotomized, ventilator dependent children in a consecutive series of children admitted to our recently created stable ventilator unit. We retrospectively reviewed the medical records of all tracheotomized, chronically ventilator dependent children < 48 months of age who had been hospitalized in this unit from the initial opening in September 1990 to January 1993. Data collected consisted of patient demographics, gestational age, cognitive abilities, age at onset of mechanical ventilation, age at tracheostomy, age at myringotomy, presence of nasogastric and gastroenterostomy tubes and evidence of gastric-esophageal reflux. All children underwent a tracheostomy procedure subsequent to the onset of mechanical ventilation. Of these patients, 9/12 (75%) later required myringotomy with tympanostomy tube placement following the occurrence of chronic otitis media with effusion. Ventilation tubes for chronic otitis media with effusion were not required in 3 patients. Using a case control study design, we examined the need of myringotomy tubes for children requiring continuous mechanical ventilation versus those requiring night-time only ventilation. The risk of myringotomy tubes in the continuously ventilated group (9/9) was significantly greater than the risk in the intermittently ventilated group (0/3) P < 0.01.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836031 TI - Factors that influence successful decannulation after surgery for laryngo tracheal stenosis in children. AB - The process to decannulation requires attention to details from the time of initial tracheostomy, through the pre- and peri-operative period up until the decannulation event. Important points to consider during this process are: a formal tracheostomy rather than a tracheotomy; other potential sites of obstruction than the laryngeal stenosis; gastroesophageal reflux; prevention and control of infection and the use of prophylactic antibiotics; method and type of suture material; stenting; movement and method of feeding. Decannulation itself requires attention to removal of granulation tissue and control of tracheomalacia and tracheostenosis. PMID- 7836032 TI - Tympanic membrane atrophy, scarring, atelectasis and attic retraction in persistent, untreated otitis media with effusion and following ventilation tube insertion. AB - Two hundred and twenty two children with persistent bilateral otitis media with effusion (OME) were treated with unilateral ventilation tube insertion and no treatment to the contralateral ear. The tympanic membrane changes in the operated and unoperated ears were compared during a 12 year follow-up. Segmental atrophy resulted from tube insertion whereas minor scarring and thickening of the pars tensa was related to the middle ear condition. Eight three percent of untreated ears and 85% of those treated with tubes did not develop atelectasis. Sixty percent of untreated ears and 64% of treated ears did not develop attic retraction. Very few cases (1.5 and 2%) in untreated and treated ears, respectively developed severe atelectasis. The overall duration of OME was assessed from the pre-operative history of hearing loss, the 3 month period of pre-operative observation and the post-operative time with effusion. There is a relationship between duration of the disease and development of both atelectasis and attic retraction. PMID- 7836033 TI - Familial occurrence of pleomorphic adenoma. AB - Pleomorphic adenoma is the most common neoplasm found in the parotid gland. The familial occurrence of any salivary gland neoplasm is rare. There are 8 previous reports in the literature of familial occurrence of salivary gland tumors. Two of these report the occurrence of pleomorphic adenoma of the parotid gland in siblings; all 4 patients were adults. We report here an 11-year-old male who presented with a left parotid mass and underwent parotidectomy. The mass proved to be a pleomorphic adenoma. His sister presented 9 years later at the age of 15 years with a similar mass also in the left parotid area. She underwent superficial parotidectomy which revealed the mass to be a pleomorphic adenoma. We believe these are the youngest siblings reported to date in which familial pleomorphic adenoma has occurred. PMID- 7836034 TI - Chronological changes of auditory brainstem responses in Cockayne's syndrome. AB - Cockayne's syndrome (CS) is a rare autosomal recessive premature-aging disorder which is clinically characterized by physical and mental retardation, retinal pigmentation, sensorineural deafness and other neurological abnormalities. Auditory brainstem responses (ABRs) and behavioral audiometry were studied in 4 cases of confirmed CS chronologically. In one case, ABRs were normal at first but became abnormal. Initially, ABRs revealed only wave I with prolonged latency and thereafter no response. In another case, ABRs revealed the absence of all waves beyond wave III and then revealed the disappearance of all waves. In 2 other cases, ABRs were absent from the first testing. Behavioral levels were elevated in all 4 cases. In 2 cases, behavioral levels did not change in spite of partial disappearance of ABR waves, but they had elevated severely since all waves including wave I disappeared. Our findings suggest that the disease spreads from the upper brainstem to the cochlear nerve and that the site of the lesion causing hearing loss in CS is in the brainstem lesion as well as the peripheral one. PMID- 7836035 TI - Congenital absence of the epiglottis and its potential role in obstructive sleep apnea. AB - A 3 month old girl with congenital absence of the epiglottis presents with inspiratory stridor. Over the next 8 years frank obstructive sleep apnea (OSA) develops, confirmed by polysomnography. She has no difficulty in swallowing or phonation as assessed clinically and with barium swallow. This suggests that the epiglottis may help stabilize the upper airway, and any role in swallowing or phonation may, in its absence, be compensated by other mechanisms. PMID- 7836036 TI - Iatrogenic hyponatremia: a cause of death following pediatric tonsillectomy. AB - Death following pediatric tonsillectomy is very rare. If deaths occur, they are most commonly due to bleeding or aspiration. In this presentation, we would like to illustrate another potentially lethal complication following the pediatric tonsillectomy, iatrogenic hyponatremia. We have encountered 3 patients who have developed post-operative hyponatremia. This has resulted in 2 deaths. The third patient was successfully treated and developed no permanent sequela. We will discuss the etiology and pathophysiology of post-operative hyponatremia including guidelines for administering fluid and electrolytes intra-operatively and post operatively. We expect that fatal post-operative hyponatremia can be avoided in the pediatric tonsillectomy patients. PMID- 7836037 TI - Sarcoidosis of the upper respiratory tract in children. AB - Sarcoidosis is a multisystemic granulomatosis of unknown etiology which mainly affects young adults. It is characterized primarily by bilateral hilar adenopathies, a pulmonary infiltrate and cutaneous and ocular lesions. It rarely occurs in children under the age of 16. Localization in the upper respiratory tract (URT) is infrequent and sarcoidosis of the URT in children is exceptional, with only 13 cases reported in the literature. In the present report we describe the clinical, diagnostic explorations, histological and therapeutic aspects of 2 new cases in children. PMID- 7836038 TI - Endoscopic sublabial transnasal approach for correction of congenital choanal atresia. PMID- 7836039 TI - 8th Autoimmunity meeting. Dedicated to M. Eric Gershwin. Tel-Hashomer, Israel, 25 January 1994. PMID- 7836040 TI - Dominant epitopes and synthetic peptides in myasthenia gravis. PMID- 7836041 TI - A new experimental model for Wegener's granulomatosis. PMID- 7836042 TI - Beta 2GP-1 cofactor and anticardiolipin antibodies. PMID- 7836043 TI - New avenues in autoimmunity research. PMID- 7836044 TI - The molecular basis of primary biliary cirrhosis: interfacing clinical medicine and wet bench research. PMID- 7836045 TI - Natural (antiphospholipid-PDH,-DNA) autoantibodies and their physiologic serum inhibitors. PMID- 7836046 TI - Immunomodulation of autoimmunity by linomide. PMID- 7836047 TI - Pemphigus--identifying the autoantigen and its possible induction of epidermal acantholysis via Ca2+ signalling. PMID- 7836048 TI - Enteric viral infections in Gaza children--incidence and associated factors and phenomena. AB - Regular administration of live attenuated polio vaccine (TOPV) to babies in Gaza failed to give adequate protection against infection and disease with wild polio viruses. The possible interference of the "take" of the vaccine was investigated by obtaining demographic, socioeconomic and virological data. More than 100 babies during their first year of life, and their families, were followed. Enteroviruses were isolated in 25.3% and 7.9% of stool samples obtained from healthy babies and babies with diarrhea, respectively. In the same cases, rotaviruses were detected in only 1.9% and 1.4% respectively. It appears that the most common candidates for viral interference in this population are enteroviruses and not rotaviruses, either in healthy babies or in babies suffering from diarrhea. PMID- 7836049 TI - Subpopulations of lymphocytes and autoimmunity. PMID- 7836050 TI - Meningococcal disease in the Israel Defense Force: epidemiologic trends and new challenges. AB - To determine recent trends in its epidemiology and the need to reconsider prophylactic interventions, meningococcal disease in the Israel Defense Force (IDF) from 1975 through 1993 was studied. All cases of meningitis or meningococcemia were included. A considerable increase in the number of cases has been observed since 1991, with serogroup C becoming predominant (76% of cases) since then. Serogroup Y was the second most frequent serogroup during this period, while serogroup B, predominant in the civilian population of Israel, was rare. Most cases occurred during the first 6 months of military service. Seasonality was important, with most of the cases occurring between December and March, although a small summer peak was also noted. Since 1992, three small clusters of meningococcal disease were encountered in the IDF, for the first time, with all cases caused by group C meningococci. In one cluster, the emergence of rifampicin resistance resulted in failure of chemoprophylaxis. The rise in group C and Y cases since 1991, and the occurrence of rifampicin resistance, necessitate considering meningococcal vaccines and new antimicrobial agents for prophylaxis. PMID- 7836051 TI - Oral fluoroquinolone use in the community. AB - The use of oral fluoroquinolone in the community was evaluated in the Jezreel Valley area in northern Israel over an 8-month period. A total of 1,136 prescriptions for oral quinolones were prescribed for a population of 300,000 people. The findings of the study show that 70% of the prescriptions were initiated by outpatient clinic specialists or at hospital discharge, and that 70% of all prescriptions were justified and properly prescribed. No significant difference was found whether the initiating physician was a specialist or family practitioner or when the drug was recommended on hospital discharge. Moreover, the manner in which the different antibiotics were internally divided indicated the prescribing physicians' understanding of the properties of each drug. The results demonstrate that oral fluoroquinolones have been used in the Jezreel Valley area sparingly, judiciously, and according to each drug's properties. The high degree of justified use may reflect successful antibiotic control within the medical center serving that area. PMID- 7836052 TI - A double-blinded, randomized, controlled clinical trial to compare cefazolin and cefonicid for antimicrobial prophylaxis in clean orthopedic surgery. AB - A double-blind, prospective randomized study was performed to compare cefazolin and cefonicid given for prophylaxis to 102 patients undergoing orthopedic surgery. Risk factors (e.g., age, sex, type of operation performed) among the two groups were similar. All patients had foreign material (prosthesis or other hardware) inserted at operation. There was a total of 6 infections (3 wound and 3 urinary tract) in 6 patients among the 48 receiving cefazolin (12.5%), whereas no infections were observed among the 54 patients who received cefonicid. Cefonicid, given once daily, provides protection against postoperative infection that is not inferior to cefazolin. A larger study is needed to confirm whether cefonicid is indeed superior to cefazolin. PMID- 7836053 TI - Intravenous immunoglobulin treatment in multiple sclerosis. PMID- 7836054 TI - Telemedicine augments advanced laparoscopic surgery. PMID- 7836055 TI - A decade of difference--MADD in Hawaii. PMID- 7836056 TI - Radiofrequency catheter cure of idiopathic ventricular tachycardia--first experience in Hawaii. AB - Radiofrequency catheter ablation is a well-established technique in the therapy of many forms of supraventricular tachyarrhythmias. Its usage in ventricular arrhythmias is little known. This is a report of its first usage in Hawaii in the treatment of 2 specific forms of ventricular tachycardia in 5 patients without structural heart disease. A cure was achieved in 4 of the 5 patients. PMID- 7836057 TI - Characteristics of veterans in Hawaii with and without diagnoses of post traumatic stress disorder. AB - A total of 118 combat veterans seeking services at the VA Medical Center in Honolulu were assessed on a variety of demographic and psychometric dimensions, permitting the first systematic comparison on the measured variables between veterans with and without PTSD in the multicultural population of veterans in Hawaii. The results have implications for medical interventions with this population. PMID- 7836058 TI - Nomenclature for factors of the HLA system, 1994. PMID- 7836059 TI - European Conference on Histocompatibility 1994: selected papers. Strasbourg, France, March 7-9. PMID- 7836060 TI - Function of DQ2 and DQ8 as HLA susceptibility molecules in celiac disease. PMID- 7836061 TI - Molecular basis for degenerate T-cell recognition of one peptide in the context of several DR molecules. AB - We report the study of one CD4+ T-cell clone that recognizes peptide HA306-320 in the context of autologous DR1101 molecules as well as of allogeneic DR1301, DR0402, DR1501, and DR1601 molecules. This degenerate T-cell recognition is mediated by a single T-cell receptor (TCR) as judged by both TCR-V beta sequencing and cold-target competition assays. Restriction analysis shows that substitutions of DR residues within the third hypervariable region result in a loss of T-cell reactivity, which is restored by additional substitutions in the first and/or second hypervariable regions. Thus, there is no correlation between antigen presentation abilities of the different allelic DR products and the degree of sequence homology between these products. DR residues whose substitution is compatible with T-cell recognition potentially interact with peptides rather than with TCRs by virtue of their location in the floor of the groove or as previously documented for residues of the alpha-helix. Furthermore, antigen presentation by allogeneic DR molecules occurs independently of their affinity for the peptide, as determined in cell surface-binding assays using biotinylated HA306-320. Altogether these data suggest that degenerate T-cell recognition mainly depends on an influence of polymorphic DR residues on the configuration adopted by the peptide in the DR groove so that the epitope is left intact. PMID- 7836062 TI - The peptide-binding specificity of HLA-B27 subtype (B*2705) analyzed by the use of polyalanine model peptides. AB - Model peptides have been used to quantitate the effect on HLA-B*2705 binding of the spacing between primary anchor residues, the type of amino acid accepted in the P9 anchor position, and the type of amino acid accepted in the "secondary anchor positions" P3 and P7. Peptide binding was measured by the HLA class I alpha-chain-refolding assay. The results obtained show that (a) Among the model peptides differing in the spacing between anchor residues, the nonamer with Arg in P2 and Lys in P9 (R2, K9) has the maximum binding with B*2705 molecule. The decamer, with an extra Ala inserted between Arg and Lys (R2, K10), has much lower binding, and still lower binding is observed for the octamer, where an Ala is removed (R2, K8). (b) Besides the "classic" Lys and Arg, several other aminoacids such as Tyr, Leu, Ala, and Gln can be accepted in P9, but with significant differences in binding affinity. (c) Different amino acids in P3 have an influence on peptide binding. Trp and Phe have a favorable influence, whereas Lys and Val appear to hinder the binding. Some variations are seen also for different amino acids in P7. PMID- 7836063 TI - A 16mer peptide of the human autoantigen calreticulin is a most prominent HLA DR4Dw4-associated self-peptide. AB - The human Ca(2+)-binding (storage) protein calreticulin, located in the lumen of the endoplasmic reticulum, is proposed to play a role as autoantigen: anticalreticulin autoantibodies occur in the sera of patients with SLE and patients with onchocerciasis (calreticulin shows a high sequence homology to the Onchocerca volvulus antigen RAL-1). Here we present sequencing data of a HLA DR4Dw4-associated calreticulin peptide fragment, Cal(295-310), purified from a DR4Dw4 self-peptide pool. Cal(295-310) proved to be one of three commonest self peptides associated with DR4Dw4 molecules that were isolated from the EBV transformed B-cell line BSM (DR4Dw4, DRw53). We tested the binding of Cal(295 309) and the analogous RAL-1 peptide to HLA-DR molecules: Cal(295-309) exhibited specific binding characteristics for DR4Dw4. Binding assays using self-peptide analogues with replaced amino acids led us to a DR4Dw4-binding motif with anchor residues at relative positions 1 and 6. The sequencing data suggest that calreticulin is a frequently processed intracellular protein. The abundance of calreticulin makes the presentation of different calreticulin peptides associated with HLA-D molecules likely to occur, supporting the immunologic relevance of this molecule. PMID- 7836064 TI - Nonrandom allelic variation in the regulatory complex of HLA class I genes. AB - Recently, we have demonstrated that the HLA class I regulatory complex (CRC) is conserved in a locus-specific manner with limited allelic variation. In this study, we have analyzed the CRC sequences of the alleles that showed variation from a total of 22 well-characterized, HLA-homozygous B-LCLs, using PCR amplification of genomic DNA and direct sequencing. We compared the sequences of these alleles with their respective locus consensus sequence at kappa B1, kappa B2, the IRS, the putative NRE, and the HLA counterpart of the H-2RII region, the R x R beta-binding site. The palindromic kappa B1 sequence, an active enhancer, was found to be conserved in all HLA-A and -B alleles and in one HLA-C allele. The sequences of the kappa B2 site showed locus-specific divergence with almost no allelic variation. The IRS is strictly locus specific and HLA-B and -C have identical sequences in this region. Variation in the putative NRE sequence and RII-kappa B2 junctional sequence was apparently generated by gene conversion between B and C loci. Each locus had two sequence patterns at the putative RII site. Overall, sequence analysis of variant alleles demonstrated that there is limited variation in a nonrandom fashion. These results may provide a structural basis for locus and allele-specific modulation of these genes. PMID- 7836065 TI - New species-specific alleles at the primate MHC-G locus. AB - Six different ape MHC-G DNA sequences (four in humans: HLA-G*01011, HLA-G*II, HLA G*0103, and HLA-G*IV; one in chimpanzees: Patr-G*I; and one in gorillas: Gogo G*1) have been obtained. Only synonymous or conservative ("Thr"-to-"Ser") substitutions are allowed between the four human alleles. One allele of MHC-G exon-2 sequences has been found both in gorilla (Gorilla gorilla) and chimpanzee (Pan troglodytes). The Patr-G*I DNA sequence shows two nonsynonymous substitutions when compared with the human HLA-G*01011 sequence: "CGG"-to-"TGG" ("Arg"-to-"Trp") at codon 35 and "ATG"-to-"ATA" ("Met"-to-"Ile") at codon 76. One nonsynonymous "GAG"-to-"GGG" ("Glu"-to-"Gly") substitution is observed in the Gogo-G*I exon-2 DNA sequence, when compared with the human *01011 allele. None of these three different substitutions have been observed in humans and are, thus, considered species specific. Also, evidence is provided that the human HLA-G*II and G*0103 may have been originated after human speciation. Finally, phylogenetic relationships among the six MHC-G alleles, tamarins G-"like" alleles, and other human class I genes (both "classical" and "nonclassic") are discussed. PMID- 7836066 TI - Promiscuous and specific binding of HIV peptides to HLA-DR1 and DR103. Impact on T-cell repertoire of nonimmunized individuals. AB - The binding of immunogenic peptides to DR molecules is influenced by residues that point into the peptide-binding groove. The T-cell response toward a peptide complexed to an MHC molecule depends on the presence of a sufficient number of T cells reactive with peptide-MHC complex on the surface of APCs. From 96 overlapping HIV peptides, we have selected 11 that show a significant binding to either DR1, DR103, or both. These two DR molecules are identical except for three amino acids at positions 67, 70, and 71 on the beta chain. Peptide-specific T cell lines and clones were generated with cells from nonimmunized donors homozygous for DR1 or DR103 by using either individual peptides or peptide pools for the in vitro priming. Three of the peptides induced T-cell-specific proliferative response in both individuals, and these peptides were not among those with highest affinity. Most of the peptides induced strong responses against autologous APCs. This might reflect cross-reactivity between HIV and self peptides. Definition of peptides that both show promiscuous binding to DR and elicit a strong T-cell response is important for design of efficient synthetic vaccines. PMID- 7836067 TI - HLA class I allele (HLA-A2) expression defect associated with a mutation in its enhancer B inverted CAT box in two families. AB - The present study shows a very highly diminished HLA-A2 cell surface expression with mendelian segregation in two nonrelated Spanish families. The associated haplotype included Cblank-B38-DRB1*1301-DQ6 in both families. cDNA sequence analysis in two members, one of each pedigree, revealed the presence of the commonest HLA-A2 allele (A*0201), without repetitive mutations that could indicate inappropriate or inefficient translation. Further, the coamplified 3' untranslated region sequence was also the same described for HLA-A2. HLA-A transcription frequency by means of cDNA PCR-based cloning experiments and by Northern blotting pointed out a relatively low number of HLA-A2 mRNA molecules compared with the complementary HLA-A allele. 5'-Regulatory region sequences from two low-expressing HLA-A2 nonrelated individuals showed a unique and identical single point mutation at position -101 (T to C), when compared with all MHC class I alleles sequenced so far. Position -101 is located in the inverted CAT box associated with the MHC class I enhancer B. The fact that this is an extremely well-conserved position leads us to postulate that this change may be the only responsible for the defective expression of HLA-A2. PMID- 7836068 TI - Cellular immune recognition of HLA-A*0201 following gene transfer into a human embryonal carcinoma cell line. AB - Previously, we have established that transcription and cell surface expression of MHC class I and beta 2m genes in undifferentiated Tera-2 stem cells, a teratocarcinoma-derived cell line, was extremely low. In this study, we have transfected an HLA-A*0201-encoding cDNA driven by the CMV-promoter into Tera-2 cells. Prior to IFN gamma treatment, membrane expression of HLA-A*0201 by these Tera-2 transfectants was nearly lacking. Consequently, the HLA-A*0201 Tera-2 transfectants were not recognized by the allo-HLA-A*0201-specific CTL clone 3E7. Following IFN gamma treatment, which resulted in upregulation of HLA-A*0201, Tera 2 cells were lysed by CTL clone 3E7. In contrast, loading of HLA-A*0201 with the influenza-A-matrix peptide 58-66 resulted in partial lysis of Tera-2 cells by the influenza-A-matrix protein-specific CTL clone Q66-9, and nearly complete lysis was observed following IFN gamma treatment. These results suggest that the HLA A*0201 transgenes in Tera-2 cells can be loaded with peptides and used as targets for peptide-specific CTLs. PMID- 7836069 TI - The HLA-G gene is expressed at a low mRNA level in different human cells and tissues. AB - Recently, HLA-G transgenic mice were shown to exhibit transgene transcription in several extraembryonic tissues. To determine whether HLA-G mRNAs are also expressed in other human tissues, we have undertaken Northern blot and RT-PCR assays using HLA-G locus-specific probe and primers. These studies demonstrate that the HLA-G gene is transcribed in a variety of cells and adult tissues obtained from different individuals (peripheral blood leukocytes, placenta, skin, spleen, thymus, prostate, testicle, ovary, small intestine, colon, heart, brain, lung, liver, and kidney), as well as in fetal tissues (heart, lung, liver, and kidney). The HLA-G mRNA level observed in most tissues is orders of magnitude lower than the level of classic class I genes in the same tissues. RT-PCR studies have demonstrated that alternative splicing of the HLA-G primary transcript is different from tissue to tissue and could be regulated in a tissue-specific fashion. Sequencing of keratinocyte transcripts has confirmed previous observations: (a) three different alternative splicing transcripts are produced (a full-length transcript, an mRNA lacking exon 3, and a transcript devoid of exon 3 and 4) and (b) HLA-G polymorphism is limited in the coding regions. In view of this wide HLA-G tissue distribution, a new hypothesis dealing with possible HLA-G function is proposed. PMID- 7836070 TI - Characteristics of the cytosol-synthesized proteins generating class-I-bound peptides. AB - The proteins synthesized in the cytosol are several thousand, and the number of peptides potentially able to be bound by class I molecules they can generate is therefore huge. On the other hand, the actual number of peptide-class I complexes required for CTL activation is around 200. We focused on the peptides bound by B27 molecules and by the whole class I. By comparing our results with analogous data from other laboratories, we found that 31 peptides matched protein sequences in data bases; in four cases, two peptides are derived from the same protein. The finding of four pairs of identical samples in a sampling of 31 peptides from a pool of unknown magnitude suggests that this pool is quite small. We have estimated the size of this pool by combinatorial analysis and by computer simulation, and we have found a most probable distribution of about 100 to the number of self-proteins that can actually generate peptides bound by class I molecules. PMID- 7836071 TI - Microchimerism frequency two to thirty years after cadaveric kidney transplantation. AB - Understanding the mechanisms of unresponsiveness to allograft is crucial in order to induce long-term specific immune tolerance in organ recipients. An association between persistent microchimerism following allogeneic organ transplantation and donor-specific graft acceptance has recently been proposed. However, the frequency of chimerism and its relevance in long-lasting tolerance are still unclear. We studied 12 long-surviving (20-30 years) and eight recently grafted (2 years) cadaveric kidney transplant recipients for the systemic presence of donor alleles by using allele-specific genomic amplification of DRB1 and H-Y loci. This technique enabled the detection of a 1:4000 to 1:10,000 donor-recipient cell ratio. Among long-term tolerant recipients, microchimerism was observed in only one case in the peripheral blood and four cases in the skin. These chimeric patients did not differ from others by any clinical or immunologic parameter. In the 2-year tolerant patient group, skin chimerism was evidenced in only one patient who had simultaneously received kidney and liver transplants. No correlation was observed between the presence of chimerism and the number of HLA DR alleles shared by donor and recipient. This low frequency of microchimerism raises doubts about a major role of chimerism in development of long-lasting specific tolerance following kidney allografting. PMID- 7836072 TI - HLA-B35-subtype mismatches in ABDR serologically matched unrelated donor recipient pairs. AB - We have characterized HLA incompatibilities in a group of 17 B35-positive patients who were ABDR matched (AB serology and oligotyping for DR1-14) with their 28 (unrelated) potential bone marrow donors. High-resolution oligotyping for DR subtypes disclosed that nine combinations were in fact DR mismatched. Cytotoxic T-lymphocyte (CTL) activity was detected in nine combinations (32%). In the group matched for DR subtypes, three (16%) of 19 combinations were CTL positive. Patient-specific cytotoxic activity appeared to be directed against HLA C (two cases) or against a subtype of B35. In the group of DR-subtype-mismatched combinations, CTL activity was found in six (67%) of nine pairs. In all four cases that were studied in detail, however, CTL reactivity appeared to be directed against a variant subtype of B35. We have studied the B35 incompatibilities recognized in five different combinations by specificity analysis of the B35-specific CTLs and by partially sequencing of relevant segments of B35 exon 3. Preliminary data show that, within this relatively small Caucasoid group, at least five B35-variant subtypes could be distinguished. This would make B35 an antigen that will be frequently subtype mismatched, in particular when DR matching is done with low resolution (DR1-14) only. PMID- 7836073 TI - Through a glass darkly: predicting the future of radiation oncology. AB - To position ourselves professionally for the inevitable transition to managed care demands serious self-appraisal. Like most procedural medical specialties, radiation oncology is currently ill prepared for a capitated system of payment. To prosper under capitation, we need to increase the utility of radiation therapy per unit cost. This can be achieved by making the following adaptive responses: (a) we must ensure that the needs of medical practice drive the use of costly technology and not vice versa; (b) we must subordinate firmly held beliefs and prejudices to solid scientific data and be prepared to modify our practice when more cost-effective alternative exist; and (c) we must be increasingly conscious of outcome, not process, in deciding among treatment options; and (d) we must acknowledge the need to prioritize the use of finite resources so that the maximum effort is expended on those who have the most to gain from treatment. These changes will permit us to develop guidelines for appropriate use of radiation therapy, and to demonstrate the excellent value of the service we can provide, which is the ultimate key to success. Though the future may at times seem bleak, we can shape it with our actions: the best way to predict the future is to create it. PMID- 7836074 TI - Radiation therapy for early stage Hodgkin's disease: Australasian patterns of care. Australasian Radiation Oncology Lymphoma Group. AB - PURPOSE: Analysis of treatment outcome for Stage I-IIA supradiaphragmatic Hodgkin's disease treated solely by irradiation in Australia and New Zealand. METHODS AND MATERIALS: Patients with supradiaphragmatic Hodgkin's disease only who were treated by irradiation alone with curative intent between 1969 to 1988 were retrospectively reviewed. Ten radiation oncology departments in Australia and New Zealand contributed patient data to the study. Patient, tumor, and treatment variables were recorded. Disease-free interval, survival, and complications were analyzed. RESULTS: Eight hundred and twenty patients were reviewed. The median age was 29 years. There were 437 men and 383 women. The distribution of 310 clinically staged patients was 170 stage IA, 5 IB, and 135 IIA. Five hundred and ten patients received laparotomies, and pathologic staging was as follows: IA 214, IB 13, IIA 283. The 10-year actuarial disease-free rate was 69% and overall survival rate was 79%. Increasing age, male sex, higher number of involved sites, the use of involved field irradiation, no staging laparotomy, and earlier year of treatment were significantly associated with an increased risk of relapse and lower survival. Actuarial 10-year survival following recurrence was 48%. Acute complications requiring interruption to treatment occurred in 46 patients (6%), but < 1% had their treatment permanently suspended. Actuarial complication rates at 10 years were: cardiac 2%, pulmonary 3% and thyroid 5%. There were 44 second malignancies including 10 non-Hodgkin's lymphomas, 3 leukemias, 7 lung, and 6 breast cancers. Mean delay to the development of a second cancer was 6 years. The 10-year actuarial rate of second malignancy was 5%. CONCLUSIONS: The Australasian experience of early stage Hodgkin's disease is consistent with the results in the published literature and confirms that irradiation produces a high cure rate with minimal toxicity. PMID- 7836075 TI - The prognostic importance of Gleason grade in prostatic adenocarcinoma: a long term follow-up study of 648 patients treated with radiation therapy. AB - PURPOSE: It is common practice to histologically grade adenocarcinoma of the prostate using the Gleason system. Whereas the prognostic utility of this grading is well known, few studies have comprehensively evaluated it for patients undergoing definitive radiation therapy and generally accepted guidelines as to which Gleason grades should be "lumped" have not been established. This study reports the results of univariate and multivariate evaluation of the prognostic significance of Gleason grade in 648 patients followed for a median of 6.5 years after radiation therapy for T1 to T4, N0, or NX, MO prostate cancer. METHODS AND MATERIALS: The correlation between Gleason grade and local recurrence, metastatic relapse, any disease relapse, and patient survival was evaluated using univariate and multivariate methods. Analysis was also stratified according to whether the grading was assigned on a needle biopsy or on a transurethral resection specimen. RESULTS: The large number of Gleason grades required grouping of grades for meaningful analysis and we found that a four-tier system (grades 2 and 3, 155 patients; grades 4-6, 290 patients; grade 7, 92 patients; and grades 8-10, 111 patients) correlated best with outcome. In univariate analysis, this four-tier grouping correlated significantly with local recurrence, distant metastases, any relapse, and survival. The incidences of distant metastasis at 10 years were: grades 2 and 3, 13%; grades 4-6, 34%; grade 7, 52%; and, grades 8-10, 63%. The survival rates at 10 years were: grades 2 and 3, 64%; grades 4-6, 60%; grade 7, 46%; and grades 8-10, 24%. In multivariate analysis, Gleason grade was the single most important determinant of outcome for each endpoint. These results applied equally to needle biopsy and transurethral resection specimens. CONCLUSION: Tumor grade is the single most significant determinant of outcome following radiotherapy for clinically localized prostate cancer. The Gleason system is a valid method for grading tumors to be irradiated. A four-tier grouping into grades 2 and 3, grades 4-6, grade 7, and grades 8-10 appears to be adequate and simple. PMID- 7836076 TI - Analysis of failure following definitive radiotherapy for invasive transitional cell carcinoma of the bladder. AB - PURPOSE: To assess prognostic factors for bladder relapse and distant failure following definitive radiotherapy for invasive transitional cell carcinoma (TCC) of the bladder. METHODS AND MATERIALS: Retrospective review of patients treated in the period 1977 to 1990 by definitive radiotherapy. The factors studied included age, sex, T stage, histological grade, tumor multiplicity, ureteric obstruction, total radiation dose, and use of neoadjuvant chemotherapy. The endpoints studied were bladder relapse and distant failure. RESULTS: There were 342 patients with a mean follow-up time of 7.9 years. Bladder relapse was observed in 159 patients. The overall actuarial bladder relapse rate at 5 years was 55% (SE = 3%). Prognostic factors for a higher bladder relapse rate were: tumor multiplicity (p < 0.001), presence of ureteric obstruction (p = 0.001), and higher T stage (p = 0.044). Distant failure occurred in 39 patients. The overall actuarial distant failure rate at 5 years was 28% (SE = 3%). Prognostic factors for a higher distant failure rate were: ureteric obstruction (p = 0.003) and higher T stage (p = 0.030). CONCLUSION: In our study, patients with invasive bladder TCC fell into distinct prognostic groups determined by the three independent factors, ureteric obstruction, tumor multiplicity, and T stage. These factors provided estimated risks of bladder relapse by 5 years which ranged from 34% to 91%. Knowledge of these prognostic factors can help in the selection of patients more suited for bladder preservation by definitive radiotherapy. PMID- 7836077 TI - Adenocarcinoma of the rectum treated by radical external radiation therapy. AB - PURPOSE: To assess the long-term survival and response rates of patients with primary rectal cancer to radical radiation therapy. METHODS AND MATERIALS: Between 1978 and 1987, 229 patients were treated at the Princess Margaret Hospital with radical external radiation therapy for adenocarcinoma of the rectum. Patients were treated with radiation either because they were considered to have unresectable tumors, were medically unfit, or refused surgery, or for a combination of these factors. Doses ranged from 40 Gy in 10 fractions by a split course over 6 weeks to 60 Gy in 30 fractions in 6 weeks. The most commonly prescribed treatment was 52 Gy target absorbed dose in 20 daily fractions over 4 weeks. RESULTS: The overall 5-year actuarial survival rate was 27%; for patients with mobile tumors, it was 48%, partially fixed 27%, and fixed tumor 4%. Forty eight of the 97 patients (50%) with mobile tumors, 11 of the 37 patients (30%) with partially fixed tumors, and 7 of the 77 patients (9%) with fixed tumors had clinically complete tumor regression following radiation. Of these, 18 of the mobile, 6 of the partially fixed, and 5 of the fixed tumors later relapsed locally. Fifty patients had salvage surgery after failing to achieve complete remission or for local relapse, with a 5-year actuarial survival rate of 42% from the time of surgery. CONCLUSION: Although radiation therapy can cure some patients with mobile or partially fixed rectal adenocarcinomas who refuse or are unsuitable for surgery, local control remains a problem; salvage surgery should be considered in patients who relapse or fail to go into complete remission and who are fit to undergo surgery. For patients with fixed rectal cancers, high-dose external-beam radiation should be part of a planned preoperative regimen or be palliative in intent. PMID- 7836078 TI - Radical radiotherapy for early nonsmall cell lung cancer. AB - PURPOSE: To evaluate the results of a departmental treatment policy in a consecutive series of patients with nonsmall cell carcinoma of the lung. A second purpose was to estimate the survival of patients treated with radical intent. A third purpose was to estimate the impact of comorbidity on the selection of patients for treatment and on its outcome. METHODS AND MATERIALS: The records of 720 consecutive patients referred to a single Department of Radiation Oncology between 1979 and 1985 were reviewed. One hundred fifty patients with early stage (Stage I and II disease) were studied in detail and the results are presented for the outcome of 103 patients treated by radical radiotherapy. All patients were followed for a minimum period of five years or until death. RESULTS: Patients referred for radiation therapy were elderly and usually had squamous cell carcinoma of the lung. Comorbidity was significant as was weight loss which occurred in a third of patients. The overall survival of patients treated with radical intent was 13%. In a small subgroup of patients with T1 tumors without weight loss and aged under 70 survival reached 50% at 5 years with no treatment related mortality and with insignificant treatment-related morbidity. CONCLUSION: Highly selected subsets of patients suitable for treatment with radiotherapy can be defined equally as well as highly selected subsets of patients can be selected for surgery. Treatment outcome can be surprisingly good in these subsets indicating that the treatment of nonsmall cell lung cancer, particularly in older patients without comorbidity should not automatically be by a surgical approach. PMID- 7836079 TI - A phase III study of accelerated radiotherapy with and without carboplatin in nonsmall cell lung cancer: an interim toxicity analysis of the first 100 patients. AB - PURPOSE: In 1989 we initiated a multicenter randomized trial to determine if accelerated radiotherapy with or without concurrent carboplatin improves local control and survival in patients with limited nonsmall cell lung cancer. This interim analysis was performed on the first 100 patients to determine whether the toxicity of the four treatment arms is acceptable. METHODS AND MATERIALS: One hundred patients with limited nonsmall cell lung cancer have been randomized to receive one of four treatments: arm I, radiotherapy 60 Gray (Gy) in 30 fractions in 6 weeks; arm II, accelerated radiotherapy 60 Gy in 30 fractions in 3 weeks; arm III, radiotherapy as in arm I plus carboplatin 350 mg/m2 during weeks 1 and 5 of radiotherapy; arm IV, radiotherapy as in arm II plus carboplatin 350 mg/m2 during week 1. Survival was measured for the group as a whole and treatment related toxicities in the four arms were compared. RESULTS: The estimated median survival for all 100 patients was 17.1 months with 33% estimated survival at 2 years. The major toxicities were hematologic and esophageal. Patients receiving carboplatin had more neutropenia (p < 0.0001) and thrombocytopenia (p = 0.002) than patients receiving radiotherapy alone, and this was most marked in patients on arm III. Both carboplatin and accelerated radiotherapy separately caused more severe esophagitis when compared to conventional radiotherapy alone (p = 0.011 and p = 0.0017, respectively). Esophagitis was more prolonged in patients having accelerated radiotherapy (p < 0.0001, median duration 3.2 months compared with 1.4 months for patients receiving conventional fractionation). Six patients (23%) treated on arm II have required dilatation of esophageal stricture, one dying with a laryngo-esophageal fistula. CONCLUSION: In patients receiving radiotherapy for unresectable lung cancer, overall treatment time can be halved and carboplatin administered concurrently with increased but acceptable esophageal and hematologic toxicity. PMID- 7836080 TI - Treatment of brain metastases from primary lung cancer. AB - PURPOSE: A retrospective study of patients treated at the Peter MacCallum Cancer Institute for brain metastases from primary carcinoma of the lung is presented. METHODS AND MATERIALS: The medical records of 416 patients with the diagnosis of primary carcinoma of the lung who presented with, or subsequently developed, brain metastases during the period January 1984 to December 1987 were reviewed. Information on a number of factors of potential prognostic significance (sex, age, histology, performance status and interval between diagnosis of the primary and brain metastases) was collected. Details of surgery, radiation and steroid usage were recorded, and any steroid side effects documented. Survival was calculated from the date of diagnosis of brain metastases. Stepwise regression based on Cox's proportional hazards model was used to determine significant prognostic factors affecting survival. Patients with and without steroid side effects were compared using Yates's corrected chi-square test. RESULTS: The overall estimated median survival was only 3.3 months (95% confidence interval 2.9-3.7 months). Only two factors were found to be associated with a significantly improved survival--surgical intervention and good performance status. After taking these two factors into account, the dose of radiation used (< 30 Gy or > or = 30 Gy) did not influence survival. There was a 3% incidence of gastric bleeding or perforation in patients taking steroids, with a 40% fatality rate. Predisposing factors to gastric side effects were a prior history of peptic ulcer and/or aspirin or nonsteroidal anti-inflammatory drug consumption. CONCLUSION: Radiation of brain metastases from primary lung cancer results in modest survival benefit. Radiation dose (< 30 Gy or > or = 30 Gy) is not a significant determinant of survival. Other treatment modifications, such as concurrent radiation and chemotherapy, should be explored. Steroids should be used with caution as fatal side effects can occur. PMID- 7836081 TI - Thyroid dysfunction following radiotherapy for head and neck cancer. AB - PURPOSE: To determine the frequency of hypothyroidism (both subclinical and clinical) following external beam radiotherapy to the whole of the thyroid gland in the treatment of squamous cell cancers of the head and neck. METHODS AND MATERIALS: One hundred and four patients who had completed radiotherapy 30 days to 5 years earlier (84 patients) or who were scheduled for radiotherapy (20 patients) had a single measurement of serum-free thyroxine and thyroid stimulating hormone levels between August 1991 and May 1992. RESULTS: None of the 20 patients assessed prior to treatment showed thyroid dysfunction. Twenty of 84 (23.8%) previously treated patients had subclinical (9.5%) or clinical (14.3%) hypothyroidism. By 5 years, up to 40% of patients may become hypothyroid. Thyroid underactivity was significantly more common in patients having both laryngectomy (including hemi-thyroidectomy) and radiotherapy compared to radiotherapy alone (p < 0.001). Hypothyroidism had not been suspected clinically in any patient tested. CONCLUSION: In view of the frequency and potential morbidity of this complication, thyroid function testing should become a routine part of posttreatment follow-up for these patients. PMID- 7836082 TI - Treatment decisions in T3N0M0 glottic carcinoma. AB - PURPOSE: To analyze the results of T3N0M0 glottic carcinoma treated with radiotherapy, surgery, or both. METHODS AND MATERIALS: The records were retrospectively reviewed of 97 patients with this tumor subsite and stage seen for treatment at the Queensland Radium Institute over a 29-year period. The results for radiotherapy with surgical salvage of failure (XRT/SS) were compared to those with surgery with or without radiotherapy (SURG/SURG+XRT). For those treated initially with radiotherapy alone, the results for different ranges of biologically equivalent doses were compared. These results were compared to those of other published studies. RESULTS: The 5-year disease-specific survival rats for the XRT/SS and SURG/SURG+XRT groups were 50% and 58%, respectively; this difference is not significant. For the XRT/SS group, there was a trend towards improved 5-year recurrence-free survival (73%) and 5-year disease-specific survival (86%) in those treated to a dose equivalent to 60-64 Gy in 2 Gy fractions, when compared with higher or lower dose equivalents. CONCLUSION: A group of patients with T3N0M0 glottic carcinoma is specified for which the option of radiotherapy offers a similar chance of survival to those treated surgically. More than 50% of the XRT/SS survivors will retain their larynx. PMID- 7836083 TI - Conservative therapy of breast cancer in Queensland. AB - PURPOSE: Primary radiation therapy following breast-conserving surgery has been an accepted alternative to mastectomy in Europe and North America for many years. In Australia, however, the history of breast conservation for early invasive breast cancer is much shorter. The purpose of this study was to evaluate the results of breast conservation in a state-wide Australian radiotherapy service. METHODS AND MATERIALS: Between January 1982 and December 1989, 512 patients were treated with primary radiation therapy after breast conserving surgery. This analysis is based on a review of these patients, all of whom had Stage I or II breast cancer. RESULTS: With a median follow-up of 50 months, the 5-year actuarial rate of overall survival was 84% and disease-free survival was 80%. There have been 22 isolated local recurrences in the breast. The time to an isolated breast recurrence ranged from 12 to 83 months (median, 26 months). The 5 year actuarial rate of an isolated breast recurrence was 4%. The recurrence rate was higher for patients with involved margins (15% vs. 2%, p < 0.01). Local recurrence was also more likely in the presence of extensive ductal carcinoma in situ (DCIS), as opposed to no extensive DCIS (10% vs. 2%, p < 0.01). CONCLUSION: These results affirm that primary radiation therapy after breast conserving surgery in Queensland, has been given with a low rate of local recurrence, comparable to that obtained in other centers. PMID- 7836084 TI - Simultaneous adjuvant radiation therapy and chemotherapy in high-risk breast cancer--toxicity and dose modification: a Transtasman Radiation Oncology Group Multi-Institution study. AB - PURPOSE: To establish the toxicity profile of simultaneously administered postoperative radiation therapy and CMF chemotherapy as a prelude to a randomized controlled study addressing the sequencing of the two modalities. METHODS AND MATERIALS: One hundred and thirty eight breast cancer patients at high risk of locoregional, as well as systemic relapse, who were referred to three centers in Australia and New Zealand were treated with postoperative radiation therapy and chemotherapy simultaneously. Acute toxicity and dose modifications in these patients were compared with 83 patients treated over the same time frame with chemotherapy alone. In a separate study the long-term radiation and surgical effects in 24 patients treated simultaneously with radiation therapy and chemotherapy at Newcastle (Australia) following conservative surgery were compared with 23 matched patients treated at Newcastle with radiation therapy alone. RESULTS: Myelotoxicity was increased in patients treated simultaneously with radiation therapy and chemotherapy. The effect was not great, but may have contributed to chemotherapy dose reductions. Lymphopenia was observed to be the largest factor in total white cell depressions caused by the simultaneous administration of radiation therapy. Postsurgical appearances were found to so dominate long-term treatment effects on the treated breast that the effect of radiation therapy dose and additional chemotherapy was difficult to detect. CONCLUSION: Studies addressing the sequencing of radiation therapy and chemotherapy will necessarily be large because adverse effects from administering the two modalities simultaneously are not great. The present study has endorsed the importance in future studies of stratification according to the extent and type of surgery and adherence to a single strict policy of chemotherapy dose modification. PMID- 7836086 TI - The importance of postoperative radiation therapy in the treatment of Merkel cell carcinoma. AB - PURPOSE: To determine the role of postoperative radiation therapy in the treatment of Merkel cell carcinoma (MCC). METHODS AND MATERIALS: Eighty patients with MCC of the skin were treated with curative intent at the Queensland Radium Institute between 1981 and 1991. Fifty-one patients (63.7%) were referred after initial biopsy for further treatment and 29 patients (36.3%) were referred with locally recurrent disease following primary surgery elsewhere. Thirteen patients (16.3%) presented with nodal disease without a clinically definable primary skin lesion. RESULTS: Of the 80 patients, 38 had undergone surgery (S) alone, 34 surgery plus radiotherapy (S + RT), 7 RT after incomplete S, and 1 patient had chemotherapy (CT) plus RT. Overall survival at 36 months for all patients was 68%. All of the 38 patients treated with S alone relapsed. The median time to recurrence was 5.5 months. Ten of the 34 patients treated with S + RT relapsed. The median time to recurrence was 16.5 months. Of the 80 patients, 55 have relapsed after primary treatment, 25 have developed systemic metastases, and 26 patients have died as a direct result of MCC. CONCLUSION: Our large series confirms earlier reports from this Institute and highlights the importance of S + RT over S alone in preventing local recurrence of this highly malignant skin cancer. PMID- 7836085 TI - Further insights into the natural history and management of primary cutaneous neuroendocrine (Merkel cell) carcinoma. AB - PURPOSE: Primary cutaneous neuroendocrine (Merkel cell) carcinoma is a rare neoplasm with aggressive behavior but potential for response to radiotherapy and chemotherapy. Optimal treatment regimens are evolving based on reports of case series and a growing understanding of the natural history. METHODS AND MATERIALS: A retrospective analysis of 34 cases treated at two Australian Institutions over 13 years is presented, focusing on clinical features and response to therapy. RESULTS: The aggressive nature of this neoplasm is confirmed by the local recurrence rate of 22% following surgical excision, the development of regional node metastases in 76%, and of distant metastases in 70%. Overall median survival was 24 months with 65% of patients succumbing to metastatic disease. An association with B cell malignancies and immunosuppressive therapy is noted, with these patients having a poorer outcome, and one spontaneous remission was observed. Radiation therapy produced responses in 21 of 30 measurable sites (11 complete, 10 partial), and in 11 sites irradiated prophylactically there was only one infield relapse (9%). Responses to chemotherapy were observed in 8 of 20 applications (40%), particularly carboplatin and etoposide given in the setting of regional node disease. CONCLUSION: In this poor prognosis tumor, further investigation of adjuvant radiotherapy and chemotherapy is warranted, as responsiveness of recurrent disease is confirmed. Immunological factors appear important in the natural history, and their manipulation may offer additional therapeutic options. PMID- 7836087 TI - Normal tissue radiosensitivity in breast cancer patients. AB - PURPOSE: To investigate whether in vitro radiosensitivity of lymphocytes derived from a blood sample will predict late effects from radiotherapy in breast cancer patients. METHODS AND MATERIALS: Blood samples were collected from consenting patients who had received radiotherapy for breast cancer. Lymphocytes were extracted and transformed by the Epstein-Barr virus. The resulting lymphoblastoid cell lines (LCLs) were assessed for in vitro radiosensitivity using a tetrazolium based colorimetric assay (MTT). Survival curves were generated using doses of 0.5 to 2 Gy. For each analysis an LCL derived from an individual with the radiosensitive condition ataxia-telangiectasia (AT) was run as control. Some patients also consented to give skin biopsies from which fibroblast cultures were derived. Clonogenic assays were performed to generate survival curves using doses in the range of 0.5 to 4 Gy. Comparison was made with the data obtained from LCLs. Late effects of radiotherapy were assessed using the Radiation Therapy Oncology Group (RTOG) scoring scheme and compared with the in vitro radiosensitivity data. RESULTS: LCLs from 56 breast cancer patients were assessed for in vitro radiosensitivity. Surviving fraction to 2 Gy (SF2) generated from survival curves ranged from 0.04-0.35 with coefficient of variation for the whole group of 41%. None of the LCLs equalled the sensitivity of the AT line, but 16% showed equal or greater sensitivity to a line derived from an AT heterozygote. Comparison of LCL and fibroblast radiosensitivity showed reasonable correlation for 12 paired samples (r = 0.64). The majority of patients showed no or minimal effects after radiotherapy (Grade 0, 1 effects) but seven developed a Grade 2 reaction and four a Grade 3 or 4 reaction. Patients with a Grade 2-4 reaction were found to be more sensitive in vitro than those with a Grade 0-1 reaction (p < 0.02). CONCLUSIONS: The use of the MTT assay to assess LCL radiosensitivity has demonstrated considerable heterogeneity amongst the breast cancer population. The presence of a proportion of patients showing in vitro sensitivity but normal clinical response to radiotherapy would limit the usefulness of the assay for predictive purposes. PMID- 7836088 TI - The spectrum of in vitro radiosensitivity in four human melanoma cell lines is not accounted for by differential induction or rejoining of DNA double strand breaks. AB - PURPOSE: Radioresistance is a significant clinical problem in advanced malignant melanoma and many melanoma cell lines show a radioresistant acute x-ray survival response in vitro. Given that the DNA double strand break is the lesion most closely correlated with x-ray induced cell lethality, differences in the induction and rejoining of these lesions may account for the radioresistance of some human melanoma cell lines. METHODS AND MATERIALS: The above hypothesis was tested using pulsed field gel electrophoresis to measure x-ray induced DNA double strand break induction and rejoining in four human melanoma cell lines: MM138, MM170, MM96-L and HT 144. RESULTS: The MM138, MM170 and MM96-L cell lines were characterized in vitro by low alpha/beta ratios and broad x-ray survival curve shoulders. MM138 and MM170 were the most radioresistant and MM96-L had intermediate sensitivity. In contrast, HT144 was markedly x-ray sensitive, despite retaining a shoulder and like the other lines, having a low alpha/beta ratio. There were no significant differences in DNA double strand break induction between the cell lines, and thus no correlation existed between DNA double strand break induction and radiosensitivity. Consistent with the shoulders on the x-ray survival curves, all four cell lines showed efficient DNA double strand break rejoining. Highly efficient DNA double strand break rejoining could account for the radioresistance of one of the melanoma lines (MM138). For example, MM138 had rejoined 50% of the induced DNA double strand breaks by 5.5 min compared to 13-17 min for the other three cell lines. The development of postirradiation apoptosis was effectively excluded as the cause of the marked radiosensitivity of the HT144 cell line. CONCLUSION: Other factors (such as lesion repair fidelity or differential lesion tolerance) underlie the differences in the intrinsic radiosensitivity between these melanoma cell lines. PMID- 7836089 TI - Dose-response relationship for radiation therapy of subclinical disease. AB - PURPOSE: To determine the dose-response relationship for elective treatment of subclinical metastatic deposits and validate a model for metastatic tumor cell burden. METHODS AND MATERIALS: The incidence of overt metastases in electively irradiated potential sites of spread from carcinomas of the head and neck, breast, cervix, ovary, lung, and testis, and from melanomas and osteosarcomas, was compared with the incidence in patients not receiving elective irradiation. The reduction in incidence of metastases was analyzed as a function of radiation dose. RESULTS: The dose-response curve for control of subclinical metastases is linear and shallow, and extrapolates to a dose intercept not demonstrably different from zero. A small threshold may reflect growth of residual micrometastases between treatment for the primary and elective irradiation. The shallow linear dose response reflects interpatient heterogeneity in metastatic tumor cell burden, ranging from 1 to M cells, where M is the upper limit of clinical undetectability. While a dose of 50 Gy in 2 Gy fractions is necessary to achieve an overall 90% reduction in the incidence of metastases, the metastatic cell burden in a proportion of patients can be eliminated by low doses. Thus, worthwhile rates of control can still be achieved when "tolerance" dictates lower than optimal doses, evidenced by the linearity and lack of significant threshold in the dose-response curve. This is an important difference from treatment of gross disease. The biological effectiveness of elective treatment is measured directly by the percent reduction in failure rate. Although it depends upon the log cell kill, it relates only to that proportion of patients harboring subclinical disease, and, therefore, is not well described by the increase in the cure rate for the total patient population. The linear dose-response relationship for reduction in failure rate is independent of the "natural" (untreated) incidence of subclinical metastasis, and, therefore, of site, histology, growth rate, stage, or other characteristics of the tumor. Conversely, the clinical effectiveness of elective treatment is measured by increase in tumor control rate and depends upon the "natural" incidence of metastasis: the higher it is, the greater the absolute increase in cure rate from a constant biological effect (log cell kill). CONCLUSIONS: (a) High control rates for subclinical metastases require doses of about 50 Gy in 2 Gy fractions, but worthwhile benefits can be achieved by lower doses if necessitated by reduced tolerance; (b) elective treatment of subclinical metastases should be instituted close to the time of treatment of the primary; (c) the biological effectiveness of elective radiation (or chemotherapy) should be measured by the percentage decrease in metastasis, not by improvements in the rate of control; and (d) demonstration of success in clinical trials of adjuvant therapy is more likely the higher the incidence of metastases in untreated controls. PMID- 7836090 TI - Radiation and the lung: a reevaluation of the mechanisms mediating pulmonary injury. AB - Recent data from several investigators, including our unit, have provided additional information on the etiology of radiation-induced lung damage. These data suggest that there are two quite separate and distinct mechanisms involved: (a) classical radiation pneumonitis, which ultimately leads to pulmonary fibrosis is primarily due to radiation-induced local cytokine production confined to the field of irradiation; and (b) sporadic radiation pneumonitis, which is an immunologically mediated process resulting in a bilateral lymphocytic alveolitis that results in an "out-of-field" response to localized pulmonary irradiation. Both animal experiments and human studies show that classical radiation pneumonitis has a threshold dose and a narrow sigmoid dose-response curve with increasing morbidity and mortality over a very small dose range. Clinical pneumonitis rarely causes death, whereas in the animal and human studies of classical radiation pneumonitis, all subjects will eventually suffer irreversible pulmonary damage and death. The description of classical radiation pneumonitis is that of an acute inflammatory response to lung irradiation, which is confined to the area of irradiation. Recent studies have also shown that irradiation induces gene transcription and results in the induction and release of proinflammatory cytokines and fibroblast mitogens in a similar fashion to other chronic inflammatory states, and which ultimately results in pulmonary fibrosis. The description of classical radiation pneumonitis does not adequately explain the following observed clinical characteristics: (a) the unpredictable and sporadic onset; (b) the occurrence in only a minority of patients; (c) the dyspnoea experienced, which is out of proportion to the volume of lung irradiated; and (d) the resolution of symptoms without sequelae in the majority of patients. We have demonstrated a bilateral lymphocytic alveolitis of activated T lymphocytes and a diffuse increase in gallium lung scan uptake in patients studied before and 4 to 6 weeks after strictly unilateral lung irradiation. This is suggestive of a hypersensitivity pneumonitis, which gives rise to an "out-of-field" response to localized lung irradiation and hence more accurately describes the clinical picture of radiation pneumonitis. Reevaluation of the mechanisms of pulmonary injury from irradiation suggest that (a) a new term, sporadic radiation pneumonitis, should be introduced to describe the clinical picture of radiation pneumonitis, which is not adequately explained by the classical description and is quite clearly an entirely different process; and (b) that the chronic response to localized lung irradiation that leads to pulmonary fibrosis is largely mediated through the induction and release of tissues cytokines. PMID- 7836091 TI - Tables of equivalent dose in 2 Gy fractions: a simple application of the linear quadratic formula. AB - PURPOSE: To provide a simple method of showing the equivalent dose in 2 Gy fractions for various treatment regimens using the linear quadratic (LQ) formula. METHODS AND MATERIALS: Tables of equivalent dose for common total doses and fraction sizes have been calculated using the LQ formula for representative alpha:beta ratios (1, 3, 10). Corrections have not been made for repopulation. Examples are given. CONCLUSION: The tables offer a simple method of equating one fractionation regimen with another, recognizing the limitation of this method. PMID- 7836092 TI - Efficiency considerations in the expansion of radiation therapy services. AB - PURPOSE: An economic option appraisal to determine whether early investment in capital is an efficient means of expanding radiation therapy services. METHODS AND MATERIALS: Costs were based on 1991 data from a center in western Sydney. Two options were costed: Option 1 based on an increase in overtime performed by existing staff, using capital more intensively and possible use of shifts; Option 2 based on an investment in new capital and associated increases in levels of staffing. The health sector costs of both options were determined in one center at workloads of between 70,940 and 98,525 fields per year to assess relative efficiency. RESULTS: There was very little difference in cost between both options, with Option 1 slightly cheaper at workloads up to 98,525 fields per year. CONCLUSIONS: The results suggest that capital investment may be introduced at a fairly early stage without efficiency loss. Sensitivity analysis reinforces these conclusions and the generalizability of the results. PMID- 7836093 TI - Radiation protection recommendations on dose limits: the role of the NCRP and the ICRP and future developments. AB - The purpose of this paper is to review the role of the National Council on Radiation Protection and Measurements (NCRP) and the International Commission on Radiological Protection (ICRP) in making recommendations on dose limits for ionizing radiation exposure for workers and for the public. The text describes the new limits for workers and public recommended by ICRP in 1991 and NCRP in 1993 and the composition of the radiation health detriment on which they are based. The main component of this detriment is the risk of radiation induced cancer which is now estimated to be about three times greater than a decade or so earlier. Uncertainties in these risk estimates are discussed. Some special radiation protection problems, such as those for the embryo or fetus are described. The article also addresses future progress in radiation protection particularly with regard to future improvements in the scientific basis for radiation protection recommendations. PMID- 7836094 TI - Treatment of pediatric genitourinary malignancy with interstitial brachytherapy: Peter MacCallum Cancer Institute experience with four cases. AB - PURPOSE: To describe early outcome and technical treatment aspects of four patients with pediatric genitourinary malignancy receiving local therapy using interstitial brachytherapy at the Peter MacCallum Cancer Institute since 1991. METHODS AND MATERIALS: Two patients with primary bladder tumors and two patients with primary vaginal tumors received interstitial brachytherapy with needle template techniques following chemotherapy. Two patients were treated for salvage following local failure after primary chemotherapy and two patients electively after initial induction chemotherapy, one following limited surgical excision. Three patients were treated exclusively with brachytherapy with doses of 50-55 Gy (LDR), and one patient also received external beam radiation. RESULTS: Resultant implants, dosimetry, and dose prescriptions are described and illustrated. Follow up is short (14-27 months), but all patients remain well without significant sequelae. One child required salvage surgery for local failure. CONCLUSION: Interstitial brachytherapy using needle-template techniques described is an ideal method of local ablative therapy for pediatric genitourinary malignancy. Functional and late sequelae should be less than that of radical surgery or external beam radiation. There are technical and practical advantages compared with other brachytherapy techniques described in the literature. PMID- 7836095 TI - The effects of radiotherapy and surgery on the sexual function of women treated for cervical cancer. AB - PURPOSE: This study investigated the short- and medium-term effects of pelvic radiotherapy and surgery on the sexual function of women treated for cervical cancer. METHODS AND MATERIALS: Sixteen women with Stages I, II, or III disease referred for radiotherapy treatment were assessed. Six had undergone prior hysterectomy. The women were assessed with questionnaires prior to radiotherapy, at completion of radiotherapy, and at 6 weeks and 14 weeks after radiotherapy treatment. The clinical findings at routine follow-up were noted. RESULTS: The study showed significant changes in sexual activity and satisfaction as a result of treatment. This was due to a number of physical and psychological factors. The level of sexual activity was lowest at completion of radiotherapy treatment. A feeling of vaginal shortening was the most frequent reason and was more common in women who were treated with surgery and radiotherapy. Dyspareunia, bleeding, and concern of bleeding and/or recurrence were all significant factors. CONCLUSIONS: The questionnaires were an effective way of assessing women's sexual function. Radiotherapy caused sexual dysfunction in one-half of women. Combined treatment with radiotherapy and surgery results in a higher risk than radiotherapy alone. Women with cervical cancer and undergoing radiotherapy treatment require considerable counseling and support. PMID- 7836096 TI - Sarcomas following radiation therapy for breast cancer: a report of three cases and a review of the literature. AB - PURPOSE: First to describe clinical and pathologic features of sarcomas arising after radiation therapy for breast cancer and to report three cases of sarcoma arising 7, 15, and 20 years following radiation therapy for breast cancer. Second, to review the literature on this treatment complication. METHODS AND MATERIALS: Medline literature search. RESULTS: The most frequent histology is osteosarcoma and bone is affected more commonly than soft tissue at a median latency of 11 years. The scapula is the most frequently affected bone. The most frequently affected soft tissue site is now the conserved breast with a median latency of 5.5 years. The aetiologic factors relating to these sarcomas are not fully defined with factors of beam energy, radiation dose, chemotherapy and regional edema being inconsistently reported. CONCLUSION: The frequency of radiation-induced sarcoma at 10 years of follow-up is approximately 0.2%. This is an overestimate by an unknown factor because of the description of sarcomas arising metachromously in breast cancer patients, in nonirradiated areas. PMID- 7836097 TI - Measuring irradiated lung and heart area in breast tangential fields using a simulator-based computerized tomography device. AB - PURPOSE: To illustrate the use of a simulator based computerized tomography system (SIMCT) in the simulation and planning of tangential breast fields. METHODS AND MATERIALS: Forty-five consecutive patients underwent treatment planning using a radiotherapy simulator with computerized tomography attachment. One to three scans were obtained for each patient, calculations were made on the central axis scan. Due to the wide aperture of this system all patients were able to be scanned in the desired treatment position with arm abducted 90 degrees. Using available software tools the area of lung and/or heart included within the tangential fields was calculated. The greatest perpendicular distance (GPD) from the chest wall to posterior field edge was also measured. RESULTS: The mean GPD for the group was 25.40 mm with 71% of patients having GPDs of < or = 30 mm. The mean area of irradiated lung was 1780 sq mm which represented 18.0% of the total ipsilateral lung area seen in the central axis. Seven of the patients with left sided tumors had an average 1314 sq mm heart irradiated in the central axis. This represented 11.9% of total heart area in these patients. CONCLUSIONS: Measurements of irradiated lung and heart area can be easily and accurately made using a SIMCT device. Such measurements may help identify those patients potentially at risk for lung or heart toxicity as a consequence of their treatment. A major advantage of this device is the ability to scan patients in the actual treatment position. PMID- 7836098 TI - T3N0M0 glottic cancer: are more treatment modalities necessarily better? PMID- 7836099 TI - What else don't we know about the late effects of radiation in patients treated for head and neck cancer? PMID- 7836100 TI - Turning up the heat on nonsmall cell lung cancer: is the toxicity of concurrent cisplatin-based chemotherapy and accelerated fractionation acceptable? PMID- 7836101 TI - Local treatment for prostate cancer: 90 years later--response to M. V. Pilepich. PMID- 7836102 TI - "Alveolar septal structure in different species". PMID- 7836103 TI - Endothelins and pulmonary diseases. AB - Endothelins (ETs) are expressed in several types of cell in human lung, including airway epithelial cells, pulmonary vascular endothelial cells, submucosal glands, and type II pneumocytes. There is evidence for increased expression of ET-1 in several pulmonary diseases, including asthma, fibrosing alveolitis, and pulmonary hypertension, suggesting that ET-1 may play a pathophysiological role. ET binding sites are widely distributed and are localized to airway and pulmonary vascular smooth muscle, fibroblasts, submucosal glands, and airway nerves, indicating that ETs may have widespread effects. ET-1 and ET-3 are potent constrictors of human airway smooth muscle via a direct effect on ET receptors in airway smooth muscle; these receptors are probably ETB receptors. ETs may have other effects on airway function, including constriction of bronchial vessels, increased plasma exudation, increased mucus secretion, airway smooth muscle hyperplasia, and possibly increased fibrogenesis; these effects may be mediated via ETA receptors. ET-1 is a potent constrictor of human pulmonary vessels, whereas ET-3 is less effective, suggesting a predominance of ETA receptors. Similarly, chemotaxis and mitogenesis of pulmonary vascular fibroblasts and smooth muscle are mediated via ETA receptors. These findings implicate ETs in various pulmonary diseases and suggest that ET antagonists may be useful in their treatment. PMID- 7836104 TI - Alveolar septal structure in different species. AB - Because the retractive forces due to surface tension decrease with increasing radius of curvature, there should be a greater contribution to lung recoil attributable to the stress-bearing role of elastic elements in the lung parenchyma of species with larger alveoli. To examine alterations in lung structure that may relate to this stress-bearing role, the lungs of mice, hamsters, rats, rabbits, rhesus monkeys, baboons, and humans were preserved by vascular perfusion of fixative. The number of alveoli per lung, alveolar radius of curvature, surface area, and volume were measured by serial section reconstruction. Electron-microscopic determinations were made of the volume fraction and thickness of the epithelium, interstitium, and endothelium and of the connective tissue fibers of the alveolar septa and the portions of alveolar septa that form the alveolar ducts. The thickness of the alveolar septal interstitium increased linearly with the increase in radius of curvature of alveoli. The increase in interstitial thickness in lungs with larger alveoli was paralleled by large increases in the volume of collagen and elastin fibers present in this space. Comparable changes in the thickness of connective tissue fibers in alveolar duct walls were also found. This study demonstrates species related changes in the structure of alveolar septa and in lung collagen and elastin fibers that are consistent with connective tissue fibers having a greater stress-bearing role in both the alveolar septa and alveolar ducts of species with larger alveoli. PMID- 7836105 TI - Metabolic and ventilatory responses to anemic hypoxia in conscious rats. AB - We investigated the metabolic and ventilatory effects of anemia, which is characterized by a decrease in blood O2 content with no changes in arterial PO2 (PaO2). Anemia was obtained in conscious chronically instrumented adult male rats by substituting blood with equal volumes of Ringer lactate solution via the tail artery. Three hours later, we measured resting O2 consumption (VO2) by an open flow method and ventilation (VE) by the barometric method. Hemodilution to 80-90, 70-80, or 60-70% of the starting hematocrit and hemoglobin values had no major effects on VO2, VE, or mean arterial blood pressure (MAP). A 50-60% hemodilution reduced VO2 and MAP, with a modest increase in VE; the rats were hypocapnic, with normal PaO2. Infusion of vasopressin in a dosage sufficient to increase MAP to the basal value resulted in a reduction in VE, a further drop in VO2, and a return to normocapnia. Three days after hemodilution, hematocrit and hemoglobin were still low but ventilatory and metabolic parameters were normal. In conclusion, in this rat model of anemic hypoxia, 1) hypometabolism occurred without a drop in PaO2, implying that its manifestation does not require activation of the carotid body, and 2) the transient hypocapnia resulted from the VE stimulating effects of the hypotension. PMID- 7836106 TI - Cerebellar modulation of ventilatory response to progressive hypercapnia. AB - The cerebellar contribution to the ventilatory response to progressive hypercapnia was examined in 18 anesthetized tracheotomized spontaneously breathing cats. The absolute values for minute ventilation (VE), tidal volume (VT), respiratory frequency (f), inspiratory duty cycle (TI/TT), and mean inspiratory flow (VT/TI) were measured. Progressive hypercapnia [35-65 Torr end tidal PCO2 (PETCO2)] was induced using the rebreathing method. The respiratory variables at each level of PETCO2 and the slopes of ventilatory (VT and f) responses to hypercapnia were compared across the intact, decerebellate, and decerebellate-vagotomized preparations. In 12 cats, decerebellation preceded vagotomy, and in 6 cats the order of the surgical procedures was reversed. The results show that, compared with intact control, decerebellation had little effect on respiratory variables when PETCO2 was 30-35 Torr. However, during a hypercapneic challenge (40-65 Torr PETCO2), VE and the slope of the VE response were significantly reduced. Bilateral vagotomy increased VT and decreased f but failed to alter the ventilatory response in the PETCO2 range of 35-55 Torr. However, combination of decerebellation and vagotomy, regardless of the surgical order, severely blunted VE (35-65 Torr PETCO2) and the slopes of VE, VT and f responses. When decerebellation followed vagotomy, significant decreases in VT (absolute values and slopes) were noted with little further alteration in f response. We conclude that the cerebellum and its interaction with the vagus nerves play a facilitatory or disinhibitory role in the ventilatory responses to hypercapnia. PMID- 7836107 TI - Protein accumulation in cerebrospinal fluid during -90 degrees head-down tilt in rabbit. AB - Plasma proteins are only somewhat larger than the intercellular spaces of the cerebral microvessels that constitute the blood-brain barrier or of the choroid plexus villi that elaborate cerebrospinal fluid (CSF). We hypothesized that the integrity of these barriers in anesthetized rabbits might be compromised during head-down tilt (HDT). Plasma protein and osmolality, hematocrit, and CSF protein concentration were compared in rabbits exposed to 1 h of HDT (n = 20) and prone rabbits (n = 10). In addition, the concentration of trypan blue dye, injected intravenously at the end of HDT or the prone position, was measured in brain homogenate. Finally, arterial blood pressure was measured via a catheterized carotid artery. HDT disrupted the barrier between blood and CSF, as indicated by a significantly (P < 0.01) greater brain trypan blue concentration in the HDT rabbits [172.2 +/- 14.4 (SD) micrograms/g dry wt] than in the prone rabbits (29.8 +/- 4.4 micrograms/g dry wt). Moreover CSF protein 5 min after HDT onset was significantly increased compared with control in HDT rabbits (54.6 +/- 1.9 vs. 81.4 +/- 5.2 mg/dl; n = 8) but not in prone rabbits (55.6 +/- 2.7 vs. 57.2 +/- 5.0 mg/dl; n = 6). Changes in the plasma protein-to-hematocrit ratio in the HDT animals, but not in the prone animals, were also compatible with a loss of fluid from the vascular compartment.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836108 TI - Effects of resistance exercise on glucose tolerance in normal and glucose intolerant subjects. AB - This study was conducted to determine whether improvements in glucose tolerance could be observed after a single bout of resistance exercise in young (27.1 +/- 1.24 yr) control subjects, older (53.3 +/- 1.7 yr) patients with non-insulin dependent diabetes mellitus (NIDDM), and older (50.7 +/- 1.9 yr) age-matched control subjects. Each subject was screened for fitness level and any contraindications to exercise before inclusion in the study. A 75-g oral glucose tolerance test was administered 2 wk after the subjects were screened, and the subjects were familiarized with the exercise equipment. The maximum weight that could be lifted with one repetition was determined on seven Nautilus machines that utilized the upper and lower body. After a 48-h rest period, a 3-set x 10 repetition protocol based on the subject's one repetition maximum was completed by each participant on each machine. Eighteen hours after the lifting protocol, a second oral glucose tolerance test was administered. There was no change in the pre- to post-exercise glucose levels in any of the treatment groups, but the total insulin responses (area under the curve) of the young control and NIDDM groups were significantly lower after exercise: from 6.93 +/- 0.8 x 10(3) to 5.38 +/- 0.65 x 10(3) pM in the young control group and from 9.83 +/- 1.95 x 10(3) to 7.77 +/- 1.50 x 10(3) pM in the NIDDM group. The postexercise C-peptide levels were unchanged in all groups.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836109 TI - Pathological O2 supply dependence of diaphragmatic and systemic O2 uptake during endotoxemia. AB - Our aim was to assess whether endotoxemia impairs the ability of the diaphragm to extract O2 and whether this defect leads to a greater dependence of O2 uptake on O2 delivery. In two groups of anesthetized mechanically ventilated dogs, the left hemidiaphragm was vascularly isolated. Diaphragmatic blood flow and cardiac output (CO) were measured simultaneously in all animals. Saline (S group) or Escherichia coli endotoxin (100 mg; E group) was infused intravenously over 60 min. In both groups, CO was reduced in stages by controlled hemorrhage, and systemic and diaphragmatic O2 deliveries and consumptions were measured at each stage to construct the O2 delivery-O2 consumption relationships. In the S group, the average systemic O2 delivery below which O2 uptake became supply dependent was 7.2 ml.kg-1.min-1. At this O2 delivery, systemic O2 extraction ratio (ER) averaged 67.9%, whereas the maximum O2 ER was 91.3%. Critical diaphragmatic O2 delivery and critical and maximum diaphragmatic O2 ER, by comparison, averaged 9.0 ml.kg-1.min-1, 65%, and 81.9%, respectively. Endotoxin infusion raised critical systemic O2 delivery to 16.7 ml.kg-1.min-1 (P < 0.05) and reduced critical and maximum systemic O2 ER to 55.5 and 77% (P < 0.05), respectively. Similarly, critical diaphragmatic O2 delivery in the E group increased to 14.8 ml.kg-1.min-1 (P < 0.05), whereas critical and maximum O2 ER declined to 51.8 and 72.8%, respectively (P < 0.05). Thus, endotoxemia impairs diaphragmatic O2 extraction. This, in turn, leads to a greater dependence of diaphragmatic O2 uptake on O2 delivery. PMID- 7836110 TI - Functional and structural changes with hypoxia in pulmonary circulation of spontaneously hypertensive rats. AB - Chronic hypoxic pulmonary hypertension involves both vasoconstriction and vascular remodeling. Spontaneously hypertensive rats (SHR) have an increased systemic vascular resistance and a greater responsiveness to constricting stimuli. We hypothesized that, in contrast to age-matched normotensive Wistar Kyoto rats (WKY), SHR also display spontaneous pulmonary hypertension in normoxia and increased vascular response to acute and chronic hypoxia. Baseline mean pulmonary arterial pressure (PAP) and total pulmonary resistance (TPR) were higher in SHR than in WKY. With acute hypoxia (10% O2 for 15 min), PAP increased to the same extent in SHR and WKY and cardiac output (CO) was unchanged in WKY but increased in SHR. Thus, the rise in PAP in the SHR might be accounted for by the rise in CO, as TPR did not rise, but not that in the WKY, as TPR increased. After 12 days in hypoxia (10% O2), mean arterial pressure was unchanged in WKY but decreased significantly in SHR without a change in CO. PAP increased by 59% in SHR and 54% in WKY when the rats were taken from the hypoxic chamber for 1 h. Acute hypoxic challenge caused a further increase in PAP only in WKY. Medial wall thickness of alveolar duct and terminal bronchial vessels was similar in WKY and SHR after chronic hypoxia. We conclude that SHR exhibit mild baseline pulmonary hypertension in normoxia and that chronic hypoxia does not produce a disproportionate increase in SHR pulmonary vascular remodeling and pulmonary hypertension. PMID- 7836111 TI - Dietary effects on exercising muscle metabolism and performance by 31P-MRS. AB - To determine how diet modulates short-term exercise capacity, skeletal muscle pH and bioenergetic state were examined by 31P-magnetic resonance spectroscopy in nine healthy volunteers. Subjects performed incremental quadriceps exercise to exhaustion after 5 days of high-carbohydrate (HCHO) or high-fat (HFAT) diet randomly assigned in crossover fashion and separated by a 2.5-day period of ad libitum mixed diet. Simultaneous measurements were made of pulmonary gas exchange, minute ventilation, and quadriceps muscle pH and phosphorylation potential. At rest and peak exercise, respiratory exchange ratio and minute ventilation were higher after HCHO than after HFAT (P < 0.05), reflecting greater CHO utilization. Peak O2 consumption (VO2) was not increased after HCHO (P > 0.05), but exercise duration was (339 +/- 34 s for HCHO vs. 308 +/- 25 s for HFAT; P < 0.05). HCHO was associated with a blunted early fall of phosphocreatine (PCr)/Pi vs. VO2 (-4.1 +/- 0.7 x 10(-2) min/ml for HCHO vs. -5.6 +/- 1.2 x 10(-2) min/ml for HFAT; P < 0.05). On both study days, the slope of PCr/Pi vs. VO2, before and after the PCr threshold, was correlated with exercise time. The results suggest that a diet rich in CHO improves exercise efficiency through beneficial effects on intracellular phosphorylation potential. PMID- 7836112 TI - Vascular permeability and epithelial transport effects on lung edema formation in ischemia and reperfusion. AB - To determine the role of various Na+ transport systems in the edema fluid accumulation after ischemia and reperfusion in the lung, we evaluated the effect of amiloride (a Na+ channel blocker), ouabain (a Na(+)-K(+) adenosinetriphosphatase blocker), and phloridzin (a Na(+)-glucose cotransport blocker) in isolated rat lungs. Ischemia and reperfusion (I/R) significantly increased the edema accumulation, with the wet-to-dry weight ratios increasing to 10.14 +/- 0.58 from 6.03 +/- 0.05 in control lungs (P < 0.04). Amiloride significantly augmented the amount of edema fluid (wet-to-dry weight ratio 12.26 +/- 0.77), and ouabain further increased the amount of edema (wet-to-dry weight ratio 18.58 +/- 1.00). Phloridzin did not significantly affect edema formation associated with I/R. Isoproterenol decreased the amount of edema formation in the presence and absence of amiloride. This occurred because the endothelial permeability as assessed by filtration coefficient was restored to normal values and less edema formed. The present study indicates that Na+ channels and Na(+) K(+)-adenosinetriphosphatase, components of the active Na+ absorption transport system, are very important in opposing edema fluid accumulation in rat lungs subjected to I/R injury and operate as an edema safety factor. However, if the endothelial damage associated with I/R is allowed to persist, then the transport processes, even if operative, are insufficient to prevent continuous edema accumulation. PMID- 7836113 TI - Strength training increases insulin action in healthy 50- to 65-yr-old men. AB - The insulin resistance associated with aging may be due, in part, to reduced levels of physical activity in the elderly. We hypothesized that strength training increases insulin action in older individuals. To test this hypothesis, 11 healthy men 50-63 yr old [mean 58 +/- 1 (SE) yr] underwent a two-step hyperinsulinemic-euglycemic glucose clamp with concurrent indirect calorimetry and an oral glucose tolerance test (OGTT) before and after 16 wk of strength training. The training program increased overall strength by 47% (P < 0.001). Fat free mass (FFM; measured by hydrodensitometry) increased (62.4 +/- 2.1 vs. 63.6 +/- 2.1 kg; P < 0.05) and body fat decreased (27.2 +/- 1.8 vs. 25.6 +/- 1.9%; P < 0.001) with training. Fasting plasma glucose levels and glucose levels during the OGTT were not significantly lower after training. In contrast, fasting plasma insulin levels decreased (85 +/- 25 vs. 55 +/- 10 pmol/l; P < 0.05) and insulin levels decreased (P < 0.05, analysis of variance) during the OGTT. Glucose infusion rates during the hyperinsulinemic-euglycemic glucose clamp increased 24% (13.5 +/- 1.7 vs. 16.7 +/- 2.2 mumol.kg FFM-1.min-1; P < 0.05) during the low (20 mU.m-2.min-1) insulin infusion and increased 22% (55.7 +/- 3.3 vs. 67.7 +/- 3.9 mumol.kg FFM-1.min-1; P < 0.05) during the high (100 mU.m-2.min-1) insulin infusion. These increases were accompanied by a 40% increase (n = 7; P < 0.08) in nonoxidative glucose metabolism during the high insulin infusion. These results demonstrate that strength training increases insulin action and lowers plasma insulin levels in middle-aged and older men. PMID- 7836114 TI - Changes in satellite cell mitotic activity during acute period of unilateral diaphragm denervation. AB - The acute period of unilateral diaphragm denervation (DNV) is associated with increases in cell mitotic activity, protein synthesis, and muscle fiber hypertrophy. Our purpose was to determine whether acute unilateral diaphragm DNV is associated with changes in muscle isometric contractile properties, cross sectional area of different muscle fiber types, mitotic activity of muscle fiber satellite cells, and muscle fiber ultrastructural properties indicative of injury. Adult male Fischer 344 rats underwent a right phrenicotomy, and DNV and intact (INT) hemidiaphragms were studied 72 h later. DNV hemidiaphragm displayed a significant decline in maximal isometric force (8.7 vs. 24.3 N/cm2) and a prolonged time to peak twitch force (47.8 vs. 37.5 ms) and time to half relaxation (72.3 vs. 44.3 ms) compared with INT contralateral hemidiaphragm (P < 0.05). DNV resulted in a significant increase in cross-sectional area of types I (33%), IIa (35%), and IIb (28%) fibers relative to INT hemidiaphragm (P < 0.05). Satellite cell mitotic activity (assessed by incorporation of bromodeoxyuridine) was approximately 5.5 times greater in DNV than in INT muscle (DNV 25.0 +/- 3.8, INT 4.5 +/- 1.4 labeled satellite cell nuclei/1,000 nuclei; P < 0.05). Ultrastructural examination of electron micrographs revealed alterations in Z line and sarcomeric structure indicative of muscle injury. Cellular infiltration and segmental necrosis were also noted in some fibers. We conclude that acute unilateral diaphragm DNV results in muscle fiber injury that induces satellite cell activation. We also speculate that the specific force decrement associated with DNV is at least partially the result of muscle injury. PMID- 7836115 TI - Differential effects of nitrovasodilators and nitric oxide on porcine tracheal and bronchial muscle in vitro. AB - Nitrovasodilators and nitric oxide relax airway smooth muscle. The mechanism by which nitrovasodilators are thought to act is by release of nitric oxide, but the importance of nitric oxide in nitrovasodilator-induced airway smooth muscle relaxation is unclear. The aim of this study was to compare the relaxing effects of nitric oxide itself with those of nitrovasodilators in porcine tracheal muscle and intrapulmonary airways and to investigate the mechanisms involved. Strips of porcine tracheal smooth muscle, rings of bronchi, and strips of bronchi from the same animal were suspended in organ chambers in modified Krebs Ringer solution (95% O2-5% CO2, 37 degrees C). Tissues were contracted with carbachol, and concentration-response curves to nitric oxide, sodium nitroprusside, and SIN-1 (an active metabolite of molsidomine) were obtained. All tissues relaxed to sodium nitroprusside, SIN-1, and nitric oxide. The relaxation to nitric oxide but not to SIN-1 or sodium nitroprusside was inhibited by methylene blue. Tissues pretreated with methylene blue that failed to relax to nitric oxide were, however, relaxed by sodium nitroprusside. These results demonstrate that nitrovasodilators relax airways by a mechanism other than by or in addition to the release of nitric oxide. PMID- 7836116 TI - Effects of length and stimulation frequency on fatigue of the human tibialis anterior muscle. AB - It has been suggested that the reduced fatigability of muscles exercised at short length may result from a decrease in the metabolic cost of contractions in the shortened position. We compared the fatigue properties and metabolic cost of stimulated isometric tetanic contractions in the tibialis anterior of 10 normal subjects at the optimum length (Lo) for force production and when the muscle was shortened (Ls). Six 15-s ischemic contractions at Ls caused force to decline to 53% of the fresh value when tested at Lo, whereas muscles exercised and tested at Lo declined to 40% of fresh force. However, the extent of fatigue was proportionately greater if the muscle was exercised and tested at Ls. The apparent fatigue resistance of short muscles was found to be a consequence of recovery occurring under ischemic conditions while the muscle was changed from Ls to Lo-. 31P-nuclear magnetic resonance spectroscopy showed similar metabolic changes associated with 5-s stimulated contractions at Lo and Ls, indicating that any differences in fatigability at the two lengths were not caused by altered metabolic costs. The similarity between the force profiles of muscles fatigued at Ls and those fatigued by high-frequency stimulation supports the hypothesis that an enhanced activation failure occurs at Ls, possibly resulting from failure of sarcolemmal action potential propagation in the transverse tubules. PMID- 7836117 TI - Edema development and recovery in neurogenic pulmonary edema. AB - We determined the time course of changes in extravascular lung water (EVLW) that occur after massive sympathetic activation produced by intracisternal veratrine administration in chloralose-anesthetized dogs. Three groups of dogs were studied. In the first group (n = 9), acute increases in EVLW (occurring within minutes) were determined both by measuring extravascular thermal volume and by gravimetric analysis. In the second (n = 6) and third (n = 7) groups, changes in EVLW were followed for 2-3 h after veratrine administration. Extravascular thermal volume was measured in the second group. In the third group, right atrial injections of a vascular indicator (125I-labeled serum albumin) and an extravascular indicator (3HOH) were made while blood was sampled from the pulmonary artery (PA) and left atrium, and EVLW was determined by deconvolution of the left atrial and PA concentration-time curves. Indicator-dilution and gravimetric EVLW increased acutely only in dogs in which PA pressure exceeded 60 Torr, with two- to four-fold increases in EVLW being observed in dogs that developed the highest PA pressures (maximum 94 Torr). Thus, severe edema can develop rapidly after massive sympathetic nervous system activation but requires extreme degrees of pulmonary hypertension. In several dogs after the acute increase in EVLW associated with the pulmonary hypertension, the indicator dilution EVLW decreased with time. These decreases appear to effect clearance of edema fluid rather than alterations in perfusion. PMID- 7836118 TI - Interactive effects of K+, acidosis, and catecholamines on isolated rabbit heart: implications for exercise. AB - Intense exercise can double arterial K+ concentration, decrease pH by 0.4 units, and increase catecholamines 15-fold. Any one of these changes may be cardiotoxic in a subject at rest, yet these changes are well tolerated in exercise. We tested the interactive effects of extracellular K+ concentration ([K+]o), metabolic acidosis (pH 7.0), and raised catecholamines in the isolated working rabbit heart when they were changed with similar kinetics and concentrations to those seen in exercise. Raised [K+]o (8 and 12 mM) significantly decreased aortic flow (AF) by 23 and 76%, respectively (P < 0.01). Acidosis decreased AF by 19% (P < 0.05) and by 38% in combination with 8 mM [K+]o (P < 0.05), making their combined effect additive. Either epinephrine (80 nM), norepinephrine (80 nM) or extracellular Ca2+ concentration (5 mM) offset the negative effects of 8 and 12 mM [K+]o on AF. Norepinephrine also improved AF in 8 mM [K+]o with acidosis. Thus, there may be a beneficial interaction among changes in K+, catecholamines, and acidosis during exercise such that each could offset the others' potentially harmful effects. PMID- 7836119 TI - Mechanical interdependence in relation to age: effects of lung volume on airway resistance in rats. AB - Elastic recoil has been reported to decrease with increasing age in human subjects. In the current study, we hypothesized that aging influences mechanical interdependence, which affects the magnitude of agonist-induced airway constriction. To examine this hypothesis, we compared the effects of changing lung volume on airway resistance (Raw) under baseline conditions and during methacholine-induced constriction in adult (14 mo old, 624 +/- 14 g; n = 11) and aged (29 mo old, 629 +/- 9 g; n = 11) Sprague-Dawley rats. With use of alveolar capsules, Raw was directly measured under baseline conditions at different levels of end-expiratory transpulmonary pressure (PL; 3-11 cmH2O). Then aerosolized methacholine was delivered (125 mg/ml), and measurements were performed at different levels of PL (3 and 11 cmH2O). From measured tracheal flow and tracheal and alveolar pressures in open-chest animals during mechanical ventilation (6 ml/kg tidal volume, 1 Hz frequency), we calculated dynamic lung elastance and resistance of lung, tissue, and airway. In the baseline conditions, we found that increasing lung volume decreased Raw similarly in both groups but that lung elastance was reduced in the aged group at PL > or = 7 cmH2O. The shape constant obtained from the pressure-volume curve in the aged rats was significantly greater than that in the adult rats. During induced constriction, higher lung volume significantly lowered Raw in the adult group, whereas Raw was not significantly reduced by increasing PL in the aged group. These observations suggest that increasing age may affect the mechanical properties of the airway and/or airway-parenchymal interdependence. PMID- 7836120 TI - Effects of solution osmolality on absorption of select fluid replacement solutions in human duodenojejunum. AB - These experiments examined relationships between initial osmolality and carbohydrate (CHO) composition of an infused solution and osmolality and water and CHO absorption in a test segment. A triple-lumen tube with a 10-cm mixing segment and a 40-cm test segment was passed into the duodenojejunum. The infusion port was approximately 10 cm beyond the pyloric sphincter. Perfusion solutions were hypotonic (186 mosmol/kg; solution A), isotonic (283 mosmol/kg; solution B), and hypertonic (403 mosmol/kg; solution C). All solutions contained 18 meq Na+ and 3 meq K+. In the mixing segment, osmolality increased 83 mosmol/kg and decreased 90 mosmol/kg for solutions A and C, respectively. Corresponding changes in the test segment were an increase of 60 mosmol/kg and a decrease of 34 mosmol/kg. The osmolality of solution B did not change. In the test segment, mean osmolality and water and total solute fluxes were not significantly different among solutions, but solution C produced 27% greater fluid absorption than did solution A. When net fluid movement from mixing and test segments was determined, solution A produced 17% greater fluid absorption than did solution C. The mean increases in plasma and urine volumes over the 80-min test period were not significantly different. In the test segment, water flux correlated with CHO and Na+ fluxes but not with osmolality. In conclusion, 1) significant differences in solution osmolality were eliminated within the proximal duodenum and 2) perfusing 6% CHO solutions with osmolalities ranging from 186 to 403 mosmol/kg did not produce significant differences in fluid homeostasis (plasma volume) at the end of an 80-min test period. PMID- 7836121 TI - Influence of nonlinearities on estimates of respiratory mechanics using multilinear regression analysis. AB - To investigate the influence of nonlinearities on estimates of respiratory mechanics, differing patterns of mechanical ventilation patterns were analyzed from 8 puppies and 14 children. Respiratory mechanics were calculated using multiple linear regression to fit a linear single-compartment model, a volume dependent single-compartment model (VDSCM), and a flow-dependent single compartment model. The ratio of the compliance of the last 20% of the dynamic volume-pressure (V-P) curve to the total compliance (C20/C) and the contribution of a volume-dependent elastance to total elastance [%E2 = E2 (VT)/[(E1 + E2)VT], where E1 + E2 is total elastance, E2 is the volume-dependent component, and VT is tidal volume] were used as the indexes of over-distension. By positioning the dynamic loops on the static V-P curves, ventilation patterns were classified as overdistended or nonoverdistended. In the overdistended group, the C20/C was significantly lower (0.71 +/- 0.10 vs. 0.92 +/- 0.16; P < 0.0001) and %E2 was significantly higher (43.4 +/- 15.0 vs. 0.51 +/- 18.02%, P < 0.0001) than in the nonoverdistended group. The mode of ventilation (pressure controlled vs. volume controlled) and the resistive pressures that resulted in widening of the dynamic V-P loop were found to alter C20/C but not %E2. When the respiratory system was overdistended, i.e., ventilated up to the flattened portion of the V-P curve, the VDSCM gave more accurate estimates of respiratory mechanisms. Furthermore, %E2 calculated from VDSCM is a useful parameter for estimating respiratory system overdistension that is not affected by resistive pressures. PMID- 7836122 TI - Interaction of chronic creatine depletion and muscle unloading: effects on postural locomotor muscles. AB - In some rodent skeletal muscles, hindlimb non-weight-bearing activity induces a shift in the expression of myosin heavy chains (MHCs) that favors the type II isoforms at the expense of type I. Chemically induced chronic creatine depletion results in isomyosin shifts favoring expression of type I MHCs. In this study, creatine depletion was induced separately and in combination with non-weight bearing activity to determine if the response to lowering this metabolite would counter the MHC transitions expected from non-weight bearing. Creatine depletion was induced by feeding rats a diet supplemented with the creatine analogue beta guanidinopropionic acid (beta-GPA). Female Sprague-Dawley rats weighing 247 +/- 8 g were randomly assigned to four groups: 1) normal diet control, 2) beta-GPA control (BC), 3) normal diet suspended (NS), and 4) beta-GPA suspended (BS). BC and BS animals were fed a diet containing the creatine analogue for 68 days. Hindlimb non-weight bearing in BS and NS animals was accomplished by tail suspension for the final 30 days of this period. beta-GPA feeding lowered the creatine content of muscles sampled by 65%. Creatine depletion resulted in a 16% increase in citrate synthase activity in the soleus (SOL) and a 24% increase in the plantaris (PLN). In two postural muscles, the SOL and vastus intermedius (VI), tail suspension resulted in large decreases in the type I MHC expression and increases in type IIx and IIb MHCs. In two locomotor muscles, the PLN and medial gastrocnemius, type I MHC declined and type IIb increased with suspension.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836123 TI - Physical determinants of bronchial mucosal folding. AB - It has recently been proposed, on the basis of a theoretical analysis, that the folding of the mucosa provides a significant component of airway stiffness. The model predicted that the stiffness of an airway was directly related to the number of epithelial folds that developed. In this study we examine the possibility that the folding pattern is determined by the physical requirements that the folding membrane must stay within the boundary of the smooth muscle wall, that the submucosal mass is constant, and that the strain energy of the folding membrane is the minimum possible within the geometric constraints. Model predictions are compared with morphometric data from the noncartilaginous airways of 17 sheep lungs. The data are in agreement with our predictions, which are based on the assumption that the folding membrane thickness is proportional to the submucosal thickness (in a fully dilated airway). The outcome of this analysis is that the increase in intrinsic stiffness of the folding membrane resulting from the increased thickness outweighs the decrease in stiffness conferred by the fewer folds required by the thicker submucosa. It is suggested that the increase in folding membrane thickness observed in asthma could be viewed as a protective mechanism that tends to reduce hyperresponsiveness. PMID- 7836124 TI - Synthetic surfactant scavenges oxidants and protects against hyperoxic lung injury. AB - Injury and mortality after exposure to 100% oxygen can be diminished by surfactants that may operate by mechanisms other than those responsible for surface tension effects. We tested the hypotheses that 1) synthetic surfactant and its components function as antioxidants in vitro and 2) decrements in hyperoxic injury after treatment with a surfactant and its components are associated with decreases in oxidative stress to the lung. A synthetic surfactant (Exosurf) and its non-surface-active components tyloxapol and cetyl alcohol were incubated in an iron-containing hydroxyl radical-generating system to determine their abilities to prevent oxidation of deoxyribose. Doses of tyloxapol, cetyl alcohol, and artificial surfactant diminished the absorbance of thiobarbituric acid-reactive products of deoxyribose. Similarly, tyloxapol, cetyl alcohol, and the surfactant decreased hydroxylated products of salicylate in the same system. Rats were instilled intratracheally with saline, tyloxapol, tyloxapol plus cetyl alcohol, or artificial surfactant and immediately exposed to air or 100% oxygen. After 61 h of oxygen exposure, pleural fluid volume and wet-to-dry lung weight ratios were decreased in animals treated with surfactant and/or its components. There were also decrements in thiobarbituric acid-reactive products of lung tissue. In separate experiments, mean survival of saline-treated rats exposed to 100% oxygen was 67.3 +/- 8.1 h and > 96 h for rats given the surfactant or its components. We conclude that tyloxapol, cetyl alcohol, and Exosurf can function as antioxidants in vitro and their in vivo instillation is associated with reduction in measures of hyperoxic injury, oxidized tissue products, and mortality. PMID- 7836125 TI - Three-dimensional optical analysis of chest wall motion. AB - A method for kinematic analysis of chest wall motion is presented, based on a television-image processor that allows a three-dimensional assessment of volume change of the trunk by automatically computing the coordinates of several passive markers placed on relevant landmarks of the thorax and abdomen. The parallel computation used for the image processing allows for a real time recognition of the passive markers with the necessary accuracy. A geometric model also allows the online computation of the contribution to the chest volume by the different parts. For this purpose, the model presented here is based on 54 tetrahedrons that can be grouped into 9 compartments and 3 sections representing 1) upper thorax (mainly reflecting the action of neck and parasternal muscles and the effect of pleural pressure), 2) lower thorax (mainly reflecting the action of diaphragm and the effect of pleural and abdominal pressure), and 3) abdomen (mainly reflecting the actions of diaphragm and abdominal muscles). By this model, the volume can also be split into three vertical sections pointing out asymmetries between the right and left sides. The method is noninvasive, nonionizing, and leaves the subject maximum freedom of movement during the test, thus being suitable for routine clinical analysis. The monitoring of the subject can be prolonged in time and can be performed in different postures: standing, sitting, and supine. The method was tested on 12 healthy subjects showing its good accuracy, reliability, and reproducibility. PMID- 7836126 TI - Cerebellar role in the load-compensating response of expiratory muscle. AB - The hypothesis that the cerebellum is involved in the load-compensating response of expiratory muscles to expiratory tracheal occlusion was tested in anesthetized cats. A continuous expiratory threshold load (ETL; 5 cmH2O) was applied to elicit consistent phasic baseline electromyographic activity in the transversus abdominis muscle (EMGab). Tracheal occlusion for single expirations (TOE) were applied, and the evoked responses were compared in the intact and decerebellate preparation. Cold blockade of the dorsal spinal column (C5-7) and bilateral vagal inactivation (cold blockade or transection) were employed to determine the role of afferents from the lung, airways, chest wall, and diaphragm in shaping the cerebellar involvement in the motor response. The results showed that 1) decerebellation increased the baseline amplitude of the integrated EMGab (fEMGab) activity (P < 0.05) with little change in expiratory duration, 2) TOE applied after decerebellation markedly increased the expiratory duration compared with the intact values (P < 0.05), with little effect on the peak fEMGab, 3) cooling the dorsal spinal columns (C5-7) did not significantly affect EMGab responses in the intact or decerebellate preparations, and 4) vagal inactivation in the intact or decerebellate preparation significantly eliminated the fEMGab responses to ETL and TOE. We conclude that the cerebellum is involved in the modulation of transversus abdominis activity during ETL and TOE. Vagal afferents provide the major sensory input for the cerebellar modulation of the expiratory loading response. PMID- 7836127 TI - Capsaicin-activated bronchial- and alveolar-initiated pathways regulating tracheal ciliary beat frequency. AB - We questioned whether the prolonged stimulation of ciliary beat frequency (CBF) to a short exposure of low-dose capsaicin (Wong et al. J. Appl. Physiol. 68: 257 2580, 1990) could be due to the activation of indirect pathways involving neural reflexes initiated independently in the bronchi and alveoli. Tracheal CBF (CBFtr) was measured temporally in anesthetized groups of 10 dogs by means of heterodyne mode correlation analysis laser light scattering. To elucidate the site of the afferent neural stimulation and the efferent mediators affecting the ciliated epithelium, capsaicin (3 nM) aerosol was delivered for 4 min, either predominantly to the bronchi or to the alveolar regions, with use of pulsed aerosol techniques. This resulted in 13 pg of bronchial (85%) and 10 pg of alveolar (96%) capsaicin deposited, which caused marked stimulation of CBFtr with maxima at 7 and 35 min, respectively. Prior administration of aerosolized indomethacin to the bronchi or aerosolized cromolyn to the alveoli inhibited the bronchial and alveolar responses, respectively. Prior administration of aerosolized hexamethonium to the tracheal lumen blocked the stimulatory CBFtr responses from both capsaicin challenges. Ipratropium or propranolol aerosols delivered to the tracheal lumen also inhibited these responses. It is proposed that these pathways comprise one set of sensitive mechanisms to ensure a prolonged stimulation of CBF to effect the removal of secretions and the irritant from the lungs. PMID- 7836128 TI - Effects of detection and classification of resistive and elastic loads on endogenous event-related potentials. AB - Resistive and elastic loads added to inspiration are readily detected, and detection latencies vary as a function of load magnitude and load type. In the present study, we recorded endogenous event-related potentials (i.e., N2 and P3) to the detection and classification of large (15.0 cmH2O.1-1.s and 70.0 cmH2O/l) and small (1.45 cmH2O.1-1.s and 19.0 cmH2O/l) loads equated for subjective magnitude in 14 men (mean age 21.14 yr). In blocks of trials comprised of either large or small loads, subjects made a button-press response upon detecting a load and then classified the load as resistive or elastic. Loads were presented briefly (for approximately 200 ms) early in inspiration and at the same level of inspiratory pressure. For loads of comparable magnitude, subjects detected equivalent numbers of resistive and elastic loads but could not discriminate reliably between load types. On the other hand, the latency of N2 was shorter to larger than to smaller loads, to resistive than to elastic loads, and to correct than to incorrect load classifications. The latency of P3 was affected similarly by load magnitude and load type. These findings demonstrate that event-related potentials are elicited by brief presentations of resistive and elastic loads and that N2 and P3 latencies vary reliably as a function of load magnitude and load type. Most importantly, event-related potential latencies are sensitive to load type and to classification accuracy even when resistive and elastic loads are not distinguishable subjectively. PMID- 7836129 TI - Continuous negative airway pressure increases tonic activity in diaphragm and intercostal muscles in humans. AB - The main objective of the present study was to quantify the increase in tonic inspiratory activity (delta TIA) in response to continuous negative airway pressure (CNAP) in humans. TIA represents the activity in inspiratory muscles at the end of expiration. In 20 subjects, electromyograms (EMGs) were recorded from the diaphragm and parasternal intercostal muscles (ICM) with surface electrodes during control and at three different levels of CNAP (-0.3, -0.6, and -0.9 kPa; 1 kPa approximately 10 cmH2O). From these recordings we determined delta TIA and the amplitudes of phasic EMG activities (EMGphas) during CNAP and control. To evaluate the effects of CNAP on functional residual capacity (FRC), respiratory frequency, tidal volume, and minute ventilation, the subjects were connected to a closed breathing circuit. When the pressure at the airway opening was -0.9 kPa, mean values of delta TIA were 53 and 49% of control EMGphas for the diaphragm and ICM, respectively. In addition, EMGphas at airway opening pressure of -0.9 kPa had increased to 195 and 162% of control EMGphas for the diaphragm and ICM, respectively. The concomitant decrease in FRC was on average 18.7% of predicted FRC. Minute ventilation had increased significantly (P < 0.05) at all levels of CNAP compared with control. We conclude that CNAP is a forceful stimulus to increase TIA in humans in both the diaphragm and the ICM. PMID- 7836130 TI - Permeability of ferret trachea in vitro to 99mTc-DTPA and [14C]antipyrine. AB - Platelet-activating factor (PAF) and vasoactive drugs were tested on permeability of ferret trachea in vitro by measuring fluxes of 99mTc-diethylenetriamine pentaacetic acid (99mTc-DTPA; hydrophilic) and [14C]antipyrine ([14C]AP; lipophilic) across the tracheal wall. Tracheae were bathed on both sides with Krebs-Henseleit buffer, with luminal buffer containing either 99mTc-DTPA or [14C]AP. Luminal and abluminal radioactivities, potential difference, and tracheal smooth muscle tone were measured. Baseline 99mTc-DTPA and [14C]AP permeability coefficients were -4.7 +/- 0.6 (SE) x 10(-7) and -2.2 +/- 0.1 x 10( 5) cm/s, respectively. PAF (10 microM) increased permeability to 99mTc-DTPA to 35.3 +/- 7.6 x 10(-7) cm/s (P < 0.05), but permeability to [14C]AP did not change, suggesting that paracellular but not transcellular transport was affected. Abluminal and luminal applications of methacholine (MCh, 20 microM), phenylephrine (PE, 100 microM), and albuterol (Alb, 100 microM) caused no change in permeability to 99mTc-DTPA before or after exposure to luminal PAF, but abluminal histamine (Hist, 10 microM) significantly increased permeability. Abluminal Hist decreased permeability to [14C]AP before and after exposure to PAF. MCh, PE, and Hist increased smooth muscle tone; Alb and PAF had no effect. Thus, only PAF and Hist altered permeability to 99mTc-DTPA, and MCh, PE, and Hist changed smooth muscle tone. Tracheal permeability changes were greater for the hydrophilic than for the lipophilic agent. PMID- 7836131 TI - Effects of domperidone on neonatal and adult carotid chemoreceptors in the cat. AB - It has been postulated that the weak carotid chemoreceptor responses of neonatal mammals may be due to inhibition produced by high levels of endogenous dopamine release or exaggerated sensitivity to dopaminergic inhibition. This was studied by measuring the effect of domperidone, a selective dopamine D2-receptor antagonist, on the carotid chemoreceptor response to O2 and CO2 in anesthetized neonatal and adult cats. The animals were exposed to four levels of isocapnic O2 (arterial PO2 of approximately 35-45, 55-65, 80-90, > 300 Torr) and four levels of isoxic CO2 (end-tidal PCO2 of approximately 21, 40, 58, and 78 Torr) before and after D2-receptor blockade. Whole nerve activity was recorded from the carotid sinus nerve (CSN). Both neonatal and adult cats increase CSN activity during hypoxia and hypercapnia (P < 0.001). Domperidone caused an increase in CSN activity at all O2 levels in adults (P < 0.01) but only during hypoxia in neonates (P < 0.001). Domperidone caused an increase in CSN activity during normo and hypercapnia in adults but only during hypercapnia in neonates (P < 0.001). Domperidone approximately doubled an index of hypoxic sensitivity in the normoxia hypoxia range (100 to 40 Torr) in the neonatal group but had little effect on sensitivity to hypoxia in adults. We conclude that the inhibitory role of endogenous dopamine in the carotid chemoreceptors changes with postnatal development. PMID- 7836132 TI - TGF-beta 1 causes increased endothelial ICAM-1 expression and lung injury. AB - Neutrophil adherence to vascular endothelium is partially mediated by adhesion molecules, including intracellular adhesion molecule 1 (ICAM-1), on endothelial cells. We examined the effect of transforming growth factor-beta 1 (TGF-beta 1) on the expression of ICAM-1 in human umbilical vein endothelial cells (HUVEC). TGF-beta 1 (1 ng/ml) increased ICAM-1 and ICAM-1 mRNA expression in HUVEC, as assessed by flow cytometry and Northern blot analysis, respectively. In addition, we investigated whether exogenous recombinant TGF-beta 1 can cause neutrophil mediated lung injury in guinea pigs. The plasma half-life of 125I-labeled TGF beta 1 in guinea pigs was 4.6 +/- 0.1 min, and the 125I activity was 2.8 +/- 0.2% 8 h after injection. The ratio of 125I-labeled albumin concentration in lung tissue and bronchoalveolar lavage (BAL) fluid to that in plasma, lung wet-to-dry weight ratio, numbers of neutrophils in BAL fluid, and numbers of neutrophils per alveolus in fixed lung sections increased in guinea pigs that received a high dose of TGF-beta 1 (25 micrograms i.v. followed by 2 micrograms/h for 8 h) compared with the control group. These results suggest that TGF-beta 1 causes neutrophil-mediated lung injury, possibly through upregulation of ICAM-1 on endothelial cells, and might be important in the pathogenesis of lung injury. PMID- 7836133 TI - Removal of albumin microinjected in rat lung perimicrovascular space. AB - We used a microinjection approach to assess hydraulic properties of lung perimicrovascular adventitia (interstitial cuff surrounding microvessels). Isolated blood-perfused rat lungs held at constant airway pressure were microscopically viewed to identify subpleural venules (20 microns diam). Venular adventitia were microinjected with 20 nl of fluorescent albumin (4 g/dl), and then adventitial fluorescence was quantified at the injection site by either photometery or imaging. Nonlinear decay of adventitial fluorescence indicated liquid flux from the injection site into normal interstitium. In some experiments, we determined that the adventitial fluorescence flowed longitudinally along the venule length and filled single lymphatics. The fluorescence decay at the injection site was best described by equations of convective but not diffusive transport. The decay time constant (time to 37% initial), which relates inversely to hydraulic conductivity, increased 10-fold above baseline on lung expansion with airway pressure from 5 to 15 cmH2O (P < 0.05). However, presence or absence of blood flow, increase in filtration pressure, and tissue edema were all without effect on the time constant. Our estimate of the lower limit of baseline adventitial hydraulic conductivity was 5 x 10(-6) ml.cm-2.s-1.cmH2O-1. We conclude that hydraulic conductivity of perimicrovascular adventitia is not augmented by edema but that it is decreased by lung expansion. PMID- 7836134 TI - Effect of an inhaled corticosteroid on airway eosinophils and allergen-induced airway hyperresponsiveness in dogs. AB - The presence of airway eosinophils before allergen inhalation may contribute to the development of allergen-induced airway responses. We examined whether a reduction in airway eosinophil numbers before allergen inhalation as a result of inhalation of the corticosteroid budesonide would prevent allergen-induced airway hyperresponsiveness in seven dogs. Acetylcholine airway responsiveness was measured before and 24 h after inhalation of Ascaris suum allergen (10(-6)-10(-2) wt/vol) or its diluent on 4 test days separated by > or = 4 wk. Dogs were pretreated for 7 days before and on the morning of each test day with inhaled budesonide (2.69 mg/day) or a placebo (lactose). Airway eosinophil numbers were assessed by bronchoalveolar lavage. Inhaled budesonide significantly reduced the number of airway eosinophils before allergen inhalation from 3.6 +/- 2.38 x 10(4) (SE) cells/ml after inhaled lactose to 0.3 +/- 0.21 x 10(4) cells/ml after inhaled budesonide (P = 0.028). The decrease in eosinophil number was associated with a significant reduction in allergen-induced airway hyperresponsiveness (P = 0.005). These results support the hypothesis that the number of eosinophils in the airways before allergen inhalation is an important determinant in the development of allergen-induced airway hyperresponsiveness in dogs. PMID- 7836135 TI - Downregulation of pulmonary atrial natriuretic peptide receptors in rats exposed to chronic hypoxia. AB - We hypothesized that a downregulation in pulmonary atrial natriuretic peptide (ANP) receptors helps raise plasma ANP levels during chronic hypoxia. We measured in vivo pulmonary uptake and plasma clearance of 125I-ANP and in vitro pulmonary binding kinetics of 125I-ANP in normoxic and chronically hypoxic rats. Exposure to 21 days of hypobaric (0.5 atm) hypoxia did not decrease specific binding of 125I-ANP in the kidney, but pulmonary binding decreased 35 and 75% after 1 and 3 days of hypoxia, respectively, and increased 200% after 3 days of normoxic recovery from 21 days of hypoxia. The total binding capacity for ANP to lung membrane fractions from normoxic rats, chronically hypoxic rats, and rats that had recovered from hypoxia was 488 +/- 59, 109 +/- 17, and 338 +/- 48 fmol/mg, respectively (P < 0.05 for hypoxic vs. normoxic or recovered lung membranes). The area under the 125I-ANP plasma concentration curve for normoxic and hypoxic rats and normoxic rats that were infused with the ANP C-receptor ligand C-ANF-(4-23) was 3,292 +/- 216, 5,022 +/- 466, and 8,205 +/- 1,059 disintegrations.min-1.ml-1, respectively [P < 0.05 for hypoxic vs. normoxic or C-ANF-(4-23)-infused rats]. We conclude that pulmonary ANP clearance is reduced during chronic hypoxia secondary to a downregulation in pulmonary ANP clearance receptors. Reduced pulmonary clearance of ANP may represent an adaptation that contributes to increased plasma ANP levels during chronic hypoxia. PMID- 7836136 TI - Effect of long-term electrical stimulation on vascular supply and fatigue in chronically ischemic muscles. AB - Fast skeletal muscles of Sprague-Dawley rats [tibialis anterior (TA) and extensor digitorum longus (EDL)] were subjected to ischemia by unilateral ligation of the common iliac artery. In some animals, ischemia was combined with indirect electrical stimulation at 10 Hz either for 3 x 2 h (strenuous activity) or for 7 x 10-min bouts/day (mild activity). After 2 wk, muscle blood flow and fatigue were measured during 5-min isometric supramaximal twitch contractions at 4 Hz. Terminal arteriole diameters were assessed in TA by intravital microscopy at rest and during contractions. Vascular perfusion pressure in the muscles was estimated from measurements in the carotid and saphenous arteries below the site of ligation. Capillary supply was expressed in TA and EDL as capillary-to-fiber ratio on the basis of histochemical staining for capillaries. Strenuous stimulation of ischemic muscles increased their atrophy, failed to restore blood flow, and actually worsened fatigue. In contrast, mild stimulation improved perfusion pressure, increased capillary-to-fiber ratio in the glycolytic part of TA, restored dilatation of terminal arterioles during muscle contractions, and improved blood flow and muscle fatigue so that they were no longer significantly different from control muscles. Thus, an attenuated intermittent protocol may be indicated in the treatment of muscle ischemia. PMID- 7836137 TI - Effects of ONO-5046, a specific neutrophil elastase inhibitor, on endotoxin induced lung injury in sheep. AB - The purpose of the present study was to assess the role of polymorphonuclear leukocyte (neutrophil) elastase in endotoxin-induced acute lung injury in sheep with lung lymph fistula. We studied the effects of ONO-5046, a specific inhibitor of neutrophil elastase, on the lung dysfunction induced by the intravenous infusion of 1 microgram/kg of Escherichia coli endotoxin. Endotoxin alone produced a biphasic response as previously reported. Early (0.5-1 h) after endotoxin, pulmonary arterial pressure increased from 19.5 +/- 0.9 cmH2O at baseline to a peak of 46.8 +/- 2.4 cmH2O (P < 0.05). Pulmonary vascular resistance increased from 3.03 +/- 0.17 cmH2O.l-1.min at baseline to a peak of 9.77 +/- 0.70 cmH2O.l-1.min (P < 0.05). Circulating neutrophils decreased from 7,355 +/- 434/mm3 at baseline to a nadir of 1,762 +/- 32/mm3 (P < 0.05). Thromboxane B2 and 6-ketoprostaglandin F1 alpha concentrations in plasma and lung lymph were significantly increased. Late (3-5 h) after endotoxin, pulmonary arterial pressure and pulmonary vascular resistance returned to baseline levels, but lung lymph flow remained increased from 4.2 +/- 0.3 ml/0.5 h at baseline to 7.3 +/- 0.7 ml/0.5 h (P < 0.05), with a slight increase in lung lymph-to-plasma protein concentration ratio, suggesting increased pulmonary vascular permeability. The histopathological features of the lungs during the early period in sheep treated with endotoxin alone revealed a large increase in neutrophils per 100 alveoli and changes of pulmonary edema such as thickening of the interstitium of the lung and alveolar flooding.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836138 TI - Effect of hematocrit on systemic O2 transport in hypoxic and normoxic exercise in rats. AB - The effect of hematocrit (Hct) on O2 transport in hypoxic [inspired PO2 (PIO2) approximately 70 Torr] and normoxic (PIO2 approximately 145 Torr) exercise was studied in rats acclimatized to 3 wk of PIO2 at approximately 70 Torr (A rats) and in nonacclimatized littermates (NA rats). Isovolumic exchange transfusion of plasma or red blood cells was used to lower Hct in A rats from approximately 60 to 45% and to raise Hct of NA rats from 45 to 60%: Controls were A and NA rats exchange transfused with whole blood at constant Hct. Lowering Hct of A rats lowered the arterial O2 concentration (CaO2) and the arterial-mixed venous O2 difference and increased the maximal cardiac output (Qmax) without changes in maximal O2 uptake (VO2 max) or in the product of Qmax x CaO2, circulatory O2 convection at maximal exercise (TO2 max). Raising Hct in NA rats produced the opposite changes in CaO2, arterial-mixed venous O2 difference, and Qmax, but VO2 max and TO2 max increased significantly, both in hypoxia and normoxia, because of relatively small changes in Qmax. In NA rats, a steeper slope of the line relating VO2 max to calculated mean capillary PO2 at high Hct suggested a higher tissue O2 diffusing capacity with high Hct. For a given Hct and Qmax, systemic arterial pressure was higher in A rats. The data suggest that 1) the effect of Hct on systemic hemodynamics is different in A and NA rats, resulting in different effects on VO2 max; 2) factors in addition to Hct contribute to the high systemic vascular resistance of A rats; and 3) increased diffusive conductance for O2, as well as increased TO2 max, could be responsible for the effect of Hct on VO2 max of NA rats. PMID- 7836139 TI - Respiratory motor nerve activities during spontaneous bladder contractions. AB - We monitored spontaneous bladder contractions (SBCs) in decerebrate vagotomized paralyzed ventilated cats while recording respiratory motor nerve activities and intravesical pressure under isovolumetric conditions. Phrenic nerve discharge diminished during SBCs, as did the activities of the hypoglossal nerve, the nasolabial branch of the facial nerve, and inspiratory (posterior cricoarytenoid) and expiratory (thyroarytenoid) branches of the recurrent laryngeal nerve. Hypoglossal activity was most strikingly reduced during SBCs, disappearing completely in some animals. The triangularis sterni nerve exhibited an initial decrease, followed by an increase in activity during SBCs, whereas the cranial iliohypogastric nerve showed increased activity. The changes in nerve activities during SBCs could also be elicited by passive distension of the bladder and were abolished by bilateral section of the pelvic nerves. These findings extend the understanding of reflexes originating from the urinary bladder to include a coordinated respiratory response and suggest that these reflexes may compromise upper airway patency under some conditions. PMID- 7836140 TI - Ventilator pattern influences neutrophil influx and activation in atelectasis prone rabbit lung. AB - Both ventilator pattern and neutrophil activation influence lung injury in adult respiratory distress syndrome (ARDS). We therefore questioned whether ventilator pattern independently affects neutrophil accumulation and function in early ARDS. Thirty-five New Zealand White rabbits were anesthetized, paralyzed, and prepared using sterile techniques. Fifteen surfactant-depleted animals were randomized and ventilated for 4 h using high-frequency oscillatory ventilation (HFO) at 15 Hz with an inspired O2 fraction = 1.0 and arterial PO2 (PaO2) > 400 Torr (a pattern known to reverse atelectasis) or conventional mechanical ventilation (CMV) with PaO2 = 80-100 Torr (a pattern with some atelectasis despite positive end expiratory pressure). Eight normal animals on CMV with PaO2 > 400 Torr served as a reference group (NorCMV). NorCMV animals progressively increased circulating polymorphonuclear neutrophil (PMN) numbers and had minor pressure-volume curve alterations but no other significant changes. Lavaged CMV animals developed the characteristic gas exchange and marked pressure-volume curve abnormalities of ARDS. Circulating PMNs remained constant but developed decreased chemotactic activity, whereas lung neutrophil numbers increased significantly (P = 0.0002) and had substantially enhanced chemiluminescence (P = 0.0003 vs. NorCMV animals). Although lavaged HFO animals accumulated an intermediate number of lung neutrophils (lung myeloperoxidase > NorCMV animals; P = 0.003), the chemiluminescence and chemotaxis of these PMNs were the same as in cells from NorCMV animals. We concluded that both the degree of neutrophil activation and lung injury can be minimized by preventing cyclic alveolar/airway expansion and collapse in the surfactant-deficient lung by use of appropriate ventilator patterns. PMID- 7836141 TI - Endurance exercise training is associated with elevated basal sympathetic nerve activity in healthy older humans. AB - We tested the hypothesis that endurance training is associated with altered basal levels of muscle sympathetic nerve activity (MSNA) and responses to acute stress in healthy older adults. MSNA (peroneal microneurography) and plasma norepinephrine (NE) concentrations were measured during supine rest, a cold pressor test, and isometric handgrip (40% maximal voluntary force to exhaustion) in 16 older masters endurance athletes [10 men, 6 women; 66 +/- 1 (SE) yr] and 15 healthy normotensive untrained control subjects (9 men, 6 women; 65 +/- 1 yr). The athletes had higher levels of estimated daily energy expenditure and maximal oxygen uptake and lower levels of resting heart rate and body fat than the control subjects (all P < 0.05). MSNA during supine rest was elevated in the athletes whether expressed as burst frequency (43 +/- 2 vs. 32 +/- 3 bursts/min, respectively; P < 0.05) or burst incidence (75 +/- 4 vs. 52 +/- 5 bursts/100 heartbeats, respectively; P < 0.01). These whole group differences were due primarily to markedly higher levels of MSNA in the athletic vs. untrained women (48 +/- 4 vs. 25 +/- 3 bursts/min, 82 +/- 3 vs. 38 +/- 3 bursts/100 heartbeats, respectively, P < 0.001). In contrast, basal plasma NE concentrations were not significantly different in the athletes vs. control subjects. The MSNA and plasma NE responses to acute stress tended to be greater in the athletes. These findings indicate that vigorous regular aerobic exercise is associated with an elevated level of MSNA at rest and a tendency for an enhanced response to acute stress in healthy normotensive older humans. PMID- 7836143 TI - An approach to the study of upper airway function in humans. AB - Current methods for testing upper airway (UA) collapsibility in humans tend to produce intervention-related changes in some of the variables that affect UA stability. Therefore, their results may not reflect UA stability under the experimental conditions of interest. In the proposed method, the subject lies in a body enclosure with head and neck out. Pressure is altered in brief (approximately 0.2-s) pulses to avoid behavioral responses. The collapsibility of UA under "static" conditions is tested by delivering identical pressure pulses simultaneously to the airway and body surface inside the shell. Because the pressure applied to the respiratory system is not altered, cessation of flow indicates closure, and the pressure at which this happens is Pclosure. Collapsibility under dynamic conditions is tested by applying brief negative pulses to the shell only, thereby forcing an increase in inspiratory flow. Ten normal awake subjects were tested. None of the subjects developed closure when negative pulses (0 to -16 cmH2O) were applied to both airway and shell during inspiration or expiration with either nose or mouth breathing. There were only small reductions in flow, indicating minor narrowing. By contrast, pressure pulses of similar magnitude applied to the shell alone were associated with closure in 5 of 10 subjects. We conclude that the UA of normal awake humans is fairly stable under the influence of statistically applied pressure but susceptible to collapse under conditions of increased flow. Pclosure determined under static conditions underestimates the vulnerability of the UA to collapse under dynamic conditions. PMID- 7836142 TI - Gravitational and shear-associated pressure gradients in the abdomen. AB - The abdomen has been variously characterized as a hydrostatic system, in which pressures exhibit a gravitational gradient and pressure fluctuations are spatially uniform, and as a compartment, in which pressure gradients are not simply gravitational and pressure fluctuations differ markedly from place to place. To characterize the pressures acting on the ventral abdominal wall, we used saline-filled catheters and air-filled balloons in anesthetized dogs in various body positions during spontaneous breathing and mechanical ventilation. Pressures were measured in the stomach and at multiple sites next to the abdominal wall. Under most circumstances, measurements next to the abdominal wall exhibited a hydrostatic gravitational gradient of approximately 0.89 cmH2O/cm height and pressure fluctuations were spatially homogeneous. Deviations from this hydrostatic behavior were seen when abdominal pressures were compared with gastric pressures, when measurements were made with a balloon catheter, and when the lower abdomen was constricted with a binder. Analysis of these and previously published data suggests that the abdomen does, at times, behave like a hydraulic system but can deviate from simple hydrostatic behavior to the extent that shape stable abdominal viscera are deformed. PMID- 7836144 TI - Abdominal muscle activity during hypercapnia in awake dogs. AB - We previously found the internal abdominal muscle layer to be preferentially recruited during expiratory threshold loading in anesthetized and awake dogs. Expiratory threshold loading increases end-expiratory lung volume and hence can activate reflex pathways such as tonic vagal reflexes, which could influence abdominal muscle recruitment. Our objectives in the present study were to determine the effects of hypercapnia on abdominal muscle activation and the pattern of recruitment in awake dogs. Five tracheotomized dogs were chronically implanted with sonomicrometer transducers and fine-wire electromyogram (EMG) electrodes in each of the four abdominal muscles: transversus abdominis, internal oblique, external oblique, and rectus abdominis. Muscle length changes and EMG activity were studied in the awake dog at rest and during CO2 rebreathing. CO2 rebreathing produced a tripling of tidal volume and activation of the abdominal muscles. Despite the increase in tidal volume, there was no significant change in abdominal muscle end-inspiratory length. Both tonic and phasic expiratory shortening were greater in the internal muscle layer (transversus abdominis and internal oblique) than in the external muscle layer (external oblique and rectus abdominis). We conclude that the internal abdominal muscles are preferentially recruited by hypercapnia and vagal reflexes probably do not contribute to this differential recruitment but that segmental reflexes may be involved. The mechanical consequences of this recruitment are discussed. PMID- 7836145 TI - Alteration of plasma endothelin-1 by exercise at intensities lower and higher than ventilatory threshold. AB - The purpose of this study was to investigate whether the release of endothelin-1 (ET-1), a potent vasoconstrictor peptide produced by vascular endothelial cells, is induced by exercise. Venous plasma concentrations of ET-1 were measured by sandwich-enzyme immunoassay before and after endurance exercise with a cycle ergometer at different intensities. Male intercollegiate athletes participated in the study and performed cycle ergometer exercise of 30 min duration at intensities of 90 or 130% of their individual ventilatory threshold (VT). The plasma concentration of ET-1 was slightly but significantly increased after exercise at 90% and markedly increased after exercise at 130% of individual VT. The increase in ET-1 was greatest 30 min after exercise at both intensities. It was first demonstrated that the plasma concentration of ET-1 was significantly increased after exercise: the greater the intensity, the greater the extent of the increase in plasma ET-1 concentration. However, the precise physiological roles of ET-1 during exercise remain to be elucidated. PMID- 7836146 TI - Arm muscle sympathetic nerve activity during preparation for and initiation of leg-cycling exercise in humans. AB - We tested the hypothesis that sympathetic vasoconstrictor nerve activity to nonactive skeletal muscle (MSNA) decreases immediately before and remains suppressed during initiation of conventional large muscle upright dynamic exercise in humans. In 11 healthy young subjects, adequate recordings of MSNA from the radial nerve in the arm were obtained during upright seated rest (control) and throughout 1 min of leg-cycling exercise at one or more submaximal workloads (range 33-266 W; approximately 10-80% of peak power output). MSNA was analyzed during four consecutive time intervals; control, preparation for cycling (end of control to onset of pedal movement), initiation of cycling (onset of pedal movement to attainment of target power output), and the initial 60 s of cycling at target power output. MSNA decreased (P < 0.05) abruptly and markedly in all subjects [to 19 +/- 4% (SE) of control levels] during the preparation period before the 33-W load and remained suppressed throughout the period of initiation of cycling in 8 of 11 subjects; MSNA increased during the initiation period in three subjects in whom diastolic arterial pressure fell below control levels. This general pattern was observed at all loads. MSNA remained at or below control levels throughout the 1 min of cycling exercise at 33-166 W. MSNA increased above control levels during the latter portion of the 1 min of cycling only at loads > or = 60% of peak power output.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836147 TI - Effects of spaceflight on morphology of the rat adenohypophysis. AB - To determine the effects of spaceflight on the anterior pituitary gland, the adenohypophyses of rats after a 7-day spaceflight aboard the space shuttle Endeavor (STS-54) were investigated by histology, immunohistochemistry, morphometry, electron microscopy, and in situ hybridization and were compared with synchronous control rats. Morphometry revealed the corticotrophs of space flown rats to be significantly enlarged, demonstrating 46-48% increases in mean cell, nuclear, and cytoplasmic areas. These corticotrophs also exhibited striking ultrastructural signs of heightened secretory activity. Furthermore, their expression of proopiomelanocortin mRNA, the transcript encoding the precursor protein from which adrenocorticotropic hormone is posttranslationally cleaved, was also significantly enhanced, a finding consistent with their hypersecretory state. Gonadotrophs also exhibited significant increments in mean nuclear, cell, and cytoplasmic areas of 22, 45, and 51%, respectively; however, they were not accompanied by ultrastructural evidence of increased secretory function. There were no morphological changes in somatotrophs, lactotrophs, or thyrotrophs, nor were there any significant changes in the overall frequency of any one adenohypophyseal cell type in comparison with control. The structural integrity of all adenohypophyseal secretory and vascular elements was preserved after spaceflight, as there was neither evidence of necrosis nor other forms of cellular injury in spaceflown specimens. Capillaries were patent, and neither endothelial damage nor thrombosis was noted. These data suggest that spaceflight is accompanied by a selective morphological response in the anterior pituitary, one characterized by hypertrophy of both corticotrophs and gonadotrophs and by enhanced endocrine activity of the former. PMID- 7836148 TI - Eccentric contraction-induced injury in normal and hindlimb-suspended mouse soleus and EDL muscles. AB - The primary objective of this study was to compare the magnitude of injury in mouse extensor digitorum longus (EDL) and soleus muscles induced by high-force eccentric contractions. A second objective was to study the effect of altering the daily loading of the muscles through hindlimb suspension (HS) on the injury. One of two protocols was performed in vitro: 1) 15 eccentric contractions (n = 20: 10 EDL and 10 soleus muscles) or 2) 15 isometric contractions (n = 20: 10 EDL and 10 soleus muscles). After the protocol, the decrements in contractile performance and lactate dehydrogenase (LDH) release were measured at 15-min intervals over 1 h. Immediately after the eccentric contraction protocol, markedly greater decrements in maximal isometric tetanic force (Po) occurred in the normal EDL than in the normal soleus muscles (60.7 +/- 4.2 vs. 7.6 +/- 2.1%, P < or = 0.0001). LDH release immediately after the eccentric contraction protocol was 2.7-fold greater in the normal EDL than in the normal soleus muscles. To investigate the role of recent loading of the muscles in the injury, EDL (n = 9) and soleus (n = 10) muscles from mice subjected to HS for 14 days performed the eccentric contraction protocol. HS resulted in greater decrements in contractile performance for the soleus muscles (decreases in Po immediately after the protocol for HS and normal soleus muscles were 31.0 +/- 1.8 and 7.6 +/- 2.1%, respectively; P < or = 0.0001) but not for the EDL muscles.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836149 TI - Effect of increasing work rate on metabolic responses of the donkey (Equus asinus). AB - Oxygen consumption (VO2) and concentration of venous blood metabolites were measured in donkeys trained to run and to pull loads on a treadmill. VO2 in two donkeys running at maximal speed on a 9.8% slope was 110 +/- 2 ml.min-1.kg-1, approximately 22 times preexercise VO2. Average heart rate at maximal VO2 (VO2max) was 223 +/- 2 beats/min, five times the preexercise heart rate. Blood lactate increased 14-fold, and blood glucose did not change (P > 0.05). Animals running up a 4% incline and incremental draft loading of five donkeys walking on the level were also studied. The total energy cost of walking unloaded was 2.86 +/- 0.06 J.m-1.kg live wt-1. During low- to medium-intensity draft work for 25 min, glucose fell below preexercise values (P < 0.05), whereas plasma hematocrit and cortisol increased (P < 0.05). Blood lactate remained unchanged up to approximately 40% VO2 max but increased 170% at approximately 60% VO2max. The responses in donkeys are similar to those of exercising horses except for the rapid decline in blood glucose observed during low-intensity exercise and the lower lactate levels at both the high-intensity exercise and the apparent anaerobic threshold. PMID- 7836150 TI - Decline running produces more sarcomeres in rat vastus intermedius muscle fibers than does incline running. AB - Unaccustomed eccentric exercise, in which a muscle is lengthened while generating tension, is well known to cause injury and pain. A rapid training effect has been demonstrated in a number of eccentric exercises. The mechanism for both the damage and the training has been unknown. Morgan proposed that the damage is caused by sarcomere length instabilities during operation on the descending limb of the sarcomere length-tension curve and that the training effect is an increase in the number of sarcomeres connected in series in a muscle fiber, thus avoiding the descending limb (Biophys. J. 57: 209-221, 1990). We tested this proposal by exercising rats on a treadmill set at either an incline or a decline of 16 degrees, an exercise that has previously been shown to cause damage in untrained rats and a training effect. The vastus intermedius muscles were fixed and were digested in acid, and the fiber and sarcomere lengths of representative fibers were measured. From these measurements, the mean number of sarcomeres per fiber was found for the different training regimes. A clear and repeatable difference was found, supporting Morgan's prediction of more sarcomeres after decline running, although with some differences in response that depended on the age of the rats. PMID- 7836151 TI - Regulation of lung liquid secretion in immature fetal sheep: hormonal interaction. AB - The present studies were designed to test the hypothesis that arginine vasopressin (AVP) can interact with hydrocortisone and 3,5,3'-triiodothyronine (T3) to induce maturation of lung liquid reabsorptive processes in fetal sheep < 130 days gestation. Lung liquid production rates were measured in chronically catheterized thyroidectomized fetal sheep during eight different experimental treatments. Each experiment consisted of a 2-h control period followed by a 5-h treatment period. Net secretion or reabsorption of lung liquid was measured by using impermeant marker dilution techniques. AVP alone (50 mU/kg bolus plus 5.0 mU.kg-1.min-1 i.v. infusion) does not alter lung liquid secretion in fetal sheep 125 +/- 0.72 (SE) days gestation. In contrast, AVP (same dose as above) with T3 (30 micrograms) and hydrocortisone (6.94 mg/min) depressed lung liquid secretion and caused reabsorption of fluid. T3 alone, T3 and hydrocortisone, T3 and AVP, hydrocortisone alone, hydrocortisone and AVP, and saline did not result in net lung liquid reabsorption over a 5-h treatment period. These investigations demonstrate that AVP, T3, and hydrocortisone interact to cause lung liquid reabsorption in immature fetal lungs. PMID- 7836152 TI - Enhanced endothelin-1 and endothelin receptor gene expression in chronic hypoxia. AB - To test the hypothesis that endothelin (ET)-1 synthesis and ET receptor levels are increased selectively in the lung of rats with chronic hypoxic pulmonary hypertension, the current study examined the effects of exposure to chronic hypoxia (10% O2, 1 atm, 4 wk) on pulmonary arterial pressure, ET-1 levels in plasma and lung, and ET-1 and ETA and ETB receptor mRNA levels in lung, heart, pulmonary artery, aorta, kidney, spleen, and liver. Hypoxic exposure was associated with increases in pulmonary arterial pressure, plasma ET-1 levels, ET 1 mRNA in lung and pulmonary artery, and ET-1 stores and ETA and ETB receptor mRNA levels in lung. In thoracic aorta and the four heart chambers, ETA and ETB receptor mRNA levels were increased, but ET-1 mRNA levels were unchanged from air control levels. No change in ET-1 or ET receptor mRNA levels was seen in organs perfused by the systemic vascular bed, except in liver, where ETA receptor mRNA levels were decreased. The findings of concomitant increases in gene transcript levels for ET-1 and the ETA and ETB receptors in lung, but not in the great vessels or any other organ examined, are consistent with the hypothesis that increased ET-1 synthesis in the lung contributes to pulmonary vascular remodeling and the maintenance of chronic hypoxic pulmonary hypertension. PMID- 7836153 TI - Reduction and uptake of methylene blue from rat air spaces. AB - The use of methylene blue (MB) to estimate dilution of epithelial lining fluid, which occurs during bronchoalveolar lavage (BAL), is complicated by loss of this redox dye from the air spaces. The rate of MB uptake from the air spaces of isolated rat lungs and the effects of oxidation and reduction on this process were investigated in this study. Movement of MB from the air spaces to perfusate was compared with the corresponding transport of 125I-labeled albumin, [14C] dextran, 99mTc-labeled diethylenetriaminepentaacetate, [3H]-sucrose, and 3H2O. By the end of 2 min, MB concentrations in the BAL had fallen by 58 +/- 4% (SE; n = 11) and 3H2O by 78 +/- 2% (n = 13), whereas concentrations of the other indicators decreased by approximately 6%. All but 10% of the 3H2O lost from the air spaces was found in the perfusate, whereas 19% of the lost MB was not recovered in the perfusate, suggesting retention of MB in the pulmonary tissues. Absorption of MB from the air spaces was slowed by 20% when the lungs were left unperfused, and absorption was accelerated threefold by reduction of MB to leukomethylene blue with Na2S2O4. In contrast, MB losses from the air space were slowed by the oxidizing agent K3Fe(CN)6 and by addition of superoxide dismutase or ascorbic oxidase. It is therefore possible that ascorbic acid and O2- entering the air spaces reduce MB to the uncharged leuko form. Lowering the pH of the BAL fluid to 3.5 also slowed MB reabsorption. This suggests that acid aspiration may stimulate release of oxidants into the air spaces. PMID- 7836154 TI - Thromboxane A2 mimetic U-46619 induces systemic and pulmonary hypertension and delayed tachypnea in the goat. AB - Cardiorespiratory variables were measured continuously in five conscious goats before and after the infusion of U-46619 at a dose of either 2, 4, or 6 micrograms.kg-1.5 min-1. Infusion of U-46619 led to immediate increases in pulmonary arterial blood pressure (ABP) that were sustained for up to 15 min after the end of the infusion. Systemic ABP also increased, but the relative increase from control was less than the pulmonary pressor response. At the highest dose, U-46619 elicited a delayed tachypneic response that was greatest several minutes after the infusion was stopped. U-46619 was also infused simultaneously with sodium nitroprusside to clamp ABP pressure at baseline levels to determine whether stimulation of baroreceptors might contribute to the latency of the tachypneic response. Although sodium nitroprusside infusion prevented the increase in ABP, the increase in breathing frequency was still delayed 3-4 min from the start of the infusion. We conclude that U-46619 elicits pulmonary and systemic arterial hypertension in the conscious goat. At the higher dose U-46619 also elicits a delayed tachypnea that remains delayed even if ABP is normal. PMID- 7836155 TI - Effects of pulmonary blood flow on the fractal nature of flow heterogeneity in sheep lungs. AB - The spatial heterogeneity of pulmonary blood flow can be described by the relative dispersion (RD) of weight-flow histograms (RD = SD/mean). Glenny and Robertson (J. Appl. Physiol. 69: 532-545, 1990) showed that RD of flow in the lung is fractal in nature, characterized by the fractal dimension (D) and RD for the smallest realizable volume element (RDref). We studied the effects of increasing total pulmonary blood flow on D and RDref. In eight in situ perfused sheep lung preparations, 15-microns radio-labeled microspheres were injected into the pulmonary artery at five different blood flows ranging, in random order, from 1.5 to 5.0 l/m. The lungs were in zone 2 at the lower flows and in zone 3 at the higher flows. The lungs were removed, dried, cut into 2 x 2 x 2-cm3 pieces, weighed, and then counted for microsphere radioactivity. Fractal plots of log(weight) vs. log(RD) were constructed by iteratively combining neighboring pieces and then calculating RD with the increasingly larger portion size. D, which is one minus the slope of the fit through this plot, was 1.14 +/- 0.09 and did not change as blood flow increased. However, RDref decreased significantly (P < 0.01) as total flow increased. We conclude that the fractal nature of pulmonary blood flow distribution is not altered by changes in overall flow. PMID- 7836156 TI - Reduction and accumulation of methylene blue by the lung. AB - We studied the disposition of methylene blue added to the perfusate passing through isolated perfused rabbit lungs. Experiments were carried out in a recirculating or single-pass mode, the latter with either a steady infusion or bolus injection of the dye in its blue oxidized form (MB+) or in its colorless reduced leukomethylene blue form (MBH). The recirculation experiments revealed that the dye was taken up by the lungs and that a substantial fraction (approximately 16%) of the MB+ entering the pulmonary artery was reduced before it emerged from the pulmonary veins. Sequestration of the dye by the lungs was a relatively slow process, and the blue color of the lungs at a time when there was little dye left in the perfusate suggests that much of the sequestered dye was in the oxidized form. The results from the single-pass bolus and steady infusion experiments suggest that MBH diffuses rapidly between perfusate and tissue and that it is more soluble in the tissue than in the perfusates used in the study. In this context, the concept of "solubility" includes the impact of the rapidly equilibrating associations of the dye with the perfusate albumin and tissue components. The observed characteristics of the disposition of the methylene blue within the lungs and the rapid rate of its reduction on passage through the lungs suggest that it may be useful to evaluate the possibility that changes in reduction, uptake, and/or sequestration rates may reflect alterations in the metabolic function of the lungs. PMID- 7836157 TI - Ozone-induced loss of neuronal M2 muscarinic receptor function is prevented by cyclophosphamide. AB - We tested the hypothesis that inflammatory cells mediate the loss of neuronal M2 muscarinic receptors in the lung after ozone exposure. Pathogen-free guinea pigs treated with cyclophosphamide (30 mg.kg-1.day-1 i.p. for 7 days) before exposure to ozone were compared with untreated ozone-exposed animals. This dose of cyclophosphamide significantly reduced leukocytes in peripheral blood and bronchoalveolar lavage fluid. Twenty-four hours after ozone, muscarinic receptor function was tested in anesthetized animals. In air-exposed guinea pigs, vagally induced bronchoconstriction was attenuated by the muscarinic agonist pilocarpine (0.1-100 micrograms/kg i.v.) and potentiated by the selective M2 antagonist gallamine (0.1-10 mg/kg i.v.), indicating that the neuronal M2 muscarinic receptors were functioning. These responses were significantly reduced after ozone, indicating loss of neuronal M2 muscarinic receptor function. However, in those animals treated with cyclophosphamide, M2 muscarinic receptor function was not altered by ozone. These data suggest that ozone-induced loss of neuronal muscarinic receptor function is mediated via inflammatory cells and that the link between ozone-induced hyperresponsiveness and inflammation may be the neuronal M2 muscarinic receptor. PMID- 7836158 TI - Cardiovascular responses to exhaustive upright cycle exercise in highly trained older men. AB - It is unclear whether the markedly enhanced aerobic exercise capacity of older endurance-trained men relative to their sedentary age peers is mediated primarily by central or peripheral cardiovascular mechanisms. To address this question, we performed radionuclide ventriculography with respiratory gas exchange measurements during exhaustive upright cycle ergometry in 16 endurance-trained men aged 63 +/- 7 yr and in 35 untrained men of similar age. As expected, maximal O2 consumption during treadmill exercise was much higher in athletes than in controls. At rest and during fixed submaximal cycle work rates through 100 W, athletes demonstrated lower heart rates and greater stroke volume indexes than controls while maintaining similar cardiac indexes and O2 uptake (VO2). At exhaustion, athletes achieved 53% higher work rates and peak VO2 per kilogram body weight than the sedentary men. The higher peak VO2 in athletes was achieved by a 22.5% larger cardiac index and a 15.6% greater arteriovenous O2 difference. The larger peak cardiac index in the athletes than in sedentary controls was mediated entirely by a greater stroke volume index; peak heart rates were virtually identical. The athletes' greater stroke volume index was achieved through an 11% larger end-diastolic volume index and a 7% higher ejection fraction, both of borderline significance. At exhaustion, athletes demonstrated a lower systemic vascular resistance than controls, despite a higher value at rest. Athletes also showed greater exercise-induced increments in heart rate, stroke volume index, and cardiac index and a greater reduction in systemic vascular resistance from rest to maximal workload.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836159 TI - Peripheral vasoconstriction shortly after onset of moderate exercise in humans. AB - The immediate cardiovascular responses at the onset of supine dynamic leg exercise were studied by noninvasive methods in healthy humans. Total peripheral conductance (TPC), heart rate, and cardiac output increased very rapidly at the onset of exercise. Mean arterial pressure (MAP) showed a moderate anticipatory increase during a 10-s countdown to exercise and then decreased (but not below resting level) during the first 10 s of exercise. The TPC response was biphasic, and TPC started to fall from its peak value approximately 12 s after onset of exercise. This peripheral vasoconstriction increased MAP. After 25 s, the cardiovascular variables were stable for the rest of the 2-min exercise period. In the same subjects, cholinergic blockade was induced by atropine sulfate (0.035 mg/kg) and resting cardiac output, MAP, and TPC increased considerably. The exercise protocol was repeated after atropine, and the increase in heart rate at onset of exercise was slower and smaller. MAP decreased and remained depressed throughout the exercise period. A monophasic increase in TPC was seen. We suggest that, in the normal situation, the biphasic response in TPC reflects a baroreflex sympathetic vasoconstriction very shortly after onset of exercise and that this response is due to a rapid increase in set point for arterial pressure control at the onset of exercise. After cholinergic blockade, MAP was probably continuously well above the set point for arterial pressure control both before and during exercise and no reflex vasoconstriction was observed in this situation. PMID- 7836160 TI - Physiological dead space increases during initial hours of chronic hypoxemia with or without hypocapnia. AB - A whole body plethysmograph was used to determine the minute ventilation-to-CO2 production ratio (VE/VCO2) of intact unrestrained unanesthetized adult male Sprague-Dawley rats during 7 days of hypoxemia (arterial PO2 approximately 50 Torr). In one set of rats, normocapnia (arterial PCO2 approximately 40 Torr) was maintained. Arterial blood gases and acid-base status were determined, and arterial PCO2 was used to calculate alveolar ventilation-to-VCO2 ratio (VA/VCO2) in all situations when inhaled CO2 was not elevated. In normoxia VE/VCO2 = 25 +/- 1 (mean +/- 95% confidence limits); after 12 h of hypoxemia, VE/VCO2 was maximal, 61 +/- 5 in hypoxemic hypocapnia and 200 +/- 55 in hypoxemic normocapnia. Between 2 and 7 days of hypoxemia, VE/VCO2 had plateaued, 42 +/- 3 in hypoxemic hypocapnia and 95 +/- 19 in hypoxemic normocapnia. Dead space-to-tidal volume ratio (VD/VT) = (VE/VCO2 - VA/VCO2)/(VE/VCO2), and in normoxia VD/VT = 0.17 +/- 0.04. In hypoxemic hypocapnia, VD/VT measured between 1 and 5 h was 0.38 +/- 0.04. It remained elevated at 0.29 +/- 0.04 after 24 h, but after 4-7 days in hypoxemic hypocapnia, VD/VT had recovered to 0.15 +/- 0.03. It is postulated that the disproportionate increase in VE/VCO2 observed during the first 24 h of exposure to hypoxemic normocapnia (compared with elevated steady-state plateau levels maintained from 2 to 7 days sojourn) reflects an immediate transient increase of physiological dead space on exposure to hypoxemia. PMID- 7836161 TI - Effect of detraining on GLUT-4 protein in human skeletal muscle. AB - The present study was undertaken to examine the effect of 10 days of detraining levels of GLUT-4 protein expression and citrate synthase (CS) activity in the vastus lateralis of trained men. During the course of normal training, seven endurance-trained (T) men and eight age- and weight-matched active but untrained (UT) men underwent an oral glucose tolerance test (OGTT) after an overnight fast. Muscle samples were obtained from the vastus lateralis by needle biopsy for measurement of GLUT-4 protein and CS activity. The tests were repeated on six of the T subjects after 10 days of detraining (DT men). The area under the insulin response curve during OGTT was lower in T men than in DT and UT men (22.4 +/- 2.8, 32.1 +/- 5.9, and 39.9 +/- 4.7 x 10(-3) pmol.l-1.min-1, respectively; P < 0.05). There were no differences between groups in the glucose responses to OGTT. GLUT-4 protein levels and CS activity were higher in T men than in DT and UT men (GLUT-4: 4.37 +/- 0.40, 2.92 +/- 0.53, and 1.71 +/- 0.22 arbitrary standard units and CS: 47.12 +/- 4.75, 33.63 +/- 3.98, and 24.51 +/- 2.97 mumol.min-1.g-1, respectively; both P < 0.05). Muscle GLUT-4 protein content was correlated with CS activity in all three groups (r = 0.64, 0.68, and 0.96 for UT, T, and DT men, respectively). These results suggest that muscle GLUT-4 protein content and oxidative capacity undergo parallel adaptations after detraining in previously well-trained men. PMID- 7836162 TI - Effect of carbohydrate ingestion on glucose kinetics during exercise. AB - Six well-trained men (peak pulmonary oxygen uptake = 5.03 +/- 0.11 l/min) were studied during 2 h of exercise at 69 +/- 1% peak pulmonary oxygen uptake to examine the effect of carbohydrate (CHO) ingestion on glucose kinetics. Subjects ingested 250 ml of either a 10% glucose solution containing 6-[3H]glucose (CHO) or a sweet placebo every 15 min during exercise. Glucose kinetics were assessed by 6,6-[2H]glucose infusion corrected for gut-derived glucose in CHO. Plasma glucose was higher (P < 0.05) in CHO from 20 min. Total glucose appearance was higher in CHO due to glucose delivery from the gut (68 +/- 7 g), since hepatic glucose production was reduced by 51% (29 +/- 5 vs. 59 +/- 5 g). Glucose uptake was higher in CHO (96 +/- 7 vs. 60 +/- 6 g) with the ingested glucose supplying 67 +/- 4 g and, with the assumption that it was fully oxidized, accounted for 14 +/- 1% of total energy expenditure. In conclusion, CHO ingestion during prolonged exercise results in suppression of hepatic glucose production and increased glucose uptake. These effects appear to be mediated mainly by increased plasma glucose and insulin levels. PMID- 7836163 TI - Prior exercise suppresses the plasma tumor necrosis factor response to bacterial lipopolysaccharide. AB - This study was initiated to determine the effect of physical exercise on the in vivo tumor necrosis factor-alpha (TNF) response to Escherichia coli lipopolysaccharide (LPS). Rats familiarized with treadmill running and surgically implanted with vascular catheters were either not exercised or exercised to near exhaustion (mean run time of 102 +/- 13 min) before intravenous LPS challenge (1 mg/kg; lethality of dose is 10-20% in 24 h). Compared with time-matched nonexercised control rats, exercised rats had increased heart rates, plasma lactate, and plasma corticosterone and decreased plasma glucose at the conclusion of exercise. In response to LPS, both groups became hypotensive, exhibited transient hyperglycemia, and sustained hyperlactacidemia. By 30 min post-LPS, plasma corticosterone levels were similar in the two groups. Nonexercised rats exhibited a normal plasma TNF response to LPS with the peak value (10,400 +/- 2,000 U/ml) occurring 90 min after LPS challenge. In contrast, the TNF response in rats exercised before LPS administration was blunted to 17% of the nonexercised group, with the peak occurring at an earlier time after LPS. Addition of recombinant murine TNF to postexercise plasma was fully expressed. The TNF response remained attenuated when LPS was administered up to 6 h after completion of exercise, but it returned to normal in rats allowed to recover for 24 h. The results demonstrate that exercise, perhaps as a stress modality, markedly suppresses the systemic TNF response that is normally observed in response to LPS challenge. PMID- 7836164 TI - Entrainment of respiration to rocking in premature infants: coherence analysis. AB - Vestibular influences on breathing pattern were investigated in 18 premature infants in the neonatal intensive care nursery. Respiratory abdominal movements were recorded while the babies were manually rocked at varying rates between 30 and 60 cycles/min (cpm). Coherence spectra were estimated between the respiratory and rocker signals, and their magnitudes were evaluated at the rocking frequency, with coherence spectra > 0.85 indicative of strong entrainment to rocking. At least one incident of entrainment was seen in 15 of 18 infants, with 2:1 ratios (2 breaths/rocker cycle) occurring at rocking frequencies of 30-40 cpm (8 of 18 subjects) and 1:1 entrainment at rates of 42-50 cpm (5 of 18 subjects). More complex synchronization was observed in three infants, with patterns consisting of alternans between 2:1 and 3:2 ratios (5:3 entrainment). Infants > 35 wk postconceptional age exhibited greater coherence to rocking than infants < 35 wk (P < 0.01), indicating a maturational change in the reflex may occur. Results show that the natural stimulation of rocking a newborn provides a phasic input to its respiratory pattern generator that is capable of resetting the system's oscillation and entraining its rhythm. PMID- 7836165 TI - A buoyancy-driven squeeze-film model of intrapleural fluid dynamics: basic concepts. AB - We propose a new model of pleural liquid mechanics in the apneic animal based on the observation that the lung, in its position within the serous fluid of the chest, is a buoyant object with few physical connections to the chest. The buoyancy force due to the lung's low density causes the lung to rise within the chest, which in turn causes fluid to be squeezed out from the regions above the lung. The result is the transient component of the downward flow of intrapleural liquid and the less-than-hydrostatic vertical intrapleural pressure gradient observed by other investigators. For the purposes of mathematical simplicity, we have modeled the lung and chest wall of a horizontal animal as a pair of concentric cylinders separated by a narrow gap representing the pleural space. In this first version of the model, we treat the pleurae of the lung and chest wall as impermeable rigid boundaries, but despite these limitations, our mathematical analysis agrees with observations from a number of groups and explains the flow direction from top to bottom as well as the reported changes in vertical pressure gradient in response to a change in body orientation. PMID- 7836166 TI - Measurement of high lung volumes by nitrogen washout method. AB - Studies on human infants suggested that thoracic gas volume (TGV) measured at end exhalation may not depict the true TGV and may differ from TGV measured from a series of higher lung volumes and corrected for the volume added. This was explained by gas trapping. If true, we should expect the discrepancy to be more pronounced when functional residual capacity (FRC) and higher lung volumes are measured by gas dilution techniques. We studied lung volumes above FRC by the nitrogen washout technique in 12 spontaneously breathing rhesus monkeys (5.0-11.3 kg wt; 42 compared measurements). Lung volumes directly measured were compared with preset lung volumes achieved by artificial inflation of the lungs above FRC with known volumes of air (100-260 ml). Measured lung volume strongly correlated with and was not significantly different from present lung volume (P = 0.05; r = 0.996). The difference between measured and preset lung volume was 0-5% in 41 of 42 cases [1 +/- 0.4% (SE)]. The direction of the difference was unpredictable; in 22 of 42 cases the measured volume was larger than the preset volume, but in 17 of 42 cases it was smaller. The difference was not affected by the volume of gas artificially inflated into the lungs. We conclude that, overall, lung volumes above FRC can be reliably measured by the nitrogen washout technique and that FRC measurements by this method reasonably reflect true FRC. PMID- 7836167 TI - Skeletal muscle GLUT-4 and glucose uptake during exercise in humans. AB - The present study examined the relationship between total skeletal muscle GLUT-4 protein level and glucose uptake during exercise. Eight active non-endurance trained men cycled at 72 +/- 1% peak pulmonary oxygen consumption for 40 min, with rates of glucose appearance and disappearance (Rd) determined by utilizing a primed continuous infusion of [3-3H]glucose commencing 2 h before exercise. Muscle glycogen content and utilization, citrate synthase activity, and total GLUT-4 protein were measured on muscle biopsy samples obtained from the vastus lateralis. A direct relationship existed between preexercise muscle glycogen content and glycogen utilization during exercise (r = 0.76, P < 0.05). Citrate synthase activity and glucose Rd at the end of exercise averaged 21.9 +/- 3.0 mumol.min-1.g-1 and 27.3 +/- 2.5 mumol.kg-1.min-1, respectively. There was a direct correlation between citrate synthase activity and GLUT-4 protein (r = 0.78, P < 0.05); however, at the end of exercise, glucose Rd was inversely related to both GLUT-4 (r = -0.89, P < 0.01) and citrate synthase activity (r = 0.72, P < 0.05). Plasma insulin, which decreased during exercise, was not related to glucose Rd. In conclusion, glucose uptake during 40 min of exercise at 72% peak pulmonary oxygen consumption was inversely related to the total muscle GLUT 4 protein level. This suggests that factors other than the total GLUT-4 protein level are important in the regulation of glucose uptake during exercise. PMID- 7836168 TI - Directionally opposite left atrial and ventricular volume changes during lower body suction. AB - In animals, sympathetic responses to orthostasis are regulated in part by cardiopulmonary afferents arising from atrial and ventricular baroreceptors. To determine the relative importance of these baroreceptor regions in the cardiopulmonary baroreflex of normal humans, simultaneous measurements of left atrial and right and left ventricular volumes (cine computed tomography), invasive hemodynamics, forearm vascular resistance (plethysmography), and efferent sympathetic nerve activity to muscle (microneurography) were obtained under control conditions and with nonhypotensive lower body negative pressure ( 10 mmHg, LBNP-10) in nine normal human subjects. LBNP-10 did not alter heart rate or mean systemic arterial pressure, but it did produce significant decreases in pulmonary artery diastolic and right atrial pressures. This reduction in cardiac filling pressures resulted in efferent sympathoexcitation evidenced by increases in forearm vascular resistance and efferent sympathetic nerve activity to the muscle. LBNP-10 did not alter end-diastolic volume of the left or the right ventricle. Similarly, ventricular stroke volume was unchanged during LBNP-10, as assessed by cine computed tomography or thermodilution techniques. In contrast, LBNP-10 resulted in a significant decrease in left atrial volume. Thus, LBNP produced a significant decrease in cardiac filling pressures and left atrial volumes with resultant reflex sympathoexcitation, whereas ventricular volumes were unchanged. These observations suggest an important role for left atrial (nonventricular) baroreceptor afferents in the cardiopulmonary baroreflex of normal humans. PMID- 7836169 TI - Time constants may be meaningless in exponentials fit to pressure relaxation data. PMID- 7836170 TI - Invited editorial on "Effect of enhanced supramaximal flows on cough clearance". PMID- 7836171 TI - Effect of enhanced supramaximal flows on cough clearance. AB - Efficiency of cough for clearing mucus from the lungs is believed to be a function of peak airflow velocities in the airways. Initial transient supramaximal flows are characteristic of cough, and these peak flow rates can be enhanced by placing a triggered shutter at the mouth, serving the role of the epiglottis. Using radiolabeled monodispersed aerosols (99mTc-iron oxide) and gamma camera analysis, we measured over a 2-h period the efficacy of 60 voluntary vs. shutter coughs for clearing mucus from the airways of patients (n = 15) with chronic airway obstruction (mean ratio of forced expired volume in 1 s to forced vital capacity = 0.55). In a subset of patients (n = 9), we also measured the efficacy of forced expirations, or huffs, without glottis closure. Peak flow rate was greater for shutter than voluntary coughs [9.4 +/- 2.0 (SD) vs. 4.1 +/- 1.9 l/s; P < 0.001]. Retention at 60 min (as a fraction of initial deposition) was significantly different for the 3 study days (control, 0.83 +/- 0.17; voluntary cough, 0.69 +/- 0.18; shutter cough, 0.75 +/- 0.19; P = 0.01), but only control vs. voluntary cough values were significantly different from each other (P = 0.01). In contrast, retention at 120 min was significantly different for the 3 days, but both voluntary and shutter coughs were significantly different from control (P = 0.01 and P = 0.02, respectively) (control, 0.73 +/- 0.16; voluntary cough, 0.61 +/- 0.20; shutter cough, 0.65 +/- 0.20). Patients studied with buffs showed a clearance rate faster than control and similar to that associated with voluntary cough.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836172 TI - Prolonged pulmonary vascular hyperreactivity in conscious dogs after cardiopulmonary bypass. AB - Although cardiopulmonary bypass (CPB) is required in all surgical procedures involving open-heart surgery, the extent to which CPB alters pulmonary vascular regulation has not been systematically investigated. Our objectives were to investigate the acute, subacute, and chronic effects of CPB on the left pulmonary vascular pressure-flow (LP-Q) relationship in conscious dogs. Continuous LP-Q plots were generated in chronically instrumented conscious dogs 2-4 days pre-CPB and again 4 h and 1, 2, 7, and 14 days after 2.5 h of closed-chest hypothermic CPB. In addition, pulmonary vascular reactivity was assessed by examining the dose-response relationship to the thromboxane analogue U-46619 pre- and post-CPB. CPB resulted in an acute (4 h post-CPB) shift in the baseline LP-Q relationship, indicating an increase in pulmonary vascular resistance (P < 0.01). The baseline LP-Q relationship returned to pre-CPB values by 1 day post-CPB. Despite this return of the baseline LP-Q relationship to pre-CPB values, the pulmonary vasoconstrictor response to U-46619 was markedly potentiated 2 days post-CPB compared with the pre-CPB response (P < 0.01). This enhanced pulmonary vasoconstrictor response to U-46619 was still apparent 7 days post-CPB (P < 0.01) but was not evident 14 days post-CPB. These results indicate that CPB results in a pronounced, but transient, increase in pulmonary vascular resistance. Moreover, CPB causes a protracted increase in pulmonary vascular reactivity even when the baseline LP-Q relationship has returned to pre-CPB values.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836173 TI - Effects of a chronic aortopulmonary shunt on pulmonary hemodynamics in piglets. AB - Systemic-to-pulmonary shunting in growing pigs has been proposed as an experimental model of high-flow pulmonary hypertension associated with congenital heart defects. We investigated multipoint pulmonary arterial pressure (Ppa) vs. cardiac output (Q) plots and pulmonary vascular impedance spectra in 13 piglets aged approximately 4 mo and ventilated alternatively in hyperoxia (inspired O2 fraction 0.4) and in hypoxia (inspired O2 fraction 0.12). The measurements were done 8 wk after either an anastomosis between the thoracic aorta and the pulmonary trunk (n = 7 piglets) or a sham operation (n = 6). Cardiac output was altered by a manipulation of venous return. In the sham-operated piglets, hypoxia increased Ppa by an average of 12 mmHg over the entire range of Q studied, from 60 to 120 ml/kg, and increased both 0 Hz (Z0) and characteristic (Zc) pulmonary vascular impedance. In the shunted piglets compared with the sham-operated piglets in hyperoxia, Ppa was increased by an average of 5-6 mmHg at all levels of Q studied, from 60 to 120 ml/kg (P < 0.01), and Zc was also increased (P < 0.01), whereas Z0 was unchanged. In the shunted piglets, hypoxia increased Ppa at all levels of Q studied only to an average of 3 mmHg, and neither Z0 nor Zc was altered by hypoxia. We conclude that an aortopulmonary shunt of 2-mo duration in growing pigs increases both pulmonary vascular resistance and impedance and is associated with a blunting of pulmonary vascular reactivity to hypoxia. PMID- 7836174 TI - Additive effect of contractions and insulin on GLUT-4 translocation into the sarcolemma. AB - The maximal effects of insulin and muscle contractions on glucose transport are additive. GLUT-4 is the major glucose transporter isoform expressed in skeletal muscle. Muscle contraction and insulin each induce translocation of GLUT-4 from intracellular sites into the plasma membrane. The purpose of this study was to test the hypothesis that the incremental effect of contractions and insulin on glucose transport is mediated by additivity of the maximal effects of these stimuli on GLUT-4 translocation into the sarcolemma. Anesthetized rats were given insulin by intravenous infusion to raise plasma insulin to 2,635 +/- 638 microU/ml. The gastrocnemius-plantaris-soleus group was stimulated to contract via the sciatic nerve by using a protocol that maximally activates glucose transport. After treatment with insulin, contractions, or insulin plus contractions or no treatment, the gastrocnemius-plantaris-soleus muscle group was dissected out and was subjected to subcellular fractionation to separate the plasma membrane and intracellular membrane fractions. Insulin induced a 70% increase and contractions induced a 113% increase in the GLUT-4 content of the plasma membrane fraction. The effects of insulin and contractions were additive, as evidenced by a 185% increase in the GLUT-4 content of the sarcolemmal fraction. This finding provides evidence that the incremental effect of maximally effective insulin and contractile stimuli on glucose transport is mediated by additivity of their effects on GLUT-4 translocation into the sarcolemma. PMID- 7836175 TI - Decrease in ventricular stroke volume at apnea termination is independent of oxygen desaturation. AB - Patients with obstructive sleep apnea experience nocturnal hemodynamic oscillations in association with repetitive respiratory events. Apnea termination (recovery) is accompanied by the nadir of arterial O2 saturation (SaO2), changes in intrathoracic pressure, and arousal from sleep. To investigate separately the contributions of hypoxemia and of arousal from sleep to changes in cardiac function, we continuously measured left ventricular stroke volume (LVSV) and mean arterial pressure (MAP) in eight subjects with severe obstructive sleep apnea (apnea-hypopnea index > 30 events/h associated with SaO2 < or = 82%) during two experimental conditions: 1) subjects slept without intervention for 1-2 h and then supplemental O2 was administered to maintain SaO2 > or = 90% (mean SaO2 nadir 92.7%) throughout the apnea-recovery cycle and 2) upper airway obstructions were abolished using nasal continuous positive airway pressure and subjects were aroused from sleep by an auditory signal. Recovery was associated with an increase in MAP and a decrease in LVSV both with and without supplemental O2. Arousal from sleep on nasal continuous positive airway pressure reproduced the postapneic elevation of MAP but not a decrease in cardiac function of the magnitude that occurred at apnea termination. We conclude that elevation of blood pressure and reduction of LVSV that occurred at apnea termination may be due to different physiological mechanisms. PMID- 7836176 TI - Force-velocity and power characteristics of rat soleus muscle fibers after hindlimb suspension. AB - The effects of 1, 2, and 3 wk of hindlimb suspension (HS) on force-velocity and power characteristics of single rat soleus fibers were determined. After 1, 2, or 3 wk of HS, small fiber bundles were isolated, placed in skinning solution, and stored at -20 degrees C until studied. Single fibers were isolated and placed between a motor arm and force transducer, functional properties were studied, and fiber protein content was subsequently analyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Additional fibers were isolated from soleus of control and after 1 and 3 wk of HS, and fiber type distribution and myosin light chain stoichiometry were determined from SDS-PAGE analysis. After 1 wk of HS, percent type I fibers declined from 82 to 74%, whereas hybrid fibers increased from 10 to 18%. Percent fast type II fibers increased from 8% in control and 1 wk of HS to 26% by 3 wk of HS. Most fibers showed an increased unloaded maximal shortening velocity (Vo), but myosin heavy chain remained entirely slow type I. The mechanism for increased Vo is unknown. There was a progressive decrease in fiber diameter (14, 30, and 38%) and peak force (38, 56, and 63%) after 1, 2, and 3 wk of HS, respectively. One week of HS resulted in a shift of the force-velocity curve, and between 2 and 3 wk of HS the curve shifted further such that Vo was higher than control at all relative loads < 45% peak isometric force. Peak absolute power output of soleus fibers progressively decreased through 2 wk of HS but showed no further change at 3 wk.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836177 TI - Efficiency function: improvement of classical bioheat approach. AB - In view of the complex vascular architecture and the intricate physical heat transfer processes in the human body, convective heat transfer via the blood is generally described by simple substitutional processes ("non-vascular models"). The classical "bioheat" approach of Pennes (J. Appl. Physiol. 1: 93-122, 1948), defining the heat flow to or from the tissue as being proportional to the product of perfusion rate and the difference of arterial and tissue temperature, has been seriously questioned after having been used for > 40 yr in many applications. In our laboratory, we have at our disposal a complex three-dimensional vascular model for the special case of tissue in a human extremity. This was used to test the performance of simple nonvascular models. It turned out that the Pennes approach may deliver acceptable results if the body is in the thermoneutral zone or if heat stress acts uniformly on the whole body. However, when cold stress or local hyperthermia is present, unreliable results must be expected. As the vascular model is not generally practicable because of its extreme complexity, we offer the efficiency function concept as a simple way of correcting the classical bioheat approach by factor multiplication. Efficiency function is determined as a function of perfusion rate and tissue depth in a way that compensates for the deficiencies of the Pennes bioheat term. The results are reasonable compared with those of the vascular model and experimental results. PMID- 7836178 TI - Effect of elastase on oscillation mechanics of lung parenchymal strips. AB - Using isolated parenchymal strips from degassed rat lungs, we studied the contribution of the collagen-elastin network to lung tissue hysteretic behavior. Strips were suspended in an organ bath filled with Krebs solution (37 degrees C, pH 7.4) continuously bubbled with 95% O2-5% CO2. One end of the strip was attached to a force transducer and the other to a servo-controlled lever arm. Sinusoidal oscillations of 2.5% of resting length were applied at 1 Hz. Measurements were sampled under baseline conditions at different levels of stress (sigma = 10-26 g/cm). Porcine pancreatic elastase (0.05 IU.mg tissue-1.ml Krebs solution-1) was then added to the bath, and tension and length were measured continuously for 15 min at sigma = 15 g/cm. After washout, measurements were repeated at sigma = 10-26 g/cm. Elastance (E) and resistance (R) were calculated using the equation of motion. Hysteresivity (eta), the structural damping coefficient, was obtained using the following equation: eta = (R/E) pi 2f, where f is frequency. At baseline, we found that E and R were significantly dependent on sigma (P < 0.01), whereas eta was unchanged. During enzymatic digestion with elastase, there were significant decreases of tension, E, and R and no change in eta. Significant increases in E and R were found when these parameters were compared at the same sigma before and after treatment. Again, eta did not change. The constancy of eta after elastase suggests that disruption of the elastin collagen network does not alter the coupling between elastic and dissipative processes in lung tissue. PMID- 7836179 TI - Stability of alveolar capillary opening pressures. AB - Little is known about the stability of the process by which pulmonary capillaries open. To investigate this process, pulmonary capillary perfusion patterns in isolated pump-perfused canine lobes were studied using video microscopy. After pump flow was set to perfuse one-half of the capillaries, the pump was turned off and all of the capillaries emptied. Turning the pump back on reopened the capillaries. The on-off cycle was repeated six times. If the same capillaries were perfused during each observation, it would demonstrate that there were stable and significant differences between individual capillary opening pressures, causing consistent recruitment of those capillaries with the lowest opening pressures. Alternatively, variable perfusion patterns would result if capillary opening pressures changed between observations, if the differences in opening pressures between capillary segments were negligible, or if experimental conditions changed between cycles. The perfusion pattern was more reproducible than expected by chance alone, which indicated the existence of stable differences among alveolar capillary opening pressures. PMID- 7836180 TI - Stimulus-response relationships for isotonic shortening and isometric tension generation in rabbit trachealis. AB - Nonspecific bronchial hyperresponsiveness in asthma is characterized by increased maximal airway narrowing (reactivity) and increased sensitivity of the airways. A decreased load on airway smooth muscle (ASM) has been suggested as a mechanism of increased reactivity. We hypothesized that decreased ASM load can also cause a leftward shift in the dose-response curve and explain increased sensitivity. We tested this hypothesis using rabbit tracheal smooth muscle strips in vitro by measuring isotonic shortening and isometric force during electrical field stimulation (1-100 Hz) at the length at which maximal active tension developed (Lmax), 90% Lmax, and 110% Lmax The frequency-response relationships expressed as frequency vs. percent maximal shortening or tension were not different at Lmax or 110% Lmax, but at 90% Lmax the frequency vs. shortening relationship was significantly shifted leftward relative to the frequency vs. tension relationship (P < 0.05). The electrical field stimulation frequencies that produced 50% maximal response for isometric tension and for isotonic shortening, respectively, were 6.7 +/- 1.9 and 3.9 +/- 0.7 Hz at 90% Lmax, 9.2 +/- 2.1 and 7.5 +/- 1.9 Hz at 100% Lmax, and 2.8 +/- 1.0 and 1.2 +/- 0.5 Hz at 110% Lmax. We conclude that, at lengths below Lmax, isotonic shortening is facilitated compared with isometric tension and therefore decreased ASM load in vivo may result in increased sensitivity. PMID- 7836181 TI - Effects of hypercapnia and hypoxia on inspiratory and expiratory diaphragmatic activity in conscious cats. AB - The influence of steady-state changes in chemical stimuli on ventilation and electromyographic activity of the diaphragm during both inspiration (total DI) and expiration (total DE) was studied in unanesthetized intact adult cats before and after carotid denervation. In intact animals, during hypercapnia (2 4, and 6% CO2), tidal volume (VT) and total DI increase, whereas total DE did not consistently change. During ambient hypocapnic hypoxia (14, 12, and 10% O2), VT increased only at 10% O2, whereas total DI increased at all levels studied. Total DE increased substantially at 14% O2, persisting up to the end of expiration with 12 and 10% O2. This effect was markedly attenuated during normocapnic hypoxia. During CO hypoxemia (1,700 ppm in air), VT as well as total DI and total DE decreased because of a large reduction in inspiratory and expiratory time elicited by tachypneic breathing. The effects of hypercapnia and hypoxia persisted after carotid denervation. Therefore, 1) in contrast to hypercapnia, hypoxia markedly enhances the expiratory diaphragmatic activity, 1) this expiratory braking mechanism depends on the severity of hypoxia and is partly due to hypocapnia secondary to hypoxia; and 3) because this effect was observed after carotid denervation and during CO hypoxemia, it may arise in the central nervous system, possibly in bulbopontine structures. PMID- 7836182 TI - Effect of liquid inflation on the viscoelastic behavior of the lungs in developing piglets. AB - Viscoelastic dissipation through stress relaxation decreases during the first weeks after birth in the piglet's lungs (J. Appl. Physiol. 73: 1297-1309, 1992). To characterize the mechanism of this decrease, we compared the stress relaxation undergone by the lungs of six newborn and six 9-wk-old piglets when the airway opening was occluded in the course of air and saline inflations. The amplitude of stress relaxation, determined from the mono-exponential decay ultimately adopted by the transpulmonary pressure during the occlusions, related linearly to the increases in lung elastic recoil preceding the occlusions. The slope of this relationship was greater in the newborn than in the 9-wk-old piglets during air inflations and similar at the two ages during saline inflations. Both the ratio of stress relaxation to elastic recoil and the time constant of the relaxations were similar during air and saline inflations and were independent of inflation rate and lung volume at the start of the inflations. These findings indicate that the postnatal decrease in stress relaxation is caused primarily by developmental changes in the geometry of the gas-liquid interface. They are also consistent with the notion that the viscoelastic stresses generated by the gas liquid interface and lung tissue are well matched for a given elastic recoil. PMID- 7836183 TI - Effect of regional circulation patterns on observed HbCO levels. AB - In an earlier experiment, we briefly exposed 15 young men to high levels of CO while simultaneously monitoring arterial and peripheral venous HbCO levels. The arterial HbCO levels were considerably higher than the venous levels during the CO exposure. Furthermore, great variation in the difference between arterial and venous HbCO levels was observed, with the maximal difference for each subject ranging from 2.3 to 12.1% HbCO. In the present paper, we suggest an explanation for the observed differences between arterial and venous HbCO on the basis of the regional circulation of the forearm, where both samples were taken. Because regional circulation patterns are known to vary with physical training, the differences in physical training between subjects may account for the observed variation. An expanded model was derived from the Coburn-Forster-Kane equation, which reflects the above hypothesis. Most of the parameter values for the expanded model were measured on individual subjects. Literature values were used for other parameters. Two parameters were estimated using five of the subjects and were then used in the predictions of the expanded model for the remaining subjects. PMID- 7836184 TI - Induction of mixed apneas by inhalation of 100% oxygen in preterm infants. AB - Administration of 100% O2 to preterm infants induces an apnea that is usually central. We hypothesized that this apnea may be "mixed" at times with an obstructive component appearing late during the respiratory pause. In addition, we reasoned that obstruction would depend on the duration of the apnea. Thus, we gave 100% O2 to 61 healthy preterm infants. Group 1 was > or = 1,500 g [birth wt 1.8 +/- 0.1 (SE) kg, gestational age 32 +/- 1 wk, postnatal age 19 +/- 2 days, n = 26] and group 2 was < 1,500 g [birth wt 1.2 +/- 0.1 kg, gestational age 29 +/- 1 wk, postnatal age 30 +/- 4 days, n = 35]. Ventilation was measured using a flow through system. Respiratory efforts in the absence of flow were detected using chest and abdominal displacements or diaphragmatic electromyography. In group 1, 19% of the central apneas became obstructive at 17 +/- 3 s, whereas in group 2, 34% did so at 12 +/- 2 s. Mixed apneas were longer than those without obstruction (28 +/- 3 vs. 12 +/- 1 s; P = 0.0001). The incidence of mixed apneas was 0, 14, and 66% in group 1 and 0, 27, and 69% in group 2 in apneas of 3-10, 11-20, and > 20 s, respectively. These findings suggest that 1) a percentage of the central apneas induced by inhaling 100% O2 became obstructive, 2) the incidence of the obstructive component increased with the duration of apnea, and 3) smaller infants became obstructed sooner and had a higher incidence of obstruction than larger infants.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836185 TI - Reproducibility of core temperature threshold for sweating onset in humans. AB - The control of sweating in humans has been described quantitatively in terms of skin and core temperatures (Tsk and Tcore, respectively). However, the precision with which features of the relationship between sweat rate and Tcore at a given Tsk can be reproduced in the short term is not known. We focused on the threshold Tcore. We held Tsk at 38 degrees C until sweating began for two periods separated by a period of cooling with Tsk at 32 degrees C in six men and three women. The esophageal temperature (Tes) at which sweating began was invariably lower in the second period of heating (average difference 0.09 degree C; maximum 0.17 degree C). Also, the rate of rise in Tes was invariably higher (average 148%) during the second period of heating. Thus, although a threshold cannot be reproduced within the error of Tes measurement, the consistency and small magnitude of the downward shift recommend our protocol as a practical method for evaluating other influences on thermoregulation, provided that the effects are big enough to be seen against a background of an expected small decrease. From the fundamental point of view, the consistency of the downward displacement has provocative implications, e.g., the rate of change in Tcore influences sweating or thermosensitive units in slow-responding thermal compartments contribute to the Tcore input signal. PMID- 7836186 TI - Effects of strength training on bone mineral density: hormonal and bone turnover relationships. AB - The effects of a 16-wk strength-training program on bone mineral density (BMD) was assessed by dual-energy X-ray absorptiometry in 21 men [age 61 +/- 1 (SE) yr]. Sixteen men (age 59 +/- 2 yr) served as control subjects. To investigate the possible hormonal relationships underlying the effects on BMD, serum concentrations of growth hormone, insulin-like growth factor I, and testosterone were determined before and after training. In addition, osteocalcin and skeletal alkaline phosphatase (markers of bone formation) and tartrate-resistant acid phosphatase (a marker of bone resorption) were measured before and after training to assess bone turnover. The training program resulted in a 2.8 +/- 0.6% increase in femoral neck BMD (1.004 +/- 0.037 vs. 1.031 +/- 0.037 g/cm2; P < 0.001). However, there were no significant changes in total body, anterioposterior spine, lateral spine, Ward's triangle, or greater trochanter BMD. Moreover, there were no significant changes in growth hormone, insulin-like growth factor I, testosterone, osteocalcin, or skeletal alkaline phosphatase. There were no changes in the control group. Thus, strength training can increase femoral neck BMD, and this effect does not appear to be accompanied by changes in anabolic hormones or markers of bone formation and resorption. PMID- 7836187 TI - Effects of glucocorticoids and endurance training on cytochrome oxidase expression in skeletal muscle. AB - This investigation was undertaken to evaluate whether the mitochondrial disfunction associated with glucocorticoid treatment is expressed at the level of cytochrome-c oxidase (COX) and whether endurance training attenuates this response. Adult female rats were administered cortisol acetate (100 mg/kg body wt) or an equal volume of the vehicle solution for 11 days. Endurance training was performed by treadmill running up to 28 m/min (with intervals at 50 m/min for 2 min every 15 min), for 90 min/day, 6 days/wk, for 8-10 wk. During hormone treatments, the training animals ran every day. Exercise prevented 43-55% of the hormone-induced atrophy in various fast-twitch muscles or muscle groups. Cortisol acetate treatment produced no significant effects on COX enzyme activities or subunit mRNA content in deep red or superficial white quadriceps or mixed plantaris muscles. The levels of COX were increased as a result of training by 70 110% in plantaris and red quadriceps muscles, but no changes were seen in white quadriceps muscles. Both nuclear-encoded (COX IV) and mitochondrial-encoded (COX III) mRNAs were increased approximately twofold by the exercise program in these same muscles. These data indicate that the impaired mitochondrial functioning associated with glucocorticoids is not observed at the COX step of electron transport. The prolonged endurance-training regimen appears to induce relatively parallel increases in COX enzyme activity and mRNA expression with coordinate changes in nuclear and mitochondrial mRNAs. PMID- 7836188 TI - Maximal aerobic capacity and total blood volume in highly trained middle-aged and older female endurance athletes. AB - The primary aim of this study was to test the hypothesis that, relative to age matched sedentary controls, middle-aged and older female endurance athletes exhibit levels of maximal rate of O2 consumption (VO2max) similar to those previously reported in male endurance athletes in the same age group and, furthermore, that these high levels of VO2max are associated with elevated and total blood volume in 13 highly trained female runners and 17 healthy untrained women 50-70 yr of age. The runners had lower (P < 0.001) body mass index and estimated body fat relative to the controls. They also had higher levels of VO2max (2.70 +/- 0.08 vs. 1.74 +/- 0.06 l/min, 48.6 +/- 1.9 vs. 26.5 +/- 0.8 ml.kg-1.min-1, 58.0 +/- 1.8 vs. 38.8 +/- 1.2 ml.kg fat-free mass-1.min-1; all P < 0.001) and total blood volume (4,964 +/- 226 vs. 4,336 +/- 130 ml, P < 0.02; 89 +/- 4 vs. 64 +/- 2 ml/kg, P < 0.001; 106 +/- 4 vs. 96 +/- 3 ml/kg fat-free mass, P < 0.05). The elevated total blood volumes in the runners were due to both higher plasma and erythrocyte volumes. In addition, hematocrit and hemoglobin concentrations were higher in the runners (P < 0.007). VO2max was strongly (P < 0.001) related to total blood volume (r = 0.79), plasma volume (r = 0.76), and erythrocyte volume (r = 0.78) when all were expressed relative to body weight.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836189 TI - NMDA receptors in caudal ventrolateral medulla mediate reflex airway dilation arising from the hindlimb. AB - The caudal ventrolateral medulla (CVLM) has been shown to participate in the reflex airway dilation evoked by stimulation of thin fiber afferents innervating the hindlimb of anesthetized dogs. Nevertheless, the pharmacological mechanism in the CVLM by which hindlimb afferents evoke this reflex airway dilation is not known. Therefore, we examined the role played by excitatory amino acid receptors in the CVLM in the reflex airway dilation arising from the hindlimb. Using chloralose-anesthetized dogs, we found that bilateral microinjections into the CVLM of either (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (25 mM, 50 nl) or (+/-)-2-amino-5-phosphonovaleric acid (50 mM, 50 nl), both of which block N-methyl-D-aspartate (NMDA) receptors, reversibly attenuated the decrease in total lung resistance that was evoked by either electrical stimulation of C fibers in the sciatic nerve or by static contraction of both gastrocnemius muscles. In contrast, bilateral microinjection into the CVLM of 6-cyano-7 nitroquinoxaline-2,3-dione (39 microM, 50 nl), which blocks non-NMDA receptors, augmented the reflex decrease in total lung resistance that was evoked by either sciatic nerve stimulation or contraction of the gastrocnemius muscles. Bilateral microinjections of xanthurenic acid (100 mM, 50 nl) into the CVLM had no effect on the decrease in total lung resistance that was evoked by sciatic nerve stimulation. We conclude that NMDA, but not non-NMDA, receptors in the CVLM play an important role in the reflex arc that dilates the airways when hindlimb afferents are stimulated by either muscular contraction or electrical stimulation. PMID- 7836190 TI - Use of twitch pressures to assess diaphragmatic function and central drive. AB - Transdiaphragmatic pressures generated by phrenic nerve twitches have been proposed as a means to assess diaphragmatic function and central drive, but their validity and reliability have not been determined. We evaluated diaphragmatic twitch and twitch occlusion measurements in a rabbit model of diaphragmatic contractile dysfunction and diaphragmatic fatigue to determine whether 1) diaphragmatic twitch pressures accurately assess changes in low- and high frequency diaphragm trains during the development of, and recovery from, contractile fatigue; 2) twitch occlusion measurements accurately quantify the intensity of central drive to the diaphragm; and 3) twitch measurements are affected by thoracoabdominal binding or twitch potentiation. Single-twitch and 20 Hz double- and triple-twitch pressures accurately reflected changes in low frequency diaphragm train pressures, whereas only 80-Hz triple-twitch pressures accurately reflected changes in high-frequency trains. Twitch occlusion measurements of central drive closely mirrored central drive as reflected by phrenic nerve recordings and only slightly underestimated the absolute intensity of central drive. Thoracoabdominal binding increased twitch and train pressures, and repetitive electrical stimulations further potentiated twitch pressure. However, twitch potentiation and a lack of thoracoabdominal binding had no effect on twitch measurements of diaphragmatic function during the induction and recovery from fatigue or on twitch occlusion measurements of intensity of central drive. Thus, twitch measurements can be used to accurately assess diaphragmatic low- and high-frequency fatigue and to quantify the intensity of central drive to the diaphragm. PMID- 7836191 TI - Analysis of factors affecting gas exchange in intravascular blood gas exchanger. AB - A mathematical model of an intravascular hollow-fiber gas-exchange device, called IVOX, has been developed using a Krogh cylinder-like approach with a repeating unit structure comprised of a single fiber with gas flowing through its lumen surrounded by a coaxial cylinder of blood flowing in the opposite direction. Species mass balances on O2 and CO2 result in a nonlinear coupled set of convective-diffusion parabolic partial differential equations that are solved numerically using an alternating-direction implicit finite-difference method. Computed results indicated the presence of a large resistance to gas transport on the external (blood) side of the hollow-fiber exchanger. Increasing gas flow through the device favored CO2 removal from but not O2 addition to blood. Increasing blood flow over the device favored both CO2 removal as well as O2 addition. The rate of CO2 removal increased linearly with the transmural PCO2 gradient imposed across the device. The effect of fiber crimping on blood phase mass transfer resistance was evaluated indirectly by varying species blood diffusivity. Computed results indicated that CO2 excretion by IVOX can be significantly enhanced with improved bulk mixing of vena caval blood around the IVOX fibers. PMID- 7836192 TI - PMN cell counts and phagocytic activity of highly trained athletes depend on training period. AB - We tested the hypothesis that polymorphonuclear leukocyte (PMN) cell counts and phagocytic activity determined by latex ingestion and superoxide anion production are influenced by different training periods. We investigated long-distance runners before and up to 24 h after a graded exercise test to exhaustion during moderate training (MT) and intense training (IT) and compared them with untrained (control) subjects. Cell counts and phagocytic activity at rest and after exercise did not differ significantly between MT and control. On the contrary, IT showed a significant (P < or = 0.05) decrease in PMN cell count at rest (2.55 +/- 0.3 cells/nl) compared with MT (3.63 +/- 0.2 cells/nl) and control (3.41 +/- 0.8 cells/nl). Furthermore, phagocytic activity was significantly reduced (P < or = 0.05) in IT at rest and after exercise compared with MT and control. A strong inverse correlation (r = -0.75; P < or = 0.01) between epinephrine and superoxide anion production was found. These results provide evidence that the phagocytic activity depends on the training period and indicate impaired PMN functions during IT, which might lead to increased susceptibility to infection. PMID- 7836193 TI - Voluntary exercise decreases progression of muscular dystrophy in diaphragm of mdx mice. AB - Effects of voluntary wheel running on contractile properties of diaphragm (DIA) and soleus (SOL) of dystrophic (mdx) and control (C57BL/10SNJ) mice were evaluated. In particular, we tested the hypothesis that daily voluntary running is not deleterious to muscle function in mdx mice. Both groups of mice ran extensively (control mice approximately 7 km/day, mdx mice approximately 5 km/day). Exercise increased maximal specific tetanus tension of mdx DIA from 1.02 +/- 0.04 to 1.33 +/- 0.06 kg/cm2 but did not restore it to the control level (2.55 +/- 0.17 kg/cm2). Maximal tetanus tension of sedentary mdx SOL (2.41 +/- 0.17 kg/cm2) was reduced compared with control (3.10 +/- 0.15 kg/cm2) and was not altered by running activity. Optimal length was significantly lower in DIA of mdx mice, and exercise did not change this. Fatigability and contractile properties of muscles measured in vitro were not altered by running activity with the exception of increased contraction time in mdx DIA. In conclusion, extensive wheel running is not deleterious to muscle function in mdx mice contrary to predictions of the "work overload" theory of muscular dystrophy. Rather, this exercise is beneficial for active tension generation of mdx DIA, the muscle most closely resembling muscles of patients with Duchenne muscular dystrophy. PMID- 7836194 TI - Muscle energetics and pulmonary oxygen uptake kinetics during moderate exercise. AB - The present study tested whether, during moderate exercise, 1) the dynamic responses of ADP and changes in free energy of ATP hydrolysis (delta GATP) were similar to those of phosphocreatine [PCr; as would be expected for a simple controller of muscle respiration (QO2)] and 2) the rise in pulmonary O2 uptake (VO2) during cycle exercise would reflect the rise in muscle QO2 indicated by the calf PCr kinetics. The responses of PCr, Pi, ADP, and delta GATP were measured from the calf in five subjects during supine treadle exercise using 31P-magnetic resonance spectroscopy and compared with those for VO2, measured breath by breath during upright cycle exercise. The time constants for delta GATP [24.2 +/- 14.2 (SE) s] were not significantly different from those for PCr (26.3 +/- 17.3 s) and Pi (30.7 +/- 22.5 s) (P > 0.05). The time constants for phase 2 VO2 (29.9 +/- 16.8 s) were also similar to those of PCr. In contrast, the dynamics of ADP were distorted from those of PCr due to dynamic changes in pH. These results are consistent with mechanisms of respiratory control that feature substrate control by PCr or thermodynamic control through changes in delta GATP. However, these results are not consistent with substrate control by ADP in a simple fashion. Furthermore, the similarity of time constants for phase 2 VO2 and muscle PCr suggests that phase 2 VO2 kinetics reflect those of muscle QO2 in healthy subjects during moderate exercise. PMID- 7836195 TI - Sodium transport and fluid balance in lungs from normal and dystrophic hamsters. AB - Gravimetric and sodium transport characteristics of lungs from BIO 14.6 (dystrophic) hamsters were compared with those of lungs from golden Syrian (normal) hamsters at 30 and 150 days of age. Isolated perfused lungs were used to determine lung permeability and fluid balance differences between normal and dystrophic animals at both ages. Apparent permeability-surface area products for air space-to-vascular space sodium, sucrose, and fluorescein isothiocyanate labeled dextran fluxes were compared in the four groups of hamsters. Morphometric analysis of fixed lungs of representative hamsters from each group was also performed. Dystrophic hamsters exhibited higher lung wet-to-dry weight ratios than normal hamsters at both ages. Lungs from dystrophic hamsters were less sensitive to inhibition of sodium transport by amiloride than lungs from age matched normal hamsters. Dystrophic hamster lungs had higher absolute permeabilities of the passively transported solutes, lower permeability values for sodium, and only one-half of the amiloride-sensitive sodium transport of lungs from age-matched normal hamsters. Differences in lung fluid balance between dystrophic and normal hamsters may be related to differences in sodium clearance. PMID- 7836196 TI - Effects of lung volume and surface forces on maximal airway smooth muscle shortening. AB - The effects of lung volume and surface forces on airway smooth muscle shortening were studied in isolated perfused rat lungs. The lungs were inflated via the trachea with gas or Krebs solution (n = 12 each) to volumes equivalent to gas inflation pressures of 5 (low), 15 (medium), and 25 (high) cmH2O (n = 4 each). At each volume, two of the four lungs were perfused with methacholine (10(-2) M) and then all were perfused with Formalin for fixation. The amount of smooth muscle shortening present in transverse sections of the airways was determined by comparing the observed outer perimeter of the smooth muscle layer with its calculated relaxed perimeter. In the control lungs, mean shortening was < or = 10% in all groups except the liquid-filled lungs at low lung volumes [33 +/- 12% (SD)]. In the methacholine-stimulated lungs, mean shortening was between 45 and 56% at medium and low lung volumes in gas- and liquid-filled lungs, respectively, and approximated the degree of shortening required to cause airway closure. At high lung volume, less shortening was observed in the methacholine-stimulated lungs, either liquid (34 +/- 17%) or gas filled (16 +/- 19%; P < 0.05 compared with liquid filled). The effects of lung volume in liquid-filled lungs and the differences in response between gas- and liquid-filled lungs demonstrate, respectively, that both lung tissue recoil and surface forces act to oppose shortening of maximally stimulated smooth muscle.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836197 TI - Effect of aminophylline on plasma [K+] and hypoxic ventilatory response during mild exercise in men. AB - To examine the role of endogenous adenosine on the hypoxic ventilatory response (HVR) enhanced during exercise, we measured HVR at rest and during mild exercise (12.5 W) in nine healthy men in a supine position after pretreatment with aminophylline (5 mg/kg), an adenosine receptor blocker, or dipyridamole (0.6 mg/kg), an adenosine uptake blocker, by using a 3-day double-blind placebo controlled design. Although HVR was enhanced during exercise on all occasions, HVR with aminophylline [0.42 +/- 0.07 (SE) l.min-1.%fall-1 of arterial O2 saturation] was significantly lower than that with placebo (0.64 +/- 0.13 l.min 1.%fall-1) or dipyridamole (0.64 +/- 0.08 l.min-1.%fall-1) during exercise (P < 0.05 for both) at similar end-tidal PCO2 on the 3 days but not at rest. We then examined the changes in plasma K+ concentration ([K+]) and catecholamines, the other possible endogenous potentiators of the carotid body activity. The exercise and hypoxia-induced increases in plasma [K+] were significantly lower with aminophylline (0.23 +/- 0.09 meq/l) than with the placebo (0.51 +/- 0.10 meq/l) or dypyridamole (0.58 +/- 0.13 meq/l) (P < 0.05 for both). We therefore conclude that aminophylline attenuates the enhancement of HVR during mild exercise and that this might be due to its attenuating effect on exercise- and hypoxia associated increases in plasma [K+] rather than due to its antagonizing effect on endogenous adenosine. PMID- 7836198 TI - Mechanics of human quadriceps muscle. AB - Mechanics of human quadriceps muscle strips (vastus lateralis; n = 10) were investigated over the whole load continuum. Mechanical experiments were performed at 29 degrees C and in both twitch and tetanus modes. For a given level of isotonic total load (P) and over a large part of the contraction phase, instantaneous velocity (V) was shown to be a unique function of instantaneous length (L), regardless of time and initial length. By considering this time- and initial length-independent mechanical property between instantaneous L and instantaneous V over the whole P continuum, a three-dimensional P-V-L relationship was constructed. Any variations in stimulation conditions modified the time-independent P-V-L diagram. Such modifications in the P-V-L relationship were characteristics of changes in contractile performance. Moreover, characteristics of the P-V relationship were investigated in both twitch and tetanus modes. The curvature of the P-V hyperbola was significantly higher in tetanus at 30 Hz than in twitch mode (P < 0.001). In conclusion, our study indicates that, in human quadriceps muscles, contractility can be defined as the time- and initial length-invariant part of a three-dimensional P-V-L relationship. Moreover, our data are consistent with an increase in economy of force generation in tetanus contractions compared with that in twitches. PMID- 7836200 TI - Bioenergetic approach to transfer function of human skeletal muscle. AB - A mathematical model analogous to Chance's "transfer function" was derived on the basis of the energy consumption principle, which is suitable to describe the energetics of human skeletal muscle during aerobic activity. The implications and the characteristics of this model are that 1) the half time of phosphocreatine (PCr) hydrolysis at the onset of a mechanical constant-load exercise is independent of the imposed charge, 2) the changes of O2 consumption in the muscle at steady state when changing workload are linearly related to PCr concentration, 3) the kinetics of the intracellular oxygen consumption during a rest-to-work transient are influenced by anaerobic glycolysis, 4) it may explain the PCr-time relationship of different muscles types (e.g., skeletal, heart, trained vs. untrained), 5) it allows one to interpret correctly the significance of the oxygen consumption kinetics in the rest-to-work transient at the lung level, and 6) it is conceived for in vivo applications. PMID- 7836199 TI - Spaceflight alters autonomic regulation of arterial pressure in humans. AB - Spaceflight is associated with decreased orthostatic tolerance after landing. Short-duration spaceflight (4-5 days) impairs one neural mechanism: the carotid baroreceptor-cardiac reflex. To understand the effects of longer-duration spaceflight on baroreflex function, we measured R-R interval power spectra, antecubital vein plasma catecholamine levels, carotid baroreceptor-cardiac reflex responses, responses to Valsalva maneuvers, and orthostatic tolerance in 16 astronauts before and after shuttle missions lasting 8-14 days. We found the following changes between preflight and landing day: 1) orthostatic tolerance decreased; 2) R-R interval spectral power in the 0.05 to 0.15-Hz band increased; 3) plasma norepinephrine and epinephrine levels increased; 4) the slope, range, and operational point of the carotid baroreceptor cardiac reflex response decreased; and 5) blood pressure and heart rate responses to Valsalva maneuvers were altered. Autonomic changes persisted for several days after landing. These results provide further evidence of functionally relevant reductions in parasympathetic and increases in sympathetic influences on arterial pressure control after spaceflight. PMID- 7836201 TI - Capacity for red blood cell aggregation is higher in athletic mammalian species than in sedentary species. AB - The purpose of this study was to show that two rheological parameters, red blood cell (RBC) sedimentation rate and apparent blood viscosity at low shear rate, characterizing the degree of RBC aggregation, correlate significantly with the maximal mass-specific rate of oxygen consumption or aerobic capacity (VO2max). Comparisons were made within two groups of similarly sized athletic and sedentary species: group 1, pronghorn antelope, dog, goat, and sheep; and group 2, horse and cow. The pronghorn antelope (Antilocapra americana) is one of the most athletic mammals, and we have obtained data on the rheological properties of blood from this species for the first time. The values of apparent viscosity at hematocrit = 40% and shear rate = 0.277 s-1 measured in a rotational viscometer were 59.5, 42.6, and 9.1 cP for antelope, dog, and sheep blood, respectively, and 55.3 and 11.5 cP for horse and cow blood, respectively. The viscosity values for antelope, dog, and sheep blood can be correlated with aerobic capacity: ln viscosity = 4.48-106.3 VO2(-1)max (r2 = 0.998; P < 0.05). The values of RBC sedimentation rate at hematocrit = 40% were 12.8, 7.0, and 0 mm/h for antelope, dog, and sheep blood, respectively, and 45.3 and 0.1 mm/h for horse and cow blood, respectively. Therefore, the data showed that the athletic species exhibit a consistently higher degree of RBC aggregation than do the corresponding nonathletic species. PMID- 7836202 TI - Erythrocyte and polymorphonuclear cell transit time and concentration in human pulmonary capillaries. AB - Pulmonary capillary transit times were examined in patients who required lung resection by use of 99mTc-labeled macroaggregates (99Tc-MAA) and chromium-labeled erythrocytes (51Cr-RBC) to measure regional blood flow and volume in the resected lung. Cell flow (cells.ml-1.s-1) to each resected lung sample was determined by multiplying the number of polymorphonuclear leukocytes (PMN) per milliliter of circulating blood by the blood flow to that sample. Capillary blood volume was obtained by multiplying the morphometrically determined fraction of pulmonary blood in capillaries by the total 51Cr-RBC volume in each sample. Cell concentrations (cells/ml) in capillary blood were calculated morphometrically, and capillary transit times were obtained by dividing cell concentration by cell flow. The results show that PMN transit times were 60-100 times longer than the RBC transit times, with a 22% overlap between their distributions. We conclude that PMN are concentrated with respect to RBC in pulmonary capillary blood because of differences in their transit times and that these long transit times provide an opportunity for PMN-endothelial interactions. PMID- 7836203 TI - Rheological response of neutrophils to different types of stimulation. AB - The potential for neutrophils to obstruct microvessels was evaluated by measuring transit of individual neutrophils through 8-microns pores in an automated cell transit analyzer (CTA) or into micropipettes (4-8 microns ID). Stimulation in vitro by the chemotactic agent N-formyl-methionyl-leucyl-phenylalanine. (fMLP), cigarette smoke, or purified antineutrophil cytoplasm antibodies greatly increased flow resistance, but the response varied in its dependence on time and pore diameter. Cigarette smoke or fMLP caused rapid loss of cellular deformability, although observations were complicated by changes in cell shape: progressive bipolar shape formation (after treatment with fMLP) could facilitate entry into larger pores (approximately 8 microns), whereas blebs induced by cigarette smoke caused bridging of these pores with cell immobilization. These processes led to an underestimation of the changes in deformability by the CTA. Neutrophils responded slowly to the antineutrophil cytoplasm antibodies (approximately 30 min), with a greater increase in flow resistance evaluated by a micro-pipette (4-6 microns ID) than by the CTA. We conclude that the effect of neutrophil stimulation on flow through capillary-sized vessels is potentially great (with resistance typically increased 10-fold or even complete blockage) but may depend on the vascular and cellular geometry and may be local or disseminated, depending on the rate of the rheological response. PMID- 7836204 TI - Effect of sleep deprivation on responses to airway obstruction in the sleeping dog. AB - The effect of sleep deprivation on sleep architecture and respiratory responses to repetitive airway obstruction during sleep was investigated in four chronically instrumented tracheostomized dogs during 12-h nocturnal experiments. A 24-h period of prior sleep deprivation increased (P < 0.05) the rate at which airway obstruction could be induced from 20 +/- 3 (SE) to 37 +/- 10 times/h compared with non-sleep-deprived dogs. During non-rapid-eye-movement sleep the duration of obstruction, minimum arterial hemoglobin saturation, and peak negative inspiratory effort at arousal were 20.5 +/- 1.0 s, 91.7 +/- 0.5%, and 28.4 +/- 1.8 mmHg, respectively, in non-sleep-deprived dogs. Sleep deprivation increased (P < 0.01) the duration of obstruction to 28.0 +/- 0.9 s, worsened (P < 0.05) the minimal arterial hemoglobin desaturation to 85.4 + 3.1%, and increased (P < 0.025) the peak negative inspiratory effort at arousal to 36.1 +/- 1.6 mmHg. Sleep deprivation also caused increases (P < 0.025) in total sleep time, rapid eye-movement (REM) sleep time, and percentage of time in REM sleep in a 2-h recovery period without airway obstruction at the end of the study. We conclude that airway obstruction in the sleeping dog can reproduce the disturbances in sleep architecture and respiration that occur in obstructive sleep apnea and that prior sleep deprivation will increase apnea severity, degree of somnolence, and REM sleep rebound independent of change in upper airway collapsibility. PMID- 7836205 TI - Relationship between blood pressure and airway obstruction during sleep in the dog. AB - The relationship between airway obstruction during sleep and changes in mean arterial pressure (MAP) was investigated in four chronically instrumented tracheostomized dogs during 12-h nocturnal experiments. The MAP response was determined 1) during experimental airway obstruction whenever sleep occurred, 2) over each 12-h experiment, and 3) during a 2-h recovery period at the end of each experiment. The effects of 24 h of sleep deprivation and changes in plasma levels of renin and atrial natriuretic peptide were assessed. In non-rapid-eye-movement sleep, a period of airway obstruction caused MAP to increase (P < 0.002) from 95 +/- 3 (SE) mmHg to 112 +/- 3 mmHg, and this difference was enhanced (P < 0.04) by sleep deprivation. There was an increase of 12 +/- 2 mmHg in the overall MAP over time (P < 0.001) in non-rapid-eye-movement sleep that was sustained in the 2-h recovery period. Plasma levels of renin and atrial natriuretic peptide were constant and unrelated to changes in MAP. We conclude that in the sleeping dog airway obstruction causes an increase in MAP that can be accentuated by prior sleep deprivation and that repetitive airway obstruction will cause an increase in MAP over time that is sustained for > or = 2 h when normal airway patency is restored. PMID- 7836206 TI - Modification of forearm resistance vessels by exercise training in young men. AB - The aim of this study was to determine whether a 4-wk handgrip training program would elicit changes in endothelium-dependent and endothelium-independent vasodilatation in resistance vessels of the human forearm. Minimum vascular resistance after a 10-min ischemic stimulus, an index of peak vasodilator capacity, was also determined. Forearm blood flow response to the endothelium dependent vasodilator methacholine chloride did not change over the 4-wk intervention period either in the group undertaking training (n = 11) or in control subjects (n = 6). Similarly, the response to sodium nitroprusside was not influenced by the handgrip training program. Peak vasodilator capacity of the trained forearms significantly increased, whereas no change was evident in the untrained limbs. These results suggest that 4 wk of forearm exercise training enhances peak vasodilator capacity of the vasculature without influencing stimulated activity of the nitric oxide dilator system. PMID- 7836207 TI - Effect of pulmonary blood flow on microvascular pressure profile determined by micropuncture in perfused cat lungs. AB - To clarify the role of the pulmonary microvasculature in adjusting to increased pulmonary blood flow, we measured arteriolar and venular pressure by the servo null micropuncture method while changing the pulmonary blood flow in isolated perfused cat lungs. We divided the lung vasculature into three longitudinal segments: 1) arterial (pulmonary artery to 30- to 50-microns arteriole), 2) microvascular (between 30- to 50-microns arteriole and venule), and 3) venous (30 to 50-microns venule to left atrium). The vascular resistance was calculated by dividing the pressure gradient by the flow. The pressure gradient of the microvascular segment did not increase, whereas the pressure gradient of the arterial and venous segments increased simultaneously with flow rate. Total and microvascular resistance decreased with increase of flow rate. Resistances of the arterial and venous segments did not change with increase in flow. We conclude that the microvasculature plays a crucial role in preventing pulmonary hypertension with increases in flow by decreasing microvascular resistance. PMID- 7836208 TI - Lung function, surfactant apoprotein content, and level of PEEP in prematurely delivered rabbits. AB - To study the in vivo activity of the surfactant apoproteins (SP-A, SP-B, SP-C), we administered surfactants with defined apoprotein compositions to prematurely delivered rabbit pups. Rabbits given simple phospholipid mixtures containing dipalmitoylphosphatidylcholine and phosphatidylglycerol supplemented with both SP B and SP-C or either protein alone had significantly greater lung compliance during ventilation and lung expansion during a quasi-static pressure-volume maneuver than did saline-or lipid-treated controls. The response to the surfactants containing SP-B/C was markedly dependent on the level of end expiratory pressure used during ventilation. When the rabbits were ventilated with a positive end-expiratory pressure (PEEP) of 4 cmH2O, lung function in the pups treated with SP-B/C was not significantly different from rabbit surfactant treated controls. Addition of SP-A to the surfactants containing SP-B/C did not significantly further improve lung function if the pups were ventilated with a PEEP of 4 cmH2O. With a lower PEEP of 1 cmH2O, lung function in the pups given surfactants containing SP-B/C was no longer equivalent to the lung function of the rabbit surfactant-treated controls. At the lower PEEP, SP-A significantly improved lung function when it was added to surfactants containing SP-B and SP-C. No beneficial effect of SP-A was seen when the surfactant contained either SP-B or SP-C alone. We conclude that with assisted ventilation that includes a moderate level of PEEP, SP-B and SP-C significantly enhance the effect of a simple phospholipid mixture on the lung function of prematurely delivered rabbits. At lower levels of PEEP the effects of SP-B and SP-C on lung function are markedly reduced but can be restored by the addition of SP-A. Our results are consistent with the existence of cooperative protein-protein interactions in surfactant function in vivo and suggest that the response to a surfactant will be determined by both the ventilation strategy and the surfactant composition. composition. PMID- 7836209 TI - Acute lung injury isolated to an in situ lung preparation causes sustained reflex cardiovascular depression in dogs. AB - We tested the hypothesis that acute lung injury (ALI) isolated to a perfused in situ left lung preparation results in sustained reflex cardiovascular depression. Phorbol myristate acetate (PMA), an agent that activates neutrophils, administered into the isolated lung preparation of chloralose-anesthetized dogs resulted in ALI, as assessed by wet-to-dry weight ratios and histopathology, and significant decreases in heart rate (43%), mean arterial pressure (27%), aortic blood flow (29%) and maximum rate of change in left ventricular pressure (30%). Significant reflex effects occurred by 20 min after PMA administration and were sustained for 40 min (n = 7). Hemodynamic variables recovered when the left lung was denervated 60 min after PMA administration. Indomethacin administered into the isolated circulation before PMA (n = 5) did not significantly influence the ALI or reflex effects. Systemic atropinization (n = 6) prevented only the bradycardia. Left lung denervation before ALI (n = 3) prevented all reflex effects. We conclude that PMA administration into an isolated in situ lung preparation results in ALI and sustained reflex cardiovascular depression that is most likely elicited by pulmonary C-fiber stimulation and mediated by withdrawal of sympathetic efferent nerve activity. PMID- 7836210 TI - Lactate transport studied in sarcolemmal giant vesicles from human muscle biopsies: relation to training status. AB - The present study examined sarcolemmal lactate transport capacity in humans of widely different training status. Muscle biopsies were obtained from m. vastus lateralis in 39 subjects divided into untrained (n = 13), trained (n = 7), and athlete [sprint runners (n = 2), endurance runners (n = 5), triathletes (n = 3), and road (n = 6) and track (n = 3) bicyclists] groups. From the biopsy sample giant vesicles were produced with collagenase treatment to determine the sarcolemmal lactate transport capacity, and histochemical analyses were made. The athletes had a higher capacity to transport lactate than the untrained and trained subjects (P < 0.01). Within the group of athletes, the bicyclists had a higher lactate transport capacity than the runners (P < 0.05), whereas there was no difference among trained subjects, runners, and triathletes. The lactate transport capacity was related to the occurrence of type I muscle fibers (r = 0.48, P < 0.01). The present results suggest that the capacity to transport lactate is higher in athletes than in untrained and less trained subjects. It might indicate that lactate transport capacity in human skeletal muscle can be changed by a high volume of training including frequent high-intensity sessions. In addition, sarcolemmal lactate transport capacity appears to be related to the fiber type distribution of a muscle. PMID- 7836211 TI - Altered thermoregulatory responses after 15 days of head-down tilt. AB - To determine whether extended exposure to a simulation of microgravity alters thermoregulatory reflex control of skin blood flow, six adult males (mean age 40 +/- 2 yr) were exposed to 15 days of 6 degrees head-down tilt (HDT). On an ambulatory control day before HDT exposure and on HDT day 15, the core temperature of each subject was increased by 0.5-1.0 degree C by whole body heating with a water-perfused suit. Mean skin temperature, oral temperature (Tor), mean arterial pressure, and forearm blood flow were measured throughout the protocol. Forearm vascular conductance (FVC) was calculated from the ratio of forearm blood flow to mean arterial pressure. After HDT exposure, the Tor threshold at which reflex thermally induced increases in FVC began was elevated (36.87 +/- 0.06 to 37.00 +/- 0.09 degrees C; P = 0.043), whereas the slope of the Tor-FVC relationship after this threshold was reduced (13.7 +/- 2.3 to 9.5 +/- 1.1 FVC units/degrees C; P = 0.038). Moreover, normothermic FVC and FVC at the highest common Tor between pre- and post-HDT trials were reduced after HDT (normothermic: 4.2 +/- 0.5 to 3.0 +/- 0.4 ml.100 ml-1.min-1.100 mmHg-1, P = 0.04; hyperthermic: 12.4 +/- 1.0 to 7.8 +/- 0.7 ml.100 ml-1.min-1.100 mmHg-1, P < 0.001). These data suggest that HDT exposure reduces thermoregulatory responses to heat stress. The mechanisms resulting in such an impaired thermoregulatory response are unknown but are likely related to the relative dehydration that accompanies this exposure. PMID- 7836212 TI - Anatomy of membranous bronchioles in normal, senile and emphysematous human lungs. AB - Serial reconstructions of the membranous bronchioles (MB) were performed in randomly selected tissue blocks cut parallel to the pleural surface in fixated human lungs. Two to four normal, senile, and emphysematous lungs were examined. Three (2 in senile lungs) orders of MB were observed with a dichotomous branching pattern. Emphysematous lungs are characterized by an overall decrease in airway diameter with localized stenoses. Comparison with mean airway diameter (d) and density [n (no. of MBs per cm2 of lung tissue)] of MBs obtained using standard morphometric techniques (random sections approximately 1 cm from the pleura) showed that the values of d and n are biased because of the inclusion in the measurements of a number of respiratory bronchioles and bronchi. When these misclassifications are corrected for, it appears that d corresponds quite well to the mean diameter of the terminal bronchioles (TB) and n to approximately twice the density of TBs. After correction, n is not significantly reduced in emphysematous lungs (the grossly destroyed areas being excluded) compared with normal lungs. The estimate of the number of TBs obtained from the present data is markedly less than that calculated by Weibel (Morphometry of the Human Lung. Berlin: Springer-Verlag, 1963), which suggests that the number of bronchi was overestimated by Weibel by at least one generation. Finally, values of peripheral airway resistance computed from the present anatomic data correspond quite well to direct measurement performed on the same lungs before fixation (Verbeken et al., J. Appl. Physiol. 72:2343-2353, 1992). PMID- 7836213 TI - Human skeletal muscle adaptation in response to chronic low-frequency electrical stimulation. AB - The purpose of the study was to verify the influence of several weeks of chronic low-frequency electrical stimulation (LFES) on the metabolic profile and functional capacity of human skeletal muscle. Knee extensor muscles (KEM) of eight subjects were electrically stimulated at 8 Hz for 8 h/day and 6 days/wk. Vastus lateralis muscle samples were taken before, after 4 wk, and after 8 wk of LFES, and activities of anaerobic (creatine kinase, phosphofructokinase, glyceraldehyde-3-phosphate dehydrogenase) and aerobic-oxidative (citrate synthase, 3-hydroxyacyl-CoA dehydrogenase, cytochrome-c oxidase) enzyme markers were determined. KEM dynamic performance was also assessed before, after 4 wk, and after 8 wk of LFES. Activity levels of anaerobic enzymes were not altered, whereas the activity levels of citrate synthase (29%),3-hydroxyacyl-CoA dehydrogenase (22%), and cytochrome-c oxidase (25%) were significantly increased after 4 wk of LFES but were not further increased after 4 additional wk of LFES. KEM performance was also improved (P < 0.05) but leveled off after 4 wk of LFES. Although significant changes were observed, the results of the present study suggest that the muscle characteristics investigated in the current study have a limited capacity of adaptation in response to this form of chronic LFES. PMID- 7836214 TI - Muscle lactate metabolism in recovery from intense exhaustive exercise: impact of light exercise. AB - This study examined the effect of low-intensity exercise on lactate metabolism during the first 10 min of recovery from high-intensity exercise. Subjects exercised (61.0 +/- 5.4 W) one leg to exhaustion (approximately 3.5 min), and after 1 h of rest they performed the same exhaustive exercise with the other leg. For one leg the intense exercise was followed by rest [passive (P) leg], and for the other leg the exercise was followed by a 10-min period with low-intensity exercise at a work rate of 10 W [active (A) leg]. The muscle lactate concentration after the intense exercise was the same in the P and A legs, but after 10 min of recovery, the lactate concentration and the arterial blood lactate level were higher for the P leg than for the A leg (both P < 0.05). During the recovery, the mean blood flow was lower for the P leg than for the A leg (P < 0.05), whereas the mean lactate efflux was not significantly different. During the 10 min of recovery, lactate release accounted for approximately 60% of the change in muscle lactate for either leg. The leg excess postexercise O2 consumption during 10 min of recovery was 440 and 750 ml for the P and A legs, respectively. The present data suggest that a lowered blood lactate level during active recovery is due to an elevated muscle lactate metabolism and is not caused by a transient higher release of lactate from the exercising muscles coupled with greater uptake in other tissues.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836215 TI - Effect of arterial blood pressure and ventilation gases on cardiac depression induced by coronary air embolism. AB - In this study the time course of cardiac depression after selective intracoronary injection of air bubbles was investigated in six anesthetized pigs (30 +/- 2 kg) with different mixtures of ventilation gases and different mean arterial blood pressures (MAP). Air bubbles of 150 microns diam were injected into the left anterior descending coronary artery (LADCA) in a volume of 2 microliters/kg body wt. In each animal an injection of air bubbles was applied during ventilation with N2-O2 and a MAP of 77 +/- 3 mmHg (N2-O2/low pressure) or 111 +/- 3 mmHg (N2 O2/high pressure) and during ventilation with pure O2 and a MAP of 77 +/- 3 mmHg (O2/low pressure) or 110 +/- 3 mmHg (O2/high pressure). Systemic hemodynamic variables such as left ventricular pressure, its peak first derivatives, and MAP changed < 10% after injection of air bubbles. During N2-O2/low pressure, systolic segment length shortening in the LADCA region (SS-LADCA) decreased from baseline and did not return to baseline within the 10 min after injection of air bubbles. During N2-O2/high pressure and O2/low pressure, SS-LADCA was decreased between 60 and 120 s, whereas for O2/high pressure this period was from 60 to 90 s. By calculating the time integral of the deviation from baseline of SS-LADCA, it could be demonstrated that the depression of regional myocardial function was less severe during O2/high pressure and O2/low pressure than during N2-O2/low pressure. We conclude that, when coronary air embolism occurs during hypertension and during ventilation with pure O2 instead of a normal N2-O2 mixture, the resulting depression of regional myocardial function is reduced. PMID- 7836216 TI - Prediction of central nervous system oxygen toxicity in rats. AB - Cumulative O2 toxicity (K) can be calculated using the expression K = t2 x PO2c, where t is exposure time and the power c is to be determined; the phenomenon is liable to occur when K reaches Kc, the threshold value of K at which a symptom is manifested. Six rats were each exposed six times to 6 ATA O2 at 2-day intervals until the first electrical discharge (FED) was noted in an electroencephalogram. There was no difference in latency to FED in the series of six exposures. Thirteen rats were exposed to O2 until FED was noted in an electroencephalogram. They were exposed to four constant PO2's of 5, 6, 7, and 8 ATA and to two combined profiles of 1) 5 min at 7 ATA followed by 5 ATA and 2) 15 min at 5 ATA followed by 7 ATA. The solution of the equation for each rat was used to predict its latency to FED on the combined profile. The correlation of predicted to measured latency was significant (P < 0.0001), and the slope was not different from 1. Solving for these parameters using the combination of all the data, we obtained Kc = 5.71 x 10(6) and c = 5.39, which correctly predicted the mean latency but failed to predict individual latency. It is preferable to use each rat as its own control. The significance of the correlation supports the validity of the power equation for calculating K. PMID- 7836217 TI - Ventilatory and hyperkalemic responses to incremental exercise after propranolol treatment. AB - The purpose of the present study was to examine the relationship of plasma potassium (K+) and minute ventilation (VE) during incremental cycling (20 W/2 min) under conditions of beta-adrenergic blockade (80 mg of propranolol) and placebo in six untrained male subjects. No significant differences existed between treatments in O2 uptake, CO2 production, blood lactate, pH, or VE during the submaximal work stages of incremental exercise common to both treatments (20 220 W). During exercise with beta-blockade, plasma K+ concentrations were found to be significantly elevated compared with control levels at every work stage except 20 W. Significant positive correlations between VE and plasma K+ were found during both beta-blockade (r = 0.99) and control conditions (r = 1.00). Although the high correlation between VE and K+ was not altered with beta blockade, propranolol treatment resulted in a significant reduction in the slope of this relationship during incremental exercise (P < 0.01). These findings suggest that 1) beta-blockade decreases the VE-K+ relationship observed during exercise and 2) K+ stimulation of muscle afferents is not an important signal in the control of exercise ventilation. PMID- 7836218 TI - Acidosis stimulates beta-endorphin release during exercise. AB - Elevated blood levels of beta-endorphin have been associated with high-intensity exertion, but the stimulus for beta-endorphin release is unknown. Some studies of exercise have associated beta-endorphin release with increased exertion levels, but other evidence suggests that acidosis may stimulate the release of beta endorphin. This study examines acidosis as a possible stimulus for beta-endorphin release by examining the effects of arterial blood gases, whole blood lactate, and respiratory changes on beta-endorphin levels and by examining the effects of buffering during exercise on these levels. Initially, seven healthy adult males were evaluated during incremental exercise. During incremental exertion, indicators of acidosis correlated with endorphin levels: pH (r = -0.94), PCO2 (r = -0.85), HCO3- (r = -0.88), base excess (r = -0.94), and lactate (r = 0.89). A multivariate model showed that beta-endorphin levels were predicted best by the change in base excess. A time course analysis showed that beta-endorphin responses peaked postexercise and paralleled blood acid levels. Subsequently, subjects were compared after alkali loading and placebo during constant-intensity exercise at 85% of maximal exertion to determine whether acidosis is necessary for endorphin release. Treatment with a buffer, which effectively maintained pH above 7.40, significantly suppressed endorphin release (F = 3.07; P < 0.0001). The results of this study indicate that acidosis rather than any other physiological change associated with high-intensity exertion is the primary stimulus for beta-endorphin release. PMID- 7836219 TI - Effect of water temperature on diuresis-natriuresis: AVP, ANP, and urodilatin during immersion in men. AB - Effects of water temperature on diuresis, natriuresis, and associated endocrine responses during head-out immersion were studied in eight men (23.4 +/- 0.3 yr) during four 5-h experimental conditions: air control at 28 degrees C and immersion at 34.5 degrees C [thermoneutral (Tnt)], 36 degrees C [above Tnt (aTnt)], and 32 degrees C [below Tnt (bTnt)]. Esophageal temperature decreased by approximately 0.4 degrees C in bTnt and increased by approximately 0.5 degrees C in aTnt. Cardiac output increased by approximately 80% in aTnt and approximately 40% in bTnt while thoracic impedance, an index of central blood pooling, decreased by 7.5 omega in bTnt (NS vs. Tnt) and 8.8 omega in aTnt (P < 0.05 vs. Tnt and bTnt). Total peripheral resistance decreased at all temperatures (50% in aTnt, 20% in bTnt). Urine flow and Na+ excretion increased by sixfold in bTnt and Tnt but by only threefold in aTnt. Creatinine clearance was unchanged while osmolal clearance (but not free water clearance) increased two-fold with all immersions. Plasma atrial natriuretic peptide (ANP), urinary urodilatin, and urinary guanosine 3',5'-cyclic monophosphate increased while plasma renin activity, aldosterone, and arginine vasopressin (AVP) decreased similarly at all temperatures. bTnt did not potentiate diuresis by selective attenuation of AVP. The overall natriuretic response exhibited a higher correlation with urodilatin (r = 0.45, P < 0.001) than with ANP (r = 0.26, P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836221 TI - Oxygen uptake kinetics in cardiac transplant recipients. AB - Our purpose was to examine the gas exchange response to exercise in heart transplant (HT) patients and to characterize the O2 uptake kinetics (tau VO2) during successive square-wave on-transients from loadless cycling to moderate exercise. We hypothesized that with a slow heart rate response (and O2 transport limitation) O2 kinetics would be slowed but that with a repeated exercise initiated while the heart rate remained elevated the tau VO2 would be faster. Six male HT patients performed two ramp-function tests to determine peak O2 uptake (1.32 +/- 0.23 l/min) and ventilation threshold (1.02 +/- 0.16 l/min). Patients subsequently completed two repeats of a square-wave forcing function and repeated this on 2 days. Alveolar gas exchange was measured breath by breath. A monoexponential fit of signal-averaged data of the first exercise on-transient (between days) yielded a significantly slower tau VO2 in HT subjects than in healthy men (mean age 47 yr; n = 8) (77 +/- 26 vs. 45 +/- 4 s). With successive exercise (2nd transition) initiated while HR remained elevated the tau VO2 of HT patients was 46 +/- 17 s. The faster O2 kinetics of the second transition suggests that O2 delivery was enhanced and therefore that the tau VO2 may reflect bioenergetic processes controlling the rate of oxidative metabolism. PMID- 7836220 TI - Contractile and cellular remodeling in rabbit skeletal muscle after cyclic eccentric contractions. AB - The time course of muscle contractile and cellular properties was studied in rabbit ankle flexor muscles after injury produced by eccentric exercise. Cyclic eccentric exercise was produced by increasing the tibiotarsal angle of the rabbit while activating the peroneal nerve by use of transcutaneous electrodes. Muscle properties were measured 1, 2, 3, 7, 14, and 28 days after exercise to define the time course of muscle changes after injury. A control group receiving only isometric contraction was used to study the effect of cyclic activation itself. The magnitude of the torque decline after 1 day was the same with use of isometric or eccentric exercise, but eccentric exercise resulted in a further decrease in torque after 2 days, at which time isometrically exercised muscles had fully recovered. The most prominent morphological changes in the injured muscle fibers were the loss of antibody staining for the desmin cytoskeletal protein and deposition of intracellular fibronectin, even when the injured muscle fibers retained their normal complement of contractile and enzymatic proteins. The presence of fibronectin inside the myofibers indicated a loss of cellular integrity. Invasion by inflammatory cells was apparent on the basis of localization of embryonic myosin. Thus eccentric exercise initiates a series of events that results in disruption of the cytoskeletal network and an inflammatory response that could be the mechanism for further deterioration of the contractile response. PMID- 7836222 TI - Increased peak oxygen consumption of trained muscle requires increased electron flux capacity. AB - The importance of the training-induced increase in mitochondrial capacity in realizing the increase in maximal O2 consumption (VO2max) of trained muscle was evaluated using an isolated perfused rat hindlimb preparation at a high blood flow (approximately 80 ml.min-1.100 g-1) during tetanic contractions. Rats trained for 8-12 wk by treadmill running exhibited an approximately 25% increase in muscle VO2max (5.62 +/- 0.31 to 7.06 +/- 0.64 mumol.min-1.g-1), an increase in mitochondrial enzyme activity (approximately 70% for cytochrome oxidase and approximately 55% for NADH cytochrome-c reductase), and an increase in tissue capillarity (14%) that is expected to increase the O2 exchange capacity of the tissue. Muscle VO2max of sedentary (n = 34) and trained (n = 30) animals was determined, and electron transport capacity was acutely managed with myxothiazol, a tight-binding inhibitor of complex III. Inhibition of complex III was similar among 1) the low- and high-oxidative fibers and 2) the superficial and deep mitochondrial populations within muscle. Inhibition of NADH cytochrome-c reductase activity resulted in reductions in muscle VO2max with similar dose responses (mean effective dose of approximately 0.2 microM) of myxothiazol added to the perfusion medium. The extraction of O2 by the contracting muscle decreased as VO2max declined. The increase in muscle VO2max observed in the muscle of trained animals was eliminated when its electron transport capacity was reduced to that observed in normal sedentary rat muscle. Thus, the exercise-induced adaptation of an increased muscle mitochondrial content appears to be essential for trained muscle to exhibit its increased O2 flux capacity. The results of the present experiment illustrate the importance of mitochondrial adaptations in muscle remodeled by exercise training. PMID- 7836223 TI - Lung parenchyma and type II cell morphometrics: effect of surfactant treatment on preterm ventilated lamb lungs. AB - The effect of exogenous surfactant treatment on lung and type II cell structure of ventilated lambs of 137-138 days gestational age was studied. Thirty-four lambs were delivered and randomized to control or 100 mg/kg of natural sheep surfactant treatment groups. Lungs from one group of lambs not treated with surfactant were fixed before ventilation, and the other animals were ventilated to maintain normal blood gas values for 3, 24, or 48 h. Morphometric assessment of the inflation-fixed lung parenchyma of ventilated lungs was compared with the architectural appearance of alveoli and alveolar ducts in the unventilated lungs. Mechanical ventilation resulted in distension of alveolar ducts accompanied by the shallowing and loss of well-defined alveoli and areas of atelectasis at 3 h. These abnormalities increased in severity after 24 and 48 h of ventilation. Surfactant treatment before ventilation significantly reduced the extent and degree of dilatation and concomitant atelectasis. The fraction of normal parenchyma was 38 +/- 7% in untreated lambs vs. 64 +/- 6% in treated lambs after 24 h of ventilation. After 48 h of ventilation, significant differences between control (39 +/- 6%) and surfactant-treated (55 +/- 6%) lambs were still evident. Alveolar type II cells contained approximately 15% lamellar bodies by volume. Neither surfactant treatment nor time of ventilation altered the volume density of lamellar bodies or other organelles, except for a decrease in glycogen from 8% in nonventilated lungs to 2.5% in lungs ventilated for 24 h. These findings indicate that a surfactant treatment at birth results in the maintenance of more normal parenchyma with less atelectasis during prolonged ventilation of the immature lung.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836224 TI - Exogenous surfactant improves lung compliance and oxygenation in adult rats with meconium aspiration. AB - We studied the effects of exogenous surfactant on lung function and morphology in an adult rat model of severe meconium aspiration syndrome. Animals ventilated with 100% oxygen received 4-6 ml of human meconium (25 mg/ml) intratracheally. After 30 min, lung-thorax compliance had decreased by > 30% and arterial PO2 was < 10 kPa. Animals were then treated with no material (MECO group), 0.9% NaCl (MECO-saline group), natural porcine surfactant (NPS group) at a dose of 100 mg/kg, or modified porcine surfactant at a dose of either 100 (MPS100 group) or 200 mg/kg (MPS200 group) and were ventilated for another 180 min. Immediate and sustained improvement of arterial PO2 and compliance was observed in the MPS200 group, whereas the MPS100 and NPS groups showed less pronounced effects. There was a significant improvement of quasi-static lung volumes at maximum insufflation pressure and during deflation in the MPS200, MPS100, and NPS groups. Recordings with Wilhelmy balance showed that minimum surface tension of bronchoalveolar lavage fluid from animals receiving either type or dose of surfactant was significantly lower than in the MECO and MECO-saline groups. Meconium aspiration induced diffuse and prominent atelectasis, intra-alveolar edema, and hyaline membranes. These morphological abnormalities were reversed by exogenous surfactant, especially by the high-dose regimen. PMID- 7836225 TI - Respiratory muscle compensation for unilateral or bilateral hemidiaphragm paralysis in awake canines. AB - In humans and some animals, the surviving respiratory muscles are able to compensate fully for unilateral, and partially for bilateral, hemidiaphragm paralysis. To examine differential activity of individual respiratory muscles after unilateral or bilateral diaphragm paralysis, length and electromyogram (EMG) of left costal and crural diaphragm segments, parasternal intercostal, and transversus abdominis were measured directly in five awake canines after implantation with sonomicrometry transducers and bipolar EMG electrodes under three conditions: during normal breathing (NOFRZ), after infusion of local anesthetic (bupivacaine) through a cervical phrenic nerve cuff to induce reversible contralateral hemidiaphragm (CNFRZ), and after bilateral diaphragm (BIFRZ) paralysis. From NOFRZ to CNFRZ, costal, crural, parasternal, and transversus abdominis increased shortening and EMG activity to compensate for contralateral diaphragm paralysis, but the increase in activity was not equivalent for each muscle. With BIFRZ, parasternal and transversus abdominis showed further increases in activity, coordinated between both inspiration and expiration. Normalized intrabreath profiles revealed dynamic differences in development of muscle activity within each breath as paralysis worsened. Review of simultaneous muscle activities showed coordinated interactions among the compensating muscles: passive shortening of transversus, and lengthening of costal and crural, coincided with increased active inspiratory shortening of parasternal. We conclude that an integrated strategy of respiratory muscle compensation for unilateral or bilateral diaphragm paralysis occurs among chest wall, abdominal, and diaphragm segmental muscles, with relative contributions of individual muscles adjusted according to the degree of diaphragm dysfunction. PMID- 7836226 TI - Costal and crural diaphragm function during panting in awake canines. AB - During natural panting for thermal regulation, the pattern of activation of the major respiratory muscles, including costal and crural diaphragm segments, is not known. We measured diaphragm segmental length, shortening, and electromyographic (EMG) activity in five chronically implanted canines awake and breathing spontaneously at rest and during a mild dry heat stress. During panting, minute ventilation increased fourfold from 5.07 l/min and respiratory rate increased from 16.9 to 192.8 breaths/min or 3.2 Hz. During panting, end-expiratory length of both costal and crural segments decreased, concurrent with significant increases in end-expiratory EMG. With the onset of panting, tidal costal shortening decreased significantly from 6.29% of end-expiratory length to 3.54%, whereas crural shortening decreased from 6.04 to 2.46%. Meanwhile, segmental EMG tended to increase during panting. During panting, intrabreath costal and crural segmental function revealed differential activation; the costal segment shortened in concert with inspiratory flow, whereas peak crural shortening occurred in expiration, almost 180 degrees out of phase with costal. The divergence in segmental shortening during panting was accompanied by a lesser shift in timing of segmental EMG. In the awake spontaneously panting canine, asynchronous costal and crural shortening may enhance gas mixing in a manner analogous to high frequency ventilation. PMID- 7836227 TI - Fatigue of rapid and slow onset in isolated perfused rat and mouse diaphragms. AB - Muscle fatigue was studied in the isolated perfused rat (66% oxidative fibers) and mouse (99% oxidative fibers) diaphragms. Both muscles displayed two fatigue patterns when exposed to 333-ms trains of 20-Hz stimulation. A rapid fatigue pattern appeared within each contractile train as an immediate progressive twitch by-twitch diminution in contractility [a decrease in maximal isometric twitch tension (T) and maximal rate of T development]. An intertrain slow fatigue pattern also appeared as a progressive train-by-train diminution in contractility and an increased maximal rate of relaxation normalized to T. A reduction in the stimulatory frequency from 20 to 2 Hz caused a considerable diminution in the rapid fatigue pattern. These data suggest that rapid fatigue results from the time course of mechanical restitution, the time necessary for the Ca2+ channels of the sarcoplasmic reticulum to recover from inactivation. The slow fatigue pattern, on the other hand, is thought to be due to changes in the intracellular milieu. The difference in sensitivity of the rat and mouse diaphragms to rapid and slow fatigue is apparently related to differences in their fiber type composition. Thus, as would be expected, the mouse diaphragm, composed of only oxidative fibers, is less susceptible to slow fatigue compared with the rat diaphragm. On the other hand, it is more susceptible to rapid fatigue. PMID- 7836228 TI - Atrial septal defect blunts the impairment of left ventricular function during the Mueller maneuver. AB - To investigate whether atrial septal defect (ASD) modifies the left ventricular (LV) hemodynamic response to a fall of intrathoracic pressure (Mueller maneuver), we studied 15 patients with an uncomplicated ASD and 16 healthy control subjects. LV function was measured by M-mode and Doppler echocardiography at rest and during the maneuver. Indicator-dilution technique was used to quantify the pulmonary-to-systemic flow ratio. During comparable changes (means +/- SE) of intrathoracic pressure (-33 +/- 2 mmHg in persons with ASD vs. -34 +/- 2 mmHg in those without), LV systolic function and filling diminished in both groups but patients with ASD showed smaller reductions in LV stroke dimension (-0.9 +/- 0.5 vs. -2.5 +/- 0.4 mm; P = 0.016), peak diameter shortening rate (-4 +/- 2 vs. -12 +/- 2 mm/s; P = 0.007), transmitral velocity-time integral (-1.0 +/- 0.3 vs. -2.2 +/- 0.4 cm; P = 0.022), and cardiac output (-6 +/- 3 vs. -18 +/- 3%; P = 0.029). The pulmonary-to-systemic flow ratio increased from 2.1 +/- 0.1 to 2.6 +/- 0.2 in the ASD group (P = 0.014). In conclusion, LV function diminishes significantly in healthy persons during the Mueller maneuver. In patients with ASD, the changes are directionally similar but quantitatively smaller. An interatrial communication mitigates the impairment of LV function after an acute and sustained drop of intrathoracic pressure. PMID- 7836229 TI - Lung volumes during sustained microgravity on Spacelab SLS-1. AB - Gravity is known to influence the mechanical behavior of the lung and chest wall. However, the effect of sustained microgravity (mu G) on lung volumes has not been reported. Pulmonary function tests were performed by four subjects before, during, and after 9 days of mu G exposure. Ground measurements were made in standing and supine postures. Tests were performed using a bag-in-box-and flowmeter system and a respiratory mass spectrometer. Measurements included functional residual capacity (FRC), expiratory reserve volume (ERV), residual volume (RV), inspiratory and expiratory vital capacities (IVC and EVC), and tidal volume (VT). Total lung capacity (TLC) was derived from the measured EVC and RV values. With preflight standing values as a comparison, FRC was significantly reduced by 15% (approximately 500 ml) in mu G and 32% in the supine posture. ERV was reduced by 10-20% in mu G and decreased by 64% in the supine posture. RV was significantly reduced by 18% (310 ml) in mu G but did not significantly change in the supine posture compared with standing. IVC and EVC were slightly reduced during the first 24 h of mu G but returned to 1-G standing values within 72 h of mu G exposure. IVC and EVC in the supine posture were significantly reduced by 12% compared with standing. During mu G, VT decreased by 15% (approximately 90 ml), but supine VT was unchanged compared with preflight standing values. TLC decreased by approximately 8% during mu G and in the supine posture compared with preflight standing. The reductions in FRC, ERV, and RV during mu G are probably due to the cranial shift of the diaphragm, an increase in intrathoracic blood volume, and more uniform alveolar expansion. PMID- 7836230 TI - Ratios and regressions in body size and function: a commentary. PMID- 7836231 TI - Effect of sampling site on femoral venous blood gas values. AB - To examine whether the tip of the femoral vein catheter used for sampling femoral venous PO2 during cycling exercise is contaminated by skin or saphenous vein blood, we studied 6 healthy volunteers [21.7 +/- 0.7 (SD) yr] during three identical incremental exercise tests while breathing room air on the same day. Femoral venous blood was sampled simultaneously from two catheters inserted into the femoral vein but advanced in opposite directions (7 cm distally and 5 cm proximally). Blood sampling for measurements of PO2, PCO2, pH, hemoglobin concentration, and oxyhemoglobin saturation was done simultaneously from both catheters in duplicate at rest, at 60% of maximum workload (60% W), and at maximum symptom-limited exercise (100% W). Temperature was measured with a thermistor probe placed in the proximal catheter. At rest, distal PO2 was significantly lower than that measured proximally (24.9 +/- 4.3 vs 30.8 +/- 6.1 mmHg, respectively; P < 0.004), but no differences were found during exercise (60% W, 23.6 +/- 3.4 vs. 24.5 +/- 3.6 mmHg; 100% W, 26.0 +/- 3.6 vs. 25.5 +/- 2.8 mmHg, respectively). Comparison of blood temperatures between proximal and distal sites of sampling in two subjects showed negligible differences. Intrasubject coefficient of variation of distal femoral venous PO2 over the three bouts of exercise was 11.5% (2.9 mmHg) at rest, 5.9% (1.4 mmHg) at 60% W, and 5.6% (1.5 mmHg) at 100% W. Mean differences in distal PO2 between duplicate samples were 0.5 +/- 1.4 mmHg at rest, 0.1 +/- 0.8 mmHg at 60% W, and 0.6 +/- 0.9 mmHg at 100% W.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836232 TI - Evaluation of dynamic response of catheter-manometer systems for pulmonary arterial pressure. AB - To quantitatively evaluate the waveform distortions observed through a catheter manometer system, the tolerance range of amplitude errors and that of phase errors are defined as both within +/- 5%, and the frequency bandwidth was calculated where the frequency characteristics of amplitude and those of phase difference satisfy the two tolerance ranges by use of a second-order kinetic equation. The results were expressed by three variables, composed of the natural frequency (fn), damping coefficient (zeta), and highest frequency (fh) corresponding to the frequency bandwidth; a chart was constructed with fn on the x-axis, zeta on the y-axis, and fh as parameter. Also on the chart, the propagation delay times (td's) determined by fn, zeta, and fh were plotted. We measured the frequency characteristics of two 7-Fr Swan-Ganz catheters with lengths of 75 and 110 cm. fn's and zeta's were found to be 13.9 and 10.1 Hz and 0.23 and 0.32, respectively. Referring to this chart, the maximal fh these catheters would be able to reproduce within the tolerance ranges and the propagation td's can be predicted to be 3.2 and 2.4 Hz and 7 and 12 ms, respectively. Suppression of resonance by use of Accudynamic improved the maximal fh's to 3.9 and 2.9 Hz, respectively, but resulted in the increased td's to 14 and 19 ms due to increased zeta. PMID- 7836233 TI - Structural composition of lung parenchymal strip and mechanical behavior during sinusoidal oscillation. AB - The lung parenchymal strip is comprised of many different anatomic elements, including small vessels, small airways, and alveolar walls. We questioned whether the relative amounts of these different structures are important in determining the mechanical behavior of this preparation during dynamic oscillations. We studied 16 parenchymal strips (10 x 2 x 2 mm) from 12 Sprague-Dawley rats. The strips were suspended in an organ bath filled with Krebs solution, bubbled with 95% O2-5% CO2, and maintained at 37 degrees C. One end of the strip was attached to a force transducer, and the other end was attached to a lever system that effected length (L) changes. We oscillated the strips at various resting tensions (T) (0.9 and 1.5 g), frequencies (0.1, 0.3, 0.6, and 1.0 Hz), and amplitudes (1.1, 2.4, and 5.3% of optimal L). We obtained T vs. L curves and calculated the resistance, elastance, and hysteresivity (ratio of energy dissipated to energy stored) of the tissue. At the end of the experiment, the strips were fixed in Formalin at T = 1 g. Histological sections were examined, and the amounts of airway, blood vessel, and alveolar wall were quantified using point counting techniques. We found that whereas resistance varied significantly with frequency and T, elastance and hysteresivity varied with only T. The fractional areas of alveolar, blood vessel, and bronchial wall were 86.3 +/- 0.5 (SE), 8.4 +/- 0.3, and 5.3 +/- 0.4%. Only hysteresivity and the fractional area of alveolar wall were significantly correlated at the lower resting tension (r = -0.76, P = 0.02).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836234 TI - Ergometric studies of untrained skeletal muscle demonstrate feasibility of muscle powered cardiac assistance. AB - The feasibility of biomechanical circulatory assistance hinges on the capacity of skeletal muscle to generate significant hemodynamic work. This study quantifies linear contractile energetics via a customized hydraulic ergometer. Six normal canine latissimus dorsi (LD) muscles (200 +/- 25 g) were evaluated. The muscles were not mobilized; thereby their collateral circulation was preserved. The humeral insertion of the LD muscle was transected and connected to the ergometer. Preload was adjusted to return the LD muscle to its in situ length, and one pulse train was delivered every second. The resulting contractions generated peak pressures of 134 +/- 17 mmHg with mean pressures during shortening of 102 +/- 12 mmHg. Flow rates averaged 5.45 +/- 0.26 l/min. Mechanical work output was calculated at 1.14 +/- 0.18 J/contraction, yielding an average power production of 4.57 +/- 0.72 W during shortening. Continuous LD output power, measured at 5.76 +/- 0.90 mW/g, compares favorably with the 3.48 mW/g typically generated by a 350-g human heart. We therefore conclude that skeletal muscle of sufficient mass can sustain work rates suitable for cardiac assistance despite the 50% power losses typically experienced after muscle training. PMID- 7836235 TI - A simple handheld push-button device for in situ calibration of pneumotachographs. AB - A simple and compact flow calibrator has been devised for generating precise predetermined constant flow rates for checking the calibration of laboratory and clinical flow transducers used in respiratory measurements. The standard version delivers preset flows of 0.5 and 1 l/s, whereas a tuned-up version can produce preset flows of 2.5 and 5 l/s, with an accuracy of +/- 2%. The pressure generated is sufficient to cope with most commonly used respiratory flowmeters. The flow calibrator is built from inexpensive components that are readily obtainable: a fan, a turbine flowmeter, and a feedback circuit in a compact housing. The device is easy to connect to other equipment and to operate. Three flow calibrators have been built and are in regular use in a lung function laboratory and on intensive care wards. PMID- 7836236 TI - Vagal input enhances responsiveness of respiratory discharge to central changes in pH/CO2 in bullfrogs. AB - This study investigated the interaction between vagal afferent input and central chemosensitivity in modulating the respiratory motor output of in vitro brain stem-spinal cord preparations from adult bullfrogs. With this preparation, the spatiotemporal distribution of respiratory-related motor output emulated that of intact bullfrogs; that is, the fictive breathing pattern was mostly episodic. Recordings from cranial motor nerves (V and X) showed that, without peripheral feedback, increasing the PCO2 of the mock cerebrospinal fluid (thereby reducing pH from 8.3 to 7.7) caused a modest increase in respiration-related burst frequency. When the pulmonary branch of a vagus nerve was stimulated phasically (2 V, 20 Hz, 0.2 ms) during each fictive breath to simulate afferent pulmonary stretch receptor feedback 1) the responsiveness of the preparation to the same changes in pH was augmented nearly threefold and 2) the breathing pattern remained episodic. It appears, therefore, that episodic breathing is an intrinsic property of the central nervous system in bullfrogs. It is concluded that there is a strong interaction between vagal feedback and central chemodetection in controlling the temporal relationships that characterize this episodic breathing pattern. PMID- 7836237 TI - Nasobronchial allergy--is serum IgE level useful? PMID- 7836238 TI - Serum IgE levels and its clinical correlation with varying patterns of bronchial asthma and nasal allergy. AB - In a study of 847 cases of bronchial asthma and nasal allergy frequent association with raised serum IgE was noticed. Degree of atopy (as judged by skin allergy tests), age, sex and duration of disease tended to influence IgE levels in asthmatics. Both extrinsic and intrinsic varieties of asthma showed similar raised serum IgE levels. In subjects with nasal allergy alone, the values were considerably lower but still much higher than found in control patients. PMID- 7836239 TI - Long-term effects of thrombolytic therapy on clinical course and left ventricular function after acute myocardial infarction. AB - Sixty five cases of Acute Myocardial Infarction, of which 40 cases received thrombolytic therapy, were followed up for a period of one year for clinical course and left ventricular function. Reperfusion was achieved in 65% cases who received thrombolytic therapy. At discharge and at one year treated group fared well on Killip Scale, and ejection fraction (EF), and the overally mortality was lower. This difference was more significant in the group who achieved reperfusion. Male sex, Anterior wall infarctions, deep Q wave infarctions as also low EF at the time of discharge and late cardiac events had adverse effect on the course of infarction during follow up. PMID- 7836240 TI - Evaluation of ELISA test for serological diagnosis of tuberculosis. AB - In order to find out the usefulness of this test in the local population, 240 subjects were investigated at Indira Gandhi Medical College, Nagpur. Of these 85 were normal healthy subjects and 40 were sputum AFB positive tuberculosis cases, enabling us to determine the cut-off value. The remaining 115 were suspected cases of pulmonary or extrapulmonary tuberculosis. In proved as well as suspected cases of tuberculosis, the mean optical density was much higher than among normal controls, which was statistically significant. Thus A-60 ELISA test is a useful diagnostic aid in suspected pulmonary and extrapulmonary tuberculosis. PMID- 7836241 TI - Acquired immunodeficiency syndrome and health care professionals. AB - As health care professionals, we face a grave risk of acquiring HIV infection in the course of our work. But how many of us really know the precautions to be applied in the hospital set up in dealing with HIV infected patients? A knowledge, attitude and practice (KAP) study was conducted in Pune hospitals to assess the current status. Among the results 65% servants had not heard of AIDS, 85% nursing staff did not apply the Universal Safety Precautions (USP) approach, 13.5% resident thought that the HIV was not transmitted by blood, 30% consultants would avoid contact with an HIV positive patient. This study has shown that definite lacunae exist in knowledge specific to the particular population in question. A proposal for an education programme which is target specific and one of constant renewal is sought. PMID- 7836242 TI - Coronary heart disease and coronary risk factor prevalence in rural Rajasthan. AB - To determine the prevalence of coronary risk factors and coronary heart disease (CHD) in rural Rajasthan, 1150 randomly selected individuals in a cluster of villages in central Rajasthan have been studied. These included 805 men and 345 women. The prevalence of various coronary risk factors in the whole group were: Smoking 488 (42.4%); Diabetes (history): 5(0.4%); Alcohol intake: 146 (12.7%); Sedentary lifestyle: 797 (69.3%); Stressful life events: 48 (4.2%); Hypertension (BP > or = 140/90) 152 (13.2%); obesity (BMI > or = 27 Kg/M2): 194 (10.9%); and Truncal obesity (waist:hip > or = 0.93): 20.8%. The overall prevalence of CHD was 46.1/1000. Patients with CHD had a higher prevalence of male sex (67.9 vs 51.5%); educated persons (30.2 vs 28.8%); businessmen (13.2 vs 10.2%); smoking (47.2 vs 40.5%); sedentary lifestyle (75.5 vs 62.3%); stressful life events (7.5 vs 4.8%); and hypertension (26.4 vs 14.8%). On the other hand, persons without CHD had higher prevalence of alcohol intake (10.8 vs 7.5%); regular prayers (23.1 vs 22.6%); physically active lifestyle (37.7 vs 24.5%); obesity (13.6 vs 6.9%), and truncal obesity (21.0 vs 20.0%). The following risk factors emerged significant on statistical analysis (Odds ratio, 95% confidence intervals): male sex (1.99, 1.04 to 3.7); hypertension (2.04, 1.01 to 4.09); male smokers (1.80, 1.28 to 4.09); and sedentary lifestyle (1.86, 1.01 to 3.59). This study shows a low prevalence of CHD in rural population which is however more than previously reported studies from India. PMID- 7836243 TI - Guillain-Barre syndrome following specific viral infections--an appraisal. AB - Fifteen cases of Gullian-Barre syndrome (GBS) following specific infection are reported. The infections include varicella, 7 infective hepatitis, 4 measles, 2 and mumps, 2. There are no specific clinical or electrophysiological features which serve to distinguish GBS seen in association of these infections from those seen in other clinical settings. There is epidemiological evidence to suggest the association between GBS and hepatitis A, and non A non B hepatitis is more of a chance occurrence. Detailed epidemiological studies are needed to established a clear relationship between other specific viral infections and GBS. PMID- 7836244 TI - Role of selegiline as initial monotherapy in early Parkinson's disease. AB - Twenty patients of Idiopathic Prakinson's disease in the early phase were enrolled to study the efficacy and safety of selegiline as monotherapy. The mean duration of time before levodopa had to be initiated was 9.75 months. The UPDRS scores for activities of daily living, motor examination, tremor and total score showed significant improvement initially with subsequent worsening. Selegiline was well tolerated and there were no serious side-effects. In conclusion, selegiline may have a short lasting symptomatic effect in IPD and is well tolerated. PMID- 7836245 TI - Control of hyperglycaemia and hyperlipidaemia by plant product. AB - A herbal powder consisting of Guargum, Methi, Tundika and Meshasringi was administered to thirty control and thirty NIDDM patients twice daily before principal meals for four weeks. Oral GTT showed improvement in both control and patient groups. Serum total and LDL cholesterol also fell significantly in both the groups after the trial period. Test meal of the herbal powder with D-Xylose excretion was otherwise normal. Follow up for upto two years did not reveal any long term side effect of the powder. This powder, therefore, can be effectively used to reduce postprandial blood glucose and LDL cholesterol in NIDDM patients as a long term measure. PMID- 7836247 TI - Medical journals in India: present state and future course. PMID- 7836246 TI - Thyrotoxicosis--treatment by I131 therapy and early prediction of hypothyroidism following this therapy. AB - This study was undertaken in 68 thyrotoxic patients to assess the predictive value of various post treatment biochemical and immunological tests for early hypothyroidism after I131 therapy and to determine whether pretreatment with carbimazole protects against post I131 therapy hypothyroidism. Early changes observed in serum T3, T4, TSH, thyroid microsomal and thyroglobulin antibody levels were found to be of no predictive value. A sharp increase in TRAb levels around 3 months following I131 therapy indicated that hypothyroidism was likely to occur as this rise reflected a greater degree of thyroid damage. Lower levels of thyroglobulin in patients who became hypothyroid by 12 months after treatment would support this view. Carbimazole pretreatment for eight weeks did not appear to protect against hypothyroidism, in our study. PMID- 7836248 TI - Recertification in internal medicine and subspecialties--an Indian perspective. PMID- 7836249 TI - Sion thrombolysis trial--randomised trial of intravenous thrombolysis & primary percutaneous transluminal coronary angioplasty for acute myocardial infarction [AMI]--feasibility phase data of angioplasty limb. AB - Reperfusion in acute myocardial Infarction [AMI] can be realised by thrombolytic therapy or percutaneous transluminal coronary angioplasty [PTCA] has theoretical advantage but hardly any randomised trials have been published till recently to compare the two modalities. We started the STAT trial with this objective. Patients of AMI were randomised to thrombolytic therapy or PTCA. In the present article we present the phase I data of the PTCA limb. The procedural success rate was 100% with no procedural mortality. In-hospital mortality was 10% [Anterior Infarction 0%, Inferior infarction 20%]. Recurrence of angina occurred in 10% patients. Direct PTCA to left anterior descending artery appeared to be more rewarding than PTCA to right coronary artery. PMID- 7836250 TI - Role of routine magnesium therapy in acute myocardial infarction. PMID- 7836251 TI - Ventricular ectopics--when to treat? PMID- 7836252 TI - Non-responsiveness to drug therapy in bronchial asthma. PMID- 7836254 TI - Suicidal digoxin ingestion. PMID- 7836253 TI - Dermatofibrosarcoma protuberans. PMID- 7836255 TI - Renal replacement therapy in Fabry's disease--a report of three cases and a review of the literature. PMID- 7836256 TI - Autonomic nervous system--not forgotten. PMID- 7836257 TI - Pseudocushing's syndrome. PMID- 7836259 TI - Familial primary vesico-ureteric reflux. PMID- 7836258 TI - Dapsone syndrome. PMID- 7836260 TI - Rupture of interacranial aneurysm during angiography. PMID- 7836261 TI - Delayed hemorrhagic stroke following accidental aluminium phosphide ingestion. PMID- 7836262 TI - Intrahepatic cholestasis of pregnancy following hyperemesis gravidorum in successive pregnancies. PMID- 7836263 TI - Mazetal, diplopia and epilepsy. PMID- 7836264 TI - Safety of thrombolysis during menstruation. PMID- 7836265 TI - Proximal myopathy associated with griseofulvin therapy. PMID- 7836266 TI - Hypertension--acute and chronic. PMID- 7836267 TI - Serum alfa-one antitrypsin (AAT) in tubercular lymphadenitis. PMID- 7836268 TI - Falciparum hepatitis: where is the inflammation? PMID- 7836269 TI - Herpes simplex encephalitis. PMID- 7836270 TI - PCP in a patient of AIDS in India. PMID- 7836271 TI - Neurocysticercosis. PMID- 7836272 TI - Advances in treatment of neurocysticercosis. PMID- 7836273 TI - What is this interaction? PMID- 7836274 TI - Colchicine in diabetes mellitus. PMID- 7836275 TI - Viral encephalitis: addendum. PMID- 7836276 TI - Long term effects of thrombolytic therapy in acute myocardial infarction. PMID- 7836277 TI - Inorganic polyphosphate: toward making a forgotten polymer unforgettable. AB - Pursuit of the enzymes that make and degrade poly P has provided analytic reagents which confirm the ubiquity of poly P in microbes and animals and provide reliable means for measuring very low concentrations. Many distinctive functions appear likely for poly P, depending on its abundance, chain length, biologic source, and subcellular location. These include being an energy supply and ATP substitute, a reservoir for Pi, a chelator of metals, a buffer against alkali, a channel for DNA entry, a cell capsule and, of major interest, a regulator of responses to stresses and adjustments for survival in the stationary phase of culture growth and development. Whether microbe or human, we depend on adaptations in the stationary phase, which is really a dynamic phase of life. Much attention has been focused on the early and reproductive phases of organisms, which are rather brief intervals of rapid growth, but more concern needs to be given to the extensive period of maturity. Survival of microbial species depends on being able to manage in the stationary phase. In view of the universality and complexity of basic biochemical mechanisms, it would be surprising if some of the variety of poly P functions observed in microorganisms did not apply to aspects of human growth and development, such as aging and the aberrations of disease. Of theoretical interest regarding poly P is its antiquity in prebiotic evolution, which along with its high energy and phosphate content make it a plausible precursor to RNA, DNA, and proteins. Practical interest in poly P includes many industrial applications, among which is its use in the microbial depollution of P1 in marine environments. PMID- 7836278 TI - The old exonuclease of bacteriophage P2. AB - The Old protein of bacteriophage P2 is responsible for interference with the growth of phage lambda and for killing of recBC mutant Escherichia coli. We have purified Old fused to the maltose-binding protein to 95% purity and characterized its enzymatic properties. The Old protein fused to maltose-binding protein has exonuclease activity on double-stranded DNA as well as nuclease activity on single-stranded DNA and RNA. The direction of digestion of double-stranded DNA is from 5' to 3', and digestion initiates at either the 5'-phosphoryl or 5'-hydroxyl terminus. The nuclease is active on nicked circular DNA, degrades DNA in a processive manner, and releases 5'-phosphoryl mononucleotides. PMID- 7836279 TI - Escherichia coli peptide methionine sulfoxide reductase gene: regulation of expression and role in protecting against oxidative damage. AB - The Escherichia coli peptide methionine sulfoxide reductase gene (msrA) encodes a single-subunit polypeptide of 212 amino acid residues (M. A. Rahman, H. Nelson, H. Weissbach, and N. Brot, J. Biol. Chem. 267:15549-15551, 1992). RNA blot analysis showed that the gene is transcribed into an mRNA of about 850 nucleotides. The promoter region was characterized, and the transcription initiation site was identified by primer extension. The synthesis of the MsrA protein increased about threefold in a growth-phase-dependent fashion. In an attempt to define the in vivo role of msrA, a chromosomal disruption was constructed. This mutant was more sensitive to oxidative stress, suggesting that oxidation of methionine in proteins plays an important role in oxidative damage. PMID- 7836280 TI - Specific binding of Synechococcus sp. strain PCC 7942 proteins to the enhancer element of psbAII required for high-light-induced expression. AB - The psbAII gene of the cyanobacterium Synechococcus sp. strain PCC 7942 is a member of a three-gene family that encodes the D1 protein of the photosystem II reaction center. Transcription of psbAII is rapidly induced when the light intensity reaching the culture increases from 125 microE.m-2.s-1 (low light) to 750 microE.m-2.s-1 (high light). The DNA segment upstream of psbAII that corresponds to the untranslated leader of its major transcript has enhancer activity and confers high-light induction. We show that one or more soluble proteins from PCC 7942 specifically bind to this region of psbAII (designated the enhancer element). In vivo footprinting showed protein binding to the enhancer element in high-light-exposed cell samples but not in those maintained at low light, even though in vitro mobility shifts were detectable with extracts from low- or high-light-grown cells. When 12 bp were deleted from the psbAII enhancer element, protein binding was impaired and high-light induction of both transcriptional and translational psbAII-lacZ reporters was significantly reduced. This finding indicates that protein binding to this region is required for high-light induction of psbAII. The mutant element also showed impaired enhancer activity when combined with a heterologous promoter. PMID- 7836281 TI - The cmk gene encoding cytidine monophosphate kinase is located in the rpsA operon and is required for normal replication rate in Escherichia coli. AB - A gene encoding a polypeptide of 25 kDa is located immediately upstream of the gene for ribosomal protein S1, rpsA. In high gene copy number, this gene, mssA, was previously found to suppress defects in smbA, which is now known to be identical to pyrH, encoding UMP kinase. We show here that the 25-kDa polypeptide comprises CMP kinase and propose that the gene be designated cmk. In a strain deleted for cmk, the pools of CMP and dCMP were elevated approximately 30-fold. We constructed a plasmid from which synthesis of CMP kinase was regulated by the lac promoter-operator and measured the synthesis rates for RNA and DNA after induction in the delta cmk/lacPO-cmk+ strain. A specific increase in the rate of DNA synthesis was observed. Further analyses showed that the replication elongation rate was halved in the delta cmk strain, most likely caused by the reductions of the dCTP and dTTP pools to 30 and 70%, respectively, of the levels in the parental strain, but that this was compensated for by a doubling in the frequency of initiation. The delta cmk strain is viable at 37 degrees C but cold sensitive. The cold sensitivity may be related to defects in the synthesis of phospholipids or lipopolysaccharides. In addition to the physiological studies, the region upstream of cmk was sequenced, and 120 codons with strong homology to an uncharacterized protein of the speB operon were identified. PMID- 7836282 TI - A mutation in the rpoA gene encoding the alpha subunit of RNA polymerase that affects metE-metR transcription in Escherichia coli. AB - The DNA-binding protein MetR belongs to the LysR family of transcriptional activators and is required for expression of the metE and metH promoters in Escherichia coli. However, it is not known if this activation is mediated by a direct interaction of MetR with RNA polymerase. In a search for RNA polymerase mutants defective in MetR-mediated activation of the metE gene, we isolated a mutation in the alpha subunit of RNA polymerase that decreases metE expression independently of the MetR protein. The mutation does not affect expression from the metH promoter, suggesting that the alpha subunit of RNA polymerase interacts differently at these two promoters. The mutation was mapped to codon 261 of the rpoA gene, resulting in a change from a glutamic acid residue to a lysine residue. Growth of the mutant is severely impaired in minimal medium even when supplemented with methionine and related amino acids, indicating a pleiotropic effect on gene expression. This rpoA mutation may identify either a site of contact with an as yet unidentified activator protein for metE expression or a site of involvement by the alpha subunit in sequence-specific recognition of the metE promoter. PMID- 7836283 TI - Identification of new genes regulated by the marRAB operon in Escherichia coli. AB - Random TnphoA and TnlacZ translational fusions were introduced into an Escherichia coli strain with a deletion of the multiple antibiotic resistance (mar) locus, complemented in trans by a temperature-sensitive plasmid bearing the mar locus with a constitutively expressed mar operon. Five gene fusions (two with lacZ and three with phoA) regulated by the mar operon were identified by increased or decreased marker enzyme activity following loss of the complementary plasmid at the restrictive temperature. Expression of LacZ from both lacZ fusions increased in the presence of the mar operon; expression from the three phoA fusions was represented by the mar operon. The lacZ fusions were mapped at 31.5 and 14 min on the Escherichia coli chromosome. One of the phoA fusions was located at 51.6 min while the two others mapped at 77 min. Cloning and sequencing of a portion of the fused genes showed all of them to be different. The phoA fusions at 77 min were located in a recently identified gene, slp, a lipoprotein of unknown function (D.M. Alexander and A. C. St. John, Mol. Microb. 11:1059 1071, 1994). The others showed no homology with any known genes of E. coli. The insertions caused small but reproducible changes in the antibiotic susceptibility profile. This approach has enabled the identification of new genes in E. coli which are regulated by the marRAB operon and involved in the Mar phenotype. PMID- 7836284 TI - Analysis of clustered genes encoding both early and late steps in daunomycin biosynthesis by Streptomyces sp. strain C5. AB - We recently described the isolation and sequence analysis of the daunomycin polyketide synthase biosynthesis genes of Streptomyces sp. strain C5 (J. Ye, M. L. Dickens, R. Plater, Y. Li, J. Lawrence, and W. R. Strohl, J. Bacteriol. 176:6270-6280, 1994). Contiguous to the daunomycin polyketide synthase biosynthesis gene region in Streptomyces sp. strain C5 are four additional genes involved in daunomycin biosynthesis, two of the products of which show similarity to different types of methyltransferases. The dauC gene, encoding aklanonic acid methyltransferase (AAMT), complements dauC-blocked mutants of Streptomyces sp. strain C5, restores in vitro AAMT activities to the mutant strains, and confers in vitro AAMT activity on Streptomyces lividans. Partial purification through gel filtration, followed by photoaffinity labeling of enriched AAMT with S-adenosyl-L [3H-methyl]methionine, indicates that AAMT is a homodimer with an M(r) of ca. 48,000 (subunit M(r) of ca. 24,000), which corresponds with the size of the deduced gene product. The dauD gene, encoding aklanonic acid methyl ester cyclase, is divergently arranged with respect to dauC. Immediately downstream and apparently translationally coupled with dauD is the dauK gene, encoding carminomycin 4-O-methyltransferase. The dauK gene confers in vitro carminomycin 4 O-methyltransferase activity on S. lividans and is nearly identical to a similar gene isolated from Streptomyces peucetius and characterized. Directly downstream of dauK lies a gene encoding a deduced protein that is similar to the methyl esterases. PMID- 7836286 TI - Purification and characterization of the IM-2-binding protein from Streptomyces sp. strain FRI-5. AB - IM-2 [(2R,3R,1'R)-2-(1'-hydroxybutyl)-3-(hydroxymethyl)butanolide] of Streptomyces sp. strain FRI-5 is one of the butyrolactone autoregulators of Streptomyces species and triggers production of blue pigment as well as the nucleoside antibiotics showdomycin and minimycin. A tritium-labeled IM-2 analogue, 2,3-trans-2(1'-beta-hydroxy-[4',5'-3H]pentyl)-3-(hydroxymethyl)butano lide ([3H]IM-2-C5; 40 Ci/mmol), was synthesized for a competitive binding assay, and an IM-2-specific binding protein was found to be present in the crude cell extract of Streptomyces sp. strain FRI-5. During cultivation for 24 h, the specific IM-2-binding activity increased rapidly, reached a plateau at 10 to 14 h, and declined sharply thereafter, showing only 6% activity after 24 h of cultivation. A Scatchard plot of the binding data demonstrated that the dissociation constant (Kd) for [3H]IM-2-C5 was 1.3 nM, while the Kd for a 3H labeled virginiae butanolide (VB) analogue, 2-(1'-alpha-hydroxy-[6',7'-3H]heptyl) 3-(hydroxymethyl)butanolide ([3H]VB-C7), another butyrolactone autoregulator possessing the opposite configuration at C-1' was 35 nM. Furthermore, at a 15 fold molar excess, the effectiveness of several autoregulators as nonlabeled competitive ligands against [3H]IM-2-C5 was IM-2 type > VB-C type >> A-factor type, indicating that the binding protein in Streptomyces sp. strain FRI-5 is highly specific toward IM-2. Ultracentrifugation showed that the IM-2-binding protein is present almost exclusively in the 100,000 x g supernatant fraction, indicating that the binding protein is a cytoplasmic soluble protein. The binding protein was purified by ammonium sulfate precipitation, DEAE-Sephacel chromatography, Sephacryl S-100 HR gel filtration, DEAE-5PW high-performance liquid chromatography (HPLC), and phenyl-5PW HPLC. The apparent Mr of the native IM-2-binding protein as determined by molecular sieve HPLC was about 60,000 in the presence of 0.5, 0.3, or 0.1 M KCl, while by sodium dodecyl sulfate polyacrylamide gel electrophoresis it was about 27,000, suggesting that the native binding protein is present in the form of a dimer. PMID- 7836285 TI - Archaeal grpE: transcription in two different morphologic stages of Methanosarcina mazei and comparison with dnaK and dnaJ. AB - Transcription of the heat shock gene grpE was studied in two different morphologic stages of the archaeon Methanosarcina mazei S-6 that differ in resistance to physical and chemical traumas: single cells and packets. While single cells are directly exposed to environmental changes, such as temperature elevations, cells in packets are surrounded by intercellular and peripheral material that keeps them together in a globular structure which can reach several millimeters in diameter. grpE transcript levels determined by Northern (RNA) blotting peaked after a 15-min heat shock in single cells. In contrast, the highest transcript levels in packets were observed after the longest heat shock tested, 60 min. The same response profiles were demonstrated by primer extension experiments and S1 nuclease analysis. A comparison of the grpE response to heat shock with those of dnaK and dnaJ showed that the grpE transcript level was the most increased, closely followed by that of the dnaK transcript, with that of the dnaJ gene being the least augmented. Transcription of grpE started at the same site under normal and heat shock temperatures, and the transcript was consistently approximately 700 bases long. Codon usage patterns revealed that the three archaeal genes use most codons and have the same codon preference for 61% of the amino acids. PMID- 7836287 TI - Two enhancer elements for DNA replication of pSC101, par and a palindromic binding sequence of the Rep protein. AB - The minimal replication origin (ori) of the plasmid pSC101 has been previously defined as an approximately 220-bp region by using plasmids defective in the par region, which is a cis-acting determinant of plasmid stability. This ori region contains the DnaA binding sequence, three repeated sequences (iterons), and an inverted repeat (IR) element (IR-1), one of the binding sites of an initiator protein, Rep (or RepA). In the present study, we show that plasmids containing par can replicate at a nearly normal copy number in the absence of IR-1 but still require a region (the downstream region) between the third iteron and IR-1. Because par is dispensable in plasmids retaining IR-1, par and IR-1 can compensate each other for efficient replication. The region from the DnaA box to the downstream region can support DNA replication at a reduced frequency, and it is designated "core-ori." Addition of either IR-1 or par to core-ori increases the copy number of the plasmid up to a nearly normal level. However, the IR-1 element must be located downstream of the third iteron (or upstream of the rep gene) to enhance replication of the plasmid, while the par region, to which DNA gyrase can bind, functions optimally regardless of its location. Furthermore, the enhancer activity of IR-1 is dependent on the helical phase of the DNA double helix, suggesting that the Rep protein bound to IR-1 stimulates the activation of ori via its interaction with another factor or factors capable of binding to individual loci within ori. PMID- 7836288 TI - Homologous pairing of single-stranded DNA and superhelical double-stranded DNA catalyzed by RecO protein from Escherichia coli. AB - The recO gene product is required for DNA repair and some types of homologous recombination in wild-type Escherichia coli cells. RecO protein has been previously purified and shown to bind to single- and double-stranded DNA and to promote the renaturation of complementary single-stranded DNA molecules. In this study, purified RecO protein was shown to catalyze the assimilation of single stranded DNA into homologous superhelical double-stranded DNA, an activity also associated with RecA protein. The RecO protein-promoted strand assimilation reaction requires Mg2+ and is ATP independent. Because of the biochemical similarities between RecO and RecA proteins, the ability of RecO protein to substitute for RecA protein in DNA repair in vivo was also assessed in this study. The results show that overexpression of RecO protein partially suppressed the UV repair deficiency of a recA null mutant and support the hypothesis that RecO and RecA proteins are functionally similar with respect to strand assimilation and the ability to enhance UV survival. These results suggest that RecO and RecA proteins may have common functional properties. PMID- 7836289 TI - Nitrogen regulation of nasA and the nasB operon, which encode genes required for nitrate assimilation in Bacillus subtilis. AB - The divergently transcribed nasA gene and nasB operon are required for nitrate and nitrite assimilation in Bacillus subtilis. The beta-galactosidase activity of transcriptional lacZ fusions from the nasA and nasB promoters was high when cells were grown in minimal glucose medium containing poor nitrogen sources such as nitrate, proline, or glutamate. The expression was very low when ammonium or glutamine was used as the sole nitrogen source. The repression of the genes during growth on good sources of nitrogen required wild-type glutamine synthetase (GlnA), but not GlnR, the repressor of the glnRA operon. Primer extension analysis showed that the -10 region of each promoter resembles those of sigma A recognized promoters. Between the divergently oriented nasA and nasB promoters is a region of dyad symmetry. Mutational analysis led to the conclusion that this sequence is required in cis for the activation of both nasA and nasB. The derepression of these genes in a glnA mutant also required this sequence. These results suggest that an unidentified transcriptional activator and glutamine synthetase function in the regulation of nasA and the nasB operon. PMID- 7836290 TI - Characterization of novel yeast RAD6 (UBC2) ubiquitin-conjugating enzyme mutants constructed by charge-to-alanine scanning mutagenesis. AB - Ubiquitination of intracellular proteins by the yeast RAD6 (UBC2) ubiquitin conjugating (E2) enzyme is required for cellular processes as diverse as DNA repair, selective proteolysis, and normal growth. For most RAD6-dependent functions, the relevant in vivo targets, as well as the mechanisms and cofactors that govern RAD6 substrate selectivity, are unknown. We have explored the utility of "charge-to-alanine" scanning mutagenesis to generate novel RAD6 mutants that are enzymatically competent with respect to unfacilitated (E3-independent) ubiquitination but that are nevertheless severely handicapped with respect to several in vivo functions. Five of the nine mutants we generated show defects in their in vivo functions, but almost all of the most severely affected mutants displayed unfacilitated ubiquitin-conjugating activity in vitro. We suggest that E2 mutants obtained by this approach are likely to be defective with respect to interaction with other, trans-acting factors required for their intracellular activity or substrate selectivity and therefore will be useful for further genetic and biochemical studies of ubiquitin-conjugating enzyme function. PMID- 7836291 TI - Characterization of genetic elements required for site-specific integration of Lactobacillus delbrueckii subsp. bulgaricus bacteriophage mv4 and construction of an integration-proficient vector for Lactobacillus plantarum. AB - Temperate phage mv4 integrates its DNA into the chromosome of Lactobacillus delbrueckii subsp. bulgaricus strains via site-specific recombination. Nucleotide sequencing of a 2.2-kb attP-containing phage fragment revealed the presence of four open reading frames. The larger open reading frame, close to the attP site, encoded a 427-amino-acid polypeptide with similarity in its C-terminal domain to site-specific recombinases of the integrase family. Comparison of the sequences of attP, bacterial attachment site attB, and host-phage junctions attL and attR identified a 17-bp common core sequence, where strand exchange occurs during recombination. Analysis of the attB sequence indicated that the core region overlaps the 3' end of a tRNA(Ser) gene. Phage mv4 DNA integration into the tRNA(Ser) gene preserved an intact tRNA(Ser) gene at the attL site. An integration vector based on the mv4 attP site and int gene was constructed. This vector transforms a heterologous host, L. plantarum, through site-specific integration into the tRNA(Ser) gene of the genome and will be useful for development of an efficient integration system for a number of additional bacterial species in which an identical tRNA gene is present. PMID- 7836292 TI - Biochemical and molecular characterization of the Pseudomonas lemoignei polyhydroxyalkanoate depolymerase system. AB - Pseudomonas lemoignei has five different polyhydroxyalkanoate (PHA) depolymerase genes (phaZ1 to phaZ5), which encode the extracellularly localized poly(3 hydroxybutyrate) (PHB) depolymerases C, B, and D, poly(3-hydroxyvalerate) (PHV) depolymerase, and PHB depolymerase A, respectively. Four of the five genes (phaZ1 to phaZ4) have been cloned, and one of them (phaZ1) was studied in detail earlier (D. Jendrossek, B. Muller, and H. G. Schlegel, Eur. J. Biochem. 218:701-710, 1993). The fifth PHA depolymerase gene (phaZ5) was identified by colony hybridization of recombinant Escherichia coli clones with a phaZ5-specific oligonucleotide. The nucleotide sequence of a 3,704-bp EcoRI fragment was determined and found to contain two large open reading frames (ORFs) which coded for a polypeptide with significant similarities to glycerol-3-phosphate dehydrogenases of various sources (313 amino acids; M(r), 32,193) and for the precursor of PHB depolymerase A (PhaZ5; 433 amino acids; M(r), 44,906). The PHV depolymerase gene (phaZ4) was subcloned, and the nucleotide sequence of a 3,109 bp BamHI fragment was determined. Two large ORFs (ORF3 and ORF4) that represent putative coding regions were identified. The deduced amino acid sequence of ORF3 (134 amino acids; M(r), 14,686) revealed significant similarities to the branched chain amino acid aminotransferase (IlfE) of enterobacteria. ORF4 (1,712 bp) was identified as the precursor of a PHV depolymerase (567 amino acids; M(r), 59,947). Analysis of primary structures of the five PHA depolymerases of P. lemoignei and of the PHB depolymerases of Alcaligenes faecalis and Pseudomonas pickettii revealed homologies of 25 to 83% to each other and a domain structure: at their N termini, they have typical signal peptides of exoenzymes. The adjacent catalytic domains are characterized by several conserved amino acids that constitute putative catalytic triads which consist of the consensus sequence of serine-dependent hydrolases including the pentapeptide G-X-S-X-G, a conserved histidine and aspartate, and a conserved region resembling the oxyanion hole of lipases. C terminal of the catalytic domain an approximately 40-amino-acid-long threonine-rich region (22 to 27 threonine residues) is present in PhaZ1, PhaZ2, PhaZ3, and PhaZ5. Instead of the threonine-rich region PhaZ4 and the PHB depolymerases of A. faecalis and P. pickettii contain an approximately 90-amino acid-long sequence resembling the fibronectin type III module of eucaryotic extracellular matrix proteins. The function of the fibronectin type III module in PHA depolymerases remains obscure. Two types of C-terminal sequences apparently represent substrate-binding sites; the PHB type is present in the PHB depolymerases of A. faecalis and P. pickettii and in PhaZ2, PhaZ3, and PhaZ5 and the PHV type is present in the PHV-hydrolyzing depolymerases (PhaZ4 and PhaZ1). phaZ1 was transferred to A. eutrophus H16 and JMP222. All transconjugants of both strains were able to grow with extracellular PHB as a carbon source and produced translucent halos on PHB-containing solid media. PhaZ1, PhaZ2, PhaZ4, and PhaZ5 were purified from P. lemoignei and from recombinant E. coli; the processing sites of the precursors in E. coli were the same as in P. lemoignei, and similar substrate specificities were determined for the wild-type and the recombinant proteins. All PHA depolymerases hydrolyzed PHB at high specific activities. PhaZ1 and PhaZ4 additionally cleaved PHV, and PhaZ4 hydrolyzed poly(4-hydroxybutyrate). None of the depolymerases was able to hydrolyze polyactide or PHA consisting of monomers with more than five carbon atoms. While the wild-type depolymerase proteins were glycosylated and found to contain glucose and N-acetylglucosamine, none of the recombinant proteins was glycosylated. PHB hydrolysis was dependent on divalent cations such as Ca2+ and was inhibited by the presence of EDTA. PMID- 7836293 TI - Membrane-associated cytochrome cy of Rhodobacter capsulatus is an electron carrier from the cytochrome bc1 complex to the cytochrome c oxidase during respiration. AB - We have recently established that the facultative phototrophic bacterium Rhodobacter capsulatus has two different pathways for reduction of the photooxidized reaction center during photosynthesis (F.E. Jenney and F. Daldal, EMBO J. 12:1283-1292, 1993; F.E. Jenney, R.C. Prince, and F. Daldal, Biochemistry 33:2496-2502, 1994). One pathway is via the well-characterized, water-soluble cytochrome c2 (cyt c2), and the other is via a novel membrane-associated c-type cytochrome named cyt cy. In this work, we probed the role of cyt cy in respiratory electron transport by isolating a set of R. capsulatus mutants lacking either cyt c2 or cyt cy, in the presence or in the absence of a functional quinol oxidase-dependent alternate respiratory pathway. The growth and inhibitor sensitivity patterns of these mutants, their respiratory rates in the presence of specific inhibitors, and the oxidation-reduction kinetics of c-type cytochromes monitored under appropriate conditions demonstrated that cyt cy, like cyt c2, connects the bc1 complex and the cyt c oxidase during respiratory electron transport. Whether cyt c2 and cyt cy are the only electron carriers between these two energy-transducing membrane complexes of R. capsulatus is unknown. PMID- 7836294 TI - Characterization of the Bacillus anthracis S-layer: cloning and sequencing of the structural gene. AB - Bacillus anthracis, a gram-positive, spore-forming bacterium, is the etiological agent of anthrax. The gene coding for the S-layer protein (sap) was cloned on two contiguous fragments in Escherichia coli, and the complete sequence of the structural gene was determined. The protein, Sap, is composed of 814 residues, including a classical prokaryotic 29-amino-acid signal peptide. The mature form has a calculated molecular mass of 83.7 kDa and a molecular mass of 94 kDa on a sodium dodecyl sulfate-polyacrylamide gel. Sap possesses many charged residues, is weakly acidic, and contains only 0.9% methionine and no cysteine residues. The N-terminal region of Sap shares sequence similarities with the Acetogenium kivui S-layer protein, the Bacillus brevis middle wall protein, the Thermotoga maritima Omp alpha protein, and the Bacillus thuringiensis S-layer protein. Electron microscopy observations showed that this S-layer is not observed on B. anthracis cells in which sap has been deleted. PMID- 7836295 TI - The export systems of type 1 and F1C fimbriae are interchangeable but work in parental pairs. AB - Type 1 and F1C fimbriae are surface organelles of Escherichia coli which mediate receptor-specific binding to different host surfaces. Such fimbriae are found, among others, on strains associated with urinary tract infections. Biosynthesis of type 1 and F1C fimbrial organelles requires individual, specialized two component assembly systems. The organization of the fim and foc gene clusters encoding these fimbriae, as well as the structure of the organelles, is very similar; however, the actual sequence homology of the structural elements is not remarkable (34 to 60%). Both gene clusters encode a periplasmically located chaperone and an usher protein, located in the outer membrane, required for organelle biogenesis. Deletion of either element causes abolishment of fimbriation. The present report addresses the question of promiscuity in fimbrial biogenesis. Our data indicate that the two-component export systems of the two organelle systems are reciprocally interchangeable; however, they seem to function only in parental pairs. PMID- 7836296 TI - Posttranslational regulation of nitrogenase in Rhodospirillum rubrum strains overexpressing the regulatory enzymes dinitrogenase reductase ADP ribosyltransferase and dinitrogenase reductase activating glycohydrolase. AB - Rhodospirillum rubrum strains that overexpress the enzymes involved in posttranslational nitrogenase regulation, dinitrogenase reductase ADP ribosyltransferase (DRAT) and dinitrogenase reductase activating glycohydrolase (DRAG), were constructed, and the effect of this overexpression on in vivo DRAT and DRAG regulation was investigated. Broad-host-range plasmid constructs containing a fusion of the R. rubrum nifH promoter and translation initiation sequences to the second codon of draT, the first gene of the dra operon, were constructed. Overexpression plasmid constructs which overexpressed (i) only functional DRAT, (ii) only functional DRAG and presumably the putative downstream open reading frame (ORF)-encoded protein, or (iii) all three proteins were generated and introduced into wild-type R. rubrum. Overexpression of DRAT still allowed proper regulation of nitrogenase activity, with ADP-ribosylation of dinitrogenase reductase by DRAT occurring only upon dark or ammonium stimuli, suggesting that DRAT is still regulated upon overexpression. However, overexpression of DRAG and the downstream ORF altered nitrogenase regulation such that dinitrogenase reductase did not accumulate in the ADP-ribosylated form under inactivation conditions, suggesting that DRAG was constitutively active and that therefore DRAG regulation is altered upon overexpression. Proper DRAG regulation was observed in a strain overexpressing DRAT, DRAG, and the downstream ORF, suggesting that a proper balance of DRAT and DRAG levels is required for proper DRAG regulation. PMID- 7836297 TI - Characterization of BkdR-DNA binding in the expression of the bkd operon of Pseudomonas putida. AB - The bkd operon of Pseudomonas putida consists of the structural genes encoding the components of the inducible branched-chain ketoacid dehydrogenase. BkdR, a positive regulator of the bkd operon and a homolog of Lrp of Escherichia coli is encoded by a structural gene adjacent to, and divergently transcribed from, the bkd operon of P. putida. BkdR was purified from E. coli containing bkdR cloned into pCYTEXP1, an expression vector. The molecular weight of BkdR obtained by gel filtration indicates that BkdR is a tetramer, and the abundance of BkdR in P. putida was estimated to be about 25 to 40 copies of the tetramer per cell. BkdR bound specifically to the region between bkdR and bkdA1, the latter being the first gene of the bkd operon. One BkdR-DNA complex was observed in gel mobility shift patterns. Approximately 100 bp was protected from the action of DNase I by BkdR, and the addition of L-branched-chain amino acids enhanced the appearance of hypersensitive sites in the protected region. There are four potential BkdR-DNA binding sequences in this region based on similarity to Lrp-binding consensus sequences. Like many other transcriptional activators, BkdR regulates expression of its structural gene. DNAs from several gram-negative bacteria hybridized to a probe containing bkdR, indicating the presence of bkdR-like genes in these organisms. PMID- 7836298 TI - Analysis of the Mycobacterium tuberculosis 85A antigen promoter region. AB - A mycobacterial expression-secretion vector was constructed in which the Escherichia coli alkaline phosphatase (phoA) reporter gene was placed under the control of the Mycobacterium tuberculosis 85A promoter and secretion signal sequences. In recombinant Mycobacterium smegmatis and Mycobacterium bovis BCG, PhoA activity could readily be detected on the mycobacterial cell surface and in the culture supernatant, indicating that the 85A signals can drive heterologous expression and secretion in both species. In contrast to the mycobacteria, the 85A promoter did not function in E. coli. We mapped the promoter region by progressive deletions using BAL 31 exonuclease and by primer extension analysis. Insertion and deletion mutations within the promoter region indicated that, unlike most E. coli promoters but similar to Streptomyces promoters, the position of the putative -35 region was not critical for efficient promoter activity. In addition, we investigated the ability of the identified signals to drive the production and secretion in BCG of recombinant Schistosoma mansoni glutathione S transferase (Sm28GST), a protective antigen against schistosomiasis. BALB/c mice immunized with the recombinant BCG by a single dose exhibited a weak but specific T-cell response to Sm28GST. PMID- 7836299 TI - Activation of the Pseudomonas aeruginosa lasI gene by LasR and the Pseudomonas autoinducer PAI: an autoinduction regulatory hierarchy. AB - In Pseudomonas aeruginosa, the transcriptional activator LasR and the Pseudomonas autoinducer PAI, are necessary for efficient transcriptional activation of the lasB gene, encoding elastase (L. Passador, J. M. Cook, M.J. Gambello, L. Rust, and B. H. Iglewski, Science 260:1127-1130, 1993). The transcriptional start points of lasI in Escherichia coli and P. aeruginosa were determined by S1 nuclease mapping. In the presence of both LasR and PAI, the start site, T1, is located at position -25 relative to the ATG translational start codon. A minor transcriptional start, T2, is found at position -13 when lasI is transcribed in the absence of either LasR or PAI in P. aeruginosa and E. coli, respectively. To begin to closely examine the regulation of lasI, whose product is involved in the synthesis of PAI, a lasI-lacZ fusion on a lambda phage was constructed to form monolysogens of E. coli MG4. Lysogens supplied only with either lasI or lasR via multicopy plasmids demonstrated no significant increase in beta-galactosidase expression compared with control levels. Lysogens in which both lasR and lasI were supplied in multicopy exhibited a 62-fold increase in expression, and a lysogen in which lasR was supplied in trans and which was grown in the presence of exogenous PAI exhibited a 60-fold increase. Thus, LasR and PAI are necessary for the full expression of lasI in E. coli. The interchangeability of the P. aeruginosa and Vibrio fischeri homologs LasR and LuxR and their respective autoinducers, PAI and VAI, as activators of lasI-lacZ was examined. Only the combination of LasR and PAI significantly increased the expression of lasI. The comparison of lasI-lacZ and lasB-lacZ expression lysogens grown in the presence of lasR and PAI revealed that half-maximal expression of lasI required 0.1 nM PAI, in contrast to the 1.0 nM PAI necessary for lasB half-maximal expression. These results suggest an autoinduction regulatory hierarchy in which LasR and low PAI concentrations primarily activate lasI expression in a regulatory loop. With the accumulation of PAI, secondary activation of virulence product genes such as lasB occurs. PMID- 7836300 TI - Very short patch repair of T:G mismatches in vivo: importance of context and accessory proteins. AB - In Escherichia coli, T:G mismatches in specific contexts are corrected by a very short patch (VSP) repair system. Previous studies have shown that the product of gene vsr mediates correction of T:G to C:G in the 5'CTAGG/3'GGTCC context and in some related contexts. Amber mutations that arose in CAG sequences in gene cI of bacteriophage lambda were used to determine the effect of flanking bases on the repair of T:G mispairs arising during phage recombination. The experimental findings were combined with published data on mismatch repair of mutations in lambda gene P and E. coli gene lacI. While VSP repair was most efficient in the context 5'CTAGG, there was very significant correction when either the 5'C or the 3' G was replaced by another base. Some mismatch repair of TAG to CAG occurred in all contexts tested. Reduction in VSP repair caused by the lack of MutL or MutS was fully complemented by the addition of vsr+ plasmids when the T:G mispair was in the 5'CTAGG/3'GGTCC context. VSP repair was decreased in bacteria containing mutS+ on a multicopy plasmid. It is suggested that VSP repair maintains sequences such as the repetitive extragenic palindromic (REP) and Chi sequences, which have important roles in E. coli and closely related bacteria. PMID- 7836301 TI - Degradation of the thiocarbamate herbicide EPTC (S-ethyl dipropylcarbamothioate) and biosafening by Rhodococcus sp. strain NI86/21 involve an inducible cytochrome P-450 system and aldehyde dehydrogenase. AB - Determination of the N-terminal sequences of two EPTC (S-ethyl dipropylcarbamothioate)-induced proteins from thiocarbamate-degrading Rhodococcus sp. strain NI86/21 resolved by two-dimensional electrophoresis enabled the localization of the respective structural genes on two distinct DNA fragments. One of these strongly induced proteins is a NAD(+)-dependent dehydrogenase active on aliphatic aldehydes. The second protein was identified as a cytochrome P-450 enzyme. The cytochrome P-450 gene represents the first member of a new family, CYP116. Downstream of the cytochrome P-450 gene, two genes for a [2Fe-2S] ferredoxin (rhodocoxin) and a ferredoxin reductase are located. A putative regulatory gene encoding a new member of the AraC-XylS family of positive transcriptional regulators is divergently transcribed from the cytochrome P-450 gene. By hybridization, it was demonstrated that the aldehyde dehydrogenase gene is widespread in the Rhodococcus genus, but the components of the cytochrome P 450 system are unique to Rhodococcus sp. strain NI86/21. Overexpression in Escherichia coli was achieved for all of these proteins except for the regulatory protein. Evidence for the involvement of this cytochrome P-450 system in EPTC degradation and herbicide biosafening for maize was obtained by complementation experiments using EPTC-negative Rhodococcus erythropolis SQ1 and mutant FAJ2027 as acceptor strains. N dealkylation by cytochrome P-450 and conversion of the released aldehyde into the corresponding carboxylic acid by aldehyde dehydrogenase are proposed as the reactions initiating thiocarbamate catabolism in Rhodococcus sp. strain NI86/21. In addition to the major metabolite N-depropyl EPTC, another degradation product was identified, EPTC-sulfoxide. PMID- 7836302 TI - Studies on carbon material requirements for bacterial proliferation and spore germination under stress conditions: a new mechanism involving transmission of physical signals. AB - The growth of bacteria is often enhanced by addition of carbon materials such as graphite or activated charcoal to the growth medium. In this work, bacterial strains that strictly require such carbon materials under the ordinarily lethal stress caused by high concentrations of salt were isolated. The organisms were gram-positive, spore-forming, sugar-nonfermenting aerobic bacilli and were provisionally designated "Bacillus carbophilus" Kasumi after examination of their phenotypic traits. The growth- and germination-promoting effects of graphite and activated charcoal were demonstrated either quantitatively on agar plates containing fine crystals of the carbon materials mixed with a nonpermissive growth medium or qualitatively on agar plates on nonpermissive growth media half covered with fine carbon particles. Further experiments demonstrated a novel feature of the phenomenon; i.e., the ability to induce colony formation on the nonpermissive plate was transmissible through the air, as well as through plastic or glass barriers. The mechanism probably involves transmission of physical signals regulating cell growth. PMID- 7836303 TI - Identification of receptor binding sites by competitive peptide mapping: phages T1, T5, and phi 80 and colicin M bind to the gating loop of FhuA. AB - Previously we proposed a transmembrane model of the FhuA receptor protein in the outer membrane of Escherichia coli. Removal of the largest loop at the cell surface converted the FhuA transport protein into an open channel and rendered cells resistant to the FhuA-specific phages T1, T5, and phi 80 and to colicin M. In the present study we employed acetylated hexapeptide amides covering the entire surface loop to investigate binding of the phages and of colicin M. Competitive peptide mapping proved to be a powerful technique to uncover three ligand binding sites within a region of 34 amino acid residues. Hexapeptides derived from three specific regions of the surface loop inhibited infection of cells by the phages and killing by colicin M. Two of these regions were common among all four FhuA ligands. Electron microscopy of phage T5 revealed that one inhibitory peptide triggered a strong conformational change leading to the release of DNA from the phage head. These results suggest that the FhuA gating loop is the target for specific binding of phages T1, T5, and phi 80 and colicin M. PMID- 7836304 TI - Kinetic analysis by in vivo 31P nuclear magnetic resonance of internal Pi during the uptake of sn-glycerol-3-phosphate by the pho regulon-dependent Ugp system and the glp regulon-dependent GlpT system. AB - When sn-glycerol-3-phosphate (G3P) is taken up exclusively by the pho regulon dependent Ugp transport system, it can be used as the sole source of Pi but not as the sole source of carbon. We had previously suggested that the inability of G3P to be used as a carbon source under these conditions is due to trans inhibition of G3P uptake by internal Pi derived from the degradation of G3P (P. Brzoska, M. Rimmele, K. Brzostek, and W. Boos, J. Bacteriol. 176:15-20, 1994). Here we report 31P nuclear magnetic resonance measurements of intact cells after exposure to G3P as well as to Pi, using different mutants defective in pst (high affinity Pi transport), ugp (pho-dependent G3P transport), glpT (glp-dependent G3P transport), and glpD (aerobic G3P dehydrogenase). When G3P was transported by the Ugp system and when metabolism of G3P was allowed (glpD+), Pi accumulated to about 13 to 19 mM. When G3P was taken up by the GlpT system, the preexisting internal Pi pool (whether low or high) did not change. Both systems were inversely controlled by internal Pi. Whereas the Ugp system was inhibited, the GlpT system was stimulated by elevated internal Pi. PMID- 7836305 TI - Mutations in Escherichia coli dnaA which suppress a dnaX(Ts) polymerization mutation and are dominant when located in the chromosomal allele and recessive on plasmids. AB - Extragenic suppressor mutations which had the ability to suppress a dnaX2016(Ts) DNA polymerization defect and which concomitantly caused cold sensitivity have been characterized within the dnaA initiation gene. When these alleles (designated Cs, Sx) were moved into dnaX+ strains, the new mutants became cold sensitive and phenotypically were initiation defective at 20 degrees C (J.R. Walker, J.A. Ramsey, and W.G. Haldenwang, Proc. Natl. Acad. Sci. USA 79:3340 3344, 1982). Detailed localization by marker rescue and DNA sequencing are reported here. One mutation changed codon 213 from Ala to Asp, the second changed Arg-432 to Leu, and the third changed codon 435 from Thr to Lys. It is striking that two of the three spontaneous mutations occurred in codons 432 and 435; these codons are within a very highly conserved, 12-residue region (K. Skarstad and E. Boye, Biochim. Biophys. Acta 1217:111-130, 1994; W. Messer and C. Weigel, submitted for publication) which must be critical for one of the DnaA activities. The dominance of wild-type and mutant alleles in both initiation and suppression activities was studied. First, in initiation function, the wild-type allele was dominant over the Cs, Sx alleles, and this dominance was independent of location. That is, the dnaA+ allele restored growth to dnaA (Cs, Sx) strains at 20 degrees C independently of which allele was present on the plasmid. The dnaA (Cs, Sx) alleles provided initiator function at 39 degrees C and were dominant in a dnaA(Ts) host at that temperature. On the other hand, suppression was dominant when the suppressor allele was chromosomal but recessive when it was plasmid borne. Furthermore, suppression was not observed when the suppressor allele was present on a plasmid and the chromosomal dnaA was a null allele. These data suggest that the suppressor allele must be integrated into the chromosome, perhaps at the normal dnaA location. Suppression by dnaA (Cs, Sx) did not require initiation at oriC; it was observed in strains deleted of oriC and which initiated at an integrated plasmid origin. PMID- 7836306 TI - Identification and characterization of the Bacillus subtilis spoIIP locus. AB - We have identified an additional sporulation gene, named spoIIP, in the region of the Bacillus subtilis chromosome located immediately downstream of the gpr gene (227 degrees on the genetic map). A null mutation of spoIIP arrests sporulation at an early stage of engulfment (stage IIii), a phenotype similar to that already described for spoIID and spoIIM mutants. This gene encodes a 401-residue polypeptide, which is predicted to be anchored in the membrane, most of the protein being localized outside the cytoplasm. The spoIIP gene is transcribed from a promoter located in the interval between the gpr and the spoIIP reading frames. This promoter has the structural and genetic characteristics of a sigma E dependent promoter. Transcription of spoIIP is abolished by a mutation in spoIIGB, the gene encoding sigma E, and can be induced during exponential growth in cells engineered to produce an active form of sigma E. Plasmid integration excision experiments leading to the formation of genetic mosaics during sporulation indicate that as with SpoIID and SpoIIM, SpoIIP is required only in the mother cell. Disruption of spoIIP had little or no effect on the expression of sigma F- and sigma E-controlled regulons but inhibited transcription from sigma G-dependent promoters and abolished transcription from promoters under the control of sigma K. We propose that, together with SpoIID and SpoIIM, the SpoIIP protein is involved in the dissolution of the peptidoglycan located in the sporulation septum. PMID- 7836308 TI - Suppression of thermosensitive initiation of DNA replication in a dnaR mutant of Escherichia coli by a rifampin resistance mutation in the rpoB gene. AB - The thermosensitivity of the Escherichia coli dnaR130 mutant in initiation of DNA replication was suppressed by a spontaneous rifampin resistance mutation in rpoB, the gene for the beta subunit of RNA polymerase. Among the dnaR-suppressing rpoB alleles obtained was rpoB22, which was able to suppress the thermosensitivity of the dnaA46 or dnaA167 mutant, but not that of the dnaA5 mutant, in initiation of replication. Some dnaA-suppressing rpoB alleles obtained from rifampin-resistant derivatives of the dnaA mutants were able to suppress the dnaR defect. The dnaR mutant with the rpoB22 allele was deprived of thermoresistance by the dnaA5 mutation and of viability at low and high temperatures by the dnaA46 but not the dnaA167 mutation. The results show that the rpoB-mediated suppression of the dnaA or dnaR defect depends on the functions of both dnaA and dnaR products. I propose that the dnaR product has a key role in transcriptional activation of the replication origin for the dnaA-dependent initiation of DNA replication. PMID- 7836307 TI - Primary structure and functional analysis of the lysis genes of Lactobacillus gasseri bacteriophage phi adh. AB - The lysis genes of the Lactobacillus gasseri bacteriophage phi adh were isolated by complementation of a lambda Sam mutation in Escherichia coli. Nucleotide sequencing of a 1,735-bp DNA fragment revealed two adjacent coding regions of 342 bp (hol) and 951 bp (lys) in the same reading frame which appear to belong to a common transcriptional unit. Proteins corresponding to the predicted gene products, holin (12.9 kDa) and lysin (34.7 kDa), were identified by in vitro and in vivo expression of the cloned genes. The phi adh holin is a membrane-bound protein with structural similarity to lysis proteins of other phage, known to be required for the transit of murein hydrolases through the cytoplasmic membrane. The phi adh lysin shows homology with mureinolytic enzymes encoded by the Lactobacillus bulgaricus phage mv4, the Streptococcus pneumoniae phage Cp-1, Cp 7, and Cp-9, and the Lactococcus lactis phage phi LC3. Significant homology with the N termini of known muramidases suggests that phi adh lysin acts by a similar catalytic mechanism. In E. coli, the phi adh lysin seems to be associated with the total membrane fraction, from which it can be extracted with lauryl sarcosinate. Either one of the phi adh lysis proteins provoked lysis of E. coli when expressed along with holins or lysins of phage lambda or Bacillus subtilis phage phi 29. Concomitant expression of the combined holin and lysin functions of phi adh in E. coli, however, did not result in efficient cell lysis. PMID- 7836309 TI - MyfF, an element of the network regulating the synthesis of fibrillae in Yersinia enterocolitica. AB - The Yersinia enterocolitica surface antigen Myf is a fibrillar structure that resembles CS3 fimbriae. Gene myfA encodes the 21-kDa major subunit of the antigen, while genes myfB and myfC are required for the transport and assembly of pilin subunits at the bacterial cell surface. Here we show that the expression of Myf is regulated at the transcriptional level by temperature and pH. Gene myfA is transcribed at 37 degrees C and in acidic medium. The transcription start is preceded by a putative -10 box for the vegetative RNA polymerase as well as by sequences resembling the consensus sequence recognized by sigma 28. Thus, myfA could be transcribed either from a classical sigma 70 promoter or from a sigma 28 promoter. Transcription of myfA requires at least two genes, myfF and myfE, situated immediately upstream from myfA. The myfF product does not show similarity to any known regulatory protein. It is an 18.5-kDa protein with no typical helix-turn-helix motif and a unique hydrophobic domain in the NH2 terminal part. T7 expression, osmotic shock, fractionation experiments, and TnphoA fusion analyses carried out in Escherichia coli suggest that MyfF is associated with the inner membrane by means of its hydrophobic domain whereas the hydrophilic part protrudes in the periplasm. These features strikingly evoke ToxS, a protein involved in regulation of Tcp pilus production in Vibrio cholerae. MyfE resembles PsaE, a protein involved in regulation of pH6 antigen in Yersinia pestis. Genes myfF and myfE are presumably part of a whole regulatory network. MyfF could be an element of the signal transducing system. PMID- 7836310 TI - Cloning and characterization of the gene for a protein thiol-disulfide oxidoreductase in Bacillus brevis. AB - The gene (bdb) for protein thiol-disulfide oxidoreductase cloned from Bacillus brevis was found to encode a polypeptide consisting of 117 amino acid residues with a signal peptide of 27 residues. Bdb contains a well-conserved motif, Cys-X X-Cys, which functions as the active center of disulfide oxidoreductases such as DsbA, protein disulfide isomerase, and thioredoxin. The deduced amino acid sequence showed significant homology with those of several bacterial thioredoxins. The bdb gene complemented the Escherichia coli dsbA mutation, restoring motility by means of flagellar and alkaline phosphatase activity. The Bdb protein overproduced in B. brevis was enzymatically active in both reduction and oxidization of disulfide bonds in vitro. Immunoblotting indicated that Bdb could function at the periphery of the cell. PMID- 7836311 TI - Bacillus subtilis possesses a second determinant with extensive sequence similarity to the Escherichia coli mreB morphogene. AB - A gene with substantial sequence similarity to the mreB morphogene of Bacillus subtilis has been identified at 302 degrees on the chromosomal map by A. Decatur, B. Kunkel, and R. Losick (Harvard University; personal communication). Our characterization has revealed that the protein product of this determinant (termed mbl for mreB-like) is 55 and 53% identical in sequence to the MreB proteins of B. subtilis and Escherichia coli, respectively. The protein is 86% identical to a protein identified as MreB from Bacillus cereus, suggesting that the B. cereus protein is actually Mbl. Insertional inactivation of mbl indicated that this gene is not essential for cell viability or sporulation. Cells bearing mutant mbl alleles display a decreased growth rate and an altered cellular morphology. The cells appear bloated and are frequently twisted. Intergenic suppressor mutations which restore the growth rate to an approximately normal level arise within the mutant population. A second site mutation, designated som 1, was mapped to the hisA-mbl region of the chromosome by transduction. PMID- 7836313 TI - Recombinational rescue of the stalled DNA replication fork: a model based on analysis of an Escherichia coli strain with a chromosome region difficult to replicate. AB - To examine the physiological effects of DNA replication arrest at the terminus (Ter), we constructed a replication-blocked Escherichia coli strain so that both bidirectional replication forks would be impeded at two flanking Ter sites, one artificial and the other natural. While the blocked strain grew slightly more slowly than a control strain, it had abnormal phenotypes similar to those of E. coli dam mutants, i.e., hyper-Rec phenotype, recA(+)- and recB+ (C+)-dependent growth, and constitutive SOS induction. The observation that these two apparently unrelated mutants cause similar phenotypes led us to design a model. We propose that the following sequential events may occur in both strains. A double-strand (ds) break occurs at the blocked replication fork in the blocked strain and at the ongoing fork in the dam mutant, through which RecBCD enzyme enters and degrades the ds DNA molecule, and the degradation product serves as the signal molecule for SOS induction. When RecBCD enzyme meets an appropriately oriented Chi sequence, its DNase activity is converted to recombinase enzyme, which is able to repair the ds end, recombinationally. this model (i) explains the puzzling phenotype of recA and recB (C) mutants and the SOS-inducing phenotype of polA, lig, and dna mutants under restrictive conditions, (ii) provides an interpretation for the role of the Chi sequence, and (iii) suggests a possible key role for homologous recombination with regard to cell survival following the arrest of DNA replication. PMID- 7836312 TI - Cloning, sequence analysis, expression, and inactivation of the Corynebacterium glutamicum icd gene encoding isocitrate dehydrogenase and biochemical characterization of the enzyme. AB - NADP(+)-dependent isocitrate dehydrogenase (ICD) is an important enzyme of the intermediary metabolism, as it controls the carbon flux within the citric acid cycle and supplies the cell with 2-oxoglutarate and NADPH for biosynthetic purposes. In the amino acid-producing organism Corynebacterium glutamicum, the specific activity of ICD was independent of the growth substrate and of the growth phase at approximately 1 U/mg, indicating that this enzyme is constitutively formed. The ICD gene, icd, was isolated, subcloned on a plasmid, and introduced into C. glutamicum. Compared with the wild type, the recombinant strains showed up to 10-fold-higher specific ICD activities. The nucleotide sequence of a 3,595-bp DNA fragment containing the icd gene was determined. The predicted gene product of icd consists of 739 amino acids (M(r) = 80.091) and showed 58.5% identity with the monomeric ICD isozyme II from Vibrio sp. strain ABE-1 but no similarity to any known ICD of the dimeric type. Inactivation of the chromosomal icd gene led to glutamate auxotrophy and to the absence of any detectable ICD activity, suggesting that only a single ICD is present in C. glutamicum. From an icd-overexpressing C. glutamicum strain, ICD was purified and biochemically characterized. The native ICD was found to be a monomer; to be specific for NADP+; to be weakly inhibited by oxaloacetate, 2-oxoglutarate, and citrate; and to be severely inhibited by oxaloacetate plus glyoxylate. The data indicate that ICD from C. glutamicum is structurally similar to ICDs from bacteria of the genera Vibrio, Rhodomicrobium, and Azotobacter but different from all other known procaryotic and eucaryotic ICDs. PMID- 7836314 TI - Saccharomyces cerevisiae has a single glutamate synthase gene coding for a plant like high-molecular-weight polypeptide. AB - Purification of the glutamate synthase (GOGAT) enzyme from Saccharomyces cerevisiae showed that it is an oligomeric enzyme composed of three identical 199 kDa subunits. The GOGAT structural gene was isolated by screening a yeast genomic library with a yeast PCR probe. This probe was obtained by amplification with degenerate oligonucleotides designed from conserved regions of known GOGAT genes. The derived amino-terminal sequence of the GOGAT gene was confirmed by direct amino-terminal sequence analysis of the purified protein of 199 kDa. Northern (RNA) analysis allowed the identification of an mRNA of about 7 or 8 kb. An internal fragment of the GOGAT gene was used to obtain null GOGAT mutants completely devoid of GOGAT activity. The results show that S. cerevisiae has a single NADH-GOGAT enzyme, consisting of three 199-kDa monomers, that differs from the one found in prokaryotic microorganisms but is similar to those found in other eukaryotic organisms such as alfalfa. PMID- 7836315 TI - Identification and characterization of an outer membrane protein, OmpX, in Escherichia coli that is homologous to a family of outer membrane proteins including Ail of Yersinia enterocolitica. AB - We previously reported that a region of the Escherichia coli chromosome at 18 min increased E sigma E activity when cloned in multicopy (J. Mecsas, P. E. Rouviere, J. W. Erickson, T. J. Donohue, and C. A. Gross, Genes Dev. 7:2618-2628, 1993). In the present report, we identify and characterize the gene responsible for the increase in E sigma E activity. This gene is in a monocistronic operon with two promoters and a rho-independent terminator. Sequence analysis of this gene indicated that it encodes an outer membrane protein which is 83% identical to OmpX in Enterobacter cloacae, leading us to name this gene ompX. There are four other proteins that are homologous to OmpX. Several of these proteins, Ail of Yersinia enterocolitica and Rck and PagC of Salmonella typhimurium, have properties that allow bacteria to adhere to mammalian cells, survive exposure to human serum, and/or survive within macrophages. We therefore characterized strains deleted for ompX for their growth phenotypes, E sigma E activity, serum resistance, and adherence to mammalian cells. No differences in growth rates, serum resistance, or adherence to mammalian cells were observed; however, E sigma E activity was dependent on expression of OmpX in certain strain backgrounds. PMID- 7836316 TI - Identification of a Bordetella pertussis bvg-regulated porin-like protein. AB - Bordetella pertussis 18323 produces a bvg-regulated 39.1-kDa porin-like protein, OmpQ. OmpQ had 61% similarity to the major porin of B. pertussis and contains conserved regions common to both the neisserial and enteric porin families. The results of Southern blot analysis indicate that strains of Bordetella parapertussis and Bordetella bronchiseptica but not Bordetella avium contain this gene. PMID- 7836317 TI - Effects of multicopy LeuO on the expression of the acid-inducible lysine decarboxylase gene in Escherichia coli. AB - We previously reported that mutations in hns, the structural gene for the histone like protein H-NS, cause derepressed expression of cadA, which encodes the acid inducible lysine decarboxylase at noninducing pH (pH 8.0). This study reports the characterization of a plasmid isolated from an Escherichia coli library that suppresses the effect of an hns mutation on cadA expression. A previously sequenced open reading frame, leuO, proves to be the gene that causes the hns complementing phenotype. The mechanism for this phenotype appears to be overexpression of leuO from a multicopy plasmid, which drastically reduces production of CadC, the essential activator for cadA induction. These results show an in vivo regulatory phenotype for leuO, consistent with its proposed protein sequence. PMID- 7836318 TI - Evidence that the N-terminal region of the Vibrio fischeri LuxR protein constitutes an autoinducer-binding domain. AB - The Vibrio fischeri luminescence genes are regulated by the LuxR protein and an N acyl homoserine lactone compound termed the autoinducer. The C-terminal one-third of LuxR contains a domain that can interact with the transcription complex and activate the luminescence genes. On the basis of limited evidence it has been suggested that the N-terminal two-thirds of LuxR constitutes a domain that serves to bind the autoinducer. We show that tritium-labeled autoinducer binds to Escherichia coli cells in which LuxR is overexpressed. We also show that tritium labeled autoinducer binds to E. coli in which truncated LuxR proteins missing portions of the C-terminal domain are expressed but does not bind to E. coli cells in which truncated LuxR proteins missing portions of the N-terminal region are expressed. Our results provide evidence that the autoinducer binds to LuxR and that in E. coli the N-terminal two-thirds of LuxR can fold into a polypeptide capable of binding the autoinducer in the absence of the C-terminal domain. PMID- 7836319 TI - Enzymatic synthesis of aminocyclitol moieties of aminoglycoside antibiotics from inositol by Streptomyces spp.: detection of glutamine-aminocyclitol aminotransferase and diaminocyclitol aminotransferase activities in a spectinomycin producer. AB - Extracts of stationary-phase mycelia of the spectinomycin producer Streptomyces flavopersicus ATCC 19756 catalyzed inositol dehydrogenase, L-glutamine:inosose aminotransferase, 2-epi-streptamine:inosose aminotransferase, streptamine:inosose aminotransferase, N3-methyl-2-deoxystreptamine:inosose aminotransferase, and aminodeoxy-scyllo-inositol:inosose aminotransferase reactions, as detected with a new rapid assay procedure. These results suggest that one or both amino groups of the N1,N3-dimethyl-2-epi-streptamine moiety of spectinomycin are derived by transamination from the alpha-amino group of L-glutamine. An enzymatic procedure for distinguishing among N1- and N3-monomethyl diaminocyclitol derivatives and their diaminocyclitol biosynthetic precursors is described. A scheme showing key roles of glutamine-aminocyclitol aminotransferases in biosynthesis of major aminoglycoside antibiotics is presented. PMID- 7836321 TI - Characterization of the morphogenetic defects conferred by cold-sensitive prohead accessory and scaffolding proteins of phi X174. AB - The morphogenetic defects conferred by the cold-sensitive prohead accessory and scaffolding proteins of phi X174 were determined in vivo. The results suggest that the cold-sensitive prohead accessory protein blocks the formation of the 12S assembly intermediate. The cold-sensitive scaffolding protein most likely affects the stability of the prohead. PMID- 7836320 TI - Genetic analysis of Proteus mirabilis mutants defective in swarmer cell elongation. AB - Swarmer cell differentiation is a complex process involving the activity of many gene products. In this report, we characterized the genetic locus of Tn5 insertion in each of 12 mutants defective in swarmer cell elongation. The mutations fell into four categories affecting either flagellar biosynthesis or energetics, lipopolysaccharide and cell wall biosynthesis, cellular division, or proteolysis of peptides. PMID- 7836322 TI - Stereospecificity of hydride removal from NADH by reductases of multicomponent nonheme iron oxygenase systems. AB - The stereospecificity of hydride removal from the 4 position of the pyridine ring of NADH by reductases from all three classes of multicomponent nonheme iron oxygenases was examined. The class I and II reductases, modules of which show significant sequence similarity with and which belong to the ferredoxin-NADP+ reductase family of flavin-dependent oxidoreductases, transferred the pro-R hydrogen. By contrast, the class II enzymes, which do not show significant sequence similarity to the class I and III enzymes but modules of which belong to the glutathione reductase family of flavoenzymes, transferred the pro-S hydrogen. PMID- 7836323 TI - Preliminary structure determination of the capsular polysaccharide of Vibrio cholerae O139 Bengal Al1837. AB - Vibrio cholerae O139 Bengal has recently been identified as a cause of epidemic cholera in Asia. In contrast to V. cholerae O1, V. cholerae O139 Bengal has a polysaccharide capsule. As determined by high-performance anion-exchange chromatography and 1H nuclear magnetic resonance analysis, the capsular polysaccharide of V. cholerae O139 Bengal strain Al1837 has six residues in the repeating subunit; this includes one residue each of N-acetylglucosamine, N acetylquinovosamine (QuiNAc), galacturonic acid (GalA), and galactose and two residues of 3,6-dideoxyxylohexose (Xylhex). The proposed structure is [formula: see text] PMID- 7836324 TI - The mtrB gene of Bacillus pumilus encodes a protein with sequence and functional homology to the trp RNA-binding attenuation protein (TRAP) of Bacillus subtilis. AB - The mtrB gene from Bacillus pumilus encodes a 76-amino-acid polypeptide with 77% identity to the trp RNA-binding attenuation protein (TRAP) from Bacillus subtilis. B. pumilus TRAP binds trp leader RNA from either B. subtilis or B. pumilus in a tryptophan-dependent manner. Altering threonine 52 to alanine eliminated RNA-binding activity of B. pumilus TRAP. PMID- 7836325 TI - A spontaneous hemadsorption-negative mutant of Mycoplasma pneumoniae exhibits a truncated adhesin-related 30-kilodalton protein and lacks the cytadherence accessory protein HMW1. AB - A spontaneous, hemadsorption-negative mutant of Mycoplasma pneumoniae lacks the cytoskeleton-forming HMW1 protein and exhibits a truncated adhesin-related 30-kDa protein. Genetic analyses revealed deletion of one nucleotide in the hmw1 gene and loss of eight repeated sequences comprising 144 nucleotides in the gene for the adhesin-related 30-kDa protein. PMID- 7836326 TI - Redundant transfer of F' plasmids occurs between Escherichia coli cells during nonlethal selections. AB - Surface exclusion is the mechanism by which F plasmids prevent the redundant entry of additional F plasmids into the host cell during exponential growth. This mechanism is relaxed in cells that are in stationary phase. Using genetically marked F' plasmids and host strains, we extend this finding to Escherichia coli populations during extended nonlethal selection in bacterial lawns. We show that a high level of redundant transfer occurs between these nongrowing cells during the selection. This result has implications for the mechanism of adaptive mutagenesis. PMID- 7836327 TI - Construction and plasmid-borne complementation of strains lacking the epsilon subunit of the Escherichia coli F1F0 ATP synthase. AB - Two strains of Escherichia coli that lack the epsilon subunit of the F1F0 ATP synthase have been constructed. They are shown to be viable but with very low growth yields (28%). These strains can be complemented by plasmids carrying wild type uncC, but not when epsilon is overproduced. These results indicate that epsilon is not essential for growth on minimal glucose medium and that the level of its expression affects the assembly of the ATP synthase. PMID- 7836328 TI - Regulated expression of the histidase structural gene in Streptomyces griseus. AB - The histidase structural gene from Streptomyces griseus was expressed from a leaderless, monocistronic transcript. Multiple copies of the DNA located upstream of the hutH transcription initiation site led to a significant level of histidase activity when present in trans in the wild-type strain grown under noninducing conditions. PMID- 7836329 TI - Methanobacterium formicicum, a mesophilic methanogen, contains three HFo histones. AB - The mesophilic methanogen Methanobacterium formicicum JF-1 has been shown to contain three members of the HMf family of archaeal histones, designated HFoA1, HFoA2, and HFoB, and their encodinig genes (hfoA1, hfoA2, and hfoB) have been cloned and sequenced. The HFo histones have primary sequences that are 75 to 82% identical to the HMf sequences and appear to share ancestry with the core histones that form the eukaryal nucleosome. The HFo proteins bind and compact DNA molecules into nucleosome-like structures apparently identical to those formed by the HMf proteins, but, in contrast to the HMf proteins, this activity of the HFo proteins is lost after incubation at 95 degrees C for 5 h. PMID- 7836330 TI - Different roles for KinA, KinB, and KinC in the initiation of sporulation in Bacillus subtilis. AB - Activation (phosphorylation) of the transcription factor encoded by spo0A is essential for the initiation of sporulation in Bacillus subtilis. At least three histidine protein kinases are involved in the phosphorylation of Spo0A. Under some growth conditions, KinA was the primary kinase, but under other conditions, KinB had the more critical role. KinC was required for the initial activation of Spo0A, even in the presence of KinA and KinB. PMID- 7836331 TI - Isolation and characterization of a calmodulin-like protein from Halobacterium salinarium. AB - The first evidence for a calmodulin-like protein in an archaeon, Halobacterium salinarium, is reported here. The calmodulin-like protein, with a molecular mass of 24 kDa and an estimated pI of 4.8, stimulated cyclic nucleotide phosphodiesterase in a calcium-dependent manner. This stimulation could be suppressed by calmodulin inhibitors. The Ca(2+)-binding ability was verified by 45Ca autoradiography. PMID- 7836332 TI - The oxygen affinity of cytochrome bo' in Escherichia coli determined by the deoxygenation of oxyleghemoglobin and oxymyoglobin: Km values for oxygen are in the submicromolar range. AB - Apparent oxygen affinities for Escherichia coli cells and membranes containing a terminal oxidase with only one type of ligand-binding heme, cytochrome o', were measured with oxyleghemoglobin and oxymyoglobin as sensitive oxygen reporters. Two Km values (0.15 to 0.35 microM and 0.016 to 0.085 microM) were detected, well below values determined for the purified oxidase by insensitive electrode methods. PMID- 7836333 TI - Fluoxetine and hemostatic function: a pilot study. AB - BACKGROUND: Isolated case reports have appeared implicating fluoxetine as a cause of impaired hemostatic function. The authors attempted to investigate this phenomenon. METHOD: The hemostatic function of 10 patients with DSM-III-R major depression was investigated before and after a trial of treatment with fluoxetine. The tests included international normalized ratio, partial thromboplastin time, factors II, V, VII, VIII:C, IX, X, XI, XII, fibrinogen, thrombin time, bleeding time, euglobulin lysis time, protein kinase C, antithrombin, platelet counts, D dimer, lupus inhibitor, and platelet sensitivity studies to the following agonists: adenosine diphosphate, epinephrine, collagen, and arachidonic acid. Hemostatic data on a patient with a drug-related bleeding episode are not available. RESULTS: No significant difference was found in any of the parameters tested. CONCLUSION: This study failed to demonstrate any compromised hemostatic function associated with fluoxetine therapy. However, the possibility of a type II statistical error exists. It is possible that bleeding events may occur as an idiosyncratic reaction to fluoxetine treatment. PMID- 7836334 TI - Serum clomipramine and metabolite levels in four nursing mother-infant pairs. AB - BACKGROUND: Women with postpartum-onset obsessive compulsive disorder may elect treatment with clomipramine. There is minimal information to guide the clinician who must advise breastfeeding women about clomipramine therapy. METHOD: Four clomipramine-treated breastfeeding mother-infant pairs were assessed for serum concentrations of clomipramine, N-desmethylclomipramine, and corresponding 8 hydroxymetabolites. RESULTS: Although the mothers exhibited a wide range of serum concentrations, the parent drug and metabolites were either nondetectable or below the quantifiable limit in the sera of all infants. No adverse clinical effects were observed. CONCLUSION: This report adds to the growing literature that suggests that tricyclic use during breastfeeding rarely results in measurable drug levels in infant sera. PMID- 7836335 TI - Fatal pulmonary embolism in the catatonic syndrome: two case reports and a literature review. AB - BACKGROUND: Catatonia is associated with excess early mortality when it is unrecognized or inadequately treated. The characteristics of the lethal catatonia subtype are now well described, but the excess mortality of the remaining patients with catatonic syndrome, particularly from pulmonary embolism, appears to be inadequately recognized. The fatal risk of the catatonic syndrome is reviewed. METHOD: Two new case reports of sudden death from pulmonary embolism in catatonic syndrome are presented. The world literature on morbidity, mortality, and pulmonary embolism in catatonia was reviewed by a search of MEDLINE and PsychInfo from 1966 to the present. Additional older references were discovered by screening bibliographies from articles produced by the searches. RESULTS: Twenty cases of autopsy-confirmed pulmonary embolism were found in patients with catatonic syndrome. Catatonic patients were more likely to die of pulmonary embolism and die earlier than patients with other types of schizophrenia. Death from pulmonary embolism did not occur until after the second week of catatonic symptoms and often occurred without warning. CONCLUSION: Risk of a fatal pulmonary embolism is inherent in persistent catatonic symptoms and may explain the observed excess early mortality. Prompt resolution of the catatonic syndrome with benzodiazepines, barbiturates, or electroconvulsive therapy is the best way to reduce risk of pulmonary embolism. The prophylactic value of physical therapy or anticoagulation merits further investigation. Despite the absence of controlled trials of treatment effectiveness, the catastrophic outcome of acute pulmonary embolism warrants early and vigorous intervention in catatonic patients. PMID- 7836336 TI - Electrocardiographic screening in psychiatric patients. AB - BACKGROUND: Present recommendations vary regarding the use of screening ECGs in psychiatric patients; therefore, this study was undertaken to determine the utility of routine screening electrocardiograms (ECGs) in hospitalized psychiatric patients. METHOD: Twelve-lead ECGs were obtained on 1006 consecutive admissions to an academic freestanding 250-bed public psychiatric hospital over a period of 2 years. RESULTS: Tracings were read as normal in 765 of 1006 cases. Tracings of 148 patients were considered to be equivocal, mainly due to nonspecific T wave abnormalities seen in 118 patients. In 29 patients, no ostensible cause for the T wave abnormalities was found. Among the remaining 80 instances, abnormalities were attributed to drug abuse. Especially prevalent was recent cocaine abuse, often with concurrent alcohol abuse (N = 30); recent alcohol abuse alone (N = 10); or concurrent psychotherapeutic drugs (lithium, N = 19; thioridazine, N = 9; and miscellaneous drugs, N = 12). Subclinical hypothyroidism was found in 5 and borderline hypokalemia in 4 patients. Ninety three tracings were definitely abnormal; one half of these were among patients over 50 years of age. Only 5 of 162 tracings in patients under 20 years of age were abnormal; one of these (incomplete right bundle branch block) might have mattered had the patient been considered for treatment with drugs that lengthen intraventricular conduction times, such as tricyclic antidepressants or thioridazine. CONCLUSION: Routine screening ECGs done on psychiatric patients yielded relatively few abnormalities except in those over the age of 50 years, confirming the experience with such surveys in the general population. The prevalence of abnormalities among these patients was frequent enough to merit routine screening. For other patients regardless of age, ECGs are indicated whenever a history or physical findings suggest cardiovascular disease or whenever it is proposed to treat these patients with psychotherapeutic drugs known to increase cardiac conduction times or otherwise alter cardiac function. PMID- 7836337 TI - Are patients who are intolerant to one serotonin selective reuptake inhibitor intolerant to another? AB - BACKGROUND: The question was asked whether patients who discontinue one serotonin selective reuptake inhibitor (SSRI) because of side effects can be treated successfully with another SSRI. METHOD: 113 patients with major depression who had discontinued fluoxetine because of side effects were enrolled in an open, multicenter, 8-week study designed to evaluate the tolerability and efficacy of sertraline. After a washout period of at least 3 weeks following fluoxetine discontinuation and an additional 1-week, single-blind, placebo washout period, patients began treatment with 50 mg of sertraline once daily. Doses were titrated upward as necessary to a maximum daily dose of 200 mg. Depressive symptoms and adverse events were evaluated weekly. RESULTS: Based on the Clinical Global Impressions Scale, 79 (71.8%) of 110 patients evaluated for efficacy were "much" or "very much" improved relative to baseline. Only 11 (9.8%) of 112 patients discontinued sertraline because of adverse reactions. CONCLUSION: These results suggest that patients who discontinue one SSRI because of side effects can be treated successfully with another. PMID- 7836338 TI - Clonidine treatment of excessive sweating. PMID- 7836339 TI - Dose-related sensory distortions with zolpidem. PMID- 7836340 TI - Panic disorder and pregnancy. PMID- 7836341 TI - Fluoxetine and social phobia. PMID- 7836342 TI - Fluoxetine and sumatriptan: possibly a counterproductive combination. PMID- 7836343 TI - Compulsive buying and depression. PMID- 7836344 TI - Lithium: the present and the future. AB - In summary, Dr. Keck reported that the literature as a whole shows lithium, valproate, and carbamazepine to be about comparable in treating acute mania. Lithium appears to be clearly efficacious for the treatment of acute bipolar depression; valproate has shown equivocal results, and carbamazepine weakly positive results, when used to treat this condition. Results of controlled studies show that maintenance therapy with lithium is effective in preventing recurrence of manic depressive illness; results of valproate for maintenance therapy are pending; and carbamazepine therapy can be effective but less so compared to lithium. PMID- 7836345 TI - Course of illness and maintenance treatments for patients with bipolar disorder. AB - BACKGROUND: Both naturalistic studies and treatment research on bipolar disorder are reviewed to describe its clinical course, the need for maintenance therapy, the efficacy of current pharmacologic prophylaxis, and the empirical basis for more comprehensive approaches to treatment. METHOD: Articles were identified through computerized literature searches and from bibliographies of published studies, review articles, and textbooks. RESULTS: Bipolar disorder is marked by multiple relapses and recurrences, as well as significant interepisode psychopathology. Within 1 year of recovery from a mood episode, half of all patients will have suffered a second episode. Various clinical and demographic variables have been investigated as risk factors for recurrence. Although lithium represents the single greatest advance in the treatment of this disease, it is clear that a substantial number of patients fail lithium prophylaxis, including those with a high frequency of prior episodes, mixed (dysphoric) mania, comorbid personality disturbance, and rapid cycling. The foremost pharmacologic alternatives to lithium are the anticonvulsants carbamazepine and valproate. Increased recognition of the psychosocial sequelae of bipolar disorder and the limitations of pharmacotherapy alone have led to the investigation of psychosocial interventions. These preliminary studies are small in number and of poor quality for the most part, but have nevertheless yielded positive findings. CONCLUSION: Although lithium often fails to meet the clearly established need for prophylactic treatment, there is little evidence from rigorous clinical trials to support the wide-spread use of anticonvulsants in maintenance therapy. Treatment research should further examine these medications and the use of psychosocial treatments as adjuvants to pharmacotherapy. PMID- 7836346 TI - Alliance not compliance: a philosophy of outpatient care. AB - Over the last decade, our clinical research team has evolved effective methods for forming a strong treatment alliance with mood disorder patients. These methods, in turn, have been associated with very low rates of patient dropout (< 10%) and high rates of objectively measured medication compliance (> 85%) over multiyear treatment trials. We have every reason to believe that our technique for alliance building would be equally effective in general clinical practice. The cornerstones of our methods are education of, information for, and active participation by the patient in the treatment process. We begin by educating the patient about his or her disorder and its treatment, giving patients as much information as their clinical condition will allow them to absorb. As patients begin to improve, we provide additional information. We continuously inform patients about what to expect in treatment and when, both with respect to amelioration of symptoms and with respect to the medication side effects they may experience. We present the treatment experience as an experiment in which clinician and patient are coinvestigators, each with his or her own expertise. The clinician is the expert on the disorder and its treatment in general; the patient is the expert on his or her own disorder and his or her own experience of the treatment. We try to keep the experiment interesting and, whenever possible, to inject some humor into it. We work to engage family members as adjunct members of the experimental team by educating them as well and keeping them informed throughout the treatment process.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836347 TI - Medication compliance in the elderly. AB - The consequences of drug noncompliance may be serious in older patients. Estimates of the extent of noncompliance in the elderly vary, ranging from 40% to a high of 75%. Three common forms of drug treatment noncompliance are found in the elderly: overuse and abuse, forgetting, and alteration of schedules and doses. Some older patients who are acutely ill may take more than the prescribed dose of a medication in the mistaken belief that more of the drug will speed their recovery. Such overuse has clearly been associated with adverse drug effects. Forgetting to take a medication is a common problem in older people and is especially likely when an older patient takes several drugs simultaneously. Data suggest that the use of three or more drugs a day places elderly people at particular risk of poor compliance. The use of at least three drugs, and often more, is common in the elderly, with estimates of as many as 25% of older people taking at least three drugs. Averages of drug use among elderly hospitalized patients suggest that eight drugs taken simultaneously may be typical. Problems may also arise when dementia or depression is present, which may interfere with memory. The most common noncompliant behavior of the elderly appears to be underuse of the prescribed drug. Inappropriate drug discontinuation, furthermore, may occur in up to 40% of prescribing situations, particularly within the first year of a chronic care regimen. As many as 10% of elderly people may take drugs prescribed for others; more than 20% may take drugs not currently prescribed by a physician.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836348 TI - Psychotherapy, medication combinations, and compliance. AB - Combination treatment with antidepressants and psychotherapy is a common strategy in treating depression. Surprisingly little published literature on the effects of such combinations on antidepressant compliance is available. In contrast, literature is plentiful, particularly from the 1970s, on the effects of combined treatment on outcome. Although various negative interactions have at times been suggested, controlled trials are reassuring and indicate enhanced benefit, either by additive effects, by effects on different outcome measures such as symptoms or interpersonal relationships, or by mutual potentiation. A ceiling effect has been observed in some studies in which the better of the two single treatments produces as much benefit as can be obtained, with no additional benefit from the second treatment in its presence but benefit in its absence. However, it is important to note that the research designs used in most controlled trials are not adequate to study compliance because much effort is devoted toward maximizing compliance; compliance is better studied in the naturalistic situation. There is evidence in bipolar disorder that psychotherapy enhances compliance to lithium. In attaining good drug compliance in patients receiving psychotherapy, consideration needs to be given to collaboration between the drug therapist and psychotherapist, the nature of the psychotherapy, and the attitude of the psychotherapist. In general studies of compliance, patients who are engaged in treatment, are satisfied with it, and are better informed, also tend to comply better with medication regimens. PMID- 7836349 TI - Compliance: definitions and key issues. AB - Issues surrounding treatment compliance can be considered for a number of clinical situations. For clinicians, compliance usually means "the extent to which the patient takes the medications as prescribed." Instead of "compliance," it has been suggested that the term adherence be used, which puts more of a burden on the clinician to form a therapeutic alliance with the patient, which thereby increases behavioral compliance and possibly enhances the therapeutic effect of the medication administered. The trend toward placing more responsibility on the clinician to obtain compliance or adherence to the prescribed treatment has resulted in several strategies. These include explaining the illness and the rationale for the use of medication for its treatment, inquiring into the patient's hesitation and fears concerning medication, and using various educational approaches with the patient and the patient's significant other concerning possible side effects. Different clinical settings and situations also may modify the emphasis needed to maximize compliance. The situation of continuation and maintenance treatment may require a different treatment procedure for maximum success. The emphasis must vary quite a bit from the patient who improves and needs education to be convinced to continue maintenance treatment to the patient who has a treatment-resistant depression and needs close support and maintenance of hope to continue treatment that, up until the present, has not yielded positive results. Shifting the focus of compliance from the patient to the skill of the clinician refocuses the issue from a patient variable back to the art and science of good medicine.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836350 TI - 28-kDa mammalian heat shock protein, a novel substrate of a growth regulatory protease involved in differentiation of human leukemia cells. AB - Because of their differentiating effects in neoplastic cells in vitro, the use of retinoids in the treatment of various malignant and premalignant conditions is under investigation. To date, signal transduction pathways involved in retinoid induced differentiation remain poorly understood. Differentiation of HL-60 cells by all-trans-retinoic acid (tRA) is directly mediated by down-regulation of the serine protease myeloblastin (mbn). In this report, we investigate the possibility that the 28-kDa heat shock protein (hsp28), previously linked to differentiation of normal and neoplastic cells including HL-60, may be regulated by mbn. Using NB4 promyelocytic leukemic cells as a differentiative model, we show that tRA induces initial suppression and subsequent up-regulation of hsp28 protein, mirroring tRA-induced changes in mbn protein. The progressive reduction in hsp28 mRNA levels in response to tRA suggests that changes in hsp28 protein levels might be posttranscriptionally mediated, raising the possibility that hsp28 may be targeted by mbn. To address this, we developed an assay using purified mbn and recombinant hsp28 and now show that hsp28 is hydrolyzed by mbn but not its homologue, human neutrophil elastase. Moreover, mbn does not indiscriminately hydrolyze other proteins. Identifying hsp28 as a substrate of mbn strongly suggests that hsp28 may be a key component of the tRA signaling pathway involved in regulating cell differentiation. PMID- 7836351 TI - Molecular cloning and structural characterization of the Arg-gingipain proteinase of Porphyromonas gingivalis. Biosynthesis as a proteinase-adhesin polyprotein. AB - The identification of proteinases of Porphyromonas gingivalis that act as virulence factors in periodontal disease has important implications in the study of host-pathogen interactions as well as in the discovery of potential therapeutic and immunoprophylactic agents. We have cloned and characterized a gene that encodes the 50-kDa cysteine proteinase gingipain or Arg-gingipain-1 (RGP-1) described previously (Chen, Z., Potempa, J., Polanowski, A., Wikstrom, M., and Travis, J. (1992) J. Biol. Chem. 267, 18896-18901). Analysis of the amino acid sequence of RGP-1 deduced from the cloned DNA sequence showed that the biosynthesis of this proteinase involves processing of a polyprotein that contains multiple adhesin molecules located at its carboxyl terminus. This finding corroborates previous evidence (Pike R., McGraw, W., Potempa, J., and Travis, J. (1994) J. Biol. Chem. 269, 406-411) that RGP-1 is closely associated with adhesin molecules, and that high molecular weight forms of the proteinase are involved in the binding of erythrocytes. PMID- 7836352 TI - The hydrophobic nature of GroEL-substrate binding. AB - The molecular chaperone GroEl from Escherichia coli is a member of the highly conserved Hsp60 family of proteins that facilitates protein folding. A central question regarding the mechanism of GroEL-assisted refolding of proteins concerns its broad substrate specificity. The nature of GroEL-polypeptide chain interaction was investigated by isothermal titration calorimetry using proteins that maintain a non-native conformation in neutral buffer solutions. A single molecule of an unfolded variant of subtilisin BPN' binds non-cooperatively to GroEL with micromolar affinity and a positive enthalpy change. Additional calorimetric titrations of this chain with GroEL show that the positive enthalpy change decreases with increasing temperature between 6 and 25 degrees C, yielding a delta CP of -0.85 kcal mol-1 degree-1. alpha-Casein similarly binds to GroEL with micromolar affinity and a positive enthalpy change in the range of 15-20 degrees C, yielding a delta CP of -0.44 kcal mol-1 degree-1. The negative heat capacity change provides strong evidence for the role of hydrophobic interactions as the driving force for the association of these substrates with the GroEL chaperonin. PMID- 7836353 TI - Diphtheria toxin binds to the epidermal growth factor (EGF)-like domain of human heparin-binding EGF-like growth factor/diphtheria toxin receptor and inhibits specifically its mitogenic activity. AB - The membrane anchored form of human heparin-binding epidermal growth factor-like growth factor (HB-EGF) acts as the diphtheria toxin (DT) receptor. Transfection of human HB-EGF cDNA into mouse LC cells, L cells stably expressing DRAP27, conferred sensitivity to DT, but transfection of mouse HB-EGF cDNA did not. To define the essential regions of HB-EGF that serve as the functional DT receptor, we examined the sensitivity to DT and DT binding of cells expressing several human/mouse HB-EGF chimeras. It was found that DT binds to the EGF-like domain of the human HB-EGF. However, mouse HB-EGF does not serve as a functional DT receptor due to non-conserved amino acid substitutions in this domain. In addition, CRM197, a non-toxic mutant of DT, inhibited strongly the mitogenic activity of the secreted form of human HB-EGF, but not of mouse HB-EGF and other EGF receptor-binding growth factors. These results confirmed further that DT interacts with the EGF-like domain of HB-EGF and that this interaction is specific for human HB-EGF. PMID- 7836354 TI - Processing specificity and biosynthesis of the Drosophila melanogaster convertases dfurin1, dfurin1-CRR, dfurin1-X, and dfurin2. AB - Pro-protein and pro-hormone convertases are subtilisin/kexin-like enzymes implicated in the activation of numerous precursors by cleavage at sites mostly composed of pairs of basic amino acids. Six members of this family of enzymes have been identified in mammals and named furin (also called PACE), PC1 (also called PC3), PC2, PACE4, PC4, and PC5 (also called PC6). Multiple transcripts are produced for all the mammalian convertases, but only in the cases of PC4, PACE4, and PC5 does differential splicing result in the modification of the C-terminal sequence of these enzymes. A similar molecular diversity is also observed for the convertases of Hydra vulgaris, Caenorhabditis elegans, and Drosophila melanogaster. In the third species, two genes homologous to human furin called Dfur1 and Dfur2 have been identified. The Dfur1 gene undergoes differential splicing to generate three type I membrane-bound proteins called dfurin1, dfurin1 CRR, and dfurin1-X, which differ only in their C-terminal sequence. By using recombinant vaccinia viruses that express each of the dfurin proteins, we investigated the potential effect of the C-terminal domain on their catalytic specificities. For this purpose, these enzymes were coexpressed with the precursors pro-7B2, pro-opiomelanocortin, and pro-dynorphin in a number of cell lines, and the processed products obtained were characterized. Our studies demonstrate that these proteases display cleavage specificities similar to that of mammalian furin but not to that of PC2. In contrast, we noted significant differences in the biosynthetic fates of these convertases. All dfurins undergo rapid removal of their transmembrane domain within the endoplasmic reticulum, resulting in the release of several truncated soluble forms. However, in the media of cells containing secretory granules, such as GH4C1 and AtT-20, dfurin1 CRR and dfurin2 predominate over dfurin1, whereas dfurin1-X is never detected. While pro-segment removal occurs predominantly in the trans-Golgi network for all the dfurins, in the presence of brefeldin A, only dfurin1-CRR and dfurin2 can undergo partial zymogen cleavage. The conclusions drawn from the results of this study may well be applicable to the mammalian convertases PC4, PACE4, and PC5, which also display C-terminal sequence heterogeneity. PMID- 7836355 TI - Prothrombin activation by prothrombinase in a tubular flow reactor. AB - Thrombin production by the phospholipid-bound complex of blood clotting factors Xa and Va (prothrombinase) was studied in a tubular flow reactor. The inner wall of a glass capillary was coated with a phospholipid bilayer of 25% phosphatidylserine and 75% phosphatidylcholine. Prothrombinase was assembled on this bilayer by perfusion with a mixture containing an excess of factor Va (2 nM) and a limiting amount of factor Xa (1-100 pM), either in the absence or presence of prothrombin. The rate of assembly of prothrombinase in the presence of prothrombin appeared to be limited by the transfer rate of factor Xa to the phospholipid surface. A good agreement was found between the predicted mass transfer coefficient for factor Xa and the observed pre-steady state rate of thrombin production. The eventually obtained steady state rates of thrombin production were proportional to the prothrombin concentration and independent of the surface density of prothrombinase. The observed rate of thrombin production was in excellent agreement with the predicted mass transfer rate for prothrombin. Transport-limited prothrombin conversion was observed for prothrombinase densities exceeding 1 fmol/cm2, which corresponds to 0.05% occupation of available binding sites. The kinetic parameters of the reaction were determined at low prothrombinase densities (0.02-0.04 fmol/cm2). Even in this situation the Michaelis-Menten equation had to be corrected for substrate depletion near the catalytic surface. We hereto employed an accurate approximation of the mass transfer coefficient. The kinetic parameter kcat was 60 s-1 and the intrinsic Km had a surprisingly low value of 3 nM. Both parameters were not influenced by the wall shear rate. PMID- 7836356 TI - Non-cooperative binding of the MAP-2 microtubule-binding region to microtubules. AB - Microtubule-associated protein (MAP)-2 is a multi-domain cytoskeletal protein that copurifies with brain microtubules (MTs) through repeated cycles of warm polymerization and cold disassembly. Recent equilibrium binding studies of high molecular weight MAP-2ab to taxol-stabilized MTs suggest that the interactions are highly cooperative, as indicated by sigmoidal binding curves, non-linear Scatchard plots, and an apparent all-or-none response in MAP binding in titration experiments (Wallis, K. T., Azhar, S., Rho, M. B., Lewis, S. A., Cowan, N. J., and Murphy, D. B. (1993) J. Biol. Chem. 268, 15158-15167). To learn more about the mechanism of MAP-2 binding to MTs, we investigated the binding properties of bacterially expressed MT-binding region (MTBR) of bovine brain MAP-2. Scatchard plots of the binding data showed no evidence of cooperativity, as reflected by the linear plots of v/[MTBR]free versus v. The stoichiometry was 1-1.1 mol of MTBR/mol of tubulin dimer, and the dissociation constant for the MTBR was 1.1 microM. Bovine brain tau protein competitively inhibited MAP-2 binding, as evidenced by an increased Kd value for MTBR binding to MTs. Although the second repeat peptide m2 (VTSK-CGSLKNIRHRPGGG) is thought to play a dominant role in MAP 2 binding to MTs, a MTBR mutant (with m2 replaced by the third octadecapeptide repeat m3) displays an Kd of 2.8 +/- 0.1 microM and stoichiometry of 0.9 +/- 0.05 mol of MTBR/mol of tubulin dimer. Another mutant with additional copies of the second repeat, designated by us as MTBR[m12m2m32], displayed noncooperative binding with a Kd of 0.53 +/- 0.05 microM and a stoichiometry of 2.2 +/- 0.2 mol of mutant MTBR/tubulin dimer. Equilibrium sedimentation experiments demonstrated that the wild-type MTBR is monomeric, whereas MTBR[m12m2m32] self-associates to a stable dimer over the concentration range used in our MT binding studies. This finding indicates that only one of the two MT-binding sites on the dimer is probably linked to a microtubule at any given time. PMID- 7836357 TI - Truncation of the thyrotropin-releasing hormone receptor carboxyl tail causes constitutive activity and leads to impaired responsiveness in Xenopus oocytes and AtT20 cells. AB - We studied the activity of a truncated thyrotropin-releasing hormone receptor (TRH-R), which lacks the last 59 amino acids of the carboxyl tail, where Cys-335 was mutated to a stop codon (C335Stop) (Nussenzveig, D. R., Heinflink, M., and Gershengorn, M. C. (1993) J. Biol. Chem. 268, 2389-2392). In Xenopus laevis oocytes expressing C335Stop TRH-Rs, TRH binding was higher, whereas chloride current, 45Ca2+ efflux, and [Ca2+]i responses evoked by TRH were 23, 39, and 21%, respectively, of those in oocytes expressing wild type mouse pituitary TRH-Rs (WT TRH-Rs). In oocytes expressing C335Stop TRH-Rs, basal 45Ca2+ efflux and [Ca2+]i were twice those in oocytes expressing WT TRH-Rs; chelation of Ca2+ caused a rapid increase in holding current, which is consistent with basal activation; and coexpression with other receptors caused inhibition of the responses to the other cognate agonists. In AtT20 pituitary cells stably expressing C335Stop TRH-Rs, thyrotropin-releasing hormone (TRH)-independent inositol phosphate formation was 1.32 +/- 0.11-fold higher, basal [Ca2+]i was 1.8 +/- 0.2-fold higher, and the [Ca2+]i response to TRH was much lower than in cells expressing WT TRH-Rs. We conclude that a TRH-R mutant truncated at Cys-335 exhibits constitutive activity that results in desensitization of the response to TRH. PMID- 7836358 TI - The role of amphipathicity in the folding, self-association and biological activity of multiple subunit small proteins. AB - The effect that altering amphipathicity has on the folding process and self association of melittin, a small model protein, has been investigated using single amino acid substitutions of lysine 7, a residue distant from the contact residues involved in the hydrophobic core of tetrameric melittin. While substitutions of such a residue were not expected to interfere with the packing process, the largest alterations in the potential overall amphipathicity of melittin were found to prevent the folding into an alpha-helical conformation to occur and, in turn, to prevent the self association. Amphipathic alpha-helices were found to be a key determining feature in the early folding process of the self association of peptides and protein segments. Those substitutions, which prevented the inducible amphipathic folding ability, were also found to result in a loss in hemolytic and antimicrobial activity. These results, combined with studies of the binding to artificial liposomes and to polysialic acids, indicate that the losses in activity were due to an initial inability to be induced into an amphipathic alpha-helix and to self associate. Ultimately, melittin's self association is proposed to be required to penetrate the carbohydrate barrier present in biological membranes. PMID- 7836359 TI - Platelet shape change induced by thrombin receptor activation. Rapid stimulation of tyrosine phosphorylation of novel protein substrates through an integrin- and Ca(2+)-independent mechanism. AB - Activation of human platelets by the peptide YFLLRNP has been shown to induce shape change but not secretion, Ca2+ mobilization, or pleckstrin phosphorylation (Rasmussen, U.B., Gachet, C., Schlesinger, Y., Hanau, D., Ohlmann, P., Van Obberghen-Schilling, E., Pouyssegur, J., Cazenave, J.P., and Pavirani, A. (1993) J. Biol. Chem. 268, 14322-14328). YFLLRNP was added to washed human platelets that had been pretreated with EGTA at 37 degrees C or preincubated with the fibrinogen receptor antagonist RGDS to preclude the activation of the integrin alpha IIb beta 3 (fibrinogen receptor). YFLLRNP induced shape change and stimulated the tyrosine phosphorylation of proteins of 62, 68, and 130 kDa within 7 s. Tyrosine phosphorylation of these proteins reached maximum levels (2-3-fold) 15-30 s after addition of YFLLRNP and decreased subsequently. The chelation of intracellular Ca2+ by BAPTA-AM decreased basal tyrosine protein phosphorylation but did not inhibit the increase of tyrosine phosphorylation of P62, P68, and P130 or the shape change induced by YFLLRNP. Preincubation of platelets with the tyrosine kinase inhibitors genistein or tyrphostin A23 completely inhibited platelet shape change and protein tyrosine phosphorylation induced by YFLLRNP. The inactive structural analogs daidzein and tyrphostin A1 were barely inhibitory. P62, P68, and P130, which exhibited increased tyrosine phosphorylation upon stimulation with YFLLRNP, were found in the cytoskeleton. P130 was not identical to vinculin or the focal adhesion kinase pp125FAK. The results indicate that stimulation of G-protein-coupled thrombin receptors rapidly induces protein tyrosine kinase activation through a Ca(2+)- and integrin independent mechanism. Protein tyrosine kinase activation and tyrosine phosphorylation of novel protein substrates seem to play an essential role in the induction of platelet shape change. PMID- 7836360 TI - Degradation of the COL1 domain of type XIV collagen by 92-kDa gelatinase. AB - Type XIV collagen is a newly described member of the fibril-associated collagens with interrupted triple helices (FACITs). Expression of this collagen has been localized to various embryonic tissues, suggesting that it has a functional role in development. All FACITs thus far described (types IX, XII, XIV, and XVI) contain a highly homologous carboxyl-terminal triple helical domain designated COL1. We have studied the capacity of various matrix metalloproteinases (interstitial collagenase, stromelysin, matrilysin, and 92-kDa gelatinase) to degrade the COL1 domain of collagen XIV. We found that only 92-kDa gelatinase cleaves COL1. Furthermore, digestion of whole native collagen XIV by the 92-kDa gelatinase indicates that this enzyme specifically attacks the carboxyl-terminal triple helix-containing region of the molecule. COL1 is cleaved by 92-kDa gelatinase at 30 degrees C, a full 5-6 degrees C below the melting temperature (Tm) of this domain; native collagen XIV is also degraded at 30 degrees C. In comparison to interstitial collagenase degradation of its physiologic native type I collagen substrate, the 92-kDa enzyme cleaved COL1 (XIV) with comparable catalytic efficacy. Interestingly, following thermal denaturation of the COL1 fragment, its susceptibility to 92-kDa gelatinase increases, but only to a degree that leaves it several orders of magnitude less sensitive to degradation than denatured collagens I and III. These data indicate that native COL1 and collagen XIV are readily and specifically cleaved by 92-kDa gelatinase. They also suggest a role for 92-kDa gelatinase activity in the structural tissue remodeling of the developing embryo. PMID- 7836361 TI - The promoter of the salmon insulin-like growth factor I gene is activated by hepatocyte nuclear factor 1. AB - Hepatocyte nuclear factor 1 (HNF-1) was found to have a potent stimulatory action on the activity of the promoter of the salmon insulin-like growth factor I (IGF I) gene in transient transfection experiments. This liver-enriched transcription factor was shown to bind to an element in the proximal region of the promoter with distinct nucleotide sequence homology to the HNF-1 consensus binding sequence. Mutating this sequence to a variant no longer capable of HNF-1 binding resulted in the loss of the stimulatory effect. Since the sequence of the HNF-1 binding site is conserved in all mammalian, avian, and amphibian species from which the IGF-I promoter sequences have been derived to date, we propose that HNF 1 may be an important regulator of IGF-I gene expression in all of these species. PMID- 7836363 TI - Investigation of the early steps of molybdopterin biosynthesis in Escherichia coli through the use of in vivo labeling studies. AB - The early steps in the biosynthesis of the molybdopterin portion of the molybdenum cofactor have been investigated through the use of radiolabeled precursors. Labeled guanosine was added to growing cultures of the molybdopterin deficient Escherichia coli mutant, moeB, which accumulates large amounts of precursor Z, the final intermediate in molybdopterin biosynthesis (Wuebbens, M. M., and Rajagopalan, K. V. (1993) J. Biol. Chem. 268, 13493-13498). Precursor Z is readily oxidized to the stable, fluorescent pterin, compound Z, which contains all 10 of the carbon atoms present in molybdopterin. For these experiments, compound Z was isolated from both the cells and culture media and analyzed for the presence of label. The development of a method for sequential cleavage of the compound Z side chain carbons facilitated determination of the distribution of label between the ring and the side chain of compound Z. Addition of uniformly labeled [14C]guanosine to moeB cultures produced compound Z labeled in both the ring and the side chain. Growth on [8-14C]guanosine resulted in transfer of label to the C-1' position of compound Z. The label present in compound Z purified from cultures grown on [8,5'-3H]guanosine was lost by removal of the three terminal side chain carbons. These results indicate that although a guanosine compound serves as the initial precursor for molybdopterin biosynthesis, the early steps of this pathway in E. coli proceed via a pathway unlike that of any known pteridine biosynthetic pathway. PMID- 7836362 TI - Kinetics of bilirubin transfer between serum albumin and membrane vesicles. Insight into the mechanism of organic anion delivery to the hepatocyte plasma membrane. AB - Unconjugated bilirubin is transported in the plasma bound primarily to serum albumin, from which it is taken up and metabolized by the liver. To better characterize the mechanism of bilirubin delivery to the hepatocyte, stopped-flow techniques were utilized to study the kinetics of bilirubin transfer between serum albumin and both model phospholipid and native hepatocyte plasma membrane vesicles. The transfer process was best described by a single exponential function, with rate constants of 0.93 +/- 0.04, 0.61 +/- 0.03, and 0.10 +/- 0.01 s-1 (+/- S.D.) at 25 degrees C for human, rat, and bovine serum albumins, respectively. The observed variations in rate with respect to donor and acceptor concentrations provide strong evidence for the diffusional transfer of free bilirubin. Thermodynamic analysis suggests that the binding site on bovine serum albumin demonstrates higher specificity for the bilirubin molecule than that on human or rat serum albumin, which exhibit similar binding characteristics. Kinetic analysis of bilirubin transfer from rat serum albumin to isolated rat basolateral liver plasma membranes indicates that the delivery of albumin-bound bilirubin to the hepatocyte surface occurs via aqueous diffusion, rather than a collisional process, thereby mitigating against the presence of an "albumin receptor." PMID- 7836364 TI - Major histocompatibility class I molecules can present cryptic translation products to T-cells. AB - Self or foreign cellular proteins provide peptides for presentation by major histocompatibility complex (MHC) class I molecules on the surface of antigen presenting cells (APC). Surprisingly, several studies have shown that T-cells can recognize APC transfected with antigen genes that were not present in the appropriate translational context. To understand the basis of this phenomenon, APC were transfected with DNA constructs encoding the OVA257-264 (SL8) peptide, but with varying translation initiation codons. We report that, in addition to ATG, 6 other codons (ATT, ACG, CTG, GCG, TGG, GAT) also allowed presentation to SL8-Kb-specific T-cells. Significantly, this set includes 3 of 4 known non-ATG translation initiation codons strongly suggesting that cryptic translation accounts for this phenomenon. Although expression of the SL8-Kb complex was readily detected by T-cell activation, the amount of processed peptides was below detection limit (< 30 copies/cell) in cell extracts. Thus, the fortuitous presence of these cryptic translation initiation sites in transcribed genes can explain how peptide MHC complexes were obtained in sufficient amounts for T-cell activation. The translation initiation codons identified here could also be useful for identifying potential open reading frames that possess biological and/or immunological activities. PMID- 7836365 TI - Analysis of acyl coenzyme A binding to the transcription factor FadR and identification of amino acid residues in the carboxyl terminus required for ligand binding. AB - The Escherichia coli FadR protein regulates the transcription of many unlinked genes and operons encoding proteins required for fatty acid synthesis and degradation. Previously, we demonstrated that the ability of purified FadR to bind DNA in vitro is inhibited by long chain acyl coenzyme A esters (DiRusso, D. D., Heimert, T. L., and Metzger, A. K. (1992) J. Biol. Chem. 267, 8685-8691). In the present work, we show that FadR binds acyl-CoA directly. Ligand binding resulted in a shift in the apparent pI of FadR from 6.9 to 6.2 and in a marked decrease in intrinsic fluorescence. The Km for FadR binding of oleoyl coenzyme A was determined to be 12.1 nM using the fluorescence quenching assay. The binding site for acyl-CoA was identified by selection of non-inducible mutations in the FadR gene. One altered protein carrying the change Ser219 to Asn (S219N) was purified and shown to have a reduced affinity for oleoyl coenzyme A as evidenced by a Km of 257 nM. S219N retained the ability to bind DNA and to repress or activate transcription. Alanine substitution of amino acid residues 215 through 230 identified Gly216 and Trp223 as also required specifically for induction. This region of FadR shares amino acid identities and similarities with the coenzyme A-binding site of Clostridium thermoaceticum CO dehydrogenase/acetyl coenzyme A synthase. Due to the alteration in binding affinity of the purified S219N protein, the non-inducible phenotype of several proteins carrying alanine substitutions and similarities to CO dehydrogenase/acetyl-coenzyme A synthase we propose this region of FadR forms part of the acyl-CoA-binding domain. PMID- 7836366 TI - The FET3 gene product required for high affinity iron transport in yeast is a cell surface ferroxidase. AB - The yeast FET3 gene is required for high affinity iron transport (Askwith, C., Eide, D., Ho, A. V., Bernard, P. S., Li, L., Davis-Kaplan, S., Sipe, D. M., and Kaplan, J. (1994) Cell 76, 403-410). The gene has extensive sequence homology to the family of multi-copper oxidases. In this communication, we demonstrate that the gene product is a cell surface ferroxidase involved in iron transport. Cells that contain a functional FET3 gene product exhibited an iron-dependent non mitochondrial increase in oxygen consumption. Comparison of the rate of iron oxidation to O2 consumption yielded an approximate value of 4:1, as predicted for a ferroxidase. Spheroplasts obtained from cells grown under low iron conditions also displayed an iron-dependent increase in O2 consumption. Treatment of spheroplasts with trypsin or affinity-purified antibodies directed against the putative external ferroxidase domain of Fet3 had no effect on basal O2 consumption but inhibited the iron-dependent increase in O2 consumption. Anti peptide antibodies directed against the cytosolic domain of Fet3 had no effect on O2 consumption. These studies indicate that Fet3 is a plasma membrane ferroxidase required for high affinity iron uptake, in which the ferroxidase-containing domain is localized on the external cell surface. PMID- 7836367 TI - Evidence of increased glyceraldehyde-3-phosphate dehydrogenase and fatty acid synthetase promoter activities in transiently transfected adipocytes from genetically obese rats. AB - Previous studies have shown that the adipose tissue of young genetically obese Zucker rats was characterized by a coordinate overtranscription of lipogenic genes, suggesting that the fa mutation triggers transcription factor(s) acting in common on the promoters of these genes. To test this hypothesis, we developed a system of transient transfection of rat adipocytes with constructs containing glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and fatty acid synthetase (FAS) promoters fused to gene reporter CAT. Those transfected cells expressed high levels of promoter-driven chloramphenicol acetyltransferase (CAT) activity through correctly initiated transcription as shown by primer extension analysis. Using this system we found a direct effect of insulin on GAPDH and FAS gene expression in rat adipocytes. In transfected adipocytes from obese compared to lean rats, activity of GAPDH and FAS promoters fused to CAT, was 2.6- and 8-fold increased, respectively. In contrast when reporter gene activity was driven by either phosphoenolpyruvate carboxykinase or beta-actin promoter, no difference could be observed between lean and obese, pointing out the promoter specificity of genotype effect. 5' deletion analysis of GAPDH promoter allowed us to narrow down the fa responsive region to nucleotide -488-329. As assessed by gel retardation and DNase I footprinting analysis, adipocyte nuclear protein interactions to this 159-bp fragment were found to be identical and to footprint the same 20-bp sequence. This study pointed out that overexpression of GAPDH and FAS genes in adipose tissue of genetically obese rats relies on promoter activation, through a 159-bp cis-acting region within the GAPDH promoter. The effects of the fa mutation on trans-acting factors binding to this region remain to be identified. PMID- 7836368 TI - The retinal pigment epithelial-specific 11-cis retinol dehydrogenase belongs to the family of short chain alcohol dehydrogenases. AB - We have isolated and partially characterized a 32-kDa membrane-associated protein (p32), which forms a complex with p63, an abundant membrane protein in bovine retinal pigment epithelium. The sequence of a cDNA clone for p32 revealed an open reading frame encoding 318 amino acid residues. Several hydrophobic regions could be identified, suggesting that p32 is an integral membrane protein. A search of data bases identified p32 as a member of the superfamily of short chain alcohol dehydrogenases. Transcripts for p32 were specifically expressed in retinal pigment epithelium. Overexpression of p32 in Cos cells produced a membrane-bound stereospecific 11-cis retinol dehydrogenase, active in the presence of NAD+ as cofactor but not in the presence of NADP. We propose that p32 is the stereospecific 11-cis retinol dehydrogenase, which catalyzes the final step in the biosynthesis of 11-cis retinaldehyde, the universal chromophore of visual pigments. PMID- 7836369 TI - Existence of branched side chains in the cell wall mannan of pathogenic yeast, Candida albicans. Structure-antigenicity relationship between the cell wall mannans of Candida albicans and Candida parapsilosis. AB - Isolation of side chain oligosaccharides from mannans of Candida albicans NIH B 792 (serotype B) and Candida parapsilosis IFO 1396 strains has been conducted by acetolysis under mild conditions. Structural study of these oligosaccharides by 1H and 13C NMR and methylation analyses indicated the presence of novel branched side chains with the following structures in C. albicans mannan. [sequence: see text] It was observed that the H-1 proton chemical shifts of the second and the third mannose units from the reducing terminus in each oligosaccharide are shifted upfield by substitution with an alpha-linked mannose unit at position 6 of the 3-O-substituted mannose unit. An agglutination inhibition assay between factor 4 serum and cells of Candida stellatoidea IFO 1397 lacking the beta-1,2 linked mannose unit, with oligosaccharides obtained from these mannans, indicated that only the branched oligosaccharides were active. This finding suggests that the branched oligosaccharides correspond to the epitope of antigenic factor 4. The presence of the branched structure in other mannans was detected by the characteristic H-1-H-2-correlated cross-peak of the alpha-1,2-linked mannose unit connected with the 3,6-di-O-substituted one by two-dimensional homonuclear Hartmann-Hahn spectroscopy. PMID- 7836370 TI - A new conotoxin affecting sodium current inactivation interacts with the delta conotoxin receptor site. AB - We describe a new peptide conotoxin affecting sodium current inactivation, that competes on binding with delta-conotoxin TxVIA (delta TxVIA). The amino acid sequence of the new toxin, designated conotoxin NgVIA (NgVIA), is SKCFSOGTFCGIKOGLCCSVRCFSLFCISFE (where O is trans-4-hydroxyproline). The primary structure of NgVIA has an identical cysteine framework and similar hydrophobicity as delta TxVIA but differs in its net charge. NgVIA competes with delta TxVIA on binding to rat brain synaptosomes and molluscan central nervous system and strongly inhibits sodium current inactivation in snail neurons, as does delta TxVIA. In contrast to delta TxVIA, NgVIA is a potent paralytic toxin in vertebrate systems, its binding appears to be voltage-dependent, and it synergically increases veratridine-induced sodium influx to rat brain synaptosomes. delta TxVIA acts as a partial antagonist to NgVIA in rat brain in vivo. NgVIA appears to act via a receptor site distinct from that of delta TxVIA but similar to that of Conus striatus toxin. This new toxin provides a lead for structure-function relationship studies in the delta-conotoxins and will enable analysis of the functional significance of this complex of receptor sites in gating mechanisms of sodium channels. PMID- 7836371 TI - Phosphorylation of the N-formyl peptide receptor carboxyl terminus by the G protein-coupled receptor kinase, GRK2. AB - Attenuation of receptor-mediated signal amplification in response to external stimuli, an essential step in the balance of cellular activation, may be mediated by receptor phosphorylation. We have recently shown that the carboxyl-terminal cytoplasmic domain of the N-formyl peptide receptor (FPR) interacts with G proteins and demonstrate here that this same region of the FPR is specifically phosphorylated by a neutrophil cytosolic kinase with properties similar to the G protein-coupled receptor kinase, GRK2. Both kinase activities show a lack of sensitivity toward protein kinase A, protein kinase C, and tyrosine kinase inhibitors but demonstrate almost identical sensitivity toward the kinase inhibitor heparin. Kinetic studies demonstrated that GRK2 has a Km for the carboxyl-terminal domain of the FPR of approximately 1.5 microM and that denaturation of the substrate results in an almost complete loss of phosphorylation. Comparative studies reveal that GRK3 has approximately 50% of the activity of GRK2 toward the FPR carboxyl terminus, whereas GRK5 and GRK6 have no detectable activity. Site-directed mutagenesis of numerous regions of the FPR carboxyl terminus demonstrated that, whereas Glu326/Asp327 and Asp333 are critical for phosphorylation, the carboxyl-terminal 10 amino acids are not required. Simultaneous substitution of Thr334, Thr336, Ser338, and Thr339 resulted in an approximately 50% reduction in phosphorylation, whereas simultaneous substitution of the upstream Ser328, Thr329, Thr331, and Ser332 or merely the Ser328 and Thr329 residues resulted in an approximately 80% reduction in phosphorylation. The introduction of negatively charged glutamate residues for Ser328 and Thr329 or Thr331 and Ser332 resulted in marked stimulation of phosphorylation. These results suggest a hierarchical mechanism in which phosphorylation of amino-terminal serine and threonine residues is required for the subsequent phosphorylation of carboxyl-terminal residues. These results provide the first direct evidence that an intracellular domain of a chemoattractant receptor is a high affinity substrate for GRK2 and further suggest a role for GRK2 or a closely related kinase in the attenuation of receptor-mediated activation of inflammatory cells. PMID- 7836372 TI - Homologous proteins with different affinities for groEL. The refolding of the aspartate aminotransferase isozymes at varying temperatures. AB - The homologous cytosolic and mitochondrial isozymes of aspartate aminotransferase (c- and mAspAT, respectively) seem to follow very different folding pathways after synthesis in rabbit reticulocyte lysate, suggesting that the nascent proteins interact differently with molecular chaperones (Mattingly, J. R., Jr., Iriarte, A., and Martinez-Carrion, M. (1993) J. Biol. Chem. 268, 26320-26327). In an attempt to discern the structural basis for this phenomenon, we have begun to study the effect of temperature on the refolding of the guanidine hydrochloride denatured, purified proteins and their interaction with the groEL/groES molecular chaperone system from Escherichia coli. In the absence of chaperones, temperature has a critical effect on the refolding of the two isozymes, with mAspAT being more susceptible than cAspAT to diminishing refolding yields at increasing temperatures. No refolding is observed for mAspAT at physiological temperatures. The molecular chaperones groEL and groES can extend the temperature range over which the AspAT isozymes successfully refold; however, cAspAT can still refold at higher temperatures than mAspAT. In the absence of groES and MgATP, the two isozymes interact differently with groEL, groEL arrests the refolding of mAspAT throughout the temperature range of 0-45 degrees C. Adding only MgATP releases very little mAspAT from groEL; both groES and MgATP are required for significant refolding of mAspAT in the presence of groEL. On the other hand, the extent to which groEL inhibits the refolding of cAspAT depends upon the temperature of the refolding reaction, only slowing the reaction at 0 degrees C but arresting it completely at 30 degrees C. MgATP alone is sufficient to effect the release of cAspAT from groEL at any temperature examined; inclusion of groES along with MgATP has no effect on the refolding yield but does increase the refolding rate at temperatures greater than 15 degrees C. These results demonstrate that groEL can have significantly different affinities for proteins with highly homologous final tertiary and quarternary structures and suggest that dissimilarities in the primary sequence of the protein substrates may control the structure of the folding intermediates captured by groEL and/or the composition of the surfaces through which the folding proteins interact with groEL. PMID- 7836373 TI - Capacitative Ca2+ entry exclusively inhibits cAMP synthesis in C6-2B glioma cells. Evidence that physiologically evoked Ca2+ entry regulates Ca(2+) inhibitable adenylyl cyclase in non-excitable cells. AB - Elevation of cytosolic free Ca2+ inhibits the type VI adenylyl cyclase that predominates in C6-2B cells. However, it is not known whether there is any selective requirement for Ca2+ entry or release for inhibition of cAMP accumulation to occur. In the present study, the effectiveness of intracellular Ca2+ release evoked by three independent methods (thapsigargin, ionomycin, and UTP) was compared with the capacitative Ca2+ entry that was triggered by these treatments. In each situation, only Ca2+ entry could inhibit cAMP accumulation (La3+ ions blocked the effect); Ca2+ release, which was substantial in some cases, was without effect. A moderate inhibition, as was elicited by a modest degree of Ca2+ entry, could be rendered substantial in the absence of phosphodiesterase inhibitors. Such conditions more closely mimic the physiological situation of normal cells. These results are particularly significant, in demonstrating not only that Ca2+ entry mediates the inhibitory effects of Ca2+ on cAMP accumulation, but also that diffuse elevations in [Ca2+]i are ineffective in modulating cAMP synthesis. This property suggests that, as with certain Ca(2+)-sensitive ion channels, Ca(2+)-sensitive adenylyl cyclases may be functionally colocalized with Ca2+ entry channels. PMID- 7836374 TI - Multiple dual specificity protein tyrosine phosphatases are expressed and regulated differentially in liver cell lines. AB - An emerging subclass of protein-tyrosine phosphatases (PTPases) exhibits sequence identity to the vaccinia H-1 (VH-1) gene product. These VH-1-like PTPases possess the canonical HCXAGXXR(S/T) sequence common to all PTPases, but unlike other PTPases they exhibit dual catalytic activity toward phosphotyrosine and nearby phosphothreonine residues in substrate proteins. We have isolated a novel VH-1 like PTPase, hVH-3, from the human placenta and compared various aspects of its expression with previously isolated members of this subfamily. The mammalian members of this subfamily including hVH-3 commonly localize to the nucleus and exhibit catalytic activity toward phosphorylated extracellular signal-regulated kinase. However, while the expression of some VH-1-like PTPases is extremely transient and independent of protein synthesis, hVH-3 expression is sustained over 3 h after being cell stimulated. Tissue-specific expression of hVH-3 is also distinct from other VH-1-like PTPases. Although VH-1-like PTPases have overlapping substrate specificity, there are differences in their mRNA regulation, response to extracellular stimuli, and tissue-specific expression, suggesting they serve specific roles in cellular function. PMID- 7836375 TI - Cooperation by sterol regulatory element-binding protein and Sp1 in sterol regulation of low density lipoprotein receptor gene. AB - Regulation of the low density lipoprotein (LDL) receptor promoter by cholesterol requires a well defined sterol regulatory site and an adjacent binding site for the universal transcription factor Sp1. These elements are located in repeats 2 and 3 of the wild type promoter, respectively. The experiments reported here demonstrate that Sp1 participates in sterol regulation of the LDL receptor in an orientation-specific fashion. We present data which suggest that sterol regulatory element-binding protein (SREBP) increases the binding of Sp1 to the adjacent repeat 3 sequence. We also demonstrate that SREBP and Sp1 synergistically activate expression from the LDL receptor promoter inside the cell by cotransfecting expression vectors encoding each protein into Drosophila tissue culture cells that are devoid of endogenous Sp1. In addition, other transcription factor sites were unable to substitute for Sp1 in sterol regulation when placed next to the SREBP-binding site. These studies together with recent data from others provide the basis of a working model for sterol regulation of the LDL receptor promoter. The presence of Sp1 sites in several other regulated promoters suggests that this universal transcription factor has been recruited to participate in many regulatory responses possibly by a similar mechanism. PMID- 7836376 TI - Architecture of the yeast cell wall. The linkage between chitin and beta(1-->3) glucan. AB - To isolate the putative linkage region between chitin and beta(1-->3)-glucan, Saccharomyces cerevisiae cell walls were digested with beta(1-->3)-endoglucanase and the reducing ends of the enzyme-resistant glucose chain stubs were labeled by reduction with borotritide. The radioactive material was further digested with exochitinase to remove the bulk of the chitin, and the liberated oligosaccharides were fractionated on a sizing column. A single peak (compound I) was found to consist of N-acetylglucosamine, glucose, and glucitol residues in the ratio 1:2:1. By digestion with beta-N-acetylglucosaminidase and by NMR spectroscopy, N acetylglucosamine was identified as the nonreducing terminus, linked to laminaritriitol by a beta(1-->4) bond. Five additional oligosaccharides were recovered, two being analogs of compound I, with 1 or 3 glucose units, respectively; the remaining three were shown to be the reduced analogs of laminaribiose, laminaritriose, and laminaritetraose. The presence of N acetylglucosamine-containing oligosaccharides arises from the activity of chitinase in cleaving 2 sugar units sequentially in those chains containing an odd number of N-acetylglucosamine residues; correspondingly, oligosaccharides containing only glucose and sorbitol derived from even-numbered chitin chains, a result implying that chitinase can hydrolyze the linkage between N acetylglucosamine and glucose. It is concluded that the terminal reducing residue of a chitin chain is attached to the nonreducing end of a beta(1-->3)-glucan chain by a beta(1-->4) linkage. Experiments with appropriate mutants showed that synthesis of the chitin combined with glucan is catalyzed by chitin synthetase 3. The timing and possible mechanism of formation of the chitin-glucan linkage is discussed. PMID- 7836377 TI - Detection and characterization of a transport system mediating cysteamine entry into human fibroblast lysosomes. Specificity for aminoethylthiol and aminoethylsulfide derivatives. AB - The uptake of [3H]cysteamine by Percoll-purified human fibroblast lysosomes was investigated to determine whether lysosomes contain a transport system recognizing cysteamine. Lysosomal cysteamine uptake is a Na(+)-independent process which rapidly attains a steady state within 1 min at pH 7.0 and 37 degrees C. A biphasic Arrhenius plot is observed for cysteamine uptake, giving a Q10 of 2.2 from 17 to 26 degrees C and a Q10 of 1.2 from 27 to 35 degrees C. The rate of lysosomal cysteamine uptake is maximal at pH 8.2, half-maximal at pH 6.8, and declines approximately 50-fold from the maximum to show very little transport at pH 5.0. Cysteamine uptake into fibroblast lysosomes displays complete saturability with a Km of 0.88 mM and Vmax of 1410 pmol of beta-N acetylhexosaminidase/min at pH 7.0 and 37 degrees C. Analog inhibition studies demonstrated that all analogs recognized thus far by the cysteamine carrier are either aminothiols or aminosulfides and contain an amino group and sulfur atom separated by a carbon chain, 2 carbon atoms in length. The Ki constants for these analogs as competitive inhibitors of lysosomal cysteamine uptake are 2 (ethylthio)ethylamine (0.64 mM), 1-amino-2-methyl-2-propanethiol (0.74 mM), 2 dimethylaminoethanethiol (0.87 mM), thiocholine (1.6 mM), and bis(2 aminoethyl)sulfide (4.9 mM). L-Cysteine, D-penicillamine, and analogs lacking either a sulfur atom or amino group are not recognized by the cysteamine carrier including ethanolamine, choline, taurine, beta-mercaptoethanol, ethylenediamine, cadaverine, spermine, spermidine, histamine, dopamine, and 3-hydroxytyramine. In a cystine-depletion assay, a 2-h exposure of cystinotic fibroblasts to 1 mM 1 amino-2-methyl-2-propanethiol lowers cell cystine levels to the same low level obtained with cysteamine. Thus, all four aminothiols, known to deplete cystinotic fibroblasts of their accumulated cystine, are recognized as substrates by the lysosomal cysteamine carrier, suggesting the importance of this transporter in the delivery of aminothiols to the lysosomal compartment. PMID- 7836378 TI - In vitro characterization of the mitochondrial processing and the potential function of the 68-kDa subunit of renal glutaminase. AB - Rat renal mitochondrial glutaminase (GA) is initially synthesized in primary cultures of proximal tubule cells as a 74-kDa precursor and is processed via a 72 kDa intermediate to generate a heterotetrameric enzyme which contains three 66 kDa subunits and one 68-kDa subunit (Perera, S. Y., Chen, T. C., and Curthoys, N. P. (1990) J. Biol. Chem. 265, 17764-17770). The two mature subunits may be derived by either of two possible mechanisms: 1) alternative proteolytic processing or 2) initial synthesis of the 66-kDa subunit followed by its covalent modification to generate the 68-kDa subunit. An in vitro system was utilized to further characterize this unique processing pathway and to investigate the potential function of the 68-kDa subunit. In vitro transcription and translation of the GA cDNA yields a single 74-kDa precursor. Upon incubation with isolated rat liver mitochondria, the precursor is translocated into the mitochondria and processed via a 72-kDa intermediate to yield a 3:1 ratio of the 66- and 68-kDa subunits, respectively. The kinetics of the in vitro processing reaction also closely approximate the kinetics observed in cultured cells. Mitochondrial processing is blocked by o-phenanthroline, an inhibitor of the matrix processing peptidase (MPP). The 72-amino acid presequence of the 66-kDa subunit contains a large proportion of basic amino acids. Two-dimensional gel electrophoresis of mature GA established that the 68-kDa subunit is slightly more basic than the 66 kDa subunit. In addition, incubation of the 74-kDa precursor with purified MPP yields equimolar amounts of the two mature peptides. A cDNA construct, p delta GA, was created which lacks the nucleotides that encode the amino acid residues 32 through 72 of GA. When transcribed and translated in vitro, p delta GA yields a 70-kDa precursor. This precursor is processed by mitochondria to a single mature subunit with a M of 66 kDa. This observation suggests that the 68-kDa subunit is not produced by covalent modification of the 66-kDa subunit and further supports the conclusion that the two mature subunits of GA are produced by alternative processing reactions which can be catalyzed by MPP. However, the yield of products obtained in intact mitochondria may be determined by some unidentified accessory factor. Submitochondrial fractionation of imported GA and delta GA precursors suggest that the 68-kDa subunit may function to retain the mature GA within the mitochondrial matrix. PMID- 7836379 TI - Role of the N-terminal 118 amino acids in the processing of the rat renal mitochondrial glutaminase precursor. AB - Rat renal mitochondrial glutaminase (GA) is synthesized as a 74-kDa cytosolic precursor that is translocated into mitochondria and processed via a 72-kDa intermediate to yield a 3:1 ratio of mature 66- and 68-kDa subunits, respectively. The 66-kDa subunit is derived by removal of a 72-amino-acid presequence. The structural determinants necessary for translocation and proteolytic processing were further delineated by characterizing the processing of different chimeric constructs formed by fusing various segments of the N terminal sequence of the GA precursor to chloramphenicol acetyl transferase (CAT). GA1-118 CAT is translocated and processed in isolated rat liver mitochondria or cleaved by purified mitochondrial processing peptidase (MPP) to yield an intermediate peptide and two mature subunits that are analogous to the products of processing of the GA precursor. The two reactions also occur with kinetics which are similar to those observed for processing of the GA precursor. Thus, all of the information required for the translocation and synthesis of the mature subunits of GA reside in the N-terminal 118 amino acids of the GA precursor. In contrast, GA1-72 CAT, a construct that contains the GA presequence fused to CAT, is apparently translocated and processed less efficiently. It yields only two peptides that are analogous to the intermediate and 68 kDa forms of GA. In addition, GA1-31 CAT associates with mitochondria but is not proteolytically processed and GA1-31,73-118 CAT is slowly translocated and processed to a single peptide that is analogous to the 66 kDa form of GA. The latter results suggest that the MPP cleavage reactions which yield the GA intermediate and the 66-kDa subunit depend primarily on information that is present C-terminal to the respective sites of cleavage. PMID- 7836380 TI - DT-diaphorase. Redox potential, steady-state, and rapid reaction studies. AB - NAD(P)H:quinone oxidoreductase (DT-diaphorse) appears to be a 2-electron transfer flavoprotein, which catalyzes the conversion of quinones into hydroquinones. Upon photoreduction in the presence of dimethylformamide, the enzyme forms a red semiquinone. In the absence of dimethylformamide, only 10% of the radical form is thermodynamically stabilized. This indicates a redox potential of the enzyme bound semiquinone/reduced flavin couple that is higher than the midpoint potential for the oxidized flavin/semiquinone couple. The 2-electron redox potential was determined to be -159 +/- 3 mV at 25 degrees C, pH 7.0. In the presence of benzoquinone or 3-aminopyridine adenine dinucleotide phosphate, as NADPH analogue, there is no change in the redox properties of the enzyme flavin. A significant decrease is observed in the presence of the competitive inhibitor dicumarol (Em = -234 +/- 2 mV at pH 7.0). The reaction mechanism of the flavoprotein has been investigated by steady-state and stopped-flow kinetic methods using NADPH, NADH, deamino-NADPH, and 3-acetylpyridine adenine dinucleotide reduced form (APADH) as electron donors and K3Fe(CN)6, 4,5-dihydro 4,5-dioxo-1H-pyrrolo-[2,3-f]quinoline-2,7,9-tricarboxylic acid (PQQ), and 2,5 diaziridinyl-3,6-bis(carboethoxy-amino)-1,4-benzoquinone (AZQ) as electron acceptors in 50 mM phosphate buffer, pH 7.0, 25 degrees C. No evidence could be obtained to indicate that semiquinoid intermediates play a part in the catalytic mechanism of DT-diaphorase with quinones as acceptors. The rates of the reduction by NADPH, NADH, deamino-NADPH, and APADH (1.3 x 10(9), 8.8 x 10(8), 8.3 x 10(8) and 9.8 x 10(8) m-1 min-1, respectively) as well as the rates of the reoxidation by PQQ and AZQ (9 x 10(4) and 2.8 x 10(6) M-1 min-1, respectively) are directly proportional to substrate concentration, and there is no evidence of the formation of enzyme-substrate complexes. If such complexes do indeed exist, the affinity of the enzyme for substrate must be extremely low. Using K3Fe(CN)6 as electron acceptor, the rate of oxidation of fully reduced enzyme is 4.6 x 10(7) M 1 min-1 and it is accurately proportional to ferricyanide concentration. This rate represents that of flavin semiquinone formation, with the subsequent oxidation of the semiquinone being much faster, since no spectral evidence for semiquinone formation could be obtained. Studies were also conducted attempting to use apo-DT-diaphorase reconstituted with PQQ as coenzyme. The lack of activity toward AZQ, K3Fe(CN)6, and menadione suggests that DT-diaphorase can use PQQ only as electron acceptor and not as redox cofactor. PMID- 7836381 TI - How 434 repressor discriminates between OR1 and OR3. The influence of contacted and noncontacted base pairs. AB - The sequence of the bacteriophage 434 OR1 (ACAAAACTTTCTTGT) differs from its OR3 (ACAGTTTTCTTGT) at positions 4-6. X-ray analysis shows that the side chain of Gln33 of the 434 repressor makes van der Waals' and H-bond contacts with the T at position 4' in complex with OR1, but no specific contact is observed at this position in 434 repressor-OR3 complexes. No contacts are made by repressor to the bases at positions 5 or 6 in either binding site. The significance of the sequence differences between OR1 and OR3 in determining the operator affinity for repressor were examined by constructing synthetic variants of these operators. Measurements of the affinity of these operators for repressor as a function of ionic strength revealed that although base pairs 5 and 6 are not contacted by 434 repressor, they can nonetheless influence operator affinity for repressor by modulating the degree to which ionic interactions contribute to the overall binding energy. Both the magnitude and direction of their effect depends on the status of repressor's contacts to the bases at position 4. The role of contact made by Gln33 to position 4 was examined by mutating this amino acid to Ala and by examining the affinity of wild type repressor for an operator bearing a 5 methylcytosine at position 4' in an OR1-4G mutant. These experiments showed that repressor's preferences at operator positions 5 and 6 are linked to its position 4 preference via a van der Waals' contact between amino acid 33 and a methyl group on the base at operator position 4'. Together, the results of the experiments shown here reveal that bases that do not contact the protein alter its preferences for bases at the contacted operator position 4. PMID- 7836382 TI - Mapping peptide-binding domains of the substance P (NK-1) receptor from P388D1 cells with photolabile agonists. AB - The tachykinin substance P (SP) is a peptide transmitter of primary afferents. Its actions on both central and peripheral targets are mediated by a G-protein coupled receptor of known primary structure. To identify contact sites between the undecapeptide SP and its receptor, we prepared radiolabeled photoreactive analogs of SP (H-RPKPQQFFGLM-NH2) by replacing amino acids in the peptide with p benzoyl-L-phenylalanine (BPA). SP, BPA3-SP, and BPA8-SP bind with high affinity (Kd < 3 nM) to SP receptors on the murine cell line P388D1, triggering intracellular calcium responses. Both binding and calcium responses are blocked by the specific SP receptor antagonist CP-96345. On photolysis, radioiodinated BPA3-SP, and BPA8-SP covalently label a heterogeneously glycosylated protein of about 75 kDa; labeling is abolished by excess unlabeled SP or CP-96345. The labeled receptors were digested with V8 protease and/or trypsin, and the resulting fragments were analyzed by electrophoresis, high pressure liquid chromatography, and chemical or enzymatic modification. BPA3-SP and BPA8-SP photo incorporate into different regions of the murine SP receptor. The results establish that the third and the eighth positions of SP, respectively, interact with the NH2-terminal extracellular tail (residues 1-21) and second extracellular loop (residues 173-183) of the SP receptor. A model for the agonist peptide binding sites of the SP receptor is proposed based on photoaffinity labeling and mutagenesis studies. PMID- 7836383 TI - Murine transcription factor alpha A-crystallin binding protein I. Complete sequence, gene structure, expression, and functional inhibition via antisense RNA. AB - alpha A-crystallin binding protein I (alpha A-CRYBP1) is a ubiquitously expressed DNA binding protein that was previously identified by its ability to interact with a functionally important sequence in the mouse alpha A-crystallin gene promoter. Here, we have cloned a single copy gene with 10 exons spanning greater than 70 kb of genomic DNA that encodes alpha A-CRYBP1. The mouse alpha A-CRYBP1 gene specifies a 2,688-amino acid protein with 72% amino acid identity to its human homologue, PRDII-BF1. Both the human and the mouse proteins contain two sets of consensus C2H2 zinc fingers at each end as well a central nonconsensus zinc finger. The alpha A-CRYBP1 gene produces a 9.5-kb transcript in 11 different tissues as well as a testis-specific, 7.7-kb transcript. alpha A-CRYBP1 cDNA clones were isolated from adult mouse brain and testis as well as from cell lines derived from mouse lens (alpha TN4-1) and muscle (C2C12). A single clone isolated from the muscle C2C12 library contains an additional exon near the 5'-end that would prevent production of a functional protein if the normal translation start site were utilized; however, there is another potential initiation codon located downstream that is in frame with the rest of the coding region. In addition, we identified multiple cDNAs from the testis in which the final intron is still present. Finally, we used an antisense expression construct derived from an alpha A-CRYBP1 cDNA clone to provide the first functional evidence that alpha A-CRYBP1 regulates gene expression. When introduced into the alpha TN4-1 mouse lens cell line, the antisense construct significantly inhibited expression from a heterologous promoter that utilized the alpha A-CRYBP1 binding site as an enhancer. PMID- 7836384 TI - Purification and characterization of hypoxia-inducible factor 1. AB - Hypoxia-inducible factor 1 (HIF-1) is a DNA-binding protein that activates erythropoietin (Epo) gene transcription in Hep3B cells subjected to hypoxia or cobalt chloride treatment. HIF-1 DNA binding activity is also induced by hypoxia or cobalt in non-Epo-producing cells, suggesting a general role for HIF-1 in hypoxia signal transduction and transcriptional regulation. Here we report the biochemical purification of HIF-1 from Epo-producing Hep3B cells and non-Epo producing HeLa S3 cells. HIF-1 protein was purified 11,250-fold by DEAE ion exchange and DNA affinity chromatography. Analysis of HIF-1 isolated from a preparative gel shift assay revealed four polypeptides. Peptide mapping of these HIF-1 components demonstrated that 91-, 93-, and 94-kDa polypeptides had similar tryptic maps, whereas the 120-kDa polypeptide had a distinct profile. Glycerol gradient sedimentation analysis suggested that HIF-1 exists predominantly in a heterodimeric form and to a lesser extent as a heterotetramer. Partially purified HIF-1 bound specifically to the wild-type HIF-1 binding site from the EPO enhancer but not to a mutant sequence that lacks hypoxia-inducible enhancer activity. UV cross-linking analysis with purified HIF-1 indicated that both subunits of HIF-1 contact DNA directly. We conclude that in both cobalt chloride treated HeLa cells and hypoxic Hep3B cells HIF-1 is composed of two different subunits: 120-kDa HIF-1 alpha and 91-94-kDa HIF-1 beta. PMID- 7836385 TI - A temperature-dependent conformational rearrangement in the ribosomal protein S4.16 S rRNA complex. AB - Ribosomal protein S4 protects a characteristic set of bases in 16 S rRNA from attack by chemical probes. Use of hydroxyl radical as a probe of the RNA backbone shows that ribose residues in these same regions are also protected by S4, confirming the localization of its interactions with 16 S rRNA to the junction of five helical elements in the proximal region of the 5' domain. At 0 degrees C, the nucleotides protected by S4 from base-specific probes are confined almost exclusively to the two compound helices formed by residues 404-499. After subsequent heating of the complex briefly at 30 or 42 degrees C, nucleotides in the three adjacent helices are additionally protected, resulting in a pattern of protection that is identical to that which is observed when S4 is incubated with 16 S rRNA under in vitro reconstitution conditions. Preincubation of the protein or the RNA (or both) separately at elevated temperature does not substitute for heating the S4.RNA complex. The regions in the RNA affected by the heat step are known to interact with proteins S12 and S16, both of which depend upon S4 for their binding to the RNA. Thus, the finding that S4 recruits additional sites of interaction in the RNA following its initial binding suggests a possible mechanism to insure the sequential addition of proteins during ribosomal assembly. PMID- 7836386 TI - Site-directed mutagenesis of human glutathione transferase P1-1. Mutation of Cys 47 induces a positive cooperativity in glutathione transferase P1-1. AB - Glutathione transferase P1-1 (EC 2.5.1.18) is a dimeric enzyme composed of identical subunits each containing one binding site for GSH and a second for the co-substrate e.g. 1-chloro-2,4-dinitrobenzene. Steady-state kinetics are strictly hyperbolic toward both these substrates. Replacement of Cys-47 with alanine or serine decreases the affinity for GSH and triggers a positive kinetic cooperativity with respect to the substrate. Hill coefficients were 1.31 and 1.43 for the C47A and C47S mutants. C47A/C101S and C47S/C101S double mutants display lower affinity for GSH and higher Hill coefficients (1.57 and 1.56, respectively) when compared with C47A and C47S single mutants. Conversely, replacement of Cys 101 with alanine or serine does not yield any cooperativity and any marked change of kinetic parameters. Fluorometric experiments gave sigmoidal isothermic GSH binding curves for all the Cys-47 mutants, with Hill coefficients similar to that obtained by the kinetic approach. These data, together with the activation experiments performed in the presence of S-hexylglutathione, suggest that the substitution of Cys-47 yields a dimeric low-affinity enzyme which may be revealed by the lack of a peculiar electrostatic bond between the thiolate form of Cys-47 and the protonated amino group of Lys-54. PMID- 7836387 TI - Site-directed mutagenesis of human glutathione transferase P1-1. Spectral, kinetic, and structural properties of Cys-47 and Lys-54 mutants. AB - In the human placental glutathione transferase, Cys-47 possesses, at physiological pH values, a pK alpha value of 4.2 and may exist as an ion pair with the protonated epsilon-amino group of Lys-54. Using site-directed mutagenesis we investigate spectral, kinetic, and structural properties of Cys-47 and Lys-54 mutants. The results shown indicate that the thiolate ion detected at 229 nm should be assigned exclusively to Cys-47. The contribution of Lys-54 to the activation of Cys-47 is assessed by the spectral properties of the K54A mutant enzyme. The induced cooperativity toward glutathione, as a consequence of mutation of Lys-54 to alanine, clearly parallels that observed for the Cys-47 mutant enzymes (see the preceding paper (Ricci, G., Lo Bello, M., Caccuri, A. M., Pastore, A., Nuccetelli, M., Parker, M. W., and Federici, G. (1995) J. Biol. Chem. 270, 1243-1248) and points out the importance of this electrostatic interaction in shaping the correct spatial arrangement for the binding of glutathione and in anchoring the flexible helix alpha 2. When this ion pair is disrupted, by mutation of either residue, the flexibility of this region could be greatly increased, causing helix alpha 2 to come in contact with the other subunit and generating a structural communication, which is the basis of the observed cooperativity. PMID- 7836388 TI - The interaction between protein kinase C and lipid cofactors studied by simultaneous observation of lipid and protein fluorescence. AB - The interaction of protein kinase C (PKC) with lipids was probed by a dual approach. Pyrene-labeled lipid analogues of diacylglycerol, phosphatidylserine (PS), phosphatidylinositol (PI), phosphatidylinositol 4-phosphate (PIP), and phosphatidylcholine (PC) were used both as acceptors of tryptophan excitation energy of PKC and as membrane probes for intra- and intermolecular lipid chain collisions by measuring the ratio of excimer-to-monomer fluorescence intensity (EM). Both in micelles of polyoxyethylene 9-lauryl ether and in dioleoyl-PC vesicles, interaction of PKC with monopyrenyl PS (pyr-PS) in the absence of calcium resulted in a relatively slow decrease of the EM value. This effect on the lipid dynamics was accompanied by quenching of the tryptophan fluorescence of PKC. Addition of calcium resulted in a rapid further decrease of the EM ratio of pyr-PS and in additional quenching of the tryptophan fluorescence. When 4 mol % of pyr-PS was replaced by 0.5 mol % of dipyrenyl-labeled diacylglycerol a decrease of the intramolecular excimer formation rate and tryptophan fluorescence could only be detected in the presence of calcium and PS. Strong binding was also observed with dipyrenyl-labeled PIP (dipyr-PIP), but not with the other dipyrenyl labeled lipids: PI, PS, or PC. In addition, the EM ratios of dipyr-PIP were not affected by phorbol 12-myristate 13-acetate, indicating that phorbol 12-myristate 13-acetate and dipyr-PIP can bind simultaneously to PKC. PMID- 7836389 TI - Two distinct signalling pathways are involved in the control of the biphasic junB transcription induced by interleukin-6 in the B cell hybridoma 7TD1. AB - We have measured the level of junB mRNA in the B hybridoma cell line 7TD1, under interleukin-6 (IL-6) stimulation. IL-6 increases junB mRNA in a biphasic fashion. The first early-induced peak was transient and likely corresponds to the well documented typical junB mRNA, stimulated in response to numerous growth factors, including IL-6. At variance, the second peak which has never been reported previously, lasted several hours. As a consequence of its effect on junB mRNA, IL 6 stimulated, in a biphasic fashion, the nuclear accumulation of the JunB protein. In this study, we demonstrated that IL-6 regulation occurred exclusively at the transcriptional level and that the bimodal increase of junB mRNA and JunB protein can be accounted for by a biphasic stimulation of junB transcription. Furthermore, our data point to two major differences between the mechanism of control of the early and the late IL-6-induced junB transcription waves. First, cycloheximide strongly potentiated the transcription of the second wave, whereas it failed to affect the early-induced burst. Second, tyrphostin, a tyrosine kinase inhibitor, impaired the expression of the first but not the second junB mRNA peak. Conversely, genistein, another tyrosine kinase inhibitor, totally abolished the expression of the second peak of junB mRNA whereas it did not affect the expression of the first peak. Altogether these data indicate that, in 7TD1 cells, IL-6 controls junB transcription in a biphasic fashion by means of two separate transduction pathways. PMID- 7836390 TI - Initiation of Agrobacterium tumefaciens T-DNA processing. Purified proteins VirD1 and VirD2 catalyze site- and strand-specific cleavage of superhelical T-border DNA in vitro. AB - T-DNA processing during agroinfection of plants is initiated by site- and strand specific incision at the T-DNA border sequences of the Ti plasmid. Two proteins are required for this reaction: VirD2 (49.6 kDa), catalyzing a site-specific cleaving-joining reaction on single-stranded DNA in vitro (Pansegrau, W., Schoumacher, F., Hohn, B., and Lanka, E. (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 11538-11542), and VirD1 (16.1 kDa), an accessory protein required for VirD2 mediated specific cleavage of double-stranded DNA. Following efficient overproduction, VirD1 was isolated in active form from inclusion bodies and purified to near homogeneity. The protein was applied together with purified VirD2 protein for specific cleavage of double-stranded T-DNA border sequences in vitro. The reaction proceeds on negative superhelical DNA and requires Mg2+ ions. Relaxed DNA is not cleaved. The 5' terminus of the broken DNA strand is covalently associated with protein, most probably VirD2, and the cleavage site is located at the same position that is found in vivo, indicating that the in vitro reaction mimics the one that takes place in induced agrobacteria. Relaxation of plasmid DNA occurs only upon addition of protein denaturants, suggesting that the DNA in the VirD1/VirD2 complex is topologically constrained by strong protein-DNA interactions. The characteristics of the VirD1/VirD2-mediated cleavage reaction strongly resemble those observed with relaxosomes of IncP plasmids involved in initiation of transfer DNA replication during bacterial conjugation. PMID- 7836391 TI - Nucleotide requirements for activated RNA polymerase II open complex formation in vitro. AB - The role of nucleotides in activated RNA polymerase II transcription was studied. Permanganate footprinting confirmed that there is a strict nucleotide requirement for forming open promoter complexes that cannot be overcome by the addition of a dinucleotide primer corresponding to the start site sequence. However, higher concentrations of other nucleoside triphosphates can substitute for ATP in catalyzing open complex formation. Opening catalyzed by these nucleotides is inhibited by the ATP analogue adenosine 5'-O-(thio-triphosphate), suggesting that they may function through cross-binding to the ATP site. The KM for ATP for opening and the involvement of other nucleotides in opening differs from the characteristics reported for TFIIH helicase and C-terminal domain kinase activities. This raises the possibility that opening does not involve these activities. The results alleviate very significantly the considerable current uncertainty concerning the role of ATP in the mammalian mRNA transcription initiation pathway. PMID- 7836392 TI - Intrinsically bent DNA in a eukaryotic transcription factor recognition sequence potentiates transcription activation. AB - Many eukaryotic transcription factors induce DNA bending on binding to their recognition sequences. DNA bending could play a structural role by altering contacts between the protein and DNA. Alternatively, DNA bending could play a more direct role in transcription activation. To distinguish between these possibilities, we inserted two to eight copies of the intrinsic bending sequence, AAAAAACGTG, into a minimal promoter containing only a TATA box. The intrinsic DNA bending sequence was a potent activator of transcription in both in vivo transfection experiments and in a cell-free transcription system. A protein binds to the intrinsic bending sequence with high specificity in gel mobility shift assays and was required for its transcription in cell-free extracts. The intercalator, distamycin, which eliminates the ability of the sequence to bend, specifically reduced its transcription by about 60%. Mutations in the sequence which abolished DNA bending reduced transcription by approximately 70% in vivo. Competition gel mobility shift assays showed that the transcription factor bound equally well to mutants in which DNA bending was abolished and to the intrinsic bending sequence. These data indicate that DNA bending can play a direct role in the activation of eukaryotic transcription. PMID- 7836393 TI - A single cis-acting element in a short promoter segment of the gene encoding the interphotoreceptor retinoid-binding protein confers tissue-specific expression. AB - Interphotoreceptor retinoid-binding protein (IRBP) is the major protein component of the interphotoreceptor matrix. IRBP has a highly restricted tissue-specific expression in retinal photoreceptor cells and in a subgroup of pinealocytes. With the purpose of understanding how transcriptional regulation contributes to the expression of human IRBP, we have studied a short promoter fragment (from -123 to +18, relative to the transcription start site). We demonstrate, by analysis of the expression of the lacZ reporter gene fused to this short promoter fragment in transgenic mice, that it is sufficient to confer tissue-specific expression in retinal photoreceptors and in pinealocytes. DNA/protein binding assays, performed to identify binding sites for tissue-specific trans-acting factors, have shown that an element between -45 and -58 binds a factor present only in nuclear extracts of retinoblastoma-derived cell lines, which express IRBP. An element further upstream, between -86 and -106, binds apparently ubiquitous factors. Site directed mutagenesis was performed to disrupt a GATTAA motif included in the -45 to -58 binding site and a second inverted GATTAA motif present shortly upstream. In transgenic mice bearing the mutated version of the promoter fragment, the expression of the reporter gene was completely abolished, thus suggesting that this element is essential for tissue-specific expression. A GATTAA motif appears in the 5'-flanking regions of several photoreceptor-specific genes, suggesting that this could be the recognition site for a photoreceptor-specific factor. PMID- 7836394 TI - Pancreatic beta-cells in obesity. Evidence for induction of functional, morphologic, and metabolic abnormalities by increased long chain fatty acids. AB - To elucidate the mechanism of the basal hyperinsulinemia of obesity, we perfused pancreata from obese Zucker and lean Wistar rats with substimulatory concentrations of glucose. Insulin secretion at 4.2 and 5.6 mM glucose was approximately 10 times that of controls, whereas beta-cell volume fraction was increased only 4-fold and DNA per islet 3.5-fold. We therefore compared glucose usage at 1.4, 2.8, and 5.6 mM. Usage was 8-11.4 times greater in Zucker islets at 1.4 and 2.8 mM and 4 times greater at 5.6 mM; glucose oxidation at 2.8 and 5.6 mM glucose was > 12 times lean controls. To determine if the high free fatty acid (FFA) levels of obesity induce these abnormalities, normal Wistar islets were cultured with 0, 1, or 2 mM long chain FFA for 7 days. Compared to islets cultured without FFA insulin secretion by FFA-cultured islets (2 mM) perifused with 1.4, 3, or 5.6 mM glucose was increased more than 2-fold, bromodeoxyuridine incorporation was increased 3-fold, and glucose usage at 2.8 and 5.6 mM glucose was increased approximately 2-fold (1 mM FFA) and 3-fold (2 mM FFA). We conclude that hypersecretion of insulin by islets of obese Zucker fatty rats is associated with, and probably caused by, enhanced low Km glucose metabolism and beta-cell hyperplasia, abnormalities that can be induced in normal islets by increased FFA. PMID- 7836395 TI - Mast cell procarboxypeptidase A. Molecular modeling and biochemical characterization of its processing within secretory granules. AB - Previously, we characterized murine mast cell procarboxypeptidase A (MC-proCPA) as an inactive zymogen. To investigate the mechanisms for this lack of enzymatic activity and the processing of the zymogen to the active form, we now have performed molecular modeling of the tertiary structure of murine MC-proCPA based on the x-ray crystallographic structures of porcine pancreatic procarboxypeptidases A and B. Our model predicts that MC-proCPA retains a high degree of structural similarity to its pancreatic homologues. The globular propeptide physically blocks access to the fully formed active site of the catalytic domain and contains a salt bridge to the substrate-binding region that precludes docking of even small substrates. Based on consideration of the predicted tertiary structure and charge field characteristics of the model, the activation site (between GluA94 and Ile1) appears to be highly exposed even after MC-proCPA binds to secretory granule proteoglycans. Based on the steady-state levels of MC-proCPA versus MC-CPA, cycloheximide inhibition of protein synthesis, and brefeldin A blockage of protein sorting, we show that MC-proCPA is processed rapidly in murine mast cell line KiSV-MC14 with a half-life of 26 +/- 5 min (mean +/- S.D., n = 3), and the processing occurs within the secretory granules. The enzyme responsible for this processing may be a thiol protease since treatment of the KiSV-MC14 with 200 microM E-64d, a selective thiol-protease inhibitor, increases MC-proCPA by 2.7 +/- 0.2-fold (mean +/- S.D., n = 3) within 6 h of application. PMID- 7836396 TI - Biosynthetic modulation of sialic acid-dependent virus-receptor interactions of two primate polyoma viruses. AB - Sialic acids are essential components of the cell surface receptors of many microorganisms including viruses. A synthetic, N-substituted D-mannosamine derivative has been shown to act as precursor for structurally altered sialic acid incorporated into glycoconjugates in vivo (Kayser, H., Zeitler, R., Kannicht, C., Grunow, D., Nuck, R., and Reutter, W. (1992) J. Biol. Chem. 267, 16934-16938). In this study we have analyzed the potential of three different sialic acid precursor analogues to modulate sialic acid-dependent virus receptor function on different cells. We show that treatment with these D-mannosamine derivatives can result in the structural modification of about 50% of total cellular sialic acid content. Treatment interfered drastically and specifically with sialic acid-dependent infection of two distinct primate polyoma viruses. Both inhibition (over 95%) and enhancement (up to 7-fold) of virus binding and infection were observed depending on the N-acyl substitution at the C-5 position of sialic acid. These effects were attributed to the synthesis of metabolically modified, sialylated virus receptors, carrying elongated N-acyl groups, with altered binding affinities for virus particles. Thus, the principle of biosynthetic modification of sialic acid by application of appropriate sialic acid precursors to tissue culture or in vivo offers new means to specifically influence sialic acid-dependent ligand-receptor interactions and could be a potent tool to further clarify the biological functions of sialic acid, in particular its N-acyl side chain. PMID- 7836397 TI - Identification of band 3-like proteins and Cl-/HCO3- exchange in isolated cardiomyocytes. AB - The identification of the protein that exerts the function of Cl-/HCO3- exchange is still unresolved in cardiac tissue. We have addressed this issue by using a multiple technical approach. Western blotting analysis with an antibody raised against human erythroid whole band 3 protein, the so-called protein that mediates the Cl-/HCO3- exchange in erythrocytes, showed that adult cardiomyocytes expressed two proteins immunologically related to the erythroid band 3. These proteins migrated in SDS-polyacrylamide gel electrophoresis with apparent molecular masses of 80 and 120 kDa. They were specifically found in the membrane but not in the cytosolic or the myofibril fractions of adult cardiomyocytes. Confocal microscopy further indicated that the immunostained proteins were mainly located at the sarcolemma and along T-tubules, typical membrane structures of adult cardiomyocytes. Using an antibody raised against a cardiac amino-terminal domain of rat AE3, we found that the 120-kDa protein is the translation product of the AE3 gene specifically expressed in heart and brain. Using an antiserum raised against a specific domain of mouse erythroid band 3 (AE1), which is not shared by AE3, we showed that the 80-kDa protein is likely to be a truncated translation product of the AE1 gene. Microinjection of the anti-human erythroid whole band 3 antibody into single isolated cardiac cells significantly inhibited the Cl-/HCO3- exchange activity. Furthermore, the anti-AE1 antibody strongly decreased the efficiency of 4,4'-diisothiocyanatostilbene-2,2'-disulfonate to inhibit the ionic exchange. We thus suggest that the 80-kDa or both the 80- and the 120-kDa proteins immunologically related to the erythroid band 3 protein perform the anionic exchange in rat cardiomyocytes. PMID- 7836398 TI - Solution structure of the acetylated and noncleavable mitochondrial targeting signal of rat chaperonin 10. AB - Chaperonin 10 (Cpn10) is one of only a few mitochondrial matrix proteins synthesized without a cleavable targeting signal. Using a truncated form of Cpn10 and synthetic peptides in mitochondrial import assays, we show that the N terminal region is both necessary and sufficient for organellar targeting in vitro. To elucidate the structural features of this topogenic signal, peptides representing residues 1-25 of rat Cpn10 were synthesized with and without the naturally occurring N-terminal acetylation. 1H NMR spectroscopy in 20% CF3CH2OH,H2O showed that both peptides assume a stable helix-turn-helix motif and are highly amphiphilic in nature. Chemical shift and coupling constant data revealed that the N-terminal helix is stabilized by N-acetylation, whereas NOE and exchange studies were used to derive a three dimensional structure for the acetylated peptide. These findings are discussed with respect to a recent model predicting that targeting sequences forming a continuous alpha-helix of more than 11 residues cannot adopt a conformation necessary for proteolysis by the matrix located signal peptidases (Hammen, P. K., Gorenstein, D. G., and Weiner, H. (1994) Biochemistry 33, 8610-8617). PMID- 7836399 TI - Vesicle-associated membrane protein (VAMP)/synaptobrevin-2 is associated with dense core secretory granules in PC12 neuroendocrine cells. AB - The presence and intracellular distribution of vesicle-associated membrane protein-1 (VAMP-1) and VAMP-2 were investigated in the PC12 neuroendocrine cell line using isotype-specific polyclonal antibodies. VAMP-2 was detected in the total membrane fraction, while VAMP-1 was undetectable. Subcellular fractionation demonstrates that a substantial amount of the VAMP-2 (24-36%) is associated with dense core, catecholamine-containing granules (DCGs). This was confirmed by immunofluorescence microscopy. The L chain of tetanus neurotoxin, known to inhibit granule mediated secretion in permeabilized PC12 cells, as well as botulinum neurotoxins F and G, effectively cleaved DCG-associated VAMP-2. These data demonstrate that VAMP-2 is present on the secretory granules of PC12 cells. PMID- 7836400 TI - Myristoylation of ADP-ribosylation factor 1 facilitates nucleotide exchange at physiological Mg2+ levels. AB - Recombinant N-myristoylated bovine ADP-ribosylation factor 1 (myr-rARF1) has been expressed in bacteria and purified to near homogeneity with a high (85%) myristoylation efficiency. Myr-rARF1 and nonmyristoylated rARF1 have been compared with respect to their kinetics of guanine nucleotide exchange and their interactions with phospholipids. Myristoylation is shown to allow the release of bound GDP at physiological (mM) concentrations of Mg2+. GDP dissociation is slow in the absence of phospholipids but is accelerated 2-fold in the presence of phospholipid vesicles. On the contrary, myristoylation decreases 10-fold the rate of dissociation of GTP or guanosine 5'-O-(thiotriphosphate) (GTP gamma S) in the presence of phospholipids. As a result, myr-ARF1 can be spontaneously activated by GTP or GTP gamma S (t1/2 approximately 30 min at 37 degrees C) at 1 mM Mg2+, in the sole presence of phospholipid membranes without the need for a nucleotide exchange factor. In contrast to the nonacylated protein, the GDP-bound form of myr-ARF1 interacts with phospholipids, as demonstrated by its cosedimentation with phospholipid vesicles and its comigration with phospholipid/cholate micelles on gel filtration. The interaction is, however, weaker than for the GTP-bound form, suggesting that only the myristate in myr-ARF1GDP interacts with phospholipids, whereas both the myristate and the amino-terminal hydrophobic residues in myr-ARF1GTP bind to phospholipids. PMID- 7836401 TI - Structure and promoter analysis of the gene encoding the mouse helix-loop-helix factor HES-5. Identification of the neural precursor cell-specific promoter element. AB - HES-5 is a mammalian basic helix-loop-helix factor that has a distant sequence homology to the product of the Drosophila pair-rule gene hairy. HES-5 mRNA is present exclusively in the developing nervous system, but its level decreases as neural differentiation proceeds. In this study, to characterize the molecular mechanism of the neural-specific expression of HES-5 we isolated the mouse HES-5 gene. This gene consists of three exons, and Southern blot analysis shows that it is a single copy gene. The transcription initiation site, determined by primer extension and reverse transcriptase-mediated polymerase chain reaction, is located 26 nucleotides downstream of a TATAbox. Transient transfection analysis shows that the upstream region of the HES-5 gene can direct efficient expression in neural precursor cells and moderate expression in undifferentiated NCB20 neuroblastoma-brain hybrid cells but not in glioma or fibroblast cells. The moderate level of expression in NCB20 cells decreases when differentiation into neuron-like cells is induced. Further promoter analysis shows that this undifferentiated neural-specific expression is mediated by the multiple GC stretches present in the HES-5 promoter. Gel mobility shift analysis suggests the presence of a neural precursor cell-specific protein that binds to the GC stretches. These results raise the possibility that HES-5 expression in the developing nervous system is regulated by the GC stretch-binding protein. PMID- 7836402 TI - The human low affinity immunoglobulin G Fc receptor III-A and III-B genes. Molecular characterization of the promoter regions. AB - The human Fc receptor with low affinity for IgG (Fc gamma RIII, CD16) is encoded by two nearly identical genes, Fc gamma RIII-A and Fc gamma RIII-B, resulting in tissue-specific expression of alternative membrane-anchored isoforms. The transmembrane CD16 receptor forms a heteromeric structure with the Fc epsilon RI (gamma) and/or CD3 (zeta) subunits on the surface of activated monocytes/macrophages, NK cells, and a subset of T cells. The expression of the glycosylphosphatidylinositol-anchored CD16 isoform encoded by the Fc gamma RIII-B gene is restricted to polymorphonuclear leukocytes and can be induced by Me2SO differentiation of HL60 cells. We have isolated and sequenced genomic clones of the human Fc gamma RIII-A and Fc gamma RIII-B genes, located their transcription initiation sites, identified a different organization of their 5' regions, and demonstrated four distinct classes of Fc gamma RIII-A transcripts (a1-a4) compared with a single class of Fc gamma RIII-Bb1 transcripts. Both CD16 promoters (positions -198 to -10) lack the classical "TATA" positioning consensus sequence but confer transcriptional activity when coupled to the human lysozyme enhancer. Both promoters also display different tissue-specific transcriptional activities reflecting the expected gene expression of Fc gamma RIII-A and Fc gamma RIII-B in NK cells versus polymorphonuclear leukocytes. Within the -198/-10 fragments, the sequences of the two CD16 genes have been identified to differ in 10 positions. It is suggested that these nucleotide differences might contribute to cell type-specific transcription of Fc gamma RIII genes. PMID- 7836403 TI - Stimulation of protein kinase C during Ca(2+)-induced keratinocyte differentiation. Selective blockade of MARCKS phosphorylation by calmodulin. AB - Raising the external Ca2+ concentration from 0.05 to 1.8 mM stimulated membrane associated protein kinase Cs (PKCs) activity as strongly as the specific PKCs activator, 12-O-tetradecanoyl phorbol-13-acetate (TPA) in BALB/MK mouse keratinocytes. This was indicated by the increased phosphorylation of a PKC selective peptide substrate, Ac-FKKSFKL-NH2, by membranes isolated from the Ca(2+)- or TPA-stimulated keratinocytes. Raising the external Ca2+ concentration to 1.8 mM also triggered a 4-fold rise in the intracellular free Ca2+ concentration. As reported elsewhere (Moscat, J. Fleming, T. P., Molloy, C. J. Lopez-Barahona, M., and Aaronson, S. A. (1989) J. Biol. Chem. 264, 11228-11235), TPA stimulated the phosphorylation of the PKCs substrate, the 85-kDa myristoylated alanine-rich kinase C substrate (MARCKS) protein, in intact keratinocytes, but Ca2+ did not. Furthermore, Ca(2+)-pretreatment reduced the TPA induced phosphorylation of the 85-kDa protein in intact cells. There was no significant increase in MARCKS phosphorylation when keratinocytes were treated with a Ca2+.CaM-dependent phosphatase inhibitor, cyclosporin A, before stimulation with 1.8 mM Ca2+.Ca2+.calmodulin suppressed the ability of isolated membranes to phosphorylate the 85-kDa MARCKS holoprotein in vitro in the presence of phosphatase inhibitors such as fluoride, pyrophosphate, and vanadate, and this inhibition was overcome by a calmodulin antagonist, the calmodulin-binding domain peptide. Thus, the ability of 1.8 mM Ca2+ to strongly stimulate the membrane PKCs activity without stimulating the phosphorylation of the MARCKS protein in keratinocytes is consistent with the possibility of Ca2+.calmodulin complexes, formed by the internal Ca2+ surge, binding to, and blocking the phosphorylation of, this PKC protein substrate. PMID- 7836404 TI - beta-Amyloid peptide produced in vitro is degraded by proteinases released by cultured cells. AB - The primary histopathological feature of Alzheimer's disease is the accumulation of beta-amyloid in the brains of afflicted individuals. This peptide has been shown to be produced and liberated both in vitro and in vivo by normal physiological processes. The mechanism by which beta-amyloid is formed, as well as that by which it may be cleared, are events likely to impact on the development and progression of this disease. Thus, the fate of beta-amyloid peptides secreted by cultured mammalian cells was investigated. It was found that levels of the soluble peptide are reduced over time due to the activity of multiple types of proteinases including those from the metallo, aspartyl, and thiol classes. Inhibitors to each class of proteinase can only partially block beta-amyloid degradation, but, if used in combination, they can fully prevent its catabolism. The Kunitz serine proteinase inhibitor domain, present on two beta amyloid precursor protein isoforms, was found to be an effective inhibitor of beta-amyloid peptide degradation. These data indicate that modulations in expression of secreted proteinases and/or beta-amyloid precursor isoforms may influence levels of beta-amyloid. PMID- 7836405 TI - Activation of the Na+/H+ exchanger gene by the transcription factor AP-2. AB - We have isolated and characterized regions important for expression of the mouse Na+/H+ exchanger gene. A 1.1-kilobase fragment upstream of the 5'-untranslated region contains specific DNA motifs characteristic of promoter and enhancer elements including a TATA box, two CAAT boxes, an SP-1 site, a cyclic AMP response element-binding site, and an AP-2-like site. This 1.1-kilobase fragment directs transcription of a luciferase reporter gene in mouse fibroblasts (NIH 3T3) and human Hep G2 cells. Deletion or mutation of an AP-2-like site 100 base pairs from the start site of transcription resulted in loss of most of the reporter plasmid activity. In addition, cotransfection of an AP-2 expression plasmid and the mouse promoter/luciferase plasmid increased the amount of Na+/H+ exchanger-directed transcription in AP-2-deficient Hep G2 cells. Moreover, mobility shift analysis indicated that a putative AP-2-binding site is capable of binding purified AP-2 protein and a specific protein from nuclear extracts of NIH 3T3 cells. The results show that the transcription factor AP-2 may play an important role in regulation of transcription of the mouse Na+/H+ exchanger gene. PMID- 7836406 TI - A Xenopus nonmuscle myosin heavy chain isoform is phosphorylated by cyclin p34cdc2 kinase during meiosis. AB - There are two vertebrate nonmuscle myosin heavy chain (MHC) genes that encode two separate isoforms of the heavy chain, MHC-A and MHC-B. Recent work has identified additional, alternatively spliced isoforms of MHC-B cDNA with inserted sequences of 30 nucleotides (chicken and human) or 48 nucleotides (Xenopus) at a site corresponding to the ATP binding region in the MHC protein (Takahashi, M., Kawamoto, S., and Adelstein, R.S. (1992) J. Biol. Chem. 267, 17864-17871) and Bhatia-Dey, N., Adelstein, R.S., and Dawid, I.B. (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 2856-2859). The deduced amino acid sequence of these inserts contains a consensus sequence for phosphorylation by cyclin-p34cdc2 (cdc2) kinase. In cultured Xenopus XTC cells, we have identified two inserted MHC-B isoforms and a non-inserted MHC-A isoform by immunoblotting of cell extracts. When myosin was immunoprecipitated from XTC cells and phosphorylated in vitro with cdc2 kinase, the kinase catalyzed the phosphorylation of both inserted MHC-B isoforms but not MHC-A. Isoelectric focusing of tryptic peptides generated from MHC-B phosphorylated with cdc2 kinase revealed one major phosphopeptide that was purified by reverse-phase high performance liquid chromatography and sequenced. The phosphorylated residue was Ser-214, the cdc2 kinase consensus site within the insert near the ATP binding region. The same site was phosphorylated in intact XTC cells during log phase of growth and in cell-free lysates of Xenopus eggs stabilized in second meiotic metaphase but not interphase. Moreover, Ser-214 phosphorylation was detected during maturation of Xenopus oocytes when the cdc2 kinase-containing maturation-promoting factor was activated, but not in G2 interphase-arrested oocytes. These results demonstrate that MHC-B phosphorylation is tightly regulated by cdc2 kinase during meiotic cell cycles. Furthermore, MHC A and MHC-B isoforms are differentially phosphorylated at these stages, suggesting that they may serve different functions in these cells. PMID- 7836407 TI - Differences in pH optima and calcium requirements for maturation of the prohormone convertases PC2 and PC3 indicates different intracellular locations for these events. AB - PC2 and PC3, which is also known as PC1, are subtilisin-like proteases that are involved in the intracellular processing of prohormones and proneuropeptides. Both enzymes are synthesized as propolypeptides that undergo proteolytic maturation within the secretory pathway. An in vitro translation/translocation system from Xenopus egg extracts was used to investigate mechanisms in the maturation of pro-PC3 and pro-PC2. Pro-PC3 underwent rapid (t1/2 < 10 min) processing of the 88-kDa propolypeptide at the sequence RSKR83 to generate the 80 kDa active form of the enzyme. This processing was blocked when the active site aspartate was changed to asparagine, suggesting that an autocatalytic mechanism was involved. In this system, processing of pro-PC3 was optimal between pH 7.0 and 8.0 and was not dependent on additional calcium. These results are consistent with pro-PC3 maturation occurring at an early stage in the secretory pathway, possibly within the endoplasmic reticulum, where the pH would be close to neutral and the calcium concentration less than that observed in later compartments. Processing of pro-PC2 in the Xenopus egg extract was much slower than that of pro PC3 (t1/2 = 8 h). It exhibited a pH optimum of 5.5-6.0 and was dependent on calcium (K0.5 = 2-4 mM). The enzymatic properties of pro-PC2 processing were similar to that of the mature enzyme. Further studies using mutant pro-PC2 constructs suggested that cleavage of pro-PC2 was catalyzed by the mature 68-kDa PC2 molecule. The results were consistent with pro-PC2 maturation occurring within a late compartment of the secretory pathway that contains a high calcium concentration and low pH. PMID- 7836408 TI - Human coagulation factor V is activated to the functional cofactor by elastase and cathepsin G expressed at the monocyte surface. AB - The ability of intact peripheral blood monocytes to modulate factor V procoagulant activity was studied using electrophoretic and autoradiographic techniques coupled to functional assessment of cofactor activity. Incubation of plasma concentrations of factor V with monocytes (5 x 10(6)/ml) resulted in the time-dependent cleavage of the 330-kDa protein. Activation occurred via several high molecular mass intermediates (> or = 200 kDa) to yield peptides of 150, 140, 120, 94, 91, 82, and 80 kDa, which paralleled the expression of cofactor activity. The cleavage pattern observed differed from that obtained with either thrombin or factor Xa as an activator. The incubation time required to achieve full cofactor activity was dependent on the monocyte donor and ranged from 10 min to 1 h and was consistently slightly lower than that obtained with thrombin activated factor Va. Cofactor activity was not diminished by additional incubation. The cofactor activity generated bound to the monocyte such that a competent prothrombinase complex was formed at the monocyte membrane surface. Furthermore, within 5 min of factor V addition to monocytes, near maximal cofactor activity (approximately 70%) was bound and expressed on the monocyte membrane. The proteolytic activity toward factor V was associated primarily with the monocyte membrane, as little proteolytic activity was released into the cell free supernatant. Proteolytic activity was inhibited by diisopropyl fluorophosphate and phenylmethanesulfonyl fluoride. However, the inhibitor profile obtained with alpha 1-antiproteinase inhibitor, alpha 1-antichymotrypsin, and alpha 2-macroglobulin suggested membrane-bound forms of elastase and cathepsin G were mediating, in large part, the proteolysis observed. These data were confirmed using purified preparations of both proteases and a specific anti human leukocyte elastase antibody. Thus, expression of these proteases at the monocyte surface may contribute to thrombin generation at extravascular tissue sites by catalyzing the activation of the essential cofactor, factor Va, which binds to the monocyte surface and supports the factor Xa-catalyzed activation of prothrombin. PMID- 7836409 TI - Characterization of the murine mitochondrial glycerol-3-phosphate acyltransferase promoter. AB - Glycerol-3-phosphate acyltransferase (GPAT) catalyzes the acylation of sn glycerol 3-phosphate to form 1-acyl-sn-glycerol 3-phosphate, a committed step in triacylglycerol and phospholipid biosynthesis. We have previously reported the cDNA cloning and transcriptional regulation of the murine mitochondrial GPAT (mGPAT). We now report the cloning of the 5'-flanking region of the murine mitochondrial GPAT. The transcription start site was identified by primer extension and RNase protection assays. A TATA box-like motif (TTATTAT) was located between -34 and -29 and a reverse CCAAT box (ATTGG) was located between 78 and -74, relative to the transcription start site. To begin studying mechanisms underlying transcriptional regulation of the mGPAT gene, chimeric luciferase (LUC) plasmids containing serial deletions, from -1447 to -38, of the 5'-flanking region of the murine mGPAT gene were prepared and transfected into 3T3-L1 cells. The fusion construct -1447 GPAT.LUC showed high promoter activity and deletions to -1353, -747, -322, and -86 did not markedly change the promoter activity. With all constructs, luciferase activity was 2-fold higher when plasmids were transfected into 3T3-L1 adipocytes. However, deletion of sequences between -86 and -55 resulted in a 9-fold decrease in LUC activity in both preadipocytes and adipocytes. Deletion of sequences between -55 and -38 did not alter promoter activity. DNase I footprint analysis revealed a protected region between -95 and -65 which included the putative CTF/NF1 binding site. Electrophoretic mobility shift assays demonstrated a single protein-DNA complex formation. Oligonucleotides synthesized according to the CTF/NF1 consensus sequence or the adenovirus NF-1 site showed a different and more complex pattern of protein-DNA interaction and were not able to compete away the mGPAT promoter protein complex, indicating that a distinct protein was bound to -86/-55, a region important for the basal promoter activity in 3T3-L1 cells. Luciferase activity was increased 2.8- and 8-fold when adipocytes stably transfected with 322 GPAT.LUC were treated with 5 and 25 mM glucose, respectively, in the presence of 10 nM insulin. These results indicate that carbohydrate-responsive sequences are located within -322 base pairs of the mGPAT promoter. PMID- 7836410 TI - Structural and functional significance of cysteine residues of glutathione independent prostaglandin D synthase. Identification of Cys65 as an essential thiol. AB - Glutathione-independent prostaglandin D synthase in rat brain is composed of 189 amino acid residues and catalyzes the isomerization of prostaglandin H2 to prostaglandin D2, an endogenous sleep-promoting substance. This enzyme is the only enzyme among members of the lipocalin superfamily composed of various secretory lipophilic ligand-carrier proteins and is recently identified to be a beta-trace protein, a major constituent of human cerebrospinal fluid. We expressed the active enzyme in Escherichia coli and then systematically substituted all cysteine residues of the delta 1-29 enzyme at positions of 65, 89, and 186 with alanine or serine. The parent and mutant enzymes were purified to apparent homogeneity with a recovery of approximately 30% by chromatography with Sephadex G-50 and S-Sepharose, by which all the enzymes showed identical elution profiles. The purified enzymes, irrespective of the mutation, showed almost the same circular dichroism spectral characteristics as displayed by a highly ordered beta-structure. The recombinant enzymes containing Cys65 showed the activity comparable with that of the enzyme purified from rat brain (approximately 3 mumol/min/mg of protein) in the presence, but not in the absence, of sulfhydryl compounds. However, all of the single, double, and triple mutants without Cys65 lost the enzyme activity. The purified delta 1-29 Ala89,186 enzyme was inactivated reversibly by conjugation with glutathione at Cys65 and irreversibly by the stoichiometric chemical modification with N-ethylmaleimide. These results indicate that Cys65 is an essential thiol of the enzyme and that both the intrinsic and extrinsic sulfhydryl groups are necessary for nonoxidative rearrangement of 9,11-endoperoxide of prostaglandin H2 to produce prostaglandin D2 catalyzed by the enzyme. PMID- 7836411 TI - The Yarrowia lipolytica gene PAY2 encodes a 42-kDa peroxisomal integral membrane protein essential for matrix protein import and peroxisome enlargement but not for peroxisome membrane proliferation. AB - PAY genes are required for peroxisome assembly in the yeast Yarrowia lipolytica. Here we show that a mutant strain, pay2, is disrupted for the import of proteins targeted by either peroxisomal targeting signal-1 or -2. Electron microscopy of pay2 cells revealed the presence of small peroxisomal "ghosts," similar to the vesicular structures found in fibroblasts of patients with the human peroxisome assembly disorder, Zellweger syndrome. Functional complementation of pay2 with a plasmid library of Y. lipolytica genomic DNA identified a gene, PAY2, that restores growth of pay2 on oleic acid, import of catalase and multifunctional enzyme into peroxisomes, and formation of wild type peroxisomes. The PAY2 gene encodes Pay2p, a hydrophobic polypeptide of 404 amino acids. An antibody raised against Pay2p recognizes a polypeptide of approximately 42-kDa whose synthesis is induced by growth of Y. lipolytica on oleic acid. Pay2p is a peroxisomal integral membrane protein, as it localizes to carbonate-stripped peroxisomal membranes. Pay2p shows no identity to any known protein. Our results suggest that Pay2p is essential for the activity of the peroxisomal import machinery but does not affect the initial steps of peroxisomal membrane proliferation. PMID- 7836412 TI - Cholecystokinin stimulates the down-regulation of CTP:phosphocholine cytidylyltransferase in pancreatic acinar cells. AB - Stimulation of rat pancreatic acinar cells with cholecystokinin (CCK) is known to result in a significant inhibition of CTP:phosphocholine cytidylyltransferase (CT), a rate-limiting enzyme in phosphatidylcholine biosynthesis. Immunoprecipitation of CT from 32P-labeled acinar cells revealed that CCK treatment also caused a marked reduction in CT phosphate levels. The effects of CCK were maximal over 60 min and dependent on concentration, exhibiting an EC50 of 800 pM. Other calcium mobilizing secretagogues such as carbamylcholine (100 microM) and bombesin (10 nM) also reduced CT phosphate levels to 20 and 39% of control, respectively. Treatment of cells with thapsigargin and/or 12-O tetradecanoyl-phorbol-13-acetate established that a combination of increased intracellular Ca2+ and protein kinase C activation was necessary to decrease phosphorylated CT content. Conversely, secretin (10 nM) or 8-(4-chlorophenylthio) cAMP (100 microM) added alone had no effects. Use of the compound JMV-180 indicated CCK was acting through the low affinity state of the CCKA receptor to reduce CT phosphate levels. Further, the decrease in phosphorylated CT caused by CCK was blocked by the phosphatase inhibitors okadaic acid (3 microM) and calyculin A (100 nM). Finally, immunoblotting from whole cell lysates revealed CT was partially degraded in response to CCK, providing a novel mechanism by which the inhibition of CT enzyme activity occurs in response to the hormone. Moreover, this degradation was also blocked by a phosphatase inhibitor. These data suggest that the dephosphorylation of either CT itself or some other regulatory molecule(s) which mediates the CCK-induced protease activation may play a central role in reducing CT enzyme levels in acinar cells. PMID- 7836413 TI - Association of the invariant chain with major histocompatibility complex class I molecules directs trafficking to endocytic compartments. AB - Major histocompatibility complex (MHC) class I and class II molecules have been shown to present peptides of different origin to alpha beta T cells. Most peptides presented by class I molecules are derived from endogenously synthesized proteins, whereas most peptides presented by class II molecules are from exogenous sources. This functional dichotomy can largely be achieved by the preferential intracellular association of the invariant chain (Ii) with MHC class II molecules, which may inhibit binding of endogenous peptides to class II molecules and direct them to endocytic compartments where extracellularly derived peptides can be sampled. Here, we show that Ii also can associate with a subset of MHC class I molecules and direct them to endocytic compartments. Ii was coprecipitated with class I molecules after lysis of human lymphocytes in mild detergent such as 3-[(3-cholamidopropyl)dimethylammonio]-1-propane-sulfonic acid or digitonin, and the association was more clearly visualized by the use of dithiobis[succinimidyl-propionate], a homobifunctional chemical cross-linker. The class I.Ii complex was reconstituted in Ii negative cells by transfection of corresponding cDNA clones and was found to be transported through the Golgi to acidic endocytic compartments. These observations may explain how some exogenous antigens can be presented by MHC class I molecules and how MHC class II molecules can bind self peptides derived from MHC class I molecules in endocytic compartments. PMID- 7836415 TI - Expression and characterization of PKD, a phorbol ester and diacylglycerol stimulated serine protein kinase. AB - A novel protein kinase (named PKD) with an NH2-terminal region containing two cysteine-rich motifs has been expressed in COS-7 cells and identified as a receptor for phorbol esters. COS-7 cells transfected with a PKD cDNA construct (pcDNA3-PKD) exhibit a marked (4.8-fold) increase in [3H]phorbol 12,13-dibutyrate binding. An antiserum raised against the COOH-terminal 15 amino acids of PKD specifically recognized a single 110-kDa band in PKD-transfected cells. PKD prepared by elution from immunoprecipitates with the immunizing peptide efficiently phosphorylated the synthetic peptide syntide-2. The enzyme only poorly phosphorylated a variant syntide-2 where arginine 4 has been replaced by an alanine. The addition of [3H]phorbol 12,13-dibutyrate, 1-oleoyl-2 acetylglycerol, or 1,2-dioctanoyl-sn-glycerol in the presence of dioleoylphosphatidylserine stimulated the syntide-2 kinase activity of PKD in a synergistic fashion (4-6-fold). Furthermore, the autophosphorylation of PKD was strikingly stimulated by the same lipid activators (14-24-fold). Similar properties were found with PKD isolated from mouse lung. The substrate specificity of PKD is different from that of previously identified members of the protein kinase C family since it does not efficiently phosphorylate histone III S, protamine sulfate, or a synthetic peptide based upon the conserved pseudosubstrate region of the protein kinase C family. Taken together, these data unambiguously establish PKD as a phorbol ester receptor and as a novel phospholipid/diacylglycerol-stimulated protein kinase. PMID- 7836414 TI - Stimulation of the DNA-dependent protein kinase by RNA polymerase II transcriptional activator proteins. AB - The DNA-dependent protein kinase (DNA-PK) phosphorylates RNA polymerase II and a number of transcription factors. We now show that the activity of DNA-PK is directly stimulated by certain transcriptional activator proteins, including the human heat shock transcription factor 1 (HSF1) and a transcriptionally active N terminal 147 amino acid GAL4 derivative. Stimulation of DNA-PK activity required specific sequences in the activator proteins outside the minimal DNA binding domains. The stimulation of DNA-PK activity also required DNA and was greater with DNA containing relevant activator binding sites. Comparison of different HSF binding fragments showed that optimal stimulation occurred when two HSF binding sites were present. Stimulation with HSF and GAL4 was synergistic with Ku protein, another regulator of DNA-PK activity. DNA-PK is tightly associated with the transcriptional template, and an increase in its activity could potentially influence transcription through the phosphorylation of proteins associated with the transcription complex. PMID- 7836416 TI - Identification and characterization of a functional promoter region in the human eosinophil IL-5 receptor alpha subunit gene. AB - The molecular basis for the commitment of multipotential myeloid progenitors to the eosinophil lineage, and the transcriptional mechanisms by which eosinophil specific genes are subsequently expressed and regulated during eosinophil development are currently unknown. Interleukin-5 (IL-5) is a T cell and mast cell derived cytokine with actions restricted to the eosinophil and closely related basophil lineages in humans. The high affinity receptor for IL-5 (IL-5R) is composed of an alpha subunit (IL-5R alpha) expressed by the eosinophil lineage, that associates with a beta c subunit shared with the receptors for IL-3 and granulocyte-macrophage colony stimulating factor (GM-CSF). As a prerequisite to studies of the transcriptional regulation of the IL-5R alpha subunit gene, we used three different methods, including primer extension, RNase protection, and 5'-RACE to precisely map the transcriptional start site to a position 15 base pairs (bp) upstream of the 5' end of the published sequence of IL-5R alpha exon 1. To initially identify the IL-5R alpha promoter, 3.5 kilobases (kb) and 561 bp of the 5' sequence flanking the transcriptional start site were subcloned into the promoterless pXP2-luciferase vector. Transient transfection of these constructs into an eosinophil-committed HL-60 subline, clone HL-60-C15, induced the expression of approximately 240-fold greater luciferase activity than the promoterless vector, identifying a strong functionally active promoter region within the 561 bp of sequence proximal to the transcriptional start site and with activity equivalent to pXP2 constructs containing the entire 3.5 kb of upstream sequence. To more precisely localize the cis-acting regulatory elements in this region important for promoter activity, a series of 5' deletion mutants of the 561-bp region were generated in the pXP2-luciferase vector. Deletion of the region between bp -432 and -398 reduced promoter activity by more than 80% in the HL-60-C15 cell line. Further analyses of the activity of the IL-5R alpha promoter constructs in various other eosinophil, myeloid, and non-myeloid cell lines indicated that the promoter was relatively myeloid and eosinophil lineage specific in its expression. Consensus sequences for known transcription factor binding sites were not present in the 34-bp region of the promoter required for maximal activity, suggesting unique myeloid- and possibly eosinophil-specific regulatory elements.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7836417 TI - Step-arrest mutants of phage Mu transposase. Implications in DNA-protein assembly, Mu end cleavage, and strand transfer. AB - We describe the isolation and characterization of Mu A variants arrested at specific steps of transposition. Mutations at 13 residues within the Mu A protein were analyzed for precise excision of Mu DNA in vivo. A subset of the defective variants (altered at Asp269, Asp294, Gly348, and Glu392) were tested in specific steps of transposition in vitro. It is possible that at least some residues of the Asp269-Asp294-Glu392 triad may have functional similarities to those of the conserved Asp-Asp-Glu motif found in several transposases and retroviral integrases. Mu A(D269V) is defective in high-order DNA-protein assembly, Mu end cleavage, and strand transfer. The assembly defect, but not the catalytic defect, can be overcome by precleavage of Mu ends. Mu A(E392A) can assemble the synaptic complex, but cannot cleave Mu ends. A mutation of Gly348 to aspartic acid within Mu A permits the uncoupling of cleavage and strand transfer activities. This mutant is completely defective in synaptic assembly and Mu end cleavage in presence of Mg2+. The assembly defect is alleviated by replacing Mg2+ with Ca2+. Some Mu end cleavage is observed with this mutant in the presence of Mn2+. When presented with precleaved Mu ends, Mu A(G348D) exhibits efficient strand transfer activity. PMID- 7836418 TI - Inactivation of glycogen synthase kinase-3 by epidermal growth factor is mediated by mitogen-activated protein kinase/p90 ribosomal protein S6 kinase signaling pathway in NIH/3T3 cells. AB - The role of the p90 ribosomal protein S6 kinase/mitogen-activated protein kinase (RSK/MAPK) signaling pathway in regulating glycogen synthase kinase-3 (GSK-3) activity was investigated. In vitro studies showed that GSK-3 was inactivated by 50% upon incubation with RSK purified from epidermal growth factor (EGF) stimulated NIH/3T3 cells. Subsequently, the effect of EGF on GSK-3 activity was measured in NIH/3T3 cells that stably overexpressed mutated forms of MAPK kinase (MAPKK). The activation of RSK by EGF was markedly decreased in cell lines expressing the dominant negative MAPKK mutants S222A and K97A and was increased in cells expressing the S222E mutant as compared with control cell lines. EGF induced a rapid decrease in GSK-3 beta activity (50%) in control and S222E cells; however, only 25 and 10% inhibition in GSK-3 beta activity was observed in cell lines expressing the dominant negative mutants K97A and S222A, respectively, suggesting that inhibition of GSK-3 was partially blocked in these cells. Taken together, these results suggest that the action of EGF on GSK-3 inactivation is mediated by the RSK/MAPK signaling pathway in NIH/3T3 cells and provide evidence for a mechanism regulating GSK-3 activity in intact cells. PMID- 7836419 TI - Insulin stimulates the tyrosine dephosphorylation of pp125 focal adhesion kinase. AB - The phosphorylation state of pp125 focal adhesion kinase in response to insulin was examined in parental and transfected Rat-1 fibroblasts expressing both wild type (HIRc cells) and mutant human insulin receptor cDNAs lacking the C-terminal twin tyrosine phosphorylation sites (YF2 cells) or a deletion mutant lacking the distal 43 amino acids of the beta-subunit (delta CT cells). In HIRc cells insulin stimulated the tyrosine dephosphorylation of pp125fak, whereas IGF-I did not. In contrast, the tyrosine phosphorylation state of pp125fak was unchanged in the parental Rat-1 fibroblasts and the YF2 or delta CT mutant cell lines in response to insulin. Analysis of the supernatants revealed that pp125fak was only one component of the major M(r), 120-130-kDa phosphotyrosine band seen in HIRc cells. We conclude that: 1) in contrast to other growth factors, insulin stimulates the dephosphorylation of pp125fak; 2) the presence of the insulin receptor C-terminal tyrosines 1328 and 1334 is required for the insulin-stimulated tyrosine dephosphorylation of pp125fak, suggesting a possible SH2 domain-dependent interaction; 3) insulin may modulate integrin-mediated signaling through pp125fak by altering the phosphorylation state of pp125fak. PMID- 7836420 TI - A plasma membrane-associated component of ovarian adenocarcinoma cells enhances the catalytic efficiency of matrix metalloproteinase-2. AB - Several recent investigations have demonstrated that matrix metalloproteinase-2 (MMP-2) binds to the cell surface and undergoes zymogen activation via a plasma membrane-associated activity. The purpose of this study was to determine if association of MMP-2 with the plasma membrane also modulates the catalytic efficiency of the active enzyme. Using density gradient centrifugation, we isolated the plasma membrane fractions of two ovarian adenocarcinoma cell lines, DOV 13 and OVCA' 432, previously described either to express MMP-2 or to express no gelatinolytic metalloproteinases, respectively. While DOV 13 cells contained plasma membrane-associated MMP-2 and OVCA 432 did not, both cell types were able to bind exogenous MMP-2. Furthermore, plasma membrane fractions from these cells significantly enhanced the rate of cleavage of [14C]gelatin I substrate by both MMP-2 tissue inhibitor of metalloproteinases-2 (TIMP-2) complex (2.5-8-fold) and TIMP-2-free MMP-2 (5.9-fold). This stimulatory activity was dose-dependent, soluble in Triton X-100, and abolished by trypsin treatment of the membranes, but was stable to heat treatment. Plasma membrane stimulation of MMP-2 resulted in a 3.8-4.6-fold increase in the catalytic efficiency of gelatinolysis. These data suggest that, in addition to promoting zymogen activation, cell surface binding of MMP-2 may regulate enzyme activity by increasing the rate of substrate cleavage. Via this mechanism, tumor cell types that do not express MMPs (such as OVCA 432) nevertheless may be able to utilize exogenous MMP-2 to mediate proteolysis associated with invasion and metastasis. PMID- 7836421 TI - The biochemistry of neurotransmitter secretion. AB - The progress that has resulted from the convergence of biochemistry with yeast genetics has accelerated the pace at which the molecular events of membrane transport are being elucidated. Future research will focus not only on testing the proposed sequence of protein-protein interactions but also on identifying how calcium regulation is imposed on this system. As our understanding of the basic mechanisms of neurosecretion increases, attention will undoubtedly shift to how the molecules of release are modified to produce changes in synaptic efficacy. PMID- 7836422 TI - Ran-binding protein-1 is an essential component of the Ran/RCC1 molecular switch system in budding yeast. AB - We have performed a screen for genes that affect chromosome stability when overexpressed in the budding yeast Saccharomyces cerevisiae. Two of the genes recovered in the screen, CST17 and CST20, share a number of phenotypic properties, suggesting their involvement in the same cellular process. DNA sequence analysis of these genes revealed that they encode components of the Ran/RCC1 molecular switch system: CST17 is Ran itself (Ras-like nuclear protein) and CST20 is a novel yeast protein with a high degree of similarity to mammalian RanBP1, which is known to interact with Ran-GTP in vitro. We demonstrate that the CST20 protein can interact with Ran-GTP in vitro under similar conditions, indicating that it is the functional yeast homolog of mammalian RanBP1. The results of immunoprecipitation experiments show that the two yeast proteins form a complex in vivo. Deletion of the gene encoding RanBP1 revealed that it is essential for viability, as are Ran and RCC1. Similar phenotypic consequences of overproduction of either Ran or RanBP1 indicate that the latter protein is a functional component of the Ran/RCC1 molecular switch system, which is implicated in the control of a number of nuclear functions. Our finding that overproduction of two components of this system results in mitotic chromosome nondisjunction and sensitivity to an anti-microtubule drug benomyl suggest their involvement in mitosis as well. Thus RanBP1 is a functional component of a highly conserved molecular system that affects diverse cellular processes. The availability of this gene in S. cerevisiae provides a genetic system for the analysis of RanBP1 function in vivo. PMID- 7836423 TI - Protein kinase Byr2 is a target of Ras1 in the fission yeast Schizosaccharomyces pombe. AB - Conservation of the structure and function of Ras proteins has been observed in a variety of eukaryotic organisms. However, the nature of their downstream effectors appears to be quite divergent; adenylyl cyclase and a protein kinase Raf-1, which do not share any structural homology with each other, are effectors of Ras in the budding yeast and in higher organisms, respectively. We show here that a protein kinase Byr2, which has been known to act downstream of Ras1 in a mating pheromone signal transduction system of Schizosaccharomyces pombe, binds directly to Ras proteins in a GTP-dependent manner. The region of Byr2 responsible for the Ras binding was mapped by a gene deletion analysis to its N terminal segment of 206 amino acid residues, which does not possess any significant homology with the other effectors of Ras. The affinity of the Byr2 N terminus for Saccharomyces cerevisiae Ras2 was determined by measuring its activity to competitively inhibit Ras-dependent adenylyl cyclase activity and found to be comparable with those of yeast adenylyl cyclase and human Raf-1, with a dissociation constant (Kd) of about 1 nM. Furthermore, Byr2 inhibited a Ras GTPase-activating activity of Ira2, a S. cerevisiae homologue of neurofibromin. These results indicate that Byr2 is an immediate downstream target of Ras1 in S. pombe. PMID- 7836424 TI - A new old yellow enzyme of Saccharomyces cerevisiae. AB - In 1993, the first gene of Old Yellow Enzyme (OYE) of Saccharomyces cerevisiae was cloned (Stott, K., Saito, K., Thiele, D. J., and Massey, V. (1993) J. Biol. Chem. 268, 6097-6106) and named OYE2 to distinguish it from the first OYE gene cloned from Saccharomyces carlsbergenesis (Saito, K., Thiele, D. J., Davio, M., Lockridge, O., and Massey, V. (1991) J. Biol. Chem. 266, 20720-20724). The analysis of an OYE2 deletion mutant suggested that S. cerevisiae had at least two OYE genes. In the present study, we cloned a new OYE species named OYE3 and analyzed the OYE3 protein expressed in Escherichia coli. OYE3 consists of 400 amino acid residues and its molecular mass calculated by electrospray mass spectrometry is 44,788 daltons, in good agreement with the value of 44,920 daltons predicted from the amino acid sequence derived from the DNA sequence. In the downstream region of the OYE3 gene, the cytochrome oxidase (COX10) gene exists with a 426-base pair intermediate sequence. Some of the physicochemical and kinetic properties of OYE2 and OYE3 have been determined. Although the two enzymes are clearly closely related, they show differences in ligand binding properties and in their catalytic activities with oxygen and cyclohexen-2-one as acceptors. PMID- 7836425 TI - Effects of bradykinin and endothelin-1 on the calcium homeostasis of mammalian cells. AB - Ca2+ mobilization from intracellular stores is a major event in the signaling cascade triggered by peptide hormone receptors. The transient rise in intracellular free Ca2+ concentration ([Ca2+]i) is well characterized, but little is known about alterations of total cell Ca. Therefore we established a technique to determine changes in total cell Ca during hormone stimulation of 45Ca-loaded cells. Bradykinin and endothelin-1 reduced total cell Ca by up to 56% in HF-15 cells, COS-7 cells, and CHO K1 cells transfected with the rat B2 receptor cDNA. In Rat-1 cells and PC-12 cells, stimulation with endothelin-1 or bradykinin did not result in a net decrease in total cell Ca at physiological extracellular Ca2+ concentration. Decrease in total cell Ca was preceded by an increase in [Ca2+]i and blunting of the transient rise in [Ca2+]i by a Ca2+ chelator prevented the hormone-induced decrease in total cell Ca. Previous reduction of total cell Ca by one hormone suppressed the transient rise in [Ca2+]i induced by another. The data present evidence that the hormones bradykinin and endothelin-1 are capable of switching off the Ca(2+)-mobilizing signal transduction pathway in a cell by depleting intracellular Ca stores. This process is accompanied by a significant reduction of total cell Ca. PMID- 7836426 TI - A topological analysis of goldfish kainate receptors predicts three transmembrane segments. AB - Glutamate receptors are the most abundant excitatory neurotransmitter receptors in vertebrate brain. We have previously cloned cDNAs encoding two homologous kainate receptors (GFKAR alpha, 45 kDa, and GFKAR beta, 41 kDa) from goldfish brain and proposed a topology with three transmembrane domains (Wo, Z. G., and Oswald, R. E. (1994) Proc. Natl. Acad. Sci. U.S.A. 91, 7154-7158). These studies have been extended using an in vitro translation/translocation system in conjunction with site-specific antibodies and point and deletion mutations. We report here that the entire region between the previously proposed third and fourth transmembrane segments is translocated and likely to be extracellular in mature receptors. This was based on the following results. 1) The entire segment was protected from Proteinase K and trypsin digestion and could be immunoprecipitated by a site-specific antibody. 2) Functional sites for N glycosylation are present in the C-terminal half of the segment, and 3) a mutation, constructed with an additional consensus site for N-glycosylation in the N-terminal half of the segment, was found to be glycosylated at that site. Given the fact that the N terminus of the protein is likely to be extracellular, this would place an even number of transmembrane segments between the extracellular N terminus and the glycosylated segment. In addition, results of N glycosylation and proteolysis protection assays of GFKAR alpha mutations indicated that the previously proposed second transmembrane segment is not a true transmembrane domain. These results provide further evidence in support of a topology with three transmembrane domains that has important implications for the relationship of structure to function in ionotropic glutamate receptors. PMID- 7836427 TI - Phase transition behavior and molecular structures of monounsaturated phosphatidylcholines. Calorimetric studies and molecular mechanics simulations. AB - High resolution differential scanning calorimetric studies were performed to investigate the thermotropic phase behavior of 26 molecular species of sn-1 saturated/sn-2 monounsaturated phosphatidylcholines. In parallel with calorimetric studies, the energy-minimized structures and steric energies of the diglyceride moieties of these monoenoic lipids were determined using a molecular mechanics approach. The combined calorimetric and computational studies led to the following results and conclusions. (i) When a single cis-carbon-carbon double bond (delta) is incorporated into a saturated diacylphosphatidylcholine molecule at any position within the central segment of the long sn-2 acyl chain, the resulting monoenoic lipid molecules will, in excess water, exhibit reduced phase transition temperature (Tm) and transition enthalpy (delta H) as they undergo the gel to liquid-crystalline phase transition. The Tm and delta H-lowering effects of the delta bond can be attributed to a decrease in the chain length of the sn-2 acyl chain, a change in the chain length difference between the sn-1 and sn-2 acyl chains, and a local perturbation of the chain-chain van der Waals interaction in the vicinity of the delta bond. (ii) For a series of positional isomers of 1-stearoyl-2-cis-octadecenoylphosphatidylcholine, C(18):C(18:1 delta n)PC, with a delta bond at different positions along the sn-2 acyl chain, the Tm value depends critically on the position of the delta bond. Specifically, the Tm value is minimal as the delta bond is located at the geometric center of the linear segment of the sn-2 acyl chain, and the Tm value is progressively increased as the delta bond migrates toward either end of the sn-2 acyl chain. (iii) The various monoenoic phosphatidylcholines under study can be divided into two groups. The Tm values of most lipids in each group can be correlated in an identical manner with their structural parameters, yielding a common Tm-structure relationship. PMID- 7836429 TI - PEST sequences do not influence substrate susceptibility to calpain proteolysis. AB - Mutations lowering the PEST score of domains surrounding the calmodulin (CaM) binding region of the plasma membrane Ca(2+)-ATPase failed to influence the susceptibility of the enzyme to mu-calpain (mu-CANP). Synthetic peptides corresponding to the high PEST score C-terminal sequences A18 and B28 had no effect on the rate of pump proteolysis by mu-CANP, i.e. the peptides did not compete for a putative high PEST score recognition site for mu-CANP in the pump molecule. An accessible CaM-binding region appears to be critical for substrate (i.e. the Ca2+ pump) proteolysis and probably also for its recognition by mu CANP; phosphorylation of the CaM-binding domain of the pump or its occupation by CaM significantly decreased the rate of proteolysis. PMID- 7836428 TI - Unwinding of nucleosomal DNA by a DNA helicase. AB - We have asked whether a DNA helicase can unwind DNA contained within both isolated native chromatin and reconstituted chromatin containing regularly spaced arrays of nucleosome cores on a linear tandem repeat sequence. We find that Escherichia coli recBCD enzyme is capable of unwinding these DNA substrates and displacing the nucleosomes, although both the rate and the processivity of enzymatic unwinding are inhibited (a maximum of 3- and > 25-fold, respectively) as the nucleosome density on the template is increased. The observed rate of unwinding is not affected if the histone octamer is chemically cross-linked; thus, dissociation, or splitting, of the histone octamer is not required for unwinding to occur. The unwinding of native chromatin isolated from HeLa cell nuclei occurs both in the absence and in the presence of linker histone H1. These results suggest that as helicases unwind DNA, they facilitate nuclear processes by acting to clear DNA of histones or DNA-binding proteins in general. PMID- 7836430 TI - Differential requirement for p21ras activation in the metabolic signaling by insulin. AB - To evaluate the role of the "Ras pathway" in mediating metabolic signaling by insulin, we employed lovastatin to exhibit isoprenilation of Ras proteins in Rat 1 fibroblasts transfected with human insulin receptors (HIRc cells) and in differentiated 3T3-L1 adipocytes. Lovastatin blocked an ability of insulin to activate p21ras and mitogen-activated protein kinase. Lovastatin also significantly (p < 0.01) reduced insulin effects on thymidine incorporation and glucose incorporation into glycogen. Nevertheless, an effect of insulin on glucose uptake remained unaffected. It appears that in contrast to its mitogenic action and to its effect on glycogenesis, an effect of insulin on glucose uptake does not require p21ras activation. PMID- 7836431 TI - The expression and intracellular distribution of the heat-stable protein kinase inhibitor is cell cycle regulated. AB - The heat-stable protein kinase inhibitor (PKI) is a potent and specific inhibitor of the catalytic (C) subunit of the cAMP-dependent protein kinase. We report the isolation of a polyclonal antibody raised to purified recombinant PKI alpha. Using this antibody, the intracellular distribution of endogenous PKI alpha was assessed by immunostaining. The PKI alpha expression and intracellular distribution varied as a function of cell cycle progression. PKI alpha expression appeared low in serum-starved cells and in cells in G1 and increased as cells progressed through S phase. Its distribution became increasingly nuclear as cells entered G2/M. Nuclear levels of PKI alpha remained high through cell division and decreased again as cells reentered G1. The cell cycle regulated expression and nuclear distribution suggests a specific role for PKI alpha in the nucleus during the G2/M phases of the cell cycle. Consistent with this, microinjection of PKI alpha antibody into serum-starved cells prevented their subsequent cell cycle progression. Similarly, overexpression of C subunit in cells arrested at the G1/S boundary prevented their subsequent division. Together these results support the idea that PKI alpha plays an important role in the inhibition of nuclear C subunit activity required for cell cycle progression, although a determination of the relative amounts of endogenous nuclear PKI and C-subunit will be required to substantiate this hypothesis. PMID- 7836432 TI - Role for ceramide in cell cycle arrest. AB - The dependence of some cell types on serum factors for growth may represent a powerful, but poorly studied, model for antimitogenic pathways. In this study, we examine ceramide as a candidate intracellular mediator of serum factor dependence. In Molt-4 leukemia cells, serum withdrawal caused a significant arrest in cell cycle progression (80% of cells in G0/G1), accompanied by a modest apoptotic cell death (12%). Serum deprivation of these cells resulted in significant sphingomyelin hydrolysis (72%; corresponding to hydrolysis of 47 pmol/nmol phosphate), which was accompanied by a profound and progressive elevation (up to 10-15-fold) in endogenous levels of ceramide. Withdrawal of serum caused the activation of a distinct, particulate, and magnesium-dependent sphingomyelinase. The addition of exogenous C6-ceramide induced a dramatic arrest in the G0/G1 phase of the cell cycle comparable to the effects observed with serum withdrawal, albeit occurring much sooner. Unlike serum withdrawal, however, the addition of C6-ceramide resulted in more pronounced apoptosis. Because of the previously noted ability of exogenously added phorbol esters to inhibit ceramide mediated apoptosis, we investigated the hypothesis that endogenous activation of the diacylglycerol/protein kinase C pathway may modulate the response to serum withdrawal. Indeed, serum withdrawal resulted in 3-4-fold elevation in endogenous diacylglycerol levels. The addition of exogenous diacylglycerols resulted in selective attenuation of ceramide's effects on apoptosis but not on cell cycle arrest. Thus, the combination of ceramide and diacylglycerol recapitulated the complex effects of serum withdrawal on cell cycle arrest and apoptosis. These studies identify a novel role for ceramide in cell cycle regulation, and they may provide the first evidence for an intracellular signal transduction pathway in mammalian cells mediating cell cycle arrest. These studies also underscore the importance of lipid second messengers and the significance of the interplay between glycerolipid-derived and sphingolipid-derived lipid mediators. PMID- 7836433 TI - ATP synthase complex. Proximities of subunits in bovine submitochondrial particles. AB - The catalytic sector, F1, and the membrane sector, F0, of the mitochondrial ATP synthase complex are joined together by a 45-A-long stalk. Knowledge of the composition and structure of the stalk is crucial to investigating the mechanism of conformational energy transfer between F0 and F1. This paper reports on the near neighbor relationships of the stalk subunits with one another and with the subunits of F1 and F0, as revealed by cross-linking experiments. The preparations subjected to cross-linking were bovine heart submitochondrial particles (SMP) and F1-deficient SMP. The cross-linkers were three reagents of different chemical specificities and different lengths of cross-linking from zero to 10 A. Cross linked products were identified after gel electrophoresis of the particles and immunoblotting with subunit-specific antibodies to the individual subunits alpha, beta, gamma, delta, OSCP, F6, A6L, a (subunit 6), b, c, and d. The results suggested that the two b subunits form the principal stem of the stalk to which OSCP, d, and F6 are bound independent of one another. Subunits b, OSCP, d, and F6 cross-linked to alpha and/or beta, but not to gamma or delta. The COOH-terminal half of A6L, which is extramembranous, cross-linked to d but not to any other stalk or F1 subunit. No cross-links of subunits a and c with any stalk or F1 subunits were detected. In F1-deficient SMP, cross-linked b+b and d+F6 dimers appeared, and the extent of cross-linking between b and OSCP diminished greatly. The addition of F1 to F1-deficient particles appeared to reverse these changes. Treatment of F1-deficient particles with trypsin rapidly hydrolyzed away OSCP and F6, fragmented b to membrane-bound 18-, 12-, and 8-9-kDa antigenic fragments, which cross-linked to d and/or with one another. Trypsin also removed the COOH terminal part of A6L, but the remainder still cross-linked to subunit d. Models showing the near neighbor relationships of the stalk subunits with one another and with the alpha and beta subunits at a level near the proximal end (bottom) of F1 and at the membrane-matrix interface are presented. PMID- 7836434 TI - High hydrostatic pressure induces the dissociation of cpn60 tetradecamers and reveals a plasticity of the monomers. AB - Hydrostatic pressures up to 2 kbar have been used to form monomers from the 14 subunit oligomer of the chaperonin, Cpn60. The fluorescence of 1,1'-bi(4-anilino) naphthalene-5,5'-disulfonic acid (bisANS), followed at high pressure, demonstrated an increase in hydrophobic exposure on dissociation. Cpn60 dissociated with first order kinetics. The transition occurred between 1.3 and 2 kbar (P50 = 1.75 kbar), and it was facilitated by MgATP (P50 = 1.1 kbar). With MgATP, the fluorescence showed a rapid first order phase (t1/2 = 3.7 min) in addition to a phase that was similar to the single phase for Cpn60 alone (t1/2 = 11.4 min). The bisANS fluorescence decreased slowly after depressurization, and the relaxation was faster at 25 degrees C (t1/2 = 58 h) than at 4 degrees C (t1/2 = 86 h) and faster still if the sample at 4 degrees C contained MgATP when it was pressurized (t1/2 = 18 h). There was no significant effect if the MgATP was added after depressurization. Analytical ultracentrifugation, after depressurization, confirmed that metastable monomers were produced that slowly reassociated to form the oligomers (t1/2 = 150 h at 25 degrees C). Immediately after depressurization, the monomers (a) had all three sulfhydryl groups exposed for labeling with 6 iodoacetamidofluorescein, (b) showed a proteolytic susceptibility that was intermediate between native Cpn60 and Cpn60 in 2.5 M urea, and (c) were not able to capture a folding intermediate of the enzyme rhodanese. After incubation at atmospheric pressure, monomeric Cpn60 regained the ability to interact with rhodanese intermediates, and the sulfhydryl reactivity fell before significantly reassociating to 14-mers. The different rates of recovery of the native properties indicate that a complex series of conformational events occur following depressurization. Finally, the monomers resulting from pressure were different from those produced from Cpn60 by the action of 2.5 M urea. These results demonstrate that there is a fast, pressure-induced dissociation of the Cpn60 14-mer followed by a conformational drift of the dissociated monomers that can be influenced by the presence of MgATP. PMID- 7836435 TI - Phosphorylation modulates the function of the calcium release channel of sarcoplasmic reticulum from cardiac muscle. AB - The cardiac calcium release channel (CRC) of sarcoplasmic reticulum vesicles was incorporated into planar lipid membranes to evaluate modulation of channel activity by phosphorylation and dephosphorylation. For this purpose a microsyringe application directly to the membrane was used to achieve sequential and multiple treatments of channels with highly purified kinases and phosphatases. Cyclic application of protein kinase A (PKA) or Ca2+/calmodulin dependent protein kinase II (CalPK) and potato acid phosphatase or protein phosphatase 1 revealed a channel block by Mg2+ (-mM), that is referable to dephosphorylated states of the channel, and that the Mg2+ block could be removed by phosphorylation of the CRC by either PKA or CalPK. By contrast, activation of endogenous CalPK (end CalPK) led to channel closure which could be reversed by dephosphorylation using potato acid phosphatase or protein phosphatase 1. Calmodulin by itself (which activates end CalPK in the presence of MgATP) blocks the channel in the dephosphorylated state, which can be overcome by treatment with CalPK but not PKA. Our findings reveal important insights regarding channel regulation of the ryanodine receptor: 1) the calcium release channel must be phosphorylated to be in the active state at conditions approximating physiological Mg2+ concentrations (-mM); and 2) there are multiple sites of phosphorylation on the calcium release channel with different functional consequences, which may be relevant to the regulation of E-C coupling. Phosphorylation of the CRC may be involved in recruitment of active channels, and/or it may be directly involved in each Ca2+ contraction cycle of the heart. For example, Ca2+ release may require phosphorylation of the CRC by protein kinases at sites which overcome the block by Mg2+. Inactivation may involve CRC block by calmodulin and/or phosphorylation by endogenous CalPK at the junctional face membrane. PMID- 7836436 TI - Contribution of aromatic moieties of tyrosine 133 and of the anionic subsite tryptophan 86 to catalytic efficiency and allosteric modulation of acetylcholinesterase. AB - Substitution of Trp-86, in the active center of human acetylcholinesterase (HuAChE), by aliphatic but not by aromatic residues resulted in a several thousandfold decrease in reactivity toward charged substrate and inhibitors but only a severalfold decrease for noncharged substrate and inhibitors. The W86A and W86E HuAChE enzymes exhibit at least a 100-fold increase in the Michaelis-Menten constant or 100-10,000-fold increase in inhibition constants toward various charged inhibitors, as compared to W86F HuAChE or the wild type enzyme. On the other hand, replacement of Glu-202, the only acidic residue proximal to the catalytic site, by glutamine resulted in a nonselective decrease in reactivity toward charged and noncharged substrates or inhibitors. Thus, the quaternary nitrogen groups of substrates and other active center ligands, are stabilized by cation-aromatic interaction with Trp-86 rather than by ionic interactions, while noncharged ligands appear to bind to distinct site(s) in HuAChE. Analysis of the Y133F and Y133A HuAChE mutated enzymes suggests that the highly conserved Tyr-133 plays a dual role in the active center: (a) its hydroxyl appears to maintain the functional orientation of Glu-202 by hydrogen bonding and (b) its aromatic moiety maintains the functional orientation of the anionic subsite Trp-86. In the absence of aromatic interactions between Tyr-133 and Trp-86, the tryptophan acquires a conformation that obstructs the active site leading, in the Y133A enzyme, to several hundredfold decrease in rates of catalysis, phosphorylation, or in affinity to reversible active site inhibitors. It is proposed that allosteric modulation of acetylcholinesterase activity, induced by binding to the peripheral anionic sites, proceeds through such conformational change of Trp-86 from a functional anionic subsite state to one that restricts access of substrates to the active center. PMID- 7836437 TI - Characterization of a mitochondrial metallopeptidase reveals neurolysin as a homologue of thimet oligopeptidase. AB - We have isolated a metallopeptidase from rat liver. The peptidase is primarily located in the mitochondrial intermembrane space, where it interacts non covalently with the inner membrane. The enzyme hydrolyzes oligopeptides, the largest substrate molecule found being dynorphin A1-17; it has no action on proteins, and does not interact with alpha 2-macroglobulin, and can therefore be classified as an oligopeptidase. We term the enzyme oligopeptidase M. Oligopeptidase M acts similarly to thimet oligopeptidase (EC 3.4.24.15) on bradykinin and several other peptides, but hydrolyzes neurotensin exclusively at the -Pro+Tyr- bond (the symbol + is used to indicate a scissile peptide bond) rather than the -Arg+Arg- bond. The enzyme is inhibited by chelating agents and some thiol-blocking compounds, but differs from thimet oligopeptidase in not being activated by thiol compounds. The peptidase is inhibited by Pro-Ile, unlike thimet oligopeptidase, and the two enzymes are separable in chromatography on hydroxyapatite. The N-terminal amino acid sequence of rat mitochondrial oligopeptidase M contains 19 out of 20 residues identical with a segment of rabbit microsomal endopeptidase and 17 matching the corresponding segment of pig soluble angiotensin II-binding protein. Moreover, the rat protein is recognized by a monoclonal antibody against rabbit soluble angiotensin II-binding protein, all of which is consistent with these proteins being species variants of a single protein that is a homologue of thimet oligopeptidase. The biochemical properties of the mitochondrial oligopeptidase leave us in no doubt that it is neurolysin (EC 3.4.24.16), for which no sequence has previously been reported, and which has not been thought to be mitochondrial. PMID- 7836438 TI - The effects of wortmannin on rat skeletal muscle. Dissociation of signaling pathways for insulin- and contraction-activated hexose transport. AB - Both the anabolic hormone insulin and contractile activity stimulate the uptake of glucose into mammalian skeletal muscle. In this study, we examined the role of phosphatidylinositol 3-kinase (PI 3-kinase), a putative mediator of insulin actions, in the stimulation of hexose uptake in response to hormone and contraction. Phosphatidylinositol 3,4-bisphosphate and phosphatidylinositol 3,4,5 triphosphate accumulate in skeletal muscle exposed to insulin but not hypoxia, which mimics stimulation of the contractile-dependent pathway of hexose transport activation. The fungal metabolite wortmannin, an inhibitor of PI 3-kinase, completely blocks the appearance of 3'-phospholipids in response to insulin. Moreover, wortmannin entirely prevented the increase in hexose uptake in muscle exposed to insulin but was without effect on muscle stimulated by repetitive contraction or hypoxia. These results support the view that PI 3-kinase is involved in the signaling pathways mediating insulin-responsive glucose transport in skeletal muscle but is not required for stimulation by hypoxia or contraction. Furthermore, these data indicate that there exist at least two signaling pathways leading to activation of glucose transport in skeletal muscle with differential sensitivities to wortmannin. PMID- 7836439 TI - Rhodopsin mutants discriminate sites important for the activation of rhodopsin kinase and Gt. AB - The cytoplasmic loops of rhodopsin, the rod cell photoreceptor, play important regulatory roles in the activation of both rhodopsin kinase and the rod cell G protein, Gt. A number of studies have identified domains in rhodopsin that are important for the activation of Gt. However, less is known concerning the cytoplasmic regions that regulate phosphorylation of the photoreceptor by rhodopsin kinase. To identify regions that participate in these processes, a series of alanine mutations were generated in the three cytoplasmic loops of rhodopsin and transiently expressed in HEK-293 cells. Membranes prepared from these cells were reconstituted with the opsin chromophore, 11-cis-retinal, and characterized for their ability to undergo light-dependent phosphorylation by rhodopsin kinase and to catalyze GTP gamma S (guanosine 5'-O-(3 thiotriphosphate)) binding to Gt. We have identified mutants that fall into three distinct categories: 1) those that show altered phosphorylation but normal Gt activation, such as T62A/V63A/Q64A and R147A/F148A/G149A in Loops I and II, respectively; 2) mutants that have reduced ability to activate Gt but are phosphorylated normally, including T242A/T243A and V250A/T251A/R252A in Loop III; and 3) mutants that affect both phosphorylation and Gt activation, including A233G/A234G/A235G and A233N/A234N/A235N in Loop III. The use of these two assays in parallel have allowed us to distinguish the presence of distinct functional domains within the cytoplasmic loops which are specific for interaction with rhodopsin kinase or Gt. PMID- 7836440 TI - Conversion of bovine pancreatic phospholipase A2 at a single site into a competitor of neurotoxic phospholipases A2 by site-directed mutagenesis. AB - A 45-kDa polypeptide preferentially present in neuronal membranes was previously identified as a subunit of a binding (or receptor) protein for several phospholipase A2 variants with neurotoxicity, including crotoxin, by chemical cross-linking experiments (Yen, C.-H., and Tzeng, M.-C. (1991) Biochemistry 30, 11473-11477). The binding of crotoxin to this receptor protein was completely suppressed by sufficient F22Y, a mutated bovine pancreatic phospholipase A2 generated by site-directed mutagenesis of Phe22 of the wild-type enzyme to Tyr. The IC50 of this inhibition was estimated to be 1 microM. In sharp contrast, the wild-type enzyme gave no effect even at 50 microM. This mutation resulted in only minor and localized structural perturbations with little effect on enzymatic activity. Other phospholipase A2 molecules capable of competing with crotoxin for this binding invariably have Tyr at this position. It was concluded that this Tyr residue is an important determinant for the binding of a number of phospholipase A2 variants to the 45-kDa receptor. PMID- 7836441 TI - Stable amplification of the S-adenosylmethionine decarboxylase gene in Chinese hamster ovary cells. AB - A Chinese hamster ovary cell subline (CHO/664) > 1000-fold resistant to the S adenosylmethionine decarboxylase (AdoMetDC) inhibitor, CGP-48664 (4 (aminoiminomethyl)-2,3-dihydro-1H-inden-1-one diaminomethylenehydrazone), has been developed and characterized. The cells were also cross-resistant to the highly specific nucleoside analog inhibitor of AdoMetDC, MDL-73811. These unique cells stably overexpress AdoMetDC due to a 10-16-fold amplification of the AdoMetDC gene, which resulted in a similar increase in AdoMetDC transcript levels. In the presence of 100 microM CGP-48664, the CHO/664 cells displayed AdoMetDC activities similar to the parental line. Following removal of the inhibitor, AdoMetDC activity increased steadily over 20 days to 10-12 times that found in parental CHO cells. Decarboxylated (dc) AdoMet pools accumulated rapidly from < 5 pmol/10(6) cells to approximately 1000-1500 pmol/10(6) cells at 3 days due to diffusion away of intracellular inhibitor and to the depletion of putrescine and spermidine as aminopropyl acceptors in dcAdoMet-mediated synthase reactions. Polyamine pools shifted as putrescine, and spermidine pools were processed forward to spermine. During the period from 3 days to 20 days, dcAdoMet pools fell steadily and eventually stabilized at 100-200 pmol/10(6) cells. Providing excess putrescine at this time as an aminopropyl acceptor rapidly lowered dcAdoMet pools and led to a near normalization of polyamine pools, indicating that both dcAdoMet and putrescine are essential in maintaining steady state polyamine pool profiles. As with cell line variants that overproduce ornithine decarboxylase, polyamine transport was found to be increased in CHO/664 cells due to an apparent inability of the system to down-regulate polyamine transport in response to polyamine excess. Given the unique metabolic disturbances seen in these cells, we anticipate that in addition to providing a useful system for evaluating the specificity of newly developed AdoMetDC inhibitors, they will undoubtedly prove valuable for investigating the various regulatory interrelationships involved in polyamine homeostasis and possibly other aspects of purine metabolism. PMID- 7836442 TI - Interaction with TrkA immobilizes gp75 in the high affinity nerve growth factor receptor complex. AB - It has been proposed that the high affinity nerve growth factor (NGF) receptor required for NGF response is a complex of two receptor proteins, gp75 and the tyrosine kinase TrkA, but direct biochemical or biophysical evidence has been lacking. We have previously shown using fluorescence recovery after photobleaching that gp75 is highly mobile on NGF-nonresponsive cells, but relatively immobile on NGF-responsive cells. In this report, we show that a physical interaction with TrkA causes gp75 immobilization. We found that gp75 is relatively mobile on TrkA negative nnr5 cells, a PC12 variant which is nonresponsive to NGF. In contrast, on T14 nnr5 cells (which bear a TrkA expression vector) gp75 is relatively immobile. Similarly, using baculoviruses to express gp75 and TrkA on Sf9 insect cells, we found that TrkA immobilizes gp75 molecules. The related receptor, TrkB, caused a more modest immobilization of gp75. Immobilization was found to require intact TrkA kinase and gp75 cytoplasmic domains, paralleling the requirements of high affinity binding of NGF. Analysis of gp75 diffusion coefficients indicates that mutated gp75 and TrkA molecules may form a complex, even in the absence of the ability to bind NGF with high affinity. PMID- 7836443 TI - The conserved G/F motif of the DnaJ chaperone is necessary for the activation of the substrate binding properties of the DnaK chaperone. AB - The universally conserved DnaK and DnaJ molecular chaperone proteins bind in a coordinate manner to protein substrates to prevent aggregation, to disaggregate proteins, or to regulate proper protein function. To further examine their synergistic mechanism of action, we constructed and characterized two DnaJ deletion proteins. One has an 11-amino-acid internal deletion that spans amino acid residues 77-87 (DnaJ delta 77-87) and the other amino acids 77-107 (DnaJ delta 77-107). The DnaJ delta 77-87 mutant protein, was normal in all respects analyzed. The DnaJ delta 77-107 mutant protein has its entire G/F (Gly/Phe) motif deleted. This motif is found in most, but not all DnaJ family members. In vivo, DnaJ delta 77-107 supported bacteriophage lambda growth, albeit at reduced levels, demonstrating that at least some protein function was retained. However, DnaJ delta 77-107 did not exhibit other wild type properties, such as proper down regulation of the heat-shock response, and had an overall poisoning effect of cell growth. The purified DnaJ delta 77-107 protein was shown to physically interact and stimulate DnaK's ATPase activity at wild type levels, unlike the previously characterized DnaJ259 point mutant (DnaJH33Q). Moreover, both DnaJ delta 77-107 and DnaJ259 bound to substrate proteins, such as sigma 32, at similar affinities as DnaJ+. However, DnaJ delta 77-107 was found to be largely defective in activating the ATP-dependent substrate binding mode of DnaK. In vivo, the ability of the mutant DnaJ proteins to down-regulate the heat-shock response was correlated only with their in vitro ability to activate DnaK to bind sigma 32, in an ATP-dependent manner, and not with their ability to bind sigma 32. We conclude, that although the G/F motif of DnaJ does not directly participate in the stimulation of DnaK's ATPase activity, nevertheless, it is involved in an important manner in modulating DnaK's substrate binding activity. PMID- 7836444 TI - A derivative of NADP mobilizes calcium stores insensitive to inositol trisphosphate and cyclic ADP-ribose. AB - We have previously shown that alkaline treatment of NADP generates a derivative which can mobilize Ca2+ from sea urchin egg homogenates (Clapper, D. L., Walseth, T. F., Dargie, P. J., and Lee, H. C. (1987) J. Biol. Chem. 262, 9561-9568). In this study, the active derivative was purified and shown by high pressure liquid chromatography to be distinct from NADP and NADPH. However, its proton NMR spectrum was virtually identical to that of NADP. The mass of its molecular ion was measured by high resolution mass spectrometry to be 743.0510, one mass unit larger than the corresponding ion of NADP. These results are consistent with the active derivative being nicotinic acid adenine dinucleotide phosphate (NAADP). Ca2+ release induced by NAADP was saturable with a half-maximal concentration of about 30 nM. The release was specific since NADP and nicotinic acid adenine dinucleotide were ineffective even at 10-40-fold higher concentrations. The NAADP dependent Ca2+ release showed desensitization and was insensitive to heparin and a specific antagonist of cyclic ADP-ribose (cADPR), 8-amino-cADPR. The release mechanism did not require calmodulin. This is similar to the inositol trisphosphate-sensitive release but distinct from that of cADPR. That the NAADP sensitive Ca2+ stores were different from those sensitive to inositol trisphosphate- or cADPR was further indicated by their differences in distribution on Percoll density gradients. Microinjection of NAADP into live sea urchin eggs induced transient elevation of intracellular Ca2+ and triggered the cortical reaction, indicating the NAADP-dependent mechanism is operative in intact cells. PMID- 7836445 TI - Stabilization of calmodulin-dependent protein kinase II through the autoinhibitory domain. AB - The active 30-kDa chymotryptic fragment of calmodulin-dependent protein kinase II (CaM kinase II), devoid of the autoinhibitory domain, and the enzyme, autothiophosphorylated at Thr286/Thr287, were much more labile than was the original native enzyme. They were markedly stabilized by synthetic peptides, designed after the sequence around the autophosphorylation site in the autoinhibitory domain, such as autocamtide-2 and CaMK-(281-309), but such marked stabilizations were not observed with the ordinary exogenous substrates, such as syntide-2. These results suggest that the autoinhibitory domain of CaM kinase II plays a crucial role in stabilizing the enzyme. A nonphosphorylatable analog of autocamtide-2, AIP, strongly inhibited the activity of the 30-kDa fragment. Kinetic analysis revealed that the inhibition by AIP was competitive with respect to autocamtide-2 and CaMK-(281-289) and noncompetitive with respect to syntide-2 and ATP/Mg2+, suggesting that CaM kinase II possesses at least two distinct substrate-binding sites; one for ordinary exogenous substrates such as syntide-2 and the other for an endogenous substrate, the autophosphorylation site (Thr286/Thr287) in the autoinhibitory domain. Fluorescence analysis of the binding of 7-nitrobenz-2-oxa-1,3-diazole-4-yl labeled AIP to the 30-kDa fragment also supported this contention. Thus, the autoinhibitory domain appears to play a crucial role in keeping the enzyme stable by binding to the substrate-binding site for the autophosphorylation site. PMID- 7836446 TI - Two heads are required for phosphorylation-dependent regulation of smooth muscle myosin. AB - Recent structural evidence (Rayment, I., Holden, H. M., Whittaker, M., Yohn, C. B., Lorenz, M., Holmes, K. C., and Milligan, R. A. (1993) Science 261, 58-65) suggests that the two heads of skeletal muscle myosin interact when the protein is bound to filamentous actin. Direct chemical cross-linking experiments show that the two heads of smooth muscle myosin interact in the presence of filamentous actin and the absence of ATP (Onishi, H., Maita, T., Matsuda, G., and Fujiwara, K. (1992) Biochemistry 31, 1201-1210). Head-head interactions may be important in the mechanism of phosphorylation-dependent regulation of smooth muscle myosin. To explore the structural elements essential for phosphorylation dependent regulation, we purified a proteolytic fragment of chicken gizzard myosin containing only one head attached to an intact tail. This molecule contained a partially digested regulatory light chain, which was replaced with exogenously added intact light chain in either the thiophosphorylated or the unphosphorylated state. Control experiments showed that this replacement was nearly quantitative and did not alter the actin-activated ATPase of this myosin. Electron micrographs confirmed that the single-headed preparation contained an intact form of single-headed myosin. The unphosphorylated single-headed myosin hydrolyzed ATP rapidly and moved actin filaments in an in vitro motility assay. Phosphorylation had minimal effects upon these properties. Therefore, we conclude that phosphorylation-dependent regulation in this myosin requires two heads. These findings may have important implications in studies of other regulated motor proteins that contain two motor domains. PMID- 7836447 TI - Mat-8, a novel phospholemman-like protein expressed in human breast tumors, induces a chloride conductance in Xenopus oocytes. AB - We recently identified a novel 8-kDa transmembrane protein, Mat-8, that is expressed in a subset of murine breast tumors. We have now cloned a cDNA encoding the human version of Mat-8 and show that it is expressed both in primary human breast tumors and in human breast tumor cell lines. The extracellular and transmembrane domains of Mat-8 are homologous to those of phospholemman (PLM), the major plasmalemmal substrate for cAMP-dependent protein kinase and protein kinase C in several different tissues. PLM, which induces chloride currents when expressed in Xenopus oocytes, contains consensus phosphorylation sites for both cAMP-dependent protein kinase A and protein kinase C in its cytoplasmic domain. In contrast, the cytoplasmic domain of Mat-8 contains no such consensus phosphorylation sites and is, in fact, unrelated to the cytoplasmic domain of PLM. RNA blot analysis reveals that Mat-8 and PLM exhibit distinct tissue specific patterns of expression. We show that expression of Mat-8 in Xenopus oocytes induces hyperpolarization-activated chloride currents similar to those induced by PLM expression. These findings suggest that Mat-8 and PLM, the products of distinct genes, are related proteins that serve as Cl- channels or Cl channel regulators but have different roles in cell and organ physiology. PMID- 7836448 TI - The DnaK chaperone system of Escherichia coli: quaternary structures and interactions of the DnaK and GrpE components. AB - The DnaK (Hsp70), DnaJ, and GrpE heat shock proteins of Escherichia coli constitute a cellular chaperone system for protein folding. Substrate interactions are controlled by the ATPase activity of DnaK which itself is regulated by the nucleotide exchange factor GrpE. To understand the structure function relationship of this chaperone system, the quaternary structures of DnaK, GrpE, and DnaK-GrpE complexes were analyzed by gel filtration chromatography, dynamic light scattering, analytical ultracentrifugation, and native gel electrophoresis. GrpE formed dimers in solution. DnaK formed monomers, dimers, and higher mole mass oligomers, the equilibrium between these forms being dependent on the DnaK concentration. The behavior of DnaK and GrpE in gel filtration and dynamic light scattering suggested elongated shapes of both molecules. In the absence of added nucleotides, DnaK and GrpE formed stable complexes containing one molecule of DnaK and two molecules of GrpE. A 44-kDa N terminal ATPase fragment of DnaK also formed complexes with GrpE with the same 1:2 stoichiometry. DnaK-GrpE complex formation was unaffected by elimination of DnaK-bound nucleotides or addition of saturating concentrations of a DnaK peptide substrate. These findings allow the correlation of DnaK-GrpE interactions with a role for GrpE in the functional cycle of the DnaK chaperone system. PMID- 7836449 TI - Substructure of the amidotransferase domain of mammalian carbamyl phosphate synthetase. AB - The amidotransferase or glutaminase (GLNase) domain of mammalian carbamyl phosphate synthetase (CPSase), part of the 243-kDa CAD polypeptide, consists of a carboxyl half that is homologous to all trpG-type amidotransferases and an amino half unique to the carbamyl phosphate synthetases. The two halves of the mammalian GLNase domain have been cloned separately, expressed in Escherichia coli, and purified. The 21-kDa carboxyl half, the catalytic subdomain, is extraordinarily active. The kcat is 347-fold higher and the KGlnm is 40-fold lower than the complete GLNase domain. Unlike the GLNase domain, the catalytic subdomain does not form a stable hybrid complex with the E. coli CPSase synthetase subunit. Nevertheless, titration of the synthetase subunit with the catalytic subdomain partially restores glutamine-dependent CPSase activity. The 19-kDa amino half, the interaction subdomain, binds tightly to the E. coli CPSase large subunit. Thus, the GLNase domain consists of two subdomains which can autonomously fold and function. The catalytic subdomain weakly interacts with the synthetase domain and has all of the residues necessary for catalysis. The interaction subdomain is required for complex formation and also attenuates the intrinsically high activity of the catalytic subdomain and, thus, may be a key element of the interdomain functional linkage. PMID- 7836450 TI - Purification and characterization of human chitotriosidase, a novel member of the chitinase family of proteins. AB - Recently we noted (Hollak, C.E.M., van Weely, S., van Oers, M.H.J., and Aerts, J.M.F.G. (1994) J. Clin. Invest. 93, 1288-1292) that the clinical manifestation of Gaucher disease is associated with a several hundred-fold increase in chitotriosidase activity in plasma. We report on the purification and characterization of the protein. Two major isoforms of chitotriosidase with isoelectric points of 7.2 and 8.0 and molecular masses of 50 and 39 kDa, respectively, were purified from the spleen of a Gaucher patient. The N-terminal amino acid sequence of the two forms proved to be identical. An antiserum raised against the purified 39-kDa chitotriosidase precipitated all isozymes. Chitotriosidase activity was earlier found to be completely absent in some individuals. These findings in combination suggest that a single gene may encode the different isoforms of chitotriosidase. Both the N-terminal sequence and an internal sequence chitotriosidase proved to be homologous to sequences in proteins that are members of the chitinase family (Hakala, B.E., White,C., and Recklies, A.D. (1993) J. Biol. Chem. 268, 25803-25810). The human chitotriosidase described here showed chitinolytic activity toward artificial substrates as well as chitin and may therefore be considered to be a chitinase. PMID- 7836451 TI - Regulation of cytoplasmic pH in osteoclasts. Contribution of proton pumps and a proton-selective conductance. AB - Osteoclasts resorb bone by secreting protons into an extracellular resorption zone through vacuolar-type proton pumps located in the ruffled border. The present study was undertaken to evaluate whether proton pumps also contribute to intracellular pH (pHi) regulation. Fluorescence imaging and photometry, and electrophysiological methods were used to characterize the mechanisms of pH regulation in isolated rabbit osteoclasts. The fluorescence of single osteoclasts cultured on glass coverslips and loaded with a pH-sensitive indicator was measured in nominally HCO(3-)-free solutions. When suspended in Na(+)-rich medium, the cells recovered from an acute acid load primarily by means of an amiloride-sensitive Na+/H+ antiporter. However, rapid recovery was also observed in Na(+)-free medium when K+ was used as the substitute. Bafilomycin-sensitive, vacuolar-type pumps were found to contribute marginally to pH regulation and no evidence was found for K+/H+ exchange. In contrast, pHi recovery in high K+ medium was largely attributed to a Zn(2+)-sensitive proton conductive pathway. The properties of this conductance were analyzed by patch-clamping osteoclasts in the whole-cell configuration. Depolarizing pulses induced a slowly developing outward current and a concomitant cytosolic alkalinization. Determination of the reversal potential during ion substitution experiments indicated that the current was due to H+ (equivalent) translocation across the membrane. The H+ current was greatly stimulated by reducing pHi, consistent with a homeostatic role of the conductive pathway during intracellular acidosis. These results suggest that vacuolar-type proton pumps contribute minimally to the recovery of cytoplasmic pH from intracellular acid loads. Instead, the data indicate the presence of a pH- and membrane potential-sensitive H+ conductance in the plasma membrane of osteoclasts. This conductance may contribute to translocation of charges and acid equivalents during bone resorption and/or generation of reactive oxygen intermediates by osteoclasts. PMID- 7836452 TI - Synaptic core complex of synaptobrevin, syntaxin, and SNAP25 forms high affinity alpha-SNAP binding site. AB - SNAPs (soluble NSF attachment proteins) are cytoplasmic proteins that bind to specific membrane receptors and mediate the membrane binding of NSF (N ethylmaleimide-sensitive factor), a protein that is required for membrane fusion reactions. Three synaptic proteins in brain (SNAP25 (synaptosomal-associated protein of 25 kDa; no relation to the SNAPs for NSF), synaptobrevin/VAMP, and syntaxin) were identified as SNAP receptors by affinity chromatography on immobilized alpha-SNAP complexed to NSF (Sollner, T., Whiteheart, S. W., Brunner, M., Erdjument-Bromage, H., Geromanos, S., Tempst, P. and Rothman, J. E. (1993) Nature 362, 318-324). However, the nature of the alpha-SNAP binding site is unclear. We now show that alpha-SNAP binds tightly to the complex of syntaxin with synaptobrevin. SNAP25 is not required for tight binding of alpha-SNAP to this complex but stabilizes the syntaxin-synaptobrevin complex by forming a trimeric core complex with it. alpha-SNAP does not bind to synaptobrevin individually and binds only weakly to syntaxin and SNAP25 in the absence of synaptobrevin. These data suggest that the complex of the vesicular protein synaptobrevin with the plasma membrane protein syntaxin is required for physiological alpha-SNAP binding. Thus, alpha-SNAP probably functions in a late step of the membrane fusion reaction after the formation of the synaptobrevin syntaxin-SNAP25 core complex. PMID- 7836453 TI - Human prochymase activation. A novel role for heparin in zymogen processing. AB - Human prochymase is packaged with heparin in mast cell granules and appears to be activated by dipeptidylpeptidase I. We show that a high affinity interaction between heparin and prochymase allows the 2-residue propeptide to be cleaved by dipeptidylpeptidase I. A conserved Glu in the propeptide is necessary for this heparin effect. Following propeptide cleavage, capture of the newly generated NH2 terminus by an "activation groove" on the enzyme activates the enzyme and concurrently prevents a progressive degradation of the NH2 terminus by dipeptidylpeptidase I. Surrogate peptide studies show that the activation groove is unoccupied in prochymase and is specific for the chymase NH2 terminus. These observations indicate that heparin is an important cofactor in the prochymase activation process and explain how dipeptidylpeptidase I, a nonspecific processing enzyme, can effect a specific cleavage of the zymogen propeptide. PMID- 7836454 TI - Local and global structural properties of the HIV-MN V3 loop. AB - Studies of the feasibility of a subunit vaccine to protect against human immunodeficiency virus (HIV) infection have principally focused on the third variable (V3) loop. The principal neutralizing determinant (PND) of HIV-1 is located inside the V3 loop of the surface envelope glycoprotein, gp120. However, progress toward a PND-based vaccine has been impeded by the amino acid sequence variability in the V3 loops of different HIV isolates. Theoretical studies revealed that the variability in sequence and structure of the V3 loop is confined to the N- and C-terminal sides of the conserved GPG crest. This leaves three regions of the V3 loop conserved both in sequence and secondary structure. We present the results of NMR studies that test the validity of our theoretical predictions. Structural studies are reported for the HIV-V3 loop (HIV-MN) in the linear and cyclic (S-S-bridged) forms. For the V3 loop sequence of the HIV-MN isolate, the three conserved secondary structural elements are as underlined below: turns turn helix CTRPNYNKRKRIHIGPGRAFYTTKNIIGTIROAHC Finally, the conformational requirement of the PND in the V3 loop-antibody interaction is tested by monitoring the monoclonal antibody binding to the HIV-MN V3 loop in the linear and cyclic forms by enzyme-linked immunosorbent assay. The binding data reveal that the cyclic V3 loop is a better ligand for the monoclonal antibodies than the linear form although the latter has the same sequence. This means that the monoclonal antibodies recognize the PNDs as conformational epitopes. PMID- 7836455 TI - Rational design of a mouse granulocyte macrophage-colony-stimulating factor receptor antagonist. AB - Mouse granulocyte-macrophage colony-stimulating factor (mGM-CSF) proteins with substitutions at residues in the first alpha-helix were examined for biological activity and receptor binding properties. Substitution at the buried residue His15 affected both bioactivity and receptor binding. Of the four surface-exposed positions examined (Arg11, Lys14, Lys20, and Glu21) only substitutions at Glu21 impaired bioactivity. Proteins with charge reversal substitutions at this position were partial agonists and weak antagonists of native mGM-CSF action. All substitutions at Glu21 abrogated high affinity binding. Lys14 and Lys20 substitution proteins showed various receptor binding defects. Qualitative and quantitative measurement of these binding defects identified Lys14 as a residue that interacts specifically with the beta subunit of the mGM-CSF receptor, whereas Lys20 appeared to exist at the GM-R alpha-subunit/GM-R beta-subunit interface as substitutions at this position produce both high and low affinity binding losses. These determinations permitted the design of a more potent mGM CSF antagonist. PMID- 7836456 TI - Targeting of the 67-kDa isoform of glutamic acid decarboxylase to intracellular organelles is mediated by its interaction with the NH2-terminal region of the 65 kDa isoform of glutamic acid decarboxylase. AB - The two isoforms of glutamic acid decarboxylase (GAD), GAD67 and GAD65, synthesize the neurotransmitter gamma-aminobutyric acid in neurons and pancreatic beta-cells. Previous studies suggest that GAD67 is a soluble cytosolic protein, whereas GAD65 is membrane-associated. Here, we study the intracellular distribution of GAD67 in neurons, pancreatic beta-cells, and fibroblasts transfected either with GAD65 and GAD67 together or with GAD67 alone. Neuronal GAD67 is partially recovered with GAD65 in membrane-containing pellet fractions and Triton X-114 detergent phases. The two proteins co-immunoprecipitate from extracts of brain and GAD65-GAD67 co-transfected fibroblasts, but not when extracts of GAD65 and GAD67 transfected fibroblasts were mixed and used as a starting material for immunoprecipitation. GAD67 is concentrated in the Golgi complex region in GAD65-GAD67 co-transfected fibroblasts, but not in fibroblasts transfected with GAD67 alone. A pool of neuronal GAD67 co-localizes with GAD65 in the Golgi complex region and in many synapses. The two proteins also co-localize in the perinuclear region of some pancreatic beta-cells. GAD67 interacts with the NH2-terminal region of GAD65, even in the absence of palmitoylation of this region of GAD65. Taken together, our results indicate that GAD65-GAD67 association occurs in vivo and is required for the targeting of GAD67 to membranes. PMID- 7836457 TI - How potassium affects the activity of the molecular chaperone Hsc70. I. Potassium is required for optimal ATPase activity. AB - Several functions of the 70-kilodalton heat shock cognate protein (Hsc70), such as peptide binding/release and clathrin uncoating, have been shown to require potassium ions. We have examined the effect of monovalent ions on the ATPase activity of Hsc70. The steady-state ATPase activities of Hsc70 and its amino terminal 44-kDa ATPase fragment are minimal in the absence of K+ and reach a maximum at approximately 0.1 M [K+]. Activation of the ATPase turnover correlates with the ionic radii of monovalent ions; those that are at least 0.3 A smaller (Na+ and Li+) or larger (Cs+) than K+ show negligible activation, whereas ions with radii differing only approximately 0.1 A from that of K+ (NH4+ and Rb+) activate to approximately half the turnover rate observed with K+. Single turnover experiments with Hsc70 demonstrate that ATP hydrolysis is 5-fold slower with Na+ than with K+. The equilibrium binding of ADP or ATP to Hsc70 is unperturbed when K+ is replaced with Na+. These results are consistent with a role for monovalent ions as specific cofactors in the enzymatic hydrolysis of ATP. PMID- 7836458 TI - How potassium affects the activity of the molecular chaperone Hsc70. II. Potassium binds specifically in the ATPase active site. AB - Crystallographic anomalous scattering from potassium at 1.7 A resolution reveals two monovalent ions that interact with MgADP and P(i) in the nucleotide binding cleft of wild-type recombinant bovine Hsc70 ATPase fragment. K+ at site 1 interacts with oxygens of the beta-phosphate of ADP, whereas K+ at site 2 interacts with an oxygen of P(i). Both K+ ions also interact with specific H2O molecules in the first hydration shell of the octahedrally coordinated Mg2+ ion and with specific protein ligands. In crystals that have Na+ present, K+ is replaced by a Na+ ion at site 1 and by a Na(+)-H2O pair at site 2. The K+ ions are positioned where they could stabilize binding of a beta,gamma-bidentate MgATP complex with Hsc70, as well as a transition state during ATP hydrolysis, suggesting that monovalent ions act as specific metal cofactors in the ATPase reaction of Hsc70. PMID- 7836459 TI - Conditioned media from a cell strain derived from a patient with mastocytosis induces preferential development of cells that possess high affinity IgE receptors and the granule protease phenotype of mature cutaneous mast cells. AB - We have demonstrated for the first time that a conditioned medium from a human cell strain can induce morphologically mature mast cells that express Fc epsilon RI and three mast cell-specific proteases from normal bone marrow progenitor cells. In contrast, recombinant human Kit ligand induced the differentiation of mast cells that were tryptase-positive but negative for chymase, carboxypeptidase, and Fc epsilon RI. This data indicates that factors other than Kit ligand are critical for inducing the differentiation and maturation of mast cells in the human. The HBM-M cell was originally derived from a patient with mastocytosis. As mastocytosis is thought to represent a reactive hyperplasia rather than a mast cell malignancy, the factor secreted by the HBM-M cell strain could well be responsible for the mast cell hyperplasia seen in some patients with mastocytosis. PMID- 7836460 TI - Crystal structure of the OPG2 Fab. An antireceptor antibody that mimics an RGD cell adhesion site. AB - Cell surface receptors called integrins mediate diverse cell adhesion phenomena through recognition of the sequence arginine-glycine-aspartic acid (RGD) present in proteins such as fibronectin and fibrinogen. Platelet aggregation in hemostasis is mediated by the binding of fibrinogen to the gpIIb/IIIa integrin. The OPG2 antibody binds the gpIIb/IIIa receptor and acts as a ligand mimic due to the presence of an arginine-tyrosine-aspartic acid (RYD) sequence in the CDR3 loop of the heavy chain. The RYD loop and side chains are ordered in the 2.0-A resolution crystal structure of the Fab fragment from this antireceptor antibody. Moreover, the RYD loop assumes two clearly defined conformations that may correspond to the orientations of the loop in the free state or bound to integrin. This molecule will serve as a tool for understanding protein-integrin recognition in platelet aggregation and other RGD-mediated cell adhesion interactions. PMID- 7836461 TI - A novel LBP-1-mediated restriction of HIV-1 transcription at the level of elongation in vitro. AB - The cellular factor, LBP-1, can repress HIV-1 transcription by preventing the binding of TFIID to the promoter. Here we have analyzed the effect of recombinant LBP-1 on HIV-1 transcription in vitro by using a "pulse-chase" assay. LBP-1 had no effect on initiation from a preformed preinitiation complex and elongation to position +13 ("pulse"). However, addition of LBP-1 after RNA polymerase was stalled at +13 strongly inhibited further elongation ("chase") by reducing RNA polymerase processivity. Severe mutations of the high affinity LBP-1 binding sites between -4 and +21 did not relieve the LBP-1-dependent block. However, LBP 1 could bind independently to upstream low affinity sites (-80 to -4), suggesting that these sites mediate the effect of LBP-1 on elongation. These results demonstrate a novel function of LBP-1, restricting HIV-1 transcription at the level of elongation. In addition, Tat was found to suppress the antiprocessivity effect of LBP-1 on HIV-1 transcription in nuclear extracts. These findings strongly suggest that LBP-1 may provide a natural mechanism for restricting the elongation of HIV-1 transcripts and that this may be a target for the action of Tat in enhancing transcription. PMID- 7836462 TI - RNA polymerase II ternary complexes may become arrested after transcribing to within 10 bases of the end of linear templates. AB - In the presence of elongation factor SII, arrested RNA polymerase II ternary complexes cleave 7-17 nucleotides from the 3'-ends of their nascent RNAs. It has been shown that transcription of linear templates generates apparent run-off RNAs, which are nevertheless truncated upon incubation with SII. By using high resolution gels, we demonstrate that transcription of blunt or 3'-overhung templates with RNA polymerase II generates two populations of ternary complexes. The first class pauses 5-10 bases prior to the end of the template strand. These complexes respond to SII by cleaving approximately 9-17 nucleotide RNAs from their 3'-ends and therefore may be termed arrested. A second class of complexes, which fail to respond to SII, transcribe to within 3 bases of the end of the template strand. These complexes appear to have run off the template since they have released their nascent RNAs. Run-off transcription occurs on all types of templates, but it is the predominant reaction on DNAs with 5'-overhung ends. Thus, RNA polymerase II ternary complexes that retain 5-10 bases of contact with the template strand down-stream of the catalytic site become arrested. Further reduction of downstream template contacts can lead to termination. We also show that the addition of Sarkosyl to the elongation reactions significantly changes the pattern of transcriptional arrest near the end of linear templates. PMID- 7836463 TI - Lumenal orientation and post-translational modifications of the liver microsomal 11 beta-hydroxysteroid dehydrogenase. AB - The topology and post-translational modifications of microsomal 11 beta hydroxysteroid dehydrogenase (11 beta-DH) was investigated using the approaches of protein structure analysis. Sequence analysis of peptides generated by chemical and enzymatic cleavages revealed that carbohydrate is attached at Asn 122, -161, and -206. Enzymatic deglycosylation reactions of the protein identified the attached glycans as high mannose carbohydrates, implying that the bulk of the protein molecule is oriented on the lumenal side of the endoplasmic membrane. The carbohydrate moiety of native dehydrogenase was cleaved by endo-N acetylglucosaminidase H without significantly affecting the 11 beta-DH activity. Chemical modification of cysteinyl residues, followed by amino acid sequence analysis, identified one disulfide bond linking Cys-77 and Cys-212. This disulfide bond was inaccessible to thiol reagents, unless the protein was denatured. Contrary to the partially purified 11 beta-DH preparations, the purified enzymatically active protein failed to bind to a 2,5'-ADP affinity column, suggesting that a conformational change has occurred in the enzyme during purification. The proposed model of the 11 beta-DH has a single trans-membrane segment at the N terminus, with the bulk of the polypeptide chain projecting into the lumen of endoplasmic reticulum. Limited proteolysis studies of 11 beta-DH concluded an absence of a flexible intradomain segment between the membranous and the lumenal domains. The lumenal localization of the 11 beta-DH requires a mechanism by which cortisol is transported to the endoplasmic reticulum of the lumen. PMID- 7836465 TI - Phosphorylation of ribosomal protein S6 is inhibitory for autophagy in isolated rat hepatocytes. AB - In rat hepatocytes, autophagy is known to be inhibited by amino acids. Insulin and cell swelling promote inhibition by amino acids. Each of the conditions leading to inhibition of autophagic proteolysis was found to be associated with phosphorylation of a 31-kDa protein that we identified as ribosomal protein S6. A combination of leucine, tyrosine, and phenylalanine, which efficiently inhibits autophagic proteolysis, was particularly effective in stimulating S6 phosphorylation. The relationship between the percentage inhibition of proteolysis and the degree of S6 phosphorylation was linear. Thus, inhibition of autophagy and phosphorylation of S6 are under the control of the same signal transduction pathway. Stimulation of S6 phosphorylation by the presence of amino acids was due to activation of S6 kinase and not to inhibition of S6 phosphatase. The inhibition by amino acids of both autophagic proteolysis and autophagic sequestration of electro-injected cytosolic [14C]sucrose was partially prevented by rapamycin, a compound known to inhibit activation of p70 S6 kinase. In addition, rapamycin partially inhibited the rate of protein synthesis. We conclude that the fluxes through the autophagic and protein synthetic pathways are regulated in an opposite manner by the degree to which S6 is phosphorylated. Possible mechanisms by which S6 phosphorylation can cause inhibition of autophagy are discussed. PMID- 7836464 TI - CD45 protein-tyrosine phosphatase is specifically associated with a 116-kDa tyrosine-phosphorylated glycoprotein. AB - CD45 is a protein-tyrosine phosphatase expressed on all cells of hematopoietic origin. In an attempt to further characterize CD45 function, we set out to identify molecule(s) that specifically associate with CD45. A 116-kDa protein was detected in immunoprecipitates from CD45+ cells but not CD45- cells. The association between CD45 and this 116-kDa protein can be reconstituted by mixing lysates from CD45- cell lines with purified CD45. p116 appears to associate with CD45 through the external, transmembrane, or membrane-proximal region of CD45 since p116 is associated with a mutant form of CD45 possessing a truncated cytoplasmic domain. The association of p116 with CD45 is not isoform-specific as p116 associates equally well with various CD45 isoforms. We have determined that p116 is a tyrosine-phosphorylated glycoprotein and that it is associated with CD45 in all hematopoietic cells examined. Because of its broad distribution, it is possible that identification of p116 will provide additional insight into the function of CD45 in lymphoid as well as non-lymphoid hematopoietic cells. PMID- 7836466 TI - Cooperatively between an upstream TATA-like sequence and a CAA repeated element mediates E1A-dependent negative repression of the H-2Kb class I gene. AB - In primary rodent cells transformed by the E1A region of the highly oncogenic adenovirus type 12, repression of transcription mediated by the far upstream TATA like element was observed only in conjunction with either possible juxtaposition of a CAA repeated element in the presence of E1A and was dependent upon the relative arrangement of both the TATA-like and CAA repeated motifs in both homologous and heterologous promoter constructs. A gel shift competition study demonstrated that the TATA-binding protein (TBP) or a TBP-like protein can bind to both the upstream TATA-like sequence and the regular TATA box on the H-2Kb basal promoter. Moreover, employing immunoselection and cyclic amplification and selection of targets (CASTing) methods with nuclear extracts derived from Ad12 E1A transformants, we have identified a high affinity binding site in the H-2Kb class I promoter for E1A-associated DNA-binding proteins. The sequences of the binding sites were identified and were found to contain both the upstream TATA like motif and the CAA repeated motifs. Our results suggest that the TATA-like sequence in the far upstream region of the H-2Kb gene is one of the elements that is required for Ad12-E1A-mediated negative repression. PMID- 7836467 TI - cDNA cloning and characterization of a novel receptor-type protein tyrosine phosphatase expressed predominantly in the brain. AB - Protein tyrosine phosphatase has the potential to control various cellular events by negatively regulating the extent of tyrosine phosphorylation. Here, we report the isolation of a murine receptor protein tyrosine phosphatase, PTPBR7, which is expressed almost exclusively in the brain. Though the cytoplasmic portion of PTPBR7 reveals high similarity to HePTP/LC-PTP and STEP, these are, unlike PTPBR7, non-receptor protein tyrosine phosphatases. Unlike most receptor protein tyrosine phosphatases, PTPBR7 has only one cytoplasmic phosphatase domain, and its extracellular domain reveals no obvious structural similarity to known molecules. Thus, PTPBR7 defines a new subfamily of receptor-type protein tyrosine phosphatases. The putative extracellular domain of PTPBR7 was expressed in COS-7 cells as a chimeric fusion protein with an immunoglobulin Fc portion (PTPBR7-Fc). PTPBR7-Fc was secreted in the culture supernatant, confirming the capability of the extracellular domain of PTPBR7 to translocate across the cytoplasmic membrane. The cytoplasmic portion of PTPBR7 was expressed as a fusion protein in bacteria and was demonstrated to have catalytic activity. The expression of PTPBR7 was detectable in brain and especially in cerebellum but undetectable in liver, lung, heart, kidney, thymus, bone marrow, and spleen. In situ hybridization analysis revealed the most prominent signal in Purkinje cells. The predominant expression of PTPBR7 in the brain suggests that PTPBR7 may have role(s) in neuronal cells. PMID- 7836468 TI - Proteolysis in cultured liver epithelial cells during oxidative stress. Role of the multicatalytic proteinase complex, proteasome. AB - Exposure to various forms of mild oxidative stress significantly increased the intracellular degradation of both "short-lived" and "long-lived," metabolically radiolabeled, cell proteins in cultures of Clone 9 liver cells (normal liver epithelia). The oxidative stresses employed were bolus H2O2 addition; continuous H2O2 flux; the redox cycling quinones, menadione and paraquat; and the aldehydic products of lipid peroxidation, 4-hydroxynonenal, malonyldialdehyde, and hexenal. In general, exposure to more severe oxidative stress produced a concentration dependent decline in intracellular proteolysis, in some cases to below baseline levels. Oxidatively modified "foreign" proteins (superoxide dismutase and hemoglobin) were also selectively degraded, in comparison with untreated foreign proteins, when added to lysates of Clone 9 liver cells. As with intracellular proteolysis, the degradation of foreign proteins added to cell lysates was greatly increased by mild oxidative modification, but depressed by more severe oxidative modification. The proteinase activity was recovered in > 300-kDa cell fractions, and inhibitor profiles and immunoprecipitation studies indicated that the multicatalytic proteinase complex, proteasome, was responsible for most of the selective degradation observed with mild oxidative stress; up to approximately 95% for intracellular proteolysis and 65-80% for degradation of foreign modified proteins. Seven days of daily treatment with an antisense oligodeoxynucleotide, directed against the initiation codon region of the proteasome C2 subunit gene, severely depressed the intracellular levels of several proteasome subunit polypeptides (by Western blot analysis), and also depressed the H2O2 induced increase in intracellular proteolysis by approximately 95%, without significantly affecting baseline proteolytic rates. Extensive studies revealed only small or no increases in the overall capacity of oxidatively stressed cells to degrade oxidatively modified protein substrates; a finding supported by both Western blot and Northern blot analyses which revealed no significant increase in the levels of proteasome subunit polypeptides or mRNA transcripts. We conclude that mild oxidative stress increases intracellular proteolysis by modifying cellular proteins, thus increasing their proteolytic susceptibility. In contrast, severe oxidative stress diminishes intracellular proteolysis, probably by generating severely damaged cell proteins that cannot be easily degraded (e.g. cross-linked/aggregated proteins), and by damaging proteolytic enzymes. We further conclude that the multicatalytic proteinase complex proteasome is responsible for most of the recognition and selective degradation of oxidatively modified proteins in Clone 9 liver cells. PMID- 7836469 TI - AnkyrinG. A new ankyrin gene with neural-specific isoforms localized at the axonal initial segment and node of Ranvier. AB - We have characterized a new ankyrin gene, expressed in brain and other tissues, that is subject to extensive tissue-specific alternative mRNA processing. The full-length polypeptide has a molecular mass of 480 kDa and includes a predicted globular head domain, with membrane- and spectrin-binding activities, as well as an extended "tail" domain. We term this gene ankyrinG based on its giant size and general expression. Two brain-specific isoforms of 480 kDa and 270 kDa were identified that contain a unique stretch of sequence highly enriched in serine and threonine residues immediately following the globular head domain. Antibodies against the serine-rich domain and spectrin-binding domain revealed labeling of nodes of Ranvier and axonal initial segments. Ankyrin-binding proteins also known to be localized in these specialized membrane domains include the voltage dependent sodium channel, the sodium/potassium ATPase, sodium/calcium exchanger, and members of the neurofascin/L1 family of cell adhesion molecules. The neural specific ankyrinG polypeptides are candidates to participate in maintenance/targeting of ion channels and cell adhesion molecules to nodes of Ranvier and axonal initial segments. PMID- 7836470 TI - Activation of cytosolic phospholipase A2 by basic fibroblast growth factor via a p42 mitogen-activated protein kinase-dependent phosphorylation pathway in endothelial cells. AB - Basic fibroblast growth factor (FGF) stimulates the proliferation, differentiation, and motility of multiple cell types. Signal transduction by FGF is mediated by high affinity FGF receptors that have autophosphorylating tyrosine kinase activity and also elicit the release of low molecular weight signaling molecules, including inositol 1,4,5-trisphosphate, diacylglycerol, and arachidonate. We have shown previously that basic FGF-stimulated, phospholipase A2 (PLA2)-mediated arachidonate release regulates endothelial cell (EC) motility (Sa, G., and Fox, P.L. (1994) J. Biol. Chem. 269, 3219-3225). Here we identify the phospholipase responsible for basic FGF-mediated arachidonate release as cytosolic PLA2 (cPLA2) by demonstrating in EC lysates a requirement for micromolar Ca2+, dithiothreitol insensitivity, and inactivation by anti-cPLA2 antiserum. The role of cPLA2 is also indicated by the observed mechanisms of activation which show a requirement for p42 mitogen-activated protein kinase activity, cPLA2 phosphorylation, and cPLA2 translocation from cytosol to membranes. Phosphorylation of cPLA2, arachidonate release from prelabeled intact cells, and cell motility all have similar concentration dependencies on basic FGF. Since arachidonate release is required for basic FGF-stimulated motility of EC, our results show that p42 mitogen-activated protein kinase activation of cPLA2 may be a regulatory event in stimulation of cellular release of this important eicosanoid precursor during cellular responses to basic FGF. PMID- 7836472 TI - Differential expression of an acidic domain in the amino-terminal propeptide of mouse pro-alpha 2(XI) collagen by complex alternative splicing. AB - We isolated and sequenced genomic and cDNA clones encoding the complete amino terminal portion and the 5'-untranslated region of mouse pro-alpha 2(XI) collagen mRNA. Fourteen exons encoded the amino-terminal propeptide, which was divided into three consecutive domains (a long globular domain, an amino-terminal triple helical domain, and a telopeptide domain). The long globular domain was further divided into an upstream basic subdomain and a downstream highly acidic subdomain, as is the case for the amino-terminal propeptides of pro-alpha 1(V) and pro alpha 1(XI) collagens. We also demonstrated that the primary transcript undergoes complex alternative splicing. Three consecutive exons (exons 6, 7, and 8) encoding most of the acidic subdomain showed alternative splicing which dramatically affected the structure of the amino-terminal propeptide of pro-alpha 2(XI) collagen. Using the reverse transcription-polymerase chain reaction, we analyzed the expression of these exons in various tissues and in developing limb buds of mice. The pro-alpha 2(XI) transcripts were abundant in cartilage, but most of them lacked the 3-exon sequences encoding the acidic domain. Most of other tissues also contained mRNAs that corresponded to longer splice variants, including exons 6-8. The differential expression of specific domains of pro-alpha 2(XI) collagen may be important in modulating interactions between various components of the extracellular matrix and/or may influence heterotypic collagen assembly. PMID- 7836471 TI - Cloning of a protein that mediates transcriptional effects of fatty acids in preadipocytes. Homology to peroxisome proliferator-activated receptors. AB - Exposure of preadipocytes to long chain fatty acids induces expression of several gene markers of adipocyte differentiation. This report describes the cloning, from a preadipocyte library, of a cDNA encoding a fatty acid-activated receptor, FAAR. The cDNA had the characteristics and ligand-binding domains of nuclear hormone receptors and encoded a 440 amino acid protein related to peroxisome proliferator-activated receptors, PPAR. The deduced protein sequence was 88% homologous to that of hNUC I, isolated from human osteosarcoma cells. FAAR mRNA was abundant in adipose tissue, intestine, brain, heart, and skeletal muscles and less abundant in kidney, liver, testis, and spleen. The mRNA was undetectable in growing Ob1771 and 3T3-F442A preadipocytes, was strongly induced early during differentiation, and was increased by fatty acid. Transcription assays using hybrid receptor showed strong stimulation by fatty acid and weaker induction by fibrates. Transfection of 3T3-C2 fibroblasts, with a FAAR expression vector, conferred fatty acid inducibility of the adipocyte lipid-binding protein and the fatty acid transporter. Transcriptional induction of these genes exhibited inducer specificity identical to that described in preadipocytes. In summary, the data indicate that FAAR is likely a mediator of fatty acid transcriptional effects in preadipocytes. PMID- 7836473 TI - HLA-DR beta chains enter into an aggregated complex containing GRP-78/BiP prior to their degradation by the pre-Golgi degradative pathway. AB - HLA class II molecules are membrane proteins which are assembled in the endoplasmic reticulum shortly after synthesis of the alpha and beta and invariant chain (Ii) monomers. DR beta chains, in the absence of DR alpha, are rapidly and completely degraded by the pre-Golgi degradative pathway. Here we have examined those factors which target DR beta chains for degradation in a DR alpha deficient cell line, 9.22.3. The DR beta monomers in 9.22.3 were initially incorporated into a proteinaceous complex containing BiP. With time, the DR beta complexes were further aggregated. In wild type cells, which can assemble DR alpha-beta dimers, the secondary phase of aggregation of DR beta was not seen. Additional evidence that aggregation of DR beta in 9.22.3 cells was progressive was that a more mature form of DR beta was found exclusively in the largest DR beta complexes. Furthermore, the most highly aggregated DR beta chains were degraded more rapidly than bulk DR beta chains. These data suggest that DR beta aggregates are intermediates in the pre-Golgi pathway of DR beta degradation. They further suggest that formation of large DR beta aggregates is a proximal event to DR beta degradation. We conclude that DR beta chains are targeted for degradation as a consequence of a change of state, coincident with their aggregation into slow forming, high molecular weight complexes. PMID- 7836474 TI - The A2b adenosine receptor mediates cAMP responses to adenosine receptor agonists in human intestinal epithelia. AB - Adenosine is thought to be a major effector in immunological stimulation of Cl- secretion in intestinal epithelia. Previous studies indicate that both apical and basolateral domains of intestinal epithelial cells possess functionally defined adenosine receptors. However, it is unclear whether the same receptor subclass is expressed, what the receptor subclass(es) is, or how the receptors signal the Cl- secretory response. We now characterize the intestinal epithelial adenosine receptor subtype using the model epithelium, T84. Both apical and basolateral adenosine receptor agonist response profiles revealed a hierarchy (ED50) of 5'-(N ethylcarboxamido)adenosine > adenosine > CGS-21680. Similarly inhibition studies revealed identical ID50 hierarchies for apical and basolateral antagonism by xanthine amine congener > 1,3-diethyl-8-phenylxanthine > aminophylline. Analyses of both agonist and antagonist pharmacological hierarchies in Chinese hamster ovary cells stably expressing the A2b receptor revealed these same hierarchies. Northern blots performed on RNA extracted from polarized T84 monolayers demonstrated no detectable message for A1 or A2a adenosine receptor, but strong hybridization was detected for the A2b adenosine receptor. Subsequent Northern blots of RNA prepared from human alimentary tract revealed that A2b adenosine receptor message was heavily expressed throughout the colon, in the appendix, and more modestly expressed in the small intestine (ileum). Analyses of cAMP generation in T84 cells in response to adenosine indicated that the basolateral A2b receptor elicits Cl- secretion through this signaling pathway. Stimulation of Cl- secretion through the apical A2b receptor exhibited relatively small but significant increases in cAMP compared with basolateral stimulation. The protein kinase A inhibitor H-89, used at concentrations that did not affect short circuit current responses to the Ca(2+)-mediated agonist carbachol, effectively inhibited short circuit current elicited by either apical or basolateral adenosine. These data suggest that the major intestinal epithelial adenosine receptor is the A2b subclass, which is positively coupled to adenylate cyclase. Such observations have potentially important implications for the treatment of diarrheal diseases. PMID- 7836475 TI - The interaction of calmodulin with clathrin-coated vesicles, triskelions, and light chains. Localization of a binding site. AB - The binding of clathrin-coated vesicles, clathrin triskelions, and free clathrin light chains to calmodulin-Sepharose was compared. When isolated from bovine brain, all three components bound to calmodulin-Sepharose in the presence of calcium and could be eluted by its removal. In contrast, coated vesicles and triskelions isolated from bovine adrenal gland did not bind to calmodulin Sepharose, although the free light chains from adrenal gland bound as effectively as those from brain. As distinct isoforms of the clathrin light chains are expressed by brain and adrenal gland, these results implicate the clathrin light chains as the calmodulin-binding component of coated vesicles and triskelions. Furthermore, the insertion sequences found in the neuron-specific isoforms, although not necessary for the binding of free clathrin light chains to calmodulin, must facilitate the interaction of heavy chain-associated light chains with calmodulin. Recombinant mutants of LCa, with deletions spanning the entire sequence, were tested for binding to calmodulin-Sepharose. Those mutants retaining structural integrity, as assessed by the binding of a panel of monoclonal antibodies, exhibited varying amounts of calmodulin binding activity. However, deletion of the carboxyl-terminal 20 residues abolished calmodulin interaction. Thus, the carboxyl terminus of LCa appears to constitute a calmodulin-binding site. Peptides corresponding to the carboxyl terminus of LCa or LCb inhibited the interaction of the light chains with calmodulin, suggesting that this region forms the calmodulin-binding site of both LCa and LCb. The carboxyl-terminal peptides of LCa and LCb inhibited the interaction of light chains with calmodulin approximately 10-fold less effectively than a calmodulin binding peptide derived from smooth muscle myosin light chain kinase, but much more effectively than a calmodulin-binding peptide derived from adenylate cyclase. This comparison places the clathrin light chain-calmodulin interaction within the physiological range seen for other calmodulin-binding proteins. PMID- 7836476 TI - Analysis of the chicken GPAT/AIRC bidirectional promoter for de novo purine nucleotide synthesis. AB - GPAT and AIRC encode two enzymes that catalyze steps 1 and 6 plus 7, respectively, of the de novo purine biosynthetic pathway. The chicken genes are closely linked and divergently transcribed from an approximately 230-base pair intergenic region. The promoter was scanned by deletion mutagenesis in a bireporter vector that allowed assay of transcriptional activity in both directions in transfected HepG2 and chicken LMH cells. Three classes of deletions were obtained: those affecting bidirectional transcription, those predominantly affecting GPAT transcription, and those predominantly affecting AIRC transcription. Defects in bidirectional transcription resulted from removal of an initiator-like element overlapping the AIRC transcription start site, as well as deletions removing a series of GC and CCAAT boxes from the AIRC proximal half of the promoter and a CCAAT-containing segment from the GPAT side. Several regions in the GPAT proximal half of the promoter, including an octamer-like motif downstream from the transcription start site, were required predominantly for GPAT expression. Evidence for interaction of HeLa nuclear proteins with some of these sites was obtained by gel retardation, DNase I, and methylation interference assays. Overall, the results showed that the intergenic region is an integrated bidirectional promoter and that a novel initiator-like element plays a central role in coordinating expression of the divergently transcribed AIRC and GPAT genes. PMID- 7836477 TI - Complexity in selecting health care technology in diverse settings. AB - Nurses in diverse settings around the world work toward improving human health. Attainment of this goal depends, in part, on selecting and using appropriate technology. The article describes the framework of technology assessment and suggests ways in which nurses can be involved in evaluating health care technologies, deliberating on appropriate applications, and, if not selecting, then at least having input into the selection of technologies from the individual patient level through and including health policy. PMID- 7836478 TI - The global epidemic of human immunodeficiency virus infection: past reflections, future directions. AB - The impact of the global epidemic of human immunodeficiency virus (HIV) infection in developed countries has been far reaching, but its impact in developing countries is much more devastating. The common underlying theme that helps explain HIV and acquired immunodeficiency syndrome (AIDS) is inequality. The resources available to nurses in all these countries vary markedly. Although there are many instances of nurses responding in an altruistic manner, the evidence indicates that many nurses are reluctant to provide care for individuals with HIV infection. HIV and AIDS have enabled an examination of broader, fundamental questions about the nature of nursing in health care and in society. PMID- 7836479 TI - A clinical specialist in psychiatric-mental health nursing in rural South Australia: a consultant to the aged care assessment team. AB - A holistic view of aging states that humans are seen to be endeavoring toward wholeness from birth until death within an ever changing world. Nurses are part of that wholeness, evolving with patients throughout their lives. The Commonwealth of Australia has designed the concept of aged care assessment teams (ACATs) to address the specific and unique needs of its aging communities. The article provides an example of the role of a clinical specialist in psychiatric mental health nursing who provides a holistic approach to the assessment process as nurse consultant to two ACATs in rural South Australia. PMID- 7836480 TI - Dream telling: a means of spiritual awareness. AB - The article describes how a dream-sharing group facilitated by a nurse therapist can become the means by which the participants gain spiritual awareness. First, the characteristics of spiritual awareness are identified and discussed. Second, the practice, structure, and process of a dream-sharing group are described, with dream narratives and interactions from a particular group being used as illustrations. Finally, the attributes of a sensitive and caring listener and the leadership qualities of a nurse facilitator of such a group are outlined in the hope that nurses in different settings will be enabled and encouraged to provide this important aspect of nursing care. PMID- 7836481 TI - Impact of culture on pain management: an Australian nursing perspective. AB - Pain assessment and pain management are complex tasks. Knowledge and beliefs of patients, physicians, and nurses about pain are key determinants of clinical decision making. Despite new theoretical insights, routine approaches to pain assessment and management persist in practice. Culture is a potent force in shaping beliefs, behavior, and meaning about pain. In health care contexts, there may be conflict between care and cure and differing perceptions about the role and status of nurses that impinge on the provision of pain relief. The article explores aspects of culture, knowledge, and belief and their influence on pain management from an Australian perspective. PMID- 7836482 TI - The nurse and the environment: how one group thinks globally and acts locally. AB - Environmental issues are currently topical with the realization that natural resources are finite. With this realization has also come the knowledge of the complexity of the problem at both local and broader levels. Because of this complexity and the extent of the existing and growing environmental damage, all people in all areas of life need to be aware of and actively involved in caring for the environment, with no single group having total responsibility to help conserve the environment. As a professional body concerned with caring for people, nurses must act in a local capacity by being informed of wider environmental issues. By knowing and understanding what happens to products such as disposable items, which have become an integral part of the hospital equipment, and how they are disposed of, the nurse is better able to make choices about whether they are appropriate for use in different health care settings. PMID- 7836483 TI - Female circumcision: understanding special needs. AB - The article discusses the provision of appropriate care that is sensitive to the special physical and psychosocial needs of the circumcised client seeking midwifery services in Australia. Aspects addressed include prevalence of the practice globally; potential problems for the prenatal, intrapartum, and postnatal periods; and implications for the midwife caring for the woman during these periods. Appropriate strategies for management include gaining an awareness of individual, cultural, and personal needs; provision of appropriate education in the prenatal and postnatal periods; establishment of positive working relationships with the family as a whole; and provision of adequate pain relief at all times. Health care policy can affect the ability of midwives and other health professionals to provide for culturally specific health needs. PMID- 7836484 TI - Schizophrenia, smoking, and smog. AB - The article outlines the relationships that obtain among schizophrenia, smoking, and smog. An overview of known scientific facts concerning the pathogenesis of schizophrenia is first provided. The relationship this has with nicotine addiction is discussed next, and finally the notion is introduced that heterocyclic amines found in cigarette smoke and petroleum fumes serve as a potent environmental neurotoxin that seriously compromises mental health in biologically susceptible individuals. It is argued that such biologic susceptibility takes the form of cerebral diabetes, which accounts for the serious impairment of glucose metabolism as demonstrated by positron emission tomography. Central to this argument is the view that diabetes can be peripheral, without affecting the central nervous system, or central, without affecting the peripheral system. PMID- 7836485 TI - Health issues in nursing in Vietnam. AB - Major health concerns are not currently addressed in Vietnam as the country strives to upgrade its economic status. The current standard of medical care is rudimentary at best, as is the education and practice of Vietnamese nurses. The Ministry of Health in Vietnam has directed the Medical College of Hanoi to commence a 4-year degree in nursing in 1994. Historical, practical, political, economic, social, and cultural issues affect the development of nursing as a profession. Assistance from the West is sought by the Medical College in Hanoi. PMID- 7836486 TI - Identifying and responding to the needs of refugees: a global nursing concern. AB - Worldwide catastrophic events such as civil war have forced 1 in every 130 people in the world to flee her or his home and become a refugee or displaced person. The article draws upon contemporary refugee experiences from Afghanistan, the Sudan, and the former Yugoslavia to introduce the role of nursing during the refugee journey from flight to asylum seeking. It is hoped that the article will provide nurses with a beginning awareness of the nurse's role in the care and comfort of refugees and displaced people. Central to this role is the gathering of humanitarian, sociocultural, and personal information to enable extensive networking and relationship building with refugees for ongoing empowerment and increased problem-solving capabilities. PMID- 7836487 TI - The role and functions of the psychiatric-mental health nurse in the care and comfort of individuals, families, and communities subjected to violence. AB - Individuals, families, and communities subjected to violence experience mental health needs and mental health problems that are obstacles in their everyday living. The psychiatric-mental health nurse, as an integral part of the health delivery system, has a facilitative role in assisting individuals, families, and communities to mobilize resources in the promotion, maintenance, and restoration of their mental health. The functions of the psychiatric-mental health nurse thus include coordinator of community development, psychotherapist, mental health educator, and monitor of the use of psychotropic medications. PMID- 7836488 TI - Hallucinations following occipital lobe damage: the pathological activation of visual representations. AB - Neuropsychological investigation of hallucinations may provide insight into the nature of these subjective phenomena, as well as inform theories of perception and recall. We studied a man who described continuous visual hallucinations of object fragments (e.g., lines, corners, patterns) in the left visual field following a stroke in the right occipital cortex. The subject performed normally on standardized measures of visual perception and other cognitive abilities. He had no personality disturbance, and EEG during hallucinations was normal. Review of our records of 211 cases with focal lesions involving visual cortex revealed 5 patients with similar complaints. The hallucinatory experience of such patients probably reflects pathological activation of neural ensembles in the regions bordering an occipital lesion. These regions are presumed to contain records of visual feature fragments which are co-activated by feedback projections in the earliest visual association cortices, where they produce meaningful patterns during normal recall. PMID- 7836489 TI - Singing with and without words: hemispheric asymmetries in motor control. AB - Singing is relatively preserved and can even improve the language production of aphasic patients who have lesions of the left hemisphere but an intact right hemisphere. In contrast, singing is impaired following lesions or anesthesia of the right hemisphere, suggesting a right hemisphere role in singing. To assess the influence of singing upon hemispheric control of articulatory output in normal subjects, we measured lip opening asymmetry by single-frame photographic analysis. Spontaneous speech, reciting the words of a song, and singing with words all showed right-side lip opening superiority, revealing a major left hemisphere role in control of verbal articulation. Singing without words, on the other hand, did not show asymmetric facial motor activation, suggesting that the right hemisphere also participates in singing. In addition, we assessed auditorily perceivable differences in articulation when lip movement on one side of the mouth was artificially restricted (hemibuccal speech). Articulation quality was higher when speaking from the right side of the mouth. PMID- 7836490 TI - Age differences in academic achievement in high-functioning autistic individuals. AB - A battery of psychoeducational tests was administered to samples of high functioning (IQ > 70) autistic subjects and normal controls. A previous psychoeducational study indicated the presence of preserved procedural and mechanical academic skills accompanied by impaired comprehension and interpretive skills in high-functioning autistic individuals. The present findings indicate that this psychoeducational pattern also has a developmental aspect. Younger (< 13 years) autistic subjects performed as well or better than younger controls on psychoeducational measures of mechanical and procedural skills, and on some complex, interpretive tasks. However, they performed more poorly than controls on tasks that involve following complex linguistic instructions. Younger autistic subjects and controls did not differ significantly from each other on interpretive tasks, while the older austic subjects did significantly more poorly than the older controls on such tasks. The findings are discussed in terms of early success, but subsequent decline, in the course of academic functioning in autism. PMID- 7836491 TI - Sustained attention in adult phenylketonuria: the influence of the concurrent phenylalanine-blood-level. AB - The effect of concurrent phenylalanine levels (Phe-level) on sustained attention was tested in a group of 19 early treated adult PKU patients. Mean age was 20.5 years; WAIS IQs were in the normal range (M = 109.3). Phe-levels were manipulated in a high-low-high design by reintroduction of a strict phenylalanine-reduced diet for 4 to 5 weeks between test time 1 and 2 and returning to usual diet between test time 2 and 3. A control group of 20 healthy subjects, mean age 20.7 years was tested twice. Results of a sustained attention task are presented. In adult PKU patients with high concurrent Phe-levels, sustained attention is significantly impaired and reaction times are prolonged. In the low Phe-level condition, performance improved significantly. Nevertheless, the PKU group did not reach the level of performance of the control group. Results are not influenced by IQ and suggest a sustained attention deficit in adult PKU patients that varies according to the concurrent Phe-level. The partial reversibility of the deficits provides support for the hypothesis that biochemical mechanisms rather than structural changes of the brain underlie the relationship between concurrent Phe-level and sustained attention. PMID- 7836492 TI - Category-specific semantic impairment in Alzheimer's disease and temporal lobe dysfunction: a comparative study. AB - In this paper we report an in-depth case study of a patient suffering from Alzheimer's disease who presented with a category-specific disorder relating to processing of knowledge about animate objects in the presence of spared knowledge of inanimate objects. Impairments appeared not only in a confrontation naming task but also on a range of visual knowledge tasks, such as drawing from memory or part-whole matching. The pattern of impairment was compared to that shown by a post-encephalitic patient who manifested a well-documented category-specific deficit for animate objects. Both patients' performance was compatible with an interpretation in terms of impairment at the level of the structural description of objects within the semantic system, as general encyclopaedic knowledge was largely preserved. Temporal lobe damage may be the cause of memory breakdown in both patients. PMID- 7836493 TI - Handedness and sexual orientation. AB - Surveys of handedness distribution (i.e., the distribution across handedness categories in large samples, typically based upon self-reported right-, mixed- and left-handed classification) indicate approximately 90% of the population is right-handed (Springer & Deutsch, 1989). This distribution toward right handedness has been called right shift based on a genetic model (Annett, 1985). The present study examined possible handedness distribution differences between 141 gay, lesbian, and bisexuals and 260 heterosexuals who have a homosexual/bisexual first-degree (biological) relative. Based on a five-category self-assessment handedness questionnaire that was validated using Briggs and Nebes' (1975) reformulation of Annett's inventory (1970), non-heterosexuals showed a reduction of right shift compared to heterosexuals (i.e., a population shift toward mixed- and left-handedness), confirming the results of Lindesay (1987) and Becker et al., (1989). Sexual orientation also weakly predicted handedness. The findings indirectly support the hypothesis of Geschwind and Galaburda (1985a, 1985b) that sexual orientation and handedness may be linked, both possibly influenced prenatally by testosterone. The discussion emphasizes (a) the meaninglessness in distinguishing genetic from hormonal influences and (b) non-heterosexually biased assumptions about human sexuality. PMID- 7836494 TI - High false alarm rates on a vigilance task may indicate recreational drug use. AB - Neuropsychologists need more sensitive methods to detect and measure recreational drug use in both research and clinical settings. In a study comparing the sensitivity of information processing tasks and neuropsychological instruments to detect early HIV-related cognitive decrements, 18 of 129 subjects tested positive for recreational drugs. Sixteen of these 18 subjects had elevated false alarm rates on one of the information processing tasks, the vigilance task. Another 45 subjects who tested negative for recreational drugs also had elevated false alarm rates. Neuropsychological measures of premorbid functioning, attention, speed of information processing, and manual dexterity were lower in the high false alarm subjects than in the remaining 66 drug-negative, low false alarm subjects. These results suggest that a high false alarm rate may reflect long-standing cognitive disturbances and the effects of drug use. The vigilance task may be a sensitive and efficient screening tool for recreational drug use. PMID- 7836495 TI - Categorization of arithmetic word problems by normals, frontal and posterior injured patients. AB - An important stage in the solution of mathematical word problems is the formation of a global internal representation of the problem. There is ample evidence that the recognition of problem schemata or problem types plays a major role in this representation stage. In the present study, a sorting task is used in order to examine the knowledge of arithmetical word-problem schemata in a group of normals, a group of patients with frontal lesions, and a group of patients with left posterior brain lesions. Quantitative and qualitative analyses show that normals classify the word problems according to principles that are essential for problem solving. These analyses also reveal that the general sorting dimensions of the frontal and the left posterior brain-damaged groups, as measured by a multidimensional scaling procedure, are similar. Cluster analysis shows that both groups base their sorting behavior mainly on superficial text characteristics, such as the objects found in the various word problems. The implications of these differences in sorting behavior for arithmetical word-problem solving are discussed. PMID- 7836496 TI - Dyslexia and the ecological brain. AB - Evidence is available to show that normal and disturbed reading is a bilateral rather than an unilateral hemispheric affair. The primary subservience of reading seems to shift from right to left during the development of the learning-to-read process. Since the brain is sensitive to enriched stimulation from the environment, hemisphere-tied dyslexia may be alleviated by selective or alluding stimulation of the right (L-dyslexia) or the left (P-dyslexia) cerebral hemisphere. In general, the results of experimental group and single-case investigations show the fruitfulness of these neuropsychological treatment procedures. However, it is apparent that there are questions that remain to be answered. PMID- 7836497 TI - Determining random responding for the category, speech-sounds perception, and Seashore Rhythm tests. AB - A formula is presented for determining if scores from the Category, Speech-Sounds Perception, and Seashore Rhythm tests are significantly different from random responding. Confidence intervals for random responding are also presented. Results of published studies involving normative and non-normal subjects are reviewed, and the percentage of subjects responding in the random range are presented. Normative subjects' scores on the Category and Speech-Sounds Perception tests do not fall into the random range, but high percentages of their Seashore Rhythm Test scores do fall into the random range. PMID- 7836498 TI - Quantitative characterization of verbal learning deficits in patients with Alzheimer's disease. AB - The performance of patients with Alzheimer's Disease (AD) was compared to that of normal controls (NCs) on a free recall rote learning task involving a list of words (California Verbal Learning Test). Exponential learning functions were fitted to the observed data of the two groups. These learning functions provided estimates for the rate of learning and the theoretically expected upper limit of recall performance in each group. The rate constant of learning was higher in AD patients than in NCs, indicating less distributed learning across the given trials. The expected upper limit of recall performance was lower in AD patients than in NCs. Results suggest that AD patients benefit less from the repetition of information at the time of encoding. PMID- 7836499 TI - Fall conception increases the risk of neurodevelopmental disorder in offspring. AB - Hormonal imbalances in utero may render males more vulnerable to neurodevelopmental disorder (ND) than females. Since hormonal activity can be influenced by photoperiod, the relationship between season of conception and incidence of ND in offspring was examined within 11,578 mother/child pairs. Fall conception significantly elevated the odds for mental retardation, reading, arithmetic disability, or performance aptitude deficits (but not seizures, articulation disorder, cerebral palsy, or verbal aptitude deficits), and decreased the odds for reading talent (even when socioeconomic class, prenatal visits, infections, fever, vomiting, edema, anemia, and weight loss were covaried). Since the seasonality effect was not stronger in males, and was not specific to those NDs caused by left hemisphere dysfunction, the predictions of Geschwind and Galaburda (1985a, 1985b, 1985c) were not confirmed. PMID- 7836500 TI - Cerebral dominance for speech and handwriting of patients with cortical vascular malformations. AB - Lateralization of speech dominance was established using amobarbital for 22 patients with vascular malformations lateralized to the left cerebral hemisphere. Patients' histories were negative for clinically evident neurological events (e.g., seizures or hemorrhage) prior to adulthood. The vascular lesions were categorized as high flow arteriovenous malformations (AVMs) (n = 4), low flow AVMs (n = 6), cavernous hemangiomas (n = 10), or venous angiomas (n = 2) by reviewing angiographic findings and surgical pathology for those patients whose lesions were excised. Three of the malformations encroached upon primary language areas. The frequency of right hemisphere speech dominance was not significantly elevated in comparison with the normal population, even though the incidence of nonright-handedness was. Ninety-five percent of the patients were left hemisphere dominant for speech: only one patient, with a parietal lobe cavernous hemangioma, was found to be right hemisphere dominant for speech. This malformation did not involve the primary language areas. These findings suggest that vascular malformations do not affect speech dominance as readily as other neurological diseases, but frequently affect manual dominance. PMID- 7836501 TI - Neuropsychological performance and CD4 levels in HIV-1 asymptomatic infection. AB - The performance of 68 HIV-1 seropositive asymptomatic (HIV+) subjects stratified on CD4 levels were compared with 82 HIV-1 seronegative (HIV-) subjects on a battery of neuropsychological, mood state, and perceived health status measures. The neuropsychological test battery included measures of attention, reaction time, memory, intellectual ability, psychomotor speed, frontal lobe or "executive" function, and decision time. None of the HIV+ subjects were taking antiviral agents. The groups did not differ for age, mood state, or WAIS-R Verbal and Performance IQ scores. Due to group differences for education and weekly ethanol consumption, both variables were used as covariates in multivariate analyses of variance. Relatively few differences were observed between subgroups of HIV+ patients or between these subgroups and control subjects. These data suggest that factors other than absolute levels of immunosuppression as expressed by CD4 levels alone, appear to be responsible for the deficits observed in HIV+ asymptomatic patients. PMID- 7836502 TI - Cognitive deficits and personality patterns in maternally versus paternally inherited myotonic dystrophy. AB - Neuropsychological functioning was compared between 7 myotonic dystrophy (MD) patients with maternal inheritance (mMD), 14 MD patients with paternal (pMD) inheritance, and 10 normal controls. Both groups evidenced slowed performance on a measure of information processing speed. However, the pMD group had an otherwise normal neuropsychological profile. In contrast, the mMD group exhibited abnormal scores on measures of intelligence, visual-construction, and some, albeit not all, measures of frontal functioning. No significant differences between the three groups were detected on measures of verbal or visual memory, or on measures of visual-perception. Overall, these findings suggest that inheritance pattern is one important moderating variable in determining the impact of the MD gene on cognitive functioning. Personality assessment revealed a relatively high incidence of dependent tendencies and depressive symptoms, even among pMDs. Given the generally normal cognitive functioning among pMDs, personality/emotional disturbance observed among MD patients may largely reflect their adjustment to having a progressively disabling medical condition, rather than being a direct expression of MD related brain dysfunction. PMID- 7836503 TI - Emotional sequelae of stroke: a longitudinal perspective. AB - This study investigated emotional change following stroke at acute (2-week), 2 month, and 6-month time intervals. Five dimensions of emotional functioning were examined in a sample of 19 stroke subjects: indifference, inappropriateness, depression, mania, and pragnosia (a defect in the pragmatics of social communicative style). Results showed that, at the 2-month point, differential recovery rates become apparent depending on hemispheric side of the stroke lesion. Increased indifference, inappropriateness, and depression appear to account for these results and suggest a slower rate of recovery on these variables in the left hemisphere group (LH n = 9) compared to the right (RH n = 10). Results further indicate that, at the 6-month point, emotional functioning in RH subjects appears to worsen. In contrast, emotional recovery in LH subjects seems to stabilize at this time. Clinical implications of these findings in terms of type and timing of intervention are discussed. PMID- 7836504 TI - In-vitro growth of oocytes. The use of immature human oocytes for reproductive technology: potential risks and benefits. PMID- 7836505 TI - Immunohistochemical distribution of progesterone, androgen and oestrogen receptors in the human ovary during the menstrual cycle: relationship to expression of steroidogenic enzymes. AB - In order to characterize immunohistochemically the possible in-situ effects of gonadal steroid hormones in the human ovary during the menstrual cycle, we immunolocalized progesterone (PR), androgen (AR) and oestrogen (ER) receptors in 50 normal cycling human ovaries, and examined the relationship between these findings and the cellular localization of steroidogenic enzymes including cytochrome P-450 cholesterol side-chain cleavage (P-450scc) enzyme, 3 beta hydroxysteroid dehydrogenase (3 beta HSD), cytochrome P-450 17 alpha-hydroxylase (P-450c17) and cytochrome P-450 aromatase (P-450arom). A large number of stromal cells were positive for AR, regardless of the distance from a follicle. No steroidogenic enzymes were observed in the stromal cells. In the pre-antral follicle, AR was observed in the theca cells. P-450scc, 3 beta HSD and P-450c17 were sporadically expressed in the theca cells in relatively large-sized pre antral follicles. ER was positive in the granulosa cells only in the P-450arom positive antral or pre-ovulatory follicle, which is likely to be a selected follicle. In the corpus luteum, in the period from ovulation to the mid-secretory phase, PR immunoreactivity was observed in a large number of both the luteinized granulosa and the theca cells. All steroidogenic enzymes were observed in all corpora lutea, but ER was negative in any corpus luteum. In the atretic follicle, AR was present in the theca interna cells. P-450scc, 3 beta HSD and P-450c17 were observed in the theca interna cells in some atretic follicles.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836506 TI - The effects of gonadotrophin-releasing hormone agonist on follicular development in patients with polycystic ovary syndrome in an in-vitro fertilization and embryo transfer programme. AB - The aim of the study was to evaluate ovarian response to gonadotrophin stimulation, with and without premedication with gonadotrophin-releasing hormone (GnRH) agonist, in patients with polycystic ovary syndrome. In all, 40 women included in the in-vitro fertilization/embryo transfer programme were divided into two groups. In the first group, buserelin, 500 micrograms/day s.c., was given until pituitary desensitization was achieved. Ovarian stimulation was performed by the combination of GnRH agonist and human menopausal gonadotrophin (HMG). The second group was treated using a conventional HMG and human chorionic gonadotrophin (HCG) protocol. Desensitization was achieved in 15.2 +/- 6.3 days (mean +/- SD) and the luteinizing hormone:follicle stimulating hormone ratio decreased from 2.84 +/- 1.54 to 0.60 +/- 0.35. Comparing the duration of stimulation, the number and size of all observed and aspirated follicles, oocytes recovered and fertilized and the number of embryos replaced, no statistically significant differences were found between the groups. The average oestradiol concentration on the day of HCG administration was lower in the group treated with premedication (P < 0.05). These data suggest that short pre-treatment with GnRH agonist can temporarily correct endocrine abnormalities of polycystic ovary syndrome but do not change the ovarian response to gonadotrophin stimulation and multiple follicular development. PMID- 7836507 TI - On the dynamics between gonadotrophin surge-inhibiting factor and gonadotrophin releasing hormone (GnRH): role of self-priming and desensitization in the luteinizing hormone response to GnRH after follicle stimulating hormone treatment. AB - The effects were studied of follicle stimulating hormone (FSH)-induced production of gonadotrophin surge-inhibiting factor (GnSIF) on three phases of the pituitary responsiveness to gonadotrophin releasing hormone (GnRH): the unprimed, primed and desensitized phases. Rats were injected with FSH on two occasions during the oestrous cycle. Spontaneous luteinizing hormone (LH) surges were measured as well as GnRH-induced LH surges on the day of pro-oestrus during infusions with 100 4000 pmol GnRH/rat/10 h, in phenobarbital blocked rats. The spontaneous LH surges were attenuated or completely inhibited by the FSH treatment. FSH suppresses and prolongs the unprimed LH response and delays GnRH self-priming, especially during infusions with low concentrations of GnRH. This treatment does not affect the total LH response (area under curve) to the highest concentrations of GnRH and after ovariectomy. On the other hand, this response is suppressed during infusions with the lower concentrations of GnRH. Hence, FSH, via GnSIF, delays maximal priming of the LH response to GnRH, whereas the suppression of LH release is a consequence of the GnRH-induced progressed state of desensitization. The inconsistent effects of FSH on the mid-cycle LH surges are explained as a result of the interaction between the relative strengths of GnRH and GnSIF. PMID- 7836508 TI - Exogenous follicle stimulating hormone ovarian reserve test (EFORT): a simple and reliable screening test for detecting 'poor responders' in in-vitro fertilization. AB - Predicting ovarian response to stimulation constitutes a pivotal task in the organization of a successful in-vitro fertilization (IVF) programme. The purpose of the current study was to determine whether a new ovarian reserve test, the exogenous follicle stimulating hormone ovarian reserve test (EFORT), could improve the predictive value of the classical follicle stimulating hormone (FSH) measurements on cycle day 3 of ovarian stimulation regarding results of IVF. In this prospective study, 52 IVF candidates aged 27-42 years underwent 52 consecutive IVF cycles. These women received 300 IU of purified FSH i.m. on cycle day 3. Blood samples were taken just before the injection to measure plasma FSH and oestradiol; 24 h later, plasma oestradiol concentration was determined. Two menstrual cycles later, ovarian stimulation was performed for IVF using a time release gonadotrophin-releasing hormone agonist (GnRHa) and human menopausal gonadotrophin (HMG). For the interpretation of the EFORT results, we considered the post-FSH plasma oestradiol increment (delta E2) and the baseline plasma FSH values (bFSH). The results of these two parameters were compared with the subsequent quality of the ovarian response to stimulation for IVF and the pregnancy outcome. Our results indicated a statistically significant improvement of the predictive value of the bFSH on the ovarian stimulation outcome when the EFORT parameters (bFSH and delta E2) were analysed synergistically.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836509 TI - Follicle stimulating hormone (FSH) dynamics of low dose step-up ovulation induction with FSH in patients with polycystic ovary syndrome. AB - Pharmacodynamics of follicle stimulating hormone (FSH) were studied during low dose step-up gonadotrophin therapy in patients with polycystic ovary syndrome (PCOS). To obtain stable levels of FSH, Metrodin was administered i.v. By making daily determinations, the FSH concentration was slowly increased in steps of approximately 1 IU/l. A total of 16 patients were treated for a maximum of three treatment cycles. Out of 38 treatment cycles, in 26 (68%) a single dominant follicle developed. The overall ovulation rate was 78%. FSH concentrations were evaluated with regard to intra- and interindividual variability of the FSH threshold and with regard to the relationship between FSH concentrations, FSH dose and treatment outcome. The high variability of the FSH threshold, ranging from 5.7 to 12 IU/l, appeared to be mainly a function of inter-individual variability. Higher FSH concentrations were associated with multifollicular growth as opposed to monofollicular growth, whereas the increases in concentration from a substimulating to a stimulating level were not. Multifollicular growth might thus be associated with a higher elevation of FSH concentration above the threshold. Different patterns of FSH concentration in the course of the growth phase of the dominant follicle in mono- compared to multifollicular cycles suggested a difference in the effect of endogenous FSH on the plasma concentration. Endogenous feedback on FSH release may therefore still play a role during treatment with exogenous FSH. PMID- 7836510 TI - Long-term medical therapy for leiomyomata uteri: a prospective, randomized study of leuprolide acetate depot plus either oestrogen-progestin or progestin 'add back' for 2 years. AB - Treatment of women with leiomyomata with gonadotrophin-releasing hormone agonists (GnRHa) for > 6 months is not recommended because of concerns regarding adverse sequelae of prolonged hypoestrogenism. It has been postulated that addition of low-dose sex steroids to GnRHa treatment, i.e. 'add-back' therapy, may avert some of these adverse effects (accelerated bone resorption, vasomotor flushes) without altering the efficacy of GnRHa therapy. To evaluate the effects of long-term GnRHa therapy on uterine size, bleeding patterns, bone mass and lipids, 51 pre menopausal women with leiomyomata were treated with the GnRHa leuprolide acetate depot, 3.75 mg every 4 weeks for 2 years. After 3 months of leuprolide therapy, the women were randomized to receive either low-dose continuous oestropipate, 0.75 mg daily, plus cyclic norethindrone, 0.7 mg on days 1-14 each month (the oestrogen-progestin add-back group) or higher-dose norethindrone, 10 mg daily (the progestin add-back group), for the remaining 21 months. Mean uterine volume decreased by 40% in both treatment groups during the first 3 months on leuprolide treatment. There was no significant change in uterine size following oestrogen progestin add-back. However, mean uterine volume in the progestin add-back group increased to 87% of pre-treatment size by treatment month 12 and 95% of pre treatment size by treatment month 24. Mean bone density of the lumbar spine as measured by dual X-ray absorptiometry decreased significantly by 2.6% during the first 3 months in all patients, but did not change significantly following steroid add-back in both treatment groups during the final 21 treatment months.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836511 TI - The effect of antiprogestin (RU 486) and prostaglandin biosynthesis inhibitor (naproxen) on uterine fluid prostaglandin F2 alpha concentrations. AB - In the present study the effect of the antiprogestin RU 486 and the prostaglandin biosynthesis inhibitor, naproxen, on uterine fluid concentration of prostaglandin F2 alpha (PGF2 alpha) was investigated. RU 486, 200 mg, was administered two days after the luteinizing hormone (LH) surge and naproxen, 500 mg, was given every 12th hour five times starting 4 days after the LH surge. Uterine fluid was collected in the proliferative phase at ovulation and in the mid-luteal phase in a control and treatment cycle. The amount of PGF2 alpha was measured by gas chromatography-mass spectrometry. In the control cycle, the highest concentration of PGF2 alpha was found in the mid-luteal phase, and the lowest at the time of ovulation. Both RU 486 and naproxen reduced the PGF2 alpha concentration in uterine fluid considerably, or to 22-25% of that in the control cycle at the time of implantation. PGF2 alpha produced by the endometrium is believed to be of importance for the implantation of the blastocyst. Postovulatory treatment with RU 486 effectively prevents implantation, probably mainly by inhibiting the maturation of the endometrium during the secretory phase of the cycle. It is suggested that the inhibition of PGF2 alpha release through the uterine fluid caused by RU 486 may also be of importance. PMID- 7836512 TI - Ultrasonic control without hormone determination for ovulation induction in in vitro fertilization/embryo transfer with gonadotrophin-releasing hormone analogue and human menopausal gonadotrophin. AB - A total of 114 patients admitted to an in-vitro fertilization-embryo transfer programme for the first time, were randomly assigned to the study group or controls. Gonadotrophin-releasing hormone analogue (GnRHa) and human menopausal gonadotrophin (HMG) were used for ovulation induction. The study patients were followed up merely by ultrasonography and the controls by ultrasonography and serum determinations of oestradiol, progesterone and luteinizing hormone (LH). There was no significant difference in the duration and total amount of HMG used for ovulation induction (10.9 versus 11.5 days and 34.8 versus 37.9 ampoules, respectively). The number of oocytes retrieved (11.7 versus 13.4) and the numbers of embryos replaced (2.6 versus 2.8) and cryopreserved (1.9 versus 3.3) were also similar. Pregnancy rates were similar. Pregnancy rate per ovum retrieval was 22.2 versus 25% and per embryo transfer 27.2 versus 26.5%. Oestradiol patterns were also similar. The rate and severity of ovarian hyperstimulation syndrome were virtually identical. We conclude that 'ultrasound-only' monitoring of ovulation induction in IVF cycles treated by GnRHa-HMG in the long protocol is as effective and safe as the conventional ultrasound and hormone determination, but far simpler, swifter and more cost-effective. PMID- 7836514 TI - Investigations on the cell type responsible for the endometrial secretion of complement component 3 (C3). AB - It has been shown that rat and human endometria have the capacity to produce complement component 3 (C3). In rats, endometrial C3 is an oestrogen-dependent protein produced and secreted by glandular cells. The cell responsible for the synthesis and secretion of human endometrial C3 has not been clearly defined. Our study was aimed at answering this question. Samples of endometrium obtained from hysterectomies were either immunostained for C3 or digested with collagenase; then the stromal and glandular cells were separated and immunopurified (or not) with an antibody to CD45 coupled to magnetic beads to eliminate the endometrial lymphomyeloid cells. Cells were cultured for 2 weeks and C3 measured in the medium by an in-house radioimmunoassay. Glandular as well as stromal cells stained positively for C3 and released C3 in vitro. The release of C3 from both cell types could be inhibited by cycloheximide. Epithelial cells produced significantly more C3 than stromal cells, and endometrial C3 production was higher for both cell types when these were obtained from secretory as compared to proliferative endometria. Lymphomyeloid cells were possibly a source of C3 since after immunoadsorption of these cells, the remaining stromal or glandular cells produced significantly less C3. We conclude that endometrial stromal, glandular and lymphomyeloid cells all produce C3. PMID- 7836513 TI - Serum concentrations of dimeric inhibin during the spontaneous human menstrual cycle and after treatment with exogenous gonadotrophin. AB - A recently described two-site enzyme immunoassay incorporating a pre-assay oxidation step was validated and used to measure serum concentrations of dimeric inhibin in five normally cycling women and in 13 women undergoing gonadotrophin therapy. Recombinant human inhibin A (standard) gave an assay response curve which was parallel to those for human serum samples and recovery of exogenous inhibin added to serum samples before assay was quantitative (109 +/- 8%, n = 11). During the normal menstrual cycle dimeric inhibin concentration increased from 9.0 +/- 2.0 pg/ml during the early follicular phase to reach a mid-cycle peak of 55.3 +/- 11.1 pg/ml coincident with the pre-ovulatory gonadotrophin surge. After falling to 27.9 +/- 5.7 pg/ml 1 day after the luteinizing hormone surge, inhibin then rose in parallel with serum progesterone to reach a peak value of 115.6 +/- 19.3 pg/ml during the mid-luteal phase, before falling to 14.1 +/- 4.9 pg/ml by the onset of next menses. During the follicular phase, dimeric inhibin concentrations were closely correlated with those of serum oestradiol (r = 0.69; P < 0.001), whereas during the luteal phase they were most closely correlated with serum progesterone concentrations (r = 0.73; P < 0.001). Daily treatment with human menopausal gonadotrophin promoted a progressive increase in serum dimeric inhibin concentration which increased approximately 20-fold in 6 days. In the same period total alpha-inhibin (measured by radioimmunoassay) increased approximately 5-fold, while serum oestradiol increased approximately 30 fold.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836515 TI - The fluid dynamics of injection: variables as they relate to transvaginal gamete intra-fallopian transfer and tubal embryo transfer. AB - Transvaginal gamete intra-Fallopian transfer (GIFT) and tubal embryo transfer have not, in most cases, produced pregnancy rates as high as the equivalent transabdominal methods. We postulated that two parameters, i.e. wide dispersion of the gametes and peritoneal spill of gametes or embryos, are of prime importance in explaining this difference. We designed this study to analyse the effect of varying the rate of injection (microliter/min) of radio-opaque contrast media and the distance the transfer catheter is placed into the tubal isthmus upon these two parameters. Selective salpingography was performed on 30 patients who were allocated to one of two experiments. In the first experiment (flow rate), 20 patients were divided into four groups so that we could analyse four sets of 10 Fallopian tubes. Each group was subjected to injection of contrast at different flow rates: 100, 50, 25 or 12.5 microliters/min. Peritoneal spill occurred from 4, 2, 0 and 0 tubes and wide dispersion (> 4 cm) of contrast occurred in 6, 5, 1 and 0 tubes at the respective injection rates of 100, 50, 25 and 12.5 microliters/min. At 12.5 microliters/min contrast was localized to < 2 cm of tubal ampulla in all cases. In the second experiment (catheter placement), the remaining 10 patients were divided to allow analysis of two groups of 10 Fallopian tubes. The transfer catheter was placed either 1.5 cm or 5 cm into the tube and the radio-opaque contrast was injected at 12.5 microliters/min. No difference in the degree of dispersion of contrast along the Fallopian tube was observed. No backflow of contrast into the uterine cavity was observed in any patient following removal of the catheter.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836516 TI - Fertility drugs and risk of epithelial ovarian cancer in Italy. AB - The report of an increase of ovarian cancer risk among women who had used fertility drugs prompted us to analyse the relationship between fertility drugs and ovarian cancer in a case-control study which has been ongoing in four areas of Italy since 1992. The present analysis is based on 195 epithelial ovarian cancer cases and 1339 controls admitted to hospital for diseases other than gynaecological or malignant conditions. Fewer ovarian cancer cases than controls reported use of fertility drugs (odds ratio, after allowance for potential confounding factors: 0.7, 95% confidence interval: 0.2-3.3). Among nulligravid women, 5/177 control women compared with 0/36 cancer cases reported having ever used fertility drugs. Although only based on small numbers of women who were suffering from ovarian cancer and who had also used fertility drugs, the present study indicated that a role of ovarian stimulation in the aetiology of epithelial ovarian cancer is not established, although it is worth investigating. PMID- 7836517 TI - The tyrosine kinase domain of the insulin receptor gene is normal in women with hyperinsulinaemia and polycystic ovary syndrome. AB - The cause of hyperinsulinaemia in polycystic ovary syndrome (PCOS) is unknown, but two recent reports have implicated mutations of the tyrosine kinase domain of the insulin receptor gene in two patients. We have undertaken amplification of the insulin receptor gene using the polymerase chain reaction and single-stranded conformational polymorphism analysis in 22 hyperinsulinaemic patients with PCOS. Of these patients, 50% were polymorphic in exon 17 of the insulin receptor gene, but none of the alterations in sequence has been associated with insulin resistance. The genomic sequences in exons 18-21 were normal in all patients. We conclude that mutations involving the tyrosine kinase domain of the insulin receptor gene are a rare cause of insulin resistance in the PCOS. PMID- 7836518 TI - Relationship between stimulated hyperactivated motility of human spermatozoa and pregnancy rate in donor insemination: a preliminary report. AB - The proportion of spermatozoa exhibiting the vigorous motility behaviour termed 'hyperactivation' (HA) has been shown to be increased following removal of seminal plasma and stimulation with chemical agents such as pentoxifylline. The aim of this study was to examine the relationship between the proportion of HA in cryopreserved semen samples from sperm donors and the corresponding pregnancy rates achieved by donor insemination. Cryopreserved samples from 20 men were incubated in the presence or absence of 3 mM pentoxifylline for 1 h and the %HA determined in each sample. The relationship between pregnancy rate, the proportion of HA spermatozoa in control and pentoxifylline-treated groups and the change in %HA following pentoxifylline treatment (delta HA) as well as the mean semen characteristics for each donor [sperm count, motility (%), motility index, normal morphology (%), post-thaw motility (%) and post-thaw motility index] were examined by logistic regression of the occurrence of clinical pregnancy with each insemination. Both delta HA and mean post-thaw motility index were significantly related to pregnancy rates and together accounted for 64% of the observed variation in pregnancy rates. PMID- 7836519 TI - Comparison of the resazurin test, adenosine triphosphate in semen, and various sperm parameters. AB - The results of the resazurin test (RES) and adenosine triphosphate (ATP) concentration in semen, measured by two methods, were compared for their ability to predict sperm parameters of semen samples from 42 subfertile men as assessed by a semi-computerized system. The highest correlation of RES grade was with sperm concentration (r = 0.70, P < 0.001), concentration of motile spermatozoa, concentration of motile spermatozoa with normal morphology and the ATP concentration using the reference LKB method (all r = 0.65, P < 0.001). The RES test has a positive predictive value of 93% for a progressive motile sperm concentration of 20 x 10(6)/ml or more, and a negative predictive power of 90% for the same variable at a criterion value of 10 x 10(6)/ml. The results of ATP measurement using the reference LKB and FireZyme methods presented a strong correlation (r = 0.74, P < 0.001). The correlations between ATP measurements from the FireZyme method and sperm characteristics were better than those obtained using the reference LKB method for ATP determination. It is concluded that the RES test can be performed with a relatively small volume of semen; it is easy to perform and requires not technical equipment. The accuracy and predictive value of this test are similar to more sophisticated ATP measurements. In addition, the RES may identify a subgroup of subfertile men with a decreased reducing capacity of semen. PMID- 7836520 TI - Disordered acrosome reaction of spermatozoa bound to the zona pellucida: a newly discovered sperm defect causing infertility with reduced sperm-zona pellucida penetration and reduced fertilization in vitro. AB - It is believed that during the process of human fertilization, acrosome-intact spermatozoa bind to the surface of the zona pellucida which triggers the acrosome reaction and the enzymes released facilitate sperm penetration through the zona pellucida. We describe here reduced frequency of the acrosome reaction on the zona pellucida as a cause of infertility in 10 couples with long durations of infertility (average 6 years) and low (< 15%, n = 3) or zero (n = 7) fertilization rates in vitro. Sperm concentration, motility, velocity (Hamilton Thorn), morphology and DNA normality were within the normal range in all the patients. Electron microscopy of spermatozoa did not reveal any specific ultrastructural defects. All couples were negative for antisperm antibodies by immunobead tests. Oocytes from other patients which failed to fertilize in in vitro fertilization and normal donor spermatozoa were used as controls for sperm zona pellucida binding and penetration experiments. Acrosome status of spermatozoa bound to the zona pellucida was assessed with a fluorescent lectin and electron microscopy. The mean number of spermatozoa bound to the zona pellucida was not significantly different between patients and controls. However, the acrosome reaction of spermatozoa bound to the zona pellucida after 2 h incubation was significantly lower (P < 0.001) in the patients (mean 5%, range 0 16) than in the controls (mean 68%, range 44-96). No zona pellucida (out of 40) was penetrated by patient spermatozoa whereas most (39/40) zonae were penetrated by control spermatozoa (average 27 spermatozoa/four zonae pellucidae).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836521 TI - Morphometric characteristics of motile spermatozoa in subfertile men with an excess of non-sperm cells in the ejaculate. AB - A comparison has been made between the morphological dimensions of motile spermatozoa in subfertile men demonstrating a persistent excess of non-sperm cells in their semen and those found in spermatozoa from fertile controls. Scanning electron microscopy and image analysis were used to make a morphometric assessment of defined sperm parameters in the study and control subjects. Half of the study cohort had an excess (> 5 x 10(6)/ml) of seminal leukocytes and the remainder an excess of sperm precursors in the ejaculate. In subjects with a sperm precursor excess, the motile spermatozoa had several significantly larger head parameters than those from both the fertile controls and those men with a leukocyte excess. Mid-piece and tail measurements did not differ significantly between groups. These findings suggest that, where there are large numbers of immature germinal elements present in semen, there is aberrant morphological development of the motile, apparently mature, spermatozoa which may represent disordered spermatogenesis. PMID- 7836522 TI - Conventional in-vitro fertilization versus intracytoplasmic sperm injection for patients requiring microsurgical sperm aspiration. AB - Intracytoplasmic sperm injection (ICSI) has been successful in cases of extreme oligoasthenozoospermia in achieving pregnancies via in-vitro fertilization (IVF) with the lowest imaginable sperm counts. In azoospermia caused by congenital bilateral absence of the vas deferens (CBAVD), it has been shown that epididymal spermatozoa can be retrieved in large numbers, but fertilization rates using conventional IVF are low. Furthermore, no fertilization has ever been possible using testicular spermatozoa with conventional IVF. In the most extreme case of absence of the epididymis, spermatozoa can only be retrieved from macerated testicular biopsy specimens. In such cases, all that can be seen are free floating Sertoli cells with many spermatids attached, and only occasional spermatozoa per high power field which have only the barest, occasional, slightly twitching motion. The objective of the present study was to determine whether ICSI could achieve better results than conventional IVF with microsurgical aspiration of spermatozoa (MESA). ICSI (using epididymal or testicular spermatozoa) from men with CBAVD or irreparable obstructive azoospermia, achieved good fertilization and normal embryos in 82% of cases, compared to 19% with conventional IVF. There was an overall fertilization rate of 45%, with 85% progressing to normally cleaving embryos using ICSI, compared to 6.9% using conventional IVF. The pregnancy rate with ICSI/MESA was 47% per stimulated cycle (normal delivery rate was 30%), compared to 4.5% with conventional IVF. These results were achieved in patients who had consistently failed to fertilize in previous cycles with MESA and conventional IVF.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836523 TI - Factors influencing the outcome of in-vitro fertilization with epididymal spermatozoa in irreversible obstructive azoospermia. AB - Microsurgical epididymal sperm aspiration (MESA) and in-vitro fertilization (IVF) were found to offer limited opportunity for fatherhood to 45 men with obstructive azoospermia, due principally to poor embryo implantation. Adequate sperm preparations were obtained in 46/50 treatment cycles (92%), with the best motility found in the caput epididymis in 89% of cases. The mean fertilization rate was 11.2% and fertilization occurred in 23 cycles (50%), with embryo transfer arising from 12/26 men with vas aplasia (CAV), 4/9 with genital tract obstruction (EV) and 7/11 with irreversible vasectomy (VV). The overall implantation rate was low, 8.7% per embryo transfer (11.7% per 2-3 embryo transfers) and was not improved by Fallopian transfer. There were two pregnancies (4% per cycle), both in the EV group where embryo formation and implantation (2/4, 50% per cycle) were optimum even though sperm preparations were paradoxically inferior to the CAV and VV groups. The spermatozoa retrieved in the two successful EV cycles were appreciably blood contaminated. Analysis of the 21 failed embryo transfers showed delayed fertilization in 10 cycles, cystic fibrosis (CF) mutation or familial disease in 7/12 CAV men and the VV men were older (P < 0.001). A pregnancy which miscarried arose from a case of Young's syndrome, a carrier of CF mutation DF508. Male factors could thus be implicated in the high embryo wastage of MESA cycles and might also be influencing implantation in other IVF procedures. Where feasible, male reconstructive surgery is preferable unless fertilization can be improved, possibly by speedier retrieval techniques or by permitting sperm capacitation in vitro, but probably more effectively by micro-assisted insemination. PMID- 7836524 TI - Ascorbate-supplemented media in short-term cultures of human embryos. AB - The present study aimed to evaluate whether ascorbate, a reactive oxygen species (ROS) scavenger, can improve fertilization and development of human embryos in vitro when added to the simple salt solution human tubal fluid (HTF) or the complex tissue culture medium Ham's F-10, which contains iron and copper in its formulation. Human oocytes, spermatozoa and embryos from 83 infertile IVF couples were randomly allocated and cultured in the presence or absence of 62.5 microM ascorbate in HTF medium (39 couples) or Ham's F-10 medium (44 couples). No significant effect of ascorbate on fertilization, number of cells and embryo grade per embryo on days 2 and 3 after insemination, or percentage of embryos showing developmental block on day 3 (those embryos that were still at the 2-cell stage) was observed when data were analysed together or divided into several groups according to the cause of infertility, quality of semen sample used for insemination and women's age in either of the two media tested. Despite these results, a positive effect of ascorbate on fertilization and embryo development in vitro cannot be totally ruled out until the effects of other, non physiological concentrations of ascorbate and longer-term embryo cultures (to the blastocyst stage) have been tested. PMID- 7836525 TI - Use of lasers in assisted fertilization and hatching. AB - The erbium-yttrium-aluminium-garnet (Er:YAG) laser has been applied to micromanipulation in humans. It was used in the fertilization process for both subzonal insemination (SUZI) and for partial zona dissection (PZD). Laser assisted micromanipulation achieved significantly higher fertilization rates (34.8%) when compared to mechanical SUZI (16.1%), but use of the laser did not improve the PZD results (laser 14.8% versus mechanical 14%). The Er:YAG laser was used to assist hatching. In the mouse it significantly improved the hatching rate (80 versus 29.3%) 110 h after administration of human chorionic gonadotrophin. This technique was applied in two different centres to patients with previous in vitro fertilization (IVF) failures. the implantation rate per embryo (14.4% laser assisted hatching versus 6% control group) and the pregnancy rate per transfer (40 versus 16.2%) were improved. PMID- 7836526 TI - Co-culture of human pronucleate oocytes with their cumulus cells. AB - The aim of this prospective randomized work was to study the value of co culturing human pronucleate oocytes with their cumulus cells. A total of 550 fertilized oocytes from 95 in-vitro fertilization patients were randomly divided into two groups on the day after insemination. Group A oocytes (n = 260) were left undisturbed with their attached cumulus cells and group B oocytes (n = 290) were dissected from their cumulus cells. Both groups were incubated and examined daily for 3 days. In group A, 78% (202/260) reached the 4-cell stage 48 h after retrieval compared to 69% (200/290) in group B. At 72 h after retrieval, 70% (141/202) had reached the 8-cell stage in group A compared to 56% (112/200) in group B. The percentages of grade 1 embryos at 48 and 72 h after retrieval were 70% (141/202) and 76% (107/141) in group A compared to 50% (100/200) and 43% (48/112) in group B respectively. We concluded that co-culture of human oocytes with their cumulus cells significantly decreased their fragmentation and increased the number of embryos that reached the 4-cell and 8-cell stages with regular blastomeres. The technique is simple and avoids the use of heterogeneous cells. PMID- 7836527 TI - Sexual differentiation and preimplantation cell growth. AB - Growth rates of human preimplantation embryos fertilized in vitro were assessed and compared to the sex of the pregnancy outcome. The likelihood of a liveborn male was significantly greater than that of a female if the mean number of cells/embryo was four or greater at the scheduled time of transfer (odds ratio of 6:1). This finding suggested that the Y chromosome expresses factors which influence embryonic growth rates immediately after fertilization. PMID- 7836528 TI - Detection of fertilization in embryos with accelerated cleavage by fluorescent in situ hybridization (FISH). AB - Embryos from a couple undergoing routine in-vitro fertilization for unexplained infertility had shown cleavage by day 1 in two consecutive cycles. The response of the woman to fertility drugs had been normal, and there were no known sperm abnormalities. In a subsequent cycle, accelerated cleavage occurred again and we used a modified method of spreading whole embryos and dual fluorescent in-situ hybridization (FISH) with directly labelled probes for chromosomes X and Y to determine if fertilization had occurred in these embryos. Nine oocytes were collected, five of which had cleaved when examined for pronuclei early on day 1 following late insemination. Pronuclei were observed in one of the remaining oocytes, but in this case, three were present. On day 2, all of the oocytes/embryos had cleaved and two were transferred to the patient. The remaining seven were spread for FISH analysis but nuclei were only obtained from five. In three, a Y signal was detected, indicating that fertilization had occurred. In all five embryos, a wide range of X chromosome signals were observed. These data suggest that the embryos had undergone abnormal fertilization and accelerated cleavage. PMID- 7836529 TI - Cryopreservation of immature mouse oocytes. AB - Mouse oocytes enclosed in cumulus cells were isolated from antral follicles at the germinal vesicle (GV) stage. They were stored in straws at -196 degrees C by a conventional mouse embryo freezing method using dimethylsulphoxide (1.5 M) as the cryoprotectant. Overall survival assessed after removal of the cumulus cells was 93% (299/320). A significantly greater proportion of fresh oocytes remained arrested at the GV stage during culture (11 versus 1%), but the rate of maturation to metaphase II was not significantly different between frozen and fresh oocytes (83 versus 74%). The rate of fertilization in vitro was similar for frozen and fresh oocytes matured in vitro (70 versus 81%) but significantly less than with mature ovulated oocytes (96%). Fertilization of frozen and fresh oocytes arrested after germinal vesicle breakdown was similar (77 versus 95%). No evidence of parthenogenetic activation was found in the different groups after overnight incubation of metaphase II oocytes. Implantation was similar for embryos derived from fresh and frozen GV-stage oocytes matured in vitro and mature ovulated oocytes, but the loss of embryos after implantation was significantly higher in the in-vitro matured groups (frozen, 40% and fresh, 46% versus 24%). The overall survival of oocytes frozen at the GV stage was 27%. This compares favourably with the estimated overall survival of mature oocytes cryopreserved by a similar procedure. We conclude that the increased post implantation loss is due to suboptimal conditions for maturation in vitro rather than freezing injury. PMID- 7836530 TI - Time-course of oocyte activation, pronucleus formation and cleavage in human oocytes fertilized by intracytoplasmic sperm injection. AB - Knowledge of the timing of the stages of fertilization in humans is still limited because the time of gamete fusion is not known when pre-ovulatory or in-vitro matured cumulus-enclosed oocytes are inseminated. We therefore studied the morphological nuclear changes in 14 patients' oocytes by means of light microscopic observation at 2, 4, 6, 8, 16, 18 and at 20 h after intracytoplasmic single sperm injection (ICSI). A total of 144 metaphase II oocytes were injected with the spermatozoa of the patients' partners. Out of the 134 oocytes that survived the injection, 93 displayed two pronuclei in the course of the observation period (69%). Out of the 93 normally fertilized oocytes, 21 extruded the second polar body at 2 h after micro-injection (23%) and 63 oocytes at 4 h (68%). Pronuclei appeared as early as 6 h after ICSI in 16 normally fertilized oocytes (17%). At 8 h, 75 (80%) oocytes had two visible pronuclei, at 16 h 92 (99%), at 18 h 76 (82%) and at 20 h 63 (68%). In 24 oocytes (26%) the appearance of pronuclei was asynchronous, while the disappearance of the pronuclei was always synchronous, except in one oocyte. Nine of the 134 successfully injected oocytes showed three equal-sized pronuclei (6.7%). Four of the nine multi pronucleated oocytes did not extrude the second polar body at all, while the time sequence of appearance of pronuclei was similar to that of the normally fertilized oocytes.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836531 TI - Absence of heat treatment of serum for culture medium supplementation does not adversely affect the outcome of in-vitro fertilization. AB - This study was carried out to determine if not heat-treating serum prior to use for medium supplementation adversely affected in-vitro fertilization (IVF) of human oocytes. Morphologically mature human oocytes derived from 135 patients undergoing IVF treatment were studied. A total of 504 oocytes were incubated, inseminated and the resulting pronuclear oocytes cultured further in Earle's balanced salt solution (EBSS) supplemented with 10% non-heat-treated serum. Comparisons of fertilization rate and embryonic development were made between these and 687 control oocytes derived from the same patients but incubated, inseminated and resulting pronuclear oocytes cultured further in EBSS supplemented with 10% heat-treated serum. The fertilization rate of 74.4% (375/504) of oocytes handled in serum-supplemented medium that had not been heat treated was significantly better than the rate of 67.7% (465/687) for controls (P < 0.0125). The proportion of pronucleate oocytes that cleaved was also significantly better in the non-heat-treated serum group: 270/300 (90%) versus 307/375 (81.8%) (P < 0.0025). There was no significant difference in the proportion of embryos with four or more cells at the time of embryo transfer. The results show that the absence of heat treatment of serum used to supplement culture medium has no adverse effect on the fertilization rate and short-term embryo development in vitro; hence we suggest that serum heat treatment is an unnecessary procedure and could be abandoned. PMID- 7836532 TI - Oestrogen and progesterone receptors in endometriosis: heterogeneity of different sites. AB - The expression of receptors for the ovarian steroid hormones oestrogen and progesterone was studied immunohistochemically using monoclonal antibodies in samples of endometriosis and endometrium in 22 patients. In nine patients samples of endometriosis from more than one site were studied. There was marked heterogeneity in expression of receptors in endometriosis, both when comparing lesions with the corresponding endometrium and also between samples of endometriosis collected from different sites within the same patient. It was suggested that local environmental factors related to the site, depth and degree of fibrosis of the lesions determine the amount of steroid hormone stimulation reaching the lesions and account for the observed difference between endometriosis and endometrium and between endometriosis lesions of different sites. PMID- 7836533 TI - Infected endometriotic cysts secondary to oocyte aspiration for in-vitro fertilization. AB - Two weeks after oocyte aspiration for in-vitro fertilization, a 38-year-old woman with a history of endometriosis presented with abdominal pain and fever. On exploratory laparotomy, both ovaries were enlarged and contained seropurulent fluid. Unilateral oophorectomy and drainage of the other ovary were performed. Pathological examination revealed infected endometriotic cysts. PMID- 7836534 TI - The use of gonadotrophin-releasing hormone analogues in women receiving oocyte donation does not affect implantation rates. AB - There is conflicting clinical evidence suggesting a positive role for gonadotrophin-releasing hormone analogues (GnRHa) on implantation in humans. This potential effect was evaluated in this study taking the oocyte donation programme as a model. Patients were randomly allocated into one of the two treatment groups: group I received simultaneous treatment with GnRHa and steroids, and group II only received exogenous steroid replacement. An analysis of the donors and semen quality showed similarity between recipient groups. There was no significant difference between groups in the number and quality of embryos replaced, clinical pregnancy and implantation rates. In summary, using a model in which the endometrium can be analysed independently of the embryos, the results suggest that GnRHa are neither effective nor detrimental for embryo implantation in humans. PMID- 7836535 TI - Prospective follow-up study of 55 children born after subzonal insemination and intracytoplasmic sperm injection. AB - In 163 couples referred for assisted fertilization, pregnancy was established by subzonal insemination (SUZI), intracytoplasmic sperm injection (ICSI) or a combination of both techniques. These couples agreed to participate in a prospective study that included a prenatal diagnosis and clinical follow-up of the children. No cytogenetic aberrations were observed in 43 children tested. In 23 pregnancies occurring after SUZI, 15 women gave birth to 21 children. After replacement of combined SUZI and ICSI embryos, 10 pregnancies resulted in 8 deliveries with 10 children. Transfer of ICSI embryos led to 130 pregnancies ending in 20 deliveries with 24 children, with many others still ongoing successfully. In total, 55 children have been examined: 29 boys and 26 girls. One child from a singleton pregnancy presented multiple congenital malformations; one twin child presented a quadriparesis. In this observational study on a limited number of children, the incidence of major malformations was not different from the incidence in the general population. PMID- 7836536 TI - Hydatidiform mole with a surviving coexistent fetus following in-vitro fertilization. AB - A case of a hydatidiform mole with a surviving coexistent fetus following in vitro fertilization and embryo transfer is reported. The diagnosis was established at 12 weeks gestation and pregnancy was maintained until 31 weeks, during which time transient hyperthyroidism and lung metastasis developed. No difference was observed in pronucleus formation and early embryonic development between the two embryos, which resulted in a complete mole and a normal fetus. DNA finger-print analysis, karyotype analysis and histopathological examination confirmed that the pregnancy was a twin of a complete mole and a normal conception. DNA fingerprint analysis was performed with a single-locus probe cocktail. All DNA bands from the tumour were of paternal origin, and the bands from the placenta were of paternal and maternal origin. PMID- 7836537 TI - Three-dimensional ultrasound in obstetrics and gynaecology: technique, possibilities and limitations. AB - Three-dimensional (3D) ultrasound offers several options extending conventional two-dimensional scanning. Various imaging modes are available. Three perpendicular planes displayed simultaneously can be rotated and translated in order to obtain accurate sections and suitable views needed for diagnosis and geometric measurements. 3D ultrasound tomography combines the advantages of ultrasound, e.g. safety, simplicity of application and inexpensiveness, with the advantages of sequentially depictable sections in numerous rotatable and translatable sections. Surface rendering gives detailed plastic images if there are surrounding layers of different echogenicity allowing for the definition of a certain threshold. Transparent modes provide an imaging of structures with a higher echogenicity in the interior of the object. A combination of the two modes sequentially definable by the sonographer allows for the optimal viewing of structures. These imaging modes are innovative features which have to be evaluated for clinical applicability and usefulness. Digital documentation of whole volumes enables full evaluation without loss of information at a later point. 3D technology provides an enormous number of technical options which have to be evaluated for their diagnostic significance and limitations in obstetrics and gynaecology. PMID- 7836538 TI - The UK Human Fertilisation and Embryology Act 1990--how well is it functioning? AB - The Human Fertilisation and Embryology Act became law in the UK in 1990, and a statutory body, the Human Fertilisation and Embryology Authority, was established to administer the Act. The opinions of those persons responsible for licensed activity under the Act were canvassed anonymously to assess the initial effect of the Act on their activities, and the administration of the Act by the 'Authority'. The views expressed reflect the opinions of 80% of the 'responsible persons' and are thus likely to be of value to those responsible for administration of the Act and also those planning legislation in this field of human endeavour. PMID- 7836539 TI - Hydatidiform moles. PMID- 7836540 TI - Trend in legitimate and illegitimate multiple births. PMID- 7836541 TI - Radioimmunoassay of cytidine 3',5'-cyclic monophosphate: unambiguous assay by means of an optimized protocol incorporating a trilayer column separation to obviate cross-reactivity problems. AB - Previous assays for cytidine 3', 5'-cyclic monophosphate (cyclic CMP) have been criticized as being ambiguous. Here a modified RIA protocol, in which the production of assay components has been optimized and a novel trilayer chromatography column separation introduced which successfully separates cyclic CMP from compounds, endogenous to living tissues, which cross-react with anti cyclic CMP sera, is described. The assay is capable of assaying cyclic CMP between 0.1 and 5 pmol, can be increased in sensitivity by means of an additional acetylation step, and enables the separation of cyclic CMP, cyclic AMP and cyclic GMP so that all three can be estimated in a single sample. PMID- 7836542 TI - Procedures for Sxs antigen detection by antibody-mediated cytotoxicity tests. A comparative analysis. AB - Biological reagents used in the serological detection of Sxs antigen by antibody mediated cytotoxicity tests were compared in order to optimize the method. Our analyses showed that: (a) red cell-free spleen cells are the best target cells, (b) rabbit serum used as the complement source should be obtained from females, and absorbed with female spleen cells before use, (c) antiserum obtained by immunizing females with repeated injections of syngenic male spleen cells provides the highest anti-Sxs antibody titer, and (d) of the different biological fluids investigated, testis supernatant has highest concentration of Sxs antigen. PMID- 7836543 TI - Bufalin radioimmunoassays: in search of the endogenous digitalis-like substance. AB - The existence of a mammalian natriuretic substance similar to plant digitalis, which inhibits Na,K-ATPase, has been speculated about, but as yet no definite substance has been found. Digoxin-like immunoreactive substance (DLIS) has been reported in various clinical states including new born infants. Using bufalin (a cardioactive substance of animal origin) as antigen, four polyclonal antisera have been produced from 2 separate rabbits and characterised for cross-reactivity with 32 compounds. One antiserum showed a marked change in its cross-reactivity after resting the animal for a year. Of the endogenous substances tested, progesterone was found to be the most cross-reactive. Radioimmunoassay of foetal cord sera with different antisera, gave different levels of bufalin-like immunoactivity. However, after a novel "affinity-immunoassay" procedure, this apparent bufalin-like immunoactivity disappeared. It is concluded that bufalin like immunoactivity in the cord blood is caused by the cross-reaction of endogenous steroids with bufalin antiserum, and the same may be true for DLIS. PMID- 7836544 TI - A simple enzyme immunoassay for measurement of immune complex solubilization utilizing preformed peroxidase-antiperoxidase complexes. AB - An enzyme immunoassay (EIA) was developed for measurement of complement-mediated solubilization of immune complexes. Preformed complexes consisting of horseradish peroxidase (Pe) and anti-Pe antibodies were incubated in diluted serum. After centrifugation the soluble complexes in the supernatant were quantitated by adding peroxidase substrate followed by measurement of absorbance. Kinetic analysis of revealed significant difference between normal and EDTA-treated serum similarly to a standard assay utilising immune complexes containing radiolabelled bovine serum albumin. The difference was most pronounced after incubation of immune complexes with serum for 40 minutes. Immune complex solubilization measured by EIA was reduced in sera from 10 patients with active systemic lupus erythematosus (SLE). In serially followed patients, flares of SLE were preceded by reduction of solubilization capacity. The EIA is a simple method for determining serum capacity to solubilize preformed immune complexes and might be considered as a routine test for assessment of complement function in diseases such as SLE. PMID- 7836545 TI - Development of an ELISA for quantification of human protein S in cell culture fluids using commercial polyclonal antisera. AB - An enzyme-linked immunosorbent assay (ELISA) was developed to measure protein S antigen released into cell culture fluids. We used readily available commercial polyclonal antisera to develop the assay. This assay was sensitive with a detection limit of about 0.086 ng/ml. Between-assay precision (coefficient of variation) at levels of 0.2, 1.1, and 13.9 ng/ml was 14%, 15%, and 11% respectively. Specificity and accuracy were demonstrated from the use of: 1) culture fluids from 3-primary endothelial cell cultures and 7-cell lines known to constitutively produce protein S; 2) 2-cell lines not synthesizing protein S; and 3) from selected samples of normal and protein S deficient plasma. The ELISA described here was about 12-fold more sensitive and 40-fold more cost effective when compared to a commercial ELISA kit. Thus the assay provided a sensitive, specific, precise and economical method useful for the measurement of the nanogram amounts of protein S commonly encountered in cell culture fluids. PMID- 7836546 TI - Adverse dermatologic reactions from antiarrhythmic drug therapy. AB - Undesirable cutaneous reactions to drugs may occur early or late in the course of treatment. The ingestion of drugs may also aggravate existing dermatologic conditions. The adverse dermatologic reactions from antiarrhythmic drug therapy are reviewed. The exact incidence of dermatologic side effects from cardiovascular drugs has been difficult to estimate because of sporadic reporting. In this review, the cutaneous side effects are discussed according to drug class and the type of dermatologic reaction. PMID- 7836547 TI - Optimal sampling theory: effect of error in a nominal parameter value on bias and precision of parameter estimation. AB - The authors examined the robustness of optimal sampling theory in estimating the parameter values of two different populations of patients receiving a constant rate, half-hour intravenous infusion of theophylline. One population consisted of smokers; the other included nonsmokers. The smoking population was predicted to have a serum clearance approximately 50% greater than the nonsmokers because of an induction of the cytochrome P450 system. After an initial study to provide both patient-specific and population mean parameter values, optimal sampling strategies that were derived from each population (seven sample split designs) and the patient's seven sample and four sample design were determined. A second study was performed with an overall sampling strategy that was superset of all the above strategies. The analysis of all samples served as the reference for the parameter values. Bias and precision of the values determined with each of the optimal sampling sets (seven sample sets based on the "correct" and "wrong" populations, the patient's seven and four sample sets) were determined relative to these reference values. Irrespective of the sample set used for analysis, unbiased and precise parameter estimates, particularly of hybrid parameters were provided. With the patient's four sample set, Vss was significantly biased, but the value of (2.2%) was clinically insignificant. The authors conclude that optimal sampling theory, as implemented in this study, provides robust estimates of important pharmacokinetic parameter values, even when errors of 50% are present in the clearance of the population used to calculate the optimal sampling design. PMID- 7836548 TI - Disposition of lorazepam in Gilbert's syndrome: effects of fasting, feeding, and enterohepatic circulation. AB - The effects of fasting and feeding of a high-carbohydrate, low-fat diet on the glucuronidation and enterohepatic circulation (EHC) of lorazepam were examined in seven healthy men (age 18-30 years) and seven matched patients with Gilbert's syndrome. A simultaneous intravenous/oral dosing regimen was used, with half of each group receiving treatment with neomycin and cholestyramine (neo/chol) to block the EHC of the drug. Feeding increased the clearance of free lorazepam from 10.96 +/- 0.56 (mean +/- SD) to 14.11 +/- 1.21 mL/min/kg (P = 0.05) in patients with Gilbert's syndrome when examined in the presence of neo/chol. Clearances, on the other hand, decreased with feeding in control Gilbert's patients (7.61 +/- 0.54 versus 8.82 +/- 0.48 mL/min/kg), although the differences were not significant (P = 0.09). In contrast to both of these groups, feeding decreased lorazepam clearances (13.33 +/- 0.32 to 12.45 +/- 0.52 mL/min/kg, P = 0.17) in neo/chol-treated normals and increased clearances (9.95 +/- 1.84 to 12.38 +/- 2.05 mL/min/kg, P = 0.04) in control normals. Lorazepam clearances were also 20 40% lower in patients with Gilbert's syndrome compared with normals when studied fasting and with neo/chol, or fed and in the control state (P < 0.05 for both). Thus, the glucuronidation and EHC of lorazepam is sensitive both to diet and to the presence or absence of the Gilbert's trait. PMID- 7836549 TI - The temporal effect of food on tacrine bioavailability. AB - A four-way cross-over study was performed to assess the temporal effect of food on the rate and extent of tacrine (Cognex, THA) absorption after drug administration to healthy, older volunteers. Each volunteer received four single 40-mg THA doses at 1-week intervals. Doses were administered after an 8-hour overnight fast, 1 hour before a standard breakfast, 15 minutes after beginning a standard breakfast, and 2 hours after completion of a standard breakfast. Gastrointestinal side effects were most frequently reported after drug administration to fasted subjects. Mean Cmax and AUC(0-infinity) values after THA administration during breakfast (9.9 ng/mL and 70.2 ng.hr/mL) and 2 hours after breakfast (11.6 ng/mL and 74.2 ng.hour-1.mL-1) were significantly lower than values determined after administration of THA to fasting subjects (15.8 ng/mL, and 91.8 ng.hour-1.mL-1). Little effect was evident when THA was administered 1 hour before breakfast. PMID- 7836550 TI - Central nervous system effects of HMG CoA reductase inhibitors: lovastatin and pravastatin on sleep and cognitive performance in patients with hypercholesterolemia. AB - Sleep disturbances and decrements of daytime performance have been attributed to HMG-CoA reductase inhibitors. As a rule, lipophilic compounds more readily cross the blood-brain barrier and are more likely to affect central nervous system function. The authors compared the effects of lovastatin (40 mg), a lipophilic compound, to pravastatin (40 mg), a hydrophilic compound, in a 6-week, double blind, randomized, placebo-controlled, three-way Latin square design, cross-over study on 22 men with hypercholesterolemia. Patients had LDL cholesterol of more than 165 mg/dL and triglyceride of less than 350 mg/dL after 6 weeks of a low-fat (< 30%), low-cholesterol (< 300 mg/day) diet. Compared with placebo, there were no significant effects of lovastatin or pravastatin on the following subjective and polysomnographic sleep measures: changes in total sleep time, time in each sleep stage, sleep efficiency, sleep latency, REM density, REM activity, and number of arousals. Similarly, there were no effects of the two drugs on measures of cognitive performance. A significant increase in the duration of nocturnal tumescence (NPT) was observed after 2 weeks of treatment with both study drugs. This effect was not significant after 6 weeks of treatment. Both lovastatin and pravastatin caused significant (P < .05 compared with placebo) decreases in total cholesterol (by 20.9 and 20.6%, respectively), LDL cholesterol (by 27.8 and 29.9%), and triglycerides (by 13.6 and 3.7%). Subjects' HDL increased by 2.3% with lovastatin (NS) and by 3.1% with pravastatin (P < .05). Lipoprotein(a) increased by 20.5% with lovastatin and by 1.1% with pravastatin; these changes were not significantly different from placebo.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836551 TI - Lack of interaction between glipizide and co-trimoxazole. AB - To identify the effects of co-trimoxazole on the elimination and disposition kinetics of glipizide, eight healthy male volunteers were studied in an unblinded, randomized, cross-over trial with two phases (no treatment or co trimoxazole 160/800 mg twice a day). During each phase, subjects were treated at home for 7 days with one of the treatment regimens, followed by a 24-hour hospitalization for a single-dose challenge with 10-mg oral glipizide and detailed blood studies. A 7-day washout period was interspersed between the phases. Pharmacokinetic and pharmacodynamic parameters were determined and compared using the Student's t-test for paired observations. Glipizide area under the curve (AUC), clearance, and half life for treatment and control phases were 5758 +/- 1874 versus 5176 +/- 1505 micrograms/L/hour (P = .21), 0.41 +/- 0.15 versus 0.45 +/- 0.14 mL/min/kg (P = .27), and 5.13 +/- 2.10 versus 3.95 +/- 1.37 hours (P = .04), respectively. Twenty-four-hour glucose AUCs for treatment and control phases were 112.24 +/- 8.76 versus 114.86 +/- 11.98 mmol/L/hour (P = .55), respectively. The only parameter reaching statistical significance was glipizide half life, but the difference is of doubtful clinical significance because of difficulty in identifying a clear elimination phase in several subjects. It is concluded that co-trimoxazole administration did not significantly alter glipizide disposition and elimination kinetics in this study population. PMID- 7836552 TI - Reflections on nomadic and scattered populations. PMID- 7836553 TI - Quality of care problems among Medicare and Medicaid patients. AB - The purpose of this study was to characterize quality of care problems among Medicare and Medicaid inpatients in New York State. The patients selected for this study comprised 1991 and 1992 Medicare and all 1992 Medicaid inpatients in whom quality of care problems with actual or potential adverse effects were found. The patients in this study were drawn from public, proprietary, voluntary and teaching hospitals. A total of 1000 quality of care problems with either actual or potential adverse effects were found in 706 Medicare patients. Two hundred and seventy-five (275) quality of care problems with actual or potential adverse effects were found in 154 Medicaid patients. Premature death occurred in 53 (7.4%) of the 706 Medicare and in 42 (27.2%) of the 154 Medicaid patients. Treatment problems and monitoring failures accounted for the majority of quality of care problems with actual or potential adverse effects for both Medicare (63.0%) and Medicaid (75.7%) patients. Among Medicare patients, the treatment of infections and antibiotic use, fluid and electrolyte management, and inappropriate drug use were among the leading causes of quality of care problems. Attending physicians were associated with the majority of Medicare quality of care problems while house staff and attending physicians were associated with the majority of those among Medicaid patients. The results of this study indicate that there are several leading causes of quality of care problems among Medicare and Medicaid patients. Treatment problems and monitoring failures together comprise the majority of such problems. Among Medicare patients, it was found that most quality of care problems were associated with the treatment of infections and antibiotic use, fluid and electrolyte management, and inappropriate drug use. Most quality of care problems among Medicaid patients were associated with these categories as well as with labor and delivery problems, and poor discharge planning. The results of this study reflect the peer review process in which providers are given an opportunity to respond to physician-reviewer decisions about the presence of actual or potential adverse effects. Such a process, which permits the presentation of additional data and information by providers, produces fewer final adverse outcome determinations than a process uniquely based on chart review. The quality of care problems observed in this study are amenable to focused educational interventions. Such remedial interventions could yield significant improvements in the quality of care for all patients. PMID- 7836554 TI - Fetal deaths in Mexican-American, black, and white non-Hispanic women seeking government-funded prenatal care. AB - Hispanics of Mexican origin constitute the largest minority population in the Southwestern United States, yet little is known about their reproductive health. This study assessed ethnic differentials in fetal mortality at 20 or more weeks gestation and identified the social and behavioral predictors associated with this outcome among low-income Hispanic, black non-Hispanic and white non-Hispanic women. Records were used of 80,431 patients attending federally funded prenatal care clinics in California from 1984 through 1989. The fetal death rate per 1,000 live births and fetal deaths was 7.8 for Hispanic, 8.4 for white non-Hispanic and 20.5 for black non-Hispanic women. These rates indicated favorable reproductive outcomes for Mexican Americans despite their social risk profile. An analysis of stillbirths by gestational age showed that Hispanic women stood a significantly lower risk of short-gestational stillbirths than non-Hispanics. In contrast, Hispanic women had a higher proportion of term stillbirths. Hispanic acculturation was a significant predictor of short-term gestation fetal deaths only. The inability to pay for health care was a strong predictor of fetal deaths for all ethnic groups, underscoring the need to ensure adequate access to maternity care for low-income women. PMID- 7836555 TI - Estimating the risks and prevalence of hypertension in a suburban area of Beijing. AB - Community-oriented primary care (COPC) provides a framework for identifying and addressing a defined community's health and health care needs. The research reported upon here is based on a community health survey in a new suburban neighborhood (Tayuan region) in the Haidian district of Beijing, conducted by the Beijing Medical University Department of Preventive Medicine and Health Care, to serve as a basis for planning health care services for the residents in that community. The analyses focus on the prevalence and predictors of hypertension among older adult residents (those 45 years of age and older). Based on logistic regression analyses, the odds ratios (in parentheses) confirm that individuals with a family history of cardiovascular disease were more likely to have been diagnosed as hypertensive (1.57). Hypertensives were also more likely to have uncontrolled systolic (3.85) or diastolic (4.75) blood pressure and associated behavioral and biologic risks, such as obesity (1.87) and renal damage (2.60). These risks were even greater among current or former smokers. These analyses will inform the design of community-oriented primary care interventions in that particular community in the People's Republic of China. They also signal important implications and highlight practical methods for assessing and targeting interventions in U.S. communities facing comparable, but unexamined, risks. PMID- 7836556 TI - Drug prevention in Zuni, New Mexico: creation of a teen center as an alternative to alcohol and drug use. AB - In 1991, the Center for Substance Abuse Prevention of the Department of Health and Human Services funded a project to develop alcohol prevention-oriented messages targeting teenagers of the Zuni Tribe in New Mexico. A lengthy needs assessment determined that alcohol was the most serious drug problem on the pueblo, and that Zuni teenagers often resorted to alcohol and other drug use because they had little else to do during their free time. Communication products were developed which publicized and promoted the creation of a Zuni Teen Center as a fun and safe alternative to drug use. These products, then, are serving as a catalyst for mobilizing the Zuni community around the cause of preventing alcohol use and abuse among their teens via the conversion of an old warehouse to a Zuni Teen Center. The following article describes the needs assessment, product development and distribution, and evaluation of the project's success. PMID- 7836557 TI - Perceptions of lung cancer and smoking in an economically disadvantaged population. AB - This study assessed low socioeconomic adults' perceptions of lung cancer and smoking utilizing the Health Belief Model. A random sample of 500 Ohio residents, with an annual household income of less than $18,000, responded to a 45-item telephone survey. Thirty-six percent of respondents were aware of the prevalence of lung cancer. The majority were aware that sidestream smoke and air pollution are lung cancer risk factors (72% and 79% respectively). Forty-one percent believed there was nothing people could do to decrease their risk of developing lung cancer. Thirteen percent perceived themselves as more susceptible to lung cancer than others of their same age and sex though one in five believed that low SES people were more likely to develop lung cancer than higher SES people. Twenty five percent believed that almost everyone who develops lung cancer dies of it within five years of diagnosis. Benefits of quitting were identified as saving money (95%), feeling healthier (90%), living longer (80%), and eliminating hassles with smoking in public (79%). The most common barriers of quitting smoking were addiction (86%), habit (82%), and having friends who smoke (66%). PMID- 7836558 TI - Avoidable hospitalizations and socio-economic status in Galveston County, Texas. AB - Population-based hospitalization rates for preventable conditions are derived for a low-income population in Galveston County, Texas using discharge data from four area hospitals and demographic data from the U.S. Census. Comparisons are made with similar rates for the general populations of two eastern states (Maryland and Massachusetts) and New York City. Results support the hypothesis that low income persons lack access to primary care, leading to higher rates of hospitalization for preventable conditions. Alternative explanations for differences found are examined. PMID- 7836560 TI - Comparative distribution of neurotensin-like immunoreactivity in the brain of a teleost (Carassius auratus), an amphibian (Hyla meridionalis), and a reptile (Gallotia galloti). AB - The distribution of neurotensin (NT) was studied in the brain of three species belonging to the three major classes of cold-blooded vertebrates: teleost fishes (Carassius auratus), anuran amphibians (Hyla meridionalis), and reptiles (Gallotia galloti; Lacertidae). By using antibodies directed against synthetic bovine NT in the three species, immunoreactive cell bodies were discovered mostly in the telencephalon and diencephalon, in particular at the level of the preoptic region the mediobasal hypothalamus, and the thalamus. In the frog and the lizard, additional immunoreactive (ir) structures were observed in the optic tectum and the tegmentum of the mesencephalon. In the goldfish pituitary, an extensive innervation was consistently observed at the level of the rostral pars distalis, whereas in both frog and lizard, positive fibers were only detected in the external layer of the median eminence. In the three species there is a striking overlap between the distribution of the NT-ir cell bodies and that of the target cells for sexual steroids. The results are discussed in relation with those reported in birds and mammals, and with the possible interactions among NT, sexual steroids, and the neuroendocrine control of pituitary hormone release, in particular prolactin and gonadotrophin. PMID- 7836559 TI - GABAergic projection from the basal forebrain to the visual sector of the thalamic reticular nucleus in the cat. AB - We examined the projection from the basal forebrain to thalamic and cortical regions of the visual system in cats, with particular reference to the visual sector of the thalamic reticular nucleus, the lateral geniculate nucleus, and the striate cortex. First, we made injections of wheat germ agglutinin conjugated to horseradish peroxidase (WGA-HRP) into the visual sector of the thalamic reticular nucleus and found cells labeled by retrograde transport in the lateral nucleus basalis magnocellularis. Injection of biocytin into the basal forebrain resulted in the anterograde labeling of a dense band of fibers and terminals within the entire thalamic reticular nucleus; this labeling extended through the visual sector including the perigeniculate nucleus. No orthograde labeling was found in the lateral geniculate nucleus. Next, we addressed the issue of putative neurotransmitters used by this pathway using a variety of immunocytochemical and histochemical markers. In this fashion, we identified two populations of cells in the nucleus basalis magnocellularis of the cat; large cholinergic cells that contain choline acetyltransferase, NADPH-diaphorase, and calbindin and that project to striate cortex and smaller cells that contain gamma-aminobutyric acid (GABA), glutamic acid decarboxylase, and parvalbumin and that project to the visual sector of the thalamic reticular nucleus. We also examined at the electron microscopic level terminals in the visual sector of the thalamic reticular nucleus that were labeled from a biocytin injection in the basal forebrain. Most of these terminals form symmetric contacts onto dendrites and were revealed by postembedding immunocytochemical staining to be positive for GABA. PMID- 7836561 TI - Electron microscopic study on the development of the carotid body and glomus cell groups distributed in the wall of the common carotid artery and its branches in the chicken. AB - Development of the carotid body and the glomus cell groups in the wall of the common carotid artery and its branches was studied in chickens at various developmental stages by electron microscopy. At 8 days of incubation, the carotid body anlage consisted of mesenchyme-like cells, whereas the clusters of epithelial cells, which occasionally contained a few dense-cored vesicles and were accompanied by unmyelinated nerve fibers, were located in the region surrounding the carotid body anlage and in the wall of the common carotid artery. Subsequently, the granule-containing cells together with nerve fibers were detected in the periphery of the carotid body anlage. At 12 days of incubation, a large number of granule-containing cells (glomus cells) were dispersed throughout the carotid body parenchyma and were also widely distributed along the common carotid artery and its branches. The cells frequently extended long cytoplasmic processes that made contact with other glomus cells and nerve fibers. Synaptic junctions which showed desmosome-like thickening of pre- and postsynaptic membranes and accumulations of small clear vesicles (around 50 nm in diameter) were first detected along the contact between the long axons and glomus cells at 12 days of incubation. In the wall of the common carotid artery, interdigitations between the cytoplasmic processes of glomus cells and smooth muscle cells began to form. Sustentacular cells investing partly the glomus cells were also discerned both in the carotid body and around the arteries at this stage. At 14 days of incubation, the glomus cells expressed most of the characteristics of the mature cells, and the synaptic junctions displaying afferent morphology appeared; the secretory granules of glomus cells were accumulated near and attached to the desmosome-like thickening of apposed membranes. PMID- 7836562 TI - Parvalbumin immunoreactivity in the thalamus of guinea pig: light and electron microscopic correlation with gamma-aminobutyric acid immunoreactivity. AB - The relationship of the calcium binding protein parvalbumin (PV) with gamma aminobutyric acidergic (GABAergic) neurons differs within different thalamic nuclei and animal species. In this study, the distribution of PV and GABA throughout the thalamus of the guinea pig was investigated at the light microscopic level by using immunoperoxidase methods. Intense PV labelling was found in all the GABAergic neurons of the reticular nucleus and in scattered GABAergic neurons in the anteroventral nucleus, whereas GABAergic interneurons in the ventrobasal and lateral geniculate nuclei were not PV labelled. At the electron microscopic level, preembedding immunoperoxidase for PV was combined with postembedding immunogold for GABA. In the ventrobasal nucleus, four types of profiles were recognized: 1) terminals with flattened vesicles and forming symmetric synapses, which were labelled with both PV and GABA and could therefore be identified as afferents from the reticular nucleus; 2) boutons morphologically similar to presynaptic dendrites of interneurons, labelled only with GABA; 3) large terminals with round vesicles and asymmetric synapses, labelled only with PV, which contacted GABAergic presynaptic dendrites in glomerular arrangements and resembled ascending excitatory afferents; and 4) terminals unlabelled by either antiserum. In the ventrobasal nucleus of the guinea pig a double immunocytochemical labelling permits therefore the differentiation of two populations of GABAergic vesicle-containing profiles, i.e., the terminals originating from reticular nucleus (that are double labelled) and the presynaptic dendrites originating from interneurons (that are GABA-labelled only). The possibility to differentiate GABAergic inputs from the reticular nucleus and from interneurons can shed light to the functional interpretation of synaptic circuits in thalamic sensory nuclei. PMID- 7836563 TI - Localization and developmental expression of the NMDA receptor subunit NR2A in the mammalian retina. AB - The localization of the N-methyl-D-aspartate receptor subunit NR2A was studied, by using light microscopic immunocytochemistry, in the retina of adult rat, rabbit, cat, and monkey. Strong, punctate immunolabeling was observed in the inner plexiform layer indicating a synaptic localization of the NR2A subunit. The punctate labeling was concentrated in two bands corresponding to the on- and off sublaminae of the inner plexiform layer. The punctate character of immunofluorescence suggested a synaptic localization of the receptor. This was confirmed by electron microscopy of immunostained adult rat retina. The staining was localized postsynaptic to cone bipolar cells, and only one of the two postsynaptic elements of the dyad was labeled. Staining was not observed at extrasynaptic plasma membranes. In situ hybridization of adult rat retina showed expression of the NR2A subunit in virtually all ganglion cells and displaced amacrine cells in the ganglion cell layer and in a subset of amacrine cells in the inner nuclear layer. The postnatal developmental expression of the NR2A subunit was studied in rat retina by light microscopic immunocytochemistry. Punctate immunolabeling appeared prior to eye opening, and the developmental profile of NR2A could be compatible with a role in development of circuitry in the inner plexiform layer. PMID- 7836564 TI - Restricted expression of a new paired-class homeobox gene in normal and regenerating adult goldfish retina. AB - We describe the cloning and expression pattern of a new paired-class homeobox gene, Vsx-1, in the continuously growing retina of the goldfish. Vsx-1 belongs to a subset of paired-class homeobox genes that lack a second DNA binding domain, the paired-domain, and is closely related to the C. elegans ceh-10 gene. In the adult goldfish, Vsx-1 expression is restricted to the neural retina. In the central, mature retina, Vsx-1 mRNA is synthesized in a subset of differentiated cells in the inner nuclear layer in a pattern suggestive of bipolar cells. In immature retina, adjacent to the retinal margin, Vsx-1 is expressed in a relatively broader subset of newly postmitotic cells but is downregulated in some of these cells to form the mature expression pattern. Following retinal injury, during the early phase of regeneration, Vsx-1 mRNA synthesis appears to be upregulated in cells in the inner nuclear layer and is expressed de novo in cells outside this layer. By virtue of its identity as a transcriptional regulatory gene and its patterns of expression, we speculate that Vsx-1 may stabilize the differentiated state of a subset of cells in the inner nuclear layer and may be involved in cellular differentiation during retinal development and regeneration. PMID- 7836565 TI - The so-called calcifying epithelial odontogenic tumour in dogs and cats (amyloid producing odontogenic tumour). AB - This paper describes the microscopical features of a rare odontogenic tumour that occurs in dogs and cats and which has been referred to as the calcifying epithelial odontogenic tumour (CEOT), although it is not the counterpart of the human tumour of that name. We have proposed amyloid-producing odontogenic tumour (APOT) as an appropriate alternative term. The tumour is composed of irregularly shaped strands of squamous epithelium, which in some areas exhibit palisading of the basal cells, similar to that seen in ameloblastomas. Stellate reticulum occurs focally in some examples. The second prominent feature is the presence of amyloid which tends to calcify. Finally, in some examples, a collagenous matrix, which is apparently a form of dentine, is present focally, adjacent to the epithelium. These histological features are compared with those of the canine keratinizing ameloblastoma and the human CEOT. To date, to few examples have been reported to determine accurately the biological behaviour of APOTs, but some have recurred after excision; none has metastasized. PMID- 7836566 TI - Primary and secondary responses of the ovine lymph node to Toxoplasma gondii: cell output in efferent lymph and parasite detection. AB - Efferent lymphatic cannulation was used to study the dissemination of strain S48 of Toxoplasma gondii and the cell output from the prefemoral lymph node, after infection of both "naive" and vaccinated sheep. In the former the mean cell output decreased for 3 days before reaching a peak at 11 and 12 days, but in vaccinated ewes a similar drop in cell output and subsequent peak occurred significantly earlier, at 24 h and 5 days, respectively. The cellular response in both types of sheep was largely due to a marked increase in blast cells. The detection of live toxoplasms and parasite DNA by mouse inoculation and the polymerase chain reaction, respectively, gave similar results; the parasite was demonstrated in lymph from days 3 to 12 during a primary infection but with a sharp cut-off after day 9 coinciding with the peak blast cell response. Very little evidence of T. gondii was found in lymph of vaccinated sheep after challenge. Immunity, which is thought to be largely T-cell mediated and is sustained without continuous antigenic stimulation, suppresses dissemination of the parasite in the lymph and therefore to other sites, which might include the gravid uterus. PMID- 7836567 TI - Distribution of K-papovavirus in infected newborn mice. AB - Newborn mice were inoculated orally with 100 LD50 of K-papovavirus and the distribution of virus in fatally infected animals was studied by in-situ nuclei acid hybridization methods and immunoperoxidase staining for K virus capsid (V) antigen. Histopathologically, K virus produced extensive involvement of pulmonary endothelial cells, resulting in interstitial pneumonia, and widespread involvement of other endothelial cell populations throughout the systemic circulation. Endothelial cells in lungs, kidneys and other organs exhibited both specific hybridization for K virus nucleic acids and positive staining for K virus V antigen, indicative of productive infection. Scattered, apparently extravascular cells within brain parenchyma also exhibited both specific hybridization and immunohistological staining for K virus V antigen. In contrast, specific hybridization for K virus nuclei acids, in the absence of immunohistochemical labelling of K virus V antigen, suggesting transcription of viral DNA without expression of viral proteins, was detected in renal tubular epithelial cells and nonvascular, apparently lymphoid cells within the spleen and lymph nodes. The present study confirms the predominantly endotheliotropic nature of K virus infection in newborn mice and also demonstrates that the virus invades renal epithelial, lymphoid and possibly glial cells during primary infection. PMID- 7836568 TI - The hair follicular cycle of the cryptothrix mouse and the characteristics of its abnormal hair. AB - The hair follicular changes of the cryptothrix mutant mouse (crh mouse) were examined sequentially from birth to 365 days of age and the characteristics of the abnormal hair were observed. The homozygous crh mouse had no hair coat on the skin surface during the period of observation, but a small number of fuzzy soft hairs in the black pigmented skin of the anagen phase was seen. Cyclic folliculogenesis, however, was observed histologically in the dermis. The first anagen phase developed at 3 to 4 days of age and lasted until about 15 days of age. The hair follicles then entered the telogen phase, which lasted until about 18 to 32 days of age. Thereafter, the follicular cycles were repeated three times about every 20 days until 90 days of age. This pattern coincided well with the normal hair cyclic pattern reported for the mouse and rat. After 100 days of age, however, alternating anagen and telogen phases formed a striped pattern in the skin, with black bands. These black bands became progressively thinner and shifted anteriorly, showing a wavy pattern. The abnormal hair of the homozygous crh mouse showed separation of the hair medulla due to incomplete trichilemmal keratinization in the internal root sheath. The tips of the hair shafts were folded and collapsed under the epidermis and did not erupt on the skin surface. The hair follicles, however, did not differ from those of heterozygous crh mice. Because the homozygous crh mouse failed to form a complete hair shaft, cyclic folliculogenesis of the epidermis could be easily observed macroscopically without depilation. The homozygous crh mouse may prove useful in evaluating new drugs for hair follicular growth. PMID- 7836569 TI - Clinical and pathological description of a chronic form of bovine papular stomatitis. AB - This communication describes a hitherto unreported chronic form of bovine papular stomatitis in young cattle. Diagnosis was based on the clinical disease, histological findings, electron microscopical characterization of the causative virus, and virus isolation. A description of the acute form of the disease is presented for comparison. PMID- 7836570 TI - Pituitary gland changes in canine hypoadrenocorticism: a functional and immunocytochemical study. AB - Pituitary gland changes were evaluated immunocytochemically in three dogs with primary hypoadrenocorticism (HAC) and one dog with secondary HAC and related to the clinical, endocrinological and pathological findings. In primary HAC, the adrenocorticotrophic hormone (ACTH) immunoreactivity was increased in the pars distalis of the pituitary gland and all cortical layers of the adrenal gland were severely atrophied. This increase would be expected to reflect a high level of ACTH synthesis in the corticotrophs due to a lack of negative cortisol feed-back. In contrast, in the dog with secondary HAC the ACTH immunoreactivity was decreased in the pituitary gland, the basal plasma ACTH concentration was low and the zona fasciculata and reticularis were atrophied, but the zona glomerulosa was well preserved. These findings are consistent with a diminished synthesis of ACTH. Thus, pituitary gland changes differ in primary and secondary HAC and are consistent with the clinical, endocrinological and histopathological findings. PMID- 7836571 TI - Histopathology of the brain-stem nuclei of horses with "Mal seco", an equine dysautonomia. AB - "Mal seco" is a disease of unknown aetiology affecting horses in Argentina. It is similar to grass sickness, a primary dysautonomia of horses in Europe. A histopathological study of the brain stem nuclei of three horses with "mal seco" was performed. Changes were found that consisted of chromatolysis, cytoplasmic vacuoles, eosinophilic sphaeroids, and pyknotic and eccentric nuclei. These changes were most severe at the oculomotor, vestibular and abducent nuclei. The results provide further evidence to suggest that "mal seco" and grass sickness may be the same disease. PMID- 7836572 TI - Sequential pathology of tick-borne fever. AB - The sequential pathology and clinical responses of 12 sheep infected with the Sourhope strain of Cytoecetes phagocytophila are described. During the experimental period of 3 weeks, the clinical effects were mild, as is usual. There was transient leucopenia, affecting mainly lymphocytes, eosinophils and neutrophils. Parasitaemia was detected from days 5 to 16, approximately. A mild but consistent histopathological response up to day 21 comprised (i) pulmonary alveolitis with minimal shedding of cells, (ii) follicular and especially parafollicular lymphoreticular reactions in lymph nodes and spleen, (iii) mesangial glomerulitis, and (iv) in the cranial nervous system marked choroiditis but minimal reaction in the brain. Two forms of intracytoplasmic inclusions were found, a smaller, granular basophilic structure occurring in clumps and an intravacuolar pleomorphic form. In tissue sections they were mainly associated with lymphoid and macrophagic cells. The significance of these findings is discussed including the problems of differential diagnosis in complex infections. PMID- 7836573 TI - Candidiasis caused by Candida glabrata in the forestomachs of a calf. AB - A female Japanese black calf suffering from diarrhoea was treated with six different antibiotics for 9 days. The diarrhoea worsened and the calf was killed when 17 days old. At necropsy, the mucosal surface of the forestomachs showed diffuse haemorrhagic necrosis and pseudomembrane formation. Candida glabrata infection was diagnosed histologically, immunohistochemically, and by isolation and examination of the yeast. The intensive antibiotic treatment was considered to have been a predisposing or exacerbating factor. This is the first report of C. glabrata infection of the bovine forestomachs. PMID- 7836574 TI - Prolactinoma in a sheep. AB - This report describes the incidental finding of an acidophilic adenoma of the pituitary gland in an adult ewe with clinical signs of a nervous disorder. Immunohistochemical examination demonstrated prolactin in the tumour cells, justifying the use of the term "prolactinoma" for the first time in veterinary medicine. This tumour should be considered in the differential diagnosis of nervous diseases of sheep. PMID- 7836575 TI - Immunoreactivity to chromogranin and to vasoactive intestinal peptide in a canine phaeochromocytoma. AB - A canine phaeochromocytoma was diagnosed by (1) argyrophil methods, (2) immunoreactivity to chromogranin and to vasoactive intestinal peptide (VIP), and (3) the demonstration of typical electron-dense granules by transmission electron microscopy. This is the first report of immunoreactivity to general neuroendocrine markers such as chromogranin, and to VIP, in a phaeochromocytoma in domestic animals. The use of these markers for the differential diagnosis of phaeochromocytoma, and the role of VIP in the severe chronic diarrhoea shown by the dog in this study are discussed. PMID- 7836576 TI - Growth and viability of Bifidobacterium bifidum in cheddar cheese. AB - Bifidobacterium bifidum (ATCC 15696) was grown in MRS broth containing cysteine.HCl at 37 degrees C, and the cells were harvested by centrifuging at 1300 x g for 15 min at 4 degrees C. Equal volumes of the cell slurry and a 2.5% solution of kappa-carrageenan were mixed and transferred by drops into a solution of .3 M KCl at 20 degrees C under an atmosphere of nitrogen. The gelled beads were separated, frozen, and lyophilized immediately. This preparation and a commercial powder preparation were added to Cheddar cheese curd at milling as two treatments. Treatments did not affect cheese composition. Soluble protein increased during ripening at 7 degrees C but without differences between treatments; SDS-PAGE patterns of proteolysis were also similar. Lactic acid content of cheeses increased during ripening, but differences between treatments were minor. Acetic acid and ethanol, common metabolites of bifidobacteria, were not detected during ripening. Bifidobacteria remained viable and increased in numbers in cheese during this 24-wk study but did not affect the flavor, flavor intensity, texture, or appearance of the cheese compared with that of the control. PMID- 7836577 TI - Purification and characterization of a general aminopeptidase (St-PepN) from Streptococcus salivarius ssp. thermophilus CNRZ 302. AB - A general aminopeptidase (St-PepN) was purified from an intracellular extract of Streptococcus salivarius ssp. thermophilus CNRZ 302 by ion-exchange chromatography and hydrophobic interaction chromatography. Gel electrophoresis of the purified enzyme in denaturing or nondenaturating conditions showed a single protein band. The enzyme is a monomer with a molecular mass of 97 kDa. Its activity is maximal at pH 7 and 36 degrees C and is completely abolished by CuCl2 and ZnCl2. The enzyme is strongly inhibited by metal-chelating reagents, such as EDTA and o-phenanthroline, which suggests that St-PepN is a metalloenzyme. The enzyme showed activity toward p-nitroanilide derivatives or dipeptides and tripeptides and showed a preference for hydrophobic or basic amino acids at the N terminal position. Longer peptide chains, such as the B-chain of insulin, glucagon, or peptides generated by the hydrolysis of caseins, were degraded, too. The sequence of the first 21 residues of the mature enzyme was determined and showed high homology with that of the aminopeptidase PepN isolated from Lactococcus lactis ssp. cremoris Wg2. The properties of the enzyme are compared with those of corresponding enzymes of other species of lactic acid bacteria. PMID- 7836578 TI - Distribution of plasminogen activator forms in fractions of goat milk. AB - Distribution of plasminogen activator forms in fractions of goat milk was examined. Raw milk was centrifuged to separate skim milk, cream, and a somatic cell pellet. Somatic cell extracts were obtained by sonication. Skim milk was centrifuged to separate milk serum and casein micelles. Activity of plasminogen activator was detected in casein, serum fractions, and in association with somatic cells. Plasminogen activator forms in milk casein had approximate molecular weights of 75,000, 50,000, and 30,000. The predominant forms of plasminogen activator in milk serum and in association with milk somatic cells had molecular weights of 30,000 and 50,000. Based on fibrin dependency and inhibition of activity in the presence of amiloride, the forms at 30,000 and 50,000 represent urokinase-plasminogen activator, and the form at 75,000 represents tissue-plasminogen activator. PMID- 7836579 TI - Comparisons of freshly isolated strains of Lactobacillus acidophilus of human intestinal origin for ability to assimilate cholesterol during growth. AB - Fecal isolates of Lactobacillus acidophilus were obtained from human volunteers and tested for bile tolerance, the ability to deconjugate bile salts, and the ability to assimilate (take up) cholesterol during growth. One hundred and twenty three of the 304 isolates of lactobacilli obtained were identified as L. acidophilus. In most cases, isolates of L. acidophilus from the same volunteer varied significantly in the amount of cholesterol assimilated, bile salt deconjugated, and bile tolerance. The two cultures from each of nine volunteers that assimilated the most cholesterol were compared as a group to select the most active cultures. Lactobacillus acidophilus ATCC 43121 (an isolate from the intestines of a pig, which in an earlier study aided significantly in controlling serum cholesterol in pigs) was included in this comparison. Significant variation in the ability to assimilate cholesterol was observed among these isolates from different volunteers. Eight of 17 isolates assimilated numerically but not significantly more cholesterol than L. acidophilus ATCC 43121, and 4 isolates assimilated significantly less. Bile tolerance and bile salt deconjugation also varied significantly among the selected isolates. Six of the selected isolates were quantitatively but not significantly better able to deconjugate bile salts than L. acidophilus ATCC 43121, but none was significantly more bile tolerant. Based on characteristics tested, isolates B7, D3, L1, 016, and 017 have the most potential of those included in this study for use as dietary adjuncts to lower human serum cholesterol. PMID- 7836580 TI - Determination of organic acids during the fermentation and cold storage of yogurt. AB - The objective of the present study was the separation and quantification of orotic, citric, pyruvic, lactic, uric, formic, acetic, propionic, butyric, and hippuric acids in a single isocratic analysis by HPLC. Two methods of extraction were compared: 1) acetonitrile and water and 2) .01N H2SO4. Recoveries of orotic, lactic, acetic, and propionic acids were 90% for both methods. Recoveries of citric, pyruvic, uric, butyric, and hippuric acids were not satisfactory with the acetonitrile method, but were acceptable using the H2SO4 extraction procedure. Yogurts were manufactured under laboratory-scale conditions, and samples were analyzed during fermentation and after storage at 4 degrees C. Samples were analyzed for pH and organic acids. All of the organic acids exhibited varying degrees of increases and decreases during fermentation and storage. Formic and butyric acids were not detected under the conditions of this study. PMID- 7836581 TI - Cytokine-induced major histocompatibility complex class II antigens on cultured bovine mammary gland epithelial cells. AB - The aim of this work was to establish a simple but reliable method of collecting epithelial cells from tissue lining the gland cistern of the bovine mammary gland and to investigate the ability of cultured epithelial cells to express major histocompatibility complex class II antigens. Bovine mammary gland epithelial cells were isolated and grown as monolayers on five substrates in vitro. The cells were identified as epithelial in origin by immunofluorescent staining with anticytokeratin monoclonal antibodies. Major histocompatibility complex class II antigens were induced on epithelial monolayers by incubation with supernatants from bovine peripheral blood mononuclear cells stimulated with concanavalin A or incubation with recombinant bovine interferon-gamma. These results suggest that, in bovine mammary gland epithelium, recombinant bovine interferon-gamma, acting alone, can induce class II expression. This observation permits future investigation of the putative role of bovine mammary gland epithelial cells as accessory cells in the initiation of local immune responses and their involvement in peptide transport. PMID- 7836582 TI - Production of various forms of plasminogen activator and plasminogen activator inhibitor by cultured mammary epithelial cells. AB - We examined amounts and types of plasminogen activator and plasminogen activator inhibitor produced by cultured bovine mammary epithelial cells. The MAC-T and two other mammary epithelial cell lines, MACT-UV1 and MACT-UV2 derived from the parental MAC-T cells by subcloning, were used as model systems. Cells were cultured in a medium free of serum and protein. Data showed that MACT-UV2 cells produced 6.2 and 17.2% more plasminogen activator than MACT-UV1 and parental MAC T cells, respectively. Addition of amiloride, a specific urokinase-plasminogen activator inhibitor, dramatically decreased the activity in the culture medium of parental and subclonal lines, indicating that urokinase-plasminogen activator was present. Zymography revealed the presence of urokinase-plasminogen activator with an approximate molecular mass of 50,000 kDa in the culture medium of parental MAC T cells. The culture medium of the subclonal lines contained urokinase plasminogen activator and tissue-plasminogen activator with approximate molecular masses of 50,000 and 75,000 kDa, respectively. Complexes of both types of plasminogen activators with plasminogen activator-inhibitor-1 were detected in the culture medium of subclonal lines. PMID- 7836583 TI - Proliferation of a bovine mammary epithelial cell line in the presence of bacterial virulence factors. AB - Effects of bacterial virulence factors on bovine mammary cell structure and function are not well defined. In this study, we evaluated the influence of specific bacterial virulence factors on proliferation of a bovine mammary epithelial cell line. The MAC-T cells were cultured in the presence of medium only, Staphylococcus aureus alpha-toxin, Staph. aureus beta-toxin, Escherichia coli endotoxin, Streptococcus uberis capsule, or hyaluronidase. Cells were cultured in the presence of virulence factors for 48 h at 37 degrees C. The MAC-T cell proliferation was inhibited by all concentrations of endotoxin and alpha toxin and by most concentrations of hyaluronic acid capsule and hyaluronidase > 7.8 micrograms/ml. Staphylococcus aureus beta-toxin had no effect on MAC-T cell proliferation. Virulence factors produced by mastitis pathogens may influence mammary epithelial cell proliferation in vivo, which could be important during the periparturient period, when mammary tissue undergoes rapid differentiation and growth. PMID- 7836584 TI - Effect of whole Staphylococcus aureus and mode of immunization on bovine opsonizing antibodies to capsule. AB - Exopolysaccharide capsule is a major virulence factor of Staphylococcus aureus because it inhibits neutrophil recognition of antibodies to highly antigenic S. aureus cell wall. To circumvent this inhibition, two modes of immunization were tested for ability to induce anticapsular opsonins. Cows were immunized at drying off and boosted on d 14 and 28 by injection of Smith diffuse S. aureus plus dextran sulfate in the area of the supramammary lymph node or intramammarily. In cows immunized in the area of the supramammary lymph node, IgG1 and IgG2 sera antibody titers to capsule increased and remained elevated to the end of the study, 120 d postcalving. The IgM titers increased during the dry period but declined to preimmunization levels at calving. Response of serum IgG1 and IgM to intramammary immunization was similar to that with supramammary lymph node immunization, but more delayed and lower in magnitude. Antibodies of all four isotypes, IgG1, IgG2, IgA, and IgM, increased in dry secretions following immunization via lymph node. In cows immunized in the lymph node, IgG1 antibodies remained elevated throughout the study, but IgG2 antibodies dropped to baseline 15 d postcalving. In cows immunized intramammarily, only IgA antibodies increased significantly in lacteal secretions and remained elevated throughout the study. Immunization of cows in the lymph node during the dry period enhanced the ability of dry secretions and colostrum to support phagocytosis. PMID- 7836585 TI - Optimal replacement of mastitic cows determined by a hierarchic Markov process. AB - Farmers frequently have to decide whether to keep or to replace cows that suffer from clinical mastitis. A dynamic programming model was developed to optimize these decisions for individual cows within the herd, using the hierarchic Markov process technique. This technique provides a method to model a wide variety of cows, differing in age, productive performance, reproductive status, and clinical mastitis occurrence. The model presented was able to support decisions related to 63% of all replacements. Results--for Dutch conditions--showed the considerable impact of mastitis on expected income of affected cows. Nevertheless, in most cases, the optimal decision was to keep and to treat rather than to replace the cow. Clinical mastitis occurring in the previous lactation negligibly influence expected income. Clinical mastitis in current lactation, especially in the current month, however, had a significant effect on expected income. Total losses caused by clinical mastitis were US$83/yr per cow. Farm level treatment, which reduced incidence by 25%, on a farm with 10 clinical quarter cases per 10,000 cow days, may cost at maximum US$27/yr per cow. PMID- 7836586 TI - Effect of once daily milking and concurrent somatotropin on mammary tight junction permeability and yield of cows. AB - Six pairs of monozygous Friesian twin cows during late lactation were used to assess the effect of once daily milking and bST treatment on yields and tight junction permeability of mammary epithelial cells. During the first 7 d, all cows were milked twice daily; on d 8 through d 21, all cows were milked once daily, but one cow of each twin pair was treated daily with 20 mg of bST on d 13 through 21; and, finally, during d 22 through 28, all cows were again milked twice daily. Once daily milking, a common management practice in New Zealand, resulted in a small (7%) but significant decrease in milk yield. Treatment with bST increased milk yield by 19%, thereby exceeding the milk yield loss from once daily milking. The integrity of mammary tight junctions was assessed indirectly by measuring concentrations of plasma lactose and milk BSA. Once daily milking temporarily disrupted tight junction integrity, based on a 4- to 5-fold increase in plasma lactose and a 42 to 55% increase in the concentrations of milk BSA. In the present study, bST did not affect the permeability of mammary tight junctions. PMID- 7836587 TI - Regulation of colostrum formation in beef and dairy cows. AB - Fifteen beef cows and 13 dairy cows were used to investigate the physiological basis of breed differences in IgG1 concentration in colostrum. Concentrations of progesterone and alpha-LA in sera and IgG1 in sera and secretion were quantified in samples collected prepartum. Serum progesterone concentration decreased significantly between 30 and 10 d prepartum, but breeds did not differ. Serum alpha-LA concentration was initially low but increased to 150 ng/ml in beef cows and 720 ng/ml in dairy cows at parturition. Serum IgG1 concentrations averaged 8.4 in beef cows and 5.7 mg/ml in dairy cows between 28 d and 24 d prepartum and subsequently declined to 6.7 in beef and 1.4 mg/ml in dairy cows between 4 d prepartum and calving. Overall, IgG1 concentration was greater in secretion from beef cows (113.4 mg/ml) than from dairy cows (42.7 mg/ml). The greater disappearance of IgG1 from serum suggested that more IgG1 was transferred into secretion of dairy cows, but concentration in secretion was lower. The reduced IgG1 concentration in secretion was associated with greater lactogenic activity in dairy cows, evidenced by fivefold higher alpha-LA concentration in sera. Dilution of IgG1 in secretion may be responsible for breed differences in colostral IgG1 concentration. PMID- 7836588 TI - Conception rates. 1. Derivation and estimates for effects of estrus detection on cow profitability. AB - Objectives were to derive equations and obtain estimates per cow of days to conception, milk production, semen purchases, calvings, and reproductive failures based on the probability of estrus detection and AI conception. The net benefits of changing rates of estrus detection, including changes in milk production, semen purchases, and replacement inventories (culled cows and calves) were converted to annual values and multiplied by fixed prices to obtain estimates of the annual financial benefit of a change in rates of estrus detection. Improvement in milk production because of a 1-d decrease in DIM at conception was dependent on DIM, peak milk production, and monthly rate of decline in daily milk production. Variation was considerable in expected benefits of improved estrus detection. Under the assumption that replacement was not planned prior to breeding (in which case improved estrus detection would have no value), estimated financial benefits for increasing the probability of estrus detection from 60 to 70% with a 70% AI conception rate were $6/yr; increasing from 20 to 30% the rate of estrus detection with a 50% AI conception rate increased estimated annual benefits to $83. This wide range of values occurred with fixed costs and prices so that fluctuating prices would introduce further variation in financial benefits. Derived equations allow point estimates of expected benefits with input values estimated. PMID- 7836589 TI - Conception rates. 2. Economic value of unit differences in percentages of sire conception rates. AB - The objectives of this research were to estimate 1) the annual increase in profitability and 2) the value of a unit of semen because of an increase of 1 in percentage of AI conception rate. Factors contributing to increased annual profit per cow included more milk production, less semen purchased, more calvings, and fewer reproductive cullings. With a 7% average monthly rate of decline in milk production between peak and end of lactation, $ .24/kg of milk net income over feed cost, $ 20/unit of semen, $ 150 per calving, and $ 400 per reproductive culling, values for increased annual profitability per cow ranged from $ .88 to $ 7.36, and increased value per unit of semen ranged from $ .60 to $ 5.01, when estrus detection and AI conception were each constrained to minima of 30% and maxima of 70%. Additional probability of concept was worth less at high rates of estrus detection and of AI conception. Within-herd variation can be attributed to differences between cows in milk production, asset value of the cow based on future expectations of milk production, and seasonal differences in milk price and rates of estrus detection. Further differences between herds can be expected as producers vary in discounting values for uncertainty of information. Therefore, generalizations from a single set of assumptions may be limited, and application of methods to specific cows and producers may be desirable. PMID- 7836590 TI - Direct analysis of body composition of dairy cows at three physiological stages. AB - Holstein cows were killed at three physiological stages, prepartum (-7 d, n = 10), early lactation (63 d, n = 7), and late lactation (269 d, n = 8), for determination of chemical composition and prediction of energy changes during lactation. Cows were weighed, slaughtered, and separated into five or six fractions, including carcass, gastrointestinal tract, mammary gland, uterus, and fetus (if present); the remainder was noncarcass. Live BW and weight of all empty body components except fat were unaffected by physiological stage. Empty body fat was reduced 42.3 kg for the early lactation cows compared with that of prepartum cows. Fat-free matter was similar across physiological stages; however, the water content of fat-free matter was greater for the prepartum and early lactation cows than for late lactation cows. In early lactation cows, the percentages of total protein were less in carcass and greater in gastrointestinal tissue than in prepartum and late lactation cows, but fat distribution was not affected. The energy values of 9.2 and 5.57 Mcal/kg for fat and protein in tissue, respectively, were determined by regression and used to apportion energy associated with fat, .925, and protein, .07, during lactation using data adjusted for ash. A maximum loss of 442 Mcal of tissue energy by approximately 77 DIM was determined by regression of empty body energy on DIM). PMID- 7836591 TI - Ruminal digestion and duodenal nutrient flows in dairy cows consuming grass as pasture, hay, or silage. AB - The objective of this experiment was to quantitate ruminal digestion and flow of nutrients to the small intestine of Holstein cows grazing grass pasture or fed grass hay or silage. Three dry, nonpregnant Holstein cows fitted with ruminal and duodenal (Y-type) cannulas grazed or were given free choice access to hay or silage during three consecutive 19-d periods. Pasture intake was estimated using chromic oxide; hay and silage intakes were both measured and estimated. Intakes were similar among forages. Ruminal samples had higher VFA and ammonia when cows grazed than when cows were fed hay or silage. Ruminal pH did not differ. Based on duodenal spot sampling, cows on pasture had lower DM flows to the small intestine. Bacterial N flow, as a percentage of total N flow, was higher for cows that grazed. Most flows of AA to the small intestine were similar among forages, but Pro and Phe were lower for grazing cows. Supplementation strategies for cows on pasture should be designed to synchronize protein and carbohydrate in the rumen and to increase the supply of nutrients available in the small intestine. PMID- 7836592 TI - Intake, digestibility, and ruminal degradability of shredded hay. AB - Thirty-two Outaouais intact male lambs averaging 39.1 kg were assigned randomly to a 2 x 2 factorial arrangement of treatments consisting of two forages and two methods of harvesting to determine intake and digestibility. The four treatments fed during the experiment consisted of alfalfa and timothy hays harvested with either a prototype mat maker or a conventional mower conditioner. Hays were fed for ad libitum intake for the entire experiment, and data on digestibility and intake were collected for 9 d after a 21-d adaptation. Ruminal degradability of DM, N, and ADF of hays was estimated with two fistulated cows using nylon bags incubated up to 96 h. Harvesting with the prototype mat maker compared with the conventional mower generally increased intake and digestibility of alfalfa and timothy hays. Ruminal degradability of DM and the potentially degradable fraction of DM and ADF was higher when hay was harvested with the prototype mat maker than with the conventional mower. The increased digestibility of hay harvested with the prototype mat maker could be explained by the increased digestibility in the rumen because harvesting with the prototype mat maker increased the potentially degradable fraction of DM and ADF. These results suggest that the digestible energy content of hay was increased by shredding. PMID- 7836593 TI - Effects of concentrated separator dried beet pulp on nutrient digestibility, milk production, and preference of Holstein cattle. AB - Concentrated separator by-product was fed to cattle to determine TDN, milk production, and feed preference. The TDN content of concentrated separator by product was determined using a substitution method involving a basal diet of alfalfa and grass hay and a treatment diet of alfalfa and grass hay plus 10% added concentrated separator by-product. Four ruminally cannulated cows in a replicated 2 x 2 Latin square design were used. The estimated TDN content of concentrated separator by-product was 59.3%. Twenty midlactation dairy cows were fed either a control ration containing 20% molasses dried beet pulp or a treatment ration containing 20% concentrated separator by-product dried beet pulp. Cows in the treatment group produced significantly less daily milk and 3.5% FCM than the control group. Percentages of milk fat, protein, lactose, and SNF were not different between treatments. Eight Holstein heifers were used to determine feed preference. Heifers were given a choice among 20% molasses dried beet pulp (control) or 10, 15, or 30% concentrated separator by-product dried beet pulp. Heifers showed no preference between 10 or 15% concentrated separator by-product dried beet pulp and control, but preferred the control over the 30% concentrated separator by-product dried beet pulp. PMID- 7836594 TI - Effect of supplemental fish meal on the lactation and reproductive performance of dairy cows. AB - The influence of high protein diets (21% CP, DM basis), containing varied percentages of RUP, on lactation performance and fertility was evaluated. Sixty two Holstein cows (65% multiparous) were blocked by age and randomly assigned to a 2 x 2 x 2 factorial design from d 12 to 125 postpartum. Factor 1 was 0 or 3.5% fish meal diet, factor 2 was location (Calan door versus free stall), and factor 3 was parity (first versus second or later). The soybean meal diet consisted of alfalfa hay, corn silage, barley, and soybean meal. The fish meal diet contained 3.5% fish meal (ruminant grade menhaden) that replaced a portion of the soybean meal. Cows fed the fish meal diet (40% RUP) had DMI, BW, and body condition similar to those of cows offered the soybean meal diet (34% RUP). Cows receiving the fish meal supplement tended to have higher milk protein production throughout the trial, higher milk production during the first 6 wk, and significantly lower ruminal ammonia concentrations than cows receiving the soybean meal diet. Differences in reproductive performance were not significant except for a diet by housing location interaction for conception rates from first AI. PMID- 7836595 TI - Effect of yeast cultures on performance of lactating dairy cows: a field study. AB - Three hundred six lactating Holstein cows in the first 120 d of lactation from seven farms in Pennsylvania were used to evaluate supplementation of two Saccharomyces cerevisiae yeast cultures containing about 10(8) cfu/g viable yeast cells on milk production and composition. Cows were fed individually and grouped into three blocks based on lactation numbers 1, 2, and 3 or greater, and, within block, randomly assigned to one of three treatments for a 14-wk study. The three treatments were 1) control, 2) yeast culture fermented on ground cornmeal and corn gluten meal (5.3 x 10(10) cfu/d per cow), and 3) yeast culture fermented on cornmeal and soybean meal (5.1 x 10(10) cfu/d per cow). The three treatments were mixed with cornmeal and 114 g per cow was fed daily as a top-dressing. Milk production, milk fat and protein percentage, milk fat and protein production, and 3.5% FCM were not affected by either yeast treatment. There were no significant interactions of farm by treatment, lactation number by treatment, or week by treatment. No differences in performance were significant for early lactation cows that calved during the trial, but FCM tended to be higher for treatment than for the control cows. Daily DMI measured on 39 cows at one location did not differ among treatments. Yeast supplementation was not beneficial for any production parameters under the nutritional management programs of these seven dairy farms. PMID- 7836596 TI - Response to various amounts of Aspergillus oryzae fermentation extract on ruminal metabolism in cattle. AB - The objective of this study was to determine whether Aspergillus oryzae fermentation extract stimulated or inhibited ruminal fermentation when fed at higher than recommended doses (3 g/d). Four dietary treatments of A. oryzae fermentation extract were fed daily to six cows fitted with ruminal cannulas. For each of four periods, bromegrass hay (6% CP) with and without extract was fed for 28 d. Dacron bags containing bromegrass cell walls were ruminally incubated to determine ruminal fiber degradation. The A. oryzae fermentation extract did not affect degradation of cell walls, cellulose, or hemicellulose. Total ruminal anaerobic or cellulolytic bacteria were not different among treatments; neither were the proportions of cellulolytic species, Butyrivibrio sp., Ruminococcus albus, or Ruminococcus flavefaciens. Ruminal ammonia was not different; however, total VFA were higher, and pH tended to be lower, when 27 g/d of A. oryzae fermentation extract was fed. The proportion of VFA was not different among treatments. The A. oryzae fermentation extract fed at nine times the recommended dosage did not produce any stimulatory effects, except for total VFA, and was not inhibitory or toxic to ruminal metabolism and forage fiber degradation. PMID- 7836597 TI - Antioxidant status of dairy cows supplemented prepartum with vitamin E and selenium. AB - Possible relationships among dietary antioxidants, oxidative status, and placental retention were investigated in periparturient dairy cows. During 6 wk prepartum, 16 cows each were given daily by capsule 1000 IU of vitamin E, 3 mg of Se, both vitamin E and Se, or neither (control). alpha-Tocopherol in serum and fast-acting antioxidants in plasma increased, but, in red blood cells, thiobarbituric acid-reactive substances decreased during the last 6 wk before parturition in cows given vitamin E. These measurements were unaffected by supplementation of Se. Cows that had retained placenta > or = 12 h had lower fast acting antioxidants in plasma and glutathione peroxidase in red blood cells up to 2 wk before calving than did cows that shed fetal membranes in < 12 h. Results suggest that inadequate dietary antioxidants may increase oxidative stress, production of lipid peroxides, and incidence of retained fetal membranes in dairy cows. PMID- 7836598 TI - Macromineral element interrelationships and lactational performance: empirical models from a large data set. AB - The objectives were to model empirical interrelationships among dietary macromineral elements and cation-anion difference influencing DMI, milk yield, 4% FCM yield, and milk composition of dairy cows. The database consisted of 1022 cow period means collected from 326 midlactation cows in experiments with incomplete block designs. Dietary concentrations of elements ranged from below to above current recommendations, and cation-anion difference (Na + K-Cl) was from +5.8 to +61.2 meq/100 g of dietary DM. Interrelationships were detected for dietary concentrations of Na by K for DMI, 4% FCM yield, and milk fat percentage; Na by Ca for DMI, milk yield, and 4% FCM yield; K by Cl for DMI, 4% FCM yield, and milk protein percentage; K by Ca for 4% FCM yield, milk protein, and fat percentages; Na and P for DMI and milk protein percentage; and K by P for 4% FCM yield and milk fat percentage. Maximal DMI and milk yield were observed with .58% Na, .40% Mg, and +38 meq/100 g of dietary DM. Agreement was close for DMI and milk yield responses to dietary cation-anion difference from our database and independent data sets. The models developed are empirical, do not necessarily establish cause and effect, and should be evaluated prudently; however, they provide useful information to design future research. PMID- 7836599 TI - Natural sodium sesquicarbonate fed for an entire lactation: influence on performance and acid-base status of dairy cows. AB - Forty-eight multiparous Holstein cows were blocked according to month of parturition, age, and previous milk yield and arranged in a randomized complete block design to evaluate the effect of a naturally occurring sodium sesquicarbonate on DMI, milk yield, milk composition, milk value, and systemic acid-base status. Cows were assigned at parturition to diets containing sorghum silage, alfalfa hay, concentrate, and 0 or 1% naturally occurring sodium sesquicarbonate (DM basis); cows were fed these diets for 308 d postpartum. Blood was collected every 4 wk via jugular venipuncture for analysis of pH, HCO3, partial pressure of O2, and partial pressure of CO2. Sesquicarbonate exhibited alkalogenic properties by increasing blood HCO3, partial pressure of CO2, and total CO2 for the 308-d lactation. Buffer tended to increase DMI and increased milk protein throughout lactation. During 0 to 56 d postpartum, sodium sesquicarbonate did not affect milk yield or composition. In midlactation (56 to 252 d postpartum), buffer increased milk protein content only. During 252 to 308 d postpartum, milk fat and protein contents increased with buffer supplementation. Hence, the value of milk yielded daily was similar for all cows. Effects of dietary buffer on all variables were more pronounced during late lactation. PMID- 7836600 TI - Effect of twinning and supplemental iron-saturated lactoferrin on iron status of newborn calves. AB - Data from 53 calves by embryo transfer were collected to determine the effect of twinning and supplemental Fe-saturated lactoferrin or FeSO4 for 5 d after parturition on iron status of calves. Blood hematocrit and hemoglobin of multiple calves born from multiparous cows at d 1 postpartum were lower than those of single calves born from multiparous cows, although those of their dams were not different. Plasma Ca, inorganic P, Mg, Zn, and Cu were similar for single and multiple calves or for calves born from primiparous and multiparous cows. Blood hematocrit and hemoglobin of untreated calves decreased from 1 to 6 d postpartum. Blood hematocrit of calves treated with 40 mg of Fe/d as FeSO4 increased from 1 to 10 d postpartum, and blood hemoglobin of calves treated with 20 or 40 mg of Fe/d as ferrous Fe increased from 1 to 10 d postpartum. Blood hematocrit and hemoglobin of calves treated with 20 mg of Fe/d as Fe-saturated lactoferrin remained nearly constant for 10 d postpartum. Serum Fe of calves increased immediately after the treatment with 20 or 40 mg of Fe as FeSO4, but serum Fe of calves treated with lactoferrin was not affected. Thus, ferrous Fe may be more effective than Fe-saturated lactoferrin in elevating blood hematocrit and hemoglobin in newborn calves. PMID- 7836601 TI - Effects of housing and colostrum feeding on the prevalence of selected infectious organisms in feces of Jersey calves. AB - Neonatal Jersey calves (n = 96) were used to evaluate effects of housing (individual hutches or wooden pens in a barn) and colostrum feeding (calves were separated from the dam and fed 2 L of colostrum in nipple-bottles or allowed to nurse the dam for 3 d) on the prevalence of selected organisms in feces. Prevalence of Cryptosporidium and Eimeria were reduced, and prevalence of rotavirus tended to be reduced, when calves were housed in hutches. Prevalence of coronavirus was unaffected by treatment. Weekly prevalence of Giardia was increased when calves were left to nurse the dam for 3 d. Mean prevalence of Cryptosporidia (wk 1 to 4), Eimeria (wk 4 to 5), Giardia, rotavirus, and coronavirus (wk 1 to 5) were 34.7, 20.6, 27.1, 15.8, and 4.9%, respectively. Escherichia coli (K99 positive) were observed in 3 of 174 samples cultured. Methods of housing and colostrum feeding affected acquisition of enteropathogens in this study. PMID- 7836602 TI - Deaths and disposals in lines selected for milk yield and control lines of Jersey cattle. AB - Deaths and disposals of Jerseys from birth to 120 d of first lactation during a selection experiment were summarized. Cows were randomly assigned to the high milk yield and young sire lines. Service sires were bulls with the highest estimated breeding value for milk for the high milk line and a collection of all young unproven bulls available in AI in 1967. Cattle that were unsuitable for conditions of normal herd management were candidates for culling. Culling of uncalved heifers and of lactating cows was also permitted to maintain group sizes. Culling for herd reduction was random. Culling for low milk yield was permitted after cows reached 120 d of first lactation. Death and disposal data were analyzed through 120 d of first lactation. By 120 d of first lactation, 29.6% of females born to the young sire line had died or been involuntarily removed compared with 29.8% born to the high milk yield line. Deaths were 54.8% of total losses for the high milk yield line compared with 58.4% for the young sire line. Stillbirths were a larger proportion of total losses for animals in the high milk yield line (21.4%) than for those in the young sire line (15.3%). The most frequent cause of death was scours and pneumonia during 1st mo of life for animals in both lines. Selection of sires for high milk yield does not decrease total survival rates through the early first lactation. PMID- 7836603 TI - Response of health care to selection for milk yield of dairy cattle. AB - A selection experiment began during 1964 to measure long-term responses to selection of dairy cattle based only on milk yield. An unselected control group of cows was maintained as part of the experimental design. The four highest sires for PTA milk that were available from active AI were mated each year to cows of all generations in the selection group. Expenses for veterinary treatment, health supplies, drugs, and labor of animal attendants were recorded for each cow and categorized as mastitis, udder, edema, locomotion, digestion, ketosis, milk fever, reproduction, respiration, and other. Cows studied were born from 1975 to 1990. Over the 16-yr period, 236 selection and 227 control cows were observed while lactating. Cows in the selection group had greater health expenses as a correlated response to increased milk yield than did unselected controls. Lactational difference for genetic groups was $28.22 from an analysis of only first lactations and $49.44 from an analysis across parities. Expenses for mastitis accounted for most of the difference between genetic groups. Most health expense occurred during the first 20 d postpartum and increased for cows with successive lactations. During the 16-yr period, expense for selection cows increased more than for controls for reproduction, digestion, and ketosis, but not mastitis, udder (nonmastitis), edema, locomotion, milk fever, respiration, and other categories. Separate analyses of heifers from birth to initial calving and of dry cows provided little evidence of differences for genetic groups during nonlactating stages of life. PMID- 7836604 TI - Estimation of genotype effects for milk proteins with animal and sire transmitting ability models. AB - The objective of this work was to estimate the contribution of milk protein genotype to production traits of Holstein cattle. Two approaches were employed. The first was based on an animal model analysis of milk records in which cows were genotyped for milk protein variants. The second approach was the analysis of PTA of sires in which the sires were genotyped for their milk protein variants. Results of the animal model analysis agreed qualitatively with previously published analyses of cow records, indicating only a minor contribution of milk protein genotype to production traits. Qualitative similarity was also found between the analysis of sire transmitting abilities and the animal model. Algebraic results suggested, however, that an indirect analysis of published sire transmitting abilities does not provide unbiased estimates of differences in milk protein genotypes. Although analysis of PTA is simple, only a direct analysis of genotyped cows with an animal model provides unbiased estimates of genotype differences. PMID- 7836605 TI - Impact of different strategies and amounts of preferential treatment on various methods of bull-dam selection. AB - Three records of milk yield, fat yield, and type were simulated for each cow in 20 herds of 200 cows over 13 yr. Preferential treatment or bias was simulated by increasing milk and fat yields by an average of 0, 16, and 32% for separate copies of the simulation. The bias was given to a limited number of cows from the original herds based on four strategies. Five methods of bull-dam selection that used an index with a 2:2:1 ratio of milk to fat to type to select the top 2% of cows were compared: ETA using first lactation, using all lactations, after phenotypic minima were required, after preselection on three-generation pedigree index, and on pedigree index alone. Selection on ETA for first or all lactations gave the highest average of true breeding values at 0 and 16% for all strategies studied. In general, selection on pedigree index alone or after phenotypic minima were required gave poor results and should not be considered to be viable. Preselection of bull-dams on pedigree index proved to be extremely useful for biased and unbiased data. The optimal policy was to preselect the top 12% of the population before reranking and selecting on ETA for all lactations. PMID- 7836606 TI - Effects of correction for heterogeneity of variance on bias and accuracy of breeding value estimation for Dutch dairy cattle. AB - Data on 305-d milk yield from the Dutch dairy evaluation were used to obtain breeding value estimates from an animal model for 1984 to 1992. Changes in sire evaluations were investigated for bias and realized accuracy. Evaluations based on progeny records were generally lower than their expectation based on parent average. The average decrease was 157 kg for Black and White bulls and 73 kg for Red and White bulls. Evaluations based on test daughters changed about -50 kg when second and third lactations became available, but estimates for breeding value changed insignificantly when records on daughters from the breeding period of the bull were used. The standard deviation of changes from evaluations for first to second batch was about 14% larger than expected from population parameters. Breeding values of imported bulls, based on Dutch data, decreased 75 kg when more information became available in subsequent evaluations. Heterogeneity of variance was estimated by a quasi-likelihood approach with a model that accounted for sampling variance on estimates of variances within herd. The coefficient of variation of the variances within herd-year was 31%. A simple method for standardization of variances within herd-year decreased bias of parent averages by about 20%, and fluctuations of breeding values were within the expected range. A correction for heterogeneity of variance within herd may not remove all bias of parent averages, but a general improvement of bias and accuracy of breeding values can be expected. PMID- 7836607 TI - Timing of artificial insemination of dairy cows: fixed time once daily versus morning and afternoon. AB - Nonreturn rates to professional technician service of 7240 first AI Holstein cows were calculated to evaluate differences between once daily and a.m.-p.m. AI. To determine whether management practices affected nonreturn rates, participating herd owners were surveyed for methods used for detection of estrus. Nonreturn rates for once daily and a.m.-p.m. AI were 64.6 and 65.6% for 60-d, 60.1 and 60.6% for 75-d, and 58.4 and 57.8% for 90-d nonreturn periods. Signs of estrus for AI and interval from detection of estrus to AI were related to nonreturn rates. Nonreturn rate was highest, 63.4%, when cows were in standing estrus. Nonreturn rates were lowest, 36%, when cows were bred after treatment with PGF2 alpha without being detected in estrus or bred strictly on veterinary advice based on palpation. Nonreturn rates were similar for different times of the day when once daily AI was practiced. However, AI in the midmorning may have some advantages. The highest nonreturn rate for a 3-h period was 68.2% for 0800 and 1100 h; the lowest was 54.7% for 1300 to 1600 h. Movement before observation for estrus and an observation period > 15 min improved nonreturn rates for once daily AI. Once daily AI can be used effectively with no difference from the traditional a.m.-p.m. system; results are best when AI is based on standing estrus and performed between 0800 and 1100 h. PMID- 7836609 TI - Fermentation and utilization of grass silage. AB - The decision to utilize particular forages in support of dairy production should be based on a number of key factors, such as available land base, type of manure management, soil type and topography, climate, and availability of purchased forages and feeds. Because of the complexity and environmental concerns existing in the dairy industry today, decisions about forage and manure management should include whole farm analysis with the aid of computer software. The chemical composition and digestibility of grass are affected more by stage of maturity than by other management factors, such as species, DM, or type of harvest system. The decline in digestibility of nutrients in first growth forage is approximately .55 to .68%/d and is dependent on the method of estimation. The decline in digestible DMI in first growth is .3 to .5%/d. The use of silage additives has become an integral part of forage management, and improvements in DMI and milk production are documented. Particle size and type of harvest equipment significantly affect eating behavior and efficiency of milk production. Wilting of silage results in an increase in DMI and efficiency of microbial protein production. PMID- 7836608 TI - Efficacy of two barrier teat dips containing chlorous acid germicides against experimental challenge with Staphylococcus aureus and Streptococcus agalactiae. AB - Two postmilking teat dips were tested for efficacy against Staphylococcus aureus and Streptococcus agalactiae using experimental challenge procedures recommended by the National Mastitis Council. Both dips contained chlorous acid as the primary germicidal agent and lactic acid or mandelic acid as the chlorous acid activator. The dip activated with mandelic acid significantly reduced new IMI by Staph. aureus and Strep. agalactiae. The IMI rate was reduced 68.7% for Staph. aureus and 56.4% for Strep. agalactiae. The dip activated with lactic acid significantly reduced new Staph. aureus IMI by 69.3% but did not significantly reduce new Strep. agalactiae IMI (35.2% reduction) through the full 11-wk study period. Teat skin condition did not change from pretrial status after using either teat dip during the study. PMID- 7836610 TI - The selection index--then, now, and for the future. AB - When improvement is desired for several traits that may differ in variability, heritability, economic importance, and in the correlation among their phenotypes and genotypes, simultaneous multiple-trait index selection was more effective than independent culling levels or sequential selection. Such comparisons required definition of aggregate breeding value determined jointly by breeding values and economic importance of the component traits. The economic weight should approximate the partial regression of cost per unit of enterprise output value on breeding value for each trait. These can vary with production and marketing system, with performance of traits, and with breed role (i.e., paternal, maternal, or general) in crossbreeding systems. Genetic gains desired to maintain competitive ranking also may define the relative importance of traits. Because information available to estimate breeding values varies among the ages and categories of individuals under selection and because means are unknown, regressed (BLUP) predictions of trait breeding values are useful. They allow appropriate economic weights to be applied as the last step for predicting aggregate breeding values for individuals of different age classes, and they simplify choosing the proportions of selected breeders from each age class that maximize rate of change in aggregate breeding values. Inappropriate economic weights or errors in the parameters used to predict trait breeding values overestimate realized response in true aggregate breeding value. PMID- 7836611 TI - Present and future uses of selection index methodology in dairy cattle. AB - Selection indexes have been extensively applied in the estimation of breeding value of dairy cattle for single traits as well as for combinations of traits for selection purposes. Milestones in methodology, such as multiple-trait evaluation procedures by BLUP, (co)variance component estimation, nonlinear models, discounted gene flow, dynamic programming, and international sire evaluations, together with increased computing power and the development of integrated AI and recording schemes, have contributed to efficient implementation of selection indexes and are reviewed in this article. Results of an international survey on evaluation practices and breeding programs are presented, demonstrating wide adoption of index selection for total merit and the need for further applications. Results from a simulation study on the efficiency of index selection for total merit are also presented; when the breeding goal includes, in addition to production traits, functional nonproduction traits such as mastitis resistance and fertility, failure to consider these traits in the selection index decreases efficiency 15 to 25%. Future applications are also discussed in view of advances in the areas of genome mapping, marker detection, and international comparisons. Further research should focus on functional nonproduction traits. PMID- 7836612 TI - Oral toxicity of boric acid and other boron compounds to immature cat fleas (Siphonaptera: Pulicidae). AB - Oral toxicity was characterized in first-instar cat fleas, Ctenocephalides felis felis (Bouche), feeding on dried blood treated with boric acid. LC50 values ranged from 2.11% after 24 h to 0.21% after 7 d. In carpet tests with five different boron compounds and a number of different formulations, significant mortality for first instars was observed in all cases. In similar tests with prepupae and cocoons, there was no significant effect on mortality. The importance of these results is discussed in light of current application procedures for boron compounds, and suggestions are made for future research. PMID- 7836613 TI - Hydroprene effects on the dynamics of laboratory populations of the German cockroach (Dictyoptera: Blattellidae). AB - The influence of sterilization by hydroprene on population dynamics in the German cockroach, Blattella germanica (L.), was studied in the laboratory where more detailed and accurate assessments could be achieved than would be possible under typical field situations. The gradual accumulation of sterile adultoids (i.e., adults with twisted wings, indicating exposure to hydroprene) during treatment, or their decreasing abundance after treatment, produced distinctive patterns in the dynamics of treated populations. The percentage of gravid females (a reproductive index) was first to respond to treatments, because increases (or decreases) in the percentage of gravid females preceded reductions (or recoveries) in sample density and nymph-to-adult ratios by 4-6 wk. Trends in the percentage of adultoids were negatively correlated with the percentage of gravid females and indirectly measure the activity of hydroprene. Initial reductions in the percentage of gravid females, sample density, and nymph-to-adult ratios began at or about the time when approximately 80% of adults had twisted wings (i.e., were adultoids). As the percentage of adultoids attained (or declined below) the 80% level, we can accurately predict the subsequent decline (or recovery) in nymph-to-adult ratios and, thus, sample density. These data support a proposal to adopt the 80% level of adultoids as an action threshold for regulating juvenoid treatments to maximize population suppression. The role of this action threshold in the long-term management of chronic B. germanica infestations or insecticide resistant populations is discussed. PMID- 7836614 TI - Overwintering of the stable fly (Diptera: Muscidae) in southeastern Nebraska. AB - Adult stable flies, Stomoxys calcitrans (L.), were monitored during three winters at two, four, and 13 locations with Alsynite fiberglass traps and by examination of the interiors of buildings. No stable flies were found inside buildings during the winter. Adult stable flies were consistently caught on Alsynite traps at one location during two winters and at two other locations during one winter. Distribution and physiological age of these flies indicate that they emerged from pupae that had developed at or near the location where they were captured. Potential breeding sites were examined. A few third instars were found in silage in midwinter, but silage should not be considered a major source for overwintering stable flies. PMID- 7836615 TI - Serum constituent profiles of beef heifers infested with horn flies (Diptera: Muscidae). AB - Nine yearling crossbred beef heifers, Bos taurus L., were used to examine physiological responses to horn fly, Haematobia irritans (L.), infestation. Heifers were stanchioned indoors in individual environmentally controlled rooms. On day 0, each animal received 0, 500, or 1,000 horn flies. Fly numbers were adjusted daily to maintain an appropriate infestation for each heifer. Feed intake, respiration rate, and rectal temperature was recorded daily. In addition, blood samples were collected from each animal on days 0, 12, and 33 for serum constituent analysis. To monitor metabolic hormone status, intensive blood samples were also collected hourly for 6 h on days 0, 12, and 33. Throughout the period of treatment, feed intake values were similar among treatments resulting in comparable body weight at the end of the trial. Respiration rates on each day were similar among groups. Rectal temperature was also unaffected by horn fly infestations. Serum electrolyte analysis revealed that neither Na, K, Cl, Ca, P, nor Fe differed among treatments. Likewise, HCO3/CO2 ratio, anion gap, and serum osmolality did not differ among treatment groups. Major indicators of nutrient status (glucose, cholesterol, triglycerides, urea N, creatinine, uric acid, albumin, globulin) and insulin, growth hormone, and prolactin were also unaffected. Serum bilirubin and enzyme (alkaline phosphatase, creatine phosphokinase, gamma-glutamyl transpeptidase, lactic dehydrogenase, aspartate amino transferase, alanine amino transferase) concentrations were similar in control heifers and those infested with horn flies.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836616 TI - 44th Annual Scientific Session of the American College of Cardiology. New Orleans, Louisiana, March 19-22, 1995. Program and Abstracts. PMID- 7836617 TI - Tribute to Mildred Seelig. PMID- 7836618 TI - Neonatal hypocalcemia: to treat or not to treat? (A review). AB - The various definitions of neonatal hypocalcemia (NHC) are critically examined. The authors review the known and less known complications of NHC and of its treatment. They emphasize the need for a definition of NHC in terms of serum ionized rather than total calcium concentrations, the rationale for treating symptomatic NHC, as well as the need for further research in infants with asymptomatic NHC. PMID- 7836619 TI - Magnesium deficiency and alcohol intake: mechanisms, clinical significance and possible relation to cancer development (a review). AB - A comprehensive and critical review of the evidence relating magnesium (Mg) deficiency to alcohol consumption reveals several important types of interactions. First, alcohol acts acutely as a Mg diuretic, causing a prompt, vigorous increase in the urinary excretion of this metal along with that of certain other electrolytes. Second, with chronic intake of alcohol and development of alcoholism, the body stores of Mg become depleted. During the late stages of alcoholism, the urinary excretion of Mg may become diminished as a physiological response to reduced intake and reduction of body stores. A number of aspects of the clinical syndrome of alcoholism contribute to and intensify that already existing reduction in body Mg stores. Third, a number of manifestations of alcoholism are believed due to effects of Mg deficiency, and some therapeutic benefit has been suggested from treatment of alcoholic patients with Mg. Finally, relatively little attention has been paid to the possible value of Mg administration as a preventive measure to forestall or minimize the deleterious effects of chronic use of alcohol or to prevent the development of cancer than can occur in this setting. PMID- 7836620 TI - Magnesium transport systems: genetics and protein structure (a review). AB - Magnesium is unique among biological cations. Its volume change from hydrated cation to atomic ion is over an order of magnitude larger than that of any other biological cation. This volume change presents particular problems for a magnesium transport system and suggests that these systems may be significantly different from other classes of ion transport systems. Detailed study of Mg2+ transport in complex organisms is limited by severe technical problems. However, molecular genetic techniques have enabled the isolation of three Mg2+ transport systems from the Gram-negative bacterium Salmonella typhimurium. The MgtA and MgtB transport systems are members of the P-type ATPase superfamily of transporters but possess unique characteristics among members of this family. The CorA transport protein is the first member of an entirely new class of transport proteins. In addition, another completely new family of Mg2+ transport proteins have been identified that is present in both Gram-negative and Gram-positive bacteria. Characterization of these transporters should provide substantial insight into Mg2+ transport and cellular Mg2+ homeostasis. PMID- 7836621 TI - Consequences of magnesium deficiency on the enhancement of stress reactions; preventive and therapeutic implications (a review). AB - Stress intensifies release of catecholamines and corticosteroids that increase survival of normal animals when their lives are threatened. When magnesium (Mg) deficiency exists, stress paradoxically increases risk of cardiovascular damage including hypertension, cerebrovascular and coronary constriction and occlusion, arrhythmias and sudden cardiac death (SCD). In affluent societies, severe dietary Mg deficiency is uncommon, but dietary imbalances such as high intakes of fat and/or calcium (Ca) can intensify Mg inadequacy, especially under conditions of stress. Adrenergic stimulation of lipolysis can intensify its deficiency by complexing Mg with liberated fatty acids (FA), A low Mg/Ca ratio increases release of catecholamines, which lowers tissue (i.e. myocardial) Mg levels. It also favors excess release or formation of factors (derived both from FA metabolism and the endothelium), that are vasoconstrictive and platelet aggregating; a high Ca/Mg ratio also directly favors blood coagulation, which is also favored by excess fat and its mobilization during adrenergic lipolysis. Auto oxidation of catecholamines yields free radicals, which explains the enhancement of the protective effect of Mg by anti-oxidant nutrients against cardiac damage caused by beta-catecholamines. Thus, stress, whether physical (i.e. exertion, heat, cold, trauma--accidental or surgical, burns), or emotional (i.e. pain, anxiety, excitement or depression) and dyspnea as in asthma increases need for Mg. Genetic differences in Mg utilization may account for differences in vulnerability to Mg deficiency and differences in body responses to stress. PMID- 7836622 TI - Comparative effects of a Mg-enriched diet and different orally administered magnesium oxide preparations on ionized Mg, Mg metabolism and electrolytes in serum of human volunteers. AB - OBJECTIVE: To determine whether: 1) short-term dietary elevation in magnesium (Mg) intake could alter serum ionized Mg (IMg2+), total Mg (TMg); % ionized Mg (% IMg2+) and other cations; and 2) different formulated preparations of Mg oxide (MgO) in the presence and absence of phosphate could alter serum IMg2+, TMg, % IMg2+ and other cations in Mg-loaded subjects. METHODS: A randomized, triple cross-over study was performed on a rigorously defined group of normal male volunteers. Eighteen males were administered diets containing four to five times the United States recommended daily allowance (USRDA) of Mg followed by a randomization of three different MgO preparations, in the presence or absence of phosphate, containing equimolar amounts (12.34 mmol) of elemental Mg. Forty age matched volunteers served as reference range controls. Specific ion selective electrodes were utilized to measure IMg2+, ionized calcium (ICa2+), sodium (Na+) potassium (K+) and hydrogen ion concentration (H+). Measurement of urinary excretion of Mg as well as TMg were determined by atomic absorption spectroscopy. RESULTS: Diets enriched with different oral formulations of Mg given for 6 days result in significant elevations in serum IMg2+ and % IMg2+ but not TMg, ICa2+, K+ or H+ in normal subjects. Although such Mg-loaded subjects demonstrate significant elevation in urinary excretion of Mg, no further changes in IMg2+, TMg or any of the serum cations were produced by ingestion of either of the three MgO preparations. Subjects showing normally low basal levels of serum IMg2+, (< or = 0.54 mM/L), could easily have their serum IMg2+ level manipulated by diets enriched with Mg, whereas subjects having average normal or high normal IMg2+ levels did not have their IMg2+ elevated significantly with either diets enriched with Mg or with exogenous MgO. CONCLUSION: These results indicate that since serum IMg2+ and % IMg2+, but not TMg, can be altered by dietary intake, previous or future findings which may indicate no change in TMg by diet may not reflect changes in biologically-active Mg. PMID- 7836623 TI - Marginal zinc deficiency in older adults: responsiveness of zinc status indicators. AB - OBJECTIVE: Suspicions that mild zinc deficiency is common among the elderly cannot be confirmed or refuted because definitive indicators of zinc status are lacking. The goal of this study was to document the clinical responsiveness of parameters of zinc status in a group of older adults consuming a carefully controlled diet: first moderately low in zinc (3.97 mg/day for 15 days) and then high in zinc (28.19 mg/day for 6 days). METHODS: Fifteen older adults (mean age = 66.6 yrs) volunteered to consume a marginally zinc-deficient diet for 15 days followed by 6 days of zinc repletion. Plasma concentrations of erythrocyte metallothionein and the enzyme 5'-nucleotidase, as well as levels of zinc, alkaline phosphatase, copper and ceruloplasmin were measured before and after zinc depletion and repletion. RESULTS: Plasma zinc levels were not altered during the study. Alkaline phosphatase (AP) values did not change in the expected direction, although a small decrease in AP following zinc repletion was statistically significant. Erythrocyte metallothionein results followed a pattern similar to that of alkaline phosphatase, little change, but a small, statistically significant drop after zinc repletion. As expected, there were no diet-associated changes in plasma copper and ceruloplasmin levels. In contrast, plasma concentrations of the enzyme 5'-nucleotidase decreased (p < 0.01) from 2.7 +/- 0.5 to 1.1 +/- 0.5 U during zinc depletion and increased (p < 0.05) to 2.2 +/ 0.4 U after 6 days of repletion. CONCLUSIONS: Mild zinc deficiency is difficult to detect. In this study, traditional indicators such as plasma zinc and alkaline phosphatase did not change as would be expected in response to alterations in zinc intake. Likewise, erythrocyte metallothionein did not respond to altered zinc intakes as expected but this factor may reflect long-standing or more severe zinc depletion and thus requires additional study. Activity of the enzyme 5' nucleotidase appears responsive to acute changes in zinc intake; however, more work is needed to define how well these activities will reflect zinc intake in other types of subjects. PMID- 7836624 TI - Erythrocyte and mononuclear blood cell magnesium concentrations are normal in hypomagnesemic patients with chronic renal magnesium wasting. AB - OBJECTIVE: The purpose of this study was to determine the plasma, erythrocyte, and mononuclear blood cell (MBC) magnesium concentrations in patients with chronic, severe hypomagnesemia due to a chronic magnesium-wasting tubulopathy. METHODOLOGY: Six patients with Bartter's syndrome and five patients with magnesium-wasting tubulopathy were compared with normal subjects. We determined magnesium in plasma, erythrocytes, and MBCs. RESULTS: Patients with chronic magnesium-wasting tubulopathy had a significantly lower plasma magnesium concentration than controls, but erythrocyte magnesium concentration and MBC magnesium concentration and content did not differ significantly between patients and controls. CONCLUSION: Two disorders with chronic magnesium-wasting tubulopathies are associated with a low plasma magnesium concentration but normal erythrocyte and MBC magnesium. PMID- 7836625 TI - Effect of caffeine on circadian excretion of urinary calcium and magnesium. AB - OBJECTIVE: To determine if later renal conservation occurs in calcium (Ca) and magnesium (Mg) excretion after morning caffeine-induced increases in urinary Ca and Mg excretion. DESIGN: Before-after trial of caffeine abstinance and consumption was conducted on two consecutive days in a metabolic ward while subjects ate a controlled diet containing 11.3 mmol Ca and 12.7 mmol Mg. 17 healthy males and females, ages 17-41 yr volunteered. Two caffeine doses of 3 mg/kg lean body mass caffeine were consumed at 7 and 10 a.m. on second day. Salivary caffeine concentrations and urinary Ca, Mg, sodium and creatinine excretion were measured. RESULTS: Salivary caffeine peaked at 4.7 umol/mL at 11:30 a.m. and declined with a half-life of 7.3 hours. Urinary Ca and Mg were elevated significantly (p = 0.01 and p = 0.04) for six h after the second caffeine dose. Caffeine had no significant effect on urinary calcium or magnesium excretion between 4 p.m. and 1 a.m. Between 1 and 4 a.m., urinary Ca and Mg excretion was decreased after caffeine (p = 0.04 and p = 0.01). Creatinine excretion was not different at any time. CONCLUSIONS: Nighttime compensatory renal conservation was insufficient to offset morning caffeine-induced mineral losses, resulting in net 24-hour urinary increases of 0.32 mmol Ca and 0.16 mmol Mg. PMID- 7836626 TI - A pilot study of erythrocyte lithium-sodium countertransport in women during the menstrual cycle. AB - OBJECTIVE: The study investigated lithium-sodium countertransport in erythrocytes of normal female volunteers during different phases of the menstrual cycle or during administration of oral contraceptives. METHODS: Ten normally menstruating, and eight oral contraceptive using, normal female subjects were studied over at least one cycle. Erythrocyte lithium-sodium countertransport was determined using. standard, previously validated methods at different phases of the menstrual cycle. Hematological, electrolyte, blood pressure and other transport measures were also made and these were related to the self-reported incidence of premenstrual symptomatology. RESULTS: A correlation, (p < 0.02), was found between lithium-sodium countertransport rate and the premenstrual symptom severity score but only in the premenstrual phase. There was no correlation between any of the electrolyte, blood pressure or hematological data and lithium sodium countertransport rate nor between it and other ion transport measures. Pre menstrual symptomatology was conspicuously absent from those subjects taking oral contraceptives. Cyclical fluctuations in normally menstruating women, and differences between them and oral contraceptive users, were seen in lithium sodium countertransport rate although the groups were too small to show statistical significance. CONCLUSIONS: Care was taken to exclude influences due to circadian, dietary and diurnal variations and the present results show somewhat less within-individual variability in erythrocyte lithium-sodium countertransport during the menstrual cycle than do other reports in the literature. Some interesting features were observed which justify a much larger scale study than the present pilot experiment which should involve a larger number of subjects studied over more than one cycle and in particular a more detailed study of the ovulatory phase. PMID- 7836627 TI - Inhibitory effects of zinc on magnesium balance and magnesium absorption in man. AB - OBJECTIVE: Both zinc (Zn) and magnesium (Mg) are widely used as nutritional supplements and the possibility was considered that Zn may interfere with the absorption of Mg, similar to previously reported results [1,2] obtained with the same dose of supplemental Zn on the absorption of calcium (Ca). METHODS: Mg absorption studies and metabolic balances of Mg and of Zn were carried out in three groups of adult males in a metabolic research unit during the intake of supplemental doses of 142 mg Zn as Zn sulfate (ZnSO4) during Ca intakes of 230, 500 and 800 mg/day. RESULTS: The Zn intake of 142 mg/day decreased the Mg balance and Mg absorption only during the 500 mg Ca intake compared to control values. However, the overall effect of the high Zn intake of the three groups combined, regardless of the Ca intake, was a highly significant decrease of Mg absorption and of the Mg balance. CONCLUSION: Zn supplements of 142 mg/day decreased Mg absorption and the Mg balance significantly during all Ca intakes for the three groups combined. PMID- 7836628 TI - Effect of magnesium on the intestinal absorption of calcium in man. AB - OBJECTIVE: In view of the widespread use of magnesium (Mg) as a nutritional supplement, we investigated whether Mg would affect the absorption of calcium (Ca) as the intestinal absorption sites for Mg and Ca differ. METHODS: The intestinal absorption of Ca, using 47CaCl2 as the tracer, and metabolic balances of Ca, phosphorus (P) and Mg were determined in five adult males under strictly controlled dietary conditions in control studies and during Mg supplementation. Mg was given as magnesium oxide (MgO) in 10 studies during two Ca intakes: five studies during a low Ca intake of 241 mg/day and five studies during a normal Ca intake of 812 mg/day. Dietary Mg intake ranged from 241 to 264 mg/day in control studies. During Mg supplementation, the total Mg intake ranged from 789 to 826 mg/day. RESULTS: There was no change of the intestinal Ca absorption during Mg supplementation during the two Ca intakes. The only change was the higher 1-hour 47Ca plasma level in the 47Ca absorption studies during the high Mg intake. Urinary Ca increased during Mg supplementation only during the low Ca intake, the Ca balance became more negative but this difference was not significant. There was also no change in Ca excretion or Ca balance during the high Mg intake at the normal Ca intake of 800 mg/day. P balance studies showed a slight decrease in urinary P and an increase in fecal P, but the P balances did not change. Mg balances were negative in control studies during the two Ca intakes. Supplemental Mg increased both urinary and fecal Mg excretion and the Mg balance became positive, but these differences were not significant. CONCLUSION: The increased Mg intake of 826 mg did not affect intestinal Ca absorption determined with tracer doses of 47Ca during Ca intakes of 241 and 812 mg/day. PMID- 7836629 TI - An antihypertensive salt: crucial role of Mildred Seelig in its development. PMID- 7836630 TI - A possible beneficial effect of selenium administration in antiarrhythmic therapy. AB - OBJECTIVE: The following review of the literature on the importance of Selenium (Se) in myocardial homeostasis and of the pharmacology of this trace metal, represents an attempt to search, without prejudice to other possible explanations, for a rationale of a beneficial effect of Se substitution as an adjuvant to antiarrhythmic therapy. BACKGROUND: For several years, in the early 1980s, I had to deal with the problem of a serious ventricular arrhythmia (non sustained and sustained ventricular tachycardia) which was remarkably resistant to a battery of the most potent antiarrhythmic agents. Eventually, dramatic improvement, lasting for a period of 8 years, was achieved with Flecainide, which, however, left unsolved the episodic occurrence of disabling ventricular bigemini. Over the most recent period of 1 year and 8 months, there was a sudden and unexplained return to unbroken normal sinus rhythm. Among the multiplicity of possible reasons for this fortunate development, the concurrent introduction of Se substitution appeared as the most obvious, though very tentative explanation. Substitution of this trace metal preceded the extinction of ventricular bigemini by 1 week and actually represented the sole modification of otherwise reasonably standardized conditions of antiarrhythmic therapy, life style and diet. PMID- 7836631 TI - Magnesium sulfate loading: preeclampsia vs preterm labor (a clinical pearl). AB - OBJECTIVE: To measure the apparent volume of distribution (AVOD) for magnesium (Mg) in preeclampsia and preterm labor and determine if a standard 4 gm loading dose of magnesium sulfate (MgSO4) is sufficient to attain therapeutic levels. METHODS: Twenty-five patients with preeclampsia and 25 with preterm labor received 4 g of MgSO4 intravenously over 15 minutes. Serum Mg levels were determined before and one minute after loading and the AVOD for Mg was calculated. Stepwise linear regression with AVOD as the dependent variable was performed and comparisons between the groups were made. RESULTS: Preeclamptics were heavier, had greater surface areas, and presented at a later stage of pregnancy than did patients with preterm labor. Despite these differences AVOD did not differ between the groups. Predose magnesium levels were slightly higher in the preeclamptic group (p = .04). Post-loading levels were nearly identical due to similar AVOD's and, because of the lower levels required for seizure prevention as opposed to tocolysis, were therapeutic 88% of the time in preeclampsia but only 12% of the time in preterm labor (p < .001). Multivariate analysis revealed that only ideal body weight, degree of underweight, and current therapy with betamimetics were significantly related to AVOD. CONCLUSION: AVOD was found to be similar in preeclamptic and preterm labor patients. A 4 g loading dose of MgSO4 is usually adequate to achieve therapeutic levels in preeclampsia but not in preterm labor. PMID- 7836632 TI - The effect of medical status on the activity level of older pain clinic patients. AB - OBJECTIVE: This project sought to assess the effect of disease status on the activity level of older people suffering from chronic pain. DESIGN: A retrospective comparison of groups defined by disease attributes. SETTING: Outpatient pain management clinic for older people. SAMPLE: The sample consisted of 115 patients, of a possible 144, aged between 52 and 91 years, who were assessed upon admission to a multidisciplinary pain management clinic. Subjects were allocated to groups for comparison on the basis of the diagnosis of their pain problem and the extent of coexistent medical problems. MEASUREMENTS: Groups were compared on scores of activity level using the Human Activity Profile, with and without pain (McGill Pain Questionnaire) and depressive symptom (Geriatric Depression Scale) scores as covariates. MAIN RESULTS: Both pain diagnosis and number of additional medical problems characterized groups that were distinguishable by level of activity. A musculoskeletal disorder was associated with greater impact on activity than either postherpetic neuralgia or pain associated with a psychiatric diagnosis. Less activity was also evident among the subjects with several additional medical problems. However, this effect did not operate independently of depressive symptoms. CONCLUSIONS: Disease status is a factor that rarely explains variations in the pain experience of young adult patients with chronic pain. The results from this study suggest that disease state does influence self-reported activity level in older people with chronic pain. The influence of medical status should be acknowledged as an important factor when assessing and managing the older patient with chronic pain. PMID- 7836633 TI - Predictors of skilled nursing placement in a multilevel long-term-care facility. AB - OBJECTIVE: To determine if cognitive and functional data gathered before admission to residential care (i.e., board and care) placement can predict nursing home placement. DESIGN: Retrospective study using Cox proportional hazards analysis and pairwise assessment of adjusted relative risk factors to determine which independent variables predicted skilled nursing placement. Subjects were followed for an average of 23.7 months (SD = 18.6 months). SETTING: Multilevel 1,735-bed long-term care facility, Jewish Home for the Aging, Reseda, California. PARTICIPANTS: Of the 248 consecutive residential care admissions studied, 80% were women. Subject's mean age was 84.8 years (SD = 5.0); 67% had no significant cognitive impairment. INDEPENDENT VARIABLES: Categorical variables were classifications with respect to dementia status, incontinence, hearing, and ambulation. Interval variables were number of medications, Katz ADL, and five neuropsychological tests. Demographic variables were gender, age, language of origin, and education. OUTCOME VARIABLE: Time between preadmission testing and the move up to skilled nursing placement. RESULTS: Pairwise assessment of adjusted potential risk factors indicated that cognitive dysfunction, less than perfect Katz ADL performance, and hearing loss were the most important independent risk factors for nursing placement. CONCLUSIONS: The findings remind us to pay careful attention to residents exhibiting even relatively mild cognitive deficits upon admission because these residents are likely to need increased environmental support. PMID- 7836634 TI - Code status decision-making in a nursing home population: processes and outcomes. AB - OBJECTIVES: To examine the clinical utility of prehospital code status discussions in a nursing home (NH) setting and the health care outcomes of the decisions made. Also to identify patient factors and other variables associated with these decisions. DESIGN: Retrospective uncontrolled observational study carried out through record review. SETTING: A single skilled-level teaching NH and its affiliated university hospital. PATIENTS: All of the 350 individuals who resided at the NH during a 2-year period. MAIN RESULTS: Code status decisions were routinely sought through discussion involving primary care physician/social worker teams and residents or surrogates of demented patients. Choices were made for 80% of the NH residents, most (73%) by surrogates and most (80%) for do-not resuscitate (DNR) orders, usually within 10 weeks of NH admission. Neither short term measures of NH care intensity nor hospital use changed after a DNR decision. Most (80%) hospital transfer records included code status documentation. At the NH, both the likelihood of decisions and their directions were associated with involvement by specific physician/social worker teams. Additionally, a dementia diagnosis, white race, and older age were associated with a nursing home DNR decision. At the hospital, a DNR order was associated with white race, the presence of nursing home DNR documentation in the transfer records, hospital attending care by certain NH physicians, and a terminal hospital stay. Hospital inpatient medical and surgical therapy use, except for intensive care procedures, was similar for DNR and non-DNR inpatients. Residents with DNR orders had a higher mortality rate, yet most survived at least 1 year after the order. In the short term, a DNR order had no impact on measured health care resource consumption, but, for those in the final months of life, in-patient hospital use was less for the DNR group, and most of these died at the nursing home. CONCLUSIONS: Prehospital code status decisions can be made effectively within the NH setting. Outside of medical intensive care, DNR orders have no impact on NH and hospital care intensity in the short term. In the final 6 months of life, however, hospital use is less for the DNR subgroup. PMID- 7836635 TI - Predictors of hand function in older persons: a two-year longitudinal analysis. AB - OBJECTIVE: To validate a hierarchical model of hand function in older persons, using longitudinal data. DESIGN: Longitudinal observational study (2-year data from an ongoing longitudinal study). SUBJECTS: 689 persons older than age 60, including Continuing Care Retirement Community (n = 230), homebound (n = 204), and ambulatory (n = 255) respondents. Mean age at baseline 76.6 (SD = 8.8). MEASUREMENT: Independent variables included sociodemographics, physician measures of upper joint impairment, self-reported comorbidity, arthritis pain, depression, and anxiety. The dependent variables included grip strength and a timed manual performance test. MAIN RESULTS: Using generalized estimated equations (GEE) to test our hierarchial model, we found that gender and upper extremity joint impairment were the strongest predictors of a longitudinal measure of grip strength. Grip strength, in turn, along with demographics, comorbidity, and a measure of psychological status, was significantly related to timed manual performance. CONCLUSIONS: The longitudinal analyses confirmed a previous cross sectional finding that upper extremity joint impairment contributes significantly to reduced grip strength, which, in turn, contributes to reduced hand performance on a timed test. PMID- 7836636 TI - Validation of the Cumulative Illness Rating Scale in a geriatric residential population. AB - OBJECTIVE: To evaluate the validity of the Cumulative Illness Rating Scale (CIRS) in a geriatric institutional population by examining its associations with mortality, hospitalization, medication usage, laboratory findings and disability. DESIGN: A validation of the CIRS using self- and physician-report surveys, with archival data drawn from medical charts and facility records. SETTING: Long-term care facility with skilled nursing and congregate apartments. PARTICIPANTS: Four hundred thirty-nine facility residents selected on the basis of completeness of self-report data and physician ratings. PRIMARY MEASURES: Composite measures of illness severity and comorbidity, based on physicians' CIRS ratings; time to death or acute hospitalization after assessment; medication use, drawn from pharmacy records; medical chart data on laboratory tests; self-reported functional disability. RESULTS: CIRS illness severity and comorbidity indices, as well as individual CIRS items, were significantly associated with mortality, acute hospitalization, medication usage, laboratory test results, and functional disability. The CIRS showed good divergent validity vis a vis functional disability in predicting mortality and hospitalization. CONCLUSIONS: The CIRS appears to be a valid indicator of health status among frail older institution residents. The illness severity and comorbidity composites performed equally well in predicting longitudinal outcomes. Item-level analyses suggest that the CIRS may be useful in developing differential illness profiles associated with mortality, hospitalization, and disability. PMID- 7836637 TI - Do surgical brain lesions present as isolated dementia? A population-based study. AB - OBJECTIVE: To determine the incidence of clinically important subdural hematoma (SDH), hydrocephalus not associated with a recent intracranial bleed, and intracranial tumor that is not obviously metastatic, and to test the sensitivity of a promising decision rule for computerized tomography (CT) in dementia. DESIGN: Population-based, retrospective, sequential case series. SETTING: Staff model health maintenance organization (HMO). PATIENTS: Patients aged 65 years and older with one of the three lesions, diagnosed over a 4.5-year period, identified mainly through computerized databases of hospital discharge diagnoses and a registry of malignant tumors. MEASUREMENTS: Clinical data were based on chart review. The decision rule, based on one that had been previously proposed and tested, stated that CT would be required if any one of 11 clinical criteria were met by a patient with cognitive impairment. Rule sensitivity was evaluated using clinical information recorded before CT. MAIN RESULTS: One hundred forty-five clinically important lesions were identified among 137,100 person-years at risk. Average annual incidence per 100,000 was 46.7 (95% CI 36.0, 59.6) for SDH, 5.8 (95% CI 2.5, 11.5) for hydrocephalus not associated with a recent intracranial bleed, and 53.2 (95% CI 41.7, 66.9) for intracranial tumors that were not obviously metastatic. Using the 65 to 74- year age strata as a reference, the relative risk for SDH was 4.8 (95% CI 2.7, 8.5) in 75 to 84-year-olds and 13.1 (95% CI 7.7, 22.5) in the 85 and older strata. Among 59 patients who presented with cognitive impairment, without altered sensorium or physical evidence of trauma, decision rule sensitivity was 93.2% (95% CI 83.5%, 98.1%). Sensitivity was 90.7% (95% CI 77.9%, 97.4%) in the subgroup that presented to an ambulatory care clinic rather than to an emergency department. CONCLUSIONS: These three lesions, which are the most common surgical lesions that may present as dementia, are rare. Most cases have presentations that easily distinguish them from typical Alzheimer's disease. This case series indicates that it may be feasible to develop a decision rule for the selective use of CT in dementia. Disease spectrum will influence measures of decision rule performance such as sensitivity and specificity. PMID- 7836638 TI - Prevalence and subtypes of dementia in Taiwan: a community survey of 5297 individuals. AB - OBJECTIVE: To study the prevalence rate of dementia in Taiwan, the relative frequencies of its subtypes, and its associations with age, education, gender, and residence location. PARTICIPANTS: A total of 2753 men and 2544 women from four urban and four rural communities participated. Their age ranged from 41 to 88 years; 28% of them were at least 65 years old. Their education ranged from 0 to 20 years; 27% of them had less than 1 year of formal schooling. DESIGN: Phase I was a screening survey by trained nurses who administered a Chinese version of the Mini-Mental State Examination, the MMSE-T1, to all participants. Phase II involved the assessment for dementia by neurologists on the 1521 individuals who had scored less than 24 on the 30-point MMSE-T1. MAIN RESULTS: Thirty-one cases of dementia were identified by the DSM-III-R criteria, including 18 cases of Alzheimer's disease, 10 cases of vascular dementia, and three cases of other dementias. The prevalence rate in individuals aged 65 and over was 2.0%. Aging and illiteracy were associated with higher rates of dementia; gender and residence location made no difference. CONCLUSIONS: The prevalence rate of dementia was low in this Chinese population. Consistent with common findings from other parts of the world, a high rate of dementia was associated with older age and illiteracy, and Alzheimer's disease was the most frequent cause. PMID- 7836639 TI - Depression in Alzheimer's disease patients: caregivers as surrogate reporters. AB - OBJECTIVE: To evaluate the use of caregivers as surrogate reporters of depressive symptoms in Alzheimer's disease (AD) patients on five depression measures. DESIGN: Scale characteristics, including means, ranges, internal consistency, sensitivity, and item content of modified self-report questionnaire and interview depression measures were compared. PARTICIPANTS: Seventy-six patients, diagnosed with both depression and AD, and their family caregivers participated in this investigation. All subjects were community-residing participants in a treatment outcome investigation of behavioral treatment for depression. MEASUREMENTS: A Schedule for Affective Disorders and Schizophrenia (SADS) interview was completed on all subjects to establish a diagnosis of depression. Caregivers then completed three additional questionnaire measures about their patient: the Beck Depression Inventory (BDI), the Geriatric Depression Scale (GDS), and the Center for Epidemiological Studies-Depression Scale (CESD), all modified to provide a surrogate report of their patient's depressive symptoms. In addition, two interview measures were completed based on interviews with the caregiver and patient: the Hamilton Depression Rating Scale (HDRS) and the Cornell Scale for Depression in Dementia (CSDD). RESULTS: Mean scores for this sample were above the recommended cutoff score for mild levels of depression on all measures. Coefficient alpha levels were comparable to levels reported for the traditional self-report formats. Sensitivity varied among the measures, with the CSDD most sensitive and the HDRS least sensitive. Item content varied across measures, particularly between questionnaire and interview measures. CONCLUSIONS: Based on these results, it appears that caregivers are able to act as surrogate reporters of depression in AD patients. The modification of self-report questionnaires did not decrease their internal consistency, and they remained highly correlated with each other, supporting their validity when used in this manner. A two-step process of evaluating AD patients for depression is recommended: first, a surrogate report questionnaire completed by caregivers to screen patients, eliminating those who are unlikely to be depressed, and then a more extensive interview with those patients-and their caregivers- who appear likely to be depressed. PMID- 7836640 TI - Minimal trauma fractures in older nursing home residents: the interaction of functional status, trauma, and site of fracture. AB - OBJECTIVE: This study was conducted to determine the incidence of long bone fractures in institutionalized older persons and to describe preceding traumatic events and the functional status of individuals sustaining fractures. DESIGN: A 1 year, prospective, cumulative incidence survey. SETTING: Eleven skilled nursing care facilities in the state of Wisconsin. PATIENTS: All residents of the 11 facilities. MEASUREMENTS: All incident reports of long bone fractures, description of events preceding the fractures, and functional status of the fracture cases. In addition, demographic and medical information was collected on fracture cases and the general nursing home population. MAIN RESULTS: Overall long bone fracture incidence was 3.52 per 100 subjects per year. Minimal trauma fracture incidence was 0.84 per 100 subjects per year. Fracture location was significantly related to type of trauma. Functional status was significantly related to fracture location and to the type of trauma preceding the fracture. Minimal trauma fractures occurred in individuals who were less mobile and more likely to be bed-bound, and the location was more likely to be the lower extremity below the hip. CONCLUSION: This is the first prospective survey of long bone and spontaneous fracture incidence rates in multiple nursing home facilities. Minimal trauma fractures are common in the nursing home, and most have no clear precipitating factors other than severely impaired mobility. PMID- 7836641 TI - Changes in small-intestine permeability with aging. AB - OBJECTIVE: To evaluate small-intestine mucosal integrity and permeability with advancing age as measured by the lactulose/mannitol absorption test in healthy subjects. DESIGN: Prospective cohort study. SETTING: Clinical research unit of the USDA Human Nutrition Research Center on Aging. STUDY PARTICIPANTS: Fifty-six subjects were recruited in three age groups: 20 to 39 years (n = 20), 40 to 59 years (n = 19), and > or = 60 years (n = 17). Subjects were healthy, community dwelling volunteers. INTERVENTION: After an 8-hour fast, all subjects ingested 10 g of lactulose and 5 g of mannitol. Urine was collected for 6 hours and analyzed for lactulose and mannitol by high performance liquid chromatography. Twenty-four hour urinary creatinine clearances were determined. MAIN OUTCOME MEASURES: Percentages of lactulose and mannitol excreted, the lactulose/mannitol ratio (x100), and the 24-hour creatinine clearance. RESULTS: With increasing age, both the percentage of lactulose excreted (P = 0.09) and the percentage of mannitol excreted (P = 0.05) tended to decrease progressively. The lactulose/mannitol ratio (x100) did not change with increasing age (P = 0.65) because both the percentages of lactulose and mannitol excreted declined. The creatinine clearance decreased markedly with advancing age (P < .001) and accounted for the decline in percentages of lactulose and mannitol excreted (P < .02). CONCLUSIONS: There is a progressive decline in the ability to excrete lactulose and mannitol with increasing age. This is probably attributable to a decline in renal function with advancing age. However, because of parallel decreases in lactulose and mannitol excretion, the lactulose/mannitol ratio does not change. Thus small-intestine "leakiness" does not increase with aging as measured by the lactulose/mannitol absorption test. PMID- 7836642 TI - Weight gain impacts morbidity and mortality in institutionalized older persons. AB - OBJECTIVE: To determine if a significant weight change in previously undernourished older persons is associated with mortality and morbidity. DESIGN: Retrospective survey. SETTING: A chronic care hospital in Canada. SUBJECTS: Follow-up survey from an original data set (Time 1) on 88 previously diagnosed undernourished and 60 adequately nourished. Average age was 78 years; average length of residence was 40 months. Of the 148 subjects, 120 were male. MEASUREMENTS: Average time to follow-up (Time 2) was 319 days from Time 1. Data was collected on weight change, reported incidence of infection, use of antibiotics, number of falls, and admissions to acute centers, as well as incidence and cause of death. Three-day diet intake records were available on 15% of subjects within 1 month of Time 2. Five nutritional groups existed within this follow-up population: those previously undernourished who gained at least 5% of Time 1 weight (Group 1), those undernourished who lost at least 5% of Time 1 weight (Group 2), those undernourished who maintained their weight (Group 3), those adequately nourished who lost at least 5% of original weight (Group 4), and those who remained adequately nourished (Group 5). RESULTS: Forty-one of the 148 patients died; this was significantly associated with nutrition group (X2 = 11.23, P = 0.02), with fewer deaths in Groups 1, 3, and 5. As well, primary diagnosis (x2 = 32.6, P = 0.001), length of residence (X2 = 25.6, P = 0.01), and time to death (X2 = 26.4, P = 0.009) were significantly associated with nutrition group. Diet intake records indicated an improvement in energy and protein intake in Group 1 during the follow-up. Energy and protein change, whether increased or decreased from the original study, was significantly associated with nutrition group. Total number of feeding impairments and presence of dysphagia were significantly associated with nutrition group. Other morbidity events were not significantly associated with nutrition group, but trends suggest a positive effect of weight gain on incidence of falls, incidence of more than two infections, and incidence of recurring infections. CONCLUSIONS: A weight increase of at least 5% of body weight in previously undernourished patients is associated with a decreased incidence of death and may reduce morbidity events. Feeding impairments may affect ability of patients to gain weight, but dysphagia is associated with weight increase. Other nonnutritional variables of diagnosis, number of medications, and declining medical status also affect mortality and morbidity outcomes. PMID- 7836643 TI - Can respiratory syncytial virus and influenza A be distinguished clinically in institutionalized older persons? PMID- 7836644 TI - A simple model for predicting postoperative delirium in older patients undergoing elective orthopedic surgery. AB - OBJECTIVE: To determine the incidence, and severity of postoperative delirium (POD) in older patients undergoing elective orthopedic procedures and to identify potential preoperative risk factors. DESIGN: A prospectively studied cohort of elective orthopedic surgery patients. SETTING: A University teaching hospital. PATIENTS: Eighty patients who attended a preadmission clinic and, subsequently, underwent elective orthopedic surgery. All patients were aged 60 years or older, and all spoke English. MEASUREMENTS: Patients underwent preoperative medical, cognitive, and activities of daily living assessment with standardized instruments and were followed postoperatively with daily visits, telephone interviews with attending nurses using a modified confusion assessment model (CAM), and repeated cognitive testing. Suspected delirium was verified by direct physician assessment. RESULTS: The elective group had 14 (17.5%) cases of POD, of which six (7.5%) were severe. These incidences are low compared with those of nonelective surgery groups reported elsewhere in the literature. Stepwise multiple logistic regression identified two POD risk factors: clock-drawing scores < or = 6 (OR = 9.0, CI, 2.8 to 45.6) and male gender (OR = 5.6, CI 1.9 to 33.8). CONCLUSION: A simple model using clock-drawing scores and male gender for preoperative identification of elective patients at greatest risk for POD appears sensitive, predictive, and practical for the preadmission clinic setting, but it should be validated in a prospective trial. PMID- 7836646 TI - Geriatric medicine on the information superhighway: opportunity or road kill? PMID- 7836645 TI - Clinical problem-solving in geriatric medicine: obstacles to rehabilitation. AB - This case illustrates how multifactorial medical, neurological and psychiatric conditions can synergistically effect the functional status of elderly individuals. This case also illustrates how iatrogenically induced illness, most commonly in the form of drug therapy, can significantly affect patients' conditions and their progress in rehabilitative therapies. This case also illustrates how the atypical presentation of disease in the elderly, as well as the medical ramifications of rehabilitative therapies, need to be strongly considered during trials at functional rehabilitation. More importantly, however, this case demonstrates how even a community-based geriatrician can be instrumental in recognizing the need of more appropriate evaluations in elderly patients with functional disabilities and how even in the setting of a multidisciplinary team there can still be a consulting relationship, with each person seeing the patient individually and communicating with other members of the team as necessary. Although each team member may have a specific area of expertise, there is still a very important role for the geriatrician to play in making sure that all the different components of the rehabilitation and the medical care proceed in a way that will provide the most favorable outcome for the patient. PMID- 7836647 TI - Suicide in two patients with Alzheimer's disease. PMID- 7836648 TI - Diagnostic and prognostic value of stress testing in older persons. AB - OBJECTIVE: To review the diagnostic and prognostic utility of exercise and pharmacologic stress testing in older individuals. DATA SOURCE: A computer assisted search of the literature, followed by a manual reference review of pertinent articles. STUDY SELECTION: Studies addressing the use of exercise and pharmacologic stress testing for coronary artery disease (CAD) detection and prognosis were reviewed. Emphasis was placed on those studies applying these procedures to older populations. DATA EXTRACTION: Pertinent data were extracted regarding the diagnostic and prognostic accuracy and safety of exercise and nonexercise stress testing techniques in older patients. DATA SYNTHESIS: Available data from relevant articles were summarized and the merits and limitations of the available techniques discussed. CONCLUSIONS: Numerous studies over the past 2 decades support the usefulness of the exercise ECG and exercise thallium-201 perfusion scan for detecting CAD in older populations. Although exercise echocardiography generally appears to have diagnostic and prognostic accuracy similar to thallium-201 imaging, greater technical difficulty with this technique is frequently encountered in older patients. Non-exercise forms of stress testing, particularly those employing pharmacologic agents such as dipyridamole, adenosine, or dobutamine, combined with either thallium-201 scintigraphy or echocardiography, allow accurate CAD diagnostic and prognostic assessment in even very frail older patients. Additional studies are needed to compare the accuracy and cost-benefit ratio of the many stress testing modalities now available for older patients. PMID- 7836649 TI - Impact of nutritional status on health outcomes of nursing home residents. PMID- 7836650 TI - Pancytopenia and valproic acid--a possible association. PMID- 7836651 TI - The impact of depression on self-perceived health status. PMID- 7836652 TI - Diurnal variation in language tests and its relevance to early detection of dementia: time dependence of language test in healthy adults. PMID- 7836653 TI - Geriatric rehabilitation: what do physicians know about it and how should they use it? PMID- 7836654 TI - Physician-assisted death in The Netherlands and the US. PMID- 7836655 TI - Relationship between physical performance and self-perceived physical function. AB - OBJECTIVE: The objective of this study was to compare two methods of measuring physical function in subjects with a broad range of abilities and to evaluate the effects of cognitive, social, educational, and age factors on the relationship between the two methods. DESIGN: Multiple regression analysis was used to compare self-perceived (dependent variables) with performance measures (independent variables). Covariates included age, gender, Mini-Mental State Exam score, education, living status, and depression score. SETTING: Five community-dwelling and two nursing home sites. PARTICIPANTS: 417 community-dwelling subjects and 200 nursing home residents aged 62-98 years. MEASUREMENTS: Self-perceived physical function was assessed with the physical dimension summary score of the Sickness Impact Profile, which comprises three subscales: ambulation, mobility, and body care and movement. Physical performance was evaluated by self-selected gait speed, chair-stand time, maximal grip strength, and a balance score. RESULTS: Nursing home residents and community-dwellers were significantly different (P < .0001) in all variables except age and gender. Self-perceived and performance based measures were moderately correlated, with a range from r = -.194 to r = .625 (P < .05). Gait speed was the strongest independent predictor of self perceived physical function in both groups. Symptoms of depression were also an independent predictor of self-perceived function in nursing home residents; subjects who had such symptoms report more self-perceived dysfunction than would be predicted based on performance tests. CONCLUSIONS: Self-selected gait speed is a global indicator of self-perceived physical function over a broad range of abilities. External determinants (depressive symptoms, cognitive function, marital status, etc.) affect self-perceived function in both groups, but gait speed is the greatest single predictor of self-perceived function. In nursing home residents depressive symptomatology is related to self-perceived. PMID- 7836656 TI - PCR directed preparation and single step purification of highly active histidine tagged restriction endonuclease HgiBI (GGWCC). AB - The polymerase-chain-reaction technique is used to produce fusion proteins via deletion of any intervening piece of DNA. Here a stretch of six histidine codons is fused to the 3'-terminus of any defined gene using a standard plasmid vector or a derivative thereof. The advantage over existing methods is that no other amino acids besides the six histidines are added to the protein terminus and only one oligonucleotide needs to be synthesized as special primer. Genes of interest must only be cloned in the correct orientation into a universal multilinker. Using just one specific primer derived from the 3'-terminus of the gene and one standard primer derived from the six histidine codons the fusion is performed by amplifying the entire vector system as described for inverse PCR. As an example, we report on the modification and purification of the restriction endonuclease HgiBI (GGWCC). Enzymatically active protein was obtained in a single step purification under nondenaturating conditions with a purity greater than 95% according to polyacrylamide gel electrophoresis. PMID- 7836657 TI - Influence of the size of the polar head of non-ionic detergents on membrane proteins immunoaffinity purification. AB - Nonionic polyoxyethylene type detergents (CxEy) are widely used to solubilize and purify membrane proteins. The detergent hydrophobic moiety (Cx) replaces phospholipids at exposed hydrophobic regions of the membrane proteins. During chromatography on an immobilized anti-Kell antibody to purify Kell protein (an integral erythrocyte protein), it was observed that the size of the polar head of an non ionic detergent added to the mobile phase appeared to influence the interaction of the detergent-protein complex with the immobilized antibody. Further studies were performed using another erythrocyte membrane protein, Glycophorin C and three anti-GPC monoclonal antibodies directed against three epitopes of the extracytoplasmic domain of the protein. The interaction of GPC with the three Protein A-coupled monoclonal antibodies was studied in the presence of three detergents C12E<9>, C13E<15> and C12E<23>. It was observed in batch mode and in column chromatography experiments that the adsorption of GPC to the immunoaffinity supports decreased as the size of the detergent polar head increased. Thus, the polyoxyethylene chain of a detergent might prevent the interaction of the detergent-protein complex with the immobilized antibody. PMID- 7836658 TI - A method for determination of galactosyltransferase I activity synthesizing the proteoglycan linkage region. AB - An assay method was devised for measuring the activity of galactosyltransferase I (UDP-D-galactose:D-xylose galactosyltransferase), which is one of the enzymes synthesizing the linkage region between the core protein and glycosaminoglycan chains of proteoglycan. For this method, the reaction mixture contained a fluorescent substrate, 4-methylumbelliferyl-beta-D-xyloside as an acceptor, UDP galactose as a donor and D-galactal as a competitive inhibitor of endogenous beta galactosidase in the enzyme solution. The reaction mixture was incubated at 37 degrees C with enzyme solution prepared from an extract of cultured cells, and galactosyl-xylosyl-4-methylumbelliferone was produced as a reaction product. Measurement of galactosyltransferase I activity was performed by separation and quantitative analysis of this reaction product using high-performance liquid chromatography. Utilizing this method, easier and more sensitive detection of galactosyltransferase I activity in a cell-free system became possible. Application of the method revealed that cultured human skin fibroblasts contained galactosyltransferase I activity. PMID- 7836659 TI - Spectrophotometric determination of acadesine (AICA-riboside) in plasma using a diazotization coupling technique with N-(1-naphthyl)ethylenediamine. AB - A simple spectrophotometric assay has been developed for determining concentrations of the new cardioprotective agent, acadesine (AICA-riboside), in human plasma. The method is adapted from the Bratton-Marshall (BMA) procedure for detection of primary aromatic amines. The assay was developed to measure concentrations of the drug in plasma during i.v. infusion to patients undergoing coronary artery bypass graft (CABG) surgery. The limit of quantitation of the assay is 0.25 microgram/ml using a 0.25 ml sample of plasma. Use of 96-well titer plates and reader can rapidly process many samples at one time. The colorimetric assay correlates well (r = 0.98) with a previously described high performance liquid chromatographic (HPLC) procedure in terms of range of quantitation, limit of quantitation, and precision. PMID- 7836660 TI - The use of photoacoustic spectroscopy to determine the critical distance for electron transfer. AB - Photoacoustic spectroscopy was used to determine the critical distance for electron transfer from porphyrin to quinone molecules randomly dispersed in a polymeric matrix. An enhancement of the porphyrin signal was observed as the quinone concentration was increased. The data was analyzed according to the Perrin model and it was found that the electron transfer occurred if the porphyrin-quinone distance was less than 33 A. To confirm the validity of the method, the fluorescence quenching was also measured for the same samples. In this case, the same critical distance was obtained. PMID- 7836662 TI - Development of a continuous coupled enzymatic assay for myo-inositol monophosphatase. AB - Myo-inositol monophosphatase, an enzyme purified from brain tissues, catalyses the dephosphorylation of myo-inositol 1-phosphate. This enzyme has become the subject of intense research interest since myo-inositol is needed for the resynthesis of phosphatidylinositol in cell membranes. Since phosphate contamination has always been a problem for the assay of this enzyme activity, we have developed a coupled enzymatic assay for detecting the activity of the phosphatase with no interference by the presence of phosphate. The assay is based on the measurement of inositol release after dephosphorylation and subsequent conversion of inositol into scyllo-inosose by a second enzyme, inositol dehydrogenase from Enterobacter aerogenes. Since the second reaction requires the presence of beta-NAD+, the activity of the dephosphorylation reaction can be monitored continuously by the increase of absorbance at 340 nm spectrophotometrically. PMID- 7836661 TI - Fluorochromes with long-lived fluorescence as potential labels for pulsed laser immunocytofluorometry: photophysical characterization of pyrene derivatives. AB - An apparatus for laser-induced time-resolved fluorescence measurements, in conjunction with pyrene derivatives endowed with long-lived excited singlet states, was employed for immunocytofluorometric measurements. N-(1 pyrene)maleimide, 1-pyrenesulfonyl chloride and 1-pyreneisothiocyanate were conjugated with immunoglobulin, antimouse-IgG, and the fluorescence decays of both free and conjugated forms were investigated. Bi-exponential decays were obtained in all cases with time constants of the short-lived component in the range 3-4.7 ns and the long-lived one in the range 20-55 ns. Only the spectral distribution of the two components is essentially affected upon conjugation. The persistence of the long-lived component, well above the lifetime of autofluorescence, and of the antibody specificity, as shown by immunodiffusion tests, upon conjugation indicates that this technique could be advantageously adopted in immunocytofluorometry. PMID- 7836663 TI - Synchrotron X-ray studies of lipids and membranes: a critique. AB - This review gives a description of techniques, suitable for the study of lipid dispersions and unorientated membranes, that are available at synchrotron facilities to determine either the kinetics of transitional phenomena in the time after a temperature or pressure jump is initiated, or the phases present while a sample undergoes a phase transition. Included in this description is information about synchrotron X-ray sources, sample holders and temperature controllers, detection systems, as well as data reduction. Examples involving lipid dispersions are provided to illustrate the application of these methods using synchrotron radiation. PMID- 7836664 TI - International Symposium on Cerebral Blood Vessels '93. Proceedings. Zao, Japan, 28-30 May 1993. PMID- 7836666 TI - Cerebral vasodilatory effect of high-dose, intravascular endothelin-1: inhibition by NG-monomethyl-L-arginine. AB - The effects of intracarotid administration of endothelin-1 on the cerebral microvessels were examined in anesthetized cats. The local cerebral blood volume in the cortex, which reflects the cumulative dimensions of the cerebral microvessels, was measured by our photoelectric method. A low dose of endothelin 1 (0.1 nmol) elicited mild but significant declines in cerebral blood volume. Following a high dose of endothelin-1 (3 nmol), the cerebral blood volume was initially reduced, probably due to the marked fall in arterial blood pressure, but was subsequently increased significantly. The increase in cerebral blood volume was not secondary to the rise in blood pressure, since it was unaffected by inhibition of the blood pressure changes with BQ-123 (1 mg/kg), an endothelin antagonist. However, the cerebral blood volume increase was prevented by continuous administration of NG-monomethyl-L-arginine (0.35 mg/kg per min), an inhibitor of nitric oxide synthesis, plus BQ-123. BQ-123 itself had no significant effects on cerebral blood volume or blood pressure. We conclude that while a low dose of intravascular endothelin-1 steadily constricts the cerebral microvessels, a high dose dilates the cerebral microvessels through the induction of nitric oxide synthesis, probably in the endothelium. PMID- 7836665 TI - Cerebral pial arterial innervation with special reference to GABAergic innervation. AB - Glutamic acid decarboxylase (GAD)-immunoreactive (I) nerve fibers were observed to run parallel to other autonomic nerve fibers, especially vasoactive intestinal polypeptide (VIP)- and calcitonin gene-related peptide (CGRP)-I nerve fibers at the light microscopic level. At the ultrastructural level, GAD-immunoreactivities co-localized with CGRP immunoreactivities in nerve terminals, but not with choline acetyltransferase, VIP, tyrosine hydroxylase and neuropeptide Y immunoreactivities. GAD immunoreactivities were observed in the trigeminal ganglion, some of which were co-localized with CGRP-immunoreactivities. In the proximal portion of the internal carotid artery, GAD-I adventitial ganglion cells were observed and some were also immunoreactive for CGRP. These results strongly suggest that the origin of GABAergic innervation of the major cerebral pial arteries of the cat is mainly in the trigeminal ganglion, and partly in the adventitial ganglia of the internal carotid artery. PMID- 7836667 TI - Endothelin-A receptors mediate contraction in human cerebral, meningeal and temporal arteries. AB - Endothelin-1 (ET-1), an endothelium-derived vasoconstrictor peptide, produced strong contractions in human cerebral, meningeal and temporal arteries. The isopeptides ET-2 and ET-3 also showed potent constrictor activity; however, ET-3 was less potent. The selective ETA receptor antagonist FR 139317 mediated a shift to the right of the concentration-response curve of ET-1. These results suggest that the powerful constriction elicited by the endothelin-isopeptides in cerebral, meningeal and temporal arteries is mediated through ETA receptors. PMID- 7836668 TI - Vasoactive peptides and prostaglandin D2 in human cerebromicrovascular endothelium. AB - Prostaglandin D2 (PGD2) is the major prostanoid formed among other prostanoids in cultured microvascular endothelium derived from human brain (HBEC). Angiotensin II, arginine vasopressin and endothelium-1 stimulated the production of PGD2 and PGF2 alpha in a concentration-dependent manner, and this effect was inhibited by their specific receptor antagonists or dexamethasone (inhibitor of phospholipase A2/cyclooxygenase II). Both the peptidergic-induced PGD2 and the exogenously added PGD2 were converted in HBEC to 9 alpha, 11 beta-PGF2, a potent vasoconstrictor. Exogenous PGD2 also dose-dependently enhanced the production of vasoconstrictive PGF2 alpha, thromboxane B2, vasodilatory prostaglandin PGE2, and cAMP in these cells. The PGD2 stimulated formation of the prostanoids was inhibited by acetylsalicylic acid or indomethacin (inhibitors of cyclooxygenase I) but not dexamethasone, demonstrating for the first time that PGD2 may contribute to the production of prostanoids in HBEC. These findings strongly suggest that PGD2 may play a pivotal role in the regulation of cerebromicrovascular function. PMID- 7836669 TI - Vasopressin mediated vasodilation of cerebral arteries. AB - The bolus injection of vasopressin into the vertebral artery produced a dose dependent vasodilation in the major cerebral arteries, detected angiographically, while it elicited a decrease in vertebral blood flow. One nanomol of vasopressin was the optimal dose for producing maximal vasodilation. The basilar, posterior communicating, and internal carotid arteries showed the most dilatation, followed by the middle cerebral, the intracranial portion of the vertebral artery and the anterior spinal artery. The extracranial portion of the vertebral artery was less sensitive to vasopressin. The vasodilation was inhibited by a V1-antagonist and NG-monomethyl-L-arginine. These results suggest that the arteries of the circle of Willis at the base of the brain are more sensitive to nitric oxide release induced by vasopressin compared with other intracranial and extracranial arteries. PMID- 7836670 TI - Effects of vasopressin on regional cerebral blood flow in dogs. AB - Vasopressin may regulate the regional cerebral blood flow (rCBF) via two balancing effects: increased flow from the vessels dilated by nitric oxide from the endothelium, and decreased flow from the vessels contracted by direct stimulation of smooth muscle. The effect on the rCBF in anesthetized dogs following the intracisternal or intraarterial administration of vasopressin was investigated by laser flowmetry with the device placed on the dura over the parietal cortex. The intracisternal injection of 1 nmol vasopressin significantly increased the rCBF to 145.3 +/- 27.3% of base line. In contrast, the intravertebral arterial injection of vasopressin had no significant effect on the rCBF. This can be explained by a difference in the affected vasculature; mainly large vessels in the subarachnoid space vs. whole vascular system supplied by the vertebral artery. The intracisternal injection of 10 mumol of NG-monomethyl-L arginine (L-NMMA) reduced the rCBF; pretreatment with this agent significantly suppressed the elevation in rCBF induced by vasopressin. The intraarterial injection of L-NMMA reduced the rCBF more than its intracisternal administration. It also suppressed the rCBF induced by vasopressin. PMID- 7836671 TI - Effects of endothelium removal by saponin and of oxyhemoglobin on canine cerebrovascular responses. AB - The stainless steel cannula method was applied to isolated and perfused canine basilar arteries to examine the role of endothelium in the responses to intraluminal vasoactive substances. After intraluminal treatment with saponin to remove the endothelium, the monophasic constrictions to potassium chloride and prostaglandin F2 alpha were potentiated, while those to phenylephrine (alpha 1 adrenoceptor agonist) and 5-hydroxytryptamine were not changed. Xylazine (alpha 2 adrenoceptor agonist) and acetylcholine induced a constriction preceded by a small dilation in controls. The response to xylazine was not modified, while the constriction to acetylcholine was augmented after endothelium removal. Bradykinin, substance P and vasopressin caused a dilation in lower doses, and a dilation followed by a secondary constriction in higher doses in controls. The dilations to these peptides were reduced and the constrictions were enhanced after endothelial removal. Adenosine triphosphate produced a biphasic response, i.e., a dilation followed by a constriction, which was occasionally preceded by a small constriction in higher doses, and only the dilation in lower doses was attenuated. The monophasic dilation to adenosine was potentiated, while the papaverine-induced dilation was not influenced by endothelial removal. After extraluminal treatment with oxyhemoglobin, the dilations to calcium ionophore A23187 and thimerosal were attenuated, while the constriction to acetylcholine was enhanced. The dilations to substance P and vasopressin were depressed, and the constrictions were potentiated. The monophasic dilation to sodium nitroprusside was augmented, while that to papaverine was not changed. These results suggest that the endothelium may play important roles not only in producing endothelium-derived relaxing factors but also in modulating the calcium influx into the smooth muscle cells. The mechanisms of altered responsiveness might be implicated in cerebral vasospasm following subarachnoid hemorrhage. PMID- 7836672 TI - A possible role of calcium ion in osmotic opening of blood-brain barrier. PMID- 7836673 TI - Smooth muscle hyperpolarization and relaxation to acetylcholine in the rabbit basilar artery. AB - Acetylcholine-evoked relaxation of noradrenaline-stimulated segments of the rabbit basilar artery was accompanied by a small, transient hyperpolarization of the smooth muscle cell membrane which was diminished by repeated exposure to the agonist. In the presence of glibenclamide (10 microM) or high concentrations of potassium chloride (65 mM), the acetylcholine-evoked smooth muscle hyperpolarization was abolished, whereas the relaxation response was unaffected. Nitric oxide (NO gas in solution; 0.5-15 microM) evoked dose-dependent relaxation in noradrenaline contracted arterial segments, but had no effect on the smooth muscle membrane potential, even at a saturated concentration (150 microM), which was 10 times higher than required to stimulate maximal relaxation. Additionally, NO-evoked relaxations were unaffected by glibenclamide (10 microM), but the responses were significantly attenuated in the presence of 65 mM potassium chloride. These data show that, as in the rabbit middle cerebral artery, acetylcholine-evoked hyperpolarization in the rabbit basilar artery is mediated by glibenclamide-sensitive potassium channels. However, in contrast to the middle cerebral artery and to other vessels such as the rat mesenteric artery, the change in smooth muscle membrane potential does not make an important contribution to the relaxation evoked either by this agonist or by NO. PMID- 7836674 TI - Loss of relaxations, metabolic failure and increased calcium permeability of smooth muscle during chronic cerebral vasospasm. AB - In the canine basilar artery during chronic vasospasm following subarachnoid hemorrhage, endothelium-dependent relaxations were diminished. Release of endothelium-derived relaxing factor (EDRF), as measured by a bioassay method, was unchanged. Relaxation to nitric oxide (NO) in preparations without endothelium was smaller in the spastic arteries. Production of cyclic GMP, measured by radioimmunoassay, was reduced in the spastic arteries; the impaired production was accompanied by decrease in GTP, the substrate for the production of cyclic nucleotide. The contents of other high-energy phosphates, such as creatine phosphate and ATP were also markedly reduced. Close temporal correlation between the metabolic failure and development of vasospasm was observed. Sarcolemmal regulation of intracellular calcium concentration was impaired in the pathological condition, suggesting a link between the metabolic failure and the pathological protracted contractions. Metabolic changes, and resultant affected viability of smooth muscle cells are likely to be an important factor in the pathogenesis of chronic vasospasm. PMID- 7836675 TI - Intra-arterial papaverine for the treatment of cerebral vasospasm after subarachnoid hemorrhage. AB - Intra-arterial infusion of papaverine was used clinically as a vasodilator for spastic arteries after subarachnoid hemorrhage, since in vitro experiment demonstrated that papaverine is one of the most potent vasodilators of human cerebral arteries following subarachnoid hemorrhage. The present report describes the successful treatment of cerebral vasospasm after subarachnoid hemorrhage by intra-arterial infusion of papaverine hydrochloride and discusses the experimental background of this treatment. PMID- 7836676 TI - Cerebral ischemia alters glucose transporter kinetics across rat brain microvascular endothelium. Quantitative analysis by an in situ brain perfusion method. AB - The purpose of this study was to quantify the changes of blood-brain barrier glucose transporter kinetics following cerebral ischemia using an in situ brain perfusion technique. Sixty-four adult male Sprague-Dawley rats were divided into control and ischemia groups, and a four-vessel occlusion model was used to provide an ischemic insult. To obtain regional capillary permeability area products of glucose and regional perfusion fluid flow rates, the perfusion fluid was dually labeled with 2-deoxy[14C]glucose and [3H]diazepam, and the brain was perfused at a constant rate via the external carotid artery. After sampling tissues from the brain, dual scintillation counting was performed and both regional perfusion fluid flow rates and regional capillary permeability area products were calculated. We determined kinetic parameters, including Vmax, Km and Kd as described in the Michaelis-Menten equation, by the non-linear least squares method. In the ischemia group, a decrease in Vmax and an increase in Km were recognized, which mean decreases in the affinity and the number of functioning glucose transporters. These results suggest that cerebral ischemia downregulates the blood-brain barrier glucose transporters. PMID- 7836677 TI - Endothelin-1 induced middle cerebral artery occlusion: pathological consequences and neuroprotective effects of MK801. AB - In the present study we utilise the potent vasoconstrictor properties of endothelin-1 (Et-1) in a new model of middle cerebral artery occlusion in the anaesthetized rat. We evaluate the reproducibility of the model and examine the neuroprotective efficacy of the potent anti-ischaemic agent, MK801. Adult male SD rats received MK801 (5 mg/kg, n = 7) or saline vehicle (n = 7) 30 mins prior to the microinjection of Et-1 (60 pmol in 3 microliters) via a 31-g cannula stereotaxically positioned 0.5 mm above the middle cerebral artery. Three days after the injection of Et-1, rats were perfusion fixed, the brain removed, cryostat sectioned and processed for histological staining. Sections at eight predetermined levels were examined by light microscopy and the volume of infarction calculated. Following administration of Et-1, saline-pretreated rats exhibited a pattern of ischaemic damage similar to that previously reported following permanent occlusion of the rat middle cerebral artery. This pattern was characterised by a large volume of infarction covering the dorsal and lateral neocortex (98 +/- 12 mm3) and striatum (32 +/- 3 mm3) ipsilateral to the insult. Power analysis predicted a group size of 7 would be required for a 50% reduction in ischaemic damage to be recorded as statistically significant at the 5% level. Pretreatment with MK801 reduced cortical tissue damage by 51% (P = 0.026) but did not significantly alter either the pattern or volume of infarction (33 +/- 4 mm3; P = 0.95) in the striatum.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836678 TI - Protein kinase C modulates the protective ability of peptide growth factors during anoxia. AB - Neuronal degeneration following exposure to anoxia and nitric oxide (NO) may be modulated by peptide growth factors and the activity of signal transduction systems. Basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) are neuroprotective during anoxia and NO toxicity. Signal transduction systems that activate protein kinase C (PKC) can be detrimental to neurons and mediate the toxic effects of anoxia and NO. We therefore examined whether PKC was involved in the protective effects of bFGF and EGF during anoxia. After exposure to anoxia, approximately 20-30% of hippocampal neurons survive. In contrast, chronic down-regulation of PKC activity prior to anoxia increases hippocampal neuronal cell survival to approximately 75%. Yet, this protective effect of inhibition of PKC activity was not present with the application of peptide growth factors during anoxia. Combined inhibition of PKC activity and application of the peptide growth factors bFGF or EGF was detrimental to the hippocampal neurons during anoxia. Neuronal survival during anoxia was 68 +/- 2% with bFGF and 79 +/- 3% with EGF but decreased to 49 +/- 7% (bFGF) and 44 +/- 2% (EGF) with PKC down regulation. Addition of the growth factors with the agent H-7, an inhibitor of PKC activity, also decreased neuronal survival during anoxia. In addition, the protective effects of the growth factors during anoxia were lessened to a greater degree with the activation of PKC, decreasing hippocampal neuronal survival for bFGF to 23 +/- 2% and for EGF to 31 +/- 3%.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836679 TI - Presynaptic glutamate receptors facilitate release of norepinephrine and 5 hydroxytryptamine as well as dopamine in the normal and ischemic striatum. AB - We investigated the effects of selective glutamate (Glu) agonists on the release of monoamine neurotransmitters and their implication in the enhanced monoamine release in cerebral ischemia. In the striatum of anesthetized Sprague-Dawley rats, in vivo microdialysis was performed and the release of excitatory amino acids (Glu and aspartate (Asp)) and monoamines (dopamine (DA), norepinephrine (NE) and 5-hydroxytryptamine (5-HT)) was measured by high-performance liquid chromatography with an electrochemical detector. (1) Forebrain ischemia by 4 vessel occlusion generated significant correlations between the Glu and Asp levels and the DA, NE and 5-HT levels (r = 0.922-0.967, P < 0.01, n = 6). (2) L Glu and its selective agonists (N-methyl-D-aspartate (NMDA), alpha-amino-3 hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) and kainate (KA)) evoked a simultaneous release of striatal DA, NE and 5-HT in a dose-dependent manner (P < 0.01, ANOVA, n = 8). The maximal monoamine release evoked by the Glu agonists showed different magnitudes in the order of DA >> NE > 5-HT (118-, 16- and 9-fold from the baseline levels by 62.5 mM L-Glu, respectively). Each Glu agonist exerted a different magnitude of transmitter release and the order of agonist efficacy was different among NE, 5-HT and DA release: AMPA = KA > L-Glu = NMDA for DA release, AMPA > L-Glu = NMDA = KA for NE release, and L-Glu = NMDA = KA = AMPA for 5-HT release.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836680 TI - Metabolic and non-metabolic cerebrovasomotor mechanisms operational during hypertensive states of different origin in rats. AB - We attempted to elucidate the vasomotor mechanisms regulating the cerebral circulation of rats under arterial hypertensive states of different origin. Sudden cold exposure elicited a cerebrovasodilator response mediated primarily by an enhanced cerebral metabolic state. The response was not modified by the concomitantly enhanced cerebrovascular sympathetic action. Central inhibition of the baroreceptor reflex, as achieved by chemical inhibition of the caudal ventrolateral medulla, disinhibited a non-metabolic cerebrovasodilator mechanism. However, its action was masked by a concomitantly enhanced sympathetic vasoconstrictor action. Another type of cerebrovasodilator response, also of non metabolic origin, was elicited by chemical stimulation of the defence area within the periaqueductal grey matter. Thus, the cerebrovasomotor mechanisms are diversely activated so as to cope adequately with the individual conditions imposed on the animals. PMID- 7836681 TI - Cerebral vasoconstrictive response produced by chemical stimulation of the caudal ventrolateral medullary depressor area is mediated via the rostral ventrolateral medullary pressor area and the cervical sympathetic nerves. AB - It was investigated that the cerebral blood flow (CBF) decrease response elicited by chemical stimulation of the caudal ventrolateral medullary depressor area (VLDA) is mediated via the rostral ventrolateral medullary pressor area (VLPA) and the cervical sympathetic nerve. The CBF was determined by radiolabeled microsphere technique in urethane (1.1-1.5 g.kg-1, i.p.) anesthetized Wistar rats. (i) Microinjection of L-glutamate (1.7 nmol) into the VLDA produced a significant (P < 0.01) decrease in CBF from 64 +/- 9 (mean +/- SEM) to 48 +/- 9 ml.min-1.(100 g)-1 and a significant (P < 0.01) increase in cerebrovascular resistance (CVR) from 1.7 +/- 0.2 to 2.4 +/- 0.4 mmHg per [ml.min-1.(100 g)-1] in the cerebral cortex ipsilateral to the stimulated VLDA side (n = 9). (ii) After cervical sympathectomy, L-glutamate was unilaterally microinjected into the VLDA. The CBF and CVR did not change significantly (n = 10). (iii) After depression of the VLPA neurons with muscimol (GABA agonist), L-glutamate was unilaterally microinjected into the VLDA. The CBF and CVR did not change significantly (n = 14). These results suggest that the pathway from the VLDA to control cerebral vessels may be mediated via the VLPA and the cervical sympathetic nerves. PMID- 7836682 TI - Nicotinic cholinergic receptors associated with mammalian cerebral vessels. AB - Current evidence suggests that the cerebral vasculature may be modulated by cholinergic nerves. We used ligand binding methods to examine the presence of nicotinic cholinergic receptors in brain vasculature. We found carbachol displaceable [3H]acetylcholine (ACh) and [3H]nicotine (NIC) binding sites in preparations of intraparenchymal cerebral microvessels (CMV) and larger pial vessels from human and pig brains. Specific binding sites for [3H]ACh and [3H]NIC in cerebral microvessels were saturable and comparable in density to those in cerebral cortex. The Kds for the two ligands ranged 3-18 nM whereas the Bmaxs were 25-45 fmol/mg protein. In contrast, the binding of [3H]pirenzipine or [3H]quinuclidinyl benzilate, index for muscarinic receptors, was low (9-15% of cortex) in microvessels compared to the cerebral cortex. Our observations suggest the association of cholinergic nicotinic receptors with cerebral microvessels, which may be involved in the modulation of the cerebral circulation by cholinergic neurons. PMID- 7836683 TI - Regulation by midbrain raphe nuclei and locus ceruleus on cerebral vasomotor responses. PMID- 7836684 TI - The cerebrovascular role of the ascending serotonergic system: new vistas. PMID- 7836685 TI - Autoradiographic study of the cerebrovascular effects of stimulation of the substantia innominata: convenient stimulation paradigm. AB - The aim of this study was to determine the distribution within the whole brain of the vascular effects of stimulation of the substantia innominata. This basal forebrain nucleus is the major cholinergic input in the neocortex in the rodent. The local cerebral blood flow was measured by the autoradiographic [14C]iodoantipyrine technique in a group of control and a group of stimulated unanesthetized rats. The substantia innominata was electrically stimulated through a chronically implanted electrode. The stimulation induced blood flow increases exceeding 200% in the hemisphere ipsilateral to the stimulation and 100% in the contralateral hemisphere compared to the control group. The ipsilateral vasodilations were observed not only in the cortical areas but also in some subcortical structures. Comparison with previous data suggests that part of the effects is due to cholinergic neurons of the substantia innominata and part to non-cholinergic neurons and indirect effects. However, only two out of eight stimulated rats displayed this response. The low reproducibility of the results is discussed, considering the stimulation paradigm which has been developed for future measurements of the cerebral glucose utilization which requires a long duration stimulation period. PMID- 7836686 TI - Distribution and origins of cerebrovascular NADPH-diaphorase-containing nerve fibers in the rat. AB - Neuronal NADPH-diaphorase has been proved to be nitric oxide synthase itself. In this study, we investigated distribution and origins of NADPH-diaphorase containing nerve fibers in the cerebral vessels in the rat. Adult male Sprague Dawley rats were divided into 4 groups. Nasociliary nerves were transected bilaterally in group 1. In group 2, intracranial branches of the sphenopalatine ganglion were transected bilaterally. In group 3, both of these structures were transected. The remaining animals were served as control (group 4). Two weeks after the above procedures, they were perfused with paraformaldehyde and glutaraldehyde. The pial arteries and superior cervical, trigeminal, internal carotid, otic and sphenopalatine ganglia were dissected. All specimens were processed for NADPH-diaphorase histochemistry. Numerous NADPH-diaphorase containing nerve fibers with varicosities forming plexuses were observed in the circle of Willis and its branches. Relatively thick nerve bundles were noted in the anterior half of the circle of Willis. They are most abundant in the internal ethmoidal artery. Approximately 5% of such fibers in anterior half of the circle of Willis disappeared in group 1, 90% in group 2, and no fibers were seen to remain in group 3. NADPH-diaphorase reaction was positive in the neurons of sphenopalatine, otic trigeminal and internal carotid ganglia. Among these ganglia, the reaction was prominent in sphenopalatine, otic and internal carotid ganglia. In summary: (1) NADPH-diaphorase-containing nerve fibers distribute to the circle of Willis and its branches.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836687 TI - Nitric oxide (NO)-mediated, vasodilator nerve function and its susceptibility to calcium antagonists. AB - Our pharmacological and immunohistochemical studies have demonstrated that nitric oxide (NO) or a substance that liberates NO plays a crucial role in the neurogenic relaxation of isolated cerebral arteries of dog and monkey. Relaxation caused by nerve stimulation by nicotine or electrical pulses in dog cerebral arteries without the endothelium were attenuated by Cd2+, a non-selective Ca2+ channel antagonist. Increase in cyclic GMP by nicotine was also suppressed by Cd2+, but not by nicardipine. Treatment with capsaicin did not influence the relaxant responses of the endothelium-denuded cerebral arteries to nerve stimulation. These results suggest that neurotransmission in vasodilator nerves innervating dog cerebral arteries is mainly mediated by NO, synthesized by an NO synthase which is activated by Ca2+ influx through non-L-type Ca2+ channel, but not by vasodilator peptides. PMID- 7836688 TI - Vasodilator innervation of small cerebral arteries of guinea pigs. AB - The neuronal influence on the resistance of cerebral arteries was analyzed in middle cerebral arteries of guinea pigs. Calcitonin gene-related peptide- and vasoactive intestinal peptide-immunoreactive nerves and NADPH-diaphorase-positive nerves were present in the distal portion of the middle cerebral artery. Isolated middle cerebral arteries were cannulated and perfused at a constant flow rate (1 ml/min) and the perfusion pressure was monitored. Prostaglandin F2 alpha (PGF2 alpha) and K+ (50 mM) elicited a sustained increase of the perfusion pressure (vasoconstriction), while noradrenaline and 5-hydroxytryptamine caused only a slight constriction. Electrical field stimulation (FS) at 8 Hz did not elicit a contractile response. In tissues precontracted with PGF2 alpha, FS induced a tetrodotoxin-sensitive vasodilator response. Endothelium-denudation and removal of the effect of sensory nerves by capsaicin-treatment did not affect the FS induced vasodilation. In contrast, nitro-L-arginine, an inhibitor of NO formation, attenuated the FS-induced vasodilatation. These results show that the resistance of the cerebral vessels of guinea pigs is under the influence of vasodilator nerves and that the neurogenic vasodilator mechanism involves NO synthesis. PMID- 7836689 TI - A role of nitric oxide in vasomotor control of cerebral parenchymal arterioles in rats. AB - The present study was undertaken to determine the role of nitric oxide (NO) in the regulation of vasomotor tone in rat cerebral parenchymal arterioles under physiological and pathological conditions. Cerebral arterioles, about 60 microns in diameter, were isolated from rats and cannulated with glass pipettes. Changes in the arteriolar diameter secondary to extraluminal application of drugs were monitored continuously through a videodimension analysis system. The arterioles were dilated by L-arginine (12.2 +/- 2.2% at 10(-3) M) and were constricted by NG monomethyl-L-arginine (L-NMMA) (13.8 +/- 1.5% at 10(-4) M) in a dose-dependent manner. Pretreatment with superoxide dismutase (600 U) increased sensitivity to L arginine. These results suggest that NO plays an important role in regulation of basal vasomotor tone of cerebral parenchymal arterioles under physiological conditions. Next, NO-modification of vasomotor responses to an endogenous vasoactive substance, arginine vasopressin (AVP) was studied in cerebral parenchymal arterioles. Increasing concentrations of AVP produced biphasic responses of vasodilation (10(-11) M) and vasoconstriction (10(-10)-10(-8) M). Inhibition of NO by pretreatment with L-NMMA (10(-4) M) or oxyhemoglobin (10(-5) M) abolished the vasodilation and enhanced the vasoconstriction by AVP. Therefore, under pathological conditions in which NO function was suppressed, such endogenous substances may produce contraction in parenchymal arterioles instead of dilation with aggravation of cerebral ischemia. PMID- 7836690 TI - Nitric oxide is not the sole determinant of hypercapnic or metabolically driven vasodilation in the cerebral circulation. AB - Nitric oxide (NO) has recently been suggested to play a major role in a number of circulatory responses both within and outside the central nervous system. It has been linked to hypercapnic vasodilatation, metabolically driven changes in cerebral blood flow and hypoxia-induced changes in brain blood flow. In the studies the question of role of NO in hypercapnic vasodilatation and metabolically driven changes in flow is examined in the cat. Animals were anaesthetised with halothane and alpha-chloralose and ventilated. Cardiorespiratory parameters were monitored and kept within normal limits. Cerebral blood flow was monitored with laser Doppler flowmetry (CBFLDF) in the parietal cortex which metabolic activity was contemporaneously and continuously monitored using electrophysiological techniques. Hypercapnia was induced by increasing the end-expiratory CO2 to 8.1 +/- 0.4% and this produced a brisk rise in CBFLDF of 153 +/- 23%. Metabolic activity was increased by superfusion of the cortical surface with bicuculline (10 pmol) which increased cell firing and CBFLDF. Local administration of NG-nitro-L-arginine methyl ester (L-NAME) did affect the metabolically driven change in CBFLDF and only attenuated by 20% overall the hypercapnic vasodilator response. These studies suggest that at least in the anaesthetised cat NO does not play the pivotal role in these important vasodilator functions. PMID- 7836692 TI - Influence of cerebrovascular parasympathetic nerves on resting cerebral blood flow, spontaneous vasomotion, autoregulation, hypercapnic vasodilation and sympathetic vasoconstriction. AB - Activation of perivascular parasympathetic nerves enhances cerebral blood flow. In the present experiments, functional aspects of this flow regulating capacity were investigated. It was found that parasympathetic nerve stimulation does not facilitate the normalization of the cerebral blood flow reduced by sympathetic stimulation. In contrast, activation of sympathetic nerves may contribute to a rapid normalization of the cerebral blood flow increased by parasympathetic stimulation. The lower limit of cerebral autoregulation is shifted towards higher blood pressures in parasympathetically denervated rats. Parasympathetic nerves do not influence hypercapnic cerebral vasodilatation, but CO2 influence the effect of parasympathetic stimulation on cerebral blood flow. We conclude that activity in parasympathetic nerves does not contribute to cerebral vasomotion. PMID- 7836691 TI - Dysfunction of nitric oxide in the spastic basilar arteries after subarachnoid hemorrhage. AB - The function of nitric oxide in spastic cerebral arteries after subarachnoid hemorrhage (SAH) was angiographically investigated in dogs. On days 4 and 7, after two intracisternal injections of autologous blood, higher concentrations of L-arginine than those of endogenous L-arginine in the cerebrospinal fluid produced a transient vasodilation of the spastic basilar artery, whereas NG monomethyl-L-arginine (L-NMMA) produced no significant vasoconstriction. The vasodilator effect of L-arginine after SAH was stronger on day 4 than day 7, but less than that in intact dogs. Vasopressin, which is known to activate the endothelial L-arginine pathway, could induce a vasodilation only after the treatment with L-arginine. Intracisternal injection of superoxide dismutase (SOD), which caused no effect by itself, enhanced the duration of the vasodilator effect of L-arginine on the basilar artery on day 4 and both the magnitude and duration of that effect on day 7. Thus, the basal release of nitric oxide was impaired after SAH, but the ability to synthesize nitric oxide in the vascular wall was not abolished. Enhancement of L-arginine's effect by SOD suggested that the inactivation of nitric oxide by superoxide anion contributed to the development of vasospasm. PMID- 7836693 TI - Innervation of the human cerebral circulation. PMID- 7836694 TI - Vasoactive intestinal peptide (VIP) like peptides in the cerebral circulation of the cat. AB - The present study was designed to study the localization and effects of some VIP related peptides on the cerebral circulation in cats. A rich supply of nerve fibres containing vasoactive intestinal peptide- (VIP) was seen. Nerve fibres containing pituitary adenylate cyclase activating peptide and helospectin-like immunoreactivity (-IR) were moderate in numbers whereas only a sparse supply of fibres containing helodermin-IR was seen. Double immunostaining revealed that the majority of PACAP- and helospectin-IR nerve fibres contained VIP. Using a sensitive in vitro system prostaglandin F2 alpha-precontracted circular segments of the cat middle cerebral artery relaxed upon administration of VIP, PACAP, helospectin I, helospectin II and helodermin. These effects were non-endothelium dependent with pD2-values varying between 7.6 and 8.1. The maximum relaxation varied between 47% and 79% of precontraction. Local cerebral blood flow was studied in anaesthetised cats. Cortical injection of PACAP-38, helospectin or helodermin, 5 micrograms in a volume of 1 microliter, revealed moderate and consistent increases in flow. The increase in cerebral blood flow was rapid and concentration-dependent with maximum increases of 18 +/- 6% for PACAP, 21 +/- 5% for helodermin, 16 +/- 7% for helospectin I and 19 +/- 5% for helospectin II. The vehicle caused no significant response (2 +/- 4%). PMID- 7836695 TI - D-propoxyphene and norpropoxyphene kinetics after the oral administration of D propoxyphene: a new approach to liver function? AB - In an attempt to design a liver function test which takes into account both portal-systemic shunting and hepatocellular dysfunction, we investigated a group of patients with cirrhosis with or without surgical porta-caval shunt for d propoxyphene and its major metabolite, norpropoxyphene kinetics. A small dose of d-propoxyphene (0.7 mg/kg body weight) was given orally to seven normal subjects, 15 patients with cirrhosis and seven patients with cirrhosis and surgical portacaval shunt. D-propoxyphene and norpropoxyphene areas under the plasma concentration-time from 0 to 4-h (AUC) were determined by the trapezoidal method. As d-propoxyphene is a high extraction drug and since the production of norpropoxyphene should reflect the amount of d-propoxyphene available to the hepatocytes, we tested the hypothesis that norpropoxyphene/d-propoxyphene AUC ratios should reflect both the degree of portal-systemic shunting and the severity of hepatocyte dysfunction. Norpropoxyphene/d-propoxyphene AUC ratios were significantly lower in patients with cirrhosis (mean +/- S.D.: 0.92 +/- 0.59) than in controls (2.51 +/- 0.45) and also significantly lower in patients with cirrhosis and a surgical shunt (0.53 +/- 0.23) than in patients with cirrhosis but without surgical shunt (1.10 +/- 0.63). Moreover, there was an overall statistically significant correlation between norpropoxyphene/d propoxyphene AUC ratios and branched to aromatic amino acids ratios (rs = 0.91) and fasting venous NH4 (rs = -0.63). On the other hand, there was only a weak correlation between norpropoxyphene/d-propoxyphene AUC ratios and the 14C aminopyrine breath test (rs = 0.43). These data suggest that the norpropoxyphene/d-propoxyphene AUC ratio reflects both shunting and reduced hepatocellular function.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836696 TI - Fibrogenic and collagenolytic activity in carbon-tetrachloride-injured rats: beneficial effects of zinc administration. AB - Collagen synthesis and degradation in normal and carbon-tetrachloride-injured male Wistar rats at early and late stages of liver fibrosis, and the potential beneficial effects of zinc supplementation on liver fibrogenesis and collagenolysis have been assessed by measuring hepatic collagen content and prolyl hydroxylase and collagenase activities. No significant changes in hepatic collagen and prolyl hydroxylase activities were observed between control rats (82 +/- 25 cpm/mg protein) and rats with induced cirrhosis (107 +/- 23 cpm/mg protein) after 4 weeks of carbon tetrachloride injury. By this time, hepatic collagenase activity was significantly lower in rats with induced cirrhosis (61 +/- 9 micro units/mg protein) than in control rats (133 +/- 31 micro units/mg protein) (p < 0.05). This result was prevented by zinc administration, since hepatic collagenase activity was similar in zinc-supplemented, carbon tetrachloride-injured rats and normal rats (148 +/- 19 micromicrons/mg protein). After 16 weeks, all carbon-tetrachloride-injured rats had cirrhosis. Hepatic collagen content and prolyl hydroxylase activity were significantly higher in carbon-tetrachloride-injured rats than in controls. These effects were partially prevented by zinc administration, since only two of the seven zinc-supplemented, carbon-tetrachloride-injured rats had cirrhosis. Moreover, prolyl hydroxylase activity was significantly lower in zinc-supplemented injured rats (263 +/- 27 cpm/mg protein) than in the non-supplemented respective controls (389 +/- 52 cpm/mg protein) (p < 0.05). No significant changes in hepatic collagenase activity were observed at this stage of liver injury.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836697 TI - Muscle ammonia and glutamine exchange during chronic liver insufficiency in the rat. AB - The aim of this study was to investigate the role of skeletal muscle in ammonia and glutamine metabolism during chronic hyperammonemia induced by liver insufficiency. The hindquarter ammonia and amino acid fluxes and muscle tissue concentrations were studied in two rat models of chronic liver insufficiency, portacaval shunting and portacaval shunting plus bile-duct ligation, as well as in sham-operated animals, 7 and 14 days after surgery, and in normal, unoperated rats. To reduce nutritional influences, portacaval-shunted rats and sham-operated rats were pair-fed to portacaval shunt biliary obstruction rats. Arterial ammonia levels were elevated in both liver insufficiency groups. In the portacaval shunting plus bile-duct ligation group, arterial glutamine levels were elevated compared with sham-operated controls. No net hind-quarter ammonia uptake was observed in any of the groups, despite hyperammonemia in the chronic liver insufficiency groups. Hindquarter glutamine release was always increased in the liver insufficiency groups compared with sham-operated controls, despite similar muscle glutamine levels in the sham-operated and hyperammonemic groups, suggesting enhanced muscle glutamine synthesis in the latter groups. Muscle ammonia levels were always increased and muscle glutamate decreased in the hyperammonemic groups, probably indicating glutamate consumption by enhanced glutamine synthesis. The increased phenylalanine tissue concentrations and efflux in portacaval shunt/biliary obstruction rats suggest that enhanced net muscle protein breakdown, amino acid catabolism and transamination, rather than ammonia uptake from the blood furnish amino acids and ammonia for enhanced glutamine synthesis. These experiments suggest that nutritional factors are important in explaining altered muscle metabolism during chronic liver insufficiency. PMID- 7836698 TI - Effect of ethanol on hepatobiliary transport of cationic drugs. A study in the isolated perfused rat liver, rat hepatocytes and rat mitochondria. AB - The effect of ethanol on the hepatic uptake of various cationic drugs was studied in isolated perfused rat livers, isolated rat hepatocytes and isolated rat liver mitochondria. In isolated rat hepatocytes and in isolated perfused rat livers, the uptake of the model organic cation tri-n-butylmethylammonium was found to be markedly stimulated by ethanol in a concentration-dependent fashion. The uptake of tri-n-butylmethylammonium at 1 microM was increased to 120% and 137% at 0.5% (v/v, (= 87 mM)) and 1% (v/v. (= 174 mM)) ethanol, respectively. At 25 microM, tri-n-butylmethylammonium uptake was increased to 124% and 152% at 0.5% (v/v) and 1% (v/v) of ethanol, respectively. The uptake of the organic cations azidoprocainamide methoiodide, vecuronium, ORG 9426 and ORG 6368, the anionic compound taurocholate and the uncharged compound ouabain was not markedly increased at these ethanol concentrations. The mechanism of action of ethanol on the uptake of tri-n-butylmethylammonium was further studied. Competitive inhibitors for the type I organic cation uptake system, procainamide ethobromide and verapamil, almost completely blocked uptake of tri-n-butylmethylammonium (1 microM) in the presence of 1% (v/v) ethanol, indicating that carrier-mediated uptake is still involved and that additional passive diffusion is unlikely. Neither the plasma membrane potential nor the accumulation of the cation in mitochondria was altered after ethanol treatment, suggesting that potential driving forces for uptake and sequestration were not affected.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836699 TI - Nutritional status in cirrhosis. Italian Multicentre Cooperative Project on Nutrition in Liver Cirrhosis. AB - Malnutrition frequently occurs in patients with chronic liver disease and may represent a risk factor influencing both short- and long-term survival in these patients. Previously published studies have tended to be confined to alcoholic patients and there are few data on the prevalence of nutritional abnormalities in patients with cirrhosis not of alcoholic origin. Anthropometric measurements and a clinical evaluation of the nutritional status of 1402 patients with cirrhosis (883 males and 519 females) were recorded between January 1988 and 1989 by the Italian Multicentre Cooperative project on Nutrition in Liver Cirrhosis. The origin of liver disease was alcohol-related in 37% of patients. Child-Pugh criteria were used to establish the severity of the liver disease. Patients with cirrhosis exhibited a wide range of nutritional abnormalities. While 29% of females and 18% of males appeared to be overnourished, a significant reduction in fat stores, as estimated by the mid-arm fat area, and/or muscle mass, as estimated by mid-arm muscle area, was observed in 30% of patients with cirrhosis. The prevalence of signs of nutritional depletion increased in both sexes as liver function deteriorated. Mean values for mid-arm fat area decreased by 30% in males and by 40% in females with moderate to severe liver failure (Child-Pugh Classes B and C). The reduction in mid-arm muscle area was more evident in males (17% decrease) than in females (9% decrease). Patients with alcohol-related cirrhosis showed a higher prevalence of malnutrition and had more frequent severe liver impairment (Child-Pugh Classes B and C).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836700 TI - Clinical significance of esophageal variceal pressure in patients with esophageal varices. AB - In 40 patients with esophageal varices, esophageal variceal pressure was assessed endoscopically using a pneumatic pressure sensor. The effects of vasopressin or nitroglycerin on variceal pressure and endoscopic findings were also assessed in two groups of seven patients. The results were as follows: (1) Variceal pressure was increased above 250 mmH2O in all patients who had bled, and the mean variceal pressure was significantly higher in patients who had bled than in those who had not (301 +/- 47 vs. 230 +/- 58 mmH2O respectively, p < 0.001). (2) Variceal pressure correlated with endoscopic findings, determined using the criteria of the Japanese Research Society for Portal Hypertension. It was significantly higher when varices with a feature of F2-F3 or RC(+2)-RC(+3) were compared to those with a feature of F1 or RC(-)-RC(+), respectively. (3) Both groups given vasopressin or nitroglycerin had significant reductions in variceal pressure; however, there was little improvement in endoscopic findings in those given nitroglycerin, compared to the improvement in those given vasopressin. Thus, use of a pneumatic pressure sensor proved to be a pertinent tool for assessing esophageal varices, along with endoscopic signs. PMID- 7836701 TI - Insulin secretion in pancreatic islets from rats with cirrhosis. AB - Cirrhosis was induced in rats by subcutaneous injections of CCl4 for 13 or 17 weeks. The morphology of the pancreatic islets from the CCl4-treated rats was found to be normal. The CCl4-treated rats had lower fasting serum glucose levels and higher serum insulin levels than the controls. After an oral glucose load (3 g/kg body weight), glucose levels in CCl4-treated rats stayed within the normal range, whereas the serum insulin levels remained higher with a delayed decline of insulin with time. In vitro perifusion of islets from the CCl4-treated rats showed that the response to 16.7 mmol/l glucose was reduced with both lower total insulin output and stimulated insulin output, whereas the patterns of first and second phase of insulin release did not differ. The insulin content of the perifused islets was not affected by 13 weeks of CCl4 treatment. Islets from rats treated with CCl4 for 17 weeks showed normal secretory response to 20 mmol/l L arginine. Taken together, the results, showing normal or reduced capacity for insulin secretion, suggest that the hyperinsulinemia accompanying CCl4-induced cirrhosis is not due to increased secretion of the pancreatic islets. It may rather be associated with decreased insulin degradation by the liver with cirrhosis. PMID- 7836702 TI - The influence of cold ischemia time on biliary complications following liver transplantation. AB - Biliary complications are a continuing source of morbidity and mortality following orthotopic liver transplantation. The results of 100 whole-liver allografts performed in 92 adult patients were reviewed to determine whether cold ischemia time and preservation injury influenced both the incidence and type of biliary complications. Mean cold ischemia time was 10.2 +/- 0.5 h (range 3.6-19). Eighteen patients (19.6%) developed 25 biliary complications: there were eight anastomotic leaks, eight anastomotic strictures, six non-anastomotic strictures, two cystic duct mucoceles, and one biliary fistula following T-tube removal. Despite the high rate of reoperative surgery (68%), no death was attributable to biliary complications. Neither cold ischemia time nor early graft function influenced the rate of biliary complications or strictures of either type. Furthermore, an analysis of different factors revealed no predisposing effect of the pre-operative status of the recipient, type of biliary reconstruction, blood requirement, vascular complications, rejection or cytomegalovirus infection on the incidence of biliary complications or strictures. Only chronic rejection could be singled out as a risk factor for non-anastomotic strictures (p = 0.05). These results suggest that prolonged cold ischemia time does not seem to affect the rate or type of biliary complications following orthotopic liver transplantation. In view of these data, there is no clear reason to reconsider prolonged cold ischemia up to 15 h in University of Wisconsin solution, as it has transformed liver transplantation from an emergency operation to a semi-elective procedure and allows longer back-table preparation for graft reduction of splitting. PMID- 7836703 TI - Indirect evidence to suggest that prolactin induces salt retention in cirrhosis. AB - Prolactin is known to have renal sodium retention properties in animals. In man, only two studies have suggested a similar effect in healthy volunteers or in patients with microprolactinoma. Since hyperprolactinemia is frequently observed in liver disease, this prospective study of 19 patients evaluated the influence of prolactin on urinary electrolytes excretion in cirrhosis. Basal hyperprolactinemia was found in 14 out of 19 cases. The effect of serum prolactin elevation on renal sodium and potassium excretion was studied in all patients after thyrotropin-releasing hormone stimulation (200 micrograms), with seven consecutive hourly urinary samples. Patients were separated into two groups according to amount of prolactin discharge after thyrotropin-releasing hormone injection. Group I included patients with "low prolactin release", defined as the difference between basal and peak prolactin values (delta prolactin) < 1000 mu u/ml (n = 8), and no change in natriuresis could be observed. In contrast, in group II with a "high PRL release" (delta prolactin > 1000 mu u/ml, n = 11), significant reductions in urinary sodium (p < 0.01) and potassium (p < 0.02) excretion were observed, which lasted until the third hour after thyrotropin releasing hormone injection. A significant correlation was found between peak prolactin values and the decrements of natriuresis (r = 0.70, p < 0.02). The pattern of urinary electrolyte changes and the stability of the ratio UK/UK+Na suggest a possible sodium-retaining effect of prolactin localized proximally to the distal tubule. PMID- 7836704 TI - Analysis of hepatitis B precore region in serum and liver of chronic hepatitis B virus carriers. AB - Using an oligonucleotide hybridization assay we studied the prevalence of wild type and the predominant pre-core mutant hepatitis B virus in serum and liver of 49 antibody to hepatitis B e antigen carriers and three hepatitis B e antigen positive patients. Of the 45 serum samples from the anti-HBe carriers analyzed (no serum sample was available in four patients), 36 (80%) had hepatitis B virus DNA. In 26 of these 36 patients (72%) a mixed population was detected, wild-type genome alone was found in six patients (16%), the single mutant (nucleotide position 1896), in three cases (8%) and in one patient (2%) the viral DNA had the two nucleotide mutation (1896 and 1899). Of the liver biopsies from the 36 anti HBe patients studied (no liver biopsy was available in 13 patients), 33 (92%) had hepatitis B virus DNA. A mixed viral population was detected in 23 patients (69%), only wild-type virus or a single mutation was found in eight (34%) and two patients (8%), respectively. In all cases, wild-type was the predominant genome. In serum and liver samples from the same patient, we found a concordance of the presence of wild-type HBV and the pre-core mutants studied in 23/26 (88%) of the patients. Alanine aminotransferase levels were higher (p < 0.01) and the duration of hepatitis B surface antigen carrier lower (p < 0.02) in patients with a predominance of precore mutant in comparison to wild-type.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836705 TI - A randomized controlled trial of thymopentin therapy in patients with chronic hepatitis B. AB - Strategies of treatment of chronic hepatitis type B are currently based on the use of either antiviral or immunomodulatory agents. A randomized, controlled trial was performed to assess the safety and efficacy of 6-month thymopentin therapy in 30 patients with chronic hepatitis B. Inclusion criteria were biopsy proven chronic hepatitis, elevated alanine aminotransferase and serum HBsAg and HBV-DNA positivity for at least 12 months. At the conclusion of the study (1 year), HBV-DNA was negative and alanine aminotransferase had normalized in 13% and 20% of treated cases and in 20% and 27% of controls. None of the ten treated and one of the nine control patients who were initially HBeAg positive subsequently cleared HBeAg. None became HBsAg negative. A histologic improvement was noted in 27% of the treated patients compared with 18% of controls. These results indicate that this regimen of thymopentin therapy is not effective in treating chronic hepatitis B. PMID- 7836706 TI - Optimized analysis of recurrent bleeding and death in patients with cirrhosis and esophageal varices. Copenhagen Esophageal Varices Sclerotherapy Project. AB - The course of cirrhosis after the first episode of variceal bleeding is characterized by recurrent episodes of bleeding and bleeding-free periods, with each new stage being associated with an initially high mortality rate. Analysis of the course of this disease is usually based on traditional survival models measuring observation time from admission to hospital. This approach cannot provide valid answers to the following clinically relevant questions: 1) what is the risk of death while bleeding? 2) what is the risk of continuing bleeding? 3) what is the risk of death after bleeding has stopped? 4) what is the risk of a new bleeding episode among those who remain alive and do not bleed? and 5) do the answers to the former four questions depend on the number of previous bleeding episodes or on the time since the first episode? These questions may be addressed using the multistage, competing risks model presented here. By measuring time from the start of each new bleeding or bleeding-free period, this model synchronizes the patients with respect to disease development and, hence, to level of the rate of new clinical events. This reduces the heterogeneity of risk levels in the patient group at any given time. In an analysis of 94 patients with cirrhosis admitted for their first episode of variceal bleeding, we estimated the mortality rates during bleeding and without current bleeding, the rate of cessation of bleeding and the rate of rebleeding. The influence of number of previous rebleedings and of the time since the first bleeding was examined using a Cox regression model for competing risks.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836707 TI - Thrombocytopenia of chronic liver disease corrected by erythropoietin treatment. AB - To investigate the possibility of correcting thrombocytopenia of chronic liver disease, 19 patients (6 male and 13 female) with long-term chronic liver disease and platelet count < or = 85,000/microliters were studied. Either a short-term course (7-20 days) of recombinant human erythropoietin, 4000 U daily SQ (12 patients) or placebo (7 patients) was administered. Treatment was interrupted if the platelets rose to > or = 100,000/microliters or if no significant increase was noted after 14 days. After treatment, platelets increased in the recombinant human erythropoietin group (from a baseline value of 70,000 +/- 11,184 to 101,250 +/- 37,625/microliters), while no difference was noted in the placebo group (70,714 +/- 9928 vs 70,000 +/- 10,231/microliters). The increase in the platelet count in the recombinant human erythropoietin group was significant, both compared to baseline values (paired Student's t-test, t = -3.80, p < 0.005) and to the results of treatment in the placebo group (unpaired Student's t-test, t = 2.71, p < 0.02). Eight out of 12 recombinant human erythropoietin-treated patients (66%) reached > or = 100,000/microliters platelets while four (33%) did not. In comparison to responders, non-responders had a significantly lower baseline platelet count (58,500 +/- 7937 vs 75,750 +/- 7498/microliters, t = 3.69, p = 0.004) and failed more frequently than responders to improve their haematocrit in response to recombinant human erythropoietin (Pearson chi 2 = 4.687, p = 0.03). When treatment was discontinued, the platelet count reverted to baseline in a few weeks. In conclusion, recombinant human erythropoietin treatment transiently corrected mild thrombocytopenia in patients with chronic liver disease.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836708 TI - Effects of insulin and glucose on urea synthesis in normal man, independent of pancreatic hormone secretion. AB - We investigated the inhibitory effect of insulin and glucose on hepatic amino- to urea-nitrogen conversion independent of endogenous insulin and glucagon secretion. Alanine-stimulated urea synthesis kinetics, as quantified by functional hepatic nitrogen clearance, i.e. the slope of the linear relation between blood alpha-amino nitrogen concentration and urea synthesis rate, were measured four times in each of six healthy volunteers, namely during spontaneous hormone responses, and during hormonal control by somatostatin and maintenance of basal hormone levels and euglycaemia, hyperinsulinaemia (85 +/- 8 mU/l), or hyperglycaemia (8.4 +/- 0.5 mmol/l). Hormonal control and euglycaemia reduced functional hepatic nitrogen clearance (mean +/- SD) by two-thirds (from 32.9 +/- 5.2 l/h to 12.2 +/- 3.4 l/h, p < 0.01). Hyperinsulinaemia did not change this (13.2 +/- 2.8 l/h), whereas hyperglycaemia further reduced functional hepatic nitrogen clearance by 40% to 7.4 +/- 1.3 l/h (p < 0.01). The reduction by hormonal control and euglycaemia is attributable to the abolition of the glucagon response to alanine infusion, as glucagon is known to up-regulate functional hepatic nitrogen clearance. Insulin did not regulate hepatic amino- to urea nitrogen conversion, implying that the effect of insulin on urea production is due to its effect on blood amino acid supply to the liver. In contrast, glucose in itself reduced hepatic amino nitrogen conversion, independent of the hormonal responses to glucose. This means that the hepatic component of the amino-N sparing effect of glucose depends on hyperglycaemia but not on hyperinsulinaemia. PMID- 7836709 TI - Absence of association between HLA antigens and chronicity of viral hepatitis in haemodialyzed patients. AB - The role of HLA antigens in the chronicity of viral hepatitis is still being debated. We analyzed the relation between HLA status and viral hepatitis in 558 consecutive haemodialyzed patients who underwent kidney transplantation. HLA A, B, DR status, ABO-Rh blood group, duration of haemodialysis, and number of blood units transfused during the dialysis period were known for all patients. Serological status for hepatitis B virus and hepatitis C virus and results of liver biopsies were available in 495, 300 and 316 patients, respectively. After correction for the number of tests performed, frequencies of HLA antigens did not differ significantly for: 1. hepatitis B virus infection (compared to HBsAg positive and anti-HBc and/or anti-HBs-positive nonvaccinated patients); 2. hepatitis C virus infection (compared to anti-HCV-negative and -positive patients); 3. histopathological status (compared to patients who had chronic viral hepatitis and those who did not). These results suggest that there is no evidence for a significant role of a particular HLA antigen in the development of chronic viral hepatitis in haemodialysis patients with similar underlying immunosuppression and exposure to infection by hepatotropic viruses. PMID- 7836710 TI - Alcohol in combination with malnutrition causes increased liver fibrosis in rats. AB - Rats were malnourished for 12 months with a highly inadequate fat-rich, calorie sufficient but otherwise poly-deficient liquid diet composed of mashed potatoes with mayonnaise, comparable with the nutritional intake of many chronic alcoholics. When alcohol was incorporated into this diet, administered as whisky in drinking water available ad libitum, the livers of all eight rats showed increased fibrosis and cirrhosis as compared to the livers of the eight non alcohol-treated, isocalorically fed, paired control rats. Alcohol-treated rats developed fibrosis and cirrhosis on a dietary fat content of 38% of total caloric intake and low blood alcohol levels, ranging from 50 to 126 mg/dl, due to gradual intake over the day and to low absolute intake (mean 11.9 +/- 0.6 g/kg per day). None of the rats died spontaneously. Malnutrition is likely to be an important factor in the development of the fibrosis of alcoholic liver disease, and this rat model may be used to study aspects of the pathogenesis. PMID- 7836711 TI - The influence of cyclosporine A therapy on sex hormone levels in pre- and post menopausal women with primary biliary cirrhosis. AB - The mechanism underlying sex hormone disturbances in post-menopausal women with primary biliary cirrhosis is unclear, but these alterations may occur as a consequence of liver disease. As cyclosporine may have some therapeutic potential is this condition, we have evaluated short-term alterations in plasma sex hormone levels in 11 pre- and 19 post-menopausal women with primary biliary cirrhosis following randomisation to cyclosporine A or placebo therapy. Baseline sex hormone binding globulin levels were markedly depressed in all pre-menopausal women but were elevated for the post-menopausal group when compared to standard reference ranges. Testosterone and dihydrotestosterone levels were low or markedly depressed in both patient groups. Androstendione concentrations tended to be higher than the normal range in the post-menopausal group. Oestradiol levels were within the normal range for the pre-menopausal group but were relatively higher in the post-menopausal group than in other normal post menopausal women. Cyclosporine A therapy resulted in significant decreases in sex hormone binding globulin levels (26.6 +/- 5.0 to 16.2 +/- 4.6 nmol/l; p < 0.05) in the premenopausal group and reduction in total (336 +/- 163 to 140 +/- 132 pmol/l; p < 0.01) and free (6 +/- 5 to 2 +/- 3 pmol/l; p < 0.05) oestradiol levels in the post-menopausal group at 6 months. There were no significant alterations in other hormonal parameters. No temporal changes occurred in the placebo group. Cyclosporine A therefore induces significant but variable sex hormone changes in both pre- and post-menopausal women with primary biliary cirrhosis. PMID- 7836712 TI - Change in size, shape and radiocolloid uptake of the alcoholic liver during alcohol withdrawal, as demonstrated by single photon emission computed tomography. AB - The volume of the total liver and separate right and left lobes was studied before and after 1 week of alcohol withdrawal in 16 consecutive alcoholics by means of single photon emission computed tomography after intravenous injection of 99Tcm-human albumin colloid; the relative tissue distribution of radioactivity was also followed. The left liver lobe increased in volume more than the right lobe during drinking and decreased more rapidly after alcohol withdrawal. Median volume reductions during 1 week of alcohol withdrawal were: total liver 12%, left lobe 26%, and right lobe 8%, indicating that half of the reduction to values of a control group was achieved during this first week. The volume of the right but not of the left lobe was significantly correlated to body size in alcoholics and in controls. The left lobe had a lower capacity to concentrate the radiocolloid than the right lobe in alcoholics and in controls. The liver/spleen, liver/bone marrow and liver/background radioactivity concentration ratios in the alcoholics increased during alcohol withdrawal. We conclude that heavy drinking causes both an increased total liver volume and a change in liver shape, with a relatively more enlarged left than right lobe, as well as a decreased capacity to concentrate radiocolloid. These changes are rapidly reversible during abstinence from alcohol. PMID- 7836713 TI - Effects of octreotide on postprandial systemic and hepatic hemodynamics in patients with postnecrotic cirrhosis. AB - The effects of octreotide on postprandial hemodynamic responses were evaluated in 20 patients with postnecrotic cirrhosis. They were randomly assigned to receive either a 100-micrograms bolus with a 100-micrograms/h infusion of octreotide or a placebo. Placebo administration did not affect any of the hemodynamic values. However, after a liquid meal of 500 kcal, postprandial increases in the hepatic venous pressure gradient and hepatic blood flow were observed in patients receiving placebo, while the systemic hemodynamic values remained unchanged. In contrast, in patients receiving octreotide, the hepatic blood flow was significantly decreased 30 min after administration, while the hepatic venous pressure gradient and the systemic hemodynamic values were not affected. After ingestion of a meal, the mean values of the hepatic blood flows were not significantly different from basal values. Moreover, the wedged hepatic venous pressure, the hepatic venous pressure gradient and the systemic hemodynamic values were not affected by meal ingestion. However, during octreotide infusion, hepatic blood flow 30 min after the meal had a tendency to increase compared to before the meal. In conclusion, octreotide inhibited the postprandial increase in portal pressure in patients with postnecrotic cirrhosis. In addition, octreotide decreased hepatic blood flow in the fasting state. When given before a meal, the increase in blood flow induced by the meal restored the hepatic blood flow to basal levels. PMID- 7836714 TI - Gallbladder motor function in gallstone patients: sonographic and in vitro studies on the role of gallstones, smooth muscle function and gallbladder wall inflammation. AB - Gallbladder motility was studied by ultrasound in 100 healthy adult volunteers and 150 gallstone patients, in a subgroup of whom gallstone burden, type and number, gallbladder histology and tensiometric responses of gallbladder strips to cholecystokinin octapeptide were evaluated. Patients were divided into contractors (n = 108) and hypocontractors (n = 42), according to their gallbladder motility pattern in vivo. Contractors showed slower gallbladder emptying and increased fasting and postprandial residual volumes, although the ejected amount of bile was greater than that of controls (20.2 +/- SEM 1.1 vs 16.0 +/- 0.7 ml; p < 0.001). In contrast, hypocontractors exhibited slower and less complete gallbladder emptying than controls with a reduction in the absolute amount of ejected bile. Although gallbladder wall inflammation was mild and comparable in specimens from both groups of patients, the thickness of the muscular layer was greater in hypocontractors than in contractors (1073 +/- 76 vs 745 +/- 75 microns, p < 0.01) and related inversely to postprandial ejected volume (r = -0.42; p < 0.03; n = 32) but positively to gallstone volume (r = 0.40; p < 0.03; n = 32). Compared to contractors, gall-bladder muscle strips of hypocontractors exhibited a decrease in frequency and amplitude of spontaneous contraction and in maximal stress and receptor sensitivity to cholecystokinin octapeptide (0.1 nM-1 microM). Postprandial gallbladder evaculation was unaffected by stone number, and by the presence or absence of stone calcification. Gallstone volume was larger in hypocontractors (19.4 +/- 3.0 ml vs 9.6 +/- 0.9 ml, p < 0.001) than contractors. The comparison of in vitro contractility patterns between cholesterol, mixed and pigment stone patients showed a more severe defect in patients with cholesterol and mixed stones than in those with pigment calculi. In conclusion, in gallstone patients: (i) gallbladder motor dysfunction manifests mainly with increased fasting and postprandial residual volumes in contractors and with markedly increased postprandial residual volumes and decreased gallbladder emptying in hypocontractors; (ii) gallbladder kinetics seem to be influenced by stone volume and cholesterol content of calculi but not stone number, calcification or mild chronic cholecystitis; (iii) a form of hypertrophic leiomyopathy is observed in gallstone patients with the most impaired gallbladder motor function. PMID- 7836715 TI - Etiopathogenesis and prognosis of centrilobular necrosis in hepatic grafts. AB - The incidence, contributing etiopathogenetic factors, and prognostic significance of centrilobular necrosis were investigated in 270 hepatic transplants to 215 immunosuppressed patients in whom 837 biopsies were performed. Twenty-six (9.6%) grafts demonstrated centrilobular necrosis in one or more biopsy specimens. The immunological, clinical, histopathological, and evolutionary features of this patient group (group A) were compared with a control group of patients who had undergone 92 consecutive transplants with no necrosis (group B). Group A was younger (p < 0.01), had a higher average of warm and cold-ischemia time (p < 0.05), a higher incidence (p < 0.001) and earlier appearance of acute rejection episodes (p < 0.01), and a closer association with evolution to chronic rejection (A: 53.8% vs B: 13.1%, p < 0.001). Survival rates for grafts and patients with necrosis at 12 and 30 months were significantly lower (p < 0.001). The 26 grafts were distributed into three chronological subgroups according to when necrosis appeared: (1) First week--All these grafts were lost (four through primary graft nonfunction and one due to protal recurrent thrombosis); (2) Second week--seven grafts with associated acute rejection, with three evolving to chronic rejection; (3) After the second week (116 +/- 82 days)--five with isolated necrosis, two with associated acute rejection, four with associated ductopenia, and three with associated acute rejection and ductopenia. In 11 grafts the necrosis persisted and evolved to chronic rejection. In conclusion, these findings indicate that centrilobular necrosis is a histopathological sign associated with poor prognosis in most hepatic grafts.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836716 TI - Drug-induced hepatitis: a rare complication of oral anticoagulants. AB - Hepatotoxicity is a rare complication of coumarin anticoagulants. We present the case of a 56-year-old woman who developed a viral-hepatitis-like picture 8 months after mitral valve replacement and oral anticoagulation. Phenprocoumon-induced hepatitis was diagnosed after positive reexposure and improvement following withdrawal of the drug. There appeared to be cross-reactivity to warfarin since this drug led to a similar increase in alkaline phosphatase and gamma-glutamyl transferase after a few days of administration. Liver biopsy showed an acute viral-hepatitis-like picture. Anticoagulation was changed to a subcutaneous low molecular weight heparin and low-dose aspirin. Because of the widespread use of coumarin anticoagulants, physicians should be aware of the hepatotoxic potential of these drugs, which most frequently mimics the clinical presentation of viral hepatitis. PMID- 7836717 TI - Increasing serum creatinine and age reduce the response to hepatitis B vaccine in renal failure patients. AB - The relationship between diminished response to hepatitis B vaccine in renal failure patients and serum creatinine level, age and other factors is unknown. The immune response of patients with renal failure of varying severity to hepatitis B vaccine was determined in this study. Sixty-eight patients with renal failure of varying severity who were negative for hepatitis B markers received four doses of hepatitis B vaccine, and anti-HBs titers were determined at 0, 1, 2, 3, 6, 8 and 12 months. Maximum anti-HBs titers were seen at 8 months. At this time 86% of patients with creatinine < or = 4 mg/dl but only 37% with creatinine > 4.0 mg/dl had a protective titer of > or = 10 mIU/ml (p < 0.002). Age was inversely related to anti-HBs titer (p = 0.045) and was independent of serum creatinine in predicting antibody response. We conclude that all patients with chronic renal failure should be immunized against hepatitis B as early as possible in the development of their disease, to ensure maximum response, and to minimize the effects of elevated serum creatinine and increasing age. PMID- 7836718 TI - Hepatitis C virus transmission by intravenous immunoglobulin. AB - The polymerase chain reaction was used to detect hepatitis C virus infection in patients who had previously been reported to have developed non-A, non-B hepatitis after intravenous immunoglobulin infusion. Of the 33 patients with intravenous immunoglobulin associated non-A, non-B hepatitis studied, HCV RNA could be detected in 15 out of 17 patients (88%) who were HCV RNA negative prior to the development of non-A, non-B hepatitis after implicated intravenous immunoglobulin batches. Similarly, eight out of nine patients (89%) in whom no sample was available for polymerase chain reaction testing prior to intravenous immunoglobulin therapy, had detectable HCV RNA after intravenous immunoglobulin therapy with intravenous immunoglobulin batches implicated in non-A, non-B hepatitis transmission. Two of the three intravenous immunoglobulin preparations implicated in non-A, non-B hepatitis transmissions that were available for polymerase chain reaction testing also had detectable HCV RNA, confirming that hepatitis C virus is the implicated virus in intravenous immunoglobulin associated non-A, non-B hepatitis. PMID- 7836719 TI - Gastric endoscopic features in portal hypertension: final report of a consensus conference, Milan, Italy, September 19, 1992. PMID- 7836721 TI - Optic tract neuropathy complicating low-dose interferon treatment. AB - Optic neuritis occurred in three of our patients receiving treatment with alpha interferon-2b (Intron-A; 3MU thrice weekly) for chronic hepatitis. The complication appeared within, 1, 9 1/2 and 10 months of treatment, respectively. In all cases, blurred vision was the initial complaint and subsequent electrophysiologic investigation confirmed the presence of optic tract neuropathy. The patients had no other neurologic signs. Computerized tomography and magnetic resonance image of the brain were not remarkable. Psychiatric symptoms, in the form of an interferon-associated depressive reaction, were present in two of them; in one case, it was severe enough to require immediate discontinuation of treatment. In two patients the visual symptoms resolved and the parameters of neurophysiologic testing returned to normal within 1 month after stopping interferon. In one case, however, residual optic tract impairment associated with a unilateral central scotoma and a substantial decrease of visual acuity was present 2 years later, despite a course of methylprednizolone. In this patient the interferon treatment was continued for 3 months despite the visual symptoms, and he later received two additional interferon courses because of relapses of hepatitis. We conclude that clinically evident optic tract neuropathy may complicate interferon administration. Candidates for interferon treatment may need routine examination of optic fields and visual evoked potentials, before and during administration of the drug to avoid possibly permanent visual sequelae. PMID- 7836720 TI - Hepatitis C virus genotype and RNA titer in the progression of type C chronic liver disease. AB - Hepatitis C virus genotype and the amounts of circulating HCV RNA are the most important factors in determining the efficacy of interferon therapy for chronic hepatitis C. To clarify the correlation of these two factors to the progression of liver disease, we classified 148 Japanese patients with type C chronic liver disease into genotypes and also measured their HCV RNA titers (logarithmic transformed copy number/ml serum) by competitive reverse transcription-polymerase chain reaction. We found type II in 23 (76.7%) of 30 patients with chronic persistent hepatitis, 34 (79.1%) of 43 with chronic active hepatitis, 29 (72.5%) of 40 with cirrhosis and 30 (85.7%) of 35 with hepatocellular carcinoma. Thus, there was no significant difference in the prevalence of type II among the various stages of chronic liver disease. We also found the RNA titer to be significantly higher in patients with chronic active hepatitis (8.0 +/- 0.8) than in those with chronic persistent hepatitis (7.0 +/- 1.0, p < 0.001), and also those with cirrhosis (7.6 +/- 0.8, p < 0.05) or hepatocellular carcinoma (7.7 +/- 0.8, p < 0.05). When the titers were compared among genotypes, there was no significant difference between type II and III at any stage (type II vs. type III: chronic persistent hepatitis, 7.2 +/- 1.0 vs. 6.7 +/- 0.8; chronic active hepatitis, 8.1 +/- 0.7 vs. 7.8 +/- 1.0; cirrhosis, 7.7 +/- 0.8 vs. 7.8 +/- 0.7; hepatocellular carcinoma, 7.7 +/- 0.8 vs. 7.8 +/- 0.5). In conclusion, although genotype affects interferon therapy efficacy, it seems to have little influence on serum RNA levels and the progression of type C chronic liver disease. PMID- 7836722 TI - Frequency and consequences of acute hepatitis non-A, non-B (hepatitis C) in Slovenia. PMID- 7836723 TI - A "mini epidemic" of hepatitis A after eating Russian caviar. PMID- 7836724 TI - Serum anti-liver cytosol antibodies type 1 in hepatitis C virus infection. PMID- 7836725 TI - Chronic intrahepatic cholestasis and sicca syndrome of sarcoidosis. PMID- 7836726 TI - Retreatment with interferon in patients with chronic hepatitis C. PMID- 7836727 TI - Bibliography of the current world literature in hypertension. PMID- 7836728 TI - Echocardiography in arterial hypertension: when, why and how? PMID- 7836729 TI - Mechanical stretch increases proto-oncogene expression and phosphoinositide turnover in vascular smooth muscle cells. AB - OBJECTIVE: To determine whether changes in haemodynamic load, simulated in vitro by mechanically stretching cultured vascular smooth muscle cells, could be transduced into biochemical signals similar to those produced by growth factors. DESIGN: A system was developed which was capable of stretching cultured vascular smooth muscle cells from 0 to 20%. The effect of stretching quiescent vascular smooth muscle cells on both c-fos messenger RNA (mRNA) expression and release of total inositol phosphates was determined over a time interval of 0-360 min. METHODS: Rat mesenteric artery vascular smooth muscle cells were grown using standard cell culture methods. Induction of the proto-oncogene, c-fos, was determined by Northern blotting. Phosphoinositide breakdown was assessed by measuring [3H]-inositol phosphates released from prelabelled cells. RESULTS: A 20% fixed stretch resulted in a rapid induction of c-fos mRNA which reached maximal levels by 15 min. The amount of c-fos mRNA detected was dependent on the degree of stretch, with maximum induction obtained for 15 and 20% stretch. The effects of mechanical stretch were also assessed on phosphoinositide turnover by measuring [3H]-inositol phosphates released from prelabelled cells. A 20% fixed stretch of vascular smooth muscle cells for 20 min resulted in a 3.2-fold increase in total [3H]-inositol phosphates released compared with unstretched cells. CONCLUSIONS: Our results show that mechanical stretch increases proto oncogene expression and phosphoinositide turnover in vascular smooth muscle cells in vitro. These observations suggest that mechanical stretch and growth factors share common signal transduction pathways which may be important in the development of vascular hypertrophy. PMID- 7836731 TI - Characterization of a novel, high-molecular weight, acidic, endothelin-1 inactivating metalloendopeptidase from the rat kidney. AB - OBJECTIVE: To characterize endothelin-1 inactivating peptidase (ET-1 peptidase) recently isolated from rat kidney. METHODS: ET-1 peptidase was purified from the membranes of whole Wistar-Kyoto (WKY) rat kidneys using differential centrifugation, detergent solubilization, ion-exchange chromatography, ultrafiltration and preparative electrophoresis. The enzyme activity in the presence of increasing concentrations of unlabelled peptides, inhibitors and other substances was determined at pH 5.5 and 37 degrees C using fixed amounts of [125I]-ET-1 as the substrate. RESULTS: On non-denaturing gels, the purified enzyme migrated in the form of a compact, low-mobility (Rf 0.07), high relative molecular mass (approximately 250,000) protein band. During denaturing polyacrylamide gel electrophoresis this protein separated into three fractions with apparent relative molecular masses 158,000, 110,000 and 61,000. Using different buffers, the optimum pH for this enzyme was found to be 5.5. Zinc (3.7 mmol/l), nickel (4.0 mmol/l), citrate (0.6 mmol/l), phosphate (1.3 mmol/l) and barbital ions (2.5 mmol/l) inhibited ET-1 peptidase activity by 50%, whereas magnesium, calcium, cobalt, manganous, sodium and borate ions were without effect. The most powerful inhibitors of the enzyme included: phenanthroline [median inhibitory concentration (IC50) 28 mumol/l], phosphoramidon (IC50 8.0 nmol/l), thiorphan (IC50 32 nmol/l) and N-carboxymethyl-Phe-Leu (IC50 12 mumol/l). Also, bacitracin (25 mumol/l), cyclosporine A (20 mumol/l) and sodium dodecyl sulphate (0.5%) inhibited enzyme activity by 50%, whereas bestatin, puromycin, aprotinin, phenylmethylsulphonyl fluoride, amanitin (50-100 mumol/l) and cardiotoxin (25 micrograms/assay) had no effect. The Michaelis constant (Km) values of 70 and 66 nmol/l were found towards ET-1 and the ET(16-21) fragment, respectively, whereas the Km values in respect to big-ET-1, sarafotoxin S6b, sulphated cholecystokin octapeptide, gastrin, glucagon, insulin, gastric inhibitory peptide and growth hormone ranged from 1.5 to approximately 50 mumol/l. The enzyme showed no apparent affinity for enkephalins, bradykinin, angiotensins, cholecystokinin tetrapeptides and kyotorphin. CONCLUSIONS: The present data suggest that the ET-1 peptidase that we isolated from rat kidney displays inhibitory characteristics similar to that of other known metalloendopeptidases. However, this enzyme exhibits several unique properties such as high molecular mass, an apparent complex subunits structure, pH optimum at 5.5, and very high substrate specificity towards ET-1 and the ET(16-21) fragment compared with other peptides either related or unrelated to endothelin. PMID- 7836730 TI - Different effects of an angiotensin converting enzyme inhibitor and a calcium antagonist on protein metabolism in rats with right ventricular hypertrophy. AB - OBJECTIVE: We examined the effects of a calcium antagonist and an angiotensin converting enzyme (ACE) inhibitor on contractile and non-contractile protein metabolism and cardiac function in a monocrotaline-induced right ventricular hypertrophy model, in order to define the effects of these drugs on cardiac hypertrophy. METHODS: One week after monocrotaline injection, male Sprague-Dawley rats were given either a calcium antagonist (nilvadipine; 3 mg/kg per day) or an ACE inhibitor (delapril-HCl; 30 mg/kg per day) for 2 weeks. Right ventricular pressure, the right ventricle: (left ventricle + interventricular septum) ratio, myosin isoenzymes, collagen concentration, collagen types and contractility of right ventricular free wall were examined. RESULTS: In untreated rats significant monocrotaline-induced right ventricular hypertrophy with an increase in the proportion of collagen types III and V was observed. There were no significant changes in collagen concentration. Both drugs reduced right ventricular pressure to the same degree and decreased right ventricular hypertrophy. However, the inhibitory effect of delapril on right ventricular hypertrophy was stronger than that of nilvadipine. Nilvadipine reduced the collagen concentration and reversed changes in collagen types, whereas delapril did not have any significant effect on collagen concentration or collagen types. Cardiac contractility was improved by delapril, but not by nilvadipine. CONCLUSIONS: The results show that a calcium antagonist disproportionately inhibited contractile and non-contractile protein metabolism, whereas an ACE inhibitor proportionally inhibited them and improved cardiac function in a model of right ventricular hypertrophy. The improvement in cardiac function may be due partly to the proportional inhibition of contractile and non-contractile proteins elicited by an ACE inhibitor. PMID- 7836732 TI - Cardiovascular hypertrophy in one-kidney, one clip renal hypertensive rats: a role for angiotensin II? AB - OBJECTIVE: To investigate the role of angiotensin II (Ang II) in cardiovascular hypertrophy in the Goldblatt one-kidney, one clip (1-K, 1C) renal hypertensive rat. METHODS: Six-week-old Wistar-Kyoto (WKY) rats underwent uninephrectomy and left renal artery clipping. After surgery, rats were treated with perindopril, an angiotensin converting enzyme (ACE) inhibitor, or losartan, an Ang II type 1 (AT1) receptor antagonist, for 4 weeks. Untreated 1-K, 1C rats and uninephrectomized (sham) rats served as controls. RESULTS: The rise in systolic blood pressure in the perindopril-treated and losartan-treated rats was not significantly different from that in the untreated 1-K, 1C group throughout the treatment period. At 4 weeks after surgery the heart weight:body weight ratios of the untreated 1-K, 1C and losartan-treated 1-K, 1C groups were significantly greater than for sham-operated normotensive rats and hypertensive perindopril treated rats. The total number of smooth muscle cells in the thoracic aortae of the 1-K, 1C untreated, losartan-treated 1-K, 1C and sham groups were similar. However, after treatment the aortae of the perindopril-treated group contained significantly fewer smooth muscle cells. The medial cross-sectional wall area and wall: lumen ratio were similar in the 1-K, 1C untreated and perindopril-treated 1 K, 1C groups. CONCLUSION: These results suggest that Ang II, via its effects on cardiac and vascular AT1 receptors, does not contribute to the development of cardiovascular hypertrophy in the 1-K, 1C rat. Attenuation of cardiac and vascular growth after ACE inhibition appears to be mediated by mechanisms independent of the actions of the renin-angiotensin system. PMID- 7836733 TI - Sustained increases in aortic depressor nerve activity after acute elevation in arterial pressure. AB - OBJECTIVE: Despite the return of mean arterial pressure (MAP) to control levels, aortic depressor nerve activity remains elevated from control levels after sustained phenylephrine-induced increases in MAP in spontaneously hypertensive rats (SHR) (Kenney MJ, Morgan DA, Mark AL: Am J Physiol 1990, 258:H1476-H1481). This suggests that sustained increases in arterial pressure may produce prolonged pressure-induced changes in afferent baroreceptor nerve activity in SHR. However, because phenylephrine can exert an excitatory effect on the aortic arch baroreceptors, the increase in aortic depressor nerve activity might have resulted from a persistent direct effect of phenylephrine. The aim of the current study was to determine whether elevations in MAP induced by aortic occlusion produce increases in aortic depressor nerve activity which persist after the return of MAP to control levels. METHODS: MAP and aortic depressor nerve activity were recorded before, during and after sustained (15-30 min) periods of aortic occlusion in SHR with intact adrenal glands (n = 18) and in adrenalectomized SHR (n = 10). Control experiments were completed in which the same variables were recorded before, during and after sham aortic occlusion in intact (n = 8) and adrenalectomized (n = 8) SHR. RESULTS: Aortic occlusion increased MAP and aortic depressor nerve activity significantly from control levels. After aortic occlusion and the return of MAP to control levels, aortic depressor nerve activity remained significantly increased in 15 experiments, whereas in three experiments aortic depressor nerve activity was reduced. Aortic depressor nerve activity was increased significantly from control levels after aortic occlusion in adrenalectomized rats. Aortic depressor nerve activity remained unchanged from control levels after sham aortic occlusion in intact and adrenalectomized SHR. CONCLUSIONS: Sustained elevations in MAP induce increases in aortic depressor nerve activity in intact and adrenalectomized SHR, which persist after the return of MAP to control levels. These observations suggest that sustained increases in arterial pressure may produce prolonged pressure-induced changes in afferent baroreceptor nerve activity in SHR. PMID- 7836734 TI - Angiotensin II formation by an alternative pathway during exercise in humans. AB - OBJECTIVE: We postulated a 'kinin-tensin system' in which angiotensin II (Ang II) is cleaved by one or more serine protease independent of renin or angiotensin converting enzyme (ACE). The aim was to determine whether this alternative Ang II forming pathway by serine proteases participates in the rise in plasma levels of Ang II during exercise in humans. DESIGN AND METHODS: The study consisted of two double-blind crossover experiments. in experiment 1 six healthy volunteers who had been taking either placebo (group P) or the ACE inhibitor captopril (150 mg/day for 3 days; group C) performed a cycle ergometer graded exercise test at four different exercise intensities: stage 1, half of the intensity at the blood lactate threshold (WLT); stage 2, the intensity at WLT; stage 3, the intensity at 4 mmol/l blood lactate; and stage 4, an intensity between stage 3 and maximum intensity. In experiment 2 the same volunteers took captopril (150 mg/day for 3 days) and performed exercise at an intensity corresponding to 90% of the 4 mmol/l blood lactate intensity for 30 min during intravenous drip injection of a serine protease inhibitor, nafamostat [NAF; 0.2 mg/kg per h; NAF(+) group] or saline [NAF(-) group]. RESULTS: In experiment 1 plasma Ang II levels increased from at rest to after exercise in both groups P and C. Although there was a significant treatment effect, captopril did not significantly alter the exercise-induced changes in Ang II level. In experiment 2 the increase in Ang II level after 30 min exercise in the NAF(+) group was significantly lower than in the NAF(-) group. CONCLUSIONS: These results suggest the presence of an alternative Ang II forming pathway independent of ACE, and that one or more NAF-sensitive serine protease is responsible, at least partly, for generating Ang II during exercise. PMID- 7836735 TI - Change in blood pressure and 5-year risk of coronary heart disease among elderly men: the Finnish cohorts of the Seven Countries Study. AB - OBJECTIVE: To study the association between blood pressure and change in blood pressure with future coronary risk among elderly men. DESIGN: Cohort study. SETTING: Finnish cohorts of the Seven Countries Study. PARTICIPANTS: Four hundred and seventy-six men aged 65-84 years and free of clinically manifested coronary heart disease at baseline, in 1984. MAIN OUTCOME MEASURES: Fatal myocardial infarction (n = 29), any myocardial infarction (n = 42), and incidence of any new signs and symptoms of coronary heart disease (n = 80) during a 5-year follow-up. RESULTS: In multivariate analysis, a significant inverse U-shaped relationship was observed between baseline diastolic blood pressure and future fatal myocardial infarction, any myocardial infarction and any coronary heart disease. In models predicting the risk of coronary heart disease during 1984-1989, there was a significant interaction between both systolic (SBP) and diastolic blood pressure (DBP) in 1969-1974 and change in blood pressure between 1969-1974 and 1984. In categorical analyses, men (n = 42) who experienced a decline in DBP of > or = 4 mmHg from initial levels of > or = 90 mmHg had a higher risk of any myocardial infarction than men (n = 112) with a change of < 4 mmHg (odds ratio 4.5). For a decline of > or = 10 mmHg or more in SBP from levels of > or = 160 mmHg the corresponding odds ratio was 2.9. Men who experienced a decline in DBP or SBP from normotensive levels or an increase in blood pressure had no excess risk compared with men with stabile (change in DBP < 4 mmHg and change in SBP < 10 mmHg) blood pressure values. CONCLUSION: The present results suggest that among elderly men a decline in DBP or SBP from previously hypertensive levels may be associated with increased coronary risk. PMID- 7836736 TI - Hyperinsulinaemia and blood pressure in a general Japanese population: the Hisayama Study. AB - OBJECTIVES: To study the relationship between serum insulin and blood pressure, as well as the prevalence of hypertension according to the insulin level in a general Japanese population. DESIGN: In 1988 a cross-sectional community survey was conducted among Hisayama residents aged 40-79 years. METHODS: A total of 1073 males and 1407 females (72.5 and 80.5% of the total population, respectively) underwent comprehensive investigation, including a 75-g oral glucose-tolerance test. Fasting and 2-h serum insulin levels were measured by radioimmunoassay. RESULTS: The sum of the fasting and 2-h postloading insulin levels was significantly correlated with the systolic blood pressure (SBP; r = 0.18 and 0.26 for males and females, respectively) and the diastolic blood pressure (DBP; r = 0.24 and 0.19, respectively) in the subjects not receiving antihypertensive drugs. In multiple regression analysis the correlation with blood pressure remained significant in both sexes even after controlling for age, body mass index, alcohol intake, smoking, a family history of hypertension, serum total cholesterol and fasting plasma glucose. The age- and sex-adjusted prevalence of hypertension (SBP > or = 160 mmHg or DBP > or = 95 mmHg, or both, or receiving drug treatment) increased significantly with an increase in the sum of fasting and 2-h postload insulin levels in both the non-obese subjects (body mass index < 25 kg/m2) and the obese subjects (body mass index > or = 25 kg/m2). Multiple logistic regression showed that the sum of fasting and 2-h postload insulin levels was a significant factor with an independent relationship to hypertension, even after taking the other risk factors into account. CONCLUSION: The present study suggests that hyperinsulinaemia is related to hypertension in a general Japanese population. PMID- 7836737 TI - Dipeptidyl carboxypeptidase-1 gene polymorphism paradox in hypertension explained by 'deletion depletion'. PMID- 7836738 TI - Cerebrovascular reactivity to carbon dioxide in hypertensive patients. PMID- 7836739 TI - Perturbed development of T and B cells in mice expressing an Hlx homeobox transgene. AB - Within the lymphoid compartment of mice, the Hlx homeobox gene is expressed only at early stages of B-lymphoid differentiation. To determine whether Hlx influences lymphopoiesis, transgenic mice were developed to enforce Hlx expression throughout the B and T cell lineages. The strain with the highest transgene expression in both cell types (Hlx-94) exhibited marked perturbations in both B and T cell development. In these mice, the thymus lacked almost all mature CD4+8- and CD8+4- cells and the medulla was greatly shrunken, whereas nearly one-half the T cells in the periphery were CD4+8+, a cell type normally confined to the thymus. The peripheral CD4+8+ cells had some features of mature T cells, including responsiveness to mitogens. Presumably these cells had emigrated prematurely from the thymus and generated mature T cells in the periphery. Bone marrow transplantation experiments indicated that the defects was intrinsic to the Hlx-94 hematopoietic cells rather than support cells. Although thymocyte development in Hlx-94 mice was blocked at the stage when selection normally occurs, analysis of lymphocyte populations in the progeny of crosses with mice transgenic for an anti-HY T cell receptor indicated that neither positive nor negative selection of T cells was markedly affected. In addition to T cell defects, Hlx-94 mice had subnormal numbers of B lymphoid cells in the bone marrow and spleen, and their surface phenotype suggested that B cell development after the pro-B stage was impeded. Furthermore, the B cell response to stimulation with LPS was impaired. These striking developmental defects suggest that the Hlx gene may help to govern lymphoid maturation. PMID- 7836740 TI - Migration of skin-homing T cells across cytokine-activated human endothelial cell layers involves interaction of the cutaneous lymphocyte-associated antigen (CLA), the very late antigen-4 (VLA-4), and the lymphocyte function-associated antigen-1 (LFA-1). AB - The cutaneous lymphocyte-associated Ag (CLA) is expressed by a subset of circulating memory/effector T cells and by the vast majority of skin-infiltrating T cells. CLA is thought to target skin-associated T cells to inflammatory skin sites by interacting with endothelial cell ligand E-selectin (CD62E). We have examined adhesion molecules involved in the migration of human CLA+ and CLA- memory/effector T lymphocytes through IL-1- and TNF-alpha-activated and nonactivated HUVEC layers under static (nonflow) conditions. CLA-enriched memory/effector T lymphocytes migrated more actively across cytokine-activated HUVEC than CLA-depleted memory/effector T cells. This enhanced migration is dependent on the CLA/E-selectin interaction. mAb to very late Ag-4 (VLA-4) and vascular cell adhesion molecule-1 (VCAM-1) blocked the migration of CLA-enriched, but not of CLA-depleted, T cells across activated HUVEC. The observation that anti-VLA-4 and anti-CLA mAb did not show additional inhibition supports the concept that CLA and VLA-4 are sequentially involved in the extravasation. The fact that only CLA+ T cells were inhibited by the anti-VLA-4 mAb suggests that, in this system, CLA engagement is required for using the VLA-4/VCAM-1 pathway. Our studies demonstrate that CLA+ T cells use LFA-1/intercellular leukocyte adhesion molecule-1 (ICAM-1) for transmigration but that CLA expression is not required for the LFA-1/ICAM-1-dependent transmigration because anti-CD18/CD11a mAbs and anti-ICAM-1 mAbs were able to block T cell migration regardless of the activation state of HUVEC or the CLA expression by T cells. Taken together, our results suggest that CLA has a homing function in conducting the T cell to interact with LFA-1/ICAM-1 and/or VLA-4/VCAM-1; this results in enhanced adhesion and migration across cytokine-activated endothelial cells. PMID- 7836741 TI - Reconstitution of TCR alpha-chain expression in deletion mutants restores dinitrophenyl-specific/class I MHC-restricted suppressor molecule production. AB - A population of CD8+ T cells from dinitrobenzene sulfonate-primed mice produce soluble effector molecules that down-regulate the magnitude of dinitrophenol specific contact hypersensitivity reactions. These soluble molecules express the binding specificity and serologic determinants of alpha/beta TCR. To examine the requirement for the TCR-alpha chain in the production of these molecules, we have cloned the alpha-chain gene used to encode the surface TCR of MTs 79.1, a T cell hybridoma producing a DNP/Kd-specific soluble suppressive molecule, and tested the ability of this gene to reconstitute the production of the regulatory molecule in TCR alpha-chain gene deletion mutants. Transfection and expression of the alpha-chain construct into an alpha-chain deletion mutant of the parental hybridoma that expressed the parental beta-chain gene resulted in reconstitution of both surface TCR expression and production of the soluble suppressive molecule. As with the molecule produced by the MTs 79.1 parental cells, the inhibitory activity produced by these alpha-chain gene transfectants was DNP specific and expressed determinants bound by anti-V beta 8 Abs. Transfection of the alpha-chain gene construct into an alpha-/beta- chain gene deletion mutant did not restore the production of the soluble regulatory molecule. These results indicate that in addition to the TCR beta-chain gene, expression of the TCR alpha chain gene is also required for the production of these molecules. Our results strongly support the hypothesis that some forms of immunosuppression are mediated by soluble forms of the TCR. PMID- 7836742 TI - Functional analysis of the TCR alpha- beta+ cells that accumulate in the pneumonic lung of influenza virus-infected TCR-alpha-/- mice. AB - In mice homozygous (-/-) for a targeted TCR-alpha gene disruption, some thymocytes express a cell-surface TCR-beta chain on the cell surface in the absence of a TCR-alpha chain, and a few CD4+CD8- TCR-alpha-beta+ cells accumulate in the peripheral lymphoid organs. We have infected these mutant mice with an influenza A virus to show that large numbers of TCR-beta+ cells (most of which are CD4+) can be retrieved from the pneumonic lung. Both freshly isolated TCR alpha-beta+ cells and TCR-alpha-beta+ hybridoma cell lines derived from influenza virus-infected mutant mice respond appropriately to stimulation with anti-CD3 epsilon or the Mls-1 superantigen. It thus seems that CD4+ TCR-alpha-beta+ cells in the peripheral lymphoid organs of TCR-alpha mutant mice can signal through their TCR surface complex. However, there are no indications that CD4+ TCR-alpha beta+ lymphocytes can either recognize a complex between MHC and influenza virus peptide or act as effector or Th cells. The existence and function of such cells in wild-type mice remains to be established. PMID- 7836743 TI - In vitro transformation of murine pro-B and pre-B cells by v-mpl, a truncated form of a cytokine receptor. AB - v-mpl is a constitutively activated, truncated form of a cytokine receptor that has been transduced in a murine retrovirus, the myeloproliferative leukemia virus (MPLV). Expression of this oncogene results in the factor-independent proliferation of myeloid, erythroid, megakaryocytic, and mast precursor cells, which retain the ability to differentiate. However, no lymphoid disease was ever reported. To determine whether MPLV could infect and transform very early B cells and their precursors (BCPs), lymphoid long-term bone marrow cultures were infected with a helper-free MPLV. Within 3 wk after infection, highly proliferating BCPs could be isolated. These cells were able to clone spontaneously in semi-solid cultures, grown in the absence of feeder cell layer or exogenous growth factor and rapidly produced tumors after s.c. injection into synegic irradiated mice. In addition, MPLV transformation of pre-B cells led to the induction of an autocrine activity. Immunophenotypic and molecular analysis indicated that MPLV transformed early pro-B, pro-B, and pre-B cells, according to the expression of HSA, CD43, B220, Thy1, s-IgM and BP1 Ags, and to the rearrangements of Ig genes. Interestingly, MPLV-transformed BCPs expressed Mac1 Ag without acquiring further characteristics of macrophagic differentiation. Although the v-mpl cytoplasmic domain is devoid of tyrosine kinase consensus sequence, MPLV-transformed pre-B cells contained a major approximately 105-kDa tyrosine-phosphorylated protein that was not detected in uninfected cells or in cells transformed by the Abelson viral oncogene (v-abl). These results demonstrate that, like v-abl, the truncated cytokine receptor v-mpl is able to transform BCPs in vitro and suggest that the oncogenic transformation of BCPs by either v-mpl or v-abl use different pathways. PMID- 7836744 TI - Specific unresponsiveness to a retrovirally-transferred class I antigen is controlled through the helper pathway. AB - To investigate the potential role for gene therapy in induction of tolerance to solid organ grafts, we used a murine model based on the introduction of an allogeneic MHC class I gene (H-2Kb) into hematopoietic cells of congenic animals differing only at the class I locus. The H-2Kb gene was placed into a retroviral vector under the control of regulatory sequences of the myeloproliferative sarcoma virus long terminal repeat. Transplantation of H-2Kb retrovirus transduced autologous bone marrow into B10.AKM (Kk Ik Dq) recipients resulted in detectable levels of H-2Kb RNA and cell surface protein in lymphoid and myeloid lineages. H-2Kb expression was significant, although variable, in bone marrow Mac1+ cells, in splenic B cells, and in CD4+/CD8+ thymocytes 8 wk post-bone marrow transplantation. The recipients of the H-2Kb-transduced bone marrow showed specifically delayed rejection of B10.MBR (Kb Ik Dq) skin grafts disparate only for Kb. However, B10.MBR skin grafts were rapidly rejected when grafted simultaneously with skin grafts from B10 (Kb Ib Db) mice, a strain bearing additional third party alloantigens in association with Kb. Our experiments suggest that the hyporesponsive state induced by using the retrovirally mediated gene transfer model is characterized by the persistence of H-2Kb-specific cytolytic T cell precursors, which may be inactive because of deficient T cell help. Tolerance to Kb induced by this approach may therefore be restricted to T helper cell lineages. PMID- 7836745 TI - Role of IL-12 in human B lymphocyte proliferation and differentiation. AB - The role of IL-12 in human peripheral blood B cell responsiveness was examined. To analyze the ability of IL-12 to directly mediate B cell growth and/or differentiation, FACS-purified (> 99% pure) B cells were studied and a polyclonal B cell-activating system utilizing Cowan I Staphylococcus aureus was used. Whereas IL-2 is highly effective in this system in promoting both B cell growth and differentiation, IL-12 was observed only to augment modestly B cell growth and to be ineffective by itself as a B cell differentiation factor for S. aureus stimulated B cells. However, IL-12 markedly enhanced Ig secretion when added in the presence of IL-2. Moreover, when the ability of IL-12 to augment IL-2 dependent B cell Ig secretion was compared with the ability of several known auxiliary B cell differentiation factors, IL-12 was observed to be the most potent cytokine that could costimulate with IL-2. Analysis of IL-12-stimulated B cell cultures failed to reveal outgrowth of T cells and NK cells. In addition, assessment of IFN-gamma levels in IL-12-driven B cell culture supernatants and analysis of IFN-gamma effects on B cell responses added additional support to the conclusion that IL-12 directly modulates B cell function. Finally, these results suggest that IL-12 is a potent constimulus of B cell differentiation and that the signals conveyed by IL-12 seem to be qualitatively distinct from the differentiative signals delivered by other cytokines such as IL-2. PMID- 7836746 TI - Gamma delta T cell recognition of tumor Ig peptide. AB - Although gamma delta T cells have been postulated to act as a surveillance mechanism that eliminates transformed or otherwise damaged cells, little is known about tumor recognition by gamma delta T cells, including the Ags that are recognized and the molecules that present them. Previously, we described human gamma delta CTL that recognize the autologous B cell lymphoma. Here we report that these gamma delta CTL lyse heterologous cells transfected with the tumor Ig lambda chain gene. Furthermore, the lambda chain is recognized as processed peptide in an Id-specific manner. T cell recognition does not involve classical MHC molecules, but it could be blocked by Abs directed against the heat shock protein grp75. These findings show a specific gamma delta T cell response to a highly polymorphic Ag such as tumor Id and implicate heat shock protein as a molecule required for recognition. PMID- 7836747 TI - The NK1.1 antigen in NK-mediated F1 antiparent killing in vitro. AB - NK cells in lethally irradiated F1(A x B) hybrid mice can reject parental A or B strain bone marrow cells, a phenomenon called "hybrid resistance." The recognition mechanism used by the NK cells remains unknown. Our laboratory has previously described an in vitro model for hybrid resistance, and we have used it here to test whether the NK surface marker, NK1.1, is involved in such recognition. We found that 1) an anti-NK1.1 mAb (PK136) inhibited F1 lymphokine activated killer (LAK) antiparent lysis if the LAK expressed NK1.1. Other mAb, even a mAb such as 2B4 that recognizes the same LAK as PK136, did not produce inhibition. 2) The F(ab')2 fragment of PK136 also inhibited lysis. 3) F1 LAK generated from athymic nude mice were as effective antiparent killers as LAK from normal mice and were equally inhibitable by anti-NK1.1 mAb, strengthening the conclusion that killing is mediated by NK cells and not T cells. 4) As previously shown by others, addition of anti-NK1.1 mAb to a mixture of NK1.1+ LAK cells and NK-resistant FcR+ cells allowed lysis of the FcR+ cells via "redirected lysis," in which the anti-NK1.1 mAb binds to NK1.1 on the NK cells and FcR on the target cell. The ability of anti-NK1.1 mAb to inhibit direct lysis and enhance redirected lysis is most consistent with NK1.1 being a receptor involved in NK activation. PMID- 7836748 TI - TGF-beta 1 and cyclic AMP promote apoptosis in resting human B lymphocytes. AB - TGF-beta and agents that elevate intracellular cAMP levels are potent inhibitors of B cell activation in vitro and have been shown to arrest stimulated B cells in the G1 phase of the cell cycle. We tested the effects of TGF-beta 1 and the cAMP inducing agent, forskolin, on the viability of resting B cells from human peripheral blood, and found that both agents caused a significant, dose-dependent increase in cell death relative to spontaneous death in medium alone, as measured by vital dye staining with propidium iodide. Apoptosis was shown to be the overall mode of death by demonstrating DNA fragmentation using DNA nick end labeling and by verifying the characteristic morphologic changes. In contrast with TGF-beta 1 and forskolin, various B cell activation stimuli generally inhibited spontaneous apoptosis of resting cells. The most potent effects were observed with IL-4 and the phorbol ester, O-tetradecanoylphorbol-13-acetate (TPA), an activator of protein kinase C. IL-4 also partly inhibited TGF-beta 1 and forskolin-induced apoptosis. In contrast, TPA completely reversed cell death in forskolin-treated cultures, but had no effect on TGF-beta 1-induced apoptosis, indicating that TGF-beta 1 and forskolin promote apoptosis by different mechanisms. The relative protein expression of bcl-2, a proto-oncogene that inhibits apoptosis, was unaltered by the apoptotic as well as the survival stimuli tested, suggesting that apoptosis was regulated by a bcl-2-independent mechanism. We conclude that apoptosis is a regulated phenomenon in resting human B cells. Furthermore, TGF-beta and cAMP may inhibit B cell responses not only by blocking cell cycle progression in activated cells, but also by inducing apoptosis in resting cells. PMID- 7836749 TI - Dramatic hyperplasia of mtv-2+ lymph node grafts in mtv-2- recipients and selective stimulation of V beta 14+ T cells in recipients' lymph nodes in the DDD mouse. AB - DDD/1 (DDD) mice contrast strikingly with DDD-mtv-2/mtv-2 (DDD-mtv-2) congenics in their marked lymph node (LN) T cell paucity. To clarify the possible difference in LN function between them, reciprocal LN grafting experiments were conducted. DDD-mtv-2 LN grafts in DDD recipients underwent hyperplasia as dramatic as 10-to 20-fold increase in weight between 3 and 4 wk after implantation. Lymphoid cells in hyperplastic LN grafts were of recipient origin. Similar hyperplasia of mtv-2-heterozygous LN grafts also occurred on various hybrid backgrounds involving DDD mice. Moreover, LN grafts from BALB/c mice infected with mtv-2-derived exogenous mouse mammary tumor virus (MMTV) swelled in MMTV-free BALB/c recipients. Genetic analysis of DDD x (DDD x DDD-mtv-2)F1 backcross progeny demonstrated that LN hyperplasia was closely linked to mtv-2. The frequencies of V beta 5+ and V beta 8+ T cells unresponsive to mtv-2-encoded superantigen (SAg) changed with practically the same kinetics in both LN grafts and recipients' LN. Thus, the cells responsible for LN hyperplasia were polyclonal. V beta 14+ CD4+ cells responsive to mtv-2 SAg were specifically stimulated in recipients' LN but selectively deleted in hyperplastic LN grafts. DDD mice carrying hyperplastic mtv-2+ LN grafts or pretreated with mtv-2+ spleen cells developed an unresponsive state in terms of influx of mtv-2- lymphoid cells into mtv-2+ LN grafts. These results indicate that mtv-2 gene products including SAg may stimulate mtv-2- lymphoid cells of recipients and cause them to migrate into mtv-2+ LN grafts in a nonspecific manner with resulting LN hyperplasia. PMID- 7836750 TI - Human IL-3 receptor signaling: rapid induction of phosphatidylcholine hydrolysis is independent of protein kinase C but dependent on tyrosine phosphorylation in transfected NIH 3T3 cells. AB - Although tyrosine kinases are clearly activated after ligand engagement of the human IL-3R in both hematopoietic and nonhematopoietic cytoplasmic environments, a role for phospholipid hydrolysis and protein kinase C in IL-3R signal transduction is emerging. We have used NIH 3T3 cells transiently transfected with human IL-3R alpha- and beta-subunits to study phosphatidylcholine hydrolysis in response to human IL-3. We have found that NIH 3T3 cells expressing the complete human IL-3R respond to human IL-3 with a rapid and sustained increase in sn-1'2' diacylglycerol. Accompanying this was a rapid increase in intracellular levels of phosphorylcholine. The protein kinase C inhibitor H-7, however, was not effective in inhibiting phosphatidylcholine hydrolysis in response to human IL-3 in NIH 3T3 cells expressing the human receptor. Thus the human IL-3R induces a rapid protein kinase-C-independent hydrolysis induced by the murine receptor. Simultaneous with the increase in phosphatidylcholine hydrolysis induced by the murine receptor. Simultaneous with the increase in diacylglycerol levels was an increase in membrane-bound protein kinase C enzyme activity. Immunoblotting with isoform specific Abs against protein kinase C showed that, whereas the zeta-isoform is constitutively membrane bound, the alpha-isoform of protein kinase C is translocated to the membrane in response to IL-3. Activation of phosphatidylcholine hydrolysis and protein kinase C activation required both alpha- and beta-receptor subunits. To determine the relationship of tyrosine phosphorylation to the activation of phosphatidylcholine hydrolysis and protein kinase C translocation, we used the specific and structurally unrelated tyrosine kinase inhibitors genistein and herbimycin. Both inhibitors effectively blocked human IL-3-induced tyrosine phosphorylation. In addition, both inhibitors blocked phosphatidylcholine hydrolysis and protein kinase C translocation. These data, combined with our previous report showing that c-jun induction by IL-3 is dependent on protein kinase C, suggest that, in hematopoietic and nonhematopoietic cells expressing the human IL-3R, phosphatidylcholine hydrolysis and protein kinase C are downstream effectors of tyrosine phosphorylation in the IL-3 signal transduction cascade resulting in immediate early response gene induction. PMID- 7836751 TI - Transferrin receptor induces tyrosine phosphorylation in T cells and is physically associated with the TCR zeta-chain. AB - In addition to being an iron transporter, the transferrin receptor (TfR) has been shown to play a role in T cell activation. Stimulation of the TfR with specific Abs results in T cell proliferation, IL-2 secretion, and protein kinase C activation. In this paper we have analyzed early events caused by activation of the TfR. We have found several protein substrates to be tyrosine phosphorylated upon TfR stimulation in the human Jurkat T cell line. Interestingly, the TfR induced tyrosine phosphorylation in cell lines expressing TCR but not in TCR negative mutants. Restoration of the TCR surface expression in these mutants reestablished the ability of the TfR to induce tyrosine phosphorylation. This result suggests that activation through the TfR is functionally dependent upon the expression of the TCR. Moreover, the functional relationship of the TfR with the TCR complex is also supported by data showing that TfR stimulation resulted in the tyrosine phosphorylation of the TCR zeta-chain; conversely, stimulation of the TCR complex resulted in an increased tyrosine phosphorylation of the TfR. More importantly, the TfR is shown to associate physically with the TCR zeta chain as well as with the zeta-binding ZAP70 tyrosine kinase. The TfR/zeta complex is expressed on the cell surface independent of the expression of the other subunits of the TCR complex. We suggest that the TfR/zeta complex is responsible for transducing the TfR-induced signals, and that it could serve to amplify signals delivered by Ag binding to the TCR. PMID- 7836752 TI - Costimulatory signals can selectively modulate cytokine production by subsets of CD4+ T cells. AB - Analysis of experimental animal models and human clinical samples has indicated that the selective activation of CD4+ T cell subsets with distinct profiles of cytokine production plays an important role in the pathogenesis of human inflammatory and allergic diseases. The possibility that differential activation of costimulatory pathways is a mechanism for selectively modulating cytokine production by CD4+ T cells was tested. The proliferative response and cytokines secreted by a panel of human CD4+ T cell clones, representative of Th1 or Th2/0 cells, in response to activation of different costimulatory pathways was measured. CD28-mediated costimulatory signals induced proliferation and IFN-gamma secretion by Th1 cells. Although CD28-ligation induced Th2/0 cells to proliferate, it did not trigger IL-4 production. Ligation of LFA-1 and CD45 isoforms also generated costimulatory signals activating cytokine secretion by the different types of T cell clones. Th1 cells secreted the same profile of cytokines, irrespective of which costimulatory pathway was engaged. However, the cytokine secreted by a subset of Th2/0 cells varied, depending upon which costimulatory pathways were activated. These results suggest that the costimulatory pathways activated by APCs can selectively influence cytokine production by CD4+ T cell subsets. PMID- 7836753 TI - Stimulation of NK-like YT cells via leukocyte function-associated antigen (LFA) 1. Possible involvement of LFA-1-associated tyrosine kinase in signal transduction after recognition of NK target cells. AB - The YTA-1 anti-LFA-1 alpha mAb activates protein tyrosine kinase (PTK), augments NK cytotoxicity, and induces proliferation of fresh CD3- large granular lymphocytes. We demonstrate here that LFA-1 is physically associated in the YT human NK-like cell line cells with a PTK(s) that is distinct from Src family PTKs such as Lck, Fyn, or Lyn. In vitro kinase assays revealed similar association of protein kinase activity with LFA-1 in normal CD3- large granular lymphocytes. Tyrosine phosphorylation of the proteins associated with LFA-1 drastically increased in YT cells after stimulation with NK-sensitive K562 cells but not with NK-resistant P815 cells. Furthermore, pretreatment of YT cells with TS1/22 anti LFA-1 alpha and TS1/18 anti-LFA-1 beta mAbs abrogated not only the cytotoxicity against K562 cells but also an increase in tyrosine phosphorylation of LFA-1 associated molecules induced by K562 stimulation. These results provide biochemical evidence that the PTK(s) associated with LFA-1 is involved in the signal transduction that follows the recognition of NK target cells. PMID- 7836754 TI - Lymphoid expression and regulation of A20, an inhibitor of programmed cell death. AB - A20 is a cytokine-inducible primary response gene that encodes a protein that inhibits apoptosis. We cloned and characterized a murine A20 cDNA and mapped the gene to mouse chromosome 10, 3.5 centimorgans proximal to the c-myb locus. Using the murine cDNA, we conducted in situ hybridization studies to examine patterns of A20 expression in mouse embryos and postnatal tissues. Both temporally restricted and tissue-specific patterns of A20 expression were observed, with strikingly high levels in lymphoid organs, including the thymus, spleen, and gut associated lymphoid tissue. Northern analysis using purified human lymphocyte populations demonstrated that A20 is constitutively expressed in both immature and mature thymocyte subpopulations, as well as in resting peripheral T cells. Activation leads to a down-regulation of A20 expression in both mature thymocytes and peripheral T cells. This pattern of expression and regulation differs markedly from that observed in prior studies with cell lines in which stimulation led to an induction of A20 expression. Additionally, this is the first demonstration of constitutive expression of A20 in primary cells. The data suggest a role for A20 in the function of the lymphoid system. PMID- 7836755 TI - Activation of intracellular proteases is an early event in TNF-induced apoptosis. AB - The serine protease inhibitor tosyl-argenine methyl ester inhibits TNF-induced apoptosis, suggesting that proteolysis is necessary for this response. To test this hypothesis, we asked whether protein fragmentation occurs during the death of C3HA fibroblasts, a 3T3-like cell that was rendered sensitive to TNF by cycloheximide. Our results show that the binding of fluorescamine, which binds primary amines, was increased in apoptotic cells by approximately 50%. We also found that 10-15% of the protein in apoptotic cells was no longer precipitable by TCA. Evidence for proteolysis was also revealed by SDS-PAGE analysis and from Western blots. We observed fragmentation and/or degradation of lamin B, topoisomerase I, histone H1, protein kinase C beta 1, and cPLA2, indicating that proteolysis during apoptosis is non-specific. We also found evidence of proteolysis in C3HA cells sensitized to TNF by the adenovirus dl758 (which lacks the E3 14.7-kDa resistance gene) suggesting that protease activation is common in TNF-induced apoptosis. In contrast, the adenovirus E3 14.7-kDa resistance gene prevented proteolysis suggesting that this protein acts at, or upstream of the proteases activated in this response. Finally, because tosyl-argenine methyl ester inhibits the release of [3H]arachidonic acid from apoptotic cells, we tested whether proteolysis of cPLA2 is necessary for enzyme activation. Our results failed, however, to reveal a common proteolytic fragment in different cell types, and when tested in vitro the cytosol from apoptotic cells had less cPLA2 activity. It is unlikely, therefore, that proteolysis is necessary for the activation of this enzyme during TNF-induced apoptosis. PMID- 7836756 TI - Protein kinase C mediates activation of nuclear cAMP response element-binding protein (CREB) in B lymphocytes stimulated through surface Ig. AB - The cAMP response element-binding protein (CREB) is generally considered to be responsive to elevation of cAMP through the activity of protein kinase A (PKA). Although it is well known that cAMP-raising agents can strongly influence B cell stimulation, the regulation of CREB has been little studied. Recently, cross linking of surface Ig (sIg) was shown to result in trans-activation of a cAMP response element (CRE)-dependent promoter to which bound B cell CREB. In this study, we explored the mechanism underlying this unexpected linkage between sIg and CREB. We found that sIg cross-linking results in phosphorylation of CREB at Ser133. Although this phosphorylation step is mediated by PKA in pheochromocytoma cells, it depends on protein kinase C (PKC) in B lymphocytes. This conclusion is based on abrogation of sIg-induced CREB Ser133 phosphorylation by long-term phorbol-ester treatment to deplete PKC, and mimicking of sIg-induced CREB phosphorylation and CRE-dependent gene expression by short-term PKC agonism. Furthermore, CD40 ligand (CD40L) and LPS, two PKC-independent forms of B cell stimulation, failed to induce phosphorylation of CREB Ser133. These results suggest that CREB responds to specific surface-receptor signals in B cells and that this response is mediated by PKC. Interestingly, forskolin failed to induce phosphorylation of CREB Ser133 in B cells, although it did so in PC12 pheochromocytoma cells. Taken together with PKC mediation of CREB Ser133 phosphorylation in B cells, these results suggest that the dominant mode of CREB regulation is cell-type specific. PMID- 7836757 TI - Isolation of a gene encoding a developmentally regulated T cell-specific protein with a guanine nucleotide triphosphate-binding motif. AB - In this study, we describe a novel full length cDNA clone designated Tgtp that encodes a predicted 415-amino acid a T cell-specific guanine nucleotide triphosphate-binding protein (TGTP) bearing the characteristic motifs of a guanine nucleotide triphosphate (GTP) binding protein. Tgtp is expressed preferentially, if not exclusively, in T cells, and is up-regulated in both unfractionated and in purified CD4+8+ thymocytes upon TCR cross-linking. In contrast, expression of Tgtp is peripheral T cells is maintained at relatively high levels and is not grossly affected by TCR cross-linking. Antiserum generated against synthetic peptides from the predicted TGTP amino acid sequence recognized a single protein with a molecular mass of approximately 50 kDa, corresponding well with the computed molecular mass of 47 kDa. The only known relative of Tgtp is MUSGTP, which is reportedly expressed in B cells and bears a GTP binding motif. Thus, the discovery of Tgtp resolves a subfamily of molecules with GTP binding motifs and apparent lymphoid lineage-restricted expression. Given the restricted expression pattern in T cells, the up-regulated expression observed in response to TCR signaling in immature thymocytes, and the presence of the motifs characteristic of GTP binding proteins, we suggest that TGTP may have an important function in T cell development and/or T cell activation. PMID- 7836758 TI - Molecular cloning of the mouse polymeric Ig receptor. Functional regions of the molecule are conserved among five mammalian species. AB - Transcytosis of polymeric Ig (pIg) by mucosal epithelial cells is mediated by the polymeric Ig receptor (pIgR). Here we describe the characterization of a 3095-bp mouse pIgR cDNA, which encodes a protein of 771 amino acids. Northern blot analysis detected a single mouse pIgR transcript of 3.9 kb, expressed at high levels in small intestine and liver, and at low levels in lung. Alignment of the amino acid sequences of mouse, rat, human, bovine, and rabbit pIgR revealed that functional regions of the molecule are conserved across species. In the extracellular region, conserved motifs include: a 23-amino acid pIg-binding site, 11 intradomain disulfide bonds, consensus sites for N-glycosylation, and a putative cleavage site at which the extracellular region of pIgR (secretory component) is released from the plasma membrane. A 10-amino acid sequence within the transmembrane region is highly conserved, possibly reflecting a mechanism for transmitting signals from the extracellular region to the cytoplasmic tail. Conservation within the cytoplasmic tail of pIgR is clustered in motifs that mediate polarized sorting, endocytosis, and transcytosis. PMID- 7836759 TI - A mutated promoter of a human Ig V lambda gene segment is associated with reduced germ-line transcription and a low frequency of rearrangement. AB - Several explanations for skewed variable (V) gene usage in the expressed Ig repertoire have been put forth, ranging from cellular selection to differences in the actual rearrangement frequencies of individual V gene segments. In this report we study V gene usage in human Ig lambda rearrangements in an in vitro system, thus largely avoiding selective forces. We find a significant bias in V lambda gene usage in these rearrangements. Through deletional mapping on Southern blots, the relative chromosomal organization of members of the V lambda I, V lambda V, V lambda VI, and V lambda X families was established, which revealed that the bias in V lambda gene usage cannot be readily explained by chromosomal location. We further found that the qualities of the recombination signal sequences, nucleotide sequence/regions of homology of the coding ends or the CpG methylation patterns, do not explain this bias either. We do, however, find a direct correlation between a low frequency of rearrangement and a reduced level of germ-line transcription of a particular V gene segment. We were able to identify three mutations in the octamer motif of the promoter region of this V gene segment. This is the first report showing that mutations in important transcriptional control motifs of individual V gene segments are associated with reduced levels of transcription in the germ line, which in turn may influence the frequency of rearrangement and the shaping of the expressed Ig repertoire. PMID- 7836760 TI - Induction of long-lasting immunity to Plasmodium yoelii malaria with whole blood stage antigens and copolymer adjuvants. AB - We previously reported that protection of mice from nonlethal Plasmodium yoelii malaria by immunization with whole killed blood-stage parasites was dependent on the adjuvant and that adjuvants influenced both the specificity and isotype of Ab. Additional studies with the most effective formulations were undertaken to better define the protective responses and 100% protection from lethal P. yoelii malaria was produced by three immunizations with Ag in copolymer P1004 and detoxified RaLPS as adjuvants and 83% protection was induced by a single immunization. The protection lasted for 9 mo and was associated with an anamnestic rise in Ab titer of the IgG2a isotype during the challenge infection. Passive immunization with Ab from animals that had been immunized and challenged transferred sterile immunity. Splenectomy reduced, but did not abolish, protection. These data suggest that the effective Ab is directed against labile epitopes on the surface of blood-stage parasites. The vaccines primed animals for production of such Ab, but its synthesis was efficiently induced only by challenge with live organisms. PMID- 7836761 TI - T cell subset-dependent modulation of immunity to Borrelia burgdorferi in mice. AB - The possible involvement of specific T cells in resolution of infections with Borrelia burgdorferi (Bb), the causative agent of human Lyme disease, has not been adequately studied. To investigate the potential role of T cell subsets in resistance, we have depleted mice of CD4+ and CD8+ T cell subsets in vivo by the administration of specific mAbs and have examined outcomes after infection with Bb. Our results indicate that CD4+ T cells are required for immunologic control of spirochete levels, because their depletion in both susceptible C3H/HeN and resistant BALB/c mice increased the severity of arthritis and the numbers of spirochetes found in joints and skin, as compared with Bb-infected mice treated with a control mAb. In contrast, the CD8+ T cell compartment, particularly in susceptible C3H/HeN mice, appears to promote the disease process, possibly by interfering with the generation of protective immunity, as abrogation of this subset in vivo led to a reduction in both arthritis and in spirochete levels found in joints and skin when compared with Bb-infected control mice. Our inability to establish a correlation between resistance and Bb-specific IgG Ab levels in these mice raises the possibility that Ab-independent mechanisms are important in protection. These findings suggest that the final outcome in Bb infected hosts may be the net effect of antagonistic influences exerted by CD4+ and CD8+ T cell subsets. PMID- 7836762 TI - Superantigen-induced human CD4+ helper/killer T cell phenomenon. Selective induction of Th1 helper/killer T cells and application to tumor immunotherapy. AB - Human CD4+ T cells activated with staphylococcal enterotoxin A (SEA) were fractionated by Percoll discontinuous density gradient centrifugation to enrich SEA-reactive CD4+ T cells. The SEA-reactive CD4+ T cells showed significant cytotoxicity, so-called superantigen-dependent cell-mediated cytotoxicity, against SEA-coated class II-positive tumor cells. During lysis of SEA-coated tumor cells, SEA-reactive CD4+ T cells produced high levels of IL-2 and IFN-gamma but not IL-4 in an Ag-specific manner. The skewing of human CD4+ T cells to Th1 type helper/killer T cells was also demonstrated when SEA-reactive CD4+V beta 5.3+ clonal T cells were cultured with SEA, but not with PHA or OKT3 mAb. Interestingly, the generation of SEA-reactive helper/killer T cells was negatively regulated by IL-4, but up-regulated by IL-12. The SEA-reactive CD4+ helper/killer T cells were able to generate from PBMC of tumor patients and could be expanded to 10(9) levels in a 7-day culture. The SEA-reactive CD4+ helper/killer T cells were specifically targeted to c-erbB-2 positive human colon cancer cells using SEA-conjugated-anti-c-erbB-2 mAb. These results initially demonstrated that SEA-activated human CD4+ T cells are a Th1 type of Th cell that has both helper and killer functions which may be useful for adoptive tumor immunotherapy in combination with SEA-conjugated antitumor mAb. PMID- 7836763 TI - CD4+ alpha beta T cell and gamma delta T cell responses to Mycobacterium tuberculosis. Similarities and differences in Ag recognition, cytotoxic effector function, and cytokine production. AB - CD4+ and gamma delta T cells are activated readily by Mycobacterium tuberculosis. To examine their role in the human immune response to M. tuberculosis, CD4+ and gamma delta T cells from healthy tuberculin-positive donor were studied for patterns of Ag recognition, cytotoxicity, and cytokine production in response to M. tuberculosis-infected mononuclear phagocytes. Both T cell subsets responded to intact M. tuberculosis and its cytosolic Ags. However, CD4+ and gamma delta T cells differed in the range of cytosolic Ags recognized: reactivity to a wide m.w. range of Ags for CD4+ T cells, and a restricted pattern for gamma delta T cells, with dominance of Ags of 10 to 15 kDa. Both T cell subsets were equally cytotoxic for M. tuberculosis-infected monocytes. Furthermore, both CD4+ and gamma delta T cells produced large amounts of IFN-gamma: mean pg/ml of IFN-gamma in supernatants was 2458 +/- 213 for CD4+ and 2349 +/- 245 for gamma delta T cells. By filter-spot ELISA (ELISPOT), the frequency of IFN-gamma-secreting gamma delta T cells was one-half of that of CD4+ T cells in response to M. tuberculosis, suggesting that gamma delta T cells on a per cell basis were more efficient producers of IFN-gamma than CD4+ T cells. In contrast, CD4+ T cells produced more IL-2 than gamma delta T cells, which correlated with diminished T cell proliferation of gamma delta T cells compared with CD4+ T cells. These results indicate that CD4+ and gamma delta T cell subsets have similar effector functions (cytotoxicity, IFN-gamma production) in response to M. tuberculosis infected macrophages, despite differences in the Ags recognized, IL-2 production, and efficiency of IFN-gamma production. PMID- 7836764 TI - Limited T cell antigen receptor repertoire in tumor-infiltrating lymphocyte and inhibition of experimental lung metastasis of murine melanoma by anti-TCR antibody. AB - We analyzed the variability of T cell Ag receptor in tumor-infiltrating lymphocytes in primary and metastatic melanomas. Using a very sensitive inverse/double step PCR, we found the preferential V alpha usage of TCR in tumor infiltrating lymphocytes in which some TCR sequences were homogenous. However, the profile of TCR V alpha expression was different in primary and metastatic melanomas. V alpha 8+, V alpha 2+, V alpha 4+, and V alpha 3+ TCR were the most dominant repertoires in primary melanoma, whereas V alpha 3+ and V alpha 4+ TCR dominated metastatic melanoma. Depletion of V alpha 3 T cells by the injection of tumor-bearing mice with anti-V alpha 3 Ab resulted in protection against experimental lung metastasis, indicating that V alpha 3+ regulatory T cells exist in the tumor site and help metastatic tumor growth. PMID- 7836765 TI - Accumulation of distinct T cell clonotypes in human solid tumors. AB - Tumor-infiltrating lymphocytes (TIL) have been described in a variety of human solid tumors. It is unknown whether such T cells are nonspecific inflammatory cells or a subset of specific host immune responses. To examine this question, we have analyzed the clonotypes of TCR beta-chain messages expressed in TIL, draining lymph nodes, and PBL of 10 patients with uterine or ovarian tumors. We report here that TIL bears distinct T cell clonotype accumulations only in patients without obvious metastasis. In contrast, accumulations of clonally expanded T cells were also found in lymph nodes and PBL of patients with metastatic cancer. The numbers and locations of the accumulated T cell clonotypes seemed to correlate with the stage of tumor invasion and the degree of metastasis. These data support the existence of Ag-driven immune responses to solid tumors in vivo. PMID- 7836766 TI - Isotype switching from IgG3 to IgG1 converts a nonprotective murine antibody to Cryptococcus neoformans into a protective antibody. AB - Passively administered mAbs to Cryptococcus neoformans capsular polysaccharide can alter the course of infection in mouse models. In preliminary studies of passive Ab efficacy, most IgM, IgA, and IgG1 mAbs were protective, but the few IgG3 mAbs tested did not confer significant protection. Because IgG3 is effective in pneumococcal infections, this phenomenon was examined more rigorously by generating an IgG1 switch variant from the non-protective IgG3 mAb 3E5 and comparing its protective efficacy in a murine model of i.v. infection by using strains of both the A and D serotypes. The 3E5 IgG3 mAb did not prolong survival or reduce organ fungal burden. Rather, the IgG3 decreased survival relative to controls. In contrast, the IgG1 switch variant of 3E5 significantly prolonged survival, reduced organ colony-forming units, and reduced serum polysaccharide Ag level in infected mice. The results establish that isotype is important for Ab efficacy against C. neoformans. PMID- 7836767 TI - Human urokinase-type plasminogen activator primes neutrophils for superoxide anion release. Possible roles of complement receptor type 3 and calcium. AB - Urokinase-type plasminogen activator (uPA), which binds to cells via a specific receptor (uPAR), participates in pericellular proteolysis during leukocyte migration. Previous studies have indicated that uPAR is physically associated with CR3 (CD11b/CD18). To test the functional interactions of CR3 and uPAR, we have examined the ability of uPA to elicit changes in cytosolic calcium levels of normal neutrophils, neutrophils from a leukocyte adhesion deficiency (LAD) patient, and 3T3 transfectants expressing CR3, uPAR, or both. We found that calcium levels of neutrophils increased from 106 +/- 6 nM in untreated cells to 199 +/- 25 nM in the presence of uPA. In contrast, no significant change in calcium was observed when neutrophils from an leukocyte adhesion deficiency patient were examined. The uPA-dependent calcium rise was inhibited by mAb directed against either CR3 or uPAR and required intact uPA. To substantiate further these findings, we prepared transfectants expressing genes encoding uPAR, CR3, and both receptors; only cells expressing both receptors experienced a rise in intracellular calcium. Although uPA's calcium signal is insufficient to trigger superoxide production, FMLP dose-dependent superoxide production was greatly enhanced by incubating neutrophils with intact, but not fragmented, uPA. Flow cytometry experiments utilizing an FMLP analogue exclude the possibilities that urokinase binds to the FMLP receptor or up-regulates its expression. We suggest that calcium is a second messenger of uPA, that this message is mediated in a CR3-dependent fashion, and that this signal primes neutrophils for superoxide production. PMID- 7836768 TI - Estrogen modulation of JE/monocyte chemoattractant protein-1 mRNA expression in murine macrophages. AB - The chemotactic cytokine, monocyte chemoattractant protein-1 (MCP-1), and its murine homologue, JE, have been detected in atherosclerotic lesions but not in normal arteries, implicating that these proinflammatory cytokines may be involved in the pathogenesis of atherosclerosis. Epidemiologic studies reveal that postmenopausal women receiving estrogen replacement for treatment of osteoporosis have a greatly reduced risk of developing cardiovascular disease. Because JE/MCP 1 and estrogen play regulatory roles in the development of atherosclerotic lesions, we chose to examine the effect of estrogen treatment on JE/MCP-1 mRNA expression in macrophages. 17 beta-estradiol (E2) inhibited LPS-stimulated JE/MCP 1 mRNA expression in ANA-1 and J774A.1 murine macrophage cell lines and in thioglycolate-elicited murine peritoneal macrophages. Inhibition of JE/MCP-1 mRNA ranged from 50 to 90%, with a maximal effect occurring at a concentration of 300 pg/ml E2. Conversely, E2 had little effect on LPS-stimulated TNF-alpha mRNA production. Treatment of LPS-stimulated macrophages with moxestrol, an estrogen agonist, resulted in a similar inhibition, and the addition of the estrogen antagonist, tamoxifen, reversed E2 inhibition of JE/MCP-1 mRNA expression. Progesterone failed to inhibit LPS-induced JE/MCP-1 mRNA expression. Immunohistochemical analysis revealed the presence of estrogen receptors in ANA-1 cells, indicating that E2 inhibition of LPS-induced JE/MCP-1 mRNA expression in murine macrophages may be mediated through the estrogen receptor. Thus, another mechanism whereby estrogen exerts antiatherogenic effects may be through prevention of macrophage accumulation in the atherosclerotic lesion. PMID- 7836769 TI - Interaction of human monocyte Fc gamma receptors with rat IgG2b. A new indicator for the Fc gamma RIIa (R-H131) polymorphism. AB - Rat mAbs receive considerable interest for immunologic intervention in man. The rat IgG2b isotype has previously been found to be optimally active both in vivo and in vitro. We found that both a rat IgG2b CD3 mAb and a monovalent hybrid rat IgG2b-mouse IgG1 bispecific Ab triggered T cell activation in PBMC. Inhibition analyses with mAb blocking different human IgG Fc receptors (Fc gamma R) showed a dimorphic pattern. In donors expressing an Fc gamma RIIa-R/R131 allotype (previously defined on the basis of interaction with mouse (m) IgG1 as "high responder") anti-Fc gamma RI mAb 197 inhibited rat IgG2b induced T cell mitogenesis almost completely. In Fc gamma RIIa-H/H131 ("low responder" allotype) donors, however, both anti-Fc gamma RI mAb 197 and anti-Fc gamma RII mAb IV.3 were essential for optimal inhibition of mitogenesis. T cell proliferation experiments performed with the use of Fc gamma R-transfected fibroblasts as accessory cells showed the high affinity Fc gamma RIa (CD64) to interact with both rat IgG2b and rat IgG2b-mlgG1 hybrid CD3 mAb. The use of the two types of Fc gamma RIIa (CD32)-transfectants instead showed rat IgG2b CD3 mAb to interact solely with the IIa-H/H131 allotype. Interestingly, rat IgG2b-mlgG1 hybrid mAb did not interact effectively with this low affinity Fc gamma R. This suggests a requirement for only one rat IgG2b H chain for Fc gamma RIa-mediated binding, whereas two identical H chains seem to be necessary for proper interaction with Fc gamma RIIa. Ab-sensitized RBC-rosette experiments performed with the use of a rat IgG2b anti-NIP mAb confirmed the interaction pattern observed with rat CD3 mAb, supporting the phenomena to be isotype-, and not mAb-, dependent. These analyses point to a unique reactivity pattern for rat IgG2b Abs, interacting both with the high affinity Fc gamma RIa in all donors and Fc gamma RIIa of individuals expressing the IIa-H131 allotype. PMID- 7836770 TI - Cellular expression of the C5a anaphylatoxin receptor (C5aR): demonstration of C5aR on nonmyeloid cells of the liver and lung. AB - The small-complement C5 activation fragment, C5a, is a potent phlogistic molecule that, on binding to the C5a Receptor (C5aR), mediates contraction of smooth muscle, enhances vascular permeability, and promotes leukocyte functions such as directed chemotaxis, degranulation, mediator release, and production of superoxide anions. Although C5aR expression has traditionally been thought to be limited primarily to myeloid blood cells, including neutrophils, monocytes, macrophages, and eosinophils, we report here that C5aR is expressed by liver and lung cells as well as by cells in several other tissues. By Northern blot analysis, it was determined that mouse liver, baboon liver, human liver, and the human hepatoma-derived cell line HepG2 express a normal size (2.3 kb) C5aR mRNA; in HepG2 cells, the quantity of C5aR mRNA was comparable to that contained in dbcAMP-differentiated U937 cells. HepG2 cells were demonstrated to express the C5aR on their cell surface by flow cytometric and immunofluorescence analyses as well as by 125I-C5a binding assays. The binding data indicated that HepG2 cells express a single class of C5aR with a Kd of 1.18 nM and approximately 28,000 receptors per cell. In vivo expression of C5aR in human liver cells was demonstrated by in situ hybridization and immunohistochemistry analyses. Northern blot analysis of murine and baboon organs shows that, in addition to the liver, other tissues express C5aR mRNA in significant quantities, including the spleen, lung, heart, kidney, and intestine. Moreover, mice treated with LPS show a large increase in C5aR mRNA in all these tissues except the intestine. Immunostaining of human lung tissue demonstrated that bronchial and alveolar epithelial cells, as well as vascular smooth muscle and endothelial cells, also express the C5aR. Collectively, these data indicate that the C5aR is expressed in several different types of cells in liver and lung, and in yet undetermined cell types in spleen, heart, intestine, and kidney. Furthermore, these data suggest that the C5a anaphylatoxin mediates previously unrecognized functions by binding to tissue cells that express the C5aR. PMID- 7836771 TI - Fibrin enhances the expression of IL-1 beta by human peripheral blood mononuclear cells. Implications in pulmonary inflammation. AB - Tissue injury is accompanied by increased vascular permeability and influx of plasma proteins including fibrinogen. Fibrinogen is converted into a fibrin matrix by procoagulants activated at the site of tissue injury and inflammation. This fibrin matrix is thought to participate early in the inflammatory response by providing a temporary protein "scaffold" for inflammatory cell adhesion and migration, and subsequent remodeling of the tissue with permanent extracellular matrix proteins such as collagen. Collagen and fibronectin have been shown to regulate the expression of inflammatory cytokines, but whether fibrin can regulate cytokine expression is not known. We hypothesized that fibrin induces the expression of the proinflammatory cytokine IL-1 beta and sought to explore mechanisms responsible for this induction. In this report, we demonstrate that fibrin stimulates human PBMCs to express IL-1 beta message and protein. We show that induction of IL-1 beta by fibrin is mediated partly by the integrin receptor CD11b/CD18 and modulated by cytoskeletal rearrangement. Fibrin also suppresses production of IL-1 receptor antagonist (IL-1ra) a non-bioactive competitor of IL 1 for IL-1Rs. We propose that injured tissues where the conditions favor coagulation and fibrin accumulation, the interaction between mononuclear cells and the newly formed fibrin matrices may elicit the production of the proinflammatory cytokine IL-1 beta. This proposal is supported by immunohistochemical studies which show the co-distribution of fibrin and IL-1 beta in granulomas in lung sections from patients with the systemic granulomatous disease, sarcoidosis. PMID- 7836772 TI - Growth hormone is a human macrophage activating factor. Priming of human monocytes for enhanced release of H2O2. AB - Although many effects of growth hormone (GH) and related factors upon the immune system have been demonstrated, few studies have examined the capacity of these factors to modulate human monocyte function in vitro. Assaying a range of mediators, only GH and prolactin (PRL), at 0.3 to 1.0 micrograms/ml, and growth hormone-releasing hormone (GRH) at very high doses, primed monocytes for enhanced hydrogen-peroxide production (H2O2) in response to PMA. GH-induced priming was not caused by endotoxin, nor by production of lymphokines such as IFN-gamma. Exogenous insulin-like growth factor-I (IGF-I), alone or in combination with GH, was without effect, making it unlikely that GH mediates its effects on monocytes via an autocrine/paracrine action of IGF-I. Monocytes specifically bound radiolabeled GH and contained mRNA for the GH receptor and, in some donors, the PRL receptor. Therefore, GH probably exerts its effects as a human macrophage activating factor through either GH or PRL receptors, without requiring production of IGF-I. PMID- 7836773 TI - Immature B lymphocytes are deficient in expression of the src-family kinases p59fyn and p55fgr1. AB - Unlike mature B cells, immature B cells are highly sensitive to tolerance induction and do not proliferate in response to stimulation through their Ag receptors. Our previous studies have suggested that this differential responsiveness is caused by differences in Ag receptor-proximal signaling pathways. Because many of these pathways are regulated by tyrosine phosphorylation, we have compared the expression and activity of tyrosine kinases in immature and mature B cells. Consistent with previous studies, we demonstrate that mature B cells express syk, lyn, blk, hck, and fyn; in addition, we find that they express significant amounts of the src-family kinase p55fgr. Immature B cells from day-3 mouse spleen show similar expression and activity of syk, lyn, blk, and hck. However, these cells have marked deficiencies in fyn and fgr expression. Differential expression of fyn and fgr is also observed in immature cells from the bone marrow, indicating that this phenotype is characteristic of the immature stage of B cell development. High levels of fyn and fgr are detectable in splenic B cells beginning at 4 wk of age, coincident with the appearance of cells that proliferate in response to receptor cross-linking. These observations indicate that expression of the src-family kinases fyn and fgr is regulated developmentally in murine B lymphocytes. Moreover, they suggest that these kinases may be important for mature B cell responses to Ag receptor stimulation, and that their absence may contribute to the unresponsiveness and tolerance susceptibility of immature B cells. PMID- 7836774 TI - Circulating forms of ICAM-3 (cICAM-3). Elevated levels in autoimmune diseases and lack of association with cICAM-1. AB - The intercellular adhesion molecule-3 (ICAM-3) has been identified as the third LFA-1 ligand in addition to ICAM-1 and ICAM-2. In this report we have identified circulating forms of ICAM-3 (cICAM-3) in human serum. Using a sandwich ELISA with two monoclonal anti-ICAM-3 Abs, we detected cICAM-3 in concentrations between 40 and 360 ng/ml in all of 112 healthy controls. An analysis of patient sera from 10 different immune-mediated diseases revealed a distinct pattern of expression. Significantly elevated cICAM-3 levels were found in rheumatoid arthritis, systemic lupus erythematosus, Guillain-Barre syndrome, and multiple sclerosis, but not in type I diabetes, Grave's disease, chronic autoimmune thyroiditis, ulcerative colitis, or Crohn's disease. cICAM-3 levels were significantly higher in systemic lupus erythematosus patients with active compared with nonactive disease. Despite their binding to the same integrin receptor, serum levels of cICAM-3 did not correlate with cICAM-1 concentrations in either normal persons or in patients. The majority of patients had either elevated cICAM-3 or cICAM-1 levels but not both. In conclusion, a circulating form of ICAM-3 is present in human sera. cICAM-3 expression is elevated in certain immune-mediated diseases but occurs independently of cICAM-1. PMID- 7836775 TI - Overexpression of IL-10 in atopic dermatitis. Contrasting cytokine patterns with delayed-type hypersensitivity reactions. AB - The skin lesions of patients with atopic dermatitis provide a model to study immunoregulation in human allergy. To determine the local cytokine pattern of cells present (both endogenous and recruited) at the site of disease, we extracted RNA from skin biopsy specimens from patients with atopic dermatitis, allergic contract dermatitis, and positive tuberculin reactions and used PCR to assay for cytokine mRNA. cDNAs were normalized to the intensity of the CD3 delta PCR product as a marker of T cell mRNA. We found overexpression of IL-10 mRNA in atopic dermatitis lesions, in comparison with allergic contact dermatitis lesions and tuberculin reactions. In contrast, IL-4 mRNA was most strongly expressed in allergic contact dermatitis lesions and IFN-gamma mRNA was the predominant cytokine in tuberculin reactions. Using an anti-IL-10 mAb with immunoperoxidase, we localized IL-10 protein to large mononuclear cells in the dermal infiltrate of atopic lesions. After immunomagnetic sorting of mononuclear cell populations from PBMC of atopic dermatitis subjects, IL-10 mRNA as measured by PCR was found to be strongly expressed in CD14+ cells. Spontaneous release of IL-10 from PBMC-derived adherent cells was greater in atopic dermatitis donors than normal controls. We therefore renormalized skin biopsy cDNA according to the level of beta-actin PCR product, as a marker of total cellular mRNA, and found by PCR that IL-10 was nevertheless greatest in atopic dermatitis subjects. We conclude that the relative overexpression of IL-10 in atopic dermatitis greatest in atopic dermatitis subjects. We conclude that the relative overexpression of IL-10 in atopic dermatitis may contribute to the up-regulation of humoral responses and the down-regulation of Th1 responses. PMID- 7836776 TI - Structure and repertoire usage of rat TCR alpha-chain genes in T cells infiltrating heart allografts. AB - We have studied the structure and diversity of TCR alpha-chain genes used by graft-infiltrating lymphocytes (GIL) in the ACI-to-LEW rat cardiac allograft model. We previously reported the structure of 16 different V alpha and 17 different J alpha genes isolated in two different cDNA libraries established from LEW thymocytes and GIL. In this report, we obtained new sequence information for 17 additional V alpha and J alpha genes from the GIL cDNA library. This study completes our characterization of 33 different V alpha and 23 different J alpha genes in rats. The V alpha genes are classified into 14 different families. Nucleotide sequence comparison with mouse alpha genes revealed the existence of mouse homologues for all the J alpha and 32 of the 33 V alpha genes. One of the rat V alpha genes seemed to have no known mouse counterpart and is classified here as a V alpha 24 gene family. The definition of rat TCR alpha-chain genes derived from these studies should facilitate a better understanding of the T cell role in pathologic conditions including autoimmune diseases and graft rejection. As for the TCR alpha-chain repertoire usage in allograft rejection, we completed the characterization of 36 productively rearranged TCR alpha-chain cDNA clones from the GIL cDNA library and found 31 different V alpha and 23 different J alpha genes among these clones. Unlike the TCR beta-chain that uses a limited repertoire, the alpha-chain repertoire usage seems to be relatively more diverse in this allograft model. These results suggest that the interaction of beta-chain with allogeneic MHC-encoded determinants may dictate the T cell reaction to the heart allograft in this model. PMID- 7836777 TI - DNA mimics a self-protein that may be a target for some anti-DNA antibodies in systemic lupus erythematosus. AB - Recent studies suggest that some anti-DNA Abs in systemic lupus erythematosus may actually be Abs to specific proteins and that binding to dsDNA is a nonspecific cross-reactive event. To identify such proteins that bind to anti-DNA Abs, a cDNA expression library from human placenta was screened with mAb 3E10, a pathogenic anti-dsDNA Ab. MAb 3E10 was shown to bind to a 44-amino-acid fragment of HP8, a newly identified protein with amino acid sequence homology to the family of SPARC extracellular matrix proteins. To determine if Ab binding to both dsDNA and HP8 protein occurs through a common binding site, and therefore represents molecular mimicry, the Ab binding domains for protein and DNA were mapped. Chain recombinations between mAb 3E10 and a non-anti-DNA mAb showed that both the heavy and the light chains of mAb 3E10 were essential for anti-dsDNA and anti-HP8 reactivity. Mutagenesis experiments demonstrated that dsDNA and HP8 shared several critical binding residues located in all three complementarity determining regions of mAb 3E10 VH. Moreover, Abs to HP8 were demonstrated in the sera of a subset of lupus patients. These results indicate that DNA mimics the HP8 protein in binding a lupus Ab, and that this protein may be a target for a subpopulation of anti-dsDNA Abs in systemic lupus erythematosus. PMID- 7836779 TI - Characterization of the apoptotic effects of human tumor necrosis factor: development of highly rapid and specific bioassay for human tumor necrosis factor and lymphotoxin using human target cells. AB - Currently available bioassays for most cytokines require several days and therefore must be performed under sterile conditions. In this report we describe a bioassay for tumor necrosis factor (TNF) and lymphotoxin (LT) that is extremely rapid and specific and does not require sterile conditions. Using tritiated thymidine release, we could conveniently monitor degradation of DNA into small fragments following the incubation of human myelogenous leukemia ML-1a cells with TNF. The assay showed that TNF-dependent DNA fragmentation was potentiated by cycloheximide and occurred within 90 min. Treatment of cells to TNF lead to apoptosis as indicated by thymidine release, DNA laddering on agarose gels and morphological alterations. Under these conditions, plasma membrane were not damaged as indicated by lack of chromium release. This effect was linear with TNF concentration. This assay had high throughput, did not require sterile conditions, could be carried out in the absence of serum, and was sensitive only to TNF and LT and not to interferon (IFN)-alpha, IFN-beta, IFN-gamma, transforming growth factor beta, interleukin-4, leukemia inhibitory factor and granulocyte-monocyte colony stimulating factor; all cytokines known to inhibit different cell types. Besides detection of TNF in biological fluids, this assay may prove useful for the identification of novel inhibitors of TNF action. PMID- 7836778 TI - A new protocol for the propagation of dendritic cells from rat bone marrow using recombinant GM-CSF, and their quantification using the mAb OX-62. AB - Bone marrow (BM)-derived dendritic cells (DC) are the most potent known antigen (Ag) presenting cell in vivo and in vitro. Detailed analysis of their properties and mechanisms of action requires an ability to produce large numbers of DC. Although DC have been isolated from several rat tissues, including BM, the yield is uniformly low. We describe a simple method for the propagation of large numbers of DC from rat BM and document cell yield with the rat DC marker, OX-62. After depletion of plastic-adherent and Fc+ cells by panning on dishes coated with normal serum, residual BM cells were cultured in gelatin coated flasks using murine rGM-CSF supplemented medium. Prior to analysis, non-adherent cells were re depleted of contaminating Fc+ cells. Propagation of DC was monitored by double staining for FACS analysis (major histocompatibility complex (MHC) class II+/OX 62+, OX-19-). Functional assay, morphological analysis and evaluation of homing patterns of cultured cells revealed typical DC characteristics. MHC class II and OX-62 antigen expression increased with time in culture and correlated with allostimulatory ability. DC yield increased until day 7, when 3.3 x 10(6) DC were obtained from an initial 3 x 10(8) unfractionated BM cells. Significant numbers of DC can be generated from rat BM using these simple methods. This should permit analysis and manipulation of rat DC functions in vivo and in vitro. PMID- 7836780 TI - Eosinophils isolated with two different methods show different characteristics of activation. AB - Eosinophils can be isolated from a mixed suspension of granulocytes by different procedures. We compared functional responses of human eosinophils purified according to two different principles: (1) an fMLP-induced difference in specific gravity between eosinophils and neutrophils and (2) selective removal of neutrophils by means of immunomagnetic beads coated with CD16 mAb. The results showed that eosinophils isolated with the CD16 beads method have a higher capacity to synthesize platelet activating factor (PAF) after stimulation with serum-treated zymosan (STZ) than eosinophils purified with the fMLP method. Binding of STZ and subsequent activation of the respiratory burst were also increased in CD16-isolated eosinophils. Furthermore, eosinophils isolated with the CD16 beads showed stronger chemotactic responses towards C5a and PAF. The difference in activity of these eosinophil preparations might be explained by a loss of the more active cells during the isolation with the fMLP method: only 30 60% of the eosinophils were recovered with this method, in contrast to a recovery of more than 95% with the CD16 beads method. Indeed, this 'lost' population of eosinophils, subsequently purified with CD16-coated beads, had a higher respiratory burst activity. The alternative explanation, i.e., an enhancement of eosinophil function by the beads method, appeared not to be valid, because repurification of fMLP-isolated eosinophils in the presence of fresh neutrophils and CD16-coated beads did not change the reactivity of the eosinophils. We conclude that the fMLP method leads to selective purification of eosinophils with a resting (or 'unprimed') phenotype. PMID- 7836781 TI - Selection of monoclonal antibodies for the identification of lymphocyte surface antigens in the New World primate Saguinus oedipus oedipus (cotton top tamarin). AB - 32 monoclonal antibodies reactive with human CD antigens were tested against tamarin peripheral blood lymphocytes, ConA blasts and lymphoblastoid B cell lines derived from tamarin cells. Reagents that cross-react with MHC class I and II, B cells (CD20, -21 and -23), monocytes (CD14) and NK cells (CD16, -56) have been identified. In addition monoclonals that cross-react with T cells (CD2, CD3), the CD4/CD8 subsets of T cells and the IL-2 receptor (CD25) are reported. A monoclonal against the beta chain of LFA-1 (CD18) cross-reacted strongly, but there was only a very poor cross-reaction with a monoclonal against the alpha chain of CD11a. Two monoclonals tested against ICAM-1(CD54) were negative. PMID- 7836782 TI - Bifunctional and multimeric complexes of streptavidin fused to single chain antibodies (scFv). AB - Multivalent and multispecific antibodies with defined stoichiometry could provide valuable tools for biological and medical research and for the diagnosis and therapy of cancer. We have therefore fused single chain antibodies (scFv) with core-streptavidin. This chimeric protein, expressed by the vector pSTE-215 (plasmid for streptavidin-tagged expression), can form tetrameric complexes, binds antigen and contains the biotin binding site which may be used for further complex formation. An additional cysteine was inserted near the carboxy terminus to facilitate the construction of covalently linked bifunctional molecules. The scFv fusion protein could be purified by affinity chromatography using biotin analogues. We have also shown that the scFv fusion protein could be used for direct detection of its antigen in ELISA and Western blots when stained with biotinylated horseradish peroxidase. PMID- 7836783 TI - Difference and ratio plots: simple tools for improved presentation and interpretation of scientific data. Unexpected possibilities for the use of the conglutinin binding assay in inflammatory rheumatic diseases. AB - 11111onglutinin-binding assay (KgBa) has gained widespread use for the detection of circulating immune complexes. A recent paper questioned the interpretation of the results obtained by this method and the validity of the assay (Holmskov et al. (1992) J. Immunol. Methods 148, 225). We now present hitherto unnoted differences between controls and patients with either rheumatoid arthritis or systemic lupus erythematosus. For this we use simple, but unconventional, graphic representations of the data, based on difference plots and ratio plots. Differences between patients with Burkitt's lymphoma and systemic lupus erythematosus from another previously published study (Macanovic, M. and Lachmann, P.J. (1979) Clin. Exp. Immunol. 38, 274) are also represented using ratio plots. Our observations indicate that analysis by regression analysis may often be misleading. PMID- 7836784 TI - Pitfalls in the characterization of small intestinal lymphocytes. AB - The morphological characteristics of human intestinal lymphocytes may vary depending upon whether they are examined in tissue sections or after isolation. This study uncovered some causes of these discrepancies. The majority of intraepithelial lymphocytes (IEL) and lamina propria lymphocytes (LPL) are of the same size and granularity as peripheral blood mononuclear cells (PBMC), negating the idea that most IEL are large granular lymphocytes. LPL were previously shown to express markers of early activation by flow cytometry but not by immunohistochemistry. This study shows that it is the low density of surface antigen expression that explains this discrepancy: only the highly sensitive flow cytometric analysis can detect such low-density expression. Previous reports of intestinal macrophage and B cell numbers and functions vary markedly. This may be due to variable amounts of contamination with epithelial cells (EC) that lose their characteristic columnar appearance and cytoplasmic mucin upon isolation. They share many features of macrophages (such as morphology and binding to plastic and latex beads) but lack phagocytic ability and superoxide generation, explaining, perhaps, the wide variation in the reported functions of presumed intestinal macrophages. In addition, a large fraction of EC non-specifically strain with anti-immunoglobulin antibodies. Their contamination of intestinal lymphocyte preparations accounts for the discrepancy in B cell numbers identified by surface immunoglobulin expression versus B cell markers. Intestinal lymphocytes do indeed differ in many ways from circulating lymphocytes, but investigators must be attentive to factors that may artifactually alter their results. PMID- 7836785 TI - Flow cytometric determination of intracellular calcium changes in human peripheral blood mononuclear cells during conjugation to tumour cell lines. AB - Using a flow cytometric assay, conjugate formation between human peripheral blood mononuclear cells (PBMC) and three different human tumour cell lines has been analysed. Changes in the intracellular calcium levels of PBMC were monitored using the calcium sensitive dye Fluo-3. Target cell populations were distinguished by forward scatter or following loading with the fluorescent dye, SNARF-1. Intracellular calcium was expressed as a ratio of fluorescence of conjugated to unconjugated PBMC and followed for ten minutes after initiation of conjugation. The results demonstrate an apparent increase in intracellular calcium in PBMC conjugated to the NK-sensitive cell line K562, and that the kinetics and magnitude of this response varied considerably between individuals. Tumour cells which were resistant to lysis (as determined in a 4 h chromium release assay) were also capable of eliciting a calcium response from PBMC. Although the induction of a rise in intracellular calcium was therefore not correlated with cytotoxicity, it was greater in IL-2-activated PBMC upon exposure to the same target cell lines as PBMC. PMID- 7836786 TI - Universal cloning and direct sequencing of rearranged antibody V genes using C region primers, biotin-captured cDNA and one-side PCR. AB - Polymerase chain reaction (PCR) cloning has greatly facilitated the cloning of heavy and light chain genes from B cells and hybridomas and has been critical for the generation of natural antibody gene libraries for expression in bacteria and on filamentous phages. There remain difficulties, however, in cloning VH and VL genes from a number of mouse and rat hybridoma lines and from B cells from several other species due to insufficient sequence information. Here we describe a rapid and 'universal' strategy for cloning rearranged antibody genes from any species for which the sequence of the C segment(s) are known. First strand synthesis is primed with a biotinylated C region primer and full length cDNA is captured on streptavidin-coated magnetic beads for tailing with dGTP and terminal deoxynucleotidyl transferase. After tailing, the cDNA is captured again, amplified using polyC primers and used for direct sequencing or cloning. The use of C region primers and cDNA capture ensures that this one-side PCR procedure is efficient and rapid as well as being entirely independent of the sequence of the V segment. We demonstrate its application to the direct sequencing or cloning of the H and L chain genes from six mouse and rat hybridomas and propose that the method described will find applications in three areas: (i) cloning rearranged antibody genes in all cases in which cloning with V-J primers is not possible; (ii) repertoire studies in which an unbiased cloning procedure is required for accurate estimate of gene usage; and (iii) generation of VH and VL gene libraries from immunised animals. PMID- 7836787 TI - Comparison of antibody production to human interleukin-6 (IL-6) by sheep and chickens. AB - Chicken antibodies have been reported to provide an excellent alternative to their mammalian counterparts for immunodiagnostics, but detailed studies, particularly regarding their avidity, are limited. Prior to the development of an immunoassay for measuring human interleukin-6 (hIL-6) we compared the serum antibody responses of sheep and chickens to immunization with recombinant human IL-6 (rhIL-6) and studied the transfer of chicken serum antibodies to the egg yolk. Both chickens and sheep produced high avidity antisera (average avidity constants being 1.3 x 10(10) l/mol and 3.1 x 10(10) l/mol respectively after four immunizations) with chickens producing an unusually high avidity response after a single immunization. Although both antisera showed extremely high specificity for their ligand, both demonstrated a high degree of recognition for Chinese hamster ovary cell-derived IL-6 (CHO-IL-6), a glycosylated form of recombinant human interleukin-6 (rhIL-6) more akin to natural hIL-6. A delay of 3-4 days was found between the appearance of serum anti-IL-6 antibodies and their detection in the egg yolk; specific antibody in the latter was concentrated by a factor of 1.23 +/ 0.07 relative to serum. The binding characteristics of paired serum and yolk antibodies with respect to both rhIL-6 and CHO-IL-6 were identical. These studies demonstrate the suitability of both chickens and sheep as hosts for the production of large quantities of high quality antiserum to human IL-6. PMID- 7836788 TI - Modeling the average molecular weights of antigen-antibody complexes by probability theory. AB - A method is presented to calculate average molecular weights for linear antigen antibody complexes. Instead of determining the whole distributions and then using the distributions to calculate average properties, this method allows one to calculate the number-average, the weight-average, and the z-average molecular weights of the linear antigen-antibody complexes directly based on elementary probability theory and the recursive nature of antigen-antibody complexes. PMID- 7836789 TI - [Results of treatment of cystinuria and cystine lithiasis with alpha mercaptopropionylglycine. Apropos of 40 patients]. AB - From 1987 to 1990, 719 subjects (385 males and 334 females) were screened, by means of urocystin-kit, for cystinuria and cystine lithiasis, in Epirus district (North-West Greece). The positive results were confirmed by chromatographic analysis of urine amino acids and laboratory tests. Forty patients, belonging to six cystinuric families, were identified. These patients were excreting 3.1 +/- 1.7 mmol/24 h of cystine in urine. All patients were treated by per os administration of alpha-MPG in daily doses of 400-1,200 mg/24 h). We therefore report the results of a 4 +/- 2 year follow-up of these patients. We conclude that treatment with alpha-MPG is very effective with minimal side effects in patients suffering from cystinuria or cystine urinary calculi. PMID- 7836790 TI - [Urethral prolapse in young girls: a rare pathology in pediatric surgery. Our experience apropos of 22 cases observed at the Cocody and Yopougon University Hospitals]. AB - Twenty-two cases of prolapse of the urethral mucosa, a benign affection mainly encountered in young black girls, were observed over a 9-year period (1983-1992). This pathology is still poorly understood and the aetiology has not been clearly determined. Treatment protocols, medical and surgical, vary. We prefer exeresis of the prolapsed mucosa, followed by suture. The results have been quite satisfactory. PMID- 7836791 TI - [Contribution of urodynamic examinations in the exploration of micturition disorders in patients with Parkinson disease]. AB - 24 men (mean age 71.2 years) with micturition disorders and parkinson disease have been studied: irritative symptoms are present in 62.5%. Urodynamics were specially usefull when obstructive symptoms (37.5%). In these cases, 3/4 had a mechanical obstruction to be treated by surgery. 3 men had a neurologic bladder and needed a pharmacological treatment. In this high risk population, urodynamics seemed to be necessary. PMID- 7836792 TI - [Vesico-uterine fistulas. Analysis of 19 cases]. AB - Over a 15 year period (1977-1992), the authors have collected 19 cases of vesico uterine fistulas. These vesico-uterine fistulas rank in third place of genito urinary fistulas and occur in young patients (mean age is 30 years). Obstetrical etiology is recognised in .95% of cases (cesarean section and dystocic delivery). Leak of urine is present in 95% of cases, and is isolated in 47% or associated with intermittent hematuria in 48%. Diagnosis of this affection is based upon clinical examination with methylene blue test. Communication between bladder and uterus is proved by the issue of methylene blue through the uterus cervix. This communication may be confirmed by opacification (urography and hysterography). Perfect continence is obtained by surgical treatment. Fertility of these patients is often affected. PMID- 7836793 TI - [Sexual disorders after radical prostatectomy and their treatment. Psychological aspects]. AB - Forty-one men who had undergone radical prostatectomy and their wives were interviewed in order to evaluate the erectile disorders encountered after this operation and to facilitate therapeutic impact. Twenty-three of the women stated they were satisfied with their sexual intercourse before the operation and among them, 16 (70%) stated they were unsatisfied after their husband's operation. Among these 16 couples, 10 accepted sexual counselling which led to satisfaction with sexual intercourse in 8 couples. Sexual counselling was the only therapy needed in 1 couple, 4 men received intracavernous injections and 3 used a vacuum system. These results, as well as the impact of integrating the sexual partner in the treatment protocol for erectile impairment were discussed. PMID- 7836794 TI - [Small bowel obstruction at the site of introduction of the trocar: an unusual complication of laparoscopy]. AB - A 65 year old healthy female developed a small bowel obstruction after laparoscopic unroofing of a large, symptomatic, right renal cyst. After failure of conservative management, exploratory laparotomy revealed a very localized herniation of small intestine at a trocar site as suggested by CT scan. The hernia was reduced at the time of laparotomy and no bowel resection was necessary. The patient had an uneventful recovery. Although uncommon, bowel herniation at the site of trocar insertion should be recognized as part of the possible morbidity of laparoscopic surgery. The mechanism of development of such a complication and possible preventive measures are reviewed. A "preventive" fascial closure technique is suggested. PMID- 7836795 TI - [Inguinal-scrotal hernia of a bladder diverticulum]. AB - Bladder diverticula may be involved in inguinal hernias usually in the form of a sliding hernia. We studied three patients with scrotal herniation of bladder diverticulum, one of them having a neurogenic bladder. All our patients have had the diagnosis before undergoing hernia repair--so iatrogenic lesions of the bladder during surgical manipulations could be avoided. Methods for an early diagnosis of this rare occurrence are discussed along with aspects of surgical approach. PMID- 7836796 TI - [Emphysematous pyelonephritis caused by Candida albicans. Apropos of a new case]. AB - The authors report on a case of emphysematous pyelonephritis occurring in a diabetic patient and caused by Candida albicans. The fungal infection was proved by urine culture and histological examination of the nephrectomy specimen. The patient deceased despite intensive medical therapy and nephrectomy. PMID- 7836797 TI - Neuron-specific enolase. AB - The clinical value of neuron-specific enolase as a marker is small cell lung cancer, neuroblastoma, melanoma and seminoma has been reviewed. The role of serum and cerebrospinal NSE in benign and malignant disease of the central nervous system is discussed. PMID- 7836798 TI - Antigen "suicide": a preliminary study on the induction of specific anti immunoglobulin immunological suppression in vivo, using radiolabelled immunoglobulin as "lethal" antigen. AB - The effectiveness of immunodiagnosis and immunotherapy is limited when xenogeneic antibodies are used, due to the host's anti-immunoglobulin response. We have attempted to specifically suppress the immune response to the immunogen (immunoglobulin) administered. The concept of antigen "suicide" was used, where the antigen (immunoglobulin) was suitably radiolabelled and administered to animals. The question asked was whether immunocompetent cells that specifically interact with the radiolabelled immunogen, would be lethally irradiated and thus become inactivated rather than stimulated. When mice where primed with 111Indium labelled polyclonal human IgG (specific activity 15 mCi/mg), they responded 13% less than control animals (p = 0.0485). This suppression was IgG-specific, since all animals responded similarly to a control antigen (human albumin). However, a second boost of the same 111Indium-labelled preparation (specific activity 7 mCi/mg) did not show any statistically significant immunosuppression. In addition, rabbits primed with 125Iodine-labelled mouse monoclonal antibody (specific activity 180 mCi/mg) and boosted with the same unlabelled monoclonal antibody, showed a similar anti-mouse antibody response with the ones that received only unlabelled preparation twice. We conclude that the concept of antigen "suicide" may be effective for the induction of specific unresponsiveness; when immunoglobulins are radiolabelled with 111Indium at high specific activities, the desired state of specific immune suppression may be induced. PMID- 7836799 TI - Expression of GST-mu transferase in breast cancer patients and healthy controls. AB - The expression of glutathione S-transferase mu was measured by a qualitative immunoenzymatic assay in the blood samples of 108 women (63 breast cancer patients and 45 healthy controls) in order to analyze the relationships of GST-mu phenotype and smoking habits with tumor characteristics of breast cancer patients, such as tumor extension, nodal status, hormone receptor status and DNA content by flow cytometry. GST-mu was expressed in 53/108 (49%) of cases without any significant difference between healthy or neoplastic subjects, smokers or non smokers, pre or post-menopausal, younger or older subjects. Moreover, the percentages of the GST-mu phenotype did not differ significantly in patients with different ER and PgR tumor status, tumor extension or nodal status. By contrast, aneuploid DNA tumor content was shown to be significantly associated with GST-mu expression (24% and 76% GST-mu positive, respectively, in diploid and aneuploid cases; p < 0.003). The biological meaning of this association remains to be interpreted. PMID- 7836800 TI - Expression of the tumor-associated glycoproteins MCA, CA 125 and BW 495/36-P in epithelial tumors of the kidney and the urinary bladder. AB - The differential expression of the tumor-associated glycoproteins MCA, CA 125 and BW 495/36-P was investigated in 11 renal cell carcinomas and 11 urinary bladder carcinomas and compared with their expression in non-neoplastic tissue preparations from the kidney (n = 9) and urinary bladder (n = 12). The glycoproteins were demonstrated immunohistologically in frozen sections and additionally, in some cases, in paraffin sections. MCA and BW 495/36-P positive cells were present in all preparations except for a grade I transitional cell carcinoma of the bladder, in which no MCA-expression could be detected. In the non-neoplastic renal tissue mainly the cells of the distal tubuli were stained by the antibodies against these two glycoproteins. Carcinoma cells of the kidney and of the urinary bladder showed an increased expression of both epitopes. CA 125, in comparison, was strongly expressed in 3 of the 11 urinary bladder carcinomas investigated but could only be shown in a few cells of a single renal cell carcinoma. Normal renal tissue showed no and the urinary bladder only very isolated CA 125 positive epithelial cells. Apart from this distribution, strong staining of the connective tissue fibers with CA 125 antibody was seen in all paraffin sections, but not in the frozen sections. This leads to the supposition that in these structures there is a CA 125 cryptantigen.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836801 TI - Clinical profile of a new monoclonal antibody-based immunoassay for tissue polypeptide antigen. AB - Our preliminary evaluation of a new monoclonal antibody-based assay for tissue polypeptide antigen (TPA) has shown it to be clinically equivalent to the polyclonal antibody-based assay for TPA. The new assay (TPA-M) employs three monoclonal antibodies to epitopes on cytokeratins 8, 18 and 19. This multicenter, multinational study included 266 patients with newly diagnosed carcinomas of the lung, breast, large bowel and urinary bladder. TPA values from the two assays were compared with three other cytokeratin markers (TPS, CYFRA 21-1 and TPACyk) and with the established reference markers for these malignancies (CEA and NSE for lung, CA 15-3 for breast, CEA and CA 19-9 for colorectal tumors). Analysis of receiver operating characteristic (ROC) curves in lung, colorectal and bladder cancer showed similar sensitivities for the two assays, ranging from 50% to 80% with a specificity of 95%. In breast cancer all the markers studied showed poor sensitivity. However, TPA determination by either method could discriminate advanced stage (stages III and IV) from early stage disease (stages 0 to II). TPA showed similar discriminating ability in bladder cancer. On the basis of the results obtained in our patient series, it seems that of the cytokeratin markers studied, TPA and TPA-M are the most sensitive and offer a wide range of clinical applications. PMID- 7836802 TI - Total sialic acid as a tumor marker for oral cancer. AB - Serum sialic acid levels were measured in 80 healthy subjects, in 60 patients with benign tumors and in 110 patients with oral cancer. It was shown that these levels were significantly elevated in oral cancer patients compared to healthy controls and patients with benign tumors (p < 0.01); they were higher in patients with stage III and stage IV disease than in those with stage I and II disease (p < 0.01). However, no difference was observed between healthy controls and stage I and II cancer patients. The results of this study suggest that the determination of sialic acid levels may be of value in the diagnosis of oral cancer, but its usefulness as an adjunct in clinical staging is limited. PMID- 7836803 TI - Serum levels of carboxyterminal propeptide of type I procollagen in cancer patients with osteoblastic and osteolytic bone metastases. AB - Serial monitoring of serum and urinary markers of bone regeneration may provide an indirect assessment of the activity of bone metastases. We measured serum levels of carboxyterminal propeptide of type I procollagen (PICP), a new marker of bone formation, in 236 control subjects, stratified according to age and sex, and in 122 cancer patients: 80 with breast cancer (BC) (42 with osteolytic bone metastases) and 42 with prostate cancer (PC) (31 with osteoblastic bone metastases). An inverse correlation between age and serum PICP levels was found in healthy men (r = -0.30), but not in women, PICP levels were significantly higher in patients with osteoblastic metastases compared to age-matched control subjects and patients with advanced disease not involving the skeleton. The sensitivity of PICP was 64% for detecting osteoblastic metastases, and 12% for detecting osteolytic metastases. Serum PICP determination may have a diagnostic role for osteoblastic activity. PMID- 7836804 TI - Correlation between lipid-associated sialic acid and tumor burden in melanoma. AB - Recent studies have suggested that lipid-associated sialic acid (LSA) may be a useful tumor marker for monitoring patients with melanoma, but the relationship between LSA and tumor burden has not been previously studied. We therefore examined LSA levels in 240 patients of whom 169 had no clinical evidence of disease (NED) and 71 had metastatic disease. There was a statistically significant difference in LSA levels in patients with NED compared with metastatic disease as well as those with high tumor burden compared with low or intermediate tumor burden. There was no difference between the groups with low and intermediate tumor burden. An LSA level of 25 mg/dl provided a positive predictive value of 70% and a negative value of approximately 80%. Our data show that LSA levels correlate with tumor burden in patients with melanoma. PMID- 7836806 TI - Calcitonin in broncho-alveolar lavage of malignant and non-malignant pulmonary diseases. PMID- 7836805 TI - Cytosolic tissue-type plasminogen activator (t-PA) levels in breast tumors and hormone dependence. Role of pS2. PMID- 7836807 TI - Evaluation of serum osteocalcin and myosin in pediatric patients affected by osteosarcoma and rhabdomyosarcoma. PMID- 7836808 TI - Mucin gene expression in lung cancer tissues. PMID- 7836809 TI - [The surgical treatment of coarctation of the aorta and interruption of the aortic arch in the first three months of life--effectiveness of temporary bypass between the pulmonary artery and the descending aorta]. AB - From February 1987 to January 1994, we operated on 24 patients with coarctation of the aorta (CoA) and 9 patients with interruption of the aortic arch (IAA). A policy of staged repair was followed, consisting of reconstruction of the aortic arch with pulmonary artery banding and ligation of the ductus arteriosus in the first stage and intracardiac repair with pulmonary artery band removal in the second stage. In recent cases an extended aortic arch anastomosis was performed using a heparin-coated "shunt tube" between the pulmonary artery and the descending aorta to maintain blood flow to the lower half of the body during aortic cross-clamping. The use of the shunt increased intraoperative urine output (p < 0.05). This technique may allow patients whose condition is poor to undergo aortoplasty more safely. One patient died. This patient had CoA and total anomalous pulmonary venous return, who underwent a one-stage repair, in violation of our policy (early mortality 3.0%). There were two interim deaths before the second stage repair. At present, 18 patients have undergone staged intracardiac repair, including VSD closure (14 cases), Jatene's procedure (1), Ratelli's procedure (1), Damus-Kaye-Stansel (DKS) procedure (1), total cavo-pulmonary connection (TCPC) + DKS procedure+annuloplasty of a common atrioventricular valve (1). There were two early deaths and one late death following intracardiac repair, all in patients with IAA plus VSD. PMID- 7836810 TI - [Changes of respiratory function after lung resection--taking notice of changes during exercise test and anaerobic metabolism]. AB - Changes in the following respiratory functions during exercise test were examined before and after surgery in 31 patients undergoing pulmonary resection: VE, VCO2, and VT at a constant VO2 during exercise; and VO2, VCO2, VE and VT at constant loading (watt). At the level of 300 and 500 ml/min of VO2, VCO2 showed no significant difference before and after the operation but when VO2 reached 700 ml/min. VCO2 showed a significant increase from 542.0 +/- 78.3 ml/min to 595.5 +/ 85.2 ml/min postoperatively (p < 0.05). When exercise load was 45 watt, VE showed no significant difference before and after the operation, but when exercise load was 60 watt, VE showed a significant increase from 30.16 +/- 5.38 L/min to 33.89 +/- 4.69 L/min postoperatively (p < 0.005). These results indicated an early acceleration of ventilation in low load postoperatively. With respect to anaerobic metabolism, AT, oxygen uptake to work rate (delta VO2/delta WR), and our proposed index calculated as an area using the cumulative oxygen uptake were compared pre- and postoperatively. The results indicated that AT decreased significantly from 716.0 +/- 190.8 ml/min to 528.4 +/- 150.7 ml/min (p < 0.001), and delta VO2/delta WR also decreased significantly from 13.5 +/- 4.0 ml/min/W to 11.3 +/- 4.2 ml/min/W (p < 0.05). The index calculated as area showed a significant increase from 4070.2 +/- 3468.8 to 5095.3 +/- 3854.5 (p < 0.05). All these findings indicated that anaerobic metabolism increases postoperatively. Accordingly we conclude that postoperative increase of anaerobic metabolism causes postoperative acceleration of ventilation in low load. PMID- 7836811 TI - [Left ventricular wall stress and contractile function immediately after arterial switch operation in neonates]. AB - Dynamic changes in left ventricular function immediately after arterial switch operation in neonates are poorly understood. Accordingly we determined left ventricular end-systolic wall stress (ESWS) and rate corrected mean velocity of fiber shortening (mVcfc) by echocardiography immediately after arterial switch operation in the intensive care unit (ICU) in 11 neonates. Stress-velocity index (S-V Index: number of standard deviations from the population mean mVcfc for ESWS) was calculated from the ESWS-mVcfc relation as a load independent index of myocardial contractility. The dicrotic notch of radial arterial wave form was used to determine the end-systolic pressure (radial Pes). Left ventricular ejection time was obtained from the pulse Doppler wave form sampled from the ascending aorta. Mean ESWS after the operation was 37.8 +/- 17.3 g/cm2 (mean +/- SD) and mean S-V index was normal (0.80 +/- 3.11). S-V index was normalized within 12 hours after operation in 9 cases. In one case, which showed acute heart failure because of accidentally elevated afterload just after pump perfusion, S-V index had not recovered until 24 hours after operation. In another case, preoperative LV/RV pressure ratio was 0.63 and resulted in prolonged low level of S-V index. Preoperative conditions of left ventricle were compared with postoperative ESWS and S-V index. Preoperative end-diastolic posterior wall thickness of left ventricle (LVPWTd) was correlated with postoperative S-V index (r = 0.74, p = 0.015). Preoperative LVPWTd/LVDd (end-diastolic internal diameter of left ventricle) ratio was inversely correlated with postoperative ESWS (r = 0.66, p = 0.037) and correlated with S-V index (r = 0.80, p = 0.006). Preoperative LV/RV pressure ratio showed correlation with S-V index (r = 0.67, p = 0.023).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836812 TI - [Study of left atrial maze operation on atrial fibrillation associated with mitral valvular disease]. AB - Left atrial (LA) maze operation was performed on atrial fibrillation (af) associated with mitral valvular disease. LA maze operation consists of only left atrial side incision out of modified maze operation. We think that af associated with mitral valvular disease is brought mainly by volume- and pressure-overload to left atrium. We applied LA maze operation in 4 cases, having 2-10 years af history. Combined mitral valvular disease were 1 mitral stenosis, 1 mitral regurgitation, and 2 mitral stenoregurgitation. 2 cases had a history of cerebral thrombosis. Postoperatively, all of these cases returned to sinus rhythm, showed shortening of left atrial diameter, indicated "a" wave. Compared with simple mitral valvular operation, LA maze operation took little longer extracorporeal circulatory time and aortic crossclamping time, but similar operating time. This study suggest that LA maze operation may become effective and simple maneuver on af associated with mitral valvular disease. PMID- 7836813 TI - [The simultaneous evaluation of preoperative cardiopulmonary functions of esophageal cancer patients in the analysis of expired gas with exercise testing]. AB - By analyzing expired gas with exercise testing, we examined the relationship between test results and postoperative cardiopulmonary complications. The analysis was evaluated for its accuracy and reliability in comparison with general pulmonary function tests including spirometry, flow volume curves, diffusing capacity and arterial blood gas analysis. Enrolled were 52 of patients admitted between a period from 1991 to 1993 for thoracic esophageal cancer, who underwent a radical operation of right thoracolaparotomy. Patients were divided into two groups according to postoperative cardiopulmonary complications; one with complications (group C, n = 11) and the other without complication (group NC = 41). The two groups were compared in maximum oxygen consumption (VO2 max)/m2, anaerobic threshold (AT)/m2, VC/m2, %VC, FEV1.0/m2, V25/m, V50/V25, %DLCO and PaO2. In the results, there were significant differences between the two groups only in VO2 max/m2 (p < 0.001), AT/m2 (p < 0.001), and V50/V25 (p < 0.05), while there were no significant differences between the two groups in VC/m2, %VC, FEV1.0/m2, FEV1.0%, V25/m, %DLCO or PaO2. The above results suggest that analysis of expired gas with exercise testing is able to measure easily both cardiac and pulmonary reserve forces, which conventional pulmonary function tests are unable to do, and is evaluating surgical indications for esophageal cancer patients and predicting postoperative cardiopulmonary complications. PMID- 7836814 TI - [Surgical treatment of acute Stanford Type-A aortic dissection]. AB - Twelve cases of Stanford Type-A aortic dissection were operated in an acute phase. The male vs female ratio was 3:9, and their ages ranged from 47 to 79 (mean 61.3) years old. Most of them complained of chest and/or back pain, and four of them complained of syncope. Eight patients had the history of hypertension. As to the complications of aortic dissection, cardiac tamponade was seen in two cases, myocardial infarction in one, and transient hemiplegia and paraplegia in one case each. In five cases, moderate to severe aortic regurgitation was also noted. All but one case were operated within twenty-four hours after admission. The replacement of the ascending aorta with a tube graft was performed in all cases including the two cases whose entries were located in the aortic arch. CABG was done concomitantly in three cases, and aortic valve replacement and CABG in one case. The open distal anastomosis was carried out under the systemic circulatory arrest combined with the retrograde cerebral perfusion. The systemic perfusion was reinstituted after the distal anastomosis was completed. In cases whose dissecting pseudo-lumen of the distal aorta was not thrombosed, the arterial cannulation site was shifted from the femoral artery to the tube graft. All but two cases were discharged from the hospital in good condition. One case, who had been transferred to the operating room under cardiac massage due to myocardial infarction, was lost by severe LOS three weeks postoperatively.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836815 TI - [Warm heart surgery facilitates atrioventricular valve repair]. AB - The valve structure varies with cases in children's atrioventricular valvular regurgitation. Filling the left ventricle simply with cold saline solution and testing the valve competency in the cold cardioplegic arrest do not clarify true valve function, although it was the widely used method. Three dimensional evaluation of the lesion in the dynamic and more nearly normal state and the very fine operative procedure in the static state are required for the successful repair. For this purpose we employed the warm heart surgery on 12 children for valve repair (age 1.3-10.1 years, body weight 6.6-28.2 kg). Because no topical cooling was used, preparation of the heart from the adhesion caused by previous operation was not necessary. The aorta was cross clamped at the temperature of 34 degrees of centigrade with continuous coronary perfusion and the lesion in the valve structure and the regurgitation stream were inspected in the beating state, then the repair was performed in the arrest state obtained by infusing the potassium into the coronary perfusion line. Beating and arrest was repeated 2-5 times by on-off potassium infusion until the repair seems satisfactory. In two cases, the repair was not feasible and mitral valve replacement was performed, but in other 10 cases, the postoperative regurgitation decreased down to the grade 2. Despite prolonged aortic cross clamping (65-216 min), post-operative course was quite satisfactory without low-output syndrome in any cases. Postoperatively administered maximum dose of Dopamine was 4.0 +/- 2.2 micrograms/kg/min. CK-MB at 1 POD was also within normal range.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836816 TI - [Experimental study of an intratracheal stent made of shape memory alloy]. AB - To develop a new prosthesis for treating tracheal stenosis and tracheobronchomalacia, we examined the usefulness of an intratracheal stent made of shape memory alloy (SMA), a titanium-nickel alloy composed of 50% of each metal. At its recovery temperature (37 degrees C), the SMA stent was designed to recall the memorized shape of a coil with a diameter of 5 or 6 mm and a length of 10 mm. For the present experiment, it was transformed to a smaller coil 3 mm in diameter at a low temperature (-50 degrees C) and then loaded into the prosthesis introducer tube. An experimental model of potentially fatal tracheomalacia was made surgically by cutting and fracturing the tracheal cartilages of rabbits and tracheal collapse was confirmed by rigid bronchoscope. The introducer tube with the SMA stent was inserted and then the prosthesis was advanced into the collapsed segment of the trachea using the stent pusher. The SMA stent warmed bo body temperature and recovered its memorized shape after 1-2 min. In 3 out of 8 rabbits, follow-up bronchoscopy performed at 6, 8, and 10 months after implantation revealed satisfactory patency of the SMA stent and the trachea. After follow-up, 3 animals were sacrificed for histological observation, which showed little proliferation of granulation tissue and no dislocation of the SMA stent from the malacic portion. The remaining 5 rabbits have been followed for 18 24 months and are doing well. We conclude that the SMA stent maintains good tracheal patency, causes little reaction in the tracheal wall, and is easy to handle. Thus, it shows the potential for clinical application. PMID- 7836817 TI - [Eight cases of thymic carcinoma]. AB - Eight cases of thymic carcinoma (mean age 62 years, 5 males and 3 females) were treated in our hospital from Apr. 1988 to Mar. 1993, which were 21% of thymic epithelial tumors. The histologic subtypes of thymic carcinoma were 3 squamous, 4 undifferentiated, and 1 adenocarcinoma, respectively. Computed tomography showed extrathymic metastases to the mediastinal lymph nodes in 6 cases. All cases underwent thoracotomy, and postoperative radiotherapy or chemotherapy were performed. A case of squamous cell carcinoma in stage II who underwent total resection followed by irradiation is alive and disease free 5 years after surgery. However, the remaining 7 cases died of the disease within 29 months. 8 cases of thymic carcinoma and 7 of thymoma were studied immunohistologically on the formalin-fixed and paraffin-embedded tissues. Higher positivity of EMA in thymic carcinoma was noted comparing to ordinary thymoma, suggesting that EMA is a useful parameter of potential malignancy of the thymic epithelial neoplasms. PMID- 7836818 TI - [Surgical treatment of thrombosed aortic dissection]. AB - We have performed the graft replacement of descending thoracic aorta for 6 patients with aortic dissection having non-opacified false channel on their initial CT and aortography from April 1990 to January 1993. We report the findings obtained from preoperative CT and aortographic findings and from operation with these patients. We also report the microscopic study of aortic wall resected at operation. In all the six patients were found by CT and angiography performed at the admission non-opacified false channel. In one patient, a re-dissection occurred at the mid-descending aorta four weeks later and extended into the abdominal aorta. Intimal tears were found during operation both at distal to the left subclavian artery and at mid-descending aorta in this patient, and microscopically the outer media of aortic wall had been ruptured and the advential scarring were more conspicuous than usual. In the other 5 patients, the local opacification was gradually increased in size during the follow up period. The site of local opacification was at the distal to the left subclavian artery in 3 and at the mid-descending aorta in 2. The operation for these patients revealed the existence of intimal tear at the involved aorta but the false channel had been closed. Microscopically, the involved aorta formed pseudoaneurysm and false channel had been closed with the organized thrombus. From these findings we conclude that surgical treatment should be considered for the aortic dissection when re-dissection occurred or local opacification was increased in size during follow up period, even if initial CT and aortography showed non-opacified false channel. PMID- 7836819 TI - [Valvulo-annuloplasty for atrioventricular valvular regurgitation in univentricular heart and double outlet right ventricle]. AB - Valvulo-annuloplasty for atrioventricular (AV) valvular regurgitation was performed in 10 patients with univentricular heart and double outlet right ventricle. Kay annuloplasty alone was employed in three patients with a quadricuspid or tricuspid common AV valve. Two of them died after the operation and the remaining one is waiting for reoperation because of recurrence of severe AV valve regurgitation. The suturing-up of free margins of the anterior and posterior common leaflets was performed in 3 children with quadricuspid common AV valve and effectively reduced the regurgitation. The semicircular annuloplasty with a thin Gore-tex graft or the suturing-up of floppy leaflets combined with plasty of the chordae and papillary muscle was carried out in two patients having tricuspid AV valve, and a favourable result was obtained in the semicircular annuloplasty. In mitral AV valvular regurgitation, two patients received the suturing-up of free margins of prolapsed leaflets, and the results were satisfactory. From these results we consider that the semicircular annuloplasty for dilated tricuspid AV valve and the suturing-up of free margins of dilated or floppy leaflets in quadricuspid and bicuspid AV valves are the recommendable procedures. If more than mild AV valvular regurgitation remains after these valvuloplasties, the Kay and/or DeVega annuloplasties should be added for eliminating the regurgitation. PMID- 7836821 TI - [Reoperation for recurrent chondrosarcoma of the pulmonary trunk]. AB - A 71-year-old woman who had progressive dyspnea and edema two years after resection of a pulmonary trunk chondrosarcoma was diagnosed as severe obstruction to the pulmonary trunk due to the recurrent tumor. Magnetic resonance examination following the intravenous administration of Gd-diethylenetriamine pentaacetic acid (DTPA) revealed striking contrast enhancement within the lesion of the pulmonary trunk sarcoma. At reoperation, the recurrent mass was identified within the same site of the pulmonary trunk and total resection of the tumor and replacement of the pulmonary trunk with prosthetic graft was performed utilizing a cardiopulmonary bypass. There have been very few reports on replacements of pulmonary trunks for pulmonary artery sarcomas. It is reported that the prognosis of the pulmonary trunk sarcoma is extremely poor, however, this patient has undergone thoracotomies twice within two years and continued to be symptom-free without distant metastatic lesions. PMID- 7836822 TI - [Dissecting aortic aneurysms that occurred in aged brothers without Marfan syndrome]. AB - The occurrence of familial dissecting aortic aneurysms without Marfan syndrome is rare. This report describes two aged siblings who underwent successful surgery for this disease. Neither patient had the clinical features of Marfan syndrome, and both had histories of systemic hypertension. Case 1: A 76-year-old man had dissecting aortic aneurysm, DeBakey type IIIa, which was localized and had multiple lumina with thrombi. Case 2: A 71-year-old man (younger brother of case 1) had retrograde dissecting aortic aneurysm, DeBakey type IIIa. Histological examinations of the aortae showed cystic medial necrosis in both cases, and also showed atherosclerotic changes in case 1. These two siblings had no familial history of cardiovascular incidents and were much older than previously reported cases. Therefore it may be possible that the dissecting aortic aneurysms of these two cases occurred coincidently rather than due to hereditary factors. PMID- 7836823 TI - [Two cases of complete transection of the thoracic aorta caused by blunt chest trauma]. AB - Two patients with complete transection of the thoracic aorta, caused by blunt chest trauma, were survived after successful surgical repair. Only seven such cases are reported in the Japanese literature. The present cases were 52- and 28 year-old males injured in different accidents by rapid deceleration, both at collision with the rear of a parked trunk. The first case, on the fifth day of hospitalization, suddenly went into shock with severe thoracodorsal pain. The second case developed hemothorax soon after the accident. Both cases were diagnosed with angiography. The lesions were located in the upper portion of the descending aorta. The operations, performed on the 13th and 34th days after the respective accidents, combined median sternotomy with left thoracotomy through the 3rd intercostal space. The first case suffered complete transection of the aorta at the ductal ligament. In the second case, the intima and media of the descending aorta, at 8 cm below the branching of the left subclavian artery, were affected by complete transection. We operated with a V-A bypass of which cannulation was performed to right atrium and left femoral artery in the first case, and with an ascending aorta-left femoral artery bypass with a centrifugal pump in the second case. The lesions were repaired with 26 mm and 20 mm woven Dacron grafts, respectively. The patients have recovered sufficiently to do normal daily lives. In cases with circumferential transection of the thoracic aorta caused by blunt chest trauma, only those with pseudoaneurysm formation, who remain in a hemostatic state can be saved by surgery, We conclude that if the hemodynamic state is stable and blood pressure is strictly controlled in such cases, the elective operation can be performed. PMID- 7836820 TI - [A case of left ventricular-right atrial communication complicated with aortic regurgitation caused by active infective endocarditis]. AB - A 63-year-old man with cough and shortness of breath was diagnosed to have active infective endocarditis resulting in acute pulmonary edema with aortic regurgitation caused by a huge vegetation on the noncoronary cusp and left ventricular-right atrial (LV-RA) communication which were demonstrated by the echocardiogram and color doppler method. The LV-RA communication located at the atrioventricular portion of the membranous septum was closed with GoreTex patch through the right atrium combined with the aortic valve replacement with a bileaflet mechanical valve in emergency. The bacteriological studies demonstrated staphylococcus epidermidis. The postoperative course was uneventful and the patient is now on regular duty two years after surgery. PMID- 7836824 TI - [A case of chronic traumatic thoracic aneurysm after an injury 18 years ago]. AB - Chronic traumatic thoracic aneurysm which had passed over eighteen years since injury was reported. A 41-year-old man, who was involved in automobile accident 18 years before, complained back pain and was referred to our hospital for an aneurysm at the aortic isthmus. According to his history of trauma and location of aneurysm, it was diagnosed as chronic traumatic thoracic aneurysm. Graft replacement was performed under the left heart bypass by using the BioMedicus centrifugal pump. He has been doing well after the operation. PMID- 7836825 TI - [A successful surgical treatment for type IA cor triatriatum with an unroofed coronary sinus]. AB - The combination of type IA cor triatriatum (Lucas-Schmidt's classification) and unroofed coronary sinus is very rare in congenital heart diseases. We have presented the first successful surgical treatment for an infant who had this combination. The patient was 10-month-old infant who admitted with cardiac murmur and short stature. Echocardiography revealed that an abnormal septum in the left atrium and dilated coronary sinus. Under cardiopulmonary bypass she underwent surgical treatment which consisted of a resection of the intra-left-atrial diaphragma, closure of ASD with an equine pericardial patch. During operation, unroofed coronary sinus (partially unroofed terminal portion of the coronary sinus) was revealed. Her postoperative course was uneventful. PMID- 7836826 TI - [A case of superficial spreading esophageal cancer with a long sclerosis of the esophageal wall and dysphagia]. AB - This report describes a rare case of superficial spreading esophageal carcinoma with a long sclerosis of the esophageal wall and dysphagia. The patient was a 64 year-old male with dysphagia. An esophagogram showed a long sclerosis from the upper-third to the lower-third of the esophagus. An esophagoscopy revealed a small ulcerative tumor (approximately 3 cm in size) at the level of 33 cm from the incisor teeth, and intraepithelial spread, 16 cm in length. However, esophageal stricture was not found in preoperative examinations. Histopathologically, most of the cancerous lesions were mucosal cancers with severe lymphocyte infiltration and the marked thickening of muscularis mucosa. These findings suggest the possibility that the sclerosis of the esophageal wall and esophageal dysfunction may be caused by these pathological changes. PMID- 7836827 TI - [Application of extended transseptal approach for a patient with chronic atrial fibrillation caused by mitral stenosis and tricuspid regurgitation]. AB - A 45-year-old female of mitral valvular disease with chronic atrial fibrillation was referred to our hospital. She had received previous closed mitral commissurotomy (12 years ago) and open mitral commissurotomy combined with aortic valve replacement (6 years ago). An echocardiogram showed restenosis and regurgitation of the mitral valve (valve area 1.2 cm2 by B-mode) and severe regurgitation of the tricuspid valve. She also complained of chronic atrial fibrillation since 35 years old. Mitral valve replacement with CarboMedics bileaflet valve (25 mm) and tricuspid annuloplasty by DeVega procedure was undergone via an extended transseptal approach and cryoablastion was added to the posterior wall of the left atrium along the rim of the left pulmonary veins and around the left atrial appendage for ablation of chronic atrial fibrillation. After completion of surgery, atrial fibrillation disappeared. Post operative echocardiogram showed apparent atrial kick of both atriumns in the inflow pattern of both ventricles. The patient continues to be well with normal sinus rhythm for 6 months after surgery. An extended transseptal approach is useful in mitral reoperation, in addition, it can be applicable for the surgery of chronic atrial fibrillation. PMID- 7836828 TI - [A successful case of repeated prosthetic valve re-replacement for somatic growth in childhood]. AB - The patient who had had systemic atrio-ventricular valve replacement with Bjork Shiley 19 M at the age of 4 years was treated successfully with repeated re replacement with St. Jude Medical 23M and St. Jude Medical 27M at the age of 8 years and 16 years respectively, because of his somatic growth. Two size larger valve was easily replaced at each operation. The original disease of this patient was corrected transposition of the great arteries with ventricular septal defect and regurgitation of the left atrio-ventricular valve caused by Ebstain anomaly and severe pulmonary hypertension. This case revealed that the annulus of the atrio-ventricular valve would grow even when fixed to the prosthetic valve sawing ring, thereby permitting the use of a larger-sized valve at the time of second and third prosthetic valve re-replacement. PMID- 7836829 TI - [Three operated cases of epiphrenic esophageal diverticulum]. AB - Three cases of epiphrenic esophageal diverticulum, treated successfully by surgery, were reported. Case 1 was a 71-year-old female associated with gastroesophageal reflux and esophageal dysmotility. Case 2 was a 40-year-old female associated with gastroesophageal reflux but no esophageal dysmotility. Case 3 was a 51-year-old male who showed no abnormality in esophageal pH and manometry, and esophageal scintigraphy. Resection of the diverticulum was performed in three cases and Belsey's fundoplication was added in case 1 and 2. In the patients with epiphrenic diverticulum, concomitant esophageal dysfunction can be the cause of the diverticulum and symptom. It is essential in deciding the surgical procedure to evaluate the esophageal function in the patients with epiphrenic esophageal diverticulum. PMID- 7836830 TI - [A case of congenital ventricular diverticula]. AB - Congenital ventricular diverticula are classified into muscular type and fibrous type. Muscular diverticula may be associated with congenital midline thoracoabdominal malformations. Fibrous diverticula, also called congenital ventricular aneurysm, are often seen in black american and South African Bantus, but very few such cases have been reported in our country. A 33-year-old Japanese male was admitted to our hospital for evaluation of chest X-ray and ECG abnormalities. UCG and cineangiography revealed an outpouching of the left ventricle. As it increased in size during the four-year follow-up, surgical resection was performed. The left ventricular diverticulum was multilobular and had a thin wall, which was excised and reconstructed with a patch. There was another small diverticulum on the free wall of the right ventricle, which was directly closed with a mattress suture. A rare case of multiple congenital fibrous ventricular diverticula with successful surgical resection was reported. PMID- 7836831 TI - [A case of mediastinal mature teratoma presenting increased serum CA19-9 level]. AB - A case of mediastinal mature teratoma with elevated serum CA19-9 level is reported. A 50-year-old woman admitted to our hospital complaining of cough and chest pain. Chest X-ray showed an abnormal mass shadow with retention of the right pleural effusion. Her serum CA19-9 level was high (204.4 U/ml), while serum AFP, CEA, HCG levels were normal. On lateral thoracotomy, an anterior mediastinal tumor perforating into the right lung was revealed and the total resection of the tumor with adherent part of the right lung was performed. Postoperatively, her serum CA19-9 level returned to normal. Histological examination disclosed a mature teratoma consisting of skin, pancreatic tissue, cartilage, bronchial epithelium, etc. Immunohistochemical staining were positive in the bronchial epithelium and bronchial gland but was negative in the pancreatic tissue of the tumor. This is a rare case of mediastinal mature teratoma with elevated serum CA19-9 level and negative immunohistochemical staining for it in the pancreatic tissue of the tumor. PMID- 7836832 TI - [Two cases of esophageal fistula, in which a fibrin glue preparation was effective]. AB - Two successful cases of endoscopic therapy for esophageal fistula are reported herein. The first case was a 61-year-old man who underwent irradiation, chemotherapy and endoscopic laser beam therapy for esophageal cancer (Im T4N0M0 Stage III). Gastrografin -esophagogram revealed a fistula between esophagus and mediastinum after these therapy. Closure of the fistula was attainable using fibrin glue with a double-channel-fiber scope. The second case was a 43-year-old man who underwent chemotherapy and irradiation for lung cancer (S1,S2 T4N2M0 Stage IIIB) which invaded to mediastinum, trachea and esophagus. Bronchogram revealed a esophago-tracheal fistula one month later. We performed the same procedure as the first case, and confirmed reduction of the fistulous size. The endoscopic fibrin glue injection is an easy, safe and effective technique for the fistula even caused by malignancies, and contributes to the quality of life of these patients. PMID- 7836833 TI - [Use of the inferior epigastric artery in redo coronary artery bypass grafting--a case report]. AB - A 71-year-old man who had undergone coronary artery bypass grafting (CABG) 9 years ago, was admitted for chest compression on exertion. A severe stenotic lesion (75%) of the main trunk of the left coronary artery and occlusion of the bypass graft previously implanted to the right coronary artery were showed by coronary angiography. Redo-CABG using the left inferior epigastric artery (LIEA) and left internal thoracic artery (LITA) was successfully done, since the saphenous vein and right gastroepiploic artery were not suitable for bypass graft. Post operative cource was uneventful and good patency of LIEA and LITA graft were revealed by postoperative angiography 34 days after surgery. PMID- 7836834 TI - [A case of right atrial thrombus associated with idiopathic pericarditis]. AB - A 73-year-old man suffering from exertional dyspnea was admitted to our hospital. Transthoracic echocardiography revealed pericardial effusion. This case was diagnosed as idiopathic pericarditis from laboratory data and pathological findings of the pericardial biopsy. A right atrial mass was detected by computed tomography, transesophageal echocardiography and MRI during conservative treatment. Because of the risk of pulmonary embolism due to the presence of the right atrial mass, removal of the mass was performed. The atrial mass was diagnosed as organized thrombus by pathological examination. It was suggested that the cause of right atrial thrombus was congestion and damage of the right atrial endocardium due to idiopathic pericarditis and atrial fibrillation. This case of a right atrial thrombus associated with idiopathic pericarditis is very rare, and MRI was proven to be very useful in the differentiation of a thrombus from cardiac tumor. PMID- 7836835 TI - [Congenital coronary arterial fistula drained to the coronary sinus--a case report]. AB - We report a very rare case of an infant with coronary arterial fistula in whom the communication between a dilated right coronary artery and the coronary sinus was found. The patient was 1-year-old. She had pulmonary congestion and cardiomegaly due to the left-to-right shunt through the fistula, and underwent ligations of the fistula. Ligations of the fistula was indicated because the patient was too small to undergo a fistula resection and coronary arterial bypass grafting. Although the patient had a successful post-operative course, we are paying attention to the aneurysmal change of the dilated right coronary artery proximal to the site of ligations. PMID- 7836836 TI - Proceedings of the 6th Ataxia-Telangiectasia Workshop. Ataxia-Telangiectasia: The Effect of a Pleiotropic Gene. Birmingham, United Kingdom, 22-25 May 1994. PMID- 7836837 TI - Possible role of chromatin alteration in the radiosensitivity of ataxia telangiectasia. AB - Cells derived from individuals with ataxia-telangiectasia (A-T) are known to exhibit increased sensitivity to ionizing radiation and certain radiomimetic chemical agents. Here we summarize our findings regarding the role of chromosome damage and repair in this radiosensitivity. Lymphoblastoid cells derived from A-T homozygotes were characterized for initial chromosome (premature chromosome condensation) and DNA (neutral filter elution) damage and repair kinetics in cells from G1 and G2 cell cycle phases. Despite initial levels of DNA damage being similar to normal controls, A-T cells exhibited nearly a two-fold higher initial amount of chromosome damage. Different A-T cell lines exhibited differing chromosome repair capacities compared with control lymphoblastoid cell lines. These results suggest that A-T cells have an altered chromatin structure whereby DNA double-strand breaks are apparently more efficiently converted into chromosome breaks. Four A-T heterozygote cell lines were examined for chromosome damage and repair in the same fashion and all exhibited increased levels of chromosome damage, although the degree of sensitivity was more prominent in G2 phase cells (two-fold higher) than in G1 phase cells (1.5-fold higher than normal controls). These results suggest that A-T heterozygotes also exhibit an altered chromatin structure which impacts on chromosome damage expression. Of interest, A T cells also exhibited increased chromosome stickiness after irradiation, and telomere regions appeared to be frequently involved. While the molecular basis for preferential telomere involvement is not understood, these results again suggest that structural alterations in the chromatin of A-T cells may play an important role in A-T radiosensitivity. PMID- 7836838 TI - Enhanced chromosomal response of ataxia-telangiectasia cells to specific types of DNA double-strand breaks. AB - The chromosomal response of two ataxia-telangiectasia (A-T) lymphoblastoid cell lines (A-T-PA and A-T-KM) to restriction endonucleases (RE) is compared with that of a normal (N-SW) lymphoblastoid cell line. The RE used were PvuII (generating DNA double-strand breaks with blunt termini), BamHI (cohesive termini with 4 base, 5' overhangs) and PstI (cohesive termini with 4 base 3' overhangs). Chromatid aberrations were analysed in cells 5 h after treatment. Cells were porated using streptolysin O to allow entry of RE. Both A-T lines showed an enhanced frequency of chromatid breaks in G2 phase compared with normal cells in response to RE. The enhanced response of A-T cells was most marked in the case of PvuII treatment when the enhancement ratios were 2.5 and 4.2 for A-T-PA and A-T KM respectively. However, the frequency of DNA double-strand breaks (dsb), measured by neutral filter elution, were considerably lower in A-T-PA cells than N-SW, due to a lower efficiency of poration. When A-T-PA cells were treated with streptolysin O at a higher concentration (0.3 Units/ml), a condition that apparently led to a similar level of poration in A-T-PA as in N-SW cells treated with 0.06 Units/ml as judged by the similar number of dsb induced in the two lines for a given PvuII concentration, the enhancement ratio for A-T-PA cells treated with PvuII increased from 2.5 to 5.8. BamHI and PstI were found to be less clastogenic in all three cell lines as found previously for Chinese hamster cells, although part of this effect may be due to a lower activity, particularly in the case of PstI. However, even at a 4-6-fold higher concentration, BamHI was still less clastogenic than PvuII. It is concluded that dsb with blunt termini are more clastogenic than those with cohesive termini. The results suggest that the chromosomal sensitivity of A-T cells may result from a defect causing a higher rate of conversion of dsb into chromatid aberrations. PMID- 7836839 TI - Cloning efficiency and spontaneous mutant frequency in circulating T-lymphocytes in ataxia-telangiectasia patients. AB - The mutant frequency at the hprt locus in circulating T-lymphocytes has been determined in 16 ataxia-telangiectasia (A-T) patients, 19 A-T heterozygotes and 12 A-T sibs. Mutant frequency in the A-T patients is highly significantly elevated as a group, even when the relatively poor cloning efficiency of many of the A-T lymphocyte samples is taken into account. However, within the A-T set, considerable variation in both cloning efficiency and mutant frequency is seen. Cellular radiation sensitivity, measured by clonal survival assays and chromosome breakage, also varies, as do the clinical symptoms of the patients, including the age at which they become wheelchair bound and the severity of their telangiectasia. Here all the information available to us on this group of patients is presented in an attempt to discern if there is any relationship between those cellular characteristics we have observed and the severity of the symptoms and progression of the disease in the patients. Although we feel that it may be relevant that the adult patients in our study all have mutant frequencies that are not highly elevated, insufficient data are available at present to resolve any relationship between the heterogeneous clinical symptoms and cellular responses seen in the A-T patients as a group. PMID- 7836840 TI - The nature of ataxia-telangiectasia: problems and perspectives. PMID- 7836841 TI - Radiation checkpoints in model systems. AB - The response to DNA damaging agents includes a delay to progression through the cell cycle. Irradiation of premitotic cells causes a delay to mitosis and irradiation of G1 and S phase cells causes a delay to DNA synthesis. These delays have become known as checkpoints. The mechanisms that mediate the mitotic (or G2) checkpoint delay have recently come under study in yeast model systems. Work in the eukaryotic organisms S. cerevisiae and S. pombe has identified at least seven proteins controlling the interactions between DNA damage and cell cycle progression. Genetic analysis of this checkpoint pathway has identified substantial overlap with the feedback controls that co-ordinate progression through the cell cycle. Molecular analysis has revealed structural conservation between these highly diverged yeasts, which suggests that similar proteins may act in related pathways in mammalian cells. In addition, the rad24 and rad25 genes of S. pombe (which are involved in the radiation checkpoint) encode functionally overlapping essential proteins that are highly conserved in mammalian cells. Studies of checkpoints in the yeasts may therefore help to define the signal pathways that control cell cycle delay in mammalian cells following irradiation, some of which have been proposed to be deficient in A-T cells. PMID- 7836842 TI - Testing the role of p53 in the expression of genetic instability and apoptosis in ataxia-telangiectasia. AB - We have obtained initial evidence supporting a new model for the human disease ataxia-telangiectasia (A-T), in which the A-T and p53 genes play crucial roles in a signal transduction network that activates multiple cellular functions in response to DNA damage. Three of the model's predictions were tested. (1) Disrupting cell cycle checkpoints should increase spontaneous rates in normal cells. In order to interfere with the G1/S checkpoint, we transfected a normal cell line with vectors expressing either a dominant-negative p53ala143 mutant or a human papilloma virus E6 gene. These transformants showed 10-80-fold elevations in spontaneous recombination rates when compared with their parent. (2) A-T cells should be sensitive to DNA damage-induced apoptosis. Widespread apoptosis was detectable in four A-T fibroblast lines, but not two control lines, beginning 24 h after exposure to X-rays or streptonigrin, but not UV. Streptonigrin also induced widespread apoptosis in A-T lymphoblasts but not in control lymphoblasts. (3) Disruption of p53 function in A-T cells should increase their mutagen resistance by interfering with apoptosis. Stable transfection of either the p53143ala or the HPV18 E6 construct was associated with acquisition of streptonigrin and radiation resistance, while transfection with the p53143ala construct did not affect the streptonigrin sensitivity of a control cell line. PMID- 7836843 TI - Radiation-induced G2 delay and spontaneous chromosome aberrations in ataxia telangiectasia homozygotes and heterozygotes. AB - The extent of cell cycle delay of lymphocytes X-irradiated in G2 phase was measured by mitotic inhibition determinations in 66 controls, 14 ataxia telangiectasia (A-T) homozygotes and 27 obligate heterozygotes. Homozygotes had a significantly reduced mitotic index (MI) in unirradiated samples and showed significantly less radiation-induced mitotic inhibition than controls. This confirms our earlier disputed observations on A-T fibroblasts and demonstrates a G2 check-point defect in addition to the well-known defects in S phase and at the G1-S phase transition. There are two separate and opposite abnormal G2 responses of A-T cells; a primary event in which cells in G2 at the time of irradiation suffer less delay than controls, and a secondary event in which cells irradiated at earlier stages of the cycle are more delayed when they pass into G2. The MI of unirradiated heterozygote cells and the extent of mitotic inhibition were indistinguishable from controls. Spontaneous unstable chromosome aberrations were, as previously reported, significantly higher in homozygotes than in controls. This was true for breaks, but not for gaps. There was a suggestion of an increase in breaks in heterozygotes, but a much larger study would be required to confirm or refute this. PMID- 7836844 TI - Prenatal diagnosis of ataxia-telangiectasia and Nijmegen Breakage syndrome by the assay of radioresistant DNA synthesis. AB - Prenatal diagnosis was performed in 16 pregnancies at risk of ataxia telangiectasia (A-T) or Nijmegen Breakage Syndrome (NBS). Radioresistant DNA synthesis (RDS) was investigated in cultured chorionic villus (CV) cells and/or amniotic fluid (AF) cells. In four pregnancies, an affected foetus was diagnosed with increased RDS in cultured CV cells. In three of the four cases confirmation of the diagnosis was obtained by analysis of AF cells and/or skin fibroblasts from the foetus cultured after termination of the pregnancy; in the fourth case a fibroblast culture from the aborted foetus failed. In one case, only AF cells could be analysed in a late stage of pregnancy; pregnancy was terminated due to intermediate/equivocal results but the foetal fibroblasts showed normal RDS. Normal RDS was demonstrated in the other 11 pregnancies at 25% risk either by analysis of CV cells (nine cases) or of AF cells (two cases). In some cases the (normal) results on the CV cells were corroborated by subsequent analysis of AF cells. The results suggest that RDS analysis of CV cells allows reliable prenatal diagnosis of A-T/NBS. However, amniocentesis may be necessary to confirm normal results on CV cells if the foetus is female (because of the risk of maternal cell contamination) or in the rare case of equivocal results. PMID- 7836845 TI - Cancer risks in A-T heterozygotes. AB - It is well established that ataxia-telangiectasia (A-T) patients suffer a grossly elevated risk of cancer, particularly lymphoma and leukaemia, but the possibility of an excess cancer risk of cancer in heterozygotes carriers of A-T mutations is more controversial. A number of studies indicate that female relatives of A-T patients suffer excess risk of breast cancer; based on an overview of all currently available data the estimated relative risk of breast cancer to A-T heterozygotes is 3.9-fold (95% CI 2.1-7.2). There is some suggestion that relative risk declines with age. In contrast, there is no consistent evidence of a risk from any other cancer; the estimated risk from all studies is 1.9 (95% CI 1.5-2.5) but some studies show a larger effect whilst others show no excess risk. On the basis of these results and the likely frequency of the A-T gene, A-T heterozygotes would account for between 1 and 13% of breast cancer cases, with 3.8% being the best estimate. However, unless the breast cancer risk has been seriously underestimated, the A-T gene will make little contribution to familial breast cancer. PMID- 7836846 TI - Nijmegen Breakage syndrome: a progress report. AB - We report the findings in the first 30 patients with the Nijmegen Breakage Syndrome (NBS). All had microcephaly from birth, short stature and a 'bird-like' face. Most of them suffered from recurrent respiratory tract infections. Intelligence was normal in half of the patients. Serum immunoglobulins were disturbed in 22/25 patients investigated (IgG deficiency, IgA deficiency, IgG2 and IgG4 deficiency) and T cell defects were found in 23/24 patients tested. The immunodeficiency appears to be more severe than in A-T. Chromosomal aberrations in cultured T lymphocytes occurred preferentially in chromosomes 7 and 14 and at the same breakpoints as in A-T. However, the percentage of chromosome 7 and/or 14 rearrangements was significantly higher in NBS patients than in A-T patients (p < 0.0005). Inv(7) was amongst the most frequently detected aberration in NBS cells as it is in A-T cells. Large clones of cells with rearrangements of chromosome 14 were rare in NBS. Of the first 19 reported patients eight have already developed a malignancy: seven a lymphoma and one a meningioma. It is noteworthy that both the tendency to express rearrangements of chromosomes 7 and 14 and the tendency to develop a malignancy is much higher in NBS than in A-T. Whether there is any causal relationship is as yet unknown. PMID- 7836847 TI - Functional complementation studies with X-ray-sensitive mutants of Chinese hamster cells closely resembling ataxia-telangiectasia cells. AB - In order to isolate a human gene complementing the defect in A-T-like hamster cell mutants, the mutants were used as recipients for genomic DNA transfection, using either HeLa chromosomal DNA or DNA from a human cosmid library. Three primary transformants with an intermediate X-ray sensitivity and almost normal sensitivity to MMS, but retaining radioresistant DNA synthesis (RDS), were obtained. To identify the human chromosome that complements the defect in the A-T like mutants, and to assess the degree of complementation for survival and RDS, microcell-mediated chromosome transfer was used. At least 20 independent hybrid clones between the mutant and each one of the human chromosomes 1, 2, 4, 5, 15, 17 or 18 were isolated. All hybrid clones remained X-ray sensitive, except one with chromosome 4, and another with chromosome 15, both showing an intermediate X ray sensitivity. By using in situ hybridization we found that this partial correction was due to the presence of a mouse chromosome. In these two hybrids containing the mouse chromosome together with human chromosome 4 or 15, RDS was fully complemented only in the hybrid with chromosome 4 but not in the one containing chromosome 15, suggesting that RDS and X-ray sensitivity may be complemented independently. PMID- 7836848 TI - After-thoughts and conclusions on the nature of the A-T gene. PMID- 7836849 TI - Clinical and genetic features of ataxia-telangiectasia. AB - There are several variants of ataxia-telangiectasia (A-T): classical A-T with marked radiation sensitivity; classical A-T with intermediate levels of radiation sensitivity; mild A-T with intermediate levels of radiation sensitivity; A-T without telangiectasia; A-T without oculomotor apraxia; and A-T with microcephaly. These disorders are probably caused by different allelic mutations, because affected sibs resemble the index patients, and because there is an association of certain haplotypes of 11q22-23 with specific phenotypes. The Nijmegen Breakage Syndrome, with its lack of ataxia, seems on clinical grounds to be a different disorder. Although A-T is almost always inherited as an autosomal recessive, there are some unusual features; an unexpectedly low parental consanguinity rate, an incidence in sibs that is < 0.25, and occurrence of disease in many different races and in the offspring of mixed race unions. Moreover, looking at haplotypes from 63 UK patients, there is a remarkably low incidence of homozygosity. An autosomal recessive condition that is deficient in parental consanguinity, and in homozygosity for the region around the gene, can be explained by J. H. Edwards' hypothesis that homozygosity for alleles at a neighbouring locus are lethal early in embryogenesis. Other possible mechanisms to explain the unusual genetic features are discussed. PMID- 7836850 TI - Ataxia-telangiectasia in Italy: genetic analysis. AB - Genetic analysis was performed on 72 Italian A-T families ascertained through 91 probands. The frequency of the A-T gene was estimated through Dahlberg's formula, which uses the frequencies of first cousin marriages among the patients' parents and in the general population were obtained from the collection of Catholic Church dispensations for the period 1910-1964. Accurate estimates of the disease frequency were made by subdividing data into 5-year periods and between provinces, in order to take into account temporal (decrease over time) and spatial (higher frequency in Southern Italy) heterogeneity. The estimate of the gene frequency for the whole sample was q = 0.012 +/- 0.0065, corresponding to a heterozygote frequency of 2.34% and to a disease frequency of 1 in 7090. When considering q before and after 1970, there was an apparent increase of heterozygote frequency from 1.69 to 3.43%, perhaps due to a better ascertainment of the disease in the latter period. A segregation ratio of 0.249 +/- 0.043 was obtained by analyzing the offspring of the 72 families under the model of incomplete multiple selection. This value is not significantly different from 0.25, as expected for an autosomal recessive disease. PMID- 7836851 TI - A haplotype common to intermediate radiosensitivity variants of ataxia telangiectasia in the UK. AB - In a study of ataxia-telangiectasia (A-T) in the UK, patients in 10 out of 60 families were shown to have a much lower level of chromosomal radiosensitivity compared with the majority of patients. In some patients the level of radiosensitivity was hardly distinguishable from normal. Patients in this group, however, could be distinguished clinically from the majority either by the later onset of severe cerebellar features or the slower rate of progress of the disorder. By using highly polymorphic microsatellite repeat markers a chromosome 11q22-23 haplotype common to the majority of these patients, and not occurring in any non-A-T chromosome in 60 families, was identified on one chromosome. The haplotype probably defines the region of the A-T gene in these families and the mutation associated with this haplotype may be much less severe than the second mutation thereby producing the slightly milder phenotype. PMID- 7836852 TI - Genetic and physical mapping of the ataxia-telangiectasia locus on chromosome 11q22-q23. AB - The identification of A-T gene(s) using both positional and functional cloning techniques has been a major objective in A-T research over the past 10 years. Functional cloning, using complementation of the radiosensitivity phenotype, has met with some success, although technical problems remain to be overcome. Recent progress, however, in both genetic and physical mapping of the A-T locus on chromosome 11q22-q23, described in this review, suggests that the positional cloning of candidate genes should be achieved in the very near future. The region of the chromosome containing the gene(s) has been identified, and is no more than 1.6 Mb in size. The detailed physical characterization of this region, as a preliminary to candidate gene isolation, is now underway. There are, however, still some unresolved issues, most notably the existence of four A-T complementation groups, with the resulting supposition that these equate to a number of different genes. Although genetic linkage evidence does not support the hypothesis of genetic heterogeneity, the possibility of a cluster of genes at the 11q22-23 locus cannot be ruled out. It is likely that the explanations for this and other problems such as discrepancies in expected levels of consanguinity, and difficulties in the classification of atypical phenotypes will become much more obvious once a gene or genes have been cloned. PMID- 7836854 TI - Physical and genetic mapping at the ATA/ATC locus on chromosome 11q22-23. AB - Genetic heterogeneity in ataxia-telangiectasia (A-T) points to four different genes responsible for this disease. The two major A-T genes, ATA and ATC, were localized by genetic analysis close to each other on chromosome 11q22-23, prompting efforts of positional cloning. Essential steps in positional cloning are long-range cloning of the genomic region of interest, and derivation of highly polymorphic markers that would allow further reduction of the interval carrying the A-T gene. We constructed genomic contigs across the D11S611-D1S424 region harbouring the ATA and ATC genes in yeast artificial chromosome (YAC) vectors. These contigs were used as a fine mapping tool and enabled us to localize along the A-T region, eight microsatellite markers generated randomly by genome mapping centres. In addition, we used specific YAC clones to generate five new microsatellite markers based on polymorphic CA repeats. Recombination mapping based on Israeli A-T families indicates that the ATC gene is distal to the locus D11S1817. Further linkage analysis using these markers is expected to reduce the major A-T locus considerably to a size appropriate for cosmid cloning and identification of transcribed sequences. PMID- 7836853 TI - Genetic haplotyping of ataxia-telangiectasia families localizes the major gene to an approximately 850 kb region on chromosome 11q23.1. AB - The genotyping data given localize the major A-T gene to an approximately 850 kb region. They also localize the group A A-T gene (ATA) to a region that contains the approximately 850 kb region. They are compatible with linking A-TFresno to 11q22-23. NBS-V2 does not link to this region. Four non-linking families contain only single affecteds, suggesting that these may be spontaneous mutations rather than evidence for an A-T gene outside the 11q22-23 region. Finally, two other non linking families contain recombinant haplotypes that are compatible with a second A-T gene at 11q22-23, slightly distal to the approximately 850 kb region. However, convincing evidence for a second gene is still lacking. PMID- 7836855 TI - DNA marker D11S384 shows zero recombination with the ataxia-telangiectasia locus in North American families. AB - At the genetic locus D11S384, one probe detects a Taql RFLP and another detects a RFMP. In 52 pedigrees of North American A-T patients, parental haplotypes based on these two bi-allelic systems have a heterozygosity of 0.69 and a PIC of 0.64. No recombinant events between D11S384 and the A-T locus were detected in the 43 pedigrees in which this marker locus was informative. PMID- 7836857 TI - Cellular radiosensitivity in ataxia-telangiectasia. AB - Hypersensitivity to both the cell-killing and chromosome-damaging effects of ionizing radiations, and other agents causing DNA breakage, is a consistent feature of cells from individuals with the cancer-prone disorder ataxia telangiectasia (A-T). Evidence for a defect in DNA strand break rejoining is slight, but a higher-than-normal level of chromosomal breaks persists in irradiated A-T cells. There is also evidence for elevated frequencies of DNA recombination and deletion mutation in A-T cells; these responses may be linked through a loss of fidelity in rejoining DNA breaks through recombination mechanisms. Additionally the regulation of cell-cycle responses is altered in A-T cells: in all phases of the cycle there is some loss of 'checkpoint' function shortly after irradiation, allowing cells to continue cycling despite extensive DNA damage. However, on present evidence, radiation hypersensitivity cannot be explained simply by this loss of regulatory function. It is suggested that the A T gene product acts in the early stages of a DNA damage-recognition pathway, normally interacting with regulatory proteins such as p53, but also with proteins involved in the processing of DNA breaks. Reduced efficiency in this type of signalling function could well explain the link between radiosensitivity and cancer proneness. PMID- 7836856 TI - Expression of the candidate A-T gene ATDC is not detectable in a human cell line with a normal response to ionizing radiation. AB - Nucleotide sequence analysis of a candidate gene for A-T group D (ATDC) demonstrated that it is related to a group of proteins that contain both zinc finger and leucine zipper motifs. The presence of a leucine zipper suggested that this protein might form homodimers, and this was confirmed by means of the two hybrid system in yeast. The activity of some proteins that form homodimers can be effectively eliminated by overexpression of inactive forms of the protein that bind to the wild-type protein to create a dominant negative phenotype. An ATDC cDNA containing a 37 amino acid deletion in the zinc finger region (ATDC delta) was therefore transfected into colorectal carcinoma human tumour cells (RKO) to determine whether its expression would produce a response to radiation similar to that seen in A-T cells. RKO cells have been shown to have normal radiosensitivity and cell cycle regulation and, therefore, seemed ideal for this study. Despite the fact that the A-T gene has been found to be important in the radiation damage response, no ATDC mRNA transcripts were detectable in the RKO cell line. In addition, the RKO subclones expressing the ATDC delta mRNA showed no change in radiosensitivity or cell cycle regulation. These results do not support the conclusion that ATDC is an A-T gene, and suggest that the ATDC protein acts indirectly to suppress radiosensitivity in A-T cells. PMID- 7836858 TI - V(D)J recombination and ataxia-telangiectasia: a review. AB - I review one aspect of the A-T phenotype, the remarkable and fascinating increase of lymphocytes carrying chromosomal aberrations caused by V(D)J site-specific recombination. The review is organized to first present the facts of V(D)J recombination and the findings in this regard in A-T patients. Other populations that demonstrate similar increases in such chromosomal aberrations are then presented and a hypothesis is offered as to the basis and relevance of these increases vis-a-vis A-T. The contribution of V(D)J recombination to the clonal proliferations and frank lymphoid malignancies seen in A-T patients is briefly discussed. I conclude with some speculative comments extending the observations presented into a more global consideration of a possible function of an A-T gene. PMID- 7836859 TI - Pilocarpine incorporated into a submicron emulsion vehicle causes an unexpectedly prolonged ocular hypotensive effect in rabbits. AB - Pilocarpine, a widely used antiglaucoma drug, was incorporated into a newly developed submicron emulsion (pilocarpine emulsion) suitable for local ocular administration. Pilocarpine-Emulsion effect on the intraocular pressure (IOP) was studied following a single dose application in normotensive rabbits. Membrane filtration (steam autoclaving) was found not to affect particle size distribution, zeta potential or pH of the pilocarpine emulsion preparation. A single dose application of pilocarpine emulsion 1.7% (equivalent to 2% pilocarpine hydrochloride) induced a prolonged progressive decrease in IOP in normotensive rabbits, which started at eleven hours post instillation and reached its maximal value of 6.0 +/- 0.2 mmHg at 29 hours. The pressure decreasing effect induced by pilocarpine emulsion treatment followed a pattern different from that generated by generic pilocarpine (Pilocarpine Hydrochloride 2% eye drops); In the latter group, IOP reduction (starting at two hours) persisted during the initial five hours post-instillation, while in the former, the hypotensive effect started at a later stage, and was maintained during a twenty nine hour follow-up causing a greater IOP decrease than in the generic group (% delta IOP of 28.5% and 18%, respectively). In the contralateral eyes of Pilocarpine Emulsion treated rabbits, an ocular hypotensive effect was noted late after application (11 hours through 29 hours post-instillation), while this effect was negligible in rabbits-treated with aqueous pilocarpine. Our findings point to the possibility that the novel preparation of pilocarpine incorporated into submicron emulsion might serve as a long-acting form of pilocarpine which might require a single daily application. Further studies are required to elucidate the mechanism and action of this preparation. PMID- 7836860 TI - The effect of age on the penetration of fluorescein into the human eye. AB - The penetration into the eye of fluorescein from a normal drop was found to increase with age and averaged twelve times more in the elderly than in the young. Examination of the literature suggests that this is a result of a greater contact time with the cornea rather than a rise in epithelial permeability. PMID- 7836861 TI - Synthesis of 12(R)- and 12(S)-hydroxyeicosatetraenoic acid by porcine ocular tissues. AB - Microsomal fractions from porcine ocular tissues synthesized 12(S)-5,8,10,14 hydroxyeicosatetraenoic acid [12(S)-HETE] from arachidonic acid by a membrane bound lipoxygenase and 12(R)-HETE by the cytochrome P450-dependent monooxygenase system. Both activities were the highest in corneal microsomes. The 12(R)-HETE synthesizing activity of corneal microsomes was dependent on NADPH and inhibited by 0.1 mM SKF-525A, an inhibitor of P450 enzymes. The activity to form 12(R) enantiomer was significantly enhanced by treatment of corneal epithelium with 3 methylcholanthrene or clofibrate. The induced activity was suppressed by cycloheximide, indicating that the induction of enzyme activities involved a translational process. The effect of these inducers on 12(R)-HETE synthesizing activity appeared to be additive. The activity to form 12(S)-enantiomer was markedly stimulated by 3 mM CaCl2. The 12-lipoxygenase of corneal microsomes was capable of oxygenating linoleic acid in addition to arachidonic acid, a characteristic of 12-lipoxygenases of the leukocyte type. 12(R)-HETE at 10(-6) M inhibited almost completely the Na,K-ATPase of corneal epithelium but had little or no effect on ciliary epithelial enzymic activity. 12(S)-HETE at 10(-6) M also inhibited corneal enzymic activity but to a lesser extent, and had no significant effect on ciliary epithelial Na,K-ATPase activity. PMID- 7836862 TI - Effect of ascorbic acid 2-O-alpha-glucoside on hydrocortisone-induced cataract formation in developing chick embryos: II. Influence on glutathione and lipid peroxide contents in the lens. AB - In developing chick embryos, hydrocortisone induces cataract formation following a decrease in lens glutathione content but an increase in lipid peroxide content in lens, blood and liver. The preventive effects of ascorbic acid 2-O-alpha glucoside (AA-2G) on these parameters were compared on cataract formation with those of ascorbic acid (AsA) and ascorbic acid 2-O-phosphate (AA-2P). In these tissues, AA-2G inhibited a decrease in glutathione content and an increase in lipid peroxide content more effectively than either AsA or AA-2P. Various tissues including lens and liver have alpha-glucosidase activity, strongly suggesting that AsA is enzymatically liberated from AA-2G in these tissues. In summary, these results suggest that AA-2G exerts a potent anti-cataract activity via a reduction in oxidative damage through AsA release. PMID- 7836863 TI - Regulation of lens beta-adrenergic receptors by receptor occupancy and dexamethasone. AB - Beta-adrenergic binding sites in primary cultures of chick lens annular pad (CLAP) cells were characterized with dihydroalprenolol (DHAP). Binding site affinities and densities were similar to beta-adrenergic receptors (BARs) previously characterized on crude membranes from freshly isolated cells. In competitive displacement studies, the beta-blocker propranolol was shown to increase the number of available binding sites in a concentration dependent manner. Acute exposure of CLAP cells to propranolol prior to DHAP binding also resulted in an increase in the number of available binding sites. Finally, lens beta-adrenergic binding site levels could be modulated by dexamethasone treatment. These results indicate that lens BARs are subject to common regulatory mechanisms and further implicate ophthalmic pharmaceuticals as possible cataractogenic agents. PMID- 7836864 TI - Low dose cyclosporin-A therapy in Behcet's disease. AB - The effect of systemic low dose cyclosporin-A (5 mg/kg/day as initial dose) combined with 0.2 to 0.6 mg/kg/day prednisolone (when necessary) in clinical course of 22 patients suffering from severe forms of Behcet's disease are reviewed. All the patients had received other drugs previously and had either no response to them or developed intolerable side effects, therefore, pre treatment visual acuity (VA) was compared to post treatment VA as "self control". The average age of our patients was 30.6 years (range 19-51 years). The average duration of our therapy was 19.5 months (range 4-32 months). Improvement or stabilization of vision was achieved in 21 patients (95%). The intraocular inflammation was controlled in all of the eyes and most of the non-ocular signs and symptoms were also improved. Serious side effects included rise in creatinine in 10 (45%) of the patients, rise in bilirubin in 6 (27%) and hypertension in 1 (4.5%). These side effects disappeared as the dose of cyclosporin-A was tapered. We believe this form of therapy is of great value in the management of severe forms of Behcet's disease. PMID- 7836865 TI - Effects of an intravitreal daunomycin implant on experimental proliferative vitreoretinopathy: simultaneous pharmacokinetic and pharmacodynamic evaluations. AB - Intravitreal daunomycin (D) effectively suppresses cellular proliferation in experimental proliferative vitreoretinopathy (PVR) but has a narrow therapeutic safety range. Studies were undertaken to reduce toxicity of D by preparing a slow release implant using polysulfone capillary fiber (PCF). Fabrication of the implant involved loading PCF with 1% D in tristearin (w/w), an excipient with diffusion-retardant properties. Two dose levels of the PCF-D device (15 micrograms and 30 micrograms/device) were prepared and sterilized prior to use. To examine the kinetics and efficacy of the device, rabbits were randomized and eyes were implanted as follows: 1) control group (PCF vehicle); 2) PCF-D (15 micrograms/device); 3) PCF-D (30 micrograms/device). Immediately after implantation, all eyes received an intravitreal injection of 2.5 x 10(5) retinal pigmented epithelial (RPE) cells. Thereafter, tractional retinal detachments (TRD) were graded by ophthalmoscopic examination. Also, fluorophotometry scanning from the retina to the anterior chamber was performed to determine the intraocular bioavailability of D. Results showed a therapeutically sustained level of D up to 21 days after device implantation. Midvitreous concentration of D was greater in group 3 than group 2 at all time points examined, indicating a dose-proportional increase in D release. Results of the PVR study showed that by 7 days after treatment, all eyes implanted with the PCF vehicle developed stage 2 TRD or greater; only 1 eye in each of groups 2 and 3 developed stage 2. By 2 weeks, most eyes in groups 2 and 3 remained in stages 1 and 2 with only 2 eyes progressing to stages 3 and 4 TRD. By 5 weeks, all eyes in group 1 showed stages 4 and 5 TRD, while most eyes in groups 2 and 3 remained in stages 1 and 2. The device with 30 micrograms D was more effective in preventing TRD. In conclusion, these data indicate that PCF can reduce the toxicity of D and may be a useful implant for treatment of PVR. PMID- 7836866 TI - Intravitreal delivery of ganciclovir in rabbits by transscleral iontophoresis. AB - To avoid the side effects of systemic administration of ganciclovir (GCV) for the treatment of cytomegalovirus (CMV) retinitis, we studied transscleral iontophoresis of GCV into rabbit eyes. After a single application with 20% (w/w) aqueous solution of GCV at 1.0 mA for 15 min gave a vitreal/retinal level of GCV at 74 +/- 17 micrograms/ml at 2 hours as determined by HPLC. At 24 hours after iontophoresis the vitreal/retinal level was above therapeutic level at 4.2 +/- 0.6 micrograms/ml. At 72 hours, there was still detectable level in the vitreous/retina. Hence, transscleral iontophoresis is able to deliver effective dose of GCV into the vitreous. Multiple applications of iontophoresis should be examined as a possible means of CMV treatment. PMID- 7836867 TI - Prevention of ocular inflammation induced by lens protein, endotoxin, and interleukin-1 with synthetic interleukin-1 blockers. AB - It is well known that corticosteroids are potent anti-inflammatory agents, yet they produce serious side effects. Although arachidonate metabolite blockers have been developed for the treatment of inflammation, they are much less potent than corticosteroids. Furthermore, they still process serious side effects. In search of potent and safe non-steroidal anti-inflammatory agents (NSAIA), interleukin-1 (IL-1) blockers have been developed. Among 121 CK-analogs studied, CK-17, CK-101A and CK103A have been identified as promising anti-inflammatory agents as potent as prednisolone in inhibiting lens proteins-induced inflammation and twice as potent as prednisolone in inhibiting endotoxin-and IL-1-induced uveitis. No serious side effects could be noticed with the doses of these compounds tested to date. These results indicate that the development of potent NSAIAs is feasible. Moreover, these compounds are not related to arachidonate metabolites. PMID- 7836868 TI - Feasibility of insulin eyedrops for human use. AB - To determine the minimum effective concentration of insulin eyedrops for human use, insulin eyedrops at 0.01%, 0.05%, and 0.25% plus 0.5% Brij-78 were instilled into rabbit eyes. Brij-78 (0.5%) eyedrops were instilled as control. It was found that very low concentrations of insulin such as 0.05% plus 0.5% Brij-78 can reduce the blood glucose effectively in rabbits. The 0.05% insulin with 0.5% Brij 78 seems to be the best choice. Assuming the human body weight is approximately 25 times that of the rabbit, the concentration of insulin to be used for human patients would be 1.25% insulin (0.05% x 25), which is equivalent to 1.25 mg insulin/75 kg body weight. Because the absorption rate of insulin eyedrops plus Brij-78 is approximately 60-70%, 1.25% insulin plus Brij-78 would easily reach the therapeutic dose of insulin by injection (0.4-0.5 mg/75 kg). These results indicate that it is feasible to use insulin eyedrops to lower the blood glucose in humans. There was no statistical difference in blood glucose levels between animals instilled with 0.5% Brij-78 alone as control and those instilled with 0.01% insulin plus 0.5% Brij-78. PMID- 7836869 TI - Review: pharmacological manipulation of docosahexaenoic-phospholipid biosynthesis in photoreceptor cells: implications in retinal degeneration. AB - Docosahexaenoic acid (22:6n-3, DHA) is derived in vertebrate animals from n-3 fatty acids present in the diet (i.e., alpha-linolenic acid, 18:3n-3 and/or other n-3-long chain polyunsaturated fatty acids) and is found in very high concentrations in phospholipids from membranes of the central nervous system. Disk membranes of photoreceptor outer segments and synaptic terminals display a preferential enrichment in DHA-phospholipids that appears to be necessary for normal excitable membrane functions. Because of the relevance of adequate DHA phospholipid synthesis and sorting toward new assembled disk membranes and synaptic terminals, as well as the pathophysiological implications of abnormal DHA metabolism (including its synthesis, delivery to the retina, and incorporation into lipids by de novo and turnover pathways), we reviewed recent studies of: a) the preferential uptake and retention of DHA by photoreceptors and its metabolism as it is activated to DHA-CoA and incorporated preferentially into phospholipids; b) pharmacological manipulations using amphiphilic cationic drugs (i.e., propranolol) to show an active esterification of DHA into lipids via de novo synthesis; and c) perturbations in DHA metabolism in retinas from dogs with progressive rod-cone degeneration (prcd). PMID- 7836870 TI - Persistent age-distributions for a pair-formation model. AB - Conditions on the vital rates of a two-sex population are presented which imply the existence or nonexistence of exponentially growing persistent age distributions. PMID- 7836871 TI - The role of a transient potassium current in a bursting neuron model. AB - Presented here is a biophysical cell model which can exhibit low-frequency repetitive activity and bursting behavior. The model is developed from previous models (Av-Ron et al. 1991, 1993) for excitability, oscillations and bursting. A stepwise development of the present model shows the contribution of a transient potassium current (IA) to the overall dynamics. By changing a limited set of model parameters one can describe different firing patterns; oscillations with frequencies ranging from 2-200 Hz and a wide range of bursting behaviors in terms of the durations of bursting and quiescence, peak firing frequency and rate of change of the firing frequency. PMID- 7836872 TI - Global stability in a delayed partial differential equation describing cellular replication. AB - Here we consider the dynamics of a population of cells that are capable of simultaneous proliferation and maturation. The equations describing the cellular population numbers are first order partial differential equations (transport equations) in which there is an explicit temporal retardation as well as a nonlocal dependence in the maturation variable due to cell replication. The behavior of this system may be considered along the characteristics, and a global stability condition is proved. PMID- 7836873 TI - Posteroanterior stiffness at three locations in the lumbar spine. AB - OBJECTIVE: One commonly used clinical procedure involves the assessment of stiffness during the application of a posteroanterior force to the spinous process of a vertebra. The clinician commonly applies a force normal to the sagittal spinal curve and attempts to evaluate whether the stiffness of the response is also normal. The purpose of this study was to determine whether the stiffness of posteroanterior movements in normal subjects significantly differed when the force was applied to L3, L4 or L5 and when the rate of application changed from quasistatic to cyclical loading. DESIGN: Experimental investigation of characteristics of normal subjects. SETTING: University biomechanics laboratory. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Posteroanterior stiffness at L3, L4 and L5 during quasistatic and cyclical loading. RESULTS: The posteroanterior response was found to be stiffest at L5, least at L3 and intermediate at L4. Quasistatic loading produced lower stiffness than cyclical loading at .5 Hz. CONCLUSIONS: The clinical assessment of the low lumbar spine through manual loading requires a knowledge of the likely variations of posteroanterior stiffness. This study has established that in normal subjects there are systematic effects due to the location of load and the rate of loading. PMID- 7836874 TI - The effects of transforaminal ligaments on the sizes of T11 to L5 human intervertebral foramina. AB - OBJECTIVE: This study was designed to determine the effects of the presence of transforaminal ligaments (TFL) on the superior-to-inferior dimension (SI) and anterior-to-posterior dimension (AP) of the compartment containing the ventral ramus of the spinal nerve (VR) in the intervertebral foramen (IVF). DESIGN: Four lumbar spines, including T12 and in one case T11, were obtained from embalmed cadavers and carefully dissected to expose the contents of the IVF. All ligamentous structures in the vicinity of the IVF were preserved. The greatest SI and AP of each IVF were measured. When present, TFL help define a compartment at the exit zone of the IVF that contains the VR. The SI and AP of these compartments were also measured. RESULTS: Of 49 IVF examined, at least one TFL was present in 35. In the 34 IVF with horizontally oriented TFL, the mean SI of the compartments for the VR was 31.5% smaller than that of the IVF (one-way ANOVA, p < .01). No significant differences were seen between the AP of the IVF and compartments for the VR in the levels with vertically oriented TFL (n = 11). CONCLUSIONS: TFL were found to be present in 71% of lower thoracic and lumbar IVF. If TFL were present, the SI of the compartment containing the VR in the IVF was significantly decreased (mean = 31.5%). This finding suggests that often there may be less space at the exit zone of the IVF for the ventral ramus than traditionally thought, which could contribute to the incidence of neurological symptomatology in this region, especially after trauma or degenerative changes. PMID- 7836875 TI - The practice of chiropractic in South Dakota: a survey of chiropractors. AB - OBJECTIVE: To identify the professional and demographic characteristics of the chiropractors in South Dakota. DESIGN: Mail survey that covered four major areas: 1) demographics of the chiropractors, 2) population served, 3) factors influencing the economic aspects of the practice, and 4) practice characteristics. A reminder was sent 1 month following the first mailing. SETTING: The state of South Dakota. SUBJECTS: The questionnaire was mailed to all licensed chiropractors in South Dakota (n = 157). RESULTS: The response rate was 68%. Chiropractors responding to the survey were mostly (96%) males and the average age was 41.4 yr with an estimated average of 15 yr of experience. The chiropractors surveyed spent just less than 40 hr/wk at work averaging 128 patient visits with the majority (47%) complaining of low back pain. Data regarding income, the sources of payment, type of community of practice, and the diagnostic as well as treatment techniques were also analyzed. Further analysis was also done to compare rural to urban areas. CONCLUSION: Rural communities have fewer chiropractors than nonrural areas. Future research needs to be directed toward rural area chiropractic care delivery, with special emphasis on factors influencing recruitment and retention of chiropractors in rural areas. The study also showed a need for more involvement with the younger patient groups (18 yr and under). Health services researchers and chiropractic colleges each has an important role in the advancement of pediatric and adolescent health care. PMID- 7836876 TI - Optoelectric measurement of changes in leg length inequality resulting from isolation tests. AB - OBJECTIVE: a) Establish a precise, standardized method to assess prone leg alignment changes (functional "leg length inequality"), which have, until now, been reported clinically to occur as a result putative chiropractic subluxation isolation tests [neck flexion (C5) and extension (C1)]; and b) describe differences in leg alignment changes in a group of healthy subjects and patients with chronic spinal complaints. DESIGN: Two group, two isolation tests, descriptive, repeated measure analysis of variance. SETTING: Exercise and Sport Research Institute, Arizona State University. PARTICIPANTS: Eight healthy controls, eight patients with a history of chronic spinal complaints and observable leg alignment reactivity. INTERVENTIONS: Active cervical flexion/extension maneuvers. OUTCOME MEASURES: Optoelectric markers affixed to heels and occiput, as subjects lay prone. Marker locations sampled at 100 Hz for 10 sec during: a) three no movement trials, b) three cervical extension and c) three flexion trials. Data transformed to local reference frame approximately each subject's longitudinal axis prior to analysis. RESULTS: Heel position movement occurred during trials and were highly individualistic. Patients exhibited more asymmetrical movements than the controls during the head-up trials. No differences existed between controls and patients for range of heel displacement or net displacement. CONCLUSIONS: The results of this study allow the following to be concluded: 1) small leg displacements (< 1 mm) were recorded by the optoelectric measurement system; 2) heel position changes during isolation tests were identifiable; 3) as a result of head-up maneuvers, patients exhibited more asymmetrical heel movement than controls (t = 8.743, p < .01); 4) The heel range of motion was not different between the groups; and 5) The net change in heel position was not different between the groups. Patients exhibited more asymmetrical heel motion during head-up isolation tests, suggesting that some phenomena may separate these two groups, warranting future study. PMID- 7836877 TI - The validity of thoracolumbar paraspinal scanning EMG as a diagnostic test: an examination of the current literature. AB - OBJECTIVE: The purpose of this literature review was to assess the current validity of thoracolumbar paraspinal scanning EMG as practiced by the chiropractic profession within the context of adequate and acceptable epidemiological standards for validating a new diagnostic test. DATA SOURCES, STUDY SELECTION AND DATA EXTRACTION: Sources for the primary literature citations were obtained from several indexing services (MEDLINE--April 1993 to 1989; Index to Chiropractic Literature--1991 to 1980, Chiropractic Research Archives Collection--Vol. I-IV and Chiropractic Literature Analysis and Retrieval System) and hand searched under the subject heading of electromyography. For MEDLINE this was combined with electromyography as a title/abstract word and limited to "human." Primary literature citations were included in this review if the author, institution or journal was associated with the chiropractic profession and the paper dealt with thoracolumbar scanning EMG. Thirty-seven primary publications were identified and were systematically evaluated for contribution to any of the twelve key criteria used to validate a new diagnostic test. Secondary or tertiary citations from all sources were included if referenced in the primary literature as previous investigations supporting one of the key criteria. Additional secondary sources were included providing that the author was aware of them and the subject matter was germane to the EMG subtopic. DATA SYNTHESIS: Based upon this review, none of the 12 key criteria used to validate a new diagnostic test have been adequately satisfied. CONCLUSIONS: It is concluded that thoracolumbar paraspinal scanning EMG is premature for clinical application as a paraclinical diagnostic test. Recommendations for evaluation directions in the immediate future are provided. PMID- 7836878 TI - Fracture of a lamina in the cervical spine. AB - OBJECTIVE: To present an uncommon case of an isolated lamina fracture in the cervical spine found by taking stress films when a routine cervical series failed to demonstrate it. CLINICAL FEATURES: A 63-yr-old male was seen after suffering from mild neck pain and stiffness of 4 days' duration after a car accident. A review of emergency room X-rays demonstrated a small fragment of bone adjacent to the anterior superior end-plate of C6. Flexion/extension stress views were then done that demonstrated anterior slippage of C5 on C6 during flexion, and a cervical lamina fracture of C5 was diagnosed and confirmed with a subsequent MRI. INTERVENTION AND OUTCOME: This patient was treated with specific spinal mobilization for motion restrictions above and below the fracture site, avoiding stress on the C4-6 motor units. Soft tissue, gentle manual cervical traction and patient education on avoiding stress to the cervical spine were given. Resolution of neck pain and stiffness was achieved in three visits, and 6-wk follow-up radiographs demonstrated healing and increased stability at the fracture site. CONCLUSION: A significant percentage of the average chiropractor's practice will involve the management of cervical spine injuries from motor vehicle accidents. The inclusion of stress films in the regular cervical series can reduce the possibility of missing an occult fracture or instability. When neurological complications are absent, such cases can be managed conservatively with the judicious application of spinal manipulative and adjunctive procedures. PMID- 7836879 TI - C1 burst fracture. AB - OBJECTIVE: The presentation of a patient to a chiropractic office with an undiagnosed C1 burst fracture (Jefferson fracture) secondary to head trauma from a motor vehicle accident is introduced. CLINICAL FEATURES: A 67-yr-old real estate manager suffered from neck pain and stiffness following release from a major metropolitan medical center. Anteroposterior open mouth radiographic examination of the cervical spine revealed 10-mm displacement of the lateral masses of C1 relative to the superior articulating facets of C2, indicating the presence of a C1 burst fracture with possible disruption of the transverse ligament. INTERVENTION AND OUTCOME: The patient was transferred by ambulance to a local medical center where a CT scan of the cervical spine and neurosurgical evaluation were obtained. The patient's cervical spine was immobilized in a Philadelphia collar for 3 months. Follow-up radiographic evaluation indicated nonunion of the fracture fragments and the patient was referred for further neurosurgical consultation. CONCLUSION: The presumption of proper and competent prior medical treatment, without confirmation by radiographic examination and review of records, could have resulted in catastrophic consequences for this patient, had chiropractic manipulation been performed. A history of trauma should be a clear signal to the chiropractic practitioner that they should proceed with caution, regardless of the patient's prior history of examination and treatment. PMID- 7836880 TI - The locomotor system: Korr's "primary machinery of life". PMID- 7836881 TI - The curve of the cervical spine: variations and significance. PMID- 7836882 TI - A treatment for carpal tunnel syndrome: results of follow-up study. PMID- 7836883 TI - Valid measurements of total IGF concentrations in biological fluids. Recommendations from the 3rd International Symposium on Insulin-like Growth Factors. PMID- 7836884 TI - Glial cells and neuroendocrine function. PMID- 7836885 TI - Growth hormone and prolactin affect oxytocin, vasopressin, progesterone and cyclic nucleotide secretion by bovine granulosa cells in vitro. AB - The effects of growth hormone (GH) and prolactin (PRL) (1, 10, 100, 1000 or 10,000 ng/ml medium) on oxytocin, vasopressin, progesterone, cAMP and cGMP release by cultured bovine granulosa cells were studied. It was found that GH significantly stimulated oxytocin, vasopressin and cAMP but suppressed progesterone secretion. PRL tended to have the same pattern of action on nonapeptide, cAMP and steroid release, but its effect was not as great, with only a high supraphysiological dose (10,000 ng/ml) producing a statistically significant effect. No significant influence of GH on cGMP output was observed. Physiological doses of PRL (1, 10, 100 or 1000 ng/ml) significantly inhibited cGMP production whilst a high dose (10,000 ng/ml) resulted in stimulation. These observations suggested that GH may regulate ovarian oxytocin, vasopressin, progesterone and cAMP secretion. The effects of PRL on the release of these substances appeared to be non-specific, possibly resulting from its structural similarity to GH. PMID- 7836886 TI - The autonomy of the rabbit corpus luteum. AB - The rabbit corpus luteum possesses LH receptors that are coupled to adenylyl cyclase, but paradoxically it does not require LH as a luteotrophic factor for the maintenance of progesterone secretion. This suggests that rabbit luteal cells may not respond physiologically to LH. Therefore, the present study was undertaken to investigate the responsiveness of the rabbit corpus luteum of pseudopregnancy to human chorionic gonadotrophin (hCG) which acts on the same receptor as LH. Pseudopregnancy was induced by injection of 40 IU pregnant mare serum gonadotrophin followed 50 h later by an injection of 40 IU hCG (day 0). On days 7 and 11 of pseudopregnancy, corpora lutea were obtained and incubated for 2 or 5 h in the presence of either 0.1 or 1 microgram/ml hCG or 1 mM monobutyryl cyclic AMP (bcAMP). Neither hCG nor bcAMP stimulated progesterone production by the isolated corpus luteum, despite a sustained high rate of progesterone production by the tissue throughout the incubation period. By contrast, Graafian follicles removed from the same ovaries and incubated under the same conditions responded both to hCG and bcAMP with large increases in progesterone production. To determine whether the cyclic AMP content of the corpus luteum was altered by in vitro exposure to hCG, day 7 and day 11 corpora lutea were incubated for 5 or 15 min with various concentrations of hCG, and cyclic AMP in the tissue was then measured. Even at the highest concentration of hCG tested (10 micrograms/ml), the cyclic AMP content of the corpus luteum was unaltered.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836888 TI - The role of prolactin in the reactivation of hair follicles in relation to moulting in cashmere goats. AB - The effects of the suppression or elevation of plasma prolactin concentrations in spring on the timing of the reactivation of the hair follicles and the timing of the spring moult were investigated in cashmere goats. Thirty eight adult female goats, housed under conditions of natural photoperiod at 55 degrees 55'N from mid December until May, were allocated to four groups starting on 5 January: ten served as untreated controls, eight received 2 mg ovine prolactin subcutaneously every 12 h for 7 weeks (PRL), twelve received 35 mg bromocriptine intramuscularly every 14 days for 17 weeks (BCR) and eight received injections of both ovine prolactin and bromocriptine at the above dose rates for 7 weeks (PRL+BCR). In the PRL group there was an earlier reactivation of the secondary hair follicles (PRL vs control, proportion of secondary follicles in antigen, weeks 1-5, P < 0.01) associated with an earlier moult of secondary fibres (cashmere) but no significant difference in the activity of the primary hair follicles. In the BCR group there was a delay in the reactivation of both the secondary and primary hair follicles (BCR vs control, proportion of secondary and primary hair follicles in anagen, weeks 5-13, P < 0.01) and a delay in the moult. In the PRL+BCR group there was an early reactivation and moult similar to the PRL group. Voluntary food intake (VFI) and liveweight were also measured. Only in the BCR group was there a decrease in VFI compared with the controls but with no effect on liveweight.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836887 TI - High plasma insulin-like growth factor-II and low lipid content in transgenic mice: measurements of lipid metabolism. AB - Transgenic mice were made by introducing extra copies of the mouse insulin-like growth factor-II (IGF-II) gene driven by the bovine keratin 10 promoter (BKVI). The adult plasma IGF-II levels were elevated at least three times in one line. In this line, there was a lower lipid content of both brown and white adipose depots at 2-4 months of age, and 40% less fat in the carcass at 7-9 months. The low lipid phenotype was not detected in the carcass at 2 weeks after birth. The lean characteristic was attributed to circulating IGF-II because the transgene was not expressed in fat. At 2-4 months of age, the transgenes oxidized more oral lipid, and less of this lipid was incorporated into the whole body and the epididymal fat. In contrast, the interscapular brown adipose tissue maintained lipid incorporation and lipoprotein lipase activity despite its reduced size. The altered activity of the brown adipose tissue may account for the gradual onset and persistence of the lean feature of the transgenic mice. There were no substantial changes in lipogenesis which could account for the low fat content. The plasma levels of IGF-I, insulin, glycerol, non-esterified fatty acids, triacylglycerols and glucose were not greatly changed and the pituitary GH content was within the normal range. PMID- 7836889 TI - Angiotensin II (AII)-binding sites in nuclei from rat liver: partial characterization of the mechanism of AII accumulation in nuclei. AB - Isoelectric focusing analysis showed a single angiotensin II (AII)-receptor complex migrating to pI 6.8 in nuclear preparations, while in plasma membranes a charge heterogeneity of the AII receptor subtype AT1 was observed. 125I-Labelled AII binding sites were found in intact nuclei and were not detected in nuclear extracts. Neither disruption of cytoskeletal elements by colchicine nor prevention of endosome acidification by chloroquine had any effect on nuclear accumulation of AII. Nevertheless, the monovalent ionophore monensin inhibited nuclear accumulation of 125I-labelled AII. Our findings are consistent with the hypothesis that processing through the Golgi apparatus could be involved in the nuclear accumulation of AII. PMID- 7836890 TI - Horse plasma corticotrophin-releasing hormone (CRH): characterisation and lack of a late gestational rise or a plasma CRH-binding protein. AB - Immunoreactive corticotrophin-releasing hormone (irCRH) was present in methanolic extracts of equine peripheral blood and showed no elevation in maternal peripheral serum in late gestation (0.54 +/- 0.25 pmol/l; mean +/- S.D.) compared with control horses (0.41 +/- 0.15 pmol/l). The irCRH of methanolic extracts of pituitary venous plasma had a similar elution position following reverse-phase HPLC to synthetic human CRH(1-41) and to irCRH released from horse stalk-median eminence tissue incubated in vitro. Gel chromatographic studies showed no evidence for a plasma CRH-binding protein (CRHBP) analogous to that found in human plasma in either peripheral blood from normal or pregnant horses or in pituitary venous plasma sampled from a cannulated horse. CRH-binding activity was detectable in peripheral plasma from one horse, however the molecular size of this was indicative of a gamma-globulin rather than the 37 kDa CRHBP. These studies suggest that, unlike in the human, CRH does not rise to high values in late gestation nor circulate in a bound form in equine plasma. PMID- 7836891 TI - Effects of insulin-like growth factor-I (IGF-I) and IGF-II on the growth of antler cells in vitro. AB - The effects of insulin-like growth factors -I and -II (IGF-I and -II) on the growth of undifferentiated (fibroblast zone) cells from the growing tip of red deer velvet antlers and from cells 1.5 cm distal to the growing tip (cartilage zone) were investigated in primary cell culture. The addition of IGF-I or IGF-II to the medium of cultures preincubated in serum-free medium for 24 h increased the rate of [3H]thymidine uptake in a dose-dependent manner in both cell types, with maximal stimulation occurring when 1 nM-30 nM was added. The addition of IGF II to the incubation medium containing IGF-I did not cause a further increase in [3H]thymidine uptake in either cell type over and above each growth factor alone, indicating that there were unlikely to be synergistic effects of IGF-II on the mitogenicity of IGF-I. Binding studies were carried out using 3 x 10(5) fibroblast zone cells and cartilage zone cells after they had been incubated in serum-free medium for 24 h. 125I-Labelled IGF-I (10(-9) M) in a final volume of 200 microliters was added to each culture and incubation carried out at 4 degrees C for a further hour. 125I-Labelled IGF-I bound specifically to both fibroblasts and cartilage zone cells; binding was displaced by both unlabelled IGF-I and by IGF-I antibody.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836892 TI - The effect of germ cell complement on the presence of oxytocin in the interstitial and seminiferous tubule fluid of the rat testis. AB - In the rat testis oxytocin has been localized to the Leydig cells, and these cells have been shown to produce oxytocin in vitro. The present study was performed to determine whether oxytocin is present in the interstitial fluid (IF) and seminiferous tubule fluid (TF) of the rat and whether concentrations of the peptide vary within the two compartments following germ cell destruction. In order to destroy germ cells adult male rats were anaesthetized and their scrotal regions placed in a water bath at 43 degrees C for 20 min. Control animals were subjected to anaesthesia alone. Groups of 6 animals were killed 3, 7 and 21 days after heat treatment and their testes removed for histological examination or fluid extraction. IF and TF were separated and the oxytocin content of the fluids measured by radioimmunoassay. Immunoreactive oxytocin was detected in both the IF (100 +/- 11 pg/ml) and TF (27 +/- 4 pg/ml) of control rats and this immunoreactivity co-eluted with the authentic peptide following HPLC. Three days after heat treatment IF levels of oxytocin were significantly reduced but TF levels of the peptide were significantly increased. These changes were associated with a lack of pachytene spermatocytes in the histological sections. Seven and 21 days after heat treatment the levels of oxytocin in the IF and TF were not significantly different from control levels. Similar changes in IF and TF oxytocin levels were seen in a second experiment when pachytene spermatocytes were removed using the testicular toxicant methoxyacetic acid.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836893 TI - Pituitary-specific transcription factor Pit-1 in the rdw rat with growth hormone- and prolactin-deficient dwarfism. AB - The pituitary gland of the rdw rat (gene symbol: rdw) with hereditary dwarfism expresses 30-100 times less GH and prolactin (PRL) mRNA than normal controls. To clarify the features of rdw rats, TSH and the pituitary-specific transcription factor Pit-1, which is involved not only in the gene expression of GH and PRL but in somatotroph, lactotroph and thyrotroph development as well, were examined. The rdw pituitary contained about seven times more TSH beta mRNA than the normal control, whereas Pit-1 mRNA expression in rdw and control was the same. Nucleotide sequencing of PCR-amplified Pit-1 cDNA indicated that the deduced amino acid sequence of rdw Pit-1 was identical with that of the normal rat. Using an antibody against rat Pit-1 protein produced in E. coli, Western blotting analysis demonstrated the presence of the same amount of Pit-1 protein in rdw and normal rat pituitaries. The distribution of Pit-1-positive cells in the anterior pituitary was essentially the same in rdw and normal rats. It follows from these findings that the defective gene in the rdw rat is unrelated to the Pit-1 gene and the normal quantity of Pit-1 protein is insufficient to produce normal amounts of GH and PRL in the rdw pituitary. These and previous results suggest that the reduction in GH and PRL production in the rdw pituitary might be due to that in thyroid hormone production. PMID- 7836894 TI - Modulation of epidermal growth factor binding and receptor gene expression by hormones and growth factors in sheep pituitary cells. AB - Epidermal growth factor (EGF) is a potent mitogen for sheep pituitary cells but the factors controlling the binding and expression of EGF and its receptor (EGFR) in the pituitary are poorly understood. Regulation of EGF binding and EGFR gene expression may determine cellular responsiveness to EGF and could play a role in neoplastic development. Scatchard analysis of 125I-EGF binding in cultured sheep pituitary cells revealed two receptor binding sites (high affinity class of 2.5 +/- 0.5 x 10(3) receptors/cell with a dissociation affinity constant (Kd) of 3.2 +/- 0.7 x 10(-10) M and low affinity class of 3.3 +/- 1.0 x 10(4) receptors/cell with a Kd of 7.1 +/- 1.3 x 10(-9) M). Exposure of the cultured cells to some target gland hormones of the pituitary (oestrogen, tri-iodothyronine and hydrocortisone), pituitary growth factors (EGF, basic fibroblast growth factor, transforming growth factor-beta) and a tumour-promoting phorbol ester (TPA) resulted in an increase in the binding affinity of the high affinity receptors while reducing the receptor number and also a reduction of EGFR mRNA levels, shown by Northern blot analysis. In contrast, forskolin, an activator of adenylate cyclase, showed no significant effect on EGF binding and receptor gene expression. We conclude that the EGFR in normal pituitary cels can be modulated by several hormones and other growth factors at both receptor binding and mRNA levels. Transmodulation of EGFR by hormones and growth factors in the pituitary may be one of the regulatory mechanisms controlling the balance of normal pituitary growth and function.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836895 TI - Differential metabolic requirement for initiation and augmentation of insulin release by glucose: a study with rat pancreatic islets. AB - Insulin release, glucose utilization (3H2O formation from [5-3H]glucose), and glucose oxidation (14CO2 formation from [14C(U)]glucose) were determined in pancreatic islets from 96-h fasted rats at 37 degrees C and those from fed rats at 22 degrees C, using the islets from fed rats incubated at 37 degrees C as controls. In the islets from 96-h fasted rats and those from fed rats incubated at 22 degrees C, we could not demonstrate significant insulin release in response to high glucose concentrations of up to 16.7 mmol/l. However, 16.7 mmol/l glucose clearly augmented insulin release caused by a depolarizing concentration (50 mmol/l) of K+ in these islets: i.e. 16.7 mmol/l glucose plus 50 mmol/l K+ produced significantly greater insulin release than 50 mmol/l K+ alone. Glucose utilization and oxidation by the islet cells were suppressed by 96-h fasting of the rats or by lowering the incubation temperature to 22 degrees C, and depolarization with K+ at 50 mmol/l did not at all augment glucose utilization and oxidation by the islets. Thus we conclude that reduction of glucose metabolism in islets from fasted rats and in those incubated at low temperature eliminated initiation, but not augmentation, of insulin release by 16.7 mmol/l glucose. The data indicate that the metabolic threshold for the initiation of insulin release is significantly higher than it is for the augmentation of release by glucose. PMID- 7836896 TI - 11 beta-Hydroxysteroid dehydrogenase in the rat placenta: developmental changes and the effects of altered glucocorticoid exposure. AB - The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) catalyses the interconversion of corticosterone, the major glucocorticoid of the rat, and the biologically-inactive 11-dehydrocorticosterone. In the placenta, 11 beta-HSD is thought to regulate glucocorticoid transport between maternal and fetal compartments, and may also affect the local action of glucocorticoids. The present study assessed whether 11 beta-dehydrogenase (corticosterone to 11 dehydrocorticosterone) and 11-oxoreductase (11-dehydrocorticosterone to corticosterone) activities are both present in rat placenta, and whether these activities change with advancing pregnancy. Enzyme activity was estimated on days 16, 19 and 22 of pregnancy (term = day 23) in placental fragments incubated for 6 h with either [3H]corticosterone or [3H]11-dehydrocorticosterone. The percentage conversion of these substrates to [3H]11-dehydrocorticosterone and [3H]corticosterone, respectively, were determined at the end of the incubation. Both 11-oxoreductase and 11 beta-dehydrogenase activities were clearly evident in placental tissue fragments, and while 11-oxoreductase activity declined with advancing pregnancy (P < 0.01), 11 beta-dehydrogenase activity increased (P < 0.01). Thus, 11-oxoreductase exceeded (P < 0.05) 11 beta-dehydrogenase at day 16, but thereafter activities were similar. These changes do not appear to be glucocorticoid-induced, since pretreatment of rats with either metyrapone or dexamethasone acetate from day 15 of pregnancy did not affect placental 11 beta HSD on day 22.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836897 TI - Changes of calmodulin concentration and cyclic 3',5'-nucleotide phosphodiesterase activities in cardiac muscle of hyper- and hypothyroid rats. AB - To investigate the effect of thyroid hormone on cardiac muscle dysfunction in hyper- and hypothyroid states, we evaluated cyclic 3',5'-nucleotide metabolism by measuring cyclic 3',5'-nucleotide phosphodiesterase activity and calmodulin concentrations in the cardiac muscles of hyper- and hypothyroid rats. Cyclic AMP (cAMP) concentration was significantly high in the cardiac muscle of hyperthyroid rats and low in that from hypothyroid rats compared with control rats. Cyclic AMP and cyclic GMP phosphodiesterase activities were significantly decreased in the soluble fraction of cardiac muscle from hyperthyroid rats and markedly increased in this fraction in hypothyroid rats compared with normal animals. Calmodulin concentration was high in hyperthyroid and low in hypothyroid rats. It was concluded from these findings that low cAMP-phosphodiesterase activity might, in part, bring about the high concentration of cAMP. Calmodulin was significantly high in the cardiac muscle of hyperthyroid rats and the reverse was the case in hypothyroid rats compared with normal rats. The implication is that, in hyper- and hypothyroid states, these changes may play an important role in cardiac function via their effect on cyclic nucleotide and Ca2+ metabolism. PMID- 7836898 TI - A vitamin D analogue KH 1060 activates the protein kinase C-c-fos signalling pathway to stimulate epidermal proliferation in murine skin. AB - The cellular signalling pathways of a potent 20-epi-22-oxa vitamin D3 analogue (KH 1060) were examined in vivo in a hairless mouse model. Seventy two hours after a single topical application of KH 1060 a thickening of the epidermis (from 24.8 +/- 1.2 microns at 0.01 pmol/cm2 KH 1060 to 124.2 +/- 6 microns at 5 pmol/cm2 KH 1060, P < 0.001) was elicited due to epidermal hyperproliferation. This effect could be blocked by topical 2.5 mumol/cm2 sphingosine, an inhibitor of protein kinase C. Two hours after topical application of 2.5 pmol/cm2 KH 1060 a translocation of protein kinase C activity from cytoplasm to the membrane fractions was observed. Moreover, using a reverse-transcription polymerase chain reaction technique, a transient upregulation of c-fos gene expression was seen 2 hours after topical treatment with KH 1060. The expression of c-fos was dependent on protein kinase C activation, since after pretreatment with the protein kinase C blocker sphingosine, c-fos messenger RNA was not detected. These findings strongly suggest that KH 1060 stimulates epidermal growth through activation of the protein kinase C-c-fos signalling axis in vivo. PMID- 7836899 TI - An investigation of the ability of TSH and Graves' immunoglobulin G to increase intracellular calcium in human thyroid cells, rat FRTL-5 thyroid cells and eukaryotic cells transfected with the human TSH receptor. AB - The purpose of this study was to determine if immunoglobulin G preparations (IgGs) from patients with Graves' disease can increase intracellular calcium in thyroid cells, as has been reported for TSH. Both TSH and Graves' IgGs (prepared by protein G affinity chromatography) increased calcium in a range of thyroid cells; however, the response seen, using Fura-2-loaded coverslips of cell monolayers, varied considerably. Chinese hamster ovary (CHO/JPO9) cells transfected with a high number of human TSH receptors showed the greatest response: TSH (10 mU/ml) increased calcium in 46% of experiments and 18 out of 25 (72%) Graves' IgGs increased calcium at 0.1 mg/ml (significantly greater, P < 0.001, than for control IgGs where cells responded to 2 out of 13 preparations). Rat FRTL-5 cells only responded to TSH in 22% of experiments and to 2 out of 8 (25%) of Graves' IgGs. Similarly, human thyroid cells responded to TSH in 22% of experiments and to 2 out of 9 (22%) of Graves' IgGs. (When studying cyclic AMP responses in JPO9 cells, much higher concentrations of Graves' IgGs were required (1-3 mg/ml). However, higher concentrations (0.3 mg/ml) of both Graves' IgGs, and to a lesser extent of control IgGs, were capable of increasing calcium in cells both with and without TSH receptors (control CHO cells and normal human dermal fibroblasts). We conclude that relatively low concentrations of patient IgGs can be distinguished from control IgGs in JPO9 cells on the basis of their ability to increase calcium, but that additionally all IgG preparations possibly contain another factor which can increase calcium in a range of cells independent of the presence of the TSH receptor. PMID- 7836900 TI - Sexual dimorphism of hepatic 11 beta-hydroxysteroid dehydrogenase in the rat: the role of growth hormone patterns. AB - 11 beta-Hydroxysteroid dehydrogenase (11 beta-HSD) catalyses the reversible metabolism of corticosterone to inert 11-dehydrocorticosterone. At least two isoforms exist. 11 beta-HSD-1, the first to be characterised and the only isoform for which a cDNA has been isolated, is highly expressed in liver, kidney and hippocampus. The activity of 11 beta-HSD in rat liver is higher in males, due to oestrogen repression of 11 beta-HSD-1 gene transcription in females. Sexual dimorphism in rodent liver proteins is frequently mediated indirectly via sex specific patterns of GH release (continuous in females, pulsatile in males). We have now investigated whether this applies to 11 beta-HSD, using dwarf rats (congenitally deficient in GH) and hypophysectomised animals. 11 beta-HSD activity and 11 beta-HSD-1 mRNA expression in liver was significantly lower in control female than male rats (50% and 72% of male levels respectively). These sex differences in the liver were attenuated in dwarf rats, with both males and females showing similar levels of 11 beta-HSD activity to control males. Administration of continuous (female pattern) GH to dwarf male rats decreased hepatic 11 beta-HSD activity (30% fall) and mRNA expression (77% fall), whereas the same total daily dose of GH given in the male (pulsatile) pattern had no effect on hepatic 11 beta-HSD in female dwarf rats. Continuous GH also attenuated hepatic 11 beta-HSD activity (25% fall) and 11 beta-HSD-1 mRNA expression (82% fall) in hypophysectomised animals.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836901 TI - Binding of thyroid hormone to the goat testicular Leydig cell induces the generation of a proteinaceous factor which stimulates androgen release. AB - Leydig cells isolated from goat testis were sonicated and pure nuclear preparations obtained for 125I-3,5,3'-triiodothyronine (T3)-binding assay. Under optimum assay conditions of pH 7.2 at 37 degrees C and 90 min of incubation, binding of 125I-T3 to Leydig cell nuclei reached saturation at 1.2 nmol/l concentration. A Scatchard analysis of T3 binding exhibited a Kd of 0.535 x 10( 9) mol/l and a maximum binding capacity of 1.25 pmol/mg DNA. Competitive inhibition studies showed T3 binding to be analogue specific. The physiological relevance of T3 binding to goat Leydig cell was examined by adding increasing concentrations of T3 to the Leydig cell incubation (1 x 10(6) cells/incubation). T3 (10, 25 and 50 ng/ml or 4, 10 and 20 ng/incubation) resulted a dose dependent increase in androgen release and in all cases stimulation of androgen release was statistically significant (P < 0.01) compared with control. Stimulation of Leydig cell androgen release by T3 was significantly inhibited by actinomycin-D (P < 0.01) and cycloheximide (P < 0.01). T3 had additive stimulatory effects on LH augmented androgen release from Leydig cells. T3 (50 ng/ml or 20 ng/incubation) effected a more than twofold increase in Leydig cell protein synthesis compared with control and both actinomycin-D and cycloheximide (50 micrograms/ml) inhibited it completely. The data indicated that the stimulatory effect of T3 on androgen release is mediated via T3-induced protein(s).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836902 TI - The effect of oleic acid on the secretion of thyrotrophin and growth hormone by cultured rat anterior pituitary cells. AB - Elevation of non-esterified fatty acids (NEFA) in vivo is associated with abnormal control of TSH. To determine whether TSH secretion is directly inhibited by NEFA, as has been reported for GH, cultured rat anterior pituitary cells were exposed for 20 h to oleic acid in medium containing 7.7 x 10(-5) mol/l bovine serum albumin (BSA). In a molar ratio with albumin of 1.2 (total oleic acid 9 x 10(-5) mol/l), or greater, oleic acid inhibited basal GH secretion (maximum inhibition to 40% of control) while basal TSH was less affected, a ratio of 3 (2.3 x 10(-4) mol/l oleic acid) or greater causing a smaller degree of inhibition (maximum inhibition to 80% of control). In the presence of 10(-9) mol/l growth hormone-releasing hormone or 10(-8) mol/l TRH, inhibition was achieved at a ratio of 12 (9 x 10(-4) mol/l oleic acid) or greater. Basal TSH was less sensitive to inhibition by thyroxine (T4) in the presence of oleic acid/albumin at a ratio of 6 or greater, and inhibition by oleic acid was less than additive with T4 at a ratio of 6 or greater. Responses to tri-iodothyronine (T3) were unaffected at a ratio of 6 (4.6 x 10(-4) mol/l oleic acid), but a ratio of 12 inhibited the effects of both T3 and T4 on TSH.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7836903 TI - Opioid peptides and testicular activity in the lizard Podarcis s. sicula Raf. AB - In mammals endorphinergic systems have been shown to modulate reproductive processes and beta-endorphin (beta-EP) has been found to influence sexual functions, acting at the hypothalamus-pituitary-gonadal axis level. Using immunocytochemical and in vitro studies, evidence for a diffuse pro opiomelanocortin-related opioid system in the lizard Podarcis s. sicula was produced. In the testis, beta-EP immunoreactivity showed seasonal variation, being most pronounced in the interstitial cells of sexually quiescent lizards (December). Reverse-phase high-performance liquid chromatography, coupled with radioimmunoassay and immunocytochemistry, showed that beta-EP and acetyl beta-EP increased during December, while their concentrations were low during April, when the highest testicular activity occurred. Using in vivo studies, it was found that naltrexone treatment, blocking pituitary opioid receptor, increased androgen levels in the plasma and in the testis. It was also found with in vitro studies that the endogenous opioid system inhibits gonadotrophin release and therefore androgen production by the testis. The data reported here provide evidence for the physiological role played by opioid peptides at the pituitary level to regulate the seasonal reproductive activity of the lizard Podarcis s. sicula. PMID- 7836904 TI - Motifs and supermotifs for MHC class II binding peptides. PMID- 7836905 TI - Control of lymphopoiesis by p50csk, a regulatory protein tyrosine kinase. AB - The csk gene encodes a nonreceptor protein tyrosine kinase that acts in part by regulating the activity of src-family protein tyrosine kinases. Since the src family kinases p56lck and p59fyn play pivotal roles during lymphocyte development, it seemed plausible that p50csk might contribute to these regulatory circuits. Using a gene targeting approach, mouse embryonic stem cell lines lacking functional csk genes were generated. These csknull embryonic stem cells proved capable of contributing to many adult tissues, notably heart and brain. However, although csknull progenitors colonized the developing thymus, T and B cell differentiation were both blocked at very early stages. This represented a relatively selective interdiction of lymphocyte maturation, since csknull hematopoietic progenitors supported the development of normal-appearing MAC-1+ blood leukocytes, and the successful maturation of granulocyte/macrophage-colony forming units from fetal liver progenitors. We conclude that p50csk regulates normal lymphocyte differentiation, but that it almost certainly does so by acting on targets other than p56lck and p59fyn. PMID- 7836906 TI - Cells expressing a major histocompatibility complex class I molecule with a single covalently bound peptide are highly immunogenic. AB - The major histocompatibility complex (MHC) class I molecules expressed at the cell surface are associated with a large number of different peptides so that the density of a given MHC-peptide complex is relatively low. Here we describe the properties of MHC class I molecules genetically attached to a single antigenic peptide. Cells expressing these fusion proteins are recognized by T cells specific for the particular MHC-peptide complex. Coculture of naive splenocytes with cells expressing these MHC-peptide fusion proteins and the B7.1 antigen allows the induction of primary cytotoxic T lymphocytes (CTL) in vitro. Injection of these cells into naive mice enhances the frequency of specific CTL precursors and protects against a subsequent challenge with a tumor or a virus bearing the antigenic peptide. Soluble MHC-peptide fusions were also produced in which all three components, that is, the heavy chain, beta 2-microglobulin and the peptide, have fused into a single-chain protein. The availability of MHC class I molecules bound to a single peptide provides valuable tools for the manipulation of CTL responses and the analysis of the selection processes in the thymus. PMID- 7836907 TI - In vivo expansion of HLA-B35 alloreactive T cells sharing homologous T cell receptors: evidence for maintenance of an oligoclonally dominated allospecificity by persistent stimulation with an autologous MHC/peptide complex. AB - The nature of alloantigens seen by T lymphocytes, in particular the role of peptides in allorecognition, has been studied intensively whereas knowledge about the in vivo emergence, diversity, and the structural basis of specificity of alloreactive T cells is very limited. Here we describe human T cell clones that recognize HLA-B35 alloantigens in a peptide-dependent manner. TCR sequence analysis revealed that several of these allospecific clones utilize homologous TCR: they all express TCRAV2S3J36C1 and TCRBV4S1J2S7C2 chains with highly related CDR3 sequences. Thus peptide-specific alloreactivity is reflected in homologous CDR3 sequences in a manner similar to that described for T cells that recognize nominal peptide/self-MHC complexes. The in vivo frequency of this TCR specificity was studied in unstimulated PBL of the responding cell donor who was not sensitized against HLA-B35. The vast majority (approximately 75%) of the VA2S3J36 junctional regions obtained from two samples of PBL, isolated at a 9-yr interval, encode CDR3 identical or homologous to those of the functionally characterized HLA-B35 allospecific T cells. These data are most easily explained by a model of alloreactivity in which persistent or recurrent exposure to a foreign peptide/self-MHC complex led to the in vivo expansion and long-term maintenance of specific T cells that show fortuitous crossrecognition of an HLA-B35/peptide complex and dominate the alloresponse against HLA-B35. PMID- 7836908 TI - Cross-linking of membrane immunoglobulin D, in the absence of T cell help, kills mature B cells in vivo. AB - In vivo experiments were performed to determine whether the cross-linking of membrane immunoglobulin (mIg) D on mature B cells, in the absence of T cell help, leads to B cell death. Mice were injected with either a monoclonal antibody (mAb) that cross-links mIgD effectively or a mAb that binds to mIgD avidly but cross links it to a limited extent, and effects on B cell number and B cell Ia, mIgM, and mIgD expression were observed. In most experiments, mice were pretreated with anti-interleukin 7 mAb to prevent the generation of new bone marrow B cells, and with anti-CD4 mAb to prevent the generation of T cell help. In some experiments, mice also received anti-Fc gamma RII mAb to prevent cross-linking of mIgD with Fc gamma RII, and cobra venom factor to prevent possible mIg-complement receptor interactions and complement-mediated killing of B cells. The results of these studies demonstrate that (a) even limited cross-linking of mIgD on mature B cells can lead to B cell death; (b) increased cross-linking of mIgD leads to increased B cell death; (c) the loss of B cells is first detected 2 d after anti-IgD mAb injection and increases during the subsequent 3 d; (d) sustained modulation of mIgD may be necessary to cause B cell death; (e) mIgMdull but not mIgMbright B cells are lost in mice injected with anti-IgD mAbs; and (f) T cell help prevents or minimizes B cell death. PMID- 7836909 TI - Supermotifs enable natural invariant chain-derived peptides to interact with many major histocompatibility complex-class II molecules. AB - Class II-associated invariant chain peptides (CLIPs) compete with natural allele specific ligands for binding to several purified HLA-DR molecules. Truncation and substitution analysis showed that a minimal sequence of 13 amino acids is sufficient for excellent binding to DR17 and DR1. Hydrophobic residues at relative positions 1 and 9 (P1 and P9) which are shared among these DR-ligands, and are found to be anchored in complementary pockets by x-ray crystallography allow specific binding. Two flanking residues at either end next to the specific contact sites Met107 and Met115 contribute to binding irrespective of their side chains, suggesting H-bonds to the major histocompatibility complex (MHC) molecule. Thus, CLIPs behave like conventional ligands, however, lack their allele-specific contact sites. Introduction of the DR17-specific contact site aspartate at P4 dramatically improves invariant chain-peptide binding to DR17, but reduces DR1 binding. By contrast, binding to DR1, but not DR17 is strongly improved after introduction of the DR1-specific contact site alanine at P6. In addition, analyzing the fine specificity of the hydrophobic contact sites at P1 and P9, CLIP variants reflected the allele-specific preferences of DR17- or DR1 ligands, respectively, for aliphatic or aromatic residues. Alignment studies suggest that CLIPs are designed for promiscuous binding in the groove of many MHC class II molecules by taking advantage of one or more supermotifs. One such supermotif, for example, does not include the DR17-specific contact site aspartate at P4, which in conventional natural ligands like Apolipoprotein (2877 94) is necessary to confer a stable conformation. Introduction of aspartate at P4 generates a CLIP variant that is stable in the presence of sodium dodecyl sulfate, such as allele-specific ligands. Studying the stability of class II-CLIP complexes at pH 5, we found that CLIPs, similar to anchor-amputated ligands, can be released from class II molecules, in contrast to conventional natural ligands, which were irreversibly bound. Taken together, our data provide compelling evidence that CLIP peptides bind into the class II groove. PMID- 7836910 TI - Stimulatory and inhibitory effects of interleukin (IL)-4 and IL-13 on the production of cytokines by human peripheral blood mononuclear cells: priming for IL-12 and tumor necrosis factor alpha production. AB - The production of cytokines in monocytes/macrophages is regulated by several different cytokines that have activating or inhibitory effects. Interleukin (IL) 10, IL-4, IL-13, and transforming growth factor (TGF)-beta are usually considered to be the most important macrophage-deactivating factors, with inhibitory effects on cytokine production. Unlike IL-10 and TGF-beta, which appear to act as downmodulators of many phagocytic cell functions, the mode of action of IL-4 and IL-13 is more complex. Addition of IL-4 and IL-13 to peripheral blood mononuclear cell (PBMC) cultures inhibited production of IL-12, tumor necrosis factor (TNF) alpha, IL-10, and IL-1 beta induced by lipopolysaccharide (LPS) or Staphylococcus aureus added simultaneously with the cytokines. However, pretreatment of PBMC with IL-4 or IL-13 for > or = 20 h enhanced the production of IL-12 and TNF-alpha in response to LPS or S. aureus several fold in these cells; this IL-4-induced priming for the two cytokines was inhibited by anti-IL-4 neutralizing antibodies. IL-4 priming also enhanced the accumulation of IL-12 and TNF-alpha mRNA induced by LPS and S. aureus. The enhanced accumulation of transcripts for the IL-12 p35 and p40 chains by IL-4 priming was reflected in enhanced secretion of both the IL 12 free p40 chain and the p70 heterodimer. These results suggest an unexpected complexity in the regulatory role of IL-4 and IL-13 in immune responses. PMID- 7836911 TI - Myasthenia gravis-like syndrome induced by expression of interferon gamma in the neuromuscular junction. AB - Abnormal humoral responses toward motor end plate constituents in muscle induce myasthenia gravis (MG). To study the etiology of this disease, and whether it could be induced by host defense molecules, we examined the consequences of interferon (IFN) gamma production within the neuromuscular junction of transgenic mice. The transgenic mice exhibited gradually increasing muscular weakness, flaccid paralysis, and functional disruption of the neuromuscular junction that was reversed after administration of an inhibitor of acetylcholinesterase, features which are strikingly similar to human MG. Furthermore, histological examination revealed infiltration of mononuclear cells and autoantibody deposition at motor end plates. Immunoprecipitation analysis indicated that a previously unidentified 87-kD target antigen was recognized by sera from transgenic mice and also by sera from the majority of human MG patients studied. These results suggest that expression of IFN-gamma at motor end plates provokes an autoimmune humoral response, similar to human MG, thus linking the expression of this factor with development of this disease. PMID- 7836912 TI - Phosphatidic acid signaling mediates lung cytokine expression and lung inflammatory injury after hemorrhage in mice. AB - Because phosphatidic acid (PA) pathway signaling may mediate many basic reactions involving cytokine-dependent responses, we investigated the effects of CT1501R, a functional inhibitor of the enzyme lysophosphatidic acid acyltransferase (LPAAT) which converts lysophosphatidic acid (Lyso-PA) to PA. We found that CT1501R treatment not only prevented hypoxia-induced PA increases and lyso-PA consumption in human neutrophils, but also prevented neutrophil chemotaxis and adherence in vitro, and lung injury and lung neutrophil accumulation in mice subjected to hemorrhage and resuscitation. In addition, CT1501R treatment prevented increases in mRNA levels and protein production of a variety of proinflammatory cytokines in multiple lung cell populations after blood loss and resuscitation. Our results indicate the fundamental role of PA metabolism in the development of acute inflammatory lung injury after blood loss. PMID- 7836913 TI - Sustained signaling leading to T cell activation results from prolonged T cell receptor occupancy. Role of T cell actin cytoskeleton. AB - Using antigen-specific T cell clones and peptide-pulsed antigen-presenting cells (APCs) we investigated the mechanisms that lead to sustained signaling, known to be required for activation of effector function. Four lines of evidence indicate that the T cell actin cytoskeleton plays a crucial role in T cell activation by antigen-pulsed APCs, but is not required when T cell receptor (TCR) is cross linked by soluble antibodies. First, addition of antibodies to the major histocompatibility complex molecules recognized by the TCR aborts the ongoing intracellular calcium concentration ([Ca2+]i) increase in performed T-APC conjugates, indicating that the sustained signaling requires the continuous occupancy of TCR. Second, time-lapse image recording shows that T lymphocytes conjugated to peptide-pulsed APCs undergo a sustained [Ca2+]i increase, which is accompanied by the formation of a large and changing area of contact between the two opposing membranes. Third, drugs that disrupt the actin cytoskeleton, Cytochalasin D and and C2 Clostridium botulinum toxin induce a rapid block of [Ca2+]i rise, coincident with a block of the cyclic changes in T cell shape. Finally, the addition of Cytochalasin D or of anti-MHC antibodies to preformed conjugates inhibits interferon gamma production in an 1-antigen dose- and time dependent fashion. These results identify T cell actin cytoskeleton as a major motor for sustaining signal transduction and possibly for driving TCR cross linking and offer an explanation for how T cells equipped with low affinity TCR can be triggered by a small number of complexes on APCs. PMID- 7836914 TI - A novel class of autoantigens of anti-neutrophil cytoplasmic antibodies in necrotizing and crescentic glomerulonephritis: the lysosomal membrane glycoprotein h-lamp-2 in neutrophil granulocytes and a related membrane protein in glomerular endothelial cells. AB - Necrotizing and crescentic glomerulonephritis (NCGN) is frequently associated with circulating antineutrophil cytoplasmic autoantibodies (ANCA). It is established that ANCA are specific for soluble enzymes of granules of polymorphonuclear neutrophil granulocytes (PMN), such as myeloperoxidase (MPO) or protease 3 (PR3). The purpose of this study was to identify membrane proteins of PMNs, and/or glomerular cells, as additional autoantigenic ANCA targets. When membrane protein fractions were prepared from PMNs and isolated human glomeruli, and immunoblotted with ANCA sera of NCGN patients, two bands with apparent molecular masses of 170 and 80-110 kD (gp170/80-110) were labeled in PMNs, and a 130-kD glycoprotein (gp130) in glomeruli. Gp130 was purified, and monoclonal and rabbit antibodies (Abs) were produced which showed the same double specificity as the patient's ANCA. Using these probes, evidence was provided that gp170/80-110 is identical with human lysosomal-associated membrane protein 2 (h-lamp-2), because both proteins were immunologically cross-reactive and screening of a cDNA expression library from human promyelocytic leukemia cells with anti-gp130 Ab yielded a clone derived from h-lamp-2. Gp170/80-110 was localized primarily in granule membranes of resting PMNs, and was translocated to the cell surfaces by activation with FMLP. By contrast, gp130 was localized in the surface membranes of endothelial cells of human glomerular and renal interstitial capillaries, rather than in lysosomes, as found for h-lamp-2. Potential clinical relevance of autoantibodies to gp170/80-110 and gp130 was assessed in a preliminary trial, in which ANCA sera of patients (n = 16) with NCGN were probed with purified or recombinant antigens. Specific reactivity was detected in approximately 90% of cases with active phases of NCGN, and frequently also in combination with autoantibodies specific for PR3 or MPO. Collectively, these data provide evidence that h-lamp-2 in PMNs and a different, structurally related 130-kD membrane protein on the cell surface of renal microvascular endothelial cells are autoantigenic targets for ANCA in patients with active NCGN. PMID- 7836915 TI - Human immunoglobulin (IgG) induced deletion of IgM rheumatoid factor B cells in transgenic mice. AB - The singular ability of immunoglobulin genes to hypermutate their variable regions, while permitting the generation of high-affinity antibodies against foreign antigens, poses a problem in terms of maintenance of immunological self tolerance. Immunoglobulin gene hypermutation driven by a foreign antigen has the potential to generate antibodies that cross-react with self-components. Consequently, there must exist a mechanism in the periphery for inactivation of mature autoreactive B cell clones. The classical experimental system used to address this problem is the induction of tolerance to soluble, deaggregated human IgG. We have analyzed the mechanism of induction of tolerance to human IgG using transgenic mice that express a human IgM rheumatoid factor (IgM RF) on a large proportion of their B cells. Injection of deaggregated human IgG caused a specific deletion of those B cells that express an intact IgM RF on their cell surface. The degree of RF B cell deletion was proportional to the reduction in the proliferative response of splenocytes to antigen (aggregated human IgG), or to F(ab')2 fragments of anti-human IgM antibodies. Control experiments showed that IgG administration had little effect on the numbers of mouse Ig-bearing cells or their ability to proliferate to a nonspecific mitogen. Thus, the effects of IgG on the human IgM RF B cell are antigen specific and are not due to nonspecific toxic effects of the human IgG preparation. These experiments demonstrate that peripheral exposure to IgG induces deletion of reactive B cells, without any evidence for anergy, and differ from data obtained by other investigators studying tolerance to soluble protein antigens. The results imply that human Igs have distinct properties as soluble antigens, and that peripheral nonresponsiveness to IgG may be due to lymphocyte deletion. PMID- 7836916 TI - Monoclonal antibodies specific for murine p55 and p75 tumor necrosis factor receptors: identification of a novel in vivo role for p75. AB - Monoclonal antibodies (mAbs) specific for the murine p55 and p75 tumor necrosis factor (TNF) receptors were produced after immunization of Armenian hamsters with the purified soluble extracellular domains of each receptor protein. Four p55- (55R) and five p75 (TR75)-reactive mAbs immunoprecipitated the appropriate receptor from the surface of L929 cells. None of the mAbs cross-reacted with the other TNF receptor form. The mAbs were functionally characterized by their ability to inhibit ligand binding and influence TNF-dependent L cell cytolytic activity or proliferation of the murine cytolytic T cell clone CT6. One p55 specific mAb, 55R-593, displayed agonist activity, while two other p55-specific mAbs (55R-170 and -176) were found to be TNF antagonists. The fourth mAb (55R 286) had no functional effects on cells. Several antibodies specific for the p75 TNF receptor partially inhibited recombinant murine TNF-alpha-dependent cytolytic activity (60%). Blocking mAbs specific for p75 but not anti-p55 inhibited TNF mediated proliferation of CT6 T cells. When used in vivo, p55- but not p75 specific mAbs protected mice from lethal endotoxin shock and blocked development of a protective response against Listeria monocytogenes infection. In contrast, both p55 and p75 mAbs individually blocked development of skin necrosis in mice treated with murine TNF-alpha. These data thus demonstrate the utility of the two families of murine TNF receptor-specific mAbs and identify a novel function of the p75 TNF receptor in vivo. PMID- 7836917 TI - Major histocompatibility complex class II+B7-1+ tumor cells are potent vaccines for stimulating tumor rejection in tumor-bearing mice. AB - Mice carrying large established major histocompatibility complex (MHC) class 1+ sarcoma tumors can be successfully treated by immunization with genetically engineered sarcoma cells transfected with syngeneic MHC class II plus B7-1 genes. This approach is significantly more effective than previously described strategies using cytokine- or B7-transduced tumor cells which are only effective against smaller tumor loads, and which cannot mediate regression of longer-term established tumors. The most efficient tumor rejection occurs if both the class II and B7-1 molecules are coexpressed on the same tumor cell. Immunity induced by immunization with class II+B7-1(+)-transfected sarcoma cells involves CD4+ and CD8+ T cells, suggesting that the increased effectiveness of the transfectants is due to their ability to activate both of these T cell populations. PMID- 7836918 TI - Antagonists of monocyte chemoattractant protein 1 identified by modification of functionally critical NH2-terminal residues. AB - Monocyte chemoattractant protein (MCP)-1 analogues were designed to determine the role of the NH2-terminal region in structure and function. The NH2-terminal residue was important for function and receptor binding, as it could not be deleted or extended. However the NH2-terminal pyroglutamate residue of the wild type was not essential as it could be replaced by several other noncyclic amino acids without loss of activity. Residues 7-10 were essential for receptor desensitization, but were not sufficient for function, and the integrity of residues 1-6 were required for functional activity. A peptide corresponding to MCP-1, 1-10 lacked detectable receptor-binding activities, indicating that residues 1-10 are essential for MCP-1 function, but that other residues are also involved. Several truncated analogues, including 8-76, 9-76, and 10-76, desensitized MCP-1-induced Ca2+ induction, but were not significantly active. These analogues were antagonists of MCP-1 activity with the most potent being the 9-76 analogue (IC50 = 20 nM) The 9-76 specifically bound to MCP-1 receptors with a Kd of 8.3 nM, which was three-fold higher than MCP-1 (Kd 2.8 nM). The 9-76 analogue desensitized the Ca2+ response to MCP-1 and MCP-3, but not to other CC chemokines, suggesting that it is MCP receptor specific. The availability of these compounds will be helpful in evaluating MCP receptor antagonists as anti inflammatory therapeutics. PMID- 7836919 TI - Upregulation of surface markers on dying thymocytes. AB - Using terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) to detect cells undergoing early apoptosis, we have defined the surface markers expressed on CD4+CD8+ thymocytes undergoing spontaneous or steroid-induced apoptosis in tissue culture. Some surface markers, e.g., CD4, CD8, and heat stable antigen, are downregulated on apoptotic thymocytes. Surprisingly, however, other markers are upregulated; this applies to T cell receptor beta/CD3, CD69, and CD25 expression. Upregulation of these markers is restricted to a discrete subset of apoptotic cells. PMID- 7836920 TI - The class I-b molecule Qa-1 forms heterodimers with H-2Ld and a novel 50-kD glycoprotein encoded centromeric to I-E beta. AB - Recent biochemical characterization of the T23-encoded Qa-1 molecule revealed an additional higher molecular mass species of 50 kD coprecipitated with the 48-kD Qa-1 molecule in H-2b and H-2d mouse strains. We now demonstrate that the 50-kD protein coprecipitated with Qa-1 is the class I-a antigen Ld in all H-2Ld positive mouse strains examined. Furthers analyses of a panel of recombinants revealed that the 50-kD protein coprecipitated with Qa-1 in H-2b haplotype mouse strains is encoded or controlled by a gene centromeric to major histocompatibility complex class II I-E beta. We have designated this gene and corresponding protein product as Qsm, Qa-1 structure modifier. Both Ld and Qsm can interact with Qa-1 to form cell surface-expressed heterodimers in vivo. These Qa-1 heterodimers are not expressed in H-2k haplotype cells. The Qa-1/Ld and Qa 1/Qsm heterodimers are associated by noncovalent interactions and occur only between fully processed proteins. In addition, we show that the Qsm-encoded protein can form heterodimers with Ld as well, and that the Ld molecules participating in these interactions with Qa-1 and Qsm may be devoid of beta 2 microglobulin and/or peptide. These data represent the first demonstration that class I molecules can be expressed as heterodimers (Qa-1/Ld) on the cell surface, and map a gene (Qsm) that may potentially encode a novel class I molecule, or another protein, that associates with both Qa-1 and Ld. These interactions may enable increased levels of Qa-1 to reach the cell surface and may subsequently influence T cell recognition of Qa-1 and/or Ld molecules. PMID- 7836921 TI - Binding of major histocompatibility complex class II to the invariant chain derived peptide, CLIP, is regulated by allelic polymorphism in class II. AB - Major histocompatibility complex class II-associated invariant chain (Ii) provides several important functions that regulate class II expression and function. One of these is the ability to inhibit class II peptide loading early in biosynthesis. This allows for efficient class II folding and egress from the endoplasmic reticulum, and protects the class II peptide binding site from loading with peptides before entry into endosomal compartments. The ability of Ii to interact with class II and interfere with peptide loading has been mapped to Ii exon 3, which encodes amino acids 82-107. This same region of Ii has been described as a nested set of class II-associated Ii peptides (CLIPs) that are transiently associated with class II in normal cells and accumulate in human histocompatibility leukocyte antigen-DM-negative cell lines. Currently it is not clear how CLIP and the CLIP region of Ii blocks peptide binding. CLIP may bind directly to the class II peptide binding site, or may bind elsewhere on class II and modulate class II peptide binding allosterically. In this report, we show that CLIP can interact with many different murine and human class II molecules, but that the affinity of this interaction is controlled by polymorphic residues in the class II chains. Likewise, structural changes in CLIP also modulate class II binding in an allele-dependent manner. Finally, the specificity and kinetics of CLIP binding to class II molecule is similar to antigenic peptide binding to class II. These data indicate that CLIP binds to class II in an analogous fashion as conventional antigenic peptides, suggesting that the CLIP segment of Ii may actually occupy the class II peptide binding site. PMID- 7836922 TI - Stage-specific binding of Leishmania donovani to the sand fly vector midgut is regulated by conformational changes in the abundant surface lipophosphoglycan. AB - The life cycle of Leishmania parasites within the sand fly vector includes the development of extracellular promastigotes from a noninfective, procyclic stage into an infective, metacyclic stage that is uniquely adapted for transmission by the fly and survival in the vertebrate host. These adaptations were explored in the context of the structure and function of the abundant surface lipophosphoglycan (LPG) on Leishmania donovani promastigotes. During metacyclogenesis, the salient structural feature of L. donovani LPG is conserved, involving expression of a phosphoglycan chain made up of unsubstituted disaccharide-phosphate repeats. Two important developmental modifications were also observed. First, the size of the molecule is substantially increased because of a twofold increase in the number of phosphorylated disaccharide repeat units expressed. Second, there is a concomitant decrease in the presentation of terminally exposed sugars. This later property was indicated by the reduced accessibility of terminal galactose residues to galactose oxidase and the loss of binding by the lectins, peanut agglutinin, and concanavalin A, to metacyclic LPG in vivo and in vitro. The loss of lectin binding was not due to downregulation of the capping oligosaccharides as the same beta-linked galactose or alpha-linked mannose-terminating oligosaccharides were present in both procyclic and metacyclic promastigotes. The capping sugars on procyclic LPG were found to mediate procyclic attachment to the sand fly midgut, whereas these same sugars on metacyclic LPG failed to mediate metacyclic binding. And whereas intact metacyclic LPG did not inhibit procyclic attachment, depolymerized LPG inhibited as well as procyclic LPG, demonstrating that the ligands are normally buried. The masking of the terminal sugars is attributed to folding and clustering of the extended phosphoglycan chains, which form densely distributed particulate structures visible on fracture-flip preparations of the metacyclic surface. The exposure and subsequent masking of the terminal capping sugars explains the stage specificity of promastigote attachment to and release from the vector midgut, which are key events in the development of transmissible infections in the fly. PMID- 7836923 TI - Transfection of the c-myc oncogene into normal Epstein-Barr virus-harboring B cells results in new phenotypic and functional features resembling those of Burkitt lymphoma cells and normal centroblasts. AB - Activated c-myc gene was introduced into the cells of three normal Epstein-Barr virus (EBV)-positive lymphoblastoid B cell lines (LCL). The cells were monitored for the appearance of new phenotypic and functional features compared with the control LCL cells transfected with plasmid that did not contain the c-myc gene. The LCL-expressing c-myc constitutively did not arrest growth in low serum concentration. However, the cell number in the cultures failed to increase because of substantial cell death. Death was due to apoptosis as demonstrated by flow cytometric analysis of propidium iodide-stained cells, by typical DNA laddering in gel electrophoresis, and by the inspection of Giemsa-stained cell smears. Apoptosis was also induced by exposing the transfected cells to antibodies directed to the immunoglobulin mu chain (a-mu-ab) irrespective of the serum concentration in the culture. Exposure of the cells to CD40 ligand (CD40L) or CD40 monoclonal antibody prevented cell apoptosis. Upon transfection with c myc, the LCL cells acquired a vacuolated morphology that was never observed in control cells. Moreover, the expression of CD10 and CD38 was upregulated, while that of CD39 and especially CD23 was downregulated. Unlike that observed in certain Burkitt lymphoma (BL) cell lines that share the same surface phenotype (CD10+CD38+CD23-CD39-), the c-myc-transfected cells expressed lymphocyte function associated (LFA) 1, LFA-3, and intercellular adhesion molecule 1 and grew in large clumps rather than single-cell layers. Expression of CD10 and CD38 was particularly evident on the cells undergoing apoptosis, thus suggesting a correlation between the presence of these markers and the apoptotic process. Cells placed in conditions favoring in vitro apoptosis displayed downregulation of Bcl-2 protein. Bcl-2 expression was, however, upregulated when the cells were exposed to CD40L. These data indicate that the B cells expressing c-myc constitutively acquire some of the features of normal centroblasts and of BL cells, including the expression of CD10 and CD38, and the propensity to undergo apoptosis, which can be prevented by exposure to CD40L. Therefore, these cells can serve as a model system to study both BL lymphomagenesis as well as the process of B cell selection occurring in the germinal centers. PMID- 7836924 TI - T cell genetic background determines default T helper phenotype development in vitro. AB - A host's ability to resist certain pathogens such as Leishmania major can depend upon the phenotype of T helper (Th) subset that develops. Different murine genetic backgrounds are known to significantly alter the direction of Th subset development, although the cellular basis of this influence is poorly understood. To examine the basis of this effect we used an in vitro alpha/beta-T cell receptor (TCR) transgenic system for analysis of Th phenotype development. To control for TCR usage, we derived the DO11.10 alpha/beta-TCR transgene in several genetic backgrounds. Our findings suggest that the effects of genetic background on Th phenotype development reside within the T cell, and not the antigen presenting cell compartment. Transgenic T cells from both the B10.D2 and BALB/c backgrounds showed development toward either the Th1 or Th2 phenotype under the strong directing influence of interleukin (IL) 12 and IL4, respectively. However, when T cells were activated in vitro under neutral conditions in which exogenous cytokines were not added, B10.D2-derived T cells acquired a significantly stronger Th1 phenotype than T cells from the BALB/c background, correspondent with in vivo Th responses to Leishmania in these strains. Importantly, these cytokine differences resulted in distinct functional properties, because B10.D2- but not BALB/c-derived T cells could induce macrophage production of nitric oxide, an important antimicrobial factor. Thus, the genetically determined default Th phenotype development observed in vitro may correspond to in vivo Th subset responses for pathogens such as Leishmania which do not initiate strong Th phenotype-directing signals. PMID- 7836925 TI - Heterogeneity of autoreactive T cell clones specific for the E2 component of the pyruvate dehydrogenase complex in primary biliary cirrhosis. AB - The extraordinary specificity of bile duct destruction in primary biliary cirrhosis (PBC) and the presence of T cell infiltrates in the portal tracts have suggested that biliary epithelial cells are the targets of an autoimmune response. The immunodominant antimitochondrial response in patients with PBC is directed against the E2 component of pyruvate dehydrogenase (PDC-E2). Hitherto, there have only been limited reports on the characterization and V beta usage of PDC-E2-specific cloned T cell lines. In this study, we examined peripheral blood mononuclear cells (PBMC) for their reactivity to the entire PDC complex as well as to the E1- and E2-specific components. We also examined the phenotype, lymphokine profile, and V beta usage of PDC-specific T cell clones isolated from cellular infiltrates from the livers of PBC patients. We report that PBMC from 16/19 patients with PBC, but not 12 control patients, respond to the PDC-E2 subunit. Interestingly, this response was directed to the inner and/or the outer lipoyl domains, despite the serologic observation that the autoantibody response is directed predominantly to the inner lipoyl domain. Additionally, lymphokine analysis of interleukin (IL) 2/IL-4/interferon gamma production from individual liver-derived autoantigen-specific T cell clones suggests that both T helper cell Th1- and Th2-like clones are present in the liver. Moreover, there was considerable heterogeneity in the T cell receptor for antigen (TCR) V beta usage of these antigen-specific autoreactive T cell clones. This is in contrast to murine studies in which animals are induced to develop autoimmunity by specific immunization and have an extremely limited T cell V beta repertoire. Thus, our data suggest that in human organ-specific autoimmune diseases, such as PBC, the TCR V beta repertoire is heterogenous. PMID- 7836926 TI - Bacterial superantigens induce T cell expression of the skin-selective homing receptor, the cutaneous lymphocyte-associated antigen, via stimulation of interleukin 12 production. AB - T lymphocyte infiltration is a prominent feature of the skin inflammation associated with infections by toxin (superantigen)-secreting Staphylococcus aureus or Streptococcus bacteria. The cutaneous lymphocyte-associated antigen (CLA) has been hypothesized to be a homing receptor (HR) involved in selective migration of memory/effector T cells to the skin. Since the expression of this putative skin-selective HR is known to be under strict microenvironmental control, we sought to determine the effect of staphylococcal and streptococcal toxins on T cell expression of CLA. After in vitro stimulation of peripheral blood mononuclear cells with staphylococcal enterotoxin B, toxic shock syndrome toxin-1, and streptococcal pyrogenic exotoxins A and C, there was a significant increase in the numbers of CLA+ T cell blasts (p < 0.01), but not blasts bearing the mucosa-associated adhesion molecule alpha e beta 7-integrin, compared with T cells stimulated with phytohemaglutinin (PHA) or anti-CD3. Bacterial toxins were also found to specifically induce interleukin (IL) 12 production. More importantly, induction of toxin-induced CLA expression was blocked by anti-IL-12, and the addition of IL-12 to PHA-stimulated T cells induced CLA, but not alpha e beta 7-integrin, expression. These data suggest that bacterial toxins induce the expansion of skin-homing CLA+ T cells in an IL-12-dependent manner, and thus may contribute to the development of skin rashes in superantigen-mediated diseases. PMID- 7836927 TI - Transcription of granzyme A and B genes is differentially regulated during lymphoid ontogeny. AB - During development, thymocytes express a number of genes typical for activated peripheral T lymphocytes, including granzymes. We have now analyzed by reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry, and cytochemistry fetal liver cells and thymocytes at various developmental stages for the expression of granzyme A-G genes. At days 13-17 of gestation, only granzyme B but none of the other granzymes is expressed in fetal liver. In the most immature, Pgp-1+IL2R alpha-, thymocyte subpopulation mRNAs for granzymes A-C but not for granzymes D-G are detectable. Upon further differentiation via Pgp-1 IL-2R alpha + into more mature Pgp-1-IL-2R alpha- thymocytes the level of expression of granzymes A, B, and C gradually declines reaching its lowest level at the CD4+ 8+ double positive stage. In fetal thymic lobes depleted of lymphoid cells by treatment with deoxyguanosine, no transcripts for granzymes A, B, and C were found indicating that the PCR signals are derived exclusively from early precursor T/natural killer (NK) lineage cells rather than from residual stromal elements. In mature CD4+CD8- and CD4-CD8+ thymocytes, granzyme B mRNA is found at similar levels in both subsets whereas granzyme A mRNA is expressed selectively in the CD4-CD8+ subset. Enzymatic activity of granzyme A was only seen in a fraction of CD4-CD8+ thymocytes negative for heat stable antigen (HSA) but not in the more immature HSA+ fraction of CD4-CD8+ thymocytes. The data suggest that (a) granzyme B is a pro-thymocyte marker for all T/NK lineage cells; (b) granzyme A transcripts are associated with thymocytes with the potential to develop into the CD8+ lineage; and (c) granzyme A enzymatic activity is only expressed in the most mature CD4-CD8+ stage, suggesting that granzyme proteins are not involved in early stages of thymocyte development. PMID- 7836928 TI - Class II transactivator regulates the expression of multiple genes involved in antigen presentation. AB - CIITA (a major histocompatibility complex [MHC] class II transactivator) has been shown to be required for the expression of MHC class II genes in both B cells and interferon gamma-inducible cells. Here we demonstrate that CIITA not only activates MHC class II genes but also genes required for antigen presentation. Mutant HeLa cells, defective in the expression of classic MHC class II genes, invariant chain, and the newly described human histocompatibility leukocyte antigen-DM genes, were used to study the role of CIITA in the regulation of these genes. Upon transfection with CIITA cDNA, the mutant cells expressed all three genes, suggesting that CIITA is a global regulator for the expression of genes involved in antigen presentation. PMID- 7836929 TI - Evidence that cytokine-mediated immune interactions induced by Schistosoma mansoni alter disease outcome in mice concurrently infected with Trichuris muris. AB - In murine models of Schistosoma mansoni infection, egg production is associated with a switch from T helper cell (Th)1- to Th2-type responses to both schistosome specific and unrelated antigens. Polyparasitism is common in human populations within S. mansoni endemic areas. We have, therefore, examined whether coinfection with S. mansoni could affect the outcome of a second parasitic infection, through Th2 cytokine-dependent modifications to the host immune response. We find that when mice susceptible to infection with the gut nematode Trichuris muris are coinfected with S. mansoni, they acquire the capacity to resolve T. muris infection, thus demonstrating a resistant phenotype. This ability to expel T. muris is associated with the production of Th2-associated cytokines, and corresponding antibody isotypes, in response to S. mansoni egg antigens. The Th2 response shows that there is no compartmentalization between spleen and mesenteric lymph nodes, and that the expulsion of T. muris is not caused by any changes in the host intestine associated with excretion of schistosome eggs. This influence of schistosome infections may be important, not only for the outcome of infections with unrelated pathogens in endemic areas, but also for the efficacy of vaccines in such areas. PMID- 7836930 TI - Prostaglandin-E2 is a potent inhibitor of human interleukin 12 production. AB - During human immunodeficiency virus infection and allergic diseases, characterized by a dominant T helper (Th) 2 response, overproduction of prostaglandin E2 (PGE2) is observed. In this paper we studied the effect of PGE2 on interleukin (IL)-12 synthesis, because this cytokine has been described to be essential in induction of Th1 responses. IL-12 synthesis was induced in monocytes that were stimulated with Neisseria meningitidis-derived lipopolysaccharide in whole blood cultures. PGE2 almost completely inhibited lipopolysaccharide induced IL-12 production, whereas IL-6 production was only partially inhibited by PGE2. In contrast, the production of IL-10 was approximately twofold enhanced at these conditions. The effects of PGE2 were due to its cAMP-inducing capacity, since they could be mimicked by other cAMP inducers. Recombinant human IL-10 also inhibited IL-12 and IL-6 production. However, the inhibitory effect of PGE2 on IL 12 production was independent of IL-10 since neutralizing anti-IL-10 antibodies were unable to reverse this inhibition. These results suggest that the capacity of an antigen to induce PGE2 synthesis may play a crucial role in the development of either a Th1 or Th2 response. PMID- 7836931 TI - Increase in positive selection of CD8+ T cells in TAP1-mutant mice by human beta 2-microglobulin transgene. AB - Mice harboring a deletion of the gene encoding the transporter associated with antigen presentation-1 (TAP1) are impaired in providing major histocompatibility complex (MHC) class I molecules with peptides of cytosolic origin and lack stable MHC class I cell surface expression. They consequently have a strongly reduced number of CD8+ T cells. To examine whether selection of CD8+ T cells is dependent on TAP-dependent peptides, we partially restored MHC class I cell surface expression in TAP1-deficient mice by introduction of human beta 2-microglobulin. We show that selection of functional CD8+ T cells can be augmented in vivo in the absence of TAP1-dependent peptides. PMID- 7836932 TI - Identification of a gene encoding a melanoma tumor antigen recognized by HLA-A31 restricted tumor-infiltrating lymphocytes. AB - The availability of antitumor cytotoxic T lymphocytes which can be generated from either peripheral blood lymphocytes after stimulation in vitro or tumor infiltrating lymphocytes (TIL) has made it possible to identify a number of melanoma antigens presented by major histocompatibility complex class I molecules. The present and previous studies indicated that TIL586 recognized an antigen expressed on most melanoma and normal melanocytes in the context of the HLA-A31 molecule. We report here the cloning of a cDNA that directs the expression of the shared melanoma antigen recognized by this TIL. The DNA sequence analysis revealed that the cDNA was almost identical to the gene encoding tyrosinase-related protein 1 or glycoprotein gp75 which was originally identified by serum antibodies in a patient with melanoma. The gene was found to be expressed only in melanoma, normal melanocyte cell lines, and retina, but not in other normal tissues tested. The gp75 antigen presented by HLA-A31 may therefore constitute a useful immune target for specific treatment of patients with melanoma, since both antibody- and T cell-mediated immune responses can be generated against this antigen. PMID- 7836933 TI - Modulation of T cell development by an endogenous altered peptide ligand. AB - T cells potentially encounter numerous endogenous peptides during selection in the thymus and in the periphery. We examined the impact of an endogenous peptide on in vivo T cell development, using a TCR transgenic mouse model based on a hemoglobin-specific T cell clone. In these mice, the transgenic beta chains paired with endogenous alpha chains. This led to a serendipitous primary reactivity to Ser69 peptide, an altered peptide ligand of the Hbd (64-76) epitope of the parent clone. Two Ser69-reactive T cell populations were identified. A smaller population of the Ser69-reactive T cells responded both to Ser69 and Hbd (64-76). A majority reacted only to Ser69, and not to Hbd(64-76); in fact, Hbd(64 76) was a specific TCR antagonist for these Ser69-only-reactive T cells. Thus, in this unique experimental system, Ser69 became an agonist, and Hbd (64-76) was an antagonist. Endogenous presentation of the antagonist ligand in the thymus selectively eliminated the high-avidity cells, while sparing low-avidity cells in the Ser69-reactive T cell repertoire. These results highlight how specificity guides developing T cells through a network of ligands and indicate that the endogenous peptide pool has a profound effect on T cell development and repertoire. PMID- 7836934 TI - Interleukin 12 administration induces T helper type 1 cells and accelerates autoimmune diabetes in NOD mice. AB - T cells play a major role in the development of insulin-dependent diabetes mellitus (IDDM) in nonobese diabetic (NOD) mice. Administration of interleukin 12 (IL-12), a key cytokine which guides the development of T helper type 1 (Th1) CD4+ T cells, induces rapid onset of IDDM in NOD, but not in BALB/c mice. Histologically, IL-12 administration induces massive infiltration of lymphoid cells, mostly T cells, in the pancreatic islets of NOD mice. CD4+ pancreas infiltrating T cells, after activation by insolubilized anti T cell receptor antibody, secrete high levels of interferon gamma and low levels of IL-4. Therefore, IL-12 administration accelerates IDDM development in genetically susceptible NOD mice, and this correlates with increased Th1 cytokine production by islet-infiltrating cells. These results hold implications for the pathogenesis, and possibly for the therapy of IDDM and of other Th1 cell-mediated autoimmune diseases. PMID- 7836935 TI - Voltage-dependent regulation of modal gating in the rat SkM1 sodium channel expressed in Xenopus oocytes. AB - The TTX-sensitive rat skeletal muscle sodium channel (rSkM1) exhibits two modes of inactivation (fast vs slow) when the alpha subunit is expressed alone in Xenopus oocytes. In this study, two components are found in the voltage dependence of normalized current inactivation, one having a V1/2 in the expected voltage range (approximately -50 mV, I(N)) and the other with a more hyperpolarized V1/2 (approximately -130 mV, IH) at a holding potential of -90 mV. The I(N) component is associated with the gating mode having rapid inactivation and recovery from inactivation of the macroscopic current (N-mode), while IH corresponds to the slow inactivation and recovery mode (H-mode). These two components are interconvertible and their relative contribution to the total current varies with the holding potential: I(N) is favored by hyperpolarization. The interconversion between the two modes is voltage dependent and is well fit to a first-order two-state model with a voltage dependence of e-fold/8.6 mV and a V1/2 of -62 mV. When the rat sodium channel beta 1-subunit is coinjected with rSkM1, IH is essentially eliminated and the inactivation kinetics of macroscopic current becomes rapid. These two current components and their associated gating modes may represent two conformations of the alpha subunit, one of which can be stabilized either by hyperpolarization or by binding of the beta 1 subunit. PMID- 7836936 TI - Modulation of potassium channel gating by external divalent cations. AB - We have examined the actions of Zn2+ ions on Shaker K channels. We found that low (100 microM) concentrations of Zn2+ produced a substantial (approximately three fold) slowing of the kinetics of macroscopic activation and inactivation. Channel deactivation was much less affected. These results were obtained in the presence of 5 mM Mg2+ and 4 mM Ca2+ in the external solution and so are unlikely to be due to modification of membrane surface charges. Furthermore, the action of 100 microM Zn2+ on activation was equivalent to a 70-mV reduction of a negative surface potential whereas the effects on deactivation would require a 15-mV increase in surface potential. External H+ ions reduced the Zn-induced slowing of macroscopic activation with an apparent pK of 7.3. Treatment of Shaker K channels with the amino group reagent, trinitrobenzene sulfonic acid (TNBS), substantially reduced the effects of Zn2+. All these results are qualitatively similar to the actions of Zn2+ on squid K channels, indicating that the binding site may be a common motif in potassium channels. Studies of single Shaker channel properties showed that Zn2+ ions had little or no effect on the open channel current level or on the open channel lifetime. Rather, Zn2+ substantially delayed the time to first channel opening. Thus, K channels appear to contain a site to which divalent cations bind and in so doing act to slow one or more of the rate constants controlling transitions among closed conformational states of the channel. PMID- 7836937 TI - Regulation of apical K and Na channels and Na/K pumps in rat cortical collecting tubule by dietary K. AB - The patch-clamp technique was used to study the properties and the density of conducting K and Na channels in the apical membrane of rat cortical collecting tubule. The predominant K channel observed in cell-attached patches (SK channels) had an outward single-channel conductance (with LiCl in the pipette) of 10 pS. The inward conductance (with KCl in the pipette) was 42 pS. The channel had a high open probability that increased with depolarization. Kinetic analysis indicated the presence of a single open state and two closed states. Increasing K intake by maintaining animals on a high K diet for 12-16 d increased the number of SK channels per patch by threefold (0.7-2.0/patch) over control levels. In addition, conducting Na-selective channels, which were not observed in control animals, were seen at low density (0.5/patch). These channels had properties similar to those observed when the animals were on a low Na diet, except that the mean open probability (0.84) was higher. In other experiments, the whole-cell patch clamp technique was used to measure Na channel activity (as amiloride sensitive current, INa) and Na pump activity (as ouabain-sensitive current, Ipump). In animals on a high K diet, INa was greater than in controls but much less than in rats on a low Na diet. Ipump was greater after K loading than in controls or Na-depleted animals. These K diet-dependent effects were not accompanied by a significant increase in plasma aldosterone concentrations. To further investigate the relationship between K channel activity and mineralocorticoids, rats were maintained on a low Na diet to increase endogenous aldosterone secretion. Under these conditions, no increase in SK channel density was observed, although there was a large increase in the number of Na channels (to 2.7/patch). Aldosterone was also administered exogenously through osmotic minipumps. As with the low Na diet, there was no change in the density of conducting SK channels, although Na channel activity was induced. These results suggest that SK channels, Na channels and Na/K pumps are regulated during changes in K intake by factors other than aldosterone. PMID- 7836938 TI - Anion-cation interactions in the pore of neuronal background chloride channels. AB - Background Cl channels in neurons and skeletal muscle are significantly permeable for alkali cations when tested with asymmetrical concentrations of the same salt. Both anion and cation permeation were proposed to require binding of an alkali cation with the pore (Franciolini, F., and W. Nonner. 1987. Journal of General Physiology. 90:453-478). We tested this hypothesis by bilaterally substituting large alkali cations for Na and found no significant changes of unitary conductance at 300 mM symmetrical concentrations. In addition, all organic cations examined were permeant in a salt gradient test (1,000 mM internal@300 mM external), including triethanolamine, benzyltrimethylamine, and bis-tris-propane (BTP, which is divalent at the tested pH of 6.2). Inward currents were detected following substitution of internal NaCl by the Na salts of the divalent anions of phosphoric, fumaric, and malic acid. Zero-current potentials in gradients of the Na and BTP salts of varied anions (propionate, F, Br, nitrate) that have different permeabilities under bi-ionic conditions, were approximately constant, as if the permeation of either cation were coupled to the permeation of the anion. These results rule out our earlier hypothesis of anion permeation dependent on a bound alkali cation, but they are consistent with the idea that the tested anions and cations form mixed complexes while traversing the Cl channel. PMID- 7836939 TI - A multi-ion permeation mechanism in neuronal background chloride channels. AB - Unitary current/voltage relationships of background Cl channels of rat hippocampal neurons were determined for varied gradients and absolute concentrations of NaCl. The channels revealed permeabilities for both Cl and Na ions. A hyperlinear increase of unitary conductance, observed for a symmetrical increase of salt concentration from 300 and 600 mM, indicated a multi-ion permeation mechanism. A variety of kinetic models of permeation were tested against the experimental current/voltage relationships. Models involving a pore occupied by mixed complexes of up to five ions were necessary to reproduce all measurements. A minimal model included four equilibrium states and four rate limiting transitions, such that the empty pore accepts first an anion and then can acquire one or two cation/anion pairs. Three transport cycles are formed: a slow anion cycle (between the empty and single-anion states), a slow cation cycle (between the one- and three-ion states), and a fast anion cycle (between the three- and five-ion states). Thus, permeant anions are required for cation permeation, and several bound anions and cations promote a high rate of anion permeation. The optimized free-energy and electrical charge parameters yielded a self-consistent molecular interpretation, which can account for the particular order in which the pore accepts ions from the solutions. Although the model describes the mixed anion/cation permeability of the channel observed at elevated concentrations, it predicts a high selectivity for Cl anion at physiological ionic conditions. PMID- 7836940 TI - Permeation of Na+ through a delayed rectifier K+ channel in chick dorsal root ganglion neurons. AB - In whole-cell patch clamp recordings from chick dorsal root ganglion neurons, removal of intracellular K+ resulted in the appearance of a large, voltage dependent inward tail current (Icat). Icat was not Ca2+ dependent and was not blocked by Cd2+, but was blocked by Ba2+. The reversal potential for Icat shifted with the Nernst potential for [Na+]. The channel responsible for Icat had a cation permeability sequence of Na+ >> Li+ >> TMA+ > NMG+ (PX/PNa = 1:0.33:0.1:0) and was impermeable to Cl-. Addition of high intracellular concentrations of K+, Cs+, or Rb+ prevented the occurrence of Icat. Inhibition of Icat by intracellular K+ was voltage dependent, with an IC50 that ranged from 3.0-8.9 mM at membrane potentials between -50 and -110 mV. This voltage-dependent shift in IC50 (e-fold per 52 mV) is consistent with a single cation binding site approximately 50% of the distance into the membrane field. Icat displayed anomolous mole fraction behavior with respect to Na+ and K+; Icat was inhibited by 5 mM extracellular K+ in the presence of 160 mM Na+ and potentiated by equimolar substitution of 80 mM K+ for Na+. The percent inhibition produced by both extracellular and intracellular K+ at 5 mM was identical. Reversal potential measurements revealed that K+ was 65-105 times more permeant than Na+ through the Icat channel. Icat exhibited the same voltage and time dependence of inactivation, the same voltage dependence of activation, and the same macroscopic conductance as the delayed rectifier K+ current in these neurons. We conclude that Icat is a Na+ current that passes through a delayed rectifier K+ channel when intracellular K+ is reduced to below 30 mM. At intracellular K+ concentrations between 1 and 30 mM, PK/PNa remained constant while the conductance at -50 mV varied from 80 to 0% of maximum. These data suggest that the high selectivity of these channels for K+ over Na+ is due to the inability of Na+ to compete with K+ for an intracellular binding site, rather than a barrier that excludes Na+ from entry into the channel or a barrier such as a selectivity filter that prevents Na+ ions from passing through the channel. PMID- 7836941 TI - Surface charge and properties of cardiac ATP-sensitive K+ channels. AB - ATP-sensitive K+ (KATP) channels are present in a wide variety of tissues. The sensitivity of these channels to closure by cytosolic ATP (ATPi) varies significantly among different tissues and even within the same tissue. The purpose of this study was to test the hypothesis that negative surface charges modulate the sensitivity of the KATP channels to ATPi by influencing surface potential in the vicinity of the ATP-binding site(s) of the channel. Unitary currents through KATP channels were measured in inside-out membrane patches excised from rabbit ventricular myocytes using the patch-clamp technique. Agents known to be effective at screening negative surface charges were applied to the cytosolic surface of the patches, and their effects on ATP sensitivity were examined. These agents included Mg2+ (2-15 mM), Ba2+ (2-10 mM), and the polycations protamine (0.01-10 microM), poly-L-lysine (500 microM), and poly-L arginine (0.5 microM). The divalent cations and the various polycations all dramatically reduced the concentration of ATPi required to half-maximally suppress current through KATP channels (Kd), from approximately 100 microM in the absence of these agents to 1.6-8 microM in their presence. The effects were dose dependent. Protamine also reduced the sensitivity of KATP channels to block by cytosolic ADP. The sensitivity of KATP channels to block by ATP was independent of membrane potential, suggesting that the ATP-binding site is not located within the transmembrane voltage field. The effects of the polycation poly-L-lysine on ATP sensitivity were also independent of membrane potential or the direction (inward or outward) of current through KATP channels. In addition to increasing ATP sensitivity, Mg2+, Ba2+, and the polycations all caused dose-dependent block of inward and outward currents through KATP channels over similar concentration ranges as their effects on ATP sensitivity. The block of inward current by polycations was not associated with reduction of single-channel conductance or evidence of fast open channel block. However, the polycations did cause a modest reduction in single-channel conductance of outward current. These results are consistent with the presence of negative surface charges that reduce the local ATP concentration at the ATP-binding site(s) on the channel, relative to the bulk cytosolic ATP concentration. Screening these negative surface charges with divalent cations or polycations decreases the local ATP gradient, resulting in a decrease in the apparent Kd for ATP.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7836942 TI - Fibre type classification and myosin isoforms in the human masseter muscle. AB - Human masseter muscle is highly unusual since it contains relatively large numbers of fibres with variable myofibrillar ATPase staining as well as fibres that express neonatal and alpha-cardiac myosin heavy chain (MHC). These findings however, have not been organised together into a fibre type classification scheme. Biopsies from the anterior superficial area of masseter were collected from a large sample of healthy young adults. Biopsies were sectioned and stained for myofibrillar ATPase reactivity and the presence of MHC isoforms as detected by a series of antibodies. The MHC composition of the same biopsies was also analysed using sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS PAGE). A series of rectus abdominis muscle biopsies were analysed similarly to serve as a control for type I, IIA and IIB fibres and isoforms. From the histochemical, immunohistochemical and biochemical experiments we found the masseter to contain type I, IM, IIC, IIA and IIB fibres as previously classified, but in addition there were type neonatal, alpha-cardiac, and 'other' (three or more myosins including neonatal and alpha-cardiac). The percentage of each fibre type was highly variable in masseter biopsies, but generally type I fibres were most common, and the proportion of IIB, neonatal, alpha-cardiac and 'other' fibres was low. Even in biopsies that contained relatively large amounts of these last three fibre types, the amount of neonatal and/or alpha-cardiac MHC detected on SDS-PAGE was limited, suggesting that these MHCs are a minor component in the fibres in which they are expressed. PMID- 7836943 TI - Extracorporeal fibrinogen and platelet precipitation as a new haemorheological treatment for acute stroke. AB - In thromboembolic brain infarctions high fibrinogen levels are associated with an increase of both plasma and whole blood viscosity as well as increased aggregability of blood cells. This decreases cerebral perfusion and might reduce blood flow in the penumbra surrounding infarction. An important goal in the treatment of acute cerebral infarction is to reduce fibrinogen and thereby improve the haemorheological state. Heparin-induced extracorporeal low-density lipoprotein/fibrinogen precipitation (HELP) appears to be successful in achieving this. Such treatment reduces lipid fractions, including total cholesterol, low density lipoproteins (LDL) and triglycerides (p < 0.0001 each), as well as fibrinogen (p < 0.0001) in a safe and efficacious manner. Whole blood and plasma viscosity are also improved when measured by oscillo-rheometry. Furthermore, the number and aggregation tendency of blood cells is influenced positively as determined by Coulter counting and aggregometry. HELP improves the haemorheological profile to a degree which has not been achieved by haemorheologically active substances. PMID- 7836944 TI - Cognitive event-related potentials and brain magnetic resonance imaging in HTLV-1 associated myelopathy (HAM). AB - Auditory and visual cognitive event-related potentials (ERPs) were investigated in 14 patients with HTLV-1 associated myelopathy (HAM) and in 36 normal controls. In the HAM patients, the latencies of P300 and N200 by the auditory tone method were significantly delayed, and N100 by the auditory click method was significantly delayed in latency. No abnormal ERP components were observed with visual methods. While these auditory abnormal ERPs were present in the HAM patients, there was no evidence of visual abnormal ERPs. Abnormal lesions on the white matter were evident at magnetic resonance imaging (MRI) in 6 (75%) of 8 patients. There was no correlation between MRI lesions and the abnormalities of ERPs, but there was a significant correlation between bifrontal index on MRI and P300 amplitudes at Cz and Pz sites by auditory tone method. In one patient, atrophy of bilateral parietal lobes was seen on MRI and P300 latencies delayed using various methods. Therefore, the possibility that electrophysiological cognitive impairment in patients with HAM is related to brain atrophy rather than to white matter lesions requires attention. PMID- 7836945 TI - Autonomic nervous system and cardiac involvement in familial amyloidosis, Finnish type (FAF). AB - Familial amyloidosis, Finnish type (FAF), is a gelsolin-related inherited systemic amyloidosis. We report autonomic nervous system and cardiac findings in a study of 30 FAF patients (18 females, 12 males aged 27-74 years; mean 53.9 years). Cardiovascular reflex tests showed a significant decrease in heart rate variation in FAF patients compared with healthy controls. Orthostatic hypotension was found in 9 of 28 FAF patients, but only in 3 of 69 controls. Signs of amyloid cardiopathy were rare at clinical examination and in radio-, echocardio- and electrocardiographic examinations. Histological and immunohistochemical studies revealed amyloid deposition and immunoreactivity against the gelsolin-related FAF amyloid subunit in autonomic nervous system structures and in cardiac tissue in 3 autopsied FAF patients. The results show that minor autonomic nervous system dysfunction can be found in FAF, while clinically significant amyloid cardiopathy or autonomic neuropathy is not characteristic of this type of amyloidosis. PMID- 7836946 TI - Intrathecal synthesis of interleukin-10 (IL-10) in viral and inflammatory diseases of the central nervous system. AB - The intrathecal synthesis of interleukin 10 (IL-10) was investigated in 120 paired cerebrospinal fluid (CSF) and serum specimens from patients with various inflammatory and non-inflammatory diseases of the central nervous system (CNS). IL-10 was not demonstrated in the sera, but detectable levels were found in the CSF from: patients with acute viral ("aseptic") meningitis, but only within 48-72 h of symptom onset; human immunodeficiency virus type 1 (HIV)-infected patients with HIV-related encephalitis/leukoencephalopathy or cryptococcal meningitis; a patient with primary B cell lymphoma of the CNS, and a patient with encephalomeningeal sarcoidosis (in whom IL-10 was demonstrated in all CSF collected over a period of 6-months). In chronic meningeal infections/inflammations, IL-10 seems to be continuously produced within the CSF. Our findings suggest that IL-10, a cytokine which exerts many immunosuppressive actions, may play different immunomodulatory roles in CNS diseases; in particular, its intrathecal synthesis may explain why some infectious and inflammatory meningeal diseases may have slow development and chronic evolution. PMID- 7836947 TI - Skin abnormalities and autonomic involvement in the early stage of amyotrophic lateral sclerosis. AB - With the aim to evaluate skin abnormalities in patients affected by amyotrophic lateral sclerosis (ALS) with respect to the dermal ultrastructure, including autonomic termination, microcirculation and sweat glands, 13 ALS patients and 5 controls underwent a skin biopsy of the left forearm. Abnormalities of the collagen and elastic fibrils were found in 4 and 5 patients respectively; amyelinic axons and sweat glands showed ultrastructural abnormalities in most ALS patients but not in controls; a quantitative evaluation of the collagen fibrils showed greater diameter of fibrils, larger interfibrillar spaces and more consistent size variation in ALS patients than in controls. These results suggest autonomic involvement in ALS and changes in the collagen fibril organization during the early stages of the disease. PMID- 7836948 TI - Effect of alpha-tocopherol deficiency on indices of oxidative stress in normal and diabetic peripheral nerve. AB - We tested the hypothesis that oxidative stress can cause neuropathy by evaluating the effect of alpha-tocopherol depletion in normal and streptozotocin (STZ) diabetic peripheral nerve (known to be subject to oxidative stress). The end points were nerve electrophysiology and indices of oxidative stress. Studies were done on 6 groups of rats at 1 and 3 months: (1) Controls, normal alpha-tocopherol (Con[N]). (2) Controls, alpha-tocopherol-deficient (Con[-]) (3) Controls, alpha tocopherol supplemented (Con[+]); (4) Diabetic, normal alpha-tocopherol (STZ[N]); (5) Diabetic, alpha-tocopherol-deficient (STZ[-]) (6) Diabetic, alpha-tocopherol supplemented (STZ[+]). An alpha-tocopherol-deficient diet resulted in a rapid depletion of the vitamin in plasma and sympathetic neurones (superior cervical ganglion), and a slower depletion in sensory neurones (dorsal root ganglion) and nerve. The depletion was associated with a reduction in reduced glutathione and an increase in conjugated dienes and hydroperoxides in normal rats, and resulted in similar changes, or accentuated the abnormalities, in diabetic nerves. Changes were more pronounced at 1 than 3 months and alpha-tocopherol supplementation, for the most part, did not prevent the abnormalities. alpha-Tocopherol depletion induced or worsened nerve conduction abnormalities in both sciatic-tibial and caudal nerves. Sensory fibers were more affected than motor fibers and the changes were more pronounced at 3 than 1 month. These findings support the notion that oxidative stress may cause neuropathy and that it might be mechanistically implicated in experimental diabetic neuropathy (STZ-EDN). PMID- 7836949 TI - Participation of the limbic system and its associated areas in the dementia of amyotrophic lateral sclerosis. AB - The topographic distribution of degenerative changes in large brain sections from five sporadic amyotrophic lateral sclerosis (ALS) patients with dementia and three without dementia was examined. The dementia characteristics were impaired shifting from one line of thinking to another, perseveration, and emotional disinhibition as well as impairment of cognition, and judgment. Neuropathological examinations showed definite ALS changes in all the patients studied. In addition, the five patients with dementia showed neuronal loss, gliosis, and sponginess of the superficial layers throughout the cerebral cortices, predominantly in the dorsomedial cortex of the temporal tip and the parahippocampal, ambiens, anterior cingulate, rectal, orbital, and insular gyri as well as neuronal loss in the basolateral nucleus of the amygdala, nucleus accumbens, and subiculum of the hippocampus. Ubiquitin-immunoreactive inclusions were present in some neurons in the granular cell layers of the hippocampus. Fibrous gliosis was extensive in the subcortical and deep white matter of the frontotemporal lobes. The affected regions take in the limbic system and its associated areas which are the sources of the psychological problems, including emotional disturbance, experienced by these ALS patients. The psychological problems of ALS need to be investigated in relation to the involvement of the limbic system. PMID- 7836950 TI - Autosomal recessive distal muscular dystrophy: normal expression of dystrophin, utrophin and dystrophin-associated proteins in muscle fibers. AB - We examined 19 muscle biopsies from 14 patients with autosomal recessive distal muscular dystrophy (DisMD) histochemically and immunohistochemically to characterize the histologic features of this disease and to determine whether dystrophin and dystrophin-associated proteins (DAPs) are normally present in the muscles of patients with this disorder. The common histologic features in DisMD were active muscle fiber necrosis and regeneration with variation in fiber size, predominantly in the gastrocnemius muscle. There were occasional disorganizations of the intermyofibrillar network such as moth-eaten appearance, lobulated, whorled and targetoid fibers. In one half of the patients, small angular fibers and scattered rimmed vacuoles were also found. On immunohistochemical examination, dystrophin, DAPs, spectrin and laminin were normally expressed along the surface membrane of muscle fibers, even in the advanced stages of the disease. In contrast, dystrophin was absent and DAPs reduced in the sarcolemma of Duchenne muscular dystrophy (DMD) muscles. The overall histochemical features in DisMD were similar to those seen in DMD, though dystrophin and DAPs were normally expressed even in severely affected gastrocnemius muscle. A defect in an as yet unidentified protein rather than in DAPs and dystrophin is probably responsible for the muscle fiber necrosis in DisMD. PMID- 7836951 TI - Familial amyotrophic lateral sclerosis (ALS) in Japan associated with H46R mutation in Cu/Zn superoxide dismutase gene: a possible new subtype of familial ALS. AB - Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurological disorder that results in relentless damage to the motor neuron system. Although about 5-10% of cases are familial, the pathophysiologic process of ALS remains unknown. We identified a novel point mutation A to G in exon 2 of the Cu/Zn SOD gene, resulting in an amino acid substitution of histidine46 by arginine (H46R), in two Japanese familial ALS (FALS) families. The segregations of the mutation were evident. The enzymatic activities of Cu/Zn SOD of peripheral red blood cell lysate were reduced to about 80% in the affected members, compared with other non affected family members. The patients in these families are clinically characterized by relative late onset, initial involvement in lower extremities, relative rare impairment of bulbar muscles and much slow progression of muscular weakness and atrophy, compared with other Japanese FALS cases who have no mutation in the Cu/Zn SOD gene. These findings suggest that the H46R mutation in Cu/Zn SOD gene is highly related to this unique subtype of FALS. PMID- 7836952 TI - Response to thymectomy in Chinese patients with myasthenia gravis. AB - Myasthenia gravis was diagnosed in 48 patients between 1985 and 1991 in this Chinese community. Thymectomy was performed on 36 patients and the mean postoperative follow-up period was 49 months. Significant improvement was seen in 72% of the thymectomised patients, with 33% achieving complete remission. Patients with mild generalised myasthenia at presentation or those found to have thymic hyperplasia had the best prognosis. Patients with more severe symptoms or those with an underlying thymoma also responded favourably. Only patients with ocular myasthenia or those with a normal or atrophic thymus gland had no more than an even chance of gaining significant improvement. Although previous reports suggested a high prevalence of ocular myasthenia and of thymoma among Chinese myasthenic patients, the present study has found no evidence that they respond differently to thymectomy than their Western counterparts. PMID- 7836953 TI - Release of muscle proteins in brain stroke patients. PMID- 7836954 TI - Neurogenetics update. PMID- 7836955 TI - Upregulation of the macrophage scavenger receptor in response to different forms of injury in the CNS. AB - The monoclonal antibody 2F8 was used to localize the macrophage scavenger receptor by immunohistochemistry. In control adult mice, macrophage scavenger receptor expression in the brain was restricted to stromal and epiplexus macrophages of the choroid plexus, meningeal macrophages and to perivascular sites. Microglia did not express the receptor. In the developing mouse brain, macrophage scavenger receptor expression was high on meningeal macrophages and detectable on immature microglia in the supraventricular corpus callosum, cingulum, cavum septum and the periaqueductal area. In the aged mouse brain, the pattern of macrophage scavenger receptor expression was no different from that in the young adult brain. Macrophage scavenger receptor expression on resident microglia and recruited macrophages was detected 24 h after an intrahippocampal injection of either lipopolysaccharide or kainic acid. Macrophage scavenger receptor expression was also detected in microglia 3 days after optic nerve crush both in the nerve segment distal to the crush site and in the superior colliculus. These studies indicate a potential role for the macrophage scavenger receptor in the CNS in the clearance of debris during acute neuronal degeneration. PMID- 7836957 TI - Neurofilament proteins form an annular superstructure in guinea-pig type I vestibular hair cells. AB - Neurofilaments, the neuron-specific intermediate filaments, are composed of three immunochemically distinct subunits: NF-L, NF-M and NF-H that can be either phosphorylated or unphosphorylated. In mammals, the distribution of these subunits has been described in vestibular ganglion neurons, but there are no reports on the presence of neurofilaments in vestibular hair cells. We investigated, by immunocytochemistry, neurofilaments in vestibular hair cells from rat and guinea-pig using antibodies against the three subunits and to dephosphorylated NF-H (clone SMI 32, recognizes also NF-M on immunoblots), on Vibratome sections of the vestibular end-organs and on isolated hair cells. Various immunostaining protocols were used, as appropriate for the method of observation: laser scanning confocal microscopy (immunofluorescence) and transmission electron microscopy (immunoperoxidase, pre-embedding technique). In rat and guinea-pig cristae and utricles, neurofilament immunoreactivity was observed in axons inside and below the sensory epithelia. In guinea-pig, in addition to this staining, intensely immunoreactive annular structures were found in the basal regions of hair cells. These rings were detected with anti-NF-L, -NF M and -dephosphorylated NF-H/M antibodies, but not with anti-phosphorylation independent NF-H. Ring-containing hair cells were present in all regions of the sensory epithelia but were more abundant in the peripheral areas. All levels of observation (Vibratome and thin sections, and isolated hair cells) showed that only the guinea-pig type I hair cells contained a neurofilament ring. High resolution observations showed that the ring was located below the nucleus, often close to smooth endoplasmic reticulum and the cell membrane. PMID- 7836956 TI - Relationship between injury-induced astrogliosis, laminin expression and axonal sprouting in the adult rat brain. AB - Lesion-induced regenerative sprouting of CNS axons is accompanied by structural and metabolic changes of astrocytes. In order to evaluate the effects of these astrocytic changes on axonal regeneration, we investigated the spatio-temporal relationship of gliosis, laminin expression and axonal sprouting in the postcommissural fornix of the adult rat. Using immunocytochemical methods we observed (1) a perilesional area with a transient lack of astrocytes and axons, (2) the reappearance of reactive astrocytes followed by the ingrowth of sprouting fibres and finally an increase in laminin-immunoreactivity, (3) the absence of lesion-induced laminin-expression in reactive astrocytes and (4) the formation and long-lasting (at least 28 months) persistence of a dense plexus of laminin immunopositive blood vessels at the site of transection and in the proximal and distal stumps. These data indicate that astrogliosis is permeable for regrowing axons and that injury-induced axonal sprouting in the transected postcommissural fornix may be mediated by laminin-independent mechanisms. PMID- 7836958 TI - Glial reaction after seizure induced hippocampal lesion: immunohistochemical characterization of proliferating glial cells. AB - Kainic acid treatment (a model of temporal lobe epilepsy) induces Ammon's horn sclerosis, which is characterized by degeneration of CA3 pyramidal neurons and reactive gliosis. In the present study we have combined autoradiographic analysis of 3H-thymidine incorporation and immunocytochemistry to investigate this glial scarring phenomenon. The present results demonstrate that in the fields showing neuronal degeneration (i.e. CA3-CA4 fields of Ammon's horn and dentate hilus) the glial reaction consists of a proliferation and hypertrophy of astrocytes and microglia-macrophages. In the regions showing exclusively terminal axonal degeneration (i.e. the molecular layer of kainate-treated rats), glial cells do not proliferate but astrocytes show a transient hypertrophy. These results also demonstrate that oligodendrocytes do not proliferate in the hippocampus of kainate-treated rats. In agreement with our previous report we find that hippocampal astrocytes from kainate-treated rats express A2B5 immunoreactivity, a marker of type-2 astrocytes. A2B5 immunoreactivity was expressed by astrocytes not only in areas showing glial proliferation such as CA3-CA4 fields, but also in the molecular layer, where astrocytes do not proliferate. This suggests that in the CNS, normal resident astrocytes acquire the phenotypic properties of type-2 astrocytes. PMID- 7836959 TI - Sweat function in Parkinson's disease. AB - Sweat function was studied in patients with Parkinson's disease and in normal adults by sympathetic skin response, the bromphenol blue printing method and the silicone mould method. In patients with Parkinson's disease, dysfunction of sweating was classified into two types: one type involved the postganglionic fibres and the other involved the preganglionic fibres or the central nervous system. The latter was observed in patients with milder disease and the former was observed in patients with severe disease. The progressive involvement of sweat function in Parkinson's disease may reflect spread from the central nervous system or preganglionic fibres to postganglionic fibres. In a few patients the results of sweat tests were normal. Ceruletide increased sweating in Parkinson's disease patients, and decreased the prolonged latency of the sympathetic skin response. It is hypothesized that ceruletide facilitates the preserved somatosympathetic reflex of sweating. PMID- 7836960 TI - Dopamine D2 receptor binding and cerebral glucose metabolism recover after D penicillamine-therapy in Wilson's disease. AB - Regional cerebral glucose metabolism (rCMRGlc) and dopamine D2 receptor binding were measured in a 31-year-old, severely affected, untreated patient with Wilson's disease of 3 years' duration using positron emission tomography and 18F deoxyglucose and 18F-methylspiperone ([18F]MSP), respectively. There was a severe reduction of striatal and extrastriatal rCMRGlc as well as of striatal [18F]MSP accumulation rate. After 1 year of treatment with D-penicillamine, striatal and extrastriatal rCMRGlc and striatal [18F]MSP accumulation rate reached almost normal levels. It is hypothesized that recovery of motor functions due to copper trapping therapy was associated with an increase in basal ganglia activity and a re-expression or upregulation of dopamine D2 receptors. PMID- 7836961 TI - Disorientation following stroke: frequency, course, and clinical correlates. AB - To investigate the frequency, course, and clinical correlates of disorientation following stroke, we administered the Mini-Mental State Examination orientation subtest to 177 alert patients 7-10 days and 3 months after stroke and 240 stroke free nondemented subjects. Disorientation was defined as a score < or = 8/10. Seventy-two (40.7%) of the patients were disoriented 7-10 days after stroke and 39 patients (22.0% of the sample) remained disoriented 3 months later. A logistic regression analysis determined that persistent disorientation was significantly related to stroke status [odds ratio (OR) = 5.8], after adjusting for memory and attentional deficits and demographic variables. Among stroke patients, disorientation was associated with severe hemispheral stroke syndromes (OR = 7.7), but not infarct location or vascular risk factor history, after adjusting for memory and attentional deficits and demographic variables. Sensitivity and specificity analyses determined that disorientation was an inaccurate marker for dementia or deficits in memory or attention, while intact orientation was associated with a low probability of dementia or memory dysfunction in most patients but not preserved attention. We conclude that disorientation is common and persistent following stroke and associated with severe hemispheral stroke syndromes but not infarct location. While disorientation is a poor marker for dementia or deficits in memory or attention, intact orientation should suggest that cognitive functions are likely to be preserved. PMID- 7836962 TI - Motor neuron disease with dementia and ophthalmoplegia. A clinical and pathological study. AB - Ophthalmoplegia and dementia are not usually observed in patients with amyotrophic lateral sclerosis. We report the case of a 60-year-old female with ophthalmoplegia and frontal-type dementia which appeared at an early stage of her illness that presented with dysarthria and weakness in the upper extremities. Notable autopsy findings in the central nervous system were, in addition to the degeneration of upper and lower motor neurons, moderate neuronal loss and spongy degeneration in layer II of the frontal cortex with prominent astrocytosis, and moderate neuronal loss with astrocytosis in both the substantia nigra and the red nucleus. Central chromatolysis of a few neurons in the oculomotor nucleus was seen. This case is considered to be a new subtype of motor neuron disease. PMID- 7836963 TI - Prediction of outcome in multiple sclerosis based on multivariate models. AB - An incidence cohort of 308 multiple sclerosis patients was followed up repeatedly during at least 25 years of disease. In the patients with acute onset, multivariate survival analyses were performed and predictive models created. The endpoints DSS 6 and start of progressive disease were used. A number of variables were tested. The most important of these for prediction and therefore included in these models were: age at onset, sex, degree of remission after relapse, mono- or polyregional symptoms, type of affected nerve fibres, number of affected neurological systems. The relapse rate did not correlate with prognosis. In the predictive models, coefficients and risk ratios are provided that can be used for calculating the risk of progression and DSS 6 or to predict the median time for these endpoints in individual patients. It was also found that the risk of progression is not constant, but has a maximum a certain time after disease onset. For a patient with early onset, the risk is low in the beginning, but reaches a maximum level, which is several times higher, after about 15 years. The patient with a late onset has a much higher risk of endpoint immediately after onset, but reaches the maximum in a few years, and after that the risk decreases. PMID- 7836964 TI - Chlorpromazine versus sleep deprivation in activation of EEG in adult-onset partial epilepsy. AB - We prospectively compared the activating effect of chlorpromazine (CHLP, 50 mg, i.m.) versus sleep deprivation (SD) in 41 patients with a clinical diagnosis of partial epilepsy. Patients were selected on the basis of both seizure onset in adulthood and normal interictal awake EEG recordings. Twenty out of 41 patients (group A) were not yet treated because of either recent onset of epilepsy or misdiagnosis. The remaining 21 patients (group B) were treated with antiepileptic drugs (AED). A control group consisted of 18 healthy, volunteers (group C). All EEG recordings were scored by one observer according to a fixed protocol. In group A, SD and CHLP activated sleep EEG in 12 (60%) and 19 (95%) patients, respectively. This difference reached the limit of statistical significance (P = 0.05, McNemar test). In group B, SD and CHLP activated sleep EEG in 12 (57%) and 13 (62%) patients respectively. There was a significant (P < 0.02, exact Fisher test) intergroup difference (95% vs 62%) with respect to the activating effect of CHLP. No false-positive results were found in 18 control subjects. SD or CHLP activating procedures did not provoke any epileptic seizures in any of the groups. In conclusion, EEG activation by either SD or CHLP is highly specific in the diagnosis of adult-on-set partial epilepsy. Moreover, CHLP is more sensitive than SD in untreated patients, whereas the activating effect of CHLP may be partially attenuated by AED. PMID- 7836965 TI - The effect of space location on neglect depends on the nature of the task. AB - It has been often reported that in patients with visual neglect line bisection is more accurate in the right than in the left hemispace. However, no data are available on the effect of hemispace on reading errors associated with neglect. We examined a 62-year-old man who presented with severe left neglect following a large infarction in the right cerebral hemisphere. The patient was asked to read 180 words aloud and to bisect 90 lines. Stimuli were presented in three different spatial locations: across the centre, to the right or to the left of the body midline. Line bisection was significantly more accurate in the right hemispace compared with the centre, or the left hemispace. In contrast, reading was significantly more accurate with words presented on the left side than on the centre or right side. This is the first time that such dissociation has been reported. We hypothesize that the dissociation depends on the nature of the stimuli and on the different cognitive demands of the tasks. PMID- 7836966 TI - Sex-related asymmetries in the morphology of the left and right hippocampi? A follow-up study on epileptic patients. AB - Cell densities were determined in left and right surgically removed hippocampal tissue of epileptic patients. Pyramidal cells were studied in CA1, CA4, and the dentate gyrus. Lower densities of nucleolated cells were found for males in the right CA1 and CA4 than on the left while there was no significant left-right difference in females. Moreover, we found a probable sex difference in intercorrelations of nucleolated cells among the three subfields. In males, they were positive and significant on the left while they were low on the right. In females, positive significant intercorrelations were obtained between some subfields and not between other subfields, on either side. The present findings suggest greater hippocampal lateralization in males than in females with higher hippocampal neuronal connectivity on the left in males than on the right. PMID- 7836967 TI - Re-evaluation of classic senile plaques by three-dimensional analysis. AB - We evaluated the proportion of classic plaques among all of the senile plaques in four Alzheimer brains (frontal, temporal, occipital and hippocampal areas) by the usual method of two-dimensional analysis using a single methenamine silver stained section and three-dimensional analysis using a set of serial sections. Three-dimensional analysis showed the number and percentage of classic plaques to be 2-5 times greater than those revealed by two-dimensional analysis. In the hippocampal area of one case, no classic plaques were found by two-dimensional analysis but three-dimensional analysis showed that some classic plaques were present. From these findings, it is suggested that three-dimensional analysis using serial sections is indispensable for subclassifying senile plaques. PMID- 7836968 TI - Algorithms and the Journal of Clinical Monitoring--II. PMID- 7836970 TI - How to access Journal of Clinical Monitoring abstracts on the Internet. PMID- 7836969 TI - What is heart rate, anyway? PMID- 7836971 TI - Comparison of the sphygmooscillographic method with the direct and auscultatory methods of measuring blood pressure. AB - OBJECTIVE: The objective of this study was to compare blood pressure (BP) measured by the sphygmooscillographic method with that measured by the direct and auscultatory methods. METHODS: In 15 adult patients undergoing cardiac surgery, blood pressure was measured by the sphygmooscillographic and direct methods simultaneously on the same upper extremity. In another group of 86 children and 11 adults, blood pressure was measured by the sphygmooscillographic and auscultatory methods simultaneously, with one cuff. For the sphygmooscillographic measurement, we used sphygmomanometer-S, which measures blood pressure on the basis of the amplitude height (oscillometric) and the morphology (sphygmographic) of pulse waves recorded by a transducer placed in the cuff. RESULTS: The systolic and diastolic blood pressure measured by the sphygmooscillographic method were both 2 mm Hg higher than those from the direct method; the mean blood pressure was 0.6 mm Hg higher. These differences were not significant. Compared with the auscultatory method, sphygmooscillographic systolic values were higher by 7 mm Hg, while diastolic values were lower by 9 mm Hg. These differences were significant. CONCLUSIONS: Blood pressure measurements obtained by the sphygmooscillographic method correlate well with the direct method for measuring blood pressure in children and adults; but, they do not correlate well with the auscultatory method. PMID- 7836972 TI - Bedside hemoglobin measurements: sensitivity to changes in serum protein and electrolytes. AB - OBJECTIVE: Our objective was to compare the effect of protein and electrolyte changes associated with hemodilution on the accuracy of photometric and conductivity hemoglobin determination methods. METHODS: Blood samples from 10 patients with normal preoperative serum electrolytes and total protein levels were studied. From an indwelling arterial line, 20 ml of blood were removed; hemoglobin values were measured pre-(Baseline) and postdilution by Coulter counter, conductivity, and photometric methods. Blood samples were diluted by placing 4 ml of blood into three test tubes, and adding 1 ml of either 25% albumin, 0.9% sodium chloride, or 5% dextrose in water. RESULTS: Blood sample dilution resulted in a reported conductivity hemoglobin that was significantly different from the Coulter value (p = 0.0004) when 25% albumin, 0.9% sodium chloride, and 5% dextrose in water solution was used. Using the same dilutions, the photometric method accurately reflected Coulter hemoglobin values. The correlation between photometric and Coulter hemoglobin measurements was R2 = 0.97, p = 0.0001. Correcting the conductivity hemoglobin values for changes in total protein, chloride and sodium significantly improved correlation with Coulter hemoglobin (R2 of uncorrected versus corrected = 0.37 and 0.72; p = 0.0001). CONCLUSIONS: In the range of electrolyte and protein concentrations found in this study, the photometric method of hemoglobin assessment was more accurate than either corrected or uncorrected conductivity hemoglobin determinations, as compared to Coulter-based measurements. PMID- 7836973 TI - Lack of documentation of severe transient bradycardia by an automated anesthesia record. PMID- 7836975 TI - An introduction to bispectral analysis for the electroencephalogram. AB - The goal of much effort in recent years has been to provide a simplified interpretation of the electroencephalogram (EEG) for a variety of applications, including the diagnosis of neurological disorders and the intraoperative monitoring of anesthetic efficacy and cerebral ischemia. Although processed EEG variables have enjoyed limited success for specific applications, few acceptable standards have emerged. In part, this may be attributed to the fact that commonly used signal processing tools do not quantify all of the information available in the EEG. Power spectral analysis, for example, quantifies only power distribution as a function of frequency, ignoring phase information. It also makes the assumption that the signal arises from a linear process, thereby ignoring potential interaction between components of the signal that are manifested as phase coupling, a common phenomenon in signals generated from nonlinear sources such as the central nervous system (CNS). This tutorial describes bispectral analysis, a method of signal processing that quantifies the degree of phase coupling between the components of a signal such as the EEG. The basic theory underlying bispectral analysis is explained in detail, and information obtained from bispectral analysis is compared with that available from the power spectrum. The concept of a bispectral index is introduced. Finally, several model signals, as well as a representative clinical case, are analyzed using bispectral analysis, and the results are interpreted. PMID- 7836974 TI - The evaluation of a new intravascular blood gas monitoring system in the pig. AB - OBJECTIVE: Our objective was to investigate the accuracy of a new intravascular blood gas sensor, the Paratrend 7 (P7) (Biomedical Sensors Ltd, Pfizer Hospital Products Group, High Wycombe, England) in a porcine model. METHODS: A total of 12 sensors were inserted into 10 animals under total intravenous anesthesia. Changes in blood gas chemistry were produced over a wide range by manipulating the inspired oxygen and carbon dioxide concentrations and by adjustments in minute ventilation. Blood gas samples (BGA) were taken and analyzed during periods of stability; the results obtained were compared with the readings from the intravascular sensor. RESULTS: A total of 292 blood gas samples were taken and analyzed for pHa, PaCO2, and Po2; the results were compared with the readings from the intravascular sensor. Correlation coefficients of r = 0.98 for PCO2 and r = 0.99 for PO2 were obtained. Analysis of bias and precision as mean +/- SD of the difference (P7 - BGA) gave the following results: pH bias = -0.03, precision = +/- 0.04; PCO2 bias = 0.65 mm Hg, precision = +/- 3.1 mm Hg; and PO2 bias = 6.50 mm Hg, precision = +/- 0.6 mm Hg. No problems with clot formation on the sensor were seen, and the sensors did not appear to show the "wall effect" seen with other systems. CONCLUSIONS: The results obtained were well within the requirements for a clinically useful blood gas monitoring system. PMID- 7836976 TI - Oxygen supply failure revisited. AB - This is a report of a previously undescribed cause of oxygen supply failure during anesthesia, resulting from a worn main switch on a Narkomed 2A anesthesia machine (North American Drager Information Systems, Telford, PA). The implications of this incident are discussed. PMID- 7836977 TI - An interface to display special physiologic signals on patient monitors. AB - OBJECTIVE: The objective of this study was to develop an interface to allow special physiologic signals (e.g., in a research setting) to be displayed on the invasive pressure channel of conventional clinical monitors. The interface accepts single-ended high-level signals for display using the pressure channel of patient monitors, which use strain-gauge transducers employing direct current (DC) excitation. METHODS: By studying the electronic circuitry common to most clinical invasive pressure measurement systems (Wheatstone bridge, differential input instrumentation amplifier) it was possible to develop an interface to convert high-level single-ended signals into the low-level differential signal needed for input to an invasive pressure channel. RESULTS AND CONCLUSIONS: The device is useful when it is desired to display signals from special transducers on regular patient monitors. Schematic diagrams and sample results are provided. PMID- 7836978 TI - Electrically amplified precordial stethoscope. PMID- 7836979 TI - Write it right. PMID- 7836980 TI - Write it right, Part I: Introduction and planning. PMID- 7836981 TI - In my opinion: a debate--can succinylcholine be used routinely with safety in children? PMID- 7836982 TI - APSF supports analysis of AIMS data. PMID- 7836983 TI - The National Confidential Enquiry into Perioperative Deaths. PMID- 7836984 TI - Are we becoming too afraid? PMID- 7836985 TI - Back to the future. PMID- 7836986 TI - Labor assistants. PMID- 7836987 TI - Natural family planning. PMID- 7836988 TI - Women's perceptions of nursing support during labor. AB - OBJECTIVE: To determine which nursing support behaviors new mothers rate as most helpful in assisting them to cope with labor. DESIGN: A retrospective study using quantitative and qualitative approaches, including a ranking of means and a content analysis. SETTING: The postpartum unit of a tertiary-care hospital in eastern Canada. PARTICIPANTS: Eighty postpartum women, most of whom were married, employed, and 20-33 years of age. INTERVENTIONS: Within 72 hours of their labor women rated 25 nursing support behaviors. MAIN OUTCOME MEASURES: The perceived degree of helpfulness of 25 nursing support behaviors. RESULTS: All 25 behaviors were perceived as helpful. The most helpful behaviors included making the woman feel cared about as an individual, giving praise, appearing calm and confident, assisting with breathing and relaxing, and treating the woman with respect. Behaviors in the emotional support category were the most helpful. CONCLUSIONS: Nurses can assist women to cope with the stress of labor. They must use a high degree of interpersonal skills in the care of laboring women in addition to being technically competent. PMID- 7836989 TI - Hormone replacement therapy: evaluating the risks and benefits. AB - OBJECTIVE: To review the literature related to the benefits and risks of postmenopausal hormone replacement therapy (HRT). DATA SOURCES: Computerized searches on MEDLINE and CINAHL. STUDY SELECTION: Articles from indexed journals in the English language related to the topics in this review and published after 1986 (except for earlier classic pieces) were evaluated. DATA EXTRACTION: Data were extracted and information was organized about HRT under the following headings: indications, risks, contraindications, management of therapy, and evaluation of risks and benefits. DATA SYNTHESIS: Hormone replacement therapy is used to treat symptoms of estrogen deficiency and to prevent disease. The small risk of breast cancer associated with HRT is outweighed by the beneficial effects of such therapy in preventing cardiovascular disease and osteoporosis. CONCLUSIONS: Evidence suggests that HRT should be offered to all postmenopausal women in whom it is not contraindicated. Ideally, each woman should decide whether to receive HRT after weighing the risks and benefits. Additional research is needed on the effects of different doses, types of estrogen and progestin, and treatment duration, and on which HRT regimen offers the best risk-benefit profile. PMID- 7836990 TI - Risk management and legal issues in home care: the utilization of nursing staff. AB - A sound, integrated risk-management program in home health care can significantly reduce the potential for inclusion in lawsuits. Focusing on two clinical patient care situations (the pregnant woman receiving home uterine activity monitoring and the female patient with acquired immune deficiency syndrome), this article presents the components of risk management and their practical implications for the delivery of nursing care in the home. PMID- 7836991 TI - Essential program components for perinatal home care. AB - Home care will continue to be a rapidly expanding area of health care. This growth will be evident in the perinatal nursing specialty. There are multiple models for delivery of perinatal home services. In each case, consideration needs to be given to licensing and other standards; to operational areas such as staffing, supplies, equipment, and reimbursement; and to quality issues, such as staff development, internal and external customer service, and a continuous quality improvement program. Successful marketing of the services requires recognition that the product is nursing care. PMID- 7836992 TI - Home infusion therapies for obstetric patients. AB - This article focuses on current indications for home intravenous therapy for the high-risk obstetric patient. Therapeutic indications and clinical care for obstetric patients in need of hydration/total parenteral nutrition, heparin infusion, terbutaline pump, and antibiotic therapies are presented. PMID- 7836993 TI - Hospital-based perinatal home-care program. AB - In recent years, hospitals have established home-care programs to provide care on a continuum, meeting needs in the hospital and home setting, whichever is most appropriate and efficient in response to defined patient needs. Hospital-based home-care programs with specialization in perinatal nursing have been established to meet the care needs of patients and their families during antepartum, postpartum, and neonatal periods. One of the greatest advantages of a hospital based program is the internal availability of highly knowledgeable and skilled nursing staff. Physicians are more likely to refer patients to a program that is staffed with nurses they know and trust from the hospital setting. More cost effective and coordinated care is achieved through the appropriate use of resources across the continuum. PMID- 7836994 TI - Nursing protocols for antepartum home care. AB - Home care for women experiencing high-risk complications of pregnancy is a growing phenomenon. Home-care protocols for basic antenatal visits and the common conditions managed at home, such as preterm labor, premature rupture of membranes, bleeding, pregnancy-induced hypertension, chronic hypertension, and diabetes during pregnancy, are presented. Knowledge of protocols guiding home care of the antepartum client enhances communication, collaboration, and coordination and ultimately fosters dialogue, which can improve the quality of care for women. PMID- 7836996 TI - Patient satisfaction with an antepartum home-care program. AB - Evaluation of patient satisfaction with alternative health-care delivery models is an important component of program evaluation. Patient satisfaction occurs when there is congruence between expected care and the care received. This descriptive study investigated patient satisfaction with the Antepartum Home Care Program in Winnipeg, Canada. A convenience sample of 66 pregnant women completed the Antepartum Home Care Program Evaluation Questionnaire. Most respondents were very satisfied with the physical and emotional care they received at home, including the information they received. Ninety-eight percent of the women indicated that the care they received from the program met their expectations. Being able to receive care at home, rather than in the hospital, was the most frequently identified benefit of the Antepartum Home Care Program. These results will assist program planners with decisions concerning program improvements and growth. PMID- 7836995 TI - Home care of the high-risk pregnant woman requiring bed rest. AB - Home-care treatment of the high-risk pregnant woman often includes bed rest. Bed rest therapy has various physiologic and psychosocial side effects that generally are not recognized or treated. This article provides suggestions for providing comprehensive nursing antepartum and postpartum care of the pregnant woman requiring home bed rest and her family. Resources available to assist in this care are detailed. PMID- 7836997 TI - Education for home-care providers. AB - Continuing education for home-care nurses is necessary because of the many different levels of educational preparation among nurses working in this practice setting and the lack of a structured orientation program at many agencies. Unique educational needs include the need to feel confident with physical assessment skills, nursing diagnosis, family dynamics, patient teaching, and counseling. Competence in the use of computers and documentation forms also is a necessity. The development of any educational program should include identification of the target audience, needs assessment, planning and design of the program, strategy for implementation, and an evaluation strategy. PMID- 7836998 TI - Maternal-fetal physical assessment in the home setting: role of the advanced practice nurse. AB - Maternal-fetal physical assessment in the home setting reflects a review of the literature, AWHONN's practice guidelines, and the authors' clinical experience. The goals of prenatal home care and the role of the advanced practice nurse are described. Emphasis is placed on the maternal-fetal physical assessments that allow the advanced practice nurse to provide additive or substitutive prenatal care visits in the home. Delivering prenatal care in the home by the advanced practice nurse is an alternative type of health-care delivery for pregnant women. PMID- 7836999 TI - Perinatal home care: one entrepreneur's experience. AB - Nurses have responded to the entrepreneurial movement by entering into various nontraditional roles and starting their own businesses. This article describes the author's experience in establishing a perinatal home-care business. The characteristics of women and nurse entrepreneurs are discussed, as are the components of a business plan and how to manage a business. PMID- 7837000 TI - Double-pass and interferometric measures of the optical quality of the eye. AB - We compare two methods for measuring the modulation transfer function (MTF) of the human eye: an interferometric method similar to that of Campbell and Green [J. Physiol. (London) 181, 576 (1965)] and a double-pass procedure similar to that of Santamaria et al. [J. Opt. Soc. Am. A 4, 1109 (1987)]. We implemented various improvements in both techniques to reduce error in the estimates of the MTF. We used the same observers, refractive state, pupil size (3 mm), and wavelength (632.8 nm) for both methods. In the double-pass method we found close agreement between the plane of subjective best focus for the observer and the plane of objective best focus, suggesting that much of the reflected light is confined within individual cones throughout its double pass through the receptor layer. The double-pass method produced MTF's that were similar to but slightly lower than those of the interferometric method. This additional loss in modulation transfer is probably attributable to light reflected from the choroid, because green light, which reduces the contribution of the choroid to the fundus reflection, produces somewhat higher MTF's that are consistent with the interferometric results. When either method is used, the MTF's lie well below those obtained with the aberroscope method [Vision Res. 28, 659 (1988)]. On the basis of the interferometric method, we propose a new estimate of the monochromatic MTF of the eye. PMID- 7837001 TI - Evidence for separate pathways for color and luminance detection mechanisms. AB - We measure threshold versus contrast (TvC) functions for chromatic (red-green) and luminance sine-wave-grating stimuli for (1) the detection of luminance in the presence of color contrast and (2) the detection of color in the presence of luminance contrast. We find that, although these crossed TvC functions both display a dipperlike shape, their facilitation differs from that found for standard uncrossed dipper functions (luminance on luminance or color on color contrast). Their facilitation disappears (cross condition 1) or is reduced (cross condition 2) by randomized presentation of the phase of the test and the mask, and the remaining facilitation (cross condition 2) displays no spatial tuning. We argue that these crossed facilitatory interactions cannot be explained by detection mechanisms with common inputs from color and luminance contrast (a nonindependence of transduction), and we present evidence that instead they reflect the use of local cues in the stimuli. We also measure the luminance luminance TvC function in the presence of a fixed suprathreshold color contrast. The results demonstrate that, even when the color contrast produces a masking of the luminance thresholds, luminance-luminance facilitation still occurs. Thus the opposing effects of masking and facilitation can occur simultaneously. Furthermore, while luminance-luminance facilitation occurs independently of color contrast, masking can be produced by either contrast. This suggests that masking and facilitation have different underlying origins. Similar results are found for the color detection thresholds in the presence of a luminance pedestal. We conclude that there are separate pathways for the detection of color and luminance contrast, each with no input from the other contrast. We suggest that the cross masking reflects divisive interactions between these pathways that is restricted to high contrasts. PMID- 7837002 TI - Detection of one versus two objects in structure from motion. AB - The ability of subjects to detect whether a structure-from-motion display depicts one or two rigid objects was examined in the presence or the absence of noise points. Each object was composed of a set of points chosen randomly within the volume of a sphere. The objects rotated rigidly about different axes passing through the center of the sphere. For displays without noise points, detection increased with larger angles between the rotation axes and with more points in each object. For displays in which noise points were present, detection was above chance but, in general, worse than that for displays without noise points. The implications of these results for image segmentation in complex motion patterns is discussed. PMID- 7837003 TI - Model for perception of pulsed fluoroscopy image sequences. AB - Pulsed fluoroscopy at reduced frame rates can be used to lower x-ray dose with equivalent detection (hereafter called equivalent perception) of low-contrast, stationary objects. Experimentally average dose savings of 22%, 38%, and 49%, for pulsed fluoroscopy at 15, 10, and 7.5 acquisitions per second, respectively, are documented. Dose savings depend on object size, with fewer savings for smaller objects. To explain these data, we extend the framework of an ideal observer with three models for the spatiotemporal response of the human visual system (HVS). They are model 1, separable; model 2, nonseparable; and model 3, nonseparable with internal observer noise. With no free parameters, model 1 predicts the average dose savings within a 3% difference but does not describe the effect of object size. Models 2 and 3 explain the influence of size, and model 3, with a single free parameter, fits the measurements best. Perception of pulsed fluoroscopy is thus well described in terms of spatiotemporal processing by the HVS. PMID- 7837004 TI - Who needs ethics? PMID- 7837005 TI - Gastrointestinal problems experienced in an intensive care unit. AB - Medical emergencies involving the gastrointestinal tract include bleeding, abdominal pain, diarrhea, toxic megacolon, pancreatitis, and hepatic failure. Each can be a cause for admission to an intensive care unit or occur de novo in a patient hospitalized in such a unit. The clinical presentation, management, and consequences of these varied gastrointestinal problems seen in an intensive care unit are presented followed by a recommended course of action. PMID- 7837006 TI - Congenital thumb hypoplasia. AB - Hypoplastic thumb is a short, underdeveloped thumb with deficient or absent intrinsic muscles with or without deficient extrinsic musculotendinous structures. Thumb hypoplasia is a common congenital abnormality with five types of increasing severity. This abnormality may be associated with local musculoskeletal deficiencies or systemic diseases and syndromes. In severe cases, basic hand function, including pinch and grasp, may be adversely affected. A variety of operative reconstructive procedures can provide thumb stability, and improve motor control and overall hand function. PMID- 7837007 TI - Lithotripsy for retained common duct stones: a quasi-urological procedure. AB - A protocol for bile duct lithotripsy was formulated in early 1988 after review of the literature and encouragement by gastroenterologists. Seven cases have been treated at our center and are being reported to explain our current concept of this therapy. Failure of the Food and Drug Administration to approve gallstone lithotripsy has complicated the promulgation of this procedure. PMID- 7837008 TI - Progress toward Healthy People 2000: a preliminary look at Oklahoma. AB - Over 10,000 Oklahomans die each year from coronary artery disease or stroke. This study examined the behavioral risk factors for these illnesses present in Oklahomans. Oklahomans are at considerably higher risk than the desirable national goals for such risk factors. For example, too many Oklahomans smoke and too few exercise. The data to support these findings are included herein, and some steps to reverse these trends are recommended. PMID- 7837009 TI - Hemophilia now reportable for purposes of special state survey. PMID- 7837010 TI - Programs for persons living with HIV disease. PMID- 7837011 TI - Neural tube defects and folic acid supplements. PMID- 7837012 TI - Health care reform going underground. PMID- 7837013 TI - Results of a prospective randomized trial of botulinum toxin therapy in acute unilateral sixth nerve palsy. AB - Forty-seven patients entered a prospective randomized trial to assess the effect of early botulinum neurotoxin A treatment to the ipsilateral antagonist medial rectus on the ultimate recovery rate of acute unilateral sixth nerve palsy. Twenty-two patients received injections and 25 acted as controls. The overall etiologies were microvascular (72.3%), unknown (17%), multiple sclerosis (6%), and one case each of central nervous system (CNS) sarcoidosis and basilar artery ectasia. Eighty-three percent of the patients entered the trial within 2 weeks of the onset of symptoms and 95.7% within 3 weeks. The controls had a final recovery rate of 20/25 (80%), and the injected group had a final recovery rate of 19/22 (86%). No serious side effects were encountered. We conclude that there is no evidence for a prophylactic effect of botulinum toxin in the group that we have studied. PMID- 7837014 TI - The use of hyaluronic acid during adjustable suture surgery. AB - We prospectively studied the force required to move an extraocular muscle after adjustable suture surgery with and without the perioperative use of hyaluronic acid (Healon). The 15 muscles that received hyaluronic acid averaged 15.0 g of force to move the muscle 2.0 mm which was significantly different than the average force of 36.15 g required for the 13 control muscles. The decreased force required to adjust the muscle along with potential antiinflammatory properties of hyaluronic acid make this a useful adjunct during adjustable suture surgery. PMID- 7837015 TI - Artifacts in fusion and stereopsis testing based on red/green dichoptic image separation. AB - A red/green anaglyph stereotest (TNO) was administered to a group of patients who had anisometropic amblyopia, and the Worth 4-Dot test for fusion to two groups of strabismus patients. Both tests were administered twice, with the red/green lens position of the glasses reversed between eyes for the second administration. Twelve of 15 patients with anisometropic amblyopia exhibited a stereo acuity difference of 2:1 or more, and 18 of 89 strabismic patients changed Worth 4-Dot fusion or suppression status, between the two positions of the glasses. A group of seven strabismic patients who showed the reversal effect on the Worth 4-Dot test had the results of one glass' position discrepant with those of a geometrically identical achromatic test. It appears that the red/green format can introduce artifacts in binocular vision testing. Testing twice, with the red/green glasses reversed between trials, will prevent misinterpretation of binocular status and may provide diagnostically useful information. PMID- 7837016 TI - Prevalence of primary monofixation syndrome in parents of children with congenital esotropia. AB - The prevalence of primary monofixation syndrome (MFS) in the general population is approximately 1%. This study was performed to determine the prevalence of primary monofixation in biological parents of children with congenital esotropia. Ninety children with congenital esotropia were seen between November 1991 and June 1992 by one ophthalmologist (M.M.P.). One hundred and twenty-nine biological parents of these children were screened for sensorimotor abnormalities. Twelve parents were found to have secondary MFS and were removed from the analysis. This left 78 apparently non-strabismic families consisting of a total of 117 parents. Seven parents were identified as having primary MFS. The prevalence of primary MFS in this population is 9% of families and 6% of parents. Congenital esotropia is believed to be inherited in a multifactorial fashion. We believe that this increase in the prevalence of primary MFS compared to the general population lends support to the hypothesis that primary MFS may be a mild (subthreshold) effect of the "gene(s)" that cause congenital esotropia. PMID- 7837017 TI - Posterior retinopathy of prematurity cryotherapy from a limbal reference. PMID- 7837018 TI - Traumatically ruptured globes in children. AB - This retrospective study was designed to document the etiology of traumatically ruptured globes in children and to determine the prognostic value of several clinical parameters with respect to visual outcome. Forty-six children 16 years of age and under seen in the emergency room over a 2-year period were found to have full thickness penetration of the globe. Fifty-nine percent of injuries occurred during recreational activities, and 59% occurred outside of the home. Boys outnumbered girls by a 6:1 ratio. For children, initial visual acuity proved to be less valuable as a prognostic indicator with regard to final vision than has been reported in adults. Smaller corneal wounds offered better visual outcomes. Four eyes were enucleated. Ten ruptures (22%) were related to activity involving guns. Four of six BB gun injuries were the result of a ricocheted BB. Visual outcomes in gun-related injuries were particularly poor. PMID- 7837020 TI - Cloudy lenses and issues: a pedigree of unoperated congenital cataracts. AB - The issue of when congenital cataracts should be removed seems to be well resolved, with most recommendations stating that all significant central lens opacities should be removed by 4 months of age, with removal most commonly occurring the first month. Although there are many strong recommendations regarding congenital cataracts in the literature, little has been written about the initial decision of whether or not to operate. A pedigree is presented of multiple generations with inherited bilateral central cataracts. Two affected children, who did not undergo surgery, were followed from birth. These two children developed essentially normal vision, despite seemingly significant central opacities. This pedigree emphasizes the need to further examine prognostic factors regarding bilateral infantile cataracts and to analyze the initial surgical decision. Because this condition does not often occur and a large number of patients is necessary to determine the predictive value, a large, collaborative study is required to make significant headway in this area. If we can identify the factors that have strong predictive value for good vision after cataract surgery, we may start to define the profile of children who will have good vision, with or without surgery. PMID- 7837019 TI - Pediatric ocular trauma: a retrospective survey. AB - A retrospective, cross-sectional survey was conducted of all pediatric trauma cases seen by the ophthalmology department at our institution from January 1986 to December 1991. The study included 504 patients who were 15 years old or younger. The purpose of this study was to determine risk factors for ocular injury, especially injury resulting in severe visual impairment, and to identify trends and preventable causes. Our results were consistent with the findings of other similar studies: male patients predominated, penetrating injuries resulted in poor visual outcomes, and many of the causes of severe visual deficit were preventable with more adequate adult supervision. PMID- 7837021 TI - Functional visual deficit in children with a family history of retinitis pigmentosa. PMID- 7837022 TI - Orbital sub-periosteal abscess responding to medical therapy. PMID- 7837023 TI - Anomalous lacrimal ductule: case report and review. PMID- 7837024 TI - Congenital euryblepharon and nasolacrimal anomalies in a patient with Down syndrome. PMID- 7837025 TI - Schwannoma of the eyelid in a child. PMID- 7837026 TI - Upbeat nystagmus associated with tonic downward deviation in healthy neonates. PMID- 7837027 TI - Superior lacrimal canalicular atresia and nasolacrimal duct obstruction in the CHARGE association. PMID- 7837028 TI - Orbital aberrant fibroglial tissue (fibroglial choristoma) associated with microphthalmos. PMID- 7837029 TI - New instruments for muscle surgery. AB - Several techniques have been described and utilized for recession and resection of the extraocular muscles with various technical difficulties and complications. Two new instruments have been designed which may minimize surgical difficulties and provide more accurate and consistent measurements in muscle surgery. PMID- 7837030 TI - [Analysis of opiates in the urine of children with gas chromatography coupled to mass spectrometry]. AB - Acute intoxication by opiates is quite frequent and very serious, especially in children whence the need to assay these compounds in biological fluids. The authors have developed an assay for opiates (codeine, codethyline, morphine and pholcodine) by gas chromatography/mass spectrometry (GC/MS) on a capillary column. This assay can identify different opiates due to its high specificity. Before chromatography, urine from children undergoes acid hydrolysis and solid phase extraction. The compounds are derivatized by acetylation before being chromatographied. This assay is carried out after a first search for opiates in urine by immunoenzymology. Each sample containing opiates is then analysed by GC/MS in order to determine specifically the opiates responsible for intoxication. PMID- 7837031 TI - [The inhibitory action of a saccharide derivative on a calcium channel in the oocyte of Xenopus]. AB - Endogenous calcium channels of Xenopus oocyte membrane do not fit with pharmacological classification of calcium channels. The present study demonstrates that the saccharidic derivate, OC8-MAGlu-MAGlu, has potent inhibitory effect on this channel activity. PMID- 7837032 TI - [Absolute and relative bioavailability of germanium in the rabbit]. AB - The debated consumption of germanium suggested the authors to compare biopharmaceutical parameters of germanium oxide and germanium sesquioxide. A first evaluation, in rabbit, has been based on Germanium blood levels determined by atomic absorption spectrometry, after cross administration of both products by the I.V. and oral routes. When given orally, the apparent oxide bioavailability is very low (about 10%) but better than that of the sesquioxide. That difference could result from differences of disposition parameters of both products, which have to be studied late. PMID- 7837033 TI - Survey of European pharmaceutical journals in circulation in 1993. AB - Journals represent a very important source of information to pharmacists. This survey aimed to list current European pharmaceutical journals with their main characteristics. First, we provide a working definition of "European pharmaceutical journal". Then, the methodology and our sources which included books, databases, and questionnaires are reported. The following section details the results of the survey: journal creation for the period 1930 to 1993, geographic distribution, characteristics of the different types of journals (scientific, professional, scientific and professional/educational journals), inclusion in international bibliographic indexes. Finally, the list of the European pharmaceutical journals with their main characteristics and the list of the independent European pharmaceutical journals are reported in Appendix. PMID- 7837034 TI - [Reaction and interactions of drugs]. PMID- 7837035 TI - Harmonization and back to basics. PMID- 7837036 TI - Use of the Walden Product to evaluate the effect of amino acids on water structure. AB - The Walden Product, the product of viscosity (eta 0) and conductivity at infinite dilution of a solution (lambda 0), provides a measurement of the water structuring activity of the solute. Measuring the effect of concentration on viscosity of solutions of amino acids, together with the conductivity of solutions of sodium chloride containing increasing concentrations of the amino acids, enabled Walden Products to be determined. The classical form of the Walden Product (lambda 0 eta 0) was used, together with a modified form, lambda 0 eta c, in which eta c was the slope of the concentration/viscosity curve. Most amino acids demonstrated modest water-structure-breaking activity but L-lysine, L glutamic acid and L-aspartic acid, and their respective salts, all showed relatively higher activity. Dextrose behaved as a classical water-structure maker and, when added progressively, reversed the breaking activity of L-lysine. It is speculated that effects seen in bulk water may also occur at emulsion droplet surfaces, thereby inducing structural changes associated with the occasional rapid instability experienced when making admixtures of phospholipid-stabilized emulsions and additives such as amino acids and dextrose. PMID- 7837037 TI - A study of modified betaines as cryoprotective additives. AB - Glycinebetaine and N-modified betaines have been previously shown to be effective at reducing leakage from liposomes on freeze-thaw procedures. This study involved the preparation of a series of other modified betaines and the comparison of their abilities to reduce leakage from frozen multilamellar liposomes. All the compounds investigated, with the exception of the octyl ester of betaine, reduced the degree of leakage on freezing and thawing with additive concentrations up to 0.6 M. The betaine esters were less effective than betaine as cryoprotective additives and caused an increase in the leakage from unfrozen liposomes. Taurinebetaine, a sulphobetaine, was also less effective at reducing leakage on freezing than betaine and again increased leakage from unfrozen liposomes. Increasing the number of methylene groups between the carboxylate group and the nitrogen improved the ability to reduce leakage, particularly at lower additive concentrations. PMID- 7837038 TI - The release of macromolecules from fatty acid matrices: complete factorial study of factors affecting release. AB - A replicated complete factorial design to study the main effects and interactions of four factors: bovine serum albumin (BSA) particle size (Factor A); stearic acid particle size (Factor B); BSA loading (Factor C); and compression force (Factor D), on the release of BSA from compressed stearic acid pellets was performed in isotonic phosphate buffer pH 7.4 at 37 degrees C. Samples were withdrawn over 64 h. Analysis of variance of the percentage released at 64 h showed that A, B, and C, but not D, affected the release and the interactions AB, BC, ABC were highly significant. At low loading (5%), the surface release depended on BSA particle size. The release increased when BSA particle size was large. At high loading (20%), more release was shown when stearic acid particle size was large. More release with increasing BSA particle size occurred only when stearic acid particle size was small. It is proposed that release is due to the interconnected pore networks created, not only by BSA particles, but also by the void space between stearic acid particles. These void spaces vary according to particle size-dependent arrangements of stearic acid and BSA particles. An increase in the pellet thickness was observed probably due to the relaxation of compacted stearic acid particles. PMID- 7837039 TI - Peracylated beta-cyclodextrins as novel sustained-release carriers for a water soluble drug, molsidomine. AB - Peracylated beta-cyclodextrins with different alkyl chains (acetyl-octanoyl) were prepared by acylating all hydroxyl groups of beta-cyclodextrin (beta-CyD), and their physical properties were evaluated. These hydrophobic beta-CyDs decreased the release rate of molsidomine, a peripheral vasodilator, in proportion to the lengthening of alkyl chain and suppressed a peak plasma level of molsidomine following oral administration of peracylated beta-CyD complexes to dogs. Among the peracylated beta-CyDs tested, perbutanoyl-beta-CyD maintained sufficient plasma drug levels for a long period of time, while other peracylated beta-CyDs having shorter or longer chains were inappropriate to control the in-vivo release behaviour of molsidomine. The prominent retarding effect of perbutanoyl-beta-CyD was ascribable to the appropriate mucoadhesive property and hydrophobicity, compared with other peracylated beta-CyDs. The present results suggest that perbutanoyl-beta-CyD is particularly useful in modifying the release rate of water-soluble drugs as a novel slow-release carrier. PMID- 7837040 TI - Biodegradable controlled antibiotic release devices for osteomyelitis: optimization of release properties. AB - Controlled antibiotic release films, melt-extruded cylinders, and suspension extruded/coated cylinders were manufactured from biodegradable poly(D,L-lactide) (PDLLA) and poly(D,L-lactide-co-epsilon-caprolactone). These devices have potential application in the treatment of osteomyelitis. The in-vitro release properties of the devices were examined with drug loadings varying from 16 to 50%. Gentamicin sulphate films and melt-extruded gentamicin/PDLLA cylinders demonstrated a large initial burst and incomplete release. The films and melt extruded cylinders made from poly(D,L-lactide-co-epsilon-caprolactone), low mol. wt poly(D,L-lactide), and a mixture of D,L-lactic acid oligomer and high mol. wt poly(D,L-lactide), did not remain intact during the entire release period. While this is undesirable, these materials do have the advantage of not requiring a processing temperature of greater than 110 degrees C. Antibiotic release from high mol. wt PDLLA-coated gentamicin/PDLLA cylinders, with 40 and 50% loading, was very rapid. The antibiotic could only diffuse out through the open ends of the cylinder. Coated gentamicin sulphate cylinders with 20 and 30% drug loading gave the most promising properties in terms of a small initial burst, and a gradual and sustained release. The release rate and duration from the coated cylinders could be adjusted by cutting the cylinder into different lengths; the time required for 90% of the entrapped gentamicin to be released into water from 30% loaded PDLLA-coated cylinders 0.2, 0.4, 0.7 and 1 cm in length was 1000, 1700, 2300, and 2800 h, respectively. This offers a convenient method to adjust the release to meet the specific antibiotic requirement of different patients.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7837041 TI - Human calcitonin delivery in rats by iontophoresis. AB - In-vitro ionotophoresis (0.33 mA cm-2) of calcitonin (50 micrograms mL-1, pH 4) was performed with the hairless rat skin model. Direct current was as potent as pulse current (2.5 kHz on/off 1/1) iontophoresis in promoting transdermal permeation of calcitonin. Increase in duration of current application from 20 min to 1 h did not increase calcitonin flux. Results suggest that calcitonin can be blocked in the skin pores through which it travels or can accumulate in the skin and be progressively released from the depot. In-vivo experiments showed that transdermal iontophoretic administration of calcitonin induced a hypocalcaemic effect in rats. PMID- 7837042 TI - Manganese ions induce tonic contraction after relaxation in a high-K+ medium in ileal longitudinal smooth muscle of guinea-pig. AB - In ileal longitudinal muscle 5 mM Mn2+ inhibited completely the K+ (60 mM) induced tonic tension to the base line; however, the tension progressively increased to above the level of original tonic response evoked by K+ after 3 h in the presence of Mn2+. Tetrodotoxin 5 x 10(-5) M) had no influence on the tension development in the presence of Mn2+ in the high-K+ medium. Mn2+ also increased the tension in a high-K+, Ca(2+)-free medium. The Ca2+ antagonist, gallopamil (10(-6) M) inhibited the development of tension in the presence of Mn2+ in the high-K+ medium. The 45Ca uptake determined by the lanthanum method remained unchanged from control levels after 3 h of the 5 mM Mn2+ application in the high K+ medium in spite of the development of the tension. The manganese uptake in the high-K+ medium, increased in accordance with the increase of duration of 5 mM Mn2+ application. Gallopamil inhibited manganese uptake in the high-K+ medium. These results suggest that Mn2+ firstly reduces K(+)-induced tension by inhibition of Ca2+ influx, subsequently, Mn2+ ions accumulate in the intracellular compartments through voltage-operated Ca2+ channels and may activate contractile proteins in the ileal muscle. PMID- 7837043 TI - Effect of aminoethylpyrroles on carrageenan-induced inflammation and on lipid peroxidation in rats: some structural aspects. AB - Nine 3-(2-aminoethyl)pyrrole derivatives were investigated as anti-inflammatory agents in the carrageenan-induced rat paw oedema model and as antioxidants in the non-enzymatic lipid peroxidation assay. It was found that the derivatives which were substituted with a p-toluenesulphonyl group exhibited considerable anti inflammatory activity and some also showed antioxidant properties. However, the presence of a p-toluenesulphonyl group did not invariably lead to activity. A structural feature which was essential for both activities was the aminoethyl side chain. Although a relationship between the antiinflammatory and the antioxidant activities was not apparent, the combination of these properties could be useful. PMID- 7837044 TI - Effects of in-vivo administration of taurine and HEPES on the inflammatory response in rats. AB - The effect of in-vivo administration of N-2-hydroxyethylpiperazine-N'-2- ethane sulphonic acid (HEPES) and taurine on rat paw oedema and reactive oxidant production was examined. Carrageenan-induced paw oedema was attenuated following intraperitoneal injection of HEPES. Chemiluminescence production by isolated peripheral blood mononuclear cells (PBMC) was reduced in HEPES-treated rats. Taurine-treated rats did not exhibit attenuation of paw oedema using subcutaneous or intraperitoneal administration but intracerebroventricular administration produced a significant reduction at a dosage of 4.0 mumol. No reduction in chemiluminescence production was observed by PBMC using subcutaneous or intraperitoneal administration of taurine, but intracerebroventricular administration produced a significant reduction at a dosage of both 0.4 and 4.0 mumol. Intravenous injection of [14C]HEPES or [3H]taurine demonstrated rapid clearance with a significantly longer half-life of HEPES compared with taurine. These results support previous reports of anti-inflammatory activity of taurine when administered centrally. The lack of anti-inflammatory effect when taurine was administered subcutaneously or intraperitoneally may be a consequence of rapid distribution or clearance. The greater anti-inflammatory effects of HEPES compared with taurine may be due to its slower distribution or clearance in-vivo. PMID- 7837045 TI - Binding potency of 6-nitroquipazine analogues for the 5-hydroxytryptamine reuptake complex. AB - The in-vitro inhibition constants (Ki) of nine structural analogues of the potent 5-hydroxytryptamine (5-HT)-uptake inhibitor, 6-nitroquipazine, were determined to assess the structure-affinity relationship of these derivatives. The goal of these studies was to determine those positions on 6-nitroquipazine that could be derivatized without significantly decreasing the affinity of the drug for the binding site, so that radiolabels such as 123I, 76Br or 18F might be appended for in-vivo imaging studies of the 5-HT reuptake system. Using bromine as a steric probe, the rank order of potency of bromine-substituted 6-nitroquipazine analogues for inhibiting the binding of [3H]paroxetine to the 5-HT reuptake binding site was: 8- < 3- < 7- < 4- < 5-bromo. The in-vitro equipotent molar ratio (EPMR, Ki (analogue)/Ki(6-nitroquipazine)) of the 5-bromo analogue was 0.57, indicating that this analogue had greater affinity for the 5-HT reuptake complex than 6-nitroquipazine. Derivatization at the 5-position with fluorine and iodine also resulted in potent compounds with EPMR values of 1.1 and 0.83, respectively. Substitution of quipazine with bromo, cyano, and formyl groups at the 6-position produced less potent compounds than the 6-nitro group. Based upon the high affinities of the 5-bromo-, 5-fluoro- and 5-iodo-6-nitroquipazines for the 5-HT reuptake complex, these compounds are candidates for radiolabeling for in-vivo studies of the 5-HT reuptake site. PMID- 7837047 TI - Cyclosporin increases the CNS sensitivity to the hypnotic effect of phenobarbitone but not ethanol in rats. AB - The purpose of this investigation was to determine whether repetitive administration of cyclosporin affects the pharmacodynamics of phenobarbitone- and ethanol-induced anaesthesia. Sabra male rats received either cyclosporin (50 mg kg-1 day-1, i.m.) for four days, or the same volume of the vehicle. Two hours after the last cyclosporin dose, phenobarbitone or ethanol solutions were infused intravenously at a constant rate until the onset of anaesthesia. Repetitive treatment with cyclosporin increased the CNS sensitivity to the hypnotic action of phenobarbitone. This was evidenced by the lower CSF phenobarbitone concentration, at the onset of the hypnotic effect, in the cyclosporin-treated group vs control values (115 +/- 4 vs 93 +/- 7 mg L-1, P = 0.01). However, the same pretreatment had no apparent effect on the pharmacodynamics of ethanol induced sleep. It is suggested that anaesthesiologists must be alert to the possible increase in brain sensitivity when placing cyclosporin patients under anaesthesia with barbiturates. PMID- 7837046 TI - Analgesic effects of callus culture extracts from selected species of Phyllanthus in mice. AB - The aim of this study was to evaluate the analgesic effect of the methanolic extract from callus culture of Phyllanthus tenellus, P. corcovadensis and P. niruri in several models of pain in mice. The extracts (medium containing 2,4 dichlorophenoxyacetic acid) of P. corcovadensis, P. niruri and P. tenellus (3-90 mg kg-1, i.p.) caused graded inhibition of abdominal constrictions induced by acetic acid (0.6%), with ID50 (i.e. dose that reduced response of control by 50%) values of about 30, 19 and > 30 mg kg-1, respectively. The extract of callus of Phyllanthus obtained in indole-3-butyric acid and indole-3-acetic acid media (3 90 mg kg-1, i.p.) caused a similar analgesic effect. In the formalin test, the extract of P. tenellus obtained in indole butyric acid medium (3-100 mg kg-1, i.p.) inhibited only the second phase of formalin-induced pain with an ID50 value of about 100 mg kg-1. Both the indole acetic acid and indole butyric acid methanolic extracts of P. tenellus and P. corcovadensis (10-100 mg kg-1, i.p.) dose-dependently inhibited both phases of formalin-induced pain (ID50 values for the second phase were approx. 100 and 52 mg kg-1, respectively). However, the extract of callus from Phyllanthus failed to affect formalin-induced paw oedema, as well as the response to radiant heat in the tail-flick test. In addition, the analgesic effect of morphine, but not the analgesic effects caused by Phyllanthus callus extract, was fully antagonized by naloxone.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7837048 TI - Effect of caffeine and nicotine on avoidance learning in mice: lack of interaction. AB - Tested alone, nicotine (0.25 or 0.5 mg kg-1) improved shuttle-box avoidance learning in mice of the CD-1 strain. Caffeine had no effect at doses of 2.5 and 5 mg kg-1 and impaired performance at a dose of 10 mg kg-1. Combinations of the two drugs did not increase avoidance responses more than nicotine alone, nor was nicotine able to attenuate performance depression induced by the highest dose of caffeine. Lack of drug interaction in the avoidance test contrasts with the occurrence of interactive effects of the two drugs in a locomotor activity test. When given in combination, caffeine and nicotine increased locomotor activity at doses ineffective by themselves. The results seem to indicate no advantage in combining caffeine and nicotine to improve active avoidance learning. PMID- 7837049 TI - Effect of addition of hyaluronic acid to highly concentrated insulin on absorption from the conjunctiva in conscious diabetic dogs. AB - Insulin absorption from the conjunctiva was investigated in five pancreatectomized diabetic mongrel dogs, with the nasolacrimal ducts occluded by micro plugs to prevent insulin absorption from nasolacrimal membrane. In the anaesthetized state, highly concentrated porcine insulin (1000 units mL-1, pH 7.4) was absorbed rapidly and significantly from the conjunctiva. Plasma immunoreactive insulin concentrations increased significantly up to 3 h after insulin administration to conjunctival membranes. Plasma glucose concentration decreased significantly compared with saline control experiments after insulin administration (10 units kg-1) at 3 h (8.3 +/- 0.1 vs 15.6 +/- 0.6 mmol, P < 0.01). However, in the conscious state, there was no significant increase in the plasma insulin levels after topical insulin administration. To improve insulin absorption in the conscious state, we examined the effect of increasing viscosity of insulin preparation with hyaluronic acid. In anaesthetized experiments, there were no significant changes in the bioavailability of insulin after addition of hyaluronate (0.84 +/- 0.11 vs 0.87 +/- 0.05%). In the conscious state, with addition of hyaluronic acid, the area under the curve of plasma insulin concentration was significantly increased (1842 +/- 383 vs 75 +/- 24 m units min L-1, P < 0.01). The bioavailability of insulin absorption was significantly increased after addition of hyaluronate (0.68 +/- 0.14 vs 0.03 +/- 0.01%, P < 0.01). From this study we could demonstrate that the conjunctiva is a potential route for insulin administration, and increased viscosity by the addition of hyaluronate was found effective in increasing the bioavailability of insulin absorption from conjunctival membrane in the conscious state. PMID- 7837050 TI - Properties of the binding sites of [3H]9-methyl-7-bromoeudistomin D in bovine aortic smooth muscle microsomes. AB - [3H]9-Methyl-7-bromoeudistomin D ([3H]MBED), a powerful caffeine-like Ca2+ releaser, binds to the caffeine binding site of terminal cisternae of skeletal muscle sarcoplasmic reticulum and activates Ca(2+)-induced Ca2+ release. Properties of the binding site of [3H]MBED were investigated in aortic smooth muscle. The specific activity was higher in microsomes than in other fractions. [3H]MBED binding sites in smooth muscle microsomes were of a single class with a high affinity (KD 50nM), comparable with that in skeletal muscle sarcoplasmic reticulum. Caffeine competitively inhibited [3H]MBED binding, indicating MBED shares the same binding site with caffeine. Solubilization and fractionation of the microsomes gave two fractions of [3H]MBED binding activities. These results suggest that, in smooth muscle, there are multiple binding sites of [3H]MBED and caffeine, which might correspond to different pharmacological actions of caffeine on smooth muscle. Therefore, [3H]MBED, which binds to the different binding sites of caffeine, is useful as a probe for investigation of the actions of caffeine at the molecular level. PMID- 7837051 TI - Tissue- and subcellular-distribution of the binding site of [3H]9- methyl-7 bromoeudistomin D, a potent caffeine-like Ca2+ releaser, in rabbits. AB - Tissue and subcellular distribution of the binding site of 3H-labelled 9-methyl-7 bromoeudistomin D ([3H]MBED), a powerful caffeine-like Ca2+ releaser, were investigated in rabbits. The order of specific activities of total homogenates was liver > brain > other tissues. All binding was completely suppressed by 10 mM caffeine, indicating that all [3H]MBED binding sites are modulated by caffeine. [3H]MBED binding sites distributed mainly in membrane fractions rather than soluble fractions in most tissues. In lung and liver, [3H]MBED binding was enriched in microsomes. [3H]MBED may be useful as a probe to investigate the actions of caffeine at the molecular level not only in muscles but also in a variety of tissues including liver, kidney and lung. PMID- 7837052 TI - An overlooked issue in health care reform. PMID- 7837053 TI - Oral rehydration therapy: a simple, effective solution. AB - Nurses assess severity of dehydration as well as prescribe and supervise oral rehydration therapy to treat the following nursing diagnosis: fluid imbalance, less than body requirements, related to diarrhea. Published literature is reviewed to address the scope of the problem in the United States, provide a historical perspective, and review the components of oral rehydration solution. The nursing management of dehydration is outlined using the nursing process. The need for further nursing research, especially related to homemade oral rehydration solution, is discussed. PMID- 7837054 TI - A study of sleep during adolescence. AB - The purpose of this comparative study was to examine differences in sleep disturbance, sleep effectiveness, and sleep supplementation, as measured by the Verran/Snyder-Halpern (VSH) Sleep Scale, according to phase of adolescence as determined by chronological age and gender. Data were collected from 116 early, 116 middle, and 116 late adolescent boys and girls in classroom settings. Two-way analyses of variance (ANOVAs) were used to analyze the data. Three statistically significant findings emerged in the analyses. First, middle adolescents had the highest level of sleep disturbance among the three groups, which was statistically significantly higher than that found in late adolescents. Second, adolescent girls reported less sleep effectiveness than adolescent boys. Third, when the amount of sleep per day was analyzed, findings indicated that adolescent boys slept more than adolescent girls. The discussion of the findings includes implications for nursing research and practice. PMID- 7837055 TI - The experience of pediatric cancer pain, Part I: Impact of pain on the family. AB - This two-part article reports on the results of qualitative data derived from the study on the impact of pediatric cancer pain on the family. Part I of this two part article explores the family caregivers' description of a child with cancer, the helplessness experienced in the management of the child's pain, and the impact of pain on the entire family. Study findings support existing literature identifying inadequate assessment and management of pediatric cancer pain. Parents identified the benefits of pain management teams for the child and for themselves. Family caregivers also identified the stresses associated with managing pain at home. Part II will describe the role of the parents in managing their child's pain. This study provided valuable information that can enable health care professionals with an opportunity to intervene not only with the child but also with the family. PMID- 7837056 TI - The experience of pediatric cancer pain, Part II: Management of pain. AB - This paper reports on the results of qualitative data derived from a study on the impact of pediatric cancer pain on the family. Part I of this two-part article reported on the family caregivers' description of a child with cancer, the helplessness experienced in the management of the child's pain, and the impact of pain on the entire family. This article will describe the role of the parents in managing their child's pain, including use of pharmacological and nondrug interventions, family caregivers' perspectives on what physicians and nurses could do to improve the care of patients in pain, and family caregivers' advice to other families when placed in a similar situation of trying to manage pediatric pain. Five major themes were identified related to the role of family caregivers in managing the child's pain. Parents also identified six major ways in which physicians and nurses could help to improve care related to pain management. Although some parents were unable to identify information that may be useful for other parents in similar situations, nine major themes were identified. Study data demonstrates the experience of family caregivers in caring for a child with cancer pain and provides health care professionals with information that can promote effective pain relief for the pediatric cancer patient with pain as well as address issues affecting the family. PMID- 7837057 TI - The impact of a grief workshop for pediatric oncology nurses on their grief and perceived stress. AB - Coping with the death of a pediatric patient with whom the nurses has developed a close relationship is reported by nurses as the most stressful experience of being a pediatric nurse. Such losses are inevitable for a pediatric nurse regardless of subspecialty and can contribute to a nurse leaving the specialty or the discipline. To prevent those consequences, nurses' grief needs to be acknowledged, and their grieving needs to be facilitated. The purpose of this study was to determine the impact of a grief workshop on grief symptoms and perceived stress in two groups of pediatric oncology nurses who differed in years of experience in the specialty. Study findings indicated that the workshop affected the two groups differently, with the more experienced nurses reporting significantly higher stress levels after the workshop than did the less experienced nurses. Study findings are interpreted and recommendations for future work are offered. PMID- 7837058 TI - Parents of children with asthma: an examination of family hardiness, family stressors, and family functioning. AB - As the incidence, severity, and mortality associated with asthma has risen, the numbers of families caring for children has grown. This study used a descriptive correlational design to examine relationships among family hardiness, family stressors, and family functioning in families of children with asthma using the Resiliency Model of Family Stress, Adjustment, and Adaptation. The Family Hardiness Index, Family Stress Index, and Faces II instruments were completed by 27 parents of children with asthma. Correlations were found to be significant. Family type was also determined. PMID- 7837059 TI - A consumer's guide to causal modeling: Part II. AB - Causal modeling is a widely used technique for specifying a system of relationships among theoretical constructs. However, there are cautions or limitations that must be considered with this technique. Consumers of research that uses causal modeling techniques must evaluate the model testing results on several levels before using the findings in future research or in practice. A good fit between the model and the data does not necessarily mean that all the relationships are as posited. For the researcher intending to use causal modeling in an appropriate study, the most serious limitation of the technique is the large number of subjects required for the analysis, resulting in expensive and logistically complex studies. However, given the nature of many of the phenomena of interest to nursing, causal modeling often proves to be a highly useful technique for knowledge development. PMID- 7837060 TI - Schools and health: a partnership for a healthier future. PMID- 7837061 TI - The IV Bubbles and Boards System. PMID- 7837062 TI - Discharge education for parents of infants with tracheostomies. PMID- 7837063 TI - Coping in relation to self-care behaviors and control of blood glucose levels in Japanese teenagers with insulin-dependent diabetes mellitus. PMID- 7837064 TI - Current trends in the use of intraocular lenses in children. AB - We present an overview of current practice patterns as they apply to intraocular lens (IOL) implantation in children. Two hundred and thirty-four members of the American Association for Pediatric Ophthalmology and Strabismus (AAPOS) and 1,039 members of the American Society of Cataract and Refractive Surgery (ASCRS) responded to a questionnaire. Forty-six percent of AAPOS respondents and 27% of ASCRS respondents reported that they are currently implanting IOLs in children. Although the majority have implanted lenses in children older than six years, 16 AAPOS members and 41 ASCRS members reported implanting IOLs in patients in their first two years of life. Eighty-four percent of the respondents use the continuous curvilinear capsulorhexis technique of anterior capsulotomy in children. When a primary posterior capsulotomy is performed, 63 ASCRS surgeons (38%) reported using posterior continuous curvilinear capsulorhexis. Fixation of an IOL in the ciliary sulcus in a child was acceptable to 67% of the surgeons; however, 86% would not consider implanting an anterior chamber IOL in a child. Implications of the survey data are discussed. PMID- 7837065 TI - Intraocular lenses for pediatric implantation: biomaterials, designs, and sizing. AB - Posterior chamber intraocular lenses (IOLs) are being implanted in children with increasing frequency. However, with rare exceptions, only IOLs designed for adults are currently available. These lenses may be difficult to insert into small eyes. Since the pediatric crystalline lens is smaller than that of adults and because the capsular bag does not continue to grow after lensectomy, it is worthwhile to determine the biomaterials, designs, and sizes that may be appropriate for pediatric implantation. In a study of 50 pediatric eyes obtained postmortem, we have documented an estimated growth curve for the developing crystalline lens between birth and 16 years of age. Ninety percent of crystalline lens growth occurs during the first two years of life. Based on these data and this study using the Miyake posterior view analysis of implanted standard and prototype IOLs, we recommend the following: Clinical trials of capsular IOLs, downsized to approximately 10.0 mm diameter, are appropriate for children under two years of age. Capsular IOLs are defined as flexible open-loop, one-piece, all poly(methyl methacrylate), modified C-loop designs made specifically for in-the bag placement. Because the rapid growth phase of the lens is complete by the age of two, we believe that downsizing the IOL is not necessary after this age unless axial length measurements indicate an unusually small eye. Standard flexible 12.0 mm to 12.5 mm diameter capsular IOLs can be safely implanted. Such lenses could be tolerated throughout life, obviating the need for later IOL exchange. PMID- 7837066 TI - Intraocular lens implantation in infants with congenital cataracts. AB - We evaluated 21 eyes of 13 infants between two and eight months old who had primary posterior chamber intraocular lens (IOL) implantation for congenital cataracts between 1988 and 1993. Twelve eyes had a posterior capsulorhexis or plaque peeling at the time of implantation and one eye had a vitrectomy. Eight eyes had no posterior capsule procedure during the initial surgery. Follow-up ranged from six months to five years. All eyes developed one or multiple posterior synechias and all, except one, required secondary capsulectomy and vitrectomy between one month and one year. Twenty eyes attained stable IOL fixation and a clear visual axis. In one eye, the IOL decentered downward. Patients with bilateral cataracts had greater visual improvement than those with a cataract in one eye only. No patient could manage spectacles postoperatively. Our findings show the benefits of posterior capsulectomy and anterior vitrectomy done in the early postoperative period and that IOL implantation in infants is a reasonable treatment in some parts of the world. PMID- 7837067 TI - Cataract surgery in children with capsulorhexis of anterior and posterior capsules and heparin-surface-modified intraocular lenses. AB - Cataract surgery was performed in 21 eyes in 14 children (one to 12 years, 5.6 +/ 4.0 [mean +/- SD]). Cataract surgery was standardized and included capsulorhexis of the anterior capsule, irrigation/aspiration of the nucleus and cortex, puncture of the posterior capsule, injection of sodium hyaluronate (Healon GV, 14 mg/ml) between the posterior capsule and the vitreous, and capsulorhexis of the posterior capsule. At the end of the procedure, a heparin-surface-modified (HSM) poly-(methyl methacrylate) intraocular lens (IOL) was implanted in the capsular bag. Follow-up ranged from four to 16 months. No complications such as the appearance of vitreous in the anterior chamber occurred during surgery. A mild postoperative inflammation was seen in all cases. Opacification of the visual axis was seen in one eye ten months after surgery. Posterior synechial formation was seen in one eye. Our results suggest that capsulorhexis of the anterior and posterior capsules with implantation of an HSM IOL in the capsular bag is a safe procedure in children and produces good postoperative results. PMID- 7837068 TI - Comparison of mechanized anterior capsulectomy and manual continuous capsulorhexis in pediatric eyes. AB - Performing a continuous curvilinear capsulorhexis (CCC) can be more difficult in children than in adults because the capsular bag is more elastic. In this study we compared two capsulectomy techniques in pediatric eyes: creating a mechanized circular anterior capsulectomy using a vitrector and creating a conventional smooth-edged curvilinear tear or CCC using a forceps or needle. We used 18 pairs of eyes (36 eyes) obtained postmortem from children ranging in age from four days to 16 years. The mechanized vitrector-cut capsulectomy was unsuccessful in only one eye (from a 16-year-old child) in which a radial tear developed. Manual CCC was unsuccessful in six eyes, all from children less than five years of age. We conclude that mechanized circular capsulectomy is not only easier to perform in very young eyes than manual CCC, but it is also safe and creates a capsular opening that resists radial tearing. This mechanized technique gives the surgeon an alternative to use in pediatric eyes in which standard manual CCC may be difficult to perform and control. PMID- 7837069 TI - Pediatric cataract surgery and intraocular lens implantation techniques: a laboratory study. AB - The use of primary posterior capsulectomy and anterior vitrectomy during pediatric intraocular lens (IOL) implantation has been advocated as a means of preventing the development of posterior capsule opacification. In this study, we used pediatric eyes obtained postmortem to compare two different sequences in the surgical procedure: (1) anterior capsulectomy, lens substance removal, primary posterior capsulectomy with anterior vitrectomy, and IOL implantation in the capsular bag; (2) anterior capsulectomy, lens removal, IOL implantation in the capsular bag, and primary posterior capsulectomy with anterior vitrectomy. Both sequences could be safely performed in the laboratory setting while maintaining stable capsular fixation of the IOL. Placing the IOL in the capsular bag was easier when the posterior capsule was intact (sequence 2). However, both techniques appear feasible for clinical use. Surgeons not familiar with mechanized primary posterior capsulectomy can gain clinically relevant experience by operating on pediatric autopsy eyes in a laboratory setting. PMID- 7837070 TI - Six-month results of the multicenter phase I study of excimer laser myopic keratomileusis. AB - We report six-month results of the Summit Technology Myopic Keratomileusis Phase I multicenter study. Fifty-seven eyes of 57 patients had keratomileusis to correct high myopia. A microkeratome was used for the primary keratectomy and the excimer laser was used to ablate the stroma of the resected lenticle (cap) or the stromal bed (in situ). At six months, 31 of the 47 eyes available for follow-up (65.9%) had uncorrected visual acuity of 20/40 or better; 16 (34.0%) had uncorrected acuity of 20/25 or better. Thirty-seven eyes (78.7%) maintained the same (+/- one Snellen line) best corrected visual acuity as before surgery; seven (14.9%) lost two lines and three (6.4%) lost more than two lines. In addition to the six-month multicenter study results, we report two year results in a subset of 28 eyes (22 from the multicenter study and six fellow eyes). At six months, 17 of the 24 eyes available for follow-up (70.9%) had uncorrected visual acuity of 20/40 or better and nine (37.5%) had uncorrected acuity of 20/25 or better, including eyes that had worse than 20/80 best corrected visual acuity preoperatively. At 24 months, five of the seven eyes available for follow-up (71.4%) had uncorrected acuity of 20/25 or better. Only one patient lost two lines of best corrected vision at six months and no patient lost more than two lines; at 24 months, all patients maintained (+/- one line) best corrected vision.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7837071 TI - Topographical evaluation of centration of excimer laser myopic photorefractive keratectomy. AB - We evaluated the centration of excimer laser myopic photorefractive keratectomy by analyzing the corneal topography in 60 eyes of 37 patients. Computer-assisted analysis of corneal topography was performed preoperatively and one week postoperatively. The distance and the direction from the center of the entrance pupil to the center of the ablation was calculated using a personal computer. Downward displacement of the ablation relative to the center of the entrance pupil was observed in 51 eyes (85%). The mean distance of the center of the ablation from the center of the entrance pupil was 0.51 +/- 0.31 mm (range 0.06 mm to 1.64 mm). To achieve more precise centration, we recommend applying an eye movement tracking system to photorefractive keratectomy. PMID- 7837072 TI - Effect of cataract surgery on contrast sensitivity and glare in patients with 20/50 or better Snellen acuity. AB - The effect of cataract surgery was assessed in 103 patients whose visual acuity, as measured in dim light and with high contrast Snellen letters, was 20/50 or better. The patients desired cataract surgery. They complained of glare symptoms, had given up driving at night, or both. Contrast sensitivity was measured under simulated night conditions with a calibrated Vistech MCT 8000 device. No patient who had a contrast sensitivity of less than 27 at 6 cycles per degree (20/70 "equivalent acuity") had cataract surgery. The mean preoperative contrast sensitivity function showed abnormally low values for all frequencies (cycles/degree) tested. Postoperatively the values returned to normal. Of 99 patients who answered a postoperative questionnaire, 41 (41%) had been driving at night preoperatively and 80 (80%) were driving at night postoperatively. A control group of 24 noncataractous patients (48 eyes) was in the normal range of the test device used. These results support the view that the benefits of cataract surgery are not well predicted by Snellen acuity, even though functional vision may be significantly reduced. PMID- 7837073 TI - Relative strength of scleral corneal and clear corneal incisions constructed in cadaver eyes. AB - Square scleral corneal, square clear corneal, and rectangular clear corneal incisions were constructed in six cadaver eyes that had no previous intraocular surgery. The 3.2 mm or smaller wounds had sutureless closures. To determine their relative abilities to resist leakage and iris prolapse, eyes were tested at external pressures of up to 525 pounds per square inch (psi) at one of two intraocular pressure (IOP) ranges: 10 to 15 mm Hg or 20 to 25 mm Hg. The square scleral corneal (3.2 mm x 3.2 mm) and square clear corneal wounds (3.2 mm x 3.2 mm, 2.0 mm x 2.0 mm, 1.0 mm x 1.0 mm) withstood external pressure without effect at both IOP ranges, up to the maximum 525 psi. This level of external pressure was far greater than pressures withstood by rectangular clear corneal wounds, especially the wound usually constructed in clinical practice (3.2 mm x 2.0 mm), which leaked and demonstrated iris prolapse at 13 psi at the lower IOP. The square clear corneal wounds that were stable at 525 psi, however, are either clinically impractical (visual axis encroachment from 3.2 mm x 3.2 mm wound) or not technologically feasible until the size of phacoemulsification tips and intraocular lenses can be further reduced. Thus, of the procedures for small incision cataract surgery presently in use, the square scleral corneal incision with 1.5 mm internal corneal lip appears to offer greater stability and safety than the conventional rectangular clear corneal incision (3.2 mm x 2.0 mm). PMID- 7837074 TI - Astigmatic changes after cataract surgery with 5.1 mm and 3.5 mm sutureless incisions. AB - We evaluated postoperative keratometric astigmatism in 80 eyes that had phacoemulsification and intraocular lens implantation through sutureless corneal incisions. The eyes were separated into two groups based on the use of rigid ovoid or foldable silicone lenses inserted through 5.1 mm corneal lip incisions or 3.5 mm lip incisions, respectively. In the early postoperative period (one to three months), vector analysis showed less induced astigmatism in the 3.5 mm group than in the 5.1 mm group. Uncorrected visual acuity during the postoperative period was also better in the smaller incision group. PMID- 7837075 TI - Endocapsular hematoma with biconvex posterior chamber intraocular lenses. AB - We describe ten cases of endocapsular hematoma that developed in the early postoperative period after cataract or combined glaucoma and cataract surgery. After capsulorhexis and phacoemulsification, one of three types of posterior chamber lenses with biconvex optics was implanted in nine eyes. In one eye, a convex-plano poly(methyl methacrylate) lens was implanted. All lenses were implanted in the bag. Postoperatively, an anterior chamber hyphema was observed in four eyes and erythrocytes in another five. Subsequently observed endocapsular hematomas disappeared gradually over the next several months. A narrow space was visible between the posterior optic surface and the posterior chamber in all eyes with a biconvex lens. We believe that blood from the hematoma seeped behind the anterior capsular leaf into that space. A YAG capsulotomy was not necessary in any case. PMID- 7837076 TI - In vitro organotypic culture method to evaluate the biocompatibility of heparin surface-modified intraocular lenses. AB - Using an organotypic culture method, we evaluated the biocompatibility of two kinds of intraocular lenses: conventional poly(methyl methacrylate) (PMMA) and heparin-surface-modified (HSM) PMMA. Chicken corneal endothelium from embryos incubated for 14 days was placed on an agar medium and covered with one of three types of materials: PMMA, HSM PMMA, and a control, Thermanox. Experiments at five different times measured cell migration, cell multiplication, and cell adhesion. Scanning electron microscopy showed a low level of corneal endothelial adhesion on the HSM IOL surface. There was a significant difference between the HSM and untreated lenses in migration surface and cell density, with the HSM lenses having better biocompatibility. PMID- 7837077 TI - Collagen types in human posterior capsule opacification. AB - The fibrous type of human posterior capsule opacification was examined by electron microscopy and immunoelectron microscopy to determine which types of collagen were present. The opacification consisted of lens epithelial cells and a large amount of extracellular matrix. The extracellular matrix comprised collagen fibrils and basal lamina-like material. Immunoelectron microscopy revealed that collagen types I, III, and IV were present. Types I and III were localized to the collagen fibrils. Type IV was present in the basal lamina of the lens epithelial cells and in the basal lamina-like material of the extracellular matrix. PMID- 7837078 TI - Cataract extraction and intraocular lens implantation in an infant with a monocular congenital cataract. AB - A cataract extraction and primary capsulotomy with intraocular lens (IOL) implantation was performed on a 17-day-old infant with a monocular mature congenital cataract. The IOL power, calculated at the time of surgery, was undercorrected to compensate for the growth of the eyeball. Two additional surgical procedures were required to resolve visual axis obstruction caused by lens epithelial cell proliferation. Follow-up was 18 months, during which amblyopia prevention therapy was instituted. PMID- 7837079 TI - Clear lens extraction and intraocular lens implantation in a patient with bilateral anterior lenticonus secondary to Alport's syndrome. AB - We describe bilateral phacoemulsification and implantation of foldable silicone intraocular lenses in a 25-year-old woman with Alport's syndrome and severe anterior lenticonus. Contrary to previous reports of lens capsule fragility in Alport's syndrome, this patient had relatively tough capsules, as do most patients her age. Apart from the tough capsules and positive pressure, which required the use of a viscoelastic to maintain the anterior chamber, the surgeries were unremarkable. The patient achieved excellent visual and refractive results. PMID- 7837080 TI - Myopic shift after removal of Salzmann's nodular degeneration. AB - A patient with bilateral Salzmann's nodular degeneration developed a myopic shift of 9 diopters in the right eye and 5 diopters in the left eye after removal of his nodules. This previously unreported complication of removal of peripheral corneal pathology is discussed in light of our current understanding of keratorefractive surgery. PMID- 7837081 TI - Posterior capsulorhexis with optic capture: maintaining a clear visual axis after pediatric cataract surgery. AB - We describe a technique for preventing secondary membrane formation after pediatric cataract extraction. This technique involves capture of an intraocular lens (IOL) optic through a posterior curvilinear capsulorhexis opening in an attempt to maintain a clear visual axis in children after cataract surgery. This maneuver ensures centration of the posterior chamber IOL because the haptics remain in the capsular bag and the optic is captured in the posterior capsular opening. Also, the need for an anterior vitrectomy may be eliminated. Apposition of the anterior and posterior capsule leaflets anterior to the optic may limit the migration of Elschnig pearls, reducing the incidence of secondary membranes and the need for additional procedures. PMID- 7837082 TI - Consultation section. Postoperative atonic pupil following seemingly routine cataract extraction. PMID- 7837083 TI - Radial keratotomy on keratoconus: a question of safety. PMID- 7837084 TI - Gentamicin in ocular irrigating solutions. PMID- 7837085 TI - Young's modulus of elasticity for the human cornea. PMID- 7837086 TI - Mechanism of phacoemulsification. PMID- 7837087 TI - Clear lens extraction. PMID- 7837088 TI - Clear lens extraction. PMID- 7837089 TI - Potential risks of endocapsular polymerization. PMID- 7837090 TI - Collagen shields in cataract surgery. PMID- 7837091 TI - Control of study variables. PMID- 7837092 TI - Intraocular lens exchange on day one after surgery. PMID- 7837093 TI - The effect of intracellular anions on ATP-dependent potassium channels of rat skeletal muscle. AB - 1. We have used excised inside-out patches to study the effects of anions bathing the cytoplasmic surface of the membrane on ATP-dependent K+ channels of rat flexor digitorum brevis muscle. Channels were closed by ATP applied to the cytoplasmic face of the patch with a concentration for half-closure (Ki) of 14 microM, were highly selective for K+ and had unitary conductances of 62 pS in symmetrical 155 mM K+ and 27 pS in 5 mM [K+]o. 2. In 139 mM Cl- internal solution channel activity declined rapidly after excision of the patch. Inclusion of 40 mM potassium gluconate (substituted for KCl) in the solution both restored channel activity and greatly slowed its subsequent run-down. 3. The action of gluconate was concentration dependent. The effect did not involve a change in ATP binding, since the Ki for ATP was not significantly changed by gluconate, and was specific for the cytoplasmic face of the patch. 4. The anions pyruvate, lactate and acetate were all able to restore channel activity after run-down, though less well than gluconate, while sulphate and methylsulphate were without effect. 5. Analysis of single channel kinetics showed that gluconate did not affect mean open lifetime, but led to a decrease in the number and duration of long closings. 6. Anions are most likely to act by stabilizing the structure of the channel protein. Changes in the intracellular concentration of certain anions may play a role in regulating channel activity. PMID- 7837094 TI - Changes in potassium channel activity following axotomy of B-cells in bullfrog sympathetic ganglion. AB - 1. Whole-cell and microelectrode voltage-clamp techniques were used to investigate the changes in ionic currents and action potential shape that follow axotomy of bullfrog paravertebral sympathetic ganglion B-cells. 2. Axotomy increased M-conductance (gM; muscarine-sensitive, voltage- and time-dependent K+ conductance) by 35% at -30 mV and slowed its deactivation kinetics. 3. The delayed rectifier K+ current (IK; at +50 mV) was reduced in axotomized neurones to 61% of control without any change in activation or deactivation kinetics. Steady-state intracellular Ca2+ levels and leak conductance were unchanged. 4. The fast, voltage-sensitive, Ca(2+)-activated K+ current (IC), evoked from -40 mV, was decreased to about 71% of control (at +30 mV) in axotomized neurones, whereas that evoked from -80 mV was largely unaffected. IC kinetics were also similar in control and axotomized neurones. This suggests that IC channels are not changed after axotomy. 5. In axotomized neurones, commands to +10 from -40 mV had to be extended by 16 ms to evoke voltage-insensitive Ca(2+)-dependent K+ current (IAHP) responses that were similar in magnitude to those observed in control cells. 6. The previously documented, axotomy-induced decrease in Ca2+ current (ICa) due to increased resting inactivation can account for the reduction in IC and IAHP and for the change in the shape of the action potential. PMID- 7837095 TI - Counter-transport of potassium by the glutamate uptake carrier in glial cells isolated from the tiger salamander retina. AB - 1. To investigate the transport of potassium on the glutamate uptake carrier, the glutamate uptake current in isolated retinal Muller cells was monitored by whole cell clamping, while measuring changes of potassium concentration outside the cells ([K+]o) with an ion-sensitive microelectrode. 2. Activating glutamate uptake led to an accumulation of potassium outside the cells, consistent with the hypothesis, based on less direct evidence, that the glutamate uptake carrier transports potassium out of the cell. 3. The glutamate-evoked rise of [K+]o showed the pharmacology and sodium dependence of glutamate uptake. 4. The rise in [K+]o was proportional to the uptake current flowing between 0 and -80 mV, implying that the ratio of K+ transported to charge transported by the uptake carrier is constant over this voltage range. The K+ to charge transport ratio was the same for uptake of D-aspartate and L-glutamate. 5. By clamping cells with pipettes containing solutions of different [K+], the dependence of the glutamate and aspartate uptake currents on intracellular [K+] was determined. L- and D aspartate transport showed a smaller maximum uptake current (Imax), and a smaller apparent Michaelis constant (Km) for activation by intracellular K+, than did L glutamate transport. The ratio of Imax to Km was the same for these three analogues, a result which can be predicted from simple models of the carrier's operation. 6. Fully activating glutamate uptake in Muller cells in the intact retina would produce a K+ load into the extracellular space of about 0.6 mM s-1. Suppression of glutamate release from photoreceptors by light will reduce K+ efflux from Muller cells in the outer retina; this may contribute to the light evoked fall of [K+]o observed in the outer retina, and thus contribute to shaping the electroretinogram. PMID- 7837096 TI - Direct patch recording from identified presynaptic terminals mediating glutamatergic EPSCs in the rat CNS, in vitro. AB - 1. An in vitro brainstem slice preparation of the superior olivary complex has been developed permitting patch recording from a presynaptic terminal (calyx of Held) and from its postsynaptic target--the principal neurone of the medial nucleus of the trapezoid body (MNTB). 2. The fluorescent stain DiI (1,1' dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate) was used in fixed tissue and Lucifer Yellow in living slices, to identify calices enclosing single MNTB neuronal somata. 3. Whole-cell recording from the MNTB neurone shows evoked EPSCs preceded by a prespike, corresponding to the presynaptic action potential (AP). In some cases one patch pipette recorded from both pre- and postsynaptic elements, but confirmation of exclusively presynaptic recording was obtained using pipettes containing Lucifer Yellow in a further eleven cases. 4. Under current clamp, the pre- and postsynaptic sites could be distinguished by their response to step depolarizations; presynaptic terminals generated a train of APs at frequencies up to 200 Hz, while MNTB neurones gave a single AP. Each presynaptic AP had an after-hyperpolarization lasting less than 2 ms. 5. Under voltage clamp, step depolarizations of presynaptic terminals generated a tetrodotoxin-sensitive inward current followed by rapidly activating outward potassium currents at potentials more positive than -60 mV. The outward current exhibited little inactivation over the 150 ms steps and 4-aminopyridine (200 microM) blocked 63.0 +/- 14.5% (mean +/- S.D., n = 3) of the sustained current at 0 mV. Like the squid giant synapse, mammalian terminals express rapidly activating 'delayed rectifier'-type potassium currents. PMID- 7837097 TI - Inhibitory synaptic potentials in guinea-pig substantia nigra dopamine neurones in vitro. AB - 1. The properties of stimulus-evoked and spontaneous inhibitory synaptic potentials were examined in guinea-pig substantia nigra dopamine neurones in sagittal and coronal midbrain slices in the presence of glutamate receptor antagonists. 2. Focal electrical stimulation within the substantia nigra, cerebral peduncle, internal capsule or the striatum evoked a biphasic IPSP consisting of a fast and a slow component, with peak latencies of about 30 and 250 ms, respectively. The fast component was sensitive to chloride injection, reversed polarity at -79.4 +/- 1.1 mV and was blocked by the GABAA receptor antagonists picrotoxin and bicuculline. The slow IPSP reversed at -99.3 +/- 5.4 mV and was blocked by the GABAB receptor antagonists 2-hydroxysaclofen and CGP 35348. 3. Spontaneous IPSPs were observed in many neurones. These events reversed polarity at -77.5 +/- 2.6 mV and were completely blocked by bicuculline and/or picrotoxin. In the presence of TTX, small spontaneous events remained which probably represent miniature IPSPs. In coronal slices, application of 4 aminopyridine raised the frequency of spontaneous IPSPs, presumably by activating nigral interneurones, but failed to reveal spontaneous biphasic IPSPs or spontaneous pure slow IPSPs. 4. The amplitude of the fast IPSPs fluctuated from trial to trial. Amplitude histograms of minimal fast IPSPs displayed evenly spaced peaks, suggesting that synaptic transmission is quantal at these synapses. The measured peak spacing depended on the driving force for Cl-. 5. The fast IPSP showed little or no paired-pulse depression, and in the presence of 2 hydroxysaclofen (400-600 microM) showed paired-pulse facilitation. The GABAB agonist baclofen inhibited the fast IPSP via a presynaptic mechanism. The pharmacologically isolated slow IPSP showed marked paired-pulse facilitation. 6. It is concluded that synaptic inhibition in the substantia nigra is mediated by GABA, is relatively resistant to frequency-dependent depression and is regulated by presynaptic GABAB autoreceptors. Striatonigral and pallidonigral fibres activate both GABAA and GABAB receptors, while intranigral pathways appear to activate predominantly GABAA receptors. PMID- 7837098 TI - Na(+)-H+ exchange in frog early distal tubule: effect of aldosterone on the set point. AB - 1. Intracellular pH (pHi) regulation was investigated in frog early distal tubule. Single tubules were dissected and perfused, such that the compositions of apical and basolateral solutions could be varied independently. pHi was measured using the fluorescent probe 2',7'-bis(carboxyethyl)-5,6-carboxyfluorescein (BCECF). 2. Brief exposure to NH4+ on the basolateral aspect of the tubules elicited an intracellular acidification, followed by an active recovery. The recovery was inhibited by amiloride and its analogue 5-(N-ethyl-N-isopropyl) amiloride (EIPA) when added to the basolateral, but not the apical, solution. Omission of Na+ from the basolateral solution alone completely inhibited pHi recovery. Thus the Na(+)-H+ exchangers appear to be located on the basolateral membrane. 3. Neither amiloride nor EIPA had any effect on pHi under control conditions, suggesting that the activity of the Na(+)-H+ exchangers at the resting pHi is low. However, removal of basolateral Na+ caused an acidification that was blocked by amiloride, indicating that the Na(+)-H+ exchangers can be activated from the resting state. 4. Intrinsic buffering power (beta i) was determined by stepwise removal of ammonium from the cells in Na(+)-free conditions, to prevent pH regulation, and in the presence of Ba2+ and furosemide (frusemide), to inhibit ammonium transport. beta i was a function of pHi, increasing as pHi decreased. 5. Proton efflux was calculated during the recovery from an acid load in tubules from normal and K(+)-loaded frogs and in tubules which had been incubated for 30 min with aldosterone. Potassium loading produces a chronic increase in plasma aldosterone. Both acute and chronic aldosterone treatment caused an intracellular alkalinization. This was due to an alkaline shift in the set-point of the basolateral Na(+)-H+ exchanger, with no change in the density and/or turnover rate. PMID- 7837099 TI - Segmental differences in the effects of guanylin and Escherichia coli heat-stable enterotoxin on Cl- secretion in human gut. AB - 1. Mucosally added synthetic guanylin and Escherichia coli heat-stable enterotoxin (STa) increased short-circuit current (ISC) across isolated muscle stripped human intestine in vitro. 2. Serosal bumetanide inhibited ISC responses indicating that guanylin and STa stimulate electrogenic chloride secretion. 3. ISC responses were markedly greater in the colon than in the jejunum. 4. Pretreatment with indomethacin did not significantly alter the effects of guanylin and STa. 5. Both peptides induced concentration-dependent increases in the cyclic GMP content of human intestinal mucosa in vitro; cyclic AMP levels remained unchanged. 6. In contrast to ISC responses, increases in cyclic GMP content induced by guanylin and STa were markedly greater in the jejunum than in the colon. 7. Sodium nitroprusside (SNP) but not human alpha-atrial natriuratic peptide (CDD/ANP(99-126)) increased chloride secretion in human intestine; both agents induced small increases in intestinal cyclic GMP content. 8. Guanylin, STa and the nitric oxide (NO) donor SNP increased electrogenic chloride secretion across human intestinal mucosa in vitro by stimulation of cyclic GMP. The discrepancy between the effects on chloride secretion and intracellular cyclic GMP content suggest different cellular action sites of guanylin and STa in human small and large intestine. PMID- 7837100 TI - Alteration of the physiological responses to indomethacin by endotoxin tolerance in the rat: a possible role for central vasopressin. AB - 1. Previous studies suggest that arginine vasopressin (AVP) is released into the ventral septal area (VSA) of the rat brain during the antipyresis induced by the cyclo-oxygenase inhibitor indomethacin. In addition, there is evidence for increased AVP transmission in the VSA of animals having a reduced pyretic response following three intravenous injections of bacterial endotoxin (LPS) (endotoxin tolerant). Since ventral septal AVP receptors can also become 'sensitized' following exposure to AVP, we questioned whether the antipyretic action of indomethacin would increase, via an action involving central AVP, if this drug were administered into LPS-tolerant rats. 2. Intraperitoneal indomethacin (7.5 mg kg-1) was effectively antipyretic when administered 2 h after an intravenous challenge with LPS (50 micrograms kg-1) into conscious unrestrained rats. This dose of indomethacin had no effect on the core temperature of non-febrile rats given intravenous 0.9% pyrogen-free saline. 3. Three intravenous injections of LPS over a period of 3 days resulted in rats that were tolerant to the pyrogenic effects of LPS. When indomethacin was administered 2 h following the third LPS injection, a dose-dependent hypothermia was observed. This effect was age dependent, as profound hypothermia was seen in 8 week but not 20 week old rats. 4. A mortality rate of 41% (P = 0.02) was observed within 24 h of indomethacin treatment in 8 week old tolerant rats compared with 0% in 8 week old non-tolerant and 20 week old tolerant rats.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7837101 TI - Primary afferent depolarization of cat pudendal afferents during micturition and segmental afferent stimulation. AB - 1. This investigation examined primary afferent depolarization (PAD) of perineal afferents during micturition and evoked by electrical stimulation of perineal, hindlimb cutaneous and muscle-nerves. PAD was inferred from changes in excitability of spinal terminals of single afferents in decerebrate and chloralose-anaesthetized paralysed male cats. Observations were made on perineal afferent fibres travelling in the sensory branch of the pudendal (SPud) and superficial perineal (SPeri) nerves. 2. Micturition was evoked by distension of the bladder and excitability changes were measured in twenty-seven SPud afferents. In ten afferents, there was evidence of PAD during micturition. The time course of PAD was similar to the period of decreased activity in sphincter muscle efferents during micturition. In four afferents, there was decreased excitability during voiding that was interpreted as removal of tonic PAD. In the remaining thirteen afferents there were no detectable changes in excitability. Bladder distension in the absence of micturition failed to change the excitability of any SPud afferents tested. 3. Almost all SPud afferents were subject to PAD upon stimulation of cutaneous nerves. Superficial perineal, long saphenous, caudal cutaneous sural and the predominantly cutaneous posterior tibial nerves were particularly effective in evoking PAD. While group I strength stimulation of hindlimb muscle-nerves produced PAD of some SPud fibres, group II stimulation often increased the magnitude or incidence of PAD. The patterns and magnitude of PAD observed in SPeri afferents were similar to those observed in SPud afferents. 4. Since some SPud afferents were subject to PAD during micturition, PAD is probably one mechanism responsible for suppression of sphincter reflexes during micturition. Additional roles of PAD of perineal afferents evoked by activation of hindlimb cutaneous and muscle afferents are discussed. PMID- 7837102 TI - Inputs to group II-activated midlumbar interneurones from descending motor pathways in the cat. AB - 1. Connections from descending motor pathways to group II-activated interneurones in the midlumbar segments of the spinal cord have been examined by intracellular recording. Interneurones, many of which had axonal projections to the hindlimb motor nuclei, were tested for inputs from rubro-, reticulo-, vestibulo- or corticospinal fibres. 2. Of 138 cells, 113 were monosynaptically excited by electrical stimulation of at least one of the descending motor pathways. Monosynaptic excitation from reticulo-, vestibulo- and rubrospinal pathways was common. Monosynaptic corticospinal EPSPs were identified in fewer neurones. 3. Convergent monosynaptic inputs from pathways which descend in the ventrolateral and ventral funiculi were common. Although few neurones with monosynaptic input from the corticospinal tract were identified, most also had monosynaptic rubrospinal input. In contrast, few neurones (4.3%) had convergent monosynaptic input both from pathways in the dorsolateral funiculus and from fibres in the ventral/ventrolateral funiculi. 4. The patterns of convergence from the different descending motor pathways differ from the patterns expected if the descending connections were distributed independently. Thus there is a significant segregation between rubrospinal and reticulo- or vestibulospinal inputs, and a significant association of reticulo- and vestibulospinal inputs. 5. Since descending motor pathways make monosynaptic connections with most group II activated midlumbar neurones, many of which project to the hindlimb motor nuclei, some of these neurones provide a disynaptic pathway for the supraspinal control of hindlimb movements. The distribution of descending connections is consistent with the hypothesis that pathways descending in the dorsal part of the lateral funiculus and those descending in the ventrolateral or ventral funiculi contact different sets of interneurones. PMID- 7837103 TI - Directional asymmetries in the length-response profiles of cells in the feline dorsal lateral geniculate nucleus. AB - 1. The visual cortex provides a major synaptic input to the dorsal lateral geniculate nucleus (dLGN). Cortical layer VI cells giving rise to this projection are strongly influenced by stimulus orientation, length and direction of motion. In the dLGN, a significant component of the strong length tuning exhibited by most cells follows from the corticofugal influence. We have now checked whether there are directional biases in geniculate cell responses, and whether such biases are influenced by stimulus length. 2. The responses of A-laminae dLGN cells were assessed by single-unit extracellular recording. Length preference was examined by plotting multihistogram length-tuning curves to moving bars of light of various length. 3. Over half of the cells tested (100/183) exhibited directional bias and in many cases, this bias was highly dependent on bar length, resulting in radically different length response profiles for the two directions of motion. These asymmetries are similar to those documented for cortical hypercomplex cells, but do not equate to any known facet of the centre-surround organization of dLGN cell receptive fields. 4. We suspected the directional biases followed from the influence of the corticofugal projection. To test this, we recorded from preparations where areas 17 and 18 of the visual cortex had been removed. Surprisingly, a similar proportion of cells exhibited directional biases after removal of the corticofugal input, suggesting that the biases are generated subcortically. 5. The widespread presence of systematic biases in the response profiles of dLGN cells further underlines the possibility that geniculate mechanisms may make a far greater contribution to visual processing than hitherto suspected. PMID- 7837104 TI - Limited independent flexion of the thumb and fingers in human subjects. AB - 1. We investigated whether human subjects can activate selectively flexor pollicis longus (FPL) and digital portions of flexor digitorum profundus (FDP). These muscles were selected because they are the only flexors of the distal phalanges. 2. Electromyographic activity (EMG) was recorded with intramuscular electrodes from one digital component of the deep flexors ('test') while subjects lifted weights by flexing the distal interphalangeal joint of the other digits in turn ('lifting' digits). Only recording sites at which single motor units were recruited selectively at low forces were used. The weights lifted represented 2.5 50% of the maximal voluntary contraction (MVC). We measured the lowest weight lifted which produced phasic and tonic coactivation in the 'test' muscle. 3. The extent of coactivation varied with the 'distance' between the test and lifting digits although no significant difference occurred in the pattern of coactivation thresholds among the digital flexors. The extent of coactivation increased when angular displacement or velocity at the distal interphalangeal joint of the lifting digit increased but was not critically dependent on restraint of the hand. 4. Because mechanical 'connections' could interfere with the ability to move a distal phalanx independently, the arms of nine cadavers were studied. The separation of tendons between the thumb (FPL) and the index portion of FDP, and between the index and middle portions of FDP, usually extended more proximally in the forearm than separation between the tendons to the middle and ring fingers and between the ring and little fingers. Direct intertendinous links were also noted. 5. It is not possible to direct a sufficiently focal motor command to flex selectively the distal joint of the fingers and thumb when forces exceeding 2.5% MVC are generated. For the middle, ring and little fingers in particular, movement of adjacent digits may also involve 'in-series' mechanical links between adjacent components of FDP. PMID- 7837105 TI - Fusimotor reflexes in relaxed forearm muscles produced by cutaneous afferents from the human hand. AB - 1. This study was designed to determine whether cutaneous receptors in the hand exert reflex effects on fusimotor neurones innervating relaxed muscles. Recordings were made from fifty-four muscle spindle afferents in the radial nerve while the arm was held relaxed in a supporting frame. Cutaneous afferents were activated by trains of stimuli at non-noxious levels to the superficial radial nerve or to the palmar surface of the fingers. 2. For the population of muscle spindle afferents, the mean discharge rate was 7.1 +/- 6.4 Hz (range 0-24 Hz). Thirty-three per cent had no background discharge, and this occurred significantly more often in finger extensors than wrist extensors. 3. Trains of cutaneous stimuli produced no change in the discharge rates of the majority of spindle endings irrespective of whether the spindle afferent had a background discharge or was given one by muscle stretch. However, with two of forty afferents, the stimuli produced an increase in discharge at latencies of 135 and 155 ms. 4. With a further fourteen muscle spindle endings, the dynamic responses to stretch were measured 100-400 ms after the trains of cutaneous stimuli. For four spindle afferents there was a statistically significant change in the dynamic response to stretch occurring at conditioned-stretch intervals of 100-200 ms. For two afferents the dynamic response decreased by 17 and 26% and for two others it increased by about 24 and 37%. 5. While these results support the view that the level of background fusimotor drive is low in the relaxed state, they suggest that there is some dynamic fusimotor drive to completely relaxed muscles operating on the human hand, and that this drive can be altered reflexly by cutaneous afferent inputs from the hand. PMID- 7837106 TI - Clinical trial design: veterinary perspectives. AB - Tremendous potential exists for the use of the randomized clinical trial (RCT) in veterinary clinical research. Understanding the fundamentals of RCT design not only benefits clinical researchers, but it can enhance the ability of practitioners to interpret published RCT reports. In this article, the essential components of RCT design and implementation are described using examples from clinical veterinary medicine. PMID- 7837107 TI - Platelet dysfunction associated with immune-mediated thrombocytopenia in dogs. AB - The effect of antiplatelet antibody on in vitro platelet function was investigated in 15 dogs with immune-mediated thrombocytopenia (ITP). Platelet aggregation was assessed after addition of serum from healthy dogs (n = 5) or dogs with ITP (n = 15) to platelet-rich plasma from a healthy donor dog. The aggregation responses to adenosine diphosphate, thrombin, and collagen/epinephrine were measured as the maximum aggregation observed after 2 minutes. In 13 of 15 dogs with ITP, maximal aggregation was significantly inhibited in response to ADP, thrombin, or collagen/epinephrine. The slope of the aggregation curve was decreased after addition of serum from 9 of 15 patients. A polyclonal rabbit anti-dog platelet antiserum induced inhibition of aggregation with all 3 agonists. Serum from control dogs neither inhibited nor activated platelet aggregation. Aggregation experiments were repeated with all 3 agonists after addition of patient immunoglobulin (Ig)G or IgG from a healthy dog to platelet-rich plasma. The IgG fraction from 9 of 10 dogs with ITP suppressed platelet aggregation. The IgG fraction from polyclonal rabbit anti-dog platelet antiserum inhibited platelet aggregation with all agonists. These results suggest that many canine ITP patients have circulating antibodies that, in addition to causing platelet destruction, may cause platelet dysfunction. PMID- 7837108 TI - Neurological manifestations of hypothyroidism: a retrospective study of 29 dogs. AB - Neuromuscular signs in association with hypothyroidism are described in 29 dogs. Eleven dogs had lower motor neuron signs, 9 had peripheral vestibular deficits, 4 had megaesophagus, and 5 had laryngeal paralysis. Primarily older (mean = 9.5 years), large-breed dogs were affected, and there was no sex or breed predisposition. Duration of clinical signs before presentation ranged from 2 to 8 weeks (mean = 5 weeks). The diagnosis was based on (1) results of neurological examination (29 dogs); (2) electromyographic abnormalities (18 dogs), including fibrillation potentials (n = 18), positive sharp waves (n = 15), and complex repetitive discharges (n = 4); (3) high serum cholesterol concentration (10 dogs; mean = 335 mg/dL); (4) low response to thyroid-stimulating hormone (29 dogs; mean T4 prestimulation concentration = 0.8 micrograms/dL; mean T4 poststimulation = 1.2 microgram/dL); and (5) good response to thyroxine supplementation (26 dogs). Dogs with vestibular deficits had abnormal brainstem auditory-evoked responses (BAER), including increased latencies of P1-P6 and decreased amplitude of P4,5 N5. Seven other dogs had similar BAER abnormalities without manifesting clinical signs of vestibular involvement. Three dogs with vestibular signs had fibrillation potentials and positive sharp waves without exhibiting lower motor neuron signs. All dogs were supplemented with levothyroxine (0.02 mg/kg PO bid). The follow-up period ranged between 6 and 30 months (mean, 14 months). Serum T4 concentrations were measured at least 3 times for each dog every 2 months (mean T4 concentration = 2.6 micrograms/dL). All but 1 dog with lower motor neuron signs and 1 dog with vestibular signs recovered after 2 months (mean, 57 days).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7837109 TI - The effect of combined therapy with captopril, furosemide, and a sodium restricted diet on serum electrolyte concentrations and renal function in normal dogs and dogs with congestive heart failure. AB - Captopril, furosemide, and a sodium-restricted diet were administered to 6 normal dogs and 10 dogs with congestive heart failure. Serum electrolyte concentrations and renal function were monitored in both groups. In the normal dogs, no clinically meaningful changes in serum electrolyte, urea nitrogen, or creatinine concentrations developed during therapy with a sodium-restricted diet and 4 weeks each of furosemide alone, captopril alone, or furosemide plus captopril. Three of 6 normal dogs on furosemide and a sodium-restricted diet had at least one serum potassium concentration above the reference range during the 4 weeks of observation. One normal dog on captopril, furosemide, and a sodium-restricted diet developed azotemia, and 2 dogs had serum potassium concentrations above the reference range during the 4 weeks of observation. Ten dogs with congestive heart failure were treated with captopril, furosemide, a sodium-restricted diet, and digoxin. Etiopathogenesis of the heart failure included valvular insufficiency (n = 6), dilated cardiomyopathy (n = 3), and dilated cardiomyopathy and dirofilariasis (n = 1). Serum electrolyte concentrations and renal function were monitored for 5 consecutive weeks in 7 of the 10 dogs and for 17 weeks or longer in 6. Two dogs were euthanized after 4 weeks because of acute decompensation of heart failure, and one dog developed severe azotemia and uremia. Six of 10 dogs with congestive heart failure had at least one serum potassium concentration above the reference range sometime during the 5 weeks of observation, although the changes in the mean serum potassium concentrations were not statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7837110 TI - Actinomycin D for reinduction of remission in dogs with resistant lymphoma. AB - Twenty-five dogs with malignant lymphoma refractory to chemotherapy were treated with actinomycin D at a median dose of 0.7 mg/m2 (range, 0.5 to 0.9 mg/m2) every 3 weeks. The dogs treated had received between 2 and 8 chemotherapeutic agents (median 7), for a median of 266 days before being treated with actinomycin D. For 23 of the 25 dogs, previous chemotherapy included doxorubicin. No dog responded to actinomycin D chemotherapy. PMID- 7837111 TI - Cutaneous hemangiosarcoma in 25 dogs: a retrospective study. AB - Hemangiosarcomas confined to the skin and underlying muscle were surgically excised in 25 dogs. Tumors were staged based on their histological location (ie, dermal, hypodermal, and deep). Dermal (stage I) hemangiosarcomas were small, most commonly ventral-abdominal or prepucial in location, and were associated with prolonged survival times (median survival, 780 days). Tumors with hypodermal (stage II) and underlying muscular involvement (stage III) were grouped together because of their larger size, bruise-like appearance, lack of anatomic predilection, biological behavior, and shorter survival times (median survival of 172 and 307 days for dogs with stages II and III, respectively). We conclude that dermal hemangiosarcomas may be effectively treated with surgery alone, whereas hemangiosarcomas located within the hypodermal tissues bear a poor prognosis and warrant wide surgical excision with adjuvant chemotherapy. PMID- 7837112 TI - Fanconi's syndrome in a dog with primary hypoparathyroidism. AB - An 11-year-old castrated male mixed breed dog was referred for evaluation of muscle twitching, polyuria, polydipsia, anorexia, and periocular alopecia. Primary hypoparathyroidism was diagnosed by documenting decreased serum concentrations of parathyroid hormone and ionized calcium. Neurological, gastrointestinal, and dermatological signs resolved after calcium repletion. Initially, 1,25-dihydroxycholecalciferol PO was required to correct the hypocalcemia. Dihydrotachysterol, in combination with oral calcium supplementation, was used for long-term maintenance of normal serum calcium concentration. Aminoaciduria, glucosuria, and hyperchloremic metabolic acidosis were consistent with a diagnosis of Fanconi's syndrome. This diagnosis was further supported by the presence of hypokalemia and increased urinary fractional excretion of sodium, potassium, calcium, phosphorus, and magnesium. Renal tubular dysfunction resolved after oral supplementation with calcium and vitamin D3. Fanconi's syndrome in this dog may have been caused by decreased serum concentration of 1,25-dihydroxycholecalciferol, which was secondary to decreased parathyroid hormone production. PMID- 7837113 TI - Hemostatic disorders in feline immunodeficiency virus-seropositive cats. AB - The hemostatic function of 40 feline immunodeficiency virus (FIV) seropositive and 8 FIV and feline leukemia virus (FeLV) seropositive cats was evaluated and compared with reference values from 30 clinically healthy cats. The FIV-positive cats were divided into 3 groups: group I included asymptomatic carriers; group II comprised sick FIV-infected cats with illnesses not likely to influence the hemostatic system; and group III included FIV-positive cats with diseases potentially associated with coagulopathies. Platelet counts in FIV/FeLV-infected cats were significantly lower than in healthy cats (P < .003), whereas the differences in the 3 groups of FIV-positive cats were variable (group I, P = .009; II, P = .05; III, P = .09). Thrombocytopenia (< 145,000 platelets/microL) was present in 4 FIV-positive and 3 FIV/FeLV-positive cats. Platelet aggregation induced by collagen (0.5 and 0.25 micrograms/mL), adenosine diphosphate (ADP) (1 and 0.6 mumol/L), and thrombin (0.4 and 0.25 IU/mL) was not significantly different from that of healthy cats. The plasma coagulation system was evaluated by measuring one-stage prothrombin time (OSPT), activated partial thromboplastin time (APTT), thrombin time, fibrinogen concentration, coagulation factor assays, fibrinogen and fibrin degradation products (FDP), and plasma exchange test. The OSPT was similar in FIV-seropositive cats and in the healthy control group. Cats with FIV infection, however, had markedly shorter clotting times than healthy cats when using a modified test system (P < .05).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7837114 TI - Brainstem auditory-evoked potentials and neuropathologic correlates in 26 dogs with brain tumors. AB - Brainstem auditory-evoked potentials (BAEPs) were recorded from 26 dogs with intracranial neoplasia. The tumors were grouped according to their neuroanatomic location. Normal BAEPs were recorded from 12 dogs with cerebral (6/7), diencephalic (4/4), cerebellar (1/1), and multifocal tumors (1/5). Abnormal BAEPs were recorded from 14 dogs were cerebral (1/7), cerebellar/brainstem (4/4), brainstem (5/5), and multifocal tumors (4/5). Analysis of the multifocal neoplasms showed that alterations of BAEPs correlated with the degree of brainstem involvement. Overall, 13 of the 14 dogs with abnormal BAEPs had tumors involving the brainstem. The changes of the BAEP correlated with the extrinsic or intrinsic location of the tumor relative to the brainstem. The BAEP reflected the right, left, or median location of the tumor in 7 of the 14 abnormal recordings. In 1 dog, the BAEP was abnormal contralateral to the tumor side. A peripheral hearing disorder was excluded in most dogs based on the presence of peak I. PMID- 7837115 TI - Neuronal ceroid lipofuscinosis in Rambouillet sheep: characterization of the clinical disease. AB - A chronic progressive, neurodegenerative disease has been identified in 4 closely related flocks of purebred Rambouillet sheep. Blindness, circling, proprioceptive deficits, reduced cognition, and poor body condition are the main clinical signs. Prominent lesions include markedly decreased cerebral size and weight, enlarged cerebral ventricles, and intraneuronal accumulations of autofluorescent pigment. Affected sheep usually die between 1 and 2 years of age. The clinical signs and postmortem findings are consistent with neuronal ceroid-lipofuscinosis. PMID- 7837116 TI - Hyperlipemia in 9 miniature horses and miniature donkeys. AB - The medical records from 9 consecutive miniature horses (n = 5) and miniature donkeys (n = 4) with hyperlipemia (serum triglyceride concentration > 500 mg/dL) were reviewed. In all cases, hyperlipemia was a secondary complication of a primary systemic disease including septicemia, colitis, parasitism, esophageal obstruction, gastric impaction and rupture, fecalith, and pituitary adenoma. Therapy consisted of specific treatment for the primary disease, supportive care, and nutritional support. The mean time for resolution of hyperlipemia in cases requiring nutritional support (n = 6) was 7 days, and the duration of nutritional support in surviving patients was 11.7 days. Seven of 9 patients survived. The primary disease resulted in death in 2 patients. Enteral feeding with commercially prepared low residue diets and treatment of the primary disease was successful in reversing hyperlipemia in 5 of 6 surviving patients that required nutritional support. Parenteral administration of a glucose-based (non-lipid) solution was successful in resolving hyperlipemia in 1 patient. PMID- 7837117 TI - Adrenal neoplasia causing lactation in a castrated male goat. PMID- 7837118 TI - Dr John Oliver awarded prestigious ACVIM honor. PMID- 7837119 TI - Hysterectomy vs. resectoscopic endometrial ablation for the control of abnormal uterine bleeding. A cost-comparative study. AB - This study compared the costs of endometrial ablation using the uterine resectoscope to those of hysterectomy in a group of patients treated for abnormal uterine bleeding who were enrolled in a national managed health care organization. The cost of endometrial ablation during the periprocedural period was significantly lower than that of hysterectomy, with much of the difference coming from the hospitalization required for the latter procedure. The postprocedural cost for ablation was higher than for hysterectomy owing to the need for second ablations or hysterectomy in 13 of the 85 ablation patients. Preprocedure costs were not different between ablation and hysterectomy. A reanalysis of the data, however, that excluded patients who required a second ablation or hysterectomy suggested that these additional procedures were responsible for the higher postprocedural costs in the ablation group. Resectoscopic endometrial ablation for the treatment of abnormal uterine bleeding resulted in lower periprocedure costs and lower overall treatment costs to the health plan in the groups studied as compared with hysterectomy. Greater familiarity with the technique of resectoscopic endometrial ablation, improved patient selection for the procedure and the use of appropriate pharmacotherapy for suppressing endometrial growth prior to ablation probably substantially improve the rate of success, reduce postprocedural costs and further enhance the cost advantage of this procedure. PMID- 7837120 TI - Dysfunctional uterine bleeding in adolescents. AB - This retrospective, multicenter analysis was conducted on all adolescents admitted to three pediatric hospitals in Montreal, Quebec, Canada, over a 10-year period (1981-1991) with a primary diagnosis of dysfunctional uterine bleeding. The purpose was to assess the frequency of underlying medical disorders and their response to medical therapy. Sixty-one patient charts were identified. Newly diagnosed hematologic abnormalities were found in two patients (one with immune thrombocytopenic purpura and one with acute promyelocytic leukemia). Furthermore, all patients who were evaluated had normal factor VIII levels, partial thromboplastin times and prothrombin times. Twenty-nine percent of the patients had a past history of a significant medical problem. The mean age at presentation was 13.8 +/- 2.1 (SD) years. More than 50% of the patients had a history of irregular bleeding. Most patients (93.4%) responded to medical management. Only five (8.2%) required dilation and curettage. The history of irregular cycles, the early presentation after menarche, the infrequency of hematologic problems but high frequency of significant medical problems led us to conclude that the etiology of dysfunctional uterine bleeding in adolescence is often related to persistent immaturity of the hypothalamic-pituitary-ovarian axis. Medical therapy is highly effective in controlling such bleeding. Dilation and curettage is rarely required. PMID- 7837121 TI - Direct antisperm antibodies using enzyme immunoassay or immunobeads. A prospective cohort comparison. AB - An enzyme immunoassay for detecting antisperm antibodies directly on sperm was compared to immunobeads in a prospective cohort design. In a series of 112 divided ejaculates evaluated for assisted reproductive technologies, there was moderate overall agreement (kappa = .64) between the methods. All ejaculates positive by immunobeads were also positive by enzyme immunoassay. The enzyme immunoassay could be performed even on oligospermic specimens. When both assays could be employed, the enzyme immunoassay was positive more often (P = .001). Positive specimens by enzyme immunoassay often bound IgA-class antibodies alone, without IgG. Enzyme immunoassay results may represent false-positive results or a new, lower threshold for antibody detection. PMID- 7837122 TI - Tobacco, alcohol and illicit drug use among pregnant women. Age and racial/ethnic differences. AB - This study identified and compared the prevalence of tobacco, alcohol and illicit drug use in a large sample of low-image pregnant women, stratified by maternal age and race/ethnicity. We used a cross-sectional, population-based design and used structured interviews. All 903 patients attended university, low-risk obstetric clinics, were aged 12-41 years and were of white, black and Mexican American race/ethnicity. The results indicate that the prevalence of tobacco, alcohol and illicit drug use during pregnancy and lifetime illicit drug use varied by age, race/ethnicity and type of substance. For all age groups, whites reported higher rates of tobacco, alcohol and lifetime illicit drug use than did blacks and Mexican-Americans. Whites (7%) and Mexican-Americans (5%) < 18 years of age were more likely to report illicit drug use during pregnancy than were white (4%) or Mexican-American (2%) patients aged 18-21 and white (4%) or Mexican American (0%) patients > 21 years. Blacks > 21 years of age reported the highest rate of current illicit drug use overall (9%). The rates of substance use reported by Mexican-Americans differed according to their spoken language, with English-speaking Mexican-Americans of all ages more likely to report tobacco, alcohol or illicit drug use than were corresponding Spanish-speaking Mexican Americans. Awareness of the racial/ethnic and age differences in the rates of tobacco, alcohol and illicit drug use will assist physicians in the early identification of and intervention with pregnant women who place themselves and their fetuses at increased risk of injury from substance use. PMID- 7837123 TI - Subclinical cervicovaginal human papillomavirus infections associated with cervical condylomata and dysplasia. Treatment outcomes. AB - Seventy-seven women with subclinical cervicovaginal human papillomavirus (HPV) changes associated with cervical condylomata and/or mild or moderate cervical dysplasia were studied. All patients were treated with the CO2 laser for cervical lesions (condylomata and/or dysplasia) and, subsequently, based on their contraceptive history, were treated either with 5-fluorouracil (5-FU) cream or trichloroacetic acid (TCA). Those who did not wish to be treated were followed similarly to those who were treated. Overall there was no significant difference between those who had no treatment and those who received TCA or 5-FU. Those treated with 5-FU did more poorly as compared to the other two treatment groups with cervical condylomata and dysplasia at the three- and six-month follow-up (P < .05), and the results for TCA were not different from those in women who were observed and underwent no treatment. It appears that the treatment modalities used in this study did not have any beneficial effect on associated subclinical HPV infections. PMID- 7837124 TI - Prenatal sonographic findings in trisomy 13, 18, 21 and 22. A review of 46 cases. AB - A study of 46 patients with trisomic fetuses was performed to determine if there are one or more second-trimester ultrasonic findings predictive of aneuploidy. Videotapes of ultrasonography performed prior to amniocentesis on the 46 fetuses with autosomal trisomy and from a control group of 50 chromosomally normal fetuses were reviewed without knowledge of the karyotype. Fetuses with autosomal trisomies had short long bones, especially femurs, as well as high biparietal diameter/femur length ratios. In addition, a nuchal thickness of > 5 mm, abnormal heart anatomy, slight pyelectasis, increased bowel echogenicity and/or abnormal flexion of the hands were all predictive of autosomal trisomies. PMID- 7837125 TI - Outpatient versus inpatient cervical cerclage. AB - The outcomes in 125 cases of elective, outpatient cerclage placement were compared to those in 101 cases of elective, inpatient cerclage placement with the same technique at the same institution. There was no difference between the two groups in the rates of early and late complications or in the effect of the procedure on the duration of gestation. As expected, a statistically significantly shorter hospital stay occurred in the outpatient group. The outpatient procedure is as effective as the inpatient one, with no increased risk of early and late complications, and offers patients a shorter absence from home, thus possibly decreasing their anxiety, and considerable financial savings. PMID- 7837126 TI - Cost-effectiveness of levonorgestrel subdermal implants. Comparison with other contraceptive methods available in the United States. AB - The objective of this analysis was to evaluate and compare the cost-effectiveness of eight contraceptive methods: condoms, diaphragms, oral contraceptives, intrauterine devices, medroxyprogesterone acetate suspension, levonorgestrel subdermal implants, tubal ligation and vasectomy. Based on a comprehensive review of the literature and various additional data sources, this analysis identified, measured and compared direct costs of the methods, physician visits, treatment of adverse effects and cost of failure (i.e., mean cost for all types of deliveries or first-trimester abortion). Medical benefits (if any) resulting from each contraceptive method were calculated and considered in the analysis as cost savings. The cost of method failure proved to be the greatest influence on cost effectiveness. Sterilization was identified as the most cost-effective method overall. Of the reversible methods, the intrauterine device was found to be the most cost-effective, followed by levonorgestrel implants. PMID- 7837127 TI - Retinal and pregnancy outcomes in the presence of diabetic proliferative retinopathy. AB - The objective of this study was to examine the retinal and pregnancy outcomes of pregnancies complicated by advanced diabetic retinopathy. Twenty pregnancies complicated by advanced diabetic retinopathy were included in this retrospective study. The data were analyzed to determine trends in perinatal outcome and to document the ophthalmologic performance. Ophthalmologic management included frequent funduscopic examinations by ophthalmologists of the Yale Retina Center. Among the 20 pregnancies, spontaneous abortion occurred in 2 (10%) and stillbirth in 1 (5%); the remaining 17 (85%) pregnancies culminated in live births at a mean gestational age of 36 weeks (+/- 2.3 SD), with a mean birth weight of 2,620 g (+/ 834 SD). The perinatal survival rate was 94%. Photocoagulation therapy was necessary prior to pregnancy in 45%, during pregnancy in 60% and postpartum in 65%. No pregnancies were terminated because of progressive visual changes that did not respond to photocoagulation therapy. Retinal status should not preclude pregnancy since contemporary methods of management can result in satisfactory retinal and pregnancy outcomes even in the presence of advanced diabetic microvascular disease. PMID- 7837128 TI - Effect of obesity on the clinical and hormonal characteristics of the polycystic ovary syndrome. AB - The polycystic ovary (PCO) syndrome is frequently associated with obesity. That subset of women reportedly shows a much higher incidence of hirsutism and menstrual irregularities than do nonobese women with PCO syndrome. We evaluated the clinical features and hormonal profiles of 56 women with PCO syndrome and correlated them with the presence or absence of obesity. Thirty-eight (67.8%) of these women were obese (body mass index > or = 25 kg/m2). While presenting with the classic manifestations of PCO, they did not differ significantly from the manifestations of nonobese women with PCO syndrome. Although obese women with PCO had a lower incidence of oligomenorrhea as compared to nonobese women with PCO (57.9% vs. 83.3%, respectively) and amenorrhea was more frequent in the former group (42.1% vs. 16.6%, respectively), these findings are not statistically significant. The incidences of hirsutism and anovulatory infertility in the obese group as compared to the nonobese group were 81.6% vs. 77.8% and 28.9% vs. 27.8%, respectively (not statistically significantly different). The mean (+/- SE) serum levels of luteinizing hormone (LH), follicle stimulating hormone (FSH), LH/FSH ratios, prolactin and testosterone were not statistically significantly different among the two groups. The present study found that obesity is common in PCO syndrome but that there are no significant differences in the clinical and hormonal characteristics of obese and nonobese women with it. Further studies are warranted to clarify the impact of obesity on clinical, metabolic and hormonal changes in PCO syndrome. PMID- 7837129 TI - Trends in the frequency of cesarean delivery. A 21-year experience, 1970-1990. AB - Cesarean delivery rates in the United States increased from about 5% in 1965 to 24.7% in 1988, with the majority attributed to four indications: dystocia, fetal distress, previous cesarean delivery and breech presentation. This study calculated one hospital's cesarean delivery rate over a 21-year period to examine the trends in the rate and in their clinical indications. From 1974 to 1979, dystocia was responsible for 39.1% of the 151.2% overall increase in cesarean deliveries at the study hospital, followed by repeat cesarean deliveries (30.1%), fetal distress (8.7%) and breech presentation (3.5%). The percentage of all repeat cesarean deliveries increased, from 6.2 in 1981 to 8.0 in 1990, while the percentage of previous cesarean patients having another cesarean delivery declined from 96.6 in 1981 to 85.5 in 1990. Although there has been a reduction in the proportion of women having repeat cesarean delivery, the number of previous cesarean patients presenting for another delivery has been increasing. The cesarean experience at individual hospitals needs to be examined to provide a better understanding of the reasons for changes in their cesarean delivery rates. PMID- 7837130 TI - Maternal respiratory arrest associated with intravenous fentanyl use during labor. A case report. AB - Maternal respiratory arrest occurred secondary to fentanyl administration. There were no adverse sequelae for the patient or neonate. PMID- 7837131 TI - Safety of surgical intervention during the second trimester of pregnancy. A case report. AB - Surgical and anesthetic interventions during pregnancy are not hazard free. While an increase in fetal resorption and the abortion rate during the first trimester is well documented, a second-trimester intervention is assumed to be relatively safe. A case of acute transient oligohydramnios, fetal growth arrest and limb reduction anomaly following second-trimester abdominal surgery is reported for the first time. PMID- 7837132 TI - Repair of the traumatically ruptured gravid uterus. A report of two cases resulting in viable pregnancies. AB - In two cases of traumatic rupture of the unscarred, pregnant uterus, careful repair was able to preserve fertility even after extensive damage. Because of the extreme variations in the presentation of this uncommon problem, a high index of suspicion may be necessary to save the woman's life in cases of fetal demise after a serious car accident. PMID- 7837133 TI - Arteriovenous malformation of the upper extremity complicating pregnancy. A case report. AB - A 23-year-old, pregnant woman with an arteriovenous malformation of the left brachial artery developed worsening symptomatology that demanded early delivery. The puerperium was significant for persistent debilitating symptoms that resolved partially four months following delivery. PMID- 7837134 TI - Intramural vesical endometriosis. A case report. PMID- 7837135 TI - Use of a coagulation analyzer in managing disseminated intravascular coagulation after midtrimester pregnancy termination. A case report. AB - A case of disseminated intravascular coagulation occurred with midtrimester dilation and evacuation. The case was treated successfully but required substantial volumes of blood products. The use of a coagulation analyzer facilitated the diagnosis and treatment. PMID- 7837136 TI - Use of flutamide for self-induced androgen excess. A case report. AB - A 28-year-old woman developed hirsutism, facial edema and clitoromegaly after self-injection of long-acting synthetic androgens. The symptoms were ameliorated by administration of flutamide with a combination oral contraceptive. Flutamide appears to be useful in preventing sequelae of acute androgen excess in women and may be a rational therapy for chronic treatment of androgen excess in women. PMID- 7837137 TI - The imperious p value. PMID- 7837138 TI - Predicting outcome of ankylosing spondylitis: prognosis or hindsight? PMID- 7837139 TI - Glycosylation and rheumatic disease: more than icing on the cake. PMID- 7837140 TI - Direct degradation of articular cartilage by rheumatoid synovial fluid: contribution of proteolytic enzymes. AB - OBJECTIVE: To test the effects of synovial fluids (SF) on human cartilage in an in vitro model. METHODS: Freshly collected SF were incubated with cryostat sections of articular cartilage, and glycosaminoglycan (GAG) loss determined by microdensitometry after alcian blue staining. RESULTS: Of 20 rheumatoid SF, 11 induced significant GAG loss compared with only 3 out of 15 osteoarthritic SF. The effect of rheumatoid fluids appeared to be related to disease activity. GAG loss was partially prevented by a broad spectrum serine protease inhibitor and a specific elastase inhibitor. Cartilage degrading activity was lost on storage which may explain why it has not been widely reported before. CONCLUSION: Rheumatoid SF can directly degrade cartilage through the action of proteases. There is an involvement of serine proteases, elastase in particular. PMID- 7837141 TI - Stimulation of human synovial cell DNA synthesis by iron. AB - OBJECTIVE: To determine the effect of iron and cytokines on proliferation of synovial cells (SC), we isolated SC obtained at the time of total knee replacement from 11 patients with rheumatoid arthritis (RA) and 2 with osteoarthritis (OA) following enzymatic treatment of synovial tissue. METHODS: SC were cultured in the presence of ferric citrate or sodium citrate at concentrations of 0, 0.01, 0.1, and 1 mM for 72 h. In vitro synthesis of DNA by SC was measured by intracellular 3H-thymidine uptake. RESULTS: Synthesis of DNA by SC was significantly enhanced by ferric citrate but not sodium citrate. The maximum synthesis was observed following stimulation with 0.1 mM ferric citrate and was obtained after 3 days of culture, thereafter declining until Day 7. This stimulatory effect of ferric citrate was observed in all specimens of SC tested. In our examination of the concomitant addition of each of 8 different recombinant human cytokines with 0.1 mM ferric citrate on SC DNA synthesis, 4 of them, i.e., interleukin-1 beta (IL-1 beta), IL-7, tumor necrosis factor alpha (TNF alpha) and interferon gamma (IFN-gamma) each enhanced the synthesis of SC DNA at concentrations ranging from 1 to 100 u/ml, while IL-1 beta, IL-7, TNF alpha or IFN-gamma together showed an additive effect. No significant effect was shown by IL-2, IL-6, and IL-8, or granulocyte colony stimulating factor (G-CSF). CONCLUSION: Iron stimulated in vitro SC DNA synthesis and had an additive effect on the activity of human cytokines for SC proliferation. Iron may play a role in the proliferation of synovial cells in patients with RA synovitis. PMID- 7837142 TI - Measurement and prediction of radiological progression in early rheumatoid arthritis. AB - OBJECTIVE: To compare radiological scoring systems in early RA, and then to determine if the rate of radiological progression in the first year of disease (RRP01) predicts the subsequent rate of progression up to 8 years (RRP1-8). METHODS: Hand and feet radiographs were performed at 0, 1, 2 and 8 years in 65 patients presenting with nonerosive RA and symptoms for less than 3 years. All films were scored by Sharp's method; Sharp, Larsen and carpometacarpal (CMC) ratio methods were compared in 23 patients. RESULTS: Significant change in score was detected over the first year using Sharp (median of 15.5 vs 7.5, p < 0.00002) and Larsen (30.5 vs 22.5, p < 0.0002), but not CMC ratio (1.13 vs 1.14, p = 0.07). Sharp had greater range and sensitivity of change, and had better inter and intraobserver reproducibility. RRP01 showed a skewed distribution (median 0.7 units/month; range -0.3 to +6.1). Spearman correlation between RRP01 and RRP1-8 was r = 0.57, p < 0.001. CONCLUSION: Both Sharp and Larsen indices are sensitive to change in the first year of RA, but Sharp has advantages of greater sensitivity and reproducibility: CMC ratio is not useful. Radiological progression rate in the first year correlates only moderately with subsequent rate of progression up to 8 years. This suggests that radiological progression is nonuniform and that different patterns of progression over time may exist. PMID- 7837143 TI - Mucocutaneous reactions to gold: a prospective study of 74 patients with rheumatoid arthritis. AB - OBJECTIVE: To describe causality, morphology, course, and risk factors of mucocutaneous reactions to gold. METHODS: A prospective study of 74 patients with rheumatoid arthritis starting with gold thioglucose. RESULTS: Thirty-nine patients experienced an episode of gold dermatitis. Sixteen patients continued gold treatment. The estimated treatment withdrawal at 1 year was 26%. The clinical picture was variable and nonspecific. Gold dermatitis was associated with HLA-B35 and disease duration. CONCLUSION: Mucocutaneous reactions to gold are nonspecific, therefore a causality assessment is necessary. Incidence is high, but treatment can often be continued with dose reduction and local steroids. The predictive value of risk factors is low. PMID- 7837144 TI - Pleural fluid soluble interleukin 2 receptor in rheumatoid arthritis and systemic lupus erythematosus. AB - OBJECTIVE: To study local cellular immune reactions in the pleural fluid of patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). METHODS: Using an immunoenzymometric assay, the concentration of soluble interleukin 2 receptor (sIL-2R) was measured in the pleural fluid of 13 patients with RA, 6 patients with SLE and 72 patients with pleural effusions of other etiologies, including tuberculosis, cancer, pneumonia and congestive heart failure. RESULTS: The mean pleural fluid sIL-2R concentration was significantly higher in patients with RA (593 pM, range 252-1558) than in patients with SLE (145 pM, range 94-236; p < 0.005), cancer (224 pM, range 98-521, p < 0.01), pneumonia (177 pM, range 60-343, p < 0.005) and congestive heart failure (139 pM, range 56-228, p < 0.005), but as high in patients with tuberculous pleurisy (mean 390 pM, range 151-512). The highest mean pleural fluid to serum sIL-2R ratios were observed in patients with RA and with tuberculosis. CONCLUSION: Measurement of sIL-2R in pleural fluid is useful for the differentiation of pleural effusions in RA from those occurring in SLE. High levels of sIL-2R associated with a local T cell mediated immune reaction may serve an immunoregulatory purpose in rheumatoid pleurisy. PMID- 7837145 TI - Clinical course of cognitive dysfunction in systemic lupus erythematosus. AB - OBJECTIVE: To prospectively evaluate changes in cognitive function in a cohort of unselected patients with systemic lupus erythematosus (SLE) and controls over a 12 month period. METHODS: Seventy female patients with SLE, 25 patients with rheumatoid arthritis (RA) and 23 healthy subjects (age and sex matched) were evaluated using the Wechsler Adult Intelligence Scale-Revised (WAIS-R), the Wechsler Memory Scale-Revised (WMS-R), the California Verbal Learning Test (CVLT) and the National Adult Reading Test-Revised to identify impairment in 8 areas of cognitive function. Cumulative disease manifestations and current medications were documented, and disease activity was expressed using the SLE disease activity index (SLEDAI). Decision rules were determined for overall cognitive impairment. RESULTS: At baseline, 21% (15/70) of patients with SLE were impaired compared to 4% (1/25) of patients with RA and 4% (1/23) of healthy subjects (p = 0.042). After a mean interval of 12.8 months (range: 11-17) 84% (59/70) of patients with SLE, 44% (11/25) of patients with RA and 80% (17/23) of healthy subjects were reassessed. This included all subjects who were impaired at the initial assessment. Using the same decision rules as at baseline, 12% (7/59) of patients with SLE were impaired at followup compared to none of the patients with RA and healthy subjects. Over the period of study cognitive impairment persisted in 3 patients with SLE, resolved in 12 and evolved in 4 others. There was no apparent association between changes in cognitive function and concurrent changes in generalized disease activity, overt neuropsychiatric disease or corticosteroid medication. CONCLUSION: Our results suggest that cognitive dysfunction in patients with SLE is evanescent, does not necessarily lead to irreversible neurologic compromise and changes independently of other clinical variables. PMID- 7837146 TI - Selective expression of V beta families by T cells in the blood and salivary gland infiltrate of patients with primary Sjogren's syndrome. AB - OBJECTIVE: The T cell infiltration of the salivary gland of patients with Sjogren's syndrome (SS) has been implicated in the pathogenic process of the disease. We examined the representation of V beta subsets in the blood and salivary tissue of patients with SS. METHODS: Circulating T cells from 12 patients and paired samples of blood and labial salivary glands obtained from 8 patients were studied. A panel of monoclonal antibodies directed against the variable region of the T cell receptor was used to enumerate the cells expressing V beta families in the peripheral blood by flow cytometry, and in tissue sections by immunofluorescence. RESULTS: We found an increase of cells bearing V beta 2 family gene products in the circulation, and an increase in both V beta 2 and V beta 8 in the salivary gland infiltrate of patients with SS. No significant difference was noted between the 5 DR3+ patients and 7 DR3- patients studied with regard to the V beta families seen. CONCLUSION: Our data are consistent with a role for specific T cell families in the pathogenesis of SS. PMID- 7837147 TI - Circulating endothelin-1 levels in systemic sclerosis subsets--a marker of fibrosis or vascular dysfunction? AB - OBJECTIVE: To investigate the circulating levels of endothelin-1 (ET-1) in serum (sET-1) in patients with pulmonary disease [pulmonary fibrosis (PF) and pulmonary hypertension (PHT)], and renal involvement [hypertensive renal crisis (HRC)] in the 2 major subsets of systemic sclerosis (SSc) in order to determine the significance of sET-1 levels in relation to specific organ involvement or to the underlying pathogenic mechanisms of vascular damage and fibrosis. METHODS: In addition to the measurement of ET-1 in serum using a competitive radioimmunoassay, the circulating levels of angiotensin converting enzyme (ACE) and plasma von Willebrand factor (vWF) were measured as markers of endothelial damage in the various disease groups. RESULTS: Levels of sET-1 were significantly increased in 64 patients with diffuse systemic sclerosis (dSSc) and 17 patients with primary Raynaud's phenomenon (RP) compared with 22 healthy individuals. sET 1 levels were equally elevated in diffuse cutaneous disease (dcSSc) with only fibrotic dermal or lung pathology compared with patients with additional PHT or HRC crisis. These observations were in marked contrast to the sET-1 levels seen in patients with the limited cutaneous form of SSc (lcSSc) where only patients with lcSSc with hypertensive lung or renal disease had significantly higher levels of sET-1 than comparable lcSSc patients with only fibrotic dermal and lung disease. sET-1 levels were additionally found to correlate with plasma vWF, skin fibrosis (skin score) and duration of disease in patients with SSc. CONCLUSION: The presence of significantly raised sET-1 levels in patients with dcSSc with widespread fibrosis and patients with lcSSc with hypertensive disease and the relationship seen between sET-1 levels and markers of fibrosis and vascular damage suggest that ET-1 may be important in the pathogenesis of both the fibrotic and vascular manifestations in SSc. PMID- 7837148 TI - The contribution of resting heart rate and routine blood tests to the clinical assessment of disease activity in systemic lupus erythematosus. AB - OBJECTIVE: To contrast the contribution of simple clinical tests, such as resting heart rate (HR), complete blood count (CBC), and erythrocyte sedimentation rate (ESR), versus immunological tests in the assessment of disease activity in systemic lupus erythematosus (SLE). METHODS: During an evaluation of disease activity indices in SLE, 39 patients had a full clinical evaluation in 99 visits including a disease activity index (MEX-SLEDAI), and serial measurements of HR, ESR, CBC, complement (C3, C4) and anti-dsDNA antibody levels (Farr). RESULTS: Resting HR exhibited the highest correlation with MEX-SLEDAI scores (rs = 0.62). Thus, the disease was active (MEX-SLEDAI score of 2 or more) in all but one of 15 patients (93.3%) that had an HR > 90/min during the study. Hemoglobin levels (Hb) and ESR showed the second highest correlation (rs = -0.51, and 0.50, respectively). Seventeen patients had an Hb < 13 g/dl at least once; 14 (82.4%) had active disease during the study. Lymphocyte count, C3 levels, and anti-dsDNA levels correlated less strongly with disease activity (rs = -0.27, -0.29, and 0.30 respectively). Forward stepwise multiple regression analysis showed that HR, Ht, and C3 were independent markers of disease activity in this population (R2 = 0.51, p < 0.0001). CONCLUSION: Closer attention to resting HR and CBC results may improve the assessment of disease activity in SLE. PMID- 7837149 TI - Autonomic dysfunction in diffuse scleroderma vs CREST: an assessment by computerized heart rate variability. AB - OBJECTIVE: Autonomic dysfunction has been described in scleroderma. Heart rate variability gives information about sympathetic-parasympathetic autonomic balance, therefore it can provide insight into which division of the system is most affected. Our purpose was to determine whether the neural control of heart rate in patients with CREST syndrome differed from that in patients with diffuse scleroderma. Since low heart rate variability in some diseases is associated with an increased risk for malignant ventricular arrhythmias, assessment of patients with scleroderma with this technique might establish a marker of adverse outcome. METHODS: A short time analysis of heart rate variability was performed in 9 patients with diffuse scleroderma, 8 with CREST and 17 age/sex matched healthy controls. RESULTS: An abnormal heart rate variability was found in patients with CREST: There was a reduced standard deviation of the mean of beat-to-beat R-R intervals and a low power spectrum density in both the 0.05 to 0.15 Hz band and the 0.15 to 0.35 Hz band, a significant reduction in their total power (p < 0.05), a reduction in the high frequency to total power ratio (p < 0.05), and a reduction in the ratio between high and low frequency components of their spectrum. CONCLUSION: It is suggested that patients with CREST have a decreased parasympathetic control of heart rate, significantly different from those with diffuse disease. Whether this finding is pertinent to the differences between these subsets of patients remains to be established. PMID- 7837150 TI - The overall and temporal association of cancer with polymyositis and dermatomyositis. AB - OBJECTIVE: To summarize the association of cancer with adult polymyositis (PM) and dermatomyositis (DM) and to test whether myositis precedes or follows cancer diagnosis, with the latter suggesting that myositis is paraneoplastic. METHODS: Using primary patient data, we performed an analysis of all published case control and cohort studies evaluating the association of myositis and malignancy. We evaluated the overall association of cancer within 10 years of myositis diagnosis and separately assessed cancer occurrence in periods 5 years before and 5 years after myositis diagnosis. RESULTS: Four case control or cohort studies met inclusion criteria providing 1078 myositis cases (565 PM and 513 DM) with a comparable number of controls. One hundred fifty-three myositis patients had cancer within 10 years of diagnosis. Despite reports of no myositis association with cancer, each study's data suggested an association of both PM and DM with cancer. Overall odds ratio (OR) for the association of cancer with DM = 4.4 (9.5% CI 3.0, 6.6) and for PM, OR = 2.1 (95% CI 1.4, 3.3). Cancer risk was high both before and after DM diagnosis, but for PM, cancer risk was increased only after myositis diagnosis. CONCLUSION: DM is associated with cancer, and our results suggest that DM is often paraneoplastic. The high rate of malignancy only after PM diagnosis is consistent with cancer detection bias, but may suggest joint susceptibility of affected individuals to both cancer and myositis. PMID- 7837151 TI - Elevated soluble intercellular adhesion molecule 1 in the serum of patients with polymyalgia rheumatica: influence of steroid treatment. AB - OBJECTIVE: To determine the levels of serum soluble intercellular adhesion molecule 1 (sICAM-1) in patients with polymyalgia rheumatica (PMR) and/or giant cell arteritis (GCA) prior and during steroid therapy. METHODS: Sixteen patients with PMR and/or GCA had complete clinical and laboratory investigations at diagnosis before treatment and 9 patients were followed during 6 months of steroid therapy. Serum sICAM-1 levels were measured by ELISA: RESULTS: Serum ICAM 1 levels were higher in the patient group compared to a control population. No significant correlation was found between serum sICAM-1 levels and other indices of disease activity. After steroid administration, a dramatic fall in serum sICAM 1 levels was observed at the end of the first week and persisted until the end of the study period, paralleling clinical and laboratory disease remission. CONCLUSION: Serum sICAM-1 levels paralleled disease activity in PMR and/or GCA. Steroid treatment induced a rapid normalization of the serum sICAM-1 levels. PMID- 7837152 TI - Serum soluble CD4 and CD8 levels in polymyalgia rheumatica. AB - OBJECTIVE: Soluble CD4 (sCD4) and sCD8 were measured in the sera of 19 patients with active polymyalgia rheumatica (PMR). METHODS: We correlated the results obtained with lymphocyte subpopulations, soluble interleukin 2 receptors (sIL 2R), and clinical and laboratory variables at diagnosis. In addition 15 patients were prospectively studied during a 6 month period of prednisone therapy. Assays of the sCD4 and sCD8 molecules and of the sIL-2R were performed using an enzyme linked immunosorbent kit. RESULTS: Serum sCD8 and sIL-2R levels were significantly elevated in patients with active disease compared to normal controls, while serum sCD4 and the relative percentage of CD8+ T cell levels decreased. In the 15 patients prospectively studied sCD8 levels fell significantly after 1 week of therapy along with the remission of clinical disease and normalization of erythrocyte sedimentation rate. At the end of the study period, sCD8 values did not differ from normal controls and they were significantly reduced compared to baseline values. CD8+ lymphopenia persisted at the end of the study. sCD4 levels remained significantly lower during the study period. sIL-2R levels fell significantly at the end of the study period. However, the 6-month levels of sIL-2R remained significantly higher compared to controls. CONCLUSION: The rise of serum sCD8 levels observed in patients with PMR with active disease suggests an early activation of CD8 T cells. The therapeutic effect of steroid in PMR may be partially mediated by its effect on CD8 activated cells. PMID- 7837153 TI - Raised agalactosyl IgG and antimycobacterial humoral immunity in Takayasu's arteritis. AB - OBJECTIVE: Takayasu's arteritis is an inflammatory occlusive disease of the aorta and its main branches of unknown etiology. Some suggested causes include inapparent infection with Mycobacterium tuberculosis, or autoimmunity evoked by this organism. We have therefore sought links with mycobacterial disease. METHODS: We assayed the % agalactosyl IgG, antibody to a tuberculosis-specific 38 kDa protein, and antibody to the mycobacterial 65 kDa heat shock protein (HSP), in patients with active or inactive Takayasu's arteritis, in whom the diagnosis of tuberculosis was excluded. The results were compared with findings in tuberculosis (positive controls), normal donors and patients with Wegener's granulomatosis. RESULTS: The % agalactosyl IgG in patients with active arteritis was in the range previously seen only in rheumatoid arthritis, Crohn's disease, and the mycobacterioses. Similarly, significantly raised antibody to the purified 38-kDa protein of M. tuberculosis, and to the 65-kDa HSP of M. leprae, was found in 78% of patients with Takayasu's arteritis, and the levels were higher in those with active disease. CONCLUSION: These results suggest that Takayasu's arteritis particularly clearly illustrates the occasional relationship between mycobacteria and diseases of superficially autoimmune pathogenesis. PMID- 7837154 TI - Fracture risk in patients with ankylosing spondylitis: a population based study. AB - OBJECTIVE: To assess the risk of fractures among patients with ankylosing spondylitis (AS). METHODS: A population based cohort study compared fracture incidence in an inception cohort of 158 Rochester, Minnesota residents newly diagnosed with AS between 1935 and 1989 with expected rates from the same community. RESULTS: In 2,398 person-years of observation, there was no increase in the risk of limb fractures, but there was a pronounced increase in the risk of thoracolumbar compression fractures (standardized morbidity ratio = 7.6; 95% CI, 4.3-12.6) among those with AS. CONCLUSION: These data point to the importance of measures aimed at maintaining axial skeletal status in patients with AS. PMID- 7837155 TI - Predictive factors for the longterm outcome of spondyloarthropathies. AB - OBJECTIVE: To determine the predictive factors of outcome in patients with spondyloarthropathy (European Spondyloarthropathy Study Group or Amor criteria) monitored by a single investigator. METHODS: Classification of longterm outcome on a 3-grade scale. Candidate predictive factors: presence or not of 12 clinical or biological variables during the first 2 years of the disease, collected by history at the time of the first visit. Univariate analysis to pick up the factors statistically correlated with severity and then odds ratio and 95% confidence interval (CI) for each variable were calculated. RESULTS: Of the 328 patients with spondyloarthropathy, 151 had a followup of > or = 10 years and minor disease (81), severe (28), or moderate disease (42). Seven variables at entry were correlated with disease severity (odds ratio; CI 95%); hip arthritis (22.85; 4.43-118); erythrocyte sedimentation rate > 30 mm/h (7; 4.84-9.50); poor efficacy of nonsteroidal antiinflammatory drugs (8.33; 2.56-27.10); limitation of lumbar spine (7; 2-25); sausage-like finger or toe (8.45; 1.48-9); oligoarthritis (4.25; 1.38-13.10); onset < or = 16 years (3.47; 1.06-12.75). If none of these factors is present at entry a mild outcome can be predicted (sensitivity: 92.5%; specificity: 78%). If a hip is involved or if 3 factors are present, a severe outcome is predictable (sensitivity: 50%) and a mild disease practically excluded (specificity: 97.5%). CONCLUSION: Predictive factors of poor or benign longterm outcome could be defined very early after onset of spondyloarthropathy in a set of patients monitored by one observer. PMID- 7837156 TI - Nitric oxide synthesis and its regulation by rabbit synoviocytes. AB - OBJECTIVE: To determine whether rabbit synovial fibroblasts can synthesize nitric oxide (NO) and, if so, how production is regulated by cytokines. METHODS: Primary cultures of synovial fibroblasts (type B synoviocytes) were established from synovia excised from the knee joints of New Zealand white rabbits. Synthesis of NO was measured as nitrite accumulation in conditioned media in the presence or absence of various cytokines and other activators. RESULTS: Resting cultures of synoviocytes normally produced little or no NO. However, production of this free radical was induced by interleukin 1 (IL-1), tumor necrosis factor alpha (TNF alpha) or the phagocytosis of latex beads; in some cultures, the synthesis of NO occurred spontaneously. In each case, NO synthesis began approximately 9 h after the addition of cytokines, suggesting the involvement of an inducible form of NO synthase. Antagonists of this phenomenon included interferon gamma (IFN-gamma), which weakly inhibited NO production, and transforming growth factor beta (TGF beta), a very strong inhibitor. Platelet derived growth factor (PDGF) inhibited NO synthesis by cells stimulated with IL-1, but not by cells stimulated with TNF alpha. Synovial autocrine factors (CAF) modestly induced NO synthesis, but inhibited synthesis by IL-1; TGF-beta was identified as an inhibitory component of CAF. Phorbol myristate acetate (PMA) had only a small inductive effect, and inhibited induction by IL-1. However, the protein kinase inhibitor staurosporin was a strong inducer. Modulators of cyclic nucleotides, in contrast, had relatively modest effects on NO synthesis. Inhibition of NO biosynthesis by NG monomethyl-L-arginine (NMA) had no effect upon the increase in the production of prostaglandin E2 (PGE2), matrix metalloproteinases (MMP) or lactate by synoviocytes responding to IL-1. The rabbit synoviocyte cell line, HIG-82, did not synthesize detectable NO under any of the culture conditions tested. CONCLUSION: Synoviocytes are a potential source of NO in arthritic joints. PMID- 7837158 TI - The effect of pulsed electromagnetic fields in the treatment of osteoarthritis of the knee and cervical spine. Report of randomized, double blind, placebo controlled trials. AB - OBJECTIVE: We conducted a randomized, double blind clinical trial to determine the effectiveness of pulsed electromagnetic fields (PEMF) in the treatment of osteoarthritis (OA) of the knee and cervical spine. METHODS: A controlled trial of 18 half-hour active or placebo treatments was conducted in 86 patients with OA of the knee and 81 patients with OA of the cervical spine, in which pain was evaluated using a 10 cm visual analog scale, activities of daily living using a series of questions (answered by the patient as never, sometimes, most of the time, or always), pain on passive motion (recorded as none, slight, moderate, or severe), and joint tenderness (recorded using a modified Ritchie scale). Global evaluations of improvement were made by the patient and examining physician. Evaluations were made at baseline, midway, end of treatment, and one month after completion of treatment. RESULTS: Matched pair t tests showed extremely significant changes from baseline for the treated patients in both knee and cervical spine studies at the end of treatment and the one month followup observations, whereas the changes in the placebo patients showed lesser degrees of significance at the end of treatment, and had lost significance for most variables at the one month followup. Means of the treated group of patients with OA of the knee showed greater improvement from baseline values than the placebo group by the end of treatment and at the one month followup observation. Using the 2-tailed t test, at the end of treatment the differences in the means of the 2 groups reached statistical significance for pain, pain on motion, and both the patient overall assessment and the physician global assessment. The means of the treated patients with OA of the cervical spine showed greater improvement from baseline than the placebo group for most variables at the end of treatment and one month followup observations; these differences reached statistical significance at one or more observation points for pain, pain on motion, and tenderness. CONCLUSION: PEMF has therapeutic benefit in painful OA of the knee or cervical spine. PMID- 7837157 TI - Serum levels of insulin in overweight patients with osteoarthritis of the knee. AB - OBJECTIVE: Obesity is often associated with knee osteoarthritis (OA) and with chronic hyperinsulinemia. The aim of our study was to investigate the relationship between overweight patients and OA of the knee. METHODS: Forty-eight overweight outpatients (40 women and 8 men) were recruited into the study. They were separated into 2 groups: Group 1 patients with OA of the knee and Group 2 subjects without OA of the knee. Serum insulin levels were determined in all patients. RESULTS: Insulin levels were statistically higher in patients with OA (p < 0.01) compared to subjects without OA. CONCLUSION: Our data suggest that insulin may play a role in the pathogenesis of OA of the knee in overweight patients. PMID- 7837159 TI - Performance of online biomedical databases in rheumatology. AB - OBJECTIVE: To compare the performance of MEDLINE, EMBASE, and BIOSIS in selected rheumatology topics. METHODS: Online literature searches were conducted with regard to the epidemiology of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and ankylosing spondylitis (AS), as well as for 3 specific questions representing clinical, clinical/laboratory, and therapeutic topics in rheumatology. Total number of citations retrieved, type and language of publication, percentage of contribution from rheumatology journals, and degree of overlap among the databases were recorded. Publications retrieved for the 3 specific questions were also graded for relevance. RESULTS: For 1991, each online biomedical database (OBD) retrieved more than 1,100 citations for RA, over 600 for SLE, and over 110 for AS. For the epidemiology subtopic, fewer than 25% of the citations were retrieved by more than one of the databases. About 3/4 of the citations obtained for the specific search questions were retrieved by a single database. No major differences were observed among databases in relation to number of relevance of citations retrieved. Over 60% of the papers assessed had low relevance in relation to the topic of the search. Efficiency was estimated as the percentage of all relevant citations retrieved by each OBD. Results varied according to the topic, but in most cases each database retrieved at least 50% of the relevant citations. About 45% of the citations retrieved for the 3 search questions were published in nonrheumatology journals. CONCLUSION: No database was superior in all respects. The majority of the citations were retrieved by a single database. A high percentage of the articles retrieved were not relevant, implying low specificity. If a comprehensive online search in rheumatology is required, 2 or more databases should be utilized. PMID- 7837160 TI - Intermittent cyclic therapy with etidronate in the prevention of corticosteroid induced bone loss. AB - OBJECTIVE: To assess the potential efficacy of intermittent cyclic therapy (ICT) with etidronate in the treatment of patients with corticosteroid induced osteoporosis. METHODS: Cohort study in a tertiary care university affiliated hospital in corticosteroid treated patients, with polymyalgia rheumatica, asthma, systemic lupus erythematosus, rheumatoid arthritis, or temporal arteritis, examining the effects of ICT etidronate. Patients were included if they were taking corticosteroids for a minimum of one year. Comparison patients were those who had been taking corticosteroids for a minimum of one year and who had not been treated with etidronate or other medication which might alter bone metabolism. A total of 68 patients were included from 253 considered. The mean (SD) dose of prednisone in the ICT etidronate treated patients was 9.3 (6.2) mg and in the comparison patients 9.4 (5.9) mg. The duration of prednisone therapy was 7.8 (5.8) years and 3.4 (4.2) years, respectively (p2 < 0.001). An analysis of covariance demonstrated that this difference did not alter our primary outcome measure. The primary outcome measure was the difference in the percentage change from baseline to one year of followup in bone mineral density (BMD) of the lumbar spine between treatment and comparison groups. RESULTS: ICT etidronate resulted in a statistically significant and clinically important increase in BMD. The BMD of the lumbar spine increased by 3.82% (0.65%), [95% confidence interval (CI), 2.51 to 5.14%] in the 35 ICT etidronate treated patients and decreased by 1.78% (0.76%), [95% CI, -3.34 to -0.23%] in the 33 comparison patients after 12 months (p2 < 0.0001). CONCLUSIONS: ICT etidronate prevented loss of vertebral bone density in patients with corticosteroid induced osteoporosis. Controlled, double blind, prospective trials with longer followup are needed to confirm these results and to demonstrate that increases in bone mass translate into decreased fracture rates. PMID- 7837161 TI - Musculoskeletal complaints and associated consequences in elderly Chinese aged 70 years and over. AB - OBJECTIVE: To determine the prevalence and sites of musculoskeletal complaints and some associated health consequences among elderly Chinese. METHODS: A random sample of all subjects aged 70 years and over stratified by age and sex. Information collected by questionnaire at an interview. RESULTS: Nineteen to 41% of subjects complained of pain at various sites restricting activities, with a higher prevalence for women. The most common 4 sites involved in order of frequency were knee, upper back, ankle/foot, and shoulder. Back pain increased with age in men to reach the same frequency as women in the 90+ age group. Between 6 to 10% of men and 9 to 14% of women used nonsteroidal antiinflammatory drugs. Pain limiting activities were associated with a lower Barthel index, use of walking aids, increased frequency of doctor consultations, sleep disturbance, and higher depressive symptom scores. CONCLUSION: Prevention of conditions resulting in musculoskeletal complaints would be important in the promotion of healthy active life expectancy in the elderly. PMID- 7837163 TI - ILAR postcongress educational workshop on public education. Gran Sitges Hotel, Sitges, Spain, July 10-11, 1993. PMID- 7837162 TI - The spectrum of myositis and rhabdomyolysis associated with bacterial infection. AB - OBJECTIVE: (1) To describe the clinical and radiographic features of 6 patients with myositis or rhabdomyolysis associated with bacterial infection. (2) To analyze the role of computed tomography (CT) in myositis associated with bacterial infection. METHODS: Review of cases treated by the authors with literature review. RESULTS: Two patients had classical pyomyositis with Staphylococcus aureus as the etiologic agent. One patient had pyomyositis with Enterobacter cloacae (the first reported to our knowledge), 2 had myositis/fasciitis (one due to Clostridium perfringens and one due to S. aureus), and one had fatal toxic rhabdomyolysis in association with C. perfringens bacteremia without evidence of gas gangrene. No patient had a completely normal CT scan of affected muscles, but CT scans in 3 patients failed to show abscesses that were subsequently discovered at surgery, while in another patient CT scanning falsely suggested a large abscess that was not present at surgery. CONCLUSION: Infection associated muscle involvement represents a spectrum of clinical manifestations that include pyomyositis, myonecrosis, fasciitis/myositis, and toxic rhabdomyolysis. Diagnosis may be delayed by the often mild clinical presentation. CT scanning alone may be unreliable in distinguishing muscle abscess from swollen muscle unless combined with CT guided needle biopsy. PMID- 7837165 TI - Phospholipase A2 in juvenile rheumatoid arthritis: correlation to disease type and activity. AB - OBJECTIVE: Secretory nonpancreatic phospholipase A2 (snpPLA2) is a proinflammatory enzyme and its activity in serum correlates with disease activity in adults with rheumatoid arthritis. Juvenile rheumatoid arthritis (JRA) may be stratified into 3 clinical types with differing degrees of disease activity. Since in JRA there are no reliable indices of disease activity, our objective was to find whether the level of circulating snpPLA2 correlates with the severity of inflammation and with JRA activity. METHODS: PLA2 enzymatic activity was assayed using E. coli membranes labelled with (14C)-oleic acid. SnpPLA2 immunoreactivity was tested by ELISA technique using monoclonal antibodies against recombinant human (rh) snpPLA2. SnpPLA2 activity was determined in sera of 127 children including 25 with systemic (S-JRA), 50 with polyarticular (Po-JRA) and 52 with pauciarticular (Pa-JRA) types of JRA. Twenty-five patients with active disease, were subsequently restudied in an inactive phase. RESULTS: Markedly increased snpPLA2 (> mean + 2 SD of normal mean, i.e., > 575 U/ml) was found during the active disease in 100% S-JRA, 57% Po-JRA and 25% Pa-JRA patients. The differences in the mean and median PLA2 activity among these 3 subtypes of JRA were highly significant (p < 0.001) with the highest levels found in S-JRA and the lowest in Pa-JRA. Presence of rheumatoid factor and/or of antinuclear antibody had no relation to the level of snpPLA2. SnpPLA2 activity became markedly lower when active inflammation became quiescent. In the whole group, snpPLA2 activity correlated highly with the Lansbury index, number of involved joints and number of effusions. A significant positive correlation was also found between snpPLA2 and erythrocyte sedimentation rate (ESR) and neutrophil count, while a significant negative correlation was noted with the level of albumin and hemoglobin. With the exception of snpPLA2, other laboratory variables did not correlate with the number of effusions or the number of active joints. However a negative correlation was noted between both hemoglobin and albumin, and Lansbury index. CONCLUSION: Circulating snpPLA2 significantly correlates with JRA activity and may serve as an index of activity in JRA especially in patients with systemic type of disease. PMID- 7837164 TI - Relationship between maternal and neonatal levels of antibodies to 48 kDa SSB(La), 52 kDa SSA(Ro), and 60 kDa SSA(Ro) in pregnancies complicated by congenital heart block. AB - OBJECTIVE: Since there is suggestive but, to date, indirect evidence that maternal anti-SSA(Ro) and SSB(La) antibodies are pathogenic in congenital heart block (CHB), we explored the hypothesis that binding to fetal tissues would result in selective depletion of autoantibodies from the neonatal circulation. METHODS: Maternal and umbilical cord levels of anti-48 kDa SSB(La), anti-52 kDa SSA(Ro) and anti-60 kDa SSA(Ro) antibodies were measured by ELISA and immunoprecipitation at parturition in 15 pregnancies complicated by CHB. A control group consisted of 13 pregnancies in which the mother was known to have antibodies to either SSA(Ro) and/or SSB(La) and the children did not have CHB. RESULTS: The ratios of maternal to cord serum levels of anti-48 SSB(La), anti-52 SSA(Ro) and anti-60 kDa SSA(Ro) antibodies ranged from 0.71 to 2.38 in both affected and unaffected pregnancies. The mean ratio obtained for each of the 3 autoantibodies was not significantly different between the 2 groups. Moreover these ratios did not significantly differ from the mean ratios obtained for total IgG levels in either group. CONCLUSION: These data demonstrate that maternal antibodies to all components of the SSA(Ro) SSB(La) system are efficiently transported across the placenta and are not selectively depleted in the circulation of neonates with CHB. PMID- 7837166 TI - Progression of childhood linear scleroderma to fatal systemic sclerosis. AB - An 8-year-old girl presented with linear scleroderma, no evidence of systemic disease, and a negative antinuclear antibody (ANA) test. Over the next 12 months, she functioned normally. However, over the subsequent 5 months, she developed dyspnea, progressive pulmonary hypertension, a positive ANA test, and died 17 months after presentation. At autopsy, diffuse pulmonary interstitial fibrosis, small pulmonary arterial fibroplasia, tricuspid and mitral valve subendocardial fibrosis, and distal esophageal fibrosis were seen. Contrary to suggestions in the rheumatology literature, childhood linear scleroderma, even when ANA negative at presentation, may progress to fatal systemic sclerosis. PMID- 7837167 TI - Chronic arthritis in a boy with 18q- syndrome. AB - We describe a boy with a terminal deletion of the long arm of chromosome 18 and chronic arthritis involving both knees, one ankle and the temporomandibular joints. In contrast to the majority of patients with 18q- syndrome he has only slight mental disability. His serum IgA is normal. PMID- 7837168 TI - Rheumatoid nodulosis of the meninges. AB - Rheumatoid nodulosis of the brain and leptomeninges has been reported only rarely, usually in patients with severe rheumatoid arthritis (RA). We describe the occurrence of leptomeningeal rheumatoid nodulosis occurring in a patient with nondeforming RA occurring in the setting of methotrexate therapy. PMID- 7837169 TI - Partial splenic embolization for Felty's syndrome: a 10-year followup. AB - Partial splenic embolization was performed in a case of Felty's syndrome in 1980. The granulocyte count has since remained normal without serious infections for the 10 years after the procedure. This is the first report of partial splenic embolization in this syndrome. This treatment may have an advantage over splenectomy because the defense mechanisms of the spleen are preserved and overwhelming infections may occur less frequently. PMID- 7837170 TI - Rhabdomyolysis in a patient with discoid lupus erythematosus. PMID- 7837171 TI - Antiphospholipid and anti-beta 2 glycoprotein I antibodies in monozygotic twin sisters. AB - We describe an 18-year-old woman with primary antiphospholipid syndrome whose monozygotic twin sister is as yet an asymptomatic carrier of the lupus anticoagulant, anticardiolipin, and anti-beta 2 glycoprotein I (beta 2GPI) antibodies. Serum concentrations of beta 2GPI were normal in the patient and elevated in her sister. HLA and complement C4 phenotypes showed the presence of class II antigens DR7 and DRw53 and of a C4AQ0 allele. This supports the theory that a genetic predisposition may influence the appearance of these autoantibodies. PMID- 7837172 TI - Recurrent leukocytoclastic vasculitis as the initial manifestation of acute myelomonocytic leukemia. AB - The association between cutaneous and systemic leukocytoclastic vasculitis and myeloproliferative and lymphoproliferative malignancies has been reported. We describe a patient who developed recurrent episodes of leukocytoclastic vasculitis 10 months before the diagnosis of acute myelomonocytic leukemia. To our knowledge, this is the first documented case of leukocytoclastic vasculitis presenting as the initial manifestation of acute myelomonocytic leukemia, a subtype of acute myelogenous leukemia. PMID- 7837173 TI - Imaging of synovitis in rheumatoid arthritis with radionuclide tracers. PMID- 7837174 TI - Precapillary pulmonary hypertension dramatically improved with high doses of corticosteroids during systemic lupus erythematosus. PMID- 7837175 TI - Intestinal erythema and palpable purpura in the antiphospholipid syndrome. PMID- 7837176 TI - Sex ratio in spondyloarthropathies. PMID- 7837177 TI - Silicone breast implants and connective tissue disease. PMID- 7837178 TI - The autopsy in inner cities. PMID- 7837179 TI - The surgery of ano-rectal anomalies. PMID- 7837180 TI - 'I can tell': an impediment to progress in musculoskeletal medicine. PMID- 7837182 TI - National industry's interest in colorectal cancer screening programmes. AB - The interest of the largest 200 British industries in developing and financing colorectal screening services for employees was determined. A standard questionnaire asked if the company would advertise screening supply names of employees to local hospitals and finance faecal occult blood testing. The reasons for rejection were noted. Eighty-six companies returned the questionnaire (43% response rate) of which 78 firms (39% of the total mailed) were prepared to advertise screening programmes at the workplace. A quarter of the companies were prepared to both advertise and release employee details. Companies willing to participate employed significantly more people (mean of 17,000 employees) than those rejecting screening (mean of 6100 employees, Mann-Whitney U test = 7, P < 0.05). Fifty-nine industries would consider financing screening, although only five made a definite decision to do so. All companies rejecting (36/36) were concerned about releasing employee information to hospitals. If screening does reduce mortality and community programmes are developed industry could and is prepared to advertise such programmes. If a partnership between hospitals and industry is developed, concerns about employee confidentiality needs to be addressed. PMID- 7837181 TI - Natural gastrointestinal ulcer healing mechanism? PMID- 7837183 TI - Auditing the British Medical Journal. AB - The purpose of this study was to audit the outcome in terms of change in practice of the published research from one volume of the British Medical Journal. All original papers and short reports from one Volume 296 of the British Medical Journal (BMJ) 1988 were read and classified into theoretical only, practical and theoretical and practical. Those papers with any practical message were reviewed by one of a panel of specialists in the subject of the paper to assess if the recommendation made by the paper had become common clinical practice. The results show that most papers originated from teaching centres and research institutes in the UK. Only 8% of main papers and 6% of short reports had a solely practical application, although a further 18% and 22% had practical elements. The majority of the recommendations aimed at changing practice were of relevance to hospital specialists rather than general practitioners (GPs). Of the papers with any practical implications 48% (12% of the total) of main papers and 41% (11% of the total) of short reports were considered to be current practice. The reasons why the papers failed to change practice are discussed. In conclusion, the majority of the original research papers published in the BMJ in 1988 were of a theoretical nature and only about 20% of papers made recommendations for a change in practice. About 50% of the recommendations are now current practice. PMID- 7837184 TI - An audit of autopsy rates in an inner London general hospital. AB - Low autopsy rates are of continuing concern to pathologists. The aim of this study was to investigate the reasons why autopsy did not happen, and to determine whether carrying out the investigation and providing some feedback of the results would have any effect on autopsy rates. The main reasons why autopsy did not happen were that junior doctors considered it unnecessary because the diagnosis and cause of death appeared to be well established, and that patients' relatives declined to give permission for autopsy. No increase in autopsy rates was demonstrated, but possible avenues of approach were suggested and these are being implemented. PMID- 7837185 TI - A comparison of stress test referral rates and outcome between Asians and Europeans. AB - The Asian population is at greater risk from a myocardial infarction than their European counterparts. Fewer Asians are referred for coronary angiography. We studied referral rates for exercise stress testing following acute myocardial infarction in Asians and Europeans and also examined stress test outcome. A retrospective analysis was performed using hospital activity analysis data, ward admission book and stress test referral forms and reports. There were 962 acute myocardial infarctions with 90% being European. Fewer Asian patients were referred for stress testing (32.3% versus 45%, P < 0.001). Asian patients were more likely to have a positive test (42.9% versus 31.3%, P < 0.02). Fewer Asian patients completed the test (14.3% versus 31.3%, P < 0.001). Possible reasons for the decreased referral rates include communication difficulties and real or perceived poor exercise tolerance. More Asian patients should be referred for stress testing. Interpreters and information leaflets in multiple languages may help achieve this aim. PMID- 7837186 TI - The emergency department and the community: a model for improved cooperation. AB - Improved emergency care may be achieved by closer integration of hospital and community management. This has been promoted in Salford by the appointment of an Emergency Services Practice Manager jointly funded by the Family Health Services Authority and Salford Health Authority. Communication has improved, complementary working relationships developed and health promotion initiatives established. PMID- 7837187 TI - Facts of primary care in USA and UK: problems in comparisons. PMID- 7837188 TI - New approaches in oral microbiology. PMID- 7837189 TI - The surprising Doctor Welwood: physician and polemicist. PMID- 7837190 TI - The portrayal of the physician in non-medical literature: career choices. PMID- 7837191 TI - The cost effectiveness of combined rapid tests (Multistix) in screening for urinary tract infections. AB - Urinary tract infections (UTI) are relatively common in the urology outpatient's department and the renal transplant unit. Clinical diagnosis is imprecise and laboratory methods take time and are costly. Combined rapid tests (Multistix) were used to screen 400 consecutive mid stream specimens of urine: 200 from urology outpatients and 200 from renal transplant patients. All specimens were also tested in the laboratory. The negative predictive value for excluding UTI was excellent (> 98%) but positive predictive value for confirming presence of UTI was only 50%. However, with this simple screening method, up to 75% of urines can be excluded from laboratory analysis. Since there is a 20-fold difference in cost between dipstix and laboratory testing, the potential savings from this simple screening test is considerable. PMID- 7837192 TI - Madness and Maastricht: a review of reactive psychoses from a European perspective. AB - Brief reactive psychosis has had a chequered career as a valid diagnostic entity, and lack of an international consensus has undermined the concept, but clinical observation attests to its durability. As the European community derestricts its labour boundaries, resulting in psychiatrists increasingly practising outside their country of training, I would suggest that this examination of 'brief reactive psychosis' becomes particularly pertinent with respect to differing diagnostic trends across Europe and elsewhere. PMID- 7837194 TI - Female sexual abuse of children: 'the ultimate taboo'. PMID- 7837193 TI - HIV and psychoimmunology: evidence promising and forthcoming. PMID- 7837195 TI - Long-term faecal continence in infants born with anorectal malformations. AB - In a retrospective study of 92 patients admitted between 1975 and 1986 with anorectal malformations, we reviewed the faecal continence according to the level of their anomaly using a scoring system taken from Pescatori et al. The results of the different operative procedures were compared. Forty-seven of the 50 patients in the low anomaly group had complete faecal continence. Two died from associated anomalies and one infant had incomplete continence. This child had an associated neural tube defect. Of eight patients in the intermediate group, three had good results while two were incontinent: three patients died from associated anomalies. There were 34 patients with high anomalies, 27 of whom showed a wide range of faecal control from complete continence to different degrees of incontinence. Seven infants died from septicaemia and/or associated anomalies. The anatomical level of the lesion and the presence or absence of any associated neurological defect were the main determinants of outcome. The sex of the child and the operative procedure employed to correct the anomaly appeared to be less important. PMID- 7837196 TI - The role of the accident and emergency registrar. PMID- 7837197 TI - Intra-operative monitoring of the common peroneal nerve during total knee replacement. AB - We present a method allowing intra-operative monitoring of the common peroneal nerve during total knee arthroplasty using a magnetic stimulator. Previous reports have shown no pre-operative method successful in selecting those patients prone to develop a post-operative palsy. The device, placed beneath the lumbar spine, stimulates the cauda equina; common peroneal nerve function is assessed via the response in extensor digitorum brevis. There is a loss of signal from the nerve with the use of a tourniquet 25 min following its application. The protocol therefore requires that a tourniquet is used at least only for fixation of the prosthetic components. The method is quick, safe, non-invasive and reproducible, and is of use both in at-risk patients and in research work. PMID- 7837198 TI - Surveillance of duodenal polyps in familial adenomatous polyposis: progress report. AB - Familial adenomatous polyposis (FAP) is characterized by the presence of premalignant adenomas of the large and small bowel. Prophylactic colectomy deals with the risk for colon cancer, leaving duodenal cancer as the leading cause of death. Although most FAP patients have duodenal adenomas, only approximately 5% develop duodenal cancer. This study looks at progression of duodenal polyps with time. The outcome of endoscopic surveillance in the duodenum of 70 patients with familial adenomatous polyposis was determined. A mean of 40 months elapsed between endoscopies. Outcome was measured using video comparison and a staging system that includes histological assessment. Duodenal cancer developed in one patient, and was suspected in two others. The stage of duodenal polyposis worsened in another seven patients. When histology was ignored, comparison of video recordings in 52 patients showed a worsening in 21 (40%). In conclusion, further surveillance appears warranted so that patients at high risk for duodenal cancer might receive early treatment. Should slow progression of duodenal polyposis be shown to be associated with low risk, then most patients can be safely offered less frequent endoscopies than hitherto. PMID- 7837199 TI - Angiokeratoma corporis diffusum in fucosidosis. PMID- 7837200 TI - A case of solitary rectal ulcer syndrome. PMID- 7837201 TI - La Nausee. PMID- 7837202 TI - The population Doomsday forecast. PMID- 7837203 TI - Diagnosis and management of arteritis. PMID- 7837204 TI - Potency equivalence of botulinum toxin preparations. PMID- 7837205 TI - Management of alcohol abusing patients in accident and emergency departments. PMID- 7837206 TI - Drug misusers in police custody. PMID- 7837207 TI - Breast feeding retention rates and supplementary feeds. PMID- 7837208 TI - Call selection of the helicopter emergency medical service. PMID- 7837209 TI - Criteria for an informative trial of left ventricular hypertrophy regression. AB - Although many studies have been made of hypertensive left ventricular (LV) hypertrophy regression, most have been marred by small numbers of subjects, unrepresentative populations, short study duration, lack of comparison between agents, unblinded echocardiographic readings and inappropriate statistical methods. Meta-analysis and critical reviews of this flawed literature suggest, but do not prove, that some antihypertensive drug classes may reverse LV hypertrophy more effectively than others. Eagerly awaited multicentre trials have not provided definitive answers because of pre-emptive success of concomitant nonpharmacological therapy in reversing both hypertension and LV hypertrophy or excessive drop-out of study participants. Future studies that avoid the above limitations are needed to address three sets of questions: relatively small ones (n > or = 40 to 60) to investigate pathophysiology in detail or explore the effects of new agents; medium-sized ones (n > or = 300-400, time > or = 1 year) to determine definitively whether inter-agent differences in reduction of LV mass exist; and large long-term trials (n > or = 1200, time > or = 4 years) to determine whether LV hypertrophy reversal improves prognosis over and above blood pressure reduction and the type of treatment used. PMID- 7837210 TI - Left ventricular mass in hypertension: correlation with casual, exercise and ambulatory blood pressure. AB - The purpose of this work was to assess the best haemodynamic determinant of left ventricular hypertrophy (LVH) in patients with essential hypertension. We studied the relationships between left ventricular mass (LVM) and casual, exercise and 24h ambulatory blood pressure monitoring (ABPM) in 60 newly discovered patients with mild to moderate essential hypertension. LVM was only weakly related to both casual and exercise blood pressure, while it was significantly related to average ABPM values. Diastolic hypertensive load, calculated as the percentage of diastolic measurements > 90 mmHg, was the best predictor of the development of LVH (r = 0.51, P < 0.001). Six of six patients with a diastolic load > 50% had LVH, whereas only two of 18 patients (11%) with a diastolic load < 10% had LVH (P < 0.001). In conclusion, in patients with mild to moderate essential hypertension, LVM is poorly related to both casual and exercise blood pressure, but is related to ABPM. Blood pressure load is the best determinant of LVH. These findings suggest that blood pressure load should be considered when analysing ABPM. PMID- 7837211 TI - Modulation of natriuresis and renal dopamine excretion by sympathetic activity and the renin-angiotensin-aldosterone system. AB - The involvement of the sympathetic nervous system and the renin-angiotensin aldosterone system in renal dopamine (DA) synthesis and sodium excretion (UNaV) were studied in 11 healthy volunteers. On a low sodium diet (LoSo, 50 mmol Na+) saline infusions were given without pretreatment or after oral intake of 50 mg captopril or 300 micrograms clonidine. On a high sodium diet (HiSo, 250 mmol Na+) saline was infused without or after intake of 300 micrograms clonidine. UNaV, the excretion rates of the DA precursor 3,4-dihydroxyphenylalanine (DOPA; UDOPAV), DA (UDAV), and noradrenaline (NA; UNAV), hormonal parameters, blood pressure (BP), glomerular filtration parameters, blood pressure (BP), glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured. Saline infusion alone during LoSo increased natriuresis without changes in catechol excretion or suppression of plasma renin activity (PRA) or plasma aldosterone (PALD). Sympatho inhibition by clonidine resulted in marked antinatriuresis, decrease in BP and decrease in UDOPAV and UDAV, whereas plasma DOPA, GFR, and ERPF remained unchanged. PRA and PALD rose as indication of activation of the RAA system, probably by the reduced renal perfusion pressure after clonidine. Captopril significantly stimulated the saline-induced natriuresis without affecting UDOPAV and UDAV. On HiSo, when sympathetic tone is relatively suppressed, saline infusion alone stimulated natriuresis but did not affect catechol excretion or PRA. In the first and second hour after saline infusion PALD was suppressed. Clonidine again reduced BP and natriuresis, while PRA, PALD, and UDOPAV and UDAV were unaffected. These results suggest that sympathetic nerve activity may stimulate the intrarenal DA production.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7837212 TI - Does insulin resistance participate in an impaired glucose tolerance in primary aldosteronism? AB - It has been reported that glucose intolerance is occasionally found in primary aldosteronism. In this study, we measured insulin sensitivity by the euglycaemic hyperinsulinaemic glucose clamp technique and ability to release insulin by 75 g oral glucose tolerance test (OGTT) in primary aldosteronism. Seven patients with primary aldosteronism (PA) (53.7 +/- 3.4 years; mean +/- SEM) and eight normotensive subjects (NS) (57.5 +/- 2.6 years) were employed in this study. The two-hour euglycemic hyperinsulinaemic glucose clamp technique was performed in seven PA before adrenalectomy, six PA after adrenalectomy and eight NS. The 75 g OGTT was also done in five PA before and after adrenalectomy and eight NS. The mean rate of glucose infusion to maintain euglycemia for the last 30 minutes of the clamp technique was used as an indicator of insulin sensitivity (M-value). The total blood glucose levels during 75 g OGTT (area under the curves) (sigma blood glucose) were significantly higher in PA than those in NS, and the total insulin levels during 75 g OGTT (area under the curves) (sigma IRI) were significantly lower in PA than those in NS. After adrenalectomy in PA, blood glucose levels were significantly decreased and IRI were significantly increased compared with the normal range. There was a significant positive correlation (P < 0.05, r = 0.71) between serum potassium levels and IRI in PA which were determined before and after adrenalectomy. In PA, M-values (240.7 +/- 14.6 mg/m2/min) were significantly higher than those in NS (199.0 +/- 12.3 mg/m2/min).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7837213 TI - Endothelin in mild to moderate essential hypertension: relationship between ambulatory and clinic blood pressure values. AB - We investigated in a post hoc analysis the relationship between plasma endothelin (ET-1) levels (immunoreactive ET-1-like material: ir-ET-1) with both casual and noninvasive 24h ambulatory blood pressure monitoring (24h ABPM) values in EH. Fifteen uncomplicated EH patients (casual supine DBP > or = 100 mmHg), 10 males, age 54 +/- 6 years, 13 previously treated, enrolled in an antihypertensive drug trial (casual DBP > or = 100 mmHg), were evaluated. After a four week single blind placebo wash-out period, measurements of supine casual SBP and DBP (three consecutive readings) and a 24h ABPM (Spacelabs 90207; automatic reading every 15 minutes) were carried out. Plasma ir-ET-1 was measured by radioimmunoassay kit (Amersham, UK). Pearson correlation coefficient tests were used for statistical evaluations. Mean (SD) casual SBP/DBP values were 166(5)/104(2) mmHg. The 24h ABPM mean values were 148(7)/87(3) mmHg. Daytime (07.00-23.00h) and nighttime (23.00-07.00h) SBP/DBP were 153(7)/91(3) and 137(10)/78(5) mmHg, respectively. Plasma ir-ET-1 levels were 0.9(0.5) pmol/l (range 0.3-2.1 pmol/l). Plasma ir-ET-1 was not correlated with casual SBP and DBP, age, serum creatinine and duration of EH. Positive and significant correlations were observed with 24h SBP (r = 0.59), daytime SBP (r = 0.58), nighttime SBP (r = 0.53) and DBP (r = 0.60). Unlike casual BP, ABPM mean values correlate positively with plasma ir-ET-1 in mild to moderate EH. PMID- 7837214 TI - Cigarette smoking in pregnancy and risk of pre-eclampsia. AB - The relationship between smoking in pregnancy and the development of pre eclampsia has not been well studied. Smoking habits were prospectively evaluated in 117 patients with pre-eclampsia and 468 normotensive control pregnancies. Twenty cases (17.1%) and 120 controls (25.6%) reported smoking at any time during pregnancy. In stepwise multiple logistic regression analysis, smoking in pregnancy was a significant protective factor against the occurrence of pre eclampsia (adjusted odds ratio = 0.50; 95% confidence interval 0.28-0.80, P = 0.018). On the other hand, a history of pre-eclampsia in previous pregnancies, low (< 6th grade) educational level, a body mass index > 24 and maternal blood group AB were factors independently associated with an increased risk of pre eclampsia. In conclusion, this study confirms that smoking in pregnancy reduces the risk of pre-eclampsia. However, the harmful consequences of smoking on pregnancy outcome far outweigh this risk reduction. PMID- 7837215 TI - Lisinopril versus slow release nifedipine in patients with essential hypertension: a multicentre study. AB - The present study was performed to investigate the efficacy and safety of the angiotensin converting enzyme (ACE) inhibitor lisinopril compared with those of the calcium channel blocker nifedipine in 293 patients with mild to moderate essential hypertension (supine diastolic blood pressure (DBP) 95-115 mmHg) in a multicentre, randomised, double-blind parallel group study after a two week single-blind placebo run-in period. Thus, the haemodynamic effects as well as side-effects during antihypertensive treatment were examined in 146 patients receiving lisinopril (20 mg once daily) and in 147 patients receiving slow release nifedipine (20 mg twice daily) who entered the six weeks' treatment period. From the analysis of efficacy one patient from the lisinopril and two patients from the nifedipine groups were excluded because their supine DBP after run-in was < 95 mmHg. Adverse reactions, mostly transient during the initial treatment period, and withdrawals occurred in six (4.1%) and three (2.1%) patients of the lisinopril group and in 12 (8.2%; NS) and three (2.0%) patients of the nifedipine group, respectively. After the six weeks' treatment period the lisinopril group showed 19 nonresponders (supine DBP > or = 95 mmHg) of the remaining 142 patients and the nifedipine group revealed 20 nonresponders of the remaining 142 patients. Initial supine and standing heart rates were similar in both groups. Supine heart rate fell significantly in the lisinopril group, whereas standing heart rate in this group and supine and standing heart rates in the nifedipine group did not change significantly with treatment. Thus, lisinopril proved to be as effective and safe as nifedipine with responder rates of 86.6% and 85.9%, respectively. PMID- 7837216 TI - Comparison of the effects of cilazapril in an elderly and nonelderly hypertensive general practice population. AB - The ACE inhibitor cilazapril was studied in mild to moderate hypertensive patients in general practice to evaluate the effect of age on hypotensive response to low (0.5 and 1 mg) doses. Six hundred and seventy-one patients entered a two week single-blind placebo run-in period and 524 patients were eligible to receive active treatment titrated up to a maximum dose of 5 mg. All patients received 0.5 mg of cilazapril once daily for four weeks. The dose was titrated at monthly intervals to 1, 2.5 and 5 mg once daily if DBP remained > 90 mmHg. If DBP < or = 90 mmHg patients remained at their current dose level until the end of the study. Three hundred and twenty-nine patients < 65 years old and 195 patients > or = 65 years old took active treatment. Binary logistic regression detected no statistically significant difference in response between the two groups (P > 0.2) at low doses of cilazapril. Cumulative response rates (DBP < or = 90 mmHg) for all patients were 24.5%, 40.4%, 54.5% and 62.7% for the escalating dose groups. Cumulative augmented response rate (DBP < or = 90 mmHg and/or reduction in DBP of > or = 10 mmHg) at the 5 mg dose level was 76.7% for all patients. Cilazapril was well tolerated with the pattern of adverse events reflecting those currently documented. A higher proportion of patients than expected responded to the low doses of cilazapril. This effect was not age dependent. These doses are lower than the recommended maintenance doses of 2.5-5 mg in the UK data sheet.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7837217 TI - Shall we treat isolated systolic hypertension in 1994? PMID- 7837218 TI - Economics of hypertension control: a statement by the World Hypertension League. AB - While expenditures for hypertension are on the increase in developed countries, and potentially also in the developing world, resource constraints, even in the most affluent countries, need to consider hypertension control in the context of other demands of society. This position paper sums up the key aspects of the debate: problems of estimating the economic burden of hypertension and hypertension-related disease; the use of economic models; and opportunities for containing the costs. Direct healthcare costs of hypertension are amenable to calculations; but more information is needed on the population attributable risk of hypertension in various countries, indispensable to estimate the part of hypertension in the burden of stroke and heart disease. The population and the high-risk approach to hypertension control also have economic consequences; these may vary in different societies and need to be assessed to ensure appropriate allocation of resources. Cost containment can be achieved i.a. by more selective diagnostic investigations, and by opting for cheaper drugs, though the choice of treatment is difficult owing to uncertainties in the quality-of-life estimates. The economics of hypertension is a complex field, calling for continued research and monitoring. PMID- 7837219 TI - Validity and reliability of 24h blood pressure monitoring in children and adolescents using a portable, oscillometric device. PMID- 7837220 TI - Anti-human immunodeficiency virus and anti-hepatitis-B virus activities and toxicities of the enantiomers of 2'-deoxy-3'-oxa-4'-thiocytidine and their 5 fluoro analogues in vitro. PMID- 7837221 TI - Pyrrolo[1,2-a]benzimidazole-based quinones and iminoquinones. The role of the 3 substituent on cytotoxicity. AB - The influence of the 3-substituent on the cytotoxicity of the 6 aziridinylpyrrolo[1,2-a]-benzimidazole quinones (PBIs), the 6 acetamidopyrrolo[1,2-alpha]benzimidazole quinones (APBIs), and the 6 acetamidopyrrolo[1,2-alpha]benzimidazole iminoquinones (imino-APBIs) was investigated by comparing LC50 mean graphs consisting of 60 cancer lines. Increasing lipophilicity of the 3-substituent of PBIs and APBIs increased the cytotoxicity specifically in melanoma cell lines. The 3-substituent does not influence DNA cleavage by reduced PBIs, except for the 3-carbamate derivative which shows enhanced cleavage. This property of the 3-carbamate is rationalized in terms of the PBI major groove binding model. The imino-APBIs show enhanced cytotoxicity in melanoma and renal cancer cell lines; the correlation coefficient for log LC50 vs log lipophilicity is 0.8 to 0.9. COMPARE correlations revealed that the PBIs are activated by DT-diaphorase but that the APBIs and imino-APBIs are inactivated by this enzyme. Thus, the latter two agents are cytotoxic only as quinones. It was noted that APBIs possess a similar cytotoxic profile to three anthracycline analogues. This observation suggests mechanistic similarities between both types of cytotoxic agents. Major conclusions of this study pertain to the design of agents displaying cytotoxicity specifically against melanoma and renal cancers and to the use of 60-cell line mean graphs and COMPARE in cancer drug QSAR. PMID- 7837222 TI - Calcium entry blockers and activators: conformational and structural determinants of dihydropyrimidine calcium channel modulators. AB - Dihydropyrimidines 4, 6, and 15, uniquely designed to unambiguously establish structural and conformational determinants for DHP receptor occupation and for modulation of calcium channel function, were prepared and examined for calcium channel modulation. Our results confirm and firmly establish a preference for syn orientation of an unsymmetrically substituted aryl moiety at the DHP receptor (15d vs 15e). We propose a normal vs capsized DHP boat model to explain structural and conformational requirements for modulation of calcium channel function that requires an obligatory left-hand side alkoxy cis-carbonyl interaction for maximal DHP receptor affinity, the effect of channel function being determined by orientation of the 4-aryl group. Enantiomers having an up oriented pseudoaxial aryl group (normal DHP boat) will elicit calcium antagonist activity, whereas enantiomers having a down-oriented pseudoaxial aryl group (capsized DHP boat) will elicit calcium agonist activity. Single enantiomers of macrocyclic lactone 15b demonstrate opposite channel activity. Antagonist activity resides in enantiomer 15b-A (S-configuration, left-hand side alkoxy cis carbonyl with up-oriented pseudoaxial aryl group and normal DHP boat), whereas agonist activity resides in enantiomer 15b-B (R-configuration, left-hand side alkoxy cis-carbonyl with down-oriented pseudoaxial aryl group and capsized DHP boat). Moreover, this model is consistent with and provides a rational explanation of previous literature in this area, most notably the observation of chiral inversion and potency diminution upon replacement of ester by hydrogen in the Bay K 8644 series. PMID- 7837223 TI - Benzophenone- and indolecarboxylic acids: potent type-2 specific inhibitors of human steroid 5 alpha-reductase. PMID- 7837224 TI - New antianginal nitro esters with reduced hypotensive activity. Synthesis and pharmacological evaluation of 3-[(nitrooxy)alkyl]-2H-1,3-benzoxazin-4(3H)-ones. AB - New nitro ester 3-[(nitrooxy)alkyl]-2H-1,3-benzoxazin-4(3H)-ones show marked inhibitory activity against ischemia-induced electrocardiographic changes, with only limited systemic hemodynamic effects, and are reported in the present study. These new nitro vasodilators are potent inhibitors of the electrocardiographic T wave and S-T segment elevation induced by intravenous or intracoronary administration of Arg-vasopressin or methacholine in the anesthetized rat. The most active compounds are up to 300- and 600-fold more potent than glyceryl trinitrate or Nicorandil, respectively. These nitro esters relax in a concentration-dependent manner the isolated rabbit aorta, at higher concentrations (2-40-fold) than glyceryl trinitrate, and reduce the mean arterial blood pressure at doses 7-300-fold higher than those required by glyceryl trinitrate to exert a similar hypotensive effect. Remarkably, these compounds retain their anti-ischemic and hemodynamic profile after oral (po) administration. These new nitro ester derivatives, endowed with a marked antianginal activity, which is not associated with concurrent and pronounced falls in systemic blood pressure, represent the leads of a new class of selective nitrovasodilators having a preferential action on large coronary vessels, which could be clinically relevant in the treatment of coronary artery diseases. PMID- 7837225 TI - Ac-[3- and 4-alkylthioproline31]-CCK4 analogs: synthesis and implications for the CCK-B receptor-bound conformation. AB - It has been reported that substitution of the Met31 residue in Boc-CCK4 (Boc Trp30-Met31-Asp32-Phe33-NH2, CCK33 numbering) by trans-3-propyl-L-proline yields a highly potent and selective CCK-B agonist. To further explore the structural requirements of the Met31 side chain in the receptor-bound conformation of CCK4, we have synthesized several Ac-CCK4 analogs containing substitution of Met31 by 3 and 4-(alkylthio)-substituted proline derivatives. To this end we have developed novel synthetic routes to enantiomerically pure N-Boc-4-cis- and -trans (methylthio)prolines and racemic N-Boc-3-cis and -trans-[(4 methylbenzyl)thio]prolines. The protected mercaptoprolines were incorporated into Ac-CCK4 analogs using SPPS and were alkylated using various electrophiles following cleavage from the solid support. Binding assays reveal that 3 (alkylthio)prolines analogs have higher affinities at the CCK-B receptor than the corresponding 4-(alkylthio)proline analogs, and that trans-3-(alkylthio)proline analogs had higher affinities than corresponding cis-3-(alkylthio)proline analogs. Within both the cis- and trans-3-(alkylthio)proline series, the order of potency was found to be Me < Et < n-Pr. The trans-3-(n-propylthio)-L-proline analog demonstrates a higher affinity than that reported for Boc-CCK4[trans-3 propyl-L-Pro31]. Comparison of the low-energy structures calculated for several high-affinity Ac-CCK4 analogs reveal a common geometry which we propose to be the CCK-B receptor-bound conformation. This model shows grouping of the hydrophobic side chains of Trp, Met, and Phe at one side of the molecule and the hydrophilic side chain of Asp and the C-terminal carboxamide at the other side. PMID- 7837226 TI - Potential anxiolytic agents. Pyrido[1,2-a]benzimidazoles: a new structural class of ligands for the benzodiazepine binding site on GABA-A receptors. PMID- 7837227 TI - Glycosylated peptide hormones: pharmacological properties and conformational studies of analogues of [1-desamino,8-D-arginine]vasopressin. AB - Two analogues of the antidiuretic drug [1-desamino,8-D-arginine]vasopressin (DDAVP), which have a glycosylated serine at position 4, have been prepared by Fmoc solid phase peptide synthesis. The glycosylated analogues had significantly higher bioavailabilities than the nonglycosylated [D-Tyr2,Ser4]DDAVP and DDAVP on intraintestinal administration in rat. The improved bioavailability resulted from an increased absorption from the small intestine and most likely from an increased stability toward enzymatic degradation, whereas plasma clearance was either unaffected or slightly increased by the glycosylation. The glycosylated analogues displayed only very low agonistic and antagonistic activities at the vasopressin V2-receptor. Conformational studies performed by 1H NMR spectroscopy did not reveal any major influence from glycosylation on the conformation of the peptide backbone. The lack of receptor binding displayed by the analogues is therefore most likely explained by steric repulsion between the carbohydrate moiety and the vasopressin receptor which prevents receptor binding. PMID- 7837228 TI - X-ray crystal structure, partitioning behavior, and molecular modeling study of piracetam-type nootropics: insights into the pharmacophore. AB - To detect possible molecular determinants of amnesia-reverting activity, the conformational properties of a number of rigid and flexible piracetam-type cognition enhancers have been assessed by X-ray diffraction, NMR spectroscopy, and ab initio and high-temperature-quenched molecular dynamics (QMD) calculations. The structures of the preferred conformers in solution derived from 1H-NMR spectral analysis were in good agreement with those found by QMD calculations. Interestingly, the calculation of the average molecular lipophilicity potential on the water-accessible surface of the selected conformers was helpful in interpreting the partitioning behavior observed by measuring octanol-water partition coefficients and capacity factors in reversed phase high-performance liquid chromatography. While lipophilicity does not play a relevant role, the distance between polar groups, accounted for by the distance between carbonyl oxygens, emerges as a factor, among others, which should influence the amnesia-reversal activity of piracetam-type nootropics. PMID- 7837229 TI - Design and synthesis of piperidine-3-carboxamides as human platelet aggregation inhibitors. AB - A detailed structure-activity analysis was carried out using eight 1 alkyl(aralkyl)nipecotamides (type 5), 33 bis-nipecotamidoalkanes and aralkanes (type 6), and 7 N,N'-bis(nipecotoyl)-piperazines (type 7) as inhibitors of human platelet aggregation. Steric factors played an important role in determining the activity of type 5 compounds possessing an an appropriate degree of hydrophobic character. Types 6 and 7 compounds were more potent than the corresponding type 5 molecules. Hydrophobic character appeared to influence the activity of type 6 compounds. A 3-substituent on the piperidine ring was necessary for antiplatelet activity; the substituent should be preferably an amide with its C attached directly to the ring. 3,5-Disubstitution and 2-substitution led to a decline in activity. Optimal activity was attained when the two nipecotoyl ring N atoms were connected by an aralkyl group, and separated by approximately 7 A. It is suggested that van der Waals forces and pi interactions may govern the inhibitor platelet interaction. The most potent type 6 inhibitor was alpha,alpha'-bis[3-(N ethyl-N-butylcarbamoyl)piperidino]-p-xylene (6i). The most potent type 5 compound was 1-decyl-3-(N,N-diethylcarbamoyl)piperidine (5a). Any substitution on the piperazine ring of type 7 compounds led to a decline in activity, the most active analog being N,N'-bis(1-decylnipecotoyl)piperazine (7a). It is suggested that nipecotamides interact with anionic platelet sites located 7 A from each other and connected by a hydrophobic well. PMID- 7837230 TI - Synthetic routes to 4-amino-3-carboxy-beta-carboline derivatives: incidental formation of novel furo[3,4-c]-beta-carbolin-2-ones displaying high affinities for the benzodiazepine receptor. AB - The synthesis of the first 4-amino-3-carboxy-beta-carboline derivative (35) is described. This synthesis is based on ozonolysis of the 4-vinyl-beta-carboline-3 carboxamide 17 to give the 4-aldehyde 20 and potassium permanganate oxidation of the latter to the 4-carboxylic acid 34 followed by a DPPA-promoted Curtius rearrangement. During the course of these transformations, a number of furo[3,4 c]-beta-carbolin-2-ones, differing in substituents at the C-10 position, were formed. While these beta-carboline lactones (15,25,26,33) generally displayed good affinities for the central type benzodiazepine receptor in vitro (IC50's in the 10-50 nM range), one compound, 29, demonstrated an exceptionally high binding affinity (IC50 = 0.2 nM). Compound 29 was shown in electrophysiological and behavioral studies to act as a benzodiazepine receptor antagonist. The unusually high binding affinity of compound 29 corroborates the hypothesis that the benzodiazepine receptor preferentially recognizes the C-3 carbonyl function of 3 carboxy-beta-carbolines in an s-cis conformation (i.e., the carbonyl oxygen on the same side as the pyridinyl nitrogen). PMID- 7837231 TI - Synthesis and cytotoxic activity of 6-vinyl- and 6-ethynyluridine and 8-vinyl-and 8-ethynyladenosine. AB - It is well-known that the introduction of vinyl and ethynyl moieties into nucleosides is of crucial importance for cytostatic, antiviral, or other biological activities. In this study 6- and 8-vinyl-and -ethynyluridine and adenosine were prepared by a general procedure involving the palladium-catalyzed cross-coupling of trimethylsilylacetylene or vinyltributyltin. The introduction of a vinyl group at C-6 of uridine or an ethynyl group at C-8 of adenosine resulted in nucleoside derivatives showing cytostatic activity against several murine and/or human tumor cell lines. Interestingly, 8-vinyladenosine had pronounced selective inhibitory effects on human (Molt/4F and MT-4) versus murine (L1210 and FM3A) tumor cell lines. PMID- 7837232 TI - Synthesis and activity of some antimalarial bisquinolines. AB - A new type of bisquinoline antimalarial, in which the basic side chain of chloroquine is retained, has been evaluated. Nine bisamides were prepared from aliphatic diacids with 6-amino- and 8-amino-((4-(diethylamino)-1 methylbutyl)amino)quinoline, and screened against chloroquine-sensitive and resistant strains of Plasmodium falciparum in vitro. The resistance indices for all compounds were lower than for chloroquine. The position of attachment and length of the linker chain markedly affected activity. The most active (IC50 = 120 nM against the chloroquine-resistant FAC8 strain) was the -(O)C(CH2)4C(O)- linked 8-amino compound. PMID- 7837234 TI - Discovery of 6,11-ethano-12,12-diaryl-6,11-dihydrobenzo[b]quinolizinium cations, a novel class of N-methyl-D-aspartate antagonists. AB - 6,11-Ethano-12,12-diaryl-6,11-dihydrobenzo[b]quinolizinium cations 8, a novel class of N-methyl-D-aspartate (NMDA) antagonists acting at the phencyclidine site, have been identified. Structure-activity relationship studies around the lead compound 8a led to the identification of 12g (WIN 67870-2), one of the most potent compounds in this series. Compound 12g has a Ki = 1.8 +/- 0.2 nM vs [3H]TCP binding, has 700-fold selectivity for binding to the open state of the NMDA receptor-ionophore, and was devoid of MK-801- and PCP-like behavioral effects in rats. Compound 12g was neuroprotective in cultured mouse cortical neurons and exhibited antiischemic activity in a rat middle cerebral artery occlusion/reperfusion model of focal ischemia. PMID- 7837233 TI - CCK-A receptor selective antagonists derived from the CCK-A receptor selective tetrapeptide agonist Boc-Trp-Lys(Tac)-Asp-MePhe-NH2 (A-71623). AB - Analogs of the CCK-A receptor selective agonist Boc-Trp-Lys(Tac)-Asp-MePhe-NH2 (A 71623) were prepared in which the lysine residue was replaced with L-4 aminophenylalanine and D-or L-3-aminophenylalanine. These new analogs were moderately potent antagonists of CCK-8 in the isolated guinea pig gallbladder with exceptional CCK-A receptor selectivity as evaluated in membrane preparations from CHO K1 cells stably transfected with human CCK-A and CCK-B receptors. PMID- 7837235 TI - Nonpeptidic inhibitors of human leukocyte elastase. 6. Design of a potent, intratracheally active, pyridone-based trifluoromethyl ketone. AB - Further modification of the 3-amino substituent in a trifluoromethyl ketone-based series of 3-amino-6-phenylpyridin-2-ones that had been optimized for oral activity led to analogs that were potent intratracheal inhibitors in a model of HLE-induced lung damage in the hamster. The best 3-amino substituent for intratracheal activity is [4-[N-[(4-chlorophenyl)sulfonyl] carbamoyl]phenyl]sulfonyl. At a 30 min prechallenge interval, compound 9, which incorporates this substituent, had an ED50 of approximately 2 nmol/animal and, qualitatively, afforded a very similar dose-response relationship to that found with a peptidic trifluoromethyl ketone inhibitor, ICI 200,355. PMID- 7837236 TI - (+)-cis-4,5,7a,8,9,10,11,11a-octahydro-7H-10-methylindolo[1,7- bc][2,6] naphthyridine: a 5-HT2C/2B receptor antagonist with low 5-HT2A receptor affinity. AB - The indolonaphthyridine 8 is described as a selective 5-HT2C/2B vs 5-HT2A receptor antagonist. The compound was synthesized in seven steps starting from indoline and isonicotinic acid chloride. The key step is a photocyclization of the indolinyl tetrahydropyridinocarbamic acid ethyl ester 4 to the cis octahydroindolo[1, 7-bc][2,6]naphthyridinecarbamic acid ethyl ester 5. The synthesis was accomplished by reduction with aluminum hydride and racemic resolution. The indolonaphthyridine 8 exerted the binding profile of a selective 5-HT2C receptor ligand (pKD 7.8) and behaved as an antagonist on the 5-HT-induced accumulation of inositol phosphates in pig choroid plexus cells (pKB 7.13). Compound 8 dose-dependently inhibited the ACTH response to MK-212 in rats and the MK-212-induced hypophagic effect with an ID50 value of 0.3 mg/kg sc. Compound 8 acted as a 5-HT2B receptor antagonist at the rat stomach fundus with a pKB value of 7.34. PMID- 7837237 TI - Novel thiazole-based heterocycles as selective inhibitors of fibrinogen-mediated platelet aggregation. AB - The synthesis and biological activity of novel thiazole-based heterocycles as inhibitors of thrombin-induced human platelet aggregation are described. Further evaluation of selected compounds show they inhibit platelet aggregation as stimulated by a variety of agonists. The more active compounds also were found to inhibit fibrinogen binding to platelets. To further delineate the mechanism of action of these compounds, direct binding studies with the purified glycoprotein (GP) IIb/IIIa receptor were performed. Flow cytometry analyses of 24 and 32 indicate that these compounds block the activation process of the GPIIb/IIIa receptor without denaturing the integrin receptor. On the basis of these studies, 32 exhibited the best profile as a novel nonpeptide inhibitor of fibrinogen mediated platelet aggregation. PMID- 7837238 TI - Relative binding free energies of peptide inhibitors of HIV-1 protease: the influence of the active site protonation state. AB - Hydrogen bonding plays an important role in the stabilization of complexes between HIV-1 protease (HIV-1 PR) and its inhibitors. The adequate treatment of the protease active site protonation state is important for accurate molecular simulations of the protonation state is important for accurate molecular simulations of the protease-inhibitor complexes. We have applied the free energy simulation/thermodynamic cycle approach to evaluate the relative binding affinities of the S vs R isomers of the U85548E inhibitor of the protease. Several mono- and diprotonation states of the catalytic aspartic acid residues of the protease active site were considered in the course of molecular simulations. The calculated difference in binding free energy of the S vs R isomers strongly depended on the location of proton(s), but in all cases the binding free energy of the S inhibitor was higher. On the basis of our calculations, we propose that in the HIV-1 PR-inhibitor complex only one catalytic aspartic acid residue is protonated and that the binding free energy of the S isomer is ca. 2.8 kcal/mol higher than that of the R isomer. The accuracy of these predictions shall be evaluated when binding affinities of both isomers become available. PMID- 7837239 TI - Synthesis, properties, and pharmacokinetic studies of N2-phenylguanine derivatives as inhibitors of herpes simplex virus thymidine kinases. AB - Two series of selective inhibitors of herpes simplex virus types 1 and 2 (HSV1,2) thymidine kinases (TK) have been developed as potential treatment of recurrent virus infections. Among compounds related to the potent base analog N2-[m (trifluoromethyl)phenyl]guanine (mCF3-PG), none was a more potent inhibitor than mCF3PG itself. Compounds related to the nucleoside N2-phenyl-2'-deoxyguanosine (PhdG), but with alkyl, hydroxyalkyl, and related substituents at the 9-position in place of the glycosyl group of PhdG, retained significant but variable inhibitory potencies against the HSV TKs. The most potent inhibitor of HSV1 TK among 9-substituted derivatives, 9-(4-hydroxybutyl)-N2-phenylguanine (HBPG), was a competitive inhibitor with respect to the substrate thymidine but was not itself a substrate for the enzyme. Water solubilities and 1-octanol:water partition coefficients for the 9-substituted N2-phenylguanines were linearly but oppositely related to the sum of hydrophobic fragmental constants (sigma f) of the 9-substituents. Four of the inhibitors were given as solutions to mice by iv and ip routes, and the time course of their plasma concentrations was determined by HPLC analysis of the parent compounds. HBPG was completely absorbed by the ip route, and the plasma concentration could be prolonged by use of suspension formulations. HBPG is a candidate for animal trials of the ability of TK inhibitors to prevent recurrent herpes virus infections. PMID- 7837240 TI - Preparation of 18F-labeled muscarinic agonist with M2 selectivity. PMID- 7837241 TI - Tyrosine kinase inhibitors. 4. Structure-activity relationships among N- and 3 substituted 2,2'-dithiobis(1H-indoles) for in vitro inhibition of receptor and nonreceptor protein tyrosine kinases. AB - A series of 3-substituted 2,2'-dithiobis(1H-indoles) were synthesized and evaluated for their ability to inhibit the tyrosine kinase activity of both the epidermal growth factor receptor (EGFR) and the nonreceptor pp60v-src tyrosine kinase, to extend the available structure-activity relationships for this series. The majority of the compounds were prepared either by reaction of 2-chloro-1 methylindole-3-carbonyl chloride with amines, followed by thiomethylation, demethylation, and oxidative dimerization, or by reaction of isocyanates with the anion of 1-methyl-2-indolinethione followed by dimerization. Overall, inhibitory activity is retained by analogues having a wide variety of side chains. A series of 3-carboxamide analogues had moderate to good activity against isolated EGFR (IC50s 1-20 microM), with monoalkyl substitution of the carboxamide being optimal. Polar side chains were generally less effective than lipophilic ones, with benzyl being particularly effective. However, N,N-disubstitution was the most effective pattern for inhibition of pp60v-src. A variety of substituted N phenylcarboxamides had lower activity against EGFR than the parent derivative, and a N-thienylcarboxamide also had low activity. A series of 3-ketones, including methyl, phenyl, and furyl derivatives, showed moderate activity against the pp60v-src kinase, but were less effective against EGFR. The mechanism of inhibition of both kinases by these drugs was shown to be noncompetitive with respect to both ATP and peptide substrate. Selected compounds inhibited the growth of Swiss 3T3 cells with IC50s in the low micromolar range and inhibited bFGF-mediated intracellular tyrosine phosphorylation in the same cell line. Thiol inhibits the effects of the compounds, suggesting that one possible mechanism of inhibition is thiol-disulfide exchange with thiol-containing residues in the catalytic sites. Crystal structures of two representative compounds show a folded, V-shaped structure, with the disulfide bridge exposed, consistent with this hypothesis. PMID- 7837242 TI - Derivatives of 2-[[N-(Aminocarbonyl)-N-hydroxyamino]methyl]-1,4- benzodioxan as orally active 5-lipoxygenase inhibitors. AB - N-Hydroxyureas based on the 1,4-benzodioxan template were prepared from appropriately substituted 1,4-benzodioxan-2-methanols as the key intermediates and evaluated in the in vitro guinea pig polymorphonuclear leukocyte 5 lipoxygenase (5-LO) assay for their 5-LO inhibitory activity. Placement of a 7 phenoxy or 7-p-fluorophenoxy substituent resulted in a dramatic increase in in vitro potency. Selected compounds were subsequently assayed in an ex vivo dog model of LTB4 synthesis at a dose of 1.0 mg/kg. The 7-phenoxy derivatives 16 and 17 showed modest duration of action (DA) in this dog model. The 6-regioisomers 21 and 22 were less potent. Replacement of the 7-phenoxy group of 16 with the p fluorophenoxy moiety enhanced the DA dramatically. Compound 18 (CGS 25667), which had an IC50 value of 100 nM in the in vitro guinea pig 5-LO assay, had a DA of 8.5 h (zileuton, DA = 8.5 h) at the oral dose of 1.0 mg/kg. Optical antipodes (24, 26) of 18 were independently synthesized in high (> 95%) enantiomeric purity from commercially available optically active glycidyl tosylates and evaluated. In the in vitro assay, the 2S-(-)-enantiomer (24, CGS 25997, IC50 = 85 nM) was found to be twice as active as the 2R-(+)-counterpart (26, CGS 25998, IC50 = 180 nM). In the ex vivo experiment, 24, which dose dependently inhibited plasma 5-LO activity, was shown to be significantly longer acting than 26, with a DA of 8.4 h when dosed orally at 1.0 mg/kg. PMID- 7837243 TI - Peptidyl alpha-ketoheterocyclic inhibitors of human neutrophil elastase. 2. Effect of varying the heterocyclic ring on in vitro potency. AB - A series of peptidyl alpha-ketoheterocycles were synthesized and evaluated for their in vitro inhibition of human neutrophil elastase (HNE). Several heterocycles, including oxazoline and benzoxazole, afforded extremely potent inhibitors of HNE (1p-r) with nanomolar to subnanomolar Ki values. The structure activity relationships revealed that for compounds with a Ki < 1000 nM potency tends to be positively correlated with the sigma I value of the heterocycle. Furthermore, the results in this study support the hypothesis that, in the covalent enzyme-inhibitor adduct, the azole nitrogen atom of the inhibitor heterocycle participates in a hydrogen-bonding interaction with the active-site His-57. PMID- 7837244 TI - Non-peptidic inhibitors of human leukocyte elastase. 4. Design, synthesis, and in vitro and in vivo activity of a series of beta-carbolinone-containing trifluoromethyl ketones. AB - A novel series of human leukocyte elastase (HLE) inhibitors containing the beta carbolinone ring system are reported. The design of these trifluoromethyl ketone based inhibitors used a combination of structural information obtained from X-ray crystallography and molecular modeling investigations. The beta-carbolinone ring in these compounds serves as a highly efficient peptidiomimetic for the P2-P3 region of peptidyl trifluoromethyl ketone inhibitors of HLE. Several of the beta carbolinones exhibit significant in vitro potency, with Ki values in the nanomolar range. Using aqueous molecular dynamics simulations, realistic models for the molecular recognition of these inhibitors by HLE have been obtained and are discussed. This series of compounds are found to have excellent selectivity for HLE over a number of other proteolytic enzymes, including closely related enzymes such as porcine pancreatic elastase. PMID- 7837246 TI - Nonpeptidic inhibitors of human leukocyte elastase. 5. Design, synthesis, and X ray crystallography of a series of orally active 5-aminopyrimidin-6-one containing trifluoromethyl ketones. AB - The effects of changes in substitution in a series of 5-amino-2-pyrimidin-6-ones on both in vitro activity and oral activity in an acute hemorrhagic assay have been explored. These compounds contained either a trifluoromethyl ketone or a boronic acid moiety to bind covalently to the Ser-195 hydroxyl of human leukocyte elastase (HLE). Boronic acid-containing inhibitors were found to be more potent than the corresponding trifluoromethyl ketones in vitro but were less active upon oral administration. Compound 13b was found to offer the best combination of oral potency, duration of action, and enzyme selectivity and, as such, was selected for further biological testing. X-ray crystallography of a cocrystallized complex of compound 19m and porcine pancreatic elastase demonstrated that the inhibitor is bound to the enzyme in a manner similar to that found previously for a closely related series of pyridone-containing inhibitors of HLE. PMID- 7837245 TI - Potent non-peptide fibrinogen receptor antagonists which present an alternative pharmacophore. PMID- 7837247 TI - The genetic testing of children. PMID- 7837248 TI - Genetic linkage to the type VII collagen gene (COL7A1) in 26 families with generalised recessive dystrophic epidermolysis bullosa and anchoring fibril abnormalities. AB - To strengthen the evidence for genetic linkage to COL7A1, we have studied 26 generalised recessive dystrophic epidermolysis bullosa (EB) families of British, Italian, Irish, and South African origin. We chose two linkage markers, a COL7A1 PvuII intragenic polymorphism and a highly informative anonymous microsatellite marker, D3S1100, which maps close to the COL7A1 locus at 3p21.1-3. Diagnosis was established by family history, clinical examination, immunofluorescence, and ultrastructural studies. The PvuII marker was informative in 16 families with a maximum lod score (Zmax) of 3.51 at recombination fraction (theta) = 0. The D3S1100 microsatellite was informative in 24 out of 25 families with Zmax = 6.8 at theta = 0.05 (Z = 4.94 at theta = 0) and no obligatory recombination events. These data strongly suggest that COL7A1 mutations cause EB in these families and, combined with previous studies, indicate locus homogeneity. The importance of anchoring fibrils for dermal-epidermal adhesion is further underlined. D3S1100 may later prove useful in prenatal diagnosis of this disease, if used in combination with other markers. PMID- 7837250 TI - X inactivation patterns in female monozygotic twins and their families. AB - X inactivation studies have been carried out on 22 pairs of female monozygotic twins, one set of female monozygotic triplets, and their mothers and singleton sisters, using the probe M27 beta. Forty-eight per cent of the twins, 55% of their mothers, and 42% of their singleton sisters showed skewed X inactivation. Two of the triplets and their mother had random X inactivation, while the third triplet showed skewed X inactivation. Their singleton sister was homozygous with M27 beta. Of the twins, six pairs showed skewed X inactivation in favour of the same X chromosome, one pair showed skewed X inactivation favouring opposite X chromosomes, in seven pairs one twin showed skewed X inactivation while her co twin showed random X inactivation, and in eight pairs both twins were random. A higher frequency of skewed pattern of X inactivation was not observed in the monozygotic twins when compared to a series of non-twin females (mothers and singleton sisters) and, so, the results in this study do not lend support to the theory that skewed X inactivation predisposes to the twinning process. PMID- 7837249 TI - Mosaic uniparental disomy in Beckwith-Wiedemann syndrome. AB - Beckwith-Wiedemann syndrome (BWS) is a congenital overgrowth syndrome with variable expression. The major features are anterior abdominal wall defects, macroglossia, and gigantism and less commonly neonatal hypoglycaemia, organomegaly, congenital renal anomalies, hemihypertrophy and embryonal tumours occur. BWS is a genetically heterogeneous disorder; most cases are sporadic but approximately 15% are familial and a small number of BWS patients have cytogenetic abnormalities involving chromosome 11p15. Genomic imprinting effects have been implicated in familial and non-familial BWS, and uniparental disomy (UPD) for chromosome 11 has been reported in sporadic cases. We investigated the incidence, pathogenesis, and clinical associations of UPD in 49 patients with non familial BWS and a normal karyotype. UPD for chromosome 11p15 was detected in nine of 32 (28%) informative patients. A further two patients appeared to be disomic at the WT1 locus in chromosome 11p13, but were uninformative at chromosome 11p15.5 loci tested. In all cases with UPD the affected person was mosaic for a paternal isodisomy and a normal cell line indicating that UPD had arisen as a postzygotic event. Compared to cases in which paternal isodisomy for chromosomes 11p15.5 had been excluded (n = 23), BWS patients with UPD was more likely to have hemihypertrophy (6/9 versus 1/23, p < 0.001) and less likely to have exomphalos (0/9 versus 13/23, p < 0.01), but there were no significant differences between disomic and non-disomic cases in the incidence of hypoglycaemia, nephromegaly, neoplasia, and developmental delay. The detection of UPD in BWS patients allows accurate genetic counselling to be provided and provides an insight into the molecular pathogenesis of BWS. PMID- 7837251 TI - Cephalometric analysis of Rapp-Hodgkin syndrome. AB - Rapp-Hodgkin syndrome (RHS) is a rare form of ectodermal dysplasia with variable involvement of the hair, eyes, sweat glands, nails, and teeth. Oral findings may include hypodontia, hypoplastic enamel, cleft lip/palate, and a pronounced midfacial hypoplasia. The objective of this study was to determine if the pronounced midfacial hypoplasia is the result of a true tissue hypoplasia or displacement of midfacial tissues. We have identified a family in which three members, a mother and two daughters, display clinical features characteristic of RHS. Clinical and intraoral examination of these affected persons showed manifestations characteristic of RHS, and several new findings were observed, including subcutaneous abscesses, palmoplantar keratosis, and keratotic lesions located on the chest and trunk. To assess the midfacial hypoplasia, lateral cephalometric analysis was performed on lateral headplates. Results of the cephalometric analysis suggest that the midfacial hypoplasia results from both a deficiency and a displacement of the maxilla. These findings are significant because successful dental treatment of RHS relies upon accurate assessment of current and projected orofacial development, particularly for the skeletal relations of the maxilla and mandible. PMID- 7837252 TI - Phenotypic variation of tuberous sclerosis in a single extended kindred. AB - Tuberous sclerosis complex (TSC) is an autosomal dominant disorder with a great degree of phenotypic variability. Given the presence of two gene loci underlying this disorder, locus heterogeneity may account for some of the variability. However, significant within family variation suggests that different genes do not explain the majority of this variation. The purpose of this research is to identify physical and behavioural variation in expression of TSC in a single large extended kindred. TSC in this kindred is cosegregating with markers localised to chromosome 16p13.3. The expression of TSC in this kindred is quite variable with a substantial proportion of persons showing very mild physical expression of TSC. In contrast to very mild physical expression of TSC in some family members, there is a significant clustering of psychiatric disorders among persons affected with TSC compared to their unaffected relatives. This finding, coupled with the mild physical expression of TSC in some family members, supports a hypothesis that the TSC2 gene may present phenotypically as mild skin signs and significant behavioural problems. PMID- 7837253 TI - Absence of linkage between idiopathic dilated cardiomyopathy and candidate genes involved in the immune function in a large Italian pedigree. AB - Idiopathic dilated cardiomyopathy (IDC) is a heart disease of unknown aetiology characterised by impaired ventricular function usually associated with dilatation of the cardiac chambers. In order to test the hypothesis of an immunological cause for the disease at the genetic level, we performed linkage analysis between the putative disease locus and some of the potential candidate genes involved in the immune response or coding for the targets for autoantibodies in a large multigeneration family (63 members) from southern Italy with autosomal dominant transmission of the disease. Twenty-nine polymorphic markers on 18 different chromosomal locations were investigated, including markers linked to the genes coding for the HLA antigens, the immunoglobulin heavy and light chains, the receptors for the immunoglobulin Fc fragments, the subunits of the T cell receptor and the associated CD3, CD4, CD8, and CD45 antigens, interleukins 1, 3, 4, 5, 6, 9, and 11, the interleukin 1 and 2 receptors, and the genes coding for the beta 1 adrenoreceptor, the adenine nucleotide translocator-1, and the cardiac alpha and beta myosin heavy chains. No evidence for genetic linkage to IDC was found at any of these candidate loci. These results indicate that the still unidentified IDC gene maps outside several loci involved in the regulation of immune reactivity. PMID- 7837254 TI - Osteocraniostenosis. AB - We report a multiple congenital anomalies (MCA) syndrome in three unrelated fetuses consisting of extremely thin, dense, fishbone-like diaphyses, flared metaphyses, mild micromelic dwarfism, brachydactyly, facial dysmorphism, ocular malformations (microphthalmia, aniridia), cloverleaf skull deformity, and splenic hypoplasia. Histopathological investigations showed abnormalities of the metaphyseal cartilage and adjacent diaphyseal ossification, excessive modelling of the metaphyses, and, in one case, dysplasia of the epiphyseal cartilage. We review three previously reported cases. We suggest the name osteocraniostenosis to describe this radiological and clinical disorder, pinpointing its major clinical and radiological features. PMID- 7837255 TI - Albright's hereditary osteodystrophy. PMID- 7837256 TI - The genetic testing of children. Working Party of the Clinical Genetics Society (UK) PMID- 7837257 TI - Intrachromosomal triplication of 15q11-q13. AB - A 7 year old girl with intrachromosomal triplication 46,XX,-15,+der(15)(pter- >q13::q13-->q11::q11-->qter) resulting in tetrasomy of 15q11-q13 is reported. Fluorescence in situ hybridisation confirmed that the tetrasomic region included the entire segment normally deleted in Prader-Willi and Angelman syndrome patients, and breakpoints were similar to those reported in two tandem duplications of 15q11-q13. The middle repeat was inverted, suggesting a possible origin through an inverted duplication intermediate. Microsatellite analysis showed that the rearrangement was of maternal origin and involved both maternal homologues. Clinical findings included multiple minor anomalies (a fistula over the glabella, epicanthic folds, downward slanting palpebral fissures, ptosis of the upper lids, strabismus, a broad and bulbous tip of the nose, and small hands and feet), motor and mental retardation, a seizure disorder, and limited verbal abilities. In addition, immunological examination disclosed a selective immunodeficiency. The overall phenotype did not clearly resemble that of cases with tetrasomy 15pter-q13 associated with an extra inv dup(15)(pter-->q13:q13- >pter) chromosome. The latter aberration causes more severe mental deficit and intractable seizures, but less marked phenotypic alterations, although some overlap in mild facial dysmorphic features is present. A number of features common to Angelman syndrome were also observed in the patient. PMID- 7837258 TI - A newborn with ring chromosome 10, aganglionic megacolon, and renal hypoplasia. AB - A newborn infant is reported who had aganglionic megacolon, renal hypoplasia, severe growth retardation, generalised hypotonia, and various dysmorphic features. Chromosome analysis of lymphocytes and fibroblasts showed a ring chromosome 10 with breakpoints at p13-15 and q26. AluI digestion showed that the ring chromosome was monocentric. FISH with an alpha satellite probe specific for chromosome 10 showed one signal only in about 20% of interphase nuclei. It is suggested that aganglionic megacolon could result from dynamic somatic mosaicism owing to loss of the ring chromosome. PMID- 7837259 TI - Down-Turner syndrome: case report and review. AB - We present a male patient with Down-Turner mosaicism (45,X/46,X,+21/47,XY,+21) and review 27 similar cases reported so far. Clinical features of Down's syndrome were present in all cases, whereas a combination of features of both Ullrich Turner syndrome and Down's syndrome was reported in 61% of the patients. However, one has to bear in mind that several stigmata of Ullrich-Turner syndrome can also be present in patients with Down's syndrome and vice versa. In most of the patients two different cell lines were encountered, although cases with one, three, and even four different cell lines have been reported. Of 28 patients, 21 showed female external genitalia, four were phenotypically male, and three showed ambiguous genitalia. Only six patients (21%) carried a Y chromosome, which is far less than expected. PMID- 7837260 TI - Chimaerism shown by cytogenetics and DNA polymorphism analysis. AB - A child with ambiguous genitalia, brought up phenotypically male, had a 46,XX/46,XY karyotype. At laparotomy, he had a left sided ovary and uterus, and a right sided scrotal testis. The 46,XX line made up 50% of cells in the blood and 90% of cells in a skin biopsy. There were no cytogenetic polymorphisms. Analysis of lymphocyte DNA with seven polymorphic DNA markers showed him to be chimaeric, with four, three, and two parental alleles at different loci. He had one paternal and one maternal X chromosome at the marker DXS1053. Based on our data, we would suggest that chimaerism arose as a result of postzygotic fusion of two embryos. We have shown by DNA polymorphisms the presence of autosomal chimaerism in a case of sex chromosome chimaerism, and indicated the usefulness of DNA polymorphisms in determining the origin of chimaerism. PMID- 7837261 TI - Huntington's disease in two unrelated Arab kindreds and in an Afghani family resident in Saudi Arabia. PMID- 7837262 TI - Arthrogryposis multiplex congenita, renal dysfunction, and cholestasis syndrome. PMID- 7837263 TI - The Prader-Willi-like phenotype in fragile X patients: a designation facilitating clinical (and molecular) differential diagnosis. PMID- 7837264 TI - Determination of Km and kcat for signal peptidase I using a full length secretory precursor, pro-OmpA-nuclease A. AB - An effective method for the determination of the activity of signal peptidase I (SPase I) of Escherichia coli is established using the hybrid protein pro-OmpA nuclease A as substrate. Pro-OmpA-nuclease A, a hybrid secretory precursor was purified to homogeneity under denaturing conditions. When this protein was refolded, it could be quantitatively processed by purified SPase I. The Km of signal peptidase I was 0.0165 mM. The kcat was 8.73 s-1. The Km is 50 to 100 times lower than that obtained with peptide substrates indicating that SPase I has a significantly greater affinity for the protein substrate. The turnover number, kcat, is two to four orders of magnitude greater as well. Thus, the specificity constant, kcat/Km is six orders of magnitude greater with pro-OmpA nuclease A than with peptide substrates. This is the first determination of kinetics of SPase I with a protein substrate. PMID- 7837265 TI - An intact protein translocating machinery is required for mitochondrial import of a yeast cytoplasmic tRNA. AB - In Saccharomyces cerevisiae, one of the two cytoplasmic lysine-tRNA isoacceptors, tRNA(LysCUU), is the only nuclear-coded tRNA species to be mitochondrially imported. Using an in vitro assay of tRNA import, we have studied if the mitochondrial protein translocation machinery is also involved in the mitochondrial targeting of this tRNA. As for protein import, tRNA import also requires the integrity of proteins exposed onto the mitochondrial outer membrane and is dependent upon energy and membrane eletrochemical potential. Furthermore, partial ATP-depletion of the import system leads to stabilization of a translocation intermediate containing the tRNA. In this case, the import of the tRNA can be completed after addition of a new source of energy, even without restoration of the membrane electrochemical potential and without further addition of cytoplasmic proteins. Outer and inner mitochondrial membrane receptors shown to participate in translocation of mitochondrial pre-proteins (MOM19 and MPI1/MIM44, respectively) are also important for import of the tRNA, in vitro as well as in vivo. In contrast, the outer membrane receptor MOM72 is dispensable for the import. Taken together, these results demonstrate that a functional mitochondrial protein translocation apparatus is required for the mitochondrial import of the yeast tRNA(LysCUU). PMID- 7837266 TI - Ligand binding to wild-type and E-B13Q mutant insulins: a three-state allosteric model system showing half-site reactivity. AB - By using ultra-violet and visible absorbance in conjunction with high field 1H nuclear magnetic resonance spectroscopy, the insulin hexamer has been shown to undergo two allosteric transitions in solution involving three allosteric states (T6<-->T3 R3<-->R6). A simple mathematical model consisting of four variables has been derived that quantitatively describes the complex homotropic and heterotropic interactions that modulate these allosteric transitions. The mutation of one residue, Glu-B13 to Gln, results in an unexpected change in the T3R3 to R6 equilibrium by a factor of 10(7). PMID- 7837267 TI - Inhibition of transcription initiation by lac repressor. AB - Initiation of transcription of the lac operon by RNA polymerase (R) is inhibited by binding of lac repressor (L) to an operator site which overlaps the lac promoter (P). We have investigated repression of the lac UV5 promoter in vitro for a choice of the repressor--operator binding constant and ranges of thermodynamic activities of L and R which appear to be relevant in vivo. Effects of [L] on the extent of formation and the kinetics of association and dissociation of abortively-initiating open complexes (RPinit) were examined using fluorescence detected abortive initiation and KMnO4 chemical probing. The nitrocellulose filter assay was used to measure the dissociation rate constant and the equilibrium constant for binding for L to its operator site in the absence of R. For the chosen solution conditions, we find that both the observed velocity of abortive RNA oligomer synthesis and the KMnO4 reactivities of bases in the open region are functions of [L] and [R], demonstrating that formation of both RPinit and the repressor-operator complex (PL) are reversible processes under these conditions, and requiring the use of a relaxation-to-equilibrium analysis to interpret the kinetics. The agreement between dissociation rate constants of RPinit when challenged with either lac repressor or heparin, and the dependences on [L] and [R] of abortive synthesis velocities at binding equilibrium and of relaxation rate constants for reversible formation of RPinit from PL, all provide evidence for a simple competition mechanism. In this mechanism, and in contrast to recent proposals from other laboratories, lac repressor inhibits formation of RPinit and hence the observed rate of abortive product synthesis by reducing the equilibrium extent of formation of the first closed complex (RPc1), without affecting either the nature of RPinit or steps in formation of RPinit from RPc1. PMID- 7837268 TI - In vitro analysis of a constitutively active mutant form of the Escherichia coli global transcription factor FNR. AB - The Escherichia coli transcription factor FNR regulates expression of genes required for the metabolic switch between aerobic and anaerobic respiration. In order to investigate how FNR controls transcription of its target operons, DNA binding was examined for both the wild-type (WT) FNR protein and an altered function FNR* protein (DA154) that exhibits enhanced activity in the presence of oxygen both in vivo and in vitro, apparently due to the fact that DA154 is able to dimerize to a greater extent than WT FNR. Electrophoretic mobility shift assays, using a consensus symmetrical FNR target site, revealed that both DA154 and WT FNR gave rise to protein-DNA complexes of indistinguishable electrophoretic mobilities. In addition, an estimate of the molecular weight from the mobility of the DA154-DNA complex indicated that both mutant and WT FNR were dimeric when bound to DNA. Under the same binding conditions, DA154 showed an observed constant of approximately 3 x 10(8) M-1 for the consensus symmetrical target site. In addition, the results of DNA binding competition assays provided evidence that DA154 was a site-specific DNA binding protein, since this mutant protein bound to the consensus symmetrical target site with approximately 40-fold and 250-fold higher affinity than a natural target site from the nar promoter or a non-specific DNA target, respectively. Electrophoretic mobility shift DNA bending assays demonstrated protein-induced DNA bending by both DA154 and WT FNR. In addition, in vitro transcription assays using an FNR-dependent variant of the lac P1 promoter demonstrated levels of transcription activation by DA154 comparable to those observed in vivo. These results provide several new insights into how FNR functions to activate transcription of target genes. PMID- 7837269 TI - Prion protein gene variation among primates. AB - Prion diseases are manifest as genetic, sporadic or infectious neurodegenerative disorders in humans and animals. The prolonged incubation times that accompany the transmission of prions between species are due, at least in part, to differences in prion protein (PrP) sequence. To examine the species barriers between non-human primates and humans, we sequenced the open reading frames (ORF) of 25 PrP genes from apes and monkeys. Comparison of the PrP genes of these animals with that of humans showed amino acid identities ranging from 92.9 to 99.6%. While phylograms of primate PrP sequences revealed a novel branching pattern for the apes, the genomic organization of all the primate PrP genes was similar, with the entire ORF contained within a single exon. Alignment of variant residues in primates, rodents and domestic animals showed no concordance with the mutations that segregate with human prion diseases or with polymorphisms that modulate disease in humans, mice and sheep. Most substitutions were conservative and, characteristically, clustered outside the four putative alpha-helical regions that are thought to form a four-helix bundle in the cellular isoform of PrP (PrPC). Deletion of one of five Gly-Pro rich octarepeats from the N-terminus of PrP was seen in some species, while squirrel monkeys had an additional octarepeat; squirrel monkeys have been frequently used as experimental hosts for transmission of human prions. Alignment of primate and other mammalian PrP sequences suggests that codons between 90 and 130 have a profound influence on the transmissibility of prions from one species to another. PMID- 7837270 TI - Expression and structural analysis of 14-3-3 proteins. AB - The 14-3-3 family of proteins plays a role in a wide variety of cellular functions including regulation of protein kinase C and exocytosis. Using antisera specific for the N termini of 14-3-3 isoforms described previously and an additional antiserum specific for the C terminus of epsilon isoform, protease digestion of intact 14-3-3 showed that the N-terminal half of 14-3-3 (a 16 kDa fragment) was an intact, dimeric domain of the protein. Two isoforms of 14-3-3, tau and epsilon, were expressed in E. coli and their secondary structure was shown by circular dichroism to be identical to wild-type protein, and expression of N-terminally-deleted epsilon 14-3-3 protein showed that the N-terminal 26 amino acids are important for dimerization. Intact 14-3-3 is a potent inhibitor of protein kinase C, but the N-terminal domain does not inhibit PKC activity. Site-specific mutagenesis of several regions in the tau isoform of 14-3-3, including the mutation of a putative pseudosubstrate site to a potential substrate sequence, did not alter its inhibitory activity. Intact 14-3-3 proteins are phosphorylated by protein kinase C with a low stoichiometry, but truncated isoforms are phosphorylated much more efficiently by this kinase. This may imply that the proteins may adopt a different structural conformation, possibly upon binding to the membrane, which could modulate their activity. 14-3-3 proteins are found at high concentration on synaptic plasma membranes and this binding is mediated through the N-terminal 12 kDa of 14-3-3. PMID- 7837271 TI - Tetrabrachion: a filamentous archaebacterial surface protein assembly of unusual structure and extreme stability. AB - The surface (S-) layer of the hyperthermophilic archaebacterium Staphylothermus marinus was isolated, dissected into separate domains by chemical and proteolytic methods, and analyzed by spectroscopic, electron microscopic and biochemical techniques. The S-layer is formed by a poorly ordered meshwork of branched, filiform morphological subunits resembling dandelion seed-heads. A morphological subunit (christened by us tetrabrachion) consists of a 70 nm long, almost perfectly straight stalk ending in four straight arms of 24 nm length that provide lateral connectivity by end-to-end contacts. At 32 nm from the branching point, tetrabrachion carries two globular particles of 10 nm diameter that have both tryptic and chymotryptic protease activity. Tetrabrachion is built by a tetramer of M(r) 92,000 polypeptides that form a parallel, four-stranded alpha helical rod and separate at one end into four strands. These strands interact in a 1:1 stoichiometry with polypeptides of M(r) 85,000 to form the arms. The arms are composed entirely of beta-sheets. All S-layer components contain bound carbohydrates (glucose, mannose, and glucosamine) at a ratio of 38 g/100 g protein for the complete tetrabrachion-protease complex. The unique structure of tetrabrachion is reflected in an extreme thermal stability in the presence of strong denaturants (1% (w/v) SDS of 6M guanidine): the arms, which are stabilized by intramolecular disulphide bridges, melt around 115 degrees C under non reducing conditions, whereas the stalk sustains heating up to about 130 degrees C. Complete denaturation of the stalk domain requires treatment with 70% (v/v) sulfuric acid or with fuming trifluoromethanesulfonic acid. The globular protease can be heated to 90 degrees C in 6M guanidine and to 120 degrees C in 1% SDS and represents one of the most stable proteases characterized to date. PMID- 7837272 TI - Structural similarity between two-layer alpha/beta and beta-proteins. AB - This paper demonstrates that overall folds of two-layer alpha/beta-proteins and beta-proteins with aligned beta-sheet packings have a number of common features. First of all, there are similar recurrent folding units, the so-called abcd units, in proteins of both the classes. There are also some larger commonly occurring structures in many representatives of these classes. The fact that these proteins belong to different structural classes and have different functions supports the idea that some physical principles governing the polypeptide chain folding rather than the evolutionary divergence or functional convergence of proteins are the basis of such similarities. The analysis reported here shows that practically all the known protein structures of these classes can be obtained by stepwise addition of secondary structure element to the abcd-units taking into account three simple rules: (1) crossing of connection regions is prohibited; (2) alpha-helices should be packed into the alpha-layer and beta strands in to the beta-layer of the growing structure; (3) beta alpha beta-units should be folded into right-handed superhelices; three consecutive beta-strands can be folded into the similar right-handed beta beta beta-superhelix if there is at least one additional beta-strand in the layer between the first and third ones. A possible selection of a conformation of a polypeptide chain segment by its protein environment is also discussed. PMID- 7837274 TI - The kinetics of the thermal denaturation of collagen in unrestrained rat tail tendon determined by differential scanning calorimetry. AB - This paper shows that the position and shape of the denaturation endothem of collagen fibrils are governed by the kinetics of an irreversible rate process. This was proved by measuring the rate of denaturation in rat tail tendons held isothermally at different temperatures, thereby determining rate constant characteristics such as the activation enthalpy and entropy and predicting endotherm position and shape therefrom. Comparison with actual scanning results showed good correspondence. Isothermal measurements of the rate of collagen denaturation, measured continuously using a calorimetric method, were used to determine rate constants for collagen denaturation in tendons immersed in water and 0.5 M acetic acid. The temperature dependence of the rate constants were fitted to the three rate process models, previously examined theoretically: the D and z formulation, the Arrhenius equation and the absolute rate theory. For example, in water the activation enthalpy was 0.518 (+/- 0.016) Mj mol-1 and the activation entropy 1.485 (+/- 0.049) kj mol-1 K-1, while in acetic acid the corresponding figures were 1.306 (+/- 0.099) Mj mol-1 and 4.142 (+/- 0.323) kj mol-1 K-1. These characteristics are discussed in terms of the thermal activation of a region of the molecule, the co-operative unit. The ratio of the activation enthalpy to the calorimetry enthalpy of denaturation indicated a co-operative unit that was 66 (+/- 5) residues long when fibrils were swollen in acetic and the collagen molecules acted essentially independently. On the other hand the intact fibrils in water gave a co-operative unit of 26 (+/- 1) residues long. The reason for the reduction in size of the co-operative unit is that it is surrounded, and therefore stabilized by other molecules in the fibre. It is interesting to note that the suggested co-operative unit lies almost entirely within the "gap" zone of the collagen fibril in its quarter-staggered arrangement of molecules. We believe that the co-operative unit would be represented by a domain that is free of stabilising hydroxyproline residues. Indeed such a domain exists near the C terminus of the triple helix from Gly877 to Pro941, i.e. 65 residues. In acetic acid, activation is similar to that of collagen molecules in solution. All the inter alpha-chain hydrogen bonds in the co-operative unit are broken and the separate chains in this short region are free to flail around under the action of thermal collisions relatively unimpeded by intermolecular interactions.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7837273 TI - Structural and functional effects of apolar mutations of the distal valine in myoglobin. AB - High-resolution structures of the aquomet, deoxy, and CO forms of Ala68, Ile68, Leu68, and Phe68 sperm whale myoglobins have been determined by X-ray crystallography. These 12 new structures, plus those of wild-type myoglobin, have been used to interpret the effects of mutations at position 68 and the effects of cobalt substitution on the kinetics of O2, CO, and NO binding. Molecular dynamics simulations based on crystal structures have provided information about the time dependent behavior of photolyzed ligands for comparison with picosecond geminate recombination studies. The Val68-->Ala mutation has little effect on the structure and function of myoglobin. In Ala68 deoxymyoglobin, as in the wild-type protein, a water molecule hydrogen-bonded to the N epsilon atom of the distal histidine restricts ligand binding and appears to be more important in regulating the function of myoglobin than direct steric interactions between the ligand and the C gamma atoms of the native valine side-chain. This distal pocket water molecule is displaced by the larger side-chains at position 68 in the crystal structures of Leu68 and Ile68 deoxymyoglobins. The Leu68 side-chain can rotate about its C alpha-C beta and C beta-C gamma bonds to better accommodate bound ligands, resulting in net increases in overall association rate constants and affinities due to the absence of the distal pocket water molecule. However, the flexibility of Leu68 makes simulation of picosecond NO recombination difficult since multiple starting conformations are possible. In the case of Ile68, rotation of the substituted side-chain is restricted due to branching at the beta carbon, and as a result, the delta methyl group is located close to the iron atom in both the deoxy and liganded structures. The favorable effect of displacing the distal pocket water molecule is offset by direct steric hindrance between the bound ligand and the terminal carbon atom of the isoleucine side-chain, resulting in net decreases in affinity for all three ligands and inhibition of geminate recombination which is reproduced in the molecular dynamics simulations. In Phe68 myoglobin, the benzyl side-chain is pointed away from the ligand binding site, occupying a region in the back of the distal pocket. As in wild-type and Ala68 myoglobins, a well-defined water molecule is found hydrogen bonded to the distal histidine in Phe68 deoxymyoglobin. This water molecule, in combination with the large size of the benzyl side-chain, markedly reduces the speed and extent of ligand movement into the distal pocket. (ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7837275 TI - Conformational transitions linked to active site ligation in human thrombin: effect on the interaction with fibrinogen and the cleavable platelet receptor. AB - An experimental strategy based on solution viscosity perturbation allowed us to study the energetics of amide-substrates, p-aminobenzamidine (p-ABZ) and proflavin binding to the catalytic site of two proteolyzed forms of alpha thrombin, i.e. zeta- and gamma T-thrombin. These thrombin derivatives are cleaved at the Leu144-Gly150 loop and at the fibrinogen recognition exosite (FRS), respectively. A phenomenological analysis of thermodynamic data showed that the amide substrates and p-ABZ interactions with zeta-thrombin were respectively, associated with a chemical compensation (i.e. the linear relationship between entropy and enthalpy of binding) and a hydrophobic phenomenon (i.e. a change in the standard heat capacity). The latter was slightly lower than that previously observed for a alpha-thrombin (0.78 +/- 0.25 versus 1.01 +/- 0.17 kcal/mol K). Both phenomenon were absent in gamma T-thrombin. The interaction of a alpha-, zeta- and gamma T-thrombin with macromolecular substrates that "bridge-bind" to both the catalytic site (CS) and fibrinogen recognition exosite (FRS), such as fibrinogen and the cleavable platelet receptor (CPR), was also evaluated. These interactions were studied by following fibrinopeptide A (FpA) release and by measuring intraplatelet Ca2+ changes induced by thrombin-CPR interaction. It was found that the free energy of activation (RT ln Kcat/Km) for both fibrinogen and CPR hydrolysis followed the same hierarchy, i.e. alpha > zeta > gamma. Moreover, the values of delta Cp for alpha-, zeta- and gamma T-thrombin interaction with p ABZ were found to be linearly correlated to the free energy of activation for both fibrinogen and CPR cleavage. In conclusion, these data demonstrate that: (1) the Leu144-Gly150 loop and the FRS are both involved in the conformational transition linked to the binding of p-aminobenzamidine to the thrombin active site; (2) the extent of thrombin's capacity to undergo conformational transitions in alpha-, zeta- and gamma T forms is positively correlated to the free energy of activation for hydrolysis of macromolecular substrates interacting with both the catalytic domain and the FRS. PMID- 7837276 TI - Effects of anisosmotic conditions on the cytoskeletal architecture of cultured PC12 cells. AB - PC12 cells show a classical volume regulatory process when submitted to hypo osmotic conditions. The present study examined the effects of such osmotic shock on the structural organization of different cytoskeletal elements. Results were obtained by use of different light and electron microscopy techniques combined with immunostaining methods. It appeared that the osmotically induced changes in cell volume were concomitant with important modifications in the organization of the microfilament network. Microfilaments concentrated in the perinuclear area, leaving only radial extensions of poorly organized structures in the cytoplasm. The latter were the only actin structures immunologically stained in the cytoplasm and seemed to anchor to the plasma membrane. Measurements of the fluorescence intensity of PC12 cells treated with FITC-labeled phalloidin indicated a progressive depolymerization, followed by a repolymerization of F actin. This occurs in parallel with microfilament reorganization and volume regulatory processes. The appearance of microfilament reorganization was a function of both the incubation period and the amplitude of the osmolarity changes. During the first minutes of osmotic shock, a decrease was observed in the density and length of microvilli, which normally cover the PC12 cell surfaces, suggesting an early reorganization of the underlying microfilament network. Microtubules and intermediate filament networks were not affected by the hypo-osmotic conditions. PMID- 7837277 TI - Animate models of human head injury. AB - A review of animal models of nonpenetrating head injury caused by mechanical energy is presented that focuses on the ability of various categories of models and their relationships to the types of head injury seen in humans. Basic hypotheses of animal modeling of human disease and outcome measures are addressed. Current models are reviewed and compared for their differences and similarities regarding behavioral, pathologic, physiologic, and biochemical fidelity to human head injury. PMID- 7837278 TI - Workshop on intraspinal transplantation and clinical application. AB - The following general conclusions were reached at the workshop: 1. Laboratory studies suggest a potential benefit of cellular transplant therapy for SCI. 2. Some evidence supporting the safety of human fetal transplants is available from clinical studies of transplants in Parkinson's disease and SCI. 3. Assessment criteria and methodology are available, including imaging approaches, validated neurologic scoring systems, detailed electrophysiologic studies of conduction and spinal cord reflexes, and functional scoring approaches. 4. More controlled animal studies are needed (a) to demonstrate efficacy and to evaluate the necessity for immunosuppressive therapy and the overall safety of intraspinal transplantation, (b) to obtain more supporting evidence (e.g., electrophysiologic, histopathologic, MRI, molecular) that would provide insights into ways that transplanted tissue could mediate function, (c) to provide guidance for the procurement, harvesting, preparation, storage, and other logistics related to the use of human cells for transplantation into the spinal cord, (d) to define more thoroughly the cell type(s) that would be most likely to have benefit and the conditions that affect their viability, migration, gene expressions, and proliferation after transplantation, (e) to determine the most optimal time after injury for transplantation, and (f) to clarify patient selection characteristics that might optimize success (i.e., complete vs incomplete injuries, spinal level involved, age of recipient). PMID- 7837279 TI - Fluid percussion injury causes loss of forebrain choline acetyltransferase and nerve growth factor receptor immunoreactive cells in the rat. AB - Memory dysfunction is a common sequela of human traumatic brain injury (TBI). Cholinergic forebrain neurons are recognized for their role in memory. We tested the hypothesis that forebrain cholinergic neurons are vulnerable to fluid percussion injury (FPI), a model of human TBI. Rodents were subjected to a moderate parasagittal FPI, sham injury, or fimbria/fornix axotomy and then killed 10 days after the procedure. Additional animals underwent FPI or sham injury and were killed 7, 14, and 28 days after the procedure. Neurons in the medial septal nucleus and vertical limb of the nucleus of the diagonal band of Broca were identified and quantitated using choline acetyltransferase (ChAT) and low affinity nerve growth factor receptor (NGF-R) immunohistochemistry. Our results showed a significant decrease in ChAT (17% +/- 5%) and NGF-R (24% +/- 8%) immunoreactive cells in FPI animals killed after 10 days when compared to sham injured animals. Animals undergoing fimbria/fornix axotomy showed a greater reduction in ChAT (53% +/- 13%) and NGF-R (55% +/- 5%) immunoreactive cells 10 days postaxotomy. The number of ChAT and NGF-R immunoreactive neurons was reduced at all time points. However, statistical significance was present 10 and 14 days postinjury for ChAT immunoreactive neurons and 10 days only for NGF-R immunoreactive neurons. These studies have shown that FPI produces transient loss of ChAT and NGF-R immunoreactive neurons. PMID- 7837280 TI - Direct measurement of hydroxyl radicals, lipid peroxidation, and blood-brain barrier disruption following unilateral cortical impact head injury in the rat. AB - We present data correlating the time courses of hydroxyl radical (.OH) production, lipid peroxidation, and blood-brain barrier (BBB) damage following unilateral head injury in the rat. Using a controlled cortical impact device to inflict head injury, we have directly measured brain .OH levels via the salicylate trapping method, and phosphatidylcholine hydroperoxide (PCOOH) levels via the HPLC-chemiluminescence technique, at 5, 30, and 60 min postinjury. These results were then correlated with the time course of BBB disruption, as measured by the extravasation of Evans blue dye (EB) into the injured cortex, over the same time period. In the present study, .OH levels were 62% higher than sham at 5 min postinjury, 25% higher at 15 min (both p < or = 0.05), and no different from sham at 60 min. PCOOH, on the other hand, increased linearly between 5 and 60 min postinjury. Whereas PCOOH levels were 25% greater than sham at 5 min, they were 35% and 52% higher than sham at 30 and 60 min, respectively (both p < or = 0.05 vs sham). Blood-brain barrier disruption followed a similar time course to PCOOH generation, except that the magnitude of the effect was much greater. Whereas EB extravasation was only slightly elevated in the injured cortex at 5 min postinjury, there was nearly an 8-fold increase at 30 min and an 11-fold increase at 60 min (all p < or = 0.05 vs sham). An additional experiment demonstrated that BBB damage can be attenuated by treatment with the 21-aminosteroid lipid peroxidation inhibitor, tirilazad mesylate (U-74006F). Rats were given a single i.v. injection of 3 or 10 mg/kg of U-74006F 5 min postinjury and killed 30 min postinjury. The 10 mg/kg dose of U-74006F reduced EB extravasation 52% (p < 0.025) in comparison to vehicle-treated controls. This is the first study to correlate the time courses of .OH formation, lipid peroxidation, and BBB disruption in injured brain. The results suggest that there is an immediate, posttraumatic burst in .OH formation, followed by a progressive increase in lipid peroxidation and a similar, although slightly delayed, time-related opening of the BBB. The attenuation of BBB damage by U-74006F suggests that this chain of events can be interrupted by administration of an antioxidant/lipid peroxidation inhibitor. PMID- 7837281 TI - Regional levels of free fatty acids and Evans blue extravasation after experimental brain injury. AB - The recently developed controlled cortical-impact (CCI) model of brain injury in rats serves as an excellent tool to understand some of the neurochemical mechanisms mediating the pathophysiology of traumatic brain injury. In this study, rats were subjected to lateral CCI brain injury of low-grade severity. Their brains were frozen in situ at various times after injury to measure regional levels of free fatty acids. Tissue total free fatty acids at the injury site within the left cortex were increased at 30 min, 2.5 h, and 24 h postinjury. In injured animals, increases in stearic and arachidonic acids were slightly greater than those in palmitic and oleic acids. The levels of total free fatty acids in the cortex adjacent to the injury site were also increased in injured animals at 2.5 h and 24 h after injury (p < 0.05). Only stearic and arachidonic acids were observed to be significantly increased (p < 0.05) in the adjacent cortex of injured animals at all times after injury. Although no significant increases in total free fatty acids were observed in the left hippocampus adjacent to the injury site, stearate and arachidonate concentrations were increased at 30 min and 2.5 h after injury (p < 0.05). Extravasation of Evans blue was found to be significantly increased in the ipsilateral cortex of injured animals at 30 min and 10 h after brain injury. These results indicate the degradation of membrane phospholipids and blood-brain barrier breakdown in the ipsilateral cortex after lateral CCI brain injury. These results also suggest that arachidonic acid and its metabolites may play a role as a mediator in the blood-brain barrier breakdown associated with cortical impact brain injury in rats. PMID- 7837282 TI - Bilateral frontal cortical contusion in rats: behavioral and anatomic consequences. AB - The purpose of this study was to develop a bilateral model of frontal cortical contusion in the rat that would demonstrate reproducible deficits typically found after frontal lobe injury in humans. We used a pneumatically controlled cortical impactor to create bilateral contusions of the medial prefrontal cortex (PFC) in adult male Sprague-Dawley rats. Cognitive, neurologic, physiologic, and histopathologic measures were used to evaluate changes caused by the injury. The cognitive task employed the Morris water maze (MWM). Contused rats performed worse than sham-operated controls on measures of time taken to find a submerged platform, distance to the platform, and swim strategy. Neurologic measures revealed impairments of tongue mobility and transient deficits of forelimb placing. Body weights of the contused rats were chronically reduced with respect to controls, indicating that cortical contusion produces disruption in homeostasis. All rats given bilateral PFC contusions developed marked necrotic cavities at the site of impact. The borders surrounding the cavities were heavily lined with astrocytes and ameboid microglia. There was subcortical gliosis in the medial caudate that extended throughout the rostral-caudal length of the caudate putamen and into the mediodorsal (MD) and ventrolateral (VL) nuclei of the thalamus. The thalamus was also the site of distal transneuronal degeneration. In both the MD and the VL, there was significant neuronal loss in the contused rats as compared with sham-operated controls. This method of bilateral cortical contusion demonstrates clear, reproducible results that would be required for the development of future pharmacologic therapies designed to promote functional recovery. PMID- 7837283 TI - 4-Aminopyridine-sensitive neurologic deficits in patients with spinal cord injury. AB - 4-Aminopyridine (4-AP) is a potassium channel blocking agent with the ability to restore conduction in demyelinated internodes of axons of the spinal cord. The present investigation sought to obtain electrophysiologic evidence of the effect of 4-AP in ameliorating central conduction deficits in a group of patients (n = 6) with spinal cord injury (SCI). The group was selected on the basis of having temperature-dependent central conduction deficits. 4-AP (24-25 mg total dose) was delivered intravenously at 6 mgh-1 or 15 mgh-1 while somatosensory evoked potentials (SEPs) and motor evoked potentials (MEPs) were recorded as indices of central conduction. Two patients exhibited marked increases in the amplitude of cortical SEPs, and in one of these, 4-AP brought about a reduced central conduction time from L1 to cortex. Four patients revealed increased amplitude MEPs with concomitant reduction in latency indicative of enhanced conduction in corticospinal or corticobulbospinal pathways. Two of these patients demonstrated increased voluntary motor unit recruitment following 4-AP. Clinical examination revealed reduced spasticity (n = 2), reduced pain (n = 1), increased sensation (n = 1), improved leg movement (n = 3), and restored voluntary control of bowel (n = 1). These results support the hypothesis that 4-AP induces neurologic benefits in some patients with SCI. They are also consistent with the emerging concept that pharmaceutical amelioration of central conduction deficits caused by focal demyelination may contribute to the management of a select group of patients with compressive or contusive SCI. PMID- 7837284 TI - Affinity isolation of neuron-reactive antibodies in MRL/lpr mice. AB - Autoantibodies from the MRL/lpr mice react with numerous proteins on neuronal cell surfaces. The purpose of this study was to isolate and characterize a population of autoantibodies reactive preferentially or exclusively with nervous system tissue. Using a purified plasma membrane preparation from brain cortex of balb/c mice coupled to diaminopropylamine agarose gel, we affinity-isolated antineuronal antibodies from pooled MRL/lpr immunoglobulins. The isolated immunoglobulins reacted with brain cortex plasma membranes and neuroblastoma cells (but not liver, kidney, or fibroblasts) by Western blot and indirect immunofluorescence with confocal microscopy. By Western blot, the epitopes in the brain cortex were proteins of apparent molecular weights 101, 63, 53, 43, 39, and 33, kd; the epitopes in the neuroblastoma cells were 63, 57, and 53 kd. Lectin column isolation revealed that the 101 and 63 kd epitopes were glycosylated. Indirect immunofluorescence revealed that the antibodies bound to the cell soma more intensely than to the cell processes of viable cultured neuroblastoma cells. The cell surface localization of this binding was confirmed by confocal microscopy. Within the central nervous system the antibodies bound more intensely to primary cultures of isolated neurons from fetal cortex than to hippocampal or neostriatal cells. With these antibodies we can begin studies of their potential pathogenic effects. PMID- 7837285 TI - Motoneuron survival is not affected by the proximo-distal level of axotomy but by the possibility of regenerating axons to gain access to the distal nerve stump. AB - The aim of this study was to examine whether axotomy-induced motoneuron death in adult mammals differ: (1) with the distance between the site of injury and the nerve cell body, and (2) if contact between the transected nerve stumps is established after the injury, compared with cases where contact is prevented. The hypoglossal nerve of adult rats was transected either proximally in the neck (proximal injury) or close to the tongue (distal injury). The nerve stumps were then either deflected from each other in order to prevent axon regeneration into the distal nerve stump, or sutured. Three months later, the extent of nerve cell loss was examined bilaterally in cresyl violet-stained sections of the hypoglossal nucleus. In addition, we examined hypoglossal neuron survival twelve months after a proximal nerve transection with prevented regeneration. Our results show that there was no significant difference in neuronal survival after a proximal nerve transection compared with a distal one, neither if contact between the nerve stumps was established nor if it was prevented. However, contact between the transected nerve stumps increased the likelihood of neuronal survival significantly after both proximally and distally located injury compared to nerve injury with prevented regeneration. There was no significant decrease in nerve cell survival after twelve months with prevented reinnervation compared with survival after three months. These observations indicate that the extent of axotomy-induced motoneuron death in adult mammals does correlate with the proximo distal level of peripheral injury.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7837286 TI - Neuronal progenitors identified by their inability to express class I histocompatibility antigens in response to interferon-gamma. AB - Interferon-gamma (IFN-gamma) can induce class I major histocompatibility complex (MHC) antigen (H-2) expression on virtually all neuroepithelial cells isolated from embryonic day 9 (E9) mice. However, a subpopulation of cells become refractory to H-2 induction (H-21-) by E10 and the percentage of H-2 noninducible cells increases during development. Cell sorting, by flow cytometry or magnetic bead immunoselection, has shown that H-21- cells give rise exclusively to neuronal cells, and by E12, the majority of the neuronal progenitors are found within this population. It has also been found that 98% of the H-21- also express the neuron-associated marker, A2B5. Cells of the glial cell lineage retain the ability to express class I antigens throughout development. From these studies, it is clear that the neuroepithelium contains cells committed to the neuronal cell lineage as early as E10 in the mouse. PMID- 7837287 TI - Protection by an ACTH4-9 analogue against the toxic effects of cisplatin and taxol on sensory neurons and glial cells in vitro. AB - Sensory neuropathy is a serious side effect of anti-tumour drugs such as cisplatin and taxol. There are indications that an analogue of the adrenocorticotrophic hormone 4-9 fragment (ACTH4-9: Met(O2)-Glu-His-Phe-D-Lys Phe) can prevent these neurotoxic effects. We studied the potential protective effects of this analogue in cultures of chick dorsal root ganglia and rat Schwann cells treated with cisplatin or taxol to gain insight into the mode of action and characteristics of this neuroprotection. Neurite outgrowth of sensory neurons in vitro was dose-dependently inhibited by cisplatin and taxol; after 48 hr, 10 micrograms/ml cisplatin reduced outgrowth from 431 +/- 17 microns to 220 +/- 6 microns and 0.01 micrograms/ml taxol from 344 +/- 3 microns to 200 +/- 43 microns. Co-treatment of 10 micrograms/ml cisplatin with the ACTH4-9 analogue (0.1 nM-1 nM) resulted in about 35% more outgrowth than cisplatin alone. In contrast, the analogue could not prevent taxol neurotoxicity. Migration of neurons and satellite cells from the DRG-body is completely inhibited by 10 micrograms/ml cisplatin. Taxol had no effect on the migration of these cells. In addition, cisplatin was more toxic to Schwann cells than taxol; 3-10 micrograms/ml cisplatin significantly reduced their laminin content, total protein, 2',3'-cyclic nucleotide 3'-phosphodiesterase activity, and cell division. The ACTH4-9 analogue (0.01 nM-100 nM) had no effect on the migration of cells out of the DRGs and could not prevent the toxic effect on the Schwann cells. These data support our hypothesis that the neuroprotective effect of ACTH4 9 analogue is brought about by a direct action on neurons, possibly by replacing a Schwann-/satellite-cell derived trophic factor. PMID- 7837288 TI - Long-lasting accumulation of hemopexin in permanently transected peripheral nerves and its down-regulation during regeneration. AB - We have previously demonstrated that hemopexin is present in the intact sciatic nerve and is overproduced in the distal stump after nerve transection (Swerts et al.: J Biol Chem 267:10596-10600, 1992). To get further insight into the function of this hemoprotein in nervous tissue, we have documented long-term changes in hemopexin levels in permanently degenerated (transected) and regenerating (crush lesioned) sciatic nerves of adult rats, using immunochemical techniques. As early as a couple of days after nerve transection, the amount of hemopexin was raised in the distal stump and at the end of the proximal stump. Similarly, after a crush lesion hemopexin was rapidly increased at the injury site and in the distal part of the nerve. Subsequently, in transected nerves the level of hemopexin rose steadily and remained elevated, representing, three months after injury, over 20 times the amount found in intact contralateral nerves. In contrast, in crush lesioned nerves, hemopexin level declined progressively in a proximodistal direction and returned to basal values 2 months after injury, together with axonal regeneration. This long-term increase in hemopexin in permanently degenerated nerves and its progressive return to normal levels during nerve regeneration suggests that hemopexin content could be regulated negatively, directly or indirectly, by growing axons. In turn, these results support the idea that hemopexin could be involved in the process of Wallerian degeneration and/or in nerve repair. PMID- 7837289 TI - Neurotrophin-3 acquires NGF-like activity after exchange to five NGF amino acid residues: molecular analysis of the sites in NGF mediating the specific interaction with the NGF high affinity receptor. AB - Despite the large sequence similarity around 55-60% among the known NGF-related neurotrophins, the members display different activities on different subset of neurons. Recent studies have shown that the various neurotrophins are ligands with high affinity to different receptors of the Trk family of tyrosine kinase receptors. We wanted to elucidate what specific parts of NGF replaced in neurotrophin-3 (NT-3) would result in NGF-like receptor binding and biological activity. By studying evolutionarily conserved amino acid sequences not shared by NT-3 and NGF and excluding parts which have been examined in earlier work with NGF and BDNF chimeras as well as taking advantage of the crystallographic data available for NGF, we decided to exchange three specific blocks of two or three amino acids in the human NT-3 backbone for the corresponding residues in NGF. The NGF residues Asn-Ile-Asn (43-45), Val-Phe (48,49) and Gln-Ala-Ala (96-98) were combined in pairs and are all shown to contribute NGF-like activity in the context of NT-3. The most efficient NGF-like transformation was obtained by the exchange of Pro-Val and Leu-Val-Gly in NT-3 to the NGF residues Val-Phe and Gln Ala-Ala. This mutant reached 90% NGF activity, based on survival of sympathetic neurons, stimulation of fibre outgrowth from sympathetic ganglia, the ability to block high affinity NGF binding to PC12 cells and phosphorylation of gp140trk. Thus, the three mutants with paired combinations of the NGF residues as well as the NT-3 housing all three blocks of NGF residues were able to mimic NGF activity. This activity is gained, although the mutated neurotrophin proteins do not lose the original NT-3 activity as ascertained by the stimulation of neurite outgrowth from the Remak ganglion. The three mutated sites are situated in two beta-loops at one end of the NGF molecule, forming a cleft that could specifically interact with high affinity to the signalling NGF receptor gp140trk. PMID- 7837290 TI - Neurotrophin-3 enhances neurite outgrowth in cultured hippocampal pyramidal neurons. AB - Low density dissociated cultures of embryonic rat hippocampal cells were used to study the effects of neurotrophin-3 (NT-3) on neuronal morphogenesis. The results obtained indicate that NT-3 enhances neurite outgrowth and branching; this is a dose-dependent effect, detected in approximately 50% of the neurons, and prevented by K-252a, an inhibitor of the trk family of receptor protein kinases. NT-3 also accelerates the development of neuronal polarity, a phenomenon preceded by a dramatic accumulation of bundles of looped microtubules within axonal growth cones; these microtubule bundles contain tyrosinated, detyrosinated, and acetylated alpha-tubulin. Taken collectively, our data suggest that even though the basic shape of hippocampal neurons may be endogenously determined, critical aspects of their morphological development may be modulated by trophic factors such as NT-3. In addition, our observations suggest that at least some of the neuritogenic effects of NT-3 involve a stimulation of microtubule assembly and/or transport. PMID- 7837291 TI - [Single dose toxicity studies of lactitol (NS-4) in mice and rats]. AB - The single dose toxicity studies of lactitol, a hepatic encephalopathy drug, were performed in ddY mice and SD rats of both sexes by administering the drug orally, intravenously or subcutaneously. The drug was administered as a single dose followed by a 14-day observation. Oral LD50 values of lactitol were estimated to be between 23 and 30 g/kg in male mice, approximately 30 g/kg in female mice, and more than 30 g/kg in male and female rats. Lethal dose was more than 10 g/kg intravenously and subcutaneously in mice and rats of both sexes. The signs of toxicity in mice and rats observed following the administration of this drug included the following: decreased spontaneous movement [p.o., i.v., s.c.]; diarrhea, oligopnea or prone position, transient decreased body weight [p.o]. There were no treatment-related changes in gross examination. Based on these results, it was found that lactitol had a very low acute toxicity when administered by a single dose method in mice and rats. PMID- 7837292 TI - [Single dose toxicity study of lactitol (NS-4) in dogs]. AB - Male beagle dogs were orally given lactitol, a hepatic encephalopathy drug, in a single dose of 7.5, 15.0 or 30.0 g/kg. Vomiting was seen within 30 minutes after dosing in all treated groups. Diarrhea was observed 3 or 5 hours after dosing in the 15.0 and 30.0 g/kg dose groups. There were no drug related effects on survival, food and water consumption, body weight gain or tissues and organs. PMID- 7837293 TI - [13-week oral toxicity study of lactitol (NS-4) in rats followed by 5-week recovery test]. AB - Twenty male and 20 female Slc : SD rats were orally given lactitol, a hepatic encephalopathy drug, for 13 weeks at doses of 0, 0.625, 2.5 or 10 g/kg/day. A 5 week recovery test was conducted after the discontinuation of the drug treatment. Soft stool and decreased food consumption were seen in the 2.5 and 10 g/kg groups. In the 10 g/kg group, there were diarrhea, soiled fur, abdominal distention, salivation, piloerection, decreased body weight gain and increased water consumption. Urinalysis showed decreased urine volume and K+ excretion in the 10 g/kg group. In this dose group, biochemical examination showed decreased ALP, total cholesterol, triglyceride, glucose, Ca, Na+, Cl- and total protein. In the pathological examination, the cecum weight was increased in all dose groups. In the 2.5 and 10 g/kg groups, cecum distention with mucosal hyperplasia was observed. The adrenal weight was increased in the 10 g/kg group and hypertrophy of zona fasciculata of adrenal gland were seen in the 2.5 and 10 g/kg groups. The thymic weight was decreased in the 10 g/kg group. Ophthalmoscopic and hematologic examinations failed to reveal any drug induced changes. The increased cecum weight in the 0.625 g/kg group was regarded as toxicologically insignificant because of the failure of the association with any clinical or morphological findings. The above mentioned changes were satisfactorily reversible except for those in the cecum. Based on the results obtained, the NOAEL of this study was suggested to be 0.625 g/kg/day. PMID- 7837294 TI - [13-week oral toxicity study of lactitol (NS-4) in dogs followed by 4-week recovery test]. AB - 13-week repeated dose toxicity studies were conducted on lactitol, a hepatic encephalopathy drug. In the experiment I, male and female dogs were orally treated with lactitol at doses of 0, 1.0, 2.5 and 6.25 g/kg/day for 13 weeks, followed by 4 weeks recovery period. In the experiment II, male and female dogs were orally treated with lactitol at doses of 0, 0.25, 0.50 and 1.0 g/kg/day for 13 weeks in order to require the no-toxic dose. RESULTS: 1. Soft stool and diarrhea were observed at the 0.50 g/kg group and above, and vomiting was observed at the 1.0 g/kg group and above. Increased water consumption was observed at the 6.25 g/kg group. No deaths occurred at all groups. 2. In urinalysis, increased urine volume was observed at the 6.25 g/kg group. 3. Blood chemistry showed decreased BUN at the 6.25 g/kg group. 4. There were no drug related changes in body weight, food consumption, ophthalmological examination, electrocardiography, hematology and pathology. 5. At the end of the recovery period, all these changes observed at the end of the administration period were disappeared. Based on these results, it was considered that the no-toxic dose of lactitol is 0.25 g/kg/day. PMID- 7837295 TI - [52-week oral toxicity study of lactitol (NS-4) in rats followed by 9-week recovery test]. AB - Twenty five male and 25 female Slc:SD rats were given orally lactitol, a hepatic encephalopathy drug, for 52 weeks at doses of 0, 0.4, 2 or 10 g/kg/day. A 9 week recovery test was conducted after the discontinuation of the drug treatment. Treatment related death, soft stool, diarrhea, decreased body weight gain and food intake and increased water consumption were observed in the 10 g/kg group. Urinalysis showed increased Ca excretion in the 2 and 10 g/kg groups. In the 10 g/kg group, there were increased Ca++ excretion and urine specific gravity and decreased K+ and Na+ excretion and urine volume. Hematologic examination showed decreased platelet count in the 10 g/kg group. Biochemical examination revealed higher A/G ratio in the 2 and 10 g/kg groups. In the 10 g/kg group, there were lowered level of total cholesterol, triglyceride, phospholipid, Na+, Cl- and total protein. Distention of the cecum with increased organ weight was seen pathologically in the 2 and 10 g/kg groups. In the 10 g/kg group, cecal mucosa was hyperplasic. The adrenal gland was hypertrophic in the zona glomerulosa in the 2 and 10 g/kg groups. In the 10 g/kg group, the adrenal weight was increased. Dilatation of renal tubules was also found in the 10 g/kg group. The above mentioned changes were satisfactorily reversible except for the increased cecum weight in the 10 g/kg group. Based on the results obtained, the NOAEL of this study was suggested to be 0.4 g/kg/day. PMID- 7837296 TI - [52-week oral toxicity study of lactitol (NS-4) in dogs followed by 9-week recovery test]. AB - Five male and 5 female beagle dogs were orally given lactitol, a hepatic encephalopathy drug, for 52 weeks at doses of 0, 0.25, 1.25 or 6.25 g/kg/day. A 9 week recovery test was conducted after the discontinuation of the drug treatment. Soft stool, diarrhea, and vomiting were seen in the 1.25 and 6.25 g/kg groups. In the 6.25 g/kg group, bloody stool and increased water consumption were also observed. Urinalysis showed larger amount of the urine volume in the 6.25 g/kg group. The cecum weight of this group was increased without any morphological changes. There were no drug related effects on survival, body weight gain and food consumption. Electrocardiographic, ophthalmoscopic, hematologic and biochemical examinations failed to show any abnormalities related to the drug treatment. The above mentioned changes were satisfactorily reversible. Based on the results obtained, the NOAEL of this study was suggested to be 0.25 g/kg/day. PMID- 7837297 TI - [Reproductive and developmental toxicity studies of lactitol (NS-4) (1)- Fertility study in rats by oral administration]. AB - A study of fertility and fetal development was conducted in Sprague-Dawley rats. Male rats were given lactitol, a hepatic encephalopathy drug, orally from 63 days before mating to the end of mating period. Female rats were given from 14 days before mating to day 7 of pregnancy. The dose levels for both males and females were 0 (control), 0.7, 2.65 and 10 g/kg. The females were sacrificed on day 20 of pregnancy for examination of their fetuses. The decrease in food consumption in either male or female was observed in the intermediate and high dose groups. The high dose caused soft stool, diarrhea and increase in water consumption in either male or female. Moreover, the high dose caused salivation and suppression of body weight gain in male. In the pathological examination, the enlargement of cecum were observed in male of the intermediate and high dose groups. The increase in cecum weight were observed in male in all lactitol groups, and in female of the high dose group. Lactitol did not affect on copulation and fertility indexes in either male or female rats. Lactitol failed to affect on estrous cycle in female rats, and number of corpora lutea, implantations and preimplantation egg losses. In the fetal examination, lactitol did not affect on the development of live fetuses. The results show that no-effect dose levels of lactitol are less than 0.7 g/kg in male rats and 0.7 g/kg in female rats for general toxicity, and 10 g/kg for reproductive function in parent animals and fetuses. PMID- 7837298 TI - [Reproductive and developmental toxicity studies of lactitol (NS-4) (2)- Teratogenicity study in rats by oral administration]. AB - A teratogenicity study of lactitol, a hepatic encephalopathy drug, was conducted in Sprague-Dawley rats. Female rats were given lactitol orally at dose levels of 0 (control), 0.7, 2.65 and 10 g/kg from day 7 to day 17 of pregnancy. Twenty-two female rats per dose level were sacrificed on day 20 of pregnancy for examination of their fetuses, and thirteen pregnant rats per dose level were allowed to deliver naturally for postnatal examination of their offspring. The high dose of lactitol caused diarrhea or soft stool in pregnant rats. The food consumption of female rats decreased in the intermediate and high dose groups. The water consumption of female rats increased in the high dose group. The drug failed to alter the body weight of female rats. The weights of cecum of dams increased in the intermediate and high dose group. The high dose caused enlargement of cecum in dams. The drug failed to alter the numbers of corpora lutea and implantations, fetal mortality, the number of live fetuses, body weight of live fetus, sex ratio, and external, visceral and skeletal development of fetuses. Lactitol did not affect the delivery of dams, the number of live newborns, birth index, external development, body weight, viability index, weaning index, and sex ratio of weanlings. Nor did lactitol have any adverse effect on the postnatal development of the first (F1) generation offspring, such as differentiation, emotionality, motor ability, learning ability or reproductive performance. Nor did lactitol have any adverse effect on the second (F2) generation offspring. The results show that no-effect dose levels of lactitol are 0.7 g/kg for general toxicity in mother animals, 10 g/kg for reproductive function in mother animals and their offspring. PMID- 7837299 TI - [Reproductive and developmental toxicity studies of lactitol (NS-4) (3)- Teratogenicity study in rabbits by oral administration]. AB - Lactitol, a hepatic encephalopathy drug, was administered by oral gavage to pregnant New Zealand White rabbits during organogenesis from day 6 to day 18 of gestation inclusive, at dosages of 0, 0.25, 0.75 or 4.5 g/kg/day. On day 29 of gestation, females were killed to allow examination of their uterine contents. There was a slight reduction in food intake and faecal output among females receiving 4.5 g/kg. One female receiving 4.5 g/kg aborted following a prolonged period of weight loss. No adverse effects on litter parameters were recorded that could be attributed to treatment. Foetal morphogenesis was unaffected by treatment with lactitol. The results show that no-effect dose levels of lactitol are 0.75 g/kg in mother rabbits for general toxicity and for reproductive functions, and 4.5 g/kg for their fetuses. PMID- 7837300 TI - [Reproductive and developmental toxicity studies of lactitol (NS-4) (4)- Perinatal and postnatal study in rats by oral administration]. AB - A perinatal and postnatal study of lactitol, a hepatic encephalopathy drug was conducted in Sprague-Dawley rats. Female rats were given lactitol orally at dose levels of 0 (control), 0.7, 2.65 and 10 g/kg from day 17 of pregnancy to day 21 after delivery. All pregnant rats per level were allowed to deliver naturally for postnatal examination of their offspring. The high dose caused diarrhea or soft stool in dams. The high dose suppressed the body weight of dams during the perinatal period. The food consumption of dams decreased in the intermediate and high dose groups. The water consumption of dams increased in the high dose group. The high dose caused enlargement of cecum and increase of weights of cecum in dams. The drug failed to affect the delivery of dams and gestation index. However, high dose caused prolongation of gestation period. Two dams in the high dose group failed to nurse their all newborns during early lactation. The drug did not affect the number of live newborns, birth index, external appearance, body weight, viability index, weaning index, and sex ratio of weanlings. Nor did lactitol have any adverse effect on the postnatal development of the first (F1) generation offspring, such as differentiation, emotionality, motor ability, learning ability or reproductive performance. Nor did lactitol have any adverse effect on the second (F2) generation offspring. The results show that the no effect dose levels of lactitol are 0.7 g/kg for general toxicity in mother animals, 2.65 g/kg for reproductive function in mother animals, and 10 g/kg for their offspring. PMID- 7837301 TI - [Mutagenicity studies of lactitol (NS-4)]. AB - Lactitol (NS-4), a hepatic encephalopathy drug, was examined for mutagenicity in the reverse mutation test in bacteria, the chromosome aberration test with cultured mammalian cells, and the micronucleus test in mice. 1. In the reverse mutation test using Salmonella typhimurium (TA1535, TA100, TA1537, and TA98) and Escherichia coli (WP2uvrA), the drug did not significantly increase revertant colonies in any of the test strains with or without metabolic activation system (S-9mix). 2. In the chromosome aberration test with cultured Chinese hamster lung cells (CHL/IU), the drug did not significantly increase aberrant cells in the direct method or in the metabolic activation method. 3. In the micronucleus test with Slc:ddY male mice, the drug did not significantly increase micronucleated polychromatic erythrocytes in the bone marrows. These results suggest that lactitol has no mutagenicity in vitro or in vivo. PMID- 7837302 TI - [Antigenicity study on lactitol (NS-4)]. AB - Lactitol hydrate (lactitol) was tested for its antigenicity in guinea pigs and mice. The following results were obtained. 1. No active systemic anaphylaxis reactions were found in guinea pigs sensitized subcutaneously with lactitol alone or in combination with Freund's complete adjuvant (FCA). 2. No 24 hr heterologous passive cutaneous anaphylaxis reactions were elicited in rats by sera from mice sensitized intraperitoneally with lactitol alone or in combination with 3% aluminum hydroxide gel. 3. No passive hemagglutination reactions were elicited by sera from mice sensitized subcutaneously with lactitol in combination with FCA. From these results, it is concluded that lactitol has no antigenicity under the present experimental conditions. PMID- 7837303 TI - [Increased serum alkaline phosphatase induced by DT-5061, an oral contraceptive, in rats]. AB - DT-5061, a steroid oral contraceptive which contains norethisterone (NET) and ethinyl estradiol (EE) in a ratio of 100:7, was administered orally to rats for 14 days in order to investigate a possible origin of the increased serum alkaline phosphatase (ALP). Increased serum total ALP was noted in rats receiving DT-5061 at 5.35 mg/kg/day or EE at 0.35 mg/kg/day. Electrophoresis of serum ALP revealed that both liver and bone-type ALP isozymes were increased in the DT-5061 5.35 mg/kg and EE 0.35 mg/kg groups, and the ratio of increase in the liver-type was greater than that in the bone-type although the increase in concentration of the bone-type was greater as compared to the liver-type. ALP level in the liver was elevated together with an increase in liver weight, consistently with the increased serum liver-type isozyme. However, neither histological changes indicative of cholestasis nor increase in serum leucine aminopeptidase, bilirubin, GOT or GPT were seen. No changes were observed in bone ALP activity; hence inconsistent with the increased serum bone-type isozyme. From these results, it is considered that the increased serum ALP induced by this drug was due to the increased liver-type isozyme induced in the liver and to the increased bone-type isozyme, and among the ingredients of this oral contraceptive, EE was mainly involved in the increased serum ALP induced by this drug. PMID- 7837304 TI - [Effects of adrenalectomy on the increased serum alkaline phosphatase activity induced by DT-5061, an oral contraceptive, in rats]. AB - DT-5061, a steroid oral contraceptive which contains norethisterone (NET) and ethinyl estradiol (EE) was administered orally to adrenalectomized rats for 3 days to investigate involvement of the adrenals in the increased serum alkaline phosphatase (ALP). In addition, corticosterone or aldosterone were administered to the adrenalectomized rats to examine their effects on serum ALP. Increases in serum total ALP, liver-type and bone-type ALP isozymes were observed in rats with intact adrenals following administration of DT-5061, but these responses were not noted in adrenalectomized rats. Increases in liver weight and ALP activity in the liver after administration of the drug were reduced but not abolished in the adrenalectomized rats. The adrenalectomized rats receiving corticosterone showed increases in serum total ALP, liver-type ALP isozyme and liver weight but did not exhibit any increase in bone-type ALP isozyme. On the other hand, aldosterone did not increase and even reduced serum ALP although ALP activity in the liver was increased in the adrenalectomized rats. PMID- 7837305 TI - [A procedure for recording electroretinogram (ERG) with a contact lens-type electrode, and effect of sodium iodate on ERG in rats]. AB - A procedure for recording the electroretinogram (ERG) in rats with a contact lens type electrode was developed in order to examine visual toxicity overtime. Rats received a single intravenous injection of sodium iodate (SI), a retinotoxic compound, via the tail vein at a dose of 12.5, 20, 25 or 50 mg/kg, and the ERG was recorded for 10 days after dosing. Histopathologic examination of the retinas was then conducted. 1. The rats were anesthetized with ketamine hydrochloride (50 mg/kg, i.m.) after 90 to 120 min of dark-adaptation. Thirty-two responses to repetitive 1.2 joule light stimuli at 0.5 Hz interstimulus intervals were averaged by a microcomputer. Under these conditions, stable ERG a-wave, b-wave and oscillatory potentials could be recorded for 10 days. 2. At 12.5 mg/kg of SI, no treatment-related abnormalities were observed on the ERG. Doses of 20 mg/kg or more of SI caused depression of the amplitudes of the ERG a-wave and oscillatory potentials 2 hrs or 1 day after dosing. Following these changes, the amplitude of the ERG b-wave decreased 1 or 2 days after dosing. 3. Upon histopathologic examination of the retina, folding of the outer nuclear layer, disarrangement of the rods and cones and swelling and decrease of the pigment epithelial cells were observed at 20 mg/kg or more. The severity of the retinal lesions correlated well with the changes in the ERG. 4. Using this recording technique, it was confirmed that a stable ERG could be recorded repeatedly in rats, and the effects of SI on the ERG could be detected. Furthermore, histopathologic examination revealed that the severity of the retinal lesions correlated well with the changes in the ERG. These results indicate that the ERG recording technique employed in this study is useful for evaluating retinal toxicity in rats. PMID- 7837306 TI - Fractional mercury levels in Brazilian gold refiners and miners. AB - A field study survey of individuals residing in the region of Para, Brazil, was conducted to determine fractional mercury levels in individuals at risk for exposure in the Brazilian Amazon region. Subjects with a history of exposure to mercury either in the gold mining or refining industry, or exposure to these processes through proximity were included. Three groups were identified as either having recent (less than 2 d since last exposure), intermediate (less than 60 d), or remote (greater than 60 d) exposure to mercury vapors. Fractional blood and urinary mercury levels were assessed for these groups. Group I (recent) had the highest geometric mean blood 24.8 (SD 44.1, range 7.6-158.8) micrograms/L and urine 75.6 (SD 213.4, range 6.5-735.9) micrograms/g-cr (microgram mercury per gram of creatinine) mercury; intermediate (group II) geometric mean blood 7.6 (SD 5.5, range 2.2-19.4) micrograms/L and urine levels 23.8 (SD 84.0, range 7.8 297.0) micrograms/g-cr; the lowest levels in remote exposure (group III): geometric mean blood 5.6 (SD 3.3, range 3.1-14.3) micrograms/L and urine 7.0 (SD 9.8, range 3.1 to 32.9) micrograms/g-cr. The fraction of organic was lowest in group I (32.4%), higher in group II (65.7%), and highest in group III (72.2%). While the frequency of symptoms was comparable in the recent and intermediate groups (2.6 mean, SD 2.3, range 0-8, and 3.1 mean, SD 1.9, range 0-7, symptoms per patient), those with remote exposure demonstrated the highest rate of reporting (6.4 mean, SD 4.1, range 0-11, symptoms per patient). There is significant exposure to mercury for those working in or living near the mining and refining industry. Blood and urine levels are a better marker of recent than remote exposure. The fraction of organic mercury increases with time since exposure. Symptoms may be persistent and low levels of blood and urine mercury do not exclude remote or cumulative toxicity. PMID- 7837307 TI - Time series forecasts of poison center call volume. AB - We tested the hypothesis that time series analysis can provide accurate predictions of future poison center telephone call volume by a prospective stochastic time series modeling of calls to a university-based regional poison center. All callers evaluated and managed during two sequential years had the time and date of the call recorded in a computer database. Time series variables were formed for poison center calls per hour. Prediction models were developed from the 1992 data and included four types: raw observations, moving average, means with moving average smoothing, and autoregressive integrated moving average. Forecasts from each model were tested against observations from the first 26 weeks of 1993. Each model's adequacy was tested on residuals by autocorrelation functions, integrated periodograms, linear regression, and differences among the variances. A total of 44,584 calls were received in 1992 and 24,781 in the first half of 1993. Large periodic variations in call volume with time of day were found (p < 0.001). The model based on arithmetic means of each hour of the week with three-point moving average smoothing yielded the most accurate forecasts and explained 58.5% of the variation observed in the 1993 test series (p < 0.001). Time series analysis can provide powerful, accurate short range forecasts of future poison center telephone call volume. Simpler, less expensive models performed best in this study. PMID- 7837308 TI - The ultimate poison center call--Bhopal. PMID- 7837309 TI - Aluminum phosphide poisoning--a review. AB - Aluminum phosphide poisoning is common in the rural belt of Northern India. The release of cytotoxic phosphine gas primarily affects the heart, lungs, gastrointestinal tract and kidneys, although all organs can be involved. The cellular site of action of phosphine requires further definition. Diagnosis is made by clinical suspicion, silver nitrate test and biochemical examination of the gastric aspirate and viscera. Treatment consists of early gastric lavage, vasopressors and supportive care. Specific therapy with intravenous magnesium sulphate is recommended. PMID- 7837310 TI - Alcohol intoxication in young children. AB - This article presents two cases of severe ethyl alcohol intoxication in pediatric patients, with one of these cases resulting in the death of a child. A review of the current literature is provided along with a comparison of our regional poison control centers and the national intoxication statistics regarding pediatric alcohol ingestion. Medical evaluation is recommended for all symptomatic children; hourly observations x 6 h are recommended for asymptomatic children. PMID- 7837311 TI - Stereoselectivity of the TDxADx/FLx Amphetamine/Methamphetamine II amphetamine/methamphetamine immunoassay--response of urine specimens following nasal inhaler use. AB - The TDxADx/FLx Amphetamine/Methamphetamine II fluorescence polarization immunoassay (Abbott Diagnostic) for the detection of amphetamine and methamphetamine in urine was evaluated for stereoselectivity and response to specimens collected following as recommended and double the recommended dose use of Vicks Nasal Inhaler. The assay is calibrated with d-amphetamine, at cutoff concentration of 300 ng/mL for a positive response. Cross-reactivity studies demonstrated a positive result with 1000 ng/mL l-amphetamine, 300 ng/mL d methamphetamine, and approximately 2000 ng/mL desoxyephedrine. A good correlation was observed between urines obtained following ingestion of d-amphetamine simultaneously analyzed by TDxADx/FLx Amphetamine/Methamphetamine II and gas chromatography/mass spectrometry: r2 = 0.954, N = 100. However, urine obtained following ingestion of racemic methamphetamine showed no correlation between TDxADx/FLx Amphetamine/Methamphetamine II and gas chromatography/mass spectrometry results: r2 = 0.420, N = 28. Urines collected following as recommended use for five consecutive days of Vicks Nasal Inhaler containing l desoxyephedrine did not yield positive TDxADx/FLx Amphetamine/Methamphetamine II results. Only two urines from a subject using twice the recommended inhaler dose yielded positive TDxADx/FLx Amphetamine/Methamphetamine II results. These urines contained 1560 and 1530 ng/mL desoxyephedrine when analyzed by gas chromatography/mass spectrometry. Greater than recommended use of Vicks Nasal Inhaler may yield false positive TDxADx/FLx Amphetamine/Methamphetamine II results for amphetamine use when calibrated at 300 ng/mL d-amphetamine. If calibrated at 1000 ng/mL, d-amphetamine, the TDxADx/FLx Amphetamine/Methamphetamine II is unlikely to yield false positive results for amphetamine, even following excessive inhaler use. PMID- 7837312 TI - Prevention of drug absorption in simulated theophylline overdose. AB - To assess the effectiveness of oral activated charcoal and catharsis in preventing theophylline absorption, 12 healthy subjects, aged 20-35 years, received 3 x 200 mg sustained-release theophylline tablets and 16 radio-opaque placebo tablets on six occasions. On each occasion, they received either no treatment (control) or one of five treatments. Treatments were a) oral activated charcoal (Carbomix): 50 g at 1 h, 25 g at 5 h and 9 h; b) sorbitol 70%: 150 mL at 1 h; c) activated charcoal: 50 g at 6 h, 25 g at 10 h and 14 h; d) sorbitol 70%: 150 mL at 6 h; e) charcoal commencing at 6 h plus sorbitol at 6 h (i.e. a combination of treatments c and d). Plasma theophylline concentrations were measured and all stools collected over 36 h to assess placebo tablet recovery by radiography. Charcoal administration at 1 h was 91.2% effective in preventing theophylline absorption and at 6 h was 57.3% effective, while combined charcoal and catharsis at 6 h was 63.3% effective. Sorbitol-induced catharsis at 1 h and 6 h did not reduce theophylline absorption despite greater tablet recovery. Oral activated charcoal may be the most effective treatment for sustained-release theophylline overdose, with maximum benefit when administered soon after an overdose, though later administration might still be of value. Sorbitol catharsis is of no benefit either alone or in combination with charcoal. PMID- 7837313 TI - Response to glucagon in imipramine overdose. AB - A 25-year-old woman, severely hypotensive following a massive imipramine overdose, had an immediate and sustained rise in blood pressure following intravenous glucagon (10 mg bolus followed by an infusion of 10 mg over 6 h). The QRS interval on the electrocardiogram shortened from 129 to 89 msec. Glucagon should be considered in hypotension following tricyclic antidepressant overdose; it may also be antiarrhythmic. PMID- 7837314 TI - Magnesium sulfate in the treatment of ventricular arrhythmias due to digoxin toxicity. AB - Although digoxin antibodies are the definitive treatment of cardiac arrhythmias due to digoxin toxicity, magnesium can also be effective especially with low serum magnesium levels. The case report describes a patient with digoxin toxicity, ventricular tachycardia and a slightly elevated serum magnesium. Two 10 mmol doses of intravenous magnesium sulfate were associated with a more stable junctional rhythm with bigeminy. Magnesium is known to suppress early after depolarizations, and in supraphysiological doses, may act as an indirect antagonist of digoxin at the sarcolemma Na(+)-K(+)-ATPase pump. Intravenous magnesium may be used to treat cardiac arrhythmias due to digoxin poisoning where there is likely to be a delay in the availability of digoxin antibodies, even in the presence of elevated serum magnesium. PMID- 7837315 TI - Survival after a severe iron poisoning treated with intermittent infusions of deferoxamine. AB - Iron poisoning is the most common cause of overdose mortality in children under six years of age and there are no reports of survival with iron levels > 2687 mumol/L (> 15,000 micrograms/dL). A 22-month-old male was brought to the emergency department by his parents after ingesting an estimated 50 ferrous sulfate tablets (60 mg elemental iron/tablet) several hours earlier. Despite spontaneous emesis and gastric lavage his condition deteriorated and he was found to have a serum iron of 2992 mumol/L (16,706 micrograms/dL). During the first four days in the intensive care unit, he developed coma, metabolic acidosis, hypovolemic and cardiogenic shock, liver failure, coagulopathy and adult respiratory distress syndrome. He was treated with a unique deferoxamine dosage schedule (25 mg/kg/h for 12 h/d x 3 d), mechanical ventilation, Swan-Ganz catheter monitoring, dopamine/nitroprusside therapy, blood product, bicarbonate, electrolyte and volume replacement. After a prolonged hospital course complicated primarily by gastric outlet obstruction he was dismissed on full oral feedings, gaining weight, and neurologically intact. Swan-Ganz catheter monitoring guided the management of this patient's shock, iron-induced cardiac failure, and deferoxamine mesylate induced adult respiratory distress syndrome. Further experience and research is required to determine the most appropriate deferoxamine mesylate dosing schedule and our experience expands the range for possible survival after massive iron overdose. PMID- 7837316 TI - Acute tubular necrosis following endosulphan insecticide poisoning. AB - Endosulphan is a chlorinated hydrocarbon insecticide with potential toxicity for the respiratory and central nervous systems. Renal toxicity has been rarely reported. We describe a man who developed renal failure due to acute tubular necrosis following a suicidal attempt with endosulphan in the absence of significant hypotension or sepsis. PMID- 7837317 TI - Paresthesia in envenomation by the scorpion Leiurus quinquestriatus. AB - We observed two patients with systemic paresthesia as the sole systemic manifestation of envenomation by L. quinquestriatus. A prospective study of the incidence of local and systemic paresthesia in 20 consecutive patients stung by this scorpion was done. Sixteen patients (80%) had only local complaints and 4/20 (20%) had mild systemic manifestations. Eleven patients (55%) had local paresthesia and in 2 patients (10%) systemic paresthesia was noted involving all four extremities in one patient and the perioral area in the other. The possible mechanism of paresthesia following a scorpion sting is discussed. PMID- 7837318 TI - Urginea maritima (squill) toxicity. AB - A 55 year-old female ingested two bulbs of Urginea maritime (squill) plant as a folk remedy for her arthritic pains. Her past history was significant for Hashimoto thyroiditis and she was hypothyroid upon presentation. Subsequent effects resembling those seen with cardiac glycoside intoxication included nausea, vomiting, seizures, hyperkalemia, atrioventricular block and ventricular arrhythmias resembling digitalis toxicity. A serum digoxin level by an enzyme immunoassay method was 1.59 ng/mL. Despite supportive treatment and pacing, the patient expired from ventricular arrhythmias 30 h after ingestion. Squill has been recognized since antiquity for the clinical toxicity of its cardiac glycosides, but this appears to be the first report of a fatality since 1966. PMID- 7837319 TI - Squill through the ages. PMID- 7837320 TI - [Teaching sociology in medical school]. AB - As early as in 1994 medical education was criticised by the Royal College of Physician in London. Nevertheless until 1978 D. C. Maddision was still asking the question: "What's wrong with medical education?", and Abrahamson writing a paper called "Disease of the (medical) curriculum". Since the 1950s social and behavioural sciences have been gradually brought into the curriculum in order to pursue better medical care. In the 1970s critics of medicine went beyond its economical and political aspects, ie. its maldistribution etc., to its cultural side. Not only the efficacy of modern medicine but its moral neutrality and benevolence were called into question. This paper is mainly based on the writer's personal experience of teaching sociology and medical sociology in a medical school in Taiwan. The debate on relevance, the difficulties and problems in teaching and suggestions for the future are covered. PMID- 7837321 TI - Seroepidemiological study of coxsackievirus type A24 variant (CA24v) in Taiwan. AB - In October 1985 and June 1986, for the first time, Taiwan experienced two outbreaks of acute hemorrhagic conjunctivitis (AHC) caused by a variant of coxsackievirus A24 (CA24v). Sera of virologically and clinically confirmed cases were studied together with the pre- and post-epidemic serum samples by the microneutralization method (cut-off titer, 1:8). The serum samples included 16 cases of virologically confirmed AHC and 18 cases of clinically diagnosed AHC which were collected during the period of January to July, 1987 (i.e., 7 to 21 months after the epidemic). In the same period of time, 374 serum samples were randomly collected as a post-epidemic control group. Meanwhile, 206 serum samples, which were randomly collected in 1980, were studied as a pre-epidemic control group. The results showed that in terms of CA24v neutralizing antibody (NTAb) positivity, a significant difference was found between the pre- and post epidemic random sample groups (5.3% vs. 28.1%, P < 0.001) while no significant differences among the virologically confirmed, the clinically diagnosed and the post-epidemic random sample groups were noticed (31.3% vs. 28.1%; 44.4% vs. 28.1%, P > 0.05). For comparison, the enterovirus 70 (EV70) NTAb of the samples was studied simultaneously. The results showed that the positive rate and geometric mean titer of CA24v NTAb were lower than those of EV70 even in the post epidemic serum samples collected shortly after the CA24v epidemic. PMID- 7837322 TI - Hallux valgus: soft tissue procedure versus bony procedure. AB - Hallux valgus is one of the most common fore-foot problem in civilized populations. 49 feet of 33 cases, 8 males and 25 females with an average age of 50 years old, were treated surgically from 1987 to 1992 for hallux valgus and followed up for an average of 47.8 months, comprising 20 feet with McBride's soft tissue procedure and 29 feet of Mitchell metatarsal osteotomy. The clinical criteria for follow up included pain relief, cosmetic out look, shoe wearing comfort, metatarsophalangeal motion etc. 87.5% of the cases in the McBride's group and 95% of the cases in the Mitchell group were satisfied with the clinical results. The immediate post-operative metatarsophalangeal (MP) angle and intermetatarsal (IM) angle were both well corrected, but there was a significantly higher recurrence rate of hallux valgus in the group with the McBride's procedure (P < 0.05). One case in the McBride's group had the complication of hallux varus and one case from the Mitchell group had delayed union. The Mitchell bony procedure has a more stable result compared to the McBride's soft tissue procedure for the correction of moderate hallux valgus, and the modified Mitchell osteotomy is less invasive, easier to perform, easier to care for, and has more satisfactory long-term results. PMID- 7837323 TI - [The evaluation of the anti-shivering effect of tramadol during epidural anesthesia]. AB - 60 patients (except parturients) suffering from shivering after receiving epidural anesthesia were randomly divided into 2 equal groups. In order to evaluate the effect of Tramadol on the shivering, i.v. Tramadol (1 mg/Kg), in contrast to distilled water (20 ml) for the control group, was administered to the patients in the experimental group. We compared the arrest time between the two groups in addition to systolic blood pressure, diastolic blood pressure, heart rate, arterial O2 saturation, respiratory rate and body surface temperature. Furthermore, the degree of shivering was also compared sequentially. The systolic pressure of the control group declined significantly in the first 30 minutes (P < 0.05). The other data, including the diastolic pressure, heart rate, arterial O2 saturation, respiratory rate and body surface temperature, showed no significant difference (P > 0.05). The arrest time in the experimental group was 179 +/- 71.25 seconds in contrast to 2790 +/- 440.23 seconds in the control group, a large significant difference (P < 0.001). 10% of the patients in the experimental group experienced nausea or vomiting and 6.67% of the patients showed sedation which did not disturb consciousness level of psychomotor status. Since the exact mechanism of shivering during epidural anesthesia is not established, we sincerely hope more information about the effect to Tramadol on shivering can be uncovered. PMID- 7837324 TI - [Physiological changes in the metabolism of football trainees following a match under high temperature]. AB - The effects of a football match on the muscle metabolism of long-term football players were studied. Twenty-two senior high school students (Age: 16.95 +/- 0.82 y/o) were divided into two groups. Group A, included the subjects with longer histories of playing football (7 years) and group B were those with a shorter histories (6 years). There was no statistical difference between the two groups (p > 0.05). The temperature of all muscles tested showed statistical differences after exercise (p < 0.05). After 24 hours, all muscles except the gluteus maximus returned to the normal state while the skin temperature of the latissimus dorsi did not have any change. Body temperature, pulse rate, respiratory rate, and diastolic pressure all significantly increased immediately after the match (p < 0.05) and they all returned to their normal resting rate within one hour, except the body temperature, which required two hours to return to normal. A comparison between groups A and B showed a significant difference (p < 0.01) in creatine kinase level immediately and one hour after the match. It is inferred that energy is derived from the aerobic system. PMID- 7837325 TI - Sick sinus syndrome with normal atropine response--a case report. AB - A 76-year-old woman was admitted due to recurrent syncope. Sinus bradycardia and intermittent sinus pauses (up to 2.24 sec) were documented by 24 hour Holter electrocardiogram. Although intravenous atropine can increase the sinus rate up to 100 bpm, electrophysiologic study showed marked prolongation of sinus node recovery time both at the control state and after autonomic blockades. Sick sinus syndrome was diagnosed, even with a normal atropine test, and a permanent pacemaker resulted in resolution of the syncope. PMID- 7837326 TI - Asymptomatic sacral arachnoid cyst in a patient with ankylosing spondylitis. AB - A sacral arachnoid cyst was found incidentally in a patient with ankylosing spondylitis. The clinical manifestations were perithecal bony erosions and thecal sac displacement while no associated neurological deficit was detected. This peculiar situation is of special interest as cauda equina syndrome invariably presented in such clinical complex. The pathogenesis of the arachnoid cyst remains unclear. And surgical intervention is only indicated in patients with evidence of nerve root compression. PMID- 7837327 TI - Regression formula for estimation of fetal weight with use of abdominal circumference and femur length: a prospective study. AB - Ultrasonographic fetal measurements from 293 singleton pregnancies were obtained within 7 days of delivery. Biparietal diameter, abdominal circumference, femur length, and actual birth weight data of the first 93 fetuses in the study were used as variables to determine the best mathematical model for relating estimated fetal weight to biparietal diameter, abdominal circumference, and femur length. With the aid of a computer, three regression equations were derived. The best model was Log10 (weight) = 0.77125 + 0.13244 (AC) - 0.12996 (FL) - 1.73588 (AC x AC)/1000 + 3.09212 (FL x AC)/1000 + 2.18984 (FL/AC); (R2 = 0.987). The accuracy of this formula was then compared prospectively, first with the formulas published by Shepard and coworkers, Rose and McCallum, and Hadlock and colleagues in the entire sample of 200 patients, second in 46 large, 101 appropriate, and 53 small for gestational age fetuses, and then in 44 fetuses of pregnancy complicated by diabetes. The difference between actual and estimated birth weights generated by the study formula had no systematic error (Student's t-test, P > 0.05) in cumulative data, and in small or appropriate and large for gestational age fetuses. As this derived formula is very cumbersome to manipulate, tables have been prepared with computer assistance to read the estimated fetal weight directly. PMID- 7837328 TI - Gray scale and color flow Doppler characterization of uterine tumors. AB - The aim of this study was to investigate gray scale and color flow characteristics of a group of patients with a suspected uterine pathologic condition. One hundred and twenty-two consecutive patients at the Women's Cancer Center, University of Minnesota, undergoing transvaginal sonography and color flow Doppler imaging for suspected uterine corpus abnormality made up the study group. After gray scale morphologic assessment, color flow Doppler imaging of the tumor and uterus was performed, including the ipsilateral uterine artery. Malignant tumors were confirmed pathologically in all 35 patients who had them. In comparing patients with benign versus malignant tumors, gray scale morphologic assessment confirmed that malignant uterine tumors (31 endometrial cancers and four sarcomas) were more likely to have a thickened echoic endometrium (P = < 0.0001), be enlarged (P = 0.004), to be retroverted (P = 0.02), and to lack a subendometrial halo (P < 0.0001). Patients with four benign and 13 malignant tumors demonstrated increased flow when assessed by CFD. The calculated sensitivity of increased color flow in predicting malignancy was 39%, with a specificity of 92%, a positive predictive value of 77%, and a negative predictive value of 71%. No difference existed between the benign and malignant groups for the systolic, diastolic, and mean velocities and for the calculated pulsatility index and resistive index in both sampled uterine and intramyometrial or tumor vessels.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7837329 TI - Fetal choroid plexus vascularization assessed by color flow ultrasonography. AB - We investigated the development of intracranial vascularization in the human fetus, with particular emphasis on the choroid plexus. The fetal brain was visualized in 102 patients with healthy pregnancies between 9 and 16 weeks' gestation. Imaging was done transvaginally except in the pregnancies of longer duration with unfavorable fetal positions. Color flow imaging was used to identify vessels in the cranium and within the choroid plexus. Pulsed Doppler signals were obtained from an internal carotid-middle cerebral artery and from a choroid plexus vessel. The pulsatility index was calculated from the Doppler spectral envelope. A major cerebral vessel could be seen at 9 weeks' gestation. Choroid plexus vessels were first seen at 10 weeks 3 days. Visualization rates ranged from 35 to 75% for plexus vessels, and 65 to 100% for cerebral vessels. Visualization of choroid plexus vessels was maximal at 13 weeks. The pulsatility index for the cerebral arteries at this gestational period averaged 2.6 +/- 0.6. The result for the choroid plexus was 1.66 +/- 0.5. (P < 0.001). Visualization of the vessels of the choroid plexus increases and decreases as the gland develops and shrinks. This developmental period also is the time of active neurogenesis. PMID- 7837330 TI - Evaluation of pelvic masses with magnetic resonance imaging and ultrasonography. AB - Magnetic resonance imaging is becoming increasingly useful in characterizing adnexal masses, whereas endovaginal ultrasound is an invaluable technique for examining the uterus and adnexa. This pictorial essay depicts the internal architectural details necessary for characterization of various adnexal masses imaged with both EVU and MR imaging. Forty consecutive examinations that revealed 51 adnexal masses were reviewed. All patients had MR imaging and EVU examinations within 1 week of each other. T1- and T2-weighted images in coronal, axial, and sagittal planes were included. Fat suppression technique also was used in selected cases. EVU, because of its high spatial resolution, was able to depict better internal architectural details, allowing specific diagnosis of most adnexal masses, whereas MR imaging was superior in differentiating hemorrhagic masses from dermoids when specific fat suppression techniques were used. PMID- 7837331 TI - Ultrasound measurement of umbilical cord length. PMID- 7837332 TI - Prospective sonographic and arthroscopic evaluation of proliferative knee joint synovitis. AB - The objective of this study was to verify the accuracy of ultrasonography in assessing the topography, morphology, and extent of synovial proliferation in rheumatoid and psoriatic knee joint synovitis. Findings were compared to those obtained using prospective arthroscopy as the gold standard; in addition, topographically defined sonographic findings before and after arthroscopic synovectomy were compared. Sonographic examination was performed in 12 patients with rheumatoid arthritis (13 knees) and 13 patients with psoriatic arthritis (14 knees) who had synovitis of the knee using an electronic linear transducer (7.5 MHz) or a mechanical sector transducer (10 MHz). This examination was followed within 1 week by arthroscopy, to compare the topography (intra-articular localization) and the morphology (sonographic patterns) of synovial proliferation. In 15 knees undergoing arthroscopic synovectomy, preoperative sonographic measurement of synovial thickness in the suprapatellar, medial parapatellar, and lateral parapatellar recesses was compared with arthroscopic visualization of synovial proliferation; 13 knees were reevaluated 2 months after arthroscopic synovectomy by sonography at the same sites. Three distinct sonographic patterns of synovial proliferation were confirmed by arthroscopic examination: a villonodular aspect in 12 knees; uniform thickening in eight knees, and overlapping layers in seven knees. About 50% of the knees showed more than one sonographic pattern, with no differences in pattern distribution between rheumatoid arthritis and psoriatic arthritis patients. A significant correlation was found between sonographic and arthroscopic evaluations of synovial thickness in the suprapatellar (P < 0.02) and medial parapateoffr recesses (P < 0.02), the sites of maximal synovial proliferation in our patients.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7837333 TI - Ultrasonographic features of gastrointestinal duplications. AB - The variable sonographic appearance of duplication cysts is presented. Eighteen sonograms from 14 patients, aged 1 day to 8 years, were reviewed over an 8 year period. Water and other aqueous contrast agents were used in six patients as part of the sonographic evaluation. All lesions were confirmed by surgery. All but two patients were symptomatic. Twenty-four cysts were detected, ranging in size from 1.7 to 15.5 cm. The duplication cysts revealed a spectrum of sonographic findings (cystic to solid appearing masses). The mass characteristics, including the "muscular rim sign," and internal debris or hemorrhage, were demonstrated. Multiple unsuspected cysts (3 of 14 or 20%) and complications such as perforation were readily seen with ultrasonography. Serial sonograms demonstrated the changing morphology of two cysts. Other unsuspected intra-abdominal and pelvic pathologic conditions, including pyloric stenosis and ovarian cysts, were identified. Identification of the muscular rim sign is the most reliable indication of a duplication cyst. Multiple masses as well as possible accompanying anomalies in the abdomen and pelvis are readily evaluated with sonography. Lesions are easily followed with serial studies if there is no surgical intervention. PMID- 7837334 TI - Prenatal visualization of cranial sutures and fontanelles with three-dimensional ultrasonography. AB - The anatomy of the cranial sutures and fontanelles in the developing fetus is difficult to evaluate using conventional two-dimensional ultrasonography (2DUS). Three-dimensional sonographic imaging (3DUS) was performed on eight normal volunteer pregnant patients after informed consent with conventional 2DUS equipment that had been adapted to obtain 3DUS images. 3DUS images of the cranium were evaluated for the presence of specific cranial sutures and fontanelles. Cranial sutures and fontanelles were identified with 3DUS in all fetuses scanned. The sutures most commonly identified included coronal, lambdoidal, and squamosal. The fontanelles most often identified included anterior, posterior, mastoid, and sphenoid. 3DUS offers the capability of identifying cranial sutures and fontanelles more clearly because volume rendered images show the cranial surface in its entirely rather than as a cross-sectional slice, offering the potential to identify pathologic cranial lesions currently not seen with 2DUS. PMID- 7837335 TI - Sonographic detection of hematomas and fluid after imaging guided core breast biopsy. AB - We investigated sonographic changes to the breast after imaging guided core breast biopsy. We studied 31 breast lesions in 29 patients before, immediately after, and 2 to 9 days after core biopsy looking for hematomas. We found sonographic changes to the breast consistent with fluid collections after core biopsy in seven of 31 breast lesions (23%). Of the biopsy sites with sonographic changes, evidence suggested that six of 31 (19%) likely had hematomas. Sonographic changes after core breast biopsy are common and the formation rate of suspected hematomas is greater than previously believed although generally not clinically significant. PMID- 7837336 TI - Solid masses on the fetal surface of the placenta: differential diagnosis and clinical outcome. AB - We identified 10 cases of solid masses on the fetal surface of the placenta prospectively that were thought to represent chorioangiomas. Pathologic assessment of the placenta revealed five chorioangiomas and five placental hemorrhages. The five chorioangiomas ranged in size from 4 to 10 cm and four of these five fetuses were delivered uneventfully at term. Only one fetus showed evidence of cardiac decompensation and did not survive. Three of the five women with placental bleeds delivered their infants between 33 and 34 weeks' gestation, but all five infants did well. This series shows that the sonographic appearance of chorioangioma was indistinguishable from placental hemorrhage, and even large chorioangiomas may be associated with good neonatal outcome. PMID- 7837337 TI - Experimental and numerical models of acute intracranial hypertension and basilar artery blood flow velocity. AB - A numerical model based on Navier-Stokes equations was used in conjunction with an experimental model in rabbits to study the effects of acute intracranial hypertension on basilar artery blood flow velocity. The hypertension was induced by pressure transmission via an epidural pressure sensor inserted into a parietal intracranial opening. A critical value of half of the diastolic arterial pressure for the intracranial cerebral pressure was determined by both numerical and experimental models. At this intracranial cerebral pressure level, the total input resistance and total input compliance, determined by the numerical model, exhibited an increase of 27% and 10%, respectively, and the tissular compliance a decrease of 25% from their physiologic baseline values. When the intracranial cerebral pressure reaches the level of the diastolic arterial pressure, a zero diastolic flow is observed into the cerebral vascular system. This study validates the theoretical model, which could be used in assessing intracranial cerebral pressure noninvasively in humans when O2 pressure can be stabilized. PMID- 7837338 TI - Congenital microgastria: absence of the fetal stomach and normal third trimester amniotic fluid volume. PMID- 7837339 TI - Prenatal ultrasonographic evidence of transient dacryocystoceles. PMID- 7837340 TI - Sonographic diagnosis of Klippel-Trenaunay-Weber syndrome presenting as a sacrococcygeal mass at 14 to 15 weeks' gestation. PMID- 7837341 TI - Prenatal sonographic diagnosis of Carpenter syndrome. PMID- 7837342 TI - An unusual presentation of Rokitansky-Mayer-Kuster-Hauser syndrome. PMID- 7837343 TI - Will schools add insurance to the 3 Rs? PMID- 7837344 TI - Institute of Medicine calls for coordinated studies of Gulf War veterans' health complaints. PMID- 7837346 TI - Smallpox virus destruction delayed yet again. PMID- 7837345 TI - Anesthesia-related risks have plummeted. PMID- 7837347 TI - From the Centers for Disease Control and Prevention. Injuries associated with use of snowmobiles--New Hampshire, 1989-1992. PMID- 7837348 TI - From the Centers for Disease Control and Prevention. Race-specific differences in influenza vaccination levels among Medicare beneficiaries--United States, 1993. PMID- 7837349 TI - From the Centers for Disease Control and Prevention. Asthma--United States, 1982 1992. PMID- 7837350 TI - From the Centers for Disease Control and Prevention. Multistate outbreak of viral gastroenteritis associated with consumption of oysters--Apalachicola Bay, Florida, December 1994-January 1995. PMID- 7837351 TI - A piece of my mind. The night doctor. PMID- 7837352 TI - Inappropriate drug prescribing. PMID- 7837353 TI - Inappropriate drug prescribing. PMID- 7837354 TI - Inappropriate drug prescribing. PMID- 7837355 TI - Inappropriate drug prescribing. PMID- 7837356 TI - Inappropriate drug prescribing. PMID- 7837357 TI - Inappropriate drug prescribing. PMID- 7837358 TI - Inappropriate drug prescribing. PMID- 7837359 TI - Childhood lead poisoning in 1994. PMID- 7837360 TI - Childhood lead poisoning in 1994. PMID- 7837361 TI - The war on drugs: time to relocate the battlefield? PMID- 7837362 TI - Community-academic health care partnership. PMID- 7837363 TI - The risk of death to trekkers and hikers in the mountains. PMID- 7837364 TI - An outbreak of Norwalk virus gastroenteritis associated with eating raw oysters. Implications for maintaining safe oyster beds. AB - OBJECTIVE: To determine the characteristics and the cause of an outbreak of gastroenteritis associated with eating raw oysters. DESIGN: Survey of groups of persons reporting illness to the health department after eating oysters; survey of convenience sample of oyster harvesters; and tracing of implicated oysters. SETTING: General community. MAIN OUTCOME MEASURES: Relative risk for illness after oyster consumption, source bed of contaminated oysters, presence of antibodies to Norwalk virus in serum, presence of a Norwalk virus in stool by direct electron microscopy and reverse transcription-polymerase chain reaction (RT-PCR), and DNA sequences of RT-PCR products. RESULTS: Seventy (83%) of 84 persons who ate raw oysters became ill vs three (7%) of 43 people who did not eat raw oysters (relative risk, 11.9; 95% confidence interval, 4.0 to 34.2). Eleven (79%) of 14 serum pairs had at least a fourfold increase in antibody to Norwalk virus. All 12 stool samples tested were positive by electron microscopy and/or RT PCR for Norwalk virus. The RT-PCR products from all seven stool samples tested had identical DNA sequences. Implicated oysters were harvested November 9 through 13, 1993, from a remote oyster bed. Crews from 22 (85%) of 26 oyster harvesting boats working in this area reported routine overboard disposal of sewage. One harvester with a high level of antibodies to Norwalk virus reported having gastroenteritis November 7 through 10 and overboard disposal of feces into the oyster bed. CONCLUSIONS: This outbreak was caused by contamination of oysters in the oyster bed, probably by stool from one or more ill harvesters. Education of oyster harvesters and enforcement of regulations governing waste disposal by oyster harvesting boats might prevent similar outbreaks. PMID- 7837365 TI - National assessment of physicians' breast-feeding knowledge, attitudes, training, and experience. AB - OBJECTIVE: Previous reports have demonstrated that physician counseling can improve rates of breast-feeding initiation and duration but suggest that physicians are ill-prepared for this role. It is unclear whether residency training for pediatricians, obstetrician/gynecologists, and family physicians provides the knowledge and skills necessary for effective breast-feeding promotion. DESIGN: Survey. PARTICIPANTS: A national random sample of 3115 residents and 1920 practicing physicians in pediatrics, obstetrics/gynecology, and family medicine. OUTCOMES: Assessment of breast-feeding knowledge, attitudes, training, and experience. RESULTS: Overall response rate was 68%. All groups demonstrated significant deficits in knowledge of breast-feeding benefits and clinical management; for example, less than 50% of residents chose appropriate clinical management for a breast-fed jaundiced infant or a breast abscess. Practicing physicians performed slightly better, but still more than 30% chose incorrect advice for mothers with low milk supply. Residents reported that their breast-feeding instruction consisted mainly of didactic lecture, not patient experience. Only 55% of senior residents recalled even one instance of precepting related to breast-feeding, and less than 20% had demonstrated breast-feeding techniques at least five times during residency. Regarding preparation for breast feeding counseling, more than 50% of all practicing physicians rated their residency training as inadequate. Overall, physician involvement in breast feeding promotion was endorsed by 90% of respondents, yet only half rated themselves as effective in counseling breast-feeding patients. The greatest predictor of physician self-confidence was previous personal or spousal breast feeding experience. CONCLUSIONS: In this national sample of residents and practicing physicians in three specialties, physicians were ill-prepared to counsel breast-feeding mothers. Deliberate efforts must be made to incorporate clinically based breast-feeding training into residency programs and continuing education workshops to better prepare physicians for their role in breast-feeding promotion. PMID- 7837366 TI - Adolescents' exposure to violence and associated symptoms of psychological trauma. AB - OBJECTIVE: To examine the extent to which adolescents are exposed to various types of violence as either victims or witnesses, and the association of such exposure with trauma symptoms; specifically, the hypotheses that exposure to violence will have a positive and significant association with depression, anger, anxiety, dissociation, posttraumatic stress, and total trauma symptoms. DESIGN AND SETTING: The study employed a survey design using an anonymous self-report questionnaire administered to students (grades 9 through 12) in six public high schools during the 1992-1993 school year. PARTICIPANTS: Sixty-eight percent of the students attending the participating schools during the survey participated in the study (N = 3735). Ages ranged from 14 to 19 years; 52% were female; and 35% were African American, 33% white, and 23% Hispanic. RESULTS: All hypotheses were supported. Multiple regression analyses of the total sample revealed that violence exposure variables (and to a lesser extent, demographic variables) explained a significant portion of variance in all trauma symptom scores, including depression (R2 = .31), anger (R2 = .30), dissociation (R2 = .23), posttraumatic stress (R2 = .31), and total trauma (R2 = .37). CONCLUSIONS: A significant and consistent association was demonstrated linking violence exposure to trauma symptoms within a diverse sample of high school students. Our findings give evidence of the need to identify and provide trauma-related services for adolescents who have been exposed to violence. PMID- 7837367 TI - Telemedicine technology and clinical applications. PMID- 7837368 TI - Chaparral ingestion. The broadening spectrum of liver injury caused by herbal medications. AB - Unconventional medical practices, including the use of herbal remedies, are prevalent in the United States. Chaparral is an herbal preparation made from a desert shrub and used for its antioxidant properties. We report the case of a 60 year-old woman who took chaparral for 10 months and developed severe hepatitis for which no other cause could be found. Despite aggressive supportive therapy, the patient deteriorated and required orthotopic liver transplantation. She is now well, more than 1 year after her transplant. This case suggests that chaparral can cause serious liver injury and fulminant hepatic failure. Herbal medications should be considered as potential causes of liver toxicity. PMID- 7837370 TI - Herbal hepatotoxicity. Revisiting a dangerous alternative. PMID- 7837369 TI - NIH consensus conference. Ovarian cancer. Screening, treatment, and follow-up. NIH Consensus Development Panel on Ovarian Cancer. AB - OBJECTIVE: To provide physicians with a current consensus on screening, prevention, diagnosis, and treatment of ovarian cancer. PARTICIPANTS: A nonfederal, nonadvocate, 14-member consensus panel representing the fields of gynecologic, medical, and radiation oncology, obstetrics/gynecology, and biostatistics; 25 experts in obstetrics/gynecology and gynecologic, medical, and radiation oncology who presented data to the consensus panel; and a conference audience of approximately 500. EVIDENCE: The literature was searched through MEDLINE, and an extensive bibliography of references was produced for the panel and the conference audience. Experts prepared abstracts with relevant citations from the literature. Scientific evidence was given priority over clinical anecdotal experience. CONSENSUS: The panel, answering predefined consensus questions, developed their conclusions based on the scientific evidence presented in open forum and the scientific literature. CONSENSUS STATEMENT: The panel composed a draft statement that was read in its entirety and circulated to the experts and the audience for comment. The panel resolved conflicting recommendations and released a revised statement at the end of the conference. The panel finalized the revisions within a few weeks after the conference. CONCLUSIONS: There is no evidence available yet that the current screening modalities of CA-125 and transvaginal ultrasonography can be effectively used for widespread screening to reduce mortality from ovarian cancer nor that their use will result in decreased rather than increased morbidity and mortality. Women with stage IA grade 1 and stage IB grade 1 ovarian cancer do not require postoperative adjuvant therapy. Many remaining stage I patients do require chemotherapy. Subsets of stage I must be fully defined and ideal treatment determined. Women with stages II, III, and IV epithelial ovarian cancer (other than low malignant potential tumors) should receive postoperative chemotherapy. PMID- 7837371 TI - Exercise to reduce 'potbelly'. PMID- 7837372 TI - Mandated choice. A plan to increase public commitment to organ donation. AB - OBJECTIVES: To estimate the impact of mandated choice--a system that requires competent adults to decide prospectively whether or not they wish to be organ donors when they die--on public commitment to organ donation; and to explore who is best suited to provide consent--the family or the individual? DESIGN: A national, random-digit telephone survey conducted by the Gallup Organization in July 1993. PARTICIPANTS: A representative sample (n = 1002) of adults (aged 18 years and older) living in homes with telephones in the continental United States. RESULTS: Although the majority of respondents had given at least some thought to organ donation, only 25% had carefully considered this issue. Overall, 30% had decided to donate, but 58% were undecided and only 38% had made their wishes known to a family member. Yet the vast majority (82%) believes that the best way to obtain consent is for each adult to decide for himself or herself, rather than leaving this decision for the family. Under mandated choice, which is designed to encourage such self-determination, 63% would sign up to donate, 24% would not, and 13% were unsure. CONCLUSIONS: Only a small fraction of the US public is currently committed to organ donation and relatively few people have carefully considered and communicated their wishes regarding this important issue. Therefore, the difficult question of consent is often left for the family. Yet most people believe that ideally all adults should answer this question for themselves, in contrast to our present family-oriented approach, but consistent with the design of mandated choice. If mandated choice became law, it appears that most adults would sign up to donate, thereby increasing the pool of desperately needed committed donors. PMID- 7837373 TI - A piece of my mind. The taste of lemonade on a summer afternoon. PMID- 7837374 TI - Do specialists screen for breast cancer? PMID- 7837375 TI - Environmental tobacco smoke and lung cancer in nonsmoking women. PMID- 7837376 TI - Physical activity and risk of gastrointestinal hemorrhage in the elderly. PMID- 7837377 TI - Are the peers peers? PMID- 7837378 TI - Are the peers peers? PMID- 7837379 TI - Are the peers peers? PMID- 7837381 TI - Leader in war on cancer looks ahead: talking with Vincent T. DeVita, Jr, MD. PMID- 7837380 TI - Effect of CLIA 88 on Minnesota physicians' office laboratories. PMID- 7837382 TI - 'Essential components now in place' for clinical testing of cancer vaccine strategies, experts say. PMID- 7837383 TI - Efforts to raise supply of two prophylactic agents. PMID- 7837384 TI - From the Centers for Disease Control and Prevention. Attitudes toward smoking policies in eight states--United States, 1993. PMID- 7837385 TI - From the Centers for Disease Control and Prevention. Jimson weed poisoning- Texas, New York, and California, 1994. PMID- 7837386 TI - From the Centers for Disease Control and Prevention. Ectopic pregnancy--United States, 1990-1992. PMID- 7837387 TI - A collaborative survey of 80 mutations in the BRCA1 breast and ovarian cancer susceptibility gene. Implications for presymptomatic testing and screening. AB - OBJECTIVES: To report the initial experience of an international group of investigators in identifying mutations in the BRCA1 breast and ovarian cancer susceptibility gene, to assess the spectrum of such mutations in samples from patients with different family histories of cancer, and to determine the frequency of recurrent mutations. DESIGN: Nine laboratories in North America and the United Kingdom tested for BRCA1 mutations in DNA samples obtained from a total of 372 unrelated patients with breast or ovarian cancer largely chosen from high-risk families. Three of these laboratories also analyzed a total of 714 additional samples from breast or ovarian cancer cases, including 557 unselected for family history, for two specific mutations that had been found to recur in familial samples. PARTICIPANTS: A total of 1086 women with either breast or ovarian cancer. MAIN OUTCOME MEASURE: The detection of sequence variation in patients' DNA samples that is not found in sets of control samples. RESULTS: BRCA1 mutations have now been identified in a total of 80 patient samples. Thirty eight distinct mutations were found among 63 mutations identified through a complete screen of the BRCA1 gene. Three specific mutations appeared relatively common, occurring eight, seven, and five times, respectively. When specific tests for the two most common mutations were performed in larger sets of samples, they were found in 17 additional patients. Mutations predicted to result in a truncated protein accounted for 86% of the mutations detected by complete screening. CONCLUSIONS: The high frequency of protein-terminating mutations and the observation of many recurrent mutations found in a diverse set of samples could lead to a relatively simple diagnostic test for BRCA1 mutations. More data must be accumulated to address specifically the sensitivity and specificity of such a diagnostic testing procedure and to better estimate the age-specific risk for breast and ovarian cancer associated with such mutations. PMID- 7837388 TI - Sequential or alternating doxorubicin and CMF regimens in breast cancer with more than three positive nodes. Ten-year results. AB - OBJECTIVE: To improve current adjuvant results in patients with resectable mammary carcinoma and more than three positive axillary lymph nodes. DESIGN: A prospective randomized study was carried out to compare the effectiveness of four courses of doxorubicin hydrochloride followed by eight courses of cyclophosphamide, methotrexate, and fluorouracil (CMF) (sequential regimen) vs two courses of CMF alternated with one course of doxorubicin for a total of 12 courses (alternating regimen). All drug courses were recycled every 3 weeks. The median duration of follow-up at the time of current analysis was 9 years. SETTING: The study was conducted on patients operated on for primary unilateral breast cancer at the Istituto Nazionale Tumori of Milan, Italy. Adjuvant chemotherapy was delivered in the outpatient clinic of the Division of Medical Oncology. PATIENTS: A total of 405 women were entered into the study, 403 of whom met the protocol criteria. Patient characteristics were fairly well balanced between the two treatment groups, with the exception of extent of nodal involvement: 38% with more than 10 positive nodes were randomized to the alternating regimen compared with 29% in the sequential regimen (P = .08). MAIN OUTCOME MEASURE: Relapse-free and total survival at 10 years after surgery estimated according to the Kaplan-Meier product limit method. RESULTS: Treatment outcome was significantly superior for patients who received the sequential regimen compared with those given the alternating chemotherapy. The relapse-free survival was 42% vs 28% (P = .002) and total survival was 58% vs 44% (P = .002), respectively. The benefit of the sequential regimen was evident in all patient subsets. Treatment was fairly well tolerated, but we documented four cases of congestive heart failure, which was fatal in two patients. CONCLUSIONS: Current findings indicate that in women with extensive nodal involvement, sequential chemotherapy with doxorubicin followed by CMF yields superior results compared with the alternating administration of the same regimens or with classical CMF. PMID- 7837389 TI - Allele-specific chromosome 3p deletions occur at an early stage in the pathogenesis of lung carcinoma. AB - BACKGROUND: Deletions in the short arm of chromosome 3 (3p) are present in most lung carcinomas. OBJECTIVE: To investigate the role of these chromosome 3p deletions in the pathogenesis of non-small cell lung carcinomas. DESIGN: Seven archival, paraffin-embedded, surgically resected lung cancer specimens were studied. Fifty precisely identified malignant and preneoplastic lesions present in bronchi, bronchioles, and alveoli were microdissected from stained slides and analyzed for allele loss using polymerase chain reaction-based assays for dinucleotide repeat polymorphisms at three chromosome 3p loci (3p14, 3p21.3, and 3p25). SETTING: University-based medical center and affiliated hospitals. SUBJECTS: Samples were analyzed from seven patients who underwent surgical resection with curative intent for non-small cell lung cancer and whose specimens included extensive multifocal areas of preneoplastic lesions (hyperplasia, metaplasia, dysplasia, or noninvasive cancer). RESULTS: Lymphocytes from all seven cases were heterozygous (ie, informative) for all three microsatellites analyzed. Six (86%) of seven invasive cancers had loss of heterozygosity at one or more chromosome 3p sites. In the accompanying preneoplastic lesions, loss of heterozygosity was detected in none of two normal bronchioles, 13 (76%) of 17 hyperplasias, six (86%) of seven dysplasias, and four (100%) of four noninvasive cancers. Loss of heterozygosity was detected throughout the respiratory tract, in bronchi, bronchioles, and alveoli. In 18 (78%) of 23 preneoplastic lesions, the specific alleles lost were identical to those lost in the corresponding carcinomas. The probability of this happening by chance is 5.3 x 10(-3). CONCLUSIONS: Deletions in the short arm of chromosome 3 occur at the earliest stage (hyperplasia) in the pathogenesis of lung cancer and involve all regions of the respiratory tract. Allele loss is highly specific, but its mechanism remains unknown. Our findings may be of considerable biologic, prognostic, and clinical significance. PMID- 7837390 TI - Identification of the von Hippel-Lindau (VHL) gene. Its role in renal cancer. PMID- 7837391 TI - Self-fusion of the ALL1 gene. A new genetic mechanism for acute leukemia. PMID- 7837392 TI - Assessment and counseling for women with a family history of breast cancer. A guide for clinicians. AB - More women in all risk categories are seeking information regarding their individual breast cancer risk, and there is a need for their primary care clinicians to be able to assess familial risk factors for breast cancer, provide individualized risk information, and offer surveillance recommendations. Estimates of the number of women with a family history of breast cancer range from approximately 5% to 20%, depending on the population surveyed. Many of these women will not have a family history that suggests the presence of a highly penetrant breast cancer susceptibility gene. However, a small subset of such women will come from families with a striking incidence of breast and other cancers often associated with inherited mutations. The development and refinement of risk prediction models provide an epidemiologic basis for counseling women with a family history that does not appear related to a dominant susceptibility gene. contrast, the recent isolation of BRCA1, the localization of BRCA2, and the acknowledgement that additional breast cancer susceptibility genes must exist provide a molecular basis for counseling some high-risk women. We present a guide for primary care clinicians that may be helpful in defining families as moderate or high risk, in determining individual risk in women with a family history of breast cancer based on this distinction, and for counseling women in a setting where the data necessary to design surveillance and prevention strategies are lacking. We include criteria for selecting women who may be candidates for detection of inherited mutations in breast cancer susceptibility genes. PMID- 7837393 TI - HLA typing for bone marrow transplantation. New polymerase chain reaction-based methods. PMID- 7837394 TI - The genetic origins of neoplasia. PMID- 7837395 TI - Erythema gyratum repens. PMID- 7837396 TI - [Effects of volatile anesthetics on microtubule-associated protein 2 degradation during forebrain ischemia in the rat]. AB - One of the most prominent phenomena that occurs during the early phase of cerebral ischemia has been shown to be the immunohistochemical collapse of cytoskeletal proteins. Among these, microtubule-associated protein 2 (MAP 2) has been shown to be vulnerable to ischemic injuries. In order to select a suitable volatile anaesthetic from the standpoint of cytoskeletal protein breakdown during cerebral ischemia, we compared the effect of isoflurane, halothane and sevoflurane on MAP 2 degradation during 20 min of forebrain ischemia in the rat. Under 1 MAC of three volatile anesthetics, forebrain ischemia was induced by the occlusion of the bilateral common carotid artery combined with a lowering of mean arterial pressure to 50 mmHg. Immediately after cerebral ischemia, four regions of the brain, the frontoparietal cortex, brainstem, hippocampus and cerebellum, were removed separately and homogenized. Subsequently, MAP 2 from each region was quantitatively measured using an enzyme-linked immunosorbent assay. MAP 2 in the frontoparietal cortex and hippocampus was significantly protected from degradation with isoflurane anaesthesia more than with halothane and sevoflurane anaesthesia. PMID- 7837397 TI - [The inhibitory effects of ulinastatin on the increase of interleukin 8 and 6 during open heart surgery]. AB - The effects of ulinastatin on the serum interleukin 8 and 6 (IL-8, 6), granulocyte elastase (GEL), creatinphosphokinase (CK) and CK-MB were studied during open heart surgery under cardiopulmonary bypass (CPB). Eleven patients (group I) did not receive ulinastatin. Thirteen patients (group II) received 600,000 units of ulinastatin intravenously before CPB and before declamping of aorta and 12 patients (group III) received 300,000 units more added in the priming solution. The serum concentration of IL-8 and 6 increased at 60, 120, 180 min. after reperfusion compared with the preoperative value in the three groups. But, at each time point after reperfusion, IL-8 and 6 levels in group II and III were significantly lower (P < 0.01) than those in group I. GEL increased progressively after reperfusion in the three groups. There was no significant difference in the three groups with CK-MB as well CK release. These results suggest that ulinastatin is useful for protection of reperfusion injury after myocardial ischemia since ulinastatin suppresses production of IL-8 and 6. PMID- 7837398 TI - [Efficacy of oral midazolam as premedication in adult]. AB - Midazolam was administered as a premedicant to 90 patients aged from 20 to 55 years with ASA status 1 or 2. The patients were divided into 3 groups: group I 10 mg orally, group II 20 mg orally, group III 5 mg intramuscularly. All premedications were given 30 minutes before entering the operating room. The perioperative effects of midazolam on blood pressure, pulse rate, respiratory rate and SpO2 as well as sedative, hypnotic and amnemonic effects were evaluated in these patients. There were no remarkable changes in the blood pressure, pulse rate or respiratory rate. There was no problem on the upper airway tract, but a slight decrease in SpO2 was observed in a few patients. In this study, sedative and hypnotic effects were almost satisfactory. Midazolam produced significant anterograde amnesia, and the amnemonic rate was 66.7% in group I and 86.7% in group II and III. In conclusion, oral midazolam is an effective preanesthetic medication in adult. PMID- 7837399 TI - [High dose epidural fentanyl suppresses the increase in cortisol levels during open chest surgery]. AB - We investigated the effect of high dose epidural fentanyl (HEF) on plasma levels of epinephrine (E), norepinephrine (NE) and cortisol (C) during open chest surgery (OCS). Twenty five patients undergoing open chest surgery was divided randomly into two groups. Thirteen patients had HEF (F-Group) and the rest of 12 patients had epidural mepivacaine (M-Group). Epidural puncture (Th5-6) and catheterization were performed before anesthetic induction. Anesthesia was induced with thiamylal (5 mg.kg-1) and trachea was intubated after injection of vecuronium (0.1 mg.kg-1). Anesthesia was maintained with 50% N2O and isoflurane as needed. After 0.2 ml.kg-1 of fentanyl was injected through the epidural catheter, fentanyl was infused continuously (0.05 mg.h-1) in F-Group. In M-Group, after 0.2 ml.kg-1 of 1% mepivacaine was injected through the epidural catheter, 1% mepivacaine was infused continuously (10 ml.h-1). For the measurement of E, NE and C, blood samples were collected at following points; 1) before anesthetic induction, 2) before incision, 3) during open chest and 4) in the recovery room. In both groups, E and NE levels did not change significantly. In F-Group, plasma C levels decreased significantly when chest was opened. C levels in F-Group, were significantly lower than in M-Group before incision and during open chest. PMID- 7837400 TI - [Effects of volatile anesthetics on force interval relationships in guinea-pig atrial preparations]. AB - Depressant effects of halothane, enflurane and isoflurane on isolated guinea-pig left atrial muscles bathed in Tyrode's solution at 30 degrees C were examined. Contractions were elicited by stimulation through external field electrodes while tension was recorded continuously. Frequency-force relationships at stimulation rates of 0.1, 0.2, 0.5 and 1 Hz were studied. The pD2 values of these volatile anesthetics at each stimulation rates were not different significantly, suggesting the frequency-independent depressions of these anesthetics. Interval strength relationships at time intervals of 0.3-20 sec during 1 Hz-stimulation were also studied. Mechanical restitution curves after converting to logistic function reached a peak at 8-20 sec and were fitted well to double exponential functions with time constants of 200-600 msec (k1) and 2-6 sec (k2). All volatile anesthetics depressed the magnitude constants for fast response in a dose dependent manner. Accordingly, at high concentrations, mechanical resuscitation curves tended to fit single exponential function. Halothane and enflurane did not alter time constant k1, k2 significantly, while isoflurane increased k2 significantly. These results suggest that the mechanisms of myocardial depressant effects are different between these anesthetics. PMID- 7837401 TI - [Influence of sevoflurane and isoflurane anesthesia on renal function in elderly patients]. AB - We examined the influence of sevoflurane and isoflurane anesthesia on renal function in elderly patient who underwent gastrectomy. Plasma inorganic fluoride level was significantly higher in sevoflurane group compared with isoflurane group from 3 hours after the beginning of anesthesia to the 3rd operative day. In contrast, parameters such as urinary beta 2 microglobulin, urinary N-acetyl-beta D-glucosaminidase, and urinary gamma-GTP activities increased in both groups, but the increase was not significant. Serum BUN and creatinine levels were within normal limits. These results suggest that elderly patients without renal dysfunction appear unlikely to have any significant problem after prolonged sevoflurane anesthesia. PMID- 7837402 TI - [Effects of inorganic fluoride, inhalation time and dosage of sevoflurane on renal function during sevoflurane anesthesia of long duration]. AB - In sevoflurane anesthesia of long duration, we studied correlations with renal function of the area under the curve (AUC), rate of decrease and maximum level of serum inorganic fluoride (F), sevoflurane dosage, and duration of administration. In 15 neurosurgical patients, we measured serum and urine levels of F, blood urea nitrogen (BUN), creatinine, serum and urine beta 2-microglobulin (BMG), and urine N-acetyl-beta-D-glucosaminidase (NAG). AUC and the rate of decrease of serum F were calculated. There were no correlations among the maximum level, AUC, the rate of decrease of serum F, sevoflurane dosage, duration of administration, BUN, creatinine, BMG, and NAG. It is concluded that in sevoflurane anesthesia of long duration, F, sevoflurane dosage and duration of administration do not affect renal function. PMID- 7837403 TI - [The concentration effects of isoflurane-N2O anesthesia on cardiovascular responses to skin incision]. AB - To investigate the concentration effects of isoflurane-nitrous oxide anesthesia on cardiovascular responses to skin incision, we studied 24 non-premedicated patients undergoing lower abdominal operation. Anesthesia was induced with inhalation of 70% nitrous oxide and isoflurane, and maintained with 70% nitrous oxide and three different concentrations of isoflurane (1.25, 1.6, 1.95 MAC). Blood pressure and heart rate were recorded continuously before and after skin incision. Because more than half the patients with 1.95 MAC became hypotensive with systolic blood pressure of less than 80 mmHg just before the skin incision, it was difficult to define the values of MAC BAR (blocking adrenergic responses) in the present study. Cardiovascular responses at skin incision were not completely suppressed at 1.6 MAC isoflurane-N2O anesthesia and no further blocking effects were obtained at 1.95 MAC isoflurane-N2O anesthesia. These results suggest that higher concentration of isoflurane does not guarantee stronger protective effects on stimulation like skin incision. PMID- 7837404 TI - [Effect of dopamine administration on ICG-disappearance rate during prone position anesthesia]. AB - We evaluated the effect of dopamine administration (3 micrograms.kg-1.min-1) on ICG-disappearance rate during prone position in 10 patients undergoing elective spinal cord surgery. Anesthesia was maintained with isoflurane and 50% nitrous oxide in oxygen. ICG-disappearance rate was determined at 3 points, i.e., the day before surgery, during prone position and during the administration of dopamine. Systolic arterial pressure showed no significant difference before and during dopamine administration. ICG-disappearance rate during prone position was significantly lower than the preoperative value. However, ICG-disappearance rate showed no significant difference during dopamine administration and preoperative period. We conclude that dopamine administration may attenuate the depressant effect of the prone position on the hepatic blood flow. PMID- 7837405 TI - [Effects of intravenous and intramuscular atropine on bradycardia during spinal anesthesia]. AB - The effects of intravenous and intramuscular atropine on pulse rate have been studied in 40 patients undergoing gynecological surgery. Intramuscular atropine 0.5 mg was administered 30 min before induction of spinal anesthesia in 20 patients (i.m. group). Intravenous atropine 0.5 mg was administered immediately after induction of spinal anesthesia in 20 patients (i.v. group). Decrease in heart rate after spinal block was significantly less in i.v. group than in i.m. group. Although no one in i.v. group was given an additional atropine, 10% of the patients in i.m. group was given an additional atropine for bradycardia. Authors conclude that intravenous atropine has more significant effect on prevention of bradycardia during spinal anesthesia compared with intramuscular atropine. PMID- 7837406 TI - [Changes in rectal temperature during tympanoplasty under general anesthesia]. AB - We measured rectal temperature of 35 patients who underwent tympanoplasty under various types of general anesthesia. They were allocated at random to three groups according to the types of general anesthesia; 10 patients of enflurane-N2O (enflurane group); 10 patients of neuroleptic anesthesia with droperidol, pentazocine-N2O (NLA group); 15 patients of total intravenous anesthesia with droperidol, fentanyl and ketamine (DFK group). After the induction of anesthesia, their rectal temperature was continuously monitored with an electric thermometer of NEC San-ei throughout the surgical procedure. Increase in rectal temperature was observed in all three groups, and increase in DFK group was significant compared with other two groups. It is possible that the significant increase in rectal temperature in DFK group is supposedly due to normally maintained hypothalamic thermoregulatory function as well as direct surgical stimulation to central nervous system. PMID- 7837407 TI - [Anesthetic management of a multiallergic patient scheduled for cholecystectomy]. AB - A 64-year-old woman was scheduled for cholecystectomy. Her past history revealed that serious anaphylactic reactions including generalized flushing and urticaria, severe hypotension and unconsciousness which occurred after eating crab four years ago. Puncture and/or intradermal skin test and subsequent lymphocyte stimulation test to several drugs commonly used in perioperative period were performed prior to anesthesia. Positive reactions to intravenous anesthetics and muscle relaxants, and negative reactions to inhalational and local anesthetics were found. Famotidine and ketotifen fumarate were given to prevent histamine release for four days before operation. After premedication with scopolamine, a catheter was inserted into epidural space at Th9-T10 level and 2% lidocaine 2 ml was administered initially into the epidural space. Anesthesia was induced with inhalation of nitrous oxide and oxygen, and deepened gradually by the increments of sevoflurane. Tracheal intubation was performed smoothly without adjunct muscle relaxant. Anesthesia was maintained with sevoflurane and epidural anesthesia with intermittent lidocaine administration. No adverse responses were noted at the time of iopamidol injection for intraoperative cholangiography. The anesthesia and postoperative course of this patient were uneventful. PMID- 7837409 TI - [Epidural anesthesia with high dose fentanyl for a patient with dilated cardiomyopathy]. AB - Dilated cardiomyopathy is defined as a syndrome of dilated ventricles with gross impairment of ventricular systolic function. Recently, there are several anesthetic reports regarding this syndrome. But any appropriate anesthetic method has not been established. A 59-year-old man with dilated cardiomyopathy underwent low anterior resection of rectum. We employed the technique of high dose epidural fentanyl anesthesia as the anesthetic method. During surgery, mild hypotension developed, but other cardiovascular abnormalities were not observed during and after the operation. Based on this result, the authors recommend that high dose epidural fentanyl anesthesia is an anesthetic method of choice for patients with dilated cardiomyopathy. PMID- 7837408 TI - [Anesthetic management of a patient with 21-hydroxylase deficiency]. AB - 21-hydroxylase deficiency was described as a fatal disease in infancy manifested by severe adrenal insufficiency with lack of differentiation of the external genitalia in males. Patients are in adrenal insufficiency or receiving long term corticosteroid therapy and are unable to respond normally to surgery or other forms of stress. Therefore, supplementation with corticosteroids and various regimens are required for surgery and anesthetic management. A 3 year 10 months correction of 6] old phenotypic female [correction of male] with 21-hydroxylase deficiency and congenital adrenal hyperplasia was scheduled for critroplasty. Anesthesia was induced with sevoflurane, nitrous oxide and oxygen. After endotracheal intubation, a caudal epidural catheter was placed. At the induction of anesthesia, the patient received a bolus of hydrocortisone 30 mg i.v. followed by a continuous infusion of hydrocortisone. The patient's general condition was good during surgery without any major complications. Caudal epidural anesthesia is considered to be effective for anesthetic management of these patients. PMID- 7837410 TI - [Fiberscopic intubation under general anesthesia for children with Goldenhar syndrome]. AB - Goldenhar syndrome is characterised by an eye abnormality such as epibulbar dermoid and lipoma, associated with ear, mandibular, and/or vertebral anomalies. It is well documented that difficult intubation in patient with this syndrome may be expected because of mandibular hypoplasia and limitation of neck movement resulting from vertebral anomalies. We report anesthetic management of two children with Goldenhar syndrome, 9 and 14-year-old. By preoperative examination, two children were expected to be difficult in intubating trachea. We used our newly developed mask adapter which enabled us to perform fiberoptic bronchoscopy aided tracheal intubation under general anesthesia under controlled ventilation. By using this adapter, under sevoflurane/nitrous oxide anesthesia with vecuronium, we could successfully intubate with a 6 mm spiral tube through the nostril without any major problems. Anesthesia and surgery went uneventfully, and no postoperative complications were noted. We confirmed that our newly developed mask adapter for fiberoptic bronchoscopy is as useful for children with difficult intubation as for adults. PMID- 7837411 TI - [Anesthetic management of a patient with adrenocorticotropic hormone (ACTH) deficiency]. AB - A 73 year old woman with ACTH deficiency was admitted to our hospital for gastrectomy. She had taken corticosteroid for 3 years. The day before surgery, she took 25 mg of hydrocortisone per os. Hydrocortisone 100 mg was administered intravenously 30 minutes before surgery, during and after surgery, and on the next day after surgery. Serum concentrations of ACTH and cortisol were measured 1 hour after the first administration of hydrocortisone 100 mg, 2 hours after the second and 15 hours after the third administration. The ACTH concentration was always lower than the lowest limit of detection. Cortisol concentrations were 140.0, 180.0 and 14.5 micrograms.dl-1 at each measurement. Serum concentration of aldosterone after the induction of anesthesia was lower than the normal range. Her hemodynamics were very stable and electrolytes balance was not disturbed with corticosteroid treatment during and after surgery. PMID- 7837412 TI - [Preexisting seizure was enhanced under general anesthesia in a AVM patient]. AB - A 21-year-old patient with right basal ganglial AVM was scheduled twice for cranioplasty under general anesthesia (nitrous oxide oxygen isoflurane anesthesia and modified neurolept anesthesia), after a surgery for removal of hematoma from the AVM three months previously. After this operation and before anesthesia for cranioplasties, he showed tremor-like seizure around the left arm and leg about once a day. During anesthesia for cranioplasties, he developed the similar and enhanced seizure frequently in response to intravenous injections of thiopental and midazolam, needle injections into the skin, intratracheal as well as oral suctions and other stimuli. The reason of decreased cerebral perfusion is probably due to the previous operation and administrations of thiopental and midazolam. Because of decreased perfusion around this cerebral lesion, concentrations of the anesthetics might have remained low around the lesion under general anesthesia. Therefore, the resulting hypoxia and prolonged light anesthesia in the basal ganglia, might have enhanced the seizure. PMID- 7837413 TI - [Intra-ocular pressure changes during laparoscopic cholecystectomy]. AB - Intra-ocular pressure (IOP) was measured during laparoscopic cholecystectomy (n = 20) under continuous epidural block and nitrous oxide-oxygen anesthesia. There was a slight but significant increase in IOP and peak airway pressure when the abdominal CO2 insuffration was started, and the IOP recovered to the preoperative level after the postural change to the head-up position. It was not associated with any significant change in mean arterial pressure and end-tidal CO2. In one ocular hypertension case undergoing laparoscopic chorecystectomy and appendectomy, however, there was profound increase in IOP during abdominal CO2 insuffration with head down position. We speculate that it was due to the effect of increased CVP with abdominal CO2 insuffration and postural change on the IOP. Thus the laparoscopic operation with head-down position should be avoided in patients with ocular hypertension. PMID- 7837414 TI - [Anesthetic management of a patient with Kimura's disease]. AB - Kimura's disease is a rare disease characterized by granuloma in soft tissues with formation of lymphoid follicles infiltrated with eosinophils. It is accompanied by peripheral eosinophilia and elevated IgE in some patients. Although most patients with Kimura's disease were Japanese, we are not aware of reports about anesthetic management of this disease. We managed a 38-year-old woman with Kimura's disease who underwent a removal of a right preauricular mass with general anesthesia using oxygen, nitrous oxide (50%), and isoflurane (0.5 1.5%). There were no anesthesia-related complications. Anesthetic management of patients with Kimura's disease is also discussed. PMID- 7837415 TI - [Clinical evaluation of the Terumo ES H51 semi-automatic blood pressure measuring device]. AB - The relative accuracy of a semi-automated portable blood pressure (BP) measuring device, Terumo ES-H51, which is based on the auscultatory method, was assessed by comparison with simultaneous sphygmomanometric measurement on 48 patients, including hypertensive patients. During rest, mean differences and limits of agreement (mean +/- 2SD) were -1.3 mmHg, -7.9 and 5.3 mmHg, respectively for systolic BP, and -0.2 mmHg, -8.4 and 8.0 mmHg, respectively for diastolic BP. Although the differences between ES-H51 and sphygmomanometric measurement did not increase with repeated measurements or with changes of BP during the induction of anesthesia, blood pressure measurement by ES-H51 was sometimes impossible or erroneous during upper abdominal surgeries in 5 patients. We concluded that ES H51 has satisfactory accuracy, and is suitable for blood pressure assessment during the peri-operative period but not during surgery. PMID- 7837416 TI - [Necrotizing enterocolitis]. PMID- 7837417 TI - [Ileocecal syndrome]. PMID- 7837418 TI - [Brown bowel syndrome]. PMID- 7837419 TI - [Ulcerative colitis]. PMID- 7837420 TI - [Hamartomatous polyp and hamartomatous polyposis]. PMID- 7837421 TI - [Familial adenomatous polyposis]. PMID- 7837422 TI - [Colorectal cancer with family history]. PMID- 7837423 TI - [Irritable bowel syndrome]. PMID- 7837425 TI - [Granular cell tumor]. PMID- 7837424 TI - [Chagas' disease (Cruz's disease)]. PMID- 7837426 TI - [Malabsorption syndrome]. PMID- 7837427 TI - [Tubular duplication of the colon]. PMID- 7837428 TI - [Intestinal pseudo-obstruction]. PMID- 7837429 TI - [Pseudomembranous enterocolitis]. PMID- 7837430 TI - [Acute hemorrhagic rectal ulcer syndrome; AHRUS]. PMID- 7837431 TI - [Acute rectal mucosal lesion]. PMID- 7837432 TI - [Ischemic colitis and gangrenous ischemic colitis]. PMID- 7837433 TI - [Gastrointestinal perforation by ingested fish bones]. PMID- 7837434 TI - [Chilaiditi's syndrome]. PMID- 7837435 TI - [Megacolon syndrome]. PMID- 7837436 TI - [Diversion colitis and proctitis]. PMID- 7837437 TI - [Chlamydia trachomatis proctitis]. PMID- 7837438 TI - [Advanced colon cancer and advanced rectal cancer]. PMID- 7837439 TI - [Diarrhea (acute and chronic)]. PMID- 7837440 TI - [Protozoan and helminthic infection]. PMID- 7837441 TI - [Multiple primary carcinomas in the jejunum, ileum, colon and rectum]. PMID- 7837443 TI - [Crohn's disease]. PMID- 7837442 TI - [Intestinal complications of collagen vascular diseases]. PMID- 7837444 TI - [Eosinophilic enterocolitis]. PMID- 7837446 TI - [Antibiotic-associated colitis--Clostridium difficile colitis]. PMID- 7837445 TI - [Intestinal tuberculosis]. PMID- 7837447 TI - [Ossification in intestinal carcinoma]. PMID- 7837449 TI - [Bacterial food poisoning]. PMID- 7837448 TI - [Cholera]. PMID- 7837450 TI - [Shigellosis]. PMID- 7837451 TI - [Atonic constipation]. PMID- 7837452 TI - [Juvenile polyposis coli]. PMID- 7837453 TI - [Duodenocolic fistula]. PMID- 7837454 TI - [Hemorrhagic colitis]. PMID- 7837455 TI - [Cronkhite-Canada syndrome]. PMID- 7837456 TI - [Cancer of the small intestine]. PMID- 7837457 TI - [Squamous cell carcinoma of the small bowel, colon and rectum]. PMID- 7837458 TI - [Arteriomesenteric-occlusion of the duodenum]. PMID- 7837459 TI - [Diverticulum and diverticulosis of the small intestine]. PMID- 7837460 TI - [Intestinal carcinoma with serosal invasion]. PMID- 7837461 TI - [Colitis cystica profunda]. PMID- 7837462 TI - [Adult spontaneous volvulus of the sigmoid colon]. PMID- 7837463 TI - [Celiac disease]. PMID- 7837464 TI - [Annular carcinoma of the colon]. PMID- 7837465 TI - [Cancer in adenoma]. PMID- 7837466 TI - [Adenoma-carcinoma sequence]. PMID- 7837467 TI - [Congenital intestinal atresia and stenosis]. PMID- 7837468 TI - [de novo cancer]. PMID- 7837469 TI - [Early carcinoma of the intestine and intramucosal carcinoma]. PMID- 7837470 TI - [Mucosal bridge of the colon]. PMID- 7837471 TI - [Hemangiopericytoma of the colon]. PMID- 7837472 TI - [Transitional polyp of colon and rectum]. PMID- 7837473 TI - [Inflammatory polyp and polyposis of colon and rectum]. PMID- 7837474 TI - [Metaplastic (hyperplastic) polyp and polyposis of the colon]. PMID- 7837475 TI - [Experimental colitis induced by dextran sulfate]. PMID- 7837476 TI - [Carcinoma of the colon and rectum involving the urinary bladder]. PMID- 7837477 TI - [Diverticular disease and diverticulitis of the colon]. PMID- 7837478 TI - [Gastrointestinal abnormalities in alpha-chain disease]. PMID- 7837479 TI - [Neoplastic polyp of the large intestine and polyposis (tubular adenoma and tubulovillous adenoma)]. PMID- 7837480 TI - [Large intestinal carcinoma associated with cancers of the other organs, double cancer of the large intestine and stomach]. PMID- 7837481 TI - [Nodule-aggregating lesion of the large intestine (colorectal flat elevation with conglomerated nodular surface)]. PMID- 7837482 TI - [Benign lymphoid polyp and polyposis]. PMID- 7837483 TI - [Simple ulcer of the intestine]. PMID- 7837484 TI - [Short bowel syndrome]. PMID- 7837485 TI - [Gardner's syndrome]. PMID- 7837486 TI - [Protein-losing gastroenteropathy]. PMID- 7837487 TI - [Angiodysplasia of the intestine]. PMID- 7837488 TI - [Dieulafoy's ulcer of intestine]. PMID- 7837489 TI - [Intestinal goblet cell mucus release]. PMID- 7837490 TI - [Inflammatory fibroid polyp of the intestine]. PMID- 7837491 TI - [Linitis plastica type of carcinoma of the intestine]. PMID- 7837492 TI - [Lipohyperplasia of the ileocecal valve]. PMID- 7837493 TI - [Intestinal lipoid granuloma]. PMID- 7837494 TI - [Malignant lymphoma of mucosa-associated lymphoid tissue (MALT) arising from the intestines]. PMID- 7837495 TI - [Hirshprung's disease, neuronal intestinal dysplasia, hypoganglionosis]. PMID- 7837496 TI - [Multiple lymphomatous polyposis]. PMID- 7837497 TI - [Pleomorphic giant cell carcinoma of the intestine]. PMID- 7837498 TI - [Spindle cell tumor of the intestine]. PMID- 7837499 TI - [Vanishing tumor of the intestine]. PMID- 7837500 TI - [Intestinal vascular ectasia]. PMID- 7837501 TI - [Malignant fibrous histiocytoma]. PMID- 7837502 TI - [Heterotopic (ectopic) gastric mucosa]. PMID- 7837503 TI - [Foreign body of the intestine]. PMID- 7837504 TI - [Signet-ring cell carcinoma of colon]. PMID- 7837505 TI - [Indeterminate colitis]. PMID- 7837506 TI - [Enterocolitis]. PMID- 7837508 TI - [Hamartoma of the intestine]. PMID- 7837507 TI - [Malrotation]. PMID- 7837509 TI - [Carcinoid tumor of the intestine]. PMID- 7837510 TI - [Intestinal amyloidosis and amyloid colitis]. PMID- 7837511 TI - [Intestinal Behcet's disease]. PMID- 7837512 TI - [Pneumatosis cystoides intestinalis; PCI]. PMID- 7837513 TI - [Duplications of the alimentary canal]. PMID- 7837514 TI - [Mesenteric vascular insufficiency]. PMID- 7837515 TI - [Arteriovenous malformation of bowel tract]. PMID- 7837517 TI - [Colon cancer with the sign of Leser-Trelat]. PMID- 7837518 TI - [Obstructing carcinoma of the intestine]. PMID- 7837516 TI - [Ulcer formation at intestinal anastomotic site]. PMID- 7837519 TI - [Perforative carcinoma of the intestine]. PMID- 7837520 TI - [Mesenteric cyst]. PMID- 7837521 TI - [Intestinal teratoma]. PMID- 7837522 TI - [Incomplete intestinal obstruction]. PMID- 7837524 TI - [Vascular tumors of the intestine]. PMID- 7837523 TI - [Fistula of enteric diverticulum]. PMID- 7837525 TI - [Intestinal hemangioendothelioma]. PMID- 7837526 TI - [Enterolithiasis]. PMID- 7837527 TI - [MRSA enteritis]. PMID- 7837528 TI - [Intestinal eosinophilic granuloma]. PMID- 7837529 TI - [Intestinal malignant melanoma]. PMID- 7837530 TI - [Intestinal geotrichosis]. PMID- 7837531 TI - [Enteric endometriosis]. PMID- 7837532 TI - [Lipoma and liposarcoma of the jejunum, ileum, coecum, colon and rectum]. PMID- 7837534 TI - [Villous adenoma]. PMID- 7837533 TI - [Intussusception in children and adult]. PMID- 7837535 TI - [Unclassified tumors of intestine]. PMID- 7837536 TI - [Tumors of the intestine (benign, malignant: epithelial, non-epithelial)]. PMID- 7837537 TI - [Small cell (neuroendocrine) carcinoma of the intestine]. PMID- 7837538 TI - [Intestinal varices]. PMID- 7837539 TI - [Peutz-Jeghers syndrome]. PMID- 7837540 TI - [Mycosis of the intestine]. PMID- 7837541 TI - [Neurogenic tumor of small and large intestine]. PMID- 7837542 TI - [Intestinal aganglionosis and intestinal segmental oligoganglionosis]. PMID- 7837543 TI - [Fibrolipoma (lipoma) of the intestine]. PMID- 7837544 TI - [Adenocarcinoma of the intestine]. PMID- 7837545 TI - [Perforation of the intestine]. PMID- 7837546 TI - [Adenoma (tubular adenoma, tubulo-villous adenoma, villous adenoma, and adenomatosis)]. PMID- 7837547 TI - [Adenosquamous carcinoma of the intestine]. PMID- 7837548 TI - [Embryonal carcinoma of the intestine]. PMID- 7837549 TI - [Enterovaginal fistula (including enterouterine fistula)]. PMID- 7837550 TI - [Typhoid fever]. PMID- 7837551 TI - [Intestinal cancer with peritoneal metastasis]. PMID- 7837552 TI - [Poorly differentiated carcinoma of intestine]. PMID- 7837553 TI - [Endocrine cell carcinoma of the intestine]. PMID- 7837554 TI - [Mucinous carcinoma of the intestine]. PMID- 7837555 TI - [Submucosal tumor of the intestine]. PMID- 7837556 TI - [Enterogenous cyst]. PMID- 7837557 TI - [Intraabdominal abscess due to intestinal perforation]. PMID- 7837558 TI - [Colorectal paraffinoma]. PMID- 7837559 TI - [Enterocutaneous fistula]. PMID- 7837560 TI - [Smooth muscle tumor of the intestine]. PMID- 7837561 TI - [Intestinal obstruction]. PMID- 7837562 TI - [Sigma elongatum or dolichosigma]. PMID- 7837563 TI - [Intramural hematoma of the small intestine]. PMID- 7837564 TI - [Vesicoenteric fistula]. PMID- 7837565 TI - [Actinomycosis of intestine]. PMID- 7837566 TI - [Colonic polyp and polyposis]. PMID- 7837567 TI - [Intestinal malakoplakia]. PMID- 7837568 TI - [Intestinal undifferentiated carcinoma]. PMID- 7837569 TI - [Heterotopic pancreas in the intestine]. PMID- 7837570 TI - [Tubo-intestinal fistula]. PMID- 7837571 TI - [Elevated lesion of intestine]. PMID- 7837572 TI - [Intestinal lymphangiectasia]. PMID- 7837573 TI - [Intestinal changes in Schonlein-Henoch purpura]. PMID- 7837574 TI - [Lymphangioma of the colon and mesenteric cyst]. PMID- 7837575 TI - [Lymphoid hyperplastic diseases of the intestine, lymphoid hyperplasia of the intestine, malignant lymphoma of the intestine, and Burkitt's lymphoma of the intestine]. PMID- 7837576 TI - [Solitary ulcer syndrome of the rectum]. PMID- 7837577 TI - [Rectocele]. PMID- 7837578 TI - [Mucosal prolapse syndrome of the rectum]. PMID- 7837579 TI - [Barium granuloma of the rectum]. PMID- 7837580 TI - [Metastatic neoplasms of the bowel]. PMID- 7837581 TI - [Idiopathic megacolon]. PMID- 7837582 TI - [Idiopathic constipation]. PMID- 7837583 TI - [Turcot's syndrome]. PMID- 7837584 TI - [Myxedema megacolon]. PMID- 7837585 TI - [Nonspecific multiple ulcers of the small intestine]. PMID- 7837586 TI - [Non-occlusive mesenteric ischemia]. PMID- 7837587 TI - [Diffusely infiltrating carcinoma of the colon]. PMID- 7837588 TI - [Splenic flexure syndrome]. PMID- 7837589 TI - [Abdominal wall involvement in carcinoma of the colon]. PMID- 7837590 TI - [Indeterminate colitis]. PMID- 7837591 TI - [Obstructive colitis]. PMID- 7837592 TI - [Flat & depressed type tumors]. PMID- 7837593 TI - [WDHA syndrome]. PMID- 7837594 TI - [Constipation]. PMID- 7837595 TI - [Phlegmonous enterocolitis]. PMID- 7837596 TI - [Radiation enteritis]. PMID- 7837597 TI - [Radiation-induced cancer of the intestine]. PMID- 7837598 TI - [Melanosis coli]. PMID- 7837599 TI - [Blind loop syndrome]. PMID- 7837600 TI - [Pericecal abscess]. PMID- 7837601 TI - [Polypoid type of early colorectal cancer]. PMID- 7837602 TI - [Acute appendicitis]. PMID- 7837603 TI - [Tubercular appendicitis]. PMID- 7837604 TI - [Duplication of vermiform appendix]. PMID- 7837605 TI - [Crohn's disease of the appendix]. PMID- 7837606 TI - [Appendiceal-sigmoid fistula]. PMID- 7837607 TI - [Metaplastic polyp of the appendix vermiformis]. PMID- 7837608 TI - [Carcinoid tumor of the appendix]. PMID- 7837609 TI - [Diverticulitis of the vermiform appendix]. PMID- 7837610 TI - [Appendiceal calculi]. PMID- 7837611 TI - [Endometriosis of the vermiform appendix]. PMID- 7837612 TI - [Villous adenoma of the appendix]. PMID- 7837613 TI - [Tumors of the appendix (epithelial, non-epithelial, benign and malignant)]. PMID- 7837614 TI - [Adenocarcinoma]. PMID- 7837615 TI - [Aphthoid colitis and aphthous lesions of the colon]. PMID- 7837616 TI - [Adenoma of appendix]. PMID- 7837617 TI - [Metastatic carcinoma of the appendix]. PMID- 7837618 TI - [Granuloma of the vermiform appendix]. PMID- 7837620 TI - [Mucinous cystadenocarcinoma of the vermiform appendix]. PMID- 7837619 TI - [Appendiceal mucocele]. PMID- 7837621 TI - [Mucinous cystadenoma of the vermiform appendix]. PMID- 7837622 TI - [Appendiceal abscess]. PMID- 7837623 TI - [Polypoid lesion of the appendix]. PMID- 7837624 TI - [Lymphoid hyperplasia of the appendix]. PMID- 7837625 TI - [Anal lesions observed in Crohn's disease]. PMID- 7837626 TI - [Enterocele]. PMID- 7837627 TI - [Outlet obstruction syndrome]. PMID- 7837628 TI - [Allergic enteritis]. PMID- 7837629 TI - [Spastic levator syndrome]. PMID- 7837630 TI - [Ectopic anus]. PMID- 7837631 TI - [Familial imperforate anus]. PMID- 7837632 TI - [Tuberculous anal ulcer]. PMID- 7837633 TI - [Anal ulcer]. PMID- 7837634 TI - [Anal incontinence]. PMID- 7837635 TI - [Cloacogenic carcinoma with reference to malignant tumors of the anal canal]. PMID- 7837636 TI - [Infectious diseases in anus]. PMID- 7837637 TI - [Endocrine cell carcinoma of the anal canal]. PMID- 7837639 TI - [Periproctal abscess]. PMID- 7837638 TI - [Pruritus ani]. PMID- 7837640 TI - [Periproctal abscess with chronic granulomatous disease]. PMID- 7837641 TI - [Metachronous malignancies of the intestine (especially, metachronous colorectal cancer)]. PMID- 7837642 TI - [Tumors of anus, benign epithelial, benign non-epithelial, malignant epithelial and malignant non-epithelial]. PMID- 7837643 TI - [Tumor-like lesions of the anus]. PMID- 7837644 TI - [Cryptitis]. PMID- 7837645 TI - [Adenocarcinoma and mucinous carcinoma of the anal canal]. PMID- 7837646 TI - [Peri-anal condyloma acuminatum and giant condyloma acuminata]. PMID- 7837647 TI - [Adenosquamous carcinoma of the anal canal]. PMID- 7837648 TI - [Anal papillitis]. PMID- 7837649 TI - [Perianal Bowen's disease]. PMID- 7837651 TI - [Perianal Paget's disease]. PMID- 7837650 TI - [Perianal endometriosis]. PMID- 7837652 TI - [Atypical condyloma latum of anus]. PMID- 7837654 TI - [Perineal hidradenitis suppurativa]. PMID- 7837653 TI - [Injury of anal region]. PMID- 7837655 TI - [Squamous cell carcinoma of the anal canal]. PMID- 7837656 TI - [Undifferentiated carcinoma of the anal region]. PMID- 7837657 TI - [Giant cell carcinoma originating from the heterotopic pancreas]. PMID- 7837658 TI - [Anal malignant melanoma]. PMID- 7837659 TI - [Basaloid carcinoma of anal canal]. PMID- 7837660 TI - [Supralevator abscess]. PMID- 7837661 TI - [Anal atresia]. PMID- 7837662 TI - [Hemorrhoid]. PMID- 7837663 TI - [Anorectal fistula]. PMID- 7837664 TI - [Fistula-cancer]. PMID- 7837665 TI - [Skin tag]. PMID- 7837666 TI - [Anal prolapse]. PMID- 7837667 TI - [Anorectal malformations]. PMID- 7837668 TI - [Hereditary solitary polyps (adenoma) of the colon]. PMID- 7837669 TI - [Phantom anal phenomena following amputation of the rectum]. PMID- 7837670 TI - [Rectal prolapse and concealed prolapse]. PMID- 7837671 TI - [Rectovaginal fistula]. PMID- 7837672 TI - [Mucosal prolapse syndrome of the rectum]. PMID- 7837673 TI - [Intraepithelial cancer of the anal canal]. PMID- 7837675 TI - [Cellulitis]. PMID- 7837674 TI - [Hereditary non-polyposis colorectal cancer; HNPCC]. PMID- 7837676 TI - [Pilonidal disease]. PMID- 7837677 TI - [Anal fissure]. PMID- 7837678 TI - [Stage classification of esophageal, gastric and colorectal cancer]. PMID- 7837679 TI - [Viral gastroenteritis]. PMID- 7837680 TI - [Inflammatory bowel disease]. PMID- 7837681 TI - [Inflammatory intestinal tumor]. PMID- 7837682 TI - [Recent status in drug-induced pancreatitis]. PMID- 7837684 TI - [The etiology of peptic ulceration in patients with chronic pulmonary emphysema]. AB - The purpose of this study was to determine the etiology of peptic ulceration in patients with pulmonary emphysema. We performed endoscopy in 50 patients with chronic pulmonary emphysema, these were patients with and without peptic ulcer. There was no significant differences between the patients with and without ulcer, with respect to past history of pneumonia, degree of dyspnea, current drugs, nutritional status, the extent of gastric mucosal atrophy, gastric mucosal blood flow, gastric mucosal hexosamine content and serum pepsinogen levels. But patients with peptic ulcer were significantly younger than patients without peptic ulcer. Cigarettes per day in patients with peptic ulcer 29.3 +/- 11.6 cigarettes/day were significantly higher than those without peptic ulcer 22.5 +/- 10.0 cigarettes/day. We concluded that increased incidence of peptic ulceration in patients with chronic pulmonary emphysema is related to the quantity of cigarette smoking. PMID- 7837683 TI - [Comparison of the effects between standard doses of H2-blocker (famotidine 20mg b.d.) and proton pump inhibitor (omeprazole 20mg o.d.) in the treatment of refractory reflux esophagitis by ambulatory 24-hr intra-gastroesophageal pH monitoring]. AB - Ambulatory 24-hour pH monitoring was conducted in 11 patients with H2-blocker resistant reflux esophagitis to compare the effects of standard doses of H2 blocker (famotidine 20mg twice daily) and proton pump inhibitor (omeprazole 20mg once daily) on the inhibition of intraesophageal acidity. Mean intraesophageal pH during PPI treatment was significantly higher than that during H2-blocker treatment. Proportion of abnormal intra-esophageal acidity in 24hr (%time pH < 4) during PPI treatment was significantly less than that during H2-blocker treatment (11.7 +/- 3.1% vs 31.6 +/- 4.8%). The difference of the effect was more apparent in day time (upright time) than in night time (supine time). Thus PPI is superior to H2-blocker in treatment for refractory reflux esophagitis, but proportion of abnormal intra-esophageal acidity in 24hr (%time pH < 4) could be normalized only in 4 out of 11 patients even by standard dose PPI treatment. Effects of not only long-term maintenance therapy but also high dose therapy with PPI should be examined in future studies. PMID- 7837685 TI - [Immunohistochemical study of VLA integrins in human gastric carcinoma]. AB - Using an immunohistochemical technique, we investigated expression of collagen receptor VLA-2 integrin and laminin receptor VLA-6 integrin in human gastric carcinoma. The expression of VLA integrins was compared in carcinoma of each histologic type and invasion/growth pattern. VLA-2 and VLA-6 were expressed more weakly in undifferentiated carcinoma than in non-cancerous epithelium. Non localized invasion was observed in 89% of undifferentiated carcinoma. In differentiated carcinoma, expression of VLA-2 was weak in the mucosal layer. In the submucosal layer, however, VLA-2 expression was significantly different according to the invasion/growth pattern (p < 0.01); weak expression of VLA-2 in the localized invasion type and strong expression of VLA-2 in the non-localized type. VLA-6 was strongly expressed in the mucosal and submucosal layers of the differentiated carcinoma, regardless of the invasion/growth pattern. The present study suggested that VLA-6 contributed to the histologic type and VLA-2 affected the invasion/growth pattern of the gastric carcinoma in varied manners according to the histologic type. PMID- 7837686 TI - [Analysis of immune response to Helicobacter pylori--identification of the protein recognized by anti-Helicobacter pylori antibodies from sera of patients with gastroduodenal diseases]. AB - HP-specific antibodies were measured in each collected fraction obtained from gel filtrated separation method with selected patients sera by enzyme-linked immunosorbent assay (ELISA). Most of the fractions reacted with the patients sera also responded to HP urease-specific monoclonal antibodies. In addition, the fractions which showed urease activity strongly correlated with the HP antibody positive ones. Also, we could not detect any cross-reactivity to ureases of other species. Moreover, most patient sera strongly responded to the purified HP urease B subunit separated with SDS/PAGE by western blotting analysis. These findings suggest that the major target for HP-specific antibodies appears to be HP-urease, in particular around 68kd large molecule, urease B subunit and such urease specific antibodies are isolate-species specific. PMID- 7837687 TI - [A type II b early gastric cancer associated with diffuse submucosal ectopic glands, report of a case]. PMID- 7837689 TI - [A case of follicular gastritis superficially appearing as a spreading type of gastric malignant lymphoma]. PMID- 7837688 TI - [Two cases of Cowden's disease]. PMID- 7837690 TI - [A long-term survival case of non-functioning adrenal cancer which recurred with invasion to the liver and duodenal cap fifteen years after surgery]. PMID- 7837691 TI - [A case of non-Hodgkin's lymphoma with portal hypertension and nodular regenerative hyperplasia]. PMID- 7837692 TI - [A case of multiple focal nodular hyperplasia in the liver]. PMID- 7837693 TI - [A case of autoimmune hepatitis with rupture of the jejunal varices]. PMID- 7837694 TI - [A case of atrial fibrillation induced by interferon treatment for chronic hepatitis C]. PMID- 7837695 TI - [Intracystic hemorrhage of simple hepatic cyst simulating cystadenocarcinoma of the liver--report of two cases]. PMID- 7837696 TI - [An autopsy case of hepatocellular carcinoma producing human chorionic gonadotropin (hCG)]. PMID- 7837697 TI - [Benign biliary stricture treated successfully by implantable injection port- report of a case]. PMID- 7837698 TI - [A case of primary sclerosing cholangitis associated with ulcerative colitis and idiopathic thrombocytopenic purpura]. PMID- 7837699 TI - [Assessment of myocardial perfusion and cardiac sympathetic nerve dysfunction in patients with sick sinus syndrome--evaluation of coronary hemodynamics and 201TlCl/123I-MIBG myocardial SPECT]. AB - To clarify the coronary hemodynamics, myocardial perfusion and cardiac sympathetic nerve function in patients with sick sinus syndrome (SSS), we performed left coronary digital subtraction angiography (DSA) in 41 patients, exercise 201TlCl-myocardial scintigraphy (planar and SPECT) in 69 patients, and 201TlCl/123I-MIBG myocardial dual SPECT in 13 patients without significant organic coronary stenosis. Coronary artery spasm was documented on coronary angiography in 25/43 (58%) patients with SSS by ergonovine provocation test. Compared with normals, patients with SSS demonstrated prolongation of left coronary circulation time (CCT) on own heart beats and right atrial pacing. We suspected that prolonged CCT may be induced by increased peripheral coronary vascular resistance and impaired coronary microcirculation in patients with SSS. Forty-two patients (60.9%) developed exercise-induced 201Tl-myocardial perfusion defect on SPECT images. On myocardial dual SPECT images, 11/13 (85%) patients showed localized myocardial low uptake in 123I-MIBG-SPECT images. In eight patients with normal findings on 201Tl-SPECT, six patients showed abnormality on 123I-MIBG-SPECT. We suspected that coronary vasospasm, impaired coronary micro circulation and cardiac sympathetic nerve dysfunction are taken a part of pathophysiology in SSS (decreased beta-adrenergic receptor of peripheral coronary arteries?). PMID- 7837700 TI - [Exercise-nitroglycerine technetium-99m-2-methoxy isobutyl isonitrile tomoscintigraphic imaging for identifying diseased coronary vessels: comparison with thallium-201 standard exercise-redistribution study]. AB - A same-day double injection protocol employing 99mTc-methoxy isobutyl isonitrile (MIBI) and myocardial single-photon emission computed tomography (SPECT) for detecting coronary heart disease (CAD) was assessed in 21 patients. Our exercise nitroglycerin (NTG) MIBI study was performed as follows: 150 MBq 99mTc-MIBI was injected at peak exercise, and after 5 minutes 0.3 mg of NTG was sublingually administered. Then, SPECT was performed 1 hour later. Immediately after the 1st imaging, patients were injected of 750 MBq 99mTc-MIBI and were reimaged 1 hour later. Within 1 month, all patients were underwent standard exercise redistribution SPECT thallium (Tl) study. Of the 126 myocardial segments evaluated, 81 were judged as normal by both techniques, while the presence of stress defects were demonstrated in 37 segments (Agreement: 94%). Vessel sensitivities were 75% by MIBI and 67% by Tl. Specificities were 90% by MIBI and 93% by Tl. For the pattern of reversibility in myocardial segments with stress defects, the agreement was 73%. In conclusion, our exercise-NTG MIBI may be safely performed, giving results equivalent to those of standard stress redistribution thallium studies. PMID- 7837701 TI - [Thyroid scintigraphy in patients with thyroid tumors using 99mTc-hexakis 2 methoxy isobutyl isonitrile]. AB - Early and delayed thyroid scintigraphy with 99mTc-hexakis 2-methoxy isobutyl isonitrile (99mTc-MIBI) was performed in 18 patients with thyroid tumor, including 8 with papillary carcinoma, 1 each with follicular carcinoma, anaplastic carcinoma, and malignant lymphoma, and 7 with thyroid adenoma. Scintigrams obtained were compared with those taken with other radionuclides. In all 11 patients with malignant tumors, increased 99mTc-MIBI uptake was noted in the tumors on early images, although anaplastic carcinoma and malignant lymphoma had mild uptake. On delayed images, 99mTc-MIBI washout was noted in 45.4% (5/11). In one patient with extensive cervical lymph node metastasis, 99mTc-MIBI concentration was evident in the metastatic foci. In the 4 where, the thyroid adenoma consisted mainly of cystic degeneration, a focal defect was noted, but two of the three patients whose thyroid adenoma consisted mainly of a solid component had an intense tracer uptake in the tumors on early and delayed images. In conclusion, there were increased 99mTc-MIBI accumulations in all of the 14 solid thyroid tumors. The quality of 99mTc-MIBI scintigraphic images of thyroid tumors was equal or slightly superior to that taken with 201Tl scintigraphy. 99mTc-MIBI thyroid scintigraphy may be useful in detecting a solid thyroid tumor and its metastasis, although it cannot be used to differentiate between benign and malignant tumors. PMID- 7837702 TI - [Myocardial SPECT with iodine-123-labeled beta-methyl-branched fatty acid in patients with angina pectoris]. AB - To evaluate the usefulness of 123I-BMIPP as a tracer of fatty acid metabolism in patients with angina pectoris, we performed rest BMIPP myocardial SPECT and stress 201Tl SPECT in 20 patients with angina pectoris. BMIPP SPECT was evaluated in the defected regions with Tl redistribution. Abnormal findings in BMIPP were observed in 11 of 20 patients and in 14 of 29 myocardial segments with Tl redistribution. Such decreased uptake was observed more often in patients with multivessel disease (64% vs. 12%). In addition, the decreased BMIPP uptake was seen more often in the segments exhibiting hypokinesis than the segments showing with normal wall motion. Thus, BMIPP imaging may be available to detect myocardial ischemia, particularly in patients with severe coronary disease. PMID- 7837703 TI - [A case of hepatocellular carcinoma with lumbar bone metastasis with high uptake of 18F-fluorodeoxygalactose in PET]. AB - 18F-fluorodeoxygalactose (18FDGal) is a tracer for the evaluation of galactose metabolism in the tissue. PET with 18FDGal was performed in a hepatoma (HCC) patient with lumbar bone metastasis. The image at 45 min after i.v. injection of 18FDGal demonstrated very high uptake by the bone metastasis with tumor-to surrounding normal tissue ratio of 36. The tumor uptake expressed by differential absorption ratio was much higher than that in the cirrhotic liver and kidney. The result indicated that the HCC maintained high activity of galactose metabolism and rises the potential of this tracer for detecting extrahepatic metastases of HCC using PET. PMID- 7837704 TI - [Detection of neural crest tumors by 123I-MIBG scintigraphy]. AB - From January 1993 to January 1994, scintigraphy with 123I-MIBG and/or 131I-MIBG were performed in 22 patients and their scintigraphic usefulness was evaluated. Iodine-123 MIBG and 131I-MIBG scintigrams were obtained 24 hours after injection of 222 MBq of 123I-MIBG and 48 hours after injection of 20 MBq of 131I-MIBG, respectively. In two patients with pheochromocytoma, the 123I-MIBG and 131I-MIBG scans were performed and both images were compared. In a patient with single intraadrenal pheochromocytoma, the lesion not detected with 131I-MIBG was clearly visualized with 123I-MIBG. In the other patient with multiple metastatic pheochromocytoma, much more lesions were distinctly demonstrated on the 123I-MIBG images than on the 131I-MIBG images. All of the lesions were detected with 123I MIBG in a patient with pheochromocytoma, 3 patients with neuroblastoma and a patient with medullary thyroid cancer. Most of the normal adrenal glands (86%) were visualized on the 123I-MIBG scintigrams, in 7 patients without neural crest tumor and adrenal diseases, while 131I-MIBG scintigraphy failed to visualize normal adrenal glands in 2 hypertensive patients. The main reason for the superiority of 123I-MIBG to 131I-MIBG is considered to be as follows: 1) higher specific activity of 123I-MIBG. 2) the larger amount of 123I-MIBG used. 3) gamma ray energy of 123I is ideal for gamma camera. In conclusion, 123I-MIBG appears to be a more suitable imaging agent than 131I-MIBG in depicting neural crest tumors. PMID- 7837705 TI - [Exercise and rest myocardial scintigraphy with 201TlCl/99mTc-MIBI dual energy acquisition using triple-energy window scatter correction]. AB - We carried out dual 201Tl/99mTc-MIBI imaging, to reduce the time required for exercise myocardial scintigraphy. We investigated 4 different protocols. In protocol (A), Tl was injected at rest followed by the injection of MIBI at peak exercise. Dual SPECT images were obtained by 201Tl/99mTc simultaneous acquisition. Protocol (B) means reverse either, in which MIBI was injected at rest followed by the administration of Tl at peak exercise. In protocol (C), exercise was performed first with MIBI-injection, and then Tl was injected at rest after one hour later. Simultaneous acquisition was also performed. In protocol (D), after the rest Tl-imaging, MIBI was injected at peak exercise, and then the MIBI-imaging was done. In protocol (A), (B) and (C), simultaneous acquisition was performed using TEW (Triple-Energy Window) scatter correction. Thanks to using dual isotopes, all procedures could be completed within 1-2 hours, which was much shorter than the conventional myocardial perfusion imaging. Scatter correction was useful for accurate diagnoses, when the simultaneous imaging is performed. PMID- 7837706 TI - [Superimposition of MR angiography and three dimensional radionuclide brain perfusion image with personal computer]. AB - To investigate the correlation of arterial obstruction with brain perfusion, MR angiography (MRA) and three dimensional (3D) radionuclide brain perfusion image were superimposed. Eleven cases with intracranial artery obstructive patients were studied. Three dimensional brain perfusion images were generated based on the ray-tracing method. Superimposition of MRA on to 3D brain perfusion image was performed on a personal computer. Reconstructing time for 3D image was about 15 minutes for each patient, Superimposing time was about 5 minutes for each image. Correlation of arterial obstruction with decrease in brain perfusion was demonstrated clearly by superimposed image. With a personal computer, it was possible to produce clinically useful synthesized images with relatively short time and conveniently. PMID- 7837707 TI - [Usefulness of newly developed 99mTc-labeled STA-R12 for tumor imaging]. AB - We synthesized four new tumor imaging agents, 99mTc-labeled metalloporphyrins (99mTc-STA-R12, -STA-R21, -STA-RN101 and -ATN-12) for the tumor imaging. We compared the differences of tumor imaging potency among these agents in CDF1 mice implanted with colon 26 tumor. Tumor images with these agents were obtained by using digital gamma-camera (RC135-E, Hitachi, Tokyo) and the biodistributions were analyzed by computerized medical radionuclide imageanalyser (RP-200, Hitachi, Tokyo). The highest tumor organ ratio and the excellent tumor image were obtained by 99mTc-STA-R12 (13,17-Bispropanyl aspartic acid-3-ethenyl-8 [N,N',N",N"-tetrakis (carboxylmethyl-2,7,12,18-tetramethyl-porphyrinato]-manga nes e(III). The maximum concentration of 99mTc-STA-R12 in tumor tissue was observed at around 120 minutes after i.v. injection. On the contrary, the uptake rates of other organs and tissues such as liver, brain, muscle, lung, bone and blood continuously decreased. The rapid accumulation of STA-R12 in cancer tissue and the clearance from other tissue suggested a potential usefulness of this compound for tumor imaging agent. PMID- 7837708 TI - [New trends of pulmonary nuclear medicine]. AB - Radionuclide study for pulmonary diseases is divided in three large categories, respiratory function of ventilation and perfusion, non-respiratory function such as mucocilliary movement, epithelial permeability, and tumor imaging. Ventilation and perfusion scintigraphy are useful for the diagnosis and follow up of pulmonary embolism, obstructive lung disease, etc. A new ventilatory agent, 99mTc technegas, is now available and many studies with this gas have been reported. As a tumor imaging agent, 201TlCl is coming popular for the diagnosis of lung cancer and early detection of metastatic lesions. Tumor detection with 99mTc-MIBI is also tried to differentiate the malignant tumor from the benign process. As applications of nuclear medicine for the interstitial lung disease, 67Ga scintigraphy and measurement of epithelial permeability with 99mTc-DTPA are available for an evaluation of activity of the disease and damage of lung epithelial integrity. In this report, significance and useful application of the radionuclide methods were summarized. PMID- 7837709 TI - [History and overviews of the clinical nurse specialist role]. PMID- 7837710 TI - [A model for advanced nursing practice]. PMID- 7837711 TI - [Current status and future of nurse specialists in Japan]. PMID- 7837712 TI - [Clinical nurse specialist (CNS) roles and educational preparation]. PMID- 7837714 TI - [Current status of nurse specialists in Japan. I. Nurse specialist system by Japanese Nursing Association]. PMID- 7837713 TI - [Current status and future of the clinical nurse specialist (CNS) role]. PMID- 7837715 TI - [Current status of nurse specialists in Japan. II. Activity as a psychiatric liaison nurse]. PMID- 7837716 TI - [Current status of nurse specialists in Japan. III. Activity of ET nurse in Center Hospital of National Cancer Institute]. PMID- 7837717 TI - [Current status of nurse specialists in Japan. IV. Role and current status of expert nurse in operating room]. PMID- 7837718 TI - [Current status of nurse specialists in Japan. V. Current status and future of transplant coordinator]. PMID- 7837719 TI - [Time-course of adenosine deaminase activity in the cerebrospinal fluid in patients with tuberculous meningitis]. AB - The level of adenosine deaminase (ADA) activity in the cerebrospinal fluid is used as a supportive diagnostic measure for tuberculous meningitis. However the time-course of adenosine deaminase activity of the cerebrospinal fluid in patients with tuberculous meningitis remains unknown. The present study describes 4 patients with tuberculous meningitis in whom ADA activity in the cerebrospinal fluid was serially determined in order to clarify the effects of anti-tuberculous chemotherapy on ADA activity in the cerebrospinal fluid. In two of these patients the ADA did not show a high activity in the early stage of the disease. But in all cases the ADA showed a high activity after all, and gradually declined and reached the normal level at approximately 1 month after the initiation of chemotherapy. It seems that the decrease in the ADA activity was seen when T cells in the cerebrospinal fluid returned to a static state upon removal of mycobacterial antigen by the treatment. The level of ADA in the cerebrospinal fluid is considered to be one of the useful measures for diagnosis and follow-up in patients with tuberculous meningitis. PMID- 7837720 TI - [Six-month short course chemotherapy containing pyrazinamide for initial treatment of pulmonary tuberculosis]. AB - From January 1991 to December 1992, 419 patients with pulmonary tuberculosis were initially treated at Fukujuji Hospital. Among them, 190 patients, who were younger than 80 years old and had pulmonary tuberculosis with cavities or infiltration of extension 2 or 3, and/or were sputum-smear positive, had been treated by 6-month short course regimen containing pyrazinamide, 2HRS(E)Z/4HRE. And were eligible for the evaluation of the clinical usefulness of pyrazinamide containing regimen for the initial treatment of pulmonary tuberculosis. The dose of pyrazinamide was 1.2 g per day irrespective of body weight. The patients of this treatment group consisted of 151 males and 39 females, and mean age of the males was 45.3 and that of the females was 43.8 years old. At the start of the treatment, 74% of the cases were smear positive, 70% were cavitary, and 6 cases each showed primary resistance to isoniazid and to streptomycin, respectively, and only one case showed resistance to both of isoniazid and streptomycin. There was no primary resistant case to either rifampicin or ethambutol. Bacteriologic negative conversion rates were 95% and 90% after 2 months of treatment by PZA containing regimen and by the standard regimen, respectively, and treatment durations required to achieve the negative conversion of all cases were 3 and 6 months for respective regimens. Of 90 patients who completed 6-month PZA containing regimen and could be followed-up, only one bacteriologic relapse (1.1%) was noticed. Elevation of serum GPT level higher than 150 IU/ml during the treatment was noticed in 6.3% of 175 cases under PZA-containing regimen in comparison with 4.0% of 174 cases under the standard regimen (not significant). The interval between the onset of the treatment and the detection of abnormal liver function was much shorter (mean 31.3 days) in the PZA-containing regimen than in the standard regimens (mean 63.4 days). Hyperuricaemia (> 10 mg/ml) was noticed in 46.7% of 57 males and 59.4% of 19 females tested, but pyrazinamide was not discontinued in any case due to arthralgia. These results clearly show that pyrazinamide can be used rather safely for Japanese tuberculosis patients. If the pyrazinamide-containing regimen [2HRS(E)Z/4HRE] is adopted as the new standard regimen in place of on-going standard regimen in Japan, 6HRS(E)/3HR, the duration of chemotherapy could be shortened by three months with the same level of both efficacy and safety. We recommended pyrazinamide-containing 6-month regimen, 2HRS(E)Z/4HRE, as the new standard regimen for the initial treatment of pulmonary tuberculosis. PMID- 7837721 TI - [Clinical studies on nine cases with miliary tuberculosis: serum level of tumor markers and bronchoscopy in differential diagnosis]. AB - We analyzed retrospectively the clinical data of 9 patients with miliary tuberculosis who had been treated in Kyoto City Hospital during the past 12 years. Majority of our patients were female (7 of 9) and were of elder age-groups (mean age: 68.5 years, range: 56-85 years). The most common symptoms at the first visit were fever, fatigue and loss of appetite, but respiratory symptoms were rather rare and moderate. Some cases showed normal chest radiograms at the onset, but during the course of the disease miliary shadows were noticed in all cases. Tuberculin test and smear examination of sputum were not diagnostic. In 4 cases, fiberoptic bronchoscopy had been performed together with bronchoalveolar lavage (BAL), bronchial washing and transbronchial lung biopsy (TBLB). Smear examination BAL-fluid or bronchial washing for acid-fast bacilli was positive in all 4 cases tested. In 7 cases, serum level of tumor markers (CEA, TPA, SLX, NSE, SCC, CA19 9, CA125, DU-PAN 2 and Elastase I) had been measured under the suspicion of malignant diseases. CEA had elevated in 6 cases, NSE in 2 cases, SLX, TPA, CA19 9, CA125 and DU-PAN 2 in 1 case each, and, as a whole, at least one tumor marker had elevated in 6 of 7 cases tested. Though the degree of such elevation of tumor markers had not been so remarkable except for CA125 in a patient who had been complicated with tuberculous peritonitis, but from these results malignancy had not been' able to rule out.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7837722 TI - [A case of tuberculous anal fistulae complicated by pulmonary tuberculous]. AB - Tuberculous involvement of the anus is very rare at present as the result of BCG Vaccination and improvement of public health. We report a juvenile case of tuberculous anal fistulae complicated to pulmonary tuberculosis. A 22-year-old male was admitted with symptoms of 13 month- history of intermittent anal pain, low grade fever and cough. Chest X-ray showed bilateral middle zone infiltrates with cavitation. Perianal inspection revealed a large ulcer with purulent exudate and a few fistulae. Sputum smears showed acid fast bacilli. A biopsied specimen of perianal fistulae showed granulomatous lesions with central necrosis, epitheloid cells and multi-nucleated giant cells. With three-drug antituberculous regimen, his symptoms resolved, radiographic infiltrates improved, and the perianal fistulae were cured. It was speculated that the tuberculous anal fistulae in this case were caused by the dissemination from the pulmonary focus via the hematogeneous and lymphogeneous routes, because any tuberculous lesion was not detected in the gastrointestinal tract and rectum. PMID- 7837723 TI - [A case of pulmonary tuberculosis with HIV infection--review of 5 cases in Japan]. AB - Recently we encountered a case of pulmonary tuberculosis with HIV infection. The patient was 54-years old male. His chief complaints were anemia, emaciation and severe diarrhea. He was admitted to our hospital on September 18, 1992. He had been diagnosed in another clinic as having pulmonary tuberculosis before the admission to our hospital. His chest films taken on admission revealed homogeneous infiltrates with cavitation in right upper lobe. Serial chest X-rays consisted with the findings of post-primary tuberculosis. Sputum smear for acid fast bacilli was positive. From his clinical manifestations and life-history, we had a suspicion that he had infected with HIV. Laboratory findings were as follows: serum albumin level was 1.9 g/dl, CRP was 10.2 mg/dl, serological tests for HIV were positive by EIA, IFA and western blott method, total lymphocyte count was 819/microliters, CD4+ T lymphocyte count was 120/microliter CD4+/CD8+ ratio was 0.2. He was treated with AZT, isoniazid, streptomycin and rifampicin. The disease progressed rapidly and interstitial pneumonia, jaundice and clouding of consciousness appeared at the terminal stage. He expired on October 14, 1992. In this paper, the authors reported a case of pulmonary tuberculosis with HIV infection and also reviewed 5 cases of pulmonary tuberculosis associated with HIV in Japan. PMID- 7837724 TI - [Studies on therapeutic efficacy of a new anti-tuberculous drug, benzoxazinorifamycin, against murine experimental mycobacterial infections: attempt at various regimens and protocols]. AB - Because of the recent AIDS endemic, there is a worldwide increase in intractable mycobacterial infections including extrapulmonary tuberculosis due to multidrug resistant M. tuberculosis and disseminated M. avium complex (MAC) infections. Therefore, development of new anti-tuberculous drugs having an excellent antimycobacterial activity and protocols for clinical use of presently available antimicrobials are urgently desired. In this study, we performed in vitro and in vivo experiments to assess the chemotherapeutic efficacy of a newly synthesized benzoxazinorifamycin derivative, KRM-1648 (KRM), against experimental infections due to MAC and M. tuberculosis. In addition, we attempted to improve the therapeutic efficacy of the KRM against MAC infections by changing its administration protocols and timing or by combined use with other antimicrobials, including clarithromycin (CAM), clofazimine (CFZ), sparfloxacin (SPFX), streptomycin (SM), and ethambutol (EB). Furthermore, we examined therapeutic efficacy of KRM against rifampicin (RFP)-resistant M. tuberculosis in details. KRM showing much more potent in vitro activity against the MAC organisms compared to rifabutin (RBT) and RFP, also exerted markedly greater therapeutic efficacy against the MAC infections induced in mice or rabbits in terms of reducing the incidence and the extent of gross pulmonary lesions and the bacterial loads in the lungs and spleens. However, in the case of mouse experimental infections, regrowth of the organisms was initiated after week 4 to 6 even in the animals given KRM. Since KRM-resistant organisms could not be isolated from infected mice given continuous KRM administrations, some unknown mechanisms other than the acquisition of drug resistance by infected organisms may be important for the establishment of the regrowth of MAC organisms.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7837725 TI - [New drugs against tuberculosis and nontuberculous mycobacterial infections: a review]. AB - The number of cases with tuberculosis is again increasing in many countries, and recently several nosocomial outbreaks of multidrug-resistant tuberculosis have occurred in the United States. The number of patients with disseminated Mycobacterium avium complex (MAC) infections in AIDS population, and patients with MAC pulmonary disease unassociated with HIV seem to be also increasing. It takes at least 6 to 9 months for an initial treatment of active tuberculosis due to drug-sensitive strains with the standard regimen which includes isoniazid (INH) and rifampicin (RFP). Treatment for the diseases caused by drug-resistant M. tuberculosis and MAC is much more time-consuming and more toxic than for the diseases caused by drug-sensitive strains, and often unsuccessful. For the reasons described above, the developments of new agents with potent antimycobacterial activities are highly desired. The new agents should also be useful for treating patients who have acquired resistance to many of the currently available drugs. In this review the new antimycobacterial drugs are summarized. Some of them have already been used clinically, but many are still in experimental evaluations. 1) Rifamycin derivatives: rifabutin (RBT), KRM-1648 (KRM), rifapentin (RPT), FCE-22250, FCE-22807, CGP-7040, SPA-S-565 and other rifamycin derivatives. New rifamycin derivatives including RBT, KRM have increased in vitro antimycobacterial activities. RBT and KRM are much more active in vitro and in vivo than RFP against both M. tuberculosis and MAC. KRM seems to be more potent than RBT against MAC in experimental studies.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7837726 TI - [Analysis of host defense mechanism against mycobacterial infection and its application to therapy with biological response modifiers]. AB - Recently, tuberculosis have been increasing among the immunocompromised patients. In patients with acquired immunodeficiency syndrome (AIDS), multi-drug resistant mycobacteria are often detected, which make the therapy difficult. In these patients, chemotherapy alone is often insufficient and some treatment to augment their host defense activity has been desired. Therefore, to know the host defense mechanism against mycobacterial infection will be helpful to develop an adjuvant therapy for intractable tuberculosis. In this study, IFN-gamma mRNA was induced in murine lungs after mycobacterial infection, and anti-IFN-gamma monoclonal antibody (mAb) prevented the activation of pulmonary intraparenchymal macrophages by M. bovis BCG and the elimination of M. tuberculosis from lungs. In addition, this mAb inhibited the activation of Mac1+CD4-CD8- T cells bearing alpha beta antigen receptor by BCG, which were found in murine lungs and might be involved in the host defense mechanism against mycobacterial infection, and administration of IFN-gamma significantly increased this population in lungs. Thus, IFN-gamma was suggested to be a candidate cytokine for the treatment of intractable tuberculosis. Next, CD4+ T cell-depleted mice were prepared by injecting anti-CD4 mAb and used as an immunocompromised model. When infected with M. tuberculosis, the multiplication of the bacilli within the lungs of such immunocompromised mice was much more enhanced in comparison with the control mice with intact CD4+ T cells. Administration of IFN-gamma significantly reduced the number of the bacilli in lungs. Further, in an in vitro study with human lung macrophages, IFN gamma enhanced the killing activity of macrophages against M. tuberculosis in a dose dependent manner, and suboptimal dose of 1 alpha, 25-dihydroxyvitamin D3 synergistically augmented the effect of IFN-gamma. PMID- 7837727 TI - [Therapeutic efficacy of macrolide in pulmonary nontuberculous mycobacteriosis]. AB - Clarithromycin (CAM) is semi-synthetic macrolide antimicrobial agent, differing from erythromycin by an O-methyl substitution at position 6 of the 14-membered lactate ring. CAM is one of the very few antimicrobial agents that show activity against that Mycobacterium avium complex (MAC) in vivo, in vitro, and in AIDS patients with disseminated infections. The purpose of the present study was to evaluate the therapeutic efficacy of CAM against MAC in patients with chronic pulmonary MAC infection. In vitro activity against clinically isolated MAC; MIC was evaluated by liquid medium dilution method. CAM was the most effective than other antitubercular drugs against M. avium, but less effective than RFP against M. intracellulare. Activity in animal model of infection; In vivo activity was evaluated by the murine models of hematogenous pulmonary MAC infection. A dose related reduction in lung cell counts was noted with treatment at 10, 50, 150, and 300 mg/kg of body weight administrated daily. Histopathological examinations were revealed also the reduction of the numbers of granulomas in the lungs with treatment CAM at 300 mg/kg. Therapeutic efficacy of CAM in chronic pulmonary MAC infection; Thirty patients with chronic pulmonary MAC infection were given CAM with other antitubercular drugs. Nineteen of 30 patients had previously received combination antimycobacterial therapy. The overall efficacy rates were 23.3%, and ten patients (33.3%) had negative sputum culture for MAC. Eradication of MAC from sputum has been almost observed within 3 months of initiating treatment, and the patients those who had no cavitation were effective. In conclusion, CAM was considerably effective against chronic pulmonary MAC infection, and the effect was observed relatively rapid. PMID- 7837728 TI - [Evaluation of aerosol therapy of streptomycin for tracheobronchial tuberculosis]. AB - The clinical features of tracheobronchial tuberculosis are distinct from those of pulmonary tuberculosis in some aspects. Streptomycin (SM) is claimed by some investigators that it has a tendency to promote the development of bronchial stenosis. The purpose of the present investigation is to point out that aerosol therapy of SM is useful for patients with tracheobronchial tuberculosis. Prior to clinical application of the inhalation therapy, we confirmed that the therapy was not harmful. Serum concentration of SM, when inhaled, was measured in 9 volunteers. Before and after administration of SM aerosol, spirograms were examined in 4 volunteers, and no special abnormality was recognized. It seemed that serum concentration of SM after the administration was too low to evoke adverse reactions (less than 3.0 gamma). In 6 patients, blood gases were measured, and no obvious change was observed. In 41 patients with bronchial tuberculosis, bronchofiberscopic examinations were performed twice or more. We observed the ulcerous lesions of bronchial tuberculosis at various stages of healing, and could classify the ulcerous lesions into the following three stages. Active Stage: stage A; ulcer formation without regenerating epithelium, Healing Stage: stage H; ulcer formation with regenerating epithelium, Scarring Stage: stage S; and no ulcer formation. Only the lesions of stage A were observed before treatment. In many patients during the first and second month of treatment, the lesions were at stage A or H. It was found that healing of the lesions of tracheobronchial tuberculosis progressed through the stages A, H, and S, in this order.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7837729 TI - Indian Child Welfare Act: what it means for nurses. PMID- 7837730 TI - Repackaging nursing practice through supply redistribution.... PMID- 7837732 TI - Talk back: as I see it. Nursing and health care reform: do we have a future? PMID- 7837731 TI - Collaboration: directions for advanced practice. PMID- 7837733 TI - A vision of professional nursing in 2020. PMID- 7837734 TI - [Surgical wound infections and their prevention]. PMID- 7837735 TI - [Renal failure in surgery of abdominal aorta aneurysms]. AB - The authors analyse the experience in operations for resection of an aneurysm of the abdominal aorta in 70 patients, which were performed at the Vishnevsky Institute of Surgery, AMS of Russia, from 1983 to 1991. Preoperative examination revealed renal insufficiency in 8 (11.4%) patients. Resection of the aneurysm of the abdominal aorta with one-stage prosthetics of the renal arteries was carried out in 10 cases. To prevent ischemic damage to the renal parenchyma and acute renal insufficiency, local methods of kidney protection (isolated cold perfusion- 2 and normothermic aorto-renal perfusion--2) were applied in 4 of 70 cases. The work discusses the methods of kidney protection and the indications and contraindications for their use, and factors promoting the development of postoperative renal insufficiency. Postoperative complications are shown and their causes are identified. PMID- 7837736 TI - [Indications for replantation of lower limbs after their traumatic amputation at the shin level]. AB - From analysis of the results of replantation of 37 lower limbs at the level of the leg, which were amputated as the result of injury in 33 patients, the authors determine the tactical approach to the choice of indications for replantation. The authors believe that replantation at the level of the leg is always indicated in children if it is executable technically and the patient's somatic status presents no general contraindications. In other cases the formation of a stump and subsequent prosthetics should be considered more advisable. PMID- 7837737 TI - [Diagnostic possibilities of retrograde pelvic phlebography through the contralateral limb in varicosities]. AB - The regular features of the passage of vertical blood reflux from the pelvic veins to the veins of the lower limbs were studied in 65 patients with varicosity by means of retrograde pelvic phlebography (RPP). The following atypical forms of varicosity were found to be absolute indications for RPP: varicosity of the gluteal veins, the veins of the ischiatic and pubic regions, the posterior and medial surface of the upper third of the thigh, and the veins of the genitals. The relative indications are recurrent varicosity with varicose veins in the inguinal region and operative scars preventing puncture of the femoral vein of the limb under study, and the development of various complications in puncture retrograde phlebography which make the examination difficult. PMID- 7837738 TI - [Results of the treatment of open heart injuries at a central regional hospital]. AB - In a period of 10 years seven patients with open injury to the heart were treated. Their ages ranged from 17 to 39 years. One patient had a gunshot injury, in six the injury was inflicted with a knife. In three patients the injuries were combined (concurrent injury to the lung in 2 and to the diaphragm in one) and in four isolated. Perforating injury of both ventricles and damage of the interventricular septum were found in one case. All patients underwent emergency closure of the heart wounds with an atraumatic synthetic thread and drainage of the pleural cavity. Complications developed in the postoperative period in six patients: suppuration of the operative wound in one and pericarditis in five. One patient died. Analysis of the obtained data testifies to the expediency of two stage treatment with rehabilitation in cardiological departments. This shortens the period of rehabilitation of patients with open injuries to the heart treated in a central regional hospital. PMID- 7837739 TI - [Decompression of the biliary tract in preparation for radical surgery of patients with obstructive jaundice and cholangitis]. AB - Rational use of mildly invasive percutaneous and endoscopic instrumental interventions for decompression of the biliary tract in patients with cicatricial and tumor strictures of the pancreaticobiliary zone rapidly arrests the manifestations of obstructive jaundice. This reduces considerably the risk of the subsequent operation. Analysis of the results of radical surgical treatment of 12 patients with posttraumatic cicatricial strictures and tumors of the biliary tract showed the advantages of two-stage tactics in the management of these patients. The use of such tactics in the clinic led to a decrease of the incidence of postoperative complications to 42.8% and was attended with a favorable outcome in all cases. PMID- 7837740 TI - [Substantiation of the thoracic duct drainage in diseases of the liver and biliary tract]. AB - Morphological study of the hepatic lymph vessels in 16 patients with diseases of the liver and biliary tract and the thoracic duct in individuals of different ages showed that the number and diameter of the lymphatic vessels and the diameter of the thoracic duct increase in the phase of inflammation, Proliferation of connective tissue in cirrhosis reduces the number of lymph vessels, induces valvular incompetence in the thoracic duct attended by ascites. Sixteen patients with diseases of the liver and biliary tract underwent operation for drainage of the thoracic duct. Biochemical parameters and the flow of lymph indicated that the diminished lymph issue is attended on the second day by decrease of the intoxication indices by one third, which is revealed by endotoxin -bile acids, bilirubin, the liver reduces in size and pruritus disappears. The results of the study substantiate the operation for drainage of the thoracic duct and show its importance as a method for the prevention of hepatic insufficiency and for detoxification. PMID- 7837741 TI - [Use of tumor markers in the differential diagnosis of voluminous formations of the liver]. AB - The radioimmunological method was used to determine the content of tumor markers APP, REA, CA 19-9, and CA 72-4 in 53 patients with nonmalignant three-dimensional structures in the liver (hemangioma, nonparasitic cysts, alveococcosis, hydatid cysts), in 9 patients with primary carcinoma of the liver, and in 24 healthy individuals. The significance of APP determination and complex study of tumor markers in the recognition and differential diagnosis of benign and malignant structures in the liver is shown. It allowed the percentage of disparity between the laboratory and the verified diagnosis to be reduced to 4.8%. PMID- 7837742 TI - [Reoperations in patients with pyloroduodenal ulcers]. AB - From analysis of the results of treatment of 35 patients who underwent previously unsuccessful operations for pyloroduodenal ulcers, the authors discuss the term and the most adequate method of surgical correction. Poor results in the early period after the operation are mainly due to technical errors made during the performance of the first operation. Affection of organs adjacent to the stomach prevail in the later periods. The use of methods of surgical correction suggested by the authors made it possible to achieve adequate medical, social, and occupational rehabilitation in 26 patients. PMID- 7837743 TI - [Use of laparoscopic suturing devices in abdominal surgery]. AB - The article deals with the results of clinical use of a laparoscopic suturing instrument in appendectomy in 2 patients with acute appendicitis. The authors describe the techniques of laparoscopic appendectomy with application of a mechanical suture to the mesentery and stump of the process. The advantages of this operation over the traditional interventions in acute appendicitis are shown: the absence of the pain syndrome after the operation, shorter duration of in-patient treatment, and the best cosmetic effect. PMID- 7837744 TI - [Aggressive fibromatosis of the small pelvis]. AB - Experience in the treatment of 25 patients with aggressive fibromatosis of the true pelvis is discussed. To establish a precise diagnosis obligatory and special methods of examination were applied. Secondary changes in the adjacent organs and structures were found in 24 patients. Radical operations were conducted on 19 (76%) patients, in 13 of them the interventions were combined. The mean duration of the operations was 5.3 hours. Complications developed in 17 out of 19 patients. Hemorrhage was the most frequent (in 12 out of 19 patients) and menacing complication. The blood loss was 3036.8 ml on the average. Recurrences were registered in 8 out of 19 (42.1%) patients. PMID- 7837745 TI - [Spermatic index of intoxication, a method of the assessment of blood toxicity]. AB - The article deals with a new method for determining the degree of intoxication in patients with peritonitis of various etiology. Bull sperm cells were used as the test-object. The degree of intoxication is judged according to the ratio of the mean life time of the spermatozoa in the studied filtrate, obtained from the blood serum of patients with peritonitis by filtration through polysulfone membranes with a pass band of up to 70,000 daltons, to the life time in a control glucose-nitrate solution. The authors called this ratio as the spermatic index of toxicity. It was 80.1 +/- 18.7% in the donors. The spermatic index of toxicity was 35.0 +/- 9.0% in the first day after the operation, 44.6 +/- 16.7% on the fifth day, and 70.8 +/- 27.7% before discharge from the hospital. The method is automatic, which excludes subjective a appraisal of the results, and may be suggested for use in clinical practice. PMID- 7837746 TI - [Optic attachment to a microsurgical forceps]. AB - The authors suggest an original optic attachment to a microsurgical forceps which removes the shortcomings of the traditional optic apparatuses used in microsurgery. The attachment allows the lens to be brought directly to the operative zone and combines the functions of two instruments--forceps and magnifying glass. Such a combination expands considerably the possibilities of the operator and creates optimal conditions for precision manipulations. The optic attachment is used in reconstructive and restorative operations on the bile ducts and in operations on the large intestine at the stage of precision suture application. PMID- 7837747 TI - [Use of sandostatin in abdominal surgery (data of foreign publications)]. PMID- 7837748 TI - [Bleeding postbulbar ulcers]. PMID- 7837749 TI - [Pre- and postoperative ultrasonic study in gunshot wounds of parenchymal organs]. AB - Timely discovery of the bullet or its fragments in the human body and determination of the character and size of the damage inflicted to the internal organs guarantee adequate treatment of the injured. USE makes it possible to exclude or recognize injury to the parenchymal organs (subscapular and intra tissue hematomas, complete crushing of the organ), and to reveal free or bounded fluid in the abdominal and pleural cavities and in the retroperitoneal space. Moreover, USE may be applied for identifying the location of the bullet or fragment in he parenchymal organ, the subcutaneous fat or the retroperitoneal fat. Intraoperative USE proves to be of great aid in many cases because it allows complete examination of the structure of the internal organs and the abdominal spaces in all planes and the condition of the retroperitoneal fat. The article describes cases in which USE helped in precise localization of the bullet and in revealing the character of the damage, as the result of which an optimal plan of surgical intervention was chosen. PMID- 7837750 TI - [Gunshot injury of the sacrum and rectum]. PMID- 7837751 TI - [One-stage intervention in primary multiple cancer of the esophagus and stomach]. PMID- 7837752 TI - [Results of the treatment of closed isolated retroperitoneal rupture of the duodenum at a central regional hospital]. PMID- 7837753 TI - [Pneumatosis of the sigmoid complicated by subserosal perforation by small fecal stones and peritonitis]. PMID- 7837755 TI - [Techniques of surgical interventions]. PMID- 7837754 TI - [A centennial of the first successful operation in closing of penetrating gastric ulcer]. PMID- 7837756 TI - [Regulation of wound process by the method of vacuum therapy in middle-aged and aged patients]. AB - Comparative analysis of the wound process in patients of various age groups allowed the conclusion that in elderly and old-age patients the wounds heal longer because of prolongation of the inflammatory phase, poorer local defence reactions, and sluggish reparative processes. This allows scientific substantiation of the postponed removal of the sutures in elderly and old patients. The method of vacuum therapy applied in patients over 60 produces a positive effect in the form of rapid abatement of the inflammatory reaction in the wound. This creates real preconditions for mobilization of the reparative property of the tissues which is diminishes at old age, active proliferation of the connective tissue elements, which results in the formation of a strong and mature scar in a shorter time. Vacuum therapy brings the terms of wound healing in elderly and old patients close to the terms of wound healing by first intention in the young and middle-aged. PMID- 7837757 TI - A novel mtDNA deletion in an infant with Pearson syndrome. AB - Pearson syndrome is a multisystem mitochondrial disorder of infancy that is associated with deletions in the mitochondrial DNA (mtDNA) genome. We report a study on a male infant with Pearson syndrome. Assessment of oxidative phosphorylation activity indicated combined respiratory-chain defects in muscle, liver and fibroblasts; in particular, activity of complex I was reduced. Analysis of the patient's mtDNA identified a novel heteroplasmic 2.461 kb deletion, present at levels greater than 50% of the total mtDNA in the tissues examined. The deletion spanned nucleotides 10368 to 12828 and was flanked by a 3 bp GCC direct repeat sequence. Gene sequences affected are subunits 3, 4, 4L and 5 of complex I, and tRNAs for arginine, histidine, serine and leucine. Our findings correlate with the multiorgan involvement observed in Pearson syndrome. PMID- 7837758 TI - Impaired degradation of phytanic acid in cells from patients with mitochondriopathies: evidence for the involvement of ETF and the respiratory chain in phytanic acid alpha-oxidation. AB - Phytanic acid alpha-oxidation was studied in cultures of skin fibroblasts and myoblasts from patients with various defects of the respiratory chain in order to obtain information on the subcellular site and the mechanism of this pathway. In fibroblasts from patients with complex IV (cytochrome c oxidase) deficiency or glutaricaciduria type II, phytanic acid alpha-oxidation was reduced to 14% of normal, whereas in myoblasts from patients with complex I (NADH-Q reductase) deficiency, it was normal. Apparently, at least one step of phytanic acid alpha oxidation occurs in mitochondria and in this process electrons are transferred to the respiratory chain via the electron-transfer flavoprotein (ETF). PMID- 7837759 TI - Normal N-oligosaccharyltransferase activity in fibroblasts from patients with carbohydrate-deficient glycoprotein syndrome. PMID- 7837760 TI - Mucolipidosis IV fibroblasts synthesize normal amounts of hyaluronic acid. AB - Mucolipidosis IV (ML IV) (McKusick 252650) is an autosomal recessive metabolic disorder that displays signs of both lipid and mucopolysaccharide (glycosaminoglycan) storage. It has been reported that fibroblasts from ML IV patients exhibit abnormally high synthesis of hyaluronic acid in culture. In our search for a biochemical marker that will enable positive identification of ML IV, we studied glycosaminoglycan synthesis in fibroblast cultures from patients with this disease. ML IV and normal control fibroblasts were incubated with [3H]glucosamine and [35S]sulphate. Labelled glycosaminoglycans were extracted from the cell layer and medium. Chondroitin sulphate and hyaluronic acid were determined by analysis of disaccharides after digestion with chondroitinase ABC. Synthesis of neither of these two glycosaminoglycans differed significantly between control and ML IV fibroblasts. Synthesis of hyaluronic acid was nearly linear for 24 h, with mean calculated values of 11.7 +/- 1.4 and 14.4 +/- 1.6 pg/cell per 24 h in control and ML IV cultures respectively. The variability within the two groups is attributed primarily to population variability and possibly to culture density. These experiments exclude the possibility that a general metabolic defect in hyaluronic acid synthesis is responsible for the ML IV phenotype, nor can such a defect be used as a diagnostic tool for the disease. PMID- 7837761 TI - Plasma cis-dec-4-enoic acid measured by isotope dilution mass spectrometry; an improved assay to diagnose medium-chain acyl-CoA dehydrogenase deficiency. AB - An isotope dilution mass spectrometric assay for plasma cis-dec-4-enoic acid is described. It is quicker, more reliable and more accurate than previous methods. It confirmed previous findings that cis-dec-4-enoic acid is a reliable indicator for medium-chain acyl-CoA dehydrogenase deficiency (MCAD). The plasma cis-dec-4 enoic acid levels of both asymptomatic and symptomatic MCAD patients (3.5-71 mumol/L) are demonstrably higher than those of normal children (0.2-1.7 mumol/L), MCAD heterozygotes (0.1-1.5 mumol/L), those with other fatty acid oxidation defects (0.2-2.2 mumol/L) or those receiving high doses of valproic acid (0.2-0.4 mumol/L). PMID- 7837762 TI - Effect of betaine on S-adenosylmethionine levels in the cerebrospinal fluid in a patient with methylenetetrahydrofolate reductase deficiency and peripheral neuropathy. AB - A 16-year-old Japanese girl with 5,10-methylenetetrahydrofolate reductase deficiency showed peripheral neuropathy. There were no significant responses to vitamin B6, vitamin B12 or folate, given alone or in combination. With the addition of betaine monohydrate, she has been free from gait disturbance and muscle weakness. The concentration of S-adenosylmethionine in cerebrospinal fluid, which was undetectable before receiving betaine monohydrate, increased to about the normal level 24 months after treatment with betaine monohydrate. PMID- 7837763 TI - Menstrual cycle and gonadal steroid effects on symptomatic hyperammonaemia of urea-cycle-based and idiopathic aetiologies. AB - We report two female patients, one with a known inborn error of ureagenesis and the other of unknown cause, in whom recurrent, transient episodes of severe hyperammonaemia increased in frequency and severity with sexual maturity and parturition. Both responded to ovarian steroids administered continuously to suppress ovulation and menstruation, and ultimately to simple hysterectomy. These studies suggest a new therapeutic approach to defective ureagenesis in female patients and a relationship between ammonia production or disposal and the menstrual cycle. PMID- 7837764 TI - Brain magnetic resonance imaging in children with optimally controlled hyperphenylalaninaemia. AB - This study was undertaken to investigate whether the white-matter changes on MRI and the EEG abnormalities detectable in treated adolescents and adults with hyperphenylalaninaemia (HPA) can be detected in younger children on an optimally controlled diet. The study included 17 children, 7-12 years of age, with HPA. The MRI of five healthy children were included in the blind evaluation of the MR images. According to mutation genotype and dietary tolerance of phenylalanine, 9 patients have severe HPA and 8 have moderate HPA, all requiring dietary treatment. Mild white-matter hyperintensity was detected in 1 of the 5 healthy children and in 10 of 17 patients. EEG was abnormal in 2 patients. This group of children was compared with a previously reported group of adolescents with HPA who had been treated according to the same dietary regimen. MRI changes and EEG abnormalities were significantly less frequent in the group of children than in the group of adolescents. It is suggested that the more frequent MRI changes and EEG abnormalities seen in adolescents are related to the fact that a relaxation of the dietary treatment after the age of 8 years is often accepted. PMID- 7837765 TI - Personality disorder in young women with treated phenylketonuria. AB - Twenty-eight young women with phenylketonuria (PKU) attending a Maternal PKU Summer Camp were interviewed and administered a personality inventory, the Minnesota Multiphasic Personality Inventory (MMPI). The 12 young women who were either late-treated (treatment initiated after 90 days) or who had terminated the diet for a period of at least 5 years (the extended exposure group) were compared to the 16 women who were early-treated and had remained continuously on diet (the continuously treated group). Although the mean blood phenylalanine and tyrosine concentrations at the camp for the two groups were comparable (973 +/- 344 and 1033 +/- 284 mumol/L for phenylalanine and 43 +/- 16 and 40 +/- 25 mumol/L for tyrosine), the women in the extended exposure group evidenced significantly greater psychopathology as measured by the MMPI and self-report; thought disorder and mood disturbances were associated with diet termination in PKU. PMID- 7837766 TI - Molecular genetics of Tay-Sachs disease in Japan. PMID- 7837768 TI - Influence of ageing on onset of mitochondrial disease. PMID- 7837767 TI - Molecular analysis by Southern blot for the N-acetylgalactosamine-6-sulphate sulphatase gene causing mucopolysaccharidosis IVA in the Japanese population. PMID- 7837769 TI - Urinary propionylcarnitine analysis for monitoring carnitine supplementation in inherited disorders of propionate metabolism. PMID- 7837771 TI - Prenatal diagnosis in a new peroxisomal disease by the W-particle separation method. PMID- 7837770 TI - Measurement of blood holoceruloplasmin by EIA using a mouse monoclonal antibody directed to holoceruloplasmin. Implication for mass screening of Wilson disease. PMID- 7837772 TI - Peroxisomal functions in mulibrey nanism. PMID- 7837773 TI - Measurement of pyruvate dehydrogenase complex (PDHC) in interleukin-2 (IL-2) stimulated lymphocytes. PMID- 7837774 TI - Fatty acid supplementation in a case of maternal phenylketonuria. PMID- 7837775 TI - Monitoring of a one-month ascorbic acid therapy in an alcaptonuric child; determinations by HPLC. PMID- 7837776 TI - Variable clinical expression associated with the mutation 3243 np of mitochondrial DNA. PMID- 7837777 TI - Association of malonyl-CoA decarboxylase deficiency and heterozygote state for haemoglobin C disease. PMID- 7837778 TI - Citrullinaemia and isolated sulphite oxidase deficiency in two siblings. PMID- 7837779 TI - Dihydropyrimidine dehydrogenase deficiency presenting with psychomotor retardation and ocular abnormalities. PMID- 7837780 TI - Phenylketonuria with familial hyperglycinuria. PMID- 7837781 TI - Formiminoglutamic/hydantoinpropionic aciduria in three patients with different tumours. PMID- 7837782 TI - Renal disease: the two faces of nitric oxide. PMID- 7837784 TI - Subacute combined degeneration in the spinal cords of totally gastrectomized rats. Ornithine decarboxylase induction, cobalamin status, and astroglial reaction. AB - BACKGROUND: The totally gastrectomized (TGX) rat is a new experimental model with which to produce widespread spongy vacuolation in spinal cord (SC) white matter, strongly reminiscent of that observed in subacute combined degeneration (SCD) of human SC. EXPERIMENTAL DESIGN: We did in long-term experiments combined biochemical and histologic studies on SCs from both TGX-rats and rats fed a cobalamin-deficient (Cbl-D) diet. We also investigated the effects of single in vivo administration of some neurotrophic growth factors on the activity of L ornithine decarboxylase (ODC) (the key-point in the polyamine biosynthetic pathway) in rat SC. RESULTS: Biochemically, ODC activity was still induced 3 and 6 months after total gastrectomy (TG), while it did not change significantly even after 9 months of feeding a Cbl-D diet. Both TG and feeding the Cbl-D diet greatly decreased the cobalamin level in both serum and SC, although these decreases occurred more slowly in rats fed a Cbl-D diet. Nerve growth factor did not induce ODC in either Cbl-D myeloneuropathy; epidermal growth factor induced ODC in both Cbl-D myeloneuropathies. Basic fibroblast growth factor induced SC ODC only in TGX-rats. Histologically, spongy vacuolation was still widespread 3 and 6 months after TG, while it was spotty even after 9 months of feeding a Cbl-D diet. There was massively increased staining of astrocytes positive for glial fibrillary acidic protein, mainly in the gray matter, in both Cbl-D myeloneuropathies. Finally, repeated in vivo injections of cobalamin to TGX rats only partially reduced ODC induction, the severity of spongy vacuolation, and the increase in glial fibrillary acidic protein-positive astrocytes. CONCLUSIONS: These results suggest: (a) ODC induction is a persistent and inherent feature in the TG-induced SCD of rat SC; (b) an increase in glial fibrillary acidic protein positive astrocytes in rat SC is not mandatorily connected with an increase in polyamine biosynthesis; (c) a mere deficiency of Cbl seems to be not the only key point in the pathogenesis of the ODC induction and of the SCD-like lesions, both brought about in rat SC by TG. PMID- 7837783 TI - Stathmin expression is a feature of proliferating cells of most, if not all, cell lineages. AB - BACKGROUND: Stathmin is a phylogenetically conserved protein which was identified initially as a prominent cytosolic protein in hemopoietic cells, endocrine cells, brain, and testis. In these tissues, it has been suggested that the level of stathmin expression is important in development and cell proliferation. Furthermore, stathmin phosphorylation appears to be involved in the regulation of cell growth arrest, terminal differentiation, and hormone secretion. Elevated levels of expression of stathmin have been described in leukemia and lymphoma cells. The aim of this study was to characterize the distribution of cells that express the stathmin protein in a wide variety of normal human and rodent tissues. EXPERIMENTAL DESIGN: First, antisera against a synthetic stathmin peptide have been raised in rabbits and the specificity of these antisera confirmed by their reactivity with stathmin on 1-dimensional and 2-dimensional Western blots. Second, the most appropriate means of fixing tissues in order to stain stathmin has been investigated. Finally, using the optimized conditions of tissue fixation, the antisera have been used to immunostain sections taken from a wide variety of tissues. RESULTS: Immunopositivity was found in cells of all the lineages studied, with the stained cells present within the proliferating compartment of tissues. Conversely, most nonproliferating mature cells did not stain with the antisera to stathmin. The only nonproliferating cells that appeared to express stathmin were a subpopulation of glial cells, neurons, and anterior pituitary cells. CONCLUSIONS: It is proposed that stathmin is necessary for cell proliferation in most, or all, cell lineages and that its primary function relates to some aspect of cell division. PMID- 7837785 TI - Metalloproteinases and tumor cell invasion. PMID- 7837786 TI - Nitric oxide mediates immunologic injury to kidney mesangium in experimental glomerulonephritis. AB - BACKGROUND: Nitric oxide (NO), produced from L-arginine by an inducible NO synthase, is an important effector molecule in inflammatory and immunologic tissue injury. The role of NO generation in immunologic injury to glomerular mesangial cells and the effect of dietary restriction of L-arginine on this injury was investigated. EXPERIMENTAL DESIGN: Acute glomerulonephritis was induced by injection of anti-thymocyte serum (ATS) which binds to an antigen on the glomerular mesangial cell. Complement-mediated mesangial cell lysis follows. The effect of blocking NO production in vivo by administration of the NOS inhibitor NG-monomethyl-L-arginine (L-NMMA) 60 minutes before ATS injection on mesangial cell lysis, and on the severity of disease was assessed. The effect of dietary restriction of L-arginine on mesangial cell lysis in response to ATS injection was also determined. RESULTS: We report here that blocking NO production in vivo with L-NMMA prevented mesangial cell lysis by 90%. Injection of L-NMMA caused transiently elevated systolic blood pressure, but did not diminish ATS binding to mesangial cells or recruitment of monocyte/macrophages into glomeruli indicating that L-NMMA pretreatment did not limit injury by insufficient glomerular perfusion. ATS-induced proteinuria and increases in urinary nitrite excretion were prevented. Glomerular expression of transforming growth factor-beta and accumulation of extracellular matrix were suppressed by the L-NMMA treatment. Low protein diet (6%), but also selective dietary L arginine restriction, given for 7 days before induction of the disease mimicked L NMMA treatment, significantly decreasing mesangial cell lysis. The effect of a low protein diet was abolished by dietary L-arginine supplementation. CONCLUSIONS: This study strongly implicates NO as a mediator in immune-mediated mesangial cell lysis. The data suggest that limiting NO production by limiting arginine intake might decrease glomerular injury and subsequent glomerulosclerosis. PMID- 7837787 TI - Complement system promotes transfer of immune complex across glomerular filtration barrier. AB - BACKGROUND: The solubilizing effect of complement (C) on immune complexes (IC) in the fluid phase is well known, however effects on tissue-deposited IC have not been analyzed in detail. We studied the influence of C depletion on the movement of IC across the glomerular basement membrane in a rat model of passive in situ IC nephritis. EXPERIMENTAL DESIGN: The left kidneys of intact rats, rats given cobra venom factor (C-depleted) or rats given anti-polymorphonuclear granulocyte antiserum (PMN-depleted) were perfused with cationized ferritin (electron-dense tracer antigen), followed by intravenous injection of rabbit anti-ferritin antibody 15 minutes later. The glomerular distribution of rabbit IgG (antibody) and rat C3 was visualized by immunogold staining. RESULTS: In intact, nephritic rats (non C-depleted), the distribution of antigen, antibody, and C3 (IC) was mainly subendothelial 2 and 6 hours after antibody injection, at 24 hours about 75% and by 48 hours virtually all 3 IC components were localized on the subepithelial side of the glomerular basement membrane in all glomeruli. In C depleted rats, the distribution of IC was as in intact rats, up to 6 hours. At 24 hours, two patterns of IC distribution within individual glomeruli could be distinguished. About 2/3 of the capillary wall area revealed a distribution similar to the C-intact animals; however in 1/3 of the capillary wall area, IC was still predominantly subendothelial at 24 hours. By 48 hours, some accumulation in the lamina densa was noted. At day 7, some IC was still subendothelial, in limited areas, even though serum C3 level had returned to 60% of normal. On the other hand, the distribution of IC in polymorphonuclear leukocyte-depleted, C-intact rats, showed no difference to that in control nephritic rats. Proteinuria was significantly decreased in both C-depleted rats and polymorphonuclear leukocyte-depleted rats. Thus, enhanced glomerular permeability itself does not guarantee complete, rapid IC movement. CONCLUSIONS: The C system promotes effective transfer of IC across the glomerular basement membrane, probably due to the solubilizing effect of C on IC lattices. PMID- 7837788 TI - Serine proteinases are regionally segregated within mast cell granules. AB - BACKGROUND: By ultrastructure, human skin mast cell granules exhibit amorphous regions situated next to crystalline regions with scroll, lamellar, and grating/lattice-like configurations. The composition and function of these structural domains is unknown. These granules also contain large amounts of three serine proteinases termed tryptase, chymase, and cathepsin G. In this study, subgranular proteinase distribution is correlated with granule ultrastructure. EXPERIMENTAL DESIGN: Human skin sections were immunolabeled for each proteinase, visualized with gold-conjugated antibodies, and then stained with heavy metals to enhance granule features. Both single and double labeling experiments were analyzed. RESULTS: Comparison of the immunogold labeling patterns revealed nonrandom distributions for each proteinase within most granules. At low magnification, chymase and cathepsin G immunoreactivity was found preferentially over more electron-dense granule subregions, whereas tryptase immunoreactivity was found preferentially over less electron-dense subregions. The complimentary staining pattern of the proteinases was also observed in double labeling experiments where tryptase immunoreactivity was compared directly with that of chymase or cathepsin G. Higher magnification of sections revealed that electron dense granule areas corresponded to amorphous regions, whereas less dense regions most often demonstrated crystalline structures. CONCLUSIONS: These observations correlate the subgranular distribution of serine proteinases with specific granule ultrastructure and suggest that the different morphologic features within granules may be related, in part, to the packaging of serine proteinases. Human mast cells differ from human basophils and rat mast cells by virtue of the presence of high amounts of tryptase and the presence of crystalline substructures. This raises the possibility that association of tryptase with crystalline structures reflects a specialized form of packaging permitting efficient storage of high levels of this proteinase within mast cell granules. PMID- 7837789 TI - Molecular pathogenesis of beta-amyloidosis in Alzheimer's disease and other cerebral amyloidoses. PMID- 7837790 TI - Immunohistochemical analysis of the Bcl-2 oncoprotein in human neuroblastomas. Comparisons with tumor cell differentiation and N-Myc protein. AB - BACKGROUND: The bcl-2 gene encodes a 26-kilodalton integral membrane oncoprotein that is noteworthy for its function as a blocker of programmed cell death, and ability to render cells resistant to killing by chemotherapeutic drugs and x irradiation. EXPERIMENTAL DESIGN: To determine the in vivo patterns of bcl-2 expression in neuroblastomas (NBs), tumor specimens derived from 17 children with NB or ganglioneuromas were immunohistochemically evaluated using formalin-fixed, paraffin-embedded material and antibodies specific for the Bcl-2 and N-Myc proteins, or various markers typically used to assess the differentiation status of these tumors, including neuron-specific enolase, S-100 protein, beta 2 microglobulin (beta 2M) and the intermediate filament proteins, vimentin, and neurofilament light- and medium-chains. RESULTS: Using two-color immunohistochemical methods, Bcl-2 protein was found exclusively in tumor cells that did not contain N-Myc, an oncoprotein previously associated with poor prognosis in NB. Levels of Bcl-2 immunostaining were heterogeneous in the undifferentiated small, round cells typically seen in tumors with aggressive histology, and ranged from essentially undetectable, to strong in intensity. Somewhat higher levels of Bcl-2 immunostaining were found in the slightly larger, more differentiated neuroblastic cells that had more generous cytoplasm in these neoplasms. In contrast to the heterogeneous levels of Bcl-2 seen in undifferentiated NBs, Bcl-2 immunoreactivity was uniformly present at high levels in tumor cells that were more differentiated and judged to be similar to immature ganglion cells at an intermediate stage of neuronal differentiation, based on morphologic characteristics and immunophenotyping with antibodies specific for various differentiation markers. The still more differentiated ganglionic cells seen in ganglioneuroblastomas and ganglioneuromas exhibited much less intense immunoreactivity with anti-Bcl-2 antibodies, suggesting down-regulation of bcl-2 during final terminal differentiation. In contrast to cells with neuronal features, the stromal Schwann cells were uniformly negative for Bcl-2 protein in all histologic grades of tumors. Thus, bcl-2 expression in NBs was limited to cells of the neuronal lineage and tended to be highest in tumor cells with the characteristics of ganglionic cell precursors. The expression of bcl-2 in the normal fetal and postnatal adrenal medulla and sympathetic ganglia paralleled that seen in NBs, consistent with previous suggestions that NB reflects a block in the normal differentiation process. CONCLUSIONS: Taken together, these findings indicate that the levels of the Bcl-2 protein are developmentally regulated in normal and neoplastic cells of the sympathetic branch of the autonomic nervous system, and suggest that this oncoprotein may be useful as a differentiation marker for subclassification of NBs for prognostic purposes and for investigations of normal neuronal maturation. Furthermore, strong Bcl-2 immunoreactivity was detected in islets of residual tumor cells in 6 of 7 specimens obtained from 5 patients after therapy, suggesting that this oncoprotein may be cytoprotective for NB cells in vivo. PMID- 7837791 TI - Expression of osteopontin in human glioma. Its correlation with the malignancy. AB - BACKGROUND: Osteopontin (OPN) is a phosphorylated glycoprotein that contains a functional Gly-Arg-Gly-Asp-Ser (GRGDS) cell-binding sequence. It is reported that the expression of OPN is increased in a number of transformed cell lines. This study demonstrates the expression of OPN in human glioma representative of brain tumors. EXPERIMENTAL DESIGN: The expression of OPN in human gliomas was determined with: (a) Northern blot analysis; (b) Southern blot analysis; (c) Immunofluorescent cytochemistry; (d) Western blot analysis; (e) Cloning and sequencing of complementary DNAs (cDNAS); (f) Immunohistochemistry. RESULTS: OPN mRNA was detected in all glioma cell lines examined, and Southern blot analysis showed that OPN DNA most likely exists as a single copy gene in these cell lines. Immunofluorescent cytochemistry showed strong staining mainly in the cytoplasm. These cell lines produced two major forms of OPN protein migrating at 53 and 47 kilodaltons, and two minor forms at 38 and 31 kilodaltons on 12% sodium dodecyl sulfate-polyacrylamide gel electrophoresis gels. We also isolated and sequenced three types of splice variants in OPN from human glioma cell lines through polymerase chain reaction. In addition, Northern blot analysis was carried out on RNA from human astrocytoma tissues of various malignancy grades. Expression of OPN mRNA was high in malignant astrocytomas, but low in benign astrocytomas and non-neoplastic tissue. Immunohistochemistry also showed strong staining in malignant astrocytomas and slight staining in benign astrocytomas. CONCLUSIONS: These findings indicate that OPN mRNA and proteins are expressed in human glioma cells, and that the extent of OPN expression may correlate with the malignancy grade of gliomas. PMID- 7837792 TI - Expression of bone matrix protein messenger ribonucleic acids in human breast cancers. Possible involvement of osteopontin in development of calcifying foci. AB - BACKGROUND: Development of calcifying foci is a fairly common finding in human breast cancers, and the deposition of calcium phosphate is observed in such foci. The calcium phosphate is a physiologic component of bones and teeth. Since the expression of messenger (m) RNAs of osteopontin (OPN), osteocalcin (OC), osteonectin (ON), and matrix gla protein (MGP) has been described in bones and teeth, we examined the mRNA expression of OPN, OC, ON, or MGP in the calcifying foci that were observed in human breast cancers. EXPERIMENTAL DESIGN: Cell types expressing mRNAs of OPN, ON or MGP were identified with combination of in situ hybridization and immunohistochemistry. RESULTS: The OPN mRNA-expressing cells clustered around the necrotic foci within cancer cell nests, and the examination with anti-OPN antibody revealed that OPN protein was localized in such necrotic foci where calcium phosphate deposited. The OPN mRNA-expressing cells were identified as macrophages by staining the adjacent section with the anti-CD68 PG M1 monoclonal antibody which specifically recognizes macrophages. Neither ON mRNA expressing cells nor MGP mRNA-expressing cells appeared to correlate with the deposition of calcium phosphate. CONCLUSIONS: The OPN protein produced by macrophages appeared to play a significant role for development of calcifying foci within necrotic area of breast cancers. PMID- 7837793 TI - Testicular seminomas are aneuploid tumors. AB - BACKGROUND: Distinct ploidy patterns of germ cell tumors and aneuploidy of classic seminoma are of central importance in a current concept designating seminoma as a stage in tumor evolution preceding all nonseminomatous germ cell tumors. Whereas cytogenetic studies almost constantly revealed numerical chromosomal aberrations in seminomas in line with this pathogenetic model, ploidy determination by DNA cytometry yielded highly controversial results on the frequency of diploid seminomas. EXPERIMENTAL DESIGN: Twenty-two classic seminomas were investigated in a comparative manner by DNA flow and DNA image cytometry on nuclei isolated from fresh as well as formalin-fixed tumors. The cellular composition of the tumors, i.e., the number of neoplastic, interstitial, and lymphoid cells was quantified in each case. RESULTS: Irrespective of the tissue preparation and fixation method, all of the tumors that were analyzed were aneuploid by image cytometry. Diploid cases were only found by flow cytometry. Thus, 1/22 cases from paraffin-embedded and 4/11 cases of native tumors showed a single diploid stemline by flow cytometry, however, they exhibited aneuploidy by image cytometry. The quantity of tumor infiltrating lymphocytes was clearly correlated with false diploidy detected by flow cytometry. CONCLUSIONS: Classic testicular seminomas are aneuploid tumors. Previous reports on diploid cases detected by flow cytometry have most likely been caused by extensive lymphocytic infiltration. PMID- 7837794 TI - Apolipoprotein A-II gene and development of amyloidosis and senescence in a congenic strain of mice carrying amyloidogenic ApoA-II. AB - BACKGROUND: Apolipoprotein A-II (ApoA-II), a major apoprotein of serum high density lipoprotein (HDL) deposits as an amyloid fibril (AApoAII) in murine senile amyloidosis. Type C ApoA-II gene (Apoa2c) in the SAMP1 strain of mice, a murine model of severe senile amyloidosis and accelerated senescence was transferred on the genetic background of the SAMR1 strain, in which senile amyloidosis is rare and has a normal aging process, and a congenic strain of mouse (R1.P1-Apoa2c) was developed (Higuchi K, Kitado H, Kitagawa K, Kogishi K, Naiki H, Takeda T. FEBS Lett 1993;317:207-10). EXPERIMENTAL DESIGN: We identified AApoAII amyloid deposits in the 14-month-old congenic R1.P1-Apoa2c strain and compared these findings with the deposits in the progenitor SAMP1 and SAMR1 strains. The progression of senescence was estimated using a grading system and the age-associated changes in the metabolism of ApoA-II and HDL were investigated in the three strains of mice. RESULTS: At 14 months of age, severe amyloid deposition as compared with the donor SAMP1 strain was present in the congenic R1.P1-Apoa2c strain, but AApoAII was not evident in the progenitor SAMR1 strain which has type B ApoA-II. No obvious differences in the progression of senescence were observed between the R1.P1-Apoa2c and SAMR1 strains. In the R1.P1-Apoa2c strain, the serum HDL-cholesterol concentrations decreased in parallel with ApoA II levels with advancing age and the decrease was much accelerated compared with the decrease seen in SAMR1 mice. CONCLUSIONS: Based on these results, we propose that the genetic type of ApoA-II plays an important role in the development of senile amyloidosis and age-associated changes in HDL metabolism. However, it has a minor role in the accelerated senescence in the mouse strains we used. PMID- 7837795 TI - Induction of an acute phase response in rats stimulates the expression of alpha 1(I) procollagen messenger ribonucleic acid in their livers. Possible role of interleukin-6. AB - BACKGROUND: In response to nonspecific inflammatory stimuli, circulating monocytes produce several cytokines that regulate the expression of liver acute phase protein genes. Patients with alcoholic liver disease have several manifestations of the acute phase response, including elevated serum levels of interleukin (IL)-1 (IL-1), IL-6 and tumor necrosis factor-alpha (TNF-alpha). However, the role of the acute phase response on liver fibrogenesis has not been explored. EXPERIMENTAL DESIGN: In this communication we report experiments performed to investigate whether turpentine, an acute phase response inducer in rats has any effect on alpha 1 (I) procollagen gene expression in the liver. We also investigated which of the cytokines is responsible for the turpentine effect and whether IL-6 and TNF-alpha had an effect on alpha 1 (I) procollagen mRNA expression by liver fat-storing cells (FSC). RESULTS: We show that alpha 1 (I) procollagen mRNA is increased in livers of turpentine-treated rats, and that an antibody to IL-6 as well as colchicine inhibit this effect. We also show that rIL 6 induces the expression of alpha 1 (I) procollagen mRNA in cultured FSC but not in hepatocytes. We demonstrated that the IL-6 effect is a transcriptional event that requires "de novo" protein synthesis. In addition to its effect on collagen gene expression, rIL-6 also stimulates expression of transforming growth factor beta and fibronectin mRNAs. TNF-alpha inhibits alpha 1 (I) procollagen expression in FSC by 24 to 48 hours. However, TNF-alpha induces a transient expression of alpha 1 (I) procollagen mRNA by 2 to 3 hours. This increase is preceded by the induction of IL-6 mRNA. CONCLUSIONS: We conclude that IL-6 produced during the acute phase response, alone or in conjunction with other cytokines, could play an important role in liver fibrogenesis by inducing the expression of collagen, fibronectin, and transforming growth factor-beta mRNAs in FSC. PMID- 7837796 TI - In situ hybridization analysis of hepatic cytochrome P450 2E1 messenger ribonucleic acid in mice. Modulation of expression by acetone. AB - BACKGROUND: Cytochrome P450 2E1 is a distinct enzyme induced by diverse agents and notably by solvents including acetone. The P450 2E1 apoprotein is predominantly localized in the centrilobular region of the hepatic lobule in the constitutive state and after induction with acetone. In this study, we investigated the level and pattern of distribution of the 2E1 mRNA within the hepatic lobule in control mice and in mice exposed to acetone under acute and chronic conditions. EXPERIMENTAL DESIGN: Male CD-1 mice were administered acetone acutely (5 ml/kg) or chronically (1% in drinking water for 8 days). Cytochrome P450 2E1 mRNA was detected in liver tissues, using in situ hybridization with a 3H-labeled RNA probe coupled with quantitative image analysis. RESULTS: Acetone exposure did not alter the distance spanning a central vein and an adjacent portal vein. In control mice, 2E1 mRNA transcripts were localized most abundantly in the centrilobular zone of the hepatic lobule; intermediate levels were found in the midzonal region, and minimal levels were found in the periportal region. In acetone-treated mice, 2E1 mRNA expression within the hepatic lobule was significantly reduced and was manifested, firstly, in a decreased hepatocyte population with high expression, as assessed by reduction of total acinar areas containing 2E1 mRNA transcripts, and, secondly, in reduced 2E1 mRNA content within the hepatocytes. These alterations were observed to a significantly greater extent in mice after chronic versus acute acetone exposure. CONCLUSIONS: Our results showed that acetone exposure in mice results in both a reduction and a more restricted distribution of 2E1 mRNA within the hepatic lobule. Furthermore, these findings suggest that 2E1 enzyme induction is associated with post-transcriptional events that are more marked after chronic than after acute exposure. PMID- 7837797 TI - An overview of the American Cancer Society screening guidelines. PMID- 7837798 TI - Confusion and weakness following coronary artery bypass graft. PMID- 7837799 TI - Progressive dyspnea and weight loss. PMID- 7837800 TI - Tension-free repair of giant ventral hernias. PMID- 7837801 TI - Loss prevention case of the month. Watch closely. PMID- 7837802 TI - EKG case of the month. Hypokalemia. PMID- 7837803 TI - Prophylaxis. PMID- 7837804 TI - TMA's domestic violence program. PMID- 7837805 TI - Who is counseling the pregnant women who smoke? A pediatric viewpoint. PMID- 7837806 TI - What does KNA do for me? PMID- 7837807 TI - Developing ethical competence. PMID- 7837809 TI - A midwife's day. PMID- 7837808 TI - A trip to Poland examines their midwifery. PMID- 7837810 TI - An advanced nursing role in need of community awareness. PMID- 7837811 TI - Nurse managed care for the homeless of Lexington. PMID- 7837812 TI - Mission nursing in the Third World--is it for you? PMID- 7837813 TI - Nursing in France; or, it's a small world after all! PMID- 7837814 TI - Functional properties of HL60 cells matured with all-trans-retinoic acid and DMSO: differences in response to interleukin-8 and fMLP. AB - All-trans-retinoic acid (ATRA) causes granulocyte differentiation in patients with acute promyelocytic leukemia. HL60 cells are frequently used as an in vitro model for studying granulocytes during maturation. We have previously studied actin polymerization in response to fMLP in HL60 cells undergoing DMSO induced maturation, and reported that IL-8 causes actin polymerization in neutrophils in a manner similar to fMLP. We now compare chemotaxis and actin polymerization in response to IL-8 and fMLP, and nitroblue tetrazolium (NBT) reduction in HL60 cells matured with ATRA and DMSO. Cells cultured for 4 days with ATRA and DMSO showed morphologic evidence of maturation. NBD-phallacidin staining and flow cytometry were used to measure changes in F-actin content in response to IL-8 and fMLP. Uninduced cells were not capable of actin polymerization or chemotaxis. Cells matured with ATRA exhibited a 2.6-fold increase in F-actin content in response to IL-8, but only a 1.2-fold increase in response to fMLP. Cells matured with DMSO responded to both IL-8 and fMLP in an equal manner with 1.6-fold increases in F-actin. The 2 h migration for ATRA induced cells was 124 microns in response to IL-8, 107 microns with fMLP, and 105 microns in buffer. DMSO induced cells migrated 89 microns in response to IL-8, 106 microns with fMLP, and 66 microns in buffer. With maturation, 65% of the ATRA induced cells reduced NBT compared with only 15% of the DMSO induced cells. In summary, HL60 cells cultured in ATRA develop greater functional maturity than those cultured in DMSO, and a greater responsiveness to IL-8 than fMLP, a finding distinct from previously reported work in neutrophils. PMID- 7837815 TI - Cytokine expression in adherent layers from patients with myelodysplastic syndrome and acute myelogenous leukemia. AB - We have previously shown that long-term cultures of adherent layers derived from patients with chronic myelogenous leukemia in blast crisis express high levels of interleukin (IL)-1 beta and that this cytokine may participate in disease progression. In this study, we analyzed cytokine expression in bone marrow adherent layers derived from patients with myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). IL-6 messenger RNA (mRNA) was expressed in adherent layers established from four of nine MDS patients, and from 10 of 17 AML patients (including all four individuals in whom AML had evolved from an antecedent MDS state). Similarly, IL-1 beta mRNA was expressed in adherent layers derived from two of nine MDS patients and from three of 17 AML patients. Cultures from two of 10 AML patients who expressed IL-6 also expressed granulocyte (G) colony-stimulating factor (CSF) mRNA. In contrast, IL-1 beta, IL-6, and G-CSF mRNA were not discernible in adherent layers from any of 14 normal volunteers. Transforming growth factor-beta 1, macrophage (M) CSF, IL-7, and leukemia inhibitory factor mRNA as well as IL-6 protein were constitutively expressed in adherent layers derived from both MDS patients, AML patients, and normal bone marrows, whereas IL-1 alpha, tumor necrosis factor-alpha, and GM-CSF were not expressed in either the normal-, MDS- or AML-derived adherent layers. These results indicate that cultured stroma from a subset of MDS and AML patients produce IL-1 beta and/or IL-6. Although, exposure of adherent layers to exogenous IL-1 beta was able to induce IL-6 expression, in 9 of the 14 samples constitutively expressing cytokines, IL-6 transcript levels were elevated without a concomitant increase in IL-1 beta, suggesting that IL-6 transcription was independently dysregulated. PMID- 7837816 TI - Interleukin-1 beta (IL-1 beta) and acute leukemia: in vitro proliferative response to IL-1 beta, IL-1 beta content of leukemic cells and treatment outcome. AB - We evaluated the in vitro proliferative response to exogenous IL-1 beta in terms of tritiated thymidine (3H-TdR) incorporation in leukemic cells obtained from 119 patients with various types of acute leukemia. The content of IL-1 beta in leukemic cells was measured by enzyme-amplified sensitivity immunoassay. We observed a significant proliferative response to exogenous IL-1 beta in leukemic cells from 27/66 patients with de novo AML, 1/29 patients with ALL, 2/3 patients with AUL, 8/12 patients with AML arising from MDS, 4/7 patients with myeloid crisis of CML, and 0/4 patients with lymphoid crisis of CML. Proliferation was marked in myeloid leukemic cells of a more premature stem cell origin. There were no significant differences in proliferative responses among the different FAB classes of de novo AML. The IL-1 beta content of leukemic cells was low in patients with lymphoid leukemia, but there was no significant difference among the various types of myeloid leukemia. There was no correlation between the proliferative response to exogenous IL-1 beta and the IL-1 beta content of leukemic cells. When we correlated the proliferative response to exogenous IL-1 beta with treatment outcome in patients with de novo AML, we found the rate of complete remission (CR) to be lower in those with a high proliferative response. We noted a longer duration of CR (p = 0.07) and of survival (p < 0.05) in patients with a low proliferative response. Thus, a high proliferative response to IL-1 beta in the cells of AML patients may indicate a poor prognosis. PMID- 7837817 TI - Sensitivity of camptothecin-resistant human leukemia cells and tumors to anticancer drugs with diverse mechanisms of action. AB - Human leukemia U-937 cell clones resistant to 9-nitrocamptothecin (9NC) appear after exposure to increase 9NC-concentrations. Drug resistance is irreversible, regardless of whether the 9NC-resistant (U-937/CR150) cells grow in media with or without 9NC. U-937/CR150 cells are more sensitive than wild type U-937 (U-937/wt) cells to topoisomerase II-directed drugs, amsacrine, daunorubicin, and etoposide. The mitotic inhibitor, vincristine, induces hyperdiploidy in U-937/wt, but not in U-937/CR150 cells, whereas the antimetabolites, cytarabine and methotrexate, and the nitrosourea, carmustine, elicit similar responses in both U-937/wt and U 937/CR150 cells. U-937/CR150-generated tumors in nude mice are sensitive to etoposide. The clinical implications of increased sensitivity of 9NC-resistant tumors to some anticancer drugs are discussed. PMID- 7837818 TI - Expression of cell surface antigens during the differentiation of HL-60 cells induced by 1,25-dihydroxyvitamin D3, retinoic acid and DMSO. AB - HL-60 cells were induced to differentiate by 1,25-dihydroxyvitamin D3, retinoic acid or DMSO. In order to investigate to which extent this maturation mimics the in vivo monocytic or myeloid differentiation, we compared induced HL-60 cells with peripheral blood monocytes and granulocytes by using a panel of mAbs directed against myeloid cell surface antigens. Upon exposure to 1,25-(OH)2D3, HL 60 cells acquired a differentiation phenotype close to that of mature monocytes. The changes in myeloid cell surface antigens induced by retinoic acid or DMSO paralleled the expression pattern of these molecules in normal granulopoiesis, although maturation was not achieved and partially defective. PMID- 7837819 TI - Vitamin D3 analogs: effect on leukemic clonal growth and differentiation, and on serum calcium levels. AB - In vitro, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) induces differentiation of HL-60 cells and inhibits their proliferation as well as the proliferation of leukemic cells from patients. In vivo, the survival of mice challenged with syngeneic leukemic cells is enhanced by treatment with 1,25(OH)2D3. Patients treated with 1,25(OH)2D3 develop hypercalcemia at a serum level of 2 x 10(-10) mol/l which is a concentration too low to achieve an antileukemic effect in vitro. Several interesting vitamin D3 analogs have recently been developed. We initially examined the effect of 1,25(OH)2-16ene-23yne-19-nor-26,27-F6-D3 and 24a,26a,27a tri-homo-22,24-diene-1-alpha,25-(OH)2-D3 on clonal growth and differentiation of HL-60 cells. Each of the analogs had comparable effects on clonal growth with 50% inhibition (ED50) at concentrations of 0.2-0.5 x 10(-9) M; 1,25(OH)2D3 was about 20- to 50-fold less active in inhibiting growth. Differentiation was determined by induction of superoxide production, as measured by nitroblue tetrazolium (NBT) reduction and by expression of a macrophage-specific enzyme (alpha napthyl acetate esterase (ANAE)). The 24a,26a,27a-tri-homo-22,24-diene-1-alpha,25-(OH)2 D3 and 1,25(OH)2-16ene-23yne-19-nor-26,27-F6-D3 were about 5- to 14-fold more potent than 1,25(OH)2D3. The hypercalcemia inducing side-effects of these analogs and three other previously identified, extremely potent vitamin D3 compounds, as well as 1,25(OH)2D3, were studied. The analogs were administered intraperitoneally every other day (qod) for 5 weeks; serum was collected weekly and Ca2+ measured by atomic absorption spectrophotometry. The highest tolerated dose of each analog leaving all mice alive was for 1,25(OH)2D3: 0.25 micrograms; 1,25(OH)2-24a,26a,27a-tri-homo-22,24-diene-D3: 0.25 micrograms; and 1,25(OH)2 16ene-23yne-19-nor-26,27-F6-D3: 0.0625 micrograms. Another hexafluoro compound with potent abilities to induce differentiation (1,25(OH)2-16ene-23yne-26,27-F6 D3) was very toxic, all mice died in the second week while receiving 0.0625 micrograms qod. Prior studies showed that the most potent compound in inducing differentiation of HL-60 was 1,25(OH)2-20-epi-D3; but it is very toxic as only one mouse survived a dose of > or = 0.0125 micrograms qod for 5 weeks. 1,25(OH)2 16ene-23yne-D3 is an extremely active inducer of differentiation but, on the other hand, it has low potential to produce hypercalcemia; mice maintained normal serum calcium levels even while receiving 2 micrograms qod for 5 weeks.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7837820 TI - Bryostatin-5 stimulates normal human hematopoiesis and inhibits proliferation of HL60 leukemic cells. AB - In this study we explored the effects of bryostatin-5 on the clonogenic response of normal bone marrow mononuclear (BM) cells and HL60 myeloid leukemia cells. Leukemic HL60 colony formation was strongly inhibited by bryostatin-5 depending on dose and schedule. An inhibitory effect on HL60 colony formation was readily demonstrated after 1 h of exposure, reaching a maximal inhibitory effect at 96 h. Normal BM cells differed in their clonogenic response: short-term exposure to bryostatin-5 resulted in increased clonogenicity while longstanding exposure to bryostatin-5 permitted the survival of a substantial fraction of committed progenitors. This differential modulation of normal and leukemic myeloid clonogenicity by bryostatin-5 suggests a possible role for bryostatin-5 in the treatment of acute myeloid leukemia. PMID- 7837821 TI - A population-based approach to monitoring adverse outcomes of medical care. AB - A population-based approach to monitoring quality of care combining small-area analysis and outcomes assessment is proposed. While adverse outcomes due to poor surgical technique have long been targeted for quality-of-care review, in this study, giving similar attention to adverse outcomes produced by high rates of interventions is proposed. A population-based approach will strengthen traditional review efforts that currently begin and end at the hospital door. Excluded from these reviews have been questions such as the following: Should the procedure have been performed in the first place? Did the benefits outweigh the risks? Were there other patients not operated on who might have benefited more? Traditional approaches can identify less competent hospitals or practitioners: population-based approaches can identify the surgical enthusiasts who may pose equal risks to the populations of the areas they serve. Applying a population based approach to review of coronary artery bypass graft surgery for Medicare patients in five cities in the United States demonstrates that at least as many deaths could have been prevented by decreasing surgical rates to the U.S. average as by improving the technical quality of care with which the procedure was performed. A similar population-based analysis of complications (as judged by re admissions within 30 days of surgery) associated with hysterectomy across regions of Manitoba, Canada, is presented. In summary, negligent acts in the delivery of health care in institutions are rare and are difficult to detect because medicine is an inexact science and because adverse outcomes are more likely in high-risk patients, regardless of the quality of care. However, from a population perspective, adverse events are predictable, occur relatively frequently, and are directly related to the frequency of a population's exposure to surgical intervention. Efforts to improve quality of care could be made more effective by including the rates at which populations are exposed to treatments and the technical quality of care delivered. PMID- 7837822 TI - The effect of an education and feedback intervention on group-model and network model health maintenance organization physician prescribing behavior. AB - The authors evaluated the effect of an educational and feedback intervention on H2-blocker prescribing patterns and determined, if such effects differed for network- versus group-model health maintenance organization (HMO) physicians and in academic versus nonacademic settings. Physicians were randomized to receive an educational memorandum alone or combined with feedback regarding their individual prescribing behavior. The memo suggested preferred use of an H2-blocker (cimetidine) that would be less expensive to the HMO. Prescribing was monitored during the 6 months before and after the intervention. The study was undertaken at the primary care practices of a mixed group- and network-model university affiliated HMO. Thirty group-model (at two academic and four nonacademic sites) and 33 network-model (all in full-time private practice) primary care physicians participated in the study. The analysis utilized weighted and unweighted analysis of covariance of the change in physicians' cimetidine-prescribing rates between the baseline and study periods. A significant response to the intervention was noted among academic and nonacademic group-model HMO physicians, but not among network physicians (adjusted mean absolute prescribing changes of +9.9% and +8.9% versus -2.8%, P = .02). There was no difference in prescribing change based on type of intervention (education versus feedback). The authors conclude that a simple passive educational intervention can be effective at changing group-model HMO physician behavior. PMID- 7837823 TI - Comparison of the Medical Outcomes Study Short-Form 36-Item Health Survey in black patients and white patients with acute chest pain. AB - Few data are available regarding the performance of the Medical Outcomes Study (MOS) Short-Form 36-Item Health Survey (SF-36) in black patients. In this article, the reliability and validity of the MOS SF-36 is compared in a population of black patients and white patients with acute chest pain. The MOS SF 36 was administered to 1,160 patients (31% black) who presented to the emergency department of an urban teaching hospital with acute chest pain from October 1990 to May 1992. In unadjusted analyses, black patients had significantly lower scores compared with white patients for several dimensions of the SF-36. Correlations among the eight subscales were similar, and the internal consistency of each of the eight subscales was excellent for both groups (Cronbach's coefficient alpha range .64 to .93). Each subscale had similar clinical and nonclinical correlates in black patients and white patients. In multivariate models, race was not a significant independent correlate of any of the eight subscales. Thus, the MOS SF-36 had similar reliability and validity in this population of black patients and white patients with acute chest pain who presented to an urban teaching hospital. If these findings are confirmed in other populations, they suggest that results from the MOS SF-36 may be interpreted similarly in black patients and white patients, after adjusting for clinical and sociodemographic data. Whether these findings are generalizable to other conditions and less acute settings requires further investigation. PMID- 7837824 TI - Do doctors stop giving quit-smoking advice when other programs are reaching their patients? AB - The authors attempted to determine if the self-reported practices of hospital doctors regarding smoking cessation advice to their patients, would be influenced by the introduction of a scheme in which smokers were routinely identified on admission to hospital and were subsequently mailed letters including cessation advice. The second objective was to assess the relative levels of cessation counselling among different categories of doctors. Five hundred and fifteen doctors from two large public teaching hospitals in Melbourne, Australia participated in the study. Mail-out cessation advice took place in one hospital (the intervention hospital). In both hospitals, half of the doctors were surveyed 6 weeks before the mailing had commenced, and the remaining half were surveyed 6 months after. There were no significant differences between doctors at the intervention hospital and doctors at the control hospital in the self-reported advice to patients. Most doctors "encouraged patients to quit whenever possible." However, this encouragement seemed to be limited to talking to patients about the risks of smoking. Doctors less frequently gave advice concerning how to stop smoking. Compared with other doctors, internists seemed to be the most willing to encourage patients to quit and they reported higher levels of assisting patients to quit. There was no evidence that reminding doctors regularly that their patients were receiving mailed cessation advice significantly increased or decreased doctor's reporting smoking cessation activities with their patients. Internists are more involved in smoking cessation counselling than other types of doctors. PMID- 7837825 TI - Does the hospital board need a doctor? The influence of physician board participation on hospital financial performance. AB - In this study, the authors attempted to determine if physician board participation enhances or impairs the operational performance of a hospital. Two theories--managerialism and agency theory--are compared to determine if participation on the hospital board by inside (i.e., medical staff) and outside physicians provides informational advantages (managerialism) or poses the threat for opportunism (agency theory). Using hospital operating margin to measure hospital performance for a 4-year period (1985-1988), the findings indicate that boards with inside physician (medical staff) participation had significantly better performance than those without such physician participation. Supportive of the managerialist perspective, the findings strongly suggest that medical staff board participation can enhance operational performance. Implications of physician-hospital relations for future hospital strategies as well as health care reform issues are discussed. PMID- 7837826 TI - Interpreting the Health Care Financing Administration's mortality statistics. AB - In this article, the methodology used by the Health Care Financing Administration in the 1992 release of 1990 mortality statistics is described, and the performance of one outlier hospital is evaluated as a case study. The study hospital is compared to all other hospitals, and to a smaller cohort of 200-to 299-bed minor teaching hospitals, in terms of predicted and observed mortality rates and mortality model determinants. Proportionately more patients treated in the study hospital were women and had cerebrovascular degeneration or chronic renal disease; fewer patients had cardiovascular disease. Substantially more patients from this hospital were transfers from a skilled nursing facility. Fewer patients were admitted through the emergency department. Although patients tended to be more seriously ill overall compared with other hospitals in the country, observed mortality rates were still higher than predicted. Possible explanations for the discrepancy were coding inconsistencies, inability to control adequately for the severity of illness of transfers from skilled nursing facilities, or quality of care problems. PMID- 7837827 TI - A survey of current problems in meta-analysis. Discussion from the Agency for Health Care Policy and Research inter-PORT Work Group on Literature Review/Meta Analysis. AB - The United States Agency for Health Care Policy and Research brought together representatives from each of the Patient Outcomes Research Teams (PORTs) as the Inter-PORT Meta-Analysis Work Group. The purpose of the meeting was to discuss a wide range of problems the panel had encountered in the area of meta-analysis. Several actual problems were presented, and tentative solutions to those problems were given. The PORTs had to consider issues such as quality assessment, survival analysis, rare events, sensitivity and specificity, and random effects models. The solutions presented represent the methods used by several researchers who are active in the area of meta-analysis. PMID- 7837828 TI - Rat anococcygeus: a dynamic smooth muscle preparation for experimental pharmacology. PMID- 7837829 TI - L-NAME augments the antinociceptive effects of intracerebroventricularly applied ET-1 and ET-3. AB - The interaction between endothelin-1 (ET-1) (5 pmol/mouse, i.c.v.) and endothelin 3 (ET-3) (5 pmol/mouse, i.c.v.) with NG-nitro-L-arginine methyl ester (L-NAME) (5 mg/kg i.p., 30 min pretreatment) was investigated in mice by the use of two experimental procedures: hot plate and tail flick tests in mice. L-NAME showed slight insignificant antinociceptive action, but augmented significantly the antinociceptive effects of i.c.v. administered ET-1 and ET-3 in both experimental tests. PMID- 7837830 TI - Induction of hypertension and cardiac hypertrophy in guinea pig by DOCA salt. AB - Experimental hypertension can be induced in rats by uninephrectomy, administration of deoxycorticosterone acetate (DOCA) and sodium chloride. We developed this model in the guinea pig, because it presents an isoenzymic myosin pattern and calcium-induced calcium release similar to those of humans. Unilateral nephrectomy was performed in 33 guinea pigs, after which they were given DOCA (300 mg/kg pellets, s.c.; n = 11, or 10 mg, i.m.; n = 12, 5 days a week for 5 weeks). One week after surgery, drinking water was supplemented with NaCl 9 g/l and KCl 2 g/l for 5 weeks. Control guinea pigs (n = 10) were nephrectomized but not treated. Five weeks after surgery, hemodynamic measurements were recorded and the animals sacrificed to assess the degree of left ventricular hypertrophy. Left ventricular hypertrophy was considered significant if the ratio of left ventricular weight/body weight was > 2.3 and if the thickness of the left ventricle free wall was > 3.5 mm. Results showed that the systolic, diastolic and mean blood pressures of the treated groups were 36% higher than in the control group. Cardiac hypertrophy occurred within 5 weeks, and resulted in an increase in left ventricle weight and in left ventricular hypertrophy. The possibility of using the DOCA salt model of experimental hypertension in the guinea pig could help to elucidate the mechanisms responsible for hypertension and induced left ventricular hypertrophy, and thus improve prevention and treatment. PMID- 7837831 TI - Protective effects of a monoclonal antibody against lipid A in endotoxic shock. AB - Bacterial lipopolysaccharide given intravenously at 30 mg/kg to anesthetized rats results in rapid systemic hypotension and hypovolemia, elaboration of cytokines, increased proteolysis and vascular endothelial dysfunction. When a monoclonal antibody SdJ5-1.17.15 (SdJ5) directed against the lipid A moiety of lipopolysaccharide was administered at (1.25 or 5.0 mg/kg) 5 min prior to the endotoxin, significant protection was afforded to rats. This protection was manifested by a significant reduction in the early hypotension, as well as attenuation of hypovolemia and proteolysis. To evaluate endothelial function, superior mesenteric artery rings were isolated from endotoxemic rats 4 h after endotoxic challenge. Lipopolysaccharide (LPS) significantly reduced superior mesenteric artery vasorelaxation to acetylcholine and A23187, two endothelium dependent vasodilators, but not to NaNO2, an endothelium-independent vasodilator. SdJ5 significantly preserved vasorelaxation responses to both acetylcholine and A23187, indicating a marked degree of endothelial preservation by this anti-lipid A monoclonal antibody. The protection was dose-dependent since 0.3 mg/kg of SdJ5 did not provide significant protection in any variable measured. Moreover, there was no significant difference between the 1.25 mg/kg and 5.0 mg/kg dose of SdJ5. Furthermore, plasma concentrations of TNF-alpha, a cytokine involved in mediating many of the effects associated with endotoxemia, was significantly reduced in SdJ5-treated animals. Thus, SdJ5 appears to be capable of counteracting many of the in vivo sequelae of endotoxemia in rats. PMID- 7837832 TI - Pancuronium effect on the neuromuscular function of hypoglycemic rats. AB - An expected response in a hypoglycemic patient to a muscle relaxant formed the basis for the research presented in this study. There was no information available in the accessible literature and references gave no data on this subject. But because perioperative hypoglycemia is not unusual, we scheduled this experimental work. Four groups of 6 white adult Wistar albino rats were used in the study. Group A was the normoglycemia control group, with blood glucose levels of 80-120 mg/dl. Groups B, C and D were made hypoglycemic by i.v. injection of insulin 1 IU/100 g b.w. Blood glucose levels were reduced to 50% of the control values in hypoglycemic animals, which were sacrificed 40 min later. Phrenic nerve hemidiaphragm preparations were placed in a 100 ml bath containing Paradelis Zaimis solution, 37 degrees C, pH 7.2, aerated with O2/CO2:95/5%. After stabilization and recording of neuromuscular activity, pancuronium bromide was administered in doses of 1.5 x 10(-9) M in groups A and B, 3 x 10(-9) M in group D. Statistical analysis between A-B, A-C, A-D groups was done with Student's paired t test. Results showed that under hypoglycemic conditions the amount of pancuronium bromide needed for complete neuromuscular blockade was 2.5-fold greater than that needed in normoglycemic conditions. These findings suggest that the integrity of the neuromuscular junction is altered during hypoglycemia. PMID- 7837833 TI - On the absorption of drugs using chronic dog ileal loop method. AB - The absorption rate of three model drugs, i.e., pentacaine (highly lipophilic), stobadine (moderately lipophilic) and acetylsalicylic acid (hydrophilic), was studied using the chronic dog ileal loop method. The drugs were dissolved either in 0.9% unbuffered solution of NaCl or in antacid mixture. When using 0.9% NaCl, the half-lives of absorption (t1/2 (dis)) of pentacaine and stobadine were (mean +/- SD) 23.2 +/- 7.8 min and 20.8 +/- 7.2 min, respectively. For stobadine a good agreement was found between its t1/2 (dis) from the ileum and its absorption half life determined from blood concentrations after oral administration to dogs. The absorption of acetylsalicylic acid accounted for only 10-20% of the dose introduced into the loop over 45 min; thus, a reliable value of t1/2 (dis) could not be determined. The administration of unbuffered solution of NaCl into the loop was accompanied by rapid increase of pH from acidic to basic value. The antacid mixture failed to affect the absorption rate of the drugs studied. Sampling from the ileum was limited to 35-55 min due to rapid absorption of water. These results suggest that: 1) measurement of the absorption rate of some drugs, e.g., stobadine, by using the chronic dog ileal loop method may adequately predict their absorption rate after peroral administration to the dog, 2) interactions of antacids with drug absorption in the ileum may not play a significant role because of the strong buffering capacity of the ileum, and 3) rapid absorption of water from the ileum does not allow to reliably determine the value of t1/2 (dis) for slowly absorbed drugs. PMID- 7837835 TI - [Investigate child health services!]. PMID- 7837834 TI - Bioequivalence of two commercially available tamoxifen tablet formulations in healthy male volunteers. AB - Tamoxifen, a non-steroidal antiestrogen, is used in the palliative treatment of advanced breast cancer and as an adjuvant therapy after mastectomy. The bioequivalence of tamoxifen following single oral doses of Zemide 20 and a commercially available tablet formulation (reference formulation), each containing 30.4 mg tamoxifen dihydrogencitrate corresponding to 20 mg tamoxifen was investigated in 12 healthy male subjects. In a randomized, crossover study with a washout period of 13 weeks the volunteers received one pharmaceutical unit of both formulations after an overnight fast on an empty stomach. Plasma concentrations of tamoxifen were determined at predose and predetermined time points up to 20 days after administration using a validated HPLC method. The two tamoxifen formulations were proven to be bioequivalent for tamoxifen regarding rate and extent of absorption. The bioequivalence decision was based on Cmax, tmax and AUC0-t. PMID- 7837836 TI - [What should we demand from health care? Assessments by the HSAN are preposterously exaggerated]. PMID- 7837837 TI - [How are we supposed to deal with ulcer and thrombolysis?]. PMID- 7837838 TI - [Out-of date Medical Society?]. PMID- 7837839 TI - [Drug industry and continuing education]. PMID- 7837840 TI - [Is lambskin dangerous for infants?]. PMID- 7837841 TI - [Who should handle drivers' licensing?]. PMID- 7837842 TI - [A new system for drug control in the EEC. Role of Sweden in an active monitoring of adverse effects]. PMID- 7837843 TI - [When should the therapeutic effect be measured? Intermediary markers are still at the experimental stage]. PMID- 7837844 TI - [Rapid development in nuclear radiology. Improved diagnosis of heart diseases]. PMID- 7837845 TI - [Psychiatric specialists have a positive attitude to electroshock therapy. Patients and relatives have negative or ambivalent attitude]. PMID- 7837846 TI - [Surgical treatment of atrial fibrillation. Experimental clinical activity in progress]. PMID- 7837847 TI - [A regional center for reporting adverse drug reactions in Umea. Prompt handling results in quick feedback]. PMID- 7837848 TI - [Does chronic fatigue syndrome have physiological or psychological causes? A wrongly formulated question may result in information]. PMID- 7837849 TI - [Future and limits of immunohemotherapy. Great possibilities with apheresis]. PMID- 7837850 TI - [Aggression--a biological perspective]. PMID- 7837851 TI - [Medical students and physicians, alcohol and narcotics. "We will not swear loyalty until death"]. PMID- 7837852 TI - [New attitudes, reliable therapy, networks, professional responsibility. The way of better support to addicted physicians]. PMID- 7837853 TI - [Good results of pulmonary surgery in children. Few complications and short hospitalization]. PMID- 7837854 TI - [Borreliosis may cause hearing defects in children. Screening of Borrelia infection]. PMID- 7837855 TI - [From Thomas Browne to Dannie Abse. English physicians-writers over four centuries]. PMID- 7837856 TI - Wellcome's will. PMID- 7837857 TI - Trans fatty acids and coronary heart disease: weighing the evidence against hardened fat. PMID- 7837858 TI - Time to stop culturing silence. PMID- 7837859 TI - Incompetent patient on the slippery slope. PMID- 7837860 TI - After the honeymoon in measles control. PMID- 7837861 TI - trans isomers of oleic and linoleic acids in adipose tissue and sudden cardiac death. AB - trans isomers of unsaturated fatty acids are formed by biological or industrial hydrogenation. A population case-control study of sudden cardiac death in mean was done to test the hypothesis that trans isomers of oleic acid and linoleic acid increase the risk of sudden cardiac death due to coronary artery disease. In adipose tissue obtained at necropsy from 66 cases of sudden cardiac death and taken from 286 healthy age and sex matched controls, the proportions of trans isomers of oleic and linoleic acid were measured by gas-liquid chromatography. In cases, the mean (SE) percentage of total trans fatty acids (C18:1 plus C18:2), expressed as a proportion of all fatty acids, was significantly lower (2.68 [0.08]%) than in healthy controls (2.86 [0.04]%; p < 0.05). trans C18:1 was 2.1 (0.7)% in cases compared with 2.27 (0.04)% (p < 0.05) in controls. The proportion of all trans isomers of linoleic acid was 0.58 (0.02)% in cases compared with 0.59 (0.01)% in controls (p = 0.98). The estimated relative risk for sudden cardiac death of trans C18:1 and C18:2 fatty acids combined did not differ significantly from 1.0 in relation to the distribution of these trans isomers by quintile in the control population. The relative risk (95% CI) of sudden cardiac death in the top quintile was 0.40 (0.15-1.02) for C18:1 and 1.08 (0.48-2.74) for C18:2 compared with the bottom quintiles of their respective control distributions. When these univariate relations for trans fatty acids were adjusted for coronary risk factors, smoking was the only factor that remained independently associated with risk of sudden cardiac death (2.27 [1.23-4.17]). Overall, there was no evidence of a relation between trans isomers of oleic and linoleic acids combined and sudden cardiac death. However, trans oleic acid was negatively associated with risk of sudden cardiac death, whereas no association with trans forms of linoleic acid was seen. This study does not support the hypothesis that trans isomers increase the risk of sudden cardiac death. PMID- 7837862 TI - Multicentre evaluation of reduced-osmolarity oral rehydration salts solution. International Study Group on Reduced-osmolarity ORS solutions. AB - In developed countries, use of oral rehydration salts (ORS) solution with osmolarity lower than that of plasma has been recommended because of the risk of hypernatraemia. We compared the clinical efficacy of reduced-osmolarity ORS and standard ORS solutions in children with acute diarrhoea in four developing countries. 447 boys aged 1-24 months, admitted to hospitals in four countries with acute diarrhoea and signs of dehydration, were randomly assigned either standard ORS (311 mmol/L) or reduced-osmolarity ORS (224 mmol/L) solution. Total stool output was 39% greater (95% CI 11-75), total ORS intake 18% greater (3-33), and duration of diarrhoea 22% longer (2-45) in the standard ORS group than in the reduced-osmolarity ORS group. The risk of requiring intravenous infusion after completion of the initial oral rehydration was greater in children given standard ORS solution than in those given reduced-osmolarity ORS solution in three of the four countries (all-country relative risk 1.4 [0.9-2.4]). This relative risk was significantly increased only in non-breastfed children (2.0 [1.0-3.8], p < 0.05). In breastfed children, the relative risk of requiring intravenous infusion was not affected by the ORS solution (0.9 [0.4-2.0]). The mean sodium concentration 24 h after admission was significantly lower in the reduced-osmolarity ORS group than in the standard ORS group (135 [134-136] vs 138 [136-139] mmol/L, p < 0.01). Reduced-osmolarity ORS solution has beneficial effects on the clinical course of acute diarrhoea. Our findings support the use of reduced-osmolarity ORS solution in children with acute non-cholera diarrhoea in developing countries. Further studies are needed to find the best formulation and whether such a solution would be satisfactory for the treatment of cholera. PMID- 7837863 TI - Effect of neonatal circumcision on pain responses during vaccination in boys. AB - Using data from one of our randomised trials, we investigated post-hoc whether male neonatal circumcision is associated with a greater pain response to routine vaccination at 4 or 6 months. Pain response during routine vaccination with diphtheria-pertussis-tetanus (DPT) alone or DPT followed by Haemophilus influenzae type b conjugate (HIB) was scored blind. 42 boys received DPT and 18 also received HIB. After DPT, median visual analogue scores by an observer were higher in the circumcised group (40 vs 26 mm, p = 0.03). After HIB, circumcised infants had higher behavioural pain scores (8 vs 6, p = 0.01) and cried longer (53 vs 19 s, p = 0.02). Thus neonatal circumcision may affect pain response several months after the event. PMID- 7837864 TI - Hepatocyte growth factor: a multifunctional cytokine. PMID- 7837865 TI - Environmental determinants of asthma. PMID- 7837867 TI - Measles and pertussis in developing countries with good vaccine coverage. PMID- 7837868 TI - Labour's invisible health agenda. PMID- 7837866 TI - Reproductive tract infections and abortion among adolescent girls in rural Nigeria. AB - Few studies from developing countries have investigated reproductive tract infections or other indicators of sexual health among unmarried adolescent girls in rural areas. We have obtained baseline demographic, clinical, and microbiological data on reproductive tract infections and induced abortion in girls in a rural area of southeast Nigeria, in order to assess the need for health care for adolescents. 868 females attended for interview and examination: 458 aged 20 and above and 410 aged 12-19, the latter representing 93.4%of the adolescent population. 43.6% of those < 17 and 80.1% aged 17-19 years were sexually active and at least 24.1% had undergone an induced abortion; only 5.3% had ever used a modern contraceptive. Vaginal discharge was reported by 82.4%, though few sought treatment. 94.1% of sexually active adolescents and 97.6% of sexually active women 20 years old or over were gynaecologically examined and screened for reproductive tract infections. Of those aged less than 17, 19.8% had symptomatic candida and 11.1% trichomonas infections. Among those aged 17-19 years, chlamydia was detected in 10.5%, and symptomatic candidosis in 25.6%; this was the group most likely to have any infection (43.8%). 42.1% of sexually active adolescents had experienced either an abortion or a sexually transmitted disease. Syphilis was the only infection for which the incidence clearly increased with age. Health-care services for adolescents in this community are needed and should include sex education, contraceptive provision (especially barrier methods), and access to treatment for reproductive tract infections. Investments in health for this age group will have an effect on subsequent reproductive health. PMID- 7837869 TI - Danish haemophiliacs court case nears conclusion. PMID- 7837870 TI - HIV in England and Wales. PMID- 7837871 TI - Cancer surgery without histological proof. PMID- 7837872 TI - Gait disturbances after measles, mumps, and rubella vaccine. PMID- 7837873 TI - Effect of praziquantel on protozoan parasites. PMID- 7837874 TI - Childbearing and risk of ovarian cancer. PMID- 7837875 TI - Childbearing and risk of ovarian cancer. PMID- 7837876 TI - Polio eradication. PMID- 7837877 TI - Prenatal detection of fetal RhD DNA sequences in transcervical samples. PMID- 7837878 TI - Silicone implant controversy. PMID- 7837879 TI - Respiratory rehabilitation. PMID- 7837880 TI - Respiratory rehabilitation. PMID- 7837881 TI - Myocardial infarction, Arg 506 to Gln factor V mutation, and activated protein C resistance. PMID- 7837882 TI - Respiratory rehabilitation. PMID- 7837883 TI - Rwanda. PMID- 7837884 TI - Rwanda. PMID- 7837885 TI - Rwanda. PMID- 7837886 TI - Managed care. PMID- 7837887 TI - Shared care. PMID- 7837888 TI - WHO's current policies and plans for reform. PMID- 7837889 TI - Red wine consumption and oxidation of low-density lipoproteins. PMID- 7837890 TI - Carcinogenicity of coal-tar shampoo. PMID- 7837891 TI - Bird attacks on milk bottles and Campylobacter infection. PMID- 7837892 TI - Dinitrochlorobenzene and Chagas' disease. PMID- 7837893 TI - Coronary heart disease, shared care, and cholesterol. PMID- 7837894 TI - Coronary heart disease, shared care, and cholesterol. PMID- 7837895 TI - Coronary heart disease, shared care, and cholesterol. PMID- 7837896 TI - Cataracts, glaucoma, and femoral avascular necrosis caused by topical corticosteroid ointment. PMID- 7837897 TI - Reversing risk in coronary disease. PMID- 7837898 TI - Candida albicans endophthalmitis after anabolic steroid abuse. PMID- 7837899 TI - Ankle jerk assessment. PMID- 7837900 TI - Ankle jerk assessment. PMID- 7837902 TI - Pointing to the word. PMID- 7837901 TI - Interferon-alfa-2b for meningioma. PMID- 7837903 TI - Contextual insensitivity in thought-disordered schizophrenic patients: evidence from pauses in spontaneous speech. AB - The distribution of pauses in spontaneous speech of schizophrenic patients was studied. Normal control subjects and schizophrenic patients without thought disorder pause more frequently before nouns not suggested by the context, and less frequently before nouns suggested by the context. No context dependency of the pauses before nouns was found in thought-disordered schizophrenic patients. The data are interpreted in terms of a reduced signal-to-noise ratio in semantic associative networks responsible for lexical access in thought-disordered schizophrenic patients. PMID- 7837904 TI - Trends in the management of alcohol withdrawal syndrome. AB - Alcohol use among head and neck cancer patients is common. Alcohol withdrawal (especially delirium tremens) poses significant potential morbidity to postsurgical patients. Treatment with newer benzodiazepines (BZDs) such as lorazepam and midazolam has become more widespread, and mortality rates from severe alcohol withdrawal have decreased in recent years. The authors retrospectively studied 102 patients with a diagnosis of alcohol withdrawal, including 20 patients undergoing surgery for cancer of the head and neck. There were 81 men and 21 women, with a mean (+/- standard deviation [SD]) age of 52.3 (+/- 16.1) years. Many of these patients (46%) were treated with more than one BZD or other neuroleptic, while 49% received single agent therapy of either chlordiazepoxide (26%) or lorazepam (23%). Delirium tremens occurred in 12% of all patients undergoing withdrawal and in 10% of head and neck cancer patients, with a mortality rate of 9% and 0%, respectively. Single agent use was successful in greater than 95% when either lorazepam or chlordiazepoxide was used. Instances of combination treatment where older BZDs were used yielded a 69% success rate. The higher complication rate and lower treatment success with combination treatment was multifactorial. Optimal management of the alcohol withdrawal syndrome requires an understanding of its pathophysiology and the principles of its prevention along with a familiarity of BZD pharmacokinetic drug profiles. The authors present a treatment plan which is cost-effective, keeps morbidity low, and should allow a continued decreasing trend in mortality rates from delirium tremens. PMID- 7837905 TI - Antidromic stimulation of the greater superficial petrosal nerve in middle fossa surgery. PMID- 7837906 TI - Directory of Otolaryngological Societies. PMID- 7837907 TI - Maxillomandibular fixation with intraoral cortical bone screws. PMID- 7837908 TI - Fate of liposuctioned and purified autologous fat injections in the canine vocal fold. AB - Injection of autologous fat obtained by liposuction has been reported as an augmentation technique for vocal fold paralysis. Unfortunately, it is not known whether this technique is associated with long-term graft survival. The purpose of this study, using a canine model, was to determine the volume of viable injected fat grafts when the tissue was harvested and processed by two different methods: 1. by liposuction alone, and 2. by "purification," i.e., excision of adipose tissue, followed by tissue homogenization and centrifugation in a buffering solution. The results of this study confirm that injected fat grafts survive long-term; however, the average volumetric "take" was only about 20%. Surprisingly, significantly more liposuctioned fat survived than grafts prepared by the purification method (P < .05). At 12 weeks, there was relatively little inflammation present in the tissues surrounding the injected fat, suggesting a stable fat graft volume. PMID- 7837909 TI - A tissue-culture model for the study of canine vocal fold fibroblasts. AB - A tissue-culture model has been developed for the study of fibroblasts from the canine vocal fold. Laryngeal tissue (lamina propria) obtained from euthanized dogs is rinsed, cut into 1-mm3 pieces, and incubated in 5% carbon dioxide at 37 degrees C. A confluent monolayer is established within several days. Detectable levels of elastin in the tissue culture supernatant are measured by an indirect enzyme-linked immunosorbent assay. Various external agents have been shown to affect elastin production. The effects of KTP laser irradiation, hydrocortisone (1.3 mumol/L), transforming growth factor-beta (10 ng/mL), and human leukocyte elastase have been measured. Thus the canine vocal fold fibroblast tissue culture is established as a model for further investigations to improve wound healing and to understand the wound-healing process following laryngeal microsurgery. PMID- 7837910 TI - Amplification of mitochondrial DNA from archival temporal bone specimens. AB - Archival temporal bone collections are an invaluable resource for studying the molecular genetics of many types of otopathology. The irreplaceable nature of temporal bone sections makes efficiency of DNA extraction of paramount importance. Several protocols are available for extracting DNA from fresh and preserved tissue. To establish the best protocol for reliably extracting DNA from celloidin-embedded temporal bone sections, a variety of DNA extraction techniques were tested. Using the optimum protocol, mitochondrial DNA fragments ranging in size from less than 100 base pairs to more than 400 base pairs were amplified, and the authenticity of polymerase chain reaction (PCR) products was confirmed through comparative sequence analysis. PMID- 7837911 TI - Laryngeal function in postpolio patients. AB - Of the 250,000 survivors of the polio epidemics, approximately 25% experience progressive muscle weakness known as postpolio syndrome (PPS). Laryngeal function in postpolio patients previously has not been studied. This paper presents data detailing laryngeal function in a group of postpolio patients who had been evaluated for swallowing complaints. Nine patients underwent comprehensive history and physical exam, acoustical voice analysis, and laryngeal videostroboscopic endoscopy. Three patients underwent laryngeal electromyography (EMG) evaluation. Results indicated some degree of phonatory or laryngeal deficit in all subjects. Subjects with dysphagia also demonstrated vocal fold paralysis. EMG revealed decreased recruitment and increased amplitude, findings consistent with EMG studies in skeletal muscle in postpolio patients. Results suggest that postpolio patients who complain of swallowing difficulties are at risk for laryngeal pathology. PMID- 7837912 TI - Qualitative and quantitative immunoglobulin production by specific bacteria in chronic tonsillar disease. AB - Tonsillar tissue lymphocyte (TTL) function as measured by immunoglobulin production was assessed in vitro in 60 tonsils, 51 diseased and 9 normal controls. The diseased specimens were from children (aged 3 to 10 years) clinically classified as having recurrent tonsillitis (RT), idiopathic tonsillar hyperplasia (ITH), or recurrent tonsillitis with hyperplasia (RT/H). TTLs were challenged with intact, heat-inactivated bacteria found in the core of diseased tonsils--Streptococcus pyogenes (SP) and Haemophilus influenzae type B (HIB) as well as the dominant bacterium (DB) grown from that particular tonsillar core. The phytomitogen, leukoagglutinin (LA), was used as a nonspecific activator. Qualitative immunoglobulin production was assessed for the immunoglobulin G (IgG), immunoglobulin M (IgM), and immunoglobulin A (IgA) classes. Immunoglobulin specific production was quantified at the basal level, and at 2, 4, and 6 days following stimulation. Stimulation with HIB produced the greatest amount of IgG and IgM in TTLs from control tonsils. The DB was a relatively weak stimulator of normal (control) TTLs, yet produced relatively brisk IgG responses in the RT and ITH categories. It did, however, yield only marginal IgM secretion in these groups. IgA was consistently produced after stimulation in diseased TTLs, yet was not elicited from normal TTLs. The aforementioned findings suggest a differential qualitative and quantitative immunoglobulin response for healthy, recurrently infected, and hyperplastic tonsils. Lymphocyte hypofunction along with structural changes associated with hyperplasia may be central to the etiology of chronic tonsillar disease. The tonsillar immunologic response in disease and health is discussed. PMID- 7837913 TI - Endoscopic diode laser welding of mucosal grafts on the larynx: a new technique. AB - Epithelial coverage of a laryngotracheal wound is an important factor in preventing stenosis, and endoscopic transplantation of a free mucosal graft without stents or sutures would be a significant therapeutic advance. In vitro and in vivo canine studies were performed to explore the feasibility of transplantation with a low-power diode laser (400 mW) enhanced by indocyanine green dye-doped albumin. The tensile strength of graft adherence in 10 cadaver larynges was strong (35.25 +/- 10.39 g). Survival studies in live canine models with a specially designed endoscopic instrument set showed excellent healing at 6, 14, and 28 days. Healing was documented with photography and by histologic examination. Successful endoscopic transplantation of a free mucosal graft should improve results of treatment for laryngotracheal stenosis and laryngeal reconstructive surgery. PMID- 7837914 TI - Transoral laser resection with staged discontinuous neck dissection for oral cavity and oropharynx squamous cell carcinoma. AB - Transoral laser resection of oral cavity and oropharynx squamous cell carcinoma (OOSCC) is a widely accepted approach in the absence of cervical lymph node metastases. This study investigated the results of transoral laser surgery and discontinuous neck dissection (ND) for OOSCC with clinically obvious or suspected cervical node metastases. One hundred seventeen patients with infiltrating oral carcinoma were treated for cure with transoral resection of the primary and staged ND. Twenty-nine primaries were classified as T1, 50 as T2, 35 as T3, and 3 as T4. Lymph node metastases were identified in the ND specimen of 36 patients. All patients were followed for a minimum of 3 years unless they died. Estimated tumor-related survival after 5 years is 81% for stage I and II disease of the oral cavity, 86% for stage I and II disease of the oropharynx, 73% for stage III disease of the oral cavity, 65% for stage III disease of the oropharynx, and 21% for stage IV disease of the oral cavity and the oropharynx. Local and regional control of cancer was achieved in 72 (62%) of the 117 patients. Forty-five local and regional recurrences were diagnosed during the follow-up period. Two patients died of distant metastases with no evidence of local or regional recurrence. The combination of transoral laser resection and staged ND for the treatment of OOSCC seems to offer satisfactory cure rates for a selected group of patients. These two minor surgical interventions cause less morbidity than commando-type surgery and lead to low perioperative mortality and morbidity. PMID- 7837915 TI - Prognostic significance of prostaglandin E2 production by mononuclear cells and tumor cells in squamous cell carcinomas of the head and neck. AB - Prostaglandin E2 (PGE2) has been implicated as a cause of immunosuppression in patients with head and neck cancer. To determine the relative contribution of tumor cells and mononuclear cells to PGE2 levels in vivo, tumor cells and tumor infiltrating mononuclear cells (TIMC) were isolated from fresh tumor biopsy specimens of 23 patients with squamous cell carcinoma of the head and neck (SCCHN) by using enzymatic digestion and differential gradient centrifugation. Peripheral blood mononuclear cells (PBMC) and lymph node mononuclear cells (LNMC) from metastatic and nonmetastatic lymph nodes were also isolated. Cell fractions were cultured for 24 hours, and PGE2 levels of supernatant were determined by radioimmunoassay. PGE2 production by LNMC was significantly decreased compared to tumor cells, TIMC, and PBMC (P = .0002). LNMC from metastatic lymph nodes produced significantly higher levels of PGE2 (P = .02) compared to nonmetastatic lymph nodes. Although T stage was not correlated with PGE2 production by TIMC or tumor cells, advanced N stage (N1-3) was associated with decreased PGE2 production by TIMC (P = .006). These results suggest that both tumor cells and TIMC are sources of PGE2 in tumor tissues of patients with SCCHN and that decreased PGE2 production by host inflammatory cells may have clinical significance in the development of cervical metastases. PMID- 7837916 TI - Human papillomavirus (HPV) in sinonasal papillomas: a study of 78 cases using in situ hybridization and polymerase chain reaction. AB - To determine the role of human papillomavirus (HPV) in the etiology of sinonasal papillomas, 57 inverted papillomas including 5 cases associated with carcinomas, 16 exophytic papillomas, and 5 cases of columnar cell papillomas were examined for the presence of HPV DNA by in situ hybridization and polymerase chain reaction (PCR). The genetic studies were performed on the formalin-fixed, paraffin-embedded material. In only 6% of the 52 benign inverted papillomas was HPV DNA identified, whereas 69% of the exophytic papillomas were infected by HPV DNA. In none of the 5 cases with columnar cell papillomas could HPV be demonstrated. HPV 6/11 was identified in all of these HPV-positive cases. In the carcinoma area, HPV was detected in 2 (1 HPV 6/11 and 1 HPV 18) of the 5 inverted papillomas associated with carcinomas. The findings confirm the presence of HPV DNA in sinonasal papillomas. The results also indicate that HPV 6/11 may be involved in the pathogenesis of, solely, exophytic papillomas. We found that in situ hybridization and PCR seem equally sensitive in detecting HPV in sinonasal papillomas. PMID- 7837917 TI - Sinonasal papillomas: a report of 82 cases in Copenhagen County, including a longitudinal epidemiological and clinical study. AB - The present epidemiological and clinical study comprises 82 patients with sinonasal papillomas diagnosed from 1975 to 1993. Histology showed 58 cases of inverted papillomas including 5 cases of associated carcinoma, 19 cases of exophytic papilloma, and 5 cases of columnar cell papilloma. The incidence of sinonasal papillomas in Copenhagen County was 0.74 per 100,000 inhabitants per year. The inverted and columnar cell papillomas were typically located in the middle meatus with a varying degree of involvement of the adjacent sinuses. The exophytic papillomas were predominantly located multicentrically on the nasal septum. Good results of treatment, especially with regard to inverted papillomas, were not correlated to the aggressiveness of surgery. A lateral rhinotomy with medial maxillectomy was performed as primary surgery in 28 patients. In 50% of these patients there were recurrences. The preliminary results of endonasal endoscopic surgery revealed a high success rate, i.e., no recurrences in 5 cases so far. The septal papillomas were typically resected by a simple endonasal procedure. There were recurrences in 66% of these cases. The midfacial degloving procedure may be advocated instead of or as a supplement to the lateral rhinotomy if the tumor cannot be visualized sufficiently by endoscopy. Smoking may dispose to sinonasal papillomas. PMID- 7837918 TI - Management of traumatic hypopharyngeal injuries. AB - Violation of the hypopharynx by external penetrating trauma is an uncommon occurrence that may lead to life-threatening infectious complications if not recognized promptly and treated appropriately. A retrospective review of 48 such injuries seen during a 10-year period showed that flexible fiberoptic endoscopic examination is the best screening tool for recognition of a possible hypopharyngeal mucosal violation. Direct laryngopharyngoscopy is the best method of definitively diagnosing the injury. Size of the visualized mucosal violation alone is not sufficient information on which to base the decision for medical management versus surgical intervention (i.e., immediate exploration and drainage). Rather, the size, exact site of injury, and mechanism of the injury must be considered to have equal importance. Associated vertebral body fractures may negatively influence acute outcome if diagnosis and treatment of the hypopharyngeal injury are delayed by the cervical spine injury. PMID- 7837919 TI - Parotid duct transposition for xerophthalmia and facial paralysis. PMID- 7837920 TI - Laryngotracheal separation for intractable aspiration: a retrospective review of 34 patients. AB - LTS is an effective surgical procedure that results in the elimination of intractable aspiration. Most of these patients have major neurologic impairment due to progressive neurologic disease or devastating injury secondary to stroke, trauma, or surgery. The procedure can be performed in ill, debilitated patients and is well tolerated, even with local anesthesia. Few patients lose communicative speech, and some patients gain the ability to swallow following the procedure. LTS should be considered in the management of patients with intractable aspiration before performance of a tracheotomy because the procedure is technically easier to perform at this time and may reduce the risk of a wound healing complication. Postoperative nursing care is decreased, and most patients can be discharged or transferred to a chronic-care facility within 2 to 3 weeks following the procedure. PMID- 7837921 TI - Nasal obstruction in the neonate secondary to nasolacrimal duct cysts. PMID- 7837922 TI - Reconstruction of the floor of the mouth by means of an anteriorly based buccinator myomucosal island flap. PMID- 7837923 TI - Surgical management of the head and neck cancer patient following concomitant multimodality therapy. AB - The simultaneous use of chemotherapy and radiotherapy (concomitant therapy) has exceptional promise in the treatment of head and neck cancer. In this limited review, seven head and neck cancer patients who underwent prior concomitant therapy and subsequent surgery developed wound-healing complications that were delayed (22-day average) in onset. Paranasal sinus and base of skull operations had less significant wound morbidity than those cases requiring simultaneous transgression of the neck and upper aerodigestive tract. The use of arterialized flaps did not in itself prevent wound breakdown. The formation of controlled fistulae, delay of reconstruction, and avoidance of simultaneous neck and upper aerodigestive tract entry are important considerations in avoiding wound-healing complications after concomitant therapy. In this select group of patients, surgery should be approached with extreme caution and conservatism. PMID- 7837924 TI - U-73122 inhibits carbachol-induced increases in [Ca2+]i, IP3, and insulin release in beta-TC3 cells. AB - We studied the effects of the aminosteroid U-73122, a putative phospholipase C (PLC) inhibitor, on carbachol-induced increases in insulin release, [Ca2+]i, and IP3 in beta-TC3 cells. Carbachol (0.1-100 microM) increased [Ca2+]i and carbachol (0.1-1000 microM) increased insulin release dose-dependently. Carbachol (100 microM) also increased inositol 1,4,5-trisphosphate (IP3) production. U-73122 (2 12 microM) inhibited the effects of carbachol on [Ca2+]i and insulin release in a dose-dependent manner, and at the highest dose studied (12 microM) it abolished or greatly attenuated all three effects of carbachol. In contrast, U-73343 (12 microM), the analog of U-73122 that does not inhibit PLC, only inhibited the effect of carbachol on [Ca2+]i by 20%, and did not inhibit the effect of carbachol on insulin release. Since carbachol increases IP3, [Ca2+]i, and insulin release by activating PLC, these results suggested that U-73122 inhibits phospholipase C-dependent processes in beta-TC3 cells. PMID- 7837925 TI - Stimulatory effect of angiotensin II on calcium efflux from cultured bovine adrenal chromaffin cells. AB - The effect of angiotensin II on Ca2+ mobilization in cultured bovine adrenal chromaffin cells was examined. Angiotensin II (10(-7)M) increased the intracellular free Ca2+ level ([Ca2+]i) to a peak in the presence or absence of extracellular Ca2+, followed by decrease with time. Angiotensin II (10(-9)-10( 6)M) also stimulated 45Ca2+ efflux from cultured bovine adrenal chromaffin cells in a concentration-dependent manner. Its stimulatory effect on 45Ca2+ efflux was inhibited by the angiotensin II antagonist [Sar1, Ile8]-angiotensin II or [Sar1, Val5, Ala8]-angiotensin II. The increase in angiotensin II-stimulated 45Ca2+ efflux was dependent on the extracellular Na+ concentration. Angiotensin II also increased 22Na+ influx into the cells. These results indicate that stimulation of the angiotensin II receptor induces extracellular Na(+)-dependent Ca2+ efflux from cultured bovine adrenal chromaffin cells, probably by acceleration of Na+/Ca2+ exchange. PMID- 7837926 TI - Decreased spinal morphine/clonidine antinociceptive synergism in morphine tolerant mice. AB - The antinociceptive interactions between spinally administered opioids and the alpha 2 agonist clonidine were examined in placebo and morphine pellet-implanted mice using the tail flick test. In placebo pellet-implanted animals, coadministered morphine and clonidine produced a synergistic antinociceptive effect. In mice implanted with morphine pellets, the synergism decreased to an additive interaction. The interactions between clonidine and the mu agonist Tyr-D Ala-Gly-N-Me-Phe-Gly-ol (DAMGO), the delta agonist D-Pen2-D-Pen5-Enkephalin (DPDPE), and the kappa agonist U50-488H were also synergistic in placebo pelleted animals. In morphine pellet treated mice the DPDPE/clonidine interaction decreased to an antagonistic interaction, the DAMGO/clonidine remained synergistic and the U50-488H/clonidine interaction decreased to additive. These results support the proposal that the morphine spinal/supraspinal synergism depends upon the interaction between spinal opioid and alpha 2 receptors and a decrease in this interaction is a mechanism involved in development of tolerance to morphine. In addition, delta and kappa receptors appeared to be more involved in the morphine/clonidine decrease interaction than did mu opioid receptors. PMID- 7837927 TI - Oxyhemoglobin enhancement of vasopressin-induced constriction in rat cerebral arterioles. AB - This study was undertaken to determine the effects of oxyhemoglobin on vasopressin-induced responses in cerebral arterioles. Rat intracerebral arterioles about 60 microns in diameter were isolated and cannulated using pipettes. Changes in diameter secondary to the extraluminal application of drugs were monitored through a video micro-scaler. Vasopressin produced a triphasic, dose-dependent response consisting of vasodilation (10(-11) M), vasoconstriction (10(-9)-10(-8) M) and a decrease in vasoconstriction (10(-7)-10(-6) M). Pretreatment with oxyhemoglobin (10(-5) M) abolished the vasodilation induced by the lower dose vasopressin and doubled the vasoconstriction induced by the higher dose. The combination of L-arginine (10(-4) M) and superoxide dismutase (600 U) restored low-dose vasopressin vasodilation and suppressed high-dose vasoconstriction in oxyhemoglobin-pretreated arterioles, while they showed little effect when used singly. This study indicates that oxyhemoglobin enhances vasopressin-induced constriction of intracerebral arterioles and these effects can be inhibited by the combination of L-arginine and superoxide dismutase. PMID- 7837928 TI - Human small cell lung cancer cells express high affinity naloxone-insensitive [125I]-endorphin binding sites. AB - Previous reports have demonstrated that beta-endorphin stimulates the clonal growth of human small cell lung carcinoma (SCLC) cell lines. In this study, the human SCLC lines, NCI-H69, NCI-H345, and NCI-N417, were observed to be highly enriched in saturable, high-affinity binding sites which are labeled by [125I]beta-endorphin. In contrast to conventional opioid receptors, [125I]beta endorphin SCLC binding was insensitive to naloxone and other mu, delta, or kappa opioid ligands. Further analysis of the NCI-H69 cells demonstrated that specific (naloxone-insensitive) binding was dependent on receptor concentration, reversible, sensitive to sodium ion, but insensitive to the GTP analogue, Gpp(NH)p. These results suggest a role for naloxone-insensitive beta-endorphin in modulating SCLC metabolism. PMID- 7837929 TI - Tetrandrine: a new ligand to block voltage-dependent Ca2+ and Ca(+)-activated K+ channels. AB - Extensive pharmacological investigations on tetrandrine, one of the traditional medicinal alkaloids, are reviewed. Tetrandrine has been used clinically in China for centuries in the treatment of many diseases. A recent series of studies has revealed major mechanisms underlying its multiple pharmacological and therapeutic actions. One of the most interesting discoveries is that tetrandrine is a new kind blocker of the voltage-activated, L-type Ca2+ channel in a variety of excitable cells, such as cardiac, GH3 anterior pituitary and neuroblastoma cells, as well as in rat neurohypophysial nerve terminals. Although tetrandrine does not belong to any of the three classical Ca2+ channel blocker groups, electrophysiological and radioligand binding studies show that tetrandrine is an L-type Ca2+ channel blocker with its binding site located at the benzothiazepine receptor on the alpha 1-subunit of the channel. In addition, tetrandrine is a blocker of the voltage-dependent T-type Ca2+ channel. It is clear that tetrandrine's actions in the treatment of cardiovascular diseases, including hypertension and supraventricular arrhythmia, are due primarily to its blocking of voltage-activated L-type and T-type Ca2+ channels. Furthermore, this alkaloid is a potent blocker of the Ca(2+)-activated K+ (K(Ca)) channels of neurohypophysial nerve terminals. The blocking kinetics of tetrandrine on the K(Ca) channel is quite different from that of typical K(Ca) channel blockers such as tetraethylammonium and Ba2+. Although the clinical role of tetrandrine as a blocker of the K(Ca) channels is unclear, it is a promising ligand for the study of K(Ca) channel function. PMID- 7837930 TI - Expression of the peroxisome proliferator-activated receptor gene is decreased in experimental alcoholic liver disease. AB - Peroxisome proliferator-activated receptor (PPAR) and retinoid x receptor (RXR) play important roles in fatty acid metabolism. The present study examined the regulation of retinoic acid receptor (RAR alpha, beta, and gamma), RXR (alpha, beta, and gamma), PPAR, cytochrome P450 2E1 (CYP2E1), catalase, and beta-actin gene expression in chronic alcoholic liver disease in the rat. The results demonstrated that the expression of genes for RAR and RXR isoforms and catalase were not altered by ethanol in the fatty liver. In contrast, the levels of PPAR and CYP2E1 mRNAs were down- and up-regulated by ethanol in the liver, respectively. The levels of CYP2E1 mRNAs correlated positively with blood alcohol levels (BAL). In addition, ethanol induced expression of beta-actin mRNA was also proportional to the BAL. The level of PPAR mRNA and the content of polyunsaturated fatty acid decreased in ethanol-fed rat livers. Decreased PPAR gene expression in ethanol-fed rats might result from a decrease in the content of polyunsaturated fatty acid in the liver. However, the activities of enzymes involved in hepatic lipid metabolism, including acyl CoA synthetase, acyl CoA oxidase, catalase, and protein kinase C, were not changed by ethanol treatment. The significance of down-regulation of PPAR gene in alcohol liver disease is discussed. PMID- 7837931 TI - A multiple-dose safety trial of eptastigmine in Alzheimer's disease, with pharmacodynamic observations of red blood cell cholinesterase. AB - A placebo-controlled multiple dose study was conducted to evaluate the safety, tolerability, and pharmacodynamics of multiple dose levels of eptastigmine in 25 patients with probable Alzheimer's disease (AD). Twenty patients (12 M, 8 F; mean age 74, range 57-84) were randomized to receive 12mg (N = 3), 20mg (N = 6), 28mg (N = 6) or placebo (N = 5) tid on a double-blind basis for 14 days, followed by seven days of single blind placebo, in successively rising dose groups. All patients completed the study without intolerable or severe adverse events. All doses significantly (p < 0.001) reduced peak and trough RBC cholinesterase (AChE) activity as compared to baseline. Percent inhibition for Day 14 peak and trough RBC AChE peak and trough values, respectively, appeared proportional to dose: 18% and 21% (12mg); 36% and 35% (20mg); 40% and 44% (28mg). In order to determine the maximum tolerated dose of eptastigmine, an additional single-blind study was performed in five patients (2 M, 3 F; mean age 78, range 72-80) utilizing a rising dose schedule of eptastigmine (N = 4) or placebo (N = 1), starting with the previously tolerated 28mg tid dose and increasing by 4mg tid up to a potential maximum of 56mg tid. Dose-limiting adverse events occurred requiring discontinuation of medication in one patient at 48mg tid and two patients at 52mg tid; RBC AChE inhibition was proportional to dose, with peak values up to 70% inhibition at 48mg tid. The maximum tolerated dose of 48mg tid was identified as a basis for potential Phase II multicenter efficacy trials. PMID- 7837932 TI - Serotonin-induced platelet calcium mobilization is enhanced in mania. AB - The time-course of 5-HT-induced intracellular Ca2+ mobilization in platelets displays biphasic curves; a rapid peak occurs within 10 sec, followed by a prolonged plateau phase. In platelets of patients with affective disorders, many reports have suggested that there is an increase in the rapid peak in intracellular Ca2+ mobilization, but there is no report concerning the plateau phase in intracellular Ca2+ mobilization. We, then, assessed the time course of 5 HT-induced Ca2+ mobilization to compare untreated manic patients with euthymic bipolar disorders and normal subjects. Not only peak amplitude but also plateau phase were more significantly enhanced in the platelets of untreated manic patients than in those of normal controls. These results suggest that the serotonergic neural transmission by means of intracellular Ca2+ was enhanced by the prolonged plateau phase as well as by increased peak amplitude in platelets of mania. The enhanced rapid peak and plateau phase in untreated bipolar mania were restored to their control levels in treated euthymic bipolar disorders. These findings suggest that the reduction of the enhancement in Ca2+ mobilization might be related to either the effects of chronic treatment with lithium or the affective states of the patients. PMID- 7837933 TI - Mode of action of bullatacin, a potent antitumor acetogenin: inhibition of NADH oxidase activity of HeLa and HL-60, but not liver, plasma membranes. AB - Bullatacin, a potential antitumor substance isolated from plants of the Annonaceae, and analogs of bullatacin, known collectively as acetogenins, have been reported previously to show potent activity in the inhibition of growth of murine tumors and human tumor xenografts grown in athymic mice as well as an ability to inhibit mitochondrial electron transport. In this report, we show activity of bullatacin in inhibition of NADH oxidase activity of plasma membrane vesicles isolated from HeLa cells and HL-60 cells but not with plasma membrane vesicles isolated from rat livers which, unlike the inhibition of mitochondrial activity, correlated with the ability of the acetogenins to kill tumor cells. Additionally, bullatacin is active against HL-60 cells that are resistant to adriamycin which may suggest utility for bullatacin in management of drug resistant cells and cell lines. PMID- 7837937 TI - The role of doctorally prepared nurses and clinical practice. PMID- 7837936 TI - MNA presents testimony on nursing staffing before Institute of Medicine. PMID- 7837935 TI - The major histocompatibility complex: its genes and their roles in antigen presentation. PMID- 7837938 TI - Gerontological nursing offers new opportunities. PMID- 7837934 TI - Aminooxy analogues of spermidine evidence the divergent roles of the charged amino nitrogens in the cellular physiology of spermidine. AB - Two recently devised spermidine analogues, N-[2-aminooxyethyl]-1,4-diaminobutane (AOEPU) and 1-aminooxy-3-N-[3-aminopropyl]-aminopropane (APAPA), were used to elucidate the role of charge distribution in the functions of spermidine in cultured baby hamster kidney cells. The drugs did not affect cell proliferation nor did they relieve the growth-arrest but potentiated the metabolic disturbances caused by DL-alpha-difluoromethyl-ornithine (DFMO). Neither drug affected spermidine uptake but both competed with putrescine uptake. Neither drug could replace spermidine in the control of S-adenosylmethionine decarboxylase and accumulation of the reaction product. APAPA prevented spermine synthesis and showed that modest putrescine synthesis take place in the presence of DFMO. AOEPU, but not APAPA, interfered with cellular constituents resulting in enzymatic formation, accumulation and excretion to culture medium of UV-absorbing catabolites. PMID- 7837939 TI - New regulations for delivery of health care services to Medicaid-enrolled children. PMID- 7837940 TI - Patient safety meeting draws over 200 MNA members. PMID- 7837941 TI - Nursing's response to domestic violence. MNA Task Force on Domestic Violence. PMID- 7837942 TI - Domestic violence resource list. PMID- 7837943 TI - Identifying abuse in the home by listening to the children. PMID- 7837944 TI - Managed care: the shape of things to come. Information--impact--strategies. PMID- 7837945 TI - Assessing victims of domestic violence: what are the "PITFALLS"? PMID- 7837946 TI - Responding to violence in acute care settings. PMID- 7837947 TI - A call for political action. PMID- 7837948 TI - The effect of exercise on serum and salivary cortisol in male children. AB - The purpose of this study was to examine serum and salivary cortisol responses to cycling exercise in male children, 10.6 +/- 0.2 yr (mean +/- SE). Each child performed a graded exercise test on a cycle ergometer to determine VO2max. On a separate day, a 30-min bout of exercise at 70% of VO2max was performed. Blood, obtained from a venous catheter, and saliva samples were collected at rest, at 15 and 30 min of exercise, and 15 min post-exercise. The mean serum cortisol level at 15 min (7.94 +/- 1.43 micrograms.dl-1) and 30 min (8.72 +/- 1.77 micrograms.dl 1) of exercise and at 15 min post-exercise (8.21 +/- 1.59 micrograms.dl-1) were significantly greater than rest (5.54 +/- 0.86 micrograms.dl-1). The increase in salivary cortisol levels over time approached (P = 0.08), but did not reach significance. However, effect size analyses indicated that the increase in salivary cortisol at 30 min of exercise (0.64) and 15 min post-exercise (0.62) was similar to the change in serum cortisol at these same two time points (0.72 and 0.66, respectively). Serum and salivary cortisol were correlated (P < 0.05) at 15 min of exercise (r = 0.77), 30 min of exercise (r = 0.90), and 15 min post exercise (r = 0.84), but not at rest (r = 0.46). In conclusion, 30 min of submaximal exercise at 70% of VO2max significantly increased serum cortisol level; and salivary and serum cortisol are correlated during and after exercise. PMID- 7837949 TI - Indomethacin potentiates exercise-induced reduction in renal hemodynamics in athletes. AB - Nonsteroidal anti-inflammatory drugs (NSAID) are frequently used in sports medicine but few studies have documented their potential importance in modifying exercise-induced changes in renal function. The effects of indomethacin (50 mg orally every 8 h for 36 h) on renal blood flow (RBF) and glomerular filtration rate (GFR) were investigated in eight fit healthy males (age 21-42) before and after 30-min treadmill exercise at 80% VO2max and during 120-min recovery. Each volunteer served as their own control. There were no differences between control and indomethacin for the resting values of RBF, GFR, or renal vascular resistance (RVR). Using analysis of variance for repeated measures, indomethacin produced a significant reduction in RBF compared with control (P = 0.009) that was associated with a significant elevation in RVR (P = 0.027). Changes in GFR mirrored the changes in RBF but differences failed to reach statistical significance. These results suggest that with sustained exercise indomethacin can compromise renal function and potentiate the risk of developing acute renal failure. Indomethacin and other NSAID are widely used in the sports arena, and athletes should be warned of the potential danger of their use when renal function may be compromised. PMID- 7837950 TI - Comparable effects of diet and exercise on body composition and lipoproteins in older men. AB - Changes in body composition, fat distribution and lipoprotein lipids in response to weight loss elicited by a 10-month program of hypocaloric diet (HD) therapy alone or combined with aerobic exercise training (AEX+HD) were examined in sedentary obese older males. Body composition was assessed by hydrodensitometry and fat distribution was evaluated with skinfold thickness and circumference measures. The HD group underwent a dietary/behavioral modification program to reduce caloric intake. The AEX+HD group underwent a similar dietary modification program combined with aerobic exercise training. Following completion of the study, 15 subjects from each group were individually pair matched based on age (57.1 +/- 1.7 vs 61.3 +/- 2.4 yrs) and their reduction in body mass (-7.6 +/- 1.3 vs -8.0 +/- 1.1 kg). Reductions in fat and fat-free mass and skinfold thickness and circumferences were similar in both groups. In both the AEX+/HD and HD groups there were significant reductions in the ratio of low-density lipoproteins to high-density lipoproteins (HDL-C) and triglycerides and a significant increase in HDL2-C. There were no differences in final values or absolute and relative changes in the various lipoprotein values between the two groups. These results suggest weight loss induced by diet alone or combined with aerobic exercise cause similar changes in body composition and lipoprotein lipids. PMID- 7837951 TI - Glucose metabolism and radioactive labeling: what are the real dangers? PMID- 7837952 TI - Characterization of VO2 kinetics during heavy exercise. AB - Characterizing oxygen uptake (VO2) kinetics yields valuable information regarding both a) the effectiveness of the coupling of O2 delivery to tissue metabolic demands, and b) the ability of the muscle itself to utilize O2 for oxidative phosphorylation. During moderate exercise VO2 reaches a new steady state within 3 min in normal subjects, with little or no sustained rise in blood lactate. The steady state VO2 increases linearly with work rate. The time constant for VO2 in Phase 2 (after first 15-20 s) is constant across work intensities, and appears to reflect muscle oxygen utilization kinetics. However, when heavier exercise is performed, which elevates blood lactate throughout the exercise, the VO2 response becomes more complex. The predominant, Phase 2 response continues to rise exponentially with about the same time constant as for moderate exercise, and the amplitude continues to be linearly related to work rate. However, an additional, slowly developing rise in VO2 is also usually observed, beginning 100-200 s into exercise. This additional VO2 delays attainment of a steady state, increases the overall O2 "cost" of the exercise, and is statistically associated with the rate and magnitude of increase in blood lactate. Interestingly, in children, neither the slow component nor blood lactate rise as much during heavy exercise. PMID- 7837953 TI - Role of exercising muscle in slow component of VO2. AB - This paper: 1) Reviews evidence for the location of the slow component of VO2 kinetics either within the exercising limbs or alternatively at some site in the rest of the body, e.g., ventilatory, cardiac or accessory muscles. 2) Presents evidence in support of both the fast and slow components (i.e., < 3 min and > 3 min from exercise onset, respectively) of the exercise VO2 response residing predominantly in the exercising muscle. For a pulmonary VO2 slow component in excess of 600 ml O2.min-1, more than 80% could be attributed to an augmented VO2 across the exercising limbs. 3) Assesses the potential for the lactate ion per se to exert a metabolic stimulatory effect in exercising muscle in the absence of the potentially confounding influences of changes in muscle temperature, H+, blood flow or O2 delivery. Within the surgically isolated, electrically stimulated canine gastrocnemius, square wave infusions that increased arterial blood [lactate] by approximately 10 mM and intramuscular [lactate] to in excess of 9 mM did not increase muscle VO2. In summary, these investigations demonstrate that the exercising muscle is the predominant site of the VO2 slow component. However, despite the close temporal association between changes in blood lactate and VO2 during intense exercise, lactate itself does not mandate an additional VO2 demand in exercising dog muscle. PMID- 7837954 TI - Influence of endurance training and catecholamines on exercise VO2 response. AB - For constant-load, heavy exercise (i.e., above the lactate threshold (TLac)), a slow component of oxygen uptake (VO2) is observed. Endurance training reduces the magnitude of the slow component and, hence, end-exercise VO2. Reductions in exercise VO2 have been reported after 7-8 wk of training; unpublished observations suggest that the VO2 slow component may be attenuated after just 2 wk of training. A minimum training intensity for eliciting reductions in constant load exercise VO2 has not been established; however, in the elderly, training at an intensity below TLac resulted in similar reductions in exercise VO2 as did training above TLac. Mechanisms responsible for the reduced slow component of VO2 after training remain to be firmly established. Evidence both for and against blood lactate concentration ([L-]) as a mediator of the slow component has been published; high correlations between [L-] and the slow component, and between the training-induced reductions in these variables, appear to be more coincidental than causal. Decreased pulmonary ventilation after training may account for between 14% and 30% of the reduction in the slow component of VO2. Epinephrine infusion does not augment exercise VO2, nor does beta-adrenergic blockade diminish the magnitude of the slow component of VO2. PMID- 7837955 TI - Mitochondrial function during heavy exercise. AB - Maximal rates, coupling, and control of oxidative phosphorylation were studied in isolated skeletal muscle mitochondria from rat and rabbit. Mitochondria were incubated under various conditions of temperature, pH, and substrate availability. A 20% decrease in coupling (ADP/O) was observed at 43 degrees C as compared to 37 degrees C in rat mixed skeletal muscle mitochondria. Changes in pH from 7.00 to 6.20 affected neither coupling nor maximal (state 3) respiration rates. Changing the substrate supply from pyruvate to palmitoyl-carnitine (+ malate) did not alter ADP/O, but markedly degraded the energy state sustained at submaximal ATP turnover. Thus, carbohydrate depletion may be associated with inhibition of contractile function and the recruitment of less economical higher threshold motor units. State 3 respiration of mitochondria from rabbit Type IIb fibers oxidizing pyruvate+malate+alpha-glycerophosphate was 27% higher than that of mitochondria from Type I rabbit skeletal muscle. However, the ADP/O ratio in the Type IIb preparation was 18% lower. The experimental findings suggest that temperature, substrate supply, and energetic differences between slow twitch and fast twitch motor units may impact the economy of mitochondrial oxygen utilization during heavy aerobic exercise, and thus contribute to the slow component of oxygen uptake. PMID- 7837956 TI - VO2 slow component: physiological and functional significance. AB - This paper offers a brief synopsis of the five preceding papers which constitute the proceedings of the symposium "Mechanistic basis of the slow component of VO2 kinetics during heavy exercise." The key features have been taken from each paper and a coherent position regarding the site and potential underlying mechanisms for the "excess" VO2 is presented. The hypothesis is developed that some aspect of fiber type recruitment patterns might be responsible for this phenomenon. Elucidation of the precise determinants of VO2 during heavy exercise is fundamental to our understanding of muscle energetics. Furthermore, certain patient populations, whose exercise tolerance is limited by impaired cardiovascular and/or respiratory capacity, may benefit from interventions designed to constrain the magnitude of the VO2 slow component. PMID- 7837957 TI - Tendon force measurements and movement control: a review. AB - Knowledge of the mechanical and electrical output from skeletal muscle is of interest to investigators from several disciplines including physiology, biomechanics, neuroscience, orthopedics, and physical rehabilitation. Estimates of muscle output (i.e., force) have generally been made using indirect calculations. Forward solution (e.g., EMG) and optimization models have recently been developed using a wide variety of input parameters to estimate force output of individual muscles. These estimates, however, have lacked comparison values necessary for validation. In vivo measurements of muscle force have been made in both animals and humans using a "buckle" type tendon transducer surgically implanted on the tendons of the muscles under study. Investigations utilizing these transducers have addressed a wide range of questions regarding muscle function. This review examines the use of this technology and discusses the significance of the future use of "buckle" transducers in studies exploring load sharing among muscles and in the validation of existing models that estimate muscle force. PMID- 7837958 TI - Wheelchair propulsion efficiency: movement pattern adaptations to speed changes. AB - Low mechanical efficiency values in wheelchair propulsion are usually explained on the basis of the supply of force and power generated during the push phase. The purpose of this study is to analyze the movement and muscular activity pattern in handrim wheelchair propulsion, focusing on both the push and recovery phases. Data on cardiorespiratory and propulsion technique parameters were obtained from 40 wheelchair basketball players with extensive experience in wheelchair propulsion in six situations: two exercise levels (60% and 80% of individual VO2peak), and three velocities (1.11, 1.67, and 2.22 m.s-1) with constant power output on a treadmill. A two-factor analysis of variance with repeated measurements was applied with "exercise level" and "speed" as the main factors. A significant effect on gross mechanical efficiency was found when the velocity was increased from 1.67 to 2.22 m.s-1. Decreased mechanical efficiency could be explained by a significant change in the acceleration of the wheelchair user system during recovery, caused by arm and trunk movements, inducing inertial forces to act on the wheelchair. Consequently, mechanical work increased significantly during the recovery phase. These findings indicate that studies on mechanical efficiency in wheelchair propulsion should not only be focussed on power supply during the push phase, but also on the movement pattern during recovery. PMID- 7837959 TI - The measurement conundrum in exercise adherence research. AB - This paper has two purposes. It first prefaces a symposium titled "Exercise adherence and behavior change: prospects, problems, and future directions." The symposium describes the progress made during the past 5 years toward understanding the adoption and maintenance of physical activity and exercise. Specifically, research is discussed that has tested the applicability to physical activity of four psychological models of behavior: Reasoned Action, Planned Behavior, Social-Cognitive Theory, and the Transtheoretical Model of stages of change. Recent exercise interventions in clinical/community settings also are discussed to illustrate how theoretical models can be implemented to increase and maintain exercise. The second purpose of this paper is to provide a brief summary of the contemporary literatures on the determinants of physical activity and interventions designed to increase and maintain physical activity. The summary focuses on the measurement problems that have limited the advances made in theory and application in these areas of research. Progress toward resolving the measurement problems during the past 5 years is contrasted with earlier scientific consensus. PMID- 7837960 TI - Theories of reasoned action and planned behavior: usefulness for exercise promotion. AB - The following paper gives a summary of the published studies that have applied the theories of reasoned action and planned behavior to the prediction of exercising intentions and behavior. The paper focuses primarily on the knowledge gained from the application of these theories and how these theoretical frameworks could potentially be used in guiding the development of exercise promotion programs. PMID- 7837961 TI - Physical activity determinants: a social cognitive approach. AB - This paper presents Bandura's social cognitive theory as a utilitarian framework to study the determinants of physical activity. I provide an overview of social cognitive theory assumptions and stress the importance of studying self-efficacy in concert with other key cognitive processes. Research addressing when there is a cognitive-behavioral relationship is identified. The paper concludes with the practical implications of social cognitive theory. PMID- 7837962 TI - The transtheoretical model: applications to exercise behavior. AB - The transtheoretical model has been used to understand the stages individuals progress through, and the cognitive and behavioral processes they use while changing health behaviors. The model postulates that individuals engaging in a new behavior move through the stages of Precontemplation, Contemplation, Preparation, Action, and Maintenance. Movement through these stages does not always occur in a linear manner, but may also be cyclical as many individuals must make several attempts at behavior change before their goals are realized. The amount of progress people make as a result of intervention tends to be a function of the stage they are in at the start of treatment. Instruments have been developed to measure the stages and processes of exercise adoption and maintenance and the related constructs of exercise specific self-efficacy and decision making. Psychometric data on these instruments are reviewed. Additionally, data collected on these measures from worksites in the U.S. and Australia are presented along with data from interventions aimed at increasing the adoption of physical activity among community volunteers and worksite employees. Applications of the transtheoretical model for the initiation, adoption, and maintenance of exercise behavior from clinical, community, and public health perspectives are discussed. PMID- 7837963 TI - Community and public health approaches to the promotion of physical activity. AB - Research in the exercise adherence area over the past several decades has resulted in the identification of a number of promising methods for influencing physical activity on the individual level. The substantial prevalence of underactivity across most sectors of the American population, however, demands that higher-level approaches to physical activity promotion that include environmental, organizational, and policy-level strategies be increasingly brought to bear on this problem. This paper compares individual and community approaches to physical activity intervention and provides examples of how the community/public health approach to physical activity promotion can be implemented to facilitate increases in population-wide physical activity. PMID- 7837964 TI - Increase in blood lactate during ramp exercise: comparison of continuous and threshold models. AB - Controversy persists regarding the mechanism underlying the lactate threshold. It has recently been argued that there is in fact no "threshold" and that blood lactate increases as a continuous function during exercise (Hughson J. Appl. Physiol. 62:1975-1981, 1987). In comparing continuous and threshold models, questions have been raised regarding the ramp rate, data sampling, and the mathematical models employed (Morton J. Appl. Physiol. 67:885-888, 1989). To address some of these concerns, we evaluated 61 subjects (mean age 45 +/- 15), who underwent maximal ramp treadmill tests with the ramp rate individualized such that test duration was approximately 10 min for each subject. The relationship between changes in blood lactate and oxygen uptake were evaluated using a modification of the log-log transformation model described by Beaver (J. Appl. Physiol. 59:1936-1940, 1985) and a continuous exponential plus constant model described by Hughson et al. (J. Appl. Physiol. 62:1975-1981, 1987). Model fitting, using mean squared error (MSE) and coefficient of determination (CD) for each method were as follows: [table: see text] The modified log-log model had a better fit as indicated by the lower MSE and higher CD, suggesting the change in lactate was better described by this model. However, the differences were so slight as to suggest: 1) a meaningful difference does not exist between the two; or 2) these methods may not be capable of detecting a difference, if one exists. PMID- 7837965 TI - HIV/AIDS policies in sports. PMID- 7837966 TI - The treatment of rheumatic carditis: a review and meta-analysis. AB - We performed a meta-analysis of the literature on the treatment of established rheumatic carditis to determine if corticosteroid therapy is superior to salicylates in preventing the sequela of inflammation--valvular damage. We identified 22 reports of comparative trials published since the introduction of corticosteroids in 1949. Five of the 22 studies met the criteria we established for the meta-analysis, which included using randomization and a 1-year follow-up for the presence of a new pathologic apical systolic murmur. Based on the meta analysis, the advantage of corticosteroid treatment over salicylates in preventing a pathologic murmur at 1 year posttreatment is not statistically significant (estimated odds ratio 0.88; 95% confidence interval: 0.53 to 1.46). However, the meta-analysis is dominated by 1 large negative trial, and there was significant heterogeneity in the results obtained from the studies in the meta analysis; thus, the question of whether corticosteroid therapy is marginally superior to salicylates for the prevention of valvular heart disease from rheumatic fever remains open. PMID- 7837967 TI - Fascioliasis in developed countries: a review of classic and aberrant forms of the disease. AB - Cases of human infestation by Fasciola hepatica are not uncommon in Spain and other European countries. We report our experience with 20 patients diagnosed from 1982 to 1991 and present a critical review of published cases from western countries. Because F. hepatica has a special tropism for the liver, abdominal pain, hepatomegaly, and constitutional symptoms are among the most common manifestations of acute-stage fascioliasis. However, in the chronic stage, biliary colic and cholangitis are the predominant manifestations. The clinical spectrum of fascioliasis is variable, and patients may present with extrahepatic abnormalities, such as pulmonary infiltrates, pleuropericarditis, meningitis, or lymphadenopathy. Therefore, a high index of suspicion is required to establish a correct diagnosis. Eosinophilia is the most frequent laboratory abnormality. The CT scan has become a useful technique in the diagnostic work-up. A definitive diagnosis may be established by the observation of parasite ova in the feces, but most cases may be diagnosed by serologic methods. Triclabendazole and bithionol are the most effective drugs against F. hepatica. The efficacy of praziquantel is controversial. PMID- 7837968 TI - Hypocomplementemic urticarial vasculitis syndrome. Clinical and serologic findings in 18 patients. AB - We identify and describe clinical findings in hypocomplementemic urticarial vasculitis syndrome (HUVS), an uncommon to rare illness related to systemic lupus erythematosus (SLE). A patient with recurrent, idiopathic urticaria-like lesions was diagnosed as having HUVS if a lesional biopsy showed leukocytoclastic vasculitis, the serum C1q was markedly decreased, and antibody to C1q was detected in the patient's serum. The clinical characteristics, serologic findings, and outcome of patients who met these criteria were determined from prospective and retrospective data, including hospital and office records, patient interviews, previously banked serum samples, and freshly drawn sera. Eighteen patients with HUVS were identified, and high incidences of angioedema, ocular inflammation, glomerulonephritis, and obstructive pulmonary disease were found. Renal and lung biopsies showed mesangial or membranoproliferative glomerulonephritis and severe pulmonary emphysema without vasculitis. Pulmonary function was measured in 17 patients, 11 of whom had dyspnea. All dyspneic patients had moderate to severe airflow obstruction, which progressed in all 11 and subsequently improved in only 1. Six of these 11 patients died of respiratory failure, 1 underwent lung transplantation, and 3 of the remaining 4 have moderately severe to life-threatening respiratory insufficiency. Treatment did not appear to alter the progression of obstructive lung disease. In contrast, renal insufficiency improved with treatment in 2 of 2 patients. Angioedema, ocular inflammation, obstructive lung disease, and glomerulonephritis appear to be common in HUVS, and lung disease causes substantial morbidity and mortality. The pathogenesis of HUVS may involve humoral autoimmunity, although it is not clear how autoimmunity would participate in development of obstructive lung disease. Cigarette smoking appears to be a risk factor for fatal lung disease in HUVS. All patients with HUVS should be made aware of this possibility and should be advised, encouraged, and helped to avoid tobacco smoke. PMID- 7837969 TI - Diagnostic criteria for cystic fibrosis in men with congenital absence of the vas deferens. AB - The high frequency of cystic fibrosis (CF) mutations in males with absence of vas deferens supported the hypothesis of a primarily genital phenotype of CF disease. To consider the idea of an attenuated form of CF, we investigated 14 men with congenital bilateral aplasia of the vasa deferentia. All patients were consulting for infertility and none was known to have CF. The median age was 30.5 years (range, 20-38 yr). DNA analysis for 22 CF mutations showed at least 1 mutation in 10 patients (71%), whereas the CF carrier frequency is only 4% in the general population. Three compound heterozygotes were identified, all carriers of the R117H mutation. The sweat test was considered positive in 6 patients (43%), and a high frequency of radiologic evidence of sinus disease (8 patients) and of elevated antibodies to Pseudomonas (8 patients) was found. Only 2 patients were free of all these criteria for CF disease. This study strengthens the hypothesis that absence of vas deferens is an attenuated form of CF. We propose a combination of tests including DNA study, computerized tomographic scan of the paranasal sinuses, and testing of anti-Pseudomonas antibodies when the sweat test is inconclusive. PMID- 7837970 TI - Cystic fibrosis: a new outlook. 70 patients above 25 years of age. 1977. PMID- 7837971 TI - Slippage--misalignment: to what extent does it contribute to mammalian cell mutagenesis? AB - Mutations in mammalian genomes are the result of several mutagenic processes that are intrinsic to cell metabolism. Analysis of the mutation spectrum of a chromosomal gene is a valuable tool for assessing the contribution of these mechanisms to mutagenesis in the cell. We have studied the specificity of mutations induced by various mutagens in a cDNA hprt gene integrated in a chromosome of a mouse cell line. To understand the mechanisms underlying mammalian cell mutagenesis, we compiled a list of more than 250 sequenced hprt mutations that arose spontaneously or were induced by mutagens, and compared it with the published mutation data. There are at least two distinct processes of mutagenesis in eukaryotic cells: one is mispairing, while another is errors in translesion synthesis. The alkylating agent methylnitrosourea causes G:T mispairing; consequently, most mutations it induces are G to A transitions. The second process can occur spontaneously or be caused by exposure to X-rays, Trp P2, a tryptophan pyrolysate, or acetylaminofluorene. A variety of premutagenic lesions are produced in DNA by these mutagens, but spectra of the mutations resemble each other, especially in the high frequency of deletions at the sites of short direct repeats. The slippage--misalignment mechanism accounted well for the greater part of the observed deletions. A similar spectrum of mutations was observed in the tumor suppressor gene APC from colorectal tumors; about 40% are deletions at the sites of short repeats. These findings led us to propose that slippage--misalignment is an ubiquitous mechanism of mutagenesis and is responsible for a significant proportion of spontaneous mutations in mammalian cells. PMID- 7837972 TI - A reverse mutagenicity assay for alkylating agents based on a point mutation in the beta-lactamase gene at the active site serine codon. AB - The serine at the active site of beta-lactamase is responsible for the ester link to the acyl group of beta-lactam during hydrolysis of the substrate to its acid derivatives. A construct was made from a plasmid in which the active-site serine of beta-lactamase was substituted by glycine by site-directed mutation. This mutation results in the loss of beta-lactamase activity. This plasmid was used to transform Salmonella typhimurium TA1535. When the new strain JK947 was treated with a mutagen such as N-methyl-N'-nitro-nitrosoguanidine (MNNG), the bacteria could be recovered as they became ampicillin resistant. The sequence of the active-site serine codon in these revertants was mutated from GGC to AGC. Based upon these findings, we developed a model reverse mutagenicity assay. In this procedure, we treated JK947 with a test chemical, such as N-methyl-nitrosourea (MNU), dimethyl sulphate (DMS) or methylmethane sulphonate (MMS), for 30 min, and then scored the revertants on agar plates containing 50 micrograms/ml ampicillin after incubation at 37 degrees C for 16 h. MNU and MNNG were more potent than DMS and MMS in this assay. Treatment with MNU and MNNG resulted in larger colony numbers in our test than in the Ames test. However, our test was less sensitive to DMS and MMS than the Ames test. PMID- 7837973 TI - The induction of adaptive response to alkylating agents in Escherichia coli reduces the frequency of specific C-->T mutations in chloroacetaldehyde-treated M13 glyU phage. AB - The mutagenicity and repair of cytosine adducts formed in reactions of chloroacetaldehyde (CAA), a metabolite of the human carcinogen vinyl chloride, have been studied. The treatment of single-stranded DNA M13 JCM15472 (glyU313) phage with CAA and subsequent transfection of Escherichia coli K-12 JC15419 (trpA461) tester strain resulted in a dose-dependent increase of phage C-->T transitions and a decrease of phage survival. The induction of the adaptive response to alkylating agents in bacterial cells significantly decreased the frequency of examined C-->T transitions and increased phage survival. The results indicate that both CAA adducts to cytosine, the initially formed 3,N4-(N4-alpha hydroxyethano)cytosine and the product of its dehydration, 3,N4-ethenocytosine, provoke C-->T transitions and are repaired in adapted bacteria. The role of 3 methyladenine-DNA glycosylase II, which is a part of the adaptive response system in E. coli, in excision of CAA adducts to cytosine, is discussed. PMID- 7837975 TI - AT base pairs are the main target for mutations at the hprt locus of rat skin fibroblasts exposed in vitro to the monofunctional alkylating agent N-ethyl-N nitrosourea. AB - Spectra of N-ethyl-N-nitrosourea (ENU)-induced mutations differ widely among various in vitro and in vivo mutational systems. To investigate possible reasons for these differences, a mutational system is needed in which the same target gene is used for comparison in the same type of cells in vitro and in vivo. In the present study, this was achieved by analysing at the molecular level 35 hprt mutant rat fibroblast clones obtained from cell populations exposed in vitro to ENU and comparing the mutational spectrum with the previously determined spectrum of ENU-induced hprt mutants in the same target cells exposed in vivo. Twenty eight mutants contained a single base pair alteration in the hprt coding sequence. Most of these changes were found at AT base pairs (19/28), the AT to TA transversion being the most frequent kind of mutation (12/19), which is probably caused by O2-ethylthymine. Transversions at AT base pairs showed all mutated T's to be located in the nontranscribed strand of the hprt gene, suggesting a strand specific fixation of mutations induced by O2-ethylthymine, which appears to be a general feature of ENU- and ENNG-induced hprt mutations in mammalian cells. GC to AT transitions, probably caused by O6-ethylguanine, were detected at a lower frequency (7/28). This in vitro mutational spectrum was very similar to that of the same target cells exposed in vivo to ENU. A comparison of the mutational spectra in AGT-proficient and AGT-deficient rodent cells exposed to ethylating agents showed that in contrast to the situation in AGT-proficient rat fibroblasts, GC to AT base pair changes (and not AT to TA) are the predominant mutations in AGT-deficient hamster cells. PMID- 7837974 TI - Is micronucleus induction by aneugens an early event leading to mutagenesis? AB - This study was designed to investigate a previously unidentified potential mechanism for mutation induction as well as to clarify a biological consequence of micronuclei with mutation induction as measured by trifluorothymidine (TFT) resistance in mouse L5178Y cells using four aneugens: colcemid, diethylstilbestrol, griseofulvin and vinblastine. All four compounds induced micronuclei which appeared in the first cell cycle after treatment. More than 85% of the micronuclei induced by each compound stained positive for the presence of kinetochores implying that the micronuclei contained whole chromosomes. However, these same compounds were unable to induce TFT resistance under three different treatment regimes. We concluded that these compounds, under conditions where they induce primarily kinetochore positive micronuclei, were not able to induce mutations. Thus, the induction of micronuclei containing whole chromosomes harboring a selectable gene is not an early event leading to mutations in these cells. PMID- 7837976 TI - Use of microsatellite DNA polymorphisms on mouse chromosome 11 for in vitro analysis of thymidine kinase gene mutations. AB - The mouse lymphoma (L5178Y tk+/- 3.7.2C) in vitro mutagenesis assay can measure the genotoxic effects of a wide variety of chemical agents by inactivation of a single functional thymidine kinase (tk-1) gene. We have previously demonstrated, using cytogenetic and molecular techniques, that the types of molecular lesions associated with tk-1 gene inactivation span a wide range similar to that seen in tumor cells at specific oncogene and tumor suppressor gene loci. We have identified, using polymerase chain reaction techniques, 21 microsatellite, or 'simple sequence repeat', polymorphisms between chromosomes 11a and 11b in 3.7.2C cells. These microsatellite polymorphisms span virtually the entire chromosome, from mapping positions of 3-78 centiMorgans (cM) from the centromere, thus providing landmarks to study loss of genetic material across the entire chromosome. Four of the microsatellite polymorphisms lie within 12 cM of tk-1, and provide a means of mapping loss of genetic material in the immediate vicinity of tk-1, a capability that we have not previously had in the mouse lymphoma assay. Loss of alleles (i.e. loss of heterozygosity) is an important feature of tumor development, having to do with tumor suppressor gene expression. Therefore, the ability to detect loss of heterozygosity in the mouse lymphoma assay will make the assay an extremely valuable tool in the detection of agents capable of inducing loss of heterozygosity. PMID- 7837977 TI - Dichloroacetic acid and related compounds: induction of prophage in E. coli and mutagenicity and mutation spectra in Salmonella TA100. AB - We performed three types of studies to evaluate the genotoxicity of the chlorinated organic solvent perchloroethylene (PERC or tetrachloroethylene) and its volatile metabolites, trichloroacetyl chloride (TCAC) and trichloroacetic acid (TCA), as well as the volatile metabolites of trichloroethylene, i.e. dichloroacetyl chloride (DCAC), dichloroacetic acid (DCA), and 2,2,2 trichloroethanol (TCE). In the first set of studies, which involved the evaluation of these chemicals in the Microscreen prophage-induction assay, only DCA (+S9) was genotoxic, producing 6.6-7.2 plaque-forming units/mM. This places DCA among the weakest of the > 100 chemicals that have been identified previously as inducers of prophage in this assay. In the second set of studies, which involved the evaluation of these chemicals in the vapor state in Salmonella TA100 using a Tedlar bag vaporization technique, DCA (+/-S9), DCAC (-S9), and TCAC (+/ S9) were mutagenic, producing 3-5x increases in revertants/plate relative to the background. S9 enhanced the mutagenic potency of DCA but had no effect on the mutagenic potency of TCAC. The potencies ranged from 0.7 to 3.9 rev/p.p.m., resulting in a potency ranking of DCA > DCAC approximately TCAC. The lowest effective concentrations were 50-300 p.p.m., which are similar to those for ethylene oxide and epichlorohydrin in this assay. In the third set of studies, the mutation spectra of DCA, DCAC, and TCAC were determined at the base substitution allele hisG46 of Salmonella TA100. DCA and DCAC induced primarily G.C-->A.T transitions, whereas TCAC induced primarily G.C-->T.A transversions, which was also the predominant mutation among the background revertants.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7837978 TI - On the mechanisms of genotoxicity and metabolism of quercetin. AB - Quercetin has been the subject of numerous studies on its genetic toxicity and carcinogenicity. Despite its well-proven genetic damaging activity for various genetic end-points (reverse mutations, induction of SOS functions, induction of sister chromatid exchanges, chromosomal aberrations and micronuclei), the mechanisms of genetic damage by quercetin remain, by and large, unknown. The present study aims to further extend the observations on the possible active oxygen species mediated DNA-damaging activity of quercetin and the role of cytochrome P450-dependent metabolism on the genotoxicity of quercetin. The results reported in this work show that quercetin can produce the OH. radical, as assessed by deoxyribose degradation in the presence of Fe3+/EDTA (ethylenediaminetetraacetic acid), and that it induces strand breakage in isolated plasmidic DNA (pUC18). The data support the hypothesis that the production of OH. is mediated by H2O2. The results with genetically engineered V79 cells expressing rat cytochromes 1A1, 1A2 and 2B1 failed to demonstrate metabolism of quercetin, as indicated by the fact that neither an enhancement nor a decrease in the genotoxicity of quercetin was observed. Results obtained on the pH dependence of the induction of chromosomal aberrations by quercetin in V79 cells show that, as the pH value of the medium is increased to 8.0, there is a significant increase in the number of aberrant cells, as expected if oxygen radicals are responsible for the formation of chromosomal aberrations. PMID- 7837979 TI - Sequence spectra of spontaneous lacZ gene mutations in transgenic mouse somatic and germline tissues. AB - As a critical step in determining whether transgenic mouse gene mutation systems are suitable models for the detection and quantification of induced gene mutations in vivo, spontaneous mutant frequencies and mutation spectra have been characterized for liver, bone marrow, and male germ cells of the lacZ transgenic mouse strain 40.6. The lacZ transgene is carried on a recombinant bacteriophage lambda shuttle vector that is recovered from mouse genomic DNA, and analysed in vitro for mutations that occurred in the mouse tissues. Mutations are detected visually as clear or pale blue plaques when X-gal is the substrate for beta galactosidase; whereas, the wild-type plaques are dark blue. There was no statistical difference in the mutant frequency among the three tissues studied, the pooled mutant frequency being 2.23 +/- 0.41 per 10(5) pfu. The predominant type of mutation was GC-->AT transitions, with most occurring in 5'-CpG dinucleotides, suggesting that the deamination of 5-methylcytosine is the main mechanism of mutagenesis. There was, however, a statistically significant difference in the base pair substitution mutation spectrum for the liver and bone marrow when mutations were grouped according to GC or AT base-pairs. The proportion of transition versus transversion mutations was also statistically different among the three tissues, resulting mainly from the fact that germ cells were different from both bone marrow and liver. A lower number of spontaneous transitions in male germ cells was accompanied by an increase in transversions, with the proportion of GC-->AT transitions in 5'-CpG sites also declining.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7837980 TI - Photomutagenicity assays in bacteria: factors affecting assay design and assessment of photomutagenic potential of para-aminobenzoic acid. AB - Photomutagenicity assays are required for regulatory submissions of some chemicals. As yet there are no well-validated protocols available for these assays. Critical factors which may contribute to the ability of a bacterial assay to detect photomutagens (e.g. dose of UV and test chemical, exposure conditions, light source, bacterial strains) were investigated using two known photomutagens, chlorpromazine and 8-methoxypsoralen. Salmonella typhimurium strains TA98, TA102 and TA1537 and Escherichia coli strains WP2 and WP2(pKM101) were used and differences in the responsiveness of these strains were observed with these substances. Both chemicals were detected using either UV exposure in suspension or on the agar plates. On the basis of these observations and on other results reported in the literature, recommendations are made on protocol aspects for assessing photomutagenic potential in routine screening tests. Using these recommendations the sunscreen para-aminobenzoic acid was tested in S.typhimurium strains TA98, TA100, TA1535, TA1537 and E. coli strains WP2 and WP2 (pKM101), using both plate irradiation and suspension exposure conditions. No evidence of mutagenic potential was detected. PMID- 7837981 TI - Cytogenetic studies of sodium fluoride in mice. AB - The cytogenetic effects of sodium fluoride (NaF) were measured in mice following administration in the drinking water for 6 weeks. Bone fluoride levels were determined and showed a dose-related incorporation of fluoride. Micronuclei were measured in peripheral blood erythrocytes following 1 and 6 weeks of NaF administration. Bone marrow cell preparations were examined for the presence of chromosome aberrations following 6 weeks of treatment; metaphase and anaphase cells were examined. Anaphase cells were scored in three independent laboratories, two of which also scored metaphase cells from the same slides. No increases in micronuclei were seen in peripheral erythrocytes at either time point, and no increases in chromosome aberrations were seen in bone marrow cells when metaphase or anaphase cells were examined. A concurrent positive control, cyclophosphamide, produced significant increases in peripheral blood cell micronuclei and in chromosome aberrations in bone marrow cells in metaphase. No increases in aberrations were seen in the same cyclophosphamide-treated mice when anaphase cells were examined. PMID- 7837982 TI - Genotoxicity of 2-halocinnamaldehydes in two bacterial assays. Induction of SOS repair and frame-shift mutation. AB - 2-Chlorocinnamaldehyde and 2-bromocinnamaldehyde, compounds of practical interest, for example, as bacteriocides and fungicides or for utilization in light sensitive layers, were tested in the Ames preincubation test with various Salmonella typhimurium strains, and in the SOS chromotest with Escherichia coli PQ 37.2-Chlorocinnamaldehyde was clearly mutagenic in strain TA 100 (6081 revertants/mumol) and in strain TA 98 (3050 revertants/mumol) without S9 mix, and was clearly positive in the SOS chromotest (SOSIP = 0.181). 2-Bromocinnamaldehyde was a strong mutagen in strain TA 100 (105, 500 revertants/mumol), in strain TA98 (41567 revertants/mumol) and in strain TA 1538 (15825 revertants/mumol), and also unambiguously mutagenic in strain TA 1535 (2110 revertants/mumol) without S9 mix. The SOSIP in the SOS chromotest was 1.5. Addition of S9 mix led to a marked decrease in the mutagenic activity of 2-bromocinnamaldehyde in all strains tested. In the case of strain TA 1535, mutagenic activity was abolished or not significant in the presence of S9 mix. The possible primary mechanisms underlying these mutagenic effects are discussed. Frame-shift activity of these halocinnamaldehydes can be explained by their planar structure. PMID- 7837983 TI - Genetic analysis of mitomycin C-hypersensitive Chinese hamster cell mutants. AB - The genetic diversity of Chinese hamster cell mutants exhibiting hypersensitivity to the bifunctional alkylating agent mitomycin C has been examined. The eight mutants irs3, VH4, UV1, MC5, MMC1, MMC3, MMC4 and MMS2, are between 4- and 30 fold more sensitive to mitomycin C than their respective wildtype parental lines. A number of the mutants show phenotypic similarities to cultured cells from the human cancer-prone syndrome Fanconi's anaemia. Hybrids were formed between pairs of mutants using the thioguanine/ouabain resistant (TOR) hybridization and hypoxanthine/aminopterin/thymidine (HAT)/ouabain selection system and the mitomycin C response of pooled populations of hybrids assessed by constructing survival curves. In every case, hybrids formed between pairs of mutants exhibited a mitomycin C response indistinguishable from that of wildtype cells, indicating complementation. Therefore, the eight mutant lines examined represent eight distinct complementation groups for mitomycin C-hypersensitivity. The results are in contrast to the complementation analysis of UV-sensitive Chinese hamster cell mutants and indicate that the response of mammalian cells to mitomycin C-induced DNA damage is complex and involves a large number of genes. PMID- 7837984 TI - Antimutagenicity of Maillard reaction products from amino acid/sugar model systems against 2-amino-3-methylimidazo-[4,5-f]quinoline: the role of pyrazines. AB - The antimutagenicity of dichloromethane extracts from eight amino acid/sugar model systems was determined using Salmonella typhimurium TA98 against 2-amino-3 methyl-imidazo[4,5-f]quinoline (IQ) in the presence of Aroclor 1254-induced rat hepatic S9. The Maillard reaction products in the dichloromethane extracts were then quantified and qualified by capillary gas chromatography and gas chromatography-mass spectrometry, respectively. Pyrazines and furans were found to be the major Maillard reaction products yielded in the extracts. Moreover, the antimutagenicity of dichloromethane extracts correlated positively with the total amounts of pyrazines and furans. To elucidate the mechanism of antimutagenicity of dichloromethane extracts, the inhibitory effect of pyrazines on ethoxycoumarin deethylase activity in Aroclor 1254-induced hepatic microsomes was examined. We also studied the effects of pyrazines on IQ metabolism by Aroclor 1254-induced microsomes using high-performance liquid chromatography. The antimutagenicity of pyrazines correlated positively with both the inhibition of cytochrome P-450 IA2 linked ethoxycoumarin deethylase in hepatic microsomes and the inhibition of N hydroxy-IQ formation from IQ metabolism by hepatic microsomes. Thus we concluded that pyrazines in dichloromethane extracts from eight amino acid/sugar model systems play an important role in the antimutagenicity of IQ. Moreover, we concluded that the modifying effect of pyrazines on the mutagenicity of IQ is mediated through interaction with microsomal activating enzymes to inhibit the major active metabolite in N-hydroxy-IQ formation. PMID- 7837985 TI - Population control. PMID- 7837986 TI - Evaluation of the meta-analyses on the effects, on both mother and baby, of the various components of 'active' management of the third stage of labour. AB - In their comprehensive review of controlled trials, Prendiville and Elbourne (1989) used the technique of meta-analysis to study the effects, on both mother and baby, of various aspects of third stage management, acknowledging some of the shortcomings of the trials used. This paper questions some of the conclusions which these authors drew and, drawing on other evidence (some of which has been published since the review), puts forward alternative interpretations of some of the meta-analyses. Reference is also made to the updated meta-analyses in the Cochrane Pregnancy and Childbirth Database (Elbourne, 1994a-h). In addition, this paper examines the extent to which the findings of the Bristol and Dublin third stage trials (Prendiville et al, 1988; Begley, 1990) add to our understanding of what is effective care during the third stage of labour. PMID- 7837987 TI - Preparing for breast feeding: treatment of inverted and non-protractile nipples in pregnancy. The MAIN Trial Collaborative Group. AB - OBJECTIVE: to determine the effectiveness of recommending Hoffman's nipple stretching exercises or breast shells (or both) to pregnant women with inverted or non-protractile nipples who intend to breast feed. DESIGN: randomized controlled trial with a two treatment by two level factorial design. SETTING: in the UK, antenatal clinics in hospital and community settings in 10 centres and the antenatal network of the National Childbirth Trust; in Ontario, Canada, antenatal clinics in six hospital centres and one public health unit. PARTICIPANTS: 463 women with at least one inverted or non-protractile nipple and a singleton pregnancy, recruited between 25 completed and 35 completed weeks of pregnancy. PRIMARY OUTCOME MEASURE: rate of breast feeding as reported by postal questionnaire six weeks postnatally. FINDINGS: 107 out of 234 (46%) women allocated to use Hoffman's exercises compared with 100/229 (44%) women not allocated to use exercises were breast feeding at six weeks after delivery (difference 2%, 95% confidence interval -7% to 11%). One hundred and three out of 230 (45%) women allocated to use shells compared with 104/233 (45%) women not allocated to use breast shells were breast feeding at six weeks after delivery (difference 0%, 95% confidence interval -9% to 9%). CONCLUSIONS: in the light of the findings from this and a previous single centre trial, there is not basis for recommending the use of either Hoffman's nipple stretching exercises or breast shells as antenatal preparation for women with inverted and nonprotractile nipples who wish to breast feed. Given the lack of evidence to support these and other antenatal preparations there are no grounds for midwives to continue routine breast examination in pregnancy for this purpose. PMID- 7837988 TI - A descriptive study of childbirth education provided by midwives in Sweden. AB - OBJECTIVE: to describe the content, modes of working and reaction/interaction of childbirth education provided by midwives in Sweden. DESIGN: qualitative, using non-participant observation to collect the data. Grounded theory approach was used. SETTING: antenatal classes provided in the community in Sweden. PARTICIPANTS: twelve midwives with varying lengths of experience in teaching antenatal classes, and the prospective parents who attended these classes. MEASUREMENTS AND FINDINGS: three perspectives on the content and three modes of working were found. Combinations of the differing perspectives and working modes provided differing interactions within the classes. KEY CONCLUSIONS: the confirming/mixed model resulted in dialogue in the classes. It was assumed that this model would contribute to an increased understanding of the coming experience of giving birth. IMPLICATIONS FOR PRACTICE: the findings provide midwives with a basis for reflection on their experiences as leaders in the childbirth preparation part of education for parenthood. PMID- 7837989 TI - Towards an integrated model of competence in midwifery. AB - Currently in the UK, there is no consensus as to what constitutes an adequate definition of a competent midwife. Yet, given the rapidly changing midwifery needs of childbearing women and society, such clarification has never been more important. In this paper some concepts of competence taken from a review of midwifery, nursing, educational and industrial literature are reviewed, and it is hoped that discussion leading to conceptualisation of an integrated model of competence in midwifery will be stimulated. Questions raised include--What is it that makes midwives competent? Can competence be inferred from performance? How can capability be recognised? Can competence be broken into elements for assessment without losing meaning? PMID- 7837990 TI - A cross-national analysis of midwifery politics: six lessons for midwives. AB - Research based on interviews and analysis of documentary sources on the politics of midwifery in Canada, Denmark, the Netherlands, the UK and the US, suggests six political lessons for midwives and the organisations that represent them. The lessons are: general health reforms represent both an opportunity and a threat to midwives' status, and midwives must learn to communicate in ways policy makers understand; research matters; coalition building is essential; the media cares (a little); it is much easier to defend the status quo than create new policy; it is essential to clarify who is to be considered a midwife. A constant grass roots awareness of and involvement in a country's political and policy making process is seen as a necessity if midwives are to prosper as a profession. PMID- 7837991 TI - Ultrasound examinations in pregnancy: some suggestions for debate. AB - OBJECTIVE: to ascertain the number of ultrasound examinations a sample of women received in pregnancy. DESIGN: a retrospective review of 50 sets of case notes of women delivering consecutively in one maternity unit. SETTING: a large maternity unit in Northern England (approximately 5000 deliveries per year). FINDINGS: the mean number of scans received was 2.6 indicating that many women receive an early 'dating' scan as well as a second trimester 'routine' scan. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: first trimester and early mid-trimester scans may be clinically indicated, but we are concerned that they are becoming routine without fundamental questions of safety and efficacy being answered by large controlled trials. In addition, little is known about the possible positive or negative psychological effects of early scans and there is no evidence that they are cost effective. PMID- 7837992 TI - Fine structure of elongate polyhedral bodies (carboxysomes) in two Oscillatoria (Cyanophyceae) isolates. AB - Polyhedral bodies (carboxysomes) in two Oscillatoria isolates were of two morphological forms. Some were typical polygonal bodies with many straight sides and were approximately 0.2 micron in diameter. Most of the bodies in these isolates were elongate being up to 2.6 microns in length, 33 nm in width and approximately 0.1 micron in depth. Some of the bodies were polygonal with an elongate extension. All of the bodies were limited by a membrane monolayer of approximately 20 A. The function of polyhedral bodies (carboxysomes) is discussed in relation to their observed morphology. PMID- 7837993 TI - Interaction between Yersinia pseudotuberculosis and Y. enterocolitica and fish cells. AB - Virulent strains of Yersinia pseudotuberculosis and Y. enterocolitica cultured at 10 degrees C were studied with respect to their interaction with cultured fish cells. Infection with Yersinia at 25 degrees C resulted in the formation of pseudopodia and the adherence of bacteria to the cell surface. The adherent bacteria were ingested 2 h after infection. Yersinia was found to be cytotoxic for the cells and the intracellular bacteria seemed to reside in phagosomes and were found in stages of division but were never observed in the nucleus. PMID- 7837994 TI - Isolation and purification of U7 and snRNP particles. AB - A procedure was developed for the isolation of U7 small nuclear ribonucleoprotein particles involved in the processing of histone pre-mRNAs. U7 snRNP particles were fractionated from the rest of the snRNPs by means of a series of gel filtration and affinity chromatography steps. The isolated assembly of U7 snRNP particles appeared to be intact and pure as judged by gel electrophoresis of their RNA. No detectable RNA species were monitored other than U7 RNA. PMID- 7837995 TI - Application of nuclear magnetic resonance spectrometry to measure the activity of bacterial macrolide esterase. AB - A new method of measuring the activity of macrolide antibiotic esterase in whole bacteria and in crude enzyme extracts was determined through the application of nuclear magnetic resonance spectrometry. The structure of the enzymatically esterolytic cleavage compound of oleandomycin was clearly shown to be the cyclic hemiacetal between the C-9 keto and the hydroxy group of C-13 in the open macrolide nucleus by physicochemical techniques. PMID- 7837996 TI - Near-UV light protection effect against lethality induced by stannous chloride in Escherichia coli. AB - Stannous chloride (SnCl2) is a reducing agent largely employed in industry and in medical procedures. To evaluate its potential genotoxicity, several Escherichia coli strains were treated with SnCl2 and their survival rates determined. Results showed that the double mutant on specific genes for the repair of deoxyribonucleic acid damage was the most sensitive strain. Simultaneous near-UV illumination inhibited the lethal effect of SnCl2 in the wild type strain. Although the nature of the induced lesions are not known these results indicate the potential genotoxicity of SnCl2. PMID- 7837997 TI - Lipid content of microparticulate (1-->3)-beta-D-glucan isolated from Saccharomyces cerevisiae. AB - The preparation of pharmaceutical grade (1-->3)-beta-D-glucans from Saccharomyces cerevisiae requires that the microparticulate glucans which are employed as the starting material for drug production be of the highest purity. Potential contaminants of the (1-->3)-beta-D-glucan isolation process are yeast cell wall lipids, which are frequently found in association with glucans. The lipid content of yeast-derived (1-->3)-beta-D-glucan during various stages of the isolation process by methyl esterification and total ion gas chromatography and mass spectrometry (GC-MS) was examined. Following sequential alkaline and acid hydrolyses, the total lipid content of (1-->3)-beta-D-glucan was 100.4 nmol/mg with 9-cis-C 18:1 fatty acid accounting for 45.3 nmol/mg glucan (45%). Following ethanol extraction of the (1-->3)-beta-D-glucan, lipid was not detected. Indeed, fatty acid methyl esters were not detectable by total ion GC-MS in all twelve samples investigated. These data demonstrate that the isolation process for yeast derived (1-->3)-beta-D-glucan effectively reduces contamination by yeast cell wall lipids. PMID- 7837998 TI - Theory about aging in humans and hypotheses about its possible delay. AB - Living beings can maintain their metastable state, e.g. can escape from the first law of thermodynamics by being open systems, by taking up high energy molecules and by dissipating waste products, heat and work. According to the present theory they can stay alive as long as they can escape from the external chaos which is due to the second law of thermodynamics. It is argued that aging is caused by penetration of this chaos into our body in the form of excess trace elements and as xenobiotic elements which either stop the functioning of our living cells or bring it out of neural or hormonal control. Aging might be delayed by the fact that sulfur metabolism maintains an H2S tension in the human body able to precipitate the xenobiotic elements from our tissues. For our defense we depend further on phagocytes to transport the precipitates to organs where they can be dissolved and excreted. It is suggested that the regular passing of kaoline, a natural cation exchanger, through the intestinal tract will help to extract the xenobiotic elements from the body. As far as cardiovascular diseases are concerned, they start with the inevitable tendency of triglycerides to form crystalline precipitates at the surface of the intima in the arteries and capillary vessels. It is hypothesized here that cholesterol serves as a complex former, together with yet unknown plasma protein factors to the triglycerides enabling the solubilization of the precipitates. It is supposed to act as a sort of hormone.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7837999 TI - A possible explanation for growth hormone resistance in chronic renal failure. AB - Perhaps the liver in renal failure significantly alters its pH in order to attempt to maintain homeostasis. This alteration might explain the growth hormone resistance found in children with chronic renal failure. PMID- 7838000 TI - Neurasthenic fatigue, chemical sensitivity and GABAa receptor toxins. AB - Following observation of fatigue syndromes in people who have been occupationally exposed to pesticides and insecticides which exert their toxicity through the GABAa receptor, we have formulated the hypothesis that fatigue syndromes in general may be secondary to altered sensitivity of the GABAa receptor. We discuss the possible involvement of organochlorine compounds which are widespread in the environment. Organophosphate compounds may have similar toxic effects through damaged cholinergic input to the dentate gyrus of the hippocampus where cholinergic and GABAergic transmission are closely linked. PMID- 7838001 TI - Cultural transitions and epidemiology. AB - The analysis of cultural patterns, as an observational and qualitative tool in epidemiological research, is advanced. This approach to epidemiology, biomedicine, human and cultural ecology, focuses on the following theoretical points of view: (i) the intrinsic non-linearity of natural dynamics, (ii) the role of fluctuations in the evolution of self-organized systems, (iii) the reformulation of the homeostasis concept, through the hypothesis of the co existence of different levels of boundaries of stability (the non-linear processes of adaptation) and the dynamics of transitions (the physiological jumps) between them, (iv) the image of the psychobiological status in peripheral cells (i.e. blood lymphocytes) due to the morphofunctional unity of neuroendocrine and immune systems, (v) the significance of emic/ethic operations used in cultural anthropology. In this conceptual framework, transitions among migrants or within populations, following sudden changes in cultural patterns, are particular events that can also be very interesting for epidemiological research; they can leave the marks of underlying intertwined psychobehavioral, metabolic and immune physiology; they can also be informative as regards the modulation of autonomy, disability, morbidity and mortality curves. PMID- 7838002 TI - Potential applications of apoptosis in modifying the biological behavior of therapeutically refractory cancers. AB - Recent information about apoptosis or programmed cell death, the anti-apoptotic gene, BCL2, its interaction with reactive oxygen species and the role of these agents in senescence and apoptosis, suggests a discussion of their relationships could be of interest. Such information may eventually provide alternative approaches to modifying the biological behavior of therapeutically resistant cancers. Some of these comments probably are self-evident, others may be less so and provide ideas for further studies. PMID- 7838003 TI - Immunological studies on Crohn's disease. X. Conclusion: a new tentative hypothesis. AB - Although much progress has been made in understanding the pathogenesis of Crohn's disease, the precise etiology of Crohn's disease still remains unknown. In our serial studies on Crohn's disease, we found a decrease in NK and ADCC activities as well as a decrease in the phagocytic activity by monocytes, whereas an increased superoxide production activity by monocytes was evident. On the other hand, the characterization of lymphocyte subpopulations has demonstrated no abnormalities. According to these findings, we would like to propose a new tentative hypothesis for the pathogenesis of Crohn's disease. It has been suggested that impaired killing system activities, such as phagocytic activity as well as NK and ADCC activities, are primarily responsible for the promotion and perpetuation of chronic inflammation and ulceration. When our attention is directed to the most common target substances of these protective mechanisms, viral antigens appear as the most likely causative organism. Therefore, a lot of attention has been focused on viral infection as a causative factor. Furthermore, based on this hypothesis, strategies for effective treatment of this disease are also discussed. PMID- 7838004 TI - Intracranial pressure and Alzheimer's disease: a hypothesis. AB - Several neuropathological and epidemiological data on Alzheimer's disease (AD) are considered in relation to data from other scientific sources. The correlation between all these data provides support for the hypothesis that high intracranial pressure (ICP) could play a role in the pathogenesis of AD. PMID- 7838005 TI - The pathophysiology of reactive oxygen intermediates in the central nervous system. AB - Current evidence for the participation of free radicals in diseases of the central nervous system is reviewed. We conclude that the pathogenesis is based on a uniform mechanism: free radicals preferentially attack myelin, which contains easily peroxidizable phospholipids. The basal ganglia seem to be a brain area that is especially susceptible to radical damage which is possibly related to the synthesis of neurotransmitters. The clinical picture of the resulting cell death is dominated by convulsions and retardation in childhood and by psychomotoric disability and dementia in adulthood. PMID- 7838006 TI - The free radical flux theory of sleep. AB - A theory of sleep is proposed in which cerebral free radicals accumulate during wakefulness and are removed during sleep. Removal of excess free radicals during sleep is accomplished by decreased rate of formation of free radicals, and increased efficiency of endogenous antioxidant mechanisms. Thus, sleep functions essentially as an antioxidant for the brain. PMID- 7838007 TI - Lactulose--a potential drug for the treatment of inflammatory bowel disease. AB - Lactulose is a drug mainly used as a laxative and for the treatment of porto systemic encephalopathy. Following oral administration, intact lactulose reaches the colon, where it is split by bacteria, leading to a reduction in faecal pH and creating intestinal conditions beneficial to Lactobacillus acidophilus and inhibitory to coliform bacteria, bacteroides, Salmonella and Shigella. It was shown that lactulose therapy clears faecal salmonella and shigella species and reduces the prevalence of urinary-tract infection and respiratory tract infections. Oral administration of lactulose abolishes and prevents systemic endotoxemia of gut origin. Therefore lactulose may be used for treatment of inflammatory bowel disease as bacteria and bacterial endotoxin have an important role in the pathogenesis of this disease. PMID- 7838008 TI - Are neuropsychiatric manifestations of folate, cobalamin and pyridoxine deficiency mediated through imbalances in excitatory sulfur amino acids? AB - Folate, cobalamin and pyridoxine deficiency are associated with psychiatric or neurological symptomatology. Disturbances in sulfur amino acid metabolism leading to accumulation of homocysteine occurs in all three conditions as the metabolism of homocysteine depends on enzymes requiring these vitamins as cofactors. Oxidation products of homocysteine (homocysteine sulfinic acid and homocysteic acid) and cysteine (cysteine sulfinic acid and cysteic acid) are excitatory sulfur amino acids and may act as excitatory neurotransmitters, whereas taurine and hypotaurine (decarboxylation products of cysteic acid and cysteine sulfinic acid) may act as inhibitory transmitters. Homocysteic acid and cysteine sulfinic acid have been considered as endogenous ligands for the N-methyl-D-aspartate (NMDA) type of glutamate receptors. The profile of these sulfur amino acid neurotransmitters could be altered in a similar fashion in states of decreased availability of folate, cobalamin or pyridoxine. It is proposed that the mechanism of neuropsychiatric manifestations in all three conditions result from a combination of two insults to homocysteine catabolism in the brain. PMID- 7838009 TI - The secret of clozapine: to sleep while awake? AB - A dramatic increase in REM sleep time at the expense of slow wave sleep has been reported in patients on clozapine monotherapy (5). It is now suggested that this effect of clozapine on the sleep pattern could be due to a dissociation of the NREM/REM sleep cycle, and that the epileptogenic EEG abnormalities induced by clozapine in daytime recordings (2) would represent a dose-dependent activation on NREM sleep mechanism during wakefulness. The implications of this theory in relation to the concept of schizophrenia are discussed. PMID- 7838010 TI - Enhancing central and peripheral insulin activity as a strategy for the treatment of endogenous depression--an adjuvant role for chromium picolinate? AB - Depression is often associated with insulin resistance, owing to cortisol overproduction; conversely, many studies suggest that diabetics are at increased risk for depression. Recent evidence indicates that insulin is transported through the blood-brain barrier and influences brain function via widely distributed insulin receptors on neurons. These receptors are particularly dense on catecholaminergic synaptic terminals, and, while effects are variable dependent on brain region, several studies indicate that insulin promotes central catecholaminergic activity, perhaps by inhibiting synaptic re-uptake of norepinephrine. Additionally, it is well known that insulin enhances serotonergic activity in increasing blood-brain barrier transport of tryptophan. Since impaired monoaminergic activity in key brain pathways is believed to play an etiological role in depression, techniques which promote effective insulin activity, both centrally and peripherally, may be therapeutically beneficial in this disorder. This may rationalize anecdotal reports of improved mood in clinical depressives and diabetics receiving the insulin-sensitizing nutrient chromium picolinate. This nutrient, perhaps in conjunction with other insulin sensitizing measures such as low-fat diet and aerobic exercise training (already shown to be beneficial in depression), should be tested as an adjuvant for the treatment and secondary prevention of depression. PMID- 7838011 TI - Longevity effect of chromium picolinate--'rejuvenation' of hypothalamic function? AB - The first rodent longevity study with the insulin-sensitizing nutrient chromium picolinate has reported a dramatic increase in both median and maximal lifespan. Although the observed moderate reductions in serum glucose imply a decreased rate of tissue glycation reactions, it is unlikely that this alone can account for the substantial impact on lifespan; an effect on central neurohormonal regulation can reasonably be suspected. Recent studies highlight the physiological role of insulin as a modulator of brain function. I postulate that aging is associated with a reduction of effective insulin activity in the brain, and this contributes to age-related alterations of hypothalamic functions that result in an 'older' neurohormonal milieu; consistent with this possibility, diabetes leads to changes of hypothalamic regulation analogous to those seen in normal aging. Conversely, promoting brain insulin activity with chromium picolinate may help to maintain the hypothalamus in a more functionally youthful state; increased hypothalamic catecholamine activity, sensitization of insulin-responsive central mechanisms regulating appetite and thermogenesis, and perhaps trophic effects on brain neurons may play a role in this regard. Since both the pineal gland and thymus are dependent on insulin activity, chromium may aid their function as well. Thus, the longevity effect of chromium picolinate may depend primarily on delay or reversal of various age-related changes in the body's hormonal and neural milieu. A more general strategy of hypothalamic 'rejuvenation' is proposed for extending healthful lifespan. PMID- 7838012 TI - On the disentangling modes of ortho- and para-braids in mitosing mammalian spermatogonia. AB - This note complements a previous one (1), regarding in particular, mitotic separation of replica homologs from their templates, in mammalian spermatogonia. Topological differences between Ortho- and Para-braids determine different modes of antipodal segregation of paired homologs prior to onset of meiosis. PMID- 7838013 TI - Bronchodilators: beta-agonists. PMID- 7838014 TI - Infectious diseases. PMID- 7838015 TI - Laparoscopic or open repair of inguinal hernias? PMID- 7838016 TI - Laparoscopic or open repair of inguinal hernias? PMID- 7838017 TI - Laparoscopic or open repair of inguinal hernias? PMID- 7838018 TI - Laparoscopic or open repair of inguinal hernias? PMID- 7838019 TI - Restrictions on HIV-infected health care workers. PMID- 7838020 TI - Cerebral palsy: the courts catch up with sad realities. PMID- 7838021 TI - Mifepristone (RU486) and emergency contraception. PMID- 7838022 TI - Total hepatectomy and liver transplantation as a two-stage procedure in fulminant hepatic failure. PMID- 7838023 TI - Dramatic increase in incidence of insulin-dependent diabetes mellitus in Western Australia. PMID- 7838024 TI - Drug product information published in the journal. PMID- 7838025 TI - Heat exhaustion in the Sun-Herald City to Surf fun run. PMID- 7838026 TI - GnRH agonists for endometriosis. These newly approved agents are effective but expensive. PMID- 7838027 TI - Familial hypertrophic cardiomyopathy and the new genetics. DNA analysis promises earlier and more accurate diagnosis. PMID- 7838028 TI - Eye injuries in Victoria, Australia. AB - OBJECTIVE: To outline the spectrum of eye injuries in the Victorian population. DESIGN AND SETTING: Prospective survey of all eye injuries treated at the Royal Victorian Eye and Ear Hospital; and a review of morbidity data from all Victorian hospitals to estimate the incidence of ocular trauma across the State. RESULTS: During a 12-month period, 6308 patients were treated at the hospital. Most had superficial injuries, but 401 (6%) were admitted for severe trauma. Most were male and young; children aged under 15 years comprised 25% of hospitalisations (severe injuries). The workplace accounted for 44% of all injuries and 19% of severe trauma, including ruptured globes and internal bleeding. Sports injuries accounted for 5% of all injuries, but 19% of severe injuries. The incidence estimate for penetrating eye injuries was 3.6 per 100,000 population. The incidence of eye injuries requiring hospitalisation was 15.2 per 100,000. Annual medical costs were estimated conservatively at $15.8 million a year for this hospital alone and projected at $39 million a year for 29,000 eye injuries in Victoria and $155 million a year for 116,000 cases nationwide. CONCLUSIONS: Most ocular trauma occurs in young people and could be prevented by proper use of safety eyewear. PMID- 7838029 TI - Educational program to improve the dosage prescribing of allopurinol. AB - OBJECTIVE: To perform and evaluate an educational intervention program aimed at improving the dosage prescribing of allopurinol by general practitioners and based on the application of academic detailing. DESIGN, SETTING AND PARTICIPANTS: General practitioners in southern Tasmania were sent educational material about allopurinol, high-lighting the need to adjust dosages in accordance with the renal function of the patient. Most general practitioners then discussed the rational prescribing of allopurinol directly with a visiting pharmacist. MAIN OUTCOME MEASURES: Pharmacoepidemiological data provided by a statewide database containing dispensing data from community pharmacies throughout Tasmania, and Pharmaceutical Benefits Scheme (PBS) and Repatriation Pharmaceutical Benefits Scheme (RPBS) data. The key variable was the percentage of prescriptions for allopurinol that were for the 100 mg form. RESULTS: The program's success was indicated by a statistically significant increase in the prescribing of 100 mg allopurinol in the intervention region. The database showed an increase from 14.8% to 22.1% of all prescriptions for allopurinol (P < 0.05), while PBS and RPBS data revealed an increase from 12.5% to 22.2% of all prescriptions for allopurinol dispensed under both schemes (P < 0.0001). CONCLUSIONS: A program incorporating academic detailing can modify prescribing practices within the community. A statewide pharmacoepidemiological database provides a valuable means of evaluating interventions designed to improve prescribing. PMID- 7838030 TI - Morbidity, medication and trigger factors in a community sample of adults with asthma. AB - OBJECTIVES: To determine asthma morbidity, use of medications and trigger factors for asthma attacks in an adult community sample. METHODS: Follow-up questionnaires were sent to respondents indicating a history of asthma or any respiratory symptom on a screening questionnaire. A new scale to measure asthma severity was developed. RESULTS: Questionnaires were returned by 74% (589/795). Respondents with diagnosed asthma had more frequent symptoms and more disruption to lifestyle than those with non-specific respiratory symptoms. Inhaled beta agonist and oral theophylline preparations were used by 61% and 16% of asthmatics, respectively. Preventive medications such as inhaled corticosteroids and cromoglycate were used daily by only 15% and 4%, respectively. The most frequently reported trigger factors were viral upper respiratory tract infections, cigarette smoke, house dust, smog and other non-specific irritants. Twenty per cent of asthmatics reported occupational exacerbation of symptoms. CONCLUSIONS: There is substantial morbidity from asthma in Victorian adults, which could be reduced by greater use of preventive medications, avoidance of trigger factors, peak flow monitoring and action plans. The asthma severity scale proved to be reliable and valid. PMID- 7838032 TI - Systemic adverse reactions with betaxolol eye drops. PMID- 7838031 TI - Impact of an information and consent form on patients having chemotherapy. AB - Of 100 patients having chemotherapy who were given a written information and consent form, only 34 understood the purpose of the form and only one considered it the major source of information; 75 patients could not name any of their drugs, 26 did not know the goal of therapy and only 15 remembered all of four general side effects. Such forms may not satisfy the requirements of informed consent. PMID- 7838033 TI - The origins of cerebral palsy--a consensus statement. The Australian and New Zealand Perinatal Societies. PMID- 7838034 TI - Diabetic dyslipidaemia. Australian Diabetes Society position statement. PMID- 7838035 TI - Developing a measure of health outcomes in survivors of childhood cancer: a review of the issues. AB - The success of treatment for childhood cancer has prompted greater attention to issues of quality of life for the survivors. Work on health-related quality of life has proceeded faster for adults than for children. This paper reviews the results of such work for adults and points to the potential for applications in children. Specific problems in adapting measures and in interpreting the results in the context of a child's development are discussed. An approach to the assessment of the health-related quality of life for survivors of childhood cancer is proposed. PMID- 7838036 TI - Pharmacokinetics of HD-MTX in infants, children, and adolescents with non-B acute lymphoblastic leukemia. AB - A retrospective pharmacokinetic analysis was done of methotrexate serum levels after high-dose treatment (HD-MTX, four cycles at two-week intervals of 5 g/sq.1m. over 24 h i.v.) in children with non-B acute lymphoblastic leukemia (ALL) with the specific aim of seeking differences in patients of different ages, including infants under one year. A total of 122 children (seven infants aged 3 months-1 year, 26 children aged 1-3 years, 68 children aged 3-10 years and 21 adolescents aged 10-15 years) with normal liver and renal function, receiving consolidation therapy at the Pediatric Clinic of Monza between May 1988 and April 1992, were enrolled in this study. MTX was given as an intravenous infusion in 24 h and serum concentrations were measured up to at least 72 h after the start of infusion by an enzyme immunoassay (TDX Abbot, Dallas, TX) in order to modulate folinic acid rescue. Pharmacokinetic analysis of MTX levels according to a two compartment open model indicated that, compared to all children up to 10 years old, in adolescents older than 10 years the drug reached higher concentrations in serum and was cleared at a lower rate. Steady-state levels and AUC were from 60% higher to more than double and the total clearance of the compound, expressed either per square meter surface area or per kg body weight, in each cycle was significantly lower in adolescents > 10 years of age, sometimes being only one third of the clearance in infants (0.2 vs. 0.6 1/h/kg and 6.6 vs. 10.7 1/h/sq.m). The relationship between each age and systemic clearance was highly significant as measured by regression analysis. Methotrexate systemic clearance progressively decreased as a function of age. Subsequent treatments did not induce changes in MTX pharmacokinetics. These data suggest that the better tolerance of HD-MTX in children may have a pharmacokinetic basis. The faster elimination of MTX in infants, who usually show the worst prognosis, suggests that full doses could be safely used in order to maximize the antileukemic effect without a high risk of toxicity. PMID- 7838037 TI - Survival after retinoblastoma: long-term consequences and family history of cancer. AB - Retinoblastoma (Rb) is a rare childhood tumor of the eye. In the heritable form, tumors are often bilateral and survivors have a greatly increased risk both for a second malignancy and for having children with Rb. Familial patterns of both cancer and birth defects are poorly understood in families with a heritable cancer, and little is known of the ways that a heritable cancer affects the lives of long-term survivors. To find out more about these and other issues in the lives of long-term survivors of childhood and adolescent cancer, we interviewed 56 adult survivors of retinoblastoma (15 with the heritable form) and 84 brothers and sisters as controls, who formed part of a large retrospective cohort study. Rb survivors were interviewed between 1980 and 1983, when they were 30 years old on average. Types of employment and health problems did not differ between survivors and controls, regardless of sight, but the income of blind survivors was considerably less than that of partially sighted survivors. Despite similar marriage rates, fewer survivors than controls reported a pregnancy (RR = 0.45; 95% CI; 0.24-0.83 for both sexes combined). Parents of children with heritable Rb seemed more likely to have had cancer than parents in families with nonheritable Rb (P = 0.06), and mothers were more likely than fathers to be affected (P = 0.01). This small series suggests that having retinoblastoma may have many long term consequences, reaching beyond genetic and physical effects to touch family life and income attainment and the health of other family members. Follow-up of more modern cohorts and the use of molecular tools will clarify the long-term consequences of more recent therapies, and patterns of familiar cancer. PMID- 7838038 TI - Juvenile chronic myelogenous leukemia: in vitro characterization before and after allogeneic bone marrow transplantation. AB - In previously published studies on patients with juvenile chronic myelogenous leukemia (JCML), excessive proliferation of malignant monocyte-macrophage elements and impaired growth of normal hematopoietic progenitors were demonstrated. A selective hypersentivity of granulocyte-macrophage progenitors (CFU-GM) to granulocyte-macrophage colony stimulating factor (GM-CSF) seems to represent the main pathogenetic mechanism. Allogeneic bone marrow transplantation (BMT) has been demonstrated to be the only curative strategy for patients with JCML. In this study, we evaluated the growth of peripheral blood hematopoietic progenitors in semisolid cultures in two children with JCML before and after allogeneic BMT. Serum levels of GM-CSF, interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) were also assessed. IL-1-beta, GM-CSF and TNF-alpha serum levels of the patients before and after BMT did not differ significantly from those obtained in 45 healthy controls. After marrow transplant, the engraftment of donor hematopoietic stem cell was associated with the disappearance of both pretransplant GM-CSF hypersensitivity and CFU-GM spontaneous growth. The inhibitory effect on the growth of normal hematopoietic progenitors also resolved. This confirms that the substitution of the pathological hematopoietic progenitors represents the basis for the curvative effect of allogeneic BMT in the treatment of JCML, abolishing both the excessive responsiveness of JCML progenitor cells even to very low concentrations of GM-CSF and the growth-inhibitory effect on normal hematopoiesis. PMID- 7838039 TI - Cyclophosphamide/doxorubicin vs. cisplatin/teniposide in the treatment of children older than 12 months of age with disseminated neuroblastoma: a Pediatric Oncology Group Randomized Phase II study. AB - This prospective study was designed to estimate the response rates and to compare two drug pairs, cyclophosphamide/doxorubicin (Cy/A) and cisplatin/teniposide (P1/VM) in previously untreated patients with disseminated neuroblastoma > 12 months of age at diagnosis. Estimated complete clinical response rates after five courses of therapy were 13% (70 patients) and 22% (64 patients) for Cy/A and P1/VM, respectively (P = 0.17). After surgical removal of residual tumors in patients with partial response, the complete response rates were 27% and 34% (P = 0.50), respectively. The overall CR/PR rates after induction and surgery were 59% and 73% (P = 0.077). There was no significant difference in event free survival (P = 0.48) or survival (P = 0.40). Five year survival on the two arms were 14% (SE = 5%) and 12% (SE = 4%), respectively. Toxicity was significant but manageable. The Cy/A arm had significantly higher hematopoietic toxicity but significantly lower GI toxicity. Significant allergic reactions were seen with the P1/VM arm, none in the Cy/A arm. Given the activity of these two regimens, further therapy with a combination of these regimens is suggested. PMID- 7838040 TI - Treatment combined with bone marrow transplantation for advanced neuroblastoma: an analysis of patients who were pretreated intensively with the protocol of the Study Group of Japan. AB - One hundred and ten patients with advanced neuroblastoma were treated with the protocol of the Study Group of Japan between January 1985 and March 1991. Patients received six cyclic courses of regimen A1, consisting of cyclophosphamide (1,200 mg/m2), vincristine (1.5 mg/m2), tetrahydropyranyl adriamycin (40 mg/m2), and cisplatin (90 mg/m2). Primary tumors and regional lymph node metastases were removed some time during the first six cycles of regimen A1. After six cycles of A1, the patients were divided into three groups. Patients in group 1 received alternating treatment with regimen B (cyclophosphamide and ACNU) and intensified A1, and those in group 2 were treated with alternating administration of regimen C (cyclophosphamide and DTIC) and intensified A1. Patients in group 3 were treated with supralethal therapy and bone marrow transplantation (BMT). Event-free survival rates at five years were 38.8% in the chemotherapy group (groups 1 and 2) and 50.0% in the transplant group (group 3). Because of the study design that was not in truly randomized fashion and because of the small number of patients in each risk group, it is indicated, though not concluded, that the transplant group had a better prognosis than the chemotherapy group in the cases with stage III disease or with amplified N-myc oncogene, based on the statistical calculations. Differences in survival rates for patients who underwent BMT when complete remission (CR) was achieved and for those who achieved CR but who did not undergo marrow transplant were statistically insignificant. BMT-related death occurred in 3 of 31 cases (9.7%) undergoing marrow transplant, and the causes of the death included hemorrhagic pneumonia, myocardial disturbance and hemorrhagic uremia. PMID- 7838041 TI - Carboplatin in childhood medulloblastoma/PNET: feasibility of an in vivo sensitivity test in an "up-front" study. AB - Sixteen patients with high risk MB/PNET at diagnosis were included in a pilot study employing carboplatin (CBDCA) as a single drug prior to conventional therapy. The main goal of the study was to identify in a short-term trial a significant response that would predict further response to CBDCA in the single patient. Exploration of CBDCA activity was focused on response after the first course as compared to the response following the second course. A course consisted of CBDCA 600 mg/m2 on days 1 and 2 administered in a 1 h infusion to be repeated 3-4 weeks later. After two cycles we observed 1 CR and 9 PR, that is a 62% response rate. The first course resulted in 5 PR, 5 MR, 5 SD, and 1 PD; after the subsequent course in all responding patients, response persisted or improved whereas in no patient with SD any improvement was observed. The correlation of response to the first course with response to the second course was statistically significant (P = 0.0009). The main toxicity of the single course was hematologic and consisted of rapidly reversible grade 3-4 neutropenia and thrombocytopenia in 94% of patients. Pharmacokinetic studies showed a very limited interpatient variability of both Cmax 57.6 +/- 9.9 micrograms/ml) and AUC (15.3 +/- 1.5 mg/ml.min) of free CBDCA, which eliminates an important variable in the evaluation of response. In conclusion, this "in vivo test" appears effective, reasonably safe, and reproducible in identifying patients likely to benefit from CBCDA: after a period of time as short as 3-4 weeks following the first course, multidrug chemotherapy including CBDCA may be employed in the responding patients, whereas an alternative regimen would be indicated in the non-responding patients. PMID- 7838042 TI - Unusual secondary tumors after childhood lymphoid malignancy. AB - Second malignant neoplasms (SMN) in individuals who survived childhood cancer have been reported with increasing frequency during the last decades. The overall probability of developing second malignancy for children treated for cancer was estimated at about 2-5% at 25 years. In children, the tumors most often associated with the development of SMN are retinoblastoma and Hodgkin's disease. We report two cases of unusual second tumors in two patients cured of lymphoid malignancy: one boy cured of acute lymphoblastic leukemia developed mediastinal ganglioneuroma nine years later and one girl had gastric carcinoma seven years after Hodgkin's disease. Both developed a tumor in nonirradiated areas. Gastric carcinoma and ganglioneuroma are not reported as recurrent SMN in survivors after childhood cancer, with one single case of gastric carcinoma and one of ganglioneuroblastoma having been reported as second tumor in survivors after childhood cancer. PMID- 7838043 TI - Cytomegalovirus-associated stage 4S neuroblastoma relapsed stage 4. AB - Neuroblastoma is one of the most frequent solid tumors in childhood, rarely recurrent after five years from diagnosis. Cytomegalovirus (CMV), a major pathogen causing congenital birth defects and severe opportunistic diseases, has been shown to have teratogenic, immunodepressive and oncogenic properties. The case of a girl with stage 4S neuroblastoma diagnosed at three months and relapsed as stage 4 five years later is reported. In both circumstances, active CMV infection was revealed by positive CMV-specific IgM and IgA antibodies, CMV DNAemia and CMV culture. At three months, the patient presented with subcutaneous nodules, hepatosplenomegaly and increased aminotransferase levels, and the opsolonus-myoclonus syndrome. Mental retardation developed later on. At 5 years, relapsed neuroblastoma was preceded by a mononucleosis-like syndrome concomitant with active CMV infection and decreased levels of immune cells and natural killer activity. Clinical, virologic, and immunologic findings suggest an immune mediated pathogenic role for CMV in this tumor. PMID- 7838044 TI - Cardiac tamponade as the initial manifestation of primary pericardial mesothelioma. AB - Although cardiac tamponade is a known complication of malignancy, it is rarely the initial manifestation. We report a 46-year-old male who presented with malignant cardiac tamponade 6 months prior to the definitive diagnosis of primary pericardial mesothelioma. A thorough literature search has not revealed a similar care. PMID- 7838045 TI - Occurrence of Henoch-Schonlein purpura in a child with Wilms' tumor. PMID- 7838046 TI - The spectral dependence of electron central-axis depth-dose curves. AB - Electron linac fields are usually characterized by the central-axis practical range in water, Rp, and the depth of half maximum dose, R50, for dosimetry, quality assurance, and treatment planning. The quantitative relations between the range parameters and the intrinsic linac beam's energy structure are critically reviewed. The spectral quantity * is introduced which is defined as the mean energy of the incident spectral peak, termed the "peak mean energy." An analytical model is constructed to demonstrate the predicted relation between polyenergetic spectral shapes and the resulting depth-dose curves. The model shows that, in the absence of electrons at the patient plane with energies outside about * +/- 0.1 *, Rp and R50 are both determined by *. This analytical approximation is confirmed by a Monte Carlo calculation comparing two different idealized incident spectra. The effect of contaminant lower energy or wide-angle scattered electrons is also discussed. The effect of the width of the intrinsic energy spread on the shape of the depth-dose curve is investigated using Monte Carlo depth-dose simulations based on measured linac energy spectra having energy spreads (full width at half maximum) as large as 20%. These simulations show that the energy spread has only a small effect on the shape of the central-axis depth-dose curve. PMID- 7838047 TI - A solution to the Yang equation with electron energy loss following Harder's formula. AB - The Yang diffusion transport equation for charged particles was modified to allow the linear angular scattering power to vary with penetration depth in the scattering medium. Assuming charged particle energy loss to be a linear function of depth, conditional solutions to this transport equation have been found for the two cases of interest specified by Yang. The normalized excess path length distributions predicted for a 10-MeV electron beam show a shift toward larger excess path lengths compared to Yang's solutions. PMID- 7838048 TI - A Monte Carlo study of accelerator head scatter. AB - The production of off-focus x rays in the head of a 6 MV linac has been investigated using the EGS4 Monte Carlo code. The purpose of the study was to identify the sources of off-focus radiation and the relative contribution for each source. Even though a particular energy and linac were modeled, the broad conclusions are expected to be general since the effects of head scatter are similar for most conventional head designs, regardless of manufacturer, energy, and model. The head components that were modeled include the exit window of the accelerating structure, target, beam stopper, flattening filter, monitor chamber, primary and secondary collimators, and air. Monoenergetic 6 MeV electrons were followed through the exit window, target, and beam stopper until all energy was expended. Primary- and higher-order x rays produced throughout the head were followed until they were either absorbed or passed through a plane at the isocenter. Sites of off-focus radiation were found to be diffusely distributed throughout the head, with the most intense sources being the primary collimator, flattening filter, and beam stopper. Data analysis shows that the collimator effect is determined primarily by the volume of the extended head-scatter source that is exposed to the point of measurement through the collimating system. The results of this study provide a rationale for developing extended source models to calculate the collimator factor for fields defined by arbitrary collimation. An additional advantage is an improvement in the agreement between measured and calculated isodose distributions. PMID- 7838049 TI - Convolution calculations of dose in the buildup regions for high energy photon beams obliquely incident. AB - The central dose received from high energy photon beams that are obliquely incident on an absorber is markedly different from that absorbed when such beams are normally incident at the surface. In this work, we calculate the dose differences using a convolution of energy deposition kernels in a phantom presenting an oblique entrance surface. The dose distributions were calculated with oblique incident 1.25, 3, and 6 MeV monoenergetic and polyenergetic photon beams angled from 0 degrees to 80 degrees. In order to study the dose variations with surface obliquity, we introduced an obliquity factor. For each energy, the obliquity factor was calculated as a function of depth and field size. We found that, ignoring the electron contamination from the air and from the treatment machine head, the influence of obliquity can be described in terms of upstream and downstream contribution of the electrons set in motion by the primary photons. In actual beams, especially for large field sizes, the electron contamination becomes significant and tends to reduce the influence of surface obliquity. Results indicate that the obliquity factor is highly dependent on the beam energy and depth, and are in good agreement with our experimental results measured for 10 and 25 MV x-ray beams. In this paper a theoretical explanation of these dose variations due to oblique incidence of the beam is presented. PMID- 7838050 TI - An improved bolus configuration for commercial multielement ultrasound and microwave hyperthermia systems. AB - A simple modification is presented for two commercially available hyperthermia applicators which dramatically improves the regulation and dynamic control of the temperature at the bolus/tissue interface. This alteration requires the addition of a variable speed pump, bubble trap, simple heat exchanger, and a few minor changes to the existing system. With this modified design, the water within the bolus is directly circulated and temperature controlled. The convective nature of the circulating system ensures uniform temperature throughout the extended bolus and increases the thermal energy transfer at the bolus/tissue interface. This modification also provides significantly improved flexibility in controlling the treatment temperature distributions since the bolus/tissue interface temperature can now be dynamically varied during a treatment, in addition to adjusting the applicator power output and frequency. PMID- 7838051 TI - Dosimetric parameters of a modified set of wedges for use with asymmetric fields of a 6 MV linear accelerator. AB - A set of standard wedge filters has been modified for use with half-collimated beams of a 6 MV linear accelerator. The position of the standard size wedge filter has been shifted as far to one side of the wedge plate to ensure optimum half-collimated field coverage (up to 20 x 30 cm) required in certain clinical situations. Dosimetric parameters were normalized at 1.5 cm depth and at an off axis reference point (3.5 cm from the central axis of the collimator at 100 cm SSD. The shapes of the wedged profile and isodose curves of the modified wedges remained similar to those of standard wedges. Data presented include wedge transmission factors, wedge angles, beam profiles, and isodose distributions. The clinical advantages of using modified wedge filters (larger field size, larger transmission, and smaller weight) over standard large wedges is discussed. PMID- 7838052 TI - Quantitative bremsstrahlung imaging of yttrium-90 using a Wiener filter. AB - Yttrium-90 (90Y), a pure beta emitter, is an attractive radionuclide for radioimmunotherapy of cancer. Therapeutic management requires quantitative imaging to measure the pharmacokinetics of the radionuclide in the patient for radiation dosimetric calculations. The bremsstrahlung emissions can be utilized to acquire an image of beta sources using a gamma camera. Quantitation of 90Y by bremsstrahlung imaging is difficult because of poor image quality that results from septal penetration and scatter secondary to the broad bremsstrahlung energies. In this work, quantitative methods for bremsstrahlung imaging of 90Y sources that involved the use of (a) a Wiener filter to deconvolve the septal penetration and scatter while suppressing image noise, and (b) the geometric mean of the conjugate view (GM) and effective point source (EPS) methods to quantify activities were investigated. An abdominal phantom was prepared with 90Y activities in the liver, spleen, tumors, and background volumes that were similar to those observed in patient studies. A twofold improvement in resolution recovery for full width at tenth maximum of the line spread function at 11 cm depth in water was achieved using Wiener restoration. Definition of the organ and tumor edges was greatly enhanced and cross talk between adjacent sources was suppressed after Wiener restoration. These improvements in image quality led to more accurate estimation of organ and tumor activities. Using the optimum attenuation correction method for GM and EPS quantitation of filtered bremsstrahlung images, estimates of individual activities (< or = 17% error) and cumulated activities (< or = 8% error) in all of the sources were accurate except for a tumor of 2 cm diameter. The results of this study provide the basis for a method to quantify beta source distribution and demonstrate the potential use of bremsstrahlung imaging in clinical settings. PMID- 7838053 TI - An automated image-registration technique based on multiple structure matching. AB - A new image-registration technique that matches multiple structures on complementary imaging data sets (e.g., CT and MRI) has been developed and tested with both phantom and patient data. The algorithm assumes a rigid-body transformation and is suitable for correlating structures within the cranium or at the skull base. The basic premise of the new technique is that an optimum transformation is achieved when the relative volume lying outside of the intersection between a structure and its transformed counterpart is a minimum. This relative volume is calculated numerically using a random sampling approach, and a binary searching algorithm was used to step through the nine-dimensional parameter space consisting of three rotation angles, three scaling factors and three components of a translation vector. For the nine tests using phantom data, the automated structure-matching technique was able to predict the correct rotation angles to within +/- 1 degree. The expected clinical performance of the new technique was assessed by comparing results obtained with the new method to those obtained using other techniques for 12 patients who were treated with charged particles at Lawrence Berkeley Laboratory (LBL) and who had image registration studies performed as part of their treatment plan. For 9 of the 12 patients considered, the new structure-matching technique produced a significantly better registration than the older methods, as measured by the resultant average relative volume lying outside of the intersection between any structure and its transformed counterpart. For the other three patients, results were not significantly different for the new structure-matching method and the older techniques. PMID- 7838054 TI - Unfolding patient motion with biplane radiographs. AB - A method of unfolding patient movement between biplane radiographs is presented. This method requires biplane projections of two points with a known separation to determine a translation motion or biplane projections of two or three point pairs to determine a general patient motion. Such a point pair can be provided by two ends of a line source or two radiopaque marks, with a fixed distance between them. The point pairs can be taped on skin, implanted in the target volume, or embedded in the bony structures. After obtaining the point locations on each film, the three-dimensional coordinates of points of interest at the instant of each view can be reconstructed, with an error of less than 0.5 mm. The motion parameters, characterized by a pseudotranslation vector and three axial rotational angles for the region of interest relative to the machine coordinate system, are also provided. In comparing with some other reconstruction algorithms, the point pair method can significantly improve source localization or point reconstruction in the presence of patient motion. Computer simulations and phantom experiments demonstrates the feasibility and accuracy of the method. PMID- 7838055 TI - Optimal radiographic magnification for portal imaging. AB - Two approaches to estimate the optimal radiographic magnification for a TV camera based portal imaging system and portal films have been used. The first approach optimizes signal transfer while the second optimizes signal-to-noise ratio (SNR) transfer. In order to perform these optimization calculations, the physical characteristics of the imaging system (modulation transfer function and noise power spectrum) as well as the sizes of the radiation sources of our medical linear accelerators have been measured. Using these data, the optimal magnification considering signal transfer alone (M signal) has been calculated to range between 2.0 and 2.3 for the TV camera-based imaging system and is about 1.0 for portal films. Conversely, the optimal magnification considering SNR transfer (MSNR) has been calculated to range between 1.5 and 1.7 for the TV camera-based imaging system and is about 1.0 for portal films. The results suggest that most portal imaging systems are operated close to their optimal radiographic magnification. PMID- 7838056 TI - Input/output characteristics of a matrix ion-chamber electronic portal imaging device. AB - The input/output characteristics of a matrix liquid ion-chamber electronic portal imaging device (EPID) are investigated to elucidate the imaging properties of EPIDs. The radiation input to the detector, represented by dose rate, and the pixel value output from the device are related by a characteristic curve. Various incident radiation intensities are obtained by changing the source-to-detector distance (SDD). For each incident radiation intensity, an electronic portal image is obtained using a field size of 5 x 5 cm2. The output pixel value of the EPID is represented by the average pixel value of a region of interest of 9 x 9 pixels centered at a selected point. The effects of various accelerator settings, such as the repetition-rate setting and photon energy, gantry angle, field size, SDD, and acquisition mode of the EPID on characteristic curves are investigated at the central axis. The off-axis response of the detector is also examined. The derivative of the pixel value with respect to the input dose rate is used to analyze the detector contrast. Results indicate that the output pixel value is not a linear function of the incident radiation intensity. The detector contrast is comparable between photon energies of 10 and 6 MV and increases at low dose rates. The response of the imaging device varies substantially with acquisition mode, but is less sensitive to the SDD used for calibration. Characteristic curves are consistent for different gantry angles at the central axis and with the off-axis locations when the gantry angle is used for imaging and calibration, but vary with off-axis locations when the gantry angle is not at the calibration direction. Characteristic curves are also found to vary with different field sizes, but are similar in shape. PMID- 7838057 TI - Incorporation of scattered radiation into dual-energy radiologic theory and application to mammography. AB - A previous analysis of dual-energy imaging is extended to incorporate scattered radiation. The analysis is general and can include polyenergetic beams and nonideal detectors. In the dual-material basis plane, scatter generates a displacement of the vectors representing the imaged materials. This changes the target versus background signal difference and the projection angle for cancellation of background contrast due to varying amounts of two materials. Complete cancellation is not possible, because vectors representing various mixtures of the two background constituents are displaced differently and thus no longer lie on a straight line in the dual-material plane. The effect can be minimized by allowing a typical amount of scatter to reach the image receptor when determining the parameters of the transformation from log attenuation to equivalent materials thicknesses. The analysis has been applied to dual-energy mammography. The presence of scatter has minimal effect on the optimum beam energies with an ideal detector, which are about 20 and 70 keV. PMID- 7838058 TI - A model for optimization of spectral shape in digital mammography. AB - X-ray mammography is the most sensitive imaging modality available for the detection of breast cancer. The highest performance can only be achieved, however, if the complete imaging system is optimized. The development of digital mammography offers an opportunity to obtain improved sensitivity in mammography. In such systems, the decoupling of the recording and display processes allows each component of the imaging system to be optimized separately. In this paper we describe a method for optimizing the recording process for digital mammographic techniques. Our method uses an energy transport model of the propagation of signal and noise through the imaging system. The computations make use of experimentally determined data wherever possible so that the number of assumptions in the model can be minimized. The model predicts the signal-to-noise ratio for a constant dose to the breast, and therefore allows comparison and optimization both for different x-ray spectra and for different imaging tasks. The major energy-dependent components of the model have been verified, and good agreement is demonstrated between predictions by the model of both contrast and SNR and experimentally measured values. Calculations for a particular imaging task, detection of a 200-microns cubic calcification in a 6-cm, 50% adipose-50% glandular breast, illustrate application of the model for optimization of spectral shape. PMID- 7838059 TI - Optimization of spectral shape in digital mammography: dependence on anode material, breast thickness, and lesion type. AB - It has been proposed that breast cancer detection can be improved through the use of digital mammography. It is hypothesized that the choice of proper shape of the x-ray spectrum incident upon the breast can yield an improved image signal-to noise ratio (SNR) for a given dose. To test this hypothesis, an energy transport model incorporating measured breast tissue attenuation coefficients and published exposure-to-dose conversion values was developed to describe the image acquisition process. The choice of applied kilovoltage and filter for Mo and W target x-ray sources has been optimized with respect to SNR and absorbed dose for detectors based on a Gd2O2S scintillating screen under the conditions of perfect coupling of light between the screen and a solid state photodetector. For the W spectra, the optimum filter-kVp combinations could provide 41%, 13%, and 42% improvements in SNR for 2-cm, 6-cm and 8-cm breasts, respectively, over the conventional Mo filtration, for a practical imaging time of 1.0 s. W and Mo spectra produce similar SNR values for a given filter thickness except for the 4 cm breast. Given the limitations of current technology, however, the W spectra produce the optimum SNRs in a shorter imaging time for breast thicknesses greater than and less than 4 cm. The maximum SNR for imaging both infiltrating ductal carcinoma and calcifications is provided by the same filter-kVp combination, allowing optimization based on breast thickness and composition only. The model can now be used to compare and improve upon novel detector designs. PMID- 7838060 TI - Objective performance characteristics of a new asymmetric screen-film system. AB - A study of the objective imaging characteristics of a new asymmetric screen-film system is presented herein. The system is characterized by high x-ray absorption asymmetric screens, and a low-noise, high-contrast asymmetric film having near zero crossover. Comparisons are made with the imaging characteristics of two widely used conventional screen-film systems. Sensitometry, modulation transfer function, and noise power spectra were measured using standard methods. Granularity, noise equivalent quanta, and detective quantum efficiency were computed from these. The new screen-film system has an average gradient at lung field densities between the two conventional systems studied, while the mediastinum contrast exceeds both conventional systems. The lung-field modulation transfer function half bandwidth of the new asymmetric system exceeds that of both conventional systems by 60%. At mid exposures the detective quantum efficiency of the new asymmetric system is comparable to those of the conventional systems studied. However, the exposure range over which detective quantum efficiency remains high is substantially wider. PMID- 7838061 TI - Spatial variation of section sensitivity profile in spiral computed tomography. AB - The section sensitivity profile (SSP) is widely used to describe the longitudinal image resolution in computed tomography (CT). Due to asymmetry in spiral CT interpolation, the SSP depends on the transverse position of the associated longitudinal line. Spatial variation in the spiral CT SSP has not been investigated previously. To determine the SSP variation over the scan field, the SSP for the half-scan interpolation method in terms of its transverse position was formulated. Based on the SSP formula, mathematical analysis and numerical simulation were performed. It was shown that the SSP associated with a transverse slice is antisymmetric with respect to the abscissa axis (which connects the slice center and the source location in the slice). Moment analysis was conducted on the SSP up to order three. The area under the SSP is equal to that under the longitudinal detector response function. As a result, with a normalized SSP the total mass of an object approximately remains after reconstruction. The mean of the SSP is equal to zero, although the SSP is asymmetric. The standard deviation and skewness of the SSP were numerically simulated and plotted for typical imaging parameters. It was demonstrated that for a 50 degrees fan angle (which is extended by two extreme rays in a fan beam) the relative change in the slice thickness is no more than 10%, while the skewness of the SSP is within about 0.15. The smaller the fan angle, the less the SSP spatial variation. Therefore, in spiral CT the SSP along the longitudinal axis can be used as a representative of the SSP family. PMID- 7838062 TI - Attenuation properties of diagnostic x-ray shielding materials. AB - Single- and three-phase broad-beam x-ray attenuation data have been obtained using lead, steel, plate glass, gypsum wallboard, lead acrylic, and wood. Tube voltages of 50, 70, 100, 125, and 150 kVp were employed and the resulting curves were compared to transmission data found in the literature. To simplify computation of barrier requirements, all data sets were parametrized by nonlinear least-squares fit to a previously described mathematical model. High attenuation half value layers and the lead equivalence of the alternate materials were also determined. PMID- 7838064 TI - Effects of ornithine aminotransferase inactivation by 5-fluoromethylornithine in rats following portacaval anastomosis. AB - 5-Fluoromethylornithine (5FMOrn) is a selective inactivator of ornithine aminotransferase. Administration of this compound to rodents causes a prominent increase of tissue ornithine concentrations, and prevents the neurological consequences of acute ammonia intoxication. However, long-term treatment with 5FMOrn of rats with portacaval shunts did not result in decreased circulating ammonia concentrations, nor did it prevent other pathologic manifestations of shunting. The sensitivity to ammonia intoxication of rats with portacaval shunts was also unaffected by pretreatment with 5FMOrn, although liver ornithine concentrations were significantly elevated; specific activities of urea cycle enzymes were slightly higher in portacaval shunted compared to sham-operated controls following 5-FMOrn treatment. Administration of 5FMOrn dramatically elevated urinary excretion of several amino acids in rats with portacaval shunts, but not in sham-operated animals, suggesting that the reabsorption of amino acids from the glomerular filtrate may be impaired in shunted rats. These results suggest that, in contrast to acute hyperammonemic syndromes, 5-FMOrn may be of limited therapeutic value in chronic hyperammonemia syndromes in which there is significant portal-systemic shunting. PMID- 7838065 TI - An immunohistochemical study of parvalbumin containing interneurons in the gerbil hippocampus after cerebral ischemia. AB - We investigated postischemic changes of non-pyramidal neurons in the gerbil hippocampus 1 h - 7 days after 10 min of cerebral ischemia, with parvalbumin and microtubule-associated protein 2 (MAP2)-immunohistochemistry. Parvalbumin immunoreactive interneurons in the hippocampus were unaffected up to 24 h after ischemia. A slight reduction of the immunoreactivity in neuronal processes was seen in the hippocampal CA1 sector 48 h after ischemia. Seven days after ischemia, a marked loss of parvalbumin-immunoreactive interneurons was observed in the hippocampal CA1 and CA3 sectors. Furthermore, reduced staining in the dentate granular and molecular layers was observed. MAP2-immunoreactive pyramidal neurons in the hippocampus were unchanged up to 48 h after ischemia. Seven days after ischemia, a severe loss of MAP2 immunoreactivity was found in the hippocampal CA1 and CA3 neurons and dentate hilar neurons. However, scattered CA1 neurons, most likely interneurons, preserved MAP2 immunoreactivity. The results demonstrate that transient cerebral ischemia can cause a loss of parvalbumin immunoreactive interneurons in the hippocampus. Furthermore, some interneurons seem to lose parvalbumin synthesis. Although dentate granule cells are resistant to ischemia, considerable reductions of afferent input was suggested by parvalbumin staining. PMID- 7838066 TI - Protein synthesis in the hippocampal slice: transient inhibition by glutamate and lasting inhibition by ischemia. AB - Protein synthesis was measured in hippocampal slices which were exposed to glutamate (1 mM or 10 mM) or which were deprived of glucose and oxygen ('in vitro ischemia') for 15 min. Glutamate at 1 mM, a concentration estimated to occur during in vivo ischemia did not affect protein synthesis. Ten mM glutamate inhibited protein synthesis immediately after exposure (50% of control values) and reduced ATP levels to about 30% of the control. After two hours, slices fully recovered their protein synthesis and energy metabolism. The effect of 10 mM glutamate was not receptor-mediated, as NMDA, AMPA, or metabotropic receptor antagonists failed to block the glutamate effect. Immediately after ischemia, protein synthesis was reduced to 30% of control values, and 2 hours later it was still depressed to one-half of control values. Energy charge, however, recovered completely. Ischemic inhibition of protein synthesis was not reversed by glutamate receptor antagonists. The data indicate that inhibition of protein synthesis in hippocampal slices during ischemia is not glutamate-dependent. PMID- 7838063 TI - Thiamine in excitable tissues: reflections on a non-cofactor role. PMID- 7838067 TI - Ammonia added in vitro, but not moderate hyperammonemia in vivo, stimulates glutamate uptake and H(+)-ATPase activity in synaptic vesicles of the rat brain. AB - The uptake of radiolabelled neurotransmitters: glutamate (GLU), GABA, and dopamine (DA) and the activity of the vacuolar type H(+)-pumping ATPase (H(+) ATPase), were measured in crude synaptic vesicles treated in vitro with a neurotoxic (3 mM) dose of NH4+ (acetate or chloride), or isolated from rats with a moderate increase of brain ammonia (to approximately 0.6 mM) induced by i.p. administration of ammonium acetate (HA rats) or a hepatotoxin-thioacetamide (HE rats). In vitro treatment with ammonium salts increased the sodium-independent, chloride-dependent uptake of GLU but did not stimulate the uptake of GABA or DA. The in vitro treatment also stimulated the H(+)-ATPase activity. Since H(+) ATPase generates the electrochemical gradient driving synaptic vesicular neurotransmitter transport, its stimulation by ammonia may have facilitated GLU uptake. However the GLU specificity of the effect must be related to other factors differentially affecting GLU uptake and the uptake of other neurotransmitters. Enhanced GLU accumulation in the synaptic vesicles may contribute to the increase of synaptic GLU exocytosis previously reported to accompany acute increases of brain ammonia to toxic levels. However, GLU uptake and H(+)-ATPase activity, but also the uptake of GABA and DA, were unchanged in synaptic vesicles prepared from rats with HA or HE. This indicates that changes in GLU and/or GABA release reported for moderate hyperammonemic conditions must be elicited by factors unrelated to the synaptic vesicular transport of the amino acids. PMID- 7838068 TI - Densities of binding sites for the "peripheral-type" benzodiazepine receptor ligand 3H-PK11195 are increased in brain 24 hours following portacaval anastomosis. AB - Quantitative receptor autoradiography was used to measure the densities of binding sites for the "peripheral-type" benzodiazepine receptor ligand 3H-PK11195 in regions of the rat brain 1, 3, 7 and 28 days following portacaval anastomosis (PCA) and in sham-operated control animals. The results demonstrate that densities of 3H-PK11195 binding sites were significantly increased in the cerebral cortex (by 40%, p < 0.05) as early as 24 hours following PCA. In the thalamus significant increases in densities of 3H-PK11195 binding sites were seen 3 days after PCA, whereas in brain regions such as the striatum and cerebellum, significant increases in 3H-PK11195 binding sites were not evident until 7 days following PCA. By 28 days following PCA increased densities of 3H-PK11195 binding sites were well established and widespread throughout the brain. Previous studies demonstrate early increases of brain ammonia following PCA. PTBRs or their endogenous ligands could play an important role in the early astrocytic response (mitochondrial proliferation, swelling) to ammonia following PCA. PMID- 7838070 TI - "Functional" postoperative stridor following cesarean section under general anesthesia. PMID- 7838069 TI - Interaction between histamine and adenosine in human cerebromicrovascular endothelial cells: modulation of second messengers. AB - This study demonstrates the presence of histamine H1 and H2 receptors and purinoreceptors A1 and A2 on endothelial cells derived from human brain microvessels (HBEC). Histamine induced formation of both inositol triphosphate (IP3) (EC50 = 10.2 +/- 0.9 microM) and cyclic adenosine monophosphate (cAMP) (EC50 = 5.2 +/- 0.9 microM) in HBEC in a concentration-dependent fashion. IP3 formation was inhibited by H1 receptor antagonists mepyramine maleate and chlorphenyramine, but not by H2 receptor antagonist cimetidine. Production of cAMP was efficiently inhibited by cimetidine. Selective A1 receptor agonists decreased, whereas A2 receptor agonists increased cAMP production in HBEC. When added together with histamine to HBEC cultures, both A1 and A2 receptor agonists diminished histamine-induced IP3 stimulation. This effect was reversed in the presence of specific A1 and A2 receptor antagonists, respectively. Marked augmentation of histamine-induced cAMP production by HBEC was observed in the presence of A2 agonist. This response was dependent on H1 receptors, since it was reduced in the presence of H1-receptor antagonist. It is suggested that interaction between histamine and adenosine modulating induction of second messengers in HBEC may influence endothelium-dependent responses of brain microvascular compartments. PMID- 7838071 TI - Heat-related illnesses. PMID- 7838072 TI - Malignant hyperthermia--a case report. AB - An acute episode of a malignant hyperthermia-like syndrome is described which occurred after suxamethonium and halothane anesthesia in a 32 year old healthy male patient undergoing a tendon repair operation to his right thumb. Dantrolene therapy rapidly reversed the life threatening signs. PMID- 7838073 TI - Intraarticular opioid-local anesthetic combinations for chronic joint pain. PMID- 7838074 TI - FIO2 of 1 and CPAP 10 during one lung ventilation. PMID- 7838075 TI - The swivel connector for attenuation of hypoxemia during tracheal suctioning. PMID- 7838076 TI - The direction of educational leadership. PMID- 7838077 TI - Should nurses be studying bioscience? A discussion paper. AB - The growth of bioscience knowledge over the last two decades has increased the potential benefits of scientifically based patient care by contributing to the theory of clinical care. However, there is little evidence that knowledge, derived from the human biosciences is being fully incorporated into nursing theory and practice. Nursing has developed its own unique professional body of knowledge, heavily influenced by behavioural science. If nursing theory leans towards behavioural science, but practice is devoted to problems of biological disturbance, nursing may be facing a widening theory-practice gap, greater than other professions. The theory-practice gap in nursing may be widened by the exclusion of bioscience from nursing theory. Nurses' relative disinterest in the natural sciences can be attributed both to sociological reasons and to problems stemming from the symbol-object dichotomy that recur in the teaching of natural sciences. Reflection on practice and examination of education method are suggested as strategies for re-introducing bioscience into nursing theory and practice. A challenge facing nurse educators is the integration of biological science into the nurses' conceptual ecologies. For, if nursing fails to make bioscience its own, much of the clinical welfare of patients will become a medical monopoly. PMID- 7838078 TI - A comparison between the roles of part-time and full-time clinical tutors: is there a difference? AB - Recent changes in pre-registration radiographer education required quality issues concerning students' clinical experience to be reviewed. This investigation was undertaken to illuminate one important aspect of clinical education: the way in which clinical tutors spend their time. The study described, quantified and compared the role of part-time tutors with those who are employed full-time. From the data, three main roles for tutors emerged: duties associated with students, duties of a professional nature, and duties which were considered to be developmental. On the basis of the results, it seems reasonable to suggest that, because part-time tutors devote as much time to students as those employed full time, there is no disadvantage to students. However, further research is required concerning the role and duties of clinical tutors. In addition, recommendations for improving the current methodology are made, if the study is repeated. PMID- 7838079 TI - A survey of the teaching and learning of biological sciences on undergraduate nursing courses. AB - Curriculum planners developing degree courses in nursing have to decide how much time to allocate to each of the academic disciplines including biological sciences. There is no research-based evidence to suggest what depth and detail of knowledge of biological sciences is required to support nursing practice. There is also some debate about the teaching methods used and who should teach the biological sciences. This paper reports the results of a small survey investigating the teaching of biological sciences on 16 nursing degree courses in the UK. The survey uncovered great variation in the number of hours spent on biological sciences in the different universities and in the science entry requirements of the different universities. Most teachers of biological sciences had a first degree in the subject but few were nurses. The possible implications of these findings are discussed. Problems associated with shared learning and didactic teaching methods are also highlighted. Although the biological sciences input will largely be a matter of institutional preferences, nursing needs to develop a research-based framework to aid curriculum planning. PMID- 7838080 TI - Teaching social and behavioural sciences: have we delivered--have they got it? AB - The inception of Project 2000 and its new curriculum has set a requirement for the teaching of Social and Behavioural Sciences in the nursing programme. Subjects covered are Health Promotion, Sociology/Social Policy, Psychology, Research and Computers. These subjects are complex and this paper outlines the problems and difficulties experienced by teachers since the start of the course in 1991. The problems experienced by the students in relating theory to practice are also discussed. PMID- 7838081 TI - Meeting the learning needs of post-myocardial infarction patients. AB - The current emphasis on programme evaluation and the gravitation towards total quality management models have challenged health care professionals to determine the effectiveness of available services in facilitating measurable changes in patient behaviour and in reducing acute care costs. This paper examines the current state of knowledge regarding the effectiveness of in-patient teaching programmes for clients sustaining acute myocardial infarction. A critical review of the literature examining this is presented and an alternative model for education programmes for this patient population is proposed. The new model incorporates adult learning theory, principles of self-directed learning and recognises the negative effect of stress on learning. This multidimensional approach may be more useful in facilitating long term changes in patient behaviour and, ultimately, in reducing acute care costs. PMID- 7838082 TI - Clinical staff and the new student nurse: anticipating change. AB - This article focuses on the feelings and perceptions of clinical staff who are about to encounter Project 2000 students. It makes use of selected findings from a small exploratory study in which interviews were used to gather qualitative data from such staff. There is a brief consideration of the historical context of nurse education from which Project 2000 has arisen and the legislation that has been instrumental in its development. Embodied within this change is the expectation that clinical staff will continue to contribute to the education of student nurses on clinical placements. The target population for this study was identified as clinical staff who would be working with Project 2000 students within a large general teaching hospital. Through means of taped informal interviews, the study explored the world of the clinical staff in relation to their expectations of Project 2000 students. It identified feelings of threat, lack of communication and issues of change and its implementation. For successful implementation and wide acceptance of such a radical change in nurse education, consistency of knowledge and communication was shown to be essential. PMID- 7838083 TI - Fecal occult blood testing in a community cancer screening center. PMID- 7838084 TI - Clinical ethics: must nurses be forever in the middle? PMID- 7838085 TI - Health care groups join together to oppose provider participation in executions. PMID- 7838086 TI - Update: AIDS among women--United States, 1994. AB - In 1993, human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) was the fourth leading cause of death among women aged 25-44 years in the United States (1); in addition, the incidence of AIDS is increasing more rapidly among women than men (2). Women with AIDS reported in 1994 represented 13% of the cumulative total of 58,448 cases among women. This report presents characteristics of women and men reported with AIDS in 1994, summarizes trends in cases reported during 1985-1994, and describes findings of an HIV seroprevalence survey among childbearing women during 1989-1993. PMID- 7838087 TI - Update: influenza activity--United States, 1994-95 season. AB - Influenza activity has increased throughout the United States since late November 1994; however, the level of activity has varied widely in different parts of of the country. This report summarizes results of influenza surveillance in the United States from October 2, 1994, through January 28, 1995.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7838088 TI - Human rabies--West Virginia, 1994. AB - On October 15, 1994, a 41-year-old male resident of Wirt County, West Virginia, died from rabies. This report summarizes the clinical course, epidemiologic investigation, and probable exposure history of this case.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7838089 TI - Pregnancy-related mortality--Georgia, 1990-1992. AB - Many pregnancy-related deaths are preventable. State-based surveillance is important for identifying such deaths and developing prevention strategies. Surveillance for pregnancy-related deaths based only on ascertainment through death certificates underestimates actual deaths (1-7). However, when this surveillance method has been supplemented by linking death certificates of reproductive-aged women to birth and fetal death records, ascertainment has increased 1%-153% (1,2,4,6,7). In 1994, the Division of Public Health, Georgia Department of Human Resources, assessed the completeness of reporting of pregnancy-related deaths during 1990-1992 by comparing current death-certificate based surveillance with a supplemental method of linking women's death records and infants' birth records. This report characterizes the increase in the total number of pregnancy-related deaths identified and presents specific causes of pregnancy-related deaths in Georgia.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7838090 TI - Publication of guidelines for the prevention and treatment of B virus infections in exposed persons. PMID- 7838091 TI - [Progress on various fields of medicine and education of surgery]. PMID- 7838092 TI - [Molecular biology and surgery]. PMID- 7838093 TI - [Treatment of multiple trauma]. PMID- 7838094 TI - [Management of postoperative complications]. PMID- 7838095 TI - [Significance of image diagnosis of acute abdomen]. PMID- 7838096 TI - [Surgical treatment in patients with various diseases]. PMID- 7838097 TI - [Management of post-gastrectomy disorders]. PMID- 7838098 TI - [Quality of life after surgical treatment of patients with liver, biliary and pancreatic neoplasms]. PMID- 7838099 TI - [Surgical techniques and treatment of Crohn disease]. PMID- 7838101 TI - [Therapy of recurrent breast neoplasms]. PMID- 7838100 TI - [Clinical study on the progress of assisted circulation and heart-assisted devices prior to heart transplantation]. PMID- 7838102 TI - [Surgical treatment and adjuvant therapy of patients with neoplasms]. PMID- 7838103 TI - [Progress and problems in the treatment of neuroblastoma]. PMID- 7838104 TI - [An experimental study on radiotherapy for esophageal cancer using intraluminal administration of radiosensitizer]. AB - This study was undertaken to evaluate the efficacy of intraluminal administration of 5-bromo-2'-deoxyuridine (BUdR) as a radiosensitizer during radiotherapy for esophageal cancer. Lipid-surfactant mixed micelles (MM) was used as an absorption promoter. VX2 carcinoma cells were endoscopically injected into the esophageal wall of rabbits. Two weeks after tumor inoculation, BUdR (100 mg/body) with MM was administered into the esophageal lumen and kept for 3 hours. Subsequently, animals were irradiated with 60Co at dosages of either 5 or 10 Gy. Twelve days after, animals were sacrificed to determine tumor diameter and to evaluate histological effect of radiation. BUdR uptake rates of tumor tissue were determined two weeks after tumor inoculation. Tumor diameters in control animals and those treated with simple irradiation at a dose of 5 Gy were similar. In contrast, irradiation at a dose of 5 Gy significantly reduced tumor diameters when combined with intraluminal administration of BUdR with MM. In cancer bearing animals receiving irradiation under intraluminal injection of BUdR with MM, the histological effect were apparently enhanced as compared to animals receiving simple irradiation. BUdR uptake rates of primary tumors showed a significant increase in animals with the intraluminal administration of the drug as compared the those with intravenous one shot bolus and intravenous drip infusion. Based on those results, we conclude that preoperative radiotherapy combined with intraluminal administration of radiosensitizer could be an effective method. PMID- 7838105 TI - [Function of the upper esophageal sphincter after denervation of recurrent laryngeal nerves and intramural nerves of the cervical esophagus in dogs]. AB - The upper esophageal sphincter prevents reflux into the pharynx. If it functions improperly, aspiration pneumonia can result. We studied the functioning of the sphincter in unanesthetized dogs after denervation under anesthesia of the recurrent laryngeal nerves. The pressure of the sphincter at rest was measured by manometry with a transducer that measured pressure around the tip of a catheter. Then the pressure in response to inflation of a balloon to the diameter of 1.5, 2.0 and 2.5 cm at 5 and 10 cm aboral to the sphincter was measured. Next, the pressure during perfusion of 0.1 N HCl or NaOH 10 cm aboral to the sphincter was measured. These studies were done first in 10 dogs that had undergone only gastrostomy for measurements (controls). Measurements were repeated after the left recurrent laryngeal nerve in the controls was cut (L group), after the right recurrent laryngeal nerve in the L group was cut (B group), and after transection of the esophagus 7 cm aboral to the sphincter in the B group (T group). The differences in the pressure at rest were not significant. In each group, balloon inflation to any diameter tested and at either position made the pressure rise above that at rest. This pressure in the L, B, and T groups, however, was significantly lower than in the controls. When the balloon was inflated to 2.5 cm when it was 10 cm aboral to the sphincter, the pressure in the T group was significantly lower than in the B group. When HCl or NaOH were perfused, the pressure increased gradually in the controls, but not in the other groups. In conclusion, although recurrent laryngeal nerves did not affect the function of the sphincter at rest, they were the afferent routes of the contraction by the sphincter as a reflex following distension or chemical stimulation of the esophagus. The intramural nerve network of the cervical esophagus may be another reflex route of contraction of the upper esophageal sphincter. PMID- 7838106 TI - [Inhibitory effects of OK-432 administered orally on colon carcinoma induced by DMH in rats]. AB - Inhibitory effects of OK-432 administered orally on DMH-induced colon tumors in rats were examined. As for the immunological parameter, NK activity was measured. ODC activity and nuclear DNA ploidy pattern of the tumor involved areas were evaluated and the histological examination was done in the process of the occurrence of tumors. Rats were divided into four groups as follows; control group, OK-432 group, DMH group and DMH+OH-432 group. As for the appearance of DMH induced colon tumors, the average numbers of tumors per rat in the DMH+OK-432 group were inhibited significantly compared with those in the DMH group, and the rate of cancer in situ in the DMH+OK-432 group significantly increased compared with that in the DMH group. NK activity of lymphocytes in the spleen and lymph nodes in the colon was increased after the oral administration of OK-432, but it was decreased following the peak activity, and it was lower level than that of the control group. An appropriate oral administration of OK-432 may be effective against chemically induced carcinoma of the colon. PMID- 7838107 TI - [Effect of RES on liver regeneration and survival after 90% partial hepatectomy]. AB - In previous studies, 90% partial hepatectomy in the rat was invariably accompanied by 100% mortality within 40 hr. This paper describes the effect of enhanced reticuloendothelial system (RES) on liver regeneration after 90% partial hepatectomy. RES was activated using 5 K.E. of OK-432 injected intraperitoneally 24 hr before 90% partial hepatectomy. Ninety per cent of the liver mass was resected and rats were provided with tap water or 20% glucose orally and subcutaneously. Survival time was strikingly different. In rats provided with tap water only; 100% of rats died before 42 hr. In rats provided with 20% glucose; 44.2% of rats survived beyond 42 hr. In rats pretreated with OK-432 and provided with 20% glucose; 87.0% of rats survived beyond 42 hr. This regimen results in severe hypoglycemia and dead within 42 hr. When RES was activated before 90% partial hepatectomy, significantly higher blood glucose level was observed. BrdU labeling index was significantly higher in rats pretreated with OK-432 than in control rats. The results indicate that enhancement of RES before 90% partial hepatectomy provides acute metabolic support and enhancement of liver regeneration resulting in improved survival. PMID- 7838108 TI - [The role of intestinal flora in the pathogenesis of infection and aggravation of experimental acute pancreatitis in rats]. AB - This study was undertaken to determine the role of bacterial translocation in the pathogenesis of infection and aggravation of the course of experimental acute pancreatitis in rats. Acute pancreatitis was induced by the injection of 3% sodium taurocholate. The rats were divided into following 3 groups: acute pancreatitis only (AP), total colectomy + pancreatitis (TCAP), acute pancreatitis with ED preparation (EDAP). The positive rate of bacteriological culture of pancreatic tissue was 40.7% at 24 hours in AP group and 50.0% in EDAP group, but in TCAP group, pancreatic tissue was sterile at 6.12 hours and at 24 hours positive rate was only 6%. There was a significant reduction of bacterial contamination in TCAP group compared with AP and EDAP groups. In the bacteriological culture of the liver, spleen and MLN, bacterial contamination was reduced in TCAP group. Blood endotoxin level elevated gradually compared to the level before induction of acute pancreatitis. At 24 hours, there was a significant difference between TCAP group and EDAP group. In TCAP group, survival rate was improved at 24 hours compared to AP group and EDAP group. Infectious complication during the experimental acute pancreatitis in rats can be explained by the bacterial translocation of intestinal flora, especially colonal bacteria, which may result in aggravation of pancreatitis. PMID- 7838109 TI - [Effect of LAK cells and BRM on the growth of pancreatic cancer cells injected into nude mice]. AB - Effect of lymphokine activated killer (LAK) cells induced by in vitro or in vivo stimulation with biological response modifier (BRM) such as recombinant interleukin-2 (rIL-2) or OK-432 on the growth of pancreatic cancer cells injected into nude mice were studied. Human rIL-2 stimulated spleen cells from BALB/c nu/nu mice were used as effector LAK cells. Human pancreatic cancer cell lines PK 1 and PK-9 were used as target for cytolytic activities against pancreatic cancer. Cytolysis was estimated by 51Cr release assay in vitro, and tumor growth inhibition was estimated by Winn assay in vivo. NK, LAK and pancreatic cancer cell killing activities of LAK cells were elevated to significantly high level of 82%, 70% 51% (PK-1) and 33% (PK-9) respectively on the 2nd day after cultivation with rIL-2. Significantly high level of tumor inhibition rate (98%) was obtained when PK-1 cells were injected into nude mice subcutaneously with LAK cells compared with injection of PK-1 cells only (control). Spleen cells induced from nude mice injected intraperitoneally with rIL-2 or OK-432 showed significantly high cytolytic activities. These results indicate that LAK cells induced by in vitro or in vivo stimulation with BRM could inhibit the growth of pancreatic cancer. PMID- 7838110 TI - [Splenic autotransplantation restores the immune function of the spleen]. AB - Splenectomy has been reported to reduce the immune function. Fischer rats were subjected to 1), splenectomy, 2) splenectomy and autotransplantation and 3) sham control, respectively and examined for the production of antibodies against heterogeneic red blood cells, natural killer (NK) activity of peripheral blood lymphocytes (PBL), and the effects against tumor metastasis. Autotransplanted spleen started to produce antibody against the intravenously injected the sheep red blood cells (SRBC) even 2 weeks after autotransplantation and produce high titer of antibody as like sham operated rats 8 weeks after the operation. NK activity was decreased 2 weeks after splenectomy, but not after splenic autotransplantation. Immunohistopathological examination with monoclonal antibody against rat's lymphocytes showed the similar regeneration of B cells and T cells with normal spleen. Fischer rats which had been inoculated with FMC7 (fibrosarcoma) had their tumors resected 12 days after the inoculation and were divided into the 3 groups according to the operative procedures mentioned above and were operated on respectively. Then FMC7 were challenged intravenously or intraperitoneally, and their survival times were examined. No significant difference was found in the groups of intraperitoneal inoculation. But in the case of intravenous challenge, averaged survival time was significantly prolonged in the group of sham operation. These results suggested the spleen worked against intravenous antigens including even tumor cells. Heterotopic splenic autotransplantation is a method to restore some parts of the splenic immune function. PMID- 7838111 TI - [Changes in luminal diameter of internal thoracic arteries five years after coronary artery bypass grafting]. AB - Five years after coronary artery bypass grafting, 23 internal thoracic arteries (ITAs) were reexamined angiographically, and their luminal diameters were compared with those of one month after the operation. Proximal diameter, just below the subclavian artery, and distal diameter, just above the anstomosis, were measured. One month after surgery, these were 2.38 +/- 0.48 mm and 1.69 +/- 0.39 mm, respectively. After five years, the proximal diameter had not changed significantly (2.48 +/- 0.47 mm), but the distal diameter had increased to 1.96 +/- 0.58 mm (p < 0.05). Especially when there was no competitive flow with the ITA, the distal diameter showed a marked increase from 1.80 +/- 0.35 mm to 2.27 +/- 0.42 mm (p < 0.01). Twelve ITAs were grafted to coronary arteries having less than critical stenosis, and five of them showed distal narrowing or so-called string sign after five years. This seemed to be a form or physiological atrophy resulting from competitive flow, and the patients had no anginal pain in spite of their poor ITA runoff. When coronary artery stenosis is less than 75%, a choice is difficult between an ITA or a saphenous vein graft. We think that the graft must be selected considering the possibility of stenosis progression, if the jeopardized area is important for the patient. An ITA graft would be advisable in such cases. PMID- 7838112 TI - [A case report of allergic granulomatous angitis with the perforation of ileum]. AB - A case of allergic granulomatous angitis (AGA) complicated with the perforation of the ileum was described. A 52-year-old male had suffered from bronchial asthma since 1990, and two years later he had severe attack of asthma and manifestation of systemic vasculitis. He was diagnosed a AGA with the symptom of vascultitis, history of asthma, and the abnormal hematological findings (WBC 13000/mm3, eosinophilia 11.1%, IgE 1290U/ml, RA 2+). The treatment with adrenal corticoid hormone was started. In April 1992, he complained of severe right lower abdominal pain. He was diagnosed the gastrointestinal perforation by the abdominal X-ray examination and emergency operation was performed. Two ileal perforations were found at the operation and the ileectomy was carried out. Only 11 cases of AGA complicated with the gastrointestinal perforation have ever been reported in Japan. The perforation occurred often at the small intestine and the poor prognosis was referred. The administration of adrenal corticoid hormone should be continued after operation. PMID- 7838113 TI - [Identical twins with different types of jejunal atresia]. AB - This is a report of identical twins who were associated with different types of jejunal atresia, whose mother had no problems during her gestation. One was associated with a membranous atresia, and the another multiple jejunal atresia. Identical twins, both of whom are associated with intestinal atresia are very rare. The anomalies of these infants might be resulted from congenital factor and secondary circulatory disturbance. PMID- 7838114 TI - [Hepatobronchial fistula caused by intrahepatic bile duct carcinoma]. AB - A 49-year-old female was complaining of persistent cough. CT-scan revealed abscess in the right hepatic lobe. Diagnostic percutaneous trans-hepatic abscessography disclosed hepatobronchial fistula, and biopsy of the lesion revealed intrahepatic bile duct carcinoma. She underwent right hepatic lobectomy, right pulmonary lower lobectomy and partial resection of the diaphragm, with removal of the fistulous tract. After operation, cough disappeared, but she died of intraabdominal hemorrhage, 40 days after operation. PMID- 7838115 TI - [A case of Gardner's syndrome associated with thyroid carcinoma]. AB - We report a 22-year-old female who was diagnosed as familial adenomatous polyposis (FAP) associated with thyroid carcinoma. Total thyroidectomy and bilateral neck lymph nodes dissection were performed. Gardner's syndrome was pointed out after an investigation of her family. Total colectomy and ileo-rectal anastomosis were carried out. Colon cancer was not found pathologically. We reviewed 10 cases of FAP with thyroid carcinoma in Japan. Ten out of 11 cases including this patient were female. Thus it is important to pay careful attention to the presence of thyroid carcinoma in the case of FAP or Gardner's syndrome. PMID- 7838116 TI - [A case of superior lumbar hernia]. AB - A 64-year-old man was admitted to our hospital on July 1, 1992, complaining of right flank mass. Physical examination revealed a 7 x 8 cm soft, non-tender, smooth-surfaced mass which protruded under abdominal pressure. A CT scan of the abdomen demonstrated a defect of the aponeurosis of the transverse abdominis muscle and a protrusion of the retroperitoneal fat through the defect. Under the diagnosis of right superior lumbar hernia, surgery was done. The defect about 2 cm in diameter in the center of the superior lumbar triangle was closed by several interrupted sutures. The patient had an uneventful recovery. PMID- 7838117 TI - Site-selective photoaffinity labeling of the Torpedo californica nicotinic acetylcholine receptor by azide derivatives of ethidium bromide. AB - Three azido derivatives of ethidium bromide, a potent noncompetitive antagonist of the nicotinic acetylcholine receptor from Torpedo californica, were synthesized, namely 8-azido-ethidium chloride, 3-azido-ethidium chloride, and 3,8 diazido-ethidium chloride. These derivatives were tested for their ability to interact with the noncompetitive antagonist binding site and the acetylcholine binding sites on the acetylcholine receptor. The derivatives bound to the noncompetitive antagonist site with 2-5-fold lower affinity than did ethidium bromide, as determined by competitive inhibition of [3H]phencyclidine binding, indicating a moderate effect of the azide groups upon binding. Inhibition of [3H] acetylcholine binding by ethidium and its azide derivatives indicated differential binding to the two agonist sites, with high affinity binding to the same site that exhibits high affinity for d-tubocurarine. Photoaffinity labeling by these derivatives revealed reaction with the alpha and gamma subunits that was specific for the acetylcholine binding sites. Inhibition of labeling by d tubocurarine showed reaction with alpha subunits at both of the acetylcholine binding sites, whereas reaction with the gamma subunit was consistent with reaction only at the site with high affinity for d-tubocurarine. There was no corresponding reaction with the delta subunit, which forms part of the second acetylcholine binding site, despite reaction with the apposing alpha subunit. The azides, therefore, display preferential reaction with the gamma subunit. The selectivity of the reaction must reflect structural differences between the two sites, and subsequent determination of the labeled site(s) should reveal the nature of the differences. PMID- 7838118 TI - Expression and characterization of cloned human bombesin receptors. AB - Little is known about the pharmacology or cell biology of human bombesin (Bn) receptors, because they are usually present at low levels and both subtypes are frequently present in the same tissues. Human gastrin-releasing peptide (GRP) receptors (huGRP-R) and human neuromedin B (NMB) receptors (huNMB-R) were stably transfected into BALB/3T3 fibroblasts. Both receptor types were glycosylated, with 35% of the huGRP-R and 38% of the huNMB-R representing carbohydrate residues. The extent of glycosylation of the transfected huGRP-R was the same as that seen in the human glioblastoma cell line U-118. Radiolabeled agonist ligands were rapidly internalized, whereas noninternalized ligand readily dissociated in a temperature-dependent fashion. The affinities of various agonists for binding to the huGRP-R were Bn (Ki = 1.4 +/- 0.2 nM) = 4 x GRP = 300 x NMB. In contrast, affinities for the huNMB-R were NMB (Ki = 8.1 +/- 5.2 nM) = 4 x Bn = 600 x GRP. [F5-D-Phe6,D-Ala11]Bn(6-13)methyl ester was the most potent huGRP-R antagonist, whereas D-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Nal-NH2 was the most potent huNMB-R antagonist. Agonist binding to either receptor type caused activation of phospholipase C and increased cellular [3H]inositol phosphate levels. GRP was potent at increasing [3H]inositol phosphate generation in cells expressing the huGRP-R (EC50 = 13.6 +/- 1.3 nM), whereas NMB was similarly potent when acting upon cells expressing the huNMB-R (EC50 = 9.3 +/- 1.4 nM). However, neither receptor type, when stimulated with agonist, caused an increase in cAMP levels. These data show that stably transfected huGRP-R exhibit similar pharmacology for agonists and antagonists, are appropriately glycosylated, and function similarly with respect to their ability to alter biological activity, compared with natively expressed receptors. Minimal native huNMB-R data are available for comparison, but in general the huNMB-R is similar to the rat NMB receptor in its pharmacology and cell biology. PMID- 7838119 TI - ADP and ATP activate distinct signaling pathways in human promonocytic U-937 cells differentiated with 1,25-dihydroxy-vitamin D3. AB - We investigated the effects of purinergic P2 agonists on cell adhesion, as well as the signaling pathways involved, in U-937 human promonocytic cells differentiated to a more mature monocytic phenotype with 1,25-(OH)2-vitamin D3. In cell adhesion studies, ATP was more potent than ADP, whereas ADP showed greater efficacy. The time course of the intracellular calcium concentration ([Ca2+]i) response to ATP was biphasic (a spike followed by a plateau), whereas ADP evoked a plateau after a time lag of several seconds. The spike [Ca2+]i response evoked by ATP was due to both myo-inositol-1,4,5-trisphosphate-induced Ca2+ mobilization and influx, whereas the ADP effect was Ca2+ influx dependent. Moreover, ADP and ATP activated distinct Ca2+ influx mechanisms, as shown by Mn2+ quenching of the fura-2 signal, which was slow and long-lasting for ADP but rapid for ATP. Treatment with phorbol dibutyrate shifted the EC50 of the [Ca2+]i spike response to the right and abolished the plateau response. Accordingly, phorbol dibutyrate inhibited the ADP-evoked response but only partly inhibited the ATP evoked Ca2+ influx. cAMP-raising agents had no effect on the [Ca2+]i spike or on Ca2+ influx but delayed or transiently inhibited the plateau phase. The plateau response thus appears to be independent of the spike response, because it can be directly evoked by ADP and undergoes distinct regulation. This suggests that ADP and ATP activate U-937 cells through distinct signaling pathways, probably involving specific receptors. PMID- 7838120 TI - Elucidation of the insurmountable nature of an angiotensin receptor antagonist, SC-54629. AB - SC-54628 [1-(2-methylphenyl)-4-butyl-1,3-dihydro-3-[[6-[2-(1H- tetrazol-5 yl)phenyl]-3-pyridinyl]methyl]-2H-imidazol-2-one] and its 1-(2,6-dimethylphenyl) 2H-imidazol-2-one derivative SC-54629 were potent inhibitors of 125I-angiotensin II (125I-AII) binding to rat adrenal cortex angiotensin type 1 (AT1) receptors. SC-54628 and SC-54629 antagonized AII-induced contraction of rabbit vascular smooth muscle in a surmountable fashion and an insurmountable fashion, respectively. Binding experiments with SC-54629 were undertaken to determine the nature of receptor interaction, which might explain the insurmountable mode of antagonism of SC-54629. The presence of a high concentration of SC-54629 did not affect the dissociation of membrane-bound 125I-AII induced by an excess of unlabeled AII, indicating that the antagonist binds to the agonist binding site and not an allosteric domain. Incubation of adrenal cortex membranes with SC 54629 decreased the density of 125I-AII binding sites. When incubation of the SC 54629-treated membranes with radiolabeled AII was prolonged, the SC-54629-induced decrease in AT1 receptor density was attenuated, suggesting that binding of the antagonist is slowly reversible. Furthermore, the dissociation of [3H]SC-54629 was 5-fold slower than that of 125I-AII bound to AT1 receptors. These results suggest that the insurmountable antagonism of AII by SC-54629 is most likely due to the slow reversibility of SC-54629 binding to the AT1 receptor. PMID- 7838121 TI - Characterization of cloned human dopamine D1 receptor-mediated calcium release in 293 cells. AB - Dopamine (DA) D1 receptors are generally known to couple only to Gs and cAMP production. Recently, D1 receptors expressed in mouse Ltk- cells have been shown to induce cAMP production, phosphoinositide (PI) hydrolysis, and calcium mobilization [Mol. Endocrinol. 6: 1815-1824 (1992)]. To further evaluate second messenger systems that could be activated by the D1 receptor, we examined the effects of DA, (R)-(+)-SKF-38393, and DA antagonists on cAMP production and calcium release in human embryonic kidney 293 cells stably expressing three different levels (Bmax = 0.12, 1.4, and 23 pmol/mg of protein) of the human D1 receptor. DA and (R)-(+)-SKF-38393 activated cAMP production and calcium release in all three D1-293 clones, and their potency was proportional to receptor density. The efficacy of SKF-38393 was also increased with receptor density in both cAMP and calcium studies. The effect of DA on calcium release consisted of a transient peak response (< 20 sec) that declined to an ethylene glycol bis(beta aminoethyl ether)-N,N,N',N'-tetraacetic acid-sensitive plateau level above the base-line (>5 min). The effect of DA on cAMP and calcium release was selectively inhibited by SCH23390, a selective D1 antagonist, and not by spiperone, a selective D2 antagonist. DA did not induce PI hydrolysis in any of the three receptor-expressing clones. A 24-hr pretreatment with cholera toxin (2 micrograms/ml) greatly attenuated the effect of DA on cAMP formation and calcium release. To address how DA could activate calcium release without enhancing PI hydrolysis, the effects of forskolin, thapsigargin, and isoproterenol (Iso) were studied. Similarly to the effects of DA, forskolin and Iso stimulated cAMP production and calcium release from D1-293 cells. Cells that were stimulated with Iso or forskolin showed a reduced response to subsequent addition of DA. Pretreatment of D1-293 cells with thapsigargin, a selective Ca2+-ATPase inhibitor, elicited calcium release from the inositol-1, 4, 5-trisphosphate sensitive calcium store and attenuated the response to subsequent addition of DA. Carbachol stimulated PI hydrolysis and calcium release but had little effect on cAMP production. Prestimulation with carbachol abolished the calcium response to DA, Iso, or forskolin. These studies indicate that D1 receptor-mediated calcium mobilization in 293 cells is dependent on cAMP production and the cAMP-dependent calcium store is part of the inositol-1,4,5-trisphosphate-sensitive calcium pool. PMID- 7838122 TI - Glutamate-induced destabilization of intracellular calcium concentration homeostasis in cultured cerebellar granule cells: role of mitochondria in calcium buffering. AB - The exposure of cultured cerebellar granule cells for 4 min to glutamate (50 microM) in a Mg2+-free medium containing 10 microM glycine elicited a prompt increase of the intracellular Ca2+ concentration ([Ca2+]i) to 5 microM, which was followed by a decline to 1.5 microM (as measured using fura-2); both events occurred while the glutamate pulse increased the intracellular sodium concentration ([Na+]i) to an estimated 60-100 mM. Because under these circumstances the plasma membrane Na+/Ca2+ exchanger cannot extrude Ca2+, other mechanisms should operate in causing the [Ca2+]i decline. To evaluate a possible role of intracellular Ca2+ stores in Ca2+ buffering, thapsigargin, ryanodine, and dantrolene were tested. Thapsigargin (1 microM) and ryanodine (10 microM) failed to modify the glutamate-elicited [Ca2+]i transients; results with dantrolene could not be considered because this drug by itself affected the fura-2 fluorescence. In contrast, carbonyl cyanide m-chlorophenylhydrazone (1 microM) and antimycin A1 (1 microM), which dissipate mitochondrial membrane potential by different mechanisms, virtually abolished the [Ca2+]i decline occurring either during glutamate application or after its removal. Moreover, when the residual [Na+]i increase persisting after glutamate removal was artificially abated, the Ca2+-buffering capacity of neurons was significantly improved. These data suggest that most of the Ca2+ entering the neurons during excitotoxic glutamate exposure is diverted to mitochondria and that the glutamate-induced increase of [Na+]i limits this mitochondrial Ca2+-buffering capacity, presumably via activation of the mitochondrial Na+/Ca2+ exchanger. PMID- 7838123 TI - Functional effects of mutations in the putative agonist binding region of recombinant alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. AB - Structural correlates of ligand binding to alpha-amino-3-hydroxy-5-methyl- 4 isoxazolepropionic acid (AMPA) receptors were examined by altering conserved lysine residues to either glutamate or glutamate at position 445 of the GluR-A subunit and position 449 of the GluR-B subunit. Receptors were expressed in human embryonic kidney 293 cells and in Xenopus oocytes as homomeric GluR-A or heteromeric combinations of GluR-A/B. The functional properties of the resulting receptors were measured with patch-clamp and voltage-clamp electrophysiology. These mutations, which reduced the total positive charge at the lysine 445 position, selectively altered the affinity of some ligands and had no obvious effect on receptor desensitization properties. The L-glutamate EC50 was 10.2 microM when wild-type GluR-A was coexpressed with GluR-B (GluR-A/B) and 38.9 microM when GluR-A445Q/B449Q receptors were tested. The AMPA EC50 was similarly reduced (wild-type, 3.71 microM; GluR-A445Q/B449Q, 21.4 microM). Receptors containing a glutamate residue at this position were even less sensitive to L glutamate and AMPA. Whereas the apparent potency of L-glutamate varied inversely with the total positive charge regardless of the subunit, the affinity of AMPA was more sensitive to mutations in GluR-A than to those in GluR-B. Interestingly, the EC50 of kainate was unaffected by most of these mutations and actually increased slightly with GluR-A445E/B449E receptors. The affinity of 6-cyano-2,3 dihydroxy-7- nitroquinoxaline (CNQX) was slightly reduced with GluR-A445E/B449E receptors, whereas the apparent affinity of GYKI52466 was unchanged. These data confirm that structural correlates of binding to AMPA receptors vary among different ligands. PMID- 7838124 TI - Receptor binding characterization in kidney membrane of [3H]U-37883, a novel ATP sensitive K+ channel blocker with diuretic/natriuretic properties. AB - U-37883 (4-morpholinecarboximidine-N-1-adamantyl-N-cyclohexyl), a known blocker of ATP-sensitive K+ (KATP) channels, produces natriuresis/diuresis in vivo by a direct effect on the kidney. In the present study, the binding characteristics of the U-37883 receptor were investigated using pig kidney cortex microsomes. [3H]U 37883 (0.5-5 nM, 50 Ci/mmol) exhibited specific binding, which was reversible, increased linearly with protein concentration (50-500 micrograms/ml), and was destroyed after treatment with proteases. Scatchard plots derived from the competition experiments suggested the presence of a single class of low affinity binding sites, with a Kd of 225 nM and a Bmax of 7.8 pmol/mg of protein. A similar Kd value was derived from complementary studies dealing with association and dissociation kinetics. The binding of [3H]U-37883 was tissue specific, because very little specific binding could be detected in microsomes from rat insulinoma cells (RINm5F) and brain. In contrast, these membranes displayed high affinity specific binding of [3H]glyburide, another KATP channel blocker. Finally, analogs of U-37883 that were found to be active KATP channel blockers in isolated rabbit mesenteric artery and active in vivo as diuretics/natriuretics were also found to be active in displacing specific binding of [3H]U-37883, whereas the inactive analogs (no vascular KATP channel-blocking activity and no in vivo diuresis/natriuresis) were inactive in this binding assay. We suggest that the U-37883 binding site represents a functional receptor that mediates the KATP channel antagonism and natriuresis observed with this class of compounds. PMID- 7838125 TI - Characterization of a series of anabaseine-derived compounds reveals that the 3 (4)-dimethylaminocinnamylidine derivative is a selective agonist at neuronal nicotinic alpha 7/125I-alpha-bungarotoxin receptor subtypes. AB - Investigation of the naturally occurring, nicotinic agonist anabaseine and novel derivatives has shown that these compounds have cytoprotective and memory enhancing effects. The hypothesis that these arise at least in part through actions on brain nicotinic receptors was evaluated by examining the ability of these compounds to displace the binding of nicotinic ligands and to affect the function of the alpha 4 beta 2 and alpha 7 receptor subtypes expressed in Xenopus oocytes. The derivative 3-(4)-dimethylaminocinnamylidine anabaseine (DMAC) was found to be a selective alpha 7 receptor agonist; it was more potent than nicotine, acetylcholine, anabaseine, and other derivatives at activating the alpha 7 receptor subtype, while displaying little agonist activity at alpha 4 beta 2 and other receptor subtypes. Compared with anabaseine and the other derivatives, DMAC was the most potent at displacing 125I-alpha-bungarotoxin binding (putative alpha 7) and the least potent at displacing [3H]cytisine binding (putative alpha 4 beta 2) to brain membranes. Independently of agonist activities, all of the novel compounds displayed secondary inhibitory activity at both receptor subtypes. At the alpha 4 beta 2 receptor subtype, inhibition by the 3-(2,4)-dimethoxybenzylidene derivative was enhanced by coapplication of acetylcholine, suggesting a noncompetitive form of inhibition. Anabaseine and nicotine prolonged the time course of activation of alpha 4 beta 2 receptors, compared with acetylcholine, suggesting sequential channel-blocking activity. As selective agonists, anabaseine derivatives such as DMAC may be useful for elucidating the function of alpha 7 nicotinic receptors, including their potential role(s) in the cytoprotective and memory-enhancing effects of nicotinic agents. PMID- 7838126 TI - Agonist selectivity for three species of natriuretic peptide receptor-A. AB - We determined the nucleotide sequence of mouse natriuretic peptide receptor-A (NPR-A) cDNA and compared the revised deduced amino acid sequence with those of rat and human NPR-A. The ligand selectivity of these three receptor/guanylyl cyclases was examined by whole-cell stimulation of cGMP production. The 28-amino acid atrial natriuretic peptide (ANP) has only one difference among these three species, i.e., human Met-12 versus rat and mouse Ile-12. However, despite the nearly invariant ANP sequence among these species, ANP analogs have marked differences in ED50 values and maximal cGMP responses among the three receptors. With the natriuretic peptide analogs we tested, human NPR-A is less sensitive than rat or mouse NPR-A to changes in the 17-amino acid, disulfide-bonded ring of ANP and to the species differences in brain natriuretic peptide (BNP) but is more sensitive to deletions in the carboxyl tail of ANP. The ANP determinants of agonist potency have therefore changed for different species of NPR-A. This is reflected in the amino acid sequence divergence in the receptor extracellular domains and in the divergence and specificity of BNP among species. Our results suggest that the coevolution of NPR-A and BNP has thus been constrained within the context of the conserved ANP sequence. PMID- 7838127 TI - Blockade of multiple human cardiac potassium currents by the antihistamine terfenadine: possible mechanism for terfenadine-associated cardiotoxicity. AB - Use of the antihistamine terfenadine has been associated with QT prolongation and torsade de pointes. One possible mechanism is blockade of cardiac potassium channels. We therefore characterized the effects of terfenadine on potassium currents recorded from isolated human cardiac myocytes. We demonstrated terfenadine block of the transient outward current and a novel, ultra-rapidly activating, delayed rectifier K+ current (IKur), which is very sensitive to 4 aminopyridine. IKur is probably produced by the protein product of Kv1.5a, a Shaker-like potassium channel cDNA cloned from human heart. We also compared terfenadine blockade of fHK (Kv1.5a) currents stably expressed in a human embryonic kidney cell line with terfenadine blockade of IKur in human atrial myocytes. Using the patch-clamp technique, we found that terfenadine produced a time-dependent reduction in Kv1.5a current that was consistent with blockade from the cytoplasmic side of the channel. The terfenadine-sensitive Kv1.5a current in human embryonic kidney cells was similar to the 4-aminopyridine-sensitive current in human atrial myocytes. In addition to blockade of the transient outward current and IKur, terfenadine at clinically relevant concentrations blocked both the rapidly and slowly activating components of the delayed rectifier in human atrial myocytes. Blockade of these K+ currents may contribute to the cardiotoxicity associated with terfenadine usage. PMID- 7838128 TI - Cyclic AMP and protein kinase A mediate 5-hydroxytryptamine type 4 receptor regulation of calcium-activated potassium current in adult hippocampal neurons. AB - In the CA1 region of the hippocampus, activation of serotonin receptors of the 5 hydroxytryptamine (5-HT)4 subtype increases membrane excitability by reducing the calcium-activated potassium current responsible for the slow afterhyperpolarization observed in these cells. In the present study, the signaling mechanism by which 5-HT4 receptors reduce the afterhyperpolarization in the CA1 region was examined using intracellular recording in brain slices. Administration of the membrane-permeable cAMP analog 8-bromo-cAMP mimicked the effect of serotonin on the afterhyperpolarization, whereas administration of the protein kinase inhibitor staurosporine inhibited the effects of serotonin. These observations suggested a role for protein kinase A in this response. This was confirmed by intracellular injection of the selective protein kinase A inhibitor Rp-adenosine 3',5'-cyclic monophosphothioate ((Rp)-cAMPS), which noncompetitively inhibited the ability of serotonin to reduce the after-hyperpolarization. Additional evidence for the involvement of cAMP in the signaling by 5-HT4 receptors was obtained using the general phosphodiesterase inhibitor 3-isobutyl-1 methylxanthine. When this compound was bath administered at concentrations sufficient to enhance a known cAMP-mediated response, a significant enhancement of the ability of 5-HT4 receptors to reduce the afterhyperpolarization was observed. Together, these results indicate that serotonin reduces the afterhyperpolarization in the CA1 region by acting on 5-HT4 receptors that increase intracellular cAMP levels and activate protein kinase A. PMID- 7838129 TI - Mechanism of clofilium block of the human Kv1.5 delayed rectifier potassium channel. AB - The effect of clofilium on potassium conductance was studied in excised membrane patches from Chinese hamster ovary cells stably transfected with the Kv1.5/hPCN1 delayed rectifier K+ channel gene. Bath application of clofilium resulted in current inhibition, displaying concentration-dependent acceleration of the apparent channel inactivation in both outside-out and inside-out patches. The steady state half-inhibition concentration in inside-out patches was 140 +/- 80 nM (n = 10), which was less than the half-inhibition concentration of 840 +/- 390 nM (n = 10) observed in outside-out patches. Clofilium accelerated apparent current inactivation but did not influence the kinetics of current activation or deactivation. The rate of onset of channel block induced by clofilium was not voltage dependent. In contrast, the rate of recovery from channel block was slower at more hyperpolarized membrane potentials. Elevation of extracellular K+ levels accelerated recovery from channel block without influencing the rate of onset of block. These data suggest that clofilium may induce channel block by an "activation trap" mechanism. Clofilium may be trapped near the conductivity pore so that permeating K+ ions promote recovery from clofilium-induced block. PMID- 7838130 TI - Structural analogs of interleukin-2: a point mutation that facilitates biological response. AB - Interleukin-2 (IL-2) is an immunoregulatory cytokine whose biological effects are mediated through interaction with specific receptors on the surface of target cells. Due to its presumed role in generating a normal immune response, IL-2 is being evaluated for the treatment of a variety of tumors, in addition to infectious diseases. During the study of the structure-activity relationships for IL-2 and its receptors, one analog in which threonines at positions 41 and 51 were replaced by prolines (T41/51P) was found to possess apparent signaling abnormalities. Bioassays and receptor binding assays with human peripheral blood lymphocytes revealed the EC50 and Kd values of this analog to be 200 pM and 5.9 nM, respectively. Although the EC50 is greater and the receptor affinity of T41/51P is much weaker than that of wild-type IL-2, receptor occupancy versus biological response comparisons indicated that a much lower receptor occupancy was required to generate an equivalent biological response. Competitive receptor binding analyses with both intermediate affinity (beta/gamma subunit complex) and low affinity (alpha subunit) receptors were carried out to assess the origin of this phenomenon. Similar analyses of the singly substituted T41P and T51P analogs were carried out. From these studies, it was apparent that facilitated signaling was mainly attributable to position 51, whereas mutations at position 41 primarily influenced low affinity binding. The observation that the T51P analog facilitates response, compared with wild-type IL-2, may indicate a signaling dependent conformational change in IL-2 upon receptor binding. PMID- 7838131 TI - Precipitated morphine withdrawal stimulates multiple activator protein-1 signaling pathways in rat brain. AB - Morphine dependence is a long lasting form of neuronal plasticity. Naloxone precipitated morphine withdrawal, a model of opioid dependence, induces brain region-specific changes in activator protein-1 (AP-1) transcription factor gene expression. Rapid increases in c-fos, fos-B, jun-B, and c-jun mRNA levels accompany withdrawal, with the relative level of induction correlating with the severity of physical dependence. Altered patterns of c-fos mRNA expression were limited to neuronal circuits mediating stress responses, motivation, and cognition. AP-1 DNA-binding activity and dimer composition also exhibited regulation after withdrawal, presumably as a result of both transcriptional and post-translational events. Thus, morphine dependence results in the alteration of diverse, brain region-specific, signal transcription pathways involving AP-1 transcription factors. PMID- 7838132 TI - Expression of the bovine striatal D2 receptor, but not the D1 receptor, in bovine adrenal medulla. AB - At 37 degrees, the specific binding of [3H]SCH23390 to purified adrenal medullary plasma membranes accounted for only 20% of total binding. At 4 degrees, the binding did not saturate; therefore, equilibrium binding constants could not be estimated. Similar results were obtained with 125I-SCH23982, a ligand that exhibits 25-fold higher specific activity, compared with [3H]SCH23390. Of 11 dopamine receptor ligands used, only (+)-SCH23390 and (+/-)-SKF83566 inhibited the binding of [3H]SCH23390, but with very low affinities (IC50 values of 446 and 635 nM, respectively). In striatal membranes, binding of [3H]SCH23390 and of 125I SCH23982 followed saturation isotherms. [3H]SCH23390 exhibited a Kd of 383 pM and a Bmax of 479 fmol/mg of protein, and 125I-SCH23982 exhibited a Kd of 664 pM and a Bmax of 453 fmol/mg of protein. The radioligand was displaced by the D1 selective compounds (+)-SCH23390 (IC50 of 3 nM), (+/-)-SKF83556 (IC50 of 5 nM), and (+)-SKF38393 (IC50 of 17 nM); spiperone and quinpirole were ineffective. [3H]Spiperone binding to bovine striatal and adrenal medullary plasma membranes exhibited similar characteristics, compatible with a typical D2 receptor. Northern blot analysis revealed the presence of D1 receptor mRNA in poly(A)+ RNA preparations from bovine brain striatum. When Northern blots containing poly(A)+ from bovine adrenal medulla were probed, no specific hybridization band for D1 receptors was observed; in contrast, a band of the expected size for D2 receptors was obtained. Similar results were obtained with in situ hybridization techniques and with more sensitive reverse transcription-polymerase chain reaction methods. The data support the idea that the peripheral D2 receptor present in bovine adrenal medulla is similar to striatal D2 receptors; in contrast, striatal D1 receptors do not seem to have a counterpart in bovine adrenal medullary tissues. PMID- 7838133 TI - Evidence for transcriptional control of human mdr1 gene expression by verapamil in multidrug-resistant leukemic cells. AB - We investigated the mechanism of verapamil (VRP) effects on mdr1 gene expression in two leukemic multidrug-resistant (MDR) cell lines, K562/ADR and CEM VLB100. Exposure to VRP for 24 hr resulted in a decrease in mdr1 mRNA levels that was dose related at concentrations between 15 and 50 microM. The maximal decrease of mdr1 mRNA levels was found to be 6-fold in the K562/ADR cells and 3-fold in the CEM VLB100 cells. The effect of VRP on mdr1 mRNA levels was, however, biphasic. At 100 microM VRP, which strongly inhibited cell proliferation, a 2-fold increase of mdr1 mRNA levels was observed in the K562/ADR cells. To determine whether the decrease of mRNA levels resulted from post-transcriptional mechanisms, mRNA stability was studied after blocking of transcription with actinomycin D in VRP treated cells and in control cells. This study revealed that mdr1 mRNA was stable in both cell lines and no increase in mdr1 mRNA degradation was observed in the 30 microM VRP-treated cells versus control cells (half-lives of 23 hr versus 14 hr for the K562/ADR cells and 15.5 hr versus 10.0 hr for the CEM VLB100 cells). The suggestion of a transcriptional mechanism was confirmed by nuclear run-on assays. A 4-fold decrease in the mdr1 gene transcription rate was observed in the 30 microM VRP-treated CEM VLB100 cells. The decreased transcription rate could be due to the decrease in mdr1 proximal promoter activity observed in CEM VLB100 cells transiently transfected with the mdr1 promoter fused to the chloramphenicol acetyltransferase gene. Indeed, after exposure to 30 microM VRP, chloramphenicol acetyltransferase activity was decreased by 2-fold. This study reports for the first time a down-regulation of mdr1 gene transcription by a pharmacological agent. These results provide further identification of the regulatory mechanisms involved in the overexpression of mdr1 in MDR cells and may help in the development of new strategies for MDR reversal. PMID- 7838134 TI - Divergent regulation of cytochrome P450 enzymes by morphine and pethidine: a neuroendocrine mechanism? AB - We have studied the effects of opiates on cytochrome P450 (CYP) expression in rats and, intriguingly, found that these compounds have divergent effects on this system. Morphine induced a selective down-regulation of hepatic 16 alpha hydroxylation of androstenedione, which was associated with a reduction in the expression of the 16 alpha-hydroxylation-associated CYP2C11. In addition, other enzymes from the CYP2C, CYP3A, and CYP4A gene families were also suppressed, whereas CYP1A2, CYP2B1, and CYP2E1 were induced. These changes were reflected in the mRNA levels, indicating that they were due to alterations at the transcriptional level. alpha 2-Adrenoceptor blockade with yohimbine augmented the effects of morphine on proteins identified by antibodies against CYP2C11 and CYP3A, indicating an involvement or influence of the alpha 2-adrenergic receptor system. In contrast, pethidine had completely different effects. No CYPs were suppressed by this compound. CYP1A2, CYP2B1, CYP2C6, CYP2C7, CYP3A, and CYP4A1 were all induced by pethidine treatment, whereas CYP2C11 and CYP2E1 were unchanged. Our results demonstrate for the first time the divergent effects of pethidine and morphine on the hepatic CYP system, indicating that an opioid receptor mechanism is not involved. These differences are probably mediated by different influences on growth hormone secretion. The mechanisms by which this may occur are discussed. PMID- 7838135 TI - Relationship of cytochrome P450 activity to Clara cell cytotoxicity. IV. Metabolism of naphthalene and naphthalene oxide in microdissected airways from mice, rats, and hamsters. AB - Parenteral administration of naphthalene produces a dose-dependent and tissue-, species-, and cell-selective lesion of murine Clara cells. The rate and stereoselectivity of naphthalene metabolism by microsomal preparations correlate with tissue and species differences in cytotoxicity. Because earlier studies used microsomes obtained from whole tissue, differences in susceptibility of proximal and distal airways could not be related to differences in the metabolic activation or detoxication of naphthalene. Specific subcompartments of the respiratory system, obtained by microdissection, have been used to study the cytochrome P450-dependent metabolism of naphthalene and the epoxide hydrolase/glutathione transferase-dependent metabolism of naphthalene oxide. The rates of naphthalene metabolism were substantially higher in mouse airways than in comparable airways of hamsters or rats. Rates of metabolism were higher in distal airways than in the trachea of all species studied. Metabolism in mouse airways was highly stereoselective, whereas that in hamster and rat tissues was not. Nonciliated cells at all airway levels in mice were heavily labeled with an antibody to cytochrome P450 2F2; little labeling was observed in any portion of rat and hamster lungs. Postmitochondrial supernatants prepared from mouse and hamster airways metabolized racemic naphthalene oxide to diol and glutathione adducts at substantially higher rates than did comparable preparations from rats. Although glutathione levels varied 2-4-fold at different airway levels in the three species studied, levels at the most susceptible site (mouse distal bronchioles) were as high as or higher than those at other, less susceptible, sites. These studies support the view that the rate and stereoselectivity of naphthalene metabolism to naphthalene 1R,2S-oxide catalyzed by cytochrome P450 2F2 are critical determinants in the species-specific and region-selective cytotoxicity of naphthalene in mice. The lack of major differences in the catalytic activity or enantioselectivity of putative detoxication enzymes (epoxide hydrolase or glutathione transferases) between mouse and hamster tissue, combined with data showing that the differences in the metabolic fate of naphthalene oxide in proximal versus distal airways are not dramatic, suggests that the initial epoxidation of naphthalene is an important factor in site selective toxicity. These studies support the need to use tissue from defined airway levels for studies on the relationship of biochemical and metabolic factors important in cellular injury by lung toxicants, such as naphthalene, where there are dramatic regional differences in susceptibility to injury within the respiratory system. PMID- 7838136 TI - A single amino acid substitution in somatostatin receptor subtype 5 increases affinity for somatostatin-14. AB - Four of the five somatostatin receptor (SSTR) subtypes bind the two native forms of somatostatin, i.e., somatostatin-14 (S-14) and amino-terminally extended somatostatin-28 (S-28), with comparable affinities (approximately 0.2 nM). The SSTR5 subtype exhibits 10-50-fold higher affinity for S-28 than for S-14 (0.2 and 5 nM, respectively). To determine which domains in SSTR5 are responsible for the observed pharmacological selectivity, a series of SSTR2/SSTR5 chimeras were constructed and expressed in Chinese hamster ovary cells. Saturation and competition radioligand binding studies demonstrated that the region encompassing transmembrane domain 6 (TM6) through the carboxyl terminus plays a critical role in the lower binding affinity of S-14 for SSTR5. Substitution of this region with the corresponding region of SSTR2 produced chimeric receptors with high affinity for both S-28 and S-14. Examination of amino acid sequences revealed both a specific conserved hydrophobic residue and a conserved tyrosine in TM6 of SSTR1 4. At comparable positions in SSTR5, these residues are glycine (G258) and phenylalanine (F265), respectively. Substitution of G258 with phenylalanine did not alter the preference of SSTR5 for S-28 over S-14. However, substitution of F265 with tyrosine increased the binding affinity of S-14 by 20-fold, to an affinity comparable to that observed for the SSTR2 subtype. These data indicate that replacement of phenylalanine with tyrosine at position 265 in SSTR5 can modify ligand binding selectivity and abolish the preference for S-28 over S-14. This finding suggests that the tyrosine in the predicted TM6 may be an important contact point between somatostatin and SSTR. PMID- 7838137 TI - Probing of the location of the allosteric site on m1 muscarinic receptors by site directed mutagenesis. AB - In an attempt to locate the allosteric site on muscarinic receptors to which gallamine binds, 21 residues in the putative external loops and loop/transmembrane helix interfaces have been mutated to alanine. These residues are conserved in mammalian m1-m5 receptors. All mutant receptors can be expressed in COS-7 cells at high levels and appear to be functional, in that acetylcholine binding is sensitive to GTP. The gallamine binding site does not appear to involve the first, second, and most of the third extracellular loops. Tryptophan 400 and -101 inhibit gallamine binding when mutated to alanine or to phenylalanine and may form part of the allosteric site. Several mutations also affect antagonist binding. Surprisingly, tryptophan-91, a residue conserved in monoamine and peptide receptors, is important for antagonist binding. This residue, present in the middle of the first extracellular loop, may have a structural role in many G protein-coupled receptors. Antagonist binding is also affected by mutations of tryptophan-101 and tyrosine-404 to alanine or phenylalanine. In a helical wheel model, trytophan-101 and tyrosine-404, in conjunction with serine-78, aspartate-105, and tyrosine-408, form a cluster of residues that have been reported to affect antagonist binding when mutated, and they may therefore be part of the antagonist binding site. It is suggested that the allosteric site may be located close to and just extracellular to the antagonist binding site. The binding of methoctramine, an antagonist with allosteric properties, is not substantially affected by mutations at tryptophan 91, -101, and -400 and tyrosine-404, and thus these amino acids are not important for its binding. The binding of himbacine, another antagonist with allosteric properties, is affected by these mutations but in a manner different from that of gallamine or competitive antagonists. It has not been possible to determine whether methoctramine and himbacine bind exclusively to the allosteric site or to both the competitive site and the allosteric site. PMID- 7838138 TI - Identification of 5-hydroxytryptamine7 receptor binding sites in rat hypothalamus: sensitivity to chronic antidepressant treatment. AB - Due to the high level of expression of mRNA for the 5-hydroxytrytamine (5-ht7) receptor in the hypothalamus and the high affinity of 5-HT for this receptor, [3H]5-HT binding was performed in rat hypothalamus to determine whether 5-ht7 receptor binding sites are present in animal tissue. [3H]5-HT binding was performed in the presence of 100 nM pindolol, which is inactive at 5-ht7 receptors but prevents the binding of [3H]5-HT to 5-HT1A and 5-HT1B receptor binding sites. Under these conditions, [3H]5-HT bound to a binding site with an affinity of 1.94 nM. Displacement studies showed the pharmacology of the hypothalamic binding site to correlate well with the published pharmacology of the 5-ht7 receptor (r = 0.921). The treatment of rats with fluoxetine (5 mg/kg/day, orally) for 21 days caused a significant reduction in the number of hypothalamic 5-ht7 receptor binding sites. These data suggest that the 5-ht7 receptor binding site is expressed in rat hypothalamus and that this receptor binding site is down-regulated after a chronic increase in the synaptic level of 5-HT. PMID- 7838139 TI - Citrate inhibition of rat-kidney cortex phosphofructokinase. AB - The regulatory properties of citrate on the activity of phosphofructokinase (PFK) purified from rat-kidney cortex has been studied. Citrate produces increases in the K0.5 for Fru-6-P and in the Hill coefficient as well as a decrease in the Vmax of the reaction without affecting the kinetic parameters for ATP as substrate. ATP potentiates synergistically the effects of citrate as an inhibitor of the enzyme. Fru-2,6-P2 and AMP at concentrations equal to Ka were not able to completely prevent citrate inhibition of the enzyme. Physiological concentrations of ATP and citrate produce a strong inhibition of renal PFK suggesting that may participate in the control of glycolysis in vivo. PMID- 7838140 TI - The partial purification and characterization of purine nucleoside phosphorylase from mammalian mitochondria. AB - Cytosolic purine nucleoside phosphorylase (PNPase) is a well known, and described enzyme which exists in a variety of organisms, both procaryotic and eucaryotic. More recently this enzyme was found in bovine liver mitochondria. The mitochondrial purine nucleoside phosphorylase was purified 63 fold and has a molecular weight of 48-60 kD. From Lineweaver-Burk plots apparent KM's of 23 microM for inosine, 42 microM for deoxyinosine, 40 microM for phosphate, 2 microM for hypoxanthine, and 163 microM for ribose-1-phosphate were calculated. Both 8 aminoguanosine (Ki = 0.5 microM) and araG (Ki = 381 microM) are inhibitors of the enzyme. The protein's isoelectric point (pI) was calculated at a pH of 4.2. Preliminary immunological work showed no cross-reactivity between epitopes on the mitochondrial protein and those on PNPase from human erythrocytes. The apparent KM's calculated for the mitochondrial enzyme are, with the exception of that using hypoxanthine, within the range commonly associated with KM's from the cytosolic species. The mitochondrial enzyme's molecular weight and pI are less than normally described. The enzyme's isolation from mitochondria, together with several unique characteristics, suggest that it is a separate protein from that found in the cytosol. PMID- 7838141 TI - Impaired FAD-glycerophosphate dehydrogenase activity in islet and liver homogenates of fa/fa rats. AB - The mitochondrial FAD-linked enzyme glycerophosphate dehydrogenase plays a key role in the pancreatic B-cell glucose sensing device. In the present study, the activity of this enzyme was examined in islets of fa/fa rats in which inherited diabetes mellitus is associated with obesity, hyperinsulinism and severe insulin resistance. The specific activity of both FAD-linked glycerophosphate dehydrogenase and glutamate dehydrogenase were decreased in islet and liver homogenates prepared from fa/fa, as compared to Fa/Fa, rats, this coinciding with a low ratio between glutamateoxalacetate and glutamate-pyruvate transaminase activity in both islet and liver extracts, islet hyperplasia, hyperinsulinemia and hepatic steatosis in the hyperglycemic fa/fa rats. It is speculated that a low activity of FAD-linked glycerophosphate dehydrogenase in the pancreatic B cell may participate to the perturbation of glucose homeostasis in fa/fa rats, like in other animal models of non-insulin-dependent diabetes mellitus. PMID- 7838142 TI - 3-aminobenzamide, a potent inhibitor of poly (ADP-ribose) polymerase, causes a rapid death of HL-60 cells cultured in serum-free medium. AB - HL-60 cells transferred from serum-supplemented to serum-free culture medium initially bound to culture plate tightly and then released from the plate on increasing the culture time and resumed exponential growth after about 8 h lag. At the initial stage of the culture, the cells became extremely sensitive to 3 aminobenzamide, a potent inhibitor of poly (ADP-ribose) polymerase, and, at 1 mM, 80 to 90% of the cells were lysed within 20 h, whereas the inhibitor was totally ineffective on the cell growth in serum-supplemented medium at the concentration. Non-inhibitory analogs of the inhibitor were ineffective. Assay of poly(ADP ribose) polymerase activity in permeable cells indicated that a transient activation of the enzyme occurred during the culture in serum-free medium (the maximum activation was observed at 8 h of the culture). The cells conditioned in serum-free medium for 24 h acquired significant resistancy to the inhibitor. A low concentration of fibronectin (5 to 10 micrograms/ml) and a relatively high concentration of bovine serum albumin (0.5 to 1 mg/ml) effectively blocked the cell attachment to plate and also the 3-aminobenzamide-induced cell lysis. These results suggest that poly(ADP-ribose) polymerase is involved in a process essential for HL-60 cells to adapt to a serum-deprived growth condition. PMID- 7838143 TI - Evaluation of hydroxyl radical-scavenging property of purpurogallin using high pressure liquid chromatography. AB - Purpurogallin (PPG) has been used as an additive to edible and non-edible oils or fats to retard oxidation. Its antioxidant mechanism is not known. We investigated the ability of PPG to scavenge exogenously generated hydroxyl radicals (.OH) using a sensitive high pressure liquid chromatographic (HPLC) method. .OH was generated by photolysis of H2O2 (1.25-10 mumoles) with UV light and was trapped with salicylic acid (500 nmoles). Salicylic acid is hydroxylated to produce .OH adduct products 2,3- and 2,5-dihydroxybenzoic acid (DHBA). H2O2 produced concentration-dependent .OH as estimated by generation of 2,3- and 2,5-DHBA. PPG (100, 200, 300, 400, 500, and 600 nmoles) produced concentration-dependent decreases in .OH adduct products (approximately 70% inhibition with 600 nmoles of PPG). It did not affect the peak of standard 2,3- and 2,5-DHBA indicating that the decrease in the adduct product generated by H2O2 is due to scavenging of .OH. These results indicate that photolysis of H2O2 by UV light produces .OH and that PPG scavenges .OH. PMID- 7838144 TI - Brefeldin A down-regulates the transferrin receptor in K562 cells. AB - The fungal metabolite brefeldin A (BFA) induces profound alterations in the morphology of intracellular organelles. Although BFA promotes the formation of extensive tubular endosomal domains, our understanding of the effects of the antibiotic on vesicle traffic events associated with endocytosis is limited. Thus, alterations in the transferrin (Tf) receptor's endocytic/recycling pathway upon treatment of human erythroleukemia K562 cells with BFA were studied as a pharmacological response. Treatment of K562 cells with BFA caused a down regulation in the number of cell surface Tf receptors. This effect is highly reminiscent of the well-known action of phorbol 12-myristate 13-acetate (PMA) on Tf receptor traffic in K562 cells. However, our results demonstrate that these two agents down-regulate the Tf receptor via different mechanisms. The effects of BFA and PMA were additive when K562 cells were incubated with both together. Using the In/Sur method, the endocytic rate constant for Tf internalization was determined and PMA was found to greatly enhance ke, from 0.28 min-1 to 0.43 min 1, while BFA had little effect (Ke = 0.20 min-1). In contrast, BFA-treatment alters the exocytic rate constant for return of internalized receptors to the cell surface, with the largest effect exerted on a 'slow-release', monensin sensitive, compartment. The sum of the endocytic and exocytic kinetic data support a model in which BFA and PMA down-regulate the Tf receptor in K562 cells by mechanistically distinct actions, with BFA targeting exocytic monensin sensitive intracellular compartments and PMA acting to exert a profound influence on elements of receptor internalization. PMID- 7838145 TI - Impairment of peroxisomal beta-oxidation system by endotoxin treatment. AB - It is now clear that peroxisomes play a crucial role in many cellular processes, including the beta-oxidation of very long chain fatty acids. Recently, mammalian peroxisomes have been shown to contain the antioxidant enzymes, superoxide dismutase and glutathione peroxidase, in addition to catalase. The presence of these enzymes in peroxisomes suggests that peroxisomes undergo oxidative stress in normal and disease states. As an indicator of the potential impact of an oxidative stress on peroxisomal functions, we evaluated the effect of endotoxin exposure on the beta-oxidation enzyme system in rat liver. Peroxisomes were isolated from liver homogenates by differential and density gradient centrifugations. Endotoxin treatment decreased the beta-oxidation of lignoceric acid to 56% of control values (p < 0.01). The specific activity of the rate limiting enzyme in the system, acyl-CoA oxidase, was decreased to 73% of control values (p < 0.05). Immunoblot analysis revealed a 25% decrease in the 21KD subunit of the acyl-CoA oxidase protein. In contrast, the protein levels of the other enzymes in the pathway, trifunctional protein and 3-ketoacyl-CoA thiolase, were increased by 10 and 15%, respectively. These findings suggest that impairment of beta-oxidation of lignoceric acid by endotoxin treatment is due primarily to a reduction in the activity and protein level of the key enzyme, acyl-CoA oxidase. Oxidative stresses such as endotoxin exposure may have deleterious effects on important peroxisomal functions, such as beta-oxidation of very long chain fatty acids. PMID- 7838146 TI - Insulin-like growth factor-1-mediated association of p85 phosphatidylinositol 3 kinase with pp 185: requirement of SH2 domains for in vivo interaction. AB - Insulin-like growth factor-I (IGF-1) stimulates the production of 3 phosphoinositides and increases the phosphatidylinositol 3-kinase activity that is immunoprecipitated by antiphosphotyrosine antibodies, a small portion of which are also associated with the IGF-1 receptor. In vitro reconstitution experiments showed that p85 associates with high affinity to the IGF-1 receptor and this interaction is mediated through the p85 SH2 groups. Moreover, in vitro, p85 is a substrate for the IGF-1 receptor tyrosine kinase activity. In this study, we analyzed the in vivo association of p85 with tyrosyl- phosphorylated proteins and its tyrosyl phosphorylation state, in response to IGF-1. After stimulation with IGF-1, the major tyrosylphosphorylated protein that was associated with p85 was a 185-kilodalton protein, identified as IRS-1. Only a small fraction of p85 was associated with the IGF-1 receptor. In contrast, the PDGF receptor was the major protein associated with p85 upon stimulation. Neither ligand stimulated the tyrosyl phosphorylation of p85 in vivo. In order to determine whether the SH2 domains of p85 were involved in its association with p185 in vivo after IGF-1 stimulation, different SH2-constructs of p85 were expressed in COS-1 cells. After stimulation with IGF-1, the expressed SH2 proteins were immunoprecipitated with specific antibodies, and associated p185 was detected on Western blots. These results show that both the p85 N-SH2 and N+C-SH2 associate with IRS-1 after IGF-1 stimulation.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7838147 TI - Dietary polyunsaturated fatty acids interfere with the insulin/glucose activation of L-type pyruvate kinase gene transcription. AB - L-type pyruvate kinase (L-PK) is a key glycolytic enzyme regulating the flux of metabolites through the pyruvate-phosphoenolpyruvate cycle (1). The regulation of L-PK is complex involving both hormones and nutrients. We have found that feeding rats diets containing polyunsaturated fatty acids (PUFA) significantly inhibits hepatic pyruvate kinase enzyme activity (> 60%) and suppresses mRNAPK abundance (> 70%). Studies with primary hepatocytes indicate that PUFA act directly on hepatocytes. Specifically, arachidonic (20:4, omega 6) and eicosapentaenoic (20:5, omega 3) acid suppressed both mRNAPK llevels and the activity of a transfected PKCAT (-4300/+12) fusion gene by > 70%. This is due to an inhibition of the insulin/glucose-mediated transactivation of L-PKCAT. Deletion analysis localized PUFA-regulated cis-acting elements to a region within the L-PK proximal promoter, i.e. between -197 and -96 base pairs. This region binds two transcription factors involved in the hormone/nutrient regulation of L-PK gene transcription, i.e. a major late transcription factor-like factor and HNF-4. Linker scanning mutation analysis localized the PUFA-regulated cis-acting elements to the vicinity of the HNF-4 binding site. Thus, PUFA-regulated factors abrogate the insulin/glucose activation of L-PK gene transcription by targeting the HNF-4 elements. These studies suggest that PUFA may have significant effects on hepatic carbohydrate metabolism by inhibiting the L-PK side of the pyruvate phosphoenolpyruvate cycle. PMID- 7838148 TI - The differential capacity of glucocorticoids and progestins to alter chromatin structure and induce gene expression in human breast cancer cells. AB - The T47D (A1-2) cell line is a human mammary carcinoma-derived cell line that has been engineered to constitutively express comparable levels of both glucocorticoid and progesterone receptors. In addition, these cells possess a stably integrated mouse mammary tumor virus (MMTV) luciferase reporter gene. Because the MMTV promoter is recognized similarly by both receptors, we have used this cell line to examine the transcriptional regulatory mechanisms employed by the two receptors. The stably integrated MMTV luciferase gene is highly inducible by glucocorticoids, whereas it is almost entirely refractory to induction by progestins. In contrast, a transiently transfected MMTV chloroamphenicol acetyl transferase reporter, while much more inducible by glucocorticoids, can be induced significantly by progestins. The differential inducibility of the stably integrated template is reflected in the superior ability of glucocorticoids to initiate alterations in the chromatin structure of the promoter. Concomitant with the changes in nuclease accessibility, glucocorticoids, unlike progestins, recruit transcription factors to the MMTV promoter. These results emphasize a central role for the modulation of the chromatin environment by steroid receptors in defining their capacity to regulate gene expression in vivo. PMID- 7838149 TI - Association of USF and c-Myc with a helix-loop-helix-consensus motif in the core promoter of the murine type II beta regulatory subunit gene of cyclic adenosine 3', 5'-monophosphate-dependent protein kinase. AB - Previous studies showed that the core promoter of the mouse cAMP-dependent protein kinase regulatory subunit type II beta (RII beta) gene was composed of two functional elements. One element was GC rich and bound the Sp1 transcription factor. The second element contained a helix-loop-helix (HLH)-motif. Each element conferred transcriptional activity when inserted upstream of a reporter gene, chloramphenicol acetyltransferase and transfected into mouse NB2a neuroblastoma cells and Chinese hamster ovary (CHO) cells. The core promoter was further characterized by mutational analysis using electrophoretic mobility shift assays and by transfection into CHO and NB2a cells. Electrophoretic mobility shift assays showed that the HLH-consensus motif, CACGTG, present in the RII beta gene bound nuclear factors present in NB2a and CHO cells. Mutations in the HLH-core motif decreased the binding of these factors and reduced the transcriptional activity of constructs containing the chloramphenicol acetyltransferase reporter when transfected into these cells. The results showed that the central nucleotides as well as the adjacent bases were important for the interaction with the nuclear binding factors. UV cross-linking, Southwestern blot analysis, and interference of the mobility shift patterns by specific antisera directed against USF and c-Myc indicated that both of these transcription factors were forming complexes with the HLH-consensus motif. The results suggest that RII beta transcription may be regulated, in part, by USF and c-Myc in NB2a and CHO cells. PMID- 7838150 TI - Antisense epidermal growth factor oligodeoxynucleotides inhibit follicle stimulating hormone-induced in vitro DNA and progesterone synthesis in hamster preantral follicles. AB - Whether FSH-induced follicular DNA synthesis in the hamster involves epidermal growth factor (EGF) message induction and translation was evaluated using antisense EGF oligodeoxynucleotides. The 15 base pair antisense oligomers synthesized according to mouse EGF cDNA sequence downstream from the 5'-ATG start site hybridized with a 4.4-kilobase message of mouse submaxillary glands and with 4.0 kilobases of mRNA of hamster submaxillary glands, kidney, and ovaries. Preantral follicles at stages 1-7 were enzymatically and mechanically isolated from adult, cyclic hamsters on day 4:0900 h (day 1 = estrus), and follicles at stages 1-5 were isolated from hamsters hypophysectomized for 10 days. Follicles were preexposed to either antisense or sense EGF thio-oligomers for 1, 12, or 24 h and then cultured for an additional 24 h in the absence or presence of ovine FSH (100 ng/ml) or recombinant murine EGF (50 ng/ml), and 1 microCi/ml [3H]thymidine. Follicular [3H]thymidine incorporation and EGF and steroid (progesterone, androstenedione, and 17 beta-estradiol) production were monitored to assess the molecular mechanism of FSH regulation of follicular development. Antisense oligomers significantly inhibited FSH-induced follicular DNA synthesis and progesterone but not androgen or estrogen production with a latency of 24 h. The oligomer inhibition of FSH action was effectively reversed by exogenous EGF. Antisense oligomers significantly inhibited follicular EGF synthesis in vitro. These results suggest that EGF message is expressed in the hamster ovary, and one of the molecular mechanisms of FSH regulation of hamster preantral folliculogenesis involves EGF mRNA induction and translation.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7838151 TI - Sry is a transcriptional activator. AB - The SRY gene functions as a genetic switch in gonadal ridge initiating testis determination. The mouse Sry and human SRY open reading frames (ORFs) share a conserved DNA-binding domain (the HMG-box) yet exhibit no additional homology outside this region. As judged by the accumulation of lacZ-SRY hybrid proteins in the nucleus, both the human and mouse SRY ORFs contain a nuclear localization signal. The mouse Sry HMG-box domain selectively binds the sequence NACAAT in vitro when challenged with a random pool of oligonucleotides and binds AACAAT with the highest affinity. When put under the control of a heterologous promotor, the mouse Sry gene activated transcription of a reporter gene containing multiple copies of the AACAAT binding site. Activation was likewise observed for a GAL4 responsive reporter gene, when the mouse Sry gene was linked to the DNA-binding domain of GAL4. Using this system, the activation function was mapped to a glutamine/histidine-rich domain. In addition, LexA-mouse Sry fusion genes activated a LexA-responsive reporter gene in yeast. In contrast, a GAL4-human SRY fusion gene did not cause transcriptional activation. These studies suggest that both the human and the mouse SRY ORFs encode nuclear, DNA-binding proteins and that the mouse Sry ORF can function as a transcriptional activator with separable DNA-binding and activator domains. PMID- 7838152 TI - Novel estrogen response elements identified by genetic selection in yeast are differentially responsive to estrogens and antiestrogens in mammalian cells. AB - A powerful and versatile system for the identification of novel response elements for members of the intracellular receptor family is presented as applied to the human estrogen receptor. In the past, a limited number of estrogen response elements (EREs) have been functionally identified in the promoter regions of estrogen-regulated genes. From these a consensus ERE has been defined that is identical to the ERE of the Xenopus laevis vitellogenin gene, i.e., 5'-GGTCA NNN TGACC-3'. In order to investigate without bias the range of sequences that could function as EREs in vivo, we have developed a genetic selection in yeast expressing the human estrogen receptor (hER) and transformed with a random oligonucleotide library in a vector where expression of a selectable marker requires insertion of an upstream activating sequence. More than 1,000,000 transformants were screened and of 726 clones that contained activating sequences, 65 were found to be hormone-dependent. Sequencing revealed that the majority contained at least one 4/5 match to a canonical ERE half-site, but only one contained a full consensus ERE as previously defined. Some contained half sites arranged as direct repeats. Twelve elements were further characterized to compare estrogen activation in yeast and mammalian cells and in vitro binding to hER. The results of these studies reveal that sequences that bind weakly to hER in vitro are fully functional as EREs in yeast and are conditionally responsive to estrogen in mammalian cells. In addition, an element was identified that is more sensitive to the partial agonist activities of tamoxifen and nafoxidine than is the consensus ERE, indicating that not only promoter context but the sequence of the binding site itself can allow distinction between receptor activated by agonist and that activated by antagonist. PMID- 7838153 TI - Serine 167 is the major estradiol-induced phosphorylation site on the human estrogen receptor. AB - Serine 167 has been identified by radiolabel and amino acid sequencing as the major estrogen-induced phosphorylation site on the human estrogen receptor (hER) from human MCF-7 mammary carcinoma cells. The phosphorylation of the hER on serine 167 was estrogen-dependent, increasing 4-fold upon estradiol treatment of MCF-7 cells and accounted for almost half of the total [32P]phosphate incorporated into the recombinant hER from Sf9 insect cells and the native hER from MCF-7 cells. Casein kinase II was found to phosphorylate the purified recombinant hER on serine 167 in vitro. In addition, estradiol binding enhanced by 2-fold the phosphorylation of the purified recombinant hER by casein kinase II in vitro. Western blot analysis and [32P]phosphate incorporation confirmed the presence of casein kinase II in Sf9 cells. These results demonstrate that the hER is phosphorylated on serine 167 by casein kinase II in a hormone-dependent manner. PMID- 7838154 TI - Mutational analysis of cysteine residues within the hormone-binding domain of the human estrogen receptor identifies mutants that are defective in both DNA-binding and subcellular distribution. AB - To further our understanding of the role played by cysteine residues in ligand recognition by the human estrogen receptor (hER), we have individually mutated residues 381, 417, 447, and 530 within the hormone-binding domain from cysteine to serine. We have also examined 10 additional nonconservative amino acid changes at C530. Four mutants were identified with defects in their ability to stimulate transcription in response to hormone: C447S, C530P, C530W, and C530G. Accumulation of the mutant proteins to comparable steady state levels after transient expression in COS-7 cells leads us to conclude that none of these substitutions results in increased turnover of receptor protein. None of these mutations had a reduced affinity for estradiol when compared with wild-type hER [dissociation constant (Kd) = 0.29 nM]. Although C447 and C530 reside outside of motifs previously defined as being necessary for DNA binding or receptor dimerization, all four of these mutants unexpectedly displayed altered DNA binding properties when analyzed using a gel mobility shift assay. Their loss of DNA binding could be overcome, at least in part, by hormone treatment or by the addition of antibody. Additionally, mutations C447S, C530S, and C530P displayed patterns of subcellular localization in the absence of hormone that differed from wild-type hER. These results argue that cysteine residues 447 and 530 within the hormone-binding domain play no direct role in the ability of this receptor to bind estradiol. These mutations, however, can effect DNA-binding activity and the distribution of hER within cells. PMID- 7838155 TI - Cell to cell contacts control the transcription activity of the glucocorticoid receptor. AB - Contact interactions between glia and neurons are required for hormonal induction of glutamine synthetase in Muller glial cells. Glucocorticoids induce a pronounced increase in glutamine synthetase gene transcription in the intact retinal tissue but not in separated retinal cells. However, if the separated cells are reaggregated and glial cells reestablish contacts with neurons, glutamine synthetase inducibility is restored. This study examines the possible involvement of the glucocorticoid receptor (GR) in cell contact control of glutamine synthetase induction. Using the glucocorticoid-inducible reporter construct, p delta G46TCO, and control constructs that are not inducible by glucocorticoids, we demonstrated that the trans-activating capability of GR markedly declines upon cell separation. Analysis of GR protein revealed that cell separation results in a pronounced decrease in GR expression. This decrease temporally correlated with the decline in glutamine synthetase gene transcription. Cell separation also results in a marked increase in c-Jun expression. This increase might be related to the decline in GR activity since elevation of c-Jun expression in the intact tissue inhibits the transcription activity of GR. Over-expression of GR by transfection of a GR expression vector or activation of endogenous GR molecules by 8-bromo-cAMP enhanced the responsiveness of separated retinal cells to glucocorticoids. These results demonstrate that transcription activity of the receptor protein depends on contact interactions between retinal cells and suggest that GR is involved in cell contact control of glutamine synthetase induction. PMID- 7838156 TI - Identification of RVR, a novel orphan nuclear receptor that acts as a negative transcriptional regulator. AB - A novel member of the steroid/thyroid/retinoid superfamily of nuclear receptors has been isolated as part of a screen to identify genes related to the recently characterized orphan receptor ROR alpha. This new orphan receptor, cloned from a mouse brain cDNA library, is closely related to the rat Rev-ErbA alpha gene product (97% and 68% identity in the DNA- and ligand-binding domains, respectively) and referred to as RVR. Northern blot analysis reveals that two RVR mRNA species are expressed during mouse embryogenesis and widely expressed in adult tissues. Studies with in vitro translated RVR protein show that it binds the DNA sequence ATAACTAGGTCA, a hormone response element composed of a 6-base pair AT-rich sequence preceding a single nuclear receptor recognition half-site core motif PuGGTCA. We show that RVR recognizes this hormone response element with a specificity similar to that of the orphan receptor ROR alpha 2. However, cotransfection studies indicate that RVR does not activate transcription when this hormone response element is linked to a reporter gene but rather acts as a potent competitive repressor of ROR alpha function. These results indicate the existence of an orphan nuclear receptor-based signaling pathway with the intrinsic ability to regulate the expression of specific gene networks through competition between transcriptional activators and repressors for the same recognition site. PMID- 7838157 TI - A chimeric thyroid hormone receptor constitutively bound to DNA requires retinoid X receptor for hormone-dependent transcriptional activation in yeast. AB - T3 receptors (TRs) regulate transcription by binding to specific DNA response elements as heterodimers with the retinoid X receptors (RXRs). To study the consequences of this heterodimerization for transcriptional regulation in the absence of complications associated with its effects on DNA binding affinity, we expressed in the yeast Saccharomyces cerevisiae a chimeric protein consisting of the rat TR beta 1 ligand-binding domain fused to the DNA-binding domain of the bacterial repressor lexA (lexATR). LexATR is a weak, T3-responsive activator of a beta-galactosidase reporter gene controlled by upstream lexA-binding sites (lexA beta-gal). In contrast, coexpression of human RXR alpha (hRXR alpha) strongly enhances both the basal and ligand-induced transcriptional activities. Both the N terminal activation domain of RXR and sequences at the extreme C terminus of lexATR are required for this T3- and RXR-dependent transcriptional activation. The lexATR chimera was also used to characterize receptor-receptor interactions using the two-hybrid system. Coexpression of B42RXR, a fusion protein of the human RXR alpha ligand-binding domain and the B42 transcriptional activation domain, strongly increases the transcriptional activity of lexATR in the absence of T3 or 9-cis-retinoic acid. We conclude that RXR is essential for full, T3 dependent transcriptional activity of the TR in yeast, and that protein-protein interaction of TR and RXR in vivo is ligand-independent. PMID- 7838158 TI - Cross-talk among ROR alpha 1 and the Rev-erb family of orphan nuclear receptors. AB - We have cloned Rev-erb beta, a novel isoform of the Rev-erb alpha orphan nuclear receptor. The DNA binding domains of Rev-erb alpha and beta are highly related to each other and to the retinoic acid related orphan receptor (ROR)/RZR subfamily of nuclear receptors. Indeed, we find that all three receptors bind as monomers to the sequence AATGT-AGGTCA. Whereas ROR alpha 1 constitutively activates transcription through this sequence, both isoforms of Rev-erb are inactive. When coexpressed, both Rev-erb isoforms suppress the transcriptional activity of ROR alpha 1. Our data define Rev-erb and ROR/RZR as a family of related receptors with opposing activities on overlapping regulatory networks. PMID- 7838159 TI - Spectrum of transcriptional, dimerization, and dominant negative properties of twenty different mutant thyroid hormone beta-receptors in thyroid hormone resistance syndrome. AB - Resistance to thyroid hormone (RTH) is usually dominantly inherited and characterized by elevated thyroid hormone levels, impaired feedback inhibition of pituitary TSH production, and variable hormonal responsiveness in peripheral tissues. We have identified 20 different mutations in the thyroid hormone beta receptor (TR beta) gene in RTH and assayed mutant receptor properties using the TSH alpha subunit gene promoter or promoters containing three different types of positive thyroid response element (TRE). Dominant negative inhibition of wild type TR beta action by mutant receptors was also tested. The mutant receptors exhibited differing transcriptional inhibitory properties and dominant negative potential with the TSH alpha promoter that correlated with their impaired hormone binding, whereas transactivation and dominant negative effects with promoters containing positive TREs varied depending on their configuration. Heterodimeric mutant receptor-retinoid X receptor (RXR) interactions, either in cultured cells or as TRE-bound complexes in gel retardation assays, were uniformly preserved, whereas homodimeric receptor interactions could not be detected in vivo, and in vitro homodimer formation on TREs was variably reduced or absent for some mutant proteins. We correlate these findings with the distribution of receptor mutations that cluster in two areas within the hormone binding domain outside putative dimerization regions and show that artificial mutations that impaired heterodimerization abrogated dominant negative activity. Therefore, we suggest that the dominant negative effect of mutant receptors in the pituitary-thyroid axis generates the characteristic biochemical abnormality of RTH and that variable resistance in other tissues may be due to response element-dependent differences in their dominant negative potential. PMID- 7838160 TI - Rab3A and Rab3B carboxy-terminal peptides are both potent and specific inhibitors of prolactin release by rat cultured anterior pituitary cells. AB - Chimeric polypeptides composed of the homeodomain of Antennapedia and of the C terminus of several low molecular weight GTP-binding proteins of the rab family have been found to translocate through the membrane of cells in culture and to accumulate in the cytoplasm and nucleus. We have used these chimeric peptides to study, in intact endocrine cells, a putative role for the C-terminal domain of rab proteins in the exocytotic process. We show that the internalization of 33- and 32-amino acid polypeptides corresponding to the C-terminal domains of rab3A and rab3B blocks calcium-triggered PRL release from adult rat anterior pituitary cells maintained in primary culture. This effect is specific to rab3 since it is not observed after internalization of either rab1 or rab2 C-terminal peptides. In addition, we demonstrate that this inhibition does not require the geranylgeranylation of the internalized C-termini. As rab3B normally shows a permissive effect on exocytosis in PRL-secreting cells, we suggest that the C terminal domains of rab3A and rab3B contain structural elements that compete with endogenous rab3 necessary for calcium-induced exocytosis. PMID- 7838161 TI - Primary biliary cirrhosis and the molecular cell biology of the nuclear envelope. AB - I hope I have demonstrated how basic research on the molecular cell biology of the nuclear envelope has provided information about the autoimmune disease PBC. I have given several examples of how highly specific immunologic reagents, obtained from patients with this disease, have been of value in experiments on the basic cell biology of the nuclear envelope. Continued work should provide further clues on how autoimmunity underlies the pathophysiology of PBC and should also provide additional reagents to study the processes of nuclear protein targeting and cell division. PMID- 7838162 TI - Approach to the patient with unexplained chest pain. AB - What are some take-home lessons on the syndrome of unexplained chest pain? Carefully exclude heart disease, which--unlike esophageally caused chest pain- may be life-threatening. Noncardiac chest pain is a common problem: at least 25% of chest pain patients in coronary care units or emergency rooms "rule out" for heart disease. It is a problem that has been vexing physicians for at least 100 years. The pain patterns in ischemic heart disease and in the unexplained pain syndromes, particularly reflux, may be identical. The mechanism may be an "irritable" esophagus, in which the visceral pain threshold is lowered. Look carefully for gastroesophageal reflux, and treat it aggressively. Finally, in all cases, try to establish a diagnosis if at all possible. When patients are told they don't have heart disease and no further workup is pursued, more than half of them continue to have significant morbidity from their chest pain, utilizing health care facilities and visiting doctors (34,35). Research over the past two decades has enlightened us about many patients with unexplained chest pain, but unfortunately we are still confused about many others, and for this group of patients a conservative therapeutic approach may be best. PMID- 7838163 TI - Neurologic complications of AIDS: new concepts and treatments. AB - As patients progress from seroconversion to progressive HIV-1 disease, a variety of neurologic disorders may occur. These include diseases of the central and peripheral nervous systems as well as primary muscle disorders. This presentation focuses on clinical, laboratory, and pathologic features of these disorders. Theories of pathogenesis and currently available treatments are reviewed. PMID- 7838164 TI - Do-not-resuscitate orders in the operating room. PMID- 7838165 TI - Remembering Irving J. Selikoff. PMID- 7838166 TI - Shoe-leather epidemiology--the footpads of mice and rats: animal tests in assessment of occupational risks. PMID- 7838167 TI - Consultation in hepatology. PMID- 7838168 TI - Consultation in thoracic surgery. AB - The thoracic surgical consultation is not limited to the technical details of the operation. It is a global evaluation of the problem, firmly rooted in a close relationship between the patient, the referring physician, and the consultant. PMID- 7838169 TI - Polymorphism of SPAG-1, a candidate antigen for inclusion in a sub-unit vaccine against Theileria annulata. AB - SPAG-1, a Theileria annulata sporozoite surface antigen, is a vaccine candidate. Data is presented, based on the clonal segregation of SPAG-1 associated RFLPs, showing that this antigen is encoded by a single copy gene. We have cloned and sequenced a full-length genomic copy of the SPAG-1 gene and a comparison of this with a previously published SPAG-1 cDNA sequence demonstrates a high degree of polymorphism. We infer that these sequences represent two distinct allelic SPAG-1 variants. The deduced polypeptides show an overall identity of 92% with the most variable stretch (60% identity) occurring towards the middle of the molecule. The N and C termini are more conserved with identities of 92% and 97% respectively. The elastin receptor ligand, VGVAPG, present 3 times in the protein sequence derived from the cDNA is not found in that deduced from the genomic copy. Evidence for 2 further SPAG-1 alleles was obtained from PCR based sequences using macroschizont clones containing different SPAG-1 associated RFLPs. In summary we have shown the existence of at least 4 highly polymorphic SPAG-1 alleles. The implications of such polymorphism between and within distinct geographical isolates for the development of a SPAG-1 based subunit vaccine is discussed. PMID- 7838170 TI - Characterization of a polymorphic family of integral membrane proteins in promastigotes of different Leishmania species. AB - Antibodies raised against a Leishmania major recombinant promastigote surface antigen 2 (PSA-2) fragment recognized three major polypeptides of approximate M(r) 96,000, 80,000 and 50,000 in promastigotes of three Israeli isolates of L. major including the cloned line LRC-L137-V121, but detected a different array of polypeptides in other L. major isolates. The pattern was different both in number of polypeptides detected and their molecular weight. The antibodies to L. major PSA-2 also recognized polypeptides in L. tropica, L. donovani and very weakly in L. mexicana promastigotes and in Crithidia lucilliae. The number and size of the polypeptides was different in each species. In addition to the membrane-bound PSA 2 polypeptides we identified water-soluble forms of PSA-2 released in promastigote culture supernatants. Peptide maps of the various L. major PSA-2 membrane polypeptides showed they were different from each other. N-terminal amino acid sequence of the three polypeptides expressed by L. major showed they are similar but distinct, consistent with being members of a polymorphic family. Because of the extensive sequence similarity between the PSA-2 genes it has been difficult to assign protein products to individual genes. As a first step towards solving this problem, we have transfected into L. mexicana a genomic clone of a L. major PSA-2 gene and shown that it produces a M(r) 35,000 polypeptide recognized by monoclonal and polyclonal antibodies to L. major PSA-2. PMID- 7838171 TI - Adult Schistosoma mansoni express cathepsin L proteinase activity. AB - This report presents the deduced amino acid sequence of a novel cathepsin L proteinase from Schistosoma mansoni, and describes cathepsin L-like activity in extracts of adult schistosomes. Using consensus primers specific for cysteine proteinases, gene fragments were amplified from adult S. mansoni cDNA by PCR and cloned. One of these fragments showed marked identity to Sm31, the cathepsin B cysteine proteinase of adult S. mansoni, whereas another differed from Sm31 and was employed as a probe to isolate two cDNAs from an adult S. mansoni gene library. Together these cDNAs encoded a novel preprocathepsin L of 319 amino acids; this zymogen is predicted to be processed in vivo into a mature, active cathepsin L proteinase of 215 amino acids. Closest homologies were with cathepsins L from rat, mouse, and chicken (46-47% identity). Southern hybridization analysis suggested that only one or a few copies of the gene was present per genome, demonstrated that its locus was distinct from that of Sm31, and that a homologous sequence was present in Schistosoma japonicum. Because these results indicated that schistosomes expressed a cathepsin L proteinase, extracts of adult S. mansoni were examined for acidic, cysteine proteinase activity. Based on rates of cleavage of peptidyl substrates employed to discriminate between classes of cysteine proteinases, namely cathepsin L (Z-phe arg-AMC), cathepsin B (Z-arg-arg-AMC) and cathepsin H (Bz-arg-AMC), the extracts were found to contain vigorous cathepsin L-like activity.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7838172 TI - The effect of (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl) adenine on nuclear and organellar DNA synthesis in erythrocytic schizogony in malaria. AB - The very effective (ID50 = 47 nM) and selective antimalarial compound (S)-9-(3 hydroxy-2-phosphonylmethoxypropyl) adenine (HPMPA) abruptly arrests Plasmodium falciparum-cultured schizonts at concentrations between 1 and 10 x ID50 as soon as their DNA content reaches 8 times that of the haploid ringform stage. Even very high HPMPA concentrations do not inhibit the first 2-3 rounds of schizogonic DNA replication. Also, in the presence of HPMPA, replication of the 6-kb mitochondrial and 35-kb chloroplast-like DNA proceeds normally and in close concert with each other, both to a 16-fold amount within 5 h during the trophozoite stage. Hence the in in vitro assays HPMPApp-sensitive plasmodial DNA polymerase gamma-like enzyme (IC50 = 1 microM)--assumed to be involved in mitochondrial DNA replication--is not the target of HPMPA in vivo (living parasites), nor seems to be the DNA polymerization activities of the--in vitro also HPMPA-sensitive (IC50 = 38 microM)--DNA polymerase alpha or of any other nuclear DNA polymerase of Plasmodium. In vitro assays demonstrated that HPMPApp does not act as an alternative substrate for plasmodial polymerases, contradicting the suggestion that the observed delayed inhibition of plasmodial schizogony might be the result of DNA strand breakage caused by HPMPApp incorporation. Neither do results support the idea that the HPMPA-induced arrest of DNA replication might be due to chain termination as a result of such incorporation. We investigated whether arrest of DNA replication by HPMPA in schizonts could be explained by inhibition of the DNA synthesis rate limiting ribonucleotide reductase enzyme.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7838173 TI - Identification of a developmentally regulated transcript expressed during encystation of Entamoeba invadens. AB - Differentiation of trophozoites into cysts in Entamoeba species has been described morphologically and to a lesser extent biochemically, but studies of stage specific gene expression have not been reported. At present Entamoeba invadens is the only species that can be induced to differentiate in axenic culture and is a useful model system for the human parasite Entamoeba histolytica. Using this model system, we performed cDNA-mRNA hybridization experiments to compare the RNA populations from trophozoites and from parasites at different stages of cyst formation. We detected the accumulation of a population of stage specific transcripts between 8 and 22 h after parasites are placed in induction medium. To identify genes involved in the trophozoite-cyst transformation we carried out a differential screening of a cDNA library. This yielded a clone that represents a stage specific gene whose transcripts are barely detectable in vegetatively grown trophozoites and maturing cysts, but are readily detected at the onset of cyst formation. Other features of the gene and its predicted protein product(s) are described. PMID- 7838174 TI - Increased levels of polyadenylated histone H2B mRNA accumulate during Entamoeba invadens cyst formation. AB - We have isolated cDNA clones of a member of the histone H2B protein family by differential screening of an Entamoeba invadens cDNA library with cDNA probes from vegetatively growing or encysting parasites. The cDNA clones reveal two polyadenylation sites, 26 nucleotides and 31 nucleotides downstream from the stop codon. RNA species recognized by E. invadens histone H2B clones are found at increased levels during cyst formation. Histone H2B RNA could be detected in both the poly(A)+ and poly(A)- RNA fractions, with stage-specific differences in the steady state levels of the two RNAs: trophozoites contain predominantly the poly(A)- RNA, while encysting parasites express predominantly the poly(A)+ RNA. Southern blot analysis suggests that both forms are transcribed from a single copy gene. PMID- 7838175 TI - A trans-spliced leader RNA sequence in plant parasitic nematodes. AB - A trans-spliced leader gene has been identified in the genomes of the potato cyst nematodes Globodera rostochiensis and G. pallida. The gene contains a 22-nt sequence identical to that of the leader sequence of Caenorhabditis elegans, a consensus splice donor site and a putative Sm antigen binding site. In common with other nematodes the spliced leader gene is present in tandem repeating units together with the 5S ribosomal RNA gene. Variation in the length of the intergenic spacer region has permitted the design of polymerase chain reaction primers which can be used to reveal repeat length variants diagnostic for G. rostochiensis and G. pallida and the Pa1 pathotype of G. pallida. PMID- 7838176 TI - Molecular characterization of the heat shock protein 90 gene of the human malaria parasite Plasmodium falciparum. AB - We report here the nucleotide sequence of hsp90 (heat shock protein 90) of Plasmodium falciparum. Computer analysis of the deduced protein sequence revealed an unusually large region of charged amino acids when compared to hsp90 from other species. This region shows striking homology to the calcium binding domain of calreticulin, the major calcium binding protein of endoplasmic reticulum. Phylogenetic tree analysis indicates that P. falciparum hsp90 is more closely related to hsp90 from plants than to hsp90 from vertebrates or other parasites. The malaria hsp90 is an ATP binding protein encoded by a single gene constitutively expressed in both asexual (trophozoite) and sexual (gametocyte) stage parasites. The hsp90 protein is homologous to a previously identified 90 kDa antigen strongly recognised by both sera from vaccinated monkeys and monoclonal antibody XIV/7. PMID- 7838177 TI - Leishmania gymnodactyli and Leishmania infantum minicircles contain the same guide RNA genes as do minicircles of Leishmania tarentolae. PMID- 7838178 TI - Molecular and serological analysis of cDNAs encoding an intermediate-filament protein from Onchocerca volvulus. PMID- 7838179 TI - Cytidine triphosphate synthetase activity in asexual blood stages of Plasmodium falciparum. PMID- 7838180 TI - A Plasmodium falciparum isolate with a chromosome 9 deletion expresses a trypsin resistant cytoadherence molecule. AB - Sequestration of Plasmodium falciparum infected erythrocytes in the cerebral circulation is strongly implicated in the pathogenesis of cerebral malaria. From previous studies it was postulated that genes essential for cytoadherence were located on the right arm of chromosome 9 as P. falciparum isolates with a deletion in this region lost the capacity to cytoadhere in vitro and no longer expressed Plasmodium falciparum erythrocyte membrane protein-1 (PfEMP-1) on the surface of the infected cells. We have selected a P. falciparum isolate from Papua New Guinea for high levels of cytoadherence to human umbilical vein endothelial cells (HUVECs) and have shown that the cloned parasite has several novel properties related to cytoadherence. The cloned parasite adheres to HUVECs, does not bind to melanoma cells, and expresses a surface molecule with most of the properties of PfEMP-1, despite a deletion in the right arm of chromosome 9. Interestingly, the surface expressed PfEMP-1 in this strain is resistant to trypsin treatment and infected cells continue to cytoadhere after trypsin digestion at a concentration of 100 micrograms ml-1. The receptor on HUVECs for the cloned parasite lines is a molecule different from any previously described, as parasitized cells do not adhere to soluble intercellular adhesion molecule 1, thrombospondin, vascular cell adhesion molecule 1, E-selectin or P-selectin, nor to CD36. Our work, taken together with the results from previous studies, suggest that the ability of parasites to cytoadhere is encoded in at least two distinct genomic locations in the parasite, and the diversity of receptor-ligand interaction is greater than previously described. PMID- 7838181 TI - Molecular characterisation of a novel, repetitive protein of the paraflagellar rod in Trypanosoma brucei. AB - A partial cDNA clone, termed 5.20, was isolated from a lambda-gt11 phage expression library using a complex antiserum to the T. brucei cytoskeleton. Antisera against the fusion protein product of this 5.20 cDNA recognized a closely-spaced polypeptide doublet of high molecular weight (ca. 180-200 kDa) on immunoblots of T. brucei cytoskeletal preparations. Immunogold labelling suggested the 5.20 protein is intracellular and localized along the entire length of the paraflagellar rod. This pattern is similar to that generated with a monoclonal antibody, ROD1, which recognizes a high molecular weight protein doublet indistinguishable from that detected by 5.20-specific antisera. ROD1 recognizes mammalian spectrin, but the use of specific anti-spectrin antibodies for immunoblotting did not support ideas that 5.20 encodes spectrin or that spectrin can be specifically detected in T. brucei by such methods. Moreover, the sequence of the 5.20 cDNA insert bears little similarity, either in its nucleotide or predicted amino acid sequence to other known proteins and appears to be a unique cytoskeletal protein characterized especially by sequential amino acid sequence repetitiveness. The location of this novel protein suggests it may be responsible for providing either paraflagellar rod-membrane links or for organizing the more abundant paraflagellar rod structural proteins. PMID- 7838182 TI - Characterization of enzymatically active Onchocerca volvulus Cu/Zn superoxide dismutase expressed in Escherichia coli. AB - The Onchocerca volvulus superoxide dismutase was expressed in Escherichia coli, using a protocol designed to produce the native enzyme rather than a fusion protein. The recombinant O. volvulus superoxide dismutase (rOVSOD) was found in the cytosol of the disrupted bacteria and represented > 10% of the total bacterial protein. The enzyme was purified to homogeneity using DEAE-Sepharose chromatography, followed by phenyl-Sepharose chromatography. The rOVSOD was enzymatically active which was demonstrated by its reactivity with O2.- produced either by the xanthine-xanthine oxidase system or by stimulated eosinophils. The specific activity was determined to be 4668 U mg-1. This activity could be blocked by rabbit antiserum raised against the rOVSOD. The maximal activity was obtained upon supplementation of the bacterial growth media and enzyme buffer with copper and zinc ions. Activity characteristics in the presence of inhibitors was also characteristic of a Cu/Zn superoxide dismutase. The rOVSOD has an apparent subunit molecular mass of 16,000 in SDS-PAGE. The active enzyme behaves as a dimer of 32 kDa as determined by gel filtration. PMID- 7838183 TI - High level arsenite resistance in Leishmania tarentolae is mediated by an active extrusion system. AB - Leishmania tarentolae cells selected for resistance to the oxyanions pentavalent or trivalent antimonials or to trivalent arsenicals exhibited cross-resistance to the other oxyanions. The basis for resistance in these mutants was studied by transport experiments using radioactive arsenite. All mutants exhibiting high level resistance to arsenite showed a marked decrease in the steady-state accumulation of arsenite. Decreased accumulation was also observed in antimonials resistant mutants cross-resistant to various concentrations of arsenite. Cells depleted of endogenous energy reserves with metabolic inhibitors were loaded with radioactive arsenite; following addition of glucose, rapid efflux of arsenite was observed from arsenite mutant cells. Mutants resistant to high levels of arsenicals exhibited amplification of the P-glycoprotein related gene ltpgpA or of a linear amplicon of unknown function. However, the efflux-mediated arsenite resistance did not correlate with the amplification of the ltpgpA gene or with the presence of the linear amplicon. The calcium channel blocker verapamil and arsenite act in synergy in cells exhibiting the efflux system. Overall the oxyanion efflux system in Leishmania shares several properties with other resistance efflux systems mediated by transporters. PMID- 7838184 TI - Differential localization of full-length and processed forms of PF83/AMA-1 an apical membrane antigen of Plasmodium falciparum merozoites. AB - A well conserved 83-kDa apical membrane antigen of Plasmodium falciparum, PF83/AMA-1, is the analogue of PK66/AMA-1, a 66-kDa P. knowlesi protective merozoite protein. PK66/AMA-1 is expressed in late-stage schizonts; is localized within the merozoite apex; and is processed to a 44/42-kDa doublet at, or around, the time of schizont rupture. The processed forms can associate with the merozoite surface. We were interested to further analyze the timing of synthesis and processing, and subcellular localization of PF83/AMA-1, a malaria vaccine candidate, using monoclonal antibodies (mAbs) developed against PF83/AMA-1. Using [35S]methionine metabolically labeled asexual blood stage parasites, in combination with indirect single and dual immunofluorescence, we have determined that, in similar fashion to PK66/AMA-1, protein expression of PF83/AMA-1 is restricted to late-stage schizonts with greater than 8 nuclei. PF83/AMA-1 is post synthetically processed rapidly by cleavage of an N-terminal peptide to a 66-kDa molecule. Both the 83- and the 66-kDa molecules are initially localized at the merozoite apex. In P. falciparum (7G8 strain and CVD-1 clone) the full-length 83 kDa molecule remains apically restricted following merozoite release. However, the processed 66-kDa form can become circumferentially associated with the merozoite surface at or around the time of schizont rupture and merozoite release. After merozoite invasion a processed form of PF83/AMA-1 is present in early ring stage parasites. Comparative analysis of a rhoptry associated protein RAP-1, shows a co-ordinated and compartmentalized release of rhoptry components. PMID- 7838185 TI - Litomosoides carinii microfilarial sheaths: partial amino acid sequences of several major polypeptide constituents. AB - Isolated sheaths from Litomosoides carinii microfilariae were disintegrated by reduction with dithiothreitol and were 14C-carboxymethylated. Five major sheath proteins thus solubilized were purified by size exclusion chromatography and reversed-phase HPLC (rpHPLC). Proteolytic fragments of complete sheaths and of the single sheath proteins were isolated by rpHPLC and were N-terminally sequenced. A library of 27 partial sheath polypeptide sequences was thus established, 21 of which could be assigned to three L. carinii sheath structural genes (shp1,2, and 3/3a) isolated on the basis of this and of previous amino acid sequence information. The remaining peptides document the presence of at least one additional major sheath constituent. PMID- 7838186 TI - Hexose-monophosphate shunt activity in intact Plasmodium falciparum-infected erythrocytes and in free parasites. AB - The hexose monophosphate shunt (HMS) produces NADPH for reductive antioxidant protection and for metabolic regulation, as well as ribose-5-phosphate needed for the synthesis of nucleic acids. Since malaria-infected red blood cells (RBC) are under endogenous oxidant stress, it was interesting to determine HMS activity in intact infected cells, as well as in free parasites. HMS activity was determined by measuring the evolution of 14CO2 from D-[1-14C]glucose in normal RBC, in intact Plasmodium falciparum-infected RBC (IRBC) and in free parasites. The HMS activity of IRBC was found to be 78 times higher than that of normal RBC. This activity increased with parasite maturation from the ring stage toward the trophozoite stage, and declined at the schizont stage. The HMS activity of the parasite contributes 82% of the total observed in the intact IRBC, and that of the host cell is increased some 24-fold. The increased reducing capacity of IRBC and free parasites were also evidenced by the larger ability for reductive accumulation of methylene blue. Since the endogenous oxidative stress is produced by the parasite digestion of the host cell's hemoglobin, inhibition of this process with protease inhibitors, by alkalinization of the parasite's food vacuole, or by the application of antimalarial drugs, resulted in 20-44% inhibition of IRBC HMS activity. A similar inhibition was observed in the presence of scavengers of oxidative radicals, uric and benzoic acids. These inhibitors had only a minor effect on the HMS activity of free parasites. D-[1 14C]glucose and D-[6-14C]glucose contributed equally to newly synthesized nucleic acids, suggesting that ribose-5-phosphate needed for this synthesis is contributed by the non-oxidative activity of HMS. These results imply that a major portion of parasite HMS activity and the activated HMS of the host cell are devoted to counteract the endogenously generated oxidative stress. PMID- 7838187 TI - Functional complementation of glycoprotein 72 in a Trypanosoma cruzi glycoprotein 72 null mutant. AB - To investigate the role of a developmentally regulated 72-kDa surface antigen of Trypanosoma cruzi (GP72), a GP72 null mutant was previously produced [Cooper et al., 1993, J. Cell Biol. 122, 149-156]. Abnormal morphology of epimastigote and metacyclic trypomastigote stages of the GP72 null mutant suggested that GP72 is associated with flagellum-cell adhesion [Cooper et al., 1993, J. Cell Biol. 122, 149-156; De Jesus et al., J. Cell Sci., in press]. In the present study, functional complementation of the GP72 null mutant was accomplished by transformation with two independent episomal vectors expressing GP72 and phleomycin or tunicamycin resistance genes. A correlation between gene copy number, RNA level, expression of GP72, and morphological phenotypes was demonstrated. Disparities were observed between gene copy number and RNA level and between the apparent level of GP72 polypeptide and the carbohydrate epitope recognized by monoclonal antibody WIC29.26. Restoration of morphology reflects recovery of the carbohydrate epitope, suggesting that the novel glycosylation of GP72 is the limiting step in the expression of its function. PMID- 7838188 TI - Developmental and neurologic status of children after heart surgery with hypothermic circulatory arrest or low-flow cardiopulmonary bypass. AB - BACKGROUND: Deep hypothermia with either total circulatory arrest or low-flow cardiopulmonary bypass is used to support vital organs during heart surgery in infants. We compared the developmental and neurologic sequelae of these two strategies one year after surgery. METHODS: Infants with D-transposition of the great arteries who underwent an arterial-switch operation were randomly assigned to a method of support consisting predominantly of circulatory arrest or a method consisting predominantly of low-flow bypass. Developmental and neurologic evaluations and magnetic resonance imaging (MRI) were performed at one year of age. RESULTS: Of the 171 patients enrolled in the study, 155 were evaluated. After adjustment for the presence or absence of a ventricular septal defect, the infants assigned to circulatory arrest, as compared with those assigned to low flow bypass, had a lower mean score on the Psychomotor Development Index of the Bayley Scales of Infant Development (a 6.5-point deficit, P = 0.01) and a higher proportion had scores < or = 80 (i.e., 2 SD or more below the population mean) (27 percent vs. 12 percent, P = 0.02). The score on the Psychomotor Development Index was inversely related to the duration of circulatory arrest (P = 0.02). The risk of neurologic abnormalities increased with the duration of circulatory arrest (P = 0.04). The method of support was not associated with the prevalence of abnormalities on MRI scans of the brain, scores on the Mental Development Index of the Bayley Scale, or scores on a test of visual-recognition memory. Perioperative electroencephalographic seizure activity was associated with lower scores on the Psychomotor Development Index (P = 0.002) and an increased likelihood of abnormalities on MRI scans of the brain (P < 0.001). CONCLUSIONS: Heart surgery performed with circulatory arrest as the predominant support strategy is associated with a higher risk of delayed motor development and neurologic abnormalities at the age of one year than is surgery with low-flow bypass as the predominant support strategy. PMID- 7838189 TI - Lower-extremity function in persons over the age of 70 years as a predictor of subsequent disability. AB - BACKGROUND: Functional assessment is an important part of the evaluation of elderly persons. We conducted this study to determine whether objective measures of physical function can predict subsequent disability in older persons. METHODS: This prospective cohort study included men and women 71 years of age or older who were living in the community, who reported no disability in the activities of daily living, and who reported that they were able to walk one-half mile (0.8 km) and climb stairs without assistance. The subjects completed a short battery of physical-performance tests and participated in a follow-up interview four years later. The tests included an assessment of standing balance, a timed 8-ft (2.4-m) walk at a normal pace, and a timed test of five repetitions of rising from a chair and sitting down. RESULTS: Among the 1122 subjects who were not disabled at base line and who participated in the four-year follow-up, lower scores on the base-line performance tests were associated with a statistically significant, graduated increase in the frequency of disability in the activities of daily living and mobility-related disability at follow-up. After adjustment for age, sex, and the presence of chronic disease, those with the lowest scores on the performance tests were 4.2 to 4.9 times as likely to have disability at four years as those with the highest performance scores, and those with intermediate performance scores were 1.6 to 1.8 times as likely to have disability. CONCLUSIONS: Among nondisabled older persons living in the community, objective measures of lower-extremity function were highly predictive of subsequent disability. Measures of physical performance may identify older persons with a preclinical stage of disability who may benefit from interventions to prevent the development of frank disability. PMID- 7838190 TI - A controlled trial of povidone-iodine as prophylaxis against ophthalmia neonatorum. AB - BACKGROUND: Neonatal conjunctivitis (ophthalmia neonatorum) continues to cause blindness because the agents used prophylactically to prevent this condition are not completely effective and are not widely available in many parts of the world. Povidone-iodine ophthalmic solution is an effective antibacterial agent with broad antibacterial and antiviral activity to which no bacteria are known to be resistant, and it is far less expensive and less toxic than the agents currently used to prevent neonatal conjunctivitis. METHODS: We conducted a masked, prospective trial involving 3117 infants born over a period of 30 months in a hospital in Kenya. Shortly after birth each infant received a 2.5 percent solution of povidone-iodine (n = 1076), a 1 percent solution of silver nitrate (n = 929), or 0.5 percent erythromycin ointment (n = 1112) in both eyes. Randomization was achieved by rotating the three medications after each was used for a week. RESULTS: Of the neonates treated with povidone-iodine, 13.1 percent had infectious conjunctivitis, as compared with 17.5 percent of those treated with silver nitrate (P < 0.001) and 15.2 percent of those treated with erythromycin (P = 0.01). Povidone-iodine was more effective against Chlamydia trachomatis than was silver nitrate (P < 0.001) or erythromycin (P = 0.008). There were 104 cases of noninfectious conjunctivitis (9.7 percent) in the povidone-iodine group, as compared with 129 in the silver nitrate group (13.9 percent, P < 0.001) and 148 in the erythromycin group (13.3 percent, P = 0.004). Many cases of noninfectious conjunctivitis were probably due to a toxic reaction to the treatment itself. The incidence of Neisseria gonorrhoeae and Staphylococcus aureus infections was similar in the three groups. CONCLUSIONS: A 2.5 percent ophthalmic solution of povidone-iodine as prophylaxis against ophthalmia neonatorum is more effective than treatment with silver nitrate or erythromycin, and it is less toxic and costs less. PMID- 7838191 TI - Brief report: a familial syndrome of arterial dissections with lentiginosis. PMID- 7838192 TI - Images in clinical medicine. Relapsing polychondritis. PMID- 7838193 TI - Treatment of psoriasis. PMID- 7838194 TI - Fine structure of a gene--DNA sequencing. PMID- 7838195 TI - Clinical problem-solving. Decision making by analogy. PMID- 7838196 TI - Functional assessment and its place in health care. PMID- 7838197 TI - Ophthalmia neonatorum in developing countries. PMID- 7838198 TI - Supporting the patient. PMID- 7838199 TI - Conflicts in managed care. PMID- 7838200 TI - Subforms of creatine kinase MB in the diagnosis of myocardial infarction. PMID- 7838201 TI - Subforms of creatine kinase MB in the diagnosis of myocardial infarction. PMID- 7838202 TI - Subforms of creatine kinase MB in the diagnosis of myocardial infarction. PMID- 7838203 TI - Subforms of creatine kinase MB in the diagnosis of myocardial infarction. PMID- 7838204 TI - Case 34-1994: laryngeal tuberculosis. PMID- 7838205 TI - Case 34-1994: laryngeal tuberculosis. PMID- 7838206 TI - Case 34-1994: laryngeal tuberculosis. PMID- 7838207 TI - Scabies. PMID- 7838208 TI - Scabies. PMID- 7838209 TI - Ivermectin for crusted (Norwegian) scabies. PMID- 7838210 TI - Dystrophin, utrophin, and muscular dystrophy. PMID- 7838211 TI - Maternal and fetal thyroid function. PMID- 7838212 TI - Self-cardioversion. PMID- 7838213 TI - Treatment of sideroblastic anemia with chloroquine. PMID- 7838214 TI - Comparison of processing treatments on the composition and functional properties of rapeseed preparations (Brassica campestris L. var. toria). AB - Rapeseed preparations viz. rapeseed meal, concentrates and isolates were prepared using different processing treatments involving organic solvents, acids, alkali, steaming and boiling. Their anti-nutritional constituents and functional properties were studied in comparison to undefatted meal. Percent decrease in phytic acid and phenolic content was maximum in seeds boiled for 30 min and isolates, respectively. Isolate II prepared by sodium hexa-metaphosphate had minimum glucosinolates, maximum content of total proteins and much improved nitrogen solubility, emulsifying and foaming properties. Water absorption and fat absorption capacities were enhanced by boiling seeds prior to grinding and ammonia-methanol extraction, respectively. Viscosity decreased in all the treatments as compared to control. PMID- 7838215 TI - Rapeseed meal-glucosinolates and their antinutritional effects. Part 5. Animal reproduction. AB - Although there is no clear evidence to fully describe the mechanism involved in glucosinolate-related effects on animal reproduction, lowered fertility in animals fed diets with rapeseed meal (RSM) inclusion is related to glucosinolate content in the diet. Negative effects can result both from multidirectional action of glucosinolates, malnutrition of mother due to the thyroid dysfunction, transfer of goitrogenic compounds to foetus and reduced transfer of nutritive compounds (e.g. iodine) through the placenta. The degree of reproduction impairment depends both on glucosinolate content and on the type of animal. Pregnant female rats are sensitive to the presence of glucosinolates, and the first symptoms of fertility impairment and lowering of offspring survival rate may occur at low glucosinolate levels, e.g. with diets containing low glucosinolate rapeseed meal (LG-RSM). In the case of swine, the limiting value above which sows fertility may be impaired is 4 mumol of total glucosinolates per g diet and 8 mmol of daily intake of these compounds. Opinions on the permitted RSM inclusion in diet for hens are very divergent. Some authors recommend limiting of the RSM inclusion to 10%, while others did not find any lowering of egg production in hens fed with two- or three-fold greater RSM inclusion rates. Most long-term experiments with heifers, cows and ewes indicate that ruminants tolerate the level of glucosinolate in LG-RSM although feeding this fodder as the only high-protein concentrate component may lead to impaired fertility. PMID- 7838216 TI - Radio-frequency microtools for particle and liver cell manipulation. AB - Single particles can be manipulated by applying high frequencies to ultramicro electrode arrays fabricated on planar structures. Heat production can be reduced to the extent that intense electric fields can be applied even to unmodified cell culture media. Animal cells grow normally in the high field (up to 100 kV/m) between such continuously energized multielectrodes. As with laser tweezers [1 3], this technique can capture particles and cells in field traps, generate linear movement, and permit cell cultivation. It can also produce micropatterns of pH gradients, field-cast objects, and control cell adhesion. These microtools may be combined to develop cell separators, microsensors, and controlled biocompatibility surfaces. PMID- 7838217 TI - [Work disability caused by airway diseases in employees of a mixed feed plant: notifiable as an occupational disease?]. PMID- 7838218 TI - [Urethral valves]. PMID- 7838219 TI - [Fear of anesthesia]. PMID- 7838220 TI - [Current developments in the diagnosis of Alport syndrome]. PMID- 7838221 TI - [Congenital urethra valves; experiences in 73 children]. AB - OBJECTIVE: To inventory symptoms of children with urethral valves, and their prognosis. DESIGN: Descriptive. SETTING: Department of paediatrics and urology, University of Nijmegen. METHODS: Symptoms were evaluated from clinical data and interviews of the parents of 73 patients. The glomerular filtration rate (GFR) was calculated from the serum creatinine level by the method of Counahan. RESULTS: Symptoms indicating an urethral obstruction, e.g. diminished urinary jet, were rare (20% of the children). General symptoms prevailed: vomiting, anorexia, growth failure, fever. After 2 years 11 out of 53 children had a GFR < 25 ml/min/1.73 m2 body surface area. CONCLUSION: Specific symptoms indicating an urethral obstruction are rare. The glomerular filtration is often diminished. There are no measures to prevent loss of renal function. PMID- 7838222 TI - [Children with a presumably isolated speech-language disorder often have medical or cognitive problems as well]. AB - OBJECTIVE: To assess the language problems of children who otherwise appear to develop normally. DESIGN: A clinical inventory. SETTING: University Hospital Groningen. METHOD: The children (n = 319) were examined according to a standard protocol consisting of: ENT examination, audiologic examination, paedogogic observation and logopaedic examination. Further psychological examination was carried out when needed according to the paedagogic observation. RESULTS: 25 per cent of the children had isolated language problems. For these children logopaedic therapy was indicated. In 75 per cent, a clear associated medical factor, or a retarded cognitive and (or) motor development, was found. Forty per cent of these children received medical treatment and 35 per cent specific paedagogic guidance. In some cases additional logopaedic therapy was given. CONCLUSION: It appears advisable to give children with language problems logopaedic therapy only after a diagnostic examination has been carried out according to a standard protocol as described. PMID- 7838223 TI - [Providing patients with an audio recording of the outpatient oncological consultation; experiences of patients and physicians]. AB - OBJECTIVE: Gaining insight into the experiences of physicians and patients who were provided with an audiotape of an oncological consultation. DESIGN: Questionnaire study. SETTING: Academic Medical Hospital, Amsterdam. METHOD: Consultations with 30 consecutive patients referred to the gynaecology or urology outpatient clinic for an initial consultation regarding the diagnosis and (or) treatment policy were taped. Afterwards, patients took the tapes home. The following week they were phoned and asked what they had done with the tape and how they appreciated the intervention. By means of a questionnaire the physicians (n = 6) were asked about their experiences. RESULTS: Two patient could not be reached. Twenty-three out of 28 patients had listened to the tape, mostly together with others (spouse, relatives). Twenty-six out of 28 patients were positive about implementation of this intervention. According to most patients the tape contained information they had forgotten. Most patients found the tape contained reassuring information. Physicians regarded the optimal transmission of information achieved by this intervention as an advantage. Three out of six saw possible misinterpretation of the imparted information as a disadvantage. For some physicians, the taping of consultations led to more careful phrasing. Most physicians saw no logistical difficulties. In general, participation in the study did not take any extra time. CONCLUSION: This first study shows that both cancer patients and physicians find it useful to provide patients with an audiotape of the initial consultation. PMID- 7838224 TI - ['Cerebral running nose': cerebrospinal rhinorrhea]. AB - Cerebrospinal fluid rhinorrhoea was diagnosed in two patients, a man of 19 and a woman of 45 years old. This is a relatively rare phenomenon and clinically often difficult to differentiate from nasal secretions caused by a rhinopathy. Although cerebrospinal fluid (CSF) fistulae usually are of traumatic origin as in the first patient, they can also be caused by a congenital malformation as in the second one or by a condition with chronic increased intracranial pressure. With adequate treatment the prognosis is good. CSF can be identified very specifically by beta-transferrin determination. PMID- 7838225 TI - [The 'one-hand' method in venipuncture with recapping of the needle: small chance of puncture accident]. PMID- 7838226 TI - [Discussion with the patient with cancer]. PMID- 7838227 TI - [Geriatrics education in Utrecht]. PMID- 7838228 TI - [Allergy for human insulin]. PMID- 7838229 TI - [Manganese poisoning caused by administration of Chien Pu Wan tablets]. PMID- 7838230 TI - [Mortality among young people: causes and background]. PMID- 7838231 TI - [Misconduct in medical-scientific publications]. PMID- 7838232 TI - Acuity vs staffing mix. PMID- 7838233 TI - After health care reform: now what? PMID- 7838234 TI - ANA testifies patient care and safety is at risk in some hospitals. PMID- 7838235 TI - Chemical dependency in nursing: the Nevada response. PMID- 7838236 TI - Special issue on clinical immunology. PMID- 7838237 TI - Clinical immunology: a clinical and laboratory discipline. PMID- 7838238 TI - Immunological and virological markers determining progression to AIDS. AB - Infection with the human immunodeficiency virus (HIV-1) results in a severe immunodeficiency characterized by a depletion of CD4+ T-helper cells. Furthermore it is well documented that in asymptomatic persons the number of CD4+ cells is also a good predictor of progression to AIDS. However, persons with similar CD4+ cell counts may differ with regard to clinical progression. For this reason the development of additional markers predictive of disease progression is of major clinical importance. In this review three additional progression markers are discussed: rate of decline of CD4+ cells, T-cell reactivity and HIV biological phenotype. Besides their usefulness as independent progression markers they also provide insight into the immunopathological mechanisms responsible for the final development of AIDS. PMID- 7838239 TI - Routine vaccination in HIV-infected patients: a review. AB - This paper reviews the literature from 1988 to November 1993 on the effectiveness of routine vaccination of HIV-infected adults. Data on the clinical benefit of vaccination in this particular group of patients are not available. In general, HIV-infected patients have suboptimal immunological responses to vaccines. In particular, an impaired responsiveness is found in patients with fewer than 200 x 10(6) CD4+ cells per litre. Consequently, it seems prudent to offer active immunization to HIV-infected subjects who are relatively immunocompetent. However, the usefulness of vaccination in those subjects who have a low CD4+ cell count is doubtful. PMID- 7838240 TI - Agammaglobulinaemia. AB - Agammaglobulinaemia is the most common of the primary immunodeficiencies. Three major types can be distinguished: X-linked agammaglobulinaemia, early-onset agammaglobulinaemia and late-onset agammaglobulinaemia. In X-linked agammaglobulinaemia, the molecular defect has been elucidated, and genetic counseling, prenatal diagnosis and carrier detection have become important issues. The pathogenesis of early- and late-onset agammaglobulinaemia is heterogeneous and usually not within the B-cell lineage. Patients with agammaglobulinaemia mainly suffer from infections caused by pneumococci or encapsulated Haemophilus influenzae located in the respiratory tract, paranasal sinuses, ears and meninges. Other prominent infections are Campylobacter jejuni bacteraemia and Giardia lamblia infection of the intestine. Among the more rare infections are those caused by Ureaplasma and Mycoplasma hominis. There is quite a number of non-infectious abnormalities which bother agammaglobulinaemic patients, especially those with late-onset agammaglobulinaemia. Of these, gastric carcinoma and intestinal lymphoma in late-onset agammaglobulinaemia and colorectal cancer in X-linked agammaglobulinaemia are the most dramatic. Life threatening bacterial infections can largely be prevented by immunoglobulin substitution, even at relatively low dosages. However, insufficient immunoglobulin substitution is associated with recurrent airway infection and cumulative damage to the respiratory tract. for adequate substitution, efficacieous and safe intravenous immunoglobulin preparations are available. For selected patients (children, adults with poor venous access, and those experiencing side-effects on intravenous immunoglobulin), 16% immunoglobulin can be given by the subcutaneous route. With optimal substitution and--in the case of infection--adequate antimicrobial treatment, these patients have a good prognosis. PMID- 7838241 TI - Anti-phospholipid antibodies and vascular pathology. AB - Over the past decade it has been recognized that there is an association between the presence of anti-phospholipid antibodies (lupus anticoagulant, anti cardiolipin antibodies) and thromboembolic phenomena. This "anti-phospholipid syndrome", which was originally described in patients with lupus erythematosus also occurs in patients without an underlying systemic disease. An answer to the question whether anti-phospholipid antibodies cause thrombosis warrants further studies. Especially the recent findings on a role of plasma proteins in the binding of these antibodies to phospholipids will have to be taken into account. To obtain guidelines for optimal treatment of patients suffering from this syndrome, additional studies will have to be performed. PMID- 7838242 TI - Anti-neutrophil cytoplasmic antibodies: a new class of autoantibodies in glomerulonephritis, vasculitis and other inflammatory disorders. AB - Anti-neutrophil cytoplasmic antibodies (ANCA) constitute a new group of antibodies that are directed against myeloid proteins. Several antigens recognized by ANCA have been described. Antibodies directed to proteinase 3, myeloperoxidase and/or elastase are closely associated with necrotizing systemic vasculitis and/or necrotizing and crescentic glomerulonephritis. Changes in levels of anti-proteinase 3 in generally reflect disease activity in Wegener's granulomatosis. The diagnostic significance of other or still unknown specificities has not yet been definitely established. Recent data from in vitro and in vivo models suggest a role for ANCA in the pathogenesis of systemic vasculitides and/or necrotising and crescentic glomerulonephritis. PMID- 7838243 TI - Pathophysiology of lupus nephritis: the role of nucleosomes. AB - Lupus nephritis is regarded as an immune complex mediated disease. Since anti-DNA antibodies are present in the circulation and in diseased glomeruli of patients with lupus nephritis, these antibodies have been assigned a pivotal role in the initiation of lupus nephritis. It remains however unclear how these antibodies become localized in the glomerulus. Contrary to the classical concept of glomerular deposition of DNA/anti-DNA complexes, it has been suggested that anti DNA antibodies can interact with intrinsic glomerular antigens. Some anti-DNA antibodies can cross-react with heparan sulphate (HS), which is such an intrinsic constituent of the glomerular basement membrane (GBM). Serum HS reactivity coincides with the occurrence of lupus nephritis. It was found that this HS reactivity was exhibited by anti-DNA antibodies complexed to nucleosomes and not by the antibody itself. Nucleosomes are DNA/histone complexes, present in the nucleus, which are released by dying cells. The histone part of the nucleosome is responsible for the binding to the GBM. Recently, it has become clear that also anti-nucleosome antibodies can bind to HS in the GBM via nucleosomes. These nucleosome-containing immune complexes exhibit anti-DNA reactivity in ELISA and Farr assay. It is now thought that nucleosomes released by dying cells bind to anti-DNA or anti-nucleosome antibodies in the circulation, giving rise to nephritogenic immune complexes. Alternatively, nucleosomes may bind to the GBM and serve then as planted antigen for subsequent binding of antibodies via an in situ mechanism. Binding of antibodies via both mechanisms leads to complement activation and damage of the GBM.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7838244 TI - Therapy of proliferative lupus glomerulonephritis: a prospective trial in The Netherlands. AB - Proliferative glomerulonephritis is a severe clinical manifestation of systemic lupus erythematosus, and it remains a major determinant of morbidity and mortality in this disease, despite the progress that has been made by treating patients with a combination of corticosteroids and cytotoxic drugs. Earlier controlled clinical trials have demonstrated the superior efficacy of a combination of pulse cyclophosphamide with steroids over treatment with steroids alone. However, cyclophosphamide carries a substantial risk of short-term and long-term toxicity in this predominantly young population, and previous trials have not convincingly shown any benefit over the milder treatment with a combination of azathioprine and steroids. We propose to conduct a Dutch multicentre trial to test whether similar renal survival can be achieved with an azathioprine-based regimen, compared to the widely used cyclophosphamide treatment, with a possibly lower risk of adverse effects. PMID- 7838245 TI - Endocrine autoimmune diseases. AB - A considerable proportion of endocrine disorders (Graves' disease, primary hypothyroidism, type 1 diabetes, Addison's disease, and some forms of ovarian failure) are due to aberrant reactions of the immune system, viz. exaggerated reactions towards self-structures (autoantigens). Autoreactive T-cells are mainly responsible for the elicitation of destructive inflammatory responses in the target endocrine glands. Autoantibodies play a minor role in such reactions, but are useful in clinical practice as markers of the disease. A special type of autoantibody is formed by those autoantibodies that have endocrine functional activity, viz. autoantibodies capable of stimulatory or blocking the hormone synthesis and/or the growth of endocrine cells. These autoantibodies interfere with receptors, e.g. the TSH receptor or the IGF-I receptor. Antibodies stimulating the TSH receptor are responsible for the hyperthyroidism of Graves' disease. PMID- 7838246 TI - Autoimmune diseases against cell surface receptors: myasthenia gravis, a prototype anti-receptor disease. AB - Autoimmune diseases against cell surface receptors are the result of a mainly antibody-mediated attack on membrane receptors. This results in a hypofunction of the target organ; occasionally antibodies can exert an agonist effect, e.g. in Graves' disease. Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction associated with a plethora of other diseases, mainly autoimmune diseases. Antibodies against the acetylcholine receptor (AChR) reduce the number of receptors necessary for efficient neuromuscular transmission. The effector mechanisms of MG can be studied elegantly in an experimental animal model in rodents immunized with AChR or injected with antibodies against AChR. The thymus is thought to play a central role in the induction of MG. Microscopic analysis of these thymuses revealed a follicular hyperplasia of the medulla or a lympho-epithelial thymoma. Thymectomy results in clinical improvement along with a decline in anti-AChR antibody titres. Additional therapeutic measures include anticholinesterase drugs, immunosuppression and plasmapheresis. PMID- 7838247 TI - HLA and disease: past, present and future. AB - This review on human leukocyte antigens (HLA) and disease associations is divided into three parts: past, present and future. In the first part the HLA system and its (main) function are presented in an historical perspective. The second part discusses the associations between HLA alleles and disease susceptibility with their present applications and implications. In the last part it is speculated that the molecular basis of the association between HLA Class II and at least one immunopathological disease will be unravelled in the near future and that this may result in new immunopreventive and immunotherapeutic strategies. PMID- 7838248 TI - CMV infection after organ transplantation: immunopathological and clinical aspects. AB - Cytomegalovirus (CMV), a member of the Herpes virus family, is a seemingly harmless infectious agent for healthy individuals. However, it is one of the most important opportunistic pathogens in immunosuppressed patients, particularly in organ transplant recipients. Due to its monocytotropic character, CMV exhibits an intimate relationship with the host immune system, and is therefore of great interest to immunologists. In this review, a summary is given of recent developments in our understanding of the interaction between CMV and the host immune system and guidelines are provided for the clinical management of this infection. PMID- 7838249 TI - T-cell regulation in allergic reactions. AB - Atopy is characterized by an increased tendency to form antibodies to airborne and food proteins. Specific IgE is central to the induction of allergic diseases through its binding of the high-affinity receptor on mast cells and basophils. Cross-linking by allergens of the bound IgE leads to an immediate release of various inflammatory mediators at the local site in the shock organ. Repeated exposure to allergens may lead to the induction of a more chronic inflammatory process where the local influx of T-lymphocytes and eosinophils appears to be an important event. There has been increasing recognition that cytokines, produced by a variety of inflammatory cell subsets, including T-cells, induce this ongoing inflammatory state. Besides, CD4+ T-helper-2 (Th2) cell products like IL-4 play a crucial role in the regulation of the production of specific IgE by B-cells. IL-4 appears to be the immunoregulatory cytokine with a relatively restricted action on reactive cells in this specific immune reaction. The effects of IL-4 are antagonised by IFN-gamma, and vice versa. Proliferation and differentiation of Th2 subsets producing predominantly IL-4 and IL-5 and no IFN-gamma provide an essential signal for isotype switching to IgE in B-cells, on the one hand, and direct the activation and influx of inflammatory effector cells such as eosinophils, on the other hand. In this report the causal relationship between the induction and expression of Th2 cells the IgE production and eosinophilia in atopic allergies is briefly reviewed.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7838250 TI - Immunosuppressive drugs in clinical medicine. AB - Immunosuppressive drugs are agents capable of suppressing the development of at least one type of immune response in vivo at doses with minimal side-effects. Some characteristics regarding the mechanism of action of corticosteroids, azathioprine, cyclophosphamide, cyclosporine and monoclonal antibodies anti-CD3 are reviewed. Corticosteroids induce a redistribution of lymphocytes and display an anti-inflammatory effect; the immunosuppressive effect of azathioprine seems to consist mainly of its suppression of the inflammatory response; cyclophosphamide and cyclosporine influence the immune system itself and anti-CD3 monoclonal antibodies suppress cellular immunity fairly specifically. Finally, a brief summary of their use in renal disease, systemic vasculitis and connective tissue diseases is given. PMID- 7838251 TI - Proximal tubular cell, proteinuria and tubulo-interstitial scarring. PMID- 7838252 TI - Plasma atrial natriuretic factor and blood pressure drops during hemodialysis. AB - The potential role of atrial natriuretic factor (ANF) in blood pressure (BP) drops during hemodialysis (HD) has been examined in 30 patients with end-stage chronic renal failure. Echocardiographic measurements and evaluation of cardiac parasympathetic function were performed prior to HD sessions, simultaneously with hormonal determinations. The plasma ANF level was correlated with the peak value of the E wave and the Doppler index of the left ventricular preload and was more elevated in 'denervated' than in intact patients. During the HD sessions, the BP fell in 18 patients (group 1) and remained stable in 12 others (group 2), despite similar weight losses. Both groups differed by the basal values of plasma ANF, greater in group 1 than in group 2 (100.0 +/- 13.3 vs. 65.7 +/- 3.4 fmol/ml; p < 0.05). The magnitude of plasma ANF decrease was identical in both groups despite the BP decrease in group 1 at the end of the session. These results suggest that the ANF release depends not only on hemodynamics but also on cardiac innervation in dialyzed patients and that high plasma ANF levels are implied in the BP drops during HD session. PMID- 7838253 TI - Pathogenetic mechanisms involved in mesangial interposition in IgA nephropathy. AB - To investigate the pathogenetic mechanisms of mesangial interposition (MI) in IgA nephropathy, we examined renal biopsy samples from 20 patients with IgA nephropathy. Electron microscopic morphometric analysis showed that cytoplasmic protrusion of mesangial cells (MCs) into endothelial cells (ECs) or capillary lumina, and widening of the lamina rara interna (LRI) were significantly more prominent in glomeruli with MI than in those without. Immunoelectron microscopy revealed that the ratio of positive endothelial staining with a polyclonal antibody against human platelet-derived growth factor (PDGF) BB was significantly higher in capillary loops with MI than in those without. Enhanced capillary staining of fibronectin related to MI was not recognized. These results suggest that MI in IgA nephropathy is caused by factors such as enhancement of cytoplasmic extensibility of the MCs, widening of the LRI and chemotactic influence of PDGF-BB located in the glomerular ECs. PMID- 7838254 TI - Omentectomy with peritoneal catheter placement in acute renal failure. AB - Catheter function was retrospectively analysed after surgical placement in 21 children requiring peritoneal dialysis for acute renal failure due to haemolytic uraemic syndrome. Substantial benefits were shown to have accrued from partial omentectomy which resulted in reliable access and trouble-free drainage in the 11 patients in whom it was carried out. Conversely 4 of 10 patients in whom partial omentectomy was not done experienced total catheter blockage whilst the other 6 experienced intermittent poor drainage. Partial omentectomy should be considered as integral to the surgical technique of peritoneal catheter placement for both short-term and long-term dialysis in children. PMID- 7838255 TI - Insulin levels and fibrinolytic activity in patients with end-stage renal disease. AB - Considering that PAI-1 is an important factor modulating the systemic fibrinolytic activity, the abnormal insulin metabolism frequently seen in end stage renal disease (ESRD) may cause decreased fibrinolytic activity in concert with PAI-1. To study this possibility, we measured insulin levels and compared it with the fibrinolytic profiles in ESRD patients. Fasting blood sugar, insulin, and C peptide levels were higher in ESRD patients than in the control group. In the ESRD patients, the insulin levels showed a positive correlation with C peptide (r = 0.612, p = 0.0001), fasting blood sugar (r = 0.334, p = 0.044), and PAI-1 antigen (r = 0.474, p = 0.0001) and a reverse correlation with euglobulin fibrinolytic activity (r = 0.5, p = 0.005), but no correlation with t-PA antigen. The euglobulin fibrinolytic activity showed a reverse correlation with PAI-1 antigen (r = 0.289, p = 0.0144), but no correlation with t-PA antigen. Our results suggest that abnormal insulin metabolism and/or insulin resistance, which occur frequently in ESRD, may play an important role in the decrease in systemic fibrinolytic activity by the regulation of the PAI-1 concentration. PMID- 7838256 TI - Laparoscopy: an alternative to surgery in patients treated with continuous ambulatory peritoneal dialysis. AB - Fifteen laparoscopic abdominal operations were performed in 14 patients treated by continuous ambulatory peritoneal dialysis for chronic renal failure. Celioscopic exploration of the abdomen and subsequent operation displayed several advantages specific to the method: identification of the etiology of scrotal dialysate outflow was achieved in 4 cases, peritoneal dialysis catheter salvage during laparoscopic cholecystectomy in 1 case, abdominal exploration during occurrence of peritonitis in 3 cases, and catheter dysfunction or abdominal examination before catheter implantation in 7 cases. The laparoscopic procedure allows early resumption of peritoneal dialysis after surgery, hence avoiding the need for transient hemodialysis. Nevertheless, it seemed unable to offer a salvage capability of infected catheters through extensive abdominal washing. Laparoscopy has been reported to decrease postoperative pain and disorders of ventilation, allowing for rapid recovery of social and professional activities following this minimal invasive surgical technique. Laparoscopy is a novel technique which enables precise diagnosis and surgical operations in patients treated by continuous ambulatory peritoneal dialysis. PMID- 7838257 TI - In vitro effects of amino-acid-based versus glucose-based continuous ambulatory peritoneal dialysis fluids on peritoneal macrophage function. AB - We studied the in vitro effects of peritoneal dialysis fluids (PDF) containing 1 and 1.5% amino acids (AA) as compared to approximately equiosmolar glucose (GLU) based PDF (1.5 and 4.25%) and control buffer, respectively, on peritoneal macrophage (PMO) function. The media were tested at original pH (5.3-5.5) and after pH adjustment to 7.4. PMO were isolated from the effluents of 10 on continuous ambulatory peritoneal dialysis (CAPD) patients and tested for luminol- and lucigenin-enhanced chemiluminescence (CL), superoxide generation measured by cytochrome c reduction, killing capacity and phagocytosis after incubation (30 min, 37 degrees C) in the PDF used. All AA-based PDF exhibited a statistically significant depressive effect on integral CL response, O2- production and bacterial killing of PMO at pH 7.4 in comparison with pH-adjusted GLU-based PDF of similar osmolality and buffer. Exposure of PMO to acidic AA-based media did not result in a significantly different suppression of the oxidative metabolism and the killing capacity as compared to fresh GLU-based fluids. Phagocytosis of PMO did not show significant differences after incubation in the solutions studied. Thus, the AA-based PDF employed compromise the oxidative metabolism and the killing capacity of PMO at pH 7.4 in vitro significantly more than GLU-based fluids. Since pH-identical and almost equiosmolar PDF were compared, the specific composition of the AA-based fluids, especially the high content of lactate and several essential AA, could be responsible for this detrimental impact. PMID- 7838258 TI - Alpha tocopherol improves focal glomerulosclerosis in rats with adriamycin induced progressive renal failure. AB - The effect of d-alpha-tocopherol on the progression of renal dysfunction was investigated in rats injected with adriamycin (ADR), a model of progressive glomerulosclerosis associated with the nephrotic syndrome. Treatment with d-alpha tocopherol was started 1 day before or 1 day after ADR injections (BE-TOC or AF TOC rats). When compared to rats without d-alpha-tocopherol treatment (ADR-CON rats), the serum total cholesterol and triglyceride levels were significantly lower in the BE-TOC and AF-TOC groups. In week 16, the LDL cholesterol level and the atherogenic index were both significantly lower in BE-TOC and AF-TOC rats than in ADR-CON rats. The urinary protein, serum creatinine, blood urea nitrogen, malondialdehyde, and systolic blood pressure levels as well as the glomerulosclerosis score were high in ADR-CON rats, and reduced in BE-TOC or AF TOC rats. There were no significant differences in body weight and serum albumin between the three groups in week 16. It is concluded that d-alpha-tocopherol can improve hyperlipidemia and ameliorate glomerulosclerosis in rats with ADR-induced progressive renal failure. Thus, d-alpha-tocopherol may have the potential for clinical application to treat focal glomerulosclerosis. PMID- 7838259 TI - Intact renal albumin downregulates the extracellular matrix expression by mesangial cells and renal fibroblasts in vitro. AB - Chronic Adriamycin (ADR) nephropathy is invariably associated with glomerulosclerosis and tubulointerstitial fibrosis. To investigate the hypothesis that severe albuminuria plays a role in the pathogenesis of both processes, we purified the protein from conditioned media of rats with advanced ADR nephropathy and tested the fibrogenic effect on renal fibroblasts and mesangial cells in vitro. Albumin was purified by pseudoligand chromatography and was identified on the basis of the NH2 amino terminus. Furthermore, it was differentiated from the urinary homologue, being more anionic and more fatted while maintaining a conserved peptide composition. The exposure of renal cells to renal albumin induced a dose-dependent reduction in collagen synthesis with a half-maximal decrease with 0.2 microgram/ml of albumin. With renal albumin levels of 0.4 microgram/ml the collagen incorporation of 3H-proline by mesangial cells and renal fibroblasts (primary cultures and cell lines) was reduced by 76, 81 and 45% respectively. A qualitative analysis by SDS-polyacrylamide electrophoresis and immunoprecipitation of radiolabelled collagens demonstrated a drastic and unselective decrease in all major collagens synthesized by mesangial cells and fibroblasts, including type I, III and V. Previous immunoprecipitation of the protein with anti-rat albumin antibodies completely reversed this phenomenon. Finally, albumin purified from urines of rats with ADR nephropathy downregulated the synthesis by renal cells of the same collagens but this effect was less evident compared to renal albumin. These findings demonstrate that renal albumin drastically reduces the synthesis of collagens by mesangial cells and renal fibroblasts, this effect being most evident on those components which constitute the extracellular matrix in glomerulosclerosis and interstitial fibrosis.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7838260 TI - Nephrotoxic serum nephritis in nude rats: the role of cell-mediated immunity. AB - The role of T cell-mediated immunity in the early phase of nephrotoxic serum nephritis (NTN) was examined by transfer of pan T, CD8-positive, and CD4-positive cells. The disease was induced by transferring rabbit gamma-globulin (RGG) sensitized T cells to nude (rnu/rnu) rats pretreated with a subnephritogenic dose (a dose insufficient to cause proteinuria) of nephrotoxic serum. Mild but abnormal proteinuria was detected, and macrophages showed significant accumulation in glomeruli. Transfer of not only RGG-sensitized CD4-positive cells but also CD8-positive cells separated by the T cell markers OX8 and OX38 using the panning method caused an increased accumulation of macrophages in isolated glomeruli. No host antibody against rabbit immunoglobulins was demonstrated either in glomeruli by immunofluorescence or sera by ELISA in the early disease phase. These findings support a pathological role of T cells in initiation of glomerular injury in NTN. PMID- 7838261 TI - Opioids modulate migration, spreading and adherence of mesangial cells. AB - Glomerular mesangial cells are considered to be modified smooth muscle cells and seem to play a role in the maintenance of glomerular hemodynamics. The present study was carried out to determine the effect of opioids on adhesiveness, spreading and migration of mesangial cells. Morphine enhanced spreading of mesangial cells at early time periods (5 mini, control 8 +/- 2% vs. morphine 15 +/- 1%, p < 0.05; 15 min, control 21 +/- 5% vs. morphine 38 +/- 2%, p < 0.05) as well as at later time periods when compared to control cells (at 2 h, control 23 +/- 1% vs. morphine 49 +/- 1%, p < 0.001; at 3 h, control 28 +/- 3% vs. morphine 63 +/- 2%, p < 0.05). beta-Endorphin also enhanced (p < 0.001) spreading of mesangial cells (at 2 h, control 23 +/- 1% vs. beta-endorphin 48 +/- 3%; at 3 h, control 28 +/- 3% vs. beta-endorphin 65 +/- 1%). Morphine decreased adhesion of mesangial cells to the plastic substrate at 24 h as well at 48 h when compared to the control cells. Naloxone attenuated the effect of morphine on adhesion to the substrate. Morphine enhanced (p < 0.05) migration (percentage of denuded area covered by mesangial cells when compared to control cells (control 26.07 +/- 1.08% vs. morphine 37.5 +/- 2.94%; n = 9). Since the morphine-induced decreased adhesiveness could be attenuated by naloxone, this effect of morphine on mesangial cells appears to be mediated by opioid receptors. PMID- 7838262 TI - Dissociation of selective renal venous plasma endothelin-1 activity and corresponding plasma renin activity in a patient with hypertension, severe stenosis of unilateral renal artery and ipsilaterally decreased renal function. AB - Plasma endothelin-1 (ET-1)-like immunoreactivity in selective renal venous blood and peripheral venous blood was measured and compared with plasma renin activity and aldosterone level in a 26-year-old woman with suspected renovascular hypertension due to stenosis of the left renal artery. Although there was no significant step-up in plasma renin activity between the right and the left renal vein, left/right ratio of plasma ET-1 in the renal vein was 2.18. This case suggests that ET-1 may be one of the hypertensive mechanisms of suspected renovascular hypertension in addition to the renin-angiotensin system. PMID- 7838263 TI - Renal oncocytoma in transplant patients: report of 2 cases. AB - We report on 2 cases of renal oncocytoma occurring in a liver transplant patient and in a kidney allograft recipient, respectively, during the posttransplant period. This neoplasm has never been reported in transplant patients; its relationship with long-term immunosuppressive therapy is questioned. PMID- 7838264 TI - Diagnosis of cortical infarction in a renal transplant using ultrasonography. PMID- 7838265 TI - A rise in antineutrophil cytoplasmic antibody in a patient with systemic vasculitis in remission. AB - We report a 42-year-old man who showed alveolar hemorrhage and glomerulonephritis as well as episcleritis and skin rash. He had an extremely high titer of cytoplasm-staining antineutrophil cytoplasmic antibody (C-ANCA) and was diagnosed as having systemic vasculitis based on histological findings of kidney and skin biopsies. After immunosuppressive therapy clinical manifestations resolved within several weeks and C-ANCA titers commensurably declined. C-ANCA titers, however, increased again and remained high despite clinical remission. In general, there is a close relationship between ANCA titers and clinical activities in ANCA associated diseases, but they displayed a large discrepancy in this patient. Indeed, the serum of the patient in remission contained the antibody against 29 kD neutrophil extracts which was detected by immunoblot analysis. These findings suggest that C-ANCA may not necessarily be, by itself, pathogenetic for the development of the vasculitis. PMID- 7838266 TI - Interplay between sugar and salt on blood pressure in spontaneously hypertensive rats. AB - Previous experience showed that sucrose ingestion exceeding 50% of total calories consistently increased systolic blood pressure (SBP) in rats, but ingesting 36 or 13% of calories as sucrose did not. In fact, the mean SBP of rats ingesting 36% of calories as sucrose was not different from rats ingesting 13% of calories as sucrose. This was not the case in the present study where the dietary salt content was increased. Adding dietary salt (NaCl) to raise low concentrations of Na (0.14% wt/wt) to higher concentrations (0.80% wt/wt) in diets with 36 and 13% of calories from sucrose significantly elevated SBP in spontaneously hypertensive rats eating both diets, but significantly more in the former. Accordingly, an interplay exists between sugar and salt in SBP regulation, and it is suggested that amounts of sugar characteristically consumed by an average human are capable of increasing BP. Composition of diets, especially with respect to sugar and salt, should be considered when interpreting results from studies on various aspects of hypertension. PMID- 7838267 TI - Chylothorax and nephrotic syndrome. PMID- 7838268 TI - Effects of calcitriol on the biogenesis of a lysosomal protease in monocytes from patients with renal failure. PMID- 7838269 TI - Situs inversus: a rare extrarenal association of Alport's syndrome. PMID- 7838270 TI - Bilateral external ophthalmoplegia in uremia. PMID- 7838271 TI - Nephrotic syndrome after extracorporeal shock wave lithotripsy. PMID- 7838272 TI - A case of rheumatoid arthritis with renal tubular amyloidosis. PMID- 7838273 TI - Spontaneous perirenal hematoma due to periarteritis nodosa. PMID- 7838274 TI - Transient ischemic jejunitis in a renal transplant recipient. PMID- 7838275 TI - Merkel cell carcinoma in renal transplant recipient. PMID- 7838276 TI - Hepatitis C virus in renal tissue of patients with glomerulonephritis. PMID- 7838277 TI - Diagnostic revolution of microhematuria by real-time confocal scanning laser microscope [Hyodo-Lino-Miyagawa (HIM) method]. PMID- 7838278 TI - IgA nephropathy associated with liver cirrhosis presenting antineutrophil cytoplasm antibody of IgA class. PMID- 7838279 TI - Renal vascular changes and uterine artery resistance in pregnant women with renal disease. PMID- 7838280 TI - A serial application study on twice daily dose of imipenem/cilastatin in patients undergoing slow hemodialysis. PMID- 7838281 TI - Intestinal permeability to 51Cr-EDTA in patients on chronic ambulatory peritoneal dialysis. PMID- 7838282 TI - Prevalence of Helicobacter pylori antibodies in uremic patients. PMID- 7838283 TI - Cytoprotective effects of ulinastatin against hypoxic injury to LLC-PK1 cells. PMID- 7838285 TI - Analysis of brain injury following intrahippocampal administration of beta amyloid in streptozotocin-treated rats. AB - It has been suggested that the vulnerability of the aged brain to Alzheimer's disease (AD) pathogenesis depends on a number of risk factors, including abnormal glycolytic metabolism and beta-amyloid accumulation. Intrahippocampal injections of beta-amyloid and related peptides were administered to chronically hyperglycemic rats to examine beta-amyloid toxicity and the interaction with imbalances of glucose metabolism. Chronic hyperglycemia was induced by systemic injection of streptozotocin (STZ) which selectively destroys pancreatic beta islet cells. Ten days after intrahippocampal injection of synthetic beta-amyloid peptides (beta 1-42, beta 25-35, scrambled beta 25-35), lesion volume, blood glucose, and plasma corticosterone concentrations, beta 1-42 immunoreactivity and gliosis were assessed to determine peptide toxicity in the normoglycemic and hyperglycemic conditions. Glucose levels correlated with plasma corticosterone concentrations (r = 0.85) and increased lesion volume size (r = 0.36). Intrahippocampal peptide injections in normoglycemic subjects did not induce significant damage as compared to control injections of vehicle alone. STZ treated groups demonstrated a trend for increased lesion volume size following injection of either vehicle, beta 1-42, or beta 25-35. The combination of the beta 1-42 peptide and streptozotocin-induced hyperglycemia was toxic and induced significantly larger lesions (p < 0.01) of the dorsal blade of the dentate gyrus as compared to injections of beta 1-42 into normoglycemic subjects. PMID- 7838284 TI - Alzheimer's disease and soluble A beta. AB - The discovery of soluble amyloid beta (sA beta) suggests that the role of amyloid in Alzheimer's disease (AD) is similar to the previously studied systemic amyloidoses and alters the notion that membrane damage is the initial event in AD. The disease state is characterized by the abnormal accumulation of a normal degradative peptide, which becomes resistant to further proteolysis due to a conformational change. Mutations in the beta PP gene have been found in a very small percentage of AD cases; hence other factors, both genetic and environmental, need to be identified. Priority needs to be given to detailed studies of the structural differences between sA beta and the A beta in amyloid deposits. This will help uncover the determining factors governing the aggregation of sA beta. These structural alterations may be critical for the possible toxic effects A beta and/or associated proteins (molecular chaperones, e.g., apolipoprotein E) have on brain cell function. PMID- 7838286 TI - Age effect on brain pH during ischemia/reperfusion and pH influence on peroxidation. AB - Older gerbils are more sensitive to ischemia/reperfusion injury (IRI) than younger ones. Utilizing 31P-NMR to monitor in vivo pH and high energy phosphates of brain cortex undergoing an IRI showed that cortical intracellular pH decreased to 6.35 after ischemia and then increased with reperfusion, but older gerbils required significantly more time to recover than younger animals. Brain high energy phosphates dropped during ischemia but rebounded within 20 min reperfusion in younger gerbil brain but remained significantly lower in older gerbil brain for 50 min. These data suggest that IRI-induced brain acidification may enhance oxidative damage. In an in vitro system it was shown in both young and old brain homogenate that peroxidation rate increased when the pH of the incubation medium was decreased from 7.4 to 6.4. This was true in the presence or absence of an ADP/Fe/Ascorbate system in both young and old brain homogenate. Enhancement of peroxidation rate by ADP/Fe/Ascorbate addition was much more pronounced at pH 7.4 (30- to 40-fold increase) as compared to pH 6.4 (7.8- to 9.5-fold increase). This data can be interpreted to indicate that the lower pH makes endogenous Fe more available to catalyze oxidative damage. The fact that brain pH and high energy phosphates remain lower in older gerbil brains during IRI suggests that brain mitochondria from older animals are less capable of responding to a large oxidative stress brought on by an IRI.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7838287 TI - Effects of aging on spinal opioid-induced antinociception. AB - Initial experiments were conducted to determine whether or not the aging process alters the ability of young, mature, or aged male Fischer 344 rats (5- to 6-, 15- to 16-, and 25- to 26-months-old, respectively) to respond to thermal nociceptive stimuli. Using the tail-flick analgesiometric assay, 25- to 26-month-old rats responded significantly faster to the heat source than 15- to 16-month-old animals, but no significant differences were noted between the 5- to 6-month-old and aged rats. Another series of investigations compared the effects of aging on the spinal antinociceptive properties of the mu opioid agonist [D-Ala2,N-methyl Phe4,Gly5-ol] enkephalin (DAMPGO) and the delta agonist [D-Pen2,D-Pen5] enkephalin (DPDPE). In these studies, young, mature, and aged rats were injected intrathecally (IT) with different doses of DAMPGO or DPDPE, and opioid-induced antinociception was tested on the tail-flick test. All three age groups responded to IT DAMPGO in a dose-dependent manner but, for the most part, higher spinal doses were required to produce significant elevations in tail-flick latency in the aged cohort of rats. The spinal analgesic effects of DPDPE also declined with advanced age. The aging process apparently alters the pain-inhibitory function of mu and delta opioid receptors in the rat spinal cord. PMID- 7838288 TI - Morphology of the inferior colliculus in C57BL/6J and CBA/J mice across the life span. AB - Basic anatomical features were evaluated in the inferior colliculus (IC) of C57BL/6J and CBA/J mice across the adult life span (1.5 to 30 months of age). C57BL/6J mice exhibit progressive age-related cochlear pathology and become severely hearing-impaired during the second year of life; CBA/J mice exhibit little hearing loss as they age. Age had little effect on the size of the IC, the size of IC neurons, or the packing density of IC neurons and there was no evidence of age-related neuron loss. However, old CBA/J mice developed numerous spongiform lesions throughout the brainstem. The absence of morphological changes in the IC of hearing-impaired C57BL/6J mice supports the hypothesis that features such as the size of neurons, survival of neurons, and volume of the neuropil are not affected by chronic sensorineural pathology in central auditory nuclei (e.g., as the IC) that do not receive direct input from primary afferent fibers. The data from both strains taken together indicate that certain basic anatomical properties of the mouse IC persist in the face of aging. PMID- 7838289 TI - Brain proteolysis of oxytocin in vitro and in vivo changes during aging in male rats. AB - Oxytocin proteolysis was studied in vitro with purified synaptic membranes and in vivo after injection into the hippocampus of male Wistar Kyoto rats of different ages. When oxytocin was incubated in vitro with brain synaptic membranes obtained from 2-, 6-, and 12-month-old rats, no difference in the content of C-terminal and N-terminal fragments formed by membrane-bound aminopeptidase-like and endopeptidase-like enzymes, respectively, was found after high performance liquid chromatography separation and quantification by amino acid analysis. In contrast, the content of all fragments decreased by about 20%-25% when membranes obtained from 18- and 24-month-old rats were used. When [3H-Tyr2]oxytocin was injected in vivo in the hippocampus of 2-, 6-, 12-, and 18-month-old rats, no difference in the content of free [3H]-tyrosine and other [3H]-labelled fragments was found in the hippocampal peptidic extract after high performance liquid chromatography fractionation. However, the content of all radioactive fragments was about 50% lower in the extract from 24-month-old rats. The findings suggest that oxytocin proteolysis in brain decreases during aging. Such a decrease might counterbalance the impairment of central oxytocinergic transmission caused by the age-related decrease of oxytocin content in brain. PMID- 7838290 TI - Aging-induced decrements in neuropeptide Y: the retention of ejaculatory behavior is associated with site-selective differences. AB - Neuropeptide Y (NPY) has been implicated in the control of reproductive and cardiovascular function. We observed an age-related decrease in the number of males copulating to ejaculation and a moderate systolic hypertension in middle aged (16- to 17-month-old) rats. NPY content was examined in microdissected brain nuclei in 5 groups of rats: 2 groups of young rats, 1 heterosexually naive and the other ejaculating in 3 successive mating test; 3 groups of middle-aged rats, 1 heterosexually naive, 1 group that had extensive sexual experience but failed to ejaculate in tests at 16.5 months of age, and the third continuing to ejaculate at 16.5 months of age. NPY levels were found to vary depending on the brain area, the age of the animals, and the maintenance of ejaculatory behavior. In sexually naive middle-aged males, NPY levels were uniformly lower than in younger males. There were no differences in NPY levels of young animals, regardless of sexual experience. In the medial preoptic area, the group that retained ejaculatory behavior through 16.5 months of age, had higher levels of NPY than those observed in young sexually experienced rats. In sexually experienced rats that were no longer ejaculating at 16.5 months of age levels were lower than all other groups except the sexually naive middle-aged group. In the hypothalamic arcuate nucleus, levels were equivalent in the young groups and in the middle-aged rats that retained ejaculatory behavior, being greater than in the middle-aged rats that were no longer ejaculating or were sexually naive.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7838291 TI - Age-related changes in the sensitivity of sympathetic nerves to altered extracellular calcium in tail arteries of F-344 rats. AB - There is a significant age-related increase in stimulation evoked norepinephrine release from adrenergic nerves in tail arteries of F-344 rats, that is not accounted for by a change in function of prejunctional alpha 2-adrenergic receptors. To further explore the mechanism of this age-related change in transmitter release, we investigated the effect of altered extracellular calcium. With short stimulation trains the effects of altered extracellular calcium were significantly greater in 20-month-old tail arteries compared to 6 months. At the highest calcium concentration (7.5 mM) when alpha 2-adrenergic receptors were active or blocked, there was a significant decline in fractional norepinephrine release only in arteries of 20-month-old animals. With long stimulation trains the effects of altered extracellular calcium were not as pronounced as with short trains, but the effect of calcium was still significantly greater in 20 month old tail arteries. With alpha 2-adrenergic receptors blocked 6 month tail arteries were insensitive to altered calcium while 20-month tail arteries remained sensitive. One explanation for these findings may be an age-related change in the efficiency of intracellular calcium buffering mechanisms leading to greater calcium transients in the nerves of older animals. PMID- 7838292 TI - Inositol 1,4,5-trisphosphate receptor and ryanodine receptor in the aging brain of Wistar rats. AB - Intracellular Ca2+ release channels are key players in the regulation of Ca2+ homeostasis. In the present study, we investigated the age-related changes of inositol 1,4,5-trisphosphate (IP3) receptor/Ca2+ release channel and ryanodine receptor/Ca2+ release channel in microsomes derived from either cerebellum or cerebrum cortex from male Wistar rats. A significant reduction (about 50%) in density of IP3 receptor/Ca2+ release channels was observed in cerebrum cortex, only, in 8- and 28-month old rats, whereas density and Kd of ryanodine binding sites were unaffected in both cerebellum and cerebrum microsomes. These findings, along with impairment of Ca(2+)-dependent protein kinase C phosphorylation of endogeneous substrates, point to coordinate, quantitative alterations of both targets of phosphoinositide metabolism, i.e., PKC and IP3 receptor, in the cerebrum cortex at least. The relevance of the present findings is discussed in relation to reported changes of neuronal Ca2+ homeostasis during aging. PMID- 7838294 TI - Identification of amyloid beta protein in the brain of the small, short-lived lemurian primate Microcebus murinus. AB - The deposition of amyloid beta (A beta) protein in the brain has been demonstrated immunocytochemically in the small Lemurian primate Microcebus murinus. Both meningocerebral vascular deposits and cortical parenchymal deposits occur. All eight aged (> 8 years old) Microcebus examined showed vascular amyloid deposits, whereas only four exhibited parenchymal plaques. The vascular amyloid infiltrated the tunica media of the leptomeningeal and cortical arteries and arterioles and was also found in capillaries. A beta was observed to be deposited in three general forms in the cortical neuropil: round or elliptical plaques that were thioflavin-negative but sometimes showed a central concentration of A beta immunoreactivity; round plaques with a densely immunoreactive core that was thioflavin-positive; extensive ribbon-like infiltrations enclosing multiple cortical blood vessels. These observations, taken together with previous descriptions of age-related neurodegenerative changes in Microcebus, indicate that this species undergoes a beta-amyloid-associated neuropathology highly similar to that seen in Alzheimer's disease. We conclude that this lemurian primate of small size and relatively short life expectancy, provides a compelling animal model of some principal features of Alzheimer's disease. PMID- 7838293 TI - D-cycloserine, a novel cognitive enhancer, improves spatial memory in aged rats. AB - D-cycloserine, a partial agonist of the NMDA receptor-associated glycine site, can enhance cognition. The present experiment examines the behavioral effects of D-cycloserine on cognitive deficits in male Fischer-344 rats, 24 months old. Rats 24 months old (n = 42) received either vehicle or one of 3 doses of D-cycloserine prior to testing. Young rats, 4 months old (n = 13), received vehicle prior to testing. Place discrimination and repeated acquisition were tested in the water maze and a variety of sensorimotor tasks were given. Aging impaired performance in all tasks. D-cycloserine improved performance in place discrimination and repeated acquisition. No doses affected sensorimotor function. These results support the hypothesis that D-cycloserine has cognition enhancing properties and that it may be useful in treating disorders involving cognitive impairment. PMID- 7838295 TI - Impaired phosphoinositide hydrolysis in Alzheimer's disease brain. AB - The effect of Alzheimer's disease (AD) on the activity of the phosphoinositide second messenger system was studied by measuring the hydrolysis of [3H]phosphatidylinositol (PI) by membranes from postmortem human prefrontal cortex. The activity of phospholipase C was similar in AD and control tissue. Activation with GTP gamma S and with carbachol demonstrated less [3H]PI hydrolysis in AD than control membranes. The concentration of Gq/11, the G proteins most likely functional in phosphoinositide metabolism, was unchanged in AD compared with controls, indicating that function of the receptor-G-protein complex rather than the G-protein concentration was the site of the impairment in AD. These results indicate that postsynaptic muscarinic receptor responses are impaired in AD, a finding that may explain, in part, the limited therapeutic responses achieved by administration of cholinomimetics to patients with AD. Also, this assay provides a means to identify cholinomimetics that are most effective in activating muscarinic receptor-coupled phosphoinositide hydrolysis in human brain, agents which should have the greatest potential for providing therapeutic responses in AD. PMID- 7838296 TI - Age-associated changes of pituitary-adrenocortical hormone regulation in humans: importance of gender. AB - In the present study the hypothesis was tested that in normal human aging an insensitivity of the glucocorticoid feedback signals is acquired. Thus, 40 healthy elderly (mean age: 69 +/- 5 years) and 20 younger (mean age: 34 +/- 8 years) individuals underwent a combined dexamethasone suppression/CRH-stimulation test. Cortisol secretion after dexamethasone (DEX) pretreatment and before CRH was increased in the older age group, but none of the subjects escaped DEX induced suppression of cortisol. However, after additional CRH administration to the DEX-pretreated volunteers, the older group released significantly more cortisol than their young counterparts. Within the group of the elderly only, a positive correlation between BASAL, DEX-pretreated cortisol concentration and post-CRH steroid responses was found. Gender profoundly affected DEX/CRH-test outcome: females, regardless of age, had an increased hormonal secretion in comparison to males. It is concluded that, during human aging, adaptive changes in glucocorticoid receptors take place, allowing for the system to maintain "peripheral" glucocorticoid homeostasis, but that more sophisticated challenge procedures such as the DEX/CRH test reveal an age-related increase in HPA system activity. PMID- 7838297 TI - Etiology of the neurodegenerative disorders: a critical analysis. PMID- 7838298 TI - Neuronal death in development, aging, and disease. PMID- 7838299 TI - Blood-brain barrier in toxic encephalopathies. PMID- 7838300 TI - Epidemiology and neurobiology of the multiple determinants of Alzheimer's disease. PMID- 7838301 TI - Hereditary components in the neurodegerative diseases: Alzheimer's disease and myotonic dystrophy. PMID- 7838302 TI - Mutant mouse models of ALS. PMID- 7838303 TI - Neurotrophic growth factors and neurodegenerative diseases: therapeutic potential of the neurotrophins and ciliary neurotrophic factor. AB - The recent molecular cloning of BDNF and CNTF based on traditional protein purification and protein sequencing and the identification and cloning of NT-3 and NT-4 by homology cloning strategies has led to a tremendous flurry of interest in the biology of these proteins and initiation of studies to assess their potential utility in neurological disorders ranging through degenerative disease, stroke and ischemia, trauma and peripheral neuropathies. Tissue culture studies have been very useful in identifying neuronal specificities of the neurotrophins and CNTF and in combination with localization studies of these growth factors and their receptors have provided the basis for in vivo studies. Initial animal studies with BDNF indicate efficacy of BDNF in models of Alzheimer's and Parkinson's disease and small fiber sensory neuropathy. Studies with CNTF have similarly progressed from in vitro findings, especially the discovery that CNTF is a growth factor for motor neurons, to in vivo findings where CNTF has been shown to be effective in slowing symptoms of motor neuron dysfunction in three genetic models. Based on these positive animal data, CNTF is currently in clinical trials for the potential treatment of motor neuron disease or amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease. PMID- 7838304 TI - APP processing, A beta-amyloidogenesis, and the pathogenesis of Alzheimer's disease. PMID- 7838305 TI - Beta amyloid neurotoxicity and neuronal degeneration in Alzheimer's disease. PMID- 7838306 TI - Excitatory transmitter neurotoxicity. AB - The major excitatory neurotransmitters in the mammalian CNS--glutamate (Glu) and acetylcholine (ACh)--have vitally important beneficial functions but also harbor treacherous neurotoxic potential which, as described in this review, can be expressed in several different ways. PMID- 7838307 TI - Metabotropic glutamate receptors and neuronal degenerative disorders. PMID- 7838308 TI - On the etiology and pathogenesis of chemically induced neurodegenerative disorders. PMID- 7838309 TI - NMDA receptor involvement in two animal models of Parkinson's disease. PMID- 7838310 TI - Therapeutic potential of NMDA antagonists in neurodegenerative diseases. PMID- 7838311 TI - Huntington's disease, energy, and excitotoxicity. PMID- 7838312 TI - Potential parkinsonian protoxicants within and without. PMID- 7838313 TI - Infectious amyloid, prions, unconventional viruses, and disease. PMID- 7838314 TI - A model systems approach to the study of disorders of learning and memory. PMID- 7838315 TI - Alzheimer's disease: therapeutic strategies for the 1990s. PMID- 7838316 TI - Role of NMDA, AMPA and kainate receptors in mediating glutamate- and 4-AP-induced dopamine and acetylcholine release from rat striatal slices. AB - Striatal slices, preincubated with [3H]dopamine and [14C]choline, were superfused continuously and subjected to electrical field stimulation (3 Hz) and perfused with amino acid analogues or 4-amino pyridine (4-AP). The released radioactivity was used to monitor release of the neurotransmitters dopamine (DA) and acetylcholine (ACh). Glutamate, NMDA (in the absence of Mg2+), AMPA, kainic acid, domoate and 4-AP all induced DA and ACh release in a concentration-dependent manner. The DA and ACh release induced by NMDA (15 microM) and glutamate (1 mM) was essentially abolished by Mg2+ (1.15 mM), whereas release induced by AMPA (100 microM), kainic acid (100 microM) or 4-AP (30 microM) was not reduced. Tetrodotoxin (1 microM) essentially abolished the effects of NMDA, markedly reduced the effects of glutamate, AMPA and 4-AP, whereas the effect of kainic acid was only modestly affected. MK-801 (30 nM) reduced NMDA-induced DA release by some 70% and ACh release by 30%. MK-801 reduced 4-AP-induced DA release by 40% but not ACh release. CNQX in a concentration (10 microM) that scarcely affected NMDA-induced ACh release, but blocked that induced by AMPA, kainic acid or domoate, reduced the ACh release induced by 4-AP. In summary, DA and ACh release from rat striatum can be stimulated by activation of NMDA and non-NMDA glutamate receptors, and this mechanism is activated by the potassium channel blocker 4-AP. PMID- 7838317 TI - Inhibition of adenosine kinase increases endogenous adenosine and depresses neuronal activity in hippocampal slices. AB - Endogenous adenosine in the extracellular space inhibits neuronal activity. The roles of adenosine kinase, S-adenosylhomocysteine-hydrolase and adenosine deaminase activities in the regulation of the adenosine levels were investigated in rat hippocampal slices. Iodotubercidin, an inhibitor of adenosine kinase, added to the perfusion fluid at 5 microM increased the release of adenosine from the slices more than 2-fold. Iodotubercidin treatment caused inhibition of population spike discharges and hyperpolarization of pyramidal cells, mimicking the effects of exogenously applied adenosine. Adenosine dialdehyde, an inhibitor of S-adenosylhomocysteine hydrolase, and erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA), an inhibitor of adenosine deaminase had little or no effect on the parameters tested. The action of iodotubercidin was greater during deaminase inhibition. The A1-receptor antagonist DPCPX had actions opposite to those of adenosine and blocked the electrophysiological effects of exogenous adenosine and of iodotubercidin. Thus adenosine kinase activity is a significant factor in the regulation of adenosine levels in the hippocampus. PMID- 7838318 TI - In vitro translation and membrane topology of rat recombinant mGluR1 alpha. AB - The structure and post-translational processing of the metabotropic glutamate receptor 1 alpha (mGluR1 alpha) was analysed by in vitro cell-free translation, protease protection and deglycosylation. We show that mGluR1 alpha can be synthesized in the rabbit-reticulocyte translation system to yield a predominant polypeptide product with an apparent molecular weight of 142 kDa. In the presence of dog-pancreatic microsomes this polypeptide was processed to an apparent molecular weight of 147 kDa. Treatment with the enzyme peptide-N-glycosidase F (PNGF) demonstrated that the increase in the apparent molecular weight of the processed translation product was due to N-linked glycosylation. Addition of the non-selective protease, proteinase K; resulted in the loss of this 147 kDa band and the appearance of a protected fragment of approx 92 kDa. A carboxy-terminal deletion mutant of mGluR1 alpha was almost completely protected from protease action. These data show that the amino terminal of mGluR1 alpha is translocated into the lumen of the endoplasmic reticulum and will consequently be located extracellularly when targeted to the plasma membrane. The data presented here on mGluR1 alpha indicates the potential of in vitro translation and protease protection in the study of the molecular structure and processing of glutamate receptors. PMID- 7838319 TI - N-methyl-D-aspartate-induced excessive formation of nitric oxide in CHP100 neuroblastoma cells produces death of BMEL melanoma cells in co-culture. AB - In the present experiments we planned to ascertain whether an abnormal production of nitric oxide (NO) by human CHP100 neuroblastoma cells in culture following stimulation of N-methyl-D-aspartate (NMDA) receptors, produced lethal effects in co-cultured human BMEL melanoma cells. Human BMEL melanoma cells in culture were found to be positive to the nicotinamide adenine dinucleotide phosphate diaphorase (NADPH diaphorase) histochemical reaction and produced NO as revealed by measurements of nitrite under basal culture conditions. Exposure for 50 min to aspartate (1-2 mM) or to NMDA (0.5-1.5 mM) did not evoke significant melanoma cell death. The dose of 1.0 mM NMDA applied for 1 min to BMEL cell cultures did not increase significantly nitrite concentrations in comparison to controls. Incubation for 50 min of human CHP100 neuroblastoma cells with NMDA (0.5-1.5 mM) elicited dose-dependent death of BMEL melanoma cells co-cultured in trans-wells. Under these experimental conditions, nitrite levels in cell culture-inserts containing melanoma cells increased by 120% 1 min after application of the excitotoxin (1 mM) to CHP100 neuroblastoma cultures. The lethal effects produced in BMEL cell culture-inserts by application of NMDA (1.0 mM) to CHP100 cultures were prevented by pretreatment of neuroblastoma cultures with MK801 (200 nM). Similar protection was also afforded by N omega-nitro-L-arginine methyl ester (L NAME; 0.2 mM) and N omega-monomethyl-L-arginine (L-NMMA; 0.2 mM), two inhibitors of nitric oxide synthase, and by haemoglobin (10 microM), a nitric oxide trapping agent.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7838320 TI - A marked increase in intracellular Ca2+ concentration induced by acromelic acid in cultured rat spinal neurons. AB - Acromelic acid, a kainate derivative of natural origin, markedly increased intracellular Ca2+ concentration ([Ca2+]i) in cultured rat spinal neurons in a concentration dependent manner; the half effective concentration (EC50) was 1.3 microM. Acromelic acid was more potent in increasing [Ca2+]i than any other glutamate receptor agonists tested, and the rank order of the activity was as follows: acromelic acid > alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) > kainate > N-methyl-D-aspartate (NMDA) > L-glutamate. Acromelic acid did not increase the [Ca2+]i in a Ca(2+-)free medium. 2,3-Dihydroxy-9-nitro-7 sulfamoylbenzo(F)quinoxaline (NBQX) completely inhibited the [Ca2+]i increase induced by acromelic acid. These results suggest that the [Ca2+]i increase was not through Ca2+ mobilization from intracellular stores but due to Ca2+ influx mediated by the activation of non-NMDA receptors. Acromelic acid increased the [Ca2+]i in rat hippocampal neurons as well; however, the EC50 (6 microM) was considerably higher than that in spinal neurons. The marked increase of [Ca2+]i in cultured spinal neurons would explain, at least in part, the earlier findings that systemic administration of acromelic acid causes selective degeneration confined to lower spinal interneurons. PMID- 7838321 TI - Sensitivity of the circadian rhythm of kainic acid-induced convulsion susceptibility to manipulations of corticosterone levels and mineralocorticoid receptor binding. AB - Increases in corticosterone levels have been associated with enhanced susceptibility and decreases in corticosterone levels have been associated with decreased susceptibility to convulsions in mice. The proconvulsant effects of corticosterone are believed to be mediated by central mineralocorticoid receptors (MR). Both convulsion susceptibility and plasma corticosteroid levels display circadian rhythmicity. When corticosterone levels are at their lowest, hippocampal MR binding is submaximal, whereas when corticosterone levels are at their circadian peak, hippocampal MR binding is maximal. In the present experiments the relationship between circadian rhythms of susceptibility to kainic acid-induced convulsions and plasma corticosterone levels was investigated. In addition, the effects of exogenously administered corticosterone and the MR antagonist spironolactone were examined at times of different convulsion susceptibility. In general, lower plasma corticosterone levels were associated with decreased convulsion susceptibility and higher plasma corticosterone levels were associated with greater convulsion susceptibility. Corticosterone, administered when endogenous levels were low, had a proconvulsant effect. Spironolactone, administered when corticosterone levels were higher and hippocampal MR were presumably maximally occupied, had an anticonvulsant effect. These results indicate that the circadian rhythm in susceptibility to kainic acid induced convulsions is sensitive to manipulations of corticosterone levels and MR binding. Degree of central MR occupancy may, in part, mediate convulsion susceptibility in humans as well as laboratory animals. PMID- 7838322 TI - Phencyclidine prevents spatial navigation and passive avoidance deficits in ibotenate lesioned rats. AB - The potential neuroprotective effects of phencyclidine (5 mg/kg i.p.) were assessed in rats which had been treated with the excitotoxin, ibotenic acid (IBO) (0.015 M) to lesion the nucleus basalis magnocellularis. IBO treated rats showed a significant impairment in 13 of the 25 test trials in the spatial navigation Morris water maze task and deficits in passive avoidance learning. Phencyclidine was found to prevent the IBO-induced impairment in 4 of the 13 test trials in which the IBO Morris maze deficit was observed and also successfully prevented the passive avoidance learning deficits. Neurochemically, IBO was shown to reduce the levels of gamma amino-n-butyric acid (GABA) in the cortex. This effect of IBO on the inhibitory GABAergic system may contribute to the direct toxic effects of IBO which is mediated through excitatory amino acid receptors. Phencyclidine had no effect on the changes in GABA produced by IBO. The effect of phencyclidine treatment on IBO behavioural toxicity observed in this study demonstrates that antagonism of the phencyclidine receptor site on the N-methyl-D-aspartate receptor complex may be partially protective against the excitotoxic damage induced by IBO. PMID- 7838323 TI - Increased sensitivity to the antinociceptive activity of (+/-)-baclofen in an animal model of chronic neuropathic, but not chronic inflammatory hyperalgesia. AB - Modulation of sensory afferent inputs to the spinal cord by GABA appears to be an important physiological mechanism and may provide an antinociceptive control system. In the present study we have evaluated the antinociceptive activity of the GABAB receptor agonist, (+/-)-baclofen, in rats with unilateral chronic inflammatory or neuropathic hyperalgesia. (+/-)-Baclofen was antinociceptive in untreated control animals and both animal models. In the neuropathic model the sensitivity to (+/-)-baclofen was significantly increased by 3-fold in the ipsilateral limb. By contrast, in animals with chronic inflammation no difference in sensitivity between ipsilateral and contralateral limbs to (+/-)-baclofen was observed. Receptor autoradiographic analysis in spinal cord sections revealed no increase in the density of GABAB receptor binding sites and no change in receptor affinity in the neuropathic model. PMID- 7838324 TI - The role of postsynaptic 5-HT1A receptors in the anticonflict effect of ipsapirone. AB - In the present paper we have studied the anticonflict effect (in the Vogel test) of ipsapirone, a partial agonist of 5-hydroxytryptamine1A (5-HT1A) receptors, administered to the hippocampus of rats. In addition, a comparison of the effect of ipsapirone with the effect of other 5-HT1A receptor ligands (busipone, gepirone and 8-OH-DPAT) has been carried out. Finally, the interaction between ipsapirone and NAN-190 (an antagonist of 5-HT1A receptors and alpha 1 adrenoceptors) has also been examined. It has been found that ipsapirone injected intrahippocampally (i.hp.) in doses of 0.3, 1 and 3 micrograms (bilaterally) shows an anticonflict effect by increasing the number of punished licks by about 36, 151 and 109%, respectively. A similar effect has also been found after i.hp. injections of buspirone (0.3-3 micrograms), gepirone (3-30 micrograms) and 8-OH DPAT (0.3-3 micrograms). We have also demonstrated that the anticonflict effect of ipsapirone injected i.hp. is antagonized by NAN-190 administered i.hp. (0.3 or 1 microgram) or intraperitoneally (i.p., 1 mg/kg). Furthermore, NAN-190 injected i.hp. (0.3 microgram) antagonizes the anticonflict effect of ipsapirone administered i.p. (5 mg/kg). At the same time, the anticonflict effects of ipsapirone are not affected by prazosin (0.3-1 microgram i.hp. or 0.5-1 mg/kg i.p.), a selective antagonist of alpha 1-adrenoceptors. Our results seem to indicate that the anticonflict effect of ipsapirone stems from stimulation of postsynaptic 5-HT1A receptors in the hippocampus. PMID- 7838325 TI - Design of a desipramine dosing regimen for the rapid induction and maintenance of maximal cortical beta-adrenoceptor downregulation. AB - Chronic administration of desipramine to rats causes a gradual reduction in cortical beta-adrenoceptor density. We examined the relationship between the duration of treatment with desipramine, and the rate and intensity of cortical beta-adrenoceptor downregulation. Male Sprague-Dawley rats were administered a 3.75 mg/kg/12 hr dose of desipramine for 4, 8 or 16 days. After 4 and 8 days of treatment, cortical beta-adrenoceptor density was reduced by 14 and 26% respectively. After 16 days of treatment, cortical beta-adrenoceptor density was maximally reduced by 36%. In our next series of experiments, we tested the hypothesis that the dose of desipramine required to rapidly induce maximal beta adrenoceptor downregulation was higher than the dose required to maintain maximal beta-adrenoceptor downregulation. Initially, cortical beta-adrenoceptors were rapidly, and maximally downregulated with a four day, 10 mg/kg/12 hr induction regimen of desipramine. Trough, steady-state brain/cortical concentrations of desipramine plus desmethyldesipramine at the end of this regimen were approx 4000 ng/gm. Subsequently, maintenance desipramine regimens of 3.75 mg/kg/12 hr and 1.87 mg/kg/12 hr or vehicle were initiated for the next four days. Inspite of a 20-fold drop in brain/cortical concentrations of desipramine plus its metabolite, the 3.75 mg/kg maintenance regimen sustained maximal cortical beta-adrenoceptor downregulation. The 1.87 mg/kg maintenance regimen did result in a marked (25%) but non-significant recovery in the density of beta-adrenoceptors. Animals administered a vehicle maintenance regimen showed a large (50%) and statistically significant recovery of cortical beta-adrenoceptor density. PMID- 7838326 TI - Multiple intracranial aneurysms in a defined population: prospective angiographic and clinical study. AB - Multiple intracranial aneurysms (MIA) have been detected in up to one-third of patients with cerebral aneurysms. Three main external factors influence these figures as follows: the quality of angiographies, the quantity of vessels studied, and referral policy. In a 1-year prospective study, we determined the incidence of MIA in a defined catchment area in East Finland by investigating all of the patients with intracranial aneurysms with panangiography. In 114 unselected patients, a total of 170 intracranial aneurysms were detected, and, of these, 39 (34%) harbored MIA. In contrast to most other reports, there was a male predominance in patients with MIA, and half of these men had hypertension. Intracavernous carotid and pericallosal aneurysms were more frequent in patients with MIA. The number of asymptomatic vertebrobasilar aneurysms was extremely low, and most of the nonruptured aneurysms were found in bilateral carotid angiograms. In spite of the active search, the proportion of vertebrobasilar aneurysms remained at 6%. Although our surgical policy was most active, one-third of the asymptomatic aneurysms remained untreated, mainly because of the poor condition of the patient. PMID- 7838327 TI - Surgical treatment of extracranial internal carotid artery dissecting aneurysms. AB - Aneurysms of the extracranial internal carotid artery (ICA) are uncommon. A significant proportion of such aneurysms are now recognized to be caused by arterial dissection. In some patients, surgical treatment may become necessary. The surgical treatment of 22 patients with spontaneous or traumatic dissecting aneurysms arising from the extracranial ICAs is reviewed. The mean age of the 7 women and 15 men was 39 years. The aneurysm arose from the proximal third of the extracranial ICA in 1 patient, from the middle third in 1 patient, and from the distal third in 20 patients. Five patients underwent cervical carotid ligation; in 13 patients, the aneurysms were resected, and the ICAs were reconstructed, and 4 patients underwent cervical-to-intracranial ICA bypasses. There were 2 postoperative strokes (9%). Facial and lower cranial nerve palsies were commonly seen after high cervical exposure, but these cranial nerve palsies were transient. There were no long-term neurological sequelae during a mean follow-up of 6.2 years. In our relatively limited experience, extracranial ICA dissecting aneurysms can be treated with acceptable morbidity using a variety of techniques. However, the indications for surgical intervention in these aneurysms remain limited. PMID- 7838328 TI - Low-grade glial tumors in basal ganglia and thalamus: natural history and biological reappraisal. AB - The natural history of 70 patients affected by low-grade astrocytomas was recorded after the histological diagnosis was obtained by serial stereotactic biopsy. Forty-three percent of these patients died within 3 years. The value of cell kinetics assessment at the time of stereotactic biopsy was investigated, and the labeling index percent may be considered the most accurate prognostic factor in these histologically homogeneous astrocytomas. It has been confirmed that the young age of patients predicts a more favorable course, but the value of this also seems to be linked to and dependent on cell kinetics. These data are discussed in view of the opportunity to perform more aggressive "cytoreductive" treatments in deep brain tumors when these indices support an expected poor prognosis. PMID- 7838329 TI - Cytokine expression in radiation-induced delayed cerebral injury. AB - Radiation-induced delayed brain injury is a well-documented complication of both standard external beam radiation (teletherapy) and interstitial brachytherapy; however, the cause of this damage has not been determined. Cytokines and growth factors are important regulatory proteins controlling the growth and differentiation of normal and malignant glial cells, which have been implicated in the tissue response to radiation injury. Six snap-frozen brain biopsies showing radiation injury were obtained from four patients harboring malignant gliomas who underwent either postoperative external beam and/or stereotactic interstitial brachytherapy at standard dosages. The specimens showed variable amounts of gliosis, tissue necrosis, calcification, inflammation, and vascular proliferation and hyalinization. Frozen tissue sections were examined for the presence of infiltrating lymphocytes, macrophages, cytokines, and other immunoregulatory molecules by the use of a panel of specific monoclonal and polyclonal antibodies. All specimens showed diffuse T cell infiltration with both CD4+ and CD8+ cells. Infiltrating activated macrophages (CD11c+, HLA-DR+) were prominent in five of six cases. Tumor necrosis factor-alpha and interleukin-6 immunoreactivity was prominent in four of six cases and was predominately localized to macrophages. Transforming growth factor-beta astrocytic and macrophage immunoreactivity was present at moderate levels in all cases. This study suggests that in radiation necrosis, interleukin-1 alpha, tumor necrosis factor-alpha, and interleukin-6 are expressed, predominately by infiltrating macrophages. PMID- 7838330 TI - Prognostic implications of p53 overexpression in supratentorial astrocytic tumors. AB - The wild-type p53 gene is thought to play a critical role in tumor suppression and has been shown to reverse the transformed phenotype of tumor cells in vitro. Mutational inactivation of this aspect of p53 activity occurs frequently in many human neoplasms, including astrocytomas, and is thought to represent a critical step in tumor progression. We have found previously that the presence of p53 immunoreactivity was significantly associated with malignant astrocytomas arising in younger patients, although occurring infrequently in tumors in older patients. Given that young age is the most consistent clinical factor predictive of longer survival in patients with astrocytomas, this suggested that p53 protein accumulation might be a molecular predictor of enhanced survival. To test this hypothesis, we retrospectively studied the association of p53 overexpression with survival in 149 patients with astrocytomas, using univariate and multivariate analysis to determine its value in predicting survival. Although our analysis reaffirmed the strong association between young age and increased survival, we were unable to demonstrate any difference in survival between patients with Grade III and IV tumors with p53 immunoreactivity compared with those without. Presumably, once a tumor has progressed to high grade, the relative importance of p53 status as a predictor of survival is low, probably because of the large number of accumulated genetic alterations associated with malignant tumors. In contrast, the presence of p53 overexpression in Grade II astrocytomas seemed from survival curves to indicate shorter survival compared with patients who had no p53 immunoreactivity. However, this variable did not quite reach statistical significance (P = 0.08) as an independent predictive variable in multivariate analysis.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7838331 TI - Shunt failures and complications in adults as related to shunt type, diagnosis, and the experience of the surgeon. AB - Data from 95 adult patients (43 males, 52 females) treated with ventriculoperitoneal shunts during an 8-year period were analyzed to investigate risk factors in shunt surgery. All patients were seen in the authors' department and were grouped according to the cause or type of hydrocephalus. The operating surgeons were divided into two categories: specialists and residents. The shunts were classified as single- (Orbis-Sigma) or multicomponent (Holter or Hakim) systems. Two types of unfavorable events were recognized: complications and shunt malfunction. A total of 143 surgical procedures (implantations and revisions) were performed in the 95 patients; 24 patients had their shunts revised, and there were 13 complications (one fatal, five severe) resulting from the shunt surgery. The following observations were statistically significant: 1) patients with normal pressure hydrocephalus had no complications from shunt surgery; 2) the number of shunt malfunctions was lower in patients with intracranial hemorrhages than in the other groups; 3) residents performed a higher number of inadequate operations than did specialists; and 4) the infection rate was higher among patients operated on by residents. The choice of shunt type, the perioperative use of antibiotics, and the degree of surgical emergency were not correlated with complication or failure rates. PMID- 7838332 TI - Predictive value of computed tomography-based diagnosis of intracranial tuberculomas. AB - The need to obtain histological diagnoses of intracranial tuberculomas, before initiating therapy, is not universally accepted, because some clinicians believe that an image-based diagnosis is fairly accurate in patients from endemic regions. To evaluate the sensitivity, specificity, and predictive value of computed tomography (CT)-based diagnosis of an intracranial tuberculoma, we prospectively compared the preoperative imaging diagnoses with histological diagnoses in 105 consecutive patients with intracranial masses. CT differential diagnoses (first or second) of tuberculomas were considered in 21 patients. Seven of them were histologically confirmed to have tuberculomas (true-positive results); 14 had other diseases (false-positive results). The 14 false-positive cases included 6 cases of astrocytomas, 5 of metastases, and 3 with miscellaneous diagnoses. All tuberculomas were correctly diagnosed on the CT scans (5 by both surgeons and 2 by one surgeon). During the study period, we encountered 11 patients who were referred by other clinicians with diagnoses of tuberculomas on the basis of their CT scans. We concurred with their CT diagnoses in 5 of them, but only 1 patient had a histologically verified tuberculoma. Astrocytomas (4 patients), metastases (3 patients), and solitary cysticercus granulomas (3 patients) were the causes of misdiagnosis in this group of patients. Although the sensitivity of CT in the diagnosis of intracranial tuberculomas is 100%, and its specificity is 85.7%, the positive predictive value is only 33% (confidence limits, 24-42%). The negative predictive value is 100%. The low positive predictive value for a diagnosis of intracranial tuberculoma on CT alone indicates the need for a confirming histological diagnosis. PMID- 7838333 TI - Antibiotic-resistant Acinetobacter meningitis in neurosurgical patients. AB - Acinetobacter anitratus has emerged as one of the common pathogens responsible for postneurosurgical meningitis at the authors' institution. Seven patients with Acinetobacter meningitis were identified during the 4-year period of this study, five of whom acquired organisms susceptible only to imipenem and amikacin. Acinetobacter bacteremia occurred concomitantly in five patients. Despite late institution of therapy as a result either of organism misidentification on Gram stain or of unexpected acquisition of a highly resistant organism, the patients' outcome was favorable after the initiation of appropriate antibiotic therapy. Imipenem and amikacin, with or without intrathecal aminoglycosides, were effective in patients with resistant strains of Acinetobacter. PMID- 7838334 TI - Cavernous angiomas and arteriovenous malformations of the spinal epidural space: report of 11 cases. AB - We have retrospectively studied 11 cases of solitary cavernous and arteriovenous malformations of the spinal epidural space. The acute or subacute onset of symptoms was found in all cases, with a neurological deficit in five cases. A plain x-ray study revealed abnormal calcification in one case. Hyperdensity with no iodine enhancement was found on computed tomographic scans in all cases. Magnetic resonance imaging studies showed ovoid or round lesions with isosignal and gadolinium enhancement on T1-weighted images and hypersignal on T2-weighted images, except in one case with hypersignal on T1 and T2 before the administration of a contrast medium. Four lumbar cases were localized in the posterior vertebral ligament; all the thoracic cases were posterior with foraminal extension. The other cases were anterolateral. The surgical findings revealed a dark vascularized epidural lesion associated in two cases with a localized epidural hematoma. A pathological examination revealed seven cavernous angiomas and four arteriovenous malformations. These arteriovenous malformations were all lumbar, and two of four localized within the posterior ligament. The pathophysiology of these vascular malformations is discussed. In light of the good postoperative prognosis of these lesions, surgical removal is recommended for all the symptomatic cases. PMID- 7838335 TI - Surgical results of 100 intramedullary tumors in relation to accompanying syringomyelia. AB - During the period from 1977 to August 1992, 100 intramedullary tumors in 94 patients were operated on in the Department of Neurosurgery at the Nordstadt Hospital in Hannover, Germany. Of these, 45% presented with associated syringes. A syrinx was more likely to be found above (49%) than below (11%) the tumor level. In 40%, a syrinx could be identified above and below the tumor level. Ependymomas and hemangioblastomas were the most common tumor types to be associated with syringes. Astrocytomas tended to demonstrate syringes less often. Regardless of histology, the higher the spinal level, the more likely a syrinx was encountered. In general, the presence of an associated syrinx favored the resectability of the tumor, because it indicated a displacing rather than an infiltrating tumor. Patients with syringomyelia tended to recover from surgery sooner. However, surgical results and long-term prognosis were not influenced significantly by an associated syrinx. The most important factor determining long term outcome was the preoperative level of neurological function. We propose that factors independent of the tumor, disturbances of cerebrospinal fluid and extracellular fluid flow in particular, have major roles in the pathogenesis of syrinx formation associated with intramedullary tumors. PMID- 7838336 TI - Posterior fossa reconstruction: a surgical technique for the treatment of Chiari I malformation and Chiari I/syringomyelia complex--preliminary results and magnetic resonance imaging quantitative assessment of hindbrain migration. AB - Experimental models have shown that Chiari I malformation is a primary paraaxial mesodermal insufficiency occurring after the closure of the neural folds takes place. According to these hypotheses, a small posterior fossa caused by an underdeveloped occipital bone would be the primary factor in the formation of the hindbrain hernia. The main objective in the surgical treatment of Chiari I malformation and related syringomyelia is directed to restore normal cerebrospinal fluid dynamics at the craniovertebral junction. The most widely accepted surgical approach is to perform a craniovertebral decompression of the posterior fossa contents with or without a dural graft. It has been emphasized that suboccipital craniectomy should be small enough to avoid downward migration of the hindbrain into the craniectomy. This slump of the hindbrain has been verified by studies using postoperative assessment by magnetic resonance imaging. Our aim in this study is to present a modification of the conventional surgical technique, which we have called posterior fossa reconstruction (PFR). Ten patients were operated on using this technique and compared with a historical control group operated on with the classic approach of making a small suboccipital craniectomy, opening the arachnoid, and closing the dura with a graft. To evaluate the morphological results in both groups objectively, preoperative and postoperative measurements of the relative positions of the fastigium and upper pons above a basal line in the midsagittal T1-weighted magnetic resonance images were obtained. In those cases with syringomyelia, syringo-to-cord ratios were calculated. The mean age of the PFR group was 35 +/- 16 years (mean +/- SD); in the control group it was 35.2 +/- 12 years. In the PFR group, the formation of an artificial cisterna magna was observed in every case; it was observed in only one case in the control group. An upward migration of the cerebellum was seen in all cases in the PFR group, with a mean ascent of the fastigium of 6.2 mm. A significant downward migration of the cerebellum was observed in seven cases in the control group. No significant differences were found in both groups when comparing syringo-to-cord ratios. This leads us to conclude that PFR is more effective than conventional surgical approaches in restoring the normal morphology of the craniovertebral junction. This allows cranial ascent of the hindbrain verified by magnetic resonance imaging and good short-term clinical results. Because PFR is mainly an extraarachnoidal approach, complications related to surgery using this technique can be kept to a minimum. PMID- 7838337 TI - Posttraumatic syringomyelia: its characteristic magnetic resonance imaging findings and surgical management. AB - Posttraumatic syringomyelia should be considered in any patient showing a delayed neurological deterioration after spinal cord injury. The purpose of this article is to assess the posttraumatic syringomyelia on magnetic resonance images and to evaluate the results of its surgical treatment. Fourteen patients with posttraumatic syringomyelia were studied. There were 10 men and 4 women ranging in age from 25 to 67 years. Eleven patients with syringomyelia were symptomatic, and the three others were asymptomatic. The periods from spinal cord injury to onset of symptoms due to syringomyelia ranged from 3 to 33 years with a mean of 14 years. On magnetic resonance images, the mean length of the syrinx was 14 vertebral levels and ranged from 3 to 20 levels. At the rostral part of the injured cord, the syrinx was located off center. In contrast, at the caudal part of the injury, the syrinx was markedly large in size and its location was central. In 6 of 13 patients, the syringes extended into the medulla oblongata. Eleven symptomatic patients underwent surgical treatments: a syringosubarachnoid shunt was done in six patients, a syringoperitoneal shunt was done in four, and a ventriculoperitoneal shunt was carried out in one. Shunt malfunction was encountered in three of the four syringoperitoneal shunts and in the one ventriculoperitoneal shunt. Final neurological outcomes were satisfactory in all 11 patients who underwent surgery. Motor function improved in eight of nine patients, sensory disturbance improved in five of five patients, and relief of local pain or numbness was obtained in four of four patients.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7838338 TI - Evaluation of spinal laminar fixation by a new, flexible stainless steel cable (Sof'wire): early results. AB - Segmental spinal stabilizations have been carried out in 72 patients (age, 5-79 yr) during the first 2 years of the availability of a new, flexible, multistranded stainless steel cable (Sof'wire, Hillway Surgical Ltd., London). A total of 519 sublaminar and occipital cables have been passed at 280 levels to fix an occipitocervical loop (36 patients) or contoured rectangle (14 patients). In 15 other patients, a Gallie fusion was combined with a C1-C2 lateral mass screw fixation; a cable-bone construct was used in five patients. Clinical and radiological follow-up at 1, 3, 6 (61 patients), 12 (48 patients), and 18 months (29 patients) and at 2 years (8 patients) has demonstrated no cable breakage or loosening. One postoperative death was due to inadequate transoral decompression before posterior fixation, and, in the 32 patients who underwent spinal monitoring, there were no major changes noted during surgery and no new postoperative neurological symptoms or signs. These preliminary observations are encouraging and merit further multicenter investigations. PMID- 7838339 TI - The microsurgical anatomy of the superior hypophyseal artery. AB - Interest in the anatomy of the proximal segment of the intracranial internal carotid artery has been kindled by the recognition that there are multiple potential sites of aneurysm formation in this region. These various aneurysm locations have characteristic hemodynamic and clinical features as well as surgical considerations. Recently recognized as a distinct clinical and anatomical entity are aneurysms that are hemodynamically related to the superior hypophyseal artery. Although aneurysms arising in proximity to the superior hypophyseal artery are not rare, the anatomy of this vessel arising from the medial or posteromedial aspect of the proximal internal carotid artery is poorly understood. We performed a cadaveric microsurgical anatomical study of 20 internal carotid arteries between the ophthalmic and posterior communicating arteries to develop a better understanding of the anatomical relationships of the superior hypophyseal artery. There were an average of 1.8 superior hypophyseal arteries arising from each carotid artery with an average diameter of 0.22 mm. The origin of the superior hypophyseal arteries was within 5 mm of the ophthalmic artery origin in 85% of the specimens. There were two distinct patterns of superior hypophyseal artery anatomy. In 42%, a large, dominant superior hypophyseal artery branched like a candelabra with smaller branches to the pituitary stalk, optic nerve, and chiasm. The average diameter of the larger branches was 0.3 mm. In the absence of a large dominant branch, two or three medial vessels were found. In one specimen, an incidental aneurysm was discovered at the origin of the superior hypophyseal artery on the medial aspect of the internal carotid artery at the origin of a large candelabra-like branch.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7838340 TI - Antisense expression of protein kinase C alpha inhibits the growth and tumorigenicity of human glioblastoma cells. AB - To investigate the role of protein kinase C (PKC) in the growth of astrocytic brain tumors, human glioblastoma cell line U-87 was stably transfected with the antisense complementary deoxyribonucleic acid encoding PKC alpha. The effect of selectively down-regulating the alpha isoform on other PKC isoforms, as well as serum-dependent proliferation and in vivo tumorigenicity, was determined. U-87 cells expressed high levels of PKC alpha and lesser amounts of the gamma, epsilon, and zeta isoforms, and a similar PKC isoform pattern was observed in two other human glioblastoma cell lines. Expression of the antisense PKC alpha complementary deoxyribonucleic acid resulted in no detectable PKC alpha by immunoblotting and a 95% reduction in total Ca2+/phospholipid-dependent PKC activity. U-87 cells expressing antisense PKC alpha exhibited an increase in doubling time in vitro, less serum-dependent growth, and reduced sensitivity to a selective PKC inhibitor, Ro 31-8220. The transplantation of U-87 cells expressing antisense PKC alpha into nude mice resulted in no tumor formation. These observations suggest that the inhibition of PKC alpha may be an important chemotherapeutic target for arresting the growth of glioblastomas. PMID- 7838341 TI - Stereotactic delivery of a recombinant adenovirus into a C6 glioma cell line in a rat brain tumor model. AB - The dismal results of conventional therapy for primary malignant brain tumors has justified exploring gene therapy approaches for this disease. Transduction of animal brain tumor models in vivo has been reported previously with retroviruses and herpes viruses. Because adenoviruses have the advantage of transducing quiescent and actively dividing tumor cells, they may prove to be more effective in such therapy. We used a replication-deficient recombinant adenovirus bearing the Escherichia coli beta-galactosidase gene in a rat C6 glioma tumor model. Transduced cells were detected by X-5-bromo-4-chloro-3-indolyl beta-D-galactoside staining to reveal beta-galactosidase activity. Initial experiments in vitro showed 50% and 90% transduction at vector titers of approximately 10(7) and 10(8) plaque-forming units/ml, respectively. Although no cytopathic effects were seen at 10(7) plaque-forming units/ml, more than 50% reduction in tumor cell growth was noted at 10(8) plaque-forming units/ml both in vitro and in vivo. Stereotactic delivery of the recombinant adenovirus into the frontal lobe of normal rat brains resulted in intense staining of all cell types, that is, neurons, astrocytes, and ependymal cells. Stereotactic injection into C6 glioma brain tumors in rats stained 25 to 30% of the tumor cells. We conclude that adenovirus vectors can be used to transfer genes to central nervous system tumors in vivo. Using stereotactic delivery, adenovirus vectors can transfer genes into the central nervous system intended for tumor therapy. PMID- 7838342 TI - Image analysis of proliferating cells in tumors of the human nervous system: an immunohistological study with the monoclonal antibody Ki-67. AB - Obtaining growth fractions from immunohistological preparations by the commonly used cell count calculation method is time consuming. For the first time, we investigated and compared the detection of proliferating cells in immunohistologically labeled tissue from tumors of the nervous system using the monoclonal antibody Ki-67 by a new computerized image analysis system and by cell count calculation. The two methods showed a high correlation (correlation index, 0.98) in 37 gliomas (2 pilocytic astrocytomas, 10 Grade II astrocytomas, 5 Grade III astrocytomas, 20 Grade IV astrocytomas and glioblastoma multiforme) and a heterogenous group of 10 additional tumors of the nervous system, including oligodendroglioma, pineoblastoma, primary central nervous system lymphoma, and neurofibroma. Advantages of and indications for image analysis are as follows: 1) time-saving evaluation of immunohistological preparations enables their use in neuro-oncological routine diagnostics and examination of larger cell populations, thus leading to more precisely reproducible results, especially in heterogenous tumors; 2) image analysis, calculating the area of cell nuclei rather than their number, avoids difficulties with fragmented or overlapping nuclei; 3) analysis of different antibodies (for example, Ki-67 and anti-proliferating cell nuclear antigen) may be performed with the same program; 4) investigation of a larger patient group may lead, in combination with the histopathological diagnosis and clinical parameters, to better adapted therapeutic concepts. PMID- 7838343 TI - Superoxide scavenging activity in the extracellular space of the brain in forming edema. AB - We carried out a time course study of cerebral superoxide scavenging activity using a modified microdialysis technique. Twelve cats were divided into two groups; six were the reperfusion injury models, and six were cold injury models. In the reperfusion injury model, dialysates were collected during 60 minutes of middle cerebral artery occlusion and at 300 minutes during reperfusion. In the cold injury model, dialysates were collected 240 minutes after the injury. Regional cerebral blood flow on the injured side decreased during occlusion in the reperfusion injury model and 60 minutes after injury in the cold injury model. In the reperfusion model, superoxide scavenging activity, as determined with electron spin resonance, increased in the first 30 minutes and decreased 300 and 330 minutes after occlusion. In the dialysate, albumin increased 180 minutes after cold injury, which may show the progress of vasogenic edema. An increase in water content was observed on the injured side of both models, and a correlation between water content and superoxide scavenging activity was found in the reperfusion injury model. By this technique, a method of detecting the alteration of superoxide scavenging activity in the extracellular space of the brain was established. PMID- 7838344 TI - Enhanced optical imaging of rat gliomas and tumor margins. AB - Current intraoperative methods used to maximize the extent of tumor removal are limited to intraoperative biopsies, ultrasound, and stereotactic volumetric resections. A new technique involving the optical imaging of an intravenously injected dye has the potential to localize tumors and their margins with a high degree of accuracy. In a rat glioma model, enhanced optical imaging was performed and indocyanine green was used as the contrast-enhancing agent. In all 22 animals, the peak optical change in the tumor was greater than in the ipsilateral brain around the tumor and the contralateral normal hemisphere. The clearance of the dye was significantly delayed to a greater extent in the tumor than in the brain around the tumor and the normal brain. After attempts were made at complete microscopic resection, enhanced optical imaging of the tumor margins and the histological samples demonstrated a specificity of 93% and a sensitivity of 89.5%. Enhanced optical imaging was capable of outlining the tumor even when the imaging was done through the cranium. The optical imaging of rat gliomas with a contrast-enhancing dye is able to differentiate between normal brain and tumor tissue both at the cortical surface and at the tumor margins. The application of these studies in an intraoperative clinical setting may allow for the more accurate determination of tumor margins and may increase the extent of tumor removal. PMID- 7838345 TI - Perspectives in neurosurgery: neurosurgery in Greece. PMID- 7838346 TI - Deep sylvian fissure meningioma without dural attachment in an adult: case report. AB - Meningiomas are thought to arise from arachnoid cap or meningothelial cells that not only cluster on the surface of pacchionian granulations but also can cover the arachnoid membrane in other locations. This frequent apposition to the dura mater probably accounts for the usual attachment of the neoplasm to this layer. We report a deep sylvian fissure meningioma without dural attachments in the right hemisphere of an adult patient. The patient initially presented with simple partial seizures. Magnetic resonance imaging revealed a contrast-enhancing circular mass in the superior aspect of the insular region, deep to the inferior parietal lobule. Surgical exploration confirmed the absence of dural attachments. Microscopically, the tumor was found to be a sparsely cellular meningioma with an extensive collagenous matrix. A survey of the literature reveals that the majority of cases of meningiomas without dural attachments occur either in children or below the tentorium. Extremely rare cases of supratentorial meningiomas without dural attachment have been described in adults. The uncommon locations of these tumors at sites distant from the dura mater is postulated to reflect the rare occurrence of arachnoidal cap cells in the Virchow-Robin spaces along the cerebral vasculature or in pial layers distant from the dura mater. PMID- 7838347 TI - Cerebellar pleomorphic xanthoastrocytoma: case report. AB - We report a case of pleomorphic xanthoastrocytoma occurring in the midline cerebellum of a 48-year-old woman. Radiological, histological, immunohistochemical, and flow cytometric findings are discussed. Pleomorphic xanthoastrocytoma typically occurs in the superficial cerebral hemispheres of young patients. To our knowledge, this is the first report of the occurrence of this neoplasm in the cerebellum. The English literature is reviewed with regard to the clinicopathological features of this uncommon form of astrocytoma. PMID- 7838348 TI - Gigantism in sibling unrelated to multiple endocrine neoplasia: case report. AB - The cases of gigantism sisters with somatotroph adenomas unrelated to multiple endocrine neoplasia (MEN) Type 1 are reported. The sisters grew rapidly since they were 5 or 6 years old and were diagnosed to have gigantism with pituitary adenoma by computed tomographic scan and magnetic resonance imaging. A serum endocrinological examination showed the elevated growth hormone values. After thyroxine-releasing hormone stimulation, growth hormone values exhibited a paradoxical rise. They were supposed to be unrelated to MEN Type 1, because analysis of the 11th chromosomes and the other endocrine functions were normal. They were operated on by the transphenoidal method. Immunohistochemical staining of both tumor specimens confirmed somatotroph adenomas. Pituitary adenoma associated with MEN Type 1 is a well-recognized entity. However, the sporadic occurrence of pituitary adenoma unrelated to MEN Type 1, especially in siblings, is extremely rare. Fifteen cases of pituitary adenomas in siblings were described in the literature. As for gigantism, only two brothers were reported. Our case of gigantism sisters is the second sporadic case. In our review of the isolated cases of pituitary adenoma in siblings described in the literature, 12 (70%) of 17 cases including ours are acromegaly or gigantism. This incidence is much higher than that of MEN Type 1 patients with pituitary adenomas. The cause of the familial occurrence of pituitary adenomas is still unclear, although autosomal recessive inheritance has been suggested. It has been stated that point mutations in codon 201 or 227 of the Gs alpha gene located in chromosome 20 were found in about 35 to 40% of somatotroph adenomas.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7838349 TI - Cervical paraspinous desmoid tumor in a child: case report. AB - Desmoid tumors are uncommon fibroblastic proliferative lesions usually occurring in the abdominal wall of adults. We report an unusual case of such a tumor presenting as a rapidly growing cervical paraspinous mass in a 19-month-old girl. After surgical resection without adjuvant therapy, the child is recurrence free after 17 months. The primary treatment of these lesions is surgical resection. We found magnetic resonance imaging to be the best imaging method for evaluation, because it was able to distinguish the tumor from the surrounding muscle. Careful postoperative surveillance is warranted, because these tumors have a high rate of recurrence. Although rare, desmoid tumor should be considered in the differential diagnosis of a paraspinous soft tissue tumor in a pediatric patient. PMID- 7838350 TI - Severe cervical kyphotic deformities in patients with plexiform neurofibromas: case report. AB - Two patients with cervical plexiform neurofibromas are presented. Each of these patients had severe cervical kyphosis and has undergone anterior decompression, anterior reconstruction, and posterior stabilization. We discuss the surgical management of cervical kyphotic deformities associated with plexiform neurofibromas and review the factors associated with bony changes in neurofibromatosis. PMID- 7838351 TI - Dural arteriovenous fistula of the posterior fossa draining into the spinal medullary veins--an unusual cause of myelopathy: case report. AB - In a 31-year-old male patient suffering from progressive myelopathy, a right carotid angiography disclosed an intracranial tentorial arteriovenous fistula (AVF) draining intrathecally into the spinal medullary veins. An embolization via the afferent meningohypophyseal artery was not technically feasible, and a microsurgical excision of the AVF was accomplished via a suboccipital approach, resulting in the angiographic cure of the fistula and progressive relief of the myelopathy. Fourteen reported cases of intracranial dural AVF draining intrathecally are reviewed. In most patients, authors encountered diagnostic difficulties similar to those noted in this case. Surgical and/or endovascular therapeutic methods have provided disappointing results, likely attributable to a prolonged course of spinal cord dysfunction. Pathophysiologically, a mechanism of venous congestion of the cord seems to be involved, as acknowledged by several magnetic resonance and angiographic studies. In patients who appear to have a clinical and myelographic picture of "vascular" myelopathy and who exhibit negative spinal angiography, a four-vessel cerebral angiography should be undertaken, aiming at the recognition of an intracranial AVF. PMID- 7838352 TI - Intraoperative assessment of aneurysm clip placement by intravenous fluorescein angiography. AB - Clip occlusion of intracranial aneurysms can be difficult, and intraoperative misadventures are still fairly frequent. Many complications are caused by improper clip placement. Intraoperative conventional arteriography is time consuming and requires expensive image-intensifying equipment. As an alternative, we have found that the bolus intravenous administration of fluorescein produces the necessary intra-arterial dye concentration for the direct visualization of the perforating medium and large arteries in proximity to a clipped aneurysm. The technique is straightforward, requiring little additional operating time and an inexpensive set of disposable optical filters. No adverse reactions to fluorescein have been observed. PMID- 7838354 TI - Successful treatment of an acute thrombosis of an intracranial vertebral artery endarterectomy with urokinase. AB - This is a case report of a 47-year-old man admitted with a 7-month history of disequilibrium, multiple reversible vertebrobasilar ischemic attacks, and one submaximal completed stroke in the left posterior inferior cerebellar artery distribution. Vertebrobasilar ischemic attacks continued despite anti coagulation, and orthostatic symptomatology suggested a significant hemodynamic component contributing to the posterior circulation ischemia. Angiography confirmed bilateral high-grade stenoses of the intracranial vertebral arteries. A right intracranial vertebral artery endarterectomy was performed with electroencephalographic and somatosensory evoked potential monitoring and protection with barbiturate infusion. The arteriotomy was closed with a vein patch. Postoperatively, the endarterectomy site thrombosed. This thrombosis was completely reversed with 220,000 U of urokinase selectively infused intra arterially at the site of thrombosis. This procedure was not complicated by hemorrhage or distal embolization. The vertebral artery was confirmed to be patent 24 hours and 7 days after the urokinase injection. The patient sustained a borderzone infarction in the right cerebellar hemisphere without neurological deficits and was discharged home well. PMID- 7838353 TI - Embolization with temporary balloon occlusion of the internal carotid artery and in vivo proton spectroscopy improves radical removal of petrous-tentorial meningioma. AB - A highly vascular petroclival meningioma supplied by tentorial branches of the internal carotid artery was embolized by temporary balloon occlusion of the parent vessel distal to the tumor, followed by obliteration of the tumor vascularity with polyvinyl alcohol particles. Subsequently, in vivo proton spectroscopy showed necrosis of a large portion of the tumor and helped determine the timing of surgery. Both innovative techniques considerably facilitated the subsequent radical excision of the tumor with no neurological morbidity. PMID- 7838355 TI - Emergency ventriculostomy-experience with a new screw device: technical note. AB - Emergency situations, such as acute hydrocephalus or ventricular hemorrhage, require immediate and reliable treatment by ventriculostomy. The method used has to be standardized, applicable in a fast manner, and associated with only minimum risk of infection. We present a recently developed set for external ventriculostomy, which meets the above-standing requirements, and which consists of a screw with self-biting thread, a metal cannula, and a special screwdriver. Ventriculostomy can be performed easily within 2 minutes, and the system can be fixed rigidly to the skull of the patient for a period of up to several weeks. Exchange of the cannula is possible within 1 minute. The system has been used in 90 cases so far, with a rate of possible infection of 1.1%. PMID- 7838356 TI - Retrieval of a Guglielmi detachable coil after unraveling and fracture: case report and experimental results. AB - Unraveling and fracture of electrolytically detachable coils (Guglielmi detachable coils) may occur during treatment of intracerebral aneurysms. Retrieval of the detached coil is difficult using existing snare technology, and the intraluminal coil may cause parent vessel thrombosis or distal embolization. We report a case of unraveling and fracture of a Guglielmi detachable coil that was successfully retrieved using a dual guidewire technique. The technique was evaluated in an in vitro model using 10 coils of varying sizes and diameters, and allowed successful coil retrieval in all trials. PMID- 7838357 TI - The functional role of the motor area of the cortex in the formation of riddance reactions in dogs. AB - A model of instrumental conditioning similar to the classical model (Pavlovian) is proposed. Flexion of the ipsilateral forelimb was elicited while EDS was applied to the hind limb by stimulation of the motor area of the cortex (M1); both stimuli ceased during the raising of the forelimb. Uniform combinations of this kind led to the development of forepaw flexion reactions in response to the EDS of the hind paw. Prolongation of EDS by 3 sec following cortical stimulation led to rapid extinction of the developed reactions. Thus, the possibility of the effective instrumentalization of movements induced by stimulation of the M1 is proven. This argues that the forming "instrumental" connection (drive-motor structures) is addressed directly to the M1. PMID- 7838358 TI - The correlation between changes in synaptic efficiency and cellular excitability during the development of a conditioned reflex analog. AB - The calculation of the coefficient of correlation between changes in the direct (D) and monosynaptic (I) components of the pyramidal tract (PT) response made it possible to establish the presence of a positive linear association between conditioned reflex changes in synaptic efficiency and the shifts in cellular excitability observed at the same time. The coincidence of the maximal strength of this association with the greatest increase in cellular excitability which is dependent on the activation of motivatiogenic structures points to the role of these subcortical structures in the launching of intracellular reactions which leads to the formation of the overall molecular substrate which underlies interaction of membrane and synaptic mechanisms. The preceding of the greatest enhancement of synaptic efficiency by the maximal manifestation of the interaction attests to the contribution of this process to the manifestation of the principal mechanism of the conditioned reflex (CR). PMID- 7838359 TI - Influence of different intracellular electrostimulation regimes on the dynamics of the adaptational processes of neurons. AB - The influence of rhythmic, random, and associative intracellular electrostimulation under the conditions of a controllable experiment was investigated in individual identified and nonidentified neurons of the isolated central nervous system of the pond snail. Two phases distinguished by the markedness and stability of the observed adaptive changes of the initial spike activity, which were evaluated by means of various statistical tests, were discriminated during the adaptation of the neuron to the applied regimes of influences. In the first phase, which reflects the search for a strategy of optimization of the incoming external influences, an increase in a scatter of interimpulse intervals and in the disorderliness in the discharge pattern takes place. In the second phase, observed only in the case of associative influences, a true adaptation of the neuron develops, accompanied by stable changes in endogenous rhythmicity, which lead to the achievement of minimization or maximization of the associated stimulations. The changes accompanying the effective optimization of external influences are most marked at the end of the epoch of the corresponding associative stimulation, and are maintained for some time following its cessation. Possible endoneuronal mechanisms of the observed adaptive reorganizations of spike activity are discussed. PMID- 7838360 TI - Identification of a latent state arising in the hippocampus following the cessation of long-term potentiation. AB - The possibility of the restoration of long-term potentiation in the CA1 region and the dentate gyrus of the hippocampus during stimulation respectively of the dorsal raphe nuclei and locus coeruleus, with stimulus parameters inducing behavioral reactions, was investigated in freely-behaving rats. It was demonstrated that stimulation of the locus coeruleus, which was ineffective prior to the tetanization of the perforant path, led to the restoration of extinguished long-term posttetanic potentiation in the dentate gyrus of the hippocampus induced by tetanization of the perforant path. Stimulation of the dorsal raphe nucleus, which was ineffective prior to the tetanization of the Schaffer collaterals, led to the restoration of long-term posttetanic potentiation in the CA1 region of the hippocampus induced by tetanization of the Schaffer collaterals. A mathematical model is proposed which has made it possible to describe the restoration of long-term posttetanic potentiation on the basis of the notion of the existence of several states of calcium/calmodulin-dependent protein kinase. The restoration of long-term potentiation during stimulation of emotiogenic zones was examined as a model of the phenomenon of emotional reminding. PMID- 7838361 TI - Secretory activity of the magnocellular nuclei of the hypothalamus of the pink salmon, Oncorhynchus gorbuscha Walbaum (Salmonidae), when it moves from sea to river and is transported back. PMID- 7838362 TI - Correlative relationships between the specific binding of labeled adrenoligands in the brain and plasma testosterone in mice. PMID- 7838363 TI - The processes of anticipation and evaluation of the results of behavior and their cellular neurochemical mechanisms. AB - The cellular neurochemical mechanisms of the goal-directed activity of cats under free behavior conditions were studied using the method of the microiontophoretic application of biologically active substances to individual neurons of the visual area of the cerebral cortex. Two experimental situations were used in the study. The first consisted of the alternation of the animal's instrumental reactions in the form of pedal-pressing with following reinforcement and of unexpected deliveries of milk in the food dispenser, and the second consisted of the alternation of the instrumental reactions with following reinforcement and of such reactions without reinforcement. An association was demonstrated of the cellular neurochemical mechanisms with the processes of the anticipation, perception, and evaluation of the results of the goal-directed activity. PMID- 7838364 TI - The features of the participation of the cholinergic mechanisms of the accumbens and caudate nuclei in the regulation of an instrumental defense reflex in dogs. AB - The influence of microinjections of carbacholine (0.1, 0.05, and 1.0 microgram) into the dorsal striatum (head of the caudate nucleus) and the ventral striatum (nucleus accumbens) on the motor components of the instrumental response and the criteria of execution of an instrumental task was studied in chronic experiments in eight dogs, based on a model of an instrumental defense reflex associated with the maintenance of a specific posture. The varied participation of the cholinoreactive structures of the caudate and accumbens nuclei in the regulation of the instrumental defense reflex was demonstrated in the dogs. Data were obtained indicating that the cholinoreactive system of the contralateral head of the caudate nucleus is structurally included in the regulation of the motor components of the instrumental response, of the main component of the reorganization of posture (the "disburdening" of the working extremity), and in the regulation of the tonic component of the voluntary movement and of its form. At the same time, the injection of carbacholine into the nucleus accumbens exerted, rather, a nonspecific activating influence on the motor systems. An improvement in attention to significant stimuli and the prolongation of the observed effects were also features of the activation of the cholinoreactive system of this nucleus. These changes took place in the case of both ipsi- and contralateral influences; this makes it possible to consider the inclusion mainly of sensory mechanisms in the realization of these influences. PMID- 7838365 TI - Influence of stimulation of movement-inhibiting areas of the pons on the activity of neurons of the medial region of the medulla oblongata. AB - The reactions of 249 neurons located in the zones of gigantocellular reticular nucleus and the nucleus raphe magnus in response to electrical stimulation of areas of the cuneate nucleus of the midbrain, the medial parabrachial nucleus, and the central raphe nucleus, which inhibit movement, were analyzed in anesthetized white rats. Reactions to stimulation of these areas of the pons were lacking in 40 cells; 25 neurons were excited antidromically; 48 responded with solitary orthodromic action potentials; prolonged inhibition was observed in 72 neurons following the phase of activation; and 64 cells were tonically excited. The functional identification of the two last groups of neurons showed that the inhibition reactions are primarily recorded in cells receiving tactile and mechano- and nociceptive information, while the neurons which tonically discharge upon stimulation apparently participate in the inhibition of the motoneurons of the hind limbs. PMID- 7838366 TI - Cholinergic synapses of the associative temporal area of the neocortex in the realization of cognitive functions. AB - The activity of choline acetyltransferase in the subsynaptic fractions of light and heavy synaptosomes of the associative temporal areas of the neocortex of cats with varying capacities for the formation of preverbal concepts was investigated. With respect to the majority of the subfractions, differences were detected between animals with normal and decreased intellect. Some theoretical conclusions were drawn relative to the origin of the individual subfractions; the role of cholinergic synapses of the area in question in the realization of the function of generalization and abstraction is discussed. PMID- 7838367 TI - The influence of cingulate cortex stimulation on the activity of neurons of the motor cortex in the white rat. PMID- 7838368 TI - Long latency reflexes and somatosensory potentials in multiple sclerosis patients. PMID- 7838369 TI - The use of the method of transcranial micropolarization to decrease the severity hyperkineses in patients with infantile cerebral palsy. PMID- 7838370 TI - Endothelins are extracellular signals modulating cytoskeletal actin organization in rat cultured astrocytes. AB - Effects of endothelin-3 on rapid morphological changes and cytoskeletal actin organization of rat cortical cultured astrocytes were examined. In serum-free medium, treatments with 1 mM dibutyryl cAMP and 5 microM cytochalasin B, an inhibitor of actin polymerization, caused astrocytic morphological changes with cytoplasmic retraction (stellation). Concurrent addition of 1 nM endothelin-3 prevented astrocytic stellation by dibutyryl cAMP and cytochalasin B. The inhibition of endothelin-3 on the astrocytic stellation was dose-dependent, where IC50 and maximal effective dose were about 50 pM and 0.1 nM, respectively. Endothelin-1 and sarafotoxin S6b prevented the cytochalasin B-induced stellation with similar potencies to endothelin-3. Endothelin-3 reversed the stellate morphology of cytochalasin B-treated cells. Sixty minutes after addition of endothelin-3, most cytochalasin B-treated astrocytes lost their apparent distinction between cell body and processes. Treatment with dibutyryl cAMP and cytochalasin B decreased actin content in a 0.5% Triton X-100-insoluble fraction (cytoskeletal fraction) of cultured astrocytes. Subsequent treatments with endothelin-3 for 2 h restored the decreased cytoskeletal actin to that of non treated cells. Rhodamine-phalloidin staining showed that a prominent structure of organized filamentous actin in protoplasmic astrocytes is stress fibers. The astrocytic stress fibers disappeared after treatment with dibutyryl cAMP and cytochalasin B. Endothelin-3 stimulated reorganization of stress fibers both in the dibutyryl cAMP- and the cytochalasin B-treated astrocytes. These results suggest that endothelins are extracellular signals to regulate cytoskeletal actin organization of astrocytes. PMID- 7838371 TI - Convergence of deep somatic and visceral nociceptive information onto a discrete ventrolateral midbrain periaqueductal gray region. AB - Pain arising from deep structures (muscles, joints, viscera) is the type of pain of most clinical relevance and also the type of pain about whose central representation we have the least knowledge. In contrast to cutaneous pain which evokes defensive behaviours, hypertension and tachycardia, the physiological reactions to most deep pain (especially if persistent) usually include quiescence, hypotension, bradycardia and decreased reactivity to the environment. Excitation of neurons within a discrete ventrolateral midbrain periaqueductal gray region evokes a reaction seemingly identical to that evoked by pain arising from deep structures. We report here, using the technique of the noxious stimulus evoked expression of the immediate-early gene, c-fos, that neurons within this same ventrolateral periaqueductal gray region are selectively activated by a range of deep somatic and visceral nociceptive manipulations. Thus we have identified a specific brain region that both receives convergent, deep somatic and visceral nociceptive input, and which mediates the behavioural and physiological reactions characteristic of most deep pain. PMID- 7838372 TI - Olfactory disturbance induced by deafferentation of serotonergic fibers in the olfactory bulb. AB - The serotonergic neurons of the brain stem project widely throughout the central nervous system, and the olfactory bulb is one of the major forebrain targets of the ascending serotonin pathway. According to physiological studies, neurons of the olfactory bulb were found to reduce their spontaneous discharge rates by electrophoretically applied serotonin. However, roles of the bulbar serotonin in the sense of smell remain unanswered. In the present study, using 5,7 dihydroxytryptamine, a specific neurotoxin for serotonin, we found that the conditioned rats who learned to avoid a repellent by olfaction lost ability of discrimination by deafferentation of the bulbar serotonergic fibers. Such olfactory dysfunction did not occur in the early stage (three days after injection of the toxin) when the serotonergic fibers disappeared in the bulb, but developed a few weeks later. Interestingly, histological examination revealed marked shrinkage of the bulbar glomerulus which is a major termination site of the bulbopetal serotonergic fibers, and also a synaptic site of olfactory receptor cells and bulbar output neurons. The results indicate that depletion of the serotonergic fibers in the olfactory bulb causes glomerular atrophy and olfactory disturbance in the rat. PMID- 7838373 TI - Odor deprivation leads to reduced neurogenesis and reduced neuronal survival in the olfactory bulb of the adult mouse. AB - Neurogenesis persists in the olfactory bulbs of adult mice, with new cells being generated in the proliferative subependymal layer. Our previous work has shown that unilateral odor deprivation through naris closure leads to a net loss of granule neurons in the ipsilateral (odor-deprived) olfactory bulb, while not affecting the contralateral bulb. Here we used several experimental approaches to determine if this loss of neurons results from reduced neurogenesis, reduced neuronal survival, or both. First, bromodeoxyuridine immunohistochemistry was used to determine the number of S-phase cells in the subependymal layer eight weeks after naris closure. Proliferation was reduced within and just caudal to the odor-deprived bulb compared to the open-side (control) bulb. Second, counts of pyknotic nuclei four weeks after naris closure were used to document a higher rate of cell death on the deprived side. Third, 3H-thymidine autoradiography was used to assess differences in granule cell survival on the two sides. Granule cell precursors were labeled by a single injection of 3H-thymidine eight weeks after naris closure, and the number of surviving labeled granule cells assessed four and 16 weeks later. Granule cell survival was significantly reduced within the odor-deprived bulbs. These data indicate that the loss of granule cells which follows odor deprivation is caused, at least in part, by reduced neurogenesis and reduced survival of these adult-generated neurons. PMID- 7838374 TI - Induction of immune system mediators in the hippocampal formation in Alzheimer's and Parkinson's diseases: selective effects on specific interleukins and interleukin receptors. AB - The present study determined whether molecules normally associated with immune signalling processes, specifically the lymphokines interleukin-1 beta, -2, -3 and -6, can be detected in the human hippocampal formation, and whether their levels are altered in neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Interleukin-1 beta, -2, -3 and -6 were measured in post mortem tissues from 14 control neurologically normal subjects, 24 patients with Alzheimer's disease and 17 patients with Parkinson's disease. In order to assess the extent of the cholinergic deficit in the Alzheimer's disease brains, choline acetyltransferase activity in the hippocampal formation was first determined. In the Alzheimer's disease tissues, choline acetyltransferase activity was significantly reduced (by 58%) compared to the control hippocampi, whereas that in the Parkinson's disease hippocampi was not significantly different from control. Using radioimmunoassays with antisera specific for the respective interleukin, marked increases in the content of immunoreactive interleukin-1 beta (99%), interleukin-2 (129%) and interleukin-3 (64%) could be detected in the Alzheimer's, but not the Parkinson's disease hippocampi. Interleukin-6 levels were not significantly different in either group, compared to the control hippocampi. Since striking elevations in various interleukins were detected in the Alzheimer's disease hippocampi, the possibility that concomitant alterations in interleukin receptor sites also occurred was investigated. Using radioligand binding to hippocampal membranes, low levels of interleukin binding were measured in the control hippocampi. In the Alzheimer's tissues, significant elevations in [125I]interleukin-1 beta (by 65%) and [125I]interleukin-2 (by 69%) binding were noted. In contrast, [125I]interleukin-3 binding was not different in the Alzheimer's disease compared to the control tissues. In the hippocampal formation of Parkinson's disease brains, only [125I]interleukin-2 binding was significantly increased (by 80%). In summary, the present results indicate that there is pronounced activation of immune system function, particularly specific immune mediators such as the interleukins, in the hippocampal formation in Alzheimer's disease, and further suggest that stimulation of immune function may be an integral component of the pathological changes that occur in this disease. PMID- 7838375 TI - Somatostatin messenger RNA-containing neurons in Alzheimer's disease: an in situ hybridization study in hippocampus, parahippocampal cortex and frontal cortex. AB - The level of expression of somatostatin messenger RNA-containing neurons in human brain was visualized and quantified by in situ hybridization with a 35S-labelled oligonucleotide complementary to amino acids 96-111 of the preprosomatostatin complementary DNA sequence. The analysis was carried out in the frontal and parahippocampal cortices and hippocampus of six age- and post mortem delay matched Alzheimer's disease and control brains. By northern blot analysis, in frontal cortex samples, 18S rRNA degradation was identical in control and Alzheimer brains and somatostatin messenger RNAs migrated as a single band of 1 kb. By in situ hybridization, specificity was demonstrated by abolition of the signal using either an excess of unlabelled antisense probe or using a labelled sense probe. Somatostatin messenger RNA-containing neurons displayed a similar regional and subregional distribution in control subjects and patients with Alzheimer's disease, being more abundant in the frontal cortex, followed by the hippocampus and the parahippocampal cortex. An overall reduction of labelled cell density was observed in patients with Alzheimer's disease (frontal cortex gray matter:--41%; white matter:--66%; hippocampus:--44%; parahippocampal cortex white matter:--40%). Due to a great variation between brains, this decrease only reached significance in the parahippocampal cortex (-59%, P < 0.05). A significantly lower level of expression of somatostatin messenger RNA per somatostatinergic cell was observed in the hippocampus of Alzheimer's disease patients (-47%, P < 0.05), but not in frontal cortex gray (-17%) and white (-36%) matter and parahippocampal cortex gray (-42%) and white (-29%) matter. These data are in accordance with the distribution of somatostatin cells as visualized by immunohistochemistry in human brain. They indicate that the ability of cortical cells to express somatostatin messenger RNA is partially preserved in Alzheimer disease brains and that the decrease in the amount of somatostatin messenger RNA per cell is restricted to the hippocampal formation. PMID- 7838376 TI - Dephosphorylation of Alzheimer's disease abnormally phosphorylated tau by protein phosphatase-2A. AB - Microtubule-associated protein tau is abnormally hyperphosphorylated in the brain of patients with Alzheimer's disease, and is the major protein subunit of paired helical filaments. There is also a significant pool of non-paired helical filament abnormally phosphorylated tau in Alzheimer's disease brain. In the present study, the site-specific dephosphorylation of this Alzheimer's disease abnormally phosphorylated tau by protein phosphatase-2A was studied and compared with that by protein phosphatase-2B. The dephosphorylation was detected by its interaction with several phosphorylation-dependent antibodies to various abnormal phosphorylation sites. Protein phosphatase-2A was able to dephosphorylate the abnormally phosphorylated tau at Ser-46, Ser-199, Ser-202, Ser-396 and Ser-404, but not at Ser-235 (the amino acids are numbered according to the largest isoform of human tau, tau441). Two major types of protein phosphatase-2A, protein phosphatase-2A1 and -2A2, dephosphorylated the abnormally phosphorylated tau at approximately the same rate. After the abnormally phosphorylated tau was dephosphorylated by protein phosphatase-2A, its relative mobility on sodium dodecyl sulfate-polyacrylamide gel electrophoresis increased. The dephosphorylation of the abnormal tau by protein phosphatase-2A1 and -2A2 was markedly stimulated by Mn2+. These results suggest that tau dephosphorylation is catalysed by protein phosphatase-2A in addition to protein phosphatase-2B. A deficiency of either protein phosphatase-2A or -2B, or both, may be involved in abnormal phosphorylation of tau in Alzheimer's disease. PMID- 7838377 TI - Correlation between reactive sprouting and microtubule protein expression in epileptic hippocampus. AB - Temporal lobe epilepsy in both human and rats is associated with a collateral sprouting of hippocampal mossy fibers (i.e. the axons of granule cells). This sprouting generates abnormal recurrent synaptic connections. We previously showed that in the experimental model of temporal lobe epilepsy induced by an intra amygdaloid injection of kainate, the synaptic remodeling of mossy fibers was preceded by a transient increased expression of alpha-tubulin in granule cells. This suggests that an overproduction of tubulin polymers may be responsible, at least in part, for the elongation and side-branching of mossy fibers, which occurs 12-30 days after seizures. In the present study we show that this increased expression of alpha-tubulin is accompanied by an increased expression of the microtubule-associated proteins MAP2 and TAU. Thus, using in situ hybridization, we observe that MAP2 messenger RNA levels increased in granule cell bodies and dendrites from day 3 to two weeks after kainate treatment. This rise is associated with a concomitant transient increase of MAP2 immunoreactivity in the granule cell dendrites. TAU messenger RNA also increases in granule cell bodies, while TAU immunoreactivity increases in their axons, the mossy fibers. The time course of these changes parallels that of alpha-tubulin, and develops before and during the axonal mossy fiber sprouting. Since MAP2 and TAU are important for the initiation, elongation and stabilization of neurites, we suggest that the overexpression of these proteins via the formation of microtubules may play an important role in the sprouting of mossy fibers in epileptic rats. PMID- 7838378 TI - Regenerating sciatic nerve axons contain the adult rather than the embryonic pattern of microtubule associated proteins. AB - Microtubule associated proteins play a central role in the control of axon growth. We have used immunohistochemical techniques to establish which microtubule-associated proteins are present in the rat hindlimb spinal cord, dorsal root ganglia and peripheral nerves during axonal growth during embryogenesis, in adulthood, and during regeneration of crushed sciatic nerves. During embryogenesis microtubule-associated protein-1b and tau are present in all neurons and axons, microtubule-associated protein-2 is present in neurons but not in axons, and there is no microtubule-associated protein-1a. In adults, microtubule-associated protein-1a and microtubule-associated protein-1b are present in all sciatic nerve axons and in motor and dorsal root ganglion neurons. Tau, in its adult form, is present in many fine probably sensory axons, but not in most larger axons, and in motor and sensory neurons. Microtubule-associated protein-2 is present only in neurons. During regeneration the pattern of microtubule-associated protein expression retains the adult pattern. All regenerating axons contain microtubule-associated protein-1a and microtubule associated protein-1b, none contain microtubule-associated protein-2, and a subset of fine axons contain tau. There is no detectable change in microtubule associated protein expression by motoneurons. While axons are clearly able to regenerate without either microtubule-associated protein-2 or tau, tau containing axons appear to regenerate faster than those which lack it. It is possible that the failure of neurons to recapitulate the embryonic pattern of microtubule associated protein expression during regeneration could be a reason why regenerative axon growth is slower and less vigorous than axon growth in embryos. PMID- 7838379 TI - Long lasting functional alterations in the rat dentate gyrus following entorhinal cortex lesion: a current source density analysis. AB - The functional consequences of lesions of the entorhinal cortex of rats were studied by analysing laminar distributions of stimulus induced field potentials in the dentate gyrus with a subsequent current source density analysis. Stimulation of the inner molecular layer elicits large excitatory postsynaptic potentials with small if any population spikes in the stratum granulare both in normal and lesioned animals. In lesioned animals middle molecular layer stimulation causes large excitatory sinks in the stratum moleculare without generation of population spikes in stratum granulare, while the same stimulation in slices from normal animals readily induces population spikes. The current source density analysis revealed a shift of current sinks induced by stimulation of either the inner or the middle molecular layer to common site. The N-methyl-D aspartate receptor contribution to the current sink and source was found to be more prominent after middle molecular layer stimulation in comparison to inner molecular layers stimulation in the control group, while such a distinction could not be made in the lesioned group. Activation of mossy fibers did not reveal any significant differences between normal and lesioned animals. Following entorhinal cortex lesion sprouting of remaining afferents (e.g. commissural fibers) into the termination zones of the degenerated perforant path has been reported suggesting a compensatory replacement of excitatory synaptic input. However, persistent transneuronal dendritic alterations of neurons in the dentate gyrus have been observed which might result in altered dentate gyrus function. Our findings suggest that the reorganization process after entorhinal cortex lesion does not lead to full functional compensation of the lost perforant path input, resulting in an altered balance between excitation and inhibition. PMID- 7838380 TI - Deep prepiriform cortex modulates kainate-induced hippocampal injury. AB - As seizure propagation within limbic structures is mediated in part by a small area of deep prepiriform cortex (area tempestas), we investigated the role of area tempestas in modulating hippocampal injury induced by systemic kainate administration. Injury was quantitated by counting the numbers of neurons that stained for the 72,000 mol. wt heat shock protein and with acid-fuchsin dye. Status epilepticus induced these markers of neuronal injury in the CA1 and CA3a regions of the hippocampus, thalamus, piriform cortex and the amygdaloid complex. Microinjection of 2-amino-7-phosphonoheptanoic acid, a competitive antagonist of the N-methyl-D-aspartate subclass of the glutamate receptor, into area tempestas prior to systemic administration of kainate attenuated both heat shock protein induction and acid-fuchsin labeling in CA1 and CA3a pyramidal neurons without reducing the duration of electrographic seizures. Injections of bicuculline, a GABA antagonist, into area tempestas produced hippocampal damage when given with subcytotoxic doses of intravenous kainate. Thus, area tempestas may be a uniquely sensitive anatomical structure involved not just in seizure propagation but also in modulating the extent and pattern of damage induced in hippocampal neurons as a result of prolonged, systemically induced seizures. These effects are due in part to excitatory and inhibitory projections to neurons in area tempestas. PMID- 7838381 TI - Role of excitatory amino acid and GABAB receptors in the generation of epileptiform activity in disinhibited hippocampal slice cultures. AB - Selective excitatory amino acid- and GABAB-receptor antagonists were used to examine the role these receptors play in epileptiform burst discharge elicited by blocking GABAA receptor-mediated inhibition in hippocampal slice cultures of the rat. Application of bicuculline caused a single ictal burst followed by interictal bursting. The N-methyl-D-aspartate receptor antagonist, D-2-amino-5 phosphonovalerate, reduced the depolarizing envelope underlying interictal discharge, and accentuated the appearance of concomitant slow oscillatory potentials, which occurred synchronously in all CA3 cells. The non-N-methyl-D aspartate receptor antagonists, 6-nitro-7sulphamoyl-benzo(F) quinoxaline and 6 cyano-7-nitro-quinoxaline-2,3-dione, blocked interictal bursting at high concentrations, and low concentrations of 6-cyano-7-nitro-quinoxaline-2,3-dione selectively eliminated the slow oscillations in an all-or-none manner, leaving the depolarizing envelope. No effects of either metabotropic glutamate receptor antagonists or of dihydropyridine Ca2+ channel agonists or antagonists on evoked interictal discharge were observed. 6-Cyano-7-nitro-quinoxaline-2,3-dione resistant interictal-like discharge could be obtained in the presence of bicuculline when the external Mg2+ concentration was reduced from 1.5-0.5 mM. The GABAB receptor antagonist CGP 35348 prolonged individual evoked interictal bursts, and caused the appearance of spontaneous ictal-like discharges. The implications of these results are discussed with regard to the mechanisms of epileptogenesis and to potential therapeutic intervention. PMID- 7838382 TI - Modulation by extracellular pH of the activity of GABAA receptors on rat cerebellum granule cells. AB - The Cl- currents activated by GABA via GABAA receptors in rat cerebellum granule cells in culture were studied by whole-cell patch-clamp. These currents were measured at various extracellular pH. The currents activated by 100 microM GABA, both the peak and the steady-state component, increase at acidic pH's and decrease at basic pH's. The transition point being at around 7.7. Interestingly, passing from pH 7.4 to 6.4 the GABA dose-response curve indicates that the increases in the peak current are related to an augmented maximal current. The increases in the steady-state component are mainly due to a higher affinity of the receptors for the neurotransmitter and disappear at saturating [GABA]. The study of the I-V curves for the GABA activated peak Cl- currents at pH 6.4, 7.4 and 8.4 reveals linearity in the latter instance. However, an outward rectification is present at the two more acidic pH's. This fact suggests that the protonation of basic amino acids at the acid pH does involve rectification of Cl- channel conductance. Overall, the data indicate that slight changes in in situ extracellular pH may have profound influences on GABAA receptor function. PMID- 7838383 TI - Glutamate-synthesizing enzymes in GABAergic neurons of the neocortex: a double immunofluorescence study in the rat. AB - L-Glutamate is the immediate precursor of the inhibitory transmitter GABA, and considered to be supplied from alpha-ketoglutarate through a transamination reaction or from glutamine through a glutaminase reaction. In the present study, the localization of aspartate aminotransferase and glutaminase in GABAergic neurons was investigated in the rat neocortex by a double immunofluorescence method. Immunoreactivities for both soluble and mitochondrial aspartate aminotransferases were detected in more than 90% of GABA-positive neurons, whereas glutaminase immunoreactivity was not found in GABA-positive neurons. All neocortical neurons with soluble aspartate aminotransferase immunoreactivity were immunopositive for GABA, but none for glutaminase. Neurons with mitochondrial aspartate aminotransferase immunoreactivity showed either glutaminase or GABA immunoreactivity. Under confocal laser scan microscopy, immunoreactivity for soluble aspartate aminotransferase was observed in many axons and axon terminals showing immunoreactivity for glutamic acid decarboxylase, whereas immunoreactivity for mitochondrial aspartate aminotransferase was seen in only a few axons displaying immunoreactivity for glutamic acid decarboxylase. The present results indicate that soluble aspartate aminotransferase is selectively localized to cell bodies and axon terminals of GABAergic non-pyramidal neurons in the cerebral neocortex. This suggests that glutamate is supplied from alpha ketoglutarate via transamination and works as the immediate precursor for GABA in axon terminals of GABAergic neurons. The absence of glutaminase immunoreactivity in GABAergic neurons indicates that glutamine is a "metabolically remote" precursor for GABA. Mitochondrial aspartate aminotransferase was located in perikarya, rather than in axon terminals of GABAergic neurons, suggesting a transmitter-irrelevant role of this enzyme in neurons. PMID- 7838384 TI - Behavioural sensitization in 6-hydroxydopamine lesioned rats involves the dopamine signal transduction: changes in DARPP-32 phosphorylation. AB - "Priming" is a phenomenon of behavioural sensitization observed in unilaterally 6 hydroxydopamine lesioned rats following exposure to a dopamine agonist. After priming, a single dose of the D1 agonist SKF 38393 (3 mg/kg) produces contralateral turning, while the same dose is inactive in drug-naive, lesioned animals. The molecular mechanisms of "priming" were investigated here by studying the phosphorylation of dopamine and adenosine 3'-5' monophosphate regulated phosphoprotein (DARPP-32), a dopamine- and cyclic AMP-regulated phosphoprotein functionally linked to D1 receptors in striatum. Dephospho-form of DARPP-32 were measured by a back-phosphorylation assay. All assays were performed in striata from both lesioned and unlesioned sides. A significant decrease of dephospho DARPP-32 (27%) was observed in the denervated striatum of primed rats, indicating an increased phosphorylation in vivo of DARPP-32 in response to the D1 agonist. The levels of DARPP-32 protein, as measured by quantitative immunoblotting, remained unchanged in all experimental groups. This study shows that priming is expressed as an increased transduction of the D1 receptor message. PMID- 7838385 TI - Peripheral nerve-dopamine neuron co-grafts in MPTP-treated monkeys: augmentation of tyrosine hydroxylase-positive fiber staining and dopamine content in host systems. AB - Previous studies of rats in our laboratory indicate that a molecule or molecules released by Schwann cells exert survival and growth-promoting effects on mesencephalic dopamine neurons. In the present study, we have begun to investigate the potential for Schwann cell augmentation of host dopamine fiber systems and embryonic dopamine neuron grafts in non-human primates. Ten adult male St Kitts African Green monkeys treated with the dopaminergic neurotoxin 1 methyl 4-phenyl 1,2,3,6-tetrahydropyridine one year previously, but behaviorally asymptomatic, served as hosts for implant studies. A segment of young adult monkey saphenous nerve was collected to serve as an implanted tissue source of Schwann cell-derived growth factors. Nerve was enclosed in a hollow semi permeable polymer fiber for implantation into the lateral ventricle, with embryonic ventral mesencephalic tissue co-grafts containing developing dopamine neurons aimed at nearby locations in the caudate nucleus. Control implants consisted of an empty polymer fiber co-grafted with embryonic ventral mesencephalon. Our morphological observations indicate that while no clear augmentation of the morphology of grafted dopamine neurons attributable to co grafted nerve was observed, this lack of influence may be related to the spatial separation of the co-grafted tissues. In contrast, some monkeys with nerve segments in the lateral ventricle exhibited increased tyrosine hydroxylase positive fiber staining in the immediately adjacent lateral septal area and the ventricular wall of the caudate nucleus. This enhancement was not associated with empty polymer implants. Levels of dopamine and its metabolite homovanillic acid derived from tissue punches in the caudate nucleus and septal area support the view that monkeys exhibiting morphological enhancement of host dopamine systems also show biochemical increases in dopamine levels and changes in the direction of normalization of the homovanillic acid/dopamine ratio. Biochemical values from a single septal area tissue punch in one animal were an exception to this rule. This study suggests that while the utility of peripheral nerve as a source of dopamine graft augmentation in non-human primates remains to be demonstrated, grafted nerve has a stimulatory effect on host brain dopamine systems in adult, dopamine-depleted monkeys, and that this morphological effect can be dissociated from previously hypothesized injury-induced regeneration. PMID- 7838386 TI - Temporal and spatial increase of astroglial basic fibroblast growth factor synthesis after 6-hydroxydopamine-induced degeneration of the nigrostriatal dopamine neurons. AB - The present study investigates the temporal and spatial changes of the cellular expression of basic fibroblast growth factor messenger RNA and immunoreactivity after a 6-hydroxydopamine-induced lesion in the nigrostriatal dopamine system. In situ hybridization revealed a sustained (from 4 h to two weeks) and strong (300 400% of control, at the peak intervals) increase of basic fibroblast growth factor messenger RNA in the pars compacta of the substantia nigra and the ventral tegmental area ipsilateral to the lesion. A short-lasting increase of basic fibroblast growth factor messenger RNA was observed in he ipsilateral pars reticulata of the substantia nigra (from 4-24 h, 300% of control) and neostriatum (24 h, 180% of control) as well as in the ipsilateral and contralateral hippocampus and neocortex (by 4 h, 200% of control). Brightfield microscopy showed an increased number of putative glial cells expressing the basic fibroblast growth factor messenger RNA signal. Basic fibroblast growth factor immunohistochemistry revealed on control brains the protein in the nuclei of glial cells throughout the forebrain and the midbrain and in the nuclei of neurons of the layer II of the retrosplenial granular cortex, the CA2 region of the hippocampus and the fasciola cinereum as well as in the nuclei of ependymal cells. The injection of 6-hydroxydopamine increased basic fibroblast growth factor immunoreactivity in the nuclei of astrocytes only within the ipsilateral substantia nigra and ventral tegmental area. By 2 h after the drug injection, the density of glial basic fibroblast growth factor-immunoreactive profiles was increased in the pars compacta of the substantia nigra and the ventral tegmental area. The density, size and intensity of the astroglial basic fibroblast growth factor immunoreactive nuclei were increased in the entire substantia nigra and the ventral tegmental area at 72 h, and peaked one week after the 6 hydroxydopamine injection. The saline injection promoted a time-dependent increase in the density of the glial basic fibroblast growth factor immunoreactivity but only in the ipsilateral pars compacta of the substantia nigra. In conclusion, the dopamine cell degeneration may give rise to extracellular signals activating the surrounding astroglia, leading to a sustained increased synthesis of astroglial basic fibroblast growth factor, which may exert neuroprotective action and increase repair on the nigrostriatal dopamine system. PMID- 7838387 TI - Distribution of basic fibroblast growth factor in the developing rat brain. AB - Previous studies in vitro indicate that basic fibroblast growth factor participates in the survival, proliferation and differentiation of immature neural cells, predicting that it may have the same types of roles in vivo. In order to evaluate a possible role of basic fibroblast growth factor in neural development, we have examined its localization in the rodent brain at critical stages of development. We characterized basic fibroblast growth factor immunoreactivity at embryonic days 13 and 18, and postnatal days 1, 4, 6, 10, 20 and 90. Our results showed that basic fibroblast growth factor was transiently expressed by different cellular phenotypes throughout development. At embryonic day 13, basic fibroblast growth factor immunoreactivity was sparsely distributed in various cell phenotypes. At embryonic day 18, the primitive cerebral cortex showed basic fibroblast growth factor immunoreactivity within its emerging laminar structure, including the cortical plate and subplate regions. At postnatal day 1, basic fibroblast growth factor immunoreactivity was mostly concentrated in the hippocampal subfields cornu Ammon 1, cornu Ammon 2 and cornu Ammon 3, and neurons of the medical septum and the vertical limb of the diagonal band nuclei. At postnatal days 4-6, astrocyte-like cells showed basic fibroblast growth factor immunoreactivity for the first time during development. At this stage, basic fibroblast growth factor in the hippocampus was mostly shown within subfields cornu Ammon 2 and cornu Ammon 1. In the medical septum, just a few neuronal profiles were weakly stained, and basic fibroblast growth factor positive astrocytes appeared to accumulate around these basic fibroblast growth factor-stained neurons. At postnatal day 20, the adult pattern of basic fibroblast growth factor immunoreactivity was fully established. Astrocytes throughout the brain expressed basic fibroblast growth factor, and neuronal basic fibroblast growth factor was restricted to particular populations such as cingulate cortex and hippocampus. The cornu Ammon 2 subfield was the main neuronal location for basic fibroblast growth factor in the mature hippocampus. Our results showed that the cellular location of basic fibroblast growth factor changes during development, suggesting that basic fibroblast growth factor has multiple and evolving roles during histogenesis and differentiation of the CNS. PMID- 7838388 TI - Single neurons in the ventral tegmental area that project to both the cerebral and cerebellar cortical areas by way of axon collaterals. AB - Recently, we have found that the ventral tegmental area of the rat sends dopaminergic and non-dopaminergic axons, respectively, to the cerebellar cortex and deep cerebellar nuclei [Ikai et al. (1992) Neuroscience 51, 719-728]. In the present study, employing fluorescent retrograde double labeling with Fast Blue and Diamidino Yellow, we examined whether individual neurons in the ventral tegmental area of the rat send their axons to both the cerebellum and other brain regions. The neurons projecting to the cerebellar cortex often issued axon collaterals to the cerebral cortical areas, including the prelimbic-anterior cingulate cortices and piriform-entorhinal cortices, but not so frequently to the subcortical regions, including the nucleus accumbens, lateral septum, amygdala, and lateral habenula. On the other hand, the neurons projecting to the deep cerebellar nuclei rarely sent axon collaterals to the cerebral cortical and subcortical regions. PMID- 7838389 TI - Histamine mediates fast synaptic inhibition of rat supraoptic oxytocin neurons via chloride conductance activation. AB - Axons from the histaminergic neurons of the tuberomammillary nucleus project to both the anterior and tuberal portions of the supraoptic nucleus. Histamine is known to activate vasopressin neurons via a histamine receptor subtype 1 and to increase release of vasopressin, but effects on oxytocin neurons have been previously unexplored. Here we investigated the effects of tuberomammillary nucleus electrical stimulation as well as of histamine antagonists on supraoptic nucleus oxytocin and vasopressin neurons in slices of rat hypothalamus. Electrical stimulation evoked short constant latency (approximately 5 ms), fast (4-6 ms onset to peak) inhibitory postsynaptic potentials in oxytocin neurons and, as shown previously, fast excitatory postsynaptic potentials in vasopressin neurons. These synaptic responses followed paired-pulse stimulus frequencies up to 100 Hz and were, thus, probably reflecting monosynaptic connections. Inhibitory postsynaptic potentials were selectively blocked by histamine receptor subtype 2 antagonists (either cimetidine or famotidine) and by picrotoxin but not by histamine receptor subtype 1 antagonists or bicuculline. Similar synaptic responses to tuberomammillary nucleus stimulation were found in 16 of 16 neurons immunocytochemically identified as oxytocinergic and in seven putative oxytocin neurons. Perifusion of the slice with low chloride medium (4.8 mM) reversed stimulus-evoked inhibitory postsynaptic potentials. We conclude that histaminergic neurons monosynaptically contact both oxytocin and vasopressin cells of the supraoptic nucleus and inhibit the former via activation of chloride channels which can be blocked by the histamine receptor subtype 2 antagonists, famotidine and cimetidine. PMID- 7838390 TI - Double orientation tuning in the cat visual cortex units. AB - Orientation tuning of 271 neurons of the cat visual cortex (area 17) was studied with a light bar flashing in the receptive field. Under different conditions, 27 57% of units were found to have double-orientation tuning: they demonstrated the main preferred orientation and an additional preferred orientation. The statistical reliability and reproducibility of additional preferred orientation were shown. The quality of orientation tuning in the second maximum did not differ statistically from the first one. The angle between preferred orientation and additional preferred orientation was either 90 degrees (29% of cases) or an acute one (60.1 +/- 3.1 degrees, 71% of cases). The ratio of discharge frequency in responses to additional preferred orientation and preferred orientation was equal to 0.74 +/- 0.05. Neurons with double-orientation tuning clearly preferred 67 degrees and 157 degrees, while monomodal units preferred 0 degrees and 90 degrees. Probability of the double-tuning increased under bar lengths of near 3 degrees and near 10 degrees and with increase of stimulus/background contrast. At the same time some neurons displayed double-orientation tuning only with relatively low stimulus/background contrast. The proportion of units with double orientation tuning was lowered by about 1.5-times under general Nembutal narcotization as compared with local anesthesia of the animal. In about one-third of units simultaneous stimulation by two flashing lines crossing in the receptive field center under an angle specific for the cell, evoked a response from 1.5 to four times larger than to the preferred orientation.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7838391 TI - Transient cerebral ischemia disrupts performance on a one-trial passive avoidance task in the domestic chick and is associated with neuronal degeneration in the central nervous system. AB - We have examined the effects of transient cerebral ischemia on performance of a one-trial passive avoidance task by chicks. Transient forebrain ischemia was induced by bilateral carotid artery occlusion for a period of 10 min. In one experimental group, ischemia was produced prior to training on the avoidance task whereas in the other group ischemic intervention was not made until 3 h after initial training. Sham-operated groups were matched to each of the experimental groups. All four groups were tested for retention of the avoidance response 24 h post-surgery. The sham-operated birds and those receiving post-training ischemia showed good retention of the avoidance response, whereas in birds which received ischemia prior to training there was significant amnesia. Neuronal damage, determined qualitatively using a silver impregnation method, was observed in several forebrain regions including the hippocampus, hyperstriatal regions, paleostriatum primitivum, ventral archistriatum, and lateral corticoid area. Damage was also observed in the Purkinje cells of the cerebellum. The behavioural and anatomical effects of transient forebrain ischemia have not been previously investigated in an avian species and the finding of significant amnesia for a learning task following ischemia is in good agreement with several behavioural studies in mammals. PMID- 7838392 TI - Alteration of inositol 1,4,5-trisphosphate receptor after six-hour hemispheric ischemia in the gerbil brain. AB - In order to evaluate the influence of cerebral ischemia on the inositol 1,4,5 trisphosphate receptor, the alterations of inositol 1,4,5-trisphosphate receptor binding sites and local cerebral blood flow were examined 6 h after occlusion of the right common carotid artery in the gerbil brain. The autoradiographic method developed in our laboratory enabled us to measure both parameters within the same brain. Animals attaining ischemic scores of more than 5, as assessed 1 h after occlusion, were utilized. The local cerebral blood flow was measured 6 h after occlusion by the [14C]iodoantipyrine method. The inositol 1,4,5-trisphosphate binding sites were evaluated in vitro using [3H]inositol 1,4,5-trisphosphate as a specific ligand. The local cerebral blood flow fell below 15 ml/100 g per min in most of the cerebral regions on the occluded side. In contrast, a significant reduction in inositol 1,4,5-trisphosphate binding sites was noted only in the hippocampus CA1 on the occluded side. Inositol 1,4,5-trisphosphate binding tended to decrease when the values of local cerebral blood flow were below 20 ml/100 g per min in this region. On the other hand, the inositol 1,4,5-trisphosphate receptor immunoreactivity in the brain examined with a monoclonal antibody against inositol 1,4,5-trisphosphate receptor protein did not reveal any differences between the ischemia and sham groups on both sides, suggesting that the inositol 1,4,5-trisphosphate receptors may not undergo significant morphological degradation. These findings indicate that the suppression of inositol 1,4,5-trisphosphate binding in the hippocampus CA1 may be attributable to a regionally specific perturbation of the inositol 1,4,5-trisphosphate metabolism in this region.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7838393 TI - Identification and characterization of rhythmic nociceptive and non-nociceptive spinal dorsal horn neurons in the rat. AB - The properties of rhythmic low-threshold and multireceptive spinal dorsal horn neurons were determined. Multiple neuron recordings were made via a single electrode in the lumbar spinal cord of pentobarbital-anesthetized or decerebrate, unanesthetized, spinalized rats. The background activity of a total of 223 neurons was analysed: 21.0% of 176 fully characterized neurons were low threshold, 73.3% multireceptive and 5.7% nociceptive-specific neurons. Twenty of 100 neurons tested were driven by antidromic stimulation at the upper cervical cord. To identify and evaluate rhythmic harmonic oscillations in the discharges of spinal dorsal horn neurons during background activity and steady-state noxious heat-evoked responses, interspike interval, autocorrelation and autospectral analysis were performed. The background activity of 99 of the 223 neurons (44.4%) of our sample was rhythmic. The distribution of the fundamental spectral frequencies has a bimodal shape, the first band between 0.5 and 2 Hz and the second between 6 and 13 Hz. Low-threshold and multireceptive neurons had a similar incidence of rhythmicity (54.1 and 43.4%, respectively). Only one of 20 neurons with long ascending projections presented rhythmic background activity. Activation of heat-sensitive nociceptors within the cutaneous receptive fields of the neurons had a strong anti-rhythmic effect in nine of 15 (60%) neurons. No change was observed in the pattern of autospectra of non-rhythmic neurons or low threshold neurons during noxious stimulation. Twenty-four of 37 (66.6%) rhythmic neurons retained their rhythmic background discharges during reversible cold block spinalization at the upper thoracic cord. The incidence of neurons with burst-like discharges was highest among multireceptive neurons (98/129, 75.9%) and non-rhythmic neurons (89/124, 71.8%). Thus, rhythmicity exists in sensory neurons of the spinal dorsal horn probably generated within its local neuronal network and partially modulated by supraspinal descending systems. Rhythmicity is depressed by activity in primary afferent nociceptors. The role of rhythmicity for information transfer and neuronal plasticity is discussed. PMID- 7838394 TI - Percutaneous burrhole trephination of the skull: a study of 519 cases. AB - We want to report on our experiences with the percutaneous trephination using a 2.35 mm round dental drill with serrated saws around it, a "Rosenbohrer". It is a methodically similar activity as described by J. Zentner [11]. From 1981 to 1992 519 patients were treated and 546 trephinations were performed. At the beginning this treatment was only used in connection with intracerebral bleedings and biopsies. In a considerable short time the indication could be extended to the subdural hematoma, tumor cyst, obstructive hydrocephalus as well as to the abscess and the subdural epyema. The rate of infection was 1.28% and the risk of bleeding 0.36%. In our opinion the advantages of this small electrical trephination are the easy handling, the universal use and mobility and the avoidable risk of anesthesia as well as the sterilisation at the same time and the stopping of blood, caused by the contact surface friction. PMID- 7838395 TI - Epileptic seizures in intracerebral hemorrhage: a clinical and prognostic study of 55 cases. AB - Fifty-five cases of epileptic siezures associated with spontaneous intracerebral hemorrhage are reported. Seizures appeared as the first symptom in 23 patients, early (within two weeks after HI) in 18 and late (later than 2 weeks after HI) in 14. From the analysis of the observed cases we noticed that: 1) partial seizures were most frequent type (63%). These appeared mainly in cases with lobar hemorrhage above all; 2) development chronic epilepsy occurred frequently in the case of patients affected by late seizures. We compare our data with those reported in literature in order to highlight main factors which affect the onset and development of seizures associated with spontaneous intracerebral haemorrhage. PMID- 7838396 TI - Spondylodiscitis after lumbar disk surgery. AB - The value of perioperative prophylactic use of antibiotics in lumbar disc surgery is investigated, based on a retrospective study of the operative results of 5041 patients. The rate of occurrence of postoperative spondylodiscitis was significantly higher during the period in which no perioperative prophylaxis was carried out, than it was during the period, in which perioperative prophylaxis was routine. Thus the perioperative prophylactic use of antibiotics seems highly recommendable. PMID- 7838397 TI - Primary intracranial arachnoid cyst in the elderly. AB - Sixteen cases of symptomatic arachnoid cyst in elderly patients (> 65 years of age) including of our own case are considered and their clinical and therapeutic features compared with those of the larger series comprising younger patients. From this study, no clinical differences emerged between arachnoid cysts in elderly patients and those of their younger counterparts. Surgical treatment was confirmed as being necessary for a good outcome in this age group when the cysts became symptomatic. PMID- 7838398 TI - Pituitary abscesses. Report of three cases. AB - Three cases of pituitary abscess are presented. In spite of improvements in radiological evaluation, preoperative diagnosis of pituitary abscess is quite difficult and definite preoperative diagnosis is rare in the literature. In our three cases, diagnosis was made postoperatively. Pituitary abscesses are associated with high mortality and morbidity. When first suspected, prompt antibiotic therapy should be considered. Early operative drainage seems to be an important factor in decreasing this high mortality and morbidity. PMID- 7838399 TI - Cerebellar medulloblastomas in adults. AB - Between 1981 and 1991, 11 adults over 16 years of age were treated for medulloblastoma at the authors' institutions. These patients were studied retrospectively. The patients were managed uniformly, and the treatment included extensive surgical resections and radiation therapy. Chemotherapy was used on only three patients with recurrence. Probable prognostic factors, including tumor location, extent of surgical resection, dose and extent of radiation therapy, and histological characteristics of the tumor such as neuronal or glial differentiation and desmoplasia were investigated. The classical form of medulloblastoma was present in seven cases while the desmoblastic subtype was found in four cases. All patients with the desmoplastic form had the tumor in cerebellar hemisphere. Gross total removal of the tumor was achieved in seven patients and subtotal excision in four patients. There was no surgical mortality in our series. The extent of surgical resection and location of the tumor had an important effect on longterm survival. The extent and dose of radiation therapy had a major effect on recurrence-free survival. Survival rates were best for patients receiving high-dose irradiation to the entire neuroaxis. Other factors such as age and sex had no major effect on prognosis. PMID- 7838401 TI - Penetration injury of the pyramis caused by a kick from a racehorse. AB - A 56-year-old man presented with an unusual cranial penetration injury due to a horse's hoof. The CT number of the hoof was 269, and thus clearly not that of a wooden fragment or bone. An emergency operation was performed to remove the foreign body. The operation went well, and no infection developed. Eight months later he could walk unaided and had only mild disorientation. PMID- 7838400 TI - Association of malignant glioma with the human leukocyte antigen, HLA-A24(9). AB - Many immune responses are controlled by genes of the major histocompatibility complex (MHC). In humans these include the loci encoding the HLA-A, -B, -C, -DR, DQ, and -DP antigens, and many diseases have been linked with these. However, little information is available about any connection between malignant tumors and HLA. In this study the possible association of HLA-A, -B, -C and -DR specificities with susceptibilities to malignant glioma was investigated in 42 patients with malignant glioma and 42 controls with non-glial intracranial tumors using the Terasaki-NIH standard method. The data were also compared with those of the 11th International HLA Workshop. The result showed that a high frequency of HLA-24(9) was observed in patients with intracranial malignant gliomas, which was not common in other, non-glial patient groups. In animals the MHC acts in defense against virally induced tumors, but until now there has been no evidence that they do so in human gliomas. Our discovery of its association with an HLA antigen is important for understanding the immunogenetic basis of susceptibility to glioma. PMID- 7838402 TI - Footballs and the principle of intracranial compliance. AB - An easy to illustrate relationship between intracranial volume and intracranial pressure is proposed: Between the bubble and the leather of a slitted football an usual epidural pressure probe is introduced. By successively inflating the ball with a pump, the exponential increment of pressure can be demonstrated. PMID- 7838403 TI - Intracisternal schwannoma of the spinal accessory nerve presenting as a normal pressure hydrocephalus syndrome. Case report and review of the literature. AB - Schwannomas of the spinal accessory nerve are rare lesions. They can be characterized by their locations as either intrajugular or intracisternal schwannomas, most of them being intrajugular. Only five cases arising in the cisterna magna are reported in literature. Clinical symptoms generally consist of 11th cranial nerve palsy associated with cerebellar signs and myelopathy. An additional case, studied by MRI, is described. The patient showed a mild cerebellar syndrome and normal pressure hydrocephalus symptoms. He was operated on and the mass completely removed with good postoperative results. The role of MRI for diagnosis of lower cranial nerve schwannomas is stressed, even though does not detect the exact nerve of origin. Total removal of these lesions is recommended, since their benign nature and unavoidable recurrence in case of partial excision. PMID- 7838404 TI - Arachnoid cyst with traumatic intracystic hemorrhage unassociated with subdural hematoma. AB - Arachnoid cysts of the middle cranial fossa may manifest themselves in several different ways. Most often they remain asymptomatic and are only diagnosed incidentally on computed tomography or at autopsy. When they are symptomatic, headache, nausea, vomiting and seizures are most common in the patients with increased intracranial pressure. Increased intracranial pressure is caused by the ball-valve mechanism of the cyst's membrane which is in communication with the general subarachnoid space or arachnoid cells which contain specialized membranes and enzymes which have secretory activity. A significant number of middle cranial fossa arachnoid cysts are associated with subdural hematoma which may, in turn, be associated with intracystic hemorrhage. We report an unusual case with posttraumatic, isolated intracystic hemorrhage of the arachnoid cyst in the sylvian area without subdural hematoma. PMID- 7838405 TI - Metastasis of breast carcinoma to intracranial meningioma. Case report. AB - A case of metastasis from breast carcinoma found within a cerebral meningioma is reported. Histological diagnosis of the cerebral tumor prompted radiological investigation that visualized the asymptomatic malignant systemic tumor and excluded other metastases elsewhere. The pathogenetic aspects of this exceptional occurrence are discussed in the light of the relevant literature. PMID- 7838406 TI - [The estimation of LHRH receptors in the tissue of human leiomyoma, myometrium and endometrium]. AB - Uterine leiomyoma is the most common female benign pelvic tumor, affecting 20-25% of women during their reproductive years. There is strong clinical evidence that these tumors are estrogen-dependent for their growth, as also supported by their clear regression after the menopause. Although large clinical trials have not yet been reported, according to the estrogen dependency of uterine fibroids, LHRH agonists have been shown to be effective in the treatment of these conditions because they produce a condition of temporary hypoestrogenism secondary to the specific hypogonadotrophinism. This study was designed to evaluate if specific binding sites for LHRH are present in human uterine leiomyomata, myometrium and endometrial tissue. These tissues were taken from the fresh operative specimens of 14 patients who had undergone total hysterectomy for uterine leiomyomata. The results of this study demonstrate the presence of a LHRH specific binding site in uterine leiomyomata in 26% of cases; this specific binding site is also present both in myometrium and in endometrial tissue in 71% of cases. Moreover our study shows, for the first time, the high specificity of binding between LHRH agonist (goserelin) and natural LHRH receptor. In accordance with our results, a direct effect of LHRH agonists on fibroid tissue can be stressed. PMID- 7838407 TI - [Diagnostic methods compared in neoplastic pathology of the endometrium]. AB - Preoperative staging is fundamentally important in endometrial carcinoma. The presence of lymph node metastasis and the risk of tumour recidivation are correlated to the degree of myometrial invasion by the tumour. The preoperative diagnosis of the absence of myometrial invasion may render pelvic lymphadenectomy superfluous. A group of 24 patients suffering from endometrial carcinoma underwent transvaginal ultrasonography and nuclear magnetic resonance prior to surgery in order to evaluate possible myometrial invasion. The study was integrated by computerised tomography (CT) to obtain a clearer image of the retroperitoneum. The authors aim to ascertain the accuracy, sensitivity and specificity of these methods in the preoperative evaluation other degree of myometrial infiltration. PMID- 7838408 TI - [Ovarian neoplasms and tumor markers]. AB - This is an experience about the utility of CA125 in diagnosis, staging, prognosis, and therapeutic response of ovarian cancer. The patients were 21 (the ages range was 38-66). They had an epithelial cancer (10 serous, 3 mucinous, 2 endometrioid, 6 non specific). The quantitative test of CA125 was performed with purified monoclonal antibody OC125 pre and post antineoplastic treatment. The reduction of CA125 was in connection with the neoplastic regression. Perservering or increasing values were related to neoplastic stasis or to non-responsive neoplasia, respectively. Even if the method we used was specific its sensibility is lower in patients with smallest residue disease. PMID- 7838409 TI - [Combined surgical and radiotherapy treatment in endometrial cancer]. AB - Early stage endometrial carcinoma is usually treated by surgery and radiotherapy if there is a substantial risk of recurrence. The aim of this study was to evaluate early and late toxicity, to determine the sites of recurrence and the prognostic factors which were statistically correlated with survival in patients who were treated with surgery plus external beam radiotherapy. MATERIALS AND METHODS. We have carried out a retrospective analysis of the records of 87 patients treated with hysterectomy plus external beam pelvic radiotherapy (50 Gy/28 Fractions), at the Radiotherapy Division of the CRO Aviano PN Italy, between 1985 and 1990. The median length of follow-up was 32.42 months. RESULTS. The treatment was well tolerated. The median time to recurrence was 6.56 months. There were 4.7% local, 5.8% distant and 3.5% local plus distant recurrences. As of May 1993 83.2% of the patients were still alive. All deaths occurred within two years from the beginning of treatment. The prognostic factors which were significantly correlated with survival were the stage of the disease (p = 0.0479), depth of myometrial invasion (p = 0.0429), age greater than 64 years (p = 0.0357) and performance status < = 80 at diagnosis (p = 0.0002). CONCLUSIONS. Our study confirms that post operative external beam pelvic RT is well tolerated and effective in achieving a good locoregional control. All the factors investigated were prognostic for survival, except histological grade, lymph node involvement and RT dose. PMID- 7838410 TI - [The efficacy of the hysteroscopic treatment of menorrhagia associated with uterine fibromyomas]. AB - Objective of our study was to determine the effectiveness of hysteroscopic surgery in the treatment of menorrhagia associated with uterine myomas. 25 women with clinical and ultrasonographic diagnosis of intramural or submucous myomas were treated for menorrhagia by hysteroscopic surgery: 9 by resection and 16 by resection and endometrial ablation. In both groups there was a significant decrease of dysmenorrhea. The mean number of pads used during the heaviest day of menses decreased significantly from 19.5 to 7.4 in women undergoing resection only, and from 20.8 to 2.9 in women treated by resection and endometrial ablation. 2 women of 9 became amenorrheic and no one underwent hysterectomy. 12 of 16 became amenorrheic and 2 underwent hysterectomy. Our study show that menorrhagia can be treated by hysteroscopic surgery of uterine myomas in some selected women. PMID- 7838411 TI - [Echographic monitoring of the endometrium with a transvaginal probe in the menopause. A clinical study of 185 women in the menopause]. AB - The aim of our study was to verify the efficacy of transvaginal ultrasound scanning as an indicator of the endometrial status in healthy menopausal women. One hundred eighty five healthy women in natural menopause were examined by vaginal sonography; the endometrial patterns were analyzed and the influence on it of body weight, menopausal age, and hormonal therapy was considered. The presence of irregular and the endometrial histology were related to the ultrasound findings. 38% of the women assumed estrogen plus progestin replacement treatment since one-two years, for menopausal complaints. 17% of all patients reported irregular bleeding during the last month. The majority of women (90%), regardless of the hormone assumption, presented en endometrial thickness less than 10 mm. 10% of untreated and treated women had an endometrial thickness between 10 and 20 mm. Among the subjects with elevated menopausal age is more frequent the imaging of endometrial layer minor than 5 mm in comparison with women in early menopause. 4% of untreated and 10% of treated women without irregular bleeding had an endometrial thickness higher than 10 mm, while 67% of women with irregular bleeding presented an endometrial layer higher than 10 mm. In treated group all women with endometrial thickness greater than 10 mm had amenorrhoea. 86% of patients had endometrial atrophy detected by biopsy; hyperplastic endometrium or endometrial cancer was not demonstrated. In conclusion, vaginal sonography is a simple and reliable method in the study of the endometrial pattern in healthy menopausal women. PMID- 7838412 TI - [The epidemiology of sideropenic anemia and beta-thalassemia in pregnancy in the Chieti area]. AB - OBJECTIVE: To evaluate the prevalence of both sideropenic anemia and B thalassemia in a group of pregnant women in the city of Chieti. EXPERIMENTAL DESIGN: 384 pregnant women who were examined at the obstetric clinic of Chieti University were introduced in the study. Serum levels of ferritin, transferrin, hemoglobin, plus blood cell count and hemoglobin electrophoresis were evaluated in each patient. Those laboratory parameters were also compared in a group of patients who early in gestation were given iron supplementation and a group of patients not supplemented. RESULTS: beta-thalassemia showed a prevalence of 1.3% while sideropenic anemia had a prevalence of 10. The group of patients supplemented with iron early in gestation showed significantly better laboratory parameters than the group not supplemented. CONCLUSIONS: Prevalence of beta thalassemia in Chieti is inferior to the national mean prevalence. Iron supplementation early in pregnancy is associated with improved haematologic parameters in the third trimester. PMID- 7838413 TI - [Injuries in pregnancy]. AB - From a review of the literature on this subject it emerges that around 6-7% of women are injured during the course of pregnancy. Road accidents, falls and domestic accidents are the most frequent events: it is therefore important to provide pregnant women with information to prevent such events which may endanger both maternal and fetal health. PMID- 7838414 TI - [The age for beginning and the frequency for performing the Pap test]. AB - The increase in sexual activity among teenagers has been well documented. One apparent result is the increasing prevalence of cervical cytological abnormalities in this age group over the last 20 years. The adolescent cervix appears to be especially vulnerable to the initiation of carcinogenesis. Consequently, the significance of early age at first coitus is thought to be related to the biologic changes that occur in the cervix during puberty. Large epidemiologic studies have implicated sexuality as the initiator of a sequence of multistage events that destabilize the healthy cervix and culminate in cervical cancer. The median interval between age at first coitus and the development of CIN1 is 9 years, with a progressive 2.5 year increase for each degree of progression from CIN 1 through 3. Unfortunately, the precise mechanism by which that biologic variable, early age at first coitus, predisposes to CIN remains enigmatic. Nevertheless, there is no doubt that the earlier the age at first coitus, the higher the risk factor. Among virgins the incidence of cervical cancer is essentially zero. Among sexually active adolescent girl no cases of invasive carcinoma have been found, but carcinoma in situ had a prevalence rate of 2.6 per 1,000 15-19 years old, whereas cervical dysplasia ranges from 0.8 to 3.5% of screened sexually active teenagers populations. Adolescents who have never been sexually active clearly do not need to be screened for cervical cancer. On the contrary teenagers with the risk factors of sexually transmitted disease or multiple sex partners should be annually screened soon after onset of sexual activity.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7838415 TI - [Familial neoplastic syndromes of the ovary. A family study]. AB - The authors describe a case of Lynch II type familial ovarian cancer syndrome. The family was first observed following the almost contemporary manifestation of ovarian cancer in two sisters. A subsequent analysis of family history among first and second degree relatives showed the presence of ovarian cancer in two maternal aunts, carcinoma of the colon in the father and breast cancer in a sister of the patients. Surgical treatment was selected for ovarian cancer associate with polychemotherapy in both cases. The patients' only living sister underwent preventive ovariectomy at the end of her reproductive programme. The latter is still undergoing follow-up due to the risk of developing neoplasia starting from the peritoneum. The diagnosis of ovarian cancer should result in a careful analysis of the pedigree of the patient suffering from the disease in order to highlight cancer at an early stage in other members of the same family. PMID- 7838416 TI - [Emergency surgical indications in pregnancy (3 rarely encountered cases)]. AB - The authors evaluated 3 cases of acute abdomen during pregnancy: Spontaneous rupture of splenic artery at 30th gestational week (gw). Torsion of left normal Fallopian tube at 33rd gw. Left adnexal torsion at 36th gw. The symptomatology, the etio-pathology and the anatomo-pathological characteristics of every case wore discussed. In women that are usually young, maternal and fetal exitus in the first case and salpingectomy or adnexectomy in the second and third case can be avoided only thanks to timely surgical intervention. PMID- 7838417 TI - [Intramuscular beta-interferon in the treatment of cervical intraepithelial neoplasia (CIN) associated with human papilloma virus (HPV) infection]. AB - In an attempt to find less aggressive and more efficacious tools for the treatment of cervical neoplasia (CIN) associated with genital HPV infection, the authors have examined a therapeutic approach based on the strengthening of natural defences. For this purpose, a group of 10 patients diagnosed with CIN associated with HPV infection received beta-IFN therapy at a dose of 300,000 UI/die i.m. for 7 days, continuing the same dose on alternate days for 2 weeks. At the end of the follow-up results were satisfactory especially if compared with those from a control group of 9 patients. These results appear to indicate beta IFN as the treatment of choice in HPV infections in young women wishing to have children in order to preserve the anatomic and functional integrity of the lower genetical tract. PMID- 7838418 TI - [Cetyltrimethylammonium naproxenate as vaginal lavage in the therapy of vulvovaginal dystrophies in the postmenopause]. AB - A peculiar aspect of the postmenopausal period is atrophy of the lower genital tract, vagina and vulva. This is due to estrogen deficiency and is accompanied by vaginal pH elevation, lower number of lactobacilli and increased incidence of aspecific vulvovaginitis. We tested a new vaginal douche with an antibacterial anti-inflammatory (non antibiotic-nonsteroidal) principle, cetyltrimethylammonium naproxenate 0.223% as an adjunct to classical estrogen topical replacement therapy. We treated 34 menopausal patients (mean age 67 yrs) in a double parallel controlled (15 A only estrogen topical therapy vs 19 B topical estrogen plus cetyltrimethylammonium naproxenate douches uid) study for 30 days. A significant reduction of symptoms was obtained in both groups although a faster reduction has been seen in the group treated with both drugs (= B). In conclusion a better replacement of physiological pH with reappearance of lactobacilli, a selective action on vaginal pathogens, a faster symptom remission and an higher psychophysical welfare can be attributed to the vaginal douche used in adjunct to classical estrogen topical therapy. PMID- 7838419 TI - [The Cytobrush and Ayre spatula in taking cervical-vaginal specimens]. AB - The authors prepare 131 cervicovaginal cytologic specimens with Ayre and Cytobrush spatulas and 94 with only the Ayre spatula and results are tested evaluating the percentage of specimens containing cells from the transformation area. The results of such tests show that the sampling methods with Cytobrush and the Ayre spatulas together is to be preferred to the use of the Ayre spatula alone for the higher presence in these specimen of cells from the transformation area, and consequently with the reduction in the number of tests to be repeated and the increase in the percentage of positive diagnoses and decrease of false negatives. PMID- 7838420 TI - Brain development and multiple molecular species of proteoglycan. AB - The occurrence of multiple proteoglycan species is a characteristic of the brain. The structural features of individually characterized proteoglycans in the brain are first introduced in brief, then some examples are shown that suggest a relationship between multiple proteoglycans and the many distinct cell types and neural circuits in the brain. Typical experiments demonstrated the neuronal activity-dependent expression of neural proteoglycans during the critical developmental period of some functional systems such as the visual and vibrissal barrel systems. In addition, the binding properties of neural proteoglycans to other cell surface molecules are discussed in conjunction with their involvement in cell-cell and cell-substratum interactions. This review also covers other potential functions of proteoglycans not only in the development and maintenance of the brain but also in the pathogenesis of Alzheimer's disease. Proteoglycans are really coming of age in neuroscience. PMID- 7838421 TI - Plasticity of excitatory synaptic transmission in kitten visual cortex depends on voltage-dependent Ca2+ channels but not on NMDA receptors. AB - Long-term potentiation (LTP) of excitatory synaptic transmission occurs in in vitro slices of cat and rat visual cortex. Earlier studies suggested that activation of N-methyl-D-aspartate (NMDA)-selective glutamate receptors is essential for the induction of LTP. However, our studies on kitten visual cortex demonstrate that LTP induction requires the activation of low-threshold Ca2+ channels in postsynaptic cells but not of NMDA receptors. PMID- 7838422 TI - Efficacy of pretransection of peripheral nerve for promoting the survival of cografted chromaffin cells and recovery of host dopaminergic fibers in animal models of Parkinson's disease. AB - Nerve growth factor (NGF) concentration in the distal stump of the transected peripheral nerve has been shown to increase more than 20 times one day after transection. We performed adrenal medullary alone grafts or cografts of adrenal medulla and acutely transected or pretransected (24 h before) sciatic nerve into the striatum of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice, and compared the survival of chromaffin cells and the recovery of the host intrinsic dopaminergic fibers using tyrosine hydroxylase immunocytochemistry and high-performance liquid chromatography. We also performed peripheral nerve alone grafting (acutely transected or pretransected) for comparison. Adrenal medullary chromaffin cells cografted with pretransected sciatic nerve survived better than those in adrenal grafts alone or those cografted with acutely transected sciatic nerve. Host dopaminergic fiber recovery was also most prominent in mice cografted with pretransected peripheral nerve. Animals receiving grafts of peripheral nerve alone showed limited recovery of host dopaminergic fibers and the degree of recovery was lower than that of animals receiving cografts of adrenal medulla with pretransected peripheral nerve. We conclude that pretransected peripheral nerve enhanced the survival of cografted chromaffin cells and this increased survival led to promote the recovery of host-intrinsic dopaminergic fibers. This grafting procedure might be promising in application to patients with Parkinson's disease. PMID- 7838423 TI - A comparison between potencies of external calcium, strontium and barium to support GABAergic synaptic transmission in rat cultured hippocampal neurons. AB - Relative potencies of external Ca2+, Sr2+ and Ba2+ to trigger GABAergic synaptic transmission were evaluated by applying the patch-clamp technique to both presynaptic and postsynaptic hippocampal neurons prepared from neonatal rats. Action potentials were evoked by application of voltage pulses to presynaptic neurons, and GABAergic synaptic currents were recorded in voltage-clamped postsynaptic neurons. No stimuli were delivered during replacement with test solutions and only five pulses were applied to the presynaptic neuron in each test solution. During the five-pulse application, the amplitude of synaptic currents was constant in Ca(2+)-containing solutions, but decreased successively in Ba(2+)- and Sr(2+)-containing solutions without Ca2+. Thus, the amplitude of synaptic currents induced by the first pulse in each ionic condition was used to evaluate the potency of divalent cations. The lowest external concentration required to trigger the transmission was 0.3 mM for Ca2+, 1 mM for Sr2+ and 2 mM for Ba2+, and the concentration required to achieve the same effect as with 2 mM Ca2+ was 6 mM for Sr2+ and 10 mM for Ba2+. These results strongly suggest that Ba2+ as well as Sr2+ can be substituted for Ca2+ in GABAergic synaptic transmission and the order of potency is Ca2+ > Sr2+ > Ba2+. PMID- 7838424 TI - Altered distribution of inhibitory synaptic terminals in reeler cerebellum with special reference to malposition of GABAergic neurons. AB - In immunohistochemical reactions against glutamic acid decarboxylase (GAD), gamma aminobutyric acid (GABA) and glycine (Gly), neurons in the mouse cerebellum showed the following reactivities: (1) the dendrites and cell bodies of the Purkinje cells were only GAD-positive, but their axonal terminals were GABA- and GAD-positive; (2) in both stellate and basket cells, the cell bodies and terminals were GABA- and GAD-positive but Gly-negative; (3) the Golgi cells were GABA-, GAD- and Gly-positive; (4) the granule cells were negative with all antibodies. Based on the populations of each type of neuron, identified by the properties mentioned above, the reeler cerebellum was divided into four regions, namely, (1) the molecular and Purkinje cell layers covering the surface of the cerebellum, where the stellate and basket cells were present as in normal mouse, (2) the granule cell layer, where the heterotopic Purkinje and stellate-type cells (including both stellate and basket cells) were present together with the granule and Golgi cells, (3) the region beneath the granule cell layer where Purkinje cells were present as clusters of several neurons, and in addition, the superficial zone of the central cell mass, where the stellate-type and Golgi cells were present among the Purkinje cells, and (4) the deep zone of the central cell mass, where the Golgi cells were exclusively present among the Purkinje cells. The heterologous synapses originating from inhibitory interneurons were formed on the Purkinje cells closely related to the distribution of these neurons. PMID- 7838425 TI - Age-related changes in levels of the beta-subunit of nerve growth factor in selected regions of the brain: comparison between senescence-accelerated (SAM-P8) and senescence-resistant (SAM-R1) mice. AB - Senescence-accelerated mice (SAM-P8) are characterized as mice in which aging is accelerated and memory disturbances occur. In several regions in the brain of SAM P8 mice at 2, 4 and 8 months of age, we examined the concentrations of the beta subunit of nerve growth factor (beta-NGF) and nine kinds of proteins such as S100 beta and alpha B-crystallin, and compared them with those in senescence-resistant mice (SAM-R1, as controls) at corresponding ages. Levels of beta-NGF in the hippocampus of SAM-R1 and SAM-P8 mice were reduced at 8 months of age. However, the decrease was more conspicuous in SAM-R1 than in SAM-P8, resulting in a significant difference between them (P < 0.01). The concentrations of beta-NGF in the cerebral cortex and cerebellum decreased to some extent with age in the control mice while it remained unchanged in the mutant mice. By contrast, the olfactory bulbs from SAM-R1 and SAM-P8 retained almost constant levels of beta NGF during the first 8 months. However, its level was already higher in SAM-P8 at 2 months than in SAM-R1. Among nine proteins measured here, the acceleration of age-related increase was apparent in the levels of S100 beta and Mn-SOD in the cerebral cortex from SAM-P8. By contrast, the cerebral cortex and cerebellum from SAM-P8 showed tendencies to contain significantly high levels of alpha B crystallin. These results suggest, at least, the presence of fibrous gliosis at quite an early age as well as the acceleration of senescence, in selected regions of the brain of SAM-P8. PMID- 7838426 TI - Somatogenic and lactogenic binding sites in rat brain and liver: quantitative autoradiographic localization. AB - The distribution of somatogenic and lactogenic binding sites in female and male rat brain as well as in liver was studied by quantitative receptor autoradiography using 125I-human growth hormone (125I-hGH) as a ligand. Quantitative measurement of binding sites for 125I-hGH showed differences in the levels of these sites in the female and male brain and liver. Moreover, regional differences in the brain were also observed in each sex. In the female brain high levels of 125I-hGH binding sites were found in the choroid plexus. Intermediate levels were observed in the striatum, the hypothalamus and the hippocampus, whereas low levels of these sites were found in the central gray, the temporal, the piriform and the entorhinal cortices. In the male brain high levels of 125I hGH binding sites were detected in the choroid plexus. Intermediate levels were observed in the parietal cortex, the hypothalamus and the hippocampus, whereas low levels were found in the tegmentum, the temporal cortex and the striatum. Quantification of 125I-hGH binding sites in the liver revealed higher levels in the female than in the male liver. In general, higher levels of binding sites (16%-77%) were observed in the female than in the male tissues. The quantification of rat growth hormone (rGH) by radioimmunoassay was also performed in this study. Varying amounts of rGH immunoreactivity were detected in the different brain regions, with the highest levels of rGH-like material being found in the midbrain and cortex of both sexes. Moreover, higher levels of rGH-like material were observed in the female than in the male brain.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7838427 TI - Adrenergic cell group in rostral ventrolateral medulla of cat: its correlation with central chemoreceptors. AB - We have proposed a hypothesis that secondary neurons mediating central respiratory chemoreception are not restricted to the medullary superficial layer. This idea was further examined in the present physiological and morphological studies. We identified the 'S' area, i.e. the medullary surface area where cold blockade produced apnea, in anesthetized, spontaneously breathing cat. We then evaluated how the apnea was modified by injection of CO2-saturated saline into the vertebral-basilar artery. The CO2 injection caused immediate reappearance of respiratory rhythm, although intensity of inspiratory activity was smaller than in the control. This incomplete recovery suggests that the responsive structure extends deeply below the surface. The extent of the cell group underlying the 'S' area was evaluated by morphological study. Medullary transverse sections including the 'S' area were treated with three distinct antisera against phenylethanolamine N-methyltransferase (PNMT), dopamine-beta-hydroxylase (DBH), and 5-hydroxytryptamine (5-HT). The PNMT-labelled cell group was found to exactly underlie the 'S' area, although the DBH- and the 5-HT-labelled cell groups did not show close topographic correlation with the 'S' area. PNMT cells were located in the region ventral to retrofacial nucleus within 0.5-1.5 mm depth beneath the surface. These results suggest that adrenergic cells in the rostral ventrolateral medulla are important candidates for secondary neurons mediating central respiratory chemoreception. PMID- 7838428 TI - Up-regulation of ERK (MAP kinase) and MEK (MAP kinase kinase) transcription after rat facial nerve transection. AB - Up-regulation of ERK (extracellular signal-regulated kinase or MAP kinase) and MEK (ERK kinase or MAPK kinase) expression after rat facial nerve injury was demonstrated by in situ hybridization histochemistry and immunohistochemistry. These two enzymes play roles in one of the major intracellular signal cascade pathways involving receptor tyrosine kinase common to growth factor receptors, and transcription factors. Significant increases in ERK1 mRNA levels were observed from day 3 after facial nerve transection, with the highest level of expression from 1 to 2 weeks after the operation. This high level of mRNA expression then decreased gradually to the normal level. ERK1-like immunoreactivity showed a similar time course to that of its mRNA expression; however, the decay profile was more prolonged. The up-regulation of MEK, the ERK kinase/MAPK kinase, was also detected by immunohistochemistry. The protein expression profiles were almost equivalent, but the MEK expression was slightly advanced, suggesting that the observed up-regulation of MEK was not due to that of ERK. The receptor tyrosine kinase signal transduction pathway via MEK-ERK located downstream of growth factor receptors seems vital as a regulator of the synthesis of molecules that play important roles in the recovery process following injury or/and regeneration. PMID- 7838429 TI - Effects of chemical deactivation of the interstitial nucleus of Cajal on the vertical vestibulo-collic reflex induced by pitch rotation in alert cats. AB - The basic circuitry for the vestibulo-collic reflex (VCR) is a three-neuron arc, and this reflex requires the temporal and spatial transformation of vestibular signals to activate the appropriate neck muscles. Signals carried by vestibulo collic neurons are insufficient to explain the responses of neck muscles. However, it is still unknown as to where the additional signal conversion is performed in the vertical VCR. We examined the effects of chemical deactivation of the interstitial nucleus of Cajal (INC) on the responses of biventer cervicis EMG induced by pitch rotation in the dark in alert head-fixed cats, and compared the results with the vertical vestibulo-ocular reflex (VOR) and also with the VCR and VOR induced by horizontal rotation. Muscimol infusion into the bilateral INC resulted in phase advance and gain drop in both the vertical VCR and the VOR, although the change was smaller in the VCR. The response phases of the horizontal VCR and VOR were not affected. Muscimol infusion outside the INC did not affect the phase of the vertical VCR or VOR. These results suggest that the INC is partially involved in temporal conversion of vestibular signals in the vertical VCR as well as in the VOR evoked by pitch rotation in alert cats. PMID- 7838430 TI - Barriers to nurse practitioner practice. PMID- 7838431 TI - Guidelines for forming an advanced practice nursing coalition: the Ohio experience. PMID- 7838432 TI - Acceptance of the nurse practitioner role by consumers in a rural community. PMID- 7838433 TI - Mammography. PMID- 7838434 TI - Primary care management of wounds. Cleaning, suturing, and infection control. AB - Nurse practitioners working in primary care are often called upon to assess and repair wounds. This article examines the physiology of wounds, and uses this information to improve assessment skills. Depending on the mechanism of injury, certain wounds may require suturing. The organized examination, appropriate cleaning and debriding, and various suturing techniques are discussed. Special wounds and after-care instructions are covered. Recent changes in infection control technique are examined in terms of their impact on wound care. PMID- 7838435 TI - Combined oral contraceptive pills: a brief review. PMID- 7838436 TI - Update on Hodgkin's disease. AB - Hodgkin's disease is a rare lymphoma usually diagnosed in adults presenting with painless lymphadenopathy. Treatment includes radiation therapy for early stages of the disease and chemotherapy for advanced stages. While the majority with Hodgkin's disease will be cured of their disease, patients must complete a period of therapy with risks of significant acute side effects and serious long-term complications. This article provides an overview of the natural history, diagnosis, and staging of Hodgkin's disease as well as a discussion about treatment modalities and associated complications. PMID- 7838437 TI - Facial cosmetic surgery: a primary care perspective. AB - Primary care providers are often the source of information regarding health matters including elective cosmetic surgery. Practitioners should know about the more common cosmetic surgical procedures to assist their clients in making informed decisions regarding these operations. This article describes facial cosmetic surgical procedures performed to modify the signs of aging, which includes rhytidectomy ("face lift"), blepharoplasty ("eyelid surgery"), chemical peels, and dermabrasion. Issues discussed include preoperative considerations, expected outcomes, length of recovery period, costs, and complications (hemorrhage, necrosis, nerve injury, psychologic sequelae). Because facial cosmetic surgery usually has a positive impact on one's self-esteem, there has been an overall increase in facial cosmetic procedures during the past decade. PMID- 7838438 TI - Guidelines for the prevention and control of tuberculosis in the elderly. AB - Tuberculosis (TB) in the elderly is on the rise although the disease is both preventable and curable. The primary practitioner plays a pivotal role in the diagnosis and prevention of TB. The article provides guidelines designed to bring the practitioner up-to-date on the latest recommendations for the prevention and control of TB in the elderly. An overview of TB, current epidemiology, and information on the uniqueness of this disease as it presents in the elderly client is addressed. An in-depth guideline and explanation for all aspects of care are included for both the institutionalized and community-based elder. Current Centers for Disease Control and Prevention recommendations and research are presented. The role of the primary practitioner in the prevention and control of this disease is included with a quick reference tool. The guidelines also address the current diagnostic testing and recommended treatment for TB. PMID- 7838439 TI - 99Tcm-DMSA SPET: tool or toy? PMID- 7838440 TI - Guidance notes for organizing the British Nuclear Medicine Society (BNMS) Autumn Meeting. PMID- 7838441 TI - NHS research and development: a research strategy for nuclear medicine. AB - The objective of the National Health Service (NHS) research and development strategy is to ensure that the content and delivery of care in the NHS is based on high quality research relevant to improving the health of the nation. In 1991 Professor Michael Peckham was appointed Director of Research and Development, with a target of 1.5% of the NHS budget to be spent on research and development by 1997/98. The Standing Group on Health Technology (SGHT) was formed to advise on the need for health technology assessment in the NHS. Health technology assessment (HTA) can be defined as the assessment of the effectiveness, costs and impact of a health technology on health care. The SGHT is aided by five advisory panels, one of which is the Diagnostics and Imaging Panel, covering all areas of Laboratory Medicine and Imaging. In 1993 the panel was asked by the SGHT to identify new and existing technologies in need of assessment, to identify technologies with insufficient evidence of value and in need of assessment prior to diffusion throughout the NHS, and to identify emerging technologies which may have a major impact on the NHS in the future. Formal consultation processes at both regional and national level were used to obtain recommendations for HTA from the NHS, patient and professional organizations, including the British Nuclear Medicine Society and European Association of Nuclear Medicine (BNMS and the EANM). Of the 197 recommendations received, 16 were considered a high priority and forwarded to the SGHT in October 1993.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7838442 TI - Non-stationary theory of blood-borne tracers. AB - Although cardiac mechanical activity causes periodic fluctuations of the regional volumes and flows through the cardiac chambers and great vessels, hitherto, the developed theory of blood-borne tracers has rested upon stationarity of flow, volume and distribution of transit time. Allowing for an arbitrary indicator injection, a more general theory is presented that accounts for periodic changes in the transport laws, flows and volumes of the system. When indicator particles are not thoroughly mixed with the entering blood, the intracycle changes violate most of the stationary equations. However, assuming complete mixing of indicator at the system inlet, in concentrations that do not change during the single cycle, this enables generalized counterparts of some of the most important stationary relations to be established. The difference between the indicator mean transit time calculated from the stationary assumptions and the one which allows for periodic kinetics is illustrated in radioangiographic assessment of the left ventricular ejection fraction. PMID- 7838443 TI - A Finnish multicentre quality assurance project in bone scintigraphy and brain SPET: a phantom study. AB - We examined all routinely used bone scintigraphy and brain single photon emission tomographic (SPET) systems in 19 laboratories in Finland. Physical performance of bone scintigraphy systems was measured with a 57Co flood source and with a NEMA resolution phantom. Total performance of the systems was evaluated with a transmission phantom simulating bone imaging of the thorax. It was acquired both with the protocol used in a given laboratory and with a fixed protocol. The participant laboratories were asked to report all accumulations on a diagrammatic thorax drawing. Tomographic uniformity, contrast and resolution (i.e. physical performance) of the SPET systems were evaluated with a special phantom. In addition, a Hoffman brain phantom was measured with routinely used acquiring and reconstruction protocols (total performance). All measurements were performed with the same test objects supervised by the same physicist. Manufacturer, age or the collimator of the camera did not correlate with the physical performance of the imaging systems (r < 0.65). This is probably due to lack of regular quality control of the gamma cameras in some laboratories. Comparison of the physical and the total performance shows that the detector itself is not necessarily responsible for inaccurate findings from the test object. Use of dual intensity and digital images in both scintigraphy could certainly increase the sensitivity of the findings: sensitivity of single intensity images was 65% (33-89%), dual 73% (28-100%), analog 65% (28-100%) and digital 74% (50-94%). Standardization of acquisition and reconstruction protocols will improve quality of brain SPET images and comparability between laboratories. This study showed the need for objective audit tests of bone scintigraphy and brain SPET systems in Finland. PMID- 7838444 TI - Comparison of 123I-IBZM SPECT and 11C-raclopride PET findings in patients with parkinsonism. AB - We compared the results of 123I-iodobenzamide (123I-IBZM) single photon emission computed tomography (SPECT) and 11C-raclopride positron emission tomography (PET) in 22 patients with parkinsonism. Nineteen patients were clinically diagnosed as having Parkinson's disease, two patients presented with atypical parkinsonism (i.e. clinical signs of Parkinson's disease and a subsequent poor response to dopamimetic drugs) and one patient was diagnosed as having Wilson's disease. All patients were drug naive. The SPECT data were semiquantitatively evaluated by calculating the ratios of striatal (basal ganglia, BG) IBZM binding to IBZM binding in various reference areas, i.e. the frontal cortex (BG/FC), the occipital cortex (BG/OC) and the cerebellum (BG/CE). In PET studies similar regions of interest were derived and ratios of striatal to cerebellar raclopride activity were determined. 123I-IBZM SPECT results significantly correlated to specific 11C-raclopride binding. This correlation was not significantly different when the frontal cortex (P = 0.05, r = 0.42), occipital cortex (P < 0.05), r = 0.44) or cerebellum (P 0.05, r = 0.45) were used as reference regions for non specific IBZM binding. In comparison to PET ratios the SPECT BG/CE showed a higher variance (S.E.M. = 0.1) than BG/FC (S.E.M. = 0.05) and BG/OC (S.E.M. = 0.06) ratios. Thus, for the calculation of specific striatal IBZM binding one would prefer the frontal or occipital cortex as reference. However, when only those 19 patients with a clinical diagnosis of Parkinson's disease and increased specific 11C-raclopride binding were considered, no significant correlation was obtained. Qualitative changes of dopamine D2 receptor binding, such as asymmetry, were equally recognized.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7838445 TI - A new method for the relative quantification of rCBF examined by 99Tcm-HMPAO SPECT. AB - A new method for the analysis of regional cerebral blood flow (rCBF) studies, the 'Min-Max' method, was compared with the conventional method, the 'Average' method. Regional CBF was examined by single photon emission computed tomography (SPECT) using 99Tcm-hexamethylpropyleneamine oxime (99Tcm-HMPAO). The two methods were used to quantify the rCBF in a population of patients with various dementia disorders, and in healthy controls. Results from a phantom were also used. In the Average method the average counts per pixel (cp-1) within irregular manually drawn regions of interest (ROIs) was registered. In the Min-Max method the minimum cp-1 and maximum cp-1 within rectangular ROIs were registered for white and grey matter, respectively. The relative rCBF (rrCBF) was calculated as the ratio between the regional and cerebellar values. The Min-Max method gave systematically lower values for rrCBF in the white matter, in both clinical studies, and in the phantom, compared to the Average method. No difference was found in the grey matter results. The variability in rrCBF in the phantom study was greater with the Min-Max method than with the Average method, but this effect was counteracted in the clinical studies by a smaller interobserver error. The average regional differences between patients and controls appeared greater with the Min-Max method than with the Average method. The Min-Max method proved to be more simple to execute, involved a smaller observer error, and with respect to ability to distinguish patients with dementia disorders from controls, it appears to function at least as well as the accepted Average method. PMID- 7838446 TI - Imaging rheumatic joint diseases with anti-T lymphocyte antibody OKT-3. AB - T lymphocytes play an important role in the pathogenesis of rheumatoid arthritis (RA). Murine monoclonal antibody OKT-3 (IgG2a), known to be specific for T lymphocyte 20 kD glycoprotein CD3 receptor was labelled with 5 mCi 99Tcm and given intravenously (i.v.) to seven RA and two psoriatic arthritis patients following informed consent to identify inflamed synovium. Anterior and posterior whole body scans and specific regional imaging was commenced 20 min later. At 1 h, approximately 20% of 99Tcm was associated with the lymphocytes. In these patients, all 41 asymptomatic joints and 43 joints with mild pain or minimal tenderness had normal scans. All 34 joints with moderate to severe pain had moderate to marked uptake of radioactivity. Two patients experienced shaking chills for 20-30 min within an hour of 99Tcm-OKT-3 infusion. These results suggest that 99Tcm-OKT-3 imaging serves as an objective surrogate for joint inflammation and could be useful as a measurement of therapeutic effectiveness in RA and other diseases with inflamed synovium. The side effect profile may limit the utility of 99Tcm-OKT-3 but other forms of antibodies directed toward lymphocyte subsets may be useful. PMID- 7838447 TI - A simplified determination of glomerular filtration rate with 99Tcm-DTPA. AB - Using 99Tcm-diethylenetriaminepentaacetate (DTPA) an acceptable estimate of glomerular filtration rate (GFR) can be obtained in adult patients by the equation GF (ml/min) = (0.14 x W + 5) x 1000 x k, where W is the 'ideal' body mass (kg) and k the slope determined by two plasma samples. This has been verified in comparison with the results of the Russell (two samples) and Christensen (one sample) methods in 50 patients. The procedure, which does not require determination of the injected dose, could be useful in patients undergoing sequential renal scintigraphy with 99Tcm-DTPA, for example, to check a doubtful value of glomerular filtration obtained by external counting. PMID- 7838449 TI - In vitro evaluation of white blood cell labelling with 99Tcm radiopharmaceuticals. AB - Several commercially available 99Tcm radiopharmaceuticals were tested as possible white blood cell labelling agents. Labelling efficiency, labelling stability and white blood cell adherence were measured in vitro. White blood cells were not successfully labelled with mebrofenin, disofenin, gluceptate or dimercaptosuccinic acid but were successfully labelled with exametazime, albumin colloid, sulphur colloid, sestamibi and teboroxime. Exametazime had the highest mean labelling efficiency of 79%. Labelling efficiency was 5-14% with albumin colloid, sulphur colloid, sestamibi and teboroxime. Labelling stability was high (> 95% at 4 h and > 80% at 24 h) for all agents except sestamibi (52% at 4 h and 5% at 24h). Exametazime did not alter white blood cell adherence. Albumin colloid, sestamibi and teboroxime decreased adherence and sulphur colloid increased adherence. Exametazime appears to be the best agent for labelling white blood cells. Teboroxime, however, is a new agent for labelling white blood cells which deserves further investigation. PMID- 7838448 TI - Assessment of left ventricular stiffness and compliance. AB - Invasive and non-invasive methods exist to assess left ventricular compliance (LVC). This work has two parts, one experimental and one clinical. We estimated left chamber stiffness in dogs by using volume data from radionuclide ventriculography (RNV) and left ventricular pressure data, synchronized with a gating system to the intraventricular dp/dt max to obtain volume and pressure data from a mean cardiac cycle. In five dogs after acute experimental ischaemia, the modulus chamber stiffness Kp rose from 30.2 +/- 4.4 to 55.4 +/- 5.9 (P < 0.01). In 10 dogs with experimental infarction after intra-aortic balloon pumping, Kp decreased from 33.7 +/- 5.0 to 15.5 +/- 3.9 (P < 0.01) and in five dogs with experimental infarction, after intravenous infusion of sodium nitroprusside, Kp decreased from 41.4 +/- 5.5 to 22.2 +/- 2.8 (P < 0.01). In eight normal volunteers and in 20 postmyocardial infarction patients, we estimated a parameter reflecting the LVC by using volume data with blood flow velocity at the mitral valve annulus. Assuming that the mitral flow-velocity variation reflects LV pressure changes, the formula LVC = (dv/dt)/(dp-dt) becomes (dv/dt)/(df/dt) = dv/df. Values obtained in normals were 0.841 +/- 0.295 m-1s and after myocardial infarction 0.331 +/- 0.10 m-1s. Both methods allow clear separation in groups of animals or patients according to the expected changes in LVC or stiffness. PMID- 7838450 TI - Relationship of alveolar permeability and lung inflammation in patients with active diffuse infiltrative lung disease detected by 99Tcm-DTPA radioaerosol inhalation lung scintigraphy and quantitative 67Ga lung scans. AB - The alveolar permeability (AP) in 21 patients with active diffuse infiltrative lung disease (ILD) was measured by 99Tcm-diethylenetriaminapentaacetate (DTPA) radioaerosol inhalation lung scintigraphy. The degree of AP damage in ILD was presented as the slope (% min-1) of the time-activity curve from the dynamic lung image. Meanwhile, the quantitative Ga lung scan (GA) was performed as a Ga uptake index (GUI) to evaluate the severity of lung inflammation in active ILD. The results show that no good correlation between the degree of AP damage and lung inflammation was found. When the patients were divided into two groups of (A) eight active ILD with normal chest X-ray (X-ray) and (B) 13 active ILD with abnormal X-ray, there was no significant difference between groups A and B for the DTPA and Ga results. In conclusion, the relationship between the degree of AP damage and lung inflammation in active ILD is not significant. This was not consistent with X-ray findings. There was, however, a significant difference between those with ILD and normal controls. PMID- 7838451 TI - Reproductive hazards in the workplace. PMID- 7838452 TI - Postpartum thrombotic thrombocytopenic purpura: report of a case and review of the literature. AB - Thrombotic thrombocytopenic purpura (TTP) is a severe multisystem disease of unknown etiology that reaches its peak incidence when the patient is between ages 20 and 40 years; it is more common in women than in men. Since 1966 there have been six reported cases of TTP occurring in the puerperium. A patient who developed TTP 24 hours after cesarean delivery is described, and the literature regarding TTP occurring in the puerperium is reviewed. Although this patient responded to plasma infusion, the recent literature suggests that plasmapheresis is the treatment of choice for TTP. PMID- 7838453 TI - OH: perceptions and awareness by NHS CHC employees. PMID- 7838454 TI - AIDS in the workplace: an OH dilemma. PMID- 7838455 TI - Another year older.... PMID- 7838456 TI - Change of philosophy and strategy at HSE. PMID- 7838457 TI - Are they still miracle drugs? PMID- 7838458 TI - Formaldehyde toxicity. PMID- 7838459 TI - Root resorption of a first molar related to an impacted third molar. PMID- 7838461 TI - Dermoid cyst in the floor of the mouth. Review of the literature and case reports. AB - Dermoid cyst, frequently used to describe three closely related histologic cysts, the dermoid, epidermoid, and teratoma, is commonly considered a rare finding in the floor of the mouth. This review, which identifies 195 case reports of dermoid cysts in the floor of the mouth, has unveiled some findings that do not support conclusions expressed in previous articles. Examination of the literature includes muscle influence on clinical presentation and surgical approaches, locations, age distribution, histologic distribution, infection rate, incidence of multiple cysts, fibrous attachments, airway problems, anesthesia administration, surgical difficulties, and diagnostic aids. Brief suggestions in treatment are made in light of the clinical, radiographic, and historic findings. Three clinical cases are also included. PMID- 7838460 TI - Randomized double-blind comparison of tiaprofenic acid and diclophenac sodium after third molar surgery. AB - OBJECTIVE: This study compares the effectiveness of tiaprofenic acid with diclophenac sodium over a 7-day period with respect to pain, facial swelling, and trismus. STUDY DESIGN: Sixty patients who required general anesthesia for removal of bilateral impacted third molar teeth were included. Intraoperatively, they received intramuscular injections of either tiaprofenic acid or diclophenac sodium followed respectively by tiaprofenic acid tablets for 5 days and placebo for an additional 2 days or diclophenac sodium tablets for the full 7 days. Surgical and anesthetic techniques were standardized. Pain levels were compared hourly for 4 hours postoperatively and thereafter twice daily for 7 days. Changes in facial swelling and trismus were compared on days 2 and 7 postoperatively. RESULTS: No statistically significant difference was found between the two treatment groups with respect to pain or facial swelling. Only with respect to recovery in mouth-opening ability (trismus) from day 2 to day 7 did diclophenac sodium reveal a statistically significant advantage (p = 0.0452). PMID- 7838462 TI - Cariogenic microflora in patients with Hodgkin's disease before and after mantle field radiotherapy. AB - Because mantle field radiotherapy is associated with partial xerostomia in patients with Hodgkin's disease, the purpose of this study was to evaluate their cariogenic microflora before and after completion of radiotherapy. We obtained samples of oral saline solution rinse from 40 patients with Hodgkin's disease before radiotherapy and from 31 patients with Hodgkin's disease who had survived 1 to 24 years after radiotherapy. We also evaluated caries experience and history of fluoride gel use for caries prevention in these patients. Mutans streptococci and lactobacilli levels were significantly higher in the postradiotherapy patients with carious teeth, particularly in those with limited home use of fluoride gels. In the postradiotherapy group, caries parameters were significantly higher (p < 0.05) than in the preradiotherapy group. Within the postradiotherapy group, both caries and microbial parameters tended to be higher in patients who were less compliant about using the recommended 0.4% stannous fluoride "brush-in" technique than in those who used the gel regularly at home. This study indicates that for patients with Hodgkin's disease who receive mantle field irradiation during the management of their disease, a sustained brush-in program with stannous fluoride gel can be of benefit for caries prevention and for limitation of oral levels of cariogenic mutans streptococci. PMID- 7838463 TI - Oral and dental manifestations in gastroesophageal reflux disease. AB - One hundred seventeen patients with reflux disease were examined with respect to the severity of their disease and oral, dental, and salivary findings. Twenty eight patients had dental erosion, whereas the remaining 89 patients did not. No mucosal changes could be observed to be linked with the reflux disease. In the mean, the patients with erosion were older (54 versus 49 years), and the mean duration of their reflux disease was longer in comparison to those without erosion (17 versus 11 years, respectively). The severity of the reflux disease was more marked among patients with erosion than in those without as assessed by esophagogastroduodenoscopy, the Maratka classification, histologic examination of gastric and esophageal biopsy specimens, and 24-hour esophageal pH monitoring. No statistically significant differences were observed between the groups in any salivary parameters studied, although the number of patients with low salivary buffering capacity was higher among those with erosion than among those without. Patients taking beta-blocking agents or tranquilizers had more erosion than those who did not take these medications. The severity of the reflux disease was not associated with any subjective symptoms in the mouth or pharynx. The frequency of consumption of acidic drinks and foodstuffs as determined by a questionnaire did not differ between the patients with and without dental erosion. Thus severe reflux disease of long duration was found to be potentially detrimental to the teeth, whereas milder forms of the disease need not cause dental side effects. PMID- 7838464 TI - Lip component of burning mouth syndrome. AB - To our knowledge there has been no previous study of factors specifically involved in the pathogenesis of patients who complain of burning sensation of the lips when the lips appear clinically normal. The complaint is akin to patients who complain of a burning sensation of the mouth when it appears clinically normal, a condition known as burning mouth syndrome. This study therefore studied precipitating factors in patients with burning mouth syndrome who reported lip involvement. Previous studies have shown that the lips are the third most common site reported as involved in patients who have burning mouth syndrome. Indeed patients with burning mouth syndrome often report multiple oral site involvement. To investigate the precipitating factors involved in the lip component of burning mouth syndrome, we studied 104 patients who reported the lips as a site affected by the condition from a total population of 312 patients with burning mouth syndrome. Hematologic, biochemical, and microbiologic parameters were studied in these patients. Sialometry, patch testing, psychological testing, and examination of denture status as well as questioning of parafunctional habits were also undertaken. No clear differences were noted in relationship to the frequency of abnormalities in burning mouth syndrome alone or burning mouth syndrome with lip involvement suggesting that similar precipitating factors apply. The precipitating factors in patients with lip involvement were found to be the same as burning mouth syndrome in general. Treatment of patients with lip involvement alone in burning mouth syndrome or lip involvement in burning mouth syndrome in conjunction with other intraoral sites gave an equally good response.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7838465 TI - Is diffuse sclerosing osteomyelitis of the mandible part of the synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome? Analysis of seven cases. AB - Diffuse sclerosing osteomyelitis of the mandible has been described as a localized disease of unknown origin. We offer evidence that mandibular involvement in the recently described synovitis acne pustulosis hyperostosis osteitis syndrome exactly fits the accepted description for diffuse sclerosing osteomyelitis of the mandible. The clinical, radiologic, and pathologic findings in seven such cases are presented and discussed. PMID- 7838466 TI - Oral hairy leukoplakia in nonimmunosuppressed patients. Report of four cases. AB - Hairy leukoplakia was first described in association with HIV infection. Today hairy leukoplakia has come to represent a sign of immunosuppression and not just of HIV infection. Although molecular mechanisms have not been fully elucidated, Epstein-Barr virus appears to play a significant role in its etiopathogenesis. We present four cases that illustrate that HL may be seen in non-HIV and nonimmunocompromised patients. The use of high potency topical steroids for the treatment of oral vesiculoerosive diseases seems to have been a contributing factor in two of these cases. PMID- 7838467 TI - Embryonal rhabdomyosarcoma of the floor of the mouth. A case report. AB - Rhabdomyosarcoma is a neoplasm composed of striated muscle. One of the most common types of soft tissue mesenchymal tumors in infants, children, and adolescents, rhabdomyosarcoma was considered an almost uniformly fatal cancer as recently as 30 years ago. Presently a multimodal approach consisting of surgery, radiation, and chemotherapy has significantly improved the outlook for the patient with rhabdomyosarcoma. This article presents a case of intraoral rhabdomyosarcoma that was initially poorly controlled because of a lack of patient compliance. After proper treatment, the cancer went into remission. The patient remained cancer-free for 7 years, albeit with significant morbidity. This case demonstrates the significantly improved prognosis achieved with multimodal therapy. PMID- 7838468 TI - Intraoral pyogenic granuloma after allogeneic bone marrow transplant. Report of three cases. AB - Allogeneic bone marrow transplant patients commonly have oral complications related to their disease or its treatment. Those reported include: xerostomia, mucositis, caries, infection, gingival hyperplasia, periodontitis, and graft versus-host disease. These complications may be responsible for significant morbidity. This article reviews commonly reported oral complications of bone marrow transplantation and presents three cases in which intraoral pyogenic granuloma occurred. The cause of these lesions in post-bone marrow transplant patients is discussed. PMID- 7838469 TI - Focal cemento-osseous dysplasia: a clinicopathologic study of 221 cases. AB - Classification of cemento-osseous lesions of the jaws has long been a dilemma for pathologists. A group of 221 cemento-osseous lesions exhibited sufficiently distinctive clinicopathologic features to be separated into a specific category: focal cemento-osseous dysplasia. This entity presents as an asymptomatic, focal, mixed radiolucent/radiopaque lesion with ill-defined borders in the tooth-bearing areas. It was found to occur with greater frequency in women (88%) and in the posterior mandible (77%). The average age at presentation was 37 years and a relative predilection for black patients was observed. At surgery these lesions were noted to be hemorrhagic, gritty, and adherent to the surrounding bone. The gross appearance of multiple hemorrhagic fragments is of diagnostic significance. Histologic features include a cellular connective tissue stroma punctuated by irregular osseous and/or cementum-like calcifications. Focal cemento-osseous dysplasia is thought to be of periodontal ligament origin and to be non neoplastic in nature. Further surgical intervention is not necessary, but periodic follow-up is recommended, because occasional cases were observed to progress into florid osseous dysplasia. Care must be taken to differentiate focal cemento-osseous dysplasia from central cementifying and/or ossifying fibromas, which are true neoplasms and require surgical treatment. PMID- 7838470 TI - Facial and perioral molluscum contagiosum in patients with HIV infection. A report of eight cases. AB - Facial and perioral molluscum contagiosum is a common and often disfiguring condition in patients with HIV infection. The purpose of this study was to report on the clinical aspects of eight HIV-positive patients with facial molluscum contagiosum. Also we describe the histopathologic and electron microscopic findings and discuss the treatment modalities for this unusual disease. PMID- 7838471 TI - Neuroepithelial hamartoma of the oral cavity. AB - We report a previously undescribed gingival lesion composed of squamous epithelial islands in close association with bundles of nonmyelinated nerves. A review of the pertinent literature is presented and the histologic differential diagnosis is discussed. We suggest the term neuroepithelial hamartoma for this lesion. PMID- 7838472 TI - Injury to the oral mucous membranes caused by the common houseplant, dieffenbachia. A review. AB - The common houseplant, dieffenbachia, causes painful edematous swelling of the oral mucous membranes when chewed. This property, which is well known to the staffs of poison control centers, can be dangerous to the unwary or to victims of practical jokes. The microscopic features of the injury are those of acute inflammation, but the nature of the plant's toxicity remains controversial. The numerous needles (raphides) of calcium oxalate, which are contained in specialized cells (idioblasts) in the plant, and proteases have both been implicated. When stimulated, the idioblasts fire the raphides with some force for a distance of two to three cell lengths. One possibility is that the local toxicity of dieffenbachia may be caused by a combination of this mechanical release of the raphides, which results in traumatic injury, and the effects of a chemical toxin carried on their surfaces and in their grooves. PMID- 7838473 TI - Microbiologic factors in endodontology. AB - The role of microorganisms in the cause of endodontic lesions has been intensively investigated. Bacterial components such as endotoxin and other cell wall components are implicated in the development of pulpal and periapical inflammation. Newer anaerobic microbiologic techniques have facilitated accurate and reproducible identification of endodontic pathogens, some of which have been reclassified. This article reviews and correlates newer microbiologic findings with clinical symptoms. PMID- 7838474 TI - Extrusion of endodontic filling material into the insertions of the mylohyoid muscle. A case report. AB - A case is presented in which an overfilling of obturation paste (N-2) extended through the lingual alveolar plate of bone as far as the insertion of the mylohyoid muscle. Pain was associated with the omolateral lingual soft tissues and the cervical region. A lingual flap retraction allowed removal of the paste, and the pain subsequently disappeared. PMID- 7838475 TI - Absence of radiometric differentiation between periapical cysts and granulomas. AB - A recent study reported that the mean density of periapical cysts was greater than that of periapical granulomas. This study, which used a larger sample size and a robust method for standardization of density and contrast between images, found no difference between the radiographic density of cysts and granulomas classified by microscopic evaluation. Cysts tend to be larger than granulomas, but there was wide variation in size of both types of lesions. There was no significant correlation between the density of a lesion and its size. PMID- 7838476 TI - Detection of simulated osteoporosis in human anterior maxillary alveolar bone with digital subtraction. AB - The purpose of this in vitro study was to examine radiographic changes in human anterior maxillary alveolar bone during simulated osteoporosis (decalcification) and to determine the minimal amount of generalized decalcifications that can be detected under optimal radiographic conditions with the use of digital subtraction. Five samples of human anterior maxillary alveolus were progressively decalcified at timed intervals with 0.1 N hydrochloric acid solutions, and the percentage of calcium lost during each interval was quantified with calcium assays. Sets of four radiographs were exposed at 70 kVp initially and after each decalcification interval. The radiographs were digitized and digitally filtered, and bone profiles (scan lines) were generated between selected points on lead markers. To further reduce corrupting film-grain noise each set of four profiles were superimposed and averaged on a pixel-by-pixel basis. The averaged profile from each stage of decalcification was subtracted from the averaged initial profile on a pixel-by-pixel basis, and the mean profile intensity change for each decalcification stage calculated. Statistical analysis was performed with repeated measures analysis of variance. Results indicate that generalized decalcification less than or equal to 5.3% was detected in all samples of human anterior maxillae with the use of digital subtraction. PMID- 7838477 TI - Location of the mandibular foramen in panoramic radiographs. AB - The reliability of two panoramic x-ray machines (Philips Orthoralix SD Ceph and Gendex Panelipse II) for determination of the location of the mandibular foramen was studied with the use of human dry mandibles. A significant correlation was found between the location of the mandibular foramen in the radiograph and the narrowest anteroposterior dimension of the ramus. A linear logistic regression equation was developed that could predict the actual location of the mandibular foramen from the radiographs. This finding will improve treatment planning of surgical splitting or fracturing of the ramus in cases that require orthognathic surgery provided the surgeon is aware of which panoramic machine was used. The Philips Orthoralix SD was found to be more reliable for this purpose than the Panelipse II (R2 = 0.94 and R2 = 0.87, respectively, in the vertical dimension and R2 = 0.87 and R2 = 0.75, respectively, in the horizontal dimension. PMID- 7838478 TI - HIV-1 antibody positive hepatitis B surface antigen serum in a dental school patient population. AB - Testing for human immunodeficiency virus antibody (anti-HIV-1) in patients positive for hepatitis B surface antigen has never been performed in a dental school patient population. In this population there was a 2.8% positive reactivity for HIV-1 antibodies in subjects who were also positive for hepatitis B surface antigen. An enzyme-linked immunoassay with a repeat test and confirmation with a Western blot technique were used. PMID- 7838479 TI - Extensive idiopathic apical root resorption. A case report. AB - Multiple idiopathic external apical root resorption is an unusual phenomenon. A brief review of cases in the literature is presented as well as a report of a patient with severe resorption. No significant systemic, dental, or familial findings could be identified as a possible cause. Careful chronologic radiographic documentation showed that roots with normal length began to resorb several years earlier, and the resorption continued over a defined period of time, terminating spontaneously before tooth loss or obvious pulp damage. Because the pathogenesis is generally unknown, no specific treatment modalities exist at present. PMID- 7838480 TI - Effects of prostacyclin on hearing recovery after repetitive noise and on histomorphology of the inner ear in the guinea pig. AB - A probable relation between prostaglandin formation and the pathophysiology of hearing loss led to the application of the potent vasodilator prostacyclin in the treatment of inner ear disorders. Two drugs may be administered to humans: (1) unstable natural prostacyclin (epoprostenol) with a strong biological potency but with a high first-pass effect, or (2) a prostacyclin analogue (taprostene) with less biological activity, but a longer biological half-life and intravenous application. Therefore, the purpose of this study was to investigate potential differences of both drugs in their effect on the inner ear. The therapeutic potency of both drugs was evaluated in a recently developed animal model consisting in the recovery of hearing after a temporary threshold shift obtained by two noise exposures at 100 dB. In addition, the ultrastructure of the stria vascularis was examined by electron microscopy after the application of the drugs. After administering epoprostenol (12 ng/kg body weight/min) and taprostene (25 ng/kg body weight/min) histomorphological alterations in the stria vascularis did not differ from the controls. In the repetitive low-level noise model, neither drug showed a significant difference in its effect on the recovery of the hearing threshold. The results indicate that in the guinea pig epoprostenol has the same effect on the hearing threshold as the stable analogue taprostene, as shown by auditory brain stem response. PMID- 7838481 TI - X-ray microanalysis and ion microscopy of guinea pig cochlea and kidney after cisplatin treatment. AB - The detection of platinum in cochlear outer hair cells (OHCs) and renal proximal tubule cells was attempted by X-ray microanalysis and ion microscopy. Platinum was not detected by X-ray microanalysis in the lysosomes of OHCs or proximal tubule cells after 10 days treatment with 1.5 mg/kg of cisplatin. In the guinea pigs treated with 1.5 mg/kg of cisplatin for 14 days, platinum was detected by a wave-length-dispersive microanalyzer in only the lysosomes of kidney fixed by freezing. Ion microscopy failed to detect platinum. Improvement of fixation methods, longer administration of cisplatin and the use of more sensitive tools will be needed to detect the platinum inside the OHCs. PMID- 7838482 TI - Comparative ototoxicity of cisplatin during acute and chronic treatment. AB - Functional and morphological alterations were compared in guinea pig cochleae treated acutely (7.5 mg/kg x 2) and chronically (1.5 mg/kg x 10) with cisplatin. Drastic and rapid hearing impairments using compound action potential were observed only after the second injection during acute treatment. During chronic treatment, threshold changes were observed abruptly after 8 or 9 days of treatment. Morphological changes of outer hair cells were stronger in the acute treatment than the chronic one, and they appeared to concur with the functional data. Partial damage in the stria vascularis was observed only after acute treatment. From these results, it was suspected that acute and chronic ototoxic mechanisms differed according to the pharmacokinetics of cisplatin in the inner ear fluid and tissues. PMID- 7838483 TI - Postcaloric nystagmus by positional change and other neurootological findings. AB - The postcaloric nystagmus (PCN) by positional change from the supine position to the upright position and other neurootological findings were studied. Twenety-one patients with a clinical diagnosis of spinocerebellar degeneration or Arnold Chiari malformation were studied. There was a significant negative correlation between maximum slow phase eye velocity in postcaloric nystagmus by positional change (V2) and maximum slow phase eye velocity in optokinetic nystagmus pattern test (r = -0.47; n = 21). Moreover, patients with vertical gaze nystagmus (VN) had significantly larger V2 than patients without VN. However, there was no significant difference for V2 between patients with and without rebound nystagmus. Through these studies, the authors discussed probable mechanisms and responsible lesions for the exaggerated PCN by positional change. PMID- 7838484 TI - Analysis of gait in patients with peripheral vestibular disorders. AB - Analysis of gait in patients with acute unilateral peripheral vestibular disorders was performed using foot switches and electromyography, with the aid of a telemetry system. Among the eight parameters set for the analysis, the occurrence rate of abnormality in the coefficient of variation (CV) was the highest (78%) for the time from heel strike to forefoot strike, followed by that of the location of maximum monophasic contraction of the gastrocnemius during stance, swing and stance. No significant laterality concerning the abnormally increased CV value in those parameters was found except for swing of the foot contralateral to the lesion side. The CV value of each parameter was significantly increased by removing visual cues, suggesting the importance of visual input for steady locomotion. No significant change in CV values of double support was obtained during the acute stage of vestibular neuronitis, indicating that weight transfer from one leg to the other could be smooth even though some difficulty was expected. Abnormal parameters at an acute stage returned to normal limits at recovery stage. The physiological background of the obtained results is discussed. PMID- 7838485 TI - Analysis of the prognosis and the recovery process of profound facial nerve paralysis secondary to acoustic neuroma resection. AB - The prognosis and the recovery process of facial nerve paralysis were reviewed in 74 patients who, despite preservation of nerve continuity, showed no facial movement after acoustic neuroma resection. In 50 or 67.6% of patients, facial movement recovered sufficiently so as not to require any reanimation procedures. However, no apparent sign of remission was observed for 7-49 months in the other 24 patients (32.4%), and hypoglossal-facial nerve anastomosis was performed in 20 of these patients. When remission was seen, the first sign of muscle movement appeared most frequently after 3-4 months but, in a small number of patients, it was also seen within 1.5 months or after 5-10 months. Based upon these results, the timing of reanimation procedures for facial nerve paralysis following acoustic neuroma resection is discussed. PMID- 7838486 TI - Auditory brainstem responses in leptomeningeal metastatic spread. Presentation of 2 cases. AB - Auditory brainstem responses (ABRs) were recorded in 2 patients with hearing loss caused by leptomeningeal metastatic spread. These recordings showed similar characteristic findings. The absolute latencies of wave V and interwave latencies I-V were exceedingly increased. Definite effects on the wave morphology and latency of wave V were observed with the use of high repetition rates. It is surmised that the hearing loss caused by leptomeningeal metastatic spread is mainly an effect on the auditory nerve and/or the cochlear nucleus. ABR examination is of clinical value in detecting functional abnormalities resulting from leptomeningeal metastatic spread. PMID- 7838487 TI - Hypopituitarism and hyponatremia in a case with nasopharyngeal carcinoma. AB - We report a case of nasopharyngeal carcinoma (NPC) accompanied by hyponatremia and polyuria which was induced by tumor invasion into the pituitary gland. Magnetic resonance imaging showed the pituitary gland pushed upward by NPC. Hypopituitarism due to an intracranial tumor and the extracellular volume excess due to chemotherapy caused hyponatremia and polyuria. As the intracranial tumor was diminished by chemotherapy and irradiation, pituitary hormones were normalized. In patients with T4 NPC, pituitary-adrenocortical function should be endocrinologically evaluated before treatment. PMID- 7838488 TI - A delayed teflonoma of the neck simulating a thyroid neoplasm. AB - Pseudotumoral granulomatous foreign body reaction to Teflon particles is a rare complication of intracordal Teflon paste injection for unilateral vocal cord paralysis. We report a case of pseudotumor of the thyroid area, which appeared 3 years after intracordal Teflon paste injection and presented as a cold thyroid nodule. At frozen section examination the presence of a giant-cell foreign body granuloma containing numerous refringent particles suggested a 'teflonoma'. The diagnosis was confirmed on permanent sections, after comparison of the intratissular particles with fresh Teflon paste, under conventional and polarized light. The histological and ultrastructural features of the lesion are presented and attention is drawn to the long delay between initial Teflon injection and the clinical manifestation of the lesion. PMID- 7838489 TI - Gunshot wound injuries. Frequency and cost analyses in south central Los Angeles. AB - Nine hundred fifty-two patients with gunshot wound injuries admitted between July 1, 1989 and June 30, 1990 in a level one trauma center in South Central Los Angeles were studied retrospectively. The authors attempted to define those periods that gunshot injuries were most likely to occur, to characterize the involved high-risk populations, and to estimate direct and indirect cost of care to society. PMID- 7838490 TI - Gunshot wounds to the spine. AB - Gunshot wounds to the spine are becoming more prevalent, especially in urban areas. Neurologic injury can occur even if the projectile does not penetrate the spinal canal. Initial treatment should consist of stabilizing the patient's medical condition followed by a careful neurologic examination. Spinal stability can be determined from plain radiographs and CT scan, with the overwhelming majority of injuries being stable. Retained bullets rarely cause problems of delayed infection, late neurologic decline, or lead toxicity, eliminating the need for prophylactic bullet removal; however, in the thoracolumbar spine, removal of bullet fragments lodged within the spinal canal has been shown to significantly improve neurologic recovery. PMID- 7838491 TI - Rehabilitation of the patient with a spinal cord injury. AB - An overview of the individual with spinal cord injury caused by gunshot wounds is presented. In addition to the demographics of the group of patients, the cost estimates of care are discussed. The authors' experience in monitoring neurologic recovery and rehabilitation expectations and outcomes are also reported. PMID- 7838492 TI - Management of civilian gunshot injuries to the hip. AB - The orthopedic surgeon at a civilian trauma center is likely to encounter a gunshot injury to the hip. The nonmilitary literature regarding this injury gives few guidelines regarding an appropriate diagnostic evaluation or the indication for arthrotomy. We found that the best diagnostic test to detect joint penetration was hip aspiration followed by an arthrogram. Selected cases can be treated successfully with antibiotic therapy without an arthrotomy. These cases involve a low-velocity missile that passes through the joint, causes minimal bone disruption, and is free of bowel contaminants. If an arthrotomy is not performed, the physician must follow the patient with repeated physical examinations, complete blood counts, and a hip aspiration whenever infection is suspected. All transbdominal hip injuries require an immediate arthrotomy. In this series, bullets left in contact with joint fluid resulted in joint destruction or infection. Each patient with a displaced femoral neck fracture had a poor outcome with internal fixation. Hip arthroplasty or fusion should be considered as elective procedures for definitive management of these injuries. PMID- 7838493 TI - The management of gunshot wounds to the femur. AB - This article is an overview of the management of femoral shaft fractures resulting from gunshot wounds. It deals with the initial patient evaluation, operative techniques of fracture stabilization and wound care, associated complications, and the postoperative rehabilitation of these complex fractures. The recommendations are based upon a large patient experience in an urban trauma center. PMID- 7838494 TI - A prospective study of fractures of the femoral shaft treated with a static, intramedullary, interlocking nail comparing one versus two distal screws. AB - In a nonrandomized prospective study, 178 comminuted or length unstable femur fractures were treated with a statically locked, slotted, titanium alloy interlocking nail. Patients were divided into two groups based on the number of distal interlocking screws that were used. The patients were followed up for an average of 17 months to determine if the use of a single distal screw provided adequate fracture stability without loss of fracture fixation. PMID- 7838495 TI - Gunshot wounds to the thigh. Evaluation of vascular and subclinical vascular injuries. AB - A retrospective review of 173 patient charts, angiograms, surgical reports, and plain radiographs were performed for all patients admitted with gunshot wounds to the thigh from May 1988 to January 1991 at Martin Luther King, Jr. Hospital. A zonal classification of gunshot wounds to the thigh was created and defined to determine if a zonal classification was predictive of a positive angiogram. Associations and relationships of patients with vascular injury are presented. PMID- 7838496 TI - Gunshot wounds to the knee. AB - Between 1989 and 1993, 67 fractures of the knee secondary to gunshot wounds were treated at the King/Drew Medical Center in Los Angeles, California. Based on this experience, a treatment protocol was devised. The protocol addresses the evaluation and management of neurovascular injuries, soft-tissue wounds, and fractures. These concepts are summarized in an algorithm. PMID- 7838497 TI - Management of gunshot wounds to the tibia. AB - The management of tibial gunshot wounds is unique because of the close proximity of the medial aspect of the bone to the skin. The minimal soft-tissue sleeve covering the medial tibia allows bullets to enter medially and strike the bone with greater energy and allows surface contaminants to reach the bone readily unlike areas such as the thigh where soft tissue can dissipate much of the energy. The consequence of this anatomic difference may affect infection rates, fracture stability, and surgical options. For these reasons, tibial gunshot wounds should be treated independently from other gunshot wounds to the extremity. PMID- 7838498 TI - Management of gunshot fractures of the tibia. AB - This article reviews the classification, principles of fracture management, and indications for type of fixation of gunshot injuries to the tibia. Also reviewed are techniques of external fixation and intramedullary nailing, as well as the methods, results, and complications of 90 patients treated at the authors' institution from 1986-1994. PMID- 7838499 TI - Gunshot wounds to the extremities in children and adolescents. AB - Thirty-seven patients from 8 months to 17 years of age were evaluated prospectively and retrospectively after sustaining gunshot wounds to the extremities. This review supports the belief that higher velocity weapons and shotgun-wound injuries cause greater morbidity, with increased length of hospital stay and increased cost of care. Late growth abnormalities were related to recognized initial physeal injury and not to unrecognized physeal injury. Immediate neurologic deficits usually resolved partially or fully, without surgical treatment. PMID- 7838500 TI - Gunshot wounds to the foot. AB - One hundred and one patients who sustained gunshot wounds to their feet were retrospectively reviewed. All patients were treated at King/Drew Medical Center between 1982 and 1994. From the authors' experience, they believe that patients with low-velocity gunshot wounds to the foot should be hospitalized and treated with at least a 3-day course of intravenous antibiotics of a first generation cephalosporin. Low-energy shotgun injuries should be treated the same as low velocity injuries. Patients with high-velocity and high-energy shotgun wounds should be hospitalized and receive broad-spectrum intravenous antibiotics with multiple irrigation and debridements. PMID- 7838501 TI - Gunshot wounds to the upper extremity. Evaluation and management of vascular injuries. AB - Gunshot wounds to the upper extremity are uncommonly life threatening but are associated with a high incidence of significant long-term disability. The identification of vascular injuries is dependent on careful clinical examination and the liberal use of arteriography. Standard techniques of vascular repair should be followed for arterial reconstruction. The rate of successful vascular repair is in excess of 90%, but long-term function is limited by a high incidence of associated nerve injury. PMID- 7838502 TI - Gunshot wounds to the shoulder. AB - The proximity of vascular, neural, osseous, and muscular structures make gunshot wounds to the shoulder area particularly challenging. This review focuses on the epidemiology, pathophysiology, diagnosis, and treatment of these injuries. Special attention is given to the usefulness of vascular and electrodiagnostic studies. PMID- 7838503 TI - Fracture brace for the treatment of humerus shaft fractures caused by gunshot wounds. AB - Humeral shaft fractures are amenable to conservative treatment. In this article, the authors define their indications and methods of treatment of gunshot-caused fractures of the humerus. They emphasize use of a humeral fracture brace. Successful fracture brace treatment requires attention to and comprehension of proper technique. When used appropriately, fracture bracing is safer, less expensive, and more effective than surgical alternatives. PMID- 7838504 TI - Surgical stabilization of humeral shaft fractures due to gunshot wounds. AB - Humeral shaft fractures resulting from gunshot wounds are challenging injuries to treat. The results of surgical stabilization depend upon the appropriate indication and operative techniques. Compression plating, intramedullary fixation, and external fixation are discussed. PMID- 7838505 TI - Gunshot wounds to the elbow. AB - Gunshot wound injuries to the elbow are rare. This article presents the experience of the King/Drew Medical Center. Classification and management of these injuries are emphasized. An algorithm is presented. PMID- 7838506 TI - Gunshot wounds to the forearm. AB - The rising incidence of civilian gunshot wounds has been well documented. Approximately 4% to 20% of these wounds consist of injuries to the forearm. An organized approach to the treatment of these injuries should be used to obtain an optimal result. Factors to be considered in treatment include the type of weapon and bullet involved, the neurovascular status of the patient, the possibility of compartment syndrome, the presence and type of fracture, and soft-tissue injury. PMID- 7838507 TI - Efficacy of ceftriaxone versus cefazolin in the prophylactic management of extra articular cortical violation of bone due to low-velocity gunshot wounds. AB - One hundred patients sustained gunshot wounds involving bone but not joint with a low-velocity bullet. Soft-tissue involvement was less than 1 cm at its greatest diameter. All patients were free from artery or nerve damage. No formal fixation of fracture was required. The results of the study suggest that patients need not be hospitalized longer than 2 days after an extra-articular, low-velocity gunshot wound that violates the cortex. In addition, through the use of long half-life antibiotics, such as ceftriaxone, the length of hospitalization may further be reduced to a day, while the potential for morbidity from infection is not increased. PMID- 7838508 TI - Gunshot wounds to the hand. The Martin Luther King, Jr, General Hospital experience. AB - This article is a retrospective review of patients who presented to Martin Luther King, Jr./Drew Medical Center with gunshot wounds and had either isolated or associated injuries to the hand. The following is an account of those injuries noting the location, soft-tissue or bony involvement, and interventional methods that were implemented in the treatment of these patients who resided primarily in South Central Los Angeles. Prompt evaluation and initiation of treatment is essential in the management of both high- and low-velocity gunshot wounds so as to decrease the potential morbidity that often follows. Society must also look at the prevalence of these injuries and address the underlying issues that often are the root of the acts of violence. PMID- 7838509 TI - [Thrombopoietin: a hematopoietic hormone of vital importance, first described in Hungary, synthetized abroad after 36 years]. PMID- 7838510 TI - [Skin as an immune system]. AB - Skin consists of three structurally and functionally distinct compartments containing resident and nonresident cells. These cells cooperative with humoral pathway of immune system in defence of healthy skin. Resident and nonresident cells are able to initiate inflammatory or immune processes of skin, although interstitial reactions (activation by bacteria, immunoglobulin or complement) also take place in such processes. In normal conditions nonresident cells can migrate through vascular endothel, however, PMN granulocytes and B lymphocytes cannot. Resident and nonresident cells of skin are capable of exerting a wide range of immunomodulatory effects, among them keratinocytes are of distinguished significance producing arachidon metabolites and IL-1 as well. Activated skin cells might induce chemotactic migration of distinct white blood cells normally absent or only a few cells being present in healthy skin. Cell migration into the interstitial space of skin is mediated by adhesion molecules expressed on cell surface of migrating cells, vascular endothel cells and on keratinocytes. Composition and density of adhesion molecules vary by type of stimuli, therefore various cytokines might induce distinct reactions mediated by certain population of cells. In addition, initiation and progress of immune- or inflammatory reactions are determined by the involved cell-populations as well. Normal regulation provides appropriate control and termination of the reaction, however, uncontrolled regulation results in development of pathological state. PMID- 7838511 TI - [Growth factors in experimental ulcer]. AB - Important role is attributed to the growth factors in the development, growth, and restitution after injury of the gastrointestinal tract. The common feature of growth factors is their ability to stimulate the growth and mitosis of quiescent cells in a nutritionally complete medium which in itself is not sufficient to initiate cell division. Epidermal growth factor prevents efficiently the experimentally induced acute gastric mucosal lesions induced by aspirin, absolute ethanol, HCl, NaCl, immobilization, and immersion and it accelerates the healing of acetic acid-induced chronic gastric and cysteamine-induced chronic duodenal ulcers. It proved to be also useful in the treatment of human gastric ulcers. Fibroblast growth factor possesses similar gastroprotective and chronic ulcer healing properties. Its effects is much more potent than that of epidermal growth factor and that of H2-receptor blockers. The "trefoil"-peptides constitute the latest family of growth factors which are supposed to be involved in the regeneration of the normal and the ulcerated gastrointestinal mucosa. Polyamines are non-peptide growth promoting compounds present in all eukaryotic cells; their gastroprotective and ulcer-healing properties have also been published. The use of some growth factors as regenerative and angiogenic therapy could open a new, alternative way in the future management of peptic ulcer disease. PMID- 7838512 TI - [Malignant and premalignant processes of myeloid systems. Guidelines of the Professional College of Hematology]. PMID- 7838513 TI - [Remembering Geza Mihalkovics (1844-1899)]. PMID- 7838514 TI - [The "modern" epidemiology of Fracastoro (1478-1553) ( Girolamo Fracastoro)]. PMID- 7838515 TI - [The concept and diagnosis of addiction. New trends in the terminology of addictive syndromes]. AB - The terms addiction, dependence, tolerance and abuse are not interchangeable and cannot be used as synonyms. Two types of addictions, chemical and behaviour addictions, have similar cycles, but the "pull" type mechanisms are more characteristic of the chemical addictions and the "push" type mechanisms of the behaviour addictions. Among the integrative, complex conceptual models, the definitions of the WHO model are most in harmony with the latest research findings, although this model too is in need of revision on several points. The modern diagnostic systems are polythetic; they advance beyond the principle of "all or nothing" and despite their shortcomings they can be used effectively in clinical practice. Aspirations in the direction of both expanding and restricting the concept addiction can be observed. PMID- 7838516 TI - [Review of drugs used in the neutropenic period following cytostatic therapy and comparative study of doxycycline and ofloxacin in the treatment of patients with testicular cancer]. AB - The authors compared the effectivity of doxycyclin or ofloxacin after combined chemotherapy of testicular cancer patients during the leukopenic periods. Between 1988 and 1991 200 patients were randomized and 194 were evaluated. One hundred and fifty two patients had been treated by cytostatic treatment earlier 2.5 or 2.9 times and 17 by irradiation. The average age was 30.1 in the doxycyclin group and 31.5 years in ofloxacin group. The patients characteristics in average age and previous treatments were not significant in the two groups. Doxycyclin was applied at the first day 200 mg and the following days 100 mg for 6.8 days and ofloxacin was given 2 times 100 mg day for 8.0 days. The preventive antibiotic treatment was insufficient in 16 or 6 cases requiring the the new antibiotic therapy. The development of the new infectional lesions was significantly higher in doxycyclin group and it needed the other antibiotic therapy. The condition of the patients did not require systemic antimycotic or antiviral therapy. The toxicity was lower in oflaxacin group. Tarivid is suitable for preventing the infection in neutropenic periods after the cytostatic therapy. The number of infections are decreased the completion with some penicillins. Regarding to previous cytostatic drugs the cephalosporins are suggested for prevention during the neutropenic periods. PMID- 7838517 TI - [Fibrinolysis in chronic liver diseases studied by in vitro blood coagulation tests]. AB - A simple and easily reproducible in vitro clot lysis test less frequently indicated increased rate of fibrinolysis in chronic hepatic disease than expected. In hepatic cirrhosis clot lysis slows down as the condition deteriorates or as the plasma concentration of von Willebrand factor increases, thus the test may have certain prognostic value. The present observations suggest that the occasional acceleration of fibrinolysis in cirrhosis may be related to either increased production or decreased clearance of tPA, and is not due to impaired fibrinolysis inhibitor system. PMID- 7838518 TI - [ESWL in renal tubular acidosis]. AB - ESWL is a suitable modality for the management of lithiasis caused by RTA, especially in case of renal or ureteric stones. Smash of calculi in ducts of Bellini is worthy to be considered if the fragments can get into the renal pelvic space and the renal function improve. At present it is still a matter of discussion. PMID- 7838519 TI - [Acute hydrops of the gallbladder in childhood]. AB - The authors discuss four cases of acute hydrops of the gallbladder being examined in the Department of Pediatrics, Medical University School of Pecs. Diagnosis was based on ultrasonography. In all cases right upper quadrant abdominal pain and fatigue were observed. The causes of hydrops were Kawasaki's disease, sepsis, and multiple trauma. In one case the cause was unknown. In one of the cases cholecystectomy was done, in three cases the hydrops resolved spontaneously. The authors discuss the aetiology, the symptomatology and the therapeutical possibilities of hydrops. On the basis of their results the authors suggest the importance of the serial ultrasound examinations. PMID- 7838520 TI - [Management of multinodular non-toxic goiter]. PMID- 7838521 TI - [Primary endoscopy of the stomach]. PMID- 7838522 TI - Differential regulation of E2F and Sp1-mediated transcription by G1 cyclins. AB - Cyclins have been demonstrated to mediate phosphorylation of the retinoblastoma tumor suppressor gene product (Rb) and/or to bind directly to Rb. Since Rb is a regulator of E2F and Sp1-mediated transcription, we have examined the effect of overexpression of cyclins on transcription mediated by E2F-dependent adenovirus E2 promoter and by Sp1 in a cotransfection assay in 3T3 cells. All the G1 cyclins tested, C, D1, D2, D3 and E, as well as cyclin A were able to stimulate E2 promoter activity to various levels with D3 showing the strongest stimulation. For stimulation of the E2 promoter by cyclins A, E and D-type cyclins was dependent upon the presence of functional E2F and ATF binding sites. Cyclin C, however, was able to stimulate both E2F and ATF-dependent transcription to the same level as the wild type E2 promoter. In addition, cyclin C was able to stimulate transcription mediated by Sp1, GAL4-Sp1 and GAL4-VP16, suggesting that cyclin C affects a general pathway of transcriptional activation. In contrast, cyclin D1 was able to repress specifically Sp1-mediated transcription through an Rb-independent pathway. These results suggest that cyclins can regulate transcription mediated by specific transcription factors in both positive and negative manners. Furthermore, the results demonstrate clear functional differences between the G1 cyclins, in particular, functional differences between the related D-type cyclins. PMID- 7838523 TI - Phosphorylation of E2F-1 by cyclin A-cdk2. AB - Transcription factor E2F-1 has a putative consensus sequence for phosphorylation by cyclin dependent kinase (Ser-Pro-X-Lys/Arg). Therefore, we studied the phosphorylation of E2F-1 in vivo and in vitro and its biological functions. E2F-1 was prepared by immunoprecipitation with anti-E2F-1 antibody from IMR32 lysates and was effectively phosphorylated by human cyclin A-cdk2 which was expressed in insect cells using baculovirus system. GST-E2F-1 was phosphorylated by cyclin A cdk2 more efficiently than by cyclin E-cdk2. Cyclin D1-cdk4 phosphorylated pRB but scarcely phosphorylated GST-E2F-1 or H1 histone. The 60 kd protein precipitated with anti-E2F-1 antibody was phosphorylated in vivo. Phospho-peptide mapping indicated that its cleavage profile was identical with that of E2F-1 phosphorylated by cyclin A-cdk2 in vitro. This 60 kd protein, which is likely to be E2F-1, was not phosphorylated during the G0 and early G1 phase. Phosphorylation of E2F-1 began from the S phase while phosphorylation of pRB started nearly at G1/S. The in vivo phosphorylation of E2F-1 was inhibited by butyrolactone I, a cyclin-dependent kinase inhibitor (Kitagawa et al., 1993, Oncogene, 8, 2425-2432). The binding of E2F-1 to E2 promoter was found to be reduced by phosphorylation of E2F-1 by cyclin A-cdk2, suggesting that phosphorylation of E2F-1 may induce shut off of gene expression at the transcriptional level. These results suggest that E2F-1 is phosphorylated by cyclin A-cdk2 in the S phase in vivo as well as in vitro and that its phosphorylation by cyclin A-cdk2 may modulate its activity. PMID- 7838524 TI - Efficient cell transformation by the Tpr-Met oncoprotein is dependent upon tyrosine 489 in the carboxy-terminus. AB - The receptor for hepatocyte growth factor/scatter factor (HGF/SF) was originally identified as an oncogene, Tpr-Met, which consists of the cytoplasmic tyrosine kinase domain of the HGF/SF receptor (Met) fused down-stream of sequences encoded by the tpr gene. As a consequence of this rearrangement the Tpr-Met fusion oncoprotein is localized to the cytoplasm and is a constitutively activated kinase. To identify signalling pathways important for Tpr-Met-mediated cell transformation we have generated tyrosine to phenylalanine mutants of Tpr-Met that are compromised in their ability to transform Fischer rat 3T3 (Fr3T3) cells in culture. We show that a single tyrosine residue in the carboxy terminus of Tpr Met (residue 489) is essential for efficient transformation of Fr3T3 cells by this oncoprotein. Mutation of tyrosine 489 to phenylalanine does not affect the exogenous kinase activity of the Tpr-Met oncoprotein toward casein, but it impairs the ability of the mutant protein to bind to and activate phosphatidylinositol 3 kinase in vivo and completely abolishes the in vivo association with the Grb2 adaptor protein as well as the association and/or phosphorylation of an unknown protein of 110 kDa. These data are consistent with a single tyrosine residue in the Tpr-Met oncoprotein being essential for the activation of several signalling pathways which lead to the transformation of Fr3T3 fibroblasts. PMID- 7838525 TI - Direct relationship between the expression of tumor suppressor H19 mRNA and c-mos proto-oncogene during myogenesis. AB - We have cloned and sequenced an almost complete c-DNA and the entire genomic sequence of rat the H19 gene, which is developmentally regulated in skeletal muscle. The data base comparison revealed a 92% homology with mouse gene H19. However the rat H19 ORFs do not display significant homology with the H19 ORFs from other species. In contrast to the mouse, the rat H19 mRNA is not easily detectable in fetal rat skeletal fibers. Its level increases after birth (up to 12 to 18 days) and remains stable thereafter. The pattern of H19 mRNA expression in rat muscle in vivo is very similar to the c-mos gene expression in this tissue, suggesting an interrelationship between H19 and c-mos products during muscle differentiation. Indeed, our results indicate that overexpression of c-mos protein in the muscle cell line C2C12 induces a concomitant increase of H19 mRNA expression. Furthermore, repression of c-mos protein expression by anti-sense RNAs extinguishes H19 mRNA expression and inhibits the differentiation process. These data suggest a relationship between c-mos and H19 expression and, in addition, the involvement of both gene products in the process of myogenesis. PMID- 7838526 TI - HPV-18 E6 mediated inhibition of p53 DNA binding activity is independent of E6 induced degradation. AB - A key activity of the p53 protein during suppression of cell growth is its ability to stimulate transcription from promoters of cellular genes which contain a p53 responsive element. The E6 proteins from the oncogenic associated Human Papillomaviruses (HPVs) have been shown to inhibit specifically the p53 transcriptional activation and this has been proposed as a mechanism whereby the virus prevents the suppression of cell cycle progression and the induction of apoptosis. However, the mechanism by which E6 exercises this function is unknown, as is the ability of E6 to associate with different oligomeric forms of p53. In this study we demonstrate that E6 induces changes within the p53 protein which result both in inhibition of DNA binding and in dissociation of p53 protein previously bound to the DNA. These activities correlate exactly with the ability of E6 to inhibit p53 transcriptional activation and are independent of the ability of E6 to direct the degradation of the p53 protein. Further, we show that E6 labels wild type tetrameric and dimeric forms of p53 proteins for ubiquitin mediated degradation more readily than monomeric forms of the protein. However, in vivo analyses indicate that E6 is capable of inhibiting the transcriptional activation induced by the tetrameric, dimeric and monomeric forms of p53. PMID- 7838527 TI - Immediate effects of reversible HTLV-1 tax function: T-cell activation and apoptosis. AB - The tax protein of Human T-cell leukemia virus type 1 (HTLV-1) is important for the transforming properties of this virus in vitro and is considered to be responsible for the early stages of leukemogenesis in infected hosts. To address the early consequences of HTLV-1 tax function, we have constructed fusion proteins containing tax sequence either aminoterminal (taxER) or carboxy-terminal (ERtax) of the hormone binding domain of the human estrogen receptor (ER). Addition of estrogen or the antagonist hydroxytamoxifen to Jurkat T-cells expressing these constructs led to the trans-activation or responsive promoters and upregulation of cell surface markers CD28, CD69 and CD5 but not CD25 (IL2R alpha subunit) or B7 (ligand for CD28). Additional stimulation of the T-cell receptor CD3 complex, led to the upregulation of CD25. B7 was upregulated by concomittent activation of ERtax and CD3 or CD28 pathways. These events were in part reversible upon withdrawal of hormone and inactivation of ERtax. Severe inhibition of proliferation, and apoptosis was observed with cells which had been subjected to short term (3 days) activation of the tax fusion proteins and the CD3 complex. Induction of ERtax activity for longer than 3 days promoted cell death independently of CD3 stimulation. Co-stimulation through the CD28 cell surface molecule did not suppress induction of apoptosis. PMID- 7838528 TI - Deletion mapping in neuroblastoma cell lines suggests two distinct tumor suppressor genes in the 1p35-36 region, only one of which is associated with N myc amplification. AB - Neuroblastoma is characterized by deletions of the short arm of chromosome 1 (1p) and amplification of the N-myc oncogene. We have made somatic cell hybrids of two human neuroblastoma cell lines, one with and one without N-myc expression and amplification. The expression of the amplified N-myc gene is completely switched off in the hybrids. This suggests that N-myc expression results from loss of a repressor function. As N-myc amplification is associated with loss of heterozygosity (LOH) of 1p36, we analysed 1p deletions in 16 neuroblastoma cell lines. The seven cell lines without N-myc amplification have no deletions or relatively small deletions, with an SRO on 1p36.23-33. This suggests that a tumor suppressor gene maps in this region. All nine cell lines with N-myc amplification have larger deletions, with an SRO from 1p35-36.1 to the telomere. This suggests that a second tumor suppressor gene which is associated with N-myc amplification maps more proximally. Fine mapping of 1p36 deletions in the two cell lines of the fusion experiment suggests that the distal locus is not a repressor of N-myc expression, but the more proximal locus could be a candidate for this function. PMID- 7838529 TI - Ligands for the receptor tyrosine kinases hek and elk: isolation of cDNAs encoding a family of proteins. AB - Hek is a member of the eph subfamily of receptor tyrosine kinases whose members include elk, hek2, sek, eph and eck among others. Using a soluble form of hek consisting of the extracellular region of the receptor fused to the Fc domain of human IgG1 and an expression cloning strategy, we have isolated two different but related cDNAs from the human T-lymphoma line HSB-2 that encode ligands for hek. The cDNAs encode proteins of 238 and 201 amino acids (44% amino acid identity) that are anchored to the membrane by glycosylphosphatidylinositol (GPI)-linkage. The proteins encoded by these cDNAs are bound by hek with affinity constants of 2 x 10(8) M-1. These proteins also bind the elk tyrosine kinase receptor. These cDNAs are related to other cDNAs that we have recently isolated from a human placental library that encode ligands for both hek and elk and define an emerging family of ligands for eph-related kinases (LERKs). PMID- 7838530 TI - Interaction between p53 and TGF beta 1 in control of epithelial cell proliferation. AB - Although loss of sensitivity to transforming growth factor beta (TGF beta) may be a key step in the escape of epithelial tumours from normal growth control, the intracellular signals determining responsiveness remain controversial, particularly the role of p53. We have investigated this question using thyroid epithelial lines as a model. We analysed (i) human thyroid cancer cell lines having either wild-type (wt) or mutant p53; (ii) rat thyroid lines derived by spontaneous immortalisation following introduction of mutant H-ras, which exhibit high levels of wt p53 but loss of p53-mediated cell-cycle control. Loss of response to TGF beta 1 was found in all human lines bearing mutant p53, and in the majority of the functionally equivalent rat lines, consistent with a role of wt p53 in mediating response. However, introduction of a dominant negative p53 mutant into TGF beta 1 responsive human lines containing wt p53 did not reduce responsiveness, demonstrating that p53 function is not necessary for TGF beta 1 response. On the other hand, expression of a temperature-sensitive (ts) p53 gene in a partially-responsive rat line demonstrated a highly significant modulation of TGF beta response, which fell from 65% inhibition of 3H-thymidine labelling index at 32.5 degrees C (wt p53 conformation) to only 14% at 37.5 degrees C (mutant conformation). The results suggest that p53 and TGF beta generate separate but interacting inhibitory signals, i.e. that p53 modulates but does not mediate TGF beta response. This conclusion explains previous conflicting data and is consistent with current models of cell cycle control by multiple inhibitors of cyclin-dependent kinases. PMID- 7838531 TI - Elongation and premature termination of transcripts initiated from c-fos and c myc promoters show dissimilar patterns. AB - RNA polymerase II seems to be prone to stop at intrinsic pause sites, thus introducing a further potential level of regulation. It was recently shown that RNA polymerase II was held at the P2 promoter of c-myc gene. We confirmed the presence of engaged polymerases in the murine fibroblastic Ltk- and pre-B lymphoid 70Z3 cell lines. High resolution run-on analysis and in vivo permanganate-dependent footprinting showed that this holds true for the c-fos gene in unstimulated cells where a strong block to transcription elongation was evidenced. In contrast to what was observed in the c-myc gene, an even more intense signal was observed in run-on experiments downstream to the promoter, on a c-fos oligonucleotide including position +385 where an in vitro transcription arrest site was previously mapped. Genomic footprinting of DNA from intact cells and isolated nuclei confirmed the involvement of several thymidines belonging to a T-rich stretch in a melted region which was not detected upon polymerase release. In order to observe a short abortive c-fos transcript accumulating in vivo we resorted to microinjection of c-fos templates in Xenopus oocytes where transcripts were stable. PMID- 7838532 TI - C-Myb acts as transcriptional activator of the quail PAX6 (PAX-QNR) promoter through two different mechanisms. AB - To understand the regulation of the Pax-6 gene, which plays an important role in eye development, we have characterized the promoter region of the quail Pax-6(Pax QNR) gene. In addition to TATA and CAAT boxes, sequence analysis revealed several putative cis-regulatory elements among which three myb-responsive elements (MRE). C-myb encodes a nuclear, DNA-binding phosphoprotein that functions as transcriptional regulator. Co-transfection in quail embryo cells of the Pax QNR/pax-6 promoter with a vector expressing the 75 kDa c-myb protein resulted in an increase in Pax-QNR promoter activity. By footprinting experiments we identified multiple binding sites for the myb protein within the promoter region. Protein containing the myb DNA-binding domain fused to the VP16-transactivation domain was fully efficient in Pax-QNR promoter transactivation, demonstrating that myb can transactivate through a direct binding on DNA. However, a myb truncated protein devoid of DNA-binding domain was also able to transactivate the Pax-QNR promoter. These results show that this promoter can be transactivated by the myb protein directly as well as indirectly. Finally we show by in situ hybridization that c-myb is strongly expressed in the developing neuroretina, simultaneously with Pax-QNR. These observations suggest that the c-myb protein may be a regulator of Pax-QNR/pax-6. PMID- 7838533 TI - A novel intracellular epithelial cell tyrosine kinase is expressed in the skin and gastrointestinal tract. AB - A portion of the catalytic domain of a novel tyrosine kinase was cloned from mouse intestinal crypt cells, in a screen designed to identify kinases that may play a role in the regeneration of the intestinal epithelium (E Siyanova, MS Serfas, IA Mazo and AL Tyner, Oncogene 9, 2053-2057). We have cloned a cDNA encoding this kinase, termed sik for src-related intestinal kinase. The sik cDNA encodes a 451 amino acid protein that shares 80% identity with the recently cloned human tyrosine kinase, brk. Sequences found in src family kinases, such as SH2 and SH3 domains and a putative regulatory tyrosine at the carboxy terminus are found in the sik kinase. In contrast, sik lacks a myristylation site. The protein encoded by the sik cDNA has tyrosine kinase activity when expressed in E. coli. We have determined that sik is expressed only in epithelial tissues, including the skin and lining of the alimentary canal, and using in situ hybridization we show that expression of sik mRNA is restricted to the cell layers immediately above the proliferative cell zone in these epithelia. The sik mRNA is first detected at day 15.5 of gestation in the mouse embryo, where it is expressed in the newly forming granular layer of the skin. The restricted expression of sik to differentiating cells of rapidly renewing epithelia suggests that sik may play a specialized role in these tissues. PMID- 7838534 TI - Heat treatment induces dephosphorylation of pRb and dissociation of T-antigen/pRb complex during transforming infection with SV40. AB - The effects of heat treatment on key cell cycle regulatory molecules is currently unknown. Using primary mouse kidney cell cultures induced to re-enter S-phase by transforming infection with SV40, the effects of thermal treatment on the phosphorylation state of the Retinoblastoma gene product (pRb) and on its ability to bind T-antigen were examined. Time course analysis showed no detectable inhibition of cellular protein and T-antigen synthesis up to 180 min treatment at 42.5 degrees C, while a gradual disappearance of the phosphorylated forms of pRb was observed after 90 min. Dephosphorylation of pRb was shown to correlate with inhibition of SV40-induced DNA synthesis. Also, large T-antigen/pRb protein complex was affected since a gradual dissociation of the hypophosphorylated pRb from large T-antigen was observed concomitant to the inhibition of DNA synthesis. The effects of heat treatment were found to be reversible after shifting the cultures to 37 degrees C. Cells were shown to resume DNA synthesis concomitant to the reappearance of the phosphorylated forms of pRb and rebinding of the hypophosphorylated form to large T-antigen within 6-8 h after recovery at 37 degrees C. In addition, no evidence for a bona fide hsp71/large T-antigen protein complex was seen under the experimental conditions used. The data strongly suggest that inhibition of DNA synthesis by heat treatment might involve either an increase in phosphatase activity or the inhibition of a pRb kinase activity. PMID- 7838536 TI - A CNS-enriched factor that binds to NF-kappa B and is required for interaction with HIV-1 tat. AB - The Human Immunodeficiency Virus type 1 (HIV-1) Tat protein is a potent activator of transcription directed by the long terminal repeat (LTR), an essential step in the life-cycle of HIV-1. While interaction of Tat with an RNA element encoded by downstream LTR sequences (termed TAR) is commonly considered essential to activation, numerous recent reports have implicated upstream transcription elements within the LTR as participants in mediating this activation. We have recently demonstrated that Tat activation occurs independent of the TAR element in certain cells derived from the central nervous system (CNS), and that this activation is mediated by the kappa B domain of the LTR. Further, CNS-derived cells were found to contain kappa B-binding activity capable of both interacting with Tat and activating LTR transcription in vitro. The present study demonstrates that the kappa B-binding transcription factor derived from CNS cells consists of a component indistinguishable from prototypical Nuclear Factor-kappa B (NF-kappa B) (in size, mobility on native gel, kinetics of activation and cognate binding sequence) as well as a supershifting component that is dissociable under certain conditions. The supershifting activity is found to stabilize binding of the presumed NF-kappa B to DNA. Further, only the form of NF kappa B which is associated with this supershifting activity is capable of binding Tat. We hypothesize a model in which Tat utilizes this interaction to activate HIV-1 through the NF-kappa B domain of the LTR in circumstances where TAR is absent. This model has implications with respect to the ability of Tat to alter cellular gene expression and perhaps contribute to the array of problems seen in HIV-1 infection such as altered immune status, CNS toxicity, and the formation of tumors. PMID- 7838535 TI - The retinoblastoma susceptibility gene product regulates Myc-mediated transcription. AB - The protein product of the retinoblastoma tumor suppressor gene (RB) has been demonstrated to bind c-Myc protein (Myc) in vitro. To determine whether RB regulates Myc transcriptional activity in vivo, GAL4-Myc chimeric expression plasmids were generated and cotransfected with a RB expression plasmid and a GAL4 dependent reporter plasmid. RB stimulated GAL4-Myc-mediated transcription, dependent upon a domain(s) in the amino-terminus of Myc. The stimulation of Myc mediated transcription by RB was cell-type specific and was inhibited by SV40 T antigen, but not by a T-antigen mutant defective in RB-binding. Moreover, RB mutants containing mutations in domain B of RB pocket were significantly reduced in their ability to stimulate GAL4-Myc mediated transcription. To determine whether RB and Myc interact in vivo either directly or indirectly, a two hybrid system was used where GAL4-Rb and Myc-VP16 expression constructs were cotransfected with a GAL4-dependent reporter plasmid. A significant increase of GAL4-dependent transcription was observed, dependent upon the presence of both GAL4-Rb and Myc-VP16 fusion proteins. Mutational analysis of the Myc-VP16 chimeric proteins suggests that the amino-terminus of Myc is essential for the interaction with RB. These results demonstrate that RB can regulate Myc-mediated transcription in vivo in a cell-type specific manner through protein-protein interactions. PMID- 7838537 TI - Enhanced expression of multiple protein tyrosine phosphatases in the regenerating mouse liver: isolation of PTP-RL10, a novel cytoplasmic-type phosphatase with sequence homology to cytoskeletal protein 4.1. AB - To elucidate the role that protein tyrosine phosphatase (PTPs) may play in liver regeneration, PTPs expressed in the mouse liver after partial hepatectomy (PH) were investigated by a PCR-based cloning method. Sequencing of 115 cDNA clones identified 10 different sequences including MPTP (T cell PTP), PTP-1B, PTP-P19, mR-PTP mu, R-PTP alpha, PTP NE-3 (PTP-P1), R-PTP-kappa and the murine homologue of human LAR. The remaining two sequences, PTP-RL9 and PTP-RL10, encoded novel PTPs. PTP-RL10 cDNA contained an open reading frame of 1176 amino acids with no apparent membrane-spanning region. The amino-terminal region had sequence homology to those of human erythrocyte protein 4.1 and ezrin, cytoskeletal proteins. In the regenerating liver, the levels of five PTP gene mRNAs (MPTP, PTP P19, R-PTP alpha, LAR homologue, and PTP-RL9) increased within 6 h, decreased to the normal level by 24 h, and increased again at 48 to 72 h after PH. The levels of PTP-1B and R-PTP-kappa mRNAs peaked within 6 h, decreased gradually, and returned to the normal level by 168 h after PH. In contrast, the levels of two PTP mRNAs (mR-PTP mu and PTP-RL10) peaked at 48 to 72 h, and returned to the normal level by 168 h after PH. No expression of PTP NE-3 was detected in the liver by Northern blotting. The differential expression of multiple PTPs during the pre-replicative and post-replicative stages of liver regeneration suggests that PTPs are involved in the regulation of growth and differentiation of liver cells. PMID- 7838538 TI - Should "associate members" be a new membership classification? PMID- 7838539 TI - What strategies are you using to maintain patient/public confidence in the clinical trials process? PMID- 7838540 TI - Head-shake vestibulo-ocular reflex testing: comparison of results with rotational chair testing. AB - The currently accepted "gold standard" for rotational testing of the vestibulo ocular reflex uses a servo-controlled chair for sinusoidal whole-body rotation. Previous work in our laboratory has shown good concordance between conventional rotational chair testing and head-on-body (or "head-shake") testing for gain and phase values of the vestibulo-ocular reflex as recorded and analyzed on our rotational chair system's software. In this article we describe results obtained from 10 normal subjects and 20 patients with reduced caloric responses using a portable system being developed in our laboratory that allows an examiner to generate both whole-body and head-on-body rotational stimuli. Test frequencies within the range 0.25 to 1.0 Hz were chosen for comparison with results obtained by conventional rotational chair testing. Visual conditions for all tests included both visually enhanced vestibulo-ocular reflex (real earth-fixed target) and mentally enhanced vestibulo-ocular reflex (imagined earth-fixed target, in darkness or with vision obscured) paradigms. Our results show general agreement between head-shake and rotational chair testing and both manual whole-body rotation and head-shake testing on our portable system for vestibulo-ocular reflex gain and phase testing, with the largest differences noted at 1.0 Hz. Portable rotational testing was well tolerated by young and elderly subjects alike. We expect manual whole-body rotation and head-shake testing will be useful adjuncts for examining vestibulo-ocular reflex function when more formal rotational chair testing is not possible. PMID- 7838541 TI - Supplemental maxillomandibular fixation with miniplate osteosynthesis. AB - Monocortical miniplate fixation provides biomechanical fixation of mandibular fractures. The ability of this system to adequately fixate fractures clinically has not been fully accepted. We analyzed our use of supplemental maxillomandibular fixation with miniplate osteosynthesis during a 5-year period, in 287 patients with 499 mandible fractures. A retrospective, matched pairing of identical fractures fixated with identical plating-schemes was carried out. Sixty five pairs of patients undergoing intraoral monocortical plating were identified. Patients in group 1 were treated with supplemental maxillomandibular fixation after surgery, whereas patients in group 2 were treated without postoperative maxillomandibular fixation. The rate of major complications was 11% with supplemental maxillomandibular fixation and 9% without supplemental maxillomandibular fixation (p > 0.05). The total rate of complications was 17% with supplemental maxillomandibular fixation and 20% without supplemental maxillomandibular fixation (p > 0.05). No statistically significant outcome advantage could be attributed to the use of maxillomandibular fixation. PMID- 7838542 TI - Sarcoidosis of the sinonasal tract: a new staging system. AB - Sarcoidosis is a chronic multisystem granulomatous disease that has a predilection for pulmonary and upper respiratory tract involvement. Because the initial signs and symptoms of sarcoidosis may be identical to those of other forms of chronic sinonasal inflammatory disease, these patients will often first seek treatment from an otolaryngologist. We present a series of 28 patients whose primary symptoms was involvement of a sinonasal tract. A new staging system is proposed to categorize the severity and sites of involvement and to guide the aggressiveness of therapy. Sarcoidosis should be considered in the differential diagnosis of inflammatory sinonasal disease. PMID- 7838543 TI - Preoperative and postoperative auditory and facial nerve function in cerebellopontine angle meningiomas. AB - Preoperative and postoperative facial nerve and auditory function were reviewed retrospectively in 13 cases of cerebellopontine angle meningiomas. According to their location within the posterior fossa and with special reference to the internal auditory canal, they were classified into a premeatal and a retromeatal group. All the tumors were removed by an otoneurosurgical team by use of a retrosigmoid approach. Postoperative results (1 year after operation) were compared within the two groups with respect to preservation of hearing (normal hearing in 31% and preservation of preoperative hearing in 69% of the cases) and facial nerve function (no or mild postoperative impairment in 69% of the cases). Both preoperative and postoperative impairment of facial nerve and auditory function prevailed in the premeatal group. For preservation of vital vascular and central nervous structures, subtotal resection with consecutive fractionated radiation therapy had to be performed in 30% of the cases. Our results provide substantial evidence that in cerebellopontine angle meningiomas a precise preoperative study of tumor location will assist in improving individual operative strategy and thus postoperative functional results. PMID- 7838544 TI - Acute postobstructive pulmonary edema. AB - Acute postobstructive pulmonary edema may occur after airway obstruction. A decrease in intrathoracic and intraalveolar pressures causes an increased blood flow into the pulmonary vasculature and favors the development of pulmonary edema. Two mechanisms for the development of acute postobstructive pulmonary edema are proposed: type 1 follows acute airway obstruction, and type 2 follows relief of chronic airway obstruction. PMID- 7838545 TI - Autologous fibrin tissue adhesive in endoscopic sinus surgery. AB - Endoscopic sinus surgery may be complicated by bleeding, formation of synechia, and infection. This study investigated the application of autologous fibrin tissue adhesive during endoscopic sinus surgery in an attempt to avoid packing, to decrease complications, and to improve healing. Fibrin tissue adhesive from pooled human blood is a hemostatic and bacteriostatic agent. Autologous fibrin tissue adhesive avoids the potential infectious and immunologic risks of the pooled blood product. Twelve patients undergoing bilateral endoscopic sinus surgery participated in the study. Phlebotomy and preparation of the adhesive were performed during the procedure. Fibrin tissue adhesive was applied to only one side, with the contralateral side used as a control. Bacitracin ointment was applied to the adhesive-treated side, and packing coated with bacitracin was placed on the contralateral side. Patients were observed for a minimum of 3 months, and results were documented with photographic and video recordings. A uniformly high degree of patient satisfaction was achieved because of the elimination of packing and a sensation of increased nasal airway patency on the fibrin-treated side. Fibrin tissue adhesive provided hemostasis, decreased crusting, accelerated mucosal healing, and diminished synechia. Autologous fibrin tissue adhesive is beneficial in endoscopic sinus surgery, and its application should be considered, especially when the risk of hemorrhage or synechia is increased. PMID- 7838546 TI - Immunologic defects in patients with chronic recurrent sinusitis: diagnosis and management. AB - Twenty patients with chronic refractory sinusitis or rhinitis were identified to have immune defects on the basis of total immunoglobulin level, immunoglobulin G subclass, and vaccine response. Eight patients were immunoglobulin A deficient, five had low immunoglobulin levels with vaccine hyporesponse, and four had low immunoglobulin levels with normal vaccine responses. Three subjects showed isolated immunoglobulin G1 deficiency. Demographic variables such as age, sex, infection pattern, and any other related disorders were studied retrospectively, which may have contributed to the diagnosis. An immunologic screen was essential for the diagnosis of immunodeficiency in these patients. Treatment options included prophylactic antibiotics, management of associated allergies, functional endoscopic sinus surgery, and replacement therapy with immunoglobulin in selected patients. PMID- 7838547 TI - Radiation exposure in paranasal sinus imaging. AB - Plain films of the paranasal sinus were the imaging technique most frequently used before the advent of computed tomography. With improved resolution, computed tomography imaging has become the standard for evaluating patients with disease of the paranasal sinuses. With the widespread availability of computed tomography scanning, patients are likely to undergo multiple examinations during the treatment of their disease. Concern has been raised over the radiation exposure to the patient, in particular, with regard to radiation-induced cataracts. The purpose of this study is to measure the radiation dose associated with a variety of techniques for imaging the paranasal sinuses. A cadaveric specimen with thermoluminescent dosimeters placed over the orbits was used to measure radiation exposure during plain-film imaging, limited computed tomography, standard axial and coronal computed tomography, thin-cut axial computed tomography, and thin-cut coronal computed tomography. The measured dose in all these techniques is less than 4% of the acute dose associated with cataract formation. PMID- 7838548 TI - Rhabdomyosarcoma of the nose and paranasal sinuses in adults and children. AB - OBJECTIVE: To determine the biologic behavior, risk factors for recurrence, and influence of multimodality therapy on outcome for children and adults with rhabdomyosarcoma of the nose and paranasal sinuses. DESIGN: Retrospective review of medical records. PATIENTS: During a 36-year period 37 patients (median age, 23.0 years) with histologically confirmed rhabdomyosarcoma of the nose and paranasal sinuses were treated for cure. Median follow-up was 28 months (range, 1 to 260 months). Histologic subtypes included embryonal, 16; alveolar, 15; mixed, 1; and unclassified, 5. Cervical metastases were present in 38%. Patients were treated with surgery, 4; radiotherapy, 3; chemotherapy, 3; surgery and radiotherapy, 1; surgery and chemotherapy, 1; chemotherapy and radiotherapy, 24; and chemotherapy, radiotherapy, and surgery, 1. RESULTS: The overall 5-year survival was 44%. For patients treated with chemotherapy and radiotherapy or chemotherapy, radiotherapy, and surgery, the 5-year survival was 60%, compared with 19% for patients treated with the other forms of therapy. Factors associated with poorer survival were adult onset of disease, alveolar histology, and treatment with systemic chemotherapy for less than 1 year. Patients receiving chemotherapy for greater than 1 year had a 5-year survival of 82%, compared with 71% for those with less than 1 year of treatment. Improved survival was associated with a lower incidence of distant metastasis. CONCLUSIONS: A combination of chemotherapy and radiotherapy may provide the best means of obtaining local-regional control for rhabdomyosarcoma arising in the nose and paranasal sinuses. The risk of regional disease is high, requiring comprehensive radiotherapy to the neck in addition to the primary site. Surgical resection should be reserved for patients with residual disease after chemotherapy and radiotherapy. Administration of chemotherapy for more than 1 year is associated with improved survival because of a decreased incidence of metastatic disease. PMID- 7838549 TI - Analysis of the pharyngoesophageal pressure profile in amyotrophic lateral sclerosis. AB - Treatment of dysphagia resulting from bulbar amyotrophic lateral sclerosis has included cricopharyngeal myotomy for many years but is successful in only a minority of cases. The purpose of this study was to explore the rationale for this procedure with modern manometric techniques. The results of pharyngoesophageal manometry in 13 patients with amyotrophic lateral sclerosis were compared with 13 age- and sex-matched healthy volunteers by Mann-Whitney analysis. There was no significant difference between patients and control subjects in distal esophageal or lower esophageal sphincter motility nor any pressure parameter of pharyngoesophageal motility. Separate analysis of the seven significantly dysphagic subjects showed a significantly reduced upper esophageal sphincter after-contraction amplitude during water and bread swallows in patients than in control subjects. These data suggest that the dysphagia of amyotrophic lateral sclerosis is not due to upper esophageal sphincter spasm and that treatment by cricopharyngeal myotomy may be inappropriate. PMID- 7838551 TI - Distribution of C cells in the thyroid gland with pyriform sinus fistula. AB - A pyriform sinus fistula can cause acute thyroiditis or recurrent infection in the neck. This fistula is believed to be a remnant of the branchial apparatus, although its origin has yet to be pinpointed. The spatial distribution of C cells in the thyroid gland was mapped by immunohistologic method in four patients with a pyriform sinus fistula. The C cells were identified immunohistologically with anticalcitonin antibody. The stained calcitonin-positive cells also crossreacted with the antibodies to carcinoembryonic antigen, chromogranin A, and neuron specific enolase. The C cells were mainly distributed near the end of the fistula, and in three patients their concentration per unit volume of thyroid tissue was found to be inversely proportional to the distance from the end of the fistulas. Comparison of distant locations of the left-sided thyroid lobe in patients and the same region in control subjects showed a similar number of C cells. Thus this limited distribution of C cells suggested that the pyriform sinus fistula was either a remnant of the ultimobranchial body, the result of disturbed migration of the C cell in the fetus, or both. PMID- 7838550 TI - Propofol-based anesthesia as compared with standard anesthetic techniques for middle ear surgery. AB - OBJECTIVE: To determine whether a totally intravenous technique with propofol and fentanyl is superior to isoflurane anesthesia in patients undergoing middle ear surgery. DESIGN: Prospective randomized study. SETTING: Inpatient otolaryngology service at a university medical center. PATIENTS: Physical status 1 and 2 nonobese patients with no significant history of diabetes, chronic cholecystitis, neuropathy, or neuromuscular disorders that could produce delayed gastric emptying. One hundred two patients were admitted to the study and randomly divided into three equal groups. INTERVENTIONS: Intravenous thiopental, 5 mg/kg, was administered for induction of anesthesia followed by 60% air/O2 with isoflurane, 1% to 2% end tidal, for maintenance anesthesia (group 1). The same anesthetic with the addition of droperidol, 25 micrograms/kg, was given after induction (group 2). Propofol, 2 mg/kg, was administered intravenously for induction of anesthesia and followed by propofol, 50 to 250 micrograms/kg/min, for maintenance anesthesia. All groups received fentanyl, 3 micrograms/kg intravenously, after induction. MEASUREMENTS AND MAIN RESULTS: Surgical duration, induction, maintenance, and total anesthesia times were recorded together with eye opening and extubation. Intergroup comparisons of postoperative nausea, vomiting, and pain, and recovery scores, we made by use of the Steward system. Patients receiving propofol, compared with the isoflurane-only group, had significantly less nausea (4/34 vs 12/34 patients, respectively; p < 0.05) and as vomiting (2/34 vs 8/34 patients, respectively; p < 0.05). Immediate recovery scores were significantly better for propofol compared with the isoflurane droperidol group. Recovery scores at 30 minutes were also faster with propofol compared with isoflurane or isoflurane-droperidol (5.7 +/- 0.1 vs 5.1 +/- 0.2 and 5.2 +/- 0.2; p < 0.05). PMID- 7838552 TI - Treatment of cervical necrotizing fasciitis with hyperbaric oxygen therapy. AB - Hyperbaric oxygen therapy has significantly improved the management of necrotizing fasciitis of the extremities and trunk. Its role in cervical necrotizing fasciitis has not been fully evaluated. Historically, necrotizing fasciitis has been associated with considerable morbidity and mortality. This report discusses our experience with cervical necrotizing fasciitis in six patients treated from 1986 to 1993 who received hyperbaric oxygen therapy. All patients survived. In all cases infection was of probable odontogenic origin. Most patients in whom necrotizing fasciitis develops have identifiable risk factors; however, two patients in this series were previously healthy, and there was no relationship between hospital course and identified risk factors. Clinical presentation and microbiology are reviewed together with the rationale for hyperbaric oxygen therapy as an adjunct to broad-spectrum antibiotics and aggressive early surgical debridement. PMID- 7838553 TI - Correlation of compound action potential and electromyography with facial muscle tension. AB - Functional electric stimulation is a new method for dynamic rehabilitation of paralyzed muscles. The output of such prosthetic devices needs to be modulated by some index of the muscle movement. In facial paralysis a measure of the muscle contractions of the normal contralateral side seems to be an appropriate input. In the rabbit, we simultaneously measured the compound action potential of the buccal branch of the facial nerve, the electromyogram of the zygomaticus major muscle, and the muscle twitch tension through strain gauge. The compound action potential, electromyogram, and strain gauge each had a sigmoidal relationship to stimulus intensity. The compound action potential peak-to-peak amplitude was found to have a linear correlation to the peak twitch tension of the corresponding facial muscle. The electromyogram response, although more variable, also had a linear correlation with muscle contraction. The possibility of predicting the contraction of facial muscles before they actually occur is discussed in the context of available and future functional electric rehabilitation models. PMID- 7838554 TI - Comparison of polydioxanone and silicone plastic in the prevention of adhesive otitis media in the Mongolian gerbil. AB - Adhesion of the tympanic membrane to the promontory may occur in chronic otitis media or in the postoperative ear. Silicone plastic sheets are commonly used to form a physical barrier to adhesion. These sheets are generally well tolerated, but they are subject to occasional extrusion, encapsulation, or foreign body reaction. The ideal barrier to adhesion formation would be a nonreactive, flexible, absorbable substance that would obviate long-term toxicity considerations. In this study polydioxanone sheets were compared with silicone plastic sheets in the middle ear of the Mongolian gerbil. The eustachian tube was cauterized to create severe tympanic membrane retraction. A fabricated sheet of polydioxanone was implanted in the middle ear of 30 Mongolian gerbils and compared with silicone plastic sheets implanted in another group of 30 animals. A sham operation was performed on the other ear to serve as a surgical control. Evaluation of the temporal bones at 5, 10, and 15 weeks showed no significant differences in the rate of adhesion formation, effusion formation, or polymorphonuclear infiltration by the Fisher exact test. There was histologic evidence that polydioxanone was still providing an effective barrier at 10 weeks. The results of this study demonstrate that polydioxanone sheets are as effective and as well tolerated as silicone plastic sheets in an animal model. Further study of polydioxanone in this role is warranted. PMID- 7838555 TI - Indoor air pollution by emissions of fossil fuel single stoves: possibly a hitherto underrated risk factor in the development of carcinomas in the head and neck. AB - We have carried out three case-control studies on the relative risk of head and neck cancer in association with indoor air pollution. The studies performed at the Department of Otorhinolaryngology of the University of Heidelberg comprised 369 male patients with squamous cell carcinoma of the oral cavity, pharynx, and larynx and 1476 healthy control subjects matched for sex, age, and residential area. The OR of laryngeal cancer related to daily exposure to fossil fuels due to stove-heating with oil, coal, gas, and wood for longer than 40 years was 2.5 (CI = 1.51 to 4.05). After adjustment for tobacco and alcohol, the OR declined slightly to 2.0 (CI = 1.10 to 3.46) but still was significant. Elevated ORs were also found for daily presence in a kitchen with an oil, coal, or wood oven for longer than 40 years (OR = 1.7, CI = 1.01 to 2.71; after tobacco and alcohol adjustment, OR = 1.4, CI = 0.76 to 2.41). The OR of pharyngeal cancer related to daily exposure to fossil fuels due to stove-heating with oil, coal, gas, and wood for longer than 40 years was 3.6 (CI = 2.04 to 6.41). After adjustment for tobacco and alcohol the OR declined slightly to 3.3 (CI = 1.43 to 7.55) but still was significant. Elevated ORs were also found for daily presence in a kitchen with an oil, coal, or wood oven for longer than 40 years (OR = 1.6, CI = 0.89 to 2.77; after tobacco and alcohol adjustment, OR = 2.5, CI = 1.03 to 6.30).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7838556 TI - Focal epithelial hyperplasia. PMID- 7838557 TI - Bilateral oncocytic cysts of the nasopharynx. AB - We describe a 59-year-old male patient noted to have bilateral oncocytic cysts of the nasopharynx. These cysts appear to represent retention cysts of peritubal mucoserous glands that have undergone oncocytic metaplasia and would be classified as lateral acquired cysts of the nasopharynx. These cysts are benign but may cause symptoms related to their location in the airway and proximity to the eustachian tube. Endoscopic surgical removal is the treatment of choice. PMID- 7838558 TI - Simultaneous cochlear implantation and acoustic neuroma resection: imaging considerations, technique, and functional outcome. PMID- 7838559 TI - Bilateral hypoglossal nerve transection. PMID- 7838560 TI - Treatment of Kimura's disease: a therapeutic enigma. PMID- 7838561 TI - Cervical thymic cyst. PMID- 7838563 TI - Improved nasal septal prosthetic button. AB - Nasal septal button prostheses are useful alternatives to surgical management of symptomatic nasal septal perforations. The new modified button appears to be superior to the conventional button in several ways. It can be trimmed or ordered with larger or asymmetric disks if needed. The two new features of this button are (1) its flexible hub, giving it plasticity and adaptability; and (2) the tapered dome or umbrella-shaped, flexible disks, which allow for greater conformity to the septum. PMID- 7838562 TI - Retained bronchial foreign bodies: is there a role for high-resolution computed tomography scan? PMID- 7838565 TI - And the bad news is... PMID- 7838564 TI - Non-Hodgkin's lymphoma of the tonsil. PMID- 7838566 TI - Quality, freedom: are we selling our souls? PMID- 7838567 TI - Some habits are dirty and dangerous. PMID- 7838568 TI - 1994 Distinguished Service Award: Living the oath. PMID- 7838569 TI - Poised for tomorrow: An inside look at the educational and scientific trust. PMID- 7838570 TI - Treating HIV in Pennsylvania. PMID- 7838571 TI - Financial planning in an age of managed care. PMID- 7838572 TI - Developing a business plan for your practice. The Health Care Group. PMID- 7838573 TI - Rocking along with Grateful Med. PMID- 7838574 TI - CDAC prepares for implementation. PMID- 7838576 TI - Lessons in humility. PMID- 7838575 TI - Federal funds expand HIV/AIDS services. PMID- 7838577 TI - Career clinic. Your references: important allies in your job campaign. PMID- 7838578 TI - Whiplash injury. PMID- 7838579 TI - Decreased activity of spontaneous and noxiously evoked dorsal horn cells during transcutaneous electrical nerve stimulation (TENS). AB - The purpose of this study was to examine the effects of TENS application to somatic receptive fields on spontaneous and noxiously evoked dorsal horn cell activity in alpha-chloralose-anesthetized cat. Carbon-filament microelectrodes were used to record extracellular action potentials from 83 spontaneously discharging cells. Using a commercial TENS unit (Medtronic Eclipse Model 7723), spontaneous cell activity was decreased in 54% (65%) of the cells. Twenty-five (30%) did not respond and 4 (5%) increased activity. It was also shown that for 36 cells which were evoked with either manual pinch (19 cells) or manual clamp (17 cells), cell activity decreased during TENS application. This study shows that dorsal horn neurons which can potentially transmit noxious information to supraspinal levels, can have their cell activity decreased during TENS application to somatic receptive fields. This is consistent with the concept of the 'gate control theory of pain' in that less noxious information would be involved in the pain perception process. PMID- 7838580 TI - The occurrence and inter-rater reliability of myofascial trigger points in the quadratus lumborum and gluteus medius: a prospective study in non-specific low back pain patients and controls in general practice. AB - The presence of a trigger point is essential to the myofascial pain syndrome. This study centres on identifying clearer criteria for the presence of trigger points in the quadratus lumborum and gluteus medius muscle by investigating the occurrence and inter-rater reliability of trigger point symptoms. Using the symptoms and signs as described by Simons' 1990 definition and two other former sets of criteria, 61 non-specific low back pain patients and 63 controls were examined in general practice by 5 observers, working in pairs. From the two major criteria of Simons' 1990 definition only 'localized tenderness' has good discriminative ability and inter-rater reliability (kappa > 0.5). This study does not find proof for the clinical usefulness of 'referred pain', which has neither of these two abilities. The criteria 'jump sign' and 'recognition', on the condition that localized tenderness is present, also have good discriminative ability and inter-rater reliability. Trigger points defined by the criteria found eligible in this study allow significant distinction between non-specific low back pain patients and controls. This is not the case with trigger points defined by Simons' 1990 criteria. Concerning reliability there is also a significant difference between the two different criteria sets. This study suggests that the clinical usefulness of trigger points is increased when localized tenderness and the presence of either jump sign or patient's recognition of his pain complaint are used as criteria for the presence of trigger points in the M. quadratus lumborum and the M. gluteus medius. PMID- 7838581 TI - Percutaneous cervical cordotomy and subarachnoid phenol block using fluoroscopy in pain control of costopleural syndrome. AB - We examined the efficacy of percutaneous cervical cordotomy (PCC) and subarachnoid phenol block using fluoroscopy (SAPB-F) for control of chest and/or back pain from costopleural syndrome. The efficacy of each block was evaluated by changes in pain score (PS), analgesic dose and performance status 1 week after the block, as well as by the complications. Between 1980 and 1986, PCC was performed in 10 patients. SAPB-F was performed in 13 patients between 1987 and 1991. Pain was not well controlled by analgesics in any of these patients. For PCC the follow-up period was 94.7 +/- 71.1 days. PS (VAS, 0-10) reduced from 8.5 +/- 0.9 to 3.0 +/- 2.7. No analgesics were needed in 4 patients. Pain recurred in 1 patient. Hemiparesis occurred in 2 patients. General fatigue occurred in 6 patients. In 4 patients with these complications performance status deteriorated and did not recover during the follow-up period. For SAPB-F the follow-up period was 71.8 +/- 44.0 days. SAPB-F was designed to achieve selective phenol deposit at the targeted nerve root. PS decreased from 7.5 +/- 1.9 to 2.7 +/- 2.6. No analgesics were needed in 5 patients. Pain recurred in 3 patients. There were no complications and no changes in performance status. From this study we concluded that PCC is an effective method of pain control for costopleural syndrome, but a risk of serious complications is involved. SAPB-F is an effective and safe method and should be the first choice of nociceptive pathway block. PMID- 7838582 TI - Autogenic training and cognitive self-hypnosis for the treatment of recurrent headaches in three different subject groups. AB - The aims of this study were to (a) investigate the efficacy of autogenic training (AT) and cognitive self-hypnosis training (CSH) for the treatment of chronic headaches in comparison with a waiting-list control (WLC) condition, (b) investigate the influence of subject recruitment on treatment outcome and (c) explore whether the level of hypnotizability is related to therapy outcome. Three different subjects groups (group 1, patients (n = 58) who were referred by a neurological outpatient clinic; group 2, members (n = 48) of the community who responded to an advertisement in a newspaper; and group 3, students (n = 40) who responded to an advertisement in a university newspaper) were allocated at random to a therapy or WLC condition. During treatment, there was a significant reduction in the Headache Index scores of the subjects in contrast with the controls. At post-treatment and follow-up almost no significant differences were observed between the 2 treatment conditions or the 3 referral sources regarding the Headache Index, psychological distress (SCL-90) scores and medication use. Follow-up measurements indicated that therapeutic improvement was maintained. In both treatment conditions, the high-hypnotizable subjects achieved a greater reduction in headache pain at post-treatment and follow-up than did the low hypnotizable subjects. It is concluded that a relatively simple and highly structured relaxation technique for the treatment of chronic headache subjects may be preferable to more complex cognitive hypnotherapeutic procedures, irrespective of the source of recruitment. The level of hypnotic susceptibility seems to be a subject characteristic which is associated with a more favourable outcome in subjects treated with AT or CSH. PMID- 7838583 TI - Pain sensitivity and temperament in extremely low-birth-weight premature toddlers and preterm and full-term controls. AB - High-technology medical care of extremely low-birth-weight (ELBW) infants (< 1001 g) involves repeated medical interventions which are potentially painful and may later affect reaction to pain. At 18 months corrected age (CCA), we examined parent ratings of pain sensitivity and how pain sensitivity ratings related to child temperament and parenting style in 2 groups of ELBW children (49 with a birth weight of 480-800 g and 75 with a birth weight of 801-1000 g) and 2 control groups (42 heavier preterm (1500-2499 g) and 29 full-birth-weight (FBW) children (> 2500 g). Both groups of ELBW toddlers were rated by parents as significantly lower in pain sensitivity compared with both control groups. The relationships between child temperament and pain sensitivity rating varied systematically across the groups. Temperament was strongly related to rated pain sensitivity in the FBW group, moderately related in the heavier preterm and ELBW 801-1000 g groups, and not related in the lowest birth-weight group (< 801 g). Parental style did not mediate ratings of pain sensitivity. The results suggest that parents perceive differences in pain behavior of ELBW toddlers compared with heavier preterm and FBW toddlers, especially for those less than 801 g. Longitudinal research into the development of pain behavior for infants who experience lengthy hospitalization is warranted. PMID- 7838584 TI - Relief of post-herpetic neuralgia with the N-methyl-D-aspartic acid receptor antagonist ketamine: a double-blind, cross-over comparison with morphine and placebo. AB - Pain and sensory thresholds were examined before and after intravenous administration of ketamine (0.15 mg/kg), morphine (0.075 mg/kg) or saline in 8 patients with post-herpetic neuralgia. A randomized, double-blind, cross-over study design was used. Post-herpetic neuralgia was associated with impaired sensory function, as shown by reduced tactile and warm sensation in the affected compared with the contralateral non-affected skin area. Neither ketamine nor morphine changed significantly the thresholds for warm, cold, heat pain or tactile sensation. However, ketamine normalized abnormal heat pain sensations in 4 patients, probably due to a central effect. Ketamine, but not morphine, produced significant relief of pain. Pain evoked by non-noxious stimulation of the skin (allodynia) was significantly inhibited by ketamine as well as by morphine. Wind-up-like pain (i.e., pain evoked by repeatedly pricking the affected skin area) was significantly inhibited by ketamine, but significantly aggravated by morphine. Side effects were observed in all the 8 patients after injection of ketamine and in 6 patients after injection of morphine. The present results support the hypothesis that the N-methyl-D-aspartic acid (NMDA) receptors are involved in the control of post-herpetic neuralgia including allodynia and wind-up-like pain. The NMDA receptors also may play a role in the modulation of thermal perception. PMID- 7838585 TI - Conditioned place preference paradigm: a novel approach for analgesic drug assessment against chronic pain. AB - In response to concerns over the clinical relevance of analgesic testing paradigms which involve acute nociceptive stimuli, the present research examined the utility of the conditioned place preference (CPP) paradigm as a novel approach for determination of analgesic drug efficacy against chronic nociception. Rats display preferences for environments that have been previously paired with positively reinforcing drugs; whether place preference to the negatively reinforcing effects of analgesic drugs in an animal model of chronic pain occurs is yet unknown. The present research sought to determine whether animals experiencing chronic pain would display a place preference for an environment paired with analgesic drug treatment. Persistent inflammatory nociception was induced by unilateral injections of complete Freund's adjuvant (0.1 ml) into the rat hind paw. Place preference to the opiate agonist morphine, the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 and the non-steroidal anti-inflammatory drug (NSAID) indomethacin was examined in 3 separate experiments. Rats received 8 counter-balanced conditioning trials (4 drug, 4 no drug) of 60 min each with various drug doses (morphine: 3.0 and 10.0 mg/kg; indomethacin: 2.5 and 5.0 mg/kg; MK-801: 0.03, 0.1 and 0.3 mg/kg, i.p.) or vehicle serving as the reinforcing stimuli in a 3 compartment (2 stimuli, 1 neutral) place preference apparatus. In general, morphine place preference was observed in both inflamed and non-inflamed groups; inflamed groups exhibited enhanced morphine place preference than non-inflamed groups. MK-801 produced a low-dose place preference in inflamed animals; higher doses of MK-801 produced a place aversion in both inflamed and non-inflamed groups. Indomethacin failed to produced place preference in either inflamed or non-inflamed groups. These data demonstrate that the negatively reinforcing properties of analgesic drugs can be assessed via the CPP paradigm. In addition, this paradigm offers greater clinical relevance as animals determine drug efficacy without the involvement of high intensity, phasic nociceptive stimulation. PMID- 7838586 TI - The development of a battery of measures for assessing physical functioning of chronic pain patients. AB - The physical performance of chronic pain patients is of major concern both for their assessment and for treatment evaluation. However, there are few widely used physical tests, a shortage of reliability and validity data on published tests, and an over-reliance on self-report or on clinical measures of dubious generalisability. A set of tests was designed to cover speed and endurance in walking, stair climbing, standing up from a chair, sit-ups, arm endurance, grip strength, and peak flow. Standard instructions and testing conditions were used by a trained tester on a population of chronic pain patients before and after a cognitive-behavioural chronic pain management programme. Reliability, validity, and acceptability of each test was examined, and recommendations made for their relative utility. PMID- 7838587 TI - The Meaning of Illness Questionnaire: further evidence for its reliability and validity. AB - Cognitive appraisal processes or the meaning a person gives a stressful event are believed to mediate an individual's reaction to an event and, as such, have been demonstrated to explain adjustment to illness. The purpose of this paper is to test this cognitive as well as other social and illness variables to explain the variance in a person's adjustment to chronic pain. Two hundred and twenty-two patients, who were randomly selected from an original sample of referrals to a chronic pain specialty clinic, completed a questionnaire by telephone interview or mail. The questionnaire consisted of psychosocial scales (PAIS-SR; Social Support) and cognitions including the Meaning of Illness Questionnaire (MIQ). Fifty-six percent of the sample had poor psychosocial adjustment to their pain problem. Seventy percent of the variance in adjustment was explained by social and cognitive variables which corroborates their importance. The MIQ 5-factor structure was supported and provides credible evidence of the role of cognitions in differentiating between the poor and well adjusted. PMID- 7838589 TI - Medullary on-cell activity during tail-flick inhibition produced by heterotopic noxious stimulation. AB - Reflex responses and neuronal excitation elicited by noxious stimuli applied to a given body site can be inhibited by application of noxious stimulation to another, even distant body region. Such heterotopic noxious stimulation (HNS) has been proposed to act via 'diffuse noxious inhibitory controls' (DNIC) which involve supraspinal components. The so-called on-cells of the rostral ventromedial medulla (RVM) in rats are thought to facilitate nociceptive transmission. Experimental manipulations that inhibit on-cells also inhibit withdrawal reflexes and nociceptive thalamic responses. In the present study on cell activity was recorded in relation to the tail flick (TF) elicited by noxious heat applied to the tail both before and during either immersion of a paw in water above 56 degrees C or application of strong pinch to various body regions. Such HNS elicited strong activation of on-cells, followed by depression even when HNS continued. When this depression was intense, tail-heating failed to elicit vigorous on-cell firing, and TF was retarded or abolished. These results are compatible with the hypothesis that antinociception elicited by HNS involves depression of on-cell firing and hence lack of facilitation of nociceptive transmission. PMID- 7838588 TI - What is the maximum number of levels needed in pain intensity measurement? AB - An important issue that has yet to be resolved in pain measurement literature concerns the number of levels needed to assess self-reported pain intensity. An examination of treatment outcome literature shows a large variation in the number of levels used, from as few as 4 (e.g., 4-point Verbal Rating scales (VRS)) to as many as 101 (e.g., 101-point Numerical Rating scales (NRS)). The purpose of this study was to provide an empirically derived guideline for determining the number of levels needed. Chronic pain patients (n = 124) provided pre- and post treatment measures of pain intensity using 101-point NRS for least, most, current, and average pain. The patients' responses to the measures were examined closely to determine the actual number of levels used. In addition, their responses to the 101-point scales were recorded to form 7 scales of varying levels (2- to 101-point scales). The sensitivity of the 7 recorded scales was examined. The results indicated that little information is lost if 101-point scales are coded as 11- or 21-point scales. Moreover, examination of the actual responses to the 101-point measure showed that almost all patients treated it as a 21-point scale by providing responses in multiples of 5 or 10, while a substantial number of patients treated it as an 11-point scale, providing responses in multiples of 10 only. The results suggest that 10- and 21-point scales provide sufficient levels of discrimination, in general, for chronic pain patients to describe pain intensity. PMID- 7838590 TI - On the absence of correlation between responses to noxious heat, cold, electrical and ischemic stimulation. AB - Is a person's response to one noxious stimulus similar to his/her responses to other noxious stimuli? This long-investigated topic in pain research has provided inconclusive results. In the present study, 2 samples were studied: one using 60 healthy volunteers and the other using 29 patients with coronary artery disease. Results showed near-zero correlations between measures of heat, cold, ischemic, and electrical laboratory pains, as well as between these laboratory pains and an idiopathic pain, the latency to exercise-induced angina in the patients. Power analyses showed that the sample sizes were sufficient to detect a correlation of 0.50 or greater at the 0.05 level 99% of the time in the healthy volunteers, and between 80 and 85% of the time in the patients. Reliability analyses indicated retest correlations on the order of 0.60 for these measures, indicating that the lack of correlation between modalities was not due to unreliability within a measure. These studies fail to demonstrate alternate-forms reliability among these tests, and also fail to support the notion that a person can be characterized as generally stoical or generally complaining to any painful stimulus. In practice, this implies that a battery of tests should generally be used to assess pain sensitivity and also that assessments of one pain modality are not generally useful for making inferences about another. PMID- 7838591 TI - Tolrestat treatment prevents modification of the formalin test model of prolonged pain in hyperglycemic rats. AB - This study examined the effects of hyperglycemia and treatment with the aldose reductase inhibitor, Tolrestat, on the pain behavior evoked by injection of formalin into the dorsum of a single hind paw. In control rats, injection of formalin (50 microliters of a 5% solution) evoked two phases of flinching of the injected paw (phases 1 and 2), separated by a quiescent period. Four weeks of streptozotocin-induced diabetes or galactose intoxication did not alter the frequency of flinching during either of the active phases but significantly (P < 0.001 and P < 0.05, respectively) enhanced flinch frequency during the quiescent period. Concurrent treatment with Tolrestat (50 mg/kg/day by gavage) during hyperglycemia prevented the accumulation of the polyol pathway metabolites sorbitol and fructose in the nerve and spinal cord of streptozotocin-diabetic rats and also significantly (P < 0.05) reduced the enhanced flinching of diabetic rats during the quiescent period. These data demonstrate that hyperglycemia induces a period of Tolrestate-preventable hyperalgesia in a paradigm that is used to model persistent pain and suggest that exaggerated flux through aldose reductase may initiate changes in nociceptive pathways that could contribute to some of the pain states experienced by patients with diabetic neuropathy. PMID- 7838593 TI - The efficacy of opioids in cancer pain syndromes. AB - The treatment of pain in the patient with cancer necessitates careful assessment and definition of factors contributing to the pain complaint. We describe 3 cases of patients who had cancer, complained of pain, and were inappropriately treated with escalating doses of opioids. Opioid analgesic medications are commonly used in the management of pain in patients with cancer. Failure to respond to this treatment, the development of increasing pain, and the report of new side effects should prompt reassessment of opioid use. PMID- 7838594 TI - Cytokine mRNA expression in skin in response to ectoparasite infection. AB - Cellular infiltration and local cytokine mRNA levels were examined during the first 48 h of infection of skin by larvae of the sheep blowfly Lucilia cuprina. At the cellular level the response involved a dramatic influx of leucocytes (CD45+ cells). Among these infiltrating cells were large numbers of granulocytes, including neutrophils and eosinophils, as well as macrophage-like cells and lymphocytes. Many of the lymphocytes expressed cell surface markers characteristic of T cells including CD4, CD8 and the gamma delta TCR. The numbers of each of these cell types increased progressively as infection continued so that by 48 h the lesions were densely populated. Expression of mRNA for IL-6 could be detected by Northern blot analysis while mRNA for other inflammatory cytokines including IL-1 alpha, IL-1 beta, IL-8 and TNF alpha was detected using the polymerase chain reaction. Coincident with the influx of granulocytes and other cells there was an increase in the level of mRNA for the cytokines IL-1 alpha, IL-1 beta, IL-6 and IL-8. In the skin of the sheep there appeared to be constitutive expression of message for the cytokines IL-1 beta, IL-6 and TNF alpha, with the level of the latter not found to increase during the 48 h of infection examined. In situ hybridization was used to determine the location of IL-6 and TNF alpha mRNA within resting and infected skin. During infection, fibroblasts, macrophage-like cells and endothelium appeared to produce high levels of IL-6 mRNA. Expression of the T cell dependent cytokines IL-2 and IFN gamma but not IL-4, increased in expression as time progressed and the population of infiltrating cells, including T cells, expanded. PMID- 7838592 TI - Partial sciatic nerve ligation results in an enlargement of the receptive field and enhancement of the response of dorsal horn neurons to noxious stimulation by an adenosine agonist. AB - In this study we examined the effect of partial sciatic nerve ligation (PSNL) on the receptive field size, the baseline firing rate (BFR) and the response of spinal dorsal horn (DH) neurons to mechanical stimulation. In addition, we tested the effect of adenosine agonist, 5'-N-ethylcarboxamide-adenosine (NECA), and the adenosine antagonist caffeine on these parameters. Adult male Sprague-Dawley animals were used. One-third to one-half of the right sciatic nerve was tightly ligated. Unanesthetized animals were tested for their response to mechanical stimulation using Von Frey filaments and a blunt probe. The mean force that produced a paw withdrawal response in the operated animals was significantly less than the force that produced withdrawal in unoperated animals (median: 103.5 vs. 259.7; P < 0.001 for the paw ipsilateral to the ligation). Extracellular recordings were made from nociceptive-specific DH neurons located in laminal I-V of chloral hydrate-anesthetized rats. Recordings were made from 38 neurons in the right and 29 cells in the left DH of unoperated and 40 cells in right and 41 cell in the left DH of operated animals. The BFRs of neurons recorded in the operated animals were not significantly different from those recorded in normal animals. The mean receptive field size (RFS) of neurons (both ipsilateral and contralateral to the ligation) in the operated animals was significantly larger than the RFS of unoperated animals (right side: 180 +/- 2.8 mm2 compared to 66 +/ 2.3 mm2; left side: 93 +/- 31 compared to 65 +/- 21). Twenty-four percent of all neurons in the operated group had bilateral receptive fields; in contrast, only 3% of the neurons in the control animals showed bilateral receptive fields. To examine the effects of adenosine agonist and antagonist, NECA and caffeine were applied next to the recording electrode.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7838595 TI - Protective antibodies against Taenia taeniaeformis in rats infected with eggs or injected with non-viable oncospheres or recombinant antigens of oncospheres. AB - Antibody responses against Taenia taeniaeformis in rats infected with eggs or injected with non-viable oncospheres or recombinant antigens of oncospheres were analysed by passive transfer of serum and Western blotting. When recipient rats were injected with 1 ml serum from donors infected with eggs (infected serum), they all showed complete resistance to oral egg challenge, whereas those injected with 1 ml serum from donors injected with either oncospheres or recombinant antigens (vaccinated serum) showed no resistance. IgG and IgG subclass responses detected by Western blotting revealed that antibody responses to oncosphere antigens in infected serum thoroughly differed from those in vaccinated serum. It is suggested that IgG2 alpha responses in infected serum should be used for screening of epitopes for candidate vaccine. PMID- 7838596 TI - Increased CD4+ T cell-dependent anti-erythrocyte antibody levels following the onset of parasite egg production in Schistosoma mansoni infected mice. AB - Anaemia has been reported to be a symptom of schistosomiasis mansoni. In other chronic infectious diseases, anti-red blood cell (RBC) antibodies have been suggested or shown to play a role in anaemia by participating in either complement or macrophage-dependent RBC elimination. To examine whether such a situation could be contributing to the anaemia of schistosomiasis, we examined RBC taken from infected mice for surface-bound antibodies. Our data show that prior to the onset of egg production infected mice have plasma haemoglobin levels that are indistinguishable from age matched controls (AMC). However, consistent with previous reports, following the initiation of egg laying, infected mice have significantly lower haemoglobin levels than AMC. Surface-bound IgM, IgG1 and IgG3 on RBC from infected mice increased markedly after egg laying began. Levels of RBC-associated IgG2b were similar on RBC from infected and normal mice. Antibody production against RBC was Th cell-dependent since it did not occur in mice depleted of CD4+ cells. Antibodies eluted from RBC of infected mice bound to isolated membranes of RBC from AMC and to a soluble extract of schistosome eggs. Furthermore, antibodies in serum from mice carrying patent infections bound to the membranes of RBC from normal mice. Taken together, these data suggest that schistosome eggs induce an antibody response which may cross react with a RBC surface antigen. PMID- 7838597 TI - Immunization with irradiated Plasmodium berghei sporozoites induces IL-2 and IFN gamma but not IL-4. AB - Protective immunity against Plasmodium induced by immunization with irradiated sporozoites (SPZ) depends on both humoral and cellular responses. Although circumsporozoite protein (CSP)-specific cytolytic T lymphocyte responses have been established as an effector system, other cell types are required for protection. We have previously demonstrated that although protective immunity and T cell proliferative reactivity to SPZ are mouse strain- and SPZ dose-dependent, no correlation between the two responses could be found. Since protective immunity involves functionally diverse T cell subsets, we asked whether the discordance between proliferative responses to SPZ and protective immunity might have resulted from selective activation of either the Th1 or Th2 cell subset. Protective immunity, in vitro proliferative responses, and lymphokine production were tested in BALB/c, C57Bl/6, and C3H/HeN mice immunized according to different SPZ regimens. The levels of IL-2 paralleled the proliferative reactivities in each mouse strain examined. Although IFN gamma levels were present in the unprimed lymphocyte cultures, they increased following each SPZ immunization, in C57Bl/6, moderate in C3H/HeN, and lowest in BALB/c splenic cultures. Surprisingly, no IL-4 was detected in splenic cultures from any mouse strain during proliferative activity or protective immunity. In contrast, elevated IL-6 production was noted after each immunization, regardless of the protective status and it correlated with anti-CSP IgG serum levels. These data establish that lymphokine profiles corresponding primarily to the Th1 cells were induced by immunization with P. berghei SPZ and that IL-4 secreting T cells were not induced by the SPZ-stage berghei antigens. PMID- 7838598 TI - Detection of Bm86 antigen in different strains of Boophilus microplus and effectiveness of immunization with recombinant Bm86. AB - The control of tick populations by using conventional strategies poses several problems, including the appearance of organophosphate resistant strains, among others. The possibility of using alternative strategies such as vaccination with tick antigens has been suggested by several authors. One particular antigen (Bm86) has been described and shown to be able to induce a protective immunity against the cattle tick Boophilus microplus. In this paper we demonstrate by means of immunohistochemical staining that this antigen is conserved among several strains of this species. These results correlate with those showing that animals vaccinated with a preparation of recombinant Bm86 were protected against challenge with the four different strains tested, including one resistant to organophosphates. These results favour the immunization with recombinant Bm86 for the control of the cattle tick B. microplus. PMID- 7838599 TI - Vaccination against gastrointestinal nematodes of sheep using purified secretory acetylcholinesterase from Trichostrongylus colubriformis--an initial pilot study. AB - Purified secretory acetylcholinesterase (sAChE) from Trichostrongylus colubriformis was used as a candidate vaccine against mixed T. colubriformis, Haemonchus contortus and C. oncophora challenge infections of sheep. Cross species protection was achieved with an average reduction in worm burden of all species of 31%, rising to 58% in individual cases. There was no consistent reduction in faecal egg counts and increases in anti-T. colubriformis sAChE IgG antibody levels following vaccination were modest. We suggest that improved antigen delivery systems will result in increased host protection. PMID- 7838600 TI - Diarrhea happens, a lot! PMID- 7838601 TI - Infectious diarrhea: introduction and commentary. PMID- 7838602 TI - Rotavirus and other viral causes of gastroenteritis. AB - Diarrheal diseases are a major cause of childhood morbidity and mortality worldwide. Viruses are the leading cause of diarrhea, and rotavirus is the major cause of severe dehydrating diarrhea in both developed and developing countries. Children with viral gastroenteritis generally present with watery non-bloody diarrhea, often with vomiting and low grade fever. Disease is self-limited and treatment is simple--fluid and electrolyte replacement, preferably via the oral route, with early refeeding. While various adjunctive therapies, such as bismuth subsalicylate and oral immunoglobulins, appear promising, they cannot be routinely recommended at this time. Prevention is the key: by good personal hygiene--particularly good handwashing, by maintaining safe water supplies, and in the future, by an effective rotavirus vaccine. PMID- 7838603 TI - Salmonella, Shigella, and Campylobacter: common bacterial causes of infectious diarrhea. AB - Salmonella, Shigella, and Campylobacter species are the most common causes of acute bacterial enteritis in the United States. These pathogens should be considered seriously in children who progress rapidly from secretory to inflammatory diarrhea syndrome or in whom diarrhea persists beyond 5 to 6 days. Furthermore, children who appear more toxic than their state of dehydration would suggest should be suspected of having an acute bacterial etiology for their diarrhea. Systemic, extraintestinal dissemination of these organisms is uncommon, with the exception of salmonella infection during the first year of life and in immunocompromised hosts. In this latter situation, culture of blood and other appropriate body fluids should be considered, along with empiric systemic antibiotic therapy. When antibiotics are warranted in patients with shigella or campylobacter infection, oral therapy is usually sufficient. Careful attention to handwashing and personal hygiene is always appropriate to prevent further spread of these organisms. The very low infectious dose of shigella infection mandates an even more compulsive attention to these latter recommendations when this organism is implicated. PMID- 7838604 TI - Aeromonas, Yersinia, and miscellaneous bacterial enteropathogens. PMID- 7838605 TI - Toxin-related diarrheas. PMID- 7838606 TI - Parasitic gastroenteritis. AB - Parasitic causes of diarrhea are common in pediatric patients and have important public health implications. Therefore, diagnosis should be pursued vigorously in the appropriate clinical setting. Giardia and Cryptosporidium infections are the most common causes of disease in the United States, and stool examination for ova and parasites is the best way to make the diagnosis. This should be performed three times, on alternate days, in order to rule out parasitic disease with confidence. In treatment of Giardia, it is important to interrupt transmission, particularly in the day-care setting. Because of the potential for major outbreaks, patients with cryptosporidiosis should be kept out of day care until their symptoms resolve. Although amebiasis is not a common problem in the United States, all patients with bloody diarrhea who have traveled to, or are from, endemic areas should be tested for amebiasis by serology and stool examination. If patients with suspected inflammatory bowel disease are being considered for therapy with corticosteroids, mucosal scrapings of colonic lesions should be examined for amoebae, because corticosteroid therapy can lead to more invasive amoebic disease. Acquired immunodeficiency syndrome patients with diarrhea can be infected with a number of pathogens and a specific diagnosis should be pursued aggressively. These patients are often infected with one or more of the parasites described in this article. The approach to diarrhea in these children is described in a separate article of this issue (Deveikis A. 'Gastrointestinal Disease in Immunocompromised Children," pages 562-569). PMID- 7838607 TI - Gastrointestinal disease in immunocompromised children. PMID- 7838608 TI - Laboratory diagnosis of infectious diarrhea. AB - The microbiology laboratory, in conjunction with the medical staff, must determine a reasonable approach to the evaluation of diarrheal stools since the cost to rule out all potential pathogens is prohibitive and control of the use of laboratory services is now a major focus in all institutions. All stool cultures should be examined for Campylobacter, Salmonella, and Shigella, the most common causes of inflammatory bacterial diarrhea in the United States. Special media for other pathogens should be added only if there is high regional endemicity or significant clinical suspicion. If a child has bloody diarrhea, a search for E coli O157:H7 is indicated. For patients with a history of raw seafood ingestion or foreign travel, the laboratory should be asked to screen specimens for Vibrio and Plesiomonas species. The report from the laboratory should specifically state what enteropathogens have been excluded, for example, "No Salmonella, Shigella, or Campylobacter isolated." A report of "negative" or "no enteric pathogens" is not very useful. Diagnosis of viral and parasitic enteritis and antibiotic associated diarrhea require a variety of additional tests. Clinicians are encouraged to discuss these issues with the pathologist or microbiologist at their local laboratory and be familiar with community microbiology practice, particularly which organisms require a special request for the laboratory to attempt identification. PMID- 7838609 TI - Sexually transmitted diseases. PMID- 7838610 TI - Can we ever get the lead out of our environment? PMID- 7838611 TI - The new CDC and AAP lead poisoning prevention recommendations: consensus versus controversy. AB - A considerable body of evidence has surfaced over the past several decades indicating that low-level lead exposure has detrimental effects for young children. As neurocognitive deficits have increasingly been found to be associated with lead levels as low as 10 micrograms/dL, the CDC has progressively lowered the threshold lead level designated as elevated to the present level of 10 micrograms/dL. The CDC also has recommended universal screening of all children for lead. These recommendations have engendered much controversy. After independently reviewing the relevant literature, the AAP and the National Academy of Science concurred with the CDC's conclusions and recommendations. As additional prevalence information becomes available, a more targeted approach to screening based on local prevalence data eventually may replace universal screening. However, as long as lead is found everywhere in the environment, children will continue to develop lead poisoning and suffer from its adverse effects. The problem of lead poisoning can be summarized best by a quote from a report of the Agency for Toxic Substances and Disease Registry to Congress, "Lead is toxic wherever it is found, and it is found everywhere." PMID- 7838612 TI - Low-level lead exposure and cognitive function in children. PMID- 7838613 TI - Management of childhood lead poisoning: strategies for chelation. PMID- 7838614 TI - Oral chelators for childhood lead poisoning. PMID- 7838615 TI - Environmental control and deleading. PMID- 7838616 TI - The role of nutrition in the prevention of lead poisoning in children. PMID- 7838617 TI - An expanded scoring system including an index of nutritional status for patients with cystic fibrosis. AB - Evaluation of success or failure of therapy for patients with cystic fibrosis (CF) commonly relies on the results of a single pulmonary function test (PFT). Most PFT measurements reflect different functional aspects of the lung. Although no single parameter can summarize all aspects of lung function, a combination of several may provide an advantage by reflecting the overall abnormality of lung function in one number. Cropp et al. (1982, Am Rev Respir Dis 126:211-216) developed a multiparameter pulmonary function score (PFS) using the results of six separate parameters obtained from a PFT. In CF, there is also the potential for declining nutritional status (NS), leading to malnutrition and skeletal muscle wasting. Our aim was to expand the PFS by including weighted information on NS, and to determine whether the expanded score (nutritional-pulmonary function score, NPFS) was more sensitive in detecting change in outcome variables than the PFS. Individual PFT parameters, percent ideal body weight (%IBW), and an index of anaerobic performance (AP) were measured in 21 patients on admission to the hospital and again at discharge. In the group as a whole, in-hospital therapy resulted in improvement (P < 0.01) in individual PFT parameters, %IBW, PFS, and NPFS, and no change in AP. While the PFS more effectively reflected improvement in lung function than did any single PFT parameter, the NPFS resulted in an even more sensitive index of change. Based on these results, we believe that the NPFS, which includes both lung and nutritional status, provides an effective and sensitive index of disease severity that can be used as a unifying measure to: 1) detect disease progression; 2) guide rehabilitation and training; 3) stratify patients for clinical trials; or 4) evaluate the effects of a therapeutic intervention. PMID- 7838618 TI - Effects of breathing a normoxic helium mixture on exercise tolerance of patients with cystic fibrosis. AB - Breathing helium-oxygen (He-O2) mixtures of 20.9% O2/79.1% He has been shown to increase exercise ventilation and peak oxygen uptake in healthy subjects. The improved exercise performance is thought to be due to the reduced density of He O2 compared to air and the resulting increases in ventilation. Patients with cystic fibrosis (CF) frequently have abnormal pulmonary function test results, low exercise ventilations and diminished exercise tolerance. This led to the hypothesis that in CF the exercise tolerance of patients might improve when breathing He-O2. To test this hypothesis, 11 patients with CF or mild to severe airway obstruction performed spirometry and progressive maximal exercise tests while breathing air or He-O2. The He-O2 mixture significantly increased (P < 0.05) forced expiratory volume in 1 sec (FEV1) by 8.2%, peak expired flow by 39%, and maximal voluntary ventilation (MVV) by 17.9% compared to air, while forced vital capacity (FVC) and forced mid-expiratory flow rate (FEF25-75%) were unchanged by breathing He-O2. Ventilation and oxygen uptake at matched submaximal power outputs were not increased while breathing He-O2, nor were peak exercise ventilation (VEpeak) or peak exercise oxygen uptake (VO2peak). Estimated hemoglobin saturation and total exercise time were also unchanged during He-O2 breathing. However, there was a trend for the subjects with the better FEV1 to increase VO2peak. Increases in VO2peak when breathing He-O2 and air were correlated (r = 0.67, P < 0.05) with the percent of predicted FEV1 values. Still, in the 11 patients as a group, breathing He-O2 did not significantly improve VO2peak, VEpeak, or exercise tolerance.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7838619 TI - The absorption and effect of dietary supplementation with omega-3 fatty acids on serum leukotriene B4 in patients with cystic fibrosis. AB - The substitution of omega-3 (n-3) fatty acids for omega-6 (n-6) fatty acids generates eicosanoids with diminished inflammatory effects. As the lungs of patients with cystic fibrosis (CF) are in a state of chronic inflammation in which increased amounts of eicosanoids are found, n-3 supplementation may reduce this level of inflammation and result in clinical improvement. The absorption and clinical effects of n-3 vs. n-6 fatty acids in CF were measured in a prospective, randomized, double-blind, crossover study in which 14 patients with CF (age: 6-16 years, mean 10.5 years; baseline Shwachman-Brasfield scores: 41-88, mean 76.7) received 6 weeks of n-3 ethyl ester concentrate from menhaden oil (100-131 mg/kg/day, mean 112.8) or n-6 fatty acids from safflower oil (102-132 mg/kg/day, mean 113.3), followed by a washout period of 6 weeks, and then 6 weeks of the other supplement. Analysis by gas chromatography showed that n-3 supplementation resulted in increased eicosapentaenoic acid (20:5n-3) in platelet phospholipids, from 0.14 to 2.16%, P < 0.05 and in increased docosahexaenoic acid (22:6n-3), from 1.33 to 3.72%, P < 0.05. Clinical effects were evaluated at weeks 0, 6, 12, and 18, and analyzed for differences among the n-3, n-6, and washout periods. No adverse effects were reported or observed. No statistically significant differences were found (ANOVA, P > 0.05) in Shwachman-Brasfield scores, sweat test, weight change, or forced expiratory volume and flow (FEV1, FEF25-75%, and FVC) percentiles. Tumor necrosis factor was not measurable in any serum sample. Serum leukotriene B4 (LTB4) levels were significantly reduced by n-3 fatty acids, mean reduction (-177 pg/mL) compared to n-6 fatty acids (+63 pg/mL) P < 0.05. These results show that both n-3 fatty acids are absorbed and incorporated into platelet phospholipids in patients with CF and reduced serum LTB4. No significant clinical differences or adverse effects were found. PMID- 7838620 TI - Benzyl-benzoate foam: effects on mite allergens in mattress, serum and nasal secretory IgE to Dermatophagoides pteronyssinus, and bronchial hyperreactivity in children with allergic asthma. AB - Home mattresses of 24 asthmatic children with house dust mite allergy were sprayed with either benzyl-benzoate foam or placebo in a double blind fashion, 10 days before the children left the residential house for asthmatic children Istituto Pio XII (located in the Italian Alps in an environment free of mites) and went back to their own home for the Christmas and Easter holidays. A further group of 8 children, whose mattresses received no treatment, was kept as an absolute control. Two days after spraying, benzyl-benzoate or placebo were vacuumed from the mattresses. Acarex test was performed immediately before spraying and at the end of each holiday period of 20 and 10 days, respectively. Bronchial hyperreactivity as well as serum and nasal secretory specific IgE for Dermatophagoides pteronyssinus were assessed in all children immediately before leaving and within 48 hr after returning to the residential house. The results of the study show that sprayed benzyl-benzoate foam was no more effective than placebo in reducing the level of house dust mite recovered from patients' mattresses, or in reducing bronchial hyperreactivity and IgE concentration in serum and nasal secretions. PMID- 7838621 TI - The use of aerosolized pentamidine for prophylaxis of Pneumocystis carinii pneumonia in children with leukemia. AB - We report our experience giving aerosolized pentamidine as prophylaxis for Pneumocystis carinii pneumonia (PCP) to 9 children (mean age, 7.33 years; range 3 17 years) with leukemia who were unable to tolerate trimethoprim-sulfamethoxazole (TMP-SMX) due to allergy or myelosuppression. The dose of pentamidine was modified for each child to correct for weight and approximate alveolar ventilation. We were able to administer the drug to younger children by using a cushioned face mask in place of the standard mouthpiece. One child experienced moderate coughing with administration of pentamidine. He and four others with a past medical history suggestive of reactive airways disease were pretreated with inhaled albuterol. No other adverse effects were noted. Treatment lasted an average of 8.11 +/- 4.1 months per child; no case of PCP occurred. We conclude that aerosolized pentamidine can be administered to even very young children and may be of benefit to all immunosuppressed children unable to use TMP-SMX prophylaxis. The adjusted dose used here appears to be safe, but further studies regarding drug delivery and efficacy are needed. PMID- 7838622 TI - Effect of dexamethasone and oxygen exposure on neonatal rat lung retinoic acid receptor proteins. AB - Retinol deficiency in animal models results in histopathologic airway changes that appear similar to those found in human premature infants with bronchopulmonary dysplasia (BPD). Dexamethasone (DEX), a steroid now often used in the treatment of BPD, might potentially affect lung vitamin A homeostasis since it alters serum and liver retinoid stores in certain models. Our objective was to determine the effect of DEX on neonatal rat lung retinoid status and the binding of retinoic acid (RA) to cytosolic and nuclear receptor proteins. We examined this effect both in room air and when the animals breathed 95% oxygen (O2). Twenty-four 1-day-old rat pups received either 1 microgram/g DEX subcutaneously, an equal volume of normal saline (NS) subcutaneously at 0 (start experiment time), 24, and 48 hours, or no injection at all, and were sacrificed at 72 hours. Twelve rats in each treatment group were housed in room air and 12 in each group were exposed to > 95% O2 for the 3 day period. Lung and liver were analyzed for retinyl palmitate (RP). Nuclear retinoic acid receptor (RAR) and cellular retinoic acid binding protein (CRABP) were measured by specific binding assays. DEX decreased liver RP by 33-55% and rat pup lung RP by over 60%; it also decreased lung RAR binding (mean dpm/microgram protein +/- SEM) in both room air and oxygen groups: Air (11.2 +/- 1.0) vs. Air/DEX (4.6 +/- 1.3, n = 6; P < 0.01), and O2 (18.2 +/- 0.6) vs. O2/DEX (3.2 +/- 0.6, n = 6; P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7838623 TI - Proximal and tracheal airway pressures during different modes of mechanical ventilation: an animal model study. AB - OBJECTIVE: To determine the differences between the mean proximal and tracheal airway pressures during 3 different modes of mechanical ventilation (MV) in an animal model of acute cardiac failure (CF) and respiratory failure (RF). DESIGN: Prospective, randomized, cross-over design. SETTING: University research laboratory. SUBJECTS: Twelve young pigs weighing 10-16 kg. INTERVENTIONS: The experimental protocol consisted of 3 stable 30 min conditions: when ventricular and pulmonary function was normal (control), after the induction of acute cardiac failure by a beta-blocking agent and after respiratory failure induced by repeated lung lavages. Modes of MV included controlled mechanical ventilation (CMV), high-frequency oscillation (HFO), and high-frequency jet ventilation (HFJV). MEASUREMENTS AND RESULTS: The tracheal mean airway pressure (P(aw)) was measured at the distal port of the Hi-lo jet tube using an air-filled pressure transducer. The mean transpulmonary P(aw) increased significantly from 0.41 +/- 0.14 kPa during the control period to 1.15 +/- 0.17 kPa (P < 0.0001) during the RF period. In all study periods both the proximal and tracheal P(aw) were lowest during HFJV. There was no difference between the proximal and tracheal P(aw) during CMV and HFJV throughout the protocol. In the cardiac and respiratory failure periods the proximal P(aw) (CF, 1.45 +/- 0.08 kPa; RF, 3.13 +/- 0.27 kPa) was significantly higher than the tracheal P(aw) (CF, 1.04 +/- 0.09 kPa, P < 0.01; RF, 2.18 +/- 0.3 kPa, P < 0.01) with HFO. When ventilated by HFO, the mean external oscillatory amplitude was 4.33 +/- 0.14 kPa and the intratracheal oscillatory amplitude was only 0.49 +/- 0.06 kPa (P < 0.0001). CONCLUSION: HFJV provides adequate respiratory support at lower P(aw) than CMV and HFO. Proximal P(aw) closely reflects tracheal P(aw) during CMV and HFJV. However, with HFO great pressure differences between the proximal and tracheal airways are evident. Therefore, additional intratracheal airway pressure monitoring seems to be very useful for optimizing ventilator settings during HFO. PMID- 7838624 TI - A new application of an old method for respiratory mechanics measurements: the passive inflation method in newborn infants during pressure-controlled ventilation. AB - We have previously described a passive inflation method during constant inspiratory flow for measuring total respiratory elastance and resistance during mechanical ventilation in newborns. The simple method for measuring respiratory mechanics had been assessed during decelerating inspiratory flow obtained with pressure controlled ventilation (PCV). We report an application of this method to preterm and full-term mechanically ventilated newborn infants and a comparison with the occlusion method. Twenty-one newborn infants (birth weight 1,060 to 3,650 g; gestational age 26 to 41 weeks), between 1 to 55 days of postnatal age, were enrolled in the study. They were ventilated with a "Servo ventilator 900C," first set in the pressure-controlled mode and then in the volume-controlled mode without changing the tidal volume (VT), inspiratory time or ventilator rate. Flow was measured through a pneumotachograph inserted between the endotracheal tube (ETT) and the breathing circuit; VT was obtained by integration of flow and airway pressure measured directly at the airway opening. Flow, volume, and pressure were plotted on analog X/Y tables to obtain pressure-volume (P/V) and flow-volume (V/V) loops, as well as pressure-time curves. Occlusion was performed by using the end-inspiratory and the end-expiratory pause buttons of the ventilator. The passive inflation method during PCV was based on the analysis of P/V and V/V loops and provided compliance (Crs(PC)infl.), resistance Rrs(PC)infl.) of the respiratory system, and intrinsic positive end-expiratory pressure (PEEP(PC)i,infl.). These values were compared with (1) compliance (Crs(PC)occl.) and intrinsic positive end-expiratory pressure (PEEP(PC)i,occl.) measured by the occlusion method during PCV; (2) static (Crs(VC),occl.) and dynamic (Crs(VC),dyn.) compliance, airway (R(aw)(VC),), tissue (Rrs(VC),visc.) and total resistance (Rrs(VC),occl.), and intrinsic positive end-expiratory pressure (PEEP(VC)i,occl.) measured by the occlusion method during volume controlled ventilation. Crs(PC),infl. correlated well with Crs(PC),occl., Crs(VC),occl., and Crs(VC),dyn.. Furthermore, Crs(PC),infl. and Crs(VC),dyn. did not differ significantly. Rrs(PC),infl. correlated well and did not differ significantly from total inspiratory resistance, i.e., the sum of R(aw)(VC) and Rrs(VC),vis. PEEPPC,i,infl. correlated well and did not differ significantly from PEEP(PC)i.occl. and from PEEP(VC),i,occl. The passive inflation method can be used during PCV with a decelerating flow waveform. It provides dynamic compliance, inspiratory resistance of the respiratory system, and intrinsic PEEP from the analysis of V/V and P/V loops recorded at the airway opening. This technique is simple to use and well tolerated by preterm and full-term ventilated newborn infants. It can be a good alternative to occlusion methods. PMID- 7838625 TI - Transtracheal oxygen use in a young girl with bronchopulmonary dysplasia. PMID- 7838626 TI - Nap studies underestimate the incidence of gastroesophageal reflux. AB - Shorter nap (1 and 4 hr) pH studies inaccurately diagnosed gastroesophageal reflux (GER) in a group of infants evaluated for apparent life threatening events (ALTE) and recurrent apnea. Twenty-five infants with a postconceptional age of 42 +/- 8 SD weeks, were evaluated by 12-hr polysomnography (PSG). Prior to the start of the 12-hr study, a 1-hr Tuttle Test was performed. By means of the 12-hr study 11 infants were diagnosed as having GER while the Tuttle Test incorrectly diagnosed 6 infants, 5 as having no GER and 1 as having GER when no GER was present (P < 0.05). No differences in the amount of periodic breathing (PB) or apnea density (AD) were found between the two studies. In addition, the first 4 hr of the 12-hr PSG segment following the first feeding was evaluated separately. In the 4-hr segment, two of the infants were incorrectly diagnosed as not having GER. In this study, nap studies failed to diagnose all of the infants with GER. Therefore, we conclude that an infant cannot be accurately diagnosed as not having GER without prolonged pH recording. PMID- 7838627 TI - Rhinovirus infection associated with severe lower respiratory tract illness and worsening lung disease in infants with bronchopulmonary dysplasia. PMID- 7838628 TI - An unusual cause of fatal hemoptysis in an adolescent. PMID- 7838629 TI - Resolution of chronic atelectasis in a child with asthma after aerosolized recombinant human DNase. PMID- 7838630 TI - Amplification of bacterial DNA using highly conserved sequences: automated analysis and potential for molecular triage of sepsis. AB - OBJECTIVE: The clinical diagnosis of sepsis remains difficult, particularly in the young child, and would be improved by a rapid and reliable method for identification of bacteria in blood and other body fluids. Polymerase chain reaction (PCR) amplification of highly conserved DNA sequences found in all bacteria would permit fast and sensitive determination of the presence of bacteria in clinical specimens. METHODOLOGY: A primer pair for highly conserved regions of bacterial DNA encoding 16S ribosomal RNA (rDNA) was utilized for PCR amplification. PCR products were analyzed by gel electrophoresis, and, after modification of the primers, by an automated 96-well plate reader. RESULTS: rDNA was amplified from 12 different species of bacteria, including Gram-negative and positive organisms. No signal was observed when total human DNA was used as template. Colorimetric analysis of amplified sequences using a 96-well format was also successful. CONCLUSIONS: We conclude that a single primer pair designed to anneal to a highly conserved region of bacterial DNA can amplify DNA specimens from a variety of different bacteria, while not amplifying human DNA. Such a molecular genetics approach can be fully automated with existing robotic technology. Because of speed, sensitivity, and cost, molecular triage of patients with signs and symptoms of possible bacterial infection will decrease morbidity and mortality among those with unrecognized bacteremia who are managed as outpatients, and will dramatically reduce hospital expenses from individuals who are admitted and are not bacteremic. PMID- 7838631 TI - Diverting managed care Medicaid patients from pediatric emergency department use. AB - OBJECTIVE: To evaluate the health outcomes of managed care Medicaid children with non-emergent conditions who were not authorized to be seen in the Pediatric Emergency Department (PED) by their primary care provider. DESIGN: Consecutive case surveillance from 6/29/92 to 2/2/93. SETTING: University based PED (17,500 visits/year) in inner city Baltimore. PARTICIPANTS: Cases were MAC children denied authorization to be seen for non-emergent conditions in the PED. Age and complaint matched MAC children were selected from the university based Pediatric Ambulatory Center (PAC) and from non-emergent PED visits (PED-seen) in order to compare utilization rates after denial. INTERVENTION: The Maryland Access to Care (MAC) Medicaid program (started in 12/91) emphasizes primary care and appropriate health care utilization by incorporating the following elements of managed care: assignment to primary care provider, gatekeeping, mandatory enrollment and fee for service. METHODS: Consecutive case surveillance from 6/29/92 to 2/2/93 was used to evaluate the health outcomes of MAC children denied authorization for non emergent care in a university based PED. One week following denial, a pediatric nurse practitioner contacted the patient's caretaker and the MAC provider to ascertain health outcome. Medicaid claims data was used to compare the six month health care utilization of the denied group to age and complaint matched children seen in the PED (PED-seen) or in a primary care clinic (PAC). RESULTS: 216 MAC patients were not authorized for a PED visit by their MAC providers. 123 (57%) saw their MAC provider within one week of the denied PED visit. 40 (18%) were not seen because their presenting complaint had resolved completely. No adverse health outcomes occurred because of delay in health care delivery. The subsequent ER utilization rate of the denied group was the same as the PED-seen comparison group, and significantly higher than that of the PAC group (P = .002). The denied group was hospitalized at a significantly higher rate relative to these comparison groups (P = .003). CONCLUSIONS: Diverting Medicaid children classified as non-emergent in an ER to their MAC providers can be a safe practice short term. However, denial of a PED visit has no impact on subsequent ER utilization by Medicaid participants and may be associated with higher hospitalization rate. Gatekeeping in this setting does not necessarily change the health care seeking behavior of these patients. PMID- 7838632 TI - Case control study of chronic fatigue in pediatric patients. AB - OBJECTIVE: To determine the demographic characteristics, medical features, psychological profile, and natural history of children with chronic fatigue. DESIGN: Case control study. SETTING: Pediatric Infectious Diseases Clinic of Kosair Children's Hospital, 1990 to 1992. PARTICIPANTS: Forty-four patients referred for persistent fatigue were evaluated. Twenty patients participated in a psychological study; 20 healthy controls of similar age and gender were recruited from community pediatric practices and 20 matched depressed controls were recruited from university psychiatry services (subjects were treated as groups in the analyses). MEASURES: Demographic data were obtained for all referred patients. Those with fatigue for at least 2 months and no alternative diagnosis received a detailed history, physical, and battery of laboratory tests (complete blood count, sedimentation rate, chemistry panel, chest X-ray thyroid stimulating hormone, thyroxine, anti-nuclear antibodies, urinalysis, immunoglobulins, and Epstein-Barr virus (EBV), toxoplasma, and cytomegalovirus serologies). Psychological study participants completed the following: background structured interview; Kaufman Brief Intelligence Test; Children's Depression Inventory; Child Behavior Checklist; Youth Self Report; Diagnostic Interview for Children and Adolescents-Revised; mail-in follow-up survey. RESULTS: The median age of fatigue patients was 14.3 years; 60% were female, 96% white, and 87% from the mid/upper socioeconomic status (SES). Fatigue patients were demographically similar to 21 patients referred for infectious mononucleosis (IM) but were older than other clinic patients (P < .0001). White race (P = .0568) and mid/upper SES (P = .0403) were over-represented among fatigue patients compared to patients referred for other diagnoses. Of 36 patients meeting criteria for further study, 5 had an IM-like illness including evidence of recent EBV infection. For the remaining 31 patients, clinical and laboratory evaluations were unrevealing. Psychological study subjects reported marked declines in quality-of-life and scored high on measures of internalizing, withdrawal, and social isolation. Nine met diagnostic criteria for depression, although depressive symptoms were not as prominent as those reported by depressed controls. Fatigue subjects scored higher on somatization than both control groups. The follow-up survey indicated symptomatic improvement in most patients. CONCLUSIONS: Chronic fatigue was a common reason for referral, with over-representation of white children from mid/upper SES. After exclusion of EBV-associated IM, screening laboratory tests were not helpful in establishing specific organic diagnoses. Whereas the natural history was favorable, chronic fatigue resulted in major quality-of-life changes and was associated with significant levels of psychosocial distress. IMPLICATIONS: Psychological evaluation is warranted in these patients, as some may have treatable psychological conditions. Given the absence of proved medical therapies, psychosocial interventions to improve quality-of-life should be studied. PMID- 7838633 TI - Clinical features and viral excretion in an infant with primary human herpesvirus 7 infection. AB - OBJECTIVE: To find clinical features of a virologically-confirmed patient with primary human herpesvirus 7 (HHV-7) infection and a relationship of the excretion of viruses between HHV-7 and human herpes-virus 6 (HHV-6). PATIENT AND METHODS: A 13-month-old boy who had a known prior history of exanthem subitum at 6 months of age developed fever for 3 days and a skin rash appeared as the fever was resolving. The course was accompanying with nonspecific signs and symptoms such as anorexia, irritability, mild diarrhea, palpebral edema, mild inflammation of pharynx, and mild occipital and cervical lymphadenopathy. Heparinized blood samples were used for isolation of HHV-6 and HHV-7 and detection of both virus DNA sequences by a nested polymerase chain reaction (PCR) amplification. Samples from other body sites were also tested for their DNA sequences using the PCR. Both virus antibody activity was measured by an indirect immunofluorescent assay or a neutralization test. RESULTS: Cultured mononuclear cells from the patient at the acute stage of the disease produced morphologic changes, which reacted only with the monoclonal antibody to HHV-7 but not with the antibody to HHV-6. Both viruses were not isolated from blood obtained at the convalescent stage. An antibody response of the patient indicated a seroconversion to HHV-7 but not to other microbial agents including HHV-6 and Mycoplasma pneumoniae. Both virus DNA sequences were detected in peripheral blood mononuclear cells at acute and convalescent stages. HHV-7 DNA was excreted into saliva and transiently into stool at an early convalescent stage followed by HHV-6 excretion into saliva. No HHV-7 and HHV-6 was excreted into urine. CONCLUSIONS: Clinical features of a virologically confirmed patient with primary HHV-7 infection were comparable with those of primary HHV-6 infection and HHV-7 infection may reactivate HHV-6. PMID- 7838634 TI - Clinical trial of glucose-oral rehydration solution (ORS), rice dextrin-ORS, and rice flour-ORS for the management of children with acute diarrhea and mild or moderate dehydration. AB - OBJECTIVE: To assess the effects of glucose (G)-oral rehydration solution (ORS), rice dextrin (RD)-ORS, and rice flour (RF)-ORS on fluid intake, rapidity of rehydration, and stool output of children with acute diarrhea and mild or moderate dehydration. METHODS: The study was a randomized, double-masked clinical trial. One hundred forty-six male infants, ages 3 to 36 months, were randomly assigned to one of three treatment groups. Clinical evaluations and fluid balances were conducted every 2 to 4 hours for 48 hours. Principal outcome variables were ORS consumption, recovery of hydration status, and fecal output. RESULTS: The groups were similar at admission with regard to age, nutritional status, history of the current episode, and clinical status. There were no differences in ORS consumption by treatment group during any period of study. During the first 6-hour period, patients in group RF had less stool output (16 +/ 14 g/kg/body weight) than those in group G (22 +/- 20 g/kg) or RD (21 +/- 19 g/kg; P < .05). After 12 hours of hospitalization, there were no differences by treatment group. Recovery of hydration status, changes in serum sodium and potassium, and duration of diarrhea in the hospital were similar in all three groups. CONCLUSION: There was a 24% to 27% reduction in stool output during the first 6 hours of treatment among children who received RF-ORS compared with those who received G-ORS or RD-ORS, but this effect did not persist after the first 12 hours of therapy. Because this difference was of small magnitude and limited duration, it has minor clinical importance. Thus, we conclude that the three solutions had similar efficacy for children with acute, watery diarrhea and mild or moderate dehydration. PMID- 7838635 TI - Manometrics for preterm and term infants: a new tool for old questions. AB - OBJECTIVE: The purpose of this study was to use low-compliance, continuous perfusion manometry to assess motor activity responses of preterm and term infants to three different methods of feeding commonly used in neonatal intensive care units. METHODS: All 48 infants who participated in this study were assigned to one of three feeding trials using a 20-calorie/oz formula. Trial 1 varied the mode of feeding, trial 2 varied the volume of feeding, and trial 3 varied the concentration of feeding. RESULTS: In trial 1, small intestinal motor activity changed similarly and significantly in response to intragastric (P < .005) and transpyloric feeding (P < .02). In trial 2, feeding containing a small volume (4 mL/kg) and a larger volume (10 mL/kg) elicited significant changes in motor activity compared to that seen during fasting (P < .005). In trial 3, motor activity differed in response to varying caloric density. Motor activity failed to change in response to feedings that contained one-third-concentration formula, but it did change in response to the feedings that contained two-thirds- and full concentration formula (P < .02). Furthermore, the onset of the motor response to feeding was inversely related to the concentration of formula (P < .01), and the duration of the fed response also was related to the concentration of formula (P < .01). CONCLUSIONS: Gastric and transpyloric feedings are equally potent in eliciting an intestinal motor response to feeding. Furthermore, a volume as small as 4 mL/kg is sufficient to elicit such a response. However, preterm intestinal motility responses are affected significantly by changes in the caloric density of formula, suggesting that diluted formula may not provide an optimal stimulant for the preterm intestinal functional responses to feeding. PMID- 7838636 TI - Gastrointestinal maturation and motility patterns as indicators for feeding the premature infant. PMID- 7838637 TI - Eating in preschool children with cystic fibrosis and healthy peers: behavioral analysis. AB - STUDY OBJECTIVE: To investigate calorie intake, behavioral eating styles, and parent perception of eating behavior of preschool children with cystic fibrosis (CF) compared with healthy peers. DESIGN: A two group comparison study. SETTING: A clinical sample of 32 preschool children with CF (aged 2 to 5 years) and a community sample of 29 healthy peers matched for age and socioeconomic status. MEASUREMENTS AND MAIN RESULTS: The two groups did not differ on the total number of calories consumed per day or the percentage of calories derived form fat. The CF sample achieved a significantly higher percent of the recommended daily allowance (RDA) of energy (95% RDA) than the control group (84% RDA), P < .05, but did not achieve the CF dietary recommendations of 120% RDA. On measures of behavioral eating style, the CF sample had significantly longer meals (24.63 min) than the control group (18.57 min), P < .01, but did not differ on pace of eating or calories consumed per bite. On a measure of parent report of mealtime behavior, parents of the CF sample identified mealtime behaviors of "dawdles" and "refuses food" as more problematic (M = .93) than parents of control children (M = .22), P < .05. CONCLUSIONS: While preschool children with CF consume as much or more than healthy peers, they are not achieving the CF dietary recommendations. Furthermore, there appear to be behavioral differences in eating and parent perception of CF children's eating that may contribute to the failure to achieve dietary recommendations. PMID- 7838638 TI - Inappropriate discharge instructions for youth athletes hospitalized for concussion. AB - OBJECTIVE: To evaluate the medical care, especially the discharge instructions regarding return to participation, received by youth athletes hospitalized for a closed head injury. METHODS: We examined the records of all patients admitted over a 5-year period (1987 through 1991) to The Children's Hospital of Alabama for a sports-related closed head injury. Descriptive information was recorded and discharge instructions reviewed. Injury severity was graded according to guidelines current during the study period, as well as those outlined most recently by the Colorado Medical Society, which have been endorsed by a number of organizations including the American Academy of Pediatrics. Discharge instructions recorded for each patient were then compared with those recommended in the guidelines. RESULTS: We identified 33 patients with sports-related closed head injuries. Grade 1 concussions (least severe) occurred in 8 patients (24.2%), grade 2 in 10 (30.3%), and grade 3 (most severe) in 15 (45.4%). Overall, discharge instructions were appropriate for only 10 patients (30.3%), including all with grade 1 concussions, but only 2 with a grade 2 (20.0%) and none with a grade 3 concussion. CONCLUSION: All who care for youth athletes must become familiar with the guidelines for management of concussion to provide appropriate care and counseling and to avoid a tragic outcome. PMID- 7838639 TI - The relationship between vigilance deficits and traffic injuries involving children. AB - OBJECTIVE: This study was designed to determine whether there is an increased frequency of deficits in impulse control, vigilance, or both, among child bicyclists or pedestrians who have been injured in traffic accidents, as assessed using objective measures and parent and teacher reports. RESEARCH DESIGN: This was a case-control study, in which cases were children injured as pedestrians or bicyclists (excluding those with severe head injuries) and controls were those injured as passengers or in some other manner in which the child's behavior was unlikely to be a factor. SETTING: Children ages 5 to 15 years presenting to the emergency room of the Montreal Children's Hospital. PARTICIPANTS: For each of 286 cases, two controls were selected, making a total of 848 subjects. Among the cases, 172 were injured as pedestrians and 114 as bicyclists. MEASURES: Children were assessed using the Continuous Performance Task and the Delayed Response Test, both parts of a computerized test battery. Parents and teachers completed the Conners Abbreviated Symptom Questionnaire to assess hyperactivity. RESULTS: Cases and controls were similar on most sociodemographic and clinical measures but showed statistically significant differences in mean scores on the Continuous Performance Task measures of omissions and commissions, pointing to differences in vigilance, and on the Delayed Response Test measures of impulsivity. Mean Conners scale scores of both parent and teacher were significantly higher for cases than controls, and those of parents were higher than those of teachers. CONCLUSIONS: Among children whose behavior may have been a factor in the occurrence of an injury, there is subjective evidence of increased hyperactivity and objective evidence of deficits in vigilance and attention when compared with closely matched controls. These findings have important implications for prevention. PMID- 7838640 TI - Coagulase-negative staphylococcal bacteremia among very low birth weight infants: relation to admission illness severity, resource use, and outcome. AB - OBJECTIVE: To examine the impact of admission-day illness severity on nosocomial bacteremia risk after consideration of traditional risk determinants such as birth weight and length of stay. METHODS: The hospital courses for 302 consecutive very low birth weight (less than 1500 g) infants admitted to two neonatal intensive care units were examined for the occurrence of nosocomial coagulase-negative staphylococcal bacteremia. Using both cumulative incidence and incidence density as measures of bacteremia risk, we explored the relation between illness severity (as measured by the Score for Neonatal Acute Physiology [SNAP]) and bacteremia both before and after birth weight adjustment. In addition, the effect of bacteremia on hospital resource use was estimated. RESULTS: Coagulase-negative staphylococcus was the most common pathogen noted in blood cultures drawn at 48 hours after admission or later. It was isolated on at least one occasion in 53 patients (cumulative incidence of 17.5 first episodes per 100 patients). These episodes occurred during 7652 days at risk, giving an incidence density of 6.9 initial bacteremias per 1000 patient-days at risk. As expected, when compared with the nonbacteremic group, bacteremic patients were of lower birth weight (888 +/- 231 vs 1127 +/- 258 g; P < .01) and gestational age (26.4 +/- 2.1 vs 28.9 +/- 2.8 weeks; P < .01). In addition, these patients were more severely ill on admission (SNAP 17.3 +/- 6.5 vs 12.2 +/- 5.8; P < .01). Even after birth weight stratification, the risk of bacteremia by both measures increased with higher SNAP scores. For example, among infants with birth weights greater than 1 kg, 25% of the most severely ill patients (SNAP 20 and higher) experienced at least one bacteremic episode, whereas the rates seen in infants with intermediate (SNAP 10 to 19) and low illness severity (SNAP 0 to 9) were 8.6% and 3.0%, respectively (chi 2 for trend = 7.25; P < .01). Multivariate linear regression showed that bacteremia was associated with a prolongation of neonatal intensive care unit stay of 14.0 +/- 4.0 days (P < .01) and an increase in hospital charges of $25,090 +/- 12,051 (P < .05), even after adjustment for birth weight and admission-day SNAP. CONCLUSIONS: Nosocomial coagulase-negative bacteremia is an important complication among very low birth weight infants. Assessment of illness severity with SNAP provides information regarding nosocomial infection risk beyond that available from birth weight alone. PMID- 7838641 TI - Biological rhythmicity in preterm infants prior to discharge from neonatal intensive care. AB - OBJECTIVE: The study of biological rhythms and the influence of environmental factors in the timing and synchronization of different rhythmic events have important implications for neonatal health. Preterm infants in the neonatal intensive care unit (NICU) are deprived of the patterned influences of maternal sleep, temperature, heart rate, and hormonal cycles. The impact of the NICU and nursing interventions on the development of the circadian system was studied in 17 stable preterm infants in the Intermediate Intensive Care Nursery at Stanford University for three consecutive days at about 35 weeks postconceptional age. OUTCOME MEASUREMENTS: Rectal temperature, abdominal skin temperature, heart rate, and activity were simultaneously recorded at 2-minute intervals during each 3-day study by a small microcomputer (Vitalog). RESULTS: Very low amplitude circadian rhythms were found for rectal and skin temperatures (maximum range 36.8 to 37.0 degrees C); population mean values for heart rate (158 bpm) and activity (3.5 counts per 2-min bin) did not differ significantly as a function of time of day. Rectal temperature, averaged in 6-hour bins over the 24-hour day as a function of both postconceptional age and postnatal age, was significantly higher during the first part of the circadian cycle. In all infants, rhythmicity in each variable was dominated by ultradian periodicities that were coincident with feedings and related interventions; moreover, several physiological variables charted during feeding differed significantly from values obtained during periods in which caregiving interventions did not occur. CONCLUSION: Quantitative data on the preterm infant circadian system may facilitate evaluation of factors that improve therapeutic responses, recovery, and outcome of neonatal intensive care patients. PMID- 7838642 TI - Continuous versus multiple rapid infusions of indomethacin: effects on cerebral blood flow velocity. AB - OBJECTIVE: Therapeutic administration of indomethacin for patent ductus arteriosus (PDA) closure has been documented to decrease cerebral blood flow velocity which may be harmful to the vulnerable premature neonate. We have therefore compared the effects of administering indomethacin by rapid injection versus slow, continuous indomethacin infusion at the same total therapeutic dose on middle cerebral artery (MCA) systolic and diastolic flow velocity, resistance index, and cerebral blood flow (as reflected by the integrated area under the curve). METHODS: Premature neonates (< 1750 g) documented echocardiographically to have a PDA were randomized to receive indomethacin either by three rapid injection doses or by continuous intravenous infusion over the ensuing 36 hours, providing an equivalent total dose. Echocardiograms and transcranial color flow mapping of the MCA flow velocity were measured at baseline and serially following initiation of therapy in both groups. Effects on cerebral blood flow velocity are presented. RESULTS: Eighteen infants [rapid injection-1.2 +/- 0.3 kg (n = 9) and continuous-1.1 +/- 0.2 kg (n = 9)] were studied. In the rapid injection treated infants decreased flow velocity in the MCA as manifested by abrupt, significant decreases in systolic (to 70 +/- 8% baseline) and diastolic (to 65 +/- 13% baseline) flow velocity and area under the curve (to 60 +/- 10% of baseline) were evident by 4 minutes and progressed to 30 minutes after treatment initiation. These changes were not observed in the group treated with continuous indomethacin. Both therapeutic modalities were equally successful in closing the ductus, although the numbers are too small to definitively determine therapeutic efficacy. CONCLUSIONS: Slow, continuous infusion eliminated the decrease in cerebral flow velocity and appears to be effective in closing the PDA. PMID- 7838643 TI - Cranial ultrasound prediction of disabling and nondisabling cerebral palsy at age two in a low birth weight population. AB - OBJECTIVE: To employ multivariate analytic techniques to assess the association between neonatal cranial ultrasound (US) abnormalities and subsequent cerebral palsy (CP), defined as disabling CP (DCP) or nondisabling CP (NDCP) depending on the level of motor dysfunction. DESIGN: Prospective cohort study. SUBJECTS AND METHODS: The Neonatal Brain Hemorrhage Study enrolled a geographically representative sample of 1105 newborns 501 to 2000 g and obtained follow-up data on 777 (86%) of the 901 survivors at age two. One hundred thirteen children (14.6%) had motor findings severe enough to classify them as having CP. The 61 (7.9%) of these children who were disabled by their motor impairment we classified as having DCP. The remaining 52 (6.7%) who had definite neurologic findings (usually mild spastic diplegia) but without evidence of interference with daily living, we classified as having NDCP. RESULTS: In a multivariate logistic regression model of perinatal and postnatal variables, the following factors were found to be significant risk factors for DCP: parenchymal echodensities/lucencies or ventricular enlargement (PEL/VE) on cranial US (OR = 15.4; 7.6, 31.1), germinal matrix/intraventricular hemorrhage (GM/IVH) (OR = 3.5; 1.7, 6.9) and mechanical ventilation (OR = 2.9; 1.2, 7.1). Fully 93.4% of infants were correctly classified as to presence or absence of DCP on the basis of this model. Birth weight, gestational age, length of hospital stay, gender, race, plurality, presence of labor and Apgar score were not significant independent predictors of DCP. For NDCP, the only risk factor significant in the multivariate model was PEL/VE (OR = 5.3; 2.2, 12.6). CONCLUSIONS: Among perinatal and postnatal factors, cranial US abnormalities are by far the most powerful predictors of disabling CP in low birth weight infants. Although PEL/VE was the strongest predictor, GM/IVH also appeared to independently contribute to the risk of DCP. NDCP in low birth weight infants appears to have a different risk profile than DCP. In particular, it is less closely related to US evidence of perinatal brain injury. PMID- 7838645 TI - Abusive head trauma: the relationship of perpetrators to their victims. AB - OBJECTIVE: Abusive head trauma is the most common cause of morbidity and mortality in physically abused infants. Effective prevention requires the identification of potential perpetrators. No study has specifically addressed the relationship of the perpetrators of abusive head trauma ("shaken baby syndrome") to their victims. The objectives of this study were to identify the abusers and their relationship to victims in these cases. METHODS: We reviewed the medical charts of 151 infants who suffered abusive head trauma to determine the perpetrator of the abuse. Caretakers were classified by level of certainty: confession to the crime, legal actions taken, or strong suspicion by the staff. The relationship of abusers to victims was analyzed. RESULTS: Male victims accounted for 60.3% of the cases. Twenty-three percent of the children died, although death rates for boys and girls did not vary significantly. Male perpetrators outnumbered females 2.2:1, with fathers, step-fathers, and mothers' boyfriends committing over 60% of the crimes. Fathers accounted for 37% of the abusers, followed by boyfriends at 20.5%. Female baby-sitters, at 17.3%, were a large, previously unrecognized group of perpetrators. Mothers were responsible for only 12.6% of our cases. All but one of the confessed abusers were with the child at the time of onset of symptoms. CONCLUSIONS: Our data suggest male caretakers are at greater risk to abuse infants. Baby-sitters are a concerning risk group, because they represent a significant proportion of abusers, and they more easily escape prosecution. In addition, no prevention efforts have been directed at baby-sitters. These statistics could help change the focus of efforts to prevent abusive head trauma. PMID- 7838644 TI - Lidocaine adrenaline tetracaine gel versus tetracaine adrenaline cocaine gel for topical anesthesia in linear scalp and facial lacerations in children aged 5 to 17 years. AB - STUDY OBJECTIVE: The purpose of the present study is to compare LAT gel (4% lidocaine, 1:2000 adrenaline, 0.5% tetracaine) to TAC gel (0.5% tetracaine, 1:2000 adrenaline, 11.8% cocaine) for efficacy, side effects, and costs in children aged 5 to 17 years with facial or scalp lacerations. DESIGN: Randomized, prospective, double-blinded clinical trial. SETTING: Inner-city Emergency Department with an Emergency Medicine residency program. PATIENTS OR OTHER PARTICIPANTS: Children aged 5 to 17 years with linear lacerations of the face or scalp. INTERVENTION: After informed consent was obtained patients had lacerations anesthetized with topical TAC or LAT gel according to a random numbers table. MEASUREMENTS AND MAIN RESULTS: A total of 95 patients were included in the statistical analysis with 47 receiving TAC and 48 receiving LAT. Physicians and patients/parents separately rated the overall pain of suturing using a modified multidimensional scale for pain assessment specifically for children. Patients/parents also stated the number of sutures causing pain. The power of the study to determine a ranked sum difference of 15 was 0.8. Multidimensional rating scale results and number and percentage of sutures causing pain were compared using Wilcoxon's rank sum test. According to patients no difference could be detected in percent of sutures causing pain in the LAT versus TAC group (P = .51). Using the multidimensional scale, physicians and patients/parents found LAT statistically the same as TAC in effectiveness (P = .80 for physicians and P = .71 for patients). Cost per application was $3.00 for LAT compared to $35.00 for TAC. Follow-up was accomplished in 85 of 95 participants in the study with no reported complications for either medication. CONCLUSION: LAT gel worked as well as TAC gel for topical anesthesia in facial and scalp lacerations. Considering the advantages of a noncontrolled substance and less expense, LAT gel appears to be better suited than TAC gel for topical anesthesia in laceration repair in children. PMID- 7838646 TI - Can magnesium sulfate reduce the risk of cerebral palsy in very low birthweight infants? AB - OBJECTIVES: To investigate whether in utero exposure to magnesium sulfate (MgSO4) was associated with a lower prevalence of cerebral palsy (CP) in infants born weighing < 1500 g. DESIGN: Singleton infants weighing < 1500 g at birth (very low birthweight, VLBW) and surviving to 3 years with moderate or severe congenital CP were identified among 155,636 children born 1983 through 1985 in four California counties. VLBW children with CP were compared with randomly selected VLBW control survivors with respect to whether their mothers received MgSO4 to prevent convulsions in preeclampsia or as a tocolytic agent, and other information abstracted from labor and delivery records. RESULTS: During the admission for delivery, 7.1% of the 42 VLBW infants with later CP and 36% of the 75 VLBW controls were exposed to MgSO4 (odds ratio (OR) .14, 95% confidence interval (CI) .05, .51). The overall association of MgSO4 with reduced risk of CP was also observed in the subgroup of infants born to women who were not preeclamptic (OR .25, CI .08, .97). Infants with CP were less often exposed antenatally to MgSO4 whether or not there was cotreatment with non-MgSO4 tocolytics (other tocolytics administered, OR for MgSO4 exposure .23, CI .06, 1.2; other tocolytics not administered, OR for MgSO4 .08, CI .02, .68), or antenatal corticosteroids (steroids given, OR for MgSO4 exposure .24, CI .06, 1.3; steroids not given, OR for MgSO4, .08, CI .02, .72). Apparent benefit of magnesium was observed in the presence or absence of a variety of characteristics of pregnancies, births, and infants. CONCLUSION: In this observational study, in utero exposure to MgSO4 was more frequent in controls than in children with CP, suggesting a protective effect of MgSO4 against CP in these VLBW infants. PMID- 7838647 TI - The education of pediatricians for primary care: the score after two score years. PMID- 7838648 TI - TIPP--the first ten years. PMID- 7838649 TI - Fatal hantavirus pulmonary syndrome in an adolescent. PMID- 7838650 TI - Condom availability for youth. Committee on Adolescence, American Academy of Pediatrics. PMID- 7838651 TI - Guidelines for the ethical conduct of studies to evaluate drugs in pediatric populations. Committee on Drugs, American Academy of Pediatrics. PMID- 7838652 TI - Children, adolescents, and advertising. Committee on Communications, American Academy of Pediatrics. PMID- 7838653 TI - Sexuality, contraception, and the media. Committee on Communications, American Academy of Pediatrics. PMID- 7838654 TI - Medication dispensing in pediatric office practice. Committee on Practice and Ambulatory Medicine, American Academy of Pediatrics. AB - The changing practice of dispensing medication in pediatric offices needs ongoing evaluation to determine the extent to which patients' and practice's needs are being met. Research should assess the extent to which in-office dispensing enhances patient compliance and patient education or whether it increases or decreases patient medication errors. Pediatricians choosing to dispense medication should monitor such research carefully, review state and federal laws periodically, and evaluate recommendations from professional organizations. The American Academy of Pediatrics holds that the practice of medication dispensing is acceptable and appropriate provided that it is legally permissible and that it is structured primarily to serve the best interests of the patient. PMID- 7838655 TI - Perinatal human immunodeficiency virus testing. Provisional Committee on Pediatric AIDS, American Academy of Pediatrics. PMID- 7838656 TI - Financing of substance abuse treatment for children and adolescents. Committee on Child Health Financing and Committee on Substance Abuse, American Academy of Pediatrics. PMID- 7838657 TI - The hazards of child labor. Committee on Environmental Health, American Academy of Pediatrics. PMID- 7838658 TI - Informed consent, parental permission, and assent in pediatric practice. Committee on Bioethics, American Academy of Pediatrics. AB - The statement on informed consent, parental permission, and patient assent has a long and extraordinary history. The first draft of this document, prepared by William G. Bartholome, MD, was presented to the original American Academy of Pediatrics (AAP) Committee on Bioethics in 1985. Bill put his soul into the manuscript and has watched over it carefully ever since. Now, a decade later, those who have worked on its continued development and urged its adoption as Academy policy applaud its publication. No one is more gratified than its primary author and champion. Those who have had the privilege to know Dr Bartholome share his sense of accomplishment, but cannot help but experience a cruel sense of irony. Just as the work Bill considers his most important contribution has become available for public appreciation, Dr Bartholome suffers from a serious illness that threatens his life. Bill always wanted "the experience, perspective, and power of children" to be taken most seriously. Through the years of the statement's revisions and re-presentation within the Academy, Bill "had faith in the power of the text and the ideas it contained, ... that its time would come." The statement embodies Bill Bartholome's dedication to children. Throughout his career, he worked to make medicine and medical research safer and more friendly for children. The AAP and its Committee on Bioethics, on behalf of all our colleagues, extend heartful thanks to Dr William G. Bartholome for helping us more fully appreciate that children are in the process of becoming, in his words, "intelligent, observant, capable, and responsible persons" who deserve our utmost respect. PMID- 7838659 TI - Deflazacort in pediatric rheumatic diseases needs a frequent follow-up of bone densitometry. PMID- 7838660 TI - The pediatrician's role in helping children and families deal with separation and divorce. PMID- 7838661 TI - Ribavirin. Red Book Committee recommendations questioned. PMID- 7838662 TI - Medical "experts" for hire! PMID- 7838663 TI - Death in the emergency department. PMID- 7838664 TI - Non-specific effects of calcium entry antagonists in mast cells. AB - Calcium entry in non-excitable cells occurs through calcium-selective currents activated secondarily to store depletion and/or through non-selective cation channels (e.g., receptor- or second-messenger-activated channels). The driving force for calcium influx can be modified by chloride or potassium channels, which set the membrane potential of cells. Together, these conductances determine the extent of calcium entry. Mast cells are an excellent model system for studying calcium influx, because calcium-release-activated calcium currents (ICRAC), second-messenger-activated non-selective currents and chloride currents are present in these cells. Whole-cell patch-clamp recordings were used to test the effects of the commonly used calcium entry blockers econazole and SK&F 96365, as well as the antiallergic and anti-inflammatory drugs tenidap, ketotifen and cromolyn on these channels. All tested drugs blocked the three different channel types with a similar order of magnitude (IC50 values ranging from micromolar to millimolar). Hence, these drugs cannot be used to discriminate between different calcium entry mechanisms. PMID- 7838665 TI - G-protein- and capacitatively regulated Ca2+ entry pathways are activated by muscarinic receptor stimulation in a human submandibular ductal cell line. AB - In the human submandibular ductal cell line (HSG) thapsigargin and carbachol stimulated Ca2+ release from the internal Ca2+ pool, resulting in the activation of capacitatively regulated Ca2+ entry (CRCE). This entry pathway was permeant to both Ca2+ and Mn2+, blocked by Ni2+ and insensitive to the muscarinic antagonist, atropine. Carbachol also stimulated an increase in cytosolic [Ca2+] in internal Ca(2+)-pool-depleted (i.e. thapsigargin-treated) cells which was dependent on the presence of external Ca2+ and blocked by Ni2+, demonstrating that it was due to Ca2+ entry. However, under the same experimental conditions, carbachol was unable to stimulate Mn2+ entry. Additionally, this latter carbachol-stimulated Ca2+ entry pathway was blocked by atropine. Pretreatment of HSG cells with AlF4 increased basal rates of Mn2+ entry due to CRCE activation, but attenuated carbachol-stimulated Ca2+ entry into thapsigargin-treated cells. The data suggest that two distinct divalent cation entry pathways are activated in muscarinic receptor-stimulated HSG cells; a CRCE mechanism, permeable to both Mn2+ and Ca2+, and a second entry mechanism, permeable only to Ca2+. The latter does not depend on internal pool depletion, but appears to be regulated via G-protein activation. PMID- 7838666 TI - Biophysical properties of Ca(2+)- and Mg-ATP-activated K+ channels in pulmonary arterial smooth muscle cells isolated from the rat. AB - A novel class of Ca(2+)-activated K+ channel, also activated by Mg-ATP, exists in the main pulmonary artery of the rat. In view of the sensitivity of these "KCa,ATP" channels to such charged intermediates it is possible that they may be involved in regulating cellular responses to hypoxia. However, their electrophysiological profile is at present unknown. We have therefore characterised the sensitivity of KCa,ATP channels to voltage, intracellular Ca2+ ([Ca2+]i) and Mg-ATP. They have a conductance of 245 pS in symmetrical K+ and are approximately 20 times more selective for K+ ions than Na+ ions, with a K+ permeability (PK) of 4.6 x 10(-13) cm s-1.Ca2+ ions applied to the intracellular membrane surface of KCa,ATP channels causes a marked enhancement of their activity. This activation is probably the result of simultaneous binding of at least two Ca2+ ions, determined using Hill analysis, to the channel or some closely associated protein. This results in a shift of the voltage activation threshold to more hyperpolarized membrane potentials. The activation of KCa,ATP channels by Mg-ATP has an EC50 of approximately 50 microM. Although the EC50 is unaffected by [Ca2+]i, channel activation by Mg-ATP is enhanced by increasing [Ca2+]i. One possible interpretation of these data is that Mg-ATP increases the sensitivity of KCa,ATP channels to Ca2+. It is therefore possible that under hypoxic conditions, where lower levels of Mg-ATP may be encountered, the sensitivity of KCa,ATP channels to Ca2+ and therefore voltage is reduced.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7838667 TI - Copper toxicity in cultured human skeletal muscle cells: the involvement of Na+/K(+)-ATPase and the Na+/Ca(2+)-exchanger. AB - Copper (Cu2+) intoxication has been shown to induce pathological changes in various tissues. The mechanism underlying Cu2+ toxicity is still unclear. It has been suggested that the Na+/K(+)-ATPase and/or a change of the membrane permeability may be involved. In this study we examined the effects of Cu2+ on the Na+ and Ca2+ homeostasis of cultured human skeletal muscle cells using the ion-selective fluorescent probes Na(+)-binding benzofuran isophatalate (SBFI) and Fura-2, respectively. In addition, we measured the effect of Cu2+ on the Na+/K(+) ATPase activity. Cu2+ and ouabain increase the cytoplasmic free Na+ concentration ([Na+]i). Subsequent addition of Cu2+ after ouabain does not affect the rate of [Na+]i increase. Cu2+ inhibits the Na+/K(+)-ATPase activity with an IC50 of 51 microM. The cytoplasmic free Ca2+ concentration ([Ca2+]i) remains unaffected for more than 10 min after the administration of Cu2+. Thereafter, [Ca2+]i increases as a result of the Na+/Ca(2+)-exchanger operating in the reversed mode. The effects of Cu2+ on the Na+ homeostasis are reversed by the reducing and chelating agent dithiothreitol and the heavy metal chelator N,N,N',N'-tetrakis (2 pyridylmethyl)ethylenediamine (TPEN). In conclusion, SBFI is a good tool to examine Na+ homeostasis in cultured human skeletal muscle cells. Under the experimental conditions used, Cu2+ does not modify the general membrane permeability, but inhibits the Na+/K(+)-pump leading to an increase of [Na+]i. As a consequence the operation mode of the Na+/Ca(2+)-exchanger reverses and [Ca2+]i rises. PMID- 7838668 TI - Histamine modulates three types of K+ current in a human intestinal epithelial cell line. AB - K+ conductance species in a human intestinal epithelial cell line (Intestine 407) were studied in connection with their sensitivities to an intestinal secretagogue, histamine, using the tight-seal whole-cell patch-clamp technique. Applications of positive command pulses rapidly induced outward K+ currents. The conductance became progressively larger with increasing command voltages, exhibiting an outwardly rectifying current voltage relation. Inward K+ currents were also rapidly activated upon applications of hyperpolarizing pulses at potentials negative to the equilibrium potential of K+ (EK), and the conductance inwardly rectified. Application of a Ca2+ ionophore, ionomycin, brought about activation of additional K+ currents. An inhibitor of protein kinase C, polymyxin B, did not affect the ionomycin-induced response. Histamine (10-200 microM) also activated a similar K+ current which was abolished by cytosolic Ca2+ chelation. Under conditions where Ca2+ mobilization was minimized, histamine was found to significantly augment inwardly rectifying K+, but suppress outwardly rectifying K+, currents. Polymyxin B blocked these effects of histamine. An activator of protein kinase C, 1-oleoyl-2-acetylglycerol, mimicked the histamine effects. It is concluded that the intestinal epithelial cell has three distinct types of K+ conductance and that histamine modulates not only Ca(2+)-activated K+ conductance via Ca2+ mobilization, but also inward- and outward-rectifier K+ conductances via activation of protein kinase C. PMID- 7838669 TI - Acetylcholine-stimulated changes of membrane potential and intracellular Ca2+ concentration recorded in endothelial cells in situ in the isolated rat aorta. AB - The intracellular free Ca2+ concentration and membrane potential changes evoked by acetylcholine were recorded from whole-cell patch-clamped endothelial cells in situ in the isolated rat aorta. The endothelium had a resting membrane potential of -52 +/- 3 mV (SEM, range -35 mV to -76 mV n = 34) and a low input resistance (32 - 54 M omega). The membrane potential hyperpolarised by 3-30 mV on continuous application of acetylcholine at concentrations that produced endothelium dependent relaxations in isolated rat aortic rings (range 1-500 nM). The response often comprised complex fluctuations of hyperpolarised membrane potential. Calcium concentration was measured with the fluorescent indicator furaptra, which has a wide range and minimises Ca2+ buffering. Acetylcholine evoked an initial rapid elevation of intracellular Ca2+ concentration, peaking in the range 6-35 microM, which declined with a half time of approximately 6 s, followed by repetitive [Ca2+] spikes of amplitude 2-18 microM in 23 of 34 cells. The initial [Ca2+] transient and hyperpolarisation were unaffected by removal of external Ca2+, whilst subsequent [Ca2+] spikes and maintained hyperpolarisations required the presence of external Ca2+. Both the hyperpolarisation and Ca2+ responses elicited by acetylcholine were abolished by atropine (1 microM). These results show that endothelial cells in situ exhibit large, fast repetitive [Ca2+] spikes in response to extracellular acetylcholine. PMID- 7838670 TI - Voltage- and concentration-dependent effects of lidocaine on cardiac Na channel gating charge movements. AB - The effects of lidocaine, a local anesthetic and cardiac antiarrhythmic agent, were studied on cardiac nonlinear Na channel and Ca channel charge movements (gating currents) of 17-day-old embryonic chick ventricular myocytes. Gating currents were recorded following the blockade of all ionic currents and the subtraction of the linear capacity currents (-P/5). From a holding potential of 100 mV the ON charge movement (QON) displayed two kinetic components: a rapidly decaying component associated with Ca channel gating, and a slower component associated with Ca channel gating. A depolarizing prepulse to -50 mV for 125 ms reduced the fast component of QON, with little effect on the slower component. Similarly, 20 microM lidocaine also reduced the fast component of QON (Na channel charge movement) and had little effect on the slower component (Ca channel charge movement). Higher concentrations of lidocaine (125 microM) reduced both the fast and the slower components of QON. The effects of either a prepulse to -50 mV, or 20 microM lidocaine on the steady-state QON/Vm relationship were nearly identical. These results suggest that lidocaine "blocks" cardiac Na (ionic) currents by a reduction in the availability of Na channel charge movement (QON), and that this reduction is similar to that produced by voltage-dependent inactivation. PMID- 7838671 TI - Plasma from patients with seronegative myasthenia gravis inhibit nAChR responses in the TE671/RD cell line. AB - Myasthenia gravis (MG) is an autoimmune disorder in which anti-acetylcholine receptor (AChR) antibodies cause muscle weakness. In 10-15% of MG patients anti AChR antibodies are undetectable (seronegative MG, SMG), though clinical and experimental evidence points to causative circulating factors. Using whole-cell patch-clamp techniques, we investigated the effects of heat-inactivated plasma from SMG patients (n = 7) on voltage-gated sodium [INa(V)] and ACh-induced nicotinic AChR (nAChR) currents in the human rhabdomyosarcoma cell line TE671/RD, comparing the results to those obtained with plasma from healthy individuals (HC, n = 6), patients with Guillain-Barre syndrome (GBS, n = 3) or those with other neurological diseases (OND, n = 3). None of the plasma samples inhibited INa(V). nAChR currents were rapidly (< 1 min) and significantly (P < 0.01) reduced by a 1:10 dilution of plasma from SMG patients compared with plasma from healthy controls and were not restored by washing. The inhibition appeared in some cases to be calcium dependent since for one of three plasmas it was prevented by 10 mM EGTA in the patch pipette. Currents were also reduced by two of three plasmas obtained from GBS patients at 1:3 dilution, but not by the three plasmas from patients with ONDs. The rapid action of plasma from SMG patients argues against an antibody-induced reduction in nAChR numbers; its calcium dependence in one case suggests action by a second messenger that might involve nAChR phosphorylation. PMID- 7838672 TI - Sensory neuron N-type calcium currents are inhibited by both voltage-dependent and -independent mechanisms. AB - The voltage dependence of gamma-aminobutyric-acid- and norepinephrine-induced inhibition of N-type calcium current in cultured embryonic chick dorsal-root ganglion neurons was studied with whole-cell voltage-clamp recording. The inhibitory action of the neurotransmitters was comprised of at least two distinct modulatory components, which were separable on the basis of their differential voltage dependence. The first component, which we term "kinetic slowing", is associated with a slowing of the activation kinetics--an effect that subsides during a test pulse. The kinetic-slowing component is largely reversed at depolarized voltages (i.e., it is voltage-dependent). The second component, which we term "steady-state inhibition", is by definition not associated with a change in activation kinetics and is present throughout the duration of a test pulse. The steady-state inhibition is not reversed at depolarized voltages (i.e., it is voltage-independent). Although the two components can be separated on the basis of their voltage dependence, they appear to be indistinguishable in their time courses for onset and recovery as well as their rates of desensitization following multiple applications of transmitter. Furthermore, neither component requires cell dialysis, as both are observed using perforated-patch as well as whole-cell recording configurations. The co-existence in nerve terminals of both voltage-dependent and -independent mechanisms to modulate calcium channel function could offer a means of differentially controlling synaptic transmission under conditions of low- and high-frequency presynaptic discharge. PMID- 7838673 TI - Ion-transporting activity in the murine colonic epithelium of normal animals and animals with cystic fibrosis. AB - Electrogenic ion transport in the isolated colonic epithelium from normal and transgenic mice with cystic fibrosis (CF mice) has been investigated under short circuit current (Isc) conditions. Normal tissues showed chloride secretion in response to carbachol or forskolin, which was sensitive to the Na-K-2Cl cotransport inhibitor, frusemide. Responses to both agents were maintained for at least 12 h in vitro, but the responses to carbachol changed in format throughout this period. By contrast CF colons failed to show the normal secretory responses to carbachol and forskolin, most preparations showing a decrease in Isc that was immediately reversed by frusemide. In CF colons addition of Ba2+ ions or tetraethylammonium (TEA+) to the apical bathing solution antagonised the reduction in Isc caused by the secretagogues. It is concluded that the reduction in Isc in CF colons is due to electrogenic K+ secretion and this was confirmed by flux studies using rubidium-86. In normal colons exposed to TEA+ the responses to forskolin were greater, but not significantly so, presumably because the minor K(+)-secretory responses are dominated by major chloride-secretory responses. Again rubidium-86 fluxes showed an increase of K+ secretion in normal colons receiving forskolin. Since the amiloride-sensitive current was not different in CF and normal colons there was no evidence that the CF mice were stressed in a way that increased mineralocorticoid levels and hence K+ secretion. Knowledge of the phenotype of the colonic epithelium of the CF mouse sets the baseline from which attempts at gene therapy for the gut must be judged. PMID- 7838674 TI - Contribution of prostaglandins in hypoxia-induced vasodilation in isolated rabbit hearts. Relation to adenosine and KATP channels. AB - The mechanism of hypoxia-induced coronary vasodilation was studied in isolated, saline-perfused rabbit hearts under constant flow conditions. Reduction in the perfusion solution PO2 (from 520 +/- 6 to 103 +/- 9 mm Hg) under control conditions halved the coronary resistance and was accompanied by a significant release of the prostaglandin (PG) 6-keto-PGF1 alpha (from 1.8 +/- 0.3 to a maximum of 4.4 +/- 0.9 pmol min-1 g-1). The cyclooxygenase inhibitor, diclofenac (1 microM), blocked the release of PGI2 and reduced hypoxia-induced vasodilation (from 47 +/- 8% to 25 +/- 5%, P < 0.05). The relative contribution of adenosine, prostaglandins, and adenosine triphosphate (ATP)-sensitive K+ channel (KATP channel) activation in hypoxia-induced vasodilation was assessed by comparing the differential change (control response minus response after treatment) in coronary perfusion pressure (CPP) during infusion of 8-phenyltheophylline (8-PT), diclofenac, and glibenclamide, respectively. The differential change in CPP with 8-PT and diclofenac given together (-48 +/- 7%) was found to be equivalent to the sum of their respective effects (-24 +/- 7 and -19 +/- 4%, respectively). Glibenclamide (0.3 microM) reduced significantly hypoxia-induced vasodilation (differential change in CPP of -27 +/- 6%) as well as the dilator response to 10 microM adenosine and to the stable PGI2-analogue, iloprost. Forskolin-induced coronary vasodilation in arrested hearts was slightly, but significantly, reduced by glibenclamide. Our results suggest that both cyclooxygenase products and adenosine, acting independently, and concomitantly, contribute to the dilator response of coronary resistance vessels to hypoxia, in part through the activation of KATP channels.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7838675 TI - The correlation of cardiac mass with arterial haemodynamics of resistive and capacitive load in rats with normotension and established hypertension. AB - In hypertensive animals and humans, cardiac hypertrophy may occur as a consequence of an external load on the heart. Several studies have suggested that the non-pulsatile components of arterial haemodynamics, such as arterial pressure and vascular resistance, do not adequately represent the ventricular afterload and are not well correlated with the degree of cardiac hypertrophy (CH). The present study was undertaken to analyse the correlation between the degree of CH and various haemodynamic parameters in the spontaneously hypertensive rat (SHR) with established hypertension. A total of 36 SHRs (6-8 months) with a tail-cuff pressure above 190 mm Hg were used. Control data were obtained from 32 age matched normotensive Wistar Kyoto rats (WKY). Animals were anaesthetized with pentobarbitone sodium (40 mg/kg i.p.) and artificially ventilated with a respirator. A Millar catheter with a high-fidelity pressure sensor was used to record the aortic pressure and an electromagnetic flow transducer to monitor the aortic flow. The pressure and flow signals were subjected to Fourier transformation for the analysis of the arterial impedance spectrum. The left ventricular weight-to-body weight ratio (LVW/BW) was taken as a measure of the degree of CH. The measured haemodynamic parameters in these anaesthetized, open chest SHRs were systolic pressure (SP) (mean +/- SE) 172 +/- 4 mm Hg, diastolic pressure (DP), 120 +/- 3 mm Hg, pulse pressure (PP) 52 +/- 2 mm Hg, peripheral resistance (Rp) 344,032 +/- 8,012 dyne.s.cm-5, characteristic impedance (Zc) 6,442 +/- 313 dyne.s.cm-5, the impedance modulus at the first harmonic (Z1) 26,611 +/- 1,061 dyne.s.cm-5, mean arterial compliance (Cm) 0.87 +/- 0.04 microliter/mm Hg and LVW/BW 3.092 +/- 0.026 mg/g.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7838676 TI - Differential time course for desensitization to muscarinic effects on K+ and Ca2+ channels. AB - The time course of muscarinic effects on K and Ca currents was investigated at 22 24 degrees C in guinea-pig atrial myocytes, using the whole-cell voltage clamp. At a holding potential of -40 or -50 mV, short exposures to 100 microM acetylcholine (ACh) or carbachol (CCh) reproducibly induced outward K currents (IK,ACh). During long exposures to these agonists, IK,ACh faded with time. In cells not dialysed with guanosine triphosphate (GTP), IK,ACh could dissipate completely following 15-20 min of agonist exposure. After agonist washout, lost sensitivity was not recovered. In cells dialysed with GTP (0.2-1 mM), IK,ACh still faded but normal sensitivity to agonists was restored with washout. Fade of IK,ACh was not prevented by intracellular heparin or dextran, excluding the involvement of either beta-adrenergic or muscarinic receptor kinase. IK,ACh induced by bethanechol or adenosine also faded, and subsequent CCh application after washout revealed a diminished response. Intracellular guanosine-5'-o-(3 thiotriphosphate (GTP gamma S) induced IK,ACh which faded, and subsequent exposure to CCh was without effect. Equally, after full desensitization with CCh, GTP gamma S failed to induce IK,ACh. The Ca current (ICa) was activated by voltage steps to 0 mV and increased with 1-3 microM isoproterenol. This increase could be reversed by CCh, even when IK,ACh had completely faded. Prolonged muscarinic agonist exposure sometimes also caused fade of the effect on ICa, which always occurred after loss of IK,ACh. The results show that desensitization is heterologous and may involve the guanine nucleotide-binding (G) protein. The differential desensitization to the effects on IK,ACh and ICa suggests the involvement of two different signalling pathways in the muscarinic control of K and Ca channels. PMID- 7838677 TI - Effects of urea on K+ fluxes and cell volume in perfused rat liver. AB - Exposure of the perfused rat liver to a perfusate made hyperosmotic by the presence of 200 mmol l-1 glucose led, as expected, to marked, transient hepatocellular shrinkage followed by volume-regulatory net K+ uptake. However, even after this volume-regulatory K+ uptake had ceased, the liver cells are still slightly shrunken. Withdrawal of glucose from the perfusate resulted in marked transient cell swelling, net K+ release from the liver and restoration of cell volume. However, when the Krebs-Henseleit perfusate was made hyperosmotic by the presence of urea (20-300 mM), there was no immediate decrease in liver mass, yet a slight and persistent cell shrinkage developing 2 min after the onset of exposure to urea. Surprisingly, urea induced concentration-dependent net K+ efflux from the liver and removal of urea net K+ reuptake from the inflowing perfusate. The urea (200 mM)-induced net K+ release resembled that observed following a lowering of the influent [NaCl]: making the perfusate hypoosmotic (245 mosmol l-1, by reducing influent [NaCl] by 30 mM) gave roughly the same K+ response as hyperosmotic exposure (505 mosmol/l) resulting from the presence of 200 mM urea. The urea-induced K+ efflux was not inhibited in the presence of ouabain (1 mM), or in Ca(++)-free perfusion, but was modified in the presence of quinidine (1 mM) or Ba++ (1 mM). The direction in which the liver was perfused had no effect on the urea-induced net K+ release.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7838678 TI - Effects of the reactive oxygen species hypochlorous acid and hydrogen peroxide on force production and calcium sensitivity of rat cardiac myofilaments. AB - Neutrophil activation occurs after myocardial infarction/ischaemia. They produce the reactive oxygen species (ROS) hypochlorous acid (HOCl) and hydrogen peroxide (H2O2) which could contribute to contractile dysfunction upon reperfusion. The myofilaments of 'skinned' rat cardiac muscle were exposed to ROS in various states of activation. Isometric force was measured at controlled degrees of activation. A single application of 10 microM HOCl for 1 min increased log [Ca2+] for half-maximal activation (log K1/2) from 5.23 to 5.32, initial maximum Ca activated force (FCa, max) was reduced by 18.8 +/- 5.8% and resting tension increased to 15.4 +/- 8.0% of FCa, max. At 50 microM, a 1-min exposure to HOCl produced a greater increase in Ca-sensitivity (log K1/2 increased from 5.23 to 5.47), a greater reduction in FCa, max (falling by 42.3 +/- 23.2%) and a greater increase in resting tension (to 25 +/- 10.7% of FCa, max). The nature of the resting tension rise was examined by reducing pH before and during exposure to HOCl; the results are consistent with 'rigor-like' cross-bridges being involved. H2O2 was without effect on the myofilaments at physiologically relevant (< 10 microM) concentrations. These results suggest that ROS associated with inflammation could contribute to post-ischaemic myocardial dysfunction. PMID- 7838679 TI - Cytoskeletal modulation of the response to mechanical stimulation in human vascular endothelial cells. AB - Possible interactions of cytoskeletal elements with mechanically induced membrane currents and Ca2+ signals were studied in human endothelial cells by using a combined patch-clamp and Fura II technique. For mechanical stimulation, cells were exposed to hypotonic solution (HTS). The concomitant cell swelling activates a Cl- current, releases Ca2+ from intracellular stores and activates Ca2+ influx. To interfere with the cytoskeleton, cells were loaded either with the F-actin stabilizing agent phalloidin (10 mumol/l), or the F-actin-depolymerizing substance cytochalasin B (50 mumol/l). These were administered either in the bath or the pipette solutions. The tubulin structure of the endothelial cells was modulated by taxol (50 mumol/l), which supports polymerization of tubulin, or by the depolymerizing agent colcemid (10 mumol/l) both applied to the bath. Immunofluorescence experiments show that under the chosen experimental conditions the cytoskeletal modifiers employed disintegrate the F-actin and microtubuli cytoskeleton. Neither of these cytoskeletal modifiers influenced the HTS-induced Cl- current. Ca2+ release was not affected by cytochalasin B, taxol or colcemid, but was suppressed if the cells were loaded with phalloidin. Depletion of intracellular Ca2+ stores by thapsigargin renders the intracellular [Ca2+] sensitive to the extracellular [Ca2+], which is indicative of a Ca2+ entry pathway activated by store depletion. Neither cytochalasin B nor phalloidin affected this Ca2+ entry. We conclude that F-actin turnover or depolymerization is necessary for Ca2+ release by mechanical activation. The tubulin network is not involved. The Ca2+ release- activated Ca2+ entry is not modulated by the F actin cytoskeleton. PMID- 7838681 TI - Flufenamate and Gd3+ inhibit stimulated Ca2+ influx in the epithelial cell line CFPAC-1. AB - The relevant influx pathway for stimulated Ca2+ entry into epithelial cells is largely unknown. Using flufenamate (Flu) and Gd3+, both known pharmacological blockers of non-selective cation currents in other epithelial preparations, we tested whether the stimulated Ca2+ entry in CFPAC-1 cells was inhibited by these agents. Transmembraneous Ca2+ influx into CFPAC-1 cells was stimulated by either ATP (10(-4) and 10(-5) mol/l), carbachol (CCH, 10(-4) mol/l) or thapsigargin (TG, 10(-8) mol/l). Three different experimental approaches were used. (1) Because the plateau phase of an agonist-induced [Ca2+]i transient reflects Ca2+ influx into these cells, we investigated the influence of Flu and Gd3+ on the level of the stimulated [Ca2+]i plateau. (2) The fura-2 Mn(2+)-quenching technique was used to visualise divalent cation entry and monitor its inhibition. (3) During the "refilling period" after agonist-induced discharge of the intracellular pools the putative influx inhibitors Flu and Gd3+ were given and subsequently the filling state of the agonist-sensitive intracellular stores tested. The results from the first experimental approach showed that both Flu and Gd3+ were potent inhibitors of the stimulated Ca2+ entry in CFPAC-1 cells. Flu reversibly decreased the ATP induced [Ca2+]i plateau in a concentration dependent manner, with an IC50 value of 33 mumol/l (n = 6). Similar results were obtained for the CCH- (n = 5) and the TG-induced (n = 5) [Ca2+]i plateau. Gd3+ concentration dependently inhibited the stimulated Ca2+ plateau. A complete block of the ATP-induced [Ca2+]i plateau was seen at 0.5 mumol/l (ATP 10(-5) mol/l, n = 8).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7838680 TI - Sodium movement into and out of corneal endothelium. AB - Rabbit corneal endothelial cells mounted in vitro were impaled simultaneously with Na(+)-selective and conventional KCl-filled microelectrodes. The membrane potential (Vm) was -30.4 +/- 0.8 mV (mean +/- SEM, n = 55) and the intracellular [Na+]i (calculated from the Na(+)-selective electrode potential, VNa) was 13.7 +/ 1.9 mM (mean +/- SEM, n = 16). When ouabain was added to the perfusate the cell depolarised, causing both Vm and VNa to increase with a very similar time course. Final Vm was -6.3 +/- 0.6 mV (mean +/- SEM, n = 15), and the final [Na+]i was 114 +/- 6.9 mM (mean +/- SEM, n = 5). The parallel increase in Vm and rise in [Na+]i suggest that a component of the ouabain-induced depolarisation of the cell (increase in Vm) is due to Na+ entry into the cell down its concentration gradient. The lateral and basal location of the Na+/K(+)-ATPase in bovine endothelial cells was confirmed (for the first time at the electron-microscopic level) using a monoclonal antibody specific for the alpha 1 subunit of Na+/K(+) ATPase. The absence of a net Na+ flux across these cells combined with the basolateral location of the ATPase suggest that Na+ exit from the cell, and its re-entry take place across the same membrane (i. e. the basolateral). PMID- 7838682 TI - cAMP-dependent activation of ion conductances in bronchial epithelial cells. AB - The cAMP-dependent activation of Cl- channels was studied in a bronchial epithelial cell line (16HBE14o-) in fast and slow whole-cell, and cell-attached patch-clamp experiments. The cells are known to express high levels of cystic fibrosis transmembrane conductance regulator mRNA and protein. Isoproterenol, forskolin and histamine (all 10 mumol/l) reversibly and significantly depolarized the membrane voltage (Vm) and increased the whole-cell Cl- conductance significantly by 34.0 +/- 0.9 (n = 3), 18.1 +/- 2.7 (n = 50), and 25 +/- 4.5 (n = 37) nS respectively. The effect of histamine was blocked by cimetidine (10 mumol, n = 5) but not by diphenhydramine (10 mumol/l, n = 4), which suggests binding of histamine to H2 receptors. The forskolin-induced current was not inhibited significantly by 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid (0.5 mmol/l, n = 9) nor glibenclamide (10 mumol/l, n = 3) and had an anion-permeability sequence of Cl = Br- > I- (n = 9). In cell-attached recordings forskolin (10 mumol/l) increased the conductance of the patched membrane from 65.5 +/- 13.6 pS to 150.8 +/- 33.2 pS (n = 30). Although the conductance was increased significantly, clear ion channel events occurring in parallel with the current activation were not detected in the cell-attached membrane. In 4 out of 30 cell attached recordings single-channel currents were observed. These channels, with a single-channel conductance of about 6 pS, were already active before forskolin was added. No effect of forskolin on the channel amplitude, open probability or kinetics of these channels was observed.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7838683 TI - Ca(2+)- and swelling-induced activation of ion conductances in bronchial epithelial cells. AB - The present study was performed to examine Ca(2+)-dependent and cell-swelling induced ion conductances in a polarized bronchial epithelial cell line (16HBE14o ). Whole-cell currents were measured in fast and slow whole-cell patch-clamp experiments in cells grown either on filters or on coated plastic dishes. In addition the transepithelial voltage (Vte) and resistance (Rte) were measured in confluent monolayers. Resting cells had a membrane voltage (Vm) of -36 +/- 1.1 mV (n = 137) which was mainly caused by K+ and Cl- conductances and to a lesser extent by a Na+ conductance. Vte was apical-side-negative after stimulation. Equivalent short-circuit (Isc = Vte/Rte) was increased by the secretagogues histamine (0.1 mmol/l), bradykinin (0.1 - 10 mumol/l). and ATP (0.1 - mumol/l). The histamine-induced Is was blocked by either basolateral diphenhydramine (0.1 mmol/l, n = 4) or apical cimetidine (0.1 mmol/l, n = 4). In fast and slow whole cell recordings ATP and bradykinin primarily activated a transient K+ conductance and hyperpolarized Vm. This effect was mimicked by the Ca2+ ionophore ionomycin (1 mumol/l, n = 11). Inhibition of the bradykinin-induced Isc by the blocker HOE140 (1 mumol/l, n = 3) suggested the presence of a BK2 receptor. The potency sequence of different nucleotide agonists on the purinergic receptor was UTP approximately ATP > ITP > GTP approximately CTP approximately [beta, gamma methylene] ATP approximately 2-methylthio-ATP = 0 and was obtained in Isc measurements and patch-clamp recordings. This suggests the presence of a P2u receptor. Hypotonic cell swelling activated both Cl- and K+ conductances.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7838684 TI - Properties of voltage-activated Na+ and K+ currents in mouse hippocampal glial cells in situ and after acute isolation from tissue slices. AB - In the present study, we were interested in a quantitative analysis of voltage activated channels in a subpopulation of hippocampal glial cells, termed "complex" cells. The patch-clamp technique in the whole-cell mode was applied to identified cells in situ and to glial cells acutely isolated from tissue slices. The outward current was composed of two components: a sustained and a transient current. The transient K+ channel had electrophysiological and pharmacological properties resembling those of the channel through which the A-currents pass. In addition, this glial A-type current possessed a significant Ca2+ dependence. The current parameters determined in situ or in isolated cells corresponded well. Due to space clamp problems in situ, properties of voltage-dependent Na+ currents were only analysed in suspended glial cells. The tetrodotoxin (TTX) sensitivity and the stationary and kinetic characteristics of this current were similar to corresponding properties of hippocampal neurons. These quantitative data demonstrate that at an early postnatal stage of central nervous system maturation, glial cells in situ express a complex pattern of voltage-gated ion channels. The results are compared to findings in other preparations and the possible consequences of transmitter-mediated channel modulation in glial cells are discussed. PMID- 7838686 TI - pH dependence of K+ conductances of rat cortical collecting duct principal cells. AB - The K+ channels of the principal cells of rat cortical collecting duct (CCD) are pH sensitive in excised membranes. K+ secretion is decreased with increased H+ secretion during acidosis. We examined whether the pH sensitivity of these K+ channels is present also in the intact cell and thus could explain the coupling between K+ and H+ secretion. Membrane voltages (Vm), whole-cell conductances (gc), and single-channel currents of K+ channels were recorded from freshly isolated CCD cells or isolated CCD segments with the patch-clamp method. Intracellular pH (pHi) was measured using the pH-sensitive fluorescent dye 2'-7' bis(carboxyethyl)-5-6-carboxyfluorescein (BCECF). Acetate (20 mmol/l) had no effect on Vm, gc, or the activity of the K+ channels in these cells. Acetate, however, acidified pHi slightly by 0.17 +/- 0.04 pH units (n = 19). Vm depolarized by 12 +/- 3 mV (n = 26) and by 23 +/- 2 mV (n = 66) and gc decreased by 26 +/- 5% (n = 13) and by 55 +/- 5% (n = 12) with 3-5 or 8-10% CO2, respectively. The same CO2 concentrations decreased pHi by 0.49 +/- 0.07 (n = 15) and 0.73 +/- 0.11 pH units (n = 12), respectively. Open probability (Po) of all four K+ channels in the intact rat CCD cells was reversibly inhibited by 8-10% CO2. pHi increased with the addition of 20 mmol/l NH4+/NH3 by a maximum of 0.64 +/- 0.08 pH units (n = 33) and acidified transiently by 0.37 +/- 0.05 pH units (n = 33) upon NH4+/NH3 removal. In the presence of NH4+/NH3 Vm depolarized by 16 +/- 2 mV (n = 66) and gc decreased by 26 +/- 7% (n = 16). The activity of all four K+ channels was also strongly inhibited in the presence of NH4+/NH3. The effect of NH4+/NH3 on Vm and gc was markedly increased when the pH of the NH4+/NH3 containing solution was set to 8.5 or 9.2. From these data we conclude that cellular acidification in rat CCD principal cells down-regulates K+ conductances, thus reduces K+ secretion by direct inhibition of K+ channel activity. This pH dependence is present in all four K+ channels of the rat CCD. The inhibition of K+ channels by NH4+/NH3 is independent of changes in pHi and rather involves an effect of NH3. PMID- 7838685 TI - Hypoxia increases the activity of Ca(2+)-sensitive K+ channels in cat cerebral arterial muscle cell membranes. AB - The cellular mechanisms mediating hypoxia-induced dilation of cerebral arteries have remained unknown, but may involve modulation of membrane ionic channels. The present study was designed to determine the effect of reduced partial pressure of O2, PO2, on the predominant K+ channel type recorded in cat cerebral arterial muscle cells, and on the diameter of pressurized cat cerebral arteries. A K(+) selective single-channel current with a unitary slope conductance of 215 pS was recorded from excised inside-out patches of cat cerebral arterial muscle cells using symmetrical KCl (145 mM) solution. The open state probability (NPo) of this channel displayed a strong voltage dependence, was not affected by varying intracellular ATP concentration [(ATP]i) between 0 and 100 microM, but was significantly increased upon elevation of intracellular free Ca2+ concentration ([Ca2+]i). Low concentrations of external tetraethylammonium (0.1-3 mM) produced a concentration-dependent reduction of the unitary current amplitude of this channel. In cell-attached patches, where the resting membrane potential was set to zero with a high KCl solution, reduction of O2 from 21% to < 2% reversibly increased the NPo, mean open time, and event frequency of the Ca(2+)-sensitive, high-conductance single-channel K+ current recorded at a patch potential of +20 mV. A similar reduction in PO2 also produced a transient increase in the activity of the 215-pS K+ channel measured in excised inside-out patches bathed in symmetrical 145 mM KCl, an effect which was diminished, or not seen, during a second application of hypoxic superfusion. Hypoxia had no effect on [Ca2+]i or intracellular pH (pHi) of cat cerebral arterial muscle cells, as measured using Ca(2+)- or pH-sensitive fluorescent probes. Reduced PO2 caused a significant dilation of pressurized cerebral arterial segments, which was attenuated by pretreatment with 1 mM tetraethylammonium. These results suggest that reduced PO2 increases the activity of a high-conductance, Ca(2+)-sensitive K+ channel in cat cerebral arterial muscle cells, and that these effects are mediated by cytosolic events independent of changes in [Ca2+]i and pHi. PMID- 7838687 TI - Characterization of the Cl- conductance in the granular duct cells of mouse mandibular glands. AB - We have previously shown that mouse mandibular granular ducts contain a hyperpolarization-activated Cl- conductance. We now show that the instantaneous current/voltage (I/V) relation of this Cl- conductance is inwardly rectifying with a slope conductance of 15.4 +/- 1.8 nS (n = 4) at negative potentials and of 6.7 +/- 0.9 nS (n = 4) at positive potentials. Thus, the inward rectification seen in the steady-state I/V relation is due, not only to voltage activation of the Cl- conductance, but also to the intrinsic conductance properties of the channel. We show further that the ductal Cl- conductance is not activated by including ATP (10 mmol/l) in the pipette solution. Finally, we show that the conductance is not blocked by the addition of any of the following compounds to the extracellular solution: anthracene-9-carboxylate (A9C, 1 mmol/l), diphenylamine-2-carboxylate (DPC, 1 mmol/l), 5-nitro-2-(3-phenylpropylamino) benzoate (NPPB, 100 mumol/l), 4,4'-diisothiocyanato-stilbene-2,2'-disulphonate (DIDS, 100 mumol/l), indanyloxyacetic acid (IAA-94, 100 mumol/l), verapamil (100 mumol/l), glibenclamide (100 mumol/l) and Ba2+ (5 mmol/l). The properties of the ductal Cl- conductance most nearly resemble those of the ClC-2 channel. Both channel types have instantaneous I/V relations that are slightly inwardly rectifying, are activated by hyperpolarization with a time-course in the order of hundreds of milliseconds, have a selectivity sequence of Br- > Cl- > I-, and are insensitive to DIDS. The only identified difference between the two is that the ClC-2 channel is 50% blocked both by DPC and A9C (1 mmol/l), whereas the ductal Cl- conductance is insensitive to these compounds. PMID- 7838688 TI - Model of bicarbonate secretion by resting frog stomach fundus mucosa. I. Transepithelial measurements. AB - In the present in vitro experiments on gastric fundus mucosa of Rana esculenta we try to define the mechanism of alkaline secretion that is observed in summer frogs in the resting stomach (blockage of HCl secretion by ranitidine, 10(-5) mol/l). The transepithelial voltage and the rate of alkalinization (ASR) of an unbuffered gastric lumen perfusate was measured as a function of serosal (and mucosal) fluid composition. ASR was high (0.88 +/- S.E. 0.09 microEq.cm-2.h-1, n = 11) during serosal bath perfusion with HCO(3-)-Ringer solution, decreased slightly to 0.50 +/- 0.07 microEq.cm-2.h-1 (n = 6) in HCO(3-)-free HEPES-buffered Ringer solution of the same pH, and decreased to approximately 20% when carbonic anhydrase was inhibited by acetazolamide. While replacement of mucosal or serosal Cl- did not--within 1 h--significantly alter ASR, replacement of serosal Na+ in the presence or absence of HCO3- strongly reduced ASR, and a similar reduction was observed after serosal application of the anion transport inhibitor DIDS (4,4 diisothiocyanatostilbene-2,2-disulphonate, 2.10(-4) mol/l), the metabolic poison rotenone (10(-5) mol/l), the uncoupler dinitrophenol (10(-4) mol/l), and the Na+ pump inhibitor ouabain (10(-4) mol/l), while serosal amiloride (10(-4) mol/l) had no effect.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7838689 TI - Model of bicarbonate secretion by resting frog stomach fundus mucosa. II. Role of the oxyntopeptic cells. AB - In the present publication we report mainly electrophysiological studies on oxyntopeptic cells of frog gastric mucosa which aim at clarifying a possible involvement of these cells in the process of resting gastric alkali (HCO3-) secretion, described in the preceding publication. The experiments were performed on intact gastric fundus mucosa of Rana esculenta mounted in Ussing chambers. After removal of the muscle and connective tissue layer oxyntopeptic cells were punctured from the serosal surface with conventional or pH-sensitive microelectrodes to measure, besides transepithelial voltage and resistance, the basolateral cell membrane potential, the voltage divider ratio, and the cell pH in response to secretagogues and/or changes in serosal ion concentration. Carbachol (10(-4) mol/l), which transiently stimulated HCO3- secretion by 0.22 mumol.cm-2.h-1, transiently acidified the cells by 0.09 +/- SEM 0.03 pH units (n = 6) and transiently induced an apical cell membrane anion conductance. According to the model of gastric HCO3- secretion presented in the preceding publication, this anion conductance could be involved in gastric HCO3- secretion, mediating, besides Cl- efflux, also apical HCO3- efflux. In addition carbachol stimulated basolateral Na+(HCO3-)n-cotransport, which according to the results from the preceding publication mediates basolateral HCO3- uptake for secretion. By contrast, cAMP-mediated secretagogues, such as histamine or others, which stimulate HCl secretion and transiently alkalinize the oxyntopeptic cells, were found to down-regulate the basolateral Na+(HCO3-)n-cotransporter.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7838690 TI - The droplet technique: measurement of calcium extrusion from single isolated mammalian cells. AB - This paper contains a description of the modified droplet technique that is designed to monitor Ca2+ extrusion from single isolated pancreatic acinar cells. A cell loaded with calcium indicator is maintained in a small droplet of solution containing another calcium indicator. Differences in the optical properties of the intracellular and extracellular indicators allows one to monitor simultaneously intracellular and extracellular calcium concentrations. The paper contains a description of the calibration procedure that is used to calculate intracellular and extracellular calcium concentrations. The advantages and disadvantages of different pairs of extracellular and intracellular indicators are discussed. PMID- 7838691 TI - Cholecystokinin participates in the mediation of fever. AB - Cholecystokinin of the central nervous system participates in the pathogenesis of lipopolysaccharide-induced fever in rats, contributing mainly to the first phase rise of this fever. The mediatory role is connected to type-B receptors of cholecystokinin. PMID- 7838693 TI - Give the gift of freedom from smoking! PMID- 7838692 TI - Differential effects of external pH alteration on intracellular pH in rat coronary and cardiac myocytes. AB - Changes in extracellular pH (pHo) induce changes in the intracellular pH (pHi) of cardiac myocytes that are slow and attenuated. Little however is known about the effects of changing pHo on the pHi of the coronary smooth muscle cells. We have therefore directly compared the effects of altering pHo on pHi of both coronary and cardiac myocytes. Carboxy-SNARF was used in single cells to measure pHi. Alteration of pHo caused corresponding changes in pHi that were large (70-80% of pHo) and rapid in coronary myocytes compared to cardiac myocytes. In contrast, changes of pHi produced by weak acids or bases produced similar pHi responses in both types of cells. It is suggested that the differential effects of pHo on coronary and cardiac cells may be functionally significant, as it will allow rapid alteration of coronary perfusion to meet tissue needs, while maintaining cardiac output. PMID- 7838694 TI - Consensus policy for RN immunization administration. PMID- 7838695 TI - Building a future for nursing together. PMID- 7838696 TI - The responsibility of health care. PMID- 7838697 TI - Tooth whitening: review of the literature. PMID- 7838699 TI - Racing the clock backwards: adventures of a Minnesota Mudlark. PMID- 7838700 TI - Be prepared for office emergencies. PMID- 7838701 TI - Leasing workers. PMID- 7838698 TI - Dental technology and the good-old-days ethics. PMID- 7838702 TI - The personal liability of trustees and how to minimize it. PMID- 7838703 TI - William Tell's dilemma; documenting a patient's refusal of treatment is not always enough. PMID- 7838704 TI - NRSub: a non-redundant data base for the Bacillus subtilis genome. AB - We have organized the DNA sequences of Bacillus subtillis from the EMBL collection to build the NRSub data base. This data base is free from duplications and all detected overlapping sequences are merged into contigs. Data on gene mapping and codon usage are also included. NRSub is publically available through anonymous FTP in flat file format or structured on the form of an ACNUC data base. Under this format, it is possible to use NRSub with the retrieval program Query--win. This program integrates a graphical interface and may be installed on any kind of UNX computer under X Window and on which the Vibrant and Motif libraries are available. PMID- 7838705 TI - Translation start site multiplicity of the CCAAT/enhancer binding protein alpha mRNA is dictated by a small 5' open reading frame. AB - The CCAAT/enhancer binding proteins (C/EBP) alpha and beta of the bZIP family of transcription factors each occur as multiple forms due to translation initiation at different in-frame AUG codons from the same messenger RNA. The C/EBP alpha mRNAs of chicken, rat and Xenopus all contain a small 5' open reading frame (5'ORF) whose size (18 nucleotides) and distance (seven nucleotides) to the C/EBP alpha cistron has been conserved in vertebrate evolution. The present studies shows that the small 5'ORF is crucial to the leaky scanning mechanism of ribosomes causing a fraction of them to ignore the first C/EBP alpha AUG codon and to start at internal AUGs. Our data challenge the view that translational start site multiplicity is mainly governed by the sequence context of the potential initiation codons. Western analysis showed that the two major chicken C/EBP alpha translation products, the full-length cC/EBP alpha-42 which acts a trans-activator in liver and the N-terminally truncated cC/EBP alpha-29 which lacks transcription activation potential, occur in a fixed ratio which is similar in different expressing tissues, like liver, lung and small intestine. The presence of a similar, thusfar unnoticed, small ORF 5' to the major initiation codon of C/EBP beta mRNA suggests that start site multiplicity from this mRNA may be governed by the same mechanism. PMID- 7838706 TI - DNA binding activities of the Caenorhabditis elegans Tc3 transposase. AB - Tc3 is a member of the Tc1/mariner family of transposable elements. All these elements have terminal inverted repeats, encode related transposases and insert exclusively into TA dinucleotides. We have studied the DNA binding properties of Tc3 transposase and found that an N-terminal domain of 65 amino acids binds specifically to two regions within the 462 bp Tc3 inverted repeat; one region is located at the end of the inverted repeat, the other is located approximately 180 bp from the end. Methylation interference experiments indicate that this N terminal DNA binding domain of the Tc3 transposase interacts with nucleotides on one face of the DNA helix over adjacent major and minor grooves. PMID- 7838707 TI - The budding yeast U5 snRNP Prp8 is a highly conserved protein which links RNA splicing with cell cycle progression. AB - The dbf3 mutation was originally obtained in a screen for DNA synthesis mutants with a cell cycle phenotype in the budding yeast Saccharomyces cerevisiae. We have now isolated the DBF3 gene and found it to be an essential gene with an ORF of 7239 nucleotides, potentially encoding a large protein of 268 kDa. We also obtained an allele-specific high copy number suppressor of the dbf3-1 allele, encoded by the known SSB1 gene, a member of the Hsp70 family of heat shock proteins. The sequence of the Dbf3 protein is 58% identical over 2300 amino acid residues to a predicted protein from Caenorhabditis elegans. Furthermore, partial sequences with 61% amino acid sequence identity were deduced from two files of human cDNA in the EST nucleotide database so that Dbf3 is a highly conserved protein. The nucleotide sequence of DBF3 turned out to be identical to the yeast gene PRP8, which encodes a U5 snRNP required for pre-mRNA splicing. This surprising result led us to further characterise the phenotype of dbf3 which confirmed its role in the cell cycle and showed it to function early, around the time of S phase. This data suggests a hitherto unexpected link between pre-mRNA splicing and the cell cycle. PMID- 7838708 TI - Radiolytic signature of Z-DNA. AB - Ionizing radiations induce various damages in DNA via the hydroxyl radical OH. generated by the radiolysis of water. We compare here the radiosensitivity of B- and Z-DNA, by using a Z-prone stretch included in a plasmid. In the supercoiled plasmid, the stretch is in the Z-form, whereas it is in the B-form when the plasmid is relaxed. Frank strand breaks (FSB) and alkali-revealed breaks (ARB) were located and quantified using sequencing gel electrophoresis. We show that B- and Z-DNA have the same mean sensitivity towards radiolytic attack, for both FSB and ARB. Nevertheless, the guanine sites are more sensitive, and the cytosine sites less sensitive in Z- than in B-DNA, leading to a characteristic signature of the Z-form. The comparison of experiments with the outcome of a Monte Carlo simulation of OH. radical attack suggests that transfer of initial damage from a guanine base to its attached sugar or the adjacent 3' cytosine is more important in Z-DNA than in B-DNA. PMID- 7838709 TI - In vivo decay kinetic parameters of hammerhead ribozymes. AB - Ribozymes offer a potentially important way to inactivate intracellular RNA from almost any gene whose nucleotide sequence is known. Recently, we found that hammerhead ribozymes directed against mRNA of tumour necrosis factor alpha (TNF alpha) and its derivatives, preferentially bind to a cellular protein(s). To better understand the effect of different 3'-terminal hairpins on ribozyme stability as well as their effect on the protein binding to the ribozyme, a mathematical treatment of the decay of three TNF alpha ribozymes that differed at their 3' ends was performed. One ribozyme contained a 3'-terminal hairpin derived from a transcription terminator of bacteriophage T7, another contained the same hairpin but modified to be highly enriched for G+C nucleotides, and a third lacked a hairpin. The TNF alpha ribozyme decay had two kinetic components. The slow component exhibited exponential decay with a half life of approximately 250 h in all cases. The 3'-terminal hairpin has no significant effect on this component. This slow phase accounted for 60-80% of ribozyme decay. The rapid phase also exhibited exponential decay. For this phase, a 3'-terminal hairpin roughly doubled the half-life (1.7-3.4). The slow phase of degradation was about three times faster for a ribozyme directed at the integrase mRNA of human immunodeficiency virus-1 than that seen with the TNF alpha ribozyme. Taken together, these results suggest that the ribozyme population is initially sensitive to degradation, with the presence of a hairpin provides some protection, and indicate that the addition of the hairpin to the ribozyme did not prevent the in vivo additional stabilizing effect of the protein(s). PMID- 7838710 TI - Molecular cloning of MSSP-2, a c-myc gene single-strand binding protein: characterization of binding specificity and DNA replication activity. AB - We have previously reported the human cDNA encoding MSSP-1, a sequence-specific double- and single-stranded DNA binding protein [Negishi, Nishita, Saegusa, Kakizaki, Galli, Kihara, Tamai, Miyajima, Iguchi-Ariga and Ariga (1994) Oncogene, 9, 1133-1143]. MSSP-1 binds to a DNA replication origin/transcriptional enhancer of the human c-myc gene and has turned out to be identical with Scr2, a human protein which complements the defect of cdc2 kinase in S.pombe [Kataoka and Nojima (1994) Nucleic Acid Res., 22, 2687-2693]. We have cloned the cDNA for MSSP 2, another member of the MSSP family of proteins. The MSSP-2 cDNA shares highly homologous sequences with MSSP-1 cDNA, except for the insertion of 48 bp coding 16 amino acids near the C-terminus. Like MSSP-1, MSSP-2 has RNP-1 consensus sequences. The results of the experiments using bacterially expressed MSSP-2, and its deletion mutants, as histidine fusion proteins suggested that the binding specificity of MSSP-2 to double- and single-stranded DNA is the same as that of MSSP-1, and that the RNP consensus sequences are required for the DNA binding of the protein. MSSP-2 stimulated the DNA replication of an SV40-derived plasmid containing the binding sequence for MSSP-1 or -2. MSSP-2 is hence suggested to play an important role in regulation of DNA replication. PMID- 7838711 TI - The solution structure of a 3'-phenazinium (Pzn) tethered DNA-RNA duplex with a dangling adenosine: r(5'G-AUUGAA3'):d(5'TCAATC3'-Pzn). AB - The 3'-Pzn group tethered to an oligo-DNA stabilizes a DNA-RNA hybrid duplex structure by 13 degrees C compared to the natural counterpart. This report constitutes the first full study of the conformational features of a hybrid DNA RNA duplex, which has been possible because of the unique stabilization of this rather small duplex by the tethered 3'-Pzn moiety (Tm approximately 40 degrees C from NMR). In this study, a total of 252 inter- and intra-strand torsional and distance constraints along with the full NOE relaxation matrix, taking into account the exchange process of imino and amino protons with water, have been used. The 3'-Pzn-promoted stabilization of the DNA-RNA hybrid duplex results in detailed local conformational characteristics such as the torsion angles of the backbone and sugar moieties that are close to the features of the other natural DNA-RNA hybrids (i.e. sugars of the RNA strand are 3'-endo, but the sugars of the DNA strand are intermediate between A- and B-forms of DNA, 72 degrees < P < 180 degrees; note however, that the sugars of our DNA strand have a C1-exo conformation: 131 degrees < P < 154 degrees). This study suggests that 3'-Pzn tethered smaller oligo-DNA should serve the same purpose as a larger oligo-DNA as a antisense inhibitor of the viral mRNA. Additionally, these types of tethered oligos have been found to be relatively more resistant to the cellular nuclease. Moreover, they are taken up quite readily through the cellular membrane (14) compared to the natural counterparts. PMID- 7838712 TI - Trinucleotide phosphoramidites: ideal reagents for the synthesis of mixed oligonucleotides for random mutagenesis. AB - Trinucleotide phosphoramidites representing codons for all 20 amino acids have been prepared and used in automated, solid-phase DNA synthesis. In contrast to an earlier report, we show that these substances can be used to introduce entire codons into oligonucleotides in excess of 98% yield, and are ideal reagents for the synthesis of mixed oligonucleotides for random mutagenesis. PMID- 7838713 TI - A young Alu subfamily amplified independently in human and African great apes lineages. AB - A variety of Alu subfamilies amplified in primate genomes at different evolutionary time periods. Alu Sb2 belongs to a group of young subfamilies with a characteristic two-nucleotide deletion at positions 65/66. It consists of repeats having a 7-nucleotide duplication of a sequence segment involving positions 246 through 252. The presence of Sb2 inserts was examined in five genomic loci in 120 human DNA samples as well as in DNAs of higher primates. The lack of the insertional polymorphism seen at four human loci and the absence of orthologous inserts in apes indicated that the examined repeats retroposed early in the human lineage, but following the divergence of great apes. On the other hand, similar analysis of the fifth locus (butyrylcholinesterase gene) suggested contemporary retropositional activity of this subfamily. By a semi-quantitative PCR, using a primer pair specific for Sb2 repeats, we estimated their copy number at about 1500 per human haploid genome; the corresponding numbers in chimpanzee and gorilla were two orders of magnitude lower, while in orangutan and gibbon the presence of Sb2 Alu was hardly detectable. Sequence analysis of PCR-amplified Sb2 repeats from human and African great apes is consistent with the model in which the founding of Sb2 subfamily variants occurred independently in chimpanzee, gorilla and human lineages. PMID- 7838714 TI - Interactions of the site-specific recombinases XerC and XerD with the recombination site dif. AB - The Xer site-specific recombination system of Escherichia coli is involved in the stable inheritance of circular replicons. Multimeric replicons, produced by homologous recombination, are converted to monomers by the action of two related recombinases XerC and XerD. Site-specific recombination at a locus, dif, within the chromosomal replication terminus region is thought to convert dimeric chromosomes to monomers, which can then be segregated prior to cell division. The recombinases XerC and XerD bind cooperatively to dif, where they catalyse recombination. Chemical modification of specific bases and the phosphate-sugar backbone within dif was used to investigate the requirements for binding of the recombinases. Site-directed mutagenesis was then used to alter bases implicated in recombinase binding. Characterization of these mutants by in vitro recombinase binding and in vivo recombination, has demonstrated that the cooperative interactions between XerC and XerD can partially overcome DNA alterations that should interfere with specific recombinase-dif interactions. PMID- 7838715 TI - Adipocyte-specific transcription factor ARF6 is a heterodimeric complex of two nuclear hormone receptors, PPAR gamma and RXR alpha. AB - Previously, we identified a novel transcription factor, ARF6, as a key regulator of the tissue-specific adipocyte P2 (aP2) enhancer. In order to identify the proteins which comprise the adipocyte ARF6 complex, we have purified this DNA binding activity from a cultured adipocyte cell line. We have developed a system for growth and differentiation of HIB-1B brown adipocytes in suspension culture that facilitates the production of large quantities of adipocyte nuclear extract. ARF6 was purified from HIB-1B nuclear extract by a combination of conventional and sequence-specific DNA affinity chromotography. Chemical sequencing and mass spectral analysis of tryptic peptides derived from the purified polypeptides identifies the ARF6 complex as a heterodimer of the retinoid X receptor alpha (RXR alpha) and the murine peroxisome proliferator activated receptor gamma (PPAR gamma). Of the known PPAR gamma isoforms, PPAR gamma is the predominant form expressed in adipose tissue. These results suggest that PPAR gamma 2 serves a unique function among PPAR family members as an important regulator of adipocyte specific gene expression. PMID- 7838716 TI - Differential association of linker histones H1 and H5 with telomeric nucleosomes in chicken erythrocytes. AB - Rat liver telomeric DNA is organised into nucleosomes characterised by a shorter and more homogeneous average nucleosomal repeat than bulk chromatin as shown by Makarov et al. (1). The latter authors were unable to detect the association of any linker histone with the telomeric DNA. We have confirmed these observations but show that in sharp contrast chicken erythrocyte telomeric DNA is organised into nucleosomes whose spacing length and heterogeneity are indistinguishable from those of bulk chromatin. We further show that chicken erythrocyte telomeric chromatin contains chromatosomes which are preferentially associated with histone H1 relative to histone H5. This contrasts with bulk chromatin where histone H5 is the more abundant species. This observation strongly suggests that telomeric DNA condensed into nucleosome core particles has a higher affinity for H1 than H5. We discuss the origin of the discrimination of the lysine rich histones in terms of DNA sequence preferences, telomere nucleosome preferences and particular constraints of the higher order chromatin structure of telomeres. PMID- 7838717 TI - Identifying differences in mRNA expression by representational difference analysis of cDNA. AB - Detection of differentially regulated genes has been severely hampered by technical limitations. In an effort to overcome these problems, the PCR-coupled subtractive process of representational difference analysis (RDA) [Lisitsyn, N. et al. (1993) Science 259, 946-951] has been adapted for use with cDNA. In a model system, RAG-1 and RAG-2, the genes responsible for activating V(D)J recombination, were identified in a genomic transfectant by cDNA RDA in a small fraction of the time taken by conventional means. The system was also modified to eliminate expected difference products to facilitate the identification of novel genes. Additional alterations to the conditions allowed isolation of differentially expressed fragments. Several caffeine up-regulated clones were obtained from the pre-B cell line 1-8, including IGF-1B, and a predicted homologue of the natural killer cell antigen, NKR-P1. The approach was found to be fast, extremely sensitive, reproducible, and predominantly lacked false positives. cDNA RDA has the capacity and adaptability to be applied to a wide range of biological problems, including the study of single gene disorders, characterization of mutant and complemented cell types, developmental or post event expression time courses, and examination of pathogen-host interactions. PMID- 7838719 TI - The fidelity of the human leading and lagging strand DNA replication apparatus with 8-oxodeoxyguanosine triphosphate. AB - A product of oxidative metabolism, 8-oxodeoxyguanosine triphosphate (8-O-dGTP), readily pairs with adenine during DNA replication, ultimately causing A.T-->C.G transversions. This study utilized 8-O-dGTP as a probe to examine the fidelity of the leading and lagging strand replication apparatus in extracts of HeLa cells. Simian virus (SV) 40 T antigen-dependent DNA replication reactions were performed with two M13mp2 vectors with the SV40 origin located on opposite sides of the lacZ alpha sequence used to score replication errors. The presence of 8-O-dGTP at equimolar concentration with each of the 4 normal dNTPs resulted in a > 46-fold increase in error rate for A.T-->C.G transversion over that observed in the absence of 8-O-dGTP. A similar average error rate was observed on the (+) and (-) strands in both vectors, suggesting that the fidelity of replication by leading and lagging strand replication proteins is similar for the dA.8-O-dGMP mispair. Replication fidelity in the presence of 8-O-dGTP was reduced on both strands when an inhibitor of exonucleolytic proofreading (dGMP) was added to the reaction. These data suggest that the majority of dA.8-O-dGMP mispairs are proofread by both leading and lagging strand replication proteins. PMID- 7838718 TI - Repair of a specific double-strand break generated within a mammalian chromosome by yeast endonuclease I-SceI. AB - We established a mouse Ltk- cell line that contains within its genome a herpes simplex virus thymidine kinase gene (tk) that had been disrupted by the insertion of the recognition sequence for yeast endonuclease I-SceI. The artificially introduced 18 bp I-SceI recognition sequence was likely a unique sequence in the genome of the mouse cell line. To assess whether an induced double-strand break (DSB) in the genomic tk gene would be repaired preferentially by gene targeting or non-homologous recombination, we electroporated the mouse cell line with endonuclease I-SceI alone, one of two different gene targeting constructs alone, or with I-SceI in conjunction with each of the two targeting constructs. Each targeting construct was, in principle, capable of correcting the defective genomic tk sequence via homologous recombination. tk+ colonies were recovered following electroporation of cells with I-SceI in the presence or absence of a targeting construct. Through the detection of small deletions at the I-SceI recognition sequence in the mouse genome, we present evidence that a specific DSB can be introduced into the genome of a living mammalian cell by yeast endonuclease I-SceI. We further report that a DSB in the genome of a mouse Ltk- cell is repaired preferentially by non-homologous end-joining rather than by targeted homologous recombination with an exogenous donor sequence. The potential utility of this system is discussed. PMID- 7838720 TI - Transcriptional regulation of the apoAI gene by hepatic nuclear factor 4 in yeast. AB - Hepatocyte Nuclear Factor 4 (HNF-4), a liver-enriched orphan receptor of the nuclear receptor superfamily, is required for the expression of a wide variety of liver-specific genes including apoAI. To explore the possibility that site A of the apoAI gene enhancer might also be the target for HNF-4 without the interference of endogenous mammalian cell proteins that also bind to site A, we tested the ability of HNF-4 to activate transcription from site A in yeast cells. Electrophoretic mobility shift assays (EMSA) and Scatchard plot analysis demonstrated that yeast produced HNF-4 binds to site A with an affinity two times higher than that of yeast produced RXR alpha. Mapping analysis indicated that the 5' portion of site A containing two imperfect direct repeats (TGAACCCTTGACC) and the sequence of the trinucleotide spacer (CCT) between these imperfect repeats are critical determinants for selective binding and transactivation by HNF-4. Similar observations were obtained when these mutated versions of site A were evaluated by transient cotransfection assays in CV1 cells. We conclude that the unique structural determinants of site A in conjunction with the differential binding affinity of HNF-4 for site A may play a fundamental role in apoAI gene regulation. PMID- 7838721 TI - Identification of a DNA binding site for the nuclear factor YY1 in the human GM CSF core promoter. AB - It has been well documented that the repeated CATT(A/T) sequence, localized between -64 and -35 in the human GM-CSF promoter, is required for the promoter activity, and this region likely serves as a core recognition sequence for a cellular transcription factor. However, the transcription factor that interacts with this site was not identified. Here, we report that this element contains a binding site for the nuclear factor YY1, which has not been reported to play a role in the regulation of cytokine gene transcription. Results from transient transfection assays of the Jurkat T cell line revealed that this repeated CATT(A/T) element exhibited enhancer activity when linked to both the human IFN gamma promoter and the TK promoter. Mutation of the YY1 binding site eliminated about 60% of the enhancer activity of the element. We have found that the YY1 binding site could form two specific DNA-protein complexes, A and B, with Jurkat nuclear proteins in the electrophoretic mobility shift assay and that the binding of these complexes correlates with the enhancer activity. UV cross-linking analysis revealed that the A complex is a multi-protein complex and in addition to YY1, other proteins are required for formation of the protein complex. Cotransfection assays with a YY1 expression vector revealed that overexpression of YY1 resulted in an inhibitory effect on the repeated CATT(A/T) element, indicating that in addition to YY1, cofactors also are required for the activator function of the A complex. PMID- 7838722 TI - Cloning and characterization of a c-myc intron binding protein (MIBP1). AB - The cDNA for a c-myc intron 1 binding protein 1 (MIBP1) in the rat was isolated from lambda gt11 and lambda ZAPII cDNA libraries. Sequencing of the cDNA clones revealed a long ORF which encoded a putative protein of 2437 amino acid residues. This protein has two widely separated zinc finger regions, each of which carries C2H2 motifs. When expressed in E. coli as a fusion protein, part of the MIBP1 showed sequence-specific binding to the target sequence, i.e., a 9-bp sequence in the rat c-myc intron 1. MIBP1 is most likely the rat counterpart of human MHC binding protein-2 (MBP-2/HIV-EP2), based on the 86% similarity in nucleotide sequence and 93% similarity in amno acid sequence. Northern blotting revealed a high level of MIBP1 mRNA in the brain. PMID- 7838723 TI - Structure and alternate tissue-preferred transcription initiation of the mouse alpha B-crystallin/small heat shock protein gene. AB - We have determined the complete nucleotide sequence (-865 to +3515) of the murine alpha B-crystallin/small heat shock protein gene, a major soluble protein of the vertebrate eye lens. Its 3 exon/2 intron structure is identical to that of the rat, hamster and human gene, with the exons being much more conserved than the introns. Previous reports indicated that there are two sizes of alpha B crystallin mRNA; a larger alpha B-crystallin mRNA predominates in the lung and brain and is also found in low levels in most other tissues (except in lens and liver), while a smaller alpha B-crystallin mRNA exists at a high level in the lens and in variable amounts elsewhere. Sequence analysis suggests that secondary structure in the 5' untranslated sequence of the longer mRNA has led to difficulty in mapping the transcription initiation site of the longer transcript. Here we provide evidence by primer extension, S1 nuclease protection, and PCR (polymerase chain reaction) experiments for a transcription initiation site in the murine lung and brain at position -474. We also detected the utilization of the -474 initiation site in lens and of the +1 site in lung and brain, indicating that the tissue preference for these sites is not absolute. In vitro transcription experiments revealed that cell-free HeLa nuclear extracts specifically initiate transcription at the -474 and +1 sites. alpha B-crystallin was immunocytochemically localized to the bronchioles of the lung. Thus, regulation of alpha B-crystallin/small heat shock protein expression involves the utilization of tissue-preferred transcription initiation sites. PMID- 7838724 TI - The fate of deleted DNA produced during programmed genomic deletion events in Tetrahymena thermophila. AB - Thousands of DNA deletion events occur during macronuclear development in the ciliate Tetrahymena thermophila. In two deleted genomic regions, designated M and R, the eliminated sequences form circles that can be detected by PCR. However, the circles are not normal products of the reaction pathway. The circular forms occur at very low levels in conjugating cells, but are stable. Sequencing analysis showed that many of the circles (as many as 50% of those examined) reflected a precise deletion in the M and R regions. The remaining circles were either smaller or larger and contained varying lengths of sequences derived from the chromosomal DNA surrounding the eliminated region. The chromosomal junctions left behind after deletion were more precise, although deletions in either the M or R regions can generate any of several alternative junctions (1). Some new chromosomal junctions were detected in the present study. The results suggest that the deleted segment is released as a linear DNA species that is degraded rapidly. The species is only rarely converted to the stable circles we detect. The deletion mechanism is different from those proposed for deletion events in hypotrichous ciliates (2-4), and does not reflect a conservative site-specific recombination process such as that promoted by the bacteriophage lambda integrase (5). PMID- 7838725 TI - Detection of circular excised DNA deletion elements in Tetrahymena thermophila during development. AB - Extensive programmed DNA deletion occurs in ciliates during development. In this study we examine the excised forms of two previously characterized deletion elements, the R- and M-element, in Tetrahymena. Using divergently oriented primers in polymerase chain reactions we have detected the junctions formed by joining the two ends of these elements, providing evidence for the presence of circular excised forms. These circular forms were detected in developing macronuclear DNA from 12-24 h after mating began, but not in micronuclear or whole cell DNA of vegetative cells. They are present at very low abundance, detectable after PCR only through hybridization with specific probes. Sequence analysis shows that the circle junctions occur at or very near the known ends of the elements. There is sequence microheterogeneity in these junctions, which does not support a simple reciprocal exchange model for DNA deletion. A model involving staggered cuts and variable mismatch repair is proposed to explain these results. This model also explains the sequence microheterogeneity previously detected among the junction sequences retained in the macronuclear chromosome. PMID- 7838726 TI - A guanosine quadruplex and two stable hairpins flank a major cleavage site in insulin-like growth factor II mRNA. AB - Insulin-like growth factor II (IGF-II) mRNAs are cleaved by an endonucleolytic event in a conserved part of their 3' untranslated region that is predicted to exhibit a complex higher-order RNA structure. In the present study, we have examined the putative secondary structures of in vitro transcripts from the conserved part of human and rat mRNAs by enzymatic and chemical probing. The results show that the cleavage site is situated between two highly structured domains. The upstream domain consists of two large hairpins, whereas the downstream domain is guanosine-rich. The guanosine-rich domain adopts a compact unimolecular conformation in Na+ or K+ but not in Li+, and it completely arrests reverse transcription in K+ but only partially in Na+, indicating the presence of an intramolecular guanosine quadruplex. The flanking higher-order structures may ensure that the cleavage site is not sequestered in stable RNA structures, thus allowing interactions with RNA or proteins at posttranscriptional stages of IGF II expression. PMID- 7838727 TI - Expression of the E.coli ada gene in S.cerevisiae provides cellular resistance to N-methyl-N'-nitro-N-nitrosoguanidine in rad6 but not in rad52 mutants. AB - The Escherichia coli ada gene protein coding region under the control of the yeast alcohol dehydrogenase promoter in the extrachromosomally replicating yeast expression vectors pADHO6C and pVT103LO6C was introduced into the wild-type yeast strains, YNN-27 and FF-18733, and the repair deficient mutants LN-1 (rad1-1), VV 5 (rad6-1), C5-6 (rad52-1) and FF-18742 (rad52::URA3). This resulted in the expression of 3950, 1900, 1870, 1620, 1320 and 1420 fmol ada-encoded ATase/mg protein respectively: transformation with the parent vectors resulted in ATase activities of 3-17 fmol/mg protein. The wild-types, rad1-1 and rad6-1 yeast expressing the bacterial ATase showed increased resistance to the toxic and mutagenic effects of N-methyl-N'-nitro-N- nitrosoguanidine (MNNG). Expression of ATase in the rad52-1 and rad52::URA3 mutants neither complemented their sensitivity, nor reduced the mutagenic effects of this agent. These results suggest that whilst a portion of the toxic and mutagenic lesions induced by MNNG can be repaired in yeast by the E.coli Ada protein in a RAD1- and RAD6 independent manner, the RAD52 gene product may be essential for the complete functioning of the Ada ATase. This is the first suggestion of a possible cofactor requirement for ATase. PMID- 7838728 TI - Cloning and expression of the Xenopus and mouse Msh2 DNA mismatch repair genes. AB - Bacterial MutS protein and its yeast and human homologs MSH2 trigger the mismatch repair process by their initial binding to mispaired and unpaired bases in DNA. We describe the cloning and sequencing of genes from Xenopus laevis and Mus musculus encoding the homolog of the Saccharomyces cerevisiae MSH2 (the major DNA mismatch binding protein). Mutations in the human homolog of this gene have recently been implicated in microsatellite instability and DNA mismatch repair deficiency in tumour cells from patients with the most common hereditary predisposition to cancer (Lynch syndrome, or hereditary non-polyposis colorectal cancer, HNPCC), as well as in a significant percentage of sporadic tumours. Expression of the amphibian and murine Msh2 gene in different tissues appears to be ubiquitous. The Xenopus gene is highly expressed in eggs, a model system for the biochemistry of DNA mismatch repair. Expression of the murine gene is low in all tissues examined, and is relatively high in a rapidly dividing cell line. These data are suggestive of a role for MSH2 during DNA replication. PMID- 7838729 TI - Abundance of nuclear DNA topoisomerase II is correlated with proliferation in Arabidopsis thaliana. AB - Topoisomerase II (TOPII) is an important enzyme involved in DNA replication and chromosome condensation. The level of TOPII expression has been correlated with the proliferative state of eukaryotic cells. Here we report the cloning and characterization of a cDNA clone AtTopII encoding the first reported TOPII from higher plants. AtTopII is 4603 base pairs (bp) in length and encodes an open reading frame of 1473 amino acid residues. One interesting feature of AtTopII is the presence of a 110 bp direct repeat in the last one-third of the cDNA. Analysis of the genomic sequence within this region by PCR revealed that this duplication includes a small intron of 89 bp. Conservation of sequences within this repeated intron suggests that this in-frame duplication may be a relatively recent event. The deduced amino acid sequence of AtTopII shows strong homologies to TOPII sequences reported from other eukaryotes, particularly in the regions that are highly conserved among different species. Southern blot analysis with Arabidopsis DNA indicates that AtTopII is a single-copy gene while Northern blots detected a 5.0 kb transcript, the level of which is substantially higher in young seedlings than in mature plants. Using a polyclonal antiserum raised against the C-terminal one-third of AtTOPII, we found that the protein is localized in the nucleus and its level is correlated with the proliferative state of the particular tissue. PMID- 7838730 TI - Characterization of the unique intron-exon junctions of Euglena gene(s) encoding the polyprotein precursor to the light-harvesting chlorophyll a/b binding protein of photosystem II. AB - The precursor to the Euglena light harvesting chlorophyll a/b binding protein of photosystem II (LHCPII) is a polyprotein containing multiple copies of LHCPII covalently joined by a decapeptide linker. cDNA and genomic clones encoding the 5' and 3' end of a 6.6 kb LHCPII mRNA were sequenced. A 3.1 kb genomic region encoding 1.05 kb of the 5' end of LHCPII mRNA contains 4 introns. A 7.6 kb genomic region encoding 3.3 kb of the 3' end of LHCPII mRNA contains 10 introns. The 5' and 3' ends of the 14 identified Euglena introns lacked the conserved dinucleotides (5'-GT and AG-3') found at the termini of virtually every characterized nuclear pre-mRNA intron. A common consensus splice site selection sequence could not be identified. The Euglena introns do not have the structural characteristics of group I and group II introns. The only structural feature common to all Euglena introns was the ability of short stretches of nucleotides at the 5' and 3' ends of the introns to base pair, forming a stable stem-loop with the 5' and 3' splice site juxtaposed for splicing but displaced by 2 nucleotides. The 26 nucleotide sequence at the 5' end of LHCPII mRNA is absent from the genomic sequence and identical to the 5' end of one of the small Euglena SL-RNAs indicating that it is post-transcriptionally added by trans-splicing. PMID- 7838731 TI - RNA editing of mat-r transcripts in maize and soybean increases similarity of the encoded protein to fungal and bryophyte group II intron maturases: evidence that mat-r encodes a functional protein. AB - We present evidence that transcripts of the mat-r (maturase-related) genes of maize and soybean contain 15 and 14 uridines (U), respectively, at positions occupied by cytosines (C) in the mat-r gene sequences. Eleven and twelve of these C-->U edits result in an amino acid replacement. Ten C-->U edits are at corresponding nucleotides in the maize and soybean transcripts and, except for a single silent edit, the remainder are at positions in one species that are Us in the other species. This results in an increase in amino acid sequence similarity of the maize and soybean MAT-R proteins. Further, of those amino acids in maize and soybean MAT-R proteins specified by edited codons, ten are conserved in the reverse transcriptase-associated and RNA splicing-associated sequences of the cox1-I2 and/or the cox1-I1 maturases of the fungus Saccharomyces cerevisiae and the bryophyte, Marchantia polymorpha, respectively. The implied strong selection for amino acid sequence conservation indicates that the MAT-R protein is functional. The possibility is discussed that initiation of translation of the mat-r transcripts is at a four nucleotide codon, ATAA or ATGA. PMID- 7838732 TI - Sequence determinants of DNA bending in the ilvlH promoter and regulatory region of Escherichia coli. AB - Previous studies have shown that the promoter/regulatory region of the ilvlH operon displays intrinsic curvature, with the bend center located at position 120 relative to the transcription start site. In this report, a 57 bp sequence spanning the bend center was mutagenized in vitro in order to study the relationship between nucleotide sequence and curvature measured by electrophoresis. The strategy used for analyzing the results consisted of determining the strengths of the relationships between electrophoretic anomaly and predicted curvature calculated by computer programs that differ in wedge angle composition. The results revealed that programs which assume that bending occurs only at AA/TT display good predictive value, with correlation coefficients between electrophoretic anomaly and predicted curvature as high as 0.93. In contrast, a program which assumes that bending occurs at all 16 dinucleotide steps exhibited lower predictive value, while there were no significant relationships between the experimental data and curvature calculated by a program that was based on all non-AA/TT wedge values. These results show that the complete wedge model which incorporates values for all dinucleotide steps does not adequately describe the electrophoretic data in this report. PMID- 7838733 TI - Direct interaction rescue, a novel filamentous phage technique to study protein protein interactions. PMID- 7838734 TI - Differential display using one-base anchored oligo-dT primers. PMID- 7838736 TI - Regulatable promoters of Saccharomyces cerevisiae: comparison of transcriptional activity and their use for heterologous expression. PMID- 7838735 TI - Rapid confirmation of single copy lambda prophage integration by PCR. PMID- 7838737 TI - Simple and efficient recovery of rare living lymphoid cells from a vast majority of dead cells. PMID- 7838738 TI - Simple methods for preparation of plasmid DNA yielding long and accurate sequence data. PMID- 7838739 TI - Diagnosis of mutations by the PCR double RFLP method (PCR-dRFLP). PMID- 7838740 TI - Professional development. Lifting and handling: knowledge for practice (continuing education credit). PMID- 7838742 TI - All taped. PMID- 7838741 TI - The last resort. PMID- 7838743 TI - Disappearing act. PMID- 7838744 TI - Making sense of the use of blood and blood products. AB - The administration of blood in hospital is a common procedure, but many health care professionals have unanswered questions about blood products such as platelets. This paper looks at some of the considerations involved in the collection and use of blood and blood products. PMID- 7838745 TI - Treatment without consent. AB - Performing invasive treatment on an adult without informed consent, except in specific circumstances, constitutes abuse. When providing similar therapy to a child the legal guidelines are less clear, and at times even contradictory. Informed consent may not be required. PMID- 7838746 TI - Testicular cancer and the value of self-examination. AB - While there are national screening programmes for breast and cervical cancer, and raised levels of awareness of lung and skin cancer, the prevalence of testicular cancer among young men has largely been ignored. The document Health of the Nation was produced by the government with the aim of stimulating public and professional interest in health awareness and considering how it could be improved. One of the five key areas selected for particular consideration and action was cancer, chosen because of the high morbidity and mortality rates associated with the disease and because some cancers, although not all, can be prevented and cured as a result of screening and early detection. Testicular cancer as a health issue was not mentioned specifically in the document, probably because it is still relatively uncommon. This paper explores means of preventing testicular cancer by screening and early detection, and by encouraging testicular self-examination. PMID- 7838747 TI - Social needs of people with mild learning disabilities. AB - Community care requires us to pay closer attention to the social and health needs of people with learning disabilities. However, much of the care is focused on people with moderate to profound learning disabilities. Perhaps the needs of those with milder disabilities could be neglected and so individuals could lose out on the support they need. This care study describes the care delivered to a woman who has mild learning disabilities. The aim is to raise people's awareness of the needs of people with mild learning disabilities so they may be met in the future. PMID- 7838748 TI - The maternity needs of the Chinese community. AB - A research project carried out from 1991 to 1993 to investigate what is taught in midwifery programmes of education about race and culture discovered that very little had been published about the maternity needs of the Chinese community. In response to this, a specific unit of learning (15 hours) on issues in health and race was included in the diploma in higher education midwifery programme validated in 1992 at Humberside College of Health. In planning the delivery of this unit of learning, efforts have been made to help student midwives gain a realistic insight into how the needs of the multiracial community may be met. PMID- 7838749 TI - Nursing abroad. Health drive. PMID- 7838750 TI - Nursing abroad. Ancient and modern ways. PMID- 7838751 TI - A fresh approach. PMID- 7838752 TI - Gut reaction. PMID- 7838753 TI - Diabetes blood glucose monitoring. PMID- 7838754 TI - Cut the calls. PMID- 7838755 TI - Education. Added value. PMID- 7838756 TI - Education. Guiding rights. PMID- 7838757 TI - Professional development. Lifting and handling: the role of the nurse (continuing education credit). PMID- 7838758 TI - Children of Goma. Interview by Daloni Carlisle. PMID- 7838759 TI - Final preparations. PMID- 7838761 TI - On duty. Interview by Renata Langford. PMID- 7838762 TI - HIV/AIDS. Maintaining confidentiality when tracing contacts. AB - The extent to which a patient who has HIV can rely on information relating to his or her status remaining confidential has been the subject of furious debate within and outside the nursing profession. This paper explores the issues, with particular reference to partner notification. PMID- 7838760 TI - Poor reward. Interview by Phil Cohen. PMID- 7838763 TI - HIV/AIDS. Counselling drug users. AB - This paper examines the uptake of the HIV test in a busy London drug dependency unit and looks at some of the specialist aspects of HIV counselling with drug users. HIV pre-test counselling is an important health education opportunity. The current guidelines for HIV pre-test counselling with drug users suggest that practitioners should adopt a more encouraging attitude. PMID- 7838764 TI - Systems of life. The lymphatic system. 1. PMID- 7838765 TI - Monitoring sickness and absence in the workplace. AB - An important part of the occupational health nurse's role lies in monitoring sickness and absence in the workforce. This paper discusses that role. PMID- 7838766 TI - Strategies to reduce children's perception of pain. AB - Pain is one of the most complex of all human stressors. This paper reviews the literature specific to children's pain and outlines the factors that influence how they perceive pain. The author also describes how children's pain is observed and how their needs are met in his own unit, and the importance of involving children in the management of their pain. PMID- 7838767 TI - Bart's: a threatened tradition. PMID- 7838768 TI - Tried and tested. PMID- 7838769 TI - A self-care approach. PMID- 7838770 TI - Stoma care: principles and product type. PMID- 7838771 TI - Students. The vital link. PMID- 7838772 TI - Students. Watching with mother. PMID- 7838773 TI - Keep talking. PMID- 7838774 TI - Cocaine abuse. PMID- 7838775 TI - Role of distance education in development of nursing. PMID- 7838776 TI - Safe motherhood: with whom the responsibility rests? PMID- 7838777 TI - An AVID dissent. AB - Despite declarations to the contrary, AVID appears to be a study that is seriously flawed. It is unfairly biased against the ICD; it entails unresolved ethical questions; and it poses a basic question that is inappropriate and subject to broad misinterpretation. Whatever the outcome of the study, harm is likely to follow unless the results are viewed very circumspectly. Rather than conducting such a study, we instead should be directing research funds toward identifying subsets of patients who might best benefit from the ICD. To optimize the use of the ICD, we need to do more patient selection, not less. We need to define subsets of patients in whom the prevention of sudden death by the ICD yields a prolonged overall survival, as well as subsets of patients in whom the device offers little or no benefit. AVID not only fails to do this, but it also threatens to inappropriately curtail (or less likely, to inappropriately expand) the proper use this efficacious tool, the ICD. PMID- 7838778 TI - "An AVID dissent": commentary. AB - Although current data suggest that the ICD is effective, the inherent unreliability of available nonrandomized observational studies make randomized trials of the ICD, such as AVID, CIDS, and CASH, ethically justified and highly desirable. Reasonable decisions regarding patient eligibility and the primary endpoint have been made by all three studies. When completed, these studies should have sufficient power to provide a clear answer as to whether or not the ICD reduces death in our highest risk patients. PMID- 7838779 TI - Report of the NASPE Policy Conference on antibradycardia pacemaker follow-up: effectiveness, needs, and resources. North American Society of Pacing and Electrophysiology. AB - On May 4-5, 1993, a policy conference was held in San Diego, California, under the sponsorship of the North American Society of Pacing and Electrophysiology (NASPE) to identify the fundamental goals of antibradycardia pacemaker follow-up, evaluate the effectiveness with which it achieves those goals, and formulate specific recommendations as to how it can be made more effective. The conference addressed clinical, administrative, and educational objectives, focusing on existing and potential resources for follow-up testing and the appropriate frequency of their application. The training of physicians and associated professionals engaged in follow-up also was addressed, as were regulatory and reimbursement issues. This report summarizes the conclusions and recommendations arrived at during the conference and subsequently approved by the NASPE Board of Trustees. PMID- 7838780 TI - Reasons for reprogramming dual chamber pacemakers to VVI mode: a retrospective review using a computer database. AB - Seven hundred seventy-one dual chamber pacemakers implanted over a 13-year period were identified using a computer database. The mean follow-up period was 40.4 +/- 30.9 months (mean +/- SD). Thirty-three (4.3%) patients were reprogrammed to the VVI mode after a mean period of 26.4 +/- 29 months. Indications for pacing in those reprogrammed were: complete heart block 45.7%, impaired AV conduction 5.7%, sick sinus syndrome 34.2%, carotid sinus syndrome 11.4%, and vasovagal syndrome 2.8%. The most common reason for reprogramming was development of sustained atrial arrhythmias (atrial fibrillation or flutter), which occurred in 25 patients (3.3% of entire group). The remaining 8 (1% of entire group) were reprogrammed because of atrial lead related problems. PMID- 7838781 TI - A technique for rapid transfemoral catheterization of the coronary sinus with multielectrode catheters. AB - To minimize procedural and fluoroscopic times and avoid the risks of vascular injury and pneumothorax, some investigators have advocated elimination of routine placement of a coronary sinus (CS) catheter during electrophysiological procedures. We hypothesized that expedient and reproducible CS catheterization could be performed with minimal patient risk by utilizing a femoral vein approach. Fifty consecutive patients referred for radiofrequency ablative procedures underwent attempted CS catheterization using a 6-French steerable, quadripolar catheter via a femoral vein. Procedures were performed utilizing single-plane fluoroscopy without contrast angiographic aid by operators experienced in the technique. Successful catheterization was defined by the attainment, in < 15 minutes, of a stable catheter position with the distal electrode at or beyond the lateral margin of the heart. Successful catheterization of the CS was achieved in 47 (94%) patients. Selective pacing of the left atrium without patient discomfort was possible in all, eliminating the need for a right atrial pacing catheter. The median time to successful catheterization was 1.4 minutes (range 0.3-14.7). Only six patients required > 5 minutes. The median fluoroscopic time required was 1.2 minutes (range 0.3-12.7). No clinical variable was predictive of catheterization failure or time to successful catheterization. No complications were observed as a result of this technique. This prospective evaluation demonstrates that catheterization of the CS via a femoral vein approach is highly successful, expedient, and safe. The ability to selectively pace the left atrium may eliminate the requirement for a right atrial catheter. PMID- 7838782 TI - Experience with two different nonthoracotomy systems for implantable defibrillator in 170 patients. AB - Implantation of a nonthoracotomy system (Medtronic PCD or CPI Endotak) was attempted in 170 patients with ventricular tachycardia (VT) or ventricular fibrillation (VF) not requiring concomitant cardiac surgery. A nonthoracotomy system could be successfully implanted in 95 of the 115 patients with the PCD system and 49 of 55 patients receiving the Endotak lead system. In 26 patients with failed nonthoracotomy system because of defibrillation threshold (DFT) > 25 joules (J), an epicardial system was implanted at the same setting. Patients receiving the two lead systems were comparable with regard to age, sex, and ejection fraction. However, since the PCD system offers tiered therapy multiprogrammable options, all attempts were made to implant this lead system in patients with VT that could be pace terminated. Mean DFT (15 +/- 4.7 vs 17 +/- 4.6 J; P = 0.03) and implant time (2.5 +/- 0.6 vs 3.3 +/- 0.7 hours; P = 0.02) were less with the Endotak lead system. There was no perioperative mortality. During a mean follow-up of 20 +/- 4 months, there were eight instances of lead dislodgment in patients receiving the PCD system. There were four nonsudden cardiac deaths and one sudden death in the Endotak group and three nonsudden deaths in the PCD group. Sudden cardiac death and total survival using the intention-to-treat analysis during this follow-up period were 99% and 95%, respectively. In conclusion, successful implantation, perioperative mortality, and survival rate are comparable with both lead systems; however, incorporating two defibrillating electrodes in one lead minimizes lead dislodgment and reduces implant time. PMID- 7838783 TI - Stimulation characteristics, complications, and efficacy of spinal cord stimulation systems in patients with refractory angina: a prospective feasibility study. AB - OBJECTIVES: In a prospective study with a 1-year follow-up we evaluated: (1) the feasibility of a method for the adjustment of spinal cord stimulator (SCS) parameters, (2) complications of SCS, and (3) efficacy of SCS. METHODS: In patients receiving an SCS for severe angina unresponsive to standard therapies, SCS characteristics were evaluated within 1 week and at 4, 14, 26, and 52 weeks after SCS treatment. Step-by-step adjustment of pulse output parameters was performed at the electrode configuration at which paresthesias occurred ("sensory threshold"), covered the anginal area ("adjusted setting"), or provoked pain ("motor threshold"). In addition, the number of anginal attacks and intake of glyceryl trinitrate (GTN) tablets were recorded at regular intervals. RESULTS: Twenty-two patients with either a bipolar (14) or a unipolar (8) system were evaluated. In the 14 patients with bipolar systems, alteration in paresthesias required 26 reprogrammings of the configuration. In the eight patients with bipolar systems who completed the follow-up without lead dislocation, the mean "sensory threshold" was 3.3 V (1.7-5.6), the mean "adjusted stimulation" output was 4.5 V (2.8-7.6), and the mean "motor threshold" was 4.9 V (2.8-7.7) after 4 weeks SCS. The mean stimulation duration per 24 hours was 14.1% (5%-24%), and the mean standardized impedance was 821 omega (748-893) after 4 weeks SCS. The unipolar group demonstrated comparable results. After 1-year follow-up the parameters had not changed significantly. During the 1-year follow-up, 6 of 22 patients experienced lead dislocation that required surgery. In all patients, anginal attacks (P < 0.003) and GTN intake (P < 0.005) were reduced significantly with SCS. The effect lasted during the 1 year. CONCLUSIONS: During a 1-year follow-up, the stimulation parameters did not change significantly in the 16 patients without lead dislocations. Our standardized method appears to be feasible for follow-up of SCS. Moreover, SCS seems to be an effective adjuvant therapy for intractable angina, despite a relatively frequent dislocation of the electrode. PMID- 7838784 TI - Behavior of different activity-based pacemakers during treadmill exercise testing with variable slopes: a comparison of three activity-based pacing systems. AB - A new generation of activity-based pacemakers incorporates an accelerometer sensitive to low frequency acceleration signals in the anteroposterior direction for sensing of bodily stress. The purpose of our investigation was to test a representative model of these new activity-based pacemakers (Relay) and compare it with current vibration- and housing pressure-sensing systems. We tested ten pacemaker patients with implanted Activitrax, Sensolog, and Relay systems during treadmill exercise testing with variable slopes. Devices from the three systems were also strapped externally to the chest of each patient and to ten normal test subjects in the control group. Exercise tests were conducted with changes of treadmill speed and/or treadmill slope. For comparable workloads during constant speed/variable slope and constant slope/variable speed, Relay had similar rate responses (difference not significant). Significant differences (P < 0.05) in rate adaptation attributable to the kind of treadmill exercise (change in treadmill speed or slopes) were observed in the housing pressure- and vibration based pacemakers. Activity-based pacemakers with an acceleration sensor adapt pacing rates during treadmill exercises independent of treadmill speed or slope better than those controlled by a conventional housing pressure or vibration sensor. PMID- 7838785 TI - Early changes in defibrillation threshold following implantation of a nonthoracotomy system in dogs. AB - BACKGROUND: Nonthoracotomy systems are rapidly becoming the preferred surgical method for implantation of cardioverter defibrillators. Testing is performed at the time of implantation to insure an adequate margin of safety for defibrillation. However, this safety margin may change with lead maturation. This study evaluated changes in defibrillation threshold following implantation of a nonthoracotomy system. METHODS AND RESULTS: Ten dogs underwent implantation of a nonthoracotomy system consisting of a single catheter with a distal coil electrode in the right ventricular apex and a proximal coil electrode in the superior vena cava forming a common anode with a subcutaneous patch over the left thorax. Defibrillation threshold testing, using a biphasic waveform, was performed on each animal under general anesthesia at implantation (day 1) and subsequently on postoperative days 3, 7, 10, 17, 24, 31, 38, and 45. E50, the energy associated with a 50% likelihood of successful defibrillation, was determined at each setting. The mean E50 was 12.2 +/- 1.1 J at the time of implantation, increasing 36% to 16.8 +/- 2.0 J by day 38 (P < 0.01). Individual increases in E50 of 10-12 J were observed in four animals. CONCLUSIONS: Energy requirements for defibrillation with a nonthoracotomy system increase during the early postoperative period, with the highest defibrillation threshold observed at 38 days. This increase may be applicable to humans and should be considered when selecting an adequate energy safety margin for defibrillation at time of implantation. PMID- 7838786 TI - Radiofrequency catheter ablation of a concealed accessory atrioventricular pathway after heart transplantation. AB - Three months after orthotopic cardiac transplantation, a 46-year-old man developed paroxysmal supraventricular tachycardia. Electrophysiological investigation of the arrhythmia led to the diagnosis of an atrioventricular reentrant tachycardia involving a left lateral concealed accessory pathway. When antiarrhythmic drugs failed to suppress the arrhythmia, radiofrequency catheter ablation of the accessory pathway was performed without complication. PMID- 7838787 TI - A minimal model of the single capacitor biphasic defibrillation waveform. AB - A quantitative model of the single capacitor biphasic defibrillation waveform is proposed. The primary hypothesis of this model is that the first phase leaves a residual charge on the membranes of the unsynchronized cells, which can then reinitiate fibrillation. The second phase diminishes this charge, reducing the potential for refibrillation. To suppress this potential refibrillation, a monophasic shock must be strong enough to synchronize a critical mass of nearly 100% of the myocytes. Since the biphasic waveform performs this protection function by removing the residual charge (with its second phase), its first phase may be of a lower strength than a monophasic shock of equivalent performance. A quantitative model was developed to calculate the residual membrane voltage, Vm, assuming a capacitive membrane being alternately charged and discharged by the first and second phases, respectively. It was further assumed that the amplitude of the first phase would be predicted by a minimum value plus a term proportional to Vm2. The model was evaluated on the pooled data of three relevant published studies comparing biphasic waveforms. The model explained 79% of the variance in the first phase amplitude and predicted optimal durations for various defibrillator capacitances and electrode resistances. Assuming a first phase of optimal duration, the optimal second phase duration appears to be about 2.5 msec for all capacitances and resistances now seen clinically. CONCLUSION: The effectiveness of the single capacitor biphasic waveform may be explained by the second phase "burping" of the deleterious residual charge of the first phase that, in turn, reduces the synchronization requirement and the amplitude requirements of the first phase. PMID- 7838788 TI - Submammary pacemaker implantation: a unique tunneling technique. AB - Submammary pacemaker implantation offers women a cosmetically acceptable alternative to the standard pectoral implant. We present a novel method of submammary implantation performed on ten women aged 13-54 years. The lead electrodes are tunneled from the infraclavicular to the inframammary incision using a long needle, guidewire, and introducers/dilators in a manner analogous to the retained guidewire technique used for standard lead insertion. The procedure can generally be performed under local anesthesia. All patients tolerated the procedure well without acute complications. Over 2- to 23-month follow-up, there were no lead dislodgments. No patients developed mastitis or incisional complications, and all have been extremely satisfied with the cosmetic results. With proper technique, submammary pacemaker implantation can be performed under local anesthesia with minimal patient discomfort and optimal cosmesis. PMID- 7838789 TI - Multimedia slide presentations. PMID- 7838790 TI - Hybrid nonthoracotomy ICD systems: lessons from the brouhaha. PMID- 7838791 TI - Migration of an epicardial pacemaker to the pericardial space in an infant. AB - We report the case of a 4-month-old infant who was implanted with an epicardial ventricular pacing system at 6 days of age for the prolonged QT syndrome, who subsequently developed migration of the pulse generator to the pericardial space. Tracking of the pulse generator through the diaphragm and into the pericardium followed the route of the myocardial lead. The possibility of pulse generator migration, as well as disruption of the diaphragm and pericardium, should be considered by those who care for infants with implanted pacemakers. PMID- 7838792 TI - Transvenous permanent pacing in a one-day-old infant. PMID- 7838793 TI - Adenosine induced torsades de pointes in a child with congenital long QT syndrome. AB - Torsades de pointes is a rare arrhythmia characterized by its bradycardia dependence and increased adrenergic discharge, whether it occurs as a congenital anomaly or as an acquired problem resulting from drug intoxication or other conditions. There are no reliable tests to assess the propensity toward torsades de pointes or evaluate the efficacy of treatment in these patients. Adenosine can result in marked slowing of sinus and ventricular rate and leads to increased sympathetic discharge when given intravenously. We induced torsades de pointes in a child with congenital long QT syndrome (Jervell-Lange-Nielsen syndrome) using 200 micrograms/kg IV adenosine bolus. Higher dosage of adenosine (600 micrograms/kg) did not lead to torsades de pointes after beta blockade. Adenosine may induce torsades de pointes in patients with the long QT syndrome and may be used as a test to reproduce the clinical arrhythmia. Whether adenosine proves to be useful for assessing the efficacy of treatment will require extensive investigation in larger series of patients. PMID- 7838794 TI - Differentiation of sinus tachycardia from ventricular tachycardia with 1:1 ventriculoatrial conduction in dual chamber implantable cardioverter defibrillators: feasibility of a criterion based on the atrioventricular interval. AB - Tachycardia discrimination in future implantable cardioverter defibrillators (ICDs) is likely to be enhanced by the addition of an atrial sensing/pacing lead. However, differentiation of sinus tachycardia (ST) from ventricular tachycardia (VT) with 1:1 VA conduction will remain problematic. We assessed the use of the AV interval as a potential criterion for correctly differentiating ST from VT. Incremental V pacing at the right ventricular (RV) apex served as a "VT" model in each of 41 patients with 1:1 VA conduction to pacing cycle lengths < or = 450 msec. High right atrial and RV apical electrograms during normal sinus rhythm (NSR) and during incremental V pacing were digitized (simulating ICD sensing). From these signals, AV interval versus pacing cycle length plots were computer generated to identify crossover cycle lengths, each defined as the cycle length at which the AV interval during V pacing equals the AV interval during NSR. At cycle lengths longer than the crossover value, the AV interval during "VT" exceeds the AV interval during NSR. In contrast, the AV interval during ST is physiologically shorter than the AV interval during NSR. Thus, ST can be readily differentiated from "VT" over a range of cycle lengths greater than the crossover value. The overall mean calculated crossover cycle length was 371 +/- 52 msec. In 11 patients paced multiple times, each crossover cycle length was reproducible (mean coefficient of variation was 1.2% +/- 0.9% per patient). AV intervals measured at the RV apex were also analyzed with incremental V pacing during catecholamine stimulation (isoproterenol, n = 5) and during alternate site "VT" (RV outflow tract [n = 8] and left ventricle [n = 2]). In all these cases, the new "VT" plots of AV interval versus pacing cycle length coincided with or fell to the left of those obtained during control RV apical pacing and recording (i.e., these AV interval values crossed the NSR baseline at cycle lengths < or = the crossover cycle length). Thus, the cycle length range for recognizable differentiation of ST from "VT" remained valid. The data suggest that the described AV interval criterion relying on the crossover cycle length: (1) is a promising approach to improve differentiation of ST from relatively slow VTs with 1:1 VA conduction, and (2) can readily be automated in future dual chamber ICDs, given its computational simplicity. PMID- 7838795 TI - Atrioventricular connections present in patients with Wolff-Parkinson-White syndrome are composed of working myocardium. PMID- 7838796 TI - Short- and long-term reproducibility of QT, QTc, and QT dispersion measurement in healthy subjects. PMID- 7838797 TI - STIMAREC report. PMID- 7838798 TI - Effect of dipyridamole on the blood flow in coronary aneurysms resulting from Kawasaki disease. AB - Dipyridamole has been widely used in Japan to treat patients with a coronary aneurysm resulting from Kawasaki disease, but its effect in these patients has not been established. In the present study we assessed the effect of dipyridamole on the coronary arteries of patients with a history of Kawasaki disease by measuring the diameter of the coronary arteries and by quantifying the disappearance time of contrast medium (runoff time) on coronary angiography. Intravenous injection of dipyridamole increased the diameter of nondilated arteries by 7.9%. Its effect on the diameter of dilated coronary arteries (coronary aneurysm) was less than 3% (p < 0.01). Runoff time of dilated coronary arteries was significantly (p < 0.01) greater than that of nondilated coronary arteries. Dipyridamole accelerated runoff time not only in nondilated coronary arteries (p < 0.01) but also in coronary arteries with various degrees of dilatation (p < 0.01). We conclude that dipyridamole increases blood flow in coronary arteries without dilating the proximal aneurysm in children with a history of Kawasaki disease. PMID- 7838799 TI - Adjustment of cardiac repolarization to changing cycle length in healthy infants. AB - This study describes the relation of cardiac repolarization (QT interval) to a changing heart rate (RR interval) in healthy infants, utilizing abbreviated electrocardiographic (ECG) recordings. A total of 105 limb lead ECG recordings were made in 53 infants of postconceptional age 30 to 52 weeks over a 5- to 15 minute period in order to obtain a heart rate variation of at least 20%. The QT and preceding RR intervals were measured during one cycle from each 3 second ECG segment (minimum 40 cycles) and the log QT-log RR relation was examined by linear regression statistics. Average RR was 387 ms (SD 42) and the average log QT/log RR slope 0.39 (SD 0.16). The slope correlated negatively with RR and was unassociated with age or sex. In 7 of the infants a single recording showed a QT RR regression that failed to meet the 5% level of significance; 6 of these infants had additional tracings with a significant regression. When the log QT log RR regression was studied in 20 continuous rhythm strips with spontaneous rate variation, the analysis of 9-32 consecutive cycles yielded an average slope of 0.13 (SD 0.07); in more than one-half of these strips the QT-RR association lacked significance at the 5% level. (ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7838800 TI - The vibratory innocent heart murmur in schoolchildren: a case-control Doppler echocardiographic study. AB - In 810 schoolchildren (aged 5-14 years) the prevalence of a grade 1-3/6 vibratory innocent heart murmur (VIHM) is 41%. Restricted to a grade 2 or 3 VIHM, the prevalence is 14%, decreasing from 21% in the age-class 5-6 years to 8% for children 13-14 years of age. The prevalence of a grade 3 VIHM is 1%. Together with a matched control, 84 children with a grade 2 or 3 VIHM underwent further cardiologic examination including electrocardiography, phonocardiography, and Doppler echocardiography. A positive correlation was found between the presence of a VIHM and higher left ventricular voltages on the ECG, but within the normal range; lower heart rate; smaller diameter of the ascending aorta (AAO); and higher blood flow velocity and higher maximal acceleration of the blood flow in the LVOT and the AAO. In 40% of the children with a VIHM, a systolic aortic valve vibration was seen with a frequency > or = 100 Hz and an amplitude > or = 1 mm, whereas this type of vibration was present in only one case control. No significant difference was found concerning the prevalence of false tendons in the left ventricle, systolic and diastolic diameter of the left ventricle, systolic time intervals, and shortening fraction of the left ventricle. The VIHM is strongly associated with a smaller AAO, with higher velocity and acceleration of the blood flow in the LVOT and AAO, and with a vibratory phenomenon of the aortic valve, pointing towards the LVOT-aortic valve region as the site of origin of the VIHM. PMID- 7838801 TI - The vibratory innocent heart murmur in schoolchildren: difference in auscultatory findings between school medical officers and a pediatric cardiologist. AB - In 810 schoolchildren heart auscultation was performed by both a school medical officer (SMO) and a pediatric cardiologist (PC). The prevalence for a grade 1, 2, or 3 vibratory innocent heart murmur (VIHM), a grade 2 or 3 VIHM, and a grade 3 VIHM heard by the PC was 41%, 13%, and 1%, respectively. The SMO noted such murmurs in 26%, 9%, and 1%, respectively. In 30% of the cases in which the PC had noted a grade 2 or 3 VIHM, the SMO agreed; in 30% of such cases the SMO did not hear any heart murmur. If the PC heard a grade 2 or 3 VIHM phonocardiography was performed in a case-control study in which the controls did not have a heart murmur (94 pairs). In four children with a grade 2 or 3 VIHM no heart murmur could be registered and in three other children the murmur did not have the typical diamond shape. In contrast, in three children without a heart murmur at school a VIHM was seen on the phonocardiogram. In 26 children with a phonocardiographically proven grade 2 or 3 VIHM the SMO did not hear any heart murmur. One child with a grade 3 VIHM (both by the PC and SMO) had a minor subvalvular aortic stenosis. There is quite a difference in auscultatory detection of a venous hum: 9% (PC) and 2% (SMO). The prevalence of the pulmonary ejection murmur is identical at 4%. The carotid bruit is heard in 4% (PC) and 2% (SMO).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7838802 TI - Atrial natriuretic peptide concentrations in children with pulmonary hypertension: correlation with hemodynamic measurements. AB - To define the relation between atrial natriuretic peptide (ANP) and hemodynamic parameters in children with pulmonary artery hypertension, we measured the ANP concentrations of the femoral vein, right atrium, pulmonary artery, left atrium and left ventricle, or femoral artery in 32 patients during right or left heart catheterization. There is a strong correlation among the ANP levels obtained from different locations (p < 0.001), and these ANP levels are positively correlated with pulmonary arterial pressures and pulmonary resistance. Patients were divided into two groups according to their pulmonary arterial pressure. The group with pulmonary arterial systolic pressure higher than 31 mmHg had higher ANP levels than the group with pulmonary arterial systolic pressure lower than 31 mmHg. When patients were grouped according to their pulmonary resistance, ANP levels in the group with pulmonary resistance over 2 U/m2 were higher than those in the group with pulmonary resistance lower than 2 U/m2. In this study ANP levels showed a correlation with the right ventricular systolic pressure. A correlation was not seen between ANP levels and the flow ratios or the presence of shunt. The results of our study suggest that ANP should be considered an important factor in pulmonary hypertension, independent of other factors. PMID- 7838803 TI - Pharmacodynamics and pharmacokinetics of esmolol, a short-acting beta-blocking agent, in children. AB - Esmolol, a short-acting intravenous cardioselective beta-blocking agent, was evaluated for age-dependent pharmacodynamic and pharmacokinetic features in 17 young patients (6 months to 14 years). A loading dose (500 micrograms/kg/min) alternating with a maintenance dose (25-200 micrograms/kg/min, titrating by 25 micrograms/kg/min every 4 min) was infused until the heart rate or mean arterial pressure decreased 10%. Cardiac index, left ventricular shortening fraction, and systemic vascular resistance were measured at baseline, peak esmolol effect, and recovery. Serum esmolol concentrations were obtained to determine the half-life and the elimination rate constant. Esmolol reduced the heart rate, blood pressure, shortening fraction, and cardiac index in all patients, but it did not change systemic vascular resistance. Maintenance esmolol dose was 118 +/- 49 micrograms/kg/min, and the half-life was 2.88 +/- 2.67 min. Blood pressure and heart rate returned to normal within 2-16 min, but cardiac index and shortening fraction took longer to recover. There were no statistically significant age dependent pharmacodynamic effects, but blood pressure decreased prior to heart rate and cardiac index took longer to recovery in patients who weighed < or = 15 kg. The pharmacokinetic profile in young patients was similar to that of older patients, but the half-life was shorter. The only side effect was transient nausea and vomiting in one patient. Esmolol is a safe and efficacious beta blocking agent in young patients. PMID- 7838805 TI - Acute pseudoaneurysm formation complicating balloon dilation of native coarctation: treatment by delayed surgical repair. AB - An 11-year-old boy developed an acute aortic pseudoaneurysm during balloon dilation of unoperated coarctation of the aorta. The pseudoaneurysm occurred despite the fact that the balloon catheter size did not exceed the diameter of the aorta at the diaphragm. Elective delayed surgical repair was successfully performed after 3 weeks of antihypertensive treatment when serial magnetic resonance imaging had demonstrated a reduction in the local tissue swelling. PMID- 7838804 TI - Embolization of a coronary fistula with a controlled delivery platinum coil in a 2-year-old. AB - Congenital coronary artery disorders are rare. Elective closure is proposed in view of the morbidity reported later in life. Excellent results have been reported with surgery, and recently catheter occlusions have been successful. We report the case of a 2-year-old girl whose coronary artery fistula was occluded with a special controlled delivery coil system. PMID- 7838806 TI - Magnetic resonance imaging of musculoskeletal tumors. AB - In summary, MRI is the preferred modality for the evaluation of a soft-tissue mass following radiography. The radiologic appearance of certain soft-tissue tumors or tumor-like processes such as benign fatty tumors, intramuscular hemangiomas, pigmented villonodular synovitis, and certain hematomas may be sufficiently unique to allow a strong presumptive radiologic diagnosis. It must be emphasized that MRI cannot reliably distinguish between benign and malignant lesions and, when radiologic evaluation is nonspecific, one is ill advised to suggest a lesion is benign or malignant solely on its MR appearance. The role of MRI in the evaluation of bone tumors is predominantly one of staging. MRI is superb to evaluate the extent of intraosseous and soft-tissue involvement as well as the relationship of the lesion to the neurovascular bundle. Unfortunately, MRI remains nonspecific and is unable to predict lesion histology. Finally, the value of Gd-DTPA enhanced imaging is still to be determined. PMID- 7838807 TI - Magnetic resonance imaging of the shoulder. AB - MRI has rapidly become a commonly used technique for evaluation of the shoulder. It provides a wealth of information regarding the entire shoulder girdle, and it is the most accurate noninvasive method available for imaging the rotator cuff. There have been numerous technical improvements in MRI in the relatively short time that clinical MRI has been in existence. Further refinements in design, new imaging sequences, and additional clinical experience should help to increase the accuracy and flexibility of this imaging modality. PMID- 7838808 TI - Magnetic resonance imaging of the elbow. AB - Technical improvements in MR imaging have resulted in the ability to detect soft tissue and bone pathology, with great facility in the elbow joint. This allows application of MRI to the elbow in the same valuable ways it has been used in other joints for a much longer period. PMID- 7838809 TI - Magnetic resonance imaging of the wrist. AB - As improvements in surface coil technology and imaging sequences continue, increased applicability of MRI to small yet complex structures such as the wrist is assured. Almost certainly, the full potential of MRI in the wrist has yet to be realized, and its versatility is perhaps limited only by the radiologist's experience. As we become more adept at this modality, it will become an increasingly important component in the radiology armamentarium. PMID- 7838810 TI - Magnetic resonance imaging of the pelvis and hips. PMID- 7838811 TI - Magnetic resonance imaging of the knee. PMID- 7838812 TI - Magnetic resonance imaging of the ankle and foot. PMID- 7838813 TI - Radiologic case study. Os odontoideum. PMID- 7838815 TI - An emigrating patient with possible MS. PMID- 7838814 TI - Magnetic resonance imaging of muscle injuries. PMID- 7838816 TI - Organising a lipid control regime. PMID- 7838817 TI - Tackling the new-look MCQ. PMID- 7838818 TI - Driving after and during neurological disorders. PMID- 7838820 TI - Coronary bypass or angioplasty? PMID- 7838819 TI - Drugs for angina: how good? How safe? PMID- 7838821 TI - ACE inhibitors: a patient lifeline? PMID- 7838822 TI - The link between diet and CHD. PMID- 7838824 TI - 1st International Meeting of World Placenta Associations. Sydney, Australia, 24 28 October 1994. Abstracts. PMID- 7838825 TI - 2nd Meeting of the Japan Placenta Group. Ohmiya, Saitama Prefecture, 10-11 November 1994. Abstracts. PMID- 7838823 TI - Prescribing in children. PMID- 7838826 TI - Human trophoblast interferons enhance major histocompatibility complex class I antigen expression on human term trophoblast cells in culture. AB - The expression and regulation of major histocompatibility complex class I (MHC class I) antigens by virus-induced human trophoblast interferons (tro-IFNs) were examined in term trophoblast cultures. Flow cytometry studies using fluorescence monoclonal antibodies against MHC class I antigens revealed that isolated cytotrophoblasts can express MHC class I antigens. The expression of these antigens increased with stimulation of trophoblast cultures with tro-IFN-alpha and -beta. One hundred IU tro-IFN-alpha and -beta/ml induced no significant higher levels of MHC class I antigens as compared with the control, whereas 1000 IU tro-IFN-alpha and -beta/ml did. The tro-IFN-enhanced expression of MHC class I antigens may be important as it increases the efficiency of local and viral antigen presentation, cytotoxicity by T cell response and local inflammatory processes, thereby preventing virus spread from mother to fetus. PMID- 7838827 TI - Atrial natriuretic peptide counteracts the vasoconstrictor effects of 5 hydroxytryptamine, U46619 and endothelin-1 in the human umbilical artery. AB - A role for atrial natriuretic peptide (ANP) in maintaining low vascular resistance within the fetoplacental circulation was investigated using isolated strips of human umbilical artery (HUA). Physiological levels of ANP significantly reduced the isometric contractile response of the HUA to U46619 (a stable thromboxane A2 mimetic), to 5-hydroxytryptamine and to endothelin-1, though no effect on agonist sensitivity could be demonstrated. These data suggest that ANP may modify vascular tone in vivo thereby counterbalancing several humoral factors which act to increase vascular resistance within the fetoplacental circulation. PMID- 7838828 TI - Protein phosphatase activity against protein kinase C-phosphorylated substrates in human placenta. AB - The presence of endogenous modulators of protein kinase C (PKC) in human placenta has not been reported. The specific activity of PKC in human placental cytosol was 20.52 +/- 1.8 pmol/min x mg protein. Partial purification of placental cytosol on diethylaminoethyl cellulose (DEAE) resulted in recovery of 145 per cent of original enzyme activity. Placental cytosol mixed with a control preparation of PKC significantly inhibited the control enzyme activity (control 42.42 +/- 2.8 pmol/min; control+placental cytosol 27.44 +/- 2.8 pmol/min, P < 0.05). The PKC-inhibitory activity was abolished by the addition of phosphatase inhibitors calyculin A (0.09 nM), microcystin LR (0.8 nM), and okadaic acid (0.4 nM). Protein substrates phosphorylated by PKC were rapidly dephosphorylated upon the addition of placental cytosol; this dephosphorylation was prevented by the presence of calyculin A and was removed by fractionation of placental cytosol on DEAE. Protein but not peptide substrate supported both the PKC-inhibitory activity and the dephosphorylation of PKC-phosphorylated substrates. The placental serine-threonine protein phosphatase was active against phosphorylase a, but not against substrate phosphorylated by cAMP-dependent protein kinase. These data indicate that the human placenta contains an endogenous inhibitor of PKC which interacts with substrate rather than with the PKC and that the inhibitor is a protein phosphatase. PMID- 7838829 TI - Human placental gonadotrophin-releasing hormone (GnRH) binding sites: III. Changes in GnRH binding levels with stage of gestation. AB - We have measured the levels of gonadotrophin-releasing hormone (GnRH) binding sites in human placental villous membrane fractions obtained at different stages of gestation. There was a marked decrease in the specific activity of 125I labelled GnRH binding to membrane fractions obtained between 10-20 weeks gestation, but there was no change in either affinity or ligand specificity of these binding sites. The observed decrease in binding was not due to contamination of placental villous membranes by membranes from other tissues, since there was no gestation-dependent decrease in the specific activity of epidermal growth factor receptor or alkaline phosphatase activity in villous membrane fractions between 10-20 weeks of gestation. Furthermore, incubation of GnRH tracer with membranes from different stages of gestation, followed by re incubation of the unbound tracer fraction with fresh membranes, demonstrated unequivocally that decreased GnRH binding to 10-20 week membranes was not due to increased degradation of GnRH tracer. We conclude that the observed changes in GnRH receptor levels between 10-20 weeks gestation must reflect either decreased expression/synthesis (or increased catabolism) of placental GnRH receptors, or increased occupancy (or down-regulation) of placental GnRH receptors by an endogenous GnRH-like ligand. PMID- 7838830 TI - Free amino acid concentrations in human first and third trimester placental villi. AB - Homogenates of first (10.1 +/- 1.0 weeks) and third trimester placental villi were analysed for free amino acid concentrations. As has been previously reported, several amino acids showed increased concentrations during early pregnancy when compared to term. In addition, marked differences were seen in the levels of ethanolamine (which was increased fivefold in term placentae) and phosphoethanolamine (which was decreased by almost 97 per cent of the value measured at 10 weeks gestation). The implications of these results are discussed. PMID- 7838832 TI - Comparison of histological features in early spontaneous and induced trisomic abortions. AB - Qualitative and quantitative histological features of a series of induced (n = 6) and spontaneous (n = 24) trisomic abortions were compared. The chorionic villi of induced abortions were large and of irregular contour. The stroma contained many blood vessels and did not show fibrohyalinic change. The intact trophoblast demonstrated 'hyperplasia'. Contrastingly, spontaneous abortions were composed of smaller villi with somewhat more fibrohyalinic stroma containing a few blood vessels. The trophoblast did not show 'hyperplasia'. However, many syncytial knots were present. Although some of histological features were shown to relate to gestational age, which could not be completely matched for, it was unlikely that this could account for the observed differences. Analysis restricted to induced and spontaneous abortions of comparable gestational age demonstrated the same differences. The time-lag between first blood loss and final gestational loss in spontaneous abortions did not appear to be of influence on any of the variables. The striking histopathological differences between induced and spontaneous abortions are mainly considered to be due to cessation of circulation at some time and to disintegration of trophoblast as a result of ischaemia in spontaneous abortions. PMID- 7838833 TI - Brief communication: sliding displacement of amnion and chorion following controlled laser wounding suggests a mechanism for short-term sealing of ruptured membranes. AB - The Erbium-YAG laser was used to produce narrow wounds of defined depth in term amniochorion. The charring effect of the laser meant that sites could be readily localized in histological sections. During brief post-wounding incubations, sliding displacement of the amnion relative to the chorion occurred through the plane of the spongy layer. This suggests a possible short-term mechanism whereby a spontaneous rupture could be sealed in vivo. PMID- 7838834 TI - Trophoblast basal and microvillous membrane isolation. PMID- 7838831 TI - Ovine uteroplacental glucose and oxygen metabolism in relation to chronic changes in maternal and fetal glucose concentrations. AB - We tested whether uterine glucose uptake rate (UtGU), placental glucose transport rate to the fetus (PGT) and uteroplacental glucose consumption rate (UPGC) were altered in chronically catheterized pregnant sheep after 2-5 week intravenous infusions of glucose or insulin that produced sustained maternal and fetal hyper- or hypoglycemia. In the hyperglycemic animals, UtGU was greater than that of controls; the excess UtGU was partitioned into non-oxidative UPGC rather than PGT. The 'normal' rate of PGT observed in the hyperglycemic animals is probably related to suppression of fetal insulin concentration which would decrease fetal glucose clearance and thus the transplacental glucose concentration gradient. The increase in UPGC may help prevent an excessive supply of glucose to the fetus. In the hypoglycemic animals, weight-specific UPGC and uteroplacental oxygen uptake were not different from controls; placental weight also was reduced, an adaptation that maintained normal placental metabolism per unit tissue and did not disproportionately deprive the fetus of glucose supply. PMID- 7838835 TI - Intraductal apocrine carcinoma: a clinicopathologic study of 37 cases. AB - The clinical and pathologic features of 37 examples of intraductal apocrine carcinoma are reported along with criteria for distinguishing apocrine intraductal carcinoma (AIDCA) from apocrine hyperplasia. A majority of AIDCAs (32 cases) displayed both cytological atypia and intraluminal necrosis. Five AIDCAs lacked intraluminal necrosis but had at least subtle atypia with either epithelial bridging or a solid, mosaic-like growth pattern involving one or more ducts exceeding 2 mm in maximum cross-sectional diameter. Twenty-nine patients had mastectomy. Eight women had excisional biopsy or quadrantectomy only; two of these developed recurrences 2 and 4.5 yr following their biopsies. The original AIDCA in both patients was of the comedo type and neither woman had received any further treatment following biopsy. Both women were alive 4 and 6 yr after their respective mastectomies. The follow-up for the entire group ranged from 2.5 to 20 yr with a mean of 11.4 yr. One of the eight women died from breast cancer 4 yr after the diagnosis of her AIDCA; she had had mastectomy for a node-negative infiltrating nonapocrine carcinoma in the contralateral breast 4 yr before her AIDCA, however, and probably died from progression of the invasive carcinoma of the contralateral breast. In the absence of necrosis and significant atypia, a diagnosis of AIDCA should be made cautiously. PMID- 7838836 TI - Mucin histochemistry of ovarian borderline tumors of mucinous and mixed epithelial types. AB - Mucin histochemistry was studied in 23 intestinal-type mucinous borderline tumors, 21 endocervical-like mucinous borderline tumors, and 24 mixed-epithelial borderline tumors. The latter two tumors, which are of mullerian type, had a mucin composition similar to that of normal endocervix, with abundant neutral and acidic mucins in approximately equal amounts and a slight predominance of sialomucins over sulfomucins. Intestinal-type mucinous borderline tumors showed several patterns that most closely resembled gastric mucosa with varying degrees and types of intestinal metaplasia. In conclusion, mucin histochemistry shows striking differences between these two types of mullerian borderline tumors compared with intestinal-type mucinous borderline tumors and confirm the subclassification of mucinous borderline tumors into intestinal and endocervical types. PMID- 7838837 TI - Immunohistochemical staining for DNA topoisomerase II in frozen and formalin fixed paraffin-embedded human tissues. AB - DNA topoisomerase II is the molecular target of several clinically useful chemotherapeutic drugs. The sensitivity of cells to drugs that target topoisomerase II is dependent on the cellular content of this enzyme. Drug sensitive cells have elevated amounts of type II topoisomerase. To determine relative amounts of enzyme in malignant neoplasms, we developed an in situ immunohistochemical stain for topoisomerase II. The stain uses either polyclonal or monoclonal antibodies produced against the alpha isoform of the enzyme. Staining can be done on both frozen and formalin-fixed, paraffin-embedded tissues. By using this immunostain, we found marked differences in enzyme content in several human malignancies. PMID- 7838838 TI - Angiomyolipomas: the nature and expression of the HMB45 antigen. AB - Fifteen cases of angiomyolipoma (AML) were studied by the immunoperoxidase method to investigate the nature of the HMB45 antigen and to determine if the antigen that stains with HMB45 in AML is the same HMB45 antigen that stains melanoma cells. Other antibodies utilized to accomplish this study included vimentin, cytokeratin, S-100 protein, and muscle actin (HHF-35). Large interstitial cells of AML regularly react with two different sources of HMB45 and are often positive for vimentin. The HMB45 reactivity of both antibodies is abolished by pretreating the tissue with neuraminidase. The same cells are not immunoreactive with cytokeratin or S-100 protein. A subpopulation of cells in AML demonstrates coexpression of HMB45 and muscle-specific antigen by double-immunolabeling techniques. These results suggest that the AML antigen that reacts with HMB45 is the same antigen present in melanocytic/melanoma cells and that a pluripotent cell, which generates a divergent range of differentiation, may be involved in the genesis of AMLs. PMID- 7838840 TI - Assessment of cell proliferation in paraffin sections of normal bone marrow by the monoclonal antibodies Ki-67 and PCNA. AB - Assessment of the proliferative index of human bone marrow using immunohistology in tissue sections offers practical advantages over other techniques. It is simpler to perform and can be applied to archival material. Progress in this area has been hampered by technical problems. Ki-67 studies, limited to fresh or frozen tissues, have been contradictory, and the labeling indices have been criticized for being unrealistically low. Proliferating cell nuclear antigen (PCNA) studies have also been considered unreliable because labeling indices include nondividing cells. We stained 82 routinely processed nonneoplastic bone marrow biopsies for Ki-67 equivalent MIB 1 antibody and PCNA/PC10 using a microwave oven antigen retrieval technique. 44.7% +/- 12.0 SD of the bone marrow cells stained with Ki-67/MIB 1. PCNA/PC10 staining gave similar results (50.7% +/ 12.3 SD). Pro- and basophilic erythroblasts, myeloblasts, promyelocytes, myelocytes, and megakaryocytes stained with both monoclonal antibodies in a manner consistent with known morphologic and cytokinetic data. Patients in different clinical groups showed similar mean values, the only exception being a group of cytokine-treated patients, which showed higher values than the other cases. Immunoperoxidase staining of bone marrow sections with Ki-67/MIB 1 and PCNA/PC10 monoclonal antibodies is a reliable method for assessing proliferation of hematopoietic cells. PMID- 7838839 TI - Immunocytochemical detection of cyclin A and cyclin D in formalin-fixed, paraffin embedded tissues: novel, pertinent markers of cell proliferation. AB - Cyclin proteins in association with cyclin-dependent protein kinase subunits represent a new class of potentially oncogenic serine/threonine protein kinases that function to execute critical cell cycle transitions in all eukaryotic cells. Characterized by dramatic fluctuations in abundance, which occur in accordance with the periodicity of the cell cycle, the expression patterns of specific cyclins provide a unique and relevant indicator of cellular activation and cell cycle progression. In this study, we introduce a series of monospecific antibodies that are selective for human cyclin A and cyclin D, respectively, and we assess the feasibility of utilizing these reagents for immunocytochemical analyses. Conditions were optimized for detecting cyclin A and cyclin D in formalin-fixed, paraffin-embedded sections of the postnatal human palatine tonsil, in which normal cell proliferation is well characterized. Subsequent studies demonstrated the performance of these antibodies in the examination of pediatric bone tumors, in which decalcification methods are additionally performed. In both cases, the proliferative status of individual cells was monitored with an exceedingly high degree of resolution. Taken together with the available biochemical data, the results of these studies reveal a novel means of characterizing the proliferative status of normal as well as neoplastic tissues. The demonstrated utility of these immunochemical reagents will potentially facilitate retrospective studies aimed at examining cell proliferation in a wide variety of archival histopathologic specimens. PMID- 7838842 TI - IgG heavy-chain deposition disease. AB - A 51-yr-old man presented with renal failure, proteinuria, hematuria, and hypertension. The serum contained two monoclonal protein spikes, an IgG4 lambda and free lambda light chains. Free gamma heavy chains were absent from serum. A bone marrow biopsy did not show evidence of a plasmalymphocytic dyscrasia. Renal biopsy showed a nodular glomerulopathy with linear deposits of gamma 4 heavy chains alone along glomerular, tubular, and vascular basement membranes and in mesangial regions. No light chains were detected in the kidney despite staining with antisera directed against both free and bound light chains and the F(ab')2 fragment of IgG. The term heavy-chain deposition disease is appropriate in view of the above features. PMID- 7838841 TI - DNA ploidy in human esophageal squamous dysplasias and squamous cell carcinomas as determined by image analysis. AB - The DNA content in cells from 98 sites from 14 surgical specimens of human esophageal carcinoma, including nonpathologic epithelium; mild, moderate, and severe squamous dysplasia and squamous cell carcinoma; and in cells from 13 sites from 13 noncancerous biopsy specimens, including nonpathologic epithelium and mild and moderate dysplasia, was determined in Feulgen-stained sections by the cell analysis system (CAS 200). In surgical specimens, diploid DNA histogram patterns were observed in 16 of 17 nonpathologic epithelia, two of seven mild dysplasias, 12 of 21 moderate dysplasias, nine of 18 severe dysplasias, six of 12 intraepithelial carcinomas, and nine of 22 advanced carcinomas. In biopsy specimens, diploid patterns were observed in four of four nonpathologic epithelia, two of seven mild dysplasias, and two of two moderate dysplasias. The remaining displayed nondiploid patterns. There was a statistically significant difference in the frequency of nondiploid histogram between nonpathologic epithelium and pathologic esophageal lesions, including squamous dysplasia and carcinoma in both surgical and biopsy specimens, but not between squamous dysplasia and carcinoma in surgical specimens. We found statistically significant differences in some parameters, including the population of cells in S-phase fraction, diploid fraction, tetraploid or higher chromosome content, and peak cell number, between nonpathologic epithelium and pathologic esophageal lesions demonstrating diploid histograms. In contrast, there were no significant differences between squamous dysplasia and carcinoma demonstrating diploid histogram in those five parameters described above.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7838843 TI - Hepatic fibrosis associated with hereditary cystinosis: a novel form of noncirrhotic portal hypertension. AB - Hepatomegaly is a common feature of hereditary nephropathic cystinosis but is rarely associated with symptoms of liver disease. Aside from cystine crystal deposit within Kupffer cells, the cause of liver enlargement is unknown. We report the case of a patient with nephropathic cystinosis who died at the age of 24 yr after multiple renal transplants. In addition to classical systemic signs of advanced cystinosis, the patient had evidence of portal hypertension. At autopsy, the liver was enlarged for body size (1520 g) and very firm. Massive crystal accumulation within Kuppfer cells was accompanied by intense sinusoidal deposition of collagen types I, III, and IV, with associated hepatocyte atrophy. There was no inflammation or regenerative nodules. Numerous enlarged and fat laden Ito cells were present in association with the collagen. This case illustrates a novel form of noncirrhotic portal hypertension associated with cystinosis. Analysis of future cases may serve to highlight the role of Kupffer and Ito cells in the pathogenesis of hepatic fibrosis. PMID- 7838844 TI - Correspondence Re: R.F. Dorfman. Maude Abbott Lecture. Hematopathology: a crescendo of scholarly activity. Mod Pathol 7:226, 1994. PMID- 7838845 TI - Correspondence Re: D.F. Hardwick. George Orwell's '1984' revisited; in public bureaucracy, failure is success. Mod Pathol 6:397, 1993. PMID- 7838846 TI - Correspondence Re: T.J. Flotte. Research by pathologists in the United States: analysis of publications. Mod Pathol 6:484, 1993. PMID- 7838847 TI - Correspondence Re: P.T. Cagle, R. Wessels, and S.D. Greenberg. Concurrent mesothelioma and adenocarcinoma of the lung in a patient with asbestosis. Mod Pathol 6:438, 1993. PMID- 7838848 TI - Correspondence Re: WM Hanna, Kahn HJ, and J-AW Chapman. The correlation of Ki-67 growth factor and ERICA in breast cancer. Mod Pathol 5:220, 1992. PMID- 7838849 TI - Similarities of intraglomerular collagen synthesis in IgA nephropathy and diabetic glomerulosclerosis. PMID- 7838850 TI - The evolution of lethals in the t-haplotype system of the mouse. AB - The evolution of lethal haplotypes in the t-haplotype segregation distortion system of Mus is examined by mathematical and computer models. The models assume that there is reproductive compensation for the loss of lethal embryos, such that the net reproductive success of a females is not reduced in proportion to the frequency of lethal offspring which she produces. The initial population consists of a mixture of wild-type and homozygous male-sterile t-haplotypes. The failure of sterile males to reproduce may cause a higher fitness cost to mothers heterozygous for t-haplotypes than does elimination of a recessive lethal. Under certain conditions, a recessive lethal will spread and come to a polymorphic equilibrium. Wild-type, lethal and non-lethal haplotypes are all present at this equilibrium. If a second lethal mutation arises on a non-lethal t-haplotype in such an equilibrium population, it will increase in frequency and eventually displace the non-lethal t-haplotypes. A third lethal t-haplotype introduced at a low frequency into an equilibrium with two lethals can sometimes be selected for, although this is less likely if compensation is strong. The theoretical predictions are compared with data on natural populations. PMID- 7838851 TI - Optical imaging reveals the functional architecture of neurons processing shape and motion in owl monkey area MT. AB - We have used optical imaging based on intrinsic signals to explore the functional architecture of owl monkey area MT, a cortical region thought to be involved primarily in visual motion processing. As predicted by previous single-unit reports, we found cortical maps specific for the direction of moving visual stimuli. However, these direction maps were not distributed uniformly across all of area MT. Within the direction-specific regions, the activation produced by stimuli moving in opposite directions overlapped significantly. We also found that stimuli of differing shapes, moving in the same direction, activated different cortical regions within area MT, indicating that direction of motion is not the only parameter according to which area MT of owl monkey is organized. Indeed, we found clear evidence for a robust organization for orientation in area MT. Across all of MT, orientation preference changes smoothly, except at isolated line- or point-shaped discontinuities. Generally, paired regions of opposing direction preference were encompassed within a single orientation domain. The degree of segregation in the orientation maps was 3-5 times that found in direction maps. These results suggest that area MT, like V1 and V2, has a rich and multidimensional functional organization, and that orientation, a shape variable, is one of these dimensions. PMID- 7838852 TI - Unpredictable food and sexual size dimorphism in insects. AB - The evolution of sexual size dimorphism is likely to be affected by the amount of resources each sex invests in offspring. Male nuptial gifts, occurring in many insect species, might reduce the value of large size in females and increase the value for males. For large nuptial gifts and an accompanying shift in dimorphism to evolve, males with larger gifts should be rewarded, in effect trading the larger gift for more offspring. We suggest that food variability, causing some males to have much to provide and some females to be in great need, would be conducive to the evolution of such a mating system, and we present comparative data on butterflies supporting the suggestion. In a gift-giving mating system, growing male and female juveniles should react differently to food shortage. A female maturing at small size can to some extent buffer her disadvantage through nuptial gifts, whereas a male maturing at small size will suffer from his inability to provide substantial gifts. Thus, males benefit more than females from continued growth in the face of food shortage, leading to a shift in size dimorphism. Here we confirm this prediction in a butterfly, Pieris napi, with large nuptial gifts. PMID- 7838853 TI - Kin selection and virulence in the evolution of protocells and parasites. AB - The evolution of parasite virulence and the origin of cooperative genomes in primitive cells are both problems that balance cooperative and competitive interactions among symbionts. I analyse the trade-off among three correlated traits: competitiveness against other genotypes for resources within hosts (protocells), damage to the host (virulence), and rate of horizontal transmission from one host to another. All three life-history components are strongly influenced by kin selection. For example, when genetic relatedness within hosts is high, each genotype is competing for resources with closely related genotypes. This competition among relatives favours increased horizontal transmission to colonize new hosts and compete against non-relatives. My analysis shows that many aspects of parasite and protocell evolution must be studied with the theoretical tools of social evolution. I discuss extensions that are required for a general theory of symbiosis. PMID- 7838854 TI - Life expectancy and egg load affect oviposition decisions of a solitary parasitoid. AB - Life-history theory predicts that animals should be sensitive to both the amount of resources available and life expectancy in making reproductive decisions. Because it is easier to control the mortality of insect parasitoids (insects whose larva develop in or on another insect) than many other groups of animals, the best tests of these predictions have used them. However, because of the inter correlation of several of the variables of interest, much of this evidence is equivocal, and experimental manipulations have failed to isolate the most important factors. Here we report an experiment which circumvents such problems by comparing the superparasitism rates of fed and starved parasitoids. By using the asexual solitary hymenopteran parasitoid Venturia canescens, we demonstrate that starved wasps with a reduced life expectancy lay eggs in low-quality hosts more frequently than those with a greater expected lifespan, as do parasitoids with higher egg loads and hence more resources available for reproduction. PMID- 7838855 TI - Binocular attributes of length summation and end stopping in cat striate cortex. AB - Length selectivity for each eye was compared as response increment-decrement to optimal sine-wave grating patches, in strongly binocular, striate cortical neurons in adult cats. Neurons were characterized as simple, or as standard, intermediate or special complex, on criteria that included length summation. Length summation was characterized for stimulus length, incremented symmetrically about the receptive field, up to optimal response levels. Many neurons additionally showed end stopping: response decrement to supra-optimal lengths. Optimal length and/or end stopping for each eye differed in most neurons, although the distributions of optimal length or percentage end stopping for each eye were comparable for the overall sample and for each neuronal subclass. However, paired comparisons of length and end-stopping data for each neuron revealed a marked tendency for receptive fields to be relatively smaller on average, but more strongly end stopped, for contralateral input. On the Wilcoxon signed rank test, these differences were statistically significant for standard complex neurons. There was also a tendency for differences in end stopping to be greater and more widely scattered for neurons with near-horizontal than near vertical orientation preferences. Although the functional value of skew in the distributions of interocular differences in optimal length and end stopping remains conjectural, the scatter and balanced distribution of these differences in length specificity across the neuronal population may provide a basis for encoding visual perspective cues. PMID- 7838856 TI - Fibre reinforcing by collagen in cartilage and soft connective tissues. AB - Mechanical support in animals is performed by connective tissues. The soft tissues consist of collagen fibres embedded in a highly hydrated proteoglycan gel. By considering them as fibrous composite materials, a unifying theme can be found to explain their mechanical behaviour in terms of their structure and composition. Interactions between fibres and matrix are essential to their functioning in this way. Calculations are made of the maximum stress transfer per D-period required to enable collagen fibres of a given axial ratio to provide effective reinforcing. Weak non-specific interactions are shown to be sufficient. A mechanical function is proposed for type X collagen in the epiphyseal growth plate on the basis that it modifies and supplements the properties of the type II fibrils. This provides extra reinforcing and, hence, a greater stiffness to the cartilage to compensate for the reduced amount of extracellular matrix. PMID- 7838857 TI - Illumination partly reverses the postsynaptic blockade of the frog neuromuscular junction by the styryl pyridinium dye RH414. AB - The styryl pyridinium dye RH414, which we have used recently for optical monitoring of synaptic vesicle membrane trafficking in frog motor nerve terminals, reversibly inhibited contractions in the frog nerve-muscle preparations used for those studies. We report here the results of experiments into the basis of this inhibition and how the blocking effects can be modulated by incident light, by using conventional intracellular recording and iontophoretic techniques. Bath application of 5-42.5 microM RH414 blocked nerve evoked twitches in frog cutaneus pectoris muscles, although subthreshold endplate potentials and miniature endplate potentials could still be recorded. In the presence of the dye, illumination of the recording area with light from a mercury arc lamp over a wide range of wavelengths (340-560 nm) potentiated the amplitude of endplate potentials, miniature endplate potentials, and depolarizations resulting from iontophoretic application of acetylcholine. The magnitude of both the light-induced disinhibition of endplate and iontophoretic potentials increased with the intensity of the illumination and developed exponentially with a time constant of several hundred milliseconds. Both the dye-induced inhibition and the light-induced disinhibition disappeared after washing in dye-free physiological saline. Muscle fibre resting membrane potential, input conductance and miniature endplate potential frequency, however, were not affected by these manipulations. These data are consistent with a specific, curare-like interaction of the dye with acetylcholine receptors which can be modulated by light. PMID- 7838858 TI - Sex differences, sex ratios and sex roles. AB - Sexual selection theory predicts that sex roles will be determined by the operational sex ratio (OSR), the sex ratio among individuals searching for mates at any given time. There are two predictions: (i) the sex which is in 'excess' will be the more competitive sex with respect to access to mates; and (ii) the sex of which there is a 'shortage' will be the more choosy with respect to potential partners. We examine the second prediction and find that current OSR theory does not consider an important factor which affects mate choice. This factor is sex differences in variation in mate quality. Hence, we develop a new model of mate choice which shows that the parameter which should be optimized during mate choice is the trade-off between reproductive rate and mate quality. If mate choice is too lax, reproductive rate may be high but partners will be of low quality. If mate choice is too stringent, partners will be of high quality but reproductive rate will be low because such partners will be rare. Stringency of mate choice is, therefore, a facet of OSR theory. Indeed, our model shows that OSR theory can be used to integrate the effect of sex differences in both mating rate and variation in mate quality to predict the direction of mate choice. Our model suggests that: (i) mate choice is only selected when individuals of the opposite sex vary in their quality as mates; (ii) if the extent of variation in mate quality is equal within each sex, the sex with the lower potential mating rate will be the more choosy sex; but (iii) if there is sufficiently greater variation in mate quality among the sex with the lower potential reproductive rate, the sex with the higher potential mating rate will be the more choosy sex.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7838859 TI - [The onion--an unjustly ignored medicinal plant]. PMID- 7838860 TI - [Pharmacoepidemiology. I. A system for detection of adverse drug effects]. PMID- 7838861 TI - [International workshop on pharmacoepidemiology in Berlin]. PMID- 7838862 TI - [Methadone substitution--a crutch, or a way to learn?]. PMID- 7838863 TI - [Signal transduction by heterotrimeric G-proteins]. PMID- 7838864 TI - Structure-activity relationship studies of CNS agents. Part 14: Structural requirements for the 5-HT1A and 5-HT2A receptor selectivity of simple 1-(2 pyrimidinyl)piperazine derivatives. AB - The 5-HT1A and 5-HT2A receptor affinity of model 1-(2-pyrimidinyl)-piperazine derivatives 15-21 and 23-32 has been determined. 2-(N-Methylpiperazino)-4,6-di(2 thienyl)pyrimidine 26 is a new, highly active and selective 5-HT2A receptor ligand. The topography of a molecule and the stereoelectronic effects of the thiophene rings are the major factors responsible for the high affinity and selectivity of 26 towards 5-HT2A sites. PMID- 7838865 TI - Inhibitors of lipid peroxidation among new pyrimido[1',6':1,2]pyrido[3,4 b]indoles. AB - A series of potent inhibitors of NADPH- and Fe(2+)-dependent lipid peroxidation has been found among new pyrimido[1'6':1,2]pyrido[3,4-b]indole derivatives. According to preliminary structure-activity relationship analysis the saturated pyrimidine moiety was responsible for this effect. Some members of this family were effective in a bilateral carotid occlusion model in mice, and some derivatives showed protective effect in a mouse head injury model. PMID- 7838866 TI - Synthesis of some new heterobicyclic compounds containing spiro-1,2,4-triazine moiety as potential anti-HIV and anticancer agents. AB - A number of heterobicyclic compounds such as 1,3,5-thiazine, thiazolidinone, pyrimidine, pyrimidinedione, imidazole, quinazolinone and 1,2,4-triazinone derivatives have been sythesized by reaction of 1,6-dihydro-3(2H)-thioxo-6-spiro (9'- fluorene)-1,2,4-triazin-5(4H)-one (1) with sulphur/nitrogen compounds in neutral or alkaline media. Structure elucidation of the new compounds have been carried out with the help of elemental analysis and spectral data. Some of these compounds were tested for in vitro anti HIV and anticancer activities. PMID- 7838867 TI - Synthesis and pharmacological investigations of new 6-oxo-1,2,3,4-tetrahydro-6H pyrimido[2,1-b]quinazoline derivatives. AB - The synthesis and biological activity of a series of 6-oxo-1,2,3,4-tetrahydro-6H pyrimido[2,1-b]quinazoline is reported. Pharmacological investigations have shown that the compounds exert depressive action on the central nervous system and exhibit neuroleptic activity. PMID- 7838868 TI - Synthesis and in vitro cytotoxic activity of aza- and diazaanthraquinone derivatives. AB - Some 1,4-dihydro aza- and 1,4-dihydro diazaanthraquinone derivatives have been synthesized and submitted to in vitro cytotoxicity tests towards L 1210, MDA-MB 231 and PC3 cell lines. Some of the new substances showed significant activity. PMID- 7838869 TI - Oxygen radicals attenuate the contractility of skinned muscle fibres from the pig myocardium. AB - This study deals with the influence of oxygen radicals on the contraction of skinned muscle fibres from pig myocardium. The radicals were generated by xanthine-xanthine oxidase (X/XO) or by Fe2+/H2O2 (Fenton system). Addition of the X/XO to the incubation medium (KCl/imidazole) induced a depression of the contractility which was dependent from the incubation time and the X/XO concentration. The maximum contraction in the presence of high concentrations of free calcium ions (pCa 4.32) decreased to 52.0 +/- 15.5% (p < 0.01). The EC50 of calcium ions inducing fibre contraction increased from 2.82 +/- 0.66 mumol/l to 5.47 +/- 2.06 mumol/l (p < 0.05). The Hill plot of contraction versus concentration of calcium ions was shifted to the right and the maximum of contractility was attenuated. Replacement of X/XO by the Fenton system was without significant effects on the fibre contractility. Addition of 5.10(-4) mol/l APP 210-533 (3-amino-6-methyl-5-phenyl-1,2- dihydropyrid-2-on), a known "calcium sensitizer", increased the fibre contractility in radical impaired fibres, too. This may indicate that the radicals did not impair the troponine complex. Oxygen radicals were detected by electron spin resonance spectroscopy spin trapping using 5,5-dimethylpyrroline-1-oxide. Superoxide radicals were found in the presence of X/XO whereas addition of Fe2/H2O2 to the incubation medium resulted in the formation of hydroxyl radical adducts. The appearance of additional adducts observed in both system is discussed. The experiments indicate that free radicals can interact with components of the skinned fibre (probably with contractile proteins of the myocardial muscle cells) resulting in an impairment of the contractility.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7838870 TI - Pharmacological studies on new potential local anesthetics. AB - The results of the pharmacological screening of a series of new basic aminoalkyl aryl ethers are reported. The anesthetic effects of these compounds were evaluated by the guinea pig intradermal wheal test. Lidocaine was used as the standard and normal saline as the control. These were, generally, better than or as good as the standard, in terms of potency, onset of action, duration of effect, time of full recovery from complete anesthesia and lack of both apparent local and systemic side effects. The duration of action of their local anesthesia has shown a strong dependence on the substitution pattern of the compounds. Moreover, it seems that these compounds act selectively and reversibly by blocking nervous conduction at a localized area, as small as a skin wheal, without any obvious deleterious untoward reactions, i.e. they are structurally specific and act at the neuronal channels (receptor sites). Thus, due to their outstanding local anesthetic profiles, it is worthy to conduct additional studies on these agents, as potential candidates for the treatment of intolerable chronic pain, which does not respond to mild analgesic drugs, and other available medicines. PMID- 7838871 TI - Metal complexes of warfarin sodium. PMID- 7838872 TI - Correlation between biological activity and the structure of N,N' bis(alkyldimethyl)-1,6-hexanediammonium dibromides. Antibacterial activity and inhibition of photochemical activity of chloroplasts. PMID- 7838873 TI - In vitro antiviral effect of extracts of Kuehneromyces mutabilis on influenza virus. PMID- 7838875 TI - [The salary of a German pharmacist around 1900]. PMID- 7838874 TI - 2,5-Dihydroxy-7-methoxy-6,8-dimethylflavan-3-one a novel flavonoid from Leptospermum scoparium: in vitro affinity to the benzodiazepine binding site of the GABAA receptor-chloride channel complex. PMID- 7838876 TI - Ergot alkaloids as lead structures for differential receptor systems. PMID- 7838877 TI - Amino-substituted 1,8-naphthyridines and pyrido[2,3-d]pyrimidines: new compounds with affinity for A1- and A2-adenosine receptors. AB - Two novel classes of adenosine receptor (AR) antagonists, 4-amino-1,8 naphthyridines and 5-aminopyrido[2,3-d]pyrimidines, have been identified and investigated in radioligand binding assays. The compounds exhibit affinities for A1 and A2a AR of rat brain in the micromolar range. 1,8-Naphthyridines are non selective, or somewhat selective for either A1- or A2 AR. Pyrido[2,3 d]pyrimidines are several-fold selective for A1 AR, the most potent and selective compound being 5-n-butylamino-1,3-dimethyl-1,2,3,4-tetrahydropyrido-[2,3-d]pyr imi dine-2,4-dione (12) with a Ki value of 1.8 microM at A1 AR and greater than 10-fold A1-selectivity. PMID- 7838878 TI - Synthesis and pharmacological properties of benzothiazole, 1,3-4-oxadiazole and 1,3,4-thiadiazole derivatives. AB - The reaction of the 2-amino-substituted 1,3,4-oxadiazoles 9, 10 and the benzothiazoles 11, 12 with ethyl cyanoacetate is described. The obtained cyanoacetamide derivatives 13-16 gave the benzylidene derivatives 18-21 by condensation with benzaldehyde. 2-Phenyl-5-amino-1,3,4-oxadiazolo[3,2-a]pyrimidin 7-one (17) was also obtained. Moreover, the preparation of 6,7,8,9-tetraydro-5H 1,3,4-thiadiazolo[2,3-b]quinazolin++ +-5-thio-derivatives 22-25 and N-(1,3,4 thiadiazol-2-yl-5-substituted)-3,4-5,6-tetrahydro-anthran ilic acids 26-29 is also described. All above compounds and compounds, related to them, 1-8 were tested for their analgesic and antiinflammatory activities and the pharmacological screening results are reported and discussed. PMID- 7838879 TI - Synthesis, structures and biological activity of some 4-amino-3 cinnolinecarboxylic acid derivatives, Part 1. AB - This work describes the synthesis of 4-amino-3-cinnolinecarboxamides, which were then hydrolyzed to corresponding 4-amino-3-cinnolinecarboxylic acids. Several compounds were tested for their antibacterial and antifungal activity, and for the central nervous system effect. PMID- 7838880 TI - Activity of some Mannich bases of conjugated styryl ketones against Candida albicans. AB - A number of Mannich bases of conjugated styryl ketones displayed activity against Candida albicans strains 3153A and B311. Antifungal potency was influenced by the relative hydrophobicities of the molecules and on occasions by the electronic nature of the aryl substituents. The compounds inhibited one or more of the following enzymes in the glutathione metabolic pathway namely glutathione S transferases, glutathione reductase, gamma-glutamyl transpeptidase and glutathione peroxidase. Nearly half of the compounds examined on the yeast-to mycelium transition in C. albicans 3153A prevented this conversion from occurring. PMID- 7838881 TI - Flavonoids from Leptospermum scoparium with affinity to the benzodiazepine receptor characterized by structure activity relationships and in vivo studies of a plant extract. AB - The New Zealand Myrtacea Leptospermum scoparium Forst. contains lipophilic flavonoids which interact specifically with benzodiazepine receptors. For an indepth characterization of their binding behavior, structure activity relationships were delineated which are in accord with results obtained by quantum-chemical and spectroscopic methods. Inhibition experiments have been performed by a radio receptor assay with [3H]flunitrazepam and IC50-values of 2.1 microM for 5,7-dimethoxyflavone (1), 45 microM for 5,7-dimethoxy-6-methylflavone (2), 3.3 microM for 5-hydroxy-7-methoxy-6-methylflavone (3) and 40 microM for 5 hydroxy-7-methoxy-6,8-dimethylflavone (4) have been measured. Flavanones 5 to 8, however, at concentrations < or = 0.1 mM, did not show a 50% inhibition of the binding radiolignand. The agonistic profile of the flavones was determined indirectly by TBPS-shift experiments which revealed a negative cooperation with the TBPS/picrotoxinin-binding site. To characterize the biologically active conformations, energy minima were calculated using the semiempirical method AM1. The steric arrangement of the substituents for all global minima calculated were in accord with homonuclear NOE-experiments. A correlation of the geometry of the lowest energy conformers with corresponding IC50-values reveals an increase of the affinity towards the benzodiazepine receptor, when the substituents at the flavones are coplanar to the aromatic system and R3 represents a sterically demanding methylgroup. Analyses of the global minima of 5,7-Dimethoxyflavone and diazepam showed one conformer each, in which the methoxy substituent in R3 and the N-methyl on the one hand and the corresponding carbonyl oxygens as well as the unsubstituted phenyl rings on the other were nearly superimposable. The flavanones lacking the double bond between C-2 and C-3 have angular structures, whereby the loss of affinity to the receptor can be explained. From the locomotion study with rats, an in vivo sedating, possibly even anxiolytic effect of the dry extract of the tincture prepared from Leptospermum scoparium by use of 70% ethanol, could be concluded. At doses of 50 mg and 250 mg of the dry extract per kg of body weight, an unequivocal but not linear dose-activity relationship in respect to the moving activities of the animals was determined. Upon an application of 500 mg of this extract per kg body weight, by contrast, only a negligible reduction of the moving activity was found in relation to a control group. We suppose that at higher doses, activating compounds of the extract come to the fore pharmacologically neutralizing the primarily sedating effect. PMID- 7838882 TI - Characterization of transcripts from the Dictyostelium discoideum retrotransposable genetic element DRE. AB - All of the approximately 150 copies of the Dictyostelium discoideum retrotransposable element DRE are integrated 50 +/- 4 nucleotides upstream from different transfer RNA genes. These genomic regions are generally devoid of informative DNA why integration of the retrotransposon at these position never causes phenotypic mutations. This property makes DRE attractive as a tool in gene therapy where vectors with predictable integration specificities are still not available. Due to the nature as retrotransposon transcription is a prerequisite for the element to integrate at a new genomic position. Here we describe some transcription properties of DRE based on Northern blot analyses and on the characterization of in vitro synthesized cDNAs. PMID- 7838883 TI - Biological active acridine derivatives, 2. Chiral 9-aminoacridines. PMID- 7838884 TI - [Enzyme immunoassay for quantitative determination of beta-aescin in human serum]. PMID- 7838885 TI - [Acute toxicity of pyrrolizidine alkaloids in the "yeast test"]. PMID- 7838886 TI - Progress in pharmacology of cerebral ischemia. PMID- 7838887 TI - Carbamazepine as adjunct or alternative to lithium in the prophylaxis of recurrent affective disorders. AB - Patients with affective disorder insufficiently responding to prophylactic lithium present a major problem to maintenance pharmacotherapy. The present retrospective study tested the efficacy of carbamazepine in 73 such patients. The patients who were switched from lithium to carbamazepine monotherapy had additional benefit, but not those switched to combined lithium plus carbamazepine. This failure to replicate a number of recent pilot studies showing synergistic effects of lithium and carbamazepine may however have been due to a heterogeneity concerning the combined effects of some negative response predictors, although none of these was significant in itself. Nevertheless, synergism cannot be taken as guaranteed. Prospective controlled trials are needed. PMID- 7838888 TI - Citalopram in the treatment of social phobia: a report of three cases. AB - Social phobia is a chronic and disabling anxiety disorder. Although its pharmacological treatment has not been extensively studied, recent reports suggest that social phobia may be treated with monoamine oxidase inhibitors, beta blockers, tricyclic antidepressants, and alprazolam. A recent study has shown that fluoxetine is also effective in social phobia, and preliminary results suggest that the same may apply to other serotonin reuptake inhibitors, too. In this paper we describe the results of citalopram treatment in three patients with social phobia. PMID- 7838889 TI - BMS-181168 for protection of the human brain against hypoxia: double-blind, placebo-controlled EEG mapping studies. AB - In a double-blind, placebo-controlled, cross-over trial, the antihypoxidotic properties of BMS-181168 (previously BMY 21502)--a 1-[[1-[2-(trifluoromethyl)-4 pyrimidinyl]-4-piperidinyl]methyl]-2- pyrrolidinone alleviating impairment of learning and memory in the animal--were studied utilizing EEG mapping under an experimental hypoxic hypoxidosis. The latter was induced by a fixed gas combination of 9.8% oxygen (O2) and 90.2% nitrogen (N2) (found at 6000 m altitude), which was inhaled for 23 minutes under normobaric conditions by 16 healthy male volunteers (aged 23-35 years, mean 27.2 years). After an adaptation session, they received in randomized order at weekly intervals oral single doses of placebo, or of 100 mg, 200 mg, and 400 mg BMS-181168. Evaluation of blood gases (PO2, PCO2, SO2), adverse events, and EEG mapping was carried out prior to drug administration and 2, 4, 6 and 8 hours post-drug, on each occasion under normoxic and transient hypoxic conditions. Hypoxemia was controlled by drawing arterialized capillary blood samples from the earlobes after hyperemization of the latter (after 0, 14, and 23 minutes of hypoxic gas inhalation) and by oximetry. After 23 minutes of inhalation, analysis showed a drop in PO2 from 98 to 48 mm Hg, in PCO2 from 41 to 31 mm Hg, and in SO2 from 97 to 80%. Descriptive statistical analyses of EEG mapping data demonstrated under hypoxia/placebo conditions an increase in delta/theta activity and a decrease in alpha activity as well as a slowing of the delta/theta centroid and an increase in the alpha and beta centroid, which suggests a marked deterioration in physiological vigilance.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7838890 TI - Lithium addition in endogenous depressions resistant to tricyclic antidepressants or related drugs: relation to the status of the pituitary-thyroid axis. AB - Concentrations of TSH, TRH-induced TSH (delta-TSH), T4, FT4, T3, and FT3 were investigated in 20 patients resistant to antidepressants before and after one week of lithium addition. TSH and delta-TSH increased, whereas FT4 and FT3 decreased statistically significantly during this treatment, indicating a slight lithium-induced hypothyroid function. A statistically significant correlation between improvement and the FT3/FT4 ratio after seven days of lithium addition was found. Also, an increase or only a small decrease in FT3 and an augmenting FT3/FT4 ratio during lithium addition were correlated with a favorable outcome. Besides the possibility that a high relative FT3 concentration is an indicator of an unknown somatic condition favorable for improvement, this finding might be directly related to treatment response. It appears conceivable that even within the normal range a sufficient T3 concentration is necessary for an optimal response to lithium addition. PMID- 7838891 TI - Autoaggressive behavior is closely related to serotonin availability in schizoaffective disorder. AB - Lowered serotonin turnover has been observed in impulsive hetero- and auto aggressive behavior. Most notably the CSF 5-hydroxyindole acetic acid concentrations were decreased. However, data on CSF or blood serotonin are far from clear-cut, since similar levels in suicidal and non-suicidal patients have also been noted. Longitudinal studies of suicidal patients have revealed pronounced shifts in blood serotonin levels, whereas healthy subjects' blood serotonin levels remained stable. We investigated blood serotonin levels of female schizoaffective patients and healthy women to test whether the fluctuations correlated with changes in autoaggressive behavior. The patients were divided into three groups: nonsuicidal, acutely suicidal, and postsuicidal. Nonsuicidal and postsuicidal schizoaffective patients' and healthy women's blood serotonin levels were similar. Suicidal patients' blood serotonin levels were significantly lower than those of healthy subjects and postsuicidal patients. We interpret the serotonin augmentation after a suicide attempt as a psychobiological correlate of increased neurotransmitter function. PMID- 7838892 TI - Buspirone in obsessional compulsive disorder. A prospective case study. AB - A longitudinal case study of a man who is suffering from obsessional compulsive disorder, who failed to respond to all possible treatments, including psychosurgery. We present his good response to the recommended dose of the anxiolytic Buspirone and its effect on the severity of his obsessive compulsive symptoms. PMID- 7838893 TI - Seizures following smoking cessation in a clozapine responder. PMID- 7838894 TI - Induction of two species of superoxide dismutase in some organs of rats by low dose X-irradiation. AB - Four hours after 0.25 Gy X-irradiation, the enzymatic activity of copper and zinc activated superoxide dismutase (Cu/Zn-SOD) in the spleen of mature rats showed a significant quantitative increase (by 25%); this was accompanied by a marked increase (by 70%) in the mRNA for this enzyme as compared to the control (sham irradiation) group. Irradiation had no effect on the enzymatic activity of manganese activated superoxide dismutase (Mn-SOD). Moreover, the expression of the mRNA for Mn-SOD was similar to that of the unirradiated control group. On the other hand, the enzymatic activity of both Cu/Zn-SOD and Mn-SOD in the liver of fetal rats showed a significant quantitative increase (by 15-35%); the expression of the mRNA for the two species of SOD increased (by 20-30%) at 4 hours after 1 Gy X-irradiation as compared to the control group. These findings suggest that the increase in SODmRNA level is due to novel transcription of SODmRNA by low dose irradiation. PMID- 7838895 TI - DNA damage by various forms of active oxygens and its inhibition by different scavengers using plasmid DNA. AB - The degree of DNA damage by the treatment with various molecular species of active oxygen and its inhibition by pretreatment with different scavengers were evaluated using pUC19 plasmid DNA. DNA damage caused by O2-. generated by xanthine-xanthine oxidase system (X-XOD), .OH by Fenton reactions, and OCl- by NaOCl involved the generation of open circle DNA demonstrating single strand breaks. Catalase (Cat), diethylenetriaminepentaacetic acid (DETAPAC), desferroxiamine (Desferal), dimethyl sulfoxide (DMSO) and ethanol (EtOH) all inhibited 60-80% of DNA damage by the generated O2-.. Superoxide dismutase (SOD) inhibited all DNA damages by O2-.. Cat, DETAPAC and Desferal effectively inhibited DNA break by .OH; complete inhibition of .OH-induced DNA break was achieved by addition of DMSO and EtOH. Desferal and EtOH completely inhibited DNA damage by OCl-. These findings suggested that metal ions are associated with the mechanism of DNA damage by all forms of active oxygen species. PMID- 7838896 TI - Cellular environment in the liver of tumor-bearing rats: a 13C NMR study. AB - Although hepatic metabolism is known to be altered in the presence of a remote tumor, it is unclear whether the alterations are brought on by changes in cellular conditions or dysfunction of enzymes. Chemical shifts of 13C NMR spectral peaks are known to vary depending on the physical conditions within the molecular environment, such as pH, electrolyte concentrations and temperature. In the present study, we examined the responsiveness of 13C NMR peak positions to different experimental conditions by comparing chemical shifts of metabolite peaks in perfused and extracted livers. The sensitivity of the technique was confirmed by observing chemical shift differences between these two experimental conditions of the amino carbons (C-2's) of glutamate, glutamine, N carbamoylaspartate and aspartate. Subsequently, 13C NMR spectroscopy was employed to detect changes in the cellular environment in the livers of tumor-bearing rats. Minimal alterations in peak locations for intracellular metabolites were found in the presence of a distant tumor. This indicates that the overall cellular environment is not significantly altered by the presence of a distant tumor. Therefore, the known alterations in hepatic metabolism of tumor hosts are probably brought on by enzymatic abnormalities rather than changes in the cellular milieu. In addition, comparison of peak positions with other published reports were made, and the extent of unexplained chemical shift variations between biological studies is discussed. PMID- 7838897 TI - Preparation and characterization of two phosphopeptide fractions from calf thymus nuclei; similarity to corresponding fractions in the DNA prepared from the nuclei. AB - In this study two phosphopeptide (PP) fractions from purified, calf thymus nuclei, prepared under protective conditions were characterized. The nuclei were lysed and dialyzed, and the material in the dialysates was fractionated by anion exchange column chromatography. This revealed the presence of two main phosphopeptide (PP) fractions, numbers 1 and 5. Amino acid analysis of the fraction 1, occurring in the greatest amount, showed that, after deionization, it contained the metal ion complexes of phosphoserine, aspartic and glutamic acids in large amounts, and nine other amino acids. In the same way the two main PP fractions, P1 and P5, were obtained during the dialysis of the EDTA-reacted, highly purified DNA (N-DNA) prepared from calf thymus nuclei. Fraction 1 from nuclei had practically the same amino acid composition as fraction P1 from EDTA reacted N-DNA. In both cases, the second main fraction obtained (fraction 5) had nearly the same amino acid composition as fraction 1, but the total Pser molar ratio, was about twice as high as for fraction 1. In contrast to the low molecular weights of 900-1400 daltons observed for PPs isolated directly from the dialysates in water without exposure to HCOOH, the high molecular weight of 10,260 daltons was obtained for the PP fraction 1, after exposure to HCOOH used in the gradient for the column chromatography. PMID- 7838898 TI - Alpha 2-adrenergic receptor sensitivity in panic disorder: I. GH response to GHRH and clonidine stimulation in panic disorder. AB - Baseline levels of GH and somatomedin C (SmC) and GH responses to GHRH (1 microgram/kg b.w.) and to clonidine (150 micrograms) were measured in 10 outpatients with panic disorder before and after 30 days of 2-2.5 mg of alprazolam therapy, and in 10 psychophysically healthy controls. Basal levels of GH were normal in the patients and those of SmC significantly elevated, both before and after therapy. Basal GH responses to GHRH stimulation were normal and did not change change after alprazolam treatment. Basal GH responses to clonidine stimulation were blunted in the patients and improved after therapy, in parallel with an amelioration of the psychopathology. Our data suggest that adrenoceptor sensitivity, investigated by the clonidine test, is reduced in panic disorder. PMID- 7838899 TI - Alpha 2-adrenergic receptor sensitivity in panic disorder: II. Cortisol response to clonidine stimulation in panic disorder. AB - The cortisol responses to acute administration of saline and of clonidine (Clon), 150 micrograms IV, were examined in 12 patients with panic disorder and agoraphobia, before and after 32 days of alprazolam therapy (2.5 mg/day), and in 12 normal controls. The responses in the Clon test corrected for the responses to saline differed in the two groups, and in patients were not changed by the therapy even though significant symptomatological improvement was achieved. The results suggest that presynaptic alpha 2- or postsynaptic alpha 1-beta adrenoceptor sensitivity is impaired in panic disorder. PMID- 7838900 TI - The impact of social interaction factors on menstrual synchrony in the workplace. AB - The two objectives of this study were: (1) to examine the impact of social interaction variables (e.g., friendship, time working together, and activity) on the occurrence of menstrual synchrony; (2) to examine the menstrual synchrony of women who work together in an office. The sample consisted of 72 women soldiers in two army bases, and a civilian sample of 36 office workers. None of the samples showed significant synchrony. However, social interaction variables were found to be important factors contributing to the relative degree of synchrony. Friendship, mutual activity, and length of time working together were significantly related to the degree of synchrony. PMID- 7838901 TI - Modulation of binding sites for corticotropin-releasing hormone by chronic psychosocial stress. AB - This study was conducted to determine whether long lasting psychosocial stress would affect corticotropin-releasing hormone (CRH) binding sites in the brain, the pituitary, and the adrenal gland. As a model for sustained emotional stress we used chronic psychosocial conflict in male tree shrews. In subordinate tree shrews, repeated confrontation with a dominant conspecific results in constant hyperactivity of the HPA-axis and an elevated neurosympathetic tone. After 24 days of psychosocial conflict, CRH binding sites were quantified by in vitro autoradiography with 125I-ovine CRH in 23 discrete brain regions, the pituitaries, and the adrenal glands of subordinate and control animals. Chronic stress significantly reduced the number of binding sites (Bmax) in the anterior lobe of the pituitary, the dentate gyrus, the CA1-CA3 areas of the hippocampus, and in both the stratum griseum superficiale and the stratum opticum of the superior colliculus. In cortical area 17, the reduction of Bmax was counterbalanced by an increase in the affinity (Kd) of the radioligand for the binding sites. A significant stress-induced enhancement of Bmax was observed in the frontal cortex, cingulate cortex, claustrocortex, the central and lateral nucleus of the amygdala, and in the choroid plexus. This increase was accompanied by a significant decrease of Kd-values in the frontal and cingulate cortex, the lateral nucleus of the amygdala, and the choroid plexus. These findings represent the first in vivo demonstration of a modulation of extrahypothalamic CRH receptors by a naturally occurring form of stress. The different response patterns of the central CRH binding sites reflect distinct neuroendocrine processes which are presumed to coordinate behavioral, autonomic, endocrine, and immune responses to long-lasting psychosocial conflict. PMID- 7838903 TI - Hormonal and metabolic responses during psychosocial stimulation in aggressive and nonaggressive rats. AB - The physiological effects of a psychosocial threat (the mere presence of a potentially antagonist individual in the home cage) were studied in aggressive and nonaggressive rats. Aggressive animals spent a significantly longer time with the investigation of the opponent compared with the nonaggressive group. An increase in plasma epinephrine and corticosterone was noticed both in aggressive and nonaggressive animals. Ir beta-endorphin increased significantly only in nonfighters. Glycemia was slightly larger in nonaggressives, while lactaemia increased in both groups. The possibility is discussed that differences in psychosocial stress response may be involved in the regulation of behavior in a real encounter. PMID- 7838902 TI - Endocrine and psychological evaluation of women with recent weight gain. AB - A group of 13 consecutive regularly menstruating women who gained at least 5 kg the previous year (Group I) was compared to a control group of similar age, parity, and social class (Group II). The two groups were similar in estimated and observed food intakes; pre- and postprandial gastrin levels; hourly 24-h profiles of cortisol and insulin; urinary cortisol and 17-hydroxycorticosteroids. Group I had higher serum prolactin concentrations at all times than Group II (mean values 14.60 micrograms/l vs. 8.84 micrograms/l; p = .0121). Galactorrhea was observed in 5 women from Group I and in none of the women from Group II (p < .05). Group I also differed from Group II in a higher incidence of meaningful life-events the year preceding the study, higher prevalence of sexual dysfunction (9/13 vs. 4/13; p < .01) and higher indexes (p < .05) of several parameters in the MMPI and SCL 90. Median serum cortisol and prolactin concentrations were negatively correlated, both in Group I (R = -.669; p = .012) and in the whole sample (R = .453; p = .0298). It is suggested that the rapid weight gain is part of a neuroendocrine response to environmental stimuli also characterized by hyperprolactinemia. The significant negative correlation between serum prolactin and cortisol indicates that this response differs from, and is possibly an alternative to, the sympathoadrenal "stress" response. PMID- 7838904 TI - Repeated morphine administration down-regulates glucocorticoid, but not mineralocorticoid, receptors in the rat hippocampus. AB - Activation of the hypothalamic-pituitary-adrenal axis (HPA) is known to be an important component of a neuroendocrine response to opiates. Since this axis is under inhibitory control of hippocampal corticosteroid receptors, the present study has been designed to determine the effects of single (20 mg/kg IP) and repeated (from 20 to 100 mg/kg/day, IP, twice a day for 10 days) morphine administration on binding parameters of these receptors. Glucocorticoid (GR) and mineralocorticoid (MR) receptors were examined by an in vitro [3H]-corticosterone binding in the cytosol from the rat hippocampus, using the selective GR agonist RU 28362 to discriminate between MR and GR. Repeated, but not single, treatment with morphine significantly (by approximately 22%) reduced the density of GR at 2 h and tended to decrease it at 72 h after the last drug injection. The density of MR was unchanged at those time points. No changes in dissociation constants of either type of the receptors were found following single or repeated morphine administration. The plasma corticosterone level was significantly increased 1 h after acute and chronic administration of morphine (382 and 527%, respectively). These results indicate that repeated morphine administration downregulates GR receptors, which may impair the feedback control mechanism of the HPA activity. PMID- 7838905 TI - Abnormalities in adrenal androgens, but not of glucocorticoids, in early Alzheimer's disease. AB - In an attempt to evaluate possible adrenal abnormalities in Alzheimer's disease (AD), prestimulus levels and ACTH-stimulated serum levels of steroid hormones, corticosteroid-binding globulin (CBG), and insulin-like growth factor I (IGF-I) were measured in 18 patients with early AD (8 men, 10 women; 74.6 +/- 6.5 years, mean +/- SD) and 19 healthy controls (10 men, 9 women; 74.2 +/- 7.6 years, mean +/- SD). Steroid hormone levels were measured before and after an intravenous bolus injection of 250 micrograms ACTH. AD per se had an independent influence on hormone levels when evaluated in MANOVA models. AD patients had significantly higher prestimulus levels of dehydroepiandrosterone and androstenedione (p = .04 and p = .003, respectively) with accentuated differences after ACTH (p = .02 and p < .001 for peak responses, respectively). Serum levels of cortisol, CBG, free cortisol, 17 alpha-hydroxyprogesterone (17 alpha-OHP), and IGF-I did not differ between groups. These abnormalities may have implications for neuronal degeneration as well as for behavioural symptoms in AD. PMID- 7838906 TI - Different effects of acute and chronic immobilization stress on plasma testosterone levels in male Syrian hamsters. AB - Time-course variations in plasma testosterone levels after various periods of immobilization stress (10 min, 30 min, 2 h, 6 h) were examined in male Syrian hamsters. The immobilization stress consisted of placing the animals in a prone position and wrapping them with flexible steel wire gauze. This was done at room temperature. Testosterone levels were determined in blood samples taken after the hamsters were decapitated. Chronic (2 h, 6 h) immobilization stress produced a drastic and enduring fall in plasma testosterone levels. Reduction of plasma testosterone following the 6-h immobilization stress was observed even 18 h after the stress had been relieved. However, acute (10 min, 30 min) immobilization stress did not influence plasma testosterone. These findings indicated that the effect of immobilization stress on plasma testosterone in hamsters was not biphasic, which it is in rats. Further, these results suggest that immobilization stress in hamsters would be a valuable technique with which to investigate the effects of physiological ranges of testosterone on physiological and psychological functions. PMID- 7838907 TI - Comparison of several benzodiazepine receptor ligands in two models of anxiolytic activity in the mouse: an analysis based on fractional receptor occupancies. AB - This study compared the effects of the beta-carboline anxiolytic, abecarnil, with other benzodiazepine receptor (BZR) ligands, including the full agonists diazepam and alprazolam, and the partial agonists ZK 95962 and bretazenil (Ro 16-6028), and alpidem, in the mouse four-plate test and plus-maze. The efficacy and potency of each compound was related to the fraction of BZR occupied by the drug. Abecarnil was efficacious in both tests and showed anxiolytic effects comparable with alprazolam and diazepam. In the four-plate test, abecarnil, bretazenil, and ZK 95962 had selective effects on releasing exploratory locomotor activity suppressed by footshock (punished crossings). None of these compounds significantly altered non-punished crossings. In contrast, diazepam and alprazolam increased both unpunished and punished crossings at low to medium doses (receptor occupancies of approximately 20-60%). The number of punished and unpunished crossings fell to control levels or below at higher, more sedative doses (approximately 80% receptor occupancy). Alpidem had very weak anxiolytic like effects in this test and markedly reduced unpunished crossings at relatively low receptor occupancies (> 15%). In the plus-maze, abecarnil increased the time spent in the open arms and the percentage open arm entries to an extent equal to that observed following diazepam or alprazolam administration. Bretazenil and ZK 95962 had weak effects on the measures of anxiolytic activity in this test. Alpidem also had little anxiolytic-like activity in the plus-maze but markedly reduced the total number of arm entries.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7838908 TI - Nefiracetam (DM-9384): effect on eyeblink classical conditioning in older rabbits. AB - The nootropic compound nefiracetam was evaluated in 88 older rabbits in a 750-ms delay paradigm of eyeblink classical conditioning (EBCC). Rabbits (mean age = 28.7 months) were assigned in groups of eight to one of six conditions in experiment 1: paired tone conditioned stimulus (CS)-corneal airpuff unconditioned stimulus (US) presentations and 1, 3, or 10 mg nefiracetam/kg or sterile saline vehicle; explicitly unpaired CS and US presentations and 3 mg nefiracetam/kg or sterile saline vehicle. Animals in the paired conditions received 10 daily sessions of 90 paired trials and animals in the unpaired conditions received 10 daily sessions of 180 unpaired CS and US presentations. The six conditions in experiment 2 were 5, 10, and 15 mg nefiracetam/kg and vehicle in 15 sessions of paired presentations; 10 mg nefiracetam/kg and vehicle in 15 sessions of unpaired conditioning. In both experiments 1 and 2, acquisition measured by trials to learning criterion was significantly faster at the 10 mg/kg dose of nefiracetam. In the repeated measures analyses comparing six doses in the paired conditions, all dependent measures [percentage conditioned responses (CRs), CR amplitude, and response latency] indicated significantly better conditioning in rabbits treated with 10 mg nefiracetam/kg, but this dose did not increase motor responding or responding in the unpaired condition. Nefiracetam facilitated acquisition of EBCC in older rabbits. EBCC is performed poorly by older humans and is seriously impaired in Alzheimer's disease. These preclinical data in an animal model with clear parallels in humans suggest that nefiracetam may prove effective as a cognition enhancer in clinical trials. PMID- 7838909 TI - Sleep in a sitting position: effect of triazolam on sleep stages and EEG power spectra. AB - The effect of triazolam (0.25 mg) and placebo was investigated in healthy, male subjects who slept in a sitting position. After the intake of placebo, sleep efficiency, rapid eye movement (REM) sleep and subjective sleep quality were lower than in the preceding sleep episode in bed, while stage 1 and REM sleep latency were higher. Triazolam did not prevent this impairment of sleep. However, in comparison with the placebo condition, the percentage of slow wave sleep was higher in the first third of the night, and in the morning sleep was rated as more quite. EEG power density in nonREM sleep was reduced in the frequency range of 1.25-10.0 Hz and enhanced in the range of sleep spindles (12.25-13.0 Hz). These changes were still present in the last third of the night. In REM sleep, triazolam reduced spectral activity in some frequency bins between 4.25 and 10.0 Hz. The sitting position itself affected the nonREM sleep spectra, since the placebo level in the 2.25-21.0-Hz range exceeded the baseline level. We conclude that a 0.25 mg dose of triazolam does not effectively counteract a posture induced sleep disturbance, but induces changes in the EEG spectra which are typical for benzodiazepine receptor agonists. PMID- 7838910 TI - Influence of naloxone upon motor activity induced by psychomotor stimulant drugs. AB - Naloxone, an opioid receptor antagonist, attenuates a wide range of behavioral effects of d-amphetamine, such as the stimulation of motor activity. To investigate the pharmacological selectivity of the naloxone/amphetamine interaction, we assessed the effects of naloxone (5.0 mg/kg SC) upon motor activity induced in rats by a range of psychomotor stimulant drugs with a mechanism of action either similar to or different from that of d-amphetamine. Each of the drugs tested caused dose-dependent increases in both gross and fine activity. Naloxone attenuated the gross but not the fine activity response to d- and l-amphetamine, but had no influence upon the other catecholamine-releasing drugs, methamphetamine and phendimetrazine. In contrast, naloxone increased the gross but not the fine activity response to the catecholamine uptake inhibitors cocaine and mazindol, but had no effects upon the motor response to methylphenidate. The responses to other stimulant drugs (apomorphine, caffeine, scopolamine) were unaffected by naloxone pretreatment. The present findings extend the range of conditions under which naloxone and, by inference, endogenous opioid systems, modulate the behavioral response to psychomotor stimulants. However, the differential effects of naloxone upon the motor response to individual stimulant drugs support previous suggestions of fundamental differences in mechanisms of action among these compounds. PMID- 7838911 TI - Naloxone pretreatment blocks acute morphine-induced sensitization to naltrexone. AB - The present experiment was designed to examine whether the acute sensitization to naltrexone that is induced by a single dose of morphine could be blocked by pretreatment with naloxone. Food-deprived male Sprague-Dawley rats were trained to respond for food on a multiple-trial fixed interval 3-min schedule. Reinforcement was contingent upon a response within a 10-s limited hold period following a fixed interval of 3 min. A trial consisted of three fixed intervals separated by a 10-min timeout period during which responses were not reinforced. The rate decreasing effects of the opioid antagonist naltrexone were determined by cumulative dosing. Pretreatment with morphine (3.0 mg/kg, SC) resulted in a 70 fold increase in sensitivity to the response rate decreasing effect of naltrexone compared with saline pretreatment. The increased sensitivity was dose-dependently blocked by naloxone administration 10 min before morphine. The blockade by naloxone was overcome by increasing the pretreatment dose of morphine to 10 mg/kg. The results provide further evidence that acute agonist-induced sensitization to the rate-reducing effects of naltrexone is mediated by opioid receptors. PMID- 7838912 TI - Cocaine-induced conditioned taste aversions: comparisons between effects in LEW/N and F344/N rat strains. AB - Recent studies have found the LEW/N rat self-administers drugs of abuse at higher rates than the F344/N rat, suggesting a genetic predisposition toward the abuse potential of drugs. The current study compared the acquisition of a conditioned taste aversion (CTA) to cocaine in these strains. During an initial 20-min daily session a 0.1% saccharin solution was available and a dose (0-50 mg/kg, SC) of cocaine was given immediately after that session. Water was available during sessions on the following 3 days. Fluid consumption was assessed over three saccharin/water cycles, and a final saccharin session. Vehicle injections (0 mg/kg) that followed exposure to saccharin had no effect on subsequent saccharin consumption. In contrast, when cocaine followed exposure to saccharin, rates of saccharin consumption decreased over successive saccharin sessions in a dose related manner in both strains. The lowest dose (18 mg/kg) decreased consumption in LEW/N rats but not in F344/N rats. An intermediate dose (32 mg/kg) decreased consumption maximally in LEW/N rats and only marginally in F344/N rats. The highest dose (50 mg/kg) decreased consumption completely in LEW/N rats and almost completely in F344/N rats. These findings demonstrate that significant differences in sensitivity to stimuli paired with cocaine occur between these strains. These differences are consistent with previous reports that the LEW/N rat is uniquely sensitive to both behavioral and biochemical effects of drugs of abuse. The current report extends this sensitivity to the noxious effects of these drugs.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7838913 TI - Effects of caffeine or diphenhydramine on visual vigilance. AB - The effects of two drugs having opposite effects on the central nervous system were investigated using a newly developed visual vigilance task. Twenty-four male volunteers (median age = 20) performed the task on three separate occasions; after consuming placebo, caffeine (200 mg), or diphenhydramine (25 mg), in a double-blind, Latin Square design. At least 2 days intervened between drug administrations. Caffeine use was restricted for 10 h and smoking for 3 h before drug administration. When compared with placebo, caffeine significantly increased the number of correct responses and decreased response times, whereas diphenhydramine decreased the number of correct responses and increased response times. Low habitual consumers of caffeine (< 100 mg/day) and non-smokers had more correct responses than did high habitual caffeine consumers (> 100 mg/day) and smokers, but only in the placebo condition. Non-smokers had faster response times than smokers only in the placebo condition. Both caffeine and diphenhydramine altered certain aspects of mood. PMID- 7838914 TI - Selective antagonism of dopamine D1 and D2 receptors does not block the development of behavioral sensitization to cocaine. AB - The objective of this study was to determine whether the development of behavioral sensitization to cocaine could be prevented by either D1 or D2 selective dopamine receptor antagonists. Male Wistar rats were treated daily for 7 days with either cocaine (15 mg/kg, IP) or vehicle in combination with the D1 dopamine antagonist SCH 23390 (0.3 mg/kg, SC), the D2 dopamine antagonist sulpiride (100 mg/kg, IP), or vehicle. After the daily injections, the rats were tested for locomotor activity in photocell arenas. Twenty-four hours after the last pre-exposure test session, all rats were given a challenge injection of cocaine (15 mg/kg, IP) and tested for activity. Cocaine treatments produced a greater relative increase in locomotor activity with repeated exposure (i.e. sensitization). Moreover, this increase in cocaine-induced locomotor activity was attenuated by both SCH 23390 and sulpiride. In contrast, neither sulpiride nor SCH 23390 blocked the development of behavioral sensitization to cocaine. That is, rats pretreated with sulpiride or SCH 23390 and cocaine did not differ from rats pre-exposed only to cocaine when given a cocaine challenge injection. These results suggest that behavioral sensitization to cocaine may develop through either D1 or D2 dopamine receptor stimulation or possibly through stimulation of some non-dopaminergic receptor. PMID- 7838915 TI - Modulation of drug reinforcement by behavioral requirements following drug ingestion. AB - Eight volunteers with histories of drug abuse participated in two experiments examining the modulation of drug choice by behavioral requirements following drug ingestion. Each morning subjects ingested color-coded capsules containing triazolam (0.25 mg), d-amphetamine (15 mg), or placebo and then engaged in a relaxation or a computer vigilance activity. Experiment 1 involved two phases (i.e. a triazolam and a d-amphetamine phase), presented in counterbalanced order. Within each phase, subjects were first exposed to each of two compounds (placebo and either triazolam or d-amphetamine) once with each activity. Then every other day for 20 days subjects chose which compound they ingested with the vigilance and relaxation activities, with the restriction that they could not choose the same compound with both activities. Seven of eight subjects reliably chose d amphetamine with the vigilance activity; all subjects always chose triazolam with the relaxation activity. In experiment 2 (5 days' duration), after re-exposure to the color-coded compounds used in experiment 1, subjects chose which compound (placebo, d-amphetamine or triazolam) they ingested with the vigilance activity, and on another occasion (in counterbalanced order), which they ingested with relaxation activity. Seven of eight subjects chose d-amphetamine with the vigilance activity; all subjects chose triazolam with the relaxation activity. The relaxation and vigilance activities modulated triazolam and d-amphetamine reinforcement, thereby demonstrating a new class of environmental variable that can influence drug self-administration. PMID- 7838916 TI - Influence of rate of administration of raclopride on akathisia and prolactin response. AB - The D2-dopamine receptor antagonist raclopride was administered to eight healthy male subjects, who had previously experienced akathisia following antipsychotic drugs. The influence of administration rate on onset, severity and duration of akathisia and on prolactin response was studied. Raclopride 3, 5 or 9 mg or placebo (P) was administered as single IV infusions during 10 min (R10 min/3 mg), 1 h (R1h/5 mg) or 4 h (R4h/9 mg) according to a randomized double-blind design. Despite a 24-fold difference in administration rate a similar peak raclopride concentration of about 350 nmol/l was obtained after all three infusions. Three of the eight subjects experienced akathisia following R10 min/3 mg and R1h/5 mg, respectively. After R4h/9 mg seven subjects experienced akathisia of longer duration but not more severe than after the short infusions. The incidence and duration of akathisia seem to be mainly related to the plasma raclopride concentrations over time, whereas the rate of administration might be more important for the severity. A maximal prolactin response was induced which was not markedly affected by the rate of administration. PMID- 7838917 TI - Effects of flumazenil on cholecystokinin-tetrapeptide-induced panic symptoms in healthy volunteers. AB - The neuropeptide cholecystokinin-tetrapeptide (CCK-4) has potent anxiogenic action in human and animal subjects. On the basis of prior work which demonstrated that benzodiazepine (BZD) receptor agonists antagonized CCK-induced excitation of rat hippocampal neurons we studied whether BZD receptors mediated the anxiogenic effect of CCK-4. To examine this possibility we determined whether the BZD receptor antagonist flumazenil could antagonize the effects of CCK-4 (50 micrograms) in healthy volunteers. Thirty subjects (10 females; 20 males) were pretreated with flumazenil (2 mg in saline) or placebo (0.9% NaCl in water) 15 min prior to CCK-4 challenge in a randomized double-blind crossover design. Flumazenil had no impact on the behavioral and cardiovascular effects of CCK-4, suggesting that BZD receptors do not mediate the anxiogenic action of CCK-4. The influence of GABA and non-GABA-related mechanisms on response to CCK-4 remains to be considered. PMID- 7838918 TI - Dopamine D2 autoreceptors in rats are behaviorally functional at 21 but not 10 days of age. AB - Previous studies used either racemic 3-(3-hydroxyphenyl)-N-n-propylpiperidine [(+/-)-3-PPP] or lower doses of the mixed dopamine (DA) D1/D2 agonist apomorphine (APO) to conclude that brain DA D2 autoreceptors are not behaviorally functional until 28 days of age. The purpose of this study was to provide behavioral evidence for functional D2 autoreceptors before 28 days of age using DA agonists with greater selectivity for D2 autoreceptors. The locomotor activity of 10-, 21 , 35-day-old and adult rats was monitored after injection of a D2 autoreceptor agonist. There were significant decreases in the locomotor activity of 21-, 35 day-old, and adult rats injected with (-)-3-PPP, SND 919, or PD 128483. Lower doses of APO significantly decreased the activity of adult and 35-day-old rats but not younger rats. The only significant effect on the locomotor activity of 10 day-old rats was an increase in activity after injection of APO, 0.01 mg/kg or higher, or B-HT 920, 0.01 mg/kg. The results suggest that brain DA D2 autoreceptors are behaviorally functional at 21, but not 10, days of age. PMID- 7838920 TI - Savoxepine fails to selectively influence glucose metabolism in the rat limbic system. AB - The [14C]-2-deoxyglucose method was used to map the in vivo metabolic response of glucose to savoxepine, a novel tetracyclic cyano-dibenzoxepino-azepine. Savoxepine is reported to have higher affinity for dopamine (DA) receptors in the hippocampus than in the striatum and hence should have dose-dependent, anatomically selective actions. Two doses of savoxepine (0.05 mg/kg and 0.5 mg/kg) were compared with haloperidol (1 mg/kg) to test the hypothesis that low doses of savoxepine would display a selective action on limbic brain areas. Results failed to show that low dose savoxepine selectively modifies glucose utilization in the limbic system as previous biochemical studies suggested. In fact, low doses of the drug displayed a potent activity quite similar to haloperidol in effect and localization. The low dose did not produce significantly altered glucose metabolism in the nucleus accumbens or in the lateral habenular nucleus as observed with most other neuroleptics, suggesting a lack of antipsychotic action at this dose. Our findings demonstrate the difficulty of designing a neuroleptic with a preferential blockade of limbic DA receptors and point to the need for functional assessment of regional receptor binding differences. PMID- 7838919 TI - Morphine-conditioned analgesia using a taste cue: dissociation of taste aversion and analgesia. AB - The present study examined the ability of a taste cue to serve as a conditioned stimulus (CS) for conditioning the analgesic effect of morphine. Rats were given three pairings of a taste CS with a morphine unconditioned stimulus (US). As expected, there was a decrease in CS intake across repeated pairings, indicating that a conditioned taste aversion was obtained. More important, presentation of the CS alone also increased paw-lick latencies on a hot plate test (either 50 degrees C or 54 degrees C hot plate), suggesting that an analgesic conditioned response (CR) was obtained. The dose of morphine required to produce conditioned analgesia was higher than the dose of morphine required to produce conditioned taste aversion. Using 15 mg/kg morphine, however, both conditioned taste aversion and conditioned analgesia were present when the morphine US was given immediately following CS intake, but not when given 6 h following CS intake. In contrast to morphine, pairing a taste CS with lithium produced a conditioned taste aversion without any conditioned analgesic response. These results indicate that acquisition of an analgesic CR is not the result of stress induced by an aversion to the taste CS. PMID- 7838921 TI - Acute dose-effect relationships of caffeine and mental performance, EEG, cardiovascular and subjective parameters. AB - The present study investigated the dose-effect relationship of caffeine on mental performance using a caffeine-sensitive rapid information processing task (RIP) in a pre/post cross-over design. Twenty female nonsmoking regular coffee drinkers received 0, 1.5, 3 and 6 mg/kg caffeine in a balanced order and the measurements were extended to cardiovascular, EEG and mood parameters. Surprisingly, the dose effect curves for the different parameters were rather heterogeneous. Whereas increasing effects with increasing caffeine doses were observed for alpha- and beta-EEG frequencies, anxiety, wakefulness, and some coffee ratings, negative dose-effect relationships were obtained for RIP processing rate and blood pressure. No apparent dose-effect relationships were seen for reaction time and motor activity. Thus, it was concluded that the dose-response relationships are rather shallow and heterogeneous and that the different parameters have different ranges in which they are sensitive to caffeine. The caffeine doses which might have beneficial behavioral effects are at the lower end of the tested dose range and comparable to those found in caffeine-containing beverages. PMID- 7838922 TI - Ethological evaluation of the effects of acute and chronic buspirone treatment in the murine elevated plus-maze test: comparison with haloperidol. AB - Buspirone is renowned for its highly inconsistent effects in animal models of anxiety. In the present study, the effects of acute (0.63-5.0 mg/kg) and chronic (1.25-5.0 mg/kg, daily, 15 days) buspirone treatment on the behaviour of mice in the elevated plus-maze test were assessed using a recently developed ethological scoring method. On acute administration, a selective reduction in risk assessment behaviours was observed at 1.25 mg/kg; these mild anxiolytic-like effects were maintained at higher doses (2.5-5.0 mg/kg) which also reduced measures of general activity. Similar, though more potent, effects were observed with chronic administration; the lowest dose tested (1.25 mg/kg) reduced open arm entries and total stretch attend postures while higher doses profoundly reduced all major indices of anxiety (traditional and novel) and, concomitantly, suppressed total entries and rearing. Acute administration of haloperidol (0.0125-0.1 mg/kg) appeared to mimic the behavioural suppressant effects of buspirone without selectively affecting anxiety-related measures at any dose. It is suggested that the anti-anxiety and behavioural suppressant profile of buspirone may reflect combined action at 5-HT1A and D2 receptors, respectively. Results are discussed in relation to the utility of risk assessment as a sensitive index of anxiety in models based upon unconditioned behaviour. PMID- 7838923 TI - Studies on electroencephalogram (EEG) in rats suggest that moderate doses of cocaine or d-amphetamine activate D1 rather than D2 receptors. AB - The effects of cocaine and d-amphetamine, two psychomotor stimulant drugs with pronounced addictive properties, on the electroencephalogram (EEG) of rats were studied by telemetric recordings from the skull in non-anesthetized, freely moving rats. The electrocorticogram (ECoG) was recorded. Both cocaine (10 mg/kg IP) and d-amphetamine (0.4 mg/kg IP) produced a desynchronization, characterized by a general lowering in power in all of the frequency bands. These effects of both drugs were mimicked by the selective agonist at D1 receptors SK&F 38393 (3 mg/kg SC) and were reversed by the antagonist at D1 receptors SCH 23390 (0.2 mg/kg IP) but not influenced by haloperidol (0.1 mg/kg IP) in a dose which is likely to block D2 rather than D1 receptors. These doses of cocaine or d amphetamine did not produce stereotyped behaviour and slight, if any, increases in locomotor activity only. Large doses of cocaine (30 mg/kg IP) or d-amphetamine (4 mg/kg IP) produced stereotyped behaviour and alterations in EEG which are, based on previous own studies, characteristic for additional stimulation of D2 receptors. This was manifest in a selective increase in power of the alpha-1 band. A similar effect was also produced by the agonist both at D1 and D2 receptors, apomorphine (0.5 mg/kg SC). These results suggest that moderate, but probably rewarding doses of cocaine or d-amphetamine mainly activate D1 dopamine receptors. This activation might be relevant for the rewarding properties of these drugs. PMID- 7838924 TI - Effects of imipramine on serotonergic and beta-adrenergic receptor binding in a realistic animal model of depression. AB - Chronic exposure to mild unpredictable stress (CMS) has previously been found to cause an antidepressant-reversible decrease in the consumption of palatable sweet solutions. In the present study, in addition to confirming these behavioural observations, the binding properties of cortical beta-adrenergic and 5HT2 receptors, and hippocampal 5HT1A receptors were studied (using the ligands [3H] dihydroalprenolol, [3H]-ketanserin and [3H]-8-OH-DPAT, respectively), following 7 weeks of CMS and 4 weeks of imipramine treatment (10 mg/kg per day). CMS increased Bmax for all three receptor systems. Imipramine decreased Bmax, reversing the effect of CMS, for beta-adrenergic and 5HT2 receptor binding, but increased Bmax for 5HT1A receptor binding. KDs were unaffected by either treatment. The beta-receptor and 5HT2 receptor binding data are consistent with accounts of antidepressant action derived from studies in normal animals, but the 5HT1A receptor binding data are more difficult to reconcile. In no case was there a good correlation between receptor binding and behavioural data. PMID- 7838925 TI - Effects of nimodipine and/or haloperidol on the expression of conditioned locomotion and sensitization to cocaine in rats. AB - The development of classical conditioning of cocaine's locomotor effects can be dissociated from the development of sensitization to cocaine by co-administration of haloperidol, a dopamine D2-like receptor antagonist, and nimodipine, an L-type calcium channel antagonist. The effects of these agents on the expression of conditioning and sensitization are described in the present report. Rats were given injections of vehicle or cocaine (10 mg/kg, IP) for 10 days before placement in a specific context in which locomotor activity was recorded. Neither haloperidol (0.05 mg/kg, IP) nor nimodipine (10 mg/kg, SC) influenced the expression of classical conditioning of cocaine's locomotor effects to the situational context on a subsequent cocaine-free test. Combined treatment of rats with both drugs did block classical conditioning with cocaine. Nimodipine, but not haloperidol, blocked the expression of behavioural sensitization to cocaine after a cocaine challenge. It is concluded that the expression of cocaine-induced classical conditioning can be pharmacologically dissociated from the expression of behavioural sensitization to cocaine. Furthermore, the effects of nimodipine and haloperidol on the expression of conditioning and sensitization are different from their effects on the development of these phenomena. PMID- 7838926 TI - Interactions between diltiazem and ethanol: differences from those seen with dihydropyridine calcium channel antagonists. AB - It has previously been shown that dihydropyridine calcium channel antagonists prevent the ethanol withdrawal syndrome and potentiate the acute effects of ethanol and other central depressant drugs. We now report that, in contrast, the benzothiazepine calcium channel antagonist, diltiazem, gave no protection against the behavioural hyperexcitability seen during ethanol withdrawal, when given either acutely, on withdrawal, or chronically, during the ethanol treatment. A significant increase in convulsive behaviour on handling was seen during the withdrawal period when diltiazem was given on cessation of a mild chronic ethanol treatment schedule. Diltiazem decreased the acute general anaesthetic effects of ethanol, and did not appear to potentiate the ataxic action of ethanol. Centrally administered diltiazem did not enhance the hypothermic action of ethanol, but this effect was significantly increased by diltiazem when the calcium channel antagonist was given peripherally. When given alone by the intraperitoneal route, diltiazem decreased spontaneous locomotor activity and lowered body temperature. When the intracerebral route was used for administration of diltiazem, a significantly decrease in body temperature was seen when this compound was given alone, accompanied by a brief hyperexcitability. The interactions between ethanol and diltiazem therefore appear to differ from those seen with other calcium channel antagonists. PMID- 7838927 TI - A comparison of the acute effects of a tricyclic and a MAOI antidepressant on septal driving of hippocampal rhythmical slow activity. AB - In free-moving male rats, the function relating frequency to the threshold current required to drive hippocampal rhythmical slow activity (RSA) with septal stimulation has a minimum at 130 ms. Both classical anxiolytics (e.g. benzodiazepines) and the novel anxiolytic buspirone show similar effects on septal driving of RSA. The tricyclic antidepressant imipramine may be as effective as anxiolytic drugs in treatment of generalized anxiety disorder. The antidepressant monoamine oxidase inhibitor phenelzine has also been reported to be effective in treating anxiety, but this may reflect an action on "atypical depression" rather than "anxiety". The present study therefore compared the effects of acute administration of imipramine and phenelzine on septal driving of RSA to determine whether either would mimic anxiolytics in this test. Rats were chronically implanted with septal stimulating electrodes and subicular recording electrodes. Three groups of rats received IP injection of either imipramine (5.9 13.3 mg/kg or 13.3-30 mg/kg) or phenelzine (0.2-5.4 mg/kg). The effects produced by imipramine were very similar to the effects produced by anxiolytic drugs. In contrast, the effects produced by phenelzine were essentially opposite to those of both anxiolytic drugs and imipramine. The present experiment suggests that imipramine may act as a true anxiolytic, in addition to its conventional antidepressant properties. In contrast, phenelzine may be effective in cases where the etiology is essentially that of depression even when the symptomatology appears to be that of anxiety. PMID- 7838929 TI - Effects of glucocorticoids on 5-HT1A presynaptic function in the mouse. AB - 8-OH-DPAT, a selective 5-HT1A agonist, produced a hypothermic response in mice at a dosage of 0.5 mg/kg. Administration of corticosterone-21-acetate (0.5, 5 and 50 mg/kg, daily for 3 and 10 days) produced a dose-dependent attenuation of this hypothermic response in mice. When all controls and corticosterone treated mice were retested, 14 days after initial testing, they did not differ in the hypothermic responses induced by 8-OH-DPAT. Mice treated with aldosterone (50 mg/kg), dexamethasone (50 mg/kg) and the specific type 2 corticosteroid receptor agonist, 11b,17b-dihydroxy-21-methyl-17a-pregna-1,4,6-trien-20-yn+ ++-3-one (RU26988, 30 mg/kg) for 10 days, did not differ from vehicle treated controls in the hypothermic response to 8-OH-DPAT. Mice administered corticosterone-21 acetate (30 mg/kg, daily) for 10 days displayed a motor behavioural syndrome, which was not seen in controls, when injected with 5-hydroxytryptophan (5-HTP, 100 mg/kg) 15 min after the injection of carbidopa (25 mg/kg). This was significantly decreased by pretreatment with the 5-HT1A receptor antagonist 1-(2 methoxyphenyl)-4-(4-phthalimidobutyl)-piperazine (NAN-190 5 mg/kg, 30 min prior to administration of carbidopa). Taken together, this evidence is compatible with a specific corticosterone induced facilitation of 5-HT release due to attenuation of inhibitory 5-HT1A autoreceptor function. PMID- 7838930 TI - Effects of smoking on simple and choice reaction time. AB - Twenty-nine subjects performed a reaction time task with four levels of choice task complexity under non-smoking, sham smoking, and low, medium and high nicotine cigarette conditions. Nicotine reduced decision time, while sham smoking increased decision time. This effect was independent of subjects' habitual levels of cigarette consumption. No effect of smoking was found on movement time. PMID- 7838928 TI - Mesoaccumbens dopamine-opiate interactions in the control over behaviour by a conditioned reinforcer. AB - These experiments examined the role of dopamine-opiate interactions in the ventral tegmental area (VTA) and nucleus accumbens in the mediation of reinforcement-related behaviour. It has been shown previously that opiates induce a dopamine-dependent increase in locomotor activity in rats when infused into the VTA, and a dopamine-independent hyperactivity when infused into the nucleus accumbens. The present study investigated the generality and significance of these two findings, by examining dopamine-opiate interactions in the control over behaviour exerted by a conditioned reinforcer (CR), an arbitrary stimulus which gains control by association with primary reinforcement. Rats were trained to associate a light/noise stimulus with sucrose reinforcement, and the efficacy of the CR in controlling behaviour was assessed by measuring its ability to support a new lever pressing response. Responding on one lever (CR lever) produced the CR, responding on the other lever had no programmed consequences. In experiment 1, intra-accumbens infusions of d-amphetamine (10 micrograms), the D1 dopamine receptor agonist SKF-38393 (0.1 microgram), the D2 dopamine receptor agonist LY 171555 (quinpirole; 0.1 microgram) or the opiate receptor agonist [D-Ala2] methionine enkephalinamide (DALA; 1 microgram) selectively increased responding on the CR lever. Infusion with DALA intra-VTA had no effect. However, pretreatment with DALA intra-VTA (10 x 1 microgram/day) subsequently reduced the selectivity of the response to infusions intra-accumbens with d-amphetamine or SKF-38393, and blocked the response to LY-171555 or DALA. Pretreatment also shifted to the right the dose-response function for DALA intra-accumbens. In experiment 2, intra-accumbens infusions of d-amphetamine, SKF-38393, LY-171555 or DALA again increased responding on the CR lever only. Pretreatment with intra accumbens d-amphetamine (5 x 1 microgram/day) reduced the selectivity of the response subsequently to d-amphetamine, and blocked the response to SKF-38393, LY 171555 or DALA. In experiment 3, intra-accumbens infusions of the mu-opiate receptor agonist [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (0.003-0.1 microgram), or the delta-opiate receptor agonist [D-Pen2,5]-enkephalin (0.03-1 microgram) enhanced selectively responding on the CR lever. Thus, the dopamine-dependent locomotor-stimulant properties of intra-VTA infusions of opiates are associated with impaired conditioned reinforcer efficacy. Finally, repeated stimulation of the mesoaccumbens dopamine pathway may compromise the dopamine-independence of the opiate system within the nucleus accumbens. PMID- 7838931 TI - Nicotine increases sensory gating measured as inhibition of the acoustic startle reflex in rats. AB - Chronic nicotine administration has been reported to increase acoustic startle response (ASR) amplitude in rats, which has been offered as evidence that some dosages of nicotine can enhance attention. The present experiments examined effects of acutely administered nicotine on amplitude and pre-pulse inhibition (PPI) of acoustic startle in rats. PPI, the decrease in ASR amplitude by a stimulus preceding the startle-eliciting event, reflects pre-attentive neural processes underlying sensory gating. Nicotine had a biphasic dose effect on startle amplitude, with increases at lower dosages (0.01 mg/kg) and decreases at higher dosages (0.5-5.0 mg/kg SC). Lower dosages of nicotine (0.001-0.01 mg/kg) increased PPI and the increase at 0.001 mg/kg occurred independently of changes in ASR amplitude. These results confirm that increases in PPI are not dependent upon changes in ASR amplitude. Results are consistent with nicotine's enhancements of performance on cognitive tasks in humans and are the first reported use of the PPI paradigm to model such effects. These findings indicate that ASR paradigms are useful to study effects of nicotine. PMID- 7838933 TI - Sedentary lifestyle and state variation in coronary heart disease mortality. AB - Using linear regression, the authors demonstrated a strong association between State-specific coronary heart disease mortality rates and State prevalence of sedentary lifestyle (r2 = 0.34; P = 0.0002) that remained significant after controlling for the prevalence of diagnosed hypertension, smoking, and overweight among the State's population. This ecologic analysis suggests that sedentary lifestyle may explain State variation in coronary heart disease mortality and reinforces the need to include physical activity promotion as a part of programs in the States to prevent heart disease. PMID- 7838934 TI - The Public Health Service VD clinic in Hot Springs, AR. PMID- 7838932 TI - Platelet intracellular calcium in patients with recurrent affective disorders. AB - Forty-four subjects with a history of a major recurrent affective disorder in remission and who were either on no medication or taking a single dose of psychotropic medication were conscripted together with matched controls. The fluorescent indicator fura 2 was used to measure intracellular calcium in platelets and estimations were made of total serum and ionised calcium as well as of whole blood serotonin. Intracellular calcium was measured in the resting state as well as after stimulation with thrombin, platelet activating factor and serotonin. No significant differences were found between the 17 subjects with a diagnosis of bipolar disorder or the 27 subjects with recurrent unipolar depression and their matched controls. Intracellular calcium measures were significantly higher in the lithium treated group after stimulation with 5HT, whereas the subjects taking tricyclic antidepressants did not differ significantly from their controls on any measure. Serum calcium was found to be significantly higher in those subjects taking lithium. These findings suggest that the measurement of intracellular calcium is not a useful trait marker in affective disorders. Lithium appears to enhance the 5HT induced rise of intracellular calcium. PMID- 7838936 TI - Nearly $28 million for AIDS care programs. PMID- 7838935 TI - Tuberculosis, HIV co-epidemic to multiply sevenfold in Asia. PMID- 7838938 TI - Possession and carrying of firearms among suburban youth. AB - Despite a growing body of anecdotal evidence suggesting the spread of firearms to suburban juvenile populations, most studies of firearm activity by juveniles focus either on urban youth or on nationally representative samples that blur urban and nonurban distinctions. This study represents the first systematic empirical investigation specifically of a suburban population of juveniles. The authors examine both ownership and carrying behaviors, distinguish types of handguns involved, and assess the influence of drug activity, violent criminality, and the perception of one's social environment as dangerous upon the possession and carrying of firearms. Among the variables linked at the bivariate level to possession and carrying of guns were sex, involvement in criminal activity, involvement in drug activity, and most indicators of a dangerous social environment. At the multivariate level, however, only sex was associated with possession of a revolver, and only sex, criminal activity (for boys only), and one indicator of dangerous environment (having been threatened with a gun, for girls only) were associated with possession of an automatic or semiautomatic handgun. Aside from sex, criminal and drug activities were associated with gun carrying. Despite its importance among urban samples, in this study the dangerous environment was not linked to firearm activity. Possible reasons for this difference are explored in the conclusion. PMID- 7838937 TI - A profile of homicides on the streets and in the homes of New York City. AB - Although prior research has found that homes containing firearms and illicit drug and ethanol users are more likely to be the scene of a homicide than homes that do not contain these elements, the authors studied homicides on the streets as well as in homes so as to assess the role of firearms, cocaine, and ethanol in both settings. Using the files of the Chief Medical Examiner, the authors reviewed all 4,468 homicides occurring in New York City in 1990 and 1991. The most frequent places of occurrence were the streets and other outdoor places (49.6 percent) and the victims' homes (19.3 percent). Firearms were the cause of death for 49.6 percent of homicides in the home and 80.3 percent of those on the streets. Use of cocaine and ethanol was found more frequently among victims killed on the streets than those killed at home. In addition, victims killed on the streets were more likely to be male, ages 15-24 years, and African American. Further research in regard to prevention and intervention strategies is needed, keeping in mind the different patterns of homicide on the streets compared with those occurring in other settings. PMID- 7838939 TI - The systematic assessment of variations in medical practices and their outcomes. AB - The Health Care Financing Administration of the Department of Health and Human Services has carried out for several years the systematic assessment of variations over time and among geographic locales in patterns of care and patterns of outcomes experienced by Medicare beneficiaries. This routine monitoring focuses principally on hospitalizations and their outcomes (death and readmission) and is based on the Medicare enrollment file and the claims file for inpatient care. The period 1985-88 has been marked by declining adjusted post admission risks for mortality (down 4 percent) and readmission (down 6 percent) for Medicare beneficiaries. The downward trend in mortality risks is most evident following hospitalizations for acute myocardial infarction (down 8 percent) and stroke (down 12 percent). Hospital admission and population mortality rates, adjusted for differences in demographic and socioeconomic characteristics of the populations, vary substantially among areas as large as States and Metropolitan Statistical Areas, as do risk-adjusted post admission probabilities of death among those areas and among hospitals. Thus, if overall admission and mortality rates in the upper three quartiles of Metropolitan Statistical Areas were brought down to the average of the lowest quartile, there would be 20 percent fewer admissions and 12 percent fewer deaths within 180 days of admission for hospitalized patients. Although favorable trends in the effectiveness of the hospital care received by Medicare beneficiaries appear discernible, the existence of substantial variations suggests that further improvement may be possible. PMID- 7838940 TI - Savings achieved by giving WIC benefits to women prenatally. AB - The Special Supplemental Food Program for Women, Infants, and Children (WIC) provides supplemental food, nutrition and health education, and social services referral to pregnant, breastfeeding, and post-partum women, and their infants and young children who are both low-income and at nutritional risk. A number of statistically controlled evaluations that compared prenatal women who received WIC services with demographically similar women who did not receive WIC services have found WIC enrollment associated with decreased levels of low birth weight among enrolled women's infants. Several also have found lower overall maternal and infant hospital costs among women who had received prenatal WIC services compared with similar women who did not receive prenatal WIC services. A meta analysis of the studies shows that providing WIC benefits to pregnant women is estimated to reduce low birth weight rates 25 percent and reduce very low birth weight births by 44 percent. Using these data to estimate costs, prenatal WIC enrollment is estimated to have reduced first year medical costs for U.S. infants by $1.19 billion in 1992. Savings from a reduction in estimated Medicaid expenditures in the first year post-partum more than offset the cost of the Federal prenatal WIC Program. Even using more conservative assumptions, providing prenatal WIC benefits was cost-beneficial. Because of the estimated program cost savings, the U.S. General Accounting Office has recommended that all pregnant women at or below 185 percent of Federal poverty level be eligible for the program. PMID- 7838941 TI - A preliminary comparison between local public health units in the Canadian Province of Ontario and in the United States. AB - This comparison between public health departments in the United States and in the Canadian Province of Ontario addresses the funding and staffing and the size and program content of local health departments after Canada's national health reform provided universal access to personal health services. Ontario's local health departments are required to provide a uniform set of public health services. In the United States, there is substantial variation among jurisdictions in kinds and amounts of services delivered. Ontario health units have staff sizes and budget levels that increase in proportion to population served, like those in the United States. But in Ontario, per capita expenditures increase with decreasing population, while the reverse is true in the United States. This anomaly may be attributed to lack of critical staff or elimination of key programs in small U.S. departments. Medical care of indigents probably accounts for the increased per capita costs seen in very large U.S. health departments. An estimated price for uniform public health services meeting the Ontario requirements in all U.S. jurisdictions as they were organized in 1989 is $5.8 billion per annum (not adjusted for inflation). If smaller health departments were consolidated, a savings of more than $1 billion could be realized. Even with this reorganization, average expenditures in smaller U.S. health departments would need to be doubled, and staff sizes increased by about 50 percent to meet Ontario's uniform public health program standards. PMID- 7838942 TI - The epidemiology of pacemaker implantation in the United States. AB - Data on pacemaker implantation were obtained from the Medical Device Implant Supplement to the 1988 National Health Interview Survey, a nationally representative, population-based survey of 47,485 households (122,310 persons). The survey yielded an estimate of 456,482 noninstitutionalized adults with pacemakers (prevalence, 2.6 per 1,000). Prevalence rose significantly with age, from 0.4 per 1,000 among persons ages 18-64 to 26 per 1,000 among those ages 75 or older. Age-adjusted prevalence in males was 1.5 times that in females, and in whites 1.6 times that in nonwhites, although these differences were of borderline statistical significance. Prevalence did not vary significantly by region of residence, educational level, or income, but was significantly increased (more than threefold) in those reporting any activity limitation compared with those with no limitation. Fifteen percent of pacemakers in use were replacements; about one-fifth of these had been replaced more than twice. Sixty percent of previous pacemakers had been in place for at least 5 years. These data provide the first nationwide, population-based estimates of the epidemiology of pacemaker implantation, focusing particularly on the demographics of U.S. pacemaker recipients. PMID- 7838943 TI - Clients without health insurance at publicly funded HIV counseling and testing sites: implications for early intervention. AB - The characteristics of clients reporting no health insurance were compared with those reporting any health insurance at publicly funded human immunodeficiency virus (HIV) counseling and testing sites in the United States during 1992. Thirty of 65 funded health departments collect data on self-reported health insurance status. Data were dichotomized into two groups, clients reporting any health insurance versus those reporting none, and multivariate logistic models were developed to explore independent associations. Of the 885,046 clients studied, 440,416 reported that they lacked health insurance. Clients without health insurance were more likely to be male, members of racial or ethnic minorities, adolescent, and HIV seropositive. Prisoners (odds ratio = 0.26), clients of Hispanic ethnicity (odds ratio = 0.52), and clients receiving testing during field visits (odds ratio = 0.53) in drug treatment centers (odds ratio = 0.55) and in tuberculosis clinics (odds ratio = 0.55) were less likely to have health insurance. Injecting drug users, whether heterosexual (odds ratio = 0.65) or homosexual (odds ratio = 0.67), were less likely to have health insurance compared with other behavioral risk groups. Large numbers of clients receiving publicly funded HIV counseling and testing lack health insurance. Lack of health insurance may interfere with subsequent receipt of needed primary care services among high-risk clients, especially HIV seropositive clients in need of early intervention services. PMID- 7838944 TI - Variations in pregnancy outcomes by race among 10-14-year-old mothers in the United States. AB - This study used the 1983-86 U.S. Linked Live Birth-Infant Death Files to examine variations in pregnancy outcomes among 38,551 U.S. resident black and white adolescents ages 10 through 14. The birth rate was 4.29 per 1,000 for blacks, more than 7 times the rate for whites (.59 per 1,000). Black mothers had higher proportions of very low and low birth weight infants than did whites (very low birth weight: 3.7 versus 2.6; low birth weight: 15.0 versus 10.5). Neonatal and infant mortality rates were higher among very low birth weight and low birth weight white infants. Neonatal and infant mortality rates were similar for normal birth weight infants of both races, but were 3.7 to 7.4 times higher among black infants with birth weights more than 4,250 grams. Logistic regression indicated that black mothers were at higher risk for having infants who were low birth weight, very low birth weight, small for gestational age, preterm, and very preterm. There were no differences by race for neonatal, postneonatal, and infant mortality. While the risk for poor pregnancy outcomes is great among young adolescents, young black adolescents appear to be particularly vulnerable. Attempts to reduce unintended pregnancies in this group should receive highest priority. PMID- 7838945 TI - The revised standard certificate of live birth: analysis of medical risk factor data from birth certificates in Alabama, 1988-92. AB - The latest revision of the birth certificate features a new checkbox format designed to collect more effectively information for public health research. One of the new checkbox items, medical risk factors for this pregnancy, is designed to collect information on risk factors which result in adverse pregnancy outcomes. Data from 308,573 birth certificates filed in Alabama between 1988 and 1992 were analyzed. Although problems exist with the data collected for this item, useful information can be obtained to investigate important public health issues. First, the data can be used to determine the prevalence of medical risk factors in the population. Second, differences between subpopulations with these conditions can be examined. For example, some differences between racial groups in adverse pregnancy outcomes may be explained by the fact that black mothers are more likely to have a medical risk factor than whites. Third, some medical factors are associated with elevated risks for low birth weight, while others are associated with reduced probability of low birth weight. Although useful data can be obtained from the medical risk factor item, it and other checkbox items would be more useful if efforts were made to improve reporting. Improvements in training persons who complete the birth certificate are especially needed. Reporting of checkbox items also needs to be validated by comparing results with other sources. In future revisions of the birth certificate, new items need to be examined carefully to determine if that instrument is the appropriate medium for collecting the information. PMID- 7838946 TI - Descriptive epidemiology of animal bites in Indiana, 1990-92--a rationale for intervention. AB - Animal bites are a reality of life throughout the world. They arise out of an imperfect relationship with domestic animals and wildlife. Most bite injuries are preventable. The principal approaches to community-wide bite prevention programs include reducing the number of domestic animals roaming in the community (animal control) and teaching people to refrain from behaviors likely to provoke bites. This article addresses the epidemiologic basis and justification for a bite prevention program targeted toward children. Animal bite data from Indiana for the years 1990, 1991, and 1992 were analyzed for trends that might suggest opportunities for preventive intervention. Bites inflicted by humans were not included in this data base. Children of all age groups were disproportionately affected, with the highest incidence in the 5-9 year age group. The dog and the cat were the most commonly reported biting animals. Wild and pet rodents were the next most frequent biting group. The bites most frequently reported from nonrodent wild animals were inflicted by raccoons. The incidence of animal bites in children peaked during the spring (April-June). Boys were bitten at a higher rate than girls, but this difference between the sexes narrows with age and was not noted in the adult population. Residents of urban counties (population greater than 100,000) had higher reported bite rates than residents of nonurban counties. PMID- 7838947 TI - 5 A Day for better health--nine community research projects to increase fruit and vegetable consumption. AB - One of the national objectives in "Healthy People 2000" is for members of the public to increase their consumption of fruits and vegetables to five or more servings daily. The National Cancer Institute (NCI) began a nationwide campaign to achieve this objective in 1991. As part of this campaign, the NCI funded nine research studies in 1993. These projects are implementing and evaluating community-based programs designed to increase fruit and vegetable consumption among different segments of the population in Alabama, Arizona, Georgia, Louisiana, Maryland, Massachusetts, Minnesota, North Carolina, and Washington. The settings for these projects include the Special Supplement Food Program for Women, Infants, and Children (WIC Programs), churches, worksites, and schools. The projects are led by multidisciplinary teams and entail extensive collaboration among academic, governmental, private sector, and voluntary agencies within each State. The projects represent a model public health paradigm for conducting this type of research. PMID- 7838948 TI - Comparison of costs to the health sector of comprehensive and episodic health care for sickle cell disease patients. AB - Of 391 patients with sickle cell disease known to the health care facilities of the University of South Alabama, 194 patients used these facilities in 1989. In that year, 33.5 percent of patients seen at the University of South Alabama did not attend the Comprehensive Health Care Clinics developed for sickle cell patients. There were major differences in the patterns of use and in health care costs among sickle cell patients who attended the Comprehensive Health Care Clinics and those who did not. Patients not using these clinics, although they accounted for only 33.5 percent of the total patients, constituted 71.4 percent of visits to the emergency rooms and 42.3 percent of inpatient admissions. Patients enrolled in the Comprehensive Health Care Clinics used emergency rooms and inpatient units less frequently (P < 0.0001 and P = 0.0006, respectively) and were responsible for significantly smaller health care costs in each category (P < 0.0300). Evaluation of factors responsible for differences in the use patterns and patient education to improve use of comprehensive health care services should be considered. PMID- 7838949 TI - Cardiovascular disease in Navajo Indians with type 2 diabetes. AB - Rates of both type 2 diabetes and cardiovascular disease have risen sharply in recent years among Navajo Indians, the largest reservation-based American Indian tribe, but the association between the two conditions is not entirely clear. Rates of cardiovascular disease and some possible associations in several hundred diabetic and non-diabetic Navajos were estimated. Nearly one-third (30.9 percent) of those with diabetes had formal diagnoses of cardiovascular disease--25.3 percent had heart disease, 4.4 percent had cerebrovascular disease, and 4.1 percent had peripheral vascular disease. (The percentages exceed the total because some people had more than one diagnosis. Age-adjusted rates were 5.2 times those of nondiabetics for heart disease, 10.2 times for cerebrovascular disease, and 6.8 times for peripheral vascular disease. Accentuation of risk was most marked in young diabetics and in female diabetics. Hypertensive diabetics had a twofold increase in heart disease and more than a fivefold increase in cerebral and peripheral vascular disease over nonhypertensive diabetics. Age, blood pressure, cholesterol levels, and albumenuria were independent risk factors for cardiovascular disease. Triglyceride levels or body weight were not. Male sex and diabetes duration were independent risk factors for cerebral and peripheral vascular disease but not for heart disease. In view of the impressive segregation of cardiovascular disease in the diabetic Navajo population, the prevention of diabetes through population-based health promotion seems basic to its containment. Over the short term, vigorous treatment of hypertension in subjects who are already diabetic is mandatory. PMID- 7838950 TI - PHS mission to Goma, Zaire. PMID- 7838952 TI - Chromosome aberrations produced by radiation: the relationship between excess acentric fragments and dicentrics. AB - Most chromosome aberrations produced by ionizing radiation develop from DNA double-strand breaks (DSBs). Published data on the yield and variance of excess acentric fragments after in vitro irradiation of human lymphocytes were compared with corresponding data on dicentrics. At low LET the number of excess acentric fragments is about 60% of the number of dicentrics, independent of dose and perhaps of dose rate, suggesting that dicentrics and excess acentric fragments arise from similar kinetics rather than from fundamentally different reactions. Only a weak dependence of the ratio on LET is observed. These results are quantified using generalizations of models for pairwise DSB interactions suggested by Brewen and Brock based on data for marsupial cells. By allowing singly incomplete and some "doubly incomplete" exchanges, the models can also account for the experimental observation that the dispersion for excess acentric fragments, a measure of cell-to-cell variance, is systematically larger than the dispersion for dicentrics. Numerical estimates of an incompleteness parameter are derived. PMID- 7838951 TI - Elevated frequency of glycophorin A mutations in erythrocytes from Chernobyl accident victims. AB - In 1986, when an explosion accident occurred at the Chernobyl, Ukraine nuclear power plant, a large number of people were exposed to significant amounts of ionizing radiation. During the time between 1986 and 1992, peripheral blood samples were obtained from 102 people who either were on site during the emergency or were brought to Chernobyl shortly thereafter to assist in the cleanup of radioactive contaminants and isolate the damaged reactor from the environment. These blood samples plus samples from 13 unexposed Soviet individuals were analyzed by flow cytometry using the allele-loss somatic mutation assay for glycophorin A. Results of these assays show that the frequency of N/O variant red cells increased in proportion to the estimated radiation exposure of each individual. The radiation dose-response function derived from this population closely resembles that determined previously for atomic bomb survivors whose blood samples were obtained and analyzed 40 years after their exposure. This suggests comparable mutation induction per unit dose for these two populations and long-term persistence of the mutational damage. In addition, measurements on multiple blood samples from each of 10 donors taken over a 7-year period showed no significant changes in N/O variant cell frequencies, confirming the persistence of radiation-induced somatic mutations in long-lived bone marrow stem cells. PMID- 7838953 TI - Induction of DNA double-strand breaks by restriction enzymes in X-ray-sensitive mutant Chinese hamster ovary cells measured by pulsed-field gel electrophoresis. AB - This investigation was designed to determine whether the cytotoxic effects of different restriction endonucleases are related to the number and type of DNA double-strand breaks (DSBs) they produce. Chinese hamster ovary (CHO) K1 and xrs 5 cells, a radiosensitive mutant of CHO K1, were exposed to restriction endonucleases HaeIII, HinfI, PvuII and BamHI by electroporation. These enzymes represent both blunt and sticky end cutters with differing recognition sequence lengths. The number of DSBs was measured by pulsed-field gel electrophoresis (PFGE). Two forms of PFGE were employed: asymmetric field-inversion gel electrophoresis (AFIGE) for measuring the kinetics of DNA breaks by enzyme digestion and clamped homogeneous gel electrophoresis (CHEF) for examining the size distributions of damaged DNA. The amount of DNA damage induced by exposure to all four restriction enzymes was significantly greater in xrs-5 compared to CHO K1 cells, consistent with the reported DSB repair deficiency in these cells. Since restriction endonucleases produce DSBs alone as opposed to the various types of DNA damage induced by X rays, these results confirm that the repair defect in this mutant involves the rejoining of DSBs. Although the cutting frequency was directly related to the length of the recognition sequence for four restriction enzymes, there was no simple correlation between the cytotoxic effect and the amount of DNA damage produced by each enzyme in either cell line. This finding suggests that the type or nature of the cutting sequence itself may play a role in restriction enzyme-induced cell killing. PMID- 7838954 TI - The elimination of low-dose hypersensitivity in Chinese hamster V79-379A cells by pretreatment with X rays or hydrogen peroxide. AB - To explain increased radioresistance over the X-ray dose range approximately 0.5 1 Gy an inducible radioprotective mechanism triggered by DNA damage was proposed; hypersensitivity to doses << 0.5 Gy reflected the response prior to the activation of this system (Marples and Joiner, Radiat. Res. 133, 41-51, 1993). To test this hypothesis, cells were pre-exposed to DNA-damaging agents in an attempt to induce the process prematurely. An increase in survival was evident at X-ray doses below 0.3 Gy after a priming treatment of X rays (0.05, 0.2, 1 Gy) given 6 h earlier. The protective effect was found to be transitory, requiring time for development and diminishing after two to three cell cycle times. Cycloheximide administered in the interval between the priming and challenge doses of X rays abolished the protection conferred by pretreatment, indicating the involvement of de novo protein synthesis. Oxidative damage by nontoxic doses of hydrogen peroxide (10(-4) M, but not 10(-6) M) also produced a protective effect against subsequent X irradiation. These experiments indicate survival in the hyper radiosensitive region (<< 0.5 Gy) can be modified by pretreatment with agents known to affect DNA repair. In addition, the development of increased radioresistance after single doses of X rays was inhibited by cycloheximide treatment. These studies provide evidence to support the explanations proposed previously for the phenomena of increased radioresistance and hyper radiosensitivity observed at very low X-ray doses. PMID- 7838955 TI - Effect of caffeine on radiation-induced apoptosis in TK6 cells. AB - Apoptosis has been measured in cells of the human TK6 lymphoblastoid cell line by recording the release of endonuclease-digested DNA from affected cells using flow cytometry. In asynchronously dividing cells, DNA degradation characteristic of apoptosis was first seen 12 h after irradiation as a defined DNA fluorescent peak of sub-G1-phase content, reaching a maximum of 30-50% of the population by 24-72 h. Treating cells with 2 mM caffeine either before or up to 3 h after irradiation eliminated the degradation of DNA entirely. In addition, the percentage of cells in which apoptosis could be detected microscopically decreased from 62.4 +/- 0.95% to 16.7 +/- 1.5% 72 h after caffeine treatment. Delaying caffeine treatment for 12 h after irradiation reduced DNA degradation by approximately 50% compared to cells receiving radiation alone. DNA degradation induced by serum deprivation was unaffected by caffeine treatment. These data support the contention that irradiation of TK6 cells produces a long-lived cellular signal which triggers apoptosis. Apoptosis produced by serum deprivation does not operate through the same pathway. PMID- 7838957 TI - Low-LET and high-LET radiation action of 125I decays in DNA: effect of cysteamine on micronucleus formation and cell killing. AB - Chinese hamster ovary cells were pulse-labeled with 125I-iododeoxyuridine during early S phase, and cell samples were harvested 30 min or 5 h after labeling. The samples were frozen (with or without 25 mM cysteamine) and stored at -196 degrees C for accumulation of 125I decays. X-ray control experiments were performed at 37 degrees C and -196 degrees C. Aliquots of cells were plated for evaluating micronucleus formation and cell survival. The results demonstrated a striking shift in micronucleus formation and cell death with time after labeling. Cells frozen 30 min after labeling exhibited effects typical of low-LET radiation, but cells frozen 5 h after labeling showed a response characteristic of high-LET radiation. Cysteamine provided protection against the effects of 125I during the initial phase of effects characteristic of low-LET radiation, but no protection was seen during the phase characteristic of high-LET radiation. When cell survival was evaluated as a function of micronucleus frequency rather than dose in decays/cell, the survival curves for all treatment groups became superimposed. Previous work using the same experimental system had failed to show a direct link between 125I-induced DNA double-strand breaks and cell death. These findings are consistent with the hypothesis that DNA damage may not be the sole mechanism for cell killing and that damage to higher-order structures in the cell nucleus may contribute to (or modify) radiation-induced cell death. PMID- 7838956 TI - The role of secretory granules in radiation-induced dysfunction of rat salivary glands. AB - To investigate the possible role of secretory granules in radiation-induced salivary gland dysfunction, rats were pretreated with isoproterenol (5 mg/kg intraperitoneally) to degranulate salivary gland acini. At maximal depletion, salivary glands were locally irradiated with a single dose of 15 Gy of X rays. Parotid and submandibular/sublingual saliva samples were collected before and 1 10 days after irradiation. The lag phase, flow rate, concentrations of potassium and sodium, and amylase secretion were determined. Sham-treated, isoproterenol treated and irradiated animals provided reference data. In the parotid gland, but not in the submandibular gland, protection against radiation-induced changes in flow rate and composition of saliva occurred after pretreatment with isoproterenol. Combining morphological data from a previous study with data from the current study, it is suggested that improvement of parotid gland function is attributed predominantly to a proliferative stimulus on acinar cells by isoproterenol and not to its degranulation effect. After pretreatment with isoproterenol, an earlier expression of radiation-induced acinar cell damage leading to death was observed, followed by a faster tissue recovery. Thus the proliferative stimulus on acinar cells may accelerate the unmasking of latent lethal damage, resulting in the earlier replacement of dead cells by new, functionally intact cells. PMID- 7838958 TI - The effects of indium-111 decay on pBR322 DNA. AB - We have compared the effectiveness in causing DNA strand breaks of 111In bound to DNA or free in aqueous solution with that of gamma rays. Supercoiled DNA from pBR322 plasmid labeled with [3H]thymidine was purified and mixed with 111InCl3 in the absence or presence of diethylenetriaminepentaacetic dianhydride (DTPA), a metal chelator which prevents the binding of indium to DNA. The reaction mixtures were stored at 4 degrees C to accumulate radiation dose from the decay of 111In. The DNA was then resolved by gel electrophoresis into supercoiled, nicked circular and linear forms, representing undamaged DNA, single-strand breaks (SSBs) and double-strand breaks (DSBs), respectively. The D0 values of pBR322 DNA exposed to gamma radiation from an external 137Cs source and the decay of 111In dispersed in solution (+DTPA) are 3.1 +/- 0.1 and 2.8 +/- 0.1 Gy, respectively. In terms of accumulated 111In disintegrations cm-3 of plasmid DNA solution, the D0 value is 15.3 (+/- 0.7) x 10(10) disintegrations in the absence of DTPA and 38.2 (+/- 1.1) x 10(10) disintegrations in its presence. Since only 14.6 +/- 5% of the 111In was bound to DNA in the absence of DTPA, an effective D0 for bound 111In of 3.4 (+/- 1.1) x 10(10) disintegrations is obtained. The 11-fold (range 9 to 17-fold) increased effectiveness of this Auger electron emitter when in proximity to DNA appears to be due mainly to the higher yield of SSBs. PMID- 7838959 TI - Interpretation of mutation induction by accelerated heavy ions in bacteria. AB - In this report, a quantitative interpretation of mutation induction cross sections by heavy charged particles in bacterial cells is presented. The approach is based on the calculation of the fraction of energy deposited by indirect hits in the sensitive structure. In these events the particle does not pass through the sensitive volume, but this region is hit by delta rays. Four track structure models, developed by Katz (in Quantitative Mathematical Models in Radiation Biology, pp. 57-83, Springer-Verlag, 1988). Chatterjee et al. (Radiat. Res. 54, 479-494, 1973), Kiefer and Straaten (Phys. Med. Biol. 31, 1201-1209, 1982) and Kudryashov et al. (Proceedings of the First Soviet Congress on Microdosimetry, Atomizdat, Moscow, 1973), respectively, were used for the calculations. With the latter two models, very good agreement of the calculations with experimental results on mutagenesis in bacteria was obtained. Depending on the linear energy transfer (LET infinity) of the particles, two different modes of mutagenic action of heavy ions are distinguished: "delta-ray mutagenesis," which is related to those radiation qualities that preferentially kill the cells in direct hits (LET infinity > or = 100 keV/microns), and "track core mutagenesis," which arises from direct hits and is observed for lighter ions or ions with high energy (LET infinity < or = 100 keV/microns). PMID- 7838960 TI - Electron energy-loss distributions in solid, dry DNA. AB - Experimentally derived optical constants and X-ray attenuation cross sections were used to construct the complete dipole oscillator strength distribution for solid, dry DNA. Monte Carlo simulations of the energy loss by electrons of initial energy 5 keV to 1 MeV in DNA were performed using cumulative inelastic cross sections obtained from a formulation incorporating the constructed dipole oscillator strength distribution. The energy-loss distribution, the most probable energy loss and the mean energy loss for electrons in DNA are compared to those for liquid water, gaseous water and gaseous hexane. For the most part, the calculations show that electron energy loss in DNA is very similar to that in liquid water; however, it is quite different from both gaseous water and gaseous hexane. The mean energy losses for a 1 MeV incident electron in DNA, liquid water, gaseous water and gaseous hexane are 57.9, 56.8, 50.9 and 38.4 eV, respectively. The large differences found between the predictions for DNA and for the gaseous media bring into serious question calculations of radiation-induced damage in DNA which make use of cross sections for gaseous media. Stopping powers and continuous-slowing-down approximation ranges for the media for electrons are also presented. PMID- 7838961 TI - Killing of hypoxic cells by lowering the intracellular pH in combination with hyperthermia. AB - The acidic intracellular environment or low intracellular pH (pHi) increases the thermosensitivity of mammalian cells. The cells in a hypoxic environment produce a greater amount of acidic metabolites than those in an oxygenated environment. However, the hypoxic cells are not more thermosensitive than oxygenated cells since the decrease in pHi is minimized by the mechanisms that regulate the pHi such as Na+/H+ antiport. We hypothesized, therefore, that blocking the regulation of pHi might greatly reduce the pHi and increase the thermosensitivity of hypoxic cells. We tested our hypothesis by heating SCK tumor cells under oxygenated and hypoxic conditions in pH 7.5 or 6.6 medium with or without amiloride, an inhibitor of Na+/H+ antiport. We observed that amiloride increased the thermosensitivity of hypoxic cells markedly. Such a thermosensitization of hypoxic cells by amiloride was more pronounced in an acidic environment, with an enhancement ratio of 1.5, than in a neutral environment, with an enhancement ratio of 1.5. We concluded that lowering the pHi by blocking the regulation of pHi in combination with hyperthermia may be a useful way to eliminate the radioresistant hypoxic cells. PMID- 7838962 TI - Impact of time between X-ray fractions on acute changes in the function of the urinary bladder in the mouse. AB - Noninvasive transurethral cystometry was used in mice anesthetized with pentobarbitone to quantify the effect of the interval between X-ray fractions on acute radiation-induced changes in the function of the urinary bladder. Bladder capacity was defined at intravesical pressures of 10 and 20 mm Hg. A reduction in the storage capacity of the bladder by > or = 50% of the individual preirradiation control value, occurring at any time during the initial 30 days after radiotherapy, was the quantal end point used for dose-response analysis. Four equal-sized dose fractions were applied with intervals of 0, 0.5, 1, 1.5, 2, 4 and 8 h, respectively. The ED50 values increased from 18.2 Gy (95% confidence interval 16.8-20.6) for single-dose treatment to 28.1 Gy (26.2-29.9) in the 8-h protocol. Linear-quadratic analysis of the results, using an indirect repair model and the direct analysis approach, yielded a half-time of repair of 1.2 h (0.9-1.9) with an alpha/beta ratio of 10.4 Gy. If combined with previous data for split doses where 1 to 10 fractions were given within < or = 7 days (Dorr and Schultz-Hector, Radiat. Res. 131, 35-42, 1992), an even longer repair half-time of 1.7 h (1.3-2.7) was determined. PMID- 7838963 TI - Deoxyspergualin is a new radioprotector in mice. AB - A novel immunosuppressant, deoxyspergualin, given at doses of 2.5 to 20 mg/kg/day on days -3, -2 and -1 before X irradiation protected BALB/c mice from the lethal effects of radiation in a dose-dependent manner. The dose of radiation that killed 50% of the mice within 30 days was 5.63 Gy for mice receiving radiation alone, but was 7.13 Gy in the mice given deoxyspergualin at 20 mg/kg. Prior administration of deoxyspergualin ameliorated leukopenia and thrombocytopenia induced by sublethal irradiation, and significantly increased the number of femoral spleen colony-forming units (CFU-S) that survived irradiation. Deoxyspergualin also reduced the proportion of CFU-S in S phase, as determined by in vitro sensitivity to hydroxyurea. These findings suggest that deoxyspergualin may be effective in the prevention of hematopoietic injury caused by radiotherapy. PMID- 7838965 TI - The variation of beta with radiation quality in the alpha/beta model. PMID- 7838964 TI - Comments on "Quantification of radiation-induced hydroxyl radicals within nucleohistones using a molecular fluorescent probe" by Makrigiorgos et al. (Radiat. Res. 138, 177-185, 1994) PMID- 7838966 TI - "Patient endangerment" remark--termination: free speech. PMID- 7838967 TI - Pregnant nurse refuses to care for AIDS patient: termination. Case in point: Armstrong v. Flowers Hosp., Inc. 33 F. 3d 1308--AL (1994). PMID- 7838968 TI - Legal case briefs for nurses. CO: nurse fails to pass qualification tests: age discrimination against hospital alleged; TX: hernia pt. dies--ischemic brain damage: expert testimony re substandard care. PMID- 7838969 TI - Nurse treating AIDS patient sues: "Discovery Rule". Case in point: Casarez v. NME hospitals, Inc. 883 S.W. 2d 360--TX (1994). PMID- 7838970 TI - Family health coverage denied: nurse sues under ADA. PMID- 7838971 TI - Nursing records "missing": spoilation of evidence. Case in point: Sweet v. Sisters of Providence in Wash. 881 P. 2d 304--AK (1994). PMID- 7838972 TI - Legal case briefs for nurses. PA: nursing asst. injured in employer's vehicle: workers' compensation coverage issue; AL: failure to "strip search" psychiatric pt.: liability for suicide by hidden gun. PMID- 7838973 TI - Failure to file suit timely: doctrine of Contra Non Valentem. Case in point: Wimberly v. Schumpert Med. Center 641 So. 2d 1016--LA (1994). PMID- 7838974 TI - Study of Bacillus sp. culture conditions to promote production of unhairing proteases. AB - The substitution of chemical depilatory agents in the leather industry by proteolytic enzymes produced by Bacillus species has an important economical and environmental impact. In previous assays, a Bacillus sp. showing a promising depilatory activity was isolated. In this paper, a culture medium that stimulated the synthesis and segregation of depilatory proteases, was selected. The influence of pH, oxygen supply rate (KLaC*), and inoculum age was evaluated on cell growth and protease production. Assays were carried out in lab bioreactors (1.2-1.4 l) at 37 degrees C. Five different media that differed in carbon and nitrogen sources were tested. pH ranged from 4.0 to 8.5. KLaC* varied between 40 and 470 mmol/lh. The best medium culture for protease production contained: nutrient broth (Britania) 8 g/l, yeast extract (Britania) 3 g/l, and mineral salts. Protease production was more effective at pH of 6.7, KLaC* of 360 mmol/lh, and inoculum age of 12 hours. These experimental conditions led to the following results: maximum proteolytic activity 2700 U/ml, overall volumetric protease productivity 300 u/ml-h, average specific growth rate 0.62 h-1, and average specific protease production rate 2.50 x 10(5) U/gh. PMID- 7838975 TI - [Storage of hydrocarbon-degrading bacteria]. AB - The storage in the laboratory of hydrocarbon degrading bacteria to be used in the decontamination of polluted sites or in the enhancement of biological treatment of industrial effluents was studied. Storage was carried out at 4 degrees C in nutrient agar and in a medium with selection pressure, liquid mineral medium with hydrocarbons. Storage at 4 degrees C with selection pressure and storage at -20 degrees C of 7 gram negative bacilli were compared. The former was the easiest method for preserving the greatest number of strains viable and active. PMID- 7838976 TI - [Recovery of Staphylococcus aureus after acid injury in milk products]. AB - The growth behavior of Staphylococcus aureus in fresh Cheese (Minas and Muzzarella) during their shelf-life was studied. The possible injury of this microorganism caused by the increasing acidity was also investigated. Raw milk was inoculated with 10(6) cells/ml (S. aureus FRIA-100) and the cheese production was performed according to normal procedures. Minas and muzzarella cheese were stored at 7 degrees C for 40 and 60 days, respectively. At 2-3 days intervals, the following analysis were performed: acidity, pH, S. aureus counting using agar Baird Parker by the traditional methods and by the method recommended by the American Public Health Association to evaluate the reparation of injured cells. We had a secure indication of the presence of injured S. aureus when acidity was in the range of 0.7 to 0.8% expressed in lactic acid and when the cycle was 1.3 log higher than the traditional one. PMID- 7838977 TI - [Bacterial leaf blight affecting Syngonium podophyllum in Argentina]. AB - Bacterial leaf blight of Syngonium podophyllum caused by Xanthomonas campestris pv. syngonii is recorded for the first time in Argentina. The first symptom of the disease was an interveinal watersoaking of leaves, the tissues became chlorotic and finally necrotic over areas of about 4 cm. The identification of the causal microorganism was based on disease symptoms, morphological, physiological and biochemical characteristics and pathogenicity test. PMID- 7838978 TI - [Presentation of salmonellosis in the Tandil district, Argentina]. AB - From January 1990 to July 1992 a prospective study on the salmonellosis form of presentation, reservoirs and transmission in Tandil was carried out. Forty strains of Salmonella enterica were isolated with the following distribution: 28 humans (17 children and 11 adults), 6 in foods (1 in raw milk, 3 in well water, 1 in home made mayonnaise and 1 in chicken salad) and 6 in animals (1 in cow, 2 in chicken and 2 in calves). Salmonella Enteritidis was the most frequent isolate. Disease was evident only in a few susceptible hosts and the epidemiological chain could not be determined in all the cases. PMID- 7838979 TI - [Biological safety in dentistry: development of a useful method for quality control of sterilization]. AB - 534 autoclaves from Rosario dentist offices were controlled by a method developed in our laboratory, that consists in: a) a procedures instruction; b) a survey ; c) a colorimetric control; d) a biological control. By this method it is possible to detect the mistake in the autoclave function by only one step. The results showed that 86.90% of the autoclaves lacked thermometers, 76.60% lacked manual thermostats, 83.33% were automatic and 58.80% did not sterilize. It can be concluded the necessity of a periodic control by this method, the importance of a commercial quality control of the furnaces and the urgency of continuous education over biosafety concepts. PMID- 7838981 TI - Enrolled nursing--the future in education. PMID- 7838980 TI - [Bioassays with entomopathogenic bacteria]. PMID- 7838982 TI - Cheryl Dorron in the USA. Interview by John Moran. PMID- 7838983 TI - Good ideas for enrolled nurses. PMID- 7838984 TI - Noise study. PMID- 7838986 TI - Enrolled nurses--building the profile. PMID- 7838985 TI - Public hospital staffing. PMID- 7838987 TI - In vivo tissue dosimetry as a basis for cross-species extrapolation in cancer risk assessment of propylene oxide. AB - The potential for causing carcinogenic and mutagenic effects has been the main concern when assessing the risks associated with low-level exposures of humans to the industrially important epoxide, propylene oxide (PrO). For regulatory purposes, surface-based extrapolation has been used to determine the human equivalent dose from cancer data obtained in rodents. In this context the tissue dose will more adequately reflect inter- and intraspecies differences with respect to pharmacokinetic parameters than is the case for conventional representations of exposure. The formation of adducts in nucleophilic molecular targets by directly acting electrophilic agents, like epoxides, is thought to be closely linked to the process of cancer initiation. To investigate whether tissue dose is correlated to surface area of the exposed organism, the in vivo adduct levels in hemoglobin and DNA have been determined in mice, rats, and dogs after exposure to PrO by injection as well as by inhalation. The results obtained indicate that the dose in blood is virtually the same in the three investigated animal species, whereas surface-area based extrapolation predicts a difference by a factor of about seven between the mouse and the dog. Although the data base is more limited, this conclusion is also supported by measurements of DNA alkylation is selected tissues. The variations actually observed are not related to the surface area of the animal. No significant differences could be found between administration of PrO by injection or by inhalation. For this reason, the surface based extrapolation model for estimation of the human equivalent dose is not appropriate, and the carcinogenic potency factors for PrO as previously derived by the U.S. EPA should probably be revised downward by a factor of 10 to 13. PMID- 7838989 TI - The scientific fallacy of route specificity of carcinogenesis with particular reference to cadmium. PMID- 7838988 TI - Postmarketing surveillance of food additives. AB - Postmarketing surveillance of consumption and of anecdotal reports of adverse health effects has been recognized by a number of regulatory authorities as a potentially useful method to provide further assurance of the safety of new food additives. Surveillance of consumption is used to estimate more reliably actual consumption levels relative to the acceptable daily intake of a food additive. Surveillance of anecdotal reports of adverse health effects is used to determine the presence of infrequent idiosyncratic responses that may not be predictable from premarket evaluations. The high-intensity sweetner, aspartame, is a food additive that has been the subject of extensive evaluation during the postmarketing period and is thus used as an example to discuss postmarketing surveillance. PMID- 7838990 TI - Use of probabilistic expert judgment in uncertainty analysis of carcinogenic potency. AB - A new approach to characterizing the state of knowledge about carcinogenic potency is described. In this approach, the carcinogenic risk posed by a specific dose is characterized by a probability distribution, indicating the relative likelihood of different risk estimates. The approach utilizes expert judgment and a probability tree and is illustrated in a case study of chloroform exposure. Experts in cancer biology/toxicology, pharmacokinetics, and dose-response modeling were identified by a panel of science-policy specialists. In a workshop, experts reviewed the chloroform data, received training in probability elicitation, and constructed a consensual probability tree based on biological theories of cancer causation. Distributions of carcinogenic risk were developed based on the probability tree, chloroform data, judgmental probabilities provided by the experts, and classical statistical techniques. Risk distributions varied considerably between experts, with some predicting essentially no risk from 100 ppb chloroform in drinking water while other have at least some probability on risks generally considered of regulatory significance. Estimated human risk was much lower when extrapolating from liver tumors in animals than from kidney tumors. Issues of scientific disagreement leading to different risk distributions between experts are discussed. The resulting risk distributions are compared to standard EPA risk calculations for the same exposure scenario as well as to the expert judgement of epidemiologists about cancer risks of chlorinated drinking water. Issues in combining expert judgments are discussed, and several alternative methods are presented. Strengths and weaknesses of the distributional approach are discussed. PMID- 7838991 TI - Characterization and toxicological behavior of synthetic amorphous hydrophobic silica. AB - During almost three decades of experience with hydrophobic silicas, no adverse health effects have been observed in manufacturing and applications with appropriate handling of the materials. The oral LD50 for rodents is > 7.9 g/kg body wt. Fumed or precipitated hydrophobic silicas do not produce inflammation of the skin or mucous membranes. Likewise, acute and chronic oral tests yielded no adverse systemic effects. A limited carcinogenesis study in rats did not induce tumors and the Ames test of a toluene extract was negative. Reproductive or developmental toxicity was not observed. In general, hydrophobic silicas provide a toxicological profile essentially the same as common silicas. PMID- 7838992 TI - Estimation of a chromium inhalation reference concentration using the benchmark dose method: a case study. AB - The benchmark dose (BD) method has been proposed as an alternative to the NOAEL/UF method for setting reference levels. The BD is the 95% lower confidence limit on a dose corresponding to a 10% increase (or relative change) in an adverse effect. A case study exploring the suitability of the current Cr(III) and Cr(VI) inhalation toxicity data bases to the BD approach is presented. Because chromic acid mists, typical of many occupational Cr(VI) exposures, present a toxicological profile different from that of Cr(VI) particulates, representative of environmental exposures, Cr(VI) particulate data were evaluated separately from Cr(VI) acidic mist data. The current Cr(III) and Cr(VI) acidic mist data bases proved inadequate for BD analysis due to data and/or study quality limitations. Benchmark reference concentrations (RfCs) for particulate Cr(VI) ranging from 0.34 microgram/m3 (for lactate dehydrogenase (LDH) in bronchoalveolar lavage fluid (BALF)) to 1.4 micrograms/m3 (for increased lung weights) are derived from data taken from U. Glaser et al. (Arch. Toxicol. 57, 250-256, 1985) and U. Glaser et al. (Environmental Hygiene II, Springer-Verlag, Berlin/New York, 1990). A Cr(VI) particulate RfC of 0.34 microgram/m3 based upon LDH in BALF as the critical effect is proposed. This value may be viewed as conservative since it represents the 95% lower confidence limit on the dose associated with a 10% increase in response for a sensitive endpoint and has appropriate dosimetric adjustments and uncertainty factors incorporated. PMID- 7838993 TI - Differences in indirect risk methodologies: dioxin emissions from combustion facilities. AB - Guidance for performing indirect risk evaluations is in a state of flux; yet, EPA and the public are insisting that estimates of indirect risks associated with combustion of industrial wastes must be derived. Two different guidance documents exist for estimating these risks: one that focuses on dioxin exposures and one that has a more general application. This paper evaluates the differences in indirect risk estimates derived from methodologies presented in these two documents and discusses those assumptions that may contribute to these differences. The influence of an individual exposure pathway on indirect risk estimates varies depending on the methodology applied. Indirect risk estimates differ by 30-fold for the same exposure pathway when comparing these methodologies. Assumptions about vapor uptake, food consumption rates, and the fraction of local food consumption appear to drive final estimates. A major discrepancy between these two documents is differences in assumptions about soil dermal contact for children. Many EPA default assumptions and values are extremely conservative and often unrealistic; therefore, use of site-specific data will be essential when estimating indirect risks associated with combustor emissions. Also, application of a toxic equivalency approach may have some benefit; risk estimates are reduced 16- to 18-fold using this approach. PMID- 7838994 TI - The intake of chemicals related to age in long-term toxicity studies- considerations for risk assessment. AB - The estimation of acceptable daily intake (ADI) is generally based on results from long-term toxicity studies. Long-term exposure of rodent and nonrodent species is extrapolated to lifetime exposure in humans, using uncertainty factors to compensate inter- and intraspecies differences. Special consideration can be given to groups of humans at increased risk, such as children, due to higher susceptibility or higher predicted intake. A retrospective study of long-term carcinogenesis studies was performed at the National Toxicology Program of the National Institute of Environmental Health Sciences to gain insight into the relationship between age and intake of test compounds. In these long-term studies, average intake of feed and drinking water, and consequently chemicals dosed in these, was approximately two times higher on a body weight basis in young animals (postweaning) than in adults. Thus, estimating an ADI from the NOEL of this type of studies already includes a higher dose for the young. When maximum levels for food additives are being set using the already established ADI, it may not be necessary to add an additional uncertainty factor for different ages, unless there are other specific reasons to do so, such as unduly high exposure and toxicity at a certain age. Compared to intake per kilogram of body weight at the end of the study, the ADI already includes an extra uncertainty factor of approximately 2 for young individuals. PMID- 7838995 TI - [Rest in peace, teacher and friend. John J. Bonica]. PMID- 7838996 TI - [Characterization of propofol binding to plasma proteins and possible interactions]. AB - OBJECTIVES: a) To study the binding of propofol to proteins in plasma samples from healthy volunteers and in solutions of albumin and alpha 1-acid glycoprotein (AGA); b) to describe the nature of the bond and possible interactions with other substances that are potential displacers: salicylate, phenylbutazone, sulfisoxazole, tolbutamide, sodium valproate, sodium oleate and penbutolol; c) to assess the effect of propofol on the binding of specific markers and possible binding sites in the following proteins: 14C-warfarin, 3H-diazepam, 3H-midazolam, 3H-imidazole, 3H-penbutolol and 3H-morphine. MATERIAL AND METHODS: The free fraction was obtained in all samples by ultrafiltration and measurement of the free concentration of propofol by liquid chromatography and of the markers by scintillation spectrometry. RESULTS: The free fraction of propofol in plasma was 0.98 +/- 0.12% and binding was not saturable. Albumin seems to play an important role (95% bound), whereas the participation of AGA was low (54% bound). Propofol did not affect the binding of any of the markers studied. Nor did the presence of other drugs at therapeutic plasma concentrations affect the binding of propofol. CONCLUSIONS: The binding of propofol to plasma proteins seems unlikely to cause drug interactions in clinical practice. PMID- 7838997 TI - [Amitriptyline facilitates the analgesic effect of adrenal medulla autograft in the lumbar subarachnoid space of the rat]. AB - OBJECTIVES: To investigate the possible enhancement of analgesic effect induced by treatment with amitriptyline (AMI) after the autografting of suprarenal medulla into the subarachnoid lumbar space in the rat. MATERIAL AND METHODS: Four experimental groups were formed (control + saline solution [SS]; control + AMI; transplant + SS and transplant + AMI). AMI (10 mg/kg i.p.) or SS was administered for 28 days after surgery. The tail-flick test, with baseline values taken before surgery, was used to measure threshold pain on days 1, 4, 7, 14, 21 and 28. RESULTS: Suprarenal medullae transplantation afforded evident analgesic effect from day 1 to day 28. Analgesic effect was enhanced in transplanted rats treated with AMI from day 4 of treatment, with more evident effect on day 28. No analgesic effect per se was observed in the control group. CONCLUSIONS: Our results confirm that grafting per se has an analgesic effect and that it can be improved by systematic treatment with AMI. These results suggest new possibilities for using suprarenal medulla grafts for pain. PMID- 7838998 TI - [Analysis of induction with 5% isoflurane and 60% nitrous oxide in premedicated adults]. AB - OBJECTIVES: To analyze rapid inhalatory anesthetic induction in premedicated adults (fentanyl, droperidol, diazepam and atropine) with an inspired mixture of O2, N2O (60%) and 5% isoflurane as a means for accelerating induction time and reducing complications. PATIENTS AND METHODS: We studied a series of 35 adult ASA I patients at four times: baseline (1), premedication (2), induction (3) and postintubation (4). Measurements taken were arterial hemoglobin oxygen saturation (SpO2), arterial pressure (AP), heart rate (HR), end-tidal CO2 pressure (PETCO2) and respiratory frequency. We also recorded maximum end-tidal isoflurane pressure (FEtiso) at time 3; presence of apnea, cough and mask rejection at time 3; arrhythmia at times 3 and 4, and induction recall at time 3. Mean time of induction (time from start of induction to laryngoscopy) and the double product (HR x systolic AP) were calculated. RESULTS: Coughing was observed in 20% (7/35) and was significantly associated with smoking; mask rejection was observed in 5.71% (2/35). The lowest SpO2 measurements occurred during period 2 and the highest during 3 (98.2 +/- 0.76). The incidence of apnea (77.14%, 27/35) was high during period 3, with mean PETCO2 values (+/- SD) of 40.71 +/- 4.19 mmHg and mean maximal FEtiso values of 1.6 +/- 0.53%. Mean time of induction was 96.28 +/- 5.19 s. There were no cases of recalled induction of arrhythmia in periods 3 and 4. The highest levels of AP and HR were recorded during period 4. The only difference in AP and HR between periods 2 and 3 was in diastolic AP, which was higher (p < 0.05) in period 3. CONCLUSIONS: Rapid induction with 5% isoflurane is achieved within 1.5 min, with a 20% incidence of coughing and a 5% incidence of mask refusal. The high frequency of apnea (77%) is caused by the rapid elevation of alveolar isoflurane, which has an impact on the apneic threshold. Anesthetic induction with 5% isoflurane and 60% nitrous oxide in premedicated adults is accomplished with good maintenance of hemodynamic stability. However, tachycardia and arterial hypertension appear after laryngoscopy and tracheal intubation. PMID- 7839000 TI - [External laryngeal injuries. Study of 12 cases]. AB - Laryngeal trauma can cause severe, life-threatening damage in the upper respiratory tract. Management of trauma presents difficulties with respect to airway control and the procedural decisions are challenging. We studied 12 patients treated at our hospital after laryngeal trauma of various degrees of severity. Respiratory failure detected in some cases was critical from the moment of trauma, whereas other patients were asymptomatic at first but experienced progressive respiratory failure over the next few hours. We looked at the method applied to gain initial control of the upper airway and also considered the laryngeal lesions themselves, associated lesions and established treatment. We then looked for relationships between these and evolution and laryngeal sequelae 6 months after trauma. In agreement with other studies we found that the severity of sequelae depends on the severity of the lesion incurred and on how early treatment is established. The choice of whether to use orotracheal intubation or tracheotomy to control the upper airway was less important, as that decision would depend largely on severity of the lesion, although orotracheal intubation is recommended whenever possible. PMID- 7838999 TI - [Prevention of cross contamination, patient to anesthesia apparatus to patient, using filters]. AB - Concern for cross infections from patient to patient via apparatus is particularly relevant today. There are several ways to prevent patient contamination through anesthetic devices. Although there is no clinical evidence for using one alternative over another and each hospital establishes its own hygienic protocols, we have introduced the systematic use of filters with patients undergoing general anesthesia. We describe the features of filters available on the market and our protocol for their use. The efficacy of a filter depends on whether bacteria or viruses are to be controlled. Filters can be classified into three groups or generations based on mesh quality: 1) heat and humidity exchangers (HHE), with large mesh screens that allow water to pass through; 2) bacterial filters (FHHE), with finer mesh that is permeable to droplets of water and 3) folded membrane filters (FHHE) that are hydrophobic, with very fine mesh that stops water. We describe three basic physical tests (passage of water, passage of smoke and increase of resistance when applied to the patient) for filters to be classified. The ideal filter is hydrophobic and does not increase circuit resistance over the amount specified. Four principles are emphasized in the protocol: 1) the filter forms a part of the patient, not the apparatus; 2) proper placement of the filter is between the patient and the circuit's "Y" piece; 3) the main purpose of the filter is to prevent contamination of the apparatus, and 4) if a hydrophobic filter is used with each patient, the use of a disposable respiratory circuit is not called for. PMID- 7839001 TI - [Acute respiratory failure in chronic obstructive lung disease. Effective weaning and excess base]. AB - To establish whether the weaning from assisted mechanical ventilation (AMV) should be accompanied by continuous respiratory support (synchronized intermittent mandatory ventilation [SIMV]) or discontinuous support (O2 in T) in patients affected by chronic obstructive lung disease (COLD) who are recovering from acute respiratory failure (ARF), and also to identify any possible predictive value of gasometric measurements. Sixteen patients with COLD and ARF were studied prospectively during their stay in the intensive care unit. Ten had acute bronchitis, 3 had left ventricular failure and 2 had pneumonia. In 1 case the etiology was unknown. The following protocol was used for the first attempt at weaning: 1) SIMV for 30 min, 2) return to rest period with AMV for 2 hours, 3) O2 in T-tube for 30 min. After 30 min both SIMV and O2 in T had produced a rise in PaCO2 to 55.1 and 54.6 mmHg, respectively (p < 0.001), with a subsequent lowering of pH to 7.32 and 7.36 (p < 0.001). When weaning was well tolerated, pH decreased significantly due to an increase in PaCO2 with both techniques, while base excess (BE) remained stable. Values of pH also decreased significantly when weaning was poorly tolerated, and the fall was greater with SIMV; increases in PaCO2 were similar, but decreases in BE were significant. When pH is kept within normal range by a high BE, the withdrawal of AMV, accompanied by either support system, is usually well-tolerated. PMID- 7839002 TI - [Persistence of the left superior vena cava: apropos of an a-cyanogenic case]. PMID- 7839003 TI - [Raynaud's phenomenon and postoperative respiratory difficulty]. PMID- 7839004 TI - [The anesthesia polyclinic and risk prevention. A case of unheeded advice]. PMID- 7839005 TI - Characterization and structural localization of the reovirus lambda 3 protein. AB - The putative reovirus RNA polymerase, protein lambda 3, was characterized using antiserum prepared against a TrpE-lambda 3 fusion protein synthesized in Escherichia coli. Immunofluorescence microscopy showed that lambda 3 accumulated in perinuclear inclusion bodies in reovirus-infected cells. Analysis of lambda 3 accumulation in infected cells indicates that, once synthesized, lambda 3 is quite stable throughout the course of infection. Anti-lambda 3 serum did not immunoprecipitate virions, core particles or iodinated surface proteins of either virions or cores. These results indicate that lambda 3 is located in the inner part of the core. Experiments involving urea denaturation of purified reovirus cores indicate that lambda 3 cannot be selectively removed from the core without total denaturation of the core structure. When the dsRNA genome was eliminated from the core, lambda 3 remained associated with the other viral proteins in the core. Thus, lambda 3 appears to be a stable, structural component of the reovirus core, not bound to genomic dsRNA or free in soluble form inside the core. PMID- 7839006 TI - Polymerase-chain-reaction-based semi-quantification of hepatitis D viraemia in patients treated with high doses of alpha 2b interferon. AB - To study the antiviral efficacy of high doses of alpha 2b interferon (alpha 2b IFN) for chronic hepatitis D treatment, we used polymerase-chain-reaction(PCR) based semi-quantitative detection of HDV RNA. The semi-quantification method used was based on the appearance of a positive amplification signal as a function of the number of PCR cycles. By amplifying dilutions (10(-1)-10(-8)) of an HDV positive woodchuck liver RNA, we confirmed that exponential amplification efficacy occurred at between 20 and 30 cycles. Positive signals were observed from dilution 10(-2) (gel electrophoresis after 20 cycles of PCR) to dilution 10( 7) (hybridization after 30 cycles of PCR). To characterize the HDV RNA level in sera of 8 patients treated with alpha 2b-IFN (10 MU/3 times a week) for 1 year, we extracted RNA from serum samples taken every 6 months. All samples were amplified in parallel for 20 and 30 PCR cycles. Analysis of HDV cDNA after ethidium bromide/agarose gel electrophoresis and after molecular hybridization (100 times more sensitive than gel analysis), enabled us to grade the signals observed from negative to positive as 1+, 2+, 3+ and 4+, with all results being positive. Three types of evolution of HDV viraemia were evidenced among the 8 treated patients. HDV replication continued to occur at a high level at the 6th and 12th month in 2 patient sera. For 2 other patients, an HDV RNA decrease or disappearance was evidenced in the serum at the 6th month; however, viral replication recurred at a higher level at the 12th month.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7839007 TI - The virulence of mouse hepatitis virus 3, as evidenced by permissivity of cultured hepatic cells toward escape mutants. PMID- 7839008 TI - Genotypic diversity of reassortants between simian rotavirus SA11 and human rotaviruses having different antigenic specificities and RNA patterns. AB - A total of 200 clones of reassortants were generated in vitro between simian rotavirus SA11 (SA11-L2 strain) and each of five human rotavirus (HRV) strains with different antigenic specificities and RNA patterns. When culture fluid coinfected with parent viruses was subjected to repeated selection with anti-HRV VP4 and anti-SA11-VP7 neutralizing monoclonal antibodies, all yielded progenies were antigenic mosaic reassortants possessing VP4 and VP7 derived from SA11 and HRV, respectively. In genomic analysis of viral RNA by PAGE, two and five different genotypes were identified in 40 clones, generated between SA11 and HRV strain Hochi (G serotype 4, G4) and between SA11 and KU (G1), respectively. In contrast, 11 and 17 genotypes were found in progenies between SA11 and subgroup I G2 HRV strain HN126 or DS-1, respectively. Although SA11 genes, except for the VP7 gene, were predominant in most reassortants, gene 5 was preferentially selected from HRV. Incorporation of HRV segments 1, 3 and 10 into progenies was more frequent in SA11 x HN126 and SA11 x DS-1 reassortants than in other reassortants. These results indicated that the extent of diversity of reassortant genotypes differs between the two groups of the parental HRV strain; one has subgroup I specificity and a short RNA pattern (DS-1 genogroup), while the other has subgroup II specificity and a long RNA pattern (Wa genogroup). PMID- 7839009 TI - Amino acid sequence of the porcine rotavirus YM VP1 protein. PMID- 7839011 TI - Calomys musculinus, the natural reservoir of Argentine haemorrhagic fever, is a semipermissive host for a mouse-attenuated mutant of Junin virus. AB - C167, a mouse-attenuated strain of Junin virus derived from the XJC13 strain, also displayed reduced virulence for the South American cricetid Calomys musculinus, a natural reservoir of this virus in nature. Intracerebral inoculation of C. musculinus with 500 PFU of C167 produced only 25% mortality, whereas the parental XJC13 killed 85% of the animals. The attenuation of C167 for this cricetid was lower than for albino mice. The multiplication of C167 in C. musculinus-derived embryo or kidney fibroblasts was diminished with respect to XJC13, allowing us to define C. musculinus cells as a semipermissive system for C167, whereas murine and Vero cells were restrictive and permissive cultures, respectively. As a consequence, C167 as well as XJC13 were able to establish a persistent infection in C. musculinus embryo fibroblasts and Vero cells, but the mutant could not induce a carrier state in murine cells. Thus, the degree of susceptibility of C. musculinus to C167 was linked to the semipermissiveness of cricetid cells to virus multiplication. PMID- 7839010 TI - Plaque assay and replication of Tipula iridescent virus in Spodoptera frugiperda ovarian cells. AB - A plaque assay was developed for the study of Tipula iridescent virus (TIV) replication using a cell line derived from the fall army worm Spodoptera frugiperda (Sf9). Infection and plaque formation were monitored with time by phase contrast microscopy, video and fluorescent light microscopy. Structure of virions, viroplasmic centres and organelles of infected cells were examined by transmission electron microscopy (TEM). After 4 h postinfection, plaques were visibly detected within the cell monolayer by the presence of localized cell damage and production of numerous vesicular-like cytoplasmic structures. Quantitation of virions present per A260 unit of TIV preparation was determined by TEM. The number of visible plaques corresponded to virus concentration and 1 A260 produced approximately 10(5) plaques. DNA hybridization analysis revealed no gross differences in genomic DNA from TIV propagated in either Sf9 cells or wax moth Galleria mellonella larvae. These findings indicate that Sf9 is permissive for replication of TIV and superior by some parameters to other cell lines currently in use for the study of host cell/TIV interactions. PMID- 7839012 TI - Comparative study of single and nested PCR for the detection of proviral HIV2 DNA. AB - We have tested seven pairs of primers for the detection of HIV2 DNA by single PCR in positive cultures from 21 infected patients. Four of these primer pairs were then used in a comparative study of single and nested PCR for the detection of HIV2 in fresh lymphocytes from 33 patients infected by the virus. HIV2 DNA was detected in 17 of the 33 patients (51.5%) by single PCR and 29/33 (88%) by nested PCR. All the patients negative in both nested and single PCR were asymptomatic and had CD4+ lymphocyte counts of at least 500 x 10(6)/l. This lack of PCR sensitivity for the detection of proviral HIV2 DNA in fresh lymphocytes cannot be totally attributed to genetic variability and may be related to a low viral load in asymptomatic HIV2-infected patients. PMID- 7839013 TI - [In vitro effect against Giardia of 14 plant extracts]. AB - OBJECTIVE: To investigate antigiardiasic activity in plants used in Mexico as antidiarrheics and/or antiparasitics. MATERIALS AND METHODS: Fourteen species were evaluated. The antigiardiasic activity was measured in vitro in a blinded fashion using trophozoites of Giardia duodenalis incubated with plant extracts. The viability of trophozoites was ascertained using MTT (3-[4,5-dimethylthiazol-2 il]-2, 5-diphenyl tetrazolium bromide) which is reduced to MTT-formazan by the activity of live trophozoites. The reduced MTT was extracted with an acidified alcohol (2-propanol with HCI 0.04 M) and measured in a spectrophotometer at 570 nm. Negative (trophozoites without extract) and positive controls (incubated with tinadazol) were included. RESULTS: The scientific and trivial names of the plants are given (trivials in Spanish marked by an asterisk). They had the following trophozoite mortality (mean +/- SD in percent): Justicia spicigera (muicle*) = 91 +/- 0.5; Lipia beriandieri (oregano) = 90 +/- 0.6; Psidium guajava (guava) = 87 +/- 1.0; positive control of tinidazol = 79 +/- 1.9; Punica granutus (granado*) = 78 +/- 1.3; Magnifera indica (mango) = 77 +/- 1.0; Plantago major (lante*) = 76 +/- 1.2; Cupressus semperbirens (cipres) = 73 +/- 1.2; Castella tormentosa (chaparro amargoso*) = 70 +/- 0.7; Hematoxilon campechanum (palo de Campeche*) = 67 +/- 1.2. Without or with a low mean activity were Prosopis juliflora (mesquite*) and Rizophora mangle (mangle*) with 0%, Oriza sativa (rice) with 5%, Capsicum annum (pimiento*) with 21% and Persea americana (avocado) with 23%. There were no associations of the antigiardiasic effect with concentration or osmolality of the extracts. CONCLUSIONS: A clear in vitro antigiardiasic effects was seen in nine species. Three of them were superior to tinidazol which is a drug of common use in the treatment of giardiasis. PMID- 7839014 TI - [Tuberous sclerosis. Early diagnosis with autonomic nervous system responses in hypopigmented skin]. AB - The earliest clinical sign for the diagnosis of tuberous sclerosis (TS) is the presence of cutaneous hypopigmented macules. However, there are no clinical, histopathological or functional criteria to discriminate between hipopigmented macules of TS and those without associated pathology. In this prospective study, the responses of the autonomous nervous system, erythema and sweating induced through iontophoresis with pilocarpine, were studied in three groups of patients (20 with TS, 10 with hipomelanosis of Ito, and 10 with hipopigmented macules without associated pathology). In hipopigmented macules without associated pathology, the responses were similar to those observed in normal skin. In TS erythema and sweating were significantly diminished (p = < 0.001). In hypomelanosis of Ito the decrease in erythema and sweating were not statistically significant. In TS the degree of decrease of erythema and sweating correlated positively with the severity of the neurological alterations. Light and electronmicroscopic studies of the hypopigmented macules in the three groups showed morphologically normal sweat glands and nerves. The latter suggests a disfunction of the sweat glands in TS as a cause of their abnormal behavior. We conclude that sweat testing in hypopigmented macules is a useful mean for the early diagnosis of ET. PMID- 7839015 TI - [High prevalence of the Epstein-Barr virus in a Mexican population with Hodgkin's disease]. AB - The Epstein-Barr virus (EBV) has been demonstrated in association with cases of Hodgkin's disease (HD) indicating that, in at least in some cases, EBV may play a pathogenic role in the development of HD. To determine the prevalence of EBV in HD in a Mexican adult population, we studied 39 formalin-fixed and/or B-5, paraffin embedded samples of patients with HD, by immunoperoxidase; in situ hybridization was done in 32 of the 39 cases. We analyzed the presence of the latent membrane protein (LMP) and EBV-specific DNA sequences. Reed-Sternberg cells and mononuclear variants were positive for LMP in 28 cases (72%). LMP staining was found both on the cell surface and/or within the cytoplasm with enhancement in the Golgi area. The LMP was found in the single case of diffuse lymphocyte predominant HD, in 6/12 cases of nodular sclerosis (50%), in 10/15 cases of mixed cellularity (67%) and in all eleven cases of lymphocyte depleted HD (100%). No EBV-specific DNA sequences were found by in situ hybridization. Our results show: 1) a higher association of EBV in our population compared to the approximately 48% reported in developed countries; 2) all histologic subtypes of HD in Mexico appear to be strongly associated with EBV in contrast to the strong association with only mixed cellularity seen in Western populations; 3) the high prevalence of EBV in HD in Mexico may be a function of histology, ethnic groups, socioeconomic factors and/or geography. PMID- 7839016 TI - Fasting glucose/insulin ratio. An index to differentiate normo from hyperinsulinemic women with polycystic ovary syndrome. AB - OBJECTIVE: To evaluate a simple laboratory index useful to differentiate normo from hyperinsulinemic women with polycystic ovary syndrome. DESIGN: Open and prospective study. SETTING: Outpatient infertility clinic of a third level medical institution. PATIENTS: Twenty five women 27.8 +/- 3.4 years of age with chronic anovulation, hirsutism and hyperandrogenemia (free testosterone [free-T] > 3.4 pg/mL) but no acanthosis nigricans (group 1) were compared with ten healthy women 27.5 +/- 1.5 years of age (group 2). INTERVENTIONS: Three fasting blood samples were obtained followed by a 100-g, 2-hours oral glucose tolerance test (OGTT). MAIN OUTCOME MEASURES: Glucose, insulin, FSH, LH, E2, free-T, androstenedione (A), DHEAS and 17 alpha-hydroxyprogesterone (17-OHP) were measured in the three fasting samples. Glucose and insulin were also determined in the OGTT samples. The fasting glucose/insulin (G/I) ratio was calculated. RESULTS: In group 2 the fasting insulin was < 16.8 microU/mL, the sum of serum insulin (sigma INS) during the OGTT was < 385 microU/mL (mean + 3SD) and the fasting G/I ratio was > 4.5. The fasting LH, FSH, free-T, cortisol, and insulin were higher in group 1 than in group 2. In group 1, eleven women had a sigma INS below and fourteen above 385 microU/mL. Fasting insulin had a linear correlation with sigma INS (r = 0.780) while the fasting G/I ratio had an exponential correlation with sigma INS (r = -0.699). Fasting insulin versus the G/I ratio best fitted a reciprocal regression model (r = 0.912). For screening of hyperinsulinemia during OGTT, fasting insulin had a 75% sensitivity and 62% specificity while for the G/I ratio it was 79% and 73%, respectively. CONCLUSIONS: Both fasting hyperinsulinemia (> 16.8 microU/mL) and a fasting G/I ratio < or = 4.5 can satisfactorily differentiate women with hyperandrogenism and hyperinsulinemia from those with normoinsulinemia. However, the ratio does not require a previous definition of a normal value as for fasting or post-oral glucose insulin levels, and thus, it can be easily calculated in daily clinical practice to establish specific therapeutic maneuvers at an early stage of the evaluation of such patients. PMID- 7839017 TI - [Lymphoblastic lymphoma in children. Poor response in advanced disease with chemotherapy for non-Hodgkin's lymphoma]. AB - Fifty three pediatric patients with the histopathological diagnosis of lymphoblastic lymphoma (LL) were studied in a retrospective analysis during a 14 year period. Their age ranged from 1 to 16 years with a median of 7 years. Clinical staging was performed according to Murphy's system. There was one child in stage I (2%), 11 in stage II (21%), 14 stage III (26%) and 27 stage IV (51%). Patients in stage IV, 21 (78%) had initial bone marrow involvement, 4 (15%) central nervous system (CNS) infiltration and 2 (7%) simultaneous infiltration to the bone marrow and the CNS. The chemotherapy program consisted of induction, consolidation and maintenance with CNS prophylaxis. The whole program lasted 36 months. Out of 53 patients there were only 45 evaluable for treatment analysis response. A total of 14 (31%) are alive and in a continuous complete remission, with a median duration of remission of 66 months, 8 (18%) children abandoned treatment with a median duration of remission of 10 months. Twenty three patients (51%) are dead. The actuarial survival at 11 year is of 39% +/- 11% with a median remission rate for the whole group of 11.8 months. No patient in complete remission for more than 24 months has relapsed. We conclude that our chemotherapy program is more than adequate for early stages, but for advanced disease it has been a failure. There is a need to modify the chemotherapy program using a very similar protocol as the one used in high risk childhood acute lymphoblastic leukemia. PMID- 7839018 TI - Low levels of hepatic cytochrome P-450 in Mexicans with uncomplicated cholelithiasis. AB - The multienzymatic complex known as cytochrome P-450 represents one of the most important hemoprotein families of the liver. It participates in the metabolism of steroids, fatty acids, prostaglandins and liposoluble vitamins, and also plays a role in the bioactivation of xenobiotic compounds (generates reactive metabolites which produce acute and chronic lesions in liver tissue). This is a report on the low concentrations of total microsomal P-450 (0.093 +/- SD = 0.069 nMoles/mg protein) found in liver biopsies of 19 mexican patients diagnosed as having biliary lithiasis, as compared to an anglosaxon population with the same liver pathology (0.415 +/- 0.105 nMoles/mg protein). These low values are in agreement with the observation of a high incidence in normal mexicans (91.7%) of poor nifedipine metabolizers. Our findings justify an analyses of hepatic RNAm and cDNA of mexican individuals according to ethnic background, diet and environmental contaminants. PMID- 7839019 TI - [Essential thrombocythemia: a 35-year experience and review of the literature]. AB - Essential thrombocythemia (ET) is a clonal myeloproliferative disorder characterized by an uncontrolled rise in peripheral blood platelet count. The aim of this report was to determine the clinical and laboratory data of this disease in a 35 years revision. Of the patients with the diagnosis of ET, we selected those who fulfilled five of the six diagnostic criteria proposed by the Poli Vera Study Group. We found 14 cases (10 female and 4 male) with a median age of 54.5 years (range 29-74). The most frequent initial clinical finding was hemorrhage and in four cases the diagnosis was preoperative. Median platelet count was 1,355 x 10(9)/L (range 600 to 3,750). One case had iron deficiency which was corrected before ET was diagnosed. None has evolved to acute leukemia. Initially, most of the cases were treated with busulphan and two received alpha-interferon which was promptly changed to busulphan because of secondary effects. Three patients have died due to hemorrhagic complications and one due to thrombosis. ET has a low frequency in our country and must be considered an exclusion diagnosis. Iron deficiency may mask the diagnosis specially in the cases with a platelet count not very high. Treatment can provide in general a long survival of good quality of life. PMID- 7839020 TI - [Notification of family history of diabetes]. AB - In clinical practice the presence of a positive family history of diabetes mellitus is one of the criteria to perform a glucose screening test. However it has been shown not to be always reliable. The aim of this study is to verify the concordance between the data referred by a group of daughters about the existence of diabetes mellitus in both parents, the data given by their parents, and a corroboration by blood glucose testing of the parents. A total of 82 triads (father, mother and daughter) were studied. The daughters were healthy and belonged to a cohort of perinatal studies of the Instituto Nacional de Perinatologia in Mexico City; they were not pregnant and had both patients alive, who agreed to participate in the study. Each daughter was asked about her parents history of diabetes having three options as an answer: yes, no, do not know. The same information about themselves was asked to the parents separately, not giving a chance to the members of the triad to communicate among themselves. The necessary glucose tests were performed to integrate a diagnosis by accepted international criteria. A chi-square test was used to compare the data referred by parents and daughters; agreement percentage (kappa values) were calculated. A prespecified order test was performed to the answers given and evaluated by occurrence rates (Bartholomew's test). In the latter analysis there were significant differences (p < 0.001) between the answer given by the parents, daughter and the confirmed blood glucose values. No differences were found between what the parents said, nor in what they said and what the daughters answered. PMID- 7839021 TI - [Response to treatment and survival of adults with acute leukemia classified with immunophenotyping and cytochemistry]. AB - We studied the response to treatment and survival of 30 adults with acute lymphocytic leukemia (ALL) and 19 with acute non lymphoid leukemia (ANLL) classified on basis of immunophenotype (monoclonal antibodies) and cytochemistry. For the ALL cases 70% corresponded to common ALL (CALLA positive), 23% to B lymphocytes and 7% to T cells. We had 68% of the ANLL patients classified as myeloid, 21% as hybrid (positive both myeloid and lymphoid markers) and 11% as undifferentiated. We analyzed demographic data (gender and age), basic laboratory values (hemoglobin, leucocytes, platelets and cytomorphology in peripheral blood and bone marrow) using the French-American-British classification, and found no statistically significant differences between ALL and ANLL. Three of four patients (75%) with hybrid ANLL achieved complete remission (CR), while 46% of cases with myeloid ANLL and none of the subjects with undifferentiated ANLL reached CR; these differences were not statistically significant. Patients with common ALL had a median survival (SV) of 499 days, for B cell ALL it was of 212 days, and for T cell ALL of 285 days. Our data suggest that: a) expression of lymphoid markers in patients with ANLL is probably associated with a higher CR ratio, and b) SV in adults with common ALL seems to be longer than in those with B and T cell ALL. PMID- 7839022 TI - [Critical reading in selected groups of medical students]. AB - BACKGROUND: The shaping of professionals with a critical outlook in their field of endeavor is a goal of some educational institutions in our country. However, little participation from the students is demanded in our medical schools and this probably interferes in the development of skills for critical reading. OBJECTIVE: To evaluate critical reading in medical students with high scholastic achievement as a function of years of medical training. MATERIAL AND METHODS: We studied three groups of medical students who were homogeneous in regard to scholastic achievement (their mean was 9 or higher in a scale of 10). The groups were in the first, third and fifth year of their medical training (N was 24, 15 and 12 respectively). Two homogeneous groups of low achievers (mean of 7 or less in their first year of training with N of 20 and 16) were also included as contrast groups (no homogeneous groups of low achievers were present in higher years). The test applied was elaborated by us and has been validated. It evaluates reading comprehension (30 items) and interpretation (40 items) of medical information with questions to be answered true/false/don't know and which are scored -1 (incorrect), zero (don't know) or 1 (correct). The scores were analyzed using non-parametric techniques. We consider reading interpretation as a capacity better representing critical reading. RESULTS: In the three groups of high achievers, comprehension was the same (median of 26 out of a maximum of 30) and interpretation ranged from 21.5 to 23 with no group differences (Kruskal Wallis test). The high achievers had significantly higher scores in reading and interpretation than the low achievers (U test p < 0.01). There was also a consistent higher score of comprehension over interpretation in the five groups (chi square of proportions p < 0.01) but the association of comprehension and interpretation was present only in three groups (high achievers in 1st and 3d year and low in 1st with correlations of Spearman ranging from 0.43 to 0.56). CONCLUSIONS: We were unable to detect any significant difference of years of medical training in the ability to comprehend or interpret medical information. We were able to detect differences in these abilities between high and low achievers. PMID- 7839023 TI - [Reye's syndrome in an adult. Review of pathogenic mechanisms]. AB - Reye's syndrome is considered a disease of the pediatric age. It is characterized by a prodrome of viral illness followed by vomiting and encephalopathy with associated hepatic dysfunction. This syndrome is potentially life-threatening with high morbidity and mortality rates. There are 27 other cases of adult onset Reye's syndrome reported in the literature. We describe a 18-year-old woman who developed varicella and four days later started with vomiting, delirium and in the following day she became comatose. Laboratory tests of liver function and pathology of a liver biopsy proved the diagnosis. The patient survived. A review of the proposed pathogenic mechanisms are presented. Our patient represents case the number 28 in world literature and the first in the mexican literature. PMID- 7839024 TI - [Hemostatic system factors and endothelial function in primary pulmonary hypertension]. AB - Primary pulmonary hypertension (PPH) is a rare disorder, usually fatal. Although the cause of the disease is unknown, the vascular endothelium seems to play a key role. It has been proposed that a vascular endothelial dysfunction would provoke pulmonary vasoconstriction, platelet activation and thrombin formation; some of these events have already been proven. The presence of thrombosis in PPH patients has been demonstrated, and it seems to have a relationship with a vascular endothelium-dependent coagulation abnormality. Substances of endothelial cell origin capable of modifying the coagulation mechanisms are: heparan-sulfate, thrombomodulin, protein S, tissue factor pathway inhibitor (TFPI), tissue factor, von Willebrand factor, prostacyclin and endothelial-derived relaxing factor; functional and multimeric-pattern alterations in von Willebrand factor have already been reported in PPH patients. PMID- 7839025 TI - Patent ductus arteriosus. PMID- 7839026 TI - Cor triatriatum and caval anomalies. PMID- 7839027 TI - Pericardial disease and cardiac neoplasia. PMID- 7839028 TI - Pacemaker therapy for bradycardias. PMID- 7839029 TI - Surgical removal of heartworms. PMID- 7839030 TI - Hypothermia for cardiac surgery. AB - If the protocol described here is followed, good results will be obtained in the majority of animal patients. However, as with any procedure involving critically ill animal patients, many factors enter in to determine the results in any given case. PMID- 7839031 TI - Cardiopulmonary bypass for small animals. PMID- 7839032 TI - Cross-circulation for cardiopulmonary bypass. PMID- 7839033 TI - Pulmonic stenosis and subvalvular aortic stenosis: surgical options. PMID- 7839034 TI - Atrial septal defect and ventricular septal defect. AB - In summary, ASD and VSD sometimes do not require surgical intervention and have a good-to-excellent prognosis in animal patients in which surgical intervention is necessary. Animal patients with these diseases often do not show symptoms, but those that do and cannot be adequately managed medically are challenging but rewarding cardiac surgical cases. PMID- 7839035 TI - Tricuspid and mitral valvular disease: valve replacement. AB - Using the methods described, the author has performed AV-valve replacement surgery in seven clinical dogs with AV valve dysfunction. Two dogs received autologous tissue tricuspid valves, three dogs received autologous tissue mitral valves, one dog received a mechanical mitral prosthesis, and one dog received a mechanical mitral and autologous tricuspid prosthesis. The two dogs that received a tricuspid prosthesis recovered from surgery, one dog is normal nearly 3 years after valve replacement surgery, and the second dog was euthanized 3 weeks after replacement surgery because of complications related to other congenital cardiovascular defects (ie, pulmonary artery coartations). The dog that received the mechanical mitral valve prosthesis made a complete immediate postoperative recovery but died from hemorrhage complications related to a femoral artery catheter removal 3 days after surgery. Hemorrhage from the left atrium resulted in the death of one dog after implantation of a bioprosthetic mitral valve. Two dogs with mitral valve bioprostheses and one dog with a mitral and tricuspid valve replacement could not be weaned from the cardiopulmonary bypass pump, even with pharmacological support. Although the initial results in this small clinical trial have not been spectacular, it is apparent from the few clinical cases operated on that the equipment, supplies, and techniques have advanced sufficiently in veterinary surgical practice to perform AV-valve replacement surgery in companion animals. Prosthetic valves are available presently to perform such surgery even in small animal patients (5 kg). However, a significant obstacle that must be overcome before such techniques become routine is the selection of animal patients that have sufficient myocardial reserve to undergo valve replacement surgery.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7839036 TI - Dynamic cardiomyoplasty for dilated cardiomyopathy in dogs. PMID- 7839037 TI - [Ginkgo--myth and reality]. AB - Ginkgo biloba is one of the oldest, still existing plants. Extracts from its leaves were already used in ancient China whereas in the Western World, they have been utilized only since the Sixties when it became technically possible and feasible to isolate the essential substances of Ginkgo biloba. Pharmacologically, there are two groups of substances which are of some significance: the flavonoids, effective as oxygen-free radical scavengers, and the terpenes (i.e. the ginkgolides) with their highly specific action as platelet activating factor (PAF) inhibitors. Clinically important indications for Ginkgo biloba extracts are cerebral insufficiency and atherosclerotic disease of peripheral arteries of intermediate severity. In several placebo-controlled clinical studies, symptoms of cerebral insufficiency have been effectively and significantly influenced. Most of these investigations have examined the efficacy of Ginkgo biloba extracts such as EGb 761 and LI 1370. PMID- 7839038 TI - [Fish oil--healing principle in the Eskimo diet?]. AB - The low incidence of coronary heart disease among Eskimos is related to their diet rich in marine fatty acids, which contain large amounts of polyunsaturated omega-3 fatty acids, mainly eicosapentaenoic and docosahexaenoic acids. The beneficial effects on atherosclerotic vascular disease result from favorable influence on prostaglandin/thromboxane metabolism. Clinical studies have also reported antiinflammatory effects. PMID- 7839039 TI - [Nutritional knowledge of patients in the hypertension clinic. An evaluation using the "Nutrition IQ']. AB - In this study the nutritional knowledge of 117 patients attending a hypertension clinic was evaluated with the use of the 'Nutrition IQ' questionnaire developed by the National Heart Lung, and Blood Institute. Overweight was identified as a risk factor for hypertension by 98% of the subjects, but more than 10% of the subjects did not identify weight reduction as an important therapeutic tool in the control of hypertension. Around 30% of the patients misjudged the importance of weight reduction in the treatment of hypertension as compared to a low salt diet. 25% believed that a salt reduction will always normalise hypertension. Only 5% of the subjects failed to identify exercise and caloric restriction as the major strategies for weight control. More than two thirds of the patients believed that skipping meals is the best way to reduce energy intake. Carbohydrates were wrongly identified as the major factor for weight gain by 50% of the subjects. The same patients did not recognize reduction in fat intake as the major nutritional tool to maintain or reduce weight. Only 25% of the subjects knew that polyunsaturated fatty acids do have the same caloric content per weight as saturated fatty acids. The nutrition IQ questionnaire can be used as an easy and quick screening method of the nutritional knowledge of patients in a hypertension clinic. The data confirm that there is still a large gap between the knowledge of a certain nutritional (risk) factor and its implementation in daily life, and suggest that patient education should be targeted more on life-style issues. PMID- 7839040 TI - [A case from practice (314). HIV-A2. Persistent hepatitis B infection. Status following syphilis. 3rd trimester pregnancy]. PMID- 7839041 TI - [Garlic--a "secret miracle of God"?]. AB - Garlic belongs to the oldest traditional medicinal plants. It has already been mentioned 1500 A. D. in an ancient egyptian medical script, the Papyrus Ebers. In modern times antitumoral and antiarteriosclerotic effects are attributed to garlic-derived drugs. These effects could be demonstrated in vitro and appear to be supported by epidemiologic studies. Production of commercial products and pharmacologic studies, however, are rendered more difficult by chemical instability and low bioavailability of the active drugs. Clinical studies on effects and case reports about side effects of garlic consumption are summarized in this paper. PMID- 7839042 TI - [What is your diagnosis? Osteochondral exostosis of the base of the proximal phalanx of the left 4th finger]. PMID- 7839043 TI - [Current therapeutic possibilities in chronic inflammatory intestinal diseases]. AB - Treatment of chronic inflammatory bowel disease can be divided into therapy of active disease, strategies in chronic, active disease and prevention of relapse. In Crohn's disease as well as in ulcerative colitis steroids are of major importance in the treatment of active disease. For ulcerative colitis 5 aminosalicylic acid is used in addition, in particular with mild or moderate disease. It is used for prevention of relapse in chronic inflammatory bowel disease. Immunosuppressive drugs are indicated in chronic, active Crohn's disease, while surgery is important in ulcerative colitis. New developments are predominantly related to nonsystemic steroids, which are studied in different modalities of galenic preparations. PMID- 7839044 TI - [Gene therapy--basic principles]. AB - Recombinant DNA technology allows the cloning of genes and their expression in vitro. Cloned genes are central to human gene therapy. The principle of gene therapy is based on three different strategies: gene replacement in classic genetic diseases which are caused by a single gene defect that conforms to the rules of Mendelian inheritance; gene augmentation for the treatment of complex genetic diseases by providing the cell with a new function; block of gene expression in acquired genetic diseases such as infections and malignancies. PMID- 7839045 TI - [Gene therapy: application possibilities]. AB - In 1990 the potential use of gene therapy could be demonstrated for the first time by the successful treatment of a child suffering from adenosine deaminase deficiency. Further potential applications of gene therapy include infectious, malignant and cardiovascular diseases. Current studies focus on technical problems, such as gene transfer methods, as well as safety aspects of gene therapy. PMID- 7839046 TI - [Possibilities of gene-technological production of drugs, especially also the interferons]. AB - For a long time proteins have been used in Medicine as medication. Human Growth Hormone (isolated from Pituitaries of Cadavers) or insuline (isolated from porcine or bovine pancreas) are examples. Genetic engineering has essentially simplified the production of such well known proteins and on the other hand enabled search for and characterization of new human proteins. New active principles may thus be discovered, their physiological importance studied and if possible used for therapeutic purposes. Examples are thrombolytic proteins or interferon. Today more than 20 new proteins are already registered and more than 150 proteins are intensively tested in clinics. PMID- 7839047 TI - [Gene therapy: medical and methodological aspects]. AB - Molecular strategies of gene therapy are presently aimed at optimization of the efficiency of gene transfer, long-term expression of therapeutic genes and cellular as well as intracellular targeting of genes. Apart from these scientific aspects, safety considerations are of utmost importance. PMID- 7839048 TI - [Ethical aspects in gene therapy]. AB - Gene technology including gene therapy represents the most controversial subject in natural sciences or medicine and is discussed quite emotionally not only by the general public but also by persons within the medical profession. The ethical concerns with respect to gene therapy are complex and multifaceted. Besides categorical arguments, purely pragmatic ones are raised against this new medical procedure. Ethical aspects, primarily related to somatic gene therapy, will be evaluated in this paper from the point of view of a physician. PMID- 7839049 TI - [Respiratory syncytial virus infection in children]. PMID- 7839050 TI - [Hemoptysis: main etiologies observed in a pneumology department in Africa]. AB - The aim of this work was to ascertain the main aetiologies of haemoptysis observed in the pneumo-phtisiology unit at the University Hospital of Treichville at Abidjan, Ivory Coast. A retrospective survey covering 5 years revealed 142 cases. The annual incidence of haemoptysis was 2.5% of the unit's admissions. The mean age of the patients was 33.2 years and 56.3% were at least 41 years of age. Men were predominate (72.5%). The haemoptysis was a sign of thoracic disease in 66.9% of the cases. The chest X-ray was judged abnormal in all the cases and suggested the aetiology in 87.3%. The main aetiologies were pulmonary tuberculosis (49.3%) and acute pneumopathy (with or without abscess) (13.3%). Other causes included bronchectasis (11.2%) and pulmonary aspergilloma (7.7%), followed by bronchogenic cancer (4.2%). The results of this study indicated that tuberculosis remains one of the main causes of haemoptysis at Abidjan. PMID- 7839051 TI - [Treatment of community-acquired pneumonia by pristinamycin (Pyostacine 500). Results of a non comparative open study]. AB - Activity of natural streptogramin (NSG) appears well adapted to pathogens responsible for CAP. The goal of this multicenter pilot study was to bring first data about efficacy of NSG in treatment of CAP. PATIENTS METHOD: Ten days of a NSG (1 gr b.i.d. or t.i.d.) regimen was administered to 46 hospitalized adult patients for CAP defined with fever > 38 degrees C, respiratory symptoms and X ray opacity. Severely ill patients were excluded. A broncho-pulmonar sample (expectoration or trantracheal aspiration or protected distal sample) was performed in all patients. RESULTS: two patients were excluded because of pulmonary embolism (n = 1) or tuberculosis (n = 1) and 44 patients were analyzed. 50% of them had associated disease, 20% had failure of prior antibiotherapy. At inclusion, mean fever was 39.2 +/- 0.7 degrees C, respiratory rate was 22 +/- 5/mn, PaO2 was 74 +/- 10 mmHg, chest X-ray showed bilateral opacity in 16%, unilateral in 84% and pleural fluid level in 6 cases. Etiological diagnosis was determined in 70% of cases. Streptococcus pneumoniae (n = 14), Haemophilus influenzae (n = 5), Legionella pneumophila (n = 2), Mycoplasma pneumoniae (n = 2) and Chlamydia psittaci (n = 1) were the most frequent isolated pathogens. 40 patients (91%) were cured with NSG and delay to obtain apyrexia was 4.4 +/- 3.9 days. NSG was stopped in 4 patients: 1 clinical and bacteriological failure (Klebsiella pneumoniae), 2 clinical failures (1 pneumococcus with purulent pleurisy, 1 pneumococcus with worsening of respiratory status), 1 patient with resistant H. influenzae strain in spite of favourable clinical evolution. NSG was well tolerated in 86% of patients. CONCLUSION: these data invite to carry on evaluation of first line therapy of CAP with NSG. PMID- 7839052 TI - [Primary pulmonary hypertension in a HIV positive patient]. AB - Apparently primary pulmonary hypertension is rarely described in patients infected with the human immunodeficiency virus (HIV). We observed a case in a HIV seropositive patient with no known risk factor for pulmonary vascular disease. The characteristics of this new association are described. PMID- 7839053 TI - [Extramedullary hematopoiesis: multiple mediastinal localizations]. AB - Intrathoracic extra-medullary hematopoiesis is a compensatory mechanism usually seen in thalassemia. The authors report a case with multiple mediastinal localisations fortuitously discovered. CT has allowed diagnosis and led percutaneous biopsy. PMID- 7839054 TI - [Efficacy of octreotide acetate in the treatment of a pancreatic-pleural fistula. Apropos of a case]. AB - Diseases organs below the diaphragm should be considered in the aetiologic diagnosis of liquid effusion in the pleura. We observed a cases of pleuritis resulting from chronic pancreatitis and present here the diagnostic methods and therapeutic protocol undertake for cure. The level of amylase (including the isoforms) should be measured in the pleural effusion. The effectiveness of octreotide acetate in the treatment of pancreatico-pleural fistula was confirmed in this case. PMID- 7839055 TI - [Efficacy of slow-release betamethasone in Churg-Strauss syndrome. Apropos of a case]. AB - A case of Churg-Strauss syndrome was observed in a young woman with asthma and an elevated eosinophil count. The lungs, skin, joints, stomach and heart were involved. The diagnosis was established on the basis of the clinical picture and results of the surgical lung biopsy. Outcome has been favourable for 6 years with a chronic treatment with dipropionate and slow-release betamethazone phosphorane which has the same effectiveness as cyclophosphamide and prednisone. Clinical improvement was observed during pregnancy and lactation. PMID- 7839056 TI - [Radiologic case: diagnosis of an anterior mediastinal mass]. PMID- 7839058 TI - [9th Consensus Conference on Resuscitation and Emergency Medicine. With participation of the French Society for Anesthesia and Resuscitation. 2 July 1993. Sedation in resuscitation: concept and practice]. PMID- 7839059 TI - [Pleural plaques and thoracic imaging]. PMID- 7839057 TI - [Multiple nodular opacities]. PMID- 7839061 TI - [Coronary disease and vinorelbine]. PMID- 7839060 TI - [Bronchospastic respiratory distress disclosing legionellosis]. PMID- 7839062 TI - Ergonomic considerations in the dental laboratory environment. PMID- 7839063 TI - How to manage cumulative trauma injuries in dental laboratories. PMID- 7839064 TI - Correcting an occlusal problem in an implant retained prosthesis. PMID- 7839065 TI - A question of integrity; who should be responsible for seating crowns precisely: technicians, dentists--or attorneys? PMID- 7839066 TI - Fundamentals of opal procelain. PMID- 7839067 TI - A laboratory technique for fabricating single tooth implant restorations with optimal subgingival contours. PMID- 7839068 TI - Professionalism in dental laboratories. PMID- 7839069 TI - Defective mitogen-induced cellular cytotoxicity in untreated patients with active rheumatoid arthritis. AB - Peripheral blood mitogen-induced cellular cytotoxicity (MICC) was studied in 13 untreated patients with active rheumatoid arthritis (RA; group A) and in 5 RA patients with inactive disease (group B), using phytohemagglutinin (PHA) as stimulating agent and K562 cells as target cells in the chromium-51 release assay. MICC was found to be significantly reduced in the patients of group A compared with normal subjects (P < 0.01) and the patients of group B (P < 0.05). No differences were noted in MICC between group B patients and normal subjects. A statistically significant negative correlation was found between values of patients' MICC and serum C-reactive protein levels (r = -0.685, P < 0.01). Furthermore, patients' MICC correlated well with patients' peripheral blood natural killer cell activity (P < 0.02), as well as with the absolute number of circulating CD8+ cells. No correlation was found between MICC and duration of disease, erythrocyte sedimentation rate, serum alpha 2-globulins, or the titre of serum rheumatoid factor in the patients studied. We concluded that defective MICC in untreated patients with active RA is probably due to the diminution of the number of CD8+ cells, although a qualitative defect of these cells cannot be excluded. PMID- 7839070 TI - R-h-erythropoietin counteracts the inhibition of in vitro erythropoiesis by tumour necrosis factor alpha in patients with rheumatoid arthritis. AB - Anaemia of chronic disease (ACD) is a common extra-articular manifestation of rheumatoid arthritis (RA). Tumour necrosis factor alpha (TNF alpha) plays an important role in the development of ACD. The objective of the present study was to assess inhibition of in vitro colony-forming unit erythrocyte (CFUe) and blast forming unit erythrocyte (BFUe) growth by TNF alpha and to examine whether this suppression could be counteracted by adding increasing concentrations of recombinant human erythropoietin (EPO) (r-h-EPO) to bone marrow cultures of RA patients with ACD and without anaemia (controls). Bone marrow cells of RA patients with ACD and control patients were cultured. The cultures were incubated with increasing concentrations of r-h-EPO (0.25; 0.5; 1; 2 U/ml), each in combination with increasing quantities of TFN alpha (0; 50; 100; 200; 400 U/ml). CFUe and BFUe were assessed after 7 and 14 days, respectively. Dose-dependent inhibition of BFUe and CFUe by increasing concentrations of TNF alpha was observed in ACD and controls. Regarding CFUe (ACD patients) incubated with 0.25 U/ml EPO, 50 U/ml TNF alpha caused 28% suppression compared to cultures without TNF alpha. Increasing the concentration of r-h-EPO from 0.25 U/ml to 2 U/ml completely restored the number of CFUe. A similar pattern was observed in BFUe growth in both groups. These data demonstrated the suppressive effects of TNF alpha on erythropoiesis in vitro and that the suppressed erythropoiesis could be partly corrected by the addition of excess r-h-EPO to the cultures. No significant differences were observed between ACD and control RA patients.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7839071 TI - An 8-year follow-up study of pulmonary function in patients with rheumatoid arthritis. AB - To evaluate longitudinal alterations in pulmonary function, 63 patients suffering from rheumatoid arthritis (RA) with previously reported reduced pulmonary diffusing capacity were re-examined in an 8-year follow-up study. Cross-sectional examination revealed normal values for vital capacity (VC), forced expiratory volume in 1 s (FEV1) and diffusing capacity per litre alveolar volume (KCO). Total diffusing capacity (DLCO; P < 0.0001), maximal expiratory flow at 75% of expired VC (MEF75; P < 0.0001) and MEF50 (P < 0.01) were decreased. Longitudinal evaluation revealed unchanged MEF50, MEF75 and FEV1, whereas increases in DLCO (P < 0.0001) and KCO (P < 0.0001) and a decrease in VC (P < 0.05) were found. The longitudinal changes in diffusing capacity were unrelated to patient age, disease duration, disease activity in the study period or pulmonary function at the first examination. Thus, in patients suffering from RA, the most prominent functional pulmonary abnormality, decreased diffusing capacity, appeared to improve in the course of time, despite a slight decrease in VC and continued articular disease activity. PMID- 7839073 TI - Serial magnetic resonance imaging in juvenile dermatomyositis--delayed normalization. AB - Demonstration of myositis in juvenile dermatomyositis (JDM) has traditionally required the presence of two out of three objective findings including muscle enzyme studies, electromyography, and muscle biopsy. Magnetic resonance imaging (MRI) is considered another objective criterion and has been recommended for follow-up studies as well. We report on a 6-year-old girl with JDM, presenting with facial rash and proximal muscle weakness, in whom MRI, in conjunction with elevated creatinine kinase (CK) levels, was diagnostic, with an increased T2 signal of proximal muscles. MRI reflected exacerbation of myositis in spite of steroid therapy 2 weeks later, but failed to mirror normalization of muscle strength and CK values 10 weeks later. In fact, improvement of MRI followed clinical and laboratory normalization with a delay of 2 months. This possible delay should be considered when MRI is used to monitor the response to therapy. PMID- 7839072 TI - Suppression of arthritis by an active center analogue of Cu2Zn2-superoxide dismutase. AB - The anti-arthritic and anti-inflammatory efficacy of CuPu(Py)2 ([N,N'-bis(2 pyridylmethylene)-1,4-butanediamine] (N,N',N",N"))-Cu(II), a serum-stable active center analogue of Cu2Zn2-superoxide dismutase (SOD; EC 1.15.1.1), was tested in male DBA/1 x B10A (4R) mice suffering from potassium-peroxochromate-induced (PIA) or collagen type II-induced arthritis (CIA). Parameters including the arthritis index, the plasma SOD activity, and the inhibition of phagocytic responses in unseparated blood were used for the assessment of disease activity. A dose dependent suppression of arthritis was noted in both models. The ED50 was 2.5 +/- 0.4 mumol/kg/day of CuPu(Py)2 for PIA and 4.0 +/- 1.1 mumol/kg/day for CIA. The arthritis index correlated with both the levels of reactive oxygen species (ROS) generated by phorbol ester-activated neutrophils and monocytes in unseparated blood (r = 0.892) and the SOD-like activity in plasma (r = 0.857). CuPu(Py)2 inhibited also the lipoplysaccharide-induced release of tumor necrosis factor alpha from human monocytes and neutrophils in a dose-dependent manner. Unlike SOD, which exerts successful anti-rheumatic activity mainly upon intra-articular injection, the SOD-mimic CuPu(Py)2 can be applied systemically. Non-proteinaceous low molecular weight antioxidases may well be suited to control oxidative stress derived damage in rheumatic diseases by modulation of ROS-dependent signal transduction pathways. PMID- 7839074 TI - Intravascular lymphoma simulating vasculitis. AB - The case history of a patient with intravascular lymphoma (IL) is reported. Signs of a systemic illness including fever, muscular weakness, telangiectasias, nephrotic syndrome, and neurologic manifestation suggested vasculitis. Cyclophosphamide treatment produced almost complete remission, but the patient died of respiratory failure 13 months after presentation due to lung involvement. The diagnosis was not revealed until postmortem examination. The differential diagnosis of IL is provided. PMID- 7839075 TI - Prevalence of antihuman parvovirus B19 IgG antibodies in patients with refractory rheumatoid arthritis and polyarticular juvenile rheumatoid arthritis. AB - We investigated the prevalence of antihuman parvovirus B19 immunoglobulin G (IgG) antibody in 108 Japanese patients with rheumatoid arthritis (RA) and 11 patients with polyarticular juvenile rheumatoid arthritis (JRA). Seropositivity of anti B19 was significantly higher in patients with refractory RA (57.6%, 38/66) compared with patients with remittent RA (19.0%, 8/42; P < 0.001) or age-matched controls (24.3%, 19/78; P < 0.001). Patients with refractory polyarticular JRA had a significantly higher frequency of anti-B19 seropositivity (71.4%, 5/7) than age-matched controls (8.3%, 5/60; P < 0.001), while none of the remittent group was positive for the antibody (0/4). PMID- 7839076 TI - Intravenous dexamethasone pulse therapy in diffuse systemic sclerosis. A randomized placebo-controlled study. AB - Thirty-five patients with diffuse systemic sclerosis were studied in a randomized, placebo-controlled, double-blind study. Seventeen patients received intravenous dexamethasone "pulse" therapy, while 18 patients received placebo. Each "pulse" consisted of 100 mg dexamethasone in 250 ml 5% dextrose infused intravenously over 1 h. Pulse therapy was repeated every month for 6 months. Assessment of disease status with various parameters was done at entry and at completion of trial, i.e. after 6 months. Significant improvement in skin involvement was seen in the study group, with the total skin score (TSS) decreasing from 28.5 +/- 12.2 to 25.8 +/- 12.8, while in the control group, TSS increased from 30.6 +/- 13.2 to 34.7 +/- 10. Similarly, significant improvement was noted in the flexion index. Other parametres that included extension index, maximum oral opening, range of movement of joints, functional disability score, Raynaud's phenomenon (frequency and duration), ESR, proteinuria, chest X-ray, ECG, lung function tests, barium swallow and antinuclear antibody were unchanged. Adverse effects of therapy were limited to an increased incidence of minor chest infections. It is concluded that intravenous pulse dexamethasone may be useful in the treatment of diffuse systemic sclerosis. PMID- 7839077 TI - Deep penetration of antibodies into the articular cartilage of patients with rheumatoid arthritis. AB - This study was conducted to determine the presence of immunoglobulin G (IgG) and albumin in deep layers of articular cartilage from patients with rheumatoid arthritis or osteoarthritis and from normal organ donors. Cartilage plugs were cut into 20-microns slices with a microtome and ten consecutive slices were pooled, dividing the specimen into 200 microns sections starting from the articular surface. Each pool was extracted overnight thrice with neutral buffer, thrice with 6 M guanidine hydrochloride, and then degraded with bacterial collagenase. IgG and albumin were quantified in each extract. From the surface and deep layers significantly more IgG and albumin were extracted from rheumatoid than from normal specimens, both with neutral buffer and with guanidine. In neutral buffer extracts the molar ratios of IgG to albumin were comparable from normal and rheumatoid specimens, with a molar excess of albumin. In contrast, the molar ratios of IgG to albumin in guanidine extracts from rheumatoid cartilages were significantly higher than in normal cartilages, and the IgG was in molar excess of albumin only in rheumatoid extracts. These results show for the first time that IgG has penetrated deep into the cartilage in rheumatoid arthritis and may contribute to the degradation of cartilage by inflammation. PMID- 7839078 TI - An in vitro model to study effects of airborne pollutants on human ciliary activity. AB - A method to study the effects of airborne pollutants on ciliary activity of isolated human respiratory cells is presented. Human respiratory cells were scraped from nasal cavities of 25 healthy volunteers and washed in Ringer's solution. The cells were placed on polycarbonate membranes (3 microns pore size) and kept in macroplate holders swimming on Ringer's solution. Cells were thus kept humid and were supplied with nutrients through the pores of the membrane by capillary forces, while their surface was exposed to the gaseous environment. Isolated respiratory cells were exposed to SO2, NO2, and mixtures of SO2 and NO2 in various concentrations for 30 min and for 2 h. Exposure to synthetic air served as control. Ciliary beat frequency was measured using video-interference contrast microscopy, before and after exposure to the various gases. Exposure of isolated respiratory cells to a non-toxic gaseous environment resulted in a 20% reduction of ciliary beat frequency. A concentration-dependent decrease of ciliary beat frequency following exposure to SO2 in concentrations ranging between 2.5 and 12.5 ppm was found. Exposure to NO2 up to 2 h in concentrations ranging between 3 ppm and 15 ppm did not decrease ciliary beat frequency. No cumulative effect was found, if a mixture of SO2 (2.5 ppm) and NO2 (12 ppm) was applied. PMID- 7839079 TI - Immotile cilia syndrome: nasal mucociliary function and nasal ciliary abnormalities. AB - We present 17 patients with a typical symptomatology of immotile cilia syndrome, seven of them with complete situs inversus. Firstly, a study of the nasal mucociliary transport was made by means of the radioisotopic technique with serum albumin-Tc99m. In all cases there was absence of transport. Secondly, we studied the ultrastructure of the nasal cilia. Defects in the dynein arms were frequently found (65%). In two cases (11%) there were no cilia; in two other cases the cilia were normal, and in another two cases alterations of the central pair of microtubules were seen. Ciliary complexes were detected in all cases. We conclude that in patients with chronic or recurrent infections of the airways without known cause we must initiate a study of the nasal mucociliary transport. If this is absent or decreased, study of ciliary ultrastructure should be carried out. If mucociliary transport is normal, immotile cilia syndrome is ruled out and ultrastructural study of the cilia is not required. PMID- 7839080 TI - Nasal reactivity to histamine and methacholine: two different forms of upper airway responsiveness. AB - In 44 subjects (healthy controls and patients with allergic, non-allergic or infectious rhinitis) we compared nasal histamine and methacholine responsiveness. A weak correlation between histamine- and methacholine-induced secretion was found (r = 0.34; p = 0.02), in contrast to the highly significant association between secretion and sneezes induced by histamine (r = 0.78; p < 0.0001). Our observations suggest that histamine and methacholine responsiveness represent different forms of upper airway hyperreactivity. The contribution of glandular responsiveness as measured by methacholine challenge and the involvement of irritant receptors or reflexes as measured by histamine provocation may vary between individuals. PMID- 7839081 TI - Histamine sensitivity in the nasal mucosa during four-week use of oxymetazoline. AB - In order to objectively study the histamine sensitivity of the nasal mucosa during 30 days of regular use of oxymetazoline nasal spray (0.5 mg/ml; 0.1 ml in each nostril, thrice daily), eight healthy volunteers were examined with rhinostereometry. After 10 days on being treated, the histamine sensitivity was slightly enhanced. After a further 20 days the sensitivity was significantly increased compared to that before the start of the medication (p < 0.05). This increase in histamine sensitivity for the group is significantly greater than that of healthy drug-free volunteers, and the level is comparable with that of patients with non-allergic nasal hyperreactivity (NANH). It is concluded that a hyperreactive mucosal reaction develops after a relatively short time on oxymetazoline and that the results of this study are in line with the recommendation that the drug should not be used for more than 10 days. PMID- 7839082 TI - Turn-over of PAF in cultures of human paranasal sinus mucosa. AB - The change of PAF concentration in the culture medium was investigated by radioimmunoassay when 10(-8) M PAF or 10(-8) M lyso-PAF was incubated with a piece of normal human paranasal sinus mucosa. The PAF concentration in the medium of the former group was halved within 11.3 min and reduced to less than 5% of the initial concentration within 60 min. However, there was no significant difference in the reduction of PAF concentrations in the medium between groups with or without the mucosa. When 10(-8) M lyso-PAF was incubated with a piece of mucosa, PAF gradually increased and reached the maximum of 0.36 x 10(-8) M at 20 min, and thereafter quickly decreased to a non-detectable level. PMID- 7839083 TI - Immunological localization of neuropeptide-degrading enzymes in the nasal mucosa. AB - Neutral endopeptidase (NEP, EC 3.4.24.11), angiotensin-converting enzyme (ACE, EC 3.4.15.1) and carboxypeptidase N (CPN, EC 3.4.17.3) are potentially important enzymes which regulate the degradation of neuropeptides, such as bradykinin (BK) and substance P (SP), in the respiratory mucosa. Some neuropeptides are also degraded by these enzymes in vitro and in vivo. We investigated the localization of these enzymes in the human nasal mucosa by an indirect immunohistochemical technique (immunogold silver staining). NEP-immunoreactive areas were present in the epithelium, the serous cells of the submucosal glands, and the endothelial cells of small vessels. The epithelium and the serous cells were the predominant areas of NEP immunoreactivity in the nasal mucosa. ACE-immunoreactive areas were seen in the outer layer of the epithelium, the endothelial cells of vessels, and widely distributed in the superficial lamina propria. The endothelial cells of the vessels showed maximum positive intensity to ACE. CPN-immunoreactive areas were observed in the epithelium, the endothelium of vessels and the superficial lamina propria, except for the gland cells. The superficial lamina propria exhibited maximum immunoreactivity for CPN. We observed that the enzymes were widely distributed in the nasal mucosa. The epithelium, including the epithelial cells and glycocalyx, contains all three enzymes. These enzymes play an important role in the mucosal immunity of the respiratory mucosa by degrading active neuropeptides. These results show that NEP secretion is regulated by a glandular, cholinergic control. On the other hand, ACE and CPN secretion are regulated by vascular permeability. PMID- 7839084 TI - Radio-opacity of the paranasal sinuses. Conventional views and CT. AB - In order to examine the reliability of conventional views in predicting the degree of radio-opacity, irrespective of soft tissue or fluid seen in chronic sinusitis in adults, a comparison has been made between the results of evaluations by two routine views (Caldwell's and Waters') and by CT in axial scans. Ninety-seven sides (61 case) were included in the study. The radio-opacity was classified into three groups according to the degree of aeration or radiolucency. The diagnosis of plain films were classified into three categories (matched diagnosis, over-diagnosis, and under-diagnosis) in comparison to the radio-opacity depicted by corresponding CT scans. The incidences of matched diagnosis are, in the order of percentages: maxillary sinus (78.4%), frontal sinus (71.1%), nasofrontal area (66.0%), anterior ethmoidal cells (52.6%), and posterior ethmoidal cells (52.6%). The incidence of over-diagnosis is highest in the posterior ethmoidal cells (52.6%) and lowest in the maxillary sinus (20.6%). The incidence of under-diagnosis is highest in the anterior ethmoidal cells (24.7%) and lowest in the maxillary sinus (1.0%). PMID- 7839085 TI - Normalization of maxillary sinus mucosa after FESS. A prospective study of chronic sinusitis with nasal polyps. AB - To observe the normalization of antral mucosa after FESS, 71 patients suffering from chronic sinusitis with nasal polyps were enrolled in this study. Pre operative profiles including history, allergy skin test, and saccharin time test were done. Endoscopic findings of the antral mucosa were divided into 3 groups: polyposis, oedema, and thickening. The time sequence required for normalization of the mucosa was observed through the antromeatal opening. A patient's history of more than seven years, a saccharin time longer than 36 min, and polyposis of antral mucosa are ominous signs for recovery. The most frequent endoscopic finding of maxillary sinusitis is oedema and many of the sinus units (42%) gained complete recovery during the third month. Pre-operative profiles and endoscopic findings during surgery can serve as a reference of recovery time and treatment modality. PMID- 7839086 TI - Sensation of nasal obstruction compared to rhinomanometric results in patients referred for septoplasty. AB - In previous studies concerning correlations between subjective nasal obstruction and rhinomanometric findings the subjects quite often had normal nasal status and symptomless nasal breathing. The correlation sometimes proved to be poor. In the present study, intercorrelations between rhinomanometry and subjective sensation of nasal patency were evaluated in 102 patients referred for septoplasty. The hypothesis was that this material should give more realistic results than normal cases. In pre-operative rhinomanometry it was found that in 62 cases the nasal airway resistance (NAR) after decongestion of the nasal mucosa was pathological compared to our normal material and in 40 cases it was within normal range. The patients were asked, before rhinomanometric recording, to indicate the narrower side of the nose, right or left. After that, both baseline and post-decongestion recordings were made. The rhinomanometric results concerning the side difference were compared to the subjective assessment. Our results showed that in the 62 cases with pathological NAR the subjective and rhinomanometric evaluation was consistent in 46 of the baseline and 50 of the decongestion cases. In the 40 patients with normal NAR the figures were 19 and 20, respectively. It is obvious that if NAR is low it is more difficult for the patient to determine the more obstructed side. We conclude that rhinomanometry rather than the subjective sensation of the subject is more suited to detect subtle side difference in resistance between the nares. PMID- 7839087 TI - Minimal cross-sectional areas, nasal peak flow and patients' satisfaction in septoplasty and inferior turbinectomy. AB - Changes in minimal cross-sectional areas, measured by acoustic rhinometry as well as nasal peak flow fractions and linear analogue patients' satisfaction scores, were measured in two groups of eight patients each, undergoing septoplasty alone and septoplasty combined with trimming of the inferior turbinates, respectively. Patients who had both procedures performed showed the greatest increase in both minimal cross-sectional areas and peak flow fractions, and both of these parameters were closely correlated with patients' satisfaction, whether the patient was satisfied or not. Pre-operative nasal obstruction was worse in the dual-procedure group, but post-operative satisfaction was significantly greater in these patients. Both acoustic rhinometry and nasal peak flow fractions can be recommended as accurate and easy to perform pre-operative measurements in patients undergoing surgery for nasal obstruction. PMID- 7839088 TI - Objective assessment of posterior choanae and subglottis. AB - The assessment of children with suspected stenosis of the posterior choanae and the subglottis can be arbitrary and subjective. A study was therefore undertaken to assess the normal size of both posterior choanae and subglottis in normal children and ascertain their relationship. The size of the posterior choanae in 72 children ranged from 3-9.3 mm (3-5.5 mm when less than one year old, and 6.1 9.3 mm when older than one year). The two sides were of equal size in 51 children (p < 0.001), in 16 children the right side was larger than the left (p < 0.01), and in 5 children the left was larger than the right side. The subglottic size in 52 children ranged between 4.2-9.3 mm (1.2-5.5 mm when less than one year old, and 6.1-9.3 mm, when older than one year). The size of the subglottis was of equal size or within 1.0 mm of the average size of the two posterior choanae in 41 children (p < 0.001), and of different sizes in 11 children. Accurate and objective assessment of either area can therefore be made by measuring and comparing the two sizes in the same child. PMID- 7839089 TI - 2,500 years of nosebleeding in art. AB - In 132 objects of art (mainly paintings and drawings, a few sculptures, and one mosaic) dating from the pre-classical period in ancient Greece to our days, nosebleeding due to different reasons could be detected in museums, churches, galleries and art-books. Children and adults were bleeding from their noses because of mechanical injury, infectious diseases, haemorrhagic diathesis, and drugs. Some artists depicted nosebleeding in a very realistic manner, others represented this symptom in an exaggerated or caricaturistic way. From a total of 132 examples of nosebleeding 53 are presented, including 18 with figures. PMID- 7839090 TI - The everlasting story of classification of pancreatitis. PMID- 7839091 TI - Biomechanical properties of the oesophagus damaged by endoscopic sclerotherapy. An impedance planimetric study in minipigs. AB - BACKGROUND: The aims of the present study were to evaluate, by means of impedance plainmetry, regional differences in biomechanical properties in the normal oesophagus and the oesophagus damaged by sclerotherapy. METHODS: Four minipigs underwent a weekly session of sclerotherapy for 4 weeks. Impedance planimetry was performed before the first session of sclerotherapy and 1 week after the last session of sclerotherapy. Investigations were performed by stepwise pressure induced balloon distensions with concomitant measurements of pressure and luminal cross-sectional area (CSA) in the oesophagus 5 and 10 cm above the gastro oesophageal junction (GEJ). RESULTS: The normal oesophagus had significantly larger CSAs 5 cm than 10 cm above the GEJ (P < 0.05). Endoscopic sclerotherapy entailed an inversion (P < 0.05) of the normal oesophageal configuration, with narrowing 5 cm above the GEJ (P < 0.05) and increased CSAs 10 cm above the GEJ (P < 0.05). CONCLUSIONS: Regional differences in CSA occur in the normal oesophagus, and sclerotherapy produces profound changes in the oesophageal configuration. PMID- 7839092 TI - Quality of life and relapse of duodenal ulcer before and after eradication of Helicobacter pylori. AB - BACKGROUND: The aim of the study was to compare relapse rates and quality of life before and after eradication of Helicobacter pylori in a group of patients with documented recurrent duodenal ulcer disease. METHODS: Seventy-four patients with three endoscopically verified duodenal ulcers during the past 2 years received triple treatment consisting of bismuth subnitrate, oxytetracycline, and metronidazole for 14 days. Quality of life was measured with the Psychosocial Adjustment to Illness Scale (PAIS-SR) and H. pylori status with the 14C-urea breath test. RESULTS: After triple treatment H. pylori was eradicated in 96%, and the ulcer was healed in all. Ulcer relapse was reduced from 100% before to 1.4% during a mean observation time of 111 weeks. The H. pylori reinfection rate was 2.4% during the 1st year. The patients were more satisfied with the health care system and had better sexual relationship and less psychologic distress 1 year after eradication of H. pylori than before. CONCLUSIONS: For patients with recurrent duodenal ulcer, eradication of H. pylori with triple treatment leads to a significantly reduced ulcer relapse rate and improved quality of life. PMID- 7839093 TI - Intravenous omeprazole/amoxicillin and omeprazole pretreatment in Helicobacter pylori-positive acute peptide ulcer bleeding. A pilot study. AB - BACKGROUND: The aims of this study were to evaluate a Helicobacter pylori eradication schedule for H. pylori-positive gastroduodenal ulcer bleeding, which could be commenced intravenously after endoscopic diagnosis, and to assess the effect of omeprazole pretreatment on bacterial eradication. METHODS: In a prospective study 20 consecutive patients with H. pylori-positive acute peptide ulcer bleeding, who were managed conservatively including endoscopic injection therapy, were treated with a 2-week regimen consisting of either 40 mg omeprazole three times daily (with the exception of the loading dose of 80 mg) and 2 g amoxicillin three times daily intravenously for 3 days and 20 mg omeprazole twice daily and 1 g amoxicillin twice daily orally for 11 days (n = 10) or only with 40 mg omeprazole three times daily (with the exception of the loading dose of 80 mg) intravenously for 3 days and 20 mg omeprazole twice daily and 1 g amoxicillin twice daily orally for 11 days (n = 10). Subsequently, both groups received 20 mg omeprazole twice daily orally for 4 weeks. RESULTS: H. pylori eradication, defined as negative bacterial findings in urease test, culture and histology, or 13C-urea breath test at least 4 weeks after cessation of omeprazole medication, was achieved in 100% (10/10) of patients in the first group but only in 30% (3/10) of patients in the second group (p < 0.01). Ulcer healing was endoscopically confirmed in all but one patient in the second group. CONCLUSIONS: For the first time a promising concept for H. pylori eradication in H. pylori positive ulcer bleeding is available by using a combined intravenous and oral omeprazole/amoxicillin therapy, which can be started intravenously immediately after an emergency upper GI endoscopy. In addition, these data imply that omeprazole pretreatment may not be wise when H. pylori eradication is attempted. PMID- 7839094 TI - Distinct profiles of gastritis in dyspepsia subgroups. Their different clinical responses to gastritis healing after Helicobacter pylori eradication. AB - BACKGROUND: A contribution of Helicobacter pylori gastritis to the pathogenesis of non-ulcer dyspepsia (NUD) remains uncertain. METHODS: Administration of an appropriate clinical questionnaire followed by endoscopy allowed us to select, among 139 outpatients with dyspepsia, 87 non-ulcer dyspepsia patients with more severe and group-distinctive symptoms, 35 of whom were classified as having ulcer like (ULD). 38 as dysmotility-like (DLD), and 14 as reflux-like dyspepsia (RLD). Biopsy specimens were evaluated for H. pylori gastritis in accordance with the Sydney system. The 70 H. pylori-positive cases were treated with omeprazole, 20 mg twice daily, and amoxycillin, 1 g three times daily for 2 weeks. RESULTS: Higher rates of H. pylori colonization were found histologically in the gastric mucosa of ULD (91%) and RLD (86%) than in that of DLD (68%) or asymptomatic (42%) patients. ULD differed from RLD patients in their higher score of antritis activity. Three and 6 months after H. pylori eradication ULD (but not DLD) showed significant regression of dypspetic symptoms scores. CONCLUSIONS: It seems likely that H. pylori gastritis, with special reference to active antritis, is among causative factors of ULD. Its role in the pathogenesis of RLD and DLD needs further investigation. PMID- 7839095 TI - Duodenal mucosal bicarbonate secretion in pigs is accompanied by compensatory changes in pancreatic and biliary HCO3- secretion. AB - BACKGROUND: The purpose of the study was to examine the effect of stimulation and inhibition of duodenal mucosal bicarbonate secretion on pancreatic and hepatic bicarbonate secretion in response to acid. METHODS: The effect of inhibition (indomethacin) or stimulation (misoprostol) of duodenal mucosal bicarbonate secretion on pancreatic and biliary bicarbonate secretion in response to intraduodenal infusion of HCl or intravenous infusion of secretin was studied in anaesthetized pigs. RESULTS: The hepatic and pancreatic response to exogenous secretin was not significantly altered by stimulation/inhibition of duodenal bicarbonate secretion. However, pancreatic and biliary bicarbonate secretion in response to duodenal acidification was significantly augmented by inhibition of duodenal mucosal bicarbonate secretion; conversely, it was reduced by stimulation of duodenal bicarbonate secretion. The increase in plasma secretin levels in response to duodenal acidification was reduced by stimulation and augmented by inhibition of duodenal mucosal bicarbonate secretion. CONCLUSIONS: Duodenal mucosal bicarbonate secretion can serve as a modulator of both pancreatic and biliary bicarbonate secretion in response to luminal acidification, possibly through regulation of the release of secretin. PMID- 7839096 TI - Quantitation of duodenogastric reflux and antral motility by color Doppler ultrasonography. Study in healthy volunteers and patients with gastric ulcer. AB - BACKGROUND: Our objective was to develop a simple, noninvasive method for evaluating duodenogastric reflux, along with antral motility and gastric emptying of a liquid meal. METHODS: Antral motility and gastric emptying were measured by ordinary ultrasonography after a meal of 400 ml consomme. Duodenogastric reflux was evaluated by means of color Doppler. In a preliminary in vitro study we demonstrated that the test meal (consomme) contained oil particles suitable as a marker for color Doppler. We then investigated duodenogastric reflux, antral motility, and gastric emptying of a liquid meal in 43 asymptomatic healthy volunteers and in 24 patients with gastric ulcer. RESULTS: This approach was feasible in 65 (97.0%) of the 67 subjects studied. Duodenogastric reflux was demonstrated in 26 (61.9%) of the 42 healthy volunteers and in 20 (87.0%) of the 23 patients with gastric ulcer. The frequency of the duodenogastric reflux and the reflux index were significantly increased in patients with gastric ulcer as compared with asymptomatic healthy volunteers. Gastric emptying and the motility index of antral contractions were significantly decreased in patients with gastric ulcer as compared with asymptomatic healthy volunteers. CONCLUSIONS: Ultrasonography with color Doppler is useful for evaluating abnormalities of gastroduodenal motility and can be used to understand the pathogenesis of such disorders. PMID- 7839097 TI - Ketanserin and granisetron reduce cholera toxin-induced hypersecretion in pig jejunum. AB - BACKGROUND: Serotonin antagonists have been proven antisecretory in cholera toxin (CT)-induced hypersecretion in the small intestine of rodents. The pig small intestine is a good model for the human small intestine with regard to physiologic and pharmacologic processes. METHODS: The antisecretory effect of intraluminally administered methysergide, renzapride, ketanserin, granisetron, and tropisetron on CT-induced hypersecretion was tested in isolated pig jejunal loops in vivo. RESULTS: Methysergide, ketanserin, and granisetron reduced the hypersecretory effect of CT maximally by 25%, 80%, and 50%, respectively. Tropisetron enhanced whereas renzapride did not alter the CT response. Combination of ketanserin and granisetron gave a maximal inhibitory effect of about 85%. Surprisingly, renzapride, granisetron, and tropisetron each induced hypersecretion. Taking into account the hypersecretory effect of the antagonists, they all reduced this CT-elicited hypersecretion. CONCLUSIONS: Results suggest involvement of the 5-hydroxytryptamine-2 and 5-hydroxytryptamine-3 receptor subtypes as mediators in CT-induced hypersecretion in pig jejunum, and antidiarrheal therapeutic potentials of ketanserin and granisetron. PMID- 7839098 TI - Effect of fiber source on short-chain fatty acid production and on the growth and toxin production by Clostridium difficile. AB - BACKGROUND: Fermentable fiber promotes the growth of resident gut microbes, which modify the environment of the gastrointestinal tract and thus prevent colonization by Clostridium difficile. METHODS: An in vitro system with pigs as fecal inoculum donors was used to estimate fiber fermentability and changes in intestinal microbiota. RESULTS: Acetate and propionate production (mumol/mg substrate fermented/day) was greatest for gum arabic (1013.4 and 704.1, respectively); butyrate production was greatest for xylo-oligosaccharide (345.6). Growth of total anaerobes and clostridia was greatest for gum arabic (21.2 and 16.2 x 10(8) counts/ml, respectively) and xylo-oligosaccharides (21.0 and 19.6 x 10(8) respectively); growth of acidogenic bacteria was greatest with fructo oligosaccharide (6.7 x 10(8) counts/ml). No culturable counts of C. difficile were obtained, nor was toxin A detected. CONCLUSIONS: Fermentable fibers support the growth of indigenous intestinal bacteria, particularly acidogenic bacteria, and yield large amounts of short-chain fatty acids with decreased gut pH. These factors contribute to the prevention of growth and toxin elaboration by C. difficile. PMID- 7839099 TI - Mycobacterium paratuberculosis in intestinal tissue from patients with Crohn's disease demonstrated by a nested primer polymerase chain reaction. AB - BACKGROUND: The etiology of Crohn's disease remains unknown, but current research has concentrated on autoimmunity and/or mycobacterial infection. The polymerase chain reaction (PCR) enables the detection of genetic material even when very few microorganisms are present. METHODS: A nested primer PCR for detection of a multi copy insertional element (IS900) specific for Mycobacterium paratuberculosis was applied to DNA extracted from fresh and from paraffin-embedded intestinal tissue obtained from patients undergoing surgery. RESULTS: In fresh intestinal tissue from 11 of 24 patients with Crohn's disease, from 2 of 10 patients with ulcerative colitis, and from 3 of 28 patients with other colonic disorders, specific M. paratuberculosis DNA was found. In paraffin-embedded Crohn's disease tissue the presence of specific M. paratuberculosis DNA was also increased. CONCLUSIONS: Whether the presence of M. paratuberculosis is connected to the inflammatory bowel disease or is a mere coincidence cannot be stated. We find this presence interesting and encouraging for further investigations. PMID- 7839100 TI - Primary adenocarcinoma of the duodenum with choledochoduodenal fistula. AB - BACKGROUND: Primary adenocarcinoma of the duodenum is an uncommon clinical entity. It has been associated with a dismal prognosis because it is rare and produces no distinctive symptoms until late in its course. CASE SUMMARY: A 68 year-old man presented with a 6-month history of epigastralgia, anorexia, and progressive weight loss. Esophagogastroduodenoscopy showed a tumor mass in the deformed duodenal bulb with a fistula into the biliary tract. Upper gastrointestinal (UGI) barium studies and cholangiography confirmed a fistulous communication between the duodenum and biliary tree. CONCLUSIONS: Aggressive evaluation of minor, yet refractory, UGI symptoms and a high index of suspicion offer the best hope for early diagnosis. Esophagogastroduodenoscopy and barium UGI study are the principal methods of diagnosis of these tumors. Early diagnosis would thus prevent metastasis and complications. PMID- 7839101 TI - Gallbladder motility and cholecystokinin release during long-term enteral nutrition in patients with Crohn's disease. AB - BACKGROUND: Gallbladder bile stasis during long-term continuous enteral feeding may contribute to the high prevalence of gallstones in patients with Crohn's disease. We therefore examined the effects of continuous enteral nutrition on gallbladder motility and cholecystokinin (CCK) release in six patients. METHODS: Gallbladder volume was measured ultrasonographically for 12 h on days 1 (start), 8, 22 (6-h interruption of enteral feeding), 36, and 43 (end) of enteral feeding. Plasma CCK was assessed at several time points. RESULTS: Initial fasting gallbladder volume was 19.3 +/- 4.5 (mean +/- SEM) ml, which decreased to 4.9 +/- 3.6 ml after start of feeding. CCK increased from 1.5 +/- 0.3 to 3.9 +/- 1.1 pmol/l. On days 8 and 36 the gallbladder was almost completely contracted, and CCK increased to 7.5 +/- 2.7 and 8.3 +/- 2.6 pmol/l, respectively. On days 22 and 43 gallbladder volume increased, and CCK decreased rapidly to fasting concentrations after interruption of feeding. CONCLUSIONS: During continuous enteral nutrition the gallbladder is completely contracted, and CCK concentrations remain elevated. It is therefore unlikely that long-term enteral nutrition contributes to the increased prevalence of gallstones in patients with Crohn's disease. PMID- 7839102 TI - Mild sialoadenitis: a common finding in patients with hepatitis C virus infection. AB - BACKGROUND: Sjogren's syndrome (SS) is an autoimmune disease of presumed viral origin; sialoadenitis has been reported to occur in hepatitis C virus (HCV) infection. METHODS: Lip biopsy specimens were graded in 32 consecutive patients with either HCV-related chronic liver disease or SS. RESULTS: Seventeen of 22 HCV positive patients had sialoadenitis, although generally mild (15 of 17, grades I II). Severe inflammation (grades III-IV) was observed in 8 of 10 patients with SS (chi-square = 12.6; P < 0.0005). Moreover, HCV-positive patients with sialoadenitis differed from patients with SS in female sex prevalence (6 of 17 versus 10 of 10; chi-square = 10.9; P = 0.0001) and presence of serum antinuclear autoantibodies (0 of 17 versus 9 of 10; chi-square = 23.0; P < 0.0001). Five of 13 HCV-positive patients and 7 of 8 patients with SS were HLA-DR3-positive (chi square = 4.9; P < 0.05). CONCLUSIONS: Sialoadenitis of HCV-related liver disease is common but differs from SS with regard to predisposing genetic factors, expression of autoimmune markers, and histopathologic severity. PMID- 7839103 TI - The problem of classification and staging of chronic pancreatitis. Proposals based on current knowledge of its natural history. AB - BACKGROUND: Even though the four international meetings held so far on classification of pancreatitis have helped considerably to further our understanding of the disease, all have serious drawbacks that limit their clinical utility. The main problem with the Marseille classifications is the need for histologic proof, and the Cambridge classification relies on imaging modalities that are not sensitive or specific enough. RESULTS: Chronic pancreatic inflammation (CP) has been observed in association with several systemic diseases (such as autoimmune diseases), and since the natural history of the pancreatic affliction in these conditions is clearly distinct from that seen in other forms of CP, these need to be classified separately. Furthermore, many clinical/aetiologic forms of chronic calcifying pancreatitis (CCP) exist which differ sufficiently in their clinical features and management to deserve individual recognition. PROPOSAL: A subclassification of CCP into alcoholic, tropical, hereditary, hypercalcaemic, hyperlipoproteinaemic, drug-induced, and idiopathic is proposed. The staging of chronic alcoholic pancreatitis has been a controversial issue, mainly because of the apparent unpredictability of the course of pain. However, several large follow-up studies in the past decade suggest that recurrent acute exacerbations dominate the clinical picture in the first few years after onset of symptoms, and progressive pancreatic insufficiency is the predominant feature in the late stages of the disease. On the basis of the results of these studies it is proposed that alcoholic chronic pancreatitis be divided into four stages: I) latent or subclinical, II) early, or stage of inflammatory complications, III) late, or stage of severe pancreatic insufficiency, and IV) advanced, or stage of secondary painless pancreatitis. PMID- 7839104 TI - [Results in stent implants in pelvic arteries: follow-up with color-coded duplex ultrasonography]. AB - Thirty-one patients (26 males, 5 females), treated with percutaneously inserted endoprostheses (stents) in the iliac artery were followed up a mean 1 year (2-60 months) with regard to clinical and non-invasive results, by color duplex ultrasound and (8 cases) angiography. With one exception self-expandable stents (Wallstents) were applied. The indications for stent implantation were PTA resistant lesions in 78% and treatment of acute complications after PTA in 22%. Primary technical success with an open stent was achieved in all patients. The ankle-arm systolic pressure index (ASPI) increased from mean 0.67 +/- 0.14 to 0.88 +/- 0.17 (p < 0.001). Early stent occlusion occurred in 1 patient (3%), and 9 (24%) further complications (thrombosis, distal embolization, puncture site problems) were treated either by conservative or interventional procedures, and only once by surgical revision. Color duplex ultrasound showed all stents open without stenosis of hemodynamic significance. Angiography demonstrated intimal hyperplasia in 2 patients with stenosis of about 20-25%. At follow-up 61% of the patients were asymptomatic, 32% were improved. Remaining symptoms were due to lesions of the distal arteries and not to obstructions of the stents. Stenting of iliac arteries is a safe and effective treatment for recurrent and/or complex iliac lesions and has become a valuable adjunct in catheter interventions. We conclude that color duplex ultrasound is not only applicable in native arteries but also in stents, and gives reliable results with regard to hemodynamically relevant obstructions. PMID- 7839105 TI - [Diagnostic tomodensitometry of acute basilar thrombosis]. AB - Basilar artery thrombosis is a potentially treatable neurologic disease whose initial symptoms are sometimes difficult to recognize. The basilar artery is hyperdense on computed tomography in cases with basilar artery thrombosis. We have studied computed tomography attenuation values before and after contrast administration in a total population of 117 patients, 12 of whom were diagnosed angiographically as having basilar artery thrombosis. While it is not always possible to detect basilar artery thrombosis simply by evaluation of the tomodensitometric values before or after contrast, the differential values obtained by subtracting them (after contrast/before), or by an attenuation ratio corresponding to the differential value divided by the value before contrast, are more helpful. Indeed, the differential values and attenuation ratios in the normal population have a mean value of 51.1 and 1.37 compared with 14.47 and 0.33 in patients with basilar artery thrombosis. PMID- 7839106 TI - [Interrupted aortic arch: fortuitous diagnosis in a 72-year-old female patient with severe aortic insufficiency]. AB - Interrupted aortic arch, defined as complete luminal and anatomic discontinuity between ascending and descending aorta, is an uncommon and highly lethal anomaly. We report the case of a 72-year-old woman scheduled for aortic valve replacement because of severe regurgitation. During preoperative catheterization, it was not possible to reach the ascending aorta from a femoral puncture. Further radiological investigation demonstrated interrupted aortic arch of type A without other cardiac or vascular anomalies. Postoperative course after aortic valve replacement and ascending-to-supraceliac aortic bypass was initially uneventful. Unfortunately, pericardial tamponade developed 10 days after the operation and required re-exploration, during which no active bleeding could be found. Recurrent effusion occurred and the patient finally died from severe shock and multiorgan failure. This exceptional case prompted a review of the literature which confirmed the rarity of this presentation in adult patients. It seems interesting that only mild arterial hypertension of the upper extremities was retrospectively found in this patient. PMID- 7839107 TI - [Radiofrequency ablation in the therapy of supraventricular and ventricular arrhythmias]. AB - We summarize our experience with RF-ablation in 70 patients with symptomatic tachycardia (38 females and 32 males, age 25-73 years). 19 patients with AV reentry tachycardia in WPW-syndrome, 28 patients with node reentry tachycardia (AVNRT), 10 patients with ventricular tachycardia, 9 patients with atrial fibrillation and 4 patients with atrial flutter were treated. The primary success rate in the whole patient group is 87% and the longterm success rate (up to 1 year) 81%. RF-ablation of tachycardia is a highly effective therapy. The patients are free of symptoms and need no further medication. In patients with AVNRT in WPW-syndrome and ventricular tachycardia (structurally normal heart), RF-ablation is the therapy of choice. 32/70 patients were treated on an outpatient basis. PMID- 7839108 TI - [Gene therapy and ethics]. AB - Gene therapy represents a new strategy to treat human disorders. It was originally conceived as a cure for severe monogenetic disorders. Since its conception, the spectrum of possible application for gene therapy has been to include the treatment of acquired diseases, such as various forms of cancer and some viral infections, most notably human immune deficiency virus (HIV) and hepatitis B virus. Since somatic gene therapy does not cause substantially new ethical problems, it has gained broad approval. This is by no means the case with germ-line gene therapy. Practically all bodies who were evaluating the related ethical aspects wanted to ban its medical application on grounds of fundamental and pragmatic considerations. In this review, practical and ethical views concerning gene therapy are summarized which were presented at the "Junitagung 1994" of the Swiss Society for Biomedical Ethics in Basle. PMID- 7839109 TI - [Fatal consequences]. PMID- 7839110 TI - [Concerning: F. Cavalli: Adriamycin/cyclophosphamide: current standard in adjuvant therapy of breast carcinoma? (Schweiz Med Wochenschr 1994; 124 1882 1884)]. PMID- 7839111 TI - [Concerning: F. Cavalli: Adriamycin/cyclophosphamide: current standard in adjuvant therapy of breast carcinoma? (Schweiz Med. Wochenschr 1994; 124:1882 1884)]. PMID- 7839112 TI - [On the significance and insignificance of knowledge]. PMID- 7839113 TI - Biological pathways of radionuclides originating from the Chernobyl fallout in a boreal forest ecosystem. AB - In an attempt to understand the mechanisms governing the transfer and retention of radiocaesium in the understorey vegetation, 39 macromycetes species and 33 plant species, together with humus samples, were systematically collected from the undercover vegetation in a boreal coniferous forest. The results indicate that the main factors determining interspecific differences in contamination level are the rooting depth in plants, the depth of mycelium in fungi, and the ecophysiological behaviour of fungi, mycotrophism or plant parasitism. A comparison between the investigated species and the same species growing in similar ecosystems, albeit under different climatic conditions, resulted in an almost identical ranking in terms of radiocaesium contamination levels; the contamination ratios between species were also relatively constant. From an experiment involving humus samples, it was shown that up to 40% of the radiocaesium could be retained by the microflora, particularly by mycelia. PMID- 7839114 TI - Radionuclides in the liquid phase of the forest soils at the Chernobyl accident zone. AB - The relative content (alpha) of 137Cs (1987-1991), 106Ru, 134Cs, 144Ce (1987) and the chemical speciation of radionuclides in the liquid phase of forest soils at different plots in the 30-km Chernobyl zone were studied. One year after the accident, substantial variations in the alpha-value between the different plots and a variation in alpha along the soil profile were observed due to unequal physico-chemical properties of nuclear fallout and soils. The alpha-value calculated for the total contaminated layer (alpha av) at different plots varied within relatively narrow limits. Between 77 and 97% of 137Cs in soil solution was shown to be included in organic compounds (MMw, 10(2)-10(4) Da), the latter making a major contribution to the radionuclide transport from soil to plant. The alpha-value for 137Cs for all plots in the Chernobyl 30-km zone and the differences in alpha value between plots had a tendency to decrease with time. These data indicate that the process of 137Cs fixation by the soil solid phase was prevalent. Now, the 'soil-soil solution' system is approaching equilibrium for the radionuclide distribution between solid and liquid phases. PMID- 7839115 TI - Vertical radionuclide transfer by infiltration water in forest soils in the 30-km Chernobyl accident zone. AB - Vertical intrasoil flow within the 30-km zone of the Chernobyl nuclear power plant (ChNPP) was investigated by a lysimetric method in 1989-1990. The regularity of radionuclide migration within the flow has been found to be dependent on the contamination density, the type of radionuclide, and the type of ecosystem and depth. PMID- 7839116 TI - Novel approaches to the estimation of intake and bioavailability of radiocaesium in ruminants grazing forested areas. AB - It is difficult to measure transfer of radiocaesium to the tissues of forest ruminants because they can potentially ingest a wide range of plant types. Measurements on undomesticated forest ruminants incur further difficulties. Existing techniques of estimating radiocaesium intake are imprecise when applied to forest systems. New approaches to measure this parameter are discussed. Two methods of intake estimation are described and evaluated. In the first method, radiocaesium intake is estimated from the radiocaesium activity concentrations of plants, combined with estimates of dry-matter (DM) intake and plant species composition of the diet, using plant and orally-dosed hydrocarbons (n-alkanes) as markers. The second approach estimates the total radiocaesium intake of an animal from the rate of excretion of radiocaesium in the faeces and an assumed value for the apparent absorption coefficient. Estimates of radiocaesium intake, using these approaches, in lactating goats and adult sheep were used to calculate transfer coefficients for milk and muscle; these compared favourably with transfer coefficients previously obtained under controlled experimental conditions. Potential variations in bioavailability of dietary radiocaesium sources to forest ruminants have rarely been considered. Approaches that can be used to describe bioavailability, including the true absorption coefficient and in vitro extractability, are outlined. PMID- 7839117 TI - Influence of herbivory on caesium turnover in a forest ecosystem. AB - The effect of herbivory by bank vole (Clethrionomys glareolus) and moose (Alces alces) in relation to litterfall in a boreal forest is analysed. The main purpose is to estimate the relative importance of these processes for the transfer of caesium-137 to soil. Biomasses of litterfall and food consumption were selected from different forest biotopes. The analysis of the input and output of caesium 137 in the vole and moose populations is based on mass balance calculations for caesium-137 in steady state conditions. From this assessment, herbivory appears to be within an order of magnitude of litterfall. With due regard to the lower caesium level in litterfall than in living plant tissue, transfer of radioactive caesium by herbivory is seen to be even higher in comparison to that by litterfall, than apparent from the corresponding transfer of organic matter. In addition, the availability of caesium-137 from animal excrements is expected to be high and fast, which further emphasises the relative importance of herbivory and feed-back from vegetation to soil. PMID- 7839118 TI - Radiocaesium transfer to man from moose and roe deer in Sweden. AB - Studies of radiocaesium in the forest ecosystems in Sweden resulted in aggregated transfer factors quantified for the transfer of 137Cs from soil to moose and roe deer. These aggregated transfer factors were 0.02 m2 kg-1 for moose and 0.05 m2 kg-1 for roe deer. There seems to be no decrease in the 137Cs activity concentrations in moose harvested in our research area and therefore we suggest the use of the physical half-life of 137Cs (30 years) as the effective ecological half-life. The time-integrated transfer of 137Cs from the Chernobyl fall-out to man by moose in Sweden was calculated and found to be 115 GBq, corresponding to 1500 man Sv for moose. The time-integrated transfer by roe deer to man was estimated to be between 25-48 GBq, corresponding to 327-620 man Sv for roe deer. The annual transfer of 137Cs to man by moose has varied between 2.0-2.7 GBq, corresponding to 27-34 man Sv. Depending on the group studied, the mean annual transfer of 137Cs can be calculated to be from about 250 to 43,000 Bq. For example, the mean annual transfer of 137Cs by moose to hunters and their families in Gavle commune, the most affected commune in Sweden, was estimated to be about 26,000 Bq, corresponding to 0.34 mSv. PMID- 7839119 TI - Fungal spores in faeces as evidence of fungus ingestion by sheep. AB - In Ireland, upland areas are becoming extensively planted with coniferous forest to which sheep are allowed access. Such forest produces many more fruiting bodies of basidiomycetes than the blanket bog on which it was planted. Faecal samples taken from hill and adjacent forest (Picea abies) grazing areas showed an autumnal increase in radiocaesium in the forest samples compared with the hill samples, and there was an indication of higher in vivo radiocaesium activity in the autumn, particularly in individual animals which are known to graze the forest. The peak faecal and in vivo radiocaesium levels coincided with the fungal growing season. A new method is presented using fungal spores, which proves the ingestion of fungi by sheep and permits the identification and quantification of the fungi consumed. PMID- 7839120 TI - Strontium-90 in antlers of red deer: an indicator of environmental contamination by strontium-90. AB - The sampling procedures in connection with a very sensitive analytical method are described. Results from different areas in Austria are presented and an interpretion of the results is attempted. Some findings are in accordance with measurements from other substances, some are not. The differences most probably depend on several factors like soil type, precipitation, migration of strontium 90, concentration of stable strontium and calcium. No significant rise in the concentration could be found after 1986 thus in accordance with other measurements of strontium-90 contamination after the Chernobyl accident. PMID- 7839121 TI - Acute and long-term effects of irradiation on pine (Pinus silvestris) strands post-Chernobyl. AB - The effect of ionizing irradiation on the viability of pine stands after the fallout from the damaged nuclear energy plant at Chernobyl (ChNPP) was shown within the territory of the 10-km zone. During the period 1986-1991, irradiated and damaged forest stands, so-called 'red forest', located in this area were systematically classified by observation. Mortality rate, re-establishment, development of tree canopies, reproduction anomalies and stand viability were shown to be dependent on absorbed irradiation dose, on the age of the stand and on forest composition. For pine stands in the acutely affected zone, doses of more than 60 Gy resulted in a massive mortality and no regeneration of pine trees since 1987. The injured trees had burned or had dried-up. The drying process was accelerated by a massive production of pathogenic insects invading the dying trees. Specifically, irradiation doses of 10-60 Gy, 1-10 Gy and 0.1-1 Gy caused high, medium and low injury to the forest stands, respectively. Doses of less than 0.1 Gy did not cause any visible damage to the trees. In 1987, repair processes were displayed by the tree canopies and practically the entire viability of the forest stands had recovered except for trees in the acute and highly affected zones. The young forest was reestablished in the same place as the perished trees and new pine saplings were planted on the reclaimed areas. PMID- 7839122 TI - Histological changes in Pinus sylvestris L. in the proximal-zone around the Chernobyl power plant. AB - In September 1990, samples of wood and bark were collected from Pinus sylvestris L. at three locations exposed to different levels of radioactive fallout from the 1986 accident at the Chemobyl nuclear power plant (NPP). Cross-sections of wood from the most exposed location showed a distinct change in histology in the annual ring of 1986, a consequence of the accident on 26 April. The width of annual rings decreased after the accident, and the relative width of latewood in annual rings increased transiently in 1986 and subsequently decreased in 1987. In 1987, an increase in the number of vertical resin ducts was observed, related to contamination at the location, and the number of radial rays decreased at the two locations of higher contamination. The radionuclide content in the bark was found to correlate with the degree of damage in the wood. There are several hypotheses about the contribution from various types of radioactive contamination, but the results indicate that both 'cloud gamma' and deposited radioactivity (beta and gamma) were of importance. The present work suggests that detailed studies of dose-effect relationships after exposure to different dose rates and radiation qualities may establish the usefulness of pine trees as in situ, time-recording differential dosimeters of ionizing radiation. PMID- 7839123 TI - Main investigation results on the forest radioecology in the Kyshtym and Chernobyl accident zones. AB - As a result of the long-term studies of radionuclide migration in forest ecosystems in zones of radioactive contamination after the Kyshtym and Chernobyl accidents, the following trends were revealed: (1) High retention capacity of stand canopy with respect to radioactive fallout. This leads to high doses absorbed by apical and leaf meristems, beta-radiation giving the main part of the dose; (2) Fast self-decontamination of crowns during the growth period and relatively slow decontamination in the phase of physiological rest, regardless of amount of atmospheric precipitation. The rate of crown decontamination determines the value and duration of radiation stress on woody plants; (3) Accumulation not less than 95% of the total radionuclide amount in the forest litter 1-2 years after the cessation of radioactive fallout; (4) Relatively slow migration of strontium and cesium radionuclides along the forest soil profile; (5) High capacity of the forest when serving as a biogeochemical barrier to the routes of horizontal and vertical radionuclide migration and export out of the zone of initial contamination, including migration into the river water; (6) Considerable difference between strontium and cesium when migrating in forest soils and in the soil-plant system; (7) Broad variations in transfer factors for uptake of cesium 137 from soil into forest plants depending on the plant species and soil type. The primary radiobiological effects connected with irradiation of organisms are considered and secondary disturbances due to changes of ecological bonds between the components of irradiated forest ecosystem are discussed. PMID- 7839124 TI - Element reference values in tissues from inhabitants of the European Community. VI. Review of elements in blood, plasma and urine and a critical evaluation of reference values for the United Kingdom population. AB - Reference values for the concentration of elements in whole blood for the UK population are presented together with estimates for concentrations in plasma and urine. The blood data, when compared with other values obtained for Belgium, Denmark and Italy, obtained through the EURO-Terviht programme of the European Union, together with data from other countries, indicate similar concentrations. The data provide a basis for identifying the expected levels for the non occupational exposed population against which differences attributable to various states of well-being, morbidity and mortality can be evaluated. However, it is also apparent that significant differences do exist which are related to geography and diet. In order to consider these differences, further improvements in the determination of elements in human tissues and fluids are required. Particular attention should be paid to that proportion of an element in the environment which is bioavailable together with its toxicity. PMID- 7839125 TI - Trace element reference values in tissues from inhabitants of the European Community. VII. Review of trace elements in blood, serum and urine of the Belgian population and critical evaluation of their possible use as reference values. AB - The availability of accurate trace element reference values in human tissues represents an important indicator to the health status of the general population and occupational groups exposed to trace elements. The EURO TERVIHT project (Trace Element Reference Values In Human Tissues) aims to establish and compare trace element reference values in tissues from inhabitants of the European Community as baseline values for clinical/toxicological assessment studies (Sabbioni et al., 1992a,b). In this context one of the first steps considered is the critical evaluation (state of the art) of existing literature on trace element reference values in blood, serum and urine in the general population of each EC country. This paper reviews the Belgian situation. PMID- 7839126 TI - Trace element reference values in tissues from inhabitants of the European Union. VIII. Thallium in the Italian population. AB - In order to establish reference values of thallium in tissues of the general population the element was determined in blood (TlB) and urine (TlU) of 123 healthy inhabitants living in the Marche region, Central Italy. The analysis was carried out by inductively coupled plasma-mass spectrometry (ICP-MS; detection limit in our experimental conditions, 0.001 micrograms Tl/I), which was validated by neutron activation analysis (NAA) and laser induced fluorecence (LIF) spectroscopy. The check of pre-analytical factors indicated a low risk of contamination and loss of Tl during sampling, handling and storage before the instrumental analysis (blank of the entire procedure less than the detection limit). Mean values of TlU and TlB were 0.066 micrograms Tl/l and 0.063 micrograms Tl/l, respectively (median in both cases 0.057 microgram Tl/l). No conclusive evidence concerning the distribution followed by our data set, normal or log-normal, were drawn, although Lilliefors test and Kolmogorov's D-test showed a tendency for TlB to follow both the normal and the log-normal while TlU followed a log-normal distribution. Overall correlations between TlU and TlB are rather weak. A significant, but not high, correlation (P < 0.0004, r = 0.44) was observed in females. Age, sex, smoking habits and alcohol consumption did not seem to play any role on TlU and TlB. Tentatively proposed reference intervals are 0.019-0.17 microgram Tl/l (urine) and 0.014-0.19 microgram Tl/l (blood). PMID- 7839127 TI - Lead exposure of the child population in Greece. AB - Lead exposure of the child population was studied in three different areas in Greece: Kalamata which is a rural area of Southern Greece; Tavros, a district of Athens with a considerable industrial activity; and Lavrion, a small city near Athens where a lead-zinc mining and smelting industrial complex has existed for more than 90 years. The results were evaluated with respect to a number of individual, social and environmental variables (i.e. smelter, occupation of the father) especially those concerning the area of Lavrion which is the most heavily polluted area in Greece. The results of this study can be considered as an index for the extent of the lead pollution problem in the named areas of Greece. PMID- 7839128 TI - E. coli sequencing. PMID- 7839129 TI - E. coli sequencing. PMID- 7839130 TI - NSF FastLane goals. PMID- 7839131 TI - Risk assessments of low-level exposures. PMID- 7839132 TI - Risk assessment of low-level exposures. PMID- 7839133 TI - Other lipopeptides. AB - Several authors' changes should have been included in the response by D. B. Wheeler et al. to the technical comment "Identification of calcium channels that control neurosecretion" (4 Nov., p. 830). A sentence reading, "Comparisons with experiments using higher concentrations of carrier protein (1.0 mg/mL) revealed no significant differences in the rate of efficacy of omega-Aga-IVA action" should have been inserted before the last sentence in the legend of figure 1. The measure "30 nM" (not 20 nM) should have appeared 19 lines from the bottom of the last column on page 830. The second-to-last sentence in that paragraph should read, "Increasing the duration of exposure to 30 nM omega-Aga-IVA from 20 min (1) to 45 min revealed significant inhibition of synaptic transmission (n = 9)." Reference "(15)" (not 16) should have appeared seven lines from the top of the first column on page 831. PMID- 7839134 TI - Radiation biology. NAS to lose contract for A-bomb study. PMID- 7839135 TI - Primate genetics. Getting the poop on baboon DNA. PMID- 7839136 TI - Neurobiology. Brain center linked to perfect pitch. PMID- 7839137 TI - Protein images update natural history. PMID- 7839138 TI - Reexamining AIDS research priorities. PMID- 7839139 TI - Metal ions in the atmosphere of Neptune. AB - Microwave propagation experiments performed with Voyager 2 at Neptune revealed sharp layers of electrons in Neptune's lower ionosphere with densities of approximately 10(4) per cubic centimeter. These layers are reminiscent of the sporadic-E layers in the Earth's ionosphere, and when taken together with data from the other giant planets, these data confirm the importance of the magnetic field in layer formation. A photochemical model that incorporates species produced by meteoroid ablation predicts that singly ionized magnesium is the most likely metal to be found in the layers, although laboratory data on the kinetics of metallic atoms and ions in a reducing environment are lacking. The metal chemistry discussed here is directly relevant to the abundant metals observed at the impact site of the G fragment of comet Shoemaker Levy 9 on Jupiter. PMID- 7839141 TI - Neutron reflection study of bovine beta-casein adsorbed on OTS self-assembled monolayers. AB - Specular neutron reflection has been used to determine the structure and composition of bovine beta-casein adsorbed on a solid surface from an aqueous phosphate-buffered solution at pH 7. The protein was adsorbed on a hydrophobic monolayer self-assembled from deuterated octadecyltrichlorosilane solution on a silicon (111) surface. A two-layer structure formed consisting of one dense layer of thickness 23 +/- 1 angstroms and a surface coverage of 1.9 milligrams per square meter adjacent to the surface and an external layer protruding into the solution of thickness 35 +/- 1 angstroms and 12 percent protein volume fraction. The structure of the (beta-casein) layer is explained in terms of the charge distribution in the protein. PMID- 7839140 TI - Imaging with intermolecular multiple-quantum coherences in solution nuclear magnetic resonance. AB - A magnetic resonance imaging technique based on intermolecular multiple-quantum coherences in solution (the correlated spectroscopy revamped by asymmetric z gradient echo detection or CRAZED experiment) is described here. Correlations between spins in different molecules were detected by magnetic-field gradient pulses. In order for a correlation to yield an observable signal, the separation between the two spins must be within a narrow band that depends on the area of the gradient pulses. The separation can be tuned from less than 10 micrometers to more than 1 millimeter, a convenient range for many applications. PMID- 7839142 TI - Minor groove recognition of the conserved G.U pair at the Tetrahymena ribozyme reaction site. AB - The guanine-uracil (G.U) base pair that helps to define the 5'-splice site of group I introns is phylogenetically highly conserved. In such a wobble base pair, G makes two hydrogen bonds with U in a geometry shifted from that of a canonical Watson-Crick pair. The contribution made by individual functional groups of the G.U pair in the context of the Tetrahymena ribozyme was examined by replacement of the G.U pair with synthetic base pairs that maintain a wobble configuration, but that systematically alter functional groups in the major and minor grooves of the duplex. The substitutions demonstrate that the exocyclic amine of G, when presented on the minor groove surface by the wobble base pair conformation, contributes substantially (2 kilocalories.mole-1) to binding by making a tertiary interaction with the ribozyme active site. It contributes additionally to transition state stabilization. The ribozyme active site also makes tertiary contacts with a tripod of 2'-hydroxyls on the minor groove surface of the splice site helix. This suggests that the ribozyme binds the duplex primarily in the minor groove. The alanyl aminoacyl transfer RNA (tRNA) synthetase recognizes the exocyclic amine of an invariant G.U pair and contacts a similar array of 2' hydroxyls when binding the tRNA(Ala) acceptor stem, providing an unanticipated parallel between protein-RNA and RNA-RNA interactions. PMID- 7839143 TI - Genetic decreases in atrial natriuretic peptide and salt-sensitive hypertension. AB - To determine if defects in the atrial natriuretic peptide (ANP) system can cause hypertension, mice were generated with a disruption of the proANP gene. Homozygous mutants had no circulating or atrial ANP, and their blood pressures were elevated by 8 to 23 millimeters of mercury when they were fed standard (0.5 percent sodium chloride) and intermediate (2 percent sodium chloride) salt diets. On standard salt diets, heterozygotes had normal amounts of circulating ANP and normal blood pressures. However, on high (8 percent sodium chloride) salt diets they were hypertensive, with blood pressures elevated by 27 millimeters of mercury. These results demonstrate that genetically reduced production of ANP can lead to salt-sensitive hypertension. PMID- 7839144 TI - Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms. AB - Mammalian mitogen-activated protein (MAP) kinases include extracellular signal regulated protein kinase (ERK), c-Jun amino-terminal kinase (JNK), and p38 subgroups. These MAP kinase isoforms are activated by dual phosphorylation on threonine and tyrosine. Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase. These MKK isoforms did not activate the ERK subgroup of MAP kinases, but MKK4 did activate JNK. These data demonstrate that the activators of p38 (MKK3 and MKK4), JNK (MKK4), and ERK (MEK1 and MEK2) define independent MAP kinase signal transduction pathways. PMID- 7839145 TI - Association between X-linked mixed deafness and mutations in the POU domain gene POU3F4. AB - Deafness with fixation of the stapes (DFN3) is the most frequent X-linked form of hearing impairment. The underlying gene has been localized to a 500-kilobase segment of the Xq21 band. Here, it is reported that a candidate gene for this disorder, Brain 4 (POU3F4), which encodes a transcription factor with a POU domain, maps to the same interval. In five unrelated patients with DFN3 but not in 50 normal controls, small mutations were found that result in truncation of the predicted protein or in nonconservative amino acid substitutions. These findings indicate that POU3F4 mutations are a molecular cause of DFN3. PMID- 7839146 TI - Requirement of MADS domain transcription factor D-MEF2 for muscle formation in Drosophila. AB - Members of the myocyte enhancer binding factor-2 (MEF2) family of MADS (MCM1, agamous, deficiens, and serum response factor) box transcription factors are expressed in the skeletal, cardiac, and smooth muscle lineages of vertebrate and Drosophila embryos. These factors bind an adenine-thymidine-rich DNA sequence associated with muscle-specific genes. The function of MEF2 was determined by generating a loss-of-function of the single mef2 gene in Drosophila (D-mef2). In loss-of-function embryos, somatic, cardiac, and visceral muscle cells did not differentiate, but myoblasts were normally specified and positioned. These results demonstrate that different muscle cell types share a common myogenic differentiation program controlled by MEF2. PMID- 7839147 TI - The functional significance of arm movements in neonates. AB - Arm movements made by newborn babies are usually dismissed as unintentional, purposeless, or reflexive. Spontaneous arm-waving movements were recorded while newborns lay supine facing to one side. They were allowed to see only the arm they were facing, only the opposite arm on a video monitor, or neither arm. Small forces pulled on their wrists in the direction of the toes. The babies opposed the perturbing force so as to keep an arm up and moving normally, but only when they could see the arm, either directly or on the video monitor. The findings indicate that newborns can purposely control their arm movements in the face of external forces and that development of visual control of arm movement is underway soon after birth. PMID- 7839148 TI - Potentiation of transmitter release by ciliary neurotrophic factor requires somatic signaling. AB - Neurotrophic factors participate in the development and maintenance of the nervous system. Application of ciliary neurotrophic factor (CNTF), a protein that promotes survival of motor neurons, resulted in an immediate potentiation of spontaneous and impulse-evoked transmitter release at developing neuromuscular synapses in Xenopus cell cultures. When CNTF was applied at the synapse, the onset of the potentiation was slower than that produced by application at the cell body of the presynaptic neuron. The potentiation effect was abolished when the neurite shaft was severed from the cell body. Thus, transmitter secretion from the nerve terminals is under immediate somatic control and can be regulated by CNTF. PMID- 7839149 TI - In vivo evidence of structural brain asymmetry in musicians. AB - Certain human talents, such as musical ability, have been associated with left right differences in brain structure and function. In vivo magnetic resonance morphometry of the brain in musicians was used to measure the anatomical asymmetry of the planum temporale, a brain area containing auditory association cortex and previously shown to be a marker of structural and functional asymmetry. Musicians with perfect pitch revealed stronger leftward planum temporale asymmetry than nonmusicians or musicians without perfect pitch. The results indicate that outstanding musical ability is associated with increased leftward asymmetry of cortex subserving music-related functions. PMID- 7839150 TI - Mammalian vestibular hair cell regeneration. PMID- 7839151 TI - Regeneration and mammalian auditory hair cells. PMID- 7839152 TI - The coexistence of systemic lupus erythematosus with other autoimmune diseases: the kaleidoscope of autoimmunity. AB - Patients with systemic lupus erythematosis (SLE) often manifest features of other autoimmune diseases. In this review, we provide a detailed compendium of features of SLE that overlap with other conditions. This compendium is important because a critical feature in our understanding of autoimmunity has been the clustering of coexisting/different autoimmune diseases both within an affected patient and within a pedigree. Indeed, autoimmune disorders share a variety of similar clinical and serological defects. For example, all autoimmune disorders are associated with the elaboration of autoantibodies and/or the production of self reactive mononuclear cell populations; many have high levels of immune complexes and defects in cell-mediated immunity. Several diseases share similar genetic backgrounds, as reflected by study of loci within the major histocompatibility complex. In part the coassociation is due to common genetic tendencies with different environmental precipitating agents (trigger mechanisms). It is likely that many factors can modulate the immune system to autoimmunity in the presence of an appropriate genetic background, eg, drugs, viral infections, UV irradiation, and toxins, ie, toxic oil syndrome and L-tryptophan-induced eosinophilic myalgia. The coexistence of SLE with other autoimmune diseases is an excellent venue to understand these events, and we believe that the presence of other autoimmune diseases in patients with SLE can be called the kaleidoscope of autoimmunity. PMID- 7839153 TI - Treatment of hemorrhagic lupus pneumonitis with plasmapheresis. AB - Pulmonary hemorrhage is a rare and often fatal complication of systemic lupus erythematosus (SLE). Treatment with high-dose steroids and cyclophosphamide has been of only modest value, with a reported mortality of up to 92%. We have recently seen three patients with active SLE who developed acute life-threatening pulmonary hemorrhage. Diagnostic evaluation of these patients showed negative sputum and blood cultures, negative glomerular basement membrane antibodies, and negative antineutrophilic cytoplasmic antibodies. In two patients, an open-lung biopsy was performed, and histological examination showed granular alveolar immunofluorescence staining for immunoglobulin and complement components. Treatment with plasmapheresis was initiated with prompt resolution of symptoms and clearing of chest radiograph. Two patients had recurrent bleeds despite treatment with cyclophosphamide and high-dose steroids and required repeated intubation. Plasmapheresis resulted in rapid radiographic and clinical improvement on each occasion. Two patients survived long-term and are presently without pulmonary problems; one patient died of sepsis after initial response to plasmapheresis. The dramatic improvement of the pulmonary disease in these patients leads us to conclude that rapid initiation of plasmapheresis should be strongly considered in SLE patients with severe, life-threatening pulmonary hemorrhage. PMID- 7839154 TI - Amyloidosis: prognosis and treatment. AB - The objective of this study was to review (1) the factors that have been linked to prediction of clinical outcome and survival in amyloidosis and (2) the available studies on the therapy for localized and systemic forms of amyloidosis. We made a retrospective review of the relevant literature on treatment and prognosis in localized and systemic amyloidosis dating back to 1975. The most important prognostic factors in amyloidosis are the presence of congestive heart failure, beta 2-microglobulin, and whether peripheral neuropathy dominates the presentation. The presence of a monoclonal light chain in serum or urine, multiple myeloma, and hepatic involvement are also important adverse factors. Colchicine is beneficial in treating familial Mediterranean fever and may play a role in managing secondary amyloidosis in inflammatory bowel disease. Chlorambucil is particularly useful in juvenile rheumatoid arthritis with amyloidosis. Dimethyl sulfoxide provides benefit in bladder and lichen amyloidosis. A trial of alkylating agent-based chemotherapy is reasonable in symptomatic primary systemic amyloidosis. Advances have been made in the treatment of amyloidosis and include chemotherapy, dialysis, transplantation, and improved supportive care. Definite disease regressions with long-term survival (> 10 years) are seen. Unfortunately, alternatives still need to be developed: Of 859 patients with primary systemic amyloidosis seen at the Mayo Clinic from 1982 to 1992, the median survival was 2.1 years. PMID- 7839155 TI - Rheumatic diseases in African blacks. AB - Contrary to previous belief, there is increasing evidence that a broad spectrum of rheumatic diseases do affect African blacks. Although properly conducted epidemiological studies have yet to be performed, reports of population surveys from a variety of sub-Saharan African countries indicate that diseases such as rheumatoid arthritis (RA), gout, and the connective tissue diseases are observed, although some differences in clinical presentation may occur as a result of cultural, racial, and socioeconomic factors. Rheumatoid arthritis is common in some parts of Africa and less common in others. In particular, a significantly lower prevalence of RA in rural areas compared with urban cohorts has led to the hypothesis that environmental factors associated with urbanization may be involved in disease pathogenesis. A similar hypothesis has been suggested for hyperuricemia and gout. Clinical features of disease may also be different in Africans when compared with other population subgroups such as with systemic lupus erythematosus although this may be artefactual as different accessibility to health care and referral practices may result in only the more severe cases coming to medical attention (eg, lupus nephritis). Immunogenetic factors may reduce the prevalence of some conditions such as the spondyloarthropathies. Although the association between HLA-DR4 and RA holds true in Africans, the same is not so for the association of HLA-B27 with ankylosing spondylitis (AS). The prevalence of HLA-B27 in African blacks is 10 times less than Caucasian populations, in part accounting for the low prevalence of spondyloarthropathies, although its association with AS is low. Other conditions such as human immunodeficiency virus (HIV)-related arthropathies appear to be an increasing medical problem. The panepidemic of acquired immunodeficiency syndrome in Africa has resulted in an increased awareness of the different types of arthritis that may be associated with HIV. These are similar to those reported in other parts of the world, although risk factors are different in Africa where heterosexual transmission is a more common cause than homosexual transmission or i.v. drug usage. Information on other rheumatic diseases such as osteoarthritis and soft tissue rheumatism are slowly emerging. Rheumatic manifestations of the infectious diseases, which are endemic in Africa, remain a uniquely fascinating aspect of rheumatology practice on the African continent. Therefore, African countries will increasingly be a continued valuable source of clinical material for comparative studies to help elucidate factors that influence the development of rheumatic diseases. PMID- 7839156 TI - Second-line treatment in seronegative spondylarthropathies. AB - The literature concerning second-line treatment of seronegative spondylarethropathies from 1940 to August 1993 was reviewed. Sulfasalazine appeared to be effective in the treatment of ankylosing spondylitis (AS) and promising in reactive arthritis (ReA) and Reiters' syndrome (RS). Methotrexate and azathioprine were associated with a remarkable improvement in some cases of AS and RS. Methylprednisolone and levamisole were both efficacious in AS, but levamisole was associated with occasional severe side effects. Radiation therapy led to short-term improvement in AS, but was abandoned because of severe long term side effects. Only sulfasalazine has been studied in sufficient detail to allow definitive conclusions, but methotrexate and azathioprine may be promising drugs. PMID- 7839157 TI - Treating arthritis with locally applied heat or cold. AB - The scientific for the treatment of arthritis with locally applied heat or cold is reviewed. Experimental studies in vitro, in animals, in healthy subjects, and in patients are considered. Results of investigations of the effects of locally applied heat or cold on the deeper tissues of joints and on joint temperature in patients are not consistent. In general, locally applied heat increases and locally applied cold decreases the temperature of the skin, superficial and deeper tissues, and joint cavity. Most studies dealing with the effects of heat and cold on pain, joint stiffness, grip strength, and joint function in inflamed joints report beneficial effects. In vitro studies show that higher temperatures increase the breakdown of articular cartilage and tissues that contain collagen. Therefore, one goal of physical therapy should be to decrease intraarticular temperature in actively inflamed arthritic joints. PMID- 7839158 TI - The value of C-reactive protein measurement in rheumatoid arthritis. AB - Since 1973, assessment of serum concentrations of C-reactive protein (CRP) has been advocated as a objective measure of disease activity in rheumatoid arthritis (RA). Our review of clinical experience with CRP measurement suggests it has at least two important roles to play in the management of RA. First, persistently elevated CRP levels have prognostic value. In general, such elevated levels are found in those patients who are at greater risk for continuing joint deterioration and therefore may need more aggressive treatment and supportive care. Second, in general, improvement in CRP levels is an objective indication that a drug has produced a beneficial effect and thus may be useful to the physician for monitoring effects of therapy. Since CRP may be elevated in a number of conditions besides RA, a diagnosis of RA must be made before using CRP as a prognostic factor. PMID- 7839159 TI - Hiccups. AB - Hiccups result from a variety of causes and serve no known physiologic function. Although most episodes are time-limited, hiccups may become protracted, with serious consequences. Assessment of hiccups entails a focused history and physical examination coupled with selected laboratory tests. If a correctable malady is discovered, treatment should address the underlying disorder. However, if the cause remains unknown, therapeutic options include nonpharmacologic and pharmacologic measures. Since hiccups are common, this review provides a practical approach to the management of this bothersome symptom. PMID- 7839160 TI - Prader-Willi syndrome: effect of group home placement on obese patients with diabetes. AB - Morbid obesity and type II diabetes, common complications of Prader-Willi syndrome (PWS), are difficult to manage in the home setting. We assessed the effect of specialized group home placement on these complications in eight individuals with PWS, all of whom were obese and four of whom had type II diabetes. The group home provided diet restriction and control, a monitored exercise program, and a structured environment. Twelve months after admission, average weight loss in the eight individuals was 17.0 kg. Of the four with diabetes, all achieved euglycemia, and insulin and oral hypoglycemic doses were greatly reduced or discontinued. For individuals with PWS who are obese and have type II diabetes, placement in specialized group homes can be highly effective in controlling weight and diabetes. PMID- 7839162 TI - Predictive validity of medical student choices of practice location. AB - We compared University of Alabama medical students' 1980-1981 practice location and specialty preferences with actual practice locations and specialties in 1991 with the following results. (1) Primary care physicians were located mostly in small or large communities, whereas larger than expected numbers of subspecialists practiced in smaller cities. (2) Actual proportions in primary care and surgical subspecialties were less than in earlier preferences; more than expected chose nonsurgical subspecialties. (3) Large city practice locations showed an increase in 1991 at the expense of earlier preferences for medium-sized cities. We suggest that the shift of primary care physicians to larger cities reflects concerns about the financial viability of small town practice, coupled with greater earnings in affluent suburbs. Excess numbers of subspecialists in smaller locations may be due to a perceived oversupply of subspecialists in larger cities. PMID- 7839161 TI - Laparoscopic plication of perforated ulcer: results of a selective approach. AB - We reviewed our experience with laparoscopy for perforated ulcer from April 1, 1992, to March 31, 1993. All patients admitted to the gastrointestinal surgery service with a diagnosis of perforated viscus had evaluation for possible laparoscopic Graham plication (LGP). Of eight patients considered, five had successful diagnostic laparoscopy. Two patients with anterior duodenal ulcers had LGP. Operative times were 85 and 106 minutes; postoperative stays were 5 and 8 days. Three procedures were converted to formal laparotomy when laparoscopy revealed gastric or prepyloric ulcers. Three patients had immediate laparotomy because of known disease process. Two additional patients were treated with open plication by other surgeons; their operative times were 98 and 110 minutes and postoperative stays, 6 and 4 days. Hospital charges averaged $6,573 for the two laparoscopic plications, $7,511 for the four plications not done laparoscopically, and $20,995 for the two cases converted to open plication. A selective approach allowed two Graham patch closures to be done laparoscopically without complications, at a cost comparable to that of open surgery. PMID- 7839163 TI - Epidemiology of salmonellosis in Arkansas. AB - Human salmonellosis continues to be a major public health issue. Our epidemiologic review of cases from 1989 to 1992 was done to define the current reported rate of infection due to Salmonella species for the state of Arkansas, which might be expected to have higher rates of infection because it is a leading producer of poultry. Results showed that the reported case rate in Arkansas (18.0/100,000) did not differ from that of the United States at large (18.6/100,000). Age-specific rates, however, showed that children less than 1 year of age in Arkansas were infected at a higher rate than those in the remainder of the nation. Salmonella newport and S typhimurium were the most commonly isolated serotypes. Individuals living in a county with poultry processing plants and hatcheries were not more likely to have salmonellosis, and individuals residing in Arkansas do not appear to be at increased risk of salmonellosis because of the poultry industry. PMID- 7839164 TI - Physician understanding of the National Practitioner Data Bank. AB - National Practitioner Data Bank (NPDB) reports are part of the process for acquiring staff privileges, professional credentials, and licenses throughout a physician's entire career. We surveyed our hospital's 66 residents to assess their understanding of NPDB. Only 9 residents had heard about NPDB. A follow-up survey of the 10 medical schools in Pennsylvania and Maryland showed just 4 schools covered NPDB in their curricula. Finally, we did a third survey--of 1,410 Pennsylvania Medical Society members. Eighty-one percent did not know that denial of initial license application was not a reportable offense; 69% did not know that voluntary entrance into alcohol/drug rehabilitation was not reportable; and 75% did not know that denial of expanded privileges because of level of clinical competence was reportable. Only 13% knew how to obtain their files. Our surveys suggest physicians have a poor understanding of NPDB even though these reports could have career-jeopardizing implications, especially if the Clinton administration expands access to NPDB. PMID- 7839165 TI - Nutrition concepts for the primary care/generalist physician. AB - Important nutrition concepts will aid primary care/generalist physicians to implement practical aspects of health promotion and disease prevention in their practice, and improve the overall health of their patients. In today's society, chronic diseases that are related variably to overnutrition and dietary excesses or imbalances (obesity, diabetes mellitus, hypertension and atherosclerotic cardiovascular disease, some cancers) warrant knowledgeable diet modifications in high-risk individuals. However, serious nutritional deficiency diseases also still occur (as in alcoholic patients), and instituting appropriate diet and supplements will aid in preventing further morbidity and mortality. Nutrition knowledge changes with new scientific evidence, and the physician must be aware of reliable sources of continuing education and information appropriate for the practitioner and the patient. PMID- 7839166 TI - Hiccups due to gastroesophageal reflux. AB - Hiccups (singultus) are most often a transient phenomenon that resolves without medical therapy. Intractable hiccups can be an indication of a serious underlying disease process and should be investigated. To demonstrate the evaluation of intractable singultus, we describe a patient who had unsuccessful outpatient therapy for persistent hiccups and who was subsequently found to have gastroesophageal reflux (GER). Efforts to determine the cause of the hiccups were negative except for endoscopically proven GER. On follow-up visits, antisingultus medications were withdrawn without return of hiccups, and repeat endoscopy showed substantial healing of the esophagitis. We conclude that GER may be underestimated as a cause of hiccups. PMID- 7839167 TI - Epidural corticosteroid injections for acute radiculopathy in a 95-year-old woman. AB - A previously independent 95-year-old woman had acute, disabling left lumbosacral radiculopathy diagnosed by clinical findings and imaging studies. Significant side effects of oral nonsteroidal and narcotic medications led to treatment with epidural steroids (triamcinolone acetonide). These injections provided pain relief, allowing a short course of inpatient rehabilitation that improved the patient's function and facilitated return to independent living. At 1-year follow up, she continued to live independently and remained free of pain. We believe that epidural steroids coupled with a comprehensive rehabilitation program can lead to restoration of function in some elderly patients unable to tolerate the side effects of standard pain medications. PMID- 7839168 TI - Asymptomatic extralobar sequestration in a 43-year-old woman. AB - A 43-year-old white woman had an asymptomatic left lower lobe density on a chest roentgenogram. She had a past history of biopsy-proven sarcoidosis in 1984 that resolved without corticosteroids. A midsystolic click was heard on cardiac examination. Computed tomography (CT) revealed an extralobar pulmonary sequestration in the left base. Rapid sequence CT scanning revealed an arterial supply from the thoracic aorta and venous return to the inferior vena cava. A pleural lining and cystic parenchymal changes were also seen. After a discussion of the risks and benefits of surgical resection, the patient elected only clinical follow-up. PMID- 7839169 TI - Decompression sickness in a private pilot. AB - Although safe, civil aviation can result in some unique medical problems. Most physicians are not familiar with aviation-related medical problems. One such problem, decompression sickness, is not mentioned in most medical texts, and is not included in most medical school instruction. If not promptly recognized and treated, decompression sickness can result in permanent disability or death. I report a case of altitude-induced decompression sickness after a flight in an unpressurized aircraft. PMID- 7839170 TI - Parainfluenza virus type 2 meningitis and parotitis in an 11-year-old child. AB - We describe the case of an 11-year-old Bolivian boy with parotitis and aseptic meningitis to demonstrate that parainfluenza virus type 2 can cause disseminated infection in a normal child. Parainfluenza virus type 2 was isolated from nasopharyngeal and CSF specimens from the patient and was confirmed to be parainfluenza virus type 2 by hemadsorption inhibition and by complement fixation. Parainfluenza virus type 2 may cause aseptic meningitis and parotitis. PMID- 7839171 TI - Metastatic breast carcinoma to the os calcis presenting as heel pain. AB - A 47-year-old woman who had been treated for breast carcinoma 11 years previously developed significant heel pain of unclear etiology, which ultimately proved to be metastatic adenocarcinoma. A low index of suspicion and falsely negative plain radiographs contributed to a delay in diagnosis. No other osseous metastases besides those to the foot were identifiable at the time of diagnosis. Breast carcinoma is one of the most common malignancies and frequently metastasizes to bone. Despite this, metastases to the hands or feet (acrometastases) have been identified in only a few cases. It is likely that acrometastases are more common than reported but unrecognized. PMID- 7839172 TI - Angiotropic large cell lymphoma. AB - Lymphomas are malignant neoplasms of cells native to lymphoid tissue that can arise anywhere in the body. Angiotropic large cell lymphoma (ALCL) is characterized by a proliferation of neoplastic mononuclear cells within the lumina of small blood vessels. The clinical manifestations are usually neurologic, including progressive dementia and nonlocalizing deficits, cutaneous infiltration, adrenal masses, or fever of unknown origin. The diagnosis is made at autopsy or on skin biopsy, brain biopsy, or other surgical resection. Differential diagnoses include metastatic malignant neoplasms and vascular tumors. We report the case of a 63-year-old white man who had neurologic signs and symptoms as well as dyspnea. Autopsy revealed ALCL involving multiple organ systems, including the central nervous system. Diagnostic techniques currently used to confirm the nature of this malignant neoplasm include immunohistochemistry, ultrastructural analysis, cytogenetics, and molecular biologic studies. PMID- 7839173 TI - Bilateral breast carcinoma after radiation therapy for Hodgkin's disease. AB - The success of modern cancer therapy is resulting in an increasing number of long term cures. The price of success, however, is the incidence of treatment-related morbidity and mortality. The physician should be aware of the potential sequelae of cancer therapy. A case of bilateral breast cancer occurring 13 years after radiation therapy for Hodgkin's disease prompted me to examine the incidence of this problem and to make recommendations for surveillance of patients. PMID- 7839174 TI - Primary pulmonary non-Hodgkin's lymphoma. AB - A 48-year-old woman with an asymptomatic lung mass on a routine chest roentgenogram was found to have a primary non-Hodgkin's lymphoma involving the lung. Extensive evaluation revealed no evidence of lymphoma at any other site. She required an open lung biopsy for definitive diagnosis and was found to have unresectable tumor at thoracotomy. The patient achieved a complete remission with combination chemotherapy and remains in clinical remission 14 months after completion of therapy. PMID- 7839175 TI - Forecasting weather and making diagnoses. PMID- 7839176 TI - Scholarship program to recognize medical excellence. PMID- 7839177 TI - Rocky Mountain spotted fever versus Lyme disease. PMID- 7839178 TI - Choosing lithium, anticonvulsant, or electroconvulsant therapy for mood disorders. PMID- 7839179 TI - Choosing lithium, anticonvulsant, or electroconvulsant therapy for mood disorders. PMID- 7839180 TI - Transverse incisions for biopsies. PMID- 7839181 TI - Inhalation anaesthetics and liver damage. PMID- 7839182 TI - Alexander R. P. Walker--an appreciation. PMID- 7839183 TI - Hunter-gatherers in southern Africa. PMID- 7839184 TI - Some thoughts on parasitic diseases, nutrition and health/disease in Africa. PMID- 7839185 TI - Will growth monitoring continue to be part of primary health care? PMID- 7839186 TI - Nutritional supplementation in Africa--how important is vitamin A? PMID- 7839187 TI - Calcium requirements in pregnancy and lactation in rural Africa. PMID- 7839188 TI - Highlights of nutrition and health/ill-health research in Africa--how my interest started and developed. PMID- 7839189 TI - Recent developments in the investigation of vitamin B12 deficiency. PMID- 7839190 TI - The pros and cons of iron fortification. PMID- 7839191 TI - Diet and heart disease. PMID- 7839192 TI - Diet, blood lipids and coronary heart disease--current controversies. PMID- 7839193 TI - The rise and fall of coronary heart disease in South Africa. PMID- 7839194 TI - The dietary fibre hypothesis--does it 'work'? PMID- 7839195 TI - Dietary fibre, glycaemic index and diabetes. PMID- 7839196 TI - The nutritional impact of the intestinal microflora. PMID- 7839197 TI - Chronic bowel disease in the black population of southern Africa--enigmas and challenges. PMID- 7839198 TI - Bowel function, bowel disease and vegetarianism. PMID- 7839199 TI - Diet and cancer prevention. PMID- 7839200 TI - Caries risk prediction--the way of the future. PMID- 7839201 TI - Management of chronic diseases of lifestyle in South African populations. PMID- 7839202 TI - Research on kwashiorkor in Africa--historical aspects of causation, pathophysiology and treatment. PMID- 7839203 TI - Nutrition in the elderly. PMID- 7839204 TI - Dietary recommendations, goals and guidelines. PMID- 7839205 TI - Nutrition and health--a view from the village. PMID- 7839206 TI - Anecdotes, trials and tribulations in field studies. PMID- 7839207 TI - Protein energy malnutrition--results of rehabilitation. PMID- 7839208 TI - Judgement on AIDS confidentiality not controversial, says MASA. PMID- 7839209 TI - The South African Bone Marrow Donor Registry. PMID- 7839210 TI - Keeping the prescribing pharmacist at bay. PMID- 7839211 TI - Act 101 and the pharmacist--is it appropriate for the pharmacist to prescribe? PMID- 7839212 TI - Paracetamol poisoning. PMID- 7839213 TI - Attitudes of private general practitioners towards health care in South Africa. AB - The need for health care reform in South Africa is acknowledged by the government as well as by the non-governmental health sector. There is, however, no unanimity regarding the nature of the envisaged reform. A country-wide postal survey of 700 private sector general practitioners (GPs) from a commercial database of 5,000 was conducted to explore attitudes towards health care. A response rate of 67.4% was obtained. Respondents were mostly male (92%) and urban-based (64%). The median age was 42 years. Most respondents: (i) believed health care to be a right for all citizens; (ii) favoured private or a combination of private and public funding mechanisms with fee-for-service arrangements; (iii) opposed cost containment measures imposed by funders, e.g. medical aids; and (iv) believed doctors should be responsible for primary care in under-served areas. After sex, age, location (urban versus rural) and GP postgraduate qualification had been controlled for by means of logistic regression techniques, the university at which a respondent's basic degree was obtained emerged as the only independent predictor of attitudes to the following: (i) comprehensive care as a right; (ii) integration of the public and private sectors; (iii) preferred funding source for a future health system; and (iv) preference for fee-for-service remuneration. Both university and gender independently predicted attitudes on GPs' income. Graduates of white, Afrikaans-medium universities were strongly in favour of a privately funded and fee-for-service orientated system. Those who qualified at black universities, on the other hand, favoured public funding with less emphasison fee-for-service.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7839214 TI - How healthy is South Africa's medical schemes industry? AB - An analysis of the membership demographics, the financial health and especially the sustainability of the South African medical schemes industry is presented. From the financial and in particular the actuarial analyses it is obvious that the current system is unsustainable, and if a private health care sector is to survive at all it will have to contain costs far more effectively than it has in the past. It is suggested that medical schemes (and other mechanisms of funding health care) review their funding policies and move towards advance funding of pensioner benefits, and also that the schemes be actuarially valued on a regular basis. PMID- 7839215 TI - The availability of research journals in South African academic medical libraries. AB - Biomedical researchers depend on the journals of science as a primary source of information. The spiralling cost of journals threatens the ability of libraries to provide their users' information needs. In this study the availability of a representative sample of journals used by South African biomedical researchers was determined at each of the seven medical faculty libraries. The application of a standardised document delivery test is described and the results are interpreted in terms of: (i) the capability index, which includes material obtainable through inter-library loans; and (ii) an availability index, or measure of the probability that a user will find an item without delay in his/her own library. The current status of availability of biomedical journals was found to be high at all the libraries; indeed, the scores compare favourably with results obtained at academic libraries overseas. There is, however, real concern that the financial crisis in tertiary education will cause the situation to deteriorate. Repetition of this test is recommended to monitor the (probably declining) level of journal availability. The information would support efforts to rationalise and subsequently strengthen academic medical libraries' collective holdings as a strategic national resource. PMID- 7839216 TI - A modified isometric test to evaluate blood pressure control with once-daily slow release verapamil. AB - Blood pressure at rest is not predictive of round-the-clock values. Blood pressure should therefore be measured during effort to evaluate hypertension and its response to treatment. The effect of sustained-release verapamil (240 mg taken once a day) on blood pressure at rest and during isometric effort was therefore investigated. Overall, verapamil reduced blood pressure significantly in 41 of 45 hypertensive patients: the mean systolic blood pressure at rest (+/- SD) fell from 151 +/- 35 mmHg to 137 +/- 13 mmHg (P < 0.001) and the diastolic blood pressure from 97 +/- 21 mmHg to 83 +/- 7 mmHg (P < 0.001), while the systolic blood pressure during isometric effort fell from 186 +/- 23 mmHg to 156 +/- 13 mmHg (P < 0.001) and the diastolic blood pressure from 118 +/- 14 mmHg to 95 +/- 8 mmHg (P < 0.001). The simple, inexpensive handgrip method described is cost-effective and strongly recommended as an integral part of the evaluation of hypertensive patients. The combination of a drug to which compliance is good and a simple method of blood pressure evaluation should result in improved effectiveness of treatment in the long term. PMID- 7839217 TI - The nutritional composition of South African eggs. AB - Samples of hens' eggs produced throughout South Africa during the winter and summer of 1990 were analysed for nutrient content to obtain representative values for inclusion in food tables intended for local use. Proximate analyses and vitamin, mineral, fatty acid and amino acid determinations were carried out on all the samples. When the analysed values obtained for whole eggs, egg yolks and egg whites were compared with values listed in the Research Institute for Nutritional Diseases food tables, a number of differences were found. With regard to the inclusion of eggs in diets in general, the cholesterol content of whole eggs was found to be 23.5% lower and the total fat and saturated fatty acid contents 9% and 10% lower, respectively, than the listed values. The eggs were found to be rich sources of protein of animal origin, all the essential amino acids, thiamine, riboflavin, pantothenic and folic acids, vitamin B12, biotin, vitamin D3, vitamin E and phosphorus. Eggs are readily available and inexpensive and should be included in the diets of young children, adolescents, pregnant and breastfeeding women, adults, the elderly and particularly those of all ages who are undernourished. PMID- 7839218 TI - The effect of ethnicity on appendicular bone mass in white, coloured and Indian schoolchildren. AB - Ethnic differences in the incidence and prevalence of osteoporosis have been shown throughout the world. In South Africa the prevalence of osteoporosis is much higher in whites than in blacks. This is surprising, since factors that might predispose to reduce bone mass are more preponderant in black communities. The present research was undertaken to determine whether differences in bone mass during the period of bone accretion could explain the difference in the incidence of osteoporosis. In this paper we report on differences in appendicular bone mass between white, coloured and Indian children and teenagers (6-18 years) from Johannesburg. The effects of weight, height, puberty and skinfold thickness on bone mass were also assessed. The bone width (BW) of white boys was greater than that of Indian boys, while the bone mineral content (BMC) and BMC/BW were greater in white boys than in both Indian and coloured boys. After adjustment for differences in weight and height, the BW of coloured boys was significantly greater than that of white boys, while all differences in BMC and BMC/BW became non-significant. For girls there were no significant differences in bone mass measurements, but after adjustment for height and weight coloured girls had significantly greater BMC and BMC/BW than either white or Indian girls. This greater weight- and height-adjusted bone mass in coloured girls is consistent with the impression of a lower incidence of osteoporosis in coloured women than in white women. PMID- 7839219 TI - Prediction of amikacin dose requirements in neutropenic patients with haematological disease. AB - This study reports on the use of an easily applied Bayesian forecasting programme (OPT; Clydesoft) to predict amikacin dose requirements in 10 patients with haematological disease and neutropenic fever. OPT-determined dose adjustment achieved therapeutic drug levels for 80% of the peak and 94% of the trough measurements. PMID- 7839220 TI - Bacillary angiomatosis. The first case reported in South Africa. AB - A 28-year-old white man, positive for HIV, who was admitted to hospital for pneumonia, had for 2 months had several fluctuating cutaneous purple nodules on his legs and abdomen. Cultures of two lesions were negative, but light and electron microscopy showed organisms characteristic of bacillary angiomatosis. The patient responded well to therapy with erythromycin. This is the first reported case of bacillary angiomatosis in South Africa. PMID- 7839221 TI - Unnecessary special investigations in gynaecology. PMID- 7839223 TI - Academic health complexes. PMID- 7839222 TI - Occupational disease in a chromate producing factory. PMID- 7839224 TI - Countering alternative medicine. PMID- 7839225 TI - Malaria chemoprophylaxis. PMID- 7839226 TI - Playing ostriches about acupuncture? PMID- 7839227 TI - Medical students' attitudes to emigration. PMID- 7839228 TI - Medical aid costs of laparo-endoscopic biliary tract surgery. PMID- 7839229 TI - Occurrence of human Cyclospora infection in sub-Saharan Africa. PMID- 7839230 TI - Alcohol brain damage and treatment. PMID- 7839231 TI - 'No difference v. not enough evidence'--calculating the power and beta error. PMID- 7839232 TI - Regionalisation of obstetric services--a follow-up report. PMID- 7839233 TI - Screening test for anti-neutrophil cytoplasmic antibodies. PMID- 7839234 TI - Screening test for anti-neutrophil cytoplasmic antibodies. PMID- 7839235 TI - Recurrent otitis media in the young child. PMID- 7839236 TI - Atypical appearance of metastatic disease to the femoral head. PMID- 7839237 TI - Antiphospholipid antibodies in reproductive failure. PMID- 7839238 TI - Analgesia for pleural biopsy. PMID- 7839239 TI - Reactive arthritis, chest pain and hyperaesthesia. PMID- 7839240 TI - Clinical guidelines for HIV/AIDS sufferers. PMID- 7839241 TI - Latest research development in HIV/AIDS. PMID- 7839242 TI - [Doctors uncomfortable about AIDS patients]. PMID- 7839243 TI - Sabril--a new antiepileptic agent. PMID- 7839244 TI - Saving sight. PMID- 7839245 TI - Poliomyelitis eradication in South Africa. PMID- 7839246 TI - Community-orientated primary health care--South African legacy. PMID- 7839247 TI - Workplace health services' contribution to primary health care in South Africa. PMID- 7839248 TI - Implications of the Interim Constitution and Local Government Transition Act for the establishment of health districts. PMID- 7839249 TI - Who should manage community health worker programmes? PMID- 7839250 TI - The impaired doctor. PMID- 7839251 TI - The Pholela Health Centre--the origins of community-oriented primary health care (COPC). An appreciation of the work of Sidney and Emily Kark. AB - The health centre practice pioneered by Sidney and Emily Kark and their colleagues at Pholela during the 1940s was a forerunner of and direct contributor to what later emerged as 'the primary health care approach'. This article gives a detailed account of the context, work and methodologies used at the Pholela Health Centre, emphasising the development of concepts that are now well recognised and described as community-oriented primary health care (COPC). COPC remains highly relevant to health service development in South Africa today. PMID- 7839252 TI - A shotgun marriage--community health workers and government health services. Qualitative evaluation of a community health worker project in Khayelitsha. AB - In 1988 the Western Cape Regional Services Council (RSC) initiated a community health worker (CHW) project in Khayelitsha in order to extend its preventive services to people in the community and promote 'community upliftment'. An evaluation of this project was undertaken in 1991 and 1992 in order to examine the potential of this local health authority-run CHW project to be an appropriate primary health care model. Qualitative research methods were used to explore the nature of the work done by the CHWs, whether they were accepted in their communities, and whether the project functioned as part of an integrated health service infrastructure in Khayelitsha. The CHWs were found to provide the basis for a potentially effective, community-responsive service. However, several structural problems mitigated against this service. Relations between the CHWs and nurses in all the formal public health services in the area were superficial and fraught with problems. There were significant differences and conflicting policies between the RSC's CHW project and other neighbouring non-government CHW projects, and these posed various threats to both the RSC and the non-government projects. One of the most serious of these differences was that the RSC project had no structures or plans for community involvement in the running of the project. Before a CHW project is initiated, several critical issues need to be carefully considered and discussed with all the relevant stakeholders. Furthermore, CHWs need to be flexible, and accountable to the communities in which they work. Before employing CHWs, formal public health authorities need to consider carefully whether they are able to meet these criteria. PMID- 7839253 TI - Eradication of poliomyelitis in South Africa. AB - An international campaign under the leadership of the World Health Organisation is underway to eradicate polio from the world by the year 2000. South Africa may already be free of polio. However, to ensure eradication we need to move from a polio control programme to a polio eradication programme. This necessitates the institution of a surveillance programme for acute flaccid paralysis (AFP) and improvement of the delivery of polio vaccine. All children with AFP (including those with suspected Guillain-Barre syndrome) should be investigated with stool culture to exclude polio. Primary care services need strengthening so that oral polio vaccine coverage greater than 90% is achieved in all regions by all authorities. Outbreak response activities need to be developed. Consideration needs to be given to national immunisation days and mopping-up activities. PMID- 7839254 TI - HIV testing and informed consent--ethical considerations. AB - One of the authors (T.J.) was invited by the AIDS Advisory Group to form a widely representative committee to recommend ethical guidelines concerning the extent to which HIV testing should receive informed consent. This paper presents and argues for the recommended guidelines. The question is considered with regard to a number of distinct purposes of HIV testing: the care of a patient; research; blood, tissue and organ donation; and the protection of third parties, including the health care worker. We contend that in each case there is no good reason for the requirement of informed consent to be significantly waived. PMID- 7839255 TI - Benefits and limitations of the Witwatersrand influenza and acute respiratory infections surveillance programme. AB - OBJECTIVE: To establish an ongoing active surveillance programme for acute respiratory infections in general, and influenza in particular. DESIGN: A network of 16 sentinel primary health care providers furnished morbidity information and clinical specimens for virus characterisation supplemented by school absenteeism and regional mortality data. SETTING: General practices, hospital outpatient departments and staff clinics in the Witwatersrand area. PARTICIPANTS: Subjects treated for acute respiratory infections by 7 general practitioners, 1 specialist pulmonologist, 4 paediatric outpatient departments, 1 mine hospital and university, factory and institutional staff clinics. Absenteeism data were obtained from 8 primary and 6 high schools in the region (representing 9,000 pupils). OUTCOME MEASURES: Morbidity information and strain characterisation of influenza isolates as well as other viral respiratory pathogens, school absenteeism, seasonal excess mortality. RESULTS: The most sensitive indicator of influenza activity was virus isolation, which gives an earlier warning signal of an impending epidemic than morbidity or absenteeism parameters. Both morbidity and school absenteeism provided quantitative indicators of the severity of the epidemic. Mortality from all causes showed characteristic winter increases in the 65-year-old and older population which were not seen in younger individuals. Circulating influenza viral strains matched the strains recommended for the vaccine in 1991 and 1992, but not in 1993. CONCLUSIONS: The course and extent of the annual winter influenza epidemic can be charted by means of an active surveillance programme, with sentinel primary health care providers furnishing morbidity data and clinical material from which virus isolations can be made. Antigenic characterisation of the isolates demonstrated that circulating strains may not match recommended strains in northern hemisphere-formulated vaccines and stresses the need for a southern hemisphere vaccine formulation for South Africa. Absenteeism information provides an indicator of the impact of influenza on the economy and excess mortality data emphasise the need for routine immunisation of the elderly. PMID- 7839256 TI - 'Atypical' bacteria are a common cause of community-acquired pneumonia in hospitalised adults. AB - OBJECTIVES: To assess the proportion of cases of community-acquired pneumonia caused by 'atypical' bacteria, including the recently discovered Chlamydia pneumoniae, and to compare the clinical, radiographic and laboratory features of patients with and without 'atypical' bacteria. METHODS: A prospective serological study was carried out on consecutive adult pneumonia patients from July 1987 to July 1988. Acute and convalescent sera were tested in batches for antibodies against Legionella pneumophila serogroup 1, C. pneumoniae, Chlamydia psittaci, Coxiella burnetii (phase-2 antigen) and Mycoplasma pneumoniae (IgG and IgM). Records and chest radiographs were examined retrospectively. RESULTS: Acute and convalescent sera were available from 113 patients. The records of 4 patients could not be traced and 17 patients did not fulfil the inclusion criteria. Thirty two of these 92 patients (35.9%) were found to be infected with 'atypical' bacteria. The two most common organisms were C. pneumoniae (20.7%) and L. pneumophila (8.7%). There were no differences in the clinical and radiographic features of patients with and without 'atypical' bacteria. Clinicians prescribed erythromycin or tetracyclines with equal frequency in the two groups. CONCLUSIONS: 'Atypical' bacteria, especially C. pneumoniae, are a common cause of community-acquired pneumonia in adults in South Africa. This is the first demonstration of an aetiological role of C. pneumoniae in this country. We confirmed the finding of other studies that there are no clinical, radiographic or laboratory features characteristic of 'atypical' bacterial infection in hospitalised patients. This has major implications for therapy, as these organisms respond to erythromycin and tetracyclines, but not to beta-lactam antibiotics. PMID- 7839257 TI - The usefulness of cerebrospinal fluid tests for neurosyphilis. AB - To determine the usefulness of cerebrospinal fluid (CSF) tests for syphilis at a large academic hospital, clinical and laboratory data on 644 patients in whom such testing was requested over a 12-month period were analysed. In 198 cases (31%) the Treponema pallidum haemagglutination (TPHA) screening test could not be performed because of insufficient fluid. Thirty-eight of the remaining patients were diagnosed as having active neurosyphilis. Examination of 22 files of patients who had a positive TPHA and fluorescent treponemal antibody absorption (FTA-Abs) test together with a negative CSF Venereal Disease Research Laboratory (VDRL) test revealed that other CSF measures indicating disease activity (CSF protein, cells or IgG index) were not utilised optimally. In 10 (45%) of these patients neurosyphilis was not diagnosed despite either abnormal or incomplete CSF biochemical analysis, indicating that if the CSF VDRL is used as the sole marker for disease activity, some cases of neurosyphilis are likely to be missed. PMID- 7839258 TI - Gallium scintigraphy in the diagnosis and total lymphoid irradiation of Takayasu's arteritis. AB - Takayasu's arteritis (TA) in children causes appreciable morbidity and mortality, predominantly as a result of the complication of renovascular hypertension (RVH). Ten children with TA, complicated by RVH, were treated at our centre over the past decade. An initial raised erythrocyte sedimentation rate (ESR) and a purified protein derivative greater than 15 mm were present in every case. More recently, gallium scintigraphy has been used to demonstrate sites of active inflammation in affected vessels (3/4 patients) which became negative after total lymphoid irradiation (TLI). The latter was used in the last 6 children, and appeared to be effective in controlling disease activity as evinced in the normalisation of their ESRs and negative findings on gallium scintigraphy (in all 3 patients with prior active inflammation). Because of vascular damage caused by the vasculitic process, surgical intervention is often required to improve organ perfusion, particularly of the kidney/s. Renal autografting (or allografting) seems preferable (6/11 kidneys functional) to renal bypass grafting (5/5 kidneys clotted). Patient survival improved when TLI was used in addition to standard surgical and medical therapy; this included steroids and antituberculous therapy with TLI, and steroids and cyclophosphamide in the two relapses. Five of 6 patients treated with TLI were alive after 32-54 months' follow-up, while 4 patients who received standard medical and surgical therapy but not TLI all died within 18 months of diagnosis. Gallium scintigraphy is a helpful diagnostic tool in assessing vasculitic activity in TA; TLI is an important mode of immunosuppression, but still needs to be compared with cyclophosphamide as the major immunosuppressive. PMID- 7839259 TI - Quinsy tonsillectomy or interval tonsillectomy--a prospective randomised trial. AB - Fifty-one patients with peritonsillar abscesses were randomised to undergo either quinsy tonsillectomy (QT) or interval tonsillectomy (IT), and the two groups were compared. The QT group lost fewer (10.3 v. 17.9) working days and less blood during the operation (158.6 ml v. 205.7 ml); haemostasis was easier and the operation was technically simpler in this group. There was no significant difference in length of hospital stay and neither group had intra- or postoperative complications. Only 64% of the IT group returned for tonsillectomy. In this study QT had distinct advantages over drainage and IT in the management of peritonsillar abscesses. PMID- 7839261 TI - The status of silicone implants. PMID- 7839260 TI - Personality traits, brief recurrent depression and attempted suicide. AB - This study investigated the relationship between attempted suicide, personality factors and brief recurrent depression. Over a period of 1 year, the demographic and psychiatric factors of 307 patients who had attempted suicide and subsequently been hospitalised at H. F. Verwoerd Hospital and referred to its Department of Psychiatry were recorded. Their personality traits were evaluated clinically. After 5 years, 205 respondents were traced to complete a follow-up questionnaire and, where possible, a personality assessment was completed on clinical grounds. They were also evaluated for brief recurrent depression. Among the men, antisocial, dependent and histrionic personality traits, in that order, were most commonly noted and among the women, histrionic, dependent and antisocial traits. A clear relationship between suicidal behaviour and the syndrome of brief recurrent depression was established. The latter was also found to be related to histrionic personality traits in women. This underscores the relationship between suicide attempts and histrionic personality traits. PMID- 7839262 TI - Inappropriate use of rapid HIV antibody tests. PMID- 7839263 TI - HIV testing in the insurance industry. PMID- 7839264 TI - Good, bad and high cholesterol. PMID- 7839265 TI - Margarine and coronary heart disease. PMID- 7839266 TI - Self-advertisement. PMID- 7839267 TI - Laparoscopically assisted vaginal hysterectomy--gimmick or gain? PMID- 7839268 TI - [Laparoscopically assisted vaginal hysterectomy--gimmick or gain?]. PMID- 7839269 TI - Laparoscopic versus open cholecystectomy. PMID- 7839270 TI - Schistosomiasis and malignancy. PMID- 7839271 TI - The uses of analgesic nitrous oxide in neuropsychiatry. PMID- 7839272 TI - Evacuation after incomplete abortion. PMID- 7839273 TI - Nitrous oxide for alcohol withdrawal. PMID- 7839274 TI - Technology evaluation in sub-Saharan Africa. Can the Canadian experience be of use? PMID- 7839275 TI - [High technology medicine in the year 2000]. PMID- 7839276 TI - Supraregional funding for transplantation. PMID- 7839277 TI - Maintenance of professional competence--expectations of the public. PMID- 7839278 TI - Heart transplantation--historical perspective and the need for a national policy. PMID- 7839280 TI - Antibiotic resistance in community-acquired urinary tract infections. AB - We studied the antibiotic susceptibility of midstream urine isolates from patients with community-acquired urinary tract infections at Groote Schuur Hospital from 1986 to 1991. The majority of the isolates was resistant to amoxycillin and co-trimoxazole, and the proportion of resistant Escherichia coli isolates increased during the study period. In a prospective 4-month study in 1991 we found that the vast majority of isolates was susceptible to aminoglycosides, amoxycillin/clavulanate, second-generation cephalosporins and the new fluoroquinolones. Based on these findings amoxycillin and co-trimoxazole should no longer be prescribed for urinary tract infections unless a susceptible isolate has been cultured. Appropriate empirical oral agents are expensive and not generally available in the public sector. There is an urgent need to make these agents available in the public sector, but their use should be restricted as widespread use for the treatment of other infections would inevitably lead to the development of resistance. PMID- 7839279 TI - Determining appropriate nutritional interventions for South African children living in informal urban settlements. AB - Rapid urbanisation in South Africa has led to the creation of informal shack settlements where the health status of children is in jeopardy; it needs to be monitored so that appropriate intervention strategies can be formulated. Accordingly, the nutritional status of 190 children (3-6 years of age) living in Besters, a typical urban shack settlement north of Durban, was assessed anthropometrically. In addition the following biochemical values were determined: vitamins A and E, calcium, magnesium, phosphorus, albumin, haemoglobin, serum iron and ferritin and percentage of transferrin saturation. Malnutrition was evident in 13% of the children who were underweight (below the National Center for Health Statistics (NCHS) third weight-for-age percentile) and 27% who were stunted (below the NCHS third height-for-age percentile). Concentrations of albumin, calcium, magnesium, phosphorus and vitamin E were close to normal, with no more than 10% of the sample having values outside the normal range. However, 44% of the children had low serum retinol levels (< 20 micrograms/dl) and 21% of the children had anaemia (haemoglobin < 11 micrograms/dl). Significant positive correlations were found between serum retinol and all biochemical indicators of iron status except serum ferritin. This study highlights the fact that nutrient deficiencies are interrelated, particularly protein energy malnutrition and poor vitamin A and iron status. A broad multifaceted comprehensive health intervention programme is therefore required. PMID- 7839281 TI - Prevalence of vaginitis, syphilis and HIV infection in women in the Orange Free State. AB - OBJECTIVE: To determine the prevalence of vaginitis, syphilis and HIV infection in women in the Orange Free State. METHOD: By cluster sampling, 120 rural (farm) and 120 urban (local authority) clusters, each containing 4 women, were selected. Women aged 18-49 years who were included in the study had a cervical smear taken for cytological evaluation and blood specimens drawn for syphilis and HIV testing; they were questioned on their knowledge of AIDS. RESULTS: Trichomonas vaginalis vaginitis was present in 27.4% of the rural women and 29.6% of the urban women, Gardnerella vaginalis in 7.2% and 8.4% and Candida spp. in 2.6% and 6.7% respectively. Syphilis serology was positive in 12% of rural and 16% of urban women. HIV was present in 0.4% of rural and 1.5% of urban women. Ninety per cent of urban women and 74% of rural women knew AIDS was a sexually transmitted disease. CONCLUSIONS: The prevalences of trichomonas vaginitis and syphilis were unusually high, while HIV positivity was similar to that in other reports in South Africa. PMID- 7839282 TI - Intravenous and intramuscular magnesium sulphate regimens in severe pre eclampsia. AB - Patients with severe pre-eclampsia were randomised to receive magnesium sulphate according to an intramuscular (IM) (N = 9) or an intravenous (i.v.) (N = 8) regimen. The IM regimen consisted of a loading dose of 14 g (4 g i.v. and 10 g IM) followed by 5 g 4-hourly. Patients given the IV regimen received a 6 g i.v. loading dose followed by a maintenance infusion of 2 g/h. Clinical outcome, laboratory parameters and serum magnesium levels were recorded for both groups. There were no significant differences between groups with regard to clinical outcome of either mother or child. Similar average serum magnesium concentrations were produced by the regimens the only significant difference was that fluctuations in magnesium levels were greater with the IM than the i.v. regimen. None of the patients had seizures despite levels mostly below 2 mmol/l. PMID- 7839283 TI - Reflections on trauma and violence-related deaths in Soweto, July 1990-June 1991. AB - This is a retrospective analysis of 5,600 deaths registered in Soweto from July 1990 to June 1991. The impact of trauma and violence on the overall mortality pattern was assessed. The majority of deaths occurred in people under the age of 50 years and more men died than women. In 40% of male deaths, the cause was stated as 'ill-defined' or 'unknown'; this was the case in an even higher percentage of female deaths (50.5%). Trauma or violence accounted for 28.5% of all deaths. The gender difference was particularly visible in the trauma category, viz. 89.5% and 10.5% in men and women respectively. Young men (20-29 years) were particularly affected by trauma and violence-related deaths (38.5%). The major types of injuries inflicted were gunshot wounds (33%), unspecified multiple injuries (32%) and stab wounds (27%). Motor vehicle accidents accounted for only 8% of deaths. The urgent need for intervention programmes to prevent unnecessary loss of life, targeted especially at young adults and children, is highlighted. PMID- 7839284 TI - Angular kyphosis as an indicator of the prevalence of Pott's disease in Transkei. AB - To understand better the prevalence, distribution and major causes of sagittal spinal deformity in a rural homeland, the authors conducted a study of angular kyphosis in the spines of 2,329 Transkei patients. Thirty-one (1.33%) had angular kyphosis. Lateral chest radiographs were obtained from 22 of these patients. Radiographic kyphotic angles ranged from 28 degrees to 130 degrees (mean: 70.3 +/ 7.6). The vast majority (81%) demonstrated classical clinical and/or radiographic findings of tuberculous aetiology. Less frequent aetiologies included fractures (2), osteoporosis (1), congenital malformation (1) and kyphosis of unknown origin (2). Eleven of the kyphotic patients were seeking care for unrelated problems and were asymptomatic in respect of their kyphoses. As a subset, the asymptomatic individuals demonstrated a similar aetiological distribution, with 73% strongly suggestive of tuberculous aetiology. The prevalence of asymptomatic angular kyphosis in this unselected Transkei patient population was 0.47% +/- 0.14%. In this hospital-based study, angular kyphosis proved a valuable marker for spinal tuberculosis. Because tuberculous spondylitis is more successfully treated when detected early, spinal palpation should be included in the routine physical examination of patients or populations at risk for tuberculosis. PMID- 7839285 TI - Coexistent duodenal ulcer among patients with gastric carcinoma. AB - To examine the prevalence of coexistent duodenal ulcers among patients with gastric carcinoma in an otherwise intact stomach, we surveyed 604 endoscopically and pathologically diagnosed gastric carcinoma patients and thoroughly inspected their duodenums. Twenty-two (3.6%) of them had either active ulcers or scars in the duodenum. This prevalence was significantly less than that among 99 (16.4%) of 604 age- and gender-matched controls with endoscopically confirmed duodenal ulcers (P < 0.0001). Almost one-half of patients with coexistent cancer and duodenal ulcer experienced no change in abdominal symptoms when gastric cancer was diagnosed. Barium meal study appeared not to be sensitive enough to diagnose the coexistent ulcers. However, the nature of the lesions, including disease location, macroscopic appearance, chance of early cancer and metastasis, was no different in 22 patients with coexistent cancer and duodenal ulcer than in 582 patients with cancer alone. The present study suggests that although duodenal ulcer is unlikely to be a predisposing factor for gastric cancer, thorough screening by means of endoscopy is necessary in dyspepsic ulcer patients since duodenal ulcer and gastric cancer are not incompatible. PMID- 7839286 TI - The design of a case register for tuberculosis. A pilot study in the south western Cape. AB - The development and piloting of a tuberculosis register that aims at providing a single source of information for the surveillance of tuberculosis and the measures for its control are discussed. Old-fashioned punch cards are appropriate in both isolated rural and sophisticated urban settings. The card system proved an effective and efficient clinic-based epidemiological tool but its implementation on a broad scale depends on the rationalisation of current administrative procedures. PMID- 7839287 TI - The role of ethnicity in primary angle-closure glaucoma. AB - Primary angle-closure glaucoma is significantly more common than primary open angle glaucoma in the East, whereas in Africa and Europe the reverse is true. In order to study the role of ethnic background in the frequency of primary angle closure glaucoma in Cape Town and, in particular, in people of mixed ethnic background, the so-called 'coloureds', we retrospectively reviewed all patients with primary glaucoma who attended the glaucoma clinic at Groote Schuur Hospital during a 30-month period. Primary angle-closure glaucoma was diagnosed in 11 of 63 (17%) whites, 11 of 85 (13%) blacks and 114 of 244 (46.7%) coloureds with primary glaucoma; the difference is statistically highly significant (P < 0.001). The human leucocyte antigen frequencies in 97 coloured patients with primary angle-closure glaucoma were similar to those found in a control group of individuals with a similar ethnic background. This study highlights the fact that coloureds are more predisposed to primary angle-closure glaucoma than whites or blacks. Because of their strong historical and genetic ties with south-east Asia, this greater prevalence of primary angle-closure glaucoma might be explained by an Eastern influence on the ocular structures of the eye, as opposed to an African or European influence. PMID- 7839288 TI - Cancer of the cervix--death by disarray. PMID- 7839289 TI - A cervical screening strategy for South Africa. PMID- 7839290 TI - Nurses--abdicating their professionalism. PMID- 7839291 TI - Withholding and withdrawing life-sustaining therapy. PMID- 7839292 TI - Controversial aspects of intravenous corticosteroids in acute severe asthma. PMID- 7839293 TI - Elimination of measles--an impossible task? PMID- 7839294 TI - A potentially dangerous design fault in an oxygen analyser. PMID- 7839295 TI - Occupational health in mines. PMID- 7839296 TI - Cephalic replacement of 'Zavanelli's manoeuvre'. PMID- 7839297 TI - The taking of adequate Papanicolaou smears. PMID- 7839298 TI - Cost-benefit of medicines--indapamide compared with other thiazide diuretics. PMID- 7839299 TI - [Relations between physician and physicist. Remarks from the viewpoint of the physicist]. AB - BACKGROUND: Complication-free cooperation between physicians and physicists is widely to be found in all areas of biomedical research for a long time. Where both are involved in patient care, however, there are interfaces potentially causing frictions in their relationship. Radiotherapy is considered to be a typical example. KEY ISSUES FOR GOOD RELATIONSHIP: In order to establish a partnership free of tensions 5 attitudes are felt to be essential: interdisciplinary cooperation, recognized professional competency, mutual loyalty among colleagues, actively supported communication, and readiness for conciliation. CONCLUSION: Considering the interdisciplinary attitude of biomedical science as well as appreciating the ethical obligation to the patient good partnership between physician and physicist is necessary and achievable. PMID- 7839300 TI - [Advances in the treatment of head and neck tumors. I. Chemotherapy]. AB - PURPOSE: Cancer of the head and neck is commonly diagnosed in an advanced stage with a poor prognosis. New active agents and combinations have recently been identified. By adding chemotherapy to a multimodality approach with surgery and radiation therapy the outcome may be altered. METHODS: We reviewed the more recently published literature on induction and adjuvant chemotherapy. RESULTS: Four conclusive randomized trials of induction chemotherapy have failed to show an improved survival. No survival advantage has been shown for adjuvant chemotherapy. Organ preservation can be achieved with induction chemotherapy followed by limited surgery and radiation in approximately two thirds of the patients with laryngeal carcinoma. Patients achieving a complete response after induction chemotherapy have a better prognosis. Chemotherapy has consistently shown to reduce the frequency of distant metastases. CONCLUSION: Chemotherapy is indicated only in recurrent or metastatic disease. Induction chemotherapy is limited to laryngeal carcinoma with organ preservation as intent. Local recurrences and intercurrent morbidity are the main reasons for treatment failures. PMID- 7839301 TI - [Does primary tumor affect the prognosis in postmastectomy locoregional recurrence in breast carcinoma?]. AB - BACKGROUND: Prognosis following locoregional recurrence of breast cancer after mastectomy often is described as fatal. However, certain subgroups with better prognosis are supposed. We analysed established prognostic factors for their influence on post recurrence survival in order to discriminate favourable from unfavourable subgroups. PATIENTS AND METHODS: Between 1979 and 1989 163 patients with a local or regional recurrence of breast cancer following mastectomy were treated at the Department of Radiation Oncology of the University of Wurzburg. One hundred and forty had an isolated recurrence, without evidence of distant disease at the time of recurrence. Median follow up for patients alive at the time of analysis was 102 months from diagnosis of recurrence. Thirteen prognostic factors were tested. RESULTS: Out of the 140 patients 94 (58%) developed distant metastases within the follow-up period. Metastatic-free rate was 42% at 5 years and 38% at 10 years following recurrence. Recurrences occurred in 50% of patients within the first 2 years from primary surgery, in 83% within 5 years. In univariate analysis statistically significant influence on survival rates was found for pT, pN-status, lymphatic vessel invasion, blood vessel invasion, tumor necrosis, hormonal receptor status, presence or development of distant metastases, time to recurrence and site and extension of recurrence. Two- and 5 year survival rates ranged from 64% to 81% and from 40% to 60%, respectively in the favourable subgroups compared to a survival rate ranging from 15% to 44% at 2 years and 0% to 29% at 5 years in the unfavourable subgroups. In patients with involved axillary lymph nodes, the absolute number of nodes did not prove to have significant influence on overall survival. Histopathological grading did not reach statistical significance levels although an influence on survival was observed. Preceding adjuvant radiotherapy did not influence post-recurrence survival rates. Also preceding adjuvant systemic therapy showed no significant impact on survival. Multivariate analysis demonstrated that primary axillary status correlated most strongly with overall survival (p < 0.001) followed by tumor necrosis (p < 0.01). CONCLUSIONS: The mentioned prognostic factors may be useful in determining the adequate (local and systemic) therapy and the best time for it. Our data support previous findings, that certain subgroups with favourable prognostic features exist and they might still have a chance for cure by an adequate local treatment, whereas subgroups of patients with unfavourable prognostic factors have to receive systemic therapy immediately following local therapy because of the forthcoming systemic progression. PMID- 7839302 TI - Application of 198Au grains for carcinoma of oral cavity. AB - PURPOSE: The purpose of this study is to analyze the results of the treatment using gold grain implants over the past 9 years and to evaluate the usefulness of this treatment method. PATIENTS AND METHODS: From January 1985 through April 1993, a total of 45 patients with squamous cell carcinomas of the oral cavity and the oropharynx were treated with 198Au grain (gold grain) at the Department of Radiology, Osaka University Medical School. The initial activity of the grains supplied weekly by the Japan Radioisotope Association was usually 5 mCi (185 MBq), and single implants were usual. In case of combined external irradiation, telecobalt gamma-rays or 4 MV X-rays were used for treatment before implant. RESULTS: The local control rate for patients with T1 stages was 80% (20/25) and with T2 stages, 59% (10/17). The local control rate was 71% (10/14) for gold grain alone and 72% (13/18) for external irradiation combined with gold grain implants (combined therapy). In combined therapy, the median of the interval between external irradiation and gold grain implants was 21 days. The treatment interval for patients with recurrent diseases was 22 days, 22, 27, 39 and 46, respectively. The progression rate showed a tendency to increase in the patients with longer interval (more than 21 days), and with partial regression after external irradiation (p = 0.0085). CONCLUSION: Our findings show that the time interval between external irradiation and gold grain implantation is an important factor in combined therapy. Therefore, we emphasize that the time interval should be shorter than 3 weeks. PMID- 7839303 TI - Radiation-induced alterations of the proliferation dynamics of human skin fibroblasts after repeated irradiation in the subtherapeutic dose range. AB - PURPOSE: The aim of this study was to determine the effect of single and multiple irradiations on the differentiation and proliferation pattern of the stem cell system of human fibroblasts. METHODS: The pattern of differentiation of fibroblast cultures was analyzed by morphological criteria using colony forming assays. Proliferation rates were assessed by cell counting and measuring the incorporation of BrdU. RESULTS: Ionizing radiation both in low and high dose ranges exerts differential effects on the cellular processes of differentiation and proliferation in human fibroblasts. Single irradiations of fibroblasts in the dose range of 1 to 8 Gy induced terminal differentiation into postmitotic fibrocytes at high percentage level. Irradiation of long-term cultures of fibroblasts with repeated doses of 0.2, 0.6 and 1.0 Gy revealed that only in cultures, which were irradiated repeatedly (x 10) with 0.6 and 1.0 Gy a marked reduction of the proliferation capacity was apparent. Inhibition of proliferation by repeated irradiations with cumulative doses up to 10 Gy was not more pronounced as compared to single irradiations. CONCLUSION: 1. These results of radiation-induced changes in the proliferation and differentiation pattern of cells may be a basis for the understanding of the cellular processes leading to radiation-induced fibrosis and tissue aging. 2. Multiple irradiations with single doses up to 1 Gy and cumulative doses up to 10 Gy did not change the radiosensitivity of fibroblast cultures regarding effects on cell proliferation. PMID- 7839304 TI - The response of mouse skin to fractionated doses of fast neutrons (66 MeVp-Be) with variable interfraction and overall treatment times. AB - PURPOSE: Beam availability for neutron therapy at the National Accelerator Centre at Faure, South Africa is such that treatment fractions are given at irregularly spaced intervals. Such treatment scheduling may not be optimal. METHODS: Investigations were made using the acute skin reaction of the mouse foot to determine the effect of different numbers of regularly and irregularly spaced fractions of p(66)/Be neutrons. Assessment of results was both by average skin reaction and by ED50 values for the incidence of moist desquamation as established by probit analysis. RESULTS: Different numbers of fractions (between 6 and 11) and different times between fractions did not appear to affect the mouse foot response significantly when fractionation was completed within 11 days, i.e. before repopulation began to have an effect. When overall treatment times were longer than 11 days, the mouse foot responses to 6 and 9 fractions with variable interfraction times were similar, provided the overall treatment times were the same and the fractions were at least 24 h apart. The alpha/beta ratio was 87 +/- 27 (SE) Gy for the early response of the BALB/c mouse foot skin to p(66)/Be neutrons. CONCLUSIONS: The response of mouse skin to fractionated p(66)/Be neutrons was independent of fraction number or interfraction time, provided that the overall treatment time was the same. PMID- 7839305 TI - [Therapy trends in the prevention of radiation-induced diarrhea after pelvic and abdominal irradiation. Results of a tricenter study]. AB - PURPOSE: Radiotherapy induced diarrhea and convulsive pain are severe side effects of irradiation of the pelvis and the abdomen leading often to an interruption of the treatment. Up to now these side-effects were only treated symptomatically, prophylactic therapies are not known. PATIENTS AND METHODS: During the years 1992 and 1993 174 patients who obtained radiotherapy in the pelvis or the abdomen because of different malignancies were observed referring to the diarrhea-prophylactic effect of Smectite (= Skilpin). 80 patients received Smectite at the beginning of radiotherapy, 94 patients of the control group were treated with motility modifying drugs when diarrhea appeared. The following parameters were compared: Frequency, consistence and incontinence of stool, tenesmus and the onset of diarrhea. RESULTS: 67.0% (n = 63) of the patients in the control group developed diarrhea, whereas in the pretreated Smectite-group only 37.5% of the cases (n = 30) developed diarrhea. The first appearance of diarrhea was at day 17 in the pretreated group and averagely at day 11 in the control group. 44% of the patients in the control group suffered from tenesmus versus 25% in the Smectite-group. CONCLUSION: In comparison to the symptomatic treatment of radiation enteritis the prophylactic application of Smectite is able to reduce the diarrhea from the beginning of radiotherapy or at least to reduce the pathological frequency of stool and therefore to increase the quality of life. PMID- 7839306 TI - Phyllodes tumor of the breast. AB - PURPOSE: Presentation of the microscopical and clinical findings, prognostic factors and principles of treatment of the phyllodes tumor of the breast. PATIENTS AND METHODS: This paper reviews the published data on this rare and intriguing tumor of the breast. RESULTS AND CONCLUSIONS: The main prognostic factor is the histotype of the phyllodes tumor (benign, borderline, malignant) assessed on the basis of the criteria proposed by Azzopardi [3] and Salvadori et al. [50]. Wide local excision with an adequate marg in of normal breast tissue is the preferred initial therapy for phyllodes tumor. Mastectomy is indicated only for very large tumors compared with breast morphologic size and for recurrences of borderline and malignant tumors. PMID- 7839307 TI - [Acute side effects and treatment response in preoperative radiotherapy of rectal carcinoma]. PMID- 7839308 TI - [Immunologic presentation of P53 protein in cell nucleus of soft tissue sarcoma]. PMID- 7839309 TI - [Shortening of chemotherapy-induced thrombocytopenia by administration of interleukin-1 alpha]. PMID- 7839310 TI - [Booster in breast-conserving treatment of breast carcinoma]. PMID- 7839311 TI - Modulation of dorsal thalamic cell activity by the ventral pallidum: its role in the regulation of thalamocortical activity by the basal ganglia. AB - The actions mediated by limbic system output projections of the basal ganglia were investigated by studying the effects of ventral pallidum (VP) stimulation on the activity of neurons in thalamic target nuclei, including several of the dorsal thalamic nuclei and the nucleus reticularis, using in vivo intracellular recordings in rats. Intracellular injection of Lucifer yellow was used in a subset of experiments to identify the neurons recorded and to confirm their location with respect to the specific thalamic nuclei targeted. Stimulation of the VP evoked ipsps in 79% of the mediodorsal cells recorded. In the reticular nucleus, 73% of the neurons tested responded with evoked ipsps. In contrast, in other dorsal thalamic nuclei VP stimulation evoked depolarizations in 58% of the cells recorded. The latency to onset of the ipsps in the mediodorsal nucleus and in the reticular nucleus were not substantially different (1.7 +/- 1.1 msec vs. 2.7 +/- 1.1 msec), whereas the depolarizing response evoked in dorsal thalamic nucleus neurons typically occurred at longer and more variable latencies (3.5 +/- 2.7 msec). These experiments support a dual functional role for limbic system output from the basal ganglia in the regulation of thalamocortical activity: a) a direct inhibitory projection from the VP to the mediodorsal nucleus and b) an indirect disinhibition of neurons in other dorsal thalamic nuclei that occurs via a direct inhibitory projection to the reticular nucleus of the thalamus. Such an anatomical arrangement may be relevant to the presence of hypofrontality and the breakdown of cognitive filtering observed in schizophrenics. PMID- 7839312 TI - Properties of inhibitory and excitatory synapses between hippocampal neurons in very low density cultures. AB - The whole cell patch clamp technique was used to examine the electrophysiological properties of embryonic hippocampal neurons maintained in a very low density (VLD) culture preparation. The goal of these experiments was to establish the viability of the VLD culture as a model system in which to study regulation of neurotransmission at single monosynaptic connections, in the absence of polysynaptic innervation. Depolarization of neurons in the VLD culture revealed voltage-dependent sodium, calcium, and potassium currents which were blocked with, respectively, tetrodotoxin (TTX), cobalt, and tetraethylammonium and 4 aminopyridine. When pairs of neurons were simultaneously recorded, action potentials evoked in presynaptic neurons elicited either excitatory or inhibitory postsynaptic currents (EPSCs or IPSCs, respectively). The dual component EPSCs were due to the activation of both types of postsynaptic, ionotropic glutamate receptors: N-methyl-D-aspartate (NMDA) and non-NMDA receptors. Evoked IPSCs were due to the activation of postsynaptic gamma-aminobutyric acid (GABA) receptors. Both excitatory and inhibitory synapses exhibited short term depression in response to high frequency stimulation, although IPSCs were routinely decreased to a much greater degree than EPSCs. Spontaneous miniature EPSCs and IPSCs were found to persist in TTX, were blocked by the same pharmacological antagonists which blocked evoked responses, increased in frequency in response to hypersomotic solution, and were unaffected by changes in extracellular calcium concentration. mIPSCS were found to occur at a significantly lower frequency than mEPSCs. These experiments indicated that neurotransmission in the VLD cultures occurs in a manner consistent with the quantal hypothesis and, therefore, the VLD culture is a good model for studying excitatory and inhibitory neurotransmission between isolated pairs of neurons. In addition, these experiments, performed under comparable physiological conditions, demonstrated that there are fundamental differences underlying neurotransmitter release between excitatory and inhibitory neurons. PMID- 7839313 TI - Pharmacokinetics and in vivo specificity of [11C]dl-threo-methylphenidate for the presynaptic dopaminergic neuron. AB - dl-threo-Methylphenidate (Ritalin) was labeled with carbon-11 (t1/2:20.4 minutes) in order to measure its pharmacokinetics, to evaluate it as a radiotracer for the presynaptic dopaminergic neuron, and to examine its sensitivity to the loss of dopaminergic neurons. Positron emission tomographic (PET) studies were carried out in the baboon to determine specificity for the presynaptic dopaminergic neuron and in humans to assess sensitivity to neuronal loss. Studies with [11C]dl threo-methylphenidate ([11C]MP) in baboon demonstrated high regional uptake in the striatum. Peak uptake (0.04%/cc) occurred at 5-15 minutes post-injection. The half-time for clearance from peak uptake for [11C]MP was 60 minutes and the ratio between the radioactivity in the striatum and that in the cerebellum (ST/CB) ranged from 2.2 to 2.6 at 40 minutes. Repeated measures in the same baboon showed < or = 8% variability in the ST/CB ratio. Pretreatment with unlabeled methylphenidate (0.5 mg/kg) or GBR12909 (1.5 mg/kg) 30 minutes prior to [11C]MP injection markedly reduced the striatal but not the cerebellar uptake of [11C]MP, demonstrating the saturable and specific binding of [11C]MP to a site on the dopamine transporter in the brain. In both cases, the ratio of striatum to cerebellum (ST/CB) after pretreatment was reduced by about 43%. The ratios of distribution volumes at the steady-state for the striatum to cerebellum (ST/CB) for these two separate studies in the same baboon were reduced by 37 and 38%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7839314 TI - Acute administration of alcohol blocks cocaine-induced striatal c-fos immunoreactivity protein in the rat. AB - Immediate-early genes, such as c-fos, are induced in the brain by cocaine and other psychotropic drugs. This induction is thought to be mediated via the activation of dopamine D1 and glutamate N-methyl-D-aspartate (NMDA) receptor subtypes. Because alcohol selectively blocks NMDA receptor function, we determined the ability of alcohol to block the expression of c-fos normally induced by systemic cocaine exposure in perikarya of the rat striatum. Acute administration of alcohol (2 g/kg; IP) approximately 30 min prior to a single cocaine (20 mg/kg) injection significantly reduced the patchy appearance of intensely immunoreactive gene signal in dorsal-central quadrants of the caudate putamen. Separate administration of three doses of alcohol alone (1, 2, or 3 g/kg) was ineffectual in inducing FOS-like protein in this or other regions of the rat brain. The blockade of the encoded protein by alcohol was partial in magnitude reminiscent of that produced by MK-801 and related NMDA receptor antagonist drugs. Furthermore, the blockade of cocaine-induced FOS-like protein by alcohol occurred at a dose which produced a blood alcohol concentration of approximately 180 mg/dl (40 mM), comparable to that detected in intoxicating humans. Considering the fact that the concomitant use of alcohol and cocaine is the most common substance abuse pattern found in the addictive population, the present results suggest an antagonist effect exerted by these two drugs at the transcriptional level and further support the consensus that NMDA receptors are the plausible surface-target elements mediating some of the effects of alcohol and cocaine. PMID- 7839315 TI - Transient increase in the in vivo binding of the benzodiazepine antagonist [3H]flumazenil in deafferented visual areas of the adult mouse brain. AB - Flumazenil is an imidazobenzodiazepine, an antagonist of central benzodiazepine (BDZ) receptors. BDZ binding sites are a modulatory component located on the gamma-aminobutyric acid (GABA) receptor macromolecule. We studied the effect of monocular enucleation on [3H]flumazenil binding in deprived and intact visual areas and nonvisual areas of the adult mouse brain under in vivo conditions. [3H]flumazenil binding was examined at seven time points up to 56 days postenucleation. In some monocularly deprived mice, changes in local blood flow accompanied with the BDZ receptor response were evaluated by coinjection of [3H]flumazenil and 99mTc-HMPAO. Monocular enucleation produced a transient increase in [3H]flumazenil binding in the deprived visual cortex and superior colliculus. At 17 days postenucleation, [3H]flumazenil binding in the anterior and posterior portions of the visual cortex and the superior colliculus increased by 28%, 15% and 23%, respectively, and declined to control levels at 45 days postenucleation. The increase in [3H]flumazenil was accompanied with a decrease in blood flow. Alterations in BDZ receptors and blood flow were selective to deprived visual structures. The regional correlation between the metabolic deficit and the BDZ response provides further support that the increase in BDZ receptor binding is confined to regions of reduced neuronal activity. [11C]flumazenil is an excellent radiotracer for in vivo imaging of benzodiazepine receptors in human brain using positron emission tomography (PET). This study suggests the suitability of [11C]flumazenil for in vivo PET study of BDZ receptor response to deafferentation of visual structures in human brain. PMID- 7839316 TI - Slow recovery of human brain MAO B after L-deprenyl (Selegeline) withdrawal. AB - L-Deprenyl (Selegeline) is an enzyme-activated irreversible inhibitor of monoamine oxidase B (MAO B; EC 1.4.3.4). It is used to treat Parkinson's disease at a dose of 5 mg twice a day. Since enzyme inhibition is irreversible, the recovery of functional enzyme activity after withdrawal from L-deprenyl requires the synthesis of new enzyme. We have measured a 40 day half-time for brain MAO B synthesis in Parkinson's disease and in normal subjects after withdrawal from L deprenyl. This is the first measurement of the synthesis rate of a specific protein in the living human brain. L-Deprenyl is currently used by 50,000 patients with Parkinson's disease in the United States and its use is expected to increase with reports that it may be beneficial in Alzheimer's disease. The slow turnover of brain MAO B suggests that the current clinical dose of L-deprenyl may be excessive and that the clinical efficacy of reduced dosing should be evaluated. Such an evaluation may have mechanistic importance as well as an impact on reducing the side effects and the costs arising from excessive drug use. PMID- 7839317 TI - Ethanol differentially modulates GABAA receptor-mediated chloride currents in hippocampal, cortical, and septal neurons in rat brain slices. AB - Previous electrophysiological studies have reported conflicting results concerning the effects of ethanol on gamma-aminobutyric acid-A (GABAA) receptor mediated responses in the brain. To examine the variables that might explain these inconsistencies, the present study was designed to determine whether ethanol modulation of synaptically evoked GABA responses is brain region dependent, to identify factors that might regulate ethanol sensitivity, and to investigate the mechanism(s) underlying ethanol modulation of GABA responses. Whole-cell voltage clamp methods were used to examine the effects of ethanol on synaptically evoked GABAA inhibitory postsynaptic currents (IPSCs) recorded from neurons in hippocampus, cerebral cortex, and intermediate lateral and medial septum from rat brain slice preparations. Bicuculline-sensitive IPSCs elicited by local stimulation were pharmacologically isolated by pretreatment with the glutamate specific antagonists, DL-(-)-2-amino-5-phosphonovaleric acid (APV) and 6, 7-dinitroquinoxaline-2, 3-dione (DNQX). Superfused ethanol (80 mM) potentiated evoked GABAA IPSCs in cortical neurons and in intermediate lateral and medial septal neurons but not in CA1 hippocampal neurons. However, the mechanism by which ethanol enhanced GABAA IPSC amplitudes differed between brain regions. In cortex, ethanol induced a hyperpolarizing shift in the GABAA IPSC reversal potential (EIPSC) without modifying the underlying GABAA receptor-mediated conductance (GIPSC). In contrast, ethanol enhanced GABAA IPSC amplitudes differed between brain regions. In cortex, ethanol induced a hyperpolarizing shift in the GABAA IPSC reversal potential (EIPSC) without modifying the underlying GABAA receptor-mediated conductance (GIPSC). In contrast, ethanol enhanced GABAA IPSC amplitudes in lateral and medial septal neurons by increasing the GIPSC without modifying the EIPSC. These results suggest that ethanol differentially modulates responses to endogenous GABA released during synaptic activation and that important differences between various brain regions may reflect multiple mechanisms of ethanol action. PMID- 7839318 TI - From nurse to nurse: about changes and guarantees. PMID- 7839319 TI - Is safe, quality nursing in jeopardy? PMID- 7839320 TI - [Toward purposeful prevention. Interview by Klaus Reinhardt]. PMID- 7839321 TI - [Primary prevention: nutrition and body weight]. AB - Increased body weight is one of the most important cardiovascular risk factors. Increased body weight is often associated with high blood pressure, dyslipidemia and also impaired glucose tolerance; therefore, the control of the body weight is of crucial importance in primary prevention. The substrate balance of the different energy substrates are regulated very differently, so that in a healthy person body weight can increase only in the case of an excess ingestion of dietary fat, but not in case of an excess of carbohydrates and/or proteins. Avoiding the ingestion of fat is the major dietary strategy for the control of body weight. Eating a low-fat/high-carbohydrate diet will stabilize the body weight and in the case of overweight lead to a slow but constant decline in body weight. A low-fat diet is also the major dietary strategy for the control of dyslipidemias. A low-fat diet is characterized by a low energy density and a high nonenergy nutrient density. The increased intake of vitamins, especially antioxidative vitamins, is an additional advantageous mean for primary prevention of free-radical damage. PMID- 7839322 TI - [Prevention of venous thromboembolism--in whom, when and how?]. AB - Venous thromboembolic diseases are of major importance with respect to morbidity and mortality. Therefore, efficient prophylaxis is essential. Indication for thromboprophylaxis has to be made individually: In high risk situations, especially in orthopedic surgery, every patient should receive medical prophylaxis, e.g. with heparin, in addition to other preventive measures such as the wearing of elastic stockings or physiotherapy until full mobilization. For high-risk patients having a history of recurrent venous thromboembolism or which are suffering from a thrombogenic disease (e.g. myeloproliferative disorder, especially polycythemia vera, paroxysmal nocturnal hemoglobinuria, systemic lupus erythematosus, homocystinuria) or a hereditary thrombophilia (e.g. deficiency of antithrombin III, protein S, protein C or APC resistance), prophylactic measures should be more generally applied. In these patients, risk factors (e.g. oral contraceptive medication) or risk situations (e.g. long-distance travelling by car or airplane) have to be avoided whenever possible. In inevitable risk situations (e.g. perioperative or peripartal period) prophylaxis is mandatory. It is generally limited to the period of elevated thrombogenic risk and is often effected by application of a low molecular weight heparin. Patients with a history of recurrent thromboembolic events despite elimination of all avoidable risk factors should get a lifelong prophylaxis, usually with oral anticoagulants. PMID- 7839323 TI - [Prevention of coronary heart disease in familial hypercholesterolemia]. AB - Familial forms of isolated hypercholesterolemia are inherited autosomal dominantly and are caused by defects of the low-density lipoprotein (LDL) receptor protein or its ligand, the apolipoprotein B-100, the exclusive apolipoprotein moiety of the LDL particles. Mutations at the LDL receptor gene locus (more than 150 different mutations have been described up to now) lead to familial hypercholesterolemia (FH); the only mutation at the apolipoprotein B-100 gene locus described in detail so far leads to the so-called familial defective apolipoprotein B-100 (FDB). Both lipid disorders are characterized by an increased risk for premature atherosclerosis involving primarily the coronary arteries. An increased risk for coronary heart disease can be expressed statistically by the excess mortality. In particular, individuals between the age of 20 and 59 are affected by an excess mortality; coronary deaths are approximately 100 times more frequent in patients between 20 and 39 with familial forms of hypercholesterolemia than within the normal population. On the other hand, in patients with myocardial infarctions before the age of 60, the diagnosis of FH is approximately 20 to 30 times more frequent than within the normal population. A regression of cardiovascular lesions subsequent to an intensive lipid-lowering therapy has clearly been demonstrated in patients with familial forms of hypercholesterolemia. Because of the serious prognosis of untreated familial forms of isolated hypercholesterolemia with respect to longevity, it is important to identify patients and their relatives with FH and FDB as early as possible and to treat them, besides a lipid-lowering diet, intensively with lipid lowering drugs. PMID- 7839324 TI - [Primary prevention of coronary heart disease with drugs: wishful thinking or reality?]. AB - The primary prevention of coronary artery disease remains a controversial issue. Beside the much disputed lipid-lowering drugs we have additional possibilities for a pharmacological intervention, such as the administration of antioxidants (e.g. vitamin E), aspirine or estrogens. In this article the epidemiological data with such treatments are presented. In selected populations the relative risk of cardiovascular events could be reduced 40 to 60% by vitamin-E supplements, low dose aspirine and estrogen replacement in postmenopausal women. The protective effects are most marked in persons over 50 years with coexistent cardiovascular risk factors. There are, however, also potential dangers of a primary prophylaxis by drugs, such as the increased risk of cerebral and gastrointestinal hemorrhage with aspirine or the induction of endometrial carcinoma or breast cancer with estrogens. For this reason dietary and life style counselling should remain the most important measure in primary prophylaxis. In individuals with cardiovascular risk factors--which should be eliminated, if possible--additional administration of aspirine, estrogens or antioxidants may be considered after a careful evaluation of the overall risk/benefit ratio. PMID- 7839325 TI - [Smoking and smoking weaning]. AB - Stop-smoking counselling is a challenging task in primary health care, its efficacy being often underestimated by the physician. Health care physicians are not very inclined to advise their smoking patients to stop smoking and give specific counselling. This is in contradiction with the expectations of more than two thirds of the smoking patients, who expect their physicians to help them. The present article discusses the therapeutical methods for stop-smoking counselling in primary health care. In particular, the article illustrates the importance for this support (including the possibilities for nicotin substitution in the weaning stage). PMID- 7839326 TI - [Prevention for travel to the tropics]. AB - The Swiss Working Group for Health Advice to Travellers regularly publishes its recommendations for malaria prophylaxis and vaccination as supplement to the 'Bulletin' of the Federal Office of Public Health. In this review the strategy with respect to information, to clever behavior abroad, to chemoprophylaxis and immunization prophylaxis is analyzed. A critical evaluation of emergency self therapy describes remaining questions in particular. PMID- 7839327 TI - [Is prevention of diabetes mellitus possible?]. AB - Despite recent progress in therapy and management of diabetes mellitus, diabetes remains a serious disease with life-threatening complications. It is by far the most common metabolic disease and affects 5% of the population in industrialized countries. Noninsulin-dependent diabetes mellitus (NIDDM) is a complex disorder characterized by insulin resistance and impaired insulin secretion and is associated with an increased risk of coronary heart disease, peripheral vascular disease, arterial hypertension and dyslipidemia. Predisposing factors for NIDDM are obesity and a family history of diabetes. Greater physical activity has been associated inversely with the prevalence of NIDDM in several cross-sectional studies. Physical activity increases the sensitivity to insulin, and regular endurance exercise can induce and maintain weight loss, improve glucose tolerance and ameliorate most of the abnormalities in the metabolic syndrome. Type I diabetes mellitus arises as a consequence of immunologically mediated pancreatic islet beta-cell destruction in genetically susceptible individuals. It is an insidious process that may occur over years. During the stage of disease evolution (prediabetes), individuals may be identified by the presence of immunological markers and a decline of beta-cell function. The autoimmune nature of the disease process has led to attempts to stop this process by immune intervention strategies. A variety of immune interventions has been used, some immunosuppressive and some immunomodulatory. Several screening programs are used in order to identify high-risk subjects (i.e. first-degree relatives of individuals with type I diabetes) who may benefit from an early intervention. The ultimate goal of all these efforts is to prevent the development of overt type I diabetes mellitus in those at risk for the disease, using strategies that are both safe and specific. This review summarizes the results of the various studies conducted to date and outlines the approaches currently being tested. PMID- 7839328 TI - [Sense and usefulness of preventive diagnosis]. AB - The value of preventive screening tests is controversial. The predictive value of such testing depends on the incidence of the disease as well as of the sensitivity and specificity of the available tests. Cardiovascular and neoplastic diseases have been a model for preventive testing. We review the pertinent literature on preventive screening tests with special emphasis on the value of a thorough history and physical exam. PMID- 7839329 TI - [Pre- and postmenopause. Interview by Klaus Reinhardt]. PMID- 7839330 TI - [Endocrinological changes in pre- and postmenopause]. AB - The endocrinology of the perimenopause--the time between pre- and postmenopause- is characterized by changes in the metabolism of the steroid hormones caused by increasing insufficiency of the ovaries. Until the age of 48 the concentrations of the estrogens are relatively constant with a median level of 120 pg/ml serum for estradiol and of 75 pg/ml for estrone. Between the age of 49 and 54 the levels decrease to concentrations of 35 pg/ml for estrone and 10 pg/ml for estradiol. In the corresponding time, there is a tenfold rise of the level of FSH. The level remains constant until high age. The decrease of the estrogens causes the menopause in an age of 51 to 52. In the postmenopause the ovaries don't play a role for the concentrations of the estrogens. The concentrations are determined by the conversion of the androgens secreted by the adrenal cortex. The serum concentrations of androstenedione are five times higher than those of testosterone. The function of the adrenal cortex remains until high age; there is no 'adrenopause' comparable to the 'menopause'. The suppression of the adrenal cortex by treatment with corticoids (e.g. for asthma) causes a dramatic decrease of the androgens and consecutively for the estrogens. The lack of estrogens play an important role in the induction of osteoporosis and other disturbances of the late postmenopause, e.g. coronary heart disease. Obese women show in the pre- and the perimenopause more often dysfunctional bleedings caused by anovulation or corpus luteum insufficiency.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7839331 TI - [Pathogenesis of postmenopausal osteoporosis]. AB - Low peak bone mass and increased bone loss within the process of bone remodelling are the most important determinants for the manifestation of postmenopausal osteoporosis. Both are influenced during lifetime by a large number of risk factors additively leading to a critical low bone mass. Loss of bone substance and deterioration of architecture of bone tissue lead to an increased fragility of the skeleton. In this complex interactions menopausal decrease of endogenous estrogen secretion is of special importance. Decrease of estrogen induces by effects on calcitropic hormones and different local growth factors a high bone turnover with a high rate of bone loss. The resulting slight increase of serum calcium and the consequent decrease in the secretion of parathyroid hormones and activation of vitamin D in the kidneys lead to a decreased intestinal calcium absorption. In peri- and early postmenopausal women there is a large range of different degrees of bone turnover. It is unclear however, whether there are really two distinct groups of so-called rapid and slow bone losers. It remains to clarify which intrinsic mechanisms besides the risk factors are responsible for the individually different answer of calcium and bone metabolism to estrogen deficiency, which is the same in every women. PMID- 7839332 TI - [Therapeutic concepts in the treatment of postmenopausal osteoporosis]. AB - Postmenopausal osteoporosis is not a well-defined disease, but summarizes women with different severity of changes in bone metabolism and different clinical complaints. The only common feature in women with 'postmenopausal osteoporosis' is the deficiency of estrogen. Postmenopausal women can be subdivided into four groups, according to their risk for fractures: 1. women without evident increase of fracture risk (bone mineral content between 0 and 2 SD of age-related normal range, no known risk factors from history); 2. women with possible increase of fracture risk (bone mineral content between 0 and -2 SD of age-related normal range, with or without known risk factors from history); 3. women with clear increase of fracture risk (bone mineral content below age-related normal range, with or without known risk factors from history); 4. women with already occurred fracture (manifest osteoporosis). Therapeutic intervention in postmenopausal women should be adapted to the risk for fracture. In all four groups a secondary prevention or basic therapy should be performed, focusing on calcium intake, vitamin D supply and sufficient physical activity. Calcium intake should be 1500 mg/day in women without estrogen substitution and 1000 mg in women with estrogen substitution. In patients living mainly inside or with malnutrition, a daily substitution of 500 E. Vitamin D3 is recommended. In group 2, regular control of bone mass is recommended to start additional estrogen replacement therapy, if accelerated loss of bone mass occurs. In group 3, estrogen replacement therapy is recommended urgently and is the therapy of first choice to prevent development of fractures. In group 4 (manifest osteoporosis), therapy should aim on improvement of the patient's symptoms and on increase of bone stability to avoid further fractures. The symptomatic therapy includes pain medications and an intensive physical therapy adapted to the patient's needs. Physical therapy should be performed for long time to reduce complaints and to improve musculoskeletal function in order to prevent falls. Different agents influencing bone metabolism by inhibition of bone resorption (estrogens, calcitonin, bisphosphonates) or stimulation of bone formation (fluoride) are used in manifest osteoporosis to increase bone stability. But the present efficacy to avoid further fractures has not been shown sufficiently for all available agents, so that a final evaluation and recommendation can't be done. Therapy decisions in manifest osteoporosis are often influenced by the possible side effects of the drugs (bleeding, gastrointestinal problems, joint pain), other, not bone-related effects of the drugs (improvement of climacteric complaints, pain relief) and other concomitant diseases and medications. PMID- 7839333 TI - [Cardiovascular effects and estrogen/gestagen substitution therapy]. AB - After the menopause there is a profound increase in cardiovascular diseases which is mainly based on an enhanced development of atherosclerosis caused by an estrogen deficiency. The most important pathomechanisms are the rise in LDL cholesterol and triglycerides as a result of an impaired elimination of LDL and remnants in the liver, and an enhancement of LDL oxidation in the arterial intima. Moreover, at the site of endothelial lesions the occurrence of vasospasms and platelet aggregation is facilitated in estrogen-deficient women which may lead to ischemia. Epidemiological studies revealed that replacement therapy with natural estrogens reduces the risk of cardio-vascular diseases by 30 to 50%, whereby the protective effect is not impaired by the addition of progestogens. The mechanism of action is only partly based on the favorable effect of estrogens on lipid metabolism. Besides an increase in HDL, estrogens may reduce LDL cholesterol by means of an enhancement of receptor-mediated elimination of LDL and remnants in the liver. A rise in triglycerides is of no clinical relevance, if based on an estrogen-induced increase in triglyceride synthesis and VLDL-LDL turnover. Even in the case of an unfavorable lipid pattern estrogens may protect from atherosclerosis, as they inhibit LDL oxidation by scavenging free oxygen radicals. Finally, estrogens may cause vasodilation which is partly endothelium - dependent, but presumably is also based on the blockade of calcium influx into smooth muscle cells. This may be of particular importance in women with endothelial lesions, e.g. coronary sclerosis.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7839334 TI - [Cancer risk under hormone therapy]. AB - Estrogens are not carcinogenic. They create however a milieu, which generally stimulates cell division and growth of the target organs, also in cases of existing early neoplastic changes. This growth stimulating effect is dependent on dose and duration of the estrogen effects. Low doses exert no significant influence, medium doses are stimulating, high doses inhibit carcinoma growth, if the tumor is hormone responsive. Cyclic application of a progestogen stops proliferation and induces the specific function of the target tissue. This influence is mediated through a reduction of the number of estrogen receptors, a stimulation of the transformation of estradiol to estrone, a decrease of intracellular metabolism and a reduction of blood perfusion of the target organs. Progestogens therefore act generally preventive against cancer development at the genital organs and probably also on the breast. They should therefore principally be given together with estrogens for at least 10, optimal 12 to 14 days at month. Whether the compromise to give a progestogen only every three or six month will be acting equally carcinoma preventive as the monthly medication, ist not known. In woman bearing risk factors - except proliferative mastopathy - an estrogen progestogen substitution seems not to increase the inherent risk, rather to reduce it. However nevertheless the manifestation of genital and breast cancer occurs preponderately in women at risk. Familial-genetic immunologic, metabolic factors, weight, race, nutrition, chronic inflammation, regeneration, old age and other risks seem equally or even more important than hormonal factors. Women, who receive a long time estrogen-progestogen substitution, have a lower risk to develop endometrial and ovarian cancer. This is probably also true for mammary and colon cancer. Meta-analyses of all studies could not show so far an increased risk for mammary cancer in estrogen-progestogen substituted postmenopausal women. Women, who receive a postmenopausal long during estrogen-progestogen substitution show statistically a better prognosis of their genital and mammary cancers, if they occur, than unsubstituted controls. Following treated cervical, endometrial and ovarian cancer a strictly indicated estrogen-progestogen substitution is possible without causing drawbacks. The so far valid contraindication against estrogens in post-carcinoma patients does not longer exist. Positive influences on cure rates and survival have been described. In cases of estrogen-progestogen negative receptor mammary cancer cases a substitution is also possible. In all other cases hormones can be given after five years recidive free survival. It is recommended to prescribe not too high doses of estrogens and to combine them with an effective progestogen.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7839335 TI - [Estrogen substitution in the postmenopause--effect and compliance]. AB - At least one of four women will suffer from osteoporosis with fractures of vertebrae, forearm or hip. Maintenance of bone mass is a crucial argument for long-term estrogen replacement for prophylaxis of osteoporosis. 2 mg estradiol or 0.625 mg conjugated estrogens orally or 50 to 100 micrograms estradiol percutaneously are equally sufficient for prevention of osteoporosis. The additional use of a progestogen in women with intact uterus may support the antiresorptive effects of estrogens. Improvement of patients' compliance administered today by only 25% of postmenopausal women in Germany through sufficient information upon estrogen replacement therapy provided by the medical community is a rewarding task for physicians and scientists engaged in the field of menopause and prevention of osteoporosis. PMID- 7839336 TI - [Therapy of sterility in the premenopause]. AB - Although menopause marks the irreversible loss of female fertility, a substantial loss of the fertility potential is observed many years before menopause. In contrast to spermatogenesis, which remains active until advanced age, female fertility depends on a pool of primordial ovarian follicles and oocytes, which are formed entirely during the prenatal life and whose numbers steadily decline thereafter. The results of inseminations with donor sperm demonstrated that this decline in the number of ovarian follicles becomes clinically relevant decades before menopause. Furthermore, from the results of embryo replacements after in vitro fertilization of oocytes donated by young women, convincing evidence was provided that the age-related loss of female fertility is caused by ovarian factors, and not by the deterioration of the uterine functions. Although the increasing age of female patients is associated with reduced success rates of all homologous infertility treatments, the individual decision should be based on the measurement of the FSH concentration on the third day of an untreated menstrual cycle, because this value reflects the degree of ovarian function. PMID- 7839337 TI - [Contraception in the premenopause]. AB - Reproduction continues in the perimenopause. To prevent unintended pregnancies, the use of a highly effective reversible contraceptive is necessary. The most effective methods of contraception are hormonal contraceptive methods and the intrauterine device (IUD). Barrier contraceptives can have a high-use effective rate in motivated users, too. Hormonal contraception has both risks and benefits, but can be used safely for healthy women without risk factors during the time of perimenopause. To prevent the metabolic side effects of synthetic estrogen ethinyl-estradiol in the contraceptive pill in perimenopause, the use of natural estrogen (estradiol) in combination with a progestagen for contraception is effective, too. A major problem of IUDs has been the increased incidence of bleeding or dysmenorrhea. For these women, Progestin-releasing IUDs are recommended because of their ability to reduce the amount of uterine bleeding associated with menstruation. PMID- 7839338 TI - [Dehorning of goats and kids]. AB - The local anaesthesia used during the dehorning of goats is described. The authors recommend general anaesthesia for the disbudding (dehorning) of kids. In addition to the dehorning of goats and kids, this article also describes the use of the combination of xylazine, ketamine, and atropine, and the preparation of this 'goat anaesthetic'. PMID- 7839339 TI - [Analysis of mating management on pig farms using 'DEKT PERFEKT']. AB - 'DEKT PERFEKT' is software for the analysis of mating management on breeding and multiplier pig farms. It can be used in combination with other software already on the market and is user-friendly. So far it has been used on several farms of which one has been dealt with in detail in this article. It shows how the software can be used in the analysis of disappointing technical results due to inefficient mating management. Intensified supervision with the help of 'DEKT PERFEKT' has led to a marked improvement of technical results on pig breeding farms. PMID- 7839340 TI - [American Quarter Horses and HYPP]. AB - Hyperkalaemic periodic paralysis is a genetic disease that affects the American Quarter Horse population and is caused by a mutation. As a result of this mutation in a gene which codes for the sodium channel in muscle cells, severe muscle weakness can appear. Reliable DNA-tests can establish whether a horse is homozygous negative, heterozygous, or homozygous positive for this mutation. Therapy and prevention are discussed. PMID- 7839341 TI - [Antibiotics and chemotherapeutic agents in udders for human consumption]. PMID- 7839342 TI - [Chloramphenicol]. PMID- 7839343 TI - [Guidelines for practice management and practice equipment. "Much more effective and fewer disturbances']. PMID- 7839344 TI - [Respiration problems in a herd of heifers]. PMID- 7839345 TI - A method for typing polymorphism at the HLA-A locus using PCR amplification and immobilized oligonucleotide probes. AB - We have developed a simple and rapid method for DNA typing of the HLA-A locus using PCR amplification and hybridization of the PCR product, labeled with biotinylated primers, to an array of immobilized oligonucleotide probes in a single hybridization reaction (reverse dot or line blot). A single primer set (RAP1007 and DB337) is used to specifically amplify a 990-bp fragment containing the HLA-A locus exons 1, 2, and 3 from genomic DNA. This primer set is locus specific and amplifies all HLA-A alleles. A set of 51 sequence-specific oligonucleotide (SSO) probes, 25 for exon 2 and 26 for exon 3, was immobilized to a nylon membrane by UV-crosslinking oligonucleotide probes containing a poly thymidine "tail" added with terminal transferase. In the line blot format, all 50 SSO probes plus a control probe are immobilized on a single nylon membrane strip. The probe array was used for typing in a hybridization reaction with DNA amplified from a variety of samples. These probes can identify 37 homozygous HLA A alleles. In the analysis of heterozygous samples, 604 heterozygous types out of 633 (95.4%) possible heterozygous probe patterns can be detected as a unique probe reactivity pattern. A simple computer program has been developed to assign the alleles and genotypes based on the probe hybridization pattern. PMID- 7839346 TI - Low-resolution DNA typing for HLA-B using sequence-specific primers in allele- or group-specific ARMS/PCR. AB - The products of the human major histocompatibility complex (HLA Class I and II) have historically been detected using serological or cellular assays. With the availability of DNA sequence information for alleles of the HLA system, and with the development of molecular biological techniques it has become possible to tissue type for allelic differences in the HLA genes themselves. We describe here a polymerase chain reaction (PCR) system, based on the principle of the amplification refractory mutation system (ARMS), for low-resolution DNA typing of the HLA-B gene. The technique involves a one-step PCR from genomic DNA using sequence-specific primers in particular combinations that determine the specificity of each reaction. A low-resolution primer panel has been designed, based on published HLA-B gene nucleotide sequences, consisting of 34 sequence specific primers (SSP) in 24 PCR reactions which cover all known HLA-B alleles, to give allele-specific or group-specific amplification of DNA fragments of defined size (344-784bp). Advantages of the system are that it can be performed in under 4 hours including DNA extraction, results are easy to interpret and it does not require viable cells. PMID- 7839347 TI - A rapid method to study the relationship between IDDM and HLA-DQ beta 57 Asp. AB - We have developed a rapid and simple method to detect the relation between HLA-DQ beta 57 Asp and Chinese IDDM patients. The method involved the selective amplification of a DNA fragment from the HLA-DQ B1 gene by using the mutagenic primers. After PCR, if the HLA-DQ beta 57 was Asp, then there was an artificially created restriction enzyme cutting site. We then can accurately obtain the results by enzyme digestion and electrophoresis. Sixty-nine IDDM patients and 30 nondiabetic control subjects were analyzed using this method. Twenty-two (42%) IDDM patients had non-Asp 57 homozygous, 31/45%) were Asp/non-Asp 57 heterozygous, and 9 (13%) had Asp-57 homozygous. Of the 30 control subjects, the number of cases for these three types were 6 (20%), 18 (60%), and 6 (20%), respectively. The relative risk of homozygous DQ beta 57 non-Asp in our group was 2.9 and the p value was greater than 0.05. Using this kind of approach, we were able to provide a simple, rapid, and non-radioactive method to detect whether the HLA DQ beta 57 was Asp or not. PMID- 7839348 TI - Polylactosamine sugar chains expressed by epithelia of Henle's loop and collecting duct in rat and human kidney are selectively recognized by human cold agglutinins anti-I/i. AB - Normal rat and human kidney was mapped immunohistochemically with human monoclonal cold agglutinins against the biochemically related erythrocyte glycoconjugate antigens I and i, which represent branched and linear polylactosamines, respectively. The antibodies worked well with both cryostat and paraffin-embedded material. Anti-i gave specific staining of collecting duct cells (mostly principal cells) as evidenced by double labelling with antibodies to band 3 and a 23 kD protein of intercalated cells. In contrast, anti-I turned out to be the first exclusive marker for the ascending and descending thin limb of Henle's loop. In addition, in rat kidney, the binding of anti-I/i was preserved in primary cultures both of principal cells of the papillary collecting duct and cells of the thin limb of Henle's loop. Our results suggest that both antibodies might be interesting tools for in vitro studies of renal cell physiology and the investigation of kidney development. PMID- 7839349 TI - Gene frequencies and haplotypic associations within the HLA region in 916 unrelated Japanese individuals. AB - The gene frequencies and haplotypic associations within the HLA region have been investigated in 916 unrelated Japanese individuals. HLA class I and class II antigens were studied by conventional serology, and class II alleles, DRB1, DRB3, DQA1, DQB1 and DPB1 were typed by using polymerase-chain reaction amplification and sequence-specific oligonucleotide probe (PCR-SSOP) method. Thirty DRB1, 3 DRB3, 8 DQA1, 15 DQB1 and 13 DPB1 alleles were found in our population. DR-NJ25, a characteristic antigen in the native American and Asian populations, was observed at 3.0%. This antigen was observed mainly with the DRB1*1403 and 1406 alleles. Twenty-seven out of 30 DRB1 alleles found in this study had a high positive linkage disequilibrium with DQB1 alleles and 20 of them had an exclusive association with one specific DQA1-DQB1 combination. The strong association between DRB1 alleles and HLA-B antigens was the most striking finding in this study. Twenty-eight out of 30 DRB1 alleles had a positive linkage disequilibrium with 24 HLA-B antigens (p < 0.01). The other two alleles, DRB1*0404 and 1402, were very rare, and their frequencies were 0.2% and 0.1%, respectively. The data presented in this population study should be useful for the studies on anthropology, organ transplantation and disease susceptibility. PMID- 7839350 TI - SSOP typing of the Tenth International Histocompatibility Workshop reference cell lines for HLA-C alleles. AB - HLA-C gene products are the most poorly understood of the HLA class I molecules because they express at low level on the cell surface compared to HLA-A and -B. However, recent evidence shows that HLA-C molecules are functionally competent in eliciting T-cell responses and in controlling NK-cell recognition. Approximately 20 to 50% of HLA-C alleles type "blank" in most populations. To provide a better definition of the HLA-C alleles, we analyzed 98 extensively characterized B-cell lines from the 10th International Histocompatibility Workshop. Selective HLA-C specific DNA amplification of exons 2 and 3 from DNA prepared from the cell panel was achieved with the use of two sets of locus-specific primers. We used 64 sequence-specific oligonucleotide probes (SSOPs) complementary to variable sites in exons 2 and 3 to generate hybridization patterns. Twenty-five alleles were found among these patterns, including seven new alleles in the homozygous cell lines and seven potential new alleles in heterozygous cell lines. Differences between the new alleles and known alleles were generally small. Five major groups were identified in the Cw "blank" cells by the SSOP patterns. In addition, linkage between HLA-B specificities and HLA-C alleles was similar to previous observations. The present study demonstrated that SSOP typing was effective in identifying new alleles in homozygous typing cells but not in the heterozygous cells. Also, DNA typing can facilitate the identification of all HLA-C alleles, including those that serologically type as blanks. The HLA-C locus may be more polymorphic than was previously recognized. PMID- 7839351 TI - Susceptibility to insulin-dependent diabetes mellitus and short cytoplasmic ATP binding domain TAP2*01 alleles. AB - TAP2 genes are placed within the HLA complex, have limited genetic variability and encode two main groups of peptide transporter proteins, the so-called TAP2*01 alleles, with a short ATP-binding domain, and the TAP2*0201 allele with a long domain. These transporters carry antigenic peptides from cytoplasm across the endoplasmic reticulum membrane to release them into nascent HLA class I molecules, which will then travel towards the plasma membrane. The shorter TAP2*01 alleles are present in 99% of diabetics and 90% of controls; these alleles may add slight, although significant and independent, susceptibility to diabetes, particularly in subjects carrying non-Asp 57 at beta DQ. Moreover, this increased susceptibility is not due to linkage disequilibrium with other HLA markers (i.e.: DR4), which does not exist in our Spanish population. PMID- 7839352 TI - A novel HLA-DRB1*14 allele (DRB1*1417). PMID- 7839353 TI - Identification of two new HLA-C alleles, Cw*1203 and Cw*1402, from the sequence analysis of seven HLA homozygous cell lines carrying HLA-C blank. PMID- 7839354 TI - HLA-A, B, C, DR and DQ polymorphism in Zaireans. PMID- 7839355 TI - Improvements in HLA-C typing using sequence-specific primers (PCR-SSP) including definition of HLA-Cw9 and Cw10 and a new allele HLA-"Cw7/8v". PMID- 7839356 TI - Direct sequencing of a novel DPB1 allele (DPB1*5101) of the heterozygote from the membrane of reverse dot blot analysis. PMID- 7839357 TI - The relationship between the concentration of the pyrrolizidine alkaloid monocrotaline and the pattern of metabolites released from the isolated liver. AB - Hepatic metabolism of the pyrrolizidine alkaloid monocrotaline results in extrahepatic toxicity caused by the release of metabolites from the liver. We have quantified the release of pyrrolic metabolites into the perfusate and bile of isolated rat livers perfused with monocrotaline over the concentration range of 0.125-1.5 mM. Over a 1-hr perfusion period, the amount of dehydromonocrotaline released from the liver varied from 60 nmol/g liver at 0.125 mM monocrotaline to 460 nmol/g liver at 1.5 mM monocrotaline. As a percentage of total pyrrole release, this is a monotonic increase from 30 to 41%. The percentage of pyrroles released into the bile, representing mainly 7-glutathionyl-6,7-dihydro- 1 hydroxymethyl-5H-pyrrolizine (GSDHP), increased over the monocrotaline concentration range 0.125-1.0 mM, but fell sharply from 38% of total at the latter concentration to 21% of total at 1.5 mM monocrotaline. This is probably a reflection of glutathione depletion. Nonalkylating pyrrole released into the perfusate, represents largely 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H pyrrolizine (DHP). Pyrrole released into perfusate showed an opposite pattern. The percentage of pyrroles released as DHP into the perfusate fell from 38% at 125 microM monocrotaline to 27% at 1.0 mM monocrotaline, but increased sharply to 38% at 1.5 mM monocrotaline. When calculated on a body weight basis, concentrations of monocrotaline of 500 microM result in the release from the liver of 5.3 mumol/kg of dehydromonocrotaline. This is comparable to the amount of dehydromonocrotaline, given in vivo, required for pneumotoxicity. The amounts of other pyrrolic metabolites released over a 1-hr period of perfusion are insufficient to produce pneumotoxicity in vivo. Based on the body weight of the donor rat, pyrrole release on perfusion of the isolated liver with 1,500 microM monocrotaline can be calculated as mumol/kg body weight. These amounts can then be compared to acute doses producing pneumotoxicity in vivo (given in parentheses): DHP, 13 mumol/kg body weight released (350 mumol/kg); GSDHP, 8 mumol/kg (300 mumol/kg); and dehydromonocrotaline, 14 mumol/kg (15 mumol/kg). This suggests, therefore, that dehydromonocrotaline is the pyrrolic metabolite contributing the most to the extrahepatic toxicity of monocrotaline. PMID- 7839358 TI - Muller cell involvement in methanol-induced retinal toxicity. AB - Methanol is an ocular toxicant which causes visual dysfunction often leading to blindness after acute exposure. The physiological and biochemical changes responsible for this toxicity are poorly understood. Previously, we reported that the folate-reduced (FR) rat is an animal model which mimics the characteristic human methanol toxicities. The present study examines the hypothesis that depletion of ATP after methanol administration is the initiating event in methanol-induced retinal toxicity. ATP is reduced in retinae of methanol-treated FR rats to the same extent as is seen in retinae of FR and folate-sufficient (FS) rats treated with the Muller cell (retinal glial cell) toxin alpha-aminoadipic acid. Changes in the electroretinogram and the response of Muller cells to a potassium stimulus are also similarly eliminated in methanol-treated FR rats and alpha-aminoadipic acid-treated FR and FS rats. These results suggest that the Muller cell may be the initial target in methanol-induced visual system toxicity. PMID- 7839359 TI - Progressive losses of renal mass and the renal and hepatic disposition of administered inorganic mercury. AB - The present study was designed to evaluate, in rats, the effect of progressive losses of renal mass, from a state where renal function is not compromised significantly to a state where the early stages of renal failure are detectable, on the disposition of administered inorganic mercury. As part of this evaluation, the intrarenal, hepatic, and hematological disposition of mercury and the urinary and fecal excretion of mercury were studied and characterized in control, uninephrectomized (NPX), and 75% nephrectomized (75% NPX) rats 1, 2, and 7 days after the intravenous injection of a nontoxic 0.5 mumol/kg dose of mercuric chloride. Clearance data showed that concentration of creatinine in the plasma was increased, whole animal glomerular filtration rate (GFR) was decreased, and the fractional excretion of sodium and potassium was increased in 75% NPX rats but not in NPX rats by the 12th day after surgery. These findings confirm that 75% nephrectomy in the rat causes changes that begin to compromise renal function significantly. Renal accumulation of mercury and the intrarenal distribution of mercury were significantly different between 75% NPX rats and NPX rats, presumably because of the differences in GFR and the renal clearance of mercury between the two groups of rats. Interestingly, the contents of mercury in the blood and liver were significantly greater in 75% NPX rats than in NPX or control rats. In addition, 75% NPX rats excreted significantly more mercury in the feces over the 7 days of study than did the other two groups of rats, indicating the hepato-biliary clearance of mercury was significantly greater in 75% NPX rats. Urinary excretion of mercury was also significantly greater in 75% NPX rats than in control rats or NPX rats. This enhanced urinary excretion of mercury may be related to polyuria that occurs in 75% NPX rats. In summary, the findings from the present study clearly indicate that the renal and hepatic handling of administered inorganic mercury in rats changes significantly when renal mass is reduced from about 50% to only about 25% of the original, total renal mass. Further studies are needed to better characterize the effects of 75% nephrectomy on both the disposition and the toxicity of inorganic mercury in renal and hepatic tissues and to determine the mechanisms responsible for the effects seen in this study. PMID- 7839360 TI - Relationship between glutathione concentration and metabolism of the pyrrolizidine alkaloid, monocrotaline, in the isolated, perfused liver. AB - The influence of GSH concentration on metabolism of monocrotaline was examined in the isolated, perfused rat liver. Chloroethanol (0.37 mmol/kg), diethyl maleate (5.6 mmol/kg), and buthionine sulfoximine (72.9 mmol/kg) given in vivo reduced hepatic GSH from 3.7 mumol/g wet weight to 1.5, 0.6 and 0.9 mumol/g, respectively. Livers were then perfused in vitro for 1 hr with monocrotaline (0.5 mM). GSH depletion had no effect on the total release of pyrrolic metabolites of monocrotaline. Depletion, however, markedly affected the pattern of pyrrole release. Biliary release of 7-glutathionyl-6,7-dihydro-1-hydroxy-methyl-5H pyrrolizine (GSDHP) was reduced by up to 72%. Pretreatment with diethyl maleate or buthionine sulfoximine increased the level of protein-bound pyrroles in the liver by 107 and 84%, respectively. Such pyrroles are probably responsible for liver toxicity. GSH depletion also led to a doubling of dehydromonocrotaline release into the perfusate. This metabolite is probably responsible for the extrahepatic toxicity of monocrotaline. Release into perfusate of the relatively nontoxic metabolite, 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP) was correspondingly decreased. Hepatic GSH content was increased to 4.4 mumol/g by pretreatment with oxo-4-thiazolidine carboxylate (4.76 mmol/kg). This agent increased total pyrrolic metabolites by 54%. Biliary release of GSDHP and perfusate release of dehydromonocrotaline and DHP were all increased. Thus, hepatic GSH levels regulate the metabolism of monocrotaline and dehydromonocrotaline and, consequently, the hepatic and extrahepatic toxicity of monocrotaline. GSH depletion leads to a switch from the biliary release of the midly toxic GSDHP to the perfusate release of the highly toxic dehydromonocrotaline. GSH depletion also permits more dehydromonocrotaline in the liver to become available for macromolecular alkylation. These findings suggest that nutritional intake of sulfur-containing amino acids can influence the severity of pyrrolizidine poisoning. PMID- 7839361 TI - Increased [3H]phorbol ester binding in rat cerebellar granule cells by polychlorinated biphenyl mixtures and congeners: structure-activity relationships. AB - Our previous reports indicate that polychlorinated biphenyl (PCB) congeners in vitro perturbed cellular Ca2+ homeostasis and protein kinase C (PKC) translocation. We have now studied the structure-activity relationship (SAR) of 3 PCB mixtures, 24 PCB congeners, and 1 dibenzofuran for their effects on PKC translocation by measuring [3H]phorbol ester ([3H]PDBu) binding in cerebellar granule cells (7 days in culture). All the PCB mixtures studied increased [3H]PDBu binding significantly and in a concentration-dependent manner. However, Aroclor 1016 and Aroclor 1254 were more potent than Aroclor 1260. Of the 24 congeners studied, di-ortho congeners such as 2,2',5,5'-tetrachlorobiphenyl ( TeCB), 2,2',4,6,6'-pentachlorobiphenyl (-PeCB), 2,2',4,6-TeCB, and 2,2' dichlorobiphenyl (-DCB) were the most potent (E50 = 28-43 microM) while non-ortho congeners such as 3,3',4,4'-TeCB and 3,3',4,4'5-PeCB were not effective. The potential contaminant of PCB mixtures, 1,2,3,7,8-pentachlorodibenzofuran had no significant effect on [3H]PDBu binding. The SAR among these congeners revealed: (i) congeners with ortho-chlorine substitution such as 2,2'-DCB (EC50 = 43 +/- 3 microM) or ortho-lateral (meta, para) chlorine substitution such as 2,2',5,5' TeCB (EC50 = 28 +/- 3 microM) and 2,2'4,6-TeCB (E50 = 41 +/- 6 microM) were most potent; (ii) congeners with only para-substitution such as 4,4'-DCB or high lateral content in the absence of ortho-substitution such as 3,3',4,4',5,5'-HCB were not effective; and (iii) increased chlorination was not clearly related to the effectiveness of these congeners, although hexa- and heptachlorination was less effective than di- and tetrachlorination. Low lateral substitution, especially without para-substitution, or lateral content in the presence of ortho substitution, may be the most important structural requirement for the in vitro activity of these PCB congeners in neuronal preparations. PMID- 7839362 TI - Xenobiotic metabolizing enzyme activities and viability are well preserved in EDTA-isolated rat liver parenchymal cells after cryopreservation. AB - Rat liver parenchymal cells (PC) were isolated by EDTA perfusion and were purified by a subsequent Percoll centrifugation. The isolated PC had a viability of 95%, as judged by trypan blue exclusion. Freshly isolated PC were cryopreserved with an optimized protocol in a computer-controlled freezer. After thawing, the PC still retained a viability of 89%. The activities of representative xenobiotic metabolizing enzymes were compared between freshly isolated and cryopreserved PC after thawing. The cytochrome P450 content and the cytochrome P450 2C11 isoenzyme activity, determined by hydroxylation of testosterone in intact cells, were not affected by the cryopreservation. The following phase II enzyme activities were also well maintained after cryopreservation: Phenol sulfotransferase (92%), 1-naphthol UDP-glucuronosyl transferase (95%), soluble epoxide hydrolase (87%), and glutathione S-transferase (88%), determined with broad spectrum substrate 1-chloro-2,4-dinitrobenzene. However, there was a significant decrease in plating efficiency between freshly isolated (86%) and cryopreserved (57%) PC when they were cultured. The initial quality of the freshly isolated PC is decisive for the success of cryopreservation. These results support the use of cryopreserved PC in pharmacology and toxicology with the aim to reduce the number of experimental animals used. PMID- 7839363 TI - Methoxychlor regulates rat uterine estrogen-induced protein. AB - Methoxychlor (MXC), a proestrogenic pesticide, has adverse effects on fertility and uterine function in rodents. MXC is converted to an estrogenic substance, 2,2 bis-(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE), which binds to the estrogen receptor. We examined the similarities in mechanism between MXC (500 mg/kg) and estrogen (10 micrograms/rat) actions using the estrogen-induced protein, IP, also known as creatine kinase. Immature, female rats were treated with MXC or estradiol (E2). Concurrent treatment included actinomycin D (100 micrograms), cycloheximide (100 micrograms), or progesterone (0.5 mg). Uterine proteins were labeled in vitro with 3H for treated rats and with 14C for controls. The uteri were combined, cytosol was isolated, non-denaturing (ND) gels were run, and dpm/gel slice were plotted. In a follow-up study, labeled cytosols from MXC- and E2-treated rats were immunoprecipitated with a monoclonal antibody to creatine kinase. The immunoprecipitate was run on SDS gels. The data show that both MXC and E2 treatments result in ND gels with peaks in (a) induced protein and (b) the 3H/14C ratio, in the same position. The induction of IP by MXC is time- and dose dependent. Concurrent treatment with MXC plus actinomycin D or cycloheximide blocked IP synthesis, a result parallel to E2 action signifying the necessity of RNA and protein synthesis for IP induction. Progesterone did not block either MXC or E2 induction of IP synthesis. Immunoprecipitation of creatine kinase revealed a single peak at a molecular weight of approximately 49,000. SDS gels of cytosol after MXC or E2 treatment also yielded protein and ratio peaks at molecular weights of approximately 49,000. This estimate is near the published estimated molecular weight of creatine kinase of 46,000. We conclude that MXC action parallels that of estradiol on the induction and regulation of the estrogen induced protein in immature rat uterus. PMID- 7839364 TI - Discrepancy between the nephrotoxic potencies of cadmium-metallothionein and cadmium chloride and the renal concentration of cadmium in the proximal convoluted tubules. AB - Acute exposure to inorganic cadmium produces hepatotoxicity, but no renal injury. In contrast, chronic exposure to Cd produces nephrotoxic effects. However, a single injection of cadmium bound to metallothionein (CdMT) can produce nephrotoxicity similar to that seen with chronic exposure to Cd. It is generally thought that CdMT is nephrotoxic because more CdMT than CdCl2 distributes to the kidney. To test this hypothesis, the toxic effects and distribution of Cd were compared after iv injection of CdMT and CdCl2 to mice. CdMT increased urinary excretion of glucose, and protein indicating renal injury. This dysfunction occurred with dosages as low as 0.2 mg Cd/kg. In contrast, renal function was unaltered by CdCl2 administration, even at dosages as high as 3 mg Cd/kg. CdMT distributed almost exclusively to the kidney, whereas CdCl2 preferentially distributed to the liver. However, a high concentration of Cd was also found in the kidneys after CdCl2 administration. In fact, the renal Cd concentration after administration of a high but nonnephrotoxic dose of CdCl2 was equal to or higher than that obtained after injection of nephrotoxic doses of CdMT. Light microscopic autoradiography studies, using 0.3 mg Cd/kg as CdMT and 3 mg Cd/kg as CdCl2, indicated that Cd from CdMT preferentially distributed to the convoluted segments (S1 and S2) of the proximal tubules, whereas Cd from CdCl2 distributed equally to the various segments (convoluted and straight) of the proximal tubules. However, the concentration of Cd at the site of nephrotoxicity, the proximal convoluted tubules, was higher after CdCl2 than after CdMT administration. A higher Cd concentration in both apical and basal parts of the proximal cells was found after CdCl2 than after CdMT administration. Therefore, the reason why CdMT is nephrotoxic and CdCl2 is not nephrotoxic is not due to a higher concentration of Cd in the target cells after CdMT than after CdCl2 administration. PMID- 7839365 TI - Early changes in sex hormones are not evident in mice exposed to the uterine carcinogens chloroethane or bromoethane. AB - Chloroethane and bromoethane have been shown to cause a marked uterine tumor response in B6C3F1 mice exposed for 2 years. These chemicals are nearly unique in this regard among the nearly 400 chemicals studied by the National Toxicology Program, and the reasons for this carcinogenic activity are unclear. The possible relationship of changes in blood concentrations of sex hormones to this response was evaluated by examining the estrous cycle of mice prior to and during a 21-day exposure to concentrations of the haloethanes which resulted in the tumorigenic response in the 2-year studies. Serum concentrations of estradiol and progesterone were determined at the termination of the exposures and compared to exposure group and stage of the estrous cycle. No consistent patterns of change were found in estrous cyclicity or in blood concentrations of sex hormones. Thus, the findings suggest that early changes in circulating sex hormones are not important contributing factors in the uterine neoplasia caused by these chemicals. PMID- 7839366 TI - Effect of cisplatin on renal function in rabbits: mechanism of reduced glucose reabsorption. AB - This study was performed to determine the effect of cisplatin (cis diamminedichloroplatinum II) on renal function in rabbits. Injection of a single i.p. dose of 4 mg/kg cisplatin caused an increase in fractional excretion of Na+ and K+ and a decrease in urine osmolality (Uosm), free-water reabsorption, (TcH2O), and urine to plasma creatinine ratio (U/Pcr). Urine flow was decreased following cisplatin treatment, which was accompanied by marked reduction in GFR. Cisplatin induced glucosuria, phosphaturia, and aminoaciduria. These results suggest that cisplatin results in impaired proximal tubular reabsorptive function and the renal concentrating defect. Cisplatin treatment impaired the accumulation of PAH and TEA and ouabain-sensitive oxygen consumption in renal cortical slices. Na(+)-K(+)-ATPase activity in renal cortical microsomes and basolateral membrane vesicles was significantly depressed in cisplatin-treated animals. Cisplatin treatment did not affect the Na(+)-dependent uptake of glucose and L-glutamate by brush-border membrane vesicles (BBMV), but caused a significant decrease in Na(+) dependent succinate and H(+)-dependent TEA uptake. Morphological observations showed that cisplatin caused a focal loss of the microvillus brush border. These results suggest that (1) cisplatin induces oliguric acute renal failure in rabbits and (2) glucosuria induced by cisplatin was not due to a direct impairment of glucose transporter in brush-border membranes but due to an inhibition of Na(+)-pump activity and a decrease in area for active glucose reabsorption in the proximal tubule. PMID- 7839367 TI - Suppression of ischemia-reperfusion injury in murine models by neopterins. AB - We investigated the effects of D-neopterin (NP) and its reduced form, 5,6,7,8 tetrahydro-D-neopterin (NPH4), in two models of ischemia-reperfusion injury, i.e., ischemic paw edema in mice and gastric ischemia in rats. In ischemic paw edema, iv administration of either NP or NPH4 more potently inhibited the increase of paw thickness after release from ischemia than did administration of superoxide dismutase plus catalase or allopurinol. In gastric ischemia, NP and NPH4 also significantly suppressed the formation of gastric mucosal erosions. Lipid peroxidation in the stomach was increased by ischemia-reperfusion treatment, and the increase was inhibited by the administration of NP or NPH4. The minimum dose of NPH4 required to suppress the gastric ischemic injury in this experiment was 0.3 mg/kg of body weight. These results suggest that neopterin may be effective as a protective agent against ischemia-reperfusion injury, in which active oxygen species are believed to play a major role. PMID- 7839368 TI - Cumulative labeling indices in epithelial cell populations of the respiratory tract after exposure to ozone at low concentrations. AB - Male Sprague-Dawley and F344 rats were exposed to concentrations of 0.12 ppm of ozone for 12 hr a night or for 24 hr a day, to 0.24 ppm for 24 hr a day, and to 0.36 ppm for 8 hr a night. Cumulative labeling indices were measured during the first and the third week of exposure in the terminal bronchioles, the large intrapulmonary airways, the trachea, and the anterior nasal passages. The most sensitive indicator for exposure to ozone after a 1-week exposure was an increased labeling index in the epithelium lining the terminal bronchioles. Sprague-Dawley and F-344 rats were equally sensitive to ozone. In the large intrapulmonary airways and in the maxillar turbinates, an increased cumulative labeling index was observed only at the highest dose (concentration x time). During the third week of exposure, no increases in labeling index were found in the large intrapulmonary airways and terminal bronchioles, whereas in the nasal passages the highest ozone concentration continued to elicit a proliferative response. Animals were also exposed for 1 week to ozone and then allowed to recover in air for another week. Renewed exposure to ozone produced a smaller, but still significant, increase in the labeling index compared to that in animals exposed to ozone for the first time. It was concluded that the determination of the cumulative labeling index in the terminal bronchioles may serve as a method to explore dose and time effects of such concentrations of ozone as may be encountered in heavily polluted urban environments. PMID- 7839369 TI - Antimony-induced oxidative stress and toxicity in cultured cardiac myocytes. AB - Cardiac myocytes were exposed to concentrations of potassium antimonyl tartrate (PAT) ranging from 1 to 1000 microM for 1 to 24 hr. Toxicity was assessed by measuring lactate dehydrogenase (LDH) release and by monitoring chronotropic depression. Lipid peroxidation was assessed by measuring the release of thiobarbituric acid reactive substances (TBARS). PAT produced a concentration- and time-dependent depression in chronotropy and an increase in the release of LDH and TBARS. A 4-hr exposure to 100 microM PAT stopped beating and induced significant increases in TBARS and LDH release in the myocyte cultures. The lipid peroxidation and LDH release induced by 100-200 microM PAT at 4 hr could be prevented by pretreatment of the cardiac myocytes with vitamin E or by the simultaneous addition of other antioxidants. Vitamin E continued to protect against lipid peroxidation up to 18 hr after the addition of 100 microM PAT, but failed to provide significant protection against LDH release at this time-point. Both 50 and 100 microM PAT decreased cardiac myocyte glutathione (GSH) levels after a 4-hr exposure. A series of thiol-containing compounds was evaluated for their effects on PAT toxicity. The addition of dithiothreitol, GSH, and 2 mercaptoethanol afforded some degree of protection against lipid peroxidation and LDH release up to 18 hr after the addition of 100 microM PAT. These results suggest that PAT induces lipid peroxidation in cultured cardiac myocytes but that other mechanisms may contribute to cell death with long-term exposures to PAT. Our results also suggest that PAT interacts with thiol-containing compounds. PMID- 7839370 TI - Renal tumorigenicity of 1,1-dichloroethene in mice: the role of male-specific expression of cytochrome P450 2E1 in the renal bioactivation of 1,1 dichloroethene. AB - 1,1-Dichloroethene is used as intermediate in the manufacture of polymers. In male mice, 1,1-dichloroethene caused renal tumors after inhalation. Renal tumors were not observed in female mice or in both sexes of rats. We investigated the metabolic basis for the species- and sex-specific nephrotoxicity and tumorigenicity of 1,1-dichloroethene. Kidney microsomes from male mice biotransformed 1,1-dichloroethene to chloroacetic acid; the amounts of chloroacetic acid formed were dependent on the hormonal status of the animals and correlated well with the ability of kidney microsomes to oxidize p-nitrophenol and chlorozoxazone, specific substrates for cytochrome P450 2E1. In kidney microsomes from naive females, significantly lower rates of oxidation of 1,1 dichloroethene, p-nitrophenol, and chlorozoxazone were observed; oxidation could be induced by testosterone. With a rabbit anti-rat liver cytochrome P450 2E1 antibody, a cross-reactive protein was detected in male mouse kidney microsomes with a molecular weight very similar to that of rat liver cytochrome P450 2E1; the expression of this protein was regulated by testosterone and correlated well with the ability of the microsomes to oxidize p-nitrophenol, chlorozoxazone, and 1,1-dichloroethene. When the relative cytochrome P450 2E1 contents of renal microsomes of male mice from different strains were compared, differences in the expression of cytochrome P450 2E1 were observed. Moreover, nephrotoxicity in Swiss-Webster mice after inhalation of 1,1-dichloroethene was observed only in males and testosterone-treated females, but not in naive females. In kidney microsomes obtained from both sexes of rats and in six samples of human kidney (male donors), no p-nitrophenol oxidase activity was detected. These data suggest that cytochrome P450 2E1 or a P450 enzyme with very similar molecular weight, substrate specificities, and immunological properties is expressed only in male mouse kidney and bioactivates 1,1-dichloroethene. PMID- 7839371 TI - Behavioral evaluation of the irritant properties of formaldehyde. AB - The effects of formaldehyde were determined using a behavioral technique that permits the estimation of the aversiveness of airborne chemical irritants. Eight mice were initially trained to terminate presentations of ammonia by poking their nose into a conical sensor; five pokes terminated the presentation and produced a facial shower of clean air. Ammonia (1000 ppm) or formaldehyde (1.0-10 ppm) was delivered to the mice for a maximum of 60 sec followed by a 60-sec washout period; this cycle repeated 25 times per session. All animals consistently terminated 100% of ammonia deliveries. Mice also terminated delivery of formaldehyde. At the lowest concentration examined (1.0 ppm), significantly (p < 0.0005) more deliveries of formaldehyde were terminated than were deliveries of air. Mice differed in their sensitivity to formaldehyde: one mouse failed to terminate any more than 10% of deliveries of formaldehyde up to concentrations of 10 ppm; graded concentration-related increases in the number of deliveries terminated were observed in five mice; the two remaining mice consistently terminated 80% or more of the deliveries at each concentration of formaldehyde. As the concentration of formaldehyde increased, the amount of time taken to terminate the exposure decreased. A significant shift to the left of the concentration-effect curves occurred on the second exposure to the series of formaldehyde concentrations. These studies indicate that formaldehyde is aversive to mice at concentrations which approximate those at which humans also report sensory irritation, and that enhanced sensitivity is associated with repeated exposure. PMID- 7839372 TI - Heterogenous effects of natural flavonoids on monooxygenase activities in human and rat liver microsomes. AB - The in vitro effects of nine flavonoids on different monooxygenase activities from human and rat liver were investigated. Flavonoids belonging to different chemical classes [flavones (chrysin, tangeretin, flavone, 5,6-benzoflavone, 7,8 benzoflavone), flavonols (quercetin), and flavanones (pinocembrin, eriodictyol, flavanone)] were chosen. Ethoxyresorufin O-deethylase (EROD) and benzyloxyresorufin O-debenzylase (BROD) were selected as marker activities of P450 isoenzymes involved in carcinogen activation. Human EROD activity was inhibited by all flavonoids. Flavonoids without hydroxyl groups were more effective than those with hydroxyl groups. Flavonoids with an unsaturated flavone nucleus were more inhibitory than the corresponding saturated analogues. Similar structure-activity relationships were found in microsomes from methylcholanthrene treated rats. The effects of flavonoids on human BROD activity were quite different from those observed on EROD activity. Nonhydroxylated flavones were effective activators. Hydroxylated flavonoids showed a biphasic effect, being activators at low concentrations and inhibitors at higher concentrations. The effects of flavonoids on BROD activity were rather similar in man and control rats. PMID- 7839374 TI - Single versus multiple dose administration of all-trans-retinoic acid during organogenesis: differential metabolism and transplacental kinetics in rat and rabbit. AB - Standard teratogenicity testing is usually performed by administration of a test compound daily throughout an extended period of organogenesis (e.g., between Days 6 and 15 in rat and 6 and 18 in rabbit). On the other hand, single dose experiments during a specific period were often demonstrated to be more effective in unveiling a particular teratogenic effect. We have assessed here if toxicokinetics is an important factor for the interpretation of the differences between two administration regimens of all-trans-retinoic acid (all-trans-RA) in two species. The transplacental pharmacokinetics of a low teratogenic dose of all trans-RA administered orally were compared in a single versus multiple dose regimen in both the Wistar rat and the Swiss hare rabbit. In both species, the single dose animals were treated on Gestational Day 12, while the multiple dose animals received daily doses from Gestational Days 7 through 12. Pharmacokinetic profiles were determined for maternal plasma and embryo after dosing on Gestational Day 12 (for both the single and multiple dose regimens) and analyzed by reverse-phase HPLC. The dose used for both species was 6 mg/kg body wt/day which has recently been reported to be a marginal to low teratogenic dose when administered daily throughout organogenesis. In both rat and rabbit, the AUC of all-trans-retinoic acid in maternal plasma was much reduced (factor of 9 in the rat, factor of 2 in the rabbit) after multiple application as compared to the single administration, presumably due to enzyme induction. A similar, but not as pronounced effect was also observed in the embryo of both species. This diminished effect in the embryo indicates a relative increase of placental transfer at the lower maternal plasma concentration observed after multiple dosing, which may possibly be due to an increased availability of binding sites such as cytosolic retinoic acid binding protein and nuclear receptors in the embryo. In the rat, also the metabolite levels were reduced, while in the rabbit, the metabolites of the 13-cis-configuration were concomitantly increased. Our results suggest that multiple administration of a drug such as retinoic acid, which induces its own elimination pathways, results in substantially lowered drug levels in maternal plasma and embryo.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7839373 TI - Toxicity of mitomycin C toward cultured pulmonary artery endothelium. AB - Mitomycin C (MMC) is a bifunctional alkylating agent used in cancer chemotherapy. MMC therapy occasionally results in pulmonary vascular injury, including alterations in endothelial cells. Reactive metabolites of MMC can cross-link DNA, and its cytotoxicity has been attributed in part to this capacity, but effects in vascular cells have not been explored extensively. Accordingly, the direct effects of MMC on cultured porcine pulmonary artery endothelial cells (PECs) were examined. A single administration of MMC (0-10 microM) to PEC monolayers resulted in concentration-dependent cytolytic injury that was delayed in onset and progressive in nature. Cells treated at subconfluent densities were inhibited in their ability to proliferate. MMC treatment resulted in DNA cross-linking at concentrations (0.01-1 microM) that inhibited cell proliferation but caused only limited overt cytotoxicity, supporting an association between DNA cross-linking and impairment of cell division. This pattern of PEC injury is reminiscent of that seen after treatment with another pneumotoxic, bifunctional alkylating agent, monocrotaline pyrrole. The similarity of the endothelial cell response to different bifunctional alkylating agents suggests that DNA cross-linking may inhibit cell proliferation and thereby limit the repair capacity of endothelial monolayers. This might contribute to the progressive pulmonary vascular injury that occurs after administration of certain DNA cross-linking agents in vivo. PMID- 7839375 TI - Cantharidin effects on protein phosphatases and the phosphorylation state of phosphoproteins in mice. AB - Our earlier studies indicated that the action of cantharidin (CA) in mice is associated with binding to protein phosphatase 2A in liver cytosol and inhibition of its phosphorylase a phosphatase activity. In this investigation, we find that CA totally inhibits the phosphorylase a phosphatase activity in mouse liver, muscle, and skin cytosol at 5000 nM, with IC50s of 110-250 nM. About 50% of the phosphorylase a phosphatase activity of brain cytosol is sensitive to CA with an IC50 of approximately 80 nM and the remaining half is not inhibited even at 5000 nM. Intraperitoneal treatment of mice with CA leads to a dose-dependent decrease in phosphorylase a phosphatase activity with the aforementioned tissues displaying differential CA sensitivity. At 60 min after a 10 mg/kg CA dose, there is 90-95% inhibition of phosphorylase a phosphatase activity in liver and skin cytosol, 50% in muscle cytosol, and almost no inhibition in brain cytosol. The phosphorylation state of several phosphoproteins examined with tissue cytosol and [gamma-32P]ATP is increased by CA, in a concentration-dependent manner, as follows: endogenous glycogen phosphorylase a in muscle both in vitro and in vivo, and unidentified phosphoproteins in brain (approximately 34 and approximately 75 kDa) and skin (approximately 34 kDa) in vitro. These findings confirm the importance of protein phosphatases as primary targets of CA action in a variety of mouse tissues and, more generally, the possible use of CA and its analogs to investigate and potentially control some processes modulated by the reversible phosphorylation of proteins. PMID- 7839376 TI - Improved survival of stroke patients during the 1980s. The Minnesota Stroke Survey. AB - BACKGROUND AND PURPOSE: The underlying reasons for the decline in stroke mortality in the United States are not well understood and have been the subject of ongoing debate. This study was undertaken to determine whether survival of hospitalized stroke patients has changed during the 1980s, thereby contributing to the decline in stroke mortality during that period. METHODS: For the years 1980, 1985, and 1990, we obtained listings of discharge diagnoses from hospitals in the Minneapolis-St Paul metropolitan area and identified all hospitalizations with a discharge diagnosis code of acute cerebrovascular disease according to the International Classification of Diseases, 9th Revision. A 50% random sample of men and women aged 30 to 74 years was selected in each survey for detailed medical record abstraction. Standardized sets of criteria for stroke were then used to validate acute stroke events throughout the 1980s. Each of the three period cohorts of hospitalized stroke patients (1980, 1985, and 1990) was followed for at least 2 years for all-cause mortality end point. RESULTS: A total of 1853 patients met minimal criteria for acute stroke: 564 patients in 1980, 598 patients in 1985, and 691 patients in 1990. Controlling for age, the odds of death within 2 years after stroke were approximately 40% lower in 1990 than in 1980. The relative odds of 2-year death in 1990 (versus 1980) were 0.65 (95% confidence interval, 0.47 to 0.89) and 0.60 (95% confidence interval, 0.42 to 0.85) for men and women, respectively. The improved survival was evident in the short term (28 days) as well as for stroke patients who survived that period. Analysis according to stroke subtype revealed that improved survival of ischemic stroke and specifically of stroke with no apparent cardioembolic source largely accounted for the overall trend. The prognosis of stroke patients who were admitted in a comatose state has not changed during that decade. CONCLUSIONS: Despite the absence of any clear major advances in acute stroke therapy, survival of stroke patients substantially improved during the 1980s. The underlying reasons for this unexpected yet remarkable trend remain uncertain but may include improved supportive and rehabilitative care of stroke victims as well as a change in the natural history of the disease. PMID- 7839377 TI - Physiological outcomes of aerobic exercise training in hemiparetic stroke patients. AB - BACKGROUND AND PURPOSE: In hemiparetic individuals, low endurance to exercise may compound the increased energy cost of movement and contribute to poor rehabilitation outcomes. The purpose of this investigation was to describe how hemiparetic stroke patients responded to intense exercise and aerobic training. METHODS: Forty-two subjects were randomly assigned to an exercise training group or to a control group. Treatments were given three times per week for 10 weeks in similar laboratory settings. Baseline and posttest measurements were made of maximal oxygen consumption, heart rate, workload, exercise time, resting and submaximal blood pressures, and sensorimotor function. RESULTS: Only experimental subjects showed significant improvement in maximal oxygen consumption, workload, and exercise time. Improvement in sensorimotor function was significantly related to the improvement in aerobic capacity. After treatment, experimental subjects showed significantly lower systolic blood pressure at submaximal workloads during the graded exercise test. CONCLUSIONS: We conclude that hemiparetic stroke patients may improve their aerobic capacity and submaximal exercise systolic blood pressure response with training. Sensorimotor improvement is related to the improvement in aerobic capacity. PMID- 7839378 TI - Magnetic resonance imaging of regional cerebral blood oxygenation changes under acetazolamide in carotid occlusive disease. AB - BACKGROUND: Gradient-echo magnetic resonance imaging can demonstrate changes in cerebral blood oxygenation with high spatiotemporal resolution. We have previously shown that this technique allows monitoring of autoregulatory responses under vasodilatory stress in the healthy human brain. Here the approach has been extended to assess impairment of the autoregulatory reserve capacity in patients with carotid occlusive disease. SUMMARY OF REPORT: We studied four patients with unilateral occlusion of the internal carotid artery on a 2.0-T clinical high-field magnetic resonance system. Oxygenation-sensitive imaging was based on long-echo-time, gradient-echo sequences (repetition time, 62.5 milliseconds; echo time, 30 milliseconds) with low flip angles (10 degrees) to emphasize changes in blood oxygenation rather than flow velocity. Dynamic recording monitored signal intensities before and after injecting 1 g of acetazolamide. In sections covering the hand area of the primary sensorimotor cortex, acetazolamide-induced magnetic resonance signal increases were attenuated in the vascular territories of occluded arteries. Lateralization of responses in the left and right hemispheric parts of the section corresponded to decreased hemodynamic reserve capacity as measured globally by transcranial Doppler ultrasonography. CONCLUSIONS: The present findings indicate that magnetic resonance imaging can demonstrate exhaustion of the autoregulatory reserve capacity when monitoring cerebral blood oxygenation changes during vasodilatory stress. We suggest that this method can help to evaluate regional cerebral hemodynamics in patients with carotid occlusive disease. PMID- 7839379 TI - Acadesine reduces indium-labeled platelet deposition after photothrombosis of the common carotid artery in rats. AB - BACKGROUND AND PURPOSE: The adenosine-regulating agent acadesine has been shown to reduce the incidence of myocardial infarction and stroke after cardiopulmonary bypass surgery. The present study examined the effect of acadesine on the accumulation of indium-labeled platelet emboli and infarct size after photothrombosis of the common carotid artery. METHODS: Rats were anesthetized with halothane and preloaded with 111In-tropolone-labeled platelets (50 to 80 microCi) 30 minutes before nonocclusive common carotid artery thrombosis induced by a rose bengal-mediated photochemical insult. Intravenous infusion of acadesine (0.5, 1, or 2 mg/kg per minute) or vehicle was begun 30 minutes before right common carotid artery thrombosis and continued for an additional 15 minutes. Rats were then killed and brains processed for the autoradiographic quantitation of labeled platelet aggregates. In a separate group of rats, infarct areas and volumes were determined in treated (acadesine 1 mg/kg per minute) (n = 9) and nontreated (n = 9) rats 7 days after thrombosis. RESULTS: Although the ratio of right-to-left common carotid artery radioactivity was not affected by treatment, acadesine at 1 and 2 mg/kg per minute significantly decreased (P < .01) platelet deposition within the right cerebral cortex, hippocampus, and striatum. For example, within the frontoparietal cortex, numbers of platelet aggregates were 11.8 +/- 1.8 (mean +/- SEM), 6.1 +/- 1.4, 2.3 +/- 0.6, and 3.2 +/- 0.8 in rats infused with vehicle, 0.5, 1, and 2 mg/kg per minute acadesine, respectively. In addition, infarct volume was reduced by 48% in acadesine-treated (1 mg/kg per minute) rats, with a significant reduction in infarct area at the coronal level 3.7 mm anterior to bregma (P < .01). CONCLUSIONS: These results support a prophylactic role for acadesine in reducing the accumulation of platelet emboli during vascular thrombosis and subsequent brain infarction. Acadesine treatment in patients at risk for embolic stroke could potentially lead to cerebral protection. PMID- 7839380 TI - Cerebroprotective effect of lamotrigine after focal ischemia in rats. AB - BACKGROUND AND PURPOSE: Glutamate receptor antagonists are protective in animal models of focal cerebral ischemia. Lamotrigine (3,5-diamino-6-[2,3 dichlorophenyl]-1,2,4-triazine) is an anticonvulsant drug that blocks voltage gated sodium channels and inhibits the ischemia-induced release of glutamate. We describe the cerebroprotective effect of lamotrigine (as the isethionate salt) after middle cerebral artery occlusion in rats. METHODS: Neurological deficit and infarct volume (visualized by the lack of reduction of 2,3,5-triphenyltetrazolium chloride) 24 hours after permanent left middle cerebral artery occlusion were studied in Fischer rats (n = 8 per group per dose). RESULTS: Lamotrigine at 20 mg/kg i.v. over 10 minutes administered immediately after middle cerebral artery occlusion reduced total infarct volume by 31% and cortical infarct volume by 52%. Lamotrigine at 8 mg/kg i.v. over 10 minutes reduced cortical infarct volume by 38%. Lamotrigine at 50 mg/kg i.v. for 10 minutes was not cerebroprotective and induced a decrease of 29 +/- 15 mm Hg in mean arterial blood pressure (P < .05, n = 8). The optimum dose of lamotrigine (20 mg/kg i.v. over 10 minutes) when administered with a 1-hour delay after middle cerebral artery occlusion reduced cortical infarct volume by 41%. Lamotrigine (20 mg/kg i.v. over 10 minutes) with a 2-hour delay after middle cerebral artery occlusion was ineffective. Neurological deficits after 24 hours were improved after immediate treatment with lamotrigine at 20 mg/kg i.v. over 10 minutes. CONCLUSIONS: The cerebroprotective effect of lamotrigine in rats is limited to a narrow dose range between 8 and 20 mg/kg. Lamotrigine or analogous compounds may be useful when given shortly after the onset of stroke. PMID- 7839381 TI - Elevated transcranial Doppler ultrasound velocities following therapeutic arterial dilation. AB - BACKGROUND: Elevated transcranial Doppler (TCD) velocities seen after cerebral angioplasty are commonly interpreted as evidence of residual or recurrent stenosis but may conceivably arise from hyperemia and require different clinical management. SUMMARY OF REPORT: Four cases of abnormally elevated mean TCD velocities obtained after therapeutic arterial dilation with either balloon angioplasty or intra-arterial administration of papaverine are described. In each case, cerebral angiography revealed a dilated vessel, suggesting that hyperemia and impaired autoregulation were the causes of the high velocities. CONCLUSIONS: These examples suggest that high TCD velocities after vessel dilation may be produced by unpredictable amounts of vessel narrowing and flow alteration. Although a normalizing TCD velocity after angioplasty suggests effective vessel dilation, high velocities may be due partly to hyperemia and cannot be interpreted as arising solely from recurrent stenosis. PMID- 7839382 TI - Postpartum cerebral angiopathy possibly due to bromocriptine therapy. AB - BACKGROUND: Eight cases of benign angiopathy of the postpartum period have been reported previously, none of which involved the administration of bromocriptine. CASE DESCRIPTION: We describe a case of benign cerebral angiopathy in a 20-year old woman in the postpartum period occurring after bromocriptine therapy prescribed to suppress lactation. CONCLUSIONS: Other adverse effects due to vasoconstriction have been reported during bromocriptine therapy, such as myocardial infarction and arterial hypertension. This case suggests that a similar mechanism may be possible in cerebral arteries, although the cause of vasoconstriction remains uncertain. PMID- 7839383 TI - Progressive cerebral occlusive disease after radiation therapy. AB - BACKGROUND: A case of progressive irradiation-induced cerebral vasculopathy with abnormal netlike vessels and transdural anastomoses (moyamoya syndrome) is presented. Radiological findings in an additional 40 cases reported in the literature are analyzed, and their clinical relevance is discussed. CASE DESCRIPTION: A 19-year-old woman presented with recurrent ischemic brain lesions after radiation therapy for treatment of a craniopharyngioma during childhood. Cerebral angiography 6 and 12 years after completion of radiation therapy revealed progressive cerebral arterial occlusive disease involving the internal carotid artery on either side of the circle of Willis, with abnormal netlike vessels and transdural anastomoses (moyamoya syndrome). CONCLUSIONS: Extensive similarities between irradiation-induced cerebral vasculopathy and primary moyamoya syndrome (Nishimoto's disease) support the notion that both disorders share common pathophysiological mechanisms. The occurrence of moyamoya-like vascular changes may not depend on specific trigger mechanisms but may rather represent a nonspecific response of the developing vascular system to a number of various noxious events. PMID- 7839384 TI - Guidelines for the management of patients with acute ischemic stroke. PMID- 7839385 TI - Anticoagulation for nonrheumatic atrial fibrillation: the dilemma. PMID- 7839386 TI - Neurotransmitter release in reduced mortality and brain damage after locomotor activity. PMID- 7839387 TI - Serotonin, nerves, and cerebral blood vessels. PMID- 7839388 TI - Race-ethnicity and determinants of intracranial atherosclerotic cerebral infarction. The Northern Manhattan Stroke Study. AB - BACKGROUND AND PURPOSE: The aim of this investigation was to determine the importance of race as a determinant of intracranial atherosclerotic stroke in a community-based stroke sample. METHODS: Residents from northern Manhattan over age 39 years hospitalized for acute ischemic stroke (n = 438, black 35%, Hispanic 46%, white 19%) were prospectively evaluated. Index ischemic strokes were classified as atherosclerotic (17%), lacunar (30%), cardioembolic (21%), cryptogenic (31%), and other (1%). Atherosclerotic infarcts were subdivided into extracranial (9%) and intracranial (8%) atherosclerosis. RESULTS: The proportion of extracranial atherosclerotic stroke was similar among the three race-ethnic groups, while intracranial atherosclerosis was more frequent in blacks and Hispanics. The unadjusted odds ratio for nonwhites (blacks and Hispanics combined) was 0.8 (confidence interval [CI], 0.4 to 1.8) for extracranial and 7.8 (CI, 1.04 to 57.7) for intracranial atherosclerosis. Patients with intracranial disease were significantly younger and had an increased frequency of hypercholesterolemia and insulin-dependent diabetes compared with those with nonatherosclerotic disease. The odds ratio for the association of nonwhite race ethnicity and intracranial atherosclerosis was reduced to 5.2 (CI, 0.7 to 40) after controlling for age and to 4.4 (CI, 0.6 to 35) after controlling for age, education, insulin-dependent diabetes, and hypercholesterolemia. CONCLUSIONS: The greater prevalence of diabetes and hypercholesterolemia among blacks and Hispanics from northern Manhattan accounted for much of the increased frequency of intracranial atherosclerotic stroke. Further control of these risk factors could reduce the frequency of this stroke subtype and minimize the disparities among different race-ethnic groups. PMID- 7839389 TI - 20th International Joint Conference on Stroke and Cerebral Circulation. Charleston, South Carolina, February 9-11, 1995. Abstracts. PMID- 7839390 TI - Guidelines for carotid endarterectomy. A multidisciplinary consensus statement from the ad hoc Committee, American Heart Association. AB - BACKGROUND AND PURPOSE: Indications for carotid endarterectomy have engendered considerable debate among experts and have resulted in publication of retrospective reviews, natural history studies, audits of community practice, position papers, expert opinion statements, and finally prospective randomized trials. The American Heart Association assembled a group of experts in a multidisciplinary consensus conference to develop this statement. METHODS: A conference was held July 16-18, 1993, in Park City, Utah, that included recognized experts in neurology, neurosurgery, vascular surgery, and healthcare planning. A program of critical topics was developed, and each expert presented a talk and provided the chairman with a summary statement. From these summary statements a document was developed and edited onsite to achieve consensus before final revision. RESULTS: The first section of this document reviews the natural history, methods of patient evaluation, options for medical management, results of surgical management, data from position statements, and results to date of prospective randomized trials for symptomatic and asymptomatic patients with carotid artery disease. The second section divides 96 potential indications for carotid endarterectomy, based on surgical risk, into four categories: (1) Proven: This is the strongest indication for carotid endarterectomy; data are supported by results of prospective contemporary randomized trials. (2) Acceptable but not proven: a good indication for operation; supported by promising but not scientifically certain data. (3) Uncertain: Data are insufficient to define the risk/benefit ratio. (4) Proven inappropriate: Current data are adequate to show that the risk of surgery outweighs any benefit. CONCLUSIONS: Indications for carotid endarterectomy in symptomatic good-risk patients with a surgeon whose surgical morbidity and mortality rate is less than 6% are as follows. (1) Proven: one or more TIAs in the past 6 months and carotid stenosis > or = 70% or mild stroke within 6 months and a carotid stenosis > or = 70%; (2) acceptable but not proven: TIAs within the past 6 months and a stenosis 50% to 69%, progressive stroke and a stenosis > or = 70%, mild or moderate stroke in the past 6 months and a stenosis 50% to 69%, or carotid endarterectomy ipsilateral to TIAs and a stenosis > or = 70% combined with required coronary artery bypass grafting; (3) uncertain: TIAs with a stenosis < 50%, mild stroke and stenosis < 50%, TIAs with a stenosis < 70% combined with coronary artery bypass grafting, or symptomatic, acute carotid thrombosis; (4) proven inappropriate: moderate stroke with stenosis < 50%, not on aspirin; single TIA, < 50% stenosis, not on aspirin; high-risk patient with multiple TIAs, not on aspirin, stenosis < 50%; high-risk patient, mild or moderate stroke, stenosis < 50%, not on aspirin; global ischemic symptoms with stenosis < 50%; acute dissection, asymptomatic on heparin. Indications for carotid endarterectomy in asymptomatic good-risk patients performed by a surgeon whose surgical morbidity and mortality rate is less than 3% are as follows. (1) Proven: none. (As this statement went to press, the National Institute of Neurological Disorders and Stroke issued a clinical advisory stating that the Institute has halted the Asymptomatic Carotid Atherosclerosis Study (ACAS) because of a clear benefit in favor of surgery for patients with carotid stenosis > or = 60% as measured by diameter reduction. When the ACAS report is published, this indication will be recategorized as proven. (2) acceptable but not proven: stenosis > 75% by linear diameter; (3) uncertain; stenosis > 75% in a high-risk patient/surgeon (surgical morbidity and mortality rate > 3%), combined carotid/coronary operations, or ulcerative lesions without hemodynamically significant stenosis; (4) proven inappropriate: operations with a combined stroke morbidity and mortality > 5%. PMID- 7839391 TI - Relation between blood pressure and outcome in intracerebral hemorrhage. AB - BACKGROUND AND PURPOSE: Controversy continues to exist regarding optimal blood pressure control in acute hypertensive intracerebral hemorrhage. Persistent marked elevation of the blood pressure can promote further bleeding, increase cerebral blood flow, and raise intracranial pressure. Relative hypotension, on the other hand, may promote hypoperfusion with secondary ischemia. This study was designed to assess outcome in patient groups defined by the degree of elevation in their pretreatment and posttreatment blood pressures. METHODS: We retrospectively assessed 87 patients who were categorized according to an initial mean arterial pressure > 145 mm Hg (n = 34) compared with those with a pressure < or = 145 mm Hg (n = 53). We also studied blood pressure control within the first 2 to 6 hours of presentation with subjects categorized according to a mean arterial pressure > 125 mm Hg (n = 40) or < or = 125 mm Hg (n = 47). RESULTS: An improved outcome in both mortality and severe morbidity was observed in the < or = 145 (chi 2 = 7.0, P < .005) and the < or = 125 mm Hg (chi 2 = 6.7, P < .005) groups. CONCLUSIONS: Markedly elevated blood pressure on admission and persistent inadequate blood pressure control adversely affect the prognosis in hypertensive intracerebral hemorrhage. PMID- 7839392 TI - Isolated systolic hypertension and risk of stroke in Japanese-American men. AB - BACKGROUND AND PURPOSE: This article examines prevalence of isolated systolic hypertension (ISH) in a population of Japanese-American men living in Hawaii and compares rates of stroke among those with ISH, isolated diastolic hypertension (IDH), combined systolic/diastolic hypertension (SDH), and nonhypertension. METHODS: Eight thousand six men aged 45 to 68 years participated in a baseline examination as part of a prospective study of coronary heart disease and stroke and were followed up for 20 years for incident disease and total mortality. Men were divided into four groups according to baseline blood pressure: ISH (systolic blood pressure [SBP] > or = 160 mm Hg and diastolic blood pressure [DBP] < 90 mm Hg); IDH (SBP < 160 mm Hg and DBP > or = 90 mm Hg); SDH (SBP > or = 160 mm Hg and DBP > or = 90 mm Hg); and nonhypertension (SBP < 160 mm Hg and DBP < 90 mm Hg). RESULTS: Men with ISH had the highest rates of stroke, followed by men with SDH. Men with IDH had rates only slightly higher than men in the nonhypertension group. Relative risk adjusted for other risk factors varied by age group. For men aged 45 to 54 years, relative risks of stroke associated with ISH, IDH, and SDH compared with nonhypertensive subjects were 4.8, 1.4, and 4.3, respectively. For men aged 55 to 68 years, the same relative risks were 1.2, 1.8, and 1.7. Excluding men on antihypertensive medication at baseline did not alter results. CONCLUSIONS: ISH had a much greater impact on risk of stroke in younger than in older men. The results suggest that while ISH is more common in older men, in younger men it is associated with higher relative risk of stroke. PMID- 7839393 TI - Hypertension and diabetes mellitus as determinants of multiple lacunar infarcts. AB - BACKGROUND AND PURPOSE: We investigated the relationship between hypertension, diabetes mellitus, and lacunes. METHODS: From 1237 cases of ischemic stroke in the Stroke Data Bank of the National Institute of Neurological and Communicative Disorders and Stroke, data from 637 patients whose initial computed tomogram showed lacunar (n = 184) or nonlacunar infarcts (n = 453) were analyzed. The group with lacunar infarcts was further divided into subgroups according to whether the patients had multiple (n = 40) or single (n = 144) lacunar infarcts. The association of hypertension and diabetes mellitus with lacunar infarcts was investigated using logistic regression models that included age, sex, and cardiac disease. Similar models were used to analyze the effects of diastolic and systolic blood pressure. RESULTS: Hypertension (odds ratio [OR], 2.5; 95% confidence interval [CI], 1.1 to 6.0) and diabetes (OR, 2.3; 95% CI, 1.1 to 4.5) were significantly related to multiple but not to single lacunes. Cardiac disease was inversely associated with both single and multiple lacunes. Diastolic blood pressure significantly affected the probability of multiple lacunar infarcts (OR, 1.4; 95% CI, 1.04 to 1.9), whereas systolic pressure did not. CONCLUSIONS: There may be etiologically distinct lacunar infarct subgroups, with multiple lacunes being strongly related to hypertension and diabetes mellitus. Other stroke risk factors may be more important in patients with single lacunes. Diastolic rather than systolic pressure seems to be a major determinant of multiple lacunes. PMID- 7839394 TI - Carotid intima-media thickness and plaque in borderline hypertension. AB - BACKGROUND AND PURPOSE: In this study, we investigated intima-media thickness and plaque occurrence in the carotid arteries of men with borderline hypertension compared with that in normotensive control subjects and investigated the relations of these variables to atherosclerotic risk factors. METHODS: Using B mode ultrasonography, we compared carotid artery intima-media thickness and plaque occurrence in men with borderline hypertension (diastolic blood pressure of 85 to 94 mm Hg, n = 73) with that in age-matched normotensive control subjects (diastolic blood pressure of 80 mm Hg, n = 72). We evaluated the relationships of intima-media thickness and plaque occurrence to atherosclerotic risk factors such as age, smoking, lipoprotein levels, and fasting insulin levels. RESULTS: The borderline hypertensive group exhibited a slight increase in overall intima-media thickness (0.73 versus 0.69 mm, P = .07), which was most evident in the right carotid artery (0.72 versus 0.67 mm, P < .05). There were more borderline hypertensive subjects with plaque (26% versus 16%, NS), again more evident on the right side (18% versus 6%, P < .05). Age and high-density lipoprotein cholesterol were consistently related to intima-media thickness (t = 1.94 to 3.24 and t = 2.25 to -2.69, respectively, P < .05), whereas age was the only significant determinant for plaque/nonplaque (F = 6.4, P < .05). In addition, there was a significant difference in intima-media thickness between the right and left carotids, irrespective of group (F = 4.43, P < .05). CONCLUSIONS: Our results indicate that vascular structural changes occur even in borderline hypertension, although this seems more related to general atherosclerotic risk factors than to blood pressure alone. Additionally, a possible difference in the development of atherosclerotic lesions of the left and right carotid arteries is suggested, emphasizing the importance of measuring and reporting values from both sides when studying carotid intima-media thickness and plaque occurrence. PMID- 7839395 TI - Recent alcohol consumption, cigarette smoking, and cerebral infarction in young adults. AB - BACKGROUND AND PURPOSE: The role of recent heavy drinking of alcohol as a risk factor for ischemic brain infarction is unclear. We investigated this problem in young adults, in whom even a thorough workup often fails to reveal any predisposing factor. METHODS: This was a hospital-based case-control study comprising 75 consecutive subjects aged 16 to 40 years with first-ever ischemic brain infarction and 133 control subjects from the same hospital who were group matched with the case patients for age, sex, day of the onset of symptoms, and acuteness of disease onset. RESULTS: Multiple logistic regression analysis showed that alcohol intake exceeding 40 g of ethanol within the 24 hours preceding disease onset was a significant independent risk factor for brain infarction among both men (odds ratio [OR], 6.0; 95% confidence interval [CI], 1.8 to 20.3) and women (OR, 7.8; 95% CI, 1.0 to 60.8). Cigarette smoking was not found to be an independent risk factor in the model, whereas among men arterial hypertension was (OR, 6.2; 95% CI, 1.5 to 24.7). CONCLUSIONS: We conclude that very recent alcohol drinking, particularly drinking for intoxication, may trigger the onset of brain infarction in young adults and that there might be a variety of mechanisms behind this effect. PMID- 7839396 TI - Interrater reliability of an etiologic classification of ischemic stroke. AB - BACKGROUND AND PURPOSE: Precise identification of the cause of stroke is critical to research and clinical practice. Published series of ischemic stroke show considerable variation in the proportion of cases classified as atherosclerotic large-vessel disease, lacunar infarct, cardioembolic stroke, stroke of other known cause, and stroke of undetermined etiology. We describe the development and use of an etiology-specific classification of ischemic stroke. The interrater reliability of the classification is then evaluated. METHODS: A total of 160 cases of ischemic strokes in young adults were reviewed by paired neurologists who assigned cases to prioritized categories. The results of paired ratings were evaluated for each of the potential causes. Interrater agreement was assessed by means of kappa, which is the chance-adjusted percent agreement. RESULTS: For standard pairs, kappa was fair to good for all causes except lacunar stroke (kappa = 0.31); however, pair-to-pair variation was greatest for lacunar strokes. Strokes of undetermined cause and hematologic/other cause were of borderline fair reliability. CONCLUSIONS: The utility of a stroke classification system is dependent on its intended use. An etiologic classification is useful in studies of the epidemiology and pathophysiological basis of stroke. Fair to good reliability for an etiologic classification of stroke can be obtained when criteria are explicit. PMID- 7839397 TI - Platelet activation in the cerebral circulation in different subtypes of ischemic stroke and Binswanger's disease. AB - BACKGROUND AND PURPOSE: The sites of platelet activation in ischemic stroke are still unclear because previous reports have not identified them and various factors accompanied by stroke can activate platelets. We therefore examined the sites of platelet activation in patients with various types of ischemic stroke. METHODS: The ratio of the plasma concentration of beta-thromboglobulin (BTG) in the internal jugular vein to that in the antecubital vein (BTG-B) was calculated as an indicator of platelet activation in the cerebral circulation. Plasma BTG concentration was determined in 75 control subjects and in 186 patients with various subtypes of ischemic stroke including lacunar, atherothrombotic, and cardioembolic strokes, transient ischemic attacks, and Binswanger's disease. The BTG ratio was evaluated with regard to subtype of stroke, time of blood sampling, size of infarct, presence of vascular lesions, and the effect of ticlopidine administration. RESULTS: The mean BTG ratio was increased even in the chronic phase of most subtypes of stroke with the exception of cardioembolic stroke, which exhibited a persistent elevation of BTG-B concentrations. Patients with Binswanger's disease showed a significant (P < .01) and frequent elevation of BTG ratio. High BTG ratios occurred in cases with vascular lesions observed on cerebral angiography. There was no correlation between the BTG ratio and infarct size. Use of ticlopidine was partially associated with a lower BTG ratio. CONCLUSIONS: Platelets were activated in the cerebral circulation of patients with stroke even in the chronic phase, which suggests the development of underlying vascular lesions and of thrombogenesis with or without infarction. Platelets were activated mainly within the heart in cases of cardioembolic stroke. An enhanced release reaction secondary to platelet activation was often seen in patients with Binswanger's disease, which indicates that its pathophysiology differs from that of other subtypes of stroke. PMID- 7839398 TI - Lateralization of T-lymphocyte responses in patients with stroke. Effect of sympathetic dysfunction? AB - BACKGROUND AND PURPOSE: A number of clinical observations indicate that stroke affects the course of immune-mediated diseases by lateralization of the disease manifestations, such as arthritis. The purpose of this study was to assess the impact of early stroke on lateralization of immune responsiveness. METHODS: The delayed-type hypersensitivity (DTH) reaction to purified protein derivative was used as an in vivo measure of antigen-specific T-lymphocyte reactivity. Assessment of axon reflex vasodilation was simultaneously used to test for cutaneous sympathetic activity. RESULTS: There were no significant differences with regard to lateralization of DTH reactivity when all stroke patients were tested. However, patients with minor stroke displayed a significant (P < .001) decrease of DTH reaction on the paretic side compared with the contralateral side. In contrast, patients with major stroke showed a significant increase (P = .022) of DTH reaction on the paretic side. Patients with left hemiparesis had a significantly greater (P = .045) DTH response on the affected side than patients with a right hemiparesis. In addition, only the patients with motor deficit but not with sensory deficit or aphasia displayed side differences in DTH responses. When electrically evoked axon reflexes were studied in relation to DTH reactions, a significant correlation (r = .64; P < .001) was found between side asymmetries of DTH responses and side asymmetries of axon reflexes in an innervated skin area. No similar relation was present in skin areas where cutaneous sympathetic activity had been blocked by regional anesthesia. CONCLUSIONS: Early stroke lateralizes T-cell-mediated cutaneous inflammation. This effect depends on (1) the localization of the brain lesion, (2) the clinical course of the disease, and (3) the presence of motor deficit and may be mediated by (4) alteration of the cutaneous sympathetic nerve traffic. PMID- 7839399 TI - Monitoring combined antithrombotic treatments in patients with prosthetic heart valves using transcranial Doppler and coagulation markers. AB - BACKGROUND AND PURPOSE: The combined use of coumarin and low-dose aspirin appears to reduce the risk of systemic embolism at a low risk of bleeding. The remaining incidence of embolism of approximately 2%/y is still high. Methods for real-time detection of embolic events have not been used thus far to monitor the efficacy of therapeutic strategies. They might permit individually tailored, effective treatments. METHODS: The frequency of embolic signals in both middle cerebral arteries was monitored using a two-channel 2-MHz transcranial Doppler system. We examined five patients with mechanical prosthetic heart valves suffering from recurrent cerebral ischemic symptoms despite adequate anticoagulant therapy (international normalized ratio, 3.0 to 4.3). Measurements were performed on coumarin alone (four baseline values) and subsequent to the addition of intravenous (500 mg bolus) and oral (100 mg/d for 10 days) aspirin or intravenous (5000 IU bolus) heparin. The prothrombotic markers thrombin-antithrombin III complex, fibrinopeptide A, D-dimer, and platelet beta-thromboglobulin were measured simultaneously. RESULTS: None of the combined drug regimens led to a significant reduction of the emboli count. The values of thrombin-antithrombin III complex, fibrinopeptide A, and D-dimer were already within normal limits with coumarin alone. The beta-thromboglobulin levels, however, were increased, and additional aspirin or heparin did not reduce them. There was no correlation between the emboli count and the prothrombotic markers or between the prothrombotic markers and the different drug regimens. CONCLUSIONS: The rate of cerebral emboli measured with transcranial Doppler in the group of high-risk patients studied was not influenced by additional antiplatelet therapy. The emboli are likely to be composed at least in part of platelets, and their generation seems not dependent on thrombin or cyclooxygenase. There is an apparent discrepancy between the unchanged rate of emboli during Doppler monitoring found in this and other studies and the partial efficacy of combined treatment with coumarin and aspirin in clinical long-term studies. This may be explained by differences in the composition or size of the emboli. PMID- 7839400 TI - Risk of stroke with mitral valve prolapse in population-based cohort study. AB - BACKGROUND AND PURPOSE: The purpose of this study was to clarify whether mitral valve prolapse increases the subsequent risk of stroke. METHODS: A historical cohort study was conducted on 1079 residents of Olmsted County, Minnesota, who had an initial echocardiographic diagnosis of mitral valve prolapse between 1975 and 1989 without prior stroke or transient ischemic attack and who were followed up for first stroke occurrence. RESULTS: There was an overall twofold increase in the incidence of stroke among individuals with mitral valve prolapse relative to the reference population (standardized morbidity ratio, 2.1; 95% confidence interval, 1.3 to 3.2). Sex, duration of follow-up from the diagnosis of mitral valve prolapse, or calendar year of initial diagnosis did not modify the association. Within the cohort of patients who were at least 35 years old at diagnosis of mitral valve prolapse, a time-dependent proportional-hazards multivariate model and a person-years analysis revealed that age, ischemic heart disease, congestive heart failure, and diabetes mellitus were important determinants for stroke when person-years of observation after mitral valve replacement were excluded. Among seven persons with mitral valve replacement, three strokes occurred in 24 person-years of follow-up. For those with an auscultatory diagnosis of mitral valve prolapse only as the indication for echocardiography (44%), the risk of stroke relative to the population was 1.0 (95% confidence interval, 0.2 to 2.9); for those with another cardiac diagnosis, the standardized morbidity ratio was 2.5 (95% confidence interval, 1.5 to 4.0). CONCLUSIONS: Individuals with uncomplicated mitral valve prolapse did not have an increased risk of stroke, although a small increase in the risk may not have been detected. PMID- 7839401 TI - Determination of cognitive hemispheric dominance by "stereo" transcranial Doppler sonography. AB - BACKGROUND AND PURPOSE: Transcranial Doppler sonography (TCD) can assess blood flow velocity changes induced by focal brain activation. Therefore, TCD may have the potential to identify hemispheric dominance for cognitive tasks. METHODS: Using a system with two TCD probes ("stereo" TCD), we monitored simultaneously both middle cerebral arteries (MCAs) of 14 healthy right-handed volunteers while they performed cognitive tasks. The averaged blood flow velocity ratio of the two MCAs and the hemispheric blood flow velocity shift induced by the cognitive task were calculated. RESULTS: In every subject, language tasks resulted in blood flow velocity shift to the left compared with visuospatial tasks. Mean MCA blood flow velocity shift to the left was 1.67%, 2.01%, and 2.31% in three language tasks. Mean blood flow velocity shift to the right was 1.67% and 2.31% in two visuospatial tasks. CONCLUSIONS: Bilateral simultaneous MCA blood flow velocity monitoring and averaging during cognitive tasks can help to identify hemispheric dominance for cognitive tasks in individuals. PMID- 7839402 TI - Cerebral autoregulation dynamics in premature newborns. AB - BACKGROUND AND PURPOSE: Autoregulation of cerebral blood flow is easily disrupted, and loss of this normal physiological reflex may worsen the neurological outcome for patients undergoing intensive care. We studied the response of cerebral blood flow velocity to changes in mean arterial blood pressure. METHODS: Cerebral blood flow velocity was measured with Doppler ultrasonography in one middle cerebral artery for 5-minute periods in 33 babies of gestational age < 33 weeks admitted to a neonatal intensive care unit. Two methods of evaluating autoregulation were developed. The first used linear regression analysis of blood flow velocity on blood pressure. Records were classified as showing loss of autoregulation if the regression slope was greater than a critical value. A minimum change in mean arterial blood pressure of 5 mm Hg and a critical slope of 1.5%/mm Hg were found to be adequate criteria for the classification of records by the regression method. The second method used coherent averaging, a technique similar to that used in recording evoked potentials. Spontaneous transient increases in blood pressure were automatically detected, and the instant corresponding to its maximum rate of rise was used to synchronize averages of the blood pressure and blood velocity transients. The resulting coherent averages were classified into two groups based on the morphology of the cerebral blood flow velocity average. RESULTS: Whereas the regression method allowed the classification of only 51 of 106 records, the coherent average method classified 101 of 106 (95.3%) of the records available. For 51 records that were classified by both methods, there was agreement in 42 cases (82.3%). The coherent average of all records classified as having an active autoregulation showed cerebral blood flow velocity returning to baseline much earlier than blood pressure, suggesting that autoregulation was taking place within 1 to 2 seconds. This pattern was absent in records in which autoregulation was classified as absent. CONCLUSIONS: Computerized coherent averaging of the cerebral blood flow velocity response to spontaneous blood pressure transients offers a promising new method for noninvasive bedside assessment of autoregulation in patients undergoing intensive care. The time course for autoregulation, when present, is in agreement with that reported in adults. PMID- 7839403 TI - Estimation of cerebrovascular reactivity in migraine without aura. AB - BACKGROUND AND PURPOSE: The nature and role of vascular abnormalities in migraine are controversial. In this study we evaluated cerebrovascular reactivity to hypercapnia in patients suffering from migraine without aura with unilateral headache. METHODS: Using bilateral transcranial Doppler ultrasound, we studied the changes of flow velocity after hypercapnia in the anterior, middle, and posterior cerebral arteries of 16 migraine patients and 16 healthy control subjects. All patients were studied during an attack-free interval and during a migraine attack. Cerebrovascular reactivity was evaluated with the breath-holding index, obtained by dividing the percent increase in mean flow velocity occurring during breath-holding by the time (seconds) in which the subjects held their breath after a normal inspiration. RESULTS: The response to breath-holding was similar for all arteries considered in both control subjects and patients during the attack-free interval. During the migraine attack, the breath-holding index in patients was significantly lower than the migraine-free interval in all arteries (P < .001). No side-to-side difference in cerebrovascular reactivity was detected in migraine patients either outside or during attacks. CONCLUSIONS: These results suggest that a failure of cerebrovascular regulation occurs during attacks of migraine without aura. PMID- 7839404 TI - Hemodynamic effects of carotid endarterectomy by magnetic resonance flow quantification. AB - BACKGROUND AND PURPOSE: Blood flow can be evaluated non-invasively using magnetic resonance phase-contrast flow quantification. The purpose of this prospective study was to assess the feasibility of this method and to evaluate the hemodynamic effects of carotid endarterectomy. METHODS: Volumetric flow rates and peak systolic velocities of the internal and common carotid and the vertebral arteries were measured by magnetic resonance flow quantification. Sixteen patients undergoing 18 endarterectomies had complete flow data recorded preoperatively and 3 days after surgery. RESULTS: The inverse correlation between the angiographic stenosis degree and the preoperative flow rate in the corresponding internal carotid artery was highly significant (r = -.69, P < .001). After endarterectomy, the mean flow in the ipsilateral internal carotid artery improved from 143 to 233 mL/min (P < .001). The mean peak systolic velocity increased from 23 to 37 cm/s (P < .001). No significant changes were seen in the contralateral carotid or the vertebral arteries. The mean total blood flow improved by 81 mL/min (P = .08). In the severely stenosed bifurcations (70% to 99%, n = 11), the flow rate improved by 106 mL/min and in the moderately (30% to 69%, n = 4) or mildly (< 30%, n = 3) stenosed bifurcations by 63 mL/min. If the contralateral carotid artery was occluded or severely stenosed, the improvement was 164 mL/min. CONCLUSIONS: Magnetic resonance flow quantification provides a useful tool for the follow-up of the hemodynamic effects of carotid endarterectomy. Our results indicate that surgery is followed by a significant increase of blood flow in the ipsilateral carotid artery and that there appear to be differences in flow increase between subgroups of patients with different degrees of stenosis. PMID- 7839405 TI - Crossed cerebellar diaschisis and brain recovery after stroke. AB - BACKGROUND AND PURPOSE: Although crossed cerebellar diaschisis is well recognized after stroke, there is controversy concerning its clinical correlations and serial changes, and little is known about its prognostic value. METHODS: We studied crossed cerebellar diaschisis and cerebral hypoperfusion in 47 patients with acute middle cerebral cortical infarction using 99mTc hexamethylpropyleneamine oxime and single-photon emission computed tomography within 72 hours of stroke onset. Thirty-one of these patients had outcome studies at 3 months; 15 of the 31 underwent an additional scan after acetazolamide injection. Tissue loss was determined with computed tomography, performed at outcome in 28 patients. Clinical stroke severity was assessed with the Canadian Neurological Scale and Barthel Index. Cerebellar blood flow asymmetry was studied in 22 healthy, age-matched control subjects. RESULTS: Cerebellar blood flow asymmetry was significant in patients (mean +/- SE, 9.76 +/- 0.78%; P < .001) but not in control subjects (-0.22 +/- 0.56%). Crossed cerebellar diaschisis was strongly associated with infarct hypoperfusion volume at both acute (regression coefficient +/- SEb, b = 6.76 +/- 0.65; P < .001) and outcome stages (b = 6.13 +/ 0.63; P < .001). Cross-sectionally over the first 72 hours, infarct hypoperfusion volume decreased by 2% for each hour from onset (P < .05), while crossed cerebellar diaschisis remained unchanged. Canadian Neurological Scale score at the acute stage was negatively associated with acute crossed cerebellar diaschisis (b = -0.10 +/- 0.05; P < .05) after allowing for infarct hypoperfusion volume. Crossed cerebellar diaschisis did not change between acute-stage, outcome, and postacetazolamide scans. Acute-stage crossed cerebellar diaschisis predicted outcome Barthel Index score (b = -0.28 +/- 0.14; P = .05) and tissue loss (b = 3.81 +/- 0.96; P < .001) but was no longer an independent prognostic factor after allowing for acute-stage infarct hypoperfusion volume. CONCLUSIONS: This study shows that crossed cerebellar diaschisis is a functional phenomenon that correlates with both stroke severity and infarct hypoperfusion volume and persists despite neurological recovery. Although acute-stage crossed cerebellar diaschisis has no prognostic value independent of acute-stage hypoperfusion volume, it might indicate the proportion of nutritional to nonnutritional perfusion at the infarct site and hence be useful in the evaluation of reperfusion therapies in the acute stage. PMID- 7839406 TI - Assessment of cerebral vasomotor reactivity by transcranial Doppler ultrasound and breath-holding. A comparison with acetazolamide as vasodilatory stimulus. AB - BACKGROUND AND PURPOSE: Evaluating cerebrovascular vasomotor reactivity seems to be of prognostic relevance for patients with occlusive internal carotid artery disease. To evaluate its clinical usefulness, the recently introduced breath holding maneuver as a carbon dioxide-dependent vasodilatory stimulus was compared with the acetazolamide challenge by means of transcranial Doppler ultrasound and stable xenon-enhanced computed tomography. METHODS: In a total of 134 middle cerebral arteries of 74 patients (mean +/- SD age, 62 +/- 9 years) with unilateral or bilateral occlusive carotid artery disease, vasomotor reactivity was estimated by the increase of middle cerebral artery mean blood velocity by transcranial Doppler ultrasound, comparing the breath-holding maneuver and 1 g IV acetazolamide as vasodilatory stimuli. The carotid artery findings were classified as normal, stenosis of 50% to < 70%, 70% to < 90%, 90% to 99%, and occlusion. Eighteen of the 74 patients additionally underwent stable xenon enhanced computed tomography to calculate the increase of mean cortical regional cerebral blood flow in the middle cerebral artery territory after acetazolamide stimulation. RESULTS: The percentage of mean regional cerebral blood flow changes (n = 36 hemispheres) correlated best with the absolute mean blood velocity changes while breath-holding (P = .007, r = .4332). The absolute mean regional cerebral blood flow changes correlated best with the percentage of mean blood velocity changes after acetazolamide stimulation (P = .004, r = .4580). On all 134 middle cerebral arteries, both vasodilatory stimuli correlated highly significantly (P < .0001) when comparing increases in absolute (r = .5448) or relative (r = .3516) mean blood velocity. Both stimulation techniques similarly indicated significantly reduced vasomotor reactivity with increasing degree of internal carotid artery lesions (P < or = .01). However, the acetazolamide challenge differentiated more accurately between the various groups of internal carotid artery findings. CONCLUSIONS: The assessment of vasomotor reactivity by transcranial Doppler ultrasound correlates with cerebral blood flow changes even when different vasodilatory stimuli are used. In cooperative patients the breath holding maneuver as vasodilatory stimulus seems clinically useful for a first estimation of cerebral vasomotor reactivity. PMID- 7839407 TI - Absence of hyperacute rejection in newborn pig-to-baboon cardiac xenografts. AB - The shortage of organs for transplantation is especially severe for the critically ill newborn infant, for whom donors of the appropriate size are particularly scarce. One way to overcome this problem is to use animals in lieu of humans as organ donors. The major limitation to using animals for this purpose is the susceptibility of animal organs to hyperacute rejection, a violent rejection reaction thought to be mediated by antidonor antibody and complement. To evaluate the potential application of xenotransplantation to newborns, we tested neonatal humans and neonatal baboons and found that neither population expressed significant levels of xenoreactive anti-pig antibodies. We transplanted heterotopically hearts from newborn pigs into unmanipulated newborn baboons (n = 4). There was no evidence of hyperacute rejection in any of the grafts; the animals were killed with functioning grafts at 15, 81, 82, and 82 hr. This outcome contrasts with that of newborn pig-to-mature baboon and mature pig-to mature baboon cardiac xenografts, which were rejected within 1 hr of transplantation. The histology of pig graft biopsies from the newborn recipients was normal. Immunohistochemistry revealed only traces of IgM, C3, C4, and the membrane attack complex along graft endothelium. Fibrin deposition along endothelial surfaces was observed early after transplantation and became more extensive with time; in the absence of endothelial bound antibody or complement, this change may represent preservation injury. This study suggests that due to low levels of natural antibody, the newborn infant may permit prolonged xenograft survival. PMID- 7839408 TI - Effects of platelet-activating factor antagonist on preservation/reperfusion injury of the graft in porcine orthotopic liver transplantation. AB - To investigate the role of platelet-activating factor (PAF) in the preservation/reperfusion injury of the liver graft, the effect of treatment with a potent PAF antagonist (E5880) was evaluated in a pig orthotopic liver transplantation model. The graft liver was flushed out and preserved for 8 hr at 4 degrees C using a simplified University of Wisconsin solution. The PAF antagonist was administered into the University of Wisconsin solution (1 mg/L), into the rinsing solution (1 mg/L), and to a recipient pig (0.3 mg/kg d.i.v.) in group 1. The PAF antagonist was not given in the control group (group 2). Postoperative survival of more than 12 hr was 100% (9/9) in group 1 and 56% (5/9) in group 2 (P < 0.05). At 12 hr after reperfusion of the graft (RPF), the arterial ketone body ratio (acetoacetate to 3-hydroxybutyrate) increased to 1.54 +/- 0.15 (mean +/- SEM) in group 1, compared with 0.95 +/- 0.09 (P < 0.05) in group 2. In group 2, blood leukocyte count decreased to 8.3 +/- 0.9 (x 10(3)/microliters) at 2 hr after RPF, in contrast to a slight increase in group 1 (14.3 +/- 1.8 x 10(3)/microliter, P < 0.01). At 4 hr after RPF, glutamic oxaloacetic transaminase (461 +/- 59 vs. 712 +/- 97 U/L, P < 0.05), glutamic pyruvic transaminase (65 +/- 4 vs. 82 +/- 5 U/L, P < 0.05), and the lactate level (6.2 +/- 1.1 vs. 9.4 +/- 1.0 mmol/L, P < 0.05) in arterial blood were significantly lower in group 1 than in group 2. Light and electron microscopic study at 1 hr after RPF showed neutrophil sludging in the sinusoids and sinusoidal endothelial cell damage in group 2, while these findings were attenuated in group 1. It is suggested that PAF plays a key role in microcirculatory disturbance of the liver graft manifested on reperfusion, and that the treatment with E5880 has a protective effect against preservation/reperfusion injury of the graft in liver transplantation. PMID- 7839409 TI - Biochemical studies of pig xenoantigens detected by naturally occurring human antibodies and the galactose alpha(1-3)galactose reactive lectin. AB - The xenotransplantation of pig organs to humans is now receiving serious consideration because of the shortage of human donors for organ transplants. However, such xenografts would be hyperacutely rejected due to naturally occurring antibodies, present in all human sera, that react with pig antigens on the surface of endothelial cells, leading to complement fixation and the rapid onset of intravascular coagulation. A major target of these human natural antibodies is the terminal nonreducing disaccharide Gal alpha (1,3)Gal, and we now report on the array of molecules that are galactosylated by the alpha 1,3 galactosyltransferase. Pig lymphocytes and endothelial cells (both of which bear Gal alpha(1,3)Gal epitopes) were surface iodinated and the 125I-labeled molecules were precipitated with either human antibodies or the lectin from Griffonia simplicifolia (IB4, which binds to Gal alpha(1,3)Gal epitopes). The precipitated molecules were analyzed by gel electrophoresis and autoradiography. Five major groups of molecules were identified by one-dimensional SDS/PAGE (alpha 220 kDa, beta 160-180 kDa, gamma 120 kDa, delta 64 kDa, epsilon 40 kDa); the beta molecule was different in the 2 cell types (beta 1 of lymphocytes and beta 2 of endothelial cells). Two-dimensional SDS/PAGE analysis revealed that each of these groups of molecules resolved into further species of different charge (presumably due to different glycosylation) and also different molecular mass to give at least 20 different Gal alpha(1,3)Gal+ surface molecules. None of these molecules appeared to be present as disulfide-associated dimers. It is clear that there are many galactosylated molecules on the cell surface; indeed, using longer exposures of the autoradiographs, at least 40 different Gal alpha (1,3)Gal+ molecules could be identified. Several of these molecules are likely to have been identified by others, e.g., the 115-kDa, 125-kDa, and 135-kDa triad identified by Platt. Strategies to overcome hyperacute rejection could include modification or deletion of the alpha 1,3-galactosyltransferase gene, which would simultaneously delete all the Gal alpha(1,3)Gal epitopes on these molecules. PMID- 7839410 TI - In situ hybridization utilizing a Y chromosome DNA probe. Use as a cell marker for hepatocellular transplantation. AB - Research in hepatocellular gene therapy requires a consistently reproducible cell marker to detect transplanted hepatocytes. We have used a Y-specific genomic DNA probe to accomplish this goal. This technique enables the identification of transplanted male cells in recipient female tissues. Donor hepatocytes from male mice were transplanted into female mice via splenic injection. Recipient mouse livers were harvested 1, 24, and 48 hr after transplant. Transplanted (male) hepatocytes were detected in liver biopsy sections using in situ hybridization with the Y chromosome probe. PMID- 7839411 TI - In vitro recall of proliferative and cytolytic responses to minor histocompatibility antigens by dendritic cell enriched canine peripheral blood mononuclear cells. AB - It is difficult in vitro to demonstrate existent in vivo sensitization of dogs and humans to minor histocompatibility antigens. Using conventional one-way mixed leukocyte culture, when sensitized blood cells are stimulated with MHC antigen matched sibling PBMC bearing the minor histocompatibility antigens, there is usually no proliferative or cytotoxic response detected. We reported previously that 0 of 17 dogs sensitized by transfusion of dog leukocyte antigen-identical littermate blood had proliferative responses in mixed leukocyte culture when unfractionated sibling PBMC were used as stimulator cells. We reasoned that this result might be due to the inability of unfractionated PBMC to efficiently present minor histocompatibility antigens to the in vivo-primed T cells, a function thought best performed by dendritic cells. When we used a low buoyant density Percoll fraction of canine PBMC, shown previously to be enriched in dendritic cells, as stimulator cells, we were able to generate cytotoxic and/or proliferative responses in mixed leukocyte culture in all 5 dogs that had been sensitized to minor histocompatibility antigens by transfusions of dog leukocyte antigen-identical sibling littermate blood. By contrast, using unfractionated PBMC as stimulator cells, we found evidence of sensitization in only 1 of the 5 dogs. These data support the concept that the presentation of minor histocompatibility antigens, in contrast to major histocompatibility antigens, to the immune system may be restricted to a subpopulation of professional APC. PMID- 7839412 TI - Epithelial-derived neutrophil-activating factor-78 production in human renal tubule epithelial cells and in renal allograft rejection. AB - Chemotactic cytokines, or chemokines, are likely mediators of inflammatory cell recruitment in renal allograft rejection. A recent addition to the C-X-C super gene family branch of chemokines is epithelial-derived neutrophil-activating factor-78 (ENA-78). ENA-78 is a 78-amino acid peptide with neutrophil-activating and chemotactic properties. This chemokine is unique in that it was originally isolated and cloned from an IL-1-stimulated human pulmonary epithelial cell line, A549. In this article, we investigated whether ENA-78 could be produced by human renal epithelial cells. We found that primary cultures of human renal cortical epithelial cells with tubular cell attributes could express significantly increased steady state levels of ENA-78 mRNA when stimulated with IL-1 beta (2.0 ng/ml). In addition, these cells also secreted significantly increased ENA-78 antigen compared with controls when stimulated with IL-1 beta (2.0 ng/ml). Other proinflammatory agonists, including TNF alpha, IFN gamma, and LPS failed to stimulate ENA-78 steady state mRNA or antigenic peptide production by renal cortical epithelial cells. In addition, biopsy tissue from acutely rejecting human renal allografts had higher copy number of ENA-78 mRNA compared with nonrejecting renal allograft controls using a quantitative reverse transcriptase polymerase chain reaction method with a mutant ENA-78 transcript. In the proinflammatory milieu of the rejecting renal allograft, IL-1 beta produced by host and donor mononuclear cells may drive ENA-78 production by allograft tubule cells, thus effecting leukocyte recruitment into the tubulointerstitial compartment. PMID- 7839413 TI - Effect of early administration of donor bone marrow cells on renal allograft survival in dogs treated with antilymphocyte serum and cyclosporine. PMID- 7839414 TI - Posttransplant lymphoproliferative disorders and Epstein-Barr virus prophylaxis. PMID- 7839415 TI - Immunocytochemical detection of Epstein-Barr virus antigens in peripheral B lymphocytes after renal transplantation. PMID- 7839416 TI - The predictive value of hepatocyte glycogen content on liver allograft biopsy. Correlation with early graft function. PMID- 7839417 TI - Pathogenesis of obliterative bronchiolitis. Possible roles of platelet-derived growth factor and basic fibroblast growth factor. PMID- 7839418 TI - Fulminant hepatic failure secondary to herpes simplex virus hepatitis. Successful outcome after orthotopic liver transplantation. PMID- 7839419 TI - Extracorporeal photochemotherapy as single therapy for extensive, cutaneous, chronic graft-versus-host disease. PMID- 7839420 TI - Phototherapy in the treatment of cutaneous graft-versus-host disease. Our preliminary experience in resistant patients. AB - Graft-versus-host disease (GVHD)* is a frequent complication of allogeneic bone marrow transplantation. The potentially beneficial effect of phototherapy for treatment of cutaneous manifestations of GVHD led us to investigate retrospectively the effect of this therapy in a larger series of patients. Eleven patients with cutaneous GVHD (acute GVHD in 4 patients, chronic lichenoid GVHD in 6 patients, and chronic sclerodermatous GVHD in 1 patient) resistant to standard immunosuppressive drugs were treated with phototherapy. Skin lesions showed a complete clearing in 75% of patients with acute GVHD, and a response rate of 70% was observed in patients with chronic GVHD. No effect of phototherapy was achieved in 3 patients. Our results suggest that phototherapy is a nonaggressive treatment that may benefit patients with cutaneous GVHD, who already take high doses of immunosuppressive drugs. PMID- 7839421 TI - Successful transplant of kidneys with diffuse diabetic glomerulosclerosis. PMID- 7839422 TI - Intrathymic injection of alloantigen. PMID- 7839423 TI - Oxidative DNA damage after transplantation of the liver and small intestine in pigs. AB - Oxidative damage is thought to play an important role in ischemia/reperfusion injury, including the outcome of transplantation of the liver and intestine. We have investigated oxidative DNA damage after combined transplantation of the liver and small intestine in 5 pigs. DNA damage was estimated from the urinary excretion of the repair product 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG). In the first 1-3 hr after reperfusion of the grafts, 8-oxodG excretion was increased 2.9-fold (1.7-4.1; 95% confidence intervals; P < 0.05). A control experiment included sham surgery with clamping of the suprarenal inferior caval vein in 2 pigs during steady state infusion of 8-oxodG. While the caval vein was clamped, the urinary excretion of 8-oxodG was almost blocked, whereas after removal of the clamp, the excretion returned to and did not exceed the preclamp levels. In a separate experiment with 2 pigs, the elimination of injected 8-oxodG was shown to adhere to first-order kinetics with a clearance and a terminal elimination half life of approximately 4 ml min-1 kg-1 and 2 1/2 hr, respectively. The injected dose was completely excreted into the urine within 4 hr. It is concluded that substantial oxidative damage to DNA results from reperfusion of transplanted small intestine and liver in pigs, as estimated from the readily excreted repair product 8-oxodG. PMID- 7839424 TI - The association of lymphocytotoxic antibodies with corneal allograft rejection in high risk patients. The Collaborative Corneal Transplantation Studies Research Group. AB - The Collaborative Corneal Transplantation Studies are a pair of multicenter prospective clinical trials evaluating the effectiveness of histocompatibility matching in high risk keratoplasty patients. The antigen matching study (AMS) evaluated HLA matching in patients without circulating lymphocytotoxic antibody to HLA antigens and the cross-match study (CS) evaluated the effect of using cross-match-negative donors in patients with identified circulating lymphocytotoxic antibodies to HLA antigens. Sera from 510 patients considered for enrollment in the studies were screened preoperatively for the presence of anti class I lymphocytotoxic antibodies (LA). The 42 patients (8%) found to have detectable LA entered the CS. The 468 patients found not to have detectable LA preoperatively entered the AMS. Fifteen of the 37 transplanted CS patients were found to have donor-specific anti-class I antibody (before or after surgery). These patients were also screened for anti-class II LA and 25 had anti-class II panel reactive antibody > or = 5%. Forty-nine of the 419 transplanted AMS patients (12%) were found to have produced anti-class I LA after surgery, and in 19 patients, antibody specificities were those of donor HLA antigens. There was a significant association between the number of mismatched class I antigens and the number of donor-specific LA produced. The production of LA by AMS patients was significantly associated with reaction episodes; eighty-two percent of patients (40 of 49) with LA had reaction, compared with 63% of patients (230 of 365) without LA (P = 0.02). Likewise, production of donor-specific LA was significantly associated with immune-mediated graft failure (P = 0.025). For CS patients, there was no correlation between the production of donor-specific anti class I or nonspecific anti-class II antibodies and graft outcome. However, the CS patients had poorer graft survival than did AMS patients at 3 years (57% vs. 66%, P = 0.01). These data demonstrate that LA, especially directed against donor class I HLA antigens following corneal transplantation in high risk patients, are associated with immune graft rejection and can be an indicator of allograft rejection. PMID- 7839425 TI - Results of conversion from triple-drug to double-drug therapy in living related renal transplantation. AB - Results of 34 recipients of living related renal allografts initially treated with cyclosporine, azathioprine, and prednisolone and later electively converted to AZA and PRED are presented. Thirteen (group A), 14 (group B), and 7 (group C) patients were converted before 9 months, between 9 and 12 months, and after 12 months, respectively. Thirty-four patients who were on AZA and PRED and had never received CsA served as controls. Of the 34 patients, 33 were HLA haploidentical with their donors and 1 was HLA identical. All patients received a mean 8.62 +/- 7.39 third-party blood transfusions. In the control group, 29 patients received haploidentical grafts. The number of blood transfusions given to this group was 7.09 +/- 9.13. Of the 34 patients receiving triple-drug therapy, 9 (26%) had acute rejection within 3 months after conversion, as compared with 5 (14.7%) in the control group (P > 0.05). Although 1 case had acute rejection before conversion, all recipients had stable graft function at the time of conversion. Of these 9 recipients, 7 had conversion over 4-7 weeks, while 2 had rapid conversion. Following treatment of the rejection episodes, 4 patients in the study group responded to therapy, as compared with 3 cases in the control group (P > 0.05). After a mean follow-up of 18.62 +/- 10.31 months (range 3-41 months) following conversion, 4 patients were normal, 4 had chronic rejection (mean serum creatinine = 3.0 mg/100 ml), and 1 was back on regular dialysis. Eventually, of the 34 patients who were converted from triple-drug to double-drug therapy, 25 were normal, 5 had stable chronic rejection, 2 were back on regular dialysis, 1 was retransplanted, and 1 died due to failed graft. At the end of follow-up, graft survival in the study group was 88.2%, as compared with 85.5% in controls (P > 0.05). We conclude that conversion from triple-drug to double-drug therapy is not without risk, even in living related primary renal transplantation. Degree of HLA matching, number of pretransplant blood transfusions, and rejection before conversion did not have any significant effect on rejections following conversion, and the graft loss following conversion is unpredictable. PMID- 7839426 TI - Importance of concomitant viral infection during late acute liver allograft rejection. AB - We have determined accompanying events and reviewed the management and outcome of late acute cellular rejection episodes in 384 consecutive liver recipients. A significant proportion of patients experienced concomitant viral infection (group 1, n = 15 [41%]), with CMV infection comprising the largest group and smaller contributions from other viruses (CMV, 30%; HSV, 5%; EBV, 3%; varicella zoster virus, 3%). Thirteen (35%) patients (group 2) developed late rejection associated with low maintenance immunosuppression, and in a further 10 patients (group 3), no accompanying factor could be identified. Refractory rejection was higher in late compared with early rejection episodes in our series (29% vs. 9.2%, P < 0.05). Antiviral chemotherapy administered in rejection episodes with concomitant viral infection, either as sole treatment in cases with accompanying hepatitis or as adjunctive therapy to further supplemental immunosuppression in episodes of steroid-resistant rejection, controlled the rejection process in all treated patients. PMID- 7839427 TI - Liposomal amphotericin B prevents invasive fungal infections in liver transplant recipients. A randomized, placebo-controlled study. AB - Eighty-six consecutive liver transplant recipients were prospectively randomized in a double-blind, placebo-controlled antifungal prophylaxis study. Seventy-seven patients received 5 days of prophylaxis starting during the transplantation with either liposomal amphotericin B (AmBisome) 1 mg/kg/day or placebo. Among 40 AmBisome-treated patients, no invasive Candida infection was seen during the first month, compared with 5 invasive Candida albicans infections among 37 control patients (P < 0.05). Furthermore, 1 placebo patient experienced Aspergillus niger pneumonia. Thus, the overall incidence of invasive fungal infections was 0/40 (0%) in the AmBisome group versus 6/37 (16%) in the placebo group (P < 0.01). Patient survival at 30 days was 92% versus 94% for AmBisome- and placebo-treated patients, respectively. One patient experienced backache related to AmBisome infusion. Two patients had transient thrombocytopenia possibly caused by AmBisome treatment. AmBisome was otherwise well tolerated. The total cost for all antifungal drugs used in both groups was equal. However, prophylaxis with AmBisome was $5000 less expensive than treatment of proven invasive fungal infections among placebo patients. PMID- 7839428 TI - Evolution of diabetic nephropathy in kidney grafts. Evidence that a simultaneously transplanted pancreas exerts a protective effect. AB - Thirty-six renal transplant biopsies were obtained from 20 diabetic patients 1 6.5 years after successful combined pancreatic and renal transplantation (PKtx). An additional 36 renal transplant biopsies were obtained from 30 diabetic recipients 1-6.8 years after kidney transplantation only (Ktx). Light microscopic lesions indicating diabetic nephropathy were evaluated by a semiquantitative score ranging from 0 to 9. Within 2.5 years after transplantation, light microscopy showed no or only slight diabetic changes in both groups (nephropathy score = 0-2). Later, a nephropathy score > or = 3 was seen in only 1 of 15 biopsies (6.7%) in the combined PKtx group, but in 11 of 24 biopsies (45.8%) in the Ktx group (P < 0.05). Twenty-eight of the biopsies from the PKtx group and 26 of them from the Ktx patients were examined with electron microscopic morphometry to evaluate the glomerular basement membrane thickness (BMT) and the relative volume of the mesangial tissue (Vv). Of the biopsies taken < 2 1/2 years after transplantation in PKtx patients, and of those similarly taken in the Ktx patients, 93.8% vs. 88.9% had BMT values within 2 SD of the normal (NS). Of the kidney biopsies taken > or = 2.5 years after transplantation, 91.7% in the PKtx group still had a normal BMT, while only 35.3% of the biopsies in the Ktx group had a normal BMT (P < 0.01). In the PKtx group, the Vv was normal in 12/16 (75.0%) of the biopsies taken < 2 1/2 years after transplantation, and in 9/11 (81.8%) of the biopsies obtained > or = 2.5 years after transplantation. In contrast, the Vv was normal in only 1/9 (11.1%) and 2/17 (11.8%) of correspondingly obtained biopsies from Ktx patients (biopsies < 2.5 years after transplantation, P < 0.01, and biopsies > or = 2.5 years after transplantation, P < 0.001, respectively). We conclude that a functioning pancreatic transplant can prevent or reduce the various signs of diabetic nephropathy that eventually develop in diabetic patients with a kidney graft only. PMID- 7839429 TI - Use of low dose arginine vasopressin to support brain-dead organ donors. AB - In a prospective study, we documented the hemodynamic effects of conventional donor maintenance in 24 brain-dead organ donors. Patients were then randomized to receive either saline or a low dose arginine vasopressin (AVP) infusion. In the AVP group (n = 11), plasma hyperosmolality decreased (P < 0.05), blood pressure increased (P < 0.01), inotrope use decreased (P < 0.01), and cardiac output was maintained. In the control group (n = 13), plasma hyperosmolality increased (NS); no significant change in blood pressure, cardiac output, or inotrope infusion rate occurred. Myocardial ATP levels were higher in the AVP than the control group (NS). Early organ function was similar in the 2 groups. We conclude that the use of a low dose AVP infusion enables inotrope use to be reduced and recommend consideration be given to the use of a low dose AVP infusion in potential thoracic organ donors. PMID- 7839430 TI - N-acetylcysteine ameliorates reperfusion injury after warm hepatic ischemia. AB - Glutathione is important in cellular defense against oxidative stress. We postulated that administration of N-acetylcysteine (NAC), a glutathione precursor, might help maintain or replenish hepatic glutathione stores, thereby reducing reperfusion injury in liver grafts after warm ischemia. Eighteen pigs were subjected to 2 hr of warm hepatic ischemia and divided into a control group (group A, n = 6), a preischemia treatment group (group B, n = 6: NAC, 150 mg/kg, continuous i.v. infusion 1 hr before ischemia), and a postischemia treatment group (group C, n = 6: NAC, 150 mg/kg continuous i.v., begun 20 min before reperfusion and continued for 1 hr). At initiation of laparotomy, we measured hepatic levels of reduced glutathione (GSH), its oxidized form (GSSG), ATP, aspartate aminotransferase (AST), and lactate dehydrogenase (LDH). Before reperfusion, after 2 hr of warm ischemia, GSH, GSSG, and ATP were measured. One hour after reperfusion, we measured GSH, GSSG, ATP, AST, and LDH. Bile output was recorded every 10 min. Postoperfusion AST and LDH were significantly lower in both treatment groups than in controls. In group B, hepatic glutathione was maintained at significantly higher levels than in controls, even after ischemia (P < 0.05). In group C, although hepatic GSH levels fell until reperfusion, after administration of NAC, hepatic GSH reached the level of the preischemia treatment group. In both treatment groups, GSH 1 hr after reperfusion was significantly higher than in the controls (P < 0.01): regeneration of glutathione was seen in all 6 animals in group C, compared with 2/6 in group B and none in the control group. ATP recovery, bile output, and survival were all better in the treatment groups than in the control group. Pretreatment with NAC helps maintain hepatic glutathione during warm ischemia; given after ischemia, NAC is effective in replenishing depleted glutathione stores. Adjunctive use of NAC was associated with improved glutathione homeostasis, improved bile output and ATP regeneration, and increased survival. PMID- 7839431 TI - Distinct phenotypes of infiltrating cells during acute and chronic lung rejection in human heart-lung transplants. AB - To differentiate between acute and chronic lung rejection in an early stage, phenotypes of infiltrating inflammatory cells were analyzed in 34 transbronchial biopsies (TBBs) of 24 patients after heart-lung transplantation. TBBs were taken during during acute lung rejection and chronic lung rejection, as diagnosed by clinical data and histopathological investigation. TBBs without rejection and normal lung tissue specimens served as controls. Distinct phenotypes of inflammatory cells were found in acute and chronic lung rejection. T cells were present both in acute and in chronic rejection, but did not differentiate between them. In contrast, B cells with antibody deposition were mainly present in chronic rejection and not in acute rejection. Activated macrophages were present only in acute rejection and not in chronic rejection. In nonrejecting lung transplants, perivascular infiltrating cells were virtually absent. In the biopsy specimen, vessels had to be available for analysis, because the cell phenotypes were best recognized in perivascular infiltrates. The analysis of specific phenotypes of inflammatory cells by immunohistochemistry supports the diagnosis of acute and chronic lung rejection, in particular in those cases in which TBB provides limited tissue without airways. PMID- 7839432 TI - CD8+ activated T lymphocytes produce an in vitro skin graft-versus-host reaction in an organotypic skin culture model. AB - We adapted organotypic skin cultures to the dog as a model for skin graft-versus host reaction (GVHR) to explore the relative roles of T cells and cytokines. To produce GVHR, activated lymphocytes from bulk mixed leukocyte cultures (bMLC) from 2 dog leukocyte antigen-unrelated dogs were injected into organotypic skin cultures. Additionally, effects of separated CD4+ and CD8+ activated lymphocytes as well as cytokine-containing (TNF alpha and IFN gamma) supernatants from bMLC were studied. Noninjected cultures as well as cultures injected with autologous (cultured and uncultured) lymphocytes and allogeneic uncultured lymphocytes served as controls. The unseparated bMLC-activated cell populations induced histopathological changes similar to in vivo skin GVHR along with very prominent class II antigen expression on keratinocytes. Separated CD8+ cells were directly involved in tissue damage by producing necrosis of epidermis at the site of injection, with less class II antigen expression on keratinocytes, and predominantly distributed intraepidermally. CD4+ cells, located mostly in the dermal regions, induced prominent class II antigen expression on keratinocytes, but no histological changes of GVHR. High levels of TNF alpha and IFN gamma were found in the supernatant of allogeneic bMLC cultures, although when the supernatant was injected into the organotypic skin cultures, keratinocytes failed to express surface class II antigen and histologically did not show changes of skin GVHR. This study demonstrated that organotypic skin cultures can serve as a model for studying the etiology of GVHR, and indicated direct involvement of CD8+ cells in tissue damage. PMID- 7839433 TI - alpha/beta-T cell receptor-directed therapy in rat cardiac allograft recipients. Treatment prior to alloantigen exposure prevents sensitization and abrogates accelerated rejection. AB - An mAb directed to the alpha/beta-heterodimer of the rat T cell receptor was used to prevent rejection of cardiac allografts in sensitized (accelerated rejection) recipients. Over a wide dose range, alpha/beta-TCR-directed therapy abrogated accelerated rejection at 24-36 hr and extended cardiac allograft survival in a dose-dependent fashion, both when given after heart transplantation as well as during or before the sensitizing skin transplants (8.9 +/- 1.0 days, 12.7 +/- 0.6 days, or 8.7 +/- 1.5 days, respectively). Pretreatment with R73 completely abrogated host sensitization induced by skin grafting. As a result, post-heart transplant cyclosporine course (15 mg/kg for 7 day) has led to long-term graft acceptance (> 90 days vs. 15.2 +/- 1.6 days with postoperative CsA therapy alone). Administration of R73 mAb produced incomplete depletion (CD5+ cells) and partial modulation (alpha/beta-TCR/CD5 double-positive cells) in the peripheral blood. It suppressed in situ protein expression of many cytokines to background levels, in particular that of IL-2 and IFN-gamma, both when given after as well as before cardiac transplantation. However, only pretransplant mAb application was associated with augmented in situ elaboration of IL-4. alpha/beta-TCR directed therapy induced strong host anti-idiotypic and, to a lesser degree, anti isotypic antibody responses. Taken together, these results provide the rationale for a novel immunosuppressive strategy involving induction of hyporesponsiveness by alpha/beta-TCR-directed therapy before the alloantigenic exposure. PMID- 7839434 TI - Long-term survival of cardiac allografts in rats treated before and after surgery with monoclonal antibody to CD2. AB - The rejection of a transplanted allograft is dependent on T cell activation, which requires T cell receptor engagement by antigen and costimulatory signals delivered by T cell surface molecules such as CD2. Anti-CD2 mAbs have been shown to suppress cell-mediated immunity. The effects of anti-CD2 mAbs OX34 and OX54 on rejection of BN (RT1n) rat hearts transplanted heterotopically to LEW (RT1l) rats were investigated. Administration of OX34 (7 mg/kg/day i.p.), either for 3 consecutive days immediately before or 8 consecutive days immediately after transplantation induced indefinite allograft survival (median survival time: 7, > 150, and > 150 days for control, preoperative treatment, and postoperative treatment, respectively). In contrast, pre- or postoperative treatment with OX54 (40 mg/kg/day) prolonged median survival time to only 28 and 11 days, respectively. Administration of OX34 or OX54 to naive rats induced a transient depletion of T cells in the peripheral immune organs. In vitro studies revealed that whereas OX54 had no effect on the allogeneic mixed lymphocyte reaction, OX34 partially inhibited both the allogeneic mixed lymphocyte reaction, in an IL-2 reversible manner, and T cell proliferation in response to immobilized mAb to either the T cell receptor or CD3. OX34-treated rats in which the cardiac allograft had survived > 100 days accepted a second heart from the donor strain. Treatment with OX34 induced an alloantigen-unresponsive state in T cells. These results suggest that treatment with an appropriate anti-CD2 mAb, especially postoperatively, may prove an effective approach for preventing cardiac allograft rejection. PMID- 7839435 TI - Acute liver allograft rejection in the rat. An analysis of the immune response. AB - Liver allografts are vigorously rejected in 9-12 days in Lewis recipients of fully histoincompatible DA livers. The purpose of this study was to examine the initial events in this cascade, specifically the role of CD4+ T helper cells. Lewis recipients of DA or Lewis livers were killed at days 1, 2, 3, 4, and 7 days after transplant. Indicators of acute liver rejection, including a marked inflammatory infiltrate and decreased liver function, progressed in untreated recipients of allografts. Splenocytes taken from allogeneic recipients on days 1 4 and 7 proliferated in response to donor and third-party stimulators, whereas graft-infiltrating cells did not respond to donor and third-party antigens until day 3 after transplant, but thereafter maintained a good response. To further characterize the host T helper cell response to liver allografts, cytokine expression was analyzed in graft tissue and in the periphery. IL-4 mRNA was present in both syngeneic and allogeneic liver grafts, while message for IL-10 was present early in all liver grafts but persisted only in allografts. In contrast, IL-2 and IFN-gamma transcripts were specific to rejecting allografts. Similar patterns of cytokine expression were observed in the spleen, indicating the immune response to the graft involves the peripheral lymphoid organs. Thus, the cytokine profile detected during liver allograft rejection is extremely similar to that observed in other experimental models of transplantation. PMID- 7839436 TI - Beyond hyperacute rejection. Accelerated rejection in a discordant xenograft model by adoptive transfer of specific cell subsets. AB - If hyperacute rejection is prevented in the guineapig (GP)-to-Lewis rat (Lew) cardiac xenograft (CXg) model, an accelerated rejection involving cellular infiltration occurs in 3 to 4 days. In previous work using an adoptive transfer model, we found that this accelerated rejection was facilitated by either sensitized splenocytes or sensitized serum. In the current study, in an attempt to determine which splenocyte subset(s) facilitated this process, sensitized splenocytes, with or without subset depletion were injected, into complement- and natural antibody-depleted Lew recipients of GP CXgs. Graft survival was 4.18 +/- 0.75 days with no injection (n = 11), 4.13 +/- 0.99 days with naive splenocytes (n = 8), 1.80 +/- 0.45 days with sensitized splenocytes (n = 5), 2.67 +/- 1.03 days with CD4(W3/25+) depletion of the sensitized splenocytes (n = 6), 3.13 +/- 0.84 days with CD8(OX8+) cell depletion (n = 8), 4.70 +/- 0.68 days with macrophage depletion (n = 10), and 4.22 +/- 0.41 days with B cell depletion (n = 9). Cellular infiltrates, hemorrhage, myocyte necrosis, and endothelial deposition of IgG, IgM, and fibrin were seen in rejected grafts. In most groups, infiltrating cells consisted of CD4 (W3/25+), CD8 (OX8+), IL2R+ cells, macrophages, and natural killer (NK) cells. However, in the macrophages-depleted group, activated (ED2+) macrophages and NK cells were significantly reduced. Total IgM, anti-GP IgM, and anti-GP IgG rebounded in all groups over several days but were not consistent at the time of rejection. Lewis rats rejecting GP CXgs early had lower final titers than those rejecting later. Total IgG titers rebounded to baseline by posttransplant day 1 and were therefore similar in all groups at the time of rejection. These findings suggest that this accelerated rejection requires interaction between macrophages and B cells, since depletion of either significantly alters the rejection tempo. A possible explanation is that xenoreactive IgG antibodies, synthesized by sensitized B cells, bind their target antigens--but also bind sensitized macrophages through their Fc region, thus causing rejection by antibody-dependent cell-mediated cytotoxicity. PMID- 7839437 TI - The synergistic effects of cyclosporine, sirolimus, and brequinar on heart allograft survival in mice. AB - The effects of cyclosporine (CsA), sirolimus (RAPA), and/or brequinar (BQR) were examined in a vascularized heterotopic heart transplant model in mice. Untreated C3H (H-2k) recipients reject C57 BL/10 (H-2b) heart allografts at a mean survival time (MST) of 7.7 +/- 1.4 days. A 7-d intravenous (i.v.) infusion by osmotic pump of CsA at doses of 5.0, 10.0, or 20.0 mg/kg extended heart allograft survival to 9.8 +/- 1.3 d (NS), 15.0 +/- 5.1 d (P < 0.01) or 15.0 +/- 1.9 d (P < 0.01), respectively. RAPA delivered i.v. for 7 d at a dose of 0.1 mg/kg produced an MST of 13.0 +/- 7.5 d; 0.2 mg/kg, 20.0 +/- 10.9 d; and 0.4 mg/kg, 15.8 +/- 4.1 d (all P < 0.01). A 7-d alternate-day (q.o.d.) course of oral gavage with BQR (0.5, 1.0, or 2.0 mg/kg) produced survivals of 12.0 +/- 2.4 d, 17.6 +/- 3.4 d, and 20.0 +/- 4.1 d, respectively (all P < 0.01). The combination of 2.5 mg/kg CsA with 0.05 mg/kg RAPA extended graft survival to 18.2 +/- 2.9 d (P < 0.01), and 5.0 mg/kg CsA with 0.1 mg/kg RAPA prolonged survival to 23.0 +/- 9.0 d (P < 0.01). These combinations represent synergistic interactions based upon combination index (CI) values of 0.1-0.6. Although 7-d courses of 0.5 mg/kg CsA (7.3 +/- 1.0 d; NS), 0.01 mg/kg RAPA (7.6 +/- 0.9 d; NS), or 0.125 mg/kg BQR (7.6 +/- 0.9 d; NS) were individually ineffective, the triple-drug combination prolonged the MST to 64.6 +/- 32.7 d (P < 0.005; CI = 0.001), with 2/5 grafts beating for more than 100 d. Similar results were produced by 14-day therapy in the BALB/c (H-2d) to C3H combination. PMID- 7839438 TI - Prolongation of renal allograft survival in a large animal model by oral rapamycin monotherapy. AB - We assessed the efficacy of 5 dose levels of oral rapamycin for prolonging renal allograft survival in pigs. Untreated and triple therapy groups (cyclosporine, azathioprine, and prednisone) served as controls. Immunosuppression was administered for 28 days posttransplant and then stopped. Rapamycin whole-blood concentrations were followed weekly. Chemistry, hematology, and lipid values were monitored post-transplant. For rapamycin-treated pigs, median survival time (MST) correlated with both dose and trough levels (ng/ml). All kidneys had some degree of rejection seen on necropsy. After rejection, pneumonia was the most common cause of death. No specific end-organ toxicity was noted on histopathologic examination. Triglyceride and cholesterol levels increased in all treated pigs (both rapamycin and triple therapy) vs. untreated controls--however, all values were within normal limits. Mean ALT levels increased in weeks 2 to 4 in the higher-dose rapamycin groups but returned to baseline in pigs surviving after the drug was stopped. ALT levels did not increase above twice normal in any group. Creatinine levels correlated with the degree of rejection seen on biopsy. We noted no other toxicities. We conclude that rapamycin, given as oral monotherapy, is an effective and safe immunosuppressant in our large animal renal allograft model. Outcome correlated with dose and whole-blood levels. PMID- 7839439 TI - Survival of MHC-deficient mouse heterotopic cardiac allografts. AB - The immunologic mechanisms involved in the destruction of murine cardiac allografts were evaluated using MHC-deficient mice. Specifically, we examined the survival of immediately vascularized heterotopic adult cardiac grafts deficient in MHC class I, MHC class II, or both MHC class I and II antigens following transplantation to allogeneic hosts. We observed indefinite cardiac graft survival when donors lacked MHC class II or both MHC I and II antigens. In parallel experiments, we studied the survival of cardiac grafts harvested from normal donors in recipients severely depleted of either CD4 (class II-deficient mice) or CD8 (class I-deficient mice) T cells. Graft survival was dramatically prolonged in the absence of CD4 but not CD8 T cells. Collectively, our results demonstrate that the interaction of host CD4 T cells with donor class II antigens is critical to the rejection of murine cardiac grafts. PMID- 7839440 TI - Cold ischemia and outcome in 17,937 cadaveric kidney transplants. AB - To determine if cold preservation time continues to affect renal transplant outcome, prospectively collected data from 17,937 cadaveric renal transplants performed between 1982 and 1991 were analyzed. Cold preservation intervals of 1 16, 16-32, 32-48, and greater than 48 hr were studied by multi- and univariate methods for two time periods: 1982-1989 (n = 13,800) and 1990-1991 (n = 4137). The functional one-year graft survival for kidneys stored over different intervals was significantly different (P < 0.001) only for the 1982-1989 epoch: one-year allograft survival ranged from 76% (1-16), to 72% (16-32 and 32-48) to 74% (> 48) hr. One-year graft survival ranged from 81 to 83% for the four preservation times in 1990 through 1991 (P = NS). Overall actuarial graft survival was 76% (74% prior to 1990, and 82% after 1990). Factors significantly (P < 0.0001) affecting kidney transplant outcome before and after 1990 were delayed graft function (DGF): n = 4232, 65% one-year graft survival; retransplant status: n = 3029, 67% one-year graft survival; and HLA match at three or more loci: n = 6067, 79% one-year graft survival. While DGF occurred more often with prolonged preservation, kidneys with DGF had similar survival regardless of preservation duration. Before 1990, pretransplant transfusion was associated with better and black recipient race with worse outcome; neither transfusion nor recipient race had any effect after 1990. Patients receiving kidneys preserved for longer periods demonstrate one-year graft survival comparable to kidneys preserved for shorter periods. Prolonged cold ischemic time should no longer be a principal reason for considering organ discard. PMID- 7839441 TI - Experience with liver and kidney allografts from non-heart-beating donors. AB - Given the shortage of cadaveric organs, we began a study utilizing NHBD for OLTx and KTx. There were 24 NHBD between January 1989 and September 1993. These donors were divided into 2 groups: uncontrolled NHBD (G1) (n = 14) were patients whose organs were recovered following a period of CPR; and controlled NHBD (G2) (n = 10) were patients whose organs were procured after sustaining cardiopulmonary arrest (CA) following extubation in an operating room setting. Eight kidneys and 5 livers were discarded because of macroscopic or biopsy findings. In G1, 22/27 (81.5%) kidneys were transplanted; 14/22 (64%) developed ATN; 20/22 (95%) recipients were off dialysis at the time of discharge. With a mean follow-up of 32.7 +/- 21.1 months, sixteen (73%) kidneys are still functioning, with a mean serum creatinine of 1.7 +/- 0.6 mg/dl. The one-year actuarial patient and graft survivals are 95% and 86%. In G2, 17/20 (85%) kidneys were transplanted; 13/17 (76%) kidneys experienced ATN. All patients were off dialysis by the time of discharge. With a mean follow-up of 17.6 +/- 15.4 months, twelve (70%) kidneys are still functioning, with a mean serum creatinine of 2.5 +/- 2.1 mg/dl. The one year actuarial patient and graft survivals are 94% and 82%, respectively. In G1, 6/10 (60%) livers were transplanted; 3/6 (50%) livers functioned, the other 3 patients required ReOLTx in the first week postoperatively because of PNF (n = 2) and inadequate portal flow (n = 1). Two functioning livers were lost due to HAT (n = 1) and CMV hepatitis (n = 1). In G2, 6/7 (85.7%) livers were transplanted. All the livers (100%) functioned. 2 patients required ReOLTx for HAT at 0.9 and 1.0 months. Both patients eventually died. One patient with a functioning liver died 2 months post OLTx. The remaining 3 patients are alive and well at 27 months of follow-up. This study shows that the procurement of kidneys from both uncontrolled and controlled NHBD leads to acceptable graft function despite a high incidence of ATN. The function of liver allografts is adequate in the controlled NHBD but suboptimal in the uncontrolled NHBD, with a high rate of PNF. PMID- 7839443 TI - Auxiliary liver transplantation for fulminant and subfulminant hepatic failure. AB - We report the first series of 9 auxiliary liver transplantations performed as a bridge to recovery in 8 patients with fulminant and subfulminant hepatic failure. Hepatic failure was due to hepatitis A virus (n = 3), hepatitis B virus (n = 1), hepatotoxic drugs (n = 2), autoimmune disease (n = 1), or it was of unknown origin (n = 1). The donor liver was reduced to a left lobe (n = 2), a left liver (n = 4), or a right liver (n = 3), and was implanted in an orthotopic position beside the native liver after it was resected by a left or a right hepatectomy. Conventional immunosuppression was used to prevent rejection. Six patients regained normal consciousness within 2 weeks, without any sequelae. Two patients had persisting encephalopathy due to graft initial dysfunction, one of whom showed portal vein thrombosis, which was successfully cleared. The other one showed hepatic vein stenosis and was retransplanted at day 15. Five of eight patients had to be reoperated because of a surgical complication. Five patients showed rapid regeneration of their native liver, but one died at day 45 from severe herpes virus broncholitis. The auxiliary grafts were removed (n = 3) or left to atrophy by tapering immunosuppression (n = 1). One patient developed cirrhosis of the native liver and died of infectious complications at day 42. The native livers of the two remaining patients are still atrophic, one at 4 months and one at 1 month posttransplant. Finally, 6 of 8 patients are alive with a follow-up of 1 to 17 months. Four of them have permanently stopped their immunosuppressive therapy. Our experience demonstrates that auxiliary orthotopic liver transplantation (1) is feasible in children and adults, using either a left or a right liver graft, (2) is efficient in providing adequate liver function, and (3) gives a real chance to the native liver to regenerate, offering these patients a future free of immunosuppression. PMID- 7839442 TI - Weaning of immunosuppression in long-term liver transplant recipients. AB - Seventy-two long-surviving liver transplant recipients were evaluated prospectively, including a baseline allograft biopsy for weaning off of immunosuppression. Thirteen were removed from candidacy because of chronic rejection (n = 4), hepatitis (n = 2), patient anxiety (n = 5), or lack of cooperation by the local physician (n = 2). The other 59, aged 12-68 years, had stepwise drug weaning with weekly or biweekly monitoring of liver function tests. Their original diagnoses were PBC (n = 9), HCC (n = 1), Wilson's disease (n = 4), hepatitides (n = 15), Laennec's cirrhosis (n = 1), biliary atresia (n = 16), cystic fibrosis (n = 1), hemochromatosis (n = 1), hepatic trauma (n = 1), alpha-1 antitrypsin deficiency (n = 9), and secondary biliary cirrhosis (n = 1). Most of the patients had complications of long-term immunosuppression, of which the most significant were renal dysfunction (n = 8), squamous cell carcinoma (n = 2) or verruca vulgaris of skin (n = 9), osteoporosis and/or arthritis (n = 12), obesity (n = 3), hypertension (n = 11), and opportunistic infections (n = 2). When azathioprine was a third drug, it was stopped first. Otherwise, weaning began with prednisone, using the results of corticotropin stimulation testing as a guide. If adrenal insufficiency was diagnosed, patients reduced to < 5 mg/day prednisone were considered off of steroids. The baseline agents (azathioprine, cyclosporine, or FK506) were then gradually reduced in monthly decrements. Complete weaning was accomplished in 16 patients (27.1%) with 3-19 months drug free follow-up, is progressing in 28 (47.4%), and failed in 15 (25.4%) without graft losses or demonstrable loss of graft function from the rejections. This and our previous experience with self-weaned and other patients off of immunosuppression indicate that a significant percentage of appropriately selected long-surviving liver recipients can unknowingly achieve drug-free graft acceptance. Such attempts should not be contemplated until 5-10 years posttransplantation and then only with careful case selection, close monitoring, and prompt reinstitution of immunosuppression when necessary. PMID- 7839444 TI - Safety of the donor in living-related liver transplantation--an analysis of 100 parental donors. AB - The safety and lack of undue operative stress on the donor are documented from an analysis of 100 parental donors, whose children (3 months to 17 years old), received LRLTx at our institution between June 1992 and May 1994. Survival rate of recipients was 86%. No primary nonfunctioning liver was observed. The donors were 56 mothers and 44 fathers. Their ages ranged from 19 to 51 years and their weight ranged from 44 to 80 kg. They received partial liver resections to harvest the grafts. With regard to the liver graft, the left lobe was used in 24 cases (group L) and the left lateral segment was used in 75 cases (group S). The right lobe was used in one case. In the two groups, blood losses were 242 +/- 5 (S) and 312 +/- 14 ml (L); operation times were 6.22 +/- 0.11 (S) and 7.15 +/- 0.21 hr (L), respectively; in both groups, the postoperative hospital stay was 11 days (S, L). No significant differences between the two groups were observed in peripheral RBC and WBC count or serum AST. An increase in total bilirubin was not observed. In the exceptional case using the right lobe, blood loss of 2300 ml necessitated a blood transfusion of 1000 ml, and the total bilirubin increased up to 4.0 mg/dl on the third postoperative day, which prolonged the postoperative hospital stay to 17 days. These results conclusively suggest that safety is guaranteed when the left lobe or the left lateral segment is used as the liver graft for LRLTx. PMID- 7839445 TI - A comparison of treatment with transjugular intrahepatic portosystemic shunt or distal splenorenal shunt in the management of variceal bleeding prior to liver transplantation. AB - Recurrent variceal bleeding in liver transplant candidates with end-stage liver disease can complicate or even prohibit a subsequent transplant procedure (OLT). Endoscopic sclerotherapy and medical therapy are considered as first-line management with surgical shunts reserved for refractory situations. Surgical shunts can be associated with a high mortality in this population and may complicate subsequent OLT. The transjugular intrahepatic portosystemic shunt (TIPS) has been recommended in these patients as a bridge to OLT. This is a new modality that has not been compared with previously established therapies such as the distal splenorenal shunt (DSRS). In this study we report our experience with 35 liver transplant recipients who had a previous TIPS (18 patients) or DSRS (17 patients) for variceal bleeding. The TIPS group had a significantly larger proportion of critically ill and Child-Pugh C patients. Mean operating time was more prolonged in the DSRS group (P = 0.014) but transfusion requirements were similar. Intraoperative portal vein blood flow measurements averaged 2132 +/- 725 ml/min in the TIPS group compared with 1120 +/- 351 ml/min in the DSRS group (P < 0.001). Arterial flows were similar. Mean ICU and hospital stays were similar. There were 3 hospital mortalities in the DSRS group and none in the TIPS group (P = 0.1). We conclude that TIPS is a valuable tool in the management of recurrent variceal bleeding prior to liver transplantation. Intraoperative hemodynamic measurements suggest a theoretical advantage with TIPS. In a group of patients with advanced liver disease we report an outcome that is similar to patients treated with DSRS prior to liver transplantation. The role of TIPS in the treatment of nontransplant candidates remains to be clarified. PMID- 7839446 TI - The risk of transmission of hepatitis B from HBsAg(-), HBcAb(+), HBIgM(-) organ donors. AB - Liver allografts from HBcAb(+), IgM(-), HBsAg(-) donors can transmit HBV to uninfected recipients. We currently no longer accept these livers for transplantation while continuing to accept the kidneys. The purpose of this study is to determine the risk of donor-transmitted HBV infections from HBcAb(+), HBIgM(-), HBsAg(-) organ donors and determine if the risk of donor-transmitted HBV infections and their severity is dependent on the organ being transplanted. This study consists of a retrospective review of the posttransplant course of recipients of HBcAb(+), HBIgM(-), HBsAg(-) donors accepted at UCSF from 6/85 to 12/93. Transmitted HBV infection was defined as one in which the recipient changed from HBsAg(-) prior to transplantation to HBsAg(+) posttransplant, with no other source. There were 25 of 1190 donors who were HBcAb(+), HBIgM(-), HBsAg( ); 1/42 kidney, 3/6 liver, and 0/7 heart HBsAg(-) transplant recipients of organs from these donors became HBsAg(+) after transplantation. This difference in infection rate (liver vs. kidney and heart) is statistically significant. The clinical course of the liver recipients was also more severe. All of the patients who became infected were HBsAb(-) and HBcAb(-) prior to transplant. We conclude that (1) HBV can be transmitted from HBcAb(+), HBIgM(-), HBsAg(-) organ donors, (2) the rate of transmission is highest and severity of infection is worst in the liver recipients; and (3) we will continue to transplant kidneys from these donors, preferably into immunized recipients. PMID- 7839447 TI - Central nervous system lymphomas in organ allograft recipients. AB - Central nervous system (CNS) involvement occurred in 289 of 1332 patients (22%) with posttransplant non-Hodgkins lymphomas. The average time of appearance was 33 months (range 3 weeks to 248.5 months) posttransplantation. Lesions were confined to the CNS in 159 patients (55%), while 130 (45%) had involvement of other organs. Lesions involved the brain in 254 patients (88%), the brain and spinal cord in 5 (2%), the spinal cord in 2 (1%), unspecified locations in the CNS in 13 (4%), the meninges in 8 (3%), and the cerebrospinal fluid (CSF) in 7 (2%). All patients whose only involvement of the CNS was of the meninges or CSF had lymphomas involving multiple organs. Many tumors (48%) appeared within one year after transplantation. Brain lesions were frequently multicentric in distribution. Ninety-one (31%) of the 289 patients had no treatment and died, 70 (77%) of their malignancies and 21 (23%) from other causes. Of 198 patients who received treatment 124 (63%) died of their malignancies; 40 (20%) died of other causes, including 17 patients who had had complete remissions following treatment; 22 (11%) are currently alive and in complete remission; and 12 (6%) are alive and still undergoing therapy. The treatment of choice is local radiotherapy to the brain, which either alone (18 patients) or in combination with other modalities (14 patients) caused 32 of the 39 (82%) complete remissions. Ten of 30 patients with disease localized to the CNS survived more than 5 years, including 6 who survived more than 10 years. CNS lymphomas should be suspected whenever a transplant patient has neurologic symptoms however minor, and prompt work-up is essential to eliminate other possible causes. The dismal prognosis can be improved only by early diagnosis and prompt therapy. PMID- 7839448 TI - The facilitating effect of one-DR antigen sharing in renal allograft tolerance induced by donor bone marrow in rhesus monkeys. AB - Infusion of donor bone marrow cells (DBMC), a long-standing, successful strategy for inducing tolerance in experimental rodent transplantation models, can promote long-term acceptance of life-sustaining renal allografts in rhesus monkeys with no maintenance immunosuppression. To investigate the immunological basis for heterogeneity in duration of long-term graft acceptance following infusion of the DR-/dim fraction of DBMC into RATG-treated rhesus monkeys, we examined the relationship of recipient-donor major histo-compatibility class I and II DR matching to the development of antidonor antibody-dependent cellular cytotoxicity (ADCC) and renal allograft survival. The findings indicate a requirement for sharing one DR allele to achieve long-term graft acceptance. The observed immunological consequence of DR sharing that correlated with functional graft tolerance in this model was the suppression of early antidonor ADCC+ IgG antibody responses. Significant associations were observed between graft survival and suppression of ADCC antibody (P < 0.0005), graft survival and DR sharing (P < 0.005), and DR sharing and suppression of ADCC (P < 0.02). Early antidonor ADCC antibody responses associated with failure to maintain graft tolerance and were most consistently directed to donor class I. The required one DR antigen sharing in DBMC-induced suppression of antidonor class I antibody suggests a restriction for recipient DR, implying critical regulation of a response to donor antigen presented on recipient cells. We hypothesize a DBMC tolerogenic mechanism in which presentation of donor class I peptide by a shared DR allele configuration allows a veto effect by DBMC. Thus DR sharing would allow DBMC veto cells to reduce clonal expansion elicited by both the direct and indirect antigen presentation pathways. PMID- 7839449 TI - Mixed allogeneic chimerism and renal allograft tolerance in cynomolgus monkeys. AB - We have developed a nonmyeloablative preparative regimen that can produce mixed chimerism and renal allograft tolerance between MHC-disparate nonhuman primates. The basic regimen includes ATG, nonmyeloablative total-body irradiation (TBI, 300 rads), thymic irradiation (TI, 700 rads), and donor bone marrow infusion. Kidney allografts from MHC-mismatched donors were transplanted with various manipulations of the preparative regimen. Monkeys treated with the basic regimen alone (n = 2) rejected allografts by day 15. With the addition of cyclosporine (CsA) for one month (n = 3), one monkey developed multilineage mixed chimerism and renal allograft tolerance thereafter (> 430 days). To reduce the toxicity of the preparative regimen, TBI was fractionated to 150 rads on two successive days in subsequent studies. All monkeys receiving this modified regimen (n = 4) developed multilineage chimerism with fewer side effects and accepted renal allografts long-term with no further immunosuppression (196 days, 198 days, > 150 days, and > 40 days). In long-term survivors, donor-specific nonreactivity was confirmed by MLR and skin transplantation. Three monkeys treated with the basic regimen plus CsA but with only 150 rads of TBI (n = 1) or no TBI (n = 2) did not develop multilineage chimerism and grafts were rejected (day 40-50) soon after the CsA discontinuation. Monkeys treated with the same regimen, but without DBM (n = 2), rejected kidney allografts by day 52. Therefore, at least transient engraftment of DBM appears to be essential for induction of donor specific tolerance in this monkey model. PMID- 7839450 TI - Efficient gene transfer to pancreatic islets mediated by adenoviral vectors. AB - Genetic manipulation of pancreatic islets before transplantation has the potential to alter cellular immunity as well as islet function. The purpose of this study was to examine the feasibility of gene transfer to islets, using replication-defective adenoviral vectors. Newborn mouse islets were infected with AdHCMVsp1LacZ vector encoding Escherichia coli beta-galactosidase (beta-gal). Islets were cocultured with vector, at virus-to-target cell ratios of 10:1, for 1 hr. Gene transfer was assessed by specific histochemical stain for beta-gal (X gal). Islet DNA and RNA were analyzed by Southern and PCR for beta-gal and adeno sequences, and recombinant protein production by western and ONPG assays. Islet integrity after gene transfer was assessed by static incubations and transplantation to nondiabetic and to diabetic mice. Southern analysis and PCR confirmed the presence of E coli beta-galactosidase and the E4 adeno DNA in infected islets, but not in controls. Reverse-transcription PCR and western analysis demonstrated expression and protein production of inserted E coli beta galactosidase, but not E4 message. Insulin release in response to static incubations was unimpaired in infected islets. Syngeneic islet grafts stained positively for insulin for up to 7 days. Transplanted, genetically manipulated islets functioned similarly to control islets in reversing murine drug-induced diabetes. Thus, gene transfer into islets can be accomplished using adenovirus based vectors. The capacity of this virus to infect non-dividing cells allows insertion of cDNA into pancreatic islets, with potential application to the transplant setting. PMID- 7839451 TI - Phenotypic analysis of donor cells infiltrating the small intestinal epithelium and spleen during graft-versus-host disease. AB - One of the principal target organs during graft-versus-host disease (GvHD) is the intestinal epithelium, although the reasons for the preferential involvement of particular organs in this disease are not known. This study analyzed the subset distribution of donor and host lymphocytes in the small intestinal epithelium and the spleen during GvHD in a parent (C57BL/6J) into F1 (C57BL/6JxDBA2/J F1) model. While the donor cell population in the spleen consisted of B and T cells, the donor cell population in the intestine contained only T cells during the course of GvHD. These infiltrating donor cells resembled the host intraepithelial lymphocytes (IELs), which are predominantly CD8+ T cells. This subset distribution of donor cells in the intestinal epithelium was remarkable since they originated from a donor splenocyte population containing few CD8+ lymphocytes. In addition, although the injected donor splenic T cells were virtually all alpha/beta TCR+, several months after GvHD induction more than 30% of the donor cells in the intestine were gamma/delta TCR+, thereby resembling the host IELs not only in their expression of CD4 and CD8, but also in their TCR expression. In contrast, no gamma/delta TCR+ donor cells were detectable in the spleen of GvHD mice. The subset distribution of donor and host IELs remained constant throughout the disease, while in the spleen a decrease of both donor and host B cells and a temporary increase of both donor and host CD8+ cells was observed. These findings demonstrate that in a given target organ during GvHD the disease process affects both donor and host lymphoid populations. In addition the different tissue microenvironments eventually lead to donor cell repopulation with a subset distribution similar to the host natural lymphoid population of the particular target organ. PMID- 7839453 TI - The contribution of terminal complement components to acute and hyperacute allograft rejection in the rat. AB - Acute rejection and antibody-mediated hyperacute allograft rejection are affected by activation of the complement cascade. Split products of early complement components influence the localization, activation, and effector functions of platelets, granulocytes, monocytes, and lymphocytes, while the formation of membrane attack complex (C5b-C9) can lead to rapid cell destruction. Therefore, we compared acute and Ab-mediated hyperacute allograft rejection in a recently described model of C6 deficient PVG (C-) (RT1c) rats and their normal counterpart PVG (C+) (RT1c) rats. Cardiac allografts from fully MHC disparate ACI donors were heterotopically grafted into naive and skin graft sensitized PVG (C-) and PVG (C+) rats. ACI cardiac allografts were rejected acutely (8.3 +/- 2 days; n = 7) by naive PVG (C+) recipients, but survived significantly longer in PVG (C-) recipients (22 +/- 10 days; n = 10). Presensitized PVG (C+) rats rejected ACI cardiac allografts hyperacutely in 6.1 +/- 2.4 hr (n = 5). In contrast, ACI cardiac allografts transplanted into presensitized (PVG (C-) rats had markedly longer survival of 91 +/- 14 hr (n = 5). The alloantibody responses of naive PVG (C+) and PVG (C-) recipients 7 days after cardiac allografting, and of presensitized PVG (C+) and PVG (C-) recipients at time of cardiac allografting were not significantly different as measured by flow cytometry against ACI lymphocytes. Immunofluorescence demonstrated deposition of IgM, IgG and C3 in ACI allografts in PVG (C-) as well as in PVG (C+) recipients. Deposition of C6 was only found in grafts rejected by PVG (C+). The significantly longer survival of ACI cardiac allografts in C6-deficient PVG (C-) rats indicates that the membrane attack complex contributes to acute as well as antibody-mediated hyperacute allograft rejection. PMID- 7839452 TI - Prevention of chronic rejection and graft arteriosclerosis by tolerance induction. AB - Chronic rejection is a major cause of graft failure in solid organ transplants after the first year. A characteristic lesion in a variety of chronically rejecting organs is a fibrointimal proliferative arteriosclerosis. It has been speculated that approaches to tolerance induction may be effective in obviating not only acute, but also chronic, rejection. A picture of chronic rejection develops naturally in heart grafts transplanted from the Lewis-to-F-344 strain of rat. We examined whether tolerance induction by bone marrow transplantation and development of hematopoietic chimerism or tolerance induction by intrathymic inoculation of alloantigen could effectively prevent chronic rejection in an established model of chronic rejection. Bone marrow chimeras were developed in F 344 hosts by transplantation of T cell-depleted allogeneic marrow (TCD A BMT). Another set of F-344 hosts was inoculated with intrathymic allogeneic bone marrow cells. Heart grafts in these animals demonstrated tolerance for 120 days after transplantation. Control F-344 animals treated with a short course of cyclosporine consistently developed chronic rejection by 120 days following heart transplantation. Strikingly absent from the tolerant animals was any sign of graft arteriosclerosis, which was demonstrated in the vast majority of control animals. Analysis of cytokine mRNA profiles at 30 days following heart transplantation demonstrated differences between control and tolerant animals. These results suggest that tolerance induction can effectively prevent chronic rejection. PMID- 7839454 TI - Removal of baboon and human antiporcine IgG and IgM natural antibodies by immunoadsorption. Results of in vitro and in vivo studies. AB - The safe and effective removal of xenoreactive antibodies in the peritransplant period is likely to be critical for the clinical application of xenotransplantation involving disparate donor species, such as the pig. In an effort to develop an improved method for antibody removal in xenotransplantation, we have studied reusable antihuman antibody (Ig) columns in vitro and in vivo. Two types of columns were tested: (1) an antihuman Ig column containing polyclonal sheep antihuman IgG (heavy- and light-chain-specific) conjugated to sepharose CL-4B (Ig-Therasorb), and (2) an antihuman Ig column using polyclonal antihuman IgM (mu-chain-specific) conjugated to sepharose. Passage of human or baboon plasma through the Ig-Therasorb column resulted in 97.5% and 78.4% mean reductions in total IgG and IgM, respectively. Reductions in total IgG and IgM correlated with lowering of antipig IgG (54-486 fold) and IgM (9-54 fold) antibody titers as assessed by pig endothelial cell ELISA. The ability of the Ig Therasorb to significantly reduce IgM may be attributed to the light chain specificity of this column. With the anti-IgM column, marked reductions in total (82.6-83.9%) and antipig (27-54 fold) IgM in human and baboon plasma occurred, while levels of total and xenoreactive IgG were slightly affected. Other than a dilutional effect, neither column resulted in significant reduction in albumin, fibrinogen, factor 5, and factor 8. Repeated in vivo use of either column in baboons achieved reductions in IgG and IgM that closely followed the results of our in vitro studies. No subject morbidity or mortality occurred. Use of the Ig Therasorb column with immunosuppression in two baboons receiving pig renal xenografts achieved sustained reductions in antipig antibodies and prevented hyperacute rejection. Subjects were sacrificed at 11 and 13 days posttransplant with functioning xenografts and were found to have no evidence of vascular xenograft rejection. We conclude that anti-Ig columns represent a safe and effective method for antibody removal, without several of the limitations of other antibody removal techniques. Also, columns appear to be safe for repeated antibody removal in the posttransplant period. PMID- 7839455 TI - Inhibition of the effects of TNF in renal allograft recipients using recombinant human dimeric tumor necrosis factor receptors. AB - Tumor necrosis factor alpha (TNFa) and lymphotoxin (LT) or TNF beta are closely linked cytokines produced by macrophages and activated T lymphocytes, which play important regulatory roles in the immune response to allografts. They have also been implicated as mediators of the adverse reactions observed during OKT3 therapy. Therefore, anti-TNF agents could be useful both for immunosuppression and for limiting the systemic response observed in patients receiving OKT3. Recombinant TNFR:Fc is a fusion protein that binds TNFa and LT, thereby neutralizing their effects in vitro. The present study investigates the potential clinical application of TNFR:Fc in a nonhuman primate renal allograft model. Cynomolgus renal allograft recipients were treated with TNFR:Fc induction therapy alone or in combination with subtherapeutic doses of cyclosporine. Control animals received no immunosuppression or subtherapeutic cyclosporine. TNFR:Fc, administered as the only immunosuppressive agent, successfully prolonged renal allograft survival in the majority of treated animals. The prolongation of allograft survival was even more impressive when TNFR:Fc was combined with subtherapeutic doses of cyclosporine. Onset of rejection was significantly delayed as well in the TNFR:Fc treated groups. No adverse side effects were observed in any of the TNFR:Fc treated animals. Precursor cytotoxic T cells were detected in peripheral blood samples of treated recipients but the level of effector CTLs in vivo was below the threshold of detection. These results demonstrate that TNFR:Fc can be safely administered and is effective in prolonging renal allograft survival and in delaying the onset of rejection when administered alone or in combination with cyclosporine. PMID- 7839456 TI - Combined kidney/bone marrow transplantation--evidence of augmentation of chimerism. PMID- 7839457 TI - Indefinite survival following small intestinal transplantation after intrathymic injection of the donor with recipient-type splenocytes in a rat model. PMID- 7839458 TI - Medical treatment of hepatocellular carcinoma: any progress? AB - BACKGROUND: Hepatocellular carcinoma (HCC) remains one of the most common neoplasms worldwide. Curative treatment options include liver transplantation or resection. Unfortunately, most patients still have unresectable or untransplantable HCC due to disease extension or comorbid factors and are therefore candidate only for palliative treatments. METHODS: In this review we have analyzed the different medical approaches employed in the treatment of HCC in an attempt to better define their roles. RESULTS: Palliative medical treatments including systemic chemotherapy, immunotherapy or hormonal manipulation rarely influence survival of the patients. Although a high response rate is often reported with new local therapies such as transcatheter arterial embolization, intraarterial chemotherapy or percutaneous ethanol injection, the real impact of these treatment modalities on patient survival remains to be determined. CONCLUSION: One way to improve the diagnosis of HCC patients would be an appropriate approach to evaluate new drugs or treatment modalities. To answer all the open questions, further trials, possibly randomized, should be conducted on a substantial number of patients with homogeneous prognostic factors. PMID- 7839459 TI - The cost of hyperthermia: nine years experience at the Radiation Therapy Department of the Turin University. AB - BACKGROUND: In this paper the authors try to quantify the expenditure for the equipment, staff, treatment per patient and research, sustained at the Radiation Therapy Department of the University of Turin for the treatment of cancer with hyperthermia, METHODS: Two hyperthermic computerized devices are available: the SAPIC SVO3 multifrequencies system (915, 434 and 2-30 MHz) for external hyperthermia, and the SACEM system. working only with the frequency of 915 MHz, for interstitial and intracavitary heating. From September 1983 to December 1991, 408 patients have been treated with hyperthermia, for a total number of treated sites of 483; 2960 heating sessions were performed, with a average of six sessions per patient. RESULTS: The overall cost of our "hyperthermia project" was about 2,000,000,000 Italian liras; the equipment cost was estimated at 1,258,650,000 Liras (839,100 US$), and the cost per treatment and per heat session at about 3,985,200 (2676 US$) and 664,200 liras (443 US$), respectively. The cost of the research program can be estimated in 175,000,000 liras (116,666 US$). The National Health System provides for a partial reimbursement of 2,000,000 liras (1,333 US$) for each course of hyperthermia. Taking into account the mean expected life expectancy and increasing purchases for replacement of equipment, these costs increase 10% each year. As regards the cost-benefit problem, using the Rees formula it varies from 1112 US$ when hyperthermia is used as elective treatment to 3380 US$ when hyperthermia is used as palliative treatment. CONCLUSIONS: Hyperthermia is, in our experience, an expensive therapy. PMID- 7839460 TI - Effect of octreotide on neuroenolase levels in patients with small cell lung cancer. AB - AIMS AND BACKGROUND: The somatostatin analog octreotide has an antiproliferative effect on small cell lung cancer lines in vitro and in experimental xenograft transplantation systems in vivo. Thus it is worth investigating octreotide activity in the clinical setting. METHODS: We studied the effect of octreotide (200 micrograms three times a day subcutaneously for seven days) on serum levels of the tumor marker neuroenolase in 13 patients with small cell lung cancer. RESULTS: A decrease in neuroenolase levels was observed at day 7 during octreotide treatment, with a mean +/- SD of 32.6 +/- 42.0 ng/ml compared to basal values of 44.4 +/- 57.7 ng/ml and to washout values of 50.3 +/- 65.7 ng/ml (P < 0.03). CONCLUSIONS: Our results indicate that octreotide is effective in reducing neuroenolase levels in small cell lung cancer patients. These data suggest a possible role for octreotide in the treatment of this kind of tumor. PMID- 7839461 TI - A pilot clinical trial of surgical adjuvant treatment with high-dose 6S leucovorin/5-fluorouracil and radiation therapy for high-risk rectal carcinoma. AB - AIMS AND BACKGROUND: The study was performed to evaluate the feasibility of combining leucovorin (LV) with 5-fluorouracil (5FU) and radiation therapy as adjuvant treatment for high-risk rectal carcinoma. METHODS: Twenty-five patients with histologically proven adenocarcinoma of the rectum, at high-risk of recurrence after potentially curative resection (T3 NO, T and N1-2; MO), received 5FU (370 mg/m2) and 6S-LV (100 mg/m2) on days 1-5, 4 and 8 weeks after surgery. On treatment day 64, radiotherapy on the pelvis (50 Gy) was initiated. Finally, three further courses of 5FU/LV were given at intervals of 4 weeks beginning 28 days after the completion of radiotherapy. RESULTS: The treatment was generally well tolerated. We observed only 2 cases of grade III toxicity (diarrhea) during the third cycle of chemotherapy. No severe complications were recorded following the use of radiotherapy. The mean overall 5FU dose intensity was 92%. After a median follow-up of 24 months, 4 patients had relapsed (liver, lung, and pelvis, 2 cases). CONCLUSIONS: The association of LV to 5FU and radiation therapy seems to be feasible, with acceptable toxicity. The advantage of this combination, in terms of recurrence rate and survival with respect to 5FU/radiotherapy alone, will have to be evaluated in randomized trials. PMID- 7839462 TI - Preoperative intra-arterial mitomycin-C in the management of sigmoid adenocarcinoma: long-term results of a pilot study. AB - AIMS AND BACKGROUND: In patients undergoing potentially curative surgery for colorectal adenocarcinoma, the presence of occult disease is thought to be responsible for distant metastases, particularly of the liver. During the 1980's preoperative intra-arterial chemotherapy was used in patients with adenocarcinoma of the sigmoid colon since it was thought that the biological effects induced by radiation in rectal lesions could be induced by cytotoxic agents in sigmoid cancer which was found to be less sensitive to radiation. The aim of the present paper is to report long-term results of an early pilot study on 20 patients with sigmoid colon adenocarcinoma treated with a 6 preoperative intra-arterial infusion of mitomycin-C followed by curative surgery. METHODS: From January 1980 to December 1986, 20 patients with adenocarcinoma of the sigmoid colon were treated with a 6 hours preoperative intra-arterial infusion of mitomycin-C followed by potentially curative surgery (Group A). Eighteen hours prior to surgery the patients underwent selective arteriography of the inferior mesenteric artery through puncture of the femoral artery at the inguinal fold. The Seldinger technique was applied and Cook BP6 catheter was used. At the end of the examination, the catheter was positioned in the inferior mesenteric artery and mitomycin-C, 10 mg/m2, was infused in 500 ml of normal saline over a 6 hours period after which the catheter was definitively removed. Within 18 hours following intra-arterial mitomycin-C infusion all 20 patients underwent potentially curative surgery of their sigmoid adenocarcinoma. During the same period, 48 comparable sigmoid colon cancer patients underwent potentially curative resection alone (Group B). RESULTS: At 5 years overall recurrence rate was 30% and 39.6% in Group A and B patients, respectively (P = n.s.). In patients with Stage C disease, recurrence was less frequently observed in Group A (44.4%) than in Group B (77.7%) (P = n.s.). Overall survival at 5 years was comparable in the two groups of patients (70% and 64% for Group A and B, respectively) and median survival was > 60 months in both groups. In patients with Stage C lesions, there was a trend for improved survival at 5 years in Group A patients (55%; median > 60 months) compared to Group B (22%; median 27 months) patients (P = n.s.). CONCLUSIONS: Although the difference indicating decreased recurrences and improved survival for Stage C patients treated with preoperative intra-arterial mitomycin-C were not statistically significant, the long term results of this small pilot study are encouraging. PMID- 7839463 TI - Control of nausea and vomiting by granisetron in ovarian cancer patients treated with different cisplatin-based regimens. AB - AIMS: The study evaluated the safety and efficacy of granisetron as an antiemetic drug in ovarian cancer patients treated with cisplatin-based chemotherapy. STUDY DESIGN: Two groups of consecutive patients were considered: the first (Group A) with advanced disease, receiving 4-day cisplatin therapy in a 40 mg/m2 daily dose; the second (B), with minimal disease after radical surgery at high risk of recurrence, treated by single-day chemotherapy with a 90 mg/m2 dose. In both groups, 3.0 mg of granisetron was administered as a 10 min. intravenous infusion, 30 min. before cisplatin infusion. The treatment schedule included in all patients the administration of 125 mg i.v. of methylprednisolone 2 h before chemotherapeutic infusion. No further doses of granisetron were allowed within each 24 h study period for breakthrough nausea and vomiting. Assessment for nausea and vomiting was made at 24 h intervals through the 6-day study period for both groups using a diary card. RESULTS AND CONCLUSION: In group A, 25 patients were collected and evaluated; in group B, 25 were recruited and 13 evaluated. In both groups, excellent control of nausea and vomiting was achieved, since in group A we had a global major antiemetic efficacy of granisetron in 69.2% of patients (54.4% complete control and 14.8% major control); in group B, global major efficacy was present in 83.3% of cases (31.6% complete control and 51.7% major control). The antiemetic effect in the days following antiblastic treatment lasted longer in group A. PMID- 7839464 TI - Possible correlation between some biologic effects and the clinical course in patients treated with continuous infusion of interleukin-2 plus alpha-2 interferon for metastatic renal cell carcinoma. AB - BACKGROUND: Interleukin-2 therapy is known to cause many biologic effects, which are enhanced by the administration of interferon prior to or immediately after interleukin-2 infusion. Some of these effects could be related to the clinical response. METHODS: Sixteen patients with metastatic renal cell carcinoma were treated with continuous infusion of interleukin-2 plus alpha-2 interferon. Differential leukocyte count and lymphocyte subset evaluation were performed every 3 days during interleukin-2 treatment. At each cycle, the presence of the following antibodies was tested: antithyroid, antinuclear, antiplatelet and antierythrocyte. RESULTS: Fifteen patients were evaluable for response. No complete response was observed. Five patients obtained partial response (33%) and 3 stable disease (20%): 2 of them underwent surgical resection of metastases and obtained complete response. Some of our patients showed a significant increase in eosinophils, CD25+ lymphocytes and antithyroid antibodies. The association of these parameters, calculated with a "score" system, was also related to a better clinical response. CONCLUSIONS: Eosinophils, CD25+ lymphocytes and antithyroid antibodies could have a predictive value for the efficacy of interleukin-2 and alpha-2 interferon therapy in metastatic renal cell carcinoma. PMID- 7839465 TI - Radiation therapy of spinal metastases: results with different fractionations. AB - AIMS AND BACKGROUND: Local radiotherapy plays an important role in the palliative treatment of all skeletal metastases, particularly those of the spine, with the purpose to obtain pain relief and prevent pathologic fractures or vertebral collapse. METHODS: From June 1991 to October 1993, 95 patients with a total of 103 sites of spinal metastases were treated at the Institute of Radiology of the University of Rome "La Sapienza". Fractionations and total doses were divided as single fractions of 800 cGy, hypofractionated multiple fractions for a total dose of 20 Gy administered in 4-5 days, and conventional multiple fractions for a total dose of 30-40 Gy in 2-4 weeks. An evaluation of the efficacy of the different radiation treatments was performed with the use of a simplified descriptive pain scale. RESULTS: Seventy-three (70.9%) of 103 treatments were evaluables. An overall response rate of 82.2% was obtained: complete in 38.3% and partial in 43.8%, irrespective of total dose, fractionation and location of irradiated spinal metameres. The analysis of results did not show significant differences between the treatment courses. CONCLUSIONS: We confirm that radiation therapy has a major role in the management of pain control and prevention of fractures in patients with spinal metastases. Hypofractionated and single fraction treatments showed equal efficacy compared to more prolonged therapy, with an advantage for the patient and the radiation therapy institution. PMID- 7839466 TI - Role of postoperative radiation therapy in the management of early stage primary gastric non-Hodgkin's lymphomas: a retrospective analysis. AB - BACKGROUND: Clinical approaches to early primary gastric non-Hodgkin's lymphomas have not yet been clearly defined, and the role of postoperative radiotherapy remains a matter of discussion. METHODS: Twenty-seven patients with early primary gastric non-Hodgkin's lymphoma were observed from December 1978 to December 1990 at our Institution. They were staged according to Musshoff and Schmidt-Volmer (19) as I E (n = 16), II E 1 (n = 7) and II E 2 (n = 4). All of them underwent local combined treatment, consisting of surgery and postoperative radiotherapy; chemotherapy was also administered to 10 patients, mainly with the CHOP regimen, for 4-6 cycles before radiotherapy. Irradiation was delivered using 10 MV photons from a linear accelerator. Large abdominal fields were employed in 21 cases with daily fractions of 1.5-2 Gy up to a median total dose of 30 Gy (range: 27-36 Gy). Six patients were irradiated only on the surgical bed up to 40.5 Gy (range: 39 40.5 Gy). RESULTS: The 5-year overall and disease-free survivals were respectively 92.4% and 89.8%. The main known prognostic indicators, stage of disease, type of surgery as well as age and sex, were not found to be statistically significant in our series. No clear difference emerged between patients sequentially treated with the combination surgery-chemotherapy radiotherapy and those who did not receive adjuvant chemotherapy. Two patients recurred at distant sites, but no local failure was seen during the follow-up. CONCLUSIONS: Although no firm conclusion can be drawn, our experience, in agreement with recent published reports, points out that the use of postoperative radiotherapy is associated not only to favorable results in terms of local control and survival, but also, and moreover, to a negligible incidence of side effects and sequelae. However, in the absence of multi-institutional prospective randomized studies, whose activation is nowadays strongly warranted, the exact role of adjuvant therapies remains a matter of discussion, and the optimal treatment of early primary gastric non-Hodgkin's lymphoma still depends on individual experience and the physician's philosophy. PMID- 7839467 TI - Orchiectomy alone for clinical stage I nonseminomatous germ cell tumors of the testis (NSGCTT): a minimum follow-up period of 5 years. AB - AIMS AND BACKGROUND: Surveillance after orchiectomy alone has gained great popularity in the management of stage I NSGCTT. Preliminary results were enthusiastic, but critical voices have been raised against general use of this option as routine management. In an effort to identify patients at high risk of relapse, there has been a search for adverse prognostic factors of stage I nonseminomatous germ cell testicular tumors (NSGCTT). The aim of the study was to identify those patients in whom a surveillance policy is less likely to be successful. METHODS: Eighty patients with stage I NSGCTT were followed for at least 5 years. They were assigned to their respective clinical stage on the basis of physical examination, chest X-ray, CT of the retroperitoneum and post orchiectomy tumor markers. The criteria for inclusion in clinical stage I were normal results of these examinations. The policy of surveillance consisted of regular follow-up with tumor markers, chest X-ray and CT of the retroperitoneum. Patients who relapsed were treated with cisplatin-containing chemotherapy. In all patients, diagnostic delay, pre-orchiectomy tumor markers, T staging category, size, histopathology and vascular invasion in the primary tumor, and semen analysis were recorded. RESULTS: Follow-up revealed that 51 of the 80 patients (63.7%) were free of disease 61-110 months (mean, 83.1) after orchiectomy. Relapse was detected in 29 patients (36.3%) 3-58 months (mean, 13) after orchiectomy. The overall survival rate was 95%. The main risk factors of relapse were: vascular invasion, a major embryonal carcinoma and a minor teratoma component in the primary tumor, and low sperm count before orchiectomy. CONCLUSIONS: The authors recommend the following risk-adapted treatment procedures: retroperitoneal lymph node dissection in patients with vascular invasion and a major teratoma component, adjuvant chemotherapy in patients with vascular invasion and a major embryonal carcinoma component, and surveillance policy in patients without vascular invasion. PMID- 7839468 TI - Usefulness of the Nd:YAG laser in parenchyma-sparing resection of pulmonary nodular lesions. AB - AIMS AND BACKGROUND: The neodymium:yttrium-aluminium-garnet (Nd:YAG) laser has been successfully employed in parenchyma-sparing resection of pulmonary nodular lesions. We report our experience with limited resection using a noncontact Nd:YAG laser applied through a thoracotomic approach. METHODS: During the period March 1987-October 1993, we performed parenchyma-sparing resections of 66 pulmonary nodular lesions with a noncontact Nd:YAG laser in 47 patients. Nodules were approached through postero-lateral thoracotomy (n = 40), median sternotomy (n = 5) or staged bilateral thoracotomy (n = 2). Fifty-two lesions were located in a peripheral position and the others (n = 14) at various depths within the parenchyma. RESULTS: Fifteen lesions were benign: hamartoma (n = 5), chronic pneumonic infiltrate (n = 3), tuberculoma (n = 3), asbestosis (n = 2), Wegener's granuloma (n = 1). Twelve lesions were attributable to primary lung cancer and 33 were metastatic lesions. Another 6 lesions turned out to be necrotic metastases following chemotherapy. There were no perioperative deaths. Pulmonary re expansion was shortly obtained: mean drainage time was 4.31 +/- 3.9 days. Only one patient presented a prolonged drainage time (11 days); in this case, the air leak was successfully treated by tissue glue sealant trans-drainage infiltration. Follow-up ranged from 2 to 96 months. No case of relapse on the resection site has been observed. CONCLUSIONS: The results suggest that Nd:YAG laser resection is safe and worthwhile in patients with multiple lesions and borderline pulmonary function. PMID- 7839469 TI - Solitary plasmacytoma of bone and extramedullary plasmacytoma: two different nosological entities? AB - BACKGROUND: The relationship between solitary plasmacytoma and multiple myeloma is still unclear, but they can be distinguished by their different clinical course. Indicators of disease activity and extension, and of a possible evolution to multiple myeloma, have not been identified as yet. METHODS: Two cases of solitary plasmacytoma are described: one of the mandible and one extramedullary plasmacytoma (EMP) of the rhinopharynx. Pathologic data included immunohistochemical staining for heavy and light Ig chains, and for the proliferating cell nuclear antigen (PCNA). Analysis of the peripheral immunological status and serum parameters (beta 2 microglobulin, thymidine kinase, IL-2, IL-6 and soluble IL-2 receptor) was performed and correlation was made with the clinical status. Flow cytometry analysis of nuclear DNA content and S-phase cell fraction were also studied in both neoplasms. RESULTS: Solitary plasmacytoma of bone (SPB) showed important basal immunologic alterations and a marked increase in all serum parameters considered with respect to EMP. Ploidy analysis demonstrated an almost complete aneuploidy cell population for the SPB patient (80%), whereas in the EMP patient only 2% of the cells were aneuploid. The S-phase cells were 16% and 4%, respectively. PCNA index was 60% in SPB and 10% in EMP. CONCLUSIONS: Solitary plasmacytoma of the bone appeared to be a more aggressive form of plasmacellular neoplasia, distinct from EMP and similar to multiple myeloma. The study of serum parameters, together with analysis of PCNA, ploidy and S-phase fraction, can aid in better understanding disease activity, and in the choice of more adequate treatment. Moreover, serial analysis of some serum factors might be useful markers for monitoring the disease. PMID- 7839470 TI - Biologic characterization of pleural metastases from lung adenocarcinoma: description of the new DV90 cell line. AB - AIMS AND BACKGROUND: The characterization of pleural metastases from lung adenocarcinoma is often limited to single biologic features. METHODS: The present paper describes the cellular kinetic parameters, as well as immunocytochemical, ultrastructural and genetic characteristics of the new DV90 cell line, established from the pleural effusion of a stage IV lung adenocarcinoma. RESULTS: The cell line has a diploid DNA content, a doubling time of 24 h and 7% cloning efficiency, it is tumorigenic in nude mice. Ultrastructural investigation revealed the typical features of lung adenocarcinoma; the diagnosis was confirmed by its immunohistochemical reactivity with a panel of monoclonal antibodies specifically capable of identifying adenocarcinoma cells. Genetic analysis revealed a 46 X, -Y, +8, der (6)t(6?)(q27;?) karyotype and hyperexpression of the protein codified by genes Her2/Neu and p53. CONCLUSION: The importance of multidisciplinary biologic characterization in identifying the origin and biological behavior of pleural metastases deriving from lung adenocarcinoma is discussed. PMID- 7839471 TI - In vitro synergic effect of interferon gamma combined with liposomes containing muramyl tripeptide on human monocyte cytotoxicity against fresh allogeneic and autologous tumor cells. AB - AIMS: The purpose of the present study was to investigate whether human recombinant interferon-gamma (hrIFN-gamma) can act synergically with various activators in increasing the cytotoxicity of cancer patient monocytes against fresh autologous and allogeneic tumor cells. METHODS: Fresh target cells were obtained by means on the mechanical and enzymatic dissociation of human renal carcinomas. A 375 and SW 626 cell lines were used as positive controls. Monocytes from renal cancer patients and normal volunteers were activated in vitro with lipopolysaccharide, muramyl tripeptide (MTP-PE) or liposomes containing MTP-PE (MTP-PE liposomes), with or without a pre-incubation with hrIFN-gamma and were tested for cytotoxicity by means of a 72-hr 111indium-release assay. All of the patients were tumor free at the time of the study. RESULTS: Cancer patient peripheral blood monocytes were activated in vitro by different immunomodulators and became cytotoxic to freshly dissociated autologous or allogeneic tumor cells. A synergic effect producing maximal cytotoxicity was obtained with an appropriately scheduled combination of hrIFN-gamma (10 U/ml) and MTP-PE liposomes (50 nm/ml), free lipopolysaccharide (10 micrograms/ml) or MTP-PE (100 micrograms/ml). The synergic cytotoxicity was observed against fresh allogeneic and autologous tumor cells, as well as against cultured cells. CONCLUSIONS: All of these data support the possibility of a combined treatment using hrIFN-gamma and MTP-PE liposomes in human studies, particularly when it is borne in mind that liposomes can prevent the direct toxicity of many immunomodulators and that the low levels of hrIFN-gamma required for the synergic activation are not toxic in vivo. PMID- 7839472 TI - Congenital-infantile fibrosarcoma: study of two cases and review of the literature. AB - BACKGROUND: Congenital-infantile fibrosarcoma is a rare tumor of the pediatric age. It involves subjects under 5 years of age, and more than 200 cases have been reported in the literature. METHODS: The authors present the clinicopathologic findings of 2 cases and review the literature. RESULTS: Of our 2 patients, the first was a 2-years and 6-months-old female and the second a newborn male. The female presented a tumor in the retroperitoneum without recurrences or metastasis after 17 months, and the male on left foor with a recurrence after 3 months. Histologically, the tumors were mainly composed of spindle-shaped cells. Immunohistochemically, in both cases, neoplastic cells were positive for vimentin; focal positivity for muscular specific actin was present in the tumor of the female. Ultrastructurally, tumors were composed of mesenchymal cells with fibroblastic and myofibroblastic features. Flow cytometric analysis of the retroperitoneal tumor showed an aneuploid population of neoplastic cells. CONCLUSIONS: Congenital-infantile fibrosarcoma should be considered a borderline tumor; its biologic behavior is better than that of adult fibrosarcoma. Histologic diagnosis is not easy; the microscopic picture may be confused with fibromatosis or with malignant mesenchymal neoplasms. Only a follow-up of many years can confirm the benignancy or malignancy of any individual tumor, even though clinico-pathologic features may be distinctive enough to permit its recognition. PMID- 7839473 TI - Leiomyosarcoma of the soft tissues in a patient with nevoid basal-cell carcinoma syndrome. AB - A 57-year-old man was admitted with complaints of progressive anorexia, weight loss and right flank pain. He had been treated for basal-cell carcinoma of the skin 19 years before. On physical examination, eight moles in the face, back and left thigh were found along with palmar pits. In addition, a painful induration in his right thigh was evident. Biopsy proved that six moles were basal-cell carcinomas and the thigh mass a high-grade leiomyosarcoma. Computed tomographs revealed multiple metastases in the lungs and the liver. The patient was treated with epirubicin, with partial response, and subsequently with ifosfamide. He died 17 months after diagnosis. Whereas the world literature records several cases of soft tissue tumors in patients with nevoid basal-cell carcinoma syndrome, this is the first report of a simultaneous occurrence of leiomyosarcoma and nevoid basal cell carcinoma syndrome. PMID- 7839474 TI - [Pseudocroup]. PMID- 7839475 TI - [Pseudocroup. Treatment in hospital]. AB - Although croup is the most common form of airway obstruction in small children, there is debate as to the correct medical care for the hospitalized patient. A critical review of published articles was performed. It was found that a scoring system was essential for observation. There is only little information concerning the use of humidified air. Inhaled racemic epinephrine has a well-demonstrated effect. New studies indicate that L-epinephrine is as effective and safe as racemic epinephrine. Dexamethasone in doses greater than 0.6 mg/kg is effective in decreasing the length and the severity of respiratory symptoms associated with croup. When intubation is necessary steroids reduced the duration of intubation and the need for reintubation. PMID- 7839476 TI - [Pseudocroup treated with inhaled steroid (budesonide). A double-blind placebo controlled trial]. AB - The aim of this prospective, randomised, double blind study was to evaluate whether inhaled nebulized corticosteroid is effective in the treatment of croup. Thirty-seven children (aged 0.4-4.9 years) admitted to hospital with moderate to severe croup were allocated to treatment with either 2 mg nebulized budesonide (20) or saline (17). Disease severity was assessed by a clinical croup score based on stridor, cough, retractions, dyspnoea and cyanosis, and the overall clinical assessment was scored on a visual log scale (0-100). Two hours after treatment there was a significant improvement in croup score in the group treated with budesonide (8 to 4.5), but not in the group treated with saline (8 to 8). Furthermore, the overall clinical assessment score decreased significantly (50 to 25) in the group treated with budesonide, whereas it remained constant in the placebo group (60 to 62). The results indicate that nebulised budesonide can be used as a safe and effective alternative treatment in children with moderate to severe croup. PMID- 7839477 TI - [Use of colloids in acute hypovolemia]. AB - In Denmark several natural and synthetic colloids are available. Natural colloids are fresh frozen plasma (FFP) and human albumin (HA). Both are ideal as plasma expanders, but FFP can carry infectious agents and HA is quite expensive. The synthetic colloids or modified macromolecules are the dextrans (Macrodex (MD) and Rheomacrodex (RMD)), Haemaccel (HC), and Haes-steril (HS) in 6 and 10% solutions. HC has few indications because of a questionable volume expansion and a relatively high frequency of side effects. RMD is useful in cases of compromised regional blood flow. HS 10% and HA 20% are hyperoncotic and are effective in redistributing interstitial fluid to the intravascular space. HS and MD are both effective as volume substitutes. In addition HS and MD have beneficial side effects such as an inhibition of erythrocyte aggregation and inhibition of leucocyte marginalisation. Furthermore, MD has an anti-thrombotic effect. However, MD has in contrast to HS a dose dependent effect on the bleeding time. HS and MD are effective in restoring the colloid osmotic pressure and can in many cases replace HA in treatment of hypovolaemia. PMID- 7839478 TI - [The epidermal growth factor family]. AB - The growth and differentiation of cells are controlled by growth factors that act through binding to specific receptors on the cellular membrane. The epidermal growth factor (EGF) family consists of at least nine structurally similar peptides that activate one or more of the four receptors of the family. The family is of importance in connection with foetal development and in the adult organism in connection with tissue repair. Treatment with EGF has been used in connection with repair of gastrointestinal and corneal lesions. One or more of the EGF-receptors (HER-1-4) are present in almost all cells of the body. Both the receptors and the peptides are of importance in connection with malignant disease. Analysis of the EGF system in human tumors has shown increased expression in glioblastomas, mammary cancers, head- and neck carcinomas and bladder cancer. PMID- 7839479 TI - [Postoperative oxygen therapy at a surgery department]. AB - Late postoperative hypoxaemia is a common phenomenon, and is probably an important pathogenetic factor in the development of cardiac, cerebral and wound complications after major surgery. Thus, oxygen therapy may play an important role in the postoperative care of the surgical patient. Diagnosis of hypoxaemia is most cheaply and easily performed with pulse oximetry. The data available does not prefer one method of administering oxygen therapy to another, but patient compliance and comfort is probably greatest with the binasal cannula. There are no indications in published medical journals for scientifically based limits for hypoxaemia that requires treatment concerning the late postoperative period. Further studies of pathogenesis, treatment and clinical implications of late postoperative hypoxaemia are therefore warranted. It is our opinion, until further data is available, that monitoring of oxygenation is indicated in all patients after major surgery, and that hypoxaemia should indicate supplementary oxygen therapy. Proposed guidelines for monitoring and oxygen therapy are provided. PMID- 7839480 TI - [Laser therapy of Achilles tendinitis]. AB - The effects of low level laser treatment in soldiers with achilles tendinitis were studied in a prospective, randomized and double blind trial. Eighty-nine soldiers were enrolled in the study. Forty-six were randomized to treatment with active laser and 43 to treatment with placebo laser. No statistically significant differences in the number of consultations, morning stiffness, tenderness, crepitation, swelling, redness, VAS-score of pain and degree of unfitness for duty were found between the two treatment groups. PMID- 7839481 TI - [Hemi-alloplasty in the treatment of proximal humeral fractures]. AB - Twenty-four cases of displaced proximal humeral fractures were treated by hemiarthroplasty. No postoperative infections were seen. Follow-up was 24 month (range 12 to 62) in 19 patients. Pain relief was satisfactory in all patients but one. Functional results according to a modified Neer score system were good in nine, fair in eight and poor in two cases. No statistical differences in results in relation to postinjury delay or other parameters were found. Hemiarthroplasty is thus a safe treatment for displaced humeral fractures with a satisfactory end result. PMID- 7839482 TI - [Psychiatric admissions, continued hospital stay and community psychiatric treatment. Quality assurance of admission practice]. AB - Investigations on psychiatric admissions and length of stay at hospitals show great variations that are difficult to explain and many factors, besides relevant clinical ones, have been shown to contribute. Short hospital stays do not, in contrast to common beliefs, seem to increase the rehospitalization rate, more likely the opposite. Several places in the world have established criteria for "good practice" which use few and short intakes in combination with intensive community treatment. The results (symptoms and function) are better, the satisfaction of patients and relatives greater and the cost unchanged or less. The results have been reached by the use of "therapist case managers" in a psychiatric team. The use of coordinating case managers seems to increase hospital use. There is a need for intensive community psychiatry carried out on the patients' terms. Inpatient treatment must be a part of the system. Concurrent quality assurance of the criteria for use is recommended. PMID- 7839483 TI - [Therapeutic need of acute psychiatric patients and offered care during a 10-year period]. AB - With reference to the great changes made in recent years within the Danish psychiatric services, we compared the demand for care of acute psychiatric patients with the care offered. Over a period of three months in 1991 we prospectively registered all 243 acute psychiatric referrals to Svendborg Hospital, with regard to age, sex, way and source of referral, diagnosis, need for care and care offered. The result was compared with similar surveys in 1980 and 1985. We found that optimal treatment was not available to approximately 20% of the acute psychiatric referrals, the care we most often were unable to offer was acute admission to the psychiatric ward of Svendborg Hospital. We also found that from 1980 to 1991 there were no changes in the number of daily referrals, in the sex ratio or the age distribution of the patients. Our ability to meet the specific needs for care changes quantitatively throughout the period. The survey concludes that we are still unable to meet the specific needs for treatment of acute psychiatric referrals. Various suggestions are made as to how to improve the services offered to acute psychiatric patients. PMID- 7839484 TI - [User evaluation of a psychiatric day center]. AB - When community mental health centres were introduced in Copenhagen, day centres were attached to them. With the purpose of highlighting users' perspective in psychiatry, 48 patients in a psychiatric day centre were included in the study one year after the opening of the day centre. User satisfaction was investigated by means of a questionnaire, which was completed by the patient, while information on other aspects of the patients' lives was gathered from interviews with the patients and from case-records. The users of psychiatric day centres were mostly schizophrenic patients. The average number of years since first contact with psychiatric services was 12. In comparison with an age and sex matched population in Copenhagen, patients were more isolated. There was a insignificant tendency towards use of psychiatric bed capacity decreasing from the one year period before the opening of the day centre to the one year period after. The users were very satisfied with the treatment in the day centre. The majority expressed that they trusted the staff, and that they believed that the treatment in the centre had affected their situation in a positive way. It is concluded that psychiatric day centres are useful and should form a part of psychiatric services. PMID- 7839485 TI - [Mortality among long-term psychiatric patients in Denmark 1972-1988]. AB - By use of the computerized, nationwide psychiatric case register in Denmark, three cohorts of psychiatric patients hospitalized for at least one year during either 1972, 1977 or 1982, were identified and followed until April 1, 1988, regarding time of death. A decline in overall excess mortality compared with the general population was seen from the 1972-cohort to the 1982-cohort irrespective of sex, age group and diagnosis. This may be due to real improved survival, but could also reflect different mechanisms of selection. To analyse cause of death, 298 long-stay patients at Psychiatric hospital in Arhus were followed for 5.5 years. Lung disease caused the highest excess mortality. The authors emphasize that risk of death in long-stay patients below 50 years of age is still fourfold compared to the general population and point to the necessity of improving medical care. PMID- 7839486 TI - [Giant fecaloma]. AB - A case of a giant faecaloma of the sigmoid colon secondary to surgery is reported. The predisposing factors, the diagnostic and therapeutic approaches are discussed. PMID- 7839487 TI - [Overlooked bronchial rupture after blunt thoracic injury]. AB - A 72-year-old man developed a total atelectasis of the right lung six weeks after a blunt trauma in a motor vehicle accident. Bronchoscopy demonstrated a total fibrotic occlusion of the right main bronchus. By re-examination of earlier case sheets and chest x-rays it was suspected that the patient had suffered a partiel bronchial rupture from the accident. One and a half centimetres of the bronchus were resected with a good result. Findings and treatment of this rare complication are discussed. PMID- 7839488 TI - [Multiple liver abscesses caused by Fusobacterium necrophorum infection]. AB - A case of multiple liver abscesses caused by Fusobacterium necrophorum infection is presented. In cases with fever of unknown origin and biochemical signs of derangement of hepatic function, it is recommended that an abdominal scan is performed. Before initiating antibiotic treatment relevant specimens should be collected. Finally we describe how the use of resin-containing blood culture medium enhance the possibility of bacterial detection in patients receiving antibiotics. PMID- 7839489 TI - [Unwanted pregnancy among teenagers]. PMID- 7839490 TI - [Tuberculosis in Denmark should be considered globally]. PMID- 7839491 TI - [Myelographic headache]. PMID- 7839492 TI - [What happened to the demented patients?]. PMID- 7839493 TI - [Transportation of critically ill and injured patients]. PMID- 7839494 TI - [Patient categories and use of staff in transportation of patients between hospitals in Denmark]. AB - Questions about how many and how far patients are transported from one hospital to another in Denmark were put to assistant matrons of anaesthesiological wards. They were also asked about what type of patients they accompanied on interhospital transports. Every year roughly 4500 patients are moved from one hospital to another. The patients are mostly neurosurgical and paediatric patients. Apart from the nurse from the anaesthesiological ward, there is usually also a doctor from another ward who accompanies the patient. PMID- 7839495 TI - [Prospective registration of injuries to the staff during interhospital patient transportation]. AB - A prospective registration was carried out of all injuries or near-injuries to hospital staff that took place while the staff were engaged in transporting patients between hospitals. A total of 480 transports were registered over one year. Of these, 146 took place as emergencies, 60 with police escort. Four accidents to staff were registered (0.86% of all transports), where the staff in two cases suffered light bruising. Equipment that is brought along in order to treat and monitor patients should be able to be securely fastened during transport with a view to optimizing safety during transportation for patients and staff. PMID- 7839496 TI - [Treatment of complicated forms of anal incontinence]. AB - In recent years, several techniques for the treatment of more complex forms of faecal incontinence have emerged. These consist of either transposition of skeletal muscle (gracilis muscle or gluteus maximus muscle) around the anal canal, implantation of an artificial sphincter or implantation of a neuromuscular stimulator having previously transposed gracilis muscle. The latter method seems to hold most promise. PMID- 7839497 TI - [Chronic fatigue syndrome--a defined unity?]. AB - Chronic fatigue syndrome (CFS) is characterized by a sudden onset of an influenza like illness followed by marked chronic fatigue and abnormal exercise-induced exhaustion. The precise pathogenesis of this disorder is unknown, but viral infection triggering immune imbalance has been suggested. The literature on CFS is reviewed. We find no consistent support for chronic viral infection or immunological dysfunction. The data in the published studies are rather conflicting, and further research in order to identify parameters that differentiate CFS from other disorders is necessary. PMID- 7839498 TI - [Chronic fatigue syndrome--a controlled cross-sectional study]. AB - Twenty-one patients fulfilling the Center for Disease Control criteria for chronic fatigue syndrome (CFS) were examined in a controlled study. Viral antibodies and tests evaluating the immune system were investigated in the patients and in a control group of 21 sex- and age-matched individuals. Production in vitro of the predominantly T-cell-derived cytokines interleukin-2 and interferon-gamma was significantly higher in patients with CFS compared the control group. Furthermore, the serum concentrations of IgA and IgE were significantly lower in patients with CFS; however, the values were within the normal reference range. All other variables were similar in the two groups. This study does not suggest a clearly disordered immune system or a chronic viral infection as a major pathogenetic factor in CFS. Longitudinal studies of immunological and virological parameters in CFS are warranted as are studies on patients that are severely handicapped. PMID- 7839499 TI - [Magnetic resonance spectroscopy in fibromyalgia. A study of phosphate-31 spectra from skeletal muscles during rest and after exercise]. AB - 31phosphorus nuclear magnetic resonance (31P NMR) spectroscopy of painful calf muscle was performed in 12 patients with fibromyalgia and 7 healthy subjects during rest, aerobic and anaerobic exercising conditions, and postexercise recovery. Ratios of inorganic phosphate and creatine phosphate (Pi/PCr) and pH were calculated from the collected 31P NMR spectra. Resting values of Pi/PCr were normal in the patients. Patients only tolerated 49% of the workload tolerated by the controls (P = 0.005). Patients and controls had similar rates of Pi/PCr and pH changes during work and recovery. The controls were able to change their Pi/PCr and pH more than the patients, due to the greater workload reached. However, statistical significance was only reached for the anaerobic static exercise (P = 0.003). It was concluded that fibromyalgia patients have a reduced voluntary capacity for work, but with a biochemical response to work and recovery similar to healthy subjects. PMID- 7839500 TI - [Muscle biopsies in patients with fibromyalgia. A study based on light and electron microscopy]. AB - The value of muscle biopsy in fibromyalgia is still questioned. In this study we obtained 49 quadriceps biopsies from 20 patients and compared them blindly to 15 biopsies from five normal controls. Using light microscopy, histochemical and immunoenzymatic methods we found no definite evidence of muscle disease. Nevertheless, we subjected biopsies from nine of the patients and five other controls for further ultrastructural evaluations and demonstrated pathologic findings e.g. empty sleeves of basement membrane, many lipofuscin bodies and other degenerative changes. We conclude that ultrastructural evaluation cannot yet be used for diagnostic purposes, but the negative findings at light microscopy, including histochemical and immunoenzymatic techniques, might be of importance in evaluating difficult cases. PMID- 7839501 TI - [Calcium homeostasis]. AB - This review deals with calcium homeostasis, the calciotropic hormones and the effector organs. The extracellular calcium concentration is influenced by gains or losses of calcium via the bone remodelling system, the kidney and the gut. These fluxes are all influenced by hormones (parathyroid hormone, 1,25-dihydroxy vitamin D and calcitonin) whose secretion is partly governed by the plasma calcium level. PMID- 7839502 TI - [Venous gas embolisms]. AB - The risk of creating a venous gas embolism (VGE) exists, whenever surgery is performed in areas where venous pressures are below atmospheric pressure, or when the pressure of an insufflation gas exceeds venous pressures. Anaesthesia using N2O should be avoided in these situations. The patients should be monitored by systems offering sensitivity and specificity: Doppler, ECHO, ETCO2 and PAP measurements are the methods providing the highest sensitivities. ETCO2 monitoring is recommendable. In addition, attention should be directed towards common clinical signs: Tachypnoea, tachycardia, systemic hypotension, cardiac arrhythmias and cardiac "mill wheel" murmurs. When a diagnosis of VGE is made, further embolization must be avoided. Let the patient inhale pure oxygen. Attempt to aspirate gas through a central venous line. Put the patient in a combined Durant's and Trendelenburg's position. (During caesarean section however, use the anti-Trendelenburg's position.) Consider hyperbaric oxygen treatment in case of arterial gas embolism. PMID- 7839503 TI - [Interobserver variation in the classification of diseases]. AB - The aim of this study was to describe the variation between observers in classification of diseases, with special regard to pregnancy, birth and maternity. Four observers A, B, C and D classified 150 random cases of pregnancy, birth and maternity. The rate of agreement between the observers and their use of diagnosis was evaluated. The total agreement-rate was 58% concerning diagnoses of pregnancy, 82% concerning maternity and 13% concerning delivery; with variation between the observers at 71-85%, 86-96% and 26-54%. The diagnostic spectrum of the observers and their criteria for the use of diagnoses were variable. In conclusion, great variation was found between observers in classifying diseases, due to different diagnostic criteria being used by the observers, and due to misunderstanding of the Classification of Diseases. The setting-up of committees of branch-specialists is recommended, if we in the future want to use a public diagnostic register as a tool for research. These committees must achieve consensus concerning the need for classification within each specialty, define criteria of diagnosis and effect recommendation or education in the system of classification. PMID- 7839504 TI - [Differentiation of benign and malignant ovarian tumors by transluminal ultrasound scanning]. AB - We intended to evaluate ultrasonographic criteria for differentiation of benign and malignant ovarian tumours, and to estimate the risk of malignancy in unilocular ovarian cysts. The files of 186 women aged 40 or above, who had undergone surgery in the department of gynaecology and obstetrics at Hillerod hospital between 01.01.1988-31.12.1990 and where pathological ovarian histology was found were reviewed. Preoperative ultrasonographic examination concerning size and morphology was compared to histological diagnosis. Tumours were classified according to the ultrasonographic internal structure into a) unilocular cysts, b) unilocular cysts with solid areas, c) multilocular cysts, d) multilocular cysts with solid areas and e) solid tumours. Criteria for suspicion of malignancy were unilocular cysts > 10 cm and complex and solid tumours, whereas smaller unilocular cysts were thought to be benign. Twenty-one tumours, diagnosed by ultrasound as unilocular cysts were all histologically benign, independently of size. For complex and solid tumors there was an increased risk of malignancy, and a statistically significant correlation between tumour size and risk of malignancy was found. Using the ultrasonographic criteria for malignancy a sensitivity of 97% and a specificity of 28% was found. The suggested criteria for ultrasonographic suspicion of malignancy were found usable in differentiating benign and malignant ovarian tumours. The risk of malignancy for unilocular cysts seems to be low, independently of size. PMID- 7839505 TI - [Prognosis of children with very low birth weight in the county of Viborg. A follow-up of an unselected patient group]. AB - Neonatal mortality and follow-up examination among children with birthweight < or = 1500 g born in the period 1983-1987 inclusive has been recorded in an unselected material from a Danish county (Viborg County). There were 100 with birthweight < or = 1500 g and the low-birthweight rate was 7/1000. The neonatal survival was 72% dispersed with 32% for children with birthweight < or = 1000 g and 90% for children with birthweight 1001-1500 g. Four children died before follow-up examination. Of the surviving 68 children 66 were examined between the ages 21 months to six and a half years, the average age being about three years. The test-results were based on a questionnaire to the parents, an objective examination including neuropaediatric assessment and a Denver developmental screening test. Seven children were found to have moderate to severe handicaps, equal to 10% of surviving children. Of these seven children, three (4.5%) have cerebral paresis. Five other children were found to have small "handicaps". In conclusion 12 children or 18% had varying degrees of disability while 54 children were without demonstrable disability at follow up examination. PMID- 7839506 TI - [Iatrogenic rhinolithiasis?]. AB - A case of rhinolithiasis in a young man is presented. The radiological (CT-scan) and clinical findings of a rhinolith may be similar to other benign or malignant nasal lesion such as inverted papilloma. This similarity and the possibility that a rhinolith may have iatrogen origin is presented in this article. PMID- 7839507 TI - [Late diagnosis of severe hemophilia A]. AB - Haemophilia A and B are congenital bleeding disorders caused by a deficiency of factor VIII:C or IX:C in plasma. An early diagnosis is crucial to reduce the risk of permanent handicaps. A case of a 14 year-old boy is described. He was admitted to hospital with haematuria at the age of 12, but remained undiagnosed for another two years, when he was readmitted with an iliopsoas muscle bleeding affecting the femoral nerve. Laboratory findings showed a severe haemophilia A. The symptoms leading to the diagnosis and the differences between the various degrees of haemophilia are discussed. Retrospectively, the patient could have been diagnosed earlier if one had accounted for the more rare manifestations. In haemophilia bleeding time, platelet count, fibrinogen and factor II, VII and X are all normal. Only APTT is prolonged and should lead to further tests including factor VIII:C and IX:C. PMID- 7839508 TI - [The medical birth registry--obstetric quality development and research]. PMID- 7839509 TI - [Smoking among pregnant women]. PMID- 7839510 TI - [Levonorgestrel IUD]. PMID- 7839511 TI - [Vaccination of children]. PMID- 7839512 TI - [The childhood vaccination program. Background, status and future]. AB - Surveillance of the Danish childhood immunization programme has taken place at Statens Seruminstitut since 1980. A description of the prevalence of the diseases, which are included in the programme, is presented. The Danish childhood immunization programme has for many years been one of the best in the world although it differs markedly from other countries. The polio immunization programme with inactivated polio vaccine given first and then later live attennuated vaccine is probably the optimal polio immunization programme. The childhood immunization programme began in 1943 with free diphtheria vaccination, and tetanus immunization was added in 1949. There was a big polio epidemic in 1952/53 and the polio vaccine was introduced in 1955. All three vaccines have markedly reduced the prevalence of these diseases. Pertussis vaccine was introduced in 1961 and measles, mumps and rubella vaccination in 1987. Vaccination against Haemophilus Influenzae type b was introduced with success in 1993. In the future several changes will probably be made in the programme because of the possibility using new combined vaccines. PMID- 7839513 TI - [Vaccination status among children starting school in 1988/1989]. AB - The vaccination status of a representative sample of 5,309 children starting school in Denmark was determined. The vaccination status of subgroups distributed according to geography, parents' occupation and working hours and the children's participation in preventive health examinations by general practitioners was compared. The study was based on a questionnaire completed by local school health services. The study comprised 10% of all children starting school in 1988 based on a stratified selection of municipalities combined with a representative selection of schools in Denmark's four largest cities. Eighty-eight percent of the children were fully vaccinated against whooping cough, 98% against diphtheria, tetanus and polio and 89% against polio with live polio vaccine. Children of immigrants had a lower rate of vaccination than other children. Children of parents not working and of single parents were more likely to be incompletely or not vaccinated than children living with two parents who were both working. A geographical variation in the vaccination status was found between the different municipalities. PMID- 7839514 TI - [Lung transplantation. Indications, preoperative evaluation and postoperative treatment]. AB - Thirty-six heart-lung and lung transplantations have been performed in Denmark from January 1992 to January 1994. Heart-lung transplantations was initially carried out in patients with pulmonary vascular diseases. Single lung, double lung and heart-lung transplantation have become therapeutical alternatives and the indications have been expanded to terminal patients with pulmonary diseases. Careful selection of patients and donors, careful surgical techniques and a stringent immunosuppressive treatment have minimized the perioperative mortality. Daily lung function measurements, transbronchial biopsies and bronchoalveolar lavage have created possibilities for an early and safe diagnosis of infections and rejections. A high frequency of obliterative bronchiolitis with loss of pulmonary function is still a serious and unsolved problem. Intensive investigations with the aim of understanding, preventing and treating obliterative bronchiolitis are going on. PMID- 7839515 TI - [Obstructive sleep apnea and abnormal fatigue]. AB - Obstructive sleep apnoea syndrome is characterized by irregular snoring during sleep, excessive daytime sleepiness and in some cases unwanted sleep attacks. The patient has a disturbed night sleep with numerous wakenings. Disturbed sleep at night causes daytime problems with attention, concentration and work performance. Furthermore, it may eventually result in errors and accidents. Excessive sleepiness sometimes necessitates the suspension of the patient's driving license. It is of importance to identify patients with obstructive sleep apnoea and daytime sleepiness, because the condition can be treated effectively. Many Danish patients are still unidentified. Diagnostic and treatment possibilities vary from one part of Denmark to another. PMID- 7839516 TI - [The 1994 Nobel Prize: discovery and significance of G-proteins]. AB - Exactly how a cell responds to a hormone or transmitter substance depends on at least three factors: which type of receptors the cell has, which G-proteins are present and which amplifying system exists in precisely that cell. This means that the number of possible signalling pathways becomes extremely great. Here lies the most important aspect of the discoveries that have been rewarded with this year's Nobel prize. The translation of a message from an extracellular signal to an altered cellular function demands reoperation between a cascade of different proteins. One cell has one certain structure, another contains quite different components. In this manner, a limited number of signals and signal transmitting molecules may be combined to produce extremely varied signalling pathways. Life is characterized by simplicity in design and colossal variation in form. The G-proteins' role in signal transmission in the cell is a shining example of this principle of variations on a theme that achieve the diversity necessary to maintain life. PMID- 7839517 TI - [Peripheral thyroid hormone resistance]. AB - Peripheral thyroid hormone resistance (PTHR) was first described by Refetoff in 1967, and was characterized by raised serum hormone values of T4 and T3 and in appropriately elevated values of TSH. PTHR has been shown to be caused by a mutation in the TR beta gene resulting in impaired nuclear binding of thyroid hormones or an impaired post receptor hormone effect. The patients are often characterized phenotypically by impairment of bone, heart or cerebral function. PMID- 7839518 TI - [Oxygen therapy of chronic lung disease. Testing of a chemical oxygen generator- Vitaria]. AB - Twenty patients (11 females, nine males, mean age: 70.6 years) with chronic obstructive pulmonary disease and hypoxaemia took part in a randomized single blinded placebo-controlled clinical trial, testing the efficacy of a new transportable oxygen delivery system (VITARIA). The system consists of a container and a sodium carbonate containing powder (75 mg). When the powder is stirred in water in the container pure oxygen with a max flow of 1 l/min is delivered over a period of approximately 15 minutes. All patients had been receiving home oxygen treatment of at least 0.5 l/min for at least one month. Their baseline oxygen levels in arterial blood were mean 7.66 kPa, with a mean oxygen response to 0.5 l/min of oxygen of 2.54 kPa. In the placebo group no oxygen responses were seen, while in the Vitaria group a small but insignificant rise in arterial PaO2 was seen. No side effects were seen. In conclusion we find the system handy and easy to use but the recommended dose of powder is insufficient. PMID- 7839519 TI - [Abnormal flora in the small intestine. Diagnostic evaluation of the H2 breath test]. AB - Jejunal aspiration in order to diagnose intestinal bacterial overgrowth is more unpleasant for patients than breath testing. The object of this study was to compare the results of the glucose H2 breath test and the lactulose H2 breath test with the results of intestinal culture. On separate days, cultures of intestinal fluid collected from the Treitz region, glucose H2 breath tests (80 g glucose) and lactulose H2 breath tests (15 g lactulose) were undertaken in 20 patients with diseases predisposing to small intestinal bacterial overgrowth and in 20 controls. Twelve patients had bacterial overgrowth. Abnormal glucose H2 breath tests were observed in 11 patients, ten of whom had bacterial overgrowth. Glucose H2 breath tests were normal in seven out of eight patients without bacterial overgrowth. Only four patients had an abnormal lactulose H2 breath test. It is concluded that the glucose H2 breath test is acceptable for diagnosing bacterial overgrowth, whereas the lactulose H2 breath test in not. PMID- 7839520 TI - [CT diagnosis of pancreatic or periampullary cancer]. AB - Seventy-seven patients had abdominal computed tomography (CT) performed as part of the diagnostic work-up for suspicion of pancreatic cancer. The CT-images were reviewed by two radiologists who did not know the clinical course, the surgical procedure, or the final diagnosis. The positive predictive value of CT for the diagnosis of pancreatic or periampullary cancer was 92% (82-97%) and the negative predictive value 69% (41-89%). The 95% confidence limits of the positive predictive value of CT in staging the extent of periampullary cancer in 52 patients varied between 21-79% and 59-100%, with the lowest values in diagnosis of liver metastases. The confidence limits for the negative predictive values in staging varied between 17-56% and 67-94%, with the highest values concerning liver metastases. We conclude that CT cannot be used as the only diagnostic procedure for confirming or excluding the diagnosis of pancreatic or periampullary cancer, and that the staging of periampullary cancer by CT alone is too inaccurate for the evaluation of resectability. PMID- 7839521 TI - [Placement outside home. 1. Study of the records on 112 children and adolescents placed outside the home in 1990]. AB - A retrospective study was made of the records of 112 children and adolescents who had been placed outside their homes in 1990 in accordance with Section 66 of the Social Assistance Act. The children had been placed either in foster homes, boarding schools, group homes or youth homes. The aim of the study was to examine the social circumstances relevant to placement of the children. It was found that the parents' marital status, their means of income and the recorded problems of both children and parents, all of which were considered to be contributing factors to placement of the children, corresponded with results from previous studies. However, incest and physical abuse were not recorded as a cause of placement. Only a few children were placed directly from their own homes; most of them were transferred from one form of institution or school to another. In more than 90% of the cases, extensive measures of social support had previously been established in an attempt to avoid the first placement outside the home. Although the children received social support during placement, the support given to the parents is still considered insufficient. This is especially the case for parents of children below school age. Compared to the total sample this group seems to have the highest number of recorded parental problems. PMID- 7839523 TI - [Anterior fontanel bone--a rare normal variant]. AB - The anterior fontanel bone is a very rare true accessory bone. Radiographic demonstration is especially important in those babies suspected to have premature closure of the cranial sutures or fractures. The bone is considered as a normal variant. It does not interfere with cranial growth nor with the normal development of the child. PMID- 7839522 TI - [Placement outside the home. 2. Interviews with children and adolescents and their parents about placement outside the home]. AB - An interview study of 11 children and their parents was carried out in connection with a more comprehensive retrospective review of the records concerning children who in 1990 had been placed outside their homes. The aim of the study was to describe how children and parents experience the process of placement in order to adjust placement criteria if necessary. At the time of interview the age of the children was 12-19 years (mean 16.2 years), there were five boys and six girls. Five of the children were still placed outside the home. All the children had an intellectual understanding of the reason why they did not live at home. However, none of them had reached a corresponding emotional understanding and clarification. It was found that there were two different ways of managing separation. Those children who experienced attuned separation seemed to manage best. In these cases the problems of separation were worked through by parents and children. Some of these parents also expressed the view that their child was not really placed outside the home, but was still implicitly a member of the family. The opposite was true in non-attuned separations. The authors recommend a revision of the criteria on which the social authorities base their evaluation as to where and when a placement should be made--especially concerning children exposed to non-attuned separation. PMID- 7839524 TI - [Pneumothorax during laparoscopic cholecystectomy]. AB - One patient developed pneumothorax during laparoscopic cholecystectomy. The pneumothorax was immediately drained with an intercostal canula. A diaphragmatic lesion caused by the electrocoagulator was identified and closed, surgery was completed, and the patient was not seriously affected by the complication. Laparoscopic cholecystectomy has gained enormous popularity. Pneumothorax is a rare, but potentially fatal complication. Immediate treatment is essential and easy. This report should make anaesthetists and surgeons aware of the possibility of gas insufflated during laparoscopy producing a pneumothorax, particularly with the increased use of the technique for major upper abdominal procedures. PMID- 7839525 TI - [Aimed glucocorticoid treatment of Crohn disease]. PMID- 7839526 TI - [Epididymitis, testicular torsion and color Doppler]. PMID- 7839527 TI - [HTLV infections]. PMID- 7839528 TI - [Human T-lymphotrophic virus type I and II--diagnosis and clinical presentation]. AB - Human T-lymphotropic virus type 1, HTLV-I, was the first human oncogenic retrovirus to be isolated in 1978. HTLV-I has previously been called Human T-cell leukaemia virus or Human T-cell lymphoma virus type I. HTLV-I infection is endemic in southwestern Japan, the Caribbean basin, and parts of South America and Africa. HTLV-I is aetiologically associated with adult T-cell leukaemia lymphoma and tropical spastic paraparesis (TSP), also known as HTLV-I-associated myelopathy. HTLV-II was isolated in 1982 and is endemic among some north American Indians. HTLV-II has not been clearly linked to any specific disease. Both viruses are found worldwide, particularly among intravenous drug users (IVDU), and have also been found in blood donors in USA and Europe. HTLV-I/II are transmitted by the same routes as HIV-1: blood-borne via blood transfusions and among IVDUs by sharing contaminated needles, and by mother-to-child transmission, primarily through breast feeding. HTLV-I/II infections are also sexually transmitted and can be transmitted in utero, though less efficiently than HIV-1. The diagnosis of HTLV-I/II infections is based on the detection of antibody to the virus. Due to the high degree of cross reactivity between HTLV-I and HTLV-II, it is difficult by serology to discriminate between the two viruses. Less than 5% of individuals infected with HTLV-I develop symptoms after a latent period, which can last from a few years to several decades. No specific treatment of adult T cell leukaemia or tropical spastic paraparesis is currently available and no vaccine has yet been developed. PMID- 7839529 TI - [Effect of uterine fibromas on pregnancy]. AB - The recent published journal reports concerning the influence of uterine myomas on pregnancy are reviewed. The prevalence of uterine myomas in pregnancy is 0.1 5%, and less than half of the cases can be diagnosed by clinical investigation alone. The previous belief that continuous growth of myomas occurs during pregnancy seems incorrect. Most myomas grow during the first trimester, whereafter only few continue to enlarge. The most often recognized complication during pregnancies with uterine myomas is abdominal pain. About ten percent will suffer from this. Treatment is with non-steroidal anti-inflammatory drugs, which are extremely effective. In resistant cases epidural blockade may be used. Placental abruption is possibly more common among women with myomas that have direct contact to the placenta, and there is a trend towards shorter pregnancies in women with myomas. Further investigation on these subjects is required. No other complications are consistently reported more frequently among women with myomas than among those without. Myomectomy during pregnancy should only be performed in extreme cases. The value of myomectomy before conception to avoid pregnancy complications is doubtful, if no other pathology is present. PMID- 7839530 TI - [Gastroesophageal reflux]. AB - Gastro-oesophageal reflux is a common disorder. About 50% of patients with reflux disease have oesophagitis, a condition which is diagnosed in approximately 20% of all patients referred for gastroscopy. Effective drug regimens combined with life style modifications can keep the majority of patients free of symptoms. Relapses are frequent and prolonged or life-long maintenance therapy is often required. Complications include stricture formation and development of Barrett's epithelium, a premalignant condition. At present surgery is reserved for patients who do not respond to medical treatment and patients who do not wish to take life long medical therapy, and should be considered for patients with complications of reflux disease. The operation may be carried out laparoscopically. PMID- 7839531 TI - [The effect on health of dietary antioxidants and antioxidant supplements]. AB - Reactive free oxygen radicals are formed in the reactions involved in normal cell metabolism. This formation is closely regulated e.g. by dietary antioxidants. Present knowledge suggests that an imbalance, with surplus of free radicals, can play a role in the pathogenesis of certain types of cancer, atherosclerosis, and cataract. A number of epidemiological studies have demonstrated a reduced risk of developing these diseases in persons who consume a diet with a high content of vegetables and fruit, which contains large quantities of the antioxidants: beta carotene, vitamins C and E. Intervention studies, using supplements of these antioxidants, have so far not been able to show a beneficial effect. The apparently protective effect of fruit and vegetables may be due to other active ingredients. In Denmark the average intake of vegetables and fruit is low, and it is estimated that an increased consumption of these foods could reduce the occurrence of certain cancer types and atherosclerosis. In contrast, there is no evidence that antioxidant supplements would provide protection against disease, and their safety remains to be established. PMID- 7839532 TI - [Breast reduction surgery. County of Velje--a 12-year follow-up study]. AB - A questionnaire investigation of 299 women treated operatively over a 12-year period for breast hypertrophy in four general surgical units is presented. Different surgical techniques were used, and in one of the departments one plastic surgeon performed the operations. The results of the different techniques were compared. All techniques gave good physical relief. Pers & Bretteville Jensen's technique proved to be better in maintaining the sensitivity of the nipple, but a higher incidence of complications occurred. With McKissock's, Strombeck's and Bames-Ragnell's techniques all scars end up looking like an anchor. These methods are preferred by most women, in spite of a higher risk of losing the sensitivity of the nipple. Significantly more women who had undergone reduction mammaplasty with the Pers & Bretteville-Jensen technique, which ends up with a horizontal scar across the breast, regretted the operation. The cosmetic results were very important for the patients, and a more uniform treatment of the patients might be preferred. PMID- 7839533 TI - [Treatment of radiation-induced vesicovaginal fistula]. AB - The records of 23 patients with vesicovaginal fistulae (VVF) probably caused by irradiation treatment for cancer of the uterine cervix were analyzed. The median latency between irradiation and fistula formation was 17 years. Ten patients had histologically verified cancer recurrence besides a VVF. In addition, nine patients had a rectovaginal- and one an ileovaginal fistula. Twelve patients were treated primarily with ureteroileocutaneostomy a.m. Bricker. Six had bladder drainage, and four of these had ureteroileocutaneostomy performed at a later stage. Four patients initially underwent percutaneous nephrostomy. One patients had a unilateral ureteroileocutaneostomy performed. Eight patients are alive today (median observation time 2.5 years), and all of these had had ureteroileocutaneostomy performed. Three of these patients (38%) were completely relieved of symptoms while the rest occasionally experienced pain, vaginal discharge and bladder empyema. We conclude that ureteroilocutaneostomy a.m. Bricker is a satisfactory procedure for vesicovaginal fistulae because the socially incapacitating symptoms disappear or are considerably diminished. PMID- 7839534 TI - [Artificial respiration in patients with acute severe asthma. Mode of ventilation and survival]. AB - The purpose of the study was to register the treatment, mode of ventilation and mortality of patients with acute severe asthma treated with intermittent positive pressure ventilation (IPPV) in a Danish intensive care unit (ICU) during a ten year period. Fifty-seven patients underwent ventilation on 78 occasions. Fifty three patients were ventilated with controlled hypoventilation and low PEEP, while four patients were treated with high PEEP. One of the 53 patients receiving controlled hypoventilation and two of the four patients who received high PEEP developed a pneumothorax. All the patients were treated with intravenous steroid and infusion of a beta 2-agonist. Eighty-eight point three per cent received an infusion of theophylline whereas only 16.9% were treated with inhalation of a beta 2-agonist. Eight patients already had irreversible brain damage due to cardiac arrest before arrival to the ICU. Seven of these patients died due to brain damage. All the patients who reached the ICU without brain damage survived. After discharge from the hospital increased mortality was observed among these patients. Some of the patients died due to underestimation from doctors as well as patients of the severity of the asthma. Patients with acute severe asthma requiring IPPV should be ventilated with controlled hypoventilation. A high PEEP is associated with an increased risk of barotrauma. Continuing education of doctors and patients is necessary to increase the use of objective airflow measurement. PMID- 7839535 TI - [Causes of relapse during attempted smoking cessation using nicotine or placebo plasters]. AB - The causes of relapses to smoking when attempting smoking cessation are not fully understood, but several factors are of importance. Addiction to nicotine is one of the most prominent factors. In order to determine predictors of outcome in smoking cessation, we performed univariate and multivariate analysis of a large smoking cessation trial comprising 289 subjects. Weight gain and withdrawal symptoms were analyzed separately as predictors. To determine the relative magnitude of self-perceived reasons for relapse we created a questionnaire, which was answered by 132 relapsers. Previous attempts to stop smoking and a low Horn Russell scale were significantly associated with abstinence in the nicotine treated group. A trend towards higher abstinence rates was found in males and in subjects with low smoking saliva cotinine levels. A logistic regression analysis showed higher success rates in subjects with the largest weight gain during the first week but there was a tendency towards higher relapse rates in subjects with the greatest weight gain later. Only 20% reported weight gain to be a major problem. Minor smoking was highly correlated to later relapse. The weight gain after smoking cessation should not be prevented in the first weeks after cessation. Complete abstinence should be emphasized in smoking cessation. PMID- 7839536 TI - [Symptoms of irritable colon among the elderly]. AB - A sex stratified random sample of 70-year-old Danes living in Glostrup County was interviewed about abdominal symptoms in order to assess 1) the prevalence of colon-related symptoms and irritable bowel syndrome among the elderly and 2) to which extent different definitions of irritable bowel syndrome identify different subjects as having irritable bowel syndrome. Abdominal pain occurred with a prevalence of 17% among men and 28% among women (p < 0.01), distension with a prevalence of 29% and 40%, borborygms with a prevalence of 16% and 27%, and varying consistency of stool with a prevalence of 25% and 28%, for men and women respectively. The median number of bowel movements a week was seven for both sexes. Prevalence of irritable bowel syndrome was 3-18% among men and 6-32% among women according to various definitions. The subpopulations identified by various definitions of irritable bowel syndrome had less than 50% of the subjects in common. PMID- 7839537 TI - [Acute post-infectious Epstein-Barr encephalitis in a young man]. AB - The clinical features of infectious mononucleosis are variable. The course is often asymptomatic and/or atypical. Serious complications are rare. The prognosis is often good, even though there may have been serious neurological symptoms. However, as in the case history presented here, persistent sequelae may be seen. PMID- 7839538 TI - [Ovarian actinomycosis]. AB - A case of adnexal tumor caused by Actinomyces Israelii is reported. The patient was a 39 year-old woman admitted because of persistent fever and a palpable tumor in the right fossa. She had used an IUD for 11 years. Nine months before admission a hysterectomy had been performed due to uterine fibromyomas. PMID- 7839539 TI - [A good HIV-vaccine is not enough]. PMID- 7839540 TI - [Osteoporosis profile--maybe a not so insignificant examination]. PMID- 7839541 TI - [Clinical institutes at the University of Copenhagen. New development of empty gesture?]. PMID- 7839542 TI - [Salmonella dublin]. AB - Salmonella dublin's natural host is cattle; it may cause acute disease in calves, while adult animals may be asymptomatic carriers. In humans S. dublin is the most invasive of the zoonotic Salmonella-bacteria found in Denmark. It is much more frequently isolated from the blood than from the faeces and may give rise to serous metastatic infections in practically all organs. The number of registered human infections rose from zero to 46 per year during the period 1980-1988, but has now stabilized at a level of about 20 per year. Outbreaks have been described abroad as being caused by unpasteurised milk and cheese; in Denmark beef and cow's liver must be viewed as the dominant source of infection. The direct routes of infection are, however, unknown. Tightening of regulations for the slaughtering of animals from S. dublin infected herds, optimal hygiene in the slaughterhouses and increased cooperation between the veterinary and medical professions concerning investigation of routes of infection are necessary measures to be taken in order to reduce the number of human S. dublin infections. PMID- 7839543 TI - [Anogenital warts in children]. AB - The incidence of anogenital warts among children seems to be increasing, and the question of route of contagion is often controversial. It has earlier been emphasized that a frequent route of infection of genital human papillomavirus (HPV) is through sexual abuse of the child. However, reports published in recent years have made it more likely that one is often dealing with a non-sexually transmitted HPV infection localized to the anogenital skin and mucous membranes. This paper reviews possible routes of infection of HPV in children as well as suggestions for the investigation and treatment of the warts. PMID- 7839544 TI - [Patient satisfaction at a department of surgery and at one of internal medicine]. PMID- 7839545 TI - [Salmeterol improves control in asthmatic patients treated in general practice. A comparative study of salmeterol (Serevent) and salbutamol (Ventoline) in patients with mild to moderate asthma]. AB - This randomised, double-blind, double-dummy, cross-over study was conducted at 29 general practitioners' offices. Ninety-two patients with stable asthma were randomised to treatment with either Salmeterol 50 micrograms (b.i.d.) or Salbutamol 400 micrograms (q.i.d.). After four weeks treatment the patients continued another four weeks with the alternative treatment. During the study period the patients were allowed to use Salbutamol on a prn. basis. Inhaled steroids, if any, were continued. On diary cards patients recorded peak expiratory flow rate (PEFR) morning and evening before medication, asthma symptomscore, and use of additional doses of prn. beta 2-agonist. After the end of the last treatment period patients were asked which period they had preferred. Judged from all effect parameters, Salmeterol gave a better asthma control than Salbutamol. All improvements -except evening peak-flow and daily use of prn. salbutamol -were statistically significant. Most patients preferred Salmeterol treatment. Finally, the effect of Salmeterol was independent of any concurrent inhaled steroid treatment. PMID- 7839546 TI - [Acute lymphoblastic leukemia in children. A retrospective study: 1970-1991]. AB - From January 1970 through December 1991, 94 girls and 130 boys with a median age of 4.8 years were diagnosed with non-B cell acute lymphoblastic leukaemia (ALL) at the University Hospital, Rigshospitalet. Intensive risk-group adapted therapy based on age and white-cell count (WBC) at diagnosis, the presence of a mediastinal mass, central nervous system (CNS) or testicular leukaemia, T-cell disease, and certain cytogenetic translocations have been used since July 1981. Ninety-seven percent of all patients achieved complete remission (all patients diagnosed since July 1986). Ninety patients relapsed, all within five years from diagnosis: 59 in bone-marrow (BM), 20 in CNS (no BM-involvement), nine in testes (all isolated), one in the eye, and one in a lymph node. The five-year event-free survival increased from 0.20 to 0.72 from the first to the last five-year period (p < 0.0001). Age and WBC at diagnosis were of prognostic significance during the period 1970-1981, but not during the last 10-year period, when risk-adapted therapy was applied. Following a relapse, patients with an isolated testicular focus had the best five-year survival as compared to patients with CNS- and/or BM involvement (1.00 vs 0.19; p = 0.003). Patients relapsing following cessation of therapy had a better prognosis than did patients relapsing on therapy (five-year survival 0.58 vs 0.17; p = 0.002). Identification of new risk factors, more individualized therapy and monitoring of minimal residual disease is expected to have increasing influence on the management of children with ALL. PMID- 7839547 TI - [Attitude of Danish patients and physicians to information on cancer. A questionnaire study]. AB - This survey reports the attitude towards information of cancer patients as regards diagnosis and prognosis among gastroenterologists and patients (not suffering from cancer). The questions were based on a case history (a patient with colonic cancer). Most doctors informed their patients openly, and most patients expected that. Younger doctors in particular were more restrictive than patients as regards information of the spouse. PMID- 7839548 TI - [Attitudes to autopsy among critically ill patients and the general population]. AB - Attitudes towards autopsy were investigated by a questionnaire given to 60 cancer patients, 30 patients with severe cardiac disease and 132 healthy people without known disease. Eighty-five percent of the patients and 82% of the healthy people had a positive attitude towards autopsy. A majority (65-72%) found that permission should be given by the patient rather than the family. Only 6% of patients and 13% of the healthy people would refuse to give permission to autopsy, 71% and 47% would give permission and 10% and 25% would consent to autopsy under certain conditions. both groups were more reluctant to give consent to the performance of an autopsy on a relative. It is concluded that hospital routine should be changed so that patients should be asked whether they would permit an autopsy to be performed in event of their decease. PMID- 7839549 TI - [Traumatic hip dislocation with "spontaneous" reposition and re-luxation]. AB - A case of traumatic hip dislocation with spontaneous reduction of the hip joint is presented. The patient was involved in a car accident, and characterized as multitraumatized. On admission to the Emergency Department there were no clinical signs of traumatic hip-dislocation, but because of the severity of the trauma an X-ray of the pelvis was performed and a fracture of the acetabulum diagnosed. The patient was taken to the operating theatre for surgery of several fractures of both upper and lower extremities. This was followed by control X-rays including both anterior-posterior and lateral views of the right hip. This demonstrated that the right hip was now dislocated. The dislocation was reduced. CT showed a larger fracture of the acetabulum, and this was treated with osteosynthesis. Patients with an unstable hip due to trauma, should as a general rule have the hip X-rayed in two planes. It is further suggested that in cases of severely traumatized patients X-ray of the pelvis should be routinely performed. PMID- 7839550 TI - [Chronic volvulus of the stomach]. AB - Gastric volvulus is an abnormal rotation of the stomach. The incidence seems to be equal for men and women, and all ages are represented. Gastric volvulus may present as an emergency or as a chronic condition. Acute volvulus is potentially lethal if unrecognized, while a chronic volvulus may cause symptoms for years if not treated. Gastric volvulus may be more common than previously estimated. Approximately 700 cases have thus far been documented. Two case reports of chronic gastric volvulus are presented, of which one was treated by laparoscopic surgery. PMID- 7839551 TI - [Creativeness and psychopathology]. PMID- 7839552 TI - [Is nicotine therapy hazardous?]. PMID- 7839553 TI - [Statistics: asthma and budesonide]. PMID- 7839554 TI - [Smoking in pregnancy and testicular cancer]. PMID- 7839555 TI - Two-dimensional random arrays for real time volumetric imaging. AB - Two-dimensional arrays are necessary for a variety of ultrasonic imaging techniques, including elevation focusing, 2-D phase aberration correction, and real time volumetric imaging. In order to reduce system cost and complexity, sparse 2-D arrays have been considered with element geometries selected ad hoc, by algorithm, or by random process. Two random sparse array geometries and a sparse array with a Mills cross receive pattern were simulated and compared to a fully sampled aperture with the same overall dimensions. The sparse arrays were designed to the constraints of the Duke University real time volumetric imaging system, which employs a wide transmit beam and receive mode parallel processing to increase image frame rate. Depth-of-field comparisons were made from simulated on-axis and off-axis beamplots at ranges from 30 to 160 mm for both coaxial and offset transmit and receive beams. A random array with Gaussian distribution of transmitters and uniform distribution of receivers was found to have better resolution and depth-of-field than both a Mills cross array and a random array with uniform distribution of both transmit and receive elements. The Gaussian random array was constructed and experimental system response measurements were made at several ranges. Comparisons of B-scan images of a tissue mimicking phantom show improvement in resolution and depth-of-field consistent with simulation results. PMID- 7839556 TI - Efficient two-dimensional blocked element compensation. AB - Very large, two-dimensional, anisotropic arrays have been proposed to improve ultrasound image quality. Due to noncontiguous acoustic windows into the body, however, a significant portion of such an aperture may be blocked. Blocked elements result in high sidelobes in the point spread function, degrading image quality. To compensate for this, an object dependent method using multiple receive beams has been recently proposed. This method is effective in removing undesired sidelobes. However, previous results were for one-dimensional arrays where only lateral beams were used for estimation. With two-dimensional arrays, the distribution of blocked elements can change beam characteristics, both laterally and elevationally. In other words, receive beams must be formed in both directions for better performance. Although straightforward in principle, extension of the algorithm from one dimension to two increases computational complexity dramatically. Furthermore, the restricted elevational steering capability of anisotropic arrays also limits performance. In this paper, several computationally efficient algorithms for two-dimensional blocked element compensation are proposed and evaluated. It is shown that undesired sidelobes can be effectively removed using only a limited number of receive beams. Image quality can therefore be restored in the presence of blocked elements without significantly increasing hardware complexity. PMID- 7839557 TI - Elevational spatial compounding. AB - Spatial compounding has long been explored to reduce coherent speckle noise in medical ultrasound. By laterally translating a one-dimensional array, partially correlated measurements made at different look directions can be obtained and incoherently averaged. The lateral resolution, however, is limited by the sub array length used for each independent measurement. To reduce speckle contrast without compromising lateral resolution, a new spatial compounding technique using two-dimensional, anisotropic arrays is proposed. This technique obtains partially correlated measurements by steering the image plane elevationally with small inclinations. Incoherent averaging is then performed by adding image magnitudes. Therefore, contrast resolution is improved only at the price of a slightly wider elevational beam. Note that although anisotropic arrays have limited steering capability in elevation, grating lobes are not considered influential since only small inclinations are needed between measurements. Simulations have been performed to show both the change in spatial resolution and the improvement in contrast resolution. Results indicated minimal increase in the correlation length both laterally and axially. It was also shown that detectability can be significantly enhanced by increasing the number of measurements or increasing the differential inclination between measurements. This technique is therefore effective for reducing speckle noise while maintaining in-plane spatial resolution. Furthermore, it demonstrates a new application of two-dimensional anisotropic arrays in spite of their limited elevational steering capability. PMID- 7839558 TI - Estimation of in vivo pulses in medical ultrasound. AB - An algorithm for the estimation of one-dimensional in-vivo ultrasound pulses is derived. The routine estimates a set of ARMA parameters describing the pulse and uses data from a number of adjacent rf lines. Using multiple lines results in a decrease in variance on the estimated parameters and significantly reduces the risk of terminating the algorithm at a local minimum. Examples from use on synthetic data confirms the reduction in variance and increased chance of successful minimization termination. Simulations are also reported indicating the relation between the one-dimensional pulse and the three-dimensional, attenuated ultrasoud field for a concave transducer. Pulses are estimated from in-vivo liver data showing good resemblance to a pulse measured as the response from a planar reflector and then properly attenuated. The main application for the algorithm is to function as a preprocessing stage for deconvolution algorithms using parametric pulses. PMID- 7839560 TI - Effects of trypanosome and helminth infections on health and production parameters of village N'Dama cattle in The Gambia. AB - The effects of trypanosome and helminth infections on health and production parameters in 2000 village N'Dama cattle were assessed periodically. Blood examination showed Trypanosoma congolense and Trypanosoma vivax to be prevalent, while strongylid-type eggs were those most frequently encountered in faecal samples. A distinct seasonal fluctuation was detected for both blood levels of trypanosomes and helminth egg output. Strongylid burden and trypanosome infection had significant negative effects on packed red cell volume levels and body weights mainly in animals of 2-3 years old. Clear indications of an increased susceptibility to trypanosomosis were found in animals affected by helminths. Similarly, animals infected with trypanosomes were more frequently infested with strongyles and egg counts were higher than in cattle in which no trypanosomes were detected. PMID- 7839559 TI - A descriptive epidemiological study of coccidiosis in early lambing housed flocks. AB - Infection with Eimeria sp. was studied in 135 lambs born to 79 ewes in four early lambing housed flocks. In three of these flocks two different coccidiostats (monensin and decoquinate) were administered in the feed. Cohort lambs were examined clinically and a rectal faeces sample taken once a week. Samples with more than 300 oocyts per gram were speciated by morphology. Nine species were identified and Eimeria crandallis was the most prevalent. One of the flocks developed clinical coccidiosis before the introduction of coccidiostats. On the remaining farms no differences in the oocyst excretion rate of infected lambs were found between medicated and non-medicated lambs until Visit 6 nor in the proportion of lambs infected until Visit 8. It is suggested that cocciodiosis may be controlled without coccidiostats, by identification of the risk factors associated with disease. Morphological variation of species and collection of large enough faeces samples from young lambs constitute limiting components for further epidemiological studies of coccidiosis. PMID- 7839561 TI - Exploitation of parasite-derived antigen in therapeutic success against canine visceral leishmaniosis. Veterinary Group of Lupino. AB - In an attempt to obtain therapeutic success against canine visceral leishmaniosis, the potential of LiF2 antigen (Leishmania infantum-derived Fraction 2, 94-67 kDa), given alone or in combination with the chemotherapeutic agent N-methylglucamine antimonate, was compared with conventional chemotherapy with that drug. Absence of any parasite in direct microscopic examination of bone marrow aspirates in treated dogs was considered a parasitological cure, i.e. therapeutic success. Results showed that the disappearance of clinical symptoms did not always indicate parasitological healing in dogs. The parasitological healing rates with chemotherapy and immunotherapy alone were 37.5% and 25% respectively, in contrast to the 100% cure rate observed with chemotherapy combined with immunotherapy. The development of a protective response in dogs, as measured by the in vitro leishmanicidal activity of monocyte-derived macrophages in the presence of autologous lymphocytes, was found to correlate well with the success of therapy. The overall findings of this study give an important insight into the immunotherapeutic strategy by which therapeutic success can be achieved in canine visceral leishmaniosis. PMID- 7839562 TI - Effects of human recombinant interleukin-2 on resistance, and on the humoral and cellular response of rabbits infested with adult Ixodes ricinus ticks. AB - Rabbits were treated with subcutaneous injections of ten doses of 5 x 10(3) units of human recombinant interleukin-2 (IL-2) during a first infestation with five adult pairs Ixodes ricinus per rabbit, while untreated controls were infested by either five (direct control) or 25 pairs (resistant control) per rabbit. During the second infestation with 25 pairs per rabbit in each group, rabbits treated with IL-2 became more resistant than the rabbits in the two untreated control groups. Stronger resistance was manifested by lower engorgement and egg laying weights, and by smaller numbers of normally fed or ovipositioning ticks. IL-2 treatment had no significant effects on the rabbit anti-tick antibody production and the lymphocyte proliferation to a salivary gland extract (SGE). By contrast, the highest cutaneous responses to SGE were observed in the IL-2 treated group. IL-2 may increase rabbit cell-mediated immunity, and stimulate an increase in the production of memory cells during the induction phase of the immune response (first infestation), allowing the development of a strong resistance in lightly infested rabbits. PMID- 7839563 TI - Seasonal variation of ticks (Ixodidae) in Bos taurus x Bos indicus cattle under rotational grazing in forested and deforested habitats in northwestern Argentina. AB - The seasonal occurrence of ticks infesting cattle was monitored in a Bos taurus x Bos indicus commercial herd fed on a combination of native grasses and annual pastures in northwestern Argentina. The number of female ticks (Boophilus and Amblyomma) and the proportion of cattle infested with larvae and nymphs of Amblyomma ticks were recorded from a sample of 15 cows in 24 visits at intervals of 21-50 days from 5 December 1986 to 24 November 1988. The cattle were maintained on native grasses in forested habitats for 341 days, on native grasses in deforested habitats for 116 days and finally for 264 days on annual pastures. On 15 visits Boophilus microplus females were found, Amblyomma cajennense were detected on 11 counts, seven counts were positive for Amblyomma neumanni and two counts for Amblyomma parvum females. The peak of abundance of Boophilus microplus was found to be at the end of March 1987 with a mean of 36 females per side of cow. The peak numbers of A. cajennense (20 ticks), A. neumanni (12 ticks) and A. parvum (nine ticks) were found in December 1987, July 1987 and November 1988, respectively. The peak of Boophilus microplus was detected while cattle were on natural grasses in deforested habitats, peaks of other tick species were found when cattle were on natural grasses in forested habitats. The maximum cattle infestations with Amblyomma larvae (34% of cattle, May 1987) and nymphs (100%, August 1987) were detected while cattle were on natural grasses in forested habitats.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7839564 TI - Effect of chronic ingestion of tarbush (Flourensia cernua) on ewe lambs. AB - Efforts to increase livestock utilization of tarbush are being coupled with studies to examine tarbush toxicity. Thirty-eight (19/treatment) ewe lambs were assigned at birth to receive either tarbush or alfalfa (15%, dry matter basis) in a sorghum-based growing ration. Lambs were pen-fed this diet 60 d pre-weaning and 60 d post-weaning. No differences existed between treatments in feed consumption. In the tarbush group, 1 lamb died of unknown causes at 90 d of age, while 3 lambs died between 115 and 120 d of age. There were no deaths in the alfalfa group. Shortly before death, lambs fed tarbush appeared lethargic, disoriented and anorectic. At 122 d of age, 5 lambs were randomly selected from each group. Feces and jugular blood samples were obtained from each lamb before being euthanized and necropsied the following day. All fecal samples were negative for occult blood. Serum gamma glutamyl-transpeptidase (P < 0.001) and aspartate aminotransferase (P < 0.001) activities and platelet counts (P < 0.05) were elevated in lambs fed tarbush, while serum calcium concentrations tended (P < 0.10) to be greater. Histologic examination revealed diffuse liver apoptosis in lambs fed tarbush. These data indicate tarbush leaves cause liver damage when fed for extended periods of time. PMID- 7839565 TI - Periodicity of suicide attempts reported to a poison control center. AB - Suicide attempts make up a significant percentage of intentional overdoses and tend to utilize more poison control center (PCC) resources than any other type of call. In order to determine whether time imparts patterns on these suicide calls, we studied all suicide calls to our PCC over a 2-y period. Particular attention was given to the epidemiology and time of call. Suicide exposures (N = 4031) were extracted from PCC records from January 1988 through December 1989 with particular attention to time of day and age and sex of the patient. Data were computer analyzed using standard ANOVA, cosinor and non-linear regression techniques. Serial frequency and spectral analyses were performed using time series procedures. Significant circadian rhythms were noted for all age ranges with peak time (ie acrophase) for calling the PCC occurring in the early evening. However, individuals over the age of 50 y called earlier than younger aged groups. In addition, the 13 to 19-y age group exhibited a significant annual rhythm by peaking in suicide calls to the PCC on January 28 +/- 12.4 d. PMID- 7839566 TI - Effects of atropine in the beagle dog measured by quantitative electroencephalography and regional cortical analysis. AB - A treatment-by-subjects design was used to identify and characterize quantitative electroencephalography (qEEG) changes, at rest and under stimulus conditions, in Beagle dogs given 3 dose levels of atropine sulfate. In general, total power, absolute delta and theta amplitudes increased, while relative beta contribution and spectral frequency 90 decreased, as increased levels of atropine were administered. Regional analysis of this qEEG dataset suggests cortical mapping and contour plot imaging can be done in the dog. Through statistical analysis and visual evaluation of regional patterns may be more acceptable for interpretation in regulatory toxicology studies until normative databases are developed. PMID- 7839567 TI - Effect of iron status on endotoxin-induced mortality, phagocytosis and interleukin-1 alpha and tumor necrosis factor-alpha production. AB - The host susceptibility to endotoxin (lipopolysaccharide, LPS), production of interleukin-1 alpha (IL-1 alpha) and tumor necrosis factor-alpha (TNF-alpha) or phagocytosis in resident peritoneal macrophages were examined in iron-deficient and iron-loaded mice. Four groups of weanling male CD-1 mice were fed diet containing 7, 120, 5000 or 8000 ppm iron for 7 w. Body weight gain or hematocrit was not affected by iron consumption except for a lower weight gain in mice fed the 8000f1p4 iron diet. Iron-deficient and loaded diets produced a marked decrease and increase in liver iron concentration, respectively (P < 0.05). When challenged with an ip lethal dose of LPS, mortality was enhanced in iron deficient and loaded mice (P = 0.035). The production of TNF-alpha and IL-1 alpha was assessed in the peritoneal macrophages stimulated by LPS in vitro. The production of IL-1 alpha and TNF-alpha was not altered in macrophages from iron deficient mice. In contrast, macrophages from the 2 iron-loaded groups of mice produced more TNF-alpha (150% of control) without altering IL-1 alpha production. However, the total peritoneal leukocyte cell yield was not different among the treatment groups. Phagocytosis in the peritoneal macrophages determined by in vitro uptake of yeast cells was lower in the iron-deficient or loaded mice. This study indicates that iron deficiency and overload enhance LPS toxicity and impair phagocytosis, whereas excess iron also increases TNF-alpha production by macrophages. PMID- 7839568 TI - Evidence for the safety of coumaphos, diazinon and malathion residues in honey. AB - Residue levels of coumaphos, diazinon and malathion in honey were analysed in 177 samples of honey collected from different regions of Lugo in NW Spain in 1988 1990. One has to expect some of them as residues in honey, even if employed properly, for example coumaphos used against the parasitic mite Varroa jacobsoni. Honey samples were extracted with acetonitrile:water (2:1 v/v), partitioned with petroleum-ether, cleaned up with a manual Florisil column or Florisil Sep-Pack, evaporated to dryness, redissolved in an appropriate volume (1 mL) and then analyzed by GLC with a silica capillary column and nitrogen-phosphorus detector. Recoveries of coumaphos, diazinon and malathion varied between 80-97%. One hundred forty-eight samples contained no detectable residues, while 29 had residues of coumaphos and diazinon in ppb levels. These residues are minimal and when eating honey are harmless for the health of human beings. PMID- 7839569 TI - Acute 2,4-dichlorophenoxyacetic acid intoxication in cattle. AB - The acute toxicity of 2,4-dichlorophenoxyacetic acid (2,4-D) was studied in cattle. Steers were orally treated with 100, 300 or 600 mg 2,4-D/kg. Behavioral alterations, heart and respiratory functions, rectal temperature and ruminal movements were observed at 2, 4, 8, 12, 24, 48, 72 and 96 h after treatment. At these moments, blood and urine samples were collected and serum 2,4-D levels were determined. Results show that animals' vital function and hematocrit were not modified by the herbicide. Other signs were doses and time-dependent and included motor alterations (weakness, lethargy, decreased general activity) and decreased ruminal movements and proteinuria. The herbicide was rapidly excreted and the intoxication signs were completely reserved. 2,4-D is an herbicide of small toxicological consequences for cattle kept under in natural grazing systems. PMID- 7839570 TI - Ionophore antibiotic (narasin) poisoning in rabbits. AB - Outbreaks of narasin poisoning in rabbits from several commercial rabbit-raising farms in the state of Parana, Brazil, are reported. Approximately 5,000/35,000 rabbits died after having consumed a pelleted ration to which poultry ration premix had been added. Clinical signs included apathy, anorexia, muscle weakness, impaired walking, diarrhea, respiratory distress, and opistothonus. Gross findings were not remarkable, but varying degrees of degeneration, necrosis and regeneration of skeletal muscles were consistent histopathological features in affected rabbits. Myocardial changes were mild or absent. Thirty ppm of narasin were detected in the ration fed the rabbits. The disease was experimentally reproduced by feeding the suspected ration and by administering narasin po to rabbits. PMID- 7839571 TI - Crotalaria juncea intoxication in horses. AB - Twenty horses died 30 d after being fed a diet containing 40% of tritured Crotalaria juncea seeds. Before death, they had staggering, dyspnea and fever. At necropsy the most evident lesions were areas of lung parenchyma consolidation and enlarged and congested livers. Histopathological examination revealed diffuse fibrosing alveolitis with hyaline membranes, suggesting a blood-borne insult, and passive congestion in the liver with compression of the hepatocyte trabecules. To confirm the diagnosis, guinea pigs were given 60% of a commercial diet + 40% tritured C juncea seeds. After 4 mo of feeding the animals died with dyspnea. Their lungs had diffuse fibrosing alveolitis with discrete formation of hyaline membranes and the livers were congested. Reproduction of the lesions implicated the plant and supported the diagnosis of C juncea intoxication in the horses. PMID- 7839572 TI - Baclofen poisoning in children. AB - Six cases of acute baclofen (LIORESAL) overdose in children are reported. Rapid onset of central nervous system depression with respiratory depression was present to a greater or lesser degree in all patients. Agitation, convulsions and ataxia were also seen. The entire cohort responded to supportive management. An accurate assessment of the quantity of drug ingested was not possible. The need for education on safe drug storage and disposal is emphasized. PMID- 7839573 TI - Loperamide intoxication in a seven-week-old pup. AB - A 7-w-old Samoyed-cross pup was presented with central nervous system signs approximately 18 h following administration of the second of 2 doses of loperamide. Circling, vocalization, head pressing and unreactive pupils were present. There was no history of trauma. Improvement was seen shortly following administration of activated charcoal and 0.2 ml naloxone. Naloxone treatment was repeated at 2-h intervals over 12-h. Approximately 20 h following the initial clinical evaluation, the puppy was released to the owner for home care and observation. PMID- 7839574 TI - Aconitine poisoning due to Chinese herbal medicines: a review. AB - Both "chuanwu", the main root of Aconitum carmichaeli, and "caowu", the root of A kusnezoffii, are believed to possess anti-inflammatory, analgesic and cardiotonic effects and have been used in Chinese materia medica mainly for the treatment of musculoskeletal disorders. They contain the highly toxic C19 diterpenoid alkaloids of aconitine, mesaconitine and hypaconitine. After ingestion, patients may present with signs and symptoms that are typical of aconitine poisoning. Death may occur from ventricular arrhythmias, which are most likely to occur within the first 24 h. Management of aconitine poisoning is essentially supportive. There are no adequate studies in humans to indicate the most effective treatment of the ventricular arrhythmias. All clinicians should be alerted to the potential toxicity of "chuanwu" and "caowu". PMID- 7839575 TI - Cyanide poisoning in animals and humans: a review. AB - Cyanide (CN) is a deadly poison which animals and humans encounter from a number of sources. The following article briefly reviews many of the major studies of CN toxicology in animals and humans. The discussion focuses on sources, body levels, metabolic changes, physiopathology, experimental antidotal studies and the diagnosis and management of CN poisoning in humans. PMID- 7839576 TI - Evaluation of bovine perinatal nitrate accumulation in western Nebraska. AB - Nitrate-nitrite toxicosis causes numerous cattle deaths every year in western Nebraska. Its role in fetal abortions is complex and still speculative. This paper reports composite fetal nitrate diagnostic levels, fetal abattoir nitrate levels and observations of bovine perinates from cow-calf livestock units. PMID- 7839577 TI - Nursing attitudes towards charcoal administration--impact on patient care. AB - In 1990, the American Association of Poison Control Centers identified that for the first time activated charcoal (AC) use had surpassed that of syrup of ipecac. As nurses are given the primary responsibility for AC administration, it was important to determine how AC was being administered, as well as nursing attitudes towards AC that have an impact on patient care. Surveys were mailed to the Emergency Departments (EDs) of 60 hospitals served by the Pittsburgh Poison Center (PPC); 6 nurses/ED, 2 from each shift, were asked to respond. Forty-four EDs responded (73.3%) providing 237 surveys. Eighty-two percent of nurses stated they disliked administering AC for the following reasons: Patients did not like AC (64.4%); AC soiled clothing (54.7%); and AC took too long to give (35.5%). Prior to administration, 70.9% of the nurses responded that they shook the AC a minimum of 20 times; 9.3% commented that AC still failed to resuspend. Specific administration techniques included attempts to mask the appearance the the AC (67.1%) and attempts to increase AC's palatability by adding a flavoring agent (37.6%) or by using AC with sorbitol instead of aqueous AC (25.7%). Of note was that the flavoring agents used were those known to decrease AC's ability to adsorb toxins. As the majority of problems with AC involved its poor resuspendibility and palatability, an AC fact sheet was developed and mailed to EDs to provide suggestions on AC resuspension and means of enhancing patient acceptance without compromising AC's adsorptive capacity. By surveying nursing attitudes toward AC and the administration techniques being utilized, the PPC was able to identify specific problems and address nursing concerns in a way that positively impacts patient care. PMID- 7839578 TI - Secondary sex ratios in progenies of Iranian chemical victims. AB - I report the results of my study of the secondary sex ratio among progenies of Iranian chemical victims who survived the immediate hazards and lethal phase of chemical warfare exposure. Comparison of this ratio with the secondary sex ratio among the general population of Iran shows that these ratios are statistically significantly different. PMID- 7839579 TI - The use of ciprofloxacin in veterinary proprietary products of enrofloxacin. AB - A 3-mo chemical surveillance of 5 proprietary products of enrofloxacin for veterinary use was carried out. In all, 50 samples were analyzed by thin-layer chromatography and UV-Vis spectroscopy. Only the original brand of enrofloxacin (BAYTRIL) contained 5% of the drug while the 40 samples from the other 4 products contained 7.5% ciprofloxacin. A word of caution is given for the indiscriminate use of fluoroquinolones in veterinary medicine. PMID- 7839580 TI - The potential toxicity of preserved gallstones. PMID- 7839581 TI - Monoclonal antibody to a major outer membrane protein of feline Chlamydia psittaci: antibody specificity and anti-idiotype antibody production. AB - A murine monoclonal antibody, F1-8, was developed against the purified major outer membrane protein (MOMP) of Chlamydia psittaci feline pneumonitis (FPn). F1 8 showed a serotype-specific activity against intact Fpn elementary bodies in a micro-immunofluorescence assay. In immunoblot, F1-8 reacted only with the Fpn MOMP but did not react with the MOMPs from other strains of C. psittaci and C. trachomatis. F1-8 neutralized Fpn infectivity in L929 cell culture in a dose dependent and complement independent fashion. These results suggested that the monoclonal antibody (mAb) binds with an epitope on the MOMP region that is exposed at the cell surface and plays an important role in FPn infection. Polyclonal anti-idiotype (anti-Id) antibodies to mAb F1-8 were elicited by F1-8 coupled to keyhole limpet hemocyanin. These anti-Id antibodies inhibited F1-8 binding to FPn MOMP. PMID- 7839582 TI - Reproduction of bovine keratoconjunctivitis with a purified haemolytic and cytotoxic fraction of Moraxella bovis. AB - Evidence that the beta-haemolysin produced in vitro by Moraxella bovis is an important virulence determinant in vivo was strengthened by studies using a haemolytic preparation of greater purity than previously available. A concentrated haemolytic fraction containing outer-membrane bound vesicles was separated from the cell-free filtrate of a bacterial culture using a process comprising tangential flow ultrafiltration, ion-exchange and gel-filtration high performance liquid chromatography and centrifugal-driven filtration. The cytotoxicity of haemolytic fractions for calf-corneal epithelial cells in vitro was investigated at progressive stages of this attempted haemolysin purification procedure and the results demonstrated a positive correlation for the levels of haemolytic and cytotoxic activity throughout. Further support for the role of the haemolysin was obtained in vivo following the intra-corneal injection of calves with a crude or a purified haemolytic fraction. The ocular damage caused by both preparations, together with the healing processes and microscopic pathology of the experimentally induced damage closely resembled published descriptions of naturally occurring infectious bovine keratoconjunctivitis. No effect was obtained in vitro or in vivo from equivalent fractions prepared from a non haemolytic strain of M. bovis. PMID- 7839583 TI - Construction and vaccine potential of an aroA mutant of Pasteurella haemolytica. AB - The aroA gene, encoding 5-enolpyruvylshikimate 3-phosphate synthase, from Pasteurella haemolytica biotype A, serotype 1 was cloned by complementation of the aroA mutation in Escherichia coli strain AB2829 after electroporation with a DNA library constructed in pUC18. The cloned P. haemolytica aroA gene was inactivated by insertion of a kanamycin resistance gene and reintroduced by allelic exchange into the chromosome of the parental P. haemolytica using PbluescriptII SK+. The P. haemolytica aroA mutant was highly attenuated in a mouse septicaemic model. Mice immunized intraperitoneally with two doses of live P. haemolytica aroA mutant were protected against a lethal parental strain challenge. PMID- 7839584 TI - PCR detection of ovine herpesvirus-2 DNA in Indonesian ruminants--normal sheep and clinical cases of malignant catarrhal fever. AB - Malignant catarrhal fever (MCF), a fatal viral disease of cattle and other large ruminants, has a worldwide distribution. There are two forms of the disease, one of which, is caused by Alcelaphine herpesvirus-1 (AHV-1) and is derived from wildebeest. The other form is associated with domestic sheep and is caused by ovine herpesvirus-2 (OHV-2). The disease in Indonesia is sheep-associated with the preferred livestock of this area, Balinese cattle (Bos javanicus) and water buffalo (Bubalus bubalis), both highly susceptible to SA-MCF. The incidence in these species is thought to be high but the prevalence and economic losses attributable to SA-MCF have been difficult to assess. a polymerase chain reaction (PCR) test, based on a cloned OHV-2 gene sequence, was successfully applied to the detection of OHV-2 DNA in normal sheep and animals affected with SA-MCF. OHV 2 DNA was detected in eleven confirmed cases of SA-MCF and in the peripheral blood leucocyte (PBL) fraction of six latently infected sheep. These findings have confirmed that the PCR can be of value in establishing a diagnosis of MCF and that the aetiological agent of MCF in Indonesia is OHV-2. The amplification of DNA from the PBL of goats suggests that they are infected with a similar or identical herpesvirus. PMID- 7839585 TI - Rapid detection of bovine herpesvirus 1 (BHV 1) using the polymerase chain reaction. AB - A polymerase chain reaction (PCR) assay based on primers from the viral gI glycoprotein gene detected 3 fg pure BHV-1 DNA, 0.1-1.0 TCID50 or a single infected cell. No amplification was observed with DNA from BHV-2, BHV-3, BHV-4, OHV-1 or OHV-2. However, a fragment of the correct size was amplified using DNA from herpesviruses isolated from reindeer, red deer and goats. The PCR assay was able to detect virus in nasal swabs up to 14 days after experimental infection of cattle and there was a good correlation when PCR was compared with virus isolation for the detection of BHV-1 in clinical field samples. Detection of BHV 1 in fetal bovine serum and semen samples was also successful. PMID- 7839586 TI - Detection of feline coronaviruses in cell cultures and in fresh and fixed feline tissues using polymerase chain reaction. AB - Feline coronavirus infections in cell cultures and in fresh and fixed feline tissues were detected using a polymerase chain reaction (PCR) test. Cell cultures were inoculated with feline infectious peritonitis virus (FIPV), feline enteric coronavirus (FECV) or sham inoculum. The tissue samples of liver, kidney and spleen were taken from specific-pathogen-free (SPF) cats that were inoculated intranasally with 10(3) TCID50 of FIPV 79-1146 (n = 10), FIPV UCD1 (n = 3) or sham inoculum (n = 3), from clinical cats (n = 43), and from formalin-fixed archived feline tissues (n = 49), respectively. Additional tissue samples were taken from the FIPV-inoculated cats (n = 6) and were kept at 4 degrees C, room temperatures (20-24 degrees C) and 37 degrees C respectively for 0, 6, 12, 24, 48, 72, and 96 hours before frozen (-70 degrees C) for PCR to evaluate the effects of the ambient temperatures and post-mortem intervals on the test. The samples were also fixed in 10% neutrally buffered formalin, 95% ethanol, and Bouin's solution respectively to evaluate the effects of the fixatives on the test. Positive PCR results were obtained from the cell cultures that were inoculated with FIPV and FECV and from the FIPV-inoculated cats (13/13). Negative PCR results were obtained from the sham-inoculated cell cultures and cats (3/3). Of the 92 clinical cats, 7 of the 8 FIP-suspected cats (87.5%) and 51 of the 84 non-FIP-suspected cats (60.7%) were shown to be virus-positive in at least one of the tissue samples. There was no significant difference in the PCR results between the fresh and the formalin-fixed tissues of the clinical cats (P > 0.05). Of the FIPV inoculated cats, the virus was detectable equally well in fresh and formalin-, Bouin's solution- or ethanol-fixed tissues. However, the amounts of total RNA extracted from the fixed tissues were significantly less than those from fresh tissues (P < 0.01). In tissues that were kept at 4 degrees C, the virus was detectable up to 96 h; at room temperatures, up to 48 h; and at 37 degrees C, up to 24 h, respectively. PMID- 7839587 TI - A modified liquid phase (LP) blocking ELISA used to assess type O foot-and-mouth disease virus antigenic variation in Thailand. AB - A selection of type O foot-and-mouth disease (FMD) viruses isolated in Thailand between 1986 and 1989 were compared to the reference viruses O1 Thailand 1960 (O BKK/60) and O Nakorn Pathom 1965 (O NPT/65) using a liquid-phase blocking ELISA (LP ELISA) to derive serum titres and associated r values. Interpolation techniques were used to increase the precision for estimation of r values through a more accurate estimation of serum titres at predicted equivalent levels of antigen input. Mean r values were 0.45 (for 56 field viruses) relative to O BKK/60 reference virus and 0.56 (for 51 field viruses) relative to O NPT/65. While only two viruses showed considerable difference (r < 0.20) to a reference virus (O BKK/60), 41% and 31% gave r values less than 0.4 for O BKK/60 and O NPT/65 respectively. This indicated antigenic differences between reference and field viruses which may result in a reduction in vaccine efficacy. PMID- 7839588 TI - Biomechanical evaluation of a toggle pin technique for management of coxofemoral luxation. AB - Toggle pin stabilization is an accepted technique for the management of coxofemoral (CF) luxation in dogs. The purpose of this study was to determine, in vitro, the respective contributions of several aspects of toggle pin repair to the overall stability of fixation. Factors evaluated were the manner and frequency with which toggle pins oriented on insertion, effect of orientation on toggle pin strength, effect of suture type on ligament prosthesis strength and load sustained by the fixation, and comparison of repair using a modified toggle design to that of capsulorrhaphy. When placed in cadavers using standard technique, conventional toggle pins were found to orient significantly more frequently in one of two possible positions. Mechanical testing of fixations performed in experimentally luxated cadaver hips demonstrated a high (12/20) incidence of toggle pin failure using the conventional implant in the most common orientation. When tested alone, toggle pins were weakest mechanically in this orientation. Rotating the implant 180 degrees increased mean load to failure by 249%. There was no significant difference in load sustained by conventional toggle fixations using No. 2 braided polyester versus 50 lb test monofilament nylon as the suture ligament prosthesis. However, the higher stiffness of the polyester suture may be more favorable for use in this application. Fixation using a toggle rod designed to allow evaluation of construct stability when failure of the toggle is eliminated resulted in an increase in maximum load sustained before luxation (47% of the intact control hips). This load was not significantly different than the resistance to luxation afforded by capsulorrhaphy. This study suggests that when implanting conventional toggle pins, consideration should be given to ensuring placement in the strongest orientation. PMID- 7839589 TI - Biomechanical study of canine spinal fracture fixation using pins or bone screws with polymethylmethacrylate. AB - Five configurations of pins or screws interconnected with polymethylmethacrylate (PMMA) were applied to isolated canine lumbar spines (L2 to L5) in which a complete fracture-luxation had been produced at L3 to L4. Twenty-five repaired spines and five intact control spines were subjected to four-point bending and tested once to failure in ventral flexion. The purpose of this study was to determine the effects of pin number, pin angle, and use of 3.5-mm cortical bone screws instead of smooth 3.2-mm diameter pins on rigidity and ultimate strength of spinal fractures repaired by the implant-PMMA fixation technique. Bending moment versus the angular deformation curves were recorded. Rigidity, bending moment at 10 degrees angular deformation, moment at failure, and deformation at failure of each type of fixation were compared using analysis of variance. Spinal segments stabilized with eight pin-PMMA fixation had significantly greater rigidity and strength at failure than four pin-PMMA fixations (P < .05). Furthermore, spinal segments stabilized with eight pins angled away from the fracture failed at significantly greater bending moment than those with eight pins angled toward the fracture (P < .05). However, for four-pin fixation, greater strength was achieved by angling pins in the bone toward the fracture site (P < .05). Screw-PMMA fixations failed by screw bending and were less rigid and weaker at failure than the corresponding configuration of pin-PMMA fixation (P < .05). PMID- 7839590 TI - The immediate effect of colposuspension on resting and stressed urethral pressure profiles in anaesthetized incontinent bitches. AB - The aim of this study was to document what changes in the resting and stressed urethral pressure profile occur in the incontinent bitch with urethral sphincter mechanism incompetence (SMI) immediately after colposuspension. Resting and stressed subtracted simultaneous urethral pressure profilometry was performed immediately pre- and postcolposuspension in 26 bitches diagnosed with SMI. All of the urethral pressure profiles were measured in anaesthetized bitches using a standard technique and two orientations of the catheter transducers (dorsal and left). Readable pre- and postoperative urethral pressure profiles were obtained in 20 of the 26 bitches. Subjective and objective evaluation of the profiles showed significant differences in the profiles pre- and postcolposuspension. Immediately postoperatively there were significant (P < .05) increases in functional profile length, maximum urethral closure pressure (MUCP), and distance between the bladder neck and the first negative respiratory peak and stressed spike. There was a significant (P < .001) decrease in the percentage of negative spikes extending below the resting intravesical pressure on the subtracted profile. The pressure transmission profiles were significantly (P < .001) altered by surgery. The findings presented support the hypothesis that colposuspension may restore continence by increasing pressure transmission to the proximal urethra and bladder neck. The results also suggest that immediately after surgery functional urethral length and urethral resistance are increased. PMID- 7839591 TI - Combined resection of the nasal planum and premaxilla in three dogs. AB - Surgical techniques for removal of tumors that affect the nasal planum or the premaxilla have been described. For extensively invasive malignancies, these techniques may be inadequate if used alone to achieve wide surgical margins. An operative technique that combines resection of the nasal planum and premaxilla has been developed for extensive malignant tumors of the nasal planum or premaxilla. This technique was used in three dogs and resulted in an acceptable cosmetic appearance and good function and tumor control. Complications after surgery included minor bleeding and partial dehiscence of the suture lines in two dogs and stenosis of the nasal orifice in one dog. PMID- 7839592 TI - Renal allograft survival in outbred mongrel dogs using rabbit anti-dog thymocyte serum in combination with immunosuppressive drug therapy with or without donor bone marrow. AB - Therapeutic renal transplantation in dogs is currently being investigated as a treatment for endstage renal disease. This pilot study examines the effect of donor bone marrow (DBM) infusion and antithymocyte serum (ATS) in combination with immunosuppressive drug therapy in prolonging renal allograft survival in dogs. Seven normal outbred mongrel dogs received an unmatched renal allograft. All dogs received rabbit anti-dog thymocyte serum (RADTS), prednisone (Pr), cyclosporine-A (CsA) and azathioprine (Aza). In addition, three dogs (group 1 test) received DBM and four dogs (group 2 control) did not receive DBM. Serum CsA levels were measured throughout the study. Immunosuppressive therapy was gradually reduced with Pr, CsA, and Aza withdrawn at 200, 450, and 680 days, respectively. Allograft rejection was treated with prednisolone sodium succinate. One dog in group 1 and one in group 2 died as a result of infectious canine rhinotracheitis and rejection early in the study. Renal allograft torsion occurred in one group 1 dog. The remaining four dogs survived the 2 years of the study. The dogs in group 2 (three dogs) all rejected the renal allograft after total drug withdrawal, the surviving dog in group 1 did not. This study demonstrates that RADTS, Pr, CsA, and Aza in combination can prolong renal allograft survival in mongrel dogs, whereas DBM may enhance the unresponsive state. PMID- 7839593 TI - Evaluation of canine-derived fibrin sealant as a hemostatic agent. AB - The purpose of this study was to determine whether canine-derived fibrinogen concentrate applied with bovine thrombin was a safe and effective topical hemostatic agent. A canine liver biopsy model was selected to test this product. Cryoprecipitate was prepared from frozen canine plasma using two freeze/thaw/centrifugation cycles. Six healthy adult dogs (weighing more than 18 kg) were used in the fibrin sealant study, and an additional three dogs were used as controls for the liver biopsy. A 1 x 3 cm liver biopsy specimen was obtained, digital pressure was applied to reduce bleeding, and the fibrinogen concentrate was immediately sprayed on the bleeding surface simultaneously with bovine thrombin (1,000 IU/mL). The mean +/- standard error of the mean (SEM) blood pressure at time of biopsy was 98 +/- 9 mm Hg, and the rate of hemorrhage from the cut liver edge was 8.0 +/- 1.1 mL/min. The total blood loss during fibrin sealant application was 37 +/- 9 mL and total time for hemostasis was 5.5 +/- 1.3 minutes. There was no additional hemorrhage after application of the fibrin sealant. In the three control dogs, fibrin sealant was not applied and only digital compression was used to decrease hemorrhage. Before digital compression, the rate of hemorrhage from the cut liver edge was 13.1 +/- 3.1 mL/min. Bleeding had not stopped after 10 minutes of compression and the mean postcompression rate of hemorrhage was 4.0 +/- 2.6 mL/min. Signs of secondary bleeding after fibrin sealant was applied were not evident during the immediate postoperative period or over the next 14 days.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7839594 TI - Nonlymphomatous hepatobiliary masses in cats: 41 cases (1972 to 1991). AB - The medical and necropsy records of 41 cats diagnosed with nonlymphomatous hepatobiliary (NLHB) masses, including neoplasia and cysts, were reviewed. Overall, benign masses (n = 27) were more common than malignant ones (n = 14). The single most common malignancy was cholangiocellular carcinoma. The median age at diagnosis was significantly lower (P < .01) for cats with malignant rather than benign disease. Clinical signs associated with hepatobiliary neoplasia were usually vague and included lethargy, vomiting, and anorexia, often present for at least 2 weeks before presentation. Benign masses were an incidental finding in significantly more (P < .01) of the cases than were malignant masses. Median values for alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin were significantly higher (P < .05) in cats with malignant versus benign masses. The prognosis for malignant disease was poor, with 86% of the cats dying or being euthanatized during hospitalization. Cats with benign disease that underwent exploratory celiotomy were more likely to recover and warranted a more favorable prognosis than cats with malignant tumors. Factors associated with malignancy included age at presentation, presence of clinical signs at presentation, and specific serum chemistry changes. PMID- 7839595 TI - Effect of betamethasone and exercise on equine carpal joints with osteochondral fragments. AB - Osteochondral fragments were created arthroscopically on the distal aspect of both radial carpal bones in 12 horses. On day 14 after surgery, one middle carpal joint of each horse was injected with 2.5 mL Betavet Soluspan (3.9 mg betamethasone sodium phosphate and 12 mg betamethasone acetate per milliliter) and the contralateral joint was injected with 2.5 mL saline as a control. Intra articular treatments were repeated on day 35. On day 17, six horses began exercising 5 days per week on a high-speed treadmill. The other six horses were kept in box stalls throughout the study as nonexercised controls. On day 56, all horses were examined clinically and radiographically and then were euthanatized. Samples were obtained for histological, histochemical, and biochemical evaluation. Mild lameness was observed in five of the six exercised horses at day 56; four horses were lame in the control limb and one horse was lame in the treated limb. Of the five nonexercised horses evaluated for lameness, two were lame in the control limb, two were lame in the treated limb, and one was lame in both the control and the treated limb. No differences were noted on radiographs or palpation of steroid treated limbs versus control limbs. Firm reattachment of the osteochondral fragment to the radial carpal bone occurred in all but three joints. Gross cartilage damage was not different between steroid-treated joints and joints injected with saline. Histologically, there were no significant detrimental effects of beta-methasone with or without exercise, but there was a tendency for more pathological change in treated joints. No significant difference in the water content or uronic acid concentration was detected between treated and control joints. Intra-articular betamethasone administration in this carpal chip model was not associated with any significant detrimental effects in either rested or exercised horses. PMID- 7839596 TI - Diagnostic and operative arthroscopy of the coxofemoral joint in horses. AB - Arthroscopic examination of the hip joint was performed in mature and juvenile horses, using a lateral approach and standard or long instruments depending on body weight. Nine hip joints were examined in three cadavers and four anesthetized horses. The lateral, cranial, and caudal regions of the femoral head and acetabulum were accessible, and, after distraction of the limb, the ligament of the head of the femur and the acetabular notch were also visible. In small horses, the medial regions of the hip joint were visible but were inaccessible in larger horses. Iatrogenic injury to the sciatic nerve or periarticular vasculature was not evident at necropsy examination. Six horses with lameness localized to the hip joint were examined arthroscopically. At surgery, two horses had tearing of the ligament of the head of the femur, two horses had osteochondrosis of the femoral head or acetabulum, and two horses had degenerative joint disease, one associated with a rim fracture of the caudal aspect of the acetabulum and the other of indeterminant origin. Improvement after debridement occurred in one of the horses with partial disruption of the ligament of the head of the femur and in both horses with osteochondrosis. Diagnostic and surgical arthroscopy of the hip can be accomplished in foals and weanlings using standard equipment, but, in adults weighing more than 300 kg, longer instruments are required and the ease of access and the visible extent of the hip joint is considerably reduced. PMID- 7839597 TI - Equine demineralized bone matrix: relationship between particle size and osteoinduction. AB - The osteoinductive capability of four particle sizes of equine demineralized bone matrix (DBM) was evaluated. Matrix particles were implanted in brachiocephalicus muscle pouches in six horses and were harvested 8 weeks later. Matrix particle sizes of 2.0 mm3 to 4.0 mm3 and 5.0 mm3 to 10.0 mm3 were associated with osteoinductive activity and minimal signs of local inflammation. The two smaller particle sizes (0.425 mm3 to 0.850 mm3 and 0.850 mm3 to 2.0 mm3) were minimally osteoinductive and were associated with a greater local inflammatory response. Microscopic events associated with new bone production in the two largest particle sizes included the presence of new osteoprogenitor cells in matrix vascular spaces, multinucleated osteoclast-like giant cells, and the formation of cartilage, osteoid, and new mineralized bone. The two smaller particle sizes were associated with increased fibrous tissue ingrowth and the presence of increased numbers of inflammatory cells. The temporal events of osteoinduction in response to heterotopic implantation of allogeneic DBM were delayed in horses when compared with other species. Although the demineralization technique used was effective in previous investigations on other species, incomplete demineralization occurred in the two smaller particle sizes that was not detected until after DBM implant harvest. The demineralization process may need to be altered for equine bone and precise monitoring for complete demineralization before implantation is required. Equine DBM is osteoinductive in muscle pouch sites in horses but matrix particle size does affect osteoinductive capability. PMID- 7839598 TI - Determination of the ED50 of isoflurane and evaluation of the isoflurane-sparing effect of butorphanol in cockatoos (Cacatua spp.). AB - The use of butorphanol as an analgesic in a psittacine species was evaluated by determining its isoflurane-sparing effects. The Effective Dose 50 (ED50) of isoflurane was determined using a bracketing technique based on the purposeful movement elicited by pressure applied to a digit with a hemostat. The ED50 of isoflurane for 11 cockatoos (four greater sulfur crested, three lesser sulfur crested, and four citron crested) was determined to be 1.44 +/- 0.07%. After the administration of 1 mg/kg of butorphanol tartrate intramuscularly (IM), the ED50 was significantly (P < .05) decreased to 1.08 +/- 0.05%. Physiological variables that changed significantly included decreases in heart rate, tidal volume (Vt), inspiratory (Ti) and expiratory times (Te), and an increase in respiratory rate. No complications resulted because of these changes. Based on the results, butorphanol produces an isoflurane-sparing effect in cockatoos and has the potential to be a useful analgesic in psittacines. PMID- 7839599 TI - Interocular transfer of receptive field expansion in cat visual cortex. AB - Receptive fields in primary visual cortex have been shown to be capable of rapid expansion and contraction when exposed to an artificial scotoma, a masked segment of the visual field. To distinguish cortical from thalamic contributions to receptive field mutability, we tested interocular transfer of the effect in binocular cortical receptive fields, presenting the conditioning stimulus to the field in one eye and measuring size changes in the receptive field of the other eye. The expansion of the receptive fields in the non-conditioned eye was comparable to that in the conditioned eye. This result suggests that the expansion is due to mechanisms intrinsic to the cortex. PMID- 7839600 TI - The contributions of ON- and OFF-pathways to contrast sensitivity and spatial resolution in goldfish. AB - DL-2-amino-4-phosphonobutyric acid (APB) reduces the sensitivity of ON- and OFF responses in goldfish retina, although the ON-responses are reduced significantly more than the OFF-responses. This paper describes the effects of APB on behavioral sensitivity of goldfish to spatial sinusoidal gratings. Fish were classically conditioned to suppress respiration upon presentation of gratings drifting at 1 Hz; contrast thresholds were measured by an observer-based two alternative forced-choice procedure. Thresholds were repeated following intraocular injections of APB or physiological saline. Saline had no effect, but APB dramatically reduced contrast sensitivity and shifted contrast sensitivity functions to lower spatial frequencies. The results suggest that both ON- and OFF pathways are necessary for normal spatial vision and that the effects of APB are consistent with the disruption of both ON- and OFF-pathways. PMID- 7839601 TI - Ocular motor abnormalities in achiasmatic mutant Belgian sheepdogs: unyoked eye movements in a mammal. AB - We studied the eye movements of several members of a family of Belgian sheepdogs that includes achiasmatic mutants. Our aim was to identify the types of nystagmus and other ocular motor abnormalities exhibited by the mutants. We also recorded from several unaffected heterozygous carriers of the genetic mutation and from a normal Irish Setter. Mutant dogs exhibited nystagmus waveforms that were occasionally similar to those of humans with congenital nystagmus (CN). Foveating and braking saccades and foveation periods were seen in some waveforms. More common were pendular oscillations of both eyes that were essentially independent in amplitude and phase. At some times there was a pendular nystagmus with a 180 deg phase shift between the movements of unaffected relatives did not reveal any saccadic instabilities. However, small saccadic intrusions could have been masked by quantization artifacts. Individual dogs from this family provide an animal model of the ocular motor consequences of the disturbed visual input caused by the absence of an optic chiasm and a novel model of CN. Despite any other ocular motor abnormalities present, the CN may be studied in isolation just as in humans it is studied when strabismus and other types of nystagmus are present. Further studies of ocular motor development and function in achiasmatic dogs have the potential to reveal both the organization of the control systems for each extraocular muscle and the role of yoking of the agonist muscles of the two eyes. PMID- 7839602 TI - Recovering three-dimensional structure from motion with surface reconstruction. AB - This paper addresses the computational role that the construction of a complete surface representation may play in the recovery of 3-D structure from motion. We first discuss the need to integrate surface reconstruction with the structure from-motion process, both on computational and perceptual grounds. We then present a model that combines a feature-based structure-from-motion algorithm with a smooth surface interpolation mechanism. This model allows multiple surfaces to be represented in a given viewing direction, incorporates constraints on surface structure from object boundaries, and segregates image features onto multiple surfaces on the basis of their 2-D image motion. We present the results of computer simulations that relate the qualitative behavior of this model to psychophysical observations. In a companion paper, we discuss further perceptual observations regarding the possible role of surface reconstruction in the human recovery of 3-D structure from motion. PMID- 7839603 TI - Structure-from-motion: perceptual evidence for surface interpolation. AB - Dynamic random-dot displays representing a rotating cylinder were used to investigate surface interpolation in the perception of structure-from-motion (SFM) in humans. Surface interpolation refers to a process in which a complete surface in depth is reconstructed from the object depth values extracted at the stimulus features. Surface interpolation will assign depth values even in parts of the object that contain no features. Such a "fill-in" process should make the detection of featureless stimulus areas ("holes") difficult. Indeed, we demonstrate that such holes in our rotating cylinder can be as wide as one quarter of the stimulus before subjects can reliably detect their presence. Subjects were presented with a variation on the rotating cylinder in which all dots were oscillating either in synchrony or asynchronously. Subjects perceive a rigidly rotating cylinder even when such a percept is not in agreement with the physical stimulus. To reconcile this discrepancy between actual and perceived stimulus we propose that individual points contribute to a surface based object representation and that in this process the visual system looses access to the identity of the individual features that make up the surface. Finally we are able to explain a variety of previously documented perceptual peculiarities in the perception of structure-from-motion by arguing that the perceptual interpretation of the object's boundaries influences the surface interpolation process. These findings offer strong perceptual evidence for a process of surface interpolation and are also physiologically plausible given results from recordings in awake behaving monkey cortical areas V1 and MT. The companion paper demonstrates how such a surface interpolation process can be incorporated into a structure-from motion algorithm and how object boundaries can influence the perception of structure-from-motion as has been demonstrated before and in this paper. PMID- 7839604 TI - Computational studies on the interaction between red cone and H1 horizontal cell. AB - We propose an equivalent circuit model of a discrete formulation to describe the interaction between the red cone syncytium and the H1 horizontal cell syncytium in lower vertebrate retinas. Analytical solutions of the model provide intuitive understandings of spatio-temporal properties of light-induced responses in reference to membrane impedance, strength of chemical synapse and coupling resistance connecting neighbouring cells. Physiologically plausible values of these parameters are estimated using the solutions. Quantitative studies are made to elucidate the function of (1) the negative feedback from the H1 horizontal cell to the red cone, and (2) the resistance increase of H1 horizontal cell coupling by dopamine. PMID- 7839605 TI - Object perception by visually impaired people at different light levels. AB - We investigated the relationship between the illumination level and the ability of visually impaired subjects to detect and recognize objects in a realistic visual environment. Subjects often continued to show substantial improvement at light levels where normal subjects have reached maximum performance. Integrated contrast sensitivity, a summary measure for the contrast sensitivity function, was better at predicting performance than either visual acuity or peak contrast sensitivity. However, when combined, the latter two predicted performance as well as the former. We conclude that when we try to find the best illumination for orientation and day-to-day activities we should optimize it for both visual acuity and contrast sensitivity. PMID- 7839606 TI - Light scattering in donor lenses. AB - Light scattering for normal and cataractous lenses from 21-86 yr old donors was measured in vitro. As expected, scattering increased with severity of cataract. Scattering decreased with angle according to a power law. This corresponded to the power law finding for functional straylight measurements in early-cataract patients using white light (power around -2). In vitro, straylight increased monotonically from 700 nm (power around -2.3) towards 400 nm (power around -2.0). For extreme cataracts the angular dependence flattened at small angles. The present results suggest that the structures dominating in light scattering differ not by scattering type but by number, and that they are not very small compared to wavelength. The present results were used to specify the separate effects of light absorption and light scattering on lenticular light transmission. PMID- 7839607 TI - Cholinergic modulation of synaptic transmission in the rat visual cortex in vitro. AB - Cholinergic synaptic modulation in the rat visual cortex was studied using intracellular recordings from slice preparations. A cholinergic agonist, carbachol (CCh), reduced fast excitatory as well as fast and slow inhibitory postsynaptic potentials evoked by white matter stimulation. This effect was antagonized by atropine. CCh perfusion did not reduce glutamate- or gamma aminobutyric acid-induced depolarizations, suggesting the presynaptic mechanism of the suppression. CCh augmented firing over a long period after transsynaptic stimulation combined with a long depolarizing current pulse, not only due to a decrease in firing accommodation but also due to disinhibition. CCh also induced a large sustained depolarization and bursting of action potentials triggered by tetanic stimulation. These results suggest that cholinergic modulation results in a prolonged increase in neuronal excitability during the late phase of synaptic transmissions at least partly by the mechanism of decreasing inhibitory transmissions, particularly when the synaptic inputs are strongly activated. PMID- 7839608 TI - Moving the retina: choroidal modulation of refractive state. AB - The chick eye is able to change its refractive state by as much as 7 D by pushing the retina forward or pulling it back; this is effected by changes in the thickness of the choroid, the vascular tissue behind the retina and pigment epithelium. Chick eyes first made myopic by wearing diffusers and then permitted unrestricted vision developed choroids several times thicker than normal within days, thereby speeding recovery from deprivation myopia. Choroidal expansion does not occur when visual cues are reduced by dim illumination during the period of unrestricted vision. Furthermore, in chick eyes presented with myopic or hyperopic defocus by means of spectacle lenses, the choroid expands or thins, respectively, in compensation for the specific defocus imposed. Consequently, when the lenses are removed, the eye finds its refractive error suddenly of opposite sign, and the choroidal thickness again compensates by changing in the opposite direction. If a local region of the eye is made myopic by a partial diffuser and then given unrestricted vision, the choroid expands only in the myopic region. Although the mechanism of choroidal expansion is unknown, it might involve either a increased routing of aqueous humor into the uveoscleral outflow or osmotically generated water movement into the choroid. The latter is compatible with the increased choroidal proteoglycan synthesis either when eyes wear positive lenses or after diffuser removal. PMID- 7839609 TI - The detection and discrimination of spatial offsets. AB - By detection of spatial offsets is meant the ability to indicate whether or not a given (vernier) stimulus has a spatial offset. Discrimination, on the other hand, implies that the direction of offset has been correctly identified. We compared vernier thresholds for these two tasks and found a consistent difference by a factor of around 2 in favour of discrimination. This is to say that observers are able to correctly indicate the direction of offsets that are too small to be reliably detected by the same observers. This apparent paradox can be explained on the assumptions that one single, bipolar mechanism is involved in both tasks, and that observers use a direction selective cue such as the orientation difference of the implicit lines through the vernier stimuli. The implications for estimates of the sensitivity of hyperacuity are discussed. PMID- 7839610 TI - 1st- and 2nd-order motion and texture resolution in central and peripheral vision. AB - STIMULI. The 1st-order stimuli are moving sine gratings. The 2nd-order stimuli are fields of static visual texture, whose contrasts are modulated by moving sine gratings. Neither the spatial slant (orientation) nor the direction of motion of these 2nd-order (microbalanced) stimuli can be detected by a Fourier analysis; they are invisible to Reichardt and motion-energy detectors. METHOD. For these dynamic stimuli, when presented both centrally and in an annular window extending from 8 to 10 deg in eccentricity, we measured the highest spatial frequency for which discrimination between +/- 45 deg texture slants and discrimination between opposite directions of motion were each possible. RESULTS. For sufficiently low spatial frequencies, slant and direction can be discriminated in both central and peripheral vision, for both 1st- and for 2nd-order stimuli. For both 1st- and 2nd order stimuli, at both retinal locations, slant discrimination is possible at higher spatial frequencies than direction discrimination. For both 1st- and 2nd order stimuli, motion resolution decreases 2-3 times more rapidly with eccentricity than does texture resolution. CONCLUSIONS. (1) 1st- and 2nd-order motion scale similarly with eccentricity. (2) 1st- and 2nd-order texture scale similarly with eccentricity. (3) The central/peripheral resolution fall-off is 2 3 times greater for motion than for texture. PMID- 7839611 TI - Detecting a trajectory embedded in random-direction motion noise. AB - Human observers can easily detect a signal dot moving, in apparent motion, on a trajectory embedded in a background of random-direction motion noise. A high detection rate is possible even though the spatial and temporal characteristics (step size and frame rate) of the signal are identical to the noise, making the signal indistinguishable from the noise on the basis of a single pair of frames. The success rate for detecting the signal dot was as high as 90% when the probability of mismatch from frame-to-frame, based on nearest-neighbor matching, was 0.3. Control experiments showed that trajectory detection is not based on detecting a "string" of collinear dots, i.e. a stationary position cue. Nor is a trajectory detected because it produces stronger signals in single independent motion detectors. For one thing, trajectory detection improves with increases in duration, up to 250-400 msec, a duration longer than the integration typically associated with a single motion detector. For another, the signal dot need not travel in a straight line to be detectable. The signal dot was as reliably detected when it changed its direction a small amount (about 30 deg or less) each frame. Consistent with this, circular paths of sufficiently low curvature were as detectable as straight trajectories. Our data suggest that trajectory motion is highly detectable in motion noise because the component local motion signals are enhanced when motion detectors with similar directional tuning are stimulated in a sequence along their preferred direction. PMID- 7839612 TI - Receptive fields of P and M ganglion cells across the primate retina. AB - We studied the receptive field organization and contrast sensitivity of ganglion cells located within the central 80 (radius of 40) deg of the macaque retina. Ganglion cell activity was monitored as synaptic (S) potentials recorded extracellularly in the lateral geniculate nuclei of anesthetized and paralyzed monkeys. Receptive field center and surround regions of magnocellularly projecting (M) and parvocellularly-projecting (P) cells increase in area with distance from the fovea, with the center radii of M cells being about twice those of neighboring P cells. Peak sensitivities of center and surround regions are inversely proportional to the regions' areas, so that integrated contrast sensitivities (contrast gains) are constant across the visual field, with the gain of M cells being, on average, six times that of P cells. For both M and P cells, the average ratio of surround/center gain is 0.55. Constant gain of P cells across the visual field is achieved by increasing sensitivity to stimuli falling on the peripheral retina to an extent that counteracts the aberrations introduced by the eye's optics. PMID- 7839613 TI - Sensitivity to orientation modulation in micropattern-based textures. AB - We have measured the sensitivity of the human visual system to sinusoidal modulations of orientation in micropattern-based textured stimuli. The result is the orientation modulation function, or OMF, which describes this sensitivity as a function of the spatial frequency of orientation modulation. We found that the OMF was bandpass with peak sensitivity at spatial frequencies ranging between 0.06 and 0.2 c/deg, depending on the size of the micropatterns. The OMF was found to be scale invariant, that is its position on the spatial frequency axis did not change with viewing distance when spatial frequency was measured in object rather than retinal units. This scale invariance was shown to result from the visual system taking into account the scale rather than the density of the micropatterns as viewing distance was changed. It has been argued by Bergen [(1991) Vision and visual dysfunction (Vol. 10B) New York: Macmillan] that scale invariance in textures is a consequence of the coupling of mechanisms which detect textural features with those which detect local luminance contrasts. We reasoned that Gabor micropattern textures might therefore show narrower OMFs compared to line micropattern textures. However we found no difference in OMF bandwidth between the Gabor and line micropattern textures, suggesting that the line micropatterns were acting as selectively as the Gabor micropatterns for the spatial scale of the mechanisms which detected the orientation modulation. Evidence is presented which suggests that the mechanisms which detected the orientation modulation in our stimuli are non-linear. Finally we showed similar OMFs for sine-wave and square-wave modulations of micropattern orientation, and similar OMFs for modulations of micropattern with orientation about the horizontal and about the vertical, the direction of modulation in both cases being horizontal. The implications of these findings for the mechanisms involved in orientation-defined texture processing is discussed. PMID- 7839614 TI - An alternative three-dimensional interpretation of Hering's equal-innervation law for version and vergence eye movements. AB - In the context of Hering's equal-innervation law, this paper discusses the problem of how the three-dimensional positions of the two eyes, each expressed by a rotation vector, can be separated into contributions of the version and vergence system. As proposed by Van Rijn and Van den Berg [(1993) Vision Research, 33, 691-708], this can be done by taking the sum and difference of the position rotation vectors of each eye. In our alternative procedure the vergence signal is defined as the rotation which transforms the left eye position into the right eye position and the version signal is the common factor in both eye positions that remains after removing the vergence signal. The version and vergence contributions, defined in this way, can be interpreted straightforwardly as rotations. When Van Rijn and Van den Berg applied their definitions to their own data, they obtained the interesting result that the reconstructed version and vergence contributions were effectively limited to two dimensions (2D). The version signal was confined to Listing's plane (no torsion) whereas the vergence signal remained within a horizontal-torsional plane (no vertical vergence). They showed theoretically that a model based on 2D version/2D vergence control will indeed produce the torsional eye positions in near fixations found in their experiments. This model cannot account for a second set of data in the literature [Mok, Ro, Cadera, Crawford & Vilis (1992) Vision Research, 32, 2055-2064]. With our definitions, we found that the simple 2D version/2D vergence control strategy cannot account for the Van Rijn and Van den Berg (1993) data but is nicely compatible with the considerably smaller amount of cyclotorsion in the data collected by Mok et al. (1992). We also show that, in such a system, having 2D vergence control is compatible with minimization of torsional disparity and provides the cyclovergence signals suitable for stabilizing the eyes in the non Listing positions caused by a vertical saccade in near vision. PMID- 7839615 TI - Interocular suppression in the primary visual cortex: a possible neural basis of binocular rivalry. AB - In an attempt to demonstrate a physiological basis for the alternating suppression of perception when the two eyes view very different contours (binocular rivalry), we studied the responses of neurons in the lateral geniculate nucleus (LGN) and area 17 of cats for drifting gratings of different orientation, spatial frequency and contrast in the two eyes. Almost half of the LGN neurons studied exhibited modest inhibitory interocular interaction, but independent of interocular differences in orientation. Monocularly driven units in layer 4 of area 17 behaved similarly. However, for the majority of binocular cortical cells, the response to a grating of optimal orientation in one eye was suppressed by a grating of very different orientation shown to the other eye, over a wide range of spatial frequency and independent of relative spatial phase. This interocular suppression exhibits a remarkable non-linearity: a grating of non-preferred orientation in one eye causes significant interocular suppression only if the neuron is already responding to an appropriate stimulus in the other eye [Sengpiel and Blakemore (1994) Nature, 368, 847-850]. We propose that the switches in perceptual dominance during binocular rivalry depend on interocular interactions at the level of binocular neurons of the primary visual cortex, which might involve intracortical inhibition between adjacent ocular dominance columns. The spontaneous alternations in perceptual suppression that occur during prolonged viewing of rivalrous patterns remain to be explained, although significant variation in the strength of neuronal suppression in such conditions was occasionally seen. PMID- 7839616 TI - Contrast dependence of motion-onset and pattern-reversal evoked potentials. AB - This study deals with the effect of stimulus contrast, between 1.3% and 96%, on the visual evoked potentials (VEPs) for onset of motion and for pattern reversal of checkerboard stimuli. The VEPs for pattern reversal and for the onset of motion both contain an initial positive peak (P1; peak latency about 120 msec) followed by a later negative peak (N2; peak latency 160-200 msec). However the P1 peak dominates the pattern-reversal VEP when recorded from the midline occipital lead, where it is maximal, while the N2 peak is larger in the motion-onset VEP, especially when recorded from unipolar lateral occipital leads. Whereas the amplitude of the P1 peak in both the pattern-reversal VEP and the motion-onset VEP decreases with decreasing contrast (becoming undetectable at a contrast of about 2% for the motion-onset VEP), the amplitude of the N2 peak in both types of VEP does not vary significantly with contrast, above a contrast of 1.3%. The increase in peak latency with decreasing contrast is also more pronounced for the positive than the negative peaks of both types of VEP. Taking into account the high contrast sensitivity of the magnocellular system (thought to be involved in the processing of motion) compared with the parvocellular system (probably more concerned with the processing of form), our findings suggest that for both motion onset and pattern-reversal VEPs the negative peak is attributable to the motion processing magnocellular pathway and the positive peak to the form-processing parvocellular system. PMID- 7839617 TI - Local and global factors in spatially-contingent coloured aftereffects. AB - Dodwell and O'Shea's [(1987) Vision Research, 27, 569-580] conclusions that contingent coloured aftereffects (CAEs) depend on gobal pattern organization were investigated in four experiments. In Expt 1, we replicated findings that CAEs can be induced with complex patterns (concentric circles; radial spokes) under conditions of systematic eye movements. Contrary to Dodwell and O'Shea's argument that eye movements should uniformly cancel local orientation-colour contingencies, leaving only global effects, we reduced CAE magnitude by halving the diameter of the test stimuli. This suggests that cancellation did not occur uniformly over whole patterns, and that CAEs observed on these patterns are the residuals of uncancelled local orientation-colour contingencies. In Expt 2 we used central-fixation induction procedures to demonstrate that it is possible to induce CAEs with randomly-organized and locally-orthogonal orientation components. These findings are inconsistent with Dodwell and O'Shea's failure to observe CAEs under these conditions, and with their conclusion that global organization is necessary for CAE induction. However, CAEs induced with randomly organized components were significantly weaker than those induced with globally organized components. We examined the contribution of global organization in two additional experiments. In Expt 3 we induced CAEs with randomly-organized components under conditions in which the need for central fixation was removed, and found that CAE strength was directly related to the organization as well as the density of local-orientation components. In Expt 4, we found that the global organization of local-orientation components enhanced CAE strength only in regions away from the edges of these components: pattern organization did not affect the strength of CAEs at edges. We interpret these findings as evidence that CAEs may involve separate edge- and spread-colour components, and conclude that such components may account for observations previously attributed to global pattern geometry. PMID- 7839618 TI - Spatiotemporal visual response to suprathreshold stimuli. AB - The spatiotemporal visual response to an inducing bar of a short duration was studied by a brightness-matching procedure. The apparent brightness of a test line, presented in the centre of an inducing bar, exhibited a U-shaped dependence of the inducing-bar width with a minimum at about 4.5' width. The temporal response to a 4.5'-wide inducing stimulus consisted of three alternating phases, the middle one being the largest. The spatial spread of the response to this stimulus was initially restricted in the area of the inducing bar, later it was extended to adjacent positions achieving a triphasic form and still later faded away. These findings indicate that the response to a spatiotemporal impulse of suprathreshold luminance is triphasic in time and the spatial spread of the response depends on the time after the stimulus onset. A model was presented assuming that the spatiotemporal weighting function might be described by a spherical harmonic function modulated by a Gaussian function. The model predictions agreed with the data obtained. PMID- 7839619 TI - Photoreceptor sensitivity changes explain color appearance shifts induced by large uniform backgrounds in dichoptic matching. AB - Photoreceptor sensitivity changes explained the effect of large uniform backgrounds on the color appearance of small targets in a dichoptic asymmetric color matching experiment. Subjects viewed in each eye a target superimposed on a large background. The backgrounds presented to the two eyes had different spectral compositions. Subjects adjusted the target seen by the right eye to match the appearance of the target seen by the left eye. Receptor sensitivity changes explained the effect of numerous adapting backgrounds on the color appearance of many targets with high precision. Post-receptoral sensitivity changes provided a poorer account of the data. The apparent sensitivity of each receptor class varied inversely with changes in background light absorbed by that receptor class, but did not depend on background light absorbed by the other two receptor classes. PMID- 7839620 TI - Stereopsis due to luminance differences in the two eyes. AB - A local region in an image is seen as slanted when the two eyes are shown different luminance values in that region. The steepness of the slant depends upon the size of the region and the difference in the luminance values in the two eyes. Three examples where this phenomenon influences depth perception are given: (1) stereopsis without corresponding binocular luminance edges is shown to be a limiting case of the phenomenon; (2) edges less than 1 min arc apart can be seen in relative depth with respect to each other; and (3) regions that appear transparent or translucent can be seen in depth despite having all the luminance edges at zero disparity in simple stereo images. PMID- 7839621 TI - Saccades to large coloured targets stepping in open fields. AB - Subjects tracked a 2.3 deg target that stepped 5 deg, in a randomly chosen direction, each time it was foveated. Targets were coloured patches that were fairly close to white; in some cases precise matches ensured equiluminosity with the background. Viewing conditions provided good colour rendering and neutral colour adaptation. Pale colours were surprisingly well tracked. Multiple regressions showed that the colour and spatial characteristics of the target are important determinants of a primary saccade's latency. Significant factors included target size, achromatic contrast, tritanopic purity difference, and chromatic saturation. Colour-normal subjects always responded more slowly to yellow or blue targets which a deuteranomalous subject tracked quite well. Severely blurring the target had a consistent minor effect. PMID- 7839622 TI - Spatio-temporal model for subjective colours based on colour coded ganglion cells. AB - We propose a mathematical model for the generation of the subjective colour phenomenon through Benham's disk stimuli. The model relates to the spatial and temporal properties of three colour coded retinal ganglion cells: L+/M-, M+/L- and S-/(L+M)+ [or (L+M)-/S+]. It is suggested that the phenomenon is based on both the opponent mechanisms in the cells' receptive fields, and the "rebound response"--a common cell response to turning off of an inhibitory stimulus (nonlinear cell dynamics). A physiological mechanism is suggested for this response. The integrated cell responses to Benham disk-stimuli create imbalances between the colour pathways that are interpreted as actual colours. The model also predicts the shift in the perceived colours when the disk rotation rate is varied. PMID- 7839623 TI - The effects of spatial filtering and contrast reduction on visual search times in good and poor readers. AB - Recent experiments with reading disabled children have shown that image blurring (produced with frosted acetate overlays) results in an immediate benefit in search performance, eye movement pattern and reading comprehension. This suggests that the contrast and spatial frequency content of visual stimuli are important factors for these children. In the present experiment, spatial frequency filtering and contrast reduction were employed to determine whether either of these factors contributes to the beneficial effects observed. Letter arrays were spatially filtered to produce low pass (< 3.5 c/deg) and high pass (> 7.0 c/deg) images. In addition, a low contrast control image was generated to match the low contrast of the high pass image. Children classified as good reader controls (CON), specific reading disabled (SRD), attention deficit disordered (ADD) or comorbid SRD/ADD (COM) were asked to perform a visual search task with each type of image. With high contrast, unfiltered arrays, the search times for the CON and ADD groups were much shorter than those of the SRD and COM groups. While both high pass and low pass filter conditions improved the search speed for the COM group, improvement for the SRD group was only obtained with low contrast stimuli. These results support the notion that the beneficial results of image blurring with SRDs derives from the contrast reduction produced by such manipulations. PMID- 7839624 TI - High-pass resolution perimetry: central-field neuroretinal correlates. AB - Minimum angles of resolution (MAR) were measured at 0-10 deg horizontal eccentricity in three normal subjects, using high-pass spatial frequency filtered targets, at four different contrast levels. Results were correlated with recent data on human cone and ganglion cell separations in corresponding retinal locations. MARs and cone separations showed a close proportionality through the origin for all contrast levels. Ganglion cell correlates were more difficult to elucidate as the cell bodies are displaced from their input cones. Taking a functional estimate of the displacement into account, the number of ganglion cells appeared to be large enough to uphold an "effective" distribution that obeys the same proportional relationship to MAR that previously has been demonstrated outside 10 deg. Analysis of the nature of age effects provided support for this model. PMID- 7839625 TI - Interobserver agreement for measurement of grating acuity and interocular acuity differences with the teller acuity card procedure. AB - Interobserver reliability of the Teller acuity card (TAC) procedure for estimating acuity and interocular acuity differences (IADs) was assessed with 342 infants and children who had been treated in a neonatal intensive care unit for preterm birth and/or perinatal complications. Subjects were tested binocularly at term and monocularly at 4, 8, 11, 17, 24, 30, 36, and 48 months corrected age with TACs. Testers were masked to the location and spatial frequency of the grating on each card. Of the interobserver test-retest scores, 67% differed by no more than 0.5 octave, and 87% of the test pairs differed by no more than 1 octave. Of the test-retest comparisons of a subject's IAD, 54% showed agreement of 0.5 octave or better, and 76% differed by no more than 1 octave. Interobserver agreement for binocular and monocular tests was similar to that reported previously for visually and neurologically at-risk infants and children tested with the forced-choice preferential-looking procedure or with prototype acuity cards. Interobserver agreement for IAD estimates was somewhat less than that reported for a sample of infants with ocular disorders. There were no systematic differences in interobserver agreement between eyes tested first and eyes tested second, nor was interobserver agreement related to subject's medical diagnosis. Interobserver agreement was influenced, however, by the spatial frequencies of the particular gratings used during testing and, to a limited extent, by the age of the child. The duration of individual tests and observers' ratings of confidence in their acuity estimate were not reliable indicators of test-retest pairs that were not in agreement. The results demonstrate the reliability of the TAC procedure, but suggest that acuity estimates critical to a patient's diagnosis or treatment should be confirmed by repeat testing. PMID- 7839626 TI - [Minor glomerular abnormalities in chronic tubulointerstitial nephritis]. AB - The authors examined consecutive renal biopsies from 43 patients with minor glomerular abnormalities and from 35 patients with chronic tubulointerstitial nephritis (in the least affected glomeruli). The findings were evaluated according to WHO criteria of minor abnormalities. They found that significantly more frequently lipid drops were found in minor abnormalities (6:0), as well as changes in the capillaries of glomeruli (breakdown 1:7), wrinkling (15:29-highly significant even after correction of p)) in tubulointerstitial nephritis. The incidence in another 15 compared indicators there was not significantly different. With regard to the assembled results the authors consider the morphological finding of minor glomerular abnormalities as non-specific changes, and adaptational glomerular changes in response to various noxious substances. Therefore it is necessary to evaluate purely morphological findings of minor abnormalities carefully and in a differentiated manner, in particular in conjunction with treatment. PMID- 7839627 TI - [The role of the HUT test (head upright tilt table test) in patients with syncope of uncertain etiology]. AB - The authors have examined 73 patients at the mean age of 36.8 +/- 15.3 (M:34, F:39). All the pts have suffered from recurrent presyncopes or syncopes the etiology of which has not been diagnosed by previous internal, neurological or psychiatric examination. Before the HUT the patients have undergone a complete cardiological examination. The HUT has been carried out according to the modificated Westminster protocol, the blood pressure and the heart rate have been monitored continuously. The end-point of the HUT has been a presyncope or a syncope, viewed as positive. The positive pts have been divided into 4 groups according to the changes of their blood pressure and heart rate during a presyncope or a syncope-mixed, cardioinhibitory A, cardioinhibitory B and vasodepressor responses. Out of 73 pts there have been 27 pts (37%) with positive responses and 46 (63%) with negative responses. The mixed type has been achieved in 12 pts, cardioinhibitory A-in 5 pts, cardioinhibitory B-in 2 pts, vasodepressoric in 8 pts. The mean time needed for positive response during the native HUT has been 17.7 +/- 11 min, after activating with isoproterenol for 2.6 +/- 1 min. The achieved results correlate with data in medical literature. The test activated with isoproterenol increases its sensitivity. There have not been any complications marked within the examined group. CONCLUSION: The HUT has been unambiguously included into screening algorithms of syncopes as an easy, cheap, safe examination with good sensitivity and specificity. PMID- 7839628 TI - [Complications of central venous catheterization in hematologic patients- prospective study of 193 catheterizations]. AB - A Prospective Study of 193 Catheterizations 193 central venous catheters introduced in 142 patients with haematological diseases were studied prospectively for complications in 1984-1992. 165 polyethylene, 14 Hickman and 14 polyurethane catheters were inserted into subclavian vein via infraclavicular access using Seldinger technique exclusively. Except bleeding, that was not serious, immediate complications occurred in 4%. Cumulative duration of catheterizations was 6370 days with median duration of one cannulation of 15 days, range 1 to 489 days. In polyethylene catheters duration of catheterization was influenced significantly by tunnelization. More than half of cannulations were accompanied by technical complications. Incidence of clinical thrombosis was 6.7%. Infectious complications were the most serious with the incidence of proven and suspected catheter-related sepsis of 25.8%, local inflammation of 41.4% and tunnel inflammation of 12.8%. They were caused in 82% of cases by gram-positive bacteria. Catheter-related sepsis was significantly associated with local inflammation, duration of cannulation and leukopenia and application of parenteral nutrition. Hickman catheters had the best "complication to catheterization duration" ratio, that give reasons for using these catheters in this group of patients. PMID- 7839630 TI - [Resistance to activated protein C, so-called APC resistance: the first two cases in Slovakia]. AB - For the anticoagulant action of activated protein C (APC) in addition to protein S another newly detected cofactor is essential. Its deficiency is described as APC-resistance. This defect which is closely associated with the molecule of the factor V seems to be the most frequent cause of thrombophilia. The authors describe two patients where APC-resistance was diagnosed for the first time in Slovakia. PMID- 7839629 TI - [The Pelger-Huet anomaly]. AB - The authors describe a case-history of Pelger-Huet anomaly in a 53-year-old patient with bronchogenic carcinoma. It was not possible to reveal whether an inborn or acquired anomaly was involved. Recent knowledge of this problem is discussed. PMID- 7839631 TI - [Is oral contraception safe?]. PMID- 7839632 TI - [Anticoagulation therapy in patients with valvular prostheses]. AB - Thromboembolism and haemorrhage are the most frequent complication in patients after valvular prostheses or provision of a mechanical replacement. Optimal anticoagulant treatment reflects efforts to reduce these main two complications to a minimum. The author summarizes contemporary recommendations for anticoagulant treatment of these patients under standard conditions and therapeutic procedures in complications such as surgery, pregnancy and embolism into the CNS. PMID- 7839633 TI - [Is it possible to prevent mycotic infections in oncology patients?]. AB - The authors give an account on prophylactic provisions focused on reduction of the risk of mycotic infections in oncological patients. After a brief introduction where they point out the importance of mycotic infections they pay their main attention to the prophylactic administration of drugs. They deal with procedures used and in the majority they quote original sources. Main emphasis is laid on the probably most perspective preparation-fluconazol. The authors present also their own views. PMID- 7839635 TI - [Current problems in the training of specialists in the organization of medical support for the troops]. PMID- 7839634 TI - [Cisplatin and carboplatin in the treatment of malignant lymphoma and multiple myeloma]. AB - Experiences with cisplatin and carboplatin are summarized in this paper. The treatment response to monotherapy with cisplatin or carboplatin was proved in non Hodgkin's lymphomas. This is necessary condition for the application of the drug in polychemotherapy. Cisplatin and carboplatin based combinations are not used as an initial therapy. The indications for these two drugs are primary resistant malignant lymphoma and multiple myeloma, or relapses of these diseases not responding to conventional therapy. Cisplatin based combination therapy can in these indications prolong the survival in 30-40% of patients. The role of carboplatin in malignant lymphoma is not clear yet and is under investigation. The effective antiemetic therapy (ondansetron, granisetron) miligated the fear of vomiting and therefore these combinations are used in resistant malignant lymphoproliferative diseases more then some years ago. In the tables are shown the chemotherapeutic combinations used in non-Hodgkin's lymphomas, Hodgkin disease and multiple myeloma. PMID- 7839636 TI - [The reform of military medical education and the tasks of the Military Medical Academy in improving personnel training]. AB - The Military Medical Academy is a military educational institution which carries out the primary profile training of physicians for the Armed Services and all types of post-graduation training and advanced training of the scientific pedagogical and medical specialists. Internship as a first stage of the post graduation training is intended to improve practical medical training of the graduates of the Russian Military Medical Academy and other medico-military educational institutions by means of their primary specialization in one of the clinical or profile branches of medicine. The reforming of the post-graduation training rest system in the Military Medical Academy aims at its further development and putting specialists' training system into accordance with the Armed Forces reorganizations. This will make it possible to ensure high professional qualification of military doctors at the level of national and international standards. PMID- 7839637 TI - [The results of a poll of military pharmacists on postgraduate instruction]. PMID- 7839638 TI - [A complex approach to creating a system of medical support for mobile forces (materials from a scientific and theoretical conference)]. PMID- 7839639 TI - [The combined use of ultrasound and the laser in treating patients with osteomyelitis of the ribs and sternum]. AB - The article deals with the mechanism of low-frequency ultrasound and low-energy laser radiation beneficial influence on the processes of purulent wounds and cavities cleaning and healing. The authors describe the methods and results of their associated usage in 17 cases of costal and sternal osteomyelitis treatment. PMID- 7839640 TI - [Experience with the surgical treatment of teeth with chronic periapical foci of odontogenic infection]. PMID- 7839641 TI - [Croupous pneumonia: current problems and means for their resolution]. AB - Croupous pneumonia makes up to 7-8% of all pneumonia cases in different regions of the country. 83 lethal outcomes have been studied. In 46 cases pneumonia was primary illness and the direct cause of death. In case a pneumonia is diagnosed an urgent hospitalization and penicillin treatment (maximum effect on pneumococcus is ensured with 1.8-2.4 million units per day) are necessary. For the prevention of acute cardiovascular insufficiency camphor is prescribed for 2 3 days. Mucolytic preparations and--after normalization of temperature- physiotherapeutic methods and therapeutic exercises are used for treatment. In 25 46.6% of lethal cases pneumonia is not diagnosed in their lifetime. Late hospitalization influencing illness's outcome takes place in 73% of cases. PMID- 7839642 TI - [The implantation of intraocular lenses as the surgical rehabilitation of cataract patients]. PMID- 7839643 TI - [Current problems of tropical medicine (based on materials of the Military Medical Conference of Countries of the Asian-Pacific Ocean Region)]. AB - The scientific messages presented at the 3rd Asia Pacific Military Medical Conference are scrutinized. The encounter of about 200 military doctors from 14 countries of the appropriate region was heed in Jakarta in 1993, hosted by the Indonesian Army and sponsored by the United States Army Pacific Command. The Conference comprises 3 symposia on: military medicine and humanitarian assistance; malaria and parasitic diseases of military relevance; protecting the troops during tropical deployments. There were 53 reports in all, the leading ones belonged to American authors. Detailed discussions concluded every working day. In the whole the Conference reminded a regional seminar of military doctors in the shape of continuing medical education. The participants got qualification eredits in the field of tropical medicine. PMID- 7839644 TI - [The tasks of improving the organization of medical support for the Army and Navy]. PMID- 7839645 TI - [The dicynone treatment of hemorrhagic fever with renal syndrome]. PMID- 7839646 TI - [Body adaptive reactions to a change in the work and rest regimen]. AB - The authors report that a transition of a human organism to a non-standard work and rest regimen in conditions of hermetization is followed by the development of adaptation reactions of body protecting functions. The strength of these reactions is determined by the correspondence of the twenty-four-hour activity cyclogram to the circadian physiologic rhythm. The depression of protecting reactions, the slowing down of adaptation process and the appearance of disadaptation sings occur more often among operators, whose twenty-four-hour activity algorithm demands working from 04.00 to 12.00 and from 16.00 to 24.00 with a four-hour shift cycle. The correspondence of the work and rest regimen to the twenty-four-hour cycle of physiologic functions in the conditions of chronophysiologic tension, decreases adaptation changes and prevents the development of body protective and accommodative insufficiency. PMID- 7839647 TI - [The physical work capacity indices of servicemen during adaptation to a mountainous desert locale]. PMID- 7839648 TI - [Familiarization drills with barochamber ascents for flight personnel as an element in their psychophysiological training for high-altitude flights]. AB - A new method of altitude chamber climbs of flight personnel (for familiarization and training) has been worked out. The aim of this method is to form among aircrew members the skills to recognize hypoxia in flight and to train them in taking practical measures to remove it. This method appeared to be informative: hypoxia awareness was registered after 3-9 minutes of staying at an altitude of 5000-6000 m in 93% of tested persons. The time necessary to carry out such a familiarization climb in an altitude chamber in comparison with a high-altitude test is 2.5-3 times shorter. This method is safe for pilot's health, practicable in the conditions of any military air unit and flying school, and can also be used for the examination of flying personnel health and functional status of their organism. PMID- 7839649 TI - [Medical support for submarine crew members in the case of an atomic power plant accident]. PMID- 7839650 TI - [A universal field trauma (orthopedic) table]. PMID- 7839651 TI - [A demountable splint for skeletal traction]. PMID- 7839652 TI - [The organization of medical support for the troops in the Byelorussian Offensive Operation (the 50th anniversary of the operation)]. PMID- 7839653 TI - [The Western group of our troops will remain in history]. PMID- 7839654 TI - [The 35th expanded plenum of the Academic Medical Council of the Main Military Medical Directorate of the Ministry of Defense and the assembly of the medical service command staff of the Armed Forces of the Russian Federation]. PMID- 7839655 TI - [The 25th anniversary of the Institute of Military Medicine]. PMID- 7839656 TI - [The 50th anniversary of the course on military medical geography at the Military Medical Academy]. PMID- 7839657 TI - [The effect of emotional-painful stress, hypoxia, and adaptation to it on the activity of enzymes for metabolizing glutathione and concentration of glutathione in rat organs]. AB - The stress activates glutathione peroxidase in the heart, liver, and kidney, glutathione transferase in the heart and liver, inhibits gamma-glutamyl transferase in the liver; the activity of glutathione reductase and the content of reduced glutathione were unchanged. Two-four-minute hypercapnic hypoxia unchanged the activity of glutathione metabolic enzymes. The activity of the above enzymes decreases in some organs at the death caused by 2-15-minute hypoxia. Long-term intermittent adaptation to hypobaric hypoxia lowers the activity of glutathione peroxidase, -transferase and -reductase. The biological value of the two types of enzymatic responses may be different: stress-induced activation of glutathione metabolic enzymes can enhance resistance to stress and xenobiotics; however, their inhibition during hypoxic adaptation may produce the opposite effect. PMID- 7839658 TI - [Metabolism of neutral lipids in hemopoietic organs and in the liver of mice with alloxan diabetes]. AB - The metabolism of neutral lipids (free and ester-bound cholesterols, mono-, di- and triacylglycerides) was greatly impaired in liver, spleen, thymus tissues and ileocecal lymph nodes of BALB/c mice with subacute alloxan diabetes (content of sugar in blood was no less than 14 mmol/l) as shown by 3H-acetate and 14C palmitate incorporation into the corresponding lipid fractions. The rate of neutral lipid turnover was specifically decreased in all the tissues studied. However, a considerable accumulation of these lipid fractions was found in thymus tissue. Incorporation of labelled palmitate into triacylglycerides was increased in the spleen but without obesity of the organ. PMID- 7839659 TI - [Metallothionein level in liver, bone marrow, and lymphocytes of rats after administering ethanol]. AB - The levels of metallothioneins in the rat liver, bone marrow and lymphocytes were shown to be increased 24 hours after intraperitoneal administration of ethanol in doses of 1 to 5 mg/kg. There was a linear dependence of the hepatic levels of metallothioneins upon the dose of alcohol. The increase in the levels of metallothioneins was less pronounced in the bone marrow and lymphocytes than in the liver. The effect detected is likely to be associated with the redistribution of zinc during alcoholic intoxication. It is suggested that the increase in the pool of metallothioneins in the bone marrow and lymphocytes is an essential stage for protecting the cells that determine the body's immunity in intoxication. PMID- 7839660 TI - [Metabolism of the basic component of connective tissue at various stages of developing experimental liver cirrhosis]. AB - A system of GAG-hydrolase was studied in liver tissue and blood plasma during development of CCl4-produced cirrhosis of liver tissue in series of experiments involving 400 adult rat males. Dissimilar pathways of the matrix formation, related to dynamics of the GAG-hydrolases activity, were detected within various steps of the chronic CCL4-produced liver tissue impairments in these rats. Alterations in the enzymatic activity were stable and regular in each series of the experiment and correlated with dynamics of the adaptation-compensatory responses. PMID- 7839661 TI - [A hormonally-active form of vitamin D3--1,25-dihydroxyvitamin D3--an inhibitor of leukocyte lipoxygenase]. AB - The effect of the hormonally active vitamin D3 formulation on the activity of porcine leukocyte lipoxygenase was studied. The rate of enzyme inhibition was vitamin dose-dependent and increased if pH values raised, while the vitamin inhibitory effect was decreased as the content of linoleic acid used as a substrate was increased. PMID- 7839662 TI - [Changes in phospholipids in the gray and white matter of the rat brain during postmortem autolysis dynamics]. AB - Content of total phospholipids and their individual fractions, studied in rat brain grey and white substances during postmortal autolysis, was distinctly and dissimilarly altered in these tissues and the rate of alterations depended on time of incubation. Relative content of phosphatidyl serines + sphingomyelins, phosphatidic acids + polyglycerophosphatides in grey substance as well as of phosphatidylinositides, phosphatidic acids + polyglycerophosphatides in white substance were increased, while phosphatidylinosidtides in grey substance and phosphatidyl serines + sphingomyelins in white substance were decreased within later (4 and 24 hrs) periods of autolysis. Content of phosphatidyl cholines, phosphatidyl ethanolamines, glycerophosphates and lysophospholipids was also dissimilarly altered in brain grey and white substances both within early and later periods of autolysis. The schemes of metabolic interrelations between phospholipids of rat brain grey and white substances during autolysis are considered involving hydrolase, transferase and other reactions of lipids biotransformation. This multiple complex of biochemical reactions may be among the reasons responsible for dissimilar and time-dependent deteriorations of individual brain structures after death. PMID- 7839663 TI - [Isolation of lactate dehydrogenase-C4 from human spermatozoa]. AB - Lactate dehydrogenase-C4 (LDH) is a specific cell isoenzyme of spermatogenesis and spermatozoa of man and animals. Due to the lower levels of contaminating proteins, isolation of LDH C4 from spermatozoa had a lot of advantages. LDH C4 was isolated as follows: precipitation with ammonium sulfate, separation of LDH C4 from other LDH isoenzymes using immunosorbents, purification from contaminating proteins of oxamate-Sepharose. Antibodies to LDH1-3 immobilized on tresyl-Sepharose were used as immunosorbents. Elution of LDH C4 from oxamate Sepharose by means of lithium lactate appeared inadequate therefore LDH C4 was eluted using 0.63 mM sodium pyruvate. PMID- 7839664 TI - [Effect of ucrinol on lipid metabolism in liver tissue]. AB - Alterations in content of phospholipids as well as dynamics of lipid free-radical oxidation were studied in the hepatocytes of the rats poisoned with various doses of the toxic agent ucrinol within 1.3 and 6 months. Low concentrations of the toxin (1.5 mg/kg) did not cause any detectable alterations of the patterns studied. However, higher concentrations of ucrinol (15-150 mg/kg) produced markedly pronounced destructions which were dose- and time-dependent. PMID- 7839665 TI - [Effect of cystamine on formation and repair of post-irradiation single-strand DNA breaks]. AB - Content of breaks in single-strand DNA, activity of superoxide dismutase and concentration of malonic dialdehyde were studied in blood lymphocytes of irradiation-impaired rats after treatment with cystamine. Cystamine decreased the effects of irradiation as showed all the patterns studied. The protective action exhibited by the drug in radiation shielding of DNA involved both direct and indirect effects. PMID- 7839666 TI - [The effect of lipid peroxidation on the lipid and phospholipid composition of mitochondrial membranes during thermal incubation]. AB - Alterations in the content of lipids and phospholipids were studied in rat liver mitochondrial membranes after long-term heating at 37 degrees, pH 7.4, using FeSO4-ascorbate as inductors of lipid peroxidation. Under these conditions, activation of lipid peroxidation in mitochondrial membranes led to a marked increase in the rate of hydrolysis of phosphatidylethanolamine and lysophosphatidylethanolamine, to elevated synthesis of phosphatidylserine, sphingomyelin, phosphatidic and lysophosphatidic acids, diglycerides and cholesterol esters as well as to inhibit hydrolysis of phosphatidylcholine, cardiolipin and their lyso-derivatives. PMID- 7839667 TI - [The effect of various types of dry starch syrup on the rate of glucose utilization in lipid, carbohydrate, and protein components of rat liver]. AB - Effect of a diet, containing dextran maltose and dry starch syrup, on some patterns of liver tissue metabolism were studied in young Wistar rats within 30 days. The animals of Control Group 1 were kept on a diet containing corn starch as a source of carbohydrates; in Group 2 the starch was replaced by the dry starch syrup enriched with disaccharides and especially with maltose; the dry starch syrup added into the Group 3 diet containing mainly oligosaccharides and polymers with high levels of glucose residues. The label mixtures of 6-3N- and 6 14C-glucose as well as of 6-3H- and I-14C-glucose were administered into the animals on the day of death. Analysis of the findings has shown that the products of starch hydrolysis may the specific parameters of glucose metabolism. Incorporation of the label into liver tissue lipids was similar to the control values in the group of animals kept on a diet enriched with maltose as compared with group 3. The glycolytic pathway of glucose utilization was more activated than the pentosephosphate pathway after substituting starch for dry starch syrup as shown by differences in the rates of carbon incorporation at positions 1 and 6 of a glucose molecule. PMID- 7839668 TI - [Participation of neutrophils in the pathogenesis of allergic inflammation: inhibitory-protease index in assessing and predicting atopic illnesses]. AB - Total trypsin-like (BAEE esterase), elastase-like (BOC esterase) and antitryptic activities were studied in blood serum of patients with atopic diseases. The elastase-like activity was increased in blood serum of all the patients examined during the acute period of the disease; the enzyme activation depended on the pathology severity and clinical picture manifestations. The increase in blood plasma total proteolytic activity correlated with reverse alteration in blood antitryptic potential. The data obtained suggest that activation of neutrophils occurred in atopic diseases, thus the rate of elastase-like activity in blood might be used as an objective pattern in examination of patients and in checking of treatment course. The developed inhibitory-protease index may serve also as a criterion in evaluation of the pathological state severity. PMID- 7839669 TI - [The effect of withdrawal from L-DOPA compounds on pathochemical changes of motor structures of the brain caused by them]. AB - Activities of enzymes of protein metabolism (aminopeptidase, acid phosphatase), of neurotransmitters (monoamine oxidase, acetylcholinesterase) and oxidative metabolism (glutamate- and glucose-6-phosphate dehydrogenases) were studied by quantitative cytochemical procedures in brain motor structures (sensomotor cortex, caudate nucleus) as well as in brain tissues not related directly to locomotory functions (n. accumbens, hippocampus) of rats exhibiting high and low locomotory activities after repeated L-DOPA administration within 14 days as well as within 14 days after drug discontinuation. That of L-dopa (madopare) caused alterations in the enzymatic activity in the brain motor structures of rats, mainly, with a high locomotory activity. It may be suggested that madopare withdrawal-induced decreases in MAO activity might be, to a certain extent, a cause of dyskinesias occurring after discontinuation of L-DOPA drugs. PMID- 7839670 TI - [Change in the composition of human skeletal muscles in amyotrophic lateral sclerosis]. AB - Protein composition of human skeletal muscle impaired with lateral amyotropic sclerosis was studied by means of two-dimensional electrophoresis. Some protein fractions were altered. Characteristic property of all the preparations studied proved to be disappearance of three protein fractions of 35 kDa molecular mass and with pI 5.9, 6.0 and 6.1. PMID- 7839671 TI - [Two forms of aldose reductase in erythrocytes from patients with insulin dependent diabetes mellitus]. AB - Erythrocytes of patients with insulin-dependent diabetes mellitus contained two forms of aldose reductase a and b (EC No. 1.1.1.21) (the key enzyme in the sorbitol pathway of glucose utilization) as compared with those of healthy donors in whom the form b of the enzyme was only found. The aldose reductase a exhibited a higher maximal rate (Vmax = 16.7 +/- 3.2 IU/D280) and a lower substrate affinity (Km = 6.5 = 19 mM) than the enzyme b, Vmax = 43.8 +/- 0.6 IU/D280, Km = 3.0 = 4.0 mM, respectively. More severe development of the disease was observed in the patients whose erythrocytes contained only aldose reductase a (HbA1c = 14.56 +/- 0.69%) as compared with those in whom the enzyme a and b were found (HbA1c = 11.5 +/- 0.4%). Kinetic parameters of the enzyme showed that aldose reductase a may be active in hyperglycemia of diabetes mellitus, thus contributing to intensification of the sorbitol pathway in these patients. PMID- 7839672 TI - [Fatty acid composition of blood plasma lipids and erythrocytes in lung cancer patients]. AB - The fatty acid spectrum of blood plasma and erythrocytic membrane lipids were studied in 47 patients with lung cancer. The changes in the plasma and erythrocyte fatty acid composition were found to be identical irrespective of the clinical cancer form. In blood plasma of these patients with lung cancer, a decrease in the level of polyunsaturated fatty acids was observed with the normal levels of arachidonic acid and the proportion of monoenic fatty acids was increased. Changes in the lipid composition of erythrocyte membranes were characterized by less pronounced polyunsaturated fatty acid deficiency than that in the plasma, which accompanied by decreases in arachidonic acid levels. The appearance of significant levels of nonadecanoic acid also seems striking. PMID- 7839673 TI - [Fatty acid composition of separate fractions of lipids from tumor tissue in breast cancer]. AB - The distribution of major fatty acids in neutral lipids and phospholipids was studied in breast tumor tissue. The most pronounced differences in the content of individual fatty acids were found in the fractions of diacylglycerol and phosphatidylethanolamine, which mainly applies to unsaturated acids. Possible impairments of transacetylation mechanisms in carcinogenesis are discussed. PMID- 7839675 TI - [Cholesterol metabolism in patients with ischemic heart disease with varying supplies of omega-3 polyunsaturated fatty acids]. AB - Patients with ischemic heart disease and with hyperlipidemia of the IIa, IIb and IV types as well as not exhibiting any pronounced alterations in cholesterol metabolism were treated with various amounts of omega-3 polyunsaturated fatty acids (PUFA) introduced into the basic antiatherosclerotic diet: 1 group--content of the essential factor 0.2 g/day, 2 group--increased content of natural products with PUFA up to 1 g/day, 3 group--increased PUFA content due to the drug "euconol" 5 g/day. Administration of the PUFA omega-3 into the basic antiatherosclerotic diet contributed to development of adequate clinico biochemical alterations; under these conditions content of alpha-cholesterol in blood correlated directly to concentration of polyunsaturated cholesterol esters and PUFA omega-3 (eicosapentaenate and docosahexaenate) as well as reverse correlation was found between content of total cholesterol and these molecular forms of cholesterol esters studied. Enrichment of the diet with PUFA omega-3 did not cause any alterations in content of primary bile acids in blood thus suggesting that PUFA omega-3 did not affect the cholesterol catabolism. These data enabled us to plot the graph for individual evaluation of cholesterol metabolism in patients with ischemic heart disease involving alterations in the spectrum of esterified cholesterols in blood before and after the treatment course. PMID- 7839674 TI - [Middle molecule levels in patients with spinal cord trauma]. AB - The levels of medium-weight molecules was estimated in the serum of 46 patients, including 36 patients with cerebrospinal injury and 10 patients with craniocerebral injury, 5 healthy volunteers were in the control group. The toxic metabolites studied were markedly increased in all these patients as compared with the controls. However, the highest alterations were detected in the patients with cerebrospinal injury in early periods of observation, thus suggesting that the trauma and duration might be responsible for intoxication manifestations. Estimation of the levels of medium-weight molecules in blood may be used in evaluation of the degree of intoxication in spinal patients. PMID- 7839676 TI - [Method for fractionating phosphoinositides on a thin layer of silica gel]. AB - A procedure is described for fractionation of phosphoinositides using silica gel thin layer chromatography. The procedure may be used in routine studies as this makes it possible to isolate phosphoinositides by using only one system of solvents. The evidence for isolation of phosphoinositide fractions is discussed. PMID- 7839677 TI - [Ubiquinones and the body's antimutagenic defense]. AB - The effects of ubiquinone-10 given in oral doses of 0.2-20 mg/kg on cytogenetic effects of intraperitoneal photrinum (7 and 14 mg/kg), dioxydinum (100 and 300 mg/kg) and cyclophosphanum (20 mg/kg) were studied in the bone marrow metaphasic cells of male C57Bl/6 mice. Ubiquinone-10 (2 to 20 mg/kg) statistically significantly reduced the clastogenic action of these mutagens, except photrinum used in a dose of 7 mg/kg. The antimutagenic effect of the drug was dose independent and no more than 50%. The findings enable ubiquinone-10 be considered as an endogenous antimutagen. It is suggested that the antimutagenic activity of the compound is due to its antioxidative properties. PMID- 7839678 TI - Changing values. PMID- 7839679 TI - The epistemology of expectant parenthood. AB - A secondary analysis of information obtained from 288 interviews, conducted with 62 childbearing couples in the course of a qualitative and longitudinal study, suggests that much of the work of expectant parenthood is oriented toward getting to know the fetus. This article emphasizes the epistemological (as opposed to the emotional) relationship between parent and fetus. PMID- 7839680 TI - Hispanic mothers' beliefs and practices regarding selected children's health problems. AB - The purpose of this study was to identify and describe the Hispanic mothers' initial sources of advice and help with children's illnesses; beliefs about the etiology and seriousness of certain children's illnesses, namely, fever, cough, diarrhea, vomiting, conjunctivitis, skin rash, minor wounds, and burns; practices for the management of these children's health problems, including the use of home remedies, if any. Interviews were conducted with 100 women of Hispanic origin who had at least one child age 5 years or less and who were attending a community clinic in a rural area of central California. Mothers' beliefs about problem etiologies varied widely and revealed several misconceptions, folk beliefs, and lack of knowledge. The findings also revealed that only 32% of the mothers used or would use health professionals as the initial source of advice or help with children's problems. The majority of the subjects (81%) admitted to using home remedies to manage children's problems; 17% sought the help of a folk healer (mainly for the treatment of empacho). The various types of home remedies used by mothers were described and included the ingestion or application of certain foods, fluids, herbal teas, or other materials as well as methods to eliminate the perceived causes of the problems. It is important to note that 11% of the mothers had used azarcon or greta (substances containing lead) for treating empacho and other stomach problems in children. The need for culturally responsive and sensitive health care is discussed. PMID- 7839681 TI - Lesbians' health-related experiences of care and noncare. AB - In this feminist narrative study using in-depth interviews, focus groups, and a multistaged narrative analytic approach, a racially and economically diverse sample of 45 lesbians conveyed their health care experiences. Participants recounted a total of 332 health care interactions across a wide range of health care facilities, health care providers, and health conditions; 23% of these interactions they evaluated positively and 77%, negatively. In their stories, lesbians described the pivotal dimensions of face-to-face health care from their perspective as clients. Each of these interactional dimensions is defined by a fundamental experiential contrast gleaned from their descriptions of caring and noncaring clinical situations. They are as follows: existence: reflection versus facelessness; bodily integrity: intimate care versus intrusion; emotional integrity: sheltered versus shamed; worth: sustained versus abandoned; expression: voiced versus silenced; and power: solidarity versus dominance. PMID- 7839682 TI - Using Gilligan's framework to analyze nurses' stories of moral choices. AB - The manner in which nurses address and eventually solve ethical and moral questions and institutional problems is not yet well explained. This is a qualitative descriptive study examining the moral decision-making processes used by 24 nurses. The work of Carol Gilligan provides the framework for this study. The perspectives of the nurses was explored and a determination was made as to whether the justice or caring orientation prevailed in the situation. The method described by the Gilligan group is explained. Three stories are presented to serve as exemplars of the various orientations and of institutional forces that were active in the nurses' stories. The caring orientation was clearly present, as was the justice orientation to a lesser degree. Other issues such as power and financial security also were apparent. PMID- 7839683 TI - Values influencing neonatal nurses' perceptions and choices. AB - The purpose of this research was to identify the values influencing the nurses' perception and choice of behavior in a hypothetical clinical situation. The theoretical framework was Rokeach's theory on the nature of human values and value systems. A descriptive study using a mailed survey was conducted on a random sample of 331 members of the National Association of Neonatal Nurses. Data on individual nurse's values, perception of information, and behavioral choices were collected with an investigator-developed questionnaire consisting of a values scale, and an information scale and choice alternatives related to three hypothetical vignettes: a low-birthweight infant, an infant with chromosomal anomalies, and a chronically ill infant. Results of this study indicate that nurses identified a hierarchy of values related to their practice. Information related to infant characteristics was consistently most important; however, in uncertain situations, rules or external protocols had an increased influence on the behavioral choice process. The behavioral choice option with the greatest agreement was different for each situation. A consistently negative correlation between the options within each vignette indicates that nurses have clearly defined choice preferences. Model testing revealed a consistent relationship across the three vignettes between the variable being just and protocol, doing right and infant characteristics, and infant characteristics and the choice options (p < .05). PMID- 7839684 TI - Nutrition preparation and the geriatric nurse. AB - The purpose of this study was to determine whether or not geriatric nurses are prepared to implement nutrition interventions for high-risk elderly patients. Many factors can influence poor dietary intakes among the elderly, thus contributing to disease and impeding recovery from illness. The nurse, the main caregiver, must be prepared to care for this vulnerable population. Seventy-one geriatric nurses from randomly selected nursing homes and swing-bed facilities within a midwestern state were selected for participation in this descriptive correlational study. The nurses were evaluated for nutrition knowledge as well as for demographic and educational correlates. This study supports a moderate correlation between the number and type of nutrition-related continuing education programs and nutrition knowledge levels of the geriatric nurses. Significant differences were found in geriatric nurses' nutrition knowledge scores in the following nutrition content areas: nutrient digestion, absorption, and metabolism; nutrition throughout the life cycle; diet and disease; cultural and regulatory considerations for food and nutrition; and nutrient quality. PMID- 7839685 TI - Time series analysis of physiological response during ICU visitation. AB - Time series analysis (TSA) is an important statistical procedure for clinical nursing research. The current paucity of nursing research reports using TSA may be due to unfamiliarity with this technique. In this article, TSA is compared with the ordinary least squares regression model; validity concerns of time series designs are discussed; and concomitant and interrupted TSA of data collected on the effects of family visitation on intracranial pressure (ICP), heart rate, and blood pressure of patients in ICUs are presented. The concomitant TSA of the effect of family on ICP suggested that family presence tended to be associated with decreased ICP. Interrupted TSA indicated the effect of family on heart rate and blood pressure was not as consistent: The overall effect on blood pressure appeared to be negligible, and heart rate may increase overall. Restrictive visiting policies, once typical of intensive care units, should be reconsidered. PMID- 7839686 TI - Serendipity in the pursuit of wisdom in mental illness research. PMID- 7839687 TI - Teaching nursing students to critique research for gender bias. PMID- 7839688 TI - [The significance of lipoprotein(a) in assessment of risk for atherosclerosis]. AB - Lipoprotein(a) [Lp(a)] consists like the low-density-lipoprotein (LDL) in the structure protein apolipoprotein B, but is additionally connected with apolipoprotein(a), which is highly homologous to plasminogen. The physiological function of Lp(a) is yet not entirely clear. Lp(a) is established to be an independent factor in the genesis of atherosclerosis however. With occurrence of high Lp(a) Lp(a) plasma levels and other atherogenous risk factors at the same time a potentiation of their effects on genesis of atherosclerosis is observed. Unfortunately the therapeutic possibilities of counteracting the high atherogenicity of Lp(a) are still limited, because LDL apheresis as the only known effective technique today cannot be applied in all cases. In several studies it has been shown, that Lp(a) concentrations can be reduced mainly by long term treatment with lipid-lowering sustained-release bezafibrate, ACE inhibitor fosinopril, alpha-tocopheryl-nicotinate and N-acetylcysteine. Because of the synergistic effects of atherogenous risk factors patients with high Lp(a) concentrations should avoid additional risk factors such as hypertension, smoking, diet increasing LDL, etc. PMID- 7839689 TI - [Austrian anomalous data in sex-specific trends in suicide rates of central Europe]. AB - To report on suicides among a nation's population over time 4 types of figures, hierarchically related, are used. The total yearly number (1), the crude rate (2), the set of age adjusted rates (3) and the standardized rate (4). Only the latter 2 figures can be used for comparisons among different nations as they adjusted for confounding by age. For the period 1970 to 1990 Austria's 24.4/100,000 person-years (women 13.2, men 38.0), is higher than all of its neighbors except Hungary. We observed, in contrast to reports from other countries, a sex differential in time trends for the same period: male rates increased, whereas those for females decreased over time. Trends in neighboring nations indicated for both sexes always in the same direction. A recent (1986 to 1991) drop in both male and female suicide rates could indicate an end to the observed exception. Thus the sex differential in Austrian rates should be monitored closely in the future. PMID- 7839690 TI - [Work and life style of homeopathic physicians in Austria. A descriptive study]. AB - This study is based on a survey involving 117 physicians in Austria, working in private practice and under the National Health Plan on a homeopathic basis. The questionnaire covered such topics as socio-demographic data, individual methods of working, office organization, application of alternative therapies, health awareness, and perception of the general acceptance of homeopathy. The results showed that considerably more time is taken for treating patients homeopathically than for patients treated traditionally under the National Health Plan. More than half the physicians use homeopathic remedies exclusively, whereas homeopathic combination remedies were rarely administered. Neural therapy, microbiological therapy (bacterial immunostimulation) and phytotherapy are those alternative therapies most frequently used in addition. A spiritual approach seems to be a significant component of the working methods of these doctors. Their working method is generally traditional: exact medical history and physical examination are ranked high, whereas biochemical data are regarded to be less important for diagnosis. PMID- 7839691 TI - [Pernicious anemia in a patient with primary biliary cirrhosis]. AB - A 54 years old female patient with primary biliary cirrhosis and pernicious anemia is reported. Primary biliary cirrhosis has been reported with numerous other autoimmune disorders, but it has to our knowledge not previously been reported in association with pernicious anemia. PMID- 7839692 TI - [How to lie with statistics--how easily does it start?]. PMID- 7839693 TI - WHO Expert Committee on Biological Standardization. PMID- 7839694 TI - Metabolism of lofepramine and imipramine in liver microsomes from rat and man. AB - 1. The in vitro metabolism of lofepramine was studied in comparison with imipramine. Both compounds were hydroxylated and demethylated by a NADPH generating system in rat and human liver microsomes. 2. Three metabolites were in common for the two drugs, namely desipramine (DMI), 2-hydroxydesipramine (2-OH DMI) and didesmethylimipramine (DDMI). 3. Lofepramine was also metabolized to three unique tricyclic metabolites. Comparisons with authentic reference compounds suggested that two of these metabolites were 2-hydroxylofepramine and desmethyllofepramine. 4. The ratio between the concentrations of DDMI and DMI was higher for lofepramine than imipramine. This is probably due to DDMI formation via two parallel metabolic pathways of lofepramine, i.e. DMI and desmethyllofepramine, respectively. 5. It is speculated that the different metabolic pattern of lofepramine as compared with desipramine and imipramine is of importance for the therapeutic profile of the drug. PMID- 7839695 TI - Biotransformation of furaltadone by pig hepatocytes and Salmonella typhimurium TA 100 bacteria, and the formation of protein-bound metabolites. AB - 1. The major metabolite resulting from the biotransformation of furaltadone (5 morpholinomethyl-3-[5-nitrofurfurylidene-amino]-2-oxazoli dinone) by pig hepatocytes was shown to result from the N-oxidation of the tertiary nitrogen in the morpholino-ring, leaving the nitrofuran ring unchanged. 2. No evidence could be obtained for the formation of an open-chain cyano-metabolite, a minor metabolite in the case of the related nitrofuran drug furazolidone (N-(5-nitro-2 furfurylidene)-3-amino-2-oxazolidinone). This metabolite was the major metabolite, following incubation of furaltadone and furazolidone with Salmonella typhimurium bacteria. 3. The N-oxide was not further metabolized by pig hepatocytes or bacteria, and gave negative test results in the Ames-test (TA 100, no S9-mix) at the highest tested dose of 1 microgram/plate. Furaltadone gave a positive result at 10 ng/plate. 4. The biotransformation of both drugs by pig hepatocytes and bacteria resulted in the formation of protein-bound metabolites, with no clear quantitative differences between the two drugs. The intact 3-amino 2-oxazolidinone (AOZ) and 5-morpholinomethyl-3-amino-2-oxazolidinone (AMOZ) side chains of furazolidone and furaltadone, respectively, could be released from these metabolites by mild acid treatment. 5. Hepatocytes incubated with the AMOZ side-chain of furaltadone showed a decreased monoamine oxidase activity at high dose levels (IC50 3.7 mM), whereas exposure to the AOZ side-chain of furazolidone resulted in a clear inhibition at 10,000-fold lower concentrations (IC50 0.5 microM). In the presence of 1% dimethylsulphoxide (DMSO), the MAO-inhibition by AMOZ and especially AOZ was remarkably reduced. 6. It is concluded that protein bound metabolites containing an intact and releasable side-chain might be present in tissues of animals treated with furaltadone. However, these residues might be of less toxicological concern than those of furazolidone. PMID- 7839696 TI - In vitro biotransformation of thiazopyr by rat liver microsomes: oxidative cleavage of a carboxylic methylester by monooxygenases. AB - 1. Thiazopyr was metabolized by liver microsomes from male Sprague-Dawley rats to a previously unidentified metabolite. 2. The new metabolite was identified by coelution with an authentic standard in hplc and by electrospray lc/ms as the corresponding carboxylic acid. 3. Formation of the carboxylic acid metabolite was inhibited in the presence of mono-oxygenase inhibitors including piperonyl butoxide, 1-aminobenzotriazole, metyrapone and tetcyclacis. 4. Transformation of thiazopyr to its carboxylic acid by rat liver microsomes is mediated by mono oxygenases and not hydrolases. PMID- 7839697 TI - Structure-activity relationships in the formation of amides from substituted N benzylanilines. AB - 1. The in vitro hepatic microsomal metabolism of certain substituted N benzylanilines was studied in the male hamster to establish the mechanism(s) and process(es) involved in the formation of the corresponding amides. 2. N-Benzyl 2,4,6-trihalogeno, N-benzyl-4-cyano- and N-benzyl-4-nitroanilines were only metabolized by N-debenzylation. However, N-benzyl-4-methyl- and N-benzyl-2,4,6 trimethylanilines gave rise to both the corresponding amide and nitrone metabolites together with dealkylation products. These latter two substrates also produced hydroxymethyl metabolites as major products. Metabolism of N-(2,4,6, trimethylbenzyl)aniline also led to the formation of an amide metabolite. The dealkylation products, the corresponding imine and an unknown metabolite, probably an hydroxylated product were also detected with this substrate. 3. N (2,4-Dichlorobenzyl) and N-(2,6-dichlorobenzyl) anilines yielded the corresponding nitrone metabolites; but no amide metabolite was detected. Oxidative dealkylation leading to the formation of the corresponding primary anilines and aldehydes, together with para hydroxylation of aniline rings, were established as major routes of metabolism for both compounds. Similarly, neither N-(2,4,6-trifluorobenzyl) nor N-(4-nitrobenzyl) anilines produced any amide metabolite although dealkylation products were detected. 4. The pattern of amide formation observed for these N-benzylsubstituted anilines is discussed in terms of the steric and electronic effects of their aromatic substituents. PMID- 7839698 TI - Toxicokinetics and biotransformation of pentachlorophenol in the sea urchin (Strongylocentrotus purpuratus). AB - 1. The toxicokinetics and biotransformation of pentachlorophenol (PCP) were determined in the purple sea urchin (Strongylocentrotus purpuratus). 2. In a static chamber, urchins (n = 9) were individually exposed to 50 micrograms/l of [U-14C]PCP for 24 h to determine bioconcentration and the absorption rate constant (Ka), elimination rate constant (Ke), and elimination half-life (t1/2). Determination was by direct quantitation of radioactivity in the exposure water. 3. After exposure, urchins were placed in a flow-through chamber for 24 h to allow depuration of retained residues, which were identified by hplc and quantified by lsc. The Ka and Ke, calculated using a simplified model, were 0.12 +/- 0.06 h and 0.43 +/- 0.22 h, respectively, whilst the 24-h total concentration factor was 316.3 +/- 209.7, and the t1/2 was 1.6 +/- 0.8 h. 4. Whereas urchins depurated 40.6% of retained residues, only a small amount of PCP was excreted unchanged (17.0%), as the more polar conjugates pentachlorophenyl-beta-D glucoside (72.4%) and pentachlorophenylsulphate (10.6%) were also formed. PMID- 7839699 TI - Influence of the type of halogen substituent on in vivo and in vitro phase II metabolism of 2-fluoro-4-halophenol metabolites formed from 3-halo fluorobenzenes. AB - 1. The influence of a change in the type of halogen substituent on phase II metabolism of 2-fluoro-4-halophenol metabolites formed from 3-halo-fluorobenzenes was studied in vivo and in vitro using 19F nmr and spectroscopic assays. 2. The ratio of sulphation to glucuronidation of 2-fluoro-4-halophenol metabolites formed from 3-halofluorobenzenes decreased from 48 to 13 to 6 when the halogen substituent varied from fluorine to chlorine to bromine. 3. When the 2-fluoro-4 halophenols themselves were administered to the rats, the ratio of sulphation to glucuronidation was not affected by the type of halogen substituent at C4 and at a constant value of 0.6, i.e. significantly lower. 4. Kinetic data for P450 catalysed hydroxylation of the 3-halo-fluorobenzenes and for sulphation and glucuronidation of their 2-fluoro-4-halophenol metabolites were obtained from in vitro microsomal and cytosolic incubations. These data demonstrate that the effects of varying the halogen substituent on phase II metabolism of the 2-fluoro 4-halophenol metabolites can be mainly ascribed to an apparently decreased Km for the glucuronidation of the 2-fluoro-4-halophenols with a change in the halo substituent from fluorine to chlorine to bromine. 5. Results from calculations on electronic and structural characteristics of the three 4-halo-2-fluorophenols demonstrate that the best explanation for the decrease in the apparent Km of the glucuronidation from 2,4-difluoro- to 4-chloro-2-fluoro- to 4-bromo-2 fluorophenol might be an increase in the hydrophobicity of the phenol. An increase in the hydrophobicity of the phenol would provide an increased possibility for substrate accumulation in the hydrophobic membrane environment of the UDP-glucuronyltransferases, resulting in an apparently decreased Km. PMID- 7839700 TI - Metabolism of 3,5,3',5'-tetrachlorobiphenyl by rat liver microsomes and purified P4501A1. AB - 1. The metabolism of 3,5,3',5'-tetrachlorobiphenyl (TCB) was investigated with liver microsomes and purified P450 from the male Wistar rat. 2. One novel metabolite was produced after incubation with liver microsomes derived from the 3 methylcholanthrene (MC)- and 3,4,5,3',4'-pentachlorobiphenyl-pretreated rat, but not after incubation with those from the untreated or phenobarbital (PB) pretreated rat. These results suggest that P450 isozyme(s) induced by MC-type inducers is involved in 3,5,3',5'-TCB metabolism. 3. The chemical structure of this metabolite was identified to be 4-hydroxy-3,5,3',5'-TCB by comparison of its retention time in glc and the ms with those of a synthetic sample. 4. Purified rat P4501A1, a major MC-inducible P450 isozyme, catalyzed the 4-hydroxylation of 3,5,3',5'-TCB, but P4502B1, a major PB-inducible isozyme, was inactive. 5. Reduced glutathione completely inhibited the formation of the hydroxylated metabolite, suggesting that 4-hydroxylation of 3,5,3',5'-TCB proceeded via the 3,4-epoxide. PMID- 7839701 TI - Effect of an experimental malaria infection on the metabolism of phenacetin in the rat isolated perfused liver. AB - 1. The effect of infection with the rodent malaria parasite Plasmodium berghei on the metabolism of phenacetin has been investigated in a rat isolated perfused liver preparation. 2. A bolus dose of phenacetin (10 mg) was introduced into the perfusate reservoir of both control (n = 4) and malaria-infected (n = 4) liver preparations, and samples of bile and perfusate were collected (0-4 h) for hplc analysis of phenacetin, paracetamol and its phase II metabolites. 3. Whereas malaria had no effect on the hepatic clearance of phenacetin (control: 0.64 +/- 0.15 versus malaria: 0.66 +/- 0.14 ml min-1), there was a significant reduction in the hepatic clearance of generated paracetamol (control: 1.22 +/- 0.15 versus malaria: 0.41 +/- 0.08 ml min-1) and the total recovery in bile and perfusate of paracetamol glucuronide (control: 1.18 +/- 0.44 versus malaria: 0.29 +/- 0.20 mg). There was no significant change during malaria infection in the total recovery of either phenacetin (control: 1.30 +/- 0.73 versus malaria: 0.79 +/- 0.36 mg) or paracetamol sulphate (control: 0.81 +/- 0.25 versus malaria: 0.74 +/- 0.16 mg), PMID- 7839702 TI - Metabolism of [3-14C] coumarin by human liver microsomes. AB - 1. The metabolism of 50 microM [3-14C] coumarin has been studied in a panel of 12 human liver microsomal samples of known P450 isoenzyme profile. 2. [3-14C] coumarin was metabolized by human liver microsomes to various polar products including 3-, 4- and 7-hydroxycoumarins (3-HC, 4-HC and 7-HC) 6,7 dihydroxycoumarin (6,7-DiHC), o-coumaric acid (o-CA), o-hydroxyphenyl acetaldehyde (o-HPA), o-hydroxyphenylethanol (o-HPE), o-hydroxyphenylacetic acid (o-HPAA) and o-hydroxyphenylpropionic acid (o-HPPA) and to product(s) that bind covalently to microsomal proteins. 3. For all 12 subjects, mean rates of [3-14C] coumarin metabolism to total polar products (metabolism to all products except product(s) covalently bound to microsomal proteins), 7-HC, the 3-hydroxylation pathway (sum of 3-HC, o-HPA, o-HPE and o-HPAA), o-HPPA, 6,7-DiHC and covalent binding were 1420, 1230, 73.8, 52.5, 9.5 and 4.8 pmol/min/mg protein respectively. 4. Marked interindividual differences in [3-14C] coumarin metabolism to total polar products (30-fold variation) and 7-HC (2250-fold variation) were observed. 5. Good correlations were observed between [3-14C] coumarin metabolism and total polar products, 7-HC, o-HPPA and 6,7-DiHC, but not to 3-hydroxylation pathway products and levels of 2A6 and 2B6 in human liver microsomes. 6. [3-14C] coumarin metabolism to any polar products did not correlate with levels of 1A2, 2C8, 2C9, 2E1, 3A3/4 and 4A1 in human liver microsomes. PMID- 7839703 TI - Disposition of gemcitabine in rat and dog after single and multiple dosings. AB - 1. The disposition of radioactivity has been studied in rat and dog after intravenous administration of a single 10 mg/kg dose or multiple 1 mg/kg/day doses of 14C-gemcitabine. 2. Radioactivity was eliminated from the blood in a biphasic manner with half-lives of approximately 2 and 15 h in both the male and female rat. The concentration of radioactivity in the blood 24 h after the fifth dose was 4.4 times higher than that found after the first dose. In the male dog, the concentration of radioactivity in the blood showed a plateau during the first 2 h post-dose administration. 3. Radioactivity was rapidly and widely distributed throughout the body in both the male and female rat at 5 min after administration. Radioactivity was rapidly eliminated from the tissues with no evidence of accumulation. 4. After 120h, male rat excreted 95.2 and 1.9% of the dose in the urine and faeces respectively. Similar excretion patterns were observed in female rat and male dog. In rat, excretion of radioactivity in the urine 24 h after daily dosing was nearly constant, but excretion of radioactivity in the faeces slightly increased with increasing number of doses. PMID- 7839704 TI - Application of pharmacokinetic studies to a novel antidepressant, E2011. AB - 1. The original drug tested here, (5R)-3-[2-(3-cyanopropyl)benzothiazol-6-yl]-5 methoxymethyl-2-oxaz olidinone (ER-4539), exhibited strong MAO-A inhibitory activity in vitro, but its bioavailability in rat was very low. After ER-4539 was administered orally to dog, a metabolite was found in plasma. 2. The metabolite was isolated by hplc after incubation with dog liver microsomal preparations. Its structure, determined by ms and nmr analysis, was alpha-hydroxy-ER-4539. The configuration of the alpha-hydroxy metabolite was (S), determined in comparison with the authentic sample of (R) and (S) by hplc. The isolated metabolite had potent MAO-A inhibitory action in vitro, indicating that it would have antidepressant action. 3. (5R)-3-[2-((1S)-3-Cyano-1-hydroxypropyl)benzothiazol-6 yl]-5- methoxymethyl-2-oxazolidinone (E2011), the synthesized metabolite, has been improved in regard to biopharmaceutical characteristics in rat and dog. PMID- 7839705 TI - [Immunopathogenesis of inflammatory rheumatic diseases--autoimmunity versus infection]. PMID- 7839706 TI - [The current status in diagnosis of Sjogren syndrome with reference to the practical value of examination methods]. PMID- 7839707 TI - [Interstitial lung manifestations in systemic scleroderma. Correlation between alveolitis, autoantibodies and clinical manifestations]. PMID- 7839708 TI - [Indications and value of radiologic procedures in diagnosis of osteoporosis]. PMID- 7839709 TI - [Vasculitis in inflammatory-rheumatic diseases--current diagnosis and therapy]. PMID- 7839710 TI - [Autoantibodies as diagnostic markers in congenital heart block]. PMID- 7839711 TI - [Therapy of rheumatic diseases with methylprednisolone--mechanism of action and clinical applications]. PMID- 7839712 TI - [Regulatory processes and disease dynamics of the arthritic joint. 1: The concept of arthrosis and biomechanical functional load bearing]. PMID- 7839713 TI - [Regulatory processes and disease dynamics of the arthritic joint. 2: Bioelectric mechanisms and synovial pO2 at rest]. PMID- 7839714 TI - [From general practice of an expert witness service: postoperative fragment malposition should be recognized immediately]. PMID- 7839715 TI - [Sex related risk of especially type II diabetes in a rural area]. PMID- 7839716 TI - [Prognosis of diabetic patients in Northeast Germany]. PMID- 7839717 TI - [Electro- and electronic refuse from the toxicologic viewpoint]. PMID- 7839718 TI - [Simon Pallas (1694-1770) and surgical education in Berlin]. PMID- 7839719 TI - A framework for the evaluation of vaccines for use in the expanded programme on immunization. AB - Since 1974, the Expanded Programme on Immunization (EPI) has provided technical support for the immunization of the world's children and women of childbearing age. Today, the vast majority of vaccines administered to these groups are delivered through the immunization programmes that have been established in developing countries. As these national programmes share many characteristics, the global use of a new or improved vaccine could be largely dependent on its compatibility with the priorities, existing antigens and vaccine delivery system of this network. Consequently, a framework has been developed for the systematic evaluation of candidate vaccines for use in EPI. PMID- 7839720 TI - Barriers to immunization--an examination of factors that influence the application of pneumococcal vaccine by house staff. AB - Pneumococcal infection is a leading cause of adult morbidity and mortality in the United States. Immunization against this infection is a valuable strategy in preventive medicine. An effective pneumococcal vaccine has been available in this country for over a decade, but it remains poorly utilized. The purpose of the present investigation was to analyse the factors that affect the use and administration of the pneumococcal vaccine and to identify barriers to use. Upper level internal medicine residents (n = 33) from two medical clinics associated with an academic medical centre completed an explanatory survey. This explored the levels of house-staff knowledge, perception and attitudes regarding the vaccine and the existence of practical barriers against its utilization. chi 2 analyses and z tests were carried out to determine significance, where appropriate. The majority of the house staff (22, 66.7%) answered correctly regarding vaccine target groups, and all residents indicated that they generally obtain a vaccination history in adult patient evaluation. However, a sizeable number (14, 42.4%) did not indicate a time of the year when they routinely administered vaccines to patients. They were not confident about their knowledge regarding vaccine guidelines (23, 69.7%) and had an exaggerated fear of hypersensitivity reactions from immunization (20, 60.6%). Neither the expense of the vaccine nor adverse publicity were impediments to immunization (24, 72.7% and 28, 84.8%, respectively). Although most physicians knew of the usefulness of the vaccine (31, 93.9%), many failed to translate this knowledge into clinical practice (22, 66.7%). 'Pressing' clinical issues were viewed as barriers to vaccination (18, 54.5%) and placed the practice of preventive medicine in a subordinate position.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7839721 TI - Immunization of cottontop tamarins and rabbits with a candidate vaccine against the Epstein-Barr virus based on the major viral envelope glycoprotein gp340 and alum. AB - The Epstein-Barr virus (EBV) is associated with a range of life-threatening diseases in humans. Development of an effective vaccine has therefore been an important objective. One problem in the development of a subunit vaccine for human administration is the selection of a satisfactory adjuvant since the only one currently licensed for human use is alum, although this is not considered to be very effective. The present study demonstrated that a subunit vaccine composed of the EBV envelope glycoprotein gp340 with alum as the adjuvant did elicit protective immunity against EBV-induced lymphoma in three out of five cottontop tamarins. Furthermore, rabbits immunized with gp340/alum developed the same range of antibody responses as rabbits immunized with gp340/SAF-1, an experimental adjuvant claimed to be more effective than alum. Therefore, these results indicate that alum should be evaluated as an adjuvant as part of a human trial of a gp340-based subunit vaccine. PMID- 7839722 TI - Immune response to influenza vaccination of elderly people. A randomized double blind placebo-controlled trial. AB - The objective of this study was to determine the immune response to influenza vaccination in elderly people, using a randomized, double-blind, placebo controlled trial. Venous blood was taken from 1838 people aged 60 years and older, prior to injection with the influenza vaccine or a placebo. A second blood sample was taken three weeks later. The antibody reaction was measured by comparing the geometric mean titre and the percentage of participants who had a protective antibody titre before and after vaccination and for all sera of each strain. A protective antibody titre was found in 43-68% of those who had received the vaccine, depending on the strain investigated. Patients potentially at risk showed a response similar to the other participants. We conclude that influenza vaccination in elderly people provides a reasonable to good immune response. Research is needed on whether a good immune response decreases the incidence of influenza. PMID- 7839723 TI - Enhancement of the efficacy of a replication-defective adenovirus-vectored vaccine by the addition of oil adjuvants. AB - We previously constructed a recombinant adenovirus with a defective E1A gene, which expresses high levels of the pseudorabies virus gp50 in non transcomplementing cells. The virus is unable to replicate in mice. It elicited the production of anti-gp50 antibodies only when high concentrations (10(8) TCID50 per dose) of the virus were used and it gave mice little protection. The combination of the recombinant adenovirus at several concentrations (10(8), 10(7.4), 10(6.4) TCID50 per dose) with certain oil adjuvants in different galenic forms (water-in-oil, oil-in-water, water-in-oil-in-water) led to an increase in specific antibody responses and protection for the host when challenged with a virulent pseudorabies virus under very severe conditions, i.e. where 100% of unvaccinated mice died. A water-in-oil-in-water formulation induced a very high level of anti-gp50 antibodies even with a low concentration of adenovirus. These results could be correlated to the induction of cytokines, such as IL6, which is observed with this galenic form. The oil-adjuvanted emulsions induced IL2, suggesting that they were able to activate T-helper cells. Different oil formulations elicited the different IgG subclasses (IgG1, IgG2a, IgG2b, IgG3). These results can be extended to other live replication-defective vaccines expressing different proteins. PMID- 7839724 TI - The cell-binding carboxyterminal undecapeptide of SV40 tumour antigen provides protective cell-dependent immunity. AB - This paper describes the use of the synthetic carboxyterminal undecapeptide of large SV40 tumour antigen, lys698-thr708 (KT) to protect Balb/c mice against growth of subcutaneously transplanted tumorigenic SV40-transformed cells (VLM). The vaccine was prepared by conjugation of KT with 3-(2-pyridyldithio)propionic acid N-hydroxysuccinimide (SPDP). Addition of the SPDP-derivative of KT to syngeneic spleen cells rendered KT covalently linked to free thiol-groups of the cell membranes by the formation of -S-S-CH2-CH2-CO-epsilon-NH-lys698 bonds. Vaccination with KT-conjugated cells was intraperitoneal. Alternatively, KT conjugated cells were generated in the peritoneum by injection of PDP-KT ((2 pyridyldithio)propionic acid-KT). As a control 60Co-irradiated VLM cells were used. In five experiments all VLM-vaccinated and the majority of the PDP-KT-(or KT-spleen cell)-vaccinated mice were protected against tumour growth. However, mice pretreated with saline, unconjugated spleen cells, free KT, KT conjugated to bovine serum albumin, or KT with incomplete Freund's adjuvant developed tumours. Treatment of PDP-KT-vaccinated mice with anti-CD4 or anti-CD8 immunoglobulin abolished tumour immunity completely. Thus, covalent binding of the carboxyterminal undecapeptide of SV40 tumour antigen to viable, untransformed cells yielded a vaccine which protects Balb/c mice against SV40 tumours. PMID- 7839725 TI - Broadly reactive HIV-2 and SIVmac specific antibody-dependent cellular cytotoxicity in immunized and infected cynomolgus monkeys. AB - Antibody-dependent cellular cytotoxicity (ADCC) was analysed in groups of cynomolgus monkeys that had been immunized with either HIV-2 (strains SBL6669 or SBL-K135) or SIVmac. HIV-2- and SIVmac-infected monkeys were also studied for ADCC. Sequential serum samples were collected from the animals, which were followed for 1 to 3 years. Sera from the HIV-2-immunized monkeys had ADCC against both homologous and heterologous HIV-2 strains as well as cross-reactivity against SIVmac-infected target cells. This broadly reactive ADCC response could be detected within the first weeks after immunization. Homologous ADCC was also seen in seven of eight SIVmac-immunized monkeys which were all protected from later challenge with SIVmac or SVsm. ADCC titres sometimes decreased after a few months if the immunized monkeys were not boosted whereas most of the HIV-2-and SIVmac-infected monkeys developed a rapid and persistent ADCC response. The presence of ADCC, like the presence of neutralization in previous studies, did not predict whether the immunized monkeys would be protected upon challenge with live virus. PMID- 7839726 TI - Effect of a lipopeptidic formulation on macrophage activation and peptide presentation to T cells. AB - We studied a 45-69 lipopeptide obtained by N-terminal modification with a N epsilon-palmitoyl lysine residue of the 45-69 peptide derived from the nef protein of HIV. T cells from animals immunized intraperitoneally with 45-69 lipopeptide proliferated in vitro in the presence of 45-69 peptide while no response was obtained after intraperitoneal immunization with 45-69 peptide. The efficiency of the 45-69 lipopeptide is supported by the covalent association to the N epsilon-palmitoyl lysine moiety. The immunogenicity of the 45-69 lipopeptide or of the unmodified peptide is dependent on the route of immunization but is not related to a mitogenic effect on cells or to an increase of the peptide antigenicity. Moreover, only 45-69 lipopeptide induces the secretion of cytokines such as IL-1, IL-6 and TNF-alpha by peritoneal macrophages. Finally, the use of 45-69 lipopeptide permits the activation of highly purified T cells without the addition of antigen-presenting cells. These results have implications for the formulation of synthetic vaccines. PMID- 7839727 TI - Protection of immunosuppressed mice against translocation of Pseudomonas aeruginosa from the gut by oral immunization with recombinant Pseudomonas aeruginosa outer membrane protein I expressing Salmonella dublin. AB - AroA Salmonella dublin was used as recipient for a plasmid coding for the outer membrane protein I (OprI) of Pseudomonas aeruginosa. Oral immunization of Balb/c mice with recombinant S. dublin induced serum IgG and IgA antibodies against P. aeruginosa. In spleen and Peyer's patches anti-P. aeruginosa IgG- and IgA secreting cells could be measured by the ELISPOT technique. In an oral challenge of immunosuppressed mice with P. aeruginosa the orally immunized animals had a 58 fold higher LD50 than control animals. PMID- 7839728 TI - Measles seroprevalence and vaccine response in HIV-infected adults. AB - Measles in HIV-infected patients can be a severe, even fatal, illness. The prevalence of measles seropositivity in HIV-infected adults and the durability of these antibody levels are uncertain. A prospective survey of 210 HIV-infected adults found that 95% of the adults had demonstrable antibodies using a standard ELISA technique. Seropositivity was no different in patients with CD4 counts over 400, from those with more advanced disease and CD4 counts under 200 (p = 0.8). Six seronegative patients were vaccinated and had serial antibody determinations: two of six (33%) patients had a durable positive antibody response at 1 year, and none had any observed toxicity. Vaccination of the identified measles seronegative HIV-infected adults who are at high risk for measles is recommended, but a measurable antibody response may be expected in only a minority of cases. PMID- 7839729 TI - Demonstration of a virulent subpopulation in a prototype live attenuated turkey rhinotracheitis vaccine. AB - A prototype live attenuated turkey rhinotracheitis (TRT) vaccine, which was known to cause occasional disease in young poults following multiple back passage, was tested for the presence of a virulent subpopulation by a novel combined in vitro and in vivo screening technique. When vaccine was inoculated at high titres into chick embryo tracheal organ cultures, 17% of aliquots were found to cause ciliostasis, and when these aliquots, in turn, were inoculated into 1-day-old poults, approximately one-quarter caused clinical disease. Removal of the subpopulation by plaque purification led to viruses which had reduced tendency to revert to virulence but remained protective. The technique proved valuable in identifying virulent subpopulations in specific prototype TRT vaccines. The principle may have more general application. PMID- 7839730 TI - Effects of cholera toxin adjuvant on IgE antibody response to orally or nasally administered ovalbumin. AB - Effects of cholera toxin B subunits supplemented with 0.1% cholera toxin (CTB*) on systemic IgE antibody responses to ovalbumin (OVA) were examined in BDFI (H 2b/d), Balb/c (H-2d) and C3H (H-2k) mice given OVA intragastrically or intranasally. Two successive doses of OVA intragastrically administered to Balb/c and C3H mice induced little IgE response and resulted in almost complete unresponsiveness to subsequent intraperitoneal challenge with OVA in Al(OH)3, while the intragastric administration to BDF1 mice induced high IgE response and resulted in abrogation of the unresponsiveness to the subsequent challenge. The intranasal administration of OVA induced little IgE response and suppressed response to the subsequent challenge in any strain of mice. On the other hand, two successive doses of intragastric or intranasal OVA together with CTB* enhanced IgE response in all three strains and the subsequent challenge with OVA in Al(OH)3 induced higher IgE responses. These results suggest that CTB* augments IgE response to OVA and abrogates the unresponsiveness when administered orally or intranasally into mice together with OVA, regardless of the H-2 haplotype of the mice. PMID- 7839731 TI - Activation of systemic and mucosal immune response following nasal administration of liposomes. AB - Adjuvant effects of liposomes on systemic and mucosal immune response were investigated following nasal administration to Balb/c mice. Bovine serum albumin (BSA)-specific serum IgG and salivary IgA levels were significantly elevated when BSA-associated liposomes were administered intranasally twice at 4-week intervals. Systemic immune response was activated only by negatively charged liposomes, while activation of mucosal immune response was independent of liposomal charge. Antigen localization in liposomes affected immune adjuvant effect; the mucosal immune response could be activated only by liposomes to whose surface BSA was attached, but the systemic immune response was activated by both liposomes to which antigens were attached and in which the encapsulating antigens occurred. The results suggest that the contribution of antigen-presenting cells in activation of systemic and mucosal immunity following intranasal administration is different. PMID- 7839732 TI - Actual daily dietary intake of selenium in Belgium, using duplicate portion sampling. AB - The dietary selenium (Se) intake in Belgium has been re-evaluated. Duplicate meal collection, wet acid destruction and flow injection hydride generation atomic absorption spectrometry were used as techniques. The daily intake ranged from 28.4 micrograms (Liege, Walloon part of the country) to 61.1 micrograms (Vilvoorde, central part of the country). Compared with intakes recently published for other countries, the actual Belgian value corresponds to intermediate ranges of Se intake. PMID- 7839733 TI - Reversed-phase HPLC analysis of peptides in standard and dairy samples using on line absorbance and post-column OPA-fluorescence detection. AB - Absorbance and post-column o-phthalaldehyde (OPA)-fluorescent detection were used to analyse standard and dairy peptides following reverse-phase HPLC. Using both detection systems on-line provides additional information on the presence of peptides in dairy products. The detection response depends on the amino acid composition of the peptide involved. Among the peptides used, glutathione, lysine containing peptides and peptides with glycine as the N-terminal residue give the highest fluorescence after the OPA post-column reaction. Absorbance is more sensitive than fluorescence for peptides with aromatic amino acids. Different parameters, such as the flow rate of OPA, the amount of mercaptoethanol in the OPA reagent and the temperature of reaction, substantially influence the fluorescent response of peptides. The interest of using on-line absorbance and fluorescence detection is highlighted by analysing peptides from skim milk and from a tryptic hydrolysate. PMID- 7839734 TI - [The decomposition of Maillard reaction products by amylolytic enzymes. 1. Reversible inhibition of alpha- and glucoamylase and alpha-glucosidase by oligosaccharide Amidori compounds]. AB - The influence of Amadori-compounds (fructosyl-, maltulosyl- and maltotriulosylglycin) on the activity of the enzymes alpha-glucosidase (from Saccharomyces cerevisiae), glucoamylase (from Aspergillus niger) and alpha amylase (from porcine pancreas) was studied. Fructosylglycin was not hydrolyzed by all three enzymes. alpha-Glucosidase hydrolyzes maltulosylglycin 10 times slower than maltotriulosylglycin. Glucoamylase and alpha-amylase catalyze only the cleavage of maltotriulosylglycin to form glucose and maltulosylglycin. The activities of alpha-glucosidase and glucoamylase are inhibited through the Amadori-compounds fructosyl- and maltulosylglycin. These Amadori-compounds don't influence the activity of alpha-amylase. Electronic effects or interactions between the secondary amino function of Amadori-compounds and the carboxyl- or carboxylate groups of active centres could be responsible for such an inhibition. PMID- 7839735 TI - [Determination of the activities of lipase, lipoxygenase and peroxidase in native and extruded cereal brans]. AB - To avoid fat deterioration in grain products during storage the cereal inherent enzymes lipase, lipoxygenase and peroxidase have to be inactivated. Known methods for the determination of the enzymes activity are tested and their applicability evaluated. Own optimized methods are presented. In laboratory and semiindustrial extrusion tests (laboratory single screw extruder, twin screw extruder, short screw extruder) the degree of enzyme inactivation of wheat bran, rye and maize bran, and oat bran is determined in dependence on the extrusion parameters. The enzymes mentioned already had been inactivated at mild extrusion conditions (temperature < 120 degrees C, moisture 20%, low mechanical stress). Only in brans of high fat content (10-14%) or high moisture (> 25%) minor residual activities of peroxidase and lipase were observed. PMID- 7839736 TI - Temperature dependence of lipoxygenase heat inactivation; evaluation with linearly increasing temperature profiles. AB - A non-isothermal kinetic method for evaluating the temperature dependence of enzyme heat inactivation has been developed from theoretical considerations. By using a non-linear regression software programme and enzyme activity data obtained along linearly increasing temperature profiles, z values of lipoxygenase were obtained in single experiments, substantially reducing time, cost, and labour. The z values so obtained were slightly dependent on heating rate, varying from 4.11 degrees C at a rate of heating of 2.56 degrees C/min to 4.66 degrees C at a heating rate of 1.48 degrees C/min. PMID- 7839737 TI - Characterization of fat replacers. AB - Effects of commercial fat replacers on rheological properties of emulsions have been studied under a second-order design. The corresponding functions of regression have been calculated to describe the measured effects mathematically. On the basis of a figured three-dimensional plan of response, combinations of variables (fat, fat replacer, water) could be determined showing a similar consistency to the corresponding full-fat foodstuff. PMID- 7839738 TI - Microparticulation of whey protein: related factors affecting the solubility. AB - Solubility of Simplesse 100, the only whey-based fat substitute, was found to be good, considering the fact that technology for preparation of Simplesse 100 is a sequence of thermal steps. To characterize this phenomen, gel chromatography on Sephadex G-100, Sephacryl S-1000 and SDS-PAGE were used, supported by high-speed separation, UV studies and analytical procedures. Results show that the unusual solubility characteristic of microparticulated whey protein is related to two molecular effects: (1) optimal defolding of protein molecules and (2) stabilization of the defolded status by carbohydrate. Both effects were considered to favour non-covalent bonds, which contribute to the outstanding physico-functional and nutritive properties of microparticles. PMID- 7839739 TI - [Chemiluminescence method for the detection of radiation-induced oxidation products in fat-containing foods]. AB - Radiation-induced oxidation of fatty foods was detected by a chemiluminescence method. Hazelnuts, peanuts and poultry were used as foodstuff samples. Additional investigations were performed with a model system and sunflower oil. The irradiation of the samples was carried out in a x-ray-fluorescence-apparatus. Thereby it is to note that the G-value of the x-ray-radiation is much higher than the G-value of a cobalt-60-source normally used for irradiation of food. A dependence of the integral of the light curve on the irradiation doses could be proved. Investigations with model systems which contained different amounts of alpha-tocopherol showed a decreasing chemiluminescence signal at low irradiation doses in presence of alpha-tocopherol. At higher doses the chemiluminescence signal enlarges with increasing amounts of alpha-tocopherol because irradiation products of alpha-tocopherol overlay its antioxidative effect. Irradiated poultry samples differ significantly from unirradiated samples after a deep-freeze storage of 26 weeks. A quantification of the doses is not possible without knowledge of the storage time, because the integrals decrease differently after irradiation during storage. In any case the chemiluminescence method is useful as a "screening method" for the detection of irradiation of foodstuffs with the possibility of automation and high sensitivity. PMID- 7839740 TI - [The efficiency of photometric determination of skatole in slaughtered swine]. AB - In a group of 264 boars, including both cryptorchides and hermaphrodites, skatole was measured using a photometric method developed in Denmark. It resulted in a concentration of skatole equivalents (SE) in the fat of 0.14 ppm in belly tissue and 0.18 ppm in flomen tissue on average, respectively. 10.6% of belly and 16.3% of flomen tissue exceeded the limiting value of 0.25 ppm skatole for boar taint. The photometric determination of skatole is based on a relatively unspecific reaction according to Ehrlich. Therefore, other derivatives of indole concerning the decomposition of tryptophan are recorded, and the results must be declared as SE. In comparison with HPLC, the photometric method yields values that are too high, indole is always found with skatole in a considerable amount, and the other skatole equivalents seem to play a subordinate part. PMID- 7839741 TI - Analysis of purine compounds and creatinine by ion-pair high-performance liquid chromatography (HPLC) as a method for the detection of yeast extracts in commercial meat flavourings. AB - The purine patterns of five industrially produced yeast extracts and nine yeast extract-based commercial meat flavourings were analysed by ion-pair HPLC after acid hydrolysis of the purine-containing compounds and a clean-up step via cation exchange. The results indicate that there is a good correlation between the adenine contents of the flavourings and the yeast extract percentages used for their manufacture. The possible addition of authentic meat constituents (e.g. meat extract) would contribute likewise to the adenine contents of commercial meat flavourings. To recognize those products the characteristic meat constituent creatinine was analysed simultaneously. PMID- 7839742 TI - Polychlorinated phenols in total diet. AB - A method has been developed for the isolation, separation and determination of chlorinated phenols in total diet. The isolation takes place following acid hydrolysis of the conjugates and is performed by simultaneous extraction and distillation with water vapour and toluene. The isolated chlorophenols are removed by clean-up on a Florisil column using a mixture of 15% dichloromethane in toluene for elution. The separation and determination is carried out by capillary gas chromatography with electron capture detection. The recovery of the method ranged between 70.1 +/- 5 and 96.8 +/- 4.9% for the individual chlorophenols. The determination limits were 0.5 to 1.0 microgram.kg-1. The method was applied in a study aimed at estimating the chlorophenol burden in two population groups (children up to the age of 6 years and students up to the age of 18 years). In two successive years, 80 total diet samples were analysed. Average contents of the individual chlorophenols were from 0.7 to 33.5 micrograms.kg-1 and were higher for the dichlorophenol isomers. The calculated average daily intake ranged from 0.04 to 1.69 micrograms.kg-1 body weight for the individual phenols. PMID- 7839743 TI - Invasion and replication of Brucella abortus in three different trophoblastic cell lines. AB - This study was performed to compare the replication of the pathogenic strain Brucella abortus 2308 in three trophoblastic cell lines derived bovine placentas at different gestational stages. The trophoblastic cell lines were obtained from a 13-15 day embryo, from 5-month placentomal tissue and from an 8-month extra placentomal portion of the placenta. The infection rate was similar in all cell lines at 4 h. Colony-forming Units were counted at 4, 8, 12, 24 and 30 h post inoculation. At 12, 16, 24 and 30 h B. abortus rapidly replicated within the 5 month and 8-month trophoblastic cell lines, but grew slowly within trophoblastic cells derived from embryonic tissue. Electron microscopic studies consistently showed clusters of B. abortus in trophoblastic cells derived from 5- and 8-month placentas, while few cells of the embryonic line were infected and these contained only 1-2 bacteria per cell. It was concluded that B. abortus can infect trophoblastic cells throughout the gestational period but bacterial multiplication does not occur in these cells before middle or late gestation. PMID- 7839744 TI - Access to the abomasum of sheep via a rumen fistula for follow-up studies during trichostrongylid infections. AB - A technique is described for the examination of the abomasum of adult sheep via a rumen fistula. The size of the fistula allowed a manual exploration of the rumen which was necessary to achieve an access to the abomasum. In four adult sheep, two of them infected with Haemonchus contortus, fibreoptic endoscopy was used to investigate the abomasal mucosa macroscopically as well as histopathologically and ultrastructurally by means of mucosal biopsy specimen. The acidity of the abomasal contents was measured directly by introducing an electrode into the abomasum or indirectly in abomasal fluid which was obtained via a stomach catheter through the rumen fistula. The measured values in all four sheep ranged between pH2 and 4. The fibreoptic examination of the abomasum did not influence the plasma pepsinogen and gastrin levels. The possibility of combining histological, serological and coprological data in follow-up studies on the pathophysiology of trichostrongylid infections in the abomasum of individual sheep seems to be useful for the investigation of primary and secondary infections and may contribute to a reduction of the number of experimental animals in such studies. PMID- 7839745 TI - Canine-coronavirus (CCV) characterization in Spain. Epidemiological aspects. AB - In this paper the characterization of a canine-coronavirus (CCV) strain isolated in Spain is reported. The CCV cellular-infection cycle on A-72 cells was studied using electron-microscopy techniques. The isolate was found to have similar electrophoretic profile and antigenic properties to an American reference strain. Sera samples were obtained from several canine populations and tested for viral antibodies using two immunoenzymatic methods. Sera specificity was confirmed using immunoblot analysis. The agreement between both ELISA tests produced adequate results (kappa value = 0.64). PMID- 7839746 TI - Tissue distribution and binding to plasma proteins of norfloxacin nicotinate after intramuscular administration in pigs. AB - Three clinically normal pigs were given a single intramuscular injection of an aqueous solution of norfloxacin nicotinate (NFN) at 14 mg/kg body weight. Animals were killed 4 h after treatment and the concentrations of norfloxacin in various biological fluids and tissues were determined by chemical (high performance liquid chromatography, HPLC) and microbiological assay methods. Drug distribution throughout the body was presented as actual concentrations (micrograms/ml and ppm) in each sample and as the ratio of drug concentration in tissue to drug concentration in plasma. Highest concentrations were found in the urine, kidney, liver and bile. The drug was not detected in ocular fluid, brain tissue (by microbiological assay), fat (by HPLC) and skin (by HPLC). Tissue-to-plasma concentrations ratios were near to, or greater than, 1.0 (HPLC assay) for the kidney, liver, spleen, muscle, lung, adrenals, salivary glands, pleural and synovial fluid, and smaller than 1.0 for cerebrospinal fluid, brain tissue and lymph nodes. Agreement between the chemical and microbiological assay results was variable, depending on the type of tissue and biological fluid tested. Binding of norfloxacin to plasma proteins in pig is low (23%-29%). The distribution pattern of the drug in pig, laboratory animals and humans is very similar; it can be characterized as extensive, with tissue-to-serum ratios reaching 2:1 or more in certain non-excretory organs. These values may reflect intracellular concentrations of the drug. PMID- 7839747 TI - Virological and pathological findings in sheep fetuses following experimental infection of pregnant ewes with cytopathogenic-bovine-virus diarrhoea virus. AB - Eighteen pregnant Merino ewes were inoculated intravenously between days 65 and 68 of gestation with the unpurified cytopathogenic (cp) bovine virus diarrhoea virus (BVDV) strain Indiana (experiment I). In experiment II, three ewes were inoculated with the same virus after two successive plaque isolations in order to compare its pathogenicity for the fetus with special regard to lesions in the fetal brain. In experiment I, fetal blood and tissue samples, allantoic fluids and placentomes were collected sequentially between 10 and 80 days post inoculation (p.i.). BVDV was recovered from 6 of 19 fetuses examined during the first 3 weeks after inoculation. From fetuses sampled between 30 and 50 days p.i. virus was isolated from three cases only, and from 60 days p.i. onwards virus was no longer recovered. BVDV was longer detected in the allantoic fluid than in fetal tissues and continued to be present until 80 days post-inoculation. From tissue samples of two fetuses of experiment I, only non-cytopathogenic BVDV was isolated, whilst samples from seven fetuses contained the cp BVDV biotype as revealed by an immunoplaque assay. The cp biotype was also isolated from placentomes. In experiment II, virus was not isolated from any of the tissue samples of two living fetuses collected at 67 days post-inoculation. In both experiments, cp BVDV was recovered from allantoic fluid samples. In contrast to the developing fetal brain, other tissues or organs seemed to be less vulnerable to the cp BVDV strain Indiana. The partial purification of this virus strain did not affect its pathogenicity for the brains of the developing fetuses. PMID- 7839748 TI - Grouping of porcine enteroviruses by indirect immunofluorescence and description of two new serotypes. AB - Porcine enteroviruses (PEV) types 1-11 were assigned to three serologic groups by indirect immunofluorescence (IIF). Serotype group I consists of PEV types 1-7 and 11 and is correlated with CPE-type I. Serotype group II is represented by PEV type 8, producing CPE-type II, while PEV types 9 and 10 are classified as serotype group III and cause CPE-type III. Three PEV isolates from the central nervous system of pigs with polioencephalomyelitis were assigned to serotype group I by IIF but to none of the established 11 serotypes by cross neutralization. It is concluded that these isolates are representatives of two new PEV types for which the designation PEV12 and 13 is suggested. PMID- 7839749 TI - Effect of terdecamycin on experimentally induced Mycoplasma hyopneumoniae infection in pigs. AB - The effect of terdecamycin, a new antibiotic, was evaluated on experimentally induced Mycoplasma hyopneumoniae infection in pigs. Tylosin and josamycin were used as the positive control drugs. Five to 7-week-old pigs were inoculated intranasally with homogenate of pig lung lesions containing M. hyopneumoniae. In experiments 1 and 2, drugs were given in feed for 42 days, from 7 days before inoculation to 35 days after inoculation, and necropsy was carried out 35 days after inoculation. In experiment 3, drugs were given in feed for 10 days, from 3 days before inoculation to 7 days after inoculation and necropsy was carried out 28 days after inoculation. Drug efficacy was evaluated on the basis of clinical signs, lung lesions, (including percentage of gross lung lesion area), isolation of M. hyopneumoniae and growth performance data. The total number of days on which coughing was observed and the mean percentage of lung lesion area in pigs given feed containing terdecamycin at 50 ppm or above were lower than those in unmedicated control pigs. Average daily weight gain in terdecamycin-treated pigs was higher than that in unmedicated control pigs. Treatment with terdecamycin showed equal or better efficacy as compared with treatment with tylosin or josamycin. PMID- 7839750 TI - Origin of lymphocytic-choriomeningitis-virus-bearing mice in Japan. AB - Mice found in the port areas in Japan, where antibody to lymphocytic choriomeningitis virus (LCMV) was detected, may have originated or partially originated from a southern Asian subspecies, Mus musculus castaneus. PMID- 7839751 TI - Bovine spongiform encephalopathy in Germany. AB - Bovine spongiform encephalopathy (BSE) has been described as an epidemic central nervous disorder in cattle from the United Kingdom. The disease is thought to have emerged by an interspecies transmission of the scrapie agent of sheep to cattle, after feeding scrapie-contaminated meat and bone meal (MBM). The disease has caused substantial economic losses for the British cattle industry. Because of strict veterinary regulations for the import of adult British cattle by the European Union and for MBM by most of the member states the spread of BSE to continental Europe could be efficiently controlled, and only few cases have been described outside the UK. Here we report the first German case of BSE diagnosed in a Scottish Highland cow. The affected cow was imported into Germany before the import ban for cattle from the UK was implemented. BSE was confirmed by histopathology, immunohistochemistry, animal experiments, immunoblotting and by electron microscopic detection of scrapie-associated fibrils (SAFs). PMID- 7839752 TI - Mucosal immune responses in calves orally vaccinated with a live auxotrophic aroA Salmonella dublin strain. AB - The mucosal immune responses were studied in two calves orally vaccinated with the live aroA mutant strain, Salmonella dublin SL5631, and in two non-vaccinated control calves. Intestinal secretions were collected through a permanent fistula in place during a 5-week period. Vaccinated calves responded with high IgM and IgA titres against the S. dublin lipopolysaccharide. Both IgA and the IgM titres appeared already after 3 days and IgM somewhat earlier than the IgA titres. Both antibody titres remained high for 2 weeks after the third and final vaccine dose. The calves also showed marked T-cell responses in lymphocytes collected from mesenterial lymph nodes and the spleen. PMID- 7839753 TI - Validation of an inhibition ELISA using a monoclonal antibody for foot-and-mouth disease (FMD) primary diagnosis. AB - An inhibition ELISA (IH-ELISA) test for foot-and-mouth disease virus (FMDV) was validated using 106 epithelial samples from suspected cases of FMD in Argentina submitted to the Argentine National Diagnostics Laboratory (GELAB) over a period of 12 months and examined in parallel with the complement fixation test (CFT). IH ELISA was found to be more sensitive, detecting 25% (26 samples) more FMDV positives than the CFT in original suspensions of field samples. The effect of storage conditions on 12S stability was examined. Plates stored at 4 degrees C blocked with 1% ovalbumin and plates stored at -20 degrees C with or without blocking buffer could be used for at least 90 days. When various brands of polystyrene plates were compared for 12ps adsorption it was found that those microplates of higher binding capacity were more efficient. PMID- 7839754 TI - Salmonella contamination of the environment and its incidence in wild birds. AB - In 1984-1991, the incidence of salmonellas was studied in wild birds from various sites in the Czech Republic. On an agricultural farm with salmonellosis in calves, salmonellae were isolated from eight birds (seven Passer domesticus, one Serinus serinus) of 31 birds examined. On various agricultural farms with no salmonellosis in farm animals, salmonellae were found in two birds (Columba livia f. domestica) of 2186 birds examined. Of 35 birds caught at a municipal waste dump site, salmonellae were isolated from one specimen (Larus canus). No salmonellae were found in birds living in reed growths and in various military training areas (557 and 116 birds examined, respectively). In black-headed gulls (Larus ridibundus) from various areas with bodies of water, salmonellae were found in 4.2% of 189 adults and 19.2% of 740 non-flying young examined. S. typhimurium was the most common serotype isolated from gulls. Phage type 141 [corrected] represented 32% of 48 phage-typed strains. This study shows a relationship between the contamination of the environment with salmonellae and their incidence in wild birds. PMID- 7839755 TI - Virulence for mice of Staphylococcus aureus strains from bovine mastitis related to colonial morphology and serological types in serum-soft agar. AB - Six Staphylococcus aureus strains isolated from bovine mastitic milk representing the typical growth types in soft agar media were injected into mice via the intraperitoneal route. Strains showing diffuse colony morphology (DCM) in serum soft agar (SSA) as a permanent characteristic which reacted against anti-capsular sera types A, B, and D were virulent for mice. A strain showing DCM in SSA that reacted only against anti-capsular serum D behaved as a compact-colony-morphology type strain in the peritoneal cavity of the mouse. Diffuse-type colony morphology and presence of capsular antigens type A, B, and D correlated with increased virulence for mice, but a capsule could not be demonstrated. PMID- 7839756 TI - Identification of Moraxella bovis and related species from calves with IBK and goats by qualitative genetic transformation assay. AB - Eight Moraxella bovis strains isolated from bovine pink eye, 16 Moraxella bovis related strains isolated from healthy goats nasal flora, one nonhemolytic Moraxella sp. isolated from bovine conjunctivitis and different collection strains of Moraxella and Branhamella genus were studied through the combined use of qualitative genetic transformation assay and the ability to grow on a moraxella bovis defined medium (medium MB). Crude DNA extracted from the strains studied were used to transform two mutant auxotroph competent strains of Moraxella bovis CIP 103741 and CIP 103743. Non-specific positive transformation was obtained with mutant assay strain CIP 103743 when treated with DNA from caprine or bovine Moraxella strains, collection strains of Moraxella bovis, Moraxella lacunata, Moraxella nonliquefaciens and strains of Branhamella genus, whereas specific transformation was observed with mutant assay CIP 103741 when treated only with DNA from all the Moraxella bovis (collection and clinical isolates) and 14 of the 16 caprine Moraxella bovis related strains. The specificity and the simplicity of the test make it suitable for use in clinical laboratories. PMID- 7839757 TI - Bovine clinical mastitis due to coagulase-negative staphylococci and their susceptibility to antimicrobials. AB - A total of 168 coagulase-negative staphylococci (CNS) strains were isolated from milk samples taken from cows with clinical mastitis. The samples were collected between January 1990 and August 1992 from cows in the veterinary surveillance area of the Ambulatory Clinic, College of Veterinary Medicine, Hautjarvi, Finland. In 100 cases the effect of antibiotic treatment was evaluated 3-4 weeks after initial sampling. Clinical symptoms of the animals were recorded, and the inflammatory status of their udders was evaluated using the CMT test and assessing milk NAGase activity. CNS mastitis was most common in young cows during early lactation. Staphylococcus hyicus, S. simulans and S. epidermidis were the most frequently isolated CNS. Clinical symptoms were most severe with S. hyicus. Cure rates for CNS induced mastitis were high. PMID- 7839758 TI - Experimental studies of Elaphostrongylus rangiferi in reindeer (Rangifer tarandus tarandus): life cycle, pathogenesis, and pathology. AB - A total of 12 reindeer calves (Rangifer tarandus tarandus) were given 200-1,000 infective larvae of Elaphostrongylus rangiferi and autopsied 2 1/2-196 days post inoculation (p.i.). The larvae penetrated venules of the abomasal wall and followed the bloodstream via the liver to the lungs. In the lungs the larvae entered pulmonary venules and spread to all tissues via the general circulation. Many larvae that lodged in arterial vessels outside the spinal cord migrated into the cord along the spinal nerves. Nematodes matured in the central nervous system (CNS), and then migrated to the skeletal muscles (SM) via the spinal nerve roots. Eggs were deposited into veins and carried via the venous blood to the lungs. Here, the first stage larvae hatched and entered the airways. Pathological lesions consisting of focal necroses and interstitial accumulations of inflammatory cells were observed in the abomasal wall, liver, lungs, myocardium and kidneys. Infarcts were observed in the myocardium, kidneys and CNS. Other lesions in the nervous system were encephalomyelitis, focal traumatic encephalomyelomalacia, axon and myelin sheath degenerations, meningitis, choroiditis, perineuritis, neuritis and ganglioradiculitis. A multifocal verminous pneumonia persisted from day 103 p.i., and nematode-induced inflammatory oedema was observed in the intermuscular connective tissue of the SM at 196 days p.i. PMID- 7839759 TI - Psychosocial aspects and mental health in children after permanent pacemaker implantation. AB - The present study was designed to evaluate the psychosocial status and the mental health of children receiving a permanent pacemaker during childhood. Nineteen children under the age of 19 years had a permanent pacemaker implanted. Contact was established to 15 of these patients, 7 girls and 8 boys, and they were given a child-psychiatric evaluation consisting of a semi-structured and a child psychiatric interview. The psychological interview used intelligence tests and the Draw-A-Person test as well as the Rorschach test. The patients had had their pacemakers during an average of 6.7 years (range 3-14). Generally the psychological condition was strained in 7 families, in which psychiatric and social therapy had been necessary. The children's intelligence was within normal ranges, average IQ being 110 (range 80-135). The children had abnormal body image related to the pacemaker. Adults virtually incorporate the pacemaker in their body image without disturbance, but children who are forming their body image and identity, are influenced by having a pacemaker. This may give psychosocial implication. PMID- 7839760 TI - The diagnostic value of the determination of troponin T in the diagnosis of unstable angina. AB - The purpose of the study is the predictive value of determination of Tr-T in diagnosis of unstable angina. METHODS: 35 pts (24 male, 11 female, mean age 53.4 +/- 5 years) were studied. Group A: 20 pts (15 male, 5 female, mean age 50 +/- 6 years) with unstable angina. Group B: 15 pts (9 male, 6 female, mean age 56.4 +/- 4 years) with stable angina RESULTS: pts with stable angina (group B) had normal value of CPK-MB, SGOT, LDH, Tr-T. Eight pts with unstable angina (group A) had increased value of Tr-T with normal value of CPK-MB, SGOT, LDH. In conclusion the determination of Tr-T is helpful in diagnosis of unstable angina and it may be useful in the prognosis of these pts. PMID- 7839761 TI - The relationship between the sympathetic nervous system and the renin-angiotensin system in renovascular hypertension. AB - The aim of this study is to evaluate and compare the activity of the sympathetic nervous system and the renin-angiotensin system in patients with unilateral or bilateral renovascular hypertension. Plasma noradrenaline (plNA) levels and plasma renin activity (PRA) were measured simultaneously in blood samples obtained both from a peripheral vein and from the renal veins, during catheterization of the venous cava system, in 17 patients with unilateral (group A) and in 9 patients with bilateral renal artery stenoses (group B). RESULTS: peripheral plNA levels were elevated in 6/17 patients of the group A and 3/9 patients of the group B, while in the remaining 11/17 and 6/9 were normal, respectively. The comparison of plNA levels between the renal veins showed that in both groups plNA levels were higher in the renal vein of the ischaemic (group A) or the more ischaemic kidney (group B), and the difference was statistically significant. Renal vein renin ratio was above 1.5 in both groups. Renin hypersecretion from the ischaemic or the more ischaemic kidney compared to renin suppression from the normal or the less ischaemic kidney showed statistically significant difference. PMID- 7839762 TI - Left ventricular function determined by Doppler echocardiography in adolescents with type I (insulin-dependent) diabetes mellitus. AB - Sixty-one children with insulin-dependent diabetes mellitus and twenty-three healthy subjects were investigated. The patients with diabetes mellitus aged 4 to 20 years (13.4 +/- 4.0) had had diabetes for 1 to 16 years (6.4 +/- 3.5). There were no cardiovascular risk factor other than diabetes. Patients received no medication other than insulin. The following echocardiographic and Doppler parameters of the left ventricle were analyzed in both groups: systolic and diastolic dimensions, systolic time intervals, fractional shortening, mean velocity of circumferential fiber shortening, percent relaxation of the left ventricular posterior wall at 50% of diastole, peak velocity of early (E) and late atrial (A) mitral flow. E/A ratio, deceleration of the E-wave, and the isovolumetric relaxation time. None of the parameters were significantly different between the groups. There was no relation observed between duration of diabetes and any of the parameters analyzed. It is concluded that there is not echocardiographic data to support the concept of diabetic cardiomyopathy in adolescents with type I (insulin-dependent) diabetes mellitus. PMID- 7839763 TI - Plasma levels of antioxidant vitamins and oxidative stress in patients with acute myocardial infarction. AB - Of 138 patients with suspected acute myocardial infarction (AMI), 29 were excluded. Remaining 109 patients and 182 healthy controls of similar age and sex and same population were studied in detail for demographic variables, clinical and biochemical data for comparison. Mean age, sex, body weight, body mass index and blood pressures were comparable in the two groups whereas blood lipids, blood glucose and cardiac enzymes were raised in AMI patients compared to controls. Mean levels of vitamin C, E, A and beta-carotene were significantly less in AMI patients than controls whereas the lipid peroxides were significantly higher in AMI patients. The reduction in vitamin C and beta-carotene was more marked than decrease in other vitamins. With in AMI patients, those 28 patients who had cardiac arrhythmias showed greater decrease in vitamins compared to rest of the patients. Within both groups, smokers and diabetes patients had greater reduction in vitamin C and beta-carotene than other patients and subjects without confounding factors. Smokers also had higher lipid peroxides level than non smokers. The inverse relation between AMI and low plasma vitamin levels remained significant after exclusion of patients with smoking and diabetes. These findings suggest that vitamin deficiency may be a risk factor of AMI and these patients may benefit by administration of these antioxidant vitamins for primary and secondary prevention of coronary artery disease. PMID- 7839765 TI - Non-fistulous idiopathic coronary artery aneurysm. Report of three cases and literature review. AB - Non-fistulous idiopathic aneurysm of coronary arteries is a rare anomaly, often localized on the left coronary trunk and diagnosed in young patients following myocardial ischemia. Diagnosis before death is only possible since advent of selective coronary angiography. Idiopathic etiology can be inferred when the aneurysm is found in the absence of atherosclerosis and calcification of other arteries and if there is an absence of risk factors for atherosclerosis. Inflammatory etiology is excluded by a negative clinical history and lack of histologic inflammatory features. However, cumulating observations suggest that angeitis or other acquired process cannot definitely be disapproved. Advances in coronary artery surgery have permitted resection of aneurysms and grafting of involved coronary artery since the early seventies. Three cases of non-fistulous idiopathic aneurysms of coronary arteries are presented. The literature has been reviewed and the clinical, anatomic, angiographic findings and management are discussed. PMID- 7839764 TI - Diet, antioxidant vitamins, oxidative stress and risk of coronary artery disease: the Peerzada Prospective Study. AB - The prevalence of coronary artery (CAD) disease in the Indian urban population is comparable to British population. Dietary intakes, antioxidant vitamins, prevalence of risk factors and CAD, were studied in a random sample of 152 adult urban subjects between 26-65 years of age (80 males, 72 females) from Peerzada street, Moradabad and compared with Indian immigrants to U.K. and a British comparison group. There was no significant relation with vitamin A. Smoking and diabetes were the confounding factors. Plasma antioxidant vitamin C (21.6 +/- 3.3 vs 42.5 +/- 4.5 mumol/L), vitamin E (15.2 +/- 2.8 vs 21.4 +/- 3.2 mumol/L) and beta-carotene (0.33 +/- 0.6 vs 0.55 +/- 0.08 mumol/L) were significantly lowered and lipid peroxides higher (2.82 +/- 0.22 vs 1.3 +/- 0.20 nmol/ml) in patients with CAD compared to subjects without any risk factors. The relation between low plasma level of vitamin C and E levels and carotene remained independently and inversely related after adjustment for smoking, diabetes and other risk factors. Regression analysis showed that after adjustment. Odd's ratio for carotene (1.82, 95% C.I. 0.50 to 3.72), vitamin C (2.23, 95% C.I. 1.14 to 5.26) and vitamin E (2.35, 95% C.I. 1.29 to 5.30) were significantly related to CAD. Underlying these changes, dietary intake of vitamin A, E, C and beta-carotene was significantly less in patients with CAD. Vitamin C and beta-carotene intake were less in smokers and diabetes. Compared with British population, the Indian urbans consumed less total and saturated fat and cholesterol and more polyunsaturated fat and complex carbohydrates. The plasma total and low density lipoprotein cholesterol levels were less in Indian urbans compared to Britons and so were mean body weight, body mass index and waist-hip ratio. Plasma insulin levels were comparable. The fatty acid composition of the diet, blood lipids, central obesity and insulin levels do not appear to account for high rates of CAD among Indians. The findings suggest that urban population in India may benefit from eating diets rich in antioxidant vitamin C, E and beta-carotene. PMID- 7839766 TI - Acute pulmonary oedema in patients with primary pulmonary hypertension and normal pulmonary capillary wedge pressure. AB - Acute pulmonary oedema with normal pulmonary capillary wedge pressure, occurred in 2 patients with primary pulmonary hypertension, probably due to venoocclusive diseases. In both cases an increase in cardiac output induced by vasodilator therapy with a calcium antagonist or a viral infection with fever lead to an increase in hydrostatic pulmonary capillary pressure which was not identical to the pulmonary capillary wedge pressure. PMID- 7839767 TI - Acute lung injury and inhaled NO. The reduction of pulmonary capillary pressure has implications for lung fluid balance. PMID- 7839768 TI - The spread of epidural analgesia. PMID- 7839769 TI - Splanchnic ischaemia and its role in multiple organ failure. AB - Multiple organ failure remains the leading cause of death in the intensive care unit. Increasing numbers of investigators have focused their attention on the role of gastrointestinal tract in the pathogenesis of this syndrome. Their data indicate that inadequate gut perfusion leads to a measurable imbalance between oxygen delivery and the needs of the tissues, i.e., ischaemia. Gut ischaemia of sufficient duration impairs gastrointestinal tract barrier function, facilitating the passage of enteric bacterial endotoxin into the circulation. It has been hypothesized that production of tumor necrosis factor alpha, and other biologic mediators by endotoxin-stimulated macrophages, triggers a generalized and uncontrolled inflammatory response that ultimately leads to multiple organ failure. Preliminary evidence suggests that survival can be improved significantly if gut ischaemia is promptly identified and aggressively treated by administration of fluids and inotropic drugs, using gastric intramucosal pH as the therapeutic endpoint. Future studies are needed to determine whether additional treatment modalities can improve outcome once the inflammatory response has fully developed. PMID- 7839770 TI - Inhaled nitric oxide lowers pulmonary capillary pressure and changes longitudinal distribution of pulmonary vascular resistance in patients with acute lung injury. AB - In acute lung injury (ALI), where pulmonary microvascular permeability is increased, transvascular fluid filtration depends mainly on the hydrostatic capillary pressure. In the presence of intrapulmonary vasoconstriction pulmonary capillary pressure (PCP) may increase thereby promoting transvascular fluid filtration and lung oedema formation. We studied the effect of 40 ppm inhaled nitric oxide (NO) on PCP and longitudinal distribution of pulmonary vascular resistance (PVR) in 18 patients with ALI. PCP was estimated by visual analysis of the pressure decay profile following pulmonary artery balloon inflation. Contribution of venous pulmonary resistance to total PVR was calculated as the percentage of the pressure gradient in the pulmonary venous system to the total pressure gradient across the lung. Inhalation of 40 ppm NO produced a prompt decrease in mean pulmonary artery pressure (PAP) from 34.1 +/- 6.8 to 29.6 +/- 5.7 (s.d.) mmHg; (P < 0.0001). PCP declined from 24.8 +/- 6.2 to 21.6 +/- 5.2 mmHg; (P < 0.0001) while pulmonary artery wedge pressure (PAWP) did not change. PVR decreased from 166 +/- 73 to 128 +/- 50 dyn.sec.cm-5; (P < 0.0001). Pulmonary venous resistance (PVRven) decreased to a greater extent (from 76 +/- 41 to 50 +/ 28 dyn.sec.cm-5; (P < 0.001) than pulmonary arterial resistance (PVRart) (from 90 +/- 36 to 79 +/- 29 dyn.sec.cm-5; (P < 0.01). The contribution of PVRven to PVR fell from 44.3 +/- 10.8 to 37.8 +/- 11.9%; (P < 0.01). Cardiac output (CO) remained constant. The findings demonstrate that NO has a predominant vasodilating effect on pulmonary venous vasculature thereby lowering PCP in patients with ALI. PMID- 7839771 TI - A multifactorial analysis of the spread of epidural analgesia. AB - The controversies about the factors determining the spread of epidural analgesia are partly due to inappropriate methodology or sample size of previous studies. We performed a multivariate regression analysis on 803 ASA class 1-2 non atherosclerotic adults, undergoing lumbar epidural anaesthesia according to a predefined standardised procedure. The spread of epidural analgesia is more accurately studied by analysing dose/segment (R2 = 0.671) instead of spread (R2 = 0.271) as dependent variable. The impact of local anaesthetic (2% lidocaine CO2 or 0.5% bupivacaine) and addition of adrenaline is not significant. Spread significantly increases with increasing age, weight, body-mass index, dose of local anaesthetic, addition of fentanyl, higher site of injection, and decreasing body height. The impact of age and dose is higher under the age of 40 and at doses lower than 20 ml. Increasing the total dose increases the dose needed to block one spinal segment. Unknown idiosyncratic factors still determine a certain proportion of the sample variance. The addition of adrenaline to lidocaine and the use of bupivacaine improve the predictability of spread. In conclusion, we found clinically significant correlations between a group of factors and epidural spread. Alternative anaesthetic solutions lead to different degrees of predictability. PMID- 7839772 TI - The effect of plain 0.5% 2-chloroprocaine on venous endothelium after intravenous regional anaesthesia in the rabbit. AB - The possible venous endothelial toxicity of 0.5% 2-chloroprocaine without additives in intravenous regional anaesthesia (IVRA) was evaluated in rabbits. After exsanguination of a hind limb with an Esmarch's bandage a neonatal blood pressure cuff around the thigh was inflated (250 mmHg). For IVRA 4 ml of either plain 0.5% 2-chloroprocaine (pH 3.7), 0.9% NaCl (pH 6.0) or acidified NaCl (pH 3.7) was injected i.v. to the exsanguinated limb in a randomized, double-blind fashion. Each group comprised 15 rabbits. Eleven rabbits received 4 ml of 0.5 M or 1.0 M KCl, for the production of positive controls. Two hours after injection of the test solution the tourniquet was deflated and venous biopsies were taken one and 24 hours later for histological and immunocytochemical examination. Five to eight 24-hour samples from each group were also processed for electron microscopy. A macroscopic thrombus formation was observed in four rabbits after KCl and in two after acidified NaCl administration. No inflammatory changes were observed at histologic and immunocytochemical examination of any of the vein samples. Electron microscopy revealed that KCl had caused severe damage to the venous endothelium of four out of five samples and acidified NaCl had caused moderate damage to the endothelium of two out of seven samples. 2-chloroprocaine had caused moderate damage in four and severe damage in two of the vein samples; two samples were normal. No thrombus formation occurred. It is concluded that additive-free 2-chloroprocaine caused damage to the venous endothelium in rabbits when used for IVRA. PMID- 7839773 TI - The potential of an anaesthesiologist-manned ambulance service in a rural/urban district. AB - The use of anaesthesiologists in prehospital emergency care is controversial. We wanted to assess the impact of an anaesthesiologist and a short time interval from acceptance of a mission to take-off at survival rates in a rural/urban emergency medical service. Prospectively registered data for 991 consecutive patients through a 12-month period were retrospectively evaluated by an independent foreign expert. Of all primary missions, 3.3% were considered probably lifesaving from site of injury to receiving hospital. Of these, the lifesaving result in 50% were dependent on both the qualifications of the anaesthesiologist and a short response time. Survival from hospital admission to discharge was 44%. All patients were discharged to their own homes, able to live a fully functional life. The consistent use of anaesthesiologists compared to less qualified personnel and the maintaining of response times below presently required minima doubles the potential for lives saved in services comparable to the one studied. PMID- 7839774 TI - Comparison of propofol/alfentanil anaesthesia with isoflurane/N2O/fentanyl anaesthesia for renal transplantation. AB - Total intravenous anaesthesia (TIVA) with propofol and alfentanil was compared with balanced anaesthesia (BA) in 30 uraemic patients undergoing renal transplantation. TIVA (n = 15) was induced with propofol and alfentanil and maintained with propofol and alfentanil infusions, which were started immediately after induction. Thereafter the infusion rates were adjusted as needed. Ventilation was with oxygen in air. BA (n = 15) was induced with thiopentone and fentanyl and maintained with isoflurane/N2O/fentanyl. Vecuronium was used for muscle relaxation in both groups. Mean infusion rates for propofol and alfentanil were 10 +/- 1.8 mg kg-1 h-1 and 70 +/- 9 micrograms kg-1 h-1, respectively. To control hypertension during TIVA, larger amounts of propofol and alfentanil were needed and slower recovery was observed than in previous studies in ASA 1-2 patients. Also, significantly more vecuronium was needed during TIVA than during BA (P < 0.05). The recovery parameters were similar in both groups, except for the occurrence of nausea, which was less after TIVA. In conclusion, TIVA had no clinical advantages over BA. PMID- 7839775 TI - Renal effects of human atrial natriuretic peptide in patients after major vascular surgery. AB - The effects were studied postoperatively of an infusion of atrial natriuretic peptide (ANP) 7.5 pMol.kg-1.min-1 on renal function and haemodynamics in seven patients who had been operated with insertion of an abdominal aortic graft. Urine flow, glomerular filtration rate (GFR), renal plasma flow (RPF) and excretion of electrolytes and osmoles were measured for three periods of 20 minutes during infusion of ANP, in the morning of the day after surgery. Haemodynamic studies were conducted, and serum levels of ANP, catecholamines and plasma renin activity were measured. ANP levels increased from 52 to approximately 250 pMol.L-1 during ANP infusion and decreased after infusion to a level equal to baseline. GFR increased from 92 mL.min-1 by 58, 20 and 21%, respectively. RPF was unchanged. Urine flow rate increased from 1.99 mL.min-1 by 81, 151 and 173%, respectively. Fractional clearances of sodium, chloride and osmoles were increased during the second and third ANP periods whereas fractional potassium clearance did not change during the study. There were no changes in catecholamine levels or plasma renin activity during the study. Heart rate, mean arterial pressure and calculated systemic and pulmonary vascular resistance did not change whereas reductions occurred in cardiac index, mean pulmonary artery pressure, pulmonary artery wedge pressure and mean right atrial pressure. We conclude that infusion of ANP also in the postoperative situation increases GFR, diuresis and sodium excretion. PMID- 7839776 TI - Simulation of inhalational anaesthetic uptake using a lung model with charcoal. AB - A physical lung model for simulation of volatile anaesthetic uptake is described. Two communicating water-filled chambers simulate pulmonary mechanics allowing adjustment of functional residual capacity, resistance and compliance. The uptake of the volatile anaesthetics is reproduced by pumping gas from the lung chamber through a charcoal absorber at different rates; using a second pump for a bypass an arterial to end-tidal gradient can be generated. Changes of cardiac output are simulated by adjusting pump speed and of alveolar ventilation by adapting the ventilator setting. The results are reproducible and correspond with patient studies and computer stimulation, not necessitating empirical correction factors as in a previously described oil-based lung model. The model can serve as a teaching instrument, for the comparison and testing of anaesthetic equipment and the development of feedback systems. PMID- 7839777 TI - The Gothenburg study of perioperative risk. I. Preoperative findings, postoperative complications. AB - The Gothenburg study of Perioperative Risk is a prospective clinical epidemiological study designed to elucidate factors affecting the perioperative risk in unselected adult patients undergoing elective general or orthopaedic surgery. In this report reference data regarding preoperative characteristics and postoperative complications are presented. 1770 adult patients scheduled for elective general, urological, peripheral vascular or orthopaedic operative procedures were invited to a preoperative clinic. 81% agreed to participate and were assessed in a standardised way by means of questionnaires, interview, physical examination and laboratory screening. 82% had a previous or present condition in the medical history of some concern to the assessor. 71% had a finding of significance on physical examination. In 8% the assessment prompted further investigations or precautions. Throughout their hospital stay, all the 1361 participating patients were visited daily by an especially trained nurse with the task of registering the occurrence of complications. In 30% an untoward event occurred postoperatively--in 1% a severe one, in 21% a mild event, and in 8% an intermediate one. The complication rate was higher in vascular surgery (69%) than in orthopaedic (33%) and general/urological surgery (26%). Not only the severe and intermediate but also the mild complications affected the number of days in hospital. PMID- 7839778 TI - Spinal anaesthesia with 29 gauge Quincke point needles and post dural puncture headache in 2,378 patients. AB - Two thousand three hundred and seventy-eight spinal anaesthetics using a 29 G Quincke point needle were administered in a District Hospital between May 1983 and December 1991. The overall post dural puncture headache rate (PDPH) was 1.2% with a maximum of 2.5% in patients between age 30 and 39. PDPH was related to the experience of using 29 G needles (0.5% in consultants versus 2.0% in trainees, P < 0.05). PMID- 7839779 TI - Propofol-nitrous oxide versus thiopentone-isoflurane-nitrous oxide anaesthesia for uvulopalatopharyngoplasty in patients with sleep apnea. AB - A randomized prospective study was performed to compare the recovery in 41 patients undergoing uvulopalatopharyngoplasty (UPPP) with either propofol-nitrous oxide-fentanyl or thiopentone-isoflurane-nitrous oxide-fentanyl anaesthesia. The patients were referred to UPPP after examination including polysomnography and otorhinolaryngological examination. The propofol group received propofol 2 mg.kg 1 for induction followed by an infusion of 10 mg.kg-1.h-1 after intubation. The thiopentone-isoflurane group received 5 mg.kg-1 of thiopentone for induction followed by isoflurane (0.5-2%) after intubation. Other medication was similar in both groups. In the propofol group the patients had a significantly better oxygen saturation during the first postoperative hour (P < 0.05), and a higher rate of breathing (P < 0.05), indicating a more rapid recovery of the physiologic control of breathing. Pain as measured by visual analogue score was lower (P < 0.05) during the second postoperative hour compared with the isoflurane group. Apneic episodes occurred with similar frequency in both groups, and they were related to the severity of obstructive sleep apnea (OSA). We conclude that propofol is preferable to thiopentone-isoflurane in UPPP operations, because physiologic respiratory control recovers faster and postoperative pain is less intense. PMID- 7839780 TI - Possible errors in diagnosis of bacterial sinusitis in tracheal intubated patients. AB - Bacterial sinusitis is recognized as a complication of prolonged nasotracheal intubation. Verification of the diagnosis, however, requires culture findings from a "true" sample from the maxillary antrum. A "true" antral sample can only be obtained after passing either the nasal or oral mucosae with their rich aerobic and anaerobic bacterial flora. No properly controlled study has been made into the problem of contaminated samples in bacterial sinusitis complicating prolonged nasotracheal intubation. The design of the study was a case series in an intensive care unit. The patients had either had endotracheal tube or tracheal cannula for seven days or were septic, having an endothracheal tube or a tracheal cannula and therefore due to an investigation of infection foci. Antral cultures obtained via the canine fossa were compared with oral cultures to exclude the contribution of oral bacterial contamination and thereby to improve the reliability of diagnosis based on culture results. The contamination rate was lowered significantly from 67% to 5% when an area of free bone was prepared in the canine fossa thus avoiding instrument contact with the oral mucosa. A high contamination risk can be dealt with by adjusting the technique of sampling thereby increasing the culture reliability. PMID- 7839781 TI - Effects of five amino-amide local anaesthetic agents on human polymorphonuclear leukocytes measured by chemiluminescence. AB - The aim of this study was to assess the influence of five amino-amide local anesthetic agents on the production of oxygen metabolites in the human polymorphonuclear leukocyte (PMNL), both intra- and extracellularly. Ropivacaine, a new long-acting amino-amide local anaesthetic agent, bupivacaine, lidocaine, mepivacaine and prilocaine in concentrations 1-5 micrograms.ml-1 up to 500-1000 micrograms.ml-1 were compared to an untreated control. PMNLs were isolated from heparinized blood (healthy adult volunteers). Cells were incubated with the various local anaesthetics (37 degrees C, 30 min), then placed in a Biolumat (luminol-amplified chemiluminescence) and stimulated by formyl-methionyl-leucyl phenylalanine (FMLP), phorbol myristate acetate (PMA) or ionomycin. Horseradish peroxidase (HRP) was added to discriminate between an intra- or extracellular response. In general, a decrease in chemiluminescence-response was seen with higher concentrations (500-1000 micrograms.ml-1) of the various local anaesthetics. Lidocaine showed a decrease even at lower concentrations. A marked increase in intracellular response for prilocaine 1000 micrograms.ml-1 (3894 mumol.l-1) accompanied by a reduction in extracellular response, using FMLP +/- HRP as a stimuli, was noted. Ropivacaine 1000 micrograms.ml-1 (3216 mumol-l-1) showed a decrease both intra- and extracellularly that was similar to, and even somewhat more pronounced than lidocaine 1000 micrograms.ml-1 (3692 mumol.l-1), when using PMA with or without HRP as the stimuli. PMID- 7839782 TI - Fentanyl and propofol uptake by the lung: effect of time between injections. AB - The effect of time between the administrations of fentanyl and propofol on the first pass uptake of propofol in the cat lung was studied using double indicator dilution technique. The pulmonary first pass uptake of propofol (mean +/- s.e. mean) was 58 +/- 6% in six cats (control group) that had received no fentanyl prior to propofol (1 mg/kg) administration. The uptake was significantly reduced to 32 +/- 3% in animals pretreated with fentanyl (1 microgram/kg) 30 seconds before propofol administration (n = 6). However, when fentanyl was administered 3 minutes (n = 6) or 10 minutes (n = 6) prior to propofol, the pulmonary uptake of propofol (45 +/- 5%, 50 +/- 7% respectively) was not significantly reduced. The results demonstrate that the ability of fentanyl to inhibit pulmonary removal of propofol depends on its time of administration prior to propofol. These data may have clinical implication with respect to timing of the preinduction opiate injection. PMID- 7839783 TI - Decreased incidence of headache after accidental dural puncture in caesarean delivery patients receiving continuous postoperative intrathecal analgesia. AB - To examine the effects of prolonged (> 24 h) intrathecal catheterization with the use of postoperative analgesia on the incidence of post-dural puncture headache (PDPH), charts of 45 obstetric patients who had accidental dural puncture following attempts at epidural block were reviewed retrospectively. Three groups were identified: Group I (n = 15) patients had a dural puncture on the first attempt at epidural block, but successful epidural block on a repeated attempt; Group II (n = 17) patients had a dural puncture with immediate conversion to continuous spinal anaesthesia with catheterization lasting only for the duration of caesarean delivery; Group III (n = 13) patients had an immediate conversion to spinal anaesthesia and received post-caesarean section continuous intrathecal patient-controlled analgesia consisting of fentanyl 5 micrograms.ml-1 with bupivacaine 0.25 mg.ml-1 and epinephrine 2 micrograms.ml-1 with catheterization lasting > 24 h. No parturient in group III developed a PDPH. This was substantially lower (P < 0.009) than the 33% incidence for group I and the 47% incidence for group II. The incidence of a PDPH did not differ between group I and II. Similarly, there was no difference between group I and II with regard to requests for a blood patch. Patients receiving continuous intrathecal analgesia had excellent pain relief, could easily ambulate and none complained of pruritus, nausea, vomiting, sensory loss or weakness. In conclusion, indwelling spinal catheterization > 24 h with continuous intrathecal analgesia following accidental dural puncture in parturients may for some patients be a suitable method for providing PDPH prophylaxis and postoperative analgesia. PMID- 7839784 TI - Changes in the EEG power spectrum after midazolam anaesthesia combined with racemic or S- (+) ketamine. AB - Changes in the EEG power spectrum were studied in 50 patients (ASA status I or II), receiving either 2 mg.kg-1 of racemic ketamine or 1 mg.kg-1 of S-(+) ketamine in a randomized and double-blind manner after prior administration of 0.1 mg.kg-1 of midazolam. The patients receiving intramuscular premedication with midazolam about 45 minutes prior to induction of anaesthesia showed, in a deliberately quiet environment and mostly in the early morning, a delta dominated EEG (56% delta power) with a reduced alpha peak (17% alpha power) and an average median of 4 Hz as the baseline findings of the EEG power spectrum. The intravenous administration of midazolam led to activation of the lower beta range (13-18 Hz) and the subsequent injection of ketamine caused an increase in activity in the fast beta range (21-30 Hz), both being accompanied by a reduction of delta power from 56% to 40%. Correspondingly, an increase in the median frequency was noted. Causing nearly the same changes in EEG, S-(+) ketamine was confirmed to be twice as potent as racemic ketamine. PMID- 7839785 TI - Effects of intrathecal clonidine on duration of bupivacaine spinal anaesthesia, haemodynamics, and postoperative analgesia in patients undergoing knee arthroscopy. AB - Clonidine, an alpha-2-adrenergic agonist, may have a clinically relevant analgesic action but also a hypotensive action, when administered spinally. In this study, therefore, the analgesic and circulatory effects of intrathecal clonidine were studied in patients undergoing knee arthroscopy under spinal anaesthesia. Forty ASA I-II patients were randomly divided to two groups. One group received clonidine 3 micrograms.kg-1 mixed with 15 mg 0.5% bupivacaine and the other group an identical saline volume mixed with bupivacaine as above, in a double-blind fashion. Sensory analgesia, blood pressure, heart rate and sedation were followed during and after the operation. Oxycodone 0.14 mg.kg-1 i.m. or ketoprofen 100 mg p.o. was administered when needed. The duration of sensory analgesia (until regression of the block to L2) was longer in the clonidine group (mean 217 min) than in the control group (mean 160 min) (P < 0.05). Duration of motor blockade was also longer in the clonidine group (mean 215 min) compared to the control group (161 min) (P < 0.05). Mean arterial pressure and heart rate were significantly lower in the clonidine group compared to the control group. The clonidine patients needed fewer supplemental doses of oxycodone (8 doses) than those in the control group (16 doses) (P < 0.05). More patients in the clonidine group were sedated 3-6 h after the injection (P < 0.05). Addition of clonidine prolonged the bupivacaine spinal block. However, marked haemodynamic changes and sedation may limit the usefulness of intrathecal clonidine. PMID- 7839786 TI - Response of pial vessel diameter and regional cerebral blood flow to CO2 during midazolam administration in cats. AB - Midazolam has been demonstrated to preserve the response of cerebral blood flow to CO2. However, the responsiveness of cerebral vessels or microcirculation during midazolam administration related to alteration of cerebral blood flow has not been explored. The purpose of this study was to examine the effects of midazolam on cerebral microcirculation. Nine cats were paralyzed and mechanically ventilated under nitrous oxide/oxygen anaesthesia. Using the closed cranial window technique and laser Doppler flowmetry, diameter of pial vessels and regional cerebral blood flow (rCBF) were examined on the surface of the cerebral cortex which was perfused by the middle cerebral artery. Before midazolam administration, haemodynamic variables, blood gases, rCBF, and diameter of pial vessels were determined as a control under normocapnia, hypocapnia, and hypercapnia conditions. After midazolam administration, given initially at 0.8 mg.kg-1.min-1 for 10 min and subsequently at 0.04 mg.kg-1.min-1 (total dose 10 mg.kg-1), the same variables were again analyzed. With regard to CO2 responsiveness, an 8.85% increase in rCBF was demonstrated for a Paco2 elevation of 1 kPa before midazolam administration, compared with a 7.47% increase after midazolam administration. With regard to the correlation between CO2 response and vessel diameter, arterioles less than 50 microns in diameter were more sensitive than those more than 50 microns in diameter, although there were no significant differences before or after midazolam administration. We conclude that CO2 responsiveness is preserved in terms of rCBF and vessel diameter after high doses of midazolam (10 mg.kg-1) in cats. PMID- 7839787 TI - Pharmacokinetics and pharmacodynamics of eltanolone (pregnanolone), a new steroid intravenous anaesthetic, in humans. AB - Eltanolone, a new intravenous steroid anaesthetic agent was administered intravenously in a dose of 0.6 mg.kg-1 over 45 s to eight healthy male volunteers to evaluate some of its pharmacokinetic and pharmacodynamic effects. Drug concentration-time data were analysed by PCNONLIN, a non-linear regression programme, showing data consistent with a three-compartment model with initial distribution half-life t1/2 lambda 1 between 0.3 and 2 min, intermediate distribution half-life t1/2 lambda 2 between 12 and 29 min and terminal half-life t1/2 lambda z between 72 and 212 min. The total body clearance of eltanolone was rapid and with individual values in the range 1.6-2.3 l.h-1.kg-1. Eltanolone was initially distributed into a relatively large central compartment V1 between 0.09 and 0.98 l.kg-1 and then extensively further distributed (Vss between 1.80 and 5.44 l.kg-1 and V between 4.87 and 11.87 l.kg-1). The excretion of unchanged of eltanolone in urine was very small, the renal clearance was less than 0.5% of the total clearance. Induction of anaesthesia was trouble free with onset and duration of anaesthesia between 1-2 min and 6-13 min, respectively. There was slight respiratory depression, a small transient increase in heart rate, and a maximum reduction in arterial blood pressure of 23%, as compared with the resting level. Pain on injection and venous sequelae were not seen. Involuntary movements were seen in one subject. We conclude that eltanolone has a favourable pharmacokinetic profile with relatively rapid half-lives, large distribution volumes and rapid total body clearance.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7839788 TI - Neurologic symptoms after epidural anaesthesia. Report of three cases. AB - We describe 3 patients, who exhibited neurological symptoms after single dose epidural anaesthesia. In patient 1 an unrecognized spinal arteriovenous fistula (AVF) caused paraparesis following epidural block. The dilated veins draining an AVF are space-occupying structures and the injection of the anaesthetic solution may have precipitated latent ischaemic hypoxia of the spinal cord due to raised venous pressure. In patient 2, epidural block was followed by postoperative permanent saddle pain and hypoaesthesia. The injection of the anaesthetic in a narrow spinal canal with multiple discal protrusions and restriction of interlaminar foramina may have acutely produced mechanical compression of the spinal cord or roots. Patient 3 exhibited post-epidural block spinal arachnoiditis. Although the few reported cases of this syndrome exhibit severe neurological damage, our patient presented with scarse symptoms. Our cases point out the importance of accurate neurological history and examination of candidates for epidural anaesthesia and of accurate anaesthetic history for neurological patients. PMID- 7839789 TI - The split laryngeal mask and the difficult airway. PMID- 7839790 TI - Combination of light general and topical anaesthesia, and the laryngeal mask to facilitate diagnostic fibreoptic bronchoscopy. PMID- 7839791 TI - Neurotrophy and regeneration in vivo. AB - Neural regeneration is a multistep event which appears to be controlled by neurotrophic factors such as neurotrophins and/or neurotrophic cytokines. Following traumatic, age- and/or disease-related responses, these molecules may be expressed and/or released by innervated target cells, neuron-ensheathing glial cells, recruited macrophages or by the neural somata themselves which altogether provide possible cues for neurotrophic strategies in vivo. In this respect, neurotrophic molecules may follow either paracrine, autocrine or even intracrine pathways in order to attenuate or even prevent neuronal degeneration. As neurotrophic molecules may have important functions as putative therapeutic agents for patients suffering from CNS disorders or from peripheral neuropathies, adequate and reliable animal lesion paradigms are of importance as in vivo assay systems. Axotomy models or selective neurotoxin-lesion models of anatomically well-defined neuron target connections are a first step towards assaying of neurotrophic actions in vivo. In lesioned central neural pathways, the existence of multineuronal networks, diffuse nuclear topography and a high degree of collateralization should be considered when studying regenerative potentials of trophic factors. Because of their simple organization and accessibility, peripheral neural pathways are particularly appealing as assay systems. As neurotrophic requirements and vulnerability vary among neural subsystems, in vivo lesion paradigms reveal pharmacological rather than physiological effects which have to be elucidated by more sophisticated experimental paradigms and molecular tools. PMID- 7839792 TI - Invasiveness of mouse trophoblastic cells in connective tissue. AB - Ectoplacental cones from 8-day-old mouse embryos were grafted into the dorsal subcutaneous tissue of host mice. The grafts were collected between the 3rd and 8th days after transfer and processed for morphological analysis by light and electron microscopy. Approximately 60% of the grafts formed hemorrhagic nodules in which only invasive, giant trophoblastic cells developed. These cells shared many morphological features with the trophoblastic cells involved in normal implantation. At the periphery of the nodules, trophoblastic giant cells were frequently seen growing toward the host connective tissue. The association between the trophoblast and fibrilar components of the extracellular matrix was examined. No direct association with collagen fibrils was noted; however, many areas of the surface of invasive cells were in close proximity with microfibrils of the extracellular matrix. Since only the invasive trophoblast cells exhibited such an association, a direct comparison was made with the process of trophoblast migration within the connective tissue. PMID- 7839793 TI - How repair cementum becomes attached to the resorbed roots of human permanent teeth. AB - Human premolars extracted for orthodontic reasons were fixed with a mixture of formaldehyde and glutaraldehyde and processed for light and transmission electron microscopy. About 15% of all available teeth showed signs of superficial root resorption. Quantitatively, the resorption lacunae were more frequent at the apical third of the root, when compared to the mid-root and the cervical levels. Qualitatively, the resorption areas appeared as shallow irregular concavities. The degree of resorption and/or repair varied considerably both within and between sites, ranging from arrested resorption to advanced repair. An about 1- to 2-microns-thick seam of exposed collagen fibrils of the residual dentinal matrix lined the resorbed root surfaces in the arrested stage of resorption. A particular class of mononuclear cells repopulated these surfaces and commenced to attach newly produced collagenous matrix fibrils to the exposed dentinal matrix. Increasing fibril formation and bundling resulted in a collagenous fiber fringe oriented perpendicular to the bottom of Howship's lacunae. Following the implantation and establishment of this initial fiber fringe, the junctional zone between the two matrices and further portions of the repair matrix became progressively obscured by a fine granular and electron-dense material, indicating the advancing front of mineralization. In addition, the junctional zone later attained a high degree of electron density and basophilia. Subsequently formed matrix derived from cementoblasts was structurally heterogeneous and resembled cellular intrinsic fiber cementum (CIFC). It is suggested that the initially produced matrix along resorbed root surfaces closely resembles that seen during initial formation of acellular extrinsic fiber cementum (AEFC), whereas further apposition results in a tissue with the characteristics of CIFC. PMID- 7839794 TI - Presence or absence of glycogen-beta particles in sinoatrial node cells. AB - The sinoatrial node is formed by specialized cells, the main ultrastructural differences of which, as compared with ordinary atrial myocardium, are a pale cytoplasm and sparse myofibrils. Moreover, nodal cells have been described to contain large amounts of glycogen particles in their pale cytosol; these glycogen inclusions are often used as the main criterion for identifying nodal cells. Nevertheless, the presence of glycogen cytosolic inclusions has been discussed by several authors. This paradox was solved by the description of some undesirable effects of uranyl acetate when used en bloc. To prove the presence of glycogen granules in nodal cells and the effects of uranyl acetate en bloc, we performed an ultrastructural study of the sinoatrial node in rats of different ages using different staining techniques. Our results do not reveal any beta-particles in nodal cells in tissues processed by either general or glycogen-specific methods. Uranyl acetate staining did not cause any change of appearance in the nodal or ordinary myocardium. From these results, one could conclude that, on the one hand, sinoatrial nodal cells do not show deposits of beta-particles of glycogen which can be detected with ultrastructural techniques, and, on the other hand, that uranyl acetate does not cause any morphological artifacts. PMID- 7839795 TI - Short- and long-term effects of streptozotocin-induced diabetes on the dorsal motor nucleus of the vagus nerve in the rat. AB - The present study describes ultrastructural changes in the dorsal motor nucleus of the vagus nerve of male Wistar rats after induction of diabetes by streptozotocin. During the acute phase (3-7 days), degenerating electron-dense dendrites and axon terminals were dispersed in the neuropil. Degenerating dendrites were characterized by an electron-dense cytoplasm containing short segments of dilated rough endoplasmic reticulum, swollen mitochondria and scattered ribosomes, while degenerating axon terminals were characterized by an electron-defense cytoplasm, clustering of small spherical agranular vesicles and swollen mitochondria. Some of these degenerating axon terminals formed axodendritic synapses with seemingly normal as well as degenerating dendrites. During the mid phase (1-6 months), most of the degenerating neuronal profiles had been engulfed or removed by macrophages that infiltrated the neuropil. During the late phase (9-12 months), a second wave of degeneration occurred in the dorsal motor nucleus of the vagus nerve, similar to that of the acute phase. In addition to the degenerating dendrites and axon terminals, several neuronal cell bodies with electron-dense cytoplasm were observed. Numerous macrophages containing degenerating debris were also present in the neuropil. It is concluded that the ultrastructural changes in the dorsal motor nucleus of the vagus nerve are the result of streptozotocin-induced diabetes. PMID- 7839796 TI - Motoneurons innervating two regions of rat medial gastrocnemius muscle with differing contractile and histochemical properties. AB - The medial gastrocnemius (MG) muscle, which receives its innervation by two extramuscular nerve branches, is representative of muscles which show a particular form of muscle compartmentalization (i.e. a regional specialization of muscle fibers) in which there is a 'deep' oxidative region and a 'superficial' low-oxidative region. Differential recruitment of motor units from these two regions of the MG has been reported for different functional tasks. Our goal was to determine if the organization of the MG motoneuron pool-muscle complex with its two extramuscular nerve branches could account for the phenomenon of regional specialization of muscle fibers. The two extramuscular nerve branches innervated muscle subvolumes which differed in contractile properties and fiber type percentages. The MG proximal nerve branch (NBr) innervated mostly high-oxidative and slow fibers, but with some low-oxidative fast fibers. The distal NBr innervated mostly low-oxidative fibers, but also a small proportion of high oxidative and slow fibers. These results suggest that the two nerve branches do not strictly define a superficial/deep organization of fiber types in the MG. The number and soma size characteristics of motoneurons supplying the two extramuscular nerve branches showed that the motoneurons innervating the deep more oxidative muscle region, supplied by the proximal NBr, were smaller than those innervating the superficial, primarily low-oxidative, region supplied by the distal NBr. Our findings indicate that the MG motoneuron pool-muscle complex of the Sprague-Dawley rat will lend itself to studies of how the various motor unit types within a given spinal motor complex adapt to different conditions (e.g. aging, disease, injury, exercise). PMID- 7839797 TI - Anatomical observations on the musculi suprahyoidei and apparatus hyoideus with special reference to the musculus jugulohyoideus and os stylohyoideum of the mouse, hamster and rat. AB - The musculi suprahyoidei and apparatus hyoideus were investigated using a combination of gross dissection and histological techniques in the mouse, hamster and rat. The new findings with regard to these are as follows: (1) the musculus jugulohyoideus, which runs from the processus jugularis to the os stylohyoideum, exists in the mouse and hamster, but is absent in the rat; (2) the m. jugulohyoideus is innervated with the ramus jugulohyoideus from the nervus facialis; (3) the os stylohyoideum and the os tympanohyoideum exist on the lateral surface of the bulla tympanica in the mouse, hamster and rat, and (4) four kinds of muscle (m. stylohyoideus, m. styloglossus, m. stylopharyngeus, m. jugulohyoideus) attach to the os stylohyoideum in the mouse and hamster; however, no muscles attach to the os stylohyoideum in the rat. PMID- 7839798 TI - The "non-Alzheimer" degenerative dementias. PMID- 7839799 TI - [Contribution of positron-emission tomography to the study of language]. AB - Language is the most evolved and complex of cognitive functions. During recent years, its study has largely benefited from new medical imaging technologies among which positron emission tomography (PET), allowing for direct observation of in vivo human brain activity. This paper reviews some of the important advances in the understanding of single-word processing provided by PET, integrating them in the context of other fields of investigation such as cognitive neuropsychology. It also points out the limitations of the technique and some of its recent developments, opening the way for further comprehension of language processing. PMID- 7839800 TI - Comparison of cerebral haemodynamic and oxygen metabolic changes due to cavernous angiomas and arteriovenous malformations of the brain. A positron emission tomography study. AB - The cerebral haemodynamic and metabolic changes due to cavernous angiomas in three patients and to arteriovenous malformations in four patients were compared by positron emission tomography, using the steady state technique with 15O. In the brains with a cavernous angioma no important changes in blood flow were observed. Only a decreased oxygen consumption was present in the cortex supplied by the arterial branches of the angioma, most probably related to neuronal deafferentation. In the four cases of arteriovenous malformation cerebral blood flow was significantly increased in the territory of the feeding vessels of the angioma. In the two huge ones the oxygen extraction rate was increased in the other vascular areas remote from the supply territory of the angioma, indicating chronic ischaemia. The present study confirms that chronic vascular steal phenomena can occur in large arteriovenous malformations, while cavernous angiomas do not induce important haemodynamic changes. PMID- 7839801 TI - Limited clinical significance of traditional and quantitative EEG in multiple sclerosis. PMID- 7839802 TI - Somatosensory central conduction time after sural and tibial nerve stimulation. AB - We recorded spinal and cortical somatosensory evoked potentials (SEPs) after sural and tibial nerve stimulation at the ankle in 34 normal subjects. Spinal SEPs were reproducible with sural nerve stimulation in only 65% of normal subjects. The spinal amplitudes were significantly smaller after sural nerve stimulation. Central conduction time (CCT) was significantly shorter when measured from onset instead of peak latencies. There was a significant difference between CCT with tibial nerve and sural nerve stimulation. Our results are consistent with the idea that CCT measures from onset and peak latencies do reflect the travel of the afferent volley in different spinal fiber populations. PMID- 7839803 TI - The vanishing pituitary adenoma. AB - In a female patient, a pituitary tumour was discovered incidentally. Regular follow-up by magnetic resonance imaging first showed no evolution and later an almost complete disappearance of the lesion. The patient was never treated; a silent infarction of the tumour could explain the spontaneous regression. PMID- 7839804 TI - Cardiac arrest in Guillain-Barre syndrome and the use of suxamethonium. AB - A patient is described with severe Guillain-Barre syndrome resulting in tetraplegia. Artificial ventilation was necessary. There were signs of autonomic dysfunction such as systolic hypertension and excessive sweating. He developed fatal cardiac electromechanic dissociation after intravenous suxamethonium administration for a second endotracheal intubation because of respiratory failure. PMID- 7839805 TI - [Non-epileptic crisis: which therapeutic strategy to follow?]. AB - About 20% of patients with intractable epilepsy do not have epileptic seizures. The exact diagnosis is in fact difficult because most of the time, the seizures are not directly visualized. In case of uncertainty, prolonged EEG/Video monitoring and clinical observation are necessary to avoid escalated drug therapy and behavioural problems. We describe two such cases. The diagnosis of non epileptic attacks was told to the patients, the antiepileptic drugs were progressively withdrawn and an intensive psychotherapy was started. The seizures decreased in number and severity. In both cases, sexual abuse in childhood was discovered. PMID- 7839806 TI - A study of parkinsonism in multiple system atrophy: clinical and MRI correlation. AB - We investigated clinical and MRI correlation in 18 patients with clinically diagnosed multiple system atrophy (MSA) and 16 age-matched controls, using 1.5 T magnetic resonance imaging (MRI). We evaluated the severity of parkinsonism in each MSA patient. In assessing the MRI findings, we examined three parameters quantitatively: width of the pars compacta of the substantia nigra (SNc); putaminal hypointensity on T2-weighted images; and putaminal atrophy. As in previous studies, SNc width was narrowed and the putaminal signal intensity was decreased in patients with MSA compared with controls. The clinical severity of parkinsonism did not correlate significantly with the SNc width or the score of putaminal hypointensity in MSA. However, not only did putaminal atrophy occur, but correlated well with the severity of parkinsonism in MSA. A significant correlation could not be established between narrowing of SNc and shrinkage of the putamen. These findings suggest that putaminal atrophy is associated with the clinical manifestations of parkinsonism and do not support the hypothesis that transsynaptic degeneration occurs in MSA. PMID- 7839808 TI - Subclavian steal phenomenon. Clinical and hemodynamic aspects. AB - Fifty-eight patients with subclavian artery stenosis were classified as having definite or probable vertebrobasilar symptoms, carotid symptoms or no symptoms. The vertebral artery flow pattern was graded as no subclavian steal (Grade 0), systolic deceleration (Grade 1), alternating flow (Grade 2), or reversed flow (Grade 3). We found a statistically significant association between the occurrence of vertebrobasilar symptoms and the subclavian steal phenomenon Grades 2-3. No significant association could be established between time course, type or severity of symptoms and grade of steal phenomenon. The flow disturbance is probably one causal factor for the occurrence of symptoms. Reversed vertebral artery flow is commonly asymptomatic, however, and other non-identified cofactors must be operative in symptomatic patients. PMID- 7839807 TI - Epileptic seizures, arthrogryposis, and migrational brain disorders: a syndrome? AB - INTRODUCTION: Arthrogryposis multiplex congenita (AMC) may be associated with multiple developmental defects. In some severely affected newborns with AMC, autopsy studies have suggested a common mechanism of malmigration at the spinal and cerebral levels. To our knowledge, a constellation of arthrogryposis, epileptic seizures, and brain migrational anomalies in adult patients has not previously been described in a clinical material. MATERIAL AND METHODS: Six consecutive adult patients with arthrogryposis multiplex congenita and epileptic seizures form the basis of the present study. Five patients had joint contractures and reduced muscle volume restricted to the lower extremities, whereas one patient had predominantly upper extremity affection. They were studied with magnetic resonance imaging (MRI), EEG, EMG, a neuropsychological test battery, and chromosome analysis. RESULTS: Four of them had clear evidence of migrational brain disorders, demonstrated by MRI, in three of them roughly corresponding to the focal epileptiform EEG activity. Five of the patients had partial seizures, whereas one only had generalized tonic-clonic seizures. The MRI findings included polymicrogyria, pachygyria, and fused schizencephaly. Four had neurogenic EMG changes, one had myopathic EMG features, and one had an unremarkable EMG pattern in affected muscles. All patients with demonstrable migrational disorders showed abnormal neuropsychological features. Three patients were mentally retarded. A chromosome abnormality in the form of a ring chromosome 18 was present in one patient. CONCLUSION: We suggest that AMC, epileptic seizures, and migrational brain disorders may form the integral parts of a hitherto undescribed syndrome in adults. A wide-spread defect in neuronal migration along the entire neural axis may be the underlying mechanism of the cerebral and the peripheral symptoms. PMID- 7839809 TI - Which are the major determinants for outcome in aneurysmal subarachnoid hemorrhage? A prospective total management study from a strictly unselected series. AB - In this prospective study we report the outcome for all patients with a verified aneurysmal SAH managed at the Department of Neurosurgery at the University Hospital in Lund, Sweden during the four-year span from June 1, 1989 to May 31, 1993. A total of 275 patients were admitted during the study period. The vast majority of patients (196 individuals, i.e. 71%) was admitted within 24 h after the bleed. Mean age was 54.3 years and the female/male ratio 1.8/1. Nimodipine was administered in 231 (84%) of the 275 patients. We clipped the ruptured aneurysm in 199 patients. At follow-up 3 months after the bleed 161 patients were classified as having made a good neurological recovery (59%). The morbidity was 20% and 59 patients (21%) had died. The overwhelming cause for morbidity and mortality was damage from the initial bleed (62 patients, 23%). Notably, considering morbidity and mortality, delayed ischemia was less frequent than both surgical complications and rebleeding, respectively. Of the 275 patients, 13 (5%) patients made an unfavorable outcome due to delayed ischemic deterioration. There was a strict correlation between the initial clinical condition and final outcome. Of 51 grade V patients, only 2 made a good recovery. There was also a strict correlation between the amount of extravasated blood and outcome. There was no difference in clinical outcome between patients with arterial hypertension versus normotensive individuals. The mortality rate was worse for posterior circulation aneurysms.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7839810 TI - Cerebrovascular disease in children. AB - Stroke although rare in children, is an important cause of morbidity in the paediatric age group. Over a period of 8 years, 43 children (17 boys and 26 girls) in the age groups of 1-16 years (mean 8.02 yrs) presented with stroke which constituted 10% of all strokes in the young and 0.7% of all paediatric admissions. The chief clinical features were hemiplegia (86%), convulsions (27%), fever (23%), dysphasia (23%), headache (11%) and altered level of consciousness (11%). Routine laboratory tests were non-contributory. Cranial computerized tomography (CCT) on 21 patients was abnormal in 95% and was useful in revealing the extent of infarction. Infarction was confined to middle cerebral artery territory, often involving basal ganglionic structures and was associated with focal or diffuse atrophy. Angiograms were abnormal in 78% of the patients (18/23) and were complimentary to the CCT. Etiological factors identified were: Moya-moya disease 6, arteritis 5, fibromuscular dysplasia 2, scorpion sting 2, and venous sinus thrombosis and small vessel occlusion one each. Though 23% of the patients had fever at onset, no obvious evidence of systemic or CNS infection was noticed. Stroke in children continues to pose a diagnostic challenge. PMID- 7839811 TI - The antioxidant tirilazad does not affect cerebral blood flow or histopathologic changes following severe ischemia in rats. AB - We studied the effect of tirilazad, an aminosteroid with radical scavenging effect, or its vehicle on cerebral blood flow and neuronal death when given before 15 min of severe global ischemia achieved by hypotensive bilateral carotid clamping in rats. Ischemic blood flows less than 1% of the non-ischemic values were seen in the forebrain regions. Hypoperfusion occurred in all regions 60 min after the insult with flow values 21-58% of those in the non-ischemic group. Tirilazad had no effect on cerebral blood flow in the non-ischemic rats, nor in those decapitated during or after the insult. Five days postischemia neuronal damage had developed in all regions examined, but no significant differences were seen between the tirilazad- and the vehicle-treated rats. PMID- 7839812 TI - EEG as predictor of dementia following first ischemic stroke. AB - INTRODUCTION: Predictive factors for occurrence of vascular dementia may help identify patients at increased risk of developing this condition. Our purpose was to evaluate the prognostic value of early EEG findings in patients after first ischemic cerebral stroke on the development of dementia. MATERIAL AND METHODS: We performed routine EEG recordings in 199 consecutive non-demented patients with first-ever ischemic stroke, within 48 h of the event. The patients were subsequently followed for their mental state for 2 years. Survival analysis, wherein onset of dementia was the end-point, was performed on the total sample population and conducted separately on those who had normal EEG at time of the event and on those who had abnormal EEG findings (focal or diffuse slowing). RESULTS: Patients with abnormal EEG at baseline had 2.6 times the risk of developing dementia than those who had normal EEG; this odds ratio was statistical significant (CL: 1.3-5.1, p = 0.003). Development of dementia was not related to any specific EEG abnormal pattern. CONCLUSIONS: Abnormal EEG performed close to the first ischemic stroke appears to be an indicator of subsequent cognitive decline, probably because it indicates cortical involvement by the stroke or an underlying indolent cerebral degeneration. PMID- 7839813 TI - Correlation between clinical, electromyographic and dysautonomic evolution of familial amyloidotic polyneuropathy of the Portuguese type. AB - To assess the correlation between the severity of clinical symptoms and sensorymotor and autonomic function in familial amyloidotic polyneuropathy of the Portuguese type (FAP-PT), clinical grade (CG), electromyographic score (ES), sympathetic (SS) and parasympathetic score (PS) were compared in 47 patients. SS and PS were both abnormal in 72% of patients with ES = 0% and in 73% of patients with CG = 0. When SS and PS were compared with either CG and ES, PS progressed more rapidly and stabilized earlier than SS. As a whole, SS and PS were greater as CG and ES were higher. This pattern of autonomic involvement should be taken into account when assessing the course of the disease and evaluating new forms of therapy. PMID- 7839814 TI - Upper limb pain in chronic demyelinating polyneuropathy: electrophysiological correlates. AB - Pain is not usually considered a symptom of chronic relapsing demyelinating polyneuropathy. We report two patients with chronic demyelinating polyneuropathies in whom clinical and electrophysiological worsening was associated with the development of deep and distressing upper limb aching discomfort. One patient had a MGUS-associated hypertrophic demyelinating and prednisone-dependent polyneuropathy, followed over a course of two and a half years. His discomfort regularly predicted electrophysiological relapse of neuropathy, before more obvious clinical signs had emerged. Resolution of the discomfort also predicted subsequent clinical and electrophysiological improvement. Upper limb pain may be an important feature of early relapse in some patients with demyelinating polyneuropathies. Standardized serial electrophysiological testing in patients with chronic demyelinating polyneuropathy can be an important management tool in conjunction with clinical signs and symptoms. PMID- 7839815 TI - Steadiness of amyotrophic lateral sclerosis in the province of Parma, Italy, 1960 1990. AB - A clinical and epidemiological study on amyotrophic lateral sclerosis (ALS) was conducted in the province of Parma, Italy, from 1960-1990. A total of 121 cases were collected from hospital records. The average annual incidence was 0.98 per 100,000 inhabitants, with a male/female ratio of 1.1. Age-specific incidence was maximal in the age group 60-69 years. No difference between rural and urban areas was found. Prevalence on October 26th, 1981 was 2.5 per 100,000. Mean age at onset was 60 years, with no significant sex difference. Mean duration of the disease was 30 (sd 21.4) months. Bulbar forms were significantly (p < 0.05) shorter than conventional forms, with a mean duration of 23.4 (sd 21.4) months. Age at onset did not influence prognosis. A comparison of three decades was made, to verify whether possible variations of the disease had occurred with time. From our data a definite stability was found in such epidemiological parameters as incidence, prevalence, mean duration and mortality of ALS in the period. PMID- 7839816 TI - Benign mitochondrial myopathy with decreased succinate cytochrome C reductase activity. AB - In most of the cases previously described, the defect on complex II was suggested by low activity of succinate cytochrome C reductase (SCCR). The clinical pattern of the previous 10 cases is heterogeneous and may be limited to one particular tissue or be of a more general nature. We report a 22-year-old-woman, daughter of consanguineous parents, with generalized muscle weakness, easy fatigability and benign course, who showed a decrease of SCCR activity in mitochondria of muscle fibers. Free carnitine (FC) concentration was decreased in muscle as well. The muscle biopsy showed a mild variation in fiber size, with fiber type I predominance, subsarcolemmal oxidative DPNH accumulations, excess of neutral lipids and abnormally large mitochondria with paracrystalline inclusions. A possible inheritance pattern is discussed. Coenzyme Q10 therapy in this patient induced a significant increase of global MRC index score and a decrease of the turns-mean amplitude ratio in the automatic analysis of the EMG. PMID- 7839817 TI - Staging the severity of dementia: comparison of clinical (CDR, DSM-III-R), functional (ADL, IADL) and cognitive (MMSE) scales. AB - The Helsinki Aging Study is based on a random sample of 795 subjects aged 75 years (N = 274), 80 years (N = 266) and 85 years (N = 255). Ninety-three demented patients were found. All were assessed for severity of dementia by Clinical Dementia Rating (CDR) scale by a general practitioner and according to the DSM III-R criteria by a neurologist. The Mini-Mental State Examination (MMSE) was carried out by a community nurse and the Index of ADL and the IADL-scale by a close informant. The correlation of the severity of dementia between the DSM-III R criteria and the CDR scale was moderate. The overall agreement was 64.5% and the Kappa index 0.56. The CDR scale tended to put patients in milder categories than the DSM-III-R criteria. The correlation between the clinical scales and categorized MMSE was moderate to fair. The overall agreement between MMSE and DSM III-R criteria was 64% (Kappa 0.44) and between MMSE and CDR scale 55% (Kappa 0.33%). The dispersion of the functional scales (ADL, IADL) was much greater indicating that there were also other factors influencing the functional capacity than the degree of dementia. Different methods in staging dementia give different results thus influencing for instance the results of epidemiological studies. Functional scales are needed in clinical practice in addition to the assessment of the severity of dementia. The CDR scale is useful in assessing the need for support services. PMID- 7839818 TI - Effect of K+ channel blockers on the clinical course and histological features of experimental allergic encephalomyelitis. AB - INTRODUCTION: Beneficial clinical effects of 4-aminopyridine (4-AP) in multiple sclerosis (MS) have been reported. The use of 4-AP in MS is based upon its ability to facilitate conduction in axons blocked by demyelination. This improvement is due to blocking of potassium (K+) channels in these fibres. Because K+ channels also play an important role in immune mechanisms successful treatment with K+ channel blockers in neuroimmunological diseases may have several causes. Therefore it seems important to study effects of K+ channel blockers in animal models of autoimmune disease. MATERIAL & METHODS: We studied the effects of 4-AP and quinidine on actively induced acute experimental allergic encephalomyelitis (EAE) in Lewis rats. RESULTS: There was no effect on the incidence of the disease. The severity of the disease was also unchanged although the disease duration was slightly diminished in the treated groups. Immunohistological comparison between the animals of different groups showed no differences. CONCLUSION: We conclude that 4-AP and quinidine are not capable of significantly changing the clinical course of EAE. PMID- 7839819 TI - On an autosomal dominant form of retinal-cerebellar degeneration: an autopsy study of five patients in one family. AB - We describe a family with an autosomal dominant form of retinal-cerebellar atrophy. There is an extreme variability in age of onset and severity of the clinical symptoms: some patients remain nearly asymptomatic throughout their entire life; others develop severe retinal and cerebellar symptoms after the age of 35 years; others suffer from a severe disorder with onset in adolescence and death during the third decade of life; in others the onset is in early childhood with prevalence of cerebellar symptoms. There is neither dementia nor epilepsy in any of the patients. Four out of five autopsies showed a severe retinal atrophy, and all five autopsies were also characterized by (1) a cerebellar atrophy affecting the spinocerebellar and olivocerebellar tracts, the cerebellar cortex and the efferent cerebellar pathways, (2) an involvement of the pyramidal pathways and of the motor neurons of brain stem and spinal cord, and (3) an atrophy of the subthalamic nucleus and to a much lesser extent of the pallidum, with also some damage to the substantia nigra. The posterior columns are much less affected except in one patient. In this family, we have excluded linkage with the two loci for spinocerebellar ataxia, i.e., SCA1 on chromosome 6p and SCA2 on chromosome 12q as well as with the locus for Machado-Joseph disease (MJD) on chromosome 14q. A genome-wide search is currently being performed to detect the disease locus responsible. PMID- 7839820 TI - Electrolyte-induced demyelination in rats. 1. Role of the blood-brain barrier and edema. AB - The blood-brain barrier (BBB) was studied in rats with electrolyte-induced demyelination (EID), an experimental model for central pontine myelinolysis. Intravenously injected peroxidase was extravasated at 3 h post hypertonic saline injection (PHS) into regions frequently involved in EID. Increased pinocytotic activity and focal interendothelial gaps were seen at 3 h PHS and less frequently at 48 h PHS. Measurement of total cerebral water content revealed an increase during the hyponatremic phase. This was followed by a marked increase at 3 h PHS with continued increment at 48 h PHS. Intracellular edema with accumulation of fluid within neurites and astrocytic processes was noted during the hyponatremic phase, whereas extracellular edema developed after hypertonic saline injection. The implications of disrupted BBB and its role in the pathogenesis of EID are discussed. PMID- 7839821 TI - Electrolyte-induced demyelination in rats. 2. Ultrastructural evolution. AB - This study presents the electron microscopic evolution of lesions in electrolyte induced demyelination (EID) in rats, a lesion which bears striking histological and clinical similarity to central pontine myelinolysis. The earliest change was observed during the hyponatremic phase and consisted of minimal intracellular edema present throughout the brain. Following the injection of hypertonic saline, additional changes were observed which were restricted to sites previously reported to be frequently involved in EID. Early dilatation of the inner tongue of oligodendrocyte cytoplasm in myelinated nerve fibers was observed at 3 h post hypertonic saline injection (PHS). This was followed, at 48 h PHS, by the appearance of degenerative changes consistent with dying oligodendrocytes. Well delineated, vacuolar and spongy lesions, seen by light microscopy, were present by 48 h PHS at the same sites as above. Electron microscopically, this appearance was found to be due to striking intramyelinic edema. By 96 h PHS, macrophages containing myelin and other cellular debris were frequently present at these sites. Concomitantly, myelin sheaths underwent vesicular disruption and disintegration. This sequence of events suggests a lesion of the oligodendrocyte myelin complex, secondary to initial blood-brain barrier damage and edema. PMID- 7839822 TI - Immunohistological localization of mycobacterial antigens within the peripheral nerves of treated leprosy patients and their significance to nerve damage in leprosy. AB - The presence and distribution of Mycobacterium leprae-specific and cross-reacting antigens within the peripheral nerves of multidrug-treated patients with leprosy was investigated to gain a better understanding of the mechanism of nerve damage and the effect of multidrug therapy (MDT) on it. There was no specific qualitative difference in the type of antigens in the leprosy spectrum. However, our results indicate that there may be differential handling of antigens by the macrophages as compared to Schwann cells. This could play a key role in the pathogenesis of the disease. Multidrug treatment is effective in arresting the progression of the disease process as well as in reducing the viable bacterial load, both in borderline lepromatous and lepromatous (MB) and borderline tuberculoid and tuberculoid (PB) cases. However, the presence of M. leprae antigens in all the multidrug-treated MB nerve lesions and 87% of PB nerve lesions suggest that the antigens persist for a prolonged period. Hence, the risk of immunological reaction and antigen-associated silent nerve damage may continue even after majority of M. leprae were killed. The findings give further support to the view that most of the nerve damage is due to bacterial antigens. PMID- 7839823 TI - The volume of Purkinje cells decreases in the cerebellum of acrylamide intoxicated rats, but no cells are lost. AB - The effects of acrylamide intoxication on the numbers of granule and Purkinje cells and the volume of Purkinje cell perikarya have been evaluated with stereological methods. The analysis was carried out in the cerebella of rats that had received a dose of 33.3 mg/kg acrylamide, twice a week, for 7.5 weeks. The total numbers of cerebellar granule and Purkinje cells were estimated using the optical fractionator and the mean volume of the Purkinje cell perikarya was estimated with the vertical rotator technique. The volumes of the molecular layer, the granular cell layer and the white matter were estimated using the Cavalieri principle. The mean weight of the cerebellum of the intoxicated rats was 7% lower than that of the control rats (2P = 0.001). The numbers of the Purkinje cells and granule cells were the same in both groups, but the mean volume of the perikarya of the Purkinje cells in the intoxicated rats was 10.5% less than that of the control group (2P = 0.004). The volume of the granular cell layer was reduced by 15% (2P = 0.006) but there were no differences in the volumes of the molecular layer and the white matter in the intoxicated and control animals. PMID- 7839824 TI - Hippocampal loss of the GABAA receptor alpha 1 subunit in patients with chronic pharmacoresistant epilepsies. AB - Alterations of gamma aminobutyric acid (GABA)-mediated neurotransmission have been implicated in the pathogenesis of epilepsies. Here we examine the distribution of the GABAA receptor in the hippocampus of 78 surgical specimens from patients with chronic pharmacoresistant focal epilepsies. The receptor was localized immunohistochemically with the monoclonal antibody bd-24 which selectively recognizes the alpha 1 subunit of the GABAA receptor. The results were compared with the receptor distribution of 28 normal hippocampal specimens obtained at autopsy. In the great majority of the surgical specimens a loss of GABAA receptor immunoreactivity was present in CA1 (92.3%), CA4 (78.2%), the dentate granular cell layer (70.5%) and the molecular layer of the dentate gyrus (65.4%). The subiculum revealed a normal staining pattern in all but 4 cases. In no instance did we observe an increase of immunoreactivity in any region or cell population. The decrease of GABAA receptor immunoreactivity was closely related to neuronal loss in the respective specimen and to Ammon's horn sclerosis. There was no correlation between GABAA receptor loss and the patient's age at surgery, duration of seizures, age at onset of seizures and to the presence or absence of secondary generalized tonic clonic seizures. The data suggest that the observed loss of GABAA receptor immunoreactivity is a secondary phenomenon rather than an event that is relevant for the pathogenesis of epileptic seizures. PMID- 7839825 TI - Cortical and striatal neurone number in Huntington's disease. AB - The total cortical and striatal neurone and glial numbers were estimated in five cases of Huntington's disease (three males, two females) and five age- and sex matched control cases. Serial 500-microns-thick gallocyanin-stained frontal sections through the left hemisphere were analysed using Cavalieri's principle for volume and the optical disector for cell density estimations. The average cortical neurone number of five controls (mean age 53 +/- 13 years, range 36-72 years) was 5.97 x 10(9) +/- 320 x 10(6), the average number of small striatal neurones was 82 x 10(6) +/- 15.8 x 10(6). The left striatum (caudatum, putamen, and accumbens) contained a mean of 273 x 10(6) +/- 53 x 10(6) glial cells (oligodendrocytes, astrocytes and unclassifiable glial profiles). The mean cortical neurone number in Huntington's disease patients (mean age 49 +/- 14 years, range 36-75 years) was diminished by about 33% to 3.99 x 10(9) +/- 218 x 10(6) nerve cells (P < or = 0.012, Mann-Whitney U-test). The mean number of small striatal neurones decreased tremendously to 9.72 x 10(6) +/- 3.64 x 10(6) (-88%). The decrease in total glial cells was less pronounced (193 x 10(6) +/- 26 x 10(6)) but the mean glial index, the numerical ratio of glial cells per neurone, increased from 3.35 to 22.59 in Huntington's disease. Qualitatively, neuronal loss was most pronounced in supragranular layers of primary sensory areas (Brodmann's areae 3,1,2; area 17, area 41). Layer IIIc pyramidal cells were preferentially lost in association areas of the temporal, frontal, and parietal lobes, whereas spared layer IV granule cells formed a conspicuous band between layer III and V in these fields. Methodological issues are discussed in context with previous investigations and similarities and differences of laminar and lobar nerve cell loss in Huntington's disease are compared with nerve cell degeneration in other neuropsychiatric diseases. PMID- 7839826 TI - Structural and ultrastructural characteristics of human pineal gland, and pineal parenchymal tumors. AB - We have studied 20 pineal parenchymal tumors (PPT) and 4 normal or cystic pineal glands both by light and electron microscopy and immunohistochemistry with antibodies against glial markers [glial fibrillary acidic protein (GFAP) and protein S-100] or neural/neuroendocrine markers [neurofilaments (NF), synaptophysin and chromogranin A]. Light microscopy revealed the cellular organization of pinealocytes in the normal gland and in different morphological types of pineal tumors (typical pineocytomas, PPT with intermediate differentiation, mixed PPT exhibiting elements of both pineocytoma and pineoblastoma and pineoblastomas). Immunohistochemistry showed the presence of GFAP and protein S-100 in interstitial cells in non-neoplastic pineal gland. Cell processes were labeled with anti-synaptophysin and anti-NF antibodies. No immunoreactivity was found for chromogranin A in non-neoplastic pineal gland. In pineocytomas, GFAP and protein S-100 were observed in interstitial cells. Synaptophysin and NF were present in the large rosettes of pineocytomas. Synaptophysin, NF and chromogranin A were present in pineocytomas with a lobular arrangement of cells. Anti-chromogranin A immunoreactivity was also seen in lobular areas of some PPT with intermediate differentiation. Analysis of normal human pineal gland by electron microscopy showed the presence of vesicle-crowned rodlets (VCR or synaptic ribbons), fibrous filaments (F), paired twisted filaments but few dense-core vesicles (DCV) in normal pinealocytes. Tumoral pineal cells appeared to differentiate either towards a neurosensory pathway characterized by the presence of sensory cells elements (VCR and F), or towards a neuroendocrine pathway, with the occurrence of many DCV. Immunogold labeling demonstrated the presence of chromogranin A in neurosecretory granules. PMID- 7839827 TI - Neurofilament phosphorylation is enhanced in cultured chick spinal cord neurons exposed to cerebrospinal fluid from amyotrophic lateral sclerosis patients. AB - Amyotrophic lateral sclerosis (ALS), a neurodegenerative disease, is characterized by degeneration of lower and upper motor neurons. Serum and cerebrospinal fluid (CSF) of ALS patients have been found to exert toxic effects on neurons in culture. We report here increased phosphorylation of neurofilaments (NF) in the soma of chick spinal cord neurons in culture when exposed to CSF of ALS patients. Spinal cord neurons were cultured from 10-day embryonic chick and exposed to culture medium supplemented with CSF or serum (10%) from ALS and non ALS patients for 48 h. There was a significant increase in the number of neuronal soma staining with antibodies against phosphorylated NF, following exposure to CSF from ALS patients. Such an increase, however, was not observed in cultures exposed to serum from ALS patients and also serum and CSF from non-ALS patients. These results suggest that the CSF of ALS patients may contain factor(s) which induces aberrant phosphorylation of NF in the soma, a probable forerunner to the formation of neurofibrillary tangles and eventual degeneration of neurons. PMID- 7839828 TI - The spatial patterns of beta/A4 deposit subtypes in Down's syndrome. AB - The spatial patterns of diffuse, primitive and classic beta/A4 deposits were studied in coronal sections of the hippocampus and adjacent gyri in 11 cases of Down's syndrome (DS) varying in age from 38 to 67 years. The objectives of the study were first, to compare the spatial patterns of beta/A4 deposits revealed in DS with those reported in cases of Alzheimer's disease (AD) and second, to study how the spatial patterns of beta/A4 deposits may develop in the tissue. The spatial patterns revealed in DS exhibited a number of similarities with those reported in AD: (1) the range and frequency of the different types of spatial pattern revealed were similar, (2) beta/A4 deposits occurred in clusters and in many cortical tissues, the clusters were distributed in a regular pattern parallel to the pia, (3) the clusters of diffuse and primitive beta/A4 deposits occurred in an alternating pattern along the cortex, and (4) the clusters of classic beta/A4 deposits were not correlated with the clusters of the diffuse and primitive deposits. Primitive deposits may develop from the diffuse deposits in regions of the cortex where extracellular paired helical filaments were formed. However, clusters of the classic beta/A4 deposits, which are formed in older cases, appear to develop independently of the diffuse and primitive deposits. PMID- 7839829 TI - Neurotoxic effects of aluminium on embryonic chick brain cultures. AB - Toxic damage of brain cells by aluminium (Al) is discussed as a possible factor in the development of neurodegenerative disorders in humans. To investigate neurotoxic effects of Al, serum-free cultures of mechanically dissociated embryonic chick (stage 28-29) forebrain, brain stem and optic tectum, and for comparison meningeal cells, were treated with Al (0-1000 microM) for 7 days. Effects of Al on cell viability (lysosomal and mitochondrial activity) and differentiation (synthesis of cell-specific proteins) were found to the brain area specific with the highest sensitivity observed in optic tectum. No inhibiting effects on cell viability could be observed in cultures of forebrain and meninges in the concentration range tested. In all three brain tissue cultures, threshold levels for the reduction of cell differentiation parameters were found at lower concentrations [concentration resulting in a 50% decrease (IC50) > 180 microM] than for the inhibition of cell viability (IC50 > 280 microM), indicating a specific toxic potential of Al for cytoskeletal alterations. The culture levels of nerve cell-specific markers microtubule associated protein type 2 (the most sensitive parameter) and the 68-kDa neurofilament were inhibited at lower concentrations (IC50 180-630 microM) than the astrocyte-specific glial fibrillary acidic protein (IC50 700-approximately 1000 microM), demonstrating a particularly high sensitivity of neurons in comparison to astrocytes. Based on these differences in Al sensitivity observed for different cell markers in the various brain tissue cultures, the in vitro system used in the present study proved to be a suitable model to assess brain area and cell type-specific neurotoxic effects of Al. PMID- 7839830 TI - Clinical and pathological study of three Tunisian siblings with L-2 hydroxyglutaric aciduria. AB - This report describes three brothers belonging to a consanguineous family suffering from a progressive neurological disorder associated with L-2 hydroxyglutaric aciduria. Clinically this disorder is characterized by childhood onset, pyramidal signs, cerebellar and pseudobulbar syndromes and epilepsy. Pathological examination of the brain in the oldest patient, who died at the age of 30 years, showed bilateral and diffuse spongiosis with notable cystic cavitations of the cerebral white matter without abnormal storage in neurons and glial cells. We consider that these findings are related to L-2 hydroxyglutaric aciduria. To our knowledge this present case represents the first to be reported with neuropathological examination. PMID- 7839831 TI - Hereditary cerebral hemorrhage with amyloidosis (Dutch): a model for congophilic plaque formation without neurofibrillary pathology. AB - Plaque-like lesions and amyloid angiopathy were investigated in the frontal cerebral cortex of four patients with hereditary cerebral hemorrhage with amyloidosis (Dutch) (HCHWA-D), using immunohistochemical [antibodies to beta amyloid protein (A beta), beta protein precursor (beta PP), synaptophysin, ubiquitin (UBQ), cathepsin D, paired helical filaments (PHF) and glial fibrillary acidic protein (GFAP)], enzymehistochemical (acid phosphatase) and silver [methenamine silver (MS) and Palmgren] staining methods. Whereas A beta- and MS positive diffuse plaques were found in all patients, only the three older patients showed neuritic or congophilic plaques, which were acid phosphatase and cathepsin D positive and contained beta PP-, synaptophysin- and UBQ-positive, but PHF-negative neurites. These plaques were surrounded by reactive astrocytes. Similar immuno- and enzymereactivity was found around congophilic blood vessels. Thus, apart from neuronal degeneration in a subset of plaque-like lesions and around blood vessels, this study shows an age-related morphology of the plaques in HCHWA-D, corresponding to that in Down's syndrome (DS), with the difference that neurofibrillary (NF) pathology is absent in HCHWA-D in contrast to DS. HCHWA D may be considered as a model for congophilic plaque formation not associated with NF pathology. PMID- 7839832 TI - Abnormal cytoskeletal pathology peculiar to corticobasal degeneration is different from that of Alzheimer's disease or progressive supranuclear palsy. AB - An autopsy case of clinically diagnosed "corticobasal degeneration (CBD)" was investigated. In addition to status spongiosus and neuronal achormasia around the central sulcus, cortical pyramidal neurons and thread-like structures were densely stained by Gallyas stain and tau immunohistochemistry, but apparent fibrillary structures like Alzheimer's disease neurofibrillary tangle were absent. Bodian, methenamine-Bodian, Congo red, thioflavin S, or Bielshowsky stains failed to visualize these structures. They were not stained by immunohistochemical stain with anti-ubiquitin antibody. The widespread cytoskeletal pathology, which is distinct from that in Alzheimer's disease or progressive supranuclear palsy, is suggestive of CBD. PMID- 7839833 TI - Primary osteosarcoma of the cerebrum with immunohistochemical and ultrastructural studies: report of a case. AB - A 57-year-old woman with primary intracerebral osteosarcoma is reported. The tumor was identified by computed tomography as a mass with hemorrhage in the right parietal lobe. The surgical and pathological examinations confirmed an osteosarcoma of intracerebral origin. She suffered from repeated local recurrence of the tumor and died about 1 year after the onset. The pathological findings showed features of osteoblastic osteosarcoma with numerous osteoclast-like multinucleated giant cells. Immunohistochemically, tumor cells were positive for vimentin, and partially for actin. Multinucleated giant cells were reactive with vimentin and CD68 antibodies. Ultrastructurally, tumor cells were rich with rough endoplasmic reticulum. These findings are consistent with the histological features of skeletal or extraskeletal osteosarcoma. This is the third case of primary intracerebral osteosarcoma reported in the literature and the first one analyzed ultrastructurally. PMID- 7839834 TI - Idiopathic peripheral neuropathy in a horse with knuckling. AB - We report the pathological findings of the skeletal muscle and peripheral nerves from a male 14-months-old thoroughbred horse showing idiopathic knuckling. The affected animal, when in staining position, presented knuckling at the fetlock joint of both forelegs, and dragged both fore- and hindlegs when attempting forward movement. The skeletal muscles demonstrated neurogenic atrophy characterized by the scattering of single angular fibers, groups consisting of five to ten angular fibers, and multiple fascicles of atrophic and hypertrophic fibers. The severity of changes tended to be a distal gradient. While there was no evidence of fiber loss on light microscopy, a diffuse scattering of myelin ovoid, Wallerian-like degeneration and onion-bulb formations were observed in almost all peripheral nerves collected. The characteristic features in electron microscope were swollen axons, which contained accumulations of organelles, especially degenerative mitochondria and neurofilamanets. Onion-bulb formations were frequently found and were associated with Schwann cell processes and occasional collagen pockets. Other prominent feature were Bungner bands which contained myelin debris and regenerating axons or sprouts. These findings suggested that the nature of this disease was a disturbance in axonal transport and were indicative of a distal axonopathy. PMID- 7839835 TI - Tangier neuropathy in Italy. PMID- 7839837 TI - Legg-Calve-Perthes' disease. PMID- 7839836 TI - Neuroblastic differentiation in ethyl-nitrosourea-induced brain tumors. PMID- 7839838 TI - Sonography and intracapsular pressure in Perthes' disease. 39 children examined 2 36 months after onset. AB - 39 children with Legg-Calve-Perthes Disease (LCPD) and with a radiographically unsatisfactory development were examined with sonography regarding synovitis and with intracapsular pressure recording and aspiration performed 15 (2-36) months after the onset of symptoms. The mean anterior sonographic capsular distension was 3.0 (1.0-7.0) mm greater than that of the contralateral, asymptomatic hip. The mean intracapsular pressure was 4.5 (0-11.5) kPa with the hips in extension and neutral rotation, 9.7 (1.3-27.3) kPa with the hips in extension and inward rotation and 0.9 (-0.8-4.7) kPa in 45 degrees of flexion. We conclude that these children have synovitis as diagnosed sonographically. This synovitis is probably symptomatically and prognostically important in LCPD due to increased intracapsular pressure, with pain, a decreased range of motion and, potential joint contracture. PMID- 7839839 TI - Arthroscopy in 19 children with Perthes' disease. Pathologic changes of the synovium and the joint surface. AB - Arthroscopy of the hip joint was performed in 19 children with Legg-Calve Perthes' disease. Proliferation of the synovium was pronounced both in the acetabular fossa and over the inner wall of the capsule. Hypervascularity was seen on the acetabular labrum in every stage of the disease. Microscopically, hyperplasia of the synovial lining cells was observed, but inflammatory changes in the synovial tissue were inconspicuous in the early stage of the disease. Although hypertrophy of the endothelial cells of the vessels was seen in the late stage of the disease, it was not distinct in the initial or fragmentation stages. Joint pain improved after irrigation during arthroscopy. PMID- 7839840 TI - Destructive synovitis in contralateral Perthes' disease. A report of 2 cases. AB - 2 boys had unilateral Perthes' disease at the age of 5 years. After 6 and 7 years, respectively, both patients developed contralateral femoral head necrosis with rapid destruction leading to ankylosis of the hip. Histology of the synovium showed nonspecific synovitis. Both patients fulfilled criteria for oligo articular juvenile chronic arthritis (JCA). The association with Perthes' disease suggests a common etiology. PMID- 7839841 TI - Incorporation of allograft for acetabular reconstruction. Single photon emission CT in 21 hip arthroplasties followed for 2.5-5 years. AB - We studied 21 hips in 20 patients who had acetabular reconstruction with a femoral head allograft in primary (n 2) and secondary (n 19) total hip arthroplasty. The fate of the graft was evaluated by serial bone SPECTs (single photon emission computed tomography). With a mean follow-up period of 37 (30-60) months, 14 of the 21 hips showed evidence of incorporation at earliest 13 (6-18) months after operation. There was no correlation between the fate of allograft and the compatibility of A, B, O blood typing between host and donor, the use of bone cement in the fixation of acetabular component, or loosening of the acetabular component. PMID- 7839842 TI - Postphlebitic syndrome after hip arthroplasty. 43 patients followed at least 5 years. AB - We reviewed 43 patients using clinical scoring for evidence of postphlebitic syndrome at least 5 years after hip replacement. All had had a venogram as part of a screening study at the time of surgery. The postphlebitic syndrome was identified in 13 patients and was disabling in 6. The syndrome was present in 9 of the 11 patients with a venographically proven deep vein thrombosis (DVT) and in 4 of the 32 without DVT. Postphlebitic sequelae had developed despite anticoagulant therapy for the acute DVT. The postphlebitic syndrome following asymptomatic deep vein thrombosis is an important long-term complication of total hip replacement. PMID- 7839843 TI - Increased metal release from cemented femoral components made of titanium alloy. 19 hip prostheses followed with radiostereometry (RSA). AB - In 19 patients the concentrations of metal were measured in serum, urine and joint fluid 2 years after implantation of uncemented commercially pure titanium acetabular cups and cemented or uncemented femoral components made of titanium alloy. A ceramic against the polyethylene articulation was used. The fixation of the components was followed with radiostereometry (RSA). Samples from 12 patients scheduled for hip or knee prostheses and without any metallic implant were used as controls. High levels of titanium were found in cemented hips and when large acetabular cups had been inserted. Increased aluminum levels were also noted in the cemented hips. Vanadium was not detected in any of the samples. Micromotions were detected in most of the implants, but the magnitude of these movements could not be used to predict the release of metal into the synovial fluid. PMID- 7839844 TI - Knee ligament injury, surgery and osteoarthrosis. Truth or consequences? AB - We reviewed reports that describe development of osteoarthrosis of the knee after anterior cruciate ligament or meniscus injury. The occurrence of posttraumatic osteoarthrosis varied considerably from one report to another. The literature does not lend support to the efficacy of cruciate ligament repair or reconstruction in retarding the progression of osteoarthrosis after knee injury. We encourage prospective, controlled, randomized and masked studies that aim to evaluate the utility of ligament reconstruction, meniscus suture or meniscus transplantation for preventing posttraumatic osteoarthrosis. PMID- 7839845 TI - Treatment of femoral fracture above a knee prosthesis. 18 cases followed 0.5-14 years. AB - We reviewed 16 patients who sustained 18 fractures above a total knee prosthesis. 5 fractures were undisplaced and were treated with either skeletal traction or a plaster cylinder. 3 did well, 1 patient suffered a cerebral vascular accident while still in plaster and 1 patient died of heart failure while on skeletal traction. 7 displaced fractures were treated initially with skeletal traction. 1 patient had a nonunion of the fracture and 2 a malunion and malfunction of the knee. 4 underwent various operations later because of malalignment and nonunion of the fracture with poor functional results. 6 displaced fractures were treated with immediate internal fixation. 5 recovered well and returned to pre-fracture activities. 1 patient's plate broke and further surgery was needed. We conclude that displaced fractures above a knee prosthesis should be treated with immediate stable internal fixation and early mobilization. Nonoperative treatment was satisfactory only for minor undisplaced fractures. PMID- 7839846 TI - Decrease in valgus stiffness after medial knee ligament injury. A 4-year clinical and mechanical follow-up study in 38 patients. AB - The clinical outcome after partial rupture of the medial collateral knee ligament is reported to be good, but there is a lack of objective assessment of persistent valgus laxity. We prospectively followed 38 consecutive patients with an isolated partial medial ligament rupture. After diagnostic arthroscopy, all patients were treated by early functional rehabilitation. At 4 years, besides clinical routine laxity tests, varus/valgus rotation, internal/external tibial rotation, initial and endpoint valgus stiffnesses, initial and endpoint internal/external rotational stiffnesses were measured by instrumented computerized passive motion analysis (Genucom). Most patients had normal knee function and muscle strength as early as 3 months after injury and returned to their pre-injury activity level without problems. At 4 years, 2 knees had minor residual valgus laxity at the manual examination, all other knees appeared stable. The instrumented tests also showed equal varus/valgus rotations and internal/external rotational stiffnesses in injured and healthy knees, but a decrease in the initial valgus stiffness and a decrease in the internal/external tibial rotation of the injured knee. PMID- 7839847 TI - Union after multiple anterior cervical fusion. 21 cases followed for 1-6 years. AB - With a mean follow-up of 3 (1-6) years, we report on 21 patients who underwent multiple level cervical fusion, using autologous iliac crest grafts. Dissectomies were performed in 14 patients and corpectomies in another 7. Instrumentation was used in all patients with corpectomies and in 2 patients who underwent 2-level and 3-level dissectomies. Non-union occurred in 1 patient at 1 level. Graft displacement requiring reoperation was observed in 2 patients with massive corpectomies, in 1 of them as a consequence of trauma. In both patients complete bony fusion was obtained after reoperation and no other complications were observed. We conclude that the success rate with multiple-level fusion is comparable to that of single-level fusion when adequate fixation is achieved. PMID- 7839848 TI - No relation between ulnar variance and scapholunate dissociation. A comparison between 42 patients and 125 controls. PMID- 7839849 TI - Soft tissue infections from drug abuse. A clinical and microbiological review of 145 cases. AB - We evaluated clinical and microbiological aspects in 145 hospitalizations of 89 intravenous drug abusers with acute soft tissue infections at the injection site. There were 58 superficial abscesses, 27 deep abscesses, 57 cellulitis with or without concomitant ulcer, 1 purulent arthritis, 1 tenosynovitis and 1 incompletely categorized abscess. The commonest location was the groin. Serious complications occurred in 17 cases, including 4 lower-extremity amputations due to arterial lesions. There was a predominance of polybacterial infections (53 percent polybacterial, 38 percent monobacterial, 9 percent sterile). The commonest bacteria isolates were Streptococcus species with a preponderance of oropharyngeal bacteria, Staphylococcus aureus, and anaerobes, especially Bacteroides species. Typical intestinal bacteria were rare. In addition to surgical treatment we recommend that aerobic and anaerobic culturing with susceptibility tests always are carried out, that primary antibacterial therapy should consist of an antistaphylococcal agent, such as dicloxacillin plus metronidazole, and that free injection paraphernalia with disinfection swabs are easily available. PMID- 7839851 TI - Ethylene oxide sterilization of bone grafts. Residual gas concentration and fibroblast toxicity. AB - We examined the concentration of ethylene oxide in bone allografts after gas sterilization. Chips of the human femoral head were investigated. Residual gas concentration was determined by gas chromatography after the bone chips had been subjected to defatting and freeze-drying, followed by ethylene oxide gas sterilization. Bones were prepared in various ways in an attempt to reduce the concentration of residual ethylene oxide. The concentration was higher when gas sterilization was performed before freeze-drying than when it was done afterwards. An experiment performed with fibroblasts showed the high toxicity of residual ethylene oxide in bone chips, even when the concentration was very low. The growth of fibroblast was reduced more in medium which had been shaken with bones sterilized with ethylene oxide before freeze-drying than in medium which had been shaken with bones sterilized after freeze-drying. The higher residual ethylene oxide concentrations resulted in a decrease in fibroblastic culture activity. Our experiment showed the importance of reducing the residual ethylene oxide gas concentration. Defatting and freeze-drying result in lower residual ethylene oxide concentrations. PMID- 7839850 TI - Vasoconstrictive action of neuropeptide Y in bone. The porcine tibia perfused in vivo. AB - The hemodynamic effects of neuropeptide Y (NPY) and norepinephrine (NE) in bone were studied by infusion into the nutrient artery of an in vivo and in situ perfused tibia in 19 pigs. NPY and NE caused elevation of the perfusion pressure and decline in intraosseous pressure, which was evidence of intraosseous vasoconstriction. The study suggests that NPY, along with NE, acts as a sympathetic neurotransmitter in the control of vascular tone in bone. PMID- 7839852 TI - Clodronate prevents immobilization osteopenia in rats. AB - We investigated the effect of clodronate on immobilization osteopenia (IO) induced by sciatic neurectomy in rats. 100 Wistar female rats were divided into 5 groups of 20 animals each: 1) sham-operated, control group, 2) IO+saline control group, 3) IO+clodronate 3 mg/kg/day, 4) IO+clodronate 10 mg/kg/day, and 5) IO+clodronate 30 mg/kg/day. Clodronate was administered subcutaneously beginning on the day after nerve sectioning. After 7 weeks, the animals were killed and both tibiae were removed. Bone mineral density, ash weight and calcium, phosphorus and magnesium contents of the ash of the tibiae were analyzed. The weight of the rats did not differ between the groups during the experiment. The ash weight of the tibiae decreased by 6.6 percent and the mineral density decreased by 5.1 percent after neurectomy. Clodronate reduced IO in a dose dependent manner and the highest dose neutralized the effect of neurectomy. The calcium content of the ash decreased after neurectomy as compared to the sham operated group, and clodronate increased it to the sham-operated level. The bone Ca/P ratio remained normal. PMID- 7839853 TI - Distraction effects on muscle. Leg lengthening studied in rabbits. AB - We investigated changes in the anterior tibial muscle during lengthening of the lower leg in rabbits. In 37 rabbits, an osteotomy of the right middle tibia was performed and was fixed by a unilateral external fixator. The rabbits were randomized into 6 groups. In groups 1, 2, and 3 the tibiae were distracted 0.5 mm/day. In groups 1 and 2, the rabbits were killed after 14 and 28 days of distraction, respectively, and in group 3 after 28 days of distraction, followed by 14 days of rest. Groups 1a, 2a, and 3a served as controls. They were treated similarly as groups 1, 2, and 3, but no distraction was performed. Proliferating cell nuclei were labeled with 5-bromo-2-deoxyuridine and were identified by immunohistochemical staining. The weight of the muscle was measured. During bone lengthening the muscle showed signs of growth, as indicated by increasing weight and number of proliferating cell nuclei. This was observed only during lengthening and it ceased when the lengthening was stopped. PMID- 7839854 TI - Easy extraction of a fractured hip screw. A technical note. PMID- 7839855 TI - Ruptured pectoralis major tendon. A case report on delayed repair with muscle advancement. AB - A total rupture at the humeral insertion of the pectoralis major tendon was repaired 3 months after the injury by sutures through 3 pairs of drill holes in the crest of the greater tubercle. To unload the sutures and to facilitate early mobilization, the muscle was advanced by fascial detachment in the medial inferior origin of the muscle. Full mobility was achieved in 1 month and full activity was allowed 1 month later. PMID- 7839856 TI - Implant stability, histology, RSA and wear--more critical questions are needed. A view point. AB - I discuss the radiostereometry (RSA) of prosthetic micromovement from clinical and histological viewpoints. Even in non-migrators there is a wide variety of interfaces with various resistances to trigger factors, such as mechanical forces and sequels of wear. I suggest that the various forms of bone resorption seen with conventional radiography are caused by such trigger factors and that their anatomical appearance is determined by the structure of the interface obtained at surgery. PMID- 7839857 TI - Pituitary adenylate cyclase activating polypeptide induces vascular relaxation and inhibits non-vascular smooth muscle activity in the rabbit female genital tract. AB - In vitro effects of two bioactive forms of pituitary adenylate cyclase activating polypeptide (PACAP): PACAP-38 and PACAP-27 were studied on rabbit vascular and non-vascular smooth muscle. Segments of the ovarian artery and muscle strips from the fallopian tube were used. Two series of experiments were performed on vessels: the dose-response relationship of PACAP-38 (10(-10)-10(-7) M) was established on noradrenaline- (NA, 10(-6) M) contracted vessels. In the other set of experiments the contractile effect of 10(-8)-10(-4) M NA added cumulatively, was studied on arterial segments incubated with PACAP-38 (10(-7) M), PACAP-27 (10(-7) M) or VIP (10(-7) M). The effect of PACAP-38, PACAP-27 and VIP (10(-10) 10(-6) M) was investigated on spontaneously contracting smooth muscle of the fallopian tube. Longitudinally as well as transversally cut specimens were investigated. PACAP-38 produced a significant dose-related relaxation on the NA precontracted vessels. However, pre-incubation of the vessels with 10(-7) M PACAP 38, PACAP-27 and vaso active intestinal polypeptide (VIP) did not induce a general rightward shift of the NA concentration-response curves, although a tendency to inhibition in the low-dose interval was observed. The peptides caused a significant, dose-dependent inhibition of both frequency and amplitude on the fallopian tube smooth muscle activity. The effects of the three peptides on longitudinally as well as transversally cut specimens were alike. PMID- 7839859 TI - Rhythmic contractions of isolated, pressurized small arteries from rat. AB - The present study was undertaken to examine the influence of transmural pressure on vasomotion and to determine if any such influence was endothelium-dependent. Responses to changes in intravascular pressure of cannulated mesenteric small arteries were investigated under no-flow conditions. Both intact and endothelium denuded arteries dilated passively when intravascular pressure was increased stepwise from 20 to 140 mmHg. When tone was induced by noradrenaline, pressure increase resulted only in dilatation, independent of endothelium. The sensitivity to noradrenaline was significantly increased in vessels without endothelium, indicating a relaxing influence of the endothelium. Rhythmic contractions in response to noradrenaline occurred in all intact arteries, but were absent when the endothelium was removed. The amplitude of the rhythmic contractions decreased significantly when transmural pressure was elevated. The frequency increased when pressure was elevated from 20 to 80 mmHg and then remained rather constant during further pressure increases. As shown previously in non-pressurized arteries, exogenous cyclic GMP induced oscillations in endothelium-denuded arteries. Pressure-related effects on vasomotion were not dependent on an intact endothelium. Ryanodine, ouabain or verapamil inhibited the rhythmic activity, confirming previous results in non-pressurized arteries. Thus, changes in transmural pressure can modulate vasomotion, but this effect does not appear to be mediated by the endothelium. Generation of vasomotion may depend on release of Ca2+ from intracellular stores, the activity of the Na+, K(+)-pump and transmembrane Ca2+ inflow in a pressurized artery as shown previously in these arteries under isometric conditions. PMID- 7839858 TI - Light-dependent effects of zinc protoporphyrin IX on endothelium-dependent relaxation resistant to N omega-nitro-L-arginine. AB - Acetylcholine (ACh) induces an N omega-nitro-L-arginine (L-NOARG)-resistant relaxation and hyperpolarization in the rat isolated hepatic artery. The possibility that carbon monoxide (CO) produced by haem oxygenase (HO) is an endogenous mediator of this response was investigated. Exogenously applied CO evoked a concentration-dependent relaxation, and the CO 'scavenger' oxyhaemoglobin (10 microM) reduced the maximum ACh-induced relaxation by 25%. The HO inhibitor zinc protoporphyrin IX (ZnPP, 10 microM) virtually abolished the ACh induced relaxation in experiments carried out under ordinary light conditions. However, ZnPP did not affect the ACh-induced relaxation under dark conditions, even after exposure of ZnPP to intense light before the preincubation period. Biliverdin (0.1 mM), a feedback inhibitor of HO, was also inactive under dark conditions, and the HO substrate haematin (0.1 mM) did not facilitate the ACh induced relaxation. The relaxation induced by the nitric oxide (NO) donor 3 morpholino-sydnonimin was not affected by ZnPP in the presence of light. However, ZnPP inhibited the relaxation evoked by the potassium channel opener levcromakalim and the tonic component of the contractile response to 60 mM potassium, indicating that ZnPP has effects distinct from HO inhibition in the presence of light. ZnPP should therefore be protected from light when used to inhibit HO-mediated CO formation. The results do not suggest that CO generated by HO mediates the endothelium-dependent, L-NOARG-resistant relaxation induced by ACh in the rat hepatic artery. PMID- 7839860 TI - Moderate fatigue studied at great sarcomere lengths in frog single muscle fibres. AB - Single fibres from the anterior tibialis muscle of Rana temporaria (temperature, 2-3 degrees C) were moderately fatigued at a prestretched sarcomere length (approximately 3.6 microns) by reducing the intervals between 2 s tetani from 240 to 20 s. Changes in length of marked segments along the muscle fibre were monitored during fixed-end tetani using a photoelectric recording system. In contrast to the situation at 2.2 microns sarcomere length, the central region of the fibre was elongated during tetanus at the prestretched fibre length, whereas the segments next to the fibre-tendon junctions (end segments) shortened correspondingly. These length changes were associated with a slow climb of force (tension creep). During development of fatigue, the maximum tetanic tension was reduced to about 78% of the control value and the time course of the tetanus was markedly changed. The tension creep observed in control tetanus was greatly reduced during fatigue, the tetanic tension remaining nearly constant after an initial rising phase. The change in shape of the force myogram during fatigue was associated with a considerable reduction in the amplitude of segment movements along the fibre. The results are explainable by assuming that the end segments (having shorter sarcomeres) become more fatigued than other parts in series along the fibre. At the same time the central segments are likely to have acquired a higher ability to resist stretch by the end segments. PMID- 7839861 TI - Inhibition of SKF 89976-A of the gamma-aminobutyric acid release from primary neuronal chick cultures. AB - Neuronal cultures were made from the 8-d-old embryonic chick telencephalon. The primary culture model was further improved, the medium composition was modified, and the cells grown for 10 d, which allowed the development of relatively differentiated neurones. A superfusion protocol was developed and applied to study the release of [3H]-gamma-aminobutyric acid ([3H]GABA). High endogenous activity levels of glutamate decarboxylase (GAD) and of a Ca-dependent potassium stimulated [3H]GABA release were used as criteria for GABAergic differentiation. The influence of the non-substrate inhibitor of GABA transport, SKF 89976-A, on the GABA release, was studied using the primary neuronal culture. The release was found to be inhibited by SKF 89976-A at higher concentrations (= 400 microM). PMID- 7839862 TI - Substrate transport and utilization in fish erythrocytes. AB - In contrast to mammalian erythrocytes which fulfil their energy requirements via anaerobic glycolysis, fish erythrocytes obtain most of their energy aerobically via the Krebs cycle. This enables them to use various substrates, including monocarboxylic acids, glucose and amino acids. This review discusses the membrane permeability of these substrates, and their relative importance in the energy production of fish erythrocytes. Agnathans are characterized by a high permeability to all of the potential substrates, glucose, monocarboxylic and amino acids. In contrast, teleost erythrocytes are often characterized by low glucose permeability. It appears that monocarboxylic acids and certain amino acids such as glutamine may be more important in energy production of teleost erythrocytes than glucose. PMID- 7839863 TI - The evolution of hormonal sex pheromones in teleost fish: poor correlation between the pattern of steroid release by goldfish and olfactory sensitivity suggests that these cues evolved as a result of chemical spying rather than signal specialization. AB - It is becoming increasingly evident that many teleost fish use hormones and their metabolites as sex pheromones. Although hormonal pheromone systems of several species of fish have now been characterized, that of the goldfish is the best understood. Reproductively-active female goldfish sequentially release derivatives of three steroidal hormones and two prostaglandins which have specific and potent actions on the goldfish olfactory sense and subsequently conspecific reproductive behaviour and physiology. Three goldfish hormonal pheromones are unmodified sex hormones which are also found in the blood of many other species of fish and are therefore unlikely to be species-specific. This scenario evokes two related questions. First, how did these systems evolve? Second, do hormonal pheromones represent specialized signals used for communication or rather simple metabolites which fish have evolved the ability to detect because of their intrinsic meaning ('spying')? Here we review hormonal pheromone function in fish and then describe a study of the goldfish which tests whether hormonal pheromones are specialized communicatory signals by comparing the profile of steroids released by goldfish with their olfactory responsiveness to these compounds. Little correlation between signal production and detection was found and we conclude that the goldfish hormonal pheromone system most likely exemplifies spying. PMID- 7839864 TI - Olfaction and gustation in fish: an overview. AB - Living in an aquatic environment, often devoid of light but rich in dissolved compounds, fish have highly developed chemosensory and chemical signalling systems. The olfactory and gustatory systems comprise the major chemosensory pathways. Despite considerable variations in structural organization of the peripheral olfactory organ throughout fish species, ultrastructural organization of the olfactory sensory epithelium is extremely consistent. The olfactory receptor cell is a bipolar neurone which is directly exposed to the external environment and sends information to the brain by its own axon (cranial nerve I). Four major classes of chemicals have been identified as specific olfactory stimuli and their stimulatory effectiveness characterized: amino acids, sex steroids, bile acids/salts and prostaglandins. Olfactory signals such as those involved in reproduction and feeding may be processed independently through two distinct subsystems: the lateral and medial olfactory systems. The taste buds constitute the structural basis of the gustatory organ. Taste buds may occur not only in the oropharyngeal cavity, but on the whole body surface. Chemical information detected by specialized epithelial cells, gustatory cells, is transmitted to the central nervous system by cranial nerve VII (facial), IX (glossopharyngeal), and X (vagal). Besides diverse sensitivities and specificities for amino acids, fish gustatory receptors detect various organic acids, nucleotides and bile salts. Putative receptors, molecular mechanisms of transduction and the role played by olfaction and gustation in feeding, reproduction, migration and other fish behaviours are discussed. PMID- 7839865 TI - Role of the endothelium in regulation of vascular functions in two teleosts. AB - Functional and structural aspects of the vascular endothelium were studied in major blood vessels from two distantly related species, the Atlantic salmon (S. salar) and the cod (G. morhua). The ventral aorta (VA) of both teleosts and the dorsal aorta (DA) and the coeliaco mesenteric artery (CMA) of the cod and the salmon respectively were examined for endothelium dependent and independent responses to acetylcholine (ACh), adrenaline (A) and endothelin-1 (ET-1). In the salmon, endothelial probing resulted in reduced contractile responses to high K+ in both VA and CMA while the responses to ACh and A were reduced only in CMA. Indomethacin, but not L-NMMA, enhanced vasoconstrictions to high K+, ACh and A in the unprobed CMA. In the cod vessels the endothelial probing caused reduced contractile responses to the two effective vasoconstrictors in both vessels, to high K+ and A in VA and to high K+ and ET-1 in DA. Both indomethacin and L-NMMA enhanced contractile tension to A in VA, while indomethacin, but not L-NMMA, enhanced the constrictions by high K+ in VA and by ET-1 in DA. These experiments have revealed heterogeneous patterns of endothelial function in blood vessels of two teleosts, reflecting differences in endothelial morphology and in production of potent endothelial derived contracting factors as well as prostanoic and non prostanoic endothelium-derived dilating factors. PMID- 7839866 TI - Mammography screening methods and diagnostic results. AB - Mammograms from 12,636 women aged 40-54 years were examined by one screener first as one-view screening and later as two-view screening. With one-view screening, 542 (4.3%) women were recalled and 31 breast cancers were detected. With two-view screening, 349 (2.8%) women were recalled and 32 breast cancers were detected. Mammograms from 11,343 women aged 41-75 years were independently screened by 2 experienced screeners. A total of 76 breast cancers were diagnosed by 131 surgical biopsies. Both screeners detected 56 cancers. One screener detected 14 cancers alone, and the other detected 6 cancers alone. Thus, 15% more cancers were detected because of double reading. Five experienced screeners reviewed 120 sets of mammograms from the first screening round, including 74 women with breast cancer diagnosed in the first round or later. The mean increase in sensitivity by using two views, instead of one, was 2%. The median of the increase in cancer detection because of independent double reading was 14.5% with one-view screening and 12% with two-view screening. We invited 48,517 women aged 40-74 years to mammography screening. 86% participated, of which 4.8% were recalled for further examinations, and 1.0% were referred to surgery. A total of 241 (0.58%) breast cancers were diagnosed. Only 20% of the invasive cancers had lymph node metastasis and the median size was 16 mm. A total of 43,074 women aged 40-69 years were invited to screening. The attendance rate was 87% in the first screening round and 78% in the second screening. The recall rate was 4.6% and 5.7%, respectively. The breast cancer rate was 0.48% in both screening rounds. The rate of stage II or more advanced breast cancers decreased significantly from 0.16% in the first screening round to 0.08% in the second (p = 0.007). PMID- 7839867 TI - Liver-specific contrast media for MRI and CT experimental studies. AB - MRI and CT are modalities appropriate for liver imaging. To obtain higher sensitivity in diagnoses of focal lesions in the liver, contrast media (CM) are used. Non-specific extracellular CM are not optimal as they rapidly diffuse into both normal tissue and tumorous tissue. By two different mechanisms, the hepatobiliary route and targeting to the reticuloendothelial system, agents may accumulate in normal liver tissue, thereby giving liver-specific CM. So far no such agents have been approved for clinical use. In the present studies, animal models were used to investigate the imaging efficacy of experimental liver specific CM and answer the following questions: i) Do these new liver-specific CM result in enhancement of normal liver? ii) If enhancement in normal liver is present, does this result in higher contrast of normal liver to tumorous tissue? iii) If higher contrast of normal liver to tumorous tissue is present, does this result in higher tumour detection-rates? Relative to non-enhanced and contrast enhanced CT, what tumour detection-rate is obtained using non-enhanced and contrast-enhanced MRI? All the liver-specific CM studies possessed the ability to significantly alter the signal in normal liver tissue. Compared to precontrast values, the liver-specific CM studied in MRI (Mn-DPDP) and CT (IEEC-particles and iodixanol-liposomes) were able to increase significantly the contrast of normal liver tissue to tumorous tissue and the tumour detection-frequency in VX2 carcinoma liver tumour-bearing rabbits. In CT using a non-specific extracellular CM, iohexol, no improvement in contrast or tumour detection-frequency was obtained. As reflected in the values of contrast-to-noise obtained, MRI and CT have the same potential for tumour detection in the liver model used in the present studies. Liver-specific CM have the property of improving the contrast of normal liver tissue to tumorous tissue in MRI and CT, giving higher tumour detection-rates. Permitting intravenous administration and the use of long imaging-windows, liver-specific CM are easy to use. PMID- 7839868 TI - [Family planning in Latin America: development, costs, and future]. PMID- 7839869 TI - [Family planning: the key to a better future]. PMID- 7839870 TI - [Advances in hormonal contraception]. PMID- 7839871 TI - [Oral contraceptives: 30 vs 20 micrograms of ethinyl estradiol (EE)]. PMID- 7839872 TI - [Advances in ambulatory female surgical contraception]. PMID- 7839873 TI - [Anti-progestins and contraception]. PMID- 7839874 TI - [New perspectives for injectable contraceptives]. PMID- 7839875 TI - Malaria and the problem of drug resistant Plasmodium falciparum. PMID- 7839876 TI - Morbidity and mortality from postpartum hypertension in Nigerian women. AB - Two hundred and ten patients who were normotensive during pregnancy and labour but developed hypertension during puerperium have been studied. Two groups were identified with this unexpected postpartum hypertension. Although the patients in group A who had earlier onset hypertension were younger and mainly nulliparas, there was no significant difference between both groups with respect to age, serum creatinine, blood urea, blood pressures and presence of abnormal urine sediment at the onset of illness. The incidence of postpartum hypertension was 3.5. per cent; there was remission of hypertension in 8 patients (3.8%) without treatment, recurrence in 17 (8%) while cardiac failure occurred in (5.4%), cerebrovascular accident in 3 (1.4%) and acute oliguric renal failure in 3 (1.4%). Overall mortality was 0.9 per cent while persistent or chronic hypertension was observed in 52 (23.8%) Postpartum hypertension is a definite clinical entity with significant morbidity and mortality. Frequent monitoring of blood pressure in the puerperium is advocated to avoid or reduce cardiovascular, cerebrovascular and renal complications of postpartum hypertension in susceptible women. PMID- 7839877 TI - Cancer in Libya--a retrospective study (1981-1985). AB - Between 1981 and 1985, 1124 patients with histopathologically confirmed malignant disease were registered at the sole oncology clinic of Libya, 664 (59%) were males and 460 (41%) were females. Overall, malignant lymphoma (ML) was the most common cancer (180/1124, 16%), with non-Hodgkin's lymphoma (NHL) being more common (57.2%) than Hodgkin's disease (HD) (42.8%). Considered separately, lung cancer was the most common tumour (22.4%) in males with a male to female ratio among the highest in the world (18.6:1), 85% of our male patients were smokers and more than 50% had been smoking heavily for 20 years or more. Breast cancer was the most frequent tumour (29.8%) of females and the majority of our patients were of a younger age group (72.3% below 50 years). Almost all our patients were multiparous and had breast-fed their babies. Cancer of the cervix uteri was less frequent (4.5%) than ovarian cancer (7.8%). The incidence of colorectal cancer was higher (4.6%) than other African countries. Contrarily the primary tumours of liver (1.9%) and bladder (0.5%) were less frequent. Among the children, aged less than 10 years, the common solid tumours of childhood occurred in the following frequency, ML 31.2%, nervous system 19.2%, Wilm's tumour 16.8% and bone tumours 9.6%. PMID- 7839878 TI - The efficacy of traditional medicine in the management of diabetes mellitus in southwestern Nigeria. AB - A survey of traditional healers in Ibadan, Nigeria, demonstrated that fewer than 10% of them were involved in the treatment of patients with diabetes mellitus and the total number of such patients under their care was less than 100, compared to those receiving western-type of medical treatment (up to 1000 at the University College Hospital, Ibadan, alone). An interview of 20 native practitioners revealed that they had little understanding of the nature of diabetes mellitus. Their diagnosis of diabetes was based largely on intuition and the disease was often confused with other medical problems like urinary tract infection or venereal disease. In a parallel study, 10 diabetic patients being treated exclusively by traditional healers were followed up on an ambulatory basis for periods of up to 16 weeks and another group of 8 patients had a hospital-based trial of traditional anti-diabetic medicines for about 4 weeks. Most of the patients reported improvement in their symptoms with less polyuria and improved sense of well-being. However, no objective improvement in the blood glucose was demonstrated. For the hospitalized group, n = 8, pre and post-treatment blood glucose respectively were, mean (+ SD), 13.9 (3.5) mmols/l and 14.9 (4.3) mmols/l, P > 0.50. It is concluded that the effectiveness of traditional anti diabetic drugs in lowering blood glucose still remains to be demonstrated. Any claims of "cure" of diabetes using native medicines can be firmly rejected. However, further studies into the potential usefulness of native herbs in the treatment of diabetes must be pursued. PMID- 7839879 TI - Testicular morphometric studies in Nigerian males. AB - A total of 102 autopsy subjects found to have seemingly normal testicular picture were analysed to determine acceptable normal morphometric values. The mean tubular diameter in the last trimester of intrauterined life is 43.8 mu in contrast to adult value of 173.0 mu. The mean basement membrane thickness increases from 3.2 mu in the last trimester to 6.9 mu in the 10-14 years age range. The adult mean testicular score count is 19.3 in contrast to 5.3 observed in the last trimester. While Sertoli cells predominate in the last trimester of intrauterine life, many spermatozoa are seen during the period 15-19 years. PMID- 7839880 TI - Variation of total hyoscine content of cultivated Datura metel Linn. AB - A titrimetric method is described for rapid assay of hyoscine content of organs of locally cultivated Datura metel Linn. Raw materials required (approximately 1.5 gm) are much less than those required for conventional percolation processes. Using the procedure, the flowers have been shown to be richest in hyoscine, only minimal levels of alkaloids being detected in the fruits. Furthermore, the total alkaloid content of D. metel has been shown to peak in the hot dry season, and at its lowest during the rainy season in Ibadan. PMID- 7839881 TI - Cerebral malaria in non-paediatric subjects resident in southwestern Nigeria. AB - Seven previously healthy, non-immuno compromised adolescents and adults with cerebral malaria were seen over a nine-month period in an endemic area where the disease was previously thought to be rare in persons above the age of 11 years. Six of these, treated with quinine responded promptly to therapy with mean parasite and fever clearance times of 58.0 +/- 4.9 hrs and 30.0 +/- 16.5. hrs respectively and regained consciousness in 20.0 +/- 14.5 hrs. One patient treated with chloroquine regained consciousness in 28 hrs, with parasite and fever clearance times of 120 hrs and 48 hrs respectively. No neurological deficit was observed on discharge in any of the subjects. PMID- 7839882 TI - Breast cancer in sub-Saharan African women. AB - The literature on breast cancer in sub-Saharan women is reviewed. In general, breast cancer is the second most common malignancy of women in the region, after cancer of the uterine cervix. Available reports indicate that data on the disease are incomplete and mostly, of epidemiological or clinical nature. Breast cancer is less common in sub-Saharan Africa compared to the Western countries (USA or Europe), occurs in younger individuals with peak incidences about a decade younger and the majority present late, with advanced, sometimes terminal disease. Absence of health educational programmes on cancer as well as lack of screening facilities in nearly all countries in the region are contributory factors to the late presentation of the cases. The need for more in-depth studies of the disease in the black African population has been highlighted. PMID- 7839883 TI - Severe morbidity among children in a trial malaria chemoprophylaxis with pyrimethamine or chloroquine in Ibarapa, Nigeria. AB - In a controlled trial of weekly malaria chemoprophylaxis with chloroquine and pyrimethamine there were no significant differences in type and frequency of severe morbidity during chemoprophylaxis. Administration of chemoprophylaxis during the current and immediately preceding month was associated with significantly fewer episodes of severe morbidity in the chloroquine and pyrimethamine groups when each was compared with the control multivite group. After chemoprophylaxis had been stopped, significantly more episodes of severe morbidity occurred in the chloroquine group than the control group, but a similar trend in the pyrimethamine group was not statistically significant. In the control group most of the episodes of severe morbidity, including those episodes which were associated with heavy parasitaemia, occurred below the age of 4 years. In contrast, the children who received chemoprophylaxis continued to experience such illness at older ages. The difference between the chloroquine group and the control group in respect of age at time of severe morbidity was statistically significant. PMID- 7839884 TI - Prediction and detection of ovulation: an evaluation of the cervical mucus score. AB - The use of cervical mucus scoring (modified Insler Score) in prediction and detection of ovulation in ovulatory cycles has been evaluated against serial ultrasonic follicular monitor and estimation of mid-luteal phase progesterone assay using the WHO match reagent system. The study showed that there was a very high positive correlation (r = +0.96) between the determination of day of ovulation by serial Insler score assessment and serial ultrasonography. Being simple to perform, cheap, rapid and reasonably accurate method of ovulation prediction and detection, cervical score assessment is recommended for use in fertility management in our environment with limited manpower, infrastructure and resources. PMID- 7839885 TI - Quantitative analysis of 1-naphthol in urine of neonates exposed to mothballs: the value in infants with unexplained anaemia. AB - In Nigeria, severe NNJ is common in babies exposed to mothballs and other icterogenic agents. High-performance liquid chromatographic (HPLC) method was employed for quantitative analysis of 1 and 2-naphtol in the urine of 50 neonates aged one to 19 days. Five of the 25 babies who had a history of exposure to mothballs, and none of the babies without a history of exposure had 1-naphtol in their urine. The value of 1-naphtol ranged between 0.75 and 11.69 micrograms/ml with mean of 5 +/- 5 micrograms/ml. The overall correlation coefficient (r) between bilirubin values and 1-naphtol was 0.1 while it was 1 in the three G-6-PD deficient infants. The procedure will be very useful in the evaluation of infants with unexplained NNJ, anaemia, acute haemolytic jaundice and haemoglobinuria if naphthalene poisoning is suspected. PMID- 7839886 TI - Aberrations in serum proteins and thyroid size in Nigerians on the Jos Plateau and their relation to thyrometabolic function. AB - Controlled serum protein and thyroid function studies were carried out among 208 African patients with endemic goitre. The changes seen in the serum protein constituents were studied and evaluated in relation to thyroid hormone levels, goitre grade and the clinical state of the patient. Mean serum TBG and thyroglobulin values rose sharply in the early phase of goitre, and remained elevated throughout. Although the mean serum total T4 was statistically and significantly higher in endemic goitre compared with the normal subjects (t = 3.72. P = 0.005), the free thyroxine index was significantly lower and serum T4 fell progressively (r = 0.975) with increasing thyroid grade. In contrast, mean serum T3 rose continuously (r = 0.910) but appeared inflated due to a proportionate increase in TBG in several cases, giving a misleading picture of T3 -thyrotoxicosis in otherwise clinically normal subjects. An increase in T3/T4 ratio and consequently in thyroid function, therefore occurs with advancing thyroid size. Inconsistent binding of T4 to TBG causes wide variations in thyroxine index. Mean serum albumin and betalipoprotein appeared inversely related to thyroid function. These changes imply that in order to evaluate a patient with endemic goitre accurately a detailed biochemical investigated of the thyroid may be necessary. PMID- 7839887 TI - Correlation of ultrasound assessment of endometrial growth and plasma steroid concentrations during superovulation for in vitro fertilization. AB - Endometrial and follicular development were investigated by ultrasound in 25 normally cycling women who received clomiphene citrate and human menopausal gonadotrophin to induce multiple follicular development for in vitro fertilization. Ultrasonic determination of endometrial thickness and reflectivity grading and follicular number were correlated with daily concentrations of estradiol (E2) and progesterone (p) in peripheral serum. Serum E2 showed a better positive correlation with endometrial thickness than with total number of developing follicles. There was a significant inverse correlation between endometrial thickness and plasma p concentration. The E2 value per follicle and E2/p ratio were both weakly correlated respectively with endometrial thickness. These data indicate that ultrasound determination of endometrial thickness is a useful ultrasonic parameter for monitoring ovarian function for in vitro fertilization. However, endometrial thickness should always be combined with total number of developing follicles, in order to reach decisions concerning timing of oocyte recovery. PMID- 7839888 TI - The postgraduate doctor and training in hospital administration. PMID- 7839889 TI - Human immunodeficiency virus and the nervous system: some aspects of the molecular pathology. PMID- 7839890 TI - Drug resistance and plasmids of Bacillus isolated from locally fermented foods. AB - In an epidemiological survey of antibiotic resistance in this environment, Bacillus bacteria were isolated from commonly consumed fermented foods. The fifty strains isolated were tested for susceptibility to antibiotics and screened for the presence of plasmids. Majority (72%) were resistant to Cloxacillin and Penicillin (70%) while 40% harbour plasmids ranging from 3.0kb-36.3kb in molecular weight. A 4.6kb plasmid was found to be common to all plasmid-bearing strains. The implication for the epidemiology of antibiotic resistance is discussed. PMID- 7839891 TI - Bacterial air contamination of operating theatres and surgical wards of a university teaching hospital. AB - A study of the level and significance of air contamination in the four operating theatres and four surgical wards of the University of Nigeria Teaching Hospital, Enugu, Nigeria was carried out. A total of 48 air samples were taken from each of the operating theatres while a total of 36 air samples were taken from each surgical ward, using a "Casella slit Sampler". The means of the bacterial carrying particles per cubic foot of air varied, from theatre to theatre, from 12.29 to 14.29 (in the mornings) and 9.79 to 11.4 (in the evening). Statistically, these differences were insignificant (t-value < 1.96). Recognised pathogens were not recovered from both the air and the fomites in the operating theatres. However, free-living fungi were isolated. The air of the surgical wards showed levels of contamination from 20.39 to 35.28 (in the mornings) and 20.33 to 39.55 (in the evenings) bacterial carrying particles per cu.ft. of air. The differences between the counts in the mornings and evenings were also not statistically significant. Some pathogens were isolated from the air in the wards. The findings indicated that the level of air contamination of the surgical wards influenced the rates of post-operative wound sepsis. PMID- 7839892 TI - Childhood convulsions: a hospital survey on traditional remedies. AB - A study of one hundred and thirty five children with convulsions admitted in the University of Port Harcourt Teaching Hospital, Nigeria over a 15-month period, October 1986 to December 1987 showed that 65 (48%) of the children received some traditional remedy at home prior to presentation in hospital. Crude oil and palm kernel oil either singly or in combination were the most commonly administered remedies. The central nervous system was more affected by remedies containing crude oil than others (P < 0.05). Administration of cow's urine to convulsing children, reported from other parts of Nigeria, was not observed in the present study and would appear to be uncommon in this part of the country. PMID- 7839893 TI - Role of indomethacin-induced peptic ulceration in gastric acid secretion in pregnant rats. AB - The role of indomethacin-induced peptic ulceration in gastric acid secretion was investigated using albino rats of Wistar strain in early, mid and late pregnancy. The weight ranged between 120 and 180 gm. Non-pregnant rats in estrus served as control. Estrus was induced using the method of Dejalon, Bayo and Dejalon[1] while pregnancy was induced using the method of Bolarinwa and Amure[2,3]. Stomach for perfusion was prepared according to Ghosh[4] with some modification and perfusion was done with 0.15M NaCl solution, using the modified Langerdoff's apparatus. Gastric acid secretion was induced with histamine and carbachol. In general, gastric acid secretion was found to be higher after indomethacin administration than in a control study, and the secretory response was higher to carbachol than to histamine in either case. In rats to which indomethacin had been administered, basal and induced gastric acid secretion was highest in the non-pregnant rats and least in the early-pregnant rats. PMID- 7839894 TI - Exercise induced bronchoconstriction in Nigerian asthmatics. AB - This study describes the result of free-running exercise performed on 40 asthmatic subjects and 40 age and sex matched controls. A percentage fall of more than 15% in PEFR was used for the diagnosis of exercise-induced asthma (EIA). 77.5% of our asthmatic patients had exercise-induced bronchoconstriction (EIB) while none of the control subjects exhibited EIB. Twenty-seven patients gave positive history of EIA out of which 25 (92.59%) had positive exercise testing. Conversely, 13 patients with asthma did not give history of EIA but 6 of this (46.15%) were found to have EIB on exercise. History alone is therefore insufficient to diagnose patients with exercise-induced asthma. PMID- 7839895 TI - Cloning and characterization of the tetracycline resistance determinant from enteropathogenic Escherichia coli p1479. AB - As part of an epidemiological study, R plasmids coding for tetracycline resistance were isolated from enteropathogenic Escherichia coli. A 1.4kb Pst 1 fragment of one of them p1479 (size 5.7kb) has been cloned into plasmid pGL101. This recombinant plasmid containing the tetracycline gene was then transformed into E. coli DHI where the tetracycline resistant gene was fully expressed. Attempts to develop this clone to a diagnostic probe is now in progress. PMID- 7839896 TI - A follow up study of adult nephrotic syndrome in Nigerians: outcome and predictors of endstage renal failure. AB - Clinical data from 88 patients who presented with the nephrotic syndrome and biopsy proven glomerular disease were analysed to determine the outcome after 8 years of follow up, and to find out the influence of glomerular histology, sex, age, plasma creatinine, creatinine clearance, hypertension, 24-hour urinary protein excretion and microscopic haematuria, on the clinical course and outcome. The results showed that at the end of follow up (8 years), 13 patients (14.8%) had died from renal failure while 24 patients (27.2%) were in chronic renal failure. Persistent renal disease was still present in 29 patients (33.0%). Of the whole group (88), mortality and endstage renal failure were highest amongst patients with focal segmental glomerulosclerosis and membrano-proliferative glomerulonephritis. Male sex, hypertension, impaired plasma creatinine and creatinine clearance in patients from these two groups were associated with progression to chronic renal failure and death from uraemia. At final observation hypertension and microscopic haematuria were marked features of these two histological groups. Prognosis in minimal change nephropathy was quite good with remission occurring in 20 patients (66.6%); persistent renal disease however occurred in 8 patients (26.6%) while 1 patient died from uraemia. PMID- 7839897 TI - Serum trehalase activities in controlled and uncontrolled diabetes and the impact of oral glucose, high carbohydrate and glycosuria on serum levels. AB - Nineteen healthy volunteers, made up of two groups were subjected to an extended oral glucose tolerance study. In one group, each had 50g glucose and in the other a high carbohydrate meal. Blood glucose and serum trehalase activities were determined on fasting blood samples and specimens collected half-hourly for 4 hours. The values obtained for both at each stage of the investigations were compared with one another. Correlation coefficient (r) between blood glucose and serum trehalase were 0.4923 for the fasting samples and 0.4762 at 1 hr. The impact of diabetes and glycosuria on serum trehalase activities in 50 diabetics consisting of treated (controlled) and untreated (uncontrolled) cases was also studied. Our study reveals a slight fall in serum trehalase values from the initial fasting level, but thereafter a gradual and progressive rise during the course of the glucose tolerance investigations. Serum trehalase values were higher in diabetics compared to normal subjects (t = 7.0168, P = 0.005). Diabetics with glycosuria had a significantly higher mean serum trehalase compared to the controlled group (t = 5.233, P = 0.005). High serum trehalase values were seen in diabetics with renal glycosuria at comparatively low levels of blood glucose. The significance of these findings is discussed in relation to the possible place of serum trehalase assay in the management of diabetes, especially when this is made difficult by renal glycosuria. PMID- 7839898 TI - Rapid control of chronic granulocytic leukaemia. AB - Sixty patients with chronic granulocytic leukaemia (CGL), anaemia, hyperleucocytosis and hepatosplenomegaly were randomized into 3 treatment schedule consisting of: (i) cyclophosphamide 600 mg/m2 intravenously (i.v.) on day 1. (ii) cytosine arabinoside 100 mg/m2 subcutaneously (sc) 12 hourly for days 1-5. (iii) combination of i.v. cyclophosphamide 600 mg/m2 one day 1 and cytosine arabinoside 100 mg/m2 12 hourly sc for days 1-5. Each cycle of treatment lasted 7 days. Patients on combined chemotherapy achieved laboratory and clinical remission within 28 days of treatment, while patients on single agent chemotherapy of cytosine arabinoside or cyclophosphamide still had hyperleucocytosis and hepatosplenomegaly after 28 days of treatment. Six patients treated with cyclophosphamide only had thrombocytopenic bleeding, but no patient treated with either cytosine arabinoside only or a combination of cytosine arabinoside and cyclophosphamide bled. It is suggested that patients with CGL, anaemia, hyperleucocytosis, and hepatosplenomegaly can be rapidly controlled with a combination of cytosine arabinoside and cyclophosphamide. PMID- 7839899 TI - The influence of socio-economic status on the severity of sickle cell disease. AB - The influence of socio-economic status on morbidity was studied in 122 unselected consecutive patients with homozygous sickle cell disease in steady state. They included 65 females and 57 males, divided into three social classes (I, II and III, from highest to lowest). The morbidity indices used were, frequency of bone pain crisis, leg ulceration, growth index and the degree of anaemia as denoted by the mean steady haemoglobin level. It was found that the frequency of bone pain crisis was significantly higher in social class III patients than in social class I and social class II (P < 0.01). Leg ulceration was significantly more common in patients of social class III than in patients of social class I (P < 0.05). There was no correlation between the growth index and social class (r = 0.067, P > 0.05). The mean haemoglobin level was found to fall slightly from the highest to the lowest social class although the differences were not statistically significant. Our findings suggest that socio-economic status has some modifying influence on morbidity in sickle cell disease. PMID- 7839900 TI - Chloroquine-induced retardation of foetal lung maturation in rats. AB - Chloroquine (CQ) is a widely used drug and its administration has been reported to increase surfactant- associated phospholipids in lungs. We have used histomorphometric techniques to study the effects of CQ on foetal lung maturation in rats. CQ (40mg/kg BW) or saline was administered to pregnant rats on days 20 and 21 of gestation. A third group received the same dose of CQ on days 20 and 21, and in addition, hydrocortisone (HD; 25 mg/kg BW) on day 21 of pregnancy. Foetuses were delivered by hysterotomy on day 22. The lungs were weighed, fixed in Bouin's fixative and embedded in paraffin. Morphometric studies were performed on 5 microns-thick sections. The lung weight/100g BW, the volume density of lung saccular spaces, and the cross-sectional area and volume of the saccular spaces were reduced but the numerical density of the saccules was not decreased in foetuses exposed to CQ. With the exception of lung weights, which were lower in the foetuses exposed to CQ and HD, there were no other differences between this group and that exposed to CQ only. The results suggest that CQ attenuates the expansion of saccular spaces which occurs in preparation for post-natal gaseous exchange, and thus CQ retards foetal lung maturation. Although HD further reduced lung weights as expected from its reported action on foetal lungs, it did not reverse the CQ-induced retardation in lung maturation. PMID- 7839901 TI - Factors affecting morbidity and mortality from road traffic accidents: a Nigerian peri-urban study. AB - Road traffic census was taken along major roads linking Ilorin, Nigeria, with the north, east, south and north-west at different times on three randomly selected days per month during 16 months of 1982 and 1983. Road physical characteristics thought to affect safe and free traffic flow were also documented along the same roads. Trauma patients at the University of Ilorin Teaching Hospital were prospectively studied between 1983 and 1984. Of 715 road traffic accident (RTA) victims 78.6% were males, 48% suffered multiple injuries while 43.7% were managed non-operatively. Seventy-nine patients (11.0%) died. Of 10 variables analysed, outcome was significantly affected by non-operative management (P < 0.01) while patients' primary admission versus referral status was of borderline significance (P = 0.05). In addition to these indices of trauma severity, high truck-trailer traffic and high frequency of narrow bridges, bends and vehicle wrecks per kilometer of road were associated with high RTA rates. PMID- 7839902 TI - Base-line village health profiles in the E.Y.N rural health programme area of north-east Nigeria. AB - In order to document the health profile of rural farming communities not yet reached by the EYN Rural Health Programme, based at Garkida, Nigeria, four villages were surveyed by a Sheffield medical student who lived for several weeks in each village, working alongside local women. Villagers helped in separate surveys of village environment and water sources, of compound (household) hygiene, of male heads of compounds, of women of childbearing age, and of children. Stagnant rain-water ponds and widespread animal faeces litter were the main village environmental hazards and hardly any satisfactory pit latrines were seen. One person in nearly 2000 surveyed treated the drinking water. Infant mortality was estimated at 200 per 1000. Commonly reported health problems included abdominal pain, coughs and colds, filariasis, diarrhoea, scabies, worms, blood in stool, fever, back pain and eye infections. In each village fewer than 20% of the men and fewer than 10% of the women had received any education. Average completed family size was 6 or 7 children per woman with 3 other non surviving children. The causes of malaria and of diarrhoea were each known by fewer than 10% of mothers in each village. About a quarter of the under fives had suffered from diarrhoea in the past fortnight, a quarter had received any immunisation and one fifth were at least mildly malnourished. One quarter of children aged 6-12 years attended school. PMID- 7839903 TI - Effects of adrenoceptor blockers on the cardiorespiratory response to nicotine in rats. AB - Three groups of anaesthetized rats, consisting of 8 rats per group, were studied. Group 1 was the control and received intravenous injection of nicotine, 50 micrograms/kg, only. Groups II and III were pretreated with propranolol, 0.5mg/kg and prazosin, 1mg/kg respectively before 50 micrograms/kg of nicotine was injected i.v. Blood pressure, heart rate, respiratory rate and amplitude of respiratory excursion were monitored continuously before and for 1 hr after the injections. Index of Pulmonary Ventilation Rate was computed as a product of amplitude of respiratory excursion and respiratory rate. The results showed that nicotine caused an initial fall in blood pressure followed by a rise. The initial fall in blood pressure was abolished by prazosin, while propranolol abolished the pressor response. Nicotine had no effect on heart rate in the three groups. Nicotine caused an increase in respiratory rate and this effect was abolished by prazosin. Nicotine also caused an initial increase in pulmonary ventilation which was due mainly to increase in respiratory rate. It was concluded that nicotine exerts most of its cardiorespiratory effect via stimulation of alpha and beta adrenoceptors. PMID- 7839904 TI - Multifocal (dimelic) chondrosarcoma--report of a case. AB - Estraosseous origin, implantation, and multifocal origin are some of the peculiar behaviour of chondrosarcoma. A case is presented of osseous chondrosarcoma arising from multiple sites in the same patient to illustrate the problem involved in the treatment of such a case. PMID- 7839905 TI - Reflections on the state of the art of human reproduction. PMID- 7839906 TI - Cloning and restriction mapping of the L-sorbose utilization genes from a clinical isolate of Escherichia coli (1). AB - About 30% of clinical isolates of Escherichia coli tested utilized L-sorbose as a carbon and energy source. Escherichia coli K-12 is naturally sorbose negative. The genes for L-sorbose utilization (sor+) is being used as a prototype for studying variable genes amongst bacterial pathogens. The sor+ genes from seven isolates were transferable to E. coli K-12. The (sor+) region was cloned into plasmid pBR322 to give pDOK1. Plasmid pDOK1 is approximately 20kb in size. A restriction endonuclease map of pDOK1 is presented. PMID- 7839907 TI - Electroencephalographic findings in Tanzanian epileptic patients. AB - Electroencephalogram (EEG) of 524 Tanzanian epileptic patients seen between 1985 and 1987 were reviewed. Over two thirds were young patients between the ages of five and thirty. Four hundred and fifty (86%) had abnormal records. Eighty nine per cent of abnormal records had focal abnormality and 11% had centrencephalic abnormality. Grand mal seizures did not imply centrencephalic abnormality, only 13% had such abnormality. Petit mal seizures are rare, over one third of these had temporal focal abnormality. Partial seizures were associated highly with focal abnormality. However, complex partial seizures did not imply temporal focal abnormality. Implications of EEG findings to correlation with epileptic seizures is discussed. PMID- 7839908 TI - Chromosomal aberrations in Nigerians with haematological malignancies: preliminary report. AB - Cytogenetic studies were carried out on the blood/bone marrow samples of three patients with chronic granulocytic leukaemia (CGL) and one patient with Burkitt's lymphoma. The karyotypes determined were 46, XY, Ph+ for patient O. A; 46, XY, t(9q+, 22q) for T. A. and 46, XX, t(9q+, 22q) for patient E. O. Patient O. L. with Burkitt's lymphoma presented two karyotypes: 46, XY and 46, XY, +18. The results showed that Philadelphia (Ph1) chromosome was detected in all the patients with CGL and a chromosome marker for African Burkitt's lymphoma in the boy with the disease. PMID- 7839909 TI - Five-year multiple drug therapy in Bendel State leprosy control service--an overview. AB - The effect of multiple drug therapy (MDT) on the prevalence rate of leprosy over a five year period is analysed and discussed. Prevalence rate dropped by about 37%. It is envisaged that the effect on the incidence rate takes much longer to manifest. PMID- 7839910 TI - Village health survey of Sina Mala, Gongola State, Nigeria. AB - A survey of the environment, life-style, and health status, knowledge, attitudes and practices in the village of Sina Mala was carried out prior to the introduction of a village health post by a church-run rural health programme. In addition to the perceived needs of the villagers for a school, easier access to medicine and external assistance with well drilling, the study identified the need to train traditional midwives in hygienic delivery, to make local health workers more aware of onchocerciasis and to educate the community on sanitation and hygiene, including the harmful effects of the guinea corn beer. PMID- 7839911 TI - Plasma lecithin cholesterol acyl transferase activity, high density lipoprotein cholesterol and cholesterol ester in cholestasis. AB - Lecithin cholesterol acyl transferase activity, cholesterol ester and high density lipoprotein cholesterol concentrations were determined in Nigerian subjects suffering from cholestatic jaundice. Plasma lecithin cholesterol acyl transferase activities in all the study groups were similar. High density lipoprotein cholesterol and cholesterol ester were significantly increased in extrahepatic cholestasis while reduced levels were found in intrahepatic cholestasis. Enhanced cholesterol esterification may occur in extrahepatic cholestasis. PMID- 7839912 TI - The prevalence of ABO blood group antigens and antibodies in Lagos State, Nigeria. AB - A total of 1239 normal donors from the Lagos University Teaching Hospital (LUTH) and 111 staff of the National Institute for Medical Research (NIMR) Yaba were screened for ABO antibodies. Of the number from LUTH, 220 (17.8%) were found to be in group A, 282 (22.8%) in group B, 85 (6.9%) in group AB and 652 (52.6%) in group O. The number from NIMR consisted of 20 (18.0%) in group A, 25 (22.5%) in group B 8(7.2%) in group AB and 58 (52.3%) in group O. The mean tile avidity time of sera from 789 (62.66%) potent LUTH donors was less than 35 seconds. Only 97 (6.91%) of this reacted within 10 seconds. On the other hand, only 11(9.9%) of the NIMR sera reacted within 35 seconds and none reacted within 10 seconds. Group O individuals from LUTH and NIMR did not always have anti-A and anti-B components of their sera with equal avidity or potency. It was also observed that high avidity of antibody did not necessarily correspond with high potency. The commonest titre for group B (anti-A) sera was 256 and that for group A (anti-B) was 512. In general, anti-B titres tended to be consistently higher than anti-A. There was a bimodal peak at titres 32 and 256 in group B (anti-A) sera. This repeated itself in the anti-A component of group O sera (i.e., anti-A+B), but here the peaks occurred at 32 and 128.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7839913 TI - Plasma progesterone, estradiol-17 beta and testosterone in maternal and cord blood, and maternal human chorionic gonadotropin at parturition. AB - To understand the endocrine control of normal parturition in man and interactions of foetal and maternal hormones involved, it is desirable to estimate the hormone levels in the maternal and foetal blood around parturition time. Blood was obtained from the umbilical vessels of 22 male and 30 female neonates and the antecubital veins of their mothers during labour at term. The maternal and neonatal plasma levels of progesterone (P), testosterone (T) and estradiol-17 beta (E2) and maternal plasma levels of human chorionic gonadotrophin (hCG) were determined by radioimmunoassay (RIA). The effect of the foetal sex on the maternal hormones at term was also evaluated. Mean values, with the standard errors of means, of plasma, P, T and E2 in cord blood were 5.3 +/- 0.3, 8.4 +/- 1.2 and 5.0 +/- 0.3 ng/ml, respectively; in the maternal plasma the values were 18.2 +/- 1.2, 1.2 +/- 0.1 and 4.3 +/- 0.4 ng/ml, respectively. The mean T level was significantly higher in cord than in maternal blood, while P was significantly higher in the maternal than in cord blood. The plasma concentrations of P, T and E2 in the mothers delivering male babies were 16.9 +/- 2.2, 1.2 +/- 0.4 and 4.5 +/- 0.7 ng/ml, respectively; in those delivering female babies, the levels were 16.1 +/- 2.4, 1.1 +/- 0.1 and 4.3 +/- 0.4 ng/ml, respectively. Mean plasma levels of hCG in the women was 0.9 +/- 0.1 microgram/ml with no significant difference between the values in the mothers of male and female babies.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7839914 TI - Clinically-diagnosed dementing illnesses in Ibadan: features, types and associated conditions. AB - In this hospital-based study of dementing illnesses in Ibadan, 37 cases were seen over a 6 year period from 1984 to 1989 out of 57,440 cases admitted. The average hospital frequency was 64 cases per 100,000 admissions. Eighteen cases (48.7%) had vascular dementia. The other types encountered were: secondary dementias (8), mixed (5), probable primary degenerative (1) and the remaining 5 cases were unclassifiable. The associated conditions were mainly hypertension, parkinsonism, diabetes mellitus and benign prostatic hyperplasia. The findings confirm the relative rarity of primary degenerative dementia in Nigeria and raise the possibility of prevention of the predominant type by identifying the stroke-prone individuals early and intervening. PMID- 7839915 TI - Influence of size of primary breast tumour on local control. AB - Four hundred and five (405) patients with histologically proven primary breast carcinoma were analysed in this study. There was complete response of 64.2% after surgery and radiotherapy. This is a better result in comparison with developing countries, for example, Nigeria where over 90% of cancer patients report at a late stage before treatment and inadequate radiotherapy facilities lead to long waiting list. A tumour regression rate (complete and partial) of 98.3% was obtained. This work has shown that most women with breast cancer could be cured when the lesions are detected very early and sizes smaller. PMID- 7839917 TI - Reading medical literature: a select bibliography. PMID- 7839916 TI - Crush injuries of the hand. AB - A retrospective review of 58 patients presenting with crush injuries of the hand within the 6 year period April 1984 to March 1990 was undertaken. The male-female ratio was 3:1, with a mean age of 25.13 +/- 15.1 years. The peak incidence was in the 3rd decade of life. Machines (55.17%) were the commonest cause with the pepper grinder featuring most prominently. The dorsum (60.3%), little (55.1%) and ring (53.5%) fingers of the right hand were the most commonly involved. Most of the injuries were multiple. Management was mainly conservative and entailed initial limited debridement, thorough washing with soap and water under adequate anaesthesia, bulky boxing glove dressing, elevation, antibiotics and early hand physiotherapy with late reconstruction. Results were excellent in 13 (22.41%), good in 19 (32.76%) poor in 23 (39.66%) and unknown in 3 (5.17%) who were lost to follow-up. Our poor result is perhaps the warning signal that we should abandon our extreme conservative stance and be more aggressive in our attitude to these injuries. PMID- 7839918 TI - Leucocyte alkaline phosphatase activity in solid malignant tumours. AB - Quantitation of leucocyte alkaline phosphatase activity has been found to be a useful index in the diagnosis and the monitoring of activity in a variety of disease states. Low levels are found in some haematological disease conditions, but elevated values are found in acute stress states, in pyogenic infections, myocardial infarction, trauma, diabetes mellitus etc. Studies on the pattern of activity in solid neoplasms are scanty and the published results are often contradictory. Observations made on nine different groups of solid neoplasms suggest that certain malignant tumours are associated with elevated LAP activity levels. These high levels fail to return to normal values following treatment even when there are no clinical signs of residual tumour or of recurrence. The results suggest that while LAP quantitation has a useful role in the detection of certain malignant neoplasms, it is not a sensitive tool for monitoring tumour reactivity of quiescence. PMID- 7839919 TI - Group B streptococcal carriage among parturients and their neonates in Zaria, Nigeria. AB - In an epidemiological study of Group B streptococcal (GBS) carriage carried out on 100 mothers and their newborns in Zaria, 14 mothers were found to be vaginal and perineal carriers while 13 infants were found to be colonised at birth. The colonization rate of infants born to colonised mothers was 93%. The results also showed no association between carriage of (GBS) and frequency of coitus, polygamous union, multiparity, low educational status and lack of prenatal care. In terms of morbidity, neither the colonised women nor the infants developed clinical GBS infection. The study also revealed that all the GBS isolated were sensitive to penicillin and resistant to sulphatriad. The findings suggest that although carriage is fairly high in this environment, GBS is not a common cause of perinatal infection. PMID- 7839920 TI - Plasmid profiles of Shigella and Salmonella spp. isolated from diarrhoeic humans in Ibadan, Nigeria. AB - Clinical isolates of Shigella flexneri, S. dysentariae, S. boydii and Salmonella spp. were screened for the presence of plasmids. Most of the isolates harboured more than one plasmid ranging in molecular size from 1.3 to 36.1 x 10(6) daltons. Very large plasmids were not encountered. PMID- 7839921 TI - HBsAg, aflatoxins and primary hepatocellular carcinoma. AB - Nigeria is a very high risk area for primary hepatocellular carcinoma and this is the first study to utilize measurements of both hepatitis B virus status and aflatoxin levels in the same patients to determine the role of these factors in the causation of liver cancer in this environment. We have shown that there is a higher prevalence of hepatitis B surface antigen (P < 0.005) and higher 'pathologic' serum levels of aflatoxins (P < 0.05) in patients with primary hepatocellular carcinoma than in matched controls. It is considered that the results of this study may strengthen the hypothesis that hepatitis B virus may be an important aetiological factor in the development of primary hepatocellular carcinoma. Further work is in progress to correlate the level of aflatoxin serum albumin adducts with liver damage in order to assess the value of the albumin adduct as a marker of risk of liver cancer development. PMID- 7839923 TI - Septic shock. PMID- 7839922 TI - Intracranial subdural empyema: burr hole exploration for diagnosis and treatment. AB - An analysis of 19 confirmed cases of subdural empyema treated in our unit during a 29-month period ending in May 1990 revealed that this was a disease of young males (mean age 19.6 yrs: male:female ratio 5:1) that was frequently associated with paranasal sinusitis. We have identified a characteristic symptom complex which when present together with focal neurological deficits makes the diagnosis highly probable. This consists of fever, headache, altered level of consciousness and frontal scalp swelling. In a practice setting where neuroradiological confirmation of the diagnosis is not always practicable, this clinical syndrome is helpful and should prompt early burr hole exploration of the subdural space. The only deaths (2 patients; 11%) occurred in patients who presented in coma. The remaining were either normal (6 patients) or continued to improve after treatment, which consisted of multiple burr hole drainage, broad spectrum antimicrobial treatment and eradication of the source of infection. PMID- 7839924 TI - Effects of adrenergic receptor blockers on adrenaline and nicotine-induced hyperglycaemia in the rat. AB - Studies in fasted, anaesthetized rats have shown that adrenaline and nicotine induced hyperglycaemia is mediated via activation of beta-adrenoceptors. The hyperglycaemic response to nicotine is different from that of adrenaline in that, unlike adrenaline hyperglycaemia, nicotine hyperglycaemia is characterized by a long latent period, delayed attainment of peak of response and sustained hyperglycaemia throughout the 120 minutes post-injection observation. Comparison with previous studies in dogs showed that different receptors are involved in nicotine hyperglycaemia in fasted dogs and fasted rats. PMID- 7839925 TI - Dysgenesis of the corpus callosum: computed tomographic changes. AB - The CT findings in 32 cases of DCC are presented classifying them into three groups: Type I: Anatomical changes primarily due to callosal dysgenesis. Type II: Associated central nervous system anomalies. Type III: Incidental findings. The findings were compared with those of others. This study confirms that the CT findings which are of a high diagnostic index are those of Type I changes which include enlargement and elongation of the interventricular foramen, enlargement and continuity of the interhemispheric fissure with the third ventricle, which is invariably enlarged, elevation and anterior displacement of the third ventricle. Separation and parallelism of the lateral ventricle is also one of the most diagnostic features. Three rare syndromes (Soto's, Aicardi's and De Morsier's) and the rare occurrence of associated teratoma which were encountered as part of the associated congenital abnormalities are mentioned. The embryological basis of the CT findings is discussed. PMID- 7839926 TI - The rarity of minimal change disease in Nigerian patients with the nephrotic syndrome. AB - Minimal change disease (MCD), mesangial proliferative glomerulonephritis (MPGN) and focal glomerulosclerosis (FGS) may be indistinguishable at some stage when examined by light microscopy, but MCD in adults has over 80% response rate to prednisolone therapy. In search of MCD, we treated 22 patients with biopsy reported MCD (1 patient), MPGN (15 patients), and FGS (6 patients), out of 84 adult patients with the nephrotic syndrome (NS) seen over 55 months, with prednisolone 60mg daily for 6 weeks (4 patients) or 8 weeks (18 patients). Two patients with MPGN showed partial remissions with proteinuria dropping to 0.8g/24 hours and 1.2g/24 hrs. All the others were non-responsive with proteinuria remaining above 2g/24 hours. Allowing that 20% of patients may not respond to prednisolone, 4 patients may have been missed. It is concluded that MCD as defined by minor glomerular changes and good response to steroids is rare in adult Nigerian patients with the NS. PMID- 7839927 TI - Morphological changes found in the testes of 177 Nigerian males investigated for infertility. AB - One hundred and seventy-seven men who had testicular biopsies done for infertility investigations over a 5-year period (1983-1987) were studied. Twenty per cent had normal histological pictures. Varying degrees of hypospermatogenesis were seen in 49% while 19% had chronic non-specific orchitis. The remaining 12% had various other pathological changes. PMID- 7839928 TI - Clinical presentation of atopic dermatitis in Negroid children. AB - Clinical findings in 54 consecutive negroid children with atopic dermatitis (AD) are presented. The age range was 0.25 to 10.25 years. Male:Female ratio was 1.2:1. Time of onset range between 1 week and 8 years with onset before the age of 1 year in 81.1%. Facial and flexural involvement were observed in 81.5% and 70.4% of patients respectively. The latter was more common after the age of two years. Keratosis pilaris, repeated skin infections and ichthyosis were observed in 72, 45, and 40 per cent of the children. Allergic conjunctivitis was present in 11.8%. The findings suggest that the clinical presentation of AD in Negroid children is similar to that in white children. PMID- 7839929 TI - Effect of levamisole hydrochloride on the guinea-pig atrium. AB - The effects of levamisole on the guinea-pig atrial preparation were determined. At 3 micrograms/ml, levamisole and lignocaine prevented electrically induced arrhythmia in 3 and 5 out of 5 preparations respectively. It was concluded that levamisole at the therapeutic anthelmintic dose would not abolish clinical atrial arrhythmia. Levamisole even at 3 micrograms/ml had definite salutary effect on the hypodynamic state induced by continuous electrical stimulation. The dose related positive inotropic effect of levamisole 5-200 micrograms/ml was not antagonised by practolol but was absent in atria from reserpinized animals. Therefore, cAMP may not be involved in the positive inotropic effect. Levamisole antagonised verapamil-induced negative inotropic effect and no positive inotropic effect was observed when the Ca2+ content of the Ringer-Locke solution was below normal. These suggested that Ca2+ must be involved in the inotropic effect. The negative chronotropic effect due to levamisole was not antagonised by hexamethonium but was antagonised by atropine, thus indicating that stimulation of M1 or M2 receptors in the atria may be responsible. PMID- 7839930 TI - Hydrophobic response of Escherichia coli exposed to subminimal inhibitory concentrations of ampicillin and chloramphenicol. AB - Hydrophobicity generally increased as the cells passed from lag to exponential phases of growth and declined in the stationary phase. All concentrations of ampicillin used increased hydrophobicity, although still subject to effect of phase of growth. Chloramphenicol caused decline in hydrophobicity. Combination of the two antibiotics gave a concentration dependent balance of the two forces observed. Protein synthesis inhibition may render cells resistant to phagocytic uptake by lowering surface hydrophobicity. This phenomenon is probably involved in cases of therapeutic failures, persistent of recurrent infections. This is a further indication of the undesirability of antibiotic abuse. PMID- 7839931 TI - Soluble immune complexes and immunoglobulin (IgG, IgA and IgM) levels in Nigerians with primary liver cell carcinoma. AB - Circulating soluble immune complexes and serum immunoglobulins (G,A and M) levels were determined in patients with primary liver cell carcinoma (PLCC) and healthy subjects by the polyethylene glycol precipitation and single radial immunodiffusion methods respectively. A considerably higher proportion of the patients than the controls had elevated levels of soluble immune complexes, IgG and IgM were significantly higher in the patients than the controls, that of IgA was lower. Correlation studies showed association between serum concentration of IgG, IgA and IgM and the levels of circulating soluble immume complexes. Several factors may influence our findings of elevated concentrations of soluble immune complexes and serum immunoglobulins G and M as well as the positive correlations between these indices. It could be as a result of increased rate of production and release of antigen from the tumour; enhanced interaction of antibody with membrane antigens at the tumour cell surface which promoted release of immune complexes or/and decreased rate of elimination of the complexes from the body of phagocytosis. That antibodies are required for the formation of immune complexes may explain our observation of increased levels of IgG and IgM. PMID- 7839932 TI - A modified medium for the in vitro cultivation of trypanosomes. AB - A modified medium (ME-99) for the in vitro cultivation of trypanosomes was developed and evaluated in our laboratory. The medium comprised of Eagle MEM as a base and various components of medium 199 not found in MEM. Trypanosoma brucei brucei, T. b. gambiense and T. vivax were grown in ME-99 and various other media combinations such as MEM/RPMI 1640, MEM/BCM, MEM/199, RPMI 1640/BCM, RPMI 1640/199, BCM/199 for comparison. Both growth and infectivity of these parasites were compared in these media. Parasites grew better and maintained their infectivity for longer periods in ME-99 than in any other medium or combination of media. PMID- 7839933 TI - Meeting the challenges of the African health crisis in the decade of the nineties. PMID- 7839934 TI - HIV seropositivity in Nigerians with lymphoproliferative malignancies. AB - One hundred and four Nigerians with lymphoproliferative malignancies were tested for antibodies to human immunodeficiency virus types 1 and 2 (HIV-1 and 2). All the patients with high grade lymphomas in this series were seronegative for HIV-1 and 2. Only 1 of the 104 patients had antibody to HIV-1 and none had antibody to HIV-2. Although the single positive result would suggest a higher HIV-1 seropositivity rate among the patients compared with the general Nigerian population, it should be interpreted with caution. This preliminary data emphasizes the need for an urgent countrywide study of the problem among this category of patients in Nigeria in view of the low prevalence rate of HIV-1 and 2 in the country. PMID- 7839935 TI - HBsAg and aflatoxins in sera of rural (Igbo-Ora) and urban (Ibadan) populations in Nigeria. AB - The purpose of this study was to screen for the presence of hepatitis B surface antigen and aflatoxins in the sera of 100 non-hospitalized individuals from the rural population of Igbo-Ora and 89 non-hospitalized individuals from the urban population of Ibadan, Nigeria. Hitherto, such a study as this has not been undertaken in this environment. The proportions of hepatitis B surface antigen carriage and serum 'pathologic' levels of aflatoxins were high (47-49%, 8.2-9.0% respectively) but varied very little between the two different populations sampled. These findings indicate that determined efforts should be instituted to reduce or eliminate hepatitis B virus infection and aflatoxin contamination of high risk foodstuffs from this environment. PMID- 7839936 TI - Cervical ripening and induction of labour by breast stimulation. AB - The value of gentle, unilateral breast stimulation in the ripening of cervix and induction of labour was studied. Three hundred patients with uncomplicated term pregnancies, (38-42 weeks) were recruited into the study, consisting of three separate randomised double blind prospective trials. The first trial was to evaluate the effectiveness of breast stimulation in ripening the cervices of 200 term primigravid patients. There was a mean change of 3.90 +/- 2.39 points in cervical score among the study group compared to 0.50 +/- 0.67 among the control group. Thirty-three per cent of the study group went into labour when compared with 4% among the control group. In a second study of cross-over trial involving 78 of the original 200 patients, the study (ex-control) group had a mean change in cervical score of 3.84 +/- 2.24 when compared with the control (ex-study) group, (1.43 +/- 1.08). In a third study involving 100 multiparous patients, a mean change in cervical score of 2.74 +/- 1.16 was observed in the study group when compared with the control group, 0.92 +/- 1.07. Forty-six per cent of the patients went into labour compared with 12% in the control group. All findings were highly significant and there were no maternal or fetal side-effects. The study confirmed the efficacy of breast stimulation in cervical ripening and induction of labour. PMID- 7839937 TI - Cervical carcinoma in Nigeria--a need for early detection. PMID- 7839938 TI - Aneurysm of the vein of Galen presenting with proptosis. AB - A case of proptosis, arterio-venous malformation and aneurysm of the Vein of Galen in a 12 year old schoolboy is presented. This is in addition to the literature of the rare aneurysm involving the Great Vein of Galen. This is the first time this syndrome will be described in association with ophthalmic presentation. It is however remarkable that with such a huge sized aneurysm and A V malformation, the patient did not have any other neurological deficit except visual field loss. Perhaps the previous series had undetectable visual field loss which was missed as patients might not have complained of visual symptoms. PMID- 7839939 TI - The characteristics of the menstrual cycle in Nigerian schoolgirls and the implications for school health programmes. AB - The present study examines the characteristics of menstrual cycle among 361 Nigerian postmenarcheal schoolgirls derived from seven public secondary schools. Survey questions covered preparation for menstruation, duration of flow, cycle length, regularity, premenstrual syndrome and dysmenorrhea. For the study subjects the mean age (years) at the time of interview, at menarche, and completed since menarche are 16.5 +/- 3.3, 13.7 +/- 2.6 and 2.9 +/- 1.2 respectively. Premenstrual counselling was reported in 84.2%; and 48.6% was provided by parents and guardians, and 23.7% by school teachers. The findings indicate that menstrual flow < or = 2 days, and cycle length < or = 20 days are common; occurring in 20-30% of schoolgirls. Abnormal patterns such as cycle length > or = 38 days, flow duration > or = 8 days and heavy menstruation occurred in less than 5% of study subjects. Irregular menstrual cycles were recorded in 13%, and severe dysmenorrhea in 17.2%. Severe premenstrual syndrome occurred in about 20% of schoolgirls, with symptom-complex mainly of behavioural change, arousal and impaired concentration. The need for a multi-disciplinary school health counselling program that would provide relevant information on menstrual pattern and its common variation, identify abnormal patterns for early referral, provide psychological support and drug relief of distressing menstrual symptoms, and provide information on other contemporary adolescent problems is discussed. PMID- 7839940 TI - Tetanus antibodies at booking in a Nigerian obstetric population. AB - Eighty-four consenting ante-natal patients at the University of Nigeria Teaching Hospital, Enugu, were examined for tetanus antibodies at booking. Only 28.6% had detectable serum antibodies. Although 73.8% were immunized within three years prior to investigation, only 37.1% had measurable antibodies. It was found that the longer the interval from previous immunization, the fewer the number with detectable antibodies and the lower the titres. Possible explanations for these findings are discussed and recommendations made. PMID- 7839941 TI - Right aortic arch: CT. diagnosis. AB - Computer Tomography (CT) can be helpful in the detection and diagnosis of aortic arch malformations, particularly the retro-oesophageal right side aortic arch with aberrant left subclavian artery. Three adult Saudi patients with this anomaly where recently encountered and are herein presented. All the three patients had CT scans with clear demonstration of the right aortic arch. CT can confirm the presence of this aortic arch anomaly suspected from plain chest radiographs or can detect the vascular anomaly when the radiographs suggest the presence of a mediastinal mass. The condition of congenital anomalous right aortic arch is also briefly discussed. PMID- 7839942 TI - Effects of minor surgery on some aspects of platelet function. AB - Blood from 33 patients undergoing elective surgery for non-malignant disorders was examined before operation and on the third post-operative day. The following parameters were measured: (a) total platelet count (b) platelet volume (c) released adenine nucleotides (ATP and ADP). Whole blood platelet count (WBPC) levels increased significantly after surgery and there was significant correlations between its pre- and post-operative values (r = 0.616, p < 0.05). The relationship between mean arithmetic volume after operation (MAVA) and the whole blood platelet count after operation (WBPC A) was negative and significant (r = -0.425, p < 0.05). The results also revealed no significant differences between total and released nucleotides before and after surgery. The significant increase in whole blood platelet count post operatively may have been due to release of the splenic platelet stores. Platelets in the spleen are said to be old platelets hence the lack of a significant change in platelet volume may be due to sampling taking place three days after surgery which may not have corresponded to the time of the optimum production of young larger platelets. Also, the trauma of minor surgery may not have been strong enough to stimulate platelet production in the marrow. In the light of the above findings further investigations may be conducted in which post-operative samples would be collected at varying intervals to determine whether post-operative changes in platelet volume occur at all and when. PMID- 7839943 TI - Laboratory investigations in patient care. AB - The accurate diagnosis and management of disease almost always involves the judicious use of laboratory investigation. The increasing sophistication, diversity and expense of laboratory tests must however impose a moratorium on the use of these tests. This article reviews the justification for tests in clinical biochemistry and the general classes and varieties of tests available. Furthermore, factors that may make a test result normal or abnormal are discussed, with emphasis on the mechanisms, other than disease, that may have contributed to an unexpected result. The review ends with a discussion on the implications and modalities for extending clinical biochemical tests from the laboratories locations closer to the patient's bedside. PMID- 7839944 TI - Serum electrolyte and protein changes after intravenous injection of sodium and meglumine diatrizoate (urograffin-370). AB - Serum electrolyte and protein changes in 35 Nigerian patients undergoing intravenous urography were evaluated after injection of 60 mls sodium and meglumine diatrizoate (Urograffin-370). Statistically, significant changes were noted in the values of serum calcium, proteins and albumin at 5 and 30 minutes after the injection (P < 0.005). The mean percentage decreases noted were calcium 13%, protein 17% and albumin 13%. At 30 minutes post-injection, the serum protein and albumin levels had incompletely recovered while calcium values continued to decrease. Non-statistically, significant changes were observed in the values of serum sodium, potassium and phosphate at 5 and 30 minutes respectively following contrast medium injection. Alterations in the levels of serum electrolytes especially calcium are most probably responsible for such adverse effects as convulsions and cardiac arrhythmias. PMID- 7839945 TI - An evaluation of the reactivity of the card agglutination test for trypanosomiasis (CATT) reagent in the Fontem sleeping sickness focus, Cameroon. AB - The TestrypR Card Agglutination Test for Trypanosomiasis (CATT) used for the serodiagnosis of gambiense trypanosomiasis is based on the variant antigen type (VAT) LiTat 1.3. This antigen is rarely expressed by trypanosomes in the Fontem focus of Cameroon, but the CATT has been used for serodiagnosis in the focus since 1985. We give here a summary of results obtained with the CATT in Fontem from 1985 to 1989. The CATT is specific for trypanosome antibodies since: (a) sera from persons with other parasitoses from areas non endemic for trypanosomiasis fail to react and (b) an enzyme-linked immunosorbent assay (ELISA) based on the detection of antibodies to somatic antigens of T.b gambiense from Fontem concorded with the CATT. CATT reactions in Fontem seem to be specific for the variant surface glycoprotein (VSG) since absorption of CATT reactive sera with formalin fixed bloodstream T. gambiense from Fontem and with culture produced procyclics of T. gambiense from Fontem failed to abrogate CATT reactivity. CATT on serum failed to confirm 37% of CATT positive cases on whole blood. Although immunoconglutinin (IK), anti-human red blood cell (RBC) antibodies and complement fixing immune complexes (ICs) were found in sera from Fontem, our results failed to incriminate immunoconglutination of RBCs, reactions of RBCs with their autoantibodies and immune adherence hemagglutination as contributory factors in this lack of agreement between CATT on serum and whole blood. Further, comparison of whole blood and serum CATT results of parasitologically confirmed patients leads to the conclusion that screening with the CATT in the Fontem focus should be done on whole blood, not serum or plasma. CATT reactions in Fontem are based on cross-reactions with as yet undefined VATs. PMID- 7839946 TI - Antimalarial activity of cyclosporins A, C and D. AB - Cyclosporin A (CsA) is an immunosuppressive drug widely used in organ transplants. It is also accumulated by the erythrocyte, a site that accommodates one of the stages of malaria parasite. We observe that CsA and its less potent immunosuppressive analogues CsC and CsD were as effective as chloroquine in inhibiting P. berghei malaria parasite development in vivo (when administered orally) and P. falciparum parasite in vitro. They were, however, not inhibitory to the liver stages and the gametocytes. In vivo the minimum effective dose was 10 mg/Kg administered on two consecutive days whereas, in vitro CsA and its analogues inhibited parasite development at concentrations of 10 micrograms/ml and above. PMID- 7839947 TI - A review of teratomas in Ibadan. AB - Teratomas accounted for 3.4 cases per 1,000 surgical biopsies received in the Pathology Department of UCH Ibadan, between 1960 and 1985. The commonest site of teratomas was in the ovaries which accounted for 83.2% of the cases, followed by the sacrococcygeal region which accounted for a further 6.3%. Other sites of occurrence included the neck, testes, mediastinum, abdominal cavity and buccal cavity in descending order of frequency. Rare sites of occurrence were extracranial, intracranial, uterine cervix and intraocular regions. There was a female to male ratio of 18 to 1 and the average age of the patients was 25.8 years. Sixty per cent of ovarian and mediastinal teratomas contained hair and sebaceous material permitting their gross identification. Eighty-eight per cent of the teratomas reviewed histologically were classified as mature, a further 8% were immature, and 4% were malignant. PMID- 7839948 TI - Cardiovascular systemic invasion by hepatocellular carcinoma: incidence and pattern in a west African population. AB - To determine the frequency of cardiovascular systemic invasion by hepatocellular carcinoma (HCC). Eighty-one Nigerian patients who had autopsy examinations were studied. Of these, 36 (44%) had tumour thrombi within the cardiovascular system (CVS) or metastases to the heart itself. Compared with the patients without CVS invasion, no clinicopathologic findings distinguished these two groups from each other. Furthermore, CVS invasion did not worsen the generally bad prognosis of these patients with liver cancer. It is concluded that CVS invasion is frequent and difficult to diagnose by clinical examination. Patients who are selected to undergo hepatic resection must be assessed by imaging techniques to exclude CVS invasion. However, it is unlikely that frequent and routine imaging procedures will affect the generally bad prognosis of the majority of the patients. PMID- 7839950 TI - Radiological appearances of dermoid tumours (with emphasis on fat fluid levels). AB - Nine cases of dermoid tumours, one in the chest and eight in the abdomen are reported with various radiological findings on plain films, ultrasound and computed tomographic (CT) scans. The various radiological appearances at ultrasound and CT are described. The incidence and frequency of fat-fluid interfaces on ultrasound and CT scans are highlighted. Since the appearances of fat on ultrasound are variable, CT is therefore more specific in showing in fat fluid levels. Moreover the dermoid tissue plugs seen on CT and ultrasound scans, with their surrounding fat, are highlighted as the so-called "iceberg" sign or as "target" signs. The paper concludes that the presence of fat fluid levels, a finding not previously emphasized, with a positive "iceberg" or "target" sign on CT or ultrasound scans, are pathognomonic of dermoid cysts. PMID- 7839949 TI - Symmetrical lesions in the basal ganglia. AB - Bilateral and symmetrical non-space occupying lesions in the basal ganglia of 27 cases were studied. Nine cases had low attenuation lesions while the remaining 18 had high attenuation lesions due to bleeding or calcifications. The clinical presentations and final diagnosis were collated and related to these changes. In the low-attentuation cases, definite hypoxic-ischaemic insults were the aetiological basis for low attenuation lesions in 3 cases; and hypothesised to be the basis in the remaining six. Amongst the high attenuation group, bleeding was noted in 4 cases with trauma or cardiac arrest. The remainder had calcifications. It is suggested that a hypoxic-ischaemic pathophysiological phenomenon might have also accounted for some of these calcifications. The co-existence of both low and high attenuation lesions in the same patients in some of our cases tends to lend credence to this hypothesis. PMID- 7839951 TI - Anti-inflammatory, antipyretic and anti-malarial activities of a West African medicinal plant--Picralima nitida. AB - A preliminary pharmacological screening of the methanolic extract of Picralima nitida fruit was carried out. The extract showed potent and dose-dependent anti inflammatory, antipyretic and anti-malarial activities. Given intraperitoneally, it inhibited carrageenan-induced rat paw oedema with IC50 of 102mg/kg, and with the highest dose tested (300mg/kg) producing 72.2% inhibition. On the LPS-induced pyrexia in rabbits, 50mg/kg of the extract produced a mean percentage antipyrexia of (38.7%) compared with (29.0%) by 200mg/kg of aspirin. In a 4-day in vivo schizontocidal test in mice infected with P. berghei berghei, up to 300mg/kg daily for 4 days was ineffective in preventing the development of parasitaemia or the consequent mortality. However, marked inhibitory activity was obtained on multi-drug resistant human P. falciparium parasites cultured in in vitro. The dose causing 50% inhibition of parasite growth was 1.75 micrograms/ml compared with (0.14 microgram/ml for chloroquine. The results confirm the medicinal value of this plant and thus justify its use by natives of W. Africa. PMID- 7839952 TI - Cyclical menouria syndrome: a case report. AB - Cyclical menouria, a rare syndrome, occurred in a 32-year old Nigerian, who presented with cyclical haematuria. She was continent of urine. Hysterosalpingography revealed a vesicocervical fistula, which was successfully repaired at surgery. PMID- 7839953 TI - Mantoux test tuberculin reaction in Nigerians. AB - Thirty-seven Nigerian tuberculosis patients and 75 control volunteers were Mantoux-tested with 1 or 5 or 10 tuberculin units of Tween-80 stabilised purified protein derivative (P.P.D.) in order to relate tuberculosis infection to skin reactivity. Serum transferrin and albumin levels determined by radial immunodiffusion technique showed some overlap but test patients tended to have lower values than controls. Skin reaction was not significantly affected by age which varied from 6 to 55 years or the extend of tuberculosis treatment at Mantoux testing. For comparable P.P.D. doses Mantoux readings greater than 9.9mm showed 86.5% sensitivity for tuberculosis but presented low (28%) specificity in contrast to readings greater than 15mm with specificity of 74.7%. Significantly higher proportion of test patients than controls showed skin reaction greater than 9.9mm (p < 0.05) whereas the difference was insignificant at 9mm. With improving nutrition there is need for a large-scale reappraisal of the value of intradermal tuberculin test in diagnosing active tuberculosis in Nigerian reactors. PMID- 7839955 TI - Health care in a single-payer system. PMID- 7839954 TI - Reducing imaging costs in Manitoba, Canada. AB - Manitoba, Canada, has serious debt and deficit problems and spends one-third of its revenue on health care. Manitoba Health, the single government carrier, has requested a 5-year management plan from the Provincial Imaging Advisory Committee to maintain and improve the present services within reduced funding [1]. The committee members are radiologists, nuclear medicine specialists, physicists, physicians, hospital officials, and senior government staff. In 1993, each Manitoba hospital prepared a 5-year plan for imaging equipment purchases based on projected patient and attending staff needs. The requests for services and new imaging technology exceed planned resource allocations. I was asked by Manitoba Health in July 1993 to prepare a cost restraint position paper with a target of 10% savings to help with government restraint and to allow some transfer of resources for continuing growth in imaging. The approach was to consult widely and to seek methods of significant cost savings that Canadian society might accept (Table 1). Areas of potential savings now are being considered by ad hoc committees appointed by hospitals and Manitoba Health. Several are being implemented on a trial basis. PMID- 7839956 TI - Helicobacter pylori and peptic ulcer disease. AB - Since William Beaumont's classic description of gastric physiology in 1847, the focus of clinical practice and basic research concerning gastric and duodenal ulcers has centered on the secretion of acid and pepsin. In addition to these well-known factors (largely determined by heredity, age, and oral intake), the search for other agents that alter the mucosal barrier has identified a bacillus, Helicobacter pylori, as a significant agent in the development of chronic gastritis and benign gastric and duodenal ulcers. This review explores the scientific evidence for an important causal role of H. pylori in the development of peptic ulcers on the basis of pathologic, pathophysiologic, and pharmacologic data. PMID- 7839957 TI - Adverse effects of biliary obstruction: implications for treatment of patients with obstructive jaundice. AB - The development of hypotensive complications, renal failure, and cholangitis in patients with jaundice [1-4] has particular implications for radiologists asked to perform diagnostic studies that require IV contrast material and for radiologists, gastroenterologists, and surgeons who do invasive procedures to relieve bile duct obstruction. Although systemic effects of obstruction eventually are eliminated by reestablishment of the free flow of bile, all invasive procedures are painful, require sedation or anesthesia, and can induce fluid shifts, electrolyte abnormalities, hemorrhage, bile peritonitis, and sepsis. A patient with jaundice is less able to respond to and easily decompensates after such stresses [4]. An awareness of the pathophysiologic effects of biliary obstruction is essential because proper preparation of patients with jaundice before invasive diagnostic and therapeutic procedures avoids complications and decreases morbidity and mortality [5-8]. An overview of the systemic effects of bile duct obstruction and their implications for patients who require invasive diagnostic and therapeutic procedures is provided in this article. PMID- 7839958 TI - Diffuse pulmonary hemorrhage: clinical, pathologic, and imaging features. AB - Diffuse pulmonary hemorrhage (DPH) is a syndrome characterized by the presence of widespread hemorrhage from the pulmonary microvasculature leading to hemoptysis, iron deficiency anemia, and a chest radiography showing bilateral airspace consolidation. Diagnostic imaging consists primarily of chest radiography, but CT and MR imaging may be helpful in selected cases. There are many causes of DPH, and the differential diagnosis and diagnostic approach depend on whether the patient is immunocompetent or immunocompromised. This review summarizes the clinical, pathologic, and imaging features of DPH and the treatment of its more common causes. PMID- 7839959 TI - Noninvasive assessment of myocardial perfusion and metabolism: feasibility of registering gated MR and PET images. AB - OBJECTIVE: Positron emission tomography (PET), the reference technique for in vivo noninvasive assessment of myocardial perfusion and metabolism, is hampered by limited resolution and low signal-to-noise ratio. Cardiac MR imaging, on the other hand, provides excellent soft-tissue contrast. This study examines the feasibility of combining the information of these two complementary techniques by the three-dimensional superimposition of regional myocardial blood flow or substrate metabolism as depicted in cardiac PET images on comparable MR images at the same cardiac phase and spatial location. SUBJECTS AND METHODS: Three dimensional, gated PET and MR images of the heart were acquired at different phases of the cardiac cycle from six normal volunteers and from one patient with coronary artery disease that had been detected by coronary angiography. An interactive algorithm using morphologic operators was developed to contour the left ventricle on the MR and PET images. A three-dimensional surface-fitting technique was used to register the left ventricle surfaces. The accuracy of registration was estimated using 80 internal landmarks from six volunteer scans. RESULTS: These techniques yielded PET images resliced along the same spatial location and orientation as the MR images both in the transaxial and short-axis views. The average residual, a measure of the goodness of fit, was 26 (+/- 5.6) for the systolic and 13 (+/- 6.1) for the diastolic images compared with an increase of that index from 9.3 at the best fit to 13.2 when the images were deliberately misaligned by 2 mm in each of two directions. We verified that MR and PET images could be aligned with an accuracy of 1.95 mm (+/- 1.6), which was approximately equal to the larger of the two pixel sizes (i.e., 1.6 mm on PET images). CONCLUSION: MR and PET images of the heart at identical cardiac phases can be accurately superimposed. Both transaxial and short-axis views can be obtained, the latter being more useful for PET quantification. This technique offers the potential for characterizing regional interactions among contractile function, blood flow, and substrate metabolism, especially when these are altered regionally in cardiac diseases. PMID- 7839960 TI - Mammography in patients with breast cancer treated by breast conservation (lumpectomy with or without radiation) AB - The woman with breast cancer who undergoes breast-conserving treatment (lumpectomy with or without radiation) is a challenge for the mammographer. The preoperative mammograms of women undergoing breast-conserving treatment, unlike those of women who will be treated by mastectomy, must be evaluated for the extent of tumor to determine if limited surgery can be done with good cosmetic results. In some cases, postoperative mammographic assessment of the breast is done to determine whether any residual tumor exists in the breast. Finally, there is the long-term follow-up of the treated breast to detect any new or recurrent cancer as early as possible. These tasks require knowledge of the mammographic patterns of breast cancer and scar formation, an appreciation of the alterations that occur in the mammogram after breast irradiation, and an understanding of the benign changes that can mimic new breast cancer in these women. The purpose of this review is to discuss the role of mammography in the diagnosis and treatment of these women, including recommendations for when to obtain mammograms, and to present the spectrum of findings that may occur. PMID- 7839961 TI - Seat belt injuries of the breast: findings on mammography and sonography. AB - OBJECTIVE: The purpose of this study was to determine the mammographic and sonographic findings of injuries of the breast caused by seat belts in automobile accidents. The imaging findings of such injuries must be differentiated from those of carcinoma, so that inappropriate treatment is avoided. MATERIALS AND METHODS: Five patients who had breast injuries caused by seat belts with shoulder restraints between 1988 and 1993 and who underwent mammography were included in this study. Four of these women had imaging studies done in our department, and one was examined elsewhere. The initial mammograms for four patients were obtained 1-2 months after trauma to the breast. For the fifth patient, the initial study was obtained 13 months after injury. For all women, follow-up examinations were performed from 3 months to 4 years after injury. Two patients also underwent sonography of the breast during the course of their evaluation. RESULTS: At 1-2 months after breast injury caused by a seat belt, mammograms showed thin-walled fat-density cysts in a linear distribution and, in less dense breasts, an associated 2-3-cm band of increased density. The band of increased density was not seen in more dense breasts. These findings correlated with the line of contusion across the breast and resultant fat necrosis, which ultimately led to the formation of lipid cysts. By 3-4 months after the injury, the lipid cysts and contusion were less apparent, and a line of fibrosis had developed. On sonography, the lipid cysts were smoothly marginated; such cysts may be either anechoic or hypoechoic. Parenchymal calcification may develop 3.5-4 years after such an injury. CONCLUSION: Mammograms in women with breast injuries caused by seat belts show areas of contusion, lipid cysts, and parenchymal calcifications occurring in a bandlike distribution corresponding to the path of the seat belt shoulder restraint across the chest. Lipid cysts are seen sonographically as smoothly marginated anechoic or hypoechoic nodules. PMID- 7839962 TI - Papillary carcinoma of the breast: imaging findings. AB - Papillary carcinoma is a rare malignant tumor of the breast for which the survival rate is better than for most breast carcinomas. Histologically, invasive and in situ forms occur; the in situ form can extend throughout a ductal system (intraductal) or can be confined within a cystic structure (intracystic). Invasive papillary carcinoma can spread from either of the in situ forms but spreads more commonly from the intracystic type. Many reports in the literature have failed to differentiate invasive from in situ papillary carcinomas; similarly, the different mammographic patterns of the two in situ forms of these lesions have not been delineated clearly. Our review of 16 new cases of papillary carcinoma showed a frequent correlation between the histologic types and the mammographic appearance. The intraductal in situ form usually was characterized by clustered microcalcifications. The intracystic in situ type was associated with well-circumscribed masses on mammograms; these masses often were complex on sonograms. The purpose of this essay is to illustrate the mammographic and sonographic features of the histologic varieties of papillary carcinoma. Color Doppler sonograms and MR images of intracystic and invasive tumors also are included. PMID- 7839963 TI - Use of contrast material for spiral CT of the abdomen: comparison of hepatic enhancement and vascular attenuation for three different contrast media at two different delay times. AB - OBJECTIVE: The purpose of this study was to determine the relative effects of delay time, contrast agent concentration, and contrast agent volume on hepatic enhancement and on aortic and portal vein attenuation for contrast-enhanced spiral CT of the abdomen. The effect of delay time was evaluated by comparing two different delay times for each of three IV contrast media. Three different media were tested to identify whether the effects were different with different iodine concentrations and doses or with different volumes of contrast medium. SUBJECTS AND METHODS: A total of 169 patients who underwent contrast-enhanced CT of the abdomen with spiral CT imaging were evaluated for enhancement of the liver parenchyma and for postenhancement attenuation of the aorta and portal vein. Total iodine doses of 30 g as 100 ml of iohexol 300 or 125 ml of ioversol 240 and of 40 g as 125 ml of ioversol 320 were evaluated at delay times of 45 and 60 sec and with a low-flow monophasic injection at a rate of 2 ml/sec. RESULTS: For each contrast medium tested, a 60-sec delay provided greater hepatic enhancement than did a 45-sec delay (43 vs 32 H for iohexol 300, 37 vs 28 H for ioversol 240, and 50 vs 39 H for ioversol 320; all comparisons, p < or = .0001). The aortic attenuation achieved in the abdomen after contrast medium administration was significantly greater with a 45-sec delay than with a 60-sec delay for iohexol 300 (p = .0290) but not for the other contrast media. The portal vein attenuation achieved after contrast medium administration was significantly greater with a 60 sec delay than with a 45-sec delay for all three contrast media (p = .0051). CONCLUSION: When IV contrast material was injected with a low-flow-rate monophasic bolus, a delay time of 60 sec, longer than that typically used for dynamic incremental scanning, provided greater hepatic enhancement in spiral CT. This result was significant for the three contrast media tested. Aortic attenuation was significantly greater at shorter delay times when a smaller volume of contrast material was injected. Portal vein attenuation was greater at longer delay times, suggesting that the optimal delay time may be longer than 60 sec. Further work to determine the optimal scanning window for hepatic enhancement in spiral CT by use of time-density curves is indicated. PMID- 7839964 TI - Does advanced cirrhosis with portosystemic shunting affect the value of CT arterial portography in the evaluation of the liver? AB - OBJECTIVE: The purpose of this study was to determine the extent to which reduced portal blood flow in patients with advanced cirrhosis affects contrast enhancement of the liver during CT arterial portography (CTAP). We postulated that reduced and/or irregular hepatic enhancement would limit the efficacy of CTAP for the detection of hepatic tumors in these patients. MATERIALS AND METHODS: We reviewed the records of 82 patients who had biopsy-proved advanced cirrhosis and who underwent CTAP. Three experienced radiologists evaluated the CTAP studies for adequacy of hepatic parenchymal enhancement. The presence or absence of varices also was documented in an attempt to select a subgroup of patients in whom CTAP showed better hepatic parenchymal enhancement. RESULTS: Forty-seven (57%) of 82 patients had inadequate hepatic parenchymal enhancement to allow an evaluation of the entire liver. Inadequacy was attributable to areas of hyperdense parenchymal enhancement, areas of diffuse nontumoral mottling, or zones of poor parenchymal enhancement (soft-tissue attenuation equal to that of the paraspinal muscle). Parenchymal enhancement was inadequate in 62% of patients with varices and in 28% of patients without demonstrable varices. CONCLUSION: Our results show that contrast enhancement of the liver during CTAP is altered significantly in patients with cirrhosis. Thus, it is likely that CTAP has limited usefulness for the detection or characterization of hepatic neoplasms in patients with cirrhosis. PMID- 7839965 TI - Hepatobiliary cysts in patients with autosomal dominant polycystic kidney disease: prevalence and CT findings. AB - OBJECTIVE: Hepatobiliary (intrahepatic and peribiliary) cysts have been described for patients with autosomal dominant polycystic disease. The purpose of this study was to determine the prevalence of these cysts and to describe the wide variation in their appearance on CT scans. MATERIALS AND METHODS: We studied CT scans for 64 patients (31 men and 33 women) who either had known autosomal dominant polycystic kidney disease or had renal cysts and a family member with polycystic kidney disease. Contrast enhancement was used for 31 patients. CT scans were retrospectively evaluated by consensus by two experienced radiologists. The presence, number, and size of hepatobiliary cysts and the presence and appearance of the two variations, peribiliary and intrahepatic cysts, were analyzed. Peribiliary cysts were determined to be present when many small (< or = 10-mm) cysts were seen adjacent to the larger (up to the third order) portal triad. Cysts present in the hepatic parenchyma but not in contact with the larger portal triad were regarded as intrahepatic cysts. RESULTS: CT showed hepatobiliary cysts in 56 of the 64 patients (24 men and 32 women; 88%). Intrahepatic cysts were noted in all 56 patients; peribiliary cysts were definitely seen on CT scans for 22 patients and were probably seen (fewer than five cysts and/or cysts located only on one side of the portal vein) on CT scans for 19 patients (73% of all patients with hepatobiliary cysts). Peribiliary cysts appeared as discrete cysts in 31 patients, as a string of cysts in six patients, and as a tubular structure in four patients. Intrahepatic cysts generally were round but occasionally were polygonal. They were variable in number, size, and location. CONCLUSION: Hepatobiliary cysts were noted in 56 of 64 patients (intrahepatic cysts in all cases and peribiliary cysts in 73% of positive cases). Intrahepatic cysts varied widely in number, size, and location, whereas peribiliary cysts were small and appeared as discrete cysts, a string of cysts, or a tubular structure adjacent to the larger portal triad. It is important to be aware of the wide variety of findings for hepatobiliary cysts so that they are not confused with other abnormalities. PMID- 7839966 TI - CT finding of transient focal increased attenuation of the liver adjacent to the gallbladder in acute cholecystitis. AB - OBJECTIVE: The purpose of this article is to report the finding of transient focal increased attenuation of the liver adjacent to the gallbladder on enhanced CT scans in patients with acute cholecystitis. This finding should not be confused with primary liver abnormalities. MATERIALS AND METHODS: Five patients with acute cholecystitis were studied. Because a thickened gallbladder wall was seen on sonography, all patients were examined preoperatively with incremental dynamic helical CT to exclude carcinoma of the gallbladder. CT findings were compared with results of sonography for five patients, MR imaging for two patients, and surgery for five patients. RESULTS: Transient focal increased attenuation of the liver adjacent to the gallbladder was seen in the early phase of incremental dynamic CT in five patients and extended into the medial segment anterior to the porta hepatis. The areas showing increased attenuation adjacent to the gallbladder had a curvilinear shape around the gallbladder. No hepatic masses were seen on sonograms, on MR images, or at surgery. CONCLUSION: Transient focal increased attenuation of the liver may occur on CT scans in patients with acute cholecystitis. The increased attenuation associated with acute cholecystitis has a typical location and pattern. This finding is probably attributable to hepatic arterial hyperemia and to early venous drainage caused by the adjacent inflamed gallbladder. This finding should be differentiated from hypervascular hepatic tumors. PMID- 7839967 TI - Imaging of percutaneous tube gastrostomies: spectrum of normal and abnormal findings. AB - Enteral alimentation is a crucial component of care for the malnourished patient who cannot eat. Until recently, long-term alimentation was delivered through nasogastric tubes or gastrostomy tubes placed at surgery. In the past few years, percutaneous endoscopic gastrostomy (PEG) has almost completely supplanted these traditional methods. PEG is a safer and better-tolerated procedure. The advantages of PEG over nasogastric tubes include greater social acceptance and improved cosmetic appearance, increased ease of feedings, and decreased nasal alar deformities and gastroesophageal reflux. Complications are less common with PEG than with open gastrostomy but still occur in as many as 15% of cases [1-3]. Percutaneous gastrostomies performed using fluoroscopic guidance have complications in approximately 10% of cases [4]. Despite a rapid increase in the use of percutaneous gastrostomies and their placement by radiologists [4], few published reports have described imaging findings after the placement of such tubes. This pictorial essay illustrates a spectrum of normal and abnormal imaging findings observed with the use of PEG tubes, including tube migration and misplacement, infection, tumor seeding along the PEG tube track, and a variety of gastric wall defects and pseudomasses. PMID- 7839968 TI - CT appearance of splenic infarction in Wegener's granulomatosis. PMID- 7839969 TI - Small renal masses (lesions smaller than 3 cm): imaging evaluation and management. AB - The current use of CT and sonography for a wide variety of indications has led to the frequent incidental discovery of small (1.5-3.0 cm) and very small (< 1.5 cm) lesions in the renal parenchyma. These lesions are usually small benign cysts, complicated cysts, or small neoplasms. Although the increased sophistication of imaging technology has certainly improved the detection of these lesions, a specific diagnosis can be elusive, and management is controversial. The question remains as to whether lesions that prove to be neoplasms warrant treatment or whether they are clinically insignificant and should be ignored. The radiologist plays a major role in making this decision. The purpose of this article is to review the literature regarding the etiology and imaging evaluation of small renal lesions and to make recommendations for their appropriate management. PMID- 7839970 TI - Staging of renal adenocarcinoma: role of various imaging procedures. AB - Since the only successful curative treatment of renal adenocarcinoma is surgery, accurate radiologic information is crucial during initial tumor staging for optimal operative planning. Accurate radiologic staging can be achieved by use of proper imaging techniques, usually a combination of contrast-enhanced CT or multiplanar MR imaging with fast scanning techniques. These techniques permit the demonstration of regional lymph nodes, vascular extension, and distant metastases. Sonography and inferior venacavography are used occasionally to supplement the information obtained from CT or MR imaging. We review the principles of staging of renal adenocarcinoma, emphasizing the strengths and weaknesses of each imaging technique. PMID- 7839971 TI - Evaluation of renal masses detected by excretory urography: cost-effectiveness of sonography versus CT. AB - OBJECTIVE: The purpose of this study was to compare the cost-effectiveness of sonography and CT for the evaluation of renal masses discovered at excretory urography. MATERIALS AND METHODS: The records of 225 patients with a renal mass shown by urography who then had either sonography or CT within 3 months were reviewed retrospectively. The number, location, and size of lesions; initial and subsequent imaging tests; and final diagnoses were determined. Using the current Medicare reimbursements for sonography and CT, we calculated the economic implications of using sonography or CT as the initial examination. Any effect of the location or size of the lesion on the most cost-effective examination was also determined. RESULTS: Twenty-one percent of patients had both initial sonography and follow-up CT because of indeterminate findings or detection of a solid mass that required further staging. When CT was done first, CT findings were equivocal in 12%, necessitating follow-up sonography. At the prevailing charges, CT would have to be needed in 70% of patients initially imaged with sonography to justify the use of CT as the initial examination. The location and size of the lesion did not affect the need for CT at a rate (greater than 70%) that would economically justify use of CT as the first imaging test. Eighty-six percent of patients with a mass detected by urography had either a simple cyst or no evidence of a mass on sonography or CT. CONCLUSION: Sonography is the most cost-effective imaging method for the workup of a renal mass detected at urography. The number of sonographic examinations in which findings are indeterminate or positive (for a solid mass) is not sufficiently high to warrant replacement of sonography by CT, regardless of the size and location of the lesion. CT should be reserved for a limited number of specific indications. PMID- 7839972 TI - Epididymal abscess. PMID- 7839973 TI - Role of the resistive index in the evaluation of acute renal obstruction. AB - Sonography is well established as a screening tool to evaluate the kidney for the presence of renal obstruction. The role of sonography in the evaluation of acute obstruction is less clear, however. Despite recent reports emphasizing the ability of gray-scale sonography and kidney/urinary/bladder films to screen for acute colic, experience indicates that the sonographic diagnosis of acute renal stone disease may be unreliable. Multiple studies have demonstrated the many potential pitfalls of the sonographic examination for acute obstruction. False negative studies may result if the kidney is evaluated before hydronephrosis occurs. Conversely, nonobstructive pyelocaliectasis and parapelvic cysts may result in false-positive studies. Because of these sonographic limitations, many imaging practices exclusively have utilized excretory urography for the evaluation of patients with symptoms of renal colic. PMID- 7839974 TI - Role of renal Doppler imaging in the evaluation of acute renal obstruction. PMID- 7839975 TI - Differentiation of benign and malignant adnexal masses: relative value of gray scale, color Doppler, and spectral Doppler sonography. AB - OBJECTIVE: The purpose of this study was to evaluate prospectively the relative usefulness of color Doppler, spectral Doppler, and gray-scale sonography in differentiating benign from malignant adnexal masses. SUBJECTS AND METHODS: A total of 170 adnexal masses in 161 patients were classified prospectively as suggestive of or not suggestive of malignant tumor on the basis of gray-scale morphology, internal flow versus peripheral or no flow, and spectral Doppler pulsatility, as measured by a pulsatility index (PI) threshold of 1.0 and a resistive index (RI) threshold of 0.4. RESULTS: Surgical pathology revealed 123 benign masses and 46 malignant masses. One malignant mass was confirmed by cytologic evaluation of ascitic fluid. On gray-scale analysis, 46 of the 47 malignant masses were classified as suggestive of tumor, and 76 of the 123 benign masses were classified as not suggestive of tumor (sensitivity, 98%; specificity, 62%; negative predictive value [NPV], 99%; and positive predictive value [PPV], 50%). The use of internal color flow as a predictor of malignant tumor yielded a sensitivity of 77%, a specificity of 69%, an NPV of 89%, and a PPV of 49%. The PI and RI values were significantly lower (p < .0001) in malignant masses than in benign masses, although the values overlapped considerably. For a PI of less than 1.0, sensitivity was 67%, specificity was 66%, NPV was 83%, and PPV was 46%. For an RI of less than 0.4, sensitivity was 24%, specificity was 90%, NPV was 73%, and PPV was 50%. CONCLUSION: In our series, a gray-scale prediction of benignity was reliable (NPV = 99%), and a prediction of malignancy was unreliable (PPV = 50%). Internal color flow was not useful as a predictor of malignancy (PPV = 49%). Although the absence of internal or peripheral color flow suggested benignity (NPV = 94%), only 17 (16 benign) of the masses (about 10%) had no flow. Spectral Doppler analysis with RI and PI was not useful, as no reliable discriminatory value with both high sensitivity and high specificity could be found for either parameter because of the overlap in values obtained for benign and malignant masses. PMID- 7839976 TI - Calcification and fibrosis in mesenteric carcinoid tumor: CT findings and pathologic correlation. AB - OBJECTIVE: The purposes of this study were to determine the frequency and characteristics of calcification and fibrosis in mesenteric carcinoid tumor as seen on CT scans and to evaluate their possible role in diagnosis. MATERIALS AND METHODS: The CT findings in 29 cases of proved mesenteric carcinoid tumor were analyzed retrospectively. Tumors were assessed for size, margin, density, radiating strands, calcification, and associated thickening of the small-bowel wall. Matching histologic sections were available for 21 of the cases. They were reviewed independently for histologic pattern, degree of fibrosis, degree of infiltration along neurovascular bundles, necrosis, lymph node architecture, and calcification or ossification within the mass. CT and pathologic findings were then assessed for possible relationships. RESULTS: Calcification was detected by CT in 70% (21 of 30) of mesenteric masses. Three patterns of calcification were noted: small, stippled calcification (n = 11); coarse, dense calcification (n = 7); and diffuse calcification (n = 3). All calcification was localized within areas of poorly cellular mature fibrous tissue. The degree of radiating strands detected by CT tended to increase with the degree of fibrosis seen histopathologically (p = .06). CONCLUSION: Calcification in mesenteric carcinoid tumors was observed by CT in most cases of this series. The triad of a calcified mesenteric mass, radiating strands, and adjacent bowel-wall thickening should be considered highly suggestive of carcinoid tumor. PMID- 7839977 TI - Benign soft-tissue tumors in a large referral population: distribution of specific diagnoses by age, sex, and location. AB - OBJECTIVE: The purpose of this study was to determine the specific diagnoses, relative prevalence, and the age, sex, and skeletal distribution of benign soft tissue tumors and to ascertain the relative frequency of these tumors in specific anatomic locations and age groups among a population of patients in a large pathologic consultation service. MATERIALS AND METHODS: The computer diagnoses of 39,179 lesions occurring in 38,484 patients seen by the Armed Forces Institute of Pathology soft-tissue pathologists during the 10-year period starting January 1, 1980, and ending December 31, 1989, were retrospectively reviewed. All lesions were placed in one of 121 major categories in accordance with the classification system used by the World Health Organization and coded to one of 32 anatomic locations such as hand, wrist, and forearm. Age and sex of the patients were also recorded. For purposes of analysis, all lesions were placed in one of 10 categories: hand and wrist, upper extremity, proximal limb girdle (axilla and shoulder), foot and ankle, lower extremity, hip and buttocks region, head and neck, trunk, retroperitoneum, and other lesions. The study group included 31,047 mesenchymal lesions, of which 18,677 were benign. RESULTS: Approximately two thirds of soft-tissue tumors were classified into seven diagnostic categories: lipoma and lipoma variants (16%), fibrous histiocytoma (13%), nodular fascilitis (11%), hemangioma (8%), fibromatosis (7%), neurofibroma (5%), and schwannoma (5%). Approximately 80% of all benign tumors were placed in seven diagnostic categories for each age and location. In the retroperitoneum, for example, approximately half the benign lesions in the 16- to 25-year old group were fibromatosis (20%), schwannoma (14%), and neurofibroma (13%). For the same location in children 5 years old or younger, almost two thirds of the benign tumors were lipoblastoma (37%) or lymphangioma (26%). CONCLUSION: Despite the large number of pathologic possibilities, most benign soft-tissue tumors are classified into a small number of specific diagnostic categories. These may be further defined when the location of the lesion and the age of the patient are considered. Knowledge of tumor prevalence will assist the radiologist in establishing a suitably ordered differential diagnosis when a soft-tissue tumor has a nonspecific radiologic appearance. PMID- 7839978 TI - MR imaging of Achilles tendon in patients with familial hyperlipidemia: comparison with plain films, physical examination, and patients with traumatic tendon lesions. AB - OBJECTIVE: The purpose of this study was to evaluate the MR imaging characteristics of Achilles tendons in patients at risk for tendon xanthomas because of familial hyperlipidemia and to compare these findings with those seen on plain radiographs and physical examination. We also wished to determine if MR imaging could be used to differentiate xanthomas from traumatic tendinopathy in a second group of patients who had no history of hyperlipidemia but who had a history of trauma to the Achilles tendon. SUBJECTS AND METHODS: We evaluated the MR imaging studies of 26 Achilles tendons in 13 patients with heterozygous familial hypercholesterolemia (n = 11) and type III dysbetalipoproteinemia (n = 2). The size, shape, and signal characteristics of the Achilles tendon were recorded. A tendon was considered abnormal by MR if there was high signal, a convex anterior border, or an anteroposterior measurement greater than 7 mm. Findings on plain radiographs and physical examination of the Achilles tendons were evaluated in the same group of patients. In the group of patients with hyperlipidemia, palpable abnormalities of the Achilles tendon were present in 14 of 26 tendons. Plain radiographs were interpreted as showing abnormalities in 18 of the 26 tendons. In a second group of 21 tendons in patients with no history of hyperlipidemia but with traumatic tendinopathy, studies were evaluated for the size, shape, and signal characteristics of the Achilles tendon. RESULTS: On MR images, 24 of 26 tendons showed signal abnormalities, and 19 of 26 were enlarged. Abnormal signal was a diffuse stippled pattern with many low-signal round structures of equal size surrounded by high-signal material on all pulse sequences. Abnormal signal was seen in tendons of both normal and abnormal size. Bilateral and symmetric changes were found in all but one patient. Tendinopathy in patients without known hyperlipidemia appeared indistinguishable from tendon xanthomas in six (29%) of 21 tendons. The other tendons (71%) were distinctly different from xanthomas without a uniform stippled signal pattern. CONCLUSION: MR imaging of patients with familial hyperlipidemia showed an abnormal stippled signal pattern with or without enlargement or abnormal configuration of the tendon. MR imaging is a more sensitive method than physical examination and plain films for detecting abnormalities in Achilles tendons of patients with hyperlipidemia. Although the MR signal pattern of xanthomas is often different from that of partial tendon tears, tendon degeneration, or tendinitis, a significant overlap in appearance can be observed and the MR appearance of a xanthoma is not pathognomonic. PMID- 7839979 TI - Abnormalities of the biceps tendon of the shoulder: sonographic findings. AB - The purpose of this essay is to illustrate sonographic findings for patients with abnormalities of the tendon of the long head of the biceps muscle of the arm. The tendon is vulnerable to a variety of injuries caused by abnormalities of its osseous and soft-tissue supports, including impingement of the tendon against the acromion and arthritis of the glenohumeral joint. These abnormalities include acute and chronic tenosynovitis, rupture, subluxation, and dislocation. PMID- 7839980 TI - MR imaging of the elbow: normal variant and potential diagnostic pitfalls of the trochlear groove and cubital tunnel. AB - The proximal portion of the ulna includes the olecranon and the coracoid process, which together form the trochlear groove that articulates with the distal humerus. The groove is constricted at the junction of the olecranon and the coracoid process. A thin, transverse, nonarticular ridge intersects the groove at this junction. Both the constriction of the groove and the nonarticular ridge may simulate disease on MR imaging of the elbow. PMID- 7839981 TI - Norplant implants: sonographic identification and localization for removal. PMID- 7839982 TI - Sonography of the fetal spine: technique, imaging findings, and clinical implications. AB - Sonographic evaluation of the fetal spine is an essential part of any fetal survey, and it is included in the current American Institute of Ultrasound in Medicine/American College of Radiology and American College of Obstetrics and Gynecology guidelines for obstetric sonography [1, 2]. In this paper, we review the current knowledge of anatomy of the normal fetal spine and the sonographic findings associated with spinal anomalies, with special emphasis on neural tube defects. Important cranial clues to a spine abnormality initially may be more obvious at sonography than the spine abnormality itself, and the general significance of these clues is provided. The expanding role of prenatal maternal serum and amniotic fluid testing is explored, as are the benefits and modifications these bring to sonographic evaluations. Finally, the potential benefits of the rapidly advancing technology of three-dimensional sonography are introduced. PMID- 7839983 TI - Lumbar spondylolysis: reactive marrow changes seen in adjacent pedicles on MR images. AB - OBJECTIVE: In a search for ancillary MR findings for the diagnosis of spondylolysis, we performed a retrospective study to characterize changes in MR signal intensity of marrow within lumbar pedicles at the level of a spondylolytic defect. These reactive marrow changes were classified according to the anatomic pathologic scheme developed for degenerative disk disease by Modic et al. MATERIALS AND METHODS: Two neuroradiologists retrospectively reviewed MR images of 60 patients with lumbar spondylolysis confirmed by conventional radiography or CT. The MR signal of each pedicle at the level of a pars defect was compared on T1- and T2-weighted sagittal images to that at the next higher level. When both observers concurred that the signal of the involved pedicle differed significantly from that of its neighbor, this signal change was classified into one of three types (type I: hypointense on T1-weighted images, hyperintense on T2 weighted images; type II: hyperintense on T1-weighted images, isointense or hyperintense on T2-weighted images; type III: hypointense on both T1- and T2 weighted images). RESULTS: Changes in MR signal intensity of pedicles adjacent to spondylolytic defects were observed in 24 (40%) of the 60 patients. Type I changes were seen in three patients, all less than 24 years old. Type II changes were seen in 17 patients with a median age of 35 years. Type III changes were seen in four patients with a median age of 51 years. The distribution of changes in signal intensity in the pedicle as a function of age was significant (p = .001). CONCLUSION: Categories of changes in MR signal intensity, similar to those described adjacent to degenerating disks, can be seen in lumbar pedicles adjacent to a spondylolytic defect of the pars interarticularis and are distributed as a function of age. Awareness of this finding may aid in establishing the correct diagnosis of spondylolysis on MR imaging and prevent erroneous interpretation of abnormal signal intensity in the pedicles in these patients. PMID- 7839984 TI - Intraorbital wood foreign bodies on CT: use of wide bone window settings to distinguish wood from air. PMID- 7839985 TI - Position of jugular oxygen saturation catheter in patients with head trauma: assessment by use of plain films. AB - OBJECTIVE: The purpose of this study was to establish a plain radiographic technique for the assessment of the position of a jugular oxygen saturation catheter in patients with head trauma. MATERIALS AND METHODS: In the experimental study, jugular oxygen saturation catheters were introduced into the internal jugular veins of four cadavers. Correct positioning of the catheter tips was monitored by CT. Concurrent anteroposterior radiographs of the skulls were obtained with the tubes angled in a transverse plane and in a sagittal plane at intervals of 5 degrees and within a total range of 70 degrees for each plane. Three radiologists judged the visibility of the catheter tips and measured the distance of the catheter tips to previously determined bony landmarks of the skull. Then, preliminary radiologic criteria for correct positioning of the catheters were defined. In the clinical study, we prospectively evaluated radiographs for 32 patients who received jugular oxygen saturation catheters. Eleven patients had digital radiographs done, and 21 patients had radiographs with a conventional screen film system done. Radiographs were analyzed for consistency of findings with the experimental results and for consistency of the suspected catheter position with laboratory data. RESULTS: Results of the cadaveric study showed that catheter position is best assessed on strict anteroposterior radiographs with the orbitomeatal-basal line perpendicular to the plane of the film. A correctly positioned catheter tip should lie cranial to a line extending from the atlantooccipital joint space and caudal to the lower margin of the orbit. The catheter tip also should lie cranial to a line connecting the tips of the mastoid processes, with a catheter tip-to-line distance averaging 20% of the overall distance between the tips of the mastoid processes. According to these criteria, the catheter was properly positioned in 26 of 32 patients. In three patients, the catheter obviously was improperly positioned. Catheter position was equivocal in three other patients; in two of these patients, the catheter was looped within the internal jugular vein. Whereas for all 26 patients with properly positioned catheters values for jugular venous oxygen saturation were congruent with other laboratory data, incongruent saturation values were recorded for five of the six patients with equivocally or obviously improperly positioned catheters. CONCLUSION: Accurate assessment of the position of a jugular oxygen saturation catheter can be made by use of specific bony landmarks seen on anteroposterior radiographs of the skull. PMID- 7839986 TI - Vertebral artery injury after acute cervical spine trauma: rate of occurrence as detected by MR angiography and assessment of clinical consequences. AB - OBJECTIVE: The purposes of this study were to assess prospectively the frequency of vertebral artery injuries after major acute cervical spine trauma as determined by MR angiography and to assess the clinical consequences of these injuries. SUBJECTS AND METHODS: During a 6-month period, 37 patients who had major acute nonpenetrating cervical spine trauma were examined with MR imaging, usually within 24 hr of the injury. Routine spin-echo and gradient-echo images were supplemented by two-dimensional time-of-flight MR angiography of the extracranial head and neck vessels. The vertebral arteries were independently assessed by two neuroradiologists for nonvisualization, focal narrowing, or focal widening. Two patients had conventional angiographic correlation. The medical records of these 37 patients were also reviewed to determine the type of spinal injury, neurologic deficit on admission, and evidence of an intracranial neurologic deficit due to vertebral artery injury. The MR angiograms of 37 control subjects were interpreted to help determine the specificity of MR angiography; those studies were assessed only for the presence or absence of the vertebral arteries. RESULTS: Findings on MR angiograms were abnormal in nine patients (24%). In seven cases, one vertebral artery was diagnosed as nonvisualized (occluded) or focally narrowed; one patient had bilateral vertebral artery injuries; and one patient had nonvisualization of the left common carotid and left vertebral arteries. In all 37 control subjects, both vertebral arteries were identified on MR angiograms. A significant difference in the frequency of vertebral artery nonvisualization (occlusion) was found between the trauma and control populations. The patient with bilateral vertebral artery injuries died 2 days after hospital admission of a massive infarction of the right cerebellar hemisphere. The other eight patients with vertebral artery injuries, and the remaining 28 patients with normal findings on MR angiograms, had no intracranial neurologic deficits that could be ascribed to a major arterial injury. CONCLUSION: In our experience, vertebral artery injuries due to major cervical spine trauma as determined by MR angiography are common. Although these vascular abnormalities usually remain clinically occult, a small percentage of patients may suffer devastating neurologic complications of posterior fossa infarction. Noninvasive assessment of the vertebral arteries by means of MR imaging should be an integral part of the evaluation of the acutely injured cervical spine. PMID- 7839987 TI - Gradient-echo MR imaging of the temporomandibular joint: diagnostic pitfall caused by the superficial temporal artery. AB - OBJECTIVE: In routine MR imaging of the temporomandibular joints, a low-signal structure posterosuperior to the mandibular condyle is occasionally seen on the two-dimensional gradient-echo sequence. The structure is ovoid and may have a higher-signal core, simulating a loose body within the joint. We undertook a clinical and cadaveric study to determine the cause of this finding. MATERIALS AND METHODS: In a clinical study, we reviewed the MR images of 100 temporomandibular joints. We scored each joint for the presence and appearance of a low-signal structure posterosuperior to the mandibular condyle: type 1 was ovoid with a low-signal rim and a higher-signal core, type 2 was ovoid with uniformly low signal, type 3 was a low-signal structure inseparable from the posterior wall of the glenoid fossa, and type 4 was normal. Using this scoring system, we determined the appearance and frequency of the finding on two dimensional gradient-echo, T1-, T2-, and proton density-weighted images. To determine the cause of the finding, we correlated the imaging and anatomic findings in a cadaveric specimen. RESULTS: Of the 100 MR images of joints reviewed, 22 showed a type 1 structure, 24 a type 2 structure, 11 a type 3 structure, and 43 were normal. The finding was seen only on the two-dimensional gradient-echo sequences, never on the spin-echo sequences. Correlation between the imaging and anatomic findings in the cadaveric specimen showed that the finding was caused by the superficial temporal artery. The variability in its appearance is thought to result from the complex manifestations of flowing blood within this artery. CONCLUSION: The finding posterosuperior to the mandibular condyle seen on two-dimensional gradient-echo MR images is a flow phenomenon within the superficial temporal artery. Recognition of the nature of this finding will avoid mistaking it for disease, such as an intraarticular loose body. PMID- 7839988 TI - Percutaneous aspiration thrombectomy of an acutely occluded aortorenal bypass graft. PMID- 7839989 TI - Percutaneous placement of a central venous access device via an intercostal vein. PMID- 7839990 TI - Computer-aided instruction in radiology: opportunities for more effective learning. AB - Little doubt remains that computers will play an important part in the future of education. What should be of special concern to radiologists, however, is the unique way that computer-aided instruction differs from printed text and its potential for facilitating education in medical imaging. Adapting to this media will require a mental shift on the part of educators as well as students. As the sophistication of the student increases, attention will shift from the novel presentational power of the computer to the opportunities that computers offer to expedite learning and to evaluate the extent to which knowledge is mastered. PMID- 7839991 TI - The Internet, World-Wide Web, and Mosaic: an overview. AB - Technology is revolutionizing education. Global networks, powerful personal computers, and user friendly, graphically oriented software are creating a new infrastructure that promotes rapid, efficient access to information. Images, text, audio, and video can be integrated into interactive multimedia presentations, providing a hierarchy of knowledge that can be traversed by the click of a mouse. The extensive use of images in our arena makes radiologic education a major beneficiary. Because the components (text, images) of educational presentations are stored electronically on a network rather than on the printed page, an individual component can be linked and bundled into as many different presentations as desired. Furthermore, components of information can exist on different computers throughout the world and yet be linked by software into a single presentation. PMID- 7839992 TI - Distributing an electronic thoracic imaging teaching file using the Internet, Mosaic, and personal computers. AB - A high quality film-based teaching file requires effort and expense to create and maintain. The effort is worthwhile because film collections are important vehicles for increasing a radiologist's personal data base of clinical experience. Expert clinical reasoning is to a large extent the process of comparing a current case to a data base of individual cases available in memory. A teaching file would be most helpful if it were available at the view box where it could be used to extend a radiologist's clinical experience. Unfortunately, a film-based file is confined to one area, usually remote from the view box. In addition, searching though a film file is difficult, the films wear out over time, and films are easily lost or stolen. Our goal is the creation of a thoracic imaging teaching file that solves these problems by providing a digital collection of images, videos, and text that can be used in the work place by many users simultaneously. The first part of this teaching file is now continuously available locally within our department and globally to users of the Internet. PMID- 7839993 TI - A World-Wide Web radiology teaching file server on the Internet. AB - OBJECTIVE: Radiology departments have traditionally used film-based collections of interesting cases for teaching purposes. Film-based files are expensive to create and duplicate, and they physically occupy considerable space. As one solution to these problems, our department created an on-line radiology teaching file in digital format. MATERIALS AND METHODS: Our teaching file resides on a Macintosh Quadra 700 computer that is connected to the Internet, a worldwide network of interconnected computers, via our campus Ethernet network. Our digital teaching file images and text are composed in HyperText Markup Language (HTML) and are made available to the world with Webserver software known as MacHTTP. These teaching files are accessed using World-Wide Web (WWW) client software such as Mosaic, MacWeb, or Netscape. RESULTS: Our digital teaching file is available at no charge to anyone in the world with access to the Internet and WWW client software. Our radiology residents can access this file via several workstations in our department. Mosaic is an easy-to-use interface, and the use of our digital teaching file has increased significantly. In the 3 months since its creation, our teaching file has been accessed not only by our radiology residents but also by hundreds of other users in 33 countries. CONCLUSION: Use of Mosaic and the WWW format has resulted in an easy-to-use hypertext interface to the Internet, which allows even persons with little computer experience to navigate through the Internet, read text files, view images (stills and movies), and download files by merely pointing with the mouse and clicking on items of interest. This has allowed us to maintain a central teaching file that is physically small and easy to share with all the hospitals in our system. We invite the worldwide radiology community to access these files and to submit cases from their own teaching files to share with the rest of the world. PMID- 7839994 TI - Hand-held digital books in radiology: convenient access to information. AB - Radiologists need constant, convenient access to current information throughout the course of their daily work. Today most learning in radiology is obtained from the printed word in books, journals, and teaching files, supplemented by the spoken word in lectures and conferences. Although learning from printed material and lectures has been proved efficacious over time, these media share the disadvantage of not being conveniently available for reference during the course of daily work at the alternator or in the examination room when accurate and up to-date information is needed the most. As a result, many important questions about patient care go unanswered. We have developed a technique--hand-held digital books--to lower this barrier to searching and retrieval. When radiologists have a digital library that can be carried with them, they will be able to incorporate current radiology information into their daily decision making. We describe a technique for creating hand-held digital books and their future use in radiology. PMID- 7839995 TI - The digital manuscript for peer review and publication: how close are we? PMID- 7839996 TI - Informed consent forms for clinical and research imaging procedures: how much do patients understand? AB - OBJECTIVE: Informed consent is often obtained in diagnostic radiology, especially for invasive procedures and research studies. However, how much the average patient actually understands of the information contained in these informed consent forms is uncertain. A cross section of the clinical and research consent forms used in diagnostic radiology was evaluated with respect to their readability, that is, how easy or difficult they were to understand. MATERIALS AND METHODS: The active members of the Association of University Radiologists were solicited to provide copies of their clinical and research informed consent forms. After eliminating duplicates, we digitized the forms and used a computer program to evaluate their readability. Computer readability assessment allows the rapid study of an entire document by a variety of readability formulas (Flesch Kincaid, Flesch, and Fog). RESULTS: We received 549 different consent forms from 156 institutions; 265 forms were intended primarily for clinical use and 284 were used primarily for research. Although the clinical consent forms were only 41% as long as those for research, a statistical comparison showed them to be harder to understand (p < 0.005). The mean readability score (years of education needed to understand) for all 265 clinical consent forms was 15 versus 12 for the research forms. The most complex clinical consent forms were those written by hospitals for any type of procedure or operation (the generic surgical or procedure consent form). On average, this type of clinical consent form required at least a college education to understand. CONCLUSION: Our results show that most consent forms used in radiology practice are too complex for the average patient to understand. The increased complexity of clinical consent forms, especially the generic surgical or procedure consent forms, as compared with research consent forms, is probably a product of the decreased attention given to the clinical consent forms, the bureaucratic and legal requirements of the clinical forms, and the lack of physician participation in preparing these forms. PMID- 7839997 TI - American martyrs to radiology. Elizabeth Fleischman Ascheim (1859-1905). 1936. PMID- 7839998 TI - The evolution of the X-ray report. PMID- 7839999 TI - Is there any role for gadopentetate dimeglumine administration when searching for mesial temporal sclerosis in patients with seizures? PMID- 7840000 TI - What is the significance of pleural tags? PMID- 7840001 TI - How can I distinguish between metastases and pulsation artifacts in contrast enhanced scans of the posterior fossa. PMID- 7840002 TI - What is the optimal time to scan patients for residual brain tumor status postcraniotomy? PMID- 7840003 TI - What is the significance of finding calcifications in pulmonary masses on CT scans? PMID- 7840004 TI - Health care reform. PMID- 7840005 TI - Helical versus spiral CT. PMID- 7840006 TI - Corticosteroid pretreatment and nonionic contrast media. PMID- 7840007 TI - Effect of varying kVp on visibility of epicardial fat stripe in pericardial effusions. PMID- 7840008 TI - Pleural effusions, diaphragm inversion, and paradox: new observations using sonography. PMID- 7840009 TI - Cause of an opaque azygos lobe on frontal chest radiographs. PMID- 7840010 TI - Leiomyoma of the male areola infiltrating the breast tissue. PMID- 7840011 TI - Oral contrast material for fluoroscopic diagnosis of esophageal rupture. PMID- 7840012 TI - Hypervascular hepatic metastases: reevaluation of unenhanced CT scans. PMID- 7840013 TI - Choledochal cyst detected by MR cholangiopancreatography. PMID- 7840014 TI - Visualization of the portal vein via the vertebral venous plexus in a patient without vena cava obstruction. PMID- 7840015 TI - Visualization of ureter on excretory urograms. PMID- 7840016 TI - Treatment of retroperitoneal fibrosis with tamoxifen. PMID- 7840018 TI - Extension tubing set for percutaneous fluid drainage: improvements in design. PMID- 7840017 TI - Assessing renal function in children prior to administration of contrast material. PMID- 7840019 TI - Otorhinolaryngological aspects of HIV infections: personal experience. AB - The involvement of the ENT sphere in HIV infections is fairly common, but the relative manifestations, though not to be considered atypical, are not pathognomonic. The present study has been set up for the otoiatric assessment of a group of HIV patients and the correlation of ENT symptoms with the various stages of the disease. To this end, 60 patients were examined (35 belonged to groups 2-3 and 25 to group 4) of whom 50% were drug addicts, 36% homosexuals and 14% heterosexuals. All patients underwent a complete ENT examination as well as the assessment of hearing and vestibular function, of olfactory and taste functions, of respiratory and nasal mucociliary functions along with an anti-HIV antibody check of nasal secretion. Results showed a prevalence of otologic and rhinosinusal symptoms as well as cervical-facial swelling. Testing revealed a hearing loss of mainly conductive origin caused by otitis and tubal stenosis; vestibular hyporeflexia; mixed hyposmia and hypogeusia owing to the involvement of multiple cranial nerves; respiratory and mucociliary changes due to rhinitis and hypertrophy of the nasal mucosa. In all cases anti-HIV antibodies were found in nasal secretion. From a diagnostic point of view there was a prevalence of specific pathologies: oropharyngeal candidosis, stage 4; cervical lymphoadenopathy, stages 2-3; chronic rhinosinusitis, nasal vestibulitis and nosebleed; mainly chronic otitis media. All such manifestations suggest a marked involvement of ENT organs, which can be attributed to the anatomical characteristics of the area, with the relative diagnostic and prognostic implications of HIV infection. PMID- 7840020 TI - Complement mediated solubilization: role of the complement in the clearance of circulating immune-complexes. AB - In 1975, Miller and Nussenzweig described a new function of the Complement (C'): the Capacity of this substance to solubilize "in vitro" antigen/antibody complexes previously formed. Subsequent studies of these authors and other researches (particularly Takahashi and his group) demonstrated that this process is mediated by activation of the alternative way of C', although it is faster when the classic way is involved. Basically, thanks to the Takahashi and group studies, it has been possible to know in detail the intimate mechanism of this phenomenon, usually known demonstrated that the key of all this process lies in the generation, through the C' alternative way, of numerous molecules of C3b that deposit over the antigen/antibody complexes (Ag/Ac), causing the breakage of the necessary mesh for such complexes to precipitate, which leads to formation of small immunocomplexes (IC) very rich in C3b which turn soluble again. ICs solubilized in this way suffer important physicochemical and biological changes, and transform into substances without inflammatory power that are not able to activate C' nor to interact with C3b receptors present in a great number of blood cells. However, they are captured by Kupffer cells in the hepatic sinusoids and quickly catabolized. CMS is closely related with another similar phenomenon, the Immuno-Precipitation inhibition (IPI), described by Schiferli and his group in the early 80's.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7840021 TI - Increased chemotactic responses of neutrophils in intrinsic and mixed asthmatic patients. AB - Neutrophils are thought to contribute actively in the pathogenesis of asthma since they infiltrate into the lung tissue. The aim of this study is to compare the chemotactic responses of neutrophil granulocytes from 10 intrinsic, 13 extrinsic and 10 mixed type asthmatic patients with each other and chemotactic response of neutrophil granulocytes from 26 healthy individuals. All patients were free of infection and not receiving systemic corticosteroids. Significant differences were not found in random migration between all of the groups. However, chemotactic activity with zymosan activated serum was significantly elevated in intrinsic and mixed asthmatic patients (p < 0.001). In conclusion, the present investigation demonstrated increased chemotactic responses of neutrophils from asthmatic patients except extrinsic type. PMID- 7840023 TI - [Inhaled and systemic corticosteroids in the treatment of asthma]. PMID- 7840024 TI - [Cetirizine: its activity against pulmonary eosinophilia]. PMID- 7840022 TI - Immunologic evaluation of 24 month course of sublingual immunotherapy. AB - 58 patients under 12 years of age, positive to mites (Dermatophagoides pteronyssinus and D. farinae) according to prick, in vitro specific IgE and challenge tests, suffering from asthma and rhinitis, have been randomly assigned on a double blind basis to receive per os either a biologically standardized extract of mites (active therapy TA = 30 patients) or a saline buffered solution (placebo TP = 28 patients). The serologic results are interesting. The specific IgE level differences of significance are, in comparison with the placebo group. In particular, we did observe the increase of the specific IgE level in the placebo group during the autumn, whereas after 12 months and after 24 months of active treatment there was a clear (p < 0.01) decline in serum specific IgE antibody. In the active group, there was a significant increase in IgG antibodies level after 12 and 24 months and a significant increase in IgG4 level after 24 months. In the placebo group, the level of IgG antibodies was unchanged. In the actively treated patients, a significant increase of CD8+ values and a significant reduction of the ratio CD4+/CD8+ was observed. PMID- 7840025 TI - Clinical and immunological effects of immunotherapy with glutaraldehyde modified house dust mite extract. AB - The aim of this study was to demonstrate the clinical effectiveness of treatment with specific immunotherapy using allergenic mite extracts modified with glutaraldehyde. The results showed an improvement both in clinical symptoms and a reduction in the complementary pharmacological therapy used. Several clinical "in vitro" and "in vivo" parameters were analysed during this study. The results obtained from the Nasal Challenge Test and the Skin Test (prick-test) were the most relevant. Patient tolerance to the diagnostic extract was increased in 45% of the patients, the result of which was registered in the Nasal Challenge Test. Evaluation of the results derived from the skin tests on conclusion of immunotherapy, showed a reduction in response in 55% of the patients. Progressive immunotherapeutic doses were applied at short intervals with no record of severe reactions. PMID- 7840027 TI - The Bethesda system and Pap smear screening. PMID- 7840026 TI - [Incidence of adverse reactions to additives. Our experience over 10 years]. AB - No published information exists about the incidence of food additives reactions in the general population. Most studies have been made in patients with urticaria and bronchial asthma. The majority of them lack an adequate design and, therefore, the reported results should be interpreted with extreme caution. In this article, we expose our ten years experience in this field. We have added up 1941 oral provocation tests, with an ample battery of additives, administering the tested substances directly or in aqueous or acid solution (1110 in patients with urticaria, mainly chronic urticaria, and 831 in asthmatic subjects, with or without aspirin intolerance). From these exhaustive data, we get the following conclusions: 1) in contrast with other-investigators, and using similar or even higher provocation doses, we get a very low incidence of adverse reactions. 2) We are sceptical that food additives play any role in chronic urticaria or in other cutaneous processes (only 0.63% provocation tests resulted in an urticarial exacerbation, and none of them was repeated after re-provocation). 3) In asthmatic patients, similar results were obtained, except with sulfites in acid solution challenge test (10% asthmatic exacerbations), possibly as a sign of nonspecific bronchial hyperreactivity. 4) The prescription of food additives free restrictive diets does not seem to be justified. The should be followed only by those patients with clear evidence of additives reactions. 5) In most cases, with punctual exceptions, the study of food additives reactions, in clinical allergy, implies a waste of time. PMID- 7840028 TI - What you need to know about childhood sexual abuse. PMID- 7840029 TI - AHCPR guideline on acute low back problems. PMID- 7840030 TI - Authors and conflict of interest. PMID- 7840031 TI - Pulse oximetry to determine severity of bronchiolitis. PMID- 7840032 TI - Diagnosing scapholunate dissociation. PMID- 7840033 TI - Anaphylactic syndromes associated with heat emergencies. PMID- 7840034 TI - Oral ketorolac: simply an ordinary NSAID. PMID- 7840035 TI - Common neurologic complications of HIV-1 infection and AIDS. AB - Complications of human immunodeficiency virus type 1 infection and acquired immunodeficiency syndrome may involve any level of the central or peripheral nervous system. Acute encephalitis, aseptic meningitis and acute demyelinating polyneuropathy may occur early in the course of HIV infection, while dementia, central nervous system-related cancer, opportunistic infections and autonomic neuropathy typically present later. Headache and mental status changes are common early manifestations of central nervous system involvement. Most severe headaches are related to an identifiable cause, including a mass lesion, opportunistic cerebral infection and medication side effect. Memory deficits, concentration difficulties and abnormalities on mental status testing may represent early AIDS dementia complex (HIV encephalopathy), the most common neurologic complication. In patients with AIDs, the differential diagnosis of cerebral mass lesions on computed tomography or magnetic resonance imaging includes cerebral toxoplasmosis, tuberculous or fungal abscess, focal viral encephalitis, metastatic resonance imaging includes cerebral toxoplasmosis, tuberculous or fungal abscess, focal viral encephalitis, metastatic Kaposi's sarcoma and primary CNS lymphoma. Peripheral neuromuscular disease, including distal symmetric polyneuropathy, autonomic neuropathy, and HIV and chronic zidovudine myopathy, affects 15 to 40 percent of all persons with HIV infection or AIDS. PMID- 7840036 TI - St. Anthony's Fire: diagnosis and management of erysipelas. AB - Erysipelas, a beta-hemolytic streptococcal infection of the skin and subcutaneous tissue, was once a common disease but nearly disappeared after the advent of antibiotics. In the past few years, however, the incidence of erysipelas has been increasing. At particular risk for infection are young patients, elderly patients and immunocompromised patients. The diagnosis is confirmed by the typical appearance of erythema and fever, constitutional symptoms and laboratory findings indicative of streptococcal infection. Penicillin and close follow-up can prevent significant morbidity and possible mortality. The prognosis for patients with erysipelas is excellent. PMID- 7840037 TI - Childhood sexual abuse: role of the family physician. AB - Sexual abuse of children is widespread and occurs in all demographic groups. Studies suggest that approximately one in three young girls and one in six young boys may experience at least one sexually abusive episode by the time they reach adulthood. Children are not yet equipped to make an informed decision about sex and, if sexually abused, may have severe and long-lasting psychologic consequences. Family physicians have an ethical and legal responsibility to report suspected child sexual abuse. In order to do so effectively, physicians must understand the problem and recognize the signs and symptoms. Physicians should also become familiar with available resources, which can provide them with guidelines and assistance. PMID- 7840038 TI - The clinical uses of dietary fiber. AB - Dietary fiber has received considerable attention in both the popular press and the scientific literature. Fiber is a complex mixture of substances, and research on its effects is difficult to interpret. Dietary fiber has significant gastrointestinal effects, and it is a mainstay of treatment for constipation and hemorrhoids. Insoluble fiber, such as wheat bran, is most effective for treatment of these conditions. Increased intake of soluble dietary fiber appears to benefit patients with diabetes mellitus and hyperlipidemia. High-fiber, low-fat diets have been recommended by a variety of authorities to decrease the incidence of heart disease and certain types of cancer. Any increase in dietary fiber intake should be accompanied by an increase in water intake. PMID- 7840039 TI - Safety counseling in children and adolescents. U.S. Public Health Service. PMID- 7840040 TI - Preventing cervical cancer: the role of the Bethesda system. AB - The Papanicolaou smear is a well-established component of preventive health protocols for women. The purpose of this screening tool is to detect precursor lesions of invasive cervical carcinoma; however, the natural progression of these lesions is unclear, and it currently is not possible to determine which of the many dysplastic findings have carcinogenic potential. Furthermore, disagreement exists concerning the time frame for the malignant transformation of dysplastic cervical lesions. Despite these concerns, cervical screening has been credited with reducing morbidity and mortality from invasive cervical carcinoma in certain populations, and almost all family physicians provide this service to their female patients. The Bethesda system of cytopathologic reporting (introduced in 1988 and revised in 1991) is designed to improve communication between pathologists and clinicians. Compared with other taxonomies, the Bethesda system allows for distinction between changes associated with inflammation and infection and those reflecting squamous cell atypia and dysplasia. PMID- 7840041 TI - Smokable methamphetamine ('ice'): an old drug in a different form. AB - Methamphetamine has long been a drug of abuse. The smokable form of methamphetamine hydrochloride, called "ice" on the street, is twice as toxic as amphetamine and has clinical effects similar to those of cocaine. In the United States, methamphetamine use has spread eastward from Hawaii and California. Ice is a strong central nervous system stimulant. Chronic use may result in serious psychiatric, cardiovascular, metabolic and neuromuscular changes. Generally, patients presenting with methamphetamine toxicity can be treated conservatively in the emergency department. Long-term treatment usually requires drug rehabilitation and inpatient counseling. PMID- 7840042 TI - Radiographic aspects of pneumothorax. AB - Pneumothorax is a common medical problem of varied etiology. Because pneumothorax has potentially severe acute consequences, it is important that all physicians know its radiographic appearance. Patient complaints are nonspecific, and physical examination findings are often subtle. The chest radiograph is the principal means of detecting and following a pneumothorax. Radiographic diagnosis on an upright film requires the detection of the visceral pleural line. For radiographs obtained with the patient in the supine position, pneumothorax may be manifested by increased lucency over the upper quadrant of the abdomen, an unusually sharp definition of the anterior diaphragmatic surface or a very wide and deep costophrenic angle. PMID- 7840043 TI - Acute low back problems in adults: assessment and treatment. Acute Low Back Problems Guideline Panel. Agency for Health Care Policy and Research. PMID- 7840044 TI - Hirschsprung's disease: a cause of chronic constipation in children. AB - Constipation is common in neonates and children. Most constipation is benign and easily treated. Hirschsprung's disease is an unusual, but well-recognized cause of chronic constipation. An example of the group of disorders known as dysganglionoses, Hirschsprung's disease is characterized by an absence of the intramural ganglionic cells at the submucosal and myenteric levels of the intestine. The course of the disease is variable, with five distinct patterns of varying severity. Without treatment, mortality approaches 50 percent by one year of age, but early diagnosis and intervention are associated with a favorable outcome. The treatment is surgical, and several approaches are currently used. PMID- 7840045 TI - ACOG issues report on hormonal contraception. PMID- 7840046 TI - Nursing ethics in a health reform environment: values at stake. PMID- 7840047 TI - Vietnam: an ethical morass. Between innocence and arrogance: a place in Vietnam. PMID- 7840048 TI - Prostacyclin: basic principles and clinical application in congestive heart failure and primary pulmonary hypertension. Proceedings of a symposium. Bologna, Italy, November 20, 1993. PMID- 7840049 TI - Pathophysiologic aspects of end-stage heart failure. AB - Heart failure is not a distinct disease, but rather a complex clinical syndrome that can result from virtually any form of heart disease. The so-called "end stages" of heart failure do not respect etiologic boundaries. Patients are characterized clinically by extreme cardiomegaly, breathlessness, and fluid retention. Despite recent advances in the pharmacologic management of congestive heart failure, it remains a highly lethal and disabling disorder. Only through an improved understanding of the basic biology of the early stages of the syndrome can heart failure be prevented or at least forestalled. There is now intense interest in understanding the mechanisms operative in early left ventricular remodeling, which has the potential to culminate in end-stage heart failure. The study of animal models has been particularly useful in this regard, as have clinical studies performed in the early stages of acute myocardial infarction. The remodeling process is characterized by myocyte loss and segmental scarring, interstitial fibrosis, myocardial slippage, and myocyte hypertrophy. Although the mechanisms responsible for these topographic changes are as yet unclear, the net result is progressive enlargement of the heart, culminating in severe left ventricular dysfunction. A long-held view that cardiomegaly is a necessary adaptive process that maintains stroke volume in the presence of a falling ejection fraction has been challenged, although undoubtedly the early responses to myocardial injury in the form of myocyte hypertrophy and maintenance of wall stress are useful adaptations. However, as the left ventricle continues to dilate and hypertrophy over time, a form of overadjustment occurs that perhaps is an important contributory factor toward end-stage failure. PMID- 7840050 TI - The hibernating myocardium: implications for management of congestive heart failure. AB - Left ventricular (LV) function is one of the most important determinants of long term outcome in patients with coronary artery disease (CAD). Patients with normal or near-normal LV function have an excellent prognosis, whereas patients with impaired LV function are at substantial risk of death during medical therapy. It is now apparent that LV dysfunction is not always an irreversible process and that LV function may improve considerably, and even normalize, after myocardial revascularization in a large subset of patients. The identification of such patients with "hibernating" myocardium that is underperfused and dysfunctional, yet viable, has important implications in the selection of patients with LV dysfunction for revascularization procedures. Both nuclear cardiology techniques and 2-D echocardiography can be used for this purpose. The radionuclide techniques include positron emission tomography to assess blood flow and metabolism (using agents such as [18F]fluorodeoxyglucose) and thallium-201 (and possibly technetium-99m sestamibi) to assess blood flow and cell membrane integrity. Alternatively, echocardiographic imaging during low-dose infusions of dobutamine can be used to assess inotropic reserve. The data available to date suggest that patients with CAD in whom hibernating myocardium is largely the cause of impaired LV function constitute a subgroup of patients who may achieve a substantial improvement in LV function and in outcome if identified and treated with revascularization. PMID- 7840051 TI - Acute hemodynamic effects of the prostacyclin analog 15AU81 in severe congestive heart failure. AB - This multicenter, open-label study provides the first assessment of the safety and acute hemodynamic effects of a short-term infusion of 15AU81, a chemically stable analog of prostacyclin, in patients with New York Heart Association class III or IV heart failure. Twelve patients underwent sequential dose escalation by increasing the rate of the infusion at 15-minute intervals until the drug was no longer tolerated. Patients then received a 90-minute infusion at their maximum tolerated dose. The infusion was then discontinued and the subjects were observed during a 90-minute washout segment. Serial hemodynamic measurements were made throughout the dose-ranging, maintenance, and washout segments. A significant decrease in systemic vascular resistance (1,935 +/- 774 vs 1,243 +/- 351 dynes.s.cm-5; p < 0.001) and pulmonary vascular resistance (395 +/- 335 vs 223 +/ 198 dynes.s.cm-5; p = 0.008) occurred from the infusion of vehicle to the maximum tolerated dose. During dose titration, there was a a significant increase in cardiac index (1.9 +/- 0.7 vs 2.6 +/- 0.6 liters/min/m2; p < 0.001) and a tendency for a mild reduction in pulmonary artery wedge pressure (18 +/- 7 vs 17 +/- 6; p = 0.055) for the 8 patients with values on vehicle and maximum tolerated dose. These hemodynamic changes persisted during the maintenance infusion and disappeared rapidly during the washout segment. The most common adverse event to limit dose-ranging was headache, which occurred at a mean maximum tolerated dose of 36 +/- 15 ng/kg/min. Administration of 15AU81 was associated with significant acute hemodynamic improvement in patients with severe heart failure.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7840052 TI - Pharmacodynamic profile of prostacyclin. AB - Since the 1930s and the discovery by von Euler of a vasoactive, lipid-soluble substance that he erroneously assumed was generated by the prostate gland and therefore should be called "prostaglandin," the family of prostaglandins has grown to some 90 substances. These lipid mediators are derived from arachidonic acid in the "arachidonic acid cascade." In 1976, while looking for the enzyme that generates the unstable prostanoid thromboxane A2 from arachidonic acid, Moncada and Vane discovered prostaglandin I2 and renamed it "prostacyclin." Prostacyclin is the main product of arachidonic acid in all vascular tissues tested to date and strongly vasodilates all vascular beds studied. It is also the most potent endogenous inhibitor of platelet aggregation yet discovered, both inhibiting aggregation and dispersing existing aggregates. It acts through activation of adenylate cyclase, leading to increased levels of cyclic adenosine monophosphate. It also appears to have a "cytoprotective" activity, as yet not completely understood. Its effects are short-lasting, disappearing within 30 minutes of cessation of infusion. A stable, freeze-dried preparation of prostacyclin (epoprostenol) is available for administration to humans, and several analogs with therapeutically desirable characteristics are currently being clinically tested and should become commercially available soon. Clinical application of prostacyclin is bedeviled by 2 characteristics: it is pharmacologically unstable, so care must be taken in its use, and the correct dosage regimens have not yet been established. PMID- 7840053 TI - Safety and efficacy of epoprostenol in patients with severe congestive heart failure. Epoprostenol Multicenter Research Group. AB - Patients with advanced heart failure often remain severely symptomatic and have a high mortality rate despite currently available therapy. We studied the safety and efficacy of a new approach to the patient with refractory heart failure: continuous intravenous treatment via a portable infusion pump with epoprostenol (prostacyclin), a potent pulmonary and systemic vasodilator. A group of 33 patients with severe heart failure (64% New York Heart Association class IV and 36% class III) and profound ventricular dysfunction (median left ventricular ejection fraction, 0.15)--despite prior treatment with diuretics (100%), digitalis (91%), angiotensin-converting enzyme inhibitors (85%), and dobutamine (30%)--underwent a baseline 6-minute walk test prior to dose titration with epoprostenol during invasive hemodynamic monitoring. Subjects responding during the dose titration were randomized, on an open basis, to receive either continuous epoprostenol infusion via an indwelling central venous catheter plus conventional therapy or conventional therapy alone for 12 weeks. The initial dose ranging study with epoprostenol produced a significant decline in systemic and pulmonary vascular resistance and a substantial increase in cardiac index despite a fall in pulmonary capillary wedge pressure. Symptoms related to vasodilation were noted within the first week after randomization to epoprostenol in 9 of 16 patients but resolved with adjustment of the infusion and concomitant medications in all but one subject. Dose adjustments during the chronic epoprostenol infusion were infrequent after the first week and complications related to the drug delivery system were rare. The change in distance walked from baseline to the last available 6-minute walk test was significantly greater in patients who received epoprostenol compared with patients assigned to standard therapy (72 +/- 40 vs -39 +/- 32 m, mean +/- SEM; p = 0.033). Our study suggests that long-term intravenous infusion of epoprostenol is feasible in patients with severe heart failure and our hemodynamic and functional results suggest clinical benefit as well. However, until recent results indicating an adverse effect of epoprostenol on survival are fully evaluated, the role of this drug in the treatment of advanced heart failure will remain uncertain. PMID- 7840054 TI - Is there a role for epoprostenol in the management of heart failure? AB - Prostacyclin (PGI2, epoprostenol), a pulmonary and systemic vasodilating agent, has recently undergone long-term intravenous administration trials in patients with severe congestive heart failure. As in many other agents that have beneficial acute hemodynamic profiles, its effects on mortality have been disappointing. However, the drug continues to have a role in the short-term management of patients with decompensated heart failure because of its short half life, lack of medium-term toxicity compared to sodium nitroprusside, and lesser tendency toward development of tolerance than intravenous nitrates. There may also be therapeutic effects other than its influence on central hemodynamics; in particular, inhibition of platelet aggregation and thrombus formation in small vessels may be of value in the long-term management of patients with primary pulmonary hypertension. It is possible that, like other agents such as vesnarinone (OPC-8212), achieving beneficial long-term effects may require identification of an ideal dose range. The most effective therapeutic doses in long-term administration may not correlate with the most effective doses during short-term hemodynamic studies. PMID- 7840055 TI - Pathology and pathophysiology of primary pulmonary hypertension. AB - Primary pulmonary hypertension (PPH) is at present little understood. It is characterized by extensive remodeling of the pulmonary vasculature, with consequent deleterious hypertrophic changes in the right ventricle. Median survival is 2.6 years, although this varies with the severity of right heart failure. Although PPH can occur at any age and in either sex, it primarily affects young to middle-aged women. A genetic predisposition appears to be a component of this disease, triggered by presentation of a stimulus (e.g., drugs or HIV infection). Symptomatic presentation includes exertional dyspnea, chest pain, and syncope. At present, therapy consists principally of anticoagulation, calcium antagonists, nitric oxide inhalation, or continuous intravenous prostacyclin. PMID- 7840056 TI - Role of pharmacologic tests in the treatment of primary pulmonary hypertension. AB - Primary pulmonary hypertension (PPH) is a rare disease of unknown etiology characterized by a constant progression toward right ventricular failure and death. Vasoconstriction is 1 of the pathophysiologic factors responsible for the increase of pulmonary vascular resistance (PVR) and pulmonary artery pressure (PAP) in patients with PPH. Thus vasodilator treatment is considered 1 of the logical approaches to medical therapy of such a condition. Acute drug challenge with a short-acting, titratable vasodilator during heart catheterization is recommended to select patients who are most likely to respond to long-term treatment. Accurate methodologic guidelines need to be followed to minimize the spontaneous variability of PAP and pulmonary arteriolar resistance. Pathophysiologic interpretation of pharmacologic trials requires analysis of the 2 components of the right ventricular hydraulic load, i.e., resistance and compliance of the pulmonary vascular bed. Reduction of the calculated PVR may be considered as a demonstration of pulmonary vasodilation only if PVR is assessed using the critical opening pressure or if it is associated with a simultaneous reduction of PAP. Only those patients in whom a reduction of PVR of > or = 20% is associated with a decrease in PAP of > or = 20% should be considered as "responders" to the acute tests. In clinical studies only 20-30% of the patients are short-term responders. The most intensively studied short-acting drug for short-term challenge is prostacyclin, but other agents such as acetylcholine, adenosine, and nitric oxide have been utilized. Prostacyclin has been shown to predict pulmonary vasodilator response to the administration of long-acting vasodilators, such as calcium channel antagonists.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7840057 TI - Medical treatment of primary pulmonary hypertension: a bridge to transplantation? AB - Primary pulmonary hypertension is a progressive disease with a mean survival of < 3 years from the time of diagnosis. Recent advances in the medical management have shown that some patients may have an extremely good outcome depending on the response to high doses of calcium antagonists. Anticoagulants are also associated with improved survival, and prostacyclin is showing great promise in patients who are refractory to conventional therapy. At the same time, lung transplantation has developed into a viable treatment option for patients who remain symptomatic and deteriorate on medical management. The role of the various medical treatment modalities, and the ideal timing of lung transplantation, is an issue that is continuing to evolve as improvements in all treatments develop. The cost and availability of the various treatments will likely affect the selection of treatments in individual patients as well. PMID- 7840058 TI - Role of prostacyclin in the treatment of primary pulmonary hypertension. AB - Over the last decade, new medical and surgical treatments have become available for primary pulmonary hypertension that have influenced the natural history of the disease. Vasodilator therapy is aimed at overcoming pulmonary vasoconstriction with consequent decrease in afterload and improved right ventricular output. The endpoint of vasodilator therapy is therefore to reduce pulmonary vascular resistance, without causing significant systemic hypotension. Prostacyclin, a potent vasodilator and antiaggregating agent, has been successfully used by continuous infusion in the treatment of severe pulmonary hypertension. The marked improvement in quality of life observed with the use of prostacyclin in these patients, as well as the increased survival time on the waiting list for transplantation, has influenced us to adopt prostacyclin infusion as a fundamental element of our therapeutic strategy for the management of this rare but fatal condition. PMID- 7840059 TI - New global perspectives on overcoming malnutrition. PMID- 7840060 TI - The role and identity of physician nutrition specialists in medical school affiliated hospitals. Committee on Clinical Practice Issues in Health and Disease. AB - This document was prepared by the Committee on Clinical Practice Issues in Health and Disease of The American Society for Clinical Nutrition (ASCN). The committee recommends that each major medical center has at least one physician nutrition specialist (PNS) who will be a regional resource for complex nutrition cases and will have a leadership role in the provision of coordinated nutrition services. The PNS will be responsible for nutrition education programs in associated schools of medicine and will be a role model for aspiring physicians. Typically, these individuals will have thorough training in human nutrition research. The PNS should be supported by a unique combination of resources including clinical earnings, teaching hospital and school of medicine salaries, state and federal funds, as well as private sector support. The ASCN should take a leadership role in developing the national identity of the PNS and in achieving recognition of board certification in nutrition. PMID- 7840061 TI - Bivariate normal values of the bioelectrical impedance vector in adult and elderly populations. PMID- 7840062 TI - The dietary recommendations of the American Academy of Pediatrics. PMID- 7840063 TI - Measurement of abdominal and visceral fat with computed tomography and dual energy x-ray absorptiometry. AB - These studies were undertaken to compare dual-energy x-ray absorptiometry (DXA) and computed tomography (CT) measurements of abdominal fat and to determine whether anthropometry could be combined with DXA to predict intraabdominal (visceral) fat mass in humans. Twenty-one volunteers underwent abdominal CT scans, DXA, and anthropometry. DXA- and CT-measured total abdominal fat were similar (8448 +/- 5005 and 8066 +/- 5354 mL, respectively; NS) and were highly correlated (r = 0.985, P < 0.001). The combination of anthropometry and DXA was a suboptimal predictor of CT-measured intraabdominal fat (r = 0.61, P < 0.05); however, the combination of a single CT slice (to assess the ratio of intraabdominal to total abdominal adipose tissue) and DXA-measured abdominal fat was an excellent predictor of CT-measured intraabdominal fat (r = 0.98, P < 0.001). We conclude that a single-slice CT scan (or other imaging technique) with or without DXA is required for accurate predictions of intraabdominal fat. PMID- 7840064 TI - Quantitative assessment of infant body fat by anthropometry and total-body electrical conductivity. AB - Measurement of total-body electrical conductivity (TOBEC) has emerged as a rapid, safe, and reproducible method for estimation of infant total body fat (TBF). Agreement of two anthropometric methods [by Dauncey et al (1977) and Weststrate et al (1989)] with TOBEC-TBF was assessed in 435 healthy infants aged 21-365 d. Dauncey-TBF correlated with TOBEC-TBF by r2 = 0.61 and exceeded TOBEC-TBF by 0.14 +/- 0.25 kg in infants < 4 mo of age. Thereafter, TOBEC-TBF exceeded Dauncey-TBF by 0.20 +/- 0.47 kg. We modified Dauncey's method, which significantly improved the correlation to r2 = 0.75. Weststrate-TBF correlated with TOBEC-TBF by r2 = 0.87, but exceeded TOBEC-TBF by 0.5 kg. Both methods showed poor agreement with TOBEC-TBF. We conclude that both methods, although suitable for comparison of TBF between groups, cannot be used to accurately assess TBF in an individual infant. PMID- 7840065 TI - Changes in adipose tissue volume and distribution during reproduction in Swedish women as assessed by magnetic resonance imaging. AB - Adipose tissue volume (ATV; total, subcutaneous, and nonsubcutaneous) was assessed by magnetic resonance imaging in the whole body and in six body compartments of 15 healthy Swedish women before pregnancy and 5-10 d, and 2, 6, and 12 mo postpartum. ATV increased by 5.43 +/- 4.72 L (mean +/- SD) during pregnancy and decreased by 3.18 +/- 4.61 L during the first 6 mo postpartum. The women had more ATV (2.86 +/- 2.32 L) 12 mo after delivery than before pregnancy. Of the ATV gained during pregnancy, 76% was placed subcutaneously and the decrease postpartum was due to a loss of subcutaneous ATV. During pregnancy, 68% of the increased ATV was placed in the trunk and 16% in the thighs. Postpartum fat was mobilized more completely from the thighs than from the trunk. For all variables studied variations between women were large. The results also show that women with a high weight gain during pregnancy retain lean tissue in their bodies. PMID- 7840066 TI - Resting metabolic rate and thermic effect of a meal in the follicular and luteal phases of the menstrual cycle in well-nourished Indian women. AB - The resting metabolic rate (RMR) and thermic effect of a standard test meal (TEM) were measured twice each during the follicular and luteal phases (confirmed by plasma concentrations of progesterone and estradiol) of a single menstrual cycle, and once during the follicular phase of the following menstrual cycle, by using indirect calorimetry, in 13 well-nourished Indian women. There was a significant increase in the TEM (P < 0.05) (6.72 +/- 1.57% vs 7.96 +/- 1.48% of the energy content of the test meal for follicular and luteal phases, respectively) of 18.5% during the luteal phase of the menstrual cycle but no significant difference in the RMR or postmeal total energy output (PMTEO). Dietary energy and macronutrient intakes in all subjects in both phases of the menstrual cycle were also similar. The RMR and the PMTEO were also similar when measured in the follicular phase of consecutive menstrual cycles. PMID- 7840067 TI - Energy balance in female distance runners. AB - Metabolic efficiency was assessed in ovulatory eumenorrheic female distance runners and untrained control subjects of similar age, body weight, and fat-free mass (FFM). Energy intake (EI) was estimated from 3-d dietary records. Energy expenditure (EE) was determined during the same 3-d period from individual heart rate oxygen uptake (HR/VO2) curves during rest and exercise, 24-h HR records, and the thermic effect of meals. The runners and control subjects did not differ in resting metabolic rate statistically adjusted for FFM (kJ/min), the thermic effect of a test meal (kJ/3 h), the energy cost of submaximal physical activity, or EI. EE was higher (P = 0.01) in the runners. Reported EI was lower than EE in both the runners (P = 0.007) and control subjects, (P = 0.006), resulting in energy deficits of -4131 +/- 1185 kJ/d and -1652 +/- 456 kJ/d, respectively. These female runners did not exhibit an enhanced metabolic efficiency compared with the control subjects. It is possible that the energy deficit for both the runners and control subjects was due to both restricted eating and underreporting during the measurement period. Additional studies using longer measurement periods, more sophisticated technology (ie, doubly labeled water, more subjects, and subjects of varying menstrual and energy intake status) are needed to truly answer this question. PMID- 7840068 TI - Brain tryptophan concentrations and serotonin synthesis remain responsive to food consumption after the ingestion of sequential meals. AB - The response of brain tryptophan concentration and serotonin synthesis to the ingestion of two sequential meals was examined in rats. Fasted rats ingested a carbohydrate meal followed 2 h later by a protein-containing meal and were examined 2 or 4 h after the first meal. Other rats ingested a protein meal first, followed by a carbohydrate meal. When the carbohydrate meal was fed first, brain tryptophan concentrations and serotonin synthesis increased at 2 h; these changes were reversed at 4 h if the second meal contained protein. When the protein meal was fed first, there were no changes in brain tryptophan or serotonin at 2 h, and a second carbohydrate meal at 2 h did not raise brain tryptophan or serotonin 2 h later. Carbohydrate ingestion 3 h after a protein meal, however, did raise brain tryptophan and serotonin 2 h later. Brain tryptophan concentrations and serotonin synthesis are thus responsive to the sequential ingestion of protein and carbohydrate meals if there is a sufficient interval between meals. PMID- 7840069 TI - Differences exist in the relationships between dietary linoleic and alpha linolenic acids and their respective long-chain metabolites. AB - Increased concentrations of cellular eicosapentaenoic acid (EPA) have been shown to be beneficial in coronary heart disease, hypertension, and inflammatory disorders. Successful long-term strategies for increasing cellular EPA concentrations require information on the relationships between cellular concentrations of EPA and dietary amounts of alpha-linolenic acid (alpha-LA), a precursor of EPA, and dietary amounts of linoleic acid (LA), an antagonist of alpha-LA conversion to EPA. A dietary intervention study with healthy human volunteers that incorporated alpha-LA-rich vegetable oil (flaxseed oil), against a background diet low in LA, allowed us to examine these relationships. Linear relationships were found between dietary alpha-LA and EPA in plasma fractions and in cellular phospholipids. By contrast there was no relationship observed between dietary LA and tissue concentrations of its metabolite, arachidonic acid (AA). There was an inverse relationship between dietary alpha-LA and docosahexaenoic acid concentrations in the phospholipids of plasma, neutrophils, mononuclear cells, and platelets. The results indicate that increasing dietary alpha-LA will elevate tissue EPA concentrations in a predictable manner. This insight will facilitate the rational planning of practical dietary strategies for the long term elevation of EPA concentrations in tissues. PMID- 7840070 TI - Chronic oat bran intake alters postprandial lipemia and lipoproteins in healthy adults. AB - This study evaluates the possible interaction between chronic oat bran intake and the postmeal metabolic response. Six normolipidemic men consumed three different diets for 14 d, at the end of which they consumed a test meal. The diets were C (control), basal low-fiber diet (15.6 g fiber/d) and a low-fiber (2.8 g fiber) test meal; OB (oat bran), basal low-fiber diet and a 40-g oat bran-enriched test meal (12.8 g fiber); and OB-A (oat bran-adaptation), 14-d oat bran (40 g/d) supplemented diet (23.8 g fiber/d) and an oat bran test meal (12.8 g fiber). The diets were fed in a random order. Fasting and postmeal blood samples were obtained for 7 h and lipoproteins were isolated. Adding oat bran to the test meals markedly reduced the postmeal insulin rise (P < 0.05). Compared with the low-fiber control diet, the effects elicited postprandially by adding oat bran to a single meal were enhanced after 14 d of oat bran feeding, ie, increased plasma triglycerides, phospholipids, and free cholesterol; decreased plasma esterified cholesterol; increased chylomicron and small-sized triglyceride-rich lipoprotein triglycerides; increased LDL and HDL free cholesterol; and decreased HDL esterified cholesterol. Thus, chronic oat bran feeding alters the postmeal response in human subjects. PMID- 7840071 TI - Effect of long-term consumption of amylose vs amylopectin starch on metabolic variables in human subjects. AB - Long-term consumption of high-amylose starch on insulin and glucose response was investigated in 24 men: 10 control and 14 hyperinsulinemic (HI) subjects. Subjects consumed products made with standard (70% amylopectin, 30% amylose) or high-amylose (70% amylose, 30% amylopectin) cornstarch for two 14-wk periods in a crossover pattern. Starch products replaced usual starches in the self-selected diet for 10 wk followed by 4 wk of a controlled diet. After a starch-tolerance test with bread made from the starch consumed during that period, the insulin response curve area was significantly lower in all subjects after amylose consumption (P < 0.002). Glucose responses in HI and control subjects were similar and did not vary with the type of starch. Fasting triglyceride concentrations were significantly lower in subjects who consumed the high-amylose compared with the standard-starch diet throughout the study. Chronic consumption of high-amylose foods normalized the insulin response of hyperinsulinemic subjects and showed a potential benefit for diabetic subjects. PMID- 7840072 TI - Effect of boron supplementation on blood and urinary calcium, magnesium, and phosphorus, and urinary boron in athletic and sedentary women. AB - It has been reported that boron may be beneficial for optimal calcium metabolism and, thus, optimal bone metabolism. Therefore, we designed a study to determine the effects of boron supplementation on blood and urinary minerals in athletic subjects and sedentary control subjects consuming self-selected typical Western diets. Serum phosphorus concentrations were lower in boron-supplemented subjects than in placebo-supplemented subjects. Compared with all other subjects, serum magnesium concentrations were greatest in the sedentary control subjects supplemented with boron and increased with time in all subjects. Exercise training diminished changes in serum phosphorus concentrations caused by boron supplementation. Calcium excretion increased over time in all groups combined, and boron excretion increased over time in all boron-supplemented subjects. The findings suggest that boron supplementation modestly affected mineral status, and exercise modified the effects of boron supplementation on serum minerals. PMID- 7840073 TI - Osteopenia in rats supported by intravenous nutrition. AB - The etiology of bone disease seen in long-term total parenteral nutrition patients is poorly defined. This study examined the question of whether abnormal bone could be induced in otherwise normal weanling rats fed a balanced nutrient solution intravenously. Young adult, male Wag/Rij rats were divided into three groups. One group was fed a commercial liquid research diet, one group received an indwelling jugular catheter and was fed an intravenous elemental solution formulated to be nutritionally complete, and one group received an indwelling catheter but was fed the commercial liquid diet orally. Significant differences were seen between groups in percent bone, femur length, growth-plate width, endosteal label area, periosteal mineral apposition rate, and periosteal and endosteal bone-formation rates. This study suggests that intravenous administration of otherwise adequate nutrients to rats results in altered bone remodeling compared to orally fed cohorts. PMID- 7840074 TI - Survival of yogurt-containing organisms and Lactobacillus gasseri (ADH) and their effect on bacterial enzyme activity in the gastrointestinal tract of healthy and hypochlorhydric elderly subjects. AB - The effect of the live bacterial yogurt cultures, namely Streptococcus thermophilus and Lactobacillus bulgaricus, and a mucosal adhering strain of Lactobacillus gasseri (ADH) on small intestinal and fecal bacterial characteristics was examined in 10 elderly subjects with atrophic gastritis and 23 elderly normal volunteers (11 received yogurt and 12 received ADH). Neither S thermophilus nor L bulgaricus was recovered from the stomach or small intestine of subjects fed yogurt or pasteurized yogurt. ADH was recovered from gastric or small intestinal aspirates in three of four subjects and in the stools of four of five subjects diagnosed with atrophic gastritis. In 11 of 12 normal subjects, ADH was isolated from stools. There was a significant reduction in fecal bacterial enzyme activity in both normal volunteers and subjects with atrophic gastritis after being fed with viable ADH. Adherent strains of bacteria such as ADH are likely to survive passage through the gastrointestinal tract and thus have greater metabolic effects. PMID- 7840075 TI - Omega-3 fatty acids in adipose tissue of obese patients with non-insulin dependent diabetes mellitus reflect long-term dietary intake of eicosapentaenoic and docosahexaenoic acid. AB - We examined the relationship between long-term dietary intake of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and the relative content of these fatty acids in adipose tissue triglycerides from 53 obese Dutch subjects--19 men and 34 women--with non-insulin-dependent diabetes mellitus (NIDDM). Adipose tissue fatty acid profiles analyzed in three samples taken from each subject at 1-y intervals showed no within-subject differences for EPA and DHA. Dietary intake was estimated from 12 3-d dietary records made over 2 y at 2-mo intervals. EPA and DHA intakes showed high within-subject variation. Correlation coefficients (Spearman) between the dietary intake of EPA (% of total fat) and EPA in adipose tissue (% of total fatty acids) were 0.76 for men and 0.57 for women. For DHA these coefficients were 0.75 for men and 0.48 for women. We conclude that the analysis of fatty acids in one adipose tissue biopsy provides information on long term EPA and DHA intakes in obese subjects with NIDDM, and can replace otherwise necessarily frequent diet analyses over a long period. PMID- 7840076 TI - Oats and buckwheat intakes and cardiovascular disease risk factors in an ethnic minority of China. AB - The relationship of oats and buckwheat intake to cardiovascular disease risk factors was studied in 850 Yi people, an ethnic minority in southwest China. Blood pressure was measured on 3 consecutive days. Serum total cholesterol, high density-lipoprotein (HDL) cholesterol, and triglycerides were measured after a 14 h fast. Oats and buckwheat intakes were assessed by questionnaire. In multiple regression analysis, oats intake (100 g/d) was associated with lower body mass index (-0.25, in kg/m2; P < 0.05), systolic (-3.1 mm Hg, P < 0.001) and diastolic (-1.3 mm Hg, P < 0.01) blood pressure, and HDL cholesterol (-0.13 mmol/L, P < 0.001). Buckwheat intake (100 g/d) was associated with lower serum total cholesterol (-0.07 mmol/L, P < 0.01) and low-density-lipoprotein cholesterol ( 0.06 mmol/L, P < 0.05) and a higher ratio of HDL to total cholesterol (0.01, P < 0.05). These findings suggest a role for oats and buckwheat consumption in the prevention and treatment of both hypertension and hypercholesterolemia. PMID- 7840077 TI - Very-low-energy diets alter the counterregulatory response to falling plasma glucose concentrations. AB - A consequence of short-term very-low-energy diets (VLEDs) in lean subjects is reactive hypoglycemia. We therefore tested the responses of overweight women on prolonged (14 d) VLEDs. Subjects lost 4.8 +/- 0.2 kg (mean +/- SEM, n = 13, P < 0.001). Group A (n = 6) was challenged with an oral-glucose-tolerance test (OGTT) and group B (n = 7) with an oral-sucrose-tolerance test (OSTT) on days 1 and 14. In group A, mean nadir plasma glucose after the OGTT was lower on day 14, 3.75 +/ 0.16 vs 4.7 +/- 0.19 mmol/L (P < 0.01), because of an accelerated rate of glucose decline (RGD, 26.7 +/- 3.3 vs 17.2 +/- 3.9 mumol.l-1.min-1, P < 0.05) late in the OGTT. Plasma insulin was also lower (P < 0.03) and the VLED suppressed two growth hormone (GH) peaks on day 14 (P < 0.05 for each). In group B on day 14, a greater RGD was also observed late in the OSTT, 16.9 +/- 4.1 vs 6.5 +/- 2.0 mumol.L.min-1 (P < 0.03). GH peaks were also significantly suppressed. We conclude that a VLED results in altered glucose regulation late after carbohydrate loading, characterized by an accelerated decline in plasma glucose and GH suppression. Patients on a VLED may be at risk for abnormally low plasma glucose concentrations when ingesting high carbohydrate loads. PMID- 7840078 TI - Diets containing soluble oat extracts improve glucose and insulin responses of moderately hypercholesterolemic men and women. AB - The high amount of soluble beta-glucans in oats may be responsible for beneficial effects on glucose tolerance and blood lipids. We studied 16 women and 7 men (aged 38-61y) with moderately high cholesterol concentrations who consumed normal diets to which oat extracts with either 1% or 10% soluble beta-glucans were added. Oat extracts comprised 10% of energy and were consumed in a 5-wk crossover design after a 1-wk equilibration period. At the end of the equilibration period and each 5-wk period, a carbohydrate tolerance test was conducted and responses to glucose, glucose plus oat extract containing 1% glucan, or glucose plus oat extract containing 10% glucan were determined. Glucose responses were reduced by both extracts in both men and women; however, in women, responses to the 10% extract were lowest. Insulin responses did not differ between men and women, but were lower after oat extracts. Glucagon responses were higher initially in men and were lowered after oat extracts in men but not in women. Modest amounts of oat extracts can be incorporated into normal diets with beneficial effects on glucose tolerance factors. PMID- 7840079 TI - Biotin supplementation affects lymphocyte carboxylases and plasma biotin in severe protein-energy malnutrition. AB - We studied the effect of a supplement of biotin (10 mg/d) or a placebo under double-blind conditions on plasma biotin concentrations and lymphocyte propionyl CoA carboxylase (PCC) and pyruvate carboxylase (PC) in 22 children with severe protein-energy malnutrition (PEM) (5 with kwashiorkor, 10 with marasmus, and 7 "sugar babies"). There were significant differences between the malnourished and control subjects only for PCC, although not among the three PEM types. Six of the patients had both PC and PCC activities below the lowest of the normal control subjects; there was no correlation between biotin concentrations and carboxylase activities in individual patients. In response to biotin supplementation, the greatest change in lymphocyte carboxylase activities was detected in patients who had abnormally decreased initial carboxylase activities, but the response was not related to initial plasma biotin concentration. These results indicate that these enzyme deficiencies are the result of a nutritionally determined biotin deficiency, that carboxylases and especially PCC are better indicators of the biotin status in individual patients than is the plasma biotin concentration, and that in some malnourished patients biotin deficiency may be rate-limiting in their nutritional homeostasis. PMID- 7840080 TI - Lack of efficacy of low-dose sitostanol therapy as an adjunct to a cholesterol lowering diet in men with moderate hypercholesterolemia. AB - Plant sterols have been shown to reduce dietary cholesterol absorption and hence, total and low-density-lipoprotein (LDL)-cholesterol concentrations in humans. In this study the cholesterol-lowering effects of dietary supplementation with the hydrogenated plant sterol sitostanol (3 g/d) were tested in 33 men with moderate hypercholesterolemia who were consuming an outpatient diet in which dietary cholesterol was restricted to < 200 mg/d. Sitostanol therapy did not significantly lower LDL cholesterol compared with the diet alone. Similarly, sitostanol therapy in conjunction with a cholesterol-lowering regimen of diet and 8 g cholestyramine did not significantly lower LDL-cholesterol concentrations. Hence, although previous reports have suggested that low-dose sitostanol therapy is an effective means of reducing LDL-cholesterol concentrations, its effectiveness may be attenuated when the diet is low in cholesterol. PMID- 7840081 TI - Does linoleic acid contribute to coronary artery disease? PMID- 7840082 TI - Limitations of dual-energy x-ray absorptiometry. PMID- 7840083 TI - Dietary trans fatty acids and lipoprotein cholesterol. PMID- 7840084 TI - Nutrition is the keystone of prevention. PMID- 7840085 TI - A new perspective for nutrition: the health connection. AB - The science of nutrition has undergone a major transformation in its objectives and approaches because of the influence of new understanding in epidemiology of oral diseases in technically developed countries, as well as in developing countries with different environmental circumstances. Recent findings of biochemical, immunological, and molecular biology investigations related to oral tissues have also added a new health dimension to this understanding. The major challenge ahead is not only to continue to expand the available scientific information, but to recognize the role that nutrition has for oral tissues, which is no different than the one it has for other tissues and organ systems. Investigators in other fields have been incorporating these new concepts about nutrition in the planning of their research during the past decade, but this emphasis has been lacking in dental research and this needs to be corrected. Still, we have one more challenge ahead, and that is to transfer to the general public the information generated by research in our laboratories and clinics in a prudent and effective way. This will ensure that consumers will take advantage of nutrition information alongside oral health concepts to maintain good general health while preventing and controlling oral diseases. There is much work ahead to be done, but the following papers have already started to set up research guidelines for the future. PMID- 7840086 TI - Nutrition, tooth development, and dental caries. AB - Many studies involving small animals have clearly shown that malnutrition affects tooth formation and causes increased dental caries. We have conducted two cross sectional studies and one longitudinal study among Peruvian children to investigate the effect of early malnutrition on oral health. The cross-sectional studies have shown that in malnourished children the pattern of caries development as a function of age is significantly altered as a result of a delayed eruption and exfoliation of the deciduous teeth. This phenomenon has made difficult the observation by other scientists of a clear effect of nutritional status on total caries experience because the comparison of age-adjusted caries data between populations of children with different nutritional status is inappropriate. The use of peak caries activity has allowed the observation of a strong association between malnutrition and increased dental caries. The longitudinal study has confirmed the results of the cross-sectional studies and has demonstrated that one mild to moderate malnutrition episode occurring during the first year of life is associated with increased caries in both the deciduous and permanent teeth many years later. PMID- 7840087 TI - Dietary models for root caries. AB - A stepwise multiple logistic regression was computed to assess which of the nutritional variables differentiate the healthy and diseased group of participants in the Forsyth Specialized Caries Center (n = 275). Variables considered as candidates for the model included the consumption per week of sugars, starch, cheese, fruits and fruit juices, noncariogenic foods, and dairy products. Two variables--sugars and cheese--were statistically significant by the stepwise procedure. Increased intake of sugar was associated with being in the root caries group, whereas high intake of cheese was negatively associated with root caries. Thus, cheese seems to have a protective effect after sugar intake is controlled for. Odds ratios were computed to quantify the influence of the variables. An increase of two exposures of sugar per day corresponded with an odds ratio of 1.26. The odds ratio continues to increase with sugar intake so that an increase to five exposures per day gives an odds ratio of 1.79. This model is consistent with past in vitro studies suggesting that cheese protects against caries formation when sugar intake is controlled for and that increasing frequency of sugar intake increases the odds of root caries. PMID- 7840088 TI - Relationship of diet to root caries. AB - A Nutrition and Oral Health Study was conducted on 141 middle-aged and elderly adults (54% female and 46% male; aged 47-83 y, mean = 67; 51% college educated; and 89% white). This study reports on the relationship between root caries and diet. Nutritional composition was derived from two 3-d food diaries. Root caries was measured according to the 1985 Adult Survey Diagnostic Criteria of the National Institute of Dental Research. When the individuals were segregated by their root DFS (decayed and filled surfaces) status into highest (> or = 7) and lowest (< or = 1) quartiles, the sucrose consumption was significantly higher in the higher DFS group. Mean energy consumption and mean number of teeth were the same in both groups. When the individuals were segregated by sucrose consumption into highest (> or = 89 g) and lowest (< or = 31 g) quartiles, DFS root status was significantly higher (P < 0.01) in the highest quartile group (7 g) vs the lowest group (4 g). By using data from subjects with two food diaries, a stepwise linear-regression model for root caries showed that 4.2% of the variance for root caries was explained by sucrose, 2.8% by plaque, 3.8% by total number of teeth, and 5.6% by gingival recession. These data suggest that root caries has a similar dietary etiology to coronal caries. PMID- 7840089 TI - Diet and nutrition in the etiology of oral cancer. AB - Epidemiological studies worldwide have implicated dietary and nutritional factors in the development of oral and pharyngeal cancer. Dietary information in these case-control studies generally was collected through food-frequency questionnaires. Consistently, these studies observed a protective effect of a diet high in fruit intake, reflected in a 20-80% reduction in oral cancer risk. A high intake of foods considered to be dietary staples in particular cultural groups, possibly indicating a generally impoverished diet, has been linked to excess risk. Indigenous dietary practices that in single studies were found to increase risk include a high intake of chili powder and wood stove cooking. Supplementation with various vitamins has been protective in a few studies. Chemoprevention trials generally have found that chemopreventive agents reduce the size of oral leukoplakia lesions or the frequency of second primary oral cancers. The most consistent dietary findings across multiple cultural settings are a protective effect of high fruit consumption and the carcinogenic effect of high alcohol intake. PMID- 7840090 TI - Discussion: nutritional aspects of oral health--new perspectives. AB - Because of the critical role of nutrition in developmental events, effects of nutritional excesses and deficiencies may be more significant than would be predicted by a steady-state model. Dietary choice is as important in oral health as it is to the health of the entire body, thus it may ultimately serve not only to prevent, but also to treat certain oral diseases. PMID- 7840091 TI - Discussion: diet and nutrition in dental health and disease. AB - The recognition in 1993 by the International Association of Dental Research (IADR) for the initiation of a Nutrition Research Group within the Association prompted this nutrition symposium related to diet and nutrition in health and disease. The IADR Nutrition Research Group is encouraged to collaborate with other nutritional research groups in important areas of medicine, food science technology, and agriculture to target health issues influenced by dietary choices, nutritional adequacy, and dental health status. PMID- 7840092 TI - Herd immunity: basic concept and relevance to public health immunization practices. 1971. PMID- 7840093 TI - Ingested arsenic and internal cancer: a historical cohort study followed for 33 years. AB - A historical cohort study was conducted to investigate the long-term effect of exposure to ingested arsenic. The 454 residents who had been identified in a list made in 1959 were followed until 1992. They lived in an arsenic-polluted area, called Namiki-cho, Nakajo-machi, in Niigata Prefecture, Japan, and used well water containing inorganic arsenic. The exposure period was estimated to be about 5 years (1955-1959). Death certificates for the people who died between 1959 and 1992 were examined, and a total of 113 of the 454 residents were estimated to have drunk well water containing a high dose of arsenic (> or = 1 ppm). The standardized mortality rate ratios of these 113 residents were 15.69 for lung cancer (observed/expected = 8/0.51; 95% confidence interval (CI) 7.38-31.02) and 31.18 for urinary tract cancer (observed/expected = 3/0.10; 95% CI 8.62-91.75). Cox's proportional hazard analyses demonstrated that the hazard ratios of the highest exposure level group (> or = 1 ppm) versus the background exposure level group (0.001 ppm) were 1.74 (95% CI 1.10-2.74) for all deaths and 4.82 (95% CI 2.09-11.14) for all cancers. The analysis according to the skin signs of chronic arsenicism in 1959 showed that they were useful risk indicators for subsequent cancer development. In the development of lung cancer, there was evidence of synergism between arsenic intake and smoking habit. PMID- 7840094 TI - Parental exposures to pesticides and risk of Wilms' tumor in Brazil. AB - Wilms' tumor is one of the most common abdominal childhood malignancies. Wilms' tumor rates in Brazil are among the highest in the world. This prompted the Brazilian Wilms' Tumor Study Group to conduct a hospital-based, multicenter, case control investigation of environmental risk factors for the disease. Between April 1987 and January 1989, the authors collected information on relevant occupational exposures by interviewing the parents of 109 Wilms' tumor cases admitted to hospitals in Sao Paulo, Salvador, Belo Horizonte, and Jau. Also interviewed were the parents of 218 age- and sex-matched control children who had been admitted for treatment of nonneoplastic diseases to the same or nearby hospitals. Odds ratios (ORs) adjusted for income and education were calculated by conditional logistic regression. Consistently elevated risks were seen for farm work involving frequent use of pesticides by both the father (OR = 3.24, 95% confidence interval (CI) 1.2-9.0) and the mother (OR = 128.6, 95% CI 6.4-2,569). These risk elevations were restricted to cases diagnosed after 2 years of age (ORs > 4), for paternal exposure, and after 4 years of age (OR = 14.8, 95% CI 2.2 98.8), for maternal exposure. Risk elevations were also more pronounced among boys (paternal exposure OR = 8.56, 95% CI 2.1-35.1; maternal exposure OR = 4.60, 95% CI 0.8-26.4) than among girls (paternal exposure OR = 1.31, 95% CI 0.4-4.1; maternal exposure OR = 2.03, 95% CI 0.5-8.9). PMID- 7840095 TI - Tuberculosis in relation to a history of peptic ulcer disease and treatment of gastric hyperacidity. AB - Previous studies described an excess of tuberculosis among persons with a history of partial gastrectomy for the treatment of peptic ulcer disease. It is unknown if any contemporary therapies for peptic ulcer disease, such as histamine type 2 antagonists and antacids, are also associated with elevated risks of tuberculosis. A case-control study was conducted during 1988-1990 in the Seattle King County Tuberculosis Clinic to address these questions. Self-administered questionnaires were completed by 135 cases with active tuberculosis and 380 controls. A history of daily antacid use was reported by 11 cases (8%) and 23 controls (6%), corresponding to an adjusted odds ratio of 0.9 (95% confidence interval 0.4-2.0). A history of daily histamine type 2 antagonist use was reported by nine cases (7%) and 18 controls (5%) with an adjusted odds ratio of 0.8 (95% confidence interval 0.3-2.1). Our results, while based on a relatively small number of subjects, suggest that treatment for peptic ulcer disease has no influence on the occurrence of tuberculosis. PMID- 7840096 TI - Decreased survival with increasing prevalence of full-body, radiographically defined osteoarthritis in women. AB - The relation between full-body, radiographically defined osteoarthritis and survival was examined in a cohort of 296 women aged 42-76 years (mean age, 57.1 years). These women were a random sample of women with very low body burdens of radium who were part of a larger cohort of women first employed in the US radium dial-painting industry between 1915 and 1945. At entry into the study between 1957 and 1982, these women had a clinical examination, and full-body radiographs were taken. Fifty-five joints (18 joint groups) of the hands, feet, cervical spine, lumbar spine, pelvis, and knees in each woman were graded for osteoarthritis by the method of J. H. Kellgren and J. S. Lawrence (Ann Rheum Dis 1957; 16:494-502). Through 1985, 18.6% (n = 55) of the women died. Cox regression showed a decreased survival for women with an increasing number of joint groups affected with osteoarthritis after adjusting for age at examination (hazard ratio = 1.45 for each increase in 3.1 joint groups (1 standard deviation) affected with osteoarthritis, 95% confidence interval 1.12-1.87). Further adjustment for a history of diabetes, smoking, alcohol use, and body mass index only slightly altered the risk. Similar results were obtained for the number of joints with osteoarthritis and the number of structures (e.g., left hand and right hand) with osteoarthritis. These results suggest that an increasing prevalence of full-body radiographic osteoarthritis is associated with decreased survival independent of age and several comorbid conditions related to osteoarthritis. PMID- 7840097 TI - Birth cohort and familial risk of epilepsy: the effect of diminished recall in studies of lifetime prevalence. AB - This study separated the effects of age, birth cohort, and generation (parents, siblings, and offspring) on familial risk of epilepsy. The study population comprised 9,741 parents, siblings, and offspring of 1,957 adult probands with epilepsy ascertained from 10 voluntary organizations in New York, New Jersey, Connecticut, and Massachusetts between 1985 and 1988. Semistructured telephone interviews with probands and selected family members were used to collect data on the history of epilepsy in the relatives. The risk of epilepsy increased in successive generations (cumulative incidence to age 40: parents, 1.8%; siblings, 2.9%; offspring, 5.6%) but, with the exception of one subgroup (offspring of female probands), these differences disappeared after controlling for age and birth year of the relatives. With age and relationship controlled, the risk of epilepsy increased approximately 50% for each 20 advancing years of birth. Population-based data indicate that age-specific incidence rates of epilepsy have not increased during the age and time periods investigated here; thus, the most plausible explanation for the findings is that epilepsy is underreported in persons born in earlier time periods. These results illustrate a general phenomenon of underreporting in studies of lifetime prevalence, and they caution against interpreting apparent cohort effects in such studies as evidence of secular changes in incidence. PMID- 7840098 TI - Mortality ascertainment in the veteran population: alternatives to the National Death Index. AB - Veterans of the US military service constitute a dynamic cohort that is suitable for epidemiologic investigations. However, the ability to ascertain vital status is paramount to the value of this population in studies having mortality as a primary endpoint. The purpose of this study was to estimate and compare the mortality ascertainment obtained from the Department of Veterans Affairs Patient Treatment File and Beneficiary Identification and Record Locator System (BIRLS) with that obtained from the National Death Index on a cohort of 17,118 male veterans hospitalized in 1970 or 1971. Based on the 4,246 deaths identified in this cohort between 1979 and 1988, the sensitivities of BIRLS, the Patient Treatment File, and the National Death Index were 94.5%, 33.0%, and 96.7%, respectively. BIRLS was comparable with the National Death Index regarding mortality ascertainment and allowed for central acquisition of 89% of the death certificates from the Department of Veterans Benefits. There was no difference detected in the completeness of the BIRLS file before and after passage of the Omnibus Act in 1981. The Patient Treatment File served as a complement to BIRLS, providing additional mortality data and identification of hospitals for recall of medical records. The National Death Index provided the best mortality ascertainment, but acquistion of death certificates from individual states was extremely time consuming and expensive. The authors recommend greater consideration by investigators of sampling the veteran population and utilizing available Veterans Affairs databases for large studies in which mortality is the primary endpoint of interest. PMID- 7840099 TI - Is it necessary to transform nutrient variables prior to statistical analyses? AB - The distributions of the intakes of many nutrients are skewed, yet this is often overlooked when standard statistical analyses are applied to nutrient data. The nutrient intakes of 5,123 men and 5,236 women, recorded by food frequency questionnaire in the Scottish Heart Health Study, were transformed to achieve approximately symmetric distributions. Power transformations were chosen using letter value analyses. A letter value analysis uses selected order statistics and their position around the median to assess symmetry. The effect that each transformation had on a comparison of nutrient intakes between those with and without prevalent coronary heart disease was determined from t tests on the untransformed and transformed variable. The effects of the logarithm and square root transformation and of the optimum Box-Cox transformation were also determined, and the results were compared with the nonparametric Mann-Whitney test. The conclusion of whether or not to reject the null hypotheses often varied, depending on the transformation and test used. The nonparametric test usually gave a conclusion similar to that of the t test on the letter value transformed data, the Box-Cox-transformed variable, and after either the logarithm or square root transformation of the data, but not always both. The results from the untransformed variable were sometimes very different. Failure to account for skewness in nutrient variables may thus lead to spurious conclusions. PMID- 7840100 TI - Bayesian estimation of disease prevalence and the parameters of diagnostic tests in the absence of a gold standard. AB - It is common in population screening surveys or in the investigation of new diagnostic tests to have results from one or more tests investigating the same condition or disease, none of which can be considered a gold standard. For example, two methods often used in population-based surveys for estimating the prevalence of a parasitic or other infection are stool examinations and serologic testing. However, it is known that results from stool examinations generally underestimate the prevalence, while serology generally results in overestimation. Using a Bayesian approach, simultaneous inferences about the population prevalence and the sensitivity, specificity, and positive and negative predictive values of each diagnostic test are possible. The methods presented here can be applied to each test separately or to two or more tests combined. Marginal posterior densities of all parameters are estimated using the Gibbs sampler. The techniques are applied to the estimation of the prevalence of Strongyloides infection and to the investigation of the diagnostic test properties of stool examinations and serologic testing, using data from a survey of all Cambodian refugees who arrived in Montreal, Canada, during an 8-month period. PMID- 7840101 TI - Re: "Miscarriages among female physical therapists who report using radio- and microwave-frequency electromagnetic radiation". PMID- 7840102 TI - Re: "Malaria and low birth weight in central Sudan". PMID- 7840103 TI - Re: "Invited commentary: studies in mechanism and prevention. Striking a proper balance". PMID- 7840104 TI - Re: "Validation studies using an alloyed gold standard". PMID- 7840105 TI - Studies on experimental rickets. XVII. The effects of diets deficient in calcium and in fat-soluble A in modifying the histological structure of the bones. 1921. PMID- 7840106 TI - A response to the commentary "Should we consider a subject's knowledge of the etiologic hypothesis in the analysis of case-control studies"? PMID- 7840107 TI - Graphical presentation of trends in rates. AB - A variety of graphical approaches have been used to visually portray and analyze temporal trends, especially annual rates of change, in disease rates. In reviewing their own work, the authors have found that they could improve on their graphical presentations by choosing an arithmetic or logarithmic scale according to the research question being addressed, by selecting scaling ratios of the axes that allow one to detect specific rates of change, and by using uniform scaling ratios to facilitate comparisons across graphs. Different presentations of the same data can result in different impressions. The authors used rates over a 40 year period to illustrate the concepts involved and to investigate the portrayal of various rates of change. These principles extend to the plotting of odds ratios or relative risks, where the choice of an arithmetic rather than a logarithmic axis also can result in a misleading plot. The authors conclude that a graph should be designed and studied with care, clearly reflect the truth, convey information, and make a point without overemphasizing. For the particular problem addressed here, displaying temporal trends in disease rates, they see advantages in justifiable uniformity. Attention to plotting techniques in the epidemiologic and medical literature should be encouraged. PMID- 7840108 TI - Sexual transmission of human T-lymphotropic virus type I among female prostitutes and among patients with sexually transmitted diseases in Fukuoka, Kyushu, Japan. AB - The authors investigated the prevalence of antibody to human T-lymphotropic virus type I (anti-HTLV-I) in 409 female prostitutes, 446 patients with an episode of sexually transmitted diseases, and 17,345 control blood donors. All subjects were Japanese and all studies were done in Fukuoka, Kyushu, Japan, in 1989. The prevalence of anti-HTLV-I was significantly higher in the prostitutes (5.1%, p < 0.001), in the male patients (2.8%, p < 0.05), and in the female patients (5.7%, p < 0.05) than in the controls (males 1.4%, females 2.2%). Prevalence of anti HTLV-I in the prostitutes increased with the number of years spent in prostitution, but the increase was not statistically significant. Among the subjects with sexually transmitted diseases, female prostitutes with syphilis, male patients with non-gonococcal urethritis, female patients with syphilis, and female patients with gonorrhea had a significantly higher prevalence of anti-HTLV I than did the controls. A longitudinal study was done on the 168 prostitutes. Two (1.3%) of the 158 initially seronegative subjects seroconverted over the period of 2 years. These data suggest that the risk of male-to-female transmission of HTLV-I through sexual contact is high among high risk groups in Japan, and they support the possibility of female-to-male transmission of HTLV-I. PMID- 7840109 TI - Does weight loss from middle age to old age explain the inverse weight mortality relation in old age? AB - The authors examined body mass index at middle age, body mass index in old age, and weight change between age 50 years and old age in relation to mortality in old age. The study population from the Established Populations for Epidemiologic Studies of the Elderly consisted of 6,387 whites age 70 years or older who experienced 2,650 deaths during the period 1982-1987. Mortality risk was highest for persons in the heaviest quintile of body mass index at age 50 (men, relative risk (RR) = 1.33, 95% confidence interval (CI) 1.13-1.57; women, RR = 1.31, 95% CI 1.12-1.53) compared with persons in the middle quintile. This pattern was reversed for body mass index in old age, with persons in the lowest quintile having the highest mortality risk (men, RR = 1.40, 95% CI 1.19-1.65; women, RR = 1.38, 95% CI 1.17-1.63) relative to persons in the middle quintile. This reversal was explained, in part, by weight change. Compared with persons with stable weight, those who lost 10 percent or more of body weight between age 50 and old age had the highest risk of mortality (men, RR = 1.69, 95% CI 1.45-1.97; women, RR = 1.62, 95% CI 1.38-1.90). Exclusion of participants who lost 10 percent or more of their weight and adjustment for health status eliminated the higher risk of death associated with low weight. The inverse association of weight and mortality in old age appears to reflect illness-related weight loss from heavier weight in middle-age. Weight history may be critical to understanding weight and mortality relations in old age. PMID- 7840111 TI - Use of capture-recapture analyses in fetal alcohol syndrome surveillance in Alaska. AB - Capture-recapture methods were used to estimate the prevalence of fetal alcohol syndrome among Alaska Natives born during the period 1982-1989. Potential cases were identified through an Indian Health Service (IHS) patient case file, a pediatric practice case file, and Medicaid claims from private physicians. A total of 74 Alaska Native children aged 3-10 years were identified with a notation of fetal alcohol syndrome by a physician in a medical record. Because not all of these cases had supporting documentation regarding the syndrome, they were classified as possible cases. Of these possible cases, 50 met all five criteria for chart verification of the syndrome: physician notation of fetal alcohol syndrome, growth deficiency, facial features of the syndrome, central nervous system impairment, and a maternal history of alcohol abuse. These data provided observed prevalence rates of chart-verified fetal alcohol syndrome of 3.1 per 1,000 live births for children born 1982-1985 (age 7-10 years), and 2.0 per 1,000 live births for children born 1986-1989 (age 3-6 years). Capture recapture analyses were conducted using cases identified by IHS and private physicians. These analyses estimated a prevalence of the syndrome of 3.8 per 1,000 live births for children born 1982-1985, and 3.1 per 1,000 live births for children born 1986-1989. Based on the capture-recapture predicted number of cases, the IHS case file ascertained a greater percentage of cases among the older cohort (75%) than among the younger cohort (56%). These data illustrate the use of capture-recapture analyses in identifying the extent to which observed trends in rates may reflect differences in cases ascertainment over time (or by birth cohort). The application of capture-recapture in fetal alcohol syndrome surveillance, however, requires careful attention to the underlying assumptions of capture-recapture methods. PMID- 7840110 TI - Diet and nuclear lens opacities. AB - Relations between diet and nuclear opacities in the lens of the eye were investigated in a population-based cohort of middle-aged and older adults who lived in Beaver Dam, Wisconsin. Nuclear sclerosis was assessed from photographs of the lens taken during 1988-1990 in 1,919 persons in the Beaver Dam Eye Study. Diets in the past (1978-1980) were assessed retrospectively with the use of a food frequency questionnaire in home interviews. Relations with intake of foods and nutrients were evaluated using logistic regression analyses. In men, after controlling for age, smoking, and heavy drinking, intakes of numerous nutrients in the highest versus lowest quintile were associated with 40-50 percent reduced odds of more severe nuclear sclerosis. Relations with some nutrients (vitamins A, C, and E, riboflavin, thiamin, niacin) were at least partly explained by previously identified inverse associations with multivitamin use. Relations with other nutrients (folate, alpha-carotene, and dietary fiber) appeared to reflect associations with intake of foods, particularly vegetables. Inverse associations with individual nutrients and foods were often weaker or nonexistent in women. These data indicate that the intake of vitamin supplements (in men and women) and certain foods (particularly in men) may explain associations of several nutrients with risk for nuclear sclerosis. PMID- 7840112 TI - Teenage and current calcium intake are related to bone mineral density of the hip and forearm in women aged 30-39 years. AB - The relation between diet and bone mineral density in premenopausal women was evaluated in a cross-sectional study of 139 women aged 30-39 years. The population consisted of volunteers recruited in Rockland County, New York, between September 1988 and August 1992. A food frequency questionnaire was used to determine nutrient intake for both the year prior to bone density measurement and for ages 13-17 years. Physical measurements included height, weight, grip strength, and percent body fat. Bone mineral density was measured in the lumbar spine, hip, and forearm. Multiple regression equations were used to relate nutrient intake to bone density while controlling for age, height, weight, and grip strength. There were no relations between lumbar spine or distal forearm bone density and any nutrient studied from either the current or teenage diet. Current dietary calcium intake was modestly related to hip bone density (beta = 0.077; p = 0.074). When fiber intake was added to the multiple regression model, the association between calcium and hip bone density was strengthened (beta = 0.101; p = 0.037); this would be expected, because fiber interferes with calcium absorption. In the teenage diet, phosphorus and calcium intake were related to hip bone density. A higher lifetime calcium intake was associated with a higher hip bone density compared with low lifetime calcium intake. An increase in teenage calcium intake from 800 to 1,200 mg per day is estimated to increase hip bone density by 6 percent. PMID- 7840113 TI - Residential exposure to magnetic fields and risk of canine lymphoma. AB - A hospital-based case-control study was conducted to determine whether residential exposure to magnetic fields increased risk for canine lymphoma in pet dogs. Cases were patients at a veterinary teaching hospital with histologically confirmed lymphoma diagnosed between 1987 and 1990. Hospital controls with other forms of cancer were obtained by frequency matching on zip code and year of diagnosis. Information regarding the dog's activity patterns, residence history, and exposure to potential confounders was obtained by telephone interview. Wire codes and magnetic fields were measured at the homes at diagnosis of 93 cases and 137 controls. When exposure was categorized into two levels (high or very high wire codes compared with low, very low, or buried lines), the risk was elevated (odds ratio (OR) = 1.6, 95% confidence interval (CI) 0.9-2.9) and increased (OR = 1.8, 95% CI 0.9-3.4) after adjustment for potential confounders. Dogs that lived in homes with very high current codes had the highest risk (OR = 6.8, 95% CI 1.6 28.5). Moderate, imprecise increases in risk (odds ratios of 1.5-1.9) were found for residence in a home with a sidewalk (plumbing), backyard, or front yard magnetic field of 2.0 mG or greater, but not for indoor measurements at this level. Risk increased among dogs that spent more than 25% of the day outdoors. Laboratory and observational studies of dogs as an animal model for the effects of magnetic fields are recommended. PMID- 7840114 TI - Physical activity and incidence of diabetes: the Honolulu Heart Program. AB - Few prospective studies have assessed the relation between physical activity and diabetes. The authors examined this relation prospectively among 6,815 Japanese American men in the Honolulu Heart Program who were aged 45-68 years and initially free of diagnosed diabetes in 1965-1968. A physical activity index was calculated based on time spent per day in different activity levels and a weighting factor correlated with estimated oxygen consumption. Incidence of clinically recognized diabetes was based on self-reported use of diabetic medication at one of two subsequent examinations. The age-adjusted 6-year cumulative incidence of diabetes decreased progressively with increasing quintile of physical activity from 73.8 to 34.3 per 1,000 (p < 0.0001, trend) in all men and from 53.9 to 21.7 per 1,000 (p < 0.0001, trend) among men with a non-fasting glucose level < 225 mg/dl one hour after a 50-gm load, the latter group being less likely to have unrecognized diabetes at baseline. When stratified by tertile of baseline glucose, trends in incidence across physical activity quintiles were statistically significant in the low and middle tertiles but not in the high tertile. Similar inverse trends were observed for men in the lower four quintiles of body mass index, however, these trends were weaker and not significant for men in the upper quintile of body mass index. Age-adjusted odds ratios for diabetes comparing the upper with the lower four quintiles of physical activity were 0.55 (95% confidence interval (CI) 0.41-0.75) for all men and 0.50 (95% CI 0.33-0.74) for men with glucose < 225 mg/dl. After adjustment for age, body mass index, subscapular/triceps skinfold ratio, systolic blood pressure, triglycerides, glucose, hematocrit, and parental history of diabetes, odds ratios were still statistically significant and similar in magnitude. Restriction of analyses to men who remained free of cardiovascular disease during the study period produced similar results, which suggests that inactivity due to subclinical cardiovascular disease is unlikely to be responsible for these findings. Risk factor-adjusted odds ratios for older men (55-68 years) demonstrated that physical activity confers at least the same degree of protection as in younger men (45-54 years). These results indicate that physical activity is associated inversely with incident diabetes and that the beneficial effect does not appear to be mediated through improvements in other risk factors assessed in this study. PMID- 7840115 TI - Estimating the degree of heterogeneity between event rates using likelihood. AB - The observed variability between mortality or morbidity rates in epidemiologic studies is partly due to random fluctuations. The same is true for rate ratios relative to reference rates. A method for estimating the distribution of true rate ratios is applied to a data set of perinatal mortality in 515 small areas in the North West Thames Health Region, England, in the period 1986-1990. Combining the random Poisson variability with the assumption that the true rate ratios are drawn from a gamma distribution (a family of positive unimodal distributions) produces a negative binomial log-likelihood for the dispersion parameter of the gamma. The maximum likelihood estimate of this parameter and its confidence interval are then found via direct numerical methods; alternatively, the hypothesis of no heterogeneity is tested by a likelihood ratio. The standardized mortality ratios (SMRs) for the data have an empirical distribution with 5th percentile at 0 and 95th percentile at 1.92, but their true variability, as described by the 5th to 95th percentiles of the fitted gamma distribution, is from 0.72 to 1.32. The likelihood ratio test confirmed this result, rejecting the hypothesis that the true rates are homogeneous (p = 0.015). The method requires only modest computing resources and is useful when assessing the need for more detailed study. PMID- 7840116 TI - Re: "Magnetic fields and cancer in children residing near Swedish high-voltage power lines". PMID- 7840117 TI - Adaptation to a stroke: the experience of one couple. AB - OBJECTIVE: Treatment of stroke, as described in the occupational therapy literature, focuses primarily on the person's physical problems, and less on the way in which the family and environment influence adaptation. This article examines family and environmental influences on adaptation to stroke. METHOD: The content of five interviews conducted over 2 years with a woman who experienced a stroke and her husband was analyzed with ethnographic research methods. RESULTS: The analysis revealed that a stroke cannot be understood as an individual phenomenon, because the life course of both this woman and her husband were profoundly affected by it. The man's roles as family member, caregiver, home maintainer, and hobbyist required change after his wife's stroke. The woman's experience of her changed body, dependence, and altered homemaking role were influenced not only by her husband's attitudes but also by societal values. CONCLUSION: The findings suggest that clinicians and researchers must pay greater attention to those living with the person who experienced a stroke and to the ways in which the person's social, cultural, and economic environments influence adaptation to disability. PMID- 7840118 TI - Medical residents' education about occupational therapy: implications for referral. AB - OBJECTIVE: The purpose of this study was to assess sources of physician education concerning occupational therapy and to determine whether these sources influence occupational therapy referral rates. METHOD: One hundred fifteen medical residents from Thomas Jefferson University Hospital, Philadelphia, Pennsylvania, were surveyed. RESULTS: Residents learn about occupational therapy through informal, direct, and interactive types of contacts (touring occupational therapy departments, having personal contact with an occupational therapist, having a family member receive occupational therapy). Perceived knowledge about occupational therapy was not significantly associated with referral rate, but it did influence a resident's desire for further education about occupational therapy. CONCLUSION: Strategies for increasing medical residents' understanding of occupational therapy and for increasing their referrals to occupational therapy include opportunities for small group role playing, structural system changes within clinical sites, and direct marketing to consumers. PMID- 7840119 TI - Perceived stressors and coping strategies of occupational therapy students. AB - OBJECTIVES: Occupational therapy students often perceive their curriculum to be stressful. Anecdotal reports have described occupational therapy students' stress and coping strategies during their academic education; this study quantifies students' perceptions. METHOD: A questionnaire was used to survey 1,095 occupational therapy students representing the major geographical regions of the United States about perceived stress and coping strategies. The data were analyzed to determine patterns and frequencies of subjects' stress and coping strategies. RESULTS: At least 86% of the subjects reported their top stressors to be examinations, amount of class work, lack of free time, long hours of study, and grades. Sixty-two percent of subjects said that the stress they experienced strengthened their commitment to their professional education. CONCLUSIONS: Academic issues and time pressures were more stressful than nonschool issues for occupational therapy students. Subjects' strategies for coping with these stressors usually included perseverance and rarely involved drugs, sex, or alcohol. PMID- 7840120 TI - Statement: occupational therapy services for persons with Alzheimer's disease and other dementias. American Occupational Therapy Association. PMID- 7840121 TI - Position paper: occupational therapy and long-term services and supports. American Occupational Therapy Association. PMID- 7840122 TI - Occupational Therapy Code of Ethics. American Occupational Therapy Association. PMID- 7840123 TI - Standards of practice for occupational therapy. American Occupational Therapy Association. PMID- 7840124 TI - Guide for supervision of occupational therapy personnel. American Occupational Therapy Association. PMID- 7840125 TI - Uniform terminology for occupational therapy--third edition. American Occupational Therapy Association. PMID- 7840126 TI - Uniform terminology--third edition: application to practice. American Occupational Therapy Association. PMID- 7840127 TI - Listing of educational programs in occupational therapy. August 1994. PMID- 7840128 TI - Bridging conflicting ideologies: the origins of American and British occupational therapy. AB - Occupational therapy practice has bridged two contradictory value systems for more than 100 years. This article describes the origins of practice ideas in both the United States and Britain and demonstrates that founding members of the occupational therapy profession all shared a core of humanistic beliefs while embracing the emerging paradigm of scientific medicine. The result has been an intellectual tension between the biological and the psychosocial aspects of practice. For more than 75 years, occupational therapists struggled to balance the art and science of patient care; recent debates on modalities, practice domains, and research priorities indicate that the unifying core of the profession is occupation that considers a person's mind and body. PMID- 7840129 TI - Adult learning through case simulation. PMID- 7840130 TI - Occupational therapy as art and science: should the older definition be reclaimed? PMID- 7840131 TI - Attempts to study Ross's Five-Stage Group program are welcome. PMID- 7840132 TI - ADL evaluations in long-term-care facilities. PMID- 7840133 TI - Clinical interpretation of "performance of typical children on the Sensory Profile: an item analysis". PMID- 7840134 TI - Relationship between visuomotor and handwriting skills of children in kindergarten. AB - OBJECTIVE: The purpose of this study was to examine the relationship between the performance of children in kindergarten on the Developmental Test of Visual-Motor Integration (VMI) and their ability to copy letters legibly. METHOD: Sixty typically developing children in kindergarten aged 64 months to 75 months (30 girls and 30 boys) were administered the VMI and the Scale of Children's Readiness In PrinTing (SCRIPT). The SCRIPT requires children to copy 26 lower case letters and 8 upper case letters from a model. RESULTS: A significant relationship was found between subjects' performance on the VMI and ability to copy letters legibly. In addition, as subjects' ability to copy the forms on the VMI increased, a concomitant increase in ability to copy letters was also found. There were no gender differences in performance on the VMI or on the SCRIPT: CONCLUSION: The findings of this study suggest that most children in kindergarten similar to those in this study will be ready for handwriting instruction in the latter part of the kindergarten year. PMID- 7840135 TI - Flow and the occupational therapy practitioner. AB - OBJECTIVE: This study examined optimal flow experience, a form of job satisfaction in occupational therapy practitioners employed at physical rehabilitation facilities in New England. METHOD: Factors associated with flow were measured over a 5-day work week with the Experience Sampling Method. Ninety seven percent of the 90 subjects' responses were analyzed and 43% of the subjects participated in the debriefing interview. RESULTS: Subjects experienced flow a relatively small amount of the time--an average of 5.24 times in a 5-day work week, with a range of 1 to 12 experiences. Flow was experienced most often (23.6%) when subjects were working with a client in some type of intervention. Perceived autonomy and self-esteem were high during a flow experience. Subjects described their flow experiences as including such moods and attitudes as "alert," "happy," "involved," creative," "excited," "productive," "accomplished," "proud," "good," "confident," "positive," and "challenged." Conversely, subjects in flow also tended to describe their mood as "tense." CONCLUSION: Retaining occupational therapy practitioners is critical to meeting and increasing the unprecedented demand for health care services. Understanding what causes occupational therapy practitioners to experience flow and how to transform an activity into a flow experience may ultimately improve job satisfaction, productivity, and the retention of practitioners. PMID- 7840136 TI - The caring occupational therapist: scope of professional roles and boundaries. AB - OBJECTIVE: This article links two dimensions of occupational therapy within the context of professionalism: the role of caring and the implications of occupational therapy being a predominantly female profession. METHOD: Seven occupational therapists representing various levels of professional experience were interviewed to determine (a) how female occupational therapists perceive caring and (b) the implications of this perception for professional role definitions. RESULTS: Participants' daily professional work role was determined by three factors: the interpretation of holistic philosophy in their everyday activities as occupational therapists, the influence of their caring attitude in broadening their responsibilities beyond the occupational therapists' role definition, and the organizational settings in which their work took place. CONCLUSION: The seven participants had a broad definition of the scope of their professional responsibilities and experienced difficulty defining the limits of their role. Caring is a central part of the occupational therapists' role; therefore, perceptions about caring are central to the role definition of occupational therapists. PMID- 7840137 TI - Mechanotransduction in vertebrate hair cells: structure and function of the stereociliary bundle. AB - The mechanosensitive hair cells of the vertebrate acousticolateralis system have an apical bundle of stereocilia, deflections of which control the opening of mechano-electrical transduction channels and thus generate receptor potentials in the cell below. This review describes current theories of hair cell function in the light of recent immunocytochemical and ultrastructural findings; in particular, the location and operation of the transduction channels are considered. The most widely accepted hypothesis of mechanotransduction by hair cells is that fine extracellular links that run between the tips of shorter stereocilia and the sides of taller ones operate the transduction channels. However, the fact that the transduction channels are amiloride sensitive has led to labeling experiments using antibodies to the amiloride-sensitive epithelial Na+ channel from kidney which suggest that the mechanotransduction channels may not be directly associated with the tip links. Instead, they appear to be located near a junctionlike structure at the point of contact between the shorter and taller stereocilia. The implications of these findings for the tip link hypothesis are discussed. PMID- 7840138 TI - G alpha q and G alpha 13 regulate NHE-1 and intracellular calcium in epithelial cells. AB - To understand the mechanisms by which G protein-coupled signaling systems regulate NHE-1 in epithelial cells, we expressed G alpha q and G alpha 13 in a renal epithelial cell line. We studied two signaling systems that have been implicated in NHE-1 regulation [intracellular Ca (Cai) and phospholipase C activity] and measured NHE-1 activity, mRNA, and antigen. Expression of alpha qWT and alpha qQ209L (a GTPase-deficient mutant) increased basal Cai and altered the kinetics of the bradykinin-induced Cai signal. The initial bradykinin-induced spike in Cai was prolonged and the plateau was higher in cells expressing alpha qWT and alpha qQ209L than in control cells. Cells expressing alpha 13WT also had a higher basal Cai and plateau after stimulation by bradykinin, but Ca release from intracellular stores was similar to that in control cells. Expression of all three alpha-chains increased NHE-1 activity, antigen, and mRNA. The alpha qQ209L had the greatest effect increasing activity by approximately twofold. The alpha 13WT increased NHE-1 activity by approximately 1.5-fold, and alpha qWT increased activity 1.2-fold. These studies demonstrate that alpha q and alpha 13 alter regulation of Cai but by different mechanisms. The Ca signal or another signal generated by alpha q and alpha 13 regulate(s) NHE-1 at the levels of activity, antigen, and mRNA. PMID- 7840139 TI - Localization of the Na/Ca exchange-dependent Ca compartment in cultured neonatal rat heart cells. AB - It has been previously established, in both adult and cultured neonatal cardiac cells, that there is a discrete Na/Ca exchange-dependent Ca compartment. It has been proposed that a component of junctional sarcoplasmic reticulum (JSR) Ca and Ca bound to the apposed inner sarcolemmal leaflet represent together the subcellular locus of the compartment. The present study examines this proposal. The amount of Ca in the total compartment is measured isotopically in intact functional cells (using the on-line "scintillation disk" technique) under a variety of perfusion conditions. Under identical labeling conditions, sarcolemmal membranes are rapidly (within a few hundred milliseconds) isolated from another set of intact cells by "gas dissection," and the amount of Ca bound to the membranes is measured. Probes that specifically decrease SR Ca content (thapsigargin, caffeine, low-dose ryanodine) decrease total cell content and sarcolemmal binding proportionally. High-dose ryanodine (producing closure of SR channels) markedly reduces sarcolemmal binding relative to total content of the compartment. The sarcolemmal sites saturate between 1 and 2 mM extracellular Ca ([Ca]o), whereas the total compartment saturates between 4 and 6 mM [Ca]o. Below 1 mM [Ca]o, sarcolemmal binding is maintained relative to total compartment content. Finally, the total compartment increases after reversal of the intracellular Na to extracellular Na ([Na]i/[Na]o) gradient with sarcolemmal content-to-total content ratio dependent on the method used to reverse the [Na]i/[Na]o ratio. The results are consistent with localization of the Na/Ca exchange-dependent compartment to the subsarcolemmal region ("cleft") where JSR Ca is in equilibrium with anionic inner sarcolemmal leaflet Ca binding sites. PMID- 7840140 TI - Role of protein kinase C and tyrosine kinase activity in IFN-gamma-induced expression of the class II MHC gene. AB - Astrocytes are induced by interferon-gamma (IFN-gamma) to express class II major histocompatibility complex (MHC) antigens. Our previous studies demonstrated that IFN-gamma-initiated signaling events important for class II expression include activation of protein kinase C (PKC) and the Na+/H+ antiporter. We have extended these studies and found that protein tyrosine kinase (PTK) activity is also required for class II expression. Treatment of astrocytes with inhibitors specific for PKC and PTK blocked INF-gamma-induced class II gene transcription, mRNA expression, and protein expression. Immunoblotting and immunoprecipitation experiments demonstrated that IFN-gamma induced tyrosine phosphorylation of the p91 component of ISGF3, which is blocked by preincubation of cells with PTK inhibitors. Treatment of astrocytes with IFN-gamma and either PKC and PTK inhibitors changed the mobility and intensity of a nuclear factor, IFN-gamma enhanced factor X, which binds to the X box of the class II MHC promoter. Taken together, these data provide evidence that activation of both PTK and PKC is required for IFN-gamma-induced expression of the class II gene. PMID- 7840141 TI - Phospholipase A2 activation in human neutrophils requires influx of extracellular Ca2+ and leukotriene B4. AB - We have demonstrated that phospolipase A2 (PLA2) activation in human neutrophils requires both the influx of extracellular Ca2+ and leukotriene B4 (LTB4). Surprisingly, the eicosanoids (LTB4 and its omega-oxidation products) formed were quantitatively very similar in both thapsigargin (Thap)- and A-23187-stimulated neutrophils. In contrast, Thap had very little effect on the activation of PLA2 when 5-lipoxygenase (5-LO) was blocked by BW755C or MK-886, whereas A-23187 caused a substantial activation. The lack of PLA2 activation in Thap-stimulated neutrophils results from the inhibition of LTB4 formation in the presence of 5-LO inhibitors. It appears that A-23187 activates both LTB4-dependent and independent PLA2, whereas Thap activates LTB4-dependent PLA2. Experiments with ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid demonstrated that activation of Thap-sensitive PLA2 and 5-LO requires the influx of Ca2+. Neither the transient elevation of cytosolic Ca2+ from intracellular stores nor the sustained Ca2+ influx alone without LTB4 appears sufficient to cause the activation of LTB4-dependent PLA2. We suggest that the activation of LTB4-dependent PLA2 involves 1) a sustained elevation of cytosolic Ca2+ coupled to the influx of extracellular Ca2+ and 2) a coupling between LTB4 and its receptor. We conclude that LTB4-dependent PLA2 plays an important role in the poststimulatory formation of lipid mediators such as prostaglandins, leukotrienes, and platelet-activating factor. PMID- 7840142 TI - Kinetics of Na+/H+ exchange in vascular smooth muscle cells from WKY and SHR: effects of phorbol ester. AB - The kinetic properties of Na+/H+ exchange were investigated in vascular smooth muscle cells (VSMC) in culture from normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). Antiport activity was measured in 2',7' bis(carboxyethyl)-5(6)-carboxyfluorescein-loaded cells after nigericin-induced cytosolic acidification. Studies were performed without (control) and with pretreatment of the cells with phorbol 12-myristate 13-acetate (PMA; 200 nM). Na+/H+ exchange markedly differed between the two strains with lower Hill coefficients [1.56 +/- 0.17 (SE) vs. 2.62 +/- 0.36] and higher maximal activity (Vmax) values (55.85 +/- 5.24 vs. 31.11 +/- 2.38 mmol H+.l-1.min-1) in SHR compared with WKY cell lines. PMA markedly altered the antiport kinetics in WKY VSMC with a decrease in the Hill coefficient (1.75 +/- 0.14) without affecting Vmax (31.88 +/- 1.55 mmol H+.l-1.min-1). In VSMC from SHR, PMA had no effect on the kinetic variables investigated. Thus two kinetic abnormalities are present with respect to Na+/H+ antiport activity in VSMC from SHR compared with WKY, i.e., increased Vmax and decreased Hill coefficient. The observation that PMA does not affect the kinetics of the Na+/H+ antiport in VSMC from SHR suggests a marked degree of antiporter prestimulation in this animal model of genetic hypertension. PMID- 7840143 TI - Osmotic activation of a Na(+)-dependent Cl-/HCO3- exchanger. AB - In many systems, osmotically induced cell shrinkage activates the Na+/H+ exchanger. To assess the role of H(+)-extruding transporters in the response to osmotic shrinkage in vascular smooth muscle (VSM) and Chinese hamster ovary (CHO) cells, intracellular pH (pHi) was measured with 2',7'-bis(carboxy-ethyl)-5(6)- carboxyfluorescein-acetoxymethyl ester (BCECF-AM) after exposing cells to hypertonic medium. In nominally HCO(3-)-free medium, addition of 200 mM sucrose caused pHi to increase 0.33 pH unit on average in VSM cells but only 0.13 pH unit in CHO cells. Permeant solutes failed to increase pHi significantly. Cytochalasin B (1-20 microM), colchicine (1-10 microM), Ca2+ removal, and downregulation of protein kinase C activity did not affect osmotic activation of H+ extrusion in either cell type. Additional work was carried out to determine why osmotic activation of H+ extrusion was less in CHO than in VSM cells. In CHO cells, the osmotically induced delta pHi was only weakly sensitive to amiloride, suggesting that osmotic forces may activate an H+ transport system other than Na+/H+ exchange. In the presence of 10 mM HCO3-, osmotically induced delta pHi decreased by 60% in VSM cells but increased by 50% in CHO cells compared with the delta pHi in HCO(3-)-free medium. Lastly, removal of extracellular Cl- did not affect osmotically induced delta pHi in VSM cells but completely abolished the response in CHO cells. We conclude that in VSM cells osmotically induced changes in pHi are mediated by Na+/H+ exchange, whereas in CHO cells they are most likely mediated by a Na(+)-dependent Cl-/HCO3- exchanger. PMID- 7840144 TI - Role for tyrosine kinases in carbachol-regulated Ca entry into colonic epithelial cells. AB - We studied a possible role of tyrosine kinases in the regulation of Ca entry into colonic epithelial cells HT-29/B6 using digital image processing of fura 2 fluorescence. Both carbachol and thapsigargin increased Ca entry to a similar extent and Ca influx was reduced by the tyrosine kinase inhibitor genistein (50 microM). Further experiments were performed in solutions containing 95 mM K to depolarize the membrane potential, and the effects of different inhibitors on influx of Ca, Mn, and Ba were compared. Genistein, but not the inactive analogue daidzein nor the protein kinase C inhibitor 1-(5-isoquinolinylsulfonyl)-2- methylpiperazine, decreased entry of all three divalent cations by 47-59%. In high-K solutions, carbachol or thapsigargin both caused intracellular Ca to increase to a plateau of 223 +/- 19 nM. This plateau was reduced by the tyrosine kinase inhibitors genistein (to 95 +/- 8 nM), lavendustin A (to 155 +/- 17 nM), and methyl-2,5-dihydroxycinnamate (to 39 +/- 3 nM). Orthovanadate, a protein tyrosine phosphatase inhibitor, prevented the inhibitory effect of genistein. Ca pumping was unaffected by genistein. Carbachol increased tyrosine phosphorylation (immunoblots with anti-phosphotyrosine antibodies) of 110-, 75-, and 70-kDa proteins, and this phosphorylation was inhibited by genistein. We conclude that carbachol and thapsigargin increase Ca entry, and tyrosine phosphorylation of some key proteins may be important for regulating this pathway. PMID- 7840145 TI - Interaction of cA-kinase and cG-kinase in mediating relaxation of dispersed smooth muscle cells. AB - The signaling pathways mediating relaxation by vasoactive intestinal peptide (VIP), peptide histidine-isoleucine amide (PHI), isoproterenol (ISO), and sodium nitroprusside (SNP) were examined in dispersed rabbit and guinea pig gastric muscle cells. In rabbit muscle cells, SNP stimulated only guanosine 3',5'-cyclic monophosphate (cGMP) and cGMP-dependent protein kinase (cG-kinase) activity; VIP stimulated adenosine 3',5'-cyclic monophosphate (cAMP) and cGMP, and both cG kinase and cAMP-dependent protein kinase (cA-kinase) activities; PHI and ISO stimulated only cAMP and cA-kinase activity, and at higher concentrations, cross activated cG-kinase. All four agents elicited concentration-dependent relaxation. N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H-89; 1 microM) selectively inhibited cA-kinase activity and abolished relaxation when only cA kinase was elevated. 8R,9S, 11S-(-)-9-methoxy-carbamyl-8-methyl-2,3,9,10 tetrahydro-8,11-epoxy- 1H,8H,11H-2,7b,11a-trizadibenzo-(a,g)-cy-cloocta-(c,d,e)- trinden-1-one (KT-5823; 1 microM) selectively inhibited cG-kinase activity and abolished relaxation when only cG-kinase was elevated. When both kinases were elevated, H-89 and KT-5823 partially inhibited relaxation and abolished relaxation in combination. In permeabilized guinea pig and rabbit muscle cells, all agents elicited relaxation and inhibited inositol 1,4,5-trisphosphate (IP3) induced Ca2+ release. Both functions were inhibited in parallel fashion by protein kinase inhibitor PKI(6-22) and by KT-5823. We conclude that cA-kinase and cG-kinase act separately and in concert to inhibit IP3-dependent Ca2+ release and induce relaxation. PMID- 7840146 TI - ATP-sensitive K channel modulation by products of PLA2 action in the insulin secreting HIT cell line. AB - Insulin secretion from the islets of Langerhans may be initiated or potentiated by increased phospholipase A2 (PLA2) activity. This patch-clamp study of the insulin-secreting HIT tumor cell line assessed whether inhibition of the ATP sensitive potassium (KATP) channel, which modulates the secretion-associated beta cell electrical activity, contributes to the secretory response to PLA2. Exogenous PLA2 (100-1,000 mU/ml) reversibly suppressed KATP channel activity in excised inside-out patches. Similarly, mellitin (0.5-5 micrograms/ml), a bee venom component that increases phospholipid susceptibility to metabolism by PLA2, suppressed KATP channel activity, suggesting that PLA2 is present in excised patches. Adding low concentrations of particular lysophospholipids or arachidonic acid also reduced KATP channel activity in excised inside-out patches. In cell attached patches, the lysophospholipids had a similar effect, whereas arachidonic acid caused channel stimulation; this latter effect was reversed by cyclooxygenase inhibitors. A recently identified ATP-stimulated PLA2 in beta cells has been proposed as an important mediator of stimulus-secretion coupling in response to nutrients. The present data illustrating that initial products of PLA2 action on membrane phospholipids reduce KATP channel activity indicate a mechanism that may contribute an early stimulatory signal in this pathway. The observation that metabolism of arachidonate via the cyclooxygenase pathway causes KATP channel stimulation demonstrates a potential counterregulatory mechanism. PMID- 7840147 TI - Cloning, functional expression, and characterization of a PKA-activated gastric Cl- channel. AB - cDNA encoding a Cl- channel was isolated from a rabbit gastric library, sequenced, and expressed in Xenopus oocytes. The predicted protein (898 amino acids, relative molecular mass 98,433 Da) was overall 93% similar to the rat brain ClC-2 Cl- channel. However, a 151-amino acid stretch toward the COOH terminus was 74% similar to ClC-2 with six amino acids deleted. Two new potential protein kinase A (PKA) phosphorylation sites (also protein kinase C phosphorylation sites) were introduced. cRNA-injected Xenopus oocytes expressed a Cl- channel that was active at pHtrans 3 and had a linear current-voltage (I-V) curve and a slope conductance of 29 +/- 1 pS at 800 mM CsCl. A fivefold Cl- gradient caused a rightward shift in the I-V curve with a reversal potential of +30 +/- 3 mV, indicating anion selectivity. The selectivity was I- > Cl- > NO3-. The native and recombinant Cl- channel were both activated in vitro by PKA catalytic subunit and ATP. The electrophysiological and regulatory properties of the cloned and the native channel were similar. The cloned protein may be the Cl- channel involved in gastric HCl secretion. PMID- 7840148 TI - Hypertonic activation of AE2 anion exchanger in Xenopus oocytes via NHE-mediated intracellular alkalinization. AB - Xenopus oocytes express endogenous Na+/H+ exchange activity but lack significant endogenous Cl-/HCO3- exchange activity. Coupled operation of Na+/H+ exchange and Cl-/HCO3- exchange contributes in many cell types to the cellular response to hypertonic stress. We therefore examined in Xenopus oocytes the osmotic regulation of chloride transport mediated by recombinant anion exchanger proteins AE2 and AE1. Hypotonicity was without effect on either anion transporter. Hypertonicity activated AE2-associated 36Cl- influx and efflux in a time- and osmolarity-dependent manner, whether incremental osmoles were charged or uncharged, but had no measurable effect on AE1 function. Hypertonic stimulation of AE2 was completely inhibited by Na+ removal or by addition of amiloride. In contrast, neither maneuver altered isotonic activity of AE2. Hypertonicity also induced amiloride-sensitive elevation of oocyte intracellular pH (pHi), and shifted the sigmoidal relationship of extracellular pH vs. AE2 activity > or = 0.5 units to the acid. Injection of pH 7.4 buffer into oocytes attenuated both hypertonic alkalinization and activation of AE2-associated 36Cl- influx, without inhibition of isotonic AE2 function. These data demonstrate that recombinant AE2 expressed in Xenopus oocytes is activated by increased pHi and that hypertonic activation of AE2 is secondary to hypertonic activation of Na+/H+ exchange. PMID- 7840149 TI - Ca(2+)-insensitive sustained contraction of skinned smooth muscle after acidic ADP treatment. AB - After an acidic treatment in the presence of ADP, Triton X-100-skinned rabbit aortic smooth muscle strips were found to develop a large sustained, Ca(2+) insensitive tension when returned to a relaxing solution with neutral pH. The presence of ADP during treatment was essential for the manifestation of the Ca(2+)-insensitive contraction. This contraction was reversibly eliminated by withdrawal of MgATP or addition of vanadate and was found to be accompanied by an extraordinarily high level of 20-kDa myosin light-chain (MLC20) phosphorylation. The rate constant for dephosphorylation of MLC20 in treated strips was about one twenty-fifth that in untreated control, when determined after removal of Ca2+, Mg2+, and ATP. Two-dimensional phosphopeptide mapping of tryptic digests of MLC20 showed that most incorporated phosphate was in the peptides which would be phosphorylated by myosin light-chain kinase. These results provide strong evidence that ADP inactivates myosin light-chain phosphatase under acidic conditions. PMID- 7840150 TI - Regulation of intracellular pH in J774 murine macrophage cells: H+ extrusion processes. AB - Mechanisms of intracellular pH (pHi) regulation were characterized in the murine macrophage cell line J774.1, using 2',7'-bis(carboxyethyl)-5(6) carboxyfluorescein to measure pHi. Under nominally HCO3(-)-free conditions, resting pHi of nonadherent J774.1 cells was 7.53 +/- 0.02 (n = 86), and of adherent cells was 7.59 +/- 0.02 (n = 97). In the presence of HCO3-/CO2, pHi values were reduced to 7.41 +/- 0.02 (n = 12) and 7.40 +/- 0.01 (n = 28), respectively. Amiloride, an inhibitor of Na+/H+ exchange, did not affect resting pHi. Inhibitors of a vacuolar type H(+)-ATPase [bafilomycin A1, N-ethylmaleimide (NEM), 7-chloro-4-nitrobenz-2-oxa-1,3-diazide (NBD), and p chloromercuriphenylsulfonic acid (pCMBS)] reduced pHi by at least 0.2 pH units. Inhibitors of other classes of H(+)-ATPases (oligomycin, azide, vanadate, and ouabain) were without effect. Inhibition of H+ efflux, measured by the change in extracellular pH of a weakly buffered cell suspension, followed the same pharmacological profile, indicating that the reduction of pHi was due to inhibition of H+ extrusion. Mechanisms of recovery from an imposed intracellular acid load were also investigated. In NaCl-Hanks' solution, pHi recovered exponentially to normal within 2 min. The initial rate of recovery was inhibited > 90% by amiloride or by replacement of extracellular Na+ concentration by N methyl-glucamine. Inhibitors of the vacuolar H(+)-ATPase also inhibited recovery. NEM and NBD nonspecifically inhibited all recovery. Bafilomycin A1 and pCMBS did not inhibit the initial amiloride-sensitive portion of recovery, but they did inhibit a late component of recovery when pHi was above 7.0. We conclude that the Na+/H+ exchanger is primarily responsible for recovery from an acid load but does not regulate resting pHi. Conversely, a vacuolar H(+)-ATPase regulates the resting pHi of J774 cells but contributes little to recovery from acidification. PMID- 7840151 TI - Corticoid-induced differentiation of amiloride-blockable active Na+ transport across larval bullfrog skin in vitro. AB - The hormone-induced differentiation of an active Na+ transport across larval bullfrog skin during metamorphosis was investigated in vitro and in vivo. In in vitro experiments, EDTA-treated larval dorsal skin from which apical cells were removed was used. Even in the absence of thyroid hormone, corticoids induced the differentiation. Although aldosterone was the most potent hormone, hydrocortisone or corticosterone was also effective. Prolactin inhibited the corticoid-induced differentiation. The differentiation of the transport system coincided almost exactly with the appearance of adult features of the epidermis, namely, the epidermis at 7 days carried the human blood group antigen A, a specific molecular marker of adult-type bullfrog epidermis. The transport system appeared to develop in cells that had been newly generated from basal cells. On the contrary, in in vivo experiments, the effect of amiloride on the short-circuit current of the skin of tadpoles raised in the presence of aldosterone was very small, suggesting that a mechanism exists to inhibit the ability of aldosterone to induce the differentiation of the transport system in vivo. PMID- 7840152 TI - alpha-Ketoacids scavenge H2O2 in vitro and in vivo and reduce menadione-induced DNA injury and cytotoxicity. AB - We demonstrate that alpha-ketoacids reduce and, in some instances, abrogate menadione-induced DNA damage and cytotoxicity in the human breast cancer cell line, MCF7. We confirm that alpha-ketoacids quench the copious amounts of H2O2 generated by menadione while these alpha-ketoacids undergo nonenzymatic oxidative decarboxylation; our data thus support enhanced H2O2 production as an important pathway for menadione-induced DNA damage and cytotoxicity. We also demonstrate that alpha-ketoacids scavenge H2O2 generated by mitochondria and microsomes when these organelles are exposed to menadione; additionally, alpha-ketoacids protect oxidant-vulnerable enzymes against functional impairment induced by H2O2. Finally, we provide the first in vivo demonstration that acute elevations in concentrations of alpha-ketoacids in rat tissues and urine scavenge H2O2. We conclude that enhanced H2O2 production is a major pathway for menadione-induced DNA damage and cytotoxicity and that the diverse alpha-ketoacids present within the cell must be considered, along with glutathione peroxidase and catalase, as part of the intracellular antioxidant defense mechanisms that regulate the ambient levels of H2O2. PMID- 7840153 TI - Thin filament regulation of force activation is not essential in single vascular smooth muscle cells. AB - To investigate thin filament regulation of force activation in smooth muscle, we recorded force and stiffness of alpha-toxin-permeabilized single smooth muscle cells. At pCa 9, the rigor state was characterized by high in-phase stiffness, low force, and low quadrature stiffness, suggesting that the attachment of rigor cross bridges does not depend on either Ca2+ or myosin light chain (MLC) phosphorylation, and cross bridges can enter a rigor state without producing force. At pCa 4, 20 microM ATP increased force, in-phase stiffness, and quadrature stiffness, while 20 microM CTP did not increase any of these parameters, suggesting that although MLC phosphorylation is not required for the formation of rigor cross bridges, MLC phosphorylation is required for detached cross bridges to attach to actin and undergo a force-producing isomerization. These results also suggest that for smooth muscle, force activation is regulated by myosin light-chain kinase. From rigor, 20 microM ATP (pCa 9) increased force and quadrature without changing in-phase stiffness. This force increase could be explained if in rigor solution both actomyosin (AM) and AM.ADP cross bridges exist (2, 32), and ATP-induced detachment of AM cross bridges is accompanied by AM.ADP cross bridges undergoing a force-producing isomerization in combination with cooperative cross-bridge reattachment (36). Thus results of our experiments suggest that thin filament-based regulation of force activation is not essential in smooth muscle, and a population of cross bridges must begin in an attached state for force to be produced in the absence of MLC phosphorylation. PMID- 7840154 TI - Sarcoplasmic reticulum gene expression in pressure overload-induced cardiac hypertrophy in rabbit. AB - Pressure overload (PO)-induced cardiac hypertrophy in rabbits has been utilized extensively to study alterations in systolic and diastolic functions of the heart. In earlier studies we showed that the levels of mRNA encoding two important sarcoplasmic reticulum (SR) proteins, the cardiac/slow-twitch muscle Ca(2+)-ATPase (SERCA2a) and phospholamban, were decreased in PO rabbit hearts. In this study, we analyzed the expression of the Ca(2+)-release channel (ryanodine receptor), calsequestrin, SERCA2a, and phospholamban in PO-induced cardiac hypertrophy after 2, 4, 8, and 16 days of pulmonary artery banding. Northern blot and slot blot analyses showed that the steady-state level of mRNA encoding the cardiac ryanodine receptor, SERCA2a, and phospholamban was decreased significantly as early as 2 days after PO. In 16-day PO hearts, SERCA2a mRNA was reduced to 7.9 +/- 3.4% (P < 0.05), phospholamban mRNA was reduced to 15.9 +/- 6.5% (P < 0.05), and ryanodine receptor mRNA was reduced to 49.2 +/- 23.6% (P < 0.05). In this study, calsequestrin mRNA levels were also reduced to 29.9 +/- 15.2% by day 16 (P < 0.05). ATP-dependent Ca2+ uptake was reduced to 78% (P < 0.05); in contrast, the steady-state formation of ATPase phosphoenzyme was reduced to 81% of control (P < 0.05) and Ca(2+)-ATPase protein was reduced to 78% of control (P < 0.05) in crude SR vesicles or total muscle homogenate obtained from 16-day PO hearts. On the basis of these data, we propose that decreases in the expression of SR proteins may contribute to dysfunctions seen in systolic and diastolic properties of the hypertrophied myocardium. PMID- 7840155 TI - Inhibition of cytochrome P-450 reduces voltage-gated K+ currents in pulmonary arterial myocytes. AB - Cytochrome P-450 (P-450) is a NADPH-requiring and O2-dependent monooxygenase system. It is present in lung and has been postulated to act as an O2 sensor in hypoxic pulmonary vasoconstriction. To determine whether P-450 is involved in the regulation of voltage-gated K+ (KV) channel activity in pulmonary artery (PA) myocytes, we used the whole cell patch-clamp technique to evaluate the effects of P-450 inhibitors on KV channel currents (IKV) and membrane potential (Em). Bath application of the P-450 inhibitors clotrimazole, miconazole, and 1 aminobenzotriazole (1-ABT) significantly and reversibly inhibited steady-state IKV (IKss) and depolarized PA cells bathed in either Ca(2+)-containing (1.8 mM) or Ca(2+)-free [0.5-1 mM ethylene glycol-bis(beta-aminoethyl ether)-N,N,N'N' tetraacetic acid present] bath solution. Clotrimazole (1 microM), miconazole (10 microM), and 1-ABT (1 mM) reversibly reduced IKss, elicited by a test potential of +80 mV, by 40, 70, and 31%, respectively. Pretreatment of PA smooth muscle cells with 10 mM 4-aminopyridine (4-AP) prevented the subsequent inhibitory effect of clotrimazole on IKV. However, pretreatment of the cells with 1 mM tetraethylammonium negligibly altered the effects of miconazole on IKV and Em. In current-clamp (I = 0) measurements, clotrimazole depolarized PA myocytes by 9 and 11 mV during perfusion with Ca(2+)-containing and Ca(2+)-free bath solution, respectively. 1-ABT also caused a 9-mV depolarization in PA myocytes bathed in Ca(2+)-free solution. These effects are similar to those induced by hypoxia, reduced glutathione, and 4-AP. Clotrimazole also decreased IKV and depolarized mesenteric arterial myocytes. These data raise the possibility that the P-450 system, due to its influence on IKV and sensitivity to O2 tension and NADPH, may play a role in linking the regulation of pulmonary vascular tone to the alteration of cellular redox status through a common pathway of KV channel activity. PMID- 7840156 TI - Kinetics of [Ca]i decline in cardiac myocytes depend on peak [Ca]i. AB - The rate of decline of free intracellular Ca concentration ([Ca]i) is a potentially useful index of the function of Ca transport systems. However, interpretations of these results may depend on multiple Ca transport systems and interaction with intracellular Ca binding sites. We measured [Ca]i in voltage clamped ventricular myocytes isolated from rat hearts using indo 1 fluorescence. Conditions were chosen where [Ca]i decline was expected to depend almost exclusively on the sarcoplasmic reticulum Ca pump. The half time of [Ca]i decline (t1/2) decreased as the amplitude of the intracellular Ca (Cai) transient increased. This is not the result that would be expected from a transport system where the transport rate is a linear function of free [Ca]i. In this case the time constant of [Ca]i decline (tau) should be independent of the peak value of [Ca]i. This is also true if linear buffering of Cai is included. We develop a simple but more realistic theoretical framework where Ca transport rate and Ca binding both depend on free [Ca]i with Michaelis-Menten type functions. We demonstrate that the observed decline in apparent tau with increasing peak [Ca]i is entirely expected on theoretical grounds and over a wide range of characteristics for Ca transport and binding. We conclude that one cannot draw inferences about the intrinsic Ca transport function based on tau values unless the Cai transient has a comparable size. PMID- 7840157 TI - Modulation of the delayed rectifier K+ current in neurons by an angiotensin II type 2 receptor fragment. AB - Angiotensin II (ANG II) stimulates the delayed rectifier K+ current (IK) in neurons cultured from rat hypothalamus and brain stem via AT2 receptors, and this effect involves activation of a Gi protein and protein phosphatase 2A (PP2A). However, there was no evidence that the AT2 receptor involved in this response was the same as the recently cloned AT2 receptor. In the present study, intracellular injection of a 22-amino acid peptide (PEP-22) corresponding to the putative third intracellular loop of the cloned AT2 receptor elicited an increase in IK in cultured neurons that was similar to the effect produced by ANG II. Furthermore, this effect of PEP-22 was abolished by pertussis toxin (200 ng/ml, 24 h) pretreatment and also by superfusion of the PP2A inhibitor okadaic acid (10 nM), suggesting the involvement of Gi protein and PP2A, respectively. Intracellular injection of a random peptide or normal pipette solution did not affect neuronal IK. This is direct evidence to link the cloned AT2 receptor to a defined response elicited by ANG II. PMID- 7840158 TI - Kinetics of 2-deoxyglucose transport in skeletal muscle: effects of insulin and contractions. AB - There is some controversy regarding whether insulin or contractile activity alters the affinity of skeletal muscle glucose transporters for glucose and its analogues. The effects of insulin and contractions on the kinetics of glucose transport were therefore reexamined in isolated rat skeletal muscles. Concentration-dependent rates of 2-deoxyglucose (2-DG) transport were measured in the absence or presence of insulin (2 mU/ml) in the epitrochlearis and split soleus muscles. The apparent half-maximal saturating substrate concentration (Km) for basal 2-DG transport (approximately 12 mM) was similar for the split soleus and epitrochlearis, and the apparent Km was not changed by insulin in either muscle type. The presence of 2 mU/ml insulin increased the maximal transport velocity (Vmax) approximately fourfold in the epitrochlearis and approximately eightfold in the split soleus. In the epitrochlearis, in vitro muscle contractions also resulted in an approximately fourfold increases in Vmax with no change in apparent Km. The combined effects of insulin and contractions on Vmax were completely additive, but the apparent Km was not different from insulin alone. The apparent Km values for basal and insulin-stimulated glucose transport were further characterized in the epitrochlearis isolated from transgenic mice overexpressing the GLUT-1 isoform in the sarcolemma and their nontransgenic littermates. The apparent Km for basal 2-DG transport in the transgenic muscle (9 mM) was not significantly different from the apparent Km for insulin-stimulated transport in the control muscle (10 mM). The present study provides evidence that insulin and contractions, either alone or in combination, increase glucose transport activity in skeletal muscle by increasing Vmax, with no significant change in Km. Our results also suggest that, in intact skeletal muscle, the Km for basal glucose transport (a process mediated primarily by GLUT-1) is similar to the Km values for stimulated transport, mediated predominantly by GLUT-4. PMID- 7840159 TI - Thrombin receptor-activating peptide sensitizes the human endothelial thrombin receptor. AB - Receptor-operated effects of alpha-thrombin and of the thrombin receptor activating peptide TRAP14 on cytoplasmic Ca2+ concentration ([Ca2+]i) were examined in fura 2-loaded endothelial cells. Experiments with hirudin showed that alpha-thrombin-induced Ca2+ influx requires the continuous presence of active alpha-thrombin. YFLLRNP, known to antagonize alpha-thrombin- and TRAP7-induced [Ca2+]i transients in platelets, did not antagonize [Ca2+]i transients in response to alpha-thrombin and TRAP14 in human umbilical vein endothelial cells (HUVEC). Repetitive short-term stimulations with alpha-thrombin desensitized [Ca2+]i transients to subsequent stimulations with either alpha-thrombin or TRAP14. In contrast, repeated short-term stimulations with TRAP14 sensitized [Ca2+]i transients to subsequent stimulations with either agonist. Blockade of Ca2+ influx by SKF-96365 abolished the sensitizing effect of TRAP14. The results indicate distinct characteristics of platelet and endothelial thrombin receptors and suggest that alpha-thrombin and TRAP14 activate the receptor differently. It appears that receptor desensitization occurs independently of TRAP14 binding and, hence, tethered ligand binding to and activation of the receptor. Persistent receptor desensitization after alpha-thrombin seems to depend on both alpha thrombin binding to the hirudin-like receptor domain and the irreversible proteolytic cleavage of the receptor. It does not involve the TRAP14/tethered ligand binding site of the receptor. TRAP14 primes the receptor by a mechanism mediated by Ca2+ influx. PMID- 7840160 TI - Effects of intracellular acidosis on Ca2+ activation, contraction, and relaxation of frog skeletal muscle. AB - The goal of this study was to determine the effects of intracellular acidosis (pH approximately 6.3) of frog skeletal muscle on force and on intracellular Ca2+ concentration ([Ca2+]i; measured at 20 degrees C using indo 1 fluorescence). Acidosis reduced tetanic force by only 11 +/- 2% (mean +/- SE, n = 8) but increased tetanic [Ca2+]i by 33 +/- 6%, suggesting that acidosis reduced the maximum Ca(2+)-activated force. During relaxation, the [Ca2+]i at half-maximal force was doubled with acidosis, suggesting that acidosis altered the Ca(2+) force relationship. Acidosis markedly slowed force relaxation and [Ca2+]i decline (time constants fitted to force and [Ca2+]i during relaxation increased by 133 +/ 20 and 68 +/- 13%, respectively, with acidosis), suggesting that slowed force relaxation with acidosis may arise from slowed Ca2+ clearance from the cytosol. Late in relaxation, at approximately 30% of initial force, there was a transient phase of [Ca2+]i increase that was delayed with acidosis in proportion to the slowing of force relaxation. This is consistent with previous suggestions that dissociation of cross-bridges from the thin filament during relaxation promotes Ca2+ release to the cytosol from troponin. This study concludes that in skeletal muscle acidosis has little effect on tetanic force and that the major effects are decreased Ca2+ sensitivity and slower relaxation. PMID- 7840161 TI - Effects of estrogens on Ca channels in myometrial cells isolated from pregnant rats. AB - Whole cell patch-clamp techniques were applied to cultured smooth muscle cells isolated from the longitudinal layer of the late pregnant rat myometrium. Effects of estrogens on Ca channels were examined. Inhibitory effects of beta-estradiol (1 microM) on Ca channel currents were recognized. The inhibitory effects of beta estradiol depended on holding potentials. beta-Estradiol shifted the steady-state inactivation curve in the negative direction by 7 mV at mid potential (n = 9). Diethylstilbestrol, a synthetic estrogen, gave similar effects on Ca channel currents at lower concentration (2 microM) to those of beta-estradiol. Strong inhibitory effects on Ca channel currents were obtained by higher concentration (20 microM). Diethylstilbestrol shifted the steady-state inactivation curve in the negative direction by 7 mV at mid potential (n = 5). The results indicate that estrogens influence the voltage dependency and the whole cell conductance of Ca channels of pregnant rat myometrial cells. The acute effect of estrogens may cause both electrical and mechanical depression of myometrium. PMID- 7840162 TI - cAMP-activated Cl- channels in primary cultures of spiny dogfish (Squalus acanthias) rectal gland. AB - Whole cell and single-channel patch-clamp techniques were used to identify and characterize the Cl- currents responsible for adenosine 3',5'-cyclic monophosphate (cAMP)-mediated Cl- secretion in the rectal gland of the spiny dogfish (Squalus acanthias). During whole cell recordings, in cultured rectal gland cells forskolin (10 microM) and 8-(4-chlorophenylthio)adenosine 3',5' cyclic monophosphate (400 microM) stimulated a 28-fold increase in Cl- conductance (n = 10). This cAMP-activated conductance pathway had a linear current-voltage (I-V) relationship that was time and voltage independent. Substitution of 235 meq Cl- with I- in the bath inhibited the cAMP-activated current at both positive and negative voltages (64%). Glibenclamide (60 microM) abolished the cAMP-stimulated current, and its effect was irreversible (n = 3). During cell-attached recording, increased cellular cAMP activated single Cl- channels in nine previously quiet patches. These channels had a linear I-V relationship with an average single-channel conductance of 5.1 +/- 0.2 pS (n = 6). Similar properties were observed in excised inside-out patches, permitting further characterization of the single-channel properties. Excised quiescent patches could be activated by the addition of ATP and protein kinase A. Replacing bath Cl- with I- inhibited both inward and outward currents (n = 3). In three inside-out patches, glibenclamide (300 microM) reversibly reduced open probability by 74%, with no effect on single-channel current amplitude. Similar results were obtained in four outside-out recordings. These results suggest that increased cellular cAMP in dogfish rectal gland activates a small linear Cl- channel that resembles human cystic fibrosis transmembrane conductance regulator in its biophysical and pharmacological properties. PMID- 7840163 TI - Stimulated osteoclastic and suppressed osteoblastic activity in metabolic but not respiratory acidosis. AB - When bone is cultured in acidic medium produced by a reduced bicarbonate concentration ([HCO(3-)]), a model of metabolic acidosis, there is greater net calcium efflux than when the same decrement in pH is produced by an increased partial pressure of carbon dioxide (PCO2), a model of respiratory acidosis. To determine the effects of metabolic and respiratory acidosis on bone cell function we cultured neonatal mouse calvariae for 48 h under control conditions (pH approximately 7.40, PCO2 approximately 41 mmHg, [HCO(3-)] approximately 25 meq/l) or under isohydric acidic conditions simulating metabolic (pH approximately 7.09, [HCO(3-)] approximately 12) or respiratory (pH approximately 7.10, PCO2 approximately 86) acidosis and measured osteoblastic collagen synthesis and alkaline phosphatase activity and osteoclastic beta-glucuronidase activity. Collagen synthesis was inhibited by metabolic (23.2 +/- 1.3 vs. 30.3 +/- 1.0% in control) but was not altered by respiratory (32.3 +/- 0.6) acidosis. Alkaline phosphatase activity was inhibited by metabolic (402 +/- 16 vs. 471 +/- 15 nmol P.min-1.mg protein-1 in control) but not altered by respiratory (437 +/- 25) acidosis. beta-Glucuronidase activity was stimulated by metabolic (1.02 +/- 0.06 vs. 0.78 +/- 0.05 micrograms phenolphthalein released.bone-1.h-1 in control) but not altered by respiratory (0.73 +/- 0.06) acidosis. Net calcium efflux in control was increased by metabolic (783 +/- 57 vs. 20 +/- 57 nmol.bone-1.48 h-1 in control) and by respiratory (213 +/- 45) acidosis; however, calcium efflux with metabolic was greater than with respiratory acidosis.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7840164 TI - Regulatory volume decrease in frog retinal pigment epithelium. AB - To measure changes in cell water during cell volume regulation, retinal pigment epithelial cells were loaded with tetramethylammonium (TMA). Regulatory volume decrease (RVD) in TMA-loaded retinal pigment epithelial (RPE) cells was measured using double-barreled K(+)-specific microelectrodes. Hyposmotic removal of 12.5 mM NaCl from the apical bath caused bullfrog RPE cells to rapidly swell by approximately 10% and to recover to control level within 10-15 min. Hyposmotic RVD was inhibited by 5 mM basal but not apical BaCl2. Raising K+ in the basal bath from 2 to 12 mM also inhibited RVD. Hyposmotic swelling was accompanied by an increase in the ratio of apical to basolateral membrane resistance (Ra/Rb). The swelling-induced increase in Ra/Rb was inhibited by 5 mM BaCl2. Together, the above findings suggest that hyposmotic swelling enhances basolateral K+ conductance such that K+ and presumably anion efflux mediate net solute and water loss during RVD. RPE cells can also regulate their volume when swollen in isosmotic Ringer solution under certain conditions. When urea or apical HCO3- was used to induce cell swelling, RPE cells underwent an RVD. In contrast, isosmotic elevation of apical K+ from 2 to 5 mM resulted in an increase in RPE cell volume with no subsequent RVD. Thus the method used to swell RPE cells is an important determinant of RVD. Because changes in RPE cell volume in vivo may alter the volume and composition of the extracellular (subretinal) space surrounding the photoreceptors, isosmotic volume regulation may play an important physiological role in maintaining the integrity and health of the neural retina under normal and pathophysiological conditions. PMID- 7840165 TI - Effect of insulin on uric acid excretion in humans. AB - Although hyperuricemia is a frequent finding in insulin-resistant states, insulin's effect on renal uric acid (UA) handling is not known. In 20 healthy volunteers, diastolic blood pressure, body weight, and fasting plasma insulin were positively (and age was negatively) related to fasting plasma UA concentrations, together accounting for 53% of their variability. During an insulin clamp, urine flow was lower than during fasting conditions (1.01 +/- 0.12 vs. 1.56 +/- 0.32 ml/min, P = 0.04), whereas creatinine clearance was unchanged (129 +/- 7 and 131 +/- 9 ml/min, P = not significant). Hyperinsulinemia did not alter serum UA concentrations (303 +/- 13 vs. 304 +/- 12 microM) but caused a significant decrease in urinary UA excretion [whether expressed as absolute excretion rate (1.66 +/- 0.21 vs. 2.12 +/- 0.23 mumol/min, P = 0.03), clearance rate (5.6 +/- 0.8 vs. 7.3 +/- 0.8 ml/min, P = 0.03), or fractional excretion (4.48 +/- 0.80 ml/min vs. 6.06 +/- 0.64%, P < 0.03)]. Hyperinsulinemia was also associated with a 30% (P < 0.001) fall in urine Na excretion. Fractional UA excretion was related to Na fractional excretion under basal conditions (r = 0.59, P < 0.01) and during the insulin period (r = 0.53, P < 0.02). Furthermore, the insulin-induced changes in fractional UA and Na excretion correlated with one another (r = 0.66, P < 0.001). Physiological hyperinsulinemia acutely reduces urinary UA and Na excretion in a coupled fashion. PMID- 7840166 TI - Differential short- and long-term effects of insulin on ANG II action in human adrenal glomerulosa cells. AB - Insulin is known to modulate several functions in bovine adrenal cells, including steroidogenesis and growth. However, the role of insulin in regulating aldosterone synthesis in human adrenal glomerulosa cells has not been studied. In the present studies, we have examined the acute and chronic effects of insulin on angiotensin II (ANG II)-induced aldosterone synthesis in cultured normal and adenomatous human adrenal glomerulosa cells. Short-term insulin treatment (1.5 h) resulted in inhibition of ANG II-induced aldosterone synthesis. In contrast, chronic treatment (30 h) resulted in potentiation of ANG II action. The 12 lipoxygenase pathway of arachidonate metabolism has been shown to play a key role in ANG II-induced aldosterone synthesis. The acute inhibitory effects of insulin were in part mediated by inhibition of the 12-lipoxygenase pathway. The chronic stimulatory effect of insulin seemed to be due at least in part to the upregulation of cytochrome P-450 side-chain cleavage enzyme levels. These findings suggest that insulin has a differential temporal effect on ANG II action and therefore may be an important regulator of ANG II-induced aldosterone synthesis in the adrenal. PMID- 7840167 TI - DHEA administration increases rapid eye movement sleep and EEG power in the sigma frequency range. AB - Dehydroepi-androsterone (DHEA) exhibits various behavioral effects in mammals, at least one of which is enhancement of memory that appears to be mediated by an interaction with the gamma-aminobutyric acidA (GABAA) receptor complex. We investigated the effects of a single oral dose of DHEA (500 mg) on sleep stages, sleep stage-specific electroencephalogram (EEG) power spectra, and concurrent hormone secretion in 10 healthy young men. DHEA administration induced a significant (P < 0.05) increase in rapid eye movement (REM) sleep, whereas all other sleep variables remained unchanged compared with the placebo condition. Spectral analysis of five selected EEG bands revealed significantly (P < 0.05) enhanced EEG activity in the sigma frequency range during REM sleep in the first 2-h sleep period after DHEA administration. In contrast, the EEG power spectra of non-REM sleep were not affected, nor were the nocturnal time course curves of plasma cortisol, growth hormone, or testosterone concentration. The results suggest that DHEA administration has a mixed GABAA-agonistic/antagonistic effect, exerted either directly or through DHEA-induced changes in steroid metabolism. Because REM sleep has been implicated in memory storage, its augmentation in the present study suggests the potential clinical usefulness of DHEA in age-related dementia. PMID- 7840168 TI - Differential release of tumor necrosis factor and IL-6 from adrenal zona glomerulosa cells in vitro. AB - In previous studies, rat adrenal zona glomerulosa (ZG) cells were demonstrated to release interleukin-6 (IL-6). In the current study, cultures of ZG cells and bioassays for tumor necrosis factor (TNF) and IL-6 were used to determine if ZG cells release TNF and to define more fully the factors that regulate ZG IL-6 release. ZG cells released IL-6 and TNF, and this release was stimulated by lipopolysaccharide, interleukin-1 alpha, interleukin-1 beta, a protein kinase C activator, and a calcium ionophore without affecting intracellular adenosine 3', 5'-cyclic monophosphate (cAMP) content. In contrast, adrenocorticotropic hormone (ACTH) increased the intracellular cAMP content, increased basal and secretagogue stimulated IL-6 release but decreased basal and secretagogue-stimulated TNF release. The effects of ACTH on IL-6 and TNF release may be mediated by increases in intracellular cAMP because ACTH and dibutyryl cAMP modified IL-6 and TNF release in an identical manner. Therefore, IL-6 and TNF release from ZG cells can be differentially regulated. Because IL-6 and TNF modify adrenal steroid release, the adrenal production of these cytokines may have a role in the stress response. PMID- 7840169 TI - Insulin-mediated changes in PD and glucose uptake after correction of acidosis in humans with CRF. AB - To test the hypothesis that acidosis contributes to the insulin resistance of chronic renal failure (CRF) and impairs the action of insulin to decrease protein degradation, eight CRF patients were studied using the combined L-[1-13C]leucine euglycemic clamp technique before (acid) and after (NaHCO3) 4 wk treatment with NaHCO3 (pH: acid 7.29 +/- 0.01 vs. NaHCO3 7.36 +/- 0.01, P < 0.001). Protein degradation (PD) was estimated sequentially from the kinetics of a primed continuous infusion of L-[1-13C]leucine in the basal state and during a hyperinsulinemic euglycemic clamp. Insulin sensitivity was measured during the clamp. The correction of acidosis significantly increased the glucose infusion rate necessary to maintain euglycemia (acid 6.44 +/- 0.89 vs. bicarbonate 7.38 +/ 0.90 mg.kg-1.min-1, P < 0.01) and significantly decreased PD in the basal state (acid 126.4 +/- 8.1 vs. bicarbonate 100.1 +/- 6.9 mumol.kg-1.h-1, P < 0.001). Hyperinsulinemia decreased PD in both studies (acid basal 126.4 +/- 8.1 vs. clamp 96.5 +/- 7.7, P < 0.001; bicarbonate basal 100.1 +/- 6.9 vs. clamp 88.2 +/- 5.5 mumol.kg-1.h-1, P = 0.06), its effect being unaltered by acidosis, with a reduction of 24% before and 12% after the correction of acidosis. In conclusion, acidosis contributes to the insulin resistance of CRF but does not affect the action of insulin on PD. PMID- 7840170 TI - Effects of epinephrine infusion on muscle glycogenolysis during intense aerobic exercise. AB - The purpose of this study was to determine whether an epinephrine (Epi) infusion would enhance muscle glycogenolysis during intense aerobic exercise. Epi was infused at rates that produced the same plasma Epi concentrations observed after caffeine (Caf) ingestion. Seven male subjects cycled for 15 min at 80% maximal O2 uptake during four different trials. Trial 1 was preceded by a 9 mg/kg oral dose of Caf to determine resting and exercise plasma Epi concentrations. Trial 2 was used to determine the Epi infusion rates needed to mimic the plasma Epi levels found with Caf. Trials 3 and 4 were randomized and consisted of either an Epi infusion or a saline infusion (control, Con). During Epi and Con trials muscle samples were obtained from the vastus lateralis at 0, 3, and 15 min of exercise. Plasma Epi levels were similar between Caf and Epi and were elevated twofold compared with Con. At 5 min of exercise the plasma Epi concentrations were 1.51 +/- 0.26, 2.61 +/- 0.34, and 2.97 +/- 0.45 nM for the Con, Caf, and Epi trials, respectively. Plasma Epi increased to 3.08 +/- 0.56, 5.45 +/- 1.11, and 5.86 +/- 1.03 nM at 14 min of exercise in the Con, Caf, and Epi trials, respectively. Muscle glycogenolysis was not different between trials (Con 220.5 +/- 25.3 vs. Epi 240.6 +/- 12.1 mmol/kg dry muscle). In addition, the degradation of muscle ATP and phosphocreatine and the accumulation of muscle lactate, ADP, and AMP were similar between trials.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7840171 TI - Growth responses to angiotensin II in bovine adrenal glomerulosa cells. AB - The effects of angiotensin II (ANG II) on growth responses of primary cultures of bovine adrenal glomerulosa cells were studied to explore the mechanism(s) by which ANG II leads to hyperplasia and hypertrophy of the glomerulosa layer in sodium deficiency. ANG II did not increase [3H]thymidine incorporation during the first 5 days of culture, but mitogenic responses to ANG II became evident after longer periods of culture and were most prominent between 8 and 11 days after seeding. At this time, cell cycle analysis showed that ANG II increased the proportion of cells in the S phase and did not cause accumulation of cells in the G2 phase. Consistent with this finding, ANG II also stimulated proliferation of glomerulosa cells during treatment for 3 days in the presence of 1% serum. The mitogenic effect of ANG II was not inhibited by pretreatment with pertussis toxin and was mediated by AT1 receptors as indicated by its sensitivity to the subtype selective antagonist DuP-753. Also, there was no emergence of AT2 receptors in glomerulosa cells during prolonged culture. These results indicate that intracellular mechanisms that mediate growth responses become more active during prolonged culture of glomerulosa cells. Thus, in addition to regulating the steroidogenic and secretory functions of the zona glomerulosa, ANG II exerts mitogenic actions that depend on the functional state of the glomerulosa cells. PMID- 7840172 TI - Codominant effects of the fatty (fa) gene during early development of obesity. AB - Expression of a single copy of the rat obesity fatty (fa) gene may affect energy balance. To test this hypothesis, the effects of zero, one, and two copies of fa on early growth were evaluated, using a molecular genetic method for counting fa alleles inherited by 7- and 14-day-old F2 offspring of a BN/Crl x Crl:ZUC-fa F1 intercross. Litter and sex effects were controlled by multiple-regression analysis, allowing genotype effects on the weights of body, inguinal adipose pads, interscapular brown adipose tissue, and liver to be isolated. At 7 days of age, the fa copy number had linear effects on body and inguinal adipose pads weight. At 14 days of age, the fa copy number had linear effects on body, inguinal adipose pads, and interscapular brown adipose tissue weights and an additional quadratic effect on inguinal adipose pads weight. Thus fa has codominant effects on growth during the first week of life. The recessive effects of fa on growth appear during the second week of life. PMID- 7840173 TI - Estimating body composition in late gestation: a new hydration constant for body density and total body water. AB - Twenty women underwent body density (DB) measurements using underwater weighing with correction of residual lung volume by nitrogen dilution and total body water (TBW) using isotope dilution of 18O to estimate body composition at 30 wk of gestation. DB and TBW were used as independent variables in the same equation. The hydration constant (HC) of fat-free mass (FFM) was estimated as 0.762; based on this HC, new body composition equations for both DB and TBW were derived. These equations were prospectively tested in an additional 20 women at 30 wk of gestation. No significant differences were detected between estimates of percent body fat (%F) using either the newly derived DB or TBW equations and estimates of %F using both DB and TBW. Ten of these forty women were evaluated postpartum. There was no significant difference in %F estimated by either TBW or DB compared with standard equations (hydration of FFM = 0.72) and %F using both DB and TBW. These results highlight the importance of either measuring both DB and TBW or using an appropriate hydration constant for FFM in estimating body composition during pregnancy or conditions associated with increased body water. PMID- 7840174 TI - Effects of BRL-47672 on growth, beta 2-adrenoceptors, and adenylyl cyclase activation in female rats. AB - The morpholine compound BRL-47672 has a chemical structure similar to that of clenbuterol and causes similar anabolic effects in rats but has no actions on beta 2-adrenoceptors in vitro. It has been argued therefore that beta 2 adrenoceptors do not mediate the anabolic effects of this family of compounds. In the present study BRL-47672 was shown to bind to rat beta 2-adrenoceptors with low affinity (dissociation constant 16 microM) relative to clenbuterol (48 nM) and to be a very weak activator of adenylyl cyclase activity in rat skeletal muscle membranes in vitro. In contrast, acute administration of the drug to anesthetized rats in vivo caused an increase in muscle adenosine 3',5'-cyclic monophosphate output, and chronic treatment of conscious rats for > 6 days caused a significant increase in weight gain (69%) accounted for by increased muscle growth. The anabolic effects of BRL-47672 were not counteracted by daily injections of the drug ICI-118551 (2 mg/day) but were prevented when the same beta 2-antagonist was administered in the diet (200 mg/kg feed, equivalent to 4.3 mg/day). The beta 1-adrenoceptor selective antagonist CGP-20712A fed in the diet (200 mg/kg feed) failed to attenuate the response to BRL-47672. These results support the conclusion that BRL-47672 has little direct action on beta 2 adrenoceptors but suggest that the compound is metabolized rapidly in vivo to a potent beta 2-agonist. Thus the stimulation of muscle growth by BRL-47672 is via beta 2-adrenoceptors, with no contribution to this response from beta 1- or beta 3-adrenoceptor activation. PMID- 7840175 TI - Relationship between dehydroepiandrosterone and calcitonin gene-related peptide in the mouse thymus. AB - Dehydroepiandrosterone (DHEA) and calcitonin gene-related peptide (CGRP) are naturally occurring substances that are reported to have both opposing and complementary effects on immune functions. In the current study, we sought to determine how they might work together to influence the mitogen-stimulated proliferation of thymocytes. In concanavalin A (ConA)-induced thymocyte proliferation assays, CGRP and DHEA each inhibited proliferation. When the CGRP antagonist CGRP-(8-37) was added to Con A-stimulated thymocytes, the proliferative response was significantly greater than the ConA response alone across a range of ConA doses. Moreover, CGRP-(8-37) blocked the inhibitory effect of DHEA. Individually, CGRP-(8-37), CGRP, DHEA, or their combination did not stimulate thymocyte proliferation in the absence of ConA. CGRP affects the proliferation of CD4+ T cells and thus may be a regional endogenous inhibitor of the proliferation of virgin mature T cells while they remain in the thymus. Furthermore, DHEA may act via endogenous CGRP on the thymus CD4+ T cell population. PMID- 7840176 TI - Whole body protein synthesis in healthy adult humans: 13CO2 technique vs. plasma precursor approach. AB - Different methods for the estimation of whole body protein synthesis (PS) in healthy adult humans were simultaneously compared in seven young adult subjects (6 males, 1 female) fed for 6 days a diet providing 1 g protein.kg-1.day-1 and approximately 188 kJ.kg-1.day-1. A 24-h intravenous tracer study with L-[1 13C]leucine was performed starting at 6 P.M. on day 6. During fasted (6 h) and fed (6 h) steady states, PS was estimated using an approach based on 13CO2 excretion (PSexcr) and on urinary nitrogen excretion data (corrected for changes in body urea pool). Simultaneously, we used the conventional two-pool model and plasma [13C]ketoisocaproate enrichment for estimating PS. The latter mean estimates of PS were significantly higher than PSexcr during fasting [861 +/- 58 (SD) vs. 663 +/- 160 mg protein.kg-1.6 h-1; P < 0.01] and feeding (985 +/- 63 vs. 779 +/- 127 mg protein.kg-1.6 h-1; P < 0.01) and were much less variable. In hourly small-meal feeding, urinary nitrogen excretion was not a reliable index of body protein oxidation when measured over short periods of 6 h, thereby introducing a lack of precision in PSexcr. We suggest that application of the 13CO2 technique to measure PS in humans is limited by the need for relatively prolonged experimental periods of urine collection and tracer infusion within a given physiological state. PMID- 7840177 TI - Insulin secretion and clearance during low-dose graded glucose infusion. AB - The present study was undertaken in normal volunteers to define the alterations in beta-cell responsiveness to glucose associated with different physiological states, including fasting and refeeding, and after prolonged intravenous glucose infusion. A low-dose graded glucose infusion protocol was used to explore the dose-response relationship between glucose and insulin secretion. Studies were performed in 10 normal volunteers, and insulin secretion rates (ISR) were calculated by deconvolution of peripheral C-peptide levels using a two compartment model utilizing individual kinetic parameters. From 5 to 9 mmol/l glucose, the relationship between glucose and ISR was linear. After a 42-h glucose infusion at a rate of 4 mg.kg-1.min-1, the ISR increased by 53% over the same glucose concentration range (P < 0.002), resulting in a shift of the dose response curve to the left. Insulin clearance rates decreased 27% after the 42-h glucose infusion (P < 0.001). After a 72-h fast, ISR decreased by 32% from baseline over the 5-8 mmol/l glucose range (P = 0.056), resulting in a shift of the dose-response curve to the right. This shift was reversed by a 42-h period of refeeding, after which ISR was increased by 77% compared with the fasting study (P < 0.02). Refeeding enhanced the beta-cell responsiveness, and ISR increased by 31% after refeeding compared with the baseline study (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7840178 TI - Effect of corticosteroids on free and sulfoconjugated catecholamines at birth in premature newborn sheep. AB - We previously demonstrated that prenatal corticosteroids attenuated the expected exponential increase in circulating catecholamines at birth. The present studies were undertaken to determine if alteration in sulfoconjugation could account for this attenuation. Catheterized fetal lambs received saline (n = 6) or corticosteroids (n = 8) intravenously for 60 h. The lambs were delivered by cesarean section at 130 +/- 1 days gestation. Ventilatory and cardiovascular responses and plasma catecholamine concentrations were measured for 2 h after birth. Although plasma free catecholamines levels were higher in controls than in corticosteroid-treated fetuses, the sulfoconjugated levels were similar in the two groups. Thus the corticosteroid-treated fetuses had a higher proportion of plasma sulfoconjugated catecholamines consistent with the possibility that sulfoconjugation was augmented during intrauterine life. After birth, the corticosteroid-treated animals showed an attenuated increase in plasma free catecholamine levels compared with controls but a similar increase in sulfoconjugated catecholamine levels to the control animals. The proportion of plasma sulfoconjugated catecholamines was higher in the corticosteroid-treated animals; however, the increase in sulfoconjugated catecholamines was insufficient to account for the attenuated overall increase in total catecholamines in the corticosteroid-treated animals. PMID- 7840179 TI - Identification of 3,3'-T2S as a fetal thyroid hormone derivative in maternal urine in sheep. AB - We measured 3,3'-diiodothyronine sulfate (T2S) in serum and urine (n = 5-6) obtained from euthyroid fetal (94-145 days of gestation, term = 150 days), newborn, and adult sheep and in serum and urine samples from ovine fetuses 13 days after total thyroidectomy conducted between 110 and 113 gestation days (n = 5). Sham-operated twin fetuses served as controls (n = 5). Mean serum T2S concentrations increased progressively from 94 days (74 ng/dl) to 130 days (420 ng/dl), decreasing thereafter to 145 days (197 ng/dl). T2S concentrations in fetal urine peaked at 110 days (117 ng/dl). In hypothyroid fetuses, mean serum and urine T2S were 60 and 53% of control values. To assess the possibility that the T2S in maternal serum/urine is derived from fetal serum 3,5,3' triiodothyronine (T3), we measured T3, T3 sulfate (T3S), and T2S in fetal serum and in maternal serum and urine after bolus infusion of T3 to the fetus (n = 4). Additionally, T3, T3S, and T2S concentrations were measured in maternal serum and urine after T3 infusion to the maternal ewes (n = 4). Fetal T3 infusion rapidly increased fetal serum T3S and T2S. Maternal serum and urine T3S and T2S concentrations increased, whereas T3 concentrations remained unchanged. Maternal T3 infusion increased in serum and urine T3S and T2S levels, but the levels, relative to T3, were less than values measured after fetal T3 infusion. We conclude that T2S is a normal thyroid hormone metabolite in the ovine fetus and suggest that a major pathway of fetal T2S production is T3 to T3S to T2S.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7840180 TI - Functional characterization of somatostatin receptors expressed on hamster glucagonoma cells. AB - We characterized somatostatin receptors expressed in hamster glucagonoma INR1G9 cells and the effects of somatostatin on glucagon secretion, proglucagon gene expression, and the adenosine 3',5'-cyclic monophosphate (cAMP)-dependent signal transduction cascade. 125I-labeled somatostatin was displaced by somatostatin-14 and somatostatin-28 with a dissociation constant of 2 nmol/l. Stable GTP analogues decreased binding of 125I-somatostatin to its receptors, suggesting an interaction of somatostatin receptors with G proteins. Chemical cross-linking of 125I-somatostatin to its receptor revealed a molecular mass of the ligand receptor complex of 47 kDa. Somatostatin inhibited forskolin-stimulated activation of adenylate cyclase [2.5 microM forskolin (161%) + 1 microM somatostatin (128%); P < 0.05] and protein kinase A [10 microM forskolin (143%) + 1 microM somatostatin (114%); P < 0.05] but did not influence basal activities of these enzymes. Forskolin-induced stimulation of cAMP generation was reduced by somatostatin [2.5 microM forskolin (306%) + 1 microM somatostatin (145%); P < 0.05]. Somatostatin inhibited forskolin, theophylline, and arginine stimulation of glucagon secretion. Basal as well as forskolin-, theophylline-, and isobutyl methylxanthine-induced proglucagon gene expression was significantly reduced by somatostatin. Our data show that, in INR1G9 cells, somatostatin receptors are at least in part coupled to the adenylate cyclase system. Somatostatin is a potent negative regulator of both basal and forskolin-stimulated proglucagon gene expression. The interaction with forskolin occurs at the level of adenylate cyclase. The effect of somatostatin on basal proglucagon gene transcription is most probably mediated by an unrelated second messenger system. Somatostatin may influence several functions of the pancreatic A cell. PMID- 7840181 TI - Effect of nonworking heterotopic transplantation on rat heart glycogen metabolism. AB - To determine whether the contractile work history of cardiac muscle influences its responsiveness to insulin, we examined the effect of insulin infusion on glycogen metabolism in the rat heart 1 wk after transplantation into a nonworking heterotopic infrarenal position. Nonworking heterografts had higher basal glycogen concentrations than did in situ working hearts of the same animals (29.9 +/- 2.7 vs. 23.3 +/- 0.8 mumol/g; P < 0.05), and a smaller fraction of their glycogen synthase enzyme activity was in the physiologically active glycogen synthase I form (8 +/- 2 vs. 22 +/- 3%; P < 0.02). During a 25-min infusion of insulin (1 U/min) and glucose (30 mg.kg-1.min-1), the fractional glycogen synthase I activity of heterografts remained lower than that of in situ hearts (29 +/- 5 vs. 56 +/- 7%; P < 0.02) and heterografts synthesized glycogen more slowly (0.126 +/- 0.07 vs. 0.352 +/- 0.06 mumol.g-1.min-1; P < 0.02). These effects could be duplicated by a 24-h fast, which similarly increased myocardial glycogen concentration (to 32.9 +/- 5.6 mumol/g). These observations suggest that the performance of repetitive contractile work is necessary to maintain the myocardium maximally responsive to insulin. Mechanical unloading increases myocardial glycogen concentration, thereby reducing the magnitude of insulin's stimulation of glycogen synthase and consequently the rate of incorporation of circulating glucose into glycogen. PMID- 7840182 TI - Effects of epinephrine on human muscle glucose and protein metabolism. AB - Systemic epinephrine infusion causes hypoaminoacidemia and inhibits whole body leucine flux (proteolysis) in humans. Its specific action on muscle protein is not known and is difficult to assess during systemic epinephrine infusions, which affect plasma insulin, amino acid, and free fatty acid concentrations. During a steady-state infusion of L-[ring-2,6-3H]phenylalanine, we examined the effect of locally infused epinephrine on the metabolism of protein and glucose in forearm muscle of 10 healthy human volunteers. During local epinephrine infusion, systemic concentrations of glucose, phenylalanine, insulin, and epinephrine were unchanged and lactate declined (P < 0.02). Compared with baseline, epinephrine induced significant increases in forearm blood flow (P < 0.01) and net lactate release (P < 0.001) and a decrease in glucose uptake (P < 0.01) at both 2 and 4 h. At 2 and 4 h phenylalanine release from muscle proteolysis was suppressed (P < 0.01), and at 4 h the net phenylalanine balance was less negative than baseline (P < 0.02), indicating an anticatabolic effect on muscle protein. We conclude that in human forearm muscle epinephrine, at physiological concentrations, has a catabolic effect on muscle glycogen but an anticatabolic action on muscle protein. The mechanism of this latter effect is not known. PMID- 7840183 TI - Hormonal regulation of albumin gene expression in primary cultures of rat hepatocytes. AB - When primary cultures of rat hepatocytes were placed in a chemically defined serum-free medium containing a combination of insulin, glucagon, and dexamethasone, the synthesis of albumin and total protein and the cellular content of RNA and DNA were maintained at constant values for 8 days. Despite the constant rate of albumin synthesis, secretion of the protein increased more than twofold during the initial 4 days in culture and was then maintained at a value similar to that observed in vivo through day 8. This observation suggested an initial defect in albumin secretion that was corrected with time in culture. Deprivation of insulin between days 2 and 5 resulted in a decline in albumin secretion to approximately 40% of the control value. The decline in albumin secretion was accompanied by proportional decreases in albumin synthesis, albumin mRNA, and albumin gene transcription. Return of insulin-deprived cells to complete medium on day 5 restored albumin synthesis and secretion as well as albumin mRNA to control values by day 8. Deprivation of either glucagon or dexamethasone also resulted in reduced albumin synthesis and secretion accompanied by proportional decreases in albumin mRNA and gene transcription. However, the magnitude of the changes in these parameters was less with glucagon or dexamethasone deprivation compared with insulin deprivation. Return of glucagon- or dexamethasone-deprived cells to complete medium on day 5 restored albumin synthesis and secretion as well as albumin mRNA to control values by day 8.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7840184 TI - In vivo insulin mimetic effects of pV compounds: role for tissue targeting in determining potency. AB - Peroxovanadium (pV) compounds activate the insulin receptor kinase in hepatocytes and inhibit the dephosphorylation of insulin receptors in hepatic endosomes with highly correlated potencies (Posner, B. I., R. Faure, J. W. Burgess, A. P. Bevan, D. Lachance, G. Zhang-Sun, J. B. Ng, D. A. Hall, B. S. Lum, and A. Shaver J. Biol. Chem. 269: 4596-4604, 1994). After intravenous administration, K2[VO(O2)2(picolinato)].2H2O [bpV(pic)], VO(O2) (picolinato) (H2O)2 [mpV(pic)], K[VO(O2)2(picolinato)].3H2O [bpV(phen)], and K[VO(O2)2(4,7-dimethyl-1,10 phenanthroline)].1/2H2O [bpV(Me2phen)] produced 50% of their maximal hypoglycemic effect at doses of 0.04, 0.04, 0.32, and 0.65 mumol/100 g body wt, respectively. In contrast, their potencies as inhibitors of dephosphorylation were bpV(pic) = bpV(phen) > mpV(pic) = bpV(Me2phen). bpV(pic) stimulated [14C]glucose incorporation into rat diaphragm glycogen in vivo, and its effect was dose dependent, synergistic with insulin, and evident in other skeletal muscles. In contrast, bpV(phen) displayed no effect on glycogen synthesis in skeletal muscle. mpV(pic) stimulated and bpV(Me2phen) had no effect on glycogen synthesis in the diaphragm. bpV(pic) augmented rat diaphragm insulin receptor kinase 2.2-fold with a time-integrated response 70% that of insulin. In contrast, the effect of bpV(phen) was delayed and much reduced. Thus, the in vivo potencies of pV compounds reflect differing capacities to act on skeletal muscle. The ancillary ligand within the pV complex may target one tissue in preference to another. PMID- 7840185 TI - Effect of prednisone on protein metabolism in Duchenne dystrophy. AB - Prednisone improves strength in Duchenne dystrophy and changes the natural history of the disease. We studied the in vivo effects of prednisone (0.75 mg.kg 1.day-1) on muscle and whole body protein metabolism in six patients with Duchenne dystrophy and three patients with Becker dystrophy. Patients were admitted to the Clinical Research Center for study and consumed a constant flesh free diet. Strength was measured by manual and quantitative muscle testing. Fractional muscle protein breakdown was estimated by the ratio of 3 methylhistidine to creatinine excretion determined in three consecutive 24-h urine collections. Whole body protein kinetics were studied in the postabsorptive state using a primed continuous infusion of L-[1-13C]leucine. Fractional muscle protein synthesis was determined from tracer incorporation into noncollagen muscle protein obtained by needle biopsy. After 6-8 wk of prednisone treatment, average muscle strength increased by 15% (P < 0.04), and 24-h creatinine excretion (an index of muscle mass) increased by 21% (P = 0.002). 3 Methylhistidine excretion decreased by 10%, but the change was not statistically significant. The ratio of 3-methylhistidine to creatinine excretion decreased by 26% (P < 0.04). Fractional muscle protein synthesis and whole body protein synthesis and breakdown did not change significantly. We conclude that the beneficial effect of prednisone on strength in Duchenne dystrophy appears to be associated with an increase in muscle mass, which may be mediated by inhibition of muscle proteolysis rather than stimulation of muscle protein synthesis. PMID- 7840186 TI - Transmembrane transport and intracellular kinetics of amino acids in human skeletal muscle. AB - We have used stable isotopic tracers of amino acids to measure in vivo transmembrane transport of phenylalanine, leucine, lysine, alanine, and glutamine as well as the rates of intracellular amino acid appearance from proteolysis, de novo synthesis, and disappearance to protein synthesis in human skeletal muscle. Calculations were based on data obtained by the arteriovenous catheterization of the femoral vessels and muscle biopsy. We found that the fractional contribution of transport from the bloodstream to the total intracellular amino acid appearance depends on the individual amino acid, varying between 0.63 +/- 0.02 for phenylalanine and 0.22 +/- 0.02 for alanine. Rates of alanine and glutamine de novo synthesis were approximately eight and five times their rate of appearance from protein breakdown, respectively. The model-derived rate of protein synthesis was highly correlated with the same value calculated by means of the tracer incorporation technique. Furthermore, amino acid transport rates were in the range expected from literature values. Consequently, we conclude that our new model provides a valid means of quantifying the important aspects of protein synthesis, breakdown, and amino acid transport in human subjects. PMID- 7840187 TI - Evidence for a single glucocorticoid regulated pool of adrenocorticotropin in sheep anterior pituitary. AB - The goal of this study was to determine whether separate glucocorticoid-sensitive releasable pools of adrenocorticotropic hormone (ACTH) could be distinguished in sheep anterior pituitary cells. Isolated cells were cultured in serum-free medium containing 0-10 nM cortisol (F) for 7-11 days to determine whether variation in the glucocorticoid environment selectively affected ACTH release stimulated by corticotropin-releasing hormone (CRH) or arginine vasopressin (AVP). Secretion was studied using a microperifusion system. The results indicated that while the concentration of F in the medium bathing the cells profoundly influenced the magnitude of ACTH released in response to either peptide, the fractional release of total ACTH was unchanged. F concentration in culture medium similarly did not alter the negative-feedback effectiveness of a larger dose of F applied to cells 45 min before treatment with CRH or AVP. These results support the existence of a single glucocorticoid-sensitive pool of ACTH in corticotrophs. PMID- 7840188 TI - Effect of acute glucagon removal on metabolic response to infection in conscious dog. AB - This study examined the acute role of glucagon in sustaining the increased hepatic gluconeogenesis observed in the conscious infected dog. After a basal sampling period, arterial glucagon levels were selectively decreased for 180 min by a peripheral infusion of somatostatin and basal intraportal infusion of insulin (GGN deficient; n = 6). In a separate protocol (GGN replaced; n = 5) glucagon was also infused intraportally to maintain the glucagon level at that seen during sepsis. Tracer and arteriovenous difference techniques were used to assess hepatic glucose metabolism and gluconeogenesis. In the GGN-deficient group the arterial plasma glucagon level fell from 416 +/- 49 to 88 +/- 21 pg/ml, whereas in the GGN-replaced group it remained elevated throughout (321 +/- 48 to 248 +/- 22 pg/ml). When glucagon was reduced, endogenous glucose production decreased by 1.6 +/- 0.3 mg.kg-1.min-1, and an exogenous glucose infusion was required to maintain euglycemia. Glucose metabolism remained unaltered when glucagon was replaced. When glucagon was deleted, net hepatic gluconeogenic precursor uptake was not altered. In contrast, the efficiency of gluconeogenesis was decreased by 33% compared with the GGN-replaced group. Liver biopsies taken at the end of the experiment indicated that a diversion of gluconeogenic carbon to glycogen accounted for 50% of the fall in gluconeogenic efficiency. In summary, the basal hyperglucagonemia seen during an infection helps sustain glucose production both through its effects on hepatic glycogen metabolism and on gluconeogenic efficiency. PMID- 7840189 TI - Vagovagal reflex control of digestion: afferent modulation by neural and "endoneurocrine" factors. AB - Vagovagal reflex control circuits in the dorsal vagal complex of the brain stem provide overall coordination of gastric, small intestinal, and pancreatic digestive functions. The neural components forming these reflex circuits are under substantial descending neural control. By adjusting the excitability of the differing components of the reflex, significant alterations in digestion control can be produced by the central nervous system. Additionally, the dorsal vagal complex is situated within a circumventricular region without a "blood-brain barrier." As a result, vagovagal reflex circuitry is also exposed to humoral influences, which can profoundly alter digestive functions by acting directly on brain stem neurons. PMID- 7840190 TI - Activation of somatostatin receptor subtype 2 inhibits acid secretion in rats. AB - Somatostatin is a potent inhibitor of gastric acid secretion. Recently, at least five distinct somatostatin receptor subtypes (SSTR) have been characterized and evaluated using relatively selective peptide analogues of somatostatin. We sought to determine which somatostatin receptor subtypes are involved in peripheral regulation of gastric acid secretion. Fasted, male Sprague-Dawley rats were anesthetized and were implanted with a double-lumen cannula in the stomach. Acid secretion was measured in gastric samples collected every 10 min by backtitration to pH 7. After a 30-min basal period, a 2-h intravenous infusion of pentagastrin (24 micrograms.kg-1.h-1 i.v.) was started. During the second pentagastrin hour, a 1-h intravenous infusion of either vehicle (0.1% canine serum albumin in 0.9% saline) or somatostatin receptor agonists was begun. The somatostatin receptor agonists included peptides with relative specificity for SSTR1-5 (somatostatin 14; 10 nmol.kg-1.h-1); SSTR2, SSTR3, and SSTR5 [SMS-(201-995); 10 nmol.kg-1.h-1]; SSTR2 (1-1,000 nmol.kg-1.h-1); SSTR3 (10-1,000 nmol.kg-1.h-1); and SSTR5 (10 1,000 nmol.kg-1.h-1). The SSTR2 agonist decreased pentagastrin-stimulated acid secretion dose dependently, from 82 +/- 7% of maximum acid output at 1 nmol.kg 1.h-1 to 4 +/- 7% of maximum at 100 nmol.kg-1.h-1. At 10 nmol.kg-1.h-1, the SSTR2 agonist inhibited acid secretion (40 +/- 7% of maximum) similarly to somatostatin (37 +/- 4% of maximum) and SMS-(201-995) (31 +/- 4% of maximum). The SSTR2 agonist inhibited acid secretion approximately 10- to 100-fold more potently than either the SSTR3 or the SSTR5 agonist. These results indicate that somatostatin regulates gastric acid secretion by activation of SSTR2 receptors. PMID- 7840191 TI - Effects of female sex hormones on mitochondria: possible role in acute fatty liver of pregnancy. AB - Acute fatty liver of pregnancy occurs in some women. As other cases of microvesicular steatosis are due to impaired mitochondrial oxidation of fatty acids, we investigated the effects of female sex hormones on liver mitochondria in female mice. Three hours after administration of both estradiol (36 mumol/kg) and progesterone (150 mumol/kg), the in vitro beta-oxidation of [U-14C]palmitic acid and the activity of the tricarboxylic acid cycle decreased 49 and 54%, whereas the in vivo oxidation of [U-14C]palmitic acid decreased 38%. One week of treatment with both sex hormones produced ultrastructural lesions of mitochondria, decreased the recovery of mitochondrial proteins by 34%, increased state 4 respiration by 54-77%, and decreased the activities per gram of liver of several enzymes involved in the activation, mitochondrial uptake, and oxidation of fatty acids by 34-54%. We conclude that female sex hormones have deleterious effects on liver mitochondria and suggest that these effects, together with other factors, may contribute to the development of acute fatty liver of pregnancy in some women. PMID- 7840192 TI - Prolactin increases mRNA encoding Na(+)-TC cotransport polypeptide and hepatic Na(+)-TC cotransport. AB - We have shown that prolactin (Prl) increases the transhepatic transport of taurocholate (TC) in postpartum rats and following treatment of ovariectomized (Ovx) rats with ovine Prl (oPrl). The present studies were designed to determine if treatment of Ovx rats with oPrl (100, 300, or 600 micrograms/day, 7 days iv) 1) increases Na(+)-TC cotransport in basolateral plasma membrane vesicles (bLPM), 2) induces a corresponding increase in the steady-state levels of Na(+)-TC cotransport polypeptide (Ntcp mRNA), and 3) if the oPrl-mediated increase in Na(+)-TC cotransport activity is blocked by cycloheximide, an inhibitor of protein synthesis. oPrl (300 micrograms/day) induced a twofold increase in the maximal velocity for Na(+)-TC cotransport in both hepatocytes and bLPM vesicles with little change in the Michaelis constant. Infusion of oPrl at a dose of 100, 300, or 600 micrograms/day increased steady-state Ntcp mRNA four-, ten-, and twofold, respectively. Finally, cycloheximide blocked the oPrl-mediated increase in Na(+)-TC cotransport but did not affect basal activity. These data support the hypothesis that an increase in Ntcp mRNA followed by increased synthesis and incorporation of Ntcp in the plasma membrane is responsible for the oPrl-mediated increase in Na(+)-TC cotransport in the basolateral plasma membrane domain of the hepatocyte. PMID- 7840193 TI - Enterocyte respiration rates in feline small intestine exposed to graded ischemia. AB - The purpose of our study was to investigate the changes in enterocyte cellular and mitochondrial respiration rates subsequent to ischemia of graded duration. The small intestine of anesthetized adult cats was assigned to one of five treatment regimens: control or ischemia of 15-, 30-, 60-, or 90-min duration. Cellular and mitochondrial respiration was measured using a Clark-type O2 electrode at 0 and 4 h postharvest. Ischemia of increasing duration caused a progressive decrease in cellular and mitochondrial respiration in enterocytes at 0 h postharvest. By 4 h postharvest, cellular and mitochondrial respiration rates for the 15-, 30-, and 60-min ischemic groups had recovered to near control levels, whereas the 90-min group showed minimal recovery. These data suggest that ischemia suppresses cellular and mitochondrial respiration of intestinal epithelial cells, the magnitude of which is related to the ischemic duration. The ischemia-induced suppression in cellular respiration primarily reflects a reduction in mitochondrial respiration. PMID- 7840194 TI - Mucosal mast cells and developmental changes in gastric absorption. AB - We aimed to establish whether gastric mucosal mast cells undergo degranulation during normal postnatal development and to correlate this with gastric electrical parameters, paracellular permeability, and macromolecular absorption. Sprague Dawley rats were studied between 10 and 30 days after birth. Gastric mucosal mast cell degranulation occurred and was maximal on days 15 and 17, measured by histology and gastric and serum levels of rat mast cell protease II. Short circuit current, transepithelial conductance, and permeability of voltage-clamped glandular stomach were elevated in younger animals, falling with age except for a transient but significant increase in conductance and permeability at 17 days, closely correlated with maximal mast cell degranulation. Macromolecular uptake was significantly increased in animals aged 10-15 days. Concanavalin A and antigen-induced mast cell degranulation increased conductance and permeability in vitro in younger animals. We conclude that 1) gastric mucosal mast cells degranulate during development, 2) the neonatal stomach has increased permeability and uptake of macromolecules, and 3) gastric mucosal mast cell degranulation during development may affect mucosal permeability. PMID- 7840195 TI - Criteria for objective definition of transient lower esophageal sphincter relaxation. AB - We developed and evaluated objective manometric criteria that define transient lower esophageal sphincter (LES) relaxation. In 23 normal subjects and 9 patients with gastroesophageal reflux disease, systematic analysis of swallow-induced LES relaxation showed that dry swallows preceded LES relaxation by a median of 1.4 s. The relaxation rate was always > 1 mmHg/s, the relaxation nadir always occurred within 7 s, and the duration of relaxation was < 9 s. During concurrent esophageal manometry and pH monitoring, 104 reflux episodes associated with a LES pressure fall that was not related to swallowing were identified and the pressure falls classified as transient LES relaxations or not by visual recognition. LES pressure was always < or = 2 mmHg at time of reflux, and relaxation was significantly longer than for swallow-induced LES relaxation. Of 88 pressure falls classified visually as transient LES relaxations, 90% reached nadir pressure within 7 s at a rate of > 1 mmHg/s. Sixteen pressure falls were classified as a gradual downward drift in LES pressure, which in 15 cases was < 1 mmHg/s. Based on the analysis, transient LES relaxation can be defined by 1) absence of swallowing for 4 s before to 2 s after the onset of LES relaxation, 2) relaxation rate of > or = 1 mmHg/s, 3) time from onset to complete relaxation of < or = 10 s, and 4) nadir pressure of < or = 2 mmHg.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7840196 TI - Adaptation of rat gastric mucosa to aspirin requires mucosal contact. AB - Adaptation of the gastric mucosa to repeated administration of aspirin is a well documented phenomenon, but the underlying mechanism is not fully understood. In this study, we tested the hypothesis that adaptation of the rat stomach to chronic aspirin administration required contact between the aspirin and the gastric mucosa. Rats were orally treated twice daily with either aspirin (100 mg/kg) or the vehicle. After various periods of treatment (< or = 20 days), the rats were given a higher dose of aspirin (250 mg/kg po), and the extent of gastric damage was assessed 3 h later. Rats receiving chronic aspirin demonstrated the development, in a time-dependent manner, of resistance to the damaging effects of aspirin. Chronic aspirin administration also significantly decreased the susceptibility of the rat stomach to damage induced by indomethacin or naproxen. The adaptation phenomenon was associated with a parallel increase in inflammatory infiltration of the mucosa, as measured by tissue myeloperoxidase activity and histology. Prostaglandin synthesis was markedly suppressed (> 80%) in all rats treated with aspirin. Gastric mucosal ornithine decarboxylase activity was not affected by chronic aspirin administration. If aspirin was administered subcutaneously or intrajejunally for 20 days, neither adaptation nor inflammation of the gastric mucosa was observed. These studies demonstrate that the rat stomach adapts to chronic oral administration of aspirin, but not to aspirin administration via other routes. Adaptation of the gastric mucosa occurred in parallel to infiltration of granulocytes. Whether these two phenomena are mechanistically or causally linked is not yet clear. PMID- 7840197 TI - Distinguishing normal and glucocorticoid-induced maturation of intestine using bromodeoxyuridine. AB - Exogenous glucocorticoids administered during the first two postnatal weeks are capable of eliciting precocious maturation of the rat intestine. However, it is not known whether this represents an alternative developmental pathway or is essentially an advancement of normal ontogeny. The goal of the present study was to address this question using the thymidine analogue 5-bromo-2'-deoxyuridine (BrdU), which is known to selectively inhibit differentiation in a number of tissues. Intestinal development was assessed by following changes in sucrase, trehalase, glucoamylase, and lactase activities. The first experiment assessed whether BrdU has any influence on the cellular differentiation that occurs continuously along the crypt-villus axis. After administration of BrdU to suckling and mature animals, there was no effect on lactase and sucrase activities, respectively. Thus BrdU does not inhibit crypt-villus differentiation in either the suckling or mature jejunum. In the second experiment, dexamethasone was used to induce precocious maturation in the rat jejunum on day 10. BrdU treatment significantly inhibited glucocorticoid-induced elevation of sucrase, trehalase, and glucoamylase but had no effect on the lactase activity. In contrast, treatment with BrdU during normal development significantly accelerated the ontogenic rise of sucrase and trehalase as well as the ontogenic decline of lactase. The acceleration of development was also seen in adrenalectomized rats, indicating that it is the glucocorticoid-independent component of normal intestinal ontogeny that is activated by BrdU. The opposite effect of BrdU on glucocorticoid-induced precocious maturation suggests that such maturation involves different molecular mediators than normal ontogeny. PMID- 7840198 TI - Duodenal pH governs interdigestive motility in humans. AB - In this study, we examined the potential influence of duodenal pH in regulating the occurrence of the interdigestive migrating myoelectric complex (IMMC). Fasting gastroduodenal motility, duodenal pH, and plasma motilin were studied in 15 healthy subjects. During phase I, duodenal pH remained stable at 7 +/- 0.2. Phase II was accompanied by a lowering of duodenal pH, which fluctuated between 2.0 and 7.5. During late phase II, the duodenal pH increased to 6.9 +/- 0.3 and remained in the alkaline range during phase III. In six of 46 episodes of the IMMC, the occurrence of gastric phase III was delayed. This was associated with a persistently low duodenal pH (< 4) during late phase II. Despite a normal cyclic increase of plasma motilin, no gastric phase III activity was observed until the duodenal pH exceeded 7.0. Further studies showed that lowering of duodenal pH by intraduodenal perfusion of HCl prevented the occurrence of gastric phase III. We concluded that regularity of IMMC is governed by duodenal pH. An alkaline pH is essential for the initiation of gastric phase III; lowering of duodenal pH prevents its occurrence despite normal cyclic increase of plasma motilin. PMID- 7840199 TI - Tobacco cigarette smoke aggravates gastric ulcer in rats by attenuation of ulcer margin hyperemia. AB - We tested the hypothesis that attenuation of the hyperemia at the margin of acetic acid-induced gastric ulcer in rats by tobacco cigarette smoke will increase the size of the ulcer in the acute and the healing stages. Compared with the adjacent mucosa, blood flow measured by hydrogen gas clearance at the ulcer margin was significantly higher (ulcer margin hyperemia). Tobacco cigarette smoke and subcutaneous nicotine but not nicotine-free smoke from non-tobacco cigarettes significantly attenuated the ulcer margin hyperemia in a dose-related fashion. Repeated exposure of the rats to tobacco cigarette smoke increases ulcer size in the acute and the healing stages. Subcutaneous nicotine but not nicotine-free smoke also increased the size of ulcers in the acute stage. These results indicate that the nicotine in tobacco cigarette smoke may be responsible in part for its adverse effects. We conclude that attenuation of the hyperemia at the ulcer margin is a plausible explanation for the mechanism of the adverse effect of the tobacco cigarette smoke on experimental gastric ulcers in rats. PMID- 7840200 TI - Effects of sex steroid hormones on gastric emptying and gastrointestinal transit in rats. AB - In vitro studies have shown that estrogen and progesterone can affect the contractile response and myoelectric activity of the gastrointestinal smooth muscle. The present study was designed to investigate the effect of sex steroid hormones on gastric emptying and gastrointestinal transit were assessed in rats 15 min after intragastric instillation of a test meal containing charcoal and 51Cr. Gastric emptying was determined by measuring the amount of labeled chromium contained in the small intestine as a percentage of the initial amount received. Gastrointestinal transit was evaluated by calculating both the geometric center of distribution of the radiolabeled marker and the charcoal transit in the intestine. The experimental animals included diestrus rats; ovariectomized rats treated with vehicle, estradiol, and/or progesterone; and normal male and orchiectomized rats treated with vehicle or testosterone. Female rats in diestrus had a slower gastric emptying and a lesser geometric center value than ovariectomized rats. Estradiol inhibited gastric emptying but did not affect gastrointestinal transit. Progesterone increased gastric emptying. Progesterone at lower dose (10 mg/kg) decreased the geometric center compared with higher doses (20 or 40 mg/kg) or vehicle controls. A mixture of estradiol (10 micrograms/kg) and progesterone (20 mg/kg) inhibited gastric emptying to a similar degree as estradiol (10 micrograms/kg) did. Testosterone had no influence on gastric emptying or gastrointestinal transit. These results suggest that estradiol and a mixture of estradiol and progesterone inhibit, whereas progesterone enhances, gastric emptying. Testosterone did not play a role in gastrointestinal motility. PMID- 7840201 TI - Nitric oxide causes hyporeactivity to phenylephrine in isolated perfused livers from endotoxin-treated rats. AB - Systemic vascular hyporeactivity to vasoconstrictors has been described in rats following endotoxin administration. Inducible nitric oxide synthase (iNOS) expression is known to occur in the liver in endotoxemia, but consequences of iNOS induction on hepatic hemodynamics are unknown. The reactivity of the hepatic circulation to phenylephrine was tested in perfused livers from normal rats and rats previously injected with endotoxin (20 mg/kg ip). In control rats (n = 5), phenylephrine-induced portal pressure increases were similar in livers perfused with Krebs-Henseleit-bicarbonate (KHB) buffer, KHB plus the NOS inhibitor NG monomethyl-L-arginine (L-NMMA, 1 mM), or KHB plus the substrate for NO synthesis, L-arginine (1 mM). In contrast, livers from endotoxin-treated rats (n = 5) exhibited a marked reduction in the vasoconstrictive response to phenylephrine (14.6 vs. 55.1% in livers from control rats, P < 0.05). Perfusion with L-NMMA restored the phenylephrine response, and the L-NMMA effect was reversible with L arginine. Perfusate NO2-/NO3- and guanosine 3',5'-cyclic monophosphate (cGMP) levels were increased in endotoxin-treated rats and significantly reduced by L NMMA perfusion. In control livers, the NO donor S-nitroso-N-acetyl-DL penicillamine blocked the portal pressure increase after phenylephrine administration. These results suggest that rat hepatic circulation takes part in the systemic vascular hyporeactivity to vasoconstrictors observed in endotoxemia and that NO is involved in this hyporeactivity to phenylephrine. PMID- 7840202 TI - Expression of sodium-independent organic anion uptake systems of skate liver in Xenopus laevis oocytes. AB - The expression of the basolateral sodium-independent organic anion uptake system of the little skate (Raja erinacea) has been studied in Xenopus laevis oocytes. Injection of oocytes with skate liver poly(A)+ RNA resulted in the functional expression of chloride-dependent sulfobromophthalein (BSP) uptake and sodium independent taurocholate uptake within 3-5 days. The expressed chloride-dependent BSP uptake activity exhibited saturation kinetics [apparent Michaelis constant (Km) 1.8 microM] and efficiently extracted BSP from its binding sites on bovine serum albumin. The chloride-sensitive portion of BSP uptake was inhibited by bilirubin (10 microM; 27%), 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (100 microM; 57%), bumetanide (100 microM; 48%), taurocholate (200 microM; 51%), and cholate (200 microM; 45%). Size fractionation of total skate liver mRNA revealed that a 1.8- to 2.9-kb size class mRNA was sufficient to express chloride dependent BSP uptake and sodium-independent taurocholate uptake. In addition, a 1 to 1.7-kb size class mRNA expressed sodium-independent taurocholate uptake but had no effects on BSP uptake. This study confirms that an organic anion transport system for chloride-dependent BSP uptake, with characteristics similar to rat liver, is already expressed in the liver of lower vertebrates and thus represents a phylogenetically old system. Sodium-independent taurocholate uptake in skate liver may be mediated by two different transport systems. PMID- 7840203 TI - Hepatocyte nitric oxide biosynthesis inhibits glucose output and competes with urea synthesis for L-arginine. AB - Inflammatory stimulation of the liver is known to induce nitric oxide (NO) biosynthesis. NO can interfere with the activity of a number of enzymes important to cellular metabolism. This study was carried out to investigate the influence of NO on rat hepatocyte glucose output and urea production. Induction of NO synthesis by incubation with a combination of cytokines and lipopolysaccharide led to a 48.8 +/- 2.4% inhibition of glucose output and to a 45.0 +/- 6.4% suppression of urea production. Inhibition of NO synthesis with NG-monomethyl-L arginine was able to totally prevent these effects. High concentrations of L arginine overcame the inhibition of urea production caused by endogenous NO synthesis. Exposure of HC to NO donors resulted in a concentration-dependent inhibition of glucose output, without having any effect on urea production. Hepatocellular glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity was also found to be inhibited by endogenously produced NO (33.5 +/- 5.2%), as well as by exogenously applied NO. However, an exact correlation between GAPDH activity and glucose output could not be established. These data indicate that NO biosynthesis may contribute to the development of hepatic dysfunction in chronic sepsis. PMID- 7840204 TI - Regulation of goblet cell degranulation in isolated pancreatic ducts. AB - Neurohumoral control of goblet cell degranulation in isolated segments of the guinea pig main pancreatic duct was examined using morphometric procedures. Goblet cells represent 25-30% of the epithelial cell population at the head of the main pancreatic duct, a percentage that decreases to 5-10% as the distance from the ampulla increases. Carbachol, bombesin, and vasoactive intestinal peptide (VIP) each stimulated degranulation of duct goblet cells, although cholecystokinin octapeptide, secretin, and histamine did not. The stimulatory effects of carbachol on goblet cell degranulation in isolated pancreatic ducts were blocked by atropine and enhanced by simultaneous exposure to VIP. These observations indicate that goblet cells in guinea pig pancreatic ducts express bombesin, VIP, and muscarinic cholinergic receptors and that multiple intracellular signaling pathways are involved in the regulation of goblet cell degranulation. PMID- 7840205 TI - Cathepsin L mediates intracellular ileal digestion of gastric intrinsic factor. AB - Although acidic proteases of lysosomal origin are implicated in the degradation of intrinsic factor (IF) during cobalamin (cbl) transport across enterocytes and proximal renal tubule cell lines, the enzyme(s) involved in this process is not known. Recombinant (baculovirus-produced) rat 125I-labeled IF (125I-rIF), 43 kDa, added in vivo to the lumen of rat ileum was converted intracellularly to peptides of 33 and 26 kDa. In vitro rat 125I-rIF was degraded to peptides of 33 and 31 kDa by addition of cathepsin L; this conversion was fully inhibited by leupeptin. Western blot analysis using antiserum against denatured native rat IF identified additional cathepsin L degradation products in the 17- to 23-kDa range. In vitro the binding of cobalamin partially inhibited cathepsin L degradation of IF. Rat rIF produced from either insect (Sf9) or mammalian (CHO) cells and native rat IF were all degraded by cathepsin L, although the prominence of the various products differed in the recombinant preparations, being 33 and 36 kDa, respectively. Native rat IF was most sensitive to proteolysis, and no degradation products were identified. Rat 125I-rIF was taken up by LLC-PK1 cells, and 125I from degraded IF appeared abundantly on the basolateral side of cell monolayers by 1 h. The intracellular products of rat rIF in LLC-PK1 cells were the same size as those produced in vitro by the action of cathepsin L. Antiserum against a human kidney cDNA cathepsin L fusion protein easily demonstrated the protease in rat intestinal mucosa, as well as in all other tissues tested. These data suggest that cathepsin L is the protease responsible for the leupeptin-sensitive intracellular degradation of IF. PMID- 7840206 TI - Do pancreatic proteases play a role in processing prolactase and/or in the postweaning decline of lactase? AB - To assess the role of pancreatic proteases in the proteolytic processing and in the postweaning decline of lactase-phlorizin hydrolase (LPH), we have determined lactase activity and the different LPH forms in postweaned rats in which a jejunal loop was excluded from contact with pancreatic secretions by a jejunal bypass procedure. As a control for the absence of pancreatic proteases, pro sucrase-isomaltase (proSI), which is known to be split by pancreatic proteases into heterodimeric SI, was used. Nearly all proLPH was processed to mature LPH, indistinguishable from LPH isolated from control animals. SI was found only in the unsplit pro form, whereas it was normally processed to the heterodimeric SI in the control tissues. There were no significant differences in lactase and sucrase activities in operated and in sham-operated control animals. We conclude that pancreatic secretions are not essential for the processing of proLPH to LPH or in the postweaning decline of LPH. PMID- 7840207 TI - Changes in circulatory status and transport function of the liver induced by reactive oxygen species. AB - To elucidate the pathogenesis of microcirculatory disturbance of the liver after ischemia and reperfusion, the effect of reactive oxygen species on hepatic circulatory status and transport function for a cholephilic compound was studied in an isolated perfused rat liver. Perfusion of the liver with a medium containing hypoxanthine and xanthine oxidase significantly increased the portal pressure, with concomitant decrease in intrahepatic vascular volume and hepatic uptake of bromosulfophthalein (BSP). Similar changes were also elicited by infusion of serotonin, which induces contraction of sinusoidal endothelial cells. Either superoxide dismutase or catalase added in the perfusion medium partially inhibited the oxidase-induced changes in portal pressure, vascular volume of hepatic sinusoid, and BSP transport. In the presence of superoxide dismutase, either catalase or erythrocytes inhibited the oxidase-induced changes completely. These results indicated that superoxide anion and hydrogen peroxide might induce contraction of hepatic resistance vessels, capacitance vessels, and/or sinusoidal endothelial cells and that this contraction decreased the vascular bed in the liver and the time for interaction of circulation substrates with hepatocytes, thereby decreasing hepatic transport for cholephilic ligands such as BSP. PMID- 7840208 TI - Inhibition of bombesin-stimulated acid secretion by immunoneutralization of gastrin in dogs. AB - Bombesin-like peptides stimulate gastrin release and gastric acid secretion. The increase in gastric acid output is thought to be secondary to gastrin release. A monoclonal antibody (MAb) directed specifically to gastrin (MAb 28.2) was used to study the role of circulating gastrin in the regulation of bombesin-stimulated acid secretion in dogs. Seven conscious, fasted dogs with gastric fistulas received intravenous bombesin infusions in fourfold increasing doses from 200 to 3,200 pmol.kg-1.h-1. Each dose was given for 45 min. On separate days, dogs were pretreated with an intravenous infusion of 7 mg of MAb 28.2 or vehicle (0.1% canine serum albumin). Samples of gastric effluent were collected by gravity drainage through the gastric fistula, and acid output was measured by titration of gastric effluent to pH 7.0, using 0.2 N NaOH. Plasma gastrin concentrations were determined by radioimmunoassay. Bombesin infusion produced dose-dependent increases in plasma gastrin concentrations and gastric acid output. Administration of gastrin MAb 28.2 abolished bombesin-stimulated gastric acid output. Immunoneutralization of circulating gastrin in vivo using a gastrin monoclonal antibody in dogs indicates that the acid stimulatory response to bombesin is mediated by gastrin. PMID- 7840209 TI - Intestinal peptide YY: ontogeny of gene expression in rat bowel and trophic actions on rat and mouse bowel. AB - The purpose of this study was twofold: 1) to characterize the profile of colonic peptide YY (PYY) gene expression in rats and 2) to examine for potential trophic effects of PYY on the intestine in rats and mice. Expression of PYY mRNA (analyzed by Northern blotting and in situ hybridization) and PYY (analyzed by high-performance liquid chromatography and radioimmunoassay) was detected initially at day 17 of gestation in colonic extracts of Sprague-Dawley and Fischer rats. Expression of colonic PYY mRNA increased until 7 days of age and remained at its highest level (approximately twofold greater than the adult level) through the end of the nursing period. After weaning (21 days of age), PYY mRNA levels declined quickly to adult levels. Colonic PYY concentrations followed, in a coordinated manner, with some temporal delay after birth, the increase and decrease of its mRNA. Administration of PYY increased the weight and DNA content of the duodenum significantly in nursing rats and adult mice. In mice, PYY treatment also increased weight and DNA content of the ileum and colon. The trophic effects of PYY were dose related, peptide specific, and independent of species and sex. From these findings, we hypothesize that PYY plays an important role in intestinal development and dietary adaptation. PMID- 7840210 TI - Gastrin and carbachol require cAMP to elicit aminopyrine accumulation in isolated pig and rat parietal cells. AB - The role of endogenous adenosine 3',5'-cyclic monophosphate (cAMP) in the mechanisms of action of gastrin and carbachol on aminopyrine accumulation in isolated pig and rat parietal cells was investigated. In pig cells, pentagastrin (100 nM) alone stimulated aminopyrine accumulation, an action significantly reduced by the protein kinase A inhibitor Rp-adenosine 3',5'-cyclic monophosphothioate (Rp-cAMP[S]; 100 microM). In rat cells, gastrin-17 (100 nM) was incapable of stimulating aminopyrine accumulation, but it potentiated the action of histamine (100 microM). Carbachol (10 microM) stimulated aminopyrine accumulation and potentiated the action of histamine, and its action was potentiated in a dose-dependent manner by Sp-adenosine 3',5'-cyclic monophosphothioate (Sp-cAMP[S]; a cAMP analogue) in both species. The effect of carbachol was dose dependently reduced by Rp-cAMP[S]. The basal cAMP in pig parietal cells was 3.5-fold higher than that in rat parietal cells. Histamine (100 microM) and 3-isobutyl-1-methylxanthine (IBMX; 100 microM) only slightly elevated the cAMP content (1.2- to 2.9-fold the basal level) in both pig and rat parietal cells. Their combination, however, increased the cAMP level by 8- to 38 fold, but it did not increase aminopyrine accumulation above that elicited by histamine alone. Gastrin did not alter the cAMP levels in parietal cells of either of the two species. Both gastrin and carbachol increased cytosolic free Ca2+ in enriched pig and rat parietal cells.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7840211 TI - Phenylalanine-stimulated secretion of cholecystokinin is calcium dependent. AB - The secretion of cholecystokinin was examined in STC-1 cells, an intestinal cholecystokinin (CCK)-secreting cell line. Exposure to the amino acid L phenylalanine increased release of CCK by 135%, 180%, and 251% of control levels after 15-min treatments with 5, 20, and 50 mM phenylalanine, respectively. L Phenylalanine-induced secretion of CCK was inhibited by the calcium channel blocker diltiazem (10 microM). L-Phenylalanine (20 mM) also significantly increased cytosolic calcium levels in fura 2-acetoxymethyl ester (fura 2-AM) loaded cells, and this increase was diltiazem sensitive. D-Phenylalanine, over the dose range of 5-50 mM, produced nonsignificant increases in CCK release. Treatment of STC-1 cells with 300 ng/ml of pertussis toxin for either 4 or 24 h did not significantly affect either basal release of CCK or L-phenylalanine stimulated secretion. Patch-clamp recordings from cell-attached membrane patches showed a stimulation in calcium channel activity after L-phenylalanine. These results indicate that, in STC-1 cells, L-phenylalanine stimulates release of cholecystokinin via a calcium-dependent process. PMID- 7840212 TI - Tonic responses of canine proximal colon: effects of eating, nutrients, and simulated diarrhea. AB - Our hypothesis was that the proximal colon relaxes to accommodate flow from the ileum. Therefore, we recorded tonic responses of the canine proximal colon to flow through the ileum and colon stimulated by 1) an 840-kcal meal, 2) nutrients perfused into the ileum and colon, or 3) rapid infusion of saline into the ileum with overflow into the colon. Saline infusion was considered to be a model of diarrhea, and the effects of an antidiarrheal (morphine sulfate) were therefore assessed. Proximal colonic tone was measured with a barostat. Tone increased before and after the arrival of chyme in the ileocolonic region. Perfusion of nutrients into the ileum and colon also significantly increased (P < 0.05) colonic tone compared with equal volumes of saline. Rapid perfusion of the ileocolonic segment with saline increased colonic tone; this increase was significantly greater (P < 0.01) when preceded by morphine. In contrast to our hypothesis, tone of the canine proximal colon increased in response to ileal flow. The increase in colonic tone during the late response to food was at least partly attributable to stimulation by intraluminal contents. PMID- 7840213 TI - Use of cultured airway myocytes for study of airway smooth muscle. AB - Cultured airway smooth muscle cells provide a convenient model system for studying the regulation of a wide range of airway responses at the cellular level. This review describes the characteristics of cultured airway smooth muscle cells and differences that exist between cultured cells and acutely dissociated cells or muscle strips. Receptor and ion-channel expression and control of coupling in cultured airway smooth muscle are reviewed. The methodology for airway smooth muscle culture is discussed. The main advantage of using cultured airway smooth muscle cells is that studies can be performed to examine long-term control of cell responses. Studies of the regulation of receptor expression and coupling, desensitization of receptor or channel-mediated responses, or regulation of the expression of important enzymes or muscle proteins can be readily performed in cell culture. In addition, cultured airway myocytes provide a useful secondary screening system for the development of novel therapeutic agents targeted at airway receptors that are expressed upon these cells. PMID- 7840214 TI - Expression of muscarinic receptor subtypes and M2-muscarinic inhibition of adenylyl cyclase in lung. AB - The relative distribution and absolute quantities of muscarinic receptor subtypes m1, m2, m3, and m4 were determined in membranes of canine trachealis muscle, bronchi, and lung parenchyma by immuno-precipitation with receptor subtype specific rabbit polyclonal antisera. Additionally, the functional coupling of muscarinic receptors to the inhibition of adenylyl cyclase was related to the presence of m2-muscarinic receptors in each region. Immunoprecipitation identified more total muscarinic receptors in trachealis muscle than in bronchi or lung. m2-Muscarinic receptor predominated in tracheal muscle (372 +/- 85 fmol/mg protein) with fewer m3 receptors (48 +/- 5 fmol/mg protein). Bronchi contained 6.6 +/- 2.0 and 9.2 +/- 1.8 fmol/mg protein of m2 and m3 receptors, respectively. Lung parenchyma contained 13.9 +/- 3.9 fmol/mg protein of m3 receptors. Adenylyl cyclase activity increased in response to guanosine triphosphate and isoproterenol in membranes from all three lung regions, but muscarinic-mediated inhibition of adenylyl cyclase occurred only in trachealis membranes. These studies provide the first quantitative assessment of muscarinic receptor subtypes in different regions of the lung and relate the ability to measure muscarinic inhibition of adenylyl cyclase to the presence of m2 receptors. PMID- 7840215 TI - Protein kinase C in ATP regulation of lung surfactant secretion in type II cells. AB - Previous studies provided indirect evidence for a role for protein kinase C (PKC) in ATP stimulation of surfactant secretion. The present study demonstrates that ATP increases PKC activity in the membrane fraction and decreases PKC activity in the cytosol fraction of alveolar type II cells, indicating translocation of PKC to the membranes. The kinetics of ATP concentration dependence of increases in phosphatidylcholine secretion and diacylglycerol content were similar, suggesting direct correlation between these two parameters. ATP also increased membrane PKC activity in a concentration-dependent manner. Almost one-half of the PKC activity in the cytosol and membrane fractions was Ca2+ independent. The ATP-induced increase was greater in membrane-associated Ca(2+)-dependent enzyme (233%) than in Ca(2+)-independent enzyme (121%). Desensitization of PKC by exposure of cells to phorbol esters decreased PKC activity in the membrane and cytosol fractions. In cells pretreated for 3 h with phorbol esters, PKC activity was near minimum, and ATP-stimulated secretion was lowest (< 40% of that observed in untreated cells). These results indicate that a major part of ATP-stimulated surfactant secretion in type II cells is mediated via activation of PKC. PMID- 7840216 TI - Interleukin-8 is a potent mediator of eosinophil chemotaxis through endothelium and epithelium. AB - Interleukin-8 (IL-8), a potent pro-inflammatory cytokine, has been shown to have chemotactic activity for neutrophils, lymphocytes, and basophils. Effects of IL-8 on eosinophil chemotaxis are unresolved. Because eosinophils accumulate at the site of allergic inflammation and may play a role in the pathogenesis of asthma, we investigated the eosinophilotactic capacity of IL-8. We examined the ability of IL-8 to induce human eosinophil migration across 3-microns pore naked filters, and human umbilical vein endothelial cell and human pulmonary type II-like epithelial cell (A549) monolayers cultured on these filters. IL-8 induced similar dose-related eosinophil migration through all three barriers. Kinetic experiments indicated more rapid migration through noncellular barriers but equivalent migration through all barriers by 3 h. Chemotactic/chemokinetic data show that IL 8-induced eosinophil migration is chemotactic. We also determined that the ability of IL-8 to induce transcellular migration was unique in comparison with other cytokines and was not dependent on the use of fresh vs. passaged monolayer cells as barriers. Therefore our data indicate that IL-8 may play a significant role in tissue eosinophilia observed in allergic respiratory diseases. PMID- 7840217 TI - Interleukin-1 pretreatment prevents interleukin-1-induced lung leak in rats. AB - We found that rats pretreated with interleukin-1 (IL-1) intraperitoneally did not develop the acute oxidative, neutrophil-dependent lung leak that occurs after administration of IL-1 intratracheally (IL-1-induced tolerance). IL-1-pretreated rats also had increased lung catalase and glucose-6-phosphate dehydrogenase (G6PDH) activity and increased plasma catalase activity compared with sham pretreated rats. In contrast to reducing lung leak, IL-1 pretreatment did not reduce the numbers of neutrophils that are increased in lung lavages of rats given IL-1 intratracheally. IL-1-induced tolerance to IL-1-mediated lung leak and the associated increases in lung catalase, lung G6PDH, and serum catalase activities were all prevented by treating rats with the IL-1-receptor antagonist or with N-acetyl-L-cysteine, an agent that increases intracellular glutathione levels. Our results indicate that IL-1 pretreatment confers tolerance to IL-1 mediated lung leak without decreasing IL-1-induced increases in lung neutrophils. The possible protective actions of IL-1 should be considered in experiments and clinical trials where IL-1 activity is reduced pharmacologically. PMID- 7840218 TI - Leukotoxin, 9,10-epoxy-12-octadecenoate causes pulmonary vasodilation in rats. AB - Leukotoxin (Lx), a cytochrome P-450-dependent metabolite of linoleate synthesized by neutrophils or synthesized by OH- and linoleate in neutrophil cell membranes, has been recovered in lung lavages of patients with the adult respiratory distress syndrome. We studied the direct vasoactive effects of Lx and linoleate, its parent compound, in the rat pulmonary circulation. In isolated rat lungs perfused at constant flow with a physiological salt solution, Lx (but not linoleate) caused a biphasic response, an initial transient vasoconstriction followed by a more prolonged vasodilation. The latter response was only evident when the pulmonary vascular tone was increased with either alveolar hypoxia (0% O2) or KCl (20 mM). The pressor response to angiotensin II was also attenuated in the presence of Lx. The vasodilatory response in perfused lungs was attenuated by methylene blue (2 x 10(-5) M), a putative inhibitor of the soluble guanylate cyclase but not by pretreatment with meclofenamate (10(-5) M), a cyclooxygenase inhibitor. In isolated pulmonary arterial (PA) rings preconstricted either with phenylephrine (5 x 10(-9) M), endothelin-1 (10(-8) M), or KCl (30 mM), Lx (but not linoleate) caused dose-dependent relaxation. The relaxing effect of Lx on endothelium-intact rings was attenuated by NG-monomethyl-L-arginine or methylene blue. The magnitude of the hypoxic contraction of PA rings was attenuated in the presence of Lx. Whereas the mechanism of Lx-induced vasoconstriction is not clear, we conclude that Lx causes vasodilation in rat lungs and that the vasodilatory component is to a large degree endothelium-derived relaxing factor dependent. PMID- 7840219 TI - Sublethal hydrogen peroxide inhibits alveolar type II cell surfactant phospholipid biosynthetic enzymes. AB - Alveolar type II cell injury by phagocytic cell-derived reactive oxygen metabolites represents a potential mechanism for the altered surfactant metabolism found in patients with the adult respiratory distress syndrome (ARDS). Previous studies demonstrated altered surfactant phospholipid metabolism after sublethal oxidant exposure. In this study, we measured intracellular ATP levels and the activities of several enzymes involved in surfactant phospholipid biosynthesis after sublethal H2O2 exposure of cultured rat alveolar type II cells. Intracellular ATP levels were reduced by 46.6% after exposure to 75 microM H2O2. The activity of CTP:phosphorylcholine cytidyltransferase was unchanged after H2O2 exposure when measured in whole cell homogenates. However, when measured in the microsomal fraction, cytidyltransferase activity significantly fell after exposure of type II cells to 75 microM H2O2. Activity in the cytosolic fractions remained unchanged. Similarly, microsomal cholinephosphotransferase was reduced after H2O2 exposure. We conclude that H2O2 decreases surfactant phosphatidylcholine biosynthesis independently of its ability to deplete intracellular ATP content. These deleterious effects may partially explain the diminished alveolar surfactant observed in patients with ARDS. PMID- 7840220 TI - Differential expression of collagen-binding receptors in fetal rat lung cells. AB - Interactions of cells with molecules of the extracellular matrix (ECM) are mediated via specific cell surface receptors. Because collagen is an important ECM component in the developing lung, we investigated the expression of collagen receptors by distal fetal lung epithelial cells and fibroblasts. Cell attachment experiments revealed that fibroblasts but not epithelial cells adhered to various types of collagen. With the use of subunit-specific antibodies, we demonstrated the presence of the collagen integrins alpha 1 beta 1, alpha 2 beta 1, and alpha 3 beta 1 at the fibroblast surface but only the integrin alpha 3 beta 1 on epithelial cells. Affinity chromatography on collagen-Sepharose identified only alpha 1 beta 1 and alpha 2 beta 1 as collagen-binding integrins in extracts of 125I surface-labeled fibroblasts. No collagen-binding receptors were detected in extracts of surface-iodinated epithelial cells. Message for alpha 1- and alpha 2 integrin was readily demonstrated for fibroblasts, but both mRNAs were hardly detectable in epithelial cells. In contrast, epithelial cells expressed significantly greater alpha 3 mRNA levels than fibroblasts. These data demonstrate that alpha 1 beta 1- and alpha 2 beta 1-integrins function as collagen-binding receptors in fetal lung fibroblasts. Distal fetal lung epithelial cells do not express the alpha 1 beta 1- and alpha 2 beta 1-integrins and do not adhere to collagen. The alpha 3 beta 1-integrin, which is expressed by both cell types, does not function as a collagen receptor. PMID- 7840221 TI - Interaction of surfactant protein A with bacterial lipopolysaccharide may affect some biological functions. AB - Cultured alveolar type II cells and alveolar macrophages were found to secrete colony-stimulating factors (CSF) into the medium. Surfactant protein A (SP-A; 0.1 5 micrograms/ml) and bacterial lipopolysaccharide (LPS; 10-20 micrograms/ml) were found to upregulate the secretion of CSF (seven-fold) from these cells. However, a reversal of the stimulatory effect was observed when the two agents were added simultaneously to the cells. SP-A-enhanced phagocytosis of bacteria by alveolar macrophages was also inhibited by simultaneous addition of SP-A and LPS. Thus some biological activities attributed to either SP-A or LPS are inhibited in the simultaneous presence of the two agents. We therefore investigated the possibility of interaction and binding between SP-A and LPS molecules. Our biochemical data that include immunoblots and enzyme-linked immunosorbent assay support the notion that SP-A is capable of binding LPS, and this interaction is time and concentration dependent. The binding was partially inhibited (60%) by antibody to SP-A. The binding was calcium independent and was not affected by excess carbohydrates such as methyl alpha-D-mannopyranoside or heparin. Lipid A, the hydrophobic component of LPS, however, inhibited the SP-A-LPS interaction and also caused a partial reversal of the binding. Thus these results indicate that lipid A is associated with this binding. The biological implication of SP-A-LPS interaction, especially during inflammatory responses, is discussed. PMID- 7840222 TI - KCa channel antagonists reduce NO donor-mediated relaxation of vascular and tracheal smooth muscle. AB - Electrophysiological studies suggest that activation of large-conductance Ca activated K channels (KCa) with nitric oxide (NO) causes hyperpolarization and relaxation of smooth muscle. We determined whether KCa blockers decreased relaxation to the NO donors S-nitroso-N-acetylpenicillamine (SNAP) and 3 morpholinosydonimine-hydrochloride (SIN-1) in isolated segments from main pulmonary artery (MPA), its left branch (LPA), aorta (Ao), carotid artery (CA), and trachea (Tr). NO donors caused concentration-dependent relaxation of tissues precontracted with histamine whereas the inactive carrier molecule C88-3934 was without effect. The rank order profiles of SNAP and SIN-1 sensitivity were CA = Ao = MPA > LPA = Tr. Compared with histamine, 80 mM KCl precontraction caused variable reductions in tissue sensitivity and maximum relaxation to SNAP. The KCa antagonists charybdotoxin, iberiotoxin, and tetraethylammonium decreased sensitivity to SNAP and SIN-1 2- to 11-fold in MPA, LPA, and Tr, with variable shifts in Ao and CA. The effect of iberiotoxin was not altered by removing the endothelium or epithelium. Furthermore, charybdotoxin or iberiotoxin did not alter basal or SNAP-stimulated guanosine 3',5'-cyclic monophosphate content. Glibenclamide, noxiustoxin, and leiurotoxin I, antagonists of ATP-dependent, delayed rectifier, and small-conductance KCa channels, respectively, had no effect. In conclusion, antagonists of KCa decrease NO donor-mediated relaxation of pulmonary arterial and tracheal smooth muscle. PMID- 7840223 TI - Smoke-induced emphysema in guinea pigs is associated with morphometric evidence of collagen breakdown and repair. AB - We have previously shown that chronic cigarette smoke exposure produces emphysema and airflow obstruction in the guinea pig. To further examine the changes in the connective tissue matrix associated with emphysema in this model, we used ultrastructural morphometry to determine the volume proportions of collagen and elastin in the alveolar walls of animals exposed to smoke or air (control) for 1, 3, 6, and 12 mo. After 1 mo of smoke exposure, there was a statistically significant (P < 0.001) decrease in the volume proportion of collagen in the smoke-exposed animals, whereas by 6 and 12 mo of smoke exposure, the proportion of collagen had significantly (P < 0.02, P < 0.03, respectively) increased. The volume proportion of elastin was increased in the smoke-exposed animals at the 12 mo time period. While our results do not exclude reorganization of elastin within the alveolar wall, we conclude that, in this model, cigarette smoke-induced emphysema appears to be associated with collagen breakdown and repair. We suggest that the currently accepted proteolysis-antiproteolysis theory is too narrow in its focus on elastin destruction as the major contributor to emphysema and should be broadened to the concept that smoke-induced emphysema reflects breakdown and resynthesis (possibly overproduction in the form of scarring) of a variety of connective tissue proteins in addition to elastin. PMID- 7840224 TI - A noninducible cystine transport system in rat alveolar type II cells. AB - Type II lung epithelial cells are different from other lung cell types in their means of processing and regulating intracellular glutathione (GSH) levels. In lung cell types, including endothelial cells, fibroblasts, smooth muscle cells, and macrophages, oxidants, sulfhydryl reagents, and electrophilic agents have been shown to induce cystine uptake and concomitantly increase GSH levels, suggesting that cysteine, formed by intracellular reduction of cystine, is a rate limiting substrate for GSH synthesis. The cystine transport increase was reportedly due to increase in activity of a sodium-independent transport system designated xc-. We have now examined cultures of rat lung type II cells exposed to diethylmaleic acid and arsenite. Although a rise in cellular GSH occurred, cystine transport was not induced. Cystine transport in type II cells was found to differ from the xc- system previously described. Type II cell cystine transport is primarily sodium dependent and is inhibitable by aspartate as well as glutamate and homocysteate. We conclude that the type II cell differs from other lung cell types in both its cystine transport mechanism and method of GSH regulation. PMID- 7840225 TI - Effect of pentoxifylline on changes in neutrophil sequestration and emigration in the lungs. AB - The response of neutrophils to inflammatory stimuli includes sequestration, adhesion, and migration. Pentoxifylline protects against many neutrophil-mediated lung injuries. This study investigated whether pentoxifylline prevented changes in neutrophil kinetics induced by infusion of complement fragments or neutrophil emigration induced by Streptococcus pneumoniae. Complement fragments were infused in New Zealand White rabbits treated with pentoxifylline or saline, and the circulating neutrophil counts in the arterial and venous blood samples were measured. Neutrophil emigration was induced by intrabronchial instillation of S. pneumoniae and quantitated morphometrically. The results show that, at doses achievable in vivo, pentoxifylline did not prevent either the CD18-dependent or independent phase of complement-mediated neutrophil sequestration within the pulmonary microvasculature or the release of neutrophils from the bone marrow. Pentoxifylline also did not alter either the deformability of unstimulated leukocytes or stimulus-induced decreases in deformability. Finally, neutrophil emigration into the alveolar space was neither attenuated nor accentuated by pentoxifylline. These data suggest that, in vivo, pentoxifylline does not protect against lung injury by inhibiting neutrophil sequestration or emigration and may act to alter the generation of mediators that affect neutrophil behavior, rather than acting directly on neutrophils. PMID- 7840226 TI - Calcium influx is required for tannin-mediated arachidonic acid release from alveolar macrophages. AB - The role of Ca2+ was investigated in the response of alveolar macrophages to cotton tannin, an agent implicated in the lung disease byssinosis in textile mill workers. A physiological concentration of extracellular Ca2+ was found to be required for tannin-mediated release of radiolabeled arachidonic acid (AA). Flow cytometry using indo 1 indicated that tannin caused a rapid and dose-dependent Ca2+ increase in macrophages that also required extracellular Ca2+. Ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid virtually abolished the Ca2+ influx mediated by tannin but had little effect on intracellular Ca2+ release induced by thapsigargin, N-formylmethionyl-leucylphenylalanine, or thimerosal. A mechanism for extracellular Ca2+ influx was demonstrated by rapid Mn2+ quenching of indo 1 by tannin. Verapamil inhibited tannin-mediated Ca2+ influx and AA release, but the effective concentration was 100 microM. 1,2-Bis(2 aminophenoxy)ethane-N,N,N',N'-tetraacetic acid chelated all Ca2+ in the cells and effectively abolished the tannin response. Exposure to tannin was not associated with cytotoxicity, as judged by 51Cr release. The data suggest that tannin induces Ca2+ influx in alveolar macrophages, which represents an important prerequisite for a cell-signaling pathway resulting in the accumulation of free AA. PMID- 7840227 TI - Glucocorticosteroids increase beta 2-adrenergic receptor transcription in human lung. AB - beta 2-Adrenergic receptors (beta 2R) are widely distributed and mediate a wide range of cellular responses in lung. Because glucocorticosteroids increase expression of beta 2R in cell lines, we have investigated the effects of glucocorticoids on the beta 2R mRNA level and the number of beta 2R in human peripheral lung in vitro. Incubation of lung tissues with dexamethasone (Dex) elevated both beta 2R mRNA level (as measured by Northern blot analysis) and beta 2R number (as measured by [125I]iodocyanopindolol binding). The increased accumulation of beta 2R mRNA could be detected at 15 min (1.27 +/- 0.1-fold) and the maximal accumulation occurred at 2 h (2.73 +/- 0.5-fold). The Dex-induced increase in beta 2R mRNA returned to the control level by 17 h. The increase in beta 2R number (1.58 +/- 0.2-fold) was slower, reaching a maximum between 17 and 24 h. Dex increased beta 2R mRNA in a time- and concentration-dependent manner that was abolished by the steroid receptor antagonist mifepristone (RU-38486 or RU-486). The stability of beta 2R mRNA was unchanged by Dex, and a nuclear run-on assay revealed that Dex approximately doubled the transcriptional rate of the beta 2R gene. These observations suggest that glucocorticoids act on steroid receptors to increase beta 2R expression by increasing the rate of beta 2R gene transcription. PMID- 7840228 TI - Neural and myogenic effects of cyclooxygenase products on canine bronchial smooth muscle. AB - In canine bronchi bathed in 10(-6) M indomethacin (IDM), prostaglandin (PG) E2 inhibited electrical field stimulation (EFS)- and acetylcholine (ACh)-mediated contractions and excitatory junction potentials (EJP) in a concentration dependent manner without altering the resting membrane potential. EFS-induced EJPs were abolished at 10(-7) M PGE2, which shifted responses to ACh 10-fold rightward. Thus PGE2 predominantly inhibited the release of ACh and secondarily decreased smooth muscle response to ACh. U-46619, an analogue of thromboxane A2 (TxA2), initiated tetrodotoxin- and atropine-insensitive contractions in a concentration-dependent manner. U-46619 (10(-9) M) did not alter significantly EFS- or ACh-stimulated contractions and potentiated EFS amplitude of EJPs without depolarizing muscle cells. Either prejunctional activation of ACh release by TxA2 or postjunctional potentiation of the response to ACh can explain these findings. U-46619 (> or = 10(-8) M) depolarized the membrane potential, initiating oscillations accompanied by a large contraction. Addition of 10(-8) M nitrendipine, but not tetraethylammonium (25 mM), blocked the oscillations selectively. Other prostanoids (PGD2, PGI2, and PGF2 alpha) had no significant effects on canine bronchi. In the absence of IDM, PGE2 accumulated, EFS contractions decreased with time, and EJPs disappeared. We conclude that in canine bronchi PGE2 predominantly inhibits ACh release and endogenous PGE2 acts similarly, whereas TxA2 excites, probably at postjunctional sites. PMID- 7840229 TI - Effect of indomethacin on lung development in postnatal rats: possible role of prostaglandin in alveolar formation. AB - We administered 1.3 mg ip of indomethacin, a prostaglandin synthetase inhibitor, per 100 g body wt to male rat pups daily on postnatal days 4-13 and examined their lungs on day 14. Indomethacin administration produced abnormal lung structure with diminished alveolar air, increased alveolar duct air, increased mean linear intercept (gas-exchanging wall distance), diminished gas-exchanging surface area and surface-to-volume ratio, increased septal wall thickness, diminished the number of alveolar crests, and increased the number of lamellar bodies in alveolar type II cells. However, this procedure did not alter quantitative lung growth (normal lung weights, volumes, and DNA and protein contents). Tissue prostaglandin content was decreased. The total amount of lung collagen or elastin was unchanged, but when collagen was analyzed into soluble and insoluble components, soluble collagen was increased. Supplementation with 1.0 g of prostaglandin E2 per 100 g body wt to animals treated with indomethacin reduced the abnormalities in pulmonary architecture. We conclude that indomethacin affects lung structure in growing rats and that it is an unusual model in that lung growth is normal, but lung development is abnormal. We also suggest that prostaglandins may play a significant role in alveolar formation in postnatal lung development in rats. PMID- 7840230 TI - Role of intra- and extracellular calcium stores in mesothelial cell response to histamine. AB - Ca2+ may play an important role in mesothelial cellular responses because Ca2+ acts as an intracellular messenger in a wide variety of cellular responses in different tissues. The present study was designed to clarify the mechanisms of cytosolic Ca2+ mobilization in the mesothelial cells. Rat pleural and pericardial mesothelial cells were maintained in vitro, and the Ca2+ movement was evaluated using fura 2. Histamine (30 microM to 10 mM) induced a biphasic elevation of intracellular levels of Ca2+ concentration ([Ca2+]i) that consisted of a rapid initial transient elevation followed by a sustained elevation. Neither removal of extracellular Ca2+ nor inhibition of Ca2+ influx by 1 microM nifedipine affected the histamine-induced initial transient elevation of [Ca2+]i in mesothelial cells. Nifedipine did not block histamine-induced sustained elevation of [Ca2+]i. KCl (25 and 50 mM) elicited a biphasic elevation of [Ca2+]i. However, this KCl induced elevation of [Ca2+]i was abolished by nifedipine treatment. Ryanodine (10 microM) induced a transient elevation of [Ca2+]i in Ca(2+)-free solution. The histamine-induced elevation of [Ca2+]i was completely blocked by H1-receptor antagonists. These results suggest that the mesothelial cells have three pathways to increase [Ca2+]i: release from intracellular Ca2+ stores, Ca2+ influx through L-type voltage-dependent Ca2+ channels, and receptor-operated Ca2+ channels. PMID- 7840231 TI - Mitochondrial superoxide dismutase induction does not protect epithelial cells during oxidant exposure in vitro. AB - The significance of manganese superoxide dismutase (MnSOD) induction in cells and tissues during oxidant stress is still poorly understood. In this study, transformed human bronchial epithelial cells (BEAS 2B) were treated with interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), or with combination of these cytokines (10 ng/ml concentrations) for 48 or 72 h and exposed to selected oxidants. TNF-alpha and IFN-gamma + TNF-alpha combination resulted in a marked increase of MnSOD protein and MnSOD activity. When cells pretreated with the cytokines were exposed to hyperoxia (95% O2, 72 h), menadione (5-50 microM, 4 h), or H2O2 (0.5 and 5 mM, 4 h), in all cases IFN-gamma and TNF alpha enhanced oxidant-related cell injury. The effect was most significant with cells pretreated with a combination of IFN-gamma and TNF-alpha. Antioxidant enzymes such as total SOD, glutathione peroxidase, glutathione reductase, and glucose-6-phosphate dehydrogenase did not change significantly during the cytokine treatment. Catalase activity was not changed by IFN-gamma or TNF-alpha but it decreased significantly (34%) in IFN-gamma + TNF-alpha-treated cells. Free radical generation was not changed by these cytokines in acute (30 min) experimental conditions or after 48-h treatment. These results suggest that cytokine-induced MnSOD does not protect bronchial epithelial cells against endogenously or exogenously generated oxidants in vitro. In fact, cells that contained the highest MnSOD activity were the most sensitive to subsequent oxidant damage. PMID- 7840232 TI - Altered expression of type I collagen, TGF-beta 1, and related genes in rat lung exposed to 85% O2. AB - The gene expressions of type I collagen and transforming growth factor-beta 1 (TGF-beta 1) were studied in lung tissue of rats exposed to air or 85% O2 for 14 days. Peak expression of type I collagen mRNA was observed by 14 days of 85% O2 exposure, at the same time as maximal immunoreactive type I collagen, which was most marked surrounding the major airways and vessels. TGF-beta 1 mRNA also significantly increased after 14, but not 4 or 6 days of 85% O2 exposure. TGF beta 1 immunoreactivity was only detected on day 14 of 85% O2 exposure and was localized primarily to the pulmonary epithelium. As an increase in immunoreactive type I collagen was evident by day 6 of O2 exposure, the gene expressions of interstitial collagenase (MMP-1), stromelysin, and the tissue inhibitor of the metalloproteinases (TIMP) were also examined. Increased mRNA expressions of interstitial collagenase and TIMP preceded those of type I collagen and TGF-beta 1, occurring at 4-6 days of exposure to 85% O2, while there was no significant change in stromelysin mRNA. These findings are compatible with the initial O2 mediated increase in type I collagen deposition being a result of an altered proteinase/antiproteinase balance in the lung, and the subsequent more marked deposition being a response to increased TGF-beta 1 synthesis. PMID- 7840233 TI - Staphylococcus aureus stimulates neutrophil recruitment by stimulating interleukin-8 production in dog trachea. AB - The present study examined whether neutrophil recruitment in dog airways by Staphylococcus aureus is mediated by interleukin-8 (IL-8). S. aureus culture supernatant was superfused into an isolated tracheal segment in six dogs, and neutrophil recruitment and IL-8 concentrations were measured in the superfusate. Dog IL-8 was cloned, expressed in Escherichia coli, purified by chromatography, and shown to be biologically active. With the use of an enzyme-linked immunoabsorbent assay (ELISA) for the measurement of dog IL-8, we showed that S. aureus supernatant induced neutrophil recruitment and increased IL-8 concentration in the superfusate in a time-dependent manner. The chemotactic activity present in the superfusate 6 h after superfusion with S. aureus was inhibited by an anti-IL-8 antibody. S. aureus supernatant also stimulated IL-8 production and gene expression by cultured canine tracheal epithelial cells. These results provide evidence that IL-8 plays a major role in S. aureus-induced neutrophil recruitment in the airways by stimulating IL-8 production in airway cells. PMID- 7840234 TI - Endothelin-A receptor antagonist prevents acute hypoxia-induced pulmonary hypertension in the rat. AB - Exposure to hypoxia is associated with increased pulmonary artery pressure and plasma endothelin-1 (ET-1) levels and with selective enhancement in ET-1 peptide and mRNA and endothelin-A (ETA) receptor mRNA levels in rat lung. The current study tested the hypothesis that endogenous ET-1 can account for hypoxia-induced pulmonary hypertension via a paracrine effect on ETA receptors in lung. Intravenous infusion of the ETA receptor antagonist BQ-123 (D-Trp-D-Asp-Pro-D-Val Leu) (0.4 mg/microliters at 1 microliter/h) into Sprague-Dawley rats beginning 4 h before and for 90 min during normobaric hypoxia (10% O2) markedly attenuated the hypoxic response: mean pulmonary artery pressure increased from 17.2 +/- 0.7 to 29.0 +/- 1.2 mmHg in saline control rats but did not increase from baseline in BQ-123-treated rats. BQ-123 did not alter systemic arterial pressure, heart rate, or plasma endothelin-1 levels. These findings suggest that ET-1 synthesized in lung in response to hypoxia acts locally on ETA receptors to cause pulmonary hypertension. PMID- 7840235 TI - Lipoxygenase product formation and cell adhesion during neutrophil-glomerular endothelial cell interaction. AB - Leukotriene (LT) and lipoxin (LX) levels were monitored in ionophore-stimulated coincubations of polymorphonuclear neutrophils (PMN) and microvascular kidney glomerular endothelial cells (GEN) to determine the profile of lipoxygenase (LO) products generated during cell-cell interactions and the relative contributions of transcellular pathways to LO product biosynthesis in this setting. LTB4 and LTC4 were the major products formed, as determined by reverse-phase high performance liquid chromatography and radioimmunoassay. LTB4 and LTC4 levels were increased by 23 and 185%, respectively, in coincubations of PMN and GEN, compared with incubations of PMN alone. In contrast, LXA4 and LXB4 levels were not changed in the presence of GEN. These data suggested that GEN utilize PMN-derived LTA4 to generate LT. In keeping with this hypothesis, LT biosynthesis was enhanced if PMN were primed with human granulocyte-macrophage colony-stimulating factor (GM-CSF), a cytokine that augments LTA4 biosynthesis by activated PMN. The influence of LT on PMN adhesion to GEN was also assessed, since adhesion appears to be a pivotal event in recruitment of PMN in acute glomerulonephritis. Under basal conditions, LTB4 provoked low levels of adhesion via a PMN-directed CD11/CD18-dependent mechanism. The level of adhesion was markedly enhanced by prior priming of PMN with GM-CSF or activation of GEN with tumor necrosis factor-alpha (TNF). LTB4 was as potent in this regard as the complement component C5a, platelet-activating factor (PAF), and interleukin-8 (IL-8), other mediators that contribute to the entrapment of PMN in inflamed glomeruli. LTC4 also provoked PMN-GEN adhesion via a CD11/CD18-dependent mechanism, but, in contrast to LTB4, via actions with GEN. This action of LTC4 appeared to be mediated, at least in part, by induction of PAF synthesis by GEN. Interestingly, LT-induced PMN-GEN adhesion was markedly attenuated following remodeling of PMN phospholipids with 15(S) hydroxyeicosatetraenoic acid, a product of 15-LO, which has been implicated as an anti-inflammatory eicosanoid in some experimental and human inflammatory diseases. Taken together, these results provide further evidence that 1) transcellular biosynthetic pathways may amplify the profiles of inflammatory mediators and thereby contribute to leukocyte recruitment in acute glomerulonephritis and 2) that products of the 5-LO and 15-LO pathways may exert opposing actions on PMN trafficking during glomerular inflammation in vivo. PMID- 7840236 TI - Modulation by Gly, Ca, and acidosis of injury-associated unesterified fatty acid accumulation in proximal tubule cells. AB - We have examined the dependence of unesterified fatty acid accumulation by intact, freshly isolated proximal tubules on Ca2+, pH, and the cytoprotective amino acid, glycine, during injury induced by hypoxia, antimycin, or antimycin plus ionomycin. In the absence of glycine, similarly high levels of fatty acid accumulation were seen during all three injury conditions irrespective of whether tubules were incubated in normal 1.25 mM Ca2+ medium or in medium where Ca2+ was buffered to 0.1 microM, a maneuver which prevented injury-associated increase of cytosolic-free Ca2+ as measured with fura 2. In the presence of glycine, which strongly suppressed development of lethal membrane damage for at least 60 min and did not have any apparent direct effects on fatty acid accumulation, both Ca(2+) independent and Ca(2+)-dependent components of fatty acid accumulation were discernible. The Ca(2+)-independent component accounted for approximately 2/3 of fatty acid accumulation and did not vary as Ca2+ ranged from 10 nM to 1 microM. Unequivocal Ca(2+)-dependent accumulation occurred when Ca2+ exceeded 10 microM. Lowering pH to 6.9 had a moderate, generalized suppressive effect on fatty acid accumulation, including the major Ca(2+)-independent component, irrespective of the presence of glycine. These data emphasize the role of Ca(2+)-independent fatty acid accumulation during proximal tubule cell injury, clarify the modulatory actions of the potent, intrinsic cytoprotective factors, glycine and reduced pH, and provide insight into the relationship between fatty acid accumulation and lethal membrane damage. PMID- 7840237 TI - Identification of a rat glomerular mesangial cell mitogenic 5-HT2A receptor. AB - Previous studies have demonstrated the presence of mitogenic serotonin [i.e., 5 hydroxytryptamine (5-HT)] receptors on glomerular mesangial cells and have linked those receptors to a complicated array of intracellular and autocrine/paracrine signaling pathways [T. Knauss and H. E. Abboud. Am. J. Physiol. 251 (Renal Fluid Electrolyte Physiol. 20): F844-F850, 1986; and N. Takuwa, M. Ganz, Y. Takuwa, R. B. Sterzel, and H. Rasmussen. Am. J. Physiol. 257 (Renal Fluid Electrolyte Physiol. 26): F431-F439, 1989]. Those studies suggested that the mesangial subtype of 5-HT receptor is a member of the 5-HT2 receptor family, which consists of three known members, designated as subtypes A, B, and C. The purpose of the current study was to identify the subtype of 5-HT2 receptor present on mesangial cells. Northern blot showed detectable mRNA for a putative 5-HT2A receptor, but not for 5-HT1A or 5-HT2C receptors. Reverse transcription-polymerase chain reaction (RT-PCR) with degenerate oligonucleotides derived from the putative third and sixth transmembrane domains of cloned 5-HT2 receptors yielded a 580 nucleotide (nt) fragment. RT-PCR with primers highly specific for the 5-HT2A receptor and designed to amplify > 95% of its coding block yielded a product of 1,320 nt. Nested PCR reactions yielded products of the predicted sizes for the 5 HT2A receptor. Partial sequence information was obtained, and the sequence corresponded exactly (627/627 nt) to that published for the cloned rat brain 5 HT2A receptor. These studies identify the mesangial cell mitogenic 5-HT receptor as a 5-HT2A receptor subtype. PMID- 7840238 TI - Triiodothyronine stimulates renal epidermal growth factor expression in adult rat. AB - To define the role that thyroid hormones play in regulation of renal epidermal growth factor (EGF) production, we characterized the effect of triiodothyronine (T3) administration on renal EGF expression in adult rats. The action of T3 to regulate EGF production was examined under one condition in which renal EGF expression is known to be diminished, posthypophysectomy, and in pituitary-intact rats. Levels of mature EGF, EGF precursor, and EGF mRNA, reduced in kidneys of hypophysectomized rats compared with pituitary-intact animals, increased significantly following the administration of T3 to hypophysectomized rats. Thus replacement of thyroid hormone alone was sufficient to enhance renal EGF expression. Induction of a hyperthyroid state in normal rats by injection of T3 for 4 days increased levels of extractable immunoreactive mature EGF, EGF precursor present in renal membranes, and EGF mRNA measured in kidneys. Levels of EGF in circulation were undetectable under all experimental conditions. We conclude that T3 enhances the renal synthesis of EGF in both hypopituitary and pituitary-intact rats. Enhancement of renal EGF expression is one mechanism that must be considered to explain the actions of thyroid hormones on kidney. PMID- 7840239 TI - Periodic high extracellular glucose enhances production of collagens III and IV by mesangial cells. AB - We examined the effects of periodic changes in extracellular glucose concentration on matrix production and proliferation using three groups of cultured rat mesangial cells (MCs): 1) MCs in medium with continuous 5 mM glucose (CL), 2) MCs in medium alternating daily between 5 and 25 mM glucose (PH), and 3) MCs in medium with continuous 25 mM glucose (CH). MCs cultured in PH for 10 days produced 329 and 110% more type III collagen protein than MCs cultured in CL and CH, respectively. MCs cultured in PH induced 31 and 14% more type IV collagen than MCs cultured in CL and CH, respectively. Extracellular glucose concentration had no effect on the amount of type I collagen produced. MCs cultured in PH or CH for 5 days also expressed increased levels of type I, III, and IV collagen mRNA compared with MCs cultured in CL. MCs cultured in PH for 8-10 days also produced significantly more DNA than MCs in CL or CH. These data suggest that the temporal pattern of exposure to high extracellular glucose plays a role in regulating matrix formation and cellular proliferation by MCs. Furthermore, periodic elevations of extracellular glucose had a greater stimulatory effect on collagen production than a sustained elevation. These results suggest that decreasing the variability of blood glucose concentration may decrease the adverse effect of elevated glucose levels on MC matrix production and the progression of diabetic glomerulopathy. PMID- 7840240 TI - Heat-shock-stimulated transepithelial daunomycin secretion by flounder renal proximal tubule primary cultures. AB - Primary monolayer cultures of winter flounder renal proximal tubule epithelium mounted in Ussing chambers were used to characterize transepithelial transport of daunomycin (Dau). Control tissues performed active net secretion of Dau (0.064 +/ 0.027 nmol.cm-2.h-1). Mild heat shock (5 degrees C elevation for 6-8 h followed by return to normal temperature) almost doubled Dau secretion (0.114 +/- 0.026 nmol.cm-2.h-1). This response was inhibited approximately 40% by addition of the protein synthesis inhibitor, cycloheximide. Dau secretion was inhibited by verapamil, vinblastine, cyclosporin A, and to a lesser degree by the organic cation, tetraethylammonium. In addition, tetraethylammonium secretion was inhibited by vinblastine. Dau secretion was not inhibited by the organic anion, p aminohippurate, and p-aminohippurate secretion was not inhibited by vinblastine. The transepithelial reabsorptive flux of Dau and the electrical characteristics of the tissues, including rheogenic glucose transport, were unaffected by any of the above treatments. Reaction of tissues with a monoclonal antibody to P glycoprotein (C219) revealed the presence of this transporter on only apical microvilli. The data indicate that flounder possess an active mechanism for the renal excretion of Dau that is stimulated by mild heat shock. This mechanism is distinct from organic anion, but not organic cation, transport and has characteristics consistent with transport by an apical P-glycoprotein. PMID- 7840241 TI - Ca(2+)-dependent protein kinases modulate proline transport across the renal brush-border membrane. AB - The cellular mechanisms controlling reabsorption of amino acids in the renal proximal tubule are unknown. Ca(2+)-dependent protein kinases modulate the activity of several ion channels and carriers in the kidney. The role of these enzymes in regulating tubular amino acid transport has not been established. We investigated the effect of Ca(2+)- and phospholipid-dependent protein kinase C (PKC) and Ca2+/calmodulin-dependent protein kinase II (CaMK II) on Na(+)- and Cl( )-dependent proline transport across the rat renal brush-border membrane (BBM). Bioassays utilizing selective peptide substrates for Ca(2+)-dependent protein kinases demonstrated the presence of PKC and CaMK II in the BBM. Renal brush border membrane vesicles (BBMV) were phosphorylated using the "hyposmotic shock" technique. Endogenous (membrane-bound) CaMK II and PKC, as well as exogenous, highly purified PKC inhibited NaCl-linked proline uptake by phosphorylated, lysed/resealed BBMV compared with control vesicles. The inhibitory effect of Ca2+ on proline transport, without the presence of other kinase activators, was mediated by activation of endogenous CaMK II. The CaMK II- and PKC-induced inhibition of proline uptake was reversed by the specific kinase inhibitor peptides CaMK II-(281-302) and PKC-(19-31), respectively. These data suggest that Ca(2+)-dependent protein kinase-mediated phosphorylation inhibits NaCl-dependent proline transport across the tubular luminal membrane. PMID- 7840242 TI - Instantaneous and steady-state gains in the tubuloglomerular feedback system. AB - The load of water and solute entering each nephron of the mammalian kidney is regulated by the tubuloglomerular feedback (TGF) mechanism, a negative feedback loop. Experiments in rats have shown that key variables of this feedback system may exhibit TGF-mediated oscillations. Mathematical modeling studies have shown that the open-feedback-loop gain is a crucial parameter for determining whether oscillations will emerge. However, two different formulations of this gain have been used. The first is the steady-state gain, a readily measurable quantity corresponding to the steady-state reduction in single-nephron glomerular filtration rate (SNGFR) subsequent to a sustained increased in ascending limb flow rate. The second is an instantaneous gain, a variable arising from theoretical considerations corresponding to the maximum reduction in SNGFR resulting from an instantaneous shift of the ascending limb flow column, with the assumption that the SNGFR response is also instantaneous. Here we show by an analytic argument how the steady-state and instantaneous open-feedback-loop gains for the ascending limb are related. In the case of no solute backleak into the ascending limb, the two formulations of gain are equivalent; however, in the presence of solute backleak, the instantaneous gain is larger in magnitude than the steady-state gain. With typical physiological parameters for the rat, calculations with a model previously devised by us show that the gains differ by 5-10%. Hence, experimental measurements of the steady-state gain may provide useful lower-bound estimates of the instantaneous gain of the feedback system in the normal rat. However, the gains may diverge significantly in pathophysiological states where ascending limb transport is compromised by abnormally high NaCl permeability. PMID- 7840243 TI - Validation of miniature ultrasonic transit-time flow probes for measurement of renal blood flow in rats. AB - This study validates the accuracy of miniature ultrasonic transit-time flow probes for measuring renal blood flow (RBF) in the rat. Probes for 1-mm and 2-mm vessels were calibrated ex vivo using excised arteries at varying flow rates and hematocrit (Hct). Correlation between measured and true flow rates for the 2-mm probe were identical (r = 1.0) at both normal and subnormal Hct values. Correlation for the 1-mm probe was high (r = 0.994) at normal Hct, but varied at both high flow rates and subnormal Hct values. In vivo correlation of RBF measurements using the 1-mm probe with the clearance and extraction of p aminohippuric acid showed a high correlation (r = 0.84; n = 72, P < 0.0001) over a wide range of flow rates (0.5-21 ml/min) and Hct (36-74%). Zero flow levels remained steady, averaging -0.2 +/- 0.2 ml/min during occlusion in the living animal and -0.1 +/- 0.3 ml/min after exsanguination. This study shows that the ultrasonic transit-time flowmeter (1-mm and 2-mm probes) is a reasonably accurate and reliable method with which to measure RBF in the anesthetized, acute instrumented rat. PMID- 7840244 TI - Electrophysiological study of luminal and basolateral vasopressin in rabbit cortical collecting duct. AB - To clarify the mechanism of action of arginine vasopressin (AVP) on ionic conductances, electrophysiological technique was applied to the rabbit cortical collecting duct (CCD) perfused in vitro. When AVP (100 pM) was added to the bath, transepithelial voltage (VT), transepithelial resistance (RT), and fractional resistance of the apical membrane (fRA) of the principal cell displayed biphasic responses: initial increase in lumen-negative VT (phase I) was associated with decreases in RT and fRA, whereas secondary decrease in VT (phase II) was associated with increases in RT and fRA. In phase I, depolarization of the luminal membrane was observed due to stimulation of Na+ conductance in the luminal membrane. In phase II, mixed responses of both hyperpolarization of the luminal membrane, due to late inhibition of Na+ conductance, and depolarization of the basolateral membrane, due to stimulation of Cl- conductance, were observed. 8-(4-Chlorophenylthio)-adenosine 3',5'-cyclic monophosphate, as a pure vascular AVP receptor 2 (V2) action, mimicked the actions of AVP. Addition of AVP (100 pM to 1 nM) in the lumen resulted in increases in lumen-negative VT and RT. Luminal AVP did not affect the electrical parameters in beta-intercalated cells. In principal cells, luminal AVP caused sustained increase in total membrane resistance (Ri), together with an initial depolarization of the luminal membrane followed by a late hyperpolarization of the basolateral membrane. Because the initial response was abolished in the presence of 2 mM Ba2+ in the lumen, an inhibition of luminal K+ conductance may be responsible for the initial phase of luminal AVP action. Late hyperpolarization of the basolateral membrane associated with an increase in membrane resistance was abolished in the absence of ambient Cl-. Under the condition where Cl- conductance of the basolateral membrane was stimulated by administration of cAMP in the bath, voltage deflections of the basolateral membrane on changing Cl- concentration in the bath from 120 to 12 mM decreased by 88% in the presence of luminal AVP. These observations are in accord with the view that the basolateral Cl- conductance was inhibited by luminal AVP in the later phase. These data indicate that AVP in the lumen inhibits basolateral Cl- conductance, which is stimulated by AVP in the bath. PMID- 7840245 TI - Role of lipid peroxidation in H2O2-induced renal epithelial (LLC-PK1) cell injury. AB - The exact sequence of events or mechanisms by which H2O2 induces renal cell injury remains undetermined. Specifically, whether the attendant lipid peroxidation is a cause or an effect remains unclear. Employing H2O2 and LLC-PK1 cells, we tested the hypothesis that lipid peroxidation is a seminal event and that its inhibition is cytoprotective. In a time course study, lipid peroxidation (thiobarbituric acid reaction) and degradation (release of [3H]arachidonic acid) preceded H2O2-induced cytolysis (51Cr and lactate dehydrogenase release). The role of preceding lipid peroxidation in cytolysis was examined with lipid radical scavengers. alpha-Tocopherol and lazaroid compound 2-methyl aminochroman dose dependently inhibited H2O2-induced lipid peroxidation and prevented cytolysis. 2 Methyl aminochroman cytoprotection was associated with blockade of lipid degradation. 21-Aminosteroid, another lazaroid, also inhibited lipid peroxidation and prevented cytolysis. These findings provide evidence that lipid alterations contribute to H2O2-mediated LLC-PK1 injury and, for the first time, demonstrate the potency of lazaroids in a renal cell line. In vivo studies with lazaroids may define the role of lipid peroxidation in acute renal injury models. PMID- 7840246 TI - Effects of endothelins on renin secretion from isolated mouse renal juxtaglomerular cells. AB - This study was performed to examine the effects of endothelin (ET)-1, ET-2, and ET-3 on renin secretion from cultured mouse renal juxtaglomerular (JG) cells. Although different ETs had no consistent effect on basal renin secretion, they equipotently inhibited adenosine 3',5'-cyclic monophosphate (cAMP)-stimulated renin release with a concentration of approximately 3 nM inhibiting 50% of maximal response. ETs did not significantly affect renin release stimulated by the nitric oxide donor sodium nitroprusside (100 microM) or that stimulated by low [2 mM ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid] or high (3 mM CaCl2) extracellular calcium. The inhibitory effect of ETs on cAMP dependent renin secretion was abolished by lowering extracellular calcium concentration to the nanomolar range. However, the action of ETs was not changed by the ETA receptor antagonist BQ-123 (100 nM) and was mimicked by ETB receptor agonists IRL-1620 (1 microM), sarafotoxin S6b (1 microM), and [Ala1,3,11,15]ET-1 (1 microM). All ETs induced calcium oscillations in JG cells that were dependent on extracellular calcium and were associated with prominent calcium-activated chloride currents. These findings suggest that ETs inhibit rather selectively the cAMP-activated pathway of renin secretion through a calcium-sensitive process. The action of ETs on renal JG cells appears to be mediated via ETB receptors and is presumably related to activation of phospholipase C and subsequent events. PMID- 7840247 TI - P-glycoprotein-mediated secretion of a fluorescent cyclosporin analogue by teleost renal proximal tubules. AB - The transport of a fluorescent cyclosporin analogue was measured in killifish (Fundulus heteroclitus) proximal tubules by means of epifluorescence microscopy and digital image analysis. Renal cells rapidly accumulated the cyclosporin analogue from the medium and attained steady state within 60 min; luminal fluorescence increased over the first 60-90 min. At steady state, luminal fluorescence intensity was two to three times higher than cellular. Cellular fluorescence intensity was a linear function of medium substrate concentration and was not affected by any treatment used. In contrast, luminal fluorescence exhibited a saturable component as the medium concentration of the cyclosporin was increased. Secretion into the lumen was blocked by metabolic inhibitors, vanadate, other cyclosporins, such as cyclosporin A and cyclosporin G, and substrates for P-glycoprotein (verapamil, vinblastine, and quinine) but not by substrates for the renal organic anion or organic cation transport systems, such as p-aminohippurate or tetraethylammonium. The data are consistent with the fluorescent cyclosporin analogue entering proximal tubule cells by simple diffusion and then being pumped into the tubular lumen by P-glycoprotein. PMID- 7840248 TI - Adaptation of inner medullary collecting duct to dehydration involves a paracellular pathway. AB - Prolonged fluid restriction in rats is accompanied by functional modifications of the terminal part of the inner medullary collecting duct (IMCD) revealed by a sustained increase in arginine vasopressin (AVP)-independent transepithelial osmotic water permeability (PTE) in vitro. The cellular basis of this adaptation was explored in isolated and perfused terminal IMCDs of Sprague-Dawley rats using video and fluorescence microscopy. Basolateral membrane osmotic water permeability (Posm), transcellular Posm, and PTE were measured in quick sequence in every tubule. They were expressed per unit area of basolateral membrane corrected for infoldings, based on previous stereological studies and assuming no major change in membrane surface area between hydrated and dehydrated animals. Compared with IMCDs of rats with a high water intake, IMCDs of rats deprived of fluid for 36 h displayed a significantly higher basal PTE (24.9 +/- 5.1 vs. 6.1 +/- 0.6 microns/s), a similar basolateral Posm, and a higher transcellular Posm, implying a higher permeability of the apical membrane, despite the absence of exogenous AVP. However, when IMCDs of thirsted rats were exposed to AVP in vitro, their transcellular Posm (36.0 +/- 2.4 microns/s) was significantly smaller than their PTE determined simultaneously (51.8 +/- 7.1 microns/s), suggesting that part of the water flow may follow a paracellular route. A change in paracellular pathways was supported by higher apparent permeabilities to [14C]sucrose (0.85 +/ 0.27 vs. 0.28 +/- 0.04 x 10(-5) cm/s) and to [methoxy-3H]inulin (0.25 +/- 0.04 vs. 0.14 +/- 0.03 x 10(-5) cm/s) in IMCDs of thirsted rats. The nonelectrolyte permeabilities were affected neither by AVP nor by urea-rich bathing solutions. We conclude that in vivo factors related to dehydration produce a conditioning effect on terminal IMCD, which includes stabilization of the apical membrane in a state of high Posm and opening up of paracellular pathways revealed by a higher permeability to water and nonelectrolytes. The role of these adaptive phenomena remains unclear but may pertain to the sudden transitions between antidiuresis and diuresis. PMID- 7840249 TI - ADH-evoked [Cl-]i-dependent transient in whole cell current of distal nephron cell line A6. AB - The effect of antidiuretic hormone (ADH) on a distal nephron cell line (A6) was studied using the whole cell patch-clamp technique. A6 cells were cultured on a permeable support filter for 10-14 days in media containing 10% fetal bovine serum without supplemental aldosterone. In the unstimulated condition A6 cells had very small conductances of Na+,K+, and Cl-. Arginine vasotocin (AVT, 140 mU/ml, 280 nM) evoked a "transient" increase in whole cell currents as did dibutyryl-adenosine 3',5'-cyclic monophosphate (5 mM). These transients consisted of two components; one was the nonselective cation conductance, and the other was the Cl- conductance. Activation of these conductances was dependent on intracellular Cl- concentration ([Cl-]i). At low [Cl-]i (< or = 50 mM) both conductances were activated, whereas when [Cl-]i was 80 mM, only the Cl- conductance was activated. At high [Cl-]i (125 mM), both conductances were inhibited. It seems likely that the [Cl-]i maintained at a low level (< or = 50 mM) is an important requirement for A6 cells to respond to AVT. PMID- 7840250 TI - Fulminant metanephric apoptosis and abnormal kidney development in bcl-2 deficient mice. AB - Apoptosis of the developing metanephric kidney plays an important role in renal organogenesis. The bcl-2 is an oncogene that inhibits apoptotic cell death in a variety of settings. The bcl-2 (-/-) mice complete embryonic development but, in contrast to bcl-2 (+/-) and bcl-2 (+/+) littermates, manifest growth retardation, hypopigmentation of hair, lymphoid apoptosis, abnormal kidney morphology, and renal failure postnatally. To provide insight into the mechanism for the latter abnormalities, we examined metanephric kidneys from bcl-2 (-/-), bcl-2 (+/-), and bcl-2 (+/+) mice, as well as embryonic day 12 (E12) mouse embryos, and compared growth and development of metanephroi in vitro. Kidneys from bcl-2 (+/-) mice developed normally. In contrast, development of kidneys from bcl-2 (-/-) mice was abnormal as reflected by a marked reduction of renal size in newborns compared with kidneys of bcl-2 (+/-) littermates. In addition, kidneys from bcl-2 (-/-) mice contained far fewer nephrons and had smaller nephrogenic zones. Although metanephroi obtained from E12 bcl-2 (+/-) and bcl-2 (-/-) mouse embryos were comparable in size, apoptosis of cells within metanephric blastemas of metanephroi from E12 bcl-2 (-/-) embryos was strikingly enhanced compared with that in blastemas of metanephroi from bcl-2 (+/-) embryos. During 3 days in culture, growth and development of metanephroi from bcl-2 (-/-) embryos were visibly reduced compared with those from bcl-2 (+/-) embryos.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7840251 TI - Morphometric analysis of effects of angiotensin II on glomerular structure in rats. AB - Micropuncture and morphometric studies related the effects of angiotensin II (ANG II) on glomerular function and structure. Compared with control animals, rats receiving an intrarenal infusion of ANG II at 40 ng.kg-1.min-1 exhibited a marked reduction in the glomerular ultrafiltration coefficient (Kf) (0.84 +/- 0.13 vs. 1.43 +/- 0.05 microliters.s-1.mmHg-1, ANG II vs. control), which caused a decrease in glomerular filtration rate (GFR) (1.04 +/- 0.11 vs. 1.27 +/- 0.11 ml/min) despite an increase in glomerular transcapillary hydraulic pressure difference (46 +/- 1 vs. 40 +/- 1 mmHg). Morphometric studies showed that these hemodynamic changes were not associated with any reduction in glomerular volume (1.27 +/- 0.05 vs. 1.31 +/- 0.07 x 10(6) microns3, ANG II vs. control), glomerular capillary volume (4.25 +/- 0.36 vs. 4.41 +/- 0.33 x 10(5) microns3), or glomerular peripheral capillary surface area (2.24 +/- 0.11 vs. 2.29 +/- 0.30 x 10(5) microns2). Higher-power electron micrographs showed that ANG II also did not alter mean foot process width (478 +/- 14 vs. 491 +/- 18 nm, ANG II vs. control), reduce the total filtration slit length overlying the peripheral capillary wall (7.0 +/- 0.6 vs. 6.6 +/- 0.5 x 10(5) microns), or reduce the average width of individual filtration slits (45 +/- 2 vs. 43 +/- 2 nm). ANG II infusion thus caused a 40% reduction in the value of Kf without causing detectable changes in epithelial cell or filtration slit structure. PMID- 7840252 TI - Sodium entry mechanisms in distal convoluted tubule cells. AB - Sodium transport across apical membranes of distal convoluted tubules is thought to be mediated by Na-Cl cotransport and conductive Na entry. Immortalized mouse distal convoluted tubule cells were used to characterize Na entry pathways. Chlorothiazide, an inhibitor of Na-Cl cotransport, and amiloride, which blocks epithelial Na channels, reduced ouabain-suppressible oxygen consumption by 40 and 35%, respectively. In simple buffer solutions, free of bicarbonate, phosphate, or formate, chlorothiazide inhibited Na uptake by 44% and Cl uptake by 48%. Michaelis constants of 21 mM for Na and 14 mM for chloride were calculated. Amiloride inhibited Na uptake by 49% and had no effect on Cl uptake. The calculated Hill coefficient of 1.07 and the equivalence of chlorothiazide sensitive Na and Cl uptake are consistent with the presence of Na-Cl cotransport. Na-Cl cotransport and amiloride-sensitive Na influx account for 85% of Na entry in distal convoluted tubule cells in the absence of phosphate and formate. The selective Na/H exchange inhibitor ethylisopropyl amiloride had no effect on Na uptake; however, it abolished formate-stimulated Na uptake. The anion exchange blocker 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) inhibited Na uptake. These findings are consistent with parallel Na/H and Cl/formate exchange. Na uptake was inhibited 8% by the selective Na/Ca exchange inhibitor, dimethylbenzamil. An additional 7% of Na entry was phosphate dependent and was abolished by phosphonoformic acid, a competitive inhibitor of Na-Pi cotransport. In summary, the majority of Na entry into distal convoluted tubule cells occurs through Na-Cl cotransport and an amiloride-sensitive pathway (75% in presence of phosphate and formate). An additional 13% may enter by Na/H exchange, with the remainder mediated by Na/Ca exchange and Na-Pi cotransport. PMID- 7840253 TI - Expression and cellular localization of mRNA encoding the "gastric" isoform of H(+)-K(+)-ATPase alpha-subunit in rat kidney. AB - The distribution of transcripts encoding the gastric H(+)-K(+) adenosinetriphosphatase (ATPase) alpha-subunit in the normal rat kidney was studied by reverse transcription-polymerase chain reaction (RT-PCR), combined with DNA sequence analysis and renal microdissection, and by nonradioactive in situ hybridization of fixed kidney sections using highly specific molecular probes. RT-PCR products corresponding to the gastric H(+)-K(+)-ATPase alpha subunit were detected in the cortex, outer and inner medulla, and in isolated cortical (CCD) and inner medullary collecting ducts (IMCD). With digoxigenin labeled cRNAs derived from the 5' and 3' ends of the gastric H(+)-K(+)-ATPase alpha-subunit cDNA, specific hybridization signal was detected prominently in all the cells of the connecting segment and CCD, the intercalated cells of the outer medullary collecting duct, the IMCD, and the renal pelvic epithelium lining the secondary pouches. Weak labeling was noted in the S3 segment of the proximal tubule, the distal convoluted tubule, and the cortical thick ascending limb of Henle. Hybridization with the sense probes produced no cellular labeling. These data provide the first direct demonstration for the expression and cellular distribution of mRNA encoding the gastric H(+)-K(+)-ATPase alpha-subunit in the normal, potassium-replete kidney, and they provide essential tools for the molecular analysis of renal acid base and potassium transport under physiological and pathophysiological conditions. PMID- 7840254 TI - Sympathectomy exaggerates antihypertensive effect of vasopressin withdrawal. AB - The role of sympathetic function in the mechanism of the decrease in arterial pressure that follows withdrawal of an intravenous infusion of arginine vasopressin (AVP) in spontaneously hypertensive rats (SHR) was studied by comparing this withdrawal-induced antihypertensive phenomenon (WAP) in rats with intact sympathetic function to those subjected to sympathectomy. Sympathectomy with guanethidine did not lower blood pressure significantly in either SHR or normotensive Wistar-Kyoto (WKY) rats despite a marked impairment of sympathetic function as judged by a dramatic attenuation of blood pressure responses to tyramine and by evidence of denervation supersensitivity to phenylephrine. Cessation of a 3-h intravenous infusion of AVP (20 ng.kg-1.min-1) was associated with large and prolonged decrease in pressure below preinfusion levels in SHR with intact sympathetic function: 5 h after stopping the infusion, pressure was 27 +/- 3 mmHg below preinfusion levels. In sympathectomized SHR, the decrease in pressure after cessation of the AVP infusion was much larger: 5 h after the infusion, pressure was 44 +/- 2 mmHg below preinfusion levels. In contrast to SHR, pressure returned to control levels in WKY with intact sympathetic function after withdrawal of AVP. A small but significant decrease in pressure occurred after withdrawal of AVP in sympathectomized WKY. The results are consistent with the hypothesis that withdrawal of sympathetic activity is a contributing factor or a prerequisite condition for development of a WAP. PMID- 7840255 TI - Contractile dysfunction and abnormal Ca2+ modulation during postischemic reperfusion in rat heart. AB - Isolated adult rat hearts in an isovolumic nonworking Langendorff preparation were loaded with the Ca2+ indicator aequorin to investigate the effects of ischemic reperfusion on free intracellular Ca2+ concentration ([Ca2+]i) homeostasis and left ventricular (LV) contractile function. In three groups (each n = 8) that underwent 10, 20, and 30 min of ischemia, recovery of developed pressure amounted to, respectively, 63% [77 +/- 3 (SE) mmHg], 48% (56 +/- 4 mmHg), and 34% (43 +/- 4 mmHg) of preischemic control (122 +/- 5 mmHg) after 60 min of reperfusion. Diastolic pressure remained elevated at 40 +/- 4, 55 +/- 3, and 65 +/- 6 mmHg, respectively (preischemic control, 12 mmHg). During early reperfusion (0-20 min), the light transient demonstrated a prolonged time to 90% decline from peak light (t90L), which was paralleled by a delayed relaxation on the LV pressure tracing in the 10- and 20-min ischemia groups. After 60 min of reperfusion, the prolongation of t90L persisted in all groups (10-min ischemia, 89 +/- 2 ms; 20 min, 95 +/- 3 ms; 30 min, 96 +/- 2 ms; control, 82 +/- 2 ms; P < 0.05). In contrast, the LV pressure tracing was abbreviated beyond the preischemic control, indicating altered myofibrillar Ca2+ responsiveness. Diastolic [Ca2+]i was elevated after 60 min of reperfusion (10-min ischemia, 0.40 +/- 0.06 microM; 20 min, 0.48 +/- 0.04 microM; 30 min, 0.51 +/- 0.06 microM; control, 0.32 +/- 0.01 microM) and had a significant positive correlation with LV diastolic pressure (r = 0.79; P < 0.001). A positive correlation was also found for the amplitude of the Ca2+ transient and LV developed pressure (r = 0.53; P < 0.05). These findings suggest that postischemic contractile dysfunction is related to altered Ca2+ modulation with impaired [Ca2+]i homeostasis following moderate to severe reperfusion injury in the rat. PMID- 7840256 TI - Fractals describe blood flow heterogeneity within skeletal muscle and within myocardium. AB - A marked perfusion heterogeneity exists within single skeletal muscles and within the left ventricular (LV) myocardium. The relative dispersion (RD) of blood flows to regions < 1 g amounts to approximately 0.35 in both organs in rabbits. RD is changed with refinement of spatial resolution because the observed variance in regional flows increases. It has been shown with fractal analyses that the fractal dimension (D) can describe the relationship between the measured RD and size of the region studied within both the myocardium and the lung. A similar study has not been done with skeletal muscle. Barbital-anesthetized rabbits, cats, and sheep were used. Regional blood flow distribution was assessed with the microsphere method. Microsphere deposition in organ regions was determined after successive regrouping of either the LV or one skeletal muscle into various sized regions. We found that the perfusion patterns could be described with fractals for both organs, with the corresponding D values of 1.22-1.37 for the myocardium and 1.30-1.46 for muscle. It appears that fractals also yield a good description of blood flow distribution within skeletal muscle. In rabbits, D for myocardium was strongly correlated to the D for muscle (correlation coefficient = 0.98). This surprising finding of the strong correlation in D sampled from two organs originating from the same rabbit has hitherto not been reported. PMID- 7840257 TI - Exercise training effects on collateral and microvascular resistances in rat model of arterial insufficiency. AB - Experiments were performed to determine if exercise training reduces collateral or microvascular resistances in the hindlimb of rats with arterial insufficiency. After right femoral arterial ligation (age 10 wk), rats were divided into sedentary (Sed) and treadmill-trained (Tr) groups (7-9 wk, final intensity: 27 m/min, 6 degree grade, 60 min/day). Minimal resistances (mmHg.ml-1.min.100 g) of the total limb (RT), collateral vessels (RC), and the microcirculations distal (Rfmc) and proximal (Rimc) to the ligation site were determined during pump perfusion of the hindlimbs. RT was lower in nonligated (open) and acutely ligated limbs of Tr than Sed rats (open: 0.69 +/- 0.011 vs. 0.93 +/- 0.071; acute: 0.92 +/- 0.028 vs. 1.18 +/- 0.070 mmHg.ml-1.min.100 g) but not in chronically ligated limbs (chronic: 0.88 +/- 0.072 vs. 1.00 +/- 0.046 mmHg.ml-1.min.100 g). RC was similar between the chronically ligated limbs of Sed and Tr rats (1.69 +/- 0.165 vs. 1.97 +/- 0.227 mmHg.ml-1.min.100 g) and was approximately 70% lower than in acutely ligated limbs of both groups. Rfmc and Rimc were not affected by arterial ligation, but Rimc was significantly lower in Tr than in Sed rats (acute: 1.05 +/ 0.026 vs. 1.54 +/- 0.163; chronic: 1.24 +/- 0.071 vs. 1.81 +/- 0.202 mmHg.ml 1.min.100 g). These results indicate that the primary site of vascular adaptations to chronic arterial ligation is in the collateral vessels. Exercise training does not significantly alter the collateralization process but may provide protection against acute arterial occlusion by stimulating microvascular growth. PMID- 7840258 TI - Capillary pressure, pulse pressure amplitude, and pressure waveform in healthy volunteers. AB - The influence of gender, local temperature, and systemic blood pressure on human capillary pressure is unknown. Finger nail fold capillary pressure was therefore directly measured in 74 healthy supine volunteers (40 female) at midaxillary level. Capillary pressure was lower in women than in men (15.9 +/- 3.0 vs. 18.2 +/- 2.3 mmHg; P = 0.001), particularly in premenopausal women, but was not related to systolic, diastolic, or mean blood pressure. Capillary pulse pressure amplitude was related to skin temperature, an effect more marked in women (P = 0.003). There was a significant association between skin temperature and the time taken for the systolic pressure rise to reach the capillary, in women only (r = 0.69, P < 0.001). Increasing age reduced the high-frequency waves in the pressure waveform [2nd harmonic percentage of fundamental: r = -0.52 and P = 0.002 (women), r = -0.52 and P = 0.004 (men)]. Thus mean capillary pressure and the pressure waveform may be influenced by gender, age, and skin temperature, illustrating the necessity to adequately match control groups during assessments of capillary pressure pathophysiology. PMID- 7840259 TI - Transarterial wall oxygen gradients at the dog carotid bifurcation. AB - The purpose of this study was to determine the effect of the carotid artery bifurcation on the delivery of oxygen to the artery wall by measuring the transarterial wall oxygen gradient. Transarterial wall oxygen gradient measurements were performed in dogs anesthetized with thiopental sodium and isoflurane by means of an oxygen microelectrode. Measurements were performed at six locations along the carotid bifurcation. Oxygen tensions at the carotid sinus were decreased in the inner 40% of the artery wall compared with control locations. Oxygen tensions at the flow divider were increased throughout the artery wall compared with control locations. These effects were noted without differences in blood pressure, arterial blood oxygen tension, or histological evidence of atherosclerotic lesion formation. These findings suggest that the delivery of oxygen to the artery wall is altered by the bifurcation of the carotid artery. Low arterial oxygen tensions at the carotid sinus support a role for artery wall hypoxia in the formation of atherosclerotic lesions. PMID- 7840260 TI - Distribution of mRNAs for natriuretic peptides in RV hypertrophy after pulmonary arterial banding. AB - It has been unclear whether the increases in transcript accumulation for atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) during pressure overload are caused by the direct hemodynamic stress imposed on the myocytes or mediated by systemic hormonal factors. We examined the levels and regional distributions of ANP and BNP mRNAs in the hypertrophied right ventricle produced by experimental coarctation of main pulmonary artery (PA) in rats and compared them with those of skeletal alpha-actin mRNA, which is known to be a genetic marker for cardiac hypertrophy. In this experimental model, the left ventricle was free from the influence of pressure overload. By Northern blot analysis, remarkable increases in mRNAs for ANP and BNP, as well as skeletal alpha-actin, were observed in the right ventricle at 1 day after PA banding. Changes of expression of these genes were minimal in the left ventricle. ANP mRNA levels in the right ventricle increased further at days 3 and 7, whereas BNP mRNA remained at its day 1 level through 7 days. Increased expression of ANP, BNP, and skeletal alpha-actin mRNAs occurred exclusively in the right ventricular (RV) free wall and in the junctional region between the RV free wall and the interseptal wall as determined by in situ hybridization. These data suggest that local stimuli caused by hemodynamic overload induce cardiac hypertrophy and its associated increases in ANP and BNP expression in the RV free wall. PMID- 7840261 TI - Asynchrony and ryanodine modulate load-dependent relaxation in the canine left ventricle. AB - Load-dependent relaxation was studied in six anesthetized dogs by inflating an intra-aortic balloon to increase peak left ventricular (LV) pressure by 1-20 mmHg within a single cardiac cycle. A series of timed and graded pressure loads was produced by inflating the balloon either during diastole (early loads) or midsystole (midsystolic pressure loads). The rate of LV pressure fall was measured with the time constant (tau). There was a significant increase in tau with 63 midsystolic pressure load [tau increased 1.4 +/- 0.1% (SE)/mmHg increase in peak LV pressure] but not with 67 early pressure loads (-0.5 +/- 0.1%/mmHg). This difference remained with LV pacing-induced asynchrony (tau increased 1.8 +/- 0.1%/mmHg with 54 midsystolic pressure loads compared with -0.2 +/- 0.1%/mmHg with 56 early pressure loads) and after 5 micrograms/kg of intravenous ryanodine (tau increased 1.0 +/- 0.2%/mmHg with 58 midsystolic pressure loads compared with -0.7 +/- 0.1%/mmHg with 59 early pressure loads). When compared with control, asynchrony significantly augmented and ryanodine significantly attenuated the effects of midsystolic pressure loads. In conclusion, asynchrony and ryanodine modulate the extent of load-dependent relaxation in the intact left ventricle. PMID- 7840262 TI - Impact of cardiopulmonary bypass and cardioplegic arrest on myocardial lymphatic function. AB - Cardioplegic arrest (CPA) is associated with interstitial myocardial edema, which has been shown to impair myocardial function. The accumulation of interstitial myocardial edema may be enhanced by impaired myocardial lymph flow. The purpose of this study was to investigate the effects of CPA on myocardial lymphatic function. In nine anesthetized dogs, we cannulated a prenodal cardiac lymphatic and measured myocardial lymph flow rate (QL), myocardial lymph driving pressure (PL), and myocardial lymph hyaluronan (Hya) concentration. We determined left ventricular function using pressure-volume curves derived by sonomicrometry and micromanometry. The dogs were placed on cardiopulmonary bypass (CPB) (28 degrees C) and subjected to 60 min of hypothermic, crystalloid CPA. With the onset of asystole both QL and PL decreased significantly from 70.7 +/- 31.8 (SD) to 3.3 +/ 4.0 microliters/min and from 19.9 +/- 8.0 to 10.4 +/- 1.8 mmHg, respectively (P < 0.01). Following return of sinus rhythm after separation from CPB, QL and PL increased significantly to 135.4 +/- 28.0 microliters/min and 27.3 +/- 7.5 mmHg, respectively (P < 0.01). Post-CPA myocardial edema was demonstrated by gravimetric wet-to-dry weight determination of 3.67 +/- 0.20 (normal 2.90 +/- 0.20, P < 0.001) and was associated with significantly decreased left ventricular function. Myocardial Hya turnover rate was 1.3 +/- 1.0% per day under baseline conditions and increased significantly to 2.7 +/- 0.9% per day post-CPA (P < 0.01). We conclude that organized myocardial contraction is the major determinant of myocardial lymph flow. Myocardial lymph flow impairment during CPA may contribute to post-CPA myocardial edema and left ventricular dysfunction. PMID- 7840263 TI - Permeability of cat skeletal muscle capillaries to small solutes. AB - Permeability-surface area products (PS) for 51Cr-EDTA, [3H]mannitol, [14C]urea, and 22Na were measured in isolated, perfused, lower hindlimb muscles of anesthetized cats. The tracers were added stepwise to the arterial inflow, and Evans blue-labeled albumin was the reference indicator. At flow rates > 70 ml.min 1.100 g-1, the PS values (+/- SE) were 5.0 +/- 0.5, 7.6 +/- 1.2, 17.8 +/- 1.4, and 21.0 +/- 1.4 (n = 7, 4, 5, and 3 animals, respectively). The ratio of simultaneous PS measurements of mannitol and urea was 0.42 +/- 0.02 (n = 9), significantly less than the free diffusion coefficient ratio (0.49), indicating the presence of restricted diffusion. PS measurements were also made during osmotic flow (4.2 +/- 0.6 ml.min-1.100 g-1) induced by 20% NaCl. The data clearly showed that osmotic transients did not alter small solute permeability. Pore models were used to show that the PS data and previously reported reflection coefficient data were consistent with a single description of the capillary wall. This model contained a water-only pathway containing 60% of the hydraulic capacity and an extracellular route modeled by pores of 4 nm radius having 21,000 cm of area per unit membrane thickness (A/delta x). PMID- 7840264 TI - Characterization and pH dependence of L-glutamate transport in sarcolemmal vesicles from rat hearts. AB - Transport of L-glutamate in purified sarcolemmal vesicles from rat heart was Na+ dependent and characterized by an apparent affinity value of 0.149 +/- 0.04 mM (n = 6). Na+ binding to the carrier was not very specific, since an inwardly directed K+ gradient could also increase vesicular uptake of L-glutamate. Uptake of L-glutamate into sarcolemmal vesicles was inhibited by L-aspartate and L cysteinate. These characteristics of glutamate uptake are typical of transport via system XAG-. Acidification of either the intravesicular or the extravesicular space led to a significant increase in L-glutamate transport. This increase was more pronounced when the intravesicular space had been acidified. Thus intracellular acidosis of hypoxic or ischemic myocardium is directly linked to an increased uptake of glutamate. PMID- 7840265 TI - Estimation of laser-Doppler flux biological zero using basilar artery flow velocity in the rabbit. AB - Laser-Doppler flowmetry has potential for continuous cerebral blood flow (CBF) measurement in man and experimental animals. However, laser-Doppler flux (LDFx) measured when perfusion is absent (the biological zero, 0biol) does not necessarily coincide with the instrument's electrical zero. To evaluate laser Doppler flowmetry further we have compared LDFx in rabbits with continuous measurement of the maximum flow velocity (FVx) in the basilar artery using Doppler ultrasonography. Arterial blood pressure (ABP), FVx, and LDFx were measured continuously in anesthetized New Zealand White rabbits. ABP was altered by controlled hemorrhage with subsequent reinfusion. 0biol was estimated from regression analysis of FVx vs. LDFx and compared with 0biol obtained after death. There was a strong linear relationship between LDFx and FVx (r = 0.94). The absolute difference between estimated 0biol and true 0biol was 5.24% of control prehemorrhage LDFx. Variations in 0biol (range 4-409) suggest that percent changes in LDFx must be related to 0biol if results between individual animals are to be compared. PMID- 7840266 TI - Cardiorespiratory reflex control in rats with left ventricular dysfunction. AB - Patients with heart failure exhibit a neurohumoral excitatory state and abnormal baroreflex control of the cardiovascular system. We determined whether arterial baroreflexes are impaired during left ventricular dysfunction (LVD) caused by chronic myocardial infarction in the absence of congestive heart failure and whether abnormal central mechanisms contribute to this impairment. Baroreceptors were stimulated in anesthetized rats with and without LVD by increasing arterial pressure with phenylephrine. Lumbar sympathetic nerve and phrenic nerve activity as well as heart rate were recorded. Rats were divided into different groups based on infarct size. Rats with moderate LVD showed impaired baroreflex control of sympathetic, ventilatory, and heart rate responses. Baroreflex gains were inversely related to the size of the infarct. The central gain for sympathetic nerve activity, obtained by using electrical stimulation of the aortic depressor nerve, also was impaired. Baroreflex control of the cardiorespiratory system is thus impaired in rats with moderate LVD in the absence of congestive heart failure. The attenuated baroreflexes are likely due to abnormal afferent mechanisms, although central mechanisms contribute to the impaired barosympathetic reflex. PMID- 7840267 TI - Dissociation between anti-infarct effect and anti-edema effect of ischemic preconditioning. AB - This study tested the hypothesis that preconditioning, by reducing catabolite accumulation during ischemia, reduces osmotic swelling and myocardial necrosis during subsequent reperfusion. Farm pigs were randomly allocated to one of three groups of treatment: a control group undergoing a 48-min coronary occlusion (CO) of the middle left anterior descending artery, a preconditioned group (2 cycles of 5-min CO and 5-min reperfusion before the 48-min CO), or an intracoronary perfusion group receiving a substrate-free anoxic buffer perfusion into the area at risk between minutes 5 and 10 of the prolonged CO. Animals were killed after 30 min (n = 23) or 6 h (n = 31) of reperfusion. Compared with the control group, both ischemic preconditioning and washout of ischemic by-products by transient anoxic perfusion reduced myocardial edema after 30 min of reperfusion (P < 0.002) by 35 and 32%, respectively, but only ischemic preconditioning reduced final infarct size (by 55%, P < 0.006). Myocardial lactate content before reperfusion, measured in an additional series of 12 experiments, was reduced by 35% in animals receiving preconditioning or intracoronary perfusion. Thus ischemic preconditioning has a marked protective effect against reperfusion edema, and this effect can be explained by reduced catabolite accumulation during ischemia. However, there is no evidence from this study indicating that reduced catabolite accumulation and limited reperfusion edema explain the important anti-infarct effect of ischemic preconditioning. PMID- 7840268 TI - Transient rheological behavior of blood in low-shear tube flow: velocity profiles and effective viscosity. AB - Velocity profiles of human blood flowing through vertical and horizontal glass tubes (25-100 microns ID) were measured as a function of time following a sudden reduction of wall shear stress (tau w) from a high value to values ranging from 2 to 100 mPa. Cell velocities at various radial positions were determined off-line from video recordings by digital image analysis. In vertical tubes, symmetric velocity profiles were obtained that developed increasing bluntness with time, particularly at lower tau w and in smaller tubes. In horizontal tubes, velocity profiles developed strong asymmetry as a function of time. Red blood cell (RBC) sedimentation was associated with uniform low flow velocities in the concentrating cell sediment, whereas faster flow and almost parabolic profiles were observed in the supernatant plasma region. Calculations of effective blood viscosity showed a decrease with time at low tau w in vertical tubes but an increase in horizontal tubes. The differences between profile shape and effective viscosity in vertical and horizontal tubes disappeared at tau w > 50 mPa. These findings are related to the cross-sectional distribution of RBC, which depends on RBC aggregation and sedimentation. PMID- 7840269 TI - Comparison between endocardial and great vessel endothelial cells: morphology, growth, and prostaglandin release. AB - The release of vasoactive mediators by vascular (VEC) and endocardial endothelial cells (EEC) has not been directly compared. In this study, in vitro morphological and cell growth characteristics and the rate of prostanoid release were compared in cultured sheep endothelial cells from great vessels (VEC; pulmonary artery and aorta) and endocardium (EEC; right and left ventricles) harvested from the same animals. Morphologically, in flasks, VEC demonstrated the classic cobblestone pattern, whereas EEC developed numerous cytoplasmic interdigitations and overlaps. Rate of cell proliferation was greater for EEC than for VEC (P < 0.05): doubling time was shorter for EEC (34 +/- 3 h) than for VEC (45 +/- 5 h). Under static (no-flow) conditions, in response to arachidonic acid and calcium ionophore A-23187, the rate of prostacyclin (PGI2) and prostaglandin E2 release by VEC and EEC was not different. In contrast, in response to flow and acute hypoxia (O2 tension = 35 Torr), the rate of PGI2 release was greater in EEC than in VEC (P < 0.0001). After 2 h of perfusion, the rate of PGI2 release was 19-fold greater for EEC than for VEC during normoxia and 34-fold greater during hypoxia. Thus our study showed anatomic site of origin-dependent heterogeneity in prostanoid release between VEC and EEC. Endocardial endothelium is a greater source of PGI2 than great vessel endothelium; in vivo, endocardial endothelial PGI2 may inhibit local platelet aggregation and modulate downstream vascular tone. PMID- 7840270 TI - Effect of erythrocyte deformability on myocardial hematocrit gradient. AB - Myocardial hematocrit gradient was determined between epicardium and endocardium of the left ventricular wall in rat heart under the influence of erythrocyte deformability alterations. Hematocrit determinations were performed by measuring two different radionuclides labeling plasma (125I-labeled albumin) and erythrocytes (99mTc) in 100-microns-thick left ventricular myocardium slices. Myocardial hematocrit gradient calculated after exchange transfusions with partially hardened red blood cell suspensions was compared with the results of the control group, in which the exchange transfusions were done using normal, hematocrit-matched blood. In the control group, the hematocrit value in the myocardium adjacent to epicardium was 0.331 +/- 0.076 l/l and decreased to 0.232 +/- 0.054 l/l near the endocardium. Myocardial hematocrit between these two was represented by a linear gradient. In the group with impaired erythrocyte deformability, the hematocrit value was 0.359 +/- 0.074 l/l in the epicardial myocardium and remained at 0.341 +/- 0.082 l/l in the endocardial layer. These results indicate that tissue hematocrit gradient in the left ventricular myocardium may be disturbed if erythrocyte deformability is altered. PMID- 7840271 TI - Proportions of rat ANP-secreting cells that are cardiomyocytes and that synthesize the hormone. AB - Atrial natriuretic peptide (ANP) is released from the heart and participates in regulating blood pressure and volume. We recently developed a reverse hemolytic plaque assay to measure the release of ANP from individual rat atrial cardiocytes. This assay determines the total proportion of atrial cardiocytes committed to releasing ANP. We combined the plaque assay with immunocytochemistry (IC) and in situ hybridization (IS). Combining the plaque assay with IC for myosin revealed that 13.5 +/- 0.9% (%myosin+ and plaque forming; mean +/- SE, n = 4) of atrial cardiocytes are cardiomyocytes that release ANP. Combination of the plaque assay with IS for ANP mRNA showed that 16.6 +/- 0.6% (%in situ+ and plaque forming; mean +/- SE, n = 4) of the cardiocytes in the rat atria synthesize and release the hormone. Incubation of atrial cardiocytes with dexamethasone to stimulate ANP gene expression did not alter the total proportion of in situ positive ANP-secreting cells. These data suggest that, within the total ANP secreting population of the rat atria, only 33% of the secreting cells are cardiomyocytes. In addition, 68% of the ANP-secreting cells do not appear to synthesize the hormone. These results imply that muscle and nonmuscle cells are involved in secreting ANP and that cardiomyocytes synthesize the hormone. PMID- 7840272 TI - Adenosine analogues prevent phorbol ester-induced PKC depletion in porcine coronary artery via A1 receptor. AB - This study was undertaken to determine the adenosine receptor involved in the modulation of protein kinase C (PKC) in porcine coronary artery. Endothelium denuded arterial rings were incubated with phorbol 12,13-dibutyrate (PDBu) in the presence or absence of adenosine receptor agonists and antagonists for 24 h. After incubation, contractile responses to endothelin-1 (ET-1) were compared in various treatment groups. Arterial rings incubated with PDBu alone failed to produce significant contractions in response to ET-1. (2s)-N6-[2-endo norbornyl]adenosine (ENBA), an A1-receptor agonist, attenuated the PDBu-induced blunting of the ET-1 contractions. Incubation with ENBA alone elevated ET-1 contractility by about twofold. Inclusion of A1-receptor antagonists completely blocked both effects of ENBA: protection against PDBu and increase in ET-1 contractility. On the contrary, arterial rings incubated with the A2-receptor agonist 2-p-(2-carboxyethyl)phenethyl-amino-5'-N-ethylcarboxamidoadenosine (CGS 21680) did not show significant alteration of the ET-1 contractility when incubated with CGS-21680 alone or in combination with PDBu. Inclusion of A2 receptor antagonist in combination with CGS-21680 mimicked the effects of ENBA alone, i.e., protected against PDBu and enhanced ET-1 contractions. Measurement of PKC activities in arteries indicated that exposure to ENBA caused a twofold increase in the enzyme activity, whereas exposure to CGS-21680 had no significant effect on PKC activity. Adenosine analogues caused an accumulation of PKC through the activation of A1- but not A2-adenosine receptors. These results indicate that the modulation of PKC by adenosine analogues is mediated through A1-adenosine receptors in the coronary artery. PMID- 7840273 TI - Reductant substrate for glutathione peroxidase modulates oxidant inhibition of Ca2+ signaling in endothelial cells. AB - Oxidant stress mediated by tert-butyl hydroperoxide (t-BOOH) inhibits agonist stimulated Ca2+ entry and internal store Ca2+ release in cultured endothelial cells. The role of intracellular glutathione in modulating the effects of oxidant stress on Ca2+ signaling was determined in cells preincubated with buthionine [S,R]-sulfoximine (BSO), an inhibitor of gamma-glutamylcysteine synthetase, or 1 chloro-2,4-dinitrobenzene (CDNB), a cosubstrate for glutathione-S-transferase. BSO and CDNB decreased endothelial cell glutathione content by 85 and 97%, respectively (control glutathione, 21.5 +/- 2.3 nmol/mg protein). Each agent accelerated the time-dependent effects of t-BOOH on Ca2+ signaling in fura 2 loaded cells and potentiated the inhibition of bradykinin-stimulated 45Ca2+ efflux induced by t-BOOH. These results indicate that decreased availability of reduced glutathione, the primary cosubstrate for glutathione peroxidase, potentiates the effect of hydroperoxide oxidant stress on receptor-operated Ca2+ entry across the plasmalemma and Ca2+ release from internal stores. The present findings suggest that intracellular glutathione availability and/or glutathione redox cycle activity are critically important modulators of oxidant inhibition of Ca(2+)-dependent signal transduction. PMID- 7840274 TI - Chronic pulmonary hypertension in utero impairs endothelium-dependent vasodilation. AB - To determine whether endothelium-dependent pulmonary vasodilation is selectively impaired by chronic intrauterine pulmonary hypertension, we compared the hemodynamic effects of an endothelium-dependent agonist, acetylcholine (ACh), with an endothelium-independent agonist, atrial natriuretic peptide (ANP), before, during, and after development of pulmonary hypertension in five late gestation fetal lambs. Pulmonary hypertension was produced over 9-12 days by progressive inflation of a vascular occluder around the ductus arteriosus. Age matched fetal lambs (n = 5) without occluders served as controls. Mean pulmonary arterial pressure increased from 44 +/- 2 (baseline) to 65 +/- 4 Torr after 10-12 days of inflation (P < 0.05). Left lung pulmonary vascular resistance (PVR) increased from 0.52 +/- 0.06 to 0.72 +/- 0.11 Torr.ml-1.min over 10 days (P < 0.05). O2 saturation remained at > 40% during the study period. Although brief intrapulmonary infusions of ACh (1.5 micrograms over 15 min) lowered left lung PVR by 29 +/- 8% before ductus arteriosus compression, ACh-induced pulmonary vasodilation was absent after 9-12 days of pulmonary hypertension. In contrast, the vasodilator response to ANP remained intact throughout the study period. ACh- and ANP-induced vasodilation did not change with time in control animals. In five hypertensive animals delivered by cesarean section, inhaled NO (20 ppm) reduced left lung PVR from levels achieved during ventilation with 100% O2 alone (0.61 +/ 0.31 to 0.24 +/- 0.007 Torr.ml-1.min), increased arterial O2 saturation from 51 +/- 14 to 84 +/- 13%, and increased arterial PO2 from 29 +/- 11 to 106 +/- 34 Torr.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7840275 TI - Role of oxygen-derived free radicals in canine reperfusion arrhythmias. AB - The role of oxygen-derived free radicals in reperfusion arrhythmias was investigated in open-chest anesthetized dogs. The left anterior descending coronary artery was cannulated and perfused by an arterial bypass shunt. Ischemia was produced for 15 min by shunt occlusion and retrograde diversion of collateral blood flow. Dogs (n = 12) were treated with saline, N-(2 mercaptopropionyl)glycine (50 mg/kg), deferoxamine (10 mg/kg), superoxide dismutase (15,000 U/kg) plus catalase (55,000 U/kg), or dimethylthiourea (500 mg/kg). All agents were infused intravenously for 1 h starting 30 min before occlusion and continuing for 5 min of reperfusion. There were no differences in mean arterial blood pressure, heart rate, antegrade coronary flow, retrograde coronary flow, or size of the risk region among the five treatment groups. None of the dogs developed ventricular fibrillation during occlusion, whereas 88% of the 60 dogs fibrillated upon reperfusion. The antioxidant interventions did not alter the incidence of reperfusion-induced ventricular fibrillation compared with the saline-treated controls. The results suggest that free radicals do not play a role in lethal canine reperfusion arrhythmias. PMID- 7840276 TI - Hypoxic vasoconstriction and intracellular Ca2+ in pulmonary arteries: evidence for PKC-independent Ca2+ sensitization. AB - The effect of hypoxia on intracellular Ca2+ ([Ca2+]i) and tension in small intrapulmonary arteries (IPA) of the rat was examined using the Ca2+ fluorophore fura 2. Induction of hypoxia in IPA preconstricted with 3 microM prostaglandin F2 alpha (PGF2 alpha) resulted in a biphasic contractile response, the first phase of which was associated with a transient rise in [Ca2+]i. No additional rise in [Ca2+]i was observed during the more slowly developing second phase constriction. Upon reoxygenation [Ca2+]i and tension returned to prehypoxic levels. Ro-31-8220 [a specific protein kinase C (PKC) inhibitor] reduced the first phase in IPA preconstricted with PGF2 alpha or 20 mM KCl, but had no effect on the second phase constriction in either of these groups. These results demonstrate that the first phase of the hypoxic constriction is associated with a transient rise in [Ca2+]i via either Ca2+ influx and/or release, and may have a PKC-dependent component, whereas the second phase involves a PKC-independent sensitization of the contractile machinery to Ca2+. PMID- 7840277 TI - Eicosanoid synthesis in cardiomyocytes: influence of hypoxia, reoxygenation, and polyunsaturated fatty acids. AB - The synthesis of eicosanoids was investigated in cultured rat ventricular myocytes. Under normoxia, the cardiomyocytes released 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) and prostaglandin (PG) E2 and smaller amounts of PGF2 alpha and thromboxane B2. Hypoxia enhanced the production of PGE2 and PGF2 alpha, whereas the synthesis of 6-keto-PGF1 alpha was not affected. Conversely, posthypoxic reoxygenation greatly increased the synthesis of 6-keto-PGF1 alpha, whereas the synthesis of PGF2 alpha, was not affected and that of PGE2 was reduced. The cardiomyocyte polyunsaturated fatty acid (PUFA) profile was altered by arachidonic acid or eicosapentaenoic acid and docosahexaenoic acid. Under normoxia, the eicosanoid production appeared to be roughly related to the cell phospholipid arachidonic acid content. Conversely, during posthypoxic reoxygenation, the production of eicosanoids was related to the cell phospholipid n-3 PUFA content, with the n-3-rich cells displaying a marked inhibition of the synthesis. This inhibition was mainly attributed to eicosapentaenoic acid and/or docosapentaenoic acid. Whether this inhibition occurs in vivo during postischemic reperfusion, it may contribute to the beneficial effect of n-3 PUFA on the heart. PMID- 7840278 TI - Changes in endothelial actin cytoskeleton at leakage sites in the rat mesenteric microvasculature. AB - The purpose of the present study was to compare the endothelial actin cytoskeleton at sites of inflammation-induced macromolecular leakage with that of intact endothelium. The circulation of a selected mesenteric window of anesthetized rats was perfused for 3 min with histamine (100 microM) plus fluorescein isothiocyanate (FITC)-albumin, or FITC-albumin alone, and was fixed at physiological pressure. The vasculature was then perfusion stained with rhodamine phalloidin to label filamentous actin (F-actin) and examined with a confocal microscope. The leakage sites were divided into three categories based on the extent of FITC-albumin leakage: 1) focal leaks, 2) mid leaks, and 3) extended leaks. The leaks were identifiable with a particular endothelial cell(s), and the structure of the endothelial actin cytoskeleton was characterized at these sites. Focal leaks occurred along a small region of endothelial cell-cell contact and in most observed cases were located at a region of specific disruption of the endothelial peripheral actin rim (PAR). Mid leaks involved the disruption of one endothelial cell, and the affected cell was observed to have extended disruption of the PAR as well as increased diffuse F actin staining throughout the cell (1.9-fold increase relative to adjacent cells). Extended leaks involved the disruption of two or more adjacent endothelial cells, and each cell exhibited an actin pattern similar to that seen at mid leaks. These results show that histamine-induced macromolecular leakage in situ is associated with significant changes in the endothelial actin cytoskeleton. PMID- 7840279 TI - Hemodynamic and microcirculatory changes during development of renal hypertension. AB - To study the progression of vessel loss (rarefaction) during the development of hypertension, a plastic window was chronically implanted over the biceps femoralis muscle of reduced renal mass (RRM) and sham-operated control (SOC) rats on a low-salt diet (0.4%). Blood pressure was measured directly via a catheter implanted in the femoral artery, and tissue blood flow was measured by laser Doppler flowmetry before and after local topical application of sodium nitroprusside. Measurements were made on the control day and after an increase in sodium intake (4.0%) in RRM rats on days 5, 10, 14, 21, and 28. SOC rats on a low salt diet served as the control group. RRM rats became hypertensive (167 mmHg), and vascular resistance increased after a change in sodium intake. Resting tissue blood flow decreased by 19% by day 28 in RRM but did not change in SOC. Sodium nitroprusside administration reduced vascular resistance to the same level in both RRM and SOC during control and at day 10; however, on all other days, sodium nitroprusside was not able to fully dilate the RRM microcirculation compared with that of SOC. At the same time, microvascular density estimated by computer fluorescence microscopy was decreased by 25% in RRM rats. These studies indicate that the development of RRM hypertension is characterized by a transition from increased tone and vessel closure (functional rarefaction) to anatomic vessel loss (structural rarefaction). PMID- 7840280 TI - Effects of hyperthyroidism on muscle blood flow during exercise in rats. AB - Hyperthyroidism is associated with exercise intolerance. Previous research, however, has shown that cardiac output is either normal or enhanced during exercise in the hyperthyroid state. We therefore hypothesized that blood flow to working skeletal muscle is augmented in hyperthyroid animals during in vivo submaximal exercise and, consequently, that noncardiovascular factors are responsible for intolerance to exercise. To test this hypothesis, rats were made hyperthyroid (Hyper) over 6-12 wk with injections of triiodothyronine (300 micrograms/kg). Hyperthyroidism was evidenced by left ventricular hypertrophy [euthyroid (Eut), 2.12 +/- 0.05 mg/g body wt; Hyper, 2.78 +/- 0.06; P < 0.005], 25-60% increases in citrate synthase activities in Hyper hindlimb muscles over those of Eut rats, and higher preexercise heart rates (Eut, 415 +/- 18 beats/min; Hyper, 479 +/- 19; P < 0.025). Regional blood flows were determined by the radiolabeled microsphere method, preexercise, and at 1-2 min of treadmill running at 15 m/min (0% grade). Total hindlimb muscle blood flow preexercise was unaffected (Eut, 31 +/- 4 ml.min-1.(100) g-1, n = 11; Hyper, 40 +/- 6, n = 9; not significant) but was higher (P < 0.025) in Hyper (127 +/- 17, n = 9) compared with Eut (72 +/- 11, n = 9) during treadmill running. During exercise, flows to individual muscles and muscle sections were approximately 50-150% higher in Hyper compared with Eut rats. Visceral blood flows were largely similar between groups. These findings indicate that hyperthyroidism is associated with augmented blood flow to skeletal muscle during submaximal exercise. Thus hypoperfusion of skeletal muscle does not account for the poor exercise tolerance characteristic of hyperthyroidism. PMID- 7840281 TI - Muscle length alters geometry of arterioles and venules in hamster retractor. AB - We investigated how changes in muscle length (Lm) would alter the geometry of arterioles and venules and whether such an effect would depend on the orientation of microvessels to muscle fibers. The parallel-fibered retractor muscle of anesthetized (pentobarbital sodium, 65 mg/kg) male hamsters (n = 20, 105 +/- 4 g) was exposed and irrigated with physiological saline solution (pH 7.4; 35 degrees C). Sarcomere length (Ls) was measured at x2,400 magnification after topical application (3 min, 10(-5) M) of a fluorescent dye [4-(4-diethylaminostyryl)-N methylpyridinium iodide]. In vivo Ls at resting Lm (i.e., at Lm = 100%) was 3.00 +/- 0.02 microns. The origin and insertion of the retractor were cut, and the muscle was reflected dorsally while the circulation arising from the ventral surface was preserved. Polystyrene "tendons" were glued to each end of the muscle to control Lm, which was varied in 10% increments from 80 to 130% of in situ Lm; Ls increased linearly (r2 = 0.82) from 2.58 +/- 0.03 to 3.89 +/- 0.07 microns, respectively. Arteriole and venule branches and the centerline of "Y" bifurcations were classified based on orientation angles (theta) with respect to muscle fibers at Lm = 100%; three categories were defined using trigonometry (detailed in the APPENDIX) based on microvessel behavior during changes in Lm: parallel (P), 0 degree < or = theta < or = 32.6 degrees; intermediate (I), 32.6 degrees < theta < 59.4 degrees; and normal (N), 59.4 degrees < or = theta < or = 90 degrees.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7840282 TI - Modulation of contractions to and receptors for endothelins in canine veins. AB - Experiments were designed to characterize endothelin receptors in canine femoral veins and to determine whether their distribution or sensitivity could be altered by chronic changes in blood flow and oxygen tension in veins proximal to an arteriovenous fistula. Endothelium was removed from unoperated or fistula operated femoral veins of anesthetized dogs. Veins were cut into rings and suspended in organ chambers for the measurement of isometric force or frozen for isolation of membrane proteins. Endothelin-1, endothelin-3, and sarafotoxin S6c caused concentration-dependent increases in tension in all rings. In rings of unoperated veins, maximal tensions were significantly less to endothelin-3 and sarafotoxin S6c than to endothelin-1. In rings of fistula-operated veins, maximal tensions to endothelin-1 and endothelin-3 were the same. Contractions to endothelin-1 or endothelin-3 in unoperated veins were not inhibited by an antagonist of endothelin-A receptors, BQ-123. Binding of 125I-labeled endothelin 1 (125I-endothelin-1) to membranes from veins without endothelium increased as a function of membrane protein. Affinity of receptors, as determined by competitive inhibition of 125I-endothelin-1 was as follows: endothelin-1 > endothelin-3 > sarafotoxin S6c. Competitive inhibition of 125I-endothelin-1 by endothelin-3 and sarafotoxin S6c was significant for a two-site binding model in all veins. The total number of binding sites was reduced significantly in fistula-operated veins; the relative proportions of high- and low-affinity binding sites did not change. Affinity of high- and low-affinity receptors increased in fistula operated veins.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7840283 TI - Na(+)-K(+)-ATPase in endothelial cell energetics: 23Na nuclear magnetic resonance and calorimetry study. AB - Sodium flux rate and energy consumption of the Na(+)-K+ pump in vascular endothelial cells of porcine aorta grown on micro-carrier beads were studied using a combination of nuclear magnetic resonance spectroscopy of intracellular 23Na and microcalorimetry. The Na+ flux into the cells was determined in the presence of the shift reagent Dy(P3O10)2(7-), while the Na(+)-K+ pump was inhibited with ouabain. Basal Na+ influx was 17 +/- 3 nmol.min-1.mg protein-1, and intracellular Na+ concentration was 23.5 +/- 3.8 mM, resulting in a complete exchange of intracellular Na+ within 5-6 min. Spin-lattice relaxation time (T1) measurements of intracellular Na+ showed a T1 of 19 +/- 1 ms under basal conditions and a T1 of 26.2 +/- 1.6 ms after pump inhibition with 50 microM ouabain. Such an increase is typical for a system in which the total amount of Na+ increases but where the amount of bound Na+ remains constant. The Na+ ionophore nystatin maximally increased the Na(+)-K+ pump rate about twofold, whereas the amount of intracellular Na+ only increased 14%. With microcalorimetry a cellular heat flux of 183 +/- 18 microW per mg endothelial protein was determined, which relates to 7.6 microW/mg endothelial protein generated by the Na(+)-K(+)-adenosinetriphosphatase. Our data demonstrate that small intracellular changes of Na+ can stimulate the endothelial Na(+)-K+ pump activity. The contribution of the Na(+)-K+ pump to total endothelial energy expenditure is approximately 4-5%. PMID- 7840285 TI - Transient ischemia induces regional myocardial glycogen synthase activation and glycogen synthesis in vivo. AB - Glycogen is consumed during ischemic preconditioning and synthesized during the subsequent period of ischemic tolerance. To better understand this sequence, we examined the effect of brief coronary artery occlusions on regional myocardial glycogen metabolism in intact, anesthetized rats. Sequential 2-min periods of left coronary artery occlusion reduced the glycogen concentration of the anterior left ventricle approximately 30% relative to the posterior region. During subsequent reperfusion, the activity of the physiologically active glycogen synthase I form of glycogen synthase increased threefold in the anterior region (0.58 +/- 0.11 vs. 0.18 +/- 0.08 mumol.g-1.min-1, P < 0.01), stimulating a similar regional increase in glycogen synthesis rate (0.24 +/- 0.04 vs. 0.08 +/- 0.03 mumol.g-1.min-1, P < 0.01). These events were preceded by a rise in regional glucose 6-phosphate concentration, which increased the activity of a myocardial glycogen synthase phosphatase. In diabetic rats glycogen synthase phosphatase activity was significantly lower, and postischemic glycogen synthase activation was significantly impaired. These data suggest the operation of a feedback loop in which transient ischemia leads to a glucose 6-phosphate-mediated increase in the activity of a phosphoprotein phosphatase active toward glycogen synthase. This suggests phospho-protein phosphatase activation may be a feature of the preconditioned myocardium. PMID- 7840284 TI - Increases in pulse pressure impair acetylcholine-induced vascular relaxation. AB - Effects of pulse pressure on acetylcholine-induced endothelium-dependent relaxation were investigated using a cascade bioassay model. Intact carotid arteries from rabbits were perfused at constant flow, and activity of endothelium derived relaxing factor (EDRF) was assayed by measuring changes in isometric tension in a detector ring without endothelium. When pulse pressure of the donor artery was raised from approximately 2 to 10 mmHg, relaxation to acetylcholine (10(-7) M) was reduced from 31 +/- 3 (means +/- SE) to 20 +/- 2% (expressed as percent relaxation of phenylephrine-induced tone). Responses of the detector ring to nitroprusside were unchanged. Superoxide dismutase (SOD) and indomethacin each prevented impairment of relaxation to acetylcholine at high pulse pressure. When the donor artery was perfused at a higher mean pressure, elevation of pulse pressure also impaired relaxation to acetylcholine, and this impairment was prevented by SOD. These findings suggest that elevation of pulse pressure inhibits acetylcholine-induced, endothelium-dependent relaxation, and this inhibitory effect is mediated by generation of oxygen radicals. PMID- 7840286 TI - Effects of nifedipine on vascular waterfall and arterial resistance in canine hindlimb. AB - Pressure-flow relations in the canine hindlimb can be well explained by a vascular waterfall at the arteriolar level. Under these conditions, P(art) = Pcrit + Q.Rart, where P(art) is the arterial pressure, Pcrit is the waterfall pressure, Q is regional flow, and Rart is the arterial resistance of the vessels upstream from the waterfall. To determine whether calcium channels in vascular smooth muscle affect Pcrit in addition to Rart, we pump perfused canine hindlimbs and measured both variables over a range of perfusion pressures (Pper) before and during the infusion of the calcium channel blocker nifedipine. Nifedipine significantly decreased Pcrit and Rart at each Pper. Increasing Pper under control conditions from 50 to 150 mmHg significantly increased Pcrit from 24.2 +/ 1.5 to 42.5 +/- 2.2 mmHg. During nifedipine infusion, increasing Pper from 25 to 100 mmHg also increased Pcrit from 14.5 +/- 1.5 to 20.2 +/- 1.9 mmHg, but the rate of increase was less. In contrast to the rise in Pcrit with increasing Pper, Rart significantly decreased from 10.7 +/- 1.1 to 8.1 +/- 1.2 mmHg.min.100 g.ml-1 before nifedipine infusion, and from 5.7 +/- 0.4 to 2.2 +/- 0.1 mmHg.min.100 g.ml 1 during nifedipine infusion. Venous resistance (Rven) significantly decreased with increases in Pper and during nifedipine infusion. The regional elastic recoil pressure (Pel, a measure of small venular pressure) increased with both an increase in Pper and nifedipine. These results suggest that nifedipine decreases Pcrit, Rart, and Rven and that at constant Pper nifedipine increases Pel. PMID- 7840287 TI - Estrogen pretreatment directly potentiates endothelium-dependent vasorelaxation of porcine coronary arteries. AB - We tested whether vasorelaxation of coronary arteries is altered after overnight (18-22 h) exposure to physiological levels of 17 beta-estradiol. Ring segments of left circumflex coronary artery from six female and six castrated male pigs were incubated in vials of sterile Dulbecco's modified Eagle's medium with 1 nM 17 beta-estradiol, 1 nM 17 beta-estradiol + 10 nM tamoxifen, 1 nM 17 alpha estradiol, or estrogen vehicle (ethanol) under normoxic conditions in an O2-CO2 incubator at 37 degrees C for 18-22 h. Coronary rings, with and without endothelium, were then suspended in vessel baths for measurement of isometric force. Vasorelaxation responses to the calcium ionophore A-23187, ADP, and nitroglycerin were examined in the rings after prostaglandin synthesis blockade and precontraction with U-46619. Sensitivity to A-23187 (-log M concentration required for 50% of maximal relaxation) was significantly enhanced in coronary rings with endothelium from females and castrated males when rings were incubated with 17 beta-estradiol but not when they were incubated with 17 alpha-estradiol or 17 beta-estradiol+tamoxifen. Acute (2h) exposure of coronary arteries to 1 nM 17 beta-estradiol did not alter responses to A-23187. 17 beta-Estradiol (1 nM) was not itself directly vasoactive in coronary arteries with or without prior incubation with the steroid. Vasorelaxation of rings with and without endothelium to ADP and nitroglycerin was not significantly different among the treatment groups. Relaxation to A-23187, but not ADP, was abolished by removal of the endothelium or exposure to 100 microM NO2-L-arginine.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7840288 TI - Facilitated ventriculoatrial conduction: effects of sequential pacing interval and basic cycle length. AB - We studied 1) the effects of pacing interval, 2) the timing of atrioventricular sequential pacing, and 3) the effects of successive premature intervals on retrograde conduction of the atrioventricular (AV) node in open-chest alpha chloralose-anesthetized dogs. The ventricles and atria were sequentially paced at one of three levels of basic cycle length and one of six sequential time intervals (V1-A1) for three basic cycles (V1-V1). Then a premature ventricular impulse was introduced at various V1-V2 intervals, and the resultant retrograde conduction time (V2-A2 interval) was measured. Successive V1-V2 intervals were applied in an incremental or a decremental fashion. The V1-V2 intervals ranged from V1-V1 to V1-V2, at which the retrograde conduction was blocked. For each level of the above three factors, we plotted retrograde conduction time (V2-A2) as a function of the various premature intervals (V1-V2). We found that the time between atrial and ventricular activations was the most important factor in determining V1-V2 and in decreasing the effective refractory period of the AV node during retrograde conduction. PMID- 7840289 TI - Activation of ANP synthesis during congestive heart failure in rats treated with monocrotaline. AB - We studied plasma concentration, content, and mRNA for atrial natriuretic peptide (ANP-mRNA) in heart chambers of monocrotaline-treated rats. Three distinct groups emerged: group 1, with moderate congestive heart failure (CHF; pleural effusion < 1 ml; no peritoneal effusion); group 2, with severe CHF (pleural and peritoneal effusion > 1 ml); and group 3, with right hypertrophy and no CHF. Group 1 and 2 rats had right atrial and ventricular hypertrophy, raised plasma ANP (from 16.31 +/- 11.32 to 98.50 +/- 22.50 and 124.09 +/- 57.29 pg/ml, respectively; P < 0.001), and depletion of right atrial ANP (from 143.23 +/- 29.79 to 21.70 +/- 17.70 and 18.12 +/- 14.64 nmol/g, respectively; P < 0.001). Ventricular ANP concentration was unchanged. ANP-mRNA rose in the right atrium [10.6 (P < 0.02) and 7.9 (P < 0.01) times] and right ventricle (53.0 and 46.6 times; P < 0.01). In left unhypertrophied chambers it also increased, although to a smaller extent. Group 3 rats had isolated right ventricular hypertrophy, normal ANP levels in plasma and tissues, and no activation of synthesis. These data suggest that 1) plasma concentration and ANP synthesis are increased only in animals with CHF, 2) activation of ANP synthesis is maximal in early stages of CHF and is not related to the degree of hypertrophy, and 3) ANP-mRNA is also expressed in unhypertrophied heart chambers of rats with CHF but is not expressed in hypertrophied chambers of animals without CHF. PMID- 7840290 TI - Effect of SR-49059, a vasopressin V1a antagonist, on human vascular smooth muscle cells. AB - The effects of SR-49059, a new nonpeptide and selective arginine vasopressin (AVP) V1a antagonist, were investigated in binding and functional studies on cultured human aortic vascular smooth muscle cells (VSMC). Characterization of human vascular V1a receptors, using a specific V1a radioiodinated ligand, showed that [125I]-linear AVP antagonist binding to human VSMC membranes was time dependent, reversible, and saturable. A single population of high-affinity binding sites (apparent equilibrium dissociation constant = 15 +/- 6 pM; maximum binding density = 36 +/- 5 fmol/mg protein, i.e., approximately 3,000 sites/cell) with the expected V1a profile was identified. Exposure of these cells to AVP dose dependently produced cytosolic free [Ca2+] increase [AVP concentration required to obtain a half-maximal response (EC50) = 23 +/- 9 nM] and proliferation (EC50 = 3.2 +/- 0.5 nM). SR-49059 strongly and stereospecifically inhibited [125I]-linear AVP antagonist binding to VSMC V1a receptors [inhibition constant (Ki) = 1.4 +/- 0.3 nM], AVP-evoked Ca2+ increase [concentration of inhibitor required to obtain 50% inhibition of specific binding (IC50) = 0.41 +/- 0.06 nM], and the mitogenic effects induced by 100 nM AVP (IC50 = 0.83 +/- 0.04 nM). OPC-21268, another nonpeptide V1a antagonist, was more than two orders of magnitude less potent than SR-49059 in these models. However, the consistent affinity (Ki = 138 +/- 21 nM) and activity found with OPC-21268 on human VSMC in comparison with the inactivity already observed for other human V1a receptors (liver, platelets, adrenals, and uterus) strongly suggested the existence of human AVP V1a-receptor subtypes.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7840291 TI - Arterial compliance may influence baroreflex function in athletes and hypertensives. AB - The present study investigated arterial compliance as a possible influence on mean arterial pressure-heart rate (MAP-HR) reflex function in athletes and hypertensives. Aortic stiffness and systemic arterial compliance (SAC) were estimated in 25 elite male athletes and 25 age-matched sedentary controls. Blood pressure did not vary between groups, but SAC was higher in the athletic compared with the sedentary group (0.46 +/- 0.04 vs. 0.37 +/- 0.02 arbitrary compliance units; P = 0.03). In five hypertensives and six age-matched normals and in a subgroup of seven athletes and seven age-matched controls the sigmoidal MAP-HR reflex was assessed using phenylephrine and nitroprusside. In athletes compared with sedentary subjects MAP-HR reflex sensitivity was the same; however, the maximum tachycardia in response to blood pressure reduction was lower in the athletic group (87.1.1 +/- 3.7 vs. 97.1 +/- 2.9 beats/min; P = 0.05). Athletes had a higher blood pressure corresponding to 95% of the HR range (64.2 +/- 3.2 vs. 54.0 +/- 2.1 mmHg; P = 0.02), but there was no difference in the blood pressure corresponding to 5% of the HR range. The blood pressure excursion necessary to traverse the baroreceptor transducer range (MAPd) was therefore less in athletes compared with normals. The beta-index of aortic stiffness correlated closely with MAPd (R = 0.70; P < 0.01). In hypertensives reflex sensitivity was reduced, the minimum HR was elevated, and the MAPd was 56% greater compared with normals.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7840292 TI - Compensated coronary microvascular growth in senescent rats with thyroxine induced cardiac hypertrophy. AB - We tested the hypothesis that coronary angiogenesis in response to chronic thyroxine (T4) treatment is not limited by age. Male Fischer 344 rats aged either 8 (young adult) or 24 (senescent) mo were studied after receiving either L thyroxine (0.2 mg/kg sc) or vehicle for 2 mo. Heart weight-to-body weight ratio, compared with age-matched controls, increased by 47 and 44% in 8- and 24-mo T4 groups, respectively. Maximal myocardial perfusion per unit mass, measured in diastole-arrested, maximally dilated, isolated hearts, was similar in T4 rats and their age group controls; however, flow tended to be lower in senescent than in young adult rats. Thus the cross-sectional area of the coronary vessels grew in proportion to the increase in cardiac mass. Morphometric analyses, based on image analysis, showed that capillary length density was slightly lower in the midmyocardium but not the epimyocardium of the 24-mo T4 group compared with their age group controls. However, volume density, surface density, and intercapillary distance were not influenced by T4 treatment and the presence of cardiac hypertrophy. We conclude that in this model of cardiac hypertrophy 1) coronary vessel growth parallels the increase in ventricular mass, 2) capillaries grow by proliferation and an increase in diameter, and 3) vascular growth is not notably compromised during senescence. PMID- 7840293 TI - Role of endogenous endothelin in normal hemodynamic status of anesthetized dogs. AB - Endothelin (ET) is a potent vasoconstrictor that may be involved in a number of cardiovascular disorders, although its role in normal hemodynamics remains unclear. Twenty-two anesthetized open-chest dogs were instrumented for measurement of systemic and pulmonary hemodynamics, cardiac output, coronary blood flow, and cardiac contractility. Big ET induced peripheral and coronary vasoconstriction, which occurred before significant elevations in plasma ET and which was nearly completely blocked by bosentan, a new nonpeptidic mixed (ETA and ETB) ET receptor antagonist. Bosentan also prevented the peripheral dilatation caused by the specific ETB receptor agonist, sarafotoxin S6c, but did not prevent the peripheral vasoconstriction induced by angiotensin II. Bosentan alone had no significant hemodynamic effect in the normal anesthetized dog, although it did induce a reactive increase in the plasma level of ET-1 and ET-3. This study demonstrates that, despite blocking both ETA and ETB receptors, bosentan alone had no hemodynamic effect, suggesting that ET does not play a major role in the normal hemodynamic status of anesthetized dogs. PMID- 7840294 TI - Propionyl-L-carnitine-mediated improvement in contractile function of rat hearts oxidizing acetoacetate. AB - Prior evidence has suggested that propionyl-L-carnitine improves function in ischemic hearts by providing carnitine for dissipation of acyl-CoA derivatives and propionate for enrichment of the citric acid cycle. Because contractile failure in hearts oxidizing ketone bodies is due to sequestration of free coenzyme A, which can be reversed by the addition of anaplerotic substrates that enrich the citric acid cycle, experiments were performed to determine whether the addition of propionyl-L-carnitine (2 mM) can improve performance in working rat hearts utilizing acetoacetate (7.5 mM). Whereas the addition of propionyl-L carnitine to acetoacetate resulted in a sustained improvement in the work output of the heart, the addition of propionate (2 mM) or L-carnitine (2 mM) alone to acetoacetate had negligible effects on contractile function. Propionyl-L carnitine increased the uptake of acetoacetate by 130%, whereas beta hydroxybutyrate release was minimal and unchanged compared with other groups. These observations show that rates of acetoacetate oxidation are increased commensurate with increased contractile function. Tissue metabolite data indicate that the utilization of propionyl-L-carnitine did not lead to accumulation of citric acid cycle intermediates in the span from citrate to 2-oxoglutarate but to an increase in the tissue content of malate. The results show that addition of propionyl-L-carnitine in hearts oxidizing acetoacetate results in improved mechanical performance that is comparable to the mechanical performance of hearts perfused with glucose as the only substrate. This improvement is most likely conferred by anaplerosis, as suggested by enhanced rates of acetoacetate utilization and citric acid flux. PMID- 7840295 TI - Limitation of reperfusion injury by a monoclonal antibody to C5a during myocardial infarction in pigs. AB - The complement system has been implicated in reperfusion injury during acute myocardial infarction. We therefore attempted to reduce reperfusion injury with a monoclonal antibody (MAb) to the complement component, C5a. In 13 control pigs and 9 pigs pretreated with this MAb, ischemia was induced by a 50-min occlusion of the left anterior descending coronary artery, followed by 3 h of reperfusion. Infarct area (as percent of risk area) was reduced from 58 +/- 5% in controls to 38 +/- 7% (P < 0.05) in MAb-treated animals. Heart rate-systolic blood pressure product, left ventricular (LV) first derivative of pressure, LV end-diastolic pressure, and coronary blood flow were similar (P > 0.05) in the two groups. At 15 min of reperfusion, immunoreactive factor Bb began to increase significantly (P < 0.05) in regional coronary venous plasma, consistent with activation of the alternative complement pathway. The anti-C5a MAb did not attenuate formation of the membrane attack complex (C5b-9) as assessed by a hemolytic complement assay. Myocardial myeloperoxidase activity, a marker of tissue neutrophil concentration, was similar in the risk regions of the two groups, suggesting that neutrophil infiltration was unaltered by the MAb. However, in vitro the MAb (15 and 30 micrograms/ml) reduced C5a-stimulated neutrophil aggregation (67.4 and 70.9%), chemotaxis (52.5 and 81.4%), degranulation (66.7 and 75.8%), and superoxide generation (26.7 and 100%). In conclusion, myocardial infarction-reperfusion is associated with activation of the alternative complement pathway. Furthermore, a MAb to C5a that inhibits neutrophil cytotoxic activity, but neither the membrane attack complex nor myocardial neutrophil accumulation, decreases infarct size in pigs. These data suggest an important role of the alternative complement pathway and C5a in the propagation of ischemia cardiac damage during reperfusion. PMID- 7840296 TI - Mathematical model that characterizes transmitral and pulmonary venous flow velocity patterns. AB - The transmitral and pulmonary venous flow velocity (TMFV and PVFV, respectively) patterns are related to the physiological state of the left heart by use of an electrical analog model. Filling of left ventricle (LV) through the mitral valve is characterized by a quadratic Bernoulli's resistance in series with an inertance. Filling of the left atrium (LA) through the pulmonary veins is represented by a lumped network of linear resistance, capacitance, and inertance. LV and LA are each represented by a time-varying elastance. A volume dependency is incorporated into the LV model to produce physiological pressure-volume loops and Starling curves. The state-space representation of the analog model consists of 10 simultaneous differential equations, which are solved by numerical integration. Model validity is supported by the following. First, the expected effects of aging and decreasing LV compliance on TMFV and PVFV are accurately represented by the model. Second, the model-generated TMFV and PVFV waveforms fit well to pulsed-Doppler recordings in normal and postinfarct patients. It is shown that the TMFV deceleration time is prolonged by the increase in LV compliance and, to a lesser extent, by the increase in LA compliance. A shift from diastolic dominance to systolic dominance in PVFV occurs when LA compliance or pulmonary perfusion pressure increases or when LV compliance or mitral valve area decreases. The present model should serve as a useful theoretical basis for echocardiographic evaluation of LV and LA functions. PMID- 7840297 TI - NEM inhibits transcytosis, endocytosis, and capillary permeability: implication of caveolae fusion in endothelia. AB - Various vesicular carriers transport select molecular cargo between intracellular compartments utilizing a budding mechanism with docking and fusion of individual vesicles with their target membranes. This fusion requires key intracellular component(s) that are sensitive to alkylation with N-ethylmaleimide (NEM). In endothelium, caveolae may mediate endocytosis and transcytosis of select macromolecules. If caveolae utilize a mechanism similar to other vesicular carriers, then their transport should also be sensitive to NEM. The following tracers were chosen based on their pathway specificity: 1) albumin-gold complexes (A-Au) that bind gp30 and gp18 for endocytosis by caveolae, 2) native albumin that binds albondin and is transported by caveolae, 3) ferritin as a fluid-phase probe transcytosed by caveolae, and 4) inulin as a paracellular probe. In culture, NEM significantly inhibited A-Au uptake and delivery to endosomes but not endothelial cell surface binding. In rat lung, NEM reduced capillary permeability to albumin and the tissue uptake of ferritin and A-Au, but not inulin, indicating inhibition of caveolae-mediated but not paracellular transport. Neutral but not charged alkylating agents inhibited A-Au uptake, consistent with their relative abilities to cross membranes and modify intracellular factors. Like other vesicular pathways, endothelial caveolae transport their select ligands utilizing a NEM-sensitive mechanism, apparently requiring vesicle-membrane fusion. PMID- 7840298 TI - Interaction of neutrophils and endothelium in isolated coronary venules and arterioles. AB - This study reports measurements of porcine neutrophil dynamics in isolated microvessels. Porcine coronary venules and arterioles were isolated, cannulated, and perfused with fluorescently labeled neutrophils at a series of flow velocities. In venules (62.50 +/- 5.41 microns diam) under control conditions, rolling neutrophils were often observed at intraluminal flow velocities ranging from 600 to 6,000 microns/s, and the rolling fraction varied inversely as a function of flow velocity. There was no significant adherence under the control conditions at any of the various flow velocities. Pretreatment of the neutrophils with human recombinant complement 5a (C5a, 10(-8) M) increased adherence at low flow velocities but did not alter the rolling fraction. In contrast to venules, rolling neutrophils were not observed in arterioles (58.80 +/- 5.6 microns diam). Furthermore, neutrophils that were pretreated with C5a did not adhere to the arteriolar endothelium even at low flow velocities. We suggest that 1) isolated microvessels perfused with fluorescently labeled neutrophils are suitable models for the study of the interaction between neutrophils and the microvascular endothelium, 2) shear force plays an important role in neutrophil rolling in coronary venules but is not the major factor that prevents neutrophil rolling and adherence in arterioles, and 3) C5a causes neutrophil adherence in venules but not in arterioles, indicating that different mechanisms underlie the interaction between neutrophils and endothelium in venules and arterioles. PMID- 7840299 TI - Noninvasive measurement of ascending aortic blood velocity in mice. AB - Mice are useful models in numerous research protocols, but monitoring cardiovascular parameters in small animals is difficult. Therefore we evaluated the use of 20-MHz pulsed Doppler ultrasound to measure ascending aortic blood velocity in intact anesthetized mice. Using a 0.5-mm-diameter 20-MHz transducer applied to the right sternal border, we recorded audio Doppler signals from the ascending aorta of 31 mice [24.4 +/- 1.5 (SD) g body wt]. The signals were played back at speed into a fast Fourier transform analyzer from which we measured heart rate (453 +/- 96 beats/min), ejection time (38 +/- 3%), peak velocity (90 +/- 11 cm/s), mean velocity (23 +/- 4 cm/s), rise time (7.3 +/- 2 ms), stroke distance (29 +/- 7 mm), and acceleration (163 +/- 63 m/s2) from the spectral envelopes. We determined aortic diameter (1.2 +/- 0.2 mm) and Doppler angle (0-20 degrees) in six mice by molding the aortic root and major systemic vessels with casting resin infused at 100 mmHg pressure. For an aortic diameter of 1.2 mm, cardiac output was estimated to be 14.8 ml/min and stroke volume to be 33 microliters. To verify the origin of the signals and to test responsiveness to known stimuli, we measured velocity signals from the aorta and other nearby vessels and varied heart rate and aortic velocity by warming or by infusion of isoproterenol in three open-chest animals. For the noninvasive applications, acoustic coupling was adequate through the moistened fur, and aortic velocity signals were obtained in all animals.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7840300 TI - Inward rectifier K+ channel from human heart and brain: cloning and stable expression in a human cell line. AB - We have cloned the human homologue of the inward rectifier K+ channel from both heart and brain tissue (HHBIRK1). The human clones were identical to each other in their coding regions and were highly homologous to the mouse macrophage (IRK1) channel. The inward rectifier currents from human and mouse clones were characterized using a novel strategy for stable ion channel expression in a human cell line. The permeability of the expressed inwardly rectifying channels was greater for K+ than for Rb+, whereas no current was observed when K+ was replaced by Na+. A prominent time- and voltage-dependent block was observed in the presence of Ba2+, whereas a small decay in the steady-state current was observed with millimolar concentrations of Na+. Single-channel conductances of 49.1 +/- 3.3 pS (n = 6) and 40.2 +/- 2.5 pS (n = 3) (P = 0.005) were obtained for the HHBIRK1 and IRK1 clones, respectively. These results indicate that sequence dissimilarities between human and mouse inward rectifier K+ channels may have significant functional consequences. PMID- 7840301 TI - Fixed patterns of bradycardia during late embryonic development in domestic fowl with C locus mutations. AB - A predictable late embryonic bradycardia (relative to normal White Leghorn chickens) has been documented in chicken strains with C locus mutations. The basis of the bradycardia remains unknown but clearly is related to a mutation at the C locus, which contains the structural gene for tyrosinase. When compared with the heart rate of normal White Leghorns (approximately 295-305 beats/min from day 8 to day 20 of incubation), ca/ca and other C locus mutants showed a 10 12% reduction in heart rate during the last 4 days of incubation. Embryonic mortality occurred in both mutant and normal strains at an equivalent rate (approximately 23%); a significant bradycardia (when compared with surviving embryos of the same strain) developed on the day before death in White Leghorn but not mutant strains. The bradycardia did not affect embryonic oxygen consumption (approximately 0.2 ml O2.egg-1.min-1 at day 14 and 0.4 ml O2.egg 1.min-1 at day 20), which showed only minor differences between strains that can be attributed to differences in embryonic mass on days 16-20. PMID- 7840302 TI - Dietary Na+ and cardiopulmonary baroreflex control of renal sympathetic nerve activity in SHR. AB - In young Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) with or without chronic sinoaortic denervation (SAD), we evaluated the effects of low, regular, and high dietary sodium intake (L-Na, R-Na, and H-Na, respectively) from 4 to 8 wk of age on cardiopulmonary baroreflex function, which was assessed by changes in renal sympathetic nerve activity (RSNA) and heart rate (HR) in response to acute volume expansion. In intact SHR H-Na increased blood pressure (BP), whereas L-Na decreased BP. No changes were observed in intact WKY. The gain of the cardiopulmonary baroreflex control of both HR and RSNA was significantly attenuated in SHR vs. WKY on R-Na. In both SHR and WKY, L-Na had no effects on the gain of RSNA and HR responses. In both strains, H-Na did not affect the gain of HR but attenuated the gain of the RSNA response. H-Na attenuated the gain of RSNA response more in SHR with SAD vs. intact SHR (52 vs. 69% of corresponding R Na control) but less in WKY with SAD vs. intact WKY (80 vs. 71% of corresponding R-Na control). These data indicate that in SHR, H-Na further desensitizes the already impaired cardiopulmonary baroreflex control of RSNA. After SAD, this attenuation is more prominent in SHR but becomes less prominent in WKY. High sodium intake, therefore, modulates the interaction between the arterial and cardiopulmonary baroreflexes in the control of RSNA oppositely in WKY vs. SHR. PMID- 7840304 TI - Vascular resistance and arterial pressure low-frequency oscillations in the anesthetized dog. AB - The spontaneous variability of heart rate and arterial blood pressure was investigated in chloralose-anesthetized dogs with the left iliac vascular bed mechanically uncoupled from the central circulation. Electrocardiogram, mean arterial pressure (ABP), iliac perfusion and venous pressures, and flow (FLOW) were recorded for 5 min in steady state. Autoregressive spectral and cross spectral analyses and digital filtering were performed. The variation coefficient (VC%), calculated from the overall variance of each signal, was 5-7%, with the exception of perfusion pressure (VC% = 1%). The frequency-related percentage of total variance was distributed among three frequency bands: two were < 0.20 Hz [lower (F1) and higher (F2; low-frequency range = F1 + F2)], and one was > 0.20 Hz (respiratory, F3). F3 was not always present in RR, which, however, oscillated also in F1 and F2, although with limited amplitude; ABP showed large respiratory and low-frequency oscillations; the FLOW oscillations were in the low-frequency range. Cross-spectral analysis showed high squared coherence in the relevant frequency bands between variables in the three couples: RR-ABP, RR-FLOW, and ABP FLOW. Changes in RR preceded changes in ABP and in FLOW by > or = 3 s, whereas FLOW was approximately in phase opposition to ABP. It was concluded that, in the chloralose-anesthetized dog, 1) arterial pressure and heart rate oscillate with frequencies corresponding to those described in conscious humans, 2) low frequency arterial pressure oscillations are due to changes in peripheral vascular resistance, and 3) peripheral vascular resistance does not display respiratory oscillations. Furthermore it was suggested that oscillations of vasomotor tone are generated by a rhythm of central origin and that F1 and F2 oscillations may recognize a common mechanism. PMID- 7840303 TI - Acute cocaine administration alters posttraumatic blood pressure and cerebral blood flow in rats. AB - Cocaine abuse is widespread, and it is possible that its two main pharmacological actions, sympathomimetic and local anesthetic, could influence the blood pressure and cerebral blood flow response to brain injury, which occurs with increased frequency in drug abusers. We tested this hypothesis in ventilated barbiturate anesthetized rats. Brain injury was induced using the fluid-percussion method, and cortical blood flow was measured using laser-Doppler flowmetry. Saline, cocaine, methamphetamine, or lidocaine was administered 10 min before injury. Upon injury, both cocaine- and saline-pretreated rats showed a similar acute hypertensive phase, which was followed by a period of more pronounced hypotension in the cocaine group (68 +/- 4 vs. 100 +/- 6 mmHg). Cortical blood flow increased dramatically 3-15 s following injury-induced hypertension in both the cocaine and saline groups (approximately 230-260%), but then fell below preinjury values within minutes. At 1 h postinjury, the blood flow in the saline group was 53 +/- 6% of the preinjury value, while in the cocaine group, flow was 74 +/- 7% of preinjury baseline. Similar to the cocaine-treated animals, methamphetamine also caused a more pronounced hypotensive event, but blood flow was not significantly different from saline controls. Lidocaine did not alter posttraumatic blood pressure but did significantly elevate blood flow throughout the 1-h postinjury period. At 60 min posttrauma, blood flow in the lidocaine group was 80 +/- 10% of the preinjury value. The mechanism by which cocaine alters blood pressure and blood flow after injury is not entirely certain.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7840305 TI - Phenylephrine contracts rat tail artery by one electromechanical and three pharmacomechanical mechanisms. AB - There are at least four mechanisms hypothesized to account for excitation contraction coupling in arterial smooth muscle. 1) Contractile agonists and changes in extracellular [K+] ([K+]o) induce contraction by depolarization, which increases Ca2+ influx; this is the only mechanism involving a change in membrane potential (Em). 2) Contractile agonists release Ca2+ from the intracellular Ca2+ store. 3) Contractile agonists increase Ca2+ influx without changing Em either by activating voltage-dependent L-type Ca2+ channels or by opening other Ca(2+) permeable channels. 4) Contractile agonists increase intracellular Ca2+ ([Ca2+]i) sensitivity of force; this is the only mechanism that does not involve changes in [Ca2+]i. Each of these mechanisms has been demonstrated in intact, skinned, or dissociated smooth muscle preparations. However, these four mechanisms have not been compared in the same preparation. The goal of this study was to determine which of these four contractile mechanisms are physiologically relevant in the intact rat tail artery. We stimulated deendothelialized rat tail artery with phenylephrine and high [K+]o. We then measured Em with microelectrodes, [Ca2+]i with fura 2, and isometric force with a strain gauge transducer. We find that all four mechanisms contributed to phenylephrine-induced rat tail artery contraction. The majority of phenylephrine-induced contraction was caused by depolarization and by increases in the [Ca2+]i sensitivity of force. Low concentrations of phenylephrine also increased [Ca2+] independent of changes in Em, potentially by increases in Ca2+ influx. Release of Ca2+ from intracellular stores was only observed with high concentrations of phenylephrine. Smooth muscle appears to invoke multiple mechanisms for excitation-contraction coupling. PMID- 7840306 TI - Effect of substrate on mitochondrial NADH, cytosolic redox state, and phosphorylated compounds in isolated hearts. AB - The effect of metabolic substrates on the relation among cytosolic redox state (NADHc/NAD+) mitochondrial NADH (NADHm), and [ATP]/([ADP] x [Pi]) was studied in isolated working rabbit hearts. Substrates were varied from 5.6 mM glucose alone to glucose in combination with 10 mM lactate and/or 10 mM pyruvate while afterload and preload were held constant. Changes in NADHm were determined from epicardial NADH fluorescence. The ratio of glycerol 3-phosphate (G-3-P) to dihydroxyacetone phosphate (DHAP), determined from tissue extracts, was used as an index of cytosolic redox. Myocardial 31P metabolites were measured using nuclear magnetic resonance spectroscopy. The addition of pyruvate to the perfusion medium caused increases in myocardial oxygen consumption (MVo2), NADHm fluorescence, phosphocreatine (PCr), and [ATP]/([ADP] x [Pi]) and a decrease in NADHc/NADc+ (decreased G-3-P/DHAP). Although the addition of lactate to the perfusion medium caused an increase in NADHm similar to pyruvate, MVo2 and PCr did not change significantly, [ATP]/([ADP] x [Pi]) increased less than with pyruvate, and there was an increase in NADHc/NADc+. The findings suggest that variations in the cytosolic redox state do not necessarily result in obligatory changes in either the mitochondrial redox state or in the [ATP]/([ADP] x [Pi]). This implies that under the conditions of this study an equilibrium is not maintained between [ATP]/([ADP] x [Pi]) and NADHc/NADc+. Furthermore, similar levels of NADHm can be associated with different values for [ATP]/([ADP] x [Pi]) and MVo2, depending on the substrates available to the heart. PMID- 7840307 TI - Aging and vasoreactivity: in vivo responses in the beagle hindlimb. AB - The purpose of this investigation was to determine whether vasodilator responses are attenuated and whether vasoconstriction is augmented with age in resistance vessels in the hindlimb of the dog. We examined blood flow (FAF) and pressure (FAP) responses in the femoral arterial system in older (109 +/- 8-mo-old) and younger mature (31 +/- 3-mo-old) female beagles during pentobarbital anesthesia. Vasodilator responses were evaluated during the intra-arterial administration of acetylcholine (ACh), which produces endothelium-dependent vasodilation, and albuterol, which mediates relaxation in vascular smooth muscle via beta adrenoceptors. The vasoconstrictor response to phenylephrine (PE), an alpha adrenergic agonist, was also examined. ACh and albuterol each induced dose dependent vasodilation in the older and in the younger dogs. Resultant changes in neither FAF nor FAP were affected by age in response to either of these vasodilator substances. Likewise, reductions in femoral vascular resistance (FVR) in response to ACh or to albuterol were not age dependent. Vasodilation following induced hindlimb ischemia resulted in similar increases in FAF in both groups, but produced a greater reduction in FAP in older vs. younger dogs (P = 0.05). Similarly, FVR decreased more in the older beagles (P = 0.02). Vasoconstriction mediated by PE resulted in similar reductions in FAF in both age groups, but the increase in FAP was less at several PE doses in older vs. younger dogs (P < 0.05). However, increases in FVR in response to PE were not statistically different in the younger and older beagles.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7840308 TI - Blood profile and balance study of rats given the putative anorectic agent satietin. AB - Satietin (SAT), a glycoprotein found in the plasma of a variety of animals, is a putative satiety agent. In experiments 1 and 2 rats received chronic third ventricle cannulas. At the start of the dark phase, in experiment 1, one group was infused with artificial cerebrospinal fluid (aCSF) and fed ad libitum (CON); a second group was infused with 100 micrograms/rat of human SAT and fed ad libitum in individual computerized pellet feeding modules; a third group was infused with aCSF and pair fed (PF) to the SAT-treated rats. The animals were killed 19.5 h later and blood was collected. Food and water intake and body weight were significantly, and comparably, reduced in the SAT-treated and PF group compared with the CON group. Plasma was assayed for a variety of nutrients, metabolites, enzymes, hormones, ions, and osmolality. Differential white cell counts were made. None of the above parameters differed significantly between the SAT and PF groups. Meal pattern analyses showed SAT treatment did not at any time alter meal size but significantly increased meal duration and intermeal interval during the first 6 h of the dark phase. In experiment 2 rats were placed in metabolic cages and infused with SAT or aCSF. Food and water intakes of the SAT group were suppressed for 1 day, whereas their body weights were significantly attenuated for 3 days. Urine volume and feces elimination were similar in the two groups over the 6-day measurement period. The normalcy of the data from experiment 1 is in accord with the possibility that SAT may act as a physiological satiety agent.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7840309 TI - Expression of the angiotensinogen gene is synergistically stimulated by 8-BrcAMP and Dex in opossum kidney cells. AB - We transiently transfected fusion genes with the 5'-flanking region of the angiotensinogen gene linked to a bacterial chloramphenicol acetyltransferase (CAT) coding sequence as a reporter into opossum kidney (OK) cells. The addition of 8-bromoadenosine 3',5'-cyclic monophosphate (8-BrcAMP) (10(-3)-10(-7) M) or forskolin (10(-9)-10(-5) M) stimulated the expression of the plasmid pOCAT [angiotensinogen nucleotide (N) -1498/+18] fusion gene in OK cells in a dose dependent manner. The addition of dexamethasone (Dex) (10(-6) M) further enhanced the stimulatory effect of 8-BrcAMP or forskolin, whereas the addition of (R)-p adenosine 3',5'-cyclic monophosphorothioate [(Rp)-cAMP[S], an inhibitor of cAMP dependent protein kinase A, I and II] blocked the stimulatory effect of 8-BrcAMP. Furthermore, the addition of 8-BrcAMP (10(-3) M) or Dex (10(-6) M) or a combination of both stimulated the expression of pOCAT (angiotensinogen N 1138/+18), pOCAT (angiotensinogen N -960/+18), pOCAT (angiotensinogen N 814/+18), and pOCAT (angiotensinogen N -688/+18), but had no effect on the expression of pOCAT (angiotensinogen N -280/+18), pOCAT (angiotensinogen N 198/+18), pOCAT (angiotensinogen N -110/+18), pOCAT (angiotensinogen N -53/+18), and pOCAT (angiotensinogen N -35/+18). To further localize the putative cAMP responsive element (CRE) in the angiotensinogen gene, we constructed fusion genes by inserting the DNA fragments angiotensinogen N -814 to N -689, angiotensinogen N -814 to N -761, and angiotensinogen N -760 to N -689 of the 5'-flanking region of the angiotensinogen gene upstream of the thymidine kinase (TK) promoter fused to a CAT gene and introduced them into OK cells.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7840310 TI - Increased renal nerve activity in cardiac failure: arterial vs. cardiac baroreflex impairment. AB - Cardiac failure is characterized by increased renal sympathetic nerve activity that is associated with an impairment of both arterial and cardiac baroreceptor reflex function. These reflex dysfunctions are in the afferent limb at the level of the peripheral baroreceptors. This study sought to define the relative quantitative magnitude of the defects in arterial and cardiac baroreceptor function in cardiac failure. Renal sympathetic nerve activity was measured in anesthetized normal control rats and rats with cardiac failure (left coronary ligation) during sequential random order sinoaortic denervation and vagotomy to interrupt afferent input from the arterial and cardiac baroreceptors, respectively. Increases in renal sympathetic nerve activity after individual or combined sinoaortic denervation and vagotomy were less (P < 0.05 for both) in cardiac failure than in normal control rats in both order sequences (42 +/- 5 vs. 87 +/- 8%; 44 +/- 5 vs. 108 +/- 7%). In cardiac failure rats, vagotomy produced lesser increases (P < 0.05 for both) in renal sympathetic nerve activity than sinoaortic denervation in both order sequences (10 +/- 4 vs. 32 +/- 5%; 13 +/- 2 vs. 30 +/- 5%). The relative magnitude of impaired cardiac baroreceptor reflex function that is associated with the increased renal sympathetic nerve activity of cardiac failure is greater than that of impaired arterial baroreceptor reflex function. PMID- 7840311 TI - Arterial and cardiopulmonary baroreflex control of renal nerve activity in cirrhosis. AB - Cirrhotic rats (common bile duct ligation; CBDL) have increased efferent renal sympathetic nerve activity (ERSNA), which contributes significantly to the observed renal sodium and water retention and edema formation. Basal ERSNA is increased and fails to suppress normally during intravenous isotonic saline volume expansion. Arterial and cardiopulmonary baroreflex control of ERSNA in CBDL and control (CTR) rats was examined. CBDL rats exhibited hyperdynamic circulation with increased cardiac index and decreased total peripheral resistance index and arterial pressure compared with CTR rats. Increases in left ventricular end-diastolic pressure (LVEDP) produced by volume expansion increased cardiac index normally in CBDL rats. The maximal gain of aortic baroreflex control of ERSNA was similar in CBDL and CTR rats. In CBDL rats, during decreased arterial pressure, there was a decreased range of the central component, which accounted for the decreased range of the overall aortic baroreflex, with the range of the afferent component being normal. For cardiopulmonary baroreflex control of ERSNA, the LVEDP threshold was increased and the gain was decreased in CBDL compared with CTR rats; this was due to an increased LVEDP threshold and a diminished gain of the afferent component while the central portion of the reflex was normal. These abnormalities in the cardiopulmonary baroreflex account for the attenuated decrease in ERSNA in CBDL compared with CTR rats during volume expansion. In CBDL rats, attenuation of cardiopulmonary baroreflex control of ERSNA contributes to both the increased basal ERSNA and its failure to normally suppress during volume expansion. PMID- 7840312 TI - Adaptive responses of GLUT-4 and citrate synthase in fast-twitch muscle of voluntary running rats. AB - Glucose transporter (GLUT-4) protein, hexokinase, and citrate synthase (proteins involved in oxidative energy production from blood glucose catabolism) increase in response to chronically elevated neuromuscular activity. It is currently unclear whether these proteins increase in a coordinated manner in response to this stimulus. Therefore, voluntary wheel running (WR) was used to chronically overload the fast-twitch rat plantaris muscle and the myocardium, and the early time courses of adaptative responses of GLUT-4 protein and the activities of hexokinase and citrate synthase were characterized and compared. Plantaris hexokinase activity increased 51% after just 1 wk of WR, whereas GLUT-4 and citrate synthase were increased by 51 and 40%, respectively, only after 2 wk of WR. All three variables remained comparably elevated (+50-64%) through 4 wk of WR. Despite the overload of the myocardium with this protocol, no substantial elevations in these variables were observed. These findings are consistent with a coordinated upregulation of GLUT-4 and citrate synthase in the fast-twitch plantaris, but not in the myocardium, in response to this increased neuromuscular activity. Regulation of hexokinase in fast-twitch muscle appears to be uncoupled from regulation of GLUT-4 and citrate synthase, as increases in the former are detectable well before increases in the latter. PMID- 7840313 TI - Identification of gastrin as a growth peptide in human pancreatic cancer. AB - The present study reports the first evidence that the gastrointestinal peptide gastrin stimulates the growth of several human pancreatic cancer cells in culture and in tumors transplanted to nude mice. Gastrin promoted growth of all cell lines tested at a dose comparable to the binding affinity, providing evidence for a physiologically relevant receptor. The stimulatory effects of gastrin were blocked by the CCK-B/gastrin receptor antagonist L-365,260 and not by the CCK-A receptor antagonist L-364,718. Growth of PANC-1 cells in culture were inhibited by L-365,260, suggesting that gastrin is tonically produced by PANC-1 cells for regulation of growth. Athymic nude mice bearing PANC-1 xenografts were treated for 24 days subcutaneously with either 1% bovine serum albumin (diluent), pentagastrin (1 mg/kg), or L-365,260 (1 mg/kg) twice daily. Tumors from the pentagastrin-treated mice were found to weigh more and have greater protein and DNA content than controls, whereas these values were all decreased in tumors of L 365,260-treated mice. Receptor binding capacity changed in tumors of animals treated with the peptide or antagonist, suggesting a regulatory process. Gastrin immunoreactivity was detected in a transplanted PANC-1 human tumor. These results identify gastrin as a potent trophic peptide that actively stimulates growth of human pancreatic cancer and does so through a CCK-B/gastrin-like receptor. PMID- 7840314 TI - Functional assessment of the 5-HT 1A-, 1B-, 2A/2C-, and 3-receptor subtypes on food intake and metabolic rate in rats. AB - The 5-hydroxytryptamine (5-HT) agonists (+/-)-8-hydroxydipropylaminotetralin hydrobromide (8-OH-DPAT), RU-24969, (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2 aminopropane hydrochloride (DOI), and 1-phenylbiguanide were administered to male Wistar rats to assess the respective involvement of the 5-HT 1A-, 1B-, 2A/2C-, and 3-receptor subtypes in the control of food intake and metabolic rate (VO2). Four series of experiments were carried out, each series addressing the effects of four doses (including saline or dose 0) of each of the agonists selected. The drugs were intraperitoneally injected in spontaneously fed animals. Injections were performed during the first 15 min of either the diurnal or the nocturnal phases of the light-dark daily cycle. Food intake and VO2 measurements were carried out over the 12-h periods ensuing after the agonist injections. The two highest doses of the 5-HT1A-receptor agonist 8-OH-DPAT led to a quickly appearing but transient elevation of diurnal VO2. During the night, VO2 was higher when the rats were treated with 8-OH-DPAT than when they were treated with saline. There was no significant effect of 8-OH-DPAT on either diurnal or noctural food intake. The highest dose of RU-24969 induced a significant increase in diurnal VO2, whereas all doses of RU-24969 blunted the nocturnal rise in metabolic rate characteristically observed in rats kept under a daily light-dark cycle. Importantly, RU-24969 induced marked diurnal and nocturnal hypophagia.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7840316 TI - Suppression of sucrose intake by continuous near-celiac and intravenous cholecystokinin infusions in rats. AB - We compared suppression of intake of 30% sucrose produced by continuous aortal (near celiac) and intravenous infusions of cholecystokinin octapeptide (CCK-8). Adult, male Sprague-Dawley rats received 21-min infusions of saline or 100-1,600 ng CCK-8. Sucrose was available for 20 min, beginning 1 min after onset of infusions. Significant reductions in intake were produced by near-celiac infusions of 400, 800, and 1,600 ng CCK-8, but only the two highest doses affected intake when infused intravenously. In a second experiment, which replicated previous observations, near-celiac bolus infusions of 70 ng CCK-8 significantly reduced sucrose intake but intravenous infusions did not. Behavioral observations indicated that although bolus infusions produced immediate disruption of feeding, suggesting an aversive effect, effects of continuous CCK-8 infusions on temporal intake patterns were consistent with enhancement of satiety. These data provide further evidence that CCK-8 acts on a site within the upper gastrointestinal tract to produce satiety. PMID- 7840315 TI - Glucocorticoids and insulin: reciprocal signals for energy balance. AB - Signals that regulate long-term energy balance have been difficult to identify. Increasingly strong evidence indicates that insulin, acting on the central nervous system in part through its effect on neuropeptide Y (NPY), inhibits food intake. We hypothesized that corticosteroids and insulin might serve as interacting, reciprocal signals for energy balance, acting on energy acquisition, in part through their effects on hypothalamic NPY, as well as on energy stores. Because glucocorticoids also stimulate insulin secretion, their role is normally obscured. Glucocorticoids and insulin were clamped in adrenalectomized rats with steroid replacement and streptozotocin-induced diabetes. Glucocorticoids stimulated and insulin inhibited NPY mRNA and food intake. Glucocorticoids inhibited and insulin increased energy gain as determined by the change in body weight. When adrenalectomized diabetic rats were treated, corticosterone stimulated and insulin inhibited food intake, and, respectively, inhibited and increased overall energy gain. More than 50% of the variance was explained by regression analysis of the two hormones on food intake and body weight. Thus glucocorticoids and insulin are major, antagonistic, long-term regulators of energy balance. The effects of corticosterone and insulin on food intake may be mediated, in part, through regulation of hypothalamic NPY synthesis and secretion. PMID- 7840317 TI - Hemodynamic response to vasopressin during V1-receptor antagonism in baroreflex deficient subjects. AB - Six quadriplegic subjects and 6 control subjects received high-dose arginine vasopressin (AVP) infusions at rates of 500, 1,000, 2,000, and 4,000 microU.kg 1.min-1 in consecutive 10-min intervals. Six additional quadriplegic subjects received low-dose AVP infusions at rates of 50, 100, 200, 400, and 800 microU.kg 1.min-1. All subjects were studied once with and once without administration of a selective V1-receptor antagonist. During high-dose AVP infusions without V1 receptor blockade, mean arterial pressure (MAP) increased from 80 +/- 4 to 87 +/- 5 mmHg (P < 0.05) in quadriplegic subjects but was unchanged in control subjects. In the presence of V1-receptor blockade, MAP decreased from 75 +/- 4 to 58 +/- 4 mmHg (P < 0.001), and heart rate (HR) increased from 61 +/- 5 to 80 +/- 5 beats/min (P < 0.001) in quadriplegic subjects. In the studies on control subjects, MAP decreased only from 75 +/- 3 to 72 +/- 5 mmHg (P < 0.05), whereas HR increased from 64 +/- 4 to 87 +/- 4 beats/min (P < 0.001). Plasma renin activity (PRA) increased in both quadriplegic and control subjects. The effects of low-dose AVP infusions on MAP, HR, and PRA in quadriplegic subjects were similar to those observed during high-dose infusions. Thus, in the absence of baroreceptor-mediated sympathetic nervous system responses, a vasodilatory effect of AVP that is capable of producing marked reductions in MAP can be demonstrated in the presence of V1-receptor blockade. PMID- 7840318 TI - Essential fatty acid deficiency impairs the responsiveness of renal pelvic sensory receptors. AB - The role of prostaglandins in renal sensory receptor activation was examined in rats fed an essential fatty acid-deficient (EFAD) diet to cause tissue arachidonate depletion. Littermates fed a standard diet were used as controls. In anesthetized rats, the increases in afferent renal nerve activity due to increasing ureteral pressure 2.5, 5, 7.5, 10, 12.5, and 15 mmHg were significantly reduced by the EFAD diet (P < 0.02): 3 +/- 5, 3 +/- 5, 11 +/- 5, 9 +/- 5, 19 +/- 3, and 17 +/- 5%, respectively, in EFAD rats and 23 +/- 11, 36 +/- 15, 50 +/- 15, 52 +/- 8, 72 +/- 17, and 90 +/- 19%, respectively, in control rats. In EFAD rats, addition of prostaglandin E2 (PGE2) to the renal pelvic perfusate restored the afferent renal nerve activity response to increased ureteral pressure toward that in control rats. PGE2 had no effect in control rats. Also the afferent renal nerve activity responses to renal pelvic perfusion with bradykinin at 4, 20, 100, and 500 micrograms/ml were significantly suppressed by the EFAD diet (P < 0.01): 13 +/- 15, 5 +/- 7, 60 +/- 19, and 63 +/- 20%, respectively, in EFAD rats and 122 +/- 23, 142 +/- 31, 172 +/- 19, and 190 +/- 39%, respectively, in control rats. These results demonstrate an important role for arachidonate metabolites, particularly PGE2, in renal sensory receptor activation. Together with our previous studies showing that indomethacin blocks the afferent renal nerve activity responses to increased ureteral pressure or bradykinin, the present studies provide strong evidence for an essential role of prostaglandins in renal sensory receptor activation. PMID- 7840319 TI - Corticosterone decreases nonshivering thermogenesis and increases lipid storage in brown adipose tissue. AB - Brown adipose tissue (BAT) contains glucocorticoid receptors; glucocorticoids are required for maintaining differentiated BAT in culture. These studies were performed to determine the effects of corticosterone on BAT thermogenic function and lipid storage. Rats were adrenalectomized and given subcutaneous corticosterone pellets in concentrations that maintained plasma corticosterone constant across the range of 0-20 micrograms/dl or were sham adrenalectomized. All variables were examined 5 days after surgery and corticosterone replacement. Measures of BAT function-thermogenic capacity [guanosine 5'-diphosphate (GDP) binding and uncoupling protein (UCP; a BAT-specific thermogenic protein)] and storage (BAT wet wt, protein, and DNA levels) were made. Plasma hormones (corticosterone, adrenocorticotropic hormone, insulin, 3,3',5-triiodothyronine, and thyroxine were measured. Corticosterone significantly affected BAT thermogenic measures: UCP content and binding of GDP to BAT mitochondria decreased with increasing corticosterone; GDP binding characteristics in BAT from similarly prepared rats examined by Scatchard analysis showed that maximum binding (Bmax) and dissociation constant (Kd) decreased with increasing corticosterone dose. BAT DNA was increased by adrenalectomy and maintained at intact levels with all doses of corticosterone; BAT lipid storage increased dramatically at corticosterone values higher than the daily mean level in intact rats. Histologically, the number and size of lipid droplets within BAT adipocytes increased markedly with increased corticosterone. White adipose depots were more sensitive to circulating corticosterone concentrations than were BAT depots and increased in weight at levels of corticosterone that were at or below the daily mean level of intact rats. We conclude that, within its diurnal range of concentration corticosterone acts to inhibit nonshivering thermogenesis and increase lipid storage.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7840320 TI - Regulation of NPY/NPY Y1 receptor/G protein system in rat brain cortex. AB - Neuropeptide Y (NPY) content, NPY receptors, and alpha-subunits of the G proteins Go and Gi were determined in cerebral cortex of male normotensive Wistar-Kyoto and spontaneously hypertensive rats at 3-28 wk of age and of adult female rats. NPY lacked major effects on adenylate cyclase or inositol phosphate formation. NPY content was similar in all normotensive groups but lower in spontaneously hypertensive rats at all ages. 125I-NPY labeled a homogeneous population of Y1 like receptors. The Y1 NPY receptor number gradually increased with age with similar values in both strains but was significantly smaller in female than in male rats. The Y1 NPY receptor affinity was similar in all male groups but greater in female rats. The abundance of immunodetectable Go alpha and Gi alpha and of pertussis toxin substrates was less at 3 wk than in older rats but similar in both sexes and strains. We conclude that rat cerebral cortex contains Y1-like receptors; sex, age, and blood pressure differentially regulate NPY content, Y1 NPY receptors, and Go alpha and Gi alpha. PMID- 7840321 TI - Biological actions and pharmacokinetics of C-type natriuretic peptide in conscious sheep. AB - C-type natriuretic peptide (CNP) is found in abundance in neural tissue and in endothelial cells of vascular tissue, where it may participate in the regulation of vascular tone. However, few studies have examined the metabolism and systemic actions of CNP in conscious animals. Accordingly, we investigated the hemodynamic, renal, and hormonal effects of intravenous CNP-22 administered at two doses (1 and 10 pmol.kg-1.min-1 as dose 1 and dose 10, respectively) in a vehicle-controlled study in normal conscious sheep (n = 8). Plasma CNP levels were raised from a mean baseline level of 2-3 pmol/l (detection limit) to plateau at 10 +/- 1.2 and 115 +/- 18 pmol/l during doses 1 and 10, respectively. Metabolic clearance rates were 3.15 +/- 0.39 and 2.48 +/- 0.36 l/min, respectively. The plasma half-life of CNP on termination of infusion was rapid (1.6 +/- 0.27 min). Dose 10 increased plasma guanosine 3',5'-cyclic monophosphate (P = 0.0002), reduced cardiac output by 18% (P = 0.01), but did not significantly affect mean arterial pressure. Similar suppression (15%) of cardiac output occurred during dose 1 (P = 0.078). Both doses were natriuretic. This study demonstrates that CNP is natriuretic in sheep and lowers cardiac output without significantly affecting arterial pressure. CNP may play an important role in the regulation of regional hemodynamics and fluid homeostasis. PMID- 7840322 TI - Aging and dietary modulation of elastase and interleukin-1 beta secretion. AB - Aging is associated with diminished immune function that may stem from alterations in arachidonic acid metabolism and lipid peroxidation. This study sought to determine if dietary modification of fatty acids influenced neutrophil and monocyte secretion after an in vivo inflammatory stress in older human subjects. Volunteers participated in protocols that forced their quadriceps muscles to lengthen during tension development (eccentric stress). These protocols can cause inflammatory foci in the muscle as well as alterations in circulating leukocyte function. In this study, in vivo neutrophil degranulation was assessed by plasma elastase concentrations, and mononuclear cell function was assessed by interleukin-1 beta (IL-1 beta) secretion in vitro. In response to eccentric stress, older subjects (> 60 yr old) taking a placebo had no apparent elastase response, whereas those taking fish oil supplements responded with a 142% increase in plasma elastase (P = 0.011), similar to responses of younger reference subjects (< 33 yr old) taking no supplement. Overall, elastase responses correlated with individual plasma arachidonic acid-to-eicosapentaenoic acid ratios (r = -0.881, P = 0.004). Thus apparent age-related differences in elastase release were reconciled by individual differences in fatty acid nutriture. No significant temporal changes in urinary lipid peroxide excretion or IL-1 beta secretion were observed; however, age-associated differences were found. PMID- 7840323 TI - Central actions of parathyroid hormone on blood calcium and hypothalamic neuronal activity in the rat. AB - The central actions of parathyroid hormone (PTH) on the blood ionized calcium level in anesthetized rats and the neuronal activity of the ventromedial nucleus of the hypothalamus (VMH) in vitro were investigated. An intracerebroventricular injection of PTH (0.01, 0.1, and 1 microgram) prevented urethan-induced hypocalcemia in a dose-dependent manner, whereas either an intravenous or an intracisternal injection of PTH (1 microgram) was ineffective. Eighty-three of 177 VMH neurons responded to a bath application of PTH (10(-7) or 3 x 10(-7) M): a majority (72, 83%) of the responsive cells decreased, whereas 11 increased their activity. This inhibitory effect of PTH on neuronal activity still persisted after synaptic blocking in a Ca(2+)-free/high-Mg2+ medium. A PTH receptor antagonist, [Tyr34]bPTH-(7-34)-NH2, suppressed the effect of PTH on the neuronal activity. These findings thus suggest that brain PTH has a calciotropic function and that one of the possible target sites is the VMH, where PTH inhibits its neuronal activity through a postsynaptic mechanism mediated by PTH receptors. PMID- 7840324 TI - Autonomic responses of the insular cortex in hypertensive and normotensive rats. AB - Lesion and focal cerebral ischemia of the insular cortex (IC) results in elevated renal sympathetic nerve activity (RSNA) and arterial pressure (AP) in the Wistar rat, while the opposite effect is observed in the spontaneously hypertensive rat (SHR). Acute changes in AP, heart rate (HR) and RSNA were measured in propofol anesthetized and conscious SHR (n = 17) and Wistar rats (n = 17) during pressure injection of D,L-homocysteic acid (DLH; 100 mM) and lidocaine (LID; 20 mg/ml) into the IC. DLH injections (200 nl) into the IC of anesthetized Wistar rats resulted in a significant increase in MAP (mean change = +27 +/- 7 mmHg; P < 0.05) and a significant decrease in HR (-22 +/- 9 beats/min) and RSNA (-11 +/- 4 microV.s). Neither DLH nor LID injections into the IC of anesthetized SHR affected MAP or RNA. DLH and LID injections (500 nl) into the IC of conscious Wistar rats both resulted in a significant increase in MAP (+26 +/- 5 mmHg; 11 +/ 4 mmHg, respectively). Neither DLH nor LID injections had any cardiovascular effects in the conscious SHR. It therefore appears that the IC of conscious Wistar rats has a tonic inhibitory output, while neural excitation is capable of eliciting pressor responses. Conversely, the IC of SHR appears to exert no tonic influence on MAP. PMID- 7840325 TI - Oral-pharyngeal-esophageal and gastric cues contribute to meal-induced c-fos expression. AB - We recently demonstrated that a meal induces c-fos immunoreactivity in the dorsal motor nucleus of the vagus (DMV), the nucleus of the tractus solitarius (NTS), and the area postrema (AP) of the rat brain stem. This response was not eliminated by the cholecystokinin A (CCK-A) antagonist L-364,718, a finding suggesting that feeding induces c-fos immunoreactivity by a pathway that is largely independent of CCK-A receptor activation. Consequently, the role of alternative gastrointestinal cues in the induction of c-fos was investigated. The induction of c-fos after oral-pharyngeal and esophageal stimuli was examined by use of a sham-feeding procedure via a gastric fistula. Gastric fistula-closed and fed rats displayed c-fos immunoreactivity similar to that of meal-fed rats seen previously. Fistula-open and fed rats showed the same degree of staining in the more rostral section of NTS examined as fistula-closed and fed rats, but fewer c fos-positive nuclei in the more caudal level of the NTS. The potential for gastric distension to induce c-fos was assessed after the inflation of a gastric balloon. Physiological inflation of the balloon produced marked c-fos induction primarily in the medial NTS. PMID- 7840326 TI - Dopamine-1 receptors in the proximal convoluted tubule of Dahl rats: defective coupling to adenylate cyclase. AB - We have previously reported a defect in the coupling of the renal dopamine-1 receptor (D1) to adenylate cyclase (AC) in the proximal convoluted tubule (PCT) of the spontaneously hypertensive rat (Okamoto-Aoki strain). To determine if this defect is present in another model of hypertension, we microdissected PCTs from Dahl salt-sensitive (DSS) and Dahl salt-resistant (DSR) rats on low- or high-NaCl diet. The ability of two selective D1 agonists, fenoldopam and SND-919-C12, and forskolin to stimulate AC activity in PCT was determined in each of the four groups of rats. Fenoldopam (10(-7) M) and SND-919-C12 (10(-6) M) failed to stimulate AC activity in the PCT of DSS rats whether on a low- or high-NaCl diet. In DSR rats, however, both fenoldopam and SND-919-C12 stimulated AC activity by 289-320% and 220-270%, respectively, whether on a low- or high-NaCl intake. Forskolin (10(-5) M), which directly stimulates AC activity, increased AC activity in all four groups. These studies show that in DSS rats the D1 receptor in the PCT fails to respond to D1 agonists. This defect is not a consequence of the hypertension because it was present in the DSS rats on a low-salt diet and before blood pressure elevation. PMID- 7840327 TI - Gut-brain signaling of water absorption inhibits vasopressin in rats. AB - The mechanism for inhibition of vasopressin (AVP) by gastric water infusion was examined in 24- or 48-h dehydrated conscious rats (n = 136 rats, 255 experiments; mean AVP baseline = 6.3 pg/ml). Gastric water infusions of 1 (n = 8), 2.5 (n = 19), and 4 ml (n = 10) caused a volume-dependent inhibition of plasma AVP by 0.31, -1.77*, and -3.02* pg/ml, with decreases of systemic osmolality of -1.06, 1.52, and -4.26* mosmol/kgH2O (* = significant vs. isotonic, Duncan's test). Gastric isotonic infusions (1-4 ml) had no effect or slightly increased AVP. Systemic infusions of 1.25 (n = 6), 2.1 (n = 10), and 6.3 ml (n = 8) inhibited AVP by -0.48, -1.07, and -2.51 pg/ml, with decreases in systemic osmolality of 1.61, -2.77*, and -7.21* mosmol/kgH2O. Systemic isotonic infusions (2.1 and 6.3 ml) slightly inhibited AVP by -0.71 and -0.85 pg/ml. Individual changes in AVP by gastric infusion of 2.5 ml of water did not correlate with changes in systemic osmolality, mean arterial pressure, or heart rate but highly correlated with preinfusion AVP (r = 0.74, P < 0.0001, n = 28). Pretreatment with systemic atropine methyl bromate (0.7 mg/rat), which abolishes the AVP secretion to gastric hypertonic saline, did not affect the AVP response to gastric water infusion (n = 9). Combination of 2.5 ml of gastric water and systemic hypertonic saline prevented the decrease in systemic osmolality and still significantly inhibited plasma AVP. Maximal inhibition of AVP by gastric water was reduced by 62.6% after lesion of the common hepatic vagal branch (n = 5) relative to shams with identical abdominal surgery (n = 6) and by 62.7 and 72.5% after right (n = 11) and left (n = 8) cervical vagotomy relative to 12 shams (P < 0.05). The results show that 1) gastric water absorption is signaled mainly by splanchnic osmosensors, 2) water signaling is atropine insensitive, and 3) the major water signaling pathway projects through the common hepatic vagal branch and cervical vagal nerves. PMID- 7840328 TI - Naloxone blocks that portion of feeding driven by sweet taste in food-restricted rats. AB - We evaluated the potency of naloxone on intake of normal and sweet chow in food deprived and schedule-fed rats. We found that naloxone's anorectic potency was dependent on the type of chow presented to the rats and the deprivation schedule utilized to stimulate food intake. In 24-h and 48-h deprived rats, naloxone decreased intake of normal rat chow at doses ranging from 0.3 to 3 mg/kg. In chronically deprived rats (80% of normal body wt), these doses of naloxone failed to decrease intake of normal chow. Rats eating sweet chow ate more when energy deprived and were more sensitive than rats eating normal chow to naloxone-induced limitations in food intake, both in acute and chronic food-deprived groups. Thus naloxone decreased intake of sweet chow much more effectively than normal chow even when rats were chronically food deprived. We also found that an extremely low dose of naloxone (0.03 mg/kg) decreased intake of sweet chow by almost 50% in satiated rats. PMID- 7840329 TI - Comparison of ultradian and circadian oscillations of carbon dioxide production by various endotherms. AB - Carbon dioxide emission (VCO2) was computed every 20 min from continuous CO2 concentration recordings taken during 3-30 consecutive days, in strictly controlled environmental conditions, in 54 OF1 mice, 99 Japanese quail, 66 Sprague-Dawley rats, 50 Hartley guinea pigs, 7 chicks, for 7-15 days on 2 Cynomolgus monkeys, and for 24 h on 7 premature infants. This VCO2 shows circadian and ultradian oscillations that were analyzed for frequencies and amplitudes in light-dark 12-h alternation (LD 12:12), continuous light (LL), and continuous dark (DD). Circadians were not always identified or were often masked in LL or DD (mostly in guinea pigs, quail, and rats), while ultradians (tau > or = 40 min) were found in all species, at every time, and in all light regimens. Analysis of variance and chi 2 show significant (P < 0.001) interspecies differences for ultradian (1.07 < tau < 1.40 h) intervals and for circadian and ultradian VCO2 amplitudes. Relationships between ultradian and circadian VCO2 oscillations differ according to the species, ultradians appearing as an entity characteristic for each endotherm species. PMID- 7840330 TI - Presence of insulin-like growth factor I but absence of the binding proteins in the bile of rats. AB - Whereas insulin-like growth factor I (IGF-I) has been found in various body fluids from different species, the presence or absence of IGF and associated binding proteins (IGFBPs) in bile has not been clearly defined. Bile concentration of IGF-I was measured in this study and found to be highest in the neonate and lowest in adult rats [133 +/- 15.9, 79.4 +/- 10.5, 45.3 +/- 12.7 ng/ml (mean +/- SE) in 12-day-old, 33-day-old, and adult rats, respectively]. When bile delivery rates of IGF-I (i.e., the product of IGF-I concentration in bile and the biliary flow rate) were calculated, IGF-I delivery was highest in weanling rats (469 pg.h-1.g body wt-1). When expressed as amount of IGF-I in bile delivered per day, however, delivery rates rose from 0.2 micrograms/day in the suckling and remained constant at 1.6-1.7 micrograms/day in both weanling and adult animals. Bile samples exposed to a placental membrane IGF receptor preparation showed significant dose-dependent inhibition of binding of native IGF I. Because no IGF binding proteins were identified by Western ligand blot or by Sephadex gel chromatography, the results suggest the presence of biologically significant quantities of bioactive IGF-I in bile. We speculate that IGF-I in bile may play an important role in the growth of the gastrointestinal tract, both in the suckling as well as later in life. PMID- 7840331 TI - Neuronal excitation by angiotensin II in the rostral ventrolateral medulla of the rat in vitro. AB - We examined the effects of angiotensin II (ANG II) on spontaneous unit activity in slices of the rat rostral ventrolateral medulla (RVLM), ANG II (1-3 microM) excited 61% of a population of slowly and irregularly firing RVLM neurons (predrug, 1.2 +/- 0.1 spikes/s; postdrug, 4.6 +/- 0.3 spikes/s; n = 52). ANG II had no effect on pacemaker-like rapidly firing neurons (predrug, 8.6 +/- 0.4 spikes/s; n = 33). The effect of ANG II on slowly firing cells was repeatable and was reduced 75% by 3 microM losartan (baseline, 1.7 +/- 0.4 spikes/s; ANG II, 5.3 +/- 0.7 spikes/s; ANG II+losartan, 2.4 +/- 0.6 spikes/s; n = 12). The ongoing activity of slowly firing neurons was unaffected by 0.5-1 mM kynurenic acid (an ionotropic excitatory amino acid receptor antagonist). Most ANG II-responsive neurons (10 of 11) were inhibited by the alpha 2-adrenergic receptor agonist UK 14,304, but pacemaker-like neurons were not. In conclusion, the RVLM contains neurons excited by AT1 receptor agonists. These neurons are distinct from the previously described pacemaker nonadrenergic presympathetic cells. They may be responsible for the pressor effects produced by injecting ANG II into the RVLM in vivo. PMID- 7840332 TI - Aging effects on human sympathetic neuronal function. AB - To study the effect of aging on human sympathetic nervous function, we applied kinetic methods for measuring the fluxes to plasma of neurochemicals relevant to sympathetic neurotransmission in younger (aged 20-30 yr) and older (aged 60-75 yr) healthy men. Mean plasma norepinephrine concentration was 66% higher in older men, attributable to 22% lower norepinephrine plasma clearance (P < 0.05) and 29% higher norepinephrine spillover to plasma (difference not statistically significant). Regional venous sampling disclosed that sympathetic outflow to all organs was not activated by aging. Renal norepinephrine spillover was normal in older men. Although spillover of norepinephrine from the heart was increased in older men, 21.1 +/- 11.4 ng/min compared with 11.4 +/- 8.6 ng/min (P < 0.05), diminished norepinephrine reuptake rather than increased cardiac sympathetic nerve firing was the most likely cause, although somewhat reduced intracardiac methylation of norepinephrine with aging also possibly contributed. The extraction of tritiated norepinephrine from plasma during transit through the heart was reduced, suggesting neuronal norepinephrine reuptake was lowered and overflow of the norepinephrine precursor dihydroxyphenylalanine and metabolites dihydroxyphenylglycol and 3-methoxy-4-hydroxy phenylglycol was normal, indicating that norepinephrine synthesis and release were not increased. PMID- 7840334 TI - Aging alters the phase-resetting properties of a serotonin agonist on hamster circadian rhythmicity. AB - Serotonergic mechanisms are believed to play a considerable role in mediating the effects of photic and nonphotic stimuli on circadian rhythmicity. Because aging is associated with significant changes in the responsiveness of the rodent circadian system to major synchronizing agents in the environment, this study examined the phase-shifting effects of the 5-HT1A receptor agonist, 8-hydroxy-2 (di-n-propylamino)tetralin [8-OH-DPAT; 2.0, 5.0, and 8.0 mg/kg ip at circadian time 8 (CT 8)], on the 24-h activity rhythm of young (3-4 mo old) and old (18-19 mo old) golden hamsters. Aging was associated with a dramatic attenuation of the phase-shifting effects of 8-OH-DPAT in this species. The results suggest the existence of age-related deficits in the serotonergic control of mammalian circadian rhythmicity, which could interfere with the temporal adaptation of the senescent organism to its environment. PMID- 7840333 TI - Tissue-specific HSP70 response in animals undergoing heat stress. AB - Heatstroke is a multisystem disorder that can result in death. Activities that increase the rate of heat storage predispose an organism to thermal injury. Using a 72-kDa heat shock protein (HSP72) as a marker of thermal injury, we determined 1) which organs synthesize HSP in animals after hyperthermia and 2) whether a high heating rate (HHR) resulted in more HSP72 than a low heating rate (LHR). Rats were assigned to either control, HHR (0.166 degrees C/min), or LHR (0.045 degrees C/min) groups. Heat exposure ended when colonic temperature (Tc) reached 42 degrees C. Total time in the heat and thermal load (measured as the time an animal maintained a Tc > 40.4 degrees C) were significantly lower in HHR compared with LHR animals. Hyperthermia resulted in a tissue-specific increase in HSP72 in the liver, small intestine, and kidney, but not in the brain or quadriceps muscles. In addition, HHR animals showed significantly greater accumulation of HSP72 in the liver compared with animals in the LHR group. Thus HSP72 synthesis is tissue specific at high physiological temperatures and may identify a critical target tissue susceptible to early thermal damage. PMID- 7840335 TI - Whole body energy expenditure and fuel oxidation after 2,5-anhydro-D-mannitol administration. AB - The fructose analogue 2,5-anhydro-D-mannitol (2,5-AM) increases food intake in nondeprived rats. Several lines of evidence indicate that vagal signals arising from the liver are critical for this effect. In addition, 2,5-AM decreases plasma glucose and increases lipolysis, resulting in an increase in plasma free fatty acids and ketone bodies. In these respects 2,5-AM produces a state analogous to that observed after food deprivation. Using an indirect calorimeter, we determined that 2,5-AM (300 mg/kg ip) causes a potent and long-lasting decrease in respiratory quotient, indicating a decrease in the fraction of total energy derived from carbohydrate oxidation and an increase in the fraction derived from fatty acid oxidation. These metabolic variables were altered without affecting total metabolic rate. This dose of analogue also stimulated significantly greater food intake than injections of vehicle. These results support the continued use of 2,5-AM as a tool to probe the metabolic controls of food intake. PMID- 7840336 TI - Interaction of hypertension and caloric restriction on cardiac mass and isomyosin expression. AB - Previous studies show that elevations in blood pressure induce concomitant increases in both cardiac mass and slow beta-myosin heavy chain (MHC) expression in rodents, whereas caloric restriction of 50% (CR) causes an increase in beta MHC while modestly lowering blood pressure in normotensive rats. The goals of this study were to 1) determine if beta-MHC expression could be independently regulated by CR and hypertension when these two interventions are combined and 2) determine if CR exerts a lowering of blood pressure in two contrasting models of rodent hypertension. Rodents were assigned to the following groups: 1) normal control (NC); 2) abdominal aortic constriction (Abcon), a model that induces hypertension via renin-angiotensin II; 3) nephrectomy-deoxycorticosterone acetate treatment (DOCA), a model that induces hypertension through increased salt retention; 4) CR; 5) Abcon+CR; 6) DOCA+CR. Results show that both Abcon and DOCA induced significant increases in systemic blood pressures, left ventricular (LV) weight/body weight, and the relative content of beta-MHC compared with NC. When applied in combination with either Abcon or DOCA, CR significantly blunted the changes observed in both systemic blood pressures and LV weight/body weight. In contrast, CR in conjunction with DOCA augmented % beta-MHC expression relative to either DOCA or CR alone. These data suggest 1) caloric restriction exerts a powerful impact on reducing experimentally induced hypertension in rodents and 2) the regulation of beta-MHC expression appears to be regulated by at least two processes, one associated with the stimulus of hypertension and the other involving an independent pathway linked to caloric restriction. PMID- 7840337 TI - Mesenteric vascular responses to vasopressin during development of DOCA-salt hypertension in male and female rats. AB - Deoxycorticosterone acetate (DOCA)-salt hypertension develops to a greater extent in male (M) than in female (F) rats. To determine the role of the vasculature, reactivity to arginine vasopressin (AVP) and prostanoid output were examined in the isolated perfused mesenteric vasculature of hypertensive (HT) and normotensive-control (NTC) M and F rats after acute (1-wk) and chronic (4-wk) DOCA-salt treatment. Systolic blood pressure was significantly higher in M than in F HT rats (187 +/- 3 vs. 151 +/- 3 mmHg after 4 wk; P < 0.02). After acute treatment, vascular reactivity to AVP (maximal perfusion pressure) in HT was elevated in M (181 +/- 18 mmHg; P < 0.02) but not in F (135 +/- 6 mmHg) compared with NTC (90 +/- 6 mmHg, M vs. 119 +/- 5 mmHg, F). After chronic treatment, vascular reactivity to AVP in HT was elevated in both sexes (P < 0.02), although more in F (175 +/- 13 mmHg) than in M (141 +/- 11 mmHg). In contrast, vascular responsiveness to phenylephrine did not differ significantly between M and F NTC or HT preparations after either acute or chronic treatment. Sex differences in basal and AVP-induced 6-ketoprostaglandin (6-keto-PG) F1 alpha and PGE2 output by HT and NTC vasculature were reciprocal to sex differences in the vasoconstriction responses to AVP. After acute treatment, AVP-stimulated 6-keto-PGF1 alpha output by HT was elevated slightly in F (33.6 +/- 1.7 ng/3 min; P < or = 0.02) but not in M (49.9 +/- 4.3 ng/3 min) compared with NTC (23.5 +/- 2.6 ng/3 min, F vs. 34.7 +/- 4.9 ng/3 min, M). After chronic treatment, output by HT was enhanced in both sexes (P < or = to 0.02), although more in M (109 +/- 15.4 ng/3 min) than in F (68 +/- 6.6 ng/3 min)> These findings suggest that sex differences in the relative balance between AVP-induced vasoconstriction and vasodilatory prostanoid release may contribute to male-female differences in mesenteric vascular reactivity to AVP in NT and that disturbances in this balance may be responsible, at least in part, for the sex- and time-dependent changes in reactivity to AVP observed during the development of DOCA-salt hypertension. PMID- 7840338 TI - Hepatic denervation reduces adrenal catecholamine secretion during insulin induced hypoglycemia. AB - The present study was designed to investigate the functional implication of hepatic afferent nerves in controlling adrenal medullary counterregulatory response to insulin-induced hypoglycemia in anesthetized dogs subjected to an acute surgical denervation of the liver. Aortic glucose concentration decreased similarly in the groups of dogs with hepatic denervation (n = 8) and sham denervation (n = 8) reaching a glucose nadir 30 min after insulin injection (0.15 IU/kg i.v.) from a control value of 89.46 +/- 3.15 and 88.91 +/- 2.86 mg/dl to 52.92 +/- 3.27 and 48.80 +/- 4.18 mg/dl (P < 0.05), respectively. The catecholamine output from the adrenal glands in the sham group significantly increased (P < 0.05), reaching a maximum level 45 min after insulin injection from a control value for epinephrine of 86.35 +/- 26.65 ng/min and for norepinephrine of 32.14 +/- 11.68 ng/min to 659.03 +/- 269.39 and 181.21 +/- 63.03 ng/min, respectively. By contrast, however, adrenal catecholamine output increased only slightly in the hepatic-denervated group during insulin-induced hypoglycemia, from 148.37 +/- 95.29 and 52.06 +/- 28.05 ng/min to 210.49 +/- 96.09 and 79.61 +/- 26.11 ng/min for epinephrine and norepinephrine, respectively, the difference being statistically nonsignificant compared with the corresponding preinjection control value. The maximum net response of adrenal epinephrine and norepinephrine output observed in dogs with hepatic denervation was significantly attenuated by approximately 90 and 82% of the values obtained from the sham group, respectively. In a separate series of experiments, aortic immunoreactive insulin and glucagon concentrations were measured and found to be similar between hepatic-denervated and sham-denervated groups after insulin induced hypoglycemia.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7840339 TI - Factors affecting the sensitivity of the lingual trigeminal nerve to acids. AB - Oral sensitivity to acids mediates a range of irritation, from desirable sensations of pungency in various foods and beverages to the pain associated with harmful levels of acidity and inflammation. To characterize the role of the epithelial and vascular processes in neural sensitivity to acid applied to the lingual mucosa, we measured lingual trigeminal nerve responses in rats to acidic stimuli of varying physicochemical properties. Stimulatory efficacy was strongly correlated with lipophilicity (octanol-H2O partition coefficient) for the series of straight-chain fatty acids from one to six carbons. Neither acid dissociation constant nor the pH of stimulus solutions correlated with stimulatory efficacy for the fatty acids and six other organic acids. The hypothesis that weakly acidic stimuli gain access to trigeminal nerve endings primarily through the lipid phase of the epithelium was supported by these findings. Further support for this hypothesis is the result that LaCl3, an inhibitor of epithelial tight junctions, had no effect on the neural response to n-pentanoic acid. The potential relevance of buffering-clearance in modulating responses to acid was indicated by the finding that the application of 1 mM capsaicin to the tongue reversibly inhibited the neural response to acid, as well as causing plasma extravasation in lingual epithelium. PMID- 7840340 TI - Sex differences in blood flow distribution of normothermic and heat-stressed rabbits. AB - Sex differences in blood flow (BF) distribution of male and female mature laboratory rabbits were determined in normothermic and heat-stressed states. Animals were anesthetized with alpha-chloralose, and BF distribution was determined by radioactive microspheres in the thermoneutral state and then again during hyperthermia after 2 h of heat exposure. Cardiac output did not change in either sex during heat stress. BF to the toe and ear skin and to nasal turbinates was lower in females than in males, whereas that to the diaphragm, sternum, intercostal muscles, spleen, and skeletal muscles was higher in females. A thermal state-by-sex interaction was detected in several organs, indicating that during heat stress in males, BF is significantly higher than in the controls, whereas in females a decline, no change, or only a slight increase was recorded. Males did not exhibit any decrease in inner organ BF during heat stress, whereas females did. Results show sex differences in BF distributions under normothermia and hyperthermia, suggesting that males and females differ in their BF regulation in both peripheral organs, which are active in heat dissipation, and inner body organs. PMID- 7840341 TI - Effect of liver denervation on glucose production during running in guinea pigs. AB - Activity in sympathetic liver nerves has been proposed to be important for glucose production in exercising humans. However, liver denervation does not influence the exercise-induced increase in glucose production in the rat and dog. These species have a poor sympathetic liver innervation in contrast to the rich innervation in humans. The effect of liver denervation on glucose production during exercise was therefore studied in the guinea pig, a species with a rich sympathetic hepatic innervation comparable to that of humans. Guinea pigs were selectively liver denervated (n = 9) or sham operated (n = 8) and instrumented with a carotid and a jugular catheter. One week later they ran on a treadmill at 32 m/min for 20 min. Glucose turnover was evaluated by a primed constant-rate intravenous infusion of [3-3H]glucose. Arterial blood was sampled for analysis of hormones and metabolites. At rest, liver-denervated guinea pigs had lower glucose turnover and plasma concentrations of glucose, glycerol, and cortisol than control animals. During running, the increase in hepatic glucose production was similar in the two groups (4.1 +/- 0.8 vs. 3.8 +/- 0.7 mumol.min-1.100 g-1 in control animals) and so were hepatic (247 +/- 25 vs. 246 +/- 45 mmol glucose units/kg wet wt in control animals) and muscle glycogen concentrations at the end of exercise.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7840342 TI - Osmolality-induced changes in aldosterone secretion involve a chloride-dependent process. AB - Alterations in extracellular osmolality have a powerful inverse effect on aldosterone secretion that is associated with sustained changes in cell volume. With dispersed bovine glomerulosa cells grown in primary culture, the effects of alterations in osmolality on cell volume measured by the distribution of [14C]urea and [3H]mannitol were determined in the presence and absence of chloride. In the presence of chloride, decreases in osmolality increased cell volume, whereas angiotensin II (< 4 x 10(-9) M) did not affect cell volume. When chloride was removed from the medium (replacing chloride with the impermeant methyl sulfate ion), cell volume decreased significantly, but basal aldosterone secretion was not altered. In the absence of chloride, the increases in cell volume, cytosolic calcium concentration, and aldosterone secretion induced by decreases in osmolality were significantly suppressed. The replacement of chloride with the methyl sulfate ion suppressed the increases in both cytosolic calcium concentration and aldosterone secretion induced by low (< 4 x 10(-9) M) but not high (4 x 10(-8) M) concentrations of angiotensin II. The results suggest that reductions in osmolality increase cell volume, partly by inducing an influx of chloride ions that contributes to the total net influx of water. Reductions in cell volume caused by an increase in osmolality or by replacing the chloride ion with the impermeant methyl sulfate ion may induce alterations in membrane stretch that may decrease the angiotensin II-induced increase in cytosolic calcium concentrations, which in turn suppresses aldosterone secretion. PMID- 7840343 TI - Allometry of pharmacokinetics and pharmacodynamics of the muscle relaxant metocurine in mammals. AB - We investigated the effects of body size on the pharmacokinetics and pharmacodynamics of the renally cleared muscle relaxant metocurine. We hypothesized that pharmacokinetics of the drug would change allometrically in proportion to physiological time [infinity Mb0.25, where Mb is body mass] and that pharmacodynamics would be independent of size because of the highly conserved structure of the acetylcholine receptor. Metocurine effects during general anesthesia were examined in 17 rats, 8 cats, 6 dogs, 5 pigs, 7 sheep, and 12 horses. Allometric analysis demonstrated size dependence for pharmacokinetics, which were affected by physiological time (Mb0.25). Pharmacodynamics were size independent, except for the value for effect compartment concentration associated with 50% twitch paralysis (IC50). Data from individual species had a bimodal distribution that was significant: pigs and sheep were more sensitive than other large species, and their IC50 appeared size independent. IC50 was size dependent in more active species (horse, dog, cat, rat). Although the mechanism is unknown, we speculate that this trend might relate to receptor density within the end plate. Thus pharmacokinetics changed in proportion to physiological time, and pharmacodynamics were in part size independent. PMID- 7840344 TI - HSP70 induction during exercise and heat stress in rats: role of internal temperature. AB - The purpose of this study was to determine if the accumulation of the 72-kDa heat shock protein (HSP70) is elevated in response to a prolonged bout of submaximal exercise in which colonic temperature (Tco) remained at control levels. Sprague Dawley rats were randomly assigned to one of four testing groups [n = 8 per group; ambient temperatures (Ta) for each condition are included]: 1) control (cool/rest; Ta = 24 degrees C); 2) cool and exercise (cool/exercise; Ta = 14 degrees C); 3) nonexertional heating (heat/rest; Ta = 42 degrees C); 4) heat and exercise (heat/exercise; Ta = 32 degrees C). All interventions were approximately 60 min in duration. An exercise bout consisted of treadmill running at 17 m/min and 0% grade, while the heat/rest and heat/exercise experiments consisted of heat exposure that was terminated when Tco reached 41 degrees C. Baseline Tco was similar for all four groups. In the cool/rest and cool/exercise groups, final Tco was not different from the baseline values, nor was it different between these two groups. In the heat/rest and heat/exercise groups, heating rates were similar. Tissue samples were obtained from the gastrocnemius, soleus, and extensor digitorum longus (EDL) muscles of the left hindlimb and the left ventricle 30 min after a trial was completed. An enzyme-linked immunosorbent assay specific for HSP70 was used to directly quantitate absolute levels of HSP70 in tissues. There were significant main effects of both heating and exercise for HSP70 levels in the gastrocnemius, soleus, and left ventricle (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7840345 TI - Apparent lack of beta 3-adrenoceptors and of insulin regulation of glucose transport in brown adipose tissue of guinea pigs. AB - Norepinephrine-induced thermogenesis was substantial in adipocytes from brown adipose tissue (BAT) of cold-acclimated guinea pigs but absent in adipocytes from BAT of warm-acclimated guinea pigs. There was no thermogenic response to any beta 3-adrenergic agonist (CL-316,243, ZD-7114, BRL-28410, CGP-12177). The receptor was characterized as a beta 1-adrenoceptor. Adrenergic agonists stimulated adenylate cyclase in membranes from BAT of both warm- and cold-acclimated guinea pigs also via a beta 1-adrenoceptor; beta 3-adrenergic agonists had no effect. Glucose transport by brown adipocytes from warm-acclimated guinea pigs was not stimulated by either norepinephrine or insulin. Cold acclimation induced the appearance of stimulation of glucose transport by norepinephrine in association with the appearance of a large capacity for thermogenesis, but there was little improvement in response to insulin. GLUT4 was present in membranes from BAT of both warm- and cold-acclimated guinea pigs. Insulin is known to have an antilipolytic effect on both BAT and white adipose tissue of guinea pigs. Thus there is a selective lack of insulin-regulated glucose transport that is not improved by cold acclimation. Guinea pigs may have a mutated component of the translocation mechanism for GLUT4. beta 3-Adrenoceptors appear to be absent in brown adipocytes of adult guinea pigs, as in white adipocytes of guinea pigs, yet are known to be present in the gut. Tissue-specific expression of beta 3 adrenergic receptors in guinea pigs may differ from that in rats, in which receptors are expressed in the adipose tissues and gut. PMID- 7840346 TI - The validation of psychiatric diagnosis: new models and approaches. PMID- 7840347 TI - Unstable genes--unstable mind? AB - OBJECTIVE: Over the past 3 years, reports of DNA alteration in myotonic dystrophy, fragile X syndrome (types A and E), Kennedy's disease, Huntington's disease, spinocerebellar ataxia type 1, and dentatorubral-pallidoluysian atrophy have identified a new class of human mutation, referred to as trinucleotide repeat amplification. All available evidence suggests that this unstable trinucleotide repeat DNA is the biological basis of the clinical phenomenon of genetic anticipation. Two components of anticipation, greater severity and earlier age at onset in subsequent generations, have been widely observed in schizophrenia and bipolar affective disorder. Thus, a reanalysis of the genetics of major psychosis from the perspective of unstable DNA is of significant interest. METHOD: The authors reviewed the available literature on anticipation and related phenomena in major psychosis and reevaluated the family, twin, and adoption study data. RESULTS: The unstable DNA concept competes well with the traditional multifactorial polygenic theory; many deviations from a single gene mode of inheritance in psychiatric twin and family studies, which previously served as strong proof for more than one etiologic gene, can be easily explained by the non-Mendelian behavior of unstable DNA. In addition, this new paradigm provides a simple explanation for unclear issues in the genetics of major psychosis, such as the identical rate of psychosis in the offspring of discordant monozygotic twins. CONCLUSIONS: The major advantage of the unstable DNA hypothesis over the multifactorial polygenic theory lies in the possibility of falsifying the unstable DNA hypothesis by two independent laboratory strategies: a classical linkage analysis and a set of novel methods for the direct detection of unstable DNA sites. PMID- 7840348 TI - D2 dopamine receptor occupancy during low-dose treatment with haloperidol decanoate. AB - OBJECTIVE: The aim of this study was to examine the relationships among clinical effects, central D2 dopamine receptor occupancy, and plasma concentrations of haloperidol in eight clinically stabilized schizophrenic outpatients who were responding to treatment with low doses of haloperidol decanoate. METHOD: During a 4-week interval of haloperidol decanoate dosage (dose range = 30-50 mg), the patients' D2 receptor occupancy was determined with positron emission tomography on two occasions. Plasma concentrations of haloperidol were determined with a sensitive high-performance liquid chromatography method. RESULTS: One week after injection of haloperidol decanoate, the mean D2 receptor occupancy was 73% (range = 60%-82%), and the mean plasma concentration of haloperidol was 4.6 nmol/liter (range = 2.9-9.7). After 4 weeks, the mean D2 receptor occupancy had decreased to 52% (range = 20%-74%), and the mean haloperidol concentration to 2.3 nmol/liter (range = 1.0-4.4). CONCLUSIONS: The D2 receptor occupancy 1 week after injection was high and comparable to that previously found in patients responding to acute treatment with classic neuroleptics. Prevention of relapse was maintained despite low D2 receptor occupancy during the latter part of the treatment interval. These observations indicate that continuously high D2 receptor occupancy may not be necessary to prevent schizophrenic relapses. The results emphasize the need for systematic clinical evaluation of intermittent low-dose treatment strategies. PMID- 7840349 TI - Plasma clozapine levels and clinical response for treatment-refractory schizophrenic patients. AB - OBJECTIVE: The purpose of this study was to determine if plasma clozapine levels were associated with treatment response. METHOD: To examine this question, neuroleptic nonresponsive patients with schizophrenia or schizoaffective disorder were given clozapine, which was titrated to 500 mg/day by day 14 of treatment, and the dose was held fixed at least through day 21. Subsequently, clozapine doses were adjusted as clinically indicated, up to a maximum of 900 mg/day. Plasma clozapine levels were obtained at weeks 3 and 6, and standard clinical ratings (Brief Psychiatric Rating Scale [BPRS] and Clinical Global Impression) were done at baseline and at weeks 3 and 6. RESULTS: Data from 45 subjects were analyzed. There were no correlations between plasma clozapine levels and change in BPRS scores at treatment weeks 3 and 6. However, when the subjects were classified as responders or nonresponders, therapeutic response was associated with clozapine blood levels above 350 ng/ml. CONCLUSIONS: This study suggest that clozapine blood levels are correlated with clinical response. PMID- 7840350 TI - Reduction of suicidality during clozapine treatment of neuroleptic-resistant schizophrenia: impact on risk-benefit assessment. AB - OBJECTIVE: Suicide has been reported to occur in 9%-13% of schizophrenic patients. It has been suggested that neuroleptic-resistant or neuroleptic intolerant schizophrenic patients are at higher risk for suicide than neuroleptic responsive patients. Clozapine is the treatment of choice for neuroleptic resistant patients, but its use has been greatly limited because of its ability to cause potentially fatal agranulocytosis. The purpose of this study was to compare the suicidality of neuroleptic-resistant and neuroleptic-responsive patients and to determine if clozapine treatment decreased suicidality in the former group. METHOD: Prior episodes of suicidality were assessed in a total of 237 neuroleptic-responsive and 184 neuroleptic-resistant patients with schizophrenia or schizoaffective disorder. Eighty-eight of the neuroleptic resistant patients were treated with clozapine and prospectively evaluated for suicidality for periods of 6 months to 7 years. RESULTS: There was no significant difference in prior suicidal episodes between neuroleptic-responsive and neuroleptic-resistant patients. Clozapine treatment of the neuroleptic-resistant patients during the follow-up period resulted in markedly less suicidality. The number of suicide attempts with a high-probability of success decreased from five to zero. This decrease in suicidality was associated with improvement in depression and hopelessness. CONCLUSIONS: These results suggest a basis for reevaluation of the risk-benefit assessment of clozapine, i.e., that the overall morbidity and mortality of patients with neuroleptic-resistant schizophrenia are less with clozapine treatment than with typical neuroleptic drugs because of less suicidality. This conclusion also has implications for increasing the use of clozapine with neuroleptic-responsive patients. PMID- 7840351 TI - Neurological soft signs in neuroleptic-naive and neuroleptic-treated schizophrenic patients and in normal comparison subjects. AB - OBJECTIVE: The goal of this study was to assess neurological soft signs and developmental reflexes in schizophrenic patients who had never received neuroleptic medication and those who were receiving neuroleptic medication. METHOD: Neurological soft signs and developmental reflexes were examined in 26 schizophrenic patients who had never received a neuroleptic, 126 schizophrenic patients who were currently receiving neuroleptics, and 117 normal subjects. RESULTS: Soft signs were present in 23% of the neuroleptic-naive and 46% of the medicated schizophrenic patients. Developmental reflexes were present in 19% of the neuroleptic-naive and 12% of the medicated patients. Both soft signs and developmental reflexes were absent in the normal subjects. There were significant differences between patients and normal subjects in neurological soft signs and developmental reflexes. The possibly confounding variables of age, age at onset, duration of illness, number of hospitalizations, Abnormal Involuntary Movement Scale (AIMS) scores, and Simpson-Angus Scale extrapyramidal symptom scores were assessed by using logistic regression in the patients who were receiving neuroleptics. AIMS scores and Simpson-Angus Scale scores correlated with soft signs in these patients. CONCLUSIONS: The presence of neurological soft signs in schizophrenic patients who had never received neuroleptics indicates that these signs are present independent of medication effects, but it is possible that neuroleptics contribute to the prevalence of these abnormalities, as demonstrated by the patients who were receiving neuroleptics. PMID- 7840352 TI - Severity of symptoms in chronically institutionalized geriatric schizophrenic patients. AB - OBJECTIVE: The goal of this study was to characterize the symptoms of geriatric, chronically ill, institutionalized schizophrenic patients and investigate age related differences in schizophrenic symptoms and cognitive performance from early adulthood to late senescence. METHOD: The Positive and Negative Syndrome Scale and the Mini-Mental State examination were used to assess the schizophrenic symptoms and cognitive performance, respectively, of 393 institutionalized schizophrenic patients stratified into seven groups designated by 10-year age intervals from 25 years to over 85 years. RESULTS: In the comparisons of the seven age groups, significant differences between groups in positive and negative subscale scores on the Positive and Negative Syndrome Scale and in Mini-Mental State scores were revealed. Significant correlations between Mini-Mental State scores and Positive and Negative Syndrome Scale negative symptom scores, but not positive symptom scores, were found for all age groups, except for the youngest patients studied. Current treatment with neuroleptics and prior treatment with ECT, insulin coma, or leukotomy could not account for the poor cognitive performance of the older schizophrenic patients. CONCLUSIONS: The older schizophrenic patients continued to experience psychotic and nonpsychotic symptoms in senescence. Their positive symptoms were moderately less severe and their negative symptoms and cognitive impairment were significantly more severe than those of the younger patients. Somatic treatment appeared not to be responsible for the severe cognitive impairment and negative symptoms of the older patients. These data are relevant to chronically hospitalized geriatric schizophrenic patients but not necessarily to all geriatric schizophrenic patients. PMID- 7840353 TI - Gender and age at onset in schizophrenia: impact of family history. AB - OBJECTIVE: The 1-year prevalence of schizophrenia was studied in a limited geographical area of Reunion Island (Indian Ocean) to assess the impact of family history of schizophrenia on the well-known association between gender and age at onset. METHOD: The population of schizophrenic patients meeting the DSM-III-R criteria for schizophrenia (N = 663) was identified and divided according to the presence of another schizophrenic patient among the first- and second-degree relatives. RESULTS: As previously reported, the median age at onset differed between the sexes: the males had an earlier onset (mean age = 27.8 years) than the females (31.5 years). Comparison of the ages at onset according to family history revealed that onset was later for female subjects with a negative family history than for the three other groups (i.e., males with or without a family history and females with a family history). No difference emerged in the comparison of the ages at onset of the males and females with a positive family history. CONCLUSIONS: Comparison of schizophrenic patients with familial versus sporadic disorder confirms the absence of a gender effect for age at onset in the subgroup with familial disorder. This approach also demonstrates the existence of a subgroup composed of affected females having late onset and no family history of schizophrenia. PMID- 7840354 TI - Brain potential evidence for an auditory sensory memory deficit in schizophrenia. AB - OBJECTIVE: The multiple disorders of selective attention found in schizophrenia could be secondary to disturbances in sensory processing. The authors investigated this possibility by using an event-related potential index of auditory sensory memory, called "mismatch negativity." METHOD: Medicated (N = 11) and neuroleptic-free (N = 11) patients with schizophrenia and patients with bipolar affective disorder (N = 11) were compared with age- and sex-matched healthy comparison subjects. Auditory stimuli were presented while the subjects were distracted with an attention-demanding visual task. Event-related potentials were elicited by infrequently occurring auditory stimuli (deviants) and by regularly presented auditory stimuli (standards), which differed slightly in duration. The difference in amplitude between the event-related potentials elicited by the deviant and standard stimuli was the mismatch negativity. RESULTS: The amplitude of the mismatch negativity was significantly lower in both groups of schizophrenic patients than in the healthy comparison subjects. Mismatch negativity amplitude was significantly correlated with ratings of negative schizophrenic symptoms but not with positive symptoms. Compared with the matched comparison subjects, the bipolar affective disorder patients did not show lower amplitude of mismatch negativity. There was a significant negative correlation between age and mismatch negativity amplitude. CONCLUSIONS: The abnormal auditory sensory memory processing indicated by low mismatch negativity amplitude in the schizophrenic patients cannot be accounted for by neuroleptic medication status. Because this abnormality was significantly related to measures of negative symptoms only, it may be a chronicity marker or reflect a predisposition to the development to schizophrenia. These findings implicate the auditory cortex in the pathophysiology of schizophrenia. PMID- 7840355 TI - Spurious precision: procedural validity of diagnostic assessment in psychotic disorders. AB - OBJECTIVE: Very few studies have quantified the level of agreement among alternative diagnostic procedures that use a common set of fixed operational criteria. The authors examined the procedural validity of four independent methods of assigning DSM-III-R diagnoses of psychotic disorders. METHOD: The research was conducted as a satellite study to the DSM-IV Field Trial for Schizophrenia and Related Psychotic Disorders. The setting was the National Health and Medical Research Council Schizophrenia Research Unit's Early Psychosis Prevention and Intervention Centre, which focuses on first-episode psychosis. Consecutively admitted patients (N = 50) were assessed by independent raters who used four different procedures to determine a DSM-III-R diagnosis. These procedures were 1) the diagnostic instrument developed for the DSM-IV field trial, 2) the Royal Park Multidiagnostic Instrument for Psychosis, 3) the Munich Diagnostic Checklists, and 4) a consensus DSM-III-R diagnosis assigned by a team of clinician researchers who were expert in the use of diagnostic criteria. RESULTS: Concordance between pairs of diagnostic procedures was only moderate. Corresponding levels of percent agreement, however, ranged from 66% to 76%, with converse misclassification rates of 24%-34% (assuming one procedure to be "correct"). CONCLUSIONS: These findings have significant research and clinical implications. Despite the introduction of operationally defined diagnoses, there remained an appreciable level of differential classification or misclassification arising from variability in the method of assigning the diagnostic criteria rather than the criteria themselves. Such misclassification may impede neurobiological research and have harmful clinical effects on patients with first episode psychosis. PMID- 7840356 TI - Postictal and chronic psychoses in patients with temporal lobe epilepsy. AB - OBJECTIVE: This study sought to elucidate the relation of clinical, neuropsychological, and seizure variables to chronic and postictal psychoses in patients with temporal lobe epilepsy. METHOD: Forty-four patients with treatment refractory temporal lobe epilepsy were given formal psychiatric evaluations; 29 patients had no psychiatric disorder or a nonpsychotic disorder, eight patients had postictal psychoses, and seven patients had chronic psychoses. Comparisons of clinical, neuropsychological, magnetic resonance imaging, and seizure variables were made between the nonpsychotic and the psychotic patients and, secondarily, between the patients with transient postictal psychoses and those with chronic psychoses. RESULTS: Bitemporal seizure foci, clustering of seizures, and absence of febrile convulsions were associated with both postictal psychoses and chronic psychoses. Younger age at onset of epilepsy and lower verbal and full-scale IQs differentiated the patients with chronic psychoses from those with postictal psychoses. CONCLUSIONS: Patients with temporal lobe epilepsy with chronic and postictal psychoses show similar profiles of clinical and seizure variables, suggesting shared etiologic factors. These factors may increase the propensity to develop psychotic symptoms, while other factors, such as time of onset of epilepsy and underlying neuropathology, may determine whether transient or chronic psychotic symptoms develop. Even among patients with treatment-refractory temporal lobe epilepsy, a specific subgroup of patients, characterized by bitemporal seizure foci, an absence of febrile convulsions, and a history of clustering of seizures, appears to be particularly prone to develop psychotic disorders. A process similar to secondary epileptogenesis may be involved in the development of the psychoses. PMID- 7840357 TI - Relationship between hypomania and personality disorders before and after successful treatment. AB - OBJECTIVE: To examine the effect of hypomanic states on maladaptive personality traits and personality disorders, the authors evaluated personality traits and disorders of patients during an episode of hypomania and after successful somatic treatment. METHOD: The authors used the Structured Interview for DSM-III Personality Disorders to study 66 outpatients who had a lifetime diagnosis of bipolar disorder and who met the minimum Research Diagnostic Criteria for hypomania. All patients had a knowledgeable informant separately undergo the Structured Interview for DSM-III Personality Disorders during the patient's hypomanic state. Outpatients who successfully recovered from the hypomanic episode (N = 47) and their informants were read-ministered the interview 4-8 weeks after the initial assessment. RESULTS: During the hypomanic state, informants generally reported higher levels of maladaptive personality traits among patients than patients themselves. For the patients who recovered successfully from the hypomanic episode, a reduction in all maladaptive personality traits except schizoid and dependent traits was reported by both patients and their informants; however, the decrease reported by patients generally was much greater than that reported by informants. In addition, schizoid traits actually increased after successful treatment according to patient reports but were unchanged according to informant reports. CONCLUSIONS: Hypomania may be associated with an exacerbation of maladaptive personality traits, which may be attenuated after successful treatment. Even with the attainment of euthymic mood, however, about 50% of the cohort had at least one personality disorder, which suggests that a high degree of comorbidity may exist between bipolar disorders and maladaptive personality traits or personality disorders. PMID- 7840358 TI - DSM-III-R axis II comorbidity in dysthymia and major depression. AB - OBJECTIVE: Dysthymia is generally believed to be associated with a high rate of DSM-III-R axis II comorbidity. However, it is unclear whether this rate is higher than that for other axis I disorders, how many dysthymic patients have personality disorders, and what the most common co-occurring axis II conditions are. METHOD: Ninety-seven outpatients with early-on-set dysthymia and 45 with episodic major depression were administered structured diagnostic interviews for axis I and II disorders. In addition, knowledgeable informants were independently interviewed about axis II conditions in the patients. RESULTS: A significantly greater proportion of dysthymic patients (60%) than patients with episodic major depression (18%) met criteria for a personality disorder. The most common axis II conditions among dysthymic patients were borderline, histrionic, and avoidant personality disorder. Informants' reports yielded similar results. CONCLUSIONS: These data indicate that early-onset dysthymia is associated with significantly greater axis II comorbidity than episodic major depression. Further work is necessary to elucidate the processes underlying this association. PMID- 7840359 TI - Delayed maturation of the frontal cortex in childhood autism. AB - OBJECTIVE: The authors investigated the metabolic maturation of the frontal cortex in pre-school autistic children. METHOD: Regional cerebral blood flow (CBF) in five children with primary autism diagnosed according to the DSM-III-R criteria was studied longitudinally. Regional CBF in each of the autistic children was measured with single photon emission computed tomography twice during their development: at the age of 3-4 years and 3 years later. At each stage, the autistic children were compared to an age-matched comparison group of five nonautistic children with normal development. RESULTS: A transient frontal hypoperfusion was found in the autistic children at ages 3-4 years; this corresponded to the pattern of perfusion observed in much younger normal children. By the ages of 6-7, the autistic children's frontal perfusion had attained normal values. CONCLUSIONS: Since CBF patterns in children are related to maturational changes in brain function, these results indicate a delayed frontal maturation in childhood autism. Such a delayed brain maturational process is consistent with the clinical data and cognitive performance of autistic children. PMID- 7840360 TI - Changes in pathological narcissism. AB - OBJECTIVE: This study investigated types of change that occur over time in the psychopathology of narcissistic patients. METHOD: Baseline scores on the Diagnostic Interview for Narcissism of 20 patients, clinically diagnosed as having narcissistic personality disorder, were contrasted with their scores 3 years later by means of t tests and chi-square statistics. The authors then compared these changes in narcissism with the patients' accounts of their life events during the interval between the two assessments. RESULTS: A significant decrease in the overall level of pathological narcissism was found, particularly in the areas of interpersonal relations and reactiveness. At follow-up, 60% of the subjects had reached the cutoff score on the diagnostic interview that indicated significant improvement, and 40% remained unchanged, with a high level of pathological narcissism. A high baseline level of narcissism in interpersonal relations was associated with absence of change at follow-up. Examination of life events in the interval between assessments suggests that changes in pathological narcissism are related to three kinds of experiences: achievements, new durable relationships, and disillusionments. CONCLUSIONS: The instability of narcissistic psychopathology found in this study raises questions about the construct validity of narcissistic personality disorder as a diagnostic category and about the core construct of pathological narcissism. PMID- 7840361 TI - Demographic and clinical comparison of obsessional followers and offenders with mental disorders. AB - OBJECTIVE: The purpose of this study was to compare certain demographic and clinical variables in a group of obsessional followers and in a group of offenders with mental disorders. METHOD: A static group design comprised of a nonrandom group of convenience and a randomly selected comparison group was used. Twenty obsessional followers in custody and 30 offenders with mental disorders in custody were evaluated by psychiatrists and psychologists for court-ordered reasons during their criminal proceedings. Both groups were evaluated during the same period, in the same court diagnostic clinic, and for the same psycholegal reasons. The group of obsessional followers was measured on demographic, clinical, and victim variables. Inferential comparisons that used nonparametric statistics were done between groups on selected demographic and clinical variables. RESULTS: The obsessional followers were significantly older, more intelligent, and better educated than the offenders. There were no significant differences in DSM-III-R axis I diagnoses. Axis II diagnoses showed significant differences, with the obsessional followers more likely to have a personality disorder other than antisocial personality disorder and less likely to have antisocial personality disorder. CONCLUSIONS: The likelihood of obsessional followers having a nonantisocial axis II personality disorder (related to attachment pathology) distinguishes them from offenders with mental disorders in general. They are also likely to be older, smarter, and better educated, consistent with their resourcefulness and manipulativeness. Idiographic aspects of the obsessional followers further illuminate their psychological defenses and object relations. PMID- 7840363 TI - Aspects of depression associated with borderline personality disorder. AB - OBJECTIVE: Shared symptoms between borderline personality disorder and depression have resulted in inherent difficulties in evaluating the relationship between these disorders. Some theorists have argued that depression in patients with borderline personality disorder is qualitatively distinct from depression in nonborderline patients. The purpose of this study was to empirically identify aspects of depression most associated with borderline personality disorder. METHOD: Through interview and self-report measures, the authors studied depression in 50 inpatients, 21 of whom had borderline personality disorder. RESULTS: The aspects of depression most associated with borderline personality disorder were self-condemnation, emptiness, abandonment fears, self destructiveness, and hopelessness; boredom and somatic complaints exhibited no association. CONCLUSIONS: Depression associated with borderline pathology appears to be in some respects unique, as well as distinct from nonborderline depression. The study's implications delineate the importance of considering the phenomenological aspects of depression in borderline personality disorder. PMID- 7840362 TI - Dexamethasone for the treatment of depression: a randomized, placebo-controlled, double-blind trial. AB - OBJECTIVE: The authors' goal was to assess dexamethasone for the treatment of depression. METHOD: Thirty-seven outpatients (11 men and 26 women) meeting DSM III-R criteria for major depressive disorder were randomly assigned to receive either placebo or 4 mg/day of oral dexamethasone for 4 days. Baseline Hamilton depression scale scores were compared with scores obtained 14 days after the first dose of study medication. Data were analyzed by using two-sample t tests, chi-square methods, and Fisher's exact test. RESULTS: Seven (37%) of the 19 patients given dexamethasone but only one (6%) of the 18 patients given placebo responded positively. No adverse events or side effects were reported, and all patients who entered the study completed it. CONCLUSIONS: A brief course of oral dexamethasone (4 days) was significantly more effective than placebo within 14 days for the treatment of depression in a randomized, double-blind study of depressed outpatients. PMID- 7840364 TI - Attention deficit hyperactivity disorder in adolescent mania. AB - OBJECTIVE: The purpose of this study was to examine the rate of attention deficit hyperactivity disorder in adolescents with bipolar disorder and to explore the potential effects of comorbid attention deficit hyperactivity disorder on the phenomenology of adolescent bipolar disorder. METHOD: The authors assessed the rate of attention deficit hyperactivity disorder for adolescents with bipolar disorder who were hospitalized for treatment of acute mania or hypomania. RESULTS: Eight (57%) of 14 adolescent bipolar patients also met DSM-III-R criteria for attention deficit hyperactivity disorder. Patients with both disorders were more likely to be male and Caucasian and to have mixed rather than manic bipolar disorder. Patients with attention deficit hyperactivity disorder had a higher mean total score on the Young Mania Rating Scale than patients with bipolar disorder alone. CONCLUSIONS: Although preliminary, these findings may have important implications regarding the potential relationship between bipolar disorder and attention deficit hyperactivity disorder. PMID- 7840365 TI - REM sleep enhancement by bupropion in depressed men. AB - OBJECTIVE: The authors compared the effects of bupropion, fluoxetine, and cognitive behavior therapy on EEG sleep in depressed subjects. METHOD: All-night sleep EEG studies were performed before treatment and after partial or full remission on 18 men with depression diagnosed according to Research Diagnostic Criteria and randomly assigned to treatment with either bupropion (N = 7) or fluoxetine (N = 11). Response to these drugs was measured by changes in Hamilton Depression Rating Scale scores. Pre- and posttreatment EEG sleep study results before and after treatment with cognitive behavior therapy were also available for 18 men matched in age and severity of Hamilton depression scale score, and one-time EEG sleep measures were available for 36 men who were not depressed. RESULTS: REM latency was reduced and REM sleep percent and REM time increased after treatment in the depressed men given bupropion. These effects contrasted with the effects of fluoxetine and cognitive behavior therapy. CONCLUSIONS: This study represents the first report of an antidepressant medication that shortens REM latency and increases REM sleep. If confirmed, this finding may require a revision of our current understanding of the relation among depression, REM sleep, and anti-depressant mechanisms. PMID- 7840367 TI - Comorbidity of panic disorder in bipolar illness: evidence from the Epidemiologic Catchment Area Survey. AB - OBJECTIVE: The authors' goal was to determine the rate of comorbid panic disorder in individuals with bipolar disorder. METHOD: They used the Epidemiologic Catchment Area survey database to determine the prevalence of comorbid panic disorder in individuals with unipolar depression, those with bipolar disorder, and comparison subjects without bipolar or unipolar disorder. RESULTS: The lifetime prevalence of panic disorder among subjects with bipolar disorder was 20.8%; among subjects with unipolar depression it was 10.0%, and among comparison subjects it was 0.8%. CONCLUSIONS: Individuals with bipolar disorder have a particularly high risk of comorbid panic disorder. The evaluation of patients with bipolar disorder should include screening for panic disorder. PMID- 7840366 TI - Sodium lactate response and familial risk for panic disorder. AB - OBJECTIVE: The authors used the family study method to test the hypothesis that sodium lactate response defines two subtypes of panic disorder. METHOD: Rates of panic disorder in 142 first-degree relatives of patients who responded to sodium lactate, 88 first-degree relatives of patients who did not respond to sodium lactate, and 231 first-degree relatives of never mentally ill subjects were compared. RESULTS: No difference in familial transmission of panic disorder was found between the two patient groups. CONCLUSIONS: The findings do not support the notion that panic disorder subtypes are associated with lactate sensitivity. PMID- 7840368 TI - Treatment of coprophagia with carbamazepine. PMID- 7840369 TI - Acute organic brain syndrome after fluoxetine treatment. PMID- 7840370 TI - Delirium in a patient treated with disulfiram and tranylcypromine. PMID- 7840371 TI - Clozapine-induced toxic hepatitis. PMID- 7840372 TI - Possible association of parotitis with clozapine. PMID- 7840373 TI - Clozapine-induced constipation. PMID- 7840374 TI - Origin of stimulant use for treatment of attention deficit disorder. PMID- 7840375 TI - What happened at Cornell. PMID- 7840376 TI - Anxiety sensitivity and cholecystokinin tetrapeptide challenge. PMID- 7840377 TI - Another look at oppositional defiant disorder. PMID- 7840378 TI - Development and characterization of normal colonic epithelial cell lines derived from normal mucosa of patients with colon cancer. AB - BACKGROUND: Researchers have tried for at least 20 years to develop a normal human colonic cell line suitable for in vitro studies of human colonic diseases. We report a breakthrough development of two normal colon-derived cell lines. They are designated NCM356 and NCM425. MATERIALS AND METHODS: The cells were collected from the histologically normal colonic margin of patients undergoing resection for colon adenocarcinomas and grown in culture. RESULTS: Since NCM356 and NCM425 have now been subcultured 22 and 19 times, each has undergone more than 40 population doublings. Neither cell line has shown evidence of terminal differentiation. Immunohistochemical characterization studies demonstrated that they are epithelial cells. They variably expressed subsets of other markers, including tumor markers, but did not grow in soft agar. NCM356 did not form tumors, whereas NCM425 was tumorigenic in immunodeficient mice. CONCLUSION: These two cell lines represent the first successful in vitro culture of human colonocytes derived from normal mucosa. NCM356 is closer to normal, but seems to represent an early stage of cell transformation, possibly correlated with immortalization. In contrast, in vitro culture of the NCM425 cell line appears to have selected for later progression to malignancy. These lines are important resources for studying colon cancer and the physiology of intestinal cells. PMID- 7840379 TI - Analysis of nutrient hepatic blood flow after 8-mm versus 16-mm portacaval H grafts in a prospective randomized trial. AB - BACKGROUND: In previous unrandomized studies, we demonstrated that patients undergoing 8-mm diameter portacaval H-grafts with collateral ablation (partial shunts) have lower rates of portasystemic encephalopathy (PSE) postoperatively than patients undergoing total portacaval shunts. We postulated that nutrient hepatic blood flow was greater after partial shunts because 8-mm grafts preserved some portal flow. METHODS: To test this hypothesis, we analyzed hepatic hemodynamics in 18 of 30 randomized patients who consented to be studied after complete operative recovery, grouped according to shunt size. We measured nutrient hepatic blood flow using 99m-Tc-Mebrofenin tracer elimination kinetics, and fractionated it into its portal venous and hepatic arterial components. PSE was assessed by blinded observers. Stepwise logistic regression was used to select the variable that best predicted encephalopathy. From 1989 to 1993, we conducted a randomized, prospective trial of partial (8 mm) versus total (16 mm) portacaval H-grafts. Group differences were compared using one-way analysis of variance (ANOVA). RESULTS: Hepatic encephalopathy occurred in 2 of 10 patients with partial shunts versus 5 of 8 patients with total shunts. Nutrient hepatic blood flow was significantly higher for partial shunts compared with total shunts (403 +/- 601 versus 243 +/- 17mL/min). Three variables--nutrient hepatic blood flow, portal blood flow, and hepatic arterial flow--were analyzed by stepwise logistic regression. Nutrient hepatic blood flow was selected as the best predictor of hepatic encephalopathy. In this series, PSE did not occur in any patient with more than 325 mL/min of nutrient hepatic blood flow. CONCLUSION: These findings provide a physiologic basis for clinical observations demonstrating a lower incidence of PSE with partial shunts and indicates the superiority of partial over total shunts. Partial shunts, by preserving portal flow, maintain higher nutrient hepatic blood flow than total shunts and thus minimize PSE rates. PMID- 7840380 TI - Benefits of pulmonary artery catheter and transesophageal echocardiographic monitoring in laparoscopic cholecystectomy patients with cardiac disease. AB - BACKGROUND: Because the abdominal insufflation and desufflation associated with laparoscopic procedures may adversely effect a compromised myocardium, patients with significant cardiopulmonary disease should be closely monitored during these procedures. The utility of intraoperative pulmonary artery catheter (PAC) and transesophageal echocardiography (TEE) monitoring was studied in 10 patients with moderate to severe cardiopulmonary disease to identify patients at greatest risk for cardiovascular complications during laparoscopic cholecystectomy. METHODS: Ten patients were enrolled in this prospective study; 7 had suffered a previous myocardial infarction, 6 had undergone coronary artery bypass grafting, and 9 had disease classified as Goldman's class II or greater. The heart was monitored by TEE throughout the laparoscopic cholecystectomy by using real-time, two dimensional mode to study the wall thickness and motion. Several PAC measurements were taken directly: cardiac output, systemic vascular resistance, pulmonary artery wedge pressure, and central venous pressure. Heart rate and blood pressure were also obtained at corresponding intervals. Cardiac index, stroke volume, and left and right ventricular stroke work were then calculated. RESULTS: TEE demonstrated no significant changes in ventricular wall motion throughout laparoscopy. In patients who had postoperative cardiovascular complications, significant changes in cardiac index, left ventricular stroke work, and stroke volume were seen after pneumoperitoneum release. Compared to that of patients who did not develop complications, the cardiac index in those with complications dropped 42% (3.10 +/- 0.72 versus 1.80 +/- 0.10 L/min per m2, respectively; P < 0.01); left ventricular stroke work dropped 64% (139.00 +/- 11.36 versus 50.38 +/ 10.55 g x min/beat, respectively; P < 0.01); and stroke volume dropped 51% (86.90 +/- 12.68 versus 42.50 +/- 5.08 mL/beat, respectively; P < 0.01). CONCLUSIONS: PCA monitoring in patients with compromised cardiac function is useful in identifying patients who may not tolerate hemodynamic changes after pneumoperitoneum release. Normalization of hemodynamic changes secondary to abdominal insufflation and desufflation in patients with compromised hearts may not occur in patients with compromised hearts may not occur for hours postoperatively. Abnormal hemodynamic changes occur within the first hour after desufflation in patients who later develop cardiovascular complications, which are heralded by significant drops in left ventricular stroke work, cardiac index, and stroke volume. TEE did not prove to be useful for intraoperative monitoring. PMID- 7840381 TI - A prospective, randomized comparison of laparoscopic appendectomy with open appendectomy. Laparoscopic Appendectomy Study Group. AB - BACKGROUND: While the advantages of laparoscopic cholecystectomy are clear, the benefits of laparoscopic appendectomy (LA) are more subtle. We conducted a randomized clinical trial to evaluate whether LA is deserving of more widespread clinical application than it has yet received. MATERIALS AND METHODS: Two hundred fifty-three patients with a preoperative diagnosis of acute appendicitis were randomized into three groups. LA with an endoscopic linear stapler (LAS) (U.S. Surgical Corp., Norwalk, Connecticut) was performed on 78 patients, LA with catgut ligatures (LAL) on 89, and open appendectomy (OA) on 86. LA was performed with a three-trocar technique. OA was accomplished through a right lower-quadrant transverse incision. Data with normal distributions were analyzed by analysis of variance. Nonparametric data were analyzed with either the Kruskal-Wallis H test or Fisher's exact test. RESULTS: The mean operative times for the procedures were 66 +/- 24 minutes (LAS), 68 +/- 25 minutes (LAL), and 58 +/- 27 minutes (OA). The relative brevity of OA compared to LAS and LAL was statistically significant (P < 0.01). Conversion to open procedures was approximately as frequent in the LAS group (n = 5) and the LAL (n = 6). One OA, 2 LAS, and 11 LAL patients experienced vomiting postoperatively (P < 0.05). Two intra-abdominal abscesses occurred in LAS, 4 in LAL, and 0 in OA patients (P = NS). Wound infections were more common following OA (n = 11) than LAL (n = 4) or LAS (n = 0) (P < 0.05, < 0.001). The mean length of postoperative hospital stay was 2.16 +/- 3.2 days (LAS), 2.98 +/- 2.7 days (LAL), and 2.83 +/- 1.6 (OA) (P < 0.05 OA versus LAS). The number of days patients required pain medications overall was not different between groups, but a subgroup analysis of 134 patients who rated their postoperative pain on a visual analogue scale revealed a significantly lower mean level among patients undergoing LA (LAS and LAL) versus OA (P < 0.001). Patients undergoing LA resumed regular activities sooner than those undergoing OA (9 +/- 9 days versus 14 +/- 11 days, P < 0.001). Rates of readmission to the hospital were similar for all procedures. CONCLUSIONS: Laparoscopic appendectomy appears to have distinct advantages over open appendectomy. The laparoscopic procedures produced less pain and allowed more rapid return to full activities, and LAS required shorter hospital stays. The only disadvantages to the laparoscopic approach were slightly increased operative time for both procedures, and increased emesis following LAL. PMID- 7840382 TI - Postoperative fatal pulmonary embolism in a general surgical department. AB - BACKGROUND: This retrospective study describes the cases of postoperative pulmonary embolism (PE) in a general surgical department during a 3-year period. METHODS: To analyze the cases of PE, all patient data from the hospital central registry of diagnoses, pulmonary ventilation/perfusion scintigraphies (V/P scans), and autopsy records from a hospital in Denmark for the 3-year period from August 1986 to August 1989 were reviewed. Antithrombotic prophylaxis was applied routinely according to standard instructions. A total of 2,049 emergency and 2,832 elective operations were performed. The PEs were verified by autopsy or perfusion/ventilation scintigraphy. RESULTS: Postoperative PE was verified in 30 patients, which is equivalent to an incidence of 0.6% (95% confidence limits: 0.4% to 0.8%). With correction for autopsy rate (65%) the incidence is estimated to be 1.0% (0.6% to 1.3%). The incidence of fatal PE was 0.4% (0.2% to 0.5%). Fatal PE was found in 8.6% (5.0% to 13.5%) of the patients who had an autopsy performed. The incidence of fatal postoperative PE among patients who received thromboprophylaxis was 3.5%, compared with 11.2% in patients who did not receive prophylaxis, P < 0.05. Pulmonary embolism occurred in 3 patients younger than 40 years, and in 12 patients who had undergone minor surgery. CONCLUSIONS: The results of this retrospective study suggest that the incidence of fatal PE is reduced by low-dose heparin prophylaxis, and that the risk of developing PE is not limited to patients subjected to major surgery or older than 40 years of age. It is concluded that the indications for antithrombotic prophylaxis should also include minor surgery and patients aged less than 40 years. A standard instruction is strongly recommended for thromboprophylaxis in surgery, especially when dealing with emergency surgery. PMID- 7840383 TI - Current experience with pancreatogastrostomy. AB - BACKGROUND: The reconstruction technique for the pancreatic remnant remaining after pancreatoduodenectomy has most frequently been pancreatojejunostomy. Although the mortality rate has been reduced to rather low levels in many centers, the leakage rate from this anastomosis remains high, in the range of 10% or greater. An alternative reconstruction, pancreatogastrostomy, has been known for almost 50 years and has been performed on small numbers of patients. The leakage rate for this anastomosis is less than 1% in literature reports in more than 200 patients. The purpose of this report was to add to the previously reported experience with this technique and to compare it with standard reconstruction as performed in a major American medical center by experienced surgeons. METHODS: The medical records of all patients operated on at the Loyola University Medical Center and the Edward Hines, Jr., Veteran's Affairs Hospital from August 1986 to May 1993, with a procedure code relating to the pancreas, were reviewed. RESULTS: A total of 58 Whipple procedures were identified, including 34 pancreatogastrostomies, 23 pancreatojejunostomies and 1 stapled pancreatic stump. No leaks in any pancreatogastrostomies were observed in the 38 patients so treated, whereas 4 leaks and 2 deaths related to the anastomosis occurred in the group of 23 patients with pancreatojejunostomies. The average length of stay was 14.2 days for the pancreatojejunostomy group and 15.5 days for the pancreatogastrostomy group, excluding duration data from those who died or experienced leakage. There was no significant difference in the length of stay between pancreatojejunostomy and pancreactogastrostomy; there was a statistically significant lengthening of stay for those patients whose anastomosis leaked versus those whose did not leak. The 10 patients having a pylorus-sparing operation had an average postoperative stay of 16 days, including both types of reconstruction. CONCLUSIONS: The gradual adoption of this procedure at a major medical center has led to the abandonment of pancreatojejunostomy as a reconstruction technique for the pancreatic remnant remaining after pancreatoduodenectomy. PMID- 7840384 TI - Traditional surgical management of common bile duct stones: a prospective study during a 20-year experience. AB - PURPOSE: To analyze the operative findings and evaluate the hospital morbidity and mortality. This experience is documented in order to provide a basis for comparison with therapeutic alternatives. PATIENTS AND METHODS: Prospective data were collected on 579 patients who underwent elective (n = 443) or emergent (n = 136) operations between 1970 and 1990. Their mean age was 60.1 years. Prior biliary symptoms were present in 96% and suggestive of choledocholithiasis in 69%. Acute pancreatitis was associated in 3%. RESULTS: Cholecystectomy was performed with intraoperative cholangiography in 85% of cases. Stones were extracted via the cystic duct in 18%, through a choledochotomy in 79%, and through an additional sphincterotomy in 3%. Cholangioscopy has been routinely used since 1977. The incidence of extraction of the stones via the cystic duct increased and the incidence of biliary-enteric bypass decreased significantly during the second decade. Complications occurred in 24.5% of the patients. General complications were significantly fewer in the second decade than in the first (6% versus 15%). The main biliary complications were related to biliary tubes (5%) and retained stones (5%). Ten patients (2%) required early reoperation. The overall mortality rate was 0.3%. Mortality was 1.4% after emergency operations and zero after elective operations and in patients under 60 years of age. The mean stay was 16.6 +/- 7.2 days, decreasing with time. CONCLUSION: Traditional open surgery is an effective and safe option for the management of cholelithiasis with choledocholithiasis. The choice between open surgery, laparoscopic surgery, and endoscopic sphincterotomy should be made for each patient according to the local availability and efficacy of these methods. PMID- 7840385 TI - Mechanisms of sepsis in acute pancreatitis in opossums. AB - PURPOSE: To study the incidence and pathways of colonization of the pancreas by specific bacteria in a model of necrotizing pancreatitis. METHODS: Bacteremia and splanchnic organ colonization were studied in the early course of necrotizing pancreatitis following common biliopancreatic duct ligation (BPDL) of the opossum. Nonoperated animals served as controls. Intestinal lymph nodes, liver, spleen, and pancreas were cultured following bacteremia or sacrifice. RESULTS: In opossums with sterile bile, bacteria were recovered from 28.6% of blood cultures after BPDL (n = 10) and from 12.0% in controls (n = 10, P < 0.05). Animals that underwent BPDL revealed enteric microorganisms in intestinal lymph nodes (6), liver (3), spleen (4), and pancreas (4). Ten animals carried Salmonella within their bile (5 controls, 5 BPDL animals). Following BPDL, they developed rapid bacteremia and colonization of organs, pancreatic ductal rupture, and extravasation of bacteria and bile into the interstitium. CONCLUSION: There are two possible mechanisms for the development of bacterial colonization in opossum pancreatitis: bacterial translocation of enteric organisms from gut lumen to mesenteric lymph nodes and subsequent hematogenous dissemination and transductal infestation from the biliary tract. PMID- 7840386 TI - Prognosis and recurrence patterns of anal adenocarcinoma. AB - BACKGROUND: Anal adenocarcinomas are rare cancers, constituting fewer than 10% of all anal cancers. This is a retrospective review of 10 patients with anal adenocarcinoma. PATIENTS AND METHODS: Seven men and 3 women with a median age of 59 years (range 38 to 82) participated in the study. Using the 1976 World Health Organization classification, 4 patients had the rectal type of cancer, 2 had the anal duct type, and 1 had the anorectal fistula type. The 3 remaining patients had unclassifiable tumors with solely extramucosal disease. Seven patients underwent abdominoperineal resection, 1 had a radical vulvectomy and proctectomy, and 2 had local excision. RESULTS: The median survival was 29 months (range 5 to 249). Seven patients developed a recurrence at the following sites: 2 perineal, 5 inguinal, and 5 distant metastases. Five patients died from their disease a median of 28 months after surgery, and 2 patients died of unrelated causes. Three patients are alive at a median of 54 months; 2 of these patients are free of disease and 1 has a perineal recurrence. CONCLUSION: Anal adenocarcinomas were found to be a rare, heterogeneous group of tumors with a poor prognosis despite radical surgery. PMID- 7840387 TI - Hemodynamic parameters of failing infrainguinal bypass grafts. AB - PURPOSE: To assess the relationship of duplex ultrasound hemodynamic parameters in stenotic vein grafts with events such as graft thrombosis or surgical revisions. PATIENTS AND METHODS: We studied 35 patent infrainguinal bypass grafts that were observed by means of color duplex graft mapping using a surveillance protocol. RESULTS: During the 11.2 month mean follow-up interval, 10 grafts developed complications. Two stenotic grafts (1 already revised) thrombosed spontaneously, and arteriography was obtained on the basis of either clinical indications or a decreased ankle/brachial index of greater than 0.15 on 9 bypasses, leading to 12 procedures (multiple procedures on 2 grafts). The 14 duplex examinations preceding an event showed these bypasses had increased focal peak systolic velocities that ranged from 250 to 600 cm/s and velocity ratios that ranged from 3.4 to 25.0 at the stenotic segment of the graft, anastomosis, or outflow artery. None of the grafts with a stenotic peak systolic velocity less than 250 cm/s or a velocity ratio less than 3.4 thrombosed spontaneously or required revision. CONCLUSION: We conclude that stenotic vein grafts with a focal peak systolic velocity of at least 250 cm/s or a velocity ratio of at least 3.4 are at increased risk for thrombosis or need for revision. Asymptomatic stenotic vein grafts with focal peak systolic velocities and ratios less than the above values may be safely observed without immediate risk for thrombosis. PMID- 7840388 TI - Can morbidly obese patients safely lose weight preoperatively? AB - BACKGROUND: Preoperative weight loss is often suggested as a means of reducing operative risk in obese patients requiring laparotomy but there are no large studies documenting that this is feasible or helpful. Although several commercial products are available that provide high levels of protein with low levels of carbohydrates in convenient liquid preparations, recommendations regarding the extent to which weight loss can be pursued preoperatively are not available. PURPOSE: To determine whether it is practical and safe to have obese patients lose weight preoperatively. PATIENTS AND METHODS: We asked 100 severely obese patients requesting gastric bypass surgery to diet before their operations. Seventy patients agreed to diet by consuming a 420 Kcal, 70 g protein liquid diet daily for at least 1 month. RESULTS: Forty-seven patients lost at least 7.5 kg (mean +/- SD 17.1 +/- 0.7). The patients who successfully lost weight preoperatively (dieters group) were significantly heavier than patients (nondieters group) who did not lose weight (251% +/- 45% of ideal body weight [IBW] versus 229% +/- 33% IBW, respectively; P < 0.01), had a significantly higher ratio of men to women, and had psychiatric evaluations and psychological test scores that suggested significantly more psychopathology. Other biosocial and medical characteristics were similar. Postoperatively, the dieters and nondieters had similar rates for morbidity. Dieters and nondieters had no differences in wound-healing complications, and subgroups who had collagen deposition measured experimentally had similar amounts of hydroxy-proline accumulation in their wounds. CONCLUSION: These results suggest that a preoperative diet program appeals more to certain subgroups of severely obese patients than to others. An aggressive preoperative weight loss program that encourages patients to lose an average of 17 kg is safe and can be accomplished practically using available commercial products. PMID- 7840389 TI - Is simultaneous hepatectomy and intestinal anastomosis safe? AB - BACKGROUND: To assess the safety of simultaneous, "one-stage," hepatectomy and intestinal anastomosis, we retrospectively studied 53 patients who underwent such a procedure, with 76 digestive tract sutures. They represented 80% of all the cases eligible for one-stage procedures among 332 liver resections for malignant tumors. METHODS: The medical records of the patients were retrospectively analyzed to assess details of the surgical procedures, postoperative mortality and morbidity, and postoperative liver function, with special attention being paid to the prothrombin time and the bilirubin value on days 1, 2, 3, and 7. RESULTS: No postoperative mortality occurred and the postoperative morbidity rate was 19%. Only 2 cases of digestive tract anastomotic leakage occurred, which led to reoperation. Hepatectomy-related complications were noted in 5 patients (3 biliary fistulas, 1 hemorrhage and 1 transient liver failure), and pulmonary infections occurred 3 times. The technical difficulties of the one-stage procedure are discussed, focusing on the choice of the incision, the risk of sepsis for the liver if there is an intestinal aperture, possible repercussions of liver impairment and hepatic pedicle clamping on bowel suture healing, and the risk of digestive fistula according to the location of the bowel suture. CONCLUSION: It appears that this one-stage procedure is safe if the bowel is systematically cleaned before the operation, if an appropriate Rio-Branco incision is used, and if the risk of postoperative liver failure is low. It seems preferable to use intermittent hepatic pedicle clamping rather than continuous clamping (when feasible), and to temporarily protect a low rectal anastomosis with a colostomy. PMID- 7840390 TI - Effectiveness of extended lymphadenectomy in noncurative gastrectomy. AB - PURPOSE: We examined the efficacy of extended lymph node dissection for prolonging survival in macroscopically or histologically proven incurable gastric cancer. PATIENTS AND METHODS: We analyzed clinico-pathologic data on 119 patients with serosally invasive gastric cancer who underwent noncurative gastrectomy, with respect to the relation between the extent of lymphadenectomy and survival benefit. RESULTS: The 5-year survival rate was significantly higher among patients treated with extensive lymphadenectomy (R2/3) compared to simple gastrectomy (R1). Extensive lymphadenectomy significantly prolonged survival time even after noncurative gastrectomy in cases where there was no evidence of hepatic metastasis, peritoneal seeding, or extensive nodal metastasis beyond the tertiary lymph node, and regardless of the extent of direct invasion to adjacent organs. CONCLUSIONS: Gastrectomy combined with extended lymphadenectomy and/or resection of adjacent organs is recommended for gastric cancer patients without distant metastasis, even when the operation is histologically noncurative. Gastrectomy and perioperative intensive chemotherapy are called for when patients have distant metastasis. PMID- 7840391 TI - Cholecystokinin is partly responsible for reduced food intake and body weight loss after total gastrectomy in rats. AB - PURPOSE: To determine the cause of body weight loss after total gastrectomy. METHODS: We evaluated the acute effect of exogenous cholecystokinin (CCK) on food intake and the chronic effect of CCK receptor blockade on food intake and body weight after total gastrectomy in rats. RESULTS: Exogenous CCK significantly reduced food intake in gastrectomized rats; this was blocked by administration of a CCK-A but not a CCK-B receptor antagonist. Chronic treatment with a CCK-A or CCK-B receptor antagonist after total gastrectomy in rats significantly increased postoperative food intake and body weight. CONCLUSION: Our data indicate that endogenous CCK is partly responsible for reduced food intake and body weight loss after total gastrectomy in rats. PMID- 7840392 TI - Priorities in general surgical training. AB - PURPOSE: We wished to determine which area of surgical resident training receives the highest priority--surgical technique, surgical judgment, or "book knowledge." We were also interested in how the programs addressed each area, particularly the teaching of surgical technique. METHODS: A questionnaire was distributed to the program directors and chief residents of all 289 general surgery residency programs in the United States. RESULTS: Answers were received from 144 chief residents (50%) and 152 program directors (53%). Programs to teach surgical judgment and technique were offered by 55 (36%) and 68 (45%) of general surgical residencies. Most program directors (83%) and chief residents (72%) considered surgical judgment the most important aspect of surgical training. Sixty-four percent of chief residents felt they were receiving adequate training in the technical aspects of surgery. Approximately half of the program directors felt that residents needed better training in the technical aspects of surgery. One hundred thirty programs (86%) had specific curricula for teaching "book knowledge." CONCLUSIONS: With the advent of minimal access surgery and the constant introduction of new instruments and procedures, new demands are constantly being placed on practicing surgeons. In order to prevent the further fragmentation of general surgery, a more structured approach to the early teaching of surgical skills should be considered. PMID- 7840393 TI - Management of common bile duct stones in the era of laparoscopic cholecystectomy. AB - PURPOSE: To assess the safety and efficacy of endoscopic retrograde cholangiopancreatography (ERCP) prior to laparoscopic cholecystectomy. METHODS: In patients suspected of harboring common duct stones, we performed ERCP prior to laparoscopic cholecystectomy (LC). Indications included jaundice, gallstone pancreatitis, elevated liver function tests, and visualizing a common duct stone and/or a dilated common duct on ultrasonography. Data were analyzed retrospectively. RESULTS: Of 217 patients undergoing LC, 37 (17%) had ERCP with or without endoscopic sphincterotomy (ES). Of these 37, common duct stones were noted in 19 patients (51%). Only 1 of 11 (9%) patients with mild gallstone pancreatitis had choledocholithiasis. The only complication following ERCP was pancreatitis in 1 patient who underwent uneventful LC. There were no deaths in the entire series. CONCLUSIONS: ERCP and ES is a safe and effective method of clearing the common duct of stones prior to LC. Patients with mild gallstone pancreatitis do not require ERCP prior to LC. PMID- 7840394 TI - Temporary portocaval anastomosis with preservation of caval flow during orthotopic liver transplantation. AB - BACKGROUND: A novel technique of orthotopic liver transplantation was developed whereby both vena caval and portal venous blood flows are preserved during the entire procedure. PATIENTS AND METHODS: This method of liver transplantation was successfully performed in 51 consecutive patients and included a temporary portocaval shunt, a total hepatic resection with vena caval preservation, and an end-to-side cavocaval anastomosis. RESULTS: Preservation of vena cava and portocaval anastomosis were feasible in 51 patients (100%), including 34 patients with cirrhosis and 2 patients undergoing elective retransplantation. Both caval and portal flows were preserved during the entire procedure in 48 patients (94%). No venovenous bypass was required. Four deaths (7.8%) occurred postoperatively, all of them unrelated to the surgical procedure. CONCLUSION: We believe adoption of this orthotopic liver transplantation technique will obviate the need for venovenous bypass. PMID- 7840395 TI - The ultimate modification in the modified neck dissection. AB - PURPOSE: A study was undertaken to study the potential benefits for function and regional recurrence of preserving the sensory ventral branches of the cervical plexus in modified neck dissections. METHODS: Fifteen cases of squamous cell carcinoma or melanoma of the head and neck in which the sensory nerves were spared were matched to 15 cases in which the nerves were sacrificed. The subjects were examined for sensory loss, questioned regarding acute and chronic dysfunction, and followed for regional recurrence for a minimum of 2 years. RESULTS: The group whose nerves were preserved had significantly less sensory loss and a lower incidence of acute and chronic dysfunction. No subjects in either group had regional recurrence. CONCLUSION: The results of this initial study support a policy of routine preservation of the sensory ventral branches of the cervical plexus when there is no direct tumor involvement. PMID- 7840396 TI - Laparoscopic splenectomy. PMID- 7840397 TI - Candida sepsis in surgery. PMID- 7840398 TI - [Medical therapy for coronary heart disease. Perioperative relevance]. AB - OBJECTIVE: The aim of our review is to summarize relevant data on the perioperative use of anti-ischaemic drugs in patients at risk for or with proven coronary heart disease. DATA SOURCES: The accessible medical literature according to current electronic information sources was explored. RESULTS: One in every eight general anaesthetics is administered to a patient at risk for or with proven coronary heart disease. Of these patients, it is estimated that 20%-40% have perioperative myocardial ischaemia (PMI), the majority being non symptomatic. This figure correlates with the occurrence of postoperative cardiac complications and myocardial infarction. The anaesthetist therefore has an important role to play in reducing the rate of perioperative cardiac sequelae. This can be achieved with good control of haemodynamic stability and the timely and appropriate use of antiischaemic drugs. Nitrocompounds (nitrates, molsidomine) serve as the gold standard in current angina pectoris treatment. Acting as coronary and systemic vasodilators, they effect an immediate reduction in preload and have been shown to be the drugs of first choice for intraoperative myocardial ischaemia. Beta-blockers reduce the rate of PMI to a greater extent than nitrates. They are also effective in myocardial ischaemia not accompanied by an increased heart rate. Single pre-operative administration of beta-blockers has also been shown to be beneficial in reducing the incidence of perioperative tachycardia, hypertension, and PMI. Consequently, such one-time medication can be considered for previously untreated high-risk patients presenting for surgery. The continuation of oral calcium channel blockers to the morning of surgery also reduces the rate of PMI and myocardial infarction in coronary-bypass patients, and combination with beta-blockers enhances this effect. Intra-operative diltiazem infusions are similarly advantageous in this patient group. In addition to nitrates, calcium antagonists are the drug of choice for coronary vasospasm. Drugs inhibiting platelet aggregation have a particular role in patients with coronary heart disease, however, they also cause increased perioperative bleeding. Consequently, it is recommended that these medications be discontinued 5-10 days prior to major surgery, with the exception of high-risk patients. Pilot studies using alpha 2-agonists have shown reduced anaesthetic requirements and a reduction in PMI. The perioperative relevance of these drugs is currently being investigated. CONCLUSIONS: Beta-blockers, calcium channel blockers, nitrates, and possibly alpha 2-agonists lead to reduced rates of PMI and other cardiac complications in risk patients. Current anti-anginal medications, with the exception of anti-platelet agents, should be maintained to the day of surgery and continued as soon as possible thereafter. All of these drugs except anti-platelet agents may also be used intra-operatively, however, possible interactions with anaesthetic agents should be carefully considered. PMID- 7840399 TI - [Effect of capnoperitoneum on postoperative carbon dioxide homeostasis]. AB - After laparoscopic cholecystectomy, carbon dioxide (CO2) must be exhaled after resorption from the abdominal cavity. There is controversy about the amount and relevance of postoperative CO2 resorption. Without continuous postoperative monitoring, after laparoscopic cholecystectomy a certain risk may consist in unnoticed hypercapnia due to CO2 resorption. Studies exist on the course of end expiratory CO2 (Pe-CO2) alone over a longer postoperative period of time in extubated patients during spontaneous breathing. The goal of this prospective study was to investigate the amount of CO2 resorbed from the abdominal cavity in the postoperative period by means of CO2 metabolism. METHODS. After giving informed consent to the study, which was approved by the local ethics committee, 20 patients underwent laparoscopic cholecystectomy. All patients received general endotracheal anaesthesia. After induction, total IV anaesthesia was maintained using fentanyl, propofol, and atracurium. Patients were ventilated with oxygen in air (FiO2 0.4). The intra-abdominal pressure during the surgical procedure ranged from 12 to 14 mm Hg. Thirty minutes after releasing the capnoperitoneum (KP), CO2 elimination (VCO2), oxygen uptake (VO2), and respiratory quotient (RQ) were measured every minute for 1 h by indirect calorimetry using the metabolic monitor Deltatrac according to the principle of Canopy. Assuming an unchanged metabolism, the CO2 resorption (delta VCO2) at any given time (t) can be calculated from delta VCO2 (t) = VCO2 (t)-RQ(preop) VO2 (t). It was thus necessary to define the patient's metabolism on the day of operation. The first data were collected before surgery and after introduction of the arterial and venous cannulae for a 15-min period. Measuring point 0 was determined after exsufflation of the KP and emptying of the remaining CO2 via manual compression by the surgeon at the end of surgery. Patient's tracheas were extubated and metabolic monitoring started 30 min after release of the KP for 60 min. Simultaneously, a nasal side-stream capnometry probe was placed and the PeCO2 and respiratory frequency (RF) were obtained by the Capnomac Ultima (Datex) and registered every minute as well. Values were averaged over four periods of 15 min each. An arterial blood gas sample was drawn at the end of every 15-min period. Postoperative pain was scored by a visual analog scale and completed by a subjective index questionnaire on general well-being. All data were analysed by the Friedman or Wilcoxon test; P < 0.05 was considered significant. RESULTS. The findings do not indicate CO2 resorption in the postoperative period after laparoscopic cholecystectomy (Tables 2 and 3, Fig. 1). Arterial CO2 as well as PeCO2 were elevated postoperatively (45 mm Hg vs. 36 mm Hg intraoperatively), while VCO2 and VO2 were unchanged when compared to the preoperative measuring period. The postoperative RF was comparable to preoperative values. Calculated delta CO2 was lower than 10 ml/min and within accuracy of measurements. The post-operative pain index ranged between 3 and 4, and 3.75-15 mg piritramid was administered. All patients felt tired immediately after the operation, but scores improved slightly at the end of the 60-min period of metabolic monitoring. CONCLUSIONS. There is no significant resorption of CO2 from the abdominal cavity later than 30 min after releasing the KP. Up to this time, any CO2 remaining in the abdominal cavity after careful emptying by the surgeon has been resorbed and exhaled. An increased PeCO2 as late as 30 to 90 min postoperatively should rather be considered a consequence of residual anaesthetics and narcotics than of CO2 resorption. PMID- 7840400 TI - [Esmolol as a bolus for prevention of sympathetic adrenergic reactions following induction of anesthesia]. AB - In addition to laryngoscopy, endotracheal intubation, and other stressful intraoperative phases, hypertension occurs during recovery from anaesthesia, provoking post-operative complications like bleeding and increased intracranial or intraocular pressure. Furthermore, these hypertensive reactions result in life threatening complications, especially in patients with pre-existing cardiovascular diseases. In this study, the effect of the new, short-acting beta blocker esmolol given as a single bolus for preventing the increases in blood pressure and heart rate during recovery from anaesthesia and extubation in patients with hypertension was investigated. PATIENTS AND METHODS. Sixty-three patients with a history of hypertension over a period of more than 6 months and blood pressure (BP) more than 150/90 mm Hg undergoing intervertebral-disc, otolaryngologic, or eye surgery were included in the study. The operations were performed during thiopentone-induced isoflurane anaesthesia with relaxation by atracurium. The patients were assigned to three groups after giving witnessed oral informed consent. During the study period they received the study drug twice: (A) 30-90 s before turning off the nitrous oxide; and (B) 20-90 s before extubation. Group I (placebo) received placebo each time, group II (100 mg esmolol) placebo at A and 100 mg esmolol i.v. at B, and group III (200 mg esmolol) 100 mg esmolol i.v. each time. After each medication the cardiovascular parameters were measured noninvasively over a period of 10 min every minute and in the following 2 h every 15 min. RESULTS. After the first medication systolic and diastolic BP, heart rate (HR), and rate-pressure product (RPP) were lower in patients receiving 100 mg esmolol (Group III) than in groups I and II. After the second injection the blood pressure was lower in the two groups receiving 100 mg esmolol, than the placebo group (I: 180.1 +/- 7.4/100.7 +/- 3.6; II: 152.8 +/- 5.8/87.9 +/- 3.4; III: 157.9 +/- 5.3/91.5 +/- 3.6 mm Hg [mean 2 min +/- SEM]). The changes in HR (I: 88.2 +/- 3.8; II: 75.6 +/- 2.6; III: 72 +/- 3.1 min-1) and RPP (I: 15,800 +/- 900; II: 11,700 +/- 700; III: 11,400 +/- 600) were similar. In 8 of the 20 patients in group III the HR dropped below 60.min-1, but in none of these patients did the BP become instable. CONCLUSIONS. The sympathoadrenergic reaction during recovery from anaesthesia and extubation can be treated by beta blocking agents, but such therapy is not without risk because of the long half life and effects of the therapy on other factors such as postoperative loss of intravascular volume. Esmolol is a new, short-acting, cardioselective beta blocker with a very short plasma distribution time and a elimination half-life of 9.2 min. Thus, the potential risks of beta-blockers due to half-life are minimised. The results of this study show that a dangerous increase in BP and HR with increased myocardial oxygen consumption can be prevented by a single bolus, and better by a double bolus of 100 mg esmolol. Although bradycardia with HR below 50.min-1 in 8 patients might indicate a risk of cardiac instability, the systolic BP did not fall below 100 mm Hg, and the episode of bradycardia was so short that there was no risk to the patients. PMID- 7840401 TI - [Endocrine stress reaction, hemodynamics and recovery in total intravenous and inhalation anesthesia. Propofol versus isoflurane]. AB - This prospective, randomised study compared total intravenous anaesthesia (TIVA) and inhalation anaesthesia with respect to endocrine stress response, haemodynamic reactions, and recovery. METHODS. The investigation included two groups of 20 ASA I-II patients 18-60 years of age scheduled for orthopaedic surgery. For premedication of both groups, 0.1 mg/kg midazolam was injected IM. Patients in the propofol group received TIVA (CPPV, PEEP 5 mbar, air with oxygen FiO2 33%) with propofol (2 mg/kg for induction followed by an infusion of 12-6 mg/kg.h) and fentanyl (0.1 mg before intubation, total dose 0.005 mg/kg before surgery, repetition doses 0.1 mg). For induction of patients in the isoflurane group, 5 mg/kg thiopentone and 0.1 mg fentanyl was administered. Inhalation anaesthesia was maintained with 1.2-2.4 vol.% isoflurane in nitrous oxide and oxygen at a ratio of 2:1 (CPPV, PEEP 5 mbar). For intubation of both groups, 2 mg vecuronium and 1.5 mg/kg suxamethonium were injected, followed by a total dose of 0.1 mg/kg vecuronium. Blood samples were taken through a central venous line at eight time points from before induction until 60 min after extubation for analysis of adrenaline, noradrenaline (by HPLC/ECD), antidiuretic hormone (ADH), adrenocorticotropic hormone (ACTH), and cortisol (by RIA). In addition, systolic arterial pressure (SAP) heart rate (HR), arterial oxygen saturation (SpO2), and recovery from anaesthesia were observed. RESULTS. Group mean values are reported; biometric data from both collectives were comparable (Table 1). Plasma levels of adrenaline (52 vs. 79 pg/ml), noradrenaline 146 vs. 217 pg/ml), and cortisol (82 vs. 165 ng/ml) were significantly lower in the propofol group (Table 2, Figs. 1 and 3). Plasma levels of ADH (4.8 vs. 6.1 pg/ml) and ACTH (20 vs. 28 pg/ml) did not differ between the groups (Table 2, Figs 2 and 3). SAP (128 vs. 131 mmHg) was comparable in both groups, HR (68/min vs. 83/min) was significantly lower in the propofol group, and SpO2 (97.1 vs 97.4%) showed no significant difference (Table 3). Recovery from anaesthesia was slightly faster in the propofol group (following of simple orders 1.9 vs. 2.4 min, orientation with respect to person 2.4 vs. 3.4 min, orientation with respect to time and space 2.8 vs. 3.7 min), but differences failed to reach statistical significance. CONCLUSIONS. When compared with isoflurane inhalation anaesthesia, moderation of the endocrine stress response was significantly improved during and after TIVA with propofol and fentanyl. Slightly shorter recovery times did not lead to an increased stress response. With respect to intra- and postoperative stress reduction, significant attenuation of sympatho-adrenergic reaction comparable SAP and reduced HR, sympatholytic and hypodynamic anaesthesia with propofol and fentanyl seems to be advantageous for patients with cardiovascular and metabolic disorders. For this aim, careful induction and application of individual doses is essential. PMID- 7840402 TI - [The effect of different anesthetic procedures on hormone levels in women. Studies during an in vitro fertilization-embryo transfer (IVF-ET) program]. AB - Different anaesthetic procedures that were used during an in vitro fertilisation and embryo transfer (IVF-ET) program have been analysed in order to determine their influence on plasma levels of estradiol, progesterone, prolactin, and beta endorphin and results of IVF-ET. METHODS. Fifty-four patients awaiting transvaginal oocyte aspiration were randomised into three groups: (1) anaesthesia with ketamine as an induction agent and analgesic (n = 20); (2) general intubation anaesthesia using thiopentone for induction and enflurane for maintenance (n = 18); and (3) no anaesthesia (n = 16). Estradiol, progesterone, prolactin, and beta-endorphin were measured from day 3 to 14 referring to follicle aspiration. Differences between preoperative hormone levels and their intra- and postoperative peaks were analysed using the Kruskal-Wallis test (P < 0.03). The results were corrected using the Holms method (alpha = 0.05). RESULTS. No differences were observed in estradiol and progesterone levels (Figs. 1, 2). Prolactin levels were 1.4 times higher (P < 0.001) when ketamine was used and 2.2 times higher (P < 0.001) after short general anaesthesia than in the control group (Fig.3). Similar results were observed with respect to beta-endorphin: in comparison with the control group we found significant elevation by a factor of 2.1 when ketamine was used (P < 0.001). The discrepancy became even more marked with general anaesthesia: beta-endorphin was 3.9 times higher compared to the controls (P < 0.001) (Fig.4). Comparing the two groups who were given anaesthetics, prolactin and beta-endorphin levels were also significantly different (P < 0.001). The IVF procedure itself did not appear to be affected by different anaesthetic procedures during oocyte aspiration (Table 2). CONCLUSIONS. The increased prolactin and beta-endorphin plasma levels associated with ketamine and general anaesthesia reflect a significant alteration of the observed hormone levels. When anaesthesia is indicated, we try to avoid general intubation anaesthesia in favor of ketamine. PMID- 7840403 TI - [Different opioids in patients at cardiovascular risk. Comparison of central and peripheral hemodynamic adverse effects]. AB - Efficient analgesia may be the major objective in the cardiovascular risk patient following myocardial infarction, acute occlusion of peripheral vessels, or dissection/perforation of major abdominal vessels. It was the purpose of the study to investigate the haemodynamic and respiratory side effects of eight different opioids in 57 circulatory risk patients prior to major vascular surgery. METHODS. Patients were randomly allocated to eight groups, each receiving a different opioid within a clinical, equipotent dose range (buprenorphine, fentanyl, morphine, nalbuphine, pentazocine, pethidine, tramadol, alfentanil). A complete haemodynamic and blood gas status was obtained prior to as well as 5, 10, 15, and 20 min following opioid administration. Monitoring included a complete invasive haemodynamic and blood gas status. Statistical evaluation was performed by 1- and 2-factorial ANOVA (P < 0.05). RESULTS. Significant time effects (changes from baseline at the time of measurement) were observed for heart rate and total peripheral resistance, while significant group (group-specific differences in the course of values at the different times of measurements) and time effects were noted for mean pulmonary artery pressure, pulmonary capillary wedge pressure, stroke volume index, and PaO2. No major effects were observed following morphine, fentanyl, alfentanil, tramadol, and nalbuphine. Buprenorphine caused distinct respiratory depression accompanied by an increase in pulmonary vascular tone. Pentazocine and pethidine caused a significant increase in MPAP and peripheral vascular resistance while pethidine also produced marked respiratory depression. CONCLUSIONS. For interpretation of the results, factors such as respiratory depression, histamine release, secretion of endogenous catecholamines, and hypoxia-induced pulmonary vasoconstriction have to be discussed. Tramadol, an opioid with moderate potency, seems to offer some advantages due to its minor cardiovascular and respiratory side effects. PMID- 7840404 TI - [Diabetic coma with deep hypothermia. Successful resuscitation with hemofiltration]. AB - A 41-year-old woman with severe juvenile diabetes mellitus suffered from profound hypothermia after loss of thermoregulation in diabetic ketoacidosis. She was found unconscious, without measurable blood pressure; the electrocardiogram (ECG) showed bradycardia of 30 min and the rectal temperature was 23.7 degrees C. The patient received mechanical ventilation, fluid therapy, warmed gastric lavage, and, unfortunately, inotropic medication. She was transferred to a department of cardiac surgery in order to continue the therapy with cardiopulmonary bypass (CPB). On arrival, the patient had a rectal temperature of 27.3 degrees C, the ECG showed an absolute arrhythmia with a frequency of 70/min, and the blood pressure was 63/43 mmHg. We decided to use a rapidly available but not highly invasive venovenous hemofiltration technique for slowly rewarming the patient. Vascular access was achieved by percutaneous femoral vein cannulation with a Shaldon catheter. The hemofiltration system (Gambro AK-10, Gambro AB, Sweden) was instituted with a blood flow rate of 200 ml/min. The hemofiltration monitor controls the pumps for filtering and substituting fluid volumes and allows the infusion solutions to be heated up to 40 degrees C. Sinus rhythm resumed without antiarrhythmic medications at a temperature of 29.5 degrees C, and within 8 h the patient was rewarmed to 35.5 degrees C. After treatment of the adult respiratory distress syndrome caused by pneumonia, she was discharged from the intensive care unit to complete treatment with no evidence of any permanent organ damage. We conclude that hemofiltration may be the method of choice for rewarming deeply hypothermic patients when their circulation is preserved.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7840405 TI - [Difficult intubation due to facial malformations in a child. The laryngeal mask as an aid]. AB - Variations in anatomy of the bony and soft-tissue structures of the neck and facial cranium due to trauma, disease, or dysmorphic syndromes may lead to severe intubation problems. These patients are admitted for mandibulofacial and otolaryngologic surgery. It is important to inspect the patient's outer and inner pharyngeal structures carefully during preoperative assessment, as suggested by Mallampati. The observer estimates the facility of intubation by inspection of the faucial pillars, soft palate, and uvula. Unfortunately, even careful examination does not predict every case of difficult intubation, so that unexpected problems may occur. There may also be difficulties in ventilating these patients with a face mask. Safe intubation is possible in these cases using the laryngeal mask airway (LMA), laryngoscopy with a rigid optical aid, and the fibreoptic bronchoscope. Case report. We report a 14-month-old girl with Goldenhar's syndrome (oculo-auricular dysplasia) who presented for soft-palate surgery. This syndrome belongs to the group of cranio-mandibular-facial malformations; the main symptoms are congenital unilateral malformations in the area of the 1st and 2nd branchial arches. The patient's jaw was hypoplastic with aplasia of the temporo-mandibular joint, which led to asymmetry of the lower face and an extremely short mandible. Additionally, we observed a large tongue in relation to the small jaw. Macrostomia is part of the syndrome, and may lead to underestimation of intubation problems.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7840406 TI - [Social justice in public health--the example of transplantation medicine]. PMID- 7840407 TI - [The principal physician in emergency medicine]. AB - The implementation of an experienced pre-hospital care emergency physician as an on the-scene medical command officer (MCO) within the emergency medical service (EMS) is an essential prerequisite to guarantee qualified medical supervision during mass-casuality incidents (MCI). The MCO has four basic functions. Within the administration of the EMS system, he is responsible for the medical aspects of strategic planning for the MCI response. During the MCI the MCO is responsible for the overall assessment of the situation, triage, and supervision of medical treatment by physician and non-physician providers. Aside from extensive personal experience in pre-hospital care, the MCO needs special training to be qualified for this position. State EMS laws provide the legal basis for the MCO within the EMS system. PMID- 7840408 TI - [The cerebral effects of ketamine--a new view?]. PMID- 7840409 TI - [Actions of ketamine not related to NMDA and opiate receptors]. AB - In recent years, much interest has focused on NMDA- and opiate-receptor-mediated actions of ketamine, whereas the search for other potential neuronal effects of this phencyclidine derivative has not attracted comparable attention. Nevertheless, the superfamily of voltage-operated membrane channels (VOC), ligand operated ion channels (LOC) stimulated by acetylcholine and GABA, the non-NMDA subtypes of glutamate-activated LOC (kainate and AMPA receptor channels) and the closely related re-uptake processes of the monoamines noradrenaline, dopamine and serotonin should be considered potential targets of ketamine within the nervous system. Therefore, this review article summarizes our current knowledge of ketamine effects on these transmembrane ion channels and carrier mechanisms in the neuron. Unlike the NMDA-insensitive glutamate receptors for kainate and AMPA, the LOC activated by acetylcholine and the principal inhibitory amino acid GABA (gamma-aminobutyric acid) were both sensitive to clinical concentrations of ketamine, although in different ways. The relevance of these findings for the generation of the anaesthetic state, however, still remains to be established. Moreover, all VOC tested so far were reversibly inhibited at supra-clinical concentrations of ketamine (> 100 microM). Whereas no direct relevance to the state of general anaesthesia emerges from these data, local anaesthesia produced by comparably high concentrations of ketamine can be explained on the basis of its more or less unspecific inhibitory actions on VOC. Finally, the excellent antinociceptive activity of ketamine at the spinal and supra-spinal level may result at least in part from its inhibitory effects on the neuronal uptake of the monoamines noradrenaline, dopamine and serotonin. PMID- 7840410 TI - [Ketamine--anticonvulsive and proconvulsive actions]. AB - Animal experimentation has revealed that ketamine has anticonvulsive properties. Changes in the EEG have also been reported in animals; these have been designated non-convulsive generalized electrographic seizures because of their similarities to epileptiform potentials, even though there are no recognizable signs of seizures. The cataleptic condition of the cats in which these changes were observed led to the conclusion that ketamine could cause petit mal seizures, which took the course of petit mal status. Ketamine was therefore also seen as a dangerous anaesthetic agent predisposing to convulsions, the use of which could lead to status epilepticus and irreversible brain damage. These conflicts of opinion should be resolved, as they are based on various misconceptions. (1) The terminology used for epilepsy by specialized clinicians is not always correctly applied in the context of animal experimentation. (2) The activation of epileptiform potentials in the EEG of animals cannot be interpreted as a reliable sign of epileptogenic efficiency in humans. (3) Too little regard is paid to the different actions of anaesthetic agents in various sites of the brain, at different doses and with different routes of administration. (4) The statistical significance and biological relevance of the study results are inadequate because the numbers of observations are too small. Epileptologists regret the insufficiency of animal models as paradigma for the study of efficiency of antiepileptic drugs in humans. The degree by which extensor spasms in the front paw of Gerbils of rats induced by pentylentetrazol or electric current are reduced after application of an anticonvulsive drug is no reliable measure of its anticonvulsive effect in humans.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7840411 TI - [Neuroprotection. Models and basic principles]. AB - This review describes recently recognized pathophysiologic mechanisms responsible for brain damage during ischemia and reperfusion and new therapeutic concepts developed on a rational basis. Mediators of secondary damage include excitotoxins such as glutamate, acidosis, free radicals, and the disturbance of the microcirculation seen in the early phase of recirculation. Glutamate is an excitatory neurotransmitter, which may turn neurotoxic when the energy supply is limited. Tissue acidosis down to pH 6.0 develops regularly in cerebral ischemia and disturbs a variety of neuronal functions, causing glial swelling and neuronal death. Free radicals attack brain lipids, the cell membrane and myelin in particular, and are produced during reperfusion. Disturbance of the microcirculation aggravates ischemic damage. Suggested therapeutic approaches include glutamate antagonists, normalization of tissue acidosis, and use of new diuretics to reduce glial swelling, protection of the brain by free radical scavengers such as 21-aminosteroids, tocopherol, allopurinol or superoxide dismutase, and hypothermia. Ways of ensuring fast reperfusion, including hypervolemic hemodilution and blood pressure stabilization, are suggested for resuscitation or early stroke. All data available indicate that the combination of several successful therapeutic principles will significantly improve outcome. PMID- 7840412 TI - [Pharmacology and clinical results with peridural and intrathecal administration of ketamine]. AB - The epidural and intrathecal administration of opioids has gained wide acceptance among anaesthesiologists during recent years. Ketamine, an anaesthetic agent with an unusual pharmacological profile, has also attracted some interest in this context, as in subanaesthetic doses it provides marked analgesia without inducing respiratory depression. Since the first publication on the epidural administration of ketamine in humans in 1982, various studies on the pharmacology, toxicology and clinical use of ketamine by the epidural and intrathecal routes have been published. PHARMACOLOGY. There is a large body of evidence to show that systemically administered ketamine interacts with different neurotransmitter systems and may even produce local anaesthetic effects when used for intravenous regional anaesthesia. The results of animal studies suggest that ketamine may cause complete sensory and motor blockade after intrathecal administration, which leads to high concentrations in the cerebrospinal fluid. One study investigating the effects after epidural administration showed motor blockade only after high doses of ketamine. Binding to local opiate receptors seems to play only a minor role, whereas significant analgesia after even low doses of ketamine is the result of antagonism to NMDA receptors. In vitro and animal data also suggest an involvement of the descending inhibitory pathways, mainly through inhibition of re-uptake of neurotransmitters. NEUROTOXICITY. Data relating to the neurotoxicity of ketamine after intrathecal administration are confusing. While no neurotoxic effects have been observed in studies in primates and rabbits, experimental rats and monkeys have sustained lesions: they may have been caused by a faulty puncture technique or by inherent neurotoxicity of the drug. CLINICAL RESULTS. The only study of intrathecal administration of ketamine in humans revealed local anaesthetic effects after doses of 50 mg. For epidural use, doses up to 30 mg did not give adequate pain relief after surgery in controlled studies, but had some analgesic effect in patients with chronic pain syndromes. When doses of 30 mg and over were used, postoperative analgesia was generally assessed as good. CONCLUSIONS. When administered intrathecally, ketamine shows local anaesthetic effects in both animals and humans. Unfortunately, all commercially available ketamine preparations contain disinfectant agents whose intrathecal administration is prohibited. Epidurally administered ketamine doses of 30 mg and more seem to provide adequate postoperative analgesia, while smaller doses might be effective in chronic pain syndromes. More studies investigating the neurotoxicity and clinical effects of ketamine on the spinal cord are needed before wider use of the substance by this route of administration can be recommended. PMID- 7840413 TI - [Cerebral neuroprotection and ketamine]. AB - Ketamine is said to increase intracranial pressure (ICP), cerebral blood flow (CBF) and cerebral metabolic rate for oxygen (CMRO2) and hence to be unsuitable for neuroanaesthesia. This may require reconsideration in the light of the neuroprotective properties mediated by the interaction of ketamine with the N methyl-D-aspartate receptor (NMDA). Meta-analysis of published experimental rodent studies yields contradictory conclusions. Ketamine does not provide neuroprotection against hypoxic hypoxaemia or focal cerebral ischaemia. During complete forebrain ischaemia of 10 min duration, ketamine offers some degree of protection only if administered before (i.e. prophylactically) and after (i.e. therapeutically) a transient ischaemic episode. In experimental head injury, ketamine may be protective if administered therapeutically within 2 h after the trauma. In the case of incomplete forebrain ischaemia, ketamine provides neuroprotection if administered both before and during ischaemia. Clinical or primate studies are not available; extrapolation of results derived from rodent studies requires caution and has limitations. With respect to the pharmacodynamic action providing neuroprotection, NMDA-receptor antagonism may be just one of several mechanisms; others include scavenging of free radicals, a central sympatholytic effect and augmentation of dopamine metabolism in the caudate. The suitability of ketamine for neuroanaesthesia, which must also take account of its effects on ICP, CBF and CMRO2, is--for the time being--questionable. PMID- 7840414 TI - [Ketamine inhibits n-methyl-d-aspartate (NMDA) receptor mediated acetylcholine release from rabbit caudate nucleus slices]. AB - Slices of the rabbit caudate nucleus were incubated with [3H]choline for 30 min and then superfused continuously with Mg(2+)-free medium at 37 degrees C. Stimulation with N-methyl-D-aspartate (NMDA) caused a concentration-dependent release of [3H]acetylcholine (ACh), which was abolished in the presence of MG2+. This release of ACh was exocytotic and mediated by action potentials. NMDA channel antagonists inhibited the NMDA-evoked [3H]ACh release in a use-dependent manner, with the following rank order of potency: dizolcipine [(+)-5-methyl-10,11 dihydro-5H-dibenzo(a,d)cyclo-hepten-5,10-imine maleate; MK-801] > (+)ketamine = (+/-)ketamine < (-)ketamine > memantine > amantadine. Also, AP-5 [(+/-)-2-amino-5 phosphopentanoic acid] depressed the NMDA-induced release of [3H]ACh, acting, however, in a competitive manner. At the neuropathologic level, Parkinson's disease is characterized by an overshoot of striatal cholinergic transmission due to the decreased inhibitory dopaminergic input from the substantia nigra. The well-known antiparkinsonian effect of memantine and amantadine is most probably due to a blockade of NMDA-receptor-linked ion channels on striatal cholinergic interneurons, leading in turn to a diminished release of ACh. Since ketamine diminished cholinergic neurotransmission to a similar degree to that achieved with memantine and amantadine and even more potently than the adamantanes, and that at concentrations far below those needed for its anaesthetic and analgesic properties, it seems worthwhile to test this drug as an antiparkinsonian agent clinically. PMID- 7840415 TI - [Interaction of S-(+)-ketamine with opiate receptors. Effects on EEG, evoked potentials and respiration in awake dogs]. AB - To check for suspected opioid-receptor mediated hypnotic and antinociceptive effects of S(+)-ketamine, highly selective antagonists were used after the anaesthetic. METHODS. To determine the hypnotic effects of increasing doses of S(+)-ketamine (2-5-10-20 mg/kg given at 10-min intervals), EEG power spectra (delta, theta, alpha, beta) were derived (Lifescan), and antinociceptive potency was evaluated using the somatosensory evoked potential (SEP, Lifescan) in awake, trained dogs (n = 10). To check for an opioid-receptor-related interaction, an antagonist of the methoxymorphinane series (HS-275, 80 micrograms/kg i.v.) with higher selectivity than naloxone for the mu-receptor was given at the end. After washout the same animals were exposed to S(+)-ketamine. This time, however, the highly selective delta-antagonist naltrindole (160 micrograms/kg i.v.) was given. To show up any respiratory depression arterial blood gases were taken after each dose. RESULTS. S(+)-Ketamine induced a dose-related increase in power in the theta band (3-8 Hz), with a ceiling effect at 10 mg/kg. The changes were reversed by both antagonists. In the beta band (13-30 Hz) and in the delta domain, power decreased or increased, respectively, in a highly significant manner (P < 0.005) at 20 mg/kg. Both effects reversed after the antagonists with an overshoot in beta (+12% and +14%, respectively) and a decrease in delta (-45% and -62%, respectively) compared with control. S(+)-Ketamine induced a dose-dependent increase in peak latency and depression of the SEP amplitude by a maximum of over 50%. Latency changes were completely reversed only by HS-275. Amplitude height was only partly restored by both antagonists. A clinical relevant decrease in PaO2 and increase in PaCO2 increase were seen at 20 mg/kg. Hypoxia was reversed by both antagonists; hypercapnia was only partially reversed. CONCLUSION. The results confirm the suspicion that S(+)-ketamine induces an opioid theta- and delta-receptor-mediated deep hypnotic effect. Blockade of nociceptive impulses in afferent sensory nervous pathways suggests an efficient analgesic effect mediated partly by the opioid mu-receptor. Other mechanisms, such as an interaction with the NMDA receptor, have to be taken into consideration to account for the full antinociceptive effect. Respiratory depression may be of clinical importance when high dosages of S(+)-ketamine are given. PMID- 7840416 TI - [Topographic electroencephalometry following anesthesia induction with ketamine midazolam]. AB - The neurophysiological action of ketamine has attracted increasing interest in recent years, with special interest in receptor action and in neurophysiological differences between and psychomimetic side effects of the two enantiomorphs. Most of the neurophysiological examinations published deal with ketamine as a single anaesthetic agent, although it has been suggested to that psychomimetic side effects and haemodynamic deterioration could be avoided by combining ketamine with a sedative drug. The primary aim of our study was to examine the combined ketamine-midazolam action on cerebral activity; secondly, we planned to look at these interactions topographically at different points of the cortex to evaluate topographical differences in the combination's action; thirdly, the cerebral and haemodynamic reactions to anaesthesiological stimuli (intubation, gastric tube) were evaluated and compared. METHODS. Sixteen patients scheduled for elective aortocoronary bypass surgery were examined. Topographical electroencephalometric data were obtained by processed EEG with a CATEEM system at 17 recording points over the cortex and compared with heart rate and arterial blood pressure during the induction period. After documentation of the baseline data ketamine (3 mg/kg) and midazolam (0.15 mg/kg) were applied within 10 min by means of an automatic device. At the end of the infusion period patients were intubated, and after a further 10 min a gastric tube was placed. RESULTS. Induction resulted in increases in delta and beta 2 output (P < 0.05) in the early induction period and in significant decreases (P < 0.05) in alpha 1, alpha 2 and beta 1 activity. No significant change in theta activity was observed throughout the observation period. Intubation led to significant increases of power particularly in the temporal and parietal leads of all frequency bands, but not in the frontal area. Insertion of the gastric tube did not alter cerebral function. CONCLUSION. The interaction of ketamine and midazolam leads to increases in beta 2 and delta power and to significant decreases in the alpha bands and beta 1. Increases of theta activity, a typical effect of single-agent anaesthesia with ketamine, were not observed. Thus, the action of combined ketamine and midazolam on cerebral function is not an additive, but an interactive process. Despite a relatively high induction dosage, haemodynamic changes during intubation occurred and were accompanied by changes in cerebral activity. This can be regarded as incomplete cerebral suppression even by these induction dosages. PMID- 7840417 TI - [Psychometric changes as well as analgesic action and cardiovascular adverse effects of ketamine racemate versus s-(+)-ketamine in subanesthetic doses]. AB - The intravenous anaesthetic ketamine is widely used in subanaesthetic doses as a potent analgesic in emergency and disaster medicine. At present, ketamine is commercially available only in its racemic form, although the S(+)-isomer has proved to be approximately three times as potent than the R(-)-isomer. In first clinical trials in Germany, S(+)-ketamine was reported to be markedly advantageous with regard to analgesia in anaesthetized patients. We therefore evaluated ketamine's analgesic and psychotropic effects in subanaesthetic doses given to healthy volunteers. MATERIALS AND METHODS. After institutional approval of the study by the university's Ethics Committee, 16 volunteers received ketamine racemate (1 mg/kg) and S(+)-ketamine (0.5 mg/kg) i.m. with 1-week intervals between injections in a randomized, double-blind fashion. Analgesia (electric pain stimulation of the median nerve), long-term memory, anterograde amnesia (recognition of simple pictures), motor coordination (Trieger test), immediate recall (short test of general intelligence) and concentration capacity (CI test: recognition of a preselected symbol among several symbols) were measured over a 60-min period and mean arterial pressure, heart rate, and ketamine plasma levels in venous blood samples were determined. Values were calculated as means and data were analysed by Wilcoxon's paired test for group comparison. RESULTS. Within 15 min, both agents induced a measurable degree of analgesia. After ketamine racemate, the level of pain tolerated increased from 38.8 +/- 14.0 to 57.0 +/- 13.7 mA and after S(+)-ketamine, from 36.9 +/- 10.5 to 53.3 +/- 15.2 mA. Ketamine racemate did not exert measurable effects on long-term memory, whereas anterograde amnesia was observed in 46% and 54% of the study subjects after 15 and 30 min, respectively. However, after S(+)-ketamine, only 8% of the volunteers demonstrated anterograde amnesia (P < 0.05). Immediate recall also declined in both groups (baseline: 5 points, after 15 min: 3.5 points for ketamine racemate, 4 points for S(+)-ketamine), whereas concentration capacity worsened from 14.5 +/- 3.8 s to 35.9 +/- 18.6 s after ketamine racemate and significantly less, from 14.8 +/- 2.5 s to 22.9 +/- 7.6 s, after S(+)-ketamine (P < 0.01). Furthermore, after 15 min, ketamine racemate induced an increase in heart rates from 73 +/- 15 b/min to 97 +/- 11 b/min, while S(+)-ketamine raised heart rates from 74 +/- 13 b/min to 89 +/- 11 b/min only (P < 0.05). Mean arterial pressure increased from 97 +/- 11 mmHg to 111 +/- 9 mmHg after ketamine racemate and from 92 +/- 11 mmHg to 110 +/- 13 mmHg after S(+)-ketamine (not significantly different). CONCLUSION. S(+)-Ketamine at half-dose of ketamine racemate is as potent as ketamine-racemate in subanaesthetic doses with powerful analgesic properties. The (+)-isomer exerts less adverse effects on measurable cerebral functions and induces a significantly smaller increase in heart rate. Since states of impaired consciousness and disorientation are especially disturbing under emergency conditions, further investigations should be carried out to define S(+)-ketamine's position as a potent analgesic for therapeutic use in emergency and disaster medicine. PMID- 7840418 TI - [Ketamine racemate versus S-(+)-ketamine with or without antagonism with physostigmine. A quantitative EEG study on volunteers]. AB - The potency of S-(+)-ketamine is approximately double that of the racemic ketamine. This study was carried out to investigate the recovery of cerebral electrical function after a bolus of 1.3 mg/kg ketamine or 0.65 mg/kg S-(+) ketamine and subsequent continuous application of 4 mg/kg h ketamine per h or 2 mg/kg S-(+)-ketamine, per h for 15 min. Furthermore, the centrally acting, cholinergic agonist physostigmine has been reported to antagonize ketamine and to shorten the recovery period. Therefore, after S-(+)-ketamine 0.012 mg/kg physostigmine was tested against saline placebo. METHODS. With their own informed consent and the approval of the ethics committee 12 healthy volunteers were enrolled in a double-blind cross-over study. All drugs were dissolved in identical volumes. On three dates with intervals of at least 1 week between, ketamine/NaCl, S-(+)-ketamine/physostigmine or S-(+)-ketamine/NaCl was administered (Table 1). The sequence was randomized. The EEG was recorded from 20 sites according to the 10/20 system and after Fast-Fourier transformation computed into amplitudes within the delta, theta, alpha, and beta bands and within the total spectrum. The median, the spectral edge frequency and the dominant frequency (dF) were also determined. Mean values of all electrodes before and at 10, 15, 30, 45 and 195 min after the bolus injection were compared using two-dimensional analysis of variance (ANOVA, significance level P < 0.05). RESULTS. The characteristic increase in theta-amplitude and decrease of alpha amplitude were observed after ketamine and S-(+)-ketamine. Median and dF dropped from the alpha to the theta frequency range. Ketamine led to a greater increase in total, delta, theta and beta amplitude during anaesthesia. 3 hours after ketamine/S-(+)-ketamine anaesthesia a significant decrease in the median and dominant frequency and in total, delta, theta, alpha and beta amplitudes confirmed residual impairment of cerebral function after all study drugs. No differences were found between physostigmine and placebo. DISCUSSION. The EEG changes during ketamine/S-(+)-ketamine administration suggest a slightly deeper anaesthetic level after ketamine. The course of recovery was not different after ketamine and after S-(+)-ketamine. The spectral edge frequency did not differ between measurement points, and is therefore not suitable for assessment of the depth of anaesthesia reached with ketamine/S-(+)-ketamine. The dose of physostigmine tested was probably too low to produce antagonism of S-(+) ketamine. An increased dosage of physostigmine has yet to be studied, but is likely to cause a higher rate of side effects, such as nausea, vomiting and bradycardia, and possibly even tonic-clonic seizures. PMID- 7840419 TI - [Ketamine and evoked potentials]. AB - Ketamine-induced changes in the spontaneous and evoked electroencephalogram have been well documented in animals and humans. In contrast to the action of hypnotics, ketamine does not result in a dose-dependent suppression of neural activity. Many studies have revealed excitatory activity with induction of synchronized high-voltage slow waves in the electroencephalogram (EEG). Somatosensory evoked responses (SEP) have been found to be enhanced following induction of anaesthesia with ketamine. However, increases in amplitude were small compared with the SEP-enhancing effects of etomidate. The increase in somatosensory evoked responses may reflect dose-dependent disinhibition and/or increased excitation of cerebral neuronal activity induced by ketamine. Attenuation of late cortical somatosensory evoked responses following stimulation of thin C- and A delta-nerve fibres has been reported in volunteers given low dose ketamine. Changes in SEP amplitude correlated to changes in subjective pain sensation. From this it was concluded that the analgesic effect of ketamine can be assessed by electrophysiological measurement methods. Recent studies suggest that the analgesic effect of the racematic ketamine mixture can probably be related to the effects of S-(+)-ketamine isomer, which has been shown to be involved in the activation of an opioidergic mechanism. Auditory evoked responses (AEP) of short latencies with origins in the brain stem have been shown to be slightly altered by ketamine. From this it was concluded that these components may not be used for assessment of the depth of anaesthesia. In contrast to the effects of hypnotics, mid-latency AEP components may be recorded during ketamine anaesthesia.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7840421 TI - Simulation of bone resorption-repair coupling in vitro. AB - In the normal adult human skeleton, new bone formation by osteoblasts restores the contours of bone surfaces following osteoclastic bone resorption, but the evidence for resorption-repair coupling remains circumstantial. To investigate whether sites of prior resorption, more than the surrounding unresorbed surface, attract osteoblasts or stimulate them to proliferate or make new matrix, we developed a simple in vitro system in which resorption-repair coupling occurs. Resorption pits were produced in mammalian dentine or bone slabs by culturing chick bone-derived cells on them for 2-3 days. The chick cells were swept off and the substrata reseeded with rat calvarial osteoblastic cells, which make bone nodules in vitro, for periods of up to 8 weeks. Cell positions and new bone formation were investigated by ordinary light microscopy, fluorescence and reflection confocal laser microscopy, and SEM, in stained and unstained samples. There was no evidence that the osteoblasts were especially attracted to, or influenced by, the sites of resorption in dentine or bone before cell confluence was reached. Bone formation was identified by light microscopy by the accumulation of matrix, staining with alizarin and calcein and by von Kossa's method, and confirmed by scanning electron microscopy (SEM) by using backscattered electron (BSE) and transmitted electron imaging of unembedded samples and BSE imaging of micro-milled embedded material. These new bone patches were located initially in the resorption pits. The model in vitro system may throw new light on the factors that control resorption-repair coupling in the mineralised tissues in vivo. PMID- 7840420 TI - The neocortex. An overview of its evolutionary development, structural organization and synaptology. AB - By way of introduction, an outline is presented of the origin and evolutionary development of the neocortex. A cortical formation is lacking in amphibians, but a simple three-layered cortex is present throughout the pallium of reptiles. In mammals, two three-layered cortical structures, i.e. the prepiriform cortex and the hippocampus, are separated from each other by a six-layered neocortex. Still small in marsupials and insectivores, this "new" structure attains amazing dimensions in anthropoids and cetaceans. Neocortical neurons can be allocated to one of two basic categories: pyramidal and nonpyramidal cells. The pyramidal neurons form the principal elements in neocortical circuitry, accounting for at least 70% of the total neocortical population. The evolutionary development of the pyramidal neurons can be traced from simple, "extraverted" neurons in the amphibian pallium, via pyramid-like neurons in the reptilian cortex to the fully developed neocortical elements designated by Cajal as "psychic cells". Typical mammalian pyramidal neurons have the following eight features in common: (1) spiny dendrites, (2) a stout radially oriented apical dendrite, forming (3) a terminal bouquet in the most superficial cortical layer, (4) a set of basal dendrites, (5) an axon descending to the subcortical white matter, (6) a number of intracortical axon collaterals, (7) terminals establishing synaptic contacts of the round vesicle/asymmetric variety, and (8) the use of the excitatory aminoacids glutamate and/or aspartate as their neurotransmitter. The pyramidal neurons constitute the sole output and the largest input system of the neocortex. They form the principal targets of the axon collaterals of other pyramidal neurons, as well as of the endings of the main axons of cortico-cortical neurons. Indeed, the pyramidal neurons constitute together a continuous network extending over the entire neocortex, justifying the generalization: the neocortex communicates first and foremost within itself. The typical pyramidal neurons represent the end stage of a progressive evolutionary process. During further development many of these elements have become transformed by reduction into various kinds of atypical or aberrant pyramidal neurons. Interestingly, none of the six morphological characteristics, mentioned above under 1-6, has appeared to be unassailable; pyramidal neurons lacking spines, apical dendrites, long axons and intracortical axon collaterals etc. have all been described. From an evolutionary point of view the typical pyramidal neurons represent not only the principal neocortical elements, but also the source of various excitatory local circuit neurons. The spiny stellate cells, which are abundant in highly specialized primary sensory areas, form a remarkable case in point.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7840422 TI - Changes in volume, surface estimate, three-dimensional shape and total number of neurons of the human primary visual cortex from midgestation until old age. AB - Macroscopic features such as volume, surface estimate, thickness and caudorostral length of the human primary visual cortex (Brodman's area 17) of 46 human brains between midgestation and 93 years were studied by means of camera lucida drawings from serial frontal sections. Individual values were best fitted by a logistic function from midgestation to adulthood and by a regression line between adulthood and old age. Allometric functions were calculated to study developmental relationships between all the features. The three-dimensional shape of area 17 was also reconstructed from the serial sections in 15 cases and correlated with the sequence of morphological events. The sulcal pattern of area 17 begins to develop around 21 weeks of gestation but remains rather simple until birth, while it becomes more convoluted, particularly in the caudal part, during the postnatal period. Until birth, a large increase in cortical thickness (about 83% of its mean adult value) and caudorostral length (69%) produces a moderate increase in cortical volume (31%) and surface estimate (40%) of area 17. After birth, the cortical volume and surface undergo their maximum growth rate, in spite of a rather small increase in cortical thickness and caudorostral length. This is due to the development of the pattern of gyrification within and around the calcarine fissure. All macroscopic features have reached the mean adult value by the end of the first postnatal year. With aging, the only features to undergo significant regression are the cortical surface estimate and the caudorostral length. The total number of neurons in area 17 shows great interindividual variability at all ages. No decrease in the postnatal period or in aging could be demonstrated. PMID- 7840423 TI - Formation of extra digits in the interdigital spaces of the chick leg bud is not preceded by changes in the expression of the Msx and Hoxd genes. AB - By in situ hybridization we studied the expression patterns of Msx and Hoxd genes during the late development of the chick leg autopodium (foot) and compared them to patterns during the experimental development of interdigital extra digits. Extra digits are induced in the third interdigital space after various experimental manipulations, such as transient isolation of the interdigit, or removal of the interdigital marginal ectoderm and mesoderm. Msx1 and Msx2 are normally expressed in the interdigital tissue programmed to die. Our experiment changes the fate of the interdigital tissue from cell death to chondrogenesis and provides a good model for studying Msx involvement in defining areas of programmed cell death. Among the proposed roles of Hoxd genes is their involvement in the specification of digit identity early in development. The induction of extra digits allows us to examine whether this new morphogenetic commitment of the interdigital tissues involves changes in the domains of expression of Hoxd genes. Our results show that extra digits develop without a previous modification of the normal pattern of expression of Msx or Hoxd genes. This observation does not support the correlation between the expression of Msx genes and programmed cell death and suggests a role for these genes in maintaining the interdigital tissue in an undifferentiated state. Our results show that an increased number of digits can be formed without modifications in the pattern of expression of the 5'-located Hoxd genes and suggest the existence of latent or residual digit organization mechanisms past the time when digits are normally determined, independent of Hoxd gene expression. PMID- 7840424 TI - Localization of diazepam-binding inhibitor and peripheral type benzodiazepine binding sites in the rat ovary. AB - Diazepam-binding inhibitor (DBI) is the precursor of a family of peptides, including an octadecaneuropeptide (ODN), that share with DBI the ability to specifically displace benzodiazepines (BZD) from their receptors. An association of ODN with the peripheral type BZD receptors (PBR) has been reported in the brain and a few peripheral tissues. In order to investigate whether DBI and PBR are present in ovarian tissue, we have localized DBI by means of immunocytochemistry, in situ hybridization and autoradiography of PBR in the rat ovary. Immunocytochemical localization was achieved by means of rabbit antibodies developed against rat ODN. Immunostaining was located in the cytoplasm of the theca interna, corpus luteum and interstitial gland cells, but not in the granulosa cells. Hybridization signal obtained following in situ hybridization with a [35S]-labelled single-stranded RNA probe complementary to DBI mRNA was observed in all the steroid-secreting cells, including granulosa cells of developing and mature follicles. Autoradiographic localization of PBR obtained by incubating ovary sections with [3H] PK11195, a ligand selective for PBR, revealed the presence of specific labelling in all the steroid-secreting cells. These results, which demonstrate for the first time that the ovarian steroid-secreting cells contain both PBR and its endogenous ligand, suggest that the BZD receptor might be involved in the regulation of ovarian function. PMID- 7840426 TI - [Hepatitis E virus]. AB - Hepatitis E, a faecal-oral waterborne acute viral hepatitis, occurs most frequently in epidemic outbreaks in developing countries. Hepatitis E virus (HEV) is spherical, nonenveloped and varied in size from 27 to 34 nm with a spiked surface. Experimental HEV infection in primates, molecular cloning involving cDNA libraries and recombinant protein technology indicate that the genome can be assigned to a 7.6 kb single stranded positive polyadenylated RNA. In a 5'NS-S poly A 3' molecular structure, three partially overlapping ORF have been identified. Two strains (Burma and Mexico) have been studied and although they related to caliciviruses, the genetic organization indicates that it represents different agents ranged in a new subgroup: the alpha-like viruses. HEV is an important cause of morbidity and mortality in developing countries in the 15 to 40 year age-group and although the mortality rate is low in the general population (0.5 to 3%), it averages 17 to 20% among third-trimester pregnant women. Several sporadic cases have been recently identified among children. The prevalence of anti-HEV antibodies in blood donors ranges from 2 to 3% in North Europe and USA and from 6.8% in Spain to 70% in Thailand. The average incubation period is 6 weeks. Chronic liver disease, persistent viraemia and oncogenicity have not been observed. HEV particles are identified in stool or bile by immune electron microscopy, capture immunoassay or RT-PCR.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7840425 TI - Parcellation of cortical areas by in situ hybridization for somatostatin mRNA in the adult rat: frontal, parietal, occipital, and temporal regions. AB - The expression of somatostatin mRNA within the neocortex of the rat was examined by in situ hybridization with an alkaline phosphatase-labeled probe. We sought to determine whether parcellation of the neocortex could be based upon the number and laminar location of the hybridized cells. Our investigation demonstrated that the boundaries of the neocortical areas can be determined by the distribution pattern of neurons expressing somatostatin mRNA. Few hybridized cells were located within layer IV, and this sparsity of cells within their wide granular layer marked the primary sensory areas. The occipital region was stratified, with intensely labeled cells in layers II/III and VI and faintly labeled cells in layer V. The parietal region carried a similar stratification, but more space between intensely labeled cells in layers III and V and between layers V and VI gave the region a three-tiered appearance. The temporal region displayed intensely labeled cells dispersed throughout layers III and VI and many in layer V as well as those faintly labeled without any breaks between the laminae. The distribution of the cells hybridized for somatostatin mRNA formed two configurations within the frontal region. It was difficult to identify any lamination in the first area, whereas the second area demonstrated a stratification reminiscent of the parietal region, but with only two tiers. The conclusion of the investigation is that in situ hybridization fro somatostatin mRNA provides an exceptional means by which the area boundaries within the neocortex may be drawn. PMID- 7840427 TI - [Vitamin E: metabolism and role in atherosclerosis]. AB - Vitamin E is the term used for eight naturally occurring fat-soluble nutrients. Alpha-tocopherol predominates in many species and has the highest biological activity. Vitamin E is absorbed via the lymphatic pathway and transported in association with CM. Vitamin E is carried in plasma by lipoproteins. It is secreted by the liver in nascent VLDL with a preferential incorporation of alpha tocopherol. Most of the plasma vitamin E is in LDL and in HDL. Vitamin E is exchanged readily between lipoproteins: tocopherol in HDL readily transfers to apolipoprotein B-containing lipoproteins (VLDL, LDL), with little return of tocopherol from the apolipoprotein B-containing lipoproteins to HDL. The mechanisms of tissue uptake of vitamin E from the lipoproteins is poorly understood. This uptake may occur during catabolism of triacylglycerol-rich lipoproteins by the activity of lipoprotein lipase, via the LDL receptor or by nonreceptor-mediated uptake. Vitamin E may act to prevent the initiation/progression of spontaneous atherosclerosis. This concept is based on in-vitro data: vitamin E influences the responses of cells (vascular endothelial cells, leukocytes, vascular smooth muscle cells) and the modification of lipoproteins (especially LDL) which, at least in principle, could contribute to the initiation/progression of spontaneous atherosclerosis. In vivo studies are clearly required to establish the extent and mode of vitamin E's antiatherosclerotic impact and, hence, its therapeutic potential. PMID- 7840428 TI - Haemolyzed samples: responsibility of short catheters. AB - The haemolysis of blood samples is a source of error in the electrolytic and enzymatic determination in clinical biochemistry. This circumstance seems dependent on the material used for the venepuncture. In this study we compared three kinds of material in 350 patients who were sampled in the emergency department. This randomized study compared the haemolysis of blood samples collected with stainless steel needles and short catheters, either Teflon FEP (Cathlon Critikon) or polyurethane Vialon (Insyte Becton-Dickinson). Quantification of hemolysis was performed by assay of the optical density of plasma haemoglobin. Results were analysed, after verification of the randomization, by one-way analysis of variance by ranks. This study demonstrated a highly significant relation between occurrence of haemolysis and the sampling material, used according to its technical obligations. Haemolysis occurred frequently when short catheters were used in 42% and 55% of cases with the Teflon and Vialon catheters, respectively. Haemolysis was much less frequent with stainless steel needles (12%). This difference was even more marked for haemoglobin levels above 1.5 milligrams of plasma, where the incidence was 4.2%, 9% and 30%, respectively, for the stainless steel needles, the Teflon catheter and the Vialon catheter. This study induced our emergency department to take more blood samples with a needle, even if an infusion was to be given subsequently, or to take them using a Teflon catheter. PMID- 7840429 TI - Usefulness of reference limits and evaluation of significant differences. An example of the biological variation of serum rheumatoid factors. AB - To establish analytical quality standards based on biological variations and to evaluate the usefulness of reference values for rheumatoid factors (RF), analytical and biological variations in samples from 34 volunteers between 23 and 46 years old were estimated at monthly intervals for six months. The samples were processed in duplicate on a Hitachi 717 automatic analyzer using the manufacturer's reagents. The within- and between-subject coefficients of variation associated with RF were 8.5% and 24.5% respectively, and the individuality index was 0.45, indicating the high individuality of this parameter. The analytical standards of quality estimated as coefficients of variation (%) were: imprecision, 4.2% and inaccuracy, 6.5%. The heterogeneity index of the within-subject variances was 0.17, thus not rejecting the homogeneity hypothesis. The RF may be considered useful for monitoring purposes because of their high individuality and relatively small critical difference (25% for alpha = 0.10). However, when RF levels are normal it is difficult to interpret them because of their high between-subject variability. PMID- 7840430 TI - [Multicenter study of sialic acid deficient transferrin determined by two chromatographic techniques]. AB - Serum carbohydrate-deficient-transferrin (CDT) was measured by a micro anion exchange chromatography/enzyme immunoassay. Results obtained on 245 sera analyzed in four laboratories were compared. Moreover, one laboratory used a commercial kit with ready-to-use microcolumns and a radioimmunoassay for measuring eluted CDT. Imprecision was judged to be satisfactory. Within-assay coefficients of variation ranged from 5 to 10%, between-assay coefficients of variation ranged from 9 to 18%. Between-laboratory results were compared for 110 sera from control subjects (daily alcohol intake < 40 g), for 57 sera from chronic ethylic subjects and for 78 sera from patients suffering from non-alcoholic liver diseases. There was a large between-laboratory variation, suggesting that the method is difficult to standardize and that results are not transferable. Results of enzyme and radioimmunoassays were compared on 325 sera. The best correlation was obtained in the groups of ethylic subjects and those with non-alcoholic hepatic diseases. Finally the performance of the CDT-test was evaluated by calculating sensitivity and specificity. With both methods specificity was very high (> 85%) but sensitivity was poor (< 50%). PMID- 7840431 TI - [Determination of plasma retinol and alpha-tocopherol by HPLC]. AB - Retinol (vit A) and alpha-tocopherol (vit E), the active compounds of vitamins A and E, were assayed by reversed-phase high performance liquid chromatography (HPLC) (C18) with UV absorbance detection at 280 nm. Plasma was deproteinized and liquid-liquid extraction performed with hexane. After evaporation, the residue was dissolved in organic solvents (ether:methanol 25:75, V/V). Standard curves were prepared by adding known amounts of standards to plasma. The use of acetonitrile in the mobile phase (acetonitrile:methanol:water 64.5:33:2.5, V/V) avoided interference peaks, giving a total run time of 8 min. Analyte stability required that samples be treated in the dark. Analytical performance was good: recovery around 100%, detection limits 0.015 mg/l for vit A and 0.030 mg/l for vit E, linear range 2 mg/l for vit A and 20 mg/l for vit E, no recorded interference, and between-run and within-run precision with coefficients of variation < 11%. Analytes were stable at room temperature for 24 h (vit A) and 48 h (vit E) in plasma stored in the dark for one month at -20 degrees C. The standard solution containing both vit A and vit E increased vit A stability. Plasma concentrations (mg/l) for vit A and E were respectively: 0.63 +/- 0.17 and 9.61 +/- 3.1 in adults (n = 29), 0.39 +/- 0.17 et 7.10 +/- 2.41 in children 0 to 15 years (n = 21). This method allows regular monitoring of patients with cystic fibrosis to check for retinol and alpha-tocopherol deficiencies. The usefulness and results of the method are discussed in terms of previous studies. PMID- 7840433 TI - Nephelometric measurements of human IgG subclasses and their reference ranges. AB - IgG subclass measurements are generally performed with the radial immunodiffusion (RID) technique. With this method, results are obtained after an incubation period of 48-72 hours. We developed nephelometric assays on the Behring Nephelometer Analyzer (BNA) that allow a quantification of IgG subclass concentrations in a large number of samples quickly (less than 15 minutes for a complete IgG subclass profile) and reproducibly (intra-assay variation 2.5-5.5%, interassay variation 3.4-6.0% and inter-lab variation 5.4-10.3%). The nephelometric method was compared with the RID technique by analyzing the IgG subclass levels in sixty selected samples. For all IgG subclasses identical results and high correlation coefficients (r > 0.93) were found. In addition, the detection limits of the nephelometric method for all four IgG subclasses were identical or lower than those of the RID technique. Furthermore, the interlab variations of the nephelometric IgG subclass assays are lower than those of the RID method. However, the major advantages of the nephelometric assay are the speed, the minimal workload (automated IgG subclass determinations) and the possibility for automated bidirectional data transmission. Recently we have established new reference ranges for the human IgG subclasses in sera of adults and children. In order to validate these reference values we have measured the IgG subclasses in sera from 112 healthy children with the nephelometric method. In 1992, more than 2000 patient sera were tested by the nephelometric assay. A predominance of IgG2 abnormality was observed. In 9.8% of these sera the IgG2 concentration was decreased. Elevated IgG2 concentrations were found in 1.9% of the sera. Furthermore, the sum of the quantitated four IgG subclasses was similar to that of total IgG (less than 20% difference). PMID- 7840432 TI - [Multicenter study of commercial kits for the determination of human IgG subclasses, using the ELISA technique]. AB - We evaluated two commercially available sandwich type Elisa procedures for the measurement of IgG subclasses in human serum. Assay kits from The Binding Site and the Central Laboratory of the Netherlands Red Cross Blood Transfusion Service were tested in six laboratories. The performance of spectrophotometers, pipettes and dilutors were assessed at each center. Within-run precision was estimated according to the Valtec method (Societe Francaise de Biologie Clinique). The overall coefficient of variation ranged from 4 to 50% depending on subclass and kit. We also evaluated the IgG2 and IgG4 specificity using four sera containing a monoclonal IgG2 or IgG4 (kappa or lambda type). Using total IgG and immunoelectrophoresis as a comparative technique, IgG2 kappa and IgG4 kappa were both underestimated, IgG2 lambda was overestimated while IgG4 lambda compared favorably. Polyclonal IgG subclasses were frequently overestimated in these sera suggesting cross-reactions with either monoclonal IgG or other polyclonal IgG. Antigen excess was investigated and not encountered with either kit. Our results demonstrate that these procedures are insufficiently accurate or precise for routine clinical use. PMID- 7840435 TI - [Oncogenes and anti-oncogenes. Application of molecular biology in medicine in the field of cancer]. PMID- 7840434 TI - Homogentisic acid oxidase activity in homozygous and heterozygous alkaptonuric mice. PMID- 7840436 TI - [Biochemistry of atheroma and thrombosis]. PMID- 7840437 TI - [Mitochondrial cytopathies]. PMID- 7840438 TI - [Better understanding and to use new technologies]. PMID- 7840439 TI - Disease in evolution. Introduction. PMID- 7840440 TI - Disease in Evolution: Global Changes and Emergence of Infectious Diseases. Proceedings of a conference. Woods Hole, Massachusetts, November 7-10, 1993. PMID- 7840441 TI - Vector-borne emerging pathogens. Introduction. PMID- 7840442 TI - Vector-borne emergent disease. PMID- 7840443 TI - The emerging epidemiology of Venezuelan hemorrhagic fever and Oropouche fever in tropical South America. PMID- 7840444 TI - Marine ecosystem health. Implications for public health. PMID- 7840445 TI - The discovery of arbovirus diseases. PMID- 7840446 TI - The emergence of Lyme disease and human babesiosis in a changing environment. AB - This pattern of spread of Lyme disease and its vectors in the northeastern United States and Europe derives from the recent proliferation of deer, and the abundance of deer derives from the process of reforestation now taking place throughout the North Temperate Zone of the world. Residential development seems to favor small tree-enclosed meadows interspersed with strips of woodland, a "patchiness" much prized by deer, mice, and humans. As a result, increasingly large numbers of people live where risk of Lyme disease and babesiosis is intense. The agents of these infections, that once were transmitted enzootically by an exclusively rodent-feeding vector, have become zoonotic. PMID- 7840447 TI - Emergence of eastern encephalitis in Massachusetts. AB - The 20th century emergence in Massachusetts of zoonotic eastern encephalitis was interpreted in terms of recorded environmental change. The main mosquito vector of the infection, Cs. melanura, appears to have been scarce in eastern North America before the 1930s. Its relative scarcity resulted from destruction of the swamps that had been lumbered or drained for farming in the 18th and 19th centuries. When swamps matured once again early in the 1900s, the formation of subsurface pools of water beneath mature trees would have increased the availability of breeding sites for this mosquito. Transmission would have further been enhanced by the simultaneous proliferation of wetland-roosting robins and the extinction of such vagile birds as the passenger pigeon. Although numerous horses were maintained in Massachusetts at the time, no outbreaks of "equine sleeping sickness" came to public notice between the 1830s and the 1930s, when mature trees were scarce and the fauna was most disturbed. The severity of the first major outbreak in 1938 may have been potentiated by the absence of herd immunity in a rapidly proliferating population of reservoir birds. These considerations suggest that recent landscape and faunal changes caused zoonotic EE to emerge in Massachusetts after waning for a century. PMID- 7840448 TI - Rift Valley fever virus ecology and the epidemiology of disease emergence. PMID- 7840449 TI - The emergence of new plant diseases. The case of insect-transmitted plant viruses. PMID- 7840450 TI - Hantaviruses and the hantavirus outbreak in the United States. A case study in disease emergence. PMID- 7840451 TI - Models for new and resurgent diseases. PMID- 7840453 TI - Coastal ecosystem health. A global perspective. PMID- 7840452 TI - Evolution of mathematical models of epidemics. PMID- 7840454 TI - Characteristics of host-parasite interactions that promote parasite persistence. PMID- 7840455 TI - Virulence of vector-borne pathogens. A stochastic automata model of perpetuation. AB - To determine how virulence may be perpetuated in populations of vector-borne pathogens, we simulated their fitness in a stochastic simulation based on cellular automata. Thereby, directly transmissible pathogens that differed in virulence were permitted to compete for hosts with similarly virulent pathogens that could infect hosts remotely because they were vector-borne. Fitness was defined as the proportion of the host population infected with each pathogen at equilibrium. Virulent, directly transmitted pathogens prevailed solely when their infectivity was transient. When duration of infectivity exceeded that of host survival, the less virulent pathogen invariably prevailed. Although remotely transmitted virulent pathogens persisted somewhat longer than did virulent pathogens that were transmitted directly, they never perpetuated themselves. We conclude that populations of vector-borne pathogens may retain pathogenicity somewhat longer than do those that are directly transmitted, but that both kinds of pathogens tend to become nonvirulent. PMID- 7840457 TI - Mathematical modeling. Concept paper. PMID- 7840456 TI - Natural selection in pathogens. PMID- 7840458 TI - Emerging epidemic diseases. Anthropological perspectives. PMID- 7840459 TI - Health transitions and complex systems. A challenge to prediction? PMID- 7840460 TI - Disease, population and virulence. Thoughts about measles mortality. PMID- 7840461 TI - Economic development and tropical disease. AB - Development stands for an improved quality of life through gains in health, education, living standards, and higher income. Development is based on economic growth. Although all indicators of development: GDP per capita, average life expectancy at birth, and per capita income have been rising in almost all countries, including the "developing" countries over the past decades, economic growth did not lead to the expected disappearance of infectious diseases. Economic growth is associated with severe degradation of the natural world. Though economic growth is essential for development, it is a highly imperfect proxy for it. The people who suffer from the adverse effects of economic growth are often different from those who benefit from it. Economic development shows two faces with regard to tropical diseases: it is essential for their prevention and cure and it contributes to their transmission and severity through its impact on the environment. The pivotal point is poverty. If economic growth leads to improved education and social organization, even adverse effects can be mastered by the community. PMID- 7840462 TI - Human movements and behavioral factors in the emergence of diseases. PMID- 7840463 TI - New diseases. The human factor. PMID- 7840464 TI - Vulnerability and the distribution of exposures. Concept paper. PMID- 7840465 TI - Detection, surveillance, and response to emerging diseases. Introduction. PMID- 7840466 TI - Indirect (unanticipated) effects of intervention. PMID- 7840467 TI - Global surveillance for recognition and response to emerging diseases. PMID- 7840468 TI - Emerging infectious diseases in the United States, Improved surveillance, a requisite for prevention. AB - Emerging infectious diseases such as prolonged diarrheal illness due to water borne Cryptosporidium, hemorrhagic colitis and renal failure from food-borne E. coli O157:H7, and rodent-borne hantavirus pulmonary syndrome as well as reemerging infections such as tuberculosis, pertussis, and cholera vividly illustrate that we remain highly vulnerable to the microorganisms with which we share our environment. Prompt detection of new and resurgent infectious disease threats depends on careful monitoring by modern surveillance systems. This article focuses on five important elements of improved surveillance for emerging infections: 1) strengthening the national notifiable disease system, 2) establishing sentinel surveillance networks, 3) establishing population-based emerging infections programs, 4) developing a system for enhanced global surveillance, and 5) applying new tools and novel approaches to surveillance. PMID- 7840469 TI - Pneumonia in the United States. Shifting perceptions of causality. PMID- 7840470 TI - Diagnosis of new and resurgent diseases. Contributions from longitudinal community health research. PMID- 7840471 TI - Nosocomial amplifiers of microbial emergence. PMID- 7840472 TI - The environment, remote sensing, and malaria control. AB - Results of studies in California, Mexico and Belize demonstrate the value of remote sensing technology for studying vector-borne diseases. These studies have also shown that it is necessary to fully define the environmental factors associated with the presence of vectors and disease transmission, and to be able to detect these environmental factors with image data. These studies, and other published reports, are demonstrating many potential uses of remotely sensed data in managing and targeting vector and disease control measures. PMID- 7840473 TI - Basic elements in a conceptual framework for new and resurgent disease. Introduction--conceptual framework section. PMID- 7840474 TI - Challenging complexity. Conceptual issues in an approach to new disease. PMID- 7840475 TI - Developing paradigms to anticipate emerging diseases. Transmission cycles and a search for pattern. PMID- 7840476 TI - Framework for an integrated assessment of health, climate change, and ecosystem vulnerability. PMID- 7840477 TI - Prediction and biological evolution. Concept paper. AB - The major issue addressed was how to introduce evolutionary thinking into epidemiology, and the appropriate approach to "evolutionary epidemiology." There was general agreement that disease emergence is not a static but a dynamic process, and that dynamic approaches should therefore be emphasized. PMID- 7840478 TI - Environmental reservoir of Vibrio cholerae. The causative agent of cholera. PMID- 7840479 TI - Cholera El Tor in Latin America, 1991-1993. PMID- 7840480 TI - Harmful marine phytoplankton and shellfish toxicity. Potential consequences of climate change. PMID- 7840481 TI - Emerging diseases associated with seafood toxins and other water-borne agents. PMID- 7840482 TI - [Occupational allergic rhinitis]. AB - The frequency of occupational allergic rhinitis has grown with the development of new allergens and the prodromic characteristic of occupational asthma. The clinician must carefully assess the often unimpressive symptomatology with a characteristic work/non work cycle. The nasal mucosa is examined rhinoscopically to eliminate a possible tumoural origin. The diagnosis is based on the results of the allergy tests (skin tests, laboratory tests, nasal allergen tests) and on knowledge of the patient's work environment. The diagnosis of occupational rhinitis requires eliminating the allergen(s). A report of an occupational disease is required. In the future, informing atopic subjects early, improving working conditions and modifying industrial techniques should lead to a reduction in the prevalence of allergic rhinitis and occupational pulmonary disease. PMID- 7840483 TI - [Recurrence of nasosinusal polyposis after ethmoidectomy by endonasal approach. Functional, endoscopic, x-ray tomographic aspects and surgical implications]. AB - Recurrent polyposis after 116 endonasal ethmoidectomies performed in 61 patients were investigated on the basis of functional, endoscopic and tomodensitometric data. The results of the endoscopic examinations revealed that the anterior ethmoid was involved most often (41%) with either a single localization or in combination with other sites in the sinuses. Functional rhinosinus symptomatology was satisfactory in most cases after a mean follow-up of 22 months, especially for nasal obstruction which was initially predominant (91%). Headaches, especially fronto-orbial localizations, clearly decreased after the operation but there was no correlation between the presence of headache after the operation and the recurrence of the polyposis. Computed tomography gave results similar to those obtained by endoscopy. However, a distinction could not be made between radio-opaque images of polyposis and certain cicatricial or inflammatory reactions. Unlike the functional outcome, ethmoidectomy had little effect on these images. Recurrent polyps appeared most often on the anterior ethmoid and the role of the initial infundibulotomy can be debated. It would appear that the prognosis of polyposis is not modified by extended anterior ethmoidectomy, suggesting that a more conservative surgical approach may be appropriate for frontal ethomoidal polyps. PMID- 7840484 TI - [Hyo-sub-glosso-epiglottectomy in the surgical treatment of tumors of the vallecula and anterior laryngeal margin]. AB - Hyo-sub-glosso-epiglottectomy was performed in 56 patients with a tumour of the vallecula or the anterior laryngeal margin. Tumour classification in most of the patients was T2 and N0-N1. Survival rate at 3 years was 54% and 40% at 5 years. Major impairment of deglutition occurred in 5.4% of the cases. This operation is indicated for limited tumours of the vallecula and the anterior laryngeal margin. PMID- 7840485 TI - [Removal and replacement of the septal cartilage in noses with traumatic injuries, causing deviation. Technique--results]. AB - The nasal septum in 44 patients with deviated noses due to trauma and complex lesions of the septal cartilage leading to bilateral or unilateral nasal obstruction underwent removal then reinstallation of the nasal cartilage. The results of the surgical technique were evaluated according to the access route, external or endonasal, and demonstrated the advantages and disadvantages of this technique which is a crucial step in the treatment of severe traumatic lesions of the nasal septum. PMID- 7840486 TI - [Treatment of blepharospasm and facial hemispasm with botulinum toxin. Apropos of 58 injections in 22 patients]. AB - Through this analysis we shall report our experience about botulinum toxin in view of relieving blepharospasm and hemifacial spasm. Many Treatments have been tested with very inconstant often deceptive and sometimes even dangerous results. The present method gives us the possibility to paralyze the spasmed muscles by direct injection into the muscle. After 58 ambulatory injections, 53 effective results were obtained with complete spasm relief for a mean internal of 4 to 5 months. No systemic effect was noticed, but some transient ophthalmic incidents occurred: they can be avoided by simple technical precautions. In hemifacial spasm, the orbicularis eyelid muscle seems to be the "spasm starter" and its unique injection by toxin can often relieve the whole hemiface. This simple method appears remarkably effective, although its duration is limited to a few months; but the injections can be conveniently repeated. However, this technique has to be carefully performed by experienced physicians. It is extremely regrettable to see the enormous price increase of toxin within the last years. This limits a larger use for patients good health. PMID- 7840487 TI - [Value of hyomandibulopexia in the surgical treatment of snoring in patients with sleep apnea]. AB - The authors report their experience with hyomandibulopexia for lingual repositioning in patients with the sleep apnea syndrome. The technique was used 12 times in 11 men and 1 woman and a maximum follow-up of 3.4 years. Hypomandibulopexia was performed as first intention therapy 7 times with or without uvulo-palato-pharyngoplasty. Video-fibroscopy of the pharynx and cephalic magnetic resonance imagery revealed retrobasilingual narrowing in all 7 of these cases. Hyomandibulopexia was performed 5 times for recurrent sleep apnoea syndrome after prior surgery. In two cases, pre-operative evaluation did not reveal any topographic abnormality. Polysomnography studies showed clear improvement with a decreased apneic index and desaturation values. A second fixation of the hyoid was success fully in one case. Hyomandibulopexia is a simple and reliable technique which is useful in patients with sleep apnea syndrome with good to excellent medium term results. PMID- 7840488 TI - [Role of endoscopy and vascular decompression in the treatment of hemifacial spasm]. AB - Although it has long been hypothesized that hemifacial spasm could arise from a conflict between the nerve and the artery, it is very difficult to distinguish between a normal arterial loop and a pathological conflict leading to facial symptoms. Several new elements would help in the definition of the cause and allow less traumatic treatment of idiopathic hemifacial spasm. They include magnetic resonance imagery with CISS sequences, limited retrosigmoid approach, endoscopy of the cerebellopontine angle and monitoring the facial nerve. In our experience with 20 cases, retrosigmoid approach with a combined surgical and endoscopic procedure has led to total involution of the spasms in 80% of the cases. PMID- 7840489 TI - [Facial nerve involvement after surgery of the parotid gland]. AB - The authors report a retrospective study of 351 parotidectomies observed during a 28 years period. The average follow-up is 28 months. Preoperative and postoperative facial nerve function, type of parotidectomy, surgical management of facial nerve, and histologic diagnosis according to the revised WHO classification (1990) are presented. Type of parotidectomy and degree of tumor malignancy are statistically analyzed. It seems that occurrence of post-operative facial nerve dysfunction depends on radical parotidectomy, whereas long term dysfunction is determined by tumor malignancy. Malignant epithelial tumors of the major salivary glands proved to be radiosensitive. Apart from preoperative dysfunction, clinical involvement and impossible facial nerve dissection, the authors insist upon sparing the facial nerve, even in the case of microscopic residual tumors, and prefer postoperative radiotherapy. PMID- 7840490 TI - [Undifferentiated osteogenic carcinoma of the thyroid]. AB - A case of osteogenic thyroid carcinoma in a 68 years old male patient is reported. The WHO histopathological classification of such exceptional tumor is reminded. A review of the literature and the treatment modalities are discussed. Several etiological hypotheses are discussed. PMID- 7840491 TI - Menstrual disorders and month of birth. AB - Menstrual characteristics in a population of 23,227 women who participated in a breast cancer screening programme were considered with respect to month of birth. High and low risk months of birth were defined according to the seasonal preovulatory overripeness ovopathy (SPrOO) hypothesis. Positive associations were found in 11 out of the 14 relations studied. The results were significant for early menarche (< or = 11 years), long menstrual cycles (> or = 5 weeks), menorrhagia (> or = 7 days and profuse blood loss), and early (< or = 40 years) or late (> or = 56 years) menopause. The results not only confirm the birth excess of these women in specific months, as has been found by others. They apparently agree with the SPrOO hypothesis and with a transgenerational concept of familial subfecundability along matrilineal lines and hence, familial clustering of pathological progeny, independent of Mendelian rules. PMID- 7840492 TI - Digital and palmar dermatoglyphics and the population structure of the Upper Bologna Apennine. AB - Analysis of digital and palmar dermatoglyphics in an Italian mountain population was carried out. Dermatoglyphic variability was particularly investigated in samples from four different valleys. Microgeographical differences in qualitative and quantitative traits among valleys were found. The relationship between degree of endogamy and dermatoglyphic differences is discussed. The biological repercussion of isolation in the history of this Apennine population is also pointed out by means of comparisons with a nearby plains population characterized by low inbreeding. PMID- 7840493 TI - Body composition of the preterm infant. AB - The body composition of 23 infants was examined at postmortem. All infants were live births and lived from 1 to 192 days. Their body weights at birth ranged from 480 to 3280 g; gestational ages ranged from 24 to 42 weeks. Total body composition was determined using the nondestructive in-situ procedures of 40K counting and neutron activation analysis. The absolute amounts of K, Ca, P, Na, and Cl were measured. Although body Cl was in general agreement with estimates for the reference fetus model, body K and Na values were lower. Body Ca content was higher than the reference fetus at body weights above 2 kg, yet body P levels agreed with the reference fetus. Furthermore, those infants whose survival was brief had reduced body K, an index of body cell mass. All elements except body Cl were linearly related to fat-free mass (FFM). The correlations with gestational age were non-significant when the variation in elemental content was accounted for by FFM or body weight. The two preterm infants who survived for more than 10 weeks had significantly reduced bone growth as shown by their Ca and P deficiences. PMID- 7840494 TI - Weight and length growth of two Chinese infant groups and the seasonal effects on their growth. AB - This is a longitudinal study involving 202 Chinese infants in Chengdu City and 174 Hong Kong infants in their first two years of life. Their weight and length growth are compared, and the seasonal effects on the early age growth for the two groups are illustrated by using a multilevel model approach. The Chengdu infants are found to grow faster in the first 10 months, then stay longer, heavier and fatter for the rest of the study period. The seasonal effect on weight growth for the two groups is the same with the fastest growth in winter and slowest in summer and with a mean difference of about 0.16 kg. For length the fastest is in summer for Chengdu infants but in winter for Hong Kong infants. The difference between the slowest and fastest is about 0.49 cm for the two groups. The approach used in the paper is discussed from a practical viewpoint. The reasons for the growth differences between the two groups of Chinese infants are also discussed. PMID- 7840495 TI - Sexual dimorphism of heritability of immunoglobulin levels. AB - Heritability of IgA, IgG and IgM levels was studied in 85 MZ and DZ twin pairs of both sexes. Immunoglobulin concentrations were determined by single radial diffusion. Significantly higher geometric mean of IgM level in females than males was demonstrated. Heritability coefficients h2, F and VG/VE were higher in male than female twins. This suggests that genetic factors play a more important role in males as compared with females in regulating the three immunoglobulin levels. Quantitative comparison of genetic variances of both sexes indicated slightly greater genetic influence in the case of IgA in females. Environmental variances of IgA and IgM levels were also higher in females than males. PMID- 7840496 TI - Reliability and repeatability of 3-D body scanner (LASS) measurements compared to anthropometry. AB - The Loughborough Anthropometric Shadow Scanner (LASS) digitizes the body, to give size and shape in three dimensions. After some manipulation of data, body measurements can be taken from the computerized scan. This paper compares LASS measurements with anthropometric measurements, and examines intra- and inter observer differences of both techniques. LASS and anthropometric measurements were generally similar. Although there were small but significant (p < 0.05) differences at some sites, these differences were explained by difficulties in making horizontal tape measurements, and by differences in site location on LASS scans due to imperfect site markers. Standard errors of measurement due to intra observer differences were generally smaller by LASS (1.1-5.3 mm) than anthropometry (2.0-7.2 mm); however, inter-observer differences were similar by both techniques (3.0-13.1 mm for anthropometry compared to 1.3-8.3 mm for LASS). Repeatability of 3-D measurements taken from computerized whole-body scans was no better than that from traditional anthropometric measurements; however, the scan data have a far greater utilization, for they provide information on body shapes, segmental volumes and surface areas as well as size. PMID- 7840497 TI - Incidence of gynaecomastia in 954 young males and its relationship to somatometric parameters. AB - The incidence of gynaecomastia was evaluated in 954 healthy young men aged 18-26 years, and was correlated with several somatometric parameters (height, weight, testes size, eye colour, scalp hair colour, scalp hair density, acne, density and extent of body hair). Gynaecomastia (> 2 cm breast tissue) was found in 40.5% (bilateral 85%, left 7.8%, right 7.2%) of the subjects. Highly statistically significant differences were found between subjects with or without gynaecomastia in their weight (79.7 +/- 10.7 kg versus 69.1 +/- 7.8 kg respectively; p < 0.001) and in their body hair (subjects with gynaecomastia had more dense and extensive body hair than those without; p < 0.001). When the density and extent of body hair was analysed separately for each age, it was found that subjects with gynaecomastia had completed the development of body hair earlier, since 80% of them had completed their body hair by the age of 23 years versus only 45% of those without gynaecomastia. This observation leads to the assumption that obesity and/or an earlier maturation of the subjects with gynaecomastia may play a role in the development of breast tissue, although the possibility of an increased tissue sensitivity to hormonal action cannot be excluded. PMID- 7840498 TI - Effect of average heterozygosity on the genetic distance of several Indian tribes from the Amazon region. AB - The relationship between average heterozgosity and genetic distance estimates was evaluated among 13 Amazonian Indian tribes, using data of 24 genetic systems. The results showed that the genetic distances were negatively correlated with the average heterozygosity for each pair of tribes. The relationship between genetic and geographic distances was also examined, but no significant correlation was observed between these measures. The negative correlation between genetic distance and average heterozygosity may be attributed to the bottleneck effect or inbreeding due to the small effective size of several tribes, reducing the heterozgosity and increasing the genetic distance between them. PMID- 7840499 TI - Growth of Japanese breast-fed and bottle-fed infants from birth to 20 months. AB - Longitudinal data for weight and length from birth to the 20th month of age obtained from 318 healthy infants were analysed in relation to type of feeding during infancy (breast- or bottle-fed). Differences in the growth patterns of infants according to the type of feeding were confirmed, breast-fed infants tending to be lighter in weight between 6 and 20 months of age than bottle- or mixed-fed infants. However, our analyses of the infants' growth patterns suggest that the differences in mean weight between breast- and bottle-fed infants may be due at least in part to overfeeding of bottle-fed infants. Thus, it is advisable that the standard growth curve for breast-fed infants be based on observations of the growth of a large number of infants who are fed on breast milk only. PMID- 7840500 TI - Relative expansion of extracellular water in elite male athletes compared to recreational sportsmen. AB - This study reports total body hydration and water distribution between the extracellular water (ECW) and the intracellular water (ICW) of a group of 15 elite male athletes compared with a group of 15 male subjects practising the same sport at 'amateur' level. Total body water (TBW) and ECW were assessed by means of deuterium and bromide dilution techniques respectively. Both TBW and body hydration were significantly higher in elite athletes than in non-competitive subjects (52.3 +/- 5.0 vs 46.1 +/- 4.2 litres p < 0.001 and 63.2 +/- 1.9 vs 60.2 +/- 1.9% body weight, p < 0.003 respectively). Likewise, both ECW the ratio of ECW to TBW were significantly higher in athletes than in control subjects (20.7 +/- 2.9 vs 16.1 +/- 1.8 litres, p < 0.0001 and 0.40 +/- 0.06 vs 0.35 +/- 0.03, p < 0.005 respectively). ICW was similar in both groups but the ICW to ECW ratio was significantly higher in the athletes compared to the recreational sportsmen (0.67 +/- 0.16 vs 0.54 +/- 0.07, p < 0.01). These data suggest that assumptions regarding the chemical composition of the standard human body may not be valid in elite athletes. PMID- 7840501 TI - Prediction of body density from skinfold thickness in elderly subjects: are the existing equations valid? AB - In 33 healthy elderly subjects, body density was measured using hydrodensitometry and predicted from the sum of four skinfold thicknesses. In the men, mean measured density was 1.045 kg/l and mean predicted density 1.041 kg/l, with bias and limits of agreement 0.004 (+/- 0.016) kg/l and 95% confidence interval (CI) for the difference 0.001-0.008 kg/l. In the women, mean measured density was 1.012 kg/l and mean predicted density 1.020 kg/l, and 95% CI for the difference was -0.016-0.000 kg/l. The bias was therefore in the opposite direction in women than men, and limits of agreement were wider (-0.008 +/- 0.030 kg/l) in the women. Biases in prediction of density lead to systematic error in estimation of body fatness in elderly subjects, and this systematic error is more likely to be of practical significance in women than men. PMID- 7840502 TI - Stature and body-mass index among mid-nineteenth century south Chinese immigrants. AB - Mean values of anthropometric measurements of 150 Chinese men, taken in 1864 or 1865, were recovered. The subjects had emigrated to California and were returning to China when they were measured. Comparisons were made to measurements of other Chinese men of the late nineteenth and early twentieth centuries. The men of this sample were much taller than those in other South Chinese samples, and about as tall as those in North Chinese samples. PMID- 7840503 TI - Monitoring of anticancer drug effects in vivo by serial DNA flow cytometry of oral carcinomas treated by intra-arterial 5-fluorouracil/cisplatin induction chemotherapy. AB - Thirty-one patients with squamous cell carcinomas of the oral cavity who underwent intra-arterial induction chemotherapy with 5-fluorouracil and cisplatin were analysed by DNA flow cytometry. Seven tumors consisted exclusively of diploid cells and 24 were characterized by the presence of an aneuploid tumor cell line. Response to chemotherapy as well as survival were significantly better in the diploid group. The cytotoxic effect of the treatment on aneuploid tumor cell populations was monitored in vivo by serial DNA flow cytometric measurements. Decreasing numbers of aneuploid cells were detected in all but two cases (92%); twelve (50%) showed a complete disappearance of the aberrant cell line at the end of chemotherapy. All non-responders showed persisting aneuploid tumor cells at the end of treatment. Even if response to chemotherapy was better in the group with a complete disappearance of the aneuploid cell line in the course of treatment, the survival outcome of these patients did not differ significantly from those who showed persistence of aneuploid tumor cells. PMID- 7840504 TI - Expression of transforming growth factors beta 1, beta 2, beta 3 in neuroendocrine tumors of the digestive system. AB - Neuroendocrine tumors of the digestive system are slowly growing neoplasms which often present pronounced fibrosis around tumor cells and in the peritoneal cavity. In this study, 23 midgut carcinoids and 7 endocrine pancreatic tumors were examined for the presence of TGF-beta with affinity-purified polyclonal antibodies raised against synthetic peptides coding for a specific region of latency-associated peptide sequences of TGF-beta 1, -beta 2, -beta 3, a rabbit anti serum against TGF-beta binding protein (LTBP) and a rabbit polyclonal antibody against TGF-beta type II-receptor (TGF-beta RII). Tumor cells from most tissues expressed all three isoforms of TGF-beta but LTBP was only weakly expressed. In stromal cells abundant expression of TGF-beta 2 and LTBP was found, whereas TGF-beta 1 and TGF-beta 3 were expressed only weakly. TGF beta RII immunoreactivity was observed mostly in the stromal cells. Tissue sections from 4 of these neuroendocrine tumors were also investigated by in situ hybridization. Strong signals on tumor cells were detected with TGF-beta 2 and TGF-beta 3 cRNA probes and also weakly with TGF-beta 1 and LTBP cRNA probe. Strong positive signals were observed on stromal cells with TGF-beta 2 and LTBP probe whereas only weak signals were observed on the stromal cells with TGF-beta 3 probe. Strong signals were detected on stromal cells with TGF-beta RII probe whereas no signals were observed on tumor cells. Our data suggest that TGF-beta might play an important role in the interaction of tumor and stromal cells. Thus TGF-beta might stimulate matrix production and angiogenesis of stromal cells, whereas tumor cells themselves are unaffected by the growth inhibitory activity of TGF beta. PMID- 7840506 TI - C-erb-B2 gene amplification and serum level of c-erb-B2 oncoprotein at primary breast cancer diagnosis. AB - We studied c-erb-B2 gene amplification of DNA of primary breast tumours without distant metastasis from 236 women admitted to our institute during 1992. For 125 of them, we had a serum sample at diagnosis, before any treatment. C-erb-B2 gene amplification (> or = 2 copies) was observed in 26% (62/236) of the cases. There was a correlation with higher histological grades (p < 0.03) and with absence of hormone receptors: ER-(p < 0.0001). PgR-(p < 0.0001), association ER- and PgR-(p < 0.0000). Large tumours T3 and T4 taken together tended to present more c-erb B2 gene amplifications (p < 0.08). There was no correlation with age, histological type or nodal status. At diagnosis, mean concentration of serum c-erb-B2 oncoprotein was 8.5 +/- 18 U/ml with a median of 4 U/ml (4-150). Choosing a cut off value of 8 U/ml gave a sensitivity of 21% (26/125). Serum levels of c-erb-B2 oncoprotein were correlated with tumour spread: large tumours T3-T4 (p < 0.001), nodal involvement (N+) (p < 0.01), association T3-T4 and N+(p < 0.0005), high levels of CA 15:3 (normal value < 25 IU/ml) (p < 0.05). There was no other correlation, particularly with age, histological type, hormone receptors or c-erb B2 gene amplification. c-erb-B2 oncoprotein serum levels could be helpful to detect recurrences. Assessment of c-erb-B2 oncoprotein serum concentration, before treatment, as an independent prognostic factor is necessary. PMID- 7840505 TI - Pharmacokinetic and clinical pilot study of high-dose intermittent ubenimex treatment in patients with myelodysplastic syndrome. AB - Ubenimex is an orally active aminopeptidase inhibitor with an immunomodulating action. A pharmacokinetic and clinical pilot study of high-dose intermittent ubenimex was performed in patients with myelodysplastic syndrome. Ubenimex (150 mg/body) was administered orally, twice per day (at a 3 hr interval), twice a week, for at least 8 weeks. The concentrations of ubenimex and p-OH ubenimex, another active metabolite, increased gradually up to 7.1 +/- 4.7 micrograms/ml (mean +/- SD) at 5 hr and 0.25 +/- 0.15 mu/ml at 6 hr. The low percentage (4.2%) of the AUC ratio (p-OH ubenimex/ubenimex) suggested minimal metabolism. The plasma half-life of ubenimex was 2.1 +/- 0.7 hr and the total urinary recovery of both was 71.4% in 48 hr. Among 8 patients clinically studied, one achieved good response and another achieved minor response. These findings suggested good bioavailability, and a certain effectiveness of ubenimex in this administration method, which was worth trying, at least in restricted cases, such as cases with refractory disease or with a poor performance status. PMID- 7840507 TI - Progesterone binding cyst protein in hormone receptor positive breast cancer; a predictive factor for effect of adjuvant tamoxifen treatment. AB - Progesterone binding cyst protein (PBCP) was measured in breast cancer cytosols from 128 pre- and post-menopausal women with operable node positive (pN+) breast cancer Stage II. All patients were included in a national multicenter study on the effect of adjuvant tamoxifen treatment in hormone sensitive breast cancer, i.e. estrogen receptor content of at least 10 pmol/g cytosol protein. Patients were randomised to receive adjuvant tamoxifen 20 mg once daily for two years or no endocrine treatment. At a median follow-up of 60 months, we found PBCP content in the primary tumor to be an important factor with regard to the effect of adjuvant tamoxifen treatment. The benefit of adjuvant tamoxifen treatment on relapse-free survival and overall survival was confined to the subpopulation of patients with PBCP negative tumors. PBCP should be further evaluated as a predictive factor for the effect of tamoxifen treatment. PMID- 7840508 TI - Deferoxamine in children with recurrent neuroblastoma. AB - We examined the short-term efficacy and toxicity of high doses of intravenous deferoxamine (DFO) in children with recurrent neuroblastoma. Ten children (3 2/12 20 years, median 6 5/12 years) had measurable recurrent disease following 1-3 prior treatment regimens. DFO (120-240 mg/kg/d) was planned as a continuous i.v. infusion for five days every other week. Serum ferritins at the start of this therapy ranged from 133-->5000 ng/ml (median 611 ng/ml). Of eight patients begun at a dose of 120-150 mg/kg/d, a single patient experienced visual disturbances which resolved after DFO was discontinued. Two patients begun at 240 mg/kg/d (with serum ferritins levels of 505 and 717 ng/ml) both experienced dose-limiting toxicity including lethargy, dizziness, blurred vision and leg cramps. Although decreases in serum ferritin levels of a least 10% were noted in 4 patients, there were no partial or complete response. DFO given at a dose of 150 mg/kg/d i.v. according to this schedule appears to be ineffective as a single agent against neuroblastoma. Starting doses of 240 mg/kg/d have unacceptable short-term toxicity. PMID- 7840509 TI - Abnormal production of androgens in women with breast cancer. AB - Two long and broad streams of medical literature, from the 1950's to date, have established the existence of two unrelated abnormalities of androgen production in women with breast cancer. One is the genetically determined presence of subnormal production of adrenal androgens (i.e. DHEA and DHEAS) in women with premenopausal breast cancer and their sisters, who are at increased risk for breast cancer. The other is excessive production of testosterone, of ovarian origin, in subsets of women with either premenopausal or postmenopausal breast cancer and women with atypical breast-duct hyperplasia, who are at increased risk for breast cancer; along with the hypertestosteronism, there is frequently chronic anovulation in the premenopausal patients. The combination of ovarian hypertestosteronism and chronic anovulation is characteristic of the polycystic ovary syndrome and is also frequently seen in women with abdominal ("android") obesity; both PCOS and abdominal obesity are known to be characterized by high risk for postmenopausal cancer. The elevated testosterone levels and the increased levels of insulin, IGF-I, and IGF-II that are seen in PCOS and abdominal obesity could favor the development of breast cancer in several ways, all of which have been demonstrated experimentally: binding of testosterone to cancer cells bearing testosterone receptors, with direct stimulation; intratissular aromatization of testosterone to estradiol, with stimulation of estrogen-sensitive cells; stimulation of the production of epithelial growth factor (EGF) by testosterone, with direct mitogenic effect of EGF on cancer cells; stimulation of aromatase by insulin and IGF-I; direct mitogenic stimulation of cancer cells by insulin, IGF-I, and IGF-II; and stimulation by IGF I and IGF-II of the intratissular reduction of estrone to estradiol. Since PCOS is probably largely genetically determined, and abdominal obesity may also be, the hypertestosteronism of these conditions may represent a second genetically determined hormonal risk factor for breast cancer. PMID- 7840510 TI - EGF/TGF-alpha and progesterone in urine of ovarian cancer patients. AB - EGF/TGF-alpha and progesterone were measured in the urine of 74 ovarian carcinoma patients, 21 postmenopausal women with non-gynecological disseminated cancer, 20 premenopausal and 20 postmenopausal controls. Radically operated women excreted significantly less EGF/TGF-alpha into urine than women with residual tumour mass. The patients who died from ovarian carcinoma had significantly higher concentrations of growth factor in urine than patients who were alive and disease free at follow-up. The highest urinary concentrations were found in the premenopausal control group and among women with non-ovarian malignancies. A significant correlation between concentrations of progesterone and EGF/TGF-alpha in urine was noted. PMID- 7840511 TI - pS2 protein status fails to be an independent prognostic factor in an average breast cancer population. AB - In this study we analysed the cytosolic concentrations of the estrogen-regulated protein pS2 in tumors of 462 breast cancer patients, 16 benign breast tumors and 58 metastases. The median pS2 values were highest in breast cancer, followed by benign tumors and metastases (Kruskal-Wallis Test: p < 0.05). Information on other prognostic factors and clinical outcome was available for 354 patients (median follow-up, 35 months). We found a pS2 value of 2 ng/mg protein to be the best cut-off level to discriminate between pS2+ (63%) and pS2- (37%) tumors with respect to relapse-free survival (RFS) and overall survival (OS). The pS2 status was significantly correlated with age, estrogen receptor (ER) and progesterone receptor (PR) status. pS2 was negatively correlated with grading and was more often positive in invasive lobular than in invasive ductal carcinomas. ER, pS2 and grading were highly significantly correlated with each other. In univariate analysis pS2- patients showed a significantly shorter RFS (p = 0.0001) and OS (p = 0.0005). However, multiple regression analysis revealed that in our series of patients the pS2 status provides no independent prognostic information. PMID- 7840512 TI - Relationship between area of serosal invasion and intraperitoneal free cancer cells in patients with gastric cancer. AB - This study, we evaluated the relationship between the macroscopic area of serosal invasion by gastric carcinoma and the incidence of intraperitoneal free cancer cells which were detected by lavage of the Douglas cavity. Between 1976 and 1989, 362 patients with advanced gastric cancer (t3, t4) were gastrectomized and intraperitoneal free cancer cells were recognized in 119 patients (32.9%). Only 17.3% of patients with an area of serosal invasion of less than 10 cm2 had free cancer cells in their peritoneal cavities, however, 68.5% of patients with an area of serosal invasion greater than 20 cm2 had free cancer cells. Even, if curative surgery was performed for patients with free cancer cells, their five year survival rate was very poor. The five-year survival rate of patients with curatively operated gastric cancer without free cancer cells was 49.3%, however that of patients with free cancer cells was significantly lower (15.4%, P < 0.01). Even when we are not able to receive the cytologic diagnosis for intraperitoneal free cancer cells during the operation, patients with macroscopic areas of serosal invasion greater than 20 cm2 may have free cancer cells in a very high percentage. They should be treated with effective adjuvant chemotherapy the soon after the operation to prevent peritoneal metastatic recurrence and to prolong survival. PMID- 7840513 TI - Spontaneous endometrial hyperplasia. A prospective, 5 year follow-up of 246 patients after abrasio only, including 380 patients followed-up for 2 years. AB - The treatment of patients with endometrial hyperplasia differs widely, ranging from immediate hysterectomy to no treatment or follow-up at all. This is due to the fact that a vital question has not been answered, namely: is endometrial hyperplasia a predecessor to carcinoma or not? In order to investigate whether endometrial hyperplasia is a premalignant state we have followed up 246 patients with abrasio only for 5 years. We found that there was no higher risk of CGH and adenomatous hyperplasia developing into a carcinomatous state than in normal cases. We found it possible to follow up these patients with abrasio only as scheduled. The very few patients developing carcinoma did so already at the first control after 3 months. Among atypical endometrial hyperplasias there was an increased risk of developing endometrial carcinoma. We could divide these patients into two groups: one with very severe atypia so close to carcinoma that an immediate hysterectomy was recommended. Nine out of 12 had already developed carcinoma at the time of the operation. In another group of 21 patients followed with abrasio only, 2 had developed carcinoma at the first control. This means that among 368 patients with endometrial hyperplasia followed-up with abrasio for 2 years, 13 were found to have carcinoma. Twelve patients with very severe atypia were recommended to have an operation and 9 were found to have cancer. Among the other 356 patients, 4 were found to have cancer at the first control (2 with an initial diagnosis of CGH and 2 with atypical hyperplasia). PMID- 7840514 TI - Treatment of metastatic colorectal carcinoma with lymphoblastoid interferon and 5 fluorouracil: data of a phase II study. AB - Many clinical trials have tested the combination of 5-fluorouracil and recombinant alpha-interferons in metastatic colorectal carcinoma. The efficacy of 5-fluorouracil and lymphoblastoid interferon was evaluated in a phase II study in which 31 patients with advanced colorectal carcinoma were enrolled. 5 Fluorouracil was administered at the dose of 600 mg/sqm bolus weekly and lymphoblastoid interferon was given intramuscularly at 3 million units every two days. All patients were evaluable for toxicity. Thirty patients were available for response: no complete response was recorded, three patients reached a partial response (10%), three a minor response (10%) and 18 progressed (59.4%). Overall median survival was 8 months. No grade IV toxicity was observed: in 2 patients grade III occurred and in 8 patients grade III fever and fatigue attributable to interferon developed. It appears that this combination does not yield better results than 5-fluorouracil alone. PMID- 7840515 TI - Immunohistochemical staining and serotest markers during development of a sarcomatoid and small cell prostate tumor. AB - Prostate cancer with marked neuroendocrine (NE) differentiation belongs to the hormone resistant carcinomas. We report the development of TSH-secreting small cell prostate cancer (SCPC) from high grade adenocarcinoma (Gleason score 8) with an elevated number of chromogranin A positive cells located in benign structures adjacent to the cancer. Conversion to SCPC was followed-up during 4 years. The initial adenocarcinoma exerted a stronger positivity for PAP than for PSA (respective staining indexes, Sls, 2.2 and 1.8, maximum staining 3.0). In the developed SCPC, 2 cell subpopulations that were derived from epithelial cells were found (positive stain for EMA and CEA, respectively) and from one of them originated CEA-positive liver metastases. Blood CEA and NSE levels were elevated in SCPC (284 ng/ml and 24.5 ng/ml). However, blood TPS level which reflects proliferation of epithelial cells was within the normal range. The development of a << pure >> sarcomatoid prostatic tumor from adenocarcinoma with 2 areas of similar differentiation grades (Gleason score 7 and 9-10) that initially differ in staining for PSA and PAP (SIs for PSA were 1.2 and 0.02 and for PAP were 1.6 and 0.02, respectively) was followed-up during 4 years of treatment with Estracyt. Adenocarcinoma tissue specimens was slightly CEA-positive. The disappearance of lower grade adenocarcinoma during treatment was accompanied by the development of sarcomatoid areas that were 100% vimentin positive. In the last year of follow-up the primary tumor was composed only of vimentin positive sarcomatoid cells with a slight positivity for Chromogranin A, NSE and ACTH. In parallel, normal serum PSA and PAP values and elevated CEA and NSE serotests (12.6 ng/ml and 24.7 ng/ml, respectively) were found. Blood TPS level was at the upper limit of the normal range. Scintigraphy revealed extensive liver metastases. The recorded data indicate (i) extremely poor prognoses associated with high grade adenocarcinomas that demonstrate stronger immunohistochemical positivity for PAP than that for PSA (ii), chromogranin A positive cells in benign structures adjacent to the cancer as a possible paracrine promoter of SCPC from poorly differentiated adenocarcinoma, and (iii) a high degree of heterogeneity of both SCPC and sarcomatoid prostatic neoplasms with some evidence for definite links (EMA and CEA) to secretory epithelial cells. PMID- 7840516 TI - Biochemical modulation of fluorouracil with high dose methotrexate or folinic acid in advanced colorectal cancer patients. Gruppo Oncologico dell' Italia Meridionale (GOIM). AB - To compare the efficacy of two biochemical modulations of 5-Fluorouracil in advanced colorectal cancer, 104 patients were randomized to receive high dose methotrexate followed by 5-Fluorouracil and leucovorin rescue on day 1 (Arm A) or folinic acid and 5-Fluorouracil on day 1 to 5 (Arm B). Both treatments were repeated every 3 weeks. In the 92 evaluable patients, objective responses were observed in 34% in Arm A and 31% in Arm B, with a median duration of 7.5 and 8.5 months, respectively. Median overall survival was similar in both groups (12 versus 13 months, respectively). A statistically significant difference was found only between responders and non responders of group B (p = 0.004). Toxicity was mild. In conclusion, no difference in therapeutic activity was seen between the two treatments and additional biochemical modulation must be evaluated. PMID- 7840517 TI - Hematotoxicity of 5-fluorouracil-leucovorin in a setting of adjuvant chemotherapy. AB - Changes of granulocyte macrophage colony forming units (CFU-GM) were assessed in peripheral blood of patients treated with 5-Fluorouracil-Leucovorin adjuvant chemotherapy after removal of colon cancer. The clinical and hematological state of the patients was steady and as far normal as possible. Leucocyte counts did not show significant changes. The mean peripheral blood level of CFU-GM significantly decreased following 5FU-LV infusion, reaching nadir by day 15. These changes of hemopoietic progenitors, not detected by routine hematic cell counts, point to a perturbation of the granulopoietic system by the 5FU-LV association also at doses used in adjuvant chemotherapy. PMID- 7840518 TI - Hospital admissions for different cancer diagnosis: a comparison between two European landscapes. AB - Cancer frequency has been studied in a Department of Crete and a Department of Sweden, using in-patient data collected in the Departmental Hospitals, for a two year period. The results of the study suggest that similar trends exist in the prevalence of different forms of cancer between the two areas studied, as well as some significant differences. The differences observed concern mainly the frequency of cancers of the lung, prostate, bladder and large bowel among men and breast and large bowel among women. These findings could to a great extent be explained by life-style and environmental differences between the two areas and are consistent with data concerning the cancer mortality in the two countries. PMID- 7840519 TI - Nephrotic syndrome and adjuvant treatment with tamoxifen for early breast cancer. Case report and review of the literature. AB - A 56 year old postmenopausal patient underwent a right radical mastectomy for a stage I breast cancer. An adjuvant treatment with tamoxifen was planned, but, because of patient's choice, a regular administration of the endocrine treatment started only one year after the operation. After a very short period of drug administration, she developed a steroid responsive nephrotic syndrome. We have reviewed the international literature concerning drug-induced renal disease; this is the first case of a tamoxifen-induced nephrotic syndrome. PMID- 7840520 TI - DNA-image cytometry and clinical staging systems in multiple myeloma. AB - Clinical and hematological parameters, and three derived major staging systems were compared with DNA-cytometric parameters in 73 patients with newly diagnosed multiple myeloma (MM) and correlated in univariate analysis with survival to assess their predictive value. Regarding diagnostic validity, a multi-parameter system including STL, 5cER, PRF and MNA correctly classified 92% of MM as malignant (sensitivity 92%) at a 100% specificity. Regarding prognosis, the most powerful single clinical parameter was serum creatinine (p < 0.001, median survival [ms] 51 vs. 14 months) followed by platelet count (p < 0.01, ms 67 vs. 11 months). Mean nuclear area of plasma cells was the only cytometric parameter with prognostic relevance (p < 0.05, ms 43 vs. 14 months). Neither the original Salmon-Durie staging (p < 0.05 for I vs. II, p > 0.05 for II vs. III) nor the revised Salmon-Durie staging by Cavo et al were able to discriminate three patient groups at statistically significant levels. Only the staging system proposed by the British Medical Research Council (MRC) was found to be able to predict survival for all three groups significantly (p = 0.01 for A vs. B, p < 0.01 for B vs. C; ms A/B/C = 68/37/14 months, respectively). PMID- 7840521 TI - Identification of germ line mutation of APC gene in possible carriers of familial adenomatous polyposis (FAP). AB - In Japan 1052 FAP patients in 688 family trees have been registered at the National Polyposis Center. In Hamamatsu University School of Medicine, we have been treating 50 patients in 28 family trees. Among these families, we analysed the site of mutations of the APC gene, which so far has been clarified in 21 family trees. Presymptomatic diagnosis was possible in 12 individuals among the carriers in 6 FAP families. Most of the mutations were clustered within the 5'half of exon 15. There was no correlation between extra colonic phenotypic expression and site of mutation, however, the desmoid should be studied further, as the number of cases was limited. PMID- 7840522 TI - Nonpalpable breast cancer. AB - Thirty-seven patients with nonpalpable breast cancer treated between 1981 and 1992 were analysed. Twenty-five (68%) of the patients were detected by microcalcification of mammogram, 8 by nipple discharge and 4 by other means. Biopsy was carried out in all patients to get a final diagnosis and histopathological examinations were performed using continuous sections (especially the section with microcalcification). The incidence of noninvasive carcinoma was 59% (22 cases) and the remaining invasive carcinomas were 3 minimal lesions less than 0.5 cm, 3 lesions from 0.5 to 1.0 cm, 3 diseases more than 1.0 cm, and 6 invasive carcinomas with noninvasive ductal carcinoma predominant. Modified radical mastectomy was performed in 16 cases, partial glandectomy in 10 and other surgery including subcutaneous mastectomy in 11. All of the patients with nonpalpabl breast cancer showed a good prognosis because of early detection and early treatment. Mammography was useful to detect nonpalpable breast cancers with microcalcification. PMID- 7840523 TI - Tamoxifen or surgery plus tamoxifen as primary treatment for elderly patients with operable breast cancer: The G.R.E.T.A. Trial. Group for Research on Endocrine Therapy in the Elderly. AB - A multicentre trial in operable breast cancer in patients aged over 70 years compared tamoxifen alone (starting with a loading dose of 160 mg on the first day) with surgery plus adjuvant tamoxifen. 473 patients were recruited with a median follow up of 36 months. Local progression occurred in 15/237 patients in the surgical arm versus 60/236 in the tamoxifen alone arm (p = 0.000). There were 48 deaths in the surgical arm and 41 in the other one (p = 0.67). Distant metastases occurred in 33/237 patients in the surgical arm versus 19/236 in the tamoxifen alone arm (p = 0.058). In elderly patients with operable breast cancer surgery is indicated. Tamoxifen alone is an adequate alternative in frail patients. A loading dose of Tamoxifen may be useful in preventing the expression of the metastatizing phenotype. In any case, delayed surgery does not prejudice the overall survival. PMID- 7840524 TI - Serum transferrin and ceruloplasmin in patients with cancer of the gastrointestinal and other systems. AB - Serum transferrin and ceruloplasmin were determined in 20 healthy subjects, 23 patients with cancer of the gastro-intestinal system (G.I.S) and 22 patients with other types of cancer. Serum transferrin in patients with cancer of the G.I.S. was significantly decreased in comparison to that of healthy subjects (p < 0.05) and to that of other cancer patients (p < 0.005), but no significant difference was found between the values of healthy subjects and those with other types of cancer. Serum ceruloplasmin was significantly increased in patients with cancer of the G.I.S. (p < 0.01) and other types (p < 0.05) in comparison to that of healthy subjects. No significant difference was found between patients with cancer of the G.I.S. and those with other cancer types. In conclusion, transferrin was significantly decreased in the serum of patients with cancer of the G.I.S. while ceruloplasmin was significantly increased in both groups of patients with G.I.S. and other types of cancer. PMID- 7840525 TI - Epidemiological peculiarities of cancers of the gall-bladder and larynx that distinguish them from other human neoplasias. AB - The purpose of this study was to elucidate the nature of the lack of an East-West difference in both gall-bladder cancer and laryngeal cancer as regards in their risk variations in space--a property that distinguishes them from other cancers. In practice, statistical analysis was used to obtain relevant information from the IARC data book, 1978-1982. Results of key importance are as follows: 1) the epidemiological trait of gall-bladder cancer was found to be a mirror image of that of laryngeal cancer in many respects including sex-discrimination of cancer risk and the geological distribution of both high-risk and low-risk populations. 2) Paradoxically, gall-bladder cancer and laryngeal cancer shared in common a small number of populations in both their high-risk groups as well as low-risk groups. It was indicated that the 2 cancers are under the control of 2 distinct risk modifiers in their risk variations in space: the one exerts a unidirectional impact on the risks of the 2 cancers in response to a change of the outer environment. The other exerts bidirectional impacts to produce increased risk of one neoplasia and decreased risk of the other. 3) Evidence was presented to suggest that the contribution of the inactivated tumor suppressor gene to carcinogenesis compared to that of the activated proto-oncogene was larger in the independent subfamily of gall-bladder cancer and laryngeal cancer than in any of the 2 subfamilies (Western type subfamily and non-Western type subfamily). The above marker of the independent subfamily was detectable in the female populations of the world, but not in the male populations. The significance of our findings is discussed from the point of view of hormonal carcinogenesis. PMID- 7840526 TI - Intra-arterial hepatic chemotherapy with 5-fluorouracil and 5 methyltetrahydrofolate in the treatment of unresectable liver metastases from colorectal cancer. AB - Treatment of patients with hepatic metastases from colorectal cancer using hepatic artery fluorodeoxyuridine (FUDR) has been reported to induce high remission rates but also a high incidence of limiting hepatobiliary toxicity. In an attempt to obviate the limiting FUDR toxic effects, a phase I-II study was undertaken to establish the efficacy and tolerability of intra-hepatic 5 fluorouracil (5-FU) when given in combination with 5-methyltetrahydrofolate. Patients with colorectal liver metastases (n = 17) received escalating doses of 5 FU as a 1 h infusion with a fixed dose (100 mg/m2) of intra-hepatic 5 methyltetrahydrofolate (4 h infusion) once a week. Dose limiting toxicity was hepatic and gastrointestinal (diarrhea) and occurred at doses > or = 350 mg/m2 5 FU. Other adverse effects included nausea/vomiting and cutaneous toxicity. One patient achieved a complete response and 2 a partial response (mean duration = 9 months) while 11 had stable disease. Patients with complete or partial responses had a mean survival of 17 months, while patients with stable disease survived 13 months and those with disease progression 5.5 months on average. These results suggest that this is a well tolerated regimen although with efficacy at the lower level of the range observed with fluoropyrimidines. PMID- 7840527 TI - Small cell lung cancer (SCLC): a randomized trial of cyclophosphamide, adriamycin, vincristine plus etoposide (CAV-E) or teniposide (CAV-T) as induction treatment, followed in complete responders by alpha-interferon or no treatment, as maintenance therapy. AB - In this phase III, double-random study, we compared CAV-E to CAV-T combination as induction treatment (1st randomization) for SCLC. Subsequently, patients achieving a complete response (CR) were randomized again (2nd randomization) to receive maintenance treatment with alpha-IFN or no treatment. From June 1990 to June 1992, 75 untreated patients were enrolled in this trial. After stratification according to limited disease (LD) or extensive disease (ED), patients were randomized to receive the following treatment: cyclophosphamide 1000 mg/m2, adriamycin 50 mg/m2, vincristine 2 mg, day 1 i.v., plus etoposide (E) 100 mg/m2 (CAV-E: arm-A) or teniposide (T) 60 mg/m2 on day 2, 3, 4 i.v., every 3 weeks (CAV-T: arm-B). LD patients after 3 cycles of treatment received chest radiotherapy and 2 further cycles, whereas ED patients received 5 consecutive cycles. Patients who achieved a CR entered the 2nd randomization receiving a-IFN (3 x 10(6) I.U., i.m. daily x 9 months) or no treatment. A second-line treatment with carboplatin 300 mg/m2 plus E (if T was initially used) or T (if E was initially used) was also scheduled for patients achieving less than CR to induction treatment. Preliminary results are as follows: 75 patients were randomized, 72 were eligible for survival (arm-A = 37 and arm-B = 35) and 60 were fully evaluable for response (arm-A = 34 and arm-B = 26). In patients with LD the overall response rate was 79% (CR 21%) in arm-A vs 92% (CR 50%) in arm-B. In patients with ED, the overall response rate was 80% (CR 33%) in arm-A vs 84% (CR 7%) in arm-B. At a mean observation time of about 1 year (range 1-25 months), median survival of LD patients was 15 months in arm-A and 13 months in arm-B (Chi square = 1.55; p > 0.05); in ED patients survival was 10.8 months and 8 months respectively (Chi-square = 2.88; p > 0.05). Cumulative survival probability was identical (12 months) in all patients of both arms. Toxicity was mainly haematologic and gastrointestinal: WHO grade 3-4 myelosuppression and vomiting were observed in 20% and 11% respectively, of cycles delivered in arm-A, compared to 19% and 8%, respectively, of cycles in arm-B. Two septic deaths occurred with CAV-T, while 1 patient discontinued treatment due to persistent myelosuppression with CAV-E. After the first and second-line treatment 20 patients showed a CR.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7840528 TI - Invasive node-negative breast carcinoma: multivariate analysis of the prognostic value of peritumoral vessel invasion compared with that of conventional clinico pathologic features. AB - The prognostic value of the determination of peritumoral vessel invasion (PVI) in node-negative breast cancer (NNBC) patients is still controversial. This is mainly related to the subjective criteria of evaluation of this histologic finding using morphological methods only. In this study, to assess PVI by stricter criteria, we used both conventional morphological and immunocytochemical techniques, using antibodies specific to endothelial cells (i.e. factor VIII related antigen and the CD-31 antibody). In a series of 233 evaluable NNBC, with a median follow-up of 5 years, we found that 11% of the tumors (25 out of 233) were PVI-positive. A weak association was observed only between PVI and tumor size (p = 0.076). In univariate analysis PVI significantly predicted relapse-free survival (p = 0.0009), but not overall survival (p = 0.1208). The odds of relapse and death for patients with PVI-positive carcinomas were 4.36 and 2.24 times higher than for those with PVI-negative tumors. As far as relapse-free survival is concerned, tumor size (p = 0.0012), histologic grading (p = 0.022), estrogen receptor (p = 0.016) and progesterone receptor expression (p = 0.017) also had a significant prognostic value. Only tumor size significantly predicted overall survival (p = 0.0038) in this series. For 5-year relapse-free survival both PVI (p = 0.014) and tumor size (p = 0.017) were significant and independent prognostic variables by multivariate analysis. Our results demonstrate that PVI and tumor size are important histological features to identify high-risk NNBC patients. Further studies are needed to compare the prognostic significance of PVI and tumor size with that of novel biological prognostic indicators of emerging importance in this neoplasia. PMID- 7840529 TI - Metabolic effects of tamoxifen in postmenopause. AB - Tamoxifen is actually considered the drug of choice for the hormonal treatment of early and metastatic breast cancer due to its efficacy and low toxicity. In addition, clinical trials of adjuvant therapy have demonstrated a 35% decrease in controlateral breast cancer in women receiving tamoxifen compared with controls, suggesting a potential role for this drug in chemoprevention of breast cancer in healthy women at increased risk of disease. Although tamoxifen is usually classified as an estrogen antagonist it also has partial estrogenic effects in some tissues such as liver, bone and uterus. The estrogenic action of tamoxifen on lipid metabolism and bone mineral density suggests additional benefits in protection against cardiovascular diseases and osteoporosis in postmenopausal women. Of particular interest could be the use of tamoxifen as an alternative to traditional estrogen replacement therapy in postmenopausal women previously treated for breast cancer or at increased risk of disease due to family history or histology on breast biopsy. The potential adverse effects of tamoxifen are partially similar to those of ERT and includes an increased risk of endometrial cancer, hepatic diseases, thromboembolic alterations and ocular toxicity. The mechanism of action of tamoxifen is briefly examined and the potential toxic effects and benefits of tamoxifen treatment are discussed. PMID- 7840530 TI - Vascular space invasion and inflammatory stromal reaction as prognostic factors in patients with surgically treated cervical cancer stage IB to IIB. AB - We assessed the prognostic value of the local tumor characteristics inflammatory stromal reaction (ISR) and vascular space invasion (VSI) together with established prognostic criteria, in cervical cancer patients. One hundred and forty-two patients with carcinoma of the cervix stage IB to IIB undergoing radical hysterectomy and lymphadenectomy between October 1980 and September 1990 were included in the study. Pelvic lymph node involvement, stage, parametrial involvement, age and histological tumor type were analysed together with VSI and ISR as prognostic factors. The most important prognostic parameters for recurrence-free interval and overall survival in the univariate analysis were pelvic lymph node involvement (P-value < 0.0001/0.0001) and stage (P-value < 0.0001/0.0005). ISR and VSI showed a significant prognostic value for recurrence free interval (both P-values = 0.0014) and overall survival (ISR: P-value < 0.0001; VSI: P-value = 0.0018). In the multivariate analysis ISR showed an independent prognostic value for overall survival (P-value = 0.03, Relative Risk = 5.4, 95%-confidence interval 1.2-24.5). ISR, reflecting the biological behavior of the tumor, should be considered in the evaluation of prognosis in surgically treated squamous cell carcinoma of the cervix. PMID- 7840531 TI - The use of color-coded Doppler sonography in the diagnosis of breast cancer. AB - 87 women with mammographically suspicious breast lesions were investigated prior to surgery. Color Doppler signals were obtained in 80 patients. 32 breast carcinomas and 55 benign lesions were evaluated for the RI (resistance index), the PI (pulsatility index), the flow velocity and the Al (acceleration index). Our study showed the RI > 0.7 an optimal threshold value to differentiate benign from malignant tumors. In this series, the sensitivity of duplex Doppler ultrasound for the detection of breast carcinoma was 84%, and the specificity 80%. The positive predictive value was 71%, the negative predictive value 90% and the accuracy 82%. Color Doppler scanning is a possible method for further investigation of patients with mammographic abnormalities and can be useful to reduce the number of unnecessary breast biopsies. PMID- 7840532 TI - The role of the p53 gene in the malignant transformation of pleomorphic adenomas of the parotid gland. AB - Pleomorphic adenoma (PA), the most common neoplasm of the parotid gland in adults, undergoes malignant transformation in only two to six percent of cases. In order to determine whether or not the p53 gene is involved in the malignant transformation of PA of the parotid gland, we have analyzed archival specimens from four patients with carcinoma ex-pleomorphic adenoma (CEPA) by immunohistochemistry and sequencing of the amplified DNA. Tissue specimens from each patient contained both the CEPA and the precursor PA. Immunostaining revealed that while all CEPA were p53 positive, only one of the four precursor PA was positive for p53. In this case, DNA was isolated from both the PA and CEPA and exons five through eight were amplified using the polymerase chain reaction. The same p53 mutation (single base substitution) was found in both the PA and the CEPA at codon 248. Adjacent normal tissue contained the wild-type p53 sequence. To our knowledge, this is the first report of the same p53 point mutation in both a PA and the associated CEPA of the parotid. These results strongly suggest a role for p53 gene mutation in the malignant transformation of some PA of the parotid gland. PMID- 7840533 TI - Overexpression of p53 protein is common in premalignant head and neck lesions. AB - In order to determine whether or not the p53 gene is involved in the malignant transformation of the head and neck carcinoma HNSCC, we have analyzed archival specimens from 527 primary head and neck lesions and 27 corresponding lymph node metastases. Nuclear p53 protein was present in 107 of 190 (56%) dysplasias, 61 of 102 (60%) carcinoma in situ (CIS), and 262 of 493 (53%) carcinomas. The p53 score did not increase significantly with progression of these lesions from dysplasia to CIS and to carcinoma. All 357 normal samples of head and neck tissues were negative. The majority of the 172 sets of premalignant and malignant lesions displayed concordant p53 staining patterns. The staining was incongruous in only six cases. The p53 staining results were congruent in all 27 pairs of primary and metastatic (lymph nodes) tumors. These data strongly suggest that p53 protein could be altered in a very early phase of the head and neck tumorigenesis and is maintained during tumor progression and metastatic spread. Mutations in p53 were examined in 11 cases that exhibited high levels of p53 protein as detected by immunohistochemistry using PAb 1801 MAb. Mutation analysis was performed by direct sequencing of the PCR amplification products of exons 5 through 8, which contain greater than 90% of p53 mutations found in tumors. Three of 11 HNSCC had mutations at codon 130 (C to A), 193 (A to T), 283 (G to C), respectively. No mutations were found in the other 8 samples within the regions examined. However, they may have mutations in unsequenced regions of p53 or may have wild type protein that accumulates for other reasons. PMID- 7840535 TI - Blood groups of the Sardinian population (Italy). AB - The genetic polymorphism of eight red cell blood group systems was examined in a population sample from Sardinia (Italy). The Sardinian frequencies of most of the examined genes were found out the range of Italian populations. Relationships among Italian and other Mediterranean populations were examined by principal component analysis. This kind of analysis confirms the genetic peculiarity of the Sardinian population. PMID- 7840534 TI - Human mitochondrial DNA variation in Lithuania. AB - Variation in mitochondrial DNA (mt-DNA) was studied in a population sample of 154 Lithuanians after cleavage with 15 different restriction endonucleases and probing with cat mt-DNA. Polymorphic variations were found with 8 restriction endonucleases. The most frequent mt-DNA cleavage patterns (morphs) were HpaI-2 (98.7%), BamHI-1 (94.8%), HaeII-1 (91.0%), MspI-1 (99.3%), AvaII-1 (86.4%), and HincII-2 (99.4%). The morph HaeII-12 previously described in Finns was found in two Lithuanians. Altogether 16 mt-DNA types were observed in the Lithuanian population. Type 1 was the most common one (81.2%), type 6 less and type 21 more frequent than in other populations. Lithuanians have high index of homogeneity (F = 0.663) compared to other Caucasoid populations. However, there appeared to be some differences between the two main ethnic groups, Aukstaiciai (Highlanders) and Zemaiciai (Lowlanders) with respect to the distribution of mt-DNA types. Measurements of genetic distance based on mt-DNA types were small between Lithuanians and Finns and increased gradually in comparison between Lithuanians and Mediterranean populations, Asiatic Mongoloids and African Blacks, respectively. PMID- 7840536 TI - Blood groups, ABH saliva secretion and colour vision deficiency in Hindu castes and religious groups of West Godavari, Andhra Pradesh, India. AB - The distribution of A1A2B0 and Rh(D) blood groups, ABH saliva secretion and red green colour blindness among fourteen Hindu caste groups, besides Christian and Muslim populations of West Godavari District, Andhra Pradesh, India, is reported. All the Hindu castes except Brahmin, Kshatriya and Reddy exhibit relatively higher frequency of group B over group A. The subtyping of group A reveals that group A2 records an incidence ranging from 0.98% to 7.78%. The interpopulation chi-square tests for A1A2B0 blood group distribution indicate significant variation between several Hindu castes. The Vysya, Reddy and Adi Andhra castes not only differ from each other but also register significant variation from a majority of other populations. In the ABH saliva secretion also Vysya deviate from all other populations by recording the highest incidence (37.70%) of non secretors, while the lowest frequency (19.98%) was observed among Kamma. The Rh(D) negative blood group is observed in all Hindu castes and religious groups with an incidence ranging from 1.04% in Vysya to 8.11% in Kamma. All the sixteen populations investigated exhibit prevalence of red-green colour blindness with a relatively higher frequency of deutan type over protan. PMID- 7840537 TI - Hair distribution on the phalanges of the hands in Malays. AB - 618 Malay subjects were selected randomly to find out the frequency and patterns of hair distribution on the phalanges of their hands. Hair on the proximal phalanx was absent in 2% of the males and in 3.3% of the females. The middle phalangeal hair (MPH) was absent in 78% of the females and in 64.9% of the males. The frequency in order of MPH was found to be 4 > 3 > 5 > 2. Fifteen patterns of hair distribution on the phalanges of the hand were found. Such a large number of patterns has not been reported yet. No subject had hair on the distal phalanges. These observations when compared with earlier studies show that the Malays are similar to other Asiatic populations such as the Japanese and Nepalis. PMID- 7840538 TI - [Screening for a growth disorder using the Dr. Keller precision measuring instrument and system]. AB - The regulation of growth is as complex process involving the interaction of a number of genetic, hormonal, psychosomal, and environmental factors. Abnormal growth is an alarming sign for the worsening of health. Therefore is it necessary to provide exact and quick information about the growth of the child. With the body length device "System Dr. Keller" is it possible to collect 1. exact data about the actual height of a child, 2. information about the normal range of height for the chronological age of a child, 3. information about abnormal height (< 3., > 97. percentile) of a child. These informations are visible exclusively by application of the "System Dr. Keller". With use of this unique system and the data of corresponding national growth studies it will be possible to screen the whole population by paediatricians, general practitioners, school doctors, health care centers, outpatient departments and hospitals. While normal growth usually represents health, growth disorders should stimulate doctors to exclude possibly underlying pathological processes. PMID- 7840539 TI - [Growth in body height by children between 4 and 12 years of age--results of the Jena longitudinal study]. AB - In the autumn of 1985 an anthropological longitudinal investigation on 104 female and 98 male children at the age of 4 and 4.5 years was started in Jena. The present paper gives a short survey on this longitudinal study. Standards for body height (mean and standard deviation) of the 4-12 years old boys and girls, measured in this study, are presented and percentile curves are constructed. For the individual development of the body height increments are calculated. Comparison of the height standards with those of national and of European studies reveal only minor differences. In the higher age classes the Jena probands show the greatest values of body height. The presented percentile curves should be used by paediatricians, especially. PMID- 7840540 TI - Heritabilities of morphological and body composition characteristics in a Spanish population. AB - Different estimates of heritability are presented for a set of anthropometric characteristics taken in 844 individuals from 261 families living in the Madrid city area (Spain). The data include measurements of 10 craniofacial, 11 body skeletal (4 lengths and 7 breadths), and 13 fat-related characteristics (weight, 3 circumferences, 6 skinfold thicknesses, body mass index and arm fat and arm muscle areas). The estimates computed from parent and offspring data show a clear defined pattern (higher heritabilities for longitudinal traits, followed by breadths, circumferences, and skinfolds, respectively). Heritabilities estimated from sib-sib correlation do not show such pattern and are generally higher than those assessed through parent-offspring data, mainly for fat related traits, which is attributed to common environment effects. PMID- 7840541 TI - Some aspects on the dermatoglyphics of normal and defective children in Bulgaria. AB - By comparison with a sample of normal Bulgarian children aged 3 to 18 years, children with visual, auditory and mental insufficiency differ in the relative frequency of pattern types on the digits. These differences are particularly noticeable on the second and fourth digits. It is suggested that the restriction to these two digits is related to the differing evolutionary histories of the different digits, and differences in their innervation. PMID- 7840542 TI - Swimming upstream: the strength of women who survive homelessness. PMID- 7840543 TI - Veiled, voluminous, and devalued: narrative stories about low-income women from Brazil, Egypt, and Colombia. AB - The first purpose of this article is to argue the significance of using international and culturally diverse exemplars in developing nursing knowledge. The second is to identify some urgent priorities in the development of nursing knowledge, particularly as related to women's health. The lived experiences of three women from Brazil, Egypt, and Colombia who are in low-income, devalued, but important jobs are presented through their voices. These storied accounts highlight nursing's mission in dealing with the marginalized client as a human being whose context is historical and sociocultural. The implications for knowledge development as driven by international exemplars, diverse experiences, and narration of stories are discussed. PMID- 7840544 TI - The moral geography of home care. AB - One result of the historical division of labor between nurses and physicians is that nurses became the eyes and ears of the physician, extending their perceptual capabilities across space and time. This "gaze of medicine" has evolved with the rise of technology, hospitals, and the medical profession to a sort of scientific totalitarianism. Protecting and enhancing patient agency, which is part of the moral work of nursing practice, can be difficult under such circumstances. Yet the geography of sickness is changing as patients move from the hospital back to the home. Because home is thought of as private, as the patient's domain, nurses may think that supporting patient agency will be easier with this transformation of health care. But that assumption may not be warranted since the gaze of medicine will follow patients and change the landscape of the home. The challenge for nursing will be to sharpen the "gaze of nursing," which is an antidote to the strictly biomedical understanding of disease. PMID- 7840545 TI - A model of caregiving effectiveness for technologically dependent adults residing at home. AB - Caregiver-care-receiver interactions unique to this model of caregiving effectiveness were tested longitudinally in a randomly drawn national sample of 111 caregivers. Path analyses results indicate that variables explain variance in caregiver and patient quality of life, patient condition, and technological side effects. These findings extend nursing knowledge related to caregiving motivation to-help and mutual interactions and thus have implications for home care practice. Effective family caregiving of loved ones dependent on technology for survival can result in enhanced patient condition, return to work, normalization of family life, and for society a reduction in health care costs. PMID- 7840546 TI - Nursing theory-based practice in the home and community: the crux of professional nursing education. AB - Nursing has been viewed as a service for people wherever they may be--a service, grounded in scientific knowledge, that transcends setting. Yet nursing education has been overwhelmed by hospital institutions for the past 50 years, its attention diverted to medical entities and institutional trends, with fragmentation and depersonalization of general health care as well as nursing care as the result. Nursing theory-based practice is not feasible in institutions where medical orders overshadow all other disciplines. Community-based experiences in which nursing students learn about people and their health in the context of home and community offer the best promise for students to learn the complex human dynamics of real life and develop the holistic perspective required for independent nursing practice. The time has passed for nursing education to focus on the fraction of the population in hospitals while slighting knowledge about health as it is lived every day. Priority content for all nursing students should be a portable nursing theorybase that can be taken anywhere, focusing on health promotion, healthy environments, and quality of life. PMID- 7840547 TI - "Reducing my risks": a phenomenon of older widows' lived experience. AB - While scholars and practitioners often use the concept of "risk" in relation to older persons who live at home, there has been limited exploration of risk from the perspective of older persons themselves. During a phenomenologic study of the lived experience of seven older widows who were living alone at home, the participants articulated the risks they experienced and described the ways in which they attempted to reduce these risks. The results have meaningful implications for home care providers and policy makers. PMID- 7840548 TI - Constructing the reality of recovery: family home care management strategies. AB - Development of home health care programs for family caregivers is predicated on an understanding of problems caregivers encounter and ways in which they manage those problems. This article describes home care management strategies of family caregivers of stroke survivors. Qualitative analysis of interviews with a purposive sample of family caregivers indicated that caregivers of stroke survivors practice situational vigilance for the stroke survivor, create solutions for problems associated with functional losses of a stroke, construct the reality of recovery for themselves and the stroke survivor, and seek to find personal meaning in the caregiving experience. Implications for practice and future research are proposed. PMID- 7840549 TI - Home health nurses' use of base rate information in diagnostic reasoning. AB - This survey examined home health nurses' use of base rate data when diagnosing and explored the influence of education and experience on the use of base rate data. The relationships between education and experience and normatively appropriate diagnoses were also examined. Two hundred and fourteen nurses completed the Clinical Inference Vignettes, which included four diagnostic problems relevant to home health care nursing. Data analysis indicated an association between the use of base rate information and education and experience. Education and experience also influenced normatively correct responses. Recommendations include methods to increase awareness of base rate information, thereby improving diagnostic precision and ultimately enhancing patient outcomes. PMID- 7840551 TI - Possible role of insertion sequence IS257 in dissemination and expression of high and low-level trimethoprim resistance in staphylococci. AB - The transposon-like structure Tn4003 and related elements were found to encode high- and low-level trimethoprim resistance (Tpr) in Staphylococcus aureus and coagulase-negative staphylococci. By using transcriptional fusions in Escherichia coli, the variation in resistance levels was found to correlate with the transcriptional activity of the region presumed to carry the promoter for the operon containing the Tpr dihydrofolate reductase gene, dfrA, encoded by these elements. The reduced transcriptional activities exhibited by elements encoding low-level Tpr appear to be a consequence of deletions adjacent to the copy of IS257 which normally encodes the -35 sequences of these promoters. The data obtained not only support the involvement of IS257 in the transcription of the proposed thyE-dfrA-orf-140 operon of Tn4003 but may also implicate this insertion sequence in the mechanisms resulting in the variation in Tpr levels observed in staphylococci. PMID- 7840550 TI - Antimicrobial susceptibility of coagulase-negative staphylococci. PMID- 7840552 TI - Activity of KRM-1648, a new benzoxazinorifamycin, against Mycobacterium tuberculosis in a murine model. AB - The activity of KRM-1648 was evaluated in a murine model of tuberculosis. Approximately 10(7) viable Mycobacterium tuberculosis ATCC 35801 organisms were given intravenously to 4-week-old female outbred mice. Treatment was started 1 week postinfection and given by gavage for 4 weeks. Viable-cell counts were determined from homogenates of spleen and lung tissues. The activity of KRM-1648 was compared with those of rifampin and rifabutin at 20 mg/kg of body weight. KRM 1648 was more active than either rifampin or rifabutin against organisms in spleens and lungs. KRM-1648 alone and in combination with either isoniazid, ethambutol, pyrazinamide, or levofloxacin was evaluated. Other treatment groups received isoniazid, ethambutol, pyrazinamide, or levofloxacin as single agents. KRM-1648 was the most active single agent evaluated. KRM-1648-pyrazinamide and KRM-1648-isoniazid were the most active combinations. These combinations were more active than KRM-1648 alone. The promising activity of KRM-1648 in M. tuberculosis-infected mice suggests that it is a good candidate for clinical development as a new antituberculosis agent. PMID- 7840553 TI - An international randomized study with long-term follow-up of single versus combination chemotherapy of multibacillary leprosy. AB - A total of 307 patients with lepromatous leprosy and borderline lepromatous leprosy were randomized to dapsone monotherapy or to one of two types of drug combinations. A 3-year treatment phase was followed by a 5-year observation phase. The evaluation included 233 patients for whom together there were 1,404 years of observation. A total of 1,956 blinded histopathological specimens were processed centrally. When entering the trial isolates from 13 patients (5.6%) showed dapsone resistance in the mouse footpad test, and these patients were evaluated separately. Dapsone monotherapy (68 patients) had the same frequency of cure as the combination of dapsone and rifampin (77 patients) or the four-drug regimen consisting of dapsone, rifampin, isoniazid, and prothionamide (75 patients). We did not find a significant difference in the clearance of bacteria either between the monotherapy and the two-drug combination or the monotherapy and the four-drug combination. Six months after the initiation of treatment, disease in 15% of the patients who received dapsone monotherapy but none of the patients who received combined treatment were clinically progressive. After another 1 to 9 months of treatment the disease in all patients was stable or regressive. There was no difference in the type or frequency of reactions. Only after the end of the scheduled observation phase three relapses were reported. All three treatment regimens well tolerated. Dapsone monotherapy is highly effective in the treatment of multibacillary leprosy under the conditions of well controlled treatment. Combination regimens seem only to accelerate the regression of the active disease when they are compared with monotherapy with dapsone. The mouse footpad test does not reflect the clinical resistance and cannot be recommended for use in making therapeutic decisions. PMID- 7840554 TI - Use of beta-1,3-glucan-specific antibody to study the cyst wall of Pneumocystis carinii and effects of pneumocandin B0 analog L-733,560. AB - A new class of promising antipneumocystis agents, cyclic lipopeptide pneumocandin analogs, has been shown to effectively prevent Pneumocystis carinii cyst development in murine models. These compounds are believed to inhibit the biosynthesis of beta-1,3-glucan, a major constituent of the cell walls of various pathogenic fungi. However, all evidence of the presence of this polymer in P. carinii cysts is based on indirect methods. To address this, highly specific rabbit polyclonal antiserum was raised against a laminariheptaose-human transferrin hapten conjugate. This antiserum was used to demonstrate the presence of beta-1,3-glucan in alkaline extracts of P. carinii-infected rat lung tissue and to quantitate the degree of infection in this tissue as laminarin equivalents. The antiserum was also used to localize beta-1,3-glucan in P. carinii-infected rat lung tissue at the transmission electron microscopic level by immunogold labeling. High concentrations of beta-1,3-glucan were present in the electron-lucent layer of the P. carinii cyst wall, but beta-1,3-glucan was absent from intracystic bodies and trophozoites. Ultrastructural evaluation of lung tissue from P. carinii-infected rats treated with the pneumocandin analog L 733,560 demonstrated that the few cysts which remained are deformed, lack the translucent layer of the cyst wall, and contain minimal amounts of beta-1,3 glucan. PMID- 7840555 TI - Effect of threonine-to-methionine substitution at position 265 on structure and function of TEM-1 beta-lactamase. AB - TEM beta-lactamase variants with the amino acid substitutions R164S, E104K, G238S, and E240K (ABL numbering) display increased activity toward extended spectrum cephalosporins. The T265M substitution is frequently found to be associated with the above substitutions in extended-spectrum beta-lactamases. However, the residue is located away from the active site in the three dimensional structure and has been assumed to have no effect on catalysis. To examine the effect of the substitution on the structure and function of TEM beta lactamase we constructed the following mutants: G238S, T265M, T265M:G238S, and T265M:G238S:E240K. Each enzyme was purified to homogeneity and the kinetic parameters kcat, Km and kcat/Km were determined for cefotaxime, ceftazidime, cephaloridine, and ampicillin. The results indicate that the T265M mutation has little effect on hydrolysis. In addition, we used immunoblotting to show that the substitution has little or no effect on the in vivo steady-state levels of beta lactamase. PMID- 7840556 TI - Inhibition of influenza virus replication in mice by GG167 (4-guanidino-2,4 dideoxy-2,3-dehydro-N-acetylneuraminic acid) is consistent with extracellular activity of viral neuraminidase (sialidase). AB - We demonstrate the potent antiviral activity of a novel viral neuraminidase (sialidase) inhibitor, 4-guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid (GG167), administered by the intranasal route in comparison with those of amantadine and ribavirin in experimental respiratory tract infections induced with influenza A and B viruses. In an extended study in which mice were infected (day 0) with influenza A/Singapore/1/57 virus, with treatments given prophylactically plus twice daily over days 0 to 3 and with mice observed to day 10, we show that intranasally administered GG167 at 0.4 and 0.01 mg/kg of body weight per dose reduced mortality, lung consolidation, and virus titers in the lung, with no virus growing back following the cessation of treatment. In other studies with influenza B/Victoria/102/85 virus in which infected mice were culled after the cessation of treatment, the calculated intranasal dose required to reduce virus titers in the lungs of treated animals to 10% of that seen in untreated controls (EDAUC10 [where AUC is area under the virus titer days curve]) was 0.085 mg/kg per dose. GG167 was inactive against influenza viruses A and B when given by the intraperitoneal or oral route (EDAUC10, > 100 mg/kg per dose). GG167 was metabolically stable, with an elimination half-life of 10 min following intravenous administration. While readily bioavailable by systemic routes, it was poorly bioavailable by the oral route. Its potent efficacy by the intranasal route but lack of efficacy by other routes, relative to those of amantadine and ribavirin, was explicable in terms of its in vitro activity, bioavailability, and pharmacokinetic properties and with the extracellular activity of viral sialidase. PMID- 7840557 TI - Longitudinal study of susceptibilities of species of the Bacteroides fragilis group to five antimicrobial agents in three medical centers. AB - A total of 579 clinical isolates of the Bacteroides fragilis group collected from three Canadian hospitals were tested for susceptibility to five antimicrobial agents by using an agar dilution method. During the 4-year survey, isolates from intra-abdominal infections were collected from the following sites: abdominal abscesses (48%), peritoneal fluid (39%), blood (10%), and bile (3%). B. fragilis was the most prevalent species (35.4%), followed by B. thetaiotaomicron (19.2%), B. ovatus (15.9%), and B. vulgatus (11%). No metronidazole- or imipenem-resistant strains were found during the survey. Resistance profiles varied among the different species tested: 7.8, 2.9, and 7.3% of B. fragilis strains (n = 205) and 68.1, 17.2, and 9.4% of non-B. fragilis strains (n = 373) were resistant to cefotetan, cefoxitin, and clindamycin, respectively. B. fragilis and B. vulgatus demonstrated lower resistance rates than B. thetaiotaomicron, B. ovatus, B. distasonis, and B. caccae. During the study, rates of resistance to cefotetan and clindamycin fluctuated but rates of resistance to cefoxitin increased, particularly at one center. These data indicate a need to determine the susceptibility patterns of the B. fragilis group periodically at each hospital. PMID- 7840558 TI - Identification of antimicrobial peptides by using combinatorial libraries made up of unnatural amino acids. AB - The use of water-soluble synthetic peptide combinatorial libraries permits the systematic examination of tens to hundreds of millions of peptides in existing microdilution assays. In the present study, we prepared and determined the antistaphylococcal activities of two new synthetic peptide combinatorial libraries (one N-acetylated, the other not) composed of tetrapeptides having one position defined and the remaining three positions made up of mixtures of L-, D-, and unnatural amino acids (a total of 58 different amino acids). These libraries, when used in conjunction with an iterative selection process, allowed for the development of a series of individually defined tetrapeptides with high levels of activity against Staphylococcus aureus. The activities of the final individual peptides against two additional strains of gram-positive bacteria (methicillin resistant S. aureus and Streptococcus sanguis), a gram-negative bacterium (Escherichia coli), as well as the yeast Candida albicans were also determined. Cell viability assays showed that the identified peptides are bacteriostatic against both S. aureus and E. coli. PMID- 7840559 TI - Potential drug targets for Mycobacterium avium defined by radiometric drug inhibitor combination techniques. AB - Previously established radiometric techniques were used to assess the effectiveness of combined antimicrobial drug-inhibitory drug (drug-inhibitor) treatment on two clinical isolates of the Mycobacterium avium complex representing three colony variants: smooth opaque (dome) (SmO), smooth transparent (SmT), and rough (Rg). All variants were identified as members of the M. avium complex; however, only the SmT colony type of strain 373 possessed characteristic serovar-specific glycopeptidolipid (GPL) antigens. MICs, determined radiometrically, of drugs with the potential to inhibit the biosynthesis of GPL antigens or other cell envelope constituents were similar for all strains. These drugs included cerulenin, N-carbamyl-DL-phenylalanine, N carbamyl-L-isoleucine, trans-cinnamic acid, ethambutol, 1-fluoro-1-deoxy-beta-D glucose, 2-deoxy-D-glucose, and m-fluoro-phenylalanine. The MICs of the antimicrobial drugs amikacin, sparfloxacin, and clarithromycin varied, but overall the MICs for the SmO variant were the lowest. Radiometric assessment of drug-inhibitor combinations by using established x/y determinations revealed enhanced activity when either ethambutol or cerulenin were used in combination with all antimicrobial agents for all variants except the Rg variant of strain 424, for which ethambutol was not effective. Enhanced activity with amino acid analogs was observed with the Rg colony variants of strains 373 and 424. Two potential sites for drug targeting were identified: fatty acid synthesis, for all strains assayed, and peptide biosynthesis, particularly for Rg colony variants that possess previously identified phenylalanine-containing lipopeptides as potential targets for future drug development. PMID- 7840560 TI - In vitro and in vivo activities of azithromycin, a new azalide antibiotic, against chlamydia. AB - The in vitro and in vivo activities of azithromycin against chlamydia were investigated. The MIC of azithromycin for five standard strains of different species of chlamydia and six wild-type strains of Chlamydia pneumoniae was 0.125 microgram/ml, which was superior to that of erythromycin but inferior to those of clarithromycin and minocycline. However, the therapeutic effect of a 7-day course of azithromycin at a dose of 10 mg/kg of body weight administered orally once daily to mice with experimental Chlamydia psittaci pneumonia was excellent, with a 100% survival rate at 14 days after infection, which was the same as that for treatment with minocycline administered at 10 mg/kg twice daily; all erythromycin treated animals died within 10 days. When treatment was discontinued 3 days after the infection, the survival rate for mice treated with azithromycin was 90% and that for mice administered minocycline was 30%. These results suggest that azithromycin may be useful in the treatment of respiratory infections caused by intracellular pathogens, including chlamydia because of its excellent accumulation within host cells. PMID- 7840561 TI - Antibodies against chromosomal beta-lactamase. AB - A murine monoclonal anti-chromosomal beta-lactamase antibody was developed and an immunoblotting technique was used to study the presence of serum and sputum antibodies against Pseudomonas aeruginosa chromosomal group 1 beta-lactamase in patients with cystic fibrosis (CF). The serum antibody response was studied with serum samples collected in 1992 from 56 CF patients in a cross-sectional study and with serum samples from 18 CF patients in a longitudinal study. Anti-beta lactamase immunoglobulin G antibodies were present in all of the serum samples from the patients with chronic bronchopulmonary P. aeruginosa infection (CF + P) but in none of the CF patients with no or intermittent P. aeruginosa infection. Anti-beta-lactamase antibodies were present in serum from CF + P patients after six antipseudomonal courses (median) and correlated with infection with a beta lactam-resistant strain of P. aeruginosa. The sputum antibody response and the beta-lactamase activity in sputum samples from 14 of the CF + P patients were also studied. beta-lactamase antibodies were present in 10 of these samples. P. aeruginosa strains isolated from these samples were partially derepressed, producing group 1 cephalosporinase. We found a wide range of chromosomal beta lactamase activity in the sputum samples, with no correlation with basal or induced activity of beta-lactamase expression. The presence of anti-beta lactamase antibodies in endobronchial sputum could be an important factor in the defense against the infection. On the other hand, immune complexes between the beta-lactamase and corresponding antibodies could play a role in the pathogenesis of bronchopulmonary injury in CF by mediating hyperimmune reactions. PMID- 7840562 TI - Improvement of outer membrane-permeabilizing and lipopolysaccharide-binding activities of an antimicrobial cationic peptide by C-terminal modification. AB - Antimicrobial cationic peptides have been discovered in many different organisms and often possess a broad range of activity. In this study, we investigated the mechanisms of actions of melittin and two synthetic peptides, CEME (a cecropin melittin hybrid) and CEMA, against gram-negative bacteria. CEMA was produced by recombinant DNA procedures and is an analog of CEME with a modified C terminus resulting in two additional positive charges. All three peptides showed good antimicrobial activity against four different gram-negative bacteria, but only CEMA was able to somewhat augment the activity of some conventional antibiotics in synergy studies. Studies using the bacteria Pseudomonas aeruginosa and Enterobacter cloacae showed that the peptides all possessed the ability to permeabilize bacterial outer membranes to the hydrophobic fluorophor 1-N phenylnaphthylamine and the protein lysozyme, with CEMA being the most active. CEMA also had the strongest relative binding affinity for bacterial endotoxin (lipopolysaccharide). These data collectively indicated that these peptides all cross the outer membrane by the self-promoted uptake pathway and that CEMA is the peptide most effective at accessing this pathway. PMID- 7840563 TI - Susceptibilities of 123 strains of Xanthomonas maltophilia to eight beta-lactams (including beta-lactam-beta-lactamase inhibitor combinations) and ciprofloxacin tested by five methods. AB - This study evaluated the susceptibility of 123 Xanthomonas maltophilia strains to ticarcillin, ticarcillin-clavulanate, ampicillin, amoxicillin-clavulanate, ampicillin-sulbactam, piperacillin, piperacillin-tazobactam, imipenem, and ciprofloxacin by Kirby-Bauer disk, E test, and Sensititre dehydrated microdilution MIC and conventional agar dilution MIC methodology. Intermediate susceptibility breakpoints for members of the family Enterobacteriaceae were used. When results were analyzed as MICs for 50 and 90% of the strains tested and percentages of strains susceptible at the breakpoint, good correlation between the methods was observed, with ticarcillin-clavulanate clearly the most active beta-lactam by all four methods. However, when the various methods were compared with the agar dilution methodology by regression analysis, poor r2 values (0.3 to 0.7) were obtained for compounds with sufficient on-scale values to permit analysis. When the number of strains with log2 ratios of reference agar dilution MICs to test MICs of +3 to -3 were analyzed, correlation was also poor, with many major and very major discrepancies for all methods tested. Results obtained with time-kill studies of nine strains with discrepant ticarcillin-clavulanate MICs appeared to correlate best when compared at 24 h with agar dilution MICs. The concentration of ticarcillin-clavulanate required to reduce the colony count by > or = 2 log10 reduction values for eight of nine strains compared with that for growth controls was < or = 16.0/2.0 micrograms/ml at 6 h and ranged from 16.0/2.0 micrograms/ml to 128.0/2.0 micrograms/ml at 24 h. The susceptibility method of choice for X. maltophilia has not yet been standardized, but time-kill studies correlated best with agar dilution MICs. PMID- 7840564 TI - Possible intermolecular interaction between quinolones and biphenylacetic acid inhibits gamma-aminobutyric acid receptor sites. AB - The combination of some new quinolone antibacterial agents with 4-biphenylacetic acid (BPAA), a metabolite of fenbufen, is known to specifically induce functional blockade of the gamma-aminobutyric acid (GABA) receptors. The mechanisms of these drug interactions were further examined. Scatchard analysis of [3H]muscimol binding to rat brain plasma membranes in the presence of enoxacin and BPAA revealed that a significant decrease in the number of muscimol binding sites was produced without affecting the affinity of binding to the receptors. In the presence of norfloxacin, BPAA inhibited muscimol binding the most potently of the six BPAA-related compounds tested. Fenbufen and 9,10-dihydro-gamma-oxo-2 phenanthrenebutyric acid also inhibited the binding, and 4-biphenylcarboxylic acid and methyl 4-biphenylacetate inhibited it slightly, but 3-benzoylpropionic acid exhibited no competitive inhibition. Accordingly, hybrid molecules of norfloxacin and BPAA were synthesized for stereochemical analysis of these drug interactions. A hybrid with a -CONH(CH2)3- chain between norfloxacin and BPAA (flexible structure) inhibited muscimol binding, and intracisternal injection of this hybrid caused clonic convulsions in mice more potently than the combination of norfloxacin and BPAA did. In contrast, a hybrid linked by -CONH- (stretched structure) showed almost no such inhibitory effect. 1H NMR analysis indicated the presence of intramolecular attraction at the quinoline ring of the hybrid exhibiting the antagonistic activity. These results suggest the possibility that quinolones and BPAA interact with the GABA receptor at nearby sites and that the binding affinity of quinolones to the GABA receptors is largely enhanced by the intermolecular interaction with BPAA. PMID- 7840565 TI - Presence of the Listeria tetracycline resistance gene tet(S) in Enterococcus faecalis. AB - Two hundred thirty-eight tetracycline- and minocycline-resistant clinical isolates of Enterococcus and Streptococcus spp. were investigated by dot blot hybridization for the presence of nucleotide sequences related to tet(S) (first detected in Listeria monocytogenes BM4210), tet(K), tet(L), tet(M), tet(O), tet(P), and tet(Q) genes. The tet(S) determinant was found in 22 strains of Enterococcus faecalis, associated with tet(M) in 9 of these isolates and further associated with tet(L) in 3 of these strains. tet(M) was detected in all strains of Streptococcus spp. and in all but 10 isolates of Enterococcus spp.; tet(L) was found in 93 enterococci and tet(O) was found in single isolates of E. faecalis and Streptococcus milleri. No hybridization with the tet(K), tet(P), and tet(Q) probes was observed. Transfer of tet(S) by conjugation to E. faecalis or to E. faecalis and L. monocytogenes was obtained from 8 of the 10 E. faecalis strains harboring only this tet gene. Hybridization experiments with DNAs of four donors and of the corresponding transconjugants suggested that tet(S) was located in the chromosome. These results indicate that the genetic support of tet(S) in E. faecalis is different from that in L. monocytogenes, where it is carried by self transferable plasmids, and confirm the notion of exchange of genetic information between Enterococcus and Listeria spp. in nature. PMID- 7840566 TI - Effect of lactation on single-dose pharmacokinetics of norfloxacin nicotinate in ewes. AB - In a three-way crossover trial, six healthy Finnish-Merino-Awassi ewes were given a single intravenous injection of norfloxacin nicotinate (in a dose equivalent to 25 mg of norfloxacin base per kg of body weight) during nursing, 1 day after weaning, and 1 month after weaning. Blood and milk samples were collected at different time intervals following dosing, and norfloxacin concentrations were determined by a high-performance liquid chromatography assay. The serum drug concentration versus time data were analyzed by a noncompartmental approach which was based on the statistical-moment theory. The total body clearance values were 4.2 +/- 1.3 (injection during nursing), 1.6 +/- 0.3 (injection 1 day after weaning), and 3.1 +/- 0.8 ml/min/kg (injection 1 month after weaning). The mean residence times were 335 +/- 83, 797 +/- 129, and 481 +/- 102 min and terminal half-lives were 266 +/- 51, 603 +/- 94, and 372 +/- 68 min for the respective treatments. The estimated volumes of distribution at steady state were 1.3 +/- 0.1, 1.2 +/- 0.1, and 1.4 +/- 0.2 liter/kg for the respective treatments. Milk norfloxacin concentrations were up to 40 times higher than the corresponding concentrations in serum during lactation. Accordingly, in ewes with 1.5 liter of milk in the udder more than half of the drug in the animal appeared to be in the milk. Therapeutic concentrations of norfloxacin could be detected in the sera of suckling lambs, implicating that fluoroquinolone therapy should be discouraged during breast feeding. In lactating ewes and in ewes with full udders, moment analysis calculations did not show a significant difference between the system moment mean residence time and the system matrix mean residence time values. Thus, the pharmacokinetics of norfloxacin in the three groups could be described by the classical two-compartment open-body model with input and output occurring from the central compartment. The results did not support the existence of a distinguishable milk compartment. Milk secretion seemed to act as one of the clearance processes of the drug when milk was continuously removed. PMID- 7840567 TI - Evaluation of OPC-17116 against important pathogens that cause respiratory tract infections. AB - The antibacterial activity of OPC-17116, a new fluoroquinolone antibacterial agent, against important pathogens that cause respiratory tract infections was evaluated in vitro and in vivo and compared with those of ciprofloxacin, ofloxacin, and norfloxacin. The pharmacokinetic profiles of OPC-17116 were studied in both mice and rats given the drug orally at doses of 50 and 40 mg/kg of body weight, respectively. OPC-17116 showed a high degree of distribution in the lung tissues of both species, with maximum concentrations of 29.6 and 32.0 micrograms/g, respectively. Furthermore, the drug concentrations in lung tissue were about 10 to 15 times greater than the concentrations in plasma. OPC-17116 showed potent antibacterial activity against such pathogens as Staphylococcus aureus, Streptococcus pneumoniae, Klebsiella pneumoniae, Pseudomonas aeruginosa, Haemophilus influenzae, and Moraxella catarrhalis. The MICs of this compound for 90% of these organisms except methicillin-resistant S. aureus and P. aeruginosa ranged from < or = 0.006 to 0.78 microgram/ml. The in vitro antibacterial activity of OPC-17116 was reflected by the efficacy of a single oral dose against systemic bacterial infections in mice. OPC-17116 showed a superior effect against gram-positive bacteria, H. influenzae, and M. catarrhalis. In comparison with the other reference compounds, the efficacy of OPC-17116 was less than that of ciprofloxacin against K. pneumoniae and P. aeruginosa. OPC-17116 showed a greater therapeutic effect than the other drugs against experimental acute pneumonia caused by these organisms in mice or rats. This excellent therapeutic effect against respiratory tract infections may be a result of its high level of distribution in lung tissue. PMID- 7840568 TI - Effectiveness of rifabutin alone or in combination with isoniazid in preventive therapy of mouse tuberculosis. AB - The ever-increasing incidence of tuberculosis calls for the implementation of control measures, including new efficient, short-term preventive therapies to replace 6 to 12 months of isoniazid therapy. The efficacies of 12-week regimens of rifabutin or isoniazid given daily and the combination of the two drugs administered intermittently were evaluated in mice infected with Mycobacterium tuberculosis after vaccination with the bacillus Calmette-Guerin (BCG) to imitate some features of the natural infection in humans with a low number of persisting bacteria. Rifabutin at 10 mg/kg of body weight per day was highly effective as early as the eighth week of treatment: all spleens were sterilized and the number of bacteria was drastically reduced in the lungs (mean +/- standard deviation log CFU, 0.2 +/- 0.3, compared with 5.9 +/- 0.6 for untreated controls). No bacilli were found in the spleens or lungs of any of the animals treated for 12 weeks. The combination of rifabutin at 10 mg/kg plus isoniazid at 25 mg/kg twice weekly was almost as effective as rifabutin daily: after 8 weeks of treatment only two of six mice harbored a small number of mycobacteria in their spleens and lungs; at week 12, all spleens were sterilized and a total of eight colonies were isolated from the lungs of two of six mice. Daily isoniazid and once-weekly rifabutin plus isoniazid therapies were less effective. Colonies randomly isolated from the spleens and lungs of mice from different experimental groups were also tested for their susceptibilities to the two drugs. The three surviving colonies from rifabutin-treated mice and all colonies from those administered rifabutin plus isoniazid remained fully susceptible to either drug. In contrast, 2 (18%) of the 11 colonies randomly selected from isoniazid-treated mice became resistant to isoniazid (MIC, > 2 micrograms/ml), although they were still susceptible to rifabutin. Three months of treatment with rifabutin, either daily alone or twice a week combined with isoniazid, proved to be a valid candidate for tuberculosis preventive therapy. PMID- 7840569 TI - Pharmacodynamics of piperacillin alone and in combination with tazobactam against piperacillin-resistant and -susceptible organisms in an in vitro model of infection. AB - The pharmacodynamics of dosage regimens of piperacillin alone or in combination with tazobactam against piperacillin-resistant or -susceptible bacteria were studied in an in vitro model of infection. Experiments were conducted by using a fixed daily exposure of 12 g of piperacillin, given as 3 g alone or in combination with tazobactam at 0.375 g every 6 h, or the same total dose of the combination given as 4 g of piperacillin plus 0.5 g of tazobactam every 8 h. The addition of tazobactam to piperacillin, irrespective of the dosing interval, did not alter the killing of piperacillin-susceptible organisms (Escherichia coli J53 and Pseudomonas aeruginosa ATCC 27853). In contrast, experiments with an isogenic TEM-3-containing transconjugant of E. coli J53 (E. coli J53.2-TEM-3) that was resistant to piperacillin (MIC, 128 micrograms/ml) showed that the addition of tazobactam resulted in bacterial killing similar to that observed with the wild type strain. Although tazobactam concentrations fell to less than 4 mg/liter (the concentration associated with a reduction in the piperacillin MIC from 128 to 2 mg/liter) 2 to 3 h after a dose, a similar degree of bacterial killing was observed when the same total 24-h dose of piperacillin-tazobactam was fractionated into dosing intervals of every 6 or 8 h. Investigations with Staphylococcus aureus 7176 (piperacillin MIC, 128 micrograms/ml) showed that the addition of tazobactam, again irrespective of dosing interval, also resulted in net bacterial killing which was not seen with piperacillin alone. These data support the use of extended dosing intervals (every 8 h) of piperacillin tazobactam in the treatment of infections caused by piperacillin-resistant bacteria. PMID- 7840570 TI - Standardization of disk diffusion test and its clinical significance for susceptibility testing of metronidazole against Helicobacter pylori. AB - Susceptibilities of 121 clinical Helicobacter pylori strains to metronidazole were determined by both a 5-micrograms metronidazole disk diffusion test and a plate dilution method in duplicate and after different periods of incubation. The distribution of MICs of metronidazole against H. pylori among the strains was found to be bimodal. The diameters of inhibitory zones obtained by the disk diffusion test and the MICs obtained by the plate dilution method correlated well, especially after 4 days of incubation (r = 0.77). An inhibitory zone diameter of 20 mm was found to correspond to a MIC of 8 micrograms/ml and is recommended as a suitable zone for differentiating susceptibility and resistance with a 5-micrograms metronidazole disk. Three interpretive categories of susceptibility results were defined; strains with inhibitory zone diameters of more than 26 mm were defined as susceptible (MIC, < 4 micrograms/ml), strains with zone diameters of 20 to 26 mm were deemed intermediate (MIC, 4 to 8 micrograms/ml), and those with zone diameters of less than 20 mm were deemed resistant (MIC, > 8 micrograms/ml). Furthermore, 76 H. pylori-positive patients with duodenal ulcers or nonulcer dyspepsia were treated with a 1 week of triple therapy (colloidal bismuth subcitrate, metronidazole, and tetracycline). H. pylori strains were isolated before treatment from antral biopsies from those patients, and the metronidazole susceptibilities of the strains were determined by the disk diffusion test. H. pylori status was evaluated again 4 weeks after completion of treatment. The eradication rates for susceptible, intermediate, and resistant strains were 95.9% (47 of 49), 62.5% (5 of 8), and 52.6% (10 of 19), respectively. It is included that the 5-micrograms disk diffusion test is easy to perform and gives final results similar to those of the plate dilution method. The three interpretive categories of susceptibility may be of benefit for clinical choice of chemotherapy in eradicating H. pylori. PMID- 7840571 TI - In vitro activity of the tribactam GV104326 against gram-positive, gram-negative, and anaerobic bacteria. AB - GV104326 is the first member of a new class of antibiotics (tribactams) selected for development. It combines a particularly broad spectrum (including gram negative and gram-positive aerobes and anaerobes) with high potency, resistance to beta-lactamases, and complete stability to dehydropeptidases. Comparative MICs were determined for GV104326 against 415 recent clinical isolates (including beta lactamase producers), using representative antibacterial agents (imipenem, amoxicillin-clavulanic acid, cefpirome, ciprofloxacin, gentamicin, and erythromycin). GV104326 was particularly active against gram-positive bacteria; in general, its in vitro activity was equivalent to that of imipenem, equivalent to or better than that of amoxicillin-clavulanic acid, and superior to that of cefpirome, ciprofloxacin, and erythromycin. Against gram-negative bacteria, GV104326 possessed activity similar to that of imipenem and cefpirome against enterobacteria and Haemophilus spp. but its activity was superior to that of amoxicillin-clavulanic acid. GV104326 showed excellent antianaerobe activity. GV104326 was stable to all clinically relevant beta-lactamases and was rapidly lethal to susceptible bacteria. In Escherichia coli, GV104326 bound predominantly to PBPs 1a and 2 and at low concentrations osmotically stable round forms were observed. GV104326 showed an affinity for PBPs 2 and 4 of Staphylococcus aureus. PMID- 7840572 TI - Pharmacokinetics and distribution in tissue of FK-037, a new parenteral cephalosporin. AB - A single 1-g or 2-g intravenous dose of the cephalosporin FK-037 was given over 30 min in a cross-over-designed study, to each of six healthy male volunteers, and the concentrations of the drug were measured in plasma and cantharides induced blister fluid over the subsequent 12 h. Urine was collected over 24 h. After a washout period of 6 weeks, during which the blisters healed, the study was repeated at the other dose level. Following the 1-g dose, the mean peak concentration in plasma was 83.8 micrograms/ml, and after the 2-g dose it was 142.6 micrograms/ml. The mean peak concentrations in the inflammatory fluid were 37.9 and 63.3 micrograms/ml, respectively. The mean elimination half-lives from plasma and inflammatory fluid were 2.0 and 2.5 h, respectively, after 1 g and 2.0 h and 3.7 h, respectively, after 2 g. The amounts of penetration into inflammatory fluid (as assessed by ratios of areas under the concentration-time curves) were 109.9 and 110.5% following doses of 1 and 2 g, respectively. The proportions of the administered drug recovered in the urine by 24 h were 87.6 and 85.7%, respectively. Our results indicate that FK-037 should prove to be efficacious in the treatment of a wide range of systemic infections. PMID- 7840573 TI - The endocytic process in CHO cells, a toxic pathway of the polyene antibiotic amphotericin B. AB - We describe the fate of the polyene antibiotic amphotericin B (AmB) after its interaction with Chinese hamster ovary (CHO) cells. The global uptake of AmB by these cells was measured at 37 degrees C after a 1-h incubation in the presence of 5% fetal bovine serum. It increased with the total concentration of drug and reached a plateau of approximately 1 nmol/mg of cell protein for an external concentration of 25 microM. The same experiment performed at 5 degrees C revealed a drastic decrease in uptake. The distribution of the drug among plasma membranes, endosomes, and lysosomes was then investigated after the separation of the postnuclear fractions by a Percoll gradient. After a 10-min incubation, AmB was found only in the plasma membrane fraction, regardless of the drug concentrations used (5 to 100 microM). After 60 min, at low drug concentrations (5 and 10 microM) AmB was found to be incorporated mainly in plasma and lysosomal fractions. At high concentrations (50 microM) AmB accumulated in endosomal fractions and plasma membranes. At intermediate concentrations (25 microM) AmB was distributed among the three fractions. When the same experiment was carried out at 5 degrees C, AmB was associated only with the plasma membrane even after 60 min, which was consistent with the absence of endocytotic process at low temperature. The effect of AmB on the endocytic process resulted in the increased uptake of sulforhodamine B, a fluid-phase marker of endocytosis, as well as by the accumulation of sulforhodamine in spots scattered in the cytoplasms of AmB treated cells, in contrast to the accumulation around the nuclei observed in the control cells. These results are interpreted as indicating that AmB is internalized by the cells through endocytosis and that high concentrations of the drug block the fusion between endosomes and/or the fusion between endosomes and lysosomes. PMID- 7840574 TI - Characterization of rifampin-resistance in pathogenic mycobacteria. AB - The emergence of rifampin-resistant strains of pathogenic mycobacteria has threatened the usefulness of this drug in treating mycobacterial diseases. Critical to the treatment of individuals infected with resistant strains is the rapid identification of these strains directly from clinical specimens. It has been shown that resistance to rifampin in Mycobacterium tuberculosis and Mycobacterium leprae apparently involves mutations in the rpoB gene encoding the beta-subunit of the RNA polymerases of these species. DNA sequences were obtained from a 305-bp fragment of the rpoB gene from 110 rifampin-resistant and 10 rifampin-susceptible strains of M. tuberculosis from diverse geographical regions throughout the world. In 102 of 110 rifampin-resistant strains 16 mutations affecting 13 amino acids were observed. No mutations were observed in rifampin susceptible strains. No association was found between particular mutations in the rpoB gene and drug susceptibility patterns of multidrug-resistant M. tuberculosis strains. Drug-resistant M. tuberculosis strains from the same outbreak and exhibiting the same IS6110 DNA fingerprint and drug susceptibility pattern contained the same mutation in the rpoB gene. However, mutations are not correlated with IS6110 profiling outside of epidemics. The evolution of rifampin resistance as a consequence of mutations in the rpoB gene was documented in a patient who developed rifampin resistance during the course of treatment. Rifampin-resistant strains of M. leprae, Mycobacterium avium, and Mycobacterium africanum contained mutations in the rpoB gene similar to that documented for M. tuberculosis. This information served as the basis for developing a rapid DNA diagnostic assay (PCR-heteroduplex formation) for the detection of rifampin susceptibility of M. tuberculosis. PMID- 7840575 TI - 1-[((S)-2-hydroxy-2-oxo-1,4,2-dioxaphosphorinan-5-yl)methyl] cytosine, an intracellular prodrug for (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine with improved therapeutic index in vivo. AB - 1-[((S)-2-hydroxy-2-oxo-1,4,2-dioxaphosphorinan-5-yl)methyl]cytosi ne (cyclic [cHPMPC]) was evaluated as a novel antiviral agent in comparison with (S)-1-(3 hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC). Evaluation for in vitro activity against herpes simplex virus type 2 in MA-104 and MRC-5 cells showed that both cHPMPC and HPMPC have comparable activities and cytotoxicities. cHPMPC was found to be stable on incubation in human plasma and human liver homogenates. Intracellular metabolism studies revealed that cHPMPC was converted inside of the cells to HPMPC and then to the monophosphate, the diphosphate, and the monophosphate choline metabolites. In a mouse herpes simplex virus type 2 encephalitis model, both cHPMPC and HPMPC exhibited similar potencies in vivo. Nephrotoxicity, which is the dose-limiting toxicity of HPMPC, was assessed in a 14-day repeated-dose toxicity study in rats; cHPMPC has an improved safety margin of > or = 13-fold over that of HPMPC. PMID- 7840576 TI - Effects of localized Pasteurella haemolytica infection on erythromycin-binding properties of bovine alpha-1-acid glycoprotein, albumin, serum, and tissue chamber fluids. AB - The in vitro erythromycin-binding properties of bovine alpha-1-acid glycoprotein (AAG) and albumin were studied by using equilibrium dialysis. In addition, the proportions of free erythromycin in bovine serum and tissue chamber fluid before and 4 days after inoculation of subcutaneous tissue chambers with Pasteurella haemolytica were measured. At a concentration of 5 micrograms/ml, erythromycin was moderately bound to AAG (39% +/- 4% free) and was only slightly bound to albumin (86% +/- 2% free). Scatchard analysis of the data describing binding to pure bovine AAG indicated that erythromycin was bound to a single high-affinity (6.45 x 10(4) M-1) site on the protein. At lower total concentrations of erythromycin, the free concentrations of the antibiotic were lower in serum samples collected after infection (49% +/- 3% at 5 micrograms of erythromycin per ml) than in those collected before inoculation (55% +/- 3% at 5 micrograms of erythromycin per ml). Inoculation had no effect on binding to macromolecules in chamber fluids. Inoculated tissue chambers served as a convenient model for studying the effect of infection on drug-macromolecule interactions in interstitial fluid. PMID- 7840577 TI - Comparison of rates of intracellular metabolism of zidovudine in human and primate peripheral blood mononuclear cells. AB - 3'-Azido-3'-deoxythymidine (AZT) is a drug of choice for the treatment of AIDS. On the basis of pharmacokinetic data, the nonhuman primate Macaca nemestrina has been shown to be a suitable animal model for use in the study of the disposition of AZT. However, since AZT is activated to its metabolite, the AZT triphosphate (AZTTP), intracellularly, we investigated the intracellular activation of AZT in peripheral blood mononuclear cells (PBMCs) of healthy and simian immunodeficiency virus-infected macaques and compared it with that in PBMCs obtained from human volunteers. At 5 microM extracellular AZT, both human and macaque PBMCs rapidly convert AZT to AZT monophosphate (AZTMP) (84% of total phosphorylated products) in 4 h. Increases in AZTMP levels of 7.7- and 12-fold were observed in human and macaque PBMCs, respectively, when the extracellular AZT concentration increased from 0.45 to 14.4 microM. Similar ratios of AZT metabolites, AZT diphosphate (AZTDP)/AZTTP (0.7 to 1.4), AZTMP/AZTDP (3 to 14), and AZTMP/AZTTP (3 to 19), over the same AZT concentration range were observed in both human and macaque PBMCs, suggesting that these cells have similar capacities to phosphorylate AZT. Simian immunodeficiency virus-infected macaque PBMCs showed a fivefold increase in intracellular AZT and AZTMP levels and a twofold increase in AZTDP and AZTTP levels (picomoles per 10(7) cells) when compared with those in the uninfected cells (at 4 h with 0.9 microM extracellular concentration). This increase in AZT metabolite levels has also been reported for human immunodeficiency virus infected PBMCs. Collectively, given the similarities in phosphorylation profiles between healthy and infected human and macaque PBMCs, we conclude that the macaque is a suitable animal model for use in the study of factors that can effect the in vivo phosphorylation of AZT. PMID- 7840578 TI - Activity of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl) cytosine against human cytomegalovirus when administered as single-bolus dose and continuous infusion in in vitro cell culture perfusion system. AB - HPMPC [(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine] is a potent inhibitor of human cytomegalovirus (HCMV) replication as determined by conventional tissue culture methods in which the drug concentration remains constant over time. Previous studies have shown HPMPC to have a long intracellular half-life. Despite its relatively short extracellular half-life, HPMPC might provide significant anti-HCMV activity long after the elimination of the drug by first-order kinetics. We addressed this hypothesis by measuring the activity of HPMPC in a novel cell culture perfusion system. This system allows us to compare the activity of HPMPC when given as a continuous infusion with its activity when given as a single-bolus dose followed by elimination that simulates the drug's in vivo pharmacokinetics. We show that continuous infusions maintaining maximum concentrations (Cmaxs) of 0.05, 0.10, 0.31, and 1.0 micrograms/ml and achieving areas under the drug concentration-time curves (AUCs) of 8.4, 17, 50, and 162 micrograms.h/ml, respectively, result in 27, 56, 63, and 88% inhibition of viral DNA accumulation, respectively, compared with an untreated control. Single-bolus doses achieving Cmaxs of 0.10, 1.25, 3.0, and 7.7 micrograms/ml with an elimination half-life of 20 h achieved AUCs of 2.4, 32, 78, and 138 micrograms.h/ml and resulted in 0, 48, 69, and 87% inhibition of HCMV DNA accumulation. Single-bolus doses achieving Cmaxs of 3.9 and 12 micrograms/ml with an elimination half-life of 6.5 h achieved AUCs of 34 and 105 micrograms.h/ml, respectively, resulting in 15 and 76% inhibition of viral DNA accumulation. Comparison of Cmax-versus-effect curves for these three regimens suggests that maximum concentration is not the only important pharmacokinetic determinant of HPMPC's antiviral activity. Similar comparisons of AUC-versus-effect curves for continuous and bolus dosing suggest that the AUC is an important determinant of antiviral activity for AUCs greater than 100 micrograms . h/ml. We conclude that single-bolus doses of HPMPC potently inhibit HCMV DNA accumulation but that this activity is more heavily influenced by the AUC than the Cmax at the upper end of the AUC range tested. At lower AUCs, some other parameter may be the primary determinant of antiviral activity. Our cell culture perfusion system provides a novel, efficient, and convenient method for addressing questions relating the effects of constantly changing drug concentrations to antiviral effects. PMID- 7840579 TI - Resistance of human immunodeficiency virus type 1 to acyclic 6-phenylselenenyl- and 6-phenylthiopyrimidines. AB - Acyclic 6-phenylselenenyl- and 6-phenylthiopyrimidine derivatives are potent and specific inhibitors of human immunodeficiency virus type 1 (HIV-1). The development of in vitro resistance to two derivatives, 5-ethyl-1-(ethoxymethyl) (6-phenylthio)-uracil (E-EPU), was evaluated by serial passage of HIV-1 in increasing concentrations of inhibitor. HIV-1 variants exhibiting > 500-fold resistance to E-EPSeU and E-EPU were isolated after sequential passage in 1, 5, and 10 microM inhibitor. The resistant variants exhibited coresistance to related acyclic 6-substituted pyrimidines and the HIV-1-specific inhibitors (+)-(5S) 4,5,6,7-tetrahydro-5- pyrimidines and the HIV-1-specific inhibitors (+)-(5S) 4,5,6,7-tetrahydro-5- methyl-6-(3-methyl-2-butenyl)imidazo[4,5,1-jk]benzodiazepin 2(1H)- thione (TIBO R82150) and nevirapine, but remained susceptible to 3'-azido 3'-deoxythymidine, 2',3'-dideoxycytidine, 2',3'-dideoxyinosine, and phosphonoformic acid. DNA sequence analysis of reverse transcriptase (RT) derived from E-EPSeU-resistant virus identified a Tyr (TAT)-to-Cys (TGT) mutation at either codon 188 (Cys-188; 9 of 15 clones) or codon 181 (Cys-181; 5 of 15 clones). The same amino acid changes were found in RT from E-EPU-resistant virus, but the Cys-181 mutation was more common (9 of 10 clones) than the Cys-188 mutation (1 of 10 clones). Site-specific mutagenesis and production of mutant recombinant viruses demonstrated that both the Cys-181 and Cys-188 mutations cause resistance to E-EPSeU and E-EPU. Of the two mutations, the Cys-188 substitution produced greater E-EPSeU and E-EPU resistance. The predominance of the Cys-188 mutation in E-EPSeU-resistant variants has not been noted for other classes of HIV-1 specific RT inhibitors. HIV-1 resistance is likely to limit the therapeutic efficacy of acyclic 6-substituted pyrimidines if they are used as monotherapy. PMID- 7840580 TI - Pharmacokinetics of ceftriaxone in patients with typhoid fever. AB - Ceftriaxone in short courses has emerged as an effective alternative to chloramphenicol for the treatment of typhoid fever. To study the pharmacokinetics of ceftriaxone in acute typhoid fever, 10 febrile Nepalese adolescents and young adults with blood culture-positive illness were treated with 3 g of ceftriaxone (intravenous infusion for 30 min) daily for 3 days. On the 1st and 3rd day of treatment, blood and urine samples were collected at defined intervals for measurements of drug concentrations. Kinetic parameters including concentrations at the end of infusion (Cmax) and 24 h after the end of infusion (Cmin), elimination half-life (t1/2), area under the plasma concentration-time curve (AUC), total plasma clearance, renal clearance, percentage excreted in urine, and volume of distribution were estimated. On day 1, mean values were as follows: Cmax, 291 micrograms/ml; Cmin, 21.7 micrograms/ml; plasma t1/2, 5.2 h; AUC, 1,428 micrograms.h/ml; total plasma clearance, 37 ml/min; renal clearance, 19 ml/min; percentage excreted in urine, 49.7%; and volume of distribution, 16.1 liters. Mean values on day 3 were not significantly different from those on day 1. Compared with published values for healthy volunteers who received the same dose, our mean t1/2s and AUCs were lower and our mean total plasma clearances, renal clearances, and volumes of distribution were higher. The good clinical responses of these patients to therapy and the adequate Cmins support the use of ceftriaxone once daily for the treatment of typhoid fever. PMID- 7840581 TI - In vitro activities of 12 orally administered antimicrobial agents against four species of bacterial respiratory pathogens from U.S. Medical Centers in 1992 and 1993. AB - Clinical isolates of Haemophilus influenzae, Streptococcus pneumoniae, Streptococcus pyogenes, and Moraxella catarrhalis were gathered from 19 different clinical laboratories throughout the continental United States. The in vitro activities of 12 orally administered antimicrobial agents were compared by broth microdilution tests with 3,151 bacterial isolates. Among 890 H. influenzae isolates, 30% were capable of producing beta-lactamase enzymes (12 to 41% in different medical centers). Most of the 619 beta-lactamase-negative H. influenzae strains were susceptible to ampicillicin (MIC, < or = 1.0 micrograms/ml): 5 strains were intermediate in susceptibility (MIC, 2.0 micrograms/ml) and 1 strain was ampilicillin resistant (MIC, 4.0 micrograms/ml). Ninety-two percent of 698 M. catarrhalis strains were beta-lactamase positive. Of 799 S. pneumoniae isolates, 15% were intermediate in susceptibility to penicillin and 7% were resistant to penicillin. The prevalence of penicillin-susceptible pneumococci in different institutions ranged from 63 to 95%. Only 1% of 764 S. pyogenes isolates were resistant to the macrolides, but 5% of S. pneumoniae isolates were macrolide resistant. Only 71% of 58 penicillin-resistant S. pneumoniae isolates were erythromycin susceptible, whereas 97% of the 622 penicillin-susceptible strains were erythromycin susceptible. Penicillin-resistant pneumococci were also relatively resistant to the cephalosporins and amoxicillin. Penicillin susceptible pneumococci were susceptible to amoxicillin-clavulanic acid (MIC for 90% of isolates tested [MIC90], < or = 0.12/0.06 microgram/ml), cefixime (MIC90, 0.25 microgram/ml), cefuroxime axetil (MIC90, < or = 0.5 microgram/ml), cefprozil (MIC90, < or = 0.5 micrograms/ml), cefaclor (MIC90, 0.5 microgram/ml), and loracarbef (MIC90, 1.0 microgram/ml). Most strains of the other species remained susceptible to the study drugs other than amoxicillin. PMID- 7840582 TI - Intracellular penetration and activity of BAY Y 3118 in human polymorphonuclear leukocytes. AB - The penetration of a new quinolone (BAY Y 3118) into human polymorphonuclear leukocytes (PMNs) was evaluated by a fluorometric assay. The cellular concentration-to-extracellular concentration (C/E) ratio was higher than 6.3 at extracellular concentrations ranging from 2 to 100 mg/liter. The uptake of BAY Y 3118 was rapid, reversible and nonsaturable. The intracellular penetration of BAY Y 3118 was significantly affected by environmental temperature (C/E ratio at 4 degrees C, 5.4 +/- 0.5; control, 7.5 +/- 0.9; P < 0.05) and cell viability (C/E ratio in dead PMNs, 5.5 +/- 0.8; control 7.5 +/- 0.9; P < 0.05), but it was not affected by metabolic inhibitors. The ingestion of opsonized zymosan or opsonized Staphylococcus aureus significantly decreased the levels of PMN-associated BAY Y 3118. Cell stimulation by a membrane activator, however, significantly increased the intracellular concentration of this quinolone. At therapeutic extracellular concentrations (0.5, 2, and 5 mg/liter), BAY Y 3118 showed intracellular activity greater than that of ciprofloxacin against S. aureus in human PMNs. It was concluded that BAY Y 3118 reaches high intracellular concentrations within human PMNs and remains active intracellularly. PMID- 7840583 TI - Constitutive production of nonenveloped human immunodeficiency virus type 1 particles by a mammalian cell line and effects of a protease inhibitor on particle maturation. AB - A stable cell line encoding the sequences of all the human immunodeficiency virus type 1 proteins, with the exception of the gp160 envelope glycoprotein, was derived from transfection of monkey COS-7 cells. This cell line, referred to as CH-1, produces active viral protease that correctly processes its natural substrates and yields capsid particles. These particles contain reverse transcriptase activity and packaged viral RNA but are noninfectious. The level of expression of viral proteins is not toxic to the cells, yet it is comparable to that observed for chronically infected lymphocytes. These constitutively synthesized viral proteins provide a consistent system for the analysis of potential inhibitors of late viral functions. The lack of gp160 increases the biosafety of this assay system, while it allows the measurement of the effects on the production and release of capsid particles. A human immunodeficiency virus type 1 protease inhibitor was used to confirm the viral polyprotein maturation pathway in this system. Particles from cells treated with this protease inhibitor contain unprocessed p55gag precursor and have the same density as the mature particles. These immature particles contain viral RNA, but reverse transcriptase activity is significantly reduced. This cell line may serve to identify compounds that are able to affect viral assembly and maturation as well as to identify the interactions between the viral and cellular proteins involved in these essential processes. PMID- 7840584 TI - In vitro model to assess effect of antimicrobial agents on Encephalitozoon cuniculi. AB - We have developed a new micromethod to study the effect of drugs on microsporidia, using MRC5 fibroblasts infected by 10(5) spores of Encephalitozoon cuniculi. After 3 days of incubation with various concentrations of drugs, parasitic foci were counted in stained cultures. The inhibition of microsporidial growth exceeding 90% with albendazole (0.005 microgram/ml), fumagillin (0.001 microgram/ml), 5-fluorouracil (3 micrograms/ml), and sparfloxacin (30 micrograms/ml) was observed. Chloroquine, pefloxacin, azithromycin, and rifabutin were partially effective, at high concentrations. Arprinocid, metronidazole, minocycline, doxycycline, itraconazole, and difluoromethylornithine were not evaluable, since concentrations that inhibited microsporidia were also toxic for fibroblasts. Pyrimethamine, piritrexim, sulfonamides, paromomycin, roxithromycin, atovaquone, and flucytosine were ineffective. Our results confirm that albendazole and fumagillin have marked activity against E. cuniculi and show the antimicrosporidial activity of 5-fluorouracil and sparfloxacin. These data may form the basis for treatment of Encephalitozoon hellem and Septata intestinalis infections and represent an attempt to identify drugs effective against Enterocytozoon bieneusi. PMID- 7840585 TI - Intracellular and extracellular penetration of azithromycin into inflammatory and noninflammatory blister fluid. AB - The penetration of azithromycin into the blister fluids of six volunteers was analyzed after a 5-day regimen (total of 1.5 g). Differences in drug concentrations in a paper disk and serum and in the mass of azithromycin from inflammatory blister chamber leukocytes and noninflammatory blister chamber leukocytes were significant (P < 0.05). PMID- 7840586 TI - Sequences of CAZ-3 and CTX-2 extended-spectrum beta-lactamase genes. AB - The nucleotide sequences of blaTEM genes coding for the extended-spectrum beta lactamases CAZ-3 and CTX-2 were determined. The gene for CAZ-3 is identical to blaTEM-12b. The gene for CTX-2 differs from characterized blaTEM genes for extended-spectrum beta-lactamases by a new combination of already known mutations. We propose for CTX-2 the designation TEM-25. PMID- 7840587 TI - Safety of famciclovir in patients with herpes zoster and genital herpes. AB - Safety reporting from individual ongoing and completed clinical studies has demonstrated that famciclovir, the well-absorbed oral form of the antiherpesvirus agent penciclovir, has been well tolerated by more than 3,000 individuals worldwide. An integrated safety evaluation has been performed and includes over 1,600 patients from 11 completed, randomized, double-blind clinical trials and 2 open trials. The famciclovir population consisted of 816 herpes zoster patients (four trials), 409 patients with acute genital herpesvirus infections (seven trials), and 382 patients from two genital herpes suppression studies. Overall, the famciclovir-treated patient population was 57.7% female and ranged in age from 15 to 102 years (mean, 42.6 years), with 31.2% aged 50 years or more and 15.7% aged 65 years or more. The mean duration of exposure to famciclovir was 28.8 days (5.8 days excluding suppression studies). The total daily doses ranged from 125 mg to 2.25 g. The most common adverse experiences reported as related to study medication (famciclovir and placebo) were headache, nausea, and diarrhea. The frequencies of adverse experiences and laboratory abnormalities (hematology, clinical chemistry, and urinalysis parameters) were similar in both famciclovir and placebo recipients. Thus, safety data from the analysis of 13 completed clinical studies demonstrate that famciclovir is tolerated well by patients with either herpes zoster or genital and has a safety profile comparable to that of placebo. PMID- 7840588 TI - Biocidal action of chlorhexidine is annulled by nicotinic acid. AB - An analytical system comprising a bacterium and a protozoan was used to pinpoint the metabolic lesion whereby chlorhexidine (CLX) produced cell death. Nicotinic acid but not nicotinamide annulled the biocidal action of CLX. The results suggest that CLX may not permit bioconversion of nicotinamide to nicotinic acid to annul the growth inhibition induced by CLX. PMID- 7840589 TI - gyrA mutations in quinolone-resistant isolates of the fish pathogen Aeromonas salmonicida. AB - gyrA mutations in quinolone-resistant isolates of Aeromonas salmonicida have been detected by using PCR to amplify the quinolone resistance-determining region of gyrA and subsequent cloning and sequencing of PCR products. Comparison of nucleotide and derived amino acid sequences of PCR products from quinolone susceptible and -resistant bacteria revealed a serine 83-to-isoleucine substitution in the gyrase A protein of resistant isolates. One of the resistant isolates differed from the other by a two- to fourfold-higher MIC of the fluoroquinolone enrofloxacin and carried an additional alanine 67-to-glycine substitution, which may contribute to the higher level of resistance. PMID- 7840590 TI - In vitro activities of enoxacin, enrofloxacin, sparfloxacin, and ciprofloxacin against Escherichia coli strains isolated from diarrheic lambs and kids. AB - The in vitro activities of four fluoroquinolone compounds were tested against 92 Escherichia coli strains of ovine and caprine origin under aerobic and anaerobic incubation conditions. The four fluoroquinolones proved to be highly effective against the E. coli isolates tested. When bacteria were cultured anaerobically, at least fourfold increases in the MICs of enoxacin for the strains occurred and no detectable changes in enrofloxacin, sparfloxacin, and ciprofloxacin MICs occurred. PMID- 7840591 TI - Activity of CP 99,219 compared with those of ciprofloxacin, grepafloxacin, metronidazole, cefoxitin, piperacillin, and piperacillin-tazobactam against 489 anaerobes. AB - Agar dilution was used to compare the in vitro activity of CP 99,219 with those of ciprofloxacin, grepafloxacin, metronidazole, cefoxitin, piperacillin, and piperacillin-tazobactam against 489 anaerobes. CP 99,219 yielded a MIC for 50% of the strains tested (MIC50) of 0.25 micrograms/ml and a MIC90 of 1.0 microgram/ml, with 99.6% of the strains susceptible at a breakpoint of 2.0 micrograms/ml. Ciprofloxacin and grepafloxacin were less active (MIC50, 4.0 micrograms/ml; MIC90, 32.0 micrograms/ml and 2.0 and 16.0 micrograms/ml, respectively). Metronidazole was active against all gram-negative rods (MIC90, 4.0 micrograms/ml), but 31% of the gram-positive anaerobes were resistant at > 8.0 micrograms/ml. Cefoxitin was active against 84% of all strains at < or = 16.0 micrograms/ml, with a MIC50 of 4.0 micrograms/ml and a MIC90 of 32.0 micrograms/ml. Tazobactam enhanced the activity of piperacillin against > 95% of the beta-lactamase-producing gram-negative anaerobic rods (MIC90, 16.0 micrograms/ml). PMID- 7840592 TI - Association between double mutation in gyrA gene of ciprofloxacin-resistant clinical isolates of Escherichia coli and MICs. AB - The mutations in the quinolone resistance-determining region of the gyrA and gyrB genes from 27 clinical isolates of Escherichia coli with a range of MICs of ciprofloxacin from 0.007 to 128 micrograms/ml and of nalidixic acid from 2 to > 2,000 micrograms/ml were determined by DNA sequencing. All 15 isolates with ciprofloxacin MICs of > or = 1 micrograms/ml showed a change in Ser-83 to Leu of GyrA protein, whereas in clinical isolates with a MIC of > or = 8 micrograms/ml (11 strains), a double change in Ser-83 and Asp-87 was found. All isolates with a MIC of nalidixic acid of > or = 128 micrograms/ml showed a mutation at amino acid codon Ser-83. Only 1 of the 27 clinical isolates of E. coli analyzed showed a change in Lys-447 of the B subunit of DNA gyrase. A change in Ser-83 is sufficient to generate a high level of resistance to nalidixic acid, whereas a second mutation at Asp-87 in the A subunit of DNA gyrase may play a complementary role in developing the strain's high levels of ciprofloxacin resistance. PMID- 7840593 TI - Efficacies of different vancomycin dosing regimens against Staphylococcus aureus determined with a dynamic in vitro model. AB - A dynamic in vitro model was used to assess four different vancomycin dosing regimens against Staphylococcus aureus. These regimens achieved peak drug concentrations of 48 micrograms/ml (single dose) and 30 micrograms/ml (dosed every 12 h) and constant concentrations of 16 and 8 micrograms/ml. Analysis of the area under the bacterial concentration-time curve, area under the first moment of the bacterial concentration-time curve, and bacterial elimination rate constant showed no difference in the rate or extent of bacterial killing. The optimal dosing method may be that which achieves the lowest area under the curve while concentrations are maintained above the MBC. PMID- 7840594 TI - Detection of 4-quinolone resistance mutation in gyrA gene of Shigella dysenteriae type 1 by PCR. AB - To study 4-quinolone resistance, the N-terminal coding region of gyrA from nalidixic acid-susceptible and -resistant isolates of Shigella dysenteriae type 1 was amplified by PCR, cloned, and sequenced. DNA sequence analysis of gyrA from nalidixic acid-resistant isolates revealed a C-to-T transition at nucleotide position 248 leading to a Ser-83-to-Leu substitution which was absent in susceptible clinical isolates. Direct HinfI digestion of PCR-amplified DNA detected similar mutations. Thus, DNA gyrase A subunit mutation Ser-83 to Leu is implicated in 4-quinolone resistance in S. dysenteriae type 1. PMID- 7840595 TI - Loss of function mutation in the yeast multiple drug resistance gene PDR5 causes a reduction in chloramphenicol efflux. AB - The yeast (Saccharomyces cerevisiae) PDR5 gene product encodes a 160-kDa protein related to the large ABC family of transporters, including the human MDR1 multidrug resistance p-glycoprotein. Loss of function mutations in PDR5 result in chloramphenicol hypersensitivity. A pdr5::Tn5 loss of function mutant exhibits a markedly impaired efflux of chloramphenicol compared with that of an isogenic PDR5 (wild-type) control. PMID- 7840596 TI - Azole resistance in oropharyngeal Candida albicans strains isolated from patients infected with human immunodeficiency virus. AB - For 212 oropharyngeal isolates of Candida albicans, the fluconazole MICs for 50 and 90% of strains tested were 0.5 and 16 micrograms/ml, respectively, and those of itraconazole were 0.05 and 0.2 micrograms/ml, respectively. Of 16 isolates for which fluconazole MICs were > 64 micrograms/ml, itraconazole MICs for 14 were < or = 0.8 micrograms/ml and for 2 were > 6.4 micrograms/ml. Most fluconazole resistant strains remained susceptible to itraconazole; whether itraconazole will prove effective for refractory thrush remains to be shown. PMID- 7840597 TI - Ability of cecropin B to penetrate the enterobacterial outer membrane. AB - The cationic amphipathic insect peptide cecropin B was almost as active on wild type enteric bacteria as it was on their lipopolysaccharide and lipid A mutants that have very defective outer membrane. The polymyxin-resistant strains, which elaborate altered, less anionic lipopolysaccharide, were completely susceptible to cecropin B. No synergism was found between cecropin B and hydrophobic antibiotics. Throughout the study, the activity of cecropin B resembled that of quaternary detergents. PMID- 7840598 TI - Antimicrobial susceptibilities of clinical isolates of Acinetobacter baumannii from Singapore. AB - The in vitro activities of 17 antimicrobial agents alone or in combination against 70 clinical isolates of Acinetobacter baumannii from Singapore were determined by broth microdilution. The MICs of amoxicillin, ampicillin, ceftazidime, ceftriaxone, gentamicin, and piperacillin for 90% of the strains were > or = 128 micrograms/ml. Addition of sulbactam to ampicillin produced improved activity, whereas adding tazobactam to piperacillin did not. The MICs of amikacin, ciprofloxacin, and imipenem for 90% of the strains were 32, 32, and 16 micrograms/ml, respectively. PMID- 7840599 TI - In vitro activity of DU-6859a against anaerobic bacteria. AB - The activity of a new quinolone agent, DU-6859a, against 330 strains of anaerobic bacteria was determined by using the National Committee for Clinical Laboratory Standards-approved Wadsworth brucella laked blood agar method; the activity of DU 6859a was compared with those of amoxicillin-clavulanate (2:1), chloramphenicol, ciprofloxacin, clindamycin, fleroxacin, imipenem, lomefloxacin, metronidazole, sparfloxacin, and temafloxacin. DU-6859a and chloramphenicol inhibited all of the isolates at concentrations of 1 and 16 micrograms/ml, respectively; amoxicillin clavulanate, imipenem, and metronidazole inhibited > or = 94% of the isolates at their respective breakpoints (8, 8, and 16 micrograms/ml). MICs of DU-6859a at which 90% of the strains were susceptible were 1 to 5 twofold dilutions lower than those of the other quinolones for every group of organisms. MICs of DU-6859a at which 90% of the strains were susceptible (total numbers of strains tested are in parentheses) were < or = 0.25 micrograms/ml for Bacteroides fragilis (57), other B. fragilis group species (84), Bilophila wadsworthia (15), Clostridium species (27) (including C. difficile, C. perfringens, and C. ramosum), Fusobacterium nucleatum (16), Fusobacterium mortiferum-F. varium group species (10), Peptostreptococcus species (20), non-spore-forming gram-positive rods (20), and Prevotella species (25). PMID- 7840600 TI - Oral absorption of ofloxacin administered together with aluminum. AB - A clinical study was carried out to establish the influence of aluminum on the oral absorption of ofloxacin. Ten healthy volunteers were included in a crossover study based on a Latin square design. The treatments that all volunteers received were A, consisting of 400 mg of ofloxacin, and B, consisting of 400 mg of ofloxacin plus 11 g of colloidal aluminum phosphate. The absorption constant and other ofloxacin parameters were calculated from data on levels in plasma by using model-independent calculation methods. There were no statistically significant differences between the mean values of the areas under the curve corresponding to the administration of ofloxacin alone and those of ofloxacin with aluminum. Regarding the other pharmacokinetic parameters, a significant difference between the absorption constants was found. The presence of aluminum reduces the absorption rate of this quinolone but does not modify the percentage of the absorbed dose. PMID- 7840601 TI - In vitro activities of two new glycylcyclines, N,N-dimethylglycylamido derivatives of minocycline and 6-demethyl-6-deoxytetracycline, against 339 strains of anaerobic bacteria. AB - The in vitro activities of the N,N-dimethylglycylamido derivatives of minocycline (DMG-MINO) and 6-demethyl-6-deoxytetracycline (DMG-DMDOT) were compared with those of minocycline, tetracycline, clindamycin, and metronidazole by using the National Committee for Clinical Laboratory Standards-approved Wadsworth agar dilution method. The MICs of DMG-MINO, DMG-DMDOT, and metronidazole at which 90% of the strains were susceptible (0.5, 1, and 1 micrograms/ml, respectively) were lower than those for clindamycin, minocycline, and tetracycline (4, 8, and 32 micrograms/ml, respectively). All of the strains of anaerobes tested, except one strain of Bacteroides ovatus (MIC, 16 micrograms/ml), were susceptible to DMG MINO and DMG-DMDOT at 8 micrograms/ml. PMID- 7840602 TI - The story of Jun. PMID- 7840603 TI - Regulation of heme biosynthesis in Escherichia coli. AB - Escherichia coli is an organism that synthesizes 5-aminolevulinate (ALA), the first committed compound of the heme biosynthetic pathway, from glutamate (C-5 pathway) as opposed to glycine and succinyl CoA (C-4 pathway). While regulation of the C-4 pathway is generally acknowledged to occur at the level of formation of ALA, the mode of regulation of the C-5 pathway is currently unclear. Here we have examined one aspect of regulation of heme synthesis in E. coli: the role of the end product, heme, as a feed-back regulator of ALA production. By using plasmid-encoded ALA synthase and/or cytochrome b5 expressed in a wild type E. coli strain, it was possible to determine the role that the proposed regulatory heme pool plays in the regulation of ALA and heme production. Expression of rat soluble cytochrome b5 results in an increase of cellular heme, indicating that the cell responds to this foreign "heme sink" by producing more heme even though the cytochrome does not participate directly in normal cellular regulation. Accumulation of pathway intermediates does not occur under these conditions. Expression of plasmid-encoded mouse ALA synthase results in increased cellular heme production as well as the accumulation of pathway intermediates either in the presence or absence of plasmid encoded cytochrome b5. These data support a regulatory scheme where the heme biosynthetic pathway in this C-5 organism is regulated at the level of ALA production in part by cellular heme content. PMID- 7840604 TI - Regulation of cytochrome P4501A1 gene expression in vascular smooth muscle cells through aryl hydrocarbon receptor-mediated signal transduction requires a protein synthesis inhibitor. AB - The present studies were conducted to evaluate the pattern of cytochrome P4501A1 (CYP1A1) gene inducibility in vascular (aortic) smooth muscle cells (SMCs) upon exposure to selected aromatic hydrocarbons. Challenge of randomly cycling or synchronized subcultures of adult quail aortic SMCs with 30 microM benzo[a] pyrene (BaP) or 10 nM 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) for 24 h failed to induce CYP1A1 gene expression as determined by Northern analysis. However, challenge with either hydrocarbon in the presence of 10 micrograms/ml cycloheximide caused superinduction of CYP1A1 mRNA levels under both growth conditions. Velocity sedimentation analysis of the nuclear fraction of quail aortic SMCs treated with 10 nM [3H]-TCDD resulted in a specifically bound peak of 6.5S. Formation of the 6.5S peak was competitively inhibited by an excess of unlabeled 2,3,7,8-tetrachlorodibenzo-furan (2 microM), a known aryl hydrocarbon receptor (AhR) ligand. Gel mobility shift assays of nuclear extracts from BaP- or TCDD-treated cells using a 32P-labeled Ah-responsive element consensus sequence gave ligand-inducible retarded bands. Transient transfection of the pMCAT 5.12 plasmid into SMCs followed by treatment with 30 microM BaP or 10 nM TCDD for 48 h was associated with appreciable induction of CAT activity. A comparable challenge, however, did not induce ethoxyresorufin O-deethylase activity in aortic SMCs. These results demonstrate that adult quail aortic SMCs contain the CYP1A1 gene and exhibit intact AhR-mediated signal transduction. The CYP1A1 gene is repressed under basal conditions, but treatment with cycloheximide restores constitutive expression and affords hydrocarbon inducibility. These data suggest that in adult quail aortic SMCs a labile repressor protein of CYP1A1 gene precludes transcriptional activation of the gene but does not interfere with AhR dependent signal transduction. PMID- 7840605 TI - Recombinant porcine collagenase: purification and autolysis. AB - Collagenase is a member of the matrix metalloproteinase family whose members are all capable of degrading extracellular matrix components. The mature form of porcine collagenase has been expressed in Escherichia coli using the pAX5 expression vector. The fusion protein consists of beta-galactosidase at the N terminus joined to a collagen hinge region and a blood-coagulation factor Xa cleavage site linked to an active form of collagenase. Recombinant collagenase was biologically active in the form of a fusion protein; this was cleaved with factor Xa to yield collagenase with the authentic N terminus (phenylalanine) found in vivo and purified in a single step on a peptide hydroxamic acid affinity column. On purification the recombinant porcine collagenase undergoes autolysis at a number of different bonds in the region connecting the active site domain with the C-terminal hemopexin-like domain. This may represent a loop region of poor secondary structure, making it susceptible to relatively nonspecific cleavage. The N-terminal fragment retains a reduced level of collagenolytic activity, along with that against casein and gelatin. PMID- 7840606 TI - Oxidative stress induces activation of a cytosolic protein responsible for control of iron uptake. AB - A cytosolic protein, named iron-responsive element-binding protein (IRE-BP), is sensitive to cellular iron concentration. At low cytosolic iron level, IRE-BP is activated and binds to stem-loop untranslated regions (IRE regions) of transferrin and ferritin mRNAs, activating and inhibiting their translations, respectively. This concerted mechanism permits a fine control of iron homeostasis in the cell. The activity of IRE-BP can be measured by its binding to IRE regions, using a protein band-shift electrophoretic assay. Damage to cells by oxidative stress is known to be mediated by iron. We observed that IRE-BP is rapidly activated by exposure of V79 Chinese hamster ovary cells to H2O2. However, if cell extracts are exposed to H2O2 IRE-BP activation is not observed. Therefore, the activation is not a direct consequence of the H2O2 attack to IRE BP. The in vivo IRE-BP-activation by H2O2 is not prevented by hydroxyl radical scavengers or by the iron chelator 1,10-phenanthroline, indicating that Fenton reaction is not involved in the process. In fact, simultaneous exposure of cells to H2O2 and 1,10-phenanthroline produces an even stronger activation than exposure to H2O2 alone. The interpretation of the mechanism of IRE-BP activation by oxidative stress is hampered by the fact that the mechanism of IRE-BP modulation by cytosolic iron has not been established. It has been recently shown that the iron-sulfur cluster in IRE-BP must be completely disassembled in order for activation to occur and that this is triggered by low iron in the cell. It is likely that IRE-BP senses Fe(II) and that its oxidation to Fe(III) by H2O2 or chelation by 1,10-phenanthroline set up a program for increasing iron uptake. The physiological consequences of this activation still has to be assessed. PMID- 7840607 TI - Effects of lipids on ATPase activity of purified Chinese hamster P-glycoprotein. AB - Chinese hamster P-glycoprotein ("multidrug-resistance protein") was purified and reconstituted in proteoliposomes by the procedure of I. L. Urbatsch, M. K. al Shawi, and A. E. Senior (1994, Biochemistry 33, 7069-7076). The presence of lipid during the octylglucoside solubilization and Reactive Red 120 chromatography steps was found to be mandatory for retention of ATPase activity. Sheep brain or bovine liver lipid extracts could be substituted for the Escherichia coli lipids used previously. Stimulation of ATPase activity of purified, reconstituted P glycoprotein by vinblastine, colchicine, and daunomycin was seen with sheep brain and bovine liver lipids, but not with E. coli lipids. Basal (i.e., not drug stimulated) ATPase activity was different in the three lipids. Azidopine labeling of the drug binding sites in purified, reconstituted P-glycoprotein was carried out; vinblastine, colchicine, and daunomycin competed for labeling in all three lipids. It is therefore evident that the lipid environment can significantly influence the characteristics of purified, reconstituted P-glycoprotein ATPase activity and the apparent coupling between drug-binding and catalytic sites. PMID- 7840608 TI - The vitamin D3 hydroxylase-associated protein is a propionamide-metabolizing amidase enzyme. AB - Previously we isolated a novel protein that coimmunoprecipitates with the 1,25 dihydroxyvitamin D3-24R-hydroxylase and 25-hydroxyvitamin D3-1 alpha-hydroxylase. This kidney-specific protein found in the inner membrane of mitochondria is named the vitamin D3 hydroxylase-associated protein (VDHAP). To determine a putative function for this protein, an extensive computer search of the deduced amino acid sequence of VDHAP was performed. A BLAST homology search identified amino acid residues 133 through 321 in acetamidase from Aspergillus nidulans that exhibit 38% amino acid identify and 65% amino acid similarity to VDHAP. A protein consensus sequence dictionary, MOTIFS, identified an amidase consensus sequence in VDHAP. This sequence, G-G-S-S-G-G-E-G-A-L-I-A-G-G-G-S-L-L-G-I-G-S-D-V-A-G-S-I R-L-P-S, in VDHAP is located between amino acids 223 and 254. Propionamide, acetamide, and acrylamide were identified as substrates for an amidase activity in soluble chicken kidney mitochondria. Propionamide is the best substrate with a Vmax of 16.7 nmol NH4+/min/mg protein and an apparent Km of 7.9 mM in soluble chicken kidney mitochondria. A VDHAP monoclonal antibody, IVC2G8, immunoprecipitates 78% of the total propionamidase activity in soluble chicken kidney mitochondria. These results suggest that VDHAP is a propionamidase enzyme in soluble chicken kidney mitochondria and a member of the amidase signature gene family. PMID- 7840609 TI - 10-Formyltetrahydrofolate dehydrogenase: identification of the natural folate ligand, covalent labeling, and partial tryptic digestion. AB - 10-Formyltetrahydrofolate dehydrogenase (EC 1.5.1.6) was previously identified as a folate-binding protein in rat liver cytosol (R.J. Cook and C. Wagner, Biochemistry 21, 4427-4434, 1982) by virtue of the tetrahydrofolate polyglutamate tightly bound to the partially purified enzyme. In this current study we provide evidence to show that when liver cytosol was rapidly processed to identify the protein bound folate, large amounts of both 10-formyl- and 5 formyltetrahydrofolate were present. After overnight storage of the cytosol at 5 degrees C before processing, almost no formylfolates were present and the major protein-bound form was tetrahydrofolate. This suggests that 10 formyltetrahydrofolate polyglutamates are tightly bound to the enzyme in vivo and are converted to tetrahydrofolate forms during isolation by the hydrolase activity associated with the enzyme. Covalent binding of the stable folate analogue, 5-formyltetrahydrofolate, to the purified enzyme resulted in 2 mol bound per mole of enzyme subunit. This is consistent with earlier reports suggesting the enzyme is capable of carrying out both oxidative and hydrolytic conversion of 10-formyltetrahydrofolate to tetrahydrofolate at the same time. Partial tryptic digestion of the purified enzyme selectively inhibited dehydrogenase activity of the enzyme but did not affect the hydrolase or aldehyde dehydrogenase activities. PMID- 7840610 TI - Dietary control and tissue specific expression of branched-chain alpha-ketoacid dehydrogenase kinase. AB - The branched-chain alpha-ketoacid dehydrogenase complex, catalyst for the rate limiting step of branched-chain amino acid catabolism, is controlled by a highly specific protein kinase (branched-chain alpha-ketoacid dehydrogenase kinase) that associates tightly with the complex. The activity state (proportion of the enzyme in its active, dephosphorylated state) of the complex varies dramatically in different rat tissues. The activity state of the complex in the liver is greater than that in any other tissue, and liver contains the lowest amount of kinase protein and kinase mRNA. However, protein malnutrition, a condition under which the complex is largely phosphorylated and inactive, resulted in a three- to fourfold increase in hepatic kinase activity with an accompanying increase in amounts of kinase protein and mRNA. Refeeding a 50% protein diet restored the normal activity state and the original levels of kinase protein and mRNA. The amount of kinase protein associated with the complex rather than changes in specific activity of the kinase appears responsible for observed differences in activity states of the complex in several rat tissues tested. Accordingly, the levels of kinase protein and mRNA measured are highest in tissues with greatest kinase activity (heart > kidney > liver), correlating reasonably well inversely with activity state of the branched-chain alpha-ketoacid dehydrogenase complex in the respective tissues. These observations suggest that the amount of kinase protein expressed in various tissues and in response to dietary protein deficiency is an important factor determining the activity state of the complex. PMID- 7840611 TI - Carbon-13 NMR studies and purification of gluconate pathway enzymes from Schizosaccharomyces pombe. AB - Evidence is presented to show that D-glucose in Schizosaccharomyces pombe can be metabolized via a new alternative route (gluconate pathway) in addition to the regular D-glucose 6-phosphate route. This gluconate pathway consists of two steps: oxidation of D-glucose to D-gluconate by NADP(+)-dependent glucose dehydrogenase and phosphorylation of D-gluconate to 6-phosphogluconate by gluconate kinase. The formation of D-gluconate and 6-phosphogluconate from D glucose was monitored by 13C nuclear magnetic resonance spectroscopy using D-[1 13C]glucose and D-[U-13C]glucose. The operation of the gluconate pathway was further substantiated by the purification of its two member enzymes, glucose dehydrogenase and gluconate kinase, from the cell-free extract of the fission yeast. Glucose dehydrogenase has been purified (580-fold) to homogeneity by the combined procedures of ammonium sulfate fractionation, Sephadex gel filtration, cation-exchange chromatography, matrex gel chromatography, and agarose-NADP+ affinity chromatography. The purified enzyme is monomeric with a relative molecular weight of 6.65 x 10(4) Da. Gluconate kinase has been purified (410 fold) to near homogeneity by a combination of chromatographic procedures using Bio-gels, matrex gel, and agarose gels. The purified enzyme is monomeric with a relative molecular weight of 2.4 x 10(4) Da. The gluconate pathway presented here provides an alternative route for the D-glucose metabolism in Sch. pombe. Meanwhile, this paper documents another metabolic difference between the fission and budding yeasts. PMID- 7840612 TI - Kinetic studies of gluconate pathway enzymes from Schizosaccharomyces pombe. AB - Glucose dehydrogenase and gluconate kinase which catalyze two-step reactions of the gluconate pathway have been purified from Schizosaccharomyces pombe. Their steady-state kinetic studies were undertaken. The yeast glucose dehydrogenase requires NADP+ as an obligatory coenzyme and mediates the oxidation of D-glucose to D-gluconate via an ordered Bi Bi mechanism with NADP+ as the leading substrate. Kinetic constants for the dehydrogenase reactions have been measured. The yeast gluconate kinase requires Mg2+ as an activator. The phosphorylation catalyzed by the fission yeast gluconate kinase has been studied kinetically at a fixed concentration of Mg2+. The initial velocity and product inhibition results are consistent with a rapid equilibrium random Bi Bi mechanism with the formation of an abortive enzyme-ADP-gluconate complex. Dissociation constants of the two substrates, ATP and D-gluconate from various binary and ternary enzymic complexes, have been determined. PMID- 7840613 TI - The interaction of Candida boidinii formate dehydrogenase with a new family of chimeric biomimetic dye-ligands. AB - Seven chimeric biomimetic dye-ligands (BM) are purpose-designed and synthesized by specific structural modification of the parent anthraquinone dichlorotriazine dye Vilmafix blue A-R (VBAR). Each BM dye is composed of two enzyme-recognition moieties. The terminal biomimetic moiety bears a variable carboxylated structure linked to the triazine ring, thus mimicking the substrate of formate dehydrogenase (FDH). The anthraquinone moiety remains the same as that of the parent dye and recognizes the nucleotide-binding area of the target enzyme. Dyes are purified by liquid column chromatography (typically 99%), analyzed by liquid paper chromatography, thin-layer chromatography, and high-performance liquid chromatography, and their lambda max and epsilon values are determined. The ability of dyes to act as affinity ligands versus Candida boidinii FDH is evaluated by kinetic studies and determining KD values from both difference spectra and enzyme inactivation studies. The parent dichlorotriazine dye VBAR binds specifically and irreversibly to FDH (k3 0.19 min-1; KD 19.3 microM). The inactivation of the NAD(+)-dependent enzyme by VBAR is competitively inhibited by NAD+, NADH, and ADP. Quantitatively inhibited FDH contained approx 1 mol of dye per mole of active site. The inhibition is irreversible and activity cannot be recovered either on incubation with 10 mM each of NAD+, NADH, and ADP or by extensive dialysis or gel filtration chromatography. The monochlorotriazine BM dyes do not inactivate FDH but inhibit competitively the inactivation by VBAR. When compared to VBAR and Cibacron blue 3GA (CB3GA), all BM dye-ligands exhibited lower KD values. FDH generally preferred binding to BM ligands which bore an aromatic terminal biomimetic moiety substituted with a monocarboxyl group rather than an alpha-ketoacid. Dye binding to FDH is accompanied by a characteristic spectral change in the range 550-800 nm. This phenomenon is perturbed after titration by increasing amounts of NAD+. Electrostatic interactions appeared to play a dominant role in the dye.FDH complex. The BM dye-ligand bearing a m aminobenzoate at its terminal biomimetic moiety (BM1) exhibited the highest affinity (KD 1.6 microM, 8.0-fold decrease over CB3GA). BM1 differentiated between the binding sites of FDH, displaying uncompetitive inhibition with respect to NAD+ (Ki 15.6 microM) and competitive with respect to formate (Ki 18.1 microM). PMID- 7840614 TI - Stimulation of receptor-associated kinase, tyrosine kinase, and MAP kinase is required for prolactin-mediated macromolecular biosynthesis and mitogenesis in Nb2 lymphoma. AB - Lactogens [prolactin (Prl) and growth hormone] stimulate phosphorylation of the 40S ribosomal protein, S6, in Nb2 cells by mechanisms that do not involve participation of cAMP or protein kinase A, protein kinase C, or cGMP-dependent protein kinase. However, inhibition of tyrosine kinase (TK) abrogates Prl mediated macromolecular biosynthesis. Inasmuch as lactogen signaling may involve sequential activation of protein kinases, the effect of Prl on the well characterized mitogen-activated protein kinase (MAPK) and S6 kinase (S6K), the enzyme responsible for S6 phosphorylation in vivo, and their relationship to Nb2 macromolecular biosynthesis and mitogenesis were investigated. The results show that MAPK stimulation is transient (peak activity, 30 min) and precedes that of S6K, which reaches a maximum at 1.5-2 h, and slowly returns towards control levels at 6 h. Both staurosporine which inhibits GH receptor-associated kinase (JAK2) and genistein (GEN), an inhibitor of membrane-associated and cytoplasmic TKs, abrogate Prl-stimulated TK, MAPK, and S6K. Rapamycin (RAP), a specific inhibitor of p70S6K, completely blocks S6K but does not affect TK and MAPK. TK and MAPK activity correlates with Prl-stimulated anabolism, i.e., protein and DNA synthesis and mitogenesis. Thus, concentrations of STR and GEN which abrogate TK and MAPK inhibit anabolism virtually 100%. However, RAP, which inhibits S6K (ca. 100%) but not TK or MAPK, only delays Prl-mediated anabolism. These results indicate that Prl signaling in Nb2 cells involves a protein kinase cascade and that regulation of receptor-associated kinase, TK, and MAPK correlates with anabolism. The role of S6K (and S6 phosphorylation) appears to be ancillary. PMID- 7840615 TI - 15-substituted lanosterols: post-transcriptional suppressors of 3-hydroxy-3 methylglutaryl coenzyme A reductase. AB - The oxolanosterol oxime 3 beta-hydroxylanost-7-en-15-one 15-oxime and the structurally similar 3 beta-hydroxylanost-7-en-15-one are dual-action inhibitors of cholesterol synthesis which cause both inhibition of lanosterol 14 alpha methyl demethylase and suppression of the rate-limiting enzyme 3-hydroxy-3 methylglutaryl coenzyme A reductase (HMGR). This report examines the mechanism by which these compounds lower HMGR protein levels in Chinese hamster ovary fibroblasts. Data are presented which suggest that both sterols reduce the translational efficiency of the HMGR mRNA as well as increase the rate of enzyme degradation. The effect of these sterols on the concentration of the low-density lipoprotein receptor (LDLR) in normal human fibroblasts was also determined. In these cells, both lanosterol analogs lowered HMGR protein levels without affecting LDLR concentration. This in contrast to the previously reported coordinate transcriptional regulation of these two genes by the C27-sterol 25 hydroxy-cholesterol. These findings are consistent with the hypothesis that different sterols regulate HMGR activity through distinct mechanisms. PMID- 7840616 TI - The hepatocellular metabolism of 4-hydroxynonenal by alcohol dehydrogenase, aldehyde dehydrogenase, and glutathione S-transferase. AB - It has previously been reported that isolated rat hepatocytes rapidly and completely metabolize high concentrations of 4-hydroxy-2,3-(E)-nonenal (4-HNE). However, until this report, the degree to which oxidative-reductive and nonoxidative metabolic pathways function in the depletion of 4-HNE by isolated rat hepatocytes has been speculative. The objective of the present study was to quantitate the extent to which cellular aldehyde dehydrogenases (ALDH; EC 1.2.1.3.), alcohol dehydrogenase (ADH; EC 1.1.1.1.), and glutathione S transferases (GST; EC 2.5.1.18) function simultaneously during hepatocellular metabolism of 4-HNE. Hepatocytes were incubated with varying concentrations of 4 HNE (50, 100, 250 microM) and reversed-phase HPLC was used to quantitate 4-HNE and the oxidative and reductive metabolites, 4-hydroxy-2-nonenoic acid and 1,4 dihydroxy-2-nonene, respectively. Conjugative metabolism of 4-HNE was determined from the depletion of cellular reduced glutathione (GSH) and concomitant formation of a GSH-4-HNE adduct detected as 2,4-dinitrofluorobenzene derivatives measured by reversed-phase HPLC. Hepatocellular elimination of 4-HNE was estimated at rates of 1.666, 0.902, and 0.219 nmol min-1 10(6) hepatocytes-1 for 50, 100, and 250 microM aldehyde, respectively. At aldehyde concentrations of 50, 100, and 250 microM the maximal concentrations of oxidative (acid) metabolites formed were 5.9, 12.7, and 28.9 nmoles 10(6) hepatocytes-1, whereas the concentrations of the reductive (diol) metabolite were 0.4, 12.6, and 42.3 nmoles 10(6) hepatocytes-1, respectively. The presence of 4-methylpyrazole or cyanamide abolished formation of the reductive metabolite 1,4-dihydroxy-2-nonene or the oxidative metabolite 4-hydroxy-2-nonenoic acid in hepatocyte suspensions. At all 4-HNE concentrations evaluated, hepatocellular glutathione was not completely depleted by the aldehyde and the depletion of cellular reduced GSH corresponded to the production of the GSH-4-HNE conjugate. Metabolism by the alcohol/aldehyde dehydrogenase pathways accounted for approximately 10% of the 4-HNE elimination, while bioconversion by GST represent 50-60% of the total 4-HNE removal by hepatocytes. The enzymatic pathways responsible for the remaining 40% of 4-HNE metabolism remain to be identified. Taken together these results describe the quantitative and dynamic importance of oxidative, reductive, and nonoxidative routes in the metabolism and detoxification of 4-HNE. PMID- 7840617 TI - The rectangular hyperbolic binding equation for multivalent ligands. AB - An improved procedure for the characterization of interactions involving multivalent ligands which eliminates a previous requirement that interaction parameters for independent and equivalent binding be evaluated from a general counterpart of the Scatchard analysis is described. Binding data for the interaction of aldolase with muscle myofibrils are then used to illustrate application of the procedure, which allows the stoichiometry and intrinsic binding constant to be evaluated by standard nonlinear regression analysis in terms of a rectangular hyperbolic relationship. PMID- 7840618 TI - Functional organization of mammalian hexokinases: characterization of chimeric hexokinases constructed from the N- and C-terminal domains of the rat type I and type II isozymes. AB - Chimeric hexokinases consisting of either the N-terminal half of Type I hexokinase fused with the C-terminal half of the Type II isozyme (NICII) or the inverse pair (NIICI), along with the parental isozymes, were expressed in COS-1 cells. The thermal stability of the chimeras was intermediate between that of the highly labile Type II isozyme and the relatively stable Type I hexokinase. In their Kms for substrates, Glc and ATP, the chimeric enzymes were similar to the parental isozyme from which the C-terminal half was derived. Although the Type I and Type II isozymes were similar in their sensitivity to inhibition (competitive vs ATP) by the Glc-6-P analogs, 1,5-anhydroglucitol 6-phosphate (AnGlc-6-P), and Glc-1,6-bisphosphate, the chimeric enzymes differed markedly, with the NIICI chimera being much more sensitive and the NICII chimera much less sensitive than either parental form to these inhibitors. In contrast, the response of the chimeras to Pi, either as an antagonist of inhibition by AnGlc-6-P or, at higher concentrations, as an inhibitor, was correlated with the origin of the N-terminal domain. The results are consistent with the view that catalytic function is associated with the C-terminal domain of the Type I isozyme, with regulatory function--inhibition by Glc-6-P and its analogs and antagonism of this inhibition by Pi--being mediated by the N-terminal domain. PMID- 7840619 TI - Effect of pyridoxal 5'-phosphate on the function of the purified mitochondrial tricarboxylate transport protein. AB - The effect of pyridoxal 5'-phosphate (PLP), a lysine-selective reagent, on the function of the purified and reconstituted mitochondrial tricarboxylate transport protein has been studied. PLP caused a concentration-dependent inhibition of citrate transport with an IC50 value of 0.09 mM. At 10 mM PLP virtually complete inhibition of transport was observed (i.e. 97%), thereby indicating that modification of a residue(s) whose participation is essential to the translocation mechanism had occurred. Substrate protection studies demonstrated that substrates for the tricarboxylate transporter (i.e., citrate, isocitrate, phosphoenolpyruvate, and malate) effectively protected against PLP inhibition, whereas other organic anions which are not transported by the tricarboxylate carrier (i.e., malonate, alpha-ketoglutarate, phosphate, and succinate) afforded considerably less protection. Kinetic studies in which the transport rate was measured at varying citrate and PLP concentrations indicated that PLP caused an increase in the apparent Km of transport with little change in the Vmax, thereby resulting in a primarily competitive inhibition pattern. In combination, the above findings indicate that PLP interacts with the tricarboxylate transporter at a site(s) (i.e., a lysine residue(s) and/or the amino-terminal alanine residue) that is important in the translocation mechanism and may reside within or near the substrate binding site. PMID- 7840620 TI - The oxidation of ebselen metabolites to thiol oxidants catalyzed by liver microsomes and perfused rat liver. AB - The oxidation of 2-(methylseleno)benzanilide and 2-selenylbenzanilide, metabolites of the antioxidant drug ebselen, was examined in reactions catalyzed by rat, pig, and guinea pig liver microsomes and in perfused rat liver. Microsomes from all three species catalyzed NADPH- and oxygen-dependent oxidation of the selenide and the selenol to thiol-reactive metabolites. The oxidation product of the selenide was similar in properties to the chemically synthesized selenoxide [2-(methylseleninyl)benzanilide]. The selenoxide oxidized GSH and thiocholine at rate constants of 1.2 x 10(2) and 7.2 x 10(2) M-1 s-1, respectively at pH 7.4, 37 degrees C. n-Octylamine stimulated the oxidation of the ring-opened metabolites of ebselen catalyzed by pig and guinea pig liver microsomes but it had essentially no effect on these activities in rat liver microsomes. The selenoxidase activity of microsomes from all three species was partially (30-50%) sensitive to N-benzylimidazole. The effects of n-octylamine and the imidazole suggest that the oxidation of the selenide was catalyzed primarily by enzymes with the properties of flavin-containing and P450-dependent monooxygenases, but the nature of enzymes responsible for a small fraction of the N-benzylimidazole-sensitive activity was not fully resolved. The 2 (methylseleno)benzanilide oxidase activity of pig liver microsomes sensitive to N benzylimidazole was only partially sensitive to antisera to pig liver NADPH cytochrome P450 reductase. While neither 2-(methylseleno)benzanilide nor ebselen affected bile flow, the biliary efflux of GSSG was stimulated about fourfold in rat liver perfused with either of these selenium compounds. The increased GSSG efflux produced by 5 microM ebselen or its methyl metabolite was abolished by N benzylimidazole. PMID- 7840621 TI - Role of heparan sulfate in the terminal differentiation of growth plate chondrocytes. AB - Recent studies have demonstrated that basic fibroblast growth factor (bFGF) plays a key role in the terminal differentiation of growth plate chondrocytes during endochondral ossification. In this paper we examined the potential role of heparan sulfate in the regulation of the action of basic fibroblast growth factor (bFGF) in the terminal differentiation of rat growth plate chondrocytes. As rat growth plate chondrocytes differentiate in vitro, the percentage of heparitinase sensitive material decreases. Treatment of growth plate chondrocytes with sodium chlorate, a reversible inhibitor of glycosaminoglycan sulfation, resulted in terminal differentiation of growth plate chondrocytes even in the presence of bFGF at concentrations that normally repress their differentiation. Chlorate treatment in the presence of bFGF resulted in an increase in alkaline phosphatase activity and a decrease in cellular proliferation, both characteristics of the differentiated state. Chlorate treatment also reduced the binding of bFGF to growth plate chondrocytes and this effect could be reversed in a dose-dependent manner by the simultaneous addition of sodium sulfate. The reduced binding was a function of a reduced number of receptors and not a reduced affinity for the receptor. Pretreatment of the growth plate chondrocytes with heparitinase significantly reduced the binding of bFGF to both low- and high-affinity receptors, while pretreatment with chondroitinase ABC had no effect. Finally, addition of exogenous heparin restored bFGF binding to chlorate-treated chondrocytes in a concentration-dependent manner. These results provide evidence that a cell surface heparan sulfate is involved in the binding of bFGF to high affinity receptors and that a downregulation of this glycosaminoglycan is part of the pathway that leads to terminal differentiation of growth plate chondrocytes. PMID- 7840622 TI - Influence of carbohydrate on structure, stability, and function of gelatin binding fragments of fibronectin. AB - The gelatin-binding region of fibronectin contains three Asn-linked carbohydrate moieties, one on the second type II module and two on the eighth type I "finger" module. Carbohydrate groups were enzymatically removed from two nonoverlapping gelatin-binding fragments (GBFs), 21-kDa GBF (modular composition I8-I9) and, with much greater difficulty, 30-kDa GBF (modular composition I6-II1-II2-I7). The gelatin-binding properties of these fragments were affected only slightly or not at all. Fluorescence and calorimetric analyses indicated that module I8 was strongly destabilized by deglycosylation such that the apo form melts near physiological temperature. A similar effect was caused by decreasing the pH of the holo form to 6.0, suggesting that one or more histidines are important for stability of module I8. The 21-kDa fragment exhibited an acid-induced change in fluorescence that occurred at higher pH in the deglycosylated derivative, providing further evidence of a stabilizing role for one or both carbohydrate moieties. By contrast, the stability of module II2 was unaffected by removal of its single carbohydrate. The effects of carbohydrate on the stability of module I8 may be important in efforts to express it or fragments containing it in bacteria. PMID- 7840623 TI - Delta-aminolevulinate increases heme saturation and yield of human cystathionine beta-synthase expressed in Escherichia coli. AB - We recently expressed human cystathionine beta-synthase (CBS) in Escherichia coli and purified it to homogeneity. We showed that CBS requires heme in addition to pyridoxal 5'-phosphate for its function. Previously, CBS, only about 20% saturated with heme, was purified from transformed bacteria. In the present study, we supplemented the bacteria with 0.3 mM delta-aminolevulinate (delta ALA), a precursor of heme. While growth of the bacteria did not change, a 50-fold elevation of the heme content per milligram of total protein was observed in the cell extracts of delta ALA-supplemented cells. The increase in heme biosynthesis depended on the overexpression of a heme acceptor--CBS. Our data suggest that bacterial heme synthesis is regulated beyond delta ALA synthase. The delta ALA treatment resulted in 8 times more total CBS activity with a 3.5-fold higher yield of the purified recombinant enzyme, more than 68% saturated with heme. Increased yield, higher specific activity, and improved heme saturation of CBS will facilitate large-scale preparation of the enzyme. This method should be applicable to the overexpression of other recombinant heme proteins in bacteria. PMID- 7840624 TI - Purification and characterization of the flavoprotein tryptophan 2-monooxygenase expressed at high levels in Escherichia coli. AB - Tryptophan 2-monooxygenase from Pseudomonas savastanoi is a flavoprotein which catalyzes the formation of indoleacetamide from tryptophan. This is the first step in a two-step pathway for the formation of indoleacetic acid during infection of plants and subsequent gall formation by this and other bacteria. The enzyme has been expressed in Escherichia coli at high levels, and a purification procedure has been developed which generates micromolar amounts of protein. The purified enzyme contains tightly bound indoleacetamide; a method involving dialysis against 20% methanol has been developed for removing the indoleacetamide without significant loss of enzyme activity. Amino acids with large hydrophobic side chains are the best substrates; N-substituted phenylalanines will also act as substrates. N-ethylmaleimide, methyl methanethiol-sulfonate, and diethylpyrocarbonate act as active site-directed reagents, consistent with a histidine and a cysteine at or near the enzyme active site. Vinylglycine partially inactivates the enzyme, while propargylglycine has no effect. PMID- 7840625 TI - Primary structure and post-translational modification of ferredoxin-NADP reductase from Chlamydomonas reinhardtii. AB - The flavoprotein ferredoxin-NADP reductase (FNR) was isolated from the unicellular green alga, Chlamydomonas reinhardtii. FNR is a monomeric protein containing one FAD and exhibiting ferredoxin-dependent cytochrome c reduction activity. Its complete primary structure was investigated by sequencing overlapping peptides generated by cleavage with trypsin and SV8 protease and confirmed by partial (80%) nucleotidic sequence. C. reinhardtii FNR contains 320 residues, corresponding to a calculated mass of 35,685 and 36,470 including FAD, in agreement with the values measured by laser desorption mass spectrometry. The combination of both amino acid and nucleotidic sequencing, in association with mass spectrometry of peptides, allowed the identification of two N epsilon trimethyllysines at positions 83 and 89 and one N epsilon-dimethyllysine at position 135. Comparison of the primary structure of C. reinhardtii FNR with the known sequences shows 41-46% identity. PMID- 7840626 TI - Evidence for substrate stabilization in regulation of the degradation of Bacillus subtilis aspartate transcarbamylase in vivo. AB - Aspartate transcarbamylase (ATCase) is rapidly degraded in Bacillus subtilis cells that are starved for a carbon or nitrogen source or a required amino acid. The hypothesis that ATCase degradation may be regulated in vivo by protection of the enzyme by substrate binding was tested by studies of a mutant ATCase (Arg99 to Ala, R99A), which binds substrate so poorly that it fails to support pyrimidine-independent growth in a pyrB strain, but still has 10% of normal activity when saturated with substrates. Unlike normal ATCase, R99A ATCase was degraded rapidly in exponentially growing cells. Degradation of the mutant enzyme was two-fold slower in a relA strain, as was degradation of the normal ATCase. The stability of purified R99A ATCase to denaturation by heat or guanidine hydrochloride was identical to that of wild-type ATCase, as was its circular dichroic spectrum. The wild-type and R99A ATCase were degraded identically in vitro by subtilisin, except that the mutant enzyme was much less effectively protected against cleavage by carbamyl phosphate, as expected. The carbamyl phosphate pool in glucose-limited B. subtilis cells was only one-third of the pool in exponentially growing cells. These results indicate that protection of ATCase by carbamyl phosphate binding could be one of the elements that regulate ATCase stability in vivo. However, carbamyl phosphate pools were the same in cells grown with ammonium ions and with a mixture of 20 common amino acids, conditions under which ATCase stability in vivo differs. Thus, other means of regulating ATCase degradation must also exist. PMID- 7840627 TI - Flavin-binding and protein structural integrity studies on NADPH-cytochrome P450 reductase are consistent with the presence of distinct domains. AB - NADPH-cytochrome P450 reductase (reductase) contains FMN and FAD in 1:1 stoichiometry as tightly bound cofactors. Electrons from NADPH are transferred to cytochrome P450 through the intermediacy of reductase. A knowledge of the interactions which must occur to allow the intermolecular and intramolecular transfer of electrons is not only of intrinsic interest but is necessary to understand the regulation of the overall oxidation-reduction processes in which cytochromes P450 participate in the endoplasmic reticulum of many organs. In the present study, urea has been employed as a chaotropic agent to study the dissociation of flavins from NADPH-cytochrome P450 reductase. The results show that dissociation of FMN occurs at concentrations of urea between 0 and 1 M and that, as the concentrations of urea approach 1 M, the intrinsic protein fluorescence increases, indicating a change in protein conformation. Above 2 M urea protein fluorescence increases, reaching a plateau at 3 M urea, and FAD begins to dissociate from the enzyme. In the range of 0-1 M urea, a completely reversible dissociation of FMN occurs and, at 3 M urea, the fluorescence values representing flavin dissociation and protein conformation changes have reached a maximum. Thus, the definition of various states of the flavoprotein with both, one, or no flavins bound and the ability to remove the flavins reversibly under specific conditions have permitted the construction of a simple model to explain the various unfolding intermediates of this enzyme. Our experiments suggest that reductase is composed of distinct domains which can be examined independently by the application of chaotropic agents. PMID- 7840628 TI - The isolation and comparison of multiple forms of CYP2B from untreated and phenobarbital-treated rabbit liver microsomes. AB - At low levels of phenobarbital induction two forms of isoenzyme 2 (LM2; CYP2B4) were obtained during purification of cytochrome P450 from rabbit liver microsomes. At high levels of induction only one form (LM2A) was present. Although the two purified forms (LM2A and LM2B) were very similar they differed in: (a) peak elution on CM-Sepharose, (b) wavelength maximum of the reduced P450 CO spectrum, and (c) metabolism of several substrates, where the activities of LM2B ranged from 0.6 to 2.65 times that of LM2A. A third LM2 fraction (2C) was isolated from untreated rabbit liver and, although homogenous on sodium dodecyl sulfate-polyacrylamide gel electrophoresis, appeared to be a mixture of LM2B and a form of P450 LM2 other than LM2A. LM2A was not found in the untreated rabbit liver microsomes. On CM-Sepharose the elution of fraction 2C overlapped that of LM2B. The apparent molecular weight and immunoresponse to anti-LM2A IgG were the same for fraction 2C as for LM2A and LM2B. Peptide mapping using trypsin showed no difference between LM2A and LM2B, but consistently revealed at least one extra band with fraction 2C. After CNBr cleavage and high-pressure liquid chromatography separation of the LM2A and LM2B fragments the peptide beginning with Pro(347) of LM2A (peak 4A) eluted 1/2 min later than that of LM2B (peak 4B) indicating a difference in the fragments, although partial NH2-terminal amino acid sequences and molecular masses were the same. The corresponding CNBr fragment of fraction 2C splits into two peaks (4C:1 and 4C:2) with retention times corresponding to 4B and 4A, respectively. The mass of 4C:1 was the same as that of 4B, while the mass of 4C:2 markedly differed from that of 4A and 4B. Both fragments had the same partial NH2-terminal amino acid sequence as 4A and 4B. After comparing the physiochemical properties as well as catalytic activities of these isolated and purified LM2 forms with the cDNA-expressed forms 2B-B0, 2B-B1, 2B-B2, and 2B-Bx [see R. Ryan et al. (1993) Arch. Biochem. Biophys. 304, 454 463], the data suggest that LM2A is the form designated as 2B-B0 (LM2), LM2B is 2B-Bx, and fraction 2C is a mixture containing 2B-B1 and 2B-Bx. This is the first isolation and identification of the three isozymic LM2 proteins from rabbit liver. PMID- 7840629 TI - Targets of nitric oxide in a mouse model of liver inflammation by Corynebacterium parvum. AB - Treatment of mice with Corynebacterium parvum induces chronic inflammation. This treatment followed by an injection of lipopolysaccharide (LPS) produces hepatic necrosis and death. We examined liver tissue by using electron paramagnetic resonance (EPR) spectroscopy and found that, in addition to the previously reported nonheme nitrosyl complexes, heme nitrosyl complexes were also formed. Hemoglobin nitrosyl complexes measured in the whole blood of mice treated with C. parvum were not increased after additional LPS treatment. However, this treatment significantly increased the heme nitrosyl complexes in the liver, whereas the nonheme nitrosyl complex concentration was unaffected. EPR signals from whole blood and liver tissues from mice treated with C. parvum and C. parvum + LPS were inhibited by prolonged treatment with NG-monomethyl-L-arginine (L-NMA). Nitric oxide (.NO) is known to bind to cytochrome P450 heme, and we consistently found a suppression of EPR signals attributable to ferric low-spin cytochrome P450/P420 peaks in the livers of mice treated with C. parvum and C. parvum + LPS. By performing analyses of EPR spectra obtained from hepatocytes exposed to .NO, we were able to unambiguously identify EPR signals attributable to cytochrome P420 and nonheme nitrosyl complexes in the livers of both treatments. Deconvolution of the composite in vivo EPR spectra indicated that hemoglobin nitrosyl complexes contributed weakly in the C. parvum livers, but threefold more in the C. parvum + LPS livers, suggesting that hemorrhage may have occurred. Experiments with L-NMA treatment revealed that this additional .NO production did not correlate with hepatic necrosis and onset of death. Immunoprecipitation of liver cytosols from C. parvum- and (C. parvum + LPS)-treated mice using an antibody against mouse inducible nitric oxide synthase showed that this enzyme was indeed present in the cytosolic fractions and was absent in those from control livers. Our novel detection of cytochrome P420 nitrosyl complex in vivo may be linked to any role of hepatic P450's functions during liver inflammation. PMID- 7840630 TI - The mouse plasma membrane Ca2+ pump isoform 1 promoter: cloning and characterization. AB - The expression of plasma membrane Ca2+ pump (PMCA) is regulated by various hormones or agonists via multiple second messenger pathways. Two different 5' segments of the PMCA1 gene (isoform 1) were cloned from a mouse genomic library. While one segment contained the 3' end of intron 1 and exon 2, the other segment was found to encompass the 5'-flanking region of the gene, exon 1, and the 5' portion of intron 1. Sequence analysis of the 5'-flanking region suggested the presence of the putative promoter. Four sites for initiation of transcription (spanning 64 bp) were identified by RNase protection assay and primer extension analysis. The promoter region was very GC-rich, contained no "TATA box," but had a "CAAT box" at -51. Comparison of sequence with known cis-regulatory motifs disclosed that the 5'-flanking region has a number of potential regulatory elements including an AP-1 site at -354, AP-2 binding sites at -267 and -123, Sp1 binding sites at -127, -111, and +3, and a cyclic AMP response element binding protein site at -67. To demonstrate promoter activity, a segment containing 611 bp of the promoter region (from -442 to +169) was subcloned in front of a promoterless chloramphenicol acetyltransferase (CAT) gene. This segment was able to drive the expression of chloramphenicol acetyltransferase in transient transfections of mouse (or human) neuroblastoma cells as well as rat aortic endothelial cells. Deletion analysis demonstrated that a fragment from -256 to +169 showed strong promoter activity, while a fragment from -117 to +169 had CAT activity that was not different from the vector control. The promoter was stimulated threefold by phorbol ester and twofold by cyclic AMP. These results provide further proof indicating up-regulation of the PMCA1 gene by multiple second messenger pathways. PMID- 7840631 TI - Allosteric regulation of biosynthetic threonine deaminase from Escherichia coli: effects of isoleucine and valine on active-site ligand binding and catalysis. AB - The sigmoidal steady-state kinetics of biosynthetic threonine deaminase from Escherichia coli is allosterically controlled by isoleucine and valine, the end products of branched-chain amino acid biosynthesis. A basis for the regulation of threonine deaminase by heterotropic effectors has been studied by capitalizing on the intrinsic fluorescence of the essential pyridoxal phosphate cofactor in this enzyme in kinetic and equilibrium binding studies with the substrate analog D threonine. D-Threonine binds cooperatively to four sites on the free enzyme, with an average dissociation constant of 19.8 mM. However, in the presence of saturating valine, or isoleucine, the D-threonine binding isotherms are noncooperative and characterized by dissociation constants of 3.9 and 24.8 mM, respectively. The rate of association of D-threonine with threonine deaminase in the presence of the regulatory ligands was biphasic. Analysis of the data in terms of a two-step scheme whereby the internal aldimine Schiff base in the initial encounter complex undergoes transimination with D-threonine to form an external aldimine yielded estimates for overall binding constants that were in good agreement with those determined from equilibrium binding isotherms. These analyses indicate that the positive allosteric effector valine acts solely to alter the binding of D-threonine to the active sites of threonine deaminase by shifting the equilibrium between a low-affinity and high-affinity state, consistent with predictions from a simple two-state model. However, isoleucine has a compound effect on the enzyme. The negative allosteric ligand promotes decreases in the rate and equilibrium constants for encounter complex formation, consistent with its preferential binding to the low-affinity state of the enzyme. In addition, however, isoleucine promotes a decrease in the transimination rate and equilibrium constants. Since transimination is generally considered to be protein-catalyzed in pyridoxal phosphate requiring enzymes, it is proposed that isoleucine affects both binding and catalysis in threonine deaminase, which provides a possible explanation for the inadequacy of a simple two-state model to describe the allosteric regulation of this enzyme. PMID- 7840632 TI - Requirement of a diperoxovanadate-derived intermediate for the interdependent oxidation of vanadyl and NADH. AB - Oxygen release accompanying oxidation of vanadyl by diperoxovanadate was suppressed on addition of NADH. The added NADH was rapidly oxidized, oxygen in the medium was consumed, and the reaction terminated on exhaustion of either NADH or vanadyl. The consumption of oxygen and disappearance of NADH needed small concentrations of diperoxovanadate to initiate and increased with increase in the concentration of vanadyl and NADH or decrease of pH. The products of the reaction were found to be NAD+ from NADH and vanadate oligomers from vanadyl and oxygen. The reaction was insensitive to catalase and was not dependent on H2O2. The reaction was inhibited by superoxide dismutase, cytochrome c, EDTA, Mn2+, histidine, and DMPO, but not by hydroxyl radical scavengers such as ethanol and benzoate. The ESR spectrum of the reaction mixture showed the presence of the 1:2:2:1 quartet signal typical of a DMPO-OH adduct, but this was not modified by ethanol. This oxygen radical species, possibly of .OV type derived from diperoxovanadate, is proposed to have a role in the reactions of oxygen release and NADH oxidation. PMID- 7840633 TI - The comparative toxicity of nitric oxide and peroxynitrite to Escherichia coli. AB - The reactivity and toxicity of nitric oxide is modest in comparison to oxidants derived from nitric oxide. Exposure of Escherichia coli to 1 mM nitric oxide under aerobic or anaerobic conditions did not decrease viability of the bacteria. Peroxynitrite (1 mM), the reaction product of superoxide and nitric oxide, was completely bactericidal after 5 s. The nitrovasodilator, 3-morpholinosydnonimine N-ethylcarbamide (SIN-1), slowly decomposes to release both nitric oxide and superoxide and thereby produces peroxynitrite. SIN-1 killed E. coli in direct proportion to its concentration with an LD50 of 0.5 mM. Copper, zinc superoxide dismutase (50-400 units/ml) provided substantial but not complete protection against SIN-1 killing. Catalase (500-10,000 units/ml) partially protected in direct proportion to its concentration, while inactivated catalase was not protective. Superoxide dismutase and catalase together completely protected E. coli against SIN-1 toxicity. Oxy-hemoglobin eliminated both SIN-1 and peroxynitrite toxicity. The bactericidal activity of SIN-1 was further enhanced by pterin plus xanthine oxidase. Pterin plus xanthine oxidase alone or together with Fe3+ ethylenediamine tetraacetate produced no significant decrease in E. coli viability. Hydrogen peroxide was not directly toxic to the bacteria, but E. coli pretreated with hydrogen peroxide were more susceptible to peroxynitrite, SIN-1, and the aerobic oxidation products of nitric oxide. Hydrogen peroxide pretreatment did not increase significantly the toxicity of nitric oxide under anaerobic conditions. Our results suggest that peroxynitrite is far more toxic to E. coli than nitric oxide or its by products from aerobic oxidation. PMID- 7840634 TI - Differential responses of protein kinase C substrates (MARCKS, neuromodulin, and neurogranin) phosphorylation to calmodulin and S100. AB - Phosphorylation of three physiological substrates of protein kinase C (PKC), MARCKS, neuromodulin (Nm), and neurogranin (Ng), was analyzed to determine their relative efficacy as substrates of PKC alpha, beta, and gamma and sensitivities to inhibition by calmodulin (CaM) and S100. Comparison of the Vmax/Km of the phosphorylation of each individual substrate indicated the order of efficacy as PKC substrate was MARCKS > Nm > Ng. Phosphorylation of these proteins in a mixture by PKC beta and gamma was indistinguishable from that when each individual substrate was phosphorylated by these two isozymes. In contrast, the rates of PKC alpha-catalyzed phosphorylation of Nm and Ng in a mixture also containing MARCKS were significantly reduced as compared to that when Nm or Ng was individually phosphorylated by this isozyme. When these substrates were present in a mixture, both CaM and S100 inhibited the PKC-catalyzed phosphorylation of MARCKS to a higher degree than that of Nm or Ng. Protease activated catalytic fragment of PKC (PKM) was used to determine the effects of Ca2+ and phospholipid on the CaM and S100-mediated inhibition of PKC substrate phosphorylation. CaM and S100 inhibited the PKM-catalyzed phosphorylation of MARCKS only in the presence of Ca2+ and addition of phosphatidylserine (PS)/dioleoylglycerol (DG) did not influence the inhibitory effect. Phosphorylation of Nm or Ng by PKM was inhibited by CaM to a higher degree in the absence than in the presence of Ca2+. S100 was ineffective in inhibiting the phosphorylation of Nm and Ng without Ca2+ and only poorly effective in the presence of Ca2+. The CaM-mediated inhibition of Nm or Ng phosphorylation by PKM was also not affected by PS/DG either with or without Ca2+. The results presented here demonstrate that MARCKS is a preferred substrate of PKC and its phosphorylation by PKC is most sensitive to inhibition by regulatory proteins such as CaM and S100. PMID- 7840635 TI - Expression of liver fatty acid binding protein in L-cells: plasma membrane response to ethanol. AB - Expression of liver fatty acid binding protein (L-FABP) in transfected L-cell fibroblasts modifies plasma membrane structure and function [Incerpi et al., 1992, Arch. Biochem. Biophys. 298, 35-42]. The effect of L-FABP expression on ethanol induced fluidization of plasma membranes was examined. Ethanol in vitro selectively fluidized the exofacial leaflet of the plasma membranes from L-cells expressing low amounts of L-FABP. In contrast, the plasma membranes from L-cells expressing high amounts of L-FABP were resistant to the actions of ethanol. Furthermore, diphenylhexatriene lifetime distributional analysis demonstrated that the plasma membrane exofacial leaflet had a lower range of apparent dielectric constants than the cytofacial leaflet for both low- and high expression cells. Both the center of lifetime and the lifetime distributional width of diphenylhexatriene in the bulk plasma membrane versus the cytofacial leaflet were consistent with significantly lower apparent dielectric constant in the exofacial leaflet of high-expression versus low-expression cells. Ethanol in vitro preferentially increased the exofacial leaflet apparent dielectric properties of the plasma membranes from low-expression but not high-expression cells. In conclusion, ethanol appears to dehydrate the lipid headgroups of plasma membranes from high-expression cells, thereby conferring resistance to ethanol fluidization. In contrast, ethanol may not dehydrate the plasma membrane lipid head groups of low-expression cells, resulting in ethanol fluidizing the outer leaflet of the plasma membrane. PMID- 7840636 TI - Stereochemistry of benzylamine oxidation by copper amine oxidases. AB - Copper amine oxidases (EC 1.4.3.6) exhibit stereochemical heterogeneity in their reaction specificities. Enzymes isolated from different sources have previously been shown to catalyze the deamination of tyramine and dopamine with abstraction of the pro-R hydrogen at C-1, the pro-S hydrogen, and net nonstereo-specific protein abstraction. In this study we report on the stereochemical course of proton removal from benzylamine for six copper amine oxidases using stereo specifically deuterated benzylamines prepared by a combined chemical-enzymatic method. The product benzaldehydes from the amine oxidase reactions were reduced in situ with alcohol dehydrogenase and NADH providing benzyl alcohols which were analyzed by 1H NMR spectroscopy. The amine oxidases isolated from pea seedlings and bovine, horse, porcine, rabbit, and sheep plasma all react with abstraction of the pro-S hydrogen of benzylamine, irrespective of the stereochemical course of the oxidation of tyramine or dopamine. We also report that the enzymes isolated from horse and rabbit plasma contain 2,4,5-trihydroxyphenylalanine (topaquinone) as an organic cofactor based on visible absorbance spectroscopy of p-nitrophenylhydrazine-derivatized enzymes. PMID- 7840637 TI - Maintenance of phenobarbital-inducible Cyp2b gene expression in C57BL/6 mouse hepatocytes in primary culture as spheroids. AB - Expression of the Cyp2b-9 and Cyp2b-10 genes was investigated in primary cultured adult C57BL/6NCrj mouse hepatocytes in monolayers or during the formation of spheroids (multicellular aggregates). Both the constitutive and phenobarbital inducible expression of Cyp2b-9 and Cyp2b-10 mRNA decreased rapidly after transferring the hepatocytes to monolayer culture. The decrease was dependent on cell-density, and became more rapid in more densely seeded cells. However, in spheroid culture, the Cyp2b-9 and Cyp2b-10 mRNAs were induced by phenobarbital at high levels for at least 4 days either with continuous exposure from the start of cultivation or for 24 h before harvesting. The expression of both Cyp2b-9 and Cyp2b-10 species was confirmed by either reverse transcriptase-polymerase chain reaction or Western blotting. Although more Cyp2b-9 than Cyp2b-10 was expressed in the liver of control mice, the amounts of the latter became relatively overwhelming in untreated hepatocytes because of a faster decline of Cyp2b-9 species in culture. The level of mRNA induced by phenobarbital was concentration dependent, the highest being at 2 or 4 mM, which was equivalent to in vivo treatment levels. There was more Cyp2b-10 species than those of Cyp2b-9 after exposure to phenobarbital both in vivo and in vitro. Phenobarbital also induced CYP1A2 mRNA, which was again peculiar to spheroid culture. Although the expression levels of both Cyp2b-9 and Cyp2b-10 species was very low in hepatocytes cultured without dexamethasone even in the presence of phenobarbital, the addition of 10(-7) or 10(-6) M dexamethasone caused an increase in the mRNA. When given concomitantly with phenobarbital, the expression was greatly enhanced. Nicotinamide or isonicotinamide similarly enhanced the expression of the two mRNA species, but the levels in monolayer cultures were still far lower than those in vivo. In contrast to the findings for mRNA expression, the protein levels in the presence of nicotinamide were similar to those in vivo under both monolayer and spheroid conditions. Since previous efforts to maintain expression of the CYP2B1 and CYP2B2 genes in primary cultured rat hepatocytes, orthologous to mouse Cyp2b 9 and Cyp2b-10 genes, required special cell attachment factors, our spheroid culture system, in which mouse hepatocytes are simply seeded onto noncoated dishes, has advantages for mechanistic studies. PMID- 7840638 TI - 1-O-acyl-beta-D-glucoses as fatty acid donors in transacylation reactions. AB - Glandular trichome exudates of the wild tomato, Lycopersicon pennellii Corr. (D'Arcy), are composed of 2,3,4-tri-O-acylglucoses possessing short to medium chain length (C4-C12) straight- and branched-chain fatty acids. These fatty acids are activated via a UDP-glucose-dependent reaction to form their respective high energy 1-O-acyl-beta-D-glucopyranose derivatives. The activated 1-O-acyl moieties are then transacylated to other glucose and/or partially acylated glucose derivatives. Here we demonstrate that 1-O-acyl-beta-D-glucopyranoses participate in two types of glucose transacylation reactions. The first is anomeric exchange of the acyl moiety from 1-O-acyl-beta-D-glucopyranose to beta-glucose. The second is disproportionation between two molecules of 1-O-acyl-beta-D-glucopyranose resulting in formation of diacylglucose and glucose. Leaf extracts from cultivated tomato (Lycopersicon esculentum), which does not accumulate epicuticular acylglucoses, possess low levels of both the acyl exchange and disproportionation activities. PMID- 7840639 TI - Rigidity of the heme pocket in the cooperative Scapharca hemoglobin homodimer and relation to the direct communication between hemes. AB - The Soret spectra of the dimeric hemoglobin from Scapharca and of horse myoglobin reconstituted with protoporphyrin IX and Zn-protoporphyrin IX have been measured over the range 290-80 K. With increase in temperature the Soret band broadens and shifts to a different extent depending on the protein and the presence of the metal. In the Zn-protoporphyrin IX derivatives the spectral changes are more marked in myoglobin than in the dimeric hemoglobin. In the protoporphyrin IX derivatives, in which the spectral changes are significantly reduced, the opposite is true. The data have been analyzed in terms of coupling of the protein low-frequency vibrational motions to the porphyrin electronic transition (V. Srajer et al., 1986, Phys. Rev. Lett. 57, 1267-1270; A. Di Pace et al., 1992, Biophys. J. 63, 475-484). The analysis indicates that the heme pocket of the dimeric hemoglobin is characterized by an unusual rigidity and that the metal plays a different role in the transmission of the protein motions to the heme moiety in the dimeric hemoglobin and in myoglobin. Static and dynamic fluorescence measurements carried out at room temperature are in line with these conclusions. PMID- 7840640 TI - Lipid hydroperoxide-induced endogenous DNA adducts in hamsters: possible mechanism of lipid hydroperoxide-mediated carcinogenesis. AB - DNA of livers or kidneys of rodents contain endogenously modified nucleotides of as yet unknown structure or function. As part of our examination of the origin of endogenous DNA modifications, we examined polar adducts of hamster liver and kidney DNA by 32P-postlabeling analysis (central and upper cuts) and compared them to adducts generated by incubation of DNA with [9Z,11E,(13S)]-13 hydroperoxyoctadecadienoic acid or with malondialdehyde. The central and upper cuts of DNA adduct maps of intact female retired breeder hamsters contained one and three adducts called C1, U1, U2, and U3, respectively, which cochromatographed with similar adducts in DNA incubated with the hydroperoxide or with malondialdehyde. Concentrations of adducts C1, U1, and U2 in organs of 1 month-old hamsters were lower than those in the 5-month-old female retired breeder hamsters. Adduct concentrations increased in tandem with lipid peroxide concentrations in livers and kidneys of hamsters treated with carbon tetrachloride compared to controls. A linear dependence of the concentrations of adducts on those of lipid peroxides was demonstrated independent of the treatment conditions or the organ examined. The polar endogenous adducts U1, U2, and U3 were identified by cochromatography in five different chromatographic systems with adducts induced by linoleic hydroperoxide or malondialdehyde. Adducts U1, U2, or U3 were also formed by incubating malondialdehyde with dAMP or with dGMP, respectively. The dependence of adduct concentrations in vivo on lipid peroxide levels are taken as evidence that decomposition products of lipid peroxides such as malondialdehyde induced endogenous DNA adducts in intact animals. Moreover, these adducts may mediate carcinogenic processes induced by chemicals which raise lipid peroxide levels. PMID- 7840641 TI - Characterization of a dinucleotide-binding site in monoamine oxidase B by site directed mutagenesis. AB - Monoamine oxidase B (MAO B), an integral protein of the outer mitochondrial membrane, catalyzes the oxidative deamination of neuroactive and vasoactive amines. The oxidation step is coupled to the reduction of an obligatory FAD cofactor. In this study, we have examined the role of one amino acid (Glu34) in human MAO B that is thought to play a crucial role in binding to the 2'-hydroxy group of ribose in the AMP moiety of FAD. Glu34 is located within a region of the MAO B molecule of high sequence identity to the dinucleotide-binding site in other flavoproteins. In MAO B, this region is postulated to consist of a beta 1 sheet-alpha-helix-beta 2-sheet motif which culminates with a Glu at the C terminal end of the second beta-sheet. We used site-directed mutagenesis to convert Glu at position 34 to Asp, Gln, and Ala. The wild-type and mutant cDNAs were then transiently transfected into COS-7 cells and assayed for MAO B activity. All three variants exhibited a dramatic decrease in the enzymatic activity as compared to wild-type MAO B, and only the Asp variant retained any detectable activity. Our studies indicate that the Glu34 residue in human MAO B is essential for catalysis. Whether Glu34 is responsible only for alignment of the FAD for participation in the oxidation/reduction cycle or also for the initial binding of FAD to the apoenzyme remains to be determined. PMID- 7840642 TI - Catalytic activation of guanylate cyclase/atrial natriuretic factor receptor by combined effects of ANF and GTP gamma S in plasma membranes of Leydig tumor cells: involvement of G-proteins. AB - Guanosine 5'-(gamma-thio)triphosphate (GTP gamma S) exhibited a modulatory role in the catalytic activation of guanylate cyclase-A/atrial natriuretic factor receptor (GC-A/ANF-R) in the plasma membrane preparations of murine Leydig tumor (MA-10) cells. Both atrial natriuretic factor (ANF) and GTP gamma S synergistically stimulated the guanylate cyclase (GC) activity of GC-A/ANF-R in a dose- and time-related manner. Other nucleotides and their analogs such as ATP, adenosine 5'-(gamma-thio)triphosphate, adenosine 5'-(beta,gamma imino)triphosphate, GDP, and guanosine 5'-(2-O-thiodiphosphate) (100 microM each) did not show any discernible effect on GC catalytic activity of GC-A/ANF-R. A significant stimulation of GC activity was observed in the presence of mastoparan, AlF4-, and benzalkonium chloride. The saturation binding assay of [35S]GTP gamma S showed the dissociation constant (Kd) of 2.3 x 10(-9) M and the binding capacity (Bmax) of 76 pmol/mg protein in the plasma membrane preparations of MA-10 cells. ANF increased the [35S]GTP gamma S-binding capacity, however, without affecting its affinity constant. Pretreatment of plasma membranes with antibodies against Gs alpha subunit attenuates the GTP gamma S-stimulated GC activity, whereas antibodies against Gi alpha subunit enhanced the stimulatory effect of GTP gamma S on GC catalytic activity of GC-A/ANF-R. However, the antibodies against Go alpha subunit did not show any effect on GC activity. These results provide the evidence that both Gs and Gi subunits of G-proteins seem to be involved in the regulation of GC catalytic activity of GC-A/ANF-R in the plasma membranes of MA-10 cells. PMID- 7840643 TI - Molecular cloning and sequence analysis of Flavobacterium meningosepticum glycosylasparaginase: a single gene encodes the alpha and beta subunits. AB - A full-length insert for the Flavobacterium meningosepticum N4-(N-acetyl-beta glucosaminyl)-L-asparagine amidase gene was located on a 2500-bp HindIII fragment and cloned into the plasmid vector pBluescript. DNA sequencing revealed an open reading frame of 1020 nucleotides encoding a putative 45-amino-acid leader sequence and a deduced precursor polypeptide of 295 amino acids. In F. meningosepticum this precursor polypeptide undergoes proteolytic processing by an as yet unknown mechanism to generate an alpha-subunit and a beta-subunit, which constitute the active form of the heterodimeric mature glycosylasparaginase. The Flavobacterium glycosylasparaginase gene was expressed in Escherichia coli and found to be enzymatically active. The recombinant enzyme was purified from crude lysates and shown by sodium dodecyl sulfate-polyacrylamide gel electrophoresis to consist of the typical alpha- and beta-subunits. The recombinant beta-subunit cross-reacted to antibody specific for the rat liver beta-subunit, and Edman analysis demonstrated that its amino-terminus corresponded exactly to that of the mature native glycosylasparagine beta-subunit. A comparison of the Flavobacterium glycosylasparaginase with a mammalian glycosylasparaginase revealed 30% structural identity and 60% overall similarity between the prokaryotic and eukaryotic forms of the enzyme. Even more striking was the conservation of the amino acid sequence in both proteins where the post-translational cleavage to generate the active enzyme occurs. Our data demonstrate that deglycosylation of asparagine-linked glycans via hydrolysis of the AspNHGlcNAc linkage is an important reaction which has been preserved during evolution. PMID- 7840644 TI - Structure and function of a long alternating purine-pyrimidine sequence in the mouse alcohol dehydrogenase Adh-1 gene. AB - The mouse alcohol dehydrogenase gene Adh-1 contains an unusually long alternating purine-pyrimidine sequence within its first intron. This alternating sequence differs in length between strains that differ in the extent of Adh-1 expression, and it has been suggested that it plays a role in gene expression. We demonstrate that this alternating sequence can form Z-DNA in vitro. The alternating sequence can act as a positive regulatory element in transient transfection assays in hepatoma cell lines, but not in CV-1 (monkey kidney) cells, suggesting that it can act as a tissue-specific regulatory element. Nuclear run-on experiments showed that the differential expression of Adh-1 from high- and low-activity strains is, however, controlled at the post-transcription level. PMID- 7840645 TI - Identification of a second active site residue in Escherichia coli L-threonine dehydrogenase: methylation of histidine-90 with methyl p-nitrobenzenesulfonate. AB - Incubation of L-threonine dehydrogenase from Escherichia coli with methyl p nitrobenzenesulfonate results in a time- and concentration-dependent loss of enzymatic activity. As the concentration of the methylating agent is increased, the rate of inactivation reaches a limiting value of 0.01 min-1 at pH 7.0 and 25 degrees C, suggesting that the inhibitor is binding at a specific site prior to reaction. Approximately one methyl group is incorporated per enzyme subunit inactivated. Reaction with [14C]methyl p-nitrobenzenesulfonate followed by amino acid analysis shows that greater than 90% of the radioactivity incorporated into the enzyme is associated with a peak that coelutes with 3-methyl-N-histidine. Tryptic digestion of the inactive enzyme adduct yields a radioactive peptide corresponding to residues 85-97 of the protein; the radioactivity is associated with histidine residue-90. The Zn2+ content of the inactivated and the native enzyme remains the same. The substrate, L-threonine, and substrate analogs, L threonine methyl ester and L-threonine amide, provide about 60% protection against inactivation, whereas NAD+ has no effect. In contrast, NADH markedly enhances the rate of inactivation by this methylating agent, suggesting a possible conformational change in the vicinity of His-90 is induced by binding of the coenzyme. PMID- 7840646 TI - H+/PPi stoichiometry of membrane-bound pyrophosphatase of Rhodospirillum rubrum. AB - Two kinetic methods have been used to measure the H+/PPi stoichiometry in the chromatophores of the photosynthetic bacteria Rhodospirillum rubrum. In the first method, the fluorescent probe acridine orange was employed to infer the proton pump activity at the steady state of the delta pH generation. At this point the translocation of protons by the H(+)-PPiase in one direction is balanced exactly by the leak of protons in the opposite direction. Pyrophosphatase activity was then quickly stopped by adding EDTA, producing a relaxation of delta pH. From the initial rate of this relaxation and the rate of PPi hydrolysis measured under the same condition, the H+/PPi stoichiometry was obtained. In the second method, a mathematical model was used to describe the time course of delta pH formation. In the two methods an apparent H+/PPi stoichiometry of nearly 2 was obtained. The H+/ATP stoichiometry was determined also as an internal control, giving a value of nearly 3.6, which is in agreement with the value in different F-type H(+) ATPases. PMID- 7840647 TI - Purification and characterization of a less randomly acting endo-1,4-beta-D glucanase from the culture filtrates of Fusarium oxysporum. AB - An extracellular endo-1,4-beta-D-glucanase from Fusarium oxysporum was purified by affinity chromatography and gel filtration. The enzyme purified in this way was homogeneous when judged by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and isoelectric focusing-polyacrylamide gel electrophoresis. The protein corresponded to a molecular mass and pI value of 41.7 kDa and 6.4, respectively. It was optimally active at pH 4.5 and at 55 degrees C. The enzyme hydrolyzed carboxymethylcellulose (CMC) and unsubstituted and substituted cello oligosaccharides but was inactive on Avicel, filter paper, xylan, cellobiose, p nitrophenyl-beta-D-glucoside, and p-nitrophenyl-beta-D-xyloside. However, the enzyme effected only a small change in viscosity of CMC per unit increase of reducing sugar. When cellotriose, cellotetraose, and cellopentaose were used as substrates, the enzyme released mainly cellobiose. Use of 4-methylumbelliferyl cello-oligosaccharides and the determination of bond cleavage frequency revealed that the enzyme preferentially hydrolyzed the glycosidic bond adjacent to 4 methylumbelliferone. Thus, the purified enzyme appeared to be a less randomly acting endoglucanase. PMID- 7840648 TI - The absence of extracellular calcium potentiates the killing of cultured hepatocytes by aluminum maltolate. AB - Dose- and time-dependent killing of cultured rat hepatocytes was produced by aluminum maltolate (AlM), a neutral, water-soluble complex of aluminum 3-hydroxy 2-methyl-4H-pyran-4-one. Treatment with 10 mM AlM for 1 h killed 50% or more of the cells within 3 h. Removal of calcium from the culture medium or treatment with calcium channel blockers (verapamil, nifedipine, diltiazem) potentiated the cell killing. By contrast, inhibition by thapsigargin of the sequestration of intracellular calcium by the endoplasmic reticulum reduced the toxicity of AlM. In turn, activation of protein kinase C with 12-O-tetradecanoylphorbol 13-acetate or activation of protein kinase A with 8-[4-chlorophenyl-thio]adenosine 3',5' cyclic monophosphate also reduced the toxicity of AlM. By contrast, inhibition of protein kinase activity by staurosporine potentiated the cell killing. Staurosporine, however, did not reverse the protection afforded by thapsigargin. Hepatocytes treated with AlM for 1 h were rescued by adding deferoxamine as late as 90 min following the removal of AlM, whereas pretreatment for 1 h with deferoxamine did not prevent the toxicity of AlM. ATP depletion did not precede loss of viability. Pharmacologic probes excluded oxidative stress as a mechanism of lethal injury by AlM, and inhibition of protein synthesis by cycloheximide did not protect the hepatocytes, thereby excluding activation of a cell death program. These data define a new model in which aluminum kills liver cells by a mechanisms distinct from previously recognized pathways of lethal cell injury. It is hypothesized that aluminum binds to cytoskeletal proteins intimately associated with the plasma membrane. This interaction eventually disrupts the permeability barrier function of the cell membrane, an event that heralds the death of the hepatocyte. The intracellular calcium ion concentration and protein phosphorylation may modify the interaction of aluminum with its critical targets. Alternatively, aluminum may inhibit the phosphorylation of cytoskeletal elements, thereby interfering with their function. PMID- 7840650 TI - Reaction of human hemoglobin HbA0 and two cross-linked derivatives with hydrogen peroxide: differential behavior of the ferryl intermediate. AB - Functional concerns regarding hemoglobin-based red cell substitutes have generally centered on two parameters: (a) oxygen binding and delivery properties and (b) stabilization of the hemoglobin tetramer to prevent dimerization. Strategic chemical cross-linking and site-directed mutagenesis have produced proteins that have both physiological oxygen binding characteristics and a markedly prolonged retention time in the circulation. The presence of a large amount of redoxactive iron outside the red blood cell, however, raises some concerns about the potential for toxic side effects, many involving the production or participation of oxygen free radicals. In the present study, HPLC purified human hemoglobin HbA0 and two derivatives, one cross-linked between the lysine 99 residues of the alpha subunits (alpha-DBBF) and the other between the lysine 82 residues of the beta subunits (beta-DBBF) were tested for their susceptibility to oxidation and oxidative damage caused by H2O2. We show that chemical cross-linking resulting in alpha-DBBF induces an increased tendency to form ferryl radical in the presence of H2O2 and stabilizes the radical once formed. The in vitro oxidative modification of alpha-DBBF seen here is a plausible mechanism for some of the in vivo toxicities associated with the infusion of this hemoglobin. PMID- 7840649 TI - Metabolism of epoxyeicosatrienoic acids by cytosolic epoxide hydrolase: substrate structural determinants of asymmetric catalysis. AB - The metabolism of cis-epoxyeicosatrienoic acids (EETs), methyl cis epoxyeicosatrienoates, and cis-epoxyeicosanoic acids by cytosolic epoxide hydrolase was studied to identify substrate structural features important for stereoselective metabolism and chiral diol formation. 14(R), 15(S)-, 11(S),12(R) , and 8(S),9(R)-EET, the predominant enantiomers present endogenously in rat organs, were metabolized at substantially higher rates than their antipodes. With the exception of 8(R),9(S)-EET (Km = 41 microM), differences in enantiomer hydration rates appear to be caused by Km-independent factors since the apparent Km values for the enantiomers of 14,15-, 11,12-, and 8(S),9(R)-EET were similar (between 3 and 5 microM). Chiral analysis of the diols resulting from enzymatic hydration of homochiral EETs showed that the regio and/or stereochemistry of water addition was EET regioisomer dependent. For the 11,12-EET enantiomers, water addition was nonregioselective; whereas, with both 8,9-EET antipodes water addition occurred predominantly at C9. Importantly, for 14,15-EET the regiochemistry of water addition was enantiomer-dependent. Only with 14(R),15(S) EET did enzymatic hydration result in regiospecific addition at C15. Hence, enantioselective EET hydration is determined, principally, by enantiomer specific differences in rates of catalytic turnover and/or substrate binding parameters. On the other hand, the chirality of the diol products is determined by EET enantiomer-dependent differences in the regiochemistry of enzymatic oxirane cleavage and water addition. Esterification resulted in an overall reduction in the rates of epoxide hydration for all three EET-methyl esters (59, 89, and 68% of the EET rate for 8,9-, 11,12-, and 14,15-EET-methyl ester, respectively) and in the loss of regioselectivity during methyl 8(S),9(R)-EET oxirane cleavage. Catalytic EET hydrogenation reduced the rates of EET hydration (56, 45, and 23% of the EET rates for 8,9-, 11,12-, and 14,15-epoxyeicosanoic acids, respectively). Compared to 14,15-EET, enzyme catalyzed hydration of 14,15 epoxyeicosanoic acid was less regioselective and yielded products with a substantially lower chiral purity. Based on these data, as well as on the documentation of 14(R),15(R)-dihydroxyeicosatrienoic acid as an endogenous constituent of rat urine we concluded that: (1) cytosolic epoxide hydrolase plays a significant role in the regio- and stereoselective metabolism of endogenous EETs; (2) differences in the affinities and/or turnover rates of the enzyme for the individual EET antipodes may be responsible for enantioselective EET metabolism; and (3) for 14,15- and 8,9-EET, regioselective and/or enantioselective oxirane water addition is responsible for asymmetric diol formation.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7840651 TI - Effect of proteolysis on the state of lipid phase in rat brain synaptosomal membranes. AB - Enzymatic proteolysis of the proteins of synaptic membranes has been found to be accompanied by the promotion of lipid peroxidation probably mediated by the liberation of membrane-bound iron. As fluorescent probes pyrene and diphenylhexatriene show, the microviscosity and micropolarity of membrane lipid phase rise as a result of lipid peroxidation. Different structural changes induced by proteolysis are displayed under inhibition of lipid peroxidation. Thus, the microviscosity of the bulk lipid phase appears to be lowered and the annular lipid microviscosity raised. Another explanation of the fluorescent data for annular lipids is the exclusion of pyrene molecules from this lipid pool, leading to a reduction of the probe local concentration. The changes observed in membrane lipid phase are considered as primary structural effects of proteolysis, not mediated by a phospholipase activation. PMID- 7840652 TI - Identification of 3'-methoxy-4'-nitroflavone as a pure aryl hydrocarbon (Ah) receptor antagonist and evidence for more than one form of the nuclear Ah receptor in MCF-7 human breast cancer cells. AB - The competitive binding of 3'-methoxy-4'-nitro, 4'-amino-3'-methoxy, 4'-methoxy 3'-nitro, and 3'-amino-4'-methoxyflavone (compounds 1 to 4, respectively) to the rat cytosolic aryl hydrocarbon (Ah) receptor gave IC50 values of 2.27, 86.1, 872, and 19.4 nM. Flavones 3 and 4 were characterized as Ah receptor agonists in MCF-7 human breast cancer cells and induced CYP1A1 gene expression, whereas the 3 methoxy-substituted flavones (1 and 2) were inactive. All four compounds inhibited induction of ethoxyresorufin O-deethylase (EROD) activity by 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) in MCF-7 cells; moreover, in vitro studies with TCDD-induced rat liver microsomes showed that flavones 1 to 4 inhibited EROD activity in the presence or absence of NADPH. In MCF-7 cells cotreated with flavones 1 or 2 (0.01 to 10 microM) plus TCDD or [3H]TCDD, there was a concentration-dependent inhibition of TCDD-induced CYP1A1 mRNA levels and formation of radiolabeled nuclear Ah receptor complex. Velocity sedimentation analysis of nuclear extracts from MCF-7 cells treated with [3H]TCDD plus 1 or 10 microM concentrations of flavones 1 and 2 showed that an early eluting specifically bound nuclear Ah receptor complex was present. However, under these same conditions the flavones inhibited TCDD-induced CYP1A1 gene expression. The apparent molecular mass of this nuclear complex was 190 kDa as determined by cross-linking to a 32P-labeled bromodeoxyuridine-substituted consensus dioxin responsive element. Similar cross-linking results were obtained using the nuclear extract from MCF-7 cells treated with [3H]TCDD alone. The results of this study suggest that there are at least two forms of the nuclear Ah receptor complex in MCF-7 cells; the major transcriptionally active form binds [3H]TCDD and flavones 1 or 2 inhibit nuclear uptake of this receptor complex. The other form of the nuclear Ah receptor complex appears to be transcriptionally inactive and ligand binding with [3H]TCDD is not competitively inhibited by flavones 1 and 2. PMID- 7840653 TI - Purification and characterization of constituent testosterone 2 alpha-hydroxylase (cytochrome P450(2)alpha) from mouse liver. AB - Hepatic microsomal testosterone/androstenedione 2 alpha-hydroxylase (i.e., cytochrome P450(2)alpha) was purified from female CD-1 mice. Protein purification was monitored in eluates from Fractogel, DEAE-sephacel, and hydroxylapatite columns at heme absorbing 417 nm and by cytochrome P450 content, reactivity to a monoclonal antibody against female-specific rat cytochrome P450 2C12, and testosterone 2 alpha-hydroxylase activity. The catalytic activity of the purified cytochrome P450(2)alpha, exhibiting a high degree of regioselectivity and stereospecificity, was basically restricted to the 2 alpha-hydroxylation of testosterone and androstenedione; representing > 96% and > 92% of these respective metabolites. Polyclonal antibodies against cytochrome P450(2)alpha exhibited a dose-dependent and very selective inhibition of testosterone 2 alpha hydroxylation. The specific cytochrome P450 content of the purified cytochrome P450(2)alpha fraction was 12.06 nmol/mg protein. The specific testosterone 2 alpha-hydroxylase activity of the purified protein was 14 nmol/min/nmol cytochrome P450, which was about 60-fold higher than the respective microsomes. The apparent subunit molecular weight of cytochrome P450(2)alpha was 51,000 and the protein appeared as a single band on sodium dodecyl sulfate polyacrylamide gels. The amino-terminal sequence analysis indicates that cytochrome P450(2)alpha is a member of the murine cytochrome P450 2d family. PMID- 7840654 TI - N-ethylmaleimide profiling of yeast NADP-dependent isocitrate dehydrogenase. AB - Yeast NADP-dependent isocitrate dehydrogenase is inactivated by N-ethyl-maleimide (NEM) at pH 7.7 and 30 degrees C. Reaction with cysteine382 occurs most rapidly and is accompanied by loss of about 50% of the enzymatic activity. A slower phase of inactivation ensues during which lysine343 is the major target of NEM, while minor products result from reaction at cysteine73 and cysteine354. Protection against the second phase of inactivation is provided by NADP, NAPH, or manganous isocitrate. Comparison of the time-dependence of inactivation and the products of reaction with N-ethyl-ethylmaleimide (NEM profiling) of the pig heart (G. E. Smyth and R. F. Colman, 1991, J. Biol. Chem. 266, 14918-14925) and yeast NADP specific isocitrate dehydrogenases have been coupled with an examination of the crystal structure of the Escherichia coli isocitrate dehydrogenase. The following conclusions have been reached: while no cysteine is essential for activity, yeast Cys382/pig Cys379 is close to the adenine portion of the NADP binding site, and pig Cys269 is located in the region of the metal-isocitrate binding site. PMID- 7840655 TI - Light-dependent inhibition of protein kinase C and superoxide generation of neutrophils by hypericin, an antiretroviral agent. AB - Hypericin, a photosensitizing plant pigment, has antiretroviral activity. When exposed to light, the inhibition of Friend leukemia virus (FLV)-induced splenomegaly by hypericin was increased. The ID50 was decreased to less than 2.5 micrograms/mouse by exposure to tungsten light (29 x 10(-3) W/cm2 for 3 min). This pigment inhibited phorbol 12-myristate 13-acetate (PMA)-activated protein kinase C of rat brain in a light- and concentration-dependent manner. The ID50 of hypericin and the light intensity for inhibition of PKC were 0.1 microM under a constant light of 29 x 10(-3) W/cm2 for 3 min and 5 x 10(-3) W/cm2 in the presence of 1 microM hypericin for 3 min, respectively. The PMA-induced respiratory burst of neutrophils was inhibited in the light but stimulated in the dark by hypericin. The ID50 for inhibition of the respiratory burst was similar to that for inhibition of PKC. These results suggest that hypericin might inhibited PKC-mediated processes of intact cells, including PMA-induced superoxide generation of neutrophils by some light-dependent mechanism, and that this mechanism might underlie its light-dependent inhibition of FLV infection. PMID- 7840656 TI - The complete amino acid sequences of two serine proteinase inhibitors from the fruiting bodies of a basidiomycete, Pleurotus ostreatus. AB - The complete amino acid sequences of two isomeric endogenous inhibitors, IA-1 and IA-2, both of which specifically inhibit an intracellular serine proteinase (proteinase A) purified from the fruiting bodies of a higher basidiomycete, Pleurotus ostreatus, were determined. Both inhibitors are acidic polypeptides with respective molecular masses of 8307 and 8244 Da, as determined by plasma desorption mass spectral analyses, and their N-terminal serine residue is blocked by acetylation. The fragments generated from the inhibitors by proteolytic and chemical cleavages were subjected to amino acid composition, sequence, and mass spectral analyses. The sequence and molecular mass information for the peptides established that the inhibitors both consisted of 76 amino acid residues and differed from each other in that aspartic acid and glutamic acid residues at residues 12 and 15 of IA-1 were replaced by glycine and aspartic acid in IA-2, respectively. The molecular masses of IA-1 and IA-2 were calculated to be 8309 and 8237, based on the sequence data. The action of carboxypeptidase Y on IA-1 resulted in a complete loss of the inhibitory activity along with successive release of glutamine and threonine from the C-terminus. Cyanogen bromide cleavage of Met38-Pro39 and Met41-Lys42 in IA-1 and hydroxylamine degradation of IA-2 completely abolished their inhibitory activity. These results suggest that the whole molecules of both inhibitors are essential to their inhibitory activities. Their structural resemblance to propeptides of subtilisin family proteinases revealed their mechanism of action. PMID- 7840657 TI - In vitro processing of anthrax toxin protective antigen by recombinant PC1 (SPC3) and bovine intermediate lobe secretory vesicle membranes. AB - Protective antigen (PA), an 83-kDa protein produced by Bacillus anthracis, requires proteolytic activation at a tetrabasic site (RKKR167) before it can combine with either edema factor or lethal factor on the cell surface. The complex is then endocytosed and the target cell intoxicated. Previous work has demonstrated that furin, a ubiquitously distributed, subtilisin-like protease, can perform this cleavage. In this study, another member of the furin family, PC1 (SPC3), was tested as a putative processing enzyme for PA. Recombinant PC1, partially purified from the medium of stably transfected L-cells, cleaved PA to a 63-kDa fragment (PA63) and a 20-kDa fragment (PA20). Amino-terminal sequence analysis of the 63 kDa product demonstrated that cleavage occurred between Arg167 and Ser168. The pH optimum for in vitro PA cleavage was 6.0 and the enzymatic activity was calcium-dependent. Medium from untransfected L-cells did not cleave PA. Site-directed mutagenesis of the tetrabasic cleavage site revealed that PC1 preferred to cleave sequences containing basic residues at positions -1 and -4 relative to the wild-type cleavage site, demonstrating that PC1 can cleave substrates at a monobasic residue site in vitro. Substrates having basic residues at the -1 and -2 positions were cleaved with approximately twofold less efficiency than wild-type PA. Mutants of PA containing basic residues in positions -1 and either -2 or -4 of the cleavage site were predicted to be substrates for PC1 and were more toxic to L-cells expressing PC1 than to untransfected L-cells. These results demonstrate that PA is cleaved by PC1 in vivo. Membranes from bovine intermediate lobe secretory vesicles which contain both prohormone convertases, PC1 and PC2, also cleaved PA to PA63 with a pH optimum of 5.5. Immunodepletion studies using antisera against PC1 and PC2 showed that these are the enzymes primarily responsible for the cleavage of PA in the membrane preparation. Thus, both recombinant PC1 and a membrane preparation containing endogenous PC1 can activate PA. PMID- 7840658 TI - Effect of iron acquisition on induction of DNA single-strand breaks by erionite, a carcinogenic mineral fiber. AB - It has been proposed that iron from inhaled fibers, such as asbestos, is responsible for their toxicity and carcinogenicity. The natural fibrous zeolite erionite is far more carcinogenic than asbestos, but contains little or no iron. Fibers that persist in the lung accumulate iron on their surfaces. The ability of erionite to induce formation of single-strand breaks in phi X174 RFI DNA was investigated before and after binding of iron. Unmodified erionite did not induce DNA single-strand breaks with or without ascorbate and/or the iron chelator EDTA. When erionite (1 mg/ml) was suspended in 25, 50, 100, or 500 microM FeCl2, it readily bound iron (25, 50, 93, or 176 nmol Fe/mg, respectively, in 1 h), apparently through ion exchange. When erionite was suspended in FeCl3 at identical concentrations for 1 h, it also bound iron (24, 46, 89, or 239 nmol Fe/mg). The ferric iron did not appear to bind primarily through ion exchange, but appeared to be deposited on the surface, probably in the form of hydroxides/oxyhydroxides. When ferrous iron was bound to erionite, single-strand breaks in DNA were induced in the absence of ascorbate, but when ferric iron was bound, DNA single-strand breaks were observed only in the presence of ascorbate. When EDTA or citrate was added, this activity increased with the amount of iron mobilized from the fiber. If iron acquired by erionite in vivo is similarly mobilized, it may damage biomolecules throughout the cell, including DNA. This may explain the toxicity and carcinogenicity of erionite. PMID- 7840659 TI - Hydroxyl radical formation from cuprous ion and hydrogen peroxide: a spin trapping study. AB - Copper toxicity has been presumed to involve catalytic hydroxyl radical (.OH) formation from hydrogen peroxide. Addition of Cu1+ to a solution containing ethanol or dimethylsulfoxide (Me2SO) and the spin-trapping agent alpha-(4-pyridyl 1-oxide)-N-tert-butylnitrone (4-POBN) results in formation of the alpha hydroxyethyl radical or methyl radical adduct of 4-POBN, respectively. Adduct formation was prevented by inclusion of catalase, but not by superoxide dismutase. Inclusion of exogenous H2O2 in the reaction mixture increased the yield of ethanol- or Me2SO-derived radical adduct and also enhanced the formation of secondary radical adducts, including 4-POBN/.H and the methyl radical adduct of 2-methyl-2-nitrosopropane. The alpha-hydroxyethyl adduct of 4-POBN is rapidly decomposed in the presence of copper, but not iron salts, whereas the methyl radical adduct is relatively stable in the presence of inorganic copper. The total concentration of radical adduct detected from the reaction between Cu1+ and H2O2, determined by comparison of the integrated spectral intensity with that of the stable 2,2,6,6-tetramethyl-1-piperidinyloxy free radical, was only 1-5% of the maximum amount predicted assuming radical adduct formation from all of the added copper. A variety of copper chelators inhibit formation of carbon-centered radical adducts of 4-POBN, including penicillamine and triethylenetetramine, which are the primary drugs used to treat the copper metabolism disorder Wilson's disease. The results provide clear evidence for hydroxyl radical formation from Cu1+ and H2O2 (either added or formed during the autoxidation of reduced copper. PMID- 7840660 TI - Reactive absorption of ozone by aqueous biomolecule solutions: implications for the role of sulfhydryl compounds as targets for ozone. AB - The rates of reactive absorption of ozone by various biomolecule solutions were measured. At pH 7, the ability of various biomolecules to reactively absorb ozone was in the following sequence: thiosulfate > ascorbate > cysteine approximately methionine > glutathione. The rates of reactive absorption under a variety of conditions were then analyzed using a mathematical model in order to estimate the reaction rate constants for the various ozone-biomolecule reactions. Compared to the ozone-methionine rate constant, the relative rate constants for thiosulfate, ascorbate, cysteine, and glutathione reactions were 18 +/- 2, 12 +/- 1, 1.1 +/- 0.1, and 0.62 +/- 0.03, respectively. Using an ozone-methionine reaction rate constant of 4 x 10(6) M-1 s-1, the rate constants for thiosulfate, ascorbate, cysteine, and glutathione were 7.2 x 10(7), 4.8 x 10(7), 4.4 x 10(6), and 2.5 x 10(6) M-1 s-1, respectively. Competitive studies using tryptophan as a standard ozone target were consistent with these rate constants. Compared to tryptophan, the relative ozone reaction rate constants for methionine, cysteine, and glutathione were 0.77 +/- 0.08, 0.88 +/- 0.19, and 0.42 +/- 0.01, respectively. These relative rate constants refer to ozone consumption rather than biomolecule consumption, so they may be compared with the relative rate constants obtained from reactive absorption. In addition, various inconsistencies in the literature regarding the rates of the ozone-cysteine and the ozone-glutathione reactions were reviewed. PMID- 7840661 TI - Competitive inhibition of HIV-1 protease by biphenyl carboxylic acids. AB - A novel series of nonpeptidic compounds that contain a biphenyl carboxylic acid group have been shown to inhibit HIV-1 protease. The active compounds, most of which are highly soluble, have IC50 values in the range of 3.4-74 microM. The structure-inhibitory activity relationship demonstrates the necessity of the biphenyl carboxylic acid group for inhibition, which is enhanced by the presence of a sulfone group and by halogenation of an adjacent phenyl group. A double reciprocal plot of inhibition data on two of the compounds clearly shows that the inhibition occurs in a competitive manner, with Ki values of 1.1 and 3.4 microM. Inhibition by several of the compounds was found to be reversible and fast binding, while one of the biphenyl carboxylic acids inhibits in a reversible slow binding manner. Time-dependent inhibition studies were conducted on this compound, and it was determined to have the kinetic values of kon = 0.18 microM 1min-1, koff = 9.7 x 10(-2)min-1, and Ki = 0.14 microM. Thus, the slow-binding inhibitor is the most potent in the series. Molecular modeling has provided information on a possible binding mode for two different biphenyl carboxylic acid inhibitors of HIV-1 protease. PMID- 7840662 TI - Myristoylation cannot functionally replace the isoprenylation of Rab5. AB - C-terminal isoprenylation is necessary for the small GTPase Rab5 to associate with early endosomes and to exert its regulatory function in endocytosis. In this study, we tested whether Rab5 could retain its membrane association and biological function if the isoprenylation were replaced by another type of lipid modification (myristoylation). Rab5 mutants were constructed that contained both isoprenylation and myristoylation (Gag-Rab5), myristoylation only (Gag-Rab5 delta C4), and neither of the modifications (Rab5 delta C4), respectively. These mutants and wild-type Rab5 were expressed, via a Sindbis virus vector, in cultured BHK-21 cells and their membrane association and biological activity (stimulation of endocytosis) were examined. Wild-type Rab5 was isoprenylated, membrane associated, and biologically active. With additional myristoylation, Gag Rab5 showed increased affinity for membranes but decreased biological activity. Rab5 delta C4 contained no lipid modifications, failed to associate with membranes, and had no biological activity. With myristoylation (Gag-Rab5 delta C4), there was a significant increase in membrane association (approximately 30%). However, this increased membrane association did not result in any recovery of Rab5 activity. In light of these data, we conclude that N-terminal myristoylation cannot functionally replace the C-terminal isoprenylation of Rab5. Furthermore, myristoylation of Rab5 (Gag-Rab5) interferes with its normal function. PMID- 7840663 TI - Alpha 1-adrenergic and m3-muscarinic receptor stimulation of phosphatidylinositol 4,5-bisphosphate-specific phospholipase C are independently mediated by G alpha q/11 in rat parotid gland membranes. AB - Stimulation of m3-muscarinic cholinergic receptors (m3AChR) in the rat parotid gland increases the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) via activation of the G alpha/11 family of G-proteins (Sawaki et al. (1993) Arch. Biochem. Biophys., 546-550). Herein we report that alpha 1-adrenergic receptor (alpha 1-AR) stimulation of PIP2 hydrolysis is also mediated via alpha subunits of the G q/11 family of G-proteins. The alpha 1-AR agonist, epinephrine, induced a dose-dependent increase (1.5-fold maximum) of exogenously added PIP2 in the presence of guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S), which was inhibited by the alpha 1-AR antagonist, phentolamine, but not by the beta adrenergic receptor antagonist, propranolol. The epinephrine-stimulated component of PIP2 hydrolysis was significantly inhibited by pretreating the membranes with an antiserum against G alpha q/11. When carbachol and epinephrine were present simultaneously (with GTP gamma S), the increase in PIP2 hydrolysis obtained was not significantly different from the sum of the increases in PIP2 hydrolysis obtained with each agonist alone. PIP2 hydrolysis stimulated in the presence of carbachol and epinephrine was inhibited by alpha 1-AR and m3AChR antagonists, phentolamine and atropine respectively, to the level obtained with each agonist alone. Notably, in the presence of both agonists the inhibition of PIP2 hydrolysis by anti-G alpha q/11 antiserum was not significantly different from the sum of the inhibitions obtained with each agonist alone. These results indicate that m3AChR and alpha 1-AR stimulation of PIP2 hydrolysis in rat parotid gland membranes are independently mediated by the G alpha q/11 family of G proteins. PMID- 7840664 TI - [Omega-(adenosin-5'-O-yl)alkyl]cobalamins mimicking the posthomolysis intermediate of coenzyme B12-dependent rearrangements: kinetic investigations on methylmalonyl-CoA mutase. AB - Coenzyme-B12 analogues carrying oligomethylene chains (C3-C7) inserted between the central Co atom and the 5'-O atom of the adenosine moiety mimicking the putative posthomolysis intermediate in coenzyme B12-dependent rearrangements were synthesized and examined for their effects on methylmalonyl-CoA mutase from Propionibacterium shermanii. All analogues proved to be inhibitors of methylmalonyl-CoA mutase and in all cases competitive inhibition with respect to coenzyme B12 was found. Inhibition constants (Ki) were determined by two independent methods and showed in both cases the predicted trend: the Ki values versus chain length had minima at the C6 analogue in which the distance is about 10 A between the central Co atom and the 5'carbon of the adenosine, assuming a zig-zag chain conformation. This is the postulated distance between the Co and 5' methylene paramagnetic centers generated in the methylmalonyl-CoA-coenzyme B12 complex after homolytic cleavage of the Co-C bond. PMID- 7840665 TI - Formation of reactive intermediates from Amadori compounds under physiological conditions. AB - The Maillard or browning reaction between reducing sugars and proteins contributes to the chemical aging of tissue proteins in vivo and to the accelerated aging of proteins in diabetes. To identify reactive carbohydrate intermediates formed in the Maillard reaction under physiological conditions, we studied the decomposition of the model Amadori compound, N alpha-formyl-N epsilon fructoselysine (fFL) and of Amadori compounds on glycated collagen at pH 7.4 and 37 degrees C. Because of effects of buffer and oxidative conditions on the decomposition of Amadori compounds, the kinetics and products of decomposition were studied in varying phosphate concentrations and in N-2 hydroxyethylpiperazine-N'-2-ethanesulfonic acid (Hepes) buffer under both aerobic and anaerobic conditions. The half-life of fFL was significantly shorter in phosphate, compared to Hepes buffer, and under aerobic, compared to anaerobic, conditions. The decomposition of both fFL and Amadori adducts on glycated collagen was accelerated by increasing the phosphate concentration and/or pH. Glucose and mannose were identified as major products formed by reversal of the Amadori rearrangement, along with tetroses, pentoses, and 3-deoxyglucosone, formed by reverse aldol, rearrangement, and hydrolysis reactions. The tetrose and pentose products included both aldose and ketose sugars. These same products were also formed in similar yields on decomposition of Amadori adducts on glycated collagen in vitro. The spontaneous decomposition of Amadori compounds to more reactive sugars in vivo, including tetroses, pentoses, and 3-deoxyglucosone, provides a mechanism for generating reactive intermediates under physiological conditions and for propagating damage to protein as a result of glycation of proteins by glucose in vivo. PMID- 7840666 TI - Fructose-1,6-bisphosphatase in stage VI frog oocytes: evidence for an active enzyme in vivo. AB - The characterization of fructose-1,6-bisphosphatase in stage VI oocytes from the frog Caudiverbera caudiverbera, as well as the in vivo activity, is reported. The enzyme has a subunit molecular weight of approximately 43,500, has an apparent Km value of 17 microM for fructose-1,6-bisP, and is inhibited by substrate concentrations beyond 100 microM. AMP and fructose-2,6-bisP are strong inhibitors of oocyte fructose-1,6-bisphosphatase activity with Ki values of 9 and 2 microM respectively. Inhibition by AMP is cooperative with a nH value of 2.2. In vivo fructose-1,6-bisphosphatase activity was demonstrated by microinjection of [U 14C]- or [6-32P]fructose-1,6-bisP and subsequent chromatographic separation and identification of labeled products. The relevance of these findings for the metabolism of glucose in frog oocytes is discussed. PMID- 7840667 TI - Circular dichroism of ferriprotoporphyrin IX-morphine complexes in aqueous solution. AB - Complexes of ferriprotoporphyrin IX (FP) with (-)-morphine exhibit large optical activity in aqueous solution. Several CD bands of different signs were recorded under different conditions in the wavelength range of 300 to 450 nm. The largest CD band, centered at about 364 nm, showed molar ellipticities of about -5 x 10(5) deg.cm2.dmol-1 based on FP (rotational strength of about -3 DBM). An optimum pH range of 7.4 to 7.8 with regard to optical activity of the complex has been observed. Concomitantly with the formation of optically active complexes, large aggregates are being formed as determined by ultracentrifugation. A mole ratio of 1 between FP and morphine in the complex was estimated from both CD titration and measurement of the amounts of aggregate formed upon variation of the mole fraction of the complex components. Derivatives of morphine such as heroin or codeine do not form optically active complexes and aggregates under similar conditions. As in the analogous FP-quinine and FP-quinidine complexes investigated previously, the optical activity observed is considered to originate at least in part from optical interactions between FP molecules arrayed chirally in the FP-(-)-morphine aggregates. PMID- 7840668 TI - Oxidative damage to lipids and DNA concurrent with decrease of antioxidants in rat testes after acute iron intoxication. AB - The effect of acute iron overload was studied in rat testes 20 h after a single administration of iron-dextran (500 mg/kg body wt, ip). Total testes iron content was 6.1-fold higher in iron-treated rats compared to controls. The endogenous level of lipid peroxidation was evaluated as 2-thiobarbituric acid-reactive substances (TBARS). Testes iron concentration (0.12-2.67 mumol/g of tissue) was positively correlated (r = 0.86; P < 0.01) with testes TBARS (26.2-77.5 nmol/g tissue). Testes content of lipid-soluble antioxidants, alpha-tocopherol, ubiquinol-9, and ubiquinol-10, were inversely correlated with testes iron content. The steady-state level of 8-oxo-7,8-dihydro-2'-deoxyguanosine in testes DNA was 25% higher (P < 0.01) in iron-treated rats compared to controls (2.4 +/- 0.2 oxo8dG/10(5)dG). The content of protein carbonyl groups (1.45 +/- 0.13 nmol/mg protein) and the activity of glutamine synthase (1.32 +/- 0.07 units/mg protein) were similar for the iron-treated and control rats. Fe treatment did not affect superoxide dismutase, catalase, and glutathione peroxidase activities. The results indicate that acute iron overload causes iron accumulation in rat testes, which is associated with increased lipid and DNA oxidative damage and depletion of lipid-soluble antioxidants. PMID- 7840669 TI - Methionine biosynthesis in higher plants. I. Purification and characterization of cystathionine gamma-synthase from spinach chloroplasts. AB - Cystathionine gamma-synthase, the first enzyme specific for the methionine biosynthetic pathway, was purified to apparent homogeneity from spinach leaf chloroplasts. A nonradioactive assay based on O-phthaldialdehyde derivatization of L-cystathionine and fluorescence detection was developed to determine the cystathionine gamma-synthase activity. A unique cystathionine gamma-synthase activity was located in the stromal fraction of chloroplasts while cystathionine beta-lyase, the second enzyme of the transsulfuration pathway, was associated with both the chloroplastic and cytosolic compartments (see companion manuscript). The purified enzyme exhibited a specific activity of 13 U mg-1. As estimated by gel filtration and polyacrylamide gel electrophoresis (PAGE) under nondenaturing conditions followed by activity staining, the native enzyme had an apparent M(r) of 215,000. On the basis of sodium dodecyl sulfate-PAGE, purified cystathionine gamma-synthase migrated as two molecular species of M(r) 53,000 and 50,000 that are identical in their N-termini. The absorption spectrum obtained at pH 7.5 exhibited a peak at 425 nm due to pyridoxal 5'-phosphate (PLP). The purified enzyme catalyzed the formation of L-cystathionine or L-homocysteine depending on the sulfur-containing substrate, L-cysteine or sulfide. Maximal cystathionine gamma-synthase activity was found at pH 7.4. The apparent Km values for O-phospho-L-homoserine (the unique homoserine ester synthesized in the chloroplast), L-cysteine, and sulfide were 1.4, 0.18, and 0.6 mM, respectively. Inactivation of cystathionine gamma-synthase by DL-propargylglycine (PAG) showed pseudo-first-order kinetics and data were consistent with the existence of an intermediate reversible enzyme-inhibitor complex (Kappi = 140 microM) preceding the formation of a final enzyme-inhibitor complex (kd = 24 x 10(-3) s-1). The irreversibility of the inhibition and the partial restoration of the activity by pyridoxal-phosphate suggest that PAG interacts with the PLP prosthetic group of the enzyme. Kinetic and equilibrium binding studies showed that PAG binding to PLP was considerably enhanced in the enzyme binding pocket compared to that with PLP free in solution. PMID- 7840670 TI - Methionine biosynthesis in higher plants. II. Purification and characterization of cystathionine beta-lyase from spinach chloroplasts. AB - Cystathionine beta-lyase, the second enzyme of the transsulfuration pathway leading to homocysteine synthesis was purified over 16,000-fold from spinach (Spinacia oleracea L.) leaf chloroplasts (soluble fraction). Enzyme activity was followed along the purification scheme by either a colorimetric method for the determination of cysteine or by fluorescence detection of the bimane derivative of L-homocysteine after reverse-phase HPLC. Cystathionine beta-lyase has a molecular mass of 170,000 +/- 5000 Da and consists of four identical subunits of 44,000 Da. The enzyme exhibits an absorption spectrum in the visible range with a maximum at 418 nm due to pyridoxal 5'-phosphate. The chloroplastic enzyme catalyzes alpha,beta-cleavage of the thioether L-cystathionine and the dithioacetal L-djenkolate with apparent Km values of 0.15 and 0.34 mM, respectively, and apparent Vm values corresponding to a specific activity of 13 Units mg-1. However, no activity was detected toward the disulfide L-cysteine. With either L-cystathionine and L-djenkolate as substrate, maximal activity was obtained between pH 8.3 and pH 9.0. Besides the chloroplastic enzyme form, anion exchange chromatography of a total spinach leaf extract allowed the detection of a second pool of cystathionine beta-lyase activity that is associated with the cytosolic compartment and eluted at a lower salt concentration than the chloroplastic isoform. Kinetics of inactivation of cystathionine beta-lyase by the L-alpha-(2-aminoethoxyvinyl) glycine (AVG), an analogue of L-cystathionine, are consistent with the existence of an intermediate reversible enzyme inhibitor complex (apparent inhibition constant Kappi of 110 microM) preceding the irreversible formation of a final inactivated state of the enzyme (kd = 4.8 x 10( 3) s-1). Pyridoxal 5'-phosphate free in solution binds AVG with an apparent dissociation constant Kapp in the order of 350 microM. The comparison between the Kapp (free pyridoxal 5'-phosphate) and Kappi (enzyme inactivation) values indicate that the prosthetic group of spinach chloroplast cystathionine beta lyase is freely accessible to the inhibitor compound AVG. PMID- 7840671 TI - Effect of exogenous hyaluronan and hyaluronan oligosaccharides on hyaluronan and aggrecan synthesis and catabolism in adult articular cartilage explants. AB - The addition of hyaluronan to the culture medium of explant cultures of articular cartilage was shown to suppress the synthesis of hyaluronan and aggrecan, the major proteoglycan present in cartilage, and resulted in a greater proportion of the newly synthesized aggrecan and hyaluronan appearing in the culture medium. This effect of exogenous hyaluronan on aggrecan and hyaluronan synthesis was concentration-dependent and reversible on removal of the glycosaminoglycan from the culture medium. The addition of tetra- and hexasaccharides derived from Streptomyces sp. hyaluronidase digestion of hyaluronan to explant cultures of articular cartilage did not change the rate of synthesis of aggrecan or hyaluronan or their ultimate distribution between tissue and medium. However, the addition of tetra- and hexasaccharides of hyaluronan resulted in a decrease in the rate of loss of hyaluronan from the tissue but not that of aggrecan, which remained the same as in control cultures. This suppression of the rate of loss of hyaluronan was eliminated on removal of the hyaluronan oligosaccharides from the culture medium. Analysis of the hydrodynamic size of the newly synthesized hyaluronan indicated that the presence of hyaluronan tetra- and hexasaccharides brought about an accumulation of hyaluronan of intermediate molecular mass. Since no radiolabeled hyaluronan was detected in the culture medium, it was concluded that the tetra- and hexasaccharides inhibited the internalization and intracellular catabolism of hyaluronan by the cartilage explant cultures. Regardless of whether hyaluronan or tetra- and hexasaccharides of hyaluronan were added to the culture medium, newly synthesized hyaluronan underwent depolymerization at a rate consistent with a mechanism involving oxygen-derived radicals. PMID- 7840672 TI - 5-Aminolevulinic acid induces iron release from ferritin. AB - 5-Aminolevulinic acid (ALA), a heme precursor accumulated in acute intermittent porphyria (AIP) and lead poisoning, undergoes metal-catalyzed oxidation in air equilibrated solutions buffered at neutral pH, yielding free radicals (O2, HO. and ALA.). The capacity of ALA to release iron from horse spleen and rat liver ferritin in vitro and to concomitantly initiate liposome lipid peroxidation was characterized. ALA induced iron release from ferritin in normally aerated solutions, in a dose (0.05-1 mM)- and time (0-120 min)-dependent manner; no reaction occurs under nitrogen. Superoxide dismutase partially inhibited (50% at 100 U/ml) iron release by 0.5 mM ALA, whereas the addition of catalase (50 U/ml) had no effect under these conditions. In phosphatidylcholine: cardiolipin (80:20) liposomes, and in the presence of 2 microM EDTA, ALA (0.025-1 mM) per se had a subtle effect on lipid peroxidation, while after addition of ferritin (0.25 mg/ml) there was a significant increase in lipid peroxidation as evaluated by dose-dependent formation of 2-thiobarbituric-reactive substances and diene conjugation. In vivo, iron accumulation in the liver of ALA-treated rats was observed. Altogether, these data demonstrate the ability of ALA-generated free radicals to release iron from ferritin and to affect iron metabolism in vivo. ALA mediated iron release from ferritin, therefore, may aggravate oxidative damage to cell components and contribute to the pathology observed in AIP (eg., primary liver cancer) and lead poisoning. PMID- 7840673 TI - Cloning and expression in Escherichia coli of a novel thioesterase from Arabidopsis thaliana specific for long-chain acyl-acyl carrier proteins. AB - An Arabidopsis thaliana partial cDNA was previously identified with a sequence similar to the lauroyl-acyl carrier protein (ACP) thioesterase from Umbellularia california (Grellet et al., 1993, Plant Physiol. Biochem. 31, 599-602). Using this DNA fragment, we isolated a 1.8-kb cDNA coding for a 412-amino-acid preprotein. The deduced amino acid sequence is 51% identical to the lauroyl-ACP thioesterase but only 39% identical to safflower oleoyl-ACP thioesterase. The cDNA was expressed in Escherichia coli and the gene product showed thioesterase activity for long-chain acyl-ACPs (14:0, 16:0, 18:0, 18:1 delta 9cis). When expressed in beta-oxidation mutants of E. coli, lipid analysis revealed that cells transformed with the thioesterase produced high amounts of free fatty acids that mostly consisted of 16:0 and some 14:0, 16:1 delta 9cis, and 18:1 delta 11cis. Antibodies were raised to the recombinant protein and used to determine tissue-specific and developmental expression in A. thaliana and Brassica napus. A 40-kDa protein was detected by immunoblots in A. thaliana siliques, leaves, and roots. A maximal expression of the B. napus protein between 18 and 31 days after flowering was found, which correlates with the rapid accumulation of triacylglycerols in the seeds. Based upon these results, we suggest that this long-chain acyl-ACP thioesterase may be a ubiquitous enzyme in plants which is involved in the synthesis of long-chain fatty acids. PMID- 7840674 TI - Protein expression, selective isotopic labeling, and analysis of hyperfine shifted NMR signals of Anabaena 7120 vegetative [2Fe-2S]ferredoxin. AB - Two alternative T7 RNA promoter/polymerase systems have been employed for the heterologous expression of a plant-type [2Fe-2S]ferredoxin, Anabaena 7120 vegetative ferredoxin, in Escherichia coli at high levels (approximately 20 mg/liter of culture). One system was used when 15N-labeling the ferredoxin uniformly by growing E. coli with 15NH4Cl as the nitrogen source; the other was used in conjunction with auxotrophic host strains to enrich the protein selectively by incorporating 2H-, 13C-, and 15N-labeled amino acids. The labeled ferredoxin samples were studied by 1H, 2H, 13C, and 15N NMR spectroscopy. Results from 1H and 2H NMR studies of samples containing [2H alpha]Cys, [2H beta 2, beta 3]Cys, [13 C beta]-Cys, and [15N]Cys have confirmed previous cysteinyl proton resonance assignments (L. Skjeldal, W. M. Westler, B.-H. Oh, A. M. Krezel, H. M. Holden, B. L. Jacobson, I. Rayment, and J. L. Markley (1991) Biochemistry 30, 7363-7368). All four 13C NMR peaks arising from the four cysteinyl beta-carbons and all four 15N NMR peaks from the four cysteinyl nitrogens were resolved in spectra of both the oxidized and reduced ferredoxins. The nitrogen resonance of Cys46, which is located in a unique (Ala-Cys) dipeptide, was assigned by detection of 13Ci-15Ni+1 coupling in a ferredoxin sample with incorporated [13C']Ala and [15N]Cys. The nitrogen signal of Cys 41 was assigned tentatively on the basis of its chemical shift and T1 relaxation time. The cysteinyl beta-carbon resonances in the reduced state have been assigned to individual residues on the basis of correlations with their (previously assigned) beta-protons. The beta carbons resonance from Cys46 in the oxidized state has been assigned by its correlation with the corresponding resonance in the reduced state; this was accomplished by following the progressive air oxidation of a protein sample reduced by dithionite in the presence of methyl viologen. The spin-lattice relaxation times of the beta-carbons of the two cysteines coordinated to Fe)III) were similar in the oxidized and reduced states. This suggests that the antiferromagnetic coupling present in the reduced cluster has little influence on the electronic relaxation time of the Fe(III). Studies of the temperature dependence of the 1H, 13C, and 15N signals of the cysteinyl ligands to the [2Fe 2S] cluster show that the slope of the temperature dependence (delta delta/delta T-1) can be different for different atom types within a given residue. For example, in the reduced ferredoxin, although delta delta/delta T-1 is positive for Cys49 1H beta 2 and 1H beta 3, it is negative for Cys49 13C beta. Although delta delta/delta T-1 is negative for protons of cysteines ligated to Fe(II) and positive for protons of cysteines ligated to Fe(III), it is positive for all the cysteinyl nitrogens.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7840675 TI - Divalent cations and chelators as regulators of brain fructose-1,6 bisphosphatase. AB - Purified fish and rat brain FruP2ase(s) are stimulated by a number of chelators, viz., histidine, EDTA, citrate, imidazole, and a number of histidine analogues. These also impart 5'-AMP sensitivity to the otherwise insensitive enzyme. Beyond 3 mM concentration, histidine inhibits the enzyme activity, which can be prevented by Mn2+. Atomic absorption spectrophotometry showed the presence of 5-6 mol of Mn2+ and Zn2+ bound to both fish and rat brain FruP2ase, which can be removed by exhaustive EDTA-dialysis. The EDTA-dialyzed brain FruP2ase records an absolute Mn2+ requirement and 5'-AMP sensitivity without any chelator treatment. The 5'-AMP sensitivity of such enzyme is abolished by prior incubation with Zn2+. The Zn(2+)-treated brain FruP2ase fails to bind to a Blue-Sepharose column, in contrast to that seen using the untreated enzyme. These results suggest that rat and fish brain FruP2ase(s) are actually Mn(2+)- and Zn(2+)-containing proteins with Zn2+ bound at or near the nucleotide-binding site. PMID- 7840676 TI - Isolation and identification of a protoheme IX derivative released during autolytic cleavage of human myeloperoxidase. AB - Myeloperoxidase (MPO) is a functionally important component of the normal human neutrophil host defense system. This enzyme possesses a dimeric structure composed of two heavy-subunit/light-subunit protomers, with a heme-like prosthetic group covalently linked to each heavy subunit. Although MPO exhibits unusual spectral and enzymatic properties, the nature of the prosthetic group and its mode of linkage with the apoenzyme have not been determined. In an earlier report (K.L. Taylor, J. Pohl, and J.M. Kinkade, Jr. (1992) J. Biol. Chem. 267, 25282-25288), characterization of the autolytic cleavage of MPO led to the proposal that the prosthetic group was covalently linked to the apoenzyme via a methionyl sulfonium bond with Met409. In the present study, we have demonstrated that autolytic cleavage of MPO, followed by protease digestion under nonreducing conditions, effects the release of a macrocycle with visible and Raman spectral properties consistent with that of a protoheme IX derivative. Mass spectrometric analysis, in conjunction with metabolic labeling studies and recent X-ray crystallographic data, have led to the structural assignment of this macrocycle as 1,5-dihydroxymethyl-3,8-dimethyl-4-vinyl-2-(2'-methylthio) ethenylporphine-6,7 dipropionic acid-iron complex. Based on the mechanism of methionyl sulfonium bond cleavage, this structure is consistent with our earlier proposal that the MPO prosthetic group is covalently linked to the enzyme via a methionyl sulfonium bond and suggests that this linkage occurs through a peripheral vinyl substituent. PMID- 7840677 TI - Electromagnetic purification of endocytic vacuoles and acidosomes from Dictyostelium. AB - Earlier studies have shown that, in Dictyostelium discoideum, approximately 90% of the vacuolar proton pump (V-H(+)-ATPase) activity is present in a buoyant membrane fraction called "acidosomes." In the presence of Mg2+, acidosomes and endocytic vacuoles copurified on equilibrium sucrose gradients, suggesting their reversible association. The association depended on Mg2+ and cytosolic proteins (H. Padh et al., 1991, J. Biol. Chem. 266, 5514-5520, 12123-12126). To further characterize the putative association of acidosomes and endocytic vacuoles, cells were fed dextran-coated superparamagnetic iron colloid plus FITC-dextran to load and label their endocytic vacuoles. The endocytic vesicles were then purified approximately 20-fold at > 60% yield by their retention on a column of fine steel wire in an electromagnetic field in the absence of Mg2+. The fraction retained on a magnet column contained only about 5% of total cellular V-H(+)-ATPase and traces of other organelle markers. In the presence of 1.5 mM Mg2+, however, the retention of V-H(+)-ATPase as well as FITC-dextran was approximately 60% with only traces of contaminant markers. When such preparations were washed with buffer lacking Mg2+ while still in the magnetic field, the endocytic marker (FITC dextran) remained on the column while V-H(+)-ATPase was eluted selectively. The elute was shown by negative-stain electron microscopy to contain purified acidosomes (saccular membranes studded with V-H(+)-ATPase). The parent material, recovered from the column in the presence of Mg2+, was rich in endocytic vacuoles bearing colloidal iron. In an electron microscope, the endocytic vacuoles were often seen associated with pump-studded acidosomes. The results independently support and extend earlier observation that acidosomes and endocytic vacuoles physically associate in a Mg(2+)-dependent manner. In addition, the procedure provides a rapid method of purifying acidosomes. PMID- 7840678 TI - Different inducibility of cytochrome P-4501A1 mRNA of human and mouse by omeprazole in culture cells. PMID- 7840679 TI - Structure of the green heme in myeloperoxidase. AB - A 3-A-resolution X-ray crystal structure of canine myeloperoxidase has previously revealed the overall structure of the molecule, including the polypeptide backbone conformation, but did not provide an unambiguous structure for the covalently bound heme. A higher resolution (2.28 A) X-ray crystal structure of human myeloperoxidase has now shown that the heme is a novel derivative of protoporphyrin IX in which three ring substituents form covalent bonds with amino acid side chains in the protein. Modified methyl groups on pyrrole rings A and C form ester linkages with glutamate 242 and aspartate 94, while a covalent bond between the vinyl group on ring A and the sulfur atom of methionine 243 results in a sulfonium ion linkage. The heme tetrapyrrole ring also shows considerable distortion from the planar conformation seen in most heme-containing proteins. The observed bending appears to result from these covalent bonds between diametrically opposed pyrrole rings A and C and the protein. Sequence comparisons suggest that the two ester linkages to the heme may also occur in other homologous mammalian peroxidases, but that the sulfonium ion linkage may be a unique feature of myeloperoxidase. PMID- 7840680 TI - Reactive oxygen species produced by liver mitochondria of rats in sepsis. AB - Reactive oxygen species (ROS) can be generated in experimental shock states through several different mechanisms. We measured ROS production in metabolically active liver mitochondria from rats rendered septic by cecal ligation and puncture. By polarography, the State 4 and State 3 respiration rates of liver mitochondria isolated from septic animals were no different from control organelles. During oxidation of succinate, however, nonenzymatic hydroxylation of salicylic acid to 2,3-dihydroxybenzoic acid by mitochondria from septic rats was increased, indicating generation of hydroxyl radical (OH.). Inhibition of electron transport at Complex I with rotenone had no effect on this pattern of OH. production, but rotenone and cyanide abolished the differences in OH. formation between control and septic liver mitochondria. Measurements of H2O2 release suggested that septic mitochondria will increase rates of H2O2 production in the presence of succinate. Additional investigations revealed no difference in the release of iron between septic and control mitochondria. When referenced to respiration rate, both OH. and H2O2 production were greater in septic liver mitochondria. The reproducible effect of sepsis on generation of reactive oxygen species by liver mitochondria utilizing FAD-linked but not NAD-linked substrates suggests that enhanced mitochondrial oxidative stress in sepsis is related to alterations in the activity of Complex II of the electron transport chain. PMID- 7840681 TI - Distinct systems mediate the unidirectional efflux of methotrexate and cholate in human CCRF-CEM cells. AB - Human CCRF-CEM cells were shown to contain energy-dependent and unidirectional efflux systems for the extrusion of methotrexate and cholate. Efflux activity was sensitive to temperature and to energy deprivation by treatment with antimycin A and to various other compounds which do not affect energy metabolism. A comparison of inhibitor sensitivities revealed that methotrexate and cholate efflux exhibit substantial differences in half-maximal inhibition (IC50) by indomethacin, reserpine, ethacrynic acid, ketoprofen, probenecid, and bromosulfophthalein, although these systems could not be distinguished by their responses to prostaglandin A1, meclofenamic acid, indoprofen, and biphenylacetic acid. Comparisons between cell lines showed that methotrexate efflux in CCRF-CEM cells exhibits an inhibitor response comparable to a secondary efflux system for methotrexate in L1210 cells (system II), whereas the inhibitor response of cholate efflux in CCRF-CEM cells resembles efflux system I in L1210 cells, the primary efflux route for both methotrexate and cholate. These results indicate that CCRF-CEM cells contain similar but separate systems for the efflux of methotrexate and cholate. CCRF-CEM cells thus differ from L1210 cells in that the latter mediate the efflux of methotrexate and cholate primarily via a single system. PMID- 7840682 TI - Dynamics of xanthine oxidase- and Fe(3+)-ADP-dependent lipid peroxidation in negatively charged phospholipid vesicles. AB - Superoxide (O2-)-dependent lipid peroxidation on addition of xanthine oxidase (XO) and Fe(3+)-ADP was induced in egg phosphatidylcholine (PC) liposomes containing dicetylphosphate (DCP), which are negatively charged like biological membranes, but not in uncharged egg PC liposomes. Positively charged Fe(3+)-ADP interacted more with negatively charged egg PC-DCP liposomes than with uncharged egg PC liposomes. The activities of Fe(3+)-chelates for initiating O(2-) dependent lipid peroxidation were in the order Fe(3+)-ADP > Fe(3+)-citrate > Fe(3+)-oxalate = Fe(3+)-malonate > Fe(3+)-EDTA = 0. This order was the same as that for the reduction rates of these Fe(3+)-chelates to Fe(2+)-chelates by O(2-) generated by XO. Lineweaver-Burk plots showed that the chelators inhibited XO by different mechanisms: uncompetitively by ADP and adenosine and non-competitively by organic acid chelators (citrate and oxalate) and EDTA. These results suggest that ADP interacts with XO in a manner different from the other chelators. Lipid peroxidation by XO-xanthine and Fe(3+)-ADP was induced in egg PC liposomes containing a trace (0.31-0.35 mol%) of peroxidized egg PC (PC-OOH), but not in PC OOH-free liposomes of egg PC obtained by their pretreatment with triphenylphosphine. PC-OOH incorporated into dimyristoyl phosphatidylcholine (DMPC) liposomes was degraded on addition of both XO-xanthine and Fe(3+)-chelate, but not of either one alone. alpha-Tocopherol in DMPC liposomes was oxidized on addition of XO-xanthine and Fe(3+)-chelates in the presence, but not in the absence of PC-OOH. Furthermore, PC-OOH was required for decrease of the ESR spectrum of the spin probe 12-(N-oxyl-4,4'-dimethyloxazolidin-2-yl)stearic acid, which labels the hydrophobic region of egg PC liposome membranes, on addition of XO-xanthine and Fe(3+)-chelates. These results indicate that the "induction message of lipid peroxidation," which is associated with reduction of Fe(3+)-ADP by O2- and concurrent degradation of PC-OOH, must be transferred from the membrane surface to the inner hydrophobic region of the membranes. PMID- 7840683 TI - Mn(2+)-activated luminescence of the photoprotein obelin. AB - The light emission of obelin may be initiated by Mn2+ under alkaline conditions. The luminescence takes place in a pH range from 7 to 12 with a sharp optimum at 11.75. The first-order rate constant for Mn(2+)-activated luminescence decay is more than 9 s-1, while that for Ca(2+)-activated luminescence decay is only 6.9 s 1. The Mn2+ concentration-effect curve for obelin determined with simple dilutions of manganese salt is a sigmoid curve. The slope of the curve is moderately dependent on the pH and was not more than 1 within the pH range tested. The maximal light emission, which is initiated by 3.6 x 10(-5) M Mn2+ at pH 11.75 was about 10% of the maximal Ca(2+)-activated luminescence. Mg2+ ions inhibit the Mn(2+)-activated luminescence of obelin. The addition of OH. and O2- scavengers did not influence the Mn(2+)-activated luminescence, but when singlet oxygen quenchers were added, the Mn(2+)-dependent light emission was inhibited. This suggests that the 1O2 might be formed and itself be responsible for chromophore oxidation attended with light emission. NEM and Na2S2O4 inhibit the Mn(2+)-initiated light emission of obelin completely, showing that endogenous hydroperoxide and SH-group(s) of the photoprotein are essential for both Ca(2+) activated and Mn(2+)-activated light emission of obelin. PMID- 7840684 TI - New ways in public health? PMID- 7840685 TI - A highly efficient in vitro cloning procedure for asexual erythrocytic forms of the human malaria parasite Plasmodium falciparum. AB - A very reliable and productive technique for cloning of Plasmodium falciparum in vitro is proposed, as demonstrated by successive limiting dilution of suspensions of asexual erythrocytic forms of the NF 54 strain. The introduction and the study of reliable clones is of extreme importance for a better understanding of the behaviour of the parasite, also in field conditions. The method is rapid, simple and efficient. The growth of the clones was individually monitored and the culture conditions were constantly adjusted during their stay in recipients of increasing size. A yield of 18/96 (18.75%) of provisional clones was obtained, while the supercloning phase resulted in 16/80 (20%) positive cultures. The probability that the latter were derived from a single progenitor is very high (99%). It was shown that three randomly selected clones (A1A9, A1B11, and A1C10) have excellent growth characteristics before and after cryopreservation, and after a longer period of culture in standard conditions. PMID- 7840686 TI - [Aspects of the enzymatic evaluation in Plasmodium falciparum malaria infection]. AB - To try to find effects of malaria on clinical serum activity of certain enzymes, 3 groups of infants--malarial, asymptomatic carrier and normal controls--have been designed. Parasitologic data have been compared with serum concentration of lactate dehydrogenase (LDH), Hydroxybutyrate dehydrogenase (HBDH) alanine aminotransferase (ALT), gamma glutamyl transferase (GGT) and 5'nucleotidase (5'Nu). Results show that only LDH and HBDH are significantly increased. Respective coefficients of correlation r = 0.32 (p < 0.05) and r = 0.39 (p < 0.01) show that increasing in LDH and HBDH are linked to malarial parasite density. LDH and HBDH increasing might therefore constitute a marker of malaria. PMID- 7840687 TI - [Cerebral malaria in children in Yaounde, Cameroon. Clinical, paraclinical and developmental aspects]. AB - Cerebral malaria is one of the major and deadly complications of malaria. In Cameroon, recent reports indicate that severe cases of malaria are increasingly more prevalent, particularly in children. The present study aims at describing the clinical presentation and laboratory findings of cerebral malaria in children in Yaounde. All patients admitted in the paediatric ward of Yaounde Central Hospital with malaria, who presented neurological signs and were tested positive for Plasmodium in their peripheral blood were recruited into the study. 36 cases were enrolled in all, making up 2.7% of all admissions. The patients' median age was 4.5 years. 52.8% were on malaria prophylaxis. Convulsions and coma with preceding hyperthermia were present in more than 90% of the patients. Blood parasites level median was 1.3% on admission. One patient had hypoglycaemia on admission and two others had it later on after admission; 16.7% had neurological sequels at discharge and two children died (5.6%). Delay in diagnosis and initiation of treatment with quinine adversely affected the prognosis of cerebral malaria in the study group. PMID- 7840688 TI - [Control of Trypanosoma gambiense trypanosomiasis. Evaluation of a strategy based on the treatment of serologically suspected cases with a single dose of diminazene]. AB - A novel method for the control of T.b. gambiense trypanosomiasis was evaluated in an endemic focus of Zaire where a high incidence had persisted despite massive participation in active case-finding surveys based on lymph node puncture. All inhabitants of 3 villages were examined with a card agglutination serological test (CATT), and parasitological examinations were performed on those who were CATT+. Individuals in whom we detected trypanosomes were treated as usual. A lumbar puncture was carried out on CATT+/parasitology- subjects; those whose cerebrospinal fluid showed more than 3 white blood cell (WBC) per mm3 were treated with a full course of melarsoprol while those with a CSF WBC count between 1 and 3 per mm3 were given a single injection of diminazene (7 mg/kg). Three such surveys were performed, with a 6-month interval, during which 282 "serological suspects" received diminazene, 39 "clinical cases" were given melarsoprol and 82 "parasitological cases" were treated according to standard protocols. The annual incidence of trypanosomiasis decreased rapidly from 10.4 41.1/1.000 inhabitants (mean: 17.6/1.000) during the 10 years before the intervention to 1.1-2.6/1.000 (mean: 1.7/1.000) in the 3 years following the intervention. No major adverse effect was seen with diminazene. Among the 282 serological suspects, an elevated CSF WBC count was later documented in 12 individuals, who were all cured with melarsoprol. The incidence increased 5 years after the intervention (7.1/1.000 in 1992), which may have been avoided had we carried out similar interventions in adjacent foci. PMID- 7840689 TI - [Dengue 1 epidemic in the Grand Comoro Island (Federal Islamic Republic of the Comores). March-May 1993]. AB - An epidemic of dengue fever occurred in Grande Comore island from March to May 1993. Dengue 1 virus has been isolated. The epidemic did not affect the other islands of the archipelago. No compound clinical picture, in particular hemorrhagic, was reported. A random sampling survey conducted towards the end of April showed that 26% of the population aged 5 years old or more had IgM dengue antibodies. The epidemic concerned essentially individuals under 45 years of age. The number of inhabitants of Grande Comore affected by the outbreak can be estimated between 56,000 and 75,000. The results of the sero-epidemiological survey allowed to find the serological scar of two previous epidemics of dengue: the first one around 1948, which may correspond with dengue 1, the other one in 1984, probably with dengue 2. PMID- 7840690 TI - [Evaluation of the use of diagnostic/treatment algorithms in the health centers of North Cameroon]. AB - In February 1993, four years after their introduction, an assessment was made of the use of clinical flow charts (algorithms) by 16 nurses in charge of primary medical health centers in Northern Cameroon (Diamare Division, Far North Province). A study of the knowledge, attitude and behaviour of the nurses shows the flow charts to be appreciated as a tool for diagnostic aid and for professional training. 11 nurses report an initial systematic use of the flow charts. This associates with the observation of good skills in using the charts, observed among 10 of the nurses, and also with treatment standardisation. Problems in reading the flow charts correctly hinder their systematic use in diagnostic decision making. A retrospective analysis of 800 treatment prescriptions noted in the consultation registers, shows an average rate of treatment standardisation of 75%, varying from 52 to 98% among the different health centers. Three quarters of non standardised treatment is ineffective or inefficient. Specific training is using the flow charts, given in the form of a 4 day seminar to 7 of the nurses concerned, showed no better results, after 4 years, than those obtained during a practical training session of a global nature, taking place in a functional health centre. Basic professional training, as well as previous professional experience influences the performances of the nurses. This study confirms the need to introduce rationalisation in the prescription of treatment, and shows the importance of verifying practical user skills at the end of specific training sessions. It would be advisable to include the principles of clinical algorithms in the teaching programs of medical schools. PMID- 7840691 TI - Increasing number of AIDS cases, mostly caused by HIV-1 infection, in Dakar (Senegal). PMID- 7840692 TI - Recent Advances in Treatment of Severe Cardiac Failure. Symposium proceedings. Sweden, March 3-4, 1994. PMID- 7840693 TI - Physiologic aspects in postoperative cardiac patients. AB - After a cardiac operation, there is reversible myocardial dysfunction that also involves a metabolic disorder. In patients with cardiac failure, care must be taken to reduce the strain on the heart by minimizing systemic oxygen uptake, which is, in fact, the main determinant of cardiac output. Inotropic support may improve cardiac output and tissue oxygenation in cardiac failure, but it also increases myocardial stress directly by increasing myocardial demands and indirectly by increasing systemic energy demands. Mixed venous oxygen saturation reflects the balance between cardiac output and systemic oxygen consumption and indicates whether cardiac output can adequately provide the peripheral tissues with oxygen. This physiologic view toward the treatment of postoperative cardiac failure helps us avoid overtreatment, that is, stimulating cardiac output more than necessary for adequate tissue oxygenation. In this way, the strain on the heart can be reduced and myocardial recovery, enhanced. PMID- 7840694 TI - Rationale for metabolic support with amino acids and glucose-insulin-potassium (GIK) in cardiac surgery. AB - Myocardial metabolism and the current state of metabolic intervention under conditions relevant to cardiac surgery are reviewed. The rationale for metabolic support differs considerably in various settings of cardiac surgery. Although preventive measures are theoretically attractive, their use in the preoperative setting remains to be clarified. Amino acid enrichment of blood cardioplegia seems to be justified by an abundance of animal experimental data. In the postoperative setting of cardiac surgery, metabolic abnormalities may explain reversible myocardial dysfunction. Further, the combined effects of ischemia and the systemic neuroendocrine response to surgical trauma may adversely affect recovery. Amino acids, particularly glutamate, seem vital for metabolic recovery in this setting. Treating the relative shortage of glutamate occurring during this period by the administration of exogenous glutamate and counteracting the effects of the systemic neuroendocrine stress response by high-dose glucose insulin-potassium are measures that have been shown to improve the metabolic state of the heart and subsequently myocardial performance. PMID- 7840695 TI - Glutamate and high-dose glucose-insulin-potassium (GIK) in the treatment of severe cardiac failure after cardiac operations. AB - Postischemic derangement of myocardial metabolism that is further aggravated by the systemic neuroendocrine response to surgical trauma may explain reversible myocardial dysfunction after cardiac surgical procedures. Since 1991, all patients with signs of cardiac failure after operation for ischemic heart disease (45/515 patients) were treated according to our metabolic strategy. Sixteen patients in whom we previously would have considered use of an intraaortic balloon pump were treated by prolonged unloading of the heart with cardiopulmonary bypass, by glutamate infusion, and by high-dose glucose-insulin potassium. Rapid improvement in hemodynamic performance was seen in the first hour and almost full recovery within 6 hours in the surviving patients (12/16). None of the 3 patients requiring mechanical assist survived. Our early clinical experience suggests that metabolic support with glutamate and high-dose glucose insulin-potassium is a safe treatment with a high success rate in reversible cardiac failure. PMID- 7840697 TI - New technologies in the treatment of severe cardiac failure: the Texas Heart Institute experience. AB - Various mechanical alternatives for the treatment of severe cardiac failure are currently in clinical use, and new mechanical devices are under preclinical and clinical investigation in laboratories around the world. These devices include the intraaortic balloon pump, left heart bypass pumps, left ventricular assist devices, and total artificial hearts. I describe briefly the devices and their applications with which my colleagues and I at the Texas Heart Institute have had experience. PMID- 7840696 TI - Treatment of perioperative low cardiac output syndrome. AB - New approaches to the treatment of perioperative low cardiac output are considered. In particular, use of the phosphodiesterase III inhibitors and their cardiovascular actions are reviewed and contrasted with those of conventional inotropic agents. The increasing recognition of right-sided dysfunction is highlighted, and appropriate therapeutic strategies are considered. The increasing role of pulmonary-specific vasodilators such as inhaled nitric oxide is emphasized. Strategies to preserve right heart perfusion while producing pulmonary vasodilatation are discussed. PMID- 7840698 TI - Clinical use of the Hemopump cardiac assist system for circulatory support. AB - We have used the Hemopump in 15 patients in whom weaning from cardiopulmonary bypass was unsuccessful. The median time for the patients having the device on was 1.6 days postoperatively. They spent an average of 6 days in the intensive care unit and had a total hospital stay of about 17 days. Nine of 15 patients (60%) survived and were able to leave the hospital. There were some reversible decreases in kidney function in all patients, but none of them needed hemodialysis. Coronary artery bypass grafting supported by the Hemopump instead of cardiopulmonary bypass and with the use of a short-acting beta-blocker, esmolol, was carried out successfully in 12 patients. In this method the blood is oxygenated by the patient's lungs and the heart is perfused with its own warm blood. The Hemopump supports the circulation and if the patient needs circulatory support after the operation, a left ventricular assist device is already in place. There were no device-related complications apart from two initial cable fractures. The Hemopump fits well in the intensive care unit environment; it is silent, and the management of the console is easily learned. The Hemopump has shown to be an effective and safe tool for unloading the left ventricle while maintaining multiorgan perfusion. There are several potential applications for surgeons and cardiologists. PMID- 7840699 TI - HeartMate implantable left ventricular assist device: bridge to transplantation and future applications. AB - The HeartMate implantable left ventricular assist device (LVAD) is approaching the time when it will be implanted permanently. Experience with the HeartMate 1000 IP LVAD at the Cleveland Clinic as a bridge to heart transplantation in 21 patients has shown (1) excellent hemodynamic function [improving cardiac index from a mean +/- standard deviation of 1.6 +/- 0.26 L.min-1.m-2 to 3.0 +/- 0.42 L.min-1.m-2]; (2) 81% survival before transplantation with a mean duration of 64 +/- 34 days of LVAD support; (3) 100% survival after transplantation; (4) New York Heart Association class IV and moribund patients were returned to class I or II status while on the LVAD; and (5) a remarkably low risk of thromboemboli during 1,583 patient-days of support. The multicenter experience (173 patients) confirms the low risk of embolic events (2%, including septic emboli). A "target population" for initial use of the permanent device was outlined from a retrospective review of 570 patients. A subgroup of 74 patients (13%) were between 18 and 75 years of age, had isolated cardiac failure (without multiple comorbidities), and required inotropic medications, intraaortic balloon pump support, or both. Survival for this patient group (mean age, 57 +/- 13 years; 68% male) was poor: median survival was 7 months, 21.6% died during the hospitalization, and 47.3% died after discharge. Of the survivors, only 4 patients (5% of the initial 74 patients) were in New York Heart Association class I. From the bridge-to-transplantation experience we extrapolate that survival and quality of life should improve for patients in the target population treated with the portable LVAD.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7840700 TI - The Linkoping-Lund surgical experience with the HeartMate left ventricular assist system. AB - Four transplant candidates fulfilling the Food and Drug Administration criteria for a permanent left ventricular assist device received a pneumatic HeartMate system as a bridge to heart transplantation. All patients survived and were fully rehabilitated at the time of transplantation, which was carried out 2 to 6 months after the initial operation. There were no major complications associated with the procedures. We are impressed by the effectiveness and safety of the device. PMID- 7840701 TI - Mechanical circulatory support: the Bad Oeynhausen experience. AB - From September 1987 to February 1994, we treated 147 patients ranging between 11 and 82 years old with different mechanical circulatory support systems. The applied devices were the Bio-Medicus centrifugal pump in 61 patients, the Abiomed BVS System 5000 in 49 patients, the Thoratec ventricular assist device in 42 patients, and the Novacor left ventricular assist device in 7 patients. On the basis of indication for mechanical circulatory support, the patients were divided into three groups: group 1 consisted of 72 patients with postcardiotomy cardiogenic shock; group 2, 50 patients in whom mechanical support was used as a bridge to cardiac transplantation; and group 3 (miscellaneous), 25 patients in cardiogenic shock resulting from acute myocardial infarction (n = 14), acute fulminant myocarditis (n = 3), primary graft failure (n = 2), right heart failure after heart transplantation (n = 3), and acute rejection (n = 3). Time of support ranged from 1 hour to 97 days (mean duration, 10.8 days). Seventy-five patients (51%) were discharged from the hospital. The best survival rate was achieved in group 2 with 72%, followed by group 1 with 44% and then group 3 with 28%. The most frequent complications in group 1 were bleeding (44%), multiple-organ failure (24%), neurologic disorders (18%), and acute renal failure (15%). In group 2, the major complications were bleeding (34%) and cerebrovascular disorders (22%) and in group 3, multiple-organ failure and sepsis (60%) and bleeding (32%). PMID- 7840702 TI - [A new look at the mechanism of action of antibiotics of the tetracycline series. Tetracyclines as components of radical-generating systems]. AB - Tetracyclines were shown to be able to form radical-generating systems and to affect biological structures at the account of the radical form generation. The radical-generating systems were found to be based on the phenomenon revealed in this study that the tetracyclines catalyzed oxidation of ferrous oxide by oxygen after its binding by these compounds. In the presence of ascorbate the radical formation with the involvement of oxygen could be continuous and accompanied by reduction of ferrous oxide by ascorbate in complex with tetracyclines and its subsequent oxidation as well induced by them. Ca2+ and Mg2+ forming complexes with tetracyclines had no impact on the radical formation. In complex with tetracyclines the ions did not interfere with the tetracycline ability to catalyze oxidation of ferrous oxide after its binding by these compounds. A notion of two functional centres characteristic of tetracyclines was formulated. One of them (chelating) provided the tetracycline binding to Mg2+ and Ca2+ e.g. in ribosomes and the other (toxic) affected the surrounding biological structures by the radical formation. PMID- 7840703 TI - [Small peptides with antibiotic activity]. AB - Peptide dKRFdLE showed in vitro stable activity against gram negative bacteria i.e. Escherichia coli and Pseudomonas fluorescens when grown on the minimum glucose-mineral medium. Substitutions of the N- and C-end amino acids in the molecule of the peptide decreased its antibiotic activity. Comparison of the amino acid sequences of the known peptides with antibiotic activity made it possible to conclude that the presence of the doublet of the basic amino acids at the N-end and the doublet of the hydrophobic amino acids in the peptide core is necessary for the antibiotic activity. Possible mechanisms of the antibiotic action of short peptides and the ways for the rational search of new peptide antibiotics are discussed. PMID- 7840704 TI - [Beta-lactam antibiotics (ampicillin, cefotaxime) in prevention of experimental plague in albino mice, caused by non-fractioned strains of the pathogen]. AB - The prophylactic action of betalactam antibiotics such as ampicillin and cefotaxime in plague was studied on albino mice infected subcutaneously by Fra+ (Y. pestis 231) and Fra- (Y. pestis 231 Fra-, K-16) variants of the plague microbe. Ampicillin, a semisynthetic penicillin, was prophylactically less active in experimental plague infection induced by the fraction I defect forms of Y. pestis. Cefotaxime, a 3rd generation cephalosporin, was active in experimental plague induced by both the type and the fraction-free strains of Y. pestis. PMID- 7840705 TI - [Comparative study of anti-tumor activity of the monoglucosides protopanaxadiol and betulafolientriol]. AB - Antitumor and cytotoxic activity of monoglucosides such as 3-0-panaxadiol (1), 12 0-panaxadiol (2) and 20-0-panaxadiol (3) and 3-0-betulafolientriol (4), 12-0 betulafolientriol (5) and 20-0-betulafolientriol (6) was studied. It was found that in concentrations of 10 to 50 micrograms/ml the above monosides induced marked impairment of the selective permeability of the tumor cells and the inhibition of the labeled precursor inclusion into the macromolecule biosynthesis. Administration of the monosides in a single dose of 100 mg/kg 24 hours after the inoculation of the Ehrlich tumor cells resulted in prolongation of the mean life-span of the mice by 144 per cent (1), 153 per cent (2), 144 per cent (3), 125 per cent (4), 133 per cent (5) and 178 per cent (6). A significant reduction of the tumor mass was observed at the early stages of the tumor development and later the tumor progress intensively resumed. The tests for the effect of the monoside-activated macrophages on the growth of the tumor cells showed that production of the growth factors by the macrophages was stable and had a negative action on the efficacy of the chemotherapy with the monoglucosides. PMID- 7840706 TI - [Effect of cyclosporin on various metabolic processes in fungi]. AB - Sensitivity of the representatives of Aspergillus and Piricularia to various concentrations of cyclosporine (in the submerged culture) was studied for choosing the test object for the subcellular investigation of the mechanism of the cyclosporine antifungal action. Changes in the main physiological and biochemical parameters of the fungal cells under the action of cyclosporine in concentrations of 10 to 80 micrograms per 1 ml of the medium were characterized. Low concentrations of cyclosporine (10 to 20 micrograms/ml) did not inhibit the growth of Aspergillus niger but induced stimulation of the growth processes. Only at a concentration of 80 micrograms/ml the inhibitory effect was observed. At the same time there was detected a dramatic stimulation of the culture respiration via the basic respiration chain. In the culture of Piricularia oryzae only inhibition of the culture growth even at the minimum concentration of cyclosporine (10 micrograms/ml) was recorded. Both the cyclosporine sensitive test objects i.e. A. niger and P. oryzae had an alternative cyanide resistant system of the electron transport. In the experiments with A. niger the cyclosporine effect on the synthesis of protein and RNA was revealed. The study provided data on the changes in the morphogenesis of the A. niger cells under the effect of cyclosporine. PMID- 7840707 TI - [Evaluation of the potential of chemotherapy of glanders caused by Pseudomonas mallei strains resistant to sulfanilamides and trimethoprim]. AB - A sulfanilamide resistant strain Ts-5 of Pseudomonas mallei was isolated in the experiments on sulfazine therapy of malleus. The spectrum and level of the strain cross resistance to sulfanilamides and trimethoprim were studied. The frequency of the SurTrr mutants of P. mallei was determined. Efficient antibacterial drugs for the therapy of malleus caused by the sulfanilamide resistant strain are recommended. PMID- 7840708 TI - [Operation of biological systems for sewage treatment intensified by active oxygen]. AB - The results of the study on the treatment of sewage containing high concentrations of hardly oxidizable organic compounds are presented. The procedure for the sewage treatment is highly efficient because of interaction of the resultant active oxygen with both the pollutants and the microorganisms providing the sewage treatment. PMID- 7840709 TI - [Antibiotic prophylaxis and reconstructive operations in patients with burn sequelae]. AB - The results of the clinicolaboratory investigation of the efficacy of antibiotic prophylaxis in 215 patients subjected to reconstructive operations for postburn scars are presented. The biological investigation of the postburn scars revealed the presence of microflora in about half of the patients. The microflora was mainly represented by Staphylococcus aureus and S. epidermidis. The level of the dissemination was not high. Ulcerated scars had higher levels of the bacterial contamination. The pharmacokinetic study of cefazolin, carbenicillin, aztreonam and gentamicin showed that the release of the first three drugs to the scar tissues was good. The clinical observations demonstrated that purulent inflammatory complications developed in patients with risk factors (ulceration of the scar, necrotic foci in the wound, involvement of the oral cavity and nasal passages to the operation), not treated with the antibiotics or treated with the drugs not inhibiting the microflora of the operation wounds (gentamicin, aztreonam). The results permitted to recommend the use of the antibiotic prophylaxis in reconstructive operations only in risk patients with burn consequences. With this purpose it is advisable to use antibiotics satisfactorily penetrating to the tissues of the postburn scars and active against the microflora vegetating in them (cefazolin and carbenicillin). PMID- 7840710 TI - [Clinico-pathogenetic substantiation of comprehensive therapy of Klebsiella infection with the syndrome of water diarrhea in infants]. AB - The data on the examination of 70 infants with Klebsiella infection are presented. The patho-chemical disorders in the intestine under the action of Klebsiella were followed up in the time course and the adequacy of the pathogenetic therapy of the antiinflammatory and membrane protective destination was substantiated. The efficacies of the comprehensive therapy with the use of indomethacin, essential and dimephosphone and the therapy with antibacterial drugs such as monomycin, kanamycin, polymyxin and gentamicin administered orally were compared. The laboratory investigations, pharmaco-immunologic tests and clinical time course observations demonstrated the preference of the pathogenetic therapy of the patients with Klebsiella infection at the early stages of the watery diarrhea syndrome, when the functional disorders at the cellular level prevailed over the structural-and-morphological ones. In cases with complications the combined use of the pathogenetic and antibacterial drugs was more efficient. PMID- 7840711 TI - [Use of oral macrolide and azalide antibiotics in children with bronchopulmonary diseases]. AB - The therapeutic efficacy of oral macrolides (erythromycin base and midekamycin, macropen) and azalides (azithromycin, sumamed) in the treatment of children with acute and chronic (during the aggravation) bronchopulmonary diseases was studied. The main etiological factors of acute and chronic pneumonia were Streptococcus pneumoniae and Haemophilus influenzae. The proportion of Staphylococcus aureus was high in infants with acute pleuropulmonary inflammations. The susceptibility of the isolates to the antibiotics was found to be high. The results of the trials showed that erythromycin, macropen and azithromycin were efficient in the treatment of acute and chronic pneumonia. The foci of acute pneumonia dissolved after oral administration of the drugs within the same periods as after the use of other parenteral antibiotics. The comparative estimation of the drug efficacy revealed that azithromycin was more active. The ease of the azithromycin administration (in the form of a suspension) in infants and children once a day for a shorter treatment course up to 5 days, high efficacy and no adverse reactions permitted to consider the antibiotic as the most promising antibacterial agent for the treatment of respiratory infections in children in hospitals and outpatient departments. PMID- 7840712 TI - [Itraconazole in the treatment of ophthalmomycoses]. AB - The method and results of the use of itrakonazol, a new antifungal agent of the imidazol class, in the treatment of fungal diseases of the eye are described. The clinical trials involved 50 patients with various clinical forms of ophthalmomycosis: 27 patients with fungal affection of the cornea, 3 patients with fungal endophthalmitis, 8 patients with fungal canaliculitis, 3 patients with fungal blepharitis and 9 patients with fungal conjunctivitis. The clinical trials showed that itraconazole had a sufficiently high antifungal activity in the treatment of the ophthalmomycoses. The drug is low toxic and well tolerated. PMID- 7840713 TI - [Causes and significance of micro-ecologic disorders of the digestive system]. PMID- 7840714 TI - [The evolution of sphygmomanometry]. PMID- 7840715 TI - [Ketorolac protection in damage due to myocardial ischemia and reperfusion]. AB - This study shows that the nonsteroidal anti-inflammatory drug. Ketorolac, has an ionophore-like action for calcium, such a drug may transfer calcium through an hydrophobic phase. This property does not affect the respiratory rate of mitochondria. These results indicate that the ionophoretic effect is not due to an uncoupling action of Ketorolac. The effect of this compound was tested in a reperfusion model where it was observed that Ketorolac (1 mg/Kg weight) administered 30 min before an ischemic period was induced, reverts the arrhythmic effect of reperfusion. These results are in agreement with the analysis of the plasmatic concentrations of the enzymes creatine kinase and lactic dehydrogenase. It was found that the levels of such enzymes were lower in Ketorolac treated group, than in the untreated one. The results clearly indicate that Ketorolac prevents from the myocardial damage induced by reperfusion, probably by avoiding calcium overload in myocytes. PMID- 7840716 TI - [Takayasu's arteritis. A seroimmunological test of its relationship to mycobacterial infection]. AB - Takayasu's arteritis is an inflammatory arteritis of unknown origin. It affects the aorta, its main branches and at times the pulmonary artery. Takayasu's arteritis is a worldwide disease, however, there is predilection to affect young women of mongoloid ancestry, therefore most cases do occur in the Far East and Latin America. For more than 50 years a relationship with mycobacterial infection has been sought without definite proof. In this investigation we found a circulating IgG antibody in the sera of Takayasu's arteritis patients, which recognizes a 38 kD glycoprotein of M. tuberculosis. This glycoprotein is an specific antigen in the human immune response against mycobacterial infection. PMID- 7840717 TI - [Morphofunctional correlation in congenital anomalies of the coronary arteries. II. The ectopic origin of the coronary arteries]. AB - The authors describe the morphogenesis and functional alterations of the coronary arterial net in the ectopic coronary arteries: a) with origin in the aorta or its branches and b) with origin in the pulmonary artery. The coronary arteries are developed from: 1) endothelial sprouts localized in the great arteries walls at the level of the sigmoidal values, 2) right and left subepicardial vascular network and 3) the intramyocardial sinusoids. Most of the ectopic coronary arteries result from alterations in the connection between these three embryonic elements. The deviation of one of the subepicardial vascular network in a wrong way (in direction of pulmonary artery or the opposite Valsalva sinus) will stimulate the development of endothelial sprouts which will connect such network originating abnormal connections and anomalous origin of the coronary arteries. The origin of both coronary arteries from the pulmonary artery is in compatible with life. Myocardial ischemia is absent in patients with type I (infant) or type II (adult) anomalous origin of one coronary artery from the pulmonary artery, only in the transitional phase between both types (I and II) there is myocardial ischemia previous to the formation of the collateral coronary circulation. The ectopic origin of the coronary artery from the aortic Valsalva sinus have very little hemodynamic repercussion in the patient. Although there are cases with postexercise sudden dead. These anomalies associated to atherosclerotic coronary stenosis have an impact on the evolution and prognosis of ischemic heart disease. PMID- 7840718 TI - [Radiofrequency ablation in tachycardias due to accessory pathways in a pediatric population]. AB - Catheter ablation of accessory atrioventricular pathways using radiofrequency current was attempted in 61 children and young adolescents less than 18 years of age who were referred for treatment of symptomatic supraventricular tachycardia. Thirty-three children had the Wolff-Parkinson-White syndrome and 30 tachyarrhythmias related to an accessory pathway conducting only in retrograde fashion. Ablation of left sided accessory pathways was usually attempted utilizing an arterial approach to the annulus of the mitral valve, only in one case we used the transseptal approach, while the venous route to the atrial aspect of the tricuspid valvular annulus was chosen for right sided accessory connections. Ablation of 55 of 63 accessory connections was achieved (87% success) with a range of 1 to 42 applications of radiofrequency current. The sessions were completed within 19 to 180 minutes, and we used within 16 to 45 watts of radiofrequency current. Two patients had complications as a result of their ablation procedure. One patient had complete heart block but did not require pacemaker implantation, and other one had mitral regurgitation. A second session was necessary in three patients, two of three accessory pathways were ablated, giving a success rate of 90%. During a one year period of follow-up, we had 4 recurrences (7.2%). Catheter ablation using radiofrequency current is a highly effective and safe curative approach for treating young patients with supraventricular tachycardia mediated by accessory pathways. PMID- 7840719 TI - [The echo-dobutamine pharmacological stress test in ischemic cardiopathy]. AB - We report our experience with Echo-Dobutamine stress test. In order to evaluate the sensitivity, specificity and the safety, of the pharmacologic echo-dobutamine stress test, we studied 30 patients with ischemic heart disease based on clinical history, 2D echocardiogram, standard exercise stress test and cardiac catheterization. The test was started under continuous videotape of the segmental left ventricular motility on the conventional views. Dobutamine was administer intravenously 2.5 to 40 micrograms/kg/min every 3 minutes, the mean higher dobutamine dose was 19 +/- 14.3 micrograms/kg/min, having a continuous electrocardiographic monitoring of the heart rate as well as blood pressure. The myocardial motility was recorded with each increment in the dobutamine dose. Among the cases, 22 were males and 8 females with an average age of 55 +/- 9 years. Twenty two patients had history of remote myocardial infarction and were asymptomatic at the moment of the test; 8, who had angina pectoris were on a functional class I-II of the CCS. The mean basal ejection fraction was 62.6 +/- 11.7% by echo vs 64.4 +/- 16.8% obtained by cardiac catheterization (p no significant). There were no arrhythmias in any case. The heart rate increased from 68.7 +/- 10.1 to 85.5 +/- 15.7 beats per minute (p < 0.001). The systolic B/P was increased from a mean of 124 +/- 14.5 to 138.3 +/- 14.4 mmHg (p < 0.0005) while the diastolic pressure varied from 82.3 +/- 8.2 to 90.8 +/- 9.6 mmHg (p < 0.001). There were no severe complications.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7840720 TI - [Acute myocardial infarct in the puerperium. A case report and review of the literature]. AB - The occurrence of myocardial infarction during a pregnancy is rare event and it is even less frequent during the puerperium. The literature reports only 23 cases of myocardial infarction during the puerperium. We report a case of a woman of 26 years of age without coronary risk factors, who on the seventh day postpartum presented an acute myocardial infarction of the anterior and lateral walls. On the ninth day postpartum by means of cardiac catheterization we were able to demonstrate the presence of normal coronary arteries and a left ventricular ejection fraction of 50%. Laboratory and other diagnostic tests did not demonstrate the presence of known etiological factors associated with myocardial infarction. PMID- 7840721 TI - [An evaluation of the efficacy of nitrates (transdermal and peroral) in the management of the patient with a myocardial contusion]. AB - Although thoracic trauma is frequently accompanied by myocardial injury; this later is often oversighted at early stages of trauma and misdiagnosed by the time complications are present. Myocardial abnormalities have been attributed to a reduction of cardiac flow. Nitroglycerin and isosorbide dinitrate, both agents with a known vasodilator effect on coronary arteries, might improve myocardial ischemic resulting from traumatic contusion. In order to compare safety and efficacy between two nitrates and placebo on myocardial contusion resulting from thoracic trauma, we carried out a comparative, prospective, single blind study. Subjects were randomly allocated to one of the following 3 groups: a) transdermal nitroglycerin, b) isosorbide dinitrate and c) placebo. Medication was dispensed for five days. Major endpoint were electrocardiographic abnormalities at entry and their final modifications. Other were severity injury score and myocardial enzyme levels. Twelve patients were included in each group. Four measured enzymes were high at entry, but MB fraction in the nitroglycerin group showed the most rapid normalization. Creatine phosphokinase and lactic dehydrogenase significantly correlated with severity injury index, but not MB fraction. Electrocardiographic normalization was mainly observed in the nitroglycerin group. Transdermal nitroglycerin systems demonstrated to be effective on recovering from electrocardiographic abnormalities resulting of myocardial contusion. PMID- 7840722 TI - [Reperfusion in acute myocardial infarct. The Working Group in Myocardial Reperfusion. The International Society and Federation of Cardiology (ISFC)]. PMID- 7840723 TI - [The roots of Mexican cardiology]. PMID- 7840724 TI - [The pathogenic aspects of American trypanosomiasis in the light of molecular biology]. PMID- 7840725 TI - [The vascular effects of thrombin on canine and human arteries; their independence from the metabolism of arachidonic acid]. AB - Independently of it's effects on the coagulation cascade, thrombin can interact with the endothelium and release vasodilatory mediators as prostacyclin, endothelium dependent relaxing factor and potentiate the vascular changes induced by vasoconstrictors like endothelin or cathecolamines. Therefore, in the present study we tested the effect of thrombin in the pulmonary and femoral canine arteries and compared it with the effects on human umbilical artery; we also explore the possible mechanism of action of thrombin-induced changes in vascular tone by using specific inhibitors. Thrombin induced a concentration-dependent and endothelium-dependent relaxation on canine arteries (pulmonary or femoral) and endothelium-independent contraction of human umbilical arteries, neither the relaxation nor the contraction were significantly affected by incubation of the vessels with: a cyclooxygenase inhibitor (indomethacin), lypooxygenase inhibitor (BW 755C) or a soup of antagonists (atropine, metysergyde, propanolol, meperamine or phenoribenzamine) to block muscarinic, histaminic, serotoninergic or adrenergic receptors. However, incubation of the vessels with heparin or a calcium channel blocker did prevented the vasoconstrictor effect of thrombin in human umbilical veins. This results suggests that thrombin can elicit changes in vascular tone and the effect is dependent of the vessel stimulated, and the presence of the endothelium. Thus, thrombin-dependent change in vascular tone is not mediated by arachidonic acid metabolites, sympathetic or parasympathetic neurotransmitters, histamine or serotonine receptors. Thrombin effects may be mediated by interaction with an specific receptor coupled with a calcium signal. PMID- 7840726 TI - [Scanning electronic microscopy of the myocardium: alternative technics]. AB - In scanning electron microscopy (SEM) most biological specimens lack conductance of electrons, requiring of coating with conducting element, which prevent damage from the electron beam. The present study combines the use of osmium thiocarbohydrazide-osmium (OTO) with Peldri II and hexamethyldisilazane (HMDS), as an alternative procedure to improve the image of biological specimens for SEM. We examined freeze-fractured rat's myocardium. The tissue was fixed with cacodylate buffer, followed by 2.5% glutaraldehyde in buffer. Specimens were remove and fixed for two hours at 4 degrees C. The first group of tissues were processed with standard technique, the second with OTO and Peldri II and the third was treated with OTO and HMDS. All specimens were examined in a SEM. The routine processed specimens allowed an appropriate visualization of myocytes and their subcellular elements including nucleus, myofibrils, mitochondria. Likewise tissue processed with the combination of OTO in addition HMDS and OTO plus Peldri II, allowed a high quality study. The procedure described herein may offer an alternative for the study of biological specimens by SEM. PMID- 7840727 TI - [The response of ventricular tachycardia to adenosine administration]. AB - Ten patients with ventricular tachycardia were studied. Two groups were formed. Group A included 5 patients with idiopathic ventricular tachycardia and group B included 5 patients with coronary heart disease. In all patients an electrophysiologic study was performed and monomorphic sustained ventricular tachycardia was induced through programmed stimulation. All patients received 12 mg of intravenous adenosine. The response was satisfactory in 3 of 5 patients in group A, with the presence of sinus rhythm. No response was seen in the other 2 patients. None of the patients in group B responded to the administration of intravenous adenosine. We concluded that adenosine may be useful in patients with cyclic AMP-mediated triggered activity ventricular tachycardia, in contrast to the coronary heart disease patients in which the mechanism is reentry. This interpretation is supported by results obtained in 15 experiments in canine heart. PMID- 7840728 TI - [The index of left and right diastolic ventricular filling with 2D Doppler echocardiography in normal children]. AB - Cross-sectional echocardiographic and Doppler studies were performed to study early and late diastolic inflow velocities transmitral and transtricuspid. The study group consisted of 50 normal subjects. Age varied from 5 hours to 17 years (x: 22 m). The measurements made were E/A ratio, isovolumetric relaxation time of the left ventricle, acceleration and deceleration time. Transmitral E/A ratio is higher than 1 since newborn period, increasing with age (newborn: 1.25 +/- 0.27 over 2 years of age: 1.79 +/- 0.35), and related to increase of "E" wave velocity (newborn: 0.67 +/- 0.09.m/s and over 2 years of age: 0.98 +/- 0.21 m/s). There is also a higher acceleration time (newborn: 50 +/- 10 m/s) and over 6 years of age 130 +/- 30 m/sec; isovolumetric relaxation time of the left ventricle (newborn: 60 +/- 10 msec vs. over 6 years of age: 80 +/- 20 msec). The E/A transtricuspid ratio is lower than 1 in the newborn (0.71 +/- 0.08) and (0.97 +/- 0.32) in infants less than 6 months of age; it is higher than 1 between 6 months and 2 years (1.17 +/- 0.33) and increasing in the group of six years of age and older (1.5 +/- 0.28), due to the higher velocity of "E" (newborn 0.47 +/- 0.07 m/s in relation to 6 years and older group (0.77 +/- 0.08 m/s). There is also an increase of acceleration time with aging (newborn: 50 +/- 10 msec and over six: 70 +/- 10 msec) and deceleration time (newborn: 60 +/- 10 msec and over six: 120 +/- 40 msec). The "A" wave velocities have been similar in the tricuspid and transmitral inflow, with progressive increasing since newborn period up to 2 years of age and decreasing over 6 years of age. PMID- 7840729 TI - [The long-term follow-up of 400 coronary angioplasty patients]. AB - From October 1985 to May 1992, 400 patients had coronary angioplasty of 518 stenotic lesions with a 92% success rate. Mean stenosis was reduced from 88 to 15%. We had 25 major complications (6%): 8 emergency bypass surgery (2%), MI in 12 pts (3%) and 5 deaths (1%). Follow-up was possible in 329 of the 367 patients with a successful procedure (90%), with a mean follow-up of 44 months. We performed coronary angiogram in 113 patients with clinical data suggestive of restenosis, restenosis was found in 73, progression of the coronary atherosclerosis in 18 and 22 (19%) had no evidence of restenosis. A second coronary angioplasty was performed in 44 pts with a 93% success rate, 22 were sent to coronary bypass surgery and medical treatment was given to 7 patients. The 18 pts with progression of the disease were also sent to bypass surgery. During follow-up 25% of the patients required a second angioplasty or bypass surgery. A total of 115 (35%) pts showed evidence of restenosis: in 73 pts (22%) a coronary angiogram revealed restenosis, 12 had angina, 15 myocardial infarction and 15 died of cardiovascular disease. At the end of follow-up 259 pts (79%) were free of myocardial infarction, bypass surgery or cardiovascular death. Survival rate at 3.7 years was 94.5%. In conclusion, coronary angioplasty showed to be safe, effective and with a good long term outcome. PMID- 7840730 TI - [Fasting and postprandial lipids and lipoproteins during the chronic administration of antihypertensive drugs]. AB - To evaluate the effect of various antihypertensive drugs on fasting and postprandial lipids and lipoproteins, we studied 39 normolipidemic hypertensive patients, 28 men and 11 women aged 52.3 +/- 9.0 and 58.5 +/- 7 years, respectively. After four weeks of placebo administration, lipids and lipoproteins were measured in the fasting state and every three hours for a period of nine hours after intake of a standardized fat mixed load (65 g/m2). Following this test, the patients were randomly assigned to one of four treatment groups: group I metoprolol (n = 10), 100 mg/day; group II nicardipine (n = 9), 90 mg/day; group III captopril (n = 11), 75 mg/day. At the end of week four of treatment the fasting and postprandial lipid measurements were repeated. Blood pressure mean values were significantly (p < 0.05) reduced in the four treatment groups. We found no statistically significant lipids or lipoproteins changes neither in the fasting nor in the postprandial state, but a trend toward lower concentrations in the postprandial lipemia after treatment was observed in three groups (metoprolol, nicardipine and captopril), whereas no change was observed in the chlorthalidone group. These data confirm that fasting lipids and lipoproteins in normolipidemic hypertensive patients are not unfavorably changed by low doses of the drugs studied. In addition, we inform that postprandial lipemia is not affected by these four drugs in the doses used. PMID- 7840731 TI - [Radiofrequency ablation in idiopathic ventricular tachycardia originating in the right ventricle]. AB - We present the case of a 10-year-old boy, with structurally normal heart who began two years before admission, with sustained monomorphic ventricular tachycardia with heart rate of 280 bpm and LBBB morphology, AQRS + 60 degrees, with pallor and diaphoresis. The tachycardia was treated with xylocain. He was also treated with propaphenone, verapamil, and amiodarona, in spite of these, he continued with this type of arrhythmia 2 or 3 times a month. We performed an electrophysiologic study which showed ventricular tachycardia originated in the right ventricle infundibulum. We took an endomyocardial biopsy, which was normal. He was scheduled for percutaneous catheter ablation of the tachycardia by radiofrequency energy. During the procedure the ventricular tachycardia appeared spontaneously, we mapped the most early ventricular activation and then in sinus rhythm, this site was pace mapped and resulted in similar pattern of clinical ventricular tachycardia. We identified the site of origin of the ventricular tachycardia in the posterior region of the right ventricle infundibulum, delivering radiofrequency, changing to sinus rhythm. Then we paced the apex of the right ventricle without inducing any form of arrhythmia. He is asymptomatic four months later. PMID- 7840732 TI - [The autopsy findings in 51 cases of AIDS with cardiovascular damage]. AB - We describe the cardiovascular abnormalities found at autopsy in patients with AIDS and a description of the opportunistic infections in these cases studied between January 1988 and August 1993. There were 51 cases with such diagnosis. Pericardial effusion appeared in 9, pleural effusion in 7, myocarditis in 5, 7 with pericarditis, endocarditis in 6, left ventricular hypertrophy in 20, right ventricular hypertrophy in 21 and evidence of atherosclerosis in 15. Thus, data of cardiovascular damage was present in 42.7% of our patients. The cardiovascular abnormalities in this group are common, in contrast to the paucity of clinical findings. Diagnosis of cardiac pathology was made in only 12% of them. So in every case with diagnosis of AIDS, a careful clinical examination and cardiac diagnostic oriented tests must be done for detection of these abnormalities. PMID- 7840733 TI - [Surgery in the treatment of thoracicoabdominal aortic aneurysms]. PMID- 7840734 TI - [The humanistic lesson of the Instituto de Cardiologia of Mexico]. PMID- 7840735 TI - [Esters of naproxen as potential prodrugs for skin penetration. 2. Penetration behavior in excised mice skin]. AB - Penetration of various Naproxen esters was studied in an in vitro model using excised skin of nude mice. Maximal fluxes and permeability coefficients were determined and correlated with physicochemical properties of the substances. The solubilities in octanol and water are of special importance. A model for predicting penetration behaviour was discussed. PMID- 7840736 TI - Platelet aggregation inhibiting and anticoagulant effects of oligoamines, XXIV: Interactions between oligosydnone imines and albumin or phospholipids. AB - Oligosydnone imines are strongly bound to albumin (alpha < 1%) in pure water. In saline, however, this effect is abolished (alpha approximately 80%). 4,4' Propylene-bis-3-hexyl-sydnone-5-imine hydrochloride (1) moderately binds to phosphatidylcholine liposomes (PC, alpha approximately 34%). This is increased by phosphatidylethanolamine (PE). In PC/PE vesicles alpha is about 7%. The binding is further enhanced by the incorporation of negatively charged phospholipids (PL) like phosphatidylserine (PS). In PC/PE/PS liposomes complete binding of 1 can be achieved. This holds especially true if the composition of the liposomes is similar to the PL composition of platelet membranes. The results suggest that the antiplatelet activity of 1 is mediated by the bindings to negatively charged PL in the platelet membrane. PMID- 7840737 TI - 4H-pyrrolo[1,2-a]thieno[3,2-f] and 4H-pyrrolo[1,2-a]thieno-[2,3 f][1,4]diazepines: synthesis and pharmacological evaluation. AB - As an extension of a previous work, in which a number of 4H-pyrrolo-[1,2 a]thieno[2,3-f][1,4]diazepines were described, a new series of derivatives of the isomeric pyrrolo[1,2-a]thieno[3,2-f]diazepines ring system has been synthesized. The products obtained, together with those reported in the previous paper, were tested for acute toxicity and CNS activity in mice. PMID- 7840738 TI - Synthesis and muscarinic activity of isoxazole-substituted 1,2,5,6 tetrahydropyridines. PMID- 7840739 TI - Effect of smoking cessation upon circulatory responses to reactive hyperemia and cold pressor stress. AB - Local and sympathetic nervous system stress tests were administered prior to and following a 5-d smoking cessation program to determine the effects of short term smoking cessation upon peripheral circulation. Reactive hyperemia (RH) tests were performed on the forearm as a local dilatory stressor. Finger blood flow responses to cold pressor (CP) stresses were used to access stimulation of the sympathetic nervous system. Measures of heart rate and total forearm or finger blood flow, pulse volume and rate of blood delivery were obtained continuously during each stress test. Smoking cessation produced a significant decrease (0.01 < p < 0.05) in heart rate during both the RH and CP test sequences. Grouped mean peak forearm blood flow (Mean difference = 2.11 ml.100 ml-1.min-1; p < 0.05) and pulse volume (Mean difference = 0.04 ml.100 ml-1.pulse-1; p < 0.01) were both significantly greater following occlusion during the post-cessation RH tests than during the similar test before smoking cessation. Both finger pulse volume and rate of blood delivery were significantly greater (0.01 < p < 0.05) during the recovery portion of the post-cessation CP tests than during the same period of the pre-cessation tests. Thus, smoking cessation significantly altered both the locally mediated and central nervous system controlled responses to externally applied stressors. PMID- 7840740 TI - Gravity-induced homeostatic reactions in the macular and choroidal vasculature of the human eye. AB - We quantified the changes in macular and choroidal blood flow during body inversion to elaborate their hemodynamic attributes and relate them to our previously reported effects of inversion on visual neural function. Ten healthy subjects took part in the study. The intraocular pressure (IOP) was altered through graded body tilts. Macular and choroidal pulsatile ocular blood flow (POBF) were measured with an Oculix BFS 2000 and a Langham OBF system, respectively. Body inversion caused a systematic decrease in the POBF for all subjects. Systematic changes in macular leukocyte velocity and density were also found with inversion. Six of ten subjects showed a reciprocal relationship between the leukocyte density and velocity as a function of body orientation, while parallel changes in the leukocyte density and velocity were seen during inversion for the remaining subjects. Our results may reflect individual strategies for autoregulation within the macular circulation and an absence of autoregulation in the pulsatile component of the choroidal circulation. PMID- 7840741 TI - Perceptual and eye movement responses elicited by linear acceleration following spaceflight. AB - Responses of four crewmembers were measured before and after a 9-d Spacelab Mission during inter-aural (y-axis) and longitudinal (z-axis) linear acceleration. During one test, eye movements were recorded with simultaneous sinusoidal acceleration and constant-velocity optokinetic stimulation. Postflight responses indicated changes in the horizontal sinusoidal response during the y axis trials. In another test, subjects indicated direction of acceleration during a series of low acceleration steps. More incorrect direction indications were observed postflight, and the y-axis sensitivity increased while the z-axis sensitivity decreased for three subjects. In a third test, subjects used a joystick to null pseudo-random linear motion. Not one subject showed a significantly enhanced ability to null linear motion in the y-axis, while two subjects showed an enhanced ability during z-axis testing postflight. Oculomotor and perceptual responses to linear acceleration are modified by exposure to microgravity and become more variable postflight. The observed changes may be due to an altered interpretation of inertial cues in space that is inappropriate postflight. PMID- 7840742 TI - A survey of U.S. Air Force flyers regarding their use of extended wear contact lenses. AB - We reviewed the USAF Tactical Air Command's (TAC) contact lens database for the period July 1989 through June 1991. An anonymous survey was mailed to 396 TAC aircrew members in February 1992 to assess their experiences using extended wear soft contact lenses (EWSCL). Analysis was performed on those responses to compare differences between aviators who currently wear (CW), those who discontinued wear (DCW), and flyers who wore EWSCL while deployed to S.W. Asia for Desert Shield/Desert Storm. Of the 396 surveyed, 284 (72%) returned the survey and demonstrated that the daily use of EWSCL to be logistically practical and physiologically safe. No ocular malady was reported that would preclude continued use by aircrews. Desert Shield/Storm experiences documented that the use of EWSCL by USAF aircrews in a desert environment was possible. Logistical difficulties for the small number who either deployed with inadequate supplies or required replacement lenses were shown to be the primary challenge to the wear of EWSCL during Desert Shield/Storm. Subjectively, aircrews expressed strong beliefs that EWSCL contributed to their abilities as combat aviators. PMID- 7840743 TI - The possible role of nystagmus in motion sickness: a hypothesis. AB - An alternative hypothesis to that provided by conflict theory is formulated to account for motion sickness. The new approach is predicted on the oculocardiac reflex (i.e., bradycardia produced by extra-ocular muscle traction) (18) and empirical evidence that retrobulbar anesthesia significantly lowers the incidence of emesis after strabismus surgery (14). Eye muscle traction is presumed to elicit afferent signals that ultimately stimulate the vagus nerve (15). The same neuromotor sequence is presumed to occur during reflexive eye movements under vestibular control and during more complicated combinations of reflexive and voluntary eye movements. It is proposed that the blocking of afferent signals from extra-ocular muscle in an otherwise intact vestibulo-ocular system will eliminate the signs and symptoms of motion sickness normally produced in a provocative environment. PMID- 7840744 TI - Physical performance is maintained in women consuming only foods used on the U.S. Space Shuttle. AB - In-flight reductions in caloric intake, body weight, lean body mass (LBM), aerobic capacity, and other measures of physical performance have been consistent findings in the U.S. and Russian space programs. The diet provided for astronauts in space has been suggested as a possible contributor to these changes because food selection, preparation, and storage facilities are limited on spacecraft. In this ground-based study, consuming only foods used on the Space Shuttle for 28 d did not affect aerobic capacity, LBM, or measures of muscle strength or endurance in 12 healthy women (ages 28-47 years). However, normal consumption patterns were affected by restriction to the Space Shuttle diet, namely a proportional increase in carbohydrate consumed, with compensatory decreases in protein and fat. These results suggest that physical performance and LBM can be maintained under normal gravity conditions in active women who consume a Space Shuttle food-system diet for 28 d. PMID- 7840745 TI - Ketamine's psychological effects do not contraindicate its use based on a patient's occupation. AB - Since ketamine was approved for clinical use, there has been debate over whether the psychological effects of ketamine warrant avoiding use of the drug in patients based on their occupation. This article reviews the literature to determine if such concerns are valid. After 25 years of clinical experience with ketamine, fewer than 10 cases document the occurrence of delayed psychological effects potentially attributable to that drug. In most cases, the delayed effects were temporary, resolving within 3 weeks. Further, there were no long-term psychological effects clearly attributable to ketamine. Children who manifested delayed effects had several other factors present placing them at risk for long term psychological changes independent of their receiving ketamine. Several controlled studies investigating the risk of long-term psychological effects due to ketamine fail to document that the risk of permanent psychological changes from ketamine is any greater than that from any other anesthetic. In conclusion, there is no evidence in the literature that ketamine presents a higher risk compared to other anesthetics for causing long-term psychological effects that result in a patient not being able to return to his or her occupation. The decision of whether to use ketamine should be a clinical decision weighing relative risks versus benefits, and not a decision based on the patient's career. PMID- 7840746 TI - The life of Brigadier General Theodore C. Lyster. AB - Theodore C. Lyster is a familiar name to aerospace medicine physicians. His early recognition of the unique physical requirements of aviators, the specialized training necessary for flight surgeons, and the need for altitude physiology research provided the foundation on which the specialty of aviation medicine was built. Lyster's medical career, however, encompassed much more than aviation medicine. From his earliest assignment as a contract physician in Cuba in 1899 until his entry into private practice in 1921, he was heavily involved with the fight against yellow fever. In the era before medical residencies were commonplace, Lyster sought out training in ophthalmology and otolaryngology in the U.S. and abroad. His clinical and organizational abilities made him a valuable asset during the construction of the Panama Canal and during World War I. Lyster's many talents and his philosophy about aviation medicine make him a worthy role model for flight surgeons today. PMID- 7840748 TI - How low can you experience hypoxia? PMID- 7840747 TI - Angiotensin converting enzyme (ACE) inhibitors in hypertensive aircrew. AB - Essential, uncomplicated hypertension is not uncommon in young or middle-aged aircrew. The choice of treatments available for its treatment was largely limited to diuretics and some accepted beta-adrenergic blockers. It is only 4 years since the choice was extended to the calcium-channel-blockers and the angiotensin converting enzyme (ACE) inhibitors, in civil aviation. In military aviation in the U.K., ACE inhibitors have been in use for less than 2 years. This paper surveys these choices and makes the case for the use of ACE-inhibitors, under controlled conditions. It also emphasizes that the functional studies, conducted to show the safety of ACE-inhibitors, were more comprehensive than for any of the predecessors. These methods of study should serve as models for the study of any drug in the future, before it is authorized for use in the aircrew. PMID- 7840749 TI - ARMA and pilot selection. PMID- 7840750 TI - Prior crash and violation records of pilots in commuter and air taxi crashes: a case-control study. AB - With a case-control design, this study examined the relationships of crash/incident history, violation history, pilot age, flight experience, and recent flight time with the likelihood of being involved in commuter aircraft and air taxi crashes. Cases (n = 725) were pilots who had been involved in commuter aircraft or air taxi crashes during 1983-88, identified from the National Transportation Safety Board aviation crash data base. From the Federal Aviation Administration (FAA) airmen information system, 1,555 pilots were randomly selected as controls. Controls were frequently-matched with cases on medical class and calendar year. Different data bases within the FAA's airmen information system were linked to ascertain information about crash/incident and violation records in the previous 3 years, age, total flight time, and flight time in the prior 6 months. Multivariate logistic regression models were fitted to estimate odds ratios and evaluate dose-response effects, non-linear relationships, and interactions. Cases had significantly higher prevalence rates of prior crash/incident and violation records. The estimated odds ratio of being involved in a commuter aircraft or an air taxi crash was 1.7 (95% confidence interval [CI], 1.3-2.4) for crash/incident history, and 1.6 (95% CI, 1.1-2.2) for violation history. A "dose-response effect" was found with both crash/incident history and violation history, with higher odds ratios for pilots with crashes versus incidents or with more serious violations. Total flight time showed a diminishing protective effect. Either very small or very large recent flight time increased the risk of being involved in a commuter aircraft or an air taxi crash. PMID- 7840752 TI - Thermal strain and G protection associated with wearing an enhanced anti-G protection system in a warm climate. AB - A flight trial was conducted in Cyprus to assess the thermal strain associated with and the G protection provided by the prototype Eurofighter 2000 aircrew equipment assembly (AEA) in a warm climate. Six subjects flew a standardized sortie four times in a Hawk aircraft: two while wearing the Eurofighter 2000 AEA and two wearing standard Hawk summer AEA. The sortie included high-G turns and simulated air combat. Cockpit temperatures, rectal and skin temperatures, heart rate, and sweat rate were recorded. Subjective thermal comfort, fatigue, and G protection were also assessed. Skin temperatures of the back, chest and thighs, mean skin temperatures, and sweat rate were greater when the Eurofighter AEA was worn. Rectal temperature and heart rate did not differ significantly between the two conditions. Superior G protection was provided by the Eurofighter assembly. These findings suggest that wearing the Eurofighter AEA in a warm climate is associated with an increased but not unacceptable level of thermal stress while offering enhanced G protection. These results may not generalize when ambient temperatures are higher or more insulative protective clothing is worn. PMID- 7840751 TI - Qigong and L-1 straining maneuver oxygen system requirements with and without positive pressure breathing. AB - Based on the characteristics of respiration and the intrathoracic pressure in Qigong (Q-G) maneuvering, it has been theorized that the Q-G maneuver may lessen the lack of coordination between aircraft oxygen apparatus and anti-G maneuvers and may be more compatible with positive pressure breathing (PPB). In an experiment intended to test this hypothesis, 5 male volunteers, trained in Q-G and L-1 maneuvers, performed the Q-G and the L-1 maneuvers without and with (PPB) at 4 and 6 kPa, respectively, with 14 respiratory parameters being measured. The results demonstrated that, when performing Q-G maneuver, the maximal expiratory flow rate averaged 1.175-1.645 L.s-1, the inspiratory peak flow, 1.003-1.297 L.s 1. Both these values were markedly lower than those of the L-1 maneuver, and matched well the performance of current aircraft oxygen apparatus. From the blood pressure and heart rate values, it is evident that PPB can further promote the blood pressure-raising effect of the Q-G maneuver, and alleviate pilots' fatigue. PMID- 7840753 TI - Effect of modafinil on heat production and regulation of body temperatures in cold-exposed humans. AB - Military personnel often undergo sustained operations that affect vigilance and alertness. Pharmacological agents may be used to enhance vigilance. Most such agents also have thermogenic properties. Whether a new promising stimulant, modafinil (Lyons and French, Aviat. Space Environ. Med. 1991; 62:432-435), has a beneficial effect on cold tolerance in the military context, is not known. The goal of this study was, therefore, to evaluate the effect of this new drug on thermal balance and the regulation of body temperatures in neutral conditions and when challenged by a cold exposure. Nine subjects underwent three trials each: two in the cold (3 h at rest, 10 degrees C) 0.5 h after the ingestion of either placebo or modafinil (200 mg), and one in thermal neutrality with modafinil (same conditions except Tdb = 29.3 degrees C). As expected, cold produced a drop in Tre and Tsk and an increase in Vo2. Although non-significant, there was a tendency for a slightly greater drop in Tre with modafinil (0.65 degrees C vs. 0.57 degrees C with placebo). A similar tendency was found for the heat debt (S) which was greater with modafinil than with placebo (16.1 +/- 0.7 vs. 14.7 +/- 0.6 kJ.kg 1, respectively, +9.5%, p = 0.11). This tendency appears to be the combined result of a slightly lower mean heat production during the test and a slightly greater mean dry heat loss. When tested at thermal neutrality, the drug had no effect on any thermal or metabolic parameters. The results demonstrate that the ingestion of a single dose of modafinil has no significant acute effect on thermal balance in neutral conditions and on thermoregulation in normal subjects exposed to cold. However, a tendency for slightly greater cooling was noted with modafinil. It is not known whether the use of modafinil in conjunction with sleep deprivation (a likely scenario) could magnify this effect. PMID- 7840754 TI - The return of copy-choice in DNA recombination. AB - In a recent publication, d'Alencon et al.(1) presented evidence that a form of non-homologous DNA recombination involving direct repeats is dependent upon the replication of the DNA. In addition, density-labeling experiments showed that after recombination was stimulated, progenies were present only in molecules that had undergone complete replication. These observations are consistent with a replicative and not a breakage-and-rejoining model for the DNA recombination events. These two models had of course been contrasted many years ago in mechanistic studies of homologous DNA recombination. It is therefore interesting to place the latest findings of d'Alencon et al. in this historical context. PMID- 7840756 TI - Most of the avian genome appears available for retroviral DNA integration. AB - Although retroviral integration requires specific viral DNA sequences, factors which govern the choice of a chromosomal target site within an infected cell are less clear. For example, certain chromosomal regions may be inaccessible to the viral integration machinery, while others may favor integration. A recent paper by Withers-Ward et al.(1) addresses this issue using a polymerase chain reaction based assay capable of identifying single integration events within a large population of infected cells. Their results show that integration can occur into many different chromosomal regions, and that local DNA structure can influence the site of integration within a given region. PMID- 7840755 TI - The human Alu SINE sequences--is there a role for selection in their evolution? AB - The Alu sequence is a SINE (Short INterspersed Element) that is abundant in the human genome. A new analysis (1) reveals an unexpected conservation of some bases in the DNA sequence of the element. The bases involved include those forming an RNA polymerase III promoter. An unresolved question is whether this conservation results from selection for transposability. This, in turn, is related to the larger question of the evolutionary relationship between members of the Alu sequence family. PMID- 7840757 TI - Leech segmentation: a molecular perspective. AB - A variety of leech homeobox genes have been identified by homology with genes that are known to bring about the regionalization and segmentation of the anteroposterior body axis in other organisms. Embryonic expression patterns suggest a number of interphyletic similarities in the way that these genes are utilized. However, several interesting differences have also been observed. In particular, transplantation experiments in the leech embryo have shown that axially aligned patterns of homeobox gene expression are not specified by a global pattern of positional cues. Rather, the leech independently establishes anteroposterior patterns of gene expression in each of five discrete stem cell lineages, and these patterns are brought into their final alignment through a process of morphogenetic assembly. PMID- 7840758 TI - Mitogenesis and protein synthesis: a role for ribosomal protein S6 phosphorylation? AB - It has been known for 20 years that the ribosomal protein S6 is rapidly phosphorylated when cells are stimulated to grow or divide. Furthermore, numerous studies have documented that there is a strong correlation between increases in S6 phosphorylation and protein synthesis, leading to the idea that S6 phosphorylation is involved in up-regulating translation. In an attempt to define a mechanism by which S6 phosphorylation exerts translational control, other studies have focused on characterizing the sites of phosphorylation of this protein and its location within the ribosome. Recent data show that S6 is a protein which may have diverse cellular functions and is essential for normal development, and that it may be involved in the translational regulation of a specific class of messages. PMID- 7840759 TI - Tensin: a potential link between the cytoskeleton and signal transduction. AB - Cytoskeletal proteins provide the structural foundation that allows cells to exist in a highly organized manner. Recent evidence suggests that certain cytoskeletal proteins not only maintain structural integrity, but might also be associated with signal transduction and suppression of tumorigenesis. Since the time of the discovery of tensin, a fair amount of data has been gathered which supports the notion that tensin is one such protein possessing these characteristics. In this review, we discuss recent studies that: (1) elucidate a role for tensin in maintenance of cellular structure and signal transduction; (2) implicate tensin as the anchor for actin filaments at the focal adhesion; (3) describe the phosphorylation of tensin; (4) describe potential targets for its Src homology region 2 domain; (5) describe the association between tensin and the nuclear protein p130; and (6) demonstrate that increased tensin expression in a cell line appears to reduce its transformation potential. PMID- 7840760 TI - Nervous system modification by transplants and gene transfer. AB - New possibilities to modify function and direct repair in the central nervous system (CNS) have been established by the merger of gene transfer technology with neural transplantation. Rapid advances in viral-mediated DNA-delivery procedures permit the study of novel gene expression in neurons and glial cells. Foreign genes, transferred by a virus vector, can be used to generate new cell lines, identify transplanted cells, and express growth factors or enzymes for neurotransmitter synthesis. In addition to CNS cell types, non-neural cells are also being studied with transgene technology in the nervous system. Functional effects have been obtained with grafts of genetically modified cells in animal models of several nervous system disorders, and the recent results set the stage for potential application of these techniques to human CNS gene therapy. PMID- 7840762 TI - Calmodulin's warm embrace. PMID- 7840761 TI - DNA damage tolerance, mismatch repair and genome instability. AB - DNA mismatch repair is an important pathway of mutation avoidance. It also contributes to the cytotoxic effects of some kinds of DNA damage, and cells defective in mismatch repair are resistant, or tolerant, to the presence of some normally cytotoxic base analogues in their DNA. The absence of a particular mismatch binding function from some mammalian cells confers resistance to the base analogues O6-methylguanine and 6-thioguanine in DNA. Cells also acquire a spontaneous mutator phenotype as a consequence of this defect. Impaired mismatch binding can cause an instability in DNA microsatellite regions that comprise repeated dinucleotides. Microsatellite DNA instability is common in familial and sporadic colon carcinomas as well as in a number of other tumours. Several independent lines of investigation have identified defects in mismatch repair proteins that are causally related to these cancers. PMID- 7840763 TI - Calmodulin's warm embrace. PMID- 7840764 TI - Brachyury and zebrafish. PMID- 7840765 TI - TKO'ed: lox, stock and barrel. AB - The generation of panels of mutant mice by homologous recombination has greatly increased the ability to assess the function of particular gene products in vivo. The ability to control the developmental stage, the tissue and the nature of the mutation would be an important innovation. A recent report demonstrates that the conservative site-specific recombination of bacteriophage P1, namely Cre-lox, can be used successfully in combination with homologous recombination to generate temporal- and cell-restricted mutations in vivo. This technical advance allows a greater flexibility in gene targeting and will have a significant impact on how complex gene functions are studied in vivo. PMID- 7840766 TI - Choose your partner: chromosome pairing in yeast meiosis. AB - Premeiotic association of homologous chromosomes in the yeast, Saccharomyces cerevisiae has been shown, by means of fluorescent in situ hybridization (FISH). Time course and mutant studies show that the premeiotic associations are disrupted upon entry into meiosis, to be reestablished shortly before synapsis. The data are consistent with a model in which multiple, unstable interactions bring homologues together, prior to stable joining by recombination. PMID- 7840767 TI - Dynamic remodeling of the actin cytoskeleton: lessons learned from Listeria locomotion. AB - The bacterial pathogen Listeria monocytogenes displays the remarkable ability to reorganize the actin cytoskeleton within host cells as a means for promoting cell to-cell transfer of the pathogen, in a manner that evades humoral immunity. In a series of events commencing with the biosynthesis of the bacterial surface protein ActA, host cell actin and many actin-associated proteins self-assemble to form rocket-tail structures that continually grow at sites proximal to the bacterium and depolymerize distally. Widespread interest in the underlying molecular mechanism of Listeria locomotion stems from the likelihood that the dynamic remodeling of the host cell actin cytoskeleton at the cell's leading edge involves mechanistically analogous interactions. Recent advances in our understanding of these fundamental cytoskeletal rearrangements have been achieved through a clearer recognition of the central role of oligo-proline sequence repeats present in ActA, and these findings provide a basis for inferring the role of analogous host cell proteins in the force-producing and position-securing steps in pseudopod and lamellipod formation at the peripheral membrane. PMID- 7840768 TI - Long DNA palindromes, cruciform structures, genetic instability and secondary structure repair. AB - Long DNA palindromes pose a threat to genome stability. This instability is primarily mediated by slippage on the lagging strand of the replication fork between short directly repeated sequences close to the ends of the palindrome. The role of the palindrome is likely to be the juxtaposition of the directly repeated sequences by intra-strand base-pairing. This intra-strand base-pairing, if present on both strands, results in a cruciform structure. In bacteria, cruciform structures have proved difficult to detect in vivo, suggesting that if they form, they are either not replicated or are destroyed. SbcCD, a recently discovered exonuclease of Escherichia coli, is responsible for preventing the replication of long palindromes. These observations lead to the proposal that cells may have evolved a post-replicative mechanism for the elimination and/or repair of large DNA secondary structures. PMID- 7840769 TI - Differentiation of endothelial cells: analysis of the constitutive and activated endothelial cell phenotypes. AB - Endothelial cells line the inside of all blood vessels, forming a structurally and functionally heterogeneous population of cells. Their complexity and diversity has long been recognized, yet very little is known about the molecules and regulatory mechanisms that mediate the heterogeneity of different endothelial cell populations. The constitutive organ- and microenvironment-specific phenotype of endothelial cells controls internal body compartmentation, regulating the trafficking of circulating cells to distinct vascular beds. In contrast, surface molecules associated with the activated cytokine-inducible endothelial phenotype play a critical role in pathological conditions including inflammation, tumor angiogenesis, and wound healing. Differentiation of the endothelial cell phenotypes appears to follow similar mechanisms to the differentiation of hematopoietic cells, with the exception that endothelial cells maintain transdifferentiating competence. The present review offers a scheme of endothelial cell differentiation and discusses the possible applications of differentially expressed endothelial cell molecules as targets for directed therapeutic intervention. PMID- 7840770 TI - The tails of survival curves. AB - This article focuses on the occasional individuals of many species that live longer than is usual for their populations--here called longevity outliers. They appear to be exceptions to the usual patterns of mortality rates that increase with age. There is no model of survivorship that accommodates all of these individuals. They are less vulnerable to the usual causes of death than most in their populations. There are hints of genetically based mechanisms in the form of life-prolonging genes in invertebrates and genetic resistance to fatal diseases in higher organisms. The reasons why longevity outliers ultimately die are not known. Based on well-established trends, I predict that there will be many more humans reaching very old ages in the next century. PMID- 7840771 TI - The roles of autophosphorylation and phosphorylation in the life of osteopontin. AB - Osteopontin is a secreted glycosylated phosphoprotein found in bone and other normal and malignant tissues. Osteopontin can be autophosphorylated on tyrosine residues and can also be phosphorylated on serine and threonine residues by several protein kinases. Autophosphorylation of osteopontin may generate sites for specific interactions with other proteins on the cell surface and/or within the extracellular matrix. These interactions of osteopontin are thought to be essential for bone mineralization and function. The polyaspartic acid motif of osteopontin, in combination with neighboring sequences that include serine residues phosphorylated by protein kinases, could fold and assemble into a molecular structure that participates in the mineralization of the bone matrix. PMID- 7840772 TI - The regulation of superoxide production by the NADPH oxidase of neutrophils and other mammalian cells. AB - Superoxide is produced by a NADPH oxidase of phagocytic cells and contributes to their microbicidal activities. The oxidase is activated when receptors in the neutrophil plasma membrane bind to the target microbe. These receptors recognise antibodies and complement fragments which coat the target cell. The oxidase electron transport chain, located in the plasma membrane, comprises a low potential cytochrome b heterodimer (gp 91-phox and p22-phox) associated with FAD. It is non-functional until at least three proteins, p67-phox, p47-phox and p21rac (and possibly others), move from the cytosol to dock on the cytochrome b. The docking involves the interaction of SH3 domains on p47-phox or p67-phox with a proline-rich sequence on the small subunit of the cytochrome b. These SH3 domains may become exposed following phosphorylation of p47-phox by protein kinase C or, in model systems, by addition of arachidonic acid to reconstitution mixtures. Following the docking process the electron-transporting component is able to transfer electrons from NADPH to oxygen. This electrogenic event is charge compensated by the opening of a proton channel. Components of the oxidase are expressed in non-phagocytes, where their function is uncertain but could be related to some signal function of superoxide. PMID- 7840773 TI - Cell polarity and the mechanism of asymmetric cell division. AB - During development, one mechanism for generating different cell types is asymmetric cell division, by which a cell divides and contributes different factors to each of its daughter cells. Asymmetric cell division occurs throughout the eukaryotic kingdom, from yeast to humans. Many asymmetric cell divisions occur in a defined orientation. This implies a cellular mechanism for sensing direction, which must ultimately lead to differences in gene expression between two daughter cells. In this review, we describe two classes of molecules: regulatory factors that are differentially expressed upon asymmetric cell division, and components of a signal transduction pathway that may define cell polarity. The lin-11 and mec-3 genes of C. elegans, the Isl-1 gene of mammals and the HO gene of yeast, encode regulatory factors that determine cell type of one daughter after asymmetric cell division. The CDC24 and CDC42 genes of yeast affect both bud positioning and orientation of mating projections, and thus may define a general cellular polarity. We speculate that molecules such as Cdc24 and Cdc42 may regulate expression of genes such as lin-11, mec-3, Isl-1 and HO upon asymmetric cell division. PMID- 7840774 TI - A parallel between development and evolution: germ cell recruitment by the gonads. AB - In gonad-bearing animals gametogenesis can be divided into three main phases. During embryonic development the primordial germ cells move towards the gonadal primordia. A long, intra-gonadal phase follows during which the germ cells grow and differentiate. Mature germ cells are finally released from the gonads and brought to the exterior. Thus, germ cells are successively motile, non-motile and motile again. This complex life history is given here a simple evolutionary interpretation. The basic assumption is that primitive Metazoa already had germ cells, but no gonads to harbour them. Higher animals acquired gonads, which sequestered the germ cells, thus creating the temporary confinement experienced by germ cells in most present-day Metazoa. This evolutionary scheme may explain why several steps of germ cell differentiation are totally or partially independent of the gonads. These steps presumably existed in primitive, gonad free Metazoa, and conserved their autonomy in higher animals. PMID- 7840775 TI - Pregneolone--from Selye to Alzheimer and a model of the pregnenolone sulfate binding site on the GABAA receptor. PMID- 7840776 TI - Some phosphonic acid analogs as inhibitors of pyrophosphate-dependent phosphofructokinase, a novel target in Toxoplasma gondii. AB - Pyrophosphate-dependent phosphofructokinase (PPi-PFK) was identified previously in Toxoplasma gondii as the only kinase that phosphorylates fructose-6-P to fructose-1,6-bisP. Since such an enzyme is not present in mammals, it was considered to be a good target for prospective selective inhibitors of the parasite. We have examined the effects of several phosphonic acid derivatives, analogs of pyrophosphate, on PPi-PFK activity, as well as on the replication of T. gondii in human foreskin fibroblast (HFF) cells. The most active compound in inhibiting PPi-PFK was tetrasodium carbonyldiphosphonate. Several bisphosphonates and related arylhydrazones showed inhibition of the enzyme, but with higher IC50 values. Although several phosphonoacetic acid derivatives also inhibited PPi-PFK, as a group they were less potent than the bisphosphonate derivatives. Comparison among the structures of various inhibitors and their effects against PPi-PFK indicates that a carbonyl (C=O) or amino (C=N) group between two phosphoryl moieties is associated with more potent enzyme inhibiton. Tetrasodium carbonyldiphosphonate did not show a significant effect against replication of T. gondii cells, probably because, as a charged molecule, it could not cross the cell membrane to reach the intracellular parasite. Tetraisopropyl carbonyldiphosphonate 2,4-dinitrophenylhydrazone showed some selective inhibitory effect against replication of the parasite in the HFF cells and protected the mammalian cells from damage by T. gondii. The results indicate that carbonyldiphosphonic acid is a good prototype compound that is amenable to chemical manipulation, which, in turn, may optimize selective inhibition of T. gondii PPi-PFK and increase accessibility to the intracellular parasite. PMID- 7840777 TI - Inhibition of adenylyl cyclase in rat striatal homogenates by combinations of dopamine and ferric iron compounds. AB - The adenylyl cyclase activity of homogenates of striatal tissue from rat brain has been used as a model to test the hypothesis that the products of the reaction of polyphenols with ferric iron compounds are toxic. Dopamine (DA), at levels that stimulate adenylyl cyclase, inhibited the activity in the presence of 2 mol of potassium ferricyanide (FC), methemoglobin or ferricytochrome c per mol of DA. Combinations of potassium ferrocyanide and DA were not inhibitory. Neither pyrocatechol nor hydroquinone stimulated the activity, but these polyphenols were inhibitory in the presence of FC. Tyramine, phosphorylated DA or phosphorylated pyrocatechol had no effect on the activity of the enzyme in the presence or absence of FC. Forskolin was unable to stimulate the adenylyl cyclase once the latter was inhibited by DA plus FC, and dithiothreitol could not reverse inhibition by DA plus FC. Incubation of DA with FC, in the absence of the homogenate, resulted in substances that were not inhibitory. These findings suggest that the polyphenols plus FC react to yield substances that inhibit the adenylyl cyclase by affecting the catalytic unit of the enzyme complex. PMID- 7840778 TI - Modulation of mu opioid binding by protein kinase inhibitors. AB - Several isoquinolinesulfonamide protein kinase inhibitors, including 1-(5 isoquinolinesulfonyl)-methylpiperazine dihydrochloride (H7), inhibited [3H]-[D Ala2, MePhe4, Gly5-ol]- enkephalin (DAMGO) binding to rabbit cerebellar mu opioid receptors with Ki values similar to those reported for kinase inhibition by these compounds, suggesting that their mechanism of action may involve inhibition of protein kinase activity. However, since the binding assays were performed in the absence of exogenous ATP, it is unlikely that protein phosphorylation is taking place during the binding assay, making it improbable that H7 and its congeners inhibit DAMGO binding by inhibition of protein kinase activity. In support of this hypothesis, K252a, a structurally unrelated, broad spectrum protein kinase inhibitor, was inactive in modulating DAMGO binding, even at a concentration 5 fold greater than its Ki for inhibiting protein kinase activities. Inhibition of DAMGO binding through inhibition of kinase activity implies a noncompetitive or allosteric mechanism. Scatchard analysis of [3H]DAMGO binding combined with Schild analysis demonstrated that the inhibition of DAMGO binding by the isoquinolinesulfonamides was competitive. These results show that the isoquinolinesulfonamide protein kinase inhibitors directly interact with the mu opioid receptor. Thus, these compounds are unsuitable for the investigation of the potential role of protein phosphorylation in the modulation of mu opioid receptor binding. PMID- 7840779 TI - Uptake and cytotoxicity of 9-methoxy-N2-methylellipticinium acetate in human brain and non-brain tumor cell lines. AB - 9-Methoxy-N2-methylellipticinium acetate (MMEA) was preferentially cytotoxic to human brain tumor cell lines in the in vitro primary screen of the U.S. National Cancer Institute. In the present study, the average intracellular accumulation of radioactivity derived from [14C]MMEA concentrations that were selectively cytotoxic to sensitive brain tumor cell lines was nearly 4-fold greater than in human tumor cell lines derived from the lung, kidney, ovary and colon. The extent of peak cellular accumulation of [14C]MMEA-derived radioactivity, achieved after 10-15 hr of drug exposure, was correlated positively with relative MMEA cytotoxicity in brain tumor cell lines (r2 = 0.963). A similar correlation (r2 = 0.967) was observed in selected non-brain tumor cell lines but required substantially higher (18-fold) concentrations of MMEA. [14C]MMEA radioactivity accumulation by a selected glioblastoma cell line occurred via an energy requiring system that was predominantly sodium and pH independent. PMID- 7840780 TI - Involvement of inositol 1,4,5-triphosphate and protein kinase C in thrombin induced contraction of porcine pulmonary artery. AB - The role of the intracellular messengers inositol 1,4,5-triphosphate (IP3) and protein kinase C (PKC) in the thrombin (3 U/mL)-induced contraction of endothelium-denuded porcine pulmonary arteries was investigated. Thrombin induced a sustained contractile response with an initial transient increase in IP3 to about 160% of the unstimulated control. Omission of extracellular Ca2+ or preincubation with verapamil (10 mumol/L) reduced the maximum of contraction without significantly affecting the thrombin-induced increase in IP3. To evaluate the role of PKC for the contractile response, the PKC was activated directly by phorbol 12,13-dibutyrate (PDBu, 50 nmol/L). The phorbol ester produced a slowly increasing tonic contraction without any changes in the basal IP3 level. There was a moderate inhibition of PDBu-induced contractions in Ca(2+)-free solution, while they were not inhibited after preincubation with verapamil. Preincubation with the PKC inhibitor staurosporine (50 nmol/L) significantly reduced the PDBu induced contraction (by about 80%). In thrombin-stimulated vessels staurosporine only inhibited the tonic phase of the contractile response whereas the increase in IP3 and the phasic component of contraction were still evident. These results suggest that IP3 and PKC are involved in the thrombin-induced contraction. The phasic component of contraction is associated with the generation of IP3; the tonic component might be due to the activation of PKC. PMID- 7840781 TI - Short synthetic peptides exploited for reliable and specific targeting of antibodies to the C-termini of cytochrome P450 enzymes. AB - An antibody was raised against a synthetic peptide (Ser-Glu-Asn-Tyr-Lys-Asp-Asn) corresponding to residues 290-296 of the cytochrome P450 enzyme, CYP1A2, of both rat and mouse. A cysteine residue attached to the N-terminus of the peptide during synthesis allowed coupling in a specific orientation via the thiol group to the carrier protein, keyhole limpet haemocyanin. Antiserum raised in rabbits bound specifically to CYP1A2 in the rat and mouse. To determine those amino acid residues involved in binding of the antibody, related peptides of various lengths were synthesised and the binding of the antibody was determined by an enzyme linked immunosorbent assay. These studies show that the minimum epitope is the C terminal tripeptide sequence, Lys-Asp-Asn. Other than in rat and mouse CYP1A2, this tripeptide is found as an internal sequence in a large number of proteins including bovine fibronectin, chicken gizzard myosin heavy chain, and the P450 enzymes, rabbit CYP3A6 and human CYP3A4, but the antibody did not bind to any of these proteins. However, the antibody did bind to yeast glucose-6-phosphate dehydrogenase in which the tripeptide sequence is the C-terminus. Antibodies raised against a truncated peptide (Tyr-Lys-Asp-Asn), representing the C-terminal half of the peptide, also bound to glucose-6-phosphate dehydrogenase, but failed to bind to CYP1A2; thus although the C-terminal region of the peptide 290-296 is strongly immunogenic, it appears that it is not this population of antibodies that binds to CYP1A2. As antibodies were found to bind strongly to the C-terminus of glucose-6-phosphate dehydrogenase, the C-termini of proteins as targets for anti-peptide antibodies were investigated further by immunising rabbits with four 5-residue peptides which represent the C-termini of the P450 enzymes, CYP1A1, CYP1A2, CYP2E1 and CYP2A6. The peptides were coupled to keyhole limpet haemocyanin through their N-termini via cysteine residues added to the sequences. All four antisera bound specifically to their respective target proteins, as demonstrated by immunoblotting using hepatic microsomal fractions from rat, rabbit and human. It is suggested that this method of antibody production could be of general use for the reliable production of antisera against proteins where their sequence at the C-terminus is known, and such antibodies can be highly specific as they do not bind to internal sequences. PMID- 7840782 TI - Reversal of methylmercaptopurine ribonucleoside cytotoxicity by purine ribonucleosides and adenine. AB - 6-Methylmercaptopurine ribonucleoside-5'-phosphate (MeSPuRMP), the sole metabolite of 6-methylmercaptopurine ribonucleoside (MeSPuRib), is a strong inhibitor of purine de novo synthesis, inducing depletion of intracellular purine nucleotides and subsequent cell death in several tumor cell lines. In this study prevention of MeSPuRib cytotoxicity by compounds of the purine salvage pathway was studied in Molt F4 human malignant T-lymphoblasts. Adenosine, adenine and inosine were able to prevent depletion of the adenine nucleotide pool when used in combination with 0.5 microM MeSPuRib, but had virtually no effect on depletion of guanine nucleotides. Nevertheless, these three purine compounds were able to reduce the cytotoxic effects induced by MeSPuRib. Addition of guanosine to cells treated with 0.5 microM MeSPuRib normalized the guanine nucleotide pool, but adenine nucleotides remained depleted. Under these conditions, inhibition of cell growth was significantly decreased. With the combination of guanosine and 10 microM MeSPuRib, cytotoxicity was increased compared to 10 microM MeSPuRib alone, associated with a depletion of adenine nucleotides to 9% of untreated cells. Since cell growth and cell viability of Molt F4 cells are less inhibited by MeSPuRib under conditions where adenine nucleotide depletion is prevented by purine compounds (and where the other nucleotides are depleted) we conclude that depletion of adenine nucleotides is an important factor in MeSPuRib cytotoxicity. PMID- 7840783 TI - N-ethyl maleimide stimulates arachidonic acid release through activation of the signal-responsive phospholipase A2 in endothelial cells. AB - Treatment of bovine endothelial cells with the alkylator N-ethyl maleimide results in arachidonic acid mobilization. N-ethyl maleimide-stimulated arachidonic acid release was dose and time dependent and maximum release was achieved after 10-15 min with 50 microM N-ethyl maleimide, N-ethyl maleimide stimulated arachidonic acid release could be prevented by pretreating the cells with the phospholipase A2 inhibitor quinacrine. Based on the finding that N-ethyl maleimide was not able to release oleic acid from oleic acid-preloaded cells, it was clear that the effect of N-ethyl maleimide was limited to an arachidonic acid specific phospholipase. The effect of N-ethyl maleimide does not appear to be dependent on calcium, as shown by the observation that N-ethyl maleimide was not able to increase intracellular calcium concentration in FURA2-loaded cells. Pretreatment of the cells with staurosporine totally inhibited N-ethyl maleimide stimulated arachidonic acid liberation. The tyrosine kinase inhibitor genistein was also able to significantly inhibit arachidonic acid release. It is concluded from the results obtained in this study that N-ethyl maleimide stimulates arachidonic acid release by stimulating the activity of a specific, signal responsive phospholipase A2. Furthermore this activation is not mediated by intracellular calcium fluxes but by a stimulation of intracellular kinase activity which eventually leads to the activation of this signal-responsive phospholipase A2. PMID- 7840784 TI - Endotoxin inhibits glucuronidation in the liver. An effect mediated by intercellular communication. AB - Endotoxin [lipopolysaccharide (LPS) 50 micrograms/mL] added to the perfusion medium increased glucose production and inhibited the glucuronidation of p nitrophenol in perfused mouse liver both in recirculating and non-recirculating systems, while sulfation of p-nitrophenol was unchanged. The effects of endotoxin could be prevented by the addition of cyclooxygenase inhibitors, while PGD2 and PGE2 also caused a decrease in p-nitrophenol glucuronidation in perfused liver. In isolated hepatocytes endotoxin failed to affect p-nitrophenol conjugation, while PGD2 and PGE2 decreased the rate of it. Our results suggest that endotoxin inhibits glucuronidation through an intercellular communication presumably mediated by eicosanoids. PMID- 7840785 TI - Regional selectivity in ethanol-induced pro-oxidant events within the brain. AB - Several biochemical parameters that reflect the presence of excess levels of reactive oxygen species were modulated in the brains of rats exposed acutely or subchronically to ethanol. These parameters included depression of cytosolic glutathione (GSH) concentration and of glutamine synthetase levels. However, using these indices, there was a significant difference in susceptibility to ethanol in different brain regions. After dietary exposure to ethanol for 12 days, these indices were selectively depressed in the striatum but not in the cerebral cortex or cerebellum. Eighteen hours after a single acute dose of ethanol (4.5 g/kg body wt), the striatum was also the only one of these areas in which proteolytic activity was elevated by ethanol treatment. Two injections of acetaldehyde (300 mg/kg), given 18 and 2 hr prior to tissue preparation, caused a specific reduction of glutamine synthetase in the striatum and a decrease of GSH levels in both striatum and cerebellum. Taken together, the results suggest a distinctive vulnerability of the striatum to ethanol-promoted oxidative events. Rather than ethanol exerting effects directly, the metabolite acetaldehyde may be the primary agent responsible for these changes. PMID- 7840786 TI - Identification and quantification of the indole alkaloid ibogaine in biological samples by gas chromatography-mass spectrometry. AB - A sensitive and highly selective analytical chemical method for measuring the indole alkaloid ibogaine in biological samples has been developed. The method utilizes organic extraction, derivatization with trifluoroacetic anhydride, and detection by combined gas chromatography-mass spectrometry. The deuterated analog of ibogaine, O-[Cd3]-ibogaine, was synthesized and used as an internal standard for the method. Standard curves, constructed from variable amounts of ibogaine (50-400 ng) and a fixed amount of internal standard (250 ng) were linear. The method has an approximate detection limit of at least 20 ng/mL of tissue extract (180 ng/g tissue), with a coefficient of variation of 8 to 12.5%. Chemical stability studies with the method found that aqueous ibogaine solutions (1-10 mg/mL) could be stored at 10 degrees for up to 7 months with no more than 10% loss. The method was also used to measure brain ibogaine levels in rats 1 and 19 hr after a single dose of drug (40 mg/kg, i.p.); the results suggest a rapid disappearance of the drug after i.p. dosing. The method will help reveal the pharmacokinetic properties of this putative anti-addictive agent in animals and humans. PMID- 7840787 TI - Kappa opioid receptors expressed on three related thymoma cell lines. Differences in receptor-effector coupling. AB - The mouse thymoma R1.1 cell line was shown previously to express a single high affinity kappa 1 opioid receptor that is negatively coupled through a pertussis toxin-sensitive G-protein to adenylyl cyclase. This study compared opioid receptor binding and inhibition of adenylyl cyclase activity in three unique derivatives of the R1.1 cell line. Membranes from the R1.G1 and R1E/TL8x.1.G1.OUAr.1 (R1EGO) cell lines bound both [3H]U69,593 and [3H](-) bremazocine with similar affinities compared with R1.1 membranes, whereas membranes from the R1E/TL8x.1 (R1E) cell line did not possess any opioid binding sites, detected by radioreceptor binding. The Bmax values for [3H]U69,593 and [3H]-(-)-bremazocine binding to R1.G1 and R1EGO cell membranes were, respectively, 3- and 6-fold greater than those obtained with the parent R1.1 cell line. GTP and its nonhydrolyzable analog, Gpp(NH)p, inhibited [3H]U69,593 binding to all three cell lines. Stimulation of low-Km GTPase activity by the kappa selective agonist (-)U50,488 was greatest in R1.G1 membranes, followed by R1EGO and R1.1. The maximal inhibition of forskolin-stimulated adenylyl cyclase activity by (-)U50,488 was 66 +/- 2% in R1.G1 and 49 +/- 2% in R1EGO, compared with 37 +/- 1% in R1.1 membranes. Whereas maximal inhibition of adenylyl cyclase activity did not correlate with receptor number among cell lines, the inhibition of cyclic AMP production did correlate with stimulation of low-Km GTPase activity. The R1.1 cell line and its derivatives, R1.G1 and R1EGO, express a similar type of kappa opioid receptor, which exhibits differences in coupling to G-proteins and to adenylyl cyclase among cell lines. These cell lines provide an excellent model system for studying the regulation of opioid receptor-adenylyl cyclase coupling efficiency. PMID- 7840788 TI - Effect of nitric oxide on albumin-palmitate binding. AB - Bovine serum albumin (albumin) was modified by treatment with nitric oxide (NO) to form S-nitrosoalbumin. Analysis of the reduced sulfhydryl groups showed that more than 99% of the albumin was converted to S-nitrosoalbumin. Using a 1:1 molar ratio of protein:palmitate, the unbound palmitate fraction in the presence of S nitrosoalbumin was determined to be greater (28%) than in the presence of albumin as determined by heptane: water partitioning. NO degradation products neither affected the palmitate heptane:water partition ratio in the absence of binding protein nor the hepatocyte uptake of [3H]palmitic acid. The equilibrium association constants (Ka) for albumin-palmitate and S-nitrosoalbumin-palmitate complexes were determined using the stepwise equilibrium model. The Ka for the first and second palmitate binding sites were (4.6 +/- 1.2) x 10(8) M-1 and (3.3 +/- 0.5) x 10(7) M-1 and (3.1 +/- 0.9) x 10(8) M-1 and (1.3 +/- 0.8) x 10(8) M-1 for albumin and S-nitrosoalbumin, respectively. Thus, the increased unbound fraction of palmitate in the presence of S-nitrosoalbumin was apparently due to a decreased binding affinity at the first high-affinity binding site. Palmitate uptake by hepatocyte suspensions was 27% higher in the presence of S nitrosoalbumin as compared with albumin. This increase paralleled the increased unbound palmitate fraction. When the albumin concentration was adjusted to account for the increased unbound fraction, there was no difference in the palmitate uptake rates between albumin and S-nitrosoalbumin. Our findings indicate that under conditions where NO concentrations are high (e.g. cirrhosis) and extensive S-nitrosylation of serum albumin occurs, the decreased ligand binding ability of S-nitrosoalbumin may be an important consideration when modeling drug uptake in pathological states. PMID- 7840789 TI - Differential effect of cytokines on the phenobarbital or 3-methylcholanthrene induction of P450 mediated monooxygenase activity in cultured rat hepatocytes. AB - Cultured rat hepatocytes have been used to compare the relative activities of cytokines to inhibit the phenobarbital (PB) or 3-methylcholanthrene (MC) induction of cytochrome P4502B1 and 2B2 (P4502B1/2) or P4501A1 and 1A2 (P4501A1/2), respectively. Recombinant cytokines tested were human interleukin-6 (IL-6), interleukin-1 alpha and -beta (IL-1 alpha and IL-1 beta, respectively), and rat gamma-interferon (INF gamma). Hepatocytes were cultured in the presence of 2 mM PB or 1 microgram MC/mL culture medium for 24 hr with or without the cytokines. Benzyloxyresorufin and ethoxyresorufin O-dealkylase (BROD and EROD, respectively) activities were determined as indices of P4502B1/2 and P4501A1/2, respectively. All cytokines produced a concentration-dependent inhibition of the PB induction of BROD activity. IL-1 beta and IL-6 were approximately equipotent with IC50 values of 1-2 U/mL, causing greater than 90% inhibition of PB induction of BROD activity at a concentration of 50 U/mL culture medium. IL-1 alpha tended to be less active. PB induction of BROD activity was also inhibited by INF gamma, but higher concentrations (62.5 to 500 U/mL culture medium) were required. All cytokines were less effective in inhibiting the MC induction of EROD activity than the PB induction of BROD activity. IL-1 beta and IL-6, at 50 U/mL culture medium, inhibited EROD induction by only 35% compared with the greater than 90% inhibitory effect on the PB induction of BROD activity. INF gamma was ineffective in inhibiting EROD activity at the concentrations studied. Western immunoblot analysis indicated that the cytokines prevented the ability of the inducers to increase the expression of P4502B1/2 and P4501A1/2 immunoreactive proteins, and this effect correlated with their inhibitory effect on induction of enzyme activity. The results suggest that inducible isoforms of cytochrome P450 differ in their susceptibility to regulation by the cytokines, and that cytokines possess differential activity to inhibit the induction of P450 isoforms, with IL 1 beta and IL-6 being the most effective. PMID- 7840790 TI - GSH-independent denitration of the nitrate ester of a dihydropyridine derivative in rabbit hepatic cytosol. AB - The denitration of a dihydropyridine derivative having two nitrate ester groups, 2-nitroxypropyl 3-nitrooxypropyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3, 5 pyridinedicarboxylate (NND), by rabbit hepatic cytosol was investigated. Sephadex G-150 chromatography of ammonium sulfate precipitate (30-60%) from the cytosol demonstrated the presence of two distinct activities (peak I and peak II) responsible for denitration of [14C]-NND. The first peak, peak I, was observed in the presence of dithiothreitol (DTT), but not in the presence of glutathione (GSH). Moreover, the denitration activity of peak I was not inhibited by S-hexyl GSH, an inhibitor of GSH S-transferase (GST), indicating that peak I possessed no GST activity. In contrast, the denitration activity of peak II, having GST activity, required GSH and was inhibited by S-hexyl GSH. These results strongly suggest that the GSH-independent enzyme system(s), in addition to GST, is responsible for denitration of nitrate esters of NND. PMID- 7840791 TI - Unimpaired metabolism of pyridine dinucleotides and adenylates in Chinese hamster ovary cells during oxidative stress elicited by cytotoxic doses of copper putrescine-pyridine. AB - Copper-putrescine-pyridine (Cu-PuPy) effectively dismutates superoxide but is also known to produce H2O2 in a redox cycle with glutathione. The treatment of Chinese hamster ovary (CHO) cells with 0.2 mM Cu-PuPy reduced clonogenic survival to 10(-3) in 50 min and caused significant oxidation and depletion of glutathione and continuous accumulation of protein-glutathione mixed disulfides. Remarkably, other important functional parameters of cell metabolism were not impaired: adenylate pool size, adenylate energy charge and the redox ratios of NADP(H) and NAD(H) remained constant. Moreover, within 200 min the pool size of NADP(H) increased linearly by a factor of four at the expense of the NAD(H) pool, resulting in an 8-fold increase in the ratio of NADPH to glutathione disulfide. Also, Cu-PuPy led to a dose-dependent, persistent inactivation of glutathione reductase, which could be reversed by copper chelators. In contrast to Cu-PuPy, glucose oxidase-generated H2O2 induced oxidation and loss of pyridine dinucleotides, depletion of the adenylate pool and deterioration of the energy charge. Oxidation and depletion of bulk glutathione were comparable to a Cu-PuPy treatment, but formation of protein-glutathione mixed disulfides was significantly less pronounced and reversible. The data indicate that the critical factor in Cu-PuPy cytotoxicity is not its function as catalyst of glutathione oxidation and H2O2 generation, but essentially its disruption of antioxidative cellular defence by inactivation of glutathione reductase. The data further suggest that Cu-PuPy inhibits ADP-ribosylation. This would explain why pyridine dinucleotide and adenylate pools are unaffected, and may be an essential prerequisite for the observation that cells, albeit sublethally damaged and denuded of their antioxidative defence, may be rescued by extending Cu-PuPy treatment. PMID- 7840792 TI - Inhibition of rat liver low Km aldehyde dehydrogenase by thiocarbamate herbicides. Occupational implications. AB - S-Methyl N,N-diethylthiolcarbamate (DETC-Me) is a metabolite formed during the bioactivation of disulfiram. The formation of its corresponding sulfoxide, S methyl N,N-diethylthiolcarbamate sulfoxide (DETC-MeSO), from DETC-Me is required for low Km mitochondrial aldehyde dehydrogenase (ALDH2, EC 1.2.1.3) inhibition. DETC-Me is similar in structure to thiocarbamate herbicides with the general structure R1R2NC(O)SR3. Representative herbicides studied were n-propyl, n propylthiocarbamate ethyl ester (EPTC), molinate, vernolate, ethiolate and butylate. All of these thiocarbamate herbicides inhibited rat liver ALDH2 in vivo. The dose of these thiocarbamates that inhibited rat liver ALDH2 by 50% (ID50) when administered 8 hr before determination of ALDH2, was found to be 5.2, 3.1, 1.6, 12, and 174 mg/kg, respectively. These thiocarbamates were ineffective rat liver ALDH2 inhibitors in vitro, unless rat liver microsomes and an NADPH generating system were added to the incubation. The respective thiocarbamate sulfoxides were formed when the thiocarbamates were incubated with liver microsomes and an NADPH-generating system. The thiocarbamate sulfoxides all inhibited rat liver ALDH2 in vitro. An equimolar dose of molinate and molinate sulfoxide inhibited rat liver ALDH2 in vivo to the same degree. Molinate-treated rats challenged with ethanol exhibited a disulfiram-like ethanol reaction. In conclusion, thiocarbamate herbicides inhibit ALDH2, probably due to the formation of their sulfoxide, and therefore have the potential to produce a disulfiram-like ethanol reaction in an unsuspecting population. PMID- 7840793 TI - In vitro insulinotropic action of a new non-sulfonylurea hypoglycemic agent, calcium (2s)-2-benzyl-3-(cis-hexahydro-2-isoindolinyl-carbonyl) propionate dihydrate (KAD-1229), in rat pancreatic B-cells. AB - We examined the in vitro insulinotropic action of a novel non-sulfonylurea compound, calcium (2S)-2-benzyl-3-(cis-hexahydro-2-isoindolinyl-carbonyl) propionate dihydrate (KAD-1229), which is a succinate derivative, using rat pancreatic islets and perfused pancreas. The sodium salt of KAD-1229 free acid (KAD-1229-Na) stimulated insulin secretion from isolated rat islets and perfused rat pancreas in a concentration-dependent manner at 0.1 to 10 microM. It produced a predominant first phase and a less prominent second phase response in the presence of 5.55 mM glucose. An ATP-sensitive K+ (K+ATP) channel activator, diazoxide, eliminated the insulinotropic effect of KAD-1229-Na. Glucose primed the B-cell in the perfused pancreas, but KAD-1229-Na did not. When the insulinotropic effects of 16.7 mM glucose on isolated rat islets were inhibited submaximally by 1 microM norepinephrine, the addition of 1 microM KAD-1229-Na reversed this inhibition. All of these insulinotropic effects of KAD-1229-Na were qualitatively indistinguishable from those of sulfonylurea compounds. We conclude that KAD-1229-Na acts on K+ATP channels of pancreatic B-cells despite its non sulfonylurea structure. PMID- 7840794 TI - Reversal by cytidine of cyclopentenyl cytosine-induced toxicity in mice without compromise of antitumor activity. AB - Among nine compounds surveyed, cytidine was found to be the most effective in reversing the antiproliferative effects of cyclopentenyl cytosine (CPEC) on human T-lymphoblasts (MOLT-4) in culture. Cytidine, at concentrations of 1-25 microM, enabled cells to maintain normal logarithmic growth when added up to 12 hr after exposure to a 200 nM concentration of the oncolytic nucleoside, CPEC. The most abundant CPEC metabolite, CPEC-5'-triphosphate, is a potent [K1 approximately 6 microM] inhibitor of CTP synthetase (EC 6.3.4.2). Accumulation of this inhibitor resulted in a depletion of CTP levels to 17% of their original cellular concentration. Exogenous cytidine reversed CPEC-induced cellular cytotoxicity by suppressing the formation of CPEC-5'-triphosphate by 70%, and by partially replenishing intracellular CTP to at least 60-70% of its original concentration. In vivo, cytidine (500 mg/kg) administered intraperitoneally 4 hr after each daily dose of CPEC (LD10-LD100) for 9 days reduced the toxicity and abolished the lethality of CPEC to non-tumored mice. Of greater practical importance is the finding that, under these experimental conditions, cytidine did not curtail the antineoplastic properties of CPEC in L1210 tumor-bearing mice. Moreover, the concentration range over which CPEC exhibited antineoplastic activity was extended with cytidine administration. PMID- 7840795 TI - Identification of an N-acetylated microsomal glutathione S-transferase by mass spectrometry. AB - Microsomal glutathione S-transferase (mGST) was purified to homogeneity from male Sprague-Dawley rat liver, as determined by SDS-PAGE. Removal of Triton X-100 and further separation by reversed phase HPLC revealed two proteins, mGST 1 and mGST 2, in a 1:3 ratio. Analysis of mGST 1 and mGST 2 by electrospray ionization mass spectrometry determined their molecular weights to be 17,354.2 +/- 6.6 and 17,397.9 +/- 6.6, respectively. mGST 1 was in close agreement with the calculated molecular weight of 17,348, as predicted by the previously reported cDNA sequence. Cyanogen bromide digestion and peptide mapping by fast atom bombardment mass spectrometry (FAB-MS) localized the mass increase to the N-terminal peptide, 1-7. FAB-tandem mass spectrometry of this peptide in conjunction with Edman reactions on the intact protein demonstrated the N-terminal alanine to be acetylated. PMID- 7840796 TI - 1-naphthylisothiocyanate-induced elevation of biliary glutathione. AB - 1-Naphthylisothiocyanate (ANIT) has been used for many years to study cholangiolitic hepatotoxicity in laboratory animals. Hallmarks of ANIT hepatotoxicity include portal edema and inflammation with bile duct epithelial and hepatic parenchymal cell necrosis. In rats, ANIT hepatotoxicity is dependent upon hepatic glutathione. Studies in vitro have demonstrated that ANIT combines reversibly with glutathione and suggest that intracellular formation and secretion of this glutathione-ANIT conjugate from hepatic parenchymal cells may be responsible for the efflux of glutathione observed upon exposure to ANIT. In vivo, glutathione conjugates produced within hepatic parenchymal cells are typically transported into bile for elimination. Therefore, large concentrations of ANIT in bile may result from hepatic parenchymal cell secretion of a reversible glutathione-ANIT conjugate. To investigate this hypothesis, bile and plasma concentrations of ANIT were determined in rats 1, 4, 8, 12 and 24 hr after administration (100 mg/kg, p.o.). Liver and bile glutathione concentrations were also evaluated. Plasma ANIT concentrations ranged between 2 and 5 microM at 1, 4, 8 and 12 hr and were 0.9 microM at 24 hr after administration. ANIT concentrations in bile at 1, 4, 8 and 12 hr were 60, 28, 21 and 22 microM, respectively. Thus, ANIT was concentrated in bile. Hepatic glutathione was not affected by ANIT during the first 12 hr after administration; however, a moderate elevation occurred by 24 hr. In contrast, a marked elevation in bile glutathione concentration (two times control) occurred 1, 4 and 8 hr after ANIT administration. Thus, the early accumulation of ANIT in bile was coincident with an elevation in bile glutathione. These findings support the hypothesis that glutathione functions to concentrate ANIT in bile. The large concentration of this toxicant in bile may be injurious to bile epithelium, a primary cellular target in ANIT hepatotoxicity. PMID- 7840797 TI - Cyclopentenyl uracil: an effective inhibitor of uridine salvage in vivo. AB - Cyclopentenyl uracil, a non-cytotoxic inhibitor of uridine kinase, was found to effectively block the salvage of circulating uridine by host and tumor tissues in the intact mouse. Dose-response characteristics of the inhibition were determined. Large doses (1 g/kg) of cyclopentenyl uracil were required, and the effect of a single dose fell rapidly over a 24-hr period. A sustained inhibition of uridine salvage of > 64-79% could be maintained by multiple doses of 1 g/kg given on an every 8-hr schedule. Mice given cyclopentenyl uracil (1 g/kg) every 8 hr for 5 days continued to gain weight and showed no signs of toxicity; however, the combination of cyclopentenyl uracil with a non-toxic dose of N (phosphonacetyl)-L-aspartic acid (PALA; 200 mg/kg daily for 5 days) was lethal to mice, indicating that circulating uridine modifies the toxicity of agents that act on enzymes of the de novo pyrimidine pathway. Although the duration of action and potency of cyclopentenyl uracil are not ideal, this is the first demonstration of an effective inhibition of uridine salvage in the intact mouse with a non-cytotoxic agent. This makes possible the evaluation of concurrent inhibition of de novo and salvage routes to pyrimidine nucleotides as an approach to chemotherapy. PMID- 7840798 TI - Studies on the reactivity of acyl glucuronides--VIII. Generation of an antiserum for the detection of diflunisal-modified proteins in diflunisal-dosed rats. AB - Acyl glucuronide metabolites of carboxylic drugs such as the salicylate derivative diflunisal (DF) have been shown to react with proteins to produce covalent adducts. To aid in the study of the formation and distribution of these adducts in both humans and rats, we raised an antiserum against human serum albumin modified by covalent attachment of DF via an amide bond, using a carbodiimide reagent. This antiserum had wide reactivity, reacting with all types of DF-modified proteins tested and with free DF (albeit at a lower affinity). It did not cross-react with other salicylates or other non-steroidal anti inflammatory drugs. The antiserum has been used in immunoblotting to detect proteins covalently modified by DF in the plasma and livers of rats treated with the drug for 7 days. Although some cross-reactivity was apparent on the blots, a series of DF-modified proteins was found in cytosolic, mitochondrial and mixed membrane fractions of hepatocytes, with molecular weights ranging from 28 to 130 kDa. PMID- 7840799 TI - Inhibition of reduced glutathione synthesis by cyanobacterial alkaloid cylindrospermopsin in cultured rat hepatocytes. AB - Cylindrospermopsin (CY) is a naturally occurring alkaloid produced by the cyanobacterium Cylindrospermopsis raciborskii, which has been linked to an outbreak of hepatoenteritis in humans. We previously showed that CY is cytotoxic to primary cultures of rat hepatocytes and that CY lowers cell reduced glutathione (GSH) at nontoxic doses. Lower cell GSH also potentiates CY-induced cytotoxicity (Runnegar et al., Biochem Biophys Res Commun 201: 235-241, 1994). Our current work examined the mechanism of the fall in cell GSH induced by CY. We excluded several possible explanations for the loss in GSH, namely increased formation of oxidized glutathione (GSSG), increased GSH efflux, hidden forms of GSH, decreased GSH precursor availability, or decreased cellular ATP level. To address whether the fall in GSH was due to decreased GSH synthesis or increased GSH consumption, we examined the rate of fall in total GSH after 5 mM buthionine sulfoximine (BSO, an irreversible inhibitor of GSH synthesis) treatment. The rates of fall in total GSH (nmol/10(6) cells/hr) were 8.2 +/- 2.5, 6.0 +/- 1.7 and 5.9 +/- 1.3 for control, 2.5 microM and 5 microM CY-pretreated cells, respectively. This suggests that the fall in GSH induced by CY was due to the inhibition of GSH synthesis rather than increased consumption, because in the latter case the rate of fall in GSH would have been accelerated by CY pretreatment. Furthermore, excess GSH precursor (20 mM N-acetylcysteine), which supported GSH synthesis in control cells, did not prevent the fall in GSH or toxicity induced by CY. Treatment of cells with the cytochrome P450 inhibitor alpha-naphthoflavone protected partially from CY-mediated toxicity and from the fall in cell GSH. Thus, it is likely that cytochrome P450 is involved in the metabolism of CY, and the metabolite(s) that is generated may be more toxic and/or potent in inhibiting GSH synthesis. Inhibition of GSH synthesis is most likely an important factor in the cytotoxicity of CY. PMID- 7840800 TI - Effect of thimerosal and other sulfhydryl reagents on calcium permeability in thymus lymphocytes. AB - We have studied the effects of thimerosal, a mercurial compound extensively used as a preservative, as well as other sulfhydryl reagents (e.g. p hydroxymercurybenzoate, hydrogen peroxide, bromophenacyl bromide, and mercuric chloride) on Ca2+ homeostasis and the redox status of sulfhydryl groups in thymus lymphocytes. They all induced an increase in [Ca2+]i which was blocked with dithiothreitol, suggesting that they act via the oxidation or blockade of sulfhydryl groups. [Ca2+]i increase could be directly related to the effect of the different reagents on cellular protein sulfhydryl content. Experiments with ethidium bromide indicate that the observed rise in [Ca2+]i was not due to a non specific increase in membrane permeability. Thimerosal differs from the other agents studied in its oxidative properties, which is probably linked to the production of a potent reductor molecule, thiosalicylic acid, which may modulate its oxidative capacity. PMID- 7840801 TI - Reductive activation of halothane by human haemoglobin results in the modification of the prosthetic haem. AB - The metabolic activation of halothane by human haemoglobin (Hb) under reducing conditions in vitro is reported. Absolute spectra of sodium dithionite-reduced Hb, recorded during its anaerobic incubation in the presence of the substrate, showed decreasing concentrations of reduced Hb (Hb2+) with time. The loss of Hb2+ was accompanied, although only to some extent, by a concurrent oxidation to methaemoglobin (Hb3+), suggesting that electron transfer from Hb to the substrate had occurred. Reductive halothane metabolism was observed under these conditions as indicated by a dose-dependent inorganic fluoride (F-) production, which was, however, lower than that observed with heated Hb or a water soluble haem preparation (methaemalbumin). A rapid, partial loss of Hb was found upon addition of the substrate to the incubation mixture, as indicated by a decrease of the typical peak at 418 nm in the absolute spectra recorded in the presence of carbon monoxide (CO). This effect was associated with a loss of the Hb prosthetic group, haem, as shown by a decrease of the pyridine-haemochromogen reaction. Both effects were time and dose dependent. The inhibition of the Hb inactivation reaction by adding exogenous CO or the spin trapping agent N-t-butyl-alpha phenylnitrone (PBN) to the incubation mixture beforehand indicated that (a) a reduced and free haem iron is required by Hb to activate halothane, and (b) the formation of free radical reactive metabolites of halothane is likely to be responsible for Hb inactivation. The mechanism of the reaction may involve the attack of these metabolites on the haem group of Hb, as indicated by the detection, with a reverse-phase ion-pairing HPLC system, of two Hb-derived products showing a typical haem-like absorption spectrum. The present results resemble those obtained recently with carbon tetrachloride (Ferrara et al., Alternatives to Laboratory Animals 21: 57-64, 1993) and suggest a common mechanism of activation of the two polyhalogenated alkanes by Hb. PMID- 7840802 TI - Enhancement of leukotriene A4 biosynthesis in neutrophils from patients with rheumatoid arthritis after a single glucocorticoid dose. AB - Human blood polymorphonuclear cells (PMN) from seven patients with active rheumatoid arthritis (RA) were compared for their capacities to produce leukotrienes ex vivo before (D0) and 24 hr (D1) after glucocorticoid pulse therapy. The present study shows for the first time that endogenous arachidonic acid metabolism via 5-lipoxygenase pathway is significantly increased after glucocorticoid administration, leading to increased generation of the unstable precursor leukotriene A4 (LTA4) followed by predominant non-enzymatic LTA4 opening and leukotriene B4 (LTB4) omega-hydroxylation pathway. These results are unexpected since usually glucocorticoids are usually thought to decrease inflammatory mediator biosynthesis and, moreover, they work to the detriment of the clinical improvement of the patient. The results are discussed in terms of product inactivation and cellular cooperation with monocytes and endothelial cells. PMID- 7840803 TI - Evidence for a second pathway in the action mechanism of 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD). Significance of Ah-receptor mediated activation of protein kinase under cell-free conditions. AB - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) when administered directly to a nuclear-free subcellular homogenate of guinea pig adipose tissue, caused a significant rise in protein kinase activities within 1-10 min. Such a rapid response was not expected, based on the classic transcriptional mechanism of action for TCDD, i.e. TCDD first binds with its cytosolic Ah-receptor, translocates into the nucleus, dimerizes with "arnt" (a nuclear transcription factor), and activates genes containing "xenobiotic-responsive element" (XRE). The above actions of TCDD on protein kinases were clearly blocked by two specific Ah-receptor blockers, even under cell- and nucleus-free conditions. TCDD-induced increases in protein phosphorylation occurred mainly in cytosolic preparations (i.e. 100,000 g supernatant) devoid of nucleus, microsomes and plasma membranes and were still observed in the presence of inhibitors of protein phosphatases. Furthermore, TCDD caused a rise in protein tyrosine kinase activity in a purified Ah-receptor preparation, as well as in an isolated heat shock protein 90 complex preparation containing the Ah-receptor. This activation took place in the presence of actinomycin D and cycloheximide, indicating a portion of TCDD's action that is unrelated to de novo protein synthesis in this process. We have also obtained evidence indicating that this action of TCDD triggers the protein kinase mediated growth factor signal transduction pathway, such as stimulation of mitogen activated protein kinase 2 and tyrosine kinase activity. These results clearly support the view that the basic action pathway for such a TCDD-induced activation of protein kinases is distinctly different from its conventional action pathway involving changes in gene transcription in the nucleus. PMID- 7840804 TI - Non-specific stimulatory effects of mastoparan on pancreatic islet nucleoside diphosphokinase activity: dissociation from insulin secretion. AB - We examined whether mastoparan (MAS)-induced insulin secretion might involve the activation of nucleoside diphosphokinase (NDP kinase), which catalyzes the conversion of GDP to GTP, a known permissive factor for insulin secretion. MAS and MAS 7 (which activate GTP-binding proteins), but not MAS 17 (an inactive analog), stimulated insulin secretion from normal rat islets. In contrast to their specific effects on insulin secretion, MAS, MAS 7 and MAS 17 each stimulated formation of the phosphoenzyme-intermediate of NDP kinase, as well as its catalytic activity. These effects were mimicked by several cationic drugs. Thus, caution is indicated in using MAS to study cellular regulation, since some of its effects appear to be non-specific, and may be due, in part, to its amphiphilic, cationic nature. PMID- 7840805 TI - Evaluation of computerized edge tracking for quantifying intima-media thickness of the common carotid artery from B-mode ultrasound images. AB - A new method to measure carotid intima-media thickness (IMT) from B-mode ultrasound images was developed that utilizes automatic tracking of the lumen intima and media-adventitia echoes. Phantom studies and human replicate studies under typical clinical protocols for common carotid IMT measurement were carried out to assist in evaluation of the method. A lucite step wedge phantom was used to show that incorporation of sub-pixel interpolation to locate echo boundaries allowed detection of changes in the echo separation that were 5-10 times smaller than the axial resolution of the ultrasound transducer. For average IMT measured in the distal common carotid artery (CCA) wall in 24 subjects scanned twice within 60 days, mean absolute difference was 0.036 mm with a standard deviation of 0.045 mm. Replicate scans obtained 1 week apart of eight subjects by three sonographers showed the intersonographer variability was 5.4%. In another study of 12 subjects scanned every 4 months for 48 months, the root mean square deviation of the IMT measurements from a linear regression line was 0.030 mm. These data indicate that the method is equally precise over short intervals (60 days) and over long intervals (48 months). The new automated computerized edge tracking method presented in this paper represents an advance for image analysis of B-mode ultrasound images of common carotid IMT with measurement variability substantially reduced (2 to 4 times) compared with currently available manual methods. PMID- 7840806 TI - Expression of meta-vinculin in human coronary arteriosclerosis is related to the histological grade of plaque formation. AB - In the present study we demonstrate that the quantitative reduction of meta vinculin expression parallels histological changes during the course of coronary arteriosclerosis. Immunofluorescence stainings of coronary arteries revealed that vinculin distribution resembled that of other smooth muscle-specific cytoskeletal proteins like alpha-actin, caldesmon or myosin light chain kinase in labeling smooth muscle cells brightly. Although close to arteriosclerotic plaques, the cellularity as measured by the density of nuclei was often not significantly altered. Cells of this location expressed markedly reduced amounts of vinculin, suggesting that they are smooth muscle cells of a synthetic phenotype. To determine the fractional meta-vinculin content in arteriosclerotic lesions, we performed densitometric scanning of immunoblots incubated with anti-vinculin monoclonal antibodies reacting with both meta-vinculin (150 kDa) and vinculin (130 kDa). In parallel, each tissue sample was evaluated histologically for the degree of arteriosclerotic alterations according to the morphometric atheroma score of Stratford et al. (n = 13). In type 1 lesions covering slight intimal thickening, meta-vinculin represented 36% (mean, range 35%-39%) of the total vinculin immunoreactivity. In type 2 lesions consisting of fibrous plaques of up to twice the original artery wall thickness, meta-vinculin accounted for 28% (mean, range 22%-35%) of the total vinculin content. Meta-vinculin was substantially reduced in type 3 lesions (mean 13%, range 8%-18%) which are characterized by extensive atheromatous plaques. Thus, the meta-vinculin/vinculin ratio differed significantly between early, intermediate and advanced phases of coronary arteriosclerotic plaque formation. PMID- 7840807 TI - Angiotensin-converting enzyme genotype is not associated with endothelial dysfunction in subjects without other coronary risk factors. AB - The DD genotype is a polymorphism of the angiotensin-converting enzyme (ACE) gene, and is associated with a significantly increased risk of myocardial infarction. As endothelial dysfunction is an important event in both early atherogenesis and late atherosclerosis, we hypothesised that the adverse effect associated with the ACE/DD genotype might be mediated via endothelial damage. Using high resolution ultrasound, we studied the brachial arteries of 184 subjects aged 15-73 (mean 38 +/- 14) years, who were all normotensive, non diabetic lifelong non-smokers. Arterial diameter was measured at rest, during reactive hyperaemia (with flow increase causing endothelium-dependent dilation) and after sublingual glyceryl trinitrate (GTN, an endothelium-independent vasodilator). The ACE genotype was determined in each case by DNA amplification; 49/184(27%) had DD, 89 (48%) had ID and 46 (25%) had II genotype. Flow-mediated dilation (FMD) was 8.5% +/- 3.9% in the DD, 7.8% +/- 4.1% in the ID and 7.8% +/- 4.1% in the II subjects (P = NS). GTN-induced dilation was also similar in the 3 groups. On multivariate analysis, endothelium-dependent dilation was inversely related to age (r = -0.33, P < 0.001), vessel size (r = -0.41, P < 0.001) but not ACE genotype (r = 0.002, P = 0.97). The ACE genotype is unrelated to endothelium dependent dilation in the systemic arteries of clinically well adults. This suggests that the risk associated with this polymorphism may be mediated by other mechanisms. PMID- 7840808 TI - Antiatherosclerotic activity of inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase in cholesterol-fed rabbits: a biochemical and morphological evaluation. AB - Atherosclerotic lesion development was assessed in the thoracic aorta and chronically denuded iliac-femoral artery of hypercholesterolemic New Zealand White rabbits using inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase which have previously been shown to possess varying degrees of hepatoselectivity in rats. Atorvastatin, previously known as CI-981 (2.5 mg/kg), PD135022 (1.0 mg/kg), simvastatin (2.5 mg/kg), lovastatin (2.5 mg/kg), PD134965 (1.0 mg/kg), pravastatin (2.5 mg/kg) and BMY22089 (2.5 mg/kg) were added to a 0.5% cholesterol, 3% peanut, 3% coconut oil diet and fed for 8 weeks. Although reductions in plasma total cholesterol of 27% to 60%, VLDL-cholesterol of 31% to 71% and plasma total cholesterol exposure of 37% to 43% were obtained, no correlation between these parameters and vascular lipid content, lesion size or monocyte-macrophage content was noted. Iliac-femoral lipid content was unchanged; however, atorvastatin and simvastatin significantly reduced the cholesterol content of the thoracic aorta by 45%-62%. Atorvastatin and PD135022 reduced the size of the iliac-femoral lesion by 67% and monocyte-macrophage content by 72%. Simvastatin, lovastatin and PD134965 decreased the monocyte-macrophage content; however, lesion size was unchanged. Pravastatin and BMY22089 had no effect on lesion size or content. No compound significantly reduced the extent of thoracic aortic lesions. We concluded that changes in plasma lipids and lipoproteins noted with the various HMG-CoA reductase inhibitors did not account for the beneficial effect on atherosclerotic lesion development. The antiatherosclerotic potential of the HMG-CoA reductase inhibitors was compound-specific and clearly not a class effect. PMID- 7840809 TI - A case of hyperalphalipoproteinemia associated with albumin complexing. AB - We present a 3 year follow up of a new type of hyperalphalipoproteinemia with stable high density lipoprotein (HDL) concentrations around 6.0 mmol/l in a female with persistently elevated erythrocyte sedimentation rate (ESR). By density gradient ultracentrifugation, next to the intensively colored HDL2 fraction, an additional band between HDL3 and the serum proteins was seen consistently. The patient's plasma contained an unique complex of albumin with apoprotein A-I. Her IgM was 3- to 4-fold elevated was not complexed to HDL. Familial forms of hyperalphalipoproteinemia could be excluded. As a presumed reason for the existence of the HDL-albumin complex we found that the patient's post-heparin plasma lipoprotein lipase activity was over 2-fold increased, while that of hepatic lipase was over 2-fold decreased: no common cause for the existence of the albumin complex and the increased concentration of IgM was found. PMID- 7840810 TI - Acronyms should be explained. PMID- 7840811 TI - Diet-induced hypercholesterolemia and atherosclerosis in heterozygous apolipoprotein E-deficient mice. AB - Apolipoprotein (apo) E is a ligand for the receptor-mediated uptake of lipoprotein remnant particles. Complete absence of apo E in humans leads to a severe form of type III hyperlipoproteinemia. We have used targeted inactivation in murine embryonic stem cells, as also described by others, to specifically study the effects of heterozygous Apoe gene loss on the development of hyperlipidemia. After 6 weeks on a severe semi-synthetic atherogenic diet, heterozygous null mutants, with only one functional Apoe alle, developed hypercholesterolemia as compared with controls (10.1 mM vs. 4.7 mM serum cholesterol). Interestingly, serum cholesterol levels in female heterozygotes were doubled as compared with male heterozygotes (15.0 mM vs. 7.5 mM). On this diet, heterozygous apo E deficient mice also showed an increased susceptibility to atherosclerosis, depending on gender (mean lesion area per section of 9524 microns 2 vs. 61,388 microns 2 for males and females, respectively), whereas wild type mice displayed far fewer lesions (354 microns 2 and 9196 microns 2 for males and females, respectively). This study indicates that a subnormal expression level of the Apoe gene leads to hypercholesterolemia and, consequently, to an increased susceptibility to the development of atherosclerosis. PMID- 7840812 TI - Vitamin E reverses cholesterol-induced endothelial dysfunction in the rabbit coronary circulation. AB - Hypercholesterolaemia and atherosclerosis are associated with impaired endothelium-dependent vasodilation. In this study we have examined the effects of vitamin E on cholesterol-induced endothelial dysfunction in the rabbit coronary circulation. Rabbits were maintained for 4 or 8 weeks on one of three experimental diets: (a) control chow, (b) 1% cholesterol or (c) 1% cholesterol for the first half of the treatment period followed by 1% cholesterol + 0.2% vitamin E during the last half of the treatment. After sacrifice, vasodilator responses to acetylcholine and sodium nitroprusside in the isolated perfused heart were studied. Responses to sodium nitroprusside were similar between the groups whereas responses to acetylcholine were significantly impaired in cholesterol-fed rabbits after both 4 and 8 weeks when compared to controls. In the cholesterol + vitamin E group, responses to acetylcholine were similar to controls and significantly greater than in the group receiving cholesterol alone. These results show that both 4 and 8 weeks of cholesterol-feeding induces an endothelial dysfunction in the coronary circulation of the rabbit, and that vitamin E protects against this dysfunction. By comparing responses to acetylcholine in the 4 week cholesterol group with the 8 week cholesterol + vitamin E group it was shown that vitamin E may not only prevent further deterioration of the endothelial function in the rabbit heart, but may also reverse the adverse effects of hypercholesterolaemia. PMID- 7840813 TI - Activation of the phagocytic system increases intimal proliferation in hypercholesterolemic rabbits. AB - The effect of in vivo stimulation of the phagocytic system (neutrophils, monocytes and hepatic Kupffer-cells) by inducing phagocytosis of intravenously administered latex particles on lipid peroxidation and aortic intimal proliferation was tested in cholesterol-fed rabbits. Three weeks after starting the diet, aortic intimal proliferation was measured by the intimal to medial ratios and by the incorporation of [3H]thymidine, infused into the circulation for the preceding 14 days. Intimal to medial ratios were increased (0.473 +/- 0.023 vs. 0.282 +/- 0.011, P < 0.01) and aortic [3H]thymidine contents were higher (66.8 +/- 3.5 vs. 27.8 +/- 49 counts/min per mg, P = 0.0001) in latex bead treated than in control animals. Injection of beads transiently increased plasma lipid peroxide levels. At the end of the 3 week experiment, plasma lipid peroxide levels were still elevated and lipid peroxide contents of the aortic walls were higher in the latex-treated rabbits (82.8 +/- 5.8 vs. 46.4 +/- 4.9 nmol/mg cholesterol, latex-treated vs. controls, P = 0.004). These data suggest a significant acceleration of atherogenesis by the stimulated phagocytic system, the mechanism of which may involve lipid peroxidation. PMID- 7840814 TI - Stimulation of rat vascular smooth muscle cell glycosaminoglycan production by angiotensin II. AB - Matrix production by smooth muscle cells (SMC) appears to play a major role in the intimal thickening process. Proteoglycans (PG) are the predominant extracellular matrix component of early restenotic lesions. As angiotensin II (A II) has been proposed as a mediator of restenotic process, we hypothesized that A II may directly affect PG synthesis by SMC. SMC were cultured in the presence of [35S]sulfate and angiotensin II, and both the secreted and membrane-bound proteoglycans were analyzed. A II (1 to 100 nM) evoked a dose- and time-dependent increase in both cell- and media-associated PG production, an effect abrogated by the A II receptor antagonist, saralasin. SMC constitutively synthesize small amounts of PG with a molecular mass of 170-250 kDa. After treatment with A II, the abundance of PG is increased, as well as its molecular mass (230-300 kDa). Selective degradation by chondroitinases and heparinase identified chondroitin and dermatan sulfate PG as the predominant form being induced. These results demonstrate that the effect of A II is not general and is specific to certain classes of PGs. In order to further examine the specificity of the A II effect, we compared the synthesis of PG induced by A II with that induced by platelet derived growth factors AA and BB (PDGF-AA and -BB), insulin-like growth factor I (IGF-I), and tumor necrosis factor alpha (TNF alpha). This comparison demonstrated that the profile of PG induced by A II is different from the other factors examined. Taken together, these data indicate that A II may not only function as a hypertrophic factor for SMC, but in addition may also be a potent modulator of specific PG synthesis by these same cells, which could significantly contribute to the formation of atherosclerotic and restenotic lesions. PMID- 7840815 TI - Iron induces lipid peroxidation in cultured macrophages, increases their ability to oxidatively modify LDL, and affects their secretory properties. AB - The present study demonstrates for the first time that iron ions can induce lipid peroxidation in intact macrophages without causing cell death. Macrophage lipid peroxidation increases cell-mediated oxidation of LDL, enhances the release of interleukin 1 and inhibits the release of apolipoprotein E from the macrophages. When cultured macrophages were exposed to ferrous ions (50 microM FeSO4) for 4 h at 37 degrees C, cellular lipid peroxidation (measured by analyses of malondialdehyde (MDA), conjugated dienes (CD), and lipid peroxides (PD)) increased 2-4-fold in comparison with non-treated cells. This process was iron dose dependent, reached its maximum after 4 h of incubation, and was accompanied by 68% and 53% reductions in the content of the cellular linoleic (18:2), and arachidonic acid (20:4), respectively, and by 29% and 36% reductions of cellular vitamin E and vitamin A, respectively. Cell viability (measured by trypan blue exclusion, by [3H]thymidine incorporation into DNA, by analysis of the release of lactate dehydrogenase (LDH) or [3H]adenine), and cell morphology (studied by scanning electron microscopy) were not significantly affected by the iron-induced oxidative stress. Manitol and dimethylthiourea (DMTU), but not catalase or superoxide dismutase (SOD), significantly inhibited iron-induced cellular lipid peroxide formation, suggesting that hydroxyl radical, but not superoxides or hydrogen peroxides, mediated the iron-induced cellular lipid peroxidation. Incubation of LDL (0.2 mg of protein/ml) with oxidized macrophages resulted in LDL lipids peroxidation, as evidenced by an 8-fold increase in the LDL associated MDA in comparison with LDL that was incubated under similar conditions with non oxidized macrophages. Furthermore, oxidation of LDL by oxidized macrophages in the presence of copper ions (10 microM CuSO4) was 2-fold higher in comparison with oxidation of LDL by non-oxidized macrophages. The release of apolipoprotein E from oxidized macrophages decreased by 50%, whereas macrophage release of beta glucuronidase and of interleukin-1 beta increased by 83% and by a factor of 6, respectively. This study demonstrates for the first time that iron ions induce oxidation of the cellular polyunsaturated fatty acids in intact macrophages and that this cellular lipid peroxidation can subsequently induce LDL oxidation. PMID- 7840816 TI - Measurement of antioxidant activity in lipoproteins using enhanced chemiluminescence. AB - We describe a new assay for antioxidant activity (AOA) in lipoprotein solutions based upon their potential to quench light emission from a glowing horseradish peroxidase-catalyzed enhanced chemiluminescent reaction. By comparison with the quenching activity of the tocopherol-analogue trolox the AOA can be quantified. These measurements suggest that all lipoprotein fractions have significant AOA and that this has a non-linear relationship with lipoprotein concentration increasing significantly on a per particle basis at higher concentrations. Mean AOA in very low density, low density and high density lipoprotein fractions were 39.9 +/- 5.3, 20.3 +/- 4.0 and 5.3 +/- 1.0 mumol of trolox equivalents per litre, respectively, when measured at 1 mg protein/ml. Using known values for the protein content of the lipoprotein fractions, these values correspond to 79.8 +/- 10.7, 10.3 +/- 2.0 and 0.84 +/- 0.15 equivalents per particle. Parallel measurements of light emission and conjugated diene formation suggest that the oxidative stress imposed by the peroxidase-catalyzed reaction leads to lipid peroxidation but only after all AOA has been exhausted. AOA was significantly correlated with the alpha-tocopherol content in 30 lipoprotein samples (r = 0.764). This assay offers a rapid and simple method for investigating the effects of diseases, drugs or dietary manipulation on lipoprotein AOA. PMID- 7840817 TI - Dipyridamole inhibits the oxidative modification of low density lipoprotein. AB - The oxidative modification of low density lipoprotein (LDL) is believed to play an important role in the initiation of the atherosclerotic lesion. Dipyridamole, which is used clinically as a coronary vasodilator and an antiplatelet agent, has antioxidant properties. Probucol is a lipid-lowering agent which inhibits the oxidative modification of LDL. We have compared the effect of pharmacological concentrations of dipyridamole and probucol on the oxidative modification of LDL by copper or endothelial cells in vitro. Dipyridamole protected LDL from oxidative modification by either copper ions or endothelial cells at concentrations as low as 2.5 microM while probucol had no effect at this concentration. LDL oxidized with copper in the presence of dipyridamole (20 microM) was less effective than LDL oxidized in the absence of dipyridamole at inhibiting [3H]acetyl-LDL binding to cultured human. THP-1 monocyte derived macrophages. The concentrations of dipyridamole found to inhibit the oxidative modification of LDL in vitro are achieved in vivo using clinically recommended doses. PMID- 7840818 TI - Effects of alcohol on lipoprotein lipase, hepatic lipase, cholesteryl ester transfer protein, and lecithin:cholesterol acyltransferase in high-density lipoprotein cholesterol elevation. AB - The mechanism whereby alcohol increases high-density lipoprotein cholesterol (HDL C) levels is unclear. Lipoprotein lipase (LPL), hepatic lipase (HL), cholesteryl ester transfer protein (CETP) and lecithin:cholesterol acyltransferase (LCAT) act on lipoprotein metabolism. The purpose of the present study is to determine which one or what combination of these factors is responsible for the rise in HDL-C levels following alcohol ingestion. After 3 weeks of abstinence, 12 men consumed 0.5 g/kg bw of alcohol per day for 4 weeks; 13 abstaining men served as controls. Mean plasma total cholesterol (TC) levels were unchanged in either group throughout the study. Among the alcohol consumers, plasma triglycerides (TG), HDL C, apolipoprotein (apo) A-I and A-II levels increased significantly after 3 weeks of alcohol loading but were unchanged in the control group. High-density lipoprotein3 cholesterol (HDL3-C) levels increased significantly in the alcohol consumers after 4 weeks of alcohol loading whereas high-density lipoprotein2 cholesterol (HDL2-C) levels were unaffected. In the controls, neither HDL2-C nor HDL3-C changed significantly. Post-heparin plasma (PHP) LPL activity and mass increased significantly (P < 0.01) after the alcohol ingestion (controls remained unchanged) without changing LPL specific activity. HL, CETP and LCAT activities were unaffected in both groups. We conclude that of the factors considered, LPL contributed the most to the alcohol-induced rise in HDL-C. PMID- 7840819 TI - Ultraviolet A (320-380 nm) radiation causes an alteration in the binding of a specific protein/protein complex to a short region of the promoter of the human heme oxygenase 1 gene. AB - Ultraviolet A (320-380 nm) radiation strongly stimulates expression of the human heme oxygenase 1 gene as a consequence of an enhancement in transcription rate (1). We have used a 147 bp fragment of the promoter of this gene as a probe for DNA binding activity in nuclear extracts prepared from untreated and UVA treated populations of cultured human skin fibroblasts. Analysis using gel electrophoresis mobility shift assays clearly demonstrates the appearance of a strong binding activity unique to UVA-treated extracts that is formed in the absence of de novo protein synthesis. Footprint analysis defines a binding region from -41 to -50 bp that partially overlaps with a region known to constitutively bind upstream stimulatory factor (USF). Further analysis using synthetic oligonucleotides and gel retardation has confirmed that the crucial sequence for binding the protein present in both control and UVA-treated extracts lies within a 26 bp sequence that includes the core USF binding site. UVA radiation appears to lead to a modification of the USF complex (or closely related proteins(s)) to give a structurally modified protein/protein complex which protects only the upstream half of a region originally defined by foot-printing of the promoter with USF. PMID- 7840820 TI - Rationing and the Americans With Disabilities Act. PMID- 7840821 TI - Idiotypic mimicry and the assembly of a supramolecular structure: an anti idiotypic antibody that mimics taxol in its tubulin-microtubule interactions. AB - Taxol, originally extracted from the bark of the western yew, Taxus brevifolia, is reportedly the first of a new class of anti-cancer agents. It acts by promoting and irreversibly stabilizing microtubule assembly, thus interfering with the dynamic processes required for cell viability and multiplication. With the aim of using immunological techniques to study the mechanism of action of taxol, a monoclonal anti-idiotypic antibody that mimics taxol was prepared, using an auto-anti-idiotypic strategy. It and its Fab fragment inhibited the binding of [3H]taxol to microtubules. Moreover, like taxol, both promoted the assembly of tubulin into microtubules. These findings provide an example of an anti-idiotypic antibody capable of assembling an organized supramolecular structure from soluble cellular components. In addition, it further establishes the ability of anti idiotypic antibodies to be functional mimics of ligand molecules bearing no structural similarity to immunoglobulins. The variable regions of the antibody have been sequenced. With the exception of the complementarity-determining region 3, the sequence of the heavy chain variable region is strikingly similar to that of an anti-idiotypic antibody raised to anti-insulin. The finding that a polypeptide can mimic taxol raises the possibility that taxol acts as a peptidomimetic compound that interferes with the function of an endogenous polypeptide. PMID- 7840822 TI - Evolution of homeotic gene regulation and function in flies and butterflies. AB - It has been proposed that the evolution of homeotic genes parallels, and to some degree directs, the evolution of segment diversity in the myriapod-insect lineage. But the discovery of discrete Antennapedia complex (ANT-C) and bithorax complex (BX-C) gene members in crustacea, chelicerates, annelids and various insects, as well as in vertebrates, indicates that the expansion and diversification of homeotic genes preceded the diversification of arthropods and insects. How, then, have these genes influenced the evolution of body plans? To address this question, we now examine homeotic gene expression and regulation in butterflies (Lepidoptera), which, unlike flies, possess larval abdominal limbs and two pairs of wings. We show that the difference in larval limb number between these insects results from striking changes in BX-C gene regulation in the butterfly abdomen, and we deduce that the wing-patterning genes regulated by Ultrabithorax have diverged in the course of butterfly and fly evolution. These findings have general implications for the role of homeotic genes in animal evolution. PMID- 7840823 TI - [Prognostic significance of extra-capsular invasion in cervical lymph node metastases of squamous epithelial carcinoma]. AB - In a retrospective study we evaluated the clinical and histological datas of patients with squamous cell carcinomas of the head and neck to determine the influence of extranodal spread in metastases for the prognosis. Lymph nodes were dissected from the neck dissection specimens and investigated histologically with special regard to extranodal spread. 304 patients (58%) showed positive lymph nodes and 212 of this patients had additionally extranodal spread (70%). Hence, the rate of extranodal spread in the whole investigated group (522 patients) was 40%. For the patients with carcinomas of the hypopharynx the rate of extranodal spread was especially high (70%). Most extranodal spread could be found at levels 2, 3 and 4. We found a correlation between the appearance of extranodal spread and increasing T-stage. 5-year survival rates were greatly different for patients with no metastases (77%) and patients with extranodal spread (28%). We discuss the use of the criteria extranodal spread for the planning of adjuvant chemotherapy. PMID- 7840824 TI - [Immunohistochemical studies of advanced laryngeal and hypopharyngeal carcinomas 3 days after administration of monoclonal antibody against epidermal growth factor receptor]. AB - Sixteen consecutive patients with stage III/IV laryngeal or hypopharyngeal cancer received 0, 20, 100 or 400 mg i.v. of the murine anti EGF-R IgG2a mab EMD 55900 three days before laryngectomy and neck dissection. Presence of macrophages, T cells (CD3) and T-cell subpopulations (CD4/CD8), NK-cells, complement factors (iC3b, C1q, C4c), and expression of MHC class I, MHC class II, ICAM-1 and IL-2-R were determined in cryostat sections of the surgical specimens and compared to normal tissue of the same patient. The antibody showed good binding to EGF-R of malignant and normal tissue. However, no signs of strong inflammatory reactions were noticed. Infiltration with macrophages was directly correlated with the dose of the administered antibody, even in the basal layer of the normal mucosa. No morphological signs of direct destruction of normal and malignant tissue infiltrated by macrophages or other immunocytes were noticed. This finding was underlined by random infiltration with HLA-DR positive-, T- and NK-cells. Possible long-term effects of this antibody--e.g. non-specific stimulation or improved antigenic processing--must be evaluated in further studies. PMID- 7840825 TI - [Significance of the basement membrane for growth of tumors--immunohistochemical aspects with special reference to tumors of the head/neck area]. AB - This report presents the state of current knowledge regarding the importance of basement membrane (BM) for the growth of benign and malignant tumours with special emphasis on tumours of the head and neck. The BM forms a barrier that has to be destroyed by infiltrative tumour cells. Recent immunohistochemical analyses have revealed both quantitative and qualitative changes in the BM composition following malignant transformation of the epithelial cells, thereby allowing malignant ingrowth into the stroma. This BM pattern, however, may also allow an early diagnosis of tumour invasion. Additionally, carcinomas of the larynx demonstrate a correlation between the amount of preserved BM deposition and the grade of tumour differentiation. This fact may also be important in tumour prognosis. PMID- 7840826 TI - [Immunohistochemical analysis of the basement membrane expression in squamous epithelial carcinoma of the larynx]. AB - Epithelial structures are separated from the stroma by a basement membrane (BM) which serves as a barrier for the epithelial cells. Invasive tumour growth as in laryngeal carcinoma, involves the degradation of this barrier. In our present immunohistochemical analysis, we evaluated both the quantitative and the qualitative changes in the BM composition of 50 laryngeal carcinomas. This analysis comprised the localisation of the BM components collagen IV, laminin, and fibronectin. Furthermore, we applied antibodies against BM components that have not, or only very rarely, been analysed in malignant squamous cell neoplasms -particularly collagen VII and heparan sulfate proteoglycan (HSPG). In this study we provide considerable evidence that varying amounts of preserved BM material can be found in laryngeal carcinoma of different grades of tumour differentiation. Especially by comparison of the different staining patterns for collagen IV and collagen VII, we recognised far more gaps in the staining of the BM by collagen VII than by collagen IV. This fact is underlined by the observation that even in G1 carcinomas collagen VII showed in almost 40% of the cases a complete loss of BM staining. In general, we found a correlation between the amount of preserved BM deposition and the grade of tumour differentiation. This fact may underline the significance of the immunohistochemically detectable amount of BM components as a prognostically relevant parameter. PMID- 7840827 TI - [The basement membrane in diseases of the vocal cords: electron microscopy and immunomorphologic findings]. AB - The basement lamina of the epithelium of the true vocal cords of 34 inpatients suffering from chronic laryngitis, Reinke's oedema and squamous cell carcinoma have been investigated with the electron and immunofluorescence microscope. In chronic laryngitis, the lamina fibroreticularis is thickened (due to collagen type VII), corresponding to the clinical finding. In this layer mobile cells of the connective tissue can be found. In cases of Reinke's oedema it is the lamina densa which might be thickened. In this disease, also lamina densa-like material can protrude into the lamina fibroreticularis, and the number of anchoring filaments is increased. In squamous cell carcinoma we found the basement lamina irregularly arranged and folded. The lamina densa was always interrupted by numerous small gaps and in some areas the basement membrane could not be identified over a long distance. Lamina densa-like material was also found between the tumour cells within the epithelium. With the immunofluorescence microscope this material was proven as laminin, collagen type IV and heparan sulfate proteoglycan. Our investigation shows that malignant as well as benign lesions of the true vocal cords are characterised by distinct fine structural findings even concerning the basement lamina. PMID- 7840828 TI - [Immunohistochemical studies of the antibody pattern (tumor markers) of the larynx]. AB - Tumour markers are gaining in importance for the histological differentiation of the squamous cell tumours. They can be implemented in the differentiation of precancerous lesions from cancers. Until now, such immunohistochemical methods have been reported only for the larynx for differentiating precancerous transformation from the normal epithelium by means of antigen specificity; none of these methods, however, are suitable for cytological application. We investigated via the immunopap method a palette of antibodies including our own markers (B/A 2). The proliferation marker Ki 67 is found to be specific in various cells, especially in basal cells. Markers with broad spectrum such as CEA and EMA are of little importance for routine laryngeal diagnosis because of uncharacteristic diffuse reactions. EMA antibodies marked the cylindrical cells. S-100, Vimentin, Ulex, and Factor VIII reacted as non-squamous cell markers. S 100 marked, besides the peripheral nerves, also the small salivary glands of the larynx. Ulex showed mild reaction with all squamous cells. We recommend the epithelial markers B/A 2 and CK 13 for routine histological and cytological examination of the larynx. For detection of proliferation Ki 67 is the appropriate marker. PMID- 7840829 TI - [p53: an important or most overvalued tumor gene?]. AB - Mutations in the tumour-suppressor gene p53 are the most frequent molecular alterations detected in human tumours. p53 protein, which has been called "guardian of the genome", seems to play a key role in cellular DNA repair. Loss of p53 protein function by genetic mutation thereby makes the cell vulnerable to DNA damage, and disposes it to malignant transformation. In different human tumour types the prognostic relevance of p53 alterations is quite variable: While there is evidence of poor prognosis in breast cancer carrying p53 alterations, no such prognostic correlation could be found in low grade astrocytic gliomas. In both tumour types p53 mutations are equally frequent. Malignant transformation is considered a multistep process, and p53 mutations occur at different positions in this cascade in different tumour types. While p53 mutations seem to be an early event in astrocytic gliomas, they affect e.g. colon tumours rather late, during malignant progression from adenoma to carcinoma. These observations underscore the biological importance of p53 mutations in human tumour formation, even if the simple investigation for a prognostic relevance may lead to different results in tumours of different tissues. PMID- 7840830 TI - [Fitness for flying despite laryngectomy]. AB - Fitness for flying following laryngectomy is an outstanding result of reintegration. Similar cases are not described in the literature. The pilot had to pass a lot of tests before he was allowed return to his place in the cockpit. PMID- 7840831 TI - [Closure of an esophagotracheal fistula]. PMID- 7840832 TI - [Trocar for forming an esophagotracheal fistula in secondary implantation of a voice prosthesis]. AB - In patients after laryngectomy it is sometimes difficult to form an esophagotracheal shunt for secondary implantation of an artificial larynx. We have developed a special trocar for this purpose. This new instrument allows the surgeon to form an esophagotracheal shunt in varying anatomic pharynx funnels. A special modified point helps avoid granulation and stenoses surrounding the fistula. PMID- 7840833 TI - [Retrospective and prospective studies of patients with Cogan I syndrome]. AB - Since August 1987 we documented the course of three patients with Cogan-I Syndrome (CS) (interstitial keratitis and audio vestibular disorder). The patients (2 female, 1 male) received oral protease therapy in addition to the corticosteroids. Under oral treatment with proteases the corticosteroid therapy could be discontinued. Regression of inflammatory reaction and improvement of hearing was encountered in all patients. In two cases alpha-1-antitrypsin (AAT) serum levels were profoundly reduced, reaching normal range during therapy. Concomitant to the raise of this parameter improvement of hearing and general status could be encountered. In all 3 cases pathological leukocytosis normalized under treatment with proteases. All patients had increased IgA-levels against varicella zoster virus (VZV) indicating a reactivation. PMID- 7840834 TI - [Electrotherapy--electromythology?]. PMID- 7840835 TI - [Uncertainties in preliminary calculations of overall treatment costs with special reference to costs of medical risk]. AB - This paper explains the problems in calculating global compensation for medical treatment from the physician's point of view. This new system of financing hospitals will be introduced in Germany in 1996. In routine procedures such as tonsillectomy, the costs for complications are not sufficiently included in the price calculation. Basing on "postoperative bleeding after tonsillectomy" as an example, we calculated the costs of this complication per year. A scheme for calculating these costs as well as the costs for concomitant diseases for each case is presented. Evidently the overall price does not include substantial costs, and hence foreseeable losses are inevitable. PMID- 7840836 TI - Importance of different nuclear morphologic patterns in grading prostatic adenocarcinoma. An expanded model for computer graphic filters. AB - The aim of this work was to continue the development of an interactive workstation for the nuclear grading of prostatic lesions by including a large range of nuclear patterns. A previous model was based on four groups: hyperplasia, Mostofi grade 1, Mostofi grade 2 and Mostofi grade 3. Each group included the most common nuclear patterns of the lesions. One set used to test the model included cases showing patterns different from the typical ones of the model. Poor results were obtained for low and medium grades. A review of all the cases in our database led to the conclusion that different nuclear patterns can belong to the same "nuclear grade." Thus, in this work the model was expanded to include six groups: hyperplasia, two subgroups for Mostofi grade 1, two subgroups for Mostofi grade 2 and Mostofi grade 3. A set of 900 nuclei, 150 in each group, was selected to test the model. An additional 300 nuclei, 50 in each group, were used for a test set. The overall success rate for classifying the nuclei in the test set using the new model was 93% as compared to a rate of 71% obtained for the similar test set, described above, using the previous model. Moreover, correlating karyometric features with nuclear morphology indicated a role for nucleoli in nuclear grading. The good results obtained with large and heterogeneous sets of cases indicate that the procedures used to develop this model may be adapted for the development of models for the nuclear grading of other tumors. PMID- 7840837 TI - Use of texture parameters in the classification of soft tissue tumors. AB - Soft tissue tumors are a challenging group of tumors that presents wide morphologic variety. For pathologists, the degree of cellular differentiation, the cellular and nuclear polymorphism and the mitotic rate are major criteria for diagnosis. In image analysis, the architectural organization of such tumors shows local variations that can be understood as texture variations. This study introduced a method of measuring the architectural organization of soft tissue tumors from texture analysis of tissue sections at low magnification. We studied 40 cases of soft tissue tumors classified by pathologists into three groups according to their histologic patterns. Twelve texture parameters were calculated on subimages of 128 x 128 pixels. Our results show that tissue architecture evaluated by texture analysis provides good discrimination of myxoid, spindle cell and round cell tumors. PMID- 7840838 TI - An expert system for teaching cytopathologic diagnosis of lung cancers. AB - An expert system for teaching cytopathologic skills is described. It uses Tao's cytologic criteria as graded feature parameters for comparison against a set of expert descriptors of known carcinomas. The system scores each diagnosis according to the degree of agreement along each feature axis. The system also allows the user to compare his/her description with that of the expert for any of the tumor entities. The expert knowledge base is abstracted into a numerical matrix within the system. This matrix is used for parameter comparison and score interpretation. This design is simple and compact, allowing portability and broad compatibility for small personal computers. Although testing is only at the initial stages, preliminary studies have shown that the system provides reproducible, consistent results. It is useful as a teaching tool for students, residents and staff pathologists. PMID- 7840839 TI - Morphometric and multivariate statistical detection of cancer cells in endometrial cytology. AB - Endometrial carcinoma was discriminated in cytologic studies using morphometric and multivariate statistical methods. On aspirated samples from 70 cases (10 well differentiated adenocarcinomas, 4 hyperplasias and 56 normal controls), clumps of epithelial cells that could be regarded as the most diagnostically relevant were selected in each case. Their cytologic character was reduced to a combination of five quantitative parameters (nuclear size, degree of anisokaryosis, nuclear form index, homogeneity of nuclear chromatin texture and regularity of nuclear arrangement). The five-variate cluster analysis demonstrated that the 70 cases could be classified into three groups: group A (17 cases) was characterized by cells with small nuclear size, slight anisokaryosis, homogeneous chromatin texture and regular nuclear arrangement; group C (12) by cells with large nuclear size, marked anisokaryosis, heterogeneous chromatin texture and irregular nuclear arrangement; and group B (41) by cells with intermediate parameter values. Group C was derived from 10 cases of adenocarcinoma and 2 of atypical hyperplasia, while groups A and B were not derived from any cases of malignancy. This preliminary study indicated that morphometric-statistical classification can be of great help in improving the cytodiagnostic validity and reproducibility of endometrial carcinoma, and it awaits further, practical testing within a significantly larger series of malignancy cases. PMID- 7840840 TI - Size and shape evaluation of astrocytoma nuclei with the shape analytical morphometry software system. AB - Eighteen cases of astrocytomas diagnosed as grades 1-3 of malignancy were studied with analytical morphometry to determine if different grades can be discriminated by size and shape parameters related to the nuclei. The shape analytical morphometry system was used to calculate dimensional measurements and express shape irregularities through quantitative parameters. With the shape asymmetry evaluator procedure, nuclear symmetry was evaluated. All parameters subjected to univariate and multivariate strategies were the same in easily distinguishing grade 1 from the others. Grades 2 and 3 could not be discriminated completely by either dimensional or with analytical parameters revealing strong similarities of nuclear shape and dimensions. PMID- 7840841 TI - Morphometrically assisted grading of astrocytomas. AB - Alcohol-fixed, toluidine-blue-stained smears from 24 astrocytomas (12 low grade and 12 high grade or anaplastic) were included in the study. In each case 50 nuclei from representative areas of the tumor were selected for analysis; quantitative features pertaining to both the entire nucleus and the nucleoli were computed. Nuclear features were nuclear area and total optical density. Nucleolar features were number of nucleoli per nucleus, nucleolar area, variance of the nucleolar area, and mean and variance of the distance of nucleoli from the nuclear membrane. The results showed distinct changes in a number of nuclear and nucleolar features from low to high grade astrocytomas. Features expressing the most pronounced nuclear changes were area, grey level nonuniformity and run percentage. Changes were also found in the following nucleolar features: number of nucleoli, nucleolar area, variance of nucleolar area, nucleolar location and variance of nucleolar location. Linear discriminant analysis was carried out to determine a direction in feature space along which astrocytomas of low and high grade might be ranked. The nuclear area, number of low gray value pixels and a run length feature provided a useful linear combination. The study showed that one can derive a set of objective criteria from morphometric measurements that allows an ordering of astrocytoma cases along an axis and that might be used for continuous grading. PMID- 7840842 TI - Measuring fractal dimensions. Sensitivity to edge-processing functions. AB - The fractal dimension is a useful tool in quantitative histology and cytology, and its measurement is easily implemented on computerized image analysis systems. However, the optimal conditions for capture of images and the effect of image processing functions on the measurement of the fractal dimension have not been reported. Edge-processing functions were applied to images of Euclidean (square) and fractal (Koch island, renal angiogram) objects. The fractal dimension of processed images was measured using implementation of the box-counting method, and the area of thresholded image was also recorded. The method was shown to be accurate, with errors of < 1.5% for objects with known fractal dimensions, and highly reproducible, with a reliability coefficient of 0.972 (95% confidence limits of 0.868-0.987). The fractal dimension of the fractal images showed a marked (> 15%) reduction when a binary noise reduction function was applied with the minimum neighbors limit set above 3. In contrast, the fractal dimension of the Euclidean square was unchanged by this function. The reduction in fractal dimension was due to the erosion of complex convolutions at the edge of the fractal objects. Edge-processing functions should be avoided when manipulating images of fractal objects. PMID- 7840843 TI - Heterologous protein production in transgenic plants. PMID- 7840844 TI - The role of trehalose and other carbohydrates in biopreservation. PMID- 7840845 TI - Modulation of structure and function of enzymes and other biologically active proteins by their specific antibodies. PMID- 7840846 TI - Biotechnology in aquaculture, with special reference to transgenic salmon. PMID- 7840847 TI - DNA mismatch repair systems: mechanisms and applications in biotechnology. PMID- 7840848 TI - The facts and fancy of microgravity protein crystallization. PMID- 7840849 TI - Biotechnology of cereals. PMID- 7840850 TI - Prevention of diabetes and insulitis by neonatal intrathymic islet administration in NOD mice. AB - The murine model of human insulin dependent diabetes mellitus (IDDM), the non obese diabetic (NOD) mouse, develops a T cell-dependent destruction of pancreatic islets. While the target antigens are unknown, there is clearly a lack of tolerance to them. Neonatal intrathymic (i.t.) antigen injection has been successfully employed to prevent insulitis in BB rats but previous i.t. islet antigen studies in NOD mice were done on older mice. We have injected syngeneic islets into the thymus of NOD mice at birth and found that diabetes and insulitis can be completely prevented by this procedure. The effect is islet antigen specific since other T cell responses, including autoimmune salivary infiltration, ard unaffected. Furthermore, contrary to previous studies, cyclophosphamide administration was unable to induce diabetes in treated mice which suggests that deletion or anergy might be the mechanism by which neonatal intrathymic islet injection protects from disease. However, anti-islet antigen antibodies were still present in these mice which suggests that the mechanism of disease protection may be more complex. PMID- 7840851 TI - The viable motheaten (mev) mouse--a new model for arthritis. AB - Homozygous mev mice are first identified at the age of 3-4 days by focal depigmentation of the skin, followed by patchy absence of hair and by necrotic lesions on paws, tail and ears. Of particular interest are the inflammatory reactions in the paws of these animals which consist mainly of polymorphonuclear and mononuclear cell infiltration in the subcutaneous tissue extending to the periosteum and joint, resulting in focal destructive arthritis and osteomylitis. These lesions are to some extent reminiscent of an acute form of rheumatoid-like arthritis. Since mev mice are sterile, a limited number of symptomatic offspring can be obtained by cross-breeding their heterozygous siblings which are phenotypically not distinguishable from mice lacking this mutation. In order to produce a sufficient number of diseased animals for performing pharmacological studies, we have established a model by transferring this disease in lethally irradiated, 8- to 10-week-old syngeneic mice which were grafted with mev spleen cells. Such reconstituted recipients develop first inflammatory symptoms of the paws 2 to 3 weeks after cell transfer. The arthritic inflammation finally affects all paws and toes by 30 to 50 days. This procedure increased the number of mev like mice expressing arthritis, allowing assessment of the effects of standard reference drugs used in the therapy of rheumatoid arthritis (RA). The immunosuppressants cyclosporin and rapamycin and the steroid dexamethasone at therapeutic concentrations exert a strong inhibitory effect on the development of arthritis in this novel model. In contrast, the non-steroidal anti-inflammatory drug phenylbutazone shows only a moderate effect. These results indicate the particular sensitivity of this model for efficacy of potentially new therapeutic but non-cytostatic compounds for clinical use. PMID- 7840852 TI - Involvement of CD4+ cells in lymphocytic choriomeningitis virus-induced autoimmune anaemia and hypergammaglobulinaemia. AB - Development of pathology varies widely between different strains of mice after intracerebral inoculation with the so-called 'docile' isolate of Lymphocytic Choriomeningitis (LCM) virus. The C3HeB/FeJ and B10. Br/SgSnJ mouse strains have been of special interest because they display autoimmune haemolytic anaemia with varying degrees of apparent immunological involvement. In this report, we examined the role of CD4+ T helper cells in this autoimmune response by treating mice with the CD4-specific GK1.5 monoclonal antibody. We also determined if polyclonal activation of B lymphocytes, induced either by LCM virus or by lactate dehydrogenase-elevating virus, another well known B cell activator, correlated with the development of anaemia in these mice. Our results strengthened the central role of the immune system in the anaemia in C3H mice by showing that depletion of CD4+ cells largely, if not completely, abrogated this anti erythrocyte autoimmune reaction. As reported by others, we found that the anaemia was more mild in B10.BR mice than in C3H mice. However, we could not confirm the difference in the degree of B lymphocyte polyclonal activation between these mice. Furthermore, lactate dehydrogenase-elevating virus had no apparent effect on erythrocytes, even though this virus also induced a sharp increase in plasma IgG levels. PMID- 7840853 TI - Primed lymphocytes are boosted by type II collagen of their hosts after adoptive transfer. AB - A central question in understanding autoimmunity is whether an endogenous self antigen can drive an immune response initially triggered by a foreign one. This possibility is here tested by adoptive transfer, in which T and B cells from mice primed with foreign type II collagen were transferred into irradiated syngeneic hosts. Previous work with other protein antigens has established that primed cells normally respond only if boosted after transfer with antigen. In the present case, and in respect only to that portion of the antibody response able to bind to endogenous type II collagen, that requirement did not hold. This indicates that the anti-self component is indeed driven by endogenous antigen, which the transferred lymphocytes presumably obtain from their adoptive hosts. The transfers were carried out in C57BL10.A x DBA/1 mice using donors primed with either chick or bovine collagen, and the non-boosted responses, presumably driven by endogenous antigen, could be followed in a proportion of the recipients for as long as 45 days. PMID- 7840854 TI - The bcl-2 proto-oncogene is overexpressed in systemic lupus erythematosus. AB - Systemic Lupus Erythematosus (SLE) is a disease in which lymphoid hyper reactivity occurs. Whether this is primary or secondary is not always clear. SLE occurs on a well defined genetic background including genes associated with the major histocompatibility complex (MHC) although family studies demonstrate that other genes must be involved as well. Other potential genes include those involved in intrinsic lymphoid hyper-reactivity, for example by preventing programmed cell death. Such examples exist in murine models of SLE, and in this study we provide evidence that one such controlling protein, bcl-2, is expressed in an increased proportion of both B and T cells in SLE patients. The increased expression was not readily related to disease activity measured by the SIS, nor by routine serological markers. This raises the possibility that the increased expression of bcl-2 seen in lymphoid cells from SLE patients may be of intrinsic genetic origin rather than being secondary to the auto-reactive process. Such increased expression could be expected to interfere with programmed cell death, to produce lymphoid hyper-reactivity and to contribute to the induction and maintenance of this prototypic systemic autoimmune disease. PMID- 7840855 TI - Responses of NOD congenic mice to a glutamic acid decarboxylase-derived peptide. AB - Type 1 diabetes in man and the NOD (H-2g7) mouse is frequently associated with an autoimmune response to two isoforms of glutamic acid decarboxylase (GAD), GAD65 and GAD67. GAD-specific autoantibodies produced by B cells and GAD-specific T cells have been observed in both species. In the current study, the response to a GAD65-derived peptide, GAD65 524-543, previously reported to be an epitope recognized by spleen cells obtained from 3-week-old NOD mice, was assessed in NOD MHC and non-MHC congenic strains. Although spontaneous reactivity to GAD65 524 543 was not observed in NOD mice, the peptide was immunogenic in NOD mice as well as in two NOD congenic strains which are both H-2g7, B10.H-2g7 and NOD.B6Il2 Tshb. This was surprising since the B10.H-2g7 strain does not develop diabetes or insulitis and fewer than 3% of NOD.B6Il2-Tshb mice develop diabetes. The response to GAD65 524-543 was shown to be controlled by the MHC since neither the B10 nor the NOD.H-2b strain, both of which are H-2b, responded to the peptide. This study demonstrates that T cell responsiveness to GAD-derived peptides can be elicited in strains of mice that are resistant to the development of spontaneous diabetes, suggesting that peripheral tolerance to GAD is not associated with protection from diabetes. PMID- 7840856 TI - Natural history of humoral immunity to glutamic acid decarboxylase in non-obese diabetic (NOD) mice. AB - Autoantibodies to glutamic acid decarboxylase (GAD) are present in humans before and after the onset of clinical insulin-dependent diabetes (IDD). The non-obese diabetic (NOD) mouse, a model of human IDD, develops mononuclear cell infiltration of the pancreatic islets ('insulitis') associated particularly in females with T cell-mediated destruction of the islet beta cells. In NOD mice of both sexes we detected serum antibodies to GAD (GAD Ab) that precipitate mouse brain GAD enzymatic activity. Antibodies in NOD sera also precipitate a M(r) 65,000 protein from Triton X-100 extracts of 35S-methionine-labelled NOD islets, identical in size to that precipitated by a monoclonal antibody to GAD. GAD Ab were not detected in other mouse strains. There were significant differences in the frequency, level and age at initial detection of GAD Ab between females of the NOD/Lt and NOD/WEHI lines, previously shown to have a higher and lower incidence of diabetes, respectively. Comparing NOD/Lt (n = 26) and NOD/WEHI (n = 20) females, in which diabetes occurred in 38% and 20% by 150 days, the frequency of elevated GAD Ab was 50 vs. 80%, the mean maximum GAD Ab level 21.1 vs. 30.6% and the mean age at which GAD Ab were first detected 94 vs. 45 days. No significant differences in these parameters were observed between male mice of either line. There was a significant negative correlation between the level of GAD Ab and the degree of insulitis in female mice from both lines. GAD Ab were not a prerequisite for the development of diabetes. In 7 of 10 female mice the onset of diabetes was preceded by a decrease of GAD Ab levels into the normal range. These findings indicate that, while GAD is a target of autoimmunity in the NOD mouse, GAD Ab do not necessarily correlate with the development of diabetes. Indeed, the difference between the two NOD lines and the inverse relationship with insulitis suggests that a strong humoral response to GAD may be associated with a less destructive pathology, as proposed in humans 'at-risk' for IDD. PMID- 7840857 TI - Oral administration of human insulin to NOD mice generates CD4+ T cells that suppress adoptive transfer of diabetes. AB - Oral administration of porcine insulin has been shown to be effective in preventing the spontaneous occurrence of diabetes in the Non-Obese Diabetic (NOD) mouse model. In the present study, we demonstrate that feeding 6-week-old female mice with 20 units of human insulin every 2-3 days for 30 days induces an active mechanism of suppression through the generation of regulatory T cells. Adult irradiated NOD males i.v. injected with 5 x 10(6) T cells from the spleens of diabetic female donors and the same number of T cells from the spleens of insulin fed animals had less successful diabetes transfer than controls (4/15 vs. 8/16, P < 0.001). Protection from clinical diabetes was associated with a reduction in severe insulitis (16.4 +/- 3.6% vs. 52.3 +/- 12.8%, P = 0.023). However, more than 85% of the islets were inflamed. Feeding animals for 15 days reduced the magnitude of this protection since the number of successful transfers after 1 month was comparable (12/17 vs. 14/17) despite a significant delay in diabetes onset (P < 0.001). No difference in the contribution of T cell subsets was noted by cytofluorometry in the spleens of treated animals. When T cell subsets from insulin-fed animals were co-injected with diabetogenic T cells, only purified CD4+ T cells were able to transfer protection since only 3/12 mice became diabetic after 36 days in comparison to 3/6 in the group co-injected with CD4+ T cells from PBS-fed animals, or 5/6 in the group injected with CD8+ T cells.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7840858 TI - Sera from patients with IDDM and healthy individuals have antibodies to ICA69 on western blots but do not immunoprecipitate liquid phase antigen. AB - ICA69 is a recently cloned pancreatic islet protein proposed as a potential target of autoimmunity in insulin dependent diabetes mellitus (IDDM). The aim of our study was to verify the relevance of ICA69 antibodies as markers of the disease. We measured antibodies to ICA69 in sera from newly-diagnosed IDDM patients, in age- and sex-matched normal controls, and in sera prior to the onset of IDDM (pre-IDDM). Human islet ICA69 was cloned and inserted into a bacterial expression vector and an in vitro transcription vector. Binding to affinity purified recombinant ICA69 on Western blots was found in 33/48 (68%) sera from newly-diagnosed IDDM patients and in 36/56 (64%) controls. No differences in band intensity were found between IDDM and controls. Using immunoprecipitation of 35S methionine labelled in vitro translated ICA69, none of 53 sera from newly diagnosed IDDM patients, 0 of 57 control sera and 1 of 24 pre-IDDM sera had detectable antibodies. We conclude that solid-phase assays are inappropriate for measurement of ICA69 antibodies as specific markers of IDDM and that antibodies to ICA69 are not detected by a liquid-phase immunoprecipitation assay. These data support neither a role for ICA69 as a relevant autoantigen in IDDM, nor a role for the measurement of antibodies to ICA69 in the prediction of IDDM. PMID- 7840859 TI - HLA-DQB1 genotypes and islet cell antibodies in the identification of siblings at risk for insulin-dependent diabetes (IDDM) in Finland. Childhood Diabetes in Finland (DiMe) Study Group. AB - The risk of progression to IDDM can be evaluated by diabetes-related autoantibodies such as cytoplasmic islet cell antibodies (ICA) or genetic determinants as markers. In this prospective study we wanted to estimate the predictive value of the combination of these markers in siblings of diabetic children. A sample of 770 siblings was observed from the time of diagnosis in the index case for a median period of 5.8 years (range 0.01-7.3 years) for development of ICA and insulin autoantibodies (IAA) and progression to clinical diabetes. The most important susceptibility and protection associated DQB1 alleles were defined by four sequence-specific oligonucleotide probes. DNA samples were available from 89 originally non-diabetic ICA positive siblings of whom 28 presented with IDDM during the study period, as well 100 randomly chosen ICA negative control siblings. More than half (11/28; 55%) of the siblings who had the high risk DQB1 genotypes progressed to clinical IDDM compared to 6/37 (16%) of those who had protective/neutral genotypes (P = 0.006). Of all genotyped secondary cases, 36% (n = 33) had a genotype associated with the highest risk (DQB1*0302/0201), whereas 27% had genotypes without any susceptibility alleles (P values < 0.0001 and = 0.0002, respectively, compared with ICA negative siblings). The results demonstrate the feasibility of the combination of genetic and immunological markers in the prediction of the risk for IDDM within families. PMID- 7840861 TI - Effects of 5HT3 receptor antagonism by tropisetron on the sleep EEG and on nocturnal hormone secretion. AB - Two dosages (5 mg and 25 mg) of the selective 5HT3 receptor antagonist tropisetron (ICS 205-930) were administered to healthy male controls, and the effects on the sleep EEG and nocturnal secretory activity of growth hormone (GH) and cortisol were evaluated. The lower dosage was administered to four subjects and the higher dosage to eight on 5 consecutive days, preceded and followed by 2 days of placebo treatment. After 25 mg of tropisetron, there was a slight increase in REM sleep in the first part of the sleep period, and stage 2 was decreased during the total night. In addition, plasma cortisol levels increased earlier than under placebo, and plasma GH levels were reduced in the second part of the night. Thus, only discrete effects of tropisetron upon sleep-endocrine activity were noted, making it unlikely that serotoninergic neurotransmission exerts its well-documented effects upon sleep through 5HT3 receptors. PMID- 7840860 TI - The paternally inherited insulin gene B allele (1,428 FokI site) confers protection from insulin-dependent diabetes in families. AB - Several polymorphisms of the insulin gene and its flanking regions (INS region) are in linkage disequilibrium and confer susceptibility to insulin-dependent diabetes (IDDM). We have analysed INS AA and AB-BB genotypes at the 1,428 FokI site (3' of the insulin gene) in 217 patients with IDDM, 402 non-diabetic first degree relatives negative for insulin (IAA) and islet cell autoantibodies (ICA), and 116 autoantibody positive (for ICA or IAA, or both) relatives of whom 39 became diabetic on follow-up. Most IDDM patients (83.4%, 181/217) had the AA genotype vs. 50% (25/50) of the controls (P < 10(-6)). Only 16.6% (36/217) of IDDM patients carried the AB genotype and none was BB homozygous, suggesting a protective effect of the B allele. By segregation analysis of the B allele in the IDDM offspring of informative families (only one AB parent) from the United States, the maternal B allele was inherited by 19/35 (54.2%) of the IDDM offspring. In contrast, only 4/26 (15.3%) of the IDDM offspring inherited the paternal B allele (P = 0.001), suggesting maternal imprinting of the INS region. Therefore, the INS B allele may be protective only when paternally inherited. Among the 39 of 116 autoantibody positive relatives who developed IDDM on follow up, only five of them had the B allele. The frequency of the B allele in this group was much lower (12.8%, 5/39) than that observed in non-diabetic autoantibody positive relatives (32.5%, 25/77, P = 0.02).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7840862 TI - Methylphenidate response, psychopathology and tardive dyskinesia as predictors of relapse in schizophrenia. AB - Despite the proven efficacy of acute and maintenance pharmacotherapy in schizophrenia, practical methods for identifying patients who require continuous treatment to prevent relapse have not been established. We hypothesized that a pathologic overactivity of mesolimbic and mesocortical dopamine neural systems, that mediates positive psychotic symptoms in the acute phase of the illness, persists in some outpatients who are vulnerable to relapse despite appearing clinically stable. To test and determine if putative measures of central nervous system dopamine activity predict outcome, 41 stable outpatients receiving neuroleptic maintenance treatment underwent provocative tests with methylphenidate in a randomized double-blind placebo controlled design in which behavioral, neuromotor, biochemical, and cardiovascular responses were measured. Patients were then withdrawn from medication and monitored for 52 weeks, or until relapse. The results indicate that psychotic symptoms and their activation by methylphenidate, and the presence of tardive dyskinesia are associated with each other and with a higher risk of relapse. These findings partially support our hypothesis and offer potentially useful measures for the identification of candidates for reduced dose neuroleptic maintenance treatment strategies in schizophrenia. PMID- 7840863 TI - Inhibition by lithium of cyclic GMP formation without inhibition of nitric oxide generation in the mouse neuroblastoma cell (N1E-115). AB - We investigated the effects of lithium ion (Li+) on muscarinic receptor-mediated nitric oxide (NO) generation, and guanylate cyclase (GCase) activation using the mouse neuroblastoma clone, N1E-115. The levels of released NO were determined by measuring the levels of nitrite/nitrate in the incubation medium, and the activity of GCase was measured with an assay for cellular cyclic [3H] GMP levels. We determined that Li+ had no effects on muscarinic receptor-activated elevation of nitrite/nitrate levels, which were significantly inhibited by 100 microM L-NG monomethylarginine, although it has been reported that Li+ inhibits muscarinic receptor-activated cyclic GMP formation in the cells. In addition, Li+ inhibited the cyclic GMP formation induced by an NO donor, sodium nitroprusside (SNP), in both intact cells and a crude cellular homogenate; thus, the inhibition by Li+ of muscarinic receptor-mediated cyclic GMP synthesis appeared to be at the level of GCase, but not NO synthase. PMID- 7840864 TI - Effects of gestational exposure to monoamine oxidase inhibitors in rats: preliminary behavioral and neurochemical studies. AB - Monoamine neurotransmitters are important in the development of the immature mammalian brain, prior to assuming their role as neurotransmitters. The endogenous levels of these transmitters are highly regulated by the enzyme monoamine oxidase (MAO). Thus, any change in this enzyme should have a profound effect on brain development. In order to test this hypothesis, we treated developing rat pups with the monoamine oxidase inhibitors (MAO-Is), clorgyline (MAO-A, 3 mg/kg), and deprenyl (MAO-B, 3 mg/kg) throughout gestation (MAO-I birth), or throughout gestation and to sacrifice (MAO-I-sac). The animals were analyzed for serotonin and dopamine terminal density, using 3H-paroxetine and 3H GBR 12935, respectively. Whereas there were no changes in the development of the dopamine system, the serotonin system was severely affected, particularly in the cortex that showed a significant reduction of innervation at 30 days postnatal. The animals reached all normal development milestones on schedule, and had no changes in measures of anxiety (% light/dark); however, the animals showed increased open field activity and deficits in a passive avoidance paradigm, which may be a measure of impulsivity. The MAO-I-sac animals were severely impaired, showing stereotypic behavior, seizures, and eventually visual impairments. Our results are discussed in terms of relevance to human disease states, such as atypical Norrie's disease, impulsivity, and hyperactivity. As well, our results should be used to caution against the use of MAO-Is in women of child-bearing age. PMID- 7840865 TI - Evidence that the acute behavioral and electrophysiological effects of bupropion (Wellbutrin) are mediated by a noradrenergic mechanism. AB - Bupropion (BW 323U66) has been considered a dopaminergic antidepressant based on its ability to inhibit the uptake of dopamine (DA) somewhat more selectively than it inhibits uptake of norepinephrine (NE) or serotonin (5-HT). This report describes new evidence that bupropion selectively inhibits firing rates of NE cells in the locus coeruleus (LC) at doses significantly lower than those that inhibit activity of midbrain DA cells or dorsal raphe 5-HT cells. The IC50 dose (13 mg/kg i.p.) for inhibition of LC firing produced plasma concentrations that were not significantly different from those generated by the ED50 in the Porsolt test (10 mg/kg i.p.). The fourfold higher dose needed to inhibit DA cell firing (IC50 = 42 mg/kg i.p.) was similar to the dose associated with locomotor stimulation in freely moving rats. Bupropion did not change the firing rates of 5 HT cells in the dorsal raphe nucleus at any dose. In both in vitro and in vivo tests, the metabolite 306U73 (hydroxybupropion), a weak inhibitor of NE uptake, was approximately equipotent to bupropion with regard to inhibition of LC cells. Another metabolite, 494U73, had no effect on LC firing rates over a wide range of doses. Because of species variation in metabolism, 306U73 was not detected in plasma of rats after i.v. doses of bupropion that inhibited LC firing. Only trace amounts of 306U73 were detected after bupropion dosing for the Porsolt test. Pretreatment with reserpine markedly depleted catecholamines and reduced (by 30 fold) the potency of bupropion to inhibit LC firing.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7840866 TI - Molecular neurobiology of drug addiction. AB - The purpose of this review is to illustrate the ways in which molecular neurobiological investigations will contribute to an improved understanding of drug addiction and, ultimately, to the development of more effective treatments. Such molecular studies of drug addiction are needed to establish two general types of information: (1) mechanisms of pathophysiology, identification of the changes that drugs of abuse produce in the brain that lead to addiction; and (2) mechanisms of individual risk, identification of specific genetic and environmental factors that increase or decrease an individual's vulnerability for addiction. This information will one day lead to fundamentally new approaches to the treatment and prevention of addictive disorders. PMID- 7840867 TI - Health in Europe. The 1993/1994 health for all monitoring report. PMID- 7840868 TI - Neurohormonal control of intestinal transit. AB - This review shows that numerous neuropeptides and hormones are involved in the regulation of intestinal transit. Many gastrointestinal hormones known to act on smooth muscle to influence muscle contractility also play a role in the genesis of abrupt changes associated with alimentary behaviour. In many monogastrics and ruminants, the cyclic occurrence of the migrating motor complex (MMC) is linked to peripheral hormonal factors only slightly influenced by the nature of food. Motilin is the major hormone involved in triggering the gastric migrating motor complex while somatostatine and enkephalins are implicated in the propagation along the small intestine. Other hormones, like CCK8, insulin, gastrin, and neurotensin, trigger the development of an intestinal feed pattern but CCK released at the central nervous system ventromedial hypothalamus is involved in maintaining the postprandial type of activity. Gastrointestinal transit may be altered in physiopathological situations in which CRF, TRH and some cytokines (IL1 beta, TNF alpha) play an important role. PMID- 7840869 TI - Proceedings of the symposium on animal and human nutrition. Association francaise de nutrition. Comparative physiology of digestion and metabolism. Tours, 13-14 January 1994. PMID- 7840870 TI - Effects of caseinomacropeptide (CMP) on digestion regulation. AB - Caseinomacropeptide (CMP) is a 64-amino-acid-residue peptide which is released from kappa-casein by gastric proteinases. This review sums up the knowledge concerning its effects on the digestive function. Part 1 recalls the origin and heterogeneity of CMP. Here we underline that there are various forms of CMP which differ by their glycosylation level and genetic mutation. Consequently the forms used for studying biological activities need to be defined accurately. Part 2 summarizes the effects of CMP on digestive secretions. The major effect is an inhibitory effect on acid gastric secretions. Simultaneously, the blood concentration of regulatory digestive peptides is modified. In part 3 we try to clarify the mechanisms of action of CMP. A slightly glycosylated form of CMP, the A variant, appears to be responsible for the biological activity. Evidence suggests that CMP triggers stimuli from intestinal receptors without being absorbed. The signal would be then transmitted to organs through regulatory digestive peptides. PMID- 7840871 TI - The metabolism and availability of essential fatty acids in animal and human tissues. AB - Essential fatty acids (EFA), which are not synthesized in animal and human tissues, belong to the n-6 and n-3 families of polyunsaturated fatty acids (PUFA), derived from linoleic acid (LA, 18:2n-6) and alpha-linolenic acid (LNA, 18:3n-3). Optimal requirements are 3-6% of ingested energy for LA and 0.5-1% for LNA in adults. Requirements in LNA are higher in development. Dietary sources of LA and LNA are principally plants, while arachidonic acid (AA, 20:4n-6) is found in products from terrestrian animals, and eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are found in products from marine animals. EFA are principally present in dietary triacylglycerols, which should be hydrolyzed by lipases in gastric and intestinal lumen. DHA seems to be released more slowly than the others. Its intestinal absorption is delayed but not decreased. Long chain PUFAs are incorporated in noticeable amounts in chylomicron phospholipids. However, their uptake by tissues is no more rapid than uptake of shorter chain PUFA. In tissues, LA and LNA, which constitute the major part of dietary EFA, should be converted into fatty acids of longer and more unsaturated chain by alternate desaturation (delta 6, delta 5, delta 4)-elongation reactions. Animal tissues are more active in this biosynthesis than human tissues. Liver is one of the most active organs and its role is critical in providing less active tissues, particularly the brain, with long-chain PUFA secreted in VLDL (very low density lipoprotein). In liver, many nutritional, hormonal and physiological factors act on the PUFA biosynthesis. Dietary fatty acids exert a great influence and are often inhibitory. Dietary LNA inhibits delta 6 desaturation of LA. The desaturation products AA, EPA, and DHA inhibit delta 6 desaturation of LA and delta 5 desaturation of DGLA (dihomo-gamma-linolenic acid). With regard to hormones, insulin and thyroxin are necessary to delta 6 and delta 5 desaturation activities, whereas other hormones (glucagon, epinephrine, ACTH, glucocorticoids) inhibit desaturation. Concerning the physiological factors, the age of individuals is critical. In the fetus, the liver and the brain are capable of converting LA and LNA into longer-chain EFA, but these are also delivered by the mother, after synthesis in the maternal liver and placenta. Just after birth, in animals, the delta 6 desaturation activity increases in the liver and decreases in the brain. In aging, the capacity of the whole liver to desaturate LA and DGLA is equal at 1.5 and 25 months of age in rats fed a balanced diet throughout their life and the AA and DHA content of tissue phospholipids is unchanged in aging.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7840872 TI - Influence of adiposity (genetic or hormonal) on the metabolism of amino acids and nutritional responses. AB - The data published on the modifications of amino-acid metabolism associated with variations of obesity from genetic or hormonal origin have been reviewed. In the first part monogenic models of mice and rats are described. Obesity in humans is analysed in the second part. Lastly, non-ruminant genotypes or hormone-treated ones (chickens and pigs) are reviewed in the third part. Although different mechanisms are probably at the origin of these differences, many similarities can be drawn. Obesity is always associated with: 1) less efficient utilization of dietary amino acid; 2) a high concentration of branched-chain amino acids in plasma; 3) a deviation of carbon from amino acid towards gluconeogenis and lipogenesis; and 4) a less pronounced sensitivity to amino-acid imbalance in the diet. PMID- 7840873 TI - Regulation of ATP-ubiquitin-dependent proteolysis in muscle wasting. AB - Protein breakdown plays a major role in muscle growth and atrophy. However, the regulation of muscle proteolysis by nutritional, hormonal and mechanical factors remains poorly understood. In this review, the methods available to study skeletal muscle protein breakdown, and our current understanding of the role of 3 major proteolytic systems that are well characterized in this tissue (ie the lysosomal, Ca(2+)-dependent and ATP-ubiquitin-dependent proteolytic pathways) are critically analyzed. ATP-ubiquitin-dependent proteolysis is discussed in particular since recent data strongly suggest that this pathway may be responsible for the loss of myofibrillar proteins in many muscle-wasting conditions in rodents. In striking contrast to either the lysosomal or the Ca(2+) dependent processes, ATP-ubiquitin-dependent protein breakdown is systematically influenced by nutritional manipulation (fasting and dietary protein deficiency), muscle activity and disuse (denervation atrophy and simulated weightlessness), as well as pathological conditions (sepsis, cancer, trauma and acidosis). The hormonal control of this pathway, its possible substrates, rate-limiting step, and functional associations with other proteolytic systems are discussed. PMID- 7840875 TI - Proceedings of the workshop on the corpus callosum and interhemispheric transfer. Priorij Corsendonk, Belgium, 16-19 July 1992. PMID- 7840874 TI - Nutrition, atherosclerosis and coronary heart disease. AB - The main health hazard of atherosclerosis is coronary heart disease (CHD). Its relation to nutrition (chiefly saturated fat) was shown through the Seven Countries Study and confirmed by between country comparisons. Nevertheless, cholesterol, the accepted intermediate link in blood, can no longer be used to explain differences between countries. In addition, when previous trials to decrease CHD by diet were efficient, rapid protection was observed (within a year), an effect not attributed to atherosclerosis but to thrombosis, which is responsible for myocardial infarction. Thrombogenesis is directly increased by saturated fat, but decreased only by n-3 fatty acids and alcohol through decreasing platelet reactivity. A Mediterranean diet with more cereals, vegetables, fruit, less saturated fats and more n-3 fatty acids has recently been shown to afford a rapid and exceptional protection from recurrences and death in coronary patients. The relationship between nutrition and CHD is thus as close as suggested, but more complex, because of additional nutrients, such as alcohol and natural antioxidants, and an appropriate balance between fatty acids. PMID- 7840876 TI - Some new trends in the study of the corpus callosum. AB - In recent years the corpus callosum has provided a model for the study of cortical connections in the adult and developing brain. In particular, aspects of development originally described in the corpus callosum could be generalized to other cortical connections. New frontiers include the analysis of the human corpus callosum, studies of callosal connections at the cellular level and the analysis of dynamic interactions between the hemispheres. Gross morphological parameters of the human corpus callosum have been measured and related to gender, handedness etc. The detailed dendritic and axonal morphology of individual callosal neurons and their development is being defined. Electrophysiological investigations and computer stimulations are stressing temporal aspects of the interactions between the hemispheres. PMID- 7840877 TI - A new hybrid mouse model for agenesis of the corpus callosum. AB - A three locus model of the inheritance of absent corpus callosum in mice was tested by creating F1 and F2 hybrid crosses from the strains BALB/cWah1 and 129/J which show incomplete penetrance for callosal agenesis. The model predicted that a few of the F2 hybrid mice would suffer severe reduction of the hippocampal commissure when the corpus callosum was absent, a condition that usually occurs only in the most consistently acallosal I/LnJ strain, and this prediction was confirmed. The C129F2 hybrid population expresses substantial genetic variation and an extremely wide range of defects of the corpus callosum, dorsal commissure of the fornix and hippocampal commissure. At the same time, these hybrids have exceptionally good health and reproductive performance, unlike their inbred parent strains. These characteristics make them ideal subjects for the study of brain-behaviour correlation using a noninvasive method. PMID- 7840878 TI - Laterality effects in normal subjects: evidence for interhemispheric interactions. AB - In this review we describe three methods of research that have been used to study relationships between the cerebral hemispheres in normal human subjects. We briefly mention reaction-time studies, which have been used to measure interhemispheric transmission time; more pertinent to laterality effects, however, are lateralized visual field studies, in which stimuli can be presented either unilaterally or to both visual fields simultaneously, and dichotic listening studies, wherein different stimuli are presented to the two ears simultaneously. Recent examples from the literature of experiments employing these techniques are discussed as they pertain to an understanding of interhemispheric interaction. Some suggestions are offered concerning appropriate procedures for studying interhemispheric interactions in normal human subjects. PMID- 7840879 TI - Interhemispheric control of manual motor activity. AB - The interhemispheric control of manual motor processes is reviewed, focusing on the clinical evidence from patients with commissurotomies and with agenesis of the corpus callosum. There is little evidence for a role of the corpus callosum in transferring explicit motor commands. Rather, the corpus callosum seems important for transferring lateralised information (such as verbal or visuospatial activity) of the pre-motor variety. Also, the corpus callosum may become very significant when movement begins: there appears to be a transcallosal passage of corollary motor signals and feedback sensory signals that are used to control asychronous bimanual movements and to inhibit the opposite hemisphere from interfering when a simple unimanual movement is required. PMID- 7840880 TI - Interhemispheric integration of simple visuomotor responses in patients with partial callosal defects. AB - Because of the organization of visual and motor pathways, simple manual responses to a light stimulus in the right or left visual hemifields are performed faster with uncrossed hand-field combinations than with crossed hand-field combinations. Uncrossed responses can be integrated within a single hemisphere, whereas crossed responses require a time-consuming interhemispheric transfer via the corpus callosum which is reflected in the difference between crossed and uncrossed reaction times. We investigated crossed-uncrossed differences (CUDs) in speed of simple visuomotor responses to lateralized flashes in seven subjects with an anterior section of the corpus callosum sparing the splenium and in one subject with an agenetic absence of the splenium due to a cerebrovascular malformation. There was no evidence of an abnormal prolongation of the CUDs in any of these subjects, in sharp contrast with the very long CUDs exhibited by an epileptic subject with a complete callosal section and two subjects with total callosal agenesis tested in the same experimental situation [1]. The normality of the CUDs in the subjects with partial callosal defects was not due to a postoperatory reorganization of interhemispheric communication, since there was no indication of an increased CUD in a patient tested as early as 5 days after the anterior callosotomy. These results are compatible with the assumption that both anterior and posterior callosal routes may subserve the integration of speeded manual responses to a visual stimulus directed to the hemisphere ipsilateral to the responding hand. PMID- 7840881 TI - The corpus callosum provides a massive transitory input to the visual cortex of cat and rat during early postnatal development. AB - Studies of corpus callosum development in cat revealed that the callosum must be intact during postnatal month 1 if normal visual development is to occur [11 20,25]. The use of DiI, a lipophilic carbocyanine dye that is an in vitro membrane tracer, permits a detailed search for morphological evidence to account for these functional results because many cells can be simultaneously labeled in their entirety. To search for morphological evidence, the corpus callosum was labeled in vitro with DiI in tissue from cats aged 2-277 days old [21]. To determine whether there was consistent callosal development in mammals, similar studies were carried out in tissue from rats aged 0 days old through adult [22]. Hemispheres were coronally sectioned 1-24 months later. Sections were reconstructed in photomontages to show the overall distribution of corpus callosum projections, as well as provide details about the locations of individual corpus callosum axons and their presumed terminals. The distribution of corpus callosum projections, examined in visual cortex of cat and rat, changed significantly during development. During early postnatal development, callosal axons extended throughout visual cortex to layer I. Numerous varicosities on callosal axons were located en passant and at axon terminals in layer I. In the following weeks, the density of callosal projections was reduced in all cortical areas, although many axons still extended to layer I. By postnatal month 2 the callosal axons were predominantly near the borders between adjacent cortical areas. Thus, for several postnatal weeks, many elaborately formed transitory corpus callosum axons are distributed throughout visual cortex. The transitory callosal axons appear to have terminals in layers I-VI. If some of these terminals were to for synapses, the corpus callosum could provide an extensive input to layers I-VI throughout visual cortex while the majority of cortical microcircuitry is being established. PMID- 7840882 TI - Interhemispheric transfer and the processing of foveally presented stimuli. AB - Two arguments are commonly given in favor of a nasotemporal overlap along the vertical meridian of the visual field: anatomical findings and the existence of macular sparing in hemianopia. A review of the literature, however, points to the weakness of the evidence. The anatomical indications are exclusively based on horseradish peroxidase studies, which can not give an unequivocal answer to the amount of overlap in central vision, and which were not supported by a recent study that made use of the more direct [14C]2-deoxy-D-glucose technique. The argument of macular sparing in hemianopia appears to be derived evidence that depends on the validity of the anatomical findings. In addition, behavioral studies consistently failed to find functional confirmation of the overlap. To further test the possibility of bilateral representation in central vision, a new paradigm is proposed. It is argued that if interhemispheric transfer is needed for the processing of foveally presented stimuli, the word-beginning superiority effect should be larger for subjects with left hemisphere dominance than for subjects with right hemisphere dominance. Results are in line with the hypothesis and point to the fact that interhemispheric transfer of visual information may be involved in more processing than usually accepted. It is also noted that transfer time seems to depend on the amount of information that must be transferred, and is significantly shorter than the estimates obtained in visual half field studies. PMID- 7840883 TI - Split decisions: problems in the interpretation of results from commissurotomized subjects. AB - It has been widely accepted that there is little if any interhemispheric transfer of perceptual information in subjects following section of the forebrain commissures, although there may be diffuse transfer of emotional and connotative information, and an ability to direct spatial attention between hemispheres. However Sergent has recently shown that split-brained subjects can make rapid and accurate perceptual judgments based on visual stimuli presented simultaneously to the two visual fields. These include judgments of alignment, judgments of relative quantity, and higher-order judgments such as lexical decisions about letter strings straddling the visual fields. However it is premature to conclude that these tasks are accomplished by subcortical transfer of perceptual information; at least some of them can be explained in terms of strategies based on information available to just one hemisphere, or on the transfer of rudimentary information, perhaps accomplished through cross-cueing. PMID- 7840884 TI - Left-right asymmetry of callosal transfer in normal human subjects. AB - Interhemispheric transfer (IT) of visuomotor information can be assessed by measuring the crossed-uncrossed difference (CUD) in the Poffenberger paradigm [14]. We report a series of experiments aimed at casting light on two aspects of IT: the importance of motor response variables and the nature of the left-right asymmetries found in a recent meta-analysis of studies using the Poffenberger paradigm [10]. In Experiments 1 and 2 we found no effect of varying the finger used for response while there was a larger CUD when using the left hand in comparison to the right hand. In Experiment 3, which employed visual stimuli different from the two preceding experiments, CUD asymmetries were related to hemifields rather than to hands with a CUD larger for the right than for the left visual hemifield. These findings suggests that both motor and visual variables are important for CUD asymmetries to occur and are in keeping with a horse race model according to which overall speed of IT is determined by whichever signal (visual or pre-motor) is more rapid in crossing from one side to the other. As to the issue of lateral asymmetries in the CUD, the results of Expt. 3 have also shown that asymmetries arise only in tasks requiring an IT and therefore cannot depend upon additive hemispheric effects. PMID- 7840885 TI - Is interhemispheric transfer time related to age? A developmental study. AB - In simple visuomotor reaction time tasks, the difference between reaction time (RT) in the uncrossed hand/hemifield condition from RT in the crossed hand/hemifield, known as CUD (crossed-uncrossed difference), has been interpreted as reflecting interhemispheric transmission time (IHTT). Several studies in normal adults have found a CUD of a few milliseconds (3-4), while an abnormally long CUD has been reported in patients who underwent a surgical section of the corpus callosum or in congenital acallosal subjects. The corpus callosum, which is the most important structure for interhemispheric transfer of information, completes its myelination approximately by age ten. It has been hypothesized that the functional maturity of the corpus callosum coincides with the termination of the myelination cycle. No developmental study has focused on the development of IHTT, in relation to callosal maturation. The purpose of our study has been to investigate the development of interhemispheric transfer of visuomotor information in children aged seven to eleven, using a simple RT task with lateralized visual stimuli. The results indicate an age-related decrease of CUD, which we interpret as reflecting the maturation of the corpus callosum during childhood years. PMID- 7840886 TI - Anatomical-behavioral relationships: corpus callosum morphometry and hemispheric specialization. AB - We obtained midsagittal measures of the corpus callosum in 60 healthy young adults (right-handed and left-handed males and females), and examined whether individual differences in anatomical measures of callosal connectivity are related to behavioral laterality measures in the same subjects. In an attempt to tap functionally-distinct callosal "channels", four behavioral laterality tasks were used that differed in sensory modality (visual, auditory, tactile) and/or level of cognitive processing (sensory versus semantic). In addition, the tasks had both intrahemispheric and interhemispheric conditions. Sex differences were found for measures of the posterior body (i.e. isthmus) of the corpus callosum, which, in turn, interacted with handedness. In contrast, only handedness effects were found for the behavioral laterality measures. Anatomical-behavioral correlations did not disclose relationships between callosal size and performance on task conditions requiring sensory interhemispheric integration or transfer. Instead, the correlational findings are consistent with the view that the corpus callosum participates in such higher order "control" functions as the support of bilateral representation of language, functional interhemispheric inhibition, and the maintenance of hemispheric differences in arousal. This is consistent with the finding that regional callosal size is related to the number of small diameter fibers, which are presumed to interconnect homologous association cortices in the two hemispheres. PMID- 7840887 TI - Schizophrenia and the corpus callosum: developmental, structural and functional relationships. AB - Several empirical and theoretical connections exist between schizophrenia and the corpus callosum: (1) disconnection symptoms resemble certain psychotic phenomena; (2) abnormal interhemispheric transmission could explain typically schizophrenic phenomena; (3) cases of psychosis have been found in association with complete and partial agenesis of the callosum; (4) experimental neuropsychology with schizophrenic patients has revealed abnormal patterns of interhemispheric transfer; (5) studies using magnetic resonance imaging have shown abnormal callosal dimensions in schizophrenic patients. The evidence in support of these links is discussed critically. Novel neuropsychological approaches in the study of information transfer in the visual modality between the cerebral hemispheres, consistent with callosal hyperconnectivity in schizophrenic patients but not matched psychiatric controls are highlighted. Some suggestions for further work including integrating functional and structural measures are offered. PMID- 7840888 TI - Incomplete split-brain syndrome in a patient with chronic Marchiafava-Bignami disease. AB - A 40-year-old male patient is presented who survived Marchiafava-Bignami disease and recovered sufficiently to be assessed neurologically and neuropsychologically in some detail. Besides dementia, lack of initiative, and psychomotor retardation here ascribed to extracallosal damage, he showed a number of symptoms of hemispheric disconnection such as left-sided apraxia, poor bimanual coordination in specific laboratory tests, and deficits in the interhemispheric transfer of somaesthetic information. Other commissural functions, such as interhemispheric transfer of tactile, visual and auditory information as well as bilateral coordination in previously overlearned tasks, were nearly intact. The observed dysarthria could be meaningfully discussed in relationship to postcallosotomy mutism. It is concluded, that the partial interhemispheric disconnection syndrome in Marchiafava-Bignami disease lacks functional compensation which is different from the usual course in partial commissural section. PMID- 7840889 TI - Cognitive and sensori-motor functioning in the absence of the corpus callosum: neuropsychological studies in callosal agenesis and callosotomized patients. AB - The aim of the present study was to investigate the role of the corpus callosum in cognitive and sensori-motor functioning as measured by a neuropsychological test battery. After a brief review and analysis of the literature, we report our own studies in acallosal subjects (n = 9) and callosotomized patients (n = 25). The main instrument of evaluation was the Michigan Neuropsychological Test Battery. This battery was supplemented by age-appropriate intelligence tests. The performance of the acallosal group was compared to that of two matched control groups: one group consisting of children and adolescents that attended the same school as the acallosals and a second group of subjects recruited from regular schools. The callosotomized patients, tested pre- and post-operatively, served as their own controls. Taken together, the results of the reviewed and personal studies suggest that absence of the corpus callosum does not necessarily impede cognitive functioning. However, samples drawn from clinical populations tend to show a larger variability as to their mental abilities. In keeping with previous findings, our results indicate that the corpus callosum does play a role in bimanual motor coordination although other pathways (probably ipsilateral and/or subcortical) may provide adequate compensation in many cases. The data further suggest that the corpus callosum may be important for interhemispheric transfer of tactuo-motor learning when a spatial component is involved. Finally, our results are consistent with a facilitatory role of the corpus callosum in cognitive and sensori-motor functioning which allows for interhemispheric compensation as part of cerebral reorganization in the case of unilateral brain damage. PMID- 7840890 TI - The spatial relationship between the cerebral cortex and fiber trajectory through the corpus callosum of the cat. AB - We related fiber trajectory through the feline corpus callosum to the site of fiber origin in the cortical mantle and to functional modality. The cortical fields which contribute axons to the different portions of the corpus callosum were revealed by applying horseradish peroxidase (HRP) to the cut ends of selected groups of callosal axons in twelve adult cats. Overall, the application of HRP at progressively more caudal positions in the corpus callosum labels fields of neurons at successively more caudal positions in the cerebral cortex. Comparison of these data to functionally distinct cortical zones shows that the callosal body conveys a mixture of fibers arising from functionally diverse regions of the cerebrum, whereas portions of the rostral and caudal ends appear to be essentially unimodal, conveying motor and visual signals, respectively. PMID- 7840891 TI - The neurotransmitters and postsynaptic actions of callosally projecting neurons. PMID- 7840892 TI - Neuronal interactions in cat visual cortex mediated by the corpus callosum. AB - The article summarizes three sets of physiological and anatomical studies carried out to investigate the structural basis of the functional interactions between visual cortical areas 17 and 18 in the two cerebral hemispheres of cats. (1) The visual field representations in the transcallosal sending and receiving zones are defined. (2) The consequences of severing callosal fibers on the visual field representation at the area 17/18 border are described. (3) Lastly, experiments using cooling to reversibly inactive transcallosal inputs are reported. The observations on the transcallosal sending and receiving zones show that callosal connections of area 17 are concerned with a vertical hour-glass shaped region of the visual field centered on the midline, and this region is doubly represented, once in each hemisphere. The zone represents azimuths within +/- 4 degrees of the midline at the 0 degree horizontal meridian, and azimuths out to +/- 15 to +/- 25 degrees at positions distant from the horizontal meridian. The observations suggest that, in addition to interactions between neurons concerned with positions immediately adjacent to the midline, there are positions, especially high and low in the visual field, where interactions can occur between neurons which have receptive fields displaced some distance from the midline. The extent of this double representation is reduced by approximately 2/3 when the corpus callosum is cut. The retention of some bilateral representation in these animals suggests that there are alternate routes for across-the-midline transmission of visual signals. Or, more likely, there are ganglion cells in temporal retina with crossed projections that make significant contributions to the remaining double representation of the visual field. Lastly, the results obtained using cooling inactivation of transcallosal fibers show that many excitatory and inhibitory circuits are under the direct control of transcallosal fibers in the normally functioning brain. These connections appear to be no different from intrinsic connections of area 17, and they undoubtedly contribute to the binding of the two half-field representations, one in each hemisphere, and perceptual unity across the midline. PMID- 7840893 TI - Analysis of cross-sectional area measurements of the corpus callosum adjusted for brain size in male and female subjects from childhood to adulthood. AB - Interest in anatomic evaluation of the corpus callosum is based upon the expectation that its function will be influenced by its structure. Using MR images, the size of the corpus callosum was determined by measuring its area in the midsagittal plane. A callosal index was calculated for each subject by dividing the callosal size by cerebral size, also measured from the MR image. This callosal index was designed to allow comparison of callosal size between different groups, despite differences in brain size that existed between the groups. The validity of this index was supported by the statistically significant, positive correlation between measured callosal area and cerebral size. Using MR images and the callosal index, adult males were shown to have a larger corpus callosum and larger cerebrum, compared to adult females. However, the callosal index was identical for male and female subjects. This demonstrated there relative size of the callosum was the same for males and females. Childhood development of the corpus callosum was documented through the first two decades of life by a progressive increase in the callosal index. In adults, cerebral atrophy caused a decline in callosal size, but no decline due to simple advancing age was found in normal adult subjects. This use of cerebral size to calculate a callosal index appeared to be useful in comparing callosal size between subjects and may be useful in future study of other disease states of the corpus callosum. PMID- 7840894 TI - Interhemispheric sharing of visual memory in macaques. AB - (1) In macaques with the optic chiasm transected, and forebrain commissural communication limited to the anterior commissure or the posterior 5 mm of the splenium of the corpus callosum, visual patterns viewed initially by only one eye (hemisphere) are subsequently recognized by the other with normal accuracy. (2) The efficiency of these commissural paths is further indicated by the fact that even when as many as six "target" images are presented for memorization to only one hemisphere, it makes essentially no difference as to accuracy or latency of performance which hemisphere is then required to distinguish "target" from "non target" images. (3) By electrically tetanizing structures in one or the other temporal lobe at various times in relation to visual input and/or mnemonic testing it could be shown: (a) that a memory trace restricted in its formation to a single hemisphere was available to the other via either forebrain commissure, and (b) that the memory is formed bilaterally despite unilateral input. (4) When the chiasm is split but the commissures are intact, simultaneous presentation of disparate images to each hemisphere severely perturbs performance, suggesting that the callosal system operates continuously to unify visual percepts; but when only the anterior commissure is intact, the two hemispheres accept incongruent images without perturbation. (5) In the fully "split-brain" condition, when one hemisphere cannot access memories held in the other, the accuracy of performance by each hemisphere is nevertheless burdened by the memory load of its neocortically disconnected partner. It can thus be inferred that the brainstem plays a critical, unifying role in this mnemonic process. PMID- 7840895 TI - Visual callosal connections and strabismus. AB - Strabismus is a condition that exists when the visual axes of the two eyes fail to intersect at the fixation point under binocular viewing conditions. When it occurs in mammals during the critical period which corresponds to the period of maximal plasticity early in life, strabismus is known to induce both morphological anomalies and abnormal connections from the retina to the cortex; it further leads to binocular neural changes and to spatial vision deficits, especially at the cortical level. After a brief review of the already known data about the consequences of early strabismus in cats, monkeys and humans on the development of the visual system and of visual perception, new data are presented here concerning interhemispheric connections in the cat. In normally-reared kittens, visual callosal transfer is shown to be almost adult-like as soon as 12 days after birth: it is almost limited to the 17/18 border of the visual cortex when using visual stimulations in spite of the presence of still numerous juvenile exuberant callosal projections. In contrast, callosal transfer of visual information is extended to both areas 17 and 18 after strabismus, leading to the conclusion that at least some juvenile exuberant callosal projections are not only anatomically but also functionally stabilized after such an oculomotor disease. The possibility that similar abnormalities might be present in monkeys and humans is discussed. PMID- 7840896 TI - Role of thyroid hormones in the maturation of interhemispheric connections in rats. AB - Hypothyroidism causes mental retardation secondary to changes in the organization of the CNS. These changes affect higher brain functions for which interhemispheric transfer of information is crucial. In present study, the anterior commissure (AC) and corpus callosum (CC) of normal (C) and hypothyroid (H) rats has been examined using quantitative electron microscopy. H rats received an antithyroid treatment with methimazole from embryonic day 14 (E14) and surgical thyroidectomy at postnatal day 6 (P6). In the AC, the number of axons (unmyelinated and myelinated) increased from 0.17 x 10(6) axons at E18 to 1.08 x 10(6) axons at P4 and it was almost the same at P180 (1.01 x 10(6) axons). In H rats the number of axons between P14 and P180 was similar to that of C rats. In contrast, there were only 0.11 x 10(6) myelinated axons at P180 resulting in a 66% reduction with respect to C rats (0.36 x 10(6) axons). In the CC of C rats, the number of myelinated axons increased from 1.76 x 10(3) axons at P12 to 3.34 x 10(6) axons at P184. In H rats, there were only 0.84 x 10(6) axons at P184 resulting in a 76% reduction with respect to C rats. This reduction was more important in the posterior sector of the CC (95%) than in the rest (on average 63%). Therefore these results show that thyroid hormones play an important role in the processes involved in the maturation of commissural axons. PMID- 7840897 TI - Visual hemispheric dominance induced in split brain cats during development: a model of deficient interhemispheric transfer derived from physiological evidence in single visual cortex cells. AB - The effects of cancellation of both interhemispheric callosal transfer and interocular interactions, were studied in early monocularly deprived cats. The main purpose of this study was therefore to prove whether unilateral hemispheric dominance would result under these conditions and to what extent each hemisphere will be functionally independent. Secondly, we have attempted to establish such an experimental model physiologically, on the single cell level. Interhemispheric transfer was surgically canceled by sagittal transection of the corpus callosum. In addition, the ocular projections were separated by sagittal transection of the optic chiasm in the transbuccal approach. This condition had practically induced visual split brain condition in these cats. These manipulations were carried out concurrently with monocular deprivation (SBDK group) which was surgically done by eye closure during the critical period of development of the visual system. Thus, the hemisphere ipsilaterally to the visually deprived eye had developed under conditions of deficient visual experience while the hemisphere ipsilaterally to the normal eye had developed under conditions of unaltered visual experience. A group of cats (SBK) similarly operated but equally binocularly exposed during development was served as controls. In addition, adult cats similarly operated during adulthood either chronically or acutely were studied to evaluate the effects of interhemispheric and interocular separation. Other groups of cats were also studied for comparison, and included sham operated and normal adult cats. At adulthood, electrophysiological studies were done on these cats, in which action potentials were extracellularly recorded from single cells in the visual cortex (area 17-18 boundary) following anesthesia and paralysis. Stimulation was carried out manually and by a computer driven optical system, presenting on a tangent screen light bars at various spatial positions, orientations and directions. Receptive fields were thus mapped for all neurons and their dimensions and eccentricities were measured. The responsiveness, ocular dominance and other parameters were also studied for these cells. The results in the early deprived cats and in their controls, had shown a full separation between the two hemispheres, as reflected in the almost absolute ipsilateral eye responsiveness (> 97.0% cells). In comparison, in the sham operated and in the normal control cats only minor proportions of cells (13.0-18.7%) have been found as ipsilaterally and monocularly driven, showing almost full interhemispheric and interocular interaction. The main difference, however, in the results between the early monocularly deprived cats and their controls is that in the first group the two hemispheres were asymmetric concerning the amount of visual activation and in the second one they were very symmetric.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7840898 TI - The ubiquitin-mediated proteolytic pathway: mechanisms of action and cellular physiology. AB - Ubiquitin modification of many protein targets within cells plays important roles in a variety of biological processes. Among these are regulation of gene expression, regulation of cell cycle and division, involvement in the cellular stress response, modification of cell surface receptors, DNA repair, import of proteins into mitochondria, uptake of precursors of neurotransmitters into synaptosomes, biogenesis of peroxisomes, assembly of ribosomes, and programmed cell death. The mechanisms that underlie these complex processes are poorly understood. The best studied modification occurs in the ubiquitin-mediated proteolytic pathway. Recent experimental evidence indicates that the ubiquitin system is involved in the degradation of mitotic cyclins, oncoproteins and tumor suppressors, in the removal of abnormal and otherwise damaged proteins, and in processing of antigens restricted to class I MHC molecules. Degradation of a protein via the ubiquitin system involves two discrete steps. Initially, multiple ubiquitin molecules are covalently linked in an ATP-dependent mode to the protein substrate. The targeted protein is then degraded by a specific, energy-dependent and high molecular mass protease complex into peptides and free amino acids, and free and reutilizable ubiquitin is released. In addition, stable mono-ubiquitin adducts are also found in the cell, for example, those involving nucleosomal histones. Despite the considerable progress that has been made in elucidating the mode of action and roles of the ubiquitin system, many problems remain unsolved. For example, little is known on the signals that target proteins for degradation. While a few proteins are targeted for degradation following recognition of their N-terminal amino acid residue, the vast majority of cellular proteins are targeted by other signals. The identity of the native cellular substrates of the system is another important, yet unresolved problem: only a few proteins have been recognized so far as substrates of the system in vivo. The scope of this review is to discuss the mechanisms involved in ubiquitin activation, selection of substrates for conjugation, and degradation of ubiquitin-conjugated proteins in the cell-free system. In addition, we shall summarize what is currently known of the physiological roles of ubiquitin-mediated proteolysis in vivo. PMID- 7840900 TI - Activity of ternary gelatinase A-TIMP-2-matrix metallo-proteinase complexes. AB - The progelatinase A-TIMP-2 complex behaves like a Janus. Like TIMP (tissue inhibitor of metalloproteinases) it inhibits active matrix metalloproteinases, and activation with 4-aminophenylmercury acetate leads to a gelatinolytic activity. This activity, however, amounts only to less than 10% of that of free gelatinase A not complexed with TIMP-2. When the progelatinase A-TIMP-2 complex inhibits an active matrix metalloproteinase, a ternary complex is generated. After activation with 4-aminophenylmercury acetate this ternary complex displays a more than tenfold proteolytic activity compared to activated gelatinase A-TIMP 2 complex, thus reaching the activity of free gelatinase A. The activity of the ternary complex is nearly independent from the bound matrix metalloproteinase. When the progelatinase A-TIMP-2 complex is activated at first with 4 aminophenylmercury acetate the generation of the ternary complex is made impossible and not such a significant enhancement of activity is observed. These results suggest that gelatinase A-TIMP-2 complex may be a matrix metalloproteinase of the 'second step': It starts its proteolytic attack after it has switched off the activity of other matrix metalloproteinases. PMID- 7840899 TI - Cell adhesion receptors and nuclear receptors are highly conserved from the lowest metazoa (marine sponges) to vertebrates. AB - The shift from unicellular life to multicellular, integrated organisms has been accompanied by the acquisition of adhesion proteins/receptors. Recently we succeeded to clone some genes coding for such proteins from the lowest multicellular animals, the marine sponges (model: the siliceous sponge Geodia cydonium). G. cydonium contains e.g. several lectins; cDNAs for two of them were cloned. Both lectins have a framework sequence of 38 conserved amino acids which are characteristic for the carbohydrate binding site of vertebrate S-type lectins. Next, the cDNA coding for a receptor tyrosine kinase of class II was isolated and characterized. The deduced aa sequence shows two characteristic domains; (i) the tyrosine kinase domain and (ii) an immunoglobulin-like domain. The latter part displays high homology to the vertebrate type immunoglobulin domain. This result together with the lectin data demonstrates that binding domains of such adhesion proteins are not recent achievements of higher animals but exist already in animals (sponges) which have diverged from other organisms about 800 million years ago. Considering the fact that during embryogenesis of sponges a typical anteroposterior organization pattern is seen a 'home-otic' organ-like transformation has been postulated. The subsequent search for genes provided with the homeodomain-like sequence was successful. These data support the view that the kingdom Animalia is of monophyletic origin. PMID- 7840901 TI - Analysis of oxygen radical toxicity in pancreatic islets at the single cell level. AB - Despite extensive studies on streptozotocin, alloxan and nitric oxide toxicity in pancreatic islets the mechanism of oxygen radical induced islet cell death has not been determined. The present study shows at the level of single cells that following exposure to oxygen radicals generated from xanthine oxidase DNA strand breaks occur in cell nuclei within 5-60 min and precede cell death by several hours. Similar kinetics were seen when treating islet cells with the alkylating agent streptozotocin. Immunofluorescence studies demonstrated the endogenous formation of ADP-ribose polymers in nearly all islet cell nuclei within minutes of treatment with xanthine oxidase, indicating activation of the enzyme poly(ADP ribose) polymerase (PARP). Concomitantly, cellular NAD+ depletion was noted. Nicotinamide largely prevented NAD+ depletion and in parallel resulted in islet cell survival. These findings identify islet cell nuclear DNA as a primary target of oxygen radical toxicity and suggest related pathways of oxygen radical, nitric oxide and streptozotocin toxicity. PMID- 7840902 TI - Inactivation of receptor-bound pro-urokinase-type plasminogen activator (pro-uPA) by thrombin and thrombin/thrombomodulin complex. AB - Urokinase-type plasminogen activator (uPA) binds with high affinity to a specific cell surface glycosyl phosphatidyl-inositol (GPI)-anchored receptor, the urokinase receptor (uPAR). Pro-uPA, the enzymatically inactive single-chain form of uPA after having been activated by certain proteases, converts plasminogen into plasmin. This activation of pro-uPA to enzymatically active uPA can be prevented by the action of thrombin on pro-uPA. This inactivation process is accelerated in the presence of thrombomodulin (TM). The present study investigated whether pro-uPA bound to uPAR is still susceptible to inactivation by thrombin in the presence or absence of TM. A truncated soluble form of the uPAR lacking the GPI-anchor was cloned and expressed in CHO-cells (rec-uPAR277). Rec-uPAR277 efficiently inhibited the thrombin-mediated inactivation of pro-uPA up to 90% in a concentration dependent manner. The protective effect of rec uPAR277 was far less pronounced when thrombin was complexed with TM. Enzyme kinetic experiments with varying concentrations of pro-uPA showed that in the presence of TM the catalytic efficiency (kcat/Km) of thrombin-mediated inactivation raised from 0.010 microM-1 s-1 to 0.50 microM-1 s-1 corresponding to a fifty-fold increase. In the presence of rec-uPAR277, however, the catalytic efficiency dropped by 4.1-fold (0.5 microM-1 s-1 to 0.122 microM-1 s-1). The inactivation kinetics of pro-uPA by thrombin (no TM added) in the presence of an excess of rec-uPAR277 could not be determined since virtually no inactivation occurred. Our data suggest that pro-uPA once bound to uPAR, is significantly protected from inactivation by thrombin.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7840903 TI - Identity of human extra parotid glycoprotein (EP-GP) with secretory actin binding protein (SABP) and its biological properties. AB - In this paper the identity of the salivary protein EP-GP (extra-parotid glycoprotein) is reported, also apparent in other human secretions. Immunochemical and biochemical analysis demonstrated that EP-GP is similar to the secretory actin-binding protein (SABP), also known as gross cystic disease fluid protein-15 (GCDFP-15) and prolactin-inducible protein (PIP). The molecular mass and charge microheterogeneity of EP-GP, also observed for SABP, was shown to be predominantly caused by the carbohydrate moiety. In addition, evidence was given that EP-GP is not related to the lipocalin Von Ebner's gland protein (human; VEGh). The biological significance of EP-GP and its homologues is not clear. EP GP bound to actin and fibrinogen as described for SABP and GCDFP-15. However, the affinity for these proteins does not appear to have any direct physiological role in the mucosal secretions. On the other hand, EP-GP binds to several bacteria. By electron microscopy the ultrastructural localization is demonstrated of EP-GP to the cell wall of both Streptococcus salivarius HB and its cell appendage-lacking mutant Streptococcus salivarius HB-C12. Concerning this finding we hypothesize on the possible functional aspects of this enigmatic protein EP-GP. PMID- 7840904 TI - Degradation of heme IX in rats pretreated with cobaltous chloride. A study in isolated perfused liver. AB - The effect of the administration of cobaltous chloride on the degradation of heme IX was investigated using perfusions of isolated rat livers. The presence of biliverdin IX beta (2%) in the bile fluid of cobaltous chloride treated rats support the hypothesis of the presence of a chemical oxidation of heme IX induced by the cobalt salt. In control rats the absence of biliverdin IX beta in the bile fluid was observed. When biliverdin IX beta was added to the perfusate it was excreted in the bile fluid as bilirubin IX beta without conjugation. An increase from approximately twofold to three-fold of the total bilirubins in the bile fluids of cobaltous chloride pretreated rats in relation with control rats was observed due to heme oxygenase enhanced activity. Bilirubin IX alpha diconjugates increased ca. 15% in the bile fluids of cobaltous chloride pretreated rats, after the addition of hemin IX. The increase could reflect the presence of a new molecular form of UDP-glucuronosyltransferase, which favours the formation of bilirubin IX alpha diglucuronide and therefore its preferential excretion into the bile. In the bile fluid of the rats pretreated with cobaltous chloride, other diconjugates of bilirubin IX alpha were also detected 120 min after the addition of hemin IX to the perfusate, consisting of glucose and glucuronate (5%) and xylose and glucuronate (5%). PMID- 7840906 TI - Chemical reactivity of the toxin oosponol from Gloeophyllum abietinum with nucleophilic agents. AB - It is shown that contrary to most isocoumarins the antibiotic compound oosponol from the fungus Gloeophyllum abietinum reacts instantaneously with nucleophilic agents like thiol compounds. The reason for this high reactivity is due to the vinylogous acid anhydride character of the compound which is produced by a single oxidation step of the non toxic biological precursor oospoglycol. One must assume that reactions of oosponol with HS-groups of polypeptides form the basis for its toxicity. The ring-opening reactions were studied in detail with the synthetic analogue 4-acetyl-isocoumarin. The structures of some reaction products have been analysed mainly with H-1 and C-13 NMR spectroscopy. PMID- 7840905 TI - Characterization of a 43 kD protein associated to aminopeptidase A from murine kidney. AB - SDS-PAGE of affinity-purified APA under reducing conditions showed in addition to the specific APA band of M(r) 130 kD, a second band of M(r) 43 kD. Internal amino acid sequencing of three tryptic peptides from this second band, that was cut out of the polyacrylamide gel, matched the actin sequence. The identity of the 43 kD band was also confirmed by Western blotting. PMID- 7840907 TI - Topology of the morphological domains of the chaperonin GroEL visualized by immuno-electron microscopy. AB - Electron microscopy of the tetradecameric double-ring complex of GroEL reveals a four-layered structure, indicating that the 58 kDa subunits are composed of two major morphological domains. We have used immuno-electron microscopy to assign these domains to the corresponding segments of the GroEL sequence. Upon chemical modification of GroEL with N-ethylmaleimide, protease treatment in the presence of ATP or ADP generates GroEL fragments of 15 kDa (N15; residues 1-141) and 40 kDa (C40; residues 153-531). As visualized by scanning transmission electron microscopy, affinity-purified antibodies directed against C40 recognize the outer layers, whereas antibodies against N15 interact with the equatorial portions of the GroEL double-ring. Thus, the two major domains of the subunits in the chaperonin complex are arranged in the order C40-N15:N15-C40. The single-ring chaperonin co-factor GroES interacts with the C40 domain while the ATP-binding site of GroEL is probably close to the junction between N15 and C40. PMID- 7840908 TI - Consequences of prolonged inhalation of ozone on F344/N rats: collaborative studies. Part IV: Effects on expression of extracellular matrix genes. AB - Increased deposition of lung extracellular matrix in terminal airways is associated with chronic ozone exposure. In situ hybridization was used to assess whether long-term ozone exposure causes elevated and continued expression of genes coding for connective tissue proteins. Accessory lobes were removed from the animals exposed to 0, 0.12, 0.5, or 1.0 parts per million (ppm)* ozone for 20 months as part of the National Toxicology Program (NTP)/HEI Collaborative Ozone Project. The lungs were perfused fixed under physiologic pressure and processed for in situ hybridization. Sections were hybridized with 35S-labeled probes for messenger RNA (mRNA) coding for various matrix proteins, including collagen types I and III, elastin, and fibronectin, and for interstitial collagenase, a matrix metalloproteinase. Fetal rat lung was used as a positive control for hybridization. No signal for any mRNA was detected in terminal airway stromal cells of lungs from animals exposed to ozone for 20 months or control animals breathing clean air. In all samples from animals exposed to ozone for 20 months and control animals, only a very weak signal was seen in occasional cells within the interstitial spaces around large airways and blood vessels. In contrast, a strong signal for matrix-related mRNA was detected in fetal lung tissue. These findings indicate that active or enhanced matrix production is turned off in the adult animals used in the ozone studies, suggesting that the increase in matrix deposition results from a transient and early fibrotic response. Indeed, signal for type I procollagen and tropoelastin mRNAs was seen in alveolar septal cells in lungs of rats exposed to ozone for two months. No signal was seen in alveolar cells of age-matched control animals. (These animals, exposed for two months, and age-matched controls were from earlier studies supported by the HEI.) These findings indicate that ozone mediates a transient fibrotic response that results in a sustained increase in lung extracellular matrix. Confirmation of this hypothesis would require additional studies using animals exposed to ozone for shorter times. PMID- 7840909 TI - Into the future: HIV therapy advances. Introduction. PMID- 7840910 TI - Into the future: HIV therapy advances. Satellite symposium to the 4th European Conference on Clinical Aspects of Treatment of HIV Infection. 16 March 1994. Proceedings. PMID- 7840911 TI - HIV therapy advances. Pediatric antiretroviral choices. AB - BACKGROUND: Zidovudine is the initial treatment of choice in HIV-infected children. Zalcitabine or didanosine may be used in children who do not respond adequately or who are intolerant of zidovudine. Several studies of the latter agents are reviewed. MONOTHERAPY STUDIES: Zalcitabine at 0.005 or 0.01 mg/kg three times a day was associated with stabilization of growth and a decline in p24 antigen levels in more than 50% of treated children. In a dose-ranging study of didanosine, 30% of children showed an increase in CD4 cell counts and gained weight. There was a correlation between the plasma didanosine concentration and an improvement in IQ (Intelligence Quotient) and p24 status. STUDIES ON COMBINATION THERAPY: In a 12-18 month trial of zidovudine/zalcitabine in 13 children, most gained weight and more than half showed improved CD4 cell counts. The combination of various doses of didanosine with zidovudine was associated with a reduction in viral titer, a significant increase in CD4 cell counts and a trend towards increased weight in many children. STUDY IN MOTHER TO INFANT TRANSMISSION: Zidovudine or placebo was administered to women throughout pregnancy and during labor and to their new-born infants up to 6 weeks of age. The infection rate for the zidovudine-treated group was 8.3% compared with 25.5% for the placebo group (P = 0.000056). CONCLUSION: Zalcitabine and didanosine are useful drugs in the treatment of HIV-infected children. Zidovudine is associated with a reduced rate of mother to infant viral transmission. PMID- 7840912 TI - Interferons in HIV and related diseases. AB - BACKGROUND: Since interferon-alpha has a very broad spectrum of activity it has been investigated in several clinical settings in the HIV-infected population. KAPOSI'S SARCOMA: The rate of response to interferon-alpha is low in patients with low CD4 cell counts, but response rates of over 45% have been achieved in patients with higher counts. PRIMARY THERAPY IN HIV INFECTION: In 34 asymptomatic patients, the overall percentage of CD4 cells was higher in patients taking interferon-alpha compared to those taking a placebo and the rate of opportunistic infections was lower after a long-term follow-up. A relatively high dose of interferon-alpha was associated with predictable side effects. Lower doses have been used in combination with zidovudine. In a recent trial, 180 patients took either zidovudine alone, interferon-alpha alone or both drugs in combination. So far, the CD4 cell counts have been similar in all treatment groups. HEPATITIS INFECTION: The rate of response shown by hepatitis B infection to interferon alpha in patients with both hepatitis B and HIV has been reported as less than that in patients without HIV infection. Overall, studies have shown that approximately 37% of patients are cleared of hepatitis B DNA with 3 months of interferon-alpha treatment, compared with a 17% rate of spontaneous clearance. Among hepatitis C patients, 50-75% show a reduction in serum transaminases with 3 months of treatment. CONCLUSIONS: Interferon-alpha is of benefit in some HIV infected patients, demonstrating efficacy in Kaposi's sarcoma, hepatitis B and hepatitis C. PMID- 7840913 TI - HIV therapy advances. Update on a proteinase inhibitor. AB - HIV PROTEINASE INHIBITORS: The HIV proteinase enzyme has been identified as a potential target for antiretroviral therapy, as inhibition of this enzyme leads to the generation of immature, non-infectious virions. There are several proteinase inhibitors in development; the first to enter clinical trials was saquinavir. DEVELOPMENT OF SAQUINAVIR: Saquinavir, a transition-stage analogue of an HIV proteinase cleavage site, was developed using computer-led rational design techniques. It is a highly specific inhibitor of HIV-1 and -2 proteinases, with antiviral activity at concentrations 1000-fold less than those causing cytotoxicity. EUROPEAN CLINICAL EXPERIENCE WITH SAQUINAVIR: Three European clinical studies involving 202 patients have been conducted with saquinavir at doses of 25, 75, 200 and 600 mg three times a day. Two studies were dose-ranging monotherapy trials, one in asymptomatic or mildly symptomatic patients not previously treated with zidovudine, the other in patients with advanced HIV infection who had been treated with zidovudine. The third study was a combination therapy trial with zidovudine in previously untreated patients with advanced infection. Saquinavir was well tolerated either alone or in combination with zidovudine. In the monotherapy studies, CD4 cell counts and estimates of viral load showed the best results with the 600-mg dose. The combination of saquinavir and zidovudine resulted in higher and more sustained increases in CD4 cell counts than with either drug alone. The CD4 cell counts favoured saquinavir at 200 and 600 mg in combination with zidovudine, although plasma viraemia and the RNA polymerase chain reaction indicated that the 600-mg dose (in combination) produced better responses. PMID- 7840914 TI - Treatment options in zidovudine intolerance or failure. AB - AIM: To compare the efficacy and safety of didanosine and zalcitabine in patients who could not tolerate zidovudine or who had failed to respond adequately. PATIENTS AND METHODS: A multicentre, randomly allocated, open-label clinical trial was set up with 230 patients treated with didanosine and 237 treated with zalcitabine. All had previously been treated unsuccessfully with zidovudine. The patients were followed for at least 1 year, with an average of 16 months. RESULTS: Disease progression or death occurred in 157 patients taking didanosine and 152 taking zalcitabine. There appeared to be a slight trend in favour of survival in the latter group. CONCLUSIONS: There is an urgent need for more effective and better tolerated antiretroviral agents in the treatment of HIV infection. Zalcitabine is at least as effective as didanosine and may provide a survival advantage in patients treated unsuccessfully with zidovudine. PMID- 7840915 TI - Future treatment strategies in HIV infection. AB - EFFECTIVENESS OF EARLY TREATMENT WITH ZIDOVUDINE: In terms of progression to AIDS related complex, AIDS or death, clinical trials have not yet shown any long-term benefit for early compared with deferred treatment with zidovudine. The Concorde trial showed a short-term benefit, as did two of the AIDS Clinical Trials Group studies, but the number of deaths in these short-term trials was too small to draw definitive conclusions. USE OF CD4 CELL COUNTS AS A MARKER OF AIDS: Most trials of zidovudine treatment have shown a slower decline in CD4 cell counts. However, it is still not clear whether these markers can predict long-term survival although they appear to have some value in predicting short-term benefits. SECOND-LINE THERAPY: In patients who are intolerant of or have failed to respond adequately to zidovudine, treatment with didanosine or zalcitabine has shown some short-term benefit, mainly in asymptomatic patients or those with AIDs related complex. No substantial long-term benefit was observed. Zalcitabine appeared to show a slight increase in survival compared with didanosine. FUTURE PROSPECTS: Treatment strategies still being developed include multidrug combinations, the combination of a nucleoside with a non-nucleoside reverse transcriptase inhibitor, or the use of a combination of drugs that affect different stages of the HIV life cycle, such as proteinase inhibitors. More sensitive assays, such as RNA polymerase chain reaction, may allow treatment to be tailored more closely to the needs of the individual patient. PMID- 7840916 TI - HIV therapy advances. Early antiretroviral therapy. AB - AIM: To review evidence suggesting that antiretroviral therapy should be initiated at an early stage in HIV infection. METHOD: Review of published data. CONCLUSIONS: There are arguments both for and against early antiretroviral therapy. Although the reasons against are undoubtedly valid, evidence of greater efficacy, less toxicity and a delay in the development of resistance outweigh the possible disadvantages. Moreover, for some patients, early therapy may provide a chance of future benefits from more useful but currently untried treatments. PMID- 7840917 TI - Structure of suberic acid at 18.4, 75 and 123 K from neutron diffraction data. AB - Neutron diffraction data for suberic acid [HOOC(CH2)6COOH] were collected at 18.4, 75 and 123 K using a twinned crystal. The neutron data reduction included derivation of a complete set of corrected intensities, as if from a single crystal. This was followed by full-matrix structure refinement in the usual way. The molecule has an almost fully extended conformation with the hydrocarbon chains packed in an orthorhombic mode. Molecules form infinite hydrogen-bonded chains with crystallographic inversion centers occuring at the center and at the ends of each molecule. We suggest that at the twin boundary the hydrogen bonding is different, involving only the hydroxyl groups as both donors and acceptors. Accurate bond lengths have been obtained with corrections for thermal vibration (harmonic for C--C, C--O; harmonic and anharmonic for C--H). Values at the three temperatures agree well in terms of their e.s.d.'s (0.001 A for C--C and C--O and 0.005 A for C--H). Similar agreement is obtained for the corrected bond angles (e.s.d.'s 0.1 degrees for C--C--C, 0.2 degrees for H--C--H). For the methylene groups, the observed m.s. displacement parameters at each temperature are significantly greater at the middle of the molecule than at the ends. This indicates that the molecular backbone is vibrating internally. The thermal vibrations of the molecule have been analysed in terms of a simple segmented body model. PMID- 7840918 TI - The charge-density distribution in hexamethylenetetramine at 120 K. AB - The charge-density distribution has been determined from 333 independent X-ray reflections with sin theta/lambda < 1.47 A-1, which were collected with Ag K alpha radiation. As found in a recent refinement using room-temperature data, full-matrix least squares refinement with a multipole model gives rise to an almost complete correlation between certain octapole deformation terms. This is the worst case example of a problem which will always arise to some degree when applying the multipole model in a noncentrosymmetric space group. In this example, the correlation arises between terms which are predominant for describing the bonding density between atoms of the molecule, thereby causing the deformation charge density to have little meaning. However, the total molecular electrostatic potential and the molecular octapole moment are reliably obtained. PMID- 7840919 TI - Emerging role of beta-carotene and antioxidant nutrients in prevention of oral cancer. AB - beta-carotene and other antioxidant nutrients, such as vitamin E, are well suited for widespread preventive use because they are nontoxic and easily given in supplement form. Intervention trials designed to show a reduction of cancer incidence in the general population are logistically and practically impossible for most types of cancer, including cancer of the oral cavity. Thus evidence for chemoprevention must be indirect, using laboratory and animal models, epidemiologic surveys, and trials showing reversal of premalignant lesions or cancer prevention in high-risk groups. In several animal models, beta-carotene and other antioxidant nutrients inhibit oral carcinogenesis. Epidemiologic studies consistently relate low intake of these nutrients with high cancer risk. Smokers have lower beta-carotene levels in plasma and oral mucosal cells than nonsmokers. Eight clinical trials have now shown that beta-carotene and vitamin E produce regression of oral leukoplakia, but chemoprevention studies in oral leukoplakia have limitations, which we review. All available evidence supports a significant role for antioxidant nutrients in preventing oral cancer. PMID- 7840920 TI - Purposes, problems, and proposals for progress in cancer staging. AB - OBJECTIVE: To learn the opinions of selected members of the American Society for Head and Neck Surgery about the purpose of cancer staging and the problems with the current system, and to use these opinions to suggest improvements. DESIGN: Questionnaire survey. PARTICIPANTS: One hundred one physicians, based on their prominence in the field of head and neck cancer, selected from the society membership directory. OUTCOME MEASUREMENT: Responses to the six questions and other comments provided by the responding physicians. RESULTS: Sixty-six physicians returned the questionnaire. Of the six purposes of cancer staging, comparing end results was rated most important. Considerable variation existed among the respondents in the rank order of importance of the six purposes. The TNM strengths were its simplicity, low cost, relative accuracy, objectivity, universal acceptance, and lack of need for special technology. Weaknesses included inconsistencies, inaccuracies, observer variability, and problems with various T, N, and M classification criteria. Most believed that the TNM system should be expanded to include host factors, such as functional status, severity of comorbidity, immunocompetence, and symptom severity. CONCLUSIONS: These results suggest a wide range of opinion about the purpose of cancer staging. Several problems with the present TNM system, such as the exclusion of additional prognostic factors, limit the usefulness of the system. Progress in cancer staging will occur when the current system is augmented by these prognostic factors. PMID- 7840921 TI - Demographic portrayal and outcome analysis of head and neck cancer surgery in the elderly. AB - OBJECTIVE: To analyze the outcome and risk factors for 217 elderly patients who have undergone surgery for head and neck cancer, with or without radiation therapy. DESIGN: The risk factors that were reviewed included the primary tumor size, TNM staging, disease stage, preoperative health status, and type of surgical procedure. SETTING: Head and neck oncology clinic at North Carolina Baptist Hospital, Bowman Gray School of Medicine of Wake Forest University, Winston-Salem. RESULTS: The disease stage was directly related to prognosis, while advanced age and concomitant medical conditions were not. Complications were more prevalent with increased patient age, and the 57 patients who were older than 81 years had a slightly lower 3- and 5-year survival than those who were 65 to 80 years old. Sixty-six percent of all patients were discharged at 2 weeks, and 5% remained hospitalized for longer than 1 month. At the latest follow up, 46% of the patients were alive without recurrence or had died of other causes. CONCLUSIONS: Appropriate surgical therapy of head and neck cancer can be as effective in elderly patients as in younger patients without a significant increase in complications. PMID- 7840922 TI - Role of genetic factors in the etiology of squamous cell carcinoma of the head and neck. AB - OBJECTIVE: To determine the role of genetic predisposition in the etiology of head and neck squamous cell carcinoma. DESIGN: Retrospective study. SETTING: The outpatient clinics of the departments of otorhinolaryngology and maxillofacial surgery. PATIENTS: First-degree relatives of patients with new head and neck cancer, with first-degree relatives of the patients' spouses as controls. MAIN OUTCOME MEASURE: Occurrence of cancer of the respiratory and upper digestive tract in relatives of patients with head and neck cancer and controls. RESULTS: First-degree relatives (n = 617) of 105 patients with head and neck cancer had 31 cases of cancer of the respiratory and upper digestive tract vs 10 cases in the control group (n = 618) (relative risk, 3.5; P = .0002). This higher rate of cancer was even larger in siblings (16 vs 2, relative risk, 14.6; P = .0001). CONCLUSIONS: Genetic predisposition is an important risk factor for squamous cell carcinoma of the head and neck. PMID- 7840923 TI - Surgery after organ preservation therapy. Analysis of wound complications. AB - OBJECTIVE: To determine the incidence and risk factors for the development of major wound complications in patients with squamous cell cancer of the head and neck that require surgical salvage after an initial treatment regimen of induction chemotherapy and definitive radiation therapy for organ preservation. DESIGN: Retrospective survey. SETTING: Academic tertiary care referral center. PATIENTS AND INTERVENTION: The medical records of 96 patients treated with induction chemotherapy followed by definitive radiation therapy were reviewed; 18 of these patients requiring a surgical salvage procedure after completing chemotherapy and radiation therapy and these constituted the study group. MAIN OUTCOME MEASURES: Major wound complications. RESULTS: Major wound complications occurred in 11 (61%) of the 18 patients. Surgical salvage within 1 year of initial treatment had a 77% incidence of major wound complications vs a 20% incidence if performed 1 year after initial treatment. The mean time to resolution of fistulae and flap necrosis was 7.7 months. Two deaths were attributed to major wound complications: one patient had a carotid blowout; one had postoperative pneumonia. CONCLUSIONS: Salvage surgical procedures performed after induction chemotherapy and definitive radiation therapy have a high rate of major wound complications. This should be considered when assessing organ preservation treatment strategies. PMID- 7840924 TI - T3 glottic carcinoma revisited. Transglottic vs pure glottic carcinoma. AB - OBJECTIVE: To compare results of treatment of patients who have T3 transglottic carcinoma with patients who have T3 pure glottic carcinoma. DESIGN: A retrospective cohort study from January 1976 to December 1990 with a minimum 2 year follow-up. SETTING: Eye and Ear Hospital, University of Pittsburgh Medical Center. PATIENTS: The medical records of 161 patients with T3 glottic carcinoma were reviewed. We excluded 17 patients who were unavailable for follow-up or who had died of other causes but were free of glottic carcinoma. Therefore, 144 patients were entered into this study--79 patients with transglottic carcinoma and 65 with pure glottic carcinoma. INTERVENTION: Three treatment groups consisted of the following: 30 patients in whom a full course of radiation therapy failed and who subsequently underwent salvage surgery; 92 patients who underwent surgery only; and 22 patients who underwent surgery and had postoperative radiation therapy. Seventy-five patients had total laryngectomy, and 69 had total laryngectomy with neck dissection. MAIN OUTCOME MEASURES: Cervical metastasis, extracapsular spread, local failure, stomal recurrence, distant metastasis, and 2 years with no evidence of disease. RESULTS: Patients with T3 transglottic carcinoma had a higher incidence of occult cervical metastasis (12% vs 9%), overall cervical metastasis (27% vs 17%), and extracapsular spread (43% vs 27%) than did patients with T3 pure glottic carcinoma. Two years of no disease was similar in these two groups (80% vs 79%). Extracapsular spread had a notable effect on distant metastasis and on 2 years of no disease. CONCLUSION: Patients with T3 transglottic carcinoma had a higher incidence of cervical metastasis and extracapsular spread than patients with T3 pure glottic carcinoma. Every patient with T3 transglottic carcinoma should be treated with total laryngectomy with neck dissection. PMID- 7840925 TI - Management of patients with positive surgical margins after vertical hemilaryngectomy. AB - OBJECTIVE: To evaluate the significance of positive surgical margins after vertical hemilaryngectomy for squamous cell carcinoma of the larynx. DESIGN: A retrospective review of patients undergoing hemilaryngectomy over a 20-year period. SETTING: A major academic medical center. PATIENTS: Fifty-six consecutive patients who underwent hemilaryngectomy between 1970 and 1990. Seventeen patients were excluded because of insufficient data or because they received postoperative radiation therapy. RESULTS: Eleven (28%) of 39 patients had cancer involvement of at least one margin. Two (8%) of 28 patients with negative margins and six (55%) of 11 patients with positive margins had recurrence. This difference in tumor recurrence is statistically significant. The mean disease-free interval prior to recurrence was 25 months, with no significant difference between the two groups. The mean follow-up periods for patients with positive vs negative margins were not statistically significant. There were no significant differences in survival estimates between patients with positive margins and those with negative margins. CONCLUSIONS: Despite a sevenfold increase in tumor recurrence rates for patients with positive margins after hemilaryngectomy, there was no adverse effect on overall survival when these patients were managed with close follow-up and salvage surgery with or without postoperative radiation therapy for tumor recurrence. PMID- 7840926 TI - Serum immunoglobulins specific for intracellular proteins of squamous cell carcinoma. AB - OBJECTIVE: To determine an autologous humoral immune response to squamous cell carcinoma (SCC) intracellular proteins in patients with SCC. DESIGN: Intracellular proteins were isolated from 25 different cultured SCC lines. The proteins were used as a source of antigens to measure IgA, IgE, and IgG responses in the serum samples of patients and controls. Antibody response was assessed in both unfractionated and fractionated intracellular proteins. PATIENTS: The serum samples of 65 patients with SCC and of 65 age- and gender-matched controls were tested. RESULTS: Antibodies to SCC intracellular proteins were detected in the serum samples of 40 (62%) of the 65 patients with SCC and in the serum samples of 46 (71%) of 65 controls. Thirty (46%) of the patients with SCC and 40 (62%) of the controls had IgE responses, 18 (28%) of the patients and one (2%) of the controls had IgA responses, and 17 (26%) of the patients and 14 (22%) of the controls had IgG responses. An inverse relation was noted between detectable IgE responses and IgA or IgG responses in the patients and the controls. The analysis of antibody response indicated that 28 molecules were recognized predominantly by the serum samples of patients with SCC, but not by the serum samples of controls. CONCLUSIONS: A substantial proportion of patients with SCC and of controls exhibited an autologous humoral immune response to SCC intracellular proteins. The IgE responses to SCC intracellular proteins were inversely related to IgA or to IgG responses. Different antibody isotypes normally cause markedly different immune functions, and may suggest different roles for the existent immune responses to SCC antigens. We identified many tumor-associated antigens that were selectively recognized by the serum samples of patients with SCC. These antigens could be used to define molecular studies of immune surveillance and selection, and may represent appropriate targets for immunotherapy. PMID- 7840927 TI - Effect of arginine on growth of squamous cell carcinoma in the C3H/KM mouse. AB - OBJECTIVE: To determine whether arginine supplementation affects tumor growth or metastases in well-fed and starved mice using a squamous cell carcinoma VII tumor model. DESIGN: Prospective study in a murine model. INTERVENTIONS: Simulation of the cachectic state often seen in patients with head and neck cancer, induction of squamous cell carcinoma, and administration of standard and arginine supplemented diet. MAIN OUTCOME MEASURES: Effect of arginine supplementation on tumor growth, metastases, and host weight gain. RESULTS: Tumor weight was significantly decreased in those animals receiving 5% arginine supplementation. The rate of metastases was lower in animals receiving arginine, but this difference did not reach statistical significance. All groups receiving supplemental arginine experienced weight loss, which contradicts the findings that arginine as an anabolic agent may not be present in cancer-bearing hosts. PMID- 7840928 TI - Antitumor activity of interleukin-1 alpha and cisplatin in a murine model system. AB - BACKGROUND: Interleukin-1 alpha (IL-1 alpha) has potent antitumor activity either alone or combined with alkylating agents such as cisplatin and mitomycin C or porfiromycin. Cisplatin is an effective chemotherapeutic agent in the treatment of advanced squamous cell carcinoma of the head and neck (SCCHN). In the murine SCCVII/SF squamous cell carcinoma tumor model, IL-1 alpha induced acute hemorrhagic necrosis and increased clonogenic cell kill. OBJECTIVE: To determine the efficacy of cisplatin and IL-1 alpha, singly and in combination, in the treatment of SCCHN. METHODS: Syngeneic C3H/HeN mice were treated with single dose, concurrent, intraperitoneal injections of cisplatin and interleukin-1 alpha 14 days after subcutaneous tumor implantation and were monitored for delayed tumor regrowth. RESULTS: Cisplatin alone, but not IL-1 alpha, induced significant delayed tumor regrowth when compared with control. The combination of IL-1 alpha and cisplatin was even more effective in delaying tumor regrowth than cisplatin alone. Fractional tumor volume was significantly reduced in animals treated with the combination of cisplatin and IL-1 alpha compared with those treated with IL-1 alpha alone. CONCLUSIONS: Results of interleukin-1 alpha and cisplatin dose response experiments reveal that the combination of low-dose cisplatin and interleukin-1 alpha is more effective than high-dose cisplatin alone. Our data suggest that cisplatin and IL-1 alpha may be efficacious in the treatment of SCCHN. PMID- 7840930 TI - Head and neck lymphomas associated with human immunodeficiency virus infection. AB - OBJECTIVE: To focus on clinicopathologic data of non-Hodgkin's lymphomas (NHLs) of the head and neck area (with lymph nodal or extranodal localization) arising in patients with immunodeficiency virus (HIV) infection. PATIENTS: Among 73 evaluable patients for presenting symptoms, of a total of 82 with HIV-related NHLs whose conditions were diagnosed at the Centro di Riferimento Oncologico, Aviano (Italy), between September 1984 and May 1992, 15 (21%) had primary, solitary head and neck (P-HN) lymphoma and 13 (18%) had systemic head and neck (S HN) lymphoma arising from this region. RESULTS: Ten (67%) of 15 patients with P HN NHL had stages I and II, whereas all patients with S-HN NHL had stages III and IV. Twenty-seven of 28 patients had extranodal disease at presentation, the principal sites being Waldeyer's ring and soft tissues. There were only high grade (14 cases) or intermediate-grade (three cases) NHLs, the most frequent histotypes being small noncleaved cell, Burkitt's type, and large-cell immunoblastic. Seven of 11 cases in the miscellaneous group of the working formulation were classified as Ki-1+ anaplastic large-cell lymphoma. By immunophenotypic and genotypic characterization, a B-cell derivation was suggested for 21 of 28 NHLs. After combination chemotherapy with or without radiotherapy, a complete remission was observed in seven (58%) of 12 patients with P-HN lymphoma and in only two patients with S-HN lymphoma. Median survival was 9.8 months for the patients with P-HN lymphoma and 8.3 months for the other patients. Thirteen patients died, the most common causes of death being opportunistic infections (five cases) and progression of lymphoma (four cases). CONCLUSIONS: Most HIV-infected patients with head and neck NHL had severe immunodeficiency, extranodal disease, aggressive histologic findings, and a poor treatment response. PMID- 7840929 TI - Interleukin-8 expression by head and neck squamous cell carcinoma. AB - OBJECTIVE: To test the hypothesis that interleukin-8 (IL-8) is produced by human head and neck squamous cell carcinomas (HNSCCAs) and may therefore be a possible mediator for lymphocyte recruitment and neovascularization by these tumors. METHODS: Nine fresh samples of HNSCCA were analyzed for expression of IL-8 antigen using radioimmunoassay and immunohistochemical staining techniques. Also, four short-term primary cultures of HNSCCA and two continuous HNSCCA cell lines were then analyzed for production of IL-8 expression under both baseline conditions and following stimulation with other cytokines. RESULTS: The IL-8 antigen was detected in all fresh tumor homogenates by radioimmunoassay (5.58 to 331.69 ng of IL-8 per gram of tissue), and immunohistochemical results localized staining predominantly within the tumor cells. Primary cultures of HNSCCA and continuous HNSCCA cell lines produced only low levels of IL-8 (0.04 to 4.49 ng of IL-8 per 10(6) cells) under baseline (unstimulated) conditions. Stimulation of both primary cultures and cell lines with interleukin-1 and tumor necrosis factor induced significant increases in IL-8 antigen, while other cytokines failed to induce a significant increase. CONCLUSIONS: This study demonstrates that IL-8 antigen is expressed by HNSCCA in vivo, and that cultured HNSCCA in vitro can be stimulated to express IL-8 antigen by both interleukin-1 and tumor necrosis factor. Local production of IL-8 by HNSCCA cells, and its regulation by other cytokines, may be important in both the lymphocyte recruitment and tumor neovascularization seen in HNSCCA, and may thus ultimately affect the natural history of the disease. PMID- 7840931 TI - Laryngeal preservation for advanced laryngeal and hypopharyngeal cancers. AB - OBJECTIVE: To compare a single institutional experience with combination chemotherapy and radiation for laryngeal preservation with historical age-, sex-, stage-, and site-matched controls who underwent laryngectomy for cancer of the larynx or hypopharynx. DESIGN: Fifty-five patients with stage III or IV laryngeal and hypopharyngeal squamous carcinoma were prospectively entered into a protocol to receive three cycles of cisplatin (+/- bleomycin sulfate) and fluorouracil and radiation therapy from 1986 to 1991 (group 1). Following two cycles of chemotherapy, the clinical tumor response was assessed and responders received a third cycle of chemotherapy followed by definitive radiation therapy. Nonresponders underwent surgical salvage. Two patients in the surgical control group were matched to each protocol patient (n = 110, group 2) regarding site, stage, sex, and age (+/- 7 years) without knowledge of patient outcome. SETTING: A tertiary cancer referral center, The University of Texas M. D. Anderson Cancer Center, Houston. RESULTS: Following chemotherapy, the tumor response rate for group 1 was complete in 38% and partial in 31%. With a median follow-up of 24 months (group 1) and 37 months (group 2), the Kaplan-Meier 2-year disease specific survival for group 1 and 2 was 63% and 74%, respectively (P = .251). Among group 1 patients, 67% retained their larynges. Local recurrences were more frequent among the laryngeal preservation group (P = .001), whereas distant metastasis was more frequent among controls (P = .35). Thirty-three percent (18/55) of group 1 patients required total laryngectomy. Examining these subsets of patients showed that of the 67% (n = 37) of patients who retained their larynges, their 2-year survival was 56%, not significantly different from their respective controls (n = 74), 71%. Additionally, 2-year survival among the 18 group 1 patients who required salvage laryngectomy was 75% as compared with 80% for their matched controls (n = 36). CONCLUSIONS: These results document the results of chemotherapy and radiation therapy in the treatment of patients with advanced laryngeal and hypopharyngeal cancers in preserving the larynx. Although local control is significantly compromised among these patients, there is no compromise in overall survival when combined with prompt surgical salvage. PMID- 7840932 TI - Nontuberculous mycobacterial mastoiditis. AB - Although nontuberculous mycobacterial (NTM) infections are recognized as an important cause of cervicofacial lymphadenopathy in children, NTM mastoiditis is rare. Further, NTM mastoiditis may be difficult to distinguish clinically from tuberculous mastoiditis since both may present with chronic, painless otorrhea and exuberant middle ear granulation tissue. The treatment of tuberculous mastoiditis is antituberculosis chemotherapy; however, most NTM infections are resistant to antituberculous agents, and the preferred treatment of NTM mastoiditis is mastoidectomy. We report a recent case of mastoiditis caused by Mycobacterium avium complex in an infant who presented with a temporal bone mass. PMID- 7840933 TI - Multifocal amyloidosis of the pediatric airway. AB - Amyloidosis of the upper aerodigestive tract is rare in the pediatric age group. We present the first reported case (to our knowledge) of multifocal primary upper airway amyloidosis in a child. An otherwise-healthy 15-year-old girl presented with hoarseness, nasal congestion, and odynophagia. Diagnostic evaluation included flexible nasopharyngoscopy, rigid nasal endoscopy, direct laryngoscopy, bronchoscopy, and biopsy. The results of Congo red staining of the specimen were characteristic of amyloid. The findings of an extensive immunologic and systemic evaluation were normal. We discuss the treatment and postoperative course of this patient, as well as the clinical and pathologic characteristics of amyloidosis, with particular reference to the otolaryngologic manifestations of amyloidosis. PMID- 7840934 TI - Retrofacial approach to the hypotympanum. AB - Otologic disease often extends into the hypotympanum, posterior mesotympanum, and infralabyrinthine compartments. Surgical access to these areas can be difficult because of the proximity of the facial nerve. In patients with a normal bone anatomy, these regions can be accessed by a retrofacial approach, which spares the posterior canal wall and avoids transposition of the facial nerve. The anatomy of the hypotympanum, posterior mesotympanum, and infralabyrinthine compartments will be reviewed emphasizing gross anatomic documentation. We will detail the surgical approach to these areas along the retrofacial air cell tract, and will present an appropriate case history. PMID- 7840935 TI - Among a range of transition metals and ligands vanadium.desferroxamine excels in accelerating reactivity of ferrocytochrome c toward molecular oxygen. AB - Despite early knowledge of the requirement for metals in the reactions of ferrocytochrome c with oxygen, the relative effectiveness of metals and the factors that modulate effectiveness remain unknown. We have compared the catalytic power of five metals and report the effects of pH and ligand on their effectiveness as catalysts. Catalysis by metal ions was greatest at higher pH, where the rate of aerobic oxidation was lowest. Iron (Fe2+), copper (Cu2+), vanadium(V) (V(V)), manganese (Mn2+), and aluminum (Al3+) were tested in combination with EDTA, ADP, histidine, or desferrioxamine (Des) at pH 2.6, 3.2, and 4.0. At pH 2.6, only vanadium(V) increased the initial rate of the oxidation of ferrocytochrome c (by 6.2-fold). At pH 4.0, however, all the metals markedly stimulated the oxidation of cytochrome c. The order of effectiveness was V(V).Des >> Cu.ADP2+ > Fe.EDTA2+ > Mn.Des2+ > Al.EDTA3+ (where the stated ligand represents the most stimulating one for a given metal). At pH 3.2 the metal complexes had intermediate effects, with vanadium again being the most effective. The preeminence of vanadium among the metals is novel. Where the heme crevice is closed (pH 4), transition metal ions mediated almost all of the reduction of oxygen, while at the lowest pH (2.6) transition metal ions were largely unnecessary. Vanadium(V) was the most active of the metals at all values of pH and the only metal to accelerate the oxidation of ferrocytochrome c at pH 2.6. Understanding of the range of biological actions of vanadium will not be complete without a knowledge of its redox reactivity within the components of biological systems. PMID- 7840936 TI - Effect of pH and nonphysiological salt concentrations on human immunodeficiency virus-1 protease dimerization. AB - Human immunodeficiency virus-1 (HIV-1) protease is catalytically active as a dimer of identical subunits that associate through noncovalent interactions. To investigate the forces stabilizing HIV-1 protease in its active form, we have studied the effects of pH and salts on structure and function of the enzyme. Enzymatic activity was measured by following the hydrolysis of a fluorogenic substrate. Dissociation of the dimer into its subunits was monitored by gel filtration, while conformational changes in the enzyme were probed by measurements of intrinsic tryptophan fluorescence. Mg2+ ions were capable of dissociating the dimeric enzyme with a concomitant red shift and increase in quantum yield of the tryptophan fluorescence, indicating increased accessibility of tryptophan to the aqueous environment. These structural changes also were associated with a loss of catalytic activity which was insensitive to substrate concentration, consistent with noncompetitive inhibition. Both structural and functional changes could be attributed to binding of Mg2+ ions to a site with an apparent dissociation constant of approximately 2 M. In contrast, increasing concentrations of Na ions up to 5 M were without effect. Increasing pH had similar effects on HIV-1 protease as increasing Mg2+ ions concentration, with concomitant dissociation into subunits, increase in quantum yield and red shift in tryptophan fluorescence, and loss in catalytic activity. The apparent pKa for these structural and functional transitions was 6.95 +/- 0.08. This value is consistent with that of an aspartic acid residue with an anomalously high pKa, which has been implicated in the catalytic activity of HIV-1 protease. PMID- 7840937 TI - Translocation of neutral endopeptidase 24.11 mutants with deletions of the NH2 terminal cytosolic domain. AB - Rabbit neutral endopeptidase 24.11 (NEP) is a type II membrane protein with a positively charged 27 amino acid residue NH2-terminal cytoplasmic domain, a 20 amino acid residue hydrophobic signal peptide/membrane anchor domain, and a large catalytic COOH-terminal domain exposed on the exoplasmic side of the membrane. To study the role of the cytosolic domain in anchoring NEP in the plasma membrane, we constructed two mutants in which this cytosolic domain was deleted. In the first mutant (NEP delta cyto), a Glu residue was present in NH2-terminus, while a Lys residue was substituted at the same position in the second mutant (NEP delta cyto(K)). To better understand the interaction of these mutants with the rough endoplasmic reticulum membrane, the mutated NEP cDNAs were transcribed and translated in vitro in the presence of microsomal membranes. Our studies showed that deletion of the hydrophillic cytosolic domain affects translocation of the NEP polypeptide chain. Substitution of a positively charged Lys residue for the Glu residue at the NH2-terminus of the deletion mutant only partly restored translocation of the polypeptide chain. Furthermore, carbonate extraction and trypsin digestion of the microsomal membranes indicated that the deletion mutants are inserted in the microsomal membranes as type III membrane proteins with their COOH-terminal domain exposed on the exterior of the microsomes. Thus, efficient translocation is dependent on the presence of a charged cytoplasmic domain. PMID- 7840938 TI - Activities of acetylcholinesterase, choline acetyltransferase, and catecholamine production in the spinal cord of the axolotl Ambystoma mexicanum during forelimb regeneration. AB - Amputation of an axolotl limb causes severance of the brachial nerves, followed by their regeneration into a blastema. It is known that these nerves provide a neurotrophic factor to blastemal cells. To approach the problem of the response of spinal cord nerve centers to forelimb amputation, we have studied biosynthetic activities in the nerve centers involved in axonal injury during limb regeneration. We report that the acetylcholinesterase (AChE) activity in the spinal cord is elevated 2 days (+69%) and 7 days (+28%) after limb amputation compared with levels in unamputated control animals, but is not significantly elevated at 3 h or 15 days. The percentages of slow (3.6S and 6.0S) and fast (18S) sedimenting forms of AChE progressively decrease 2 and 7 days after amputation, while those of intermediate sedimenting forms (10.5S and 14.0S) increase. Fifteen days after amputation, lower molecular weight forms return to the control level, but the heavy molecular weight form of AChE is absent as at 7 days; consequently intermediate molecular weight forms are in a greater proportion than the other two forms. Choline acetyltransferase activity was measured only 2 days after amputation (when AChE was at its highest level). It increases by about 34% with regard to the controls. Adrenaline is higher than controls 2 days after amputation, while noradrenaline is not significantly modified. The metabolic changes observed in the spinal cord during limb regeneration probably are the result of a general reaction to the stress of amputation (transection of brachial nerves) and regeneration of nerve fibers, since similar metabolic activities were observed after a simple denervation of the two unamputated forelimbs. PMID- 7840939 TI - DNA topoisomerase activity associated with simian virus 40 nucleoprotein complexes. AB - Simian virus 40 (SV40) chromatin extracted from nuclei of infected monkey cells (CV1) was sedimented in neutral sucrose gradients, before and after digestion with bovine pancreatic RNase I-A or DNase I. DNA topoisomerase (TI) activity was found associated with RNase-resistant, DNase-sensitive SV40 nucleoprotein complexes. After polyacrylamide gel electrophoresis, a number of proteins with a molecular mass between 40 and 70 kDa were seen at the level of viral DNA peaks, some of which may represent catalytically active breakdown products of the TI enzyme. Large protein complexes were observed under the electron microscope in association with the viral chromosomes and appear to correspond to the SV40 DNA replication complex, including TI. Our results suggest that TI activity is indeed associated with the viral minichromosomes undergoing replication in vivo. PMID- 7840940 TI - Structural comparison of the histidine-containing phosphocarrier protein HPr. AB - The phosphocarrier protein HPr is a central component of the bacterial phosphoenolpyruvate:sugar phosphotransferase system (PTS) that is responsible for carbohydrate uptake in many bacterial species. A number of three-dimensional structures of HPrs from both Gram-positive and Gram-negative bacteria have been determined; the overall folding topology of HPr is an open-faced beta-sandwich composed of three alpha-helices and a beta-sheet. A detailed structural comparison of these HPrs has been carried out. Besides the overall main chain folding, many detailed structural features are well conserved in all HPr structures. The three x-ray structures of HPrs from Escherichia coli, Streptococcus faecalis, and Bacillus subtilis show considerable overall similarity with respect to the positions of the C alpha atoms. A significant structural difference between HPrs from Gram-positive and Gram-negative bacteria is found in the region of Gly54, owing to the steric effects of Tyr37 in HPrs from the Gram-positive species. The region around Gly54 is involved in the binding of HPr to other PTS proteins and the differences in this region may be responsible for some of the poor functional complementation between HPrs from Gram-positive and Gram-negative species. The active center region, residues 12 18, appears to have significant differences in the comparisons between the overall structures. These differences support the proposal that phosphorylation and dephosphorylation of the active site His15 is accompanied by conformational changes. However, a local structural comparison of residues 12-18 from the x-ray structures of HPrs from E. coli and B. subtilis, and the two-dimensional nuclear magnetic resonance structure of B. subtilis HPr suggests that there is a conserved active center involving residues His15, Arg 17, and Pro18, which shows little conformational change during the phosphorylation cycle. The results of other experimental approaches, including site-directed mutagenesis and NMR spectroscopy, are in some cases difficult to rationalize with some of the details of the structures, but do appear to favour the conclusion that little conformational change occurs. PMID- 7840941 TI - Purification and characterization of a protein kinase from goat sperm plasma membrane. AB - A protein kinase that causes phosphorylation of serine and threonine residues of casein has been partially purified from goat cauda-epididymal sperm plasma membrane and characterized. The kinase, solubilized from the membrane with 1.0% Triton X-100, was purified to 480-fold by using DEAE-cellulose and casein Sepharose affinity chromatographic techniques. The kinase is a strongly basic protein with pI of 9.5. The enzyme has a molecular mass of 310 kilodaltons as estimated by Sephacryl S-300 gel exclusion. The kinase showed affinity for protein substrates in the order membrane proteins > casein > phosvitin > histone > protamine. The apparent Km values of the kinase for casein and membrane proteins were 1 and 0.15 mg/mL, respectively. The synthetic peptides Kemptide and poly(Glu80Tyr20) did not serve as substrates of the enzyme. ATP, rather than GTP or PP(i), is the donor of phosphate for the phosphorylation reaction. Cyclic AMP and GMP, NaCl (0.25 M), KCl (0.25 M), Ca2+, calmodulin, phosphatidylserine, and muscle protein kinase inhibitor had no appreciable effect on the kinase activity. Heparin (0.5 microgram/mL) showed high affinity for inhibiting only 40% of the kinase activity, whereas polyamines at a relatively high concentration (5 mM) inhibited 40-50% of the enzymic activity. The kinase appears to be distinct from other protein kinases including casein kinases. The activity of the kinase derived from the purified sperm plasma membrane was markedly (approximately 90%) lost when the intact spermatozoa were pretreated with diazonium salt of sulfanilic acid, a membrane nonpenetrating surface probe.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7840942 TI - Phosphorylation of the precursor sequence of rat B-type natriuretic peptide by p34cdc2 and MAP kinase. AB - Atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), two distinct members of the natriuretic peptide family, share many features in common. However, differences in expression indicate that the processing mechanisms must be different. The leader sequence of rat BNP contains three potential phosphorylation sites for proline-directed kinases that are not present in the leader sequence of ANP. This study has examined how these sites are used by two somewhat different proline-directed kinases. A peptide containing these sites was phosphorylated in vitro by HeLa p34cdc2 kinase and by sea star p44mpk kinase at rates that were comparable to the rates with peptide substrates that are used to assay these enzymes. Sequence analysis of the phosphopeptide shows that both kinases phosphorylate only the two potential phosphorylation sites surrounding the cleavage site of the BNP precursor. The enzymatic potential for such a phosphorylation of BNP in cardiac tissue is demonstrated by immunoblots and kinase assays, showing that in fetal and in adult rat heart both the atria and the ventricles contain a mitogen-activated protein kinase homologue that can phosphorylate this preproBNP sequence. PMID- 7840943 TI - Regulation of expression of the cyclic nucleotide phosphodiesterase gene in phosphodiesterase inhibitor-negative mutants of Dictyostelium discoideum. AB - During early development of Dictyostelium discoideum, the enzyme cyclic nucleotide phosphodiesterase (PD) is produced at a low rate during the period its specific inhibitor (PDI) is being synthesized. In addition, PD gene expression is derepressed in the aggregation-deficient (Agg-), Pdi- mutant HC35. These observations suggest that the PDI might function to regulate PD gene expression, as well as modulate its activity. To explore this idea further, five new Agg-, Pdi- mutants were isolated and analyzed. All of the mutants produced high PD activity and overexpressed PD mRNA; four exhibited elevated levels of the 2400 nucleotide aggregation transcript and one overproduced the 1900-nucleotide vegetative transcript. In contrast, PD transcripts were not elevated in two Agg-, Pdi+ mutants. To determine if PDI production regulates PD expression, HC35 cells were transformed with plasmids carrying the PDI structural gene under the control of either the vegetative or aggregative PD promoter. Neither expression of PDI by the transformants nor addition of partially purified PDI to HC35 cells affected PD transcription. These results suggest that PD overexpression in the Pdi- mutants is not a direct consequence of the inability of these cells to produce inhibitor. PMID- 7840944 TI - A 56- to 54-kilodalton non grata signal in immunoblot analysis using the horseradish peroxidase chemiluminescence system. AB - The major advantages of the horseradish peroxidase chemiluminescence (HRP-CL) immunodetection method in Western blot analysis are its high sensitivity, nonradioactive detection, economy of the primary antibody, and speed of detecting the signal. However, we observed a strong and reproducible signal that was detected regardless of the primary antibody and of the cell type used. This signal, present at 56-54 kilodaltons (kDa), is generated in absence of any primary antibody and seems to be an intrinsic reaction of the HRP-labeled second antibody anti-immunoglobulin with an unidentified cellular protein. The use of dry milk throughout all the steps of the procedure abolishes this signal. For those interested in one of the numerous proteins migrating at or close to 56-54 kDa, the question therefore arises as to which signals generated by the HRP-CL in this region are bona fide and which are non grata pseudo signals. PMID- 7840945 TI - Carbonic anhydrase in mouse skeletal muscle and its influence on contractility. AB - Carbonic anhydrase III (EC 4.2.1.1) is the most abundant cytosolic protein in type I skeletal muscle fibers. Investigations of its physiological role have mostly been conducted with rat muscles, which sometimes are unsuitable for in vitro studies. The objective of the present study was to characterize the carbonic anhydrase in the mouse soleus muscle to verify if this muscle can be used as a model to further study the enzyme's function. Total carbonic anhydrase specific activity in the mouse soleus was comparable to the value for rat. However, 60% of the total carbonic anhydrase activity in the mouse was of the sulfonamide-sensitive type and, therefore, not related to carbonic anhydrase III. Electrophoretic analysis revealed the presence of a 29-kDa protein in total and cytosolic extracts of the mouse soleus. Immunoblotting with an antibody developed against rat carbonic anhydrase III showed that it was also specific for this 29 kDa peptide, which presumably is the mouse carbonic anhydrase III. Inhibition of the sulfonamide-sensitive activity had no effect on contractile and fatigue characteristics, whereas inhibition of the sulfonamide-resistant carbonic anhydrase III activity led to a significant increase in resistance to fatigue. We conclude that the mouse soleus may represent an excellent model to understand the contribution of different carbonic anhydrase isoforms to muscle physiology. PMID- 7840946 TI - Frequency and morpho-structural organization of the thyroid gland isthmus in horses, donkeys and small ruminants. PMID- 7840947 TI - Morphological and ultrastructural observations on mouse embryo chondrocytes cultured in vitro with and without ascorbic acid. PMID- 7840948 TI - Chronic iron deficiency in a carrier of hyperaffine hemoglobin. PMID- 7840949 TI - Use of PCR-Ribotyping for the characterisation of Salmonella. PMID- 7840950 TI - Tongue reflexes during olfactory stimulation. PMID- 7840951 TI - Visually guided pointing to remembered locations and subjective representation of space. PMID- 7840952 TI - Further observations on the presence and distribution of muscle spindles in the diaphragm muscle of the hedgehog (Erinaceus europaeus) and hamster (Cricetus auratus). PMID- 7840953 TI - Effect of acute ethanol administration on serum magnesium concentration in the rabbit. PMID- 7840954 TI - Correlation between ascorbate biosynthesis and ascorbate peroxidase activity. PMID- 7840955 TI - Triticinae ploidy and ascorbate peroxidase isoforms. PMID- 7840956 TI - Isolation of nuclear extracts from fragile cells: a simplified procedure applied to thymocytes. PMID- 7840957 TI - Production of intertypic hybrids between adherent and suspended cell populations. PMID- 7840958 TI - A rapid protocol for DNA extraction and primer annealing for PCR sequencing. PMID- 7840959 TI - PCR-based detection of mycobacteria in sputum samples using a simple and reliable DNA extraction protocol. PMID- 7840960 TI - Improved adhesiveness of polyester wax sections for immunocytochemistry. PMID- 7840961 TI - An improved method for pouring DNA sequencing gels. PMID- 7840962 TI - Fluorescent automated sequencing of supercoiled high molecular weight double stranded DNA. PMID- 7840963 TI - Use of agar in selective media may give false positives in a functional complementation assay. PMID- 7840964 TI - The "looped oligo" method for generating reference molecules for quantitative PCR. PMID- 7840965 TI - Transgene detection in mouse tail digests. PMID- 7840967 TI - Visual identification of individual transfected cells for electrophysiology using antibody-coated beads. AB - Electrophysiological study of transiently transfected cells requires the identification of individual cells that express the protein of interest. We describe a simple, quick and inexpensive method for visually identifying cells that have been co-transfected with an expression plasmid for a lymphocyte surface antigen (CD8-alpha). Transfected cells are incubated briefly with polystyrene microspheres (4.5 microns diameter) that have been precoated with antibody to CD8. Cells expressing CD8 on their surface are decorated with many beads and are thus readily distinguishable from untransfected cells. Beads already coated with antibody are available commercially. The method takes less than five minutes and requires no reagent preparation or special equipment for visualization of the beads. PMID- 7840966 TI - Double-label in situ hybridization using biotin and digoxigenin-tagged RNA probes. AB - We describe a double-label in situ hybridization protocol based on the optimized synthesis of biotin-labeled RNA probes. Biotin-labeled probes are used in conjunction with digoxigenin-labeled probes to simultaneously visualize two different transcripts. One transcript is hybridized with a biotin-labeled RNA probe and visualized as a brown peroxidase reaction product, and the other transcript is hybridized with a digoxigenin-labeled RNA probe and visualized as a blue alkaline phosphatase reaction product. We present several examples in which this double-labeling method has proven useful in determining the spatial and temporal relationships between various transcripts expressed during Drosophila embryogenesis, indicating that this method should be of general use in establishing the relationship of two independent transcription patterns. PMID- 7840968 TI - Optimization of the transfection of human endothelial cells by electroporation. AB - A method for efficient transfection of human umbilical vein endothelial cells (HUVEC) is presented here. The procedure involves cell synchronization followed by electroporation and allows the detection of the activity of low-strength promoters. Sodium butyrate, added to the culture medium after electroporation, strongly potentiates the transcriptional activity of viral promoters. The method can be successfully applied to analyze the transcriptional activity of different promoters linked to reporter genes or to express foreign genes controlled by viral promoters. PMID- 7840969 TI - Microplate DNA preparation, PCR screening and cell freezing for gene targeting in embryonic stem cells. AB - We have developed a new method for genomic DNA microextraction using acetone/N,N dimethylformamide. Combining this with 96-well plate PCR allows rapid analysis of large numbers of genomic DNA samples. One application is the analysis of embryonic stem cells for rare gene targeting events. The combination of 96-well plate tissue culture procedures, DNA microextraction and PCR reduces the delays and risks associated with Southern analysis and avoids the need to freeze large numbers of cell clones. In contrast to previously described rapid genomic extraction procedures, the DNA produced using acetone/N,N-dimethylformamide microextraction is sufficiently pure to support reliable amplification of at least 2.2 kb. The efficacy of the combined microextraction and amplification procedure has been demonstrated by the identification of gene targeting events at the mOR gene locus. In addition, we have also detailed an improved 96-well plate freezing protocol for embryonic stem cells that allows long-term storage at -70 degrees C. The simple nature of the combined procedures described lend themselves to future automation. PMID- 7840970 TI - Hybrid PCR sequencing: sequencing of PCR products using a universal primer. AB - We describe a general method for making template DNA for sequencing of PCR products. The procedure may be particularly useful for PCR products where minimal sequence information is known or as an alternative to primer walking when sequencing long PCR products. A cassette containing the hybridization site for the M13 sequencing primer is ligated to a sample PCR product. Using one phosphorylated primer specific for the cassette together with one primer specific for the sample PCR product, subsequent PCR amplifies one hybrid construct directionally. This allows utilization of the universal M13 primer when sequencing of one strand after the removal of the complementary strand using lambda-exonuclease. PMID- 7840971 TI - Generation of minisatellite variant repeat codes on an automated DNA sequencer using fluorescent dye-labeled primers. AB - We demonstrate the potential to generate unambiguous minisatellite variant repeat PCR profiles on an automated DNA sequencer using fluorescent dye-labeled primers. The products of a 24-cycle PCR amplification using 100 ng of template DNA were analyzed by conventional blot hybridization and also on an Applied Biosystems 373A DNA Sequencer. The results from the sequencer were clear to the 20th repeat when using a primer labeled with 6-FAM, whereas conventional analysis allowed codes to be defined to in excess of the 60th repeat. Use of a modified Tag primer sequence, which eliminates the potential for self-annealing, did not improve the clarity of the results under the PCR cycling conditions used. PMID- 7840972 TI - Dideoxy genomic sequencing of a single-copy mammalian gene using more than two hundred cycles of linear amplification. AB - We explored the possibility of using a large number of reaction cycles to achieve genomic DNA sequencing in single-copy mammalian genes. A section of the beta globin promoter was sequenced directly from a sample of human white blood cell DNA. The sequencing fragments were extended from a single, 5'-terminal-labeled oligonucleotide primer by Taq DNA Polymerase in the presence of dideoxyribonucleotides and more than 200 thermal cycles of denaturation, annealing and extension. The labeled sequencing fragments produced in this linear amplification were detected after electrophoresis on a DNA-sequencing gel. We propose that this scheme could be adopted in some instances as an alternative to conventional sequencing. PMID- 7840973 TI - Rapid silver staining and recovery of PCR products separated on polyacrylamide gels. AB - A rapid silver-staining procedure for DNA fragments in polyacrylamide gels is described. The time required for band detection is 15 min and the limit of sensitivity 3 pg/mm2. PCR products subjected to this rapid staining protocol are readily recovered from the gel by excision and elution by incubation at 95 degrees C for 20 min. Bands of up to 3 kb have been recovered and reamplified from either recently prepared or dried gels. The rapid staining protocol significantly decreases the processing time required for silver-stained polyacrylamide gels, which is of particular importance in diagnostic situations. The recovery protocol allows individual bands from complex mixtures to be easily recovered for sequencing or probe preparation. PMID- 7840974 TI - Quantifying radiolabeled macromolecules and small molecules on a single gel. AB - A protein phosphorylation cascade involved in chemotactic signaling in Escherichia coli was investigated with purified components in vitro. CheA, an auto-phosphorylating histidine kinase, was mixed with [gamma-32P]ATP, and the labeled protein was purified for use as a reagent in the assays. CheY, a response regulator protein, can acquire phosphate groups from CheA but then undergoes rapid hydrolysis, which releases inorganic phosphate. To follow the kinetics of the CheA-CheY phospho-transfer reaction and the subsequent dephosphorylation of phospho-CheY, we separated the reaction components by polyacrylamide gel electrophoresis and measured the amount of 32P label in the CheA. CheY and inorganic phosphate bands with phosphor storage screens. By reducing the time needed to separate and quantify the reaction products, we minimized diffusive spreading of the low molecular weight inorganic phosphate, which enabled us to measure it accurately on the same gel with the much larger proteins. In principle, any radiolabeled molecules that can be separated by relatively rapid means, such as acrylamide gel electrophoresis, and that are detectable with a phosphor storage screen, should be amenable to this technique. PMID- 7840975 TI - High resolution mapping using fluorescence in situ hybridization to extended DNA fibers prepared from agarose-embedded cells. AB - Fluorescence in situ hybridization (FISH) and pulse field gel electrophoresis (PFGE) are essential techniques in physical mapping and in positional cloning. We present a technique that utilizes agarose-embedded high molecular weight DNA prepared for PFGE as a target for FISH. The agarose blocks are melted, and the DNA is extended on a poly-L-lysine-coated microscope slide. The resulting DNA fibers appear on the slide as long straight strands and are a suitable target for high resolution FISH mapping as demonstrated here with cosmid and plasmid hybridizations. PMID- 7840976 TI - Gene expression analysis by a competitive and differential PCR with antisense competitors. AB - We report a sensitive method for the reproducible and accurate measurement of gene expression from small samples of RNA. This method is based on a combination of two PCR techniques: First, an endogenous reporter gene and the gene of interest are simultaneously amplified in one tube after random-primed reverse transcription (RT) of RNA (differential RT-PCR). Second, exogenous homologous fragments of both genes with artificially introduced mutations are added and coamplified in the same reaction (competitive PCR). The first-strand cDNA, and the mutated antisense homologues of the reporter as well as the target gene compete for their respective primers and are therefore amplified with equal efficiencies. After PCR, restriction enzyme digestion allows visualization of the quantitative differences between the four resulting reaction products. The ratios of products that competed during PCR provide the quantitative information. The initial amount of a specific cDNA can be calculated from any competitor/cDNA ratio of reliably measurable PCR product amounts. Extensive competitor titration to experimentally approach the equilibrium is therefore unnecessary. The differential counterpart of competitive and differential RT-PCR (CD-RT-PCR) allows expression of the levels in reference to a reporter gene. MDR1 expression was determined in tumor cells by CD-RT-PCR. PMID- 7840977 TI - Increased protein expression through improved ribosome-binding sites obtained by library mutagenesis. AB - This report describes a method whereby library mutagenesis combined with drug selection was used to generate unique and efficient ribosome-binding sites (RBS) for expressing recombinant proteins in Escherichia coli. The RBS was deleted from a vector expressing beta-lactamase and replaced with a 16-base sequence containing a library of mutations. Selection of the library with ampicillin yielded several unique RBS sequences that were more efficient than ompA RBS for expressing a bacterial (beta-lactamase) and a mammalian protein (single-chain Fv antibody). The described approach provides a practical means to improve recombinant protein expression and, also, provides new sequences to further evaluate the complex regulatory mechanism underlying translation initiation. PMID- 7840978 TI - Fluorescence in situ hybridization of interphase nuclei isolated from whole blood of transgenic mice. AB - Homozygosity in transgenic mice is typically confirmed by the time-consuming practice of breeding suspected homozygotes to non-transgenics and looking for 100% transmittance of the transgene to offspring. We have devised a simple reproducible method for isolating white blood cell nuclei from small quantities of mouse whole blood and have utilized fluorescence in situ hybridization to confirm the presence of one (hemizygous) or two (homozygous) copies of the transgene locus in interphase nuclei fixed to microscope slides. This method should have other applications where in situ hybridization of interphase nuclei is desirable. PMID- 7840979 TI - Automated determination of beta-galactosidase specific activity. AB - We describe a modification of an automated kinetic assay for beta-galactosidase (beta-gal) activity. This modification includes an assay to quantitate the amount of protein added to each assay. The determination of specific activity includes the amount of protein in the calculation which produces a specific activity with units of pmol product produced/minute/mg protein. In addition to this modification, we present a series of macros written in Microsoft Excel for either the Macintosh or Windows on the PC. These macros decrease the amount of time required to analyze the data from beta-gal assays. PMID- 7840980 TI - Human multiple tissue western blots: a new immunological tool for the analysis of tissue-specific protein expression. AB - Human multiple tissue Western (MTW) blots are premade immunoblots prepared using proteins isolated from adult human tissue. The proteins are isolated from whole tissue homogenates under conditions designed to minimize proteolysis and to ensure maximal representation of tissue-specific proteins. Sodium dodecyl sulfate (SDS) solubilized proteins are fractionated by SDS polyacrylamide gel electrophoresis and electroblotted onto polyvinylidene fluoride membranes to generate blots ready for incubation with researcher-supplied antibodies. Each lane of an MTW blot contains an equivalent amount of total protein, allowing for the analysis of tissue-specific expression of a particular protein(s). The utility of MTW blots for Western blot applications was demonstrated by the detection of various cytoskeletal proteins and members of the annexin family of calcium-dependent, membrane-binding proteins. Several of these antigens were detected in separate cycles of antibody incubations using the same MTW blot. This approach is possible using a stripping procedure that allows the researcher to selectively remove both primary and secondary antibodies in a single incubation. The ease of multiple reprobings makes MTW blots both economical and convenient research tools for Western blot analyses of human tissue-specific proteins. PMID- 7840981 TI - Automated procedures for the quantitation of protein. AB - An entirely automated 96-well microplate-based system to perform procedures for the measurement of protein is described. This single instrument system utilizes a series of computer-controlled mechanical subsystems to move the plate, control incubations and dispense samples or reagents in order to perform the assay. This system allows the investigator to reproducibly perform these protein assays on large numbers of biological samples with minimal effort. PMID- 7840982 TI - Three-dimensional reconstruction of color Doppler jets in the human heart. AB - A computer algorithm has been developed for segmentation and three-dimensional (3D) reconstruction of Doppler color-flow images. The algorithm enables the user to select a range of velocities, represented by colors, for segmentation and subsequent 3D reconstruction. The reconstructed flows are assigned a color palette and merged with the volume-rendered gray-scale image to produce a 3D image containing both flow and anatomic information. The results demonstrate the application of the algorithm to regurgitant and shunt jets with complex spatial and velocity patterns. We conclude that 3D reconstruction of selected color spectra (e.g., velocities) of Doppler color flows and surrounding anatomy is feasible in the clinical setting. PMID- 7840983 TI - Three-dimensional imaging of cardiac mass lesions by transesophageal echocardiographic computed tomography. AB - Three-dimensional echocardiography is a new imaging technique that allows more realistic visualization of cardiac morphology. This study presents data about the diagnostic potentials of this technique concerning cardiac mass lesions, as well as its feasibility in clinical application. After the conventional investigation, multiple cross-sectional images were obtained during automatic forward advancement of a monoplane transducer mounted on a transesophageal probe. Three dimensional reconstruction and volume determination were performed off line. Twenty-four patients were studied. In 14 cases results of echocardiographic computed tomography (echo-CT) were compared with those of monoplane/biplane transesophageal echocardiography. In 23 patients a conventional transesophageal investigation with the echo-CT probe and in 20 patients tomographic scanning were possible. Data acquisition required 12 +/- 4 minutes and three-dimensional reconstruction required 35 +/- 14 minutes. In 13 patients mass lesions were found; in 11 of 13 patients echo-CT provided diagnostic information about the precise spatial orientation and morphology of cardiac structures that could not be obtained by monoplane/biplane transesophageal echocardiography. The technique revealed accurate distance measurements and volume determination of mass lesions. Echo-CT is a further step toward the application of clinically useful three dimensional echocardiography. PMID- 7840985 TI - Acoustic lability of albumin microspheres. AB - The sonication of human serum albumin produces air-filled microspheres that are used in echocardiographic studies of myocardial perfusion. Recent studies suggest that the microspheres disappear when high pressures are applied, altering the relationship between the administered microsphere dose and the echocardiographic response. Because an ultrasound pulse generates a pressure wave in insonified medium, we hypothesized that with increasing acoustic pulse pressure, the microsphere concentration decreases, hence ultrasonic backscatter decreases. We measured relative integrated backscatter from albumin microspheres diluted in normal saline solution (6152 microspheres/ml) and 5% human plasma protein fraction (24,608 microspheres/ml), with increasing acoustic pulse pressures at the transducer's focus. Backscatter was also measured in normal saline solution with increasing concentrations (up to 15,380 microspheres/ml) of albumin microspheres at an acoustic pulse pressure of 0.11 MPa (1.1 atm). Backscatter and microsphere concentration were related logarithmically: y = 3.38 x 0.32; r = 0.93. Backscatter was unchanged over time at acoustic pulse (peak compression) pressures less than 0.15 MPa (1.5 atm). However, backscatter decreased readily at acoustic pulse pressures greater than 0.33 MPa (3.3 atm), which included any mixing effects. Thus, albumin microspheres are acoustically labile. PMID- 7840984 TI - A new method for echocardiographic computerized three-dimensional reconstruction of left ventricular endocardial surface: in vitro accuracy and clinical repeatability of volumes. AB - This study evaluates the in vitro accuracy and clinical repeatability of volumes derived by a new algorithm for three-dimensional reconstruction of cavity surfaces based on echocardiographic apical images obtained by probe rotation. The accuracy of the method was tested in latex phantoms (true volumes, 32 to 349 cm3) with (n = 9) or without (n = 9) rotational symmetry around the midcavitary long axis. Repeatability of left ventricular volumes was assessed in subjects without (n = 5) or with (n = 10) myocardial disease. Estimated phantom volumes obtained from four (three) imaging planes were close to true volumes with a mean difference +/- SD of 0 +/- 2 (2 +/- 3) cm3 in symmetric and 1 +/- 3 (4 +/- 4) cm3 in asymmetric objects. Biplane and single-plane volume estimates were less accurate. Interobserver and intraobserver repeatability of three-dimensional left ventricular volumes was good for analysis (coefficients of variation: 3.5% to 6.2%) and was lower for recording (coefficients of variation: 7.4% to 10.9%). Hence the present algorithm reproduces volumes of symmetric and deformed in vitro objects accurately over a wide range of size and shape, and it produces repeatable left ventricular volumes in the clinical situation. PMID- 7840987 TI - Value of two-dimensional echocardiography for determining the basis of hemodynamic compromise in critically ill patients: a prospective study. AB - We postulated that because the first step in the management of critically ill patients with hypotension, pulmonary edema, or both is to determine whether the cause is cardiac or noncardiac, direct visualization of the heart with two dimensional echocardiography would be useful for determining the basis of hemodynamic compromise in such patients. Accordingly, 49 consecutive patients (33 men and 16 women; mean age 61 +/- 15 years) underwent two-dimensional echocardiography within 2 hours of placement of a pulmonary artery flotation catheter for determining the reason for hypotension, pulmonary edema, or both. To discriminate between cardiac and noncardiac causes, hemodynamic and two dimensional echocardiographic data were evaluated independently by two to three blinded interpreters based on predetermined criteria. There was complete agreement between pulmonary artery catheter and two-dimensional echocardiographic data in 36 (86%) of the 42 patients in whom interpretable data were available in terms of cardiac versus noncardiac causes. The two modalities agreed in all patients with hypotension alone and disagreed in 2 of the 20 patients with pulmonary edema alone and 4 of the 14 patients with combined hypotension and pulmonary edema. In cases of discordance, the two tests provided complimentary information, particularly in patients with sepsis in whom the stroke volume may be normal to high but left ventricular systolic function may be depressed. The time taken for pulmonary artery catheter placement was 63 +/- 45 minutes versus 19 +/- 7 minutes for two-dimensional echocardiography.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7840986 TI - Attenuation deforms time-intensity curves during contrast echocardiography: implications for assessment of mean transit rates. AB - The mean transit rate of microbubbles of air obtained from time-intensity curves during contrast echocardiography can be used to evaluate flow through a vascular system, provided the volume of distribution of the system remains constant. We hypothesized that attenuation commonly associated with contrast echocardiography distorts the time-intensity curves, producing an error in the estimation of the mean transit rate of the microbubbles. The purpose of this study was to characterize this distortion with computer simulations and to study the effect of attenuation on the estimation of mean transit rate in an in vitro experiment. We also sought to determine if removing the data points from the time-intensity plots that visually can be attributed to attenuation before curve fitting can minimize the error in the estimation of mean microbubble transit rate. In both computer simulations and experimentally acquired in vitro data, attenuation distorted the time-intensity curves, producing an underestimation of mean microbubble transit rates. The mean microbubble transit rate decreased with an increase in microbubble concentration. Removing the points that visually were attributed to attenuation before curve fitting did not correct this error completely in the computer-simulated data and failed to correct it at all in the experimental data. These results have major practical implications in assessing mean microbubble transit rates during contrast echocardiography. PMID- 7840989 TI - Characterization of plaque components with intracoronary ultrasound imaging: an in vitro quantitative study with videodensitometry. AB - We investigated whether videodensitometry provides a possibility of objective plaque characterization by intracoronary ultrasound imaging. Histologically matched 30 MHz ultrasound images of characteristic atherosclerotic lesions in saline solution and blood-perfused human coronary arteries in vitro were digitized, and regions of interest were analyzed by calibrated videodensitometry. Pixel gray-level distributions were represented as frequency histograms, and mean pixel gray level, skewness, and kurtosis were calculated. Similarly, images of flowing blood in vitro (n = 9; hematocrit 40%) were analyzed. Mean pixel gray levels differed between the three lesion types (lipid rich [n = 6], 71 to 92 [mean 80]; fibromuscular plaque [n = 14], 94 to 162 [mean 124]; and calcified plaques [n = 8]; 161 to 196 [mean 178]) (all comparisons p < 0.001). Ranges of mean pixel gray levels for flowing blood in vitro were within the range of those for fibromuscular plaque (86 to 103; mean 98). During blood perfusion in nine specimens, pixel gray levels were 85% +/- 7% of those during saline perfusion but with similar differences between plaque types. We conclude that homogeneous plaque types can be distinguished in vitro by videodensitometry on intracoronary ultrasound images. PMID- 7840988 TI - Values of intravenous ergonovine test with two-dimensional echocardiography for diagnosis of coronary artery spasm. AB - The purpose of this study was to evaluate the clinical validity of the bedside ergonovine test with digital echocardiography and the side-by-side continuous cineloop display method (ergonovine echocardiography) as a noninvasive diagnostic tool for coronary artery spasm. Bedside ergonovine test was performed in 66 patients who showed coronary vasospasm during coronary angiography including provocation testing (group with variant angina) and 39 patients with normal angiograms and no evidence of coronary artery spasm (group with nonanginal pain). A bolus of ergonovine maleate (0.025 or 0.05 mg) was injected at 5-minute intervals up to total cumulative dosage of 0.35 mg, and 12-lead electrocardiography and two-dimensional echocardiography were recorded every 3 minutes after each injection. Left ventricular wall motion was analyzed with a commercially available quad system. The positive criteria of bedside ergonovine test included reversible ST segment elevation or depression on electrocardiograms (ECG criteria) and reversible regional wall motion abnormalities by echocardiography (Echo criteria). The overall sensitivity and specificity of ECG criteria were 53% (35/66; 95% confidence interval 41% to 65%) and 100%, respectively. By Echo criteria the sensitivity increased to 89% (59/66; 95% confidence interval 81% to 97%), with a specificity of 95% (37/39).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7840990 TI - Intravascular ultrasound imaging of the Heartmate 1000 IP left ventricular assist device. AB - Left ventricular assist devices are increasingly used as a bridge to transplantation in patients with end-stage cardiac disease. Potential complications of these devices include thromboembolism and infection. Because conventional cardiac diagnostic techniques cannot be used to obtain an image of the interior of a left ventricular assist device, we assessed the ability of intravascular ultrasonography to obtain an image of the interior of the Heartmate 1000 IP left ventricular assist device. Feasibility of intravascular ultrasound imaging was initially demonstrated in vitro on a left ventricular assist device immersed in water. Five soft rubber masses were then placed in the device intake port adherent to the wall, and their images were obtained by intravascular ultrasonography. Excellent correlation between actual size and size as measured by intravascular ultrasonography was noted (long-axis, r = 0.98, short-axis, r = 0.89). After the device was implanted in two calves, intravascular ultrasound imaging was performed in vivo in the animals. The catheter was easily advanced through the device, and excellent images were obtained. In conclusion, intravascular ultrasonography can easily be used to obtain an image of the left ventricular assist device interior and can accurately assess the presence and size of abnormal masses inside the device. Intravascular ultrasonography may be clinically useful in evaluating cases of thrombus or vegetation related to left ventricular assist devices. PMID- 7840991 TI - Myocardial tissue characterization by autocorrelation of two-dimensional ultrasonic backscatter. AB - To evaluate a novel method for determining the spatial distribution of echocardiographic information based on the two-dimensional autocorrelation function, echocardiographic images were obtained from specific regions of interest from 10 healthy volunteers, seven patients with genetically defined hypertrophic cardiomyopathy, and nine patients with pressure-overload hypertrophy. The wavelength of distinct peaks from the two-dimensional autocorrelation of the images was compared between groups of patients and demonstrated a significant decrease in the mean length scale associated with distinct secondary correlation peaks in patients with hypertrophic cardiomyopathy or pressure-overload hypertrophy compared with healthy volunteers (p = 0.0009). With a discriminating wavelength of 3.3 mm, the sensitivity of this technique for detecting abnormal myocardium was 84% with a specificity of 89%. This study suggests that ultrasonic tissue characterization based on the two-dimensional autocorrelation function may have potential for distinguishing normal from abnormal myocardium and provides a rationale for textural approaches to ultrasonic tissue characterization. PMID- 7840992 TI - Detection of fibrous strands on prosthetic mitral valves with transesophageal echocardiography: another potential embolic source. AB - Patients with prosthetic mitral valves (MVR) have an increased incidence of cardiac embolic events, but the causes of these emboli have not been determined. Fibrous strands, detected by transesophageal echocardiography (TEE) on the left atrial side of MVRs, may be embolic precursors in these patients. However, the incidence and clinical significance of these strands are unknown. We reviewed the charts of 76 consecutive patients with MVRs who underwent a total of 83 TEE studies between January 1991 and January 1992. Of the 83 studies, 39 (47%) were of bioprostheses and 44 (53%) were of mechanical prostheses. Strands were found in 15 studies (18%) and were significantly more common in mechanical prostheses (32% vs 3%; p < 0.001). Embolic events occurred in 53% of patients with strands compared with only 18% of those without (p < 0.01). Strands were not associated with left atrial spontaneous echo contrast, left atrial thrombi, infection, prosthetic stenosis, severity of regurgitation, or left ventricular function. No physical evidence of these strands was found in the one native and three prosthetic valves examined visually during the study at the time of surgery. The data support the hypothesis that TEE evidence of strands is associated with a higher incidence of embolic events and indicate the potential for formation of intracardiac emboli on MVRs. PMID- 7840993 TI - A simplified method for calculating wall stress in infants and children. AB - Measurement of the end-systolic wall stress-mean velocity of circumferential fiber-shortening relation, a load-independent measure of contractility, has enabled cardiologists to assess ventricular function under various loading conditions and at different heart rates. Unfortunately, it is time-consuming and difficult to perform in routine pediatric practice. Because a close relationship was noted between end-systolic pressure and mean blood pressure, we estimated wall stress by mean blood pressure in 115 patients. There was an excellent correlation between end-systolic blood pressure and mean arterial pressure (r = 0.84) and end-systolic wall stress and mean systolic wall stress (r = 0.98). The difference in mean blood pressure was 5.1 mm Hg (95% confidence interval-10.5 to 20.6 mm Hg), and the difference in mean wall stress was 2.7 gm/cm2 (95% confidence interval-2.0 to 3.8 gm/cm2). More important, substitution of mean blood pressure for end-systolic pressure allowed accurate identification of patients with normal contractility (55/56) and abnormal contractility (57/59). PMID- 7840994 TI - Transesophageal echocardiographic in total anomalous pulmonary venous drainage: hypotension caused by compression of the pulmonary venous confluence during probe passage. AB - Compression of vascular and airway structures can complicate transducer passage and manipulation during transesophageal echocardiography. This case describes hemodynamic compromise caused by compression of the posterior pulmonary venous confluence by a transesophageal echocardiography probe during intraoperative evaluation in an infant with supracardiac total anomalous pulmonary venous drainage. Careful hemodynamic and airway monitoring during transesophageal echocardiography is required in all patients, particularly during initial probe insertion and esophageal passage. PMID- 7840995 TI - Transesophageal echocardiographic diagnosis of an aneurysm and thrombosis of the left anterior descending coronary artery. AB - An aneurysm of the left anterior descending coronary artery with thrombosis in its lumen in a 36-year-old woman who had an acute myocardial infarction is described. Although the aneurysm was detected by angiography, a transesophageal study provided new specific details of the exact site of origin of the aneurysm, as well as vascular thrombosis. PMID- 7840996 TI - Thromboembolus traversing a patent foramen ovale: resolution with anticoagulation. AB - This case report documents echocardiographically a thromboembolus actively traversing a patent foramen ovale in a 72-year-old man with a dilated cardiomyopathy and systemic lupus erythematosis complicated by chronic low-grade disseminated intravascular coagulation and multiple lower extremity deep venous thromboses. With intravenous heparin therapy, there was apparent resolution of this thromboembolus without clinical evidence of systemic embolization. PMID- 7840997 TI - Health promotion and disease prevention in health care reform. PMID- 7840998 TI - Immunization in medical education. Preface. PMID- 7840999 TI - Overview: the ATPM-CDC Immunization in Medical Education project. PMID- 7841000 TI - Immunization in medical education. PMID- 7841001 TI - Curriculum content on vaccine-preventable diseases in primary care and preventive medicine residency programs in the United States. PMID- 7841002 TI - Vaccine-preventable diseases core curriculum objectives. The Immunization in Medical Education Advisory Committee. PMID- 7841003 TI - Measles: virology, epidemiology, disease, and prevention. PMID- 7841004 TI - Influenza: virology, epidemiology, disease, and prevention. PMID- 7841005 TI - Curriculum content on vaccine-preventable diseases in U.S. medical schools. PMID- 7841006 TI - Hepatitis B: virology, epidemiology, disease, and prevention, and an overview of viral hepatitis. PMID- 7841007 TI - Immunization in medical education. Future directions. PMID- 7841009 TI - Directory of immunization resources. PMID- 7841008 TI - Resource materials: general recommendations on immunization. Advisory Committee on Immunization Practices. PMID- 7841010 TI - The power of prevention. PMID- 7841011 TI - Sugar consumption and dental caries. PMID- 7841012 TI - A re-evaluation of electrical resistance measurements for the diagnosis of occlusal caries. AB - Clinical and radiographic diagnosis of occlusal caries is difficult. Resistance measurements in pits and fissures have shown better sensitivity compared with the more conventional methods of diagnosis. Two machines have been manufactured for this purpose: the Vanguard and the Caries Meter L. The aims of this study were to calibrate the readouts of these machines against a variable standard resistance box and use the Vanguard to compare readings taken in vivo and in vitro after extraction of the teeth. The diagnostic accuracy of clinical, radiographic, Vanguard and Caries Meter L diagnoses were also assessed. One hundred occlusal sites in 40 teeth of 20 patients were investigated in vivo with the Vanguard, noting clinical and radiographic appearances. The teeth were then extracted and the Vanguard readings repeated in vitro, together with Caries Meter L readings. The in vivo/in vitro comparison between Vanguard readings showed excellent reproducibility (Cohen's Kappa = 0.80). The sensitivity and specificity for the different examination techniques at the enamel level of diagnosis were 27% and 89% for visual, 6% and 100% for radiographic, 81% and 78% for the Vanguard and 74% and 74% for the Caries Meter L. In conclusion, this study supports the renewed interest in resistance measurements as a diagnostic technique and indicates that the in vitro model used gives results comparable to those in vivo. PMID- 7841013 TI - A self-help group for complete denture wearers. AB - Denture provision is a frequent source of frustration and misunderstanding for both patients and dentists. This study investigates the role of a self-help group in helping denture wearers with long standing problems to come to terms with their difficulties and to reduce their demands on the dentist. Eleven people with clinically satisfactory dentures and long standing perceived problems were invited to join the programme. Evaluation at 2 and 12 months afterwards indicated everyone had benefited in some way. Benefits included eating foods previously avoided, the opportunity for social intercourse and reducing the visits to the dentist. PMID- 7841014 TI - Handpiece asepsis: a survey of the attitudes of dental practitioners. AB - The methods of handpiece asepsis employed by general dental practitioners (GDPs) in England and the problems considered to be associated with handpiece sterilisation were investigated by means of a postal questionnaire distributed to a random sample of 500 GDPs during July 1993. A total of 267 replies were received (53.4% response). The results indicated that at the time of the survey, autoclavable handpieces were possessed by 90.6% of the respondents (n = 242), with 45.9% (n = 111) of these respondents indicating that they autoclaved their handpieces routinely after every patient. Reasons given by respondents for not autoclaving handpieces routinely included insufficient handpieces, fear of handpiece damage, cost, and the consideration that sterilisation was not necessary. Handpiece asepsis procedures had been upgraded by 89% (n = 237) of respondents in the 5 years preceding the survey. Media coverage was found to have exerted influence on the respondent dentists' behaviour, with the overall incidence of routine handpiece autoclaving increasing by 20.6% after media coverage of the subject. PMID- 7841015 TI - Self-inflicted gingival injury in a young girl. AB - A case of self-inflicted gingival trauma in a 7-year-old girl is presented. The progression of the injurious behaviour over a 4-year period is described. Dental measures proved to be ineffective in resolving the habit. PMID- 7841016 TI - The bimaxillary mouthguard. AB - The bimaxillary mouthguard provides enhanced protection for the participation in contact sports. This article describes the bimaxillary mouthguard and outlines construction techniques. PMID- 7841017 TI - Behind the scenes at Baltimore. PMID- 7841018 TI - General anaesthesia: who decides and why. PMID- 7841019 TI - Human placental calreticulin: purification, characterization and association with other proteins. AB - Calreticulin is an intracellular protein known to be involved in calcium binding, but is also known to appear as an autoantigen in certain autoimmune diseases. The cDNA sequence is known but the protein has not yet been well characterized at the amino acid level. Owing to the possible involvement of this protein in autoimmune disease and with the aim of making monoclonal antibodies for use in assay development and immunohistochemistry, we have purified calreticulin using human placental material. Amino acid analysis of the purified protein confirmed the cDNA-derived composition, and only one discrepancy between the cDNA-predicted sequence and the amino acid sequence was found by peptide mapping and microsequencing. The protein contains one disulfide bridge and has one free SH group and the protein is neither glycosylated nor phosphorylated. Affinity chromatography of a placental protein extract on a column with immobilized calreticulin showed the existence of at least six proteins interacting with calreticulin. Using the purified calreticulin in Western blots, two out of eight patients with autoimmune disease diagnosed as having anti DNA antibodies in their serum were found also to contain autoantibodies to calreticulin in their serum. PMID- 7841020 TI - The structure of a toroidal, neutral, homoleptic Ni(II) complex with a chelate dithiolate ligand, [Ni6(SCH2CH2CH2S)6]. PMID- 7841021 TI - 1H-2H exchange in the perfused rat liver metabolizing [3-13C]alanine and 2H2O as detected by multinuclear NMR spectroscopy. AB - The exchange of individual protons of hepatic metabolites against the solvent deuterons has been investigated in perfused rat liver. Livers from starved rats were perfused for 20 min with a 10 mM solution of unlabeled or 3-13C-labeled L alanine in Krebs Ringer bicarbonate buffer, with or without 50% deuterium oxide (2H2O). High resolution 13C NMR analysis of deuterium-induced isotopic shifts and of 2H-13C couplings revealed a differential 1H-2H exchange depending on the chemical nature of the metabolite and on the site of 13C labeling. [3 13C]Aspartate isotopomers showed similar 2H/1H ratios in the C3 and in the C2 carbons while [2-13C]aspartate isotopomers had much smaller 2H/1H ratios in the C2 than in the C3 carbons. Similarly, [2-13C]glutamate isotopomers had 2H/1H ratios significantly smaller in the C2 than in the C3 carbon. These results suggest that the hydration-dehydration reactions of the citric acid cycle, which result in exchange at the C3 carbons of aspartate and glutamate, approach equilibrium with the perfusate faster than the aminotransferases of aspartate and alanine, which induce exchange at the C2 carbons of these amino acids. Taken together, the results obtained are consistent with a heterogeneous solvent exchange environment in the perfused liver. PMID- 7841022 TI - Non-invasive measurement of steady-state vitreous lactate concentration. AB - The cellular events leading to the proliferation of new preretinal blood vessels into the vitreous are unknown. It has been hypothesized that a metabolic trigger, such as increased lactate concentration, induces ambient growth factors to initiate this neovascularization. However, this hypothesis has not been tested in vivo because non-invasive methods for measuring vitreous lactate concentration have not been available. In this study, we identified lactate as the dominant resonance in normal rabbit vitreous using a water-suppressed, localized proton NMR method; negligible spectral contamination from lipid, alanine and threonine was demonstrated. The steady-state vitreous lactate concentration in vivo was 11.3 +/- 4 mM (mean +/- SD, n = 7 eyes) which was not statistically different (p = 0.498) to the enzymatically determined lactate content in vitreous from a parallel group of animals [12.1 +/- 0.6 mM (n = 6 eyes)]. Non-invasive measurement of steady-state vitreous lactate concentration using localized proton NMR represents the necessary first step in understanding the role of lactate in neovascularization. PMID- 7841023 TI - Structural studies of NMR detected lipids in myocardial ischemia. AB - Lipid-induced abnormalities in myocardial function have been implicated in a number of ischemic events including the accumulation of lipids in human myocardium following myocardial infarction. Although animal models have shown the source of these lipids to be triglycerides, the specific species involved has not been identified. In order to better understand the mechanism(s) defining this lipid accumulation, it follows that the identification of the lipids involved may be important in achieving this aim. Therefore, this study examined the use of NMR probes for delineating the biochemical makeup of the increased 1H NMR observed lipid signal following myocardial infarction. Specifically, the present study demonstrated the utility of the spin-echo pulse sequence for the study of alterations in myocardial lipids following ischemic injury. Spin-echo spectra allowed the analysis of subsets of lipids within the large lipid pool inherent in most myocardium. The analyses of the chemical shifts of the lipid resonances provided a simple yet powerful means for deducing lipid class associated with the ischemic injury and suggested the species arises predominantly from saturated lipids. The examination of the CH2/CH3 NMR ratio provided additional information regarding the species involved, however, because the spin-echo technique was utilized, which may distort certain signal intensities, caution must be exercised in interpreting the specific species involved. With this in mind, a tentative assignment has been given to octanoic acid. Finally, a temperature dependence of the lipid signals was noted and determined to be unique for spin-echo lipid.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7841025 TI - Optimization of magnetization transfer experiments for kinetic rate measurements. AB - A framework is developed for optimizing magnetization transfer experiments for measuring first-order rate constants of a two-component exchange network. In the analysis the spin-lattice relaxation time of the nonsaturated resonance is assumed to be known. However, we demonstrate that our work can also be applied to cases in which the spin-lattice relaxation time falls within a physiologically reasonable range for this parameter. We provide an algorithm for the parameters permitting the experimenter to optimize the selection of measurement times in order to control the error in a worst-case scenario. In addition, we compare the performance of the time-dependent saturation experiment with an inversion experiment in this framework, finding that the former always leads to a more effective design. PMID- 7841024 TI - Comparative NMR study of a differentiated rat hepatoma and its dedifferentiated subclone cultured as spheroids and as implanted tumors. AB - H4IIEC3 (H4), a differentiated rat hepatoma line and H5, its dedifferentiated subclone, were investigated as proliferating spheroids and as implanted subcutaneous tumors in juvenile rats. H4 cells formed tight, round spheroids whereas H5 cells formed loose, grape-like structures. 31P MR spectra showed that phosphocreatine was present in H5 spheroids but not in H4 spheroids or tumors. [13C]Lactate production from [13C]glucose, with no detectable uptake of [13C]alanine, indicated that energy production in H5 spheroids was primarily via glycolysis. No [13C]glucose utilization was detected in H4 spheroids, but uptake of alanine and accumulation of labeled lactate, glutamate and glutamine indicated oxidation via the tricarboxylic acid (TCA) cycle. Tumors of H4 cells were well perfused, unlike tumors of H5 cells which were highly necrotic. Following i.v. infusion with [13C]alanine, [13C]lactate and glutamate, evidence of oxidation via the TCA cycle, were observed in H4 tumors. Thus the results obtained by 31P and 13C MRS correlated with the differentiation state of H4 and H5 spheroids and tumors. PMID- 7841026 TI - Maternal and child health. Increasing frequency of low birth weight (LBW), 1981 1991. PMID- 7841027 TI - Expanded programme on immunization. Measles outbreak at a secondary school, Ontario. PMID- 7841028 TI - Food safety. Epidemiology of ciguatera poisoning. PMID- 7841029 TI - Diarrhoeal Disease Control (CDD) programme. Health worker performance in interpersonal communication skills. PMID- 7841030 TI - Expanded programme on immunization. Measles control. PMID- 7841031 TI - Who Global Programme for Vaccines and Immunization. Vaccine research and development. PMID- 7841032 TI - Mutation of the p53 gene precedes aneuploid clonal divergence in colorectal carcinoma. AB - To establish whether p53 mutation precedes or follows clonal divergence in human colorectal carcinomas, 17 tumours were analysed at multiple sites (2-5 each) for single-strand conformation polymorphisms (SSCP) within exons 5-8 of the p53 gene. A previous study had demonstrated subclones of differing DNA ploidy in these tumours, but all showed immunocytochemical evidence for p53 stabilisation, using the monoclonal antibody PAb 1801. Mutations within exons 5-8 of p53 were identified by the presence of an abnormally migrating band in 10 of the 17 carcinomas: five in exon 5, four in exon 7 and one in exon 8. In each of these positive cases, samples from different parts of the carcinoma showed identical gel migration patterns in SSCP analysis. Similarly, the remaining seven tumours were concordant for absence of band shift across all samples of each tumour. Six SSCP-positive cases contained multiple populations differing in DNA ploidy, while four were homogeneously diploid or aneuploid throughout. Very similar proportions were observed in the SSCP-negative cases. In four positive tumours the mutation was confirmed by sequencing or through alteration of nucleotide-specific restriction enzyme cleavage. Identical mutations appeared in every sample from the same tumour. The results provide unequivocal evidence that the same mutant allele of p53 is present throughout each tumour bearing a mutation, regardless of the clonal variation identified by analysis of DNA ploidy. We conclude that in colorectal tumorigenesis mutation of p53 occurs as a single event which precedes and may facilitate the aneuploid clonal divergence of carcinomas. PMID- 7841033 TI - The role of p53 inactivation in human cervical cell carcinoma development. AB - We investigated the association between human papillomavirus (HPV) infection and p53 gene mutation in 47 primary uterine cervical cancers. HPV DNA sequences were present in 43 cancers (91.5%), and one of these cancers contained a p53 gene mutation. In addition, one of the remaining four HPV-negative cancers also contained a p53 gene mutation. As a result, p53 inactivation corresponded to the development of 44 of the primary uterine cervical cancers studied (93.6%). We obtained both primary and recurrent tumours from four cases. In two of these cases, the HPV genomes that were present in an episomal state in the primary tumours were observed to have disappeared in the recurrent tumours. One of these recurrent tumours also contained a p53 gene mutation, which suggested the possibility that p53 inactivation was required in order to maintain the aggressive behaviour in this cancer either by an HPV infection or by a p53 gene mutation. No MDM2 gene amplification was observed in the tumours that carried neither HPV DNAs nor p53 gene mutations. PMID- 7841034 TI - Temperature sensitivity for conformation is an intrinsic property of wild-type p53. AB - The tumour-suppressor protein p53 is a metal-binding transcription factor with sequence-specific DNA-binding capacity. In cancer, mutation of p53 disrupts protein conformation with consequent loss of DNA binding and associated tumour suppressor function. In vitro, the conformation and DNA-binding activity of wild type p53 are subject to redox modulation and are abrogated by exposure to metal chelators. In the present study, we have used the chelator 1, 10-phenanthroline (OP) to probe the effect of temperature on the conformational stability of p53 translated in vitro. Whereas low temperature (30 degrees C) stabilised wild-type p53 conformation and protected against chelation, high temperature (41 degrees C) promoted destabilisation and enhanced chelation, indicating that temperature influences the folding of wild-type p53. Destabilisation of p53 tertiary structure induced protein aggregation through hydrophobic interactions, consistent with the notion that wild-type p53 contains a hydrophobic core which may become exposed by metal chelation. These results indicate that temperature sensitivity for conformation is an intrinsic property of wild-type p53 and suggests that small changes in temperature may directly affect p53 function. PMID- 7841035 TI - Activity of interferon alpha, interleukin 6 and insulin in the regulation of differentiation in A549 alveolar carcinoma cells. AB - The differentiation of A549, a human tumour cell line from type II pneumocytes, can be induced by a crude fibroblast-derived factor (FDF) isolated from the conditioned medium of glucocorticoid-treated lung fibroblasts. In the present report, we have used alkaline phosphatase as a differentiation marker to investigate the activity of a number of growth factors as potential candidates for this paracrine activity. This showed that insulin, interleukin 6 (IL-6), and interferon alpha (IFN-alpha) could simulate the activity of conditioned medium. Their effects were dexamethasone (DX) dependent, additive and reversible with a half-life of 1 week. Transforming growth factor alpha and beta, IL-1 alpha and epidermal growth factor, were all inhibitory, and inhibition was opposed, partially or completely, by DX. The most potent inducer was IL-6, but as DX was shown to decrease the concentration of IL-6 in lung fibroblast-conditioned medium it seems an unlikely candidate for FDF. Unlike FDF, all of the positive-acting factors were shown to induce plasminogen activator. FDF has also been shown to be active in the absence of DX. This suggests that differentiation-inducing activity may be present in several paracrine factors, but that so far a candidate for FDF has not been identified. PMID- 7841037 TI - Demonstration of smoking-related DNA damage in cervical epithelium and correlation with human papillomavirus type 16, using exfoliated cervical cells. AB - Smoking is a known aetiological risk factor for cervical cancer. Smoking-related DNA damage (DNA adducts), in cervical epithelial cells, has recently been demonstrated to suggest a causal role in the development of cervical cancer. Human papillomavirus 16 (HPV 16) is a known oncogenic virus and is also implicated as a cause of cervical cancer. It has been suggested that both smoking and HPV may act synergistically in the development of cervical cancer. We have investigated the cervical DNA adduct level and the prevalence of HPV 16 (using polymerase chain reaction) in women who had normal cervical cytology. Both the DNA adduct assay and the HPV assay were carried out on exfoliated cervical cells recovered from cervical scrapes. In 87% of the cases there was enough DNA from the exfoliative cervical cells to analyse for DNA adducts. Smokers had higher DNA adduct levels than non-smokers (P = 0.002), confirming the previous data from cervical biopsy samples. Forty-two per cent of the specimens were found to be HPV 16 positive. There was no significant difference in smoking-related DNA damage (DNA adduct levels) between HPV-positive and HPV-negative smokers. This suggests that smoking DNA damage does not augment HPV infectivity. These results do not, therefore, support the molecular synergism theory. PMID- 7841036 TI - Tumour-infiltrating lymphocytes bear the 75 kDa tumour necrosis factor receptor. AB - Tumour necrosis factor alpha (TNF-alpha) is a cytokine with a variety of immunological properties. The identification of two receptors for this molecule, i.e. the 75 kDa and the 55 kDa TNF receptors (TNF-R), recently clarified the mechanisms through which this cytokine provides its wide range of immunomodulatory activities. In this study we have investigated the expression and the functional properties of these receptors on tumour-infiltrating lymphocytes (TILs) recovered from 17 patients with solid cancers (melanoma, colorectal carcinoma and lung cancer). To this end, TIL lines and freshly isolated TILs were evaluated for (a) the expression and the functional role of TNF receptors following culture in the presence of interleukin 2 (IL-2) and (b) the production of TNF-alpha following culture with IL-2 and the role of this cytokine in IL-2-driven TIL proliferation. Flow cytometry analysis demonstrated that TILs bear the 75 kDa TNF-R. Moreover, TIL lines express detectable messages for TNF-alpha and release this cytokine. Functional in vitro studies have shown that anti-TNF-alpha, as well as anti-75 kDa TNF-R antibodies, are able to inhibit the IL-2-induced TIL proliferation. These data demonstrate that TILs are equipped with a fully functional TNF-R system and suggest a putative role for this receptor and its ligand in the activation and expression of TILs following immunotherapy with IL-2. PMID- 7841038 TI - The proliferation of multiple myeloma colonies (MY-CFUc) in vitro is independent of prognosis and is not associated with mutated N- or K-ras alleles in human bone marrow aspirates. AB - During the period September 1987 to March 1993 the proliferation of myeloma cells as colonies (MY-CFUc) in vitro was examined in bone marrow aspirates from 43 patients with multiple myeloma and two patients with Waldenstrom's macroglobulinaemia. Twenty-four samples from 45 patients, of whom three were at presentation, four were in complete remission (CR), six had achieved a partial response (PR) and 11 had progressive disease (PD), produced MY-CFUc in vitro. The same bone marrow aspirates or one taken within 2 months of that assessed for MY CFUc were used in the polymerase chain reaction (PCR). Genomic DNA was analysed for mutations in N- and K-ras by slot blotting of the amplified products from the PCR with 32P-labelled probes and by direct sequencing. No mutations were detected in N- or K-ras proto-oncogenes at codons 12, 13 or 61 in any sample. Eleven of the patients from whom MY-CFUc were produced remain alive with a median survival of 73 months (range 15-75 months). MY-CFUc have been cultured from 19 of these 24 patients on subsequent occasions, of whom nine remain alive. Among patients whose cells did not produce MY-CFUc in vitro at the time of sampling for mutated ras alleles, biopsy samples from four patients have produced MY-CFUc in vitro on subsequent occasions, of whom one patient remains alive. The data show that the proliferation of MY-CFUc in vitro occurred independently of disease status and was not indicative of prognosis. The failure to detect mutated N- or K-ras alleles in any sample suggests that if such mutations were present in the cells which form colonies in vitro they represented less than 0.1% of the tumour burden and did not affect the survival of this group of patients. PMID- 7841039 TI - The Arg-Gly-Asp-containing peptide, rhodostomin, inhibits in vitro cell adhesion to extracellular matrices and platelet aggregation caused by saos-2 human osteosarcoma cells. AB - Saos-2 cells, derived from a primary human osteosarcoma, caused dose-dependent platelet aggregation in heparinised human platelet-rich plasma. Saos-2 tumour cell-induced platelet aggregation (TCIPA) was completely inhibited by hirudin but unaffected by apyrase. The cell suspension shortened the plasma recalcification times of normal, factor VIII-deficient and factor IX-deficient human plasmas in a dose-dependent manner. However, the cell suspension did not affect the recalcification time of factor VII-deficient plasma. Moreover, a monoclonal antibody (MAb) against human tissue factor completely abolished TCIPA. Flow cytometric analysis using anti-integrin MAbs as the primary binding ligands demonstrated that the integrin receptors alpha v beta 3, alpha 5 beta 1 and alpha 6 beta 1 were present of Saos-2 cells, which might mediate tumour cell adhesion to extracellular matrix. Rhodostomin, an Arg-Gly-Asp (RGD)-containing snake venom peptide which antagonises the binding of fibrinogen to platelet membrane glycoprotein IIb/IIIa, prevented Saos-2 TCIPA as well as tumour cell adhesion to vitronectin, fibronectin and collagen type I. Likewise, the synthetic peptide Gly Arg-Gly-Asp-Ser (GRGDS) showed a similar effect. On a molar basis, rhodostomin was about 18,000 and 1000 times, respectively, more potent than GRGDS in inhibiting TCIPA and tumour cell adhesion. PMID- 7841040 TI - In vivo and in vitro invasion in relation to phenotypic characteristics of human colorectal carcinoma cells. AB - In this study we investigated the tumorigenicity, growth pattern and spontaneous metastatic ability of a series of nine human colorectal carcinoma cell lines after subcutaneous and intracaecal xenografting in nude mice. CaCo2 cells were found to be poorly tumorigenic to non-tumorigenic in either site; the other cell lines were tumorigenic in both sites. SW1116, SW480 and SW620 did not show local invasive in the NCI-H716 and LS174T cells were both invasive in the caecum, but only NCI-H716 was invasive in the subcutis. HT29 and 5583 (S and E) cells were invasive in the caecum and from that site metastatic to the lungs and/or the liver. HT29 and 5583S cells were both invasive in the subcutis, but 5583E cells were not. Of each category of in vivo behaviour in the caecum, one cell line was further investigated with regard to invasion in vitro (into embryonic chick heart fragments), E-cadherin expression in vivo and in vitro and in vitro production of u-PA and t-PA. These parameters were chosen in view of their purported role in extracellular matrix degradation and intercellular adhesion, which are all involved in the invasive and metastatic cascade. Invasion in vitro was not predictive for invasion or metastasis in vivo. In the cell line which showed invasion in embryonic chick heart tissue, heterogeneous E-cadherin expression was observed in vitro together with a relatively high production of u-PA. The non invasive cell lines showed in vitro homogeneous expression of E-cadherin with a relatively low production of u-PA. In vivo expression of E-cadherin was either absent or heterogeneous. We conclude that: (1) colorectal carcinoma xenografts show site-specific modification of in vivo invasive and metastatic behaviour; (2) invasion in vitro does not correlate with invasion and metastasis in vivo; (3) in vitro non-invasion might be associated with homogeneous E-cadherin expression and low production of u-PA; (4) E-cadherin expression in vitro differs from E cadherin expression in vivo. The results support the notion that the microenvironment in which cancer cells grow is one of the factors involved in the regulation of invasive and metastatic behaviour. PMID- 7841041 TI - Combination therapy with cisplatin and nifedipine induces apoptosis in cisplatin sensitive and cisplatin-resistant human glioblastoma cells. AB - We attempted to determine whether calcium channel blockers (CCBs) enhance the anti-tumour activity of cis-diamminedichloroplatinum (cisplatin) against both cisplatin-sensitive human glioblastoma U87 MG cells and cisplatin-resistant U87 MG-CR cells, the latter of which we developed for resistance to cisplatin. Nifedipine, a dihydropyridine class CCB, significantly enhanced the anti-tumour effect of cisplatin on these two cell types in vitro and in vivo. Our findings also indicated that, in the absence of normal extracellular Ca2+ nifedipine was capable of enhancing the cytotoxicity of cisplatin. In addition, this anti-tumour activity was partially inhibited by actinomycin D and cycloheximide, suggesting that it is possibly dependent upon new RNA and protein synthesis. Interestingly, ultrastructural analysis, DNA fragmentation assay and cell cycle analysis demonstrated that synergism between cisplatin and nifedipine results in apoptosis (programmed cell death) at a relatively low concentration of cisplatin, which when tested alone did not induce apoptosis. Furthermore, we demonstrated that nuclei from these cells lack a Ca(2+)-dependent endonuclease that degrade chromatin in the linker region between nucleosomes. In conclusion, our studies suggest that the non-cytotoxic agent nifedipine is able to synergistically enhance the anti-tumour effects of cisplatin on U87-MG and U87-MG-CR cells lacking a Ca(2+)-dependent endonuclease and subsequently to induce apoptosis via interaction of nifedipine with an as yet uncharacterised functional site other than a calcium channel on target cells. PMID- 7841042 TI - Proximal 6q, a region showing allele loss in primary breast cancer. AB - To define regions of deletion of chromosome 6q in breast cancer, we scored 18 (CA)n microsatellites for allelic imbalance (AI) in 42 paired blood/tumour samples. Heterozygosity frequencies of the markers in the sample population ranged from 31% to 92% (mean 68%). Two regions of the chromosome arm showed AI values greater than the background range of 10-22% (mean 17%) of informative cases that was observed with five markers spanning 6q21-q25.2. Firstly, seven markers gave AI values that averaged 35% in a region flanked by D6S313 (AI = 10%) at 6q13 and D6S283 (AI = 17%) at 6q16.3-21. The second region showed marginally increased AI at 6q25.2-q27 and included D6S193, previously shown to be close to a tumour-suppressor gene involved in ovarian carcinoma. Since AI of 6q in breast cancer was shown previously to be due predominantly to loss of heterozygosity, our results suggest the presence of at least two tumour-suppressor genes on 6q that are involved in breast cancer. The proximal region has not been recognised in breast cancer before and is involved in a higher frequency of tumours than the distal region. PMID- 7841043 TI - Interaction of tamoxifen with the multidrug resistance P-glycoprotein. AB - Tamoxifen is an anti-oestrogen which is currently being assessed as a prophylactic for women at high risk of breast cancer. Taxoxifen has also been shown to reverse multidrug resistance in P-glycoprotein (P-gp)-expressing cells, although the mechanism of action is unknown. In this study we demonstrate that tamoxifen interacts directly with P-gp. Plasma membranes from P-gp-expressing cells bound [3H]tamoxifen in a specific and saturable fashion. A 180 kDa membrane protein in these membranes, labelled by the affinity analogue tamoxifen aziridine and azidopine, was shown to be P-gp. Tamoxifen reduced the binding of vinblastine and azidopine to P-gp, and tamoxifen increased [3H]vinblastine accumulation in P gp-expressing cells to levels approaching those in non-P-gp-expressing cells. However, the cellular accumulation of [3H]tamoxifen itself was not influenced by the presence of P-gp. Thus, tamoxifen appears to reverse multidrug resistance by binding to P-gp and inhibiting the transport of cytotoxic drugs, but does not itself appear to be transported by the protein. PMID- 7841045 TI - Selective photodynamic inactivation of a multidrug transporter by a cationic photosensitising agent. AB - We have characterised sites of photodamage catalysed by the cationic photosensitiser tetrabromorhodamine 123, using P388 murine leukaemia cells and a subline (P388/ADR) which has a multidrug resistance phenotype and hyperexpresses mdr1 mRNA for P-glycoprotein. Fluorescence emission spectra were consistent with sensitiser localisation in hydrophobic regions of the P388 cell, and in more aqueous loci in P388/ADR. Subsequent irradiation resulted in photodamage to the P388 cells, resulting in loss of viability. In contrast, P388/ADR cells were unaffected except for an irreversible inhibition of P-glycoprotein, leading to enhanced accumulation of daunorubicin and rhodamine 123 and a corresponding increase in daunorubicin cytotoxicity. These results are consistent with the premise that substrates for P-glycoprotein are confined to membrane loci associated with the transporter, and indicate a very limited migration of cytotoxic photo-products in a cellular environment. PMID- 7841044 TI - Modification of the photodynamic action of delta-aminolaevulinic acid (ALA) on rat pancreatoma cells by mitochondrial benzodiazepine receptor ligands. AB - We have shown that addition of exogenous delta-aminolaevulinic acid (ALA) to rat pancreatoma AR4-2J cells in culture leads to the increased production of porphobilinogen (PBG) and the accumulation of photoactive protoporphyrin IX (PPix) in these cells. Exposure to light (lambda > 400 nm) at an intensity of 0.2 mW cm-2 for 8 min resulted in an ALA dose-dependent cytolysis of the cells, with an EC50 of 6.6 +/- 0.7 microM. This cytolytic effect was light intensity dependent, with greater cell destruction after exposure to light at an intensity of 0.47 mW cm-2 than at 0.2 mW cm-2; it was also dependent on the duration of illumination, cell survival decreasing with increasing illumination times. The photodestruction of the AR4-2J cells following exposure to ALA can be attributed to the production of endogenous PPix, a photoactive porphyrin that we have shown to generate singlet oxygen upon illumination, whereas ALA itself does not. Further investigation of the molecular mechanisms underlying the photodynamic action of ALA demonstrated the involvement of the mitochondrial (peripheral) benzodiazepine receptor (MBR), a high-affinity recognition site for dicarboxylic porphyrins, and especially PPix. The centrally acting benzodiazepine compounds clonazepam and flumazenil, which have negligible affinities for the MBR, had no effect on ALA-mediated phototoxicity. In contrast, both the isoquinoline carboxamide PK11195 and the benzodiazepine Ro 5-4864 ligands, displaying a high affinity for the MBR, did affect ALA-mediated phototoxicity, each markedly increasing the EC50 for cell photodestruction and thus exerting a photoprotective effect. It is concluded that the MBR may play an important role in the expression of ALA-mediated PPix phototoxicity and that MBR ligands, by diminishing the actions of endogenous PPix, have the potential to rescue cells from porphyrin induced photolysis. PMID- 7841046 TI - Radiation-induced DNA double-strand break rejoining in human tumour cells. AB - Five established human breast cancer cell lines and one established human bladder cancer cell line of varying radiosensitivity have been used to determine whether the rejoining of DNA double-strand breaks (dsbs) shows a correlation with radiosensitivity. The kinetics of dsb rejoining was biphasic and both components proceeded exponentially with time. The half-time (t1/2) of rejoining ranged from 18.0 +/- 1.4 to 36.4 +/- 3.2 min (fast rejoining process) and from 1.5 +/- 0.2 to 5.1 +/- 0.2 h (slow rejoining process). We found a statistically significant relationship between the survival fraction at 2 Gy (SF2) and the t1/2 of the fast rejoining component (r = 0.949, P = 0.0039). Our results suggest that cell lines which show rapid rejoining are more radioresistant. These results support the view that, as well as the level of damage induction that we have reported previously, the repair process is a major determinant of cellular radiosensitivity. It is possible that the differences found in DNA dsb rejoining and the differences in DNA dsb induction are related by a common mechanism, e.g. conformation of chromatin in the cell. PMID- 7841047 TI - The biological activity of cisplatin and dibromodulcitol in combination therapy. AB - The efficacy and modes of action of dibromodulcitol (DBD) and cisplatin (CDDP) were studied in several model systems. Combination treatments produced a longer survival time in mice bearing P388 solid lymphomas than either of the drugs alone. In the human metastatic melanoma HT-168 xenograft model the combined application of DBD and CDDP was also very effective, inducing a reduction in the number and volume of metastatic nodules. For V79 spheroids, DBD was mainly cytotoxic against the internal, quiescent cells, whereas cisplatin primarily killed cells in the proliferating, external regions of the spheroids. When combined, the drugs appeared to act synergistically throughout the spheroids. Studies on plasmid DNA showed that CDDP primarily generates cross-links, whereas single-strand breaks were dominant after DBD treatment. Upon using an assay for cleavage by restriction nuclease, antagonistic action of DBD and CDDP in combination may occur, nevertheless more strand breaks were always observed in these samples. These results suggest that the efficacy of combined DBD and CDDP is in part a result of 'spatial cooperation' by the drugs (i.e. affecting different cells) and in part the result of DNA damage produced by the combination treatments. PMID- 7841048 TI - Adjuvant internal radiation therapy in a model of colorectal cancer-derived hepatic metastases. AB - Selective internal radiation therapy (SIR therapy) is a technique whereby metastatic liver cancer is irradiated by embolising microspheres containing the radionuclide yttrium-90 into the hepatic arterial circulation. To date this technique has not been used as an adjuvant therapy, but rather to treat established metastases in the liver. This study evaluated the use of two intrahepatic radiation doses delivered on radioactive microspheres for the treatment of small, growing micrometastases. Three groups of five rats were each inoculated with tumour spheroids into the portal vein. The resultant liver micrometastases were treated with either 10 or 20 MBq of yttrium-90 microspheres or a sham dose of non-radioactive microspheres injected into the portal vein 2 days following tumour inoculation. The livers of each animal were examined for the presence of metastases after a further 21 days and liver function tests were performed. At the time of sacrifice there was no obvious normal liver damage in any of the rats treated with microspheres. The livers of the sham-treated animals contained extensive signs of tumour deposition. A mean of 34 tumours were taken from the livers of each of the sham-treated animals, whereas only a single tumour was found in one animal treated with 10 MBq of yttrium and eight small tumours from two animals treated with 20 MBq. Liver function tests demonstrated a significant short-term increase in alkaline phosphatase levels in the radiation treated animals compared with shams, but there were no other indications of any effects on liver function. These results indicate a potential role for SIR therapy in an adjuvant setting with colorectal cancer. PMID- 7841050 TI - The detectability of breast cancer by screening mammography. AB - We reviewed 134 patients with breast cancer (screen detected = 85, interval = 49) who had been reported as negative at previous mammographic screening in the Florence District Programme. At prior mammograms review, 12% of the cases were classified as 'screening error' (suspicious signs missed owing to misperception or poor imaging technique), 26% as 'minimal signs present', 54% as 'radiographically occult' and 7% as 'radiographically occult at diagnosis'. These results are quite consistent with those recently reported for the Nijmegen screening programme. Screening errors may be reduced either by reducing the risk of misperception (double reading) or by improving imaging quality, but this would achieve earlier detection in a minority of cancer cases. Minimal signs of cancer were present 2 years before the diagnosis in over one-third of screen-detected cancers. Increasing screening frequency (from biennial to annual) may advance detection time of most 'screening errors' and of some cancers in the 'minimal signs present' and 'mammographically occult' categories, but this would almost double screening costs, and the benefit would probably be inferior to that obtained by doubling the population invited to biennial screening. Adopting less stringent criteria for referral to diagnostic assessment would probably lead to the detection of some cases in the 'minimal signs present' category. This seems to us a more convenient policy to adopt to advance cancer detection time, although it will also sharply increase referral rates and costs. As diagnostic assessment of minimal lesions is far from being 100% accurate, this policy would also considerably increase the frequency of unnecessary benign biopsies. All these negative effects might turn out to be unacceptable. PMID- 7841049 TI - VAD chemotherapy as remission induction for multiple myeloma. AB - A total of 142 patients with multiple myeloma received VAD as remission induction therapy. Seventy-five were previously untreated and 67 had relapsed (31) or refractory disease (36). Vincristine (total dose 1.6 mg) was infused with doxorubicin 36 mg m-2 by continuous ambulatory pump over 4 days. In addition, oral dexamethasone 40 mg day-1 was given for 4 days. Intermittent dexamethasone was only given to 19 patients. Courses were repeated every 21 days. The overall response rate was 84% [27% complete response (CR)] in previously untreated patients and 61% (3% CR) in patients with relapsed and refractory disease. The median survival was 36 months for untreated patients and 10 months for those who had received prior therapy. VAD was well tolerated; however, despite prophylaxis, 54% patients received antibiotics at some time during therapy and 37% had dyspepsia. Twenty-three patients subsequently received a transplant (eight allografts, eight marrow autografts and seven peripheral blood stem cell transplants). Eight have died-four in the allogeneic group and four in the autologous group. The overall median survival of transplanted patients has not yet been reached. VAD is an effective, out-patient therapy for inducing remission in multiple myeloma. Post-remission therapy needs to be optimised, but it is likely that the needs of previously untreated patients may be different from those with relapsed and refractory disease. PMID- 7841051 TI - Human papillomavirus type 18 DNA and E6-E7 mRNA are detected in squamous cell carcinoma and adenocarcinoma of the lung. AB - To provide an accurate evaluation of the association of human papillomavirus (HPV) with lung cancer, 36 cases of lung cancer were analysed for HPV DNAs by polymerase chain reaction (PCR) with dot-blot and Southern blot analyses, and for the transcripts from the E6-E7 transforming region by in situ hybridisation (ISH). HPV-18 DNA was detected in three (8%) of 36 specimens; histologically, in one (10%) of 10 squamous cell carcinomas and two (9%) of 22 adenocarcinomas. Neither HPV-16 nor -33 DNA was detected in any cases examined. Expression of E6 E7 mRNA was confirmed in the cases which contained, HPV-18 DNA. HPV-18 may play an important role in the development and progression of cancer in some cases of both squamous cell carcinoma and adenocarcinoma of the lung. PMID- 7841052 TI - Prognostic significance of interleukin 6 serum levels in patients with ovarian cancer. AB - High levels of IL-6 were found in 50% of 114 patients with primary ovarian cancer. IL-6 sensitivity was lower than that of CA 125, and the combination of both assays did not increase the sensitivity of CA 125 alone. However, elevated IL-6 serum levels were correlated with a poor prognosis since patients with low IL-6 levels had a better survival than patients with high IL-6 levels (P = 0.0009). Multivariate analysis revealed that IL-6 positivity has an independent value. PMID- 7841053 TI - Proliferating cell nuclear antigen (PCNA) immunostaining--a prognostic factor in ovarian cancer? AB - The measurement of tumour cell proliferation is becoming increasingly recognised in defining prognostic groups. Proliferating cell nuclear antigen (PCNA) immunolocalisation can be used as an index of cell proliferation and may define the extent of departure from normal growth control. The monoclonal antibody PC10 stains PCNA in archival paraffin-embedded tissue. This study investigates its potential as a prognostic marker in early and advanced ovarian cancer. A three stage immunoperoxidase technique was developed to detect the monoclonal antibody PC10. Archival paraffin-embedded tissue from 19 stage I ovarian tumours (13 malignant and six borderline) and 79 advanced (stage IIb-IV) ovarian tumours (patients entered into the Third North-West Thames Ovarian Cancer Trial) was immunostained with PC10. PC10 immunostaining was performed successfully in 91.8% of cases. The PC10 labelling index (PC10 LI) ranged from 1.5% to 88% with a mean value of 47.4%. Stage I borderline tumours had significantly lower PCNA labelling indexes than stage I malignant tumours (P < 0.048). In advanced disease there was an inverse correlation between PC10 and overall survival, and in those patients who underwent good debulking surgery (37 patients with disease < 2 cm diameter) a low PC10 value (< 36.5%) correlated with improved survival (log-rank trend test for survival, chi 2 = 5.75, P = 0.017). PCNA immunostaining defines a good prognostic subgroup in adequately debulked patients with ovarian cancer. PMID- 7841055 TI - E-cadherin expression in renal cell cancer and its significance in metastasis and survival. AB - Decreased expression of E-cadherin (E-CD), a homotypic intercellular adhesion molecule, is considered to elicit detachment of tumour cells from primary lesions, which is the first stage of metastasis. Since renal cell cancer (RCC) shows a relatively high frequency of metastasis, we focused our interest on E-CD expression in RCC and its clinicopathological implications. We examined E-CD expression in normal kidney and RCC by immunohistochemical staining. In normal kidney, E-CD expression was localised in distal tubules and collecting ducts. In RCC, 20 of 106 primary lesions (18.9%) expressed E-CD, whereas none showed positive staining for eight metastatic lesions. There was a statistically significant correlation between loss of E-CD expression and advanced stages of RCC. Kaplan-Meier analysis showed better prognosis in the group with preserved E CD expression than without E-CD expression (Cox-Mantel test, P = 0.022, the average follow-up was 32 months or until death). This study suggests that the patients with decreased E-CD expression may be associated with metastasis, resulting in poor prognosis. However, frequency of E-CD expression in RCC is lower than in other cancers, which may be derived from the localised distribution of E-CD expression in normal kidney. PMID- 7841054 TI - EORTC (30885) randomised phase III study with recombinant interferon alpha and recombinant interferon alpha and gamma in patients with advanced renal cell carcinoma. The EORTC Genitourinary Group. AB - In the treatment of renal cell carcinoma both complete (CRs) and partial remissions (PRs) have been obtained using recombinant (r) interferon alpha (IFN alpha), with response rates ranging from 0 to 31% (mean 16%). rIFN-gamma is a potent immunostimulating agent, but the clinical experience of its use is limited and results are conflicting. In a phase II study with the combination of rIFN alpha 2c (Boehringer Ingelheim) and rIFN-gamma (Genentech, supplied by Boehringer Ingelheim) in 31 eligible patients, a response rate of 25% was recorded. Based on this observation a randomised phase III study was initiated to investigate the possible advantage of the addition rIFN-gamma to rIFN-alpha 2c treatment. Treatment consisted of rIFN-alpha 2c 30 micrograms m-2 = 10 x 10(6) IU m-2 s.c. twice weekly in arm A and the same dose of rIFN-alpha combined with rIFN-gamma 100 micrograms m-2 = 2 x 10(6) IU m-2 in arm B. Eligibility criteria included documented progression of disease; patients with bone lesions only and overt central nervous system metastases were excluded. Between November 1988 and September 1990, 102 patients were entered into the study. An interim analysis showed a response in 7/53 (13%) patients (two CRs and five PRs) in the rIFN-alpha 2c monotherapy arm and in 2/45 (4%) (one CR and one PR) patients in the combination arm. This difference was not statistically significant (P = 0.17). The probability of missing an eventual 10% advantage for the combination is 0.001. The numbers are insufficient to rule out a negative effect of the addition of rIFN-gamma. The dose intensity of IFN-alpha 2c for the two treatment arms was the same. The addition of rIFN-gamma does not improve the response rate of rIFN alpha 2c monotherapy. A possible detrimental effect cannot be excluded. PMID- 7841056 TI - Germ cell tumours in uncorrected cryptorchid testis at Institute Rotary Cancer Hospital, New Delhi. AB - Twenty-four out of 164 (14%) adult patients with primary germ cell tumours of testis seen over the last 6 years at the Institute Rotary Cancer Hospital (IRCH) of the All India Institute of Medical Sciences (AIIMS), New Delhi, were found to have cryptorchidism. Only one patient had undergone correction. As a result the testes were intra-abdominal in the vast majority, and patients presented late. Twenty-two patients presented with stage IIb or more advanced disease. Twelve patients had seminoma and the others had mixed or non-seminomatous germ cell tumour (NSGCT), i.e. 50% each. The earlier patients were managed by initial resection followed by radiation and/or chemotherapy. As experience grew the seven patients who presented late were given initial chemotherapy followed by resection in those with residual tumours. The probability of overall survival was 0.65 at 36 months and, was not significantly different from survival in 114 patients with tumours of normally descended testis. Early orchipexy facilitates the detection, but whether it reduces the incidence of tumours is controversial. Uncorrected cryptorchidism is now rarely seen in the West, but in India and many other developing countries tumours of uncorrected cryptorchid testes continue to be seen. PMID- 7841057 TI - Accumulation of 99mTc-low-density lipoprotein in human malignant glioma. AB - Low-density lipoprotein (LDL) uptake in gliomas was studied to find out if LDL has potential as a drug carrier of boron, especially for boron neutron capture therapy. Single photon emission tomography (SPET) was performed 2 h and 20 h after intravenous injection of autologous 99mTc-labelled LDL in four patients with untreated and five patients with recurrent glioma. 99mTc-LDL uptake was compared with the uptake of 99mTc-labelled human serum albumin (HSA), an established blood pool marker. The intra- and peritumoral distributions of radioactivity in the SPET images were not identical for radiolabelled LDL and HSA. The mean LDL tumour to brain ratio, determined from transversal SPET slices at 20 h post injection, was 1.5 in untreated and 2.2 in recurrent gliomas; the corresponding ratios for HSA were 1.6 and 3.4. The brain to blood ratio remained constant at 2 h and 20 h in both types of tumours. These data are not consistent with highly selective, homogeneous uptake of LDL in gliomas. However, the different tumoral distribution and rate of uptake of 99mTc-LDL, as compared with 99mTc-HSA, indicate that the uptake of LDL is different from that of HSA and that further studies on the mechanism of LDL uptake in glioma are warranted. PMID- 7841058 TI - The efficacy of audiotapes in promoting psychological well-being in cancer patients: a randomised, controlled trial. AB - Open or uncontrolled studies have suggested that providing cancer patients with audiotapes of their clinical interviews can improve information recall and reduce psychological distress. We tested these hypotheses in a 'clinician-blind', prospective, randomised controlled trial. A total of 117 patients newly referred to a medical oncology clinic who were to be given 'bad news' had their consultations audiotaped. Blind to the clinician, patients were randomly allocated to receive a copy of the tape to play at home or not (control group). At 6 months follow-up, tape group patients reported positive attitudes to the audiotape and were shown to recall significantly more information about their illness than did controls. Overall improvement in psychological distress at 1 and 6 months follow-up, as measured with the 30-item General Health Questionnaire and the Hospital Anxiety and Depression Scale was no different in the two groups. However, a second-order interaction suggested that poor-prognosis patients were disadvantaged specifically by access to the audiotape, with less improvement in psychological distress at 6 months follow-up than non-tape controls. Patient access to audiotapes of clinical interviews promotes factual retention but does not reliably reduce psychological distress and may be actively unhelpful in some subgroups of patients. PMID- 7841059 TI - Plasminogen activators and inhibitor type 1 in neoplastic colonic tissue from patients with familial adenomatous polyposis. AB - The plasminogen activation cascade is involved in carcinogenesis, invasion and metastasis. In this study plasminogen activators and their type 1 inhibitor were evaluated in colonic tissue from 19 patients with familial adenomatous polyposis coli, an inherited disorder characterised by the presence of thousands of adenomatous polyps in the colorectum which predispose to colorectal cancer. The conversion of normal-appearing colonic mucosa to neoplastic tissue in these patients was associated with an increase in urokinase-type plasminogen activator and plasminogen activator inhibitor type 1, accompanied by a decreased level of tissue-type plasminogen activator. These observations are essentially similar to those found in solitary adenomas and carcinomas of the colon, and illustrate the uniform involvement of the plasminogen activation system in colorectal carcinogenesis. PMID- 7841060 TI - Evaluation of mouth self-examination in the control of oral cancer. AB - This study was planned to evaluate the feasibility of mouth self-examination (MSE). Some 450 college students distributed to 9000 households a brochure describing the risk factors of oral cancer, the appearance of premalignant and malignant lesions of the oral cavity and the methods of MSE with pictures. All subjects with tobacco habits and/or aged 30 years or over were asked to read the brochure carefully and to report to the clinic conducted in their locality on fixed days, if they suspected an abnormality while practising MSE. Out of the approximately 22,000 eligible subjects, 8028 (36%) practised MSE. Among the 247 subjects reporting to the clinics seven (3%) had oral cancer and 85 (34%) had oral precancerous lesions; the others had either benign lesions or normal anatomical variations. Six of the seven subjects with oral cancer had stage I disease, five of whom accepted treatment and were alive disease-free 5 years later. The detection rates of oral cancer compared favourably with the previously reported detection rates using trained health workers. Although this study demonstrated that MSE is feasible, larger studies are required to evaluate whether health education could result in a sustained practice of MSE resulting in reduction in incidence of and mortality from oral cancer. PMID- 7841061 TI - Cancer incidence in Asian migrants to New South Wales, Australia. AB - Cancer incidence during 1972-90 in Asian migrants to New South Wales, Australia, is described. Overall cancer incidence was lower than in the Australia born in most migrant groups, and this reached significance in migrants born in China/Taiwan, the Philippines, Vietnam and India/Sri Lanka, and in male migrants born in Indonesia. For the majority of cancers, rates were more similar to those in the Australia born than to those in the countries of birth. For cancers of the breast, colorectum and prostate, rates were relatively low in the countries of birth, but migrants generally exhibited rates nearer those of the Australia born. For cancers of the liver and cervix and, in India/Sri Lanka-born migrants, of the oral cavity, incidence was relatively high in the countries of birth but tended to be lower, nearer Australia-born rates, in the migrants. For these cancers, environmental factors related to the migrant's adopted country, and migrant selection, appeared to have a major effect on the risk of cancer. For certain other cancers, incidence was more similar to that in the countries of birth. Nasopharyngeal cancer, and lung cancer in females, had high rates in both the countries of birth and in migrants to Australia. Nasopharyngeal cancer rates were highest in China/Taiwan and Hong Kong-born migrants, and were also significantly high in migrants from Malaysia/Singapore, Vietnam and the Philippines. Rates of lung cancer were significantly high in women born in China/Taiwan, and the excess was greater for adenocarcinoma than for squamous cell carcinoma. Melanoma had low rates in both the migrants and in the countries of birth. For these cancers, it was probable that genetic factors, or environmental factors acting prior to migration, were important in causation. PMID- 7841062 TI - Oesophageal and gastric carcinoma in the Republic of Yemen. AB - We conducted a preliminary survey on 3064 patients who underwent upper gastrointestinal endoscopy at the Al-Thawra Hospital in Sana'a, Republic of Yemen, between January and December 1991. The age/sex distribution, demographic features and social habits with respect to cigarette and water-pipe smoking and Qat chewing were compared for patients with oesophageal and gastric cancers (n = 183). A preponderance of women with carcinoma of the mid-oesophageal was noted, previously only recorded in areas of high prevalence. Unlike Western populations, smoking and alcohol consumption were not significant risk factors. A high frequency of Qat chewing and water-pipe smoking was found for both men and women and for a group with tumours of the gastro-oesophageal junction or cardia (chi 2 = 2.646, P > 0.05). Numbers were insufficient to identify independent effects of each factor individually. Dietary habits alone were insufficient to account for the excess of affected females. A case-control study is now underway to investigate further the role of dietary factors, social habits, demographic features and Helicobacter pylori infection on the development of upper gastrointestinal cancer in the Yemen. PMID- 7841063 TI - Oesophageal and gastric cancer in Scotland 1960-90. AB - In Scotland over the last 31 years the incidence of gastric cancer has significantly declined by 0.6% per annum in males and 1.1% in females. In contrast, for oesophageal cancer, incidence rates have risen significantly by 3.0% and 2.0% per annum in males and females respectively. Increasing incidence of both adenocarcinomas and squamous carcinomas of the oesophagus in men and squamous and recently adenocarcinomas in women has been observed. This cannot be entirely accounted for by a growth in the proportion of histologically verified (HV) tumours over time. The incidence of adenocarcinoma of the stomach increased over the study period, most likely because of increasing proportions of HV tumours and improved diagnostic precision. Areas with high levels of deprivation in Scotland are strongly associated with high rates of oesophageal cancer in men, and of gastric cancer in both men and women. All these observations are discussed in the context of current knowledge of risk factors for these diseases. PMID- 7841064 TI - Cancer incidence in men with Klinefelter syndrome. AB - Many case reports have suggested an association between Klinefelter syndrome (KS) and cancer, but studies of the cancer incidence in larger groups of men with KS are lacking. A cohort of 696 men with KS was established from the Danish Cytogenetic Register. Information on the cancer incidence in the cohort was obtained from the Danish Cancer Registry and compared with the expected number calculated from the age, period and site specific cancer rates for Danish men. A total of 39 neoplasms were diagnosed (relative risk = 1.1). Four mediastinal tumours were observed (relative risk = 67); all four were malignant germ cell tumours. No cases of breast cancer or testis cancer were observed. One case of prostate cancer occurred within a previously irradiated field. No excess of leukaemia or lymphoma was found. An increased risk of cancer occurred in the age group 15-30 years (relative risk = 2.7). All six tumours in this group were germ cell tumours or sarcomas. The overall cancer incidence is not increased and no routine cancer screening seems to be justified. A considerably elevated risk of mediastinal germ cell tumours occurs in the period from early adolescence until the age of 30. PMID- 7841066 TI - Cranio-pharyngioma: the answer. Proceedings of the symposium held in New York, N.Y., December 17-19, 1993. PMID- 7841065 TI - Inheritance and testicular cancer. AB - Statistical analysis of published data on the age of onset of germ cell tumours of the testis and of the prevalence of bilateral disease in familial and general cases suggest the following: 1. Patients with bilateral disease carry the same genetic predisposition as familial cases. 2. Males with the hereditary predisposition develop none, unilateral or bilateral tumours in the proportions 55%, 38% and 7% respectively. 3. One-third of all testis cancer patients are genetically predisposed to the disease. 4. The 2.2% risk to brothers of cases as reported elsewhere can be accounted for by the homozygous (recessive) inheritance of a single predisposing gene. PMID- 7841067 TI - Advances in radiation therapy for craniopharyngiomas. AB - The overall survival for patients with craniopharyngioma is excellent. However, conventional treatments that include aggressive surgery and standard irradiation have been associated with significant morbidity. Focal radiation treatment with stereotactic radiosurgery has a role in selected cases, but may also be damaging to sensitive normal tissues such as the optic chiasm. Stereotactic radiotherapy (SRT) is a technique that allows for conventionally fractionated radiation under stereotactic guidance. Thus, highly focal and precise radiotherapy is now coupled with fractionation, enabling the treatment of selected tumors with a potentially improved therapeutic index. Dose optimization with SRT for focally discrete tumors should result in equivalent local control and survival compared to patients treated with conventional irradiation. We anticipate a significant decrease in late effects, especially neuropsychological and neuroendocrine sequelae. PMID- 7841068 TI - Surgical management of recurrent craniopharyngiomas. AB - Recurrence is the most common complication of all forms of treatment of craniopharyngioma. Reoperation is the preferred treatment for unsuspected residual tumor after primary radical resection. Surgical resection can be curative in the majority of recurrences, especially those with solid tumor. Scarring from previous surgery, particularly following primary radical removal, may increase the technical difficulty of surgery. Although most patients will have a reasonable functional outcome, the morbidity following operation for recurrence is greater than primary surgery with some degree of new deficit being common. Adjuvant irradiation, interstitial irradiation or bleomycin, and serial aspiration of cystic tumors have lower cure rates than surgical resection but may have lower morbidity in selected patients. They are potential adjuvant or second line treatments for subsequent recurrence. PMID- 7841069 TI - Pathology of craniopharyngiomas: clinical import of pathological findings. AB - Craniopharyngiomas are benign neoplasms, thought to be of maldevelopmental origin, which occur in both children and adults in the sella and suprasellar regions. There are two distinctive histologic patterns, 'adamantinomatous' and 'squamous papillary', but transitional or mixed examples occur. Prior suggestions that squamous papillary tumors are found 'only' in adults, 'never' calcify, do not invade brain, and are associated with a better outcome ('no' recurrences, better clinical status) are partially correct, but rare pediatric examples occur, rare examples have calcification, and in our study of 56 patients with craniopharyngiomas treated at New York University there was no statistically significant difference in brain invasion or recurrence rates for squamous papillary as compared to adamantinomatous types. Brain invasion, commonly seen in craniopharyngioma specimens, is not a predictor of recurrence. PMID- 7841070 TI - Patient/family preparation and education for complications and late sequelae of craniopharyngiomas. AB - Craniopharyngiomas are the most common pediatric suprasellar tumor. While they are benign by histology, their location in the brain predisposes craniopharyngiomas to be associated with both acute and chronic neurologic, endocrine, visual, neuropsychologic and psychosocial problems. Because of the complexity of problems it is difficult to really prepare a patient and family for every complication or late effect that may occur with a craniopharyngioma diagnosis. Patient/family preparation for potential complications and late sequelae is an ongoing and labor-intensive process for all members of the multidisciplinary health care team. This paper will discuss this process and identify strategies for effective patient/family education for children with the diagnosis of craniopharyngioma. PMID- 7841071 TI - Craniopharyngioma: endocrine sequelae of treatment. AB - Following complete surgical resection of a craniopharyngioma, combined anterior and posterior pituitary dysfunction is present in the majority of patients. Moreover, up to three-quarters of the patients will have deficits of four or more hormones. Postsurgery, obesity is common and can be part of a clinical syndrome which includes hyperphagia and normal growth despite GH deficiency. Radiotherapy with or without conservative surgery is associated with fewer endocrine disturbances. Normal growth and sexual development should be possible in most patients with the use of appropriate hormonal substitution therapy. PMID- 7841072 TI - Vascular complications of surgery for craniopharyngioma and hypothalamic glioma. AB - Vascular complications of surgery for suprasellar tumors include carotid artery laceration, vasospasm, and delayed aneurysmal dilatation of the carotid artery. We report updated follow-up (5-11 years) of 9 patients previously reported with fusiform dilatation of the carotid artery (FDCA) following radical surgical excision of craniopharyngioma, who represent 15.7% of 57 patients operated between 1982 and 1993. None of these patients have experienced hemorrhage or other symptoms referable to the carotid artery abnormality, and none have required treatment. We also report an additional 2 cases of FDCA which were discovered 8 and 11 years after surgery for chiasmatic/hypothalamic astrocytoma. One of these patients experienced headaches and possible hemorrhage, and underwent surgery for the lesion with a poor result. Unless further experience suggests otherwise, it is recommended that asymptomatic patients with this lesion be simply observed, and that surgical exploration for FDCA be reserved for those patients who experience symptoms. PMID- 7841073 TI - Craniopharyngioma: endocrine abnormalities at presentation. AB - Craniopharyngioma is the most common childhood tumor to involve the hypothalamus and pituitary. Although endocrine disturbances can be found in 80-90% of patients at presentation, only a minority of subjects seek medical attention for an endocrine-related complaint. Hormonal studies, while limited, indicate GH deficiency in 75% of children; deficiencies of LH/FSH (40%), ACTH (25%) and TSH (25%) also are common. In contrast, diabetes insipidus has been noted in only 9 17% of subjects prior to surgery. When possible, full evaluation of pituitary function should be performed; the minimum preoperative evaluation must include testing for and treatment of ACTH-adrenal insufficiency and diabetes insipidus. PMID- 7841074 TI - Neuroimaging of childhood craniopharyngioma. AB - The imaging of craniopharyngioma may include plain skull x-rays, computer tomography (CT) scans, magnetic resonance imaging (MRI) and angiography. Coronal studies are essential to properly define the regional anatomy. The solid or cystic character of the lesion is especially apparent with contrast enhancement. MRI adds a sagittal projection which is useful, and its increasing sophistication may eventually make angiography superfluous in these tumours. The appearance of craniopharyngiomas in each modality is described, including 3D, and an ideal imaging strategy presented. Postoperative imaging is best done with both MRI and CT, and enhanced studies done within 48 h to avoid the effect of surgical trauma. PMID- 7841075 TI - The endocrine outcome after surgical removal of craniopharyngiomas. AB - The postoperative course of children undergoing surgery for craniopharyngioma was reviewed. Typically they were below height at presentation. All had an attempt at radical surgical resection of the tumor. Most developed diabetes insipidus in the postoperative period, which was permanent in all but 1 child. 94% required thyroid replacement therapy, and sex steroids were administered in 100% when they reached the age of puberty. 91% required maintenance corticosteroids. 54% required growth hormone replacement, but some children showed continued growth despite apparent growth hormone deficiency. Postoperative obesity develops in one half of patients, and may be improved with administration of growth hormone; a controlled trial is underway. PMID- 7841076 TI - History of surgery for craniopharyngiomas. AB - Craniopharyngiomas, although histologically benign, are usually so intimately associated with the hypothalamus that total extirpation of these tumors was generally followed by death from hypotension and gross endocrine deficiencies. During the first half of the present century, those recording their tribulations include the famous names of Grant, Bailey, Bucy, Peet, Kahn, Olivecrona, Norlen, Sjoqvist, Rougerie and Northfield. Matson and Sweet were the first to achieve major reductions in mortality by giving massive doses of cortisone plus meticulous dissection, which took advantage of the reactive glial envelope which surrounds the great majority of these tumors. PMID- 7841077 TI - Craniopharyngioma: results of survey of the American Society of Pediatric Neurosurgery. AB - The best management of craniopharyngioma in children remains a controversial subject for pediatric neurosurgeons. The results of a survey completed by 11 pediatric neurosurgeons documenting outcome in 139 children is presented. There were 21 children treated with limited surgery and irradiation with a good outcome in 83%. One hundred twelve underwent an attempt at gross total resection, 30 of whom required irradiation. There was a marked difference in good outcome according to experience of surgeon, 87 vs. 52% in the radical surgery group. PMID- 7841078 TI - Surgical approach to children with craniopharyngiomas and severely impaired vision: special considerations. AB - A series of 30 children with craniopharyngiomas is presented, analyzing visual sequelae following surgery. All were operated on with the goal of total removal. Surgical routes used were subfrontal prechiasmatic or translamina terminalis, pterional interopticocarotid, transcallosal, or a combination of these various avenues. The choice of the approach depended upon the type, pre- or retrochiasmatic, of the tumor expansions. Children with large cysts and preoperatively low vision, or vision at risk of rapid deterioration, were submitted to a protocol aiming to preoperatively decompress the visual pathway by repeated aspirations of the cyst with the hope this would improve vision before surgery and limit risks of postoperative visual deterioration. In these cases, the removal of the tumor was postponed until vision had reached a stable new level. The authors emphasize the interest of this procedure in reducing the rate of postoperative visual sequelae. However, they also point out that the interopticocarotid route carries a nonnegligible risk of postoperative visual worsening. PMID- 7841079 TI - Transsphenoidal removal of craniopharyngioma. AB - Transsphenoidal microsurgical removal is appropriate therapy for a significant number of craniopharyngiomas. Favorable factors for the transsphenoidal approach are enlargement of the sella, cystic lesion and preoperative hypopituitarism. A series of 76 operative cases is presented. Long-term follow-up revealed successful results in 81% of patients. PMID- 7841080 TI - An approach to radical excision of craniopharyngioma by the temporal route. AB - Attempts at radical excision of craniopharyngioma has been made increasingly possible by the advent of neuroradiological imaging and the use of microscopic technique. Between 1977 and 1993, 62 patients of The National Hospital for Neurology and Neurosurgery, London, have undergone surgical excision of craniopharyngioma by the temporal route, with a small anterior temporal resection. Surgical mortality was 4%. Forty-eight patients (76%) remain well on average follow-up of 34 months. Twelve percent had major complications (hypothalamic damage, subdural haematoma, scalp collections requiring shunt drainage). There were four recurrences in patients where the initial operations were considered as complete microscopic excision. Maximal control of tumour recurrence by removal of all tumour accessible and visible to the surgical microscope is best achieved by radical excision at the first operation. PMID- 7841081 TI - Stereotactic gamma radiosurgery of craniopharyngiomas. AB - Ten cases of solid craniopharyngioma have been treated safely and effectively by gamma knife for a mean follow-up time of 13.9 months. Gamma radiosurgery was done as an initial radiotherapy to the residual or recurrent tumor after surgery in 8 cases. One recurrent tumor from surgery and conventional radiotherapy, and another tumor without previous treatment, have also been treated. Dose planning and dosimetry were performed using both axial and coronal MRIs. The tumor had a mean diameter of 21.1 mm and volume of 6.14 cm3. The tumor was treated with a mean maximum and marginal dose of 27.6 and 14.2 Gy respectively. The dose to the optic pathways is critical and was kept as low as possible which was calculated to be < 13.0 Gy on average. As a result, marked shrinkage of the tumor in 7 and central necrosis in 3 tumors have been obtained without significant side effects. PMID- 7841082 TI - Surgery, radiation, and combination therapy in the treatment of childhood craniopharyngioma--a 20-year experience. AB - The records of 61 children treated for primary craniopharyngioma at the Children's Hospital in Boston and The Joint Center for Radiation Therapy from 1970 to 1990 were reviewed to determine if any information could be obtained regarding the efficacy of surgery versus radiotherapy or a combination of these modalities for this tumor. A select group of 9 children treated without biopsy by radiation therapy alone were all alive without disease progression at follow-up. Although 9 of the 15 children who underwent surgery alone had tumor recurrence, 7 of the 37 children treated with radiotherapy following surgery have also recurred. Treatment morbidity occurred in all groups, but the 10-year actuarial survival for all patients was 91%. Early postoperative imaging and pre- and posttreatment endocrine and neuropsychologic evaluations need to be carried out in all prospective studies of the treatment of craniopharyngioma in children. PMID- 7841083 TI - Treatment of craniopharyngiomas: the multimodality approach. AB - A Multimodality Protocol for the treatment of craniopharyngiomas, where stereotactic methods are used preferentially, give long-term results not inferior to those reported when microsurgical removal has been the first therapeutic choice. Case material, treated in accordance with this protocol, is presented in a long-term perspective. The features of the protocol are discussed. PMID- 7841084 TI - Stereotactic options in the management of craniopharyngioma. AB - Multimodality stereotactic techniques were used in the management of 39 patients with craniopharyngiomas in a 12-year interval. Monocystic craniopharyngiomas were treated successfully by intracavitary beta-irradiation using 32P (96% cyst control rate). Solid tumor progression or secondary cyst formation required repeat irradiation, radiosurgery or microsurgery in selected patients. In the future, wider and earlier application of stereotactic techniques may further reduce the still unacceptable morbidity currently associated with initial radical microsurgical resection of craniopharyngiomas. PMID- 7841085 TI - The role of radiation therapy in the treatment of craniopharyngioma. AB - The role of radiotherapy in the management of patients with craniopharyngiomas is still controversial. Many articles have been published reviewing retrospective patient information with subsequent treatment recommendations which are not randomized and are biased. Treatment at the University of California, San Francisco, with radiation and surgery yields a 10-year disease-free survival of 77%. No difference in overall survival was found based on sex, age, or type of surgery. A review of the literature shows that radiation added to surgery results in a 50-80% disease-free survival. Patients undergoing a complete resection may be observed for subsequent recurrence. If a subtotal resection or biopsy is obtained, that patient should be irradiated with modern techniques to a dose of 5,400 cGy at 180 cGy/fraction. PMID- 7841086 TI - Myocardial stunning--are calcium antagonists useful? AB - Considerable data support the point of view that calcium antagonists, whether given before the onset of ischemia or exactly at the time of reperfusion, ameliorate stunning. Benefit after the onset of reperfusion is much more controversial. It is proposed that the mechanisms whereby calcium antagonists act vary between these situations. When given before or at the onset of ischemia, then an antiischemic effect is likely. According to the hypothesis that the severity of ischemic damage determines the severity of reperfusion damage, the calcium antagonists indirectly lessen reperfusion damage. When given exactly at the time of reperfusion, the proposal is that the calcium antagonists are specifically limiting the entry of calcium ions via the calcium channel and thereby diminishing pathogenic cytosolic calcium oscillations. The reported benefit of calcium antagonists when given postreperfusion to the heart in situ, in the presence of established stunning, is of unknown mechanism and controversial significance. The hypothesis of a two-stage model of stunning with calcium as a pathogen is in accord with most of the available evidence. PMID- 7841087 TI - Review of postinfarct treatment with verapamil: combined experience of early and late intervention studies with verapamil in patients with acute myocardial infarction. Danish Study Group on Verapamil in Myocardial Infarction. AB - An overview of the published studies on the use of verapamil during and after an acute myocardial infarction is presented. Meta-analyses of the two small early intervention trials, one early intervention trial followed by a 6-month treatment period (The Danish Verapamil Infarction Trial I, DAVIT I) and one late intervention trial (DAVIT II), demonstrated a 17-20% statistically nonsignificant reduction of mortality, first reinfarctions, and first major events. In DAVIT II was found a statistically significant 20% reduction of first major events in verapamil-treated patients. In patients without heart failure during the acute event mortality, first reinfarctions and first major events were significantly reduced by 30-36% in verapamil-treated patients. No difference was found in patients treated for heart failure in the coronary care unit. A meta-analysis based on patients included in DAVIT I alive day 8 and all patients included in DAVIT II demonstrated a statistically significant 21-26% reduction of mortality, first reinfarctions, and first major events. PMID- 7841088 TI - Significance of left ventricular hypertrophy in cardiovascular morbidity and mortality. AB - Being a "classical" sequel of hemodynamic burdens (pressure and/or volume), the untoward results of left ventricular hypertrophy (LVH) were traditionally related to its underlying causes. The Framingham study was the first to demonstrate the increased independent risk associated with LVH detected by ECG and/or by echocardiography. The presence of LVH in "nonhypertensive" individuals (e.g., obese), the association of LVH with age and gender, and the possibility of genetic control of left ventricular size via "nonhemodynamic" mechanisms had underscored the importance of LVH per se as a prognostic indicator. The presence of LVH in patients with hypertensive or coronary artery disease results in a severalfold increase in risk compared to similar patients without LVH. Early studies have indicated that the presence of LVH is associated with a significantly worse prognosis in patients recovering from myocardial infarction. We have studied the effect of LVH on long-term (mean 5.5 years) mortality in patients surviving myocardial infarction registered in the SPRINT database. The LVH patients were older and had more complications during hospitalization. The 1- and 5-year mortality rates were doubled in patients with ECG-LVH. Review of the mechanisms operating in LVH reveals important changes in the anatomy and physiology of hypertrophied heart, leading to increased fibrosis, inadequate vascular growth, impaired myocardial function (systolic and diastolic), reduced coronary reserve, and abnormal electrophysiological properties. Regression of LVH by proper treatment (achieved mainly by calcium antagonists and ACE inhibitors) may correct many of the above-mentioned adverse phenomena. Whether the regression of LVH per se will lead to improved prognosis remains to be answered in the future. PMID- 7841089 TI - Ventricular dysrhythmias, left ventricular hypertrophy, and sudden death. AB - Left ventricular hypertrophy has been documented to be a powerful risk factor for sudden death, acute myocardial infarction, and other cardiovascular morbidity and mortality. The major determinant of left ventricular mass is the hemodynamic burden. However, the hypertrophic process is modified by demographic parameters (age, sex, race), nutritional parameters (salt intake, alcohol, obesity), and neuroendocrine factors (angiotensin, catecholamines, growth hormones, etc.). Ventricular ectopy and more serious arrhythmias are commonly seen in patients with left ventricular hypertrophy. Specific antihypertensive therapy will reduce left ventricular hypertrophy, although not all antihypertensive drugs are equipotent in this regard. A reduction in left ventricular hypertrophy has been shown to diminish left-ventricular-hypertrophy-associated arrhythmias. However, it remains to be shown that patients with left ventricular hypertrophy and ventricular ectopy are at a higher risk of sudden death than those without ventricular ectopy and that the reduction of left-ventricular-hypertrophy associated ventricular ectopy indeed confers a clinical benefit that exceeds the one from the reduction in arterial pressure alone. PMID- 7841091 TI - HP, GC and PI polymorphisms in sixteen central Indian tribal populations. AB - HP, GC and PI polymorphisms have been typed on 16 Central Indian tribal populations with a total of 1658 individuals. The distribution of allele frequencies shows a statistically highly significant heterogeneity, which may be caused by several microevolutionary factors, such as genetic drift, social and geographic isolation. Some new variants were observed in both the GC system (GC 2Cmah) and in the PI system (PI Yori). The PI variants are more frequent and are found in most of the 16 populations under study whereas the GC variants are rather infrequent and restricted to only three populations. PMID- 7841092 TI - Ecogenetic and pharmacogenetic studies in Hungary. AB - 12 population groups of Hungary, 1514 individuals altogether, have been studied for polymorphisms of alpha 1antitrypsin, serum cholinesterase, paraoxonase and delta-aminolevulinic acid dehydrase, N-acetyltransferase variation and aldehyde dehydrogenase deficiency. A possible relationship between their allele frequencies and environmental factors in the context of ecogenetic and pharmacogenetic phenomena in Hungary is discussed. PMID- 7841090 TI - How do calcium antagonists differ in clinical practice? AB - The majority of calcium antagonists used clinically belong to three distinct chemical classes: the phenylalkylamines, the dihydropyridines, and the benzothiazepines. In recent years their mode of action has been unravelled, their limitations recognized, and their efficacy and use in the management of patients with a broad spectrum of cardiovascular and other disorders defined. It is clear, however, that these drugs are not all alike, providing an explanation for their differing effects. The final therapeutic effect in humans depends on the mechanisms of action at the molecular level, the tissue selectivity, and the hemodynamic changes of each agent. All these aspects are examined in detail in this article. Concepts that are highlighted are as follows: (a) Molecular biology has allowed recognition of the polypeptide components of the alpha 1 subunit of the L-type Ca2+ channel and the finding of peptide segments covalently labelled by all three classes of drugs. (b) The location of these segments within the peptides is different: Binding sites for dihydropyridines are located externally, whereas those for verapamil and diltiazem are located internally, in the cytosolic part of the membrane. (c) Dihydropyridine binding is voltage dependent. This explains the selectivity of this class of drugs for vascular smooth muscle, which is more depolarized than cardiac muscle. (d) Phenylalkylamines and benzothiazepines reach their receptors at the internal surface of the sarcolemma through the channel lumen. Their binding is facilitated by the repetitive depolarization of atrioventricular and cardiac tissue, a phenomenon described as use dependence. This explains why these drugs are not highly selective, but equipotent for the myocardium, the atrioventricular conducting tissue, and the vasculature. (e) Dihydropyridines act through selective vasodilatation and may increase heart rate and contractility via a reflex mechanism. On the contrary, phenylalkylamines and diltiazem act through a combination of effects, including reduction of afterload, heart rate, and contractility. When taken together, all these differences distinguish the preferential clinical utilization of one of these compounds for a given cardiovascular pathology. PMID- 7841093 TI - Analysis of the distribution of some serum protein polymorphisms in isolated populations in the Middle Sangro Valley (Chieti-Abruzzo, Italy). AB - We studied Gc, Hp, C3 and Bf serum protein polymorphisms in the population of the Middle Sangro Valley, an area in the Abruzzo Apennine mountains on the border with the Molise region, which has maintained a highly isolated character. The gene frequency estimates obtained for the total sample of the Middle Sangro Valley were: [table: see text] The analysis of these data reveals internal heterogeneity in the population of the Middle Sangro Valley probably due to geographical and socio-cultural differences which may have give rise to local micro-evolutionary phenomena. PMID- 7841094 TI - Polymorphic DdeI restriction sites in mitochondrial d-Loop DNA from Emilian blood donors. AB - We describe two new polymorphic sites identified by DdeI digestion of human mitochondrial D-Loop DNA. Their frequencies were estimated on a random group of 54 unrelated blood donors, born and descending from female ancestors of the Province of Reggio Emilia (Central Emilia, Northern Italy). These newly detected polymorphisms were generated by A to G transitions at positions 16300 and 16482 of mt-DNA. They were found at a 5% frequency in our sample whereas the remaining 95% of the sample exhibited a Cambridge sequence restriction pattern. PMID- 7841095 TI - Genetic polymorphism in the Garfagnana population (Tuscany). AB - Blood group systems ABO, KEL, MN, RH, secretor status for ABH blood group substances, red cell enzymes ACP1, ESD, AK1, 6-PGD, PGM1 subtypes, serum markers GC, TF, PI, AHSG, ORM1 and chromosomal heteromorphism Q, C, DA/DAPI were examined in a population sample of the Garfagnana, a semi-isolated mountainous area in the province of Lucca (Tuscany, Italy). The total sample was subdivided and analysed according to the more recent historical events which have occurred in Garfagnana. The observed phenotype and gene frequencies were discussed in the context of other population samples from the same province and of the same region. As a whole, the results concur in pointing out a certain degree of heterogeneity within the area and a high differentiation from the rest of Tuscany. Such peculiar genetic features of the population have to be related to the historical, geographic and cultural isolation of the Garfagnana. PMID- 7841096 TI - Orosomucoid and haptoglobin polymorphisms in two Spanish Pyrenean populations. AB - Serum samples of autochthonous individuals from the Garrotxa prepyrenean region, and the Pallars Sobira valley were screened for HP (Haptoglobin) and ORM (Orosomucoid) types by polyacrylamide isoelectric focusing and electrophoresis. The allele frequencies estimated were HP*1 = 0.3902 and ORM1*S = 0.3697 for Pallars Sobira, and HP*1 = 0.4161 and ORMS1*S = 0.3691 in the Garrotxa. While our results for the HP system are within the range of variation of the Iberian Peninsula, the ORM1 protein shows a remarkable degree of variation among these populations. PMID- 7841097 TI - Genetic polymorphisms in a rural Osetian community. AB - Data are presented on ABO, Rhesus, MNSs, P, Duffy, Kell and Kidd blood group polymorphisms in the Dzhava district, located on the southern slopes of the Main Caucasian Mountain Range. The gene frequencies, compared with those in other Osetian populations and neighbouring ethnic groups of the Caucasus, show general similarity. An exception to the general pattern is presented only by the P blood group system, where the frequencies of the alleles are significantly different form those observed in the neighbouring populations. PMID- 7841098 TI - Stemming the trend in cerebrovascular accidents in Africa. PMID- 7841099 TI - Hepatitis B viral markers in Ghanaian pregnant women. AB - Seven hundred pregnant women referred for blood grouping were studied for the presence of some markers of Hepatitis B virus. After collection of personal data including place of permanent residence the sera were tested for the presence of HBs Ag and anti HBs. The sera positive for HBs Ag were tested for the "e" antigen and antibody. The results were analysed according to parity, age and geographical location. Six hundred and ninety-two results were available for analysis showing 464 (67.1%) to have antibodies. 215 (31.1%) had no marker whatsoever. 44 (6.4%) of the women were HBs Ag carriers. Eight of these had the e antigen indicating that 1.16 percent were therefore infective. Calculation was made to determine the extent of vertical transmission using the prevalence of the e antigen. 15% of HBV carrier rate in the population is due to perinatal transmission and this is significant. Parity, age and geographical location did not influence the prevalence of the various markers. PMID- 7841100 TI - A study on transplacental transfer of thyroid hormones in pregnant Nigerian women of Jos-Plateau State. AB - Knowledge of transplacental passage of thyroid hormones in pregnant women is very scanty. Seventy paired 'maternal-cord' blood samples were obtained at term (40 week) deliveries from the Nigerian women from Jos Plateau and its environment, and the level of serum T4, T3, TSH, TBG and TBK (thyroxine binding capacity) were determined by 'ELISA' technique (Boehringer). The serum level of FT41 (free thyroxine index) was determined subsequently by dividing the serum values of T4 with those of TBK. The results obtained were compared with those derived from a similar group assessed among white Americans, as well as with an age-matched non pregnant control group selected from Jos metropolis. Results show that the level of thyroid activity in the present group of 'mothers and neonates' assessed were lower compared to the level seen in the corresponding American group. Correlation studies carried out in this work indicated that the maternal and corresponding neonates have significant degree of positive correlations between the serum levels of T4 (r > .9; p < .005); FT4I (r > .88; p < .005); TBK (r > .8; p < .005); TBG (r > .89; p < .005) and TSH (r > .87; p .005), while T3 did not show any correlation. It is concluded, that during pregnancy there is probably significant transplacental passage of iodine (I) from the mother to the growing foetus, in an attempt to build the necessary foetal Iodine pool, and TRH (thyrotrophin releasing hormone) probably acts as mediator between the foetal and maternal 'hypothalamus--pituitary--thyroid' axis, which are, otherwise independent of each other. PMID- 7841101 TI - The etiology of community acquired pneumonia in adults in Addis Ababa. AB - Over a two year period, we prospectively studied 110 adult patients with Community Acquired Pneumonia (CAP) who presented to the Black Lion Hospital, Addis Ababa, Ethiopia. Pneumococcal infection was diagnosed in 41% by the detection of pneumococcal antigen in sputum and other biologic fluids; in 72% by Gram stain of Lung Aspirate (LA) and in 67.5% by Gram stain of sputum. Blood and Lung Aspirate culture grew Streptococcus Pneumoniae in 4 cases (6%), Staphylococcus Aureus in 4 (6%), Enterobacteriacae in 3(5%), Pseudomonas, Klebsiella Pneumoniae and Strep. Viridans in one case each. Other non-bacterial causes included Mycoplasma Pneumoniae in 4 (4%) Influenza A in 4 (4%), Influenza B in 3 (3%) and Psittacosis/LGV in a 4 (4%). There was no case of Legionnaires disease. 39% had taken treatment before coming to hospital. The mortality was 11%. The study showed that antibiotic treatment during the preceding 36 hours did not affect the outcome of the Gram stain. PMID- 7841102 TI - The utility of ethnographic methods in medical research: experience with substance use disorders. AB - Ethnographic research methodology provides investigators with the opportunity to explore various ways in which culture affects and modulates human behaviour and beliefs. These methods, even though commonly used in medical anthropology, are often neglected in the main-stream of medical research, possibly as a result of relative unfamiliarity with their principles and techniques. Drawing on experience gained in Ibadan during a WHO collaborative study in nine different countries, we demonstrate the use of key informants interview and focus group techniques. We conclude that the methods are easy to learn and apply, and have potentials for helping researchers in many areas of medicine to address important questions. PMID- 7841103 TI - Differential reactivities of antibodies to HIV and HTLV-I in sera of suspected AIDS and ARC patients. AB - Sera collection from 255 clinically diagnosed AIDS and ARC patients were analyzed for antibodies to HIV and HTLV-I by Western blot and particle agglutination methods respectively. Antibodies to HIV were detected in 37.3% of the sera collected as compared to 5.5% for HTLV-I. Most (95%) of the HIV positive sera had dual reactivity to both HIV-I and HIV-2. Antibodies to HTLV-1 were more frequently detected in HIV positive sera (11.58%) than in HIV negative sera (1.88%). Conversely, antibodies to HIV were detected twice as frequently in HTLV 1 positive sera (78.6%) than in HTLV-1 negative sera (34.85%). PMID- 7841104 TI - Urinary abnormalities in asymptomatic adolescent Nigerians. AB - Previous urinary survey studies from Nigeria have been virtually restricted to young primary school children, usually below the age of 12 years. This study focuses on adolescent population drawn from 4 secondary schools in Benin City, numbering 2169 (1143F, 1026M) with age range 13-20 years. A dipstick method (multistix 10SG) was sued for urine testing. The prevalence of urinary abnormality (proteinuria or haematuria) for both sexes was 5.25% with proteinuria and haematuria accounting for 4.7% and 0.55% respectively. Proteinuria and haematuria were more frequent in girls being 4.72% and 0.79% respectively as against 4.68% and 0.29% respectively for boys though, the difference was not statistically significant. Significantly, 6 of the girls with proteinuria (0.52%) had nephrotic range proteinuria though oedema free. One of these revealed minimal change lesion on renal biopsy and responded well to steroid therapy. Another, had spontaneous remission of her proteinuria on follow up. All subjects with urinary abnormalities had normal renal function initially and after 1 year of follow up. The study shows that in the Nigerian setting routine urinary surveys could reveal significant abnormalities which may benefit from early and relatively cheap therapeutic measures. PMID- 7841105 TI - Incidence and treatment seeking patterns for venereal diseases in Jos metropolis. AB - This is a cross-sectional survey in Jos metropolis of a sample of hospitals, clinics and other types of western drug dispensing facilities reported to have been patronised by patients seen at the sexually transmitted disease (STD) clinics in Nigeria. Its purpose was to obtain a better picture of the burden of STDs in the towns and villages in the different cultural areas of Nigeria. The results show that all the centres, from patent medicine store keepers upwards, treated STDs. A few of the non-physician manned centres denied treating STD patients. The estimated annual crude incidence rate of STDs in this town, from this study, was 6.8%, similar to the 7.4% estimated for Maiduguri town in an earlier study. Only 0.7% of the cases (compared with 0.8% in Maiduguri) were seen at the specialised STD clinic in the town. The implications of findings for the effective control of STDs in Nigeria are discussed. PMID- 7841106 TI - The diagnosis of dementia associated with alcoholism: a preliminary report of a new approach. AB - The historical, clinical, neurological and neuropsychological features of 13 subjects with independently diagnosed dementia associated with alcoholism (AlcD) were compared to 13 subjects with probable Alzheimer's disease (AD), matched for age and severity of dementia. Neurological abnormalities were present in all the subjects with AlcD even though the diagnosis of Wernicke-Korsakoff was recorded in only one of these subjects. Only one subject with probable AD demonstrated any neurological abnormality. There was no difference between the AD and AlcD subjects in either the total scores of the Mini-Mental State Examination (MMSE) or in any of the subscores. The presence of neurological signs does appear to be a useful method to assist in the diagnosis of AlcD. PMID- 7841107 TI - Comparative analysis of HIV-1 and HIV-2 indeterminate western blot patterns. AB - A comparison of HIV-1 and HIV-2 indeterminate Western blot patterns of Ghanaian sera collected between 1989 and 1990 was made. Antibodies to group specific antigen (GAG) gene products were most frequently detected both HIV-1 and HIV-2 indeterminate sera. HIV-2 GAG gene product p26 was shown to be a non-specific indicator of infection. Antibody to gp120, and envelope gene product of HIV-1 never occurred in indeterminate sera whereas antibodies to all the envelope gene products of HIV-2 were detected in indeterminate sera. PMID- 7841108 TI - Apparent hypocalcaemia in Nigerian children with kwashiorkor. AB - Thirty children with kwashiorkor had a mean +/- SEM plasma calcium (Ca) of 7.15 +/- 0.10mg/100ml; total proteins (TP) of 4.60 +/- 0.17g/100ml and albumin (A) of 1.89 +/- 0.11g/100ml. These values are significantly lower (p < 0.001) than the corresponding values of 9.07 +/- 0.10; 7.30 +/- 0.11 and 3.85 +/- 0.07 observed in thirty other age-matched normal controls. No significant differences exist in the plasma alkaline phosphatase (AP) levels in both groups. Correction of calcium for hypoalbuminaemia in the kwashiorkor group revealed that the observed hypocalcaemia in kwashiorkor is merely apparent. PMID- 7841109 TI - The prevalence of hepatitis Be antigen and anti-HBE in adults in Benin City. AB - Two hundred and seventy four adults in Benin City were screened for HBeAg in their sera using the ELISA method. The overall HBe-Antigenemia prevalence was 7.3%. 12.7% of adult males and 5.4% of 203 adult females were positive for HBeAg. Of the 91 samples available for screening for anti-HBe, an overall positivity rate of 8.8% was obtained. 10.3% of 68 adult males and 4.4% of 23 adult females were positive for anti-HBe. Reports of high carrier rate for Hepatitis B virus (HBV) markers in Nigeria is further confirmed. The high HBeAg positivity rate could further explain the high transmission rate of HBeAg from chronic carriers in this country. Compared to the Far East countries, Prevalence of HBe antigenemia is relatively lower and may further confirm that the vertical, that is neonatal maternal infant hepatitis B virus transmission might play a less important role than the later horizontal transmission in this country. Therefore in considering immunization programme, the use of hepatitis B vaccine alone, without the additional, much more expensive hepatitis B Immunoglobulin (HBIG) might be an adequate prophylactic measure. The high HBe-antigenemia as well as the already well documented endemicity of hepatitis B virus in this country however calls for urgent steps to ensure introduction of this vaccine into neonatal practice in this country. PMID- 7841110 TI - Resistant hypertension in Yaounde. AB - Sixty six consecutive patients with resistant hypertension were studied over a period of 12 months. During that same period 565 patients were seen in all for hypertension given an average prevalence of 11.7% of resistant hypertension. Men were more frequently affected, however mean systolic and diastolic blood pressure levels were higher in women. Past history of poor compliance, overweight, renal impairment and cardiac abnormalities were important predictors of poor response to therapy. Resistance to therapy was not related to the class or the type of medication taken. Side effects were more numerous in the resistant group. Biochemically, apart from abnormal renal function tests, the other baseline tests were similar in both groups of resistant and non resistant hypertensives. PMID- 7841111 TI - The diagnostic accuracy of resident doctors in the Department of Medicine University College Hospital, Ibadan. AB - A study has been undertaken of 52 "charts review" cases (postmortem) formally discussed by Resident Staff of the Department of Medicine, University College Hospital, Ibadan at meetings over a period of 24 months. The senior registrars' diagnosis were correct in 39 (75%) cases while the registrars diagnosis were correct in 34 (64.4%) cases. The senior registrars were correct more often than the registrars; though the difference between them was not statistically significant (x2-1.14, P = n.s). PMID- 7841112 TI - Relationship between load carrying on the head and cervical spondylosis in Ghanaians. AB - Three hundred and five patients (164 males and 141 females) with mean age 39.9 with standard deviation 7.3 and a range of 29-78 years were involved in a study to find out the relationship between load carrying on the head and cervical spondylosis. Out of 225 patients who carried loads on their head, 143 (63.6%) had cervical spondylosis, and of the 80 people who did not carry load on their head, 29 (36%) had cervical spondylosis. 131 (58%) of those who carried load did so regularly with an average weight of about 15 kg or more over a period 10-15 years or more. It is concluded that cervical spondylosis is not exclusively an ageing phenomenon, but that regular heavy load carrying on the head plays an aetiological role. PMID- 7841113 TI - Current trends in the incidence of cerebrovascular accidents in Accra. AB - The incidence of cerebrovascular accidents (CVA) in Accra during three periods- 1960-1968, 1976-1983, and 1990-1993, was compared. There was dramatic increase in the incidence between 1990-1993. Uncontrolled hypertension due to non-compliance with drug therapy seems to be the main cause. The economic plight of the people may explain the non compliance. The case fatality was between 41.9% to 50.3% for the years 1990-1993. Cardiovascular diseases, notably hypertension and CVA, have become the major causes of morbidity and mortality in Accra. PMID- 7841114 TI - Posterior encephalocoele: a case of difficult tracheal intubation. AB - This paper describes the anaesthetic management of a neonate with a posterior encephalocoele and discusses the management of problems encountered. The problems were difficult tracheal intubation, cardiac arrest and dislodgement of the endotracheal tube. PMID- 7841115 TI - Topography and extent of visual-field representation in the superior colliculus of the megachiropteran Pteropus. AB - It has been proposed that flying foxes (genus Pteropus) have a primate-like pattern of representation in the superficial layers of the superior colliculus (SC), whereby the visual representation in this structure is limited by the same decussation line that limits the retino-geniculo-cortical projection (Pettigrew, 1986). To test this hypothesis, visual receptive fields were plotted based on single- and multi-unit recordings in the SC of ten flying foxes. A complete representation of the contralateral hemifield was observed in the SC. Although the binocular hemifield of vision in Pteropus is 54 deg wide, receptive-field centers invaded the ipsilateral hemifield by only 8 deg, and the receptive-field borders by 13 deg. This invasion is similar to that observed at the border between visual areas V1 and V2 in the occipital cortex. The extent of the ipsilateral invasion was not affected by a lesion that completely ablated the occipital visual areas, thus suggesting that this invasion may be consequence of a zone of nasotemporal overlap in the retinal projections to the two colliculi. Neurones located in the superficial layers typically responded briskly to stimulation of both eyes, with a bias towards the contralateral eye. After cortical lesions the neuronal responses to the ipsilateral eye were depressed, and the ocular-dominance histograms shifted towards an even stronger dominance by the contralateral eye. However, cells located in the rostral pole of the SC remained responsive to the ipsilateral eye after cortical lesions. Responses in the stratum opticum and stratum griseum intermediale were more severely affected by cortical lesions than those in the stratum griseum superficiale. Our results demonstrate that the SC in flying foxes retain some generalized mammalian characteristics, such as the stronger direct projections of the contralateral eye and the location of the upper, lower, central, and peripheral representations in the SC. Nonetheless, the extent of visual representation in the SC demonstrates a specialized, primate-like pattern. These observations are consistent with the hypothesis that megachiropterans are members of a group that branched off early during the differentiation of primates from basal mammals. PMID- 7841116 TI - Influence of the superior colliculus on responses of lateral geniculate neurons in the cat. AB - The superior colliculus (SC) projects to all layers of the cat's lateral geniculate nucleus (LGN) and thus is in a position to influence information transmission through the LGN. We investigated the function of the tecto geniculate pathway by studying the responses of cat LGN neurons before, during, and after inactivating the SC with microinjections of lidocaine. The LGN cells were stimulated with drifting sine-wave gratings that varied in spatial frequency and contrast. Among 71 LGN neurons that were studied, 53 showed a statistically significant change in response during SC inactivation. Control experiments with mock injections indicated that some changes could be attributed to slow waxing and waning of responsiveness over time. However, this could not account for all of the effects of SC inactivation that were observed. Forty cells showed changes that were attributed to the removal of tecto-geniculate influences. About equal numbers of cells showed increases (22 cells) and decreases (18 cells) in some aspect of their response to visual stimuli during SC inactivation. The proportion of cells that showed tecto-geniculate influences was somewhat higher in the C layers (68% of the cells) than in the A layers (44% of the cells). In addition, among cells that showed a significant change in maximal response to visual stimulation, the change was larger for cells in the C layers (64% average change) than in the A layers (26% average change) and it was larger for W cells (61% average change) than for X and Y cells (29% average change). Nearly all of the X cells that showed changes had an increase in response, and nearly all of the Y cells had a decrease in response. In addition, across all cell classes, 80% of the cells with receptive fields < 15 deg from the area centralis had an increase in response, and 80% of the cells with receptive fields > or = 15 deg from the area centralis had a decrease in response. None of the LGN cells had significant changes in spatial resolution, and only three cells had changes in optimal spatial frequency. Ten cells had a change in contrast threshold, 25 cells had a change in contrast gain, and 29 cells had a change in the maximal response to a high-contrast stimulus. Thus, our results suggest that the tecto-geniculate pathway has little or no effect on spatial processing by LGN neurons. Rather, the major influence is on maximal response levels and the relationship between response and stimulus contrast.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7841117 TI - Behavioral estimates of absolute threshold in rat. AB - Dark-adapted thresholds of albino and pigmented rats were estimated using behavioral methods. Albino and pigmented rats who had been water deprived learned to bar press for water reinforcement when a light stimulus was presented. Absolute threshold was defined to be the light intensity at which bar pressing behavior was significantly modified by the presence of the light stimulus. Albino rats had an average threshold of -5.23 log cd/m2 and the pigmented rats had a threshold of -5.0 log cd/m2. These values are close to -5.3 log cd/m2, the psychophysical threshold of human observers in the same apparatus. Consistent with our earlier electrophysiology, these behavioral experiments provide no evidence for an albino/pigmented sensitivity difference. Comparisons are made between behavioral and electrophysiological determinations of absolute threshold in albino and pigmented rats. Thresholds determined behaviorally agree remarkably well with those derived from visual evoked potentials. PMID- 7841118 TI - A sustained input to the direction-selective mechanism in cat striate cortex neurons. AB - Direction-selective neurons in cat striate cortex were tested with bar-shaped stimuli, sequentially flashed at spatially displaced positions chosen to elicit maximal direction selectivity. Temporally overlapping flash exposures of prolonged duration (400-1000 ms) were employed at a series of onset asynchronies to explore the nature of temporal tuning of the direction-selective mechanism. In most neurons studied, direction selectivity was found to be supported by a surprisingly broad range of stimulus onset asynchronies, which was greater for longer exposure durations. These findings imply the existence of a sustained input to the direction-selective mechanism, in spite of the relatively transient nature of most cortical neurons' step responses. A model is described to illustrate how different front-end temporal filters can affect the dependence of two-flash direction selectivity on stimulus onset asynchrony. The versions of the model which successfully predict the form of the observed responses are those which combine inputs from sustained and transient filters. PMID- 7841119 TI - Nerve growth factor (NGF) uptake and transport following injection in the developing rat visual cortex. AB - Recent investigations have shown that cortical nerve growth factor (NGF) infusions during the critical period inhibit ocular-dominance plasticity in the binocular portion of the rat visual cortex. The mechanisms underlying the effects of NGF on visual cortical plasticity are still unclear. To investigate whether during normal development intracortical and/or extracortical cells possess uptake/transport mechanisms for the neurotrophin, we injected 125I-NGF into the occipital cortex of rats at different postnatal ages. Within the cortex, only a few labelled cells were observed. These cells were confined to the vicinity of the injection site and their number depended on the animal's age at the time of injection. Labelled cells were absent at postnatal day (PD) 10 but could be detected between PD 14 and PD 18. They then decreased in number over the following period and were not detected in adult animals. Outside the cortex, neurons of the lateral geniculate nucleus (LGN) were not observed to take up and retrogradely transport NGF at any age after birth. In contrast, retrogradely labelled neurons were found in the basal forebrain. Labelled cells were first observed here at PD 14 and then increased in number until reaching the adult pattern. Our results show that intrinsic and extrinsic neurons are labelled following intracortical injections of iodinated NGF. In both neuronal populations, the uptake and transport of NGF is present over a period corresponding to the critical period for visual cortical plasticity. These findings suggest that NGF may play a role, both intra and extracortically, in plasticity phenomena. PMID- 7841120 TI - Behavioral evidence of filling-in at the blind spot of the monkey. AB - In human subjects, the blind spot is perceptually filled-in by color and brightness from the surrounding visual field. The present behavioral study examined the occurrence of color filling-in at the blind spot in monkeys. First, the location of the blind spot was determined using a monocular saccade task. The blind spots were located on the horizontal meridian at approximately 15-17 deg from the fixation point in the temporal visual field. Then, filling-in at the blind spot was tested by determining if the monkey could discriminate between an annulus presented on the blind spot and a homogeneous disk in the normal visual field. In this task, the monkey was required to make a saccade to a homogeneous disk of the same color and size as an annulus presented simultaneously in the opposite field. Both stimuli were large enough to cover the blind spot and the inner circle of the annulus was confined inside the blind spot. All four monkeys tested performed this task correctly in over 80% of the trials. However, when one eye was covered and the annulus was presented on the blind spot of the uncovered eye, performance deteriorated significantly. To confirm that these results reflected filling-in, one monkey was trained to maintain fixation when two identical homogeneous disks appeared in opposite visual fields. When only one eye was uncovered, and the annulus was presented on the blind spot of the uncovered eye, the monkey maintained fixation in most of the trials. These results show that monkeys were unable to distinguish an annulus from a homogeneous disk when the annulus was presented on the blind spot. This indicates that color filling-in occurs at the blind spot in monkeys and opens possibility to physiological experiments to study the neural mechanisms of filling-in. PMID- 7841121 TI - Early appearance and transient expression of putative amino acid neurotransmitters and related molecules in the developing rabbit retina: an immunocytochemical study. AB - We have studied, by immunocytochemistry, the ontogeny of GABA, glycine, glutamate, glutamine, and taurine-containing cells in the rabbit retina. Amacrine cells show GABA immunoreactivity by embryonic day 25 (E25) and throughout postnatal life. By contrast, ganglion cells and horizontal cells are only transiently GABA-immunoreactive (-IR); few appear GABA-IR by the third postnatal week. At maturity, glycine is present in amacrine cells and in some bipolar cells. During development, putative ganglion cells transiently contained glycine between E25 and postnatal day 3 (P3), whereas immunolabelling in presumed amacrine cells and bipolar cells persists after birth. Ganglion cells, bipolar cells, photoreceptors, and some amacrine cells are glutamate-IR in the adult retina. Glutamate immunoreactivity first appears in the somata and processes of cytoblastic cells by E20 and is prominent by E25. Surprisingly, ganglion cells are not strongly glutamate-IR until just before eye-opening, at postnatal day 10 (P10), coincident with the appearance of glutamine in their somata and in Muller glial cells. Bipolar cells are glutamate-IR before they or Muller cells contain high levels of glutamine (at P10). Glutamate immunoreactivity in photoreceptors is progressively restricted to the inner segments by eye-opening. At no stage are presumed horizontal cells glutamate-IR or glutamine-IR, but some amacrine cells show glutamate- and glutamine-IR by P10. Taurine is localized to photoreceptors and Muller glial in the adult retina. Some cytoblasts are taurine-IR at E20; with ensuing development, taurine labelling becomes restricted primarily to Muller cells and photoreceptors; some putative bipolar cells may also be labelled. However, for a few days around birth, cells resembling horizontal cells, also show taurine immunoreactivity. The early appearance and often transient expression of these amino acids in retinal cells suggests that these neuroactive molecules may be involved in the structural and functional development of the retina. PMID- 7841122 TI - Cortical potentials reflecting motion processing in humans. AB - Motion processing is a fundamental task of visual systems, and in the monkey cortical areas can be identified which appear to be functionally specialized for motion processing. The human visual system is expected to be organized in a similar way. A noninvasive method to study the functional organization of the visual cortex is the recording of scalp potentials generated by neural activity of the underlying cortical areas. In the present study, we recorded slow cortical potentials from normal subjects in order to investigate how motion stimuli are processed. Three classes of object motion were realized as random dot kinematograms, namely Fourier motion, drift-balanced motion, and theta motion, because they require mechanisms of increasing complexity in order to be extracted. Large-field motion and counterphase flicker were used as control stimuli. Three basic results were obtained: (1) The responses evoked by the three classes of object motion do not differ significantly in their course and distribution of activation. (2) The distributions of cortical activation evoked by object motion, and the control stimuli are different. During object motion the maximum activation occurs over the superior parietal cortex. Large-field motion activates occipital and parietal locations to the same extent, and during counterphase flicker the activity is maximum over the occipital lobe. Thus, the parietal slow potentials are interpreted to specifically reflect the cortical processing of object motion. (3) The time course of the activation reflects changes in the spatial position of the object: the amplitude of a transient negative component (TNC) which occurs 240 ms after motion onset decreases with increasing eccentricity of motion onset. The consecutive sustained negative component (SNC), which persists until the movement stops, decreases during centrifugal and increases during centripetal object motion. These results can be understood on the basis of physiological and anatomical knowledge about the mapping of the visual field on the cortex. PMID- 7841123 TI - A visually elicited escape response in the fly that does not use the giant fiber pathway. AB - A housefly elicits an escape in response to an approaching target (Holmqvist & Srinivasan, 1991). This study tests if the giant fiber pathway, which mediates a light-off escape response in a fruitfly (Wyman et al., 1985), also mediates escape to an approaching target in a housefly. Visual stimuli simulating an approaching or receding dark disk were presented to houseflies, Musca domestica, in both behavioral and physiological experiments. Freely behaving flies escaped in response to an expanding dark disk but not to a contracting dark disk. In restrained flies, the giant fiber, here called the giant descending neuron (GDN), was recorded from intracellularly and the tergotrochanteral muscle (TTM), which provides the main thrust in an escape jump, was recorded from extracellularly. During electrical stimulation of the brain, by means of stimulating electrodes inserted into the ventral part of each compound eye, a single spike in the GDN drives the TTM. However, when the TTM responds to visual stimulation that elicits an escape response in a behaving fly, the GDN shows no activity. Similarly to the behavioral results, the TTM of restrained flies showed muscle potentials in response to an expanding dark disk, but not to a contracting disk. However, freely moving flies elicit escapes more than 100 ms on average before the first TTM spike, suggesting that this type of escape does not start with a jump powered by the TTM. In conclusion, this visually evoked escape response in the housefly is not likely to be mediated by the giant fiber pathway. The findings suggest that there exist at least two pathways mediating visually evoked escape responses in flies. PMID- 7841124 TI - Effects of angiotensin II on visual neurons in the superficial laminae of the hamster's superior colliculus. AB - Superficial layer superior colliculus (SC) neurons were recorded extracellularly with multibarreled recording/ejecting micropipettes. Angiotensin II was delivered via micropressure ejection during visual stimulation (n = 215 cells), or during electrical stimulation of either the optic chiasm (OX; n = 150 cells) or visual cortex (CTX; n = 42 cells). Application of angiotensin II decreased visual responses of SC cells to 43.8% +/- 30.7% (mean +/- S.D.) and reduced responses to electrical stimulation of the OX and CTX to 58.6% +/- 34.1% and 43.8% +/- 30.7% of control values, respectively. Angiotensin II enhanced responses by at least 30% in only 6 cells (1.5%). Of the 35 neurons tested with both OX and CTX stimulation, the correlation of evoked response suppression by angiotensin II was highly significant (r = 0.69; P < 0.001). This suggests that the suppressive effects of angiotensin II were common to both pathways. To test whether the inhibitory effects of angiotensin II were presynaptic or postsynaptic, Mg2+ ions were ejected iontophoretically to abolish synaptic responses, and the neurons were activated by iontophoresis of glutamate and then tested with angiotensin II. Angiotensin II reduced the glutamate-evoked responses to an average 29.1% +/- 21.1% of control values (n = 9 cells). This suggest that the site of action of angiotensin II is most likely postsynaptic. To identify which receptors were involved in these effects, angiotensin II was ejected concurrently with the AT1 antagonist Losartan (DUP753) or with either of two AT2 antagonists, CGP42112A or PD123177. Losartan antagonized the action of angiotensin II in 65.6% of the cells tested (n = 99) and CGP42112A and PD123177 had antagonistic effects in 58% (n = 65) and 60% (n = 5), respectively. Both classes of antagonists were tested in 29 cells; and there was no significant correlation between their effectiveness. These results suggest that both AT1 and AT2 receptors may independently mediate the suppressive effects of angiotensin II, and that collicular neurons may have either or both receptor subtypes. PMID- 7841125 TI - Responses of rod bipolar cells isolated from dogfish retinal slices to concentration-jumps of glutamate. AB - Rod on-bipolar cell light responses are mediated by a class of metabotropic glutamate receptor which is coupled via a G-protein to the control of a cGMP cascade, with cGMP acting to open cation channels, whilst off-bipolar cells possess ionotropic glutamate receptors. Whole-cell voltage-clamp recordings were obtained from on- and off-bipolar cells of dark-adapted dogfish retinal slices, identified by their light responses. Isolated cells were exposed to concentration jumps of glutamate. At negative voltage-clamp potentials, on-bipolar cells responded to glutamate with outward currents with a mean delay of 10.8 ms, whilst off-bipolar cells responded with inward currents without any delay. Neither cell type showed desensitization to applied steps of glutamate. The dose-response relation for on-bipolar cells showed no gradual saturation, but increased linearly with a sharp cutoff above 200 microM glutamate. This dose-response relation could be fitted with a theoretical expression assuming Michaelis-Menten kinetics for the action of glutamate on receptors and a linear relation between the concentration of receptors bound to glutamate and the fall in cGMP this induces. The dose-response relation of off-bipolar cells showed saturation with a limiting slope of 2 at low glutamate concentrations, suggesting that two molecules of glutamate are required to open each channel by a cooperative mechanism. The glutamate receptor coupled cGMP cascade of rod on-bipolar cells can account for high synaptic voltage gain. PMID- 7841126 TI - Glutamate-, GABA-, and GAD-immunoreactivities co-localize in bipolar cells of tiger salamander retina. AB - The presence of inhibitory bipolar cells in salamander retina was investigated by a comparative analysis of the distribution of glutamate- and GABA immunoreactivities (GLU-IR; GABA-IR) using a postembedding immunocytochemical method. GLU-IR was found in virtually all photoreceptors, bipolar cells and ganglion cells, neuronal elements that transfer information vertically through the retina. GLU-IR also was found in numerous amacrine cells in the mid and proximal inner nuclear layer as well as in the cytoplasm of horizontal cells, while the nucleus of horizontal cells was either lightly labeled or not labeled at all. GLU-IR was found in the outer plexiform layer and intensely in the inner plexiform layer, in which there was no apparent sublamination. Forty-seven percent of Type IB bipolar cells in the distal inner nuclear layer and 13% of the displaced bipolar cells were GABA-IR. All bipolar cells were also GLU-IR, indicating that GABA-IR bipolar cells were a subset of GLU-IR bipolar cells rather than a separate population. About 12% of the Type IB bipolar cells were moderately GABA-IR and likely comprised a GABAergic subtype. GLU-IR levels in the presumed GABAergic bipolar cells were higher than in other purely GLU-IR bipolar cells suggesting that these GABA-IR bipolar cells are glutamatergic as well. All of the displaced bipolar cells were only lightly GABA-IR, indicating that displaced bipolar cells comprise a more homogeneous class of glutamatergic cell than orthotopic bipolar cells. GAD-IR co-localized with GABA-IR in orthotopic but not displaced bipolar cells, further supporting the idea that some orthotopic bipolar cells are GABAergic. A small proportion of bipolar cells in salamander retina contain relatively high levels of both GABA and glutamate. Co-release of these substances by bipolar cells could contribute to the "push-pull" modulation of ganglion cell responses. PMID- 7841127 TI - A model for motion coherence and transparency. AB - A recent model for two-dimensional motion processing in MT has demonstrated that perceived direction can be accurately predicted by combining Fourier and non Fourier component motion signals using a vector sum computation. The vector sum direction is computed by a neural network that weights Fourier and non-Fourier components by the cosine of the component direction relative to that of each pattern unit, after which competitive inhibition extracts the signals of the most active units. It is shown here that a minor modification of the connectivity in this network suffices to predict transitions from motion coherence to transparency under a wide range of circumstances. It is only necessary that the cosine weighting function and competitive inhibition be limited to directions within +/- 120 deg of each pattern unit's preferred direction. This network responds by signaling one pattern direction for coherent motion but two distinct directions for transparent motion. Based on this, neural networks with properties of MT and MST neurons can automatically signal motion coherence or transparency. In addition, the model accurately predicts motion repulsion under transparency conditions. PMID- 7841128 TI - A method for determining photoreceptor signal-to-noise ratio in the time and frequency domains with a pseudorandom stimulus. AB - We have developed a method that utilizes repeated sequences of pseudorandomly modulated stimuli for calculation of the SNR either in the time or frequency domains. The method has the advantage that the distribution of SNR over relevant frequencies is readily observed. In addition, a SNR value, calculated as the ratio of the corresponding variances, is an estimate of the true SNR because it has been weighted by the cell's frequency response. The procedure offers significant advantages when studying signal transmission in nonspiking cells like photoreceptors. PMID- 7841129 TI - Reporter gene expression in cones in transgenic mice carrying bovine rhodopsin promoter/lacZ transgenes. AB - Rhodopsin gene expression has been used as a model system to study the mechanisms regulating photoreceptor gene expression. Previous transgenic experiments using rhodopsin promoter/lacZ fusion constructs identified some of the cis-acting DNA elements responsible for photoreceptor cell-specific expression. However, the issue of rod specificity vs. photoreceptor (rod and cone) specificity of the elements was not resolved. To address this issue, the specificity of reporter gene expression in the retinas of transgenic mice carrying bovine rhodopsin promoter/lacZ (beta-galactosidase) fusion genes was assessed using X-gal staining and electron microscopy. Two independent transgenic lines, one carrying a rhodopsin promoter fragment extending from -2174 to +70 base pairs (bp) relative to the messenger RNA start site and another line carrying a fragment from -222 to +70 bp, both showed reporter gene expression in cones as well as rods, although the level of staining appeared to be less in the cones than in the rods. These results demonstrate that the -2174 to +70 bp and -222 to +70 bp bovine rhodopsin promoter fragments are not rod-specific in transgenic mice and indicate that the existence of rod promoter mediated-expression in cones must be considered when interpreting results from transgenic experiments utilizing the rhodopsin promoter. PMID- 7841130 TI - 1st International workshop on cell membrane pathology in schizophrenia. Augusta, Georgia, 30-31 March 1993. Proceedings. PMID- 7841131 TI - A new paradigm for schizophrenia? PMID- 7841132 TI - The membrane hypothesis of schizophrenia. AB - The phospholipid structure of neuronal membranes is essential for normal functioning of the nervous system. Evidence is accumulating that phospholipid metabolism in both brain and red blood cells may be disturbed in schizophrenia. In particular, in patients with negative symptoms, levels of arachidonic acid and docosahexanoic acid in red blood cell membrane phospholipids are severely abnormal. The membrane hypothesis of schizophrenia may represent a new and fruitful paradigm for future research. PMID- 7841133 TI - Membrane phospholipid metabolism and schizophrenia: an in vivo 31P-MR spectroscopy study. AB - Membrane phospholipid metabolism was studied with 31P magnetic resonance spectroscopy in the left dorsal prefrontal cortex of 19 male, medicated, schizophrenic patients and compared to 18 normal male controls matched in age, education and parental education level. The schizophrenic patients had significantly decreased phosphomonoester levels (PMEs, metabolites predominantly involved in the synthesis of membrane phospholipids). Phosphodiester levels (PDEs, breakdown products of membrane phospholipids) were not statistically different in schizophrenic patients compared to controls. However, a significant increase in the PDE levels was observed in the newly diagnosed patient subgroup. This observed pattern of the PMEs and PDEs would be consistent with the presence of an abnormal neurodevelopment early in the illness of schizophrenia. PMID- 7841134 TI - Red blood cell membrane dynamics in schizophrenia. II. Fatty acid composition. AB - Fatty acid compositions were determined in red blood cell (RBC) ghost membranes of schizophrenic patients before and after haloperidol withdrawal, as well as with age-matched normal male control subjects (n = 22). Patients on haloperidol (HD) received treatment in doses between 5 and 20 mg/day for at least 5 weeks (n = 24). Drug-free patients (n = 19) were free of all psychotropic medications for an average of 40 days. A highly significant decrease in the levels (nmol/ml packed RBC) of polyunsaturated fatty acids (PUFAs), particularly 18:2(n - 6) and 20:4(n - 6), was found in both HD-treated and drug-free patients. This decrease remained in those patients who had withdrawn from HD for more than 5 weeks (n = 10). Concomitantly, the percentage of saturated and monoenoic fatty acids to total fatty acids increased significantly in schizophrenic patients. The resultant fatty acid profile consequently lowers the unsaturation index (UI), which represents the average number of double bonds per fatty acid molecule, in RBC ghost membranes of schizophrenic patients. Furthermore, the decreases in UI were significantly correlated to the increases in "structure order" of RBC ghost membranes as measured by the steady-state fluorescence anisotropy (rs) in normal control and drug-free schizophrenic subjects. Therefore, it is likely that decreased levels of PUFAs in schizophrenic patients might result from a defective uptake of 18:2(n - 6) into RBC membrane phospholipids. Since fatty acid composition of membrane phospholipids affects the relative degree of membrane fluidity, the present results lend further support that RBC membrane dynamics are altered in schizophrenia. PMID- 7841135 TI - Red blood cell membrane dynamics in schizophrenia. III. Correlation of fatty acid abnormalities with clinical measures. AB - Fatty acid composition was quantitatively analyzed in RBC ghost membranes of 20 schizophrenic patients stabilized with haloperidol (5-20 mg/day) and of the same individuals after haloperdol (HD) withdrawal. The average days on medication and drug-free period were 52 and 40 days, respectively. No significant differences were demonstrated in levels (% or nmol/ml packed RBC) of polyunsaturated fatty acids (PUFAs) between HD-treated and drug-free patients. Similarly, no significant difference was found between relapsed and nonrelapsed schizophrenic patients, although the mean levels of 20:4 (n - 6), total PUFAs or fatty acid unsaturation index (FAUI) were consistently higher in nonrelapsers than in relapsers. On the other hand, the decreases in FAUI were significantly (r = 0.46, p = 0.04) correlated to the increases in psychosis rating which is consistent with our previous reported correlation between altered membrane fluidity and the severity of symptomatology. In addition, decreases in 18:2 (n - 6) but not 20:4 (n - 6) was significantly correlated to the increases in psychosis rating. The present results lend further support that decreased levels of RBC PUFAs in schizophrenic patients lie in an initial stage of PUFAs pathway, possibly a defective uptake of 18:2 (n - 6) into RBC membranes. PMID- 7841136 TI - Abnormal growth of cultured skin fibroblasts associated with poor premorbid history in schizophrenic patients. AB - The relations of abnormal growth of cultured skin fibroblasts, as manifest in prolonged doubling time, and a history of impaired childhood premorbid functioning, separately for social and school (instrumental) functioning were examined in 22 schizophrenic patients. Prolonged doubling time (> 2 weeks) was significantly associated with poorer childhood social functioning, even after controlling for variance due to age, sex, race, and age at onset of illness. Doubling time was not associated with school performance scores. The findings indicate that the cellular or molecular process(es) underlying abnormal growth of skin fibroblasts may be involved in, or associated with, aberrant biological processes that contribute to early dyssocial behavior in schizophrenic patients. PMID- 7841137 TI - Plasma membrane phospholipid and cholesterol distribution of skin fibroblasts from drug-naive patients at the onset of psychosis. AB - Contents of plasma membrane major phospholipids, cholesterol, and cholesteryl esters of fibroblasts from drug-naive psychotic patients were compared with those from normal controls. Total membrane lipids were extracted and individual lipids were separated on high-performance thin-layer chromatography. The contents of lipid bands were quantitated by densitometric scanning and comparing with standards. Contents of total phospholipids as well as phosphatidylserine, phosphatidylinositol and phosphatidylethanolamine were significantly lower in fibroblasts from patients than in those from normal controls (P < 0.001, < 0.005, < 0.05 respectively). Total cholesterol fraction and cholesteryl esters were also significantly lower in fibroblasts from patient (P < 0.005, < 0.001 respectively). These changes were not related to differences in age or sex. These data support the hypothesis that schizophrenia is associated with disordered membrane lipid metabolism, and that this predates the onset of psychosis. PMID- 7841138 TI - Role of polyamines in the membrane pathology of schizophrenia. A study using fibroblasts from schizophrenic patients and normal controls. AB - The polyamines putrescine, spermine, and spermidine play a major role in the regulation of cell growth and differentiation, metabolic pathways, and on cell membrane functions in mammalian systems. It has recently been suggested that polyamines may be involved in the pathophysiology of schizophrenia. Moreover, several reports suggest that schizophrenia may be associated with a generalized cell membrane abnormality. In view of these findings, we measured polyamine levels in cultured skin fibroblasts from schizophrenic patients and normal control subjects. These was a significant increase in the levels of spermidine and in total polyamines in fibroblasts and spermine in the culture medium from schizophrenic patients. This preliminary report suggests that polyamines may play an important role in the membrane abnormalities that have been reported in schizophrenic patients. PMID- 7841139 TI - Tyrosine transport in schizophrenia. AB - Tyrosine transport was examined in cultured skin fibroblasts from patients with schizophrenia (DSM-III-R) and normal subjects. The transport capacity (Vmax) was lower in the patients. The results confirm previous findings of decreased tyrosine transport in schizophrenia. In cells incubated with psychotropic drugs at different concentrations, tyrosine transport was not differentially influenced across patients and normal subjects. Dopaminergic and beta-adrenergic receptor mechanisms did not seem to influence tyrosine uptake. There seems to be a primary disturbance of tyrosine transport in schizophrenia which indicates a generalized cell membrane dysfunction. PMID- 7841141 TI - Polyimide-polyethylene glycol block copolymers: synthesis, characterization, and initial evaluation as a biomaterial. AB - Block copolyimides with varying amounts of polyethylene glycol (PEG) were synthesized and characterized by copolymerization of diaminodiphenyl ether (DDE), amino terminated PEG, and benzophenone tetracarboxylic acid dianhydride (BTDA). Strong materials were obtained, with enhanced flexibility as compared to the parent DDE-BTDA polyimide homopolymer. Incorporation of PEG led to an increase in water absorption by these copolymers, and hydrophilicity was increased as reflected by a decrease in air-water-polymer contact angle. These materials supported less cell adhesion in vitro than the parent polyimide homopolymer. Short term in vivo evaluation of these copolymers showed reduced fibrous encapsulation than was observed in the absence of PEG. PMID- 7841140 TI - Neuronal development in embryonic brain tissue derived from schizophrenic women and grafted to animal hosts. AB - The distribution of schizophrenia in families supports the hypothesis of heritable risk factors in schizophrenia, but there is as yet no identification of an inherited neurobiological defect. Human embryonic brain tissue fragments, derived from first trimester abortions, can be transplanted into rat hosts, where they continue neuronal development and are accessible for neurobiological investigation. Hippocampal transplants derived from three schizophrenic women and a larger series of normal women have been studied. If there are heritable neuronal defects associated with schizophrenia, a proportion of the transplants from schizophrenic women would be expected to carry these defects. The transplants from the first two schizophrenic women showed profound abnormalities in survival and growth, compared to the series of transplants from normal women. The transplants from the third schizophrenic woman showed normal growth and development, as well as typical histological and electrophysiological features. The data must be regarded as preliminary, because of the small number of subjects that have been studied. However, they are consistent with the transmission of a defect in neuronal development to some of the offspring of schizophrenic women, a possibility consistent with other studies of the pathogenesis of schizophrenia. The mechanism of the defect in development remains to be identified. PMID- 7841142 TI - Receptor-mediated regulation of differentiation and proliferation of hepatocytes by synthetic polymer model of asialoglycoprotein. AB - Morphology and responses of hepatocytes are investigated using an artificial asialoglycoprotein model polymer--lactose-carrying polystyrene (PVLA) as a culture substratum, especially in focusing on the effect of the surface density of the PVLA substratum. The surface density of PVLA on polystyrene dishes was determined using fluorescein-labeled PVLA as a probe under a fluorescence laser microscope. PVLA-coated surfaces were observed by scanning electron microscope and atomic force microscopies under air and water, which showed that PVLA molecules were adsorbed patchily on low density surfaces and uniformly concentrated all over the dish on high density surfaces. It is suggested from the requirement of the Ca2+ ion, inhibition of galactosyl substances, and localization of receptors that the adhesion of hepatocytes to both low and high PVLA-density surfaces is mediated by galactose-specific interactions between PVLA and asialoglycoprotein receptors. At low PVLA densities (0.07 micrograms cm-2), the hepatocytes were flat and expressed high levels of 3H-thymidine uptake and low levels of bile acid secretion. Contrastingly, at high PVLA densities (1.08 micrograms cm-2), they were round and expressed a low level of 3H-thymidine uptake and a high level of bile acid secretion. The shapes, proliferation, and differentiation of hepatocytes could be regulated by varying the densities of PVLA adsorbed to polystyrene dishes. We assume that there are two recognition mechanisms operating between PVLA and hepatocytes: (1) adhesion through highly concentrated or clustered galactose-specific interaction; and (2) responses in shape, proliferation, and differentiation by PVLA-coating densities. PMID- 7841143 TI - Surface and bulk effects on platelet adhesion and aggregation during simple (laminar) shear flow of whole blood. AB - This study attempts to clarify the role of the artificial surface and the fluid bulk on platelet adhesion and aggregation events during simple shear flow of whole blood. The experimental approach involved the shearing of fresh whole blood samples over the shear rate range of 720-5680 s-1, which corresponded to a shear stress maximum of about 150 dyn cm-2. Results on platelet adhesion, measured as surface coverage by platelets, and platelet aggregation, measured in terms of reduction in platelet count and adenosine diphosphate (ADP) release, were determined as a function of the surface to volume ratio (S/V); and artificial surface used. Both shear-induced platelet adhesion and platelet count reduction showed significant variation over the range of S/V employed. The ratios between the three different S/V values used in this system (10:6:4) were about the same as the ratio of the shear rate-averaged results obtained. Also, for shear-induced hemolysis, an increase in the release of hemoglobin from red blood cells was found as S/V was increased, again with ratios between the shear rate-averaged values similar to the ratio of S/V values employed. The shear-induced release of ADP, presumably from platelets and from red blood cells indicated a different dependence of ADP release on S/V than was observed for the other parameters reported. Irreversible platelet aggregation was expected to occur because the amount of ADP that was released as a result of the shear was substantial. Models proposed to explain the experimental results were found to support a surface controlled mechanism. PMID- 7841144 TI - Oxidative degradation of Biomer fractions prepared by using preparative-scale gel permeation chromatography. AB - The possibility that some macromolecular chains within a chemically heterogeneous polyether-urethane (PEU) may be more susceptible to degradation than others has been investigated. Preparative scale gel permeation chromatography has been used to separate chemically different fractions of a sample of the commercial PEU, Biomer. The fractions were characterized and then tested for susceptibility to oxidative degradation by exposing them to hydrogen peroxide. After exposure to hydrogen peroxide, the samples were analyzed using high pressure gel permeation chromatography (HPGPC), Fourier transform infrared spectroscopy (FTIR), and X-ray photoelectron spectroscopy (XPS). By using these methods, we were able to identify chemical changes in some of the Biomer fractions but not in others. Clear differences in the chemistry and reactivity of the fractions were observed. Changes in the weight average molecular weight varied from a decrease of 55.8% to an increase of 3.9%. A decrease in hard segment content at the surface and in the bulk was observed in some samples, but opposite trends were observed in others. The evidence suggests that there may be a number of mechanisms by which hydrogen peroxide can react with PEUs. Some fractions separated from the Biomer were not significantly affected by concentrated hydrogen peroxide solutions. This suggests an intrinsic stability in some PEUs and points the way to the development of more degradation-resistant PEUs. PMID- 7841145 TI - Evidence for Fickian water transport in initially glassy poly(2-hydroxyethyl methacrylate). AB - Water sorption which is not classically Fickian has been observed in a variety of polymers. Deviation from Fickian kinetics is widely assumed to be caused by rate limiting polymer relaxation, despite minimal proof of this. To the contrary, the evidence accumulated in this work indicates that water transport in initially glassy poly(2-hydroxyethyl methacrylate) (PHEMA), an important water-swellable biomedical polymer, is controlled by Fickian diffusion. First of all, the fractional water uptake is initially linear and independent of sample thickness when plotted against the square root of time over initial thickness, as expected for a Fickian process. Furthermore, the moving solvent front also advanced with the square root of time. Temperature, polymer thermal history and initial solvent concentration all affected the sorption kinetics of PHEMA in manners consistent with a Fickian process. The invariably Fickian sorption mechanism is believed to be the consequence of the water molecule's small size and affinity for hydrophilic, swellable polymers. PMID- 7841146 TI - Controlled release systems for proteins based on gelatin microspheres. AB - The preparation and characterization of biodegradable gelatin microspheres for the controlled release of peptides and proteins has been investigated. Bovine serum albumin (BSA) was chosen for incorporation into the gelatin microspheres and the spheres were characterized for the in vitro release of BSA and other properties. BSA was labelled with fluorescein isothiocyanate (FITC) for easy analysis. FITC-BSA was entrapped into the gelatin microspheres using a polymer dispersion technique developed in our earlier studies. The morphological characteristics of microspheres were analysed by optical and scanning electron microscopy (SEM). The optical and SEM photographs of FITC-BSA microspheres showed the solid spherical nature of the spheres. The entrapment efficiency of FITC-BSA was about 62%. The in vitro release pattern of FITC-BSA showed that 51% of the entrapped drug was released during the first day and the release followed approximate zero order kinetics from day 2 onwards. The total release of FITC-BSA lasted for about 8 days. SDS-PAGE analysis revealed that BSA was not degraded by this preparation of microspheres. PMID- 7841147 TI - The effect of shear rate on the adhesion/activation of human platelets in flow through a closed-loop polymeric tubular system. AB - Three polymers, produced as reference materials of a European Communities program, namely PE, PP, and PVC, in tubular form, were comparatively evaluated for their hemocompatibility. In particular, the following parameters: platelet retention index, beta-thromboglobulin (beta-TG) release from activated platelets, and expression of the platelet protein GMP 140 (PADGEM) were measured as a function of time for whole anticoagulated human blood flowing in a closed-loop system under two different shear rates of 2000 and 500 s-1. Data up to 20 min (afterwards there was hemolysis) showed a fluctuating platelet retention index as time increased for PE and PVC and an increasing value for PP. Platelet aggregation and dislodgment from the surface could not be differentiated. Activation of platelets as expressed with beta-TG release were higher for both PE and PP in both shear rates in comparison to PVC which elicited a higher response at the high shear rate. Finally, PADGEM estimations seem to indicate a more stable platelet retention layer for PP than PE or PVC. PMID- 7841149 TI - Protein adsorption behaviour of ionogenic poly(HEMA) membranes: a fluorescence study. AB - A series of ionogenic poly(HEMA) membranes which were prepared by bulk copolymerization of 2-hydroxyethylmethacrylate (HEMA) and anionic or cationic comonomers, acrylic acid (AA), and dimethylaminoethylmethacrylate (DMAEMA), were characterized by equilibrium swelling measurements, surface free energies, and protein adsorption studies. It was found that their equilibrium water content (EWC) values are greater than 40% which increases with increasing comonomer concentration. That is why the surface free energy is approximately the same (approximately 60 erg cm-2) for all surfaces and does not depend mainly on the composition of the polymer matrix. The adsorption of two plasma proteins that have received much attention, i.e. BSA and fibrinogen, on these membranes was followed by fluorimetric measurements as a function of time. The uptake of proteins from dilute solutions appeared to be directly related to the type and density of surface charge, and also structural properties of the proteins. PMID- 7841148 TI - Copolymers of 1,5-dioxepan-2-one and L- or D,L-dilactide: in vivo degradation behaviour. AB - Copolymers of 1,5-dioxepan-2-one (DXO) and L- or D,L-dilactide have been synthesized and characterized. The molar ratio of the two monomers was around 20/80 of DXO and L- or D,L-lactide respectively. In vivo studies on rats revealed significant differences in tissue response between the semicrystalline DXO/L-LA copolymer and the amorphous DXO/D,L-LA copolymer. The materials were characterized pre- and post-implantation by size-exclusion chromatography (SEC), differential scanning calorimetry (DSC), nuclear magnetic resonance (NMR), and light-microscopy. Degradation seems to follow an autocatalytic hydrolysis mechanism. The amorphous copolymer was degraded at a faster rate and gave a less pronounced foreign body reaction as compared to the semicrystalline one. PMID- 7841150 TI - The effect of site of implantation and animal age on properties of polydioxanone pins. AB - Absorbable polymeric orthopaedic pins (Orthosorb) of 2.0 mm diameter were implanted at different sites in mature (3.5 kg, > 5 months) and immature (5 weeks old) rabbits (total 36) for 2, 4, and 5 weeks. The sites of implantation were the medullary canal of the femur, muscles of the thigh and subcutaneous tissue of the dorsum. In mature rabbits, 1.3 mm diameter pins were also implanted in the medullary canal of the femur. The shear strength of the pins harvested from the rabbits, was measured at each time period using a fixture that shears the pins into three parts symmetrically about the load axis. In both mature and immature rabbits the rate of degradation in mechanical properties was higher in the medullary canal of bone than in the muscle and in the subcutaneous tissue (p < 0.05). The strength retention was lower in immature than in mature rabbits after 4 and 5 weeks. The 1.3-mm pins had higher initial strength (174.7 +/- 7 MPa), higher strength retention and slower degradation within the medullary canal of femur of mature rabbits as compared to the 2.0-mm pins (157.5 +/- 4.8). DSC and X ray diffraction results of control and implanted pins showed higher initial crystallinity and a wider range of crystallite size in the 1.3-mm pins. After 5 weeks in vivo, the crystallinity increased indicating degradation within the amorphous phase. The smaller crystallites underwent recrystallization to form larger crystallites. The results indicate that site of implantation and age of recipient influence the degradation and associated effects on mechanical properties of absorbable implants. The size of the implant, though important in determining its properties, should be considered in association with its microstructure, which also plays an important role in determining strength and strength retention of absorbable polymeric systems. PMID- 7841151 TI - Effect of methylene chain length in phospholipid moiety on blood compatibility of phospholipid polymers. AB - To investigate the effects of the methylene chain length between the phospholipid polar group and the backbone on blood compatibility of a phospholipid polymer, copolymers of omega-methacryloyloxyalkyl phosphorylcholine (MAPC) with n-butyl methacrylate (BMA) were synthesized. The methylene chains were ethylene (n = 2), tetramethylene (n = 4), and hexamethylene (n = 6). Every MAPC copolymer with an MAPC mole fraction in the range of 0.1-0.3 was soluble in ethanol but only swelled in water, and the equilibrium water fraction of the water-swollen MAPC copolymer membrane decreased with the length of the methylene chain. When a rabbit platelet-rich plasma was applied on the MAPC copolymer surface with an 0.1 MAPC mol fraction for 180 min, the number of adhered platelets depended on the length of the methylene chain in the MAPC moiety of the copolymer. The amount of phospholipid adsorbed on the MAPC copolymer from human plasma was larger than that on hydrophobic poly(BMA) and increased with the length of the methylene chain in the MAPC moiety. That is, the reduction of platelet adhesion corresponded to the increase in the amount of phospholipid adsorbed on the MAPC copolymer. PMID- 7841152 TI - Cellular distribution of polymer particles bearing various densities of carbohydrate ligands. AB - The density effect of carbohydrate-ligands on nanometer-order particles (nanoparticles) upon cellular binding and internalization was investigated. Poly(vinylbenzyl-beta-D-lactonamide) (PVLA), a beta-galactose-carrying styrene homopolymer, was employed as a model ligand for the asialoglycoprotein receptors on hepatocytes. In order to control the surface ligand densities on the particles, PVLA was mixed with poly(vinylbenzyl-D-gluconamide) (PVGA), a PVLA analog without beta-galactose, and their mixtures were used as surface coatings. The particles with low ligand densities associated more with hepatocytes than high ligand density particles. The surface density of the ligand considerably influenced the cellular distribution. Most of the particles bearing high densities of ligands were found inside the cells, whereas particles with low ligand densities were found on the plasma membrane surface of the hepatocytes. These results were indicative of high densities of ligands on the surface requiring hepatocytes to internalize the particles promptly by receptor-mediated endocytosis, while low densities of ligands on the surface was not sufficient to internalize, but allowed particles to bind on the cell surface. These findings enabled us to regulate cellular distributions of particles by controlling ligand density on the surface. PMID- 7841153 TI - Formation of protein multilayers and their competitive replacement based on self assembled biotinylated phospholipids. AB - Based on specific recognition processes the build-up of protein multilayers was achieved using streptavidin layers as a docking matrix. For this purpose, streptavidin was organized at biotin-containing monolayers, liposomes, and self assembled layers on gold. Thus, mixed double and triple layers of streptavidin, Con A, Fab fragments, and hormones were prepared and characterized by fluorescence microscopy and plasmon spectroscopy. Using biotin analogues with lower binding constants several cycles of multilayer formation followed by competitive replacement could be achieved. PMID- 7841154 TI - Increased number of dendritic epidermal T cells associated with induced anagen phase of hair cycles. AB - With the use of immunofluorescent staining we investigated the number and the morphologic and phenotypic changes of murine dendritic epidermal T cells (DETC) at various phases of the hair cycle that were synchronized by depilation. The epidermis on day 1 after depilation contained a small number of DETC, round DETC populated at perifollicular space on day 7, and then a large number of DETC with conspicuous dendrites were found mainly at interfollicular space on day 10. This suggests that the in situ proliferation of DETC may be correlated at least partly to the hair cycle, and that hair follicles, which are major skin appendages, may be involved in cutaneous immunity. PMID- 7841155 TI - Raised beta-endorphin serum levels in children with atopic dermatitis and pruritus. AB - Atopic dermatitis (AD) is a pruritic cutaneous inflammatory condition. As pruritus and pain are very close symptoms, we determined the beta-endorphin serum concentrations in 21 atopic children with pruritus (group A) and 20 children with healed AD without pruritus (group B). Twenty-five healthy school children were the control group. The beta-endorphin serum concentrations (14.95 +/- 2.75 pmol/l) in group A were statistically (P < 0.001) elevated in our patients compared to controls (8.85 +/- 2.39 pmol/l) whereas these in group B were not elevated (9.4 +/- 2.46 pmol/l). We suggest that the elevated beta-endorphin concentrations in atopic patients with pruritus confirm the hypothesis that there is an increased activity of their opioid system and that an opioid antagonist might block itching which is their major clinical symptom. PMID- 7841156 TI - Anxiety, depression, psychosomatic symptoms and autonomic nervous function in patients with chronic urticaria. AB - Most reports on the psychological analysis of chronic urticaria have concentrated on psychodynamic theories of causation of the disease. For the present study, we used three kinds of psychological tests as well as electrocardiography to estimate anxiety, depressiveness, psychosomatic symptoms and autonomic nervous functions in 30 outpatients with chronic urticaria and 39 normal controls. For evaluation we used the manifest anxiety scale (MAS), self-rating depression scale (SDS), Cornell medical index (CMI) and convergence of variance of R-R interval (CVR-R). Psychologically positive responses to any one of the tests were seen in 70.0% of the chronic urticaria patients, but in only 25.6% of the controls. These differences all showed statistical significance (P < 0.01). The In(CVR-R) (Y) and age (X) suggested a linear regression, but although the regression slope was steeper for the urticaria group (Y = 2.924-0.027X) than for the controls (Y = 2.702-0.023X), the difference was not statistically significant. These data indicate that patients with chronic urticaria are more anxious, depressive and psychosomatic symptom-prone than normal controls. In conclusion, we suggest that chronic urticaria patients should be diagnosed and treated both dermatologically and psychologically. PMID- 7841157 TI - High calcium induces heat shock proteins 72 and 60 in cultured human keratinocytes: comparative study with heat shock and sunlamp light irradiation. AB - Expression/induction of the 72 and 60 kDa heat shock proteins (HSPS 72 and 60) in cultured human keratinocytes by high calcium was studied with immunofluorescent staining and the flow cytometric method. Normal human keratinocytes cultured in serum free, low calcium medium (Ca2+, 0.1 mM) at 3-passage weakly expressed HSP 60, but not HSP 72, as fine granules in the cytoplasm. HSP 72 was induced in the perinuclear cytosomal area and then in the nucleus after transferring the cells in high calcium medium (Ca2+, 1.8 mM). Whereas the nuclear accumulation began to decrease 24 h after the treatment, the perinuclear cytosomal staining continued. High calcium also augmented the expression of HSP 60 as coarse granules in the cytoplasm. Flow cytometric analyses quantitatively revealed the induction of HSP 72 and the upregulation of HSP 60 by high calcium treatment. Our results clearly demonstrated that extracellular calcium concentration modifies the level of expression of HSP 72 and 60 in normal human keratinocytes, indicating the importance of the careful attention to medium condition in evaluating the expression of HSPS 72 and 60 in cultured keratinocytes. PMID- 7841158 TI - Soluble intercellular adhesion molecule-1 (sICAM-1) in atopic dermatitis. AB - The serum levels of soluble intercellular adhesion molecule-1 (sICAM-1) were determined by enzyme-linked immunosorbent assay, in 88 patients with atopic dermatitis (AD), 29 patients with eczematous dermatitis (ED) and in 33 healthy controls. The sICAM-1 levels were significantly higher in both AD and ED patients than in normal individuals. The longitudinal study of patients with AD revealed a significant decrease in the levels of sICAM-1 (P < 0.05) with improvements in disease activity. In AD patients, the sICAM-1 level correlated significantly with the total numbers of leukocytes and lymphocytes (P < 0.01 and P < 0.05, respectively), whereas no such correlation was found in patients with ED. Our studies show that the levels of sICAM-1 may be a useful immunologic parameter for monitoring disease activity in some of the individuals with AD. PMID- 7841159 TI - Malignant schwannoma in a case of type 1 neurofibromatosis with decreased immunoreactivity of smooth muscle alpha-actin in tumor vessels. AB - A malignant schwannoma in the left calf of a 37-year-old man with type 1 neurofibromatosis is herein reported. Since it is known that capillaries in benign neurofibromas are accompanied by hypertrophic pericytes expressing an abundant amount of smooth muscle alpha-actin (SMAA), we examined the immunohistochemical reactivity of SMAA within this malignant tumor and then compared it with that in surrounding benign areas. In the nests of malignant cells, decreased SMAA staining was found in the capillary walls. In the benign tissues around the malignant tumor, various extents of SMAA could be visualized in the vessels and myofibroblasts. Platelet-derived growth factor (PDGF) was also detected in the tumor, suggesting that cytokines secreted by malignant cells may have an influence on the expression of SMAA as well as on the alteration of the structure of blood vessels. PMID- 7841160 TI - Longitudinal forces acting on a knitted polyester arterial prosthesis when implanted as a thoracic aorta substitute in the dog. AB - The longitudinal forces under which arterial prostheses are held in situ are of great importance. The tension caused by the longitudinal force may be one of the factors involved in the formation of anastomotic false aneurysms. In order to measure the changes in the longitudinal force at both proximal and distal end-to end anastomoses over different periods of implantation, we devised an experimental study in which the changes in length of a warp-knitted polyester VP1200K (Vascutek Ltd., Inchinnan, Scotland) arterial prosthesis, used as a thoracic aorta substitute in the dog, were recorded photographically at implantation and removal. The longitudinal forces acting at the two sites were then calculated using a linear relationship between the longitudinal force and the changes in length of a virgin prosthesis, which was found experimentally in vitro using a computerized laser calibration system. One-tailed Student's t-test showed no significant difference between the length indicator values at the two anastomotic sites at different periods of implantation except during the 1-month period. Textile analysis of the explanted prostheses and histopathologic observations confirmed this similar behavior at the two anastomotic sites. These observations were contrary to the theoretic prediction regarding the effect of forces applied by drag and tissue ingrowth. Nevertheless, analysis of variance confirmed that there was no difference evident at the two sites between different implantation periods. These observations may explain why the formation of anastomotic false aneurysms is less common at end-to-end anastomoses. PMID- 7841161 TI - Fresh venous allografts as arterial substitutes in dogs: the importance of donor recipient tissue compatibility. AB - Fresh venous allografts were investigated in dogs matched according to donor recipient tissue compatibility, either originating from the same litter or chosen at random (pound dogs). Five centimeter long segments of femoral vein were interposed as carotid substitutes in an autografting and allografting manner between paired dogs. During a 5-month implantation period, donor-specific antibody development was measured in the recipient serum by a flow-cytometric assay using cultured donor vascular endothelial cells. Autografts and allografts were investigated in terms of patency, histopathology, and endothelial cell function. Fifteen of 16 autografts remained patent. Allografts between littermate dogs, whether compatible or incompatible, showed no donor-specific antibody development and were all patent at retrieval. Compatible and incompatible allografts in littermates did not show any difference in prostacyclin (PGI2)/thromboxane A2 (TXA2) ratios. In pound dogs, both compatible allografts were patent and one dog developed donor-specific antivascular endothelial cell antibodies. Among incompatible dogs, antibody formation was detected at 1 month in five of six recipients and graft patency was as follows: two partial thromboses, two stenoses, and two patent grafts. The PGI2/TXA2 ratio was significantly lower in incompatible allografts than in compatible ones (p = .028). These results show the importance of donor-recipient histocompatibility matching in improving the outcome of vein allografts. PMID- 7841162 TI - Experimental animal model for readhesion formation study. AB - The problem of postoperative adhesions remains unsolved. The formation of readhesions after tubal reconstructive surgery reduces the success rate. We have developed a modified uterine horn model in the rat to study the influence of peritoneal transplants on readhesion formation. A total of 58 rats were operated. In 25 animals (group III) the uterine horn was scratched on both sides and then sutured together. During relaparotomy 14 days later the tight connection between both sides was cut. The resulting defect was covered by a peritoneal transplant on one side (group IIIb) and was left open on the control side (group IIIa). After 14 days the presence or absence of adhesions was explored. There was a significant difference (p < .001) between the covered (28%) and uncovered (84%) peritoneal defects with respect to incidence of adhesions. To compare the different characteristics of visceral and parietal peritoneum, a pelvic sidewall defect was induced in 33 animals. There was no significant difference between covering the defect by a peritoneal transplant (group II; 42.9%) and the control side (group I; 33.3%). These data suggest that defects on visceral peritoneum should be closed to prevent adhesion formation. The incidence of adhesions after injury of parietal peritoneum seems to be much lower and of less clinical significance. PMID- 7841163 TI - The immature goat as an animal model for Legg-Calve-Perthes disease. AB - Legg-Calve-Perthes disease (LCPD) results from avascular necrosis of the capital femoral epiphysis in growing children. This disease often yields a significant deformity of the proximal femur, which may result in osteoarthritis. Its cause is unknown, although extensive radiographic, clinical, and histologic evaluations have been performed. Attempts at developing an animal model for LCPD have been unsuccessful. Previous models have been based predominantly on determining the vascular etiology of the disease. There is a need for an animal model that mimics the growth pattern of the proximal femur seen in LCPD. Such a model would allow for the development and testing of new treatments. Thus far, no treatment strategy has been completely successful. A study involving graphic analysis of radiographs found that arrested anterolateral physeal growth with continued or accelerated perichondrial ring and posteromedial epiphyseal growth would account for the most severe morphologic changes observed in the femoral heads of patients with LCPD. A surgical procedure was performed to ablate the capital femoral physis in goat kids in an attempt to mimic the changes noted in this study. The procedure was evaluated with radiographs, gross specimens, and histopathologic slides. Graphic analysis of the radiographs revealed changes in the shape of the operated femoral head compared with the unoperated femoral head. While bone, fibrous, and fibrocartilaginous bridges were histologically observed across the physis, the resultant deformities did not mimic the changes identified in the graphic analysis study, perhaps because of inconsistencies in the surgical ablative techniques, which will require further modification. This study provides the basis for further research to develop a successful model. PMID- 7841164 TI - Effect of hyaluronic acid solution on healing of bowel anastomoses. AB - Hyaluronic acid (HA) solution has the ability to coat and lubricate serosal surfaces, and potentially prevent serosal trauma during surgery, which can result in the postoperative formation of adhesions in the abdomen. Previous animal studies utilizing HA have shown a reduction of intra-abdominal adhesion formation. Human clinical trials are currently underway. The prevention of adhesions could conceivably have deleterious effects on bowel anastomosis healing. As a result, solutions of HA were studied in rabbits to determine their effect on the healing of a bowel anastomosis. In 30 rabbits, test solutions of either HA (0.4 or 1.0%) or phosphate-buffered saline (PBS) as a control were instilled into the open peritoneal cavity just prior to the performance of small bowel anastomosis. At sacrifice 14 days later, intestinal bursting pressures were 110.5 +/- 16.0 mm Hg (SEM) in the PBS group, 108.5 +/- 15.2 mm Hg in the 0.4% HA group, and 138.7 +/- 14.1 mm Hg in the 1.0% group. Average bursting pressures among the three groups did not vary significantly (p > .05). Small sterile mucoceles formed at the anastomosis in 70% of the PBS group, in 10% of the 0.4% HA group, and in 30% of the 1.0% HA group. Histologic examination of specimens taken at the anastomosis did not reveal any differences in the level of healing between groups. HA solution, when instilled in the presence of a small bowel anastomosis in rabbits, does not appear to interfere with the healing process. PMID- 7841165 TI - A new model for posttraumatic osteomyelitis in rabbits. AB - A new animal model for posttraumatic osteomyelitis was designed. This model mimics the pathogenesis of the human disease more accurately than models presently available. Femora of New Zealand white rabbits were exposed at the greater trochanter and a stainless steel rod was inserted into the marrow cavity. A Staphylococcus aureus suspension was placed in and around a bone defect, which was drilled midshaft. The disease was evaluated by clinical observation and roentgenographic, hematologic, bacteriologic, and histologic parameters. Osteomyelitis developed in all 24 infected rabbits. None of the five rabbits receiving only an intramedullary rod developed an osteomyelitis. This model proves that an experimental posttraumatic osteomyelitis associated with a foreign body can be reliably induced, even when no infection-promoting chemical agents, small inoculum of bacteria, or minimal bone trauma is present. PMID- 7841166 TI - Epithelial sodium transport: basic autoregulatory mechanisms. AB - The epithelial cell is equipped with autoregulatory mechanisms that coordinate the rates of apical Na+ entry and basolateral Na+ extrusion, so that intracellular Na+ activity is maintained relatively constant when the rate of active Na+ transport changes. The increase of basolateral Na+ extrusion via the ouabain-inhibitable Na+,K(+)-ATPase during Na+ transport stimulation appears to be a result of both an increase in the number of operative Na+,K(+)-ATPase units in the basolateral cell membrane and in the Na+ turnover per Na+,K(+)-ATPase unit. Further, it is possible that the number of epithelial cells, which are involved in active Na+ transport, changes when the rate of Na+ transport is altered. Not only apical Na+ entry and basolateral Na+ extrusion are coupled, the basolateral membrane K+ conductance also changes in parallel with the rate of basolateral Na+ extrusion ("pump-leak parallelism"). These regulatory mechanisms serve to prevent inordinate changes in intracellular ion composition, transmembrane electrical potential difference, and cell volume. The cellular events taking place during stimulation of active transport resemble the changes during osmotic cell swelling. Hence, it is possible that cell volume changes are responsible for the coordination of apical and basolateral membrane properties. PMID- 7841167 TI - Methylene blue inhibition of oestradiol-induced increase of ceruloplasmin serum levels in rats. AB - The administration of oestrogens increases the hepatic synthesis and plasma level of ceruloplasmin both in man and laboratory animals. Methylene blue, an oxidizing agent and inhibitor of soluble guanylate cyclase, is widely used to block the effects of endothelium-derived relaxing factor (nitric oxide). We describe the inhibitory effect of methylene blue on the increase of ceruloplasmin plasma level in rats during oestradiol treatment. PMID- 7841168 TI - The effect of cyclosporin A on the proliferating chick embryo erythroblasts. AB - The proportion of proliferating erythroblasts, i.e. proerythroblasts, basophilic erythroblasts and polychromatophilic erythroblasts in blood islands of the chick embryo yolk sac, were counted during embryonic days 2-10. From day 2 when high amounts of erythroblasts signalized the onset of embryonic erythropoiesis, the percentage of less mature erythroid cells gradually decreased. Intraamniotic injection of cyclosporin A in doses 1.5 or 15.0 micrograms per embryo on day 5 led to significant changes in the proportion of proliferating erythroblasts in the yolk sac blood islands. We speculate that these changes were caused initially by the release of the more mature cells into the circulation and later by a dose dependent decrease in the number of stem cells. The estimation of proerythroblast percentage from all proliferating erythroblasts in the yolk sac blood islands may serve as a valuable indication of toxic damage in the late avian embryo. PMID- 7841169 TI - Differences in saccadic eye movement-related potentials under regular and irregular intervals of visual stimulation. AB - The saccadic eye movement-related potentials (SEMRPs) were recorded over various brain areas in a group of righthanders while they performed saccades to visual stimuli appearing either at regular or at irregular time intervals. The premotion positivity, motion execution component and lambda responses were of shorter latencies and lower amplitudes over the parietal areas as compared to the occipital ones. This finding did not depend on the regularity of intervals. With regular intervals, the positive wave starting before and peaking at the end of a saccade was found over the frontal eye fields. With irregular intervals, the premotion negativity was registered over the motor and frontal cortices. With saccades at regular intervals, the oculomotor components in the SEMRPs were less pronounced as compared to the irregular ones. These results are in accordance with the presumption that visual stimuli, appearing at irregular intervals, require higher attention and readiness to the oculomotor reaction, respectively, and also with the supposed role of the right hemisphere of righthanders in processing visual information. PMID- 7841170 TI - Relationship of muscle fibre distribution to body composition in physically trained and normally active human males. AB - This study was designed primarily to identify relationships among indices of muscle tissue structure (m. vastus lateralis) and of somatic qualities (anthropometric parameters) in 44 untrained men and 105 well-trained athletes. The ratio of glycolytic to oxidative muscle fibres was significantly less (P < 0.05) in endurance athletes as opposed to both the controls and the power athletes. Correlations between anthropometric factors and indices of muscle morphology were stronger in trained men, particularly in power athletes. Relationships between body fat and muscle fibre distribution were low in trained and untrained subjects. Documented muscle plasticity may enhance relationships between somatic and muscle tissue indices. Our results suggest that the response of the three major muscle fibre types to prolonged training may be relatively high. Finally, it was proposed that enhanced oxidative capacity of skeletal muscle might be characteristic of those resistant to heart disease. PMID- 7841171 TI - Histochemical and functional parameters in Nordic combination athletes. AB - Bioptic samples from the vastus lateralis muscle were analyzed in a group of Czechoslovak representatives in the Nordic combination (ski-jumping and 15 km cross-country skiing). The distribution of individual muscle fibre types (FG, FOG and SO) was detected and correlated with values obtained by motor and functional performance tests. Histochemical analysis of the bioptic samples revealed a considerably heterogeneous distribution of muscle fibre types in the group studied. No typical profilation for this sport discipline was found. Weak correlation between the proportion of fast muscle fibres and explosive strength parameters was ascertained. The correlation between the proportion of slow muscle fibres and the capacity of O2 utilization (VO2max) was statistically significant. Strong correlation between the proportion of fast twitch fibres and relative maximal strength of knee extensors (N/kg) was disclosed. A non-linear relation between the area of fast twitch fibres and vigour of take-off was found. PMID- 7841172 TI - Caffeine suppresses chloride current fluctuations in calcium-overloaded Xenopus laevis oocytes. AB - Calcium-induced chloride currents were studied in Xenopus oocytes using the two electrode voltage clamp technique. Fluctuations of chloride currents measured under a voltage clamp were elicited by injection of calcium into the cytoplasm. Contrary to infrequent injections of small amounts of calcium which evoked smooth transient responses, these fluctuating chloride currents are due to overloading of intracellular calcium stores which then release calcium repeatedly. Chloride current fluctuations in calcium-overloaded oocytes can be reversibly suppressed by caffeine. This effect is concentration dependent and an amplitude decrease of fluctuations is already apparent at 2 mmol/l caffeine. The analysis of power spectra density of fluctuations have displayed the pronounced effect of caffeine. These results suggest that at least a part of the endoplasmic reticulum in Xenopus oocytes is a calcium-releasable calcium store which can be activated at the resting inositol trisphosphate concentration. PMID- 7841173 TI - Temperature- and pH-controlled fusion between complex lipid membranes. Examples with the diacylphosphatidylcholine/fatty acid mixed liposomes. AB - The fusion capability of complex lipid bilayers and its pH as well as temperature sensitivity have been studied by optical and spectroscopic means. The aggregation and fusion efficiency of such lipid membranes can be optimized by controlling the phase characteristics of the individual membrane components. For a practically relevant illustration, the stoichiometric 1:2 (mol/mol) mixtures of phosphatidylcholines and fatty acids are used. Perhaps the most interesting liposomes of this kind, which are made of dipalmitoylphosphatidylcholine/elaidic acid (DPPC/ELA-COOH (1:2)), undergo a chain-melting phase transition between 42 degrees C and 48 degrees C, depending on the bulk pH value. The highest chain melting phase transition temperatures are measured with the fully protonated fatty acids at pH < or = 5.5 and involve a change into the non-bilayer high temperature state. Upon increasing pH, this transition reverts into an ordinary gel-to-fluid lamellar phase change and occurs at 42 degrees C, by and large. Simultaneously, the rate and the efficacy of fusion between the PC/FA and PC/FA- mixed vesicles decreases. The fusion efficacy of the PC/FA(-) mixed liposomes at pH > or = pK(FA) approximately 7.5 is practically negligible. This is largely due to the increased interbilayer repulsion and to the relatively high water solubility of the deprotonated fatty acid molecules at high pH. While the pH variability chiefly affects the efficacy of the intermembrane aggregation, the vesicle fusion itself is more sensitive to temperature variations. It is more likely that the temperature dependence of the intramembrane defect density is chiefly responsible for this. Optimal conditions for the fusion between DPPC/ELA COOH (1:2) mixed vesicles are thus 3.5 < or = pH < or = 5.5 (6.3) (aggregation maximum) and T > or = 41.5 degrees C = Tm(DPPC) (defect density and fusion maximum). Under such conditions the average size of PC/FA (1:2) mixed vesicles in a 1 mM suspension increases by a factor of 10 over a period of 10 min. Interbilayer fusion can also be catalyzed by the mechanically induced local membrane defects. Freshly made liposomes thus always fuse more avidly than aged vesicles. This permits estimates of the kinetics of membrane defects annihilation based on the measured temporal dependence of the maximum fusion-rate. From such studies, a quasi-exponential decay on the time scale of 1.2 h is found for the thermolabile fusogenic DPPC/ELA-COOH liposomes. PMID- 7841174 TI - Membrane/water partition of oligo(ethylene oxide) dodecyl ethers and its relevance for solubilization. AB - Mixed aqueous dispersions containing palmitoyloleoylphosphatidylcholine and oligo(ethylene oxide) dodecyl ethers C12EOn with n = 2-8 have been investigated. The aggregates composition has been determined as a function of the aqueous detergent concentration using Laurdan fluorescence spectroscopy. The partition of the detergent between the membranes and the aqueous phase has been analyzed on the basis of the regular solution model. Solubilization has been analyzed in terms of the limiting detergent fraction in the membrane, the minimal detergent fraction in micelles and the critical aqueous detergent concentration using thermodynamical coexistence conditions for the aqueous, bilayer and micellar pseudo-phases. A thermodynamic criterion for solubilization is presented. The standard chemical potential differences of the transfer of the detergents from water to the bilayer have been found to follow the empirical relation delta u o(n = 2-8) = -37.6 + 0.9 n kJ/mol. Thus, a similar conformation and localization of the oxyethylene units within the membrane are suggested. PMID- 7841175 TI - Microencapsulation of hemoglobin in liposomes using a double emulsion, film dehydration/rehydration approach. AB - A double emulsion, film dehydration/rehydration approach was developed for encapsulation of hemoglobin (Hb) at high concentration in liposomes. The liposome encapsulated Hb (LEH) membrane was formulated to contain either phosphatidylinositol (PI) or polyethyleneglycol phosphatidylethanolamine (PEG-PE) along with partially hydrogenated egg-PC, cholesterol, and alpha-tocopherol in a molar ratio of 0.1:1:1:0.02, respectively. The methods introduced in this study followed a multi-step procedure. First, a primary emulsion of Hb in organic solvent containing dissolved lipids was formed. Next, the emulsion was dispersed into an aqueous continuous phase to form a water-in-oil-in-water type double emulsion. Other than the lipids noted above, no surfactants were used in this system. The double emulsion was then converted to LEH by the following steps: evaporating the organic solvent; dehydrating the water to form a dry, thin Hb lipid film; rehydrating the film in Hb solution to form the LEH; reducing the size of the LEH using 'microfluidization' i.e., high pressure/hydrodynamic shear; and lastly washing the down-sized LEH in buffer. Physico-chemical properties of the model LEH were measured, including oxygen content, encapsulated Hb concentration, oxygen affinity and cooperativity, vesicular size distribution, viscosity, and stability. The suitability of LEH prepared in this manner as a red blood cell substitute was shown using continuous isovolemic exchange transfusion techniques in a small animal model: clearance, efficacy and acute toxicity were evaluated. PMID- 7841176 TI - An analysis of cardiac sodium channel properties using digital signal processing techniques. AB - The properties of single sodium channels in membrane patches from isolated rat ventricular myocytes were analyzed. Both cell-attached and inside-out patch configurations were examined. A digital signal processing method was used which allowed accurate determination of single-channel conductance and mean open time, even in situations where many channels coexisted in the patch. The results show that the cardiac sodium channel has a conductance of 5.3 pS at room temperature, and shows no rectification or saturation in the physiological ranges of ion concentration and membrane potential. The active channels contained in the membrane patch opened and closed independently of each other. A transition probability matrix, which describes transitions between all current levels, can also be generated, analysis of which permits an estimate of individual mean channel open time as well as the degree of coupling between channels. PMID- 7841177 TI - Calmodulin modulates protein 4.1 binding to human erythrocyte membranes. AB - Calmodulin, an abundant protein in the red cell cytosol, exerts its effects on erythrocyte membrane properties via interactions with numerous proteins. To evaluate whether calmodulin might regulate association of protein 4.1 with one of its integral membrane protein anchors, protein 4.1 binding to inside-out erythrocyte membrane vesicles (IOVs) in the presence and absence of calmodulin and Ca2+ was examined. Ca2+ plus calmodulin was found to competitively inhibit protein 4.1 association with IOVs with a Ki of 1.4 microM and a maximal inhibition of 83%. In the absence of Ca2+, calmodulin still reduce protein 4.1 binding by 43%, consistent with the known Ca2+ independent association of calmodulin with protein 4.1. Ca2+ alone had no effect on protein 4.1-membrane interactions. Digestion studies revealed that both band 3 and glycophorin sites were similarly affected by calmodulin competition, suggesting all major protein 4.1 anchors are potentially regulated. In light of other data showing regulation of the same interactions by phosphoinositides, protein kinases, and the concentration of free cytosolic 2,3-diphosphoglycerate, it can be argued that association of protein 4.1 with integral protein anchors constitutes one of the more sensitively regulated interactions of the membrane. PMID- 7841178 TI - Solubilization of the overexpressed integral membrane protein alkane monooxygenase of the recombinant Escherichia coli W3110[pGEc47]. AB - The integral membrane-bound alkane monooxygenase (AlkB) from Pseudomonas oleovorans has been overexpressed in the recombinant Escherichia coli strain W3110[pGEc47] and expression levels of 10 to 15% relative to the total cell protein were reached. The amount of phospholipids in induced cells is about 3 fold higher compared to the wild-type and AlkB has been shown to be located in small membrane vesicles. We present here a study on the solubilization of these AlkB containing membrane vesicles by different detergents with special emphasis on structural requirements for a surfactant preserving the activity of AlkB. Moreover, the effects of the detergents used on the complete alkane hydroxylase system was studied. PMID- 7841179 TI - Reversible reduction of phospholipid bound arachidonic acid after low density lipoprotein apheresis. Evidence for rapid incorporation of plasmalogen phosphatidylethanolamine into the red blood cell membrane. AB - In order to evaluate whether acute changes in fatty acids bound to phospholipids in plasma are transmitted into red blood cell membrane (RBCM) phospholipids, molecular species of phosphatidylcholine (PC) and phosphatidylethanolamine (PE) were analyzed after reduction of apo B containing lipoproteins through low density lipoprotein (LDL) apheresis in patients with severe hypercholesterolemia. As compared to the control, increases and decreases in molecular species with arachidonic acid (20:4) and with linoleic acid (18:2), respectively, at sn-2 of plasma diacyl-PC were seen in the patients before the apheresis. Directly after the procedure, the sum of species of plasma and RBCM PC plus PE with 20:4 were reduced. Two days after apheresis major species of plasma diacyl-PC reapproached preapheresis values while, in contrast, the composition of plasma alkenylacyl(plasmalogen)-PE was distinctly altered. In plasmalogen-PE of RBCM similar modifications were induced by the apheresis as in the same subgroup in plasma. In vitro experiments using vesicles with plasmalogen-PE labeled at sn-2 with either [14C]20:4 or a fluorescent pyrenedecanoyl residue indicated fast incorporation of the subgroup into the RBCM. In contrast, diacyl-PE was not taken up by the RBCM. In conclusion, apo B containing lipoproteins are partially responsible for the supply of phospholipids with arachidonic acid to RBCM, in particular by means of the fast incorporation of plasmalogen-PE. The transmission of changes induced by apheresis in plasma into those of the RBCM suggest that erythrocytes play an important role in the homeostasis of fatty acids bound to plasma phospholipids in vivo. PMID- 7841180 TI - Interaction of phthalocyanines with lipid membranes: a spectroscopic and functional study on isolated rat liver mitochondria. AB - Absorption and emission spectroscopic studies on Zn(II)-phthalocyanine (ZnPc) incorporated into unilamellar liposomes of dipalmitoylphosphatidylcholine, sometimes added with cholesterol or cardiolipin, and released to rat liver mitochondria via the three types of liposomal vesicles indicated that: (a) ZnPc predominantly dissolves in all lipid domains of biological membranes with the exception of cardiolipin-containing regions; a partial localization of ZnPc in protein binding sites is also postulated; (b) the spectroscopic properties of ZnPc, although mainly determined by the aggregation state of the dye, are somewhat influenced by the physico-chemical characteristics of the lipid environment; (c) ZnPc-binding lipid domains in mitochondria are mainly localized in the outer membrane; this conclusion is clearly deduced from the trends of Arrhenius plots of the ZnPc fluorescence quantum yield in whole mitochondria and isolated inner or outer membrane in the temperature range -10 degrees C-(+)45 degrees C; (d) the nature of the ZnPc-binding site in mitochondria is not dependent on the chemical composition of the liposome carrier, contrary to what observed for other hydrophobic dyes, such as porphyrins. This has been also confirmed by photosensitization experiments. Actually, illumination of ZnPc loaded mitochondria by 600-700 nm light causes a decline of the respiratory control ratio, which is essentially dependent on the amount of incorporated photosensitizer, irrespective of the composition of the carrier. PMID- 7841181 TI - Influence of dye and protein location on photosensitization of the plasma membrane. AB - Two membrane-photosensitizing dyes were used to investigate whether selected sites in the plasma membrane vary in their sensitivity to damage by singlet oxygen (1O2*) and, if so, what factors are responsible for the variation. The relative ability of Rose bengal (RB) and merocyanine 540 (MC540), both of which localize in the plasma membrane and produce 1O2*, to photosensitize five plasma membrane functions in P388D1 cells was evaluated. The five membrane functions assessed were: plasma membrane potential, proline transport, facilitated glucose diffusion, 5'-nucleotidase activity, and dye exclusion. Photosensitization efficiency by RB varied by a factor of 188 for these membrane functions, whereas for MC540 a range of only 24 was found. RB was a more efficient photosensitizer than MC540 but the relative efficiencies varied with the membrane function. The wide range of P50 values for RB suggests that it binds selectively to membrane sites where it causes damage with high efficiency; possibly a non-1O2* mechanism is involved. In contrast, MC540 photosensitized the three membrane functions involving integral membrane proteins about equally suggesting that differences are due to small variations in the distribution of MC540 in the plasma membrane and/or variations in the inherent reactivity of the membrane targets with 1O2*. The results indicate that the lability of membrane sites to photosensitization depends both on their inherent reactivity with 1O2* and the relative location of specific protein and dye molecules. PMID- 7841182 TI - Transmembrane potentials in cells: a diS-C3(3) assay for relative potentials as an indicator of real changes. AB - The mechanism by which the fluorescent cationic dye diS-C3(3) reports on cellular transmembrane potential has been investigated in murine haemopoietic cells. Due to the large molar absorbance of diS-C3(3) and its high quantum yield of fluorescence in cells, this dye can be used at very low labelling concentrations (5 x 10(-8) to 2 x 10(-7) M). In contrast to the quenching of fluorescence observed for the most commonly used voltage-sensitive dyes of the carbocyanine class, the fluorescence intensity of diS-C3(3) increases when the dye accumulates in the cells. The method of synchronous emission spectroscopy was used to resolve the intracellular and extracellular components of the diS-C3(3) fluorescence of suspensions of labelled cells. In comparing changes in these signals consequent on changes in transmembrane potential induced by varying the extracellular concentration of potassium ions in the presence of valinomycin, the logarithm of the ratio of intensities of these two components, as predicted theoretically, was found to be a good linear measure of transmembrane potential under these conditions. The dye was also demonstrated to be suitable for flow cytofluorimetric analysis, the logarithm of the mean population signal similarly being found to provide a good linear measure of the transmembrane potential. The conditions under which such linearity may be expected with respect to possible effects due to changes in the capacity for binding of the dye to proteins and various cytosolic structures are delineated and their validity with respect to the possibly contentious role of mitochondria in such measurements examined in particular. The use of the method in indicating changes in the transmembrane potential and/or changes in the transport numbers of the major ions determining transmembrane potential between different physiological states, the possible extension to determinations of absolute differences in potential between different cell states without calibration or comparison with potassium-ion potentials, and the conditions for validity and limitations of these partially complementary measurements, are discussed. PMID- 7841183 TI - Translocation of two glucose transporters in heart: effects of rotenone, uncouplers, workload, palmitate, insulin and anoxia. AB - Our previous studies on the acute regulation of glucose transport in perfused rat hearts were extended to explore further the mechanism of regulation by anoxia; to test the effects of palmitate, a transport inhibitor; and to compare the translocation of two glucose transporter isoforms (GLUT1 and GLUT4). Following heart perfusions under various conditions, glucose transporters in intracellular membranes were quantitated by reconstitution of transport activity and by Western blotting. Rotenone stimulated glucose uptake and decreased the intracellular contents of glucose transporters. This indicates that it activates glucose transport via net outward translocation, similarly to anoxia. However, two uncouplers of oxidative phosphorylation produced little or no effect. Increased workload (which stimulates glucose transport) reduced the intracellular contents of transporters, while palmitate increased the contents, indicating that these factors cause net translocation from or to the intracellular pool, respectively. Relative changes in GLUT1 were similar to those in GLUT4 for most factors tested. A plot of changes in total intracellular transporter content vs. changes in glucose uptake was roughly linear, with a slope of -0.18. This indicates that translocation accounts for most of the changes in glucose transport, and the basal pool of intracellular transporters is five times as large as the plasma membrane pool. PMID- 7841184 TI - Cationic liposomes improve stability and intracellular delivery of antisense oligonucleotides into CaSki cells. AB - Antisense oligonucleotides (ODNs) are promising novel therapeutic agents against viral infections and cancer. However, problems with their inefficient delivery and inadequate stability have to be solved before they can be used in therapy. To circumvent these obstacles, a wide variety of improvements, including phosphorothioate ODNs and liposomes as a carrier system, have been developed. This study was designed to compare the effects of two cationic liposomes on the intracellular delivery and stability of ODNs in CaSki cell cultures. Also the stability of 3'-end phosphorothioate ODNs were investigated. The 3'-modification neither had any effect on the delivery, nor protected the ODNs against degradation. The cellular delivery and stability of ODNs was improved with both cationic liposomes, but a cationic liposomal preparations containing dimethyldioctadecylammonium bromide and dioleoylphosphatidylethanolamine (DDAB/DOPE) was more efficient than commercially available N-(1-(2,3 dioleoyloxy)propyl)-N,N,N-trimethylammoniummethylsulf ate (DOTAP). The improved cellular delivery was largely due to the stabilization of ODNs by cationic liposomes. The improved stability in the culture medium indicates that the cationic liposomes per se protect the ODNs from enzymatic degradation. Indeed, intact ODNs were found in the cytoplasm and nucleus only when delivered by cationic liposomes. PMID- 7841185 TI - ATP-dependent transport of the linear renin-inhibiting peptide EMD 51921 by canalicular plasma membrane vesicles of rat liver: evidence of drug-stimulatable ATP-hydrolysis. AB - Certain peptide drugs, such as the linear hydrophobic renin-inhibitor EMD 51921, are rapidly eliminated via the bile. At the sinosoidal membrane of liver cells EMD 51921 is taken up via a sodium-independent carrier-mediated mechanism, competing for the uptake of bile acids. Until now, the mechanisms of biliary excretion of EMD 51921 were unknown. In this study we describe an ATP-dependent transport system for the enzymatically and metabolically stable hydrophobic linear renin-inhibiting peptide EMD 51921. The ATP-dependent uptake into the osmotic reactive intravesicular space is saturable (Km 12 microM, Vmax 663 pmol/min per mg protein), temperature dependent and specifically requires ATP. Transport is inhibited by vanadate but not by ouabain, EGTA or NaN3, and does not function in basolateral plasma membrane vesicles. Transport is not altered in canalicular membrane vesicles isolated from Tr- rats lacking the canalicular ATP dependent transport of cysteinyl leukotrienes and related anions. Transport is inhibited by taurocholate, a typical substrate of the canalicular ATP-dependent bile acid transporter, but also by vincristine and daunomycin, substrates of P glycoproteins. EMD 51921, however, only inhibits the uptake of taurocholate, whereas the transport of daunomycin is not influenced. Taurocholate and EMD 51921 are mutually non- or un-competitive transport inhibitors. Incubation of rat liver canalicular membranes with micromolar concentrations of EMD 51921 resulted in a 1.8-2.5-fold increase in the rate of ATP-hydrolysis. In contrast, ATP-hydrolysis was not affected by fragments of the peptide that are not transported in an ATP dependent manner. The apparent Km value (EMD) for ATP-hydrolysis is 68 microM. Vmax is 0.032 U/mg protein. ATPase activity is pH dependent. Stimulation of ATP hydrolysis is inhibited by vanadate, NEM, hydroxymercuribenzoate and ascorbate, but is not affected by ouabain, EGTA or NaN3. EMD 51921 does not stimulate the ATPase activity of the Na+/K(+)-ATPase isolated from kidney medulla. The EMD stimulatable ATPase seems to be distinct from the glutathione-S-conjugate stimulatable ATPase and the mdr 1a/b gene products and differs in its characteristics from that of the canalicular ecto-ATPase. PMID- 7841186 TI - Solubilization of a membrane-associated protein from rat nervous system tissues which binds anionic glycolipids and phospholipids. AB - An anionic glycolipid and phospholipid binding protein was characterized in detergent-solubilized rat brain synaptosomes using a synthetic, polyvalent radiolabeled ganglioside-protein conjugate as radioligand. Gangliosides are prominent cell surface glycoconjugates in vertebrate brain, where they may function in membrane protein regulation or in cell-cell recognition. The neoganglioprotein (GT1b)13BSA was radioiodinated and used to probe solubilized synaptosomal proteins for ganglioside binding activity using a receptor-ligand precipitation assay. Binding data revealed a high affinity (KD = 1 nM), saturable (Bmax = 173 pmol/mg protein) binding activity that was proteinase sensitive, calcium independent and maximal at neutral pH. Size exclusion chromatography of the synaptosomal (GT1b)13BSA binding activity indicated a M(r) of approximately 28 kDa. Binding activity with similar characteristics was solubilized from other rat tissues, with activity from sciatic nerve = muscle > synaptosomes > central nervous system myelin = liver. Gangliosides added as mixed detergent-lipid micelles inhibited (GT1b)13BSA binding: GT1b, GD1a and GD1b were the most effective inhibitors (IC50 approximately 200 nM), while GM1 and GM3 were 5-fold less effective. In addition, the sphingolipids sulfatide and sialylneolactotetraosylceramide were effective inhibitors, with IC50 values of 300 nM and 200 nM, respectively. The neutral sphingolipid GA1 did not block (GT1b)13BSA binding. Phosphatidylcholine and phosphatidylethanolamine were non inhibitory, however phosphatidylglycerol, phosphatidylserine, and phosphatidylinositol inhibited half-maximally at 200-300 nM. Inhibition by both gangliosides and anionic phospholipids was competitive with (GT1b)13BSA. We conclude that a binding protein for anionic glycolipids and phospholipids is distributed on nerve and muscle membranes. PMID- 7841187 TI - Self assembly of covalently anchored phospholipid supported membranes by use of DODA-Suc-NHS-lipids. AB - We present a novel preparation method for the self assembly of covalently anchored phospholipid supported membranes. The surface is gold covered by cysteamine. Vesicles containing DMPC and activated DODA-Suc-NHS-lipids assembled on this surface. The whole self-assembly process is monitored conveniently by Near Infrared Surface Plasmon Resonance (NIR-SPR). Comparing the data to those obtained by Ca(2+)-mediated vesicle fusion, confirmed this interpretation. PMID- 7841188 TI - Use of denaturing gradient electrophoresis to determine the distributions of polymorphisms in entire genes in natural populations. AB - We show here that the method of genomic denaturing gradient electrophoresis (gDGGE) can be used to examine any gene that has been previously cloned and sequenced, and to detect and approximately localize within the gene the majority of its polymorphisms. By using pooled-DNA gDGGE, many different samples can be scanned on a single gel. Further, the patterns on the gels and results from sequencing of some of the alleles shows that a variety of different kinds of polymorphism, ranging from single base changes to more substantial allelic differences, can be distinguished. The extramacrochaetae (emc) gene of Drosophila melanogaster exhibits no polymorphism in its ORF that can be detected by this method, although a rearrangement polymorphism was detected in the 3' downstream region of the gene. The suppressor-of-hairless (Su(H)) gene of D. melanogaster, however, exhibits a variety of polymorphisms in its ORF. Some are small deletions or insertions in a glutamine-rich part of the gene product that would not have been detectable by ordinary screening methods. Many of the polymorphisms detected in this preliminary survey are likely to have an impact on the function of the Su(H) gene product. PMID- 7841189 TI - Histones associated with single-stranded DNA do not preclude the formation of double-helical DNA. AB - The effect of histones on the reaction of reassociation of the two complementary strands of DNA from different sources has been investigated. The reassociation rate of denatured linear DNA from bacteriophage M13 monitored spectrophotometrically and using nuclease S1 is roughly the same in the presence and absence of core histones at physiological ionic strength. Electron microscopy reveals that in the samples containing histones a large network of duplex DNA is produced. Nevertheless, closed circular M13 DNA and a cloned DNA fragment (158 bp) from nucleosomal origin are entirely renatured in the presence of histones as demonstrated by the well-defined double-stranded DNA bands seen in electrophoretic gels. Various experiments performed using the purified (+) and ( ) strands of the cloned nucleosome DNA fragment at low ionic strength indicate that core histones initially bound to one or even to the two strands allow the formation of duplex DNA. These findings and the results obtained with partially denatured closed circular M13 DNA allow us to conclude that core histones neither prevent the nucleation nor inhibit the rapid zippering reactions leading to the formation of double-stranded DNA. The mechanism that allows the renaturation of DNA in the presence of histones may also participate in biological processes involving the pairing of complementary nucleotides. PMID- 7841190 TI - Cloning of cDNAs encoding argininosuccinate lyase and arginase from Rana catesbeiana liver and regulation of their mRNAs during spontaneous and thyroid hormone-induced metamorphosis. AB - Thyroid hormones are responsible for a change in the expression of many target genes during amphibian metamorphosis. In this study we cloned and sequenced cDNAs encoding two of the five urea cycle enzymes, argininosuccinate lyase and arginase, from adult liver of Rana catesbeiana. The cDNAs for the bullfrog argininosuccinate lyase and arginase encoded proteins of 467 and 321 amino acids with predicted molecular weights of 52,257 and 35,088, which were 72-75 and 64 68% identical to the mammalian enzymes, respectively. The accumulation of the mRNAs for argininosuccinate lyase and arginase in liver increased 26 and 4-times in a coordinated manner during spontaneous metamorphosis. Thyroid hormone treatment induced about 5 and 10-times accumulation of mRNAs for argininosuccinate lyase and arginase in liver from premetamorphosing tadpoles within 4 days. These results suggest that the mRNA levels of the two enzymes in liver are upregulated by thyroid hormone during metamorphosis. PMID- 7841191 TI - Derivation and partial analysis of two highly active myeloma cell transfectants. AB - Vectors have been designed to optimise the expression of heterologous proteins in transfected mouse myeloma cells. The over-ridingly important DNA element contained in these constructs is the classical mouse immunoglobulin heavy chain enhancer. It is shown that even in the absence of a well-known promoter element, the enhancer can drive gene expression in stable cell transfectants and the main transcriptional start site utilized in such situations has been mapped to within the previously defined enhancer region. Using chicken lysozyme as a reporter function in these vectors, two transfected myeloma cell clones have been isolated which secrete this protein at levels 50-100-times as high as those usually obtained with the same vectors and it is shown that in molar terms this is at least as high as endogenous immunoglobulin produced by a related line. Analysis of these lines show that in one case only a single copy, and in the other two to three copies, of the apparently unrearranged vector have integrated at a single locus within the genome. Possible explanations for the high-level expression are discussed. PMID- 7841193 TI - Effects of oxidants and antioxidants on nuclear factor kappa B activation in three different cell lines: evidence against a universal hypothesis involving oxygen radicals. AB - A model for NF kappa B activation involving reactive oxygen intermediates has recently been proposed. We have explored this model in three cell lines, Jurkat T cells, EL4.NOB-1 T cells and KB epidermal cells using hydrogen peroxide and two physiological activators of NF kappa B, interleukin-1 (IL1) and tumor necrosis factor (TNF) as stimuli. In agreement with earlier studies hydrogen peroxide activated NF kappa B in Jurkat, although only at much higher concentrations (10 mM) than those previously reported. However, hydrogen peroxide failed to activate in the two other cell lines under a range of conditions. Similarly, N acetylcysteine only proved inhibitory in hydrogen peroxide and TNF treated Jurkat and failed to inhibit IL1 and TNF-activated NF kappa B in EL4.NOB-1 and KB cells respectively. N-Acetylcysteine inhibited IL1-induced interleukin-2 in EL4, however, demonstrating that N-acetylcysteine was biologically active. These results suggest that the reactive oxygen model of NF kappa B activation may be cell-type restricted. In contrast to the results with N-acetylcysteine, the antioxidant and metal chelator, pyrolidine dithiocarbamate (PDTC) inhibited NF kappa B activation, although these effects may be unrelated to any antioxidant properties. PDTC also inhibited IL1-induced interleukin-2. Finally, studies with the pro-oxidant diamide showed that this could not activate NF kappa B in any of the cells and in contrast proved inhibitory. The results from this study therefore suggest that the reactive oxygen model of NF kappa B activation may be restricted to certain cell types and that the presence of such a system is not required for the activation of NF kappa B by IL1 and TNF. PMID- 7841192 TI - Expression of the axolotl homologue of mouse chaperonin t-complex protein-1 during early development. AB - Molecular chaperones assist in the folding of proteins, but their role during development is not well understood. Here we report the temporal and spatial expression pattern of the axolotl homologue of mouse chaperonin TCP-1 during normal amphibian embryogenesis and in several models of abnormal embryogenesis. A partial axolotl TCP-1 cDNA (646 bp; 519 coding bp) isolated by 3' RACE PCR shows considerable homology to mouse TCP-1. Developmental Northerns and RT-PCR analyses of whole axolot1 embryos revealed a low level of maternal TCP-1 transcripts in fertilized eggs. The maternal transcripts were down-regulated to a non-detectable level in early gastrulae. Zygotic TCP-1 transcripts first appeared during gastrulation. They were mainly expressed in mid-neurula and later stage embryos. Whole-mount in situ hybridization studies showed abundant TCP-1 transcripts in the blastopore at the mid-gastrula stage and in the brain and spinal cord beginning at the neurula stage, and in the somites (myotomes) at the tailbud stage. RT-PCR analysis of TCP-1 expression in axolotl embryos treated with either high salt (causing exogastrulation) or ultraviolet (UV) irradiation (causing ventralization) substantiated the correlation between TCP-1 expression and neural and somitic development. In high salt-induced exogastrulated embryos TCP-1 mRNA was detectable in the ectoderm part (with neural tissues) but not in its exogastrulated endoderm part. Lower levels of TCP-1 expression were detected in UV-irradiated, ventralized embryos with smaller head and reduced neural and somitic tissues. Normal levels of TCP-1 expression were detected in embryos with double axes/heads. These studies provide strong evidence that at the transcript level axolotl chaperonin TCP-1 is regulated both temporally and spatially during embryogenesis, especially in neural and somitic development. PMID- 7841194 TI - Mechanism of regulation of PDGF-A chain gene expression by serum and TPA. AB - The state of induction of the platelet-derived growth factor (PDGF) A chain markedly differs among drugs and cells. The increase in A chain mRNA by serum was due to activation of transcription. Transcription was also activated by cycloheximide (CHX) even during serum starvation, indicating that the expression of the PDGF-A chain is inhibited by transcription suppressor factor with a short life during serum starvation. On the other hand, post-transcriptional regulation played a very important role in the increase in A chain mRNA by 12-O tetradecanoylphorbol-13-acetate (TPA) and superinduction by TPA and CHX. We also analyzed the regions of PDGF-A chain gene that respond to serum and TPA by the chloramphenicol acetyltransferase (CAT) assay and the gel retardation assay. The region from TATA to -135 bp has the activity of the basal expression of PDGF-A chain gene and is considered to be involved in down regulation after the treatment with serum and TPA. Elements that respond to serum and increase the expression of PDGF-A chain gene are present in the region from -135 bp to -223 bp. Elements that inhibit the expression of PDGF-A chain gene during serum starvation are present in the region from -223 bp to -416 bp. PMID- 7841195 TI - Determination of the single strand origin of Shigella sonnei plasmid pKYM. AB - The Shigella sonnei plasmid pKYM replicates by a rolling-circle mechanism in Escherichia coli. A 571 nucleotides HincII restriction fragment of the pKYM DNA harbors two potential hairpin loops (I and II). We cloned the fragment into a ori defective M13 vector phage, M13 delta lac183. The chimera phage, MDKY5, showed a larger plaque size, and increased phage yield and rate of progeny replicative form DNA (RF) synthesis. Rifampicin reduced rate of conversion of the single- to double-stranded RF DNA. In addition, we introduced nucleotide deletions within the cloned pKYM DNA, by Bal31 nuclease digestion. Each of the deletion mutants thus constructed was lacking in a sequence containing the hairpin loops and formed smaller plaques. The in vivo analyses revealed that a 136 nucleotides sequence containing the two hairpins I and II is the pKYM minus origin for complementary strand synthesis (single strand origin, referred to as SSO) and harbors a recognition site(s) by host E. coli RNA polymerase, for primer RNA synthesis. Moreover, we found a 24 nt sequence, upstream of the SSO domain having 83% homology to the recombination site A (RSA) which functions in plasmid sitespecific recombination and/or transfer. PMID- 7841196 TI - Comparative studies on the minus origin mutants of Escherichia coli spherical single-stranded DNA phages. AB - The minus origins for complementary strand DNA synthesis (-ori) of Escherichia coli spherical single-stranded DNA (microvirid) phages G4, phi K, alpha 3, and St 1 closely resemble each other in DNA structure and contain two potential secondary hairpin loops (I and II) that have been implicated as direct recognition sites for host E. coli dnaG protein (primase). We introduced mutations (deletion or insertion) within the -ori regions of phi K and G4 by the nuclease digestion method. Mutants thus constructed produced minute plaques, showed thermosensitivity, and they remarkably reduced the phage yield and rate of viral DNA synthesis. Deletions in the phi K mutants (dTa) were ranging from 1 nucleotide (nt) to 102 nt centered at the hairpin II; a dTa8 mutant was entirely lacking in the two hairpins besides the starting point for primer RNA synthesis. On the other hand, the G4 mutants (dSa) had deletions centered at hairpin I; two mutants dSa35 and dXN completely lost the hairpin I and the primer RNA starting point. In addition, progeny phage populations of several phi K and G4 mutants contained revertant-like phages. DNA sequencing analysis revealed that these secondary phages had been generated by spontaneous DNA rearrangement with additional insertion or deletion near the parental mutation sites, via an unknown recA-independent pathway. PMID- 7841197 TI - Effect of oxidizing agents and haemin on the phosphorylation of eukaryotic elongation factor 2 in rabbit reticulocyte lysates. AB - Incubation of rabbit reticulocyte lysates in the absence of added haemin resulted in the phosphorylation of a 95 kDa protein. This protein was suggested to be elongation factor 2 (eEF-2) based on the following observations, (i) phosphorylation of the 95 kDa protein was Ca2+ and CaM-dependent. (ii) eEF-2 supplemented to the lysates became phosphorylated and co-migrated with the endogenous 95 kDa phosphoprotein upon electrophoresis in SDS gels. (iii) The tryptophane specific cleavage pattern obtained from the isolated 95 kDa phosphoprotein was identical to that of phosphorylated eEF-2. Phosphorylation of the 95 kDa protein was stimulated by oxidizing agents such as oxidized glutathione and NAD+ and inhibited by addition of haemin. The haemin concentration needed for 50% inhibition (IC50) was 2.5 microM. Haemin also had an inhibitory effect on eEF-2 phosphorylation in a system containing highly purified components (IC50 = 2 microM). In this system haemin inhibited phosphorylation of eEF-2 even in the presence of a 100-fold excess of beta-mercaptoethanol. Oxidizing agents had no effect on the kinase activity in the purified system. PMID- 7841198 TI - Differential compaction of transcriptionally competent and repressed chromatin reconstituted with histone H1 subtypes. AB - Chromatin fragments stripped of H1 histones regain the ability to form higher order structures and aggregates in 0.15 M NaCl following reconstitution with histone H1. However, transcriptionally competent chromatin fragments are resistant to chicken erythrocyte H1/H5 histone-induced 0.15 M NaCl aggregation/precipitation. In this study, we investigated the ability of stripped chromatin fragments reconstituted with one of four histone H1 subtypes (chicken erythrocyte H1, H5, trout liver H1a, H1b) at various stoichiometries to form salt precipitable higher order structures. Our results provide evidence that chicken erythrocyte histone H1 was more effective than histone H5 and trout liver histone H1b better than H1a in forming higher order structures. None of the histone H1 subtypes could render transcriptionally competent chromatin fragments insoluble in 0.15 M NaCl. These results are consistent with the ideas that the histone H1 subtypes differ in their capacities to compact chromatin fiber, and that the alterations in the structure of transcriptionally competent nucleosomes interfere with the capacity of all H1 subtypes to form higher order structures. PMID- 7841199 TI - Cloning and sequencing a putative pyrophosphate-dependent phosphofructokinase gene from Entamoeba histolytica. AB - Pyrophosphate-dependent phosphofructokinase (PPi-PFK) gene from Entamoeba histolytica was cloned from its genomic library and sequenced. The open reading frame has 1149 bp and codes for a protein of 41.5 kDa. The deduced amino acid sequence of E. histolytica PPi-PFK has 25 to 28% identity to the PPi-PFKs from Propionibacterium freudenreichii, Naegleria fowleri and potato. The amino acid residues known to contribute to the active site of PPi-PFK from P. freudenreichii are conserved. PMID- 7841200 TI - Primary sequence of a putative pyrophosphate-linked phosphofructokinase gene of Giardia lamblia. AB - Based on sequence information from a cosmid library, we obtained a genomic clone that encodes a putative inorganic pyrophosphate (PPi)-linked phosphofructokinase of Giardia lamblia. The open reading frame specified a protein of 59.8 kDa homologous to PPi- and ATP-linked phosphofructokinases. The greatest similarity (over 50% positional identity) was noted to the beta-subunits of both the Solanum tuberosum (potato) and Ricinus communis (castor bean) PPi-phosphofructokinases. PMID- 7841201 TI - Nucleotide sequence of the gene for ribosomal protein S17 from Dictyostelium discoideum. AB - The nucleotide sequence of the gene for the Dictyostelium homologue of eukaryotic ribosomal protein S17 has been assembled from cDNA and genomic DNA clones. The predicted primary structure of the S17 protein displays a similar level of sequence identity with its counterparts from higher eukaryotes (53%) as other Dictyostelium ribosomal proteins. Although Dictyostelium genes usually are organized in a rather simple manner, the rps17 gene harbors two introns. One of them, located immediately 3' from the ATG initiator codon, appears to be ubiquitously conserved in eukaryotic rps17 genes. PMID- 7841202 TI - Characterization of edg-2, a human homologue of the Xenopus maternal transcript G10 from endothelial cells. AB - We have isolated by polymerase chain reaction-amplified subtractive hybridization technique, several cDNA clones that are induced by phorbol myristic acetate in human umbilical vein endothelial cells (HUVEC). One such clone, termed edg-2, was sequenced and was found to encode a human homologue of a Xenopus maternal transcript G10. The deduced amino acid sequence of edg-2 contains a putative nuclear translocation sequence, an N-terminal acidic domain and a cysteine-rich C terminal domain containing a putative Zinc-finger structure. The structure of edg 2 polypeptide suggests that it may be a nuclear regulator of transcription. The edg-2 mRNA was expressed ubiquitously in cell lines of epithelial and mesenchymal lineages. In addition, the edg-2 polypeptide sequence is highly conserved in evolution and is expressed by lower organisms such as yeast and C. elegans, suggesting that it may be an important regulator of general nuclear function. PMID- 7841203 TI - Nucleotide sequence and expression of the porcine vascular endothelial growth factor. AB - We cloned and sequenced two cDNAs encoding the angiogenic, vascular endothelial growth factor (VEGF) from the porcine heart. Deduced amino acid sequence of the clone pPVE-18 and pPVE-5 predicted 164 (VEGF164), and 120 (VEGF120) residues of VEGF, respectively, with a putative N-terminal signal sequence of 26 amino acids. The porcine VEGF is shorter by one amino acid as compared to human VEGF, but a potential glycosylation site is present at Asn-74. PCR detection, and verification of the identity of the PCR products by Southern hybridization, confirmed wide expression of VEGF in different porcine tissues. Northern blot analysis with a radiolabeled porcine specific VEGF probe, showed one major (3.9 kb) and one minor (1.7 kb) mRNA species expressed in all four chambers of the heart. PMID- 7841204 TI - Relative abundance of bovine Hsp70 mRNA and protein. AB - A solution hybridization assay to measure bovine Hsp70 mRNA levels is used to demonstrate that skeletal muscle contains the highest amount of this mRNA while brain has the lowest amount and the level of Hsp70 mRNA is heat inducible in bovine skeletal muscle. Furthermore, this assay allowed for the comparison of relative Hsp70 protein and mRNA levels. Relative transcript levels compared to relative Hsp70 protein levels in tissues demonstrated 50- to 200-fold differences. These results, then, approximate the magnitude of the previously reported preferential translation of Hsp70 mRNA. PMID- 7841205 TI - Molecular cloning of the E1 beta subunit of the rat branched chain alpha-ketoacid dehydrogenase. PMID- 7841206 TI - Identification of disulfide bridges in a cardiotoxic peptide by electrospray ionization. AB - A new method was developed for subjecting a peptide to a specified number of Edman degradation cycles on an automated polypeptide sequencer and desorbing the residual peptide for further investigations. The procedure was applied in combination with electrospray ionization mass spectrometry to identify the four disulfide bridges present in a small tightly bound peptide. The task was accomplished using only a few nanomoles of the intact peptide. PMID- 7841207 TI - Structural characterization of synthetic model peptides of the DNA-binding cI434 repressor by electrospray ionization and fast atom bombardment mass spectrometry. AB - The structural characterization of two synthetic model peptides of the cI434 repressor is described. Unequivocal determination of the structure was achieved by means of electrospray ionization mass spectrometry of the intact peptides and by fast atom bombardment mass spectrometric identification of complementary peptide fragments obtained by tryptic and chymotrypic digestion and partial separation by reversed-phase high-performance liquid chromatography. The results show the potential of this approach for characterizing synthetic peptides of relatively high molecular weight. PMID- 7841208 TI - Peptide sequence information derived by partial acid hydrolysis and matrix assisted laser desorption/ionization mass spectrometry. AB - Partial acid hydrolysis of purified peptides followed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry of the resulting peptide mixture is a fast and simple procedure to confirm the identity of a peptide tentatively identified by its determined molecular weight. Often partial amino acid sequence information can be obtained directly. The sensitivity of the technique is in the high-femtomole to low-picomole range. PMID- 7841209 TI - Tracing 15N with chemical reaction interface mass spectrometry: a demonstration using 15N-labeled glutamine and asparagine substrates in cell culture. AB - This research demonstrates how the chemical reaction interface mass spectrometry (CRIMS) approach works for a study of amino acid metabolism in cell culture. 15N selective chromatograms from both the culture medium and the cytosol of human hepatoma Hep G2 cells that were incubated in the presence of either 12 mM (alpha 15N)glutamine or (alpha-15N)asparagine have been produced. The time course of the distribution of 15N among different amino acids, as well as the enrichment for each amino acid, were observed over a 144 h period. Labeled glutamine was quickly converted into glutamate. After 144 h of incubation, the total amount of 15N was distributed primarily among alanine (50%), proline (28%) and glutamate (21%). The 15N enrichment of alanine and proline reached 44% and 41% respectively. Asparagine was only slowly metabolized by the cells. In addition to the 82% that was retained in asparagine, the remaining 15N in the media at 144 h was found primarily in alanine (8%), glutamate (6.8%) and proline (2.2%). Their enrichments were 20%, 36% and 19% respectively. The minimum detectable amount was 17 pg of 15N entering the CRI. CRIMS appears to be a powerful, facile approach for 15N tracer experiments. PMID- 7841210 TI - Negative ion fast atom bombardment and collision-induced dissociation mass spectrometry of the 2-, 3-, 4- and 6-deoxy derivatives from methyl beta-D galactopyranoside and related compounds. AB - The fast atom bombardment collision-induced dissociation mass spectra of the [M H]- ions of the 2-, 3-, 4- and 6-deoxy derivatives from methyl beta-D galactopyranoside and some related compounds have been recorded. The fragmentation reactions of these quasimolecular ions and of OD-labelled analogues have been examined and related to the molecular structure. In some cases distinct and common mechanisms can be derived, but it is also clear from these experiments that not only the site of deprotonation of the molecules, but also the anticipated charge localization in the fragment ions strongly direct the fragmentation reactions. PMID- 7841211 TI - Application of magnetic sector thermal ionization mass spectrometry to studies of erythrocyte iron incorporation in small children. AB - The optimal evaluation of iron metabolism requires the administration of two isotopes of iron. However, high-precision measurement of isotopic ratios from blood samples obtained after administration of two stable isotopes of iron to human subjects has not previously been reported. Using a cation-exchange system to isolate iron from blood samples, we found that high-precision (< 0.2%) measurements of 58Fe/56Fe and 57Fe/56Fe could be performed using magnetic sector thermal ionization mass spectrometry. Clinical studies in four 1-year-old infants showed that this technique could be used to demonstrate a lower rate of iron absorption in small children given an iron supplement (57Fe) with milk compared to those given iron (58Fe and ferrous sulfate) with ascorbic acid. This technique will enable the evaluation of iron metabolism in populations in whom the use of radioactive iron tracers is not appropriate. PMID- 7841212 TI - Application of high-performance liquid chromatography/chemical reaction interface mass spectrometry for the analysis of conjugated metabolites: a demonstration using deuterated acetaminophen. AB - The combination of a universal high-performance liquid chromatography/mass spectrometry (HPLC/MS) interface (UI) and the element and isotope-selective capabilities of the chemical reaction interface (CRI) has potential as a comprehensive analysis system for drug conjugates. In this work, we found equal sensitivity for model compounds as their sulfate or glucuronide conjugates. We examined urine and bile samples from Syrian golden hamsters after dosing with (2H4)acetaminophen (D4-APAP), with particular emphasis on the rich range of conjugated metabolites that are known to be produced. Seventeen metabolites were quantified from a single chromatogram of urine; 14 were conjugates. With a combination of authentic standards, selective hydrolysis, and sulfur-selective CRIMS detection, at least partial identification of most of these metabolites was accomplished. The glutathione conjugate of APAP appears the dominant metabolite in bile. The quantitative pattern of APAP metabolism found here is consistent with literature values. It does appear that this HPLC/UI/CRIMS combination has substantial ability to carry out comprehensive metabolite determinations, especially for conjugated species. PMID- 7841213 TI - Profiling of basic amino acids and polyamines in microbial culture supernatants by electrospray mass spectrometry. AB - As part of our efforts to investigate the biosynthesis of proferrioxamines in Erwinia amylovora, it was of interest to develop a methodology with which a large number of basic amino acids, di- and polyamines, and C- and N-hydroxy derivatives thereof could be monitored simultaneously. Towards this end, the on-line coupling of electrospray mass spectrometry with ion chromatography or reversed-phase chromatography was explored. Tandem mass spectrometry was found to be an excellent method for obtaining relevant structural information on underivatized polyamines and basic amino acid, including N-hydroxy derivatives. However, the coupling of ion chromatography with electrospray mass spectrometry for on-line extraction and separation of the underivatized compounds is hampered by compatibility problems. For most target compounds, on-line reversed-phase liquid chromatography/electrospray mass spectrometry was the method of choice but required derivatization and in this respect dansylation was preferred over benzoylation. Neither derivatization method is suitable for N-hydroxy compounds, which are base-sensitive. PMID- 7841214 TI - Metabolism of polyamines and basic amino acids in Erwinia amylovora: application of liquid chromatography/electrospray mass spectrometry to proferrioxamine precursor feeding and inhibition studies. AB - Erwinia amylovora, the etiological agent of fire blight, produces a family of proferrioxamine siderophores, which may be essential for the pathogen to establish itself in its hosts. If so, then control of fire blight may perhaps be possible via interference with proferrioxamine biosynthesis. Proof of this hypothesis requires prior knowledge of the corresponding biosynthetic pathways in E. amylovora. As a first step towards understanding proferrioxamine biosynthesis, it was of interest to investigate the ability of the fire blight bacterium to utilize various potential biosynthetic pathways for diamines. Feeding of lysine, ornithine and diaminobutyric acid gave rise to highly elevated levels of cadaverine, putrescine and diaminopropane, respectively, indicating that the corresponding decarboxylase activities are all present in E. amylovora. The conclusion for lysine decarboxylase was confirmed with (15N2)lysine, which was converted to (15N2)cadaverine. Arginine did not increase putrescine levels substantially, but (13C6)arginine nevertheless gave rise to (13C4)putrescine while suppressing excretion of non-labeled putrescine. A serendipitous result of this study was the finding that the growth of E. amylovora can be inhibited with 5-hydroxylysine and 1,4-diamino-2-butanone. The mechanism of inhibition appears complex and is not yet understood. For 5-hydroxylysine, preliminary investigations point to a competitive inhibition of lysine decarboxylase. However, the growth inhibition cannot be reversed by providing cadaverine, the decarboxylation product of lysine. PMID- 7841215 TI - Automatic reduction of NMR spectroscopic data for statistical and pattern recognition classification of samples. AB - A general method of automatically reducing NMR spectra to provide numerical descriptors of samples has been developed and investigated. These descriptors can be used as input to pattern recognition or multivariate algorithms for sample classification. The methods have been tested using 600 MHz one-dimensional 1H NMR spectra of biofluids which are complex mixtures. The approach is, in principle, applicable to multidimensional and heteronuclear NMR spectra and to other types of liquid samples such as oils and foodstuffs as well as to situations such as 1H or 31P NMR in vivo and solid state NMR in drug formulation analysis. The method relies upon apportioning the information in the spectra to individual contiguous segments and allowing specified regions of the spectra to be omitted. Three approaches, based on the number of peaks, the summed peak heights and the summed peak areas respectively in each segment, have been tested. The effect of segment width and overlap and the effects of manipulation of the NMR spectra have been evaluated in terms of the classification of the samples using principal components analysis. A simple method of generating NMR based spectral descriptors for object classification is thus proposed. PMID- 7841216 TI - Analytical inverse supercritical fluid extraction of polar pharmaceutical compounds from cream and ointment matrices. AB - It has been shown that inverse supercritical fluid extraction (SFE) can be used to analytically isolate a polar analyte from its matrix even at low concentrations (0.016%). Inverse SFE has been shown to be successful not only for the semi-solid Neosporin ointments, but also for the semi-liquid Neosporin creams as well. The technique has been shown to be superior to solid-phase extraction in both cases and affords the analytical chemist a quicker and safer method of sample preparation of analytes from both creams and ointments. PMID- 7841217 TI - Precision and accuracy of analysis of air-filled albumin microspheres using Coulter Multisizer Mark II. AB - The suitability of the electrical sensing zone technique for routine analysis of air-filled albumin microspheres has been thoroughly investigated using three Coulter Multisizer Mark II instruments. The precision of the method, expressed as repeatability relative standard deviation (RSD), was found to be 1-2% for number distribution parameters and 3-4% for volume distribution parameters. Significant instrument-to-instrument variation as high as 11% was, however, also observed. Accuracy was evaluated from analyses of commercially available latex standards and from comparison of results from Coulter analysis with results from the following alternative techniques: light diffraction, optical microscopy and gravimetry. Accuracy, expressed as the difference from either certified values or values obtained with the alternative techniques, was found to be 100-106%. PMID- 7841218 TI - Determination of imipenem and cilastatin sodium in Primaxin by first order derivative ultraviolet spectrophotometry. AB - A UV-spectrophotometric assay to measure the concentrations of the active drug components (imipenem and cilastatin) or Primaxin for routine release testing is described. The assay is based on the use of first order derivative spectrophotometry. The trough amplitudes in the first derivative spectrophotometric spectra at 243 and 318 nm were selected to determine cilastatin and imipenem, respectively. A linear relationship (R > 0.99) between the trough amplitudes and concentrations was demonstrated over the range 14-42 micrograms ml-1 for both drug components. Commercial IV formulations and laboratory prepared mixtures containing both drugs in different proportions were assayed using the developed method with good recoveries (ave. 100.6%). The method is rapid, precise, accurate and was shown to be equivalent to the more time consuming LC method; which is currently used for routine release testing. The specificity and stability indicating properties of the method will also be addressed. PMID- 7841219 TI - Pharmacokinetic studies of alpha-difluoromethylornithine in rabbits using an enzyme-linked immunosorbent assay. AB - Using an inhibition immunoassay, the pharmacokinetics of DFMO have been evaluated. After intravenous infusion, DFMO concentration in serum is observed to reach a maximum after 2-3 h followed by a decrease. This profile is consistent with the formation of a covalent adduct between DFMO and the enzyme which it irreversibly inhibits. The adduct was isolated by immunoaffinity chromatography. PMID- 7841220 TI - Stabilization of an anthrapyrazole antitumour agent, DuP 937, on complexation with heptakis(2,6-di-O-methyl)-beta-cyclodextrin in aqueous solution. AB - DuP 937, an anthrapyrazole antitumour agent that is chemically unstable in aqueous solution, was shown, by absorption spectroscopy, to form an inclusion complex with heptakis(2,6-di-O-methyl)-beta-cyclodextrin (DM beta CD) in aqueous solution. Proton nuclear magnetic resonance spectroscopy was used to determine the stoichiometry and association constant of the complex. The 1:1 stoichiometry of the complex was established by the continuous variation method by following changes in the chemical shifts of aromatic protons of DuP 937. The complex association constants determined by different techniques used in this study were in the same order of magnitude. The kinetics of degradation of DuP 937 in aqueous solution were investigated as a function of DM beta CD concentration at pH 5.5 and 60 degrees C. The results indicated about a seven-fold increase in the stability of DuP 937 in the presence of DM beta CD in aqueous solution. PMID- 7841221 TI - Fitting a straight line when both variables are subject to error: pharmaceutical applications. AB - In many pharmaceutical applications one postulates a linear relationship between variables. The usual linear least-squares methods are appropriate when the values of the independent variable are constants, and the dependent variable is subject to error. When both variables are subject to error, as in assay validation, calibration, and general correlation, the measurement error model (also called errors-in-variables) should be used especially when independent variable error is appreciable. In this paper, the theoretical properties of errors-in-variables methods are demonstrated with examples, and a technique for assessing the variability of parameter estimates without normality assumptions is presented. Robust methods resistant to outliers and not requiring normality assumptions, are also described. PMID- 7841222 TI - Liquid chromatographic separation of zalcitabine and its stereoisomers. AB - A liquid chromatographic method capable of separating and quantitating the stereoisomers of zalcitabine has been developed and validated. The separation was achieved with an Astec Cyclobond I--RSP column and a mobile phase of 0.25% triethylamine in water adjusted to a pH of 6.5 with glacial acetic acid. All enantiomers were found to exhibit a linear response in the range of 0.1-10% in the presence of 100% zalcitabine. Precision of analysis was found to be less than 1.5% at a level of 1% relative to zalcitabine. The limit of detection for two of the three enantiomeric impurities was determined to be 0.05% relative to zalcitabine. The detection limit for the third was found to be 0.1%. This method was successfully applied to the analysis of reference standards and several production scale batches. All of these materials were found to be stereochemically pure to a level of 99.8% or better. PMID- 7841223 TI - A liquid chromatographic assay for urea in over-the-counter carbamide peroxide products. AB - A liquid chromatographic assay has been developed and validated for determining the amount of urea present in carbamide peroxide formulations. The method employs an interaction CHO-620 carbohydrate column loaded in the Ca+2 form, a flow rate of 0.6 ml min-1, a column temperature of 85 degrees C, and UV detection at 200 nm. The mobile and stationary phase variables that may have an effect on the urea separation were studied and are discussed. The method was found to be linear over a range of 20 micrograms/g to 340 micrograms/g of urea, with a limit of detection of 1 microgram/g and a quantitation limit of 15 micrograms/g. System precision was found to have a %RSD of less than 1.0% while the method precision was typically less than 5.0%. Recoveries of 97.4% (1.0% RSD) and 98.3% (1.1% RSD) of the theoretical amount of urea (6.6% on a weight to weight basis) contained in two different formulations were obtained. PMID- 7841224 TI - Isolation and biological activity of aspidospermine and quebrachamine from an Aspidosperma tree source. AB - The indolealkaloids aspidospermine and quebrachamine have been isolated in crystalline form by a relatively rapid fractionation from the extract of a powdered material designated "Quebracho" derived from an Aspidosperma tree species. We present a novel isocratic LC method that provides baseline resolution of these two compounds and of the structurally related yohimbine in less than 15 min. Gas chromatography-mass spectrometry was employed to identify these compounds as well as several minor derivatives of aspidospermine during and after the purification process. Aspidospermine and quebrachamine like yohimbine have been found to possess adrenergic blocking activities for a variety of urogenital tissues. PMID- 7841225 TI - Pharmaceutical analysis of 8-chloroadenosine 3',5'-monophosphate. AB - 8-Chloroadenosine 3',5'-monophosphate (8-Cl-cAMP) has recently entered clinical trials as a new anticancer drug. 8-Cl-cAMP can undergo metabolism/degradation to nucleotides (8-Cl-AMP; 8-Cl-IMP), nucleosides (8-Cl-adenosine; 8-Cl-inosine) and bases (8-Cl-adenine; 8-Cl-xanthine and 8-Cl-hypoxanthine). A reversed-phase, gradient elution high-performance liquid chromatographic method is described which can resolve all the above from their non-chlorinated naturally occurring counterparts and 8-Bromo-cAMP. The assay was then utilized to perform pharmaceutical evaluations on the 8-Cl-cAMP formulation. Sterilization by filtration (0.22 micron pore size) resulted in no loss of material. Stability studies carried out in the cartridges used to continuously infuse (for 7 days) the drug to patients showed no significant degradation over 17 days. Purity determinations revealed the presence of up to nine impurities (related to adenine) and yielded a purity figure of 95.9-99.3% with considerable batch to batch variation. PMID- 7841226 TI - Propafenone binding interaction with human alpha 1-acid glycoprotein: assessing experimental design and data evaluation. AB - Binding data on racemic RS-propafenone as well as individual R- and S-drug enantiomers interacting reversibly with human alpha 1-acid glycoprotein, as obtained by a high-performance liquid chromatographic method, are evaluated according to three different approaches introduced, respectively, by Scatchard, Bjerrum, and by Tobler and Engel. A non-linear curve-fitting procedure was applied to compute the binding parameters exclusively for the binary system comprising the examined protein and R- and S-propafenone, individually. The exactness of the study design rather than the numerical values were the focus of attention in the evaluation of the data found. PMID- 7841227 TI - Development of a highly sensitive and specific assay for plasma ethinylestradiol using combined extraction, liquid chromatography and radioimmunoassay. AB - A highly sensitive and specific assay for ethinylestradiol (EE2) in human plasma was developed. The assay procedure combined solid-phase extraction of plasma samples, isolation of extracted EE2 by liquid chromatography (LC), and radioimmunoassay. Samples were extracted to remove polar plasma constituents and steroid binding proteins. Chromatography was employed to separate EE2 from other steroids that were candidates for assay cross-reactivity. The radioimmunoassay was shown to be sensitive (lower limit of quantitation = 2 pg ml-1 EE2 in plasma) and accurate (mean accuracy = 102%). Recovery of EE2 through extraction and LC steps was 76.1 +/- 4.5% (mean +/- SD; n = 42). Overall assay intra- and inter assay coefficients of variation were 3.6 and 8.9%, respectively. The analyte was stable in assay buffer and assay accuracy was influenced minimally by four sample freeze-thaw cycles. This assay protocol enables the precise monitoring of low circulating levels of EE2, a prominent and potent synthetic oestrogen. PMID- 7841228 TI - Paired ion reversed-phase HPLC assay for the determination of iothalamic acid and para aminohippuric acid in urine. AB - A paired ion reversed-phase high performance liquid chromatographic method for simultaneous determination of iothalamic acid (Io) and para aminohippuric acid (PAH) in urine is described. The method uses a single internal standard for both drugs. The only sample preparation required is dilution of urine (1:100 or 1:500) with deionized water. The internal standard is added to a small aliquot of the diluted specimen and injected. For HPLC, a C8 column and a mobile phase consisting of potassium phosphate buffer with dodecyl triethylammonium phosphate IP reagent, 25% organic modifier with UV detection at 254 nm was used. Within day and between day variation for the assay were in the range of 1.48-9.46% for iothalamic acid and 1.84-10.36% for para aminohippuric acid for four levels of concentration. Limits of quantitation were 50.0 micrograms ml-1 for iothalamic acid and 75.0 micrograms ml-1 for para aminohippuric acid. Mean recovery was 98.55% for Io and 97.79% for PAH. This isocratic HPLC assay is simple, rapid and relatively inexpensive. PMID- 7841229 TI - Sulphadoxine concentrations in plasma, red blood cells and whole blood in healthy and Plasmodium falciparum malaria cases after treatment with Fansidar using high performance liquid chromatography. AB - A reversed-phase high-performance liquid chromatographic method using acetonitrile-methanol-(1M) perchloric acid-water (30:9:0.8:95, v/v/v/v) at a flow of 1.5 ml min-1 on mu-Bondapak C18 column with UV (254 nm) detection has been developed for the separation of sulphadoxine, sulphalene and sulphamethoxazole from other antimalarials. Calibration curves were linear in the range 0.5-100 micrograms ml-1. The limit of quantitation was 50 ng ml-1. Within-day and day-to day coefficients of variation averaged 2.1 and 6.45%, respectively. The extraction recovery of sulphadoxine from plasma, red blood cells and whole blood was 90.28, 92.05 and 94.69%, respectively. The method has been used for the determination of sulphadoxine concentrations in plasma, red blood cells and whole blood of eight healthy and 50 Plasmodium falciparum malaria cases after administration of two tablets of Fansidar. Mean sulphadoxine concentration in plasma was higher than red blood cells or whole blood. Sulphadoxine concentration in plasma and whole blood of P. falciparum malaria cases was significantly higher as compared to healthy volunteers while it was the same in red blood cells. Sulphadoxine was absorbed much less in red blood cells than in plasma or whole blood. PMID- 7841230 TI - Dissociation and complexation of the fluoroquinolone antimicrobials--an update. PMID- 7841231 TI - Zero-crossing first and second derivative synchronous fluorescence spectroscopic determination of aspirin metabolites in urine. PMID- 7841232 TI - Time-resolved imaging of Ca(2+)-dependent aequorin luminescence of microdomains and QEDs in synaptic preterminals. AB - Localized elevation of intracellular free calcium [Ca2+]i concentration serves as the trigger for a wide variety of physiological processes, e.g., neurotransmitter release at most chemical synapses (1-3). The details of the mechanisms that regulate these processes are still unresolved (3-6), but they must involve precise temporal sequences of molecular events initiated by a transient localized elevation of Ca2+ concentration (i.e., a Ca2+ microdomain [3,7-15]). A microdomain is defined as an autonomous compartment of minimal spatio-temporal volume within which a signaled process can occur (8, 10, 12). A quantum emission domain (QED) is a quantal signal element (3, 16, 17). The concept of a QED was first applied to Ca2+ signaling at the synaptic preterminal (3, 4) and for large diameter mitotic cells (16, 17). The concept of Ca2+ microdomains was tested by labeling preterminals of squid giant synapses with low-sensitivity aequorin (a photoprotein that emits a photon upon binding Ca2+ [18, 19]). That work confirmed earlier modeling efforts (10, 16) and showed that, upon depolarization, the [Ca2+]i profile reaches 200-300 microM within the microdomains, and that these [Ca2+]i profiles are composed of groups of short-lived 0.5 microns diameter QEDs. In those records, obtained with 2:1 interlacing devices operating at the RS-170 standard, QEDs appeared as striped dots or chevrons rather than as solid dots, indicating that a QED lasted less than 16.6 ms (one video field), and thus establishing the need for higher sampling rates to better characterize the QED.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7841233 TI - High-resolution measurement of the time course of calcium-concentration microdomains at squid presynaptic terminals. AB - Transmitter release is considered to be a secretory event triggered by localized calcium influx which, by binding to a low-affinity Ca2+ site at the presynaptic active zone, initiates vesicular exocytosis (1-7). In previous experiments with aequorin-loaded presynaptic terminals we visualized, upon tetanic presynaptic stimulation, small points of light produced by calcium concentration microdomains of about 300 microM (5). These microdomains had a diameter of about 0.5 microns (5) and covered 5-10% of the total presynaptic membrane with an average density of 8.4 microns2 per 100 microns2, corresponding closely to the size and distribution of the active zones in that junction (6, 7). To understand in more detail the nature of these concentration microdomains, we obtained rapid video images (400/s) after injecting the photoprotein n-aequorin-J into the presynaptic terminals of squid giant synapses. Using that experimental approach, we determined that microdomains evoked by presynaptic spike activation had a duration of about 800 microseconds. Spontaneous quantum emission domains (QEDs) observed at about the same locations as the microdomains were smaller in amplitude, shorter in duration, and less frequent. These results illustrate the time course of the calcium concentration profiles responsible for transmitter release. Their extremely short duration compares closely with that of calcium current flow during a presynaptic action potential and indicates that, as theorized in the past (6-8), intracellular calcium concentration at the active zone remains high only for the duration of transmembrane calcium flow. PMID- 7841234 TI - Identification of synaptophysin-like immunoreactivity in the sea anemone Condylactis gigantea (Cnidaria: Anthozoa). AB - Synaptophysin is a membrane protein of synaptic vesicles that serves as an antigenic marker for nervous and endocrine systems in mammals. Monoclonal antisera generated against synaptophysin were used for immunocytochemical staining in tissues of the tentacles of the sea anemone Condylactis gigantea (Cnidaria: Anthozoa). Specific staining, visible at the light and electron microscope levels, was found in the tentacle. Proteins were extracted from the tissues and solubilized. Using SDS-polyacrylamide gel electrophoresis and Western blotting, we identified proteins with apparent molecular weights of 38,000, 78,000, and 114,000. The data suggest the tissues of this anthozoan contain synaptophysin-like proteins with molecular properties similar to those of mammalian neurons. PMID- 7841235 TI - Women, sex, and HIV. PMID- 7841236 TI - Alcohol and blood pressure. PMID- 7841237 TI - The efficiency of male-to-female and female-to-male sexual transmission of the human immunodeficiency virus: a study of 730 stable couples. Italian Study Group on HIV Heterosexual Transmission. AB - To compare the efficiency of male-to-female and female-to-male sexual transmission of human immunodeficiency virus (HIV), we studied 524 female partners of HIV-infected men and 206 male partners of HIV-infected women in 16 Italian clinical centers. All of the partners had had a sexual relationship with the index case lasting for at least 6 months and presented no other risk factor than sexual exposure to the HIV-infected partner. Among the 730 couples, 24% of the female partners were HIV positive, in comparison with 10% of the male partners. Using logistic regression analysis, including gender and controlling for condom use, frequency of intercourse, anal sex, partner's CD4+ cell count and clinical stage, sexually transmitted diseases, genital infections, and contraceptive use, we found that the efficiency of male-to-female transmission was 2.3 (95% confidence interval = 1.1-4.8) times greater than that of female-to male transmission. Between-gender differences in the contact surfaces and the intensity of exposure to HIV during sexual intercourse are possible reasons for the difference in efficiency of transmission. PMID- 7841238 TI - Differences in the association between alcohol consumption and blood pressure by age, gender, and smoking. AB - The positive association between alcohol consumption and blood pressure is well known. Little is known, however, about effect modification by age, gender, and smoking on the alcohol-blood pressure association. We used data of a cross sectional study conducted in the Netherlands to investigate the association between alcohol consumption and blood pressure. Between 1987 and 1990, we examined about 30,000 men and women age 20-59 years. After adjustment for age, body mass index, and smoking, we found that in men systolic and diastolic blood pressure increased by 0.9 and 0.6 mmHg per daily drink, respectively. In women, systolic and diastolic blood pressure were 2 and 1 mmHg higher in those who consumed 2 or more glasses per day compared with nondrinkers, respectively. We observed a stronger association between alcohol and blood pressure in older men compared with younger men and in male and female smokers compared with nonsmokers. These data show that gender, age, and smoking all are important effect modifiers of the alcohol-blood pressure relation. PMID- 7841239 TI - Mate, coffee, and tea consumption and risk of cancers of the upper aerodigestive tract in southern Brazil. AB - Consumption of mate, a tea-like infusion of the herb Ilex paraguariensis, is common in South America. Drinkers have high risks of upper aerodigestive tract cancers, but it is conceivable that this high risk may be attributable to confounding by smoking alcohol, and other exposures. To test this hypothesis, we analyzed the data from a case-control study of upper aerodigestive tract cancers conducted in Southern Brazil. We matched noncancer controls (N = 756) to cases (N = 378) on the basis of age, sex, and period of admission. We estimated the effect of matee consumption by conditional logistic regression with adjustment for smoking, alcohol, sociodemographics, and several dietary items, considered as confounders. The unadjusted relative risk (RR) for all upper aerodigestive tract cancers was 2.1 [95% confidence interval (CI) = 1.6-2.7]. Some excess risk persisted after adjustment for potential confounders (RR = 1.6; 95% CI = 1.2 2.2). Most of the excess risk for mate drinkers was for oral (RR = 1.9; 95% CI = 1.1-3.3) and laryngeal (RR = 2.2; 95% CI = 2.2; 95% CI = 1.1-4.5) cancers. There was no evidence of associations with coffee and tea drinking. We conclude that the association of mate consumption with upper aerodigestive tract cancer risk is unlikely to result from insufficient control of confounding by critical exposures. Owing to its high prevalence in Southern South America, mate drinking may be linked to as many as 20% of all cases occurring in this region. PMID- 7841240 TI - Psychoactive medications and injurious motor vehicle collisions involving older drivers. AB - Older drivers have the second highest risk for motor vehicle collisions of any age group, after adolescents. Psychoactive medications may place older drivers at increased risk for injurious motor vehicle collisions. We conducted a population based matched case-control study of older drivers who were involved in injurious crashes during 1987 and 1988. The 234 cases and 447 controls were members of a large Seattle-based health maintenance organization. Use of anti-depressants and opioid analgesics by older drivers was associated with increased risk for injurious motor vehicle collisions. Compared with non-users, current users of cyclic antidepressants had an adjusted relative risk (RR) of 2.3 [95% confidence interval (CI) = 1.1-4.8]. Opioid analgesic use was also associated with an elevated crash risk (adjusted RR = 1.8; 95% CI = 1.0-3.4). We found no evidence of a dose-related effect with either class of drug. Current use of benzodiazepines or sedating antihistamines had little association with increased risk for injurious collisions. PMID- 7841241 TI - Effects of life-style on body mass index change. AB - The objective of this study was to determine the effects of age and life-style factors on body mass index (BMI) in a longitudinal, community-based sample. A total of 568 men and 668 women (20-60 years of age) were randomly chosen from four Northern California communities and followed for up to 7 years. Age, sex, marital status, smoking status, hours of television watched, frequency of consumption of several food items, and physical activity were used to predict rate of change of body mass index (BMI-slope). BMI increased the most for both sexes through at least age 54. The BMI-slope was higher for women compared with men, and for smokers who stopped compared with those who never smoked or continued to smoke during the study. The BMI-slopes were lower for individuals who increased activity. Other life-style variables had weak or inconsistent effects on the BMI-slope. We conclude that the BMI-slope increases over age for both sexes and that increased physical activity may reduce the BMI-slope. PMID- 7841242 TI - Breast cancer incidence before age 55 in relation to parity and age at first and last births: a prospective study of one million Norwegian women. AB - We examined the relation between breast cancer, parity, and age at first and last births in a large national cohort of young women in Norway. We estimated relative incidence rates by Poisson regression analyses of person-years at risk with parity and age at last (most recent) birth as time-dependent variables. A total of 1,071,795 women were included in follow-up, contributing a total of 16,643,883 person-years in the age range 20-54 years. Follow-up times ranged from 1 month to 34.5 years. A total of 4,302 women were diagnosed with breast cancer during follow-up. With adjustment for age at first and last births, high parity was associated with an overall reduced risk of breast cancer (incidence rate ratio = 0.46; 95% confidence interval = 0.36-0.59 for women with five or more children vs uniparous women). Among women age 20-29 years, however, the results suggested an increase in risk with increasing parity (incidence rate ratio = 1.25; 95% confidence interval = 0.64-2.45 for women with three children vs uniparous women). The protective effect of high parity was particularly strong among women with first birth before the age of 20 years and rather weak among those with first birth at age 30 years or more. Low ages at first and last births were both associated with reduced breast cancer risk in analyses with adjustment for the other factor, with the association with age at last birth being slightly stronger. PMID- 7841243 TI - Hierarchical regression analysis applied to a study of multiple dietary exposures and breast cancer. AB - Hierarchical regression attempts to improve standard regression estimates by adding a second-stage "prior" regression to an ordinary model. Here, we use hierarchical regression to analyze case-control data on diet and breast cancer. This regression yields semi-Bayes relative risk estimates for dietary items by using a second-stage model to pull estimates toward each other when the corresponding variables have similar levels of nutrients. Unlike classical Bayesian analysis, however, no use is made of previous studies on nutrient effects. Compared with results obtained with one-stage conditional maximum likelihood logistic regression, our hierarchical regression model gives more stable and plausible estimates. In particular, certain effects with implausible maximum-likelihood estimates have more reasonable semi-Bayes estimates. PMID- 7841244 TI - Empirical Bayes methods for stabilizing incidence rates before mapping. AB - The epidemiologic utility of mapping and ranking incidence rates is often questioned owing to instability of the observed incidence values in areas with small populations. Spurious fluctuations in the observed rates caused by this instability can mask true spatial and temporal trends in risk. To produce maps with the required level of geographic resolution, yet based on reliable estimates, it is desirable to reduce the random variation in the observed rates before mapping. In this paper, we describe the empirical Bayes approach for obtaining stabilized incidence estimates. We begin by deriving Bayes rate estimators and then illustrate how using the observed rates to estimate unknown distributional information leads to the empirical Bayes formulation. A drawback of the approach is that the histogram of the empirical Bayes rate estimates may be narrower than the true distribution of risk. We outline a constrained empirical Bayes approach that produces improved estimators for the true distribution of the unknown rates. We include discussions of relevant previous applications of empirical Bayes methods to rate mapping problems and an evaluation of the strengths and weaknesses of the approach. PMID- 7841245 TI - The role of cigarette smoking in the etiology of cervical dysplasia. AB - We evaluated the effect of smoking on the risk of cervical dysplasia in a large case-control study, obtaining smoking information from a mail questionnaire. We observed higher risks with increasing numbers of cigarettes smoked, but not with longer duration of smoking. The risk for ex-smokers was between those of current smokers and nonsmokers and was lower for women who had stopped more than 10 years ago than for those who had quit more recently. Starting to smoke at an early age did not increase the risk of cervical dysplasia. PMID- 7841246 TI - Improving conference abstract selection. PMID- 7841247 TI - Should policy recommendations be excluded from epidemiologic research papers? PMID- 7841248 TI - HIV revisited: preventing the spread of blood-borne viruses among injecting drug users. PMID- 7841249 TI - Measles control: a best-practice challenge in public health. PMID- 7841250 TI - The NSW health outcomes initiative and economic analysis. AB - The New South Wales Health Department's initiative on health outcomes promises some important advances in the planning and priority setting of health services. However, the potential to promote better health care will not be realised unless resources are redeployed to the programs where health outcomes (and other benefits) can be purchased most cheaply. The initiative reflects firmly the economic concept of efficiency but leaves less certainty about how concerns for equity are to be handled. This paper proposes that program budgeting and marginal analysis be used to create a framework for redeploying resources to follow the good buys--in terms of health and other outcomes. Additionally, the paper argues for creating the right incentives to promote efficiency, and expressly argues against the use of diagnostic related groups or casemix funding, as such funding is concerned, by definition, with cases and not with health per se. The goal of the initiative of trying to maximise health outcomes implies that there are no other valued gains to be had from health care. This is challenged. In reaching decisions about how best to deploy resources, more account should be taken, in a structured way, of community values. PMID- 7841251 TI - An outbreak of measles in a highly immunised population: immunisation status and vaccine efficacy. AB - An outbreak of 18 cases of measles in a primary school in the Australian Capital Territory in August and September 1993 provided the opportunity to study measles immunisation status and measles vaccine efficacy. Parents of 384 (78 per cent) of 491 children answered a questionnaire on recent illness consistent with measles and measles immunisation. Parents transcribed details of measles immunisation from the personal health record of the child to the questionnaire. Thirty-three per cent of cases and 3.4 per cent of the other children had not been immunised. Overall, 95 per cent of children had been immunised. The efficacy for all measles vaccines was estimated to be 90 per cent (95 per cent confidence interval (CI) 75 to 96) and for measles-mumps vaccine 87 per cent (CI 70 to 95). All of the immunised cases had received measles-mumps vaccine. There was no increased risk of measles infection in those who had been immunised at under 15 months of age compared with those immunised at 15 months or older, or in those who could not provide a date of immunisation compared with those who could. None of the children who had received two doses of vaccine caught measles. The date of immunisation was provided by 65 per cent of the respondents who said their children had been immunised. Asking parents to provide this date instead of viewing the health record is a less expensive way of assessing immunisation status but this method needs to be evaluated. Measles outbreaks still occur in highly immunised populations when vaccine efficacy appears to be acceptable. PMID- 7841253 TI - Immunisation practices of general practitioners in metropolitan Sydney. AB - An anonymous postal survey of all known general practitioners in the Northern Sydney Health Area (N = 987) examined the provision of immunisation services in general practice. Questions were asked about knowledge of storage of vaccines, the ages of patients administered measles-mumps-rubella vaccine, the use of reminder systems for subsequent vaccinations and whether maternal and family health was discussed at immunisation visits. There were 394 (40 per cent) respondents. Only 30 per cent used temperature monitors in their vaccine refrigerators, and 26 per cent correctly identified the period after opening that Sabin may be used (eight hours). Forty-one percent correctly injected infants in the anterolateral aspect of the thigh and 40 per cent administered measles-mumps rubella vaccine by the recommended age of 12 months. Forty-one percent of respondents always used visits for immunisation to discuss other issues of maternal and child health and 16 per cent used reminder systems for follow-up. Sixty-six per cent of general practitioners stated that they were more likely to review the immunisation status of adolescents routinely, compared to 55 per cent who reviewed adults and 44 per cent who reviewed senior citizens. Routine review of all three groups was carried out by 43 per cent. These results must be interpreted with caution because of low response rates, and cannot necessarily be generalised to all general practitioners providing immunisation services. Nevertheless, important deficiencies in knowledge and practice of immunisation have been identified. PMID- 7841252 TI - Impact of a promotion program for hepatitis B immunisation. AB - This study compared levels of hepatitis B immunisation in a group of 524 infants in Northland, New Zealand, with levels in the remainder of the country. The Northland sample had specific encouragement from an immunisation coordinator and had been followed from birth. Levels throughout the rest of the country were estimated from four samples totalling 317 infants whose parents were interviewed when the child was at least two years old. The cross-sectional nationwide sample had fewer children 'fully immunised' by two years of age (minimum estimate 61.8 per cent, maximum estimate 69.7 per cent) than the cohort of children (not lost to follow-up) who were encouraged to have the immunisations in Northland (77.5 per cent) (Z = 4.73, P < 0.001 for comparison with the minimum nationwide estimate; Z = 2.45, P = 0.014 for comparison with the maximum estimate). Of the Northland cohort, 13.5 per cent were lost to follow-up before the scheduled completion of the hepatitis B vaccinations. Assuming that every child lost to follow-up was not fully immunised, the efforts of the immunisation promotion program operated by a nurse coordinator increased the percentage of children fully immunised by between about 7.8 per cent and 15.7 per cent. A promotion program for hepatitis B immunisation, operated by an immunisation coordinator, is an effective tool for increasing immunisation coverage. PMID- 7841254 TI - Legislation for school entry immunisation certificates in Victoria. AB - In 1982 the National Health and Medical Research Council recommended that every state introduce legislation requiring immunisation certificates at school entry. Victoria was the first state to enact such legislation. This paper explores the process and difficulties encountered in achieving this legal requirement, describes the requirements under the legislation as it was finally introduced, and examines the early data available to the state health department regarding its implementation. Compliance with the legislation and immunisation status of children enrolling in government primary schools were ascertained from mid-year census data. In 1992 almost 90 per cent of children complied with the legislation, but because 10.2 per cent of children did not present a certificate it was possible to estimate only the lower limit of statewide coverage at 85 per cent against the prescribed diseases. School entry immunisation legislation may provide an important safety net to identify children with incomplete immunisation. However, the effectiveness of the legislation in Victoria remains unproven, and the requirements of the legislation are demanding for parents, local councils, and schools. The failure to document immunisation status in over 10 per cent of children indicates that further efforts to increase compliance are needed. This will require information on the vaccination status of those without certificates and the reasons they have not complied. The impact of the legislation needs further evaluation, although it may be years before its effectiveness can be gauged. Its effectiveness may depend upon enforcement of the requirement to exclude unimmunised children in disease outbreaks. PMID- 7841255 TI - An evaluation of school entry immunisation certificates in Victoria. AB - We evaluated legislation introduced into Victoria in 1991 requiring that all children enrolling in primary school certify their immunisation status. Information was requested from all local councils. All primary schools in two local government areas were followed up, providing an indication of the validity of the analysis obtained from data collected during the mid-year census. From 166 of 210 local councils in Victoria, 48,422 documents relating to school entry immunisation certificates were issued for children entering their preparatory year. At least 522 children were enrolled in school on an undertaking to complete immunisation, and were likely to have had their immunisation completed as a result of the legislation. Only 170 statutory declarations of conscientious objection to immunisation were made, indicating that few parents are willing to express firm anti-vaccine sentiments. Compliance with the immunisation certificate legislation is overestimated by the mid-year census because many schools have accepted nonstatutory evidence of immunisation. Mobile and immigrant families find it particularly difficult to achieve certification. Local councils are inconsistent in the way in which they issue certificates. Further follow-up and feedback is essential to better inform schools and parents about the legislation. Such follow-up can improve the certification rates of children then and in subsequent years. The legislation has imposed a considerable workload on councils, but without efforts to improve compliance with the legislation and to develop practical guidelines for documentation of immunisation and appropriate guidelines regarding transfer, many inadequately immunised children may remain at risk from vaccine-preventable diseases. PMID- 7841257 TI - Survival tucker: improved diet and health indicators in an aboriginal community. AB - The poor nutritional status of Aboriginal Australians is a serious and complex public health concern. We describe an unusually successful health and nutrition project initiated by the people of Minjilang, which was developed, implemented and evaluated with the community. Apparent community dietary intake, assessed by the 'store-turnover' method, and biochemical, anthropometric and haematological indicators of health and nutritional status were measured before intervention and at three-monthly intervals during the intervention year. Following intervention, there was a significant decrease in dietary intake of sugar and saturated fat, an increase in micronutrient density, corresponding improvements in biochemical indices (for example, a 12 per cent decrease in mean serum cholesterol, increases in serum and red cell folate, serum vitamin B6 and plasma ascorbic acid), decrease in mean systolic and diastolic blood pressures, a normalisation of body mass index, and a normalisation of haematologic indices. The success of this project demonstrates that Aboriginal communities can bring about improvements in their generally poor nutritional status, and that the store-turnover method provides a valid, inexpensive and noninvasive method for evaluating the resultant changes in community diet. Although the project was undoubtedly effective in the short term, further work is in progress to assess individual strategies with respect to sustainability, cost-effectiveness and generalisability. PMID- 7841256 TI - A sampling framework for rural and remote doctors. AB - A pilot survey by telephone interview, followed by a questionnaire of all rural doctors identified in Queensland, was used develop both a definition of rural practice that distinguishes it from urban general practice and a classification of rural and remote practice which assists in sampling of rural doctors. Questionnaire responses in specific geographic areas were compared using chi square and Mantel-Haenszel chi-square tests. Several factors were found to differentiate rural from urban general practice consistently, thereby enabling a functional definition of rural practice to be developed. Within the broad group of rural doctors, gradients in practice characteristics were found to differentiate doctors in larger rural centres from those in smaller, more remote communities. These gradients were related to the distance and time of travel from support services. They formed the basis of a complex classification of rural and remote general practice. This functional definition of rural and remote medical practice should be considered by researchers of rural medicine issues when sampling rural and remote doctors. The strategies used in this study could be adapted for use in considering practice characteristics of other rural health professions. PMID- 7841258 TI - Primary hepatocellular carcinoma in aboriginal Australians. AB - We identified incident cases of primary hepatocellular carcinoma (PHC) in the Northern Territory from 1980 to 1989: there were 18 Aboriginal and six non Aboriginal cases, yielding incidence rates of 5.2 per 100,000 (Aboriginal) and 0.5 per 100,000 (non-Aboriginal) with a relative risk of 10.4 (95 per cent confidence interval (CI) 4.0 to 26.6). The carcinoma was more frequent in males (2.3 per 100,000) than in females (0.7 per 100,000), with a relative risk of 3.4 (CI 1.3 to 9.3). Incidence increased with age; the trend was statistically significant in Aborigines (chi 2(1) = 4.7, P < 0.05) but not in non-Aborigines (chi 2(1) = 3.4, P > 0.05). Hepatitis B virus (HBV) serology was available for 11 Aboriginal and four non-Aboriginal cases; seven of the Aboriginal cases and two of the non-Aboriginal cases were positive for hepatitis B surface antigen (HBsAg). The prevalence of HBsAg in Aboriginal patients with the carcinoma (63.6 per cent) was much higher than that (13.1 per cent) in Aborigines surveyed from communities in the Northern Territory (chi 2(1) = 21.7, P < 0.001). Our results show that the age-specific incidence of PHC in Aborigines in the Northern Territory (30.9 for ages 40 and over) is comparable to that in high-incidence countries such as China (36.9 for ages 40 and over), and that hepatitis B is of major aetiological importance in the Aboriginal population. This underlines the importance of universal immunisation for prevention of HBV infection and for long term prevention of PHC. PMID- 7841259 TI - Participation in breast cancer screening: randomised controlled trials of doctors' letters and of telephone reminders. AB - The study used a randomised controlled trial to find out whether supporting letters from general practitioners accompanying the invitations from a screening centre affected participation in a population-based breast cancer screening program for women aged 50 to 64. A further randomised controlled trial compared the effect of postal reminders with telephone reminders for women who did not respond to an initial invitation to participate in the program. There were 482 women in the first trial and 641 in the second. Excluding women who were ineligible or could not be contacted, participation in screening was 71 per cent in the group which received letters from their general practitioners compared with 62 per cent in the group which did not receive letters (P = 0.059). In the group that received letters, 56 per cent were screened without a reminder compared with 43 per cent of the group that did not receive letters (P = 0.01). Fewer women who received letters from their general practitioners declined the invitation to be screened (P = 0.048). In the second trial, there was no difference in participation between the group receiving telephone reminders and the group receiving postal reminders. As in breast cancer screening programs in other countries, general practitioner endorsement of invitations increased participation in breast cancer screening. Postal reminders were as effective as telephone reminders in encouraging women who did not respond to an initial invitation to participate in screening. PMID- 7841260 TI - Differential and spatial aspects of suicide mortality in New South Wales and Sydney, 1980 to 1991. AB - Occupational and marital status dimensions of suicide mortality in New South Wales were examined for the periods 1980 to 1985 and 1986 to 1989-90 respectively, and marital status and birthplace group mortality profiles were examined in relation to grouped occupations, with a view to identifying the relative influence of these differentiating factors on suicide mortality. Spatial analysis was undertaken for different ages, in major regions of New South Wales and statistical local areas in Sydney for the period 1985 to 1991, and associations with socioeconomic characteristics of geographic areas were investigated. Despite residential revitalisation in inner city areas, higher mortality in several inner city localities has persisted over time while levels have risen in some outer areas. Never-married and divorced men in manual work were most at risk of committing suicide and never-married and divorced women had elevated suicide levels. Male suicide levels were elevated among farmers and related workers, and youth and adult male suicide levels were elevated in inland regions of the state. Possible explanations for the variations are discussed. PMID- 7841261 TI - Homicide victims among Australian immigrants. AB - The homicide rates for various immigrant groups in Australia were calculated, and the influence of the rate in countries of origin on immigrant rates and the relationship between the birthplace of the accused and victim were examined. Age sex standardised mortality ratios (SMRs) for homicide were calculated for the immigrant groups, based on 1984-1988 mortality data and 1986 census data. The Australian-born homicide rates were used as the standard. Standardised mortality ratios for countries of origin were derived from WHO data. A cross-tabulation of the birthplaces of the accused and the victim was compiled from 1989-1992 police records. Male SMRs ranged from 0.13 (P < 0.01) for immigrants from Africa and the Americas to 5.83 (P < 0.05) for Koreans. Several female groups had lower SMRs than the Australian-born, although none of these differences were significant. Indonesian females had the highest SMR (5.32, P < 0.01). There was a positive Spearman correlation between the ranking of homicide rates for the origin populations and the immigrants (males 0.64, P < 0.05; females 0.62, P < 0.05). Overall, 51.3 per cent of immigrants were killed by their compatriots. This ranged from zero for New Zealanders to 100 per cent for immigrants from the Middle East. In order to further identify factors contributing to the large differences in rates it is imperative to have information on the victim, the perpetrator and the circumstances surrounding the murder. PMID- 7841262 TI - The implications of underreporting in dietary studies. AB - Dietary data from the Western Sydney Dietary Survey 1989-90 (n = 512) was used to investigate: 1. the prevalence and predictors of underreporting of energy intake, 2. the effects on results of excluding data from underreporters for analysis of mean nutrient intakes, and 3. the proportion of energy intake supplied by macronutrients and proportions of subjects who met dietary goals. The proportion whose measured energy intakes from a Food Frequency Questionnaire (FFQ) were below cutpoints for biologic plausibility was 28.5 per cent; it was higher for subjects who had BMI > 25 and were female. Point estimates for mean intakes of energy and nutrients were all greater when data from underreporters were excluded, but nutrient intakes expressed as percentages of energy intake remained largely unchanged. Increases in estimated mean population intake for each nutrient ranged from 7 per cent to 14 per cent for males, and 12 per cent to 17 per cent for females. Estimates of the percentages of the sample who did not meet dietary goals were significantly lower for a number of nutrients when underreporters were excluded. We conclude that: 1. results expressed as a percentage of energy intake are not affected by the exclusion of energy underreporters, and 2. estimates of the proportion of populations meeting some nutrient goals and associations between diet and disease are likely to change meaningfully and significantly with the exclusion of data from underreporters. PMID- 7841263 TI - Cost-effectiveness of recruitment methods in a population-based epidemiological study: the Melbourne Visual Impairment Project. AB - The cost-effectiveness of five recruitment methods was evaluated to determine the best method of encouraging eligible persons to participate in the Melbourne Visual Impairment Project (a population-based epidemiological study). The evaluation was divided into two phases. Phase 1 included one of two types of initial contact, by direct personal contact or by telephone. Phase 2 involved recruiting residents after an attempt had been made by either the telephone or the doorstep approach, and included a second attempt by a field interviewer, subsequent attempts by senior field staff, and finally, financial incentives. The cost-effectiveness of each method was determined by dividing the approach's cost by the effectiveness ratio. We identified 269 eligible households with 356 eligible residents. An 89 per cent response rate was achieved at the examination centre, comprising 61 per cent from Phase 1 and 28 per cent from Phase 2. Although both recruitment methods in Phase 1 were equally cost-effective, there was a significant difference in the effectiveness of each method in actually recruiting residents. The doorstep method was more costly per attender but was far more effective at 76 per cent recruitment than the telephone method at 47 per cent (P < 0.001). We have demonstrated a practical two-stage approach (the doorstep method in Phase 1 and follow-up strategies in Phase 2) to population based recruitment involving the middle to elderly age group that should be relevant to many epidemiological studies. PMID- 7841264 TI - Knowledge and practice of sexual safety in Melbourne gay men in the nineties. AB - Despite the impact of education programs, the ability of gay men to sustain sexual safety still comes under public scrutiny. A self-administered questionnaire was distributed in 1990 to a convenience sample of 284 gay identified Melbourne men recruited from gay groups, health clinics, gay pubs and nightclubs, sex-on-premises venues, and the social networks of these men. The questionnaire measured the perceived safety of various sexual practices and the practice of unprotected anal intercourse over the previous three months. These results were compared with results from other Australian studies. Whereas nearly all the men were sexually active, only a small proportion considered activities such as oral sex without ejaculation and anal sex with condoms to be 'totally safe'. The majority considered these activities to be 'more safe than unsafe', suggesting a risk-reduction rather than a 'no-risk' approach to sex. Comparisons with other Australian studies suggest that gay men are becoming more confident in the safety of sexual activities labelled as 'safe' by the AIDS Council. There was no elevated practice of unprotected anal sex at 'sex-on-premises' venues. Most men who had anal sex used condoms all of the time, whether sexual partnerships were 'once only' or were 'ongoing', suggesting that 'condoms always' is still a viable option in various partnerships. There was some evidence that a minority of men abandoned condoms in ongoing partnerships. If specific education campaigns are developed to promote 'negotiated safety' in partnerships, then such campaigns should not contradict the 'condoms always' strategy. PMID- 7841265 TI - Increasing response rates of gynaecologists to a survey: a randomised trial of telephone prompts. AB - This study used a randomised controlled trial to evaluate the effectiveness of telephone prompts to increase the response rate of gynaecologists to a survey. A nine-page questionnaire about management of women with abnormal Pap smears was mailed to Fellows of the Royal Australian College of Obstetricians and Gynaecologists. A random sample was contacted in advance by telephone, and nonrespondents received a telephone reminder 14 days after the initial mail-out. The control group was mailed questionnaires and a reminder letter conventionally. On Day 25, nonresponders in both groups were mailed a second questionnaire. Of the intervention group, 84 per cent responded to the survey compared to 69 per cent of the control group (P = 0.005). A telephone call in anticipation of a mailed questionnaire is highly recommended. PMID- 7841266 TI - Longitudinal predictors of burnout in HIV/AIDS health professionals. AB - This study examined causes of burnout in doctors, nurses and social workers caring for patients in HIV/AIDS units. There were 84 participants at Time 1 (1990) and 134 at Time 2 (1991). The results focus on the longitudinal subsample of 32 who participated in the study at both times. Path analysis was used to explore relationships between burnout at Time 2 and age, hours per week in HIV/AIDS work, and external coping style at Time 1. Older age was related to lower levels of burnout at Time 2. Hours per week in HIV/AIDS work was related to levels of burnout. Participants using an external coping style were more likely to score highly on burnout at Time 2. Where possible, management should avoid recruiting young, inexperienced staff without addressing burnout issues. Workshops to teach staff internal coping skills are recommended. Units might promote the psychosocial achievements of staff, shifting away from the traditional cure-based achievement measures. PMID- 7841267 TI - Australian breastfeeding rates: the challenge of monitoring. AB - The Australian Bureau of Statistics has published national breastfeeding summary data collected in the 1989-90 National Health Survey. Despite expectations that these data would give, for the first time ever, national age-specific breastfeeding rates and would allow monitoring towards national breastfeeding targets, they did not. Secondary analysis has been conducted to expand the usefulness of these data. The results, presented in this paper, suggest that breastfeeding rates have fallen since the mid-1980s, and if confirmed, suggest that the national targets set for the year 2000 may be out of reach. Limitations of the 1989-90 National Health Survey breastfeeding questions and published results are highlighted and suggestions for future national breastfeeding surveys are given. PMID- 7841268 TI - Religiosity, sexual intercourse and condom use among university students. AB - There is strong evidence that religiosity among adolescents is associated with delayed onset of sexual activity. However, research on relationships between religiosity and contraceptive practices is limited and inconsistent. This paper provides data from a survey of 374 students aged between 16 and 21 at two Brisbane universities (72.4 per cent response rate). Those who perceived religion to be important in their lives were less likely to have had intercourse. Among the sexually active sample, religious youth did not differ from their peers in recent condom use, the age at which they first used condoms or the rate of partner change. Contrary to several recent assertions in review articles, this and other empirical studies do not show that religious youth are less likely than nonreligious youth to take precautions during sex. PMID- 7841269 TI - Intersectoral policy reform is critical to the National Mental Health Strategy. PMID- 7841270 TI - Position statement of the Thoracic Society of Australia and New Zealand on smokers' compensation. PMID- 7841271 TI - [Intraoperative transesophageal echocardiography--possibilities and prospects]. PMID- 7841272 TI - [Perioperative applications of transesophageal echocardiography]. AB - Transoesophageal echocardiography (TEE) is a visualising ultrasound technique that has entered the arena of anaesthesiology and intensive care shortly after its clinical introduction in the early 80s. Due to transducer positioning close to the heart, two-dimensional echocardiograms render high spatial resolution of cardiac structures and in adequate views continuously demonstrate the complete course of cardiac filling and contraction. The high sensitivity of the method, numerous options to assess morphological and functional parameters, and the low related risk involved for the patient explain the growing interest in TEE as a perioperative monitoring device. This utilisation, however, is currently limited by the high costs of the ultrasound equipment, the demand for specialists knowledge, the cost-benefit relation not yet thoroughly explored and the little propagated knowledge of the method's capacity. In addition, the need for information is growing due to the permanent technological progress of the equipment, which recurrently requires actualization in evaluating TEE. PMID- 7841273 TI - [Transesophageal echocardiography for determining left-ventricular end-diastolic myocardial tension]. AB - OBJECTIVE: Left ventricular end-diastolic wall stress (EDWS) ist an index for left ventricular preload. Utilising transoesophageal echocardiography, left ventricular dimensions can be obtained by two-dimensional (2d-) as well as M-Mode measurements, and each can be combined with pulmonary capillary wedge pressure (PCWP) for the calculation of EDWS. In the present examination, both methods were compared with regard to their technical accomplishment and reproducibility under clinical conditions. METHODS: EDWS was obtained in 24 ventilated patients by 2d echocardiography (2d-EDWS) and M-mode-echocardiography (M-EDWS) before and after a change in PCWP by 3mmHg. In 12 patients, volume therapy with hydroxyethylstarch (HAES) was started when PCWP < 11 mmHg; in another 12 patients, continuous intravenous administration of nitroglycerine was begun, when PCWP > 14 mmHg. 2d EDWS and M-EDWS were compared and their relation to thermodilution stroke volume and stroke work index analysed. RESULTS: 2d-EDWS and M-EDWS correlated well in both groups (HAES: r = 0.91; NITRO: r = 0.93), with M-EDWS being systematically lower than 2d-EDWS. The relative difference between 2d-EDWS and M-EDWS, and their mean value--calculated as the mean per cent error--was 11.2%. Directional changes in preload were reflected in all patients by 2d-EDWS and M-EDWS in accordance. Both correlated better with stroke volume and stroke work index than PCWP. Determination of 2d-EDWS showed better inter- and intraobserver variability in the echocardiographic measurements. CONCLUSIONS: With regard to direction and quantity, changes of preload as seen with echocardiographic EDWS were according reflected by the 2d- and the M-mode technique. Determination of 2d-EDWS compared to M-EDWS was superior in reproducibility and more useful for the estimation of stroke volume changes. PMID- 7841274 TI - [A possible risk for geriatric risk patients caused by intraoperative disorder of cerebral energy utilization?]. AB - OBJECTIVE: This study was carried out on cerebrospinal fluid (CSF) to investigate the perioperative course of certain ischaemic markers, namely neurone-specific enolase (NSE), creatine kinase (CK-BB), hypoxanthine, and lactate in order to identify a disturbed cerebral energy utilisation which could be responsible for the development of temporary mental dysfunctions. Those dysfunctions are characterised by preserved memory content and perception, but the coordination and association of these functions are disturbed. Typical clinical signs are motor restlessness, disordered emotions, and symptoms of dementia. Little is known about the aetiology of those symptoms, but they are most likely due to various events, such as direct drug effects, the extent of surgical trauma, sensorial deprivation, and disturbed perfusion. METHODS: Eight orthopaedic patients (ASA III or IV) scheduled for removal of their total hip replacement were anaesthetised by catheter-spinal anaesthesia (CSA) for pain relief in combination with standardised, modified neuroleptanalgesia (NLA). At six defined times (15 hours preoperatively, immediately before and after surgery and 6, 24, and 36 hours postoperatively) CSF samples were drawn and the ischaemic markers were determined by means of radioimmunoassay (NSE), electrophoresis (CK-BB), photometry (lactate), and high-pressure liquid chromatography (hypoxanthine). The release of ischaemic markers into CSF correlates linear with the extent of ischaemic brain damage. RESULTS: Mean concentrations of the following ischaemic markers increased in all patients intraoperatively: NSE from 12.3 ng/ml to 13.4 ng/ml, hypoxanthine from 1.86 mumol/l to 3.73 mumol/l, and lactate from 1.4 mmol/l to 2.0 mmol/l respectively, all of which returned to normal within 36 hours. The CK-BB concentrations were all within normal values and not affected by the operation during this investigation. CONCLUSION: Although no clinical signs of temporary mental dysfunction have been observed, the results indicate that in CSF ischaemic markers temporarily undergo certain changes in their concentrations during the removal of total hip replacements in elderly patients. These changes are reason for assuming that risk patients may suffer a temporary disturbed cerebral energy utilisation intraoperatively, even if stable clinical and cardiovascular conditions prevail under anaesthesia. Such a temporary ischaemic penumbra might be responsible for the postoperative development of temporary mental dysfunctions. PMID- 7841275 TI - [Capnometry in emergency air transport--experimental studies of the accuracy of 3 CO2 analyzers in the hypobaric chamber]. AB - AIM OF THE STUDY: The atmospheric pressure (pB) changes are much more prominently in an airplane than on the ground. Since CO2 measurements are influenced by pB changes we must ask whether accurate results are at all possible under such conditions. In our study we aimed at exposing three selected CO2 analysers to flight-specific pB changes in a hypobaric chamber while determining their accuracy and precision during such changes. METHODS: We tested Normocap CD 200 (Datex); 5250 RGM (Ohmeda) and Capnodig (Drager). Precision was tested by means of test gases having defined CO2 concentrations. The CO2 values showing up on the monitors in mmHg and vol% were compared with the relevant set values and the deviations dF (vol%) and dP (mmHg) determined. During the first flight simulation (profile I) the pressure value changed with 500 ft/min. Measurements were performed at ground level, at 4000, 6000 and 8000 ft pressure levels and again at ground level, the capnometers running continuously all the time. During a second simulation (profile II) the instruments were switched off after the 8000 ft pressure level had been attained and were then re-started. RESULTS: During simulation according to profile I, Capnodig showed dF increases with increasing pressure levels, whereas with CD 200 both dF and dP increased (dF and dP at 8000 ft with test gas containing 5.0% CO2: -0.9 vol% and +1.0 mmHg [Capnodig] or -0.3 vol% and +6mmHg [CD 200], respectively). 5250 RGM failed to indicate any numeric values after leaving the ground level. Profile II: after restarting at 8000 ft both 5250 RGM and CD 200 gave readings of satisfactory precision. Directly after the ground level pressure had been reattained, CD 200 did not yield any numeric values, whereas 5250 RGM had a dP of -6.5 mmHg (test gas with 5 vol% CO2). The results show that CO2 values indicated by such instruments should not be accepted indiscriminately. Only one of the 3 instruments tested by us was capable of long term reproducibility. CONCLUSION: It appears that the compensating mechanisms with which capnometers are provided to balance out weather-conditioned pB variations are not directly capable of coping with rapid and pronounced pB changes. Hence, it is recommended to at least roughly test the flight characteristics of an analyser by means of a test gas and by taking the cockpit pressure into consideration before using the instrument within the framework of air rescue service flights. PMID- 7841276 TI - [Randomized use of an active compression-decompression technique within the scope of preclinical resuscitation]. AB - INTRODUCTION: Despite its worldwide propagation, external chest compression is of limited efficacy. Recently a new method of cardiac resuscitation, active compression-decompression (ACD), was presented. In animals and a small series of patients resuscitated within the hospital ACD proved to augment blood flow during cardiac resuscitation as a result of greater intrathoracic pressure gradients. AIM OF THE STUDY: We investigated whether ACD does provide superior survival in patients suffering from out-of-hospital cardiac arrest. METHODS: Doctors and paramedics of the mobile intensive care unit at Mannheim University Hospital were trained in the new method. 56 patients were randomly assigned to either standard chest compression according to recommendations of the American Heart Association, AHA (Group I, 30 patients) or to ACD (Group II, 26 patients). ACD was performed by use of a hand-held suction device (CardioPump, Ambu Int.). Compression (30-50 kp) and decompression (10-15 kp) were alternately applied to the patients' chest with a frequency of 80/min. Duration of compression was 50% of the cycle. In both groups advanced life support was performed according to AHA standards. RESULTS: In Group I, 40% of the patients could be resuscitated; and 13.3% were discharged from hospital. In Group II, 38.5% of the patients regained spontaneous circulation, and 11.5% of the patients were discharged. (Group I vs. Group II: n.s.). One patient in each group survived with a severe neurological deficit. ACD caused greater physical efforts than standard chest compression. Furthermore ACD was difficult to perform in patients with ventricular fibrillation once electrode gel had been used. ACD was not feasible in five patients because of large breast (four women) and kyphoscoliosis (one patient). The rate of serious complications was lower in Group II. CONCLUSIONS: Methods to verify the efficacy of ACD in dummy training should be developed. Paramedics performing ACD should relieve each other every 5 minutes. In patients resuscitated by ACD self-adhesive defibrillation paddles instead of electrode gel should be used. Modifications in the design of the CardioPump are desirable to enhance the efficacy of ACD. With regard to future multicentre trials all paramedics should be skilled in the new technique to reach more patients in a shorter period of time. PMID- 7841277 TI - [Compensating for acidosis: pro]. AB - New insights about the pathophysiology of acidosis as well as the efficacy of various buffer solutions have once again started the discussion about the necessity and indications of buffer therapy. After evaluation of the current literature one has to conclude that the spectrum of indications for application of buffer solution is remarkably small; some indications, however, remain well accepted. It has been shown that acidosis with pH-values above 7.2 has to be buffered only rarely, especially if the underlying disease responds to causal therapy. pH-values under 7.2, however, caused by renal tubular acidosis or by certain types of lactate acidosis, respond to buffer therapy. The choice of buffer solution depends on the pathophysiology of the underlying disease. In particular the application of CO2 generating buffer solutions under the conditions of critically reduced circulation and ventilation remains doubtful. Application of CO2 generating buffers seems to be justified only if intracellular acidosis can be prevented by immediate elimination of carbon dioxide generated by the buffer reaction. PMID- 7841278 TI - [Compensating for acidosis: contra]. PMID- 7841279 TI - [Criminal processes due to crime under anesthesia]. PMID- 7841280 TI - [Mediastinal tumor and airway obstruction in general anesthesia. Case report and review of the literature]. AB - Case report of an acute airway obstruction during general anaesthesia by compression of the left main bronchus in an asymptomatic patient with unknown mediastinal mass. The patient was scheduled for a relief of a thyroid gland cyst. The compression occurred after uneventful induction of anaesthesia during the patient's positioning with flexed neck and elevated upper thorax on a pad. Increasing FiO2 from 0.5 to 1.0, repeated fiberoptic bronchoscopic examination and changing of the position of the endotracheal tube facilitated the operation. After reversal of the flexed neck position ventilation was normal. The intraoperatively suspected mediastinal tumour was confirmed by postoperative computerised tomography of thorax and neck. The teratoma was removed in toto in a second operation. In a review of the literature pathophysiological changes, preoperative assessment and anaesthetic management of patients with mediastinal tumour are discussed. PMID- 7841281 TI - [Th. Marx et al.: "Modification of duration of ventilation and length of stay of traumatized intensive care patients by quality and amount of preclinical management."]. PMID- 7841282 TI - Hospital discharge data and the uninsured. PMID- 7841283 TI - Cultural issues in the development of cancer control programs for American Indian populations. AB - Cancer is the third-leading cause of death among American Indians. The persistent disadvantage in cancer survival rates among American Indian populations emphasizes the importance of developing effective cancer control programs for prevention and early detection. However, substantial cultural differences between American Indians and whites can affect the success of these programs. This paper examines the concept of cultural sensitivity in the context of developing cancer control programs for American Indian populations. It explores fundamental differences in beliefs, behaviors, and values between American Indian and white majority cultures, and presents examples of culturally sensitive health education programs. The paper highlights insights and experiences gained in developing the North Carolina Native American Cervical Cancer Prevention Project, and gives recommendations for the development of future programs. PMID- 7841284 TI - Patterns of hospital and physician utilization among the uninsured. AB - Despite numerous studies of access to care by the uninsured, few researchers have examined whether access to hospitals among the uninsured differs from access to physicians. This study employs a correlational, two-group design (n = 102,055) to analyze cross-sectional data from the 1989 National Health Interview Survey. Multiple logistic regression was used to compare the likelihood of hospitalization for the uninsured and insured in chronically ill, acutely ill, and well nonelderly subpopulations. When compared to data from a previous study on physician visits, disparities in hospitalization among the three subgroups differed in both magnitude and relative order from disparities in physician visits. The disparities between the insured and uninsured clustered at 38 percent for hospitalization, and 20 percent for physician visits. Overall, being uninsured resulted in a larger difference for hospital utilization than for physician utilization. These findings suggest that the uninsured face even greater access barriers for hospitalization than they do for physician care. PMID- 7841285 TI - Post-hospital care for the underserved: a review. AB - Policies that encourage rapid discharge of hospitalized patients often fail to consider barriers that underserved populations face in gaining access to post discharge facilities such as nursing homes. Because of these barriers, long-stay patients (LSPs) remain hospitalized even after the successful treatment of their acute medical conditions. While the number of LSPs has increased in recent years, the plight of these patients has not been thoroughly examined. This review summarizes the characteristics of LSPs, the obstacles they encounter in obtaining post-acute care, and the potential impact of health care reform on access for underserved LSPs. It also discusses issues that policymakers must address to improve this populations's access to post-acute care. PMID- 7841286 TI - Alcohol and drug abuse treatment of homeless persons: results from the NIAAA Community Demonstration Program. AB - In a national evaluation, we assessed the implementation and outcomes of a multisite demonstration program for homeless persons with alcohol and other drug problems. We developed comprehensive case studies from data on client characteristics, utilization of services, implementation of interventions, and community systems of care at nine project sites. Client-level outcome data were analyzed to estimate the effectiveness of the interventions in a subset of projects with experimental or quasi-experimental evaluation designs. After controlling for baseline predictors, treatment clients in the majority of sites were significantly more likely than comparison clients to report improvement on one or more outcome dimensions. On alcohol use, for example, under conservative assumptions the average treatment client was drinking less at follow-up than were 57 percent of comparison clients. Analyses of predictor-by-treatment interactions suggested that clients with fewer problems benefited most from the interventions. The implementation analysis yielded a number of lessons for policymakers and program planners. PMID- 7841287 TI - Behaviour of fibroblasts during initial attachment to a glass-ceramic implant material in vitro: a time-lapse video-micrographic study. AB - The in vitro behaviour of 3T3 fibroblasts plated on a glass-ceramic implant material, Apoceram, and on tissue culture polystyrene (TCP) was monitored using phase-contrast, time-lapse video microscopy and scanning electron microscopy. Significant differences were observed in the short-term cellular response to TCP and Apoceram in the timing of the fibroblasts' morphological changes, with earlier spreading and stabilization of the cells occurring on TCP. Cell surface ruffling activity was greater on the glass-ceramic, reflecting weaker adhesions to the substratum. The experimental method used facilitates direct analysis of the dynamic activity of cells attaching to artificial substrata. PMID- 7841288 TI - Zinc phosphate cements: an evaluation of some factors influencing the lactic acid jet test erosion. AB - The lactic acid jet test was used to measure erosion rates of eight commercial zinc phosphate cements at 23 and 37 degrees C after 24 h and 2 months. Rates exceeded the ISO 9917 published limit of 0.1 mm/h when tested according to this specification (23 degrees C, 24 h), suggesting the limit should be increased. Erosion was measured by both weight loss and depth change. At 24 h erosion decreased as temperature increased, whereas after 2 months temperature had no significant effect. No trend was seen with increasing specimen maturity. Stannous fluoride may increase erosion resistance. PMID- 7841289 TI - Krypton fluoride excimer laser ablation of tooth tissues: precision tissue machining. AB - A variety of lasers using different wavelengths have been used to remove dental hard tissue. The infrared lasers produce their effects photothermally whereas ultraviolet excimer lasers remove tissue in a controlled and precise manner by photoablation. This study investigates the use of 248 nm laser radiation in the precision removal of both enamel and dentine using diffraction limited ultraviolet optics. The data showed that enamel and dentine were machined to a high level of precision (1-2 micron tolerances). The rate of removal was greater in dentine than enamel at a range of energy densities between 1.15 and 2.2 J/cm2. The method of removal of both tissues appears to be by the preferential ablation of the organic phases of each, exposing the anatomical details of their structure. An explanation of the possible method of ablation is proposed for these tissues. PMID- 7841290 TI - Chloride- and alkali-containing calcium phosphates as basic materials to prepare calcium phosphate cements. AB - Combinations of an alkali-containing calcium phosphate-like rhenanite, sodium whitlockite or calcium potassium phosphate and a chloride-containing calcium phosphate-like spodiosite or chloroapatite with or without additions of other calcium phosphates like monocalcium phosphate monohydrate, dicalcium phosphate or dicalcium phosphate dihydrate were made and mixed with water into pastes. The setting time of these pastes was determined. After soaking for a day in Ringer's solution at 37 degrees C the compressive strength and the diametral tensile strength were determined. Two of the combinations tried in this study resulted in the formation of cements at room temperature. One cement was of the type dicalcium phosphate, whereas the other gave octocalcium phosphate as the solid reaction product. The byproducts formed were an aqueous solution of NaCl and one of K2HPO4, respectively. Applications for bone repair and augmentation are envisaged. PMID- 7841291 TI - Effect of methylene blue on the fracture toughness of acrylic bone cement. AB - It has been advocated that the use of contrast acrylic bone cement (namely, a cement in which a suitable additive is included) for the fixation of a cemented arthroplasty will facilitate its revision (should this be necessary). It is useful, therefore, to determine the extent to which each of the relevant mechanical properties of the cement is affected by the presence of such an additive. It is shown, in the present work, that the addition of one contrast agent (an aqueous methylene blue solution) to a cement has no statistically significant effect on its mode-I plane-strain fracture toughness. This strengthens the case for the use of contrast cement for the aforementioned application. PMID- 7841292 TI - Evaluation of cell colonization on biomaterials: preventing cell attachment to plastic containers. AB - In biocompatibility evaluation involving cell culture models, we use samples of biomaterials of different forms and sizes. During cell seeding onto biomaterials of an inadequate size to cover the bottom of the culture wells completely, cells have the opportunity to attach to the plastic. As described in this report with two culture models and two biomaterials, we use an agarose gel sublayer to prevent this phenomenon. PMID- 7841294 TI - Cell growth on immobilized cell-growth factor. 10. Insulin and polyallylamine co immobilized materials. AB - Polyallylamine, which is cationic and enhances cell adhesion electrostatically (non-specifically), was co-immobilized with a cell growth factor, insulin, onto a surface-hydrolysed poly(methyl methacrylate) membrane. The adhesion of mouse STO fibroblast cells was accelerated by the immobilization of polyallylamine. The adhesion and growth of the cells were both markedly accelerated by the co immobilization of the polyallylamine and insulin. The co-immobilized membrane can be applied for a new technique for protein-free cell culture. PMID- 7841293 TI - Conformation of human plasma proteins at polymer surfaces: the effectiveness of surface heparinization. AB - Studies were made on the adsorption of two human plasma proteins, albumin (HSA) and fibrinogen (HFg), onto three different polymeric surfaces: commercial pellethane 2363-80AE (PU); pellethane crosslinked with a poly(amido-amine) (PUPA); and heparinized PUPA, using in situ ATR/FTIR spectroscopy (attenuated total reflection Fourier transform infrared spectroscopy). Conformational changes were found to occur on the two proteins upon adsorption onto bare PU and PUPA, and the protein unfolding on bare PU was also found to be time dependent. On the contrary, the two proteins do not change conformation when they are adsorbed onto the heparinized surface, emphasising the effectiveness of surface heparinization. PMID- 7841295 TI - Resistance and elasticity of the suture threads employed in cardiac bioprostheses. AB - The mechanoelastic features of five types of sutures were studied. The breaking stress for each was determined by means of tensile tests in which a constant strain rate was applied, and a tensile test with graduated stress and relaxation defined the elastic limit, i.e. the point beyond which deformation becomes irreversible. The study of the stress-strain curve during this elastic period enabled us to obtain the mathematical function that governs these reversible deformations, which shows excellence of fit (R2 > 0.98). The prime derivative at each point of the resulting functions is the elastic modulus, the best parameter for comparing the elasticities of the suture threads. Since breaking stress alone does not suitably define the mechanical quality of a suture, we propose the use of other parameters during the elastic period, such as percentage of elongation at a point 10 times lower than the elastic limit (safety coefficient of 10), and tensile stress and elastic modulus at the said point, which are more reliable in the assessment of the resistance and elasticity of these threads. PMID- 7841297 TI - In-vitro efficacy of an antibiotic releasing silicone ventricle catheter to prevent shunt infection. AB - Infection due to implanted polymeric devices is a major problem in modern medicine. Microbial colonization of implants in neurosurgery, e.g. cerebrospinal fluid (CSF) shunts is the main reason for their failure, and often results in the consequent removal of the infected implants. In this paper we report on new approaches in the prevention of bacterial infections by incorporation of an antibiotic (rifampicin) into the polymer devices (silicone). Drug release characteristics are investigated, and the physico-chemical mechanism of the delivery is discussed. Measurements of killing kinetics and the bacterial adhesion to the antibiotic-loaded silicone in a static adhesion assay reveal that only the liberation of high antibiotic doses over a period of weeks can prevent the bacterial colonization of the polymeric surface. PMID- 7841296 TI - Injectable collagen as a pH-sensitive hydrogel. AB - Injectable collagen is a concentrated dispersion of phase-separated collagen fibres in aqueous solution. The structure and properties of collagen fibres are defined by the magnitudes of electrostatic and hydrophobic attractive forces between neighbouring collagen molecules within collagen fibres. The structure and mechanical properties of collagen fibre dispersions were studied by dynamic rheological measurements and by polarized microscopy. Rheological measurements were performed over pHs ranging from 6 to 9 and over temperatures ranging from 283 to 298 K. At higher pHs the fibre dispersions were found to possess more rigid fibres and stronger inter-fibre attractive forces. This response is argued to result from changes in the ionization of amino acid side chains, which result in larger net-electrostatic attractive forces. Raising the temperature caused fibres to rigidify through enhanced hydrophobic attractive forces. Gels formed by lower pH-higher temperature fibre dispersions possess different properties than gels formed at higher pHs and lower temperatures. PMID- 7841298 TI - Urokinase inhibits HL-60 cell proliferation in vitro. AB - The binding of urokinase-type plasminogen activator (u-PA) to its receptor (u-PA R) is required for morphological and functional maturation during monocyte differentiation of the promyelocytic leukaemia line HL-60. This paper reports that monocyte differentiation of HL-60 cells induced by 1,25 dihydroxyvitamin D2 (vitamin D2) results in a marked increase in expression of u-PA and u-PA-R. This increase in u-PA expression is of greater magnitude than is observed after culture with interferon-gamma (IFN gamma), another potent inducer of monocytic differentiation. Dimethyl sulphoxide (DMSO), an agent that induces granulocytic differentiation, also increased expression of u-PA. However, culture with the granulocyte-inducing all-trans retinoic acid (RA) did not induce an increase in surface expression of u-PA or u-PA-R. The vitamin D2-induced increase in cell surface u-PA was not coincident with an increase in steady-state levels of u-PA mRNA, suggesting that intracellular stores of this protein, translational or post translational mechanisms of regulation, or some other regulatory mechanism may be responsible for the increase in u-PA during differentiation. To ascertain an association between the increased expression of cell-surface u-PA and reduced proliferation that accompanies differentiation, the effect of u-PA on cellular proliferation of HL-60 cells was measured. Both pro-u-PA (whole molecule) and fragments of u-PA that retained receptor-binding capability caused a marked inhibition of HL-60 proliferation in the absence of vitamin D2.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7841299 TI - Correlation of antiphospholipid antibodies and protein S deficiency with thrombosis in HIV-infected men. AB - Antiphospholipid antibodies (aPL) and free protein S (PSF) deficiency have been associated with clinical thrombosis. Previous reports described a high prevalence of these abnormalities in HIV-infected individuals, but suggested there was little associated clinical thrombosis. A cohort of 74 HIV-infected men were studied for aPL, PSF deficiency and the development of thrombosis. aPL, predominantly anticardiolipin antibodies (aCL), were detected in 86% and PSF deficiency in 33%. While 42% of men with aPL also had low PSF levels, there was no correlation between aCL titres or most measures of aPL and PSF levels. However, a strong correlation was noted between a subset of aPL that reacted to phosphatidylethanolamine by hexagonal array assay and low PSF levels. There was no significant correlation between aPL, PSF deficiency and clinical features (medication use, opportunistic infection, CD4 cell count) of HIV in 60 patients for whom clinical information was available. The overall incidence of thrombosis in this group was 18%, and thrombosis developed in 6.6% of those followed prospectively over a median follow-up of 12 months. Development of thrombosis was not significantly correlated with aPL or PSF deficiency, but the high prevalence of these abnormalities may necessitate larger study groups to determine the risk associated with these coagulation changes. Study of a larger group with careful analysis of subsets of aPL, especially those associated with low PSF levels, and longer clinical follow-up could identify the HIV-infected individuals at risk for thrombosis. PMID- 7841300 TI - Fibrinogen Milano V: a congenital dysfibrinogenaemia with a gamma 275 Arg-->Cys substitution. AB - An abnormal fibrinogen was discovered in a clinically asymptomatic woman from Italy. Routine coagulation studies revealed prolonged thrombin and reptilase clotting times and a discrepancy between the plasma fibrinogen levels determined by the clotting assay and electroimmunoassay. Release of fibrinopeptides A and B from fibrinogen Milano V by thrombin was normal. Fibrin polymerization was strongly delayed in the presence of EDTA and was partially corrected at physiological calcium concentration. Normal migration of mercaptolysed polypeptide chains was observed in polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulphate. Moreover, there was no apparent abnormality in the charge of the reduced chains of the variant fibrinogen, as judged by two dimensional gel electrophoresis. A fragment of the gamma-chain gene coding for the amino acids 259-350 was amplified and cloned. The amino acid gamma 275 arginine was found to be substituted by cysteine. Immunoblotting analysis with a rabbit antiserum against human serum albumin indicated that albumin was not linked to the odd sulphydryl group of fibrinogen Milano V. Treatment of fibrinogen Milano V with cysteamine, that is surmised to convert the mutant cysteine to a positively charged lysine analogue, did not improve the clotting properties of fibrinogen Milano V. PMID- 7841301 TI - Soluble urokinase receptor from fibrosarcoma HT-1080 cells. AB - A soluble form of urokinase-binding protein has been isolated from the human fibrosarcoma cell line HT-1080 and cell lines derived from it. Conditioned media of these cells were collected after overnight incubation under serum-free conditions, and were concentrated and passed through a column of Sepharose 4B to which high-molecular-weight urokinase had been attached. After thorough washing, a polypeptide could be eluted from the column with 1 M acetic acid. This material appeared to be a single band of approximately 60 kDa on SDS polyacrylamide gel. It cross-reacted with commercial antibodies made against urokinase receptor, and could be chemically cross-linked to the amino terminal fragment of urokinase. This material was similar to the urokinase receptor that was cleaved from HT-1080 cells by means of phosphatidylinositol-specific phospholipase C. PMID- 7841302 TI - Association of GP Ib with actin-binding protein does not require GP IX. AB - GP IX is necessary for optimal expression of the GP Ib-IX complex on the surface of transfected cells, and presumably also on the surface of the platelet. The authors investigated whether increasing complex association with the cytoskeleton is one mechanism by which GP IX exerts its effect. CHO and L cell lines that express high levels of GP Ib were used to determine whether GP Ib (GPIb alpha and GPIb beta) associated with the cytoskeleton. GP Ib in these cells was found in the insoluble cytoskeletal fraction from Triton X-100 lysates in a proportion similar to that found in cells expressing the full complex. As in platelets and cells expressing the full complex, the association of GP Ib with the cytoskeleton was shown to be mediated by actin-binding protein (ABP). This was demonstrated by the observation that a monoclonal antibody against GPIb alpha precipitated ABP from GP Ib-expressing cells, and polyclonal anti-ABP antibodies specifically coprecipitated GP Ib. In addition, colocalization of the two components in intact cells was demonstrated by confocal microscopy. These data indicate that the association of GP Ib with the cytoskeleton is independent of GP IX, which therefore must increase surface expression of the complex by another mechanism. PMID- 7841303 TI - Cloning of the complete coding sequence of rat fibrinogen B beta chain cDNA: interspecies conservation of fibrin beta 15-42 primary structure. AB - After thrombin cleavage, the newly exposed NH2-termini of the beta chains play a role in both fibrin polymerization and fibrin interactions with cells in the process of wound healing. These physiological responses have been shown to be mediated, at least in part, by beta 15-42. To compare the sequence of the beta chain of fibrin across species, the complete coding sequence of the rat fibrinogen B beta chain cDNA was cloned (designated pRB beta 3) and characterized. The sequence newly determined from pRB beta 3 encompassed nucleotides 121-589, encoding residues 9-165 of the mature polypeptide. Significant homology of pRB beta 3 cDNA and deduced amino acid sequences was found when compared with other species' B beta chains. The rat B beta-Arg14-Gly15 thrombin cleavage site is conserved; however, the fibrinopeptide B sequences are only 50% similar when rat is compared with human. In contrast, the beta 15-42 region is 100% similar when allowing for conservative amino acid substitutions. Monoclonal antibodies (MAbs) specific for human fibrinogen B beta 1-21 (1-8C6) and human fibrin beta 15-21 (59D8 and T2G1) failed to cross-react with rat fibrinogen or fibrin by ELISA, respectively, even though thrombin conversion of rat fibrinogen to fibrin was confirmed. MAb 1-8C6 reacted with reduced and denatured human fibrinogen B beta chain by Western blotting, whereas, MAb T2G1 did not blot with reduced and denatured human fibrin beta chain. A comparative analysis of the binding affinity of the human B beta fibrin(ogen) specific MAbs with B beta fibrin(ogen) from several species suggested that amino acid residues preceding and including Arg14-Gly15 are important in the epitope of the B beta 1 21 specific MAb 1-8C6, and that residues Gly15, Leu19 and/or Lys21 play an important role in the epitope shared by the beta 15-21-specific MAbs T2G1 and 59D8. PMID- 7841304 TI - Haemophilia A diagnosis by automated fluorescent DNA detection of ten factor VIII intron 13 dinucleotide repeat alleles. AB - Haemophilia A is a recessive X linked bleeding disorder caused by deficiency or functional abnormality of coagulation factor VIII. This disease usually has no visible phenotype in female carriers; hence, great efforts are made to offer all haemophilia A families accurate carrier diagnosis. Significant progress in this direction was made with the identification of the intron 13 variable number tandem repeat (VNTR), which is hitherto the most informative single marker within the factor VIII gene. The authors have established intron 13 VNTR detection in their laboratory by adapting its analysis to an automated sequencer using different primers of which one is fluorescent dye labelled. With this method, which is more rapid and convenient than that originally described, 67 haemophilia A families of German origin were screened and two new alleles (alleles 17 and 25) were identified. The informativeness of the VNTR in these families based on the patients maternal X chromosomes (134) is about 67%. PMID- 7841305 TI - Dextran sulphate inhibits phospholipid and sulphatide mediated autoactivation of factor XII. AB - In normal plasma, high molecular mass dextran sulphate (DS500) induces formation of amidolytic activity towards the chromogenic substrate H-D-Pro-Phe-Arg-p nitroanilide (S-2302) specific to factor XII and kallikrein. No amidolytic activity was formed when plasma deficient in prekallikrein was exposed to DS500. In contrast, factor XII amidolytic activity was formed upon exposure to sulphatide or acidic phospholipids. To assess whether DS500 interferes with the sulphatide and the acidic phospholipid in activating factor XII, plasma deficient in prekallikrein was incubated with phosphatidylinositol phosphate (PtdInsP) and sulphatide at the conditions necessary for activation with these surfaces and various concentrations of DS500. DS500 inhibited both the PtdInsP and the sulphatide-mediated autoactivation in an antithrombin III independent manner. Heparin also inhibited the PtdInsP mediated autoactivation but not that mediated by sulphatide. The heparin inhibition was due to enhancement of the antithrombin III activity, which could be partly blocked by preincubation of plasma with rabbit anti-human antithrombin III IgG. PMID- 7841306 TI - Hepatocyte growth factor and plasminogen activation in fulminant hepatic failure. AB - Human hepatocyte growth factor (hHGF) has considerable sequence homology with plasminogen and both proteins can be activated by plasminogen activators. The aim of this study was to investigate the relationship between plasma hHGF and fibrinolysis in patients with fulminant hepatic failure (FHF), in whom proteases of coagulation are known to be activated and hHGF levels have been shown to be raised as a consequence of hepatic regeneration. Serum hHGF measured by ELISA was increased in FHF (median 6.67 ng/ml, range 1.2-62 ng/ml), but the values did not correlate with the decreased plasminogen level (median 9%., range 0.7-35.5%) or the level of t-PA which was normal. There was a significant correlation between serum hHGF and increased plasma D-dimer (median 2,163 microgram/l, range 39-7 311 microgram/l), produced by the action of plasmin on fibrin and increased plasma thrombin-antithrombin III complexes (TAT, median 31.7 microgram/l, range 3.7-105 microgram/l). These relationship could be indicative of an involvement of blood coagulation, possibly a specific serine protease, in hHGF activity. After liver transplantation, plasma hHGF was rapidly cleared to almost normal levels, whereas D-dimer and TAT continued to be at elevated levels. PMID- 7841308 TI - A lupus anticoagulant neutralization procedure using the patient's own platelets. AB - An auto platelet neutralization procedure (APNP) which assists identification of lupus anticoagulants (LA) is described. Patient platelet-rich plasma is frozen then thawed (PRPF) and an activated partial thromboplastin time (aPTT) is performed on both platelet-poor plasma and PRPF. The degree of correction between the two plasmas is calculated and the percentage APNP is obtained. A lupus anticoagulant was suspected if a sample had a prolonged aPTT and at least two out of three of the following characteristics: (1) aPTT resistant to correction with equal parts normal plasma, (2) prolonged kaolin clotting time mixing test (delta KCT), (3) prolonged dilute Russell's Viper Venom Time that did not correct with normal plasma (DRVVR). Ten normal volunteers had mean (+/- SD) APNP of 7.7 +/- 4.3%. Fifty LA negative patients with normal aPTT, delta KCT and DRVVR, had a mean APNP of 10.0 +/- 6.3%. Twenty-eight patients suspected as LA positive had APNP > 25% with a mean of 39.0 +/- 7.5%. Twenty-one patients with prolonged aPTT attributed to factor deficiency had APNP < 25% with a mean of 6.3 +/- 12.0%. LA was also suspected in two other patients with prolonged aPTT that did not meet the above criterion but had APNP > 25%. In three patients with normal aPTT, LA was suspected and APNP ranged from 21 to 28%. An intermediate APNP range of 20 25% may be suggestive of LA in patients with normal aPTT. The APNP did not appear to be effected by platelet count in the samples tested unless the platelet count in PRP was less than 175 x 10(9)/1.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7841307 TI - Analysis of the thrombin inhibitor DuP 714 by an enzyme-linked immunosorbent assay. AB - A competition enzyme-linked immunosorbent assay (ELISA) has been developed for the quantitative detection in plasma of DuP 714, a boroarginine tripeptide (Ac (D)-Phe-Pro-boroArg) with potent antithrombin activity. The assay has been used to calculate the half-life after i.v. administration of DuP 714, as well as the percent bioavailability after oral administration of the agent. Following i.v. administration, in dogs, the clearance of compound from the circulation could best be fit to a biexponential decay with an initial half-life of approximately 9 min, and a slower elimination phase with a half-life of 40 min. There was a significant correlation between pharmacokinetic and pharmacodynamic characteristics (r = 0.9570, P < 0.01) as measured with the ELISA and the clotting assay, aPTT, following i.v. infusion in conscious dogs. A plasma concentration of 311 ng/ml doubled the aPTT. After oral administration of 1 mg/kg DuP 714, peak concentration ranged from 384 to 584 ng/ml. Oral bioavailability, determined by comparing the areas under concentration vs time curves after oral and i.v. administration, was 53 +/- 8% (n = 4). In summary, this assay offers a rapid, sensitive and specific method of examining the peptide's pharmacokinetic characteristics. PMID- 7841309 TI - Complement activation: a new participant in the modulation of fibrin gel characteristics and the progression of atherosclerosis? AB - The activation of the complement system has been implicated as an important mechanism in the progression of atherosclerosis. The relationship between fibrin gel characteristics and complement activation has, however, not been investigated. Zymosan-treated plasma with 87% complement activation as measured by C3a production using radioimmunoassay was found to induce changes in biophysical characteristics of fibrin network developed in both plasma and purified fibrinogen solution. Using already established methods to measure fibre thickness (mu T), permeability (T) and compaction, it was found that these networks are made of thinner fibres with increased tensile strength arranged into a matrix which renders the networks less permeable. Such networks are resistant to streptokinase-induced lysis. Fibrin networks with thin fibres in turn induced 3.7 times higher production of C3a than unmodified networks. These observations suggest the existence of positive feedback; complement activation induces major alterations in fibrin structure which in turn can induce further activation of the complement system. The detailed mechanism underlying this interrelationship is not clear at present, but this positive feedback system may play an important role in establishing a fibrin infrastructure ultimately responsible for the progression of atherosclerosis. PMID- 7841310 TI - Large-scale preparation of highly purified human C1-inhibitor for therapeutic use. AB - A two-step chromatographic procedure has been developed to purify human C1 inhibitor from cryoprecipitate-poor plasma after removal of vitamin K-dependent proteins and antithrombin III. The procedure, which is fully compatible with modern plasma fractionation schemes, includes anion-exchange chromatography on DMAE-Fractogel EMD, viral inactivation by solvent-detergent treatment, adsorption on SO3-Fractogel EMD and viral removal by nanofiltration on 35- and 15-nm pore size membranes. Overall yields were about 45% and 58% for antigen and activity, respectively, providing 60-70 mg of highly purified inhibitor per litre of plasma. The purified inhibitor had a specific activity of 6.5 +/- 0.5 units/mg protein, representing a more than 400-fold increase in purity compared with plasma. C1-inhibitor purity with respect to total protein was greater than 80%. The main contaminant was complement component C3 which accounted for 4-10% of the total protein. Minor contaminants included low amounts of IgM, IgG, IgA, fibrinogen and albumin. Complement component C4 was undetectable. The purified inhibitor was stable throughout the purification process and for more than 24 h at room temperature after reconstitution of the freeze-dried material. Animal tests in rats and mice demonstrated that the C1-inhibitor concentrate was well tolerated at relatively high doses. PMID- 7841311 TI - Heterogeneity of plasma tissue factor pathway inhibitor. AB - Much of tissue factor pathway inhibitor (TFPI) in plasma is bound to lipoproteins. The major form of TFPI associated with low density lipoproteins (LDL) is 34 kDa, whereas that associated with high density lipoproteins (HDL) is 41 kDa and appears in part to represent a mixed disulphide complex between TFPI and apolipoprotein AII. The native and recombinant TFPI produced by mammalian cells in tissue culture and the TFPI released by heparin in vivo, however, are 34 kDa. Western blotting with antibodies raised against specific TFPI peptides and cation exchange chromatography under denaturing conditions of partially purified plasma TFPI suggest that only a fraction of TFPI circulating in plasma is in the form of the full length molecule, the remainder consisting of variably carboxyl terminal truncated forms. Electrospray mass spectrometry of the isolated 34 kDa form of plasma TFPI, which predominantly circulates bound to LDL, confirms that it lacks a substantial portion of the carboxyl-terminus including at least a portion of the third Kunitz-type domain. PMID- 7841312 TI - alpha-thrombin bound to extracellular endothelial matrix induces pronounced fibrin deposition and platelet thrombus growth in flowing non-anticoagulated human blood. AB - Previous studies have shown that thrombin binds to the extracellular endothelial matrix and remains biologically active. In the present study, the role of matrix bound alpha-thrombin in thrombus formation was investigated by utilizing a model system of thrombogenesis. Plastic cover-slips coated with either matrix-bound alpha-thrombin or matrix-bound active site inactivated thrombin (DIP-alpha thrombin) were positioned in parallel-plate perfusion chambers and subsequently exposed to non-anticoagulated human blood at a venous wall shear rate of 100/s. The blood was drawn directly from an antecubital vein by a roller pump placed distally to the perfusion chamber. The thrombotic deposits on the matrix, fibrin deposition and platelet thrombus volume, were morphologically evaluated. Matrix bound alpha-thrombin enhanced the fibrin deposition and thrombus volume on matrices of non-stimulated endothelium with 91% (P < 0.001) and 94% (P < 0.05), respectively. In contrast, binding of DIP-alpha-thrombin to matrices of stimulated endothelium reduced the fibrin deposition by 33% (P < 0.05), but had no effect on the platelet thrombus volume. Translocation of thrombin molecules from upstream matrix areas to binding sites farther downstream on the matrix was indicated in experiments with matrices of stimulated endothelium, which showed enhanced fibrin deposition on downstream areas. Our findings are compatible with a prominent role for matrix-bound alpha-thrombin in thrombogenesis, and in particular on endothelial matrices without tissue factor. The role of matrix bound alpha-thrombin on tissue factor containing matrices appears less prominent, although it is significant. PMID- 7841313 TI - Potential-mediated and time-controlled first order activation of factor XII (Hageman factor) adsorbed to carbon surfaces. AB - Direct potential-mediated and time-controlled activation of purified human factor XII (FXII) immobilized on carbon has been demonstrated. Initial experiments were required to find a procedure for characterizing the immobilization of FXII and its activated form, factor XIIa (FXIIa). After achieving saturation of the carbon surface with FXII, surface catalytic activities could be generated under negative potential conditions. Activities depended on the duration and amplitude of the polarization applied to the immobilized FXII. The activities thus electrochemically induced in the surface-bound FXII molecules were tested biologically in the presence of normal human plasma and FXII-deficient plasma. The shortening of the activated partial thromboplastin time test suggested identity of the catalytic activities with that of activated FXII molecules. The electrochemical activation mechanism was consistently analysed according to first order kinetics. The apparent rate constants increased in the presence of zinc ions. PMID- 7841314 TI - Freeze-dried fibrinogen or fibrinogen in EDTA stimulate the tissue-type plasminogen activator-catalysed conversion of plasminogen to plasmin. AB - Both soluble and insoluble fibrin stimulate the tissue-type plasminogen activator catalysed conversion of plasminogen to plasmin. Whether fibrinogen can exert a similar effect has been a controversial issue. The present investigation shows that while fibrinogen purified by beta-alanine precipitation does not stimulate the tissue-type plasminogen activator-catalysed plasminogen activation, fibrinogen which has been either lyophilized or stripped of bound Ca2+ ions by EDTA chelation, stimulates this reaction. The data indicate that such procedures alter the molecular conformation of fibrinogen, and expose stimulatory sites which are hidden in the native fibrinogen molecule. These results may explain previous findings concerning the capacity of fibrinogen as a stimulator of the tissue-type plasminogen activator-catalysed plasminogen activation. Since even slight alteration of the molecular structure of fibrinogen leads to an increase in the tissue-type plasminogen activator stimulation, the authors suggest that this can be used to test if the fibrinogen is in a native state. PMID- 7841315 TI - The effects of intravenous Triton WR-1339 on factor VII coagulant activity and plasma lipoproteins in normocholesterolaemic and hypercholesterolaemic rabbits. AB - The hypothesis that lipolysis of large lipoproteins by lipoprotein lipase (LPL) has an important influence on the activation of the contact system of coagulation and subsequently on factor VII activation was tested in rabbits rendered hyperlipidaemic by dietary means and/or by injection of Triton WR-1339. The dietary treatment involved a control diet and two isocaloric diets containing either a 0.5% cholesterol or 0.5% cholesterol and 7.5% safflower oil supplement. Other groups of rabbits were given either a standard diet or the standard diet supplemented with 1% cholesterol. All supplemented diets increased many-fold the concentrations of cholesterol associated with the chylomicron, very low-(VLDL), intermediate-(IDL) and low-density (LDL) lipoprotein fractions. Factor VII coagulant activity (FVIIc) increased significantly in all groups of rabbits fed the cholesterol supplement. The intravenous injection of Triton WR-1339 into rabbits fed either the standard or 1% cholesterol-supplemented diet resulted in increases of plasma cholesterol and triglyceride concentrations up to 36-48 h thereafter, followed by decreases up to completion of the experiment at 72 h. Most of these increases in plasma lipids were associated with the chylomicron and VLDL fractions. Following injection of Triton into rabbits fed either the standard or cholesterol-supplemented diet, changes in FVIIc were biphasic with a decrease in activity in the early intervals when rates of accumulation of plasma lipid were constant, and a progressive increase in activity at later intervals when rates of lipid accumulation declined and then reversed.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7841316 TI - First frameshift mutation in the active protein S gene associated with a quantitative hereditary deficiency. AB - The authors used a strategy combining the amplification-refractory mutations system (ARMS) and denaturing gradient gel electrophoresis (DGGE) to screen the active protein S (PS) gene in a family with PS deficiency, and found a frameshift mutation in exon V. The protein, if expressed, would have an aberrant amino acid sequence from positions 82 to 90 and a premature stop codon in position 91. The mutation co-segregated with the deficient phenotype and was not found in 120 normal chromosomes. It is proposed that the deletion of a T in the codon corresponding to Pro 82 described here is responsible for the deficient phenotype. PMID- 7841317 TI - Evaluation of a modified procedure for Staclot LA for the confirmation of lupus anticoagulants. AB - Staclot LA is a hexagonal (II) phase phospholipid clotting assay used to confirm the presence of lupus anticoagulants (LA). However, there have been complaints that the procedure contains several incubation steps requiring 15 min of operator time. The authors were able to shorten this procedure to a single 5 min incubation without affecting assay sensitivity. Both procedures were performed on 45 known lupus anticoagulant positive specimens, 25 normal donors, eleven plasmas from patients with known factor VIII or factor V inhibitors and ten other specimens submitted for lupus anticoagulant or anticardiolipin antibody testing but without complete testing to confirm the presence of LA prior to testing with Staclot LA. Excellent agreement was observed between the two procedures with concurrence in 87 of 91 specimens (95.6%). Each method detected 39 of 45 LA positive specimens giving a sensitivity of 86.7%. This modification shortens technologist time by two-thirds without compromising assay sensitivity, which will allow for automation on commonly used coagulation analysers. PMID- 7841318 TI - Coagulation activation and reactive fibrinolysis in patients receiving oral anticoagulation after total hip or knee replacement. AB - Twenty patients having routine laboratory control of oral anticoagulation after total hip or knee arthroplasty were consecutively included in the study and were anticoagulated at an International Normalized Ratio (INR) between 2.5 and 3.5. Patients with mechanical heart valve prostheses (n = 20), deep venous thrombosis or pulmonary embolism (n = 20), at the same level of oral anticoagulation, served as control groups. Plasma concentrations of prothrombin fragment 1 + 2 and D dimer were measured and compared. In the mechanical heart valve prosthesis and deep venous thrombosis groups the median prothrombin fragment 1 + 2 concentrations were significantly lower than in the orthopaedic patient group (0.15 and 0.17 nmol/l versus 0.29 nmol/l). The D-dimer concentrations displayed a similar picture (150 and 200 micrograms/l versus 840 micrograms/l). The D dimer/prothrombin fragment 1 + 2 ratios in the patients after total hip or knee arthroplasty were significantly higher (12.4) than in the control groups (5.3 and 6.0). These data show that the fibrinolysis/coagulation balance is enhanced, mainly due to a disproportional rise in D-dimer. After assessing when the D-dimer concentration returns to normal in this anticoagulated group, this parameter may indicate the appropriate duration of oral anticoagulant treatment after surgery for total knee or hip replacement. PMID- 7841319 TI - Differences in protein S and C4b-binding protein levels in different groups of patients with antiphospholipid antibodies. AB - Total protein S (tPS), free protein S (fPS) and C4b-binding protein (C4b-BP) were measured by immunological assays in 73 patients with antiphospholipid (aPL) antibodies, in order to determine whether the previously reported abnormalities in PS levels in this group of patients could be related to the presence of lupus anticoagulant (LA) or anticardiolipin (aCL) antibodies. As compared with the normal controls (n = 44), the authors found a significant decrease of tPS, fPS and C4b-BP in 45 LA(+)aCL(+) patients (P < 0.001), a decrease of tPS (P < 0.001), fPS and C4b-BP (P < 0.01) in eight LA(-)aCL(+) patients and a decrease of only fPS (P < 0.05) in 20 LA(+)aCL(-) patients. There was no difference in the levels of tPS, fPS and C4b-BP between LA(+)aCL(+) and LA(-)aCL(+) patients. In contrast, the LA(+)aCL(+) patients had lower values of tPS, fPS and C4b-BP than LA(+)aCL(-) patients (P < 0.05). In some patients, protein S activity (PSact) was also measured and a high correlation was observed between fPS antigen and PSact (r = 0.93, P < 0.001). The data show that the presence of aCL antibodies is associated with a probably acquired deficiency of PS and C4b-BP. On the other hand, in LA patients without a CL antibodies, the fPS deficiency is unrelated to an increase in C4b-BP levels and may be due to abnormal binding of PS to C4b-BP. PMID- 7841321 TI - Pericellular enzymatic hydrolysis: implications for the regulation of cell proliferation in the vessel wall and the bone marrow. AB - The stromal microenvironment in the vessel wall as well as in the bone marrow provides specific adhesion molecules for cell-cell and cell-matrix interactions and allows a variety of growth factors to be positioned at the cell surface or the extracellular matrix for optimal signal transmission. While cell proliferation and differentiation within the different haematopoietic lineages in the bone marrow is a continuous process leading to the generation and egression of mature blood cells, endothelial and smooth muscle cells in the intact undisturbed vessel wall retain a non-proliferative quiescent cell phenotype. This changes drastically upon vascular injury, which is followed by the activation of the haemostatic system combined with a variety of growth modulatory reactions necessary for the wound healing. Several locally expressed enzymatic systems including the plasminogen activator/plasmin system, endoglycosidases and phospholipases are operative in a concerted fashion to modify the pericellular microenvironment in order to allow cell migration and invasion, but also to participate in the balance of growth regulatory processes. In particular, localization and presentation as well as mobilization and activation of growth factors are coordinated by a number of hydrolytic processes. The major components of the hydrolytic enzyme systems involved in pericellular modification as well as the consequences for the regulation of cell proliferation in the hydrolytic enzyme systems involved in pericellular modification as well as the consequences for the regulation of cell proliferation in the vessel wall and the bone marrow are discussed. PMID- 7841320 TI - A high-sensitivity thromboplastin reagent prepared from cultured human cells. AB - High-sensitivity thromboplastin reagents suitable for use in the prothrombin time (PT) assay are typically prepared from human brain and placenta, tissues that are in limited supply and subject to viral contamination. Cloning and expression of recombinant human tissue factor (TF) has enabled production of a new generation of thromboplastin reagents whose performance and utility are under active investigation. The purpose of this study was to determine the feasibility of producing a sensitive human thromboplastin reagent from a non-recombinant source: cultured human cells. Several human cell lines with apparently high constitutive TF synthesis were identified, and a viable thromboplastin reagent (Humaplastin) was produced from a human lung cell line via a non-conventional process that did not require reconstitution or rehydration of TF in cell membranes. When calibrated against BCT/253, a human brain international reference thromboplastin, Humaplastin exhibited a mean normal prothrombin time of 12.6 +/- 0.7 s (mean +/- SD: n = 20) and an International Sensitivity Index of 1.09 +/- 0.019. The performance of this reagent was well correlated (r = 0.983) with Thromborel S, a commercially available human placental thromboplastin reagent. Orthogonal least squares regression of the log PT values from the placental thromboplastin reagent versus Humaplastin and two recombinant TF-based thromboplastin reagents suggested that the latter three reagents are somewhat more sensitive than the placental thromboplastin reagent, although such differences should not be expected to have a significant impact on clinical utility. It is concluded that cultured human lung cells represent a suitable source of tissue thromboplastin for production of a high-sensitivity non-recombinant thromboplastin reagent. PMID- 7841322 TI - Synthesis and characterization of a recombinant hirudin-albumin complex. AB - The purpose of this investigation was to covalently bind recombinant hirudin (rHir) to albumin and compare alpha-thrombin inhibition by complexed rHir to rHir. rHir was radiolabelled with 125I and covalently bound to albumin using heterobifunctional cross-linking reagents. HPLC purification of the 125I-rHir SMCC-albumin complex using gel filtration chromatography resulted in four elution peaks, with the main peak containing an average M(r) of 78 kDa. This peak fraction also contained 63% (+/- 1.4%) of the total protein and 49% (+/- 6.8%) of the 125I-rHir conjugated to albumin. Purification of unbound 125I-rHir from complex was confirmed by SDS gel electrophoresis and autoradiography. 125I-rHir inhibition of alpha-thrombin, measured by an assay utilizing the chromogenic tripeptide substrate H-D-Phe-Pip-Arg-pNA (S-2238), was observed to be non competitive of linear mixed-type having a Ki of 1.61 pM and an alpha Ki of 1.09 pM. In contrast, complexed 125I-rHir was found to be a pure, non-competitive inhibitor having a Ki of 15.6 pM showing a ten-fold increase. These results demonstrate that covalently bound 125I-rHir still maintains potent alpha-thrombin affinity while losing minimal inhibitory capacity. Thus, successful modification of 125I-rHir serves as the foundation for future alternative applications for this potent inhibitor. PMID- 7841323 TI - A homozygous deletion/insertion mutation in the protein C (PROC) gene causing neonatal Purpura fulminans: prenatal diagnosis in an at-risk pregnancy. AB - A novel homozygous mutation in the protein C (PROC) gene was detected in an individual with severe type I protein C deficiency who presented with neonatal Purpura fulminans. The deletion/insertion mutation found [3351del4, 3350insA] resulted in an Asn102-->Lys substitution and the removal of codon Gly103. First trimester prenatal diagnosis was performed in a subsequent pregnancy by chorionic villus sampling and PCR/direct sequencing; the foetus was shown to be heterozygous for the lesion. This diagnosis was confirmed phenotypically after the birth of a clinically healthy child. PMID- 7841325 TI - Plasma kallikrein inhibitors in bovine plasma. PMID- 7841324 TI - A novel homozygous missense mutation (Val 325-->Ala) in the protein C gene causing neonatal purpura fulminans. AB - A novel homozygous GTG-->GCG (Val 325-->Ala) substitution was detected in the protein C gene of a newborn causing severe purpura fulminans post partum. In the consanguineous parents and two further infants a heterozygous type 1 protein C deficiency was found. Up to now the heterozygous individuals are clinically unaffected. The mutation co-segregates with the protein C deficiency state. It creates a restriction enzyme (Sac II) cleavage site. PMID- 7841326 TI - Platelets contain releasable coagulation factor IX antigen: response. PMID- 7841327 TI - Presence or absence of factor IX in normal platelets. PMID- 7841328 TI - Direct shape determination of ribosomal proteins in solution and within the ribosome by means of neutron scattering. AB - Following the 'strategy of the glassy ribosome' single protonated ribosomal proteins (r-proteins) were reconstituted into deuterated 50S subunits of Escherichia coli. The deuteration of both rRNA and r-proteins were individually adjusted to such a degree that the ribosomal matrix appeared nearly homogeneous with respect to coherent neutron scattering and had a scattering density equivalent to a D2O solution of about 90%. Neutron scattering of ribosomal subunits was recorded in reconstitution buffer containing three different concentrations of D2O around 90% D2O (contrast variation). The signal-to-noise ratio achieved allowed us to make a direct determination of the radii of gyration of r-proteins within the 50S subunit and thus provides the first information relating to the shape of these proteins in situ. We present the radii of gyration of 11 r-proteins incorporated into 50S subunits and of 9 isolated r-proteins in solution. In addition, the data concerning the overall dimensions of the r proteins we report on indicate that conformational changes of at least two individual r-proteins occur during the assembly process of the ribosome. PMID- 7841329 TI - The triple isotopic substitution method in small angle neutron scattering. Application to the study of the ternary complex EF-Tu.GTP.aminoacyl-tRNA. AB - The TIS (triple isotopic substitution) method in small angle neutron scattering was applied to determine the radius of gyration of polypeptide elongation factor Tu (EF-Tu) from E. coli associated with GDP and within the ternary complex EF Tu.GTP.aminoacyl-tRNA. The results showed that, within errors of about 1 A, there is no change in the radius of gyration of the EF-Tu moiety upon ternary complex formation. Experiments were performed in H2O buffer, in which complex formation could be followed on an absolute scale because of the relatively large contrast of both protein and tRNA. The TIS method is based on the analysis of a scattering curve that is the difference between the scattering of two solutions containing appropriately deuterium labelled particles. A necessary condition for the application of the method is that the two solutions are identical in all respects except for the extent of deuterium label. The main properties of TIS that make it very useful for the study of complex particles in solution were confirmed by this study. These are the elimination of interparticle effects in the difference curve, the 'invisibility' of unlabelled parts of the particles and the independence of the difference scattering curve on the buffer 2H2O-H2O content. The last property is of particular interest for the study of interactions that may be influenced by 2H2O, since, contrary to classical contrast variation methods, TIS experiments can be performed in H2O buffer alone. PMID- 7841330 TI - The production and X-ray structure determination of perdeuterated Staphylococcal nuclease. AB - Staphylococcal Nuclease (SNase) has been chosen as a model protein system to evaluate the improvement in neutron diffraction data quality using fully perdeuterated protein. Large quantities of the protein were expressed in Escherichia coli grown in medium containing deuterated amino acids and deuterated water (D2O) and then purified. The mean perdeuteration level of the non exchangable sites in the protein was found to be 96% by electrospray ionization mass spectrometry. The perdeuterated enzyme was crystallized and its X-ray structure determined. Crystals of perdeuterated SNase have been grown to 1.5 mm3. Crystallization conditions, space group and cell parameters were found to be the same for both native and perdeuterated forms of the protein. Comparison of these two forms of SNase revealed no significant structural differences between them at the atomic resolution of 1.9 A. Data collection using crystals of the perdeuterated protein is scheduled at the Brookhaven High Flux Beam Reactor. PMID- 7841331 TI - Location of diphenyl-hexatriene and trimethylammonium-diphenyl-hexatriene in dipalmitoylphosphatidylcholine bilayers by neutron diffraction. AB - Neutron scattering experiments have been performed on oriented dipalmitoylphosphatidylcholine (DPPC) bilayers containing diphenylhexatriene (DPH) or its trimethylammonium analog (TMA-DPH). DPH and TMA-DPH were either protonated or deuterated in one of the phenyl rings which afforded by using proton-deuterium contrast methods the location of these fluorescent probes in the model membrane. Both probes exhibit bimodal distributions in DPPC. The position, population and orientation in the two sites vary depending upon the physical state of the bilayer (gel or fluid) and the presence or absence of the TMA group. In gel (L beta') phase lipids DPH is located close and parallel to the bilayer surface (site I) and near the bilayer center, oriented at approximately 30 degrees with respect to the normal to the surface (site II). On going to the fluid (L alpha) phase, a distribution of orientations around the parallel to the surface is only observed for site II. Orientation of DPH in site I is unchanged. In the gel phase TMA-DPH is found in a position close and parallel to the bilayer surface (site I) and in a position (site II) oriented at an angle of approximately 25 degrees with respect to the bilayer normal, with the trimethylammonium group anchored in the head group domain. On going to the fluid phase there is a change in molecular orientation of each of the sites. In site I the molecule penetrates deeper in the bilayer and adopts a approximately 20 degrees tilt with respect to the surface, with an orientational distribution of +/- 10 degrees. In site II the molecule becomes perpendicular to the membrane surface. Changes in population of sites, both with DPH and TMA-DPH, are observed on going from low to high temperatures. They are however difficult to quantitate due to experimental conditions. The H2O-2H2O exchange experiments afforded an estimate of the water layer thickness as well as the maximum penetration of water into the interior of the bilayer. PMID- 7841332 TI - Protein and nucleic acid hydration and cosolvent interactions: establishment of reliable baseline values at high cosolvent concentrations. AB - Hydration and cosolvent interactions of biological macromolecules can be derived, subject to excluded volume corrections, from studies of density increments at constant chemical potentials of diffusible solutes through a semipermeable membrane. In addition to precision density determinations of solutions dialyzed to equilibrium, the analytical ultracentrifuge, static and dynamic light and small angle X-ray and neutron scattering, and combined pairwise use of, for instance, ultracentrifugation and neutron scattering, considerably strengthen the experimental analysis and its interpretation. We have examined hydration of bovine serum albumin (BSA) in the native and denatured states, and binding of the denaturant guanidinium chloride (GdmCl) to the latter form; hydration of DNA and interaction with NaCl and CsCl; revised values of the halophilic malate dehydrogenase (hMDH) tetramer hydration and 'binding' of salts; probing of nucleosome core particle hydration as distinct from and additionally to the evaluation of volume exclusion (holes), by use of variously sized sugar related probes. Conclusions presented are compared to results from precision calorimetry and from X-ray crystallography structures, whenever applicable, and comparisons made with alternative interpretations and experimental approaches. PMID- 7841333 TI - Small angle neutron scattering studies of structural characteristics of agarose gels. AB - The 30 m small angle neutron scattering facility at the National Institutes of Standards and Technology has been used to examine neutron scattering from agarose gels formed in D2O. Differential scattering cross sections have been acquired over a continuous range of Q between 0.005 and 0.3 A-1. Subtle changes in gel structure are observed when pre-gelation agarose concentration is varied. Similarly, except when the gelling solution is rapidly cooled to a low temperature, the rate at which the gels are formed does not seem to have much effect. Clearer evidence of structural rearrangement is observed when the solvent quality is changed by the addition of dimethyl sulfoxide, or when the temperature of the gel is elevated above 70 degrees C. These data are consistent with a description of a randomly structured polymer network containing discrete self similar, hydrogen-bonded, junctions normally of minimal thickness approximately 35-40 A. PMID- 7841334 TI - Conformational changes in yeast phosphoglycerate kinase upon substrate binding. AB - Small-angle neutron scattering (SANS) was used to measure the radius of gyration (Rg) of solutions of phosphoglycerate kinase (PGK) in a variety of substrate environments in D2O. The Rg of 24.0 A was measured for native PGK. A decrease in Rg was observed for the following: 23.7 A for PGK+sulphate; 23.5 A for PGK+ beta, gamma-bidentate Cr(H2O)4ATP (CrATP); 23.3 A for PGK + 3-phospho-D-glycerate (PGA)+CrATP; 22.9 A for PGK+CrATP+sulphate; 22.6 A for PGK+PGA+CrATP+sulphate. The statistical error was about +/- 0.3 A, which is less than systematic effects in this system. These results are consistent with catalysis by a hinge-bending motion of the enzyme. Since CrATP is not hydrolyzed, these results represent the conformational states of the bound substrates in the catalytically relevant ternary complex in the absence of product formation. The second virial coefficient is also measured for this system and this is consistent with that calculated from the protein volume only. PMID- 7841335 TI - Efficacy of combined chelation in lead intoxication. AB - The combination of a bone lead mobilizer, viz., CaNa2EDTA, and a soft tissue depleter such as meso-2,3-dimercaptosuccinic acid (DMSA) or the sodium salt of 2,3-dimercapto-1-propane-sulfonic acid (DMPS) was investigated for its efficacy to enhance the excretion of lead, to reduce its body burden, and to reverse certain lead-induced biochemical alterations by either of them alone in rats. The administration of CaNa2EDTA or DMSA was more effective than that of DMPS, and the combination of CaNa2EDTA and DMSA was more efficient than that of CaNa2EDTA and DMPS or the individual chelators in enhancing urinary/fecal excretion of lead, in reducing hepatic, renal, and femur concentration of lead, and in restoring lead induced inhibition of blood delta-aminolevulinic acid dehydratase and increase in blood zinc protoporphyrin and urinary delta-aminolevulinic acid levels. The brain lead was depleted by DMSA only, but the combined chelation failed to improve upon the ability of DMSA. However, chelation therapy increased diuresis and tissue depletion of zinc. PMID- 7841336 TI - Molecular orbital-based quantitative structure-activity relationship for the cytochrome P450-catalyzed 4-hydroxylation of halogenated anilines. AB - The cytochrome P450 (P450) catalyzed 4-hydroxylation of halogenated anilines was investigated with special emphasis on possible relationships between kinetic parameters and physicochemical and electronic characteristics of the substrates. The most important observation of the present study was a correlation (r = 0.96) between the natural logarithm of the apparent maximum reaction rate kcats for 4 hydroxylation of the aniline substrates in a iodosobenzene-supported microsomal cytochrome P450-catalyzed reaction and the energy of the highest molecular orbital [E(HOMO)] of the anilines. This result is in accordance with a mechanism that proceeds by an initial electrophilic attack of the P450 (FeO)3+ intermediate on the frontier pi electrons of the aniline substrates. In the iodosobenzene supported aniline 4-hydroxylation this electrophilic attack is the rate-limiting step. In the NADPH/oxygen-supported cytochrome P450-catalyzed 4-hydroxylation of the anilines a correlation of the natural logarithm of kcats with E(HOMO) was not observed and the kcats values were lower than observed in the iodosobenzene supported reaction. From this result it is concluded that, although the NADPH/oxygen-supported microsomal 4-hydroxylation of the halogenated anilines proceeds by the same cytochrome P450 (FeO)3+ intermediate and, thus, by a similar electrophilic attack of the (FeO)3+ on the pi electrons of the substrate, this attack is no longer the rate-limiting step of the reaction. Additional results of the present study demonstrate that the apparent Michaelis constant Kms of the NADPH/oxygen-supported 4-hydroxylation of the anilines decreases with increasing hydrophobicity of the aniline derivatives.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7841337 TI - Formation of NADP(H) analogs of tobacco-specific nitrosamines in rat liver and pancreatic microsomes. AB - The metabolism of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3 pyridyl)-1-butanone (NNK), and its metabolite 4-(methylnitrosamino)-1-(3-pyridyl) 1-butanol (NNAL), was examined in rat pancreatic microsomes. No pyridine N oxidation or alpha-hydroxylation were observed in these preparations. However, one unidentified metabolite of NNAL (unknown A) and two unknown metabolites of NNK (unknowns B and C) were formed. These metabolites were also detected in rat liver microsomal incubations of NNK and NNAL. Studies using [5-3H]-NNK and [Me 3H]NNK demonstrated that the metabolites contained both the pyridyl and methyl portions of the parent compound. Similar results were obtained with NNAL. Formation of unknown C required active microsomes, NADP+, and an NADPH regenerating system. The regenerating system was not required for the formation of NNAL unknown metabolite A or NNK unknown metabolite B. Chemical characterization of unknowns A and B by NMR, UV, and electrospray ionization MS demonstrated that they are NADP+ analogs in which the nicotinamide portion has been replaced by NNAL or NNK, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol adenosine dinucleotide phosphate [(NNAL)ADP+] and 4-(methylnitrosamino)-1-(3 pyridyl)-1-butanone adenosine dinucleotide phosphate [(NNK)ADP+]. Unknown C was identified as (NNK)ADPH. Both (NNK)ADP+ and (NNK)ADPH were formed from NNK while only (NNAL)ADP+ was produced from NNAL. These NADP+ derivatives were also formed when porcine brain NAD+ glycohydrolase was incubated with NADP+ and NNK or NNAL. These results indicate that NNK and NNAL are substrates for rat liver and pancreatic microsomal NAD+ glycohydrolase-catalyzed transglycosylation reactions. PMID- 7841338 TI - Cellular biochemical determinants modulating the metabolism of estrone 3,4 quinone. AB - The metabolism of the o-quinone derivative of estrone, 3,4-estrone quinone (3,4 EQ), has been investigated in human breast cancer cells. Unlike the p-quinone, diethylstilbestrol 4',4"-quinone, 3,4-EQ was not a substrate for the two-electron reduction catalyzed by the putative detoxifying enzyme, NAD(P)H:quinone reductase (DT diaphorase; DT D). Accordingly, the DNA damage induced by 3,4-EQ in human MCF 7 cells was not affected by an inhibitor of DT D. Although 3,4-EQ was not an apparent substrate for the two-electron reduction catalyzed by DT D, this o quinone was a substrate for the one-electron reduction catalyzed by cytochrome P450 reductase. The one-electron reduction of 3,4-EQ catalyzed by cytochrome P450 reductase occurred in the face of a significant and potentially physiologically relevant spontaneous reduction of 3,4-EQ by NADPH. The impact of purified superoxide dismutase (SOD) upon the production of hydrogen peroxide produced as a consequence of 3,4-EQ metabolism was evaluated; surprisingly, SOD inhibited the hydrogen peroxide produced by this o-quinone. Possible reasons for the SOD mediated inhibition of redox cycling of 3,4-EQ are discussed. In summary, important differences in the metabolism of 3,4-EQ vis-a-vis o- and p- quinones have been observed, and the implications of these differences are discussed. PMID- 7841339 TI - Molecular-modeling design of cadmium-mobilizing agents: a novel biscarbodithioate. AB - This report describes the design, synthesis, characterization, and in vivo cadmium-mobilizing properties of a novel biscarbodithioate chelating agent, namely, disodium N,N'-diglucosyl-1,9-nonanediamine-N,N'-biscarbodithioate+ ++ (C9G2DTC), HOCH2(CHOH)4CH2(CS2Na)N(CH2)9N(CS2-Na)CH2( CHOH)4CH2OH, which can coordinate to a single cadmium ion with both of its carbodithioate groups (CS2Na) in its folded configuration. When evaluated for its cadmium efficacy at 1.0 mmol/kg x 5 ip in 109Cd-pretreated rats against sodium N-benzyl-D-glucamine-N carbodithioate (BGDTC) as standard, the biscarbodithioate was found to reduce the whole-body levels of cadmium more rapidly in the rat than BGDTC which contains only one CS2Na group. The whole-body Cd depletions after the first ip injection of the new and the standard compound were 52% and 23%, respectively. The C9G2DTC was found to be more effective in removing cadmium from the liver (% Cd reductions compared to controls: C9G2DTC, 94, and BGDTC, 85), but slightly less effective in reducing renal cadmium levels (% Cd-reductions: C9G2DTC, 44, and BGDTC, 60). The ip LD50 of the bis-DTC was estimated to be slightly in excess of ca. 4.0 mmol/kg in the rat. A molecular model of this chelating agent indicates that, because of the flexibility of the nonane chain, both carbodithioate groups can approach closely enough to each other to permit complexation with the same cadmium ion to give a resulting structure without significant strain. A mechanism for the removal of Cd from CdMT by C9G2DTC is also proposed. PMID- 7841340 TI - Complexation of arsenic species in rabbit erythrocytes. AB - The binding of arsenite, As(III), and arsenate, As(V), by molecules in the intracellular compartment of rabbit erythrocytes has been studied by 1H- and 31P NMR spectroscopy, uptake of 73As, and ultrafiltration experiments. For intact erythrocytes to which 0.1-0.4 mM arsenite was added, direct evidence was obtained for entry of 76% within 1/2 h and subsequent binding of As(III) by intracellular glutathione and induced changes in the hemoglobin structure (NMR), likely due to binding of As(III). These results were compared with the effect of addition of As(V) on intact erythrocytes and revealed that a smaller amount of As(V) (approximately 25%) enters the cells; the main fraction of As(V) enters the phosphate pathway, depletes ATP, and increases Pi. In contrast, As(III) did not affect the ATP level. Both 1H- and 31P-NMR data indicated striking differences between As(III) and As(V) behavior when incubated with rabbit erythrocytes. These differences were confirmed by 73As uptake and binding experiments. meso-2,3 Dimercaptosuccinic acid (DMSA), a dithiol ligand, released glutathione from its arsenite complexes in erythrocytes. PMID- 7841341 TI - DNA sequence changes induced by two nitric oxide donor drugs in the supF assay. AB - To refine our understanding of the mutational spectra one might expect on exposure of human cells to nitric oxide (NO), we have treated the plasmid pSP189 at pH 7.4 with two compounds that generate NO spontaneously in solution, and then sequenced the mutations found when the treated plasmid was transfected into human Ad293 cells and allowed to replicate. G.C-->A.T transitions were the most abundant mutation observed with these NO donor drugs, whereas in previous work, A.T-->G.C transitions predominated when nitric oxide gas was bubbled through the plasmid solution under otherwise identical conditions. A difference in reactive intermediates formed in solution- versus gas-phase NO exposure was demonstrated by treating buffered 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonate) (ABTS) or ferrocyanide, in the presence or absence of azide, aerobically with preformed solutions of NO, with solutions of the two NO-releasing compounds, or with gaseous mixtures of equimolar NO/O2 in air; oxidation of these substrates was extensive with the gas-phase NO source whether azide was present or not, while azide almost completely quenched the oxidation pathway in the solution-phase reactions. PMID- 7841342 TI - pH-dependent one- and two-electron oxidation of 3,5-dicarbethoxy-2,6-dimethyl-4 ethyl-1,4-dihydropyridine catalyzed by horseradish peroxidase. AB - The porphyrinogenic agent 3,5-dicarbethoxy-2,6-dimethyl-4-ethyl-1,4 dihydropyridine (DDEP) is known to inactivate hepatic cytochrome P450 (P450) enzymes 2C11, 2C6, and 3A1 [Correia et al. (1987) Arch. Biochem. Biophys. 258, 436-451] by different mechanisms. The inactivation of P450 2C11 and 2C6 appears to be due to the ethylation of the heme in the active sites of the enzymes [Augusto et al. (1982) J. Biol. Chem. 257, 11288-11295], whereas the inactivation of P450 3A1 appears to involve the covalent binding of the heme to the apoprotein [Correia et al. (1987)]. Moreover, we have found that DDEP inactivates horseradish peroxidase (HRP) pretreated with hydrogen peroxide. In this system, DDEP was oxidized predominately to 3,5-dicarbethoxy-2,6-dimethyl-4-ethylpyridine (EDP) under weakly acidic conditions and predominately to 3,5-dicarbethoxy-2,6 dimethylpyridine (DP) under basic conditions. The loss of heme and the formation of altered heme products were also pH-dependent and were correlated with the formation of DP and the inactivation of HRP. Thus the inactivation of HRP appears to depend on the formation of an ethyl radical, which presumably reacts with the heme in the active site of the enzyme. Similar product ratios were obtained for the oxidation of DDEP by K3Fe(CN)6, indicating that product ratios of DP over EDP are mainly determined by the pH of buffer. These results, in addition to semiemperical calculations (AM1) for the oxidation of DDEP in the gas phase, are consistent with the idea that the inhibitor undergoes a single-electron oxidation to form the DDEP radical cation, the fate of which depends on the environment of the active site of the enzyme. The proposed formation of a radical cation by the abstraction of an electron from nitrogen is consistent with the finding of low intramolecular isotope effects of the metabolism of 3,5-dicarbethoxy-2,6-dimethyl [4-2H,4-1H]-1,4-dihydropyridine by P450 2C11 and 3A4. Under basic or aprotic conditions, the radical dissociates to form DP and the ethyl radical, which reacts with the heme, thereby inactivating the enzyme. Under acidic or polar conditions, the radical undergoes an additional one-electron oxidation to form EDP.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7841343 TI - Photochemical conversion of oligonucleotides containing 2-chloro-2' deoxyadenosine: enhanced UV sensitivity of a modified purine base induced by the nearest neighbor. AB - Irradiation of alternating dodecamers containing 2-chloro-2'-deoxyadenosine (Cl2dAdo) with ultraviolet light (254 nm) has been investigated. The photoconversion of Cl2dAdo into 2'-deoxyisoguanosine (isodGuo) and the completeness of the reaction were studied by reversed-phase HPLC and UV absorption spectra. The photosensitivity of Cl2dAdo within an oligonucleotide was found to be sequence-specific and depends on the nearest neighbor; 2' deoxyguanosine residues accelerate the rate of photoconversion by a factor of 3. PMID- 7841344 TI - Peracylation of nucleosides with methionine: foundation for a method to detect carcinogen adducts. AB - We report the chemical foundation for a new method to detect carcinogen-DNA adducts, which we have designated adduct detection by acylation with methionine (ADAM). The method is based on reaction of DNA adducts with a protected methionine derivative, (tert-butoxycarbonyl)-L-methionine N-hydroxysuccinimidyl ester (TMB-NHS). Acylation of 2'-deoxyguanosine (dGuo), used as a prototypical deoxynucleoside, and N-(deoxyguanosin-8-yl)-4-aminobiphenyl (dGuo-8-ABP), the major DNA adduct formed after in vivo exposure to 4-aminobiphenyl, a known human carcinogen, with TBM-NHS was optimized, and products were characterized by 3H radioactivity, UV absorbance, mass spectrometry, and 1H and 13C NMR. Derivatives acylated on hydroxyl (5' or 3') and/or amine (N2) groups were unambiguously determined to be mono-, bis-, and tris-TBM-acylated nucleosides. Under optimal acylation conditions [TBM-NHS (> or = 4 x 10(5) molar equivalents), pyridine (50 microL), THF (50 microL), and diisopropylcarbodiimide (DIC) (1 microL) and incubation for 2 h at 37 degrees C], the efficiency of acylation for picomole or smaller quantities of dGuo-8-ABP exceeded 95%, with the tris-TMB-acylated nucleoside representing the major product (88%). A linear correlation was obtained between the amount of [3H]dGuo-8-ABP introduced into the reaction and the total amount of TBM-acylated products formed. These results support the validity of this strategy for adaptation as an analytical method for the detection of low levels of DNA adducts through the use of (tert-butoxycarbonyl)-L [35S]-methionine N-hydroxysuccinimidyl ester. PMID- 7841345 TI - Thioredoxin alkylation by a dihaloethane-glutathione conjugate. AB - Glutathione is a thiol-containing tripeptide which functions to protect cellular constituents from endogenous and xenobiotic electrophiles via conjugation and eventual excretion. In the case of compounds such as 1,2-dihaloethanes, however, conjugate formation results in bioactivation of the species rather than detoxification. The conjugate can then act as an alkylating agent toward cellular constituents including DNA, proteins, or lipids. Alkylation of protein thiols in cells exposed to dihaloethane may contribute substantially to the toxicity produced by these compounds. We examined the reactivity of the conjugate S-(2 chloroethyl)-glutathione (CEG) toward the model protein Escherichia coli thioredoxin. At physiological pH, treatment of thioredoxin by CEG resulted in the production of several bands visible on isoelectric focusing, which were determined by matrix-assisted laser desorption ionization (MALDI) mass spectrometry to be mono-, di-, tri-, and tetra-alkylated forms of thioredoxin. A concomitant loss of in vitro enzymatic activity was observed. These products were also observed when reaction was allowed to take place at pH 11.4. Treatment at pH 4.4 resulted in lesser alkylation of thioredoxin, with only the mono- and di alkylated forms detected. Iodoacetic acid treatment of CEG-alkylated thioredoxin revealed that the iodoacetic acid-susceptible Cys32 was not carboxymethylated, suggesting that this is one of the sites alkylated by CEG. PMID- 7841346 TI - DNA-DNA interstrand cross-linking by 2,5-bis(1-aziridinyl)-3,6 bis(carbethoxyamino)-1,4-benzoquinone: covalent structure of the dG-to-dG cross links in calf thymus DNA and a synthetic DNA duplex. AB - The products of the alkylation reaction of reduced 2,5-bis(1-aziridinyl)-3,6 bis(carbethoxyamino)-1,4-benzoquinone (AZQ, 1a) with duplex DNA were studied using calf thymus DNA and a synthetic oligodeoxynucleotide. Reaction of calf thymus DNA with a mixture of AZQ and ascorbic acid followed by enzymatic digestion of the sugar phosphate backbone afforded numerous AZQ-derived products including substances identified as monoadducts of AZQ with both dG and dA (with the former in greater abundance) and two diadducts, as would be expected for intrastrand or interstrand cross-links, with one containing two dG residues per AZQ and the other one each of dG and dA (with the former adduct in greater abundance). The nucleotide connectivity and covalent structure of the dG-to-dG interstrand cross-links were studied in greater detail using a synthetic DNA duplex containing the nucleotide sequence 5'-d(GGGCCC), where it appeared that the predominant interstrand cross-links bridged dG residues on opposite strands and were separated by two intervening base pairs [5'-d(GNNC)]. The covalent structure of this lesion was tentatively identified as 2b, in which the N7 atoms of two dG residues have been alkylated by the aziridine functions of AZQ, based upon the results of piperidine fragmentation and characterization of the enzymatic and acidic hydrolysates of the cross-linked DNA. PMID- 7841348 TI - Arylamine-nucleoside adduct formation: evidence for arylnitrene involvement in the reactions of an N-acetoxyarylamine. AB - N-Acetoxyarylamines are reactive metabolites that are produced from N arylhydroxamic acids by N-arylhydroxamic acid N,O-acyltransferase and by the acetyl coenzyme A-dependent O-acetylation of N-arylhydroxylamines. Solvolytic decomposition of 7-acetyl-2-(N-acetoxyamino)fluorene (3) afforded 7-acetyl-2 aminofluorene (4) and 7,7'-diacetyl-2,2'-azofluorene (5). Solvolysis of 3 in the presence of 2'-deoxyguanosine resulted in formation of N-(deoxyguanosin-8-yl)-7 acetyl-2-aminofluorene (2), along with smaller yields of 4 and 5 than were obtained in the absence of 2'-deoxyguanosine. The inclusion of nitrene trapping agents, such as piperylene, triethyl phosphite, 1-chloro-4-nitrosobenzene, and oxygen, in the reaction medium with 3 and 2'-deoxyguanosine caused a reduction in the yields of 2, 4, and 5. Additionally, products that would be expected to be formed through reaction with an arylnitrene intermediate were obtained when triethyl phosphite, 1-chloro-4-nitrosobenzene, and oxygen were included in the incubations with 3 and 2'-deoxyguanosine. The results support the proposal that a nitrene intermediate is involved in the formation of 2, 4, and 5 from 3. PMID- 7841347 TI - Chemistry of thermal degradation of abasic sites in DNA. Mechanistic investigation on thermal DNA strand cleavage of alkylated DNA. AB - The chemistry of thermal degradation of aldehydic abasic sites in DNA was investigated. Sequencing gel analysis of duocarmycin A-treated 5'-32P-end-labeled DNA fragment indicated that upon heating at neutral pH alkylated DNA was cleaved to provide fragments possessing a modified sugar moiety which is readily decomposed to 3'-phosphate terminus by piperidine treatment. To identify the structure of modified sugar product and to investigate the mechanism of thermal cleavage, thermal degradation of various oligonucleotides containing abasic sites was investigated in detail. It was found that heating the DNA containing an abasic site induces beta-elimination to provide 3'-termini possessing a trans alpha,beta-unsaturated aldose residue together with 5'-phosphate termini. Upon prolonged heating at pH 7.0, the trans-alpha,beta-unsaturated aldose terminus is isomerized to a cis isomer or is further degraded to its hydrated products and a 3'-phosphate terminus via delta-elimination. This type of thermal degradation also occurs in the abasic site-containing calf thymus DNA. Investigation of the stereochemical course of the thermal beta-elimination reaction using a 2-pro-R-D containing abasic site has demonstrated that the reaction proceeds via a syn elimination process as observed for the enzymatic reaction of UV endonuclease V and endonuclease III. PMID- 7841349 TI - In vitro and in vivo metabolism of the carcinogen 4-nitropyrene. AB - The in vitro and in vivo metabolism of the potent mutagen and carcinogen, 4 nitropyrene, was studied. 4-Aminopyrene, 4-(acetylamino)pyrene, 9,10-epoxy-9,10 dihydro-4-nitropyrene, cis- and trans-9,10-dihydro-9,10-dihydroxy-4-nitropyrene, 9- and 10-hydroxy-4-nitropyrene, and 9- and 10-hydroxy-4-(acetylamino)pyrene were synthesized to serve as markers for the identification of 4-nitropyrene metabolites. Initially, 4-nitropyrene was metabolized by rat liver microsomes, or rat liver 9000g supernatant, to yield primarily two metabolites; one of these was identified as 4-nitropyrene-9,10-dione. The major metabolite of 4-nitropyrene in the presence of 3,3,3-trichloropropylene-1,2-oxide was 9,10-epoxy-9,10-dihydro-4 nitropyrene. In parallel studies, oral administration of 58 mg (0.3 mCi/mmol)/kg body weight of [3H]4-nitropyrene to female Sprague-Dawley rats, which are susceptible to mammary carcinogenesis by this agent, yielded 32% and 30.6% of the dose after 48 h as urinary and fecal excretion products, respectively. Excretion of the radioactivity remained slightly higher in the urine than in feces throughout 168 h after administration. Some of the fecal metabolites (isolated amounts expressed as % of dose) were identified as 4-aminopyrene (5.4), 9(10) hydroxy-4-(acetylamino)pyrene (3.3), and unmetabolized 4-nitropyrene (2.4). Sulfates (3.3) and glucuronides (2.4) of 9(10)-hydroxy-4-(acetylamino)pyrene were identified in the urine. This study indicates that nitroreduction and ring oxidation are metabolic pathways of 4-nitropyrene in vivo; similar findings were obtained previously with its structural isomers 1- and 2-nitropyrene. However, the pattern of excretion of 4-nitropyrene is different; the significance of this observation in relation to tumor induction is discussed. PMID- 7841350 TI - Reaction of lysine with estrone 3,4-o-quinone. AB - Reaction of lysine with estrone 3,4-o-quinone gave a complex mixture of products. Six compounds were isolated and identified using spectroscopic techniques. Among the reaction products isolated were 4-hydroxyestrone (2), 3-aminoisoestrone (3), 3-(N-pentyl-5-amino)-isoestrone (4), 1-lysylestrone 3,4-o-iminoquinone (5), and two dimeric products of 3,4-catechol estrone (6 and 7). PMID- 7841351 TI - Cytokine receptors: a combinative family of molecules. PMID- 7841352 TI - Cytokines in the clinics. Choose your weapon! PMID- 7841353 TI - Cytokine therapy of cancer. The importance of knowing the context. PMID- 7841354 TI - Cytokine expression in intestinal mucosal biopsies. In situ hybridisation of the mRNA for interleukin-1 beta, interleukin-6 and tumour necrosis factor-alpha in inflammatory bowel disease. AB - Etiology and pathogenesis of inflammatory bowel disease (IBD) remain obscure. There is substantial evidence that proinflammatory cytokines such as Interleukin 1 beta (IL-1 beta), Interleukin-6 (IL-6) and Tumour Necrosis Factor-alpha (TNF alpha) exhibit a key role in the the inflammatory process. In situ hybridisation can depict individual cells producing cytokine mRNA. We performed hybridisation with antisense probes specific for IL-1 beta, IL-6 and TNF-alpha on sections of paraffine-embedded biopsies. Specimens obtained from three control persons and six cases of Crohn's disease (CD) were investigated. Only few positive cells were found in tissue sections of control persons, clusters of lamina propria cells or epithelial cells containing cytokine mRNA were not observed. Inflammatory bowel disease tissue contained large numbers of cells producing mRNA specific for the three proinflammatory cytokines assayed. IL-1 beta, IL-6 and TNF-alpha mRNA were predominantly detected corresponding to cells of the lamina propria. Single cells containing mRNA specific for IL-6 were also found among the epithelial lining of intestinal crypts. Epithelial cells containing IL-1 beta and IL-6 mRNA were found in specimens derived from one patient with Crohn's disease. Notably, large amounts of cells containing cytokine mRNA were not only found in inflamed, but also in macroscopically normal mucosa. In conclusion, using proinflammatory cytokines as a model, we established in situ hybridisation on sections of mucosal biopsies permitting further insight into immune activation at individual cell level. PMID- 7841355 TI - Interleukin-13 is a monocyte chemoattractant. AB - Recombinant human IL-13 is chemotactic for purified human peripheral blood monocytes Cell migration is stimulated with a typical bell-shaped concentration curve and is maximal at 10 ng/ml. Migration is the result of chemotaxis, and not chemokinesis, as shown by checkerboard experiments. The chemotactic activity of IL-13 on monocytes is not inhibited by preincubation of the cells with pertussis toxin but is diminished by preincubation with protein kinase inhibitors. The related cytokine, IL-4, also stimulates migration of monocytes in the Boyden chamber assays at concentrations similar to those effective for IL-13. Human IL 13 is capable of attracting rabbit peripheral blood monocytes at those concentrations active on human monocytes. On the other hand, no neutrophil migration was induced by IL-13, even at 1 microM concentrations. PMID- 7841356 TI - Increased in vitro tumour necrosis factor-alpha production in iron deficiency anemia. AB - In vitro monocyte-derived tumour necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) production was assessed in iron deficient with anemia (IDA), iron deficient without anemia (ID) and control infants. The concentrations of released and cell-associated cytokines were measured before and after 3 months of iron supplementation in all groups (ferrous sulphate drops: 3 mg/Kg/day). No difference in released and cell-associated IL-1 beta was observed between either groups of infants. Lipopolysaccharide-stimulated blood mononuclear cells from IDA (n = 9) infants produced a significantly higher immunoreactive TNF alpha concentration as compared to ID (n = 9) and normal subjects (n = 18) on admission (F = 6.72; p < 0.004). After iron therapy, the LPS stimulated TNF-alpha secretion by cells of IDA infants returned to the levels observed in the other groups. Since TNF-alpha plays a key role in iron metabolism, we speculate that increased TNF production in IDA infants could exacerbate the inhibition of erythroid proliferation present in these conditions. Further studies are needed to evaluate the effect of more severe anemia as well as to clarify the biological effect of increased TNF-alpha production in iron deficiency anemia and its consequences. PMID- 7841357 TI - Human interleukin-6 acts as a co-factor for the up-regulation of C3 production by rat liver epithelial cells. AB - We investigated the role of human interleukin-6 (IL-6) in the regulation of the third component of complement (C3) biosynthesis by cultured rat liver epithelial cells. A natural human IL-6 (nh IL-6) preparation was shown to up-regulate C3 production, whereas an Escherichia coli-derived recombinant human IL-6 (rh IL-6) displayed no activity on C3 biosynthesis. However, the C3-stimulating activity of the nh IL-6 preparation was only partially reduced when treated with an antihuman IL-6 monoclonal antibody. Binding studies indicated that although it was devoid of any C3 stimulating activity, rh IL-6 specifically bound to hepatic cell receptors (Kd = 0.38 nM) and possessed the same binding affinity as nh IL-6. Furthermore, the substitution of natural IL-6 molecules for the recombinant IL-6 led to the recovery of the initial C3-stimulating activity. These studies demonstrated that human IL-6 alone does not stimulate rat liver epithelial cell C3 production but is able to accentuate the C3-stimulating activity of unrecognized components which are present in the nh IL-6 preparation. Human IL-6 thus appears to act as a co-factor for the up-regulation of hepatic C3 production. PMID- 7841358 TI - From the concept of cytokines as pathogenetic mediators to in vitro immunotoxicology testing. EEC Biotech Project on In Vitro Immunotoxicology Milan, Italy. April 16-17, 1994. PMID- 7841359 TI - Soluble or membrane-anchored? PMID- 7841360 TI - Nicotine: a new neuroprotective agent? PMID- 7841361 TI - Spinal c-fos expression is differentially induced by brief or persistent noxious stimulation. AB - The influence of stimulus duration on spinal induction of the c-fos proto oncogene was analysed in the rat by pinching or heating the skin for periods varying from 20 s to 2 h. At stimulation periods shorter than 20 min, c-fos activation occurred in laminae I-IIi following mechanical stimulation and I-IIo following thermal stimulation. Mechanical stimulation produced delayed activation in laminae III-IV, V and VII at 30 min, 60 min and 2 h, respectively, and thermal stimulation in lamina IIi at 50 min. It is suggested that late c-fos activation signals inflammatory pain and is due to sensitization of primary afferent neurones. PMID- 7841362 TI - Differential NMDA NR1 mRNA expression among spinal trigeminal neurons that project to different targets. AB - The N-methyl-D-aspartate (NMDA) NR1 glutamate receptor subtype has been proposed to play an important role in the transmission of orofacial sensory information in the spinal trigeminal nucleus (STN). The distribution of NR1 mRNA expression in the STN and its relationship to STN projection neurons has not been investigated previously. Using neuroanatomical tract tracing with in situ hybridization techniques, we found that neurons in the STN that project to the thalamus, cerebellum and spinal cord expressed more mRNA for NR1 than do nonprojection neurons. Trigeminothalamic neurons were found to express more NR1 mRNA than trigeminospinal or trigeminocerebellar neurons. Thus, NMDA-specific excitatory amino acids may be more efficacious in the relay of orofacial information to the thalamus than to the spinal cord or cerebellum. PMID- 7841363 TI - Early detection of mouse wobbler mutation: a model of pathological motoneurone death. AB - The mouse recessive mutation wobbler, carried by the C57BL/6J strain, is a naturally occurring model of motoneurone death. The gene is unknown and in the absence of predictive markers, mutants have to be diagnosed by phenotypic criteria at 4 weeks after birth. We localized the wobbler gene to chromosome 11 at 0.98 +/- 1.1 cM from the glutamine synthetase (Glns) gene. A polymorphic allele of the Glns gene was then introduced into the congenic wobbler strain by intraspecific crossing. One-quarter of the offspring expressed the same phenotypic mutation as true wobbler and were detectable by PCR, as they are homozygous for the wobbler-linked Glns allele. The new mutants exhibit motoneurone degeneration despite the new genetic background. PMID- 7841364 TI - Further evidence for two types of corticopulvinar neurons. AB - Retrograde tracing experiments suggest that corticopulvinar connections originate from at least two subpopulations: medium and giant pyramids in layer 5, each with distinctive dendritic and local axonal arborizations. The present study used extracellular injections of PHA-L to delineate extrinsic axon arbors and to assess the possibility of categories that might correlate with these specific neuronal subpopulations. Two distinct types of terminations were found. Type I have smaller caliber preterminal axons, are generally elongate, and are studded with spinelike terminal specializations. Type II have larger axons (> 1.0 microns), spherical arbors, and mainly beaded specializations, some of which are conspicuously large (approximately 3.0 microns). These two axon types may differ in conduction velocity and membrane properties, and the interactions of these different features may be important for pulvinar function. PMID- 7841365 TI - Nitric oxide modulates rhythmic slow activity in rat hippocampal slices. AB - We investigated the role of nitric oxide (NO) in controlling the rate of occurrence of muscarinic rhythmic slow activity (RSA) episodes induced by carbachol in rat hippocampal slices. Typically, a series of several short intervals (< 40 s) between RSA episodes alternated with one or two longer intervals. Treatments with inhibitors of NO synthesis (NG-nitro- or NG-methyl-L arginine) or with hemoglobin shortened and stabilized all intervals. By contrast, applications of an NO donor (sodium nitroprusside) or membrane permeant cGMP analogs (8-bromo-cGMP or dibutyryl-cGMP) during blockade of NO synthesis lengthened and destabilized the intervals. The importance of cholinergic mechanisms in learning and memory is well known and our findings suggest that NO could influence synaptic plasticity by modulating the occurrence of a muscarinic component of hippocampal RSA. PMID- 7841366 TI - Diuresis and natriuresis in non-seizing and in kindled rats from a genetically audiogenic susceptible strain. AB - Audiogenic seizures are evoked by acoustic stimulation in susceptible (S) but not in resistant (R) rats. Repeated audiogenic seizures recruit limbic areas, a model called audiogenic kindling. In order to evaluate excretory patterns (urinary volume, Na+ and K+ excretion), S and R animals were non-stimulated, submitted to one (acute) or 10 (kindled) stimulations or to two aqueous overloads (5% b.w.). Non-stimulated S animals displayed a significant increase (p < 0.05) in Na+ excretion at 60, 80, 100 and 120 min. Acutely stimulated S animals showed greater natriuresis than non-stimulated animals at 40, 60, 80 and 100 min. Kindled S animals displayed the greatest natriuresis (p < 0.005) at 40, 60, 80, 100 and 120 min and the highest diuretic response (p < 0.05) at 40, 60 and 80 min. Abnormalities of the endogenous hydroelectrolytic profile of non-stimulated S animals and their overt expression in kindled rats may be related to alterations in neuroendocrine systems regulating hydroelectrolytic balance, in addition to the long-lasting effects of kindled seizures. PMID- 7841367 TI - Reversal of mitochondrial damage in a rat model of Parkinson's disease by a neurotrophic peptide (MPF analogue). AB - We have previously shown that a metabolically stable analogue of MPF, the C terminal tetrapeptide of human beta-endorphin of structure Lys-Lys-Gly-Glu, reduces the turning behaviour of rats with unilateral lesions of their nigro striatal pathways. Transmission electron microscopy (TEM) has now revealed that this effect is related to reversal of the mitochondrial damage to substantia nigra (SN) neurones induced by the lesion. The results are consistent with the concept that an inherited defect in components of the mitochondrial enzyme system is the initial step in the genesis of Parkinson's disease (PD). They also, in conjunction with known neurotropic properties of MPF, and our unpublished finding of high concentrations of an MPF-like peptide in human basal ganglia, suggest that MPF may have physiological significance in the development and regeneration of the human CNS. PMID- 7841368 TI - NT-4/5 reduces naturally occurring retinal ganglion cell death in neonatal rats. AB - The retrograde nucleophilic tracer diamidino yellow (DY) was injected into the left superior colliculi of 2-day-old rats. Two days later, right eyes were injected with either neurotrophin NT-4/5, cycloheximide (CHX), MK-801 and DNQX (glutamate receptor antagonists), or saline. Almost all rats were perfused 6-7 h later and the numbers of normal and pyknotic DY-labelled retinal ganglion cells (RGCs) were determined from retinal whole mounts. In controls (no eye injection) the proportion of pyknotic RGCs was 1.04%. This level of naturally occurring death was significantly reduced after injection of NT-4/5 (0.34%); normal RGC density was also higher in this group. RGC pyknosis was increased after saline (1.21%), MK-801/DNQX (1.22%) or CHX (1.48%) injections but only in the latter case was the increase significantly greater than control. PMID- 7841369 TI - Reactive astrocytes express the embryonic intermediate neurofilament nestin. AB - Nestin is a neurofilament protein expressed by the immediate precursors to neurons and glia in rats and humans. Nestin immunoreactivity in the rat CNS was studied following kainic acid (KA) hippocampal lesions. Numerous nestin positive cells within the KA lesion were confirmed to be reactive astrocytes by their immunoreactivity for glial fibrillary acidic protein (GFAP). The number of these cells decreased with time after the KA lesion and no astrocyte immunostaining for nestin was observed in control animals. A subset of nestin-positive cells in the ventricular subependymal region appeared to be radial glial cells, extending to cell body layers. Nestin is one of several embryonic markers expressed by reactive astrocytes, suggesting an embryonic reversion induced by the KA lesion, possibly to enhance functional recovery. PMID- 7841370 TI - BDNF-mediated rescue of axotomized motor neurones decreases with increasing dose. AB - Direct application of brain-derived neurotrophic factor (BDNF) to the cut end of axotomized immature motor neurones had only transient survival-promoting effects. Therefore, we have examined whether additional delivery of BDNF with repeated subcutaneous injections (1 mg/ml) could potentiate this short-term rescue of the lesioned sciatic and facial motor neurones in neonatal rats. Direct application of BDNF combined with intermittent (3-day intervals) injections slightly improved motor neurone survival. However, when BDNF was injected daily in addition to the direct application, the number of surviving lesioned motor neurones was markedly reduced. These findings, corroborated by results in embryonic spinal cord cultures, show that a dose-dependent reversal of BDNF-mediated positive effects on motor neurones occurs in vivo. PMID- 7841371 TI - Apo E allele frequencies in Alzheimer's disease, Lewy body dementia, Alzheimer's disease with cerebrovascular disease and vascular dementia. AB - Apolipoprotein (Apo E) was genotyped using a fluorescent PCR-RFLP assay in 187 patients with a probable or possible clinical diagnosis of sporadic Alzheimer's disease (AD) and in 166 autopsied patients with dementia (21 presenile AD, 70 senile AD, 18 Lewy body dementia (LBD), 38 AD with cerebrovascular disease (AD CVD), 19 vascular dementia). The relative epsilon 4 allele frequency was 0.472 in LBD, 0.513 in AD-CVD, 0.405 in presenile AD, 0.364 in senile AD, and 0.079 in vascular dementia. The relative epsilon 2 allele frequency was 0.211 in vascular dementia, 0.083 in LBD, 0.047 in presenile AD, 0.100 in senile AD and 0.039 in AD with CVD. We infer that apo E is a major risk factor for structural phenotypes of dementia involving AD, alone or in conjunction with another pathology. In addition, the epsilon 2 allele is likely to represent a risk factor for vascular morbidity, as the relative epsilon 2 allele frequency was 0.211 in patients with vascular dementia compared with 0.144 in elderly controls. PMID- 7841372 TI - Calcium imaging in organotypic cultures of the rat suprachiasmatic nucleus. AB - The suprachiasmatic nucleus (SCN) of the hypothalamus contains a circadian pacemaker responsible for several circadian rhythms. Retinal cell projections to the SCN carry light information that phase shifts the pacemaker through the release of excitatory amino acids. To study this pathway, the Ca(2+)-sensitive dyes Fluo-3 and Fura-2 were used in organotypic slice cultures of rat SCN to visualize changes in intracellular Ca2+ of individual cells. After at least two weeks of culture, Ca2+ responses were measured in response to agonists of glutamate receptors in the presence of tetrodotoxin (TTX). Cells that showed a Ca2+ increase in response to N-methyl-D-aspartate (NMDA) and non-NMDA agonists also showed immunoreactivity towards vasoactive intestinal peptide (VIP), providing further evidence that VIP-containing neurons receive direct retinal input. The cells differed in their responses to the NMDA and non-NMDA agonists, suggesting that the cells contain differing densities of glutamate receptor subtypes. PMID- 7841373 TI - bcl-2 protein expression in aged brain and neurodegenerative diseases. AB - The proto-oncogene bcl-2 is involved in the regulation of cell death and is able to block apoptosis in neurones through reduced generation of reactive oxygen species (ROS). We have studied the immunohistochemical expression of bcl-2 protein in the aged brain and in various human neurodegenerative diseases. In all cases, bcl-2 was strongly enriched within lipofuscin and autophagic vacuoles of neurones, glial and vascular cells. Our data show that accumulation of bcl-2 is not disease-specific and represents a general cellular response which accompanies the increased formation of lipofuscin. Since oxidative stress is directly involved in lipofuscinogenesis, accumulation of bcl-2 may reflect a mechanism for counterbalancing ROS-mediated damage, or it might represent the impairment of bcl 2-dependent protection from ROS. PMID- 7841374 TI - Very slow oscillations of activity in geniculate neurones of urethane anaesthetized rats. AB - The spontaneous activity of neurones of the dorsal lateral geniculate nucleus (dLGN) in urethane-anaesthetized rats was examined for the presence of very slow oscillatory activity. Fifty-four of the 86 dLGN neurones (63%) recorded extracellularly displayed oscillatory activity in the 0.02-0.03 Hz range. Similar very slow oscillations were observed in the ventral part of the LGN and the nucleus lateralis posterior (LP), but not in the hippocampus. Diffuse light stimuli dampened or blocked these oscillations in 23 of the 29 neurones tested. In a second group of experiments (iontophoretic studies) the very slow oscillatory activity was efficiently blocked by N-methyl-D-aspartate. PMID- 7841375 TI - Neurotrophic factors prevent the death of CNS neurons after spinal cord lesions in newborn rats. AB - The aim of this study was to determine if the exogenous administration of neurotrophic factors can rescue immature axotomized CNS neurons in vivo. After spinal cord hemisection in newborn rats, the exogenous administration of neurotrophic factors brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT 3) and nerve growth factor (NGF), prevents the retrograde cell death of axotomized red nucleus neurons (and other brain stem spinal neurons) in vivo. Rescue of red nucleus neurons was maintained in the presence of BDNF, but only transiently maintained by NT-3 and NGF. Neurons within the nucleus dorsalis (Clarke's nucleus) of the spinal cord are also axotomized by this lesion. The application of exogenous NT-3, but not NGF or BDNF, rescued Clarke's nucleus neurons. These observations indicate that neurotrophic factors play a crucial role in the survival of CNS neurons in vivo during development and after injury. Furthermore, these results indicate that particular populations of neurons are dependent upon specific neurotrophic support after injury. PMID- 7841376 TI - Long-term stimulation attenuates the transient 40-Hz response. AB - The effect of long-term stimulation on the transient 40-Hz response was studied in 5-h long experimental sessions. Ten human subjects were presented with series of 1000 Hz tone pips occasionally replaced by 1200 Hz tone pips. The transient 40 Hz response was compared with two event-related potential (ERP) components, the N1 and the mismatch negativity (MMN) during the different phases of the long lasting sessions. The 40-Hz and N1 onset responses attenuated while the MMN did not. Thus, the 40-Hz response might indicate vigilance. PMID- 7841377 TI - Ondansetron fails to attenuate a scopolamine-induced deficit in a Stone maze task. AB - The 5-HT3 receptor antagonist ondansetron has previously been reported to improve cognition in the mouse, rat and marmoset in a variety of behavioural paradigms. The present study used the Stone maze to test the effect of ondansetron on the deficit caused by scopolamine in the performance of a highly complex spatial memory task in the rat. Ondansetron administered over a large dose range (1.0 ng kg-1-1.0 micrograms kg-1, i.p., b.d.) for a period of 10-15 days failed to attenuate the scopolamine deficit. Indeed at one dose level ondansetron (100 ng kg-1, i.p., b.d.) administered in combination with scopolamine (0.5 mg kg-1, i.p.) significantly potentiated the deficit, compared with the performance of rats receiving scopolamine alone. PMID- 7841378 TI - Hypothalamic neuropeptides could mediate the anorectic effects of fenfluramine. AB - Oxytocin, vasopressin and corticotrophin releasing factor have anorectic properties when injected centrally. We studied the kinetics of these neuropeptides by injecting fenfluramine, a drug which reduces food intake, in Long Evans rats. The drug was injected daily through a double chronic cannula implanted above the paraventricular nucleus of the hypothalamus; the rats had free access to pure macronutrients. The rats lost weight during the treatment. Their total caloric intake decreased mostly because the carbohydrate intake decreased, while the protein intake increased slightly. The synthesis and release of brain oxytocin and vasopressin were increased and the release of corticotrophin releasing factor was stimulated. The neuropeptides could be involved in fenfluramine-triggered mechanisms. PMID- 7841379 TI - Origins of excitatory drive within the respiratory network: anatomical localization. AB - This study identified several sources of excitatory drive within the rat brain stem respiratory network. Excitatory neuronal projections to the ventral respiratory group (the largest brain stem respiratory neuron population in the rat) were identified by selective retrograde labeling with tritiated aspartate. Neurons were labeled within portions of the nucleus of the tractus solitarius, the region of the ventral respiratory group, superficial to the facial nucleus, the medullary raphe nuclei and the parabrachial/Kolliker-Fuse nuclei. These findings are the first anatomical demonstration of sources of excitatory drive within the respiratory network, and are consistent with electrophysiological data localizing a source of excitatory drive within the pre-Botzinger complex subdivision of the ventral respiratory group. PMID- 7841380 TI - Cell density and exogenous CNTF affect CNTF mRNA levels in glial cell cultures. AB - Regulation of CNTF mRNA was investigated in primary cortical astrocytes cultured from newborn rats and in C6 glioma cells. Northern blot analysis indicated that semi-confluent astrocyte cell cultures. CNTF added to confluent astrocyte cultures down-regulated CNTF message in a dose-dependent fashion. In contrast, when CNTF was given to semi-confluent astrocyte cultures the level of CNTF mRNA was up-regulated. C6 glioma cells also showed a cell density-dependent expression of CNTF: cells from confluent cultures expressed detectable amounts of CNTF mRNA whereas those from semi-confluent cultures did not. Thus, CNTF mRNA expression by astroglial and glioma cells is regulated by cell contact and exogenous CNTF in vitro. PMID- 7841381 TI - [125I]-alpha-bungarotoxin binding co-varies with motoneurone density during apoptosis. AB - During chick embryogenosis, apoptosis removes 50% of the initial population of spinal motoneurones. Administration of alpha-bungarotoxin during this critical phase arrests apoptosis. Intraperitoneally administered [125I]alpha-bungarotoxin reaches and binds to the spinal cord at the onset of motoneurone apoptosis. It is not known whether specific [125I]alpha-bungarotoxin binding is directly associated with motoneurones. This study was carried out to examine the level of toxin binding after the final number of motoneurones in the lateral motor column had been experimentally manipulated during the critical period of apoptosis. The level of specific [125I]alpha-bungarotoxin binding significantly co-varied with the number of motoneurones present, suggesting that the toxin could affect receptor-mediated aspects of motoneurone function which, in turn, could regulate final motoneurone number. PMID- 7841382 TI - Developmental autoregulation of calcium currents in mammalian central neurones. AB - The influence of calcium currents expressed at early stages on the subsequent development of calcium currents was studied in embryonic rat hypothalamic neurones in culture. Voltage-activated calcium currents and spontaneous fluctuations of intracellular free calcium concentration ([Ca2+]i) were monitored. Acute application of nickel chloride (0.1 mM) to 6- to 7-day-old cultures strongly reduced calcium currents and [Ca2+]i fluctuations. When cultures were maintained for 6-7 days in the presence of NiCl2 (0.05-0.1 mM), expression of the low voltage-activated current was strongly inhibited; this treatment did not affect high voltage-activated currents. Our results suggest that spontaneous activation of calcium currents early during development promotes calcium influx that regulates expression of calcium current in mature neurones. PMID- 7841383 TI - Presence of endogenous inhibitors of benzodiazepine binding in developing chick optic lobe. AB - An endogenous inhibitor of benzodiazepine receptor binding was removed from synaptic membranes of developing chick optic lobe by an exhaustive buffer washing procedure. This treatment increased [3.H]flunitrazepam binding at all stages of development, although this effect was greater at early stages (embryonic day 14 16). Scatchard analysis performed on exhaustively washed membranes at embryonic day 16 and postnatal day 15 revealed the presence of a single population of flunitrazepam binding sites with apparent dissociation constants (Kd) of 1.99 +/- 0.11 and 3.28 +/- 0.10 nM and a maximal number of binding sites (Bmax) of 1.07 +/ 0.08 and 1.22 +/- 0.11 pmol mg-1 protein, respectively. At both stages of development, the addition of inhibitory material, present in the supernatants obtained after the washing procedure, reduced the affinity of recognition sites for [3H]flunitrazepam with Kd of 4.92 +/- 0.13 and 5.62 +/- 0.12 nM, respectively while their Bmax values remained unchanged. These studies demonstrate the presence of an endogenous material in developing chick optic lobe which competitively inhibits [3H]flunitrazepam binding to its receptor site. PMID- 7841384 TI - Expression of low-voltage activated Ca2+ channels from rat brain neurones in Xenopus oocytes. AB - Xenopus laevis oocytes were injected with total mRNA obtained from the thalamo hypothalamic complex of adult rats. In 19 out of 32 injected oocytes a Ba2+ current was expressed after 4 days which could be activated at depolarizations to -70 mV from a holding potential of -120 mV and reached a maximum value at between -30 and -20 mV. The current inactivated monoexponentially with a time constant of about 420 +/- 10 ms (n = 6); its steady state inactivation had a half value of 78 +/- 1 mV (n = 8) and a slope (k) of 11.5 +/- 3.0. These characteristics are typical of LVA (T-type) Ca2+ channels in neurones from the corresponding brain structures, except for the much slower time course of inactivation. These currents were blocked by pharmacological antagonists specific for LVA channels (amiloride, flunarizine), but remained resistant to omega-Aga-IVA and omega-Cg toxin. These results show that LVA Ca2+ channels can be expressed in oocytes provided that the corresponding mRNA is taken from brain neurones in which they are naturally well expressed. PMID- 7841386 TI - Visualization of dopamine D2 binding sites on human inferior vagal ganglia. AB - The present study used in vitro autoradiography to assess whether high affinity D2 binding sites are present on sections of human inferior vagal ganglia, where arterial baroreceptor primary afferent cell bodies are located. Incubation of tissue sections with [125I]NCQ 298 (0.5 nM) revealed dense but non-uniform binding, with a well-defined topography, consistent with the localization of binding sites over cell bodies rather than nerve axons. Coincubation with the D2 antagonist raclopride (10 microM) completely abolished binding of [125I]NCQ 298. Densitometric quantification of autoradiograms estimated 82 +/- 4% specific binding for [125I]NCQ 298 (0.5 nM). These observations indicate the presence of D2 binding sites on sensory ganglia involved in cardiovascular control pathways in the human, and may help to explain some of the documented cardiovascular effects of dopamine. PMID- 7841385 TI - NMDA-mediated potentiation of the afferent synapse in the inner ear. AB - In an isolated vestibular organ preparation from the axolotl (Ambystoma tigrinum), glycine (10-0.01 microM) perfusion had no effect in the resting control condition, but significantly modified the response of afferent fibres to mechanical stimuli, producing a slowly increasing discharge rate during sinusoidal mechanical stimulation periods. This action was dependent upon the stimulus duration and was antagonized by 7-chloro-kynurenic acid (7-ClKyn), 2 amino-5-phosphonopentanoic acid (AP5), N-allyl-nor-metazocina (MK-801) and extracellular magnesium. These results indicate that glycine modulates the afferent synapse in the vestibular organ, and that, NMDA receptors codify long lasting mechanical stimuli. PMID- 7841387 TI - GFAP transfected cells produce laminin, leading to neurite outgrowth promotion. AB - Accumulating evidence indicates the importance of astrocytes in neuronal development and regeneration. While glial fibrillary acidic protein (GFAP) is believed to mediate the morphology of developing astrocytes, its precise function remains unknown. To analyse the function of GFAP in astrocytes, we established GFAP-expressing cell lines by transfection of mouse GFAP cDNA into mouse fibroblast L cells. Stable transfectants expressed GFAP uniformly in the cytoplasm with no phenotypic changes and exhibited extended processes rich in GFAP. GFAP-expressing cells significantly promoted the neurite outgrowth of rat cerebral cortex neurones in the co-culture system. Analysis of the products of GFAP-expressing cells revealed an increase in production of laminin, but not fibronectin. These results suggest that L cells expressing GFAP increase laminin production, leading to promotion of neurite outgrowth. PMID- 7841388 TI - Aluminium in rat cerebellar primary cultures: glial cells and GABAergic neurones. AB - Experimental evidence of the preferential uptake of aluminium by GABAergic neurones and glial cells was provided by synchrotron spectromicroscopy studies. We observed rat cerebellar cultures enriched for GABAergic neurones or glial cells exposed to aluminium ions, detecting the presence and identifying the chemical status of aluminium on cell structures. PMID- 7841389 TI - Nicotine protects cultured striatal neurones against N-methyl-D-aspartate receptor-mediated neurotoxicity. AB - The role of cholinergic mechanisms in N-methyl-D-aspartate (NMDA)-mediated neuronal death was investigated using mouse striatal neurones in primary culture. A 30 min exposure of striatal neurones to increasing concentrations of NMDA resulted 24 h later in dramatic neuronal degeneration as assessed by MTT staining, crystal violet incorporation and determination of microtubule associated protein 2. The NMDA-induced neurodegeneration was strongly inhibited by the co-application of two non-selective cholinergic agonists, acetylcholine or carbachol. This protective effect appears to be mediated by nicotinic receptors since it was insensitive to the muscarinic antagonist atropine but mimicked by nicotine, nornicotine and 1,1-dimethyl-4-phenyl-piperazinium. Moreover, the nicotine-evoked neuroprotection was inhibited by the central nicotinic antagonist hexamethonium. Therefore, this study suggests that cholinergic interneurones play an important role in neuronal survival in the striatum. PMID- 7841390 TI - N-methyl-D-aspartate (NMDA)-mediated muscle relaxant action of flupirtine in rats. AB - The present study examined in urethane-chloralose anaesthetized rats whether N methyl-D-aspartate (NMDA) is involved in the depressant effect of flupirtine on the monosynaptic Hoffmann (H)-reflex recorded from plantar foot muscles and on polysynaptic flexor reflexes recorded from tibialis muscle. Intrathecal administration of both the specific NMDA antagonist (-)-2-amino-7 phosphonoheptanoate and of flupirtine depressed the polysynaptic flexor reflex without affecting the monosynaptic H-reflex. In contrast, the non-NMDA antagonist 6,7-dinitroquinoxaline-2,3-dione depressed the H-reflex without affecting the flexor reflex. The depressant effect of flupirtine on the flexor reflex was prevented by co-administration of NMDA, but not by co-administration of the non NMDA agonist alpha-amino-3-hydroxy-5-tertbutyl-4-isoxazolepropionic acid. These observations suggest that NMDA might be involved in the action of flupirtine. PMID- 7841391 TI - Protein kinase inhibitor potentiates opioid delta-receptor currents in Xenopus oocytes. AB - In Xenopus oocytes injected with RNA coding for the delta-opioid receptor a small chloride current was evoked by [D-Ala2,Ser5]leucine-enkephaline-Thr6 (DSLET), a delta 2-opioid agonist. The evoked currents were rapidly reduced upon repeated challenges of DSLET. When Gil alpha RNA was co-injected into the oocyte, the evoked currents were increased 3.8-fold and became constant after at least three repeated challenges. In oocytes injected with RNAs coding for delta-receptor and Gil alpha, pretreatment with K-252a, a potent inhibitor of protein kinases, further potentiated the delta-receptor-mediated current responses, compared with those without the inhibitor. These results suggest that signalling involving the delta-opioid receptor is inactivated through in vivo phosphorylation in the Xenopus oocyte. PMID- 7841392 TI - Muscarinic (M1) mediation of carbachol-induced theta in the cat entorhinal cortex in vitro. AB - Entorhinal cortex slice preparations obtained from the cat exhibited theta rhythm during perfusion with 50 microM carbachol. The effect of carbachol was antagonized by the muscarinic blocker atropine sulphate, but not by hexamethonium and mecamylamine, which are antagonists of the nicotinic receptor. Further analysis of the pharmacological profile of these carbachol-induced theta oscillations showed that M1 receptor subtype to be involved in mediation of this EEG activity: the theta rhythm was antagonized by the M1 receptor blocker pirenzepine, but was unaffected by gallamine, an antagonist of the M2 receptor subtype. PMID- 7841393 TI - [100 years of Rontgen rays]. PMID- 7841395 TI - [The importance of sonography before laparoscopic cholecystectomy]. AB - The increasing use of minimally invasive techniques for the treatment of symptomatic cholecystitis requires exact preoperative diagnosis. The significant sonographic findings are stones in the biliary system or indirect evidence of stones, consisting in dilatation of the bile duct to more than 10 mm, as well as free mobility of the abdominal wall to exclude peri-umbilical adhesions. Amongst 100 patients who had laparoscopic cholecystectomies there were 7 with bile ducts wider than 10 mm. In two of these cases calculi could also be demonstrated. ERCP was performed on the remaining five and in 3 of these stones were seen. Peri umbilical adhesions were seen in 6 Patients, resulting in alternative placing of the incision. The sonographic findings which are of relevance to the surgeon were analysed in these 100 cases. A standardised examination protocol is an important feature for proper patient selection. PMID- 7841394 TI - [Dynamic 3D MR mammography using a rapid gradient-echo sequence]. AB - Up to now, MR mammography is performed by two different methods: 2-D techniques with high temporal resolution and 3-D techniques with high spatial resolution. This article investigates whether a dynamic examination of the breast using a novel 3-D-gradient-echo sequence is feasible with sufficient spatial and temporal resolution. MR imaging was performed on a 1.0 Tesla imager using a gradient field strength of 15 mT/m. Phantom measurements were done to evaluate the correlation between signal intensity and contrast medium concentration for different sequences. Subsequently, 40 patients with 22 histologically verified lesions were examined using the double breast coil and a novel FLASH3D sequence (TR/TE/fa 9/3/50 degrees). Reading of the films in standardized documentation, multiplanar reconstruction (MPR), calculation and maximum intensity projection (MIP) of subtraction images as well as signal-to-time curve calculations in selected ROIs were performed for data evaluation. In the phantom measurements the FLASH3D 9/3/50 degrees sequence yielded the best correlation between signal intensity and Gd-DTPA concentration. The sequence provided good visualization even of small lesions. The 3-D postprocessing procedures facilitated the detection and localization of the lesions. Therefore, the new FLASH3D-9/3/50 degrees sequence enables a dynamic 3-D examination of the breast with a sufficient spatial and temporal resolution. PMID- 7841396 TI - [Quantitative computed tomographic determination of spleen size to assess the course of malignant lymphomas]. AB - The purpose of this study was to correlate CT-assessed spleen indices (length x width x depth) and their changes under therapy or in the follow-up, with the clinical course and morphological changes. In 66 patients with 200 CT's of the abdomen the spleen index was calculated and 134 spleen index differences (delta SI) were correlated with the clinical outcome. The normal group showed a mean of delta SI of -8 = 112, equivalent boundaries of -120 and 104. delta SI of progressive lymphomas (n = 32) was 313 (p < 0.01). In 10/14 patients of this group, morphological signs of infiltration were found. In regressive lymphomas (n = 63) we found delta SI = -211 (p < 0.001). 23/29 with delta SI < -120 showed signs of spleen involvement in the preliminary examination. Since there are only slight intraindividual changes of CT-assessed spleen indices and a good correlation of spleen index differences with the clinical outcome. the spleen index is a useful instrument in the follow-up of malignant lymphomas. PMID- 7841397 TI - [The normal CT and ultrasonic findings after a laparoscopic inguinal hernia operation]. AB - Common surgery has been revolutionised by minimal invasive surgery in a very short period of time. Laparoscopic operations of inguinal hernias are routinely done by many surgeons. For interpreting correctly postoperative complications with radiological techniques it is necessary to know the sonographical and CT changes of the normal postoperative situs. For evaluating these changes 23 patients without symptoms were examined between the first and third postoperative day. Typical sonographic findings are high echogenicity of the hernial orifice (17x) and echo-lucent thickening of the spermatic cord. The surgical clips and fleece and CO2 bubbles could not be detected by ultrasound. Using CT we found free peritoneal fluid collection (2x), streaky thickenings in the area of operation (20x), oedema at the hernial orifice (19x), residual CO2 bubbles (22x), thickening of the spermatic cord (22x) and visualisation of the surgical clips. The surgical fleece was invisible in all patients. PMID- 7841398 TI - [The value of computed tomography in persistent balance disorders following the use of stapes prostheses]. AB - 10 of 150 patients had persistent vertigo after implantation of stapes prostheses. These patients were evaluated by high-resolution CT in the axial and coronal plane. Scans showed in all cases findings which related to the symptoms. The CT findings were proved intraoperatively in 9 cases. A new indirect sign of a perilymphatic fistula is described in form of an air bulla at the end of the prosthesis. Retympanotomy could be planned better with the help of HR-CT. PMID- 7841399 TI - [Phlebography of the upper extremity. I. The technic and findings in 230 studies]. AB - We report on 230 phlebographic examinations in the shoulder arm region which were performed by conventional X-ray technique and/or digital subtraction angiography (DSA). The detailed method of examination as well as anatomical variants of the vessels are explained. The group of patients was analysed concerning its composition and was subdivided with regard to clinically relevant diagnoses. Contrary to statements in the literature, the number of pathological findings in men or women were equal. The main age was between 40 and 50 years. The brachial vein was found to be doubled so often that this might be accepted as a normal situation. Phlebographic examinations were performed in the right arm twice as often as in the left one. 172 primary examinations, more than 60% showed a pathological result. PMID- 7841400 TI - [The measurement of vascular diameter to determine stent and balloon size in percutaneous procedures in the pelvic circulation]. AB - AIM: Should the sizes of balloons and stents used in the pelvic circulation be determined by the size of the ipsilateral or contralateral vessel? STUDY DESIGN: The angiographic findings in 31 patients were analysed; in 10 an occlusion and in 21 a high grade stenosis (greater than 75%) of the common iliac artery had been treated by stenting (26) or simple PTA (5). RESULTS: In 26 of the 31 patients there was marked reduction in the lumen distal to the lesion up to 40%. In 17 patients this was reversed immediately after the procedure and in five others the lumen increased but a difference between the two sides remained. The changes on the two sides following treatment were statistically significant (external iliac artery: p = 0.00013). CONCLUSION: The results indicate that the "normal" contralateral measurements should be used rather than the distal ipsilateral vessel diameter. PMID- 7841401 TI - [The sonographic and computed radiographic findings in perigraft reactions after the surgical implantation of vascular prostheses]. AB - Between January 1988 and January 1994, 24 patients with heterologous vascular bypasses were examined with suspected diagnosis of a perigraft reaction (PGR). All patients were subjected to ultrasound and CT. PGR ist defined as a sterile inflammation along the course of a vascular prosthesis. The typical clinical presentation is a fluctuating tumour with a localised painless swelling. In all cases liquid formations could be confirmed by diagnostic imaging procedures; signs of infection could be excluded. The synopsis of the clinical presentation, the time interval after implantation of the prosthetic material and the signs of sonography and CT can reliably exclude infection of the prosthesis and confirm the diagnosis of a PGR. PMID- 7841402 TI - [MR tomography in autologous plastic repair of the anterior cruciate ligament: a comparison of 2 surgical methods]. AB - The aim of this prospective MRI study was the analysis of the post-operative signals derived from two techniques for cruciate ligament reconstruction. PATIENTS AND METHODS: Group 1 consisted of 15 patients who had undergone conventional plastic repair by patellar tendon transplant and group 2 was made up of 15 patients with arthroscopic reconstruction with semitendinosus grafts. They were examined at 6 weeks and 6 months post-operatively. RESULTS: Typical appearances of normal transplants were found in 19 patients. After 6 months 8 of the patellar tendon transplants and three of the semitendinosus transplants could not be clearly defined. At this time there was a significant increase in signal intensity in the middle third of the transplant in group 1. CONCLUSION: Bearing in mind the different operative techniques, there was a higher impingement rate in group 1. The post-operative MRI findings at 6 months after surgery allowed differentiation between pathological changes (impingement) and revascularisation (remodelling). PMID- 7841403 TI - [The correction for motion and visualization of subtraction angiographic data from the spiral CT]. AB - Conventional image subtraction of CT sequences is hampered by extended motion artifacts. In this paper a motion correction procedure for the subtraction of images from two time-separate CT investigations is introduced. Native images are obtained in the first CT sequence, and a contrast medium examination is imaged in the second. The aim of image subtraction is sole presentation of the contrast medium. In contrast to conventional digital subtraction angiography (DSA), CT angiography rules out the possibility of direct image subtraction due to occurrence of extended motion artifacts in the time-shifted images. Such shortcomings can now be corrected by means of a new registration method developed for determination of local displacement vectors between the two images. This motion pattern is used to compute a new synthetic mask of maximum congruence with the contrast medium image. The resulting three-dimensional data record is presented by means of a special-purpose hardware enabling fast rotations and cut planes. New diagnostic possibilities can be achieved such as the creation of views that are not obtainable with conventional modalities and the assessment of calcified vessels. PMID- 7841404 TI - [The civil law liability in radiology. An analysis of the administration of justice]. AB - This study comprises 76 published judgments by German and Austrian civil courts between 1966 and 1993 concerning liability in the field of radiology. There has been a marked increase in the number of legal proceedings in the 1980's and even more so in the second half of this decade. This is due to an increased tendency to sue doctors without any legal cause in the hope of possible compensation. In 40.8% of the cases the doctor was held liable and required to compensate the patient for personal injury and suffering pain. Most of the cases were related to complications during the examination procedure. The reason most frequently cited by the courts for sentencing doctors was the fact that they did not previously inform the patient adequately about the examination and its possible consequences. PMID- 7841405 TI - [The value of conventional skull x-rays after head injuries]. AB - A retrospective study was used in an attempt to clarify whether skull fractures or clinical findings can be used for diagnosing intracranial injuries and which clinical features indicate that skull X-rays are unnecessary. 78 patients (1.5%) had a skull fracture and 41 patients (0.8%) had suffered intracranial injuries. Of 57 patients with skull fractures, 40% (23) showed evidence of intracranial injury and 60% (34) did not. Amongst 41 patients with intracranial injuries, 44% (18) failed to show a skull fracture. Patients with a skull fracture (without intracranial injury) showed just as many symptoms as patients without skull fracture. Patients with intracranial injuries most commonly showed neurological deficits, unconsciousness, or required intubation. Any one of these criteria or a combination of these indicated the presence of intracranial injury with a high degree of probability. These criteria permit economy with skull X-rays and indicate when to use other diagnostic means (CT). For this the patient should be mentally quite normal. There should be a definite history and a reliable observation period of 24 hours. PMID- 7841406 TI - [The CT-guided perineal axial needle biopsy of presacral pelvic space-occupying lesions]. PMID- 7841407 TI - [A Jefferson fracture following a nonaxial force impact]. PMID- 7841408 TI - [Secondary polytopic parathyroid adenomas. Hyperparathyroidism recurrence after the dissemination of parathyroid tissue in the surgical field]. PMID- 7841409 TI - [PTA and stent placement in the superior vena cava syndrome under the temporary salvage of a venous port system]. PMID- 7841410 TI - Diagnostic and therapeutic role of ERCP in biliary ascariasis. PMID- 7841412 TI - The legacy of the night before. PMID- 7841411 TI - [Emphysematous pyelonephritis]. PMID- 7841413 TI - Do occupational physicians agree about ill-health retiral? A study of simulated retirement assessments. AB - A questionnaire survey on simulated ill-health retirement decisions was performed at a scientific conference for local authority medical advisers. Respondents were asked to make decisions based on ten case scenarios drawn from real life. The overall agreement amongst 35 physicians was low, with a kappa statistic of 0.241. There were wide variations amongst respondents, with two physicians accepting all ten cases for retirement while another accepted only one. The survey suggests that there is great potential for inconsistency and inequity in such decisions. An improvement in agreement between physicians might be achieved by training, consensus guidelines and audit. This issue should be addressed by occupational physicians and trustees of superannuation schemes. PMID- 7841414 TI - Determinants of safe behaviour in farmers when working with pesticides. AB - Despite stringent regulation, accidents occur in the use of pesticides. To explore the factors which might influence farmers' approaches to safety when handling chemicals, we interviewed 84 agricultural workers from south-west Hampshire who reported having worked with pesticides in the previous 12 months. Most of those interviewed claimed that they always followed manufacturers' instructions regarding indications for use, method of application, mixing of chemicals, cleaning up and washing hands, but compliance was lower for recommendations about personal protective equipment and disposal of containers. Only 38% of subjects said that they always read all of the manufacturer's label when using a product for the first time. The main determinant of safe behaviour was the person's approach to safety in other situations, but formal training in the use of pesticides was also associated with more frequent use of personal protective equipment. Possession of a certificate of competence in pesticide use appeared to have less influence on working methods. Future efforts should be directed at changing farmers' handling of pesticides. PMID- 7841415 TI - Two solutions to the problem of noise exposure for motorcyclists. AB - Two solutions to the problem of excessive noise exposure and consequent hearing loss in motorcyclists were investigated and are described. One was an antecedent behaviour-modifying 'prompting' strategy, where a set of earplugs and an advice sheet were provided at the point of sale to consecutive purchasers of new motorcycle crash helmets. Forty-eight riders were recruited but data for analysis were only available in 41. The earplug usage rate was significantly increased from 27% to 83% by this intervention. The second solution involves various aerodynamics and sound-proofing helmet modifications made in an effort to reduce interior noise levels. The only modification which achieved a significant reduction from previously reported average sound levels was the incorporation of a pair of 'standard' earmuffs under the helmet shell. This gave noise levels of 84 dB(A) at 22 m/s (50 mph) and 93 dB(A) at 36 m/s (80 mph), compared to known average values of 95 dB(A) and 107 dB(A), respectively. Both solutions are eminently feasible and desirable, and we hope that the motorcycle industry will act on them. PMID- 7841416 TI - Neuropsychological symptoms among tanker drivers with exposure to solvents. AB - The purpose of this study was to measure the exposure of road tanker drivers to organic solvents at work, and to study, using questionnaires, how many symptoms drivers have which might be caused by exposure to solvents. The target group for the study was all the road tanker drivers of a Finnish oil firm (n = 61 men). There were two control groups from the same firm. One control group included workers who were occasionally exposed to solvents at work (n = 56 men). The other group included workers who had no exposure to solvents (n = 31 men). Industrial hygiene measurements were made in two oil depots (n = 20). The drivers' personal exposures to organic solvents during loading of road tankers were remarkable. In seven measurements (50%) during top loading, the exposure exceeded the Swedish TLV(8h). In symptom questionnaires, the drivers had more acute symptoms which might be caused by solvent exposure compared to the control group who had no exposure. The most remarkable differences were in the symptoms of fatigue, depression, hostility, listlessness and uncertainty. Drivers had fewer symptoms which might be caused by long-term exposure to solvents than control groups. Furthermore, the differences between groups were not statistically significant. PMID- 7841417 TI - Occupational injuries among construction workers in Hong Kong. AB - Accidents on construction sites are a major cause of morbidity and mortality in Hong Kong. We studied 122 injured construction workers in a hospital and an equal number of workmate controls. Data on injuries were obtained from medical records in the hospital. Personal and occupational data were obtained from the cases by interview. Similar data were sought from controls. Single injuries were seen in 80% of cases. Of 149 injuries classified by body region, 49% were external, 26% involved either the upper or lower extremities, and 11% were spinal injuries. Healthcare and compensation costs per capita were high. Working at height was associated with the injury severity score. Safety hazards were identified in the work environment in 68% of cases. Significant odds ratios for accidents were obtained for no formal education, no safety training and current smokers. Much needs to be done in improving the work environment and promoting safety education among construction workers. PMID- 7841418 TI - Proposed protocol for a multi-centre study to compare clinical and trade tests of colour vision in firefighters. AB - Fire-brigade recruits in the UK have their colour vision screened using the Ishihara test. This is unsatisfactory because it rejects subjects with minor deficiencies in colour vision and does not test for blue defects. The Home Office is currently reviewing its recommendations on visual standards. This paper summarizes defects in colour vision, discusses alternative clinical and trade tests for the fire-brigade, and proposes a multi-centre study to collect data on the performance of fire-brigade recruits in clinical and trade tests. PMID- 7841419 TI - A suitable study to evaluate colour vision requirements for firefighters? AB - A recent paper by Rees (Occup. Med. 1994; 44: 253-256) has proposed a study to evaluate the performance of both clinical and trade tests on firefighter recruits. The paper suggests that a new trade test using painted gas cylinders and/or the BOC cylinder identification chart may be appropriate in the selection of firefighter recruits. Evaluation of pass/fail standards on these tests would be achieved by comparing the results with those obtained from the Ishihara test, the City University test and the Holmes-Wright lantern test. In this paper, we argue that the proposed battery of tests does not allow an accurate evaluation of the new trade tests. Indeed,the new trade tests are likely to result in a false sense of obvious fairness' that ultimately be an unsound means of assessing the colour vision requirements of firefighter recruits. PMID- 7841420 TI - Increased risk for hepatitis A among female day nursery workers in Belgium. AB - To assess the risk for hepatitis A virus (HAV) infection in an occupational group potentially at risk for faeco-oral contact with very young children, a prevalence study of total anti-HAV antibodies (IgG/IgM) was conducted among 591 female employees in day nurseries in Flanders, Belgium, and in a reference group of 560 healthy female blood donors, matched for age. Analysis was also performed on formally exposed persons (n = 413) versus blood donors (n = 560). The overall prevalence of HAV markers was 48.4% (95% CI: 44.2-52.5) in exposed day nursery personnel, compared with 42.9% (95% CI: 38.7-47.0) in blood donors. The age specific prevalence rates showed a steeper rise from the age of 30 years among the exposed employees than among the blood donors, with significantly higher prevalences between 35 and 44 years of age. The discrepancies levelled off above 60 years of age. Standardization for parenthood using logistic regression did not affect the odds ratio. These results are in line with recent findings of a higher prevalence of HAV markers among groups of workers professionally exposed to small children. Appropriate measures for the protection of these groups should be taken. PMID- 7841421 TI - Development of observational methods for estimation of exposure to workplace postural stress. AB - Several recent studies have illustrated the need for a simple observational instrument for the estimation of exposure to postural stress in epidemiological studies of musculoskeletal disorders. Such an instrument is particularly necessary in developing countries. This paper describes the development of an observational instrument across a spectrum of industrial occupations in South Africa. The instrument was derived from adaptations to previously published observational methods and was specifically adapted to the measurement and application constraints identified during empirical development work in various industries. The final instrument fulfilled its aims of being applicable across a broad spectrum of jobs, including a broad spectrum of exposure variables and being reasonably cost- and time-effective. Some construct validity is indicated by the fact that two out of the three main exposure variables of interest showed significant associations with neck and shoulder pain in an epidemiological analysis. These variables were the score of summed estimates of the duration of time in sustained postures in a working day and the score of estimated overall repetitiveness based on cycle-time criteria. Further investigations are needed for pain at other anatomical sites. The measurement and scoring problems identified are discussed with reference to some aspects of these results. PMID- 7841422 TI - Problem-based learning. PMID- 7841423 TI - Drug-resistant tuberculosis: issues in epidemiology and challenges for public health. PMID- 7841424 TI - High initial and acquired drug resistance in pulmonary tuberculosis in Turkey. AB - SETTING: Sureyyapasa Center for Chest Diseases and Thoracic Surgery, Istanbul, Turkey between January 1992 and December 1992. OBJECTIVE: To evaluate the prevalances of initial and acquired resistance to antituberculosis drugs in our center. DESIGN: 785 patients with pulmonary tuberculosis (both old = 525/785 and new = 260/785 cases) referred to our center were evaluated with respect to their drug resistance patterns. RESULTS: The overall resistance rate (1 or more drugs) was 35.5%, with initial resistance 26.6% (140 of 525) and acquired resistance 53.4% (139 of 260). Initial resistance to streptomycin was the most frequent (20.6%), followed by rifampicin (10.8%), isoniazid (5.1%) and ethambutol; (4.2%). Initial resistance was noted as 16.4% to 1 drug, 7.7% to 2 drugs, 1.2% to 3 drugs and 1.3% to 4 drugs. Acquired resistance to rifampicin was the most frequent (36.2%) followed by streptomycin 31.9%, and isoniazid 30%. Acquired resistance was found as 18.7% to 1 drug, 19.3% to 2 drugs, 9.6% to 3 drugs and 5.8% to 4 drugs. CONCLUSION: High initial drug resistance in Turkey may well threaten the success rates of antituberculosis treatment and it is therefore mandatory to begin antituberculosis treatment in routine practice in our country with at least 4 first-line drugs, replacing streptomycin with ethambutol due to high resistance to streptomycin. In conclusion there is an urgent need for a nationwide tuberculosis control programme in Turkey, where the treatment of old cases is still challenging, in order to combat the grave situation of high initial and acquired drug resistance. PMID- 7841425 TI - Why do our patients die of active tuberculosis in the era of effective therapy? AB - SETTING: All patients with tuberculosis as a primary or underlying cause of death who were autopsied at the Institute for Lung Diseases and Tuberculosis, Sremska Kamenica, in the former Yugoslavia, between 1981 and 1990 were investigated. OBJECTIVE: To study why people die of active tuberculosis in the era of effective chemotherapy and to identify factors contributing to death. DESIGN: In a retrospective investigation, this index group was compared with a control group consisting of patients who suffered from tuberculosis over the same period but who improved and were discharged from hospital. RESULTS: A significant difference in age (P < 0.05) was found between those patients who died with an antemortem established diagnosis and those who died with unrecognised tuberculosis (median 49 and 60 years respectively). When it came to the index group, 28 patients (56%) had one or more risk factors and the frequency of alcohol abuse was significantly higher (P < 0.001). Antituberculosis treatment had been introduced in 27 cases (54%). The median duration of hospitalization before therapy was 2 days and the median duration of antituberculosis therapy was 7 days. Of the 23 untreated tuberculosis patients, 74% died within the first 4 days. CONCLUSION: Delay in the detection of tuberculosis was the main factor contributing to death in our patients. PMID- 7841426 TI - Empiric antituberculosis treatment: benefits for earlier diagnosis and treatment of tuberculosis. AB - SETTING: Tuberculosis may be diagnosed too late, especially in HIV-infected patients, with consequences on bacillus transmission and survival. Empiric antibuberculosis treatment (EATT) may be started before diagnosis of tuberculosis is confirmed. As rifampicin is a broad spectrum antibiotic, EATT including rifampicin may be effective in infections other than tuberculosis, leading to misdiagnosis. OBJECTIVE: To define the efficiency criteria of EATT with or without rifampicin. DESIGN: Between 1988 and 1991, 20 febrile patients with suspected tuberculosis (including 15 who were HIV-positive) were started on EATT in the absence of bacteriological or histological proof of tuberculosis. 10 patients (50%) received a 4-drug non-specific EATT including rifampicin, isoniazid, pyrazinamide and ethambutol, and 10 (50%), received a 3-drug specific EATT without rifampicin. RESULTS: In 10 patients (50%), the diagnosis of tuberculosis was confirmed by positive cultures within a mean of 32 days (15-57 days) after the beginning of EATT (group TB 1). Of the 10 patients whose cultures remained negative, 4 (20%) became afebrile and showed improvement under EATT (group TB 2), and 6 (30%) remained febrile and did not improve (group No TB). Patients from groups TB 1 and TB 2 became afebrile within a mean of 11 days (1-54 days). This delay was not different between patients receiving specific or non specific EATT. In patients receiving specific EATT, rifampicin was added to the initial 3-drug treatment after resolution of fever. CONCLUSION: EATT appears to be a useful method for rapid presumptive diagnosis and treatment of tuberculosis. PMID- 7841427 TI - Rifabutin for the treatment of newly-diagnosed pulmonary tuberculosis: a multinational, randomized, comparative study versus Rifampicin. Rifabutin Study Group. AB - SETTING: Patients with newly-diagnosed drug-sensitive, radiographically active and bacteriologically confirmed pulmonary tuberculosis recruited at 6 centres in Argentina, Brazil and Thailand. OBJECTIVE: To assess the efficacy, tolerability and toxicity of two regimens containing different daily dosages of rifabutin in comparison with rifampicin. DESIGN: Multicentred, randomised, comparative study. In each group, study medications were administered daily for 6 months combined with isoniazid (6 months), and with pyrazinamide and ethambutol (both stopped after 2 months). Treatment success patients were followed-up for up to 2 years. RESULTS: A total of 520 patients were enrolled and randomly assigned to receive either rifampicin (n = 175), or rifabutin 150 mg (n = 174) or rifabutin 300 mg (n = 171). Considering all patients with positive baseline culture, the success rates at the last valid observation for each patient were 89%, 94% and 92% in the rifampicin, rifabutin 150 mg, and rifabutin 300 mg groups, respectively. The median time to culture conversion was comparable in the 3 groups and was 34 days for rifampicin and 37 days for each of the rifabutin groups. During the drug-free follow-up period, one relapse occurred in the rifampicin group, and two in each of the rifabutin groups. The 3 treatment schedules appeared well tolerated. No patients had to discontinue therapy because of an adverse event in the rifabutin 150 mg group, compared to one in the rifampicin and 5 in the rifabutin 300 mg group. CONCLUSION: All 3 regimens proved effective and well tolerated. Rifabutin at 150 mg/d showed the best risk-to-benefit ratio, in that this group had the highest proportion of patients completing treatment, the highest bacteriological conversion rates and the lowest incidence of adverse events. PMID- 7841428 TI - Six years' experience with the discontinuation of BCG vaccination. 4. Protective effect of BCG vaccination against the Mycobacterium avium intracellulare complex. AB - SETTING: In 1986, mass BCG vaccination of newborns was discontinued in an extensive territorial sample of neonates in the Czech Republic (30,000 infants annually). The non-vaccinated children have since been tuberculin tested at two year intervals; those with continual or repeated intensive contact with animals in households or on farms were also tested with Mycobacterium avium intracellulare complex sensitin in addition to tuberculin. OBJECTIVE: Within the frame work of the surveillance programme the incidence of infection and disease caused by M. avium intracellulare complex (M. avium complex) was evaluated and the protective effect of BCG vaccination analysed. DESIGN: In 1986-93, out of 190,874 non-vaccinated children, 36 were found to be infected by M. avium complex; 27 of them developed disease, i.e. mycobacteriosis other than tuberculosis (MOTT). RESULTS: The annual risk of infection with M. avium complex was 4.8/100,000 children per year, of whom 3.6/100,000 developed mycobacteriosis. 24 patients suffered from swelling of cervical lymph nodes, 2 of mediastinal lymph nodes and one child had the disease localized both in cervical and mediastinal lymph nodes. The disease was verified bacteriologically in 9 children. Most of the diseased children had impaired immunity; a marked skin reactivity of M. avium complex sensitin was present in all infected children. Animal sources infected by M. avium complex were detected in 5 cases. Another 14 children also had close contact with animals but without proven M. avium complex infection. CONCLUSION: In non-BCG vaccinated children the incidence of lymphadenitis caused by M. avium complex was considerably higher than in vaccinated children. BCG cells possess antigenic determinants which confer protective immunity probably both against M. tuberculosis and against M. avium complex infections. It may thus be assumed that BCG vaccination protects both against pathogenic tubercle bacilli and M. avium complex. This should be taken into consideration before recommending discontinuation of mass BCG vaccination of newborns in areas with a high prevalence of M. avium complex infection. PMID- 7841429 TI - Maintenance of therapeutically active levels of isoniazid for prolonged periods in rabbits after a single implant of biodegradable polymer. AB - SETTING: Poor patient compliance is the serious limiting factor in the chemotherapy of tuberculosis. OBJECTIVE: To solve this problem we have been developing depot-drug delivery of antimycobacterial drugs. Earlier studies with mice using isoniazid in polylactic-co-glycolic acid (PLGA) co-polymer have shown that a single implant of the polymer could ensure sustained levels of free isoniazid for up to 8 weeks. Similar studies were not undertaken in rabbits. DESIGN: The biodegradable PLGA polymer rods containing isoniazid were implanted on the back of the rabbits under anaesthesia in an isoniazid dose of 90 mg/kg. Concentrations of isoniazid and acetylisoniazid in serum and urine were determined by the high-performance liquid chromatography (HPLC) method at close intervals up to 96 h to study the burst-size, and later at weekly intervals up to 9 weeks to study the sustained levels. RESULTS AND CONCLUSIONS: There was no abnormal release of isoniazid in the earlier periods. Concentrations of isoniazid > or = 0.2 microgram/ml were found both in serum and urine up to 63 days after implant. Urine specimen obtained at 6 weeks after giving the implant inhibited the growth of Mycobacterium tuberculosis in vitro as measured by the radiometric (Bactec) method. These findings in non-rodent animal species confirm the usefulness of the depot-drug delivery method of drug administration and warrant hopes for the successful treatment of tuberculosis avoiding the problem of non compliance. PMID- 7841430 TI - Clinical evaluation of the diagnostic value of measuring IgG antibody to 3 mycobacterial antigen preparations in the capillary blood of children with tuberculosis and control subjects. AB - SETTING: Department of Paediatrics in a University Hospital. OBJECTIVE: To evaluate ABC-ELISA as serodiagnostic tests for tuberculosis in children. DESIGN: An avidin-biotin-peroxidase conjugated anti-human immunoglobulin (ABC) enzyme linked immunosorbent assay (ELISA) was established to measure serum immunoglobulin G (IgG) antibodies to polymerized old tuberculin (OT), tuberculin purified protein derivative (PPD) and the 30,000 dalton (30 kDa) native antigen of Mycobacterium tuberculosis, in 122 tuberculosis patients and 187 healthy children. RESULTS: In those patients who had received less than 3 months of chemotherapy the sensitivities of the tests based on OT, PPD and the 30 kDa antigen were 40.3%, 50.0% and 36.1% respectively; the positive predictive values were 92.6%, 94.7% and 93.8% respectively and the negative predictive values were 58.6%, 62.9% and 57.2% respectively. CONCLUSION: The ABC-ELISA may be useful for the diagnosis of pulmonary and extrapulmonary tuberculosis in groups of children with a high prior probability of tuberculosis. Antibodies to the 30 kDa antigen persisted longer than did those to OT and PPD. PMID- 7841431 TI - Assessment of alcohol-screening instruments in tuberculosis patients. AB - SETTING: Two samples of hospitalised tuberculosis (TB) patients were randomly selected. OBJECTIVE: To evaluate the usefulness of two alcohol-use screening instruments (AUDIT and CAGE). DESIGN: A cross-sectional analytic study was conducted with 122 patients (61 Coloured and 61 African). RESULTS: In the coloured group, AUDIT and CAGE identified 57% and 62% of patients respectively as scoring above the cut-off points for possible alcohol misuse. In the African group, AUDIT and CAGE identified 36% and 31% of patients respectively as scoring above the cut-off points. Rates for risky drinking found in community-based studies were lower than those found in this study for the Coloured sample. The male African group's CAGE result for alcohol misuse (17/46; 37%) is similar to the CAGE finding for African male mineworkers (33%), also findings from a community study in African males (34-37%). Both instruments were in agreement with each other for both groups. Slight to substantial agreement was observed between the instruments and other assessments of alcohol misuse (ward sister's perception, patient's file, self-perception and communal drinking), as well as between these assessments, for both groups. CONCLUSION: Screening instruments such as AUDIT and CAGE can play a useful role in describing alcohol misuse among TB patients and in facilitating intervention programmes. PMID- 7841432 TI - A case report of Mycobacterium chelonae keratitis and a review of mycobacterial infections of the eye and orbit. AB - Mycobacteria are unusual causes of keratitis and other ocular infections but the outcome of infection is often serious. We report a case of keratitis due to Mycobacterium chelonae, a rapidly growing environmental mycobacterium, in a soft contact-lens wearer, and discuss the difficulty and delay in identifying the organism, twice erroneously identified as Nocardia asteroides on morphological grounds. Despite in vitro susceptibility, the response to anti-bacterial agents was negligible and a second keratoplasty was required after a recurrence of disease at the donor-host junction. We review the role of mycobacteria as the cause of keratitis and other forms of ocular disease. PMID- 7841433 TI - Quantitation of mycobacteria in blood specimens from patients with AIDS. AB - OBJECTIVE: To determine the effect of a delay in processing blood specimens, that may occur by mailing them to a specialized laboratory, on the quantitation of the number of mycobacteria. DESIGN: Simulated blood specimens in sodium polyanetholium sulfonate (SPS)-containing vacutainers were spiked with Mycobacterium avium, and stored for 4 days after addition of clarithromycin or rifabutin, or remained drug-free. Daily samples were lysed with sodium desoxycholate, and inoculated onto 7H11 agar plates for the subsequent colony forming units (CFU)/ml count. The isolation rates on two media, 7H11 agar and BACTEC 12B broth, were determined with 1212 specimens from AIDS patients. RESULTS: The number of bacteria in blood specimens remained without substantial change during the period of storage, even in the presence of clarithromycin or rifabutin, especially after refrigeration for 2 or 24 h before storage. 7H11 agar and 12B broth were equally sensitive for isolation of M. avium. CONCLUSIONS: A 4 day delay in processing blood specimens in SPS vacutainers does not affect the results of quantitation of the number of mycobacteria. Combined use of 12B broth and 7H11 agar increased the overall recovery along with an opportunity to quantitate the number of CFU/ml. PMID- 7841434 TI - A comparison of fixed and disposable head Heaf guns. AB - The objective of the study was to compare the newly introduced Model 2000 disposable-head Heaf gun with the currently used fixed-head gun. The study simultaneously Heaf-tested 1410 school children on both forearms using a different gun on each arm; the tests were read blind. The results were similar for both Heaf guns. The fixed-head gun gave a stronger reaction in 202 (14%) children by one Heaf grade. The disposable head gun gave a stronger reaction in 116 (8%) children, by one Heaf grade in 113 and 2 Heaf grades in 3 children. kappa = 0.607 (95% confidence interval [CI] = +/- 0.038), indicating good agreement between the tests. chi 2 = 0.177, d.f. = 1, P = 0.7 NS. Given the practical advantages of Heaf skin testing for primary screening, it is likely that practitioners will replace the fixed-head gun with one that avoids sterilisation problems. The small variation between the tests was not considered clinically important, while the advantages of the new test were considerable. It is therefore recommended that the Model 2000 Heaf gun replace the fixed-head gun for primary screening. PMID- 7841435 TI - Tuberculosis as a cause of false-positive results in HIV screening EIA tests. PMID- 7841436 TI - Critical assessment of smear-positive pulmonary tuberculosis patients after chemotherapy under the District Tuberculosis Programme. PMID- 7841437 TI - Assessment of kaolin agglutination test. PMID- 7841438 TI - Tuberculosis is the main pulmonary complication of AIDS in Tunisia. PMID- 7841439 TI - O-gene detection by allele specific amplification in the ABO blood group system. AB - We have constructed a fast and easy method for the detection of O-gene in the ABO blood group system. Our method included allele specific amplification using polymerase chain reaction (PCR) and subsequent analysis with polyacrylamide gel electrophoresis (PAGE) and silver staining. O-gene product was observed on the gel in 25 DNA samples from group O phenotype and 20 DNA samples from group A or B (genotype AO or BO) persons. No product was found in 10 DNA samples from group AB phenotype. PMID- 7841440 TI - A Y-associated allele is shared among a few ethnic groups of Asia. AB - In our previous study, both of Y-associated alleles, Y1 and Y2, were detected in Japanese and Koreans, but only the Y1 allele was detected in each of other populations including Chinese in both Beijin and Guangzhou areas, Caucasians, Africans, and Jewish. In the present study, these observations were extended to other ethnic groups in East Asia. Evenks in central Siberia and Khalkhs in Mongolia had only the Y1 allele. On the other hand, two ethnic groups, Fo-lo and Hakka, in Taiwan had both of the Y1 and the Y2 alleles. Three of the eight Y2 positive men, 2 Fo-lo and a Hakka, shared family name Chen. Both Hakka people and ancestors of Chen families could be traced to the Province of Henan in northern China in early 4th century. They arrived in Fujian/Guangdong area in the south east China via various routes and then some of them migrated to Taiwan in the 18th century. It is tempting to speculate that the Y2 allele may be originated from an ancestral population in Henan from which, Japanese, Koreans, and some of the Taiwanese diverged. PMID- 7841441 TI - Genetic heterogeneity of dominantly inherited olivopontocerebellar atrophy (OPCA) in the Japanese: linkage study of two pedigrees and evidence for the disease locus on chromosome 12q (SCA2). AB - We did a linkage study of 2 multigenerational pedigrees with dominant olivopontocerebellar atrophy (OPCA) other than SCA1, with chromosome 12q microsatellites. Multipoint linkage analysis led to the conclusion that the disease locus locates within the 6.2 cM interval between IGF1 and D12S84/D12S105. This result coincides with that of Cuban ataxia pedigrees designated as SCA2. Our study provides genetic evidence that dominant OPCA in the Japanese consists of at least two genetically different disorders; SCA1 and SCA2. PMID- 7841442 TI - Apolipoprotein E5 and E7 in apparently healthy Japanese males: frequencies and relation to plasma lipid levels. AB - In order to determine the frequencies of apolipoproteins (apo) E5 and E7 and their relation to plasma lipid levels, apo E phenotypes were determined in 608 healthy Japanese male adults by two-dimensional gel electrophoresis. Apo E5 and E7 were observed in 2.8% of the subjects, in addition to the three common apo E isoforms, E2, E3, and E4. Apo E5 was divided into two subtypes based on the migration rate on SDS/PAGE, E5f is the type with faster migration and E5s slower migration. The gene frequencies were: the epsilon 3 allele, 0.841; the epsilon 4 allele, 0.095; the epsilon 2 allele, 0.049; the epsilon 7 allele, 0.009; the epsilon 5 allele encoding apo E5f (the epsilon 5f allele), 0.004; and the epsilon 5 allele encoding apo E5s (the epsilon 5s allele), 0.001. The five individuals with apo E5f and the eleven with apo E7 were heterozygotes and normocholesterolemic. Also plasma apo B and apo E levels were not increased in any subjects with apo E5f or apo E7. The data suggests that apo E5f and E7 are not rare in the Japanese population but that neither apo E5f nor E7 are associated with hypercholesterolemia in most of the heterozygotes. PMID- 7841443 TI - Characteristics of dynamic mutation in Japanese myotonic dystrophy. AB - To study the characteristics, if any, of unstable CTG repeat sequence in Japanese myotonic dystrophy (DM), we analyzed DNA from 351 at risk individuals (including affected and non-affected carriers and their descendants) from 105 families in Japan. A total of 93 DM families (196 affected and 116 unaffected individuals), including 84 DM parent-child pairs (44 father-child and 40 mother-child pairs), were examined, many of which had been previously tested by linkage analysis. We detected unstable CTG repeat mutations between 0.15 kb and 8.7 kb in size. The size of the mutation correlated with the age of onset of symptoms. There was a significant difference in DM allele size among the four groups (congenital, juvenile onset, classical, and minimal). Congenital DM had on average the largest repeat sizes. Comparison of parent-child pairs showed that most offspring had a larger repeat size than their parents, with only 2 of 84 showing a definite decrease in repeat size. The correlation coefficients for maternal and paternal transmission were 0.41 and 0.15, respectively. The parental age (maternal and paternal) did not correlate with intergenerational change of repeat. These observations are similar to those reported in Caucasians. PMID- 7841444 TI - Fluorescence in situ hybridization analysis of chromosomal localization of three human cytochrome P450 2C genes (CYP2C8, 2C9, and 2C10) at 10q24.1. AB - Chromosomal localization of three human cytochrome P450 genes belonging to the CYP2C subfamily (CYP2C8, 2C9, and 2C10) was identified by fluorescence in situ hybridization (FISH). An original MP-8 clone was used as a DNA probe for the assignment of the CYP2C10 gene, while two cDNA probes, a 1.37 kb fragment of CYP2C8 and a 1.19 kb fragment of CYP2C9, were obtained after amplifying the predicted fragments (MP-20 and MP-4 clones, respectively) by polymerase chain reaction using a single human liver cDNA library. The results showed that three human CYP2C8, 2C9, and 2C10 cDNAs were located at the same subchromosomal region, 10q24.1. PMID- 7841445 TI - A point mutation at ATP-binding region of the ALD gene in a family with X-linked adrenoleukodystrophy. AB - A prenatal diagnosis was performed in a family with X-linked adrenoleukodystrophy (ALD). A fetus was at high risk of suffering the disease by segregation analysis and by very long chain fatty acid-CoA synthetase activity assay. A transition (G to A) at codon 617 of the candidate ALD gene was detected by reverse transcription PCR (RT-PCR) based sequencing of the fetal liver RNA. The mutation was located in highly conserved ATP-binding site in this gene and deduced amino acid transversion R617H was thought to be the cause of ALD in this family. PMID- 7841446 TI - Paracentric inversion of chromosome 14: a case report. AB - A new case of familial heterozygous paracentric inversion in the long arm of chromosome 14 [inv(14)(q22q32)] is presented. The rearrangement was first ascertained in a fetus examined due to advanced maternal age, and then detected in the father. The phenotypes of the newborn and the father were completely normal. The parents had no history of spontaneous abortion. With reference to previous reports, the risk of clinical abnormalities are discussed for both de novo and familial paracentric inversions of chromosome 14. PMID- 7841447 TI - Role of Helicobacter pylori infection in gastro-duodenal secretion and in pathogenesis of peptic ulcer and gastritis. AB - Etiologic role for HP appears to be best established in histologically proven gastritis. The major factors mediating gastritis induced by the colonization of the "gastric type" mucosa with HP are probably cytotoxins, cytokines and free radicals activated by this organisms. The deficiency of negative feedback in somatostatin-gastrin link in antral gastritis may result in an excessive gastrin release and increased gastric acid secretion with increased duodenal acid load under basal state and after meal. Recent NIH consensus 1994 proposes that: (1) ulcer patients with HP require treatment with antimicrobial agents whether on first presentation or on recurrence; (2) the value of treatment of HP infection in non-ulcer dyspepsia remains to be determined and (3) the asymptomatic subjects with HP infection do not require treatment with antimicrobial agents. PMID- 7841448 TI - Functional and structural changes of isolated rat parietal cells during membrane potential modulation. AB - The present experiments were undertaken to extent our earlier observations (J Physiol Pharmacol 1991, 42, 367-79) relating membrane potential with membrane recycling of parietal cells. Studies were performed in vitro using gastric glands that were isolated through the use of rat stomachs transformed into "everted sacs" and filled with hyperosmolar NaCl-EDTA solution. Acid production was indirectly determined by accumulation of 14C-aminopyrine (AP) and its translocation by measurement of acridine orange fluorescence. H+/K(+)-ATPase activity was assayed by measurement of K(+)-stimulated p-nitrophenylphosphatase (pNPPase) of the proton pump. Morphologic state of parietal cells in relation to their functional activity was observed using electron microscopy. Changes in the membrane potential were obtained by the treatment of gastric glands with protonophore carbonyl cyanide m-chlorophenylhydrazone (CCCP) in the incubation media of different pH. CCCP caused time-dependent decrease in AP accumulation by parietal cells from the medium of pH 6.6 but not that of pH 7.8. pNPPase activity increased in aplical and decreased in tubulovesical membrances prepared from CCCP treated glands which were incubated in the medium being more acidic than cell cytoplasm. Electron microscopic assessment showed morphological transformation of resting parietal cells treated with CCCP in pH 6.6 from nonsecreting to secreting state. CCCP acting in acidic incubation medium also caused the decrease in acridine orange fluorescence in the cytoplasm of parietal cells with some temporary increase of its fluorescence in the lumen o gastric glands. These findings support our hypothesis that changes in parietal cell membrane potential by protonophore CCCP may translocate HCl from tubulovesicles to secretory canaliculi. While the above explanation is suggestive, the exact mechanisms controlling a membrane recycling during the secretory response of parietal cells in vitro remain to be elucidated. PMID- 7841449 TI - Nitric oxide is involved in the mediation of gastric blood flow and tissue oxygenation. AB - Endogenous nitric oxide which is enzymatically formed by endothelial cells from L arginine has been implicated in the control of gastrointestinal circulation. Its role in the mediation of gastric tissue oxygenation has not been studied. We investigated the role of NO in the control of gastric blood flow and oxygen uptake. In anesthetized dogs, total gastric blood flow, gastric mucosal blood flow, systemic arterial and portal venous pressures and the arteriovenous oxygen content difference were studied. From these measurements gastric vascular resistance and oxygen consumption were calculated. Administration of NG-nitro-L arginine (L-NNA) induced gastric tissue ischemia and hypoxia. Both, systemic arterial pressure and gastric vascular resistance were increased. Above hemodynamic and metabolic effects of L-NNA were significantly attenuated when administration of L-NNA was combined with L-arginine. Our findings suggest that endogenous NO is a tonic vasodilator modulating gastric blood flow and oxygen uptake through influence on the gastric microcirculatory structures responsible for vascular resistance and the nutrient circulation. PMID- 7841450 TI - Role of histamine in regulation of blood flow in the injured gastric mucosa of the cat. AB - Superficial mucosal damage caused by a mild irritant (2 M NaCl) results in release of histamine and probably prostaglandins giving increased GMBF. This hyperemic response contributes to protect the mucosa during the early phase of repair after damage by supplying the mucosa with bicarbonate and by eliminating back diffusing acid and other toxic substances such as ethanol. We conclude that histamine plays an important role in the blood flow regulation in the stomach. PMID- 7841452 TI - Daily pattern of EEG activity in rats with lateral hypothalamic lesions. AB - The experiment was aimed to further elucidate the phenomenon of sleep suppression observed earlier after electrolytic lesions of the lateral hypothalamus (LH). In male Wister rats the amounts of waking (W), slow wave sleep (SWS) and paradoxical sleep (PS) were counted in 1 h samples of EEG taken from the light and dark parts of the circadian cycle, as well as in the whole 12 h diurnal records before lesioning and after electrolytic or sham lesions of LH. Significant increase of W with a simultaneous reduction of SWS and PS was found in 1h and 12h diurnal records; no effect of the lesion on nocturnal EEG was observed. The results suggest that lesion-induced sleep suppression concerns the light part of the day when rats are naturally less active, and that 1h samples of diurnal EEG may be sufficient to diagnose LH insomnia. No correlation was found between the magnitude of waking-sleep disturbances and the intensity of ingestive impairments (aphagia, adipsia, body weight loss) evoked by LH lesions which suggests that LH insomnia may be a result of disruption of a mechanism directly involved in the regulation of waking-sleep cycle rather than a secondary effect of other lesion induced impairments. PMID- 7841451 TI - Influence of SIN-1 and sodium nitroprusside (NANP) on ox-LDL metabolism in macrophages. AB - Effects of NO-donors (3-morpholinosydnonimine-SIN-1 and sodium nitroprusside NaNP) on the accumulation and degradation of oxidized LDL (ox-LDL) by macrophages were studied. Ox-LDL, but not native-LDL (n-LDL) suppressed the LPS-stimulated biosynthesis of NO by macrophages. SIN-1 at low concentrations < 100 microM was without any effect while SIN-1 at high concentration (300 microM) and NaNP (30 300 microM) stimulated the accumulation and degradation of ox-LDL by macrophages. The pretreatment of macrophages with NG-monomethyl-L-arginine (L-NMMA, 3 microM) for 24 hours had the same stimulatory effect. The inhibition of endogenous formation of NO, by L-NMMA profoundly changed the pattern of action of NO-donors on ox-LDL catabolism by macrophages; the stimulatory action of SIN-1 was transformed to the inhibitory action on the accumulation and degradation of ox LDL whereas NaNP lost its stimulatory action entirely. Our interpretation of this unexpected interactions between SIN-1, NaNP and L-NMMA is as follows. Endogenous NO in macrophages inhibits the accumulation of ox-LDL and therefore, the stimulatory effect of L-NMMA has been overcome by exogenous NO from SIN-1. However, NO at high concentrations promotes lipid accumulation in macrophages and thereby, in the absence of L-NMMA, SIN-1 at high concentrations and NaNP produced a paradoxical stimulatory effect in macrophages. NaNP is not a proper NO-donor and its mode of action differed from that of SIN-1. In conclusion, NO at low physiological concentrations keeps scavenger receptors of macrophages downregulated and hence endogenous NO may show anti-atherogenic properties. PMID- 7841453 TI - Respiratory potentials recorded from the human hindbrain. AB - Using a nasopharyngeal and a neck electrode slow potentials synchronous with respiration were registered. Similar potentials were recorded in a patient with apnoea due to widespread paralysis of the Landry type. The potentials are thought to be of medullary origin. PMID- 7841454 TI - Histaminergic components in carbachol-induced pituitary-adrenocortical activity. AB - The involvement of central histaminergic mechanisms in stimulation of the hypothalamic-pituitary-adrenal (HPA) axis by carbachol, a muscarinic cholinergic agonist, was investigated in conscious rats. The HPA activity was assessed indirectly, through corticosterone secretion. Carbachol given intracerebroventricularly elicited a dose-related increase in serum corticosterone levels. The corticosterone response to carbachol was totally abolished by systemic pretreatment 2h earlier with alpha-fluoro-methylhistidine (alpha-FMH), a specific inhibitor of brain histamine synthesis, which also significantly decreased histamine level in hypothalamus. Mepyramine, a histamine H1-receptor antagonist, moderately diminished the carbachol-induced corticosterone response and abolished the rise in hypothalamic histamine levels. Ranitidine a H2-receptor antagonist, considerably diminished the corticosterone response to carbachol but did not change the elevated hypothalamic histamine levels. Also atropine, a cholinergic antagonist, abolished the corticosterone response to carbachol, but did not significantly affect the carbachol-induced increase in hypothalamic histamine concentration. Ranitidine and atropine can directly block homologous hypothalamic receptors involved in CRF secretion. Partial inhibition of the carbachol-induced corticosterone secretion by mepyramine may be connected with prevention of the carbachol-induced increase in hypothalamic histamine content. These results suggest that hypothalamic histamine and histamine receptors are involved in the HPA stimulation by the muscarinic agonist carbachol. PMID- 7841455 TI - Effect of mild psychological stress on physiological responses to exercise in men. AB - To find out whether a negative shift in subject's mood alters cardio-respiratory and endocrine responses to exercise, 20 young men performed a graded bicycle ergometer test (50, 100, 150 W): 1) when they experienced a mixed emotional and cognitive stress before exercise (1st session), 2) when they were familiarized with the laboratory and rested quietly before exercise (2nd session). The subjects' mood was assessed by the Profile of Mood State (POMS) questionnaire. In the 1st session the subjects started exercise with significantly higher scores of tension, anger, depression, confusion and global mood in comparison with the 2-nd session. They also had slightly elevated systolic blood pressure, blood lactate, plasma cortisol and noradrenaline concentrations. During exercise performed in the 1st session only plasma free and total noradrenaline and cortisol levels were higher than those in the 2nd session. IN CONCLUSION: a mild psychological stress, causing the mood worsening before standard exercise test, does not evoke pronounced alterations in cardio-respiratory responses to exercise in healthy men, but it does affect the magnitude of exercise-induced changes in both plasma free and total noradrenaline concentrations. PMID- 7841456 TI - Bis azo dye liquid crystalline micelles as possible drug carriers in immunotargeting technique. AB - Lyotropic liquid crystal mesophases, represented in this work by Congo Red bis azo dye solution, were proposed as systems to carry drugs to immuno-selected targets. The possible use of Congo Red for this aim arises from its liquid crystalline features, enabling it to attach to immune complexes as polymolecular, ordered conglomerates and simultaneously to incorporate many organic compounds into its mesophase, largely independent of the water with a specific but adaptive molecular organization. Molecules with planar rigid structure, and/or large hydrophobic fragments, especially those with a positively charged group in the molecule, are found to be incorporated best. Rhodamine B, Rhodamine 6G and adriamycine, which have the assumed binding features, were tested as model compounds and were found to be readily engaged into Congo Red mesophase. The effect of hydrophobicity on ligand binding was evaluated following the incorporation of homologic 10, 12, 14, 16 carbon chain organic acids and the effect of charge using small mobile tandem molecules of pI differing by a few pH units (lysine-norleucine, tyrosine-tyramine). Positive charge seems to affect binding especially by influencing the organization of molecules and the shape of the micelle simultaneously. Congo Red immobilized to heat-aggregated immunoglobulins and antibodies in the immune complex was found to retain its binding ability, confirming its possible usefulness for drug transport. PMID- 7841457 TI - The effect of nafamostat mesilate (FUT-175) and gabexate mesilate (FOY) on multiorgan oxidant-antioxidant balance in acute experimental pancreatitis. AB - This study was undertaken to determine whether synthetic proteinase inhibitors- nafamostat mesilate (FUT-175) and gabexate mesilate (FOY) have any influence on multiorgan oxidant-antioxidant balance in acute haemorrhagic pancreatitis induced in Wistar rats using a retrograde intraductal injection of 5% Na-taurocholate. Rats were treated with FUT-175 25 x 10(-3) g.kg-1.h-1) or FOY (2.5 x 10(-3) g.kg 1.h-1) and sacrificed at 3 h. Malondialdehyde and sulfhydryl groups concentration, as an index of oxidative stress, we measured in pancreatic, lung and liver tissue. In rats with acute pancreatitis treated with these proteinase inhibitors, oxidative stress expressed by malondialdehyde elevation and sulfhydryl groups depletion, was markedly diminished. It was observed in the pancreas and lung, and to a lesser extent in the liver. These effects of FUT-175 or FOY treatment, at least in part, may account for recently postulated favorable systemic effects of such a medication. PMID- 7841458 TI - The organization of Drosophila genes. AB - This study was designed to examine the range of size variations in the major functional elements of Drosophila genes and to test whether those size variations occur independently of each other. In a sample of 111 genes the following median values occur: leaders, 123 base pairs (bp); coding regions, 1242 bp; 3' untranslated regions (3'UTR), 246 bp; mRNAs, 1803 bp; 3' terminal exons 843 bp; and exons upstream of the last one 233 bp. Introns show a bimodal distribution with medians of 62 and 595 bp. Unexpected size correlations are evident for several of these elements. The size of the leader, for example, is correlated with the sizes of the coding region and the 3'UTR with very high levels of significance, and the size of the first intron is similarly correlated with the sizes of each of the individual components of the mature mRNA. PMID- 7841459 TI - Nucleotide sequence of the Salmonella typhimurium trpR gene. AB - The sequence of the Salmonella typhimurium trpR gene and flanking DNA was determined on both strands. The DNA sequence predicts a polypeptide product of 108 amino acids with a molecular weight of 12,274 daltons. The TrpR protein of S. typhimurium differs by three amino acid residues from that of E. coli. The promoter/operator region of trpR is completely conserved between E. coli and S. typhimurium. The nucleotide sequence of the trpR sector of the S. typhimurium genome was 87.4% identical to the corresponding region of the E. coli genome. Within the protein coding segments of the two organisms, 94.4% of the amino acid residues were identical. In S. typhimurium, as in E. coli, there is a Palindromic Unit element (PU) between the translation termination triplet of trpR and that of a divergently oriented unidentified reading frame (URF-143). However, the PU segment of S. typhimurium is 85 nucleotides shorter than its E. coli counterpart. PMID- 7841461 TI - Computer search of transcription control sequences in small plant virus DNA reveals a sequence highly homologous to the enhancer element of histone promoters. AB - The positions of nucleotide sequences which can act as binding sites for plant transcriptional trans-acting protein factors have been mapped in DNA of plant circovirus--coconut foliar decay virus (CFDV). It was found that CFDV promoter region contains sequence motif homologous to the regulatory type I element of plant histone genes. We have also found the presence of the element I motifs in DNAs of other small plant viruses. Taking into account the mechanism of regulation of histone gene expression it appears that these sequences may play a role in a cell cycle-dependent regulation of plant virus DNA transcription and replication. PMID- 7841460 TI - Cloning and characterization of zona pellucida genes and cDNAs from a variety of mammalian species: the ZPA, ZPB and ZPC gene families. AB - Full length zona pellucida cDNAs from cat, dog and pig that are homologous to the ZP2/rc75 genes from mouse, human and rabbit, a full length zona pellucida cDNA from cat and a gene and full length cDNA from human that are homologous to the rc55/ZP3 alpha genes from rabbit and pig, and full length zona pellucida cDNAs from cat, cow, dog, pig and rabbit that are homologous to the ZP3 genes from mouse, hamster, human and marmoset have been cloned and characterized. The members of these gene families are herein referred to as ZPA, ZPB and ZPC genes to avoid the confusion that currently exists in the zona pellucida of nomenclature. This report is the first to describe the presence all three major zona pellucida genes within individual mammalian species. Within the ZPA, ZPB and ZPC gene families, the DNA and deduced amino acid sequences are highly homologous to each other, and are most homologous between members of the same order within the class mammalia. These results imply that all or most mammalian species express the ZPA, ZPB and ZPC proteins, which form the zona pellucida layer surrounding the oocyte. PMID- 7841462 TI - 5' noncoding sequence of human IL-10 gene obtained by oligo-cassette PCR walking. AB - A fragment of the human IL-10 gene starting from a Hind III site and including 744 previously unknown bases of the 5' regulatory region was isolated by oligo cassette PCR walking and the nucleotide sequence was determined. It shows remarkable homology to the mouse IL-10 promoter in regions that have been associated with transcriptional regulation. PMID- 7841463 TI - Nucleotide sequence of a recA gene from Corynebacterium glutamicum. AB - The nucleotide sequence of the recA gene from Corynebacterium glutamicum AS019 was determined by sequencing a number of overlapping clones containing genomic DNA. Comparison of the C. glutamicum recA gene sequence to the sequences of other procaryotic recA genes reveals a high degree of identity of both the DNA and inferred amino acid sequences. PMID- 7841464 TI - Nucleotide sequence of the equine interferon gamma cDNA. AB - Interferon gamma, a cytokine produced by T-lymphocytes and natural killer cells, plays a central role in the modulation of the immune response, and its antiviral and antitumourigenic properties have made it a potential candidate for use in immunoprophylactic and therapeutic regimes. We have cloned the equine IFN gamma cDNA to facilitate production of this cytokine for clinical evaluation in the horse. The predicted equine IFN gamma amino acid sequence is 67% identical to that of the human equivalent and 78% to the bovine equivalent. PMID- 7841465 TI - Upstream regulatory region of the human embryonic beta-like globin gene, epsilon. AB - The sequence of the human embryonic beta-like globin gene (epsilon) upstream regulatory region has been reported previously. In the course of our own work, we found a significant number of discrepancies between our sequence and the data base sequence, which we show here to contain large clusters of errors within functional epsilon-globin regulatory domains. PMID- 7841466 TI - Fast method of homology and purine-pyrimidine mutual relations between DNA sequences search. AB - A new algorithm for scanning sequences is described. This algorithm uses the boolean operators AND and OR. The mutual information between the sequences is used as a measure of sequence interrelation. It allows evaluation of the probability of accidental sequence interrelation in a quantitative manner. The proposed algorithm was used for searching for MB1 repeats in human and other mammalian sequences. PMID- 7841467 TI - Approaches (and possible contraindications) to enhancing patients' autonomy. PMID- 7841468 TI - Discussions about the use of life-sustaining treatments: a literature review of physicians' and patients' attitudes and practices. End of Life Study Group. PMID- 7841469 TI - Should hospital policy require consent for practicing invasive procedures on cadavers? The arguments, conclusions, and lessons from one ethics committee's deliberations. PMID- 7841470 TI - Issues of consent: the use of the recently deceased for endotracheal intubation training. PMID- 7841471 TI - Reconsidering "psychosurgery": issues of informed consent and physician responsibility. PMID- 7841472 TI - Hawkeye Pierce and the questionable relevance of medical etiquette to contemporary medical ethics and practice. PMID- 7841473 TI - Can a patient refuse a psychiatric consultation to evaluate decision-making capacity? PMID- 7841474 TI - Iatrogenic ethical problems: commentary on "can a patient refuse a psychiatric consultation to evaluate decision-making capacity"? PMID- 7841475 TI - Patients' perceptions of consent. PMID- 7841476 TI - Informed consent: pondering a new piece of the puzzle. PMID- 7841477 TI - Changing the paradigm for informed consent. PMID- 7841478 TI - Commentary on discussions about life-sustaining treatments. PMID- 7841479 TI - "'How do you catch a cloud and pin it down?" (with apologies to Rogers and Hammerstein): a commentary on Layson and colleagues. PMID- 7841480 TI - Politically correct ethical thinking and intubation practice on cadavers. PMID- 7841481 TI - Life versus death: exposing a misapplication of ethical reasoning. PMID- 7841483 TI - Neuromuscular paralysis and withdrawal of mechanical ventilation. PMID- 7841482 TI - Autonomy, informed consent, and psychosurgery. PMID- 7841484 TI - Responses of the sheep blowflies Lucilia sericata and L. cuprina to odour and the development of semiochemical baits. AB - The literature relating to the attraction of the sheep blowflies Lucilia sericata and Lucilia cuprina to their ovine hosts is reviewed. The responses of the two species are similar and different components of the behaviour leading to host location and oviposition appear to involve at least two distinct sets of semiochemical cues. Activation, upwind orientation and landing appear to occur in response to putrefactive sulphur-rich volatiles, originating from bacterial decomposition products. Oviposition is elicited primarily by the presence of decomposition products. Oviposition is elicited primarily by the presence of ammonia-rich compounds; moisture, pheromones and tactile stimuli may also act as oviposition stimuli. There is a pronounced sex difference in the response of Lucilia to semiochemicals with a higher proportion of females attracted than males and a higher proportion of gravid than non-gravid females. While the mechanisms of host location by Lucilia are of intrinsic interest, understanding the responses to semiochemicals is important in the attempt to develop powerful synthetic baits for deployment with the traps or targets used for population sampling or suppression. The literature is discussed with respect to the development of synthetic semiochemical baits. PMID- 7841485 TI - Description of the larva, diagnosis of the nymph and female based on scanning electron microscopy, hosts, and distribution of Ixodes (Ixodes) venezuelensis. AB - The larva, nymph, and female of Ixodes (Ixodes) venezuelensis are diagnosed using scanning electron microscopy, and the larva is described for the first time. This ixodid tick is recorded from the northern neotropics as a parasite of five species of didelphid marsupials and eighteen species of rodents (one sciurid, two heteromyids, eleven murids, two dasyproctids, and two echimyids). Collection records of I. venezuelensis are presented for Costa Rica, Colombia, Panama and Venezuela, with the Costa Rican records being new and extending the known range of this tick by at least 300 km. Altitudinally, I. venezuelensis has been collected between elevations of 24 and 2410 m with most collections between 100 and 800 m. The possibility that I. venezuelensis may be parthenogenetic is discussed. PMID- 7841486 TI - Vectors of cutaneous leishmaniasis in north-central Venezuela. AB - An entomological survey was undertaken from January 1991 to February 1992 in El Ingenio, Miranda State, Venezuela, an endemic area of cutaneous leishmaniasis: prevalence of 10.7 cases per 100,000 inhabitants. A total of 4863 female sandflies (Phlebotominae) of fourteen species were collected in Shannon traps, then dissected and examined for leishmanial infections. Lutzomyia ovallesi (85.4%) and Lu. gomezi (11.2%) were the predominant anthropophilic species of sandfly. Fifty-one (1.19%) Lu.ovallesi and two (0.47%) Lu.gomezi had natural infection with Leishmania promastigotes. Identification of the parasites was done by using the polymerase chain reaction (PCR) and DNA hybridization. Two isolates from Lu.gomezi and forty-nine from Lu.ovallesi were typed as Leishmania braziliensis and three of the latter reacted with Le.mexicana also. This is the first report of Lu.gomezi with parasites typed as Le.braziliensis. We concluded that Lu.ovallesi is the primary vector of cutaneous leishmaniasis in the north central area of Venezuela and Lu.gomezi should be regarded as an additional vector. PMID- 7841488 TI - Comparisons of sampling methods and seasonal abundance of Drosophila repleta in caged-layer poultry houses. AB - Four sampling methods were compared to determine their practicality and suitability for detecting population fluctuations of adult Drosophila repleta, a pest in caged-layer poultry houses. Five caged-layer poultry houses with gutter flush manure removal systems in Franklin County, North Carolina, U.S.A., were sampled once every 2 weeks over 15 months, from June 1991 to August 1992. The flies were most abundant during the spring and early summer. Visual counts of adult flies resting on the feed troughs in front of cages in the aisles and counts of flies caught on a sticky ribbon lowered into the gutter used for manure removal by flushing were more satisfactory sampling methods than using counts of flies caught on sticky ribbons carried along the aisles or aspirator collections from the gutters. For the visual count method, the effects of location in the house, within each aisle, and feed trough height were determined; two counts on feed troughs in each of two inside rows of cages were sufficient to measure population changes. For routine monitoring of D. repleta populations, visual counts of flies resting on the feed troughs in the front area of two aisles and catching flies on sticky ribbons inserted into the rear gutter area are recommended. PMID- 7841487 TI - Hosts of Lutzomyia shannoni (Diptera: Psychodidae) in relation to vesicular stomatitis virus on Ossabaw Island, Georgia, U.S.A. AB - Hosts of Lutzomyia shannoni Dyar, a suspected biological vector of the New Jersey serotype of vesicular stomatitis (VSNJ) virus, were determined using an indirect enzyme-linked immunosorbent assay (ELISA) of 333 blood-fed female sandflies collected from their diurnal resting shelters on Ossabaw Island, Georgia, U.S.A. Sandflies had fed primarily on white-tailed deer (Odocoileus virginianus) (81%) and to a lesser extent on feral swine (Sus scrofa) (16%), two species of host infected annually with VSNJ. Other hosts were raccoons (Procyon lotor) and horses (Equus caballus) or donkeys (E. asinus), with only two (< 1%) mixed bloodmeals from deer/raccoon and deer/swine. A larger proportion of feedings on feral swine was detected in maritime live oak forests than in mixed hardwood forests. These findings are consistent with the hypothesis that L.shannoni is a primary vector of VSNJ virus on Ossabaw Island. PMID- 7841489 TI - The Anopheles punctulatus group of mosquitoes in the Solomon Islands and Vanuatu surveyed by allozyme electrophoresis. AB - Four species within the Anopheles punctulatus group of mosquitoes (Diptera: Culicidae) were identified by allozyme analysis of samples collected from thirty three localities in Guadalcanal, Makira, Malaita, Temotu and Western Provinces in the Solomon Islands and six localities on Efate, Espiritu Santo, Maewo and Malekula Islands in Vanuatu. Three of these species are members of the An.farauti complex. A key is given to identify five species of the An.punctulatus group known to occur in the Solomon Islands using their isoenzyme characteristics. An.farauti No. 1 was widespread in coastal areas of the Solomon Islands and was the only species detected in Vanuatu, including Efate Island (where Faureville is the type locality of An.farauti Laveran sensu stricto). An.farauti No. 2 and An.punctulatus were common in the Solomon Islands in more inland areas. An.farauti No. 7, reported here for the first time, was found as larvae in freshwater at six localities on north Guadalcanal. Three other members of the An.punctulatus group which have been reported previously from the Solomon Islands: An.koliensis, An.renellensis and an electrophoretic variant of An.farauti sensu lato, were not found in our samples. Previously recognized vectors of malaria and bancroftian filariasis in the Solomon Islands are An.farauti No. 1 (i.e. An.farauti s.s.), An.koliensis and An.punctulatus s.s. Adult females of An.farauti No. 2 and An.farauti No. 7 were not attracted to human bait in areas where their larvae occurred, indicating that these two species are not anthropophilic and therefore unlikely to transmit human pathogens. PMID- 7841490 TI - Population dynamics and density-dependent seasonal mortality indices of the tick Rhipicephalus appendiculatus in eastern and southern Africa. AB - Eight sets of previously published data on the seasonal abundance of the tick Rhipicephalus appendiculatus in Burundi, Uganda, Tanzania and Zimbabwe are analysed to yield seasonal mortality indices. Correlations between these indices and abiotic (climatic) and biotic (tick density) variables suggest that it is the stage from females to larvae that is most sensitive to adverse abiotic conditions, specifically low moisture availability. Mortality at the other stages of the tick's life cycle is strongly density-dependent. The precise nature of this density-dependence suggests that it may be caused by acquired resistance to ticks by cattle. Robust correlations between satellite-derived vegetation indices, climatic factors and mortality indices suggest that detailed climatic data, often unavailable, may be replaced by satellite data, now widely available, for use in modelling tick populations. PMID- 7841491 TI - A study on the maturation of procyclic Trypanosoma brucei brucei in Glossina morsitans centralis and G. brevipalpis. AB - Teneral Glossina morsitans centralis and G. brevipalpis were fed in vitro upon medium containing procyclic Trypanosoma brucei brucei derived from the midguts of G. m. centralis or G. brevipalpis which had immature trypanosome infections. The tsetse were then maintained on rabbits and, on day 31, were dissected to determine the infection rates. In G. m. centralis the midgut and salivary gland infection rates by T. b. brucei were 46.0% and 27.0% with procyclic trypanosomes from G. m. centralis, and 45.4% and 24.7% with procyclic trypanosomes from G. brevipalpis, respectively. In G. brevipalpis the rates were 20.2% and 0.0% with procyclic trypanosomes from G. m. centralis, and 28.0% and 0.0% with procyclic trypanosomes from G. brevipalpis, respectively. Teneral G. m. centralis and G. brevipalpis were also fed similarly upon procyclic T. b. brucei derived from G. m. centralis or G. brevipalpis on day 31 of infection, the former tsetse species had mature infections while the latter were without infections in the salivary glands. In G. m. centralis the infection rates in the midgut and salivary glands were 48.9% and 17.0%, and 38.0% and 17.0% when fed on procyclic trypanosomes from G. m. centralis and G. brevipalpis, respectively. In G. brevipalpis the rates were 21.5% and 0.0%, and 10.7% and 0.0% with procyclic trypanosomes of G. m. centralis and G. brevipalpis origin, respectively. Thus, procyclic T. b. brucei from susceptible G. m. centralis could not complete cyclical development in refractory G. brevipalpis, whereas those from G. brevipalpis developed to metatrypanosomes in the salivary glands of G. m. centralis.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7841492 TI - Attraction of Lutzomyia longipalpis to human skin odours. AB - Male and female Lutzomyia longipalpis sandfiles showed attraction to human skin emanations placed on warmed glass Petri dishes. Unfed virgin females were more strongly attracted than males, which also showed attraction. Four human subjects were tested and significant variation was found between the numbers of sandflies attracted to their skin emanations. This suggests that some individuals were more attractive than others. There was a significant difference between the response shown by sandflies from the Jacobina and Lapinha regions of Brazil, suggesting that sandflies from the Jacobina region were more anthropophilic. In addition, sandflies from Jacobina had a significantly higher level of activity than those from Lapinha. The role of sandfly attraction to humans as a risk factor in Leishmania transmission is considered. PMID- 7841494 TI - Trapping system for testing olfactory responses of the malaria mosquito Anopheles gambiae in a wind tunnel. PMID- 7841493 TI - Protein hydrolysates and associated bacterial contaminants as oviposition attractants for the mosquito Culex quinquefasciatus. AB - Six protein or protein hydrolysate solutions were tested for activity as attractants for ovipositing Culex quinquefasciatus mosquitoes in the laboratory. Four of these solutions (egg albumin, lactalbumin hydrolysate, casein hydrolysate and yeast hydrolysate) were attractive to ovipositing females at varying concentrations, when compared to distilled water controls. Soy hydrolysate was repellent at 1%, but not significantly attractive or repellent at lower concentrations. 'Nulure', a tephritid fly bait containing protein hydrolysate, also had no significant effect on oviposition behaviour. Gravid females mostly oviposited within the first 4 h of the scotophase, regardless of the presence or absence of an oviposition attractant. Lactalbumin hydrolysate 1% solution, with or without 0.1% neomycin antibiotic, was attractive to Cx quinquefasciatus. This effect was reduced by the presence of neomycin which, alone, had no effect on oviposition. Hence both lactalbumin hydrolysate and bacterial contaminants were shown to be attractive to gravid Cx quinquefasciatus. PMID- 7841495 TI - Anopheles farauti refractoriness to malaria infection with cultured gametocytes of Plasmodium falciparum. PMID- 7841496 TI - Prevention of changes in the electrophoretic mobility of overproduced esterases from organophosphate-resistant mosquitoes of the Culex pipiens complex. PMID- 7841497 TI - Rearing Amblyomma variegatum ticks in the laboratory: a simple technique to enhance attachment. PMID- 7841498 TI - Larvicidal microcystin toxins of cyanobacteria affect midgut epithelial cells of Aedes aegypti mosquitoes. PMID- 7841499 TI - Three-dimensional imaging and image analysis of hippocampal neurons: confocal and digitally enhanced wide field microscopy. AB - The microscopy of biological specimens has traditionally been a two-dimensional imaging method for analyzing what are in reality three-dimensional (3-D) objects. This has been a major limitation of the application of one of science's most widely used tools. Nowhere has this limitation been more acute than in neurobiology, which is dominated by the necessity of understanding both large- and small-scale 3-D anatomy. Fortunately, recent advances in optical instrumentation and computational methods have provided the means for retrieving the third dimension, making full 3-D microscopic imaging possible. Optical designs have concentrated on the confocal imaging mode while computational methods have made 3-D imaging possible with wide field microscopes using deconvolution methods. This work presents a brief review of these methods, especially as applied to neurobiology, and data using both approaches. Specimens several hundred micrometers thick can be sampled allowing essentially intact neurons to be imaged. These neurons or selected components can be contrasted with either fluorescent, absorption, or reflection stains. Image analysis in 3-D is as important as visualization in 3-D. Automated methods of cell counting and analysis by nuclear detection as well as tracing of individual neurons are presented. PMID- 7841500 TI - Confocal imaging of dendritic Ca2+ transients in hippocampal brain slices during simultaneous current- and voltage-clamp recording. AB - Changes in the intracellular Ca2+ concentration ([Ca2+]i) within CA1 hippocampal pyramidal neurons were imaged using confocal laser scanning microscopy in conjunction with Ca(2+)-sensitive fluorescent indicators. The imaging was performed in thick hippocampal brain slices while simultaneously measuring or controlling electrical activity with sharp microelectrodes or whole-cell patch clamp electrodes. The combination of imaging and electrophysiology was essential for interpreting the changes in [Ca2+]i. We compared the increases in [Ca2+]i produced by either of two methods--direct depolarization of the cell via the somatic electrode or high-frequency stimulations of synaptic inputs. The increases in [Ca2+]i in the soma and proximal dendrites caused by both methods were of comparable magnitude and they always decayed within seconds in healthy cells. However, the spatial patterns of distal Ca2+ increases were different. Separate sets of synaptic inputs to the same cell resulted in different spatial patterns of [Ca2+]i transients. We isolated and observed what appeared to be a voltage-independent component of the synaptically mediated [Ca2+]i transients. This work demonstrates that the combination of neurophysiology and simultaneous confocal microscopy is well suited for visualizing and analyzing [Ca2+]i changes within highly localized regions of neurons in thick brain slices. The approach should allow further analysis of the relative contribution of voltage- and agonist-dependent influences on [Ca2+]i within neurons throughout the CNS and it raises the possibility of routinely relating subcellular [Ca2+]i changes to structural and functional modifications. PMID- 7841501 TI - Quantitative three-dimensional confocal microscopy of synaptic structures in living brain tissue. AB - In order to study changes in synaptic structure that accompany learning and memory, we have developed optical methods to visualize dendritic spines and presynaptic terminals in living, electrically monitored brain slices maintained in vitro. Focal microapplication of the fluorescent lipophilic dye DiI provides Golgi-like staining of small numbers of cells and processes that can be resolved clearly using confocal microscopy; viability of stained cells is established by exclusion of the fluorescent DNA-binding dye ethidium bromide. Serial optical sections are enhanced by deconvolution and other image processing methods. The resulting high-resolution images are combined in an automated procedure to generate three-dimensional reconstructions, in which submicron synaptic structures can be viewed and measured. These unbiased methods allow volume changes in individual, living synaptic structures to be assessed quantitatively over periods of hours or days in development or in response to stimulation, drug application, or other perturbations. PMID- 7841502 TI - Localizing sites of intradendritic electrophysiological recordings by confocal light microscopy. AB - Studies were undertaken to develop microscopic methods and imaging procedures that would permit identification of sites of intradendritic microelectrode recordings from pyramidal cells in hippocampal slice preparations. Intradendritic recordings were obtained with sharp microelectrodes filled with the dye lucifer yellow. Following a recording session a neuron was iontophoretically injected with the dye and imaged by fluorescence videomicroscopy. Images were stored on videotape for later analysis. They provided a record of the location of the microelectrode recording site. After withdrawal of the microelectrode, slices were processed histologically and imaged a second time with a Bio-Rad 600 confocal attachment on an Olympus BH-2 microscope. Confocal images provided detailed anatomical information in three dimensions. In most instances, a clear identification of the recording site was achieved by comparing video images containing the recording electrode and confocal images. Neurophysiological recordings obtained from proximal and distal apical dendrites were markedly different. Proximal dendritic recordings were similar to those obtained from pyramidal cell soma. However, distal dendrites were not electroresponsive when depolarized by intracellular current injection. The techniques described here, or variations that employ patch electrodes, could provide valuable information that should further an understanding of the properties of dendrites in the central nervous system. PMID- 7841504 TI - Daubert v. Merrell Dow Pharmaceuticals: a new standard for scientific evidence in the courts? AB - The Supreme Court, in Daubert v. Merrell Dow explored the guidelines for admitting "scientific evidence" by way of expert opinion in legal cases. The Federal Rules of Evidence that were revised in 1975 did not explicitly mention the Frye standard and thus left it unclear as to what guidelines should be used by judges in federal courts. The Court held that the Frye rule was superseded by the new Rules and that the judge had to exercise some gatekeeping functions. An expert with sufficient credentials and something relevant to say was an insufficient standard. The implications of this ruling for psychiatric expert testimony are reviewed. PMID- 7841503 TI - Phorbol ester-stimulated stellation in primary cultures of astrocytes from different brain regions. AB - Stellation is the process by which astrocytes change from epithelial-like to process-bearing cells. Stellation occurs following activation of either cyclic AMP-dependent protein kinase or protein kinase C. This process occurs through tubulin-dependent rearrangement of the cytoskeleton. We have evaluated the ability of phorbol, 12-myristate, 13-acetate (PMA) to induce astrocyte stellation. Astrocytes from five brain regions (cerebellum, cerebral cortex, hippocampus, diencephalon, and brain-stem) were examined to determine if all astrocytes would exhibit similar responses to this activator of protein kinase C. Stellation was evaluated following cell fixation by either phase optics using conventional light microscopy, or scanning laser confocal light microscopy of cultures prepared using immunocytochemistry for tubulin and glial fibrillary acidic protein. Both the number of cells responding to PMA and the sensitivity to PMA varied for astrocytes from each brain region. PMA-induced stellation was most robust in cerebellar and brainstem astrocytes, with greater than 70% responding. Less than 40% of hippocampal and diencephalic astrocytes responded to PMA at the maximum dose (10(-5) M). PMA also induced different numbers of processes or branching patterns of processes on astrocytes from different brain regions. The protein kinase C induced stellation response in astrocytes supports the hypothesis that astrocytes contribute to neural plasticity. PMID- 7841505 TI - Psychiatric genetics and forensic psychiatry: a review. AB - Research in psychiatric genetics has been revolutionized by the development of new and powerful molecular genetic techniques. Family, twin, and adoption studies of antisocial personality disorder (ASPD) and criminality are reviewed, and ramifications of new research methods for the study of antisocial behavior are considered. Implications of these developments for forensic psychiatry are discussed. PMID- 7841506 TI - Washington State's unscientific approach to the problem of repeat sex offenders. AB - In 1990, Washington State enacted the Sexual Predator Act, allowing the civil commitment of sex offenders to a mental health facility for life if they are deemed to be sexual predators (repeat, hardcore offenders). They are released only upon proof that they are no longer a threat to others. This paper reviews the debate about this law and the recent literature on the treatment of sex offenders. We conclude that the Washington State law is unscientific, because the available treatments are not adequate to ensure future safety and because the law selects poor candidates for treatment. Finally, a comment is made about preventive detention effected by psychiatry, and an analogy made to the habitual drunk driver. PMID- 7841507 TI - Patterns of recall of childhood sexual abuse as described by adult survivors. AB - Issues concerning the phenomenon of delayed recall of childhood trauma have arisen in forensic settings. For example, the courts have had to address the issue of delayed recall because of legislation extending the statute of limitations for bringing lawsuits related to childhood sexual abuse. Many states now allow victims to bring suit for up to three years after their memory returns. This paper describes patterns of recall of childhood sexual abuse as recounted by 30 adult women survivors in a nonforensic setting. Eleven of the women described remembering their childhood sexual abuse after a period of amnesia. Examples are given of the types of circumstances that were associated with the delayed recall of the abuse. Implications for assessment in clinical and forensic settings are discussed. PMID- 7841508 TI - Predicting treatment outcome for incompetent defendants. AB - This study examined the prediction of outcome in a sample of defendants hospitalized for treatment of incompetency. Defendants' demographic characteristics and scores on 18 scales of the Computer-Assisted Determination of Competency to Proceed instrument (CADCOMP) were used to predict competency restoration and length of stay (LOS). During the period of study, almost 90 percent of the defendants were restored to competency after a mean stay of over 280 days. Demographic characteristics were unrelated to outcome. Several CADCOMP scales, including two scales measuring psycholegal ability and one measuring psychopathology, were correlated with both outcome criteria. Discriminant analysis using the CADCOMP scales accurately classified 76.7 percent of the defendants into short and long stay groups. Although promising, the findings are nevertheless consistent with prior research in suggesting that examiners should exercise caution in providing feedback to the courts concerning competency restoration and the period of time needed for treatment. PMID- 7841509 TI - Beyond competence and sanity: the influence of pretrial evaluation on case disposition. AB - A preliminary investigation of the impact of pretrial evaluations of trial competence and legal insanity, and the variables that mediate case outcomes is reported. Twenty-four percent of defendants evaluated as incompetent to stand trial were found competent by the court or were tried without the question of competence being adjudicated. Charges were dropped in more than half of the cases in which an evaluator considered a defendant incompetent, most frequently in cases involving misdemeanor charges and/or the clinician considered it unlikely that the defendant could be restored to competence. One third of defendants considered to meet criteria for legal insanity subsequently were acquitted NGRI; more than half did not present an insanity defense and were ultimately convicted or plea bargained a guilty verdict. The defendants considered to meet the criteria for legal insanity were more likely than their mentally ill but not insane counterparts to have treatment ordered in lieu of incarceration. The defendant's age and race and the evaluator's professional discipline were unrelated to case outcome. PMID- 7841510 TI - Factors associated with the diversion of mentally disordered offenders. AB - This study is an examination of the process of pre-trial diversion, in which prosecutors use their discretion to drop criminal proceedings against mentally disordered persons on the condition that such persons be certified and detained for treatment in a hospital setting. An attempt was made to uncover the factors relevant to understanding why mentally disordered offenders are diverted in some instances but not in others. Using data from the forensic psychiatric system of a Canadian province, it was found that accused persons were diverted into the mental health system in 13.4 percent of cases over a three-year period. Three factors were found to be significantly associated with the diversion decision: 1) offense seriousness, with persons facing less serious charges being diverted in a greater proportion of cases; 2) court jurisdiction, with courts in smaller centres and outlying areas being more likely to divert; and 3) psychiatrist, with considerable variability between psychiatrists in their use of the diversion mechanism. The significance of these results and implications for forensic psychiatric policy-making are discussed. PMID- 7841511 TI - The use of third-party information in forensic assessments: a two-state comparison. AB - There is virtually no research on the normative characteristics of forensic mental health assessment, despite the significant increase in conceptual and empirical attention devoted to such assessment within the last 10 years. The present study addressed this deficit by examining the use of third-party information, a crucial component of forensic mental health assessment, by forensic clinicians in two states: Florida (a total of 277 evaluations on the issues of competency to stand trial and sanity at the time of the offense) and Virginia (316 evaluations addressing the same legal issues). Evaluations in each state were performed in either a community or a hospital setting. Basic information about the offense, records of prior mental health evaluation or treatment, and specific statements by victims or witnesses were the variables examined comprising "third-party information" in this study. More than three fourths of all evaluations across states and settings incorporated this information. There was less consistency in the use of mental health records and victim/witness statements, with significant differences observed across settings and states. Results are discussed in light of potential influences of state, setting, and study methodology. PMID- 7841512 TI - The misperceived duty to report patients' past crimes. AB - A questionnaire survey revealed that a number of mental health professionals believed that they had a duty to report a hypothetical patient's past criminal act. The authors examine the legal context of this misperceived reporting duty and discuss its implications for training and practice. PMID- 7841513 TI - Racial differences in the criminalization of the mentally ill. AB - "Criminalization," the hypothesis that mentally ill persons are diverted to the criminal justice system, has been difficult to confirm. The few relevant studies have examined aspects of the mental health or the criminal justice systems, but not both. This study compares state hospital admissions with the admission of mentally ill persons to state prisons. There was considerable variation between counties. Counties sent more mentally ill members of their largest minority group to prison than expected. These results suggest that jurisdictions differ in their use of these two systems and that race is a factor in this difference. PMID- 7841514 TI - Inpatient seclusion: description and causes. AB - A total of 114 (31%) of 370 acute admissions to an inpatient unit over a one-year interval had at least one episode of seclusion or restraint. Four variables were significant predictors of seclusion and restraint. They were young age, diagnosis of borderline personality disorder, and two scores (irritability and total assets) on the Nurses Observation Scale for Inpatient Evaluation (NOSIE). More than 81% of the predictions were correct (Kappa = .37, p < .001). The four predictive variables were used to predict seclusion and restraint in a new sample of 80 patients. More than 79% of the predictions were correct (Kappa = .40, p < .001). PMID- 7841515 TI - On being 'too crazy' to sign into a mental hospital: the issue of consent to psychiatric hospitalization. AB - This article examines the notion of informed consent to psychiatric hospitalization. While dicta in a recent U.S. Supreme Court decision, Zinermon v. Burch, has stimulated considerable interest in applying informed consent to psychiatric hospitalization decisions, there are no extant cases that define the contours of the doctrine in the hospitalization context. The potential scope of disclosure and the level of decision-making capacity sufficient for valid consent are examined. A model of consent to admission recommended by the American Psychiatric Association Task Force on Consent to Voluntary Hospitalization is critiqued. PMID- 7841516 TI - Mental health screening and evaluation within prisons. AB - Current national standards and/or guidelines for correctional mental health care programs emphasize the importance of various levels of mental health screening and evaluation that should be performed by qualified personnel on all inmates as part of the admission process to a prison. The authors describe the results of a study that included data from all 50 state departments of corrections regarding prison mental health screening and evaluation models. The vast majority of states appear to have adopted some variation of the most recognized guidelines and/or standards (e.g., American Psychiatric Association, National Commission on Correctional Health Care, American Public Health Association) concerning correctional health care systems. Results are also provided concerning the use of standardized psychological tests and informed consent issues. PMID- 7841517 TI - Medical liability claims and lawsuits filed against the University of Texas System involving adult psychiatric patients. AB - A survey was conducted to investigate medical liability claims filed against the University of Texas System (the U.T. System), physicians, and/or institutions concerning care of adult psychiatric patients. There were 34 such claims filed between 1978 and 1991 that had closed by December 1991. In many of these cases, medical record documentation was determined to be inadequate. Of the 34 claims filed, only seven were settled on behalf of U.T. personnel or U.T. institutions. Of these seven settlements, the mean monetary amount paid per case on behalf of U.T. System and non-U.T. System parties was $98,678.57. The two categories with the largest number of claims were 1) cases involving suicides, and 2) cases involving adverse reactions to medication. The largest award was $350,000, paid on behalf of U.T. physicians, a private physician, and non-U.T. institutions for alleged negligent failure to diagnose Cushing's disease. Of this amount, only $150,000 was paid on behalf of U.T. physicians. Risk management strategies should be implemented to address areas of liability in psychiatry residency programs. PMID- 7841518 TI - Symmetric cell division in pseudohyphae of the yeast Saccharomyces cerevisiae. AB - Laboratory strains of Saccharomyces cerevisiae are dimorphic; in response to nitrogen starvation they switch from a yeast form (YF) to a filamentous pseudohyphal (PH) form. Time-lapse video microscopy of dividing cells reveals that YF and PH cells differ in their cell cycles and budding polarity. The YF cell cycle is controlled at the G1/S transition by the cell-size checkpoint Start. YF cells divide asymmetrically, producing small daughters from full-sized mothers. As a result, mothers and daughters bud asynchronously. Mothers bud immediately but daughters grow in G1 until they achieve a critical cell size. By contrast, PH cells divide symmetrically, restricting mitosis until the bud grows to the size of the mother. Thus, mother and daughter bud synchronously in the next cycle, without a G1 delay before Start. YF and PH cells also exhibit distinct bud-site selection patterns. YF cells are bipolar, producing their second and subsequent buds at either pole. PH cells are unipolar, producing their second and subsequent buds only from the end opposite the junction with their mother. We propose that in PH cells a G2 cell-size checkpoint delays mitosis until bud size reaches that of the mother cell. We conclude that yeast and PH forms are distinct cell types each with a unique cell cycle, budding pattern, and cell shape. PMID- 7841519 TI - The END3 gene encodes a protein that is required for the internalization step of endocytosis and for actin cytoskeleton organization in yeast. AB - Two Saccharomyces cerevisiae mutants, end3 and end4, defective in the internalization step of endocytosis, have previously been isolated. The END3 gene was cloned by complementation of the temperature-sensitive growth defect caused by the end3 mutation and the END3 nucleotide sequence was determined. The END3 gene product is a 40-kDa protein that has a putative EF-hand Ca(2+)-binding site, a consensus sequence for the binding of phosphotidylinositol 4,5-bisphosphate (PIP2), and a C-terminal domain containing two homologous regions of 17-19 aa. The EF-hand consensus and the putative PIP2-binding sites are seemingly not required for End3 protein function. In contrast, different portions of the End3p N-terminal domain, and at least one of the two repeated regions in its C terminus, are required for End3p activity. Disruption of the END3 gene yielded cells with the same phenotype as the original end3 mutant. An end3ts allele was obtained and this allowed us to demonstrate that End3p is specifically involved in the internalization step of endocytosis. In addition, End3p was shown to be required for proper organization of the actin cytoskeleton and for the correct distribution of chitin at the cell surface. PMID- 7841520 TI - Vma21p is a yeast membrane protein retained in the endoplasmic reticulum by a di lysine motif and is required for the assembly of the vacuolar H(+)-ATPase complex. AB - The yeast vacuolar proton-translocating ATPase (V-ATPase) is a multisubunit complex comprised of peripheral membrane subunits involved in ATP hydrolysis and integral membrane subunits involved in proton pumping. The yeast vma21 mutant was isolated from a screen to identify mutants defective in V-ATPase function. vma21 mutants fail to assemble the V-ATPase complex onto the vacuolar membrane: peripheral subunits accumulate in the cytosol and the 100-kDa integral membrane subunit is rapidly degraded. The product of the VMA21 gene (Vma21p) is an 8.5-kDa integral membrane protein that is not a subunit of the purified V-ATPase complex but instead resides in the endoplasmic reticulum. Vma21p contains a dilysine motif at the carboxy terminus, and mutation of these lysine residues abolishes retention in the endoplasmic reticulum and results in delivery of Vma21p to the vacuole, the default compartment for yeast membrane proteins. Our findings suggest that Vma21p is required for assembly of the integral membrane sector of the V-ATPase in the endoplasmic reticulum and that the unassembled 100-kDa integral membrane subunit present in delta vma21 cells is rapidly degraded by nonvacuolar proteases. PMID- 7841521 TI - A monoclonal antibody against the dynein IC1 peptide of sea urchin spermatozoa inhibits the motility of sea urchin, dinoflagellate, and human flagellar axonemes. AB - To investigate the role of axonemal components in the mechanics and regulation of flagellar movement, we have generated a series of monoclonal antibodies (mAb) against sea urchin (Lytechinus pictus) sperm axonemal proteins, selected for their ability to inhibit the motility of demembranated sperm models. One of these antibodies, mAb D1, recognizes an antigen of 142 kDa on blots of sea urchin axonemal proteins and of purified outer arm dynein, suggesting that it acts by binding to the heaviest intermediate chain (IC1) of the dynein arm. mAb D1 blocks the motility of demembranated sea urchin spermatozoa by modifying the beating amplitude and shear angle without affecting the ATPase activity of purified dynein or of demembranated immotile spermatozoa. Furthermore, mAb D1 had only a marginal effect on the velocity of sliding microtubules in trypsin-treated axonemes. This antibody was also capable of inhibiting the motility of flagella of Oxyrrhis marina, a primitive dinoflagellate, and those of demembranated human spermatozoa. Localization of the antigen recognized by mAb D1 by immunofluorescence reveals its presence on the axonemes of flagella from sea urchin spermatozoa and O. marina but not on the cortical microtubule network of the dinoflagellate. These results are consistent with a dynamic role for the dynein intermediate chain IC1 in the bending and/or wave propagation of flagellar axonemes. PMID- 7841522 TI - Nonlethal sec71-1 and sec72-1 mutations eliminate proteins associated with the Sec63p-BiP complex from S. cerevisiae. AB - The sec71-1 and sec72-1 mutations were identified by a genetic assay that monitored membrane protein integration into the endoplasmic reticulum (ER) membrane of the yeast Saccharomyces cerevisiae. The mutations inhibited integration of various chimeric membrane proteins and translocation of a subset of water soluble proteins. In this paper we show that SEC71 encodes the 31.5-kDa transmembrane glycoprotein (p31.5) and SEC72 encodes the 23-kDa protein (p23) of the Sec63p-BiP complex. SEC71 is therefore identical to SEC66 (HSS1), which was previously shown to encode p31.5. DNA sequence analyses reveal that sec71-1 cells contain a nonsense mutation that removes approximately two-thirds of the cytoplasmic C-terminal domain of p31.5. The sec72-1 mutation shifts the reading frame of the gene encoding p23. Unexpectedly, the sec71-1 mutant lacks p31.5 and p23. Neither mutation is lethal, although sec71-1 cells exhibit a growth defect at 37 degrees C. These results show that p31.5 and p23 are important for the trafficking of a subset of proteins to the ER membrane. PMID- 7841523 TI - Nucleologenesis: U3 snRNA-containing prenucleolar bodies move to sites of active pre-rRNA transcription after mitosis. AB - We have investigated the distribution of U3 snRNA and rRNA in HeLa cells and normal rat kidney cells during interphase and mitosis. U3 snRNA, known to be involved in pre-rRNA processing, was detected in nucleoli and coiled bodies during interphase, whereas rRNA was distributed in the nucleoli and throughout the cytoplasm. By comparison, ribosomal protein S6 was detected in nucleoli, coiled bodies, and in the cytoplasm. During nucleologenesis, pre-rRNA was observed in newly forming nucleoli during late telophase but not in prenucleolar bodies (PNBs), whereas U3 snRNA was detected in forming nucleoli and PNBs. Similar findings to those reported here for the localization of U3 snRNA have been reported previously for the U3 small nuclear ribonucleoprotein fibrillarin. These results suggest that components involved in pre-rRNA processing localize to discrete PNBs at the end of mitosis. The nucleolus is formed at specific telophase domains (nucleolar organizing regions) and the PNBs, containing factors essential for pre-rRNA processing, are recruited to these sites of rRNA transcription and processing. PMID- 7841524 TI - Integrin binding and cell spreading on extracellular matrix act at different points in the cell cycle to promote hepatocyte growth. AB - This study was undertaken to determine the importance of integrin binding and cell shape changes in the control of cell-cycle progression by extracellular matrix (ECM). Primary rat hepatocytes were cultured on ECM-coated dishes in serum free medium with saturating amounts of growth factors (epidermal growth factor and insulin). Integrin binding and cell spreading were promoted in parallel by plating cells on dishes coated with fibronectin (FN). Integrin binding was separated from cell shape changes by culturing cells on dishes coated with a synthetic arg-gly-asp (RGD)-peptide that acts as an integrin ligand but does not support hepatocyte extension. Expression of early (junB) and late (ras) growth response genes and DNA synthesis were measured to determine whether these substrata induce G0-synchronized hepatocytes to reenter the growth cycle. Cells plated on FN exhibited transient increases in junB and ras gene expression (within 2 and 8 h after plating, respectively) and synchronous entry into S phase. Induction of junB and ras was observed over a similar time course in cells on RGD-coated dishes, however, these round cells did not enter S phase. The possibility that round cells on RGD were blocked in mid to late G1 was confirmed by the finding that when trypsinized and replated onto FN-coated dishes after 30 h of culture, they required a similar time (12-15 h) to reenter S phase as cells that had been spread and allowed to progress through G1 on FN. We have previously shown that hepatocytes remain viable and maintain high levels of liver-specific functions when cultured on these RGD-coated dishes. Thus, these results suggest that ECM acts at two different points in the cell cycle to regulate hepatocyte growth: first, by activating the G0/G1 transition via integrin binding and second, by promoting the G1/S phase transition and switching off the default differentiation program through mechanisms related to cell spreading. PMID- 7841525 TI - Integrin alpha 2 cytoplasmic domain deletion effects: loss of adhesive activity parallels ligand-independent recruitment into focal adhesions. AB - Chinese hamster ovary (CHO) cells transfected with the integrin alpha 2 subunit formed a stable VLA-2 heterodimer that mediated cell adhesion to collagen. Within CHO cells spread on collagen, but not fibronectin, wild-type alpha 2 subunit localized into focal adhesion complexes (FACs). In contrast, alpha 2 with a deleted cytoplasmic domain was recruited into FACs whether CHO cells were spread on collagen or fibronectin. Thus, as previously seen for other integrins, the alpha 2 cytoplasmic domain acts as a negative regulator, preventing indiscriminate integrin recruitment into FACs. Notably, ligand-independent localization of the VLA-2 alpha 2 subunit into FACs was partially prevented if only one or two amino acids were present in the alpha 2 cytoplasmic domain (beyond the conserved GFFKR motif) and was completely prevented by four to seven amino acids. The addition of two alanine residues (added to GFFKR) also partially prevented ligand-independent localization. In a striking inverse correlation, the same mutants showing increased ligand-independent recruitment into FACs exhibited diminished alpha 2-dependent adhesion to collagen. Thus, control of VLA-2 localization may be closely related to the suppression of cell adhesion to collagen. In contrast to FAC localization and collagen adhesion results, VLA-2 dependent binding and infection by echovirus were unaffected by either alpha 2 cytoplasmic domain deletion or exchange with other cytoplasmic domains. PMID- 7841527 TI - Seize the moment. PMID- 7841528 TI - The soul of Dover. PMID- 7841526 TI - Cell cycle regulation of the p34cdc2 inhibitory kinases. AB - In cells of higher eukaryotic organisms the activity of the p34cdc2/cyclin B complex is inhibited by phosphorylation of p34cdc2 at two sites within its amino terminus (threonine 14 and tyrosine 15). In this study, the cell cycle regulation of the kinases responsible for phosphorylating p34cdc2 on Thr14 and Tyr15 was examined in extracts prepared from both HeLa cells and Xenopus eggs. Both Thr14- and Tyr15- specific kinase activities were regulated in a cell cycle-dependent manner. The kinase activities were high throughout interphase and diminished coincident with entry of cells into mitosis. In HeLa cells delayed in G2 by the DNA-binding dye Hoechst 33342, Thr14- and Tyr15-specific kinase activities remained high, suggesting that a decrease in Thr14- and Tyr15- kinase activities may be required for entry of cells into mitosis. Similar cell cycle regulation was observed for the Thr14/Tyr15 kinase(s) in Xenopus egg extracts. These results indicate that activation of CDC2 and entry of cells into mitosis is not triggered solely by activation of the Cdc25 phosphatase but by the balance between Thr14/Tyr15 kinase and phosphatase activities. Finally, we have detected two activities capable of phosphorylating p34cdc2 on Thr14 and/or Tyr15 in interphase extracts prepared from Xenopus eggs. An activity capable of phosphorylating Tyr15 remained soluble after ultracentrifugation of interphase extracts whereas a second activity capable of phosphorylating both Thr14 and Tyr15 pelleted. The pelleted fraction contained activities that were detergent extractable and that phosphorylated p34cdc2 on both Thr14 and Tyr15. The Thr14- and Tyr15-specific kinase activities co-purified through three successive chromatographic steps indicating the presence of a dual-specificity protein kinase capable of acting on p34cdc2. PMID- 7841529 TI - A history of women's health care. PMID- 7841530 TI - Women and the risk of cancer: guidelines for screening. PMID- 7841531 TI - Cardiovascular disease and women. PMID- 7841532 TI - Pharmacotherapy in women: do clinically important gender-related issues exist? PMID- 7841533 TI - Diagnosis and treatment of alcoholism in women. PMID- 7841534 TI - Hormone replacement therapy: the latest findings. PMID- 7841535 TI - The Women's Health Initiative Clinical Trial and Observational Study: history and overview. PMID- 7841536 TI - Concepts for a medical school curriculum on women's health. PMID- 7841537 TI - Breast cancer rates among women ages 30-49. PMID- 7841538 TI - Violence against women. PMID- 7841539 TI - Quantification of ERBB2 protein expression in breast cancer: three levels of expression defined by their clinico-pathological correlations. AB - Activation of the ERBB2 oncogene seems to be an early event in breast cancer progression and prevalent in in situ carcinomas. However, its prognosis value, albeit recognized for node-positive patients, remains controversial for those without apparent nodal involvement. One possible reason for this problem is likely to be the difficulty of defining threshold levels for ERBB2 protein overexpression. ERBB2 protein expression was therefore analyzed in primary invasive breast tumors. Quantification of the gene product by a commercial ELISA test was compared to results obtained by immunohistochemistry and western blotting, as well as to gene amplification status determined by Southern blotting. Correlations between results obtained by the different techniques were highly significant (P value < 10(-6)). Nevertheless, ELISA permitted us to determine three levels of protein expression corresponding to distinct tumor subsets. 1) Tumors with p185/ERBB2 expression levels exceeding 10 U/microgram exhibited in most cases amplification of the gene (83% of cases), DNA aneuploidy (81%) and absence of estrogen receptor (ER) (44%). Such high levels of protein expression were exclusively observed in invasive ductal carcinomas and were prevalent in those showing a significant in situ component. 2) "Intermediate" levels of expression (3-10 U/micrograms) were rarely observed in tumors exhibiting gene amplification (9%), but were preferentially found in cancers of more favorable prognosis (only 49% were aneuploid and 9% estrogen receptor negative). 3) Levels of p185/ERBB2 below 3 U/micrograms were detected in benign mastopathies and, thus, carcinomas presenting such levels were scored ERBB2 negative. Interestingly, invasive lobular carcinomas were rarely ERBB2 positive, and if so, only at intermediate levels. Moreover, our data show a complex interrelationship between p185/ERBB2 expression and ER levels. Indeed, tumors with more than 10 U/micrograms of p185 were prevalently ER, whereas those with p185 ranging from 3 to 10 U presented elevated levels of ER. PMID- 7841540 TI - Effect of 2'-deoxy-2'-(fluoromethylene) cytidine on the ultraviolet and X-ray sensitivity of HeLa cells. AB - The effects of treatment of HeLa cells with the antitumor nucleoside analog 2' deoxy-2'-(fluoromethylene) cytidine (FMdC) on ultraviolet and X-ray sensitivity were examined. A 1-h pretreatment with FMdC increased cellular sensitivity to both X-rays and ultraviolet irradiation as determined by survival curve analysis. Increased sensitivity to killing was accompanied by a clear reduction in the rate and extent of X-ray-induced DNA strand break repair and in the closure of excision repair-dependent DNA breaks following ultraviolet irradiation. These studies demonstrate that FMdC treatment compromises the repair of both ionizing ("short-patch") and nonionizing ("long-patch") DNA damage. The mechanism by which this is likely to occur is discussed. Based on these findings, it is likely that FMdC, in addition to possessing inherent antitumor activity, might provide additional antineoplastic benefit when administered in combination therapies with radiation. PMID- 7841541 TI - Intracellular doxorubicin kinetics in lymphoma cells and lymphocytes infiltrating the tumor area in vivo: a flow cytometric study. AB - Recently we have reported the development of a safe and effective chemoimmunotherapy protocol involving doxorubicin (Dox) in combination with interleukin 2 which, in C57BL/6 mice, boosts local T cell responses, and, in 50 to 80% of the cases, this resulted in the complete eradication of established syngeneic EL4 lymphoma or its Dox-resistant variant, EL4/A. Accumulation of host derived leukocytes in the peritoneal cavity was increased up to 8-fold after tumor inoculation, but, in absolute numbers, did not increase further following Dox administration. The cellular pharmacokinetic studies undertaken to clarify the role of Dox following a single IV injection indicate that 4 h later, lymphocytes found in the peritoneal cavity have detectable levels of Dox; but the lymphoma cells (both EL4 and EL4/A) have, in proportion to their larger size, taken up more drug as judged by flow cytometry. The estimated drug "concentration" (i.e., intracellular amount divided by estimated cell size) at the 4-h time point, however, was found to be essentially equivalent in both the lymphoma cells and the lymphocytes. Thereafter, the drug content and intracellular "concentration" in the EL4/A cells rapidly declined while their numbers progressively increased. In contrast, the EL4 lymphoma cells and the lymphocytes found in the peritoneal cavity in the presence of either lymphoma consistently exhibited higher levels of drug 24-48 h than at 4 h. Splenic and tumor-infiltrating mature T (CD3+) cells were completely insensitive to Dox cytotoxicity and actually showed increased CTL activity when examined ex vivo. Although EL4 cells had identical Dox uptake patterns to those of CD3+ cells, they were sensitive to the drug and their numbers decreased, resulting in increased host/tumor cell ratios in these mice. The pharmacokinetic parameters of the drug and the insensitivity of the mature T cells to the drug determined in this study can explain, in part, the efficacy of a chemoimmunotherapy protocol boosting local T-cell responses. PMID- 7841542 TI - Immunoassays of the metalloproteinase (MMP-2) and tissue inhibitor of metalloproteinase (TIMP 1 and 2) levels in noninvasive and metastatic PC-3 clones: effects of taxol. AB - We have selected and subcloned bone metastatic (PC-3 ML) and noninvasive, nonmetastatic (3 x N.I.) lines from human prostatic PC-3 parent cells. In this paper, we have compared relative levels of MMP-2 and TIMP-1 and 2 in PC-3 tumors grown in severe combined immunodeficient or SCID mice. Dot blots with polyclonal antibodies specific for MMP-2, TIMP-1 and TIMP-2 revealed that the MMP-2 levels were high in subcutaneously grown PC-3 ML clones but low in 3 x N.I. clones at days 20 and 40. The TIMP-1 levels were inversely proportional to MMP-2 in the two types of clones, respectively. The TIMP-2 levels were similar in both clones at days 20 and 40. Gelatin zymograms confirmed that PC-3 ML tumors contained MMP-2 (and not MMP-9) subcutaneously or in bone metastases in SCID mice. Slot blots of PC-3 ML bone tumors comparing MMP-2 and TIMP-1 levels showed at days 10, 15, 17, 19, 21, and 25 that the ratio of MMP-2 to TIMP-1 increased, especially at about day 21, when extensive secondary metastases to the peritoneal cavity occurred. The levels of TIMP-2 remained constant. Quantitative ELISAs confirmed the blotting data and showed that taxol blocked MMP-2 but not TIMP-1 production in these advanced tumors. We conclude that highly metastatic PC-3 ML variants contained relatively high levels of MMP-2 and low amounts of TIMP-1. PMID- 7841543 TI - Tumor-promoting phorbol ester-induced cell death and gene expression in a human prostate adenocarcinoma cell line. AB - 12-O-tetradecanoyl phorbol ester (TPA) has profound cytotoxic effects on a human prostate cancer cell line, LNCaP. The TPA effect may be mediated via a protein kinase C (PKC) pathway, since staurosporine, a potent PKC inhibitor, could reverse the cell-killing effect. Our studies, based on cellular fragmentation, chromatin condensation, and nuclear fragmentation, suggest that the cell-killing effect is due to apoptosis. Moreover, we also examined expression of early growth response genes and androgen-induced genes in association with TPA-induced apoptosis. Northern blot analysis demonstrated that androgen induction of human glandular kallikrein-1 (hKLK2) mRNA was repressed by TPA in a concentration dependent manner. A time course study showed that both hKLK2 and c-myc mRNAs were repressed by TPA as early as four hours. In contrast, the steady state mRNA levels for c-fos, c-jun, nerve growth factor induced gene A, and the orphan steroid receptor nur77 were rapidly induced within the first two hours of the treatment. Furthermore, transient co-transfection experiments demonstrated that c fos and c-jun could repress androgen receptor-mediated gene induction. The above studies suggest that (1) the repression of androgen induction of gene expression by TPA-activated PKC is at least in part due to overexpression of c-jun and c-fos and (2) PKC may be a negative growth regulator in prostate cells. PMID- 7841544 TI - Reversal of multiple drug resistance by tolyporphin, a novel cyanobacterial natural product. AB - The effects of a novel porphyrin, tolyporphin, on P-glycoprotein-mediated multiple drug resistance in human ovarian and breast cell lines were characterized. Compared with parental SKOV3 and MCF-7 cells, the P-glycoprotein overexpressing sublines SKVLB1 and MCF-7/ADR were 5- and 1.3-fold less sensitive to the cytotoxic effects of tolyporphin. Subtoxic doses of tolyporphin increased the sensitivity of the SKVLB1 and MCF-7/ADR cells to P-glycoprotein-transported drugs, but did not increase the antiproliferative effects of nontransported drugs. Tolyporphin also enhanced the accumulation of [3H]-vinblastine in SKVLB1 and MCF-7/ADR cells at doses approximately 10-fold lower than those required for similar responses to verapamil. In contrast, tolyporphin did not affect drug accumulation in SKOV3 or MCF-7 cells. Tolyporphin reduced [3H]-vinblastine efflux from SKVLB1 cells, reduced [3H]-vinblastine binding to membranes from SKVLB1 cells, and blocked the ability of [3H]-azidopine to photoaffinity-label P glycoprotein in these membranes. These results indicate that tolyporphin binds to P-glycoprotein and inhibits the transport of cytotoxic natural product drugs. This novel natural product, and related compounds, may be useful for the reversal of multiple drug resistance and for further definition of the drug binding site(s) of P-glycoprotein. PMID- 7841546 TI - Reference listing in cancer research. PMID- 7841545 TI - Increased sensitivity of tumor-bearing host macrophages to interleukin-10: a counter-balancing action to macrophage-mediated suppression. AB - Tumor growth causes macrophages (M phi) to suppress T-cell proliferation by inducing M phi production of soluble suppressor molecules. Because interleukin (IL)-10 inhibits production of most M phi-derived molecules, we investigated the effects of IL-10 on murine M phi suppressor function during tumor growth. When acting as accessory cells during alloantigen-induced CD4+ T-cell proliferation, syngeneic tumor-bearing host (TBH) peritoneal M phi suppressed normal host (NH) T cell proliferation more than their normal counterparts. Exogenous IL-10 suppressed alloantigen-stimulated CD4+ T-cell proliferation in the absence of accessory M phi, but it blocked TBH M phi-mediated suppression. IL-10 pretreatment of M phi reversed suppression mediated by TBH M phi but did not affect NH M phi activity. Supernatant transfer experiments showed that IL-10 blocked TBH M phi-mediated suppression by inhibiting soluble suppressor molecule production. Activated TBH M phi produced greater quantities of the suppressor molecules tumor necrosis factor-alpha, nitric oxide, prostaglandin E2, and granulocyte-macrophage colony-stimulating factor than NH M phi did. Exogenous IL 10 reduced production of these molecules by TBH M phi more than by NH M phi. Activated TBH M phi produced more IL-10 than NH M phi, suggesting that endogenous IL-10 contributes to increased TBH M phi sensitivity to exogenous IL-10's inhibitory action. The antibody-mediated neutralization of endogenous IL-10 activity relieved NH, but not TBH, M phi-mediated suppression of T-cell proliferation. This result supports the idea that TBH M phi are more sensitive to the inhibitory action of IL-10 on suppressor molecule production. IL-10 is known to inhibit M phi antigen-presenting cell-dependent helper T-cell proliferation. We report here that IL-10 restores TBH helper T-cell functions by blocking accessory M phi production of inhibitory molecules. This restoration suggests that IL-10's M phi deactivating activity provides an upregulatory role in immunocompromised individuals where suppressor M phi are abundant. PMID- 7841547 TI - Festschrift to Professor A. Kint. Clinical and experimental dermatology. Proceedings of a symposium. Ghent, November 18-19, 1994. PMID- 7841548 TI - Collagen VII and bullous disorders of the skin. AB - Recent advances in molecular and cell biology of the cutaneous basement membrane zone have drastically increased our knowledge of the pathomechanisms underlying skin blistering disorders. Defects in genes coding for the structural proteins of the basement membrane zone have been defined in epidermolysis bullosa (EB), and abnormal expression of the structural proteins in some of its subtypes. The underlying cause for several subtypes of dystrophic EB are mutations in the gene for collagen VII, COL7A1. In vitro studies utilizing cells derived from the skin of such patients have helped understanding the pathogenetic pathways that lead from the mutation to the symptom, skin blistering. The data accumulated from analyses of the genetic disorders will also yield indirect information on the normal physiology of the skin and be highly relevant for the clarification of the etiopathogenesis of acquired blistering diseases. PMID- 7841549 TI - Langerhans cell histiocytosis. PMID- 7841550 TI - Ehlers-Danlos syndrome type IV. Clinical and molecular aspects and guidelines for diagnosis and management. AB - The clinical, biochemical and molecular characteristics of Ehlers-Danlos syndrome type IV are reviewed. The numerous clinical manifestations result from the generalized and excessive tissue fragility characteristic for this disorder. The variability in cutaneous involvement may hamper recognition of the condition and requires careful clinical examination. Clinical diagnosis can be confirmed by demonstration of a collagen type III defect. The severity of the phenotype appears to be related mainly to the intrinsic stability of mutant type III collagen protein and its disturbing effect on normal collagen fibrillogenesis in the extracellular matrix. PMID- 7841551 TI - Pemphigus: past, present and future. AB - Pemphigus remains the archetype of the autoimmune bullous diseases with circulating and skin antibodies in patients as well as in animal models. Pemphigus antigens are desmosomal-associated glycoproteins of 130 kD in pemphigus vulgaris (desmoglein 3) and of 160 kD (desmoglein 1) in pemphigus foliaceus (fogo selvagem in Brazil, pemphigus seborrheicus in other countries). Pemphigus may be associated to drugs and/or immune system related tumors (e.g. thymoma). Two new forms of pemphigus have been described: IgA pemphigus and paraneoplastic pemphigus. Targets of the autoantibodies are various desmosomal and cellular adhesion molecules. Even if each main pemphigus variant corresponds to specific antibodies, association of various antibodies may be found, leading to the concept of dysimmunoreactivity. PMID- 7841552 TI - Palmoplantar reactions. AB - The palmoplantar skin reacts monotonously to acute causes with vesicles or pustules and to chronic or chronically recurrent noxae with hyperkeratosis. Vesicular reactions are mostly triggered by eczematogens and fungi. Among the primary pustuloses, pustular psoriasis of the palms and soles is the dominating one, while the secondary pustuloses stem from infections of vesicular reactions with pyogens. Hyperkeratotic reactions may be caused directly by mechanical irritations or dehydration of the skin but also secondarily by chronic or chronically recurrent vesicular and pustular reactions. PMID- 7841553 TI - Current concepts in psoriatic arthritis. AB - Psoriatic arthritis is an inflammatory arthropathy associated with psoriasis and characterized by absence of rheumatoid factor. Any form of psoriasis can be complicated by joint inflammation. Four groups have been identified: pauciarticular psoriatic arthritis, psoriatic spondylitis, symmetrical polyarticular psoriatic arthritis and arthritis mutilans. The etiology of psoriatic arthritis remains unclear. Genetic, immunologic and environmental factors are thought to be important in the development of the disease. The role of cytokines and adhesion molecules in the mechanism of joint destruction is highlighted, and recent therapeutic strategies are discussed. PMID- 7841554 TI - Atopic dermatitis. PMID- 7841555 TI - The porphyrias. PMID- 7841556 TI - Pigmented epidermotropic metastasis of a breast carcinoma. AB - Mammary and extramammary Paget's disease is believed to remain non-pigmented, in contrast to superficial pagetoid melanoma; the same holds true for epidermotropic metastases of breast carcinoma. We recently had the opportunity to observe intensively pigmented epidermotropic metastasis of breast carcinoma, with dispersion of melanocytes in the dermal infiltrate. Similar observations, although exceedingly rare, have been reported: melanocytes 'may' pullulate within the dermo-epidermal foci of malignant epithelial cells. The final diagnosis relies on very careful analysis and, as far as possible, on immunohistological techniques. PMID- 7841557 TI - Febrile ulceronecrotic pityriasis lichenoides et varioliformis acuta. AB - An unusually severe form of pityriasis lichenoides et varioliformis acuta (PLEVA) with a fatal outcome in an 82-year-old woman is reported. After a period of a mild eruption, extensive polymorphous, papular and ulcerohemorrhagic skin lesions developed, associated with intermittent high temperature and constitutional symptoms. Skin biopsies showed the typical histopathological changes of PLEVA. Early recognition of this severe variant of PLEVA is important, since the fulminating course can lead to death. PMID- 7841558 TI - Clinical aspects of contact allergy to corticosteroids. AB - Because of their anti-inflammatory activity, corticosteroids generally mask the clinical signs of a contact dermatitis to a corticosteroid preparation. The lesions usually present as chronic dermatitis, and the patients mostly report not exacerbations but failures to respond to corticosteroid therapy. Moreover, masking also occurs with patch-test reactions obtained with corticosteroid preparations and the corticosteroid molecules themselves. These are important reasons why contact allergy to such preparations has frequently been missed in the past. PMID- 7841559 TI - Nickel allergy in Europe: the new European legislation. AB - A new directive from the European Union (EU) will restrict the use of nickel from 1996 on. The consequences of this directive in the EU are considered. PMID- 7841560 TI - Eosinophilic pustular folliculitis and B-cell chronic lymphatic leukaemia. AB - BACKGROUND: The major problem of eosinophilic pustular folliculitis (EPF) is its generally unknown aetiology. OBJECTIVE AND METHODS: The purpose of this case report is to advise a thorough medical investigation of all patients with EPF. RESULTS: The case of EPF presented seems to be associated with a chronic B-cell lymphatic leukaemia. CONCLUSION: Before regarding EPF as an idiopathic disease of unknown aetiology a thorough immunologic and haematologic investigation has to be advocated. PMID- 7841561 TI - Physiopathology and organotypic cultures of human keratinocytes. PMID- 7841562 TI - Pseudo-factitial dermatitis: a useful clinical and/or histopathological concept. AB - The concept of pseudo-factitial dermatitis can be defined as follows: any skin condition which, by its clinical or histopathological profile, can lead the clinician to an erroneous diagnosis of factitial dermatitis. Therefore, pseudo factitial dermatitis does not exist as such; intellectually, it is of special interest for the practising dermatologist, in terms of differential diagnosis, either clinical or histopathological. PMID- 7841563 TI - Cultured myofibroblasts display a specific phenotype that differentiates them from fibroblasts and smooth muscle cells. AB - BACKGROUND: Myofibroblasts (MF) from human granulation tissue derive from perilesional cells and display similarities with fibroblasts (DF) and smooth muscle cells (SMC). OBJECTIVE: Determine additional markers to assess the phenotype of MF. METHODS: MF, DF and SMC derived from human tissues were amplified in culture. Their phenotype and response to various regulatory processes were compared in vitro. RESULTS: MF resemble SMC by their mechanical properties and cytoskeletal proteins. They resemble DF by their biosynthetic phenotype and their response to the regulation operated by the extracellular matrix and mechanical forces. CONCLUSION: In vitro MF display a phenotype that differentiates them from DF and SMC. PMID- 7841564 TI - Treatment of epidermolysis bullosa with human cultured epidermal allografts. AB - Junctional epidermolysis bullosa letalis type Herlitz Pearson is a genetically determined, life-threatening disease. Effective therapy has been lacking to date. Therefore any therapy that improves wound healing would be beneficial for these patients. Cultured epidermal grafts are known to enhance wound epithelialization and have been used with success in some epidermolysis bullosa disorders. Encouraged by these reports, we grafted cultured allogeneic keratinocytes to an infant with a junctional epidermolysis bullosa letalis type. PMID- 7841565 TI - Classification of primary cutaneous lymphomas. Historical overview and perspectives. AB - Primary cutaneous lymphomas represent a heterogeneous group of malignant B- and T cell lymphomas. In the last two decades, the diagnostic criteria, classification and terminology of these disorders have changed enormously. A historical overview of the subsequent concepts on the classification of this group of disorders is presented. Disadvantages of currently available classification schemes are discussed, and a proposal for a new classification for this group of disorders is formulated. PMID- 7841566 TI - Safety and tolerance of intravenous nimodipine. AB - OBJECTIVE: To evaluate the safety and tolerance of intravenous nimodipine administered via a peripheral vein in healthy male volunteers. DESIGN: Double blind, placebo- and vehicle-controlled trial with three fixed-dose panels. SETTING: Inpatient infusion and observation periods. SUBJECTS: 61 healthy male volunteers, aged 18-40 years. METHODS: Subjects in panel 1 received nimodipine 0.4 mg/h, vehicle 2 mL/h, or placebo 2 mL/h; subjects in panel 2 received nimodipine 1 mg/h, vehicle 5 mL/h, or placebo 5 mL/h; subjects in panel 3 received nimodipine 2 mg/h, vehicle 10 mL/h, or placebo 10 mL/h. All infusions were administered intravenously for 48 hours and volunteers were observed for 48 hours after cessation of the infusion. In addition to standard safety assessments (physical examination, electrocardiogram, laboratory studies, and adverse event reporting), supine and standing blood pressures and pulse rates were measured frequently. Plasma samples were also analyzed for nimodipine and its two demethylated metabolites. RESULTS: Of 61 subjects, 55 completed the 48-hour infusion and 6 discontinued the study because of adverse events. Intravenous nimodipine was well tolerated at 0.4 and 1 mg/h. However, all six subjects who received nimodipine 2 mg/h experienced moderate-to-severe adverse events, and one subject was discontinued because of dizziness, diaphoresis, and postural hypotension. The matched vehicle (10 mL/h) also was not well tolerated, with three subjects who discontinued because of phlebitis. Two subjects who received placebo were also discontinued during the study. Small (2 mm Hg) decreases in mean supine diastolic blood pressure were observed in the 0.4- and 1-mg/h nimodipine groups, but the 2-mg/h group showed a slight (5 mm Hg) increase in blood pressure. These changes were not clinically significant. Clearance and half life of nimodipine and its metabolites were similar at all three dosages. CONCLUSIONS: Using peripheral vein administration, nimodipine 2 mg/h and matched vehicle at 10 mL/h were not well tolerated in this healthy normal population. The maximum tolerated dose of nimodipine was found to be 1 mg/h. PMID- 7841567 TI - Preliminary comparison of predictive and empiric lithium dosing: impact on patient outcome. AB - OBJECTIVE: To evaluate whether initiating lithium with predictive dosing compared with empiric dosing improves outcome in patients with manic symptoms. DESIGN: The study was a randomized, single-blind design and used the Modified Slattery predictive method. SETTING AND PARTICIPANTS: Eighteen inpatients at an urban psychiatric hospital with a Mania Rating Scale (MRS) score greater than or equal to 24 were enrolled. OUTCOME MEASURES: The study endpoint was defined as an MRS rating less than or equal to 14 or discharge from the hospital. Assessments (MRS, Brief Psychiatric Rating Scale, Clinical Global Impression, Systematic Assessment for Treatment of Emergent Events Scale, quality of life measures) were completed at baseline, on days 3 or 4 and 7 or 8, and weekly thereafter. RESULTS: The predictive group achieved a therapeutic concentration significantly sooner than did the empiric group (p = 0.004); however, the mean serum lithium concentration at discharge did not differ between the groups. The predictive group was taking significantly higher dosages of antipsychotics in chlorpromazine equivalents on day 3 or 4 (p = 0.05). Significantly fewer gastrointestinal/genitourinary adverse effects on day 3 or 4 were reported by patients in the predictive group (p = 0.04). No difference was found between groups with any rating scale or other pharmacokinetic or medication item. Even though the difference did not meet statistical significance, the predictive group's length of stay in the acute unit was three days shorter than that of the empiric group, which may represent significant cost savings. CONCLUSIONS: The preliminary data do not suggest that patient outcome is improved by using Modified Slattery predictive dosing; however, the suggestion of a shorter length of stay in a restrictive unit merits further evaluation. PMID- 7841568 TI - Immunization requirements for pharmacy students. AB - OBJECTIVE: To identify current immunization requirements for pharmacy students throughout the US. DESIGN: Self-administered questionnaire. SETTING: Seventy-five colleges and schools of pharmacy in the US. MAIN OUTCOME MEASURES: Immunization policies, immunologic requirements, timing of vaccination in relation to the beginning of clerkship experience, payment, mechanism to revise policies. DATA ANALYSIS: Descriptive statistics. RESULTS: Overall, 57 programs (81 percent) have an immunization program in place, but 13 programs (19 percent) have no immunization program. More than 50 percent of the colleges or schools reported requiring that pharmacy students have measles, mumps, rubella, tetanus, and purified protein derivative of tuberculin (PPD) vaccinations upon entry of clerkship. Only 25 college or schools of pharmacy (44 percent) required students to have the hepatitis B vaccine and 8 (14 percent) to have a PPD evaluation upon completion of clerkship experience. Responsibility for the immunization program was shared evenly between the clerkship coordinator and the student health clinic. Approximately 65 percent of programs maintain an immunization record on file for each student. Completion of immunizations was required in 36 schools (64 percent) before entering clerkship activities, 15 (26 percent) before entrance to the professional program, and 3 (5 percent) in the first year of the program. Six schools (11 percent) had a program in place for less than one year, 27 (47 percent) between one and five years, and 24 (42 percent) for more than five years. At the majority of schools, students are responsible for the cost of immunization. CONCLUSIONS: Most schools of pharmacy do not adhere to the specific immunization recommendations described by the Centers for Disease Control and Prevention for healthcare workers. Pharmacy schools need to reexamine their immunization policies and update them to reflect the most current standards. We suggest a policy for immunization of pharmacy students. PMID- 7841569 TI - Oxaprozin-induced fulminant hepatitis. AB - OBJECTIVE: To report oxaprozin-induced fulminant hepatic failure. CASE SUMMARY: A 56-year-old woman was admitted with fulminant hepatic failure. Work-up for potential etiologies was negative except for the use of oxaprozin for the preceding two months. Results of premortem liver biopsy were consistent with drug induced hepatic injury similar to that previously reported with diclofenac. DISCUSSION: Although the literature describes elevation in hepatic transaminase concentrations associated with oxaprozin, fulminant hepatic failure has not been described previously. CONCLUSIONS: Elevations in hepatic transaminase concentrations and now fulminant hepatic failure have been shown to occur with oxaprozin, as previously seen with other nonsteroidal antiinflammatory drugs (NSAIDs). Transaminitis is a known adverse effect of NSAID use, but is usually mild and reversible with discontinuation of drug. Transaminitis may be more likely to occur in the elderly, in patients receiving concurrent potentially hepatotoxic medications, and possibly with the newer long-acting NSAIDs. The existence of fulminant hepatitis, although rare, supports the need for monitoring liver function enzymes during NSAID therapy. PMID- 7841570 TI - Possible ciprofloxacin-induced acute cholestatic jaundice. AB - OBJECTIVE: To report a case of acute cholestatic jaundice in a patient who was receiving oral ciprofloxacin. CASE SUMMARY: An 84-year-old woman residing in a long-term care facility developed acute cholestatic jaundice while being treated with ciprofloxacin for a urinary tract infection. On day 6 of ciprofloxacin therapy, she was noted to have an erythematous, pruritic rash over her chest and abdomen. At this point ciprofloxacin treatment was discontinued, as an allergy was suspected. Three days later she was noted to have jaundiced sclera and skin, and liver function test results were markedly elevated. The plasma cholesterol concentration was increased substantially; there was no decrease in plasma albumin concentration or increase in prothrombin time. The patient was treated with intravenous fluids. Within the next month, the liver function test results decreased to near normal and the patient was asymptomatic. Follow-up liver test results three months later were normal. DISCUSSION: To our knowledge, there are only a few other case reports in the literature of a possible ciprofloxacin induced liver injury. Enoxacin, a fluorinated quinolone antibiotic similar to ciprofloxacin, was reported to cause cholestatic liver injury in one patient. The exact mechanism by which fluoroquinolones may cause liver injury is unknown. CONCLUSIONS: We believe that this is only the second reported case of acute cholestatic jaundice resulting from ciprofloxacin therapy. Although this reaction seems to occur rarely, it is prudent to be alert for the signs and symptoms of cholestasis when administering ciprofloxacin. PMID- 7841572 TI - Ticlopidine and fatal aplastic anemia in an elderly woman. AB - OBJECTIVE: To report a case of aplastic anemia that developed during ticlopidine treatment. CASE SUMMARY: An 84-year-old woman was started on ticlopidine for secondary stroke prevention. Within six weeks of initiating ticlopidine therapy she developed aplastic anemia. She was hospitalized and received empiric antibiotics, antifungal agents, blood transfusions, platelets, and granulocyte colony-stimulating factor. The patient died on day 76 after beginning ticlopidine. DISCUSSION: Hematologic effects such as neutropenia, thrombocytopenia, agranulocytosis, thrombotic thrombocytopenic purpura, and pancytopenia have been described with the use of ticlopidine. Previous case reports have associated ticlopidine with the development of aplastic anemia. CONCLUSIONS: Ticlopidine can produce fatal hematologic adverse effects, and its use should be reserved as second-line therapy. PMID- 7841571 TI - Lisinopril overdose and management with intravenous angiotensin II. AB - OBJECTIVE: This report describes a case of lisinopril overdose managed in part with an infusion of angiotensin II in a patient with dilated cardiomyopathy and reviews other literature reporting angiotensin-converting enzyme (ACE) inhibitor overdose. DATA SOURCES: Information concerning this patient was obtained through review of the medical chart, conversation with the attending physician, and personal involvement late in the course of the patient's therapy. We conducted MEDLINE and PAPERCHASE searches of the English language literature (restricted to human studies) from 1976 to the present, manually searched Current Contents and references from each publication reviewed, and contacted the manufacturer of lisinopril for any further references they could provide. STUDY SELECTION: All case reports that described an ACE inhibitor overdose. DATA EXTRACTION: Case reports were evaluated for the ACE inhibitor involved, amount ingested, and therapeutic management. DATA SYNTHESIS: Ten patients with ACE inhibitor overdose have been reported, most of whom required only intravenous fluids for blood pressure support. The case presented here is the second report in which the patient's blood pressure was not adequately controlled with fluid and traditional vasopressors and required an infusion of angiotensin II. CONCLUSIONS: Although only a few cases of ACE inhibitor overdose have been reported, it is possible that with widespread use of these agents, overdose may become a more common problem. Management of ACE inhibitor overdose should include general supportive care, gut decontamination when possible, intravenous fluids, and vasopressors if necessary. Intravenous angiotensin II may be effective in situations in which traditional vasopressors fail, and is a physiologically rational treatment. PMID- 7841573 TI - Prolonged thrombocytopenia associated with procainamide in an elderly patient. AB - OBJECTIVE: To report a case of thrombocytopenia associated with the use of extended-release procainamide hydrochloride in a geriatric patient. CASE SUMMARY: A 77-year-old man was admitted to the hospital for four-vessel coronary artery bypass surgery. He subsequently developed new onset atrial fibrillation and was started on extended-release procainamide on hospital day 7. The patient's platelet count on admission was 229 x 10(9)/L. The platelet count began to decrease on hospital day 22 and was 79 x 10(9)/L by day 30 and 13 x 10(9)/L by hospital day 37. The patient exhibited gross hematuria and lower extremity petechiae. There were no signs of splenic sequestration and other hematologic indices were normal. Procainamide was discontinued on hospital day 32. There was full recovery of the platelet count to baseline 33 days after procainamide was discontinued. DISCUSSION: Other possible medical and drug-related causes of thrombocytopenia are reviewed and ruled out. Previous reports of procainamide associated thrombocytopenia describe an immune-mediated peripheral destruction of platelets with platelet recovery within three to eight days after drug discontinuation. However, the prolonged recovery period and the presence of antiplatelet antibodies suggest an immune-mediated process in the bone marrow of this patient. CONCLUSIONS: Clinicians should be aware of the possible adverse hematologic effects of procainamide in the elderly. PMID- 7841574 TI - Worsening of liver function with fluconazole and review of azole antifungal hepatotoxicity. AB - OBJECTIVE: To report a case of fluconazole worsening of liver dysfunction. CASE SUMMARY: A patient with hepatitis experienced worsening of her liver function when treated with fluconazole for a Candida infection in her urine. Elevations in aspartate aminotransferase, alanine aminotransferase, and total bilirubin concentrations along with increased prothrombin time and activated partial thromboplastin time were noted as early as the second day of therapy. After discontinuation of the fluconazole, the liver parameters returned to their normal baseline level. DISCUSSION: Hepatotoxicity associated with azole antifungal therapy is reviewed. This patient experienced elevations in liver function enzymes; the literature relating to this topic is evaluated. CONCLUSIONS: It is probable that fluconazole therapy was involved in the worsening of this patient's liver function. Liver function should be monitored during the course of fluconazole therapy in patients with underlying liver dysfunction. It appears from the published reports that HIV-positive patients may be at risk for hepatotoxicity with fluconazole. PMID- 7841575 TI - Intralipid in prophylaxis of amphotericin B nephrotoxicity. PMID- 7841576 TI - Cyclosporine for the treatment of pemphigus vulgaris. PMID- 7841577 TI - Doxycycline-induced esophageal ulceration. PMID- 7841578 TI - Gabapentin: a new agent for the management of epilepsy. AB - OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and safety of gabapentin, a new antiepileptic drug (AED). Gabapentin's potential role in the treatment of epilepsy also was assessed. DATA SOURCE: A MEDLINE search was performed to identify all published literature (manuscripts and abstracts). Abstracts presented at the American Epilepsy Society, International Epilepsy Congress, and American Academy of Neurology meetings from 1991 to 1993 also were reviewed. A copy of the proceedings from the Food and Drug Administration Peripheral and Central Nervous System Advisory Committee meeting and package insert were obtained from Parke Davis. STUDY SELECTION: All pertinent literature was reviewed. Emphasis was placed on published information, particularly placebo controlled clinical trials. DATA SYNTHESIS: Gabapentin is effective as adjunctive treatment for patients with partial seizures with or without secondary generalization refractory to the standard AEDs. It has a unique pharmacokinetic profile for an AED, including no binding to plasma proteins, primary elimination by the kidney, and dose-dependent oral absorption at high dosages. No drug interactions occur with the other AEDs. The most frequent adverse reactions noted in patients receiving gabapentin have been mild and transient central nervous system effects. No serious hypersensitivity or systemic reactions have been observed. CONCLUSIONS: Gabapentin appears to be a useful new AED. Further studies evaluating its use as monotherapy, in higher dosages, and in pediatric and elderly patients are required to better delineate its therapeutic role relative to that of other AEDs. PMID- 7841579 TI - Quality improvement for routine screening and diagnosis of diarrheal illness identified from adverse drug reaction reporting. PMID- 7841580 TI - Acute rheumatic fever despite clarithromycin treatment of beta-hemolytic streptococcal tonsillitis. PMID- 7841581 TI - Effect of octreotide on plasma lipid metabolism in acromegaly. PMID- 7841582 TI - Dystonic reaction associated with sumatriptan. PMID- 7841583 TI - Syndrome of inappropriate antidiuretic hormone secretion induced by different drugs. PMID- 7841584 TI - Ticarcillin/clavulanate desensitization protocol. PMID- 7841585 TI - Hyponatremia and benzodiazepines result in rhabdomyolysis. PMID- 7841586 TI - New versus old placebos. PMID- 7841587 TI - Comment: NSAID use and efficacy in the emergency department. PMID- 7841588 TI - Comment: Aminoglycoside nephrotoxicity following single-dose cystoscopy prophylaxis. PMID- 7841589 TI - Comment: Ondansetron for treating nausea and vomiting in the poisoned patient. PMID- 7841590 TI - [Effect of gastrin and H2-receptor antagonist on electrical control activity following canine intestinal transection]. AB - Our objective was to study the mechanism of action of gastrin and histamin H2 receptor antagonist on the motility of the gastrointestinal area. In each of 12 mongrel dogs, eight bipolar electromyograms were obtained from the antrum of the stomach to the ileum on serosal surface, and in nine dogs undergoing that the small intestine was transected 20 cm from the ligament of Treitz. The effects of tetragastrin (1.0-10.0 microgram.kg-1.h-1) were studied against the presence of atropine, cimetidine and d-chlorpheniramine maleate. The frequency of electrical control activity (ECA) along the canine small intestine, and changes in ECAs frequency were studied normal and following upper small intestinal transection. In intact, the frequency of ECAs gradient decreased aborally in a stepwise fashion in normal intestine. Although the gradient was markedly reduced or even abolished distal to the level of transection, an intrinsic ECAs frequency gradient was demonstrated, it remained at a low level indefinitely. The normal ECA pattern and its alterations following transection were significantly influenced by tetragastrin. The act of tetragastrin in a dose of 1.0 to 5.0 microgram.kg-1.h-1 had not statistically effect on ECAs frequency and its dysrhythmias, and it did cause a small increase in the frequency of ECA at the antrum, whereas, with the highest dose (10.0 microgram.kg-1.h-1) of used, the increase of mean frequency of ECA in the distal portion to the line of transection, in particular, was significantly greater compared to the change in the proximal portion. It was only cimetidine (8.0 mg.kg-1) that antagonized this action of tetragastin (10.0 microgram.kg-1.h-1). Histamine H2 receptors are suspected of being associated with the action the gastrin has of enhancing ECAs frequency. The results of this study indicate that histamine H2 receptors regularize gastrointestinal ECAs frequency. PMID- 7841591 TI - [Experimental study on intestinal movement after total gastrectomy with jejunal interposition]. AB - In order to study the physiological changes in the intestinal movement after total gastrectomy with jejunal interposition, electromyography was taken from different sites of small intestine of the dogs with and without gastrectomy. Both 6 and 12 months after surgery, the frequency of the basic electric rhythm (BER) of interposed jejunum was lower and that of distal jejunum was much lower than that of duodenum. Most of the interdigestive migrating electric complexes (IMEC) was originated in the oral side of the interposed jejunum; the rate of occurrence increased after the operation further and reached to 91.5% one year after the operation. Most of the dogs showed the propagation pattern from interposed jejunum to duodenum and to distal jejunum; this tendency increased after the operation and 80.8% of the dogs showed this pattern one year after the operation. Thus, the IMEC, conducted usual intestinal order disappeared after the operation and those originated from oral to anal side, regardless of their original order. These results suggest that the order of the propagation of IMEC were determined by the order of the portion of intestine after operation and the parietal continuity, rather than extrinsic nerves, is involved in the propagation. It is also suggested that the propagation of IMEC is not always correlated with the gradient in the difference of the BER between the replaced jejunum and duodenum. PMID- 7841592 TI - Effects of gastrectomy on motility, perfusion pressure, and caerulein-induced relaxation of sphincter of Oddi in dogs. AB - The effects of subtotal-gastrectomy (gastrectomy) on the spontaneous motility and caerulein-induced relaxation of the sphincter of Oddi (SO) were investigated in the dog. The spontaneous motility and the response to caerulein of the SO were recorded using perfusion method. The basal perfusion pressure (5.1 +/- 0.5 cmH2O) and the frequency of phasic contractions (6.1 +/- 0.5 cycles/min, c/min) of the SO increased to 8.2 +/- 0.6 cmH2O (p < 0.05) and 9.3 +/- 0.4c/min (p < 0.05) after gastrectomy, respectively. They were observed one month after operation (7.8 +/- 0.5 cmH2O and 9.1 +/- 0.9 c/min, p < 0.05), but did not change by vagotomy with sympathectomy (vagosympathectomy). In the spontaneous motility of the SO, the motility index increased to 143.7 +/- 18.7% (p < 0.05) at 4 hrs and 135.0 +/- 9.1% (p < 0.05) at one month after gastrectomy, but did not increase after vagosympathectomy. Caerulein had an inhibitory effect on the SO motility in the normal animal 48.0 +/- 4.2%). Gastrectomy reversed to the excitatory effect from the inhibitory effect to caerulein at 4 hrs (127.6 +/- 5.3%, p < 0.05) and at one month (126.6 +/- 5.3%, p < 0.05) after operation, but not reversed by vagosympathectomy and sham gastrectomy. The excitatory response to caerulein after gastrectomy was not effected by vagosympathectomy. It is concluded that gastrectomy induced the SO dysfunction, an increase of the perfusion pressure and the frequency of phasic contractions of the SO, and a change of the response to caerulein of the SO. These alterations suggests that one of the mechanisms of the regulation of the SO motility exist as the reflex from the stomach and/or uppermost duodenum through intrinsic nervous pathways. PMID- 7841593 TI - [Experimental and clinical studies on lower esophageal sphincter motor function with special reference to the influence of vagal denervation]. AB - Dysmotility of lower esophageal sphincter (LES) is common following gastric surgery. This may result in gastroesophageal reflux which frequently seen following gastric surgery. The aim of this study was to determine the effect of various surgical procedures on esophagogastric motility in dog and human. Esophago-gastric motility was investigated by strain gauge transducers during fasted and fed state in conscious dogs. Motility recordings were performed in three groups of dogs; 1) control dogs, 2) with truncal vagotomized dogs (TV), 3) with selective proximal vagotomized dogs (SPV). In human, manometric recordings were performed before and after gastric surgery (SPV or distal partial gastrectomy). In control animals, lower esophagus and LES contracted simultaneously with each contractions of the stomach during interdigestive motor contractions in fasted state. In fed state, LES showed tonic contractions, while gastric body showed receptive relaxation. These motility pattern of LES was considered to prevent gastroesophageal reflux in both fasted and fed states. These coordinated LES contractions disappeared following SPV or TV. In human, the amplitude and velocity of esophageal propagating contractions deceased after SPV or distal partial gastrectomy. In conclusion, gastric surgeries such as SPV, TV and/or distal partial gastrectomy caused LES dysmotility. These phenomena explain frequent gastroesophageal reflux following gastric surgery. Supplementation of anti-reflux procedure for gastric surgery should be required in the prevention of gastroesophageal reflux following gastric surgery. PMID- 7841594 TI - Endothelial cell function and thrombosis. AB - Healthy endothelium is a metabolically active interface between the blood and extravascular tissues. Its intimal surface is anticoagulant and antithrombotic, and it secretes a variety of molecules involved in regulating platelet function and blood coagulation. The rapid interactions between platelets, their secreted components, or thrombin and endothelial cells at sites of vessel damage ensure the local secretion of mediators such as prostacyclin and nitric oxide that limit the intravascular growth of the haemostatic plug. There is considerable evidence that a decreased ability of endothelial cells to synthesize NO contributes to the pathogenesis of arterial disease. Local deficiency of PGI2 synthesis has also been implicated in the thrombotic problems in haemolytic uraemic syndrome. Endothelium is also the source of circulating von Willebrand factor, important for efficient platelet adhesion. Chronically elevated plasma levels of vWF in a series of diseases where there is vascular pathology apparently reflect endothelial cell damage or activation, and may contribute to the prothrombotic tendency they exhibit. They may be compounded by decreased levels of the surface anticoagulant thrombomodulin, if the increased concentrations of the soluble forms of thrombomodulin detected in the circulation under similar conditions are a reflection of loss from the endothelium. Further alterations of function in a procoagulant/prothrombotic direction take place when endothelial cells are exposed to certain cytokines or lipopolysaccharide. Tissue factor synthesis is induced, thrombomodulin expression is decreased, and there is enhanced sensitivity of vWF secretion. In addition, the balance of tissue-type plasminogen activator and plasminogen activator inhibitor type I secretion is changed in favour of the latter. These processes are each likely to contribute to the occurrence of disseminated intravascular coagulation which can accompany septic shock. PMID- 7841595 TI - Possible involvement of cytokines in diffuse intravascular coagulation and thrombosis. AB - Inflammation and the cytokines clearly affect the coagulation system. Less clear are the specific influences of the coagulation system on inflammation. In this chapter only some of the coagulation systems affected by the cytokines are discussed, and the influences on the fibrinolytic system, which is also downregulated by selected cytokines are not mentioned; see Schneiderman and Loskutoff (1991) for a brief review. The major focus is on possible models by which inflammation and coagulation are linked, and examples where in vitro studies have led to correct in vivo predictions and where the results remain ambiguous. Finally, this chapter is clearly a biased perspective with the primary emphasis on the components and pathways with which the author has personal experience. PMID- 7841596 TI - Tissue factor pathway. AB - Blood coagulation is initiated in response to vessel damage in order to preserve the integrity of the mammalian vascular system. The coagulation cascade can also be initiated by mediators of the inflammatory response, and fibrin deposition has been noted in a variety of pathological states. The cascade of coagulation zymogen activations which leads to clot formation is initiated by exposure of flowing blood to tissue factor (TF), the cellular receptor and cofactor for factor VII (FVII). FVII binds to the receptor in a 1:1 stoichiometric complex and is rapidly activated. FVIIa undergoes an active site transition upon binding TF in the presence of calcium which enhances the fundamental properties of the enzyme. This results in rapid autocatalytic activation of FVII to VIIa thereby amplifying the response by generating more TF-VIIa complexes. The TF-VIIa activates both FIX and FX. Further FXa generation by the IXa-VIIIa-Ca(2+) phospholipid complex is required to sustain the coagulation mechanism, since the TF-VIIa complex is rapidly inactivated. Structure and function studies have identified a number of regions on both TF and FVII involved in this interaction. It is clear, however, that the molecular structures of TF, FVII and the TF-VII complex will have to be solved before we fully understand this complex interaction. The activity of the TF-VIIa complex is controlled by two inhibitors:tissue factor pathway inhibitor (TFPI) and antithrombin III (AT-III). TFPI circulates in plasma, is associated with vascular cell surface and is released from platelets following stimulation by thrombin. TFPI requires the formation of an active TF-VIIa complex and FXa generation before inhibition can occur. Similarly, AT-III which is unable to inhibit circulating FVIIa requires the formation of the TF-VIIa complex. TFPI prevents further participation of TF in the coagulation process by forming a stable quaternary complex, TF-VIIa-Xa TFPI. In contrast, the AT-III-VIIa complex is thought to dissociate from TF allowing it to interact with additional FVII-VIIa. TFPI has been considered the primary regulator of TF-VIIa activity during haemostasis. Whether AT-III in the presence of glycosaminoglycans on cell surfaces expressing TF can function as an auxiliary second physiological regulator is not known. PMID- 7841597 TI - Endogenous mediators and thrombophilia. AB - Platelet function is a balance between factors determined at thrombopoiesis and prothrombotic and antithrombotic mediators from the vascular wall. Nitric oxide is a crucial vasodilator and inhibitor of platelet activation synthesized constitutively by the vascular endothelium. In some pathological states this synthesis may be impaired leading to a prothrombotic state. In other situations, synthesis may be increased by a second inducible enzyme. Nitric oxide synergizes with other antithrombotic vasodilators such as prostacyclin and is opposed by prothrombotic vasoconstrictor mediators such as thromboxane. Platelets are anucleate and their reactivity is partly determined at thrombopoiesis by their progenitor cell, the megakaryocyte. In thrombotic states, such as myocardial infarction, larger, more reactive platelets from larger megakaryocytes are observed. PMID- 7841598 TI - Platelet factors predisposing to arterial thrombosis. PMID- 7841599 TI - Activation markers of coagulation. AB - Advances in our understanding of the biochemistry of the haemostatic mechanism have led to the development of sensitive methods for measuring peptides, enzyme inhibitor complexes or enzymes that are liberated with the activation of the coagulation system in vivo. Studies employing these markers indicate that a biochemical imbalance between procoagulant and anticoagulant mechanisms can be detected in the blood of humans prior to the appearance of thrombotic phenomena. Properly designed prospective studies will be required to determine whether these assay techniques will enable us to identify individuals who are entering a clinically relevant hypercoagulable state, and intervene with appropriate therapy prior to the onset of overt thrombotic disease. PMID- 7841600 TI - Antiphospholipid antibodies and thrombosis. AB - Antiphospholipid antibodies are a diverse group of immunoglobulins initially thought to have specificity to phospholipid epitopes. It is apparent that autoimmune anticardiolipin antibodies require a serum cofactor beta-2 glycoprotein I (beta 2GPI) for their binding to phospholipids. Lupus anticoagulant also may bind to phospholipids by beta 2GPI or by prothrombin. The description of binding to protein-phospholipid epitopes may explain several perplexing features of these antibodies both in vitro and in vivo. Antiphospholipid antibodies have a well-established association with clinical disease--in particular thrombosis, thrombocytopenia and recurrent fetal loss. The mechanism of the predisposition to thrombosis seen with these antibodies is poorly understood. It has been suggested that they may cause endothelial dysfunction by causing increased tissue factor expression, by inhibiting prostacyclin secretion or by inhibiting fibrinolysis. Various platelet-activating activities have also been described. The evidence that antiphospholipid antibodies promote thrombosis by effects on endothelium or platelets is inconclusive. Inhibition of protein C activation, or of activated protein C action, has been demonstrated in vitro. A poor correlation between thrombosis in vivo and these inhibitory effects has been found. Beta-2-glycoprotein I has been identified as a cofactor for binding to phospholipid by thrombogenic anticardiolipin antibodies. That beta 2GPI may be a natural anticoagulant of importance remains to be proved. Inhibition by antiphospholipid antibodies of this anticoagulant function could explain the propensity to thrombosis seen in association with these antibodies. PMID- 7841601 TI - Fibrinolysis and thrombosis. AB - In conclusion, venous and arterial thrombi contain significant amounts of fibrin. There is evidence that defective fibrinolytic mechanisms may participate in their genesis or persistence in the body. Some evidence suggests that defective fibrinolysis may presage and predict both arterial and venous thrombi; this is stronger evidence of a causal link with thrombosis. Thrombi protect themselves from lysis by incorporating inhibitors (plasminogen activator inhibitor-1 and alpha 2-antiplasmin) in their structure. Fibrinolytic mechanisms may play a role in the genesis or development of atherosclerotic lesions, in addition to thrombosis. Thrombolytic agents lyse both arterial and venous thrombi when administered shortly after their development. If it proves possible in future to enhance natural fibrinolytic mechanisms and to sustain this enhancement by pharmacological or other means, the interesting prospect of harnessing the fibrinolytic system to prevent thrombus formation, as well as to treat it, will arise. PMID- 7841602 TI - Rheological influences on thrombosis. PMID- 7841603 TI - Myeloproliferative and metabolic causes. PMID- 7841604 TI - The molecular genetics of familial venous thrombosis. AB - This study of naturally occurring mutations predisposing to venous thrombosis has led to a number of important advances in our understanding of protein structure and function relationships and the molecular basis of gene mutation. It has also potentiated the accurate and reliable presymptomatic and antenatal detection of predisposing gene lesions. Perhaps the major challenge facing us is the probabilistic nature of thromboembolism; only a certain proportion of patients with recognized gene defects predisposing to thrombosis will actually suffer from thrombotic episodes. Environmental insults of various kinds, and perhaps epistatic effects resulting from the influence of other loci, are likely to be contributory factors and will help to determine whether a thrombotic event occurs in individuals already compromised by a defect in a gene whose malfunction is known to predispose to thrombosis. Since molecular genetic techniques allow us to dissect the allelioheterogeneity of the different deficiency states by characterizing the wide spectrum of gene mutations giving rise to thrombosis, it may eventually prove possible to relate specific gene lesions to the probability of thromboembolism as well as to the severity and frequency of thrombotic episodes. The multifactorial nature of thrombosis demands a multidisciplinary approach to the analysis of its causation, early detection, treatment and prevention. The application of the new and powerful techniques of molecular genetics promises to make a substantial contribution to all aspects of thrombosis research. PMID- 7841605 TI - Genetic determinants of arterial thrombosis. AB - This chapter describes examples of genetic variation determining plasma levels of three independent risk factors for arterial thrombotic disease, namely fibrinogen, coagulation factor VII and plasminogen activator inhibitor type 1, together with a discussion of the underlying molecular mechanisms. In each case, the data suggest that there is interaction between genotype and environment in determination of the relevant plasma level, providing a possible explanation for the differential response of different individuals to their environment. PMID- 7841606 TI - Deep vein thrombosis of the lower limbs: diagnosis and management. PMID- 7841607 TI - Lipoproteins and the haemostatic system in atherothrombotic disorders. AB - The early belief that the haemostatic system has no active role in the formation of the atheromatous plaque is no longer tenable. Rather, the association between hypercholesterolaemia and atherosclerosis appears to arise in part because of various effects of high concentrations of LDL and VLDL particles on the cellular and humoral components of the system, thereby promoting plaque growth and thrombosis. These may be summarized as follows: 1. High concentrations of native LDL have been reported to promote the adhesion of monocytes to the endothelial cell, suggesting that the latter undergoes a form of activation upon such exposure. Oxidized LDL is more potent in this respect, and persistent exposure of endothelium to such particles can eventually lead to cell injury. 2. Activated endothelial cells acquire characteristics on their luminal surface conducive to thrombin generation and fibrin production. Thrombin has several actions on the endothelial cell, monocyte, smooth muscle cell and platelet which in the presence of hypercholesterolaemia will promote the formation of atheroma. 3. Oxidatively modified LDL can activate circulating monocytes, when they also acquire procoagulant properties which favour thrombin production. 4. Platelets show an increased tendency to aggregate when exposed to hypercholesterolaemic plasma. This effect may arise in part because the platelet of the hypercholesterolaemic patient expresses an increased number of fibrinogen binding sites on its surface following activation by agonists such as ADP. These hyperaggregable platelets adhere to activated endothelial cells which express von Willebrand factor on their surface, and to subendothelial proteins exposed in the gaps that open between injured endothelial cells. Platelets exposed to raised LDL levels also show a reduced sensitivity to prostacyclin, an antiaggregatory agent. Oxidatively modified LDL has been reported to stimulate aggregation of platelets in the absence of other agonists such as ADP or thrombin (spontaneous aggregation). 5. Platelet aggregation and fibrin deposition at sites of endothelial injury will create microthrombi which become incorporated into the lesion by organization, thereby increasing the fibrous and cellular content of the atheromatous plaque. 6. Lipolysis of triglyceride-rich lipoproteins at the endothelial cell surface leads to transient activation of the coagulation mechanism with activation of factor VII. Activated factor VII is a potent procoagulant when it forms a complex with tissue factor in the atheromatous lesion. Persistent hypertriglyceridaemia is accompanied by raised concentrations of factor X, factor IX, factor VII and prothrombin. 7. Hypertriglyceridaemia is associated with an increased plasma concentration of PAI-1 and a reduction in plasma fibrinolytic activity.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7841609 TI - Modern aspects of early nutrition. Proceedings of a symposium. Riccione, Italy, 21-22 May 1993. PMID- 7841608 TI - Haemostatic function, arterial disease and the prevention of arterial thrombosis. PMID- 7841610 TI - Trends in research on infant nutrition, past, present and future. AB - A review of general trends in early infant feeding is presented, with particular focus on the importance of breast feeding. That the promotion of breast feeding is highly effective is borne out by the tendency toward its prevalence in Sweden during the period 1972-94. PMID- 7841612 TI - Nutritional aspects of soy formula. AB - Soy formula is a commonly used alternative to cows' milk formula. While its primary use has been for infants with milk protein allergy and lactose intolerance, soy formula is used increasingly for infants with gastrointestinal discomfort. The nutritional composition of soy formula has been designed to cover the nutrient needs of the newborn infant; however, some aspects of its composition need further consideration. The protein level of soy formula is usually higher than that of milk-based formulae, partially because of differences in protein digestibility and partly because of differences in amino acid composition. The presence of phytic acid in soy formula presents a problem with regard to mineral and trace element bioavailability. Several steps can be taken to minimize this problem, either by reducing the phytate content of soy protein isolate or by changing levels of minerals/trace elements in the formula. Finally, the high levels of manganese in soy formula present a potential problem in that manganese absorption and retention are high during infancy. PMID- 7841611 TI - Nutritional evaluation of various protein hydrolysate formulae in term infants during the first month of life. AB - The aim of the study was to compare, during the first month of life, growth parameters, biochemical indices of protein metabolism and plasma amino acid concentrations in newborn infants fed either human milk (n = 23), three different whey hydrolysate formulae (WHF 1, n = 13; WHF 2, n = 10; WHF 3, n = 13), a soy collagen hydrolysate formula (SCHF n = 18) or a whey-casein hydrolysate formula (WCHF, n = 20). Growth parameters and the various protein concentrations determined in the infants fed WHF 1 and WHF 2 were similar to the values observed with human milk. With WHF 3, growth in weight, length and head circumference and serum total protein concentrations were reduced significantly whereas blood urea nitrogen was increased. With SCHF, growth in weight and length as well as serum total protein and transferrin concentration were decreased significantly, whereas serum IgG concentration was increased. With WCHF growth in length and serum transferrin concentration were decreased compared to the human milk group. In the various groups, the plasma amino acid pattern reflected the amino acid content of the formula. Whey hydrolysate formula induced mainly an increase in threonine and a decrease in tyrosine concentrations. Soy-collagen hydrolysate formula led to an increase of non-essential amino acids, such as glycine and hydroxyproline, and a decrease in plasma lysine and cystine. Whey-casein hydrolysate formula induced a plasma amino acid pattern close to the profile observed with human milk. Nevertheless, the plasma concentrations of most of the various amino acids were higher.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7841614 TI - Milk formulae for the normal infant. I. General considerations and historical background. PMID- 7841613 TI - Techniques of enteral feeding in the newborn. AB - Among techniques of enteral feeding, gastric bolus feeding still appears to be the method of choice for most newborn babies because it is both practical and inexpensive. Unstable preterm infants and those with severe respiratory diseases or with delayed gastric emptying time may not tolerate intermittent gastric feedings and may benefit from continuous gastric feedings. Transpyloric feedings do not seem to offer any advantage over continuous gastric feedings and should be reserved for infants at risk of aspiration, such as those with gastroesophageal reflux or delayed gastric emptying. Early low-volume feedings appear beneficial and are not associated with increased morbidity. Once enteral feedings are established, daily increments of 10-20 ml/kg appear to be safe and not associated with an increased risk of necrotizing enterocolitis. PMID- 7841615 TI - Milk formulae for the normal infant. II. Recommendations, energy, physical characteristics and protein composition. PMID- 7841616 TI - Protein nutrition, faecal flora and iron metabolism: the role of milk-based formulae. AB - This paper explores the role of milk-based formulae in achieving four aspects of nutritional health in infants and toddlers: in the suckling, to mimic the amino acid metabolism and the faecal flora of a breast-fed baby; in the weanling, to achieve adequate protein intakes in later infancy and beyond and to achieve satisfactory haemoglobin concentrations in the early toddler years. Milk-based formulae have two roles in infant nutrition: as so-called breast milk substitutes and as a safety net during the weaning period; the latter role may be the more important. PMID- 7841618 TI - Human milk fortifiers. AB - Unsupplemented human milk does not normally provide enough protein and minerals to secure optimal growth in low birthweight infants. We compared the growth and biochemical status of 21 very low birthweight infants, fed on their own mothers' fortified milk (seven infants) or a high-caloric-density formula (14 infants). The human milk fortifier is made from a mixture of cows' milk proteins (40% whey, 45% casein) and amino acids (15%) and has been demonstrated to be appropriate to achieve a plasma amino acid profile similar to that of normal infants fed exclusively on human milk. Infants receiving fortified human milk showed growth and biochemical profiles comparable to those receiving high-caloric-density formula. The supplementation that we describe here confirms the good results well documented by other authors. It is easy to perform and can be an acceptable alternative to the more sophisticated procedure of "lacto-engineering". PMID- 7841617 TI - Characterization of carbohydrates in commercial infant formulae. PMID- 7841619 TI - Implications of growth patterns of breast-fed infants for growth references. PMID- 7841620 TI - Pitfalls in the design and manufacture of infant formulae. AB - The composition of modern infant formulae is basically oriented on the "golden standard" human milk and influenced by several official regulations and recommendations (EC, ESPGAN, etc.). This article will focus on two recent improvements in the field of long-chain polyunsaturated fatty acids (LCPs) and protein hydrolysates. The addition of LCPs for preterm formulae was recommended recently by ESPGAN (the European Society for Pediatric Gastroenterology and Nutrition). Our research has focused on this problem for many years and we have found a good source of LCPs using specially prepared egg-yolk lipids. Others have used fish oils and run into the problem of growth retardation. Therefore, the possible sources of LCPs have to be discussed very critically and the alternatives will be shown. Also, new developments like the use of single-cell oils will be discussed. Second, the use of protein hydrolysates have been introduced for the so-called hypoantigenic or hypoallergenic formulae. Hypoantigenic formulae for preventive use have to be differentiated clearly from hypoallergenic formulae for treatment of proved cows' milk protein allergy. The problems of designing suitable hydrolysates that are low in antigenicity and good in taste will be outlined. The determination of the molecular weight distribution by gel chromatography will be compared critically with the newer techniques. The ELISA technique for testing the antigenicity is recommended before any in vivo evaluation. So far, the anaphylactic guinea-pig model is the most sensitive in vivo testing method. Summing up, modern infant formulae manufacture is much more dependent on modern laboratory techniques, which have to be chosen critically and must be adapted to the newest state of the art. PMID- 7841621 TI - Follow-on formulae. AB - Follow-on formulae are recommended as part of the liquid intake of the weaning diet for infants from 6 months on and children aged 12-36 months. The amount of energy and nutrients absorbed by infants from Beikost and milk differs enormously depending on a number of factors and therefore the recommended composition of follow-on formulae varies accordingly. In the future a greater understanding of the nutritional needs of infants and the possibility of choosing between high- or low-protein content formulae may provide infants with a better balanced diet. PMID- 7841622 TI - Milk formulae for the normal infant. III. Lipids and trace elements. PMID- 7841623 TI - Milk protein quantity and quality in human milk and infant formulae. PMID- 7841624 TI - Fat needs of term infants and fat content of milk formulae. AB - Term infants have precise dietary fat requirements for their metabolic, energy and structural needs. The fat content of commercial milk formulae differs from maternal milk in that it contains no long-chain polyunsaturated derivatives or cholesterol. Artificially fed children thus have less of these molecules available for their biological needs, and hence lower levels of long-chain polyunsaturated derivatives in circulating and membrane lipids than breast-fed children. The functional effects of this difference have not been investigated thoroughly in term infants. Dietary lack of essential fatty acids and their derivatives is evident also in weaned children during the second half of their first year of life. Qualitative changes in the fat content of commercial milk formulae could help to correct some widely encountered dietary imbalances, using the pattern of fats provided in breast milk as the ideal. PMID- 7841625 TI - Essential fatty acids and human tissue composition. An overview. PMID- 7841626 TI - Diet and the essential fatty acid status of term infants. AB - Long-chain polyunsaturated fatty acids with 20 and 22 carbon atoms (LCPs) seem to play an important role during the rapid development of the infant brain in the late fetal and early postnatal period. These LCPs are integral constituents of biological membranes and they are involved in the regulation of functional properties like fluidity, permeability and activity of membrane-bound enzymes. Human milk contains LCPs in an amount of 0.5-3 wt% of total fatty acids, whereas commercially available infant formulae are almost free of them. Recently, several clinical trials, primarily with preterm infants, have reported that the content of LCPs in the blood and a functional parameter like visual acuity correlate with the content of LCPs in the diet. In this clinical trial we studied the effect of different diets on the fatty acid pattern of plasma and erythrocyte lipids of healthy term infants during the first 3 months of life. Breast-fed infants were compared with formula-fed babies who received a commercially available formula without LCPs or a new experimental formula enriched with LCPs that was similar to human milk. The results indicate that the introduction of milk feeding leads to marked differences in the blood lipid composition during the first months of life, independent of the feeding regimen. Secondly, the supplementation of a formula with LCPs seems to result in a blood lipid composition similar to infants fed with human milk. This supports the hypothesis that the newborn term infant has a limited desaturating capacity and depends on an exogenous supply of LCPs during the first months of life. PMID- 7841627 TI - Aspects of neonatal metabolism of trace metals. PMID- 7841628 TI - Lactoferrin in infant formulae. PMID- 7841629 TI - Hormonally active peptides in human milk. AB - Human milk contains many hormone and hormone-like peptides. The gastrointestinal tract of newborn infants exhibits lower proteolytic activity than in adults and higher "permeability" for macromolecules. Studies in experimental animals demonstrate that several peptides (epidermal growth factors, insulin-like growth factor I and bombesin) after orogastric administration exhibit effects on the small intestine and other organs (liver or pancreas). Few studies performed in human neonates suggest a "survival" of epidermal growth factor in their gastric content. Further studies are needed to evaluate the role of milk-borne hormonally active peptides. This need is stressed by the fact that several of those known to be present in human milk were found to be low or not detectable in infant formulae (epidermal growth factor, insulin-like growth factor I, insulin, parathyroid hormone-related peptide. PMID- 7841630 TI - Nutritional requirements of extremely low birthweight infants. AB - Extremely low birthweight (ELBW) infants are unique in many developmental characteristics that determine nutritional requirements, including: low energy reserves (both carbohydrate and fat); higher metabolic rate (intrinsically, due to a higher body content of more metabolically active organs, e.g. brain, heart, liver); higher protein turnover rate (especially when growing); higher glucose needs for energy and brain metabolism; higher lipid needs to match the in utero rate of fat deposition, and for essential fatty acids for brain, neural and vascular development; excessive evaporative rates, and occasionally very high urinary water and solute losses; low rates of gastrointestinal peristalsis; limited production of gut digestive enzymes and growth factors; high incidence of stressful events (e.g. hypoxemia, respiratory distress, sepsis); and abnormal neurological outcome if not fed adequately. Postnatally, ELBW infants do not grow well, or at all, often for weeks. This leads to a virtual "growth deficit", which has unknown consequences (which for the most part are not good) and requires excessive feeding later on to catch up to normal growth rates and body composition. The major future challenge for the nutrition of these infants is to define more accurately their nutritional requirements, particularly in the early postnatal period, in order to feed them more appropriately, to reduce to a minimum the nutritional and growth deficits that they so commonly develop and to prevent neurodevelopmental handicaps that are the result of nutritional deficiencies. PMID- 7841631 TI - Neuroblastomas in Denmark 1943-80. Epidemiological and clinical studies. AB - Two-hundred-and-fifty patients were registered in a population-based study of neuroblastomas in Denmark in the period 1943-80. The major epidemiological findings were an increased incidence with an unchanged mortality rate during the study period. The increase in incidence related solely to children 0-4 years of age and was most pronounced in infants under 1 year of age. Several reasons for the observed epidemiological rates include (i) changes in the composition of the population, (ii) improved diagnostic procedures, (iii) a shift in the diagnostic criteria, and (iv) an increase in environmental carcinogens of importance in the induction of neuroblastoma. Associated with an increased risk were lower socio economic levels and young or advanced parental age, suggesting the importance of environmental as well as genetic factors for the induction of neuroblastoma. The epidemiological findings of an increased incidence with an unchanged mortality rate, which suggests the inclusion of borderline lesions in recent years, are of major importance in interpreting the results of mass screening for the disease. The clinical findings in 253 patients treated in Denmark from 1943 to 1980 (including 5 patients resident outside Denmark and excluding 2 patients without available hospital records) were analysed. The major finding was a zero-time shift, that is, earlier diagnosis of the disease during the study period, with increasing survival rates from decade to decade mostly due to a better age and stage distribution, a zero-time shift which was also apparent in the changes of the symptomatology. Independent prognostic variables were age, stage, and treatment with chemotherapy for children over 1 year of age with stage II disease, and for infants with stages III-IV disease. Analysis of data from a subset of the 253 children suggested that high proliferative activity detected by flow cytometry may be an important prognostic variable. The study also suggests that the pattern of metastatic spread might have changed as a consequence of prolonged survival obtained by improved treatment modalities, stressing the importance of a high frequency of autopsy among cancer patients. Hypotheses generated by the study included (i) that most neuroblastomas might be congenital, (ii) that the age influence on prognosis might be explained in terms of growth rate, cell cycle transit time, and duration of the disease, and (iii) that some neuroblastomas might be borderline lesions. PMID- 7841632 TI - Adenylate cyclase, a biochemical marker of alcoholism? AB - A possible biochemical vulnerability (trait) marker is examined in a cross sectional study to determine the biochemical factors associated with the development of alcoholism in a population of non-adult children of alcoholics. The activity of adenylate cyclase, an enzyme that plays a role in the signal transduction pathway of several hormones and neurotransmitters, is assessed in blood platelets. This activity was reported to be lower in blood cells of alcoholics and abstinent alcoholics compared with that in controls. In addition, dysregulation of adenylate cyclase in the CNS of animals seems to be involved in drug-seeking behaviour. The relation between these biochemical findings and psychopathology is currently being investigated in a project by the Amsterdam Institute for Addiction Research. PMID- 7841633 TI - Drug and alcohol dependency during pregnancy, long-term effects on child development. Proceedings of a symposium held in Amsterdam, September 4-5, 1993. PMID- 7841634 TI - Children of alcoholics: attention, information processing and event-related brain potentials. AB - Recent studies on biological markers and risk factors for alcoholism have distinguished between nonalcoholic individuals with a family history of alcoholism and those without such a family history on measures of event-related brain potentials. The main finding of these "high-risk" studies is a smaller amplitude of the P300 component in males with a history of paternal alcoholism. This relationship between P300 amplitude and a family history of paternal alcoholism has been observed in adults and children. Consequently, several authors have suggested that a reduced P300 amplitude could serve as a vulnerability marker for alcoholism. We address several conceptual and methodological issues involved in the study of event-related potentials in children at high risk for alcoholism. Subsequently, the ongoing high-risk study of the Amsterdam Institute for Addiction Research is described briefly. PMID- 7841635 TI - "Separation" of the mother-child couple: pregnancy and maternity of drug dependent women. AB - Children of drug addicts are at risk of neglect and scanty maternal care. The objective of the present study was to identify homogeneous subgroups within a sample of drug addicted women, according to the quality of the outcome of the mother-child relationship. A group of 13 opiate-addicted women, followed from the seventh month of pregnancy up until the child was 2 years of age, underwent psychometric evaluation and was subdivided into two distinct groups based on whether the child remained within the family nucleus or was entrusted to a foster family or institution. The psychometric instrument used, an adaptation of Osgood's semantic differential which investigates maternal representations, allowed us to identify items with a very high predictability for the outcome of the mother-child relationship. PMID- 7841636 TI - Substance use in pregnancy: do we care? AB - Two cohorts of substance-using women were compared retrospectively. From 1969 to 1979 a very high perinatal mortality rate (PMR 9.8%) was found among 92 polydrug using women (1 twin excluded). Preterm delivery occurred in 25% of all pregnancies and in 30% of the children birth weight was below the 10th percentile. Nineteen women using heroin only had a worse fetal outcome (PMR 32%, preterm delivery in 47%, birth weight < 10th percentile in 42%). These results led to a strict surveillance system. In the period 1980-1989, 240 women (4 twins excluded) delivered after 16 weeks. Total fetal loss decreased to 2.1% and PMR to 0.4%, which was similar to results in controls. However, 22% of the women still delivered before 37 weeks and 27% delivered a child < 10th percentile. Methadone using women were able to halve their dosage during pregnancy and 16 were detoxified. Multivariate analysis within the substance users of the second cohort showed that the neonatal abstinence syndrome, but not the (registered) amount of opiates used, was related to a lower birth weight. Not coping with prenatal care was related to a shorter pregnancy length. Multivariate analysis, including the controls, showed a significant relation of birth weight (345 g lower) with substance use. Also, head circumference was 0.8 cm smaller. Length of pregnancy however was related to smoking. This study shows that it is difficult to make substance users attend prenatal care, but also that women coping with prenatal care reduce substance intake. Opiate use might be responsible for lower birth weight, although not in a clear dose-response relationship, whereas lifestyle, as represented by not coping with prenatal care and the quantity of cigarette smoking, shortens the length of pregnancy. PMID- 7841637 TI - Children of alcoholics. Predictors for psychopathology and addiction. AB - Children of alcoholics have a higher risk of psychopathology and alcoholism. Therefore, in 1993 the Amsterdam Institute for Addiction Research initiated a study on vulnerability markers and risk factors in children of alcoholics, aimed at identifying predictors for the development of psychopathology and addiction in children of alcoholics. This article provides a summary of the background, rationales and aims of the study. With more specific and sensitive biological vulnerability markers that indicate risk status, more effective preventive interventions might become available. The biochemical part of the study aims at answering the question whether adenylate cyclase is a vulnerability marker for alcoholism. The psychophysiological part is directed at event-related potentials during task performance to clarify the nature of the brain and cognitive functions that may underlie or relate to vulnerability to alcoholism. The third part, the psychological component, aims at possible psychological mechanisms of enhanced risk of addition in children of alcoholics as well as the relationship with childhood psychopathology. PMID- 7841638 TI - Public health care policies for drug addicts in Amsterdam. AB - Recognizing that drug addiction is a chronic health problem for which, in the majority of cases, no curative, effective treatment exists, Amsterdam developed a coherent system of public health measures. Data on the course of the local drug epidemic, including medical complications such as AIDS, tuberculosis and mortality, are presented. PMID- 7841639 TI - Office for children of drug-addicted parents. PMID- 7841640 TI - Psychological mechanisms of enhanced risk of addiction in children of alcoholics: a dual pathway? AB - The background and rationale of a recently started project of the Amsterdam Institute for Addiction Research are outlined. This project is aimed at the psychological mechanisms underlying an enhanced risk of (later) addiction in children of alcoholics and the relationship with childhood psychopathology. A dual pathway mechanism is proposed, in which the type of alcoholism of the parent plays a major role. The child of a multigenerational primary alcoholic parent may suffer from an inherited mild dysfunction of the prefrontal cortex, expressed in neuropsychological and personality characteristics similar to those of the alcoholic parent. These are impulsive, aggressive and reward-seeking behaviour, response perseveration and, in some children, related psychopathology such as conduct disorders. For a child of a secondary alcoholic parent, another mechanism is proposed. In these children, stress and social learning may lead to negative affectivity and repressive coping style, with emotional problems at a later age, and the risk of falling into the "circle of secondary alcoholism". In both pathways, alcohol-related expectancies are suggested to constitute a "final common pathway" between different risk factors and later alcohol abuse. Specific expectancies might be related to different pathways and to gender differences in later drinking patterns. PMID- 7841641 TI - Further experience with exsanguination for descending thoracic aneurysms. AB - Resection and graft replacement of descending thoracic aortic aneurysms is associated with potential ischemic sequelae related to aortic cross-clamping. Such complications are minimized when the ischemic period is shorter than 30 minutes. We have devised a technique in which a single aortic cross-clamp is applied proximal to the lesion, and the distal anastomosis is performed in "open" fashion, with limited distal aortic dissection. This technique depends upon continuous autotransfusion, which allows distal aortic decompression by means of partial exsanguination through the open distal aorta and segmental spinal arteries. In addition, the period of cord ischemia from aortic clamping is minimized. From April 1989 to October 1993, we used this approach in 71 consecutive patients (50 men and 21 women), 8 (11.3%) of whom died during the early postoperative period. Complications included 6 cases of spinal cord dysfunction (8.5%) and 4 cases of renal failure (5.6%). Our success with this approach may contradict more accepted concepts of spinal cord protection from ischemic injury. PMID- 7841642 TI - Proceedings of the aortic surgery symposium IV. April 21-22, 1994, New York, New York. PMID- 7841643 TI - Effect of cerebrospinal fluid drainage and/or partial exsanguination on tolerance to prolonged aortic cross-clamping. AB - Paraplegia as a consequence of spinal cord ischemia associated with procedures on the thoracic and thoracoabdominal aorta has been linked to the interaction of proximal hypertension with elevated cerebrospinal fluid pressure (CSFP) during aortic cross-clamping (AXC). CSFP reduction via cerebrospinal fluid (CSF) drainage is thought to significantly prolong the cord's tolerance to AXC. Likewise, partial exsanguination is reported to effectively reduce ischemic injury by controlling proximal hypertension. To evaluate the individual and collective efficacy of both techniques, 18 mongrel dogs (25 to 35 kg), divided into three equal groups, underwent a fourth interspace left thoracotomy AXC. Baseline proximal arterial blood pressure (PABP), distal arterial blood pressure (DABP), and CSFP were established and monitored at 5-minute intervals during 120 minutes of AXC, and for 30 minutes thereafter. Group I animals were partially exsanguinated prior to AXC to maintain PABP at a mean of 115 to 120 mmHg. Group II animals had sufficient (16 +/- 5 cc) CSF withdrawn to maintain a DABP-CSFP gradient, i.e., spinal cord perfusion pressure (SCPP) of 20 mmHg. Group III animals were treated with both CSF drainage and partial exsanguination in the same manner as groups I and II, respectively. Perioperative somatosensory evoked potential (SEP) monitoring evaluated cord function. Postoperative neurological outcome was assessed with Tarlov's criteria. SEPs degenerated approximately 22 minutes following AXC for groups II and III. In contrast, group I exhibited rapid (10 +/- 7 min) SEP loss. All five surviving group I animals displayed paralysis 48 hours postoperatively.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7841644 TI - Thoracoabdominal aortic aneurysms: experience with 372 patients. AB - The purpose of this study was to review retrospectively recent results in 372 patients with thoracoabdominal aneurysm treated by a single surgeon and to identify variables associated with early death, renal failure, and postoperative neurological deficits in patients undergoing thoracoabdominal aortic resection. Between January 11, 1986 and March 1, 1994, 203 males (55%) and 169 females (45%) (mean age 65 years) were treated. Aortic dissection was present in 93 patients (25%). The extent of repair included type I (137 patients), type II (95 patients), type III (73 patients), and type IV (67 patients). The overall 30-day survival rate was 95% (352/372 patients). The overall risk of postoperative neurological deficit was 6.4% (24/372 patients). In 309 patients treated without atriofemoral bypass, paraplegia or paraparesis developed in 23 (7.4%). In 63 patients in whom atriofemoral bypass was utilized, the overall risk of paraplegia or paraparesis was 1.6% (1/63). The use of atriofemoral bypass has had a favorable impact on postoperative neurological complications in selected patients. PMID- 7841645 TI - Evolution of surgical techniques for aneurysms of the descending thoracic aorta: twenty-nine years experience with 659 patients. AB - Between 1953 and 1993, 659 patients underwent descending thoracic aneurysm resection. The most common etiology was atherosclerosis. Pain was the main presenting symptom. Perioperative mortality fell from 24.2% between 1953 and 1964 to 14.3% between 1970 and 1993. Paraplegia occurred in 4.1% (27/659) patients overall and was little affected by time of operation or use of atriofemoral bypass. Paraparesis occurred in 5.9% (39/659) patients and was reduced by use of atriofemoral bypass. The low rate of paraparesis in the earlier experience was offset by the higher perioperative mortality from hemorrhage, attributable to the use of systemic heparin. The use of heparin-free circuits with centrifugal pumps should be considered in patients likely to have a clamp time greater than 30 minutes. The major source of perioperative morbidity and mortality was cardiac causes (48%) followed by perioperative hemorrhage (14.4%), pulmonary complications (14.4%), and rupture of another aneurysmal segment (12.0%). Late mortality occurred most commonly from cardiac causes (30.6% of deaths) and rupture of another aneurysm (16.3% of deaths). Improvement in results was due to general refinements of management in all areas rather than any single factor. These results indicate that complete preoperative assessment of the patient and the entire aorta is essential and that regular life-long follow-up is critical in order to avoid unnecessary morbidity and mortality from cardiac, cerebrovascular, or subsequent aneurysmal complications. PMID- 7841646 TI - A new technique using somatosensory evoked potential guidance during descending and thoracoabdominal aortic repairs. AB - Recent work in our laboratory has demonstrated the effectiveness of somatosensory evoked potentials (SEPs) in identifying the critical intercostal arteries (CICAs) for preserving spinal cord integrity during simulated aortic aneurysm repairs in the pig. Further studies have also demonstrated increased preservation of neurological function during prolonged aortic clamping if CICAs are perfused until ligation or clipping, as opposed to transaortic identification of back bleeding intercostals and their subsequent ligation. We have developed a technique of repair of descending thoracic and thoracoabdominal aortic aneurysms and dissections that uses these principles. Since January 1993, 26 patients have undergone repair of their aortas using this new technique and SEP directed intercostal artery ablation. There were 22 (85%) long-term survivors among 10 thoracoabdominal and 16 descending aortic repairs. All patients with uncorrected abnormal SEP recordings developed paralysis; one patient who required reimplantation of an intercostal artery island into the aortic graft had normal neurological function postoperatively. Paraplegia was seen in only one of the surviving patients, but this patient had normal intra- and postoperative SEPs (4% false negative). Our experience suggests that SEP-guided obliteration of intercostal arteries while maintaining perfusion may be a useful approach to the surgical repair of descending and thoracoabdominal aortic disease. PMID- 7841647 TI - Assessment of aortic disease using three-dimensional CT angiography. AB - The recently developed technique of three-dimensional CT angiography (3D-CTA) was applied to 68 patients with aortic disease. These patients were examined using a unique method of data collection: a helical scanner with continuous tube rotation and continuous table feed. The scanner was used in conjunction with administration of dynamic intravenous contrast material to enhance the vascular image. The group of patients included 35 with aortic dissection, 19 with true thoracic aneurysms, and 14 with abdominal aortic aneurysms. Three-dimensional evaluation was achieved in all patients with no complications. Surgical intervention was used in 45 patients with aortic dissections and aortic aneurysms, and 44 of these patients (98%) survived and were discharged. Preoperative 3D-CTA findings were quite similar to intraoperative findings, and were useful in determining operative procedures. Rapid and accurate assessment of aortic disease was achieved by 3D-CTA. Three-dimensional CT angiography can play an important role in the preoperative assessment of aortic dissections and aortic aneurysms leading to successful surgical treatment. PMID- 7841648 TI - Thoracoabdominal aneurysm repair: spinal cord protection using profound hypothermia and circulatory arrest. AB - Between January 1991 and February 1993, 14 patients (11 male, 3 female) between 21 and 79 years of age (median 50 years) underwent reconstruction of the thoracic (n = 7) and thoracoabdominal aorta (n = 7). Four patients had previously undergone operation of the ascending aorta, and in three patients coronary artery bypass grafting had previously been performed. All patients were operated on a via a posterolateral thoracotomy using cardiopulmonary bypass with continuous blood cardioplegia and hypothermic circulatory arrest (11 degrees C nasopharyngeal temperature, flat-EEG). All patent lower intercostal and lumbar arteries (T3 to L5) were reimplanted. The 30-day mortality after repair of the thoracic aorta was 0%; after replacement of the thoracoabdominal aorta, mortality was 28.5% (n = 2). One patient died 70 days after replacement of the thoracic aorta as a consequence of a perioperative stroke. None of the surviving 11 patients developed a permanent neurological deficit or renal or cardiac dysfunction. The average intensive care stay was 6 days for patients after replacement of the thoracic aorta and 18 days for patients after replacement of the thoracoabdominal aorta. Our results suggest that use of elective hypothermia and circulatory arrest for spinal cord protection is highly effective. We, therefore, recommend this method for complex reconstructions of the thoracoabdominal aorta. PMID- 7841649 TI - Spinal cord protection in the absence of collateral circulation: meta-analysis of mortality and paraplegia. AB - A meta-analysis of paraplegia complicating aortic surgery on patients having neither intercostal nor spinal collaterals, epitomized by patients with acute traumatic aortic rupture, was done. Index Medicus and Medline were searched for all suitable English publications between 1972 and 1992. New paraplegia occurred in 9.9% of 1492 patients who underwent surgery. However, 19.2% of patients undergoing surgery with only simple aortic cross-clamping developed paraplegia, in contrast to 6.1% if distal aortic perfusion was augmented by either "passive" or "active" methods (p < 0.00001). The risk of paraplegia increased progressively as cross-clamp times lengthened if simple aortic cross-clamping was used (p < 0.00001), but only once did the cross-clamp time exceed 30 minutes (p < 0.05). Paraplegia occurred in 8.2% of patients with "passive" shunts from the ascending aorta (p < 0.001 vs simple cross-clamping). Shunts from the left ventricular apex, however, had an incidence of paraplegia of 26.1% and, therefore, did not decrease the risk of paraplegia. "Active" augmentation of distal perfusion had the lowest risk of paraplegia: 2.3% (p < 0.00001 vs simple cross-clamping or "passive" shunts). Mortality, however, was higher in these potentially polytraumatized patients when they were perfused distally using methods requiring full systemic heparinization (18.2%), compared to mortality with methods not requiring heparin (11.9%; p < 0.01). In conclusion, simple aortic cross-clamping has a high risk of paraplegia if the cross-clamp time extends beyond 30 minutes. "Active" modalities of augmenting distal perfusion provide optimal spinal protection. PMID- 7841650 TI - Somatosensory evoked potentials during exclusion and reperfusion of critical aortic segments in thoracoabdominal aortic aneurysm surgery. AB - Forty-three patients undergoing repair of a thoracoabdominal aortic aneurysm were monitored to evaluate spinal cord ischemia, as evidenced by somatosensory evoked potentials (SEPs). All patients were operated on using left heart bypass. In 34 patients (80%), staged clamping was used. Except for cerebrospinal fluid (CSF) drainage in 15 patients (35%), no other protective measures to preserve spinal cord function were used. The overall incidence of immediate onset paraplegia was 7%, and of immediate onset paraparesis was 5%; neither was limited only to those patients in whom potentials were lost. In 18 patients (42%), no change in the evoked potentials occurred; one of these patients (5%) awoke paraplegic after operation, and two others had a delayed onset paraplegia. In 13 patients (30%), evoked potentials were lost despite adequate perfusion; in 12 of them, potentials returned gradually, with one immediate paraplegia (8%), and in one potentials did not return at all, with subsequent immediate paraplegia (100%). In 12 patients (28%), evoked potentials decreased without being lost completely, and then recovered; in this group there were no immediate paraplegias. No relationship could be demonstrated between the extinction time, the recovery time, or the duration of loss of evoked potentials with postoperative neurological outcome. Intraoperative monitoring of SEPs is a good indicator of spinal cord ischemia, although we found a 5% incidence of false negatives. SEP monitoring offers an improvement in surgical strategy, and allows safer operations for thoracoabdominal aneurysms. PMID- 7841651 TI - Aortic dissection: a medical perspective. AB - Over the past 3 years, a greater understanding of predisposing factors and the pathology of the aortic wall has yielded more insights into the pathogenesis, as well as into more accurate diagnostic and preventive methods. This update will discuss: (1) the incidence, definition, and recent classification of aortic dissection; (2) epidemiology, medical, and recent surgical series; (3) the pathogenesis and risk factors; (4) clinical features and evolving noninvasive imaging approaches to diagnosis; and (5) management from a medical perspective. PMID- 7841652 TI - Subtypes of acute aortic dissection. AB - The technique of open distal anastomosis using deep hypothermic circulatory arrest was used in 69 cases of acute type A aortic dissection. These cases were subcategorized by site of intimal tear, which was found in the ascending aorta in 41 patients (60%), in the arch in 22 patients (32%), and in the descending aorta in 5 patients (7%). Clinical characteristics and complications are described for these subtypes. Hospital mortality, which was 14.5% overall for acute type A dissections, was 14.6% for ascending tears, 18.2% for arch tears, and 0% for descending aortic tears. Six-year survival was 69% +/- 15% for ascending tears, 69% +/- 22% for arch tears, and 80% +/- 25% for descending tears (mean +/- SEM, p = NS). A classification system for aortic dissection is proposed, based on both site of origin and propagation. PMID- 7841653 TI - Repair of the aortic arch with fibrin glue in type A aortic dissection. AB - Location of the intimal tear in the aortic arch in type A aortic dissection is for many authors an indication for replacement of the aortic arch, but this operation has a high in-hospital mortality rate: 20% to 40%. Instead, we suggest repairing the aortic arch by injecting fibrin glue, which contains a human sealer protein concentrate, between the two dissected layers under circulatory arrest while replacing the ascending aorta. To evaluate this technique, we reviewed 45 successive patients operated on for type A acute aortic dissection between January 1989 and July 1993, of which 6 had the intimal tear located on or extending into the aortic arch. Mean age was 71 +/- 4.2 years (range 68 to 74). After proximal supracoronary anastomosis with a collagen-impregnated graft, aortic arch repair was achieved by injecting fibrin glue between the two layers, using circulatory arrest at a mean temperature of 22 degrees C, with a mean duration of 24 minutes. This obliterated the dissection in the arch and also the intimal flap. The distal part of the graft was then anastomosed to the proximal portion of the aortic arch at the origin of the innominate artery under circulatory arrest. There were no early or late deaths. All patients were asymptomatic at a mean follow-up of 2.6 years. Follow-up angioscan showed obliteration of the dissection in the aortic arch in all patients; there were two patients with dilatation of the distal aortic arch of 40 and 45 mm.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7841654 TI - Late reoperations in patients with aortic dissection. AB - Aortic dissection is an evolving process that may require one or several reoperations after the initial emergency repair. From January 1977 to September 1993, 148 patients underwent emergency surgery for type A acute aortic dissection. The replacement of the ascending aorta was extended to include the transverse arch in 43 patients (29%). One hundred fifteen patients (78%) survived surgery. During the same period, 37 patients required reoperation once (28), twice (7), or three times (2), for a total of 48 reoperations. Twenty-one patients had undergone initial repair in our institution; 16 patients had been operated on elsewhere. Reoperation was indicated for: aortic valve disease (4); a new dissecting process (7); threatening aneurysmal evolution of a persisting dissection (34); or false aneurysm (3). The re-do procedure involved: the aortic root and/or ascending aorta in 12 cases (group I); the ascending aorta and the transverse arch in 6 cases (group II); the transverse arch alone in 8 cases (group III); the transverse arch and descending aorta, or the descending aorta alone in 11 cases (group IV); and the thoracoabdominal aorta in 11 cases (group V). Risk factors for reoperation were analyzed in the 115 survivors initially operated on at our institution. Seven of 20 Marfan patients (35%) versus 12 of 95 non-Marfan patients (12.6%) required reoperation (p < 0.02). None of the 31 patients surviving arch replacement at initial repair required a reoperation, versus 21 of 84 (25%) patients surviving replacement limited to the ascending aorta (p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7841655 TI - Malperfusion of the thoracoabdominal vasculature in aortic dissection. AB - Ischemic damage to vital organs supplied by the thoracoabdominal aorta greatly increases the overall risk of aortic dissection. Of 320 patients operated upon for aortic dissection since 1985, 33 (10.3%) underwent operations directed at the relief of malperfusion (15/158 acute type A; 9/18 acute type B; 4/78 chronic type A; 5/66 chronic type B). Organs affected were the kidneys in 32; the bowel in 20; and the spinal cord in 1, while critical lower extremity ischemia was present in 11 patients. In total, 64 vascular areas were affected. Fenestration of the dissecting membrane with or without infrarenal grafting was the procedure performed most frequently in 25, followed by replacement of the descending or thoracoabdominal aorta in 6, and bypass grafting or direct revascularization of individual side branches in 6. Six other operations targeted at the affected organs were done. Twenty-four patients underwent one-stage operation for malperfusion; in 11, early reoperation after primary aortic repair was necessary, while 2 patients were operated electively. Ten of 33 patients died in hospital, 7 of malperfusion-induced complications. Of three late deaths, one was related to sequelae of malperfusion. We conclude that immediate diagnosis and prompt relief of malperfusion offer the best prospects for patient survival. Membrane fenestration appears to be the method of choice for treating malperfusion in most patients, and must be directed to the level of aortic and/or side branch obstruction. PMID- 7841656 TI - Imagine having to read the Physicians' Desk Reference. PMID- 7841657 TI - Preliminary evidence of phenytoin-induced alterations in embryonic gene expression in a mouse model. AB - SWV mouse embryos collected on gestational days (GD) 9:12 and 10:00 following chronic in utero exposure to teratogenic concentrations of phenytoin were utilized for in situ transcription studies of gene expression. The substrate cDNA obtained from the frozen embryo sections was amplified into radiolabelled antisense RNA (RT/aRNA) and used as a probe to screen a panel of 20 cDNA clones representing genes that are important regulators of craniofacial and neural development. The magnitude of alteration in gene expression following phenytoin treatment was determined densitometrically by changes in the hybridization intensity of the aRNA probes to the cDNA clones immobilized to the slot blots. We found that both Wnt-1 and the calcium channel gene were developmentally regulated, as their level of expression decreased significantly between the two collection times. Phenytoin treatment produced a significant downregulation in the level of expression for 25% of the genes examined in the GD 9:12 embryos, including the growth factors TGF-beta and NT3, the proto-oncogene Wnt-1, the nicotinic receptor, and the voltage sensitive calcium channel gene. Additional changes in the coordinate expression of several of the growth and transcription factors were observed at both gestational timepoints. The application of RT/aRNA technology has extended our appreciation of the normal patterns of gene expression during craniofacial and neural development, and provided the first demonstration of multiple coordinate changes in transcription patterns following teratogenic insult. PMID- 7841658 TI - Anophthalmia and benomyl in Italy: a multicenter study based on 940,615 newborns. AB - Following the report on clusters of anophthalmia and microphthalmia in England and Wales and their possible relation to the pesticide Benomyl, we analyzed the situation in Italy for the period 1986 to 1990 using data from the Italian registries of congenital malformations and national data on Benomyl use. Of 940,615 consecutive births, 33 cases of clinical anophthalmia and 78 cases of microphthalmia were reported (birth prevalence: 0.35 and 0.83/10,000). Birth prevalence by region for 18 of Italy's 20 political regions was evaluated for the two malformations, grouped together after exclusion of defects associated with chromosomal anomalies, no dishomogeneity in space or time among registries or among regions was observed for the study period. In no region was a statistically significant difference identified between observed and expected overall birth prevalence. Correlation analysis between the prevalence of micro/anophthalmia and Benomyl use by region showed a negative, nonsignificant coefficient, and an inverse correlation was found when the 18 regions were divided into four groups by increasing levels of Benomyl use. Parental occupation in agriculture did not seem to be associated with micro/anophthalmia when compared to a control group affected with isolated prearicular tags (odds ratio 0.63; CL 0.07-2.52). On the basis of these results, though the limits intrinsic to ecologic correlation studies must be taken into account, an association between Benomyl use and congenital micro/anophthalmia appears to be unlikely. PMID- 7841659 TI - Gamma-glutamyl transferase (GGT) activity and biochemical characterization of rat visceral yolk-sac during gestation with or without trypan blue exposure. AB - Yolk-sacs from untreated Sprague-Dawley rat conceptuses were removed on gestational days (GD) 9 to 18 and examined for gamma-glutamyl transferase (GGT), alkaline phosphatase (AP), lactate dehydrogenase (LDH), and glutamic-oxaloacetic transaminase (GOT) activities. All enzyme activities were found to increase through gestation in total activity as well as in specific activity. Protein (PRO) and urea nitrogen (UN) were also found to increase through gestation whereas triglyceride (TRI) increased steadily from GD 9 to 13 and then appeared to plateau through GD 19. Additional rats were treated on GD 8 with 75 mg trypan blue (TB)/kg body weight and yolk-sacs taken on GD 9 to 18. Yolk-sac GGT and GOT activities from TB-treated rats were significantly higher than the respective controls during early gestation but recovered to or were lower than control levels during midgestation. GGT activity in treated rats was significantly higher than the controls on GD 15 and 16, and both GGT and GOT were significantly lower than controls on GD 17 and 18. AP activity in the TB-treated yolk-sacs was significantly lower than that in controls during early and midgestation but was not significantly different from the control values late in gestation. Triglyceride concentration was not affected early in gestation but significantly decreased on GD 16 and 18. Thus, the yolk-sac enzymes monitored, which are associated with nutrition and normal growth, increased in activity through GD 18. The yolk-sac toxicant, trypan blue, significantly affected enzymatic activity at various time periods during gestation and resulted in significant changes in yolk sac protein and triglyceride content. PMID- 7841661 TI - The use of teratogen information services for research: assessment of reliability of data entry. AB - Teratogen information services (TIS) have been able to prospectively follow large cohorts of women with specific exposures during pregnancy. TIS researchers have increasingly relied on computerized databases to retrieve information, although little attention has been focused on the quality of the actual data. We examined the reliability of data entry at Motherisk, one such TIS. Data abstracted from 37 semi-standardized clinic forms were entered into the database by three counselors experienced in data entry. Inter- and intracoder reliability were assessed by intraclass correlation coefficient (ICC) for continuous variables and kappa (K) or weighted kappa (Kw) for categorical variables. An ICC, K, or Kw value of > or = 0.60 with a P < 0.05 was considered adequate. Demographics, obstetric history, smoking, and caffeine intake were all reliably entered. The number of primary exposures and alcohol were not. The former stemmed from the unreliable data entry of one coder, whereas the latter resulted from misuse of the alcohol nomogram by all coders. As a result, data entry has now been assigned to one person (who will be assessed for intrarater reliability), and our quality assurance program stresses staff retraining in all aspects of data collection. PMID- 7841660 TI - Metabolism of polynuclear aromatic hydrocarbon in human term placenta influenced by cigarette smoke exposure. AB - The relative contributions of biologic and environmental factors on embryo-fetal development were elucidated in a population of pregnant women who were exposed to varying amounts of active cigarette smoke and women who were not exposed to cigarette smoke. The neonatal weight at birth, placental weight at delivery, duration of pregnancy, and placental xenobiotic (polynuclear aromatic hydrocarbon, PAH) metabolism potential were assessed in this population. The overall metabolic capability in exposed and unexposed placental tissue was measured by in vitro assays using microsomes and a PAH substrate, benzo[a]pyrene (B[a]P). Toxicity potential was determined by B[a]P-metabolite-DNA adduct generation under the same incubation condition. Cigarette smoke exposure increased the overall PAH metabolism potential in placental tissues by approximately 200% (nonsmoker 176.2 +/- 33.6, n = 25; smoker 524.5 +/- 75.5, n = 32 pmol/mg protein) whereas PAH-DNA adduct formation potential did not increase significantly over the basal level (nonsmoker 5002 +/- 830, n = 15; smoker 6172 +/- 1443, n = 22 fmol B[a]P equivalent/mumol DNA/mg protein). Exposure to cigarette smoke during pregnancy is deleterious to fetal development as reflected by reduced neonatal weight at birth. In contrast, placental weight reduction is indistinct, but placentae expressed markedly augmented overall xenobiotic (PAH) metabolism capability in response to cigarette smoke exposure during pregnancy, indicating placental metabolism may be an important mediator of adverse effects induced by such xenobiotic exposure. PMID- 7841662 TI - A survey of information provided by North American Teratogenic Information Services. AB - The appropriate method of communicating important and potentially difficult to understand information to patients varies considerably among Teratogen Information Services. A survey consisting of a sample letter in the form of a medical scenario was sent to all Teratogenic Information Services (TIS) across North America to determine their response to the given situation. A sample letter was mailed to all TIS in North America with a response rate of 87%. Eighty-two percent did not respond to the patients directly with a follow-up letter but did so by writing to their physicians. Ten percent responded to the patients, following up later by sending a short letter summarizing the conversation. Eight percent of the services did not respond. Responses among the centres varied with the level of literacy ranging from grade 10 to the postgraduate level. Of the centres surveyed, there was a notable similarity in the pattern of communication. To communicate more effectively with patients, TIS should consider assessing the reading level of letters sent to them. PMID- 7841663 TI - Sperm-damaging effects of electric current: possible role of free radicals. AB - The generation of reactive oxygen species (ROS) and sperm damage was evaluated in (a) samples obtained during electroejaculation (EE) of men with spinal cord injury and (b) in electrolyzed HAM's F-10 medium subjected to electric current in vitro. Chemiluminescence data showed a significant increase in ROS in the ejaculates (6 x 10(7) photons/ml) collected immediately after EE and in the electrolyzed medium (3 to 7 x 10(6) photons/ml) when compared to the control (4 to 7 x 10(4) photons/ml). Incubation of normal human sperm with the electrolyzed medium resulted in a significant threefold decrease in percent motility and a twofold decrease in percent viability. Sperm subjected to direct electric stimulation in vitro exhibited a significant twofold decrease in percent motility and percent viability. Superoxide dismutase (SOD) activity decreased significantly in sperm subjected to direct electric current in comparison to the control or the sample incubated with electrolyzed medium. These studies indicate that in vitro and in vivo electrical stimulation generate reactive oxygen species and affect SOD activity, which in part are responsible for decreased sperm motion and viability. PMID- 7841664 TI - Statistical variability: what does it mean in risk assessment? AB - An essential part of toxicologic research involves assessing the risk from exposure to chemicals, drugs, or other potentially harmful substances. Epidemiologic information establishes an association but not a causal relationship between risk factors and adverse health outcomes. Controlled experiments in laboratory animals, however, provide insight into the agent outcome relationship and aid in establishing low-risk exposure levels for humans. This is especially true in studies of reproduction and development since epidemiologic data are often limited. While controlled experiments reduce certain difficulties inherent in interpreting epidemiologic data, there still remains the problem of careful evaluation of statistical information. This note addresses issues in the interpretation of statistical variability in fitting dose-response models and estimating exposures associated with a low (or at least specified) level of risk. PMID- 7841665 TI - Framework for provision of Teratology Information Services. PMID- 7841666 TI - Idiopathic CD4+ T lymphocytopenia: a review and current perspective. PMID- 7841667 TI - The impact of new clinical guidelines on the North American blood economy. PMID- 7841668 TI - Understanding the polymerase chain reaction. PMID- 7841669 TI - Transfusion-related transmissible diseases: detection by polymerase chain reaction-amplified genes of the microbial agents. AB - The detection of blood-borne microbes by PCR has broadly and rapidly progressed in the past 5 years as briefly described in this article. This progress has been largely because of the scientific developments made at Roche Molecular Systems by Sninsky et al through collaborations with academic and Government institutions. This unprecedented cooperation propels the continuing work at Roche Molecular Systems to bring the PCR technology into routine laboratory diagnosis. Whether the success of EIA in virtual elimination of hepatitis and retroviral infections can be matched by the cost-effectiveness of putative application of PCR in screening blood supply remains to be determined. PMID- 7841670 TI - Mortality after blood transfusion. PMID- 7841671 TI - The Duffy blood group antigen: an update. PMID- 7841672 TI - [Perspectives for public health research in Germany]. AB - The concept of "New Public Health" is being increasingly accepted in Germany. The development of health research founded by the German Ministry of Research (BMFT), the barriers and resistance as well as perspectives are described. PMID- 7841673 TI - [Development of modern classification systems and their effects on forensic psychiatric expert assessment]. AB - The world-wide use of modern classification systems such as DSM-III and ICD-10 forces forensic psychiatry to examine the basic concepts of these systems, if the gap already existing between clinical and forensic psychiatry is not to widen. On the one hand concentrating on the historical development of these systems this article shows their limited value in forensic psychiatry. On the other hand a possible way of arriving at more empirically based forensic expert opinions with the help of these classification systems is discussed. The concept of comorbidity of these new systems is given special attention in this connection. PMID- 7841674 TI - [Methadone substitution in national public health care in Germany--patients, indications, physicians. Results of a survey of public health service facilities]. AB - Subject of this paper is methadone-maintenance given by office-based physicians in Germany in the framework of the statutory health insurance (SHI). Results of a survey of the associations of SHI-accredited physicians are presented, comprising the number of substituted patients, the distribution of indications and the number of the physicians engaged in this field. The results are presented under regional aspects and discussed. It was ascertained that in respect of the number of substituted patients, the increasing trend continues. PMID- 7841675 TI - [Hepatitis B in persons at high risk for sexually transmitted diseases. Screening and vaccination campaign--acceptance and results]. AB - The prevalence of HBV-markers in our patients in STD high-risk groups was markedly higher than the average in Vienna. 19% of the registered prostitutes, 44% of the illegal prostitutes, 29% of the bar hostesses and 39% of the STD patients were found to be positive in at least one HBV marker. I.v. drug abuse. African origin and irregular condom use were the most important risk factors in our patients. The hepatitis B vaccination campaign was successful to a high degree. 69% of the registered prostitutes and 85% of the regularly examined bar hostesses accepted the vaccination. Promotion programmes should focus on institutions caring for STD risk persons rather than on the persons themselves. PMID- 7841676 TI - [Diphtheria immunity in the German population]. AB - In the years 1991-1993 the diphtheria antitoxin titres of the blood serum of 2404 persons living in germany was determined by means of the ELISA test. Its aim was to to get an idea of the population's protection given by vaccination against diphtheria. It became evident that the average protection given by vaccination against diphtheria was on the decrease as people grew older. Thus only 3.8% of the 2-5-year olds did not have any protection given by vaccination (antitoxin titre < 0.01 IU/ml). The same was true for approximately 25% of the examined persons who were older than 30. Less than 10% of these persons had a thorough protection given by vaccination/(antitoxin titre > 0.1 IU/ml). In the age group of the 51-60-year olds better immunological protection than expected was found, which could be ascribed to the fact that there was a natural immunigation during the last wide-spread diphtheria epidemic in germany in the 'forties. Another aspect of this result could be a better motivation for-diphtheria vaccination in this age group. Furthermore, it was noticed that the average diphtheria antitoxin titres of women in all age groups were below those of men. In view of the great percentage of the adult population which is not sufficiently protected against diphtheria, it appears necessary to provide for more information of this population group to stimulate and motivate them to care for better protection by vaccination. PMID- 7841678 TI - [Evaluating the noise problem in regional town planning]. AB - While looking for enough living quarters for the town people regional planners are often confronted with high levels of noise due to traffic, highways and railways near the planning area. This may change or even stop the procedure of town planning. Generally, health authorities--who are more or less involved in the process of planning--should take the chance to demand compatibility of special planning with health care regarding noise. However, most guidelines on health-compatible noise levels are not legally binding. This paper describes the variety of health problems accompanied by moderate to high levels of noise. In regions with traffic noise problems efforts should be directed at maximum health compatibility coupled to highly imaginative planning. It is suggested that levels of noise of 55 dB(A) (daytime) and of 45 dB(A) (nighttime) should be tolerated near to the building. This would ensure tolerable levels of noise of 35 dB(A) (daytime) and of 30 dB(A) (nighttime) in the dwellings. Examples of different arrangements of buildings are shown. They demonstrate that these tolerable noise levels could even be observed in areas with traffic problems. It mostly depends on the planner's imagination whether the need for dwelling houses in problem areas could be met in keeping with health demands. PMID- 7841677 TI - [Do current evaluation criteria regarding applied genetic techniques in the area of food ensure the public health protection? An environmental medicine philosophic contribution]. AB - The liberation and use of organisms that have been manipulated by genetic engineering must be viewed against the background of criteria related to human toxicology and general and public health as far as the production of foods and foodstuffs is concerned. This interdisciplinary study yielded the result that the examinations performed for the purpose of discovering possible pathogenic effects do not by themselves safeguard human health if they are based on the classical mechanistic model. Rather, the structural changes brought about by genetic engineering result in technicalising living organisms. Concepts such as "health" can no longer be applied to organisms manipulated by genetic engineers. The loss of characteristics typical of life within the horizon of human knowledge is fraught with impeding health risks. From the viewpoint of philosophy, the conceptual areas of causality, time and spontaneity are affected by the manipulations of gene technology. The authors point out that these areas lose their pretechnological meaning subject to changes conditioned by gene technology. PMID- 7841679 TI - [Endemic mercury burden caused by a bleaching ointment in Balken refugees]. AB - In two camps in Ibbenburen occupied by refugees from Balkan countries we found in 121 inhabitants, among them 56 children, high mercury concentrations in urine and blood. The median of the urinary concentrations was 12 micrograms/l (range: 0.15 770 micrograms/l) or 11.4 micrograms/g creatinin (range: 0.2-446 micrograms/g). 12 adults and 15 children had values above 50 micrograms/l. As source, a mercury containing bleaching ointment, sold by foreign vendors, was identified. Mercury concentrations in several samples of this ointment ranged from 708 to 17,200 micrograms/g. Similar exposure to mercury may occur elsewhere. Hence, chronic mercury poisoning should by taken into differential diagnostic consideration. PMID- 7841680 TI - [Enterobacteria in mineral, spring and table water]. AB - Whereas coliform bacteria rank first, non-coliform enterobacteria can be isolated second in frequency from bottled mineral, spring and table waters in South Bavaria. Escherichia coli were found in 8, coliforms in 44 and non-coliform enterobacteria in 41 of 54 manufactories with hygienic problems. 11 different bacterial species were determined from coliforms with Enterobacter cloacae occurring most numerous in 19, Citrobacter freundii in 12 and Enterobacter amnigenus in 7 manufactories. From non-coliform enterobacteria 18 different species could be determined. Again Enterobacter cloacae was found most frequently in 17 manufactories followed by Enterobacter amnigenus in 11 and Serratia liquefaciens in 7 manufactories. The investigation of total Enterobacteriaceae is suggested as a suitable quality criterion for bottled mineral, spring and table waters. PMID- 7841681 TI - [The first cigarette]. AB - Student were asked about the circumstances smoking their first cigarette. The situation was described. In the age from 12 to 16 years one or two cigarettes were tested at a hidden place in the companion of some friends. The most important causes of smoking the first cigarette was curiosity or testing. PMID- 7841682 TI - [Quality assurance in legal social security evaluation--results and practical experiences with a quality assurance program]. AB - In the medical department of a statutory pension insurance bureau a quality assurance programme was established and tested. This programme is based on the "integrative assessment" of sociomedical expertises by means of a catalogue of 12 quality indicators. The results of a two-year period of working with this programme are discussed. The consequences with respect to qualifying procedures are also emphasised; these are based on individual and total data. Basing on the demands be made on the quality assurance programme--especially with regard to motivation, use, minimising costs, improving quality and acceptance--the handling of the procedure must be critically assessed. In addition, the author discusses the question as to which modifications would be more appropriate and promising. PMID- 7841683 TI - [Psychosocial management in the hospital--a comparison between 1884 and 1993]. PMID- 7841684 TI - Group engagement: a conceptual analysis. AB - Group engagement is an approach which further advances the concept of group engagement but is empirically weak in identifying those behaviours that are related to learning. A definition of group engagement which emphasized age appropriate, functional behaviours which fall within the set curriculum has finally been developed. This approach is the most conceptually sophisticated approach, is ideologically acceptable, and has some empirical validation. Future research should concentrate on articulating clear principles to guide operationalization and validation. The development of several different operationalizations of engagement for clearly specified different purposes is recommended. Group engagement measures should be subject to greater psychometric analysis. The use of disaggregation of group engagement to analyse the behaviour of individuals and component behaviours is recommended. PMID- 7841685 TI - The association between Coffin-Lowry syndrome and psychosis: a family study. AB - This paper discusses a family presenting with features of Coffin-Lowry syndrome, namely abnormal facies, skeletal abnormalities and mental handicap. Two of the mildly affected females had psychotic illness with predominant depressive features, and all the severely affected males had profound sensorineural deafness. PMID- 7841686 TI - Correlates of interventions with self-injurious behaviour. AB - A review was conducted of published intervention research on the self-injurious behaviour (SIB) of individuals with severe or profound mental retardation. The review comprised articles published between 1980 and 1990. Thirty-eight biodemographic and environmental variables were investigated, with type of SIB and intervention type considered primary variable classes. Efficacy was also investigated as an additional variable. Cross-tabulations were performed on selected variables with 24 significant and five marginally significant results obtained. These results indicated that there were possible biases in treatment approaches, problems in compliance with standards of practice, and differential efficacy levels related to certain variable types. Findings were discussed in relation to establishing a prototype for successful SIB interventions. PMID- 7841687 TI - A study of expressed emotion in the parental primary carers of adolescents with intellectual impairment. AB - Expressed emotion (EE) was measured in the parental primary carer (carer) of 92 adolescents with intellectual impairment to examine its associated characteristics. High EE was mainly a result of high levels of emotional overinvolvement. High EE was associated with psychological illhealth, poor quality marriage and poor practical social support of the carer, and psychiatric disorder in the adolescent with intellectual impairment. This suggests that EE may be a useful indicator of coping difficulties in these families. The subgroup of high EE emotional overinvolvement was associated with a carer with more psychological illhealth, a worse-quality marriage, less practical social support, greater professional support and an insecure style of respite care usage for an adolescent of greater intellectual impairment. The subgroup of criticism have an adolescent of less severe intellectual impairment, more behavioural disturbance and yet the carer has less professional support. Appreciation of the quality of the relationship of the carer with their dependent family member may enable greater understanding of how to improve the quality of life for both the carer and the cared for. PMID- 7841688 TI - Down's syndrome and the acquisition of phonology by Cantonese-speaking children. AB - The phonological abilities of two groups of 4-9-year-old intellectually impaired Cantonese-speaking children are described. Children with Down's syndrome did not differ from matched non-Down's syndrome controls in terms of a lexical comprehension measure, the size of their phoneme repertoires, the range of sounds affected by articulatory imprecision, or the number of consonants, vowels or tones produced in error. However, the types of errors made by the Down's syndrome children were different from those made by the control subjects. Cantonese speaking children with Down's syndrome, as compared with controls, made a greater number of inconsistent errors, were more likely to produce non-developmental errors and were better in imitation than in spontaneous production. Despite extensive differences between the phonological structures of Cantonese and English, children with Down's syndrome acquiring these languages show the same characteristic pattern of speech errors. One unexpected finding was that the control group of non-Down's syndrome children failed to present with delayed phonological development typically reported for their English-speaking counterparts. The argument made is that cross-linguistic studies of intellectually impaired children's language acquisition provide evidence concerning language-specific characteristics of impairment, as opposed to those characteristics that, remaining constant across languages, are an integral part of the disorder. The results reported here support the hypothesis that the speech disorder typically associated with Down's syndrome arises from impaired phonological planning, i.e. a cognitive linguistic deficit. PMID- 7841689 TI - Is clumsiness a marker for Asperger syndrome? AB - Although Asperger syndrome (AS) has been included in the ICD-10 as a distinct category within the pervasive developmental disorders, it is still unclear to what extent it differs from normal-intelligence autism (high-functioning autism; HFA). Persons with AS are said to be particularly clumsy. To test the hypothesis that clumsiness can reliably distinguish AS from autism, the present authors compared 11 patients with AS (ICD-10; 10 males; mean age, 13.6 years; mean IQ, 98) with nine patients with HFA (ICD-10/DSM-III-R; eight males; mean age, 12.9 years; mean IQ, 84). Clumsiness was assessed by the Bruininks-Oseretsky test. Both groups showed problems with coordination and the distribution of standard scores was virtually identical. This suggests that motor clumsiness, as measured by tests of coordination, may not reliably distinguish AS from HFA. However, qualitative differences may occur between the two groups in the manner in which movements are performed. Further research with larger samples may elicit differences into the pattern of motor deficits that occur in autism and AS. PMID- 7841690 TI - Prader-Willi syndrome in old age. AB - This case report describes a person with Prader-Willi syndrome who recently died, aged 71 years. It is suggested that her longevity was helped by being female, with a moderate degree of mental handicap and a degree of weight control which reduced the problems of diabetes and hypertension. PMID- 7841691 TI - The role of cytogenetics in studies of people with Down's syndrome. PMID- 7841692 TI - Doppler echocardiographic assessment of changes in the central circulation of the fetal sheep induced by maternal oxygen administration. AB - Eleven fetal sheep were studied to investigate if Doppler echocardiography could document redistribution of blood flow during maternal oxygen administration. Velocities through the pulmonary valve, aortic valve, common brachiocephalic trunk, aortic arch, descending aorta, umbilical and carotid artery were recorded before, during and after oxygen was delivered to the ewe by face mask. Indices of cardiac performance (shortening fraction, velocity of fiber shortening and systolic time intervals) were also obtained. The aortic arch was the only recording site where significant changes in mean velocity related to oxygen administration and withdrawal were demonstrated (p < 0.01). Changes in the velocity waveform suggesting an increase in cerebral vascular resistance during oxygen administration were found in the carotid artery. Thus, using Doppler velocimetry, the carotid artery and the aortic arch (equivalent to the human aortic isthmus) appear to be suitable sites to document changes induced by maternal oxygen administration. PMID- 7841693 TI - Cerebral blood flow velocity in term newborns following intrapartum fetal asphyxia. AB - Twenty-six term newborns with intrapartum fetal asphyxia, determined biochemically (umbilical artery base deficit > 12 mmol/l), were compared with 59 normal newborns to determine the effect of intrapartum fetal asphyxia on newborn blood pressure and cerebral blood flow velocity following delivery. Cerebral blood flow velocity observations with concurrent measures of blood pressure and heart rate were obtained during the 24 h after delivery and after 24 h. After delivery, diastolic blood pressure in the newborns of the asphyxia group was significantly greater than that of the newborns of the normal group and this difference persisted after 24 h. Cerebral blood flow velocity in the newborns of the asphyxia group was of the same order as that of the newborns of the normal group during the 24 h after delivery. However, there was a significant increase in both peak systolic and end-diastolic blood flow velocity after 24 h. The duration of metabolic acidosis may be a factor in the occurrence of this delayed cerebral blood flow velocity response. Observations of cerebral blood flow velocity should be continued for more than 24 h following delivery to determine the effect of intrapartum fetal asphyxia. PMID- 7841694 TI - Effect of sustained inflations applied directly after cord clamping on lung function in premature newborn lambs. AB - We studied the possibility of improving lung volume and therefore clinical outcome in premature newborn lambs by increasing the inspiratory volumes during the first minute after birth. Sixteen lambs from eight were delivered by hysterotomy after 130-131 days' gestation. In eight lambs the lungs were inflated with a bag with a sustained inspiratory inflation (SI) of 5 s and expiratory time of 5 s during the first four inflations after cord clamping and then mechanically ventilated. Their siblings did not receive SI and served as a control group. At 8 h postnatally, the SI and control groups showed the following results (mean +/- SEM): mean airway pressure 14.8 +/- 1.8 cmH2O versus 11.9 +/- 1.1 cmH2O, PaO2 41.5 +/- 7.3 kPa versus 31.3 +/- 7.7 kPa, alveolar-arterial oxygen gradient 359 +/- 55 mmHg versus 437 +/- 58 mmHg. Clinical course, incidence of pneumothorax, oxygenation index, total static compliance, parenchymal-alveolar air area ratio or mortality rate were not different. There was no significant difference between the two groups at this time or at any other time during the experiments. PMID- 7841695 TI - Inspiratory and expiratory times for infants ventilator-dependent beyond the first week. AB - The aim of this study was to determine optimum inspiratory and expiratory times to be used for ventilation of infants older than one week of age. Each infant was studied at a rate of 30 breaths/min (inspiratory times (TI) of 1.0, 0.67 and 0.5 s with expiratory times (TE) of 1.0, 1.33 and 1.5 s, respectively) and at a rate of 60 breaths/min (TI 0.5, 0.33 and 0.25 s and TE 0.5, 0.67 and 0.75 s, respectively). Arterial blood-gases were examined after 20 min on each setting. Fifteen infants with a median gestational age of 27 weeks were studied at a median postnatal age of 9 days and 10 infants with a median gestational age of 27 weeks at a median postnatal age of 24 days. All infants had type I chronic lung disease. Oxygenation did not consistently improve as TI was prolonged, elevating mean airway pressure but, particularly in older infants, was better at TI > or = 0.5 s compared with TI < 0.5 s. In both groups, carbon dioxide elimination was better at 60 than at 30 breaths/min. Thus we suggest that in infants fully ventilator-dependent beyond the first week of life, an inspiratory and expiratory time of 0.5 s should be used as the first choice. PMID- 7841696 TI - Morphine pharmacokinetics in premature and mature newborn infants. AB - The pharmacokinetics of a single dose of morphine was investigated in five term infants (gestational age 37-40 weeks) and eight preterm infants (gestational age 25-32 weeks). In the five term infants, median (range) volume of distribution at steady state (Vd beta) was 1758 (634-2700) ml/kg, plasma clearance (Cl) was 4.73 (1.75-6.61) ml/kg/min and terminal half-life (T1/2) was 224 (107-394) min. In the eight preterm infants, Vd beta was 2366 (1662-2876) ml/kg, Cl was 2.82 (1.88 6.60) ml/kg/min and T1/2 was 556 (248-834) min. No correlation was found between clearance and gestational age, but we found a significant negative correlation between T1/2 and gestational age. We conclude that there is considerable variation in the pharmacokinetic properties of morphine in both term and preterm newborn infants. Because of this variation, careful individual assessment of the clinical effect of therapy with morphine in newborn infants should be exercised. PMID- 7841697 TI - Growth impairment, IGF I hyposecretion and thyroid dysfunction in children with perinatal HIV-1 infection. AB - We evaluated the growth pattern, bone age, insulin-like growth factor I (IGF I) secretion and thyroid function in 24 perinatally infected children: 9 asymptomatic or paucisymptomatic (group 1) and 15 with a more advanced disease state and treated with zidovudine (group 2). Statural and ponderal growth were compared with those of 37 at-risk children who seroreverted. During the two-year follow-up, 22% of children in group 1 had impaired growth, 33% bone age delay, 45% reduced IGF I levels but none had thyroid dysfunction. In group 2, 53% had growth failure, 53% bone age delay, 86% reduced IGF I levels and 40% thyroid dysfunction. Among seroreverters, none showed growth impairment; statistically significant differences were found for height, weight and height velocity between perinatally infected children and seroreverters. Since auxological and hormonal evaluations run parallel to the clinical course of infection, these indices may be useful in monitoring disease progression. PMID- 7841698 TI - Ferritin levels in pediatric HIV-1 infection. AB - Ferritin is an acute phase protein which is often elevated in acute and chronic inflammation, as well as in neoplastic disease. In adults with human immunodeficiency virus (HIV) infection, elevated serum ferritin levels indicate advanced or progressive disease. In the present study, ferritin levels were evaluated in 88 HIV-infected children. Ferritin levels greater than 100 ng/ml were found in 93% of patients with advanced disease. Increasing levels always accompanied or closely preceded rapid disease progression. Serum ferritin levels may prove to be a useful marker to monitor disease progression and therapeutic efficacy in HIV-infected children. PMID- 7841699 TI - Cerebrospinal fluid analysis in HIV-1-infected children: immunological and virological findings before and after AZT therapy. AB - Immunological and viral studies were conducted on cerebrospinal fluid from 31 HIV 1-infected children, of whom 23 were neurologically asymptomatic and 8 had progressive encephalopathy. After AZT treatment, a second cerebrospinal fluid specimen was obtained from 15 children, 11 of whom were neurologically asymptomatic and 4 had progressive encephalopathy. Virus isolation and p24Ag detection were more frequent in children with progressive encephalopathy than in asymptomatic children (66% versus 12%) and were inversely correlated with intrathecal HIV-1-antibody detection (anti-gag AB: 25% versus 70%). High concentrations of interleukin-1 beta (IL-1 beta) and IL-6 were found in children with progressive encephalopathy (50% and 37%, respectively), but low levels were also detected in some asymptomatic children (13% and 9%, respectively). Tumour necrosis factor-alpha (TNF alpha) was not found. AZT treatment induced disappearance of p24Ag in cerebrospinal fluid, as well as a marked reduction in cytokine levels. Cytokine determination may be useful in monitoring AZT treatment in children with progressive encephalopathy. PMID- 7841700 TI - Improved arterial oxygenation in children with the adult respiratory distress syndrome: the prone position. AB - Seven ventilated children with the adult respiratory distress syndrome (ARDS) were studied. While supine and haemodynamically stable, baseline arterial blood gas analyses and haemodynamic measurements, including cardiac output, were performed. Each child was then turned prone and 30 min later a repeat set of measurements were made. Following this, the children were returned to the supine position and 30 min later a final set of measurements were performed. Ventilation and inotropic support remained unchanged during these positional changes. No significant effect on heart rate, mean systemic arterial blood pressure and cardiac output occurred following these positional changes (p > 0.05; Friedman's ANOVA). Arterial oxygen saturation significantly improved, however, when nursed in the prone position (p < 0.02). Similarly, oxygen delivery significantly increased (p < 0.02). The prone position improves arterial oxygenation and oxygen delivery in children with ARDS. By adopting the prone position, in ventilated children with ARDS, we surmise that realistic gas exchange targets may be reachable with lower levels of inspired oxygen and/or peak airway pressures. PMID- 7841701 TI - Dysgenesis of thyroid is the common type of childhood hypothyroidism in environmentally iodine deficient areas of north India. AB - Forty-five children (28 girls and 17 boys; mean age 4.5 years) with hypothyroidism referred to us from January 1989 to November 1990 were evaluated prospectively for the pattern of hypothyroidism by hormone assays, scintiscan and urinary iodine estimation. Among the 6 children from non-endemic areas, athyreosis and/or hypoplasia were seen in 3, ectopia in 2 and dyshormonogenesis in 1. Of 39 children from moderate to severe environmentally iodine deficient regions, 18 (46%) had athyreosis and/or hypoplasia and 10 (26%) ectopic thyroid. Iodine deficiency was seen in 4, dyshormonogenesis in 4, secondary/tertiary hypothyroidism in 2 and thyroiditis in 1. The mean age of these children at the onset of symptoms was 1.4 years and at clinical presentation 4.5 years. There was significant growth retardation with 54% of children being below the 5th centile of Indian standards. There was no significant difference in the age at onset of symptoms and presentation, clinical features and bone age for the different types. The levels of serum total T4 were significantly low in dysgenesis (athyreosis, hypoplasia and ectopia, p < 0.001). Dysgenesis of the thyroid is the most common type of childhood hypothyroidism in iodine deficiency endemias. We postulate that severe iodine deficiency in the intrauterine and early neonatal period may lead to dysgenesis of the thyroid. PMID- 7841702 TI - Human milk oligosaccharides. PMID- 7841703 TI - Final height in girls with central precocious puberty: comparison of two different luteinizing hormone-releasing hormone agonist treatments. AB - In order to evaluate the effects of two long-acting luteinizing hormone-releasing hormone agonists on growth, bone maturation and final height in girls with central precocious puberty, we analyzed growth data from 40 girls (15 treated with buserelin intranasal spray (group A), 15 treated with triptorelin depot im every 28 days (group B) and 10 untreated (group C)). Patients in group A started treatment when chronological age (CA) was 7.7 +/- 0.9 years, bone age (BA) was 10.2 +/- 1.1 years and height was 131.9 +/- 5.0 cm. Patients in group B started therapy when CA was 7.6 +/- 0.5 years, BA 9.8 +/- 1.0 years and height 133.2 +/- 7.6 cm. The diagnosis of untreated patients (group C) was made when CA was 7.2 +/ 0.9 years, BA 9.6 +/- 2.2 years and height 130.2 +/- 8.6 cm. Both luteinizing hormone-releasing hormone agonists appeared to control precocious puberty. Final height in group B (160.6 +/- 5.7 cm) was significantly higher than that of group A (153.2 +/- 5.0 cm: p < 0.05) and group C (149.6 +/- 6.3; p < 0.01), whereas the difference between groups A and C was not statistically significant. In group B a positive difference was observed between final height (160.6 +/- 5.7 cm) and target height (157.6 +/- 5.9 cm) (ns); on the contrary, in groups A and C, final height was lower than target height (155.5 +/- 5.3 and 156.4 +/- 1.3 cm, respectively), but only in group C the difference was statistically significant (p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7841704 TI - Incidence and clinical features of incomplete Kawasaki disease. AB - During the nine-year period from 1983 to 1991, a total of 242 patients (142 males and 100 females) presenting with Kawasaki disease were seen at one hospital. Among them, 25 (10%) patients demonstrated incomplete Kawasaki disease and 17 of these 25 (68%) lacked two of the six principal symptoms of Kawasaki disease, with the most frequently missing symptoms being cervical lymphadenopathy and polymorphous exanthema. The typical laboratory features of Kawasaki disease, such as elevated erythrocyte sedimentation rate, leukocytosis, anemia, positive C reactive protein and thrombocytosis were also seen in the incomplete cases. None of the 25 patients underwent iv gamma-globulin therapy while in 1 (4%), transient dilatation of the coronary artery was recognized. Incomplete Kawasaki disease may therefore be characterized by a less frequent association of rash, cervical lymphadenopathy and coronary involvement. PMID- 7841705 TI - Incidence rate of recurrent Kawasaki disease in Japan. AB - To calculate the incidence of recurrent Kawasaki disease and to discuss some potential risk factors for its recurrence, we observed a cohort consisting of those followed-up since the first episode of the disease. A total of 4560 persons, with 16,500.4 person-years were observed from the second month after the first episode of the disease to the end of 1989. The mean observation period was 3.62 years. The overall incidence rate was 5.21 per 1000 person-years, with a higher incidence within the 2 years from the first episode; although not statistically significant, the incidence was higher among males and those who experienced the first episode at < or = 2 years of age. The possibility of i.v. gamma globulin therapy being one of the risk factors was negated by a stratified analysis to control confounding factors but supported by univariate analysis. PMID- 7841706 TI - Increasing incidence of childhood celiac disease in Sicily: results of a multicenter study. AB - By screening the patient list of four Sicilian centers of gastroenterology and those with gluten-free product consumption, 1074 patients (607 females and 467 males) with celiac disease, diagnosed between 1975 and 1989, were identified. A maximum cumulative incidence rate by birth cohort was reached in 1986 (1.65/1000). When the incidence rate was adjusted for the years of follow-up, the actual standardized rate was 3 cases per 1000 live births. Growth failure and chronic diarrhea were the most common symptoms, but a diminishing trend for chronic diarrhea was observed when symptoms were distributed by year of diagnosis. Even though 61.1% of all cases were diagnosed within six months from the onset of symptoms, mean age at diagnosis showed an increasing trend, from less than two years to approximately four years of age. The results of our study showed an increasing incidence of celiac disease due to diagnosis of less typical cases at an older age and also to a steady increase in the rate of diagnosis of cases with a classic clinical picture. PMID- 7841707 TI - Growth as a parameter of inflammation in Crohn's disease, using roentgen stereophotogrammetric analysis. AB - Growth rate was measured in 12 children with Crohn's disease and growth retardation, using roentgen stereophotogrammetric analysis. The method was chosen as it provides an opportunity to record growth rate accurately during short periods of time. Growth was followed at variable intervals of 4-12 weeks depending on the clinical situation. Growth rate was shown to correlate with symptoms, laboratory tests and nitrogen balance. These findings indicate that growth, when it is affected, fluctuates in a similar way as albumin, acute phase proteins and symptoms, all assumed to reflect the disease activity. Short-term growth measurements appear to be helpful in monitoring the disease progress or response to therapy in children with Crohn's disease, particularly when growth retardation is the only manifestation of the disease. PMID- 7841708 TI - Depressed concentrations of oxytocin and cortisol in children with recurrent abdominal pain of non-organic origin. AB - The purpose of the present study was to measure plasma concentrations of oxytocin, cortisol and prolactin in children with recurrent abdominal pain of non organic origin (RAP). Forty children with RAP and 34 controls, matched for age and sex, participated in the study. A blood sample was collected after an overnight fast in association with clinical examinations. Oxytocin, cortisol and prolactin levels were determined by radioimmunoassay (RIA). Oxytocin and cortisol concentrations in the children with RAP were found to be significantly reduced compared with those of the controls (approximately 24 versus 63 pmol/l for oxytocin and 160 versus 300 nmol/l for cortisol, respectively). The low oxytocin and cortisol levels persisted at a second examination 3 months later. No significant differences in the prolactin levels were observed between RAP and controls. PMID- 7841709 TI - Gastro-oesophageal reflux and oesophageal dysfunction in children and adolescents with brain damage. AB - The prevalence of pathological gastro-oesophageal reflux (GOR) and oesophageal dysfunction (OD) was investigated in 32 children, 0.7-19 years of age (mean 11.2 years), with brain damage, mainly severe cerebral palsy and tetraplegia. They underwent 24-h pH monitoring in the distal oesophagus and oesophageal manometry. In addition, radiological examination of the oesophagus, chest radiography, blood counts and blood tests for iron deficiency were carried out. Fifteen (47%) patients had mild pathological acid reflux, 5 (16%) had moderately severe and 5 (16%) severe acid GOR. Seven of 32 (22%) patients had no pathological GOR. Ten patients had abnormal manometry findings and 9 had a pathological radiological oesophagus examination. Three patients had radiographic lung consolidations. Thirteen patients had iron deficiency and 5 were anaemic. Two patients with severe acid reflux have died, presumably from aspiration-induced pneumonia. Findings of OD and GOR are frequent in children with brain damage and are related to significant complications, including fatal course. PMID- 7841710 TI - A comparative magnetic resonance imaging study of the corpus callosum in neurologically normal children and children with spastic diplegia. AB - To determine the extent of brain damage in children with spastic diplegia, we analyzed the true midsagittal magnetic resonance imaging findings for the corpus callosum in 43 children with spastic diplegia and in 69 neurologically normal children. In the normal children, the thicknesses of the genu, midbody, splenium and the entire corpus callosum were found to increase with age, while the ratios of the thickness of the splenium and of the midbody to the length were constant, regardless of age. Both ratios were significantly reduced in diplegic children and the ratio for the splenium was highly correlated with the extent of motor impairment. Assessment of the morphometric changes in the corpus callosum using magnetic resonance imaging may contribute to the determination of the extent of brain damage in diplegic children. PMID- 7841711 TI - Palpable lymph nodes of the neck in Swedish schoolchildren. AB - We studied 3592 Swedish schoolchildren, 8 or 9 years old, examined for palpable submandibular, cervical and supraclavicular lymph nodes. All children were skin tested with 2 TU PPD RT23 and with 0.1 microgram of Mycobacterium avium sensitin or 0.1 microgram of M. scrofulaceum sensitin. A total of 991 children had palpable lymph nodes in any of the three locations. Among them, 811 had lymph nodes in one location, 162 in two locations and 18 in three. In 312 children, the lymph nodes were > or = 5 mm in size in any location. The most common location was submandibular. Boys had a significantly higher prevalence of palpable lymph nodes than girls. There was also seasonal variation. Children infected by atypical mycobacteria (sensitin reaction > or = 6 mm) did not have a higher prevalence of palpable lymph nodes than those not infected. PMID- 7841712 TI - Cyclical variations in cerebral blood volume during periodic breathing. PMID- 7841713 TI - A mathematical model describing catch-up growth in celiac disease. AB - Celiac disease may lead to various degrees of growth retardation. In general, catch-up growth is completed in the first 2 years after the start of therapy. A mathematical model for catch-up growth in celiac disease can be useful as a reference to which the growth pattern observed during treatment of other conditions can be compared. In this study we performed a non-linear regression analysis on individual growth data of 16 celiac disease patients using a monomolecular growth function. The goodness of fit was significant in all cases (p < 0.05), which illustrates that this function adequately describes catch-up growth in individuals with celiac disease. From the individual models we have composed a cross-sectional curve and a longitudinal description of the pattern of catch-up growth for the entire population. PMID- 7841714 TI - Cardiac status of patients with phenylketonuria. PMID- 7841715 TI - Bronchogenic cyst presenting in the neonatal period. AB - A term infant presented at birth with worsening respiratory distress which resulted in him requiring mechanical ventilation. A CT scan of the chest revealed a bronchogenic cyst, removal of which resulted in full recovery and, to date, no respiratory sequelae. PMID- 7841717 TI - How long should we go on reporting single cases of micropremies' survival? PMID- 7841716 TI - An unusual case of an aldosterone-producing adenoma in a prepubertal girl with severe post-surgical adrenal suppression. AB - An 11-year-old girl was referred with hypertension, hypokalemia, low renin activity, metabolic alkalosis and hyperaldosteronism. Adrenal computed tomography revealed the presence of a large left adrenal adenoma of 4 x 4.5 cm in size. Following adrenalectomy, the child presented an unusual acute salt-loosing syndrome which necessitated administration of a large quantity of sodium chloride and corticoids. The cells from the tumor were plated. They rapidly proliferated to a monolayer. After incubation for 24 h, basal production of aldosterone (55.4 +/- 9.07 pmol/ml) was observed. This production was stimulated by the presence of ACTH 10(-8) M and KCl 55 mM; angiotensin II 10(-8) M failed to enhance aldosterone secretion. In the four experimental conditions, however (control, ACTH, angiotensin II and KCl), ANF 10(-8) M decreased aldosterone secretion. We conclude that hyperaldosterone secretion by an adrenal adenoma is not due to resistance to the inhibitory effect of ANF but rather to cell multiplication itself. In this patient, the post-surgical salt-loosing syndrome was attributed to the combined effect of the chronic state of high ANF, low potassium and low ACTH in the contralateral gland on the one hand and a certain degree of transitory renal unresponsiveness of the renal distal tubule to aldosterone on the other. PMID- 7841718 TI - Intrathoracic extra-mediastinal cystic hygroma in infancy. AB - An infant with intrathoracic extra-mediastinal cystic hygroma is described. Fluid collection within the fetal chest was noted on routine antenatal ultrasound scan and this was subsequently drained. Postnatally, echocardiogram and thoracic CT scan demonstrated a cystic space between the pericardium and right mediastinal pleura. Thoracotomy performed at six weeks of age showed a multiloculated cystic mass adherent to the right pericardium and to the medial aspect of the diaphragm. Histology revealed the tumour to be a cystic hygroma (lymphangioma). Intrathoracic cystic hygroma occurring outside the mediastinum is extremely rare and has never been diagnosed previously in infancy. PMID- 7841719 TI - Capillary leak syndrome in patients with hemophagocytic lymphohistiocytosis. PMID- 7841720 TI - Effect of cisapride on procedure time for small bowel biopsy in children. PMID- 7841722 TI - Supplementary feeding in the maternity ward shortens the duration of breast feeding. AB - In a prospective study, feeding routines of a maternity unit and the subsequent feeding patterns of 521 newborns were analysed. During the stay in the maternity unit, 69% of newborns were exclusively breast fed and 1% received only donor's milk from the milk bank and/or formula. Nine percent received their mothers' milk by bottle at least once and 21% received one or more supplementary feedings with donor's milk from the milk bank. One-quarter of the children received supplementary feeds on the third day of life, the indications for this being birth weight less than 3.0 kg, maternal diabetes or gestational diabetes, "insufficient amounts" of milk or fussiness. At three months, 65% were being exclusively breast fed and 15% partially breast fed. In a multiple logistic regression analysis, the potential determinants (neonatal feeding, maternal characteristics, characteristics of the delivery and the child) for the duration of breast feeding were included. The adjusted relative risk (estimated as odds ratios, OR) of not being breast fed at three months was associated with maternal age (< 25 years, OR 4.2), maternal smoking (OR 4.0), neonatal feeding (supplements given, OR 3.9) and initial weight loss (10% or more, OR 2.8). Thus the administration of supplementary donor's milk or formula during the early neonatal period was associated with an increased risk of a short duration for breast feeding, even after adjustment for a number of potential confounders. PMID- 7841721 TI - Zinc intake, zinc status and growth in a longitudinal study of healthy Danish infants. AB - Mild, growth-limiting zinc deficiency might be prevalent in otherwise healthy infants according to recent studies. We examined zinc intake and status in 91 healthy term infants from birth to 12 months, as part of the Copenhagen Cohort Study on Infant Nutrition and Growth. Zinc intake was recorded monthly and the amount of zinc absorbed was estimated. These estimates were below recently published FAO/WHO/IAEA values for basal requirements in 68%, 62% and 14% of the infants at 2, 4 and 9 months of age, respectively. Serum zinc decreased significantly (p < 0.01) from 10.6 mumol/l at 6 months to 8.4 mumol/l at 9 months of age (normal range 10-18 mumol/l). Erythrocyte metallothionein values, a tentative indicator of long-term zinc status, decreased significantly from 2 to 6 months (p < 0.001) and from 6 to 9 months (p < 0.01). Serum zinc at 9 months was positively associated with growth velocity during the period from 6 to 9 months (weight: p = 0.05; knee-heel length: p = 0.002). The results provide descriptive data on zinc intake and zinc status in healthy Danish infants. Although some of our data suggest suboptimal zinc status during late infancy, evidence for this can only be obtained through a randomized intervention study. PMID- 7841723 TI - Are fathers prepared to encourage their partners to breast feed? A study about fathers' knowledge of breast feeding. AB - In order to study fathers' knowledge of breast feeding and its relationship with paternal factors, fathers of 92 breast feeding and 89 non-breast feeding newborns were compared. Paternal factors included previous children and the way they were fed, participation in prenatal care, attendance at prenatal classes, breast feeding information provided by health professionals, use of reading materials and interest in learning more about the subject. The results indicated that fathers had poor knowledge about breast feeding, especially those whose children were being bottle fed. After adjustments for confounders, fathers who had previous breast-fed child(ren), had attended prenatal classes and who received information about breast feeding from medical personnel had a significantly higher chance of having a better knowledge of breast feeding. It seems that fathers need to be better prepared to assume their new role as breast feeding supporters. Prenatal care was shown to be a good opportunity to improve fathers' knowledge of breast feeding. PMID- 7841724 TI - Inhaled nitric oxide in neonates and children with pulmonary hypertension. AB - Fourteen critically ill neonatal and paediatric intensive care patients with various primary diagnoses and signs of associated pulmonary hypertension received inhaled nitric oxide (NO), 20-80 ppm, after failure of conventional therapy to improve oxygenation. NO administration was found to be associated with a significant improvement in postductal arterial oxygen tension (pre-NO: 3.75 (SD 1.39) kPa; post-NO: 6.05 (SD 1.70) kPa; p = 0.004). In 10 patients, NO was found to increase arterial oxygen tension with more than 1 kPa. In 2 of these patients, ECMO treatment could be avoided due to the pronounced improvement in gas exchange seen after the initiation of NO administration. The remaining 4 patients failed to respond to NO administration. One patient developed methaemoglobinaemia (13.9%) which required treatment with methylthionine. Since we were unable to produce any beneficial effect of NO in the late phase of the pulmonary disease process, we believe that, in order to be successful, inhaled NO should be instituted when conventional treatment has failed and the administration of an iv vasodilator is usually considered. PMID- 7841725 TI - Antibodies against some bacterial antigens in children. AB - The prevalence of bacterial antibodies was determined in 173 children aged 0-15 years. The prevalence of IgG Borrelia burgdorferi antibodies in titres > 500 in children less than 8 years of age was 6% while none of the older children had these antibodies in titres > 400. IgG Helicobacter pylori antibodies were detected only in children older than 6 years of age, with a prevalence of 6.5%, as were IgA H. pylori antibodies, with a prevalence of 3.7%. The prevalence of high-titre IgG Campylobacter jejuni antibodies was 1.2%, that of IgA 1.8% and IgM 1.2%. The prevalence of high-titre (> 500 IU/ml) antistreptolysin O was 3%, that of antistaphylolysin-alpha (> or = 4 IU/ml) 2% and that of anti-teichoic acid antibodies (titre 2) 2%. Low-titre Yersinia antibodies were detected in 2%. High titre Bordetella pertussis antibodies were detected in 6% of recently vaccinated children and in 8% of children in their first years of school. In the latter, high-titre antibodies were mainly of the IgM and IgA classes. Altogether 35 children tested positive for bacterial antibodies other than Bordetella pertussis antibodies. Clinical evaluation revealed a possible infection, suggested by the antibody, in 5 (3%) of the children. Two (vaccinated) children had evidence of whooping cough. Eight of the 35 children with high-titre bacterial antibodies (23%) also had elevated levels of autoantibodies (but not autoimmune diseases). PMID- 7841726 TI - Prevalence of specific antibodies to Chlamydia pneumoniae in children with acute respiratory infections. AB - We investigated 56 boys and 30 girls between the ages of 1 month and 15 years with acute respiratory infections for antibodies to Chlamydia pneumoniae and Mycoplasma pneumoniae. Antibodies were only occasionally found in children less than 10 years of age (4% of boys (1/23) and 5% of girls (1/19). In the age group 10-12 years, antibodies were detected in 55% of boys (4/9) but not in the 2 girls investigated. In the age group 13-15 years, antibodies were detected in 58% of boys (14/24) and in 33% of girls (3/9). Infection caused by M. pneumoniae was found in 13% of boys in the oldest age group. PMID- 7841727 TI - Enzymatic changes in the cerebrospinal fluid in patients with infections of the central nervous system. AB - Enzymatic determinations in cerebrospinal fluid (CSF) of aspartate aminotransferase (AST), lactic dehydrogenase (LDH), gammaglutamyl transpeptidase (GGT), creatine phosphokinase (CPK) and creatine kinase BB (CK-BB) were performed in 16 patients with aseptic meningitis (AM), in 25 children with bacterial meningitis (BM) and in 15 patients with meningism. The activity of AST and GGT was significantly higher in patients with BM on admission compared with those with AM and meningism (p < 0.05 and p < 0.005, respectively) and decreased with therapy. The highest concentration of AST and LDH appeared in patients with poor outcome as well as in those with ventriculomegaly on neurosonography (p < 0.05). The concentration of CK-BB increased in all patient groups on admission and remained higher on termination of therapy. The present study confirms the high activity of AST and GGT in BM patients in the CSF whereas the increased activity of AST and LDH reflects the extent of brain injury. Nevertheless, the prognosis for individual patients cannot be established on the basis of enzyme activity alone, but depends on several factors. PMID- 7841728 TI - Eosinophil cationic protein in nasal secretion and in serum and myeloperoxidase in serum in respiratory syncytial virus bronchiolitis: relation to asthma and atopy. AB - Eosinophil cationic protein (ECP) in nasal secretions was determined in 34 infants with respiratory syncytial virus (RSV) bronchiolitis during the acute infection stage and one and six months later. ECP in serum was determined in 19 of these children at the same time. Myeloperoxidase (MPO) was determined in the same 19 children at the acute infection stage and after one month. All children were followed prospectively for two years after the infection with regard to the development of bronchial obstructive symptoms. Asthma, defined as three or more episodes of bronchial obstruction verified by a physician, developed in 18% of children and less severe obstructive symptoms in 29%. A screening test for food IgE antibodies in serum was performed six months and a skin prick test two years after the acute infection. Nasal ECP/albumin ratios after six months were significantly higher than during the acute RSV infection. MPO, but not ECP, levels in serum were significantly elevated at the time of acute infection compared with levels after one month. Nasal ECP/albumin ratios at the acute infection were compared to a control group of 27 infants with non-RSV upper respiratory tract infections and did not differ. It was not possible to predict, either from ECP/albumin ratios in nasal secretion or from ECP and MPO in serum, which children would develop asthma, other bronchial obstructive symptoms or positive IgE tests. PMID- 7841729 TI - Inhalation of racemic adrenaline in the treatment of mild and moderately severe croup. Clinical symptom score and oxygen saturation measurements for evaluation of treatment effects. AB - The aim of this study was to evaluate the immediate effect of inhaling racemic adrenaline to treat croup and to evaluate a scoring system. Two groups were investigated. One group inhaled a racemic adrenaline solution and the other group received the same solution with no racemic adrenaline. The study was double blinded and placebo-controlled. Fifty-four children (0.4-10.8 years) with mild to moderately severe croup were included in the study after clinical evaluation. The clinical score was useful when evaluating the treatment effects in mild to moderately severe croup and may be used as a quality assurance tool when treatment protocols are re-evaluated. Oxygen saturation before and after treatment did not change significantly in either group and therefore its measurement did not provide additional information on the effect of treatment. In both groups, a significant improvement in total mean clinical scores was seen 30 min after inhalation, compared with before inhalation (p < 0.001). However, racemic adrenaline was significantly better than placebo in terms of improvement in total clinical score, inspiratory stridor, retractions and air entry, and should therefore be used as first-line treatment. PMID- 7841730 TI - Iohexol and inulin clearance. PMID- 7841731 TI - Growth in children with Pierre Robin sequence and isolated cleft palate. AB - Postnatal height and weight growth were assessed in 50 children (20 boys) with Pierre Robin sequence and in 58 children (27 boys) with isolated cleft palate, born in 1967-86. The height and weight measurements from birth to 12 years were collected retrospectively from child health centers and schools. The current Finnish relative weight and SD scores for height were used for growth assessment. The birth size of children with Pierre Robin sequence did not differ from those with isolated cleft palate or from healthy children, on the basis of Finnish norms. During the first year after birth, children with Pierre Robin sequence were shorter and lighter than those with isolated cleft palate but later caught up with them and the Finnish norms. Children with Pierre Robin sequence born prematurely or with associated anomalies showed more deficient growth. PMID- 7841732 TI - Changes in craniofacial development induced by growth hormone therapy in children treated with bone marrow transplantation. AB - The effect of growth hormone (GH) treatment on craniofacial development was studied in nine children exhibiting low growth velocity after bone marrow transplantation (BMT). Comparisons were made with seven BMT children who had not received GH. Two groups of age- and sex-matched healthy children served as controls for the respective patient groups. After an average observation period of 3.5 years, the BMT children not treated with GH exhibited significantly reduced mandibular length and alveolar height (p < 0.01). The increase in mandibular length was only 30% of that found in healthy controls. Maxillary growth was less affected by BMT treatment. In the GH treated group, no significant differences were found in craniofacial growth increments compared with controls. Although exogenous GH therapy in this group of children did not induce a catch-up growth, it appears to have prevented further loss in growth potential. PMID- 7841733 TI - Lung function in adolescents with alpha 1-antitrypsin deficiency. AB - Children with alpha 1-antitrypsin deficiency, screened at birth, were followed prospectively. At 16 years of age, 150 adolescents (103 PiZ, 1 PiZ-, 1 PiS-, 45 PiSZ) were interviewed using a standardized questionnaire and asked to participate in an extensive lung function study including part or all of the following tests: FVC, FEV1 before and 15 min after four inhaled doses of salbutamol, TLC, RV and FRC. Fifty age-, sex- and height-matched adolescents participated as controls. No significant differences in age, height or weight were found between the PiZ, PiSZ and control groups. No significant differences were found in respiratory symptoms, parental smoking history or the smoking habits of PiZ, PiSZ and control subjects. Asthma occurred in 10.7% of PiZ, 6.5% of PiSZ and 4% of control adolescents (p = 0.33). Only 3 of 100 PiZ and 1 of 45 PiSZ adolescents were smokers. No significant contribution of alpha 1-antitrypsin Pi-type was found to explain the variation in lung function variables studied. We conclude that children with alpha 1-antitrypsin deficiency have a favourable prognosis and normal lung development up to 16 years of age. Anti-smoking advice was found to be reasonably successful; only 3% of those answering the questionnaire had started to smoke. PMID- 7841734 TI - Gallbladder hypocontractility in infantile colic. AB - We evaluated gallbladder contractility in 58 colicky infants and 57 age-matched controls. Gallbladder size was measured before and 1 h after feeding and the contraction index of the gallbladder was calculated. The results showed decreased contractility of the gallbladder in colicky infants: mean contraction index in colicky infants was 56% (95% confidence interval, 49-63%) and in controls 67% (61 73%). No difference was found in the fasting size of the gallbladder. Postprandial contraction was decreased in colicky infants examined in the evening (n = 14) compared with those examined in the morning (n = 44). Decreased contraction of the gallbladder was found in those colicky infants who presented colicky cry compared with colicky infants without symptoms at the time of examination. No structural abnormalities were found in the general abdominal survey. In conclusion, infants with colic have hypocontractility of the gallbladder. This indicates abnormal biliary tract physiology in association with infantile colic. PMID- 7841735 TI - Sonography in the detection of achilles tendon xanthomata in children with familial hypercholesterolaemia. AB - Patients with heterozygous familial hypercholesterolaemia (FH) are at high risk for the development of coronary artery disease. Achilles tendon xanthomata are often the first clinical manifestation of FH, but are seldom palpable earlier than during the third decade. Twenty-one FH children aged 3-18 years underwent high-frequency ultrasound examination of the achilles tendon. Hypoechoic infiltration of the normal tendon structure was demonstrated in 8 of 21 (38%) of the FH children. The findings were similar in boys and girls. Control subjects (n = 68) aged 1-25 years had no sonographically detectable tendon abnormalities. The thickness of the achilles tendon of the FH children was (mean +/- SD) 7.1 +/- 1.5 mm (range 5-10 mm). The respective values for the controls were 5.8 +/- 1.0 mm (3 7 mm. We conclude that ultrasound examination sensitively detects cholesterol accumulation in the achilles tendon of FH children before tendon xanthomata are clinically evident. PMID- 7841736 TI - A prospective study of the adverse effects of midazolam on withdrawal in critically ill children. AB - Fifty-three critically ill infants and children received midazolam as sedation in a regional intensive care unit. Assessment of the level of sedation was carried out at regular intervals on withdrawal of midazolam. Forty-nine patients were fully alert within 4 h of midazolam being stopped. Four patients took from 6 h to 1 week to become fully alert. Four patients had abnormal behaviour highly suggestive of midazolam withdrawal. The onset of abnormal behaviour was within 12 h of discontinuation of midazolam. The duration of the abnormal behaviour ranged from 3 h to 1 week. One child had a paradoxical reaction to midazolam. The overall incidence of adverse effects to midazolam in the patients studied was 17%. No adverse effects were observed in infants; all adverse effects were observed in children. We have shown that it is possible to prospectively study the toxicity of sedatives in critically ill infants and children. PMID- 7841737 TI - Consequences of caustic ingestions in children. AB - A retrospective analysis of 98 patients, less than 15 years of age, treated for caustic ingestion during 1976-1990 was performed to evaluate the modern consequences of caustic ingestion in children and to set indications for esophagoscopies and radiographic and laboratory examinations. Dishwasher detergents were ingested by 56 children. There were no lye ingestions, since lye has not been freely available in Finland since 1969. Household acetic acid (vinegar) was the most commonly (12/23) ingested acid. Primary esophagoscopy was performed in 79 of the 98 cases (80.6%). Esophageal burns were found in 20 patients. Acids caused burns more often than alkalies (9/23 (39.1%) versus 11/75 (14.7%); p = 0.011; 95% confidence intervals (CI) for the difference 5.6-43.3%) and acid burns more often developed into scars (7.4% versus 4%; p = 0.029; 95% CI for the difference 1.4-25.4%). The only esophageal stricture developed after ingestion of a Clinitest tablet. The mean time for hospitalization as a result of acid ingestion was significantly longer than after alkaline ingestion (3.2 (SD 3.5) days, n = 23 versus 1.5 (1.6) days, n = 75; p < 0.05; 95% CI for the difference 0.7-2.8 days). Prolonged drooling and dysphagia (12-24 h) predicted esophageal scar formation with 100% sensitivity and 90.1% specificity, but signs and symptoms did not predict esophageal burns after primary esophagoscopy. Radiographic examinations and leukocyte counts were of no value in predicting esophageal burns and scars. The panorama of caustic ingestion appears to have changed, probably due in part to the law banning sale of lye products since 1969. This type of law should be encouraged elsewhere. Acids cause even more caustic burns than alkalies. Vinegar should be regarded as a potent caustic substance and distributed in baby-safe bottles with appropriate information on its caustic nature. As severe esophageal lesions after accidental ingestion of caustic substances are now rare in children, primary esophagoscopies and hospitalization of patients are not indicated routinely. The decision on esophagoscopy can be made on the basis of drooling and dysphagia during follow-up. PMID- 7841738 TI - Weight at birth of singleton live births between the 23rd and 27th week of gestation delivered vaginally or by cesarean section. PMID- 7841739 TI - Socio-economic circumstances and the growth of Stockholm preschool children: the 1980 birth cohort. PMID- 7841740 TI - Congenital protein C deficiency in a Chinese family. PMID- 7841741 TI - Successful treatment of aortic thrombosis after umbilical catheterization with tissue plasminogen activator. AB - An infant presented 10 days after removal of a high umbilical arterial catheter with total occlusion of the distal abdominal aorta. Complete dissolution was achieved with a combination of i.v. tissue plasminogen activator and heparin. Ultrasound examination confirmed the diagnosis and subsequent resolution of the thrombus. PMID- 7841742 TI - Soft tissue injury associated with intravenous phenytoin in a neonate. AB - A term baby with neonatal convulsions secondary to birth asphyxia was given i.v. phenytoin via a cannula in the dorsum of the hand at 17 h of age. She developed a blue discolouration in the tissues surrounding the i.v. site. The infusion was aborted but the discolouration gradually spread to the rest of the hand. Twenty hours later, improvement could be detected although a blister appeared near the i.v. site. A further attempt two days later to administer phenytoin via an i.v. cannula sited in the left foot was aborted after the appearance of a similar reaction. PMID- 7841743 TI - Pneumopericardium: a rare cause of cardiac tamponade in an infant on a positive pressure ventilation. AB - Cardiac tamponade most commonly results from accumulation of blood, or other fluids, within the pericardial sac. However, rarely air tamponade can lead to tension pneumopericardium and death. Positive pressure ventilation in infants carries a risk of barotrauma and presents as pneumothorax, pneumomediastinum or rarely pneumopericardium. We present an infant with cardiac tamponade due to pneumopericardium to illustrate the classical signs and symptoms, and the management of this rare condition. PMID- 7841744 TI - Successful treatment with cyclosporin A in a child with acquired pure amegakaryocytic thrombocytopenic purpura. AB - Idiopathic acquired pure amegakaryocytic thrombocytopenic purpura (APATP) in young patients (non-neonates) is a rare disorder with a variable clinical course. Cure is unusual. A 13.5-year-old boy with idiopathic APATP was treated with cyclosporin A. Apparently effective, the treatment resulted in the reappearance of marrow megakaryocytes and normalization of platelet count. PMID- 7841745 TI - Early neonatal renal venous thrombosis: long-term outcome. AB - Renal venous thrombosis was diagnosed in the first week of life in 6 of 30,101 live infant births born at the Chaim Sheba Medical Center in Israel from 1984 to 1989. The thrombosis was unilateral in 5 neonates and bilateral in 1. Predisposing maternal risk factors included 2 cases of maternal diabetes and 1 case of maternal hypertension with associated intrauterine growth retardation. Perinatal risk factors included 2 cases of prematurity with severe hyaline membrane disease, 1 infant who was small for gestational age and another with asphyxia. Follow-up for 1-5 years following the acute event revealed normal growth and development in all infants. None of the patients was hypertensive and all had normal renal glomerular and tubular functions. Renal imaging and scan studies revealed loss of perfusion in 4 atrophic kidneys and diminished perfusion in the remaining 2. In conclusion, although renal venous thrombosis in neonates is associated with low mortality, long-term dysfunction in the affected kidney is common. PMID- 7841746 TI - Sonographic demonstration of multiple intrahepatic meconium masses in a newborn with meconium peritonitis. AB - We report on a patient with atresia of the colon transversum and a large meconium pseudocyst adherent to the liver. Sonography additionally revealed multiple cystic structures due to intrahepatic meconium masses. Surgical evacuation of the meconium pseudocyst resulted in massive diffuse hemorrhage from the liver which could not be stopped. The child died intraoperatively due to hemorrhagic shock. Histologically the intrahepatic meconium masses were surrounded by various degrees of necrosis and hemorrhage without a well-defined capsule of fibrous granulation tissue. PMID- 7841747 TI - Reactive arthritis due to Salmonella enteritidis complicated by carditis. AB - Reactive arthritis following infection with enteropathogenic bacteria is usually a self-limiting disease that disappears after a few months without sequela. We describe two girls who developed carditis shortly after the onset of reactive arthritis due to infection with Salmonella enteritidis. The carditis presented with fatigue and arrhythmia and involved the aortic valve in both patients leading to definite aortic regurgitation in one. A similar pattern of cardiac involvement is found in other spondyloarthropathies, including Reiter's syndrome and ankylosing spondylitis. We conclude that Salmonella reactive arthritis may be complicated by carditis. PMID- 7841748 TI - A biometrical view on chemotherapy of toxocariasis. PMID- 7841749 TI - [Effects of Tripterygiitotorum in the treatment of insulin dependent diabetes mellitus with islet transplantation]. AB - The therapeutical efficacy of islet transplantation in treating insulin-dependent diabetes mellitus (IDDM) patients is marked for a short time and the long-term efficacy is unsatisfactory. So 30 IDDM patients given tripterygiitotorum (T II) were compared with 24 IDDM patients without using any immunosuppressive agents after islet transplantation. RESULTS: prior to transplantation both the numbers of T lymphocyte subpopulations such as CD2, CD4, CD8 and the concentrations of C peptide in all IDDM patients were lowered; after transplantation the numbers of CD2, CD4 were significantly elevated (P < 0.01), the ratio of CD4/CD8 in control group was higher than that in TII group (P < 0.01), while the concentration of C peptide were greatly increased (normal: 2.24 +/- 0.34; before transplantation: 0.21 +/- 0.01; 15 days after transplantation: 3.24 +/- 1.2 ng/ml). The peak value of C-peptide in TII group began decreasing half a year after transplantation and it gradually dropped to the baseline level. The dose of insulin all were significantly reduced, and 3 patients stopped altogether. Half a year after transplantation TII group remained stable for the requirement of insulin, whereas the control group gradually increased the dose of insulin. (1) Islet transplantation could adjust the immunological disorder in IDDM patients, increase the numbers of T lymphocyte subset such as CD2, CD4, CD8 while the chronic immuno-rejective response occurred. (2) T II inhibited both the numbers and function of T lymphocyte subpopulation and normalized the ratio of CD4/CD8. (3) TII prolonged the survival time of grafts in IDDM patients and suppressed immunological rejection.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7841750 TI - [Study on relationship between brain function and syndrome differentiation-typing of TCM in non-insulin dependent diabetes mellitus]. AB - The relationship between brain function and syndrome-types of TCM in 51 patients with non-insulin dependent diabetes mellitus (NIDDM) was observed. The syndromes were divided into three types. (1) Yin Deficiency with internal excessive Heat (YDIEH), 15 cases; (2) Qi-Yin Deficiency (QYD), 21 cases; (3) Deficiency of both Yin and Yang (DYY), 15 cases. The control group consisted of 30 healthy subjects matched in age, sex and educational level. The brain function were tested by neurobehavioral and neuroelectrophysiological tests. The former included short term memory, thinking, eye-hand coordination and emotion tests; the latter consisted of brainstem auditory evoked potentials (BAEP), visual evoked potentials (VEP) and somatosensory evoked potentials (SEP). The results showed that the brain function in YDIEH group approached normal controls, and the brain function in QYD and QYY groups were significantly deteriorated. The results suggested that the brain function were correlated with the syndrome-types of patients with NIDDM. This would be valuable for diagnosis and treatment of NIDDM in TCM. PMID- 7841751 TI - [Investigation of treating steroids dependent asthmatic patients with kidney tonifying herbs and high dose beclomethasone dipropionate aerosol]. AB - The steroids dependent asthmatic(SDA) patients need prolonged oral steroids administration. Because of the significant adverse effects with long-term use of steroids, especially the damage of the hypothalamus-pituitary-adrenocortical(HPA) axis, long-term steroids administration should be avoided or withdrawn gradually. Many modes of withdrawing the oral steroids have be used. But, the results were not satisfactory. So far, recently, investigations have revealed that high dose corticosteroids inhalation, such as beclomethasone dipropionate (BDP), could provide an effective alternative; they were delivered locally in the airway and had minimal systemic absorption as well as side effects. On the other hand, it has been shown that the Kidney-Tonifying herbs (KTH) exert protective effect on the adrenocortical cells of the SDA patients by suppressing the exogenous steroids and could regulate the disorders in different levels on HPA axis in the patients. In order to provide the more effective alternative therapy for the patients, 30 SDA patients replaced their oral steroids with KTH and high dose BDP (1500 micrograms/day) inhalation were investigated. The changes of clinical features, pulmonary function and the Synacthen Test were followed up. The results showed that about 70% of the patients replaced their oral steroids successfully with the new therapy, the clinical features were improved in 16% of the patients and the ineffective rate was only 6.6%; the results also revealed that, after replacement, the pulmonary function of the patients were improved (P < 0.05); the data of Synacthen Test indicated, after alternative therapy for 3-6 months, the damaged reserve power and secretive ability of adrenal cortex of the patients were also improved partially (P < 0.001). PMID- 7841752 TI - [A study on pulmonary artery compliance and hemodynamics in patients with lung distention]. AB - A simultaneously comparative study on pulmonary artery compliance (Cpa) and pulmonary artery mean pressure (PAMP) in 89 patients with Lung-Distention in TCM by impedance pulmonary rheogram, tricuspid valve echocardiogram and right heart catheterization. Then according to Syndrome Differentiation of TCM, Lung Distention was sub-divided into four groups. The results showed that PAMP were gradually increased and Cpa decreased in these groups. It revealed that the pulmonary circulation of Lung-Distention patients has disturbed. PMID- 7841753 TI - [Clinical and experimental study on Ligusticum wallichii mixture in preventing and treating bronchial asthma]. AB - To investigate the significance of Ligusticum wallichii Mixture (LWM) and its possible therapeutical mechanism in bronchial asthma, clinical and experimental studies were carried out. RESULTS: LWM inhibited bronchospasm induced by histamine and acetylcholine in guinea pigs; the plasma level of TXB2 was decreased remarkably and the incubation period from antigen inhalation to asthma attack could be delayed by LWM; the incidence of asthma and its mortality were reduced in guinea pigs, compared with control, P < 0.01. In addition, the prolonged period of induced asthma attack was negatively correlated to the plasma level of TXB2 in guinea pigs (P < 0.01). It was observed that the plasma level of TXB2 was decreased, the forced expiratory volume in 1 sec (FEV1%) was elevated significantly in asthmatic patients after they were treated by LWM. Moreover, the total effective rate was significantly better than that in the control (92% : 62%). It indicated that: (1) The effects of airway allergic inflammation (AAI) might be the important pathological basis for the bronchial asthma, (2) TXA2 might be an important inflammatory mediator in asthma which could be taken as an useful biochemical parameter for evaluating clinical effects, (3) LWM could relax tracheal smooth muscle, improve pulmonary function, inhibit the synthesis and release of TXA2 with no side effects. PMID- 7841754 TI - [Clinical and experimental studies of feiyaning in treating pulmonary arterial hypertension in cor pulmonale]. AB - 40 Patients with chronic cor pulmonale (CCP) were treated with Feiyaning (FYN), a Yiqi Huoxue compound prescription, and ligustrazine (LT) were reported. The results showed that FYN and LT could lower the pulmonary artery pressure (PAP) significantly; decrease the pulmonary vascular resistance (PVR) as well as the consumption of oxygen in cardiac muscle; increase cardiac output (CO); improve some indices in hemorrheology; while PaO2 and SaO2 didn't change apparently. Moreover, lowering of FYN on PAP and PVR were superior to that of LT. The experimental studies showed that LT and injection of FYN could completely inhibit the hypoxia caused increase of PAP and PVR in rats; reduce the hypoxia caused pulmonary artery hypertension (PAH) and improve PVR of rats, as well as increase CO. The effects of FYN were superior to LT's. Although LT and FYN could decrease systemic arterial pressure to certain extent, they didn't induce systemic artery hypotension. It suggest that LT could reduce PAH definitely. PMID- 7841755 TI - [Effect of Salvia miltiorrhiza on lipid peroxidation antioxidant enzymes activity in patients with chronic cor pulmonale]. AB - This paper studied the effect of Salvia miltiorrhiza (SM) on plasma lipid peroxidation (LPO), RBC superoxide dismutase (SOD), glutathione peroxidase (GSH Px) and catalase (CAT) activity in patients with chronic cor pulmonale. 30 patients were randomly divided into two treatment groups (routine and SM). The four parameters have been measured in 22 healthy subjects as control and patients of two treatment groups. The results showed: (1) Before treatment both treatment groups had significantly higher LPO and SOD and markedly lower GSH-Px and CAT level than that of healthy control (P < 0.001) respectively. (2) After treatment in routine group the four parameters have normalized, P < 0.05. (3) Routine treatment was compared with SM treatment, except SOD, the other three parameters were significantly different between two treatment groups (P < 0.001). The increased levels of GSH-Px and CAT and the decreased LPO were significantly greater in SM group than routine treatment (P < 0.001). The above-mentioned results indicated patients with cor pulmonale in acute exacerbation their lipid peroxide reaction was enhanced, the antioxidant enzymes lost their balance. SM could attenuate markedly lipid peroxide reaction, adjust the imbalance of the three antioxidant enzymes, enhance body's defence capability against damage of active oxygen free radical induced lipid peroxidation. PMID- 7841756 TI - [Clinical study of naoxin sutong in the treatment of acute cerebral infarction]. AB - It was shown that the cerebral ischemia-reperfusion produced free radicals are the main factor that causes irreversible cerebral injury. The mechanism of Naoxin Sutong (NXST) treated acute cerebral infarction was elucidated. It is compared with Ligustrazine (LT), which has been proved to be an effective drug for cerebral infarction. The curative effect and the changes of serum malondialdehyde (MDA) levels, blood rheology, blood lipid, etc. of 41 patients with acute cerebral infarction within 3 days, who were confirmed by CT. The therapeutic result showed that after 4 weeks of treatment the points of progress for central nervous system deficit scoring of NXST and LT group were 10.67 +/- 5.02 and 6.85 +/- 4.49 respectively. The difference between these two groups was significant. MDA levels of the patients and the healthy subjects were 6.46 +/- 1.70 and 3.87 +/- 0.67 nmol/ml respectively, the difference was also significant (P < 0.01). After 2 weeks of treatment, MDA content of NXST was less than before (P < 0.05). However the level of LT group did not reduce, while after 3 weeks of treatment, MDA content of NXST group was 4.34 nmol/ml. It was much less than that of LT group and approached that of healthy subjects. Results also showed that blood rheology improved, blood lipid reduced after NXST treatment. All these indicated that the effect of NXST in treating acute cerebral infarction was good, and the mechanism as that NXST could scavenge free radicals, ameliorate cerebral ischemia reperfusion injury, improve blood rheology and reduce blood lipid. PMID- 7841757 TI - [Effects of plant polysaccharides on cell proliferation and cell membrane contents of sialic acid, phospholipid and cholesterol in S 180 and K 562 cells]. AB - The four kinds of plant polysaccharides, i.e., pachyman polysaccharides (PPS), Acanthopanax senticosus polysaccharides (ASPS), polysaccharides of tremella fuciformis (TF) and lentinan, have obviously inhibitory action against the animal tumor growth and have been applied to the treatment of cancer. The mechanism was that they could enhance the body immune function, but whether the tumor cells were killed is not clear. In this paper, the effects of the four plant polysaccharides on cell proliferation in mice sarcoma (ascitic type) S180 and human chronic myelogenous leukemia K562 cells were studied with MTT chromometry. Tt was found That TF and lentinan had no effect on both cell line, but PPS and ASPS could obviously inhibit the proliferation of them, the IC50 of PPS was 1.5mg/ml in both cell line, that of ASPS was 0.38 mg/ml (S180 cells) and 0.28mg/ml (K562 cells) respectively. This result indicated that the PPS and ASPS were able to kill the tumor cell directly. To investigate the mechanism of antitumor action of PPS and ASPS, the sialic acid (SA), phospholipid (PI) and cholesterol (Ch) contents of S180 cell membrane were examined after the PPS or ASPS application for 24 hours. No significant changes were observed for the Ch and Ch/Pl ratio, the amount of SA increased and that of PI lowered respectively (P < 0.05). The results suggested that the antitumor action of PPS and ASPS not only related to the action of enhancing the body immune function but also related to the changes of cell membrane. PMID- 7841758 TI - [Experimental study in treating chronic renal failure with dry extract and tannins of herba ephedra]. AB - The effects of dry extract and tannin of Herba Ephedra on adenine-induced chronic renal failure in rats and their mechanisms of action have been studied. Dry extract of Herba Ephedra in dose of 10 mg, 20 mg and 30 mg/d with adenine (for 24 days) were administered to rats. After inducing renal failure (34 days), it reduced toxins in blood significantly. The action of 30 mg-dose was highly significant, BUN decreased by 37%, creatinine (Cr) 35%, methylguanidine (MG) 76%, guanidinosuccinic acid 83%, blood phosphate 39%, while blood calcium raised for 28%. But in 25mg and 45mg-dose, MG in urine decreased by 49%-65%. The mechanisms of action might be including (1) Inhibiting the production of Cr; (2) Inhibiting the production of hydroxyl free radical, blocking the conversion of Cr into creatol, thereby reducing, the production of MG from creatol. In conclusion, dry extract of Herba ephedra could improve renal function in adenine-induced chronic renal failure in rats, correct Ca and P disorder, and especially inhibit the production of MG. Fraction 2 and fraction 3 of Ephedra tannin had no effect on this renal failure model. PMID- 7841759 TI - [Study of platelet aggregation affected by 8 classical recipes in rabbit]. AB - Arachidonic acid can induce platelet aggregation in rabbits in vitro. The experimental model was designed to observe inhibitory effect of 8 classical recipes of activating blood circulation to remove the stasis on platelet aggregation in vitro. The results showed that each one of 8 classical recipes has inhibitory effect on platelet aggregation in vitro in various degree. Among them, Gexia Zhuyu Tang (GZT), Shentong Zhuyu Tang (SZT) and Shaofu Zhuyu Tang (SFZT) were more effective. The results suggested that inhibitory effect of platelet aggregation produced by 8 classical recipes might be one of mechanisms of blood stasis treatment. PMID- 7841760 TI - [The factors on effectiveness of traditional Chinese medicine decoction]. PMID- 7841761 TI - [Characteristics of combined traditional Chinese and Western medicine]. PMID- 7841762 TI - [The anti-platelet effect of berberine and its mechanism]. PMID- 7841763 TI - A comparison of fluorescence versus chemiluminescence detection for analysis of the fluorescamine derivative of histamine by HPLC. AB - Fluorescence and chemiluminescence detection were compared for HPLC analysis of the fluorescamine derivative of histamine. The kinetic behaviour of the chemiluminescent response for the derivative was characterized in a static system. An HPLC method was optimized for the derivative using fluorescence detection. Fluorescence detection was linear over the range of 166-1666 pg on column for the fluorescamine-histamine derivative with a limit of detection of 13 pg on column. Using a detector designed for optimal use with chemiluminescence, the chemiluminescence response of the fluorescamine derivative was linear over a range of 1.66-16.6 ng on column with a limit of detection of 1.0 ng on column. These results exemplify a case in which superior detectibility is provided by fluorescence over chemiluminescence, and contradicts many reports comparing fluorescence to chemiluminescence. The authors conclude that chemiluminescence should be considered when indicated by conditions established for separation that are favourable for the observation of chemiluminescence. These conditions include sufficiently low excitation energies corresponding to an excitation maximum greater than 400 nm, favourable dipole character of analytes, mobile phases of high organic content, and an appropriate pH of the mobile phase. PMID- 7841764 TI - Polymeric reagents for derivatizations in micellar electrokinetic chromatography. AB - A polymer immobilized o-nitrobenzophenone reagent was prepared for analysis of amine drugs in micellar electrokinetic chromatography (MEKC). A model compound, propylamine, was used to characterize the reagent's performance in MEKC. Derivatizations were performed on the CE instrument with reagent in the sample vial. The yielded derivative was directly sampled from the reaction mixture, and directly injected onto the MEKC system. The derivatization reagent was also applied to the derivatization of n-alkyl amine mixtures and amino acids. The method was validated for adamantanamine in urine and in plasma by single-blind spike analysis. Precisions and accuracies for all samples were less than 6.0% for urine samples and 10% for plasma samples. The procedure was a direct injection technique requiring minimal sample preparation for the analysis of drugs in biofluids. PMID- 7841765 TI - Measurement of amiloride in airway surface liquid utilizing HPLC and fluorescence detection. AB - A high-performance liquid chromatographic method for the determination of amiloride in airway surface liquid is described. It involves extraction of the drug with methanol from filter paper on which the sample is absorbed and chromatography on a Zorbax Rx column; the mobile phase is 25% acetonitrile in 0.05 M phosphate buffer; detection by fluorescence at 360/420 nm. Triamterene is used as an internal standard. The range of the assay is 2.0-2033.4 ng/sample, with adequate precision and accuracy. A power curve y = axb best describes the relationship between the peak-height ratio and concentration. Recovery of amiloride is non-linear, probably due to an adsorption process. Accuracy of the assay at lower amounts may be affected by the choice of filter paper a well as by presence of endogenous plasma components. The assay was used to measure amiloride amount in airway surface liquid after administration of 2.5 and 4.5 mg of nebulized amiloride. PMID- 7841766 TI - A non-radioactive iothalamate and p-aminohippuric acid high-performance liquid chromatographic method for simultaneously measuring glomerular filtration rate and renal blood flow in the rat. AB - A high-performance liquid chromatographic (HPLC) assay method has been developed for the quantitative determination of iothalamate and p-aminohippuric acid (PAH) concentrations in serum and urine samples in the male rat. Glomerular filtration rate (GFR) was measured as clearance of iothalamate, while effective renal blood flow (ERBF) was measured as clearance of PAH. The method is simple, rapid and sensitive and detects iothalamate and PAH in rat serum and urine following administration of bolus doses and continuous infusions of iothalamate and PAH. Samples of serum and urine were deproteinized with two volumes of acetonitrile containing the internal standard, and an aliquot chromatographed on a C18 reversed-phase column. The mobile phase was comprised of 0.1 M sodium phosphate with 1.2 mM tetrabutylammonium phosphate: methanol, 85:15 (v/v), at a flow rate of 1.0 mL/min. The analytical column eluate was monitored with a UV detector at 254 nm with quantitation achieved using peak-height ratios. The precision of the method was 6.6 and 3.6% for iothalamate in serum and urine, and 5.6 and 4.9% for PAH in serum and urine, respectively. The lower limit of quantitation was 0.63 microgram/mL for iothalamate and 1.25 microgram/mL for PAH in serum, and 3.1 microgram/mL for iothalamate and 1.5 microgram/mL for PAH in urine. Recovery of iothalamate from serum and urine was 99.9 and 93.5%, respectively. Recovery of PAH from serum and urine was 99.8 and 92.6%, respectively. The present study demonstrated that non-radioactive iothalamate and PAH can be measured simultaneously using a HPLC assay to measure GFR and ERBF in the male rat. PMID- 7841767 TI - Quantitative determination of 21-hydroxy-deflazacort in human plasma using gradient semi-microbore liquid chromatography. AB - A sensitive and selective liquid chromatographic procedure to quantitate the deflazacort metabolite 21-hydroxy-deflazacort (DF-21OH) in human plasma was developed and validated. DF-21OH and fludrocortisone acetate (internal standard, IS) were isolated from human plasma (2 mL) by solid-phase extraction onto C-18 cartridges. Potential interferences were selectively removed and analytes were eluted with ethyl acetate. Following evaporation, the residue was reconstituted for HPLC analysis. Separation was achieved by gradient elution using a 5 microns YMC Basic column (2.0 x 100 mm) with mobile phases consisting of 20% methanol and 50% acetonitrile in 50 mM phosphate buffer (pH 3) at a temperature of 50 degrees C. Flow rate was maintained at 0.3 mL/min., and analytes were quantified spectrophotometrically at 246 nm. The assay was validated over the range 1.0 to 500 ng/mL DF-21OH. Calibration curves were prepared using a weighted (1/concentration) nonlinear quadratic regression algorithm. Peak-height ratios were proportional to the amount of DF-21OH added to plasma. Assay precision (%RSD) ranged from 4.2 to 11%, with a corresponding assay accuracy (% relative error) of +/- 2.8%. Absolute recovery of DF-21OH from plasma was 78-86% over the concentration range. The minimum quantitation limit was 1.0 ng/mL. PMID- 7841768 TI - Fluidized-bed receptor-affinity chromatography. AB - A multipurpose fluidized-bed receptor-affinity purification system based upon the biological recognition between an immobilized receptor and its soluble protein ligands is described. The fluidized affinity sorbent consists of a soluble form of interleukin-2 receptor chemically bonded to an aldehyde derivative of controlled pore glass beads, which have a pore diameter of 1000 A and a particle density of 1.2-1.3 g/mL. The fluidized-bed separation device used in this study consists of a specially designed column fitted at the inlet end with a perforated distributor plate covered with a screen and the top outlet with an adjustable piston. The fluidized-bed consisting of a loose gel matrix permits the unimpeded passage of cell debris and particulate matter, while the target protein is captured by the affinity beads. Purification of the humanized-anti-Tac monoclonal antibody is used as a model system to determine the operational parameters. Also, fluidized-bed receptor-affinity chromatography has been successfully employed in the purification of recombinant interleukin-2 and single chain anti-Tac(Fv) Pseudomonas exotoxin immunotoxin from unclarified inclusion body extracts. Overall, fluidized-bed receptor-affinity chromatography is found to be a productive affinity method suitable for the purification of recombinant human interleukin-2 and related molecules. PMID- 7841769 TI - Immunoaffinity capillary electrophoretic analysis of cyclosporin in tears. AB - An immunoaffinity capillary electrophoresis technique has been developed for the analysis of cyclosporin A in human tear fluid following topical application of the drug. The technique combines the selectivity of immunoaffinity separation with the high-resolution of capillary electrophoresis by immobilizing monoclonal antibody fragments directly onto the internal surface of the capillary. This technique was used to measure cyclosporin levels in tears obtained from corneal transplant patients during normal and drug toxicity episodes in the course of their treatment. Comparison of this technique with HPLC detection of cyclosporin in tears showed a good correlation, with the immunoaffinity CE technique having the advantage of being able to simultaneously detect toxic metabolites of cyclosporin in the same sample. PMID- 7841770 TI - A quantitative analytical method for the determination of a new thromboxane synthetase inhibitor (CGS 22652) in human plasma using high performance liquid chromatography. AB - A quantitative analytical method for the determination of a new thromboxane synthetase inhibitor (CGS 22652) in human plasma has been developed using high performance liquid chromatography (HPLC). The drug and internal standard (CGS 23298) were extracted with methylene chloride at pH 4.8. Separations were achieved by reversed phase chromatography using a mobile phase consisting of acetonitrile: 0.01M citrate/phosphate buffer (pH 3.5): methanol:tetrahydrofuran (45:45:9:1, v/v/v/v), on a 5 microns C18 column at a flow rate of 1.0 mL/min. Plasma standard curves were linear from 50 to 2000 ng/mL, with recovery of the drug being greater than 94% at all concentrations. The method was validated over a concentration range of 50 to 2000 ng/mL, with a limit of quantification of 50 ng/mL. The method was successfully applied to the analysis of clinical samples from a single-dose safety and tolerability study conducted in healthy male volunteers. PMID- 7841771 TI - Determination of flutamide and hydroxyflutamide in dog plasma by a sensitive high performance liquid chromatography method utilizing mid-bore chromatography. PMID- 7841773 TI - [36th annual meeting of the Working Group of Physicians in State and Community Blood Transfusion Service. Tubingen, 17-19 June 1993. Proceedings]. PMID- 7841772 TI - HPLC separation of pentazocine enantiomers in serum using an ovomucoid chiral stationary phase. AB - A stereospecific HPLC method was developed for the analysis of (-) and (+) pentazocine in human serum. Each enantiomer and the internal standard nalophine were isolated from serum using a liquid-liquid extraction procedure. Recoveries of 99.05 +/- 5.37 and 97.42 +/- 2.78% were obtained for (-) and (+) pentazocine, respectively. Resolution of the enantiomers was obtained by using an ovomucoid chiral stationary phase with a mobile phase of methanol:acetonitrile: 10 mM phosphate buffer, pH 5.8 (20:5.3:74.7 v/v/v). A resolution (Rs) value of 1.80 was obtained for the pentazocine enantiomers. Linear calibration curves were obtained in the 10-100 ng/mL range for each enantiomer in serum. The detection limit based on a signal-to-noise ratio of 3 was 5 ng/mL for each enantiomer in serum using fluorescence detection with excitation at 275 nm and emission set at 335 nm. The lowest quantifiable level was found to be 10 ng for each enantiomer. Precision and accuracy of the method were in the 3.8-4.8% and 1.3-4.2% ranges, respectively. PMID- 7841774 TI - [Transfusion medicine in unified Europe]. AB - The European institutions have been dealing with blood and blood products since 1956. A need for action currently exists with regard to the European Community's Directive 89/381/EEC. The aims of the Directive are: the elaboration of strict quality and safety criteria for medicinal products made from human blood and blood products, with special reference to preventing the transmission of viral diseases, and the demand for self-sufficiency within the European Community in human blood and blood products on the basis of voluntary and unremunerated blood donations. In May 1993, the Commission submitted a report on the implementation of this Directive. In principle, the Member States are in agreement that self sufficiency on the basis of unremunerated donations should be achieved. Differences of opinion exist, however, with respect to the national self sufficiency of each Member State and the definition of 'unremunerated'. Germany's standpoints enjoy greater acceptance today than they did only a few years ago; consequently, there is reason to assume that, even in the wake of developments within the European Community, the basic structures of the blood and blood products supply system in the Federal Republic of Germany will be maintained. PMID- 7841775 TI - [Transfusion medicine in unified Europe. Brief report on the status of transfusion medicine in central and east European countries]. AB - Requests of the Council of Europe are harmonization of policies, encouragement of voluntary, unremunerated donation, self-sufficiency and introduction of EC quality standards. Present conditions were evaluated by a study in 11 countries of Eastern and Central Europe. Quality control is usually done according to USSR guidelines. Alarming are decreasing numbers of blood donations of 15% within 2 years. For satisfaction of FVIII needs plasma production has to be increased 3 times. In the countries of Western Europe too self-sufficiency is not yet reached. Strong efforts should be taken in Eastern, Central and also in Western Europe to reach self-sufficiency in the evolving unified Europe. PMID- 7841776 TI - [HLA diagnosis and DNA technology]. AB - The invention of the polymerase chain reaction, for which Mullis was awarded the Nobel prize for chemistry in 1993, is one of the most significant advances to occur in the field of molecular biology during recent years. Today, precise DNA typing of the HLA class II alleles can be established as early as 90 min after DNA extraction. The classical methods of serological HLA class II typing have an error rate of up to 25%. Retrospective analyses show that the success rate of transplantations could be improved considerably by the introduction of DNA typing into donor-recipient matching in clinical kidney transplantation. The present survey attempts to provide an evaluation of the various DNA techniques in clinical practice. PMID- 7841777 TI - Molecular genetics of human platelet antigens. AB - The purpose of this article is to review the molecular genetics of human platelet antigens, the application of molecular biological techniques to detect mutations underlying polymorphisms and the importance of these techniques for clinical medicine of immune-mediated platelet destruction. Review articles, original papers and preliminary (unpublished) observations from our own laboratory are the main source for this article. The nomenclature and phenotype frequency of the platelet alloantigens in different ethnic groups are described. Recent molecular biological advances are also reviewed. It appears that the human platelet antigen systems are due to single base pair substitutions. These mutations create or are responsible for the loss of a target site for a restriction enzyme in one of the alleles. Thus, DNA typing by polymerase chain reaction and subsequently allele specific restriction enzyme analysis (PCR-ASRA) can be performed. PMID- 7841778 TI - Clinical aspects of platelet transfusion therapy. AB - Platelet transfusions are established as effective treatment for thrombocytopenic bleeding. However, the indications for prophylactic platelet transfusions are being reconsidered because of the greatly increased demand for platelet concentrates. Platelet refractoriness is the main clinical problem associated with repeated platelet transfusions. This is most frequently due to HLA alloimmunisation or non-immune platelet consumption associated with clinical factors such as septicaemia. The initial management of refractory alloimmunised patients is to use HLA-matched platelet transfusions. If there is no improvement with HLA-matched platelet transfusions, platelet crossmatching may identify the cause of the problem and help with the selection of compatible donors. Other measures used to improve responses to platelet transfusions are usually ineffective. There has been considerable interest in methods to prevent HLA alloimmunisation and platelet refractoriness and particularly in leucocyte depletion of blood components. The use of leucocyte-depleted blood components has other benefits for multitransfused patients, but further studies are needed before the routine use of leucocyte-depleted blood components can be recommended for patients likely to receive repeated platelet transfusions. PMID- 7841779 TI - [Technical aspects of autologous bone marrow transplantation]. AB - Autologous bone marrow transplantation has become an established procedure in the treatment of malignancies. Especially in patients with hematological malignant diseases, who have no compatible allogeneic bone marrow donor or in patients with solid tumors, in whom the threshold of irreversible bone marrow toxicity is reached by the intensified chemotherapy, this procedure allows the use of a myeloablative therapy. As stem cell sources, bone marrow (BM), peripheral blood derived stem cells (PBSC), and umbilical cord blood can be used. The risk of contaminating malignant cells in BM or PBSC can be reduced by an in vitro purging of the stem cells. In principle, two different methods exist: one is the negative depletion of contaminating tumor cells and the other is the positive selection of non-malignant hematopoietic pluripotent stem cells. Which of the purging principles will be most effective can only be answered through clinical studies. PMID- 7841780 TI - [Autologous bone marrow transplantation]. AB - Autologous bone marrow transplantation (ABMT) is a treatment modality increasingly used to treat a growing number of malignancies both in children and in adults. The theoretical rationale is the transfer of dose-action relationship from pharmacological theory to clinical practice. The basic principles, the important indications and the problems of this particular approach are discussed. Normally bone marrow from the iliac crest is used as stem cell source, but the possibilities of the approach become broader by using peripheral blood stem cells (PBSC). This treatment modality and its particular use in neuroblastoma is described demonstrating also the results. PMID- 7841781 TI - [Artificial oxygen carriers--perfluorocarbons]. AB - The paper summarizes chemical, physical and physiological qualities of modern perfluorinated carbons. The indications for the application of these artificial oxygentransporting substances in the biological and medical field are summarized and discussed. The characteristics of perfluorocarbons are looked at from historical and current points of view in order to indicate the fields of application and especially the limitations of their applicability. Without any doubt application as a full replacement of blood will be impossible because blood with its multifunctional property cannot be replaced by systems which cover only one or few aspects. Besides this general statement it is also clear that the special qualities of perfluorocarbons make them highly suitable for application in biological and medical fields; their low viscosity allows to improve disturbancies in perfusion. Immunological problems do not occur, and the danger of infection is eliminated compared to biological material. The most important fields of application for perfluorocarbons are the organ perfusion in organ banks for transplantation, the oxygenation of cell cultures and the diagnosis with imaging procedures. PMID- 7841782 TI - [Current legal questions in relation to autologous blood transfusion and legally controlled blood donation in Germany]. AB - If a patient suffers any damage from treatment, the persons involved in transfusion medicine might be made liable according to civil and penal law for violations against the standards prescribed by the codes of performance and ethics of the individual professions. In order to avoid organisational liability, criteria for adequate patient care must be created which regulate facilities and equipment as well as staff. The typical hazards encountered in interdisciplinary cooperation between specialists of various branches of medicine must be counteracted by a constructive division of tasks and responsibilities. The participating physicians are moreover liable within the scope of the German law forbidding so-called 'unlawful interference with the possession of another' in the case of failure to obtain legally binding consent--usually resulting from inadequacies in informing the patient. The landmark decision by the German Federal Court of Justice on instructing patients about the risks of and alternatives to blood transfusions forces all those involved to take the consequences with regard to instructing patients about the risk of transfusions and concerning the implementation of techniques for sparing and replacing allogenic blood. PMID- 7841783 TI - [Modified hemoglobin solutions as artificial oxygen carriers]. AB - At least theoretically, hemoglobin (Hb) solutions are ideal colloidal plasma substitutes because of their unique ability to take up oxygen, transport it in bound form, and release it peripherally. The present study gives an overview of the development and present status of modified Hb preparations. While human and bovine erythrocytes are used for production on the one hand, human Hb variants can also be derived from yeast or bacteria as well as via transgenic animals through recombinant DNA technology. The pronounced limitations of extraerythrocytic Hb, that is its high oxygen affinity and its inadequate intravascular persistence, can be overcome by various modifications. Intravascular half-life of free Hb can be significantly increased by intramolecular stabilization, linking to macromolecules, intermolecular cross linking (PolyHb solutions) or microencapsulation. Oxygen affinity of human Hb may be lowered by coupling of allosteric modulators to the 2,3-bisphosphoglycerate site, e.g. pyridoxal phosphate, whereas bovine Hb has an intrinsically low oxygen affinity. Human pyridoxylated PolyHb solutions and bovine PolyHb solutions presently fulfill at least 2 of the 3 principal requirements for an oxygen transporting plasma substitute, i.e. maintenance of the circulating blood volume with provision of additionally utilizable oxygen capacity. Matters of concern with all Hb preparations remain potential vasoconstrictive effects and renal toxicity. Major efforts being undertaken at present by industry and research groups give reason to hope, however, that the concept of modified Hb solutions as oxygen carriers will be realized in the foreseeable future. PMID- 7841784 TI - The proximal element is capable of determining proper temporal expression of the embryonic sea urchin U2 snRNA gene. AB - There are two gene sets for U2 snRNA in the sea urchin L. variegatus, the U2E gene, which is expressed in oogenesis and early embryogenesis and then silenced, and the U2L gene, which is expressed constitutively. There are four major promoter elements found in both U2 snRNA genes; an essential TATA box at -25 to 30, a proximal element (PSE) at -55 required for expression, an element at -100 necessary for maximal expression, and an upstream activating sequence (UAS) necessary for maximal expression. The elements of the U2E and U2L promoters were interchanged and the effect on the temporal pattern of expression determined after microinjection of the genes into sea urchin zygotes. When the U2E PSE element was introduced into the U2L gene, the temporal pattern of expression of the gene was changed to that of the U2E gene. Converting the U2L gene proximal element into the early U2 gene proximal element by altering 14 nucleotides in the promoter also changed the temporal pattern of expression of the U2L gene. Factors that interact with the U2E PSE, detected by a gel mobility shift assay and DNaseI footprinting, were present in blastula but not late gastrula embryos. In contrast, interchanging the -100 element did not greatly affect the temporal pattern of expression, and factors that interact with the U2E gene -100 box were present in both late gastrula and blastula embryos. PMID- 7841785 TI - Structure and expression of a polyubiquitin gene from the crustacean Artemia. AB - We have characterized two polyubiquitin genes from the crustacean Artemia franciscana. One of them, Ubi1, has nine ubiquitin units and an intron of a minimum size of 3.5 kb that ends 7 bp before the initiator ATG. The 5' end of the transcript from this gene has been identified by anchored PCR. The existence of the other gene (Ubi2) was inferred from several cDNA clones that differ from Ubi1 in the C-terminal extension and in the 3' untranslated region as well as in the nucleotide sequence of the coding region. We find two transcripts of ubiquitin genes, of 2.7 and 3.3 kb. Hybridization of RNA blots with an oligonucleotide specific for Ubi2 gene demonstrates that this gene codes for the 3.3 kb transcript. Ubiquitin messenger RNAs are present in the dormant embryos and their steady-state levels are maximum at 8 h after resumption of development, declining thereafter. The Ubi2 gene transcripts are less abundant but its proportion in relation to the other transcript does not vary with development. PMID- 7841786 TI - Capping signals correspond to the 5' end in four eukaryotic small RNAs containing gamma-monomethylphosphate cap structure. AB - In eukaryotic cells, the gamma-monomethylphosphate cap structure has been identified in four small RNAs, namely, U6, 7SK, B2, and plant U3 RNAs. In this study, we show that in the case of 7SK and B2, as well as in plant U3 RNAs, the 5' stem-loop followed by a short single-stranded region serves as the capping signal. We previously showed that the nucleotides 1-25 of mouse U6 snRNA, also comprised of a stem-loop followed by a short single-stranded region, function as the capping signal. These data show that capping signals in all four RNAs have common features. The length of the stem-loop among these capped RNAs varied from 20 to 108 nucleotides, with no significant variation in the capping efficiency. In addition to the capping signal, we also observed a minimum RNA length requirement of about 15-25 nucleotides following the stem-loop for efficient capping in vitro. The capping signal in plant U3 snRNA corresponds to the additional 5' stem-loop found in U3 RNAs from plants and lower eukaryotes but absent in U3 RNA from higher animals. Consistent with this observation, the human U3 RNA that lacks the additional 5' stem-loop was not a suitable substrate for capping when compared to U6 snRNA. PMID- 7841787 TI - Pax-QNR/Pax-6, a paired- and homeobox-containing protein, recognizes Ets binding sites and can alter the transactivating properties of Ets transcription factors. AB - We have previously isolated a cDNA clone encoding a protein with a paired- and homeodomain from MC29-transformed quail neuroretina cells that we have termed Pax QNR. Pax-QNR is homologous to the murine Pax-6, which is mutated in the autosomal dominant mutation small eye (Sey) of the mouse and aniridia in man. The 46 kDa Pax-QNR protein binds specifically to the e5 DNA recognition sequence present upstream of the Drosophila even-skipped gene. The Pax-QNR paired and homeobox domains expressed separately in bacteria are both able to recognize this sequence. The core sequence recognized by the paired domain of Pax genes is TTCC (GGAA), and this sequence is also present in the core recognition site bound specifically by Ets family-encoded proteins. Ets proteins are a family of transcription factors sharing a highly conserved 85 amino acid DNA binding domain. In this article we demonstrate that Pax-QNR/Pax-6 expressed in reticulocyte lysate is able to specifically recognize several Ets binding sites. In addition, we found that the transactivation mediated by the p68c-ets-1 pr p55erg through the Polyomavirus enhancer sequence is specifically inhibited by the p46kDaPax-QNR in transient transfection assay. PMID- 7841788 TI - Transactivation of the peroxisome proliferator-activated receptor is differentially modulated by hepatocyte nuclear factor-4. AB - Peroxisome proliferator-activated receptors (PPARs) stimulate the expression of several genes involved in lipid metabolism by binding to specific cis-acting peroxisome proliferator-responsive elements (PPREs) via cooper-ativity with retinoid X receptors. We demonstrate here that hepatocyte nuclear factor-4 (HNF 4), another member of the nuclear hormone receptor superfamily, bound with differing affinities to the PPREs from the genes encoding rat acyl-CoA oxidase and hydratase-dehydrogenase, the first two enzymes of the peroxisomal beta oxidation pathway. In cotransfection assays, HNF-4 repressed rat PPAR-dependent activation of a reporter gene linked to the acyl-CoA oxidase PPRE, either in the absence or presence of the peroxisome proliferator, Wy-14,643. Rat PPAR-dependent activation of a reporter gene linked to the hydratase-dehydrogenase PPRE was less efficiently repressed by HNF-4 in the absence of Wy-14,643 than was activation from the acyl-CoA oxidase PPRE. However, in the presence of Wy-14,643, HNF-4 functioned cooperatively with PPAR to significantly enhanced induction from the hydratase-dehydrogenase PPRE. These results suggest that the genes encoding the first two enzymes of the peroxisomal beta-oxidation pathway are subject to differential regulation by the interplay of multiple members of the steroid/nuclear hormone receptor superfamily, mitigated in part by the structures of the PPREs and by the presence of activators of PPARs. PMID- 7841790 TI - Carbohydrates in cellular recognition: from leucine-zipper to sugar-zipper? PMID- 7841789 TI - Molecular cloning of a novel member of the nuclear receptor superfamily related to the orphan receptor, TR2. AB - We have cloned a novel member (mTR2R1) of the nuclear receptor superfamily of transcription factors from a mouse brain cDNA library. The cDNA sequence predicts a protein primary structure of 629 amino acids with a calculated molecular weight of 68.8 kDa. The amino acid sequence of the protein contains three regions of consensus sequence that are conserved throughout the nuclear receptor superfamily. One of these regions encodes a type II zinc finger DNA binding domain that is characteristic of this family of transcription factors. Comparison of the amino acid sequence of mTR2R1 with other nuclear receptors indicates that it is most closely related to the orphan receptor, hTR2, and suggests that these proteins constitute a novel subfamily within the nuclear receptor superfamily. mTR2R1 is encoded by two mRNAs that show different but overlapping spatial patterns of expression in the adult mouse. The identification of a subfamily of TR2 receptors together with the existence of variant mRNAs for these receptors prompts a close examination of the tissue-specific regulatory role of this subfamily of nuclear receptors. PMID- 7841791 TI - Mucin genes: structure, expression and regulation. PMID- 7841792 TI - Characterization of a single glycosylated asparagine site on a glycopeptide using solid-phase Edman degradation. AB - The characterization of site-specific glycosylation is traditionally dependent on the availability of suitable proteolytic cleavage sites between each glycosylated residue, so that peptides containing individual glycosylation sites are recovered. In the case of heavily glycosylated domains such as the O-glycosylated mucins, which have no available protease sites, this approach is not possible. Here we introduce a new method to gain site-specific compositional data on the oligosaccharides attached to a single amino acid. Using a model glycopeptide from a mutant human albumin Casebrook, glycosylated PTH-Asn was recovered after sequential solid-phase Edman degradation, subjected to acid hydrolysis and the sugars were identified by high performance anion exchange chromatography with pulsed amperometric detection. The PTH-Asn(Sac) derivative was further characterized by ionspray mass spectrometry. Comparison between an endoproteinase Glu-C glycopeptide and a tryptic glycopeptide showed that the oligosaccharide attached to Asn494 was stable after at least 10 cycles of Edman degradation. PMID- 7841793 TI - Analysis of glycosylphosphatidylinositol membrane anchors by electrospray ionization-mass spectrometry and collision induced dissociation. AB - The multi-component nature of glycosylphosphatidylinositol membrane anchors makes the analysis of their structure complex. Nuclear magnetic resonance spectroscopy of delipidated glycosylphosphatidylinositol-peptide fractions can supply considerable information but requires relatively large quantities of material. High-sensitivity sequencing techniques are available for the oligosaccharide portions of glycosylphosphatidylinositol anchors, but there is no simple and generally applicable technique to complement this information. In this paper we describe the application of electrospray ionization-mass spectrometry and collision induced dissociation to study intact glycosylphosphatidylinositol peptides from a Trypanosoma brucei variant surface glycoprotein. Collision of the [M + 4H]4+ pseudomolecular ions of two glycosylphosphatidylinositol-peptide glycoforms produced easily interpretable daughter ion spectra, from which detailed information on the lipid moiety, carbohydrate sequence and site of peptide attachment could be obtained. All of the collision induced dissociation cleavage events occurred in the glycosylphosphatidylinositol portion of the glycosylphosphatidylinositol-peptide. This technique supplies complementary data to the high-sensitivity oligosaccharide sequencing procedures and should greatly assist glycosylphosphatidylinositol anchor structure-function studies, particularly when sample quantities are limiting. PMID- 7841794 TI - Purification, characterization and reconstitution of CMP-N-acetylneuraminate hydroxylase from mouse liver. AB - CMP-N-acetylneuraminate hydroxylase was isolated from mouse liver high speed supernatant with a yield of 0.4% and an apparent 1000-fold purification. The enzyme is a monomeric protein with a molecular weight of 66 kDa, as determined by gel filtration and SDS-PAGE. The hydroxylase system was reconstituted with Triton X-100-solubilized mouse liver microsomes and purified soluble or microsomal forms of cytochrome b5 reductase and cytochrome b5. The systems were characterized in detail and kinetic parameters for each system were determined. PMID- 7841795 TI - Expression of recombinant rabbit UDP-GlcNAc: alpha 3-D-mannoside beta-1,2-N acetylglucosaminyltransferase I catalytic domain in Sf9 insect cells. AB - UDP-GlcNAc: alpha 3-D-mannoside beta-1,2-N-acetylglucosaminyltransferase I (GnT I; EC 2.4.1.101) catalyses a key reaction in the conversion of oligomannose to complex and hybrid N-glycans. The cytoplasmic tail and transmembrane segment of rabbit GnT I cDNA were replaced with an in-frame cleavable signal sequence and the hybrid construct was inserted into the genome of Autographa californica nuclear polyhedrosis virus (AcMNPV) under the control of the polyhedrin promoter. Sf9 insect cells were infected with the recombinant baculovirus and the enzymatically active and soluble catalytic domain of GnT I was purified from the medium (1-5 mg l-1) in two steps to a specific activity of about 2 mumol min-1 mg 1 protein. Recombinant GnT I has been used for the chemical-enzymatic synthesis of analogues of Man alpha 1-6]GlcNAc beta 1-2Man alpha 1-3]Man beta-O-octyl. PMID- 7841796 TI - Synthetic substrate analogues for UDP-GlcNAc: Man alpha 1-6R beta(1-2)-N acetylglucosaminyltransferase II. Substrate specificity and inhibitors for the enzyme. AB - UDP-GlcNAc:Man alpha 1-6R beta(1-2)-N-acetylglucosaminyltransferase II (GlcNAc-T II; EC 2.4.1.143) is a key enzyme in the synthesis of complex N-glycans. We have tested a series of synthetic analogues of the substrate Man"'alpha 1 6(GlcNAc"beta 1-2Man'alpha 1-3)Man beta-O-octyl as substrates and inhibitors for rat liver GlcNAc-T II. The enzyme attaches N-acetylglucosamine in beta 1-2 linkage to the 2"'-OH of the Man"'alpha 1-6 residue. The 2"'-deoxy analogue is a competitive inhibitor (Ki = 0.13 mM). The 2"'-O-methyl compound does not bind to the enzyme presumably due to steric hindrance. The 3"'-, 4"'- and 6"'-OH groups are not essential for binding or catalysis since the 3"'-, 4"'- and 6"'-deoxy and -O-methyl derivatives are all good substrates. Increasing the size of the substituent at the 3"'-position to pentyl and substituted pentyl groups causes competitive inhibition (Ki = 1.0-2.5 mM). We have taken advantage of this effect to synthesize two potentially irreversible GlcNAc-T II inhibitors containing a photolabile 3"'-O-(4,4-azo)pentyl group and a 3"'-O-(5-iodoacetamido)pentyl group respectively. The data indicate that none of the hydroxyls of the Man"'alpha 1-6 residue are essential for binding although the 2"'- and 3"'-OH face the catalytic site of the enzyme. The 4-OH group of the Man beta-O-octyl residue is not essential for binding or catalysis since the 4-deoxy derivative is a good substrate; the 4-O-methyl derivative does not bind.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7841797 TI - Bi-antennary oligo-(N-acetyllactosamino)glycans of I-type are galactosylated preferentially at the GlcNAc beta 1-6Gal linked arms by alpha 1,3 galactosyltransferase of bovine thymus. AB - alpha 1,3-Galactosylation of radiolabelled bi-antennary acceptors Gal beta 1 4GlcNAc beta 1-3(Gal beta 1-4GlcNAc beta 1-6)Gal-R (R = 1-OH, beta 1-4GlcNAc or beta 1-4Glc) with bovine thymus alpha 1,3-galactosyltransferase was studied. At all stages of the reactions the three acceptors reacted faster at the 1-->6 linked arm than at the 1-->3 linked branch. Hence, in addition to the doubly alpha 1,3-galactosylated products, practically pure Gal beta 1-4GlcNAc beta 1 3(Gal alpha 1-3Gal beta 1-4GlcNAc beta 1-6)Gal-R could be obtained from the three acceptors in reactions that had proceeded to near completion. The isomeric mono alpha 1,3-galactosylated products were identified by using exoglycosidases to remove the branches unprotected by alpha 1,3-galactoses and by subsequently identifying the resulting linear glycans chromatographically. PMID- 7841798 TI - Rapid detection of the alternative N-glycosylation pathway using high pH anion exchange chromatography. AB - An alternative N-glycosylation pathway using Glc1-3Man5GlcNAc2 as a donor to be transferred to a protein acceptor is found either in Man-P-Dol synthase deficient cells or in wild type CHO cells grown in energy deprivation conditions. Discrimination between oligomannosides of this alternative pathway and oligomannosides of the major one containing the same number of sugar residues Man6-8GlcNAc2 required structural studies. Taking advantage of the specific chromatographic behaviour of glucosylated oligomannosides, in pellicular high pH anion exchange chromatography, we developed a one-step method for the identification of the alternative N-glycosylation pathway compounds differing from those of the major one. PMID- 7841799 TI - Further studies on cell adhesion based on Le(x)-Le(x) interaction, with new approaches: embryoglycan aggregation of F9 teratocarcinoma cells, and adhesion of various tumour cells based on Le(x) expression. AB - We previously proposed specific interaction of Le(x) (Gal beta 1-->4 [Fuc alpha 1 ->3]-GlcNAc beta 1-->3Gal) with Le(x) as a basis of cell adhesion in pre implantation embryos and in aggregation of F9 teratocarcinoma cells, based on several lines of evidence (Eggens et al., J. Biol Chem (1989) 264:9476-9484). We now present additional evidence for this concept, based on autoaggregation studies of plastic beads coated with glycosphingolipids (GSLs) bearing Le(x) or other epitopes, and affinity chromatography on Le(x)-columns of multivalent lactofucopentaose III (Le(x) oligosaccharide) conjugated with lysyllysine. Comparative adhesion studies of Le(x)-expressing tumour cells vs their Le(x)-non expressing variants showed that only Le(x)-expressing cells adhere to Le(x) coated plates and are involved in tumour cell aggregation, in analogy to F9 cell aggregation. The major carrier of Le(x) determinant in F9 cells is not GSL but rather polylactosaminoglycan ('embryoglycan'), and we demonstrated autoaggregation of purified embryoglycan in the presence of Ca2+, and reversible dissociation in the absence of Ca2+ (addition of EDTA). Defucosylated embryoglycan did not show autoaggregation under the same conditions. Thus, Le(x) Le(x) interaction has been demonstrated on a lactosaminoglycan basis as well as a GSL basis. A molecular model of Le(x)-Le(x) interaction based on minimum energy conformation with involvement of Ca2+ is presented. PMID- 7841801 TI - Synthesis of lipooligosaccharide nodulation signals NodBj-V(RCO, MeFuc) and NodBj IV(RCO, MeFuc) of Bradyrhizobium japonicum. PMID- 7841800 TI - Analysis of glycosphingolipid-derived oligosaccharides by high pH anion exchange chromatography. AB - As an adjunct to existing thin layer and column chromatographic methods for the identification of glycolipids a method that utilizes the high pH anion chromatographic (HPAEC) analysis of the oligosaccharides released from the glycolipids by endoglycoceramidase has been developed. Using a Dionex Carbo Pak PA1 column and elution with a linear gradient of sodium acetate in 0.2 M NaOH, the elution times of eight neutral and fourteen acidic oligosaccharides derived from glycolipids were determined. Under these conditions the neutral oligosaccharides were well separated from each other but some of the acidic oligosaccharides had overlapping elution times. The ganglioside-derived oligosaccharides could be further identified by treating them with sialidase or by mild acid hydrolysis and reanalysing the products by HPAEC. The method was applied to the analysis of mixed bovine brain gangliosides. The procedure provides an additional approach for the initial identification of glycolipids by analysing the component oligosaccharides rather than the intact glycolipids. PMID- 7841802 TI - Coexpression of cancer-associated carbohydrate antigens, Tn and sialyl Tn. AB - The expression of cancer-associated antigens, Tn and sialyl Tn, was examined using monoclonal antibodies, MLS 128 and MLS 102, recognizing these two antigens, respectively. A cell lysate from a human carcinoma cell line, LS 180 cells, was analysed by Western blotting using these two antibodies. Three glycoprotein bands were discernible with each antibody, of which two, corresponding to 250 and 210 kDa, were reactive with both the antibodies. LS 180 cells were metabolically labelled with 3H-glucosamine and then the lysate from these cells was applied to two immunoaffinity columns. Sixty-five per cent of the Tn antigenic glycoproteins, based on radioactivity, bound to the MLS 102 affinity column. On the other hand, 45% of the sialyl Tn antigenic glycoproteins bound to the MLS 128 affinity column. These results indicate that some Tn and sialyl Tn antigens were expressed on the same polypeptide chains. The presence of non-sialylated GalNAc residues on the polypeptide chain with many Sia-GalNAc residues appears to be due to the incapability of three consecutive moieties of GalNAc-Ser/Thr to accept sialic acid. PMID- 7841804 TI - The frontal lobes and neuropsychiatric illness. PMID- 7841803 TI - Characterization of porcine kidney neutral glycosphingolipids: identification of a carbohydrate antigen recognized by human natural antibodies. AB - We have investigated the glycosphingolipids of pig kidney with a special interest in identifying compounds which may be involved in the rejection of tissue in xenotransplantation. Nine neutral glycosphingolipids have been characterized in porcine kidney and structurally characterized by a combination of techniques including 1H-NMR, permethylation analysis and thin-layer chromatography (TLC) immunostaining with carbohydrate sequence-specific monoclonal antibodies. The major components are members of the globo family and represent the human pk and P antigens. Three other compounds were found to contain a neolacto core structure; the major neolacto compound carries a nonreducing terminal epitope (Gal alpha 1 3Gal beta 1-4GlcNAc) recognized by the naturally-occurring human antibody, anti Gal, and a second neolacto compound carries the blood group A trisaccharide (GalNAc alpha 1-3(Fuc alpha 1-2)Gal). These results are discussed with respect to tissue transplantation. PMID- 7841805 TI - The significance of frontal system disorders for medical practice and health policy. AB - In major chronic diseases, apathy or impaired executive cognitive function (ECF) can reduce the patient's ability to cope with the disease and its treatment and to maintain personal safety, dignity, and goal-directed activity. Psychometric and imaging studies support a causal role for frontal system dysfunction. The view that frontal system dysfunction mediates or aggravates disability in a wide range of psychiatric and nonpsychiatric disorders 1) motivates further research on how ECF deficits interact with specific physical impairments to produce disability; 2) supports policies that base entitlements to care on ECF impairments; and 3) suggests the need for a vigorous search for drugs that prevent or palliate prefrontal dysfunction, especially the syndromes of apathy and impaired ECF. PMID- 7841806 TI - Working memory dysfunction in schizophrenia. AB - Recent advances in anatomical, behavioral, and physiological techniques have produced new information about the nature of prefrontal function, its cellular basis, and its anatomical underpinnings in nonhuman primates. These findings are changing our views of prefrontal function and providing insight into possible bases for human mental disorder. A major advance is the recognition that various prefrontal areas are engaged in holding information "on line" and updating past and current information on a moment-to-moment basis. Studies of animals and of cognitive function in normal, brain-injured, and schizophrenic subjects support the theory that a defect in working memory--the ability to guide behavior by representations--may be the fundamental impairment leading to schizophrenic thought disorder. PMID- 7841807 TI - Frontal-subcortical circuits and neuropsychiatric disorders. AB - Five parallel anatomic circuits link regions of the frontal cortex to the striatum, globus pallidus/substantia nigra, and thalamus. The circuits originate in the supplementary motor area, frontal eye fields, dorsolateral prefrontal region, lateral orbito-frontal area, and anterior cingulate cortex. Open loop structures that provide input to or receive output from specific circuits share functions, cytoarchitectural features, and phylogenetic histories with the relevant circuits. The circuits mediate motor and oculomotor function as well as executive functions, socially responsive behavior, and motivation. Neuropsychiatric disorders of frontal-subcortical circuits include impaired executive function, disinhibition, and apathy; indicative mood disorders include depression, mania, and lability. Transmitters, modulators, receptor subtypes, and second messengers within the circuits provide a chemoarchitecture that can inform pharmacotherapy. PMID- 7841808 TI - Lateralization of frontal lobe functions and cognitive novelty. AB - The two hemispheres are functionally different in ways not adequately captured by the classic distinction between linguistic and nonlinguistic processes. The right hemisphere is critical for processing novel cognitive situations. The left hemisphere is key to the processes mediated by well-routinized representations and strategies. The left frontal systems appear to be critical for the cognitive selection driven by the content of working memory and for context-dependent behavior, the right frontal systems for cognitive selection driven by the external environment and for context-independent behavior. The crucial role of the right hemisphere in processing cognitively novel situations underscores the importance of the right frontal systems in task orientation and in the assembly of novel cognitive strategies. PMID- 7841809 TI - The regional prefrontal syndromes: a theoretical and clinical overview. AB - This article provides a broad theoretical and clinical overview of the three regional prefrontal syndromes. An understanding of the extended neural connectivity of the prefrontal cortex provides the template for describing the three distinct prefrontal syndromes (dysexecutive, disinhibited, and apathetic types), each associated with dysfunction in one of the three prefrontal regions. This clinical approach should aid the clinician in determining the etiology of the specific regional prefrontal syndrome and developing effective treatment strategies. PMID- 7841810 TI - Diagnosis and treatment of patients with "frontal lobe" syndromes. AB - Nine case descriptions illustrate the three major prefrontal syndromes seen in clinical practice: disorganized type, disinhibited type, and apathetic type. A mixture of symptoms from each subtype is usually seen, but dysfunction in one prefrontal system often dominates. A careful history and examination are essential for accurate diagnosis. A complete history can rarely be elicited from the patient alone. Structural brain imaging, especially MRI, and neuropsychological testing are key to the diagnostic workup. EEG, video-EEG, and functional brain imaging can be valuable in the evaluation of possible partial complex seizures of frontal lobe origin and other atypical frontal lobe disorders. Effective treatment requires educating the patient and the family about the illness and modulating environmental factors that influence the patient's behavior. Judicious use of psychoactive medication may be helpful, but adverse effects are common. PMID- 7841811 TI - Assessment of frontal lobe functions. AB - The authors describe methods for conducting a thorough assessment of functions subserved by the frontal lobes, employing both bedside and psychometric methods of assessing frontal subsystems. Qualitative or process aspects of frontal behavior observable from formal testing, interview, and social behavior are noted. It is argued that the skilled clinician must be guided by a knowledge of frontal lobe subsystems and their roles in determining specific types of abnormal behavior. The clinician will then be alert to changes in incidental behaviors that indicate frontal impairment, and bedside maneuvers can be designed to discriminate dysfunction. Given the complexity of the behaviors involved and the profound effects of maturation and aging on frontal functions, neuropsychological assessment can provide an invaluable tool for testing these functions. PMID- 7841812 TI - Treatment strategies for patients with dysexecutive syndromes. AB - Patients with prefrontal behavioral syndromes (dysexecutive, disinhibited, and apathetic) present a significant therapeutic challenge that demands the integration of psychopharmacologic, behavioral, and systemic interventions. Unfortunately, the behavioral disturbances of such patients are frequently misinterpreted and therefore inadequately treated. This article describes the various strategies that are available to the clinician in treating patients with prefrontal deficits. PMID- 7841813 TI - The frontal lobes and schizophrenia. AB - Many patients with schizophrenia show clinical signs of frontal lobe dysfunction, including blunted affect, difficulty with problem solving, and impoverished thinking. The authors present cytoarchitectural, neuropsychological, and functional neuroanatomical evidence of frontal abnormalities from recent studies of frontal dysfunction in schizophrenia. It is suggested that the failure of intracortical connectivity of the prefrontal cortex accounts for both cognitive and psychotic manifestations of this illness. PMID- 7841814 TI - Frontal lobe dysfunction in secondary depression. AB - Depression is common in patients with neurological disease, particularly with diseases involving the basal ganglia. Although the mechanisms of mood disorders in these patients are poorly understood, selective neural pathways affected directly and indirectly by basal ganglia injury provide a strategy for examining these patients with functional imaging techniques. Studies of regional cerebral glucose metabolism by use of positron-emission tomography are reviewed. These studies demonstrate bilateral hypometabolism of orbital-inferior prefrontal cortex and anterior temporal cortex in depressed subjects, independent of disease etiology. This pattern is similar to that seen in patients with primary unipolar depression. These findings suggest that disruption of paralimbic pathways linking frontal cortex, temporal cortex, and striatum may contribute to both primary depression and depression associated with basal ganglia disease. The findings support the evolving concept of a neuroanatomical locus for mood regulation. PMID- 7841815 TI - The frontal lobes and traumatic brain injury. AB - The authors review 1) the pathophysiological, neuroimaging, and neurobehavioral evidence for frontal lobe involvement in closed head injury; 2) studies elucidating the cognitive deficits and behavioral disturbance related to frontal lobe lesions associated with head injury; and 3) pharmacologic treatment of the neuropsychiatric manifestations of frontal lobe injury, including emerging therapies. PMID- 7841816 TI - The frontal lobes and content-specific delusions. AB - Contemporary research has shown that delusions are often the product of identifiable neurologic disease, particularly when the delusions have a specific theme or are confined to one topic--monosymptomatic or content-specific delusions. Although these delusions are considered rare, some of them can be found at high rates in certain populations and settings. The literature on several classes of content-specific delusions (misidentification, sexual, and somatic) is critically reviewed. The review demonstrates that when adequate diagnostic workups are conducted, a high proportion of such delusions are found to have a neurologic basis. Lesions of the frontal lobes and the right hemisphere are shown to be critical to the development and persistence of many content specific delusions. PMID- 7841817 TI - Neurosurgical treatment for refractory obsessive-compulsive disorder: implications for understanding frontal lobe function. AB - A minority of patients with obsessive-compulsive disorder (OCD) have a chronic course and extreme disability, with symptoms refractory to pharmacological and psychological treatment. Considerable uncontrolled evidence suggests such cases may respond to neurosurgical intervention. The authors update current stereotactic procedures and their efficacy, safety, and side effect profiles. The design of an ongoing placebo-controlled trial of Gamma Knife capsulotomy for refractory OCD is outlined. Drug treatment of OCD may be assumed to affect a proposed functional imbalance between the frontal lobes and other parts of the brain. As for neurosurgical treatments, both the effects and side effects may be viewed as expressions of their influence on this functional imbalance. PMID- 7841818 TI - Ethics of research in Native communities. PMID- 7841819 TI - Competition benefits both doctors and patients. PMID- 7841820 TI - Quality of care is paramount. PMID- 7841821 TI - Chronic whiplash syndrome. Psychosocial epidemic. PMID- 7841822 TI - Radiology rounds. Leiomyoma. PMID- 7841823 TI - Dermacase. Benign eccrine tumour (hidrocystoma). PMID- 7841824 TI - Traditional Native healing. Alternative or adjunct to modern medicine? AB - OBJECTIVE: To ascertain the extent to which family physicians in British Columbia agree with First Nations patients' using traditional Native medicines. DESIGN: Randomized cross-sectional survey. SETTING: Family medicine practices in British Columbia. PARTICIPANTS: A randomized volunteer sample of 79 physicians from the registry of the BC Chapter of the College of Family Physicians of Canada. Of 125 physicians contacted, 46 did not reply. MAIN OUTCOME MEASURES: Physicians' demographic variables and attitudes toward patients' use of traditional Native medicines. RESULTS: Respondents generally accepted the use of traditional Native medicines for health maintenance, palliative care, and the treatment of benign illness. More disagreement was found with its use for serious illnesses, both for outpatients and in hospital, and especially in intensive care. Many physicians had difficulty forming a definition of traditional Native medicine, and were unable to give an opinion on its health risks or benefits. A significant positive correlation appeared between agreement with the use of traditional Native medicines and physicians' current practice serving a large First Nations population, as well as with physicians' knowing more than five patients using traditional medicine. CONCLUSIONS: Cooperation between traditional Native and modern health care systems requires greater awareness of different healing strategies, governmental support, and research to determine views of Native patients and healers. PMID- 7841825 TI - Native Canadians relocating for renal dialysis. Psychosocial and cultural issues. AB - OBJECTIVE: To examine the effects of relocation from remote Native communities for dialysis treatment and explore the receptiveness of patients, caregivers, and their communities to establishing a local satellite dialysis unit. Second, to examine the methodological issues inherent in a qualitative, cross-cultural study. DESIGN: Qualitative descriptive survey using semistructured interviews. SETTING: The Moose Factory Zone (MFZ), situated along the west coast of James Bay in northern Ontario, is one of four geographically defined areas of responsibility within Ontario through which the federal government provides health care services to Native Canadians. PARTICIPANTS: Twenty-four Native residents of MFZ selected by volunteer and nominative sampling techniques. Patients with end-stage or prefailure renal disease, informal caregivers and supporters, professional caregivers, and community spokespersons were included in the study population. MAIN OUTCOME MEASURES: Identification of issues important in planning dialysis services for Native patients in remote communities in the MFZ. RESULTS: Informal caregivers and both categories of patients supported in principle a proposed satellite dialysis unit at Moose Factory General Hospital. Their criticisms of the present system necessitating relocation to urban centres included inadequate social support, inconvenience and expense, and family separation. Professional caregivers generally supported establishing a local dialysis unit but had concerns regarding staff training and continuity of care. Community spokespersons also supported the proposed unit but only if quality of care could be ensured. CONCLUSIONS: Relocation for dialysis treatment disrupts social support patterns and creates psychosocial problems. Although the psychosocial advantages of providing dialysis treatment services close to home are readily apparent, other considerations, such as cost, equipment, and expertise, and training of health care personnel, make the provision of tertiary level care more difficult in isolated areas. Additional study is required to determine the impact of methodological issues inherent in qualitative cross cultural studies such as this. PMID- 7841826 TI - Otitis media. How are First Nations children affected? AB - To determine whether otitis media affects First Nations children more severely than other children, I studied the data on otitis media occurrence among these children; on risk factors, particularly bottle feeding; and on prevention and treatment. First Nations children do seem to have more severe otitis media than other children. Health promotion might help ameliorate the situation. Supporting breastfeeding in the community is strongly recommended. PMID- 7841828 TI - Sinusitis. Diagnostic methods. AB - Sinusitis, which primarily involves the anterior ethmoid air cells, can spread to the larger sinus cavities to cause acute and chronic secondary infection. Endoscopic and computed tomographic techniques enable earlier diagnosis and treatment of sinusitis and permanent cure. Primary care physicians should try to identify the disease before it reaches a stage where endoscopic control becomes difficult. Ultrasonography is now used in Europe to diagnose sinusitis and initiate treatment. PMID- 7841827 TI - Results of the DCCT trial. Implications for managing our patients with diabetes. AB - Results of the Diabetes Control and Complications Trial (DDCT) suggest that intensive therapy can prevent or delay the microvascular complications of diabetes. This article critically appraises evidence from the DCCT and other prospective trials and concludes that the successful results for persons with insulin-dependent diabetes cannot be generalized to most family practice diabetes patients, who have non-insulin-dependent diabetes. PMID- 7841829 TI - Rapid differentiation of Streptococcus milleri from other beta-haemolytic group A, C, and G streptococci by simple screening tests. AB - Eighty five beta-haemolytic Lancefield group A(23), C(22), and G(40) streptococci were tested for sulphonamide sensitivity, ability to degrade beta-D glucuronide (groups C and G) and bacitracin sensitivity (group A). Identification of isolates was initially confirmed by the API 20 STREP system. Zones of beta-haemolysis were too variable for correct Streptococcus milleri identification in 10% of cases. However, only group C and G S. milleri were both sulphonamide-resistant and beta D glucuronide-negative. Two group A S. milleri strains could have been mis identified as Streptococcus pyogenes if combined sulphonamide and bacitracin resistance had not been noted. In a busy diagnostic laboratory, screening of beta haemolytic group A, C, and G streptococci for sulphonamide sensitivity is recommended. Sulphonamide-resistant group A S. pyogenes can be distinguished from S. milleri by bacitracin sensitivity. S. milleri can be rapidly and cheaply differentiated from other sulphonamide-resistant group C and G streptococci by a simple 4 h commercial beta-D glucuronide assay. PMID- 7841830 TI - Foreign body reactions and an associated histological artefact due to bone wax. AB - Bone wax has been used since the turn of the century as a mechanical aid to haemostasis following surgical procedures. That it may produce a foreign body giant cell reaction in a significant proportion of cases is well known. The occurrence of this material in specimens received in the laboratory is poorly documented. Four cases are described to bring attention to this exogenous agent which, it is suggested, should feature in tables of pigments and other materials occurring in tissue specimens. PMID- 7841831 TI - Serum 1,5-anhydro-D-glucitol assay by high performance anion exchange chromatography. AB - Serum 1,5-anhydroglucitol (AG) concentrations may be an indicator of glycaemic control in diabetic patients. We have therefore developed an HPLC method for assay of serum AG. Serum samples were de-proteinised with trichloroacetic acid and neutralised with the addition of an anion exchange resin. Erythritol was added to serum as an internal standard. For HPLC, CarboPac MA1 ion exchange columns were used, eluting with 80 mmol/l sodium hydroxide solution. Peak detection was by pulsed amperometry using a gold electrode. The serum AG concentration in 37 non-insulin-dependent diabetic patients was significantly lower than in 28 normal subjects: mean and range 19(4-163) vs. 134(92-203) mumol/l, P < 0.001. PMID- 7841832 TI - Hypophosphataemia and hypokalaemia in patients with hypomagnesaemia. AB - Experimental data suggest an association between hypomagnesaemia and hypokalaemia, and also with hypophosphataemia, but there have been few large studies using clinical results to study the prevalence of hypophosphataemia and/or hypokalaemia in patients with hypomagnesaemia. Our results show a two-fold increase in the prevalence of hypophosphataemia (plasma phosphate concentration < or = 0.80 mmol/l) in patients with hypomagnesaemia (plasma magnesium level < or = 0.70 mmol/l) compared with patients without this condition, and a six-fold increase in hypokalaemia (plasma potassium < or = 3.5 mmol/l). A triology consisting of hypomagnesaemia, hypophosphataemia and hypokalaemia is also described, which was found in 8% of patients with hypomagnesaemia and 17% of patients with severe hypomagnesaemia (plasma magnesium < or = 0.50 mmol/l). Patients most susceptible to this phenomenon include those in intensive therapy, post-operative patients, those with sepsis being treated with aminoglycosides, and oncology patients receiving chemotherapy. PMID- 7841833 TI - Verruciform xanthoma: an immunocytochemical study. AB - Verruciform xanthoma is a rare lesion that occurs predominantly on the oral mucosae, but also on other mucosal sites and on the skin. We report an immunocytochemical analysis of the xanthoma cells in three cases of verruciform xanthoma (two vulval and one scrotal), and also attempt to identify human papilloma virus (HPV) as a possible trigger for the production of these lesions. We employed a panel of seven histiocytic markers (CD68 [KP1], KiM1P, HAM 56, lysozyme, vimentin, peanut agglutinin and factor X111a) and two others to identify HPV involvement (CAMVIR-1 and bovine papilloma virus-1 [BPV-1]). Results showed the xanthoma cells to be positive for CD68, KiM1P, HAM 56 and vimentin, with less consistent labelling for peanut agglutinin and lysozyme. CAMVIR-1 and BPV-1 were negative in all three cases. These findings support the view that the xanthoma cells are derived from a monocyte macrophage lineage and fail to demonstrate HPV as the cause. PMID- 7841834 TI - Monocyte isolation by flow cytometer-monitored centrifugal elutriation: a preparative tool for antibody-dependent cell-mediated cytotoxicity (ADCC) assays. AB - The value of isolating monocytes by flow cytometer-monitored centrifugal elutriation (CE) after initial density gradient centrifugation (DGC) was investigated. A pooled cell suspension prepared by DGC+CE had a monocyte purity of 90% while a pool prepared by DGC alone had a monocyte purity of only 30%. Monocyte suspensions prepared from 15 separate blood donations demonstrated that, despite wide variation in initial monocyte purity following DGC (i.e. 13-32%), CE consistently increased the purity to 85-92%. Antibody-dependent cell-mediated cytotoxicity (ADCC) studies showed that the most sensitive and reproducible assays were those performed with the DGC+CE pool. At a monocyte concentration of 2 x 10(6)/ml the DGC+CE pool was almost twice as active as the DGC pool (60.2% lysis vs 31.2% lysis, respectively). Considerable variation in ADCC activity was seen when using monocytes from individual donors. We conclude that centrifugal elutriation is a valuable tool for preparing effector cells for use in monocyte driven ADCC assays. PMID- 7841835 TI - Immunocytochemistry in the diagnosis of malignant melanoma. AB - The role of immunocytochemistry in the routine diagnosis of malignant melanoma is reviewed, with particular emphasis on the potential technical and pathological interpretive problems that may occur. Careful evaluation of the appropriate panel of markers is discussed, along with details of cross-reactivity of markers with tumours of non-melanocytic derivation. Future developments in immunocytochemistry within the field of proliferation indices assessments are highlighted. PMID- 7841836 TI - Identification of Salmonella spp. with Rambach agar in conjunction with the 4 methylumbelliferyl caprylate (MUCAP) fluorescence test. AB - The utility of Rambach agar to identify Salmonella spp. was examined relative to its usefulness in clinical microbiology. Forty-four of 54 (82%) salmonella organisms isolated from faecal cultures and 66 of 82 (84%) salmonella stock cultures produced bright red colour colonies after 24 h incubation at 37 degrees C, whereas 48 of 54 (89%) salmonellae isolated from faecal cultures, and 74 of 82 (90%) salmonella stock cultures, yielded the bright red colour when the incubation time was extended to 48 h. Apart from Salmonella typhi and Salmonella paratyphi A the sensitivity of Rambach agar to detect salmonella strains belonging to five serogroups was 83% and 92% after 24 and 48 h of incubation, respectively. In contrast, other members of the family Enterobacteriaceae tested failed to give the bright red colour, except for one strain of Pseudomonas aeruginosa and another of Acinetobacter baumannii. The non-salmonella strains either gave a different colour--blue, green or orange--or were colourless. To supplement the use of Rambach agar in the detection of Salm. typhi and Salm. paratyphi A and other late or negative acid-producing salmonella species on this medium, the 4-methylumbelliferyl caprylate fluorescence (MUCAP) test was carried out, and this showed positive results with all the salmonella strains tested. These results suggest that while Rambach agar can not pre-identify Salm. typhi and Salm. paratyphi A, the use of a simple and rapid (MUCAP) test in combination would make it very useful to identify all Salmonella spp. after 24 h incubation. PMID- 7841837 TI - The pathogenesis of Campylobacter jejuni. AB - Studies on the pathogenesis of Campylobacter jejuni show that for this organism to cause disease the susceptibility of the host and the relative virulence of the infecting strain are both important. Infection with C. jejuni results from the ingestion of contaminated food or water, and the infective dose can be as low as 800 organisms. To initiate infection the organism must penetrate the gastrointestinal mucus, which it does by using its high motility and spiral shape. The bacteria must then adhere to the gut enterocytes and once adhered can then induce diarrhoea by toxin release. C. jejuni releases several different toxins which vary from strain to strain, mainly enterotoxin and cytotoxins, and these correlate with the severity of the enteritis. During infection, levels of all immunoglobulin classes rise. Of these, IgA is the most important as it can cross the gut wall. IgA immobilises organisms, causing them to aggregate and activate complement, and also gives short-term immunity against the infecting strain of organism. The other immunoglobulin classes act on bacteria entering the blood stream, thus preventing bacteraemia. C. jejuni can also stimulate the cellular immune system, but this seems to play only a small role in preventing infection. PMID- 7841838 TI - The laboratory investigation of infective keratitis. AB - Microbial keratitis is an infectious inflammation of the cornea which, if not rapidly diagnosed, may lead to loss of vision. The investigative procedures are demanding for the ophthalmologist and confirmative diagnosis a formidable challenge to the microbiologist. Most, if not all, bacteria can cause keratitis. To establish a diagnosis culture is essential, since it is not possible clinically to distinguish between one type of infective keratitis and another. A relatively new and worrying problem is acanthamoebic keratitis, which is significantly associated with contact lens wear. It is increasing in incidence as lens wear becomes more popular. Although Acanthamoebae are easily isolated, many laboratories are not familiar with laboratory methods for diagnosis. PMID- 7841839 TI - Molecular haematology. Proceedings of the 8th East Anglia Haematology Review. Cambridge, 13 March 1993. PMID- 7841840 TI - Viral, mycoplasmal and chlamydial lower respiratory tract infections in Hong Kong: cost and diagnostic value of serology. AB - A hospital virology laboratory in Hong Kong tested 10,852 sera by complement fixation (CF) for antibodies against agents of respiratory disease between 1 July 1986 and 31 December 1991. Ten commercially supplied antigens were used: influenza virus types A and B, parainfluenza virus types 1, 2 and 3, adenovirus, respiratory syncytial virus (RSV), Mycoplasma pneumoniae, Chlamydia species and Coxiella burnetii. Single sera comprised 69% of the total, including sera from 7488 patients investigated for LRTI with paired acute and convalescent samples. A total of 167 pairs (21.6%) showed rising CF titres, 82 of them against M. pneumoniae. Of the 809 patients, 365 were children under 11 years of age: 115 (31.5%) showed rising titres, including 51 with antibodies against M. pneumoniae, 21 against RSV, 17 against adenovirus and 10 against parainfluenza type 3. Viral antigen detection by immunofluorescence and virus isolation were also used: these methods yielded more positive findings than did CF test serology for the corresponding agents. The cost of the tests performed is discussed in relation to their contribution to the aetiological diagnosis of LRTI, and changes in the service to be offered are outlined. PMID- 7841841 TI - Comparing drugs of dependence. PMID- 7841842 TI - Comparing drugs of dependence. PMID- 7841843 TI - Alcohol consumption, alcohol abuse and alcohol dependence. The United States as an example. AB - This paper presents national estimates of alcohol consumption and DSM-IV alcohol abuse and dependence in the United States. Fifty-two percent of the adults surveyed were classified as current drinkers and nearly 9.0% met criteria for DSM IV alcohol abuse or dependence. Greater percentages of males and whites were classified as current drinkers and as alcohol abusers or dependent, compared with females and non-whites, respectively. There is a need for future epidemiological research to collect better data on drinking patterns as an aid to interpreting socio-demographic differentials and to estimate more precisely the association between alcohol consumption and abuse and dependence in multivariate statistical environments. The critical need to examine the unprecedented reversal of the abuse-to-dependence ratio resulting from the application of the DSM-IV classification is emphasized. The role of future longitudinal alcohol epidemiological research in elucidating the initiation and maintenance of consumption patterns and alcohol use disorders is stressed. PMID- 7841844 TI - Long-term benzodiazepine users--a mixed bag. AB - In this article it is argued that long-term benzodiazepine (BZD) users can be classified into four broad groups, namely medical, daytime, night-time and polydrug users. Although the groups are not exhaustive or mutually exclusive, such a classification may go some way to clarify our understanding of the complex psychological and sociological phenomena involved in long-term consumption of BZDs. PMID- 7841845 TI - A profile of tobacco smoking. AB - Cigarette smoking has for years been declining slowly in a number of major Western countries. It nevertheless remains highly prevalent, with one-quarter to one-third of adults being current smokers in the USA and Britain, and only some 40 per cent of those who have ever smoked cigarettes regularly have given up. Smoking is increasingly becoming a marker for deprivation and for a stressful life-style, and is also associated with consumption of other drugs. There is abundant and convincing evidence that, far from being confined to a minority of problem users, high levels of dependence on tobacco are experienced by a majority of smokers in the general population, with an onset early in the smoking career. The rewards which underpin continued smoking are unclear, but it may be that avoidance of the unpleasantness of not smoking is more significant than positively rewarding effects. PMID- 7841846 TI - Opiates: prevalence and demographic factors. AB - This paper focuses on the prevalence and profile of opiate use, primarily heroin, in the United States and Europe. Methods include representative population surveys, which understate prevalence, and targeted approaches, which reflect more problematic use. In the United States and Europe, the lifetime prevalence of opiate use reported in surveys remained stable over the 1980s (around 1%), though young adults report higher rates. Estimates for the early 1990s suggest that the prevalence of problematic heroin use in the United States was double the average for western Europe. However, in a few European countries prevalence is now approaching that of the United States. Rates in major cities are considerably higher, especially in the north-east and south-west of the United States. Higher prevalence is often, although not always, associated with socio-economic deprivation. An important trend away from injecting is observed, notably in some European countries. Heroin availability and use, as well as serious heroin related consequences, are increasing again in many European countries after an apparent pause in the mid-1980s. They are also increasing in parts of the United States. Heroin remains a public health priority, especially among vulnerable populations, including young people in central and eastern Europe. PMID- 7841847 TI - Prevalence and demographic factors of stimulant use. AB - The use of stimulants for recreation purposes has increased considerably during the 20th century. Cocaine was first considered to be a drug of potential abuse during the First World War but was only perceived as a serious threat when it became widely used in socially and economically deprived urban areas of the USA in the 1980s. Use of amphetamines was common among certain occupational groups as a means of remaining alert until the 1950s, when they were seen to be abused by a small minority of recreational users. Controls were then introduced in most developed countries. The public health issue of stimulant use is that of finding a balance between the prevention of serious social or personal harm caused by abuse of these drugs while not impeding their beneficial use. PMID- 7841848 TI - Overview: demography, epidemiology and psychopharmacology--making sense of the connections. AB - This overview discusses the five papers covering demographic and prevalence issues in terms of the commonalities and differences across psychoactive substances, particularly as they pertain to the relationship between demographic factors and the prevalence of substance abuse. This overview also concerns itself with gaps in knowledge, methodological issues and future directions for research. It begins with some basic definitions and fundamental questions. A brief review of the salient points of each paper is then provided, followed by a more synthetic discussion of methodological and theoretical issues. It closes with some speculative ideas about the meaning of demographic variables for an understanding of substance abuse. PMID- 7841849 TI - Current concepts of ethanol dependence. AB - Alcohol dependence is considered to be divisible into two types (although the divisions between these are indistinct). These are psychological dependence, in which the rewarding effects of alcohol play a primary role, and chemical dependence, in which adaptive changes in the brain initiate punishing effects on withdrawal of alcohol, and suppression of these becomes the primary motive for using the drug. The neurochemical basis for the rewarding effects of alcohol may be the potentiation of GABA at GABAA receptors (causing relaxation) and release of dopamine from mesolimbic neurones (causing euphoria). The adaptive changes which cause the alcohol withdrawal syndrome are not known for certain, but alterations in GABAA receptors, NMDA receptors and voltage-operated calcium channels all have a claim. However, it is distinctly doubtful whether these all contribute to the negatively reinforcing effects of alcohol that are important in chemical dependence, although they may be important in other pathological effects of alcohol abuse. Current research badly needs better communication between basic scientists and clinicians to establish research goals and to improve current models. PMID- 7841850 TI - Biological processes in benzodiazepine dependence. AB - The indications for the benzodiazepines include anxiety, insomnia, muscle spasm and epilepsy and each disorder has a variety of biological substrates. Limbic structures and the neurotransmitters noradrenaline, 5-HT and GABA have all been implicated. Benzodiazepines act on allosteric receptor sites and potentiate the actions of GABA in modulating chloride ionophores across nerve membranes. These effects can be blocked by the benzodiazepine antagonist, flumazenil. The molecular pharmacology of the benzodiazepine-GABA-chloride receptor is complex, with a wide range of different subunits. Animal models of dependence have suggested that the changes associated with long-term benzodiazepine use are related more to receptor-effector coupling than to the receptor characteristics themselves. Thus, benzodiazepine agonists on long-term use lose their efficacy, antagonists become partial inverse antagonists, and inverse agonists increase in efficacy. Various clinical implications are explored, including the use of flumazenil to prevent and to treat benzodiazepine withdrawal syndromes. PMID- 7841851 TI - Neural mechanisms underlying nicotine dependence. AB - There is little doubt that many habitual smokers find it difficult to quit the habit because they have become addicted to the nicotine present in the smoke. This paper addresses some of the pharmacological mechanisms underlying this addiction and discusses how an understanding of these mechanisms may contribute to the more effective use of nicotine replacement therapy during smoking cessation. It considers critically the evidence that the "rewarding" properties of nicotine, which serve to reinforce drug-seeking behaviour, are related to stimulation of the mesolimbic dopamine system of the brain. The critique focuses specifically on the evidence that many central nicotinic receptors, including those which mediate the effects of the drug on dopamine secretion, are readily desensitized by chronic exposure to agonist and that hypotheses which assume that nicotine inhaled from tobacco smoke invariably results in stimulation of the receptors must be treated with caution. Nicotinic receptors in the brain are, however, heterogeneous in nature with different molecular structures and pharmacologies. It is concluded that the reinforcing properties of nicotine sought by smokers may reflect both stimulation and desensitization of the different nicotinic receptor populations, and that smokers may adjust their smoking habits to achieve the balance of receptor stimulation and desensitization which they find most reinforcing. It seems likely that the efficacy of the different nicotine formulations during the treatment of smoking cessation may also reflect their ability to stimulate or desensitize brain nicotinic receptors. PMID- 7841852 TI - Opiate reinforcement processes: re-assembling multiple mechanisms. AB - Opiate reinforcement processes can be described within the context of operant conditioning theory. Both positive and negative reinforcing effects may motivate drug-taking behavior, although the strongest evidence attributes drug-taking to a simple positive reinforcement process. Empirical research has focused largely on a positive reinforcement mechanism involving the ventral tegmental dopamine system, but three additional reinforcement mechanisms can be argued on logical grounds. These other mechanisms involve neuroadaptive changes produced by chronic opiate administration and may contribute to the strong motivational impact of opiates following long-term drug use. PMID- 7841853 TI - Biological effects of central nervous system stimulants. AB - In both animals and man, stimulants such as the amphetamines and cocaine are reinforcing and thus motivate repeated drug-taking behaviour and leading to abuse. Although this class of drugs seems to act by different biological mechanisms in the central nervous system, it has been suggested that their action to increase dopaminergic neurotransmission is crucial to the reinforcing properties of these compounds. However, increasing evidence suggests that a number of other neurotransmitters/neuroregulators, possibly in conjunction with dopamine, are part of the complex neurochemical systems which underlies various aspects of stimulant abuse behaviours. Examples of possible influences of noradrenaline and corticosterone will be discussed. PMID- 7841854 TI - Overview: biological processes relevant to drugs of dependence. AB - Key points are highlighted from five papers that address biological processes underlying the actions of opiates, CNS stimulants, nicotine, alcohol, and benzodiazepines. It is noteworthy that: (1) positive and negative reinforcement are common processes underlying actions of drugs of dependence; (2) dopaminergic systems in the ventral tegmental area of the brain seem to be involved in the positive reinforcement of drugs of dependence; (3) GABA also may be involved in this positive reinforcement; (4) receptor sensitization and desensitization may be involved in the actions of drugs of dependence; (5) noradrenalin, 5-HT, ACh, NMDA and corticosteroids also may be involved in drug dependence; (6) motivational systems and processes in addition to positive and negative reinforcement deserve increased research attention; and (7) there may be genetic based individual differences in drug dependence processes. PMID- 7841855 TI - Alcohol withdrawal: an adaptation to heavy drinking of no practical significance? AB - Markedly differing views can be found among both clinicians and researchers regarding whether alcohol withdrawal is a phenomenon of any practical or theoretical importance. Evidence has mounted that alcohol withdrawal, even in a severe form, is rarely life-threatening and the great majority of cases can be managed in non-medical settings, including the home. There is also a widely held view among clinicians that withdrawal symptoms have little motivational significance and may be best regarded as but epiphenomena of prolonged heavy drinking. There are also experimental data from both human and animal laboratory studies to the effect that withdrawal symptoms do not readily trigger further alcohol consumption. Against this most unpromising background a case is presented for alcohol withdrawal being but one manifestation of important biological and psychological adaptive processes which occur almost whenever alcohol is consumed with any regularity. It is proposed that understanding this more general phenomenon is critical to a better understanding of the factors which maintain heavy and problematic drinking. Recent evidence also suggests that minor alcohol withdrawal symptoms are far more common in the general population than had previously been realized, and that this has important implications for prevention policy. PMID- 7841856 TI - The benzodiazepine withdrawal syndrome. AB - Physiological dependence on benzodiazepines is accompanied by a withdrawal syndrome which is typically characterized by sleep disturbance, irritability, increased tension and anxiety, panic attacks, hand tremor, sweating, difficulty in concentration, dry wretching and nausea, some weight loss, palpitations, headache, muscular pain and stiffness and a host of perceptual changes. Instances are also reported within the high-dosage category of more serious developments such as seizures and psychotic reactions. Withdrawal from normal dosage benzodiazepine treatment can result in a number of symptomatic patterns. The most common is a short-lived "rebound" anxiety and insomnia, coming on within 1-4 days of discontinuation, depending on the half-life of the particular drug. The second pattern is the full-blown withdrawal syndrome, usually lasting 10-14 days; finally, a third pattern may represent the return of anxiety symptoms which then persist until some form of treatment is instituted. Physiological dependence on benzodiazepines can occur following prolonged treatment with therapeutic doses, but it is not clear what proportion of patients are likely to experience a withdrawal syndrome. It is also unknown to what extent the risk of physiological dependence is dependent upon a minimum duration of exposure or dosage of these drugs. Withdrawal phenomena appear to be more severe following withdrawal from high doses or short-acting benzodiazepines. Dependence on alcohol or other sedatives may increase the risk of benzodiazepine dependence, but it has proved difficult to demonstrate unequivocally differences in the relative abuse potential of individual benzodiazepines. PMID- 7841857 TI - Nicotine withdrawal versus other drug withdrawal syndromes: similarities and dissimilarities. AB - Many of the symptoms of nicotine withdrawal are similar to those of other drug withdrawal syndromes: anxiety, awakening during sleep, depression, difficulty concentrating, impatience, irritability/anger and restlessness. Slowing of the heart rate and weight gain are distinguishing features of tobacco withdrawal. Although nicotine withdrawal may not produce medical consequences, it lasts for several weeks and can be severe in some smokers. Like most other drug withdrawals, nicotine withdrawal is time-limited, occurs in non-humans, is influenced by instructions/expectancy and abates with replacement therapy and gradual reduction. Unlike some other drug withdrawal syndromes, protracted, neonatal or precipitated withdrawal does not occur. Whether nicotine withdrawal is associated with tolerance, acute physical dependence, greater duration and intensity of use, rapid reinstatement, symptom stages, cross-dependence with other nicotine ligands, reduction by non-pharmacological interventions and genetic influences is unclear. Whether nicotine withdrawal plays a major role in relapse to smoking has not been established but this is also true for other drug withdrawal syndromes. PMID- 7841858 TI - Opiate withdrawal. AB - Opiate withdrawal is one of the longest studied and most well described withdrawal syndromes. Opiate withdrawal has been described as akin to a moderate to severe flu-like illness. Opiate withdrawal is appropriately described as subjectively severe but objectively mild. This paper describes the mechanisms of opiate dependence and opiate withdrawal and reviews the available instruments for the measurement of withdrawal. The time course of assisted and unassisted withdrawal is described and the range of options for the management of assisted withdrawal are described. This review concludes that the most effective and least time- and resource-consuming approach to opiate withdrawal will substantially contribute to the overall social management of opiate dependence. PMID- 7841859 TI - Stimulant withdrawal. AB - The current paper is a review of the literature on abstinence symptomatology after stimulant use. The studies performed indicate biological and physical changes during abstinence. One outpatient study suggests a phasic model of stimulant abstinence which is characterized by a 'crash', 'withdrawal', and 'extinction' phase. However, two inpatient studies do not confirm these findings. In contrast, these latter two studies did not find a crash phase and reported a gradual improvement of mood during these 21-day and 28-day inpatient stays. Biological measures suggest changes in receptor, endocrinological and neurochemical activity. One study found hyperprolactinemia throughout the 4-week period, while another study using PET and FDG ([18F]-Fluorodeoxyglucose) found increased brain glucose metabolism in the dopamine-rich areas of the basal ganglia and orbitofrontal cortex. Another study using PET and F18 Methylspiroperidol found decreased dopamine D2 receptor binding during cocaine withdrawal and also a separate study using PET and F-18-Dopa discovered low dopaminergic brain activity. To date, few studies have been performed, and the lack of clear-cut physical withdrawal symptoms as seen in alcohol, sedative, and opiate withdrawal makes it difficult to demonstrate definitively the presence of withdrawal during stimulant abstinence. Amphetamine withdrawal has been less studied, but empirical data suggest that the symptoms are similar to cocaine withdrawal. Further studies are needed to better delineate the presence of acute versus chronic post-use symptoms. PMID- 7841860 TI - Overview: a comparison of withdrawal symptoms from different drug classes. AB - Whereas early formulations of addictive behaviour placed great emphasis upon withdrawal as a defining feature, current views focus more upon compulsive use as its central characteristic. However, the withdrawal syndrome continues to occupy an important place in the study of the addictions. It is interesting both in its own right and in relation to the development and maintenance of the compulsive use of drugs. Despite the attention devoted to withdrawal phenomena over many years, precise demarcation of the withdrawal symptoms associated with drugs of dependence has proved difficult to achieve. Withdrawal from all drugs of dependence appears to lead to mood disturbances although the extent to which these are due to the pharmacological actions of the drugs or to other physiological or psychological processes is unclear. Sleep disturbance is also common, although again direct links with the pharmacological actions of the withdrawn drug are yet to be established. Withdrawal from alcohol, benzodiazepines and opiates is often associated with somatic symptoms. In the former two cases, these can involve sweating, tremor and occasionally seizures. Perceptual disturbances have also been reported. In the case of opiates, flu-like symptoms are often reported, including muscle aches and gastric disturbances. In the case of nicotine, heightened irritability has been established as a direct pharmacological withdrawal effect. Characterization of stimulant withdrawal is still uncertain. There is little evidence of somatic symptoms but depression may occur as a result of a physiological rebound. There is also uncertainty over what role pharmacological withdrawal symptoms play in maintaining compulsive use.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7841861 TI - Preventive strategies for alcohol-related problems. AB - Preventive strategies for alcohol-related problems need to be in keeping with their socio-political context. Prohibition is inappropriate except where it has widespread support within the culture. Preventive strategies focus on the population and/or high risk groups and behaviours. Primary prevention can be achieved by control policies, education and provision of alternatives. Fiscal measures are of proven value. Legislative approaches influence availability and context of drinking, such as drinking and driving. Advertising control, server training and server liability are further approaches. Encouraging the provision of alternative beverages and promoting alcohol-free environments is a further approach which should be seen as part of an integrated community response. Secondary prevention linked with early recognition of hazardous drinking at primary level is of known efficacy and would form part of a coordinated strategy. PMID- 7841862 TI - Promoting benzodiazepine withdrawal. AB - This paper presents a review of health promotion strategies to help people to stop using benzodiazepines. Four strategies are described and evaluated: health persuasion, personal counselling, state action and community development. It is argued that the first two strategies have been the most popular to date, especially among doctors, and have an important part to play in changing individual behavior. Less consideration has been given to the other two strategies, but these are equally important if a comprehensive policy is to be developed concerned with social as well as individual change. PMID- 7841863 TI - The prevention of tobacco-related disease. AB - The key components of a strategy to prevent tobacco-related disease are outlined. These measures aim to increase the cessation of tobacco use and reduce its uptake. Components are wide-ranging, including a taxation policy, a ban on advertising and promotion, a comprehensive health promotion programme including advice from primary health care professionals and the development of campaigning skills, particularly by the medical profession. The prevention of tobacco-related disease has moved into the domain of campaigners and lobbyists at political, economic and international levels. The key target is countering the activities, especially the unethical trade practices, of the wealthy and powerful tobacco industry. PMID- 7841864 TI - Opiates: are there under-utilized and unexplored areas of prevention? AB - This paper explores the varied and potentially conflicting goals of preventive measures as applied to opiate use. These goals relate both to the overall extent of opiate use and the amount of harm arising from this drug use. Prevention involves the control both of the supply side and the demand for opiates. Particular targets may include sharing equipment, injecting, progression to more harmful routes of administration, prevention of development of dependence, harmful sequelae of opiate use and co-morbidity. There may be a place for manipulating the black market for opiates to channel users in directions that achieve particular prevention goals, and being more selective about targeting particular groups of users at particular times. It is the role of scientists to quantify the dimensions of harm and the likely impact on these dimensions of particular interventions. It is then up to elected representatives to determine the priorities. PMID- 7841865 TI - The prevention of stimulant misuse. AB - The term 'stimulant' refers to a class of drugs that increase psychophysiological arousal. From the viewpoint of prevention, it is more useful to look primarily at the social consequences and functions of stimulants. Every society has a documented use of stimulants. When planning interventions the dynamics of use must be placed in the foreground. Stimulant epidemics, like problematic stimulant users, have a natural tendency to burn themselves out. Different types of stimulants may differ in their origins, but their epidemiological consequences and use functions tend to be similar. Implications for prevention can be drawn from the characteristics of stimulant use epidemics. Users at risk for socially unacceptable patterns should be targeted for prevention efforts. Mass media campaigns that single out stimulants should be avoided. Much of the harm associated with stimulants is a consequence of life-styles characterized by polydrug use and unhealthy practices. Prevention should be timed to the appropriate period of the epidemic. Interventions useful at period 1 will not work at period 2. The recommendations of the WHO Advisory Group on the Adverse Effects of Cocaine and Coca provide a good model for primary, secondary and tertiary prevention for all forms of stimulant misuse. Stimulant prevention must be creative in finding ways of encouraging the movements of the drug to the periphery of users' lives. PMID- 7841866 TI - Overview: public health, health promotion and addictive substances. AB - All of the dependence-producing substances are capable of causing harm but in most cases the harm is preventable. This paper seeks to develop some of the themes raised by the five substance-based prevention papers by presenting an outline of the Ottawa Charter for Health Promotion. The Ottawa Charter provides a strategic framework for prevention and covers public health policy, trade issues, availability, price, advertising and types of supportive environments and responses. It is suggested that an effective approach to the prevention of harm from dependence-producing substances would involve a planned response which included alcohol, tobacco and drugs. Such a response would also emphasize financial and economic consequences of drug use, and would seek to strengthen or develop links with partners outside the immediate health care arena. PMID- 7841867 TI - Treatment of alcohol problems. AB - This paper gives an overview of the variety of approaches that have been used in the treatment of alcohol problems. There is good evidence that approaches directed at improving social and marital relationships, self-control and stress management are effective. There is at present little to suggest that aversion therapies, confrontational interventions, educational lectures or films and group psychodynamic therapy are effective, nor is there good evidence yet that use of psychotropic medications is effective. However, it may be that therapies that have not proved effective with the broad range of individuals with alcohol problems might prove effective with selected cases. Future research should place more emphasis on determining the kinds of alcohol problems that are likely to respond to different kinds of treatments directed at different kinds of goals and by different kinds of practitioners. The base of treatment should be broadened to include the large numbers of individuals with alcohol problems but who could not be considered as alcohol-dependent. This would have to involve a wide range of primary care and generic workers and include use of brief interventions. PMID- 7841868 TI - The treatment of benzodiazepine dependence. AB - Withdrawal of benzodiazepines is currently advised for long-term benzodiazepine users because of doubts about continued efficacy, risks of adverse effects, including dependence and neuropsychological impairment and socio-economic costs. About half a million people in the UK may need advice on withdrawal. Successful withdrawal strategies should combine gradual dosage reduction and psychological support. The benzodiazepine dosage should be tapered at an individually titrated rate which should usually be under the patient's control. The whole process may take weeks or months. Withdrawal from diazepam is convenient because of available dosage strengths, but can be carried out directly from other benzodiazepine. Adjuvant medication may occasionally be required (antidepressants, propranolol) but no drugs have been proved to be of general utility in alleviating withdrawal related symptoms. Psychological support should be available both during dosage reduction and for some months after cessation of drug use. Such support should include the provision of information about benzodiazepines, general encouragement, and measures to reduce anxiety and promote the learning of non pharmacological ways of coping with stress. For many patients the degree of support required is minimal; a minority may need counselling or formal psychological therapy. Unwilling patients should not be forced to withdraw. With these methods, success rates of withdrawal are high and are unaffected by duration of usage, dosage or type of benzodiazepine, rate of withdrawal, symptom severity, psychiatric history or personality disorder. Longer-term outcome is less clear; a considerable proportion of patients may temporarily take benzodiazepines again and some need other psychotropic medication. However, the outcome may be improved by careful pharmacological and psychological handling of withdrawal and post-withdrawal phases. PMID- 7841869 TI - Treatments for smokers. AB - Research in treatments for smokers benefits from the feasibility of relatively large samples and well developed evaluative methodology. The field is currently dominated by nicotine replacement methods, for which some degree of efficacy has been clearly demonstrated. A number of psychological methods are widely used as well, although there is little consistent evidence that one specific method is better than any other. Two approaches to treating smokers can be distinguished, i.e. intensive clinic-based treatments and brief community-orientated interventions, e.g. in primary health care. The latter are applicable on a large scale, and aim to affect overall smoking prevalence. Among intensive treatments, the current state of the art would include nicotine replacement and group support of several weeks' duration. In primary health care, simple routine interventions are the preferred option. PMID- 7841870 TI - Opiate treatments. AB - One of the greatest of challenges facing medicine is to devise effective and appropriate treatments for opiate problems. Such treatments are based on principles derived from the disciplines of pharmacology and psychology, but are also shaped by social issues and even by the views of practitioners. There are many misconceptions about opiate problems. In this review it is suggested that there are good reasons for stating that opiate users do change over time, treatment can also lead to change and psychological interventions are of great importance. However, current methods of opiate detoxification are of low efficacy and methadone maintenance, although of benefit for some, is not a panacea for opiate problems. PMID- 7841871 TI - The treatment of stimulant dependence. AB - Rehabilitation efforts offered to individuals with stimulant dependence incorporate a series of maneuvers to accomplish three major goals. Following active detoxification, most clinicians attempt to: (1) increase motivation for abstinence and maintain a high level of commitment to this goal; (2) help individuals to rebuild a stable life-style without substances; and (3) actively work toward ways of decreasing the probability of relapse (relapse prevention). While these activities incorporate education, counseling, outreach to families and exposure to self-help groups (e.g. Cocaine Anonymous), numerous pharmacological approaches have been tested. Each mode of drug therapy is based on a reasonable hypothesis, but appropriately controlled and structured clinical trials have not yet revealed any pharmacological approach for rehabilitation of stimulant-dependent individuals for which the risks have been shown to outweight the assets. PMID- 7841872 TI - Overview: the treatment of drug dependence. AB - Addictive disorders resemble other chronic medical disorders in that they are characterized by relapses and remissions. This central feature of the addictions is addressed by many of the contributors in their individual chapters. There are also several specific points raised in the chapters which merit further discussion. For instance, any assumption that long-term anti-anxiety treatment with benzodiazepines implies a form of dependence that requires treatment could be set against an alternative view that there may be appropriate medical/psychiatric indications for such prolonged treatment. There are also interesting questions which deserve discussion surrounding the debate over treatment setting for opiate dependence treatments. The paper by Johns presents a case for inpatient treatment whereas in the United States long-term methadone maintenance is seen as one of the most effective treatments. Given the complexity of the bio-psycho-social mechanisms involved in addiction, a combination of therapeutic approaches tailored to individual needs should probably continue to be the guiding principle. PMID- 7841873 TI - Mishandling misconduct: the breast cancer trials scandal. PMID- 7841874 TI - Tuberculosis and adrenal function. PMID- 7841875 TI - Collateral arteries in the presence of obstructive coronary disease. AB - BACKGROUND: The clinical importance of coronary collaterals in the presence of obstructive coronary artery disease is not clearly defined. METHODS: We retrospectively analysed the clinical and angiographic features of 100 patients with > or = 90% luminal diameter stenosis involving at least one major coronary artery. Coronary collaterals were graded 0 to 4 (Nitzberg's classification) and studied to determine their influence on clinical parameters. RESULTS: Thirty patients had no collaterals (group I) and 70 showed collaterals (group II). There were no significant differences between groups I and II in age and sex distribution, prevalence of risk factors of coronary artery disease (hypertension, diabetes, smoking, hypercholesterolaemia), duration of symptoms of coronary artery disease and prior myocardial infarction. Groups I and II had similar types (left anterior descending 73% v. 71%; left circumflex 50% v. 50% and right coronary 37% v. 56%) and numbers of arteries involved (one 47% v. 41%; two 47% v. 40%; three 7% v. 19%). Group II had a significantly lower prevalence of rest angina (14% v. 47%, p = 0.002). This difference was also evident when the patients were re-classified according to the extent of flow through the collaterals. Those with good collateralization (Nitzberg grades 3 and 4) had a lower prevalence of rest angina (13%) compared to those with poor collateralization (Nitzberg grades 0 to 2; 35%, p = 0.02). CONCLUSION: Coronary artery collaterals may reduce the incidence of rest angina in patients with obstructive coronary artery disease. PMID- 7841876 TI - Humoral immune response to mutans streptococci associated with dental caries. AB - BACKGROUND: Mutans streptococci are important aetiological agents in dental caries and their prolonged contact with oral tissues evokes a variety of immune responses through local secretory and systemic antibodies. Patterns of such humoral responses in Indian children have not been reported and we undertook the present study to examine these. METHODS: One hundred and twenty-six children with dental caries and 55 matched controls were studied and saliva and sera collected from them. The tests on these specimens included total salivary and systemic immunoglobulins of different classes using radial immunodiffusion and Streptococcus mutans specific IgA, IgG and IgM using specifically standardized enzyme immunoassays. RESULTS: Children with caries had higher levels of IgG (1350 +/- 9.9 mg/dl; controls 1110 +/- 6.7 mg/dl) and IgA (260 +/- 1.8 mg/dl; controls 190 +/- 1 mg/dl) in the serum but their saliva had lower levels of total IgG (160 +/- 0.7 mg/dl; controls 340 +/- 2.9 mg/dl) and IgA (130 +/- 0.5 mg/dl; controls 410 +/- 3 mg/dl). IgM levels in caries children and controls were not significantly different. Higher levels of Streptococcus mutans specific IgA were detected in the saliva of 95 out of 126 (75%) children with caries compared to 13 out of 55 (22%) controls. Specific serum IgG and IgA levels were also increased in 105 and 114 children with caries, although the levels were not as high as those in saliva. Total and specific salivary and serum IgM antibodies were similar in children with caries and control subjects. CONCLUSION: The nature of the humoral immune response in Indian children with dental caries suggests that Streptococcus mutans specific salivary and serum antibodies may play a major role in pathogenesis. Our findings may have importance when devising methods for follow up and prognosis as well as for vaccination strategies. PMID- 7841877 TI - Clinical features of HIV infection in drug users of Manipur. AB - BACKGROUND: The human immunodeficiency virus was first detected in young intravenous drug users in Manipur in 1989 and it quickly reached a high prevalence in this group. Diagnostic facilities are scarce and it is thus important to suspect the presence of the infection by its clinical features. METHODS: We did a cross-sectional survey for 13 months among residents of different detoxification centres of Imphal, Manipur, to study the sensitivity, specificity and positive predictive values of different signs and symptoms occurring at the early phase of the infection. RESULTS: Most of the young injectors in this survey were found to be in the early phases (stage I 43%; stage II 32%; stage III 15% and stage IV 9.9%) of the World Health Organization clinical staging of human immunodeficiency virus infection and disease. Herpes zoster, oral candidiasis, pruritic papular eruptions, jaundice and lymphadenopathy had positive predictive values of 100%, 100%, 93%, 93% and 88% respectively. Cryptosporidial diarrhoea and tuberculosis (pulmonary and extrapulmonary) were also encountered. CONCLUSION: Intravenous drug users in Manipur who have human immunodeficiency virus infection suffer from different opportunistic infections which give rise to clinical features that are easily recognizable. It is important to be aware of these in areas which lack diagnostic facilities for confirming the infection. PMID- 7841878 TI - Dietary lipids and heart disease--the Indian context. PMID- 7841879 TI - Low birth weight and prevalence of diabetes. PMID- 7841880 TI - NSAIDs and bleeding ulcers. PMID- 7841881 TI - Rational approach to the treatment of malaria. PMID- 7841882 TI - AIDS, public health and the panic reaction (Part II). PMID- 7841883 TI - Community involvement in mental health care. PMID- 7841884 TI - Reproductive health care services. PMID- 7841885 TI - Alternatives to tetracycline chemoprophylaxis against pneumonic plague. PMID- 7841886 TI - Medical maladies. PMID- 7841887 TI - Hepatitis B virus immunization in renal disease. PMID- 7841888 TI - Children presenting with tinnitus: a retrospective study. AB - A multicentre retrospective survey of 67 children, who had attended an audiology clinic complaining of tinnitus, was carried out by questionnaire and by the study of the children's medical notes. Forty-two patient questionnaires were returned. Age of onset of tinnitus varied between infancy and 16 years. Tinnitus was more problematic in the children reported here than in those in previous studies. There was a close relationship of tinnitus to other associated symptoms, family history, personal past history and hearing loss. At the time of the study, 17% of children reported that their tinnitus had resolved. PMID- 7841889 TI - Should we routinely screen for Lyme disease in patients with asymmetrical hearing loss? AB - Asymmetrical sensorineural hearing loss is usually investigated thoroughly but a diagnosis is often elusive. It is important to identify any treatable causes. Lyme disease is a tick-borne infection caused by the spirochaete Borrelia burgdorferi, which has been shown to cause asymmetrical sensorineural hearing loss, and has been successfully treated. Its incidence varies regionally; it occurs where there is a suitable environment for the tick and its animal hosts. We conducted a prospective study of 100 patients with asymmetrical sensorineural hearing loss. Serological testing for Lyme disease was performed. One patient had positive serology, but there was no improvement in her hearing following antibiotic treatment. We cannot conclude that our patient's hearing loss was caused by Lyme disease. We suggest that routine screening is not cost effective in regions with a low incidence of Lyme disease. PMID- 7841890 TI - The causes of profound hearing impairment in a school for the deaf--a longitudinal study. AB - The study was aimed towards an evaluation of the causes of hearing loss in children attending the School for the 'Deaf' in Copenhagen in 1993-4 in comparison to causes evaluated 10 and 40 years previously (Arnvig, 1953; Holten and Parving, 1985). The 124 children attending the school in 1993 represent 0.04% of the age-matched target population of 312,715. A more detailed evaluation of two comparable cohorts born in 1969-77 and 1979-87 demonstrates a significant increase of children attending this type of school from 0.03% to 0.05% within a 10-year period, while a comparison between 1953 and 1993 demonstrates a reduction from 0.07% to 0.04%. The longitudinal evaluation of the causes of hearing loss showed a significant increase in the frequency of congenital inherited hearing impairment from 29% (1953) through 33% (1983) to 43% (1993), whereas a significant reduction of about 17% in the frequency of acquired deafness due to chronic otitis media was found. Between 1953 and 1993 a minor reduction (2%) in post-meningitic acquired hearing impairment was found, between 1953 and 1983 there was a significant increase in prenatal infections, compared with a decrease of 6% between 1983 and 1993. It is concluded that significant changes are found both in the prevalence of children referred to the school and in the factors causing severe to profound hearing impairment in children. Continuous recording of, and improvement in, diagnostic classification is necessary to obtain preventive measures. PMID- 7841891 TI - Group rehabilitation of middle-aged males with noise-induced hearing loss and their spouses: evaluation of short- and long-term effects. AB - This study aims at evaluating the short- and long-term effects of a group rehabilitation programme, designed for males with noise-induced hearing loss and their spouses. The rehabilitation programme, including four 3 h group sessions per week, intended to offer adequate information, psychosocial support and training in effective coping strategies. Fifty-three males were consecutively selected and randomly divided into an experimental and a control group. Twenty seven males were invited to participate in the group sessions together with their spouses. Although an informed consent to participate was given by the males initially, 15 couples (55.6%) refused to participate, and 12 couples agreed to participate in the group sessions. The short-term effects of the programme showed that the couples felt supported by meeting other couples in the same position. Further, the spouses' awareness of the effects of the hearing impairment was increased, which facilitated the understanding of problems related to their husbands' hearing disability. A reduction in perceived handicap, measured by the handicap sections of the Hearing Measurement Scale (P = 0.017) and by the disability/handicap factor of the Hearing Handicap and Support scale (P = 0.054), was found immediately after the rehabilitation programme in the participants compared to the controls. Four months later, no significant difference in any of the variables measured was found. Interestingly, both from a short-term and a long-term perspective, the drop-outs from the experimental group (n = 15) scored significantly higher on perceived handicap (P = 0.034 and P = 0.031, respectively) compared to the participants in the group rehabilitation programme. PMID- 7841892 TI - Use of the open-ended questionnaire with patients and their significant others. AB - One hundred and twenty-one hearing impaired people and their accompanying adult significant other answered an open-ended questionnaire. It asked them to list the difficulties they had as a result of hearing loss. As expected, the most common difficulties which patients report are those dealing with understanding speech, yet these complaints comprise only 58.5% of all the specific responses made by patients. These speech-related difficulties fell into only two of the eight categories of complaints. This would clearly indicate that there are more subtle difficulties occurring that need to be addressed and which would be missed by more standard disability/handicap questionnaires largely based on speech disability. The number of specific difficulties related to loudness of TV and radio and to the psychosocial aspects of hearing loss (such as withdrawal and unsociable behaviours) was reported by greater numbers of significant others than patients. The patient, however, was significantly more apt to list a non-specific problem related to the radio and TV. Specific medical problems were reported by a greater number of patients than significant others. PMID- 7841893 TI - Some factors influencing choice of type of hearing aid in the UK: behind-the-ear or in-the-ear. AB - Questioning potential users of National Health Service behind-the-ear (BTE) hearing aids indicated that for some the perception of stigma associated with visible aids is a powerful deterrent to acceptance and use. To investigate further the role of stigma in hearing aid acceptance, 184 individuals who had been fitted with NHS BTE hearing aids and who had also purchased in-the-ear (ITE) hearing aids through a discounted price scheme at Withington Hospital were asked why they had made the decision to purchase, and what they perceived as the benefits of the ITE aid relative to the BTE model. The primary factor both in terms of reason for purchase and perceived benefit was the greater cosmetic acceptability of the smaller aids. Comfort in wear was the second perceived benefit. Sound quality was ranked only third. Ease of use with spectacles was the second most common reason given for purchase. These studies suggest that in a small but significant percentage of hearing aid candidates the perception of stigma is a powerful deterrent to take-up and use. This perception needs to be recognized and addressed if the most effective service is to be provided to the hearing impaired. PMID- 7841894 TI - A comparison of neonatal evoked otoacoustic emissions obtained using two types of apparatus. AB - The transient evoked otoacoustic emission (TEOAE), generated by a click and recorded in the ear canal is influenced by many factors. Of these, the form of the stimulus, the characteristics of the microphone, amplifiers and filter are probably the major ones. In addition, the acoustical loading of the ear canal by the probe may interact with the TEOAE measurement. Data presented here were obtained from 64 babies tested on each of 3 days post partum. The differences in the TEOAEs produced by the ILO88 and POEMS instruments can be quite marked. The ILO88 TEOAEs consistently have larger high frequency components than do the emissions from the POEMS system. The ILO88 system also gives higher correlations between repeat recordings. Such differences point out the need for explicit standards in probe design. PMID- 7841895 TI - Reliability and predictive value of the electrically evoked auditory brainstem response. AB - The reliability and predictive value of the low-pulse-rate electrical auditory brainstem response (EABR) threshold and the high-pulse-rate psychophysical threshold used in electrode mapping of adult cochlear implant patients was assessed. Eight patients, all implanted with the Nucleus multi-channel cochlear implant and experienced users, participated in this study. The relationship between like pulse rates of the EABR and psychophysical thresholds was assessed and showed high correlations of 0.90 or higher. When the relationship between low pulse-rate EABRs and high-pulse-rate psychophysical thresholds was assessed the correlation was much poorer. The best correlation of 0.75 was shown between a 30 Hz EABR and the 500-Hz psychophysical threshold. This suggests that the low-pulse rate EABR threshold is a poor predictor of the high-pulse-rate psychophysical threshold used in electrode mapping. Hence, if the EABR is to be a clinical tool for setting the electrodes it should be used cautiously and with the proper correction formula applied. PMID- 7841896 TI - The usefulness of nimodipine, an L-calcium channel antagonist, in the treatment of tinnitus. AB - Thirty-one patients were drawn from a tinnitus clinic, screened for other medical problems and treated for 4 weeks with 30 mg nimodipine four times daily. Before and after treatment, the intensity of their tinnitus was assessed subjectively on a scale 1-10. Five patients reported to have a great improvement in their tinnitus whilst two claimed a worsening of the condition. Of the five positive responders, four were treated further with 30 mg nimodipine per day for 4 weeks and 60 mg per day for a further 4 weeks. During this treatment they were assessed more objectively by the determination of the minimal masking level using narrow band noise. There was a good correlation between the subjective and objective assessment of their responses. PMID- 7841897 TI - An experimental evaluation of the effects of transcutaneous nerve stimulation (TNS) and applied relaxation (AR) on hearing ability, tinnitus and dizziness in patients with Meniere's disease. AB - In 20 patients diagnosed with Meniere's disease, transcutaneous nerve stimulation (TNS) and applied relaxation (AR) were used as a treatment aimed at reducing tinnitus and dizziness and increasing hearing ability. The main aim of the study was to examine whether TNS could be regarded as a more beneficial treatment regimen than AR. An experimental between-group cross-over design was used. The results from the experimental phase (group comparisons) showed a significantly increased ability to hear for the TNS group when measured on visual analogue scales. During the same period, the AR-group showed a significant hearing improvement for the ear not primarily affected by Meniere's disease as measured with pure tone audiometry. The vestibular tests did not reveal any significant changes either after TNS or AR intervention. Tinnitus matching showed changes of pitch and loudness before and after both TNS and AR intervention. However, no statistically significant changes between treatment regimes were found on these measures. The results from this study did not show TNS to be superior to AR in reducing tinnitus, dizziness or increasing hearing ability. PMID- 7841898 TI - An audit of hearing aid quality in Denmark. II: Type of defects. AB - In this investigation the type of defects in hearing aids (HAs) is described, and the stability of HAs is evaluated, based on prospective longitudinal data over an observation period of 2 years. An exchange of information between the Danish national hearing health service and hearing aid manufacturers, representing the private sector, demonstrates that overall external components to which the HA user has access, are frequently defective. However, with time, internal components, to which the HA-user has no access, are frequently defective within the first year of use, whereas external components malfunction significantly more frequently after 3 years of use. Among the dispensed hearing aids, 11% were defective at the fitting, indicating insufficient quality control by the manufacturers. A prospective longitudinal investigation of 1141 defective HAs revealed that 12% of behind-the-ear HAs become defective within the first year of use, exhibiting the greatest stability. After 2 years of use, all in-the-canal HAs are defective, while only 33% of the in-the-ear HAs remain intact. It is concluded that the established exchange of information between the public and private sectors offers valid information on the quality of HAs; that the quality and stability of HAs is insufficient; and that the quality should be improved, (based on international criteria). PMID- 7841899 TI - Comparison of earphone radiation recorded from hearing impaired subjects and a resistor network simulator. AB - Electromagnetic radiation emitted by earphones is a potential source of contamination of auditory evoked potentials, particularly when long-duration stimuli are used to evoke the response. One practical solution to this problem would be to estimate the magnitude and characteristics of this earphone radiation so that an appropriate choice of earphone is made. With this aim, earphone radiation measures obtained from a resistor network simulator laid out over the dimensions of an average head were compared with those obtained from three hearing impaired subjects to determine the efficacy of the simulator in estimating the magnitude of this radiation. Results indicated a close agreement between these measures suggesting that the simulator measures are realistic. It was shown that the earphone radiation (i) increases linearly with stimulus intensity; (ii) varies systematically as a function of recording configuration; and (iii) recorded in the simulator can be used to subtract out earphone radiation contaminating evoked responses recorded from subjects using unshielded earphones. Based on these results it was concluded that the simulator provides a practical means to simulate real recordings, at least for the purposes of estimating stimulus artifact that may contaminate auditory evoked potentials to sustained stimuli. PMID- 7841900 TI - Comparison of measures of frequency resolution and recruitment in patients undergoing neuro-otological investigation. AB - Loudness recruitment and reduced frequency resolution both occur in cochlear types of hearing loss. One theory of loudness recruitment suggests that, as intensity is coded partly by spread of excitation across the nerve fibre array, recruitment is a direct consequence of the broad spread of excitation associated with poor frequency resolution. The present study investigated the relationship between these two quantities. The study involved a simple measure of frequency resolution (three-point psychoacoustical tuning curve, PTC) and conventional measures of recruitment obtained from patients undergoing neuro-otological investigation. Results from 376 ears of 226 patients without any material conductive impairment are presented. Measures of recruitment included the alternate binaural loudness balance test (ABLB) and estimates of dynamic range given by the sensation levels of the uncomfortable loudness level and the acoustic reflex threshold. Once covariation with hearing threshold level had been accounted for, no clear relationship emerged between frequency resolution and any of the measures of recruitment. This finding does not support the notion that frequency resolution and recruitment are specifically related. Rather, PTCs provide information complementary to measures of recruitment. PMID- 7841901 TI - Clinical evaluation and test-retest reliability of the IHR-McCormick Automated Toy Discrimination Test. AB - The IHR-McCormick Automated Toy Discrimination Test (ATT) measures the minimum sound level at which a child can identify words presented in quiet in the sound field. This 'word-discrimination threshold' provides a direct measure of the ease with which a child can identify speech and a surrogate measure of auditory sensitivity. This paper describes steps taken to maximize the test-retest reliability of the ATT and to enable it to measure word-discrimination thresholds in noise as well as in quiet. It then describes the results of a clinical evaluation of the ATT in which paediatric audiologists measured word discrimination thresholds in quiet from 215 successive attendees (in the age range 2 to 13 years) at a paediatric audiology clinic presenting over a 2-month period. When children with atypical cognition or delayed development of language were excluded, 72% of the children provided two word-discrimination thresholds and 83% provided at least one word-discrimination threshold. Children who failed to provide word-discrimination thresholds were generally younger than four years of age. Although a few children who could not perform pure-tone or warble-tone audiometry managed to provide word-discrimination thresholds, most children who could perform the ATT could also perform pure-tone audiometry. The average pure tone threshold in the better-hearing ear could be predicted from the word discrimination threshold with a 95% confidence interval of +/- 13 dB. The test retest reliability of the ATT was measured in two ways. First, to enable comparison with published results, the within-subjects standard deviation of word discrimination thresholds was calculated. It varied as a function of age and degree of impairment, but was never worse than 3.3 dB. Children of four years of age and older displayed the adult reliability of 2.3 dB. Second, the variability of absolute differences between word-discrimination thresholds was calculated. It was such that a change of 7 dB between two runs of the test (e.g. aided and unaided) would be expected to occur by change less than one time in 20. These results extend previous evaluations of the ATT to a clinically representative population and confirm that word-discrimination thresholds provide a useful complement to warble-tone and pure-tone audiometry. PMID- 7841903 TI - Interlibrary loan in U.S. health sciences libraries: journal article use. AB - Health sciences libraries in the United States use the National Library of Medicine (NLM) DOCLINE system to request more than two million items annually through interlibrary loan (ILL). Ninety-seven percent of all ILL requests are for journal articles. In this study, NLM analyzed four million ILL requests entered into the DOCLINE system during two twelve-month periods ending September 30, 1992. The requests were analyzed at both the journal title level and article level. Data for the two years were found to be remarkably similar. Results showed that a large number of journals are required to fill ILL requests and that there is a relatively low number of repeat requests for most journal articles. Seventy six percent of journal articles analyzed were requested only once, and fewer than 1% were requested more than ten times. About 39% of journals used to fill ILL requests were indexed in MEDLINE at some time, while 84% of the articles supplied were indexed in MEDLINE. Ninety-two percent of articles supplied were from English-language journals. Sixty-seven percent of articles were published in the most recent five years, and 85% in the most recent ten years. The 100 most frequently requested articles for each of the two years were examined to determine characteristics such as language, where they were indexed, and the subject matter. This study has provided valuable information for planning of NLM's interlibrary document delivery services and also should have significance for libraries and other organizations involved in document delivery. PMID- 7841902 TI - Document needs in a rural GRATEFUL MED outreach project. AB - An analysis of documents provided to eight rural Illinois hospital sites during a GRATEFUL MED outreach project involving end-user searching revealed significant patterns that have implications for collection development and information services in small, underserved hospitals. Document requests were analyzed by user groups making the requests, subject matter, inclusion on the Brandon/Hill lists and in Abridged Index Medicus, and publication date. Of the 359 documents requested, 86% came from health professional groups other than physicians and nurses. Eighty-five percent of all requests came from two sites that had active project-trained intermediaries, with most requests forwarded by the intermediaries. Subject analysis revealed a strong need for administrative and allied health information in addition to clinical information. Fewer than half of the titles on the recommended lists were requested during the project. Most documents requested had been published in the past five years. Introduction of end-user searching is not the complete answer to improved information access at small hospitals; the authors conclude that basic collections and library personnel are still needed locally to respond effectively to health professionals' information needs. PMID- 7841904 TI - Reorganization: premises, processes, and pitfalls. AB - As the technological environment changes and libraries assume new and more active roles in their institutions, the traditional library hierarchy ceases to be an effective organizational structure. Guided by theories that emphasize teamwork, quality, and employee empowerment and participation, libraries are developing flatter, more networked organizations. The Health Sciences Library at Columbia University in New York, New York, recently underwent a reorganization in an effort to become a more resilient, more flexible organization. The process was beneficial overall. While some errors and confusion occurred, these are seen as opportunities for learning and evidence of the library's new atmosphere of creativity and experimentation. PMID- 7841905 TI - Database search services as a basic service in academic health sciences libraries. AB - Mediated search services, usually offered for a fee, are commonplace in academic health sciences libraries. At the same time, users of these services have numerous self-service options available to them; for example, CD-ROMs and locally mounted databases. In keeping with its philosophy of access to rather than ownership of information, the University of Washington Health Sciences Library and Information Center (HSLIC) changed its policy from charging clients for mediated searching to offering mediated searches as an essential service of the library. By taking this step, HSLIC moved closer to becoming a true "library without walls." This paper describes HSLIC's experience with changing its policy and examines the issues surrounding use of the collection budget to subsidize access to online information in academic health sciences libraries. PMID- 7841906 TI - Biomedical resources on Usenet. AB - Usenet offers efficient access to health sciences information resources. The software for reading and searching Usenet includes filters that can eliminate irrelevant messages, sorts related items by topic, and allows users to reply to either the group or an individual. Usenet has more than 2,000 news groups on topics from back rubs to radiological imaging, and it provides information in various ways, including discussion groups and software distribution. PMID- 7841907 TI - Use of a multi-application computer workstation in a clinical setting. AB - The goal of this study was to assess the usage frequency, user satisfaction, and quality of literature searchers for a multi-application computer workstation in a university-based general medicine clinic. A computer with medical literature searching, textbook searching, and a decision-support program was deployed in the workroom of the clinic and made available for routine use. Data were collected for ten months. More than three quarters of the study participants used the computer, with use increasing by level of medical training. Despite physicians' known preferences for nonjournal sources of information, literature searching was the application used most frequently, followed by textbooks and decision support. The literature searches were replicated by experienced clinician and librarian searchers using first full MEDLINE and then text-word-only searching, to compare the quantities of relevant references retrieved. Novice searchers retrieved a larger number of relevant references than did the experienced searchers, but they also retrieved more nonrelevant references. For both groups of experienced searchers, the full MEDLINE feature set conferred little benefit over searching with only text words. These searching results call into question the value of traditional searching methods for both novice and experienced physicians. PMID- 7841908 TI - Connecting the health sciences community to the Internet: the NLM/NSF grant program. AB - In 1992, as part of its high-performance computing and communications initiative, the National Library of Medicine decided to provide health sciences institutions with Internet connection grants similar to those offered to universities by the National Science Foundation. Although library involvement is not required, librarian and library uses have been the most common category in the applications received. PMID- 7841909 TI - Developing a health information infrastructure for Arizona. AB - Network connectivity is critical in Arizona, where travel distances are great, academic programs dispersed, and health care practitioners often geographically isolated. Accordingly, the University of Arizona (UA) applied for $50,000.00 in National Library of Medicine/National Science Foundation (NLM/NSF) Connections Program funding to promote statewide collaboration in supporting UA's health sciences education and research programs by expanding network connectivity to hospitals and other health-related institutions. The proposal outlined three strategies: Each major nonuniversity teaching hospital would secure and maintain a leased communications line dedicated to network connectivity, and NSF funds would be used to buy some necessary hardward. NSF funds would be used to establish a modern bank for dial-up Internet access by rural practitioners and teaching sites. Co-principal investigators of the project would promote and support the use of this new statewide connectivity and foster its continued expansion. The proposal was based on a conservative philosophy: familiar technologies and, where possible, existing networks and equipment would be used. The proposal was approved, and NSF funds hastened creation of an expanded health information network in Arizona. Once that network was in place, participants moved quickly from managing the mechanics of connectivity to planning for a computing and communications platform with services. Private funds were obtained to help organize the Arizona Health Information Network to direct these expanded services. PMID- 7841910 TI - Community hospitals and the Internet: lessons from pilot connections. AB - Community hospitals in rural and isolated areas have had little access to the Internet. In 1992, the National Library of Medicine funded a pilot project to be conducted by the University of Washington and seven community hospitals in the northwestern United States. The goals of the project were to connect the hospitals to the Internet and study the uses made of this resource. A number of administrative, technical, financial, and organizational problems were dealt with in the attempt to establish the Internet connections and introduce this resource to these health care settings. This paper examines these issues and presents conclusions drawn from the experiences of the project team. PMID- 7841911 TI - The Utah education network: a collaborative model. AB - High-speed data communications networks are transforming the operations, services, and roles of libraries. While the installation of the physical network is often the focus of activity, the administrative and political issues are, in fact, fundamental. For libraries to participate in and influence the development of networks, building new partnerships has proven to be an effective strategy. This paper describes the use of this strategy in the development of the Utah Education Network. This participation is essential if libraries are to take full advantage of the technologies and to ensure that networks reflect the fundamental values of the profession. PMID- 7841912 TI - Service providers and users discover the Internet. AB - Although the Internet has evolved over more than twenty years, resources useful to health information professionals have become available on the Internet only recently. A survey conducted by the Regional Medical Libraries of the National Network of Libraries of Medicine in the fall of 1993 indicates that libraries at academic institutions are much more likely to have access to the Internet (72%) than are libraries in hospital environments (24%). Health information professionals who take on the challenge and exploit the Internet's resources find rewards for themselves and their clients. The basic electronic mail capability of the Internet allows colleagues to collaborate, communicate, and participate in daily continuing education. Internet terminal and file-transfer capabilities provide improved access to traditional resources and first-time access to new electronic resources. Through the Internet, online catalogs are available worldwide, and document delivery is faster, cheaper, and more reliable than ever before. Institutions can make organizational, full-text, online, and publication information available through Internet tools such as direct file-transfer protocol (FTP), menu-based Gopher, and hypertext-based Mosaic. The National Library of Medicine (NLM) is among organizations finding new ways to provide service through the Internet. NLM now uses electronic mail to communicate with users, FTP service to distribute publications, and tools such as Gopher and Mosaic to distribute publications and graphics and connect users to online services. The Internet allows service providers and health sciences information professionals to work in a rich, new medium whose potential is just beginning to be explored. At the same time, its characteristics--including lack of formal organization, standards, quality control, and permanence--pose a challenge. PMID- 7841913 TI - Navigating the Internet. AB - Navigating any complex set of information resources requires tools for both browsing and searching. A number of tools are available today for using Internet resources, and more are being developed. This article reviews existing navigational tools, including two developed at the Yale University School of Medicine, and points out their strengths and weaknesses. A major shortcoming of the present Internet navigation methods is the lack of controlled descriptions of the available resources. As a result, navigating the Internet is very difficult. PMID- 7841914 TI - The Internet: will this highway serve the digital library? AB - The future of the biomedical enterprise and the biomedical libraries that serve it is tied closely to digital information. The changing nature of this type of information will create new pressures on libraries, particularly in health care organizations. Libraries must learn to deal with these pressures. Currently, libraries depend on the Internet primarily for connections to resources and other libraries; thus enhancements to the Internet will impact the libraries of the present and future significantly. This paper provides an overview of the technical capabilities that will be available in the near to midterm, what libraries will be able to do with those capabilities, and how libraries can position themselves to take advantage of the impending changes. PMID- 7841915 TI - Self-directed learning program and the library: supporting instructors in development of multimedia instructional programs. PMID- 7841916 TI - Ariel: technology as a tool for cooperation. PMID- 7841917 TI - An aid for total quality searching: developing a hedge book. PMID- 7841918 TI - Nursing informatics programs at the University of Maryland at Baltimore. PMID- 7841919 TI - Protecting access to the intellectual property of the health sciences. PMID- 7841920 TI - Gertrude Louise Annan, 1904-1993. PMID- 7841921 TI - [Surgical approach to diabetic retinopathy]. AB - Progress in instrumentation and techniques may prevent from blindness patients affected with severe diabetic retinopathy. Surgery stabilizes the situation in 20% of the cases and improves vision in 70%. In 10% of the cases, however, treatment is undertaken too late and the eye may be lost. Although great improvements have been realized, early detection and screening for diabetic retinopathy, as well as adequate laser therapy, are of prime importance to save vision of diabetic patients. PMID- 7841922 TI - The etiology of adult hypertension and progressive renal injury: an hypothesis. AB - We hypothesize that retardation of renal development as occurs in individuals of low birth weight gives rise to increased postnatal risks for systemic and glomerular hypertension as well as enhanced risk of expression of renal disease. This hypothesis draws upon observations suggesting 1) a direct relationship between birth weight and nephron number, 2) an inverse relationship between birth weight and later-life hypertension, and 3) an inverse relationship between nephron number and blood pressure, irrespective of whether nephron number is reduced congenitally or in postnatal life (as from partial renal ablation or acquired renal disease). Additional clinical and epidemiological studies are needed to assess these initial impressions. PMID- 7841923 TI - [A new form of nephropathy secondary to the absorption of Chinese herbs]. AB - An outbreak of rapidly progressive renal failure was observed in Belgium in 1992 1993 and was related to a slimming regimen involving chinese herbs, namely Stephania tetrandra and Magnolia officinalis. Seventy one cases were registered on january 1994, 35 of whom being on renal replacement therapy. Renal failure has been progressing in most of the cases despite the withdrawal of the exposure to the chinese herbs. Renal biopsies showed an extensive interstitial fibrosis with loss of tubes, predominantly in the outer cortex. Chemical analyses of the chinese herbs powdered extracts delivered in Belgium demonstrated a misidentification between Stephania tetrandra and another chinese herb, Aristolochia Fang-chi, potentially nephrotoxic. These observations indicate the need of intensive search of nephrotoxins in cases of interstitial nephritis of unknown origin. Also, they underline the necessity of the introduction of measures allowing the control of correct identification of herbs preparations. PMID- 7841924 TI - [Academic eulogy of Professor Andre E. Lambert, correspondent]. PMID- 7841925 TI - [Academic eulogy for Professor Raymond Vanbreuseghem, titulary member and former president]. PMID- 7841926 TI - [Utero-trophoblastic interface: transitory stage in human placentation]. AB - In the past, the intervillous space of the human placenta has been studied on samples provided by spontaneous abortions. Using the endocavitary ultrasonography and the chorionoscopy in normal pregnancies, the intervillous space during the first trimester has been observed as filled by a plasmatic fraction cell free of the maternal blood. During the first trimester, the human placenta doesn't have its theoretical functional specificities. PMID- 7841927 TI - [Long-term development in treated cervical dysplasias]. AB - The study of 324 cervical dysplasia treated and followed from 1 to 15 years allows to draw three major risks from conservative treatment: micro invasions or invasions, non seen at diagnosis time; risk of residual lesion whatever the used treatment; risk of recurrence from 7 months to 7 years after the last treatment. The ratio of cure (actuarial analysis) is about 92% at 3 years and 88% at 6 years. Whatever the patient's age, the lesion's degree or the treatment used, the risk of recurrence can be fixed up to 6.17%. Only the concordance of diagnostical means and the long term follow up should decrease consequences of medical therapeutic failures. PMID- 7841928 TI - [Academic eulogy for Professor Pierre Dustin, titulary member]. PMID- 7841929 TI - [Insulin receptors and mechanism of action of insulin and of insulin-like growth factors]. AB - A novel mechanism of activation of the insulin and IGF-I receptors by their respective ligands is proposed, whereby the bivalent ligand bridges the two receptor alpha subunits at opposite sites in a symmetrical receptor structure. The proposed mechanism accounts for the binding stoichiometry and the phenomenon of negative cooperativity. It may play an important role in the regulation of mitogenesis. PMID- 7841930 TI - [Role of radioactive iodine in the treatment of differentiated thyroid cancer: physiopathological basis, results, considerations from the viewpoint of radioprotection]. AB - Postoperative radioiodine treatment of differentiated thyroid cancer occupies a well determined place in the treatment policy of this disease. When the external exposure rate (EER) was determined at 1 m from the patient, 72 h after the administration of the high 131-I dosis, respectively 34 and 56 patients among 80 treated cases presented, and require external help for their daily life (+/- 90% of all cases). This value could be considered as the selective limit in order to authorize them to leave the hospital when favorable socio-economical conditions exist at home. PMID- 7841931 TI - Statement on management of persons exposed to pertussis and pertussis outbreak control. National Advisory Committee on Immunization, the Advisory Committee on Epidemiology and the Canadian Paediatric Society. PMID- 7841932 TI - Antioxidant action of thiopalmitic acid on microsomal lipid peroxidation. AB - The antioxidant action of thiopalmitic acid (SH-Pal) was studied in a lipid peroxidation system using microsomes from rat liver. The Fe(II)/ascorbic acid (AsA)-induced lipid peroxidation, as measured by the amount of thiobarbituric acid-reactive substances (TBA-RS), was progressively inhibited by the addition of increasing amounts of SH-Pal. The inhibitory effect of SH-Pal in this experimental system was greater than that of alpha-tocopherol, glutathione (GSH) and palmitic acid. The antioxidative effect was abolished gradually by the addition of increasing amounts of N-ethylmaleimide to the system. Similarly, microsomal lipid peroxidation induced by Fe(III)-ADP/NADPH or CCl4/NADPH was inhibited in a dose-dependent fashion by the addition of SH-Pal. Moreover, SH-Pal was able to reduce 1,1-diphenyl-2-picrylhydrazyl (DPPH). The alpha-tocopherol content of the microsomal lipid peroxidation system decreased rapidly when no SH Pal was present. However, upon adding SH-Pal (90 microM), the decrease in the alpha-tocopherol content of the assay system was markedly reduced. These findings indicate that SH-Pal acts as an antioxidant and free radical scavenger in lipid peroxidation carried out by rat liver microsomes. PMID- 7841933 TI - Purification and characterization of 5 alpha-dihydrotestosterone 3 beta hydroxysteroid dehydrogenase from mature pig testicular cytosol. AB - NADPH-dependent 5 alpha-dihydrotestosterone 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) was purified to apparent homogeneity from mature pig testicular cytosol. The purified enzyme catalyzed the conversion of 5 alpha dihydrotestosterone (5 alpha-DHT) to 5 alpha-androstane-3 beta, 17 beta-diol. The molecular weight was estimated to be 31 kDa by sodium dodecyl sulfate polyacrylamide gel electrophoresis and 28 kDa by gel filtration chromatography, indicating that the native 3 beta-HSD is a monomer. The isoelectric point of the purified enzyme was 5.8 as determined by chromatofocusing. The purified enzyme reduced not only 5 alpha-DHT but also 5 beta-DHT, 5 alpha(or 5 beta) androstanedione, 5 alpha(or 5 beta)-dihydroprogesterone, prostaglandin E1, 13,14 dihydro-15-keto-prostaglandin F2 alpha, glyceladehyde, xylose and glucuronic acid. Moreover, the enzyme reduced other carbonyl compounds including aromatic aldehydes, aromatic ketones and quinones such as 4-nitrobenzaldehyde, 4 benzoylpyridine, phenylglyoxal, cyclohexanone and 9,10-phenanthrenequinone at high rates when compared with steroids, prostaglandins and sugars. The purified enzyme was inhibited by AgNO3, SH-reagent, disulfiram, hexesterol, stilbestrol, disulfiram and divalent cations such as Cu2+, Hg2+, Cd2+ and Co2+. Furthermore, the enzymatic properties of the purified enzyme, including catalytic activity, inhibitory effects by various agents and immunological properties, were compared with those of 3 alpha/beta-HSD enzymes from pig testicular cytosol. PMID- 7841934 TI - An acidic polysaccharide with immunological activities from the root of Paeonia lactiflora. AB - An acidic polysaccharide, called peonan PA, was isolated from the root of Paeonia lactiflora PALLAS. It was homogeneous on electrophoresis and gel chromatography, and its molecular mass was estimated to be 6.0 x 10(4). Peonan PA is composed of L-arabinose: D-galactose: D-galacturonic acid in the molar ratio of 2:1:10, in addition to small amounts of O-acetyl groups and peptide moieties. About forty percent of the hexuronic acid residues in peonan PA exist as methyl esters. Reduction of carboxyl groups, methylation analysis, lithium degradation and nuclear magnetic resonance studies indicated that its main structural features involve both alpha-1,5-linked L-arabino-beta-3,6-branched D-galactan type and alpha-1,4-linked D-galacturonan type structural units. The polysaccharide exhibited remarkable reticuloendothelial system-potentiating activity in a carbon clearance test and considerable anti-complementary activity. PMID- 7841935 TI - Preparation and antitumor activities of mitomycin C beta-(1-->6)-branched (1-->3) beta-D-glucan conjugate. AB - The conjugate of mitomycin C (MMC) with carboxymethylated schizophyllan (CMSPG) which was prepared from monochloroacetic acid and schizophyllan (SPG), a beta-(1- >6)-branched (1-->3)-beta-D-glucan from Schizophyllum commune Fries, was synthesized by using 1-ethyl-3-(3-dimethylaminopropyl)- carbodiimide. The degree of the substitution of carboxymethyl groups in CMSPG was estimated as approximately 0.87, and locations of carboxymethyl groups in CMSPG were predominantly determined at O-4, O-6, and O-4, 6 positions in glucose residues. The contents of MMC in the conjugate were estimated to be between 8 and 12% (w/w). The conjugate showed successive monoexponential liberation, with a half life of 7.2 h. Although the in vitro cytotoxicity of the conjugate against L1210 leukemia cells was similar to that of MMC when the cells were exposed for 24 and 48 h, the 50% growth-inhibitory concentration of the conjugate for L1210 was two times higher than that of MMC with exposure for 12 h. The antitumor activity of the conjugate against subcutaneously implanted sarcoma 180 solid tumor in mice by intraperitoneal (i.p.) administration was similar to that of MMC at a dose of 1.5 mg eq MMC per kg per d for both 7 times of continuous administration and 4 times of intermittent administration. However, the reduction in the number of leukocytes in the peripheral blood, which was the side effect of MMC, was suppressed by the intermittent administration of the conjugate. The conjugate maintained the ability to induce the tumor regressing factor and the neutrophil chemotactic factor in the serum. PMID- 7841936 TI - Studies on thermophile products. IX. Isofatty acid-containing phosphatidylglycerol that enhances the induction of concanavalin A-activated suppressor T cells. AB - A new enhancer of the induction of concanavalin A (Con A)-activated suppressor T (Ts) cells has been demonstrated in the ethanolysate of Bacillus stearothermophilus UBT8038. It was purified by successive silica gel column chromatographies and identified as phosphatidylglycerol with C14:0-C18:0 isofatty acids (Fr. 7-C). Mouse splenocytes activated with Con A and Fr. 7-C (0.01-1 microgram/ml) in vitro significantly suppressed the proliferative response of syngenic splenocytes by mitogen stimulation in a dose-dependent manner, compared to those stimulated by Con A alone. The immunosuppressive response enhanced by Fr. 7-C disappeared when the cell populations of Thy-1.2 or CD8 positive lymphocytes were depleted. The result strongly suggests that Fr. 7-C is an immunosuppressive substance which enhances the induction of Con A-activated CD8 positive Ts cells. PMID- 7841937 TI - Basic fibroblast growth factor stimulates the competence phase of subcultured endothelial cells and the progression phase of primary cultured smooth muscle cells from rat aorta. AB - The proliferative effects of basic fibroblast growth factor (bFGF) on the cell cycle were compared in subcultured endothelial cells (EC) and primary cultured smooth muscle cells (SMC) from rat aorta by monitoring the starting time (an index of the competence phase) and rate (an index of the progression phase) of [3H]thymidine incorporation. Persistent treatment with bFGF (1, 10 and 30 ng/ml) reduced the starting time of EC proliferation in the presence of 1% fetal bovine serum (FBS) in a concentration-dependent manner. The starting time of [3H]thymidine incorporation into EC was reduced by a maximum of 4 h by pretreatment with bFGF for 12 h but not for 3 h. DNA synthesis in EC was inhibited by pretreatment with bFGF for 24 h. The rate of [3H]thymidine incorporation into SMC was accelerated both by persistent treatment with bFGF and pretreatment for 3 h in the presence of 3% FBS. In serum-free medium, bFGF (30 ng/ml) stimulated [3H]thymidine incorporation into SMC but not into EC after incubation for 36 h. Together, bFGF (10 ng/ml) and insulin (10 micrograms/ml) synergistically stimulated [3H]thymidine incorporation into EC, but insulin alone did not. These findings indicate that bFGF is a competence factor in EC and a progression factor in SMC from rat aorta. PMID- 7841938 TI - Effect of hachimijiogan, an oriental herbal medicinal mixture, on experimental amnesia in mice. AB - The effect of Hachimijiogan on cognitive disturbance was investigated using step through passive avoidance failure techniques: scopolamine-, cycloheximide- and cerebral ischemia-induced amnesia. Pre-acquisition trial administration of Hachimijiogan (0.5 g/kg, p.o.) prolonged the step-through latency reduced by scopolamine and cycloheximide. Hachimijiogan (0.5 and 1.0 g/kg, p.o.) also ameliorated the cerebral ischemia-induced amnesia. Physostigmine (0.1 mg/kg, i.p.) ameliorated all three amnesia models. The ameliorating effects of Hachimijiogan and physostigmine on cycloheximide-induced amnesia were diminished by the combination with scopolamine. These results suggest that Hachimijiogan possesses a wide-ranging pharmacological profile in anti-amnesic actions and that its anti-amnesic activities may be related to the cholinergic neuronal system. PMID- 7841939 TI - Improving effects of DX-9386, a traditional Chinese medicinal prescription, on thymectomy-induced impairment of learning behaviors in mice. AB - The subject mice were thymectomized 4 weeks after birth. Ten months after the thymectomy, learning behaviors in passive and active avoidance performances and a spatial memory task, the contents of brain monoamines and brain choline acetyltransferase (ChAT) activity, as well as the immune response were evaluated. DX-9386, a traditional Chinese medicinal prescription consisting of ginseng, polygala, acorus and hoelen, was prepared in CE-2 mouse food (1%, w/w) and given to the thymectomized mice after the operation until all the experiments were finished. DX-9386 treatment significantly ameliorated the learning and memory ability impaired by thymectomy in passive avoidance performances and in a spatial memory task, and the mice tended to improve in the active avoidance performance of a lever press test. However, DX-9386 treatment did not improve the thymectomy reduced immune response. The contents of hypothalamic norepinephrine, 3,4 dihydroxyphenylacetic acid and homovanillic acid, and hypothalamic ChAT activity were significantly increased in thymectomized mice, and DX-9386 restored them to the control levels. These results suggested that DX-9386 mainly affected the cognitive process of the central nervous system to ameliorate the learning and memory deficit induced by thymectomy. PMID- 7841940 TI - Antinociceptive effects of Randia siamensis extract and its constituent, pseudoginsenoside-RP1 in experimental animals. AB - Analgesic activities of Randia siamensis CRAIB (R. siamensis) extract and pseudoginsenoside-RP1, a constituent of the extract, were examined in the writhing test, hot plate test and Randall-Selitto test. Oral administration of R. siamensis extract dose-dependently decreased the number of writhings and stretchings induced by 0.6% acetic acid in the writhing test in mice. Moreover, in the Randall-Selitto test in rats, the extract raised the nociceptive threshold of the carrageenan-inflamed but not of non-inflamed paw. It did not affect the nociceptive response in the hot plate test in mice. The R. siamensis extract did not affect hexobarbital-induced sleep or spontaneous motor activity in mice, suggesting that it has no sedative effect. Pseudoginsenoside-RP1 produced similar effects to the R. siamensis extract, but its effective doses in the analgesic tests were lower than those with the extract. These results suggest that R. siamensis extract produces anti-nociceptive actions similar to those of a peripherally acting analgesic drug aspirin, and that pseudoginsenoside-RP1 may partly contribute, but is not the main contributor, to the antinociceptive action of the extract. PMID- 7841941 TI - Changes of cholecystokinin octapeptide tissue levels in rat brain following dopamine neuron lesions induced by 6-hydroxydopamine. AB - Cholecystokinin octapeptide sulfated (CCK8) tissue levels in several regions of the rat brain were measured by amino terminal specific radioimmunoassay following the intracerebroventricular administration of 6-hydroxydopamine (6-OHDA) to investigate the interaction between CCK8 and dopamine (DA). Pargyline and desmethylimipramine were administered 2 h before 6-OHDA injection. The levels of CCK8-like immunoreactivity in the frontal cortex, striatum, hippocampus, substantia nigra, and nucleus accumbens increased transiently on day 1 after 6 OHDA treatment. The levels in the frontal cortex, striatum and substantia nigra fell gradually to reach a subnormal level on day 7. In the nucleus accumbens, where the coexisting CCK8 and DA neurons lie, the tissue levels fell to a subnormal level on day 3. These decreased levels were unchanged until day 28. The irreversible destruction of DA neurons induced by 6-OHDA might cause drastic changes in regional CCK8-like immunoreactivity. The changes would depend on the neuromorphological differences in each structure. These results suggest that the CCK8 systems are closely related to the DA systems in several brain regions and that DA plays an important role in CCK8 release. PMID- 7841942 TI - Distribution and chemical form of selenium in mice after administration of selenocystine. AB - To elucidate the relationship between chemical forms of selenium in tissues and subacute liver damage induced by selenocystine (T. Hasegawa et al., Arch. Toxicol., 68, 91 (1994)), the distribution and chemical form of selenium were investigated in ICR male mice treated with the chemical orally (50 mg/kg) and intravenously (5 mg/kg). The time-distribution of selenium in plasma, erythrocytes and liver after separate administration varied. However, Sephadex G 150 chromatograms of plasma, and stroma-free hemolysate from mice treated orally or intravenously with selenocystine, revealed that selenium exists mainly in the albumin and hemoglobin fractions, respectively, and is neither route- or time dependent. Sephadex G-150 chromatograms of liver cytosol of the animals 1 h after oral administration or 1 and 6 h after intravenous administration showed two selenium-containing fractions, void volume and a low-molecular fraction (Kav = 0.85); 6 h after oral treatment, however, animals had an additional high molecular fraction (Kav = 0.45). Levels of acid-volatile selenium and dialyzable selenium in the fraction with a Kav value of 0.45 were similar, being 31.2% and 30.3%, respectively. No acid-volatile selenium was recognized in the non dialyzable high-molecular fraction. The present study demonstrated that when selenocystine is administered orally to mice, the selenium which produces acid volatile selenium by acidification may bind to protein sulfhydryl groups in the liver cytosol; this was not seen in the case of intravenous administration. PMID- 7841943 TI - Adriamycin-Fe(3+)-induced inactivation of rat heart mitochondrial creatine kinase: sensitivity to lipid peroxidation. AB - Adriamycin (ADM)-Fe3+ caused inactivation of rat heart mitochondrial creatine kinase (CK) with lipid peroxidation. Superoxide dismutase, catalase and hydroxyl radical scavengers were without effect on the CK inactivation and the lipid peroxidation induced by ADM-Fe3+, indicating the lack of involvement of superoxide, hydrogen peroxide or hydroxyl radicals in these reactions. The antioxidant butylated hydroxytoluene strongly inhibited not only lipid peroxidation but also CK inactivation, indicating that mitochondrial CK was inactivated with lipid peroxidation. Reduced glutathione and dithiothreitol (DTT) prevented CK inactivation without inhibiting lipid peroxidation. The CK activity of 5,5'-dithiobis-(nitorobenzoic acid)-treated mitochondria exposed to ADM-Fe3+ was partially reversed by addition of DTT, indicating that CK inactivation was due to oxidative damage of sulfhydryl groups. In contrast, mitochondrial protein SH groups were not attacked via ADM-Fe(3+)-induced lipid peroxidation. Thus, the SH groups in mitochondrial CK are very susceptible to ADM-Fe(3+)-induced lipid peroxidation. PMID- 7841944 TI - The structure-activity relationship between phenylene-polymethylene bis-ammonium derivatives and their neuromuscular blocking action on mouse phrenic nerve diaphragm muscle. AB - The structure-activity relationship of phenylene-polymethylene bis-ammonium (PMBA) derivatives, C6H4[X(CH2)nR]2, on isolated mouse phrenic nerve-diaphragm muscle was investigated to obtain more potent and stable compounds for use as pharmacological tools to clarify the mechanism of succinylcholine (SuCh)-induced neuromuscular blockade. The neuromuscular blocking effect of all the PMBA derivatives was not reversed by neostigmine, a cholinesterase inhibitor. The potency of the neuromuscular blockade was in the order p- > o- > m- with respect to the side-chain substituents. A PMBA composed of X = CH2, n = 5 and R = N+Et3 was 5.9- and 23-fold more potent than SuCh and decamethonium, respectively. The derivatives of R = N+Et3 were observed to be more potent than those of R = N+Me3, N-Me-piperidinio and pyridinio derivatives. Replacement of X = CH2 with O, CHOH and CHOAc decreased the neuromuscular activity while replacement with S, SO and SO2 increased it. Introduction of NO2 into the phenylene ring increased the activity, while the introduction of an alcohol, aldehyde and ketone group decreased it. Removal of a carbonyl or ether group from SuCh decreased its activity, whereas the introduction of these into PMBA failed to increase it. We managed to synthesize unhydrolyzable neuromuscular blocking agents which are more potent than SuCh. PMID- 7841945 TI - Structural components of beta-eudesmol essential for its potentiating effect on succinylcholine-induced neuromuscular blockade in mice. AB - beta-Eudesmol, a sesquiterpenoid alcohol isolated from Atractylodes lancea rhizoma, potentiates the neuromuscular blocking effect of succinylcholine (SuCh). The potentiating effect is greater in diabetic muscles than in normal ones. To identify the structural components of beta-eudesmol contributing to this action, we examined the potentiating effect of newly synthesized tertiary alcohols related to beta-eudesmol in phrenic nerve-diaphragm muscle preparations of normal and alloxan-diabetic mice. Potentiating effects were exhibited by cyclohexylidene derivatives but not by cyclohexanone or cyclohexanol derivatives. The compound 2 (3-hydroxy-3-methylbutyl)cyclohexylidene exhibited a potentiating effect, but 3 (3-hydroxy-3-methylbutyl)cyclohexylidene did not. These results indicate that both the presence of an exo-methylene attached to a cyclohexane ring and the distance between the exo-methylene and the hydroxy group in beta-eudesmol are involved in the potentiating effect on SuCh-induced neuromuscular blockade. PMID- 7841946 TI - Studies of diabetic nephropathy. I. Effects of storage time and temperature on microalbuminuria. AB - The effect of storage time and temperature on the immunological turbidimetric measurement of a low concentration of albumin in urine was investigated. In storage at -20 degrees C, the albumin level decreased, but the rate of this decrease differed considerably among specimens. However, under storage at room temperature for 2 weeks, or at 4 degrees C for 5 weeks albumin levels did not show significant changes. At -40 degrees C and -80 degrees C there were only slight decreases. At -40 degrees C decreases were slightly greater than at -80 degrees C. Therefore, -80 degrees C was found to be the optimal temperature for long-term storage of urinary albumin. Some of the specimens showed a 50% decrease in albumin level after storage for 9 weeks at -20 degrees C, but remained unchanged after storage for the same period at -80 degrees C. A pair of specimens preserved at -20 degrees C and -80 degrees C were isolated by SDS-PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis). After electrophoresis, urinary proteins were stained by silver staining to observe bands, and albumin content was determined by immunoblotting. A decrease in albumin concentration was also observed by densitometric detection. PMID- 7841947 TI - Pharmacodynamics and tumoricidal effect of adriamycin entrapped in ceramide sulfate-containing liposomes. AB - Ceramide sulfate (N-acylsphingosine-1-O-sulfate), which lacks the galactose residue of sulfatide, was examined as a possibly preferable constituent of liposomes for drug delivery. Multilamellar vesicles prepared from phosphatidylcholine, cholesterol, and N-lignoceroylsphingosine-1-O-sulfate in a molar ratio of 5:4:1 efficiently entrapped adriamycin, and the retention of the drug in the liposomes in saline at 4 degrees C for 8 d was nearly 100%. In terms of entrapment efficiency and retention of the drug in liposomes, N lignoceroylsphingosine-1-O-sulfate was superior to N-stearoylsphingosine-1-O sulfate. A pharmacodynamic study revealed that the blood level of adriamycin was far higher with the drug encapsulated in N-lignoceroylsphingosine-1-O-sulfate containing liposomes than with the free drug. The drug level in the heart was remarkably reduced with the liposome-entrapped drug, which is advantageous in reducing the cardiotoxicity of this drug. The effect of N-lignoceroylsphingosine 1-O-sulfate-containing liposomes on the blood level of adriamycin was superior to that of sulfatide-containing liposomes, though the effect of the former on the heart level was comparable to that of the latter. The tumoricidal effect on ascitic P388 leukemia and Lewis lung carcinoma was higher with adriamycin entrapped in N-lignoceroylsphingosine-1-O-sulfate-containing liposomes than with the free drug. PMID- 7841948 TI - A study of embolizing materials for chemo-embolization therapy of hepatocellular carcinoma: effects of particle size and dose on chitin-containing cis diamminedichloroplatinum(II) albumin microsphere antitumor activity in VX2 hepatic tumor model rabbits. AB - We prepared chitin-containing cis-diamminedichloroplatinum(II) (CDDP) albumin microspheres with various particle sizes, and investigated in vitro CDDP release; the antitumor effect towards VX2 tumor introduced into rabbits was then examined. It was found that the rate of release of CDDP from chitin-containing CDDP albumin microspheres in vitro was increased with reduced particle size. Administration of microspheres to VX2 tumor-bearing rabbits via the hepatic artery resulted in different profiles of plasma platinum concentration depending on the particle size, and a higher concentration of platinum was released from the beginning of administration as particle size was reduced. The platinum content in hepatic tissue following the administration of CDDP microspheres was increased as the particle size decreased, although the rate of increase was not uniform. The antitumor effect of CDDP assessed by the suppression of tumor growth tended to be higher when microspheres of smaller sizes were used. However, no significant difference was observed in tumor growth rate between rabbits injected with microspheres smaller than 20 microns and those injected with sizes between 20 and 37 microns (p > 0.05). We also examined the relationship between the CDDP dose and antitumor effect using microspheres of less than 20 microns and observed a dose-dependent antitumor effect. No significant difference was observed, however, between 2 and 4 mg eq CDDP/kg dose levels (p > 0.05). From these results, we concluded that microsphere size and CDDP dose were strongly correlated with the augmentation of antitumor effect of chitin-containing CDDP albumin microspheres used in chemo-embolization therapy via the hepatic artery. PMID- 7841949 TI - Intestinal absorption of azetirelin, a new thyrotropin-releasing hormone (TRH) analogue. I. Possible factors for the low oral bioavailability in rats. AB - Absorption of azetirelin, a new thyrotropin-releasing hormone (TRH) analogue, from the gastrointestinal (GI) tract was evaluated. The bioavailability of this compound after oral administration was considerably poor in rats. Studies were undertaken to elucidate the mechanisms for this low oral bioavailability of azetirelin. The plasma azetirelin levels following intravenous and hepatoportal vein injection were virtually identical over the dose range of 0.02-0.1 mg/kg, indicating a minor contribution of the hepatic first-pass metabolism of this drug. Azetirelin was stable against peptide hydrolases both in luminal fluid and intestinal mucosal homogenates, whereas its degradation occurred when incubated with cecal contents under an anaerobic condition. In addition, complete degradation of azetirelin during the GI transit was disclosed by analyzing the fecal sample collected after oral administration of [14C]azetirelin. These results suggested that gut bacteria may be responsible for the hydrolysis of azetirelin in the GI tract. The low intestinal permeability of azetirelin was revealed by a modified everted gut experiment in various segments of the rat intestine. The poor membrane transport characteristics of azetirelin may be due to its high hydrophilicity. From these results, it was suggested that the insufficient oral bioavailability of azetirelin may be mainly attributed to its low intestinal permeability due to a lack of lipophilicity, and also to the degradation of the peptide by intestinal microflora. PMID- 7841950 TI - Gastric emptying-limited oral absorption of alpha-linolenic acid administered as a milk fat-globule membrane (MFGM) emulsion in rats. AB - As a study to assess the potential application of milk fat-globule membrane (MFGM), which is of natural origin and expected to be a safer alternative to synthetic emulsifiers, to pharmaceutical dosage forms, the oral absorption of alpha-linolenic acid was evaluated by the analysis of gastrointestinal disposition after oral administration as an MFGM emulsion to rats. A linear model incorporated with first-order gastric emptying followed by first-order intestinal absorption was fitted to the data of the remaining fraction of alpha-linolenic acid versus time profiles for the stomach and small intestine to estimate the rate constants of gastric emptying (kg) and intestinal absorption (ka). The ka (0.045 min-1) was about 4 times larger than the kg (0.011 min-1). The kg was comparable to the apparent oral absorption rate constant estimated by the pharmacokinetic analysis of plasma concentration data. These results suggest that the oral absorption of alpha-linolenic acid administered as MFGM emulsion is gastric emptying-limited and, hence, any change in the intestinal absorption process would only modestly affect its oral absorption. PMID- 7841951 TI - Effect of first-pass metabolism on enantioselective pharmacokinetics after oral administration of (+)-, (-)- and racemic homochlorcyclizine to rats. AB - The enantioselective relationship between the pharmacokinetics and hepatic metabolism of homochlorcyclizine hydrochloride (HCZ) was investigated using rats. There were no significant differences in blood concentrations between the three forms after intravenous administration (5 mg/kg) of (+)-, (-)- and racemic HCZ. On the other hand, there were significant differences in the pharmacokinetics between (-)- and (+)-HCZ and between (-)- and racemic HCZ after oral administration (50 mg/kg) of these three forms. The Cmax and AUC0-infinity of (-) HCZ were lower than those of (+)-isomer and racemate, and its CLo was clearly higher than the others. The (+)-isomer and racemate showed no significant differences in their pharmacokinetic parameters. At a lower dose (10 mg/kg), however, no enantiomeric differences were found in the pharmacokinetic parameters of (+)- and (-)-HCZ. Also examined was the cytochrome p-450-dependent-oxidative metabolism of (+)-, (-)- and racemic HCZ in vitro using rat liver 9000 x g supernatant fraction. The in vitro metabolism of (-)-HCZ was extremely fast, compared with those of the (+)-isomer and the racemate. The Vmax in vitro showed a good correlation with the CLo in vivo after oral administration (50 mg/kg) of all three forms of HCZ. In vitro study of enantiomeric inhibition of the metabolism showed that (+)-HCZ was a competitive inhibitor of (-)-HCZ metabolism, with a Ki of 6.96 microM. (-)-HCZ was also a competitive inhibitor of (+)-HCZ metabolism, with a Ki of 20.4 microM.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7841952 TI - Oral delivery of poly(lactide-co-glycolide) microspheres containing ovalbumin as vaccine formulation: particle size study. AB - The objective of the present study was to produce ovalbumin (OVA) loaded poly(lactide-co-glycolide) (PLGA) microspheres with different diameters and to evaluate their possibilities as vaccine formulation in mice following oral inoculation. Four kinds of OVA loaded PLGA microspheres with different mean average volume diameters (1.3, 4.0, 7.5, and 14.0 microns) were manufactured using a w/o/w emulsion/solvent evaporation method. Low loading efficiencies (8 20% w/w) were observed in all batches although smooth spherical particles were obtained. Single oral administrations of OVA loaded PLGA microspheres with different diameters to mice produced immune responses (serum IgG levels by ELISA) which were statistically higher than OVA solution as negative control (Fisher's paired t-test). A dose-response was observed, and single and double inoculation orally produced similar serum antibody levels. The rank of immune response was as follows: 4.0 microns- > 1.3 microns- = 7.5 microns- > 14.0 microns-microspheres. The oral inoculation with 0.13% OVA loaded PLGA microspheres having a mean volume diameter of 4.0 microns exhibited the best immune responses with values greater than those obtained after subcutaneous inoculation with complete Freund's adjuvant (CFA) as positive control, and not significantly different from those obtained after subcutaneous inoculation with the same microspheres. PMID- 7841953 TI - Mechanism of an early lysis by fatty acids from axenic Phormidium tenue (musty odor-producing cyanobacterium) and its growth prolongation by bacteria. AB - We have previously demonstrated that bacteria-containing Phormidium tenue, a cyanobacterium which produces musty odor 2-methylisoborneol, grew beyond 8 weeks, whereas axenic alga perished suddenly between the 3rd week and the 4th week while being cultured in the laboratory. This mechanism was investigated. It is assumed that when algal cells grow beyond a certain level, the supply of CO2 becomes inadequate and results in the rapid lysis of axenic alga. At that time, inhibitory substances liberated from algal cells kill the surviving alga. Since the process occurs continuously, this alga is finally annihilated. On the other hand, since inhibitory substances are metabolized or degraded by bacteria coexistent with alga, bacteria-containing P. tenue maintains growth for a long time. The growth-inhibitory substance was found to be unsaturated free fatty acids. PMID- 7841954 TI - Studies on rehmanniae radix. I. Effect of 50% ethanolic extract from steamed and dried rehmanniae radix on hemorheology in arthritic and thrombosic rats. AB - Effects of 50% ethanolic extract (JR-ext) from Chinese Rehmanniae Radix (the steamed and dried root of Rehmannia glutinosa, "Jyuku-Jio" in Japanese) on the hemorheology of inflammatory, thrombosic and intact animals were examined in the in vivo models. JR-ext (200 mg/kg, p.o.) inhibited the reduction of fibrinolytic activity and erythrocyte deformability, the decrease in erythrocyte counts and the increase in connective tissue of the thoracic artery in a chronic inflammatory model, adjuvant-induced arthritis. However, JR-ext was ineffective on the development of edema in the arthritic rats and on acute and chronic inflammation. JR-ext inhibited the reduction of erythrocyte deformability, but not the decrease of coagulative factors in a thrombosic model, endotoxin-induced disseminated intravascular coagulation (DIC). JR-ext also showed a promoting effect on erythrocyte deformability and fibrinolytic activity in intact rats. These results suggest that orally administered JR-ext can prevent an inducement of impediment in the peripheral microcirculation of various chronic diseases through the improvement of hemorheology. PMID- 7841955 TI - The core structure of ginsenan PA, a phagocytosis-activating polysaccharide from the root of Panax ginseng. AB - Controlled Smith degradation and limited hydrolysis of ginsenan PA, the main phagocytosis-activating polysaccharide isolated from the root of Panax ginseng C. A. Meyer, were performed. The reticuloendothelial system-potentiating and anti complementary activities of the degradation products were investigated. Methylation analysis of the primary and secondary Smith degradation products indicated that the core structural features of ginsenan PA include a backbone chain mainly composed of beta-1,3-linked D-galactose. Almost half of the galactose units in the backbone carry side-chains composed of beta-1,6-linked D galactosyl residues at position 6. Further 3,6-branching of D-galactose units was observed in a part of the side-chains. alpha-L-Arabinose units are connected mainly to the core galactose moieties via position 6. Removal of most of the arabinose units had a considerable effect on immunological activity. PMID- 7841956 TI - Enhancement of human papillomavirus type 18 gene expression in HeLa cells by 12-O tetradecanoylphorbol-13-acetate, 3 beta,5 alpha-dihydroxycholestan-6-one, and cholesterol. AB - Human papillomavirus type 18 (HPV18) is involved in the genesis of cervical cancer through expression of its viral oncoprotein in infected cells. A tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA), was found to increase the level of HPV18 transcripts in an HPV18-harboring cervical cancer cell line, HeLa. A similar increase in HPV18 expression was also observed on treatment of the cells with an oxygenated cholesterol, 3 beta,5 alpha-dihydroxycholestan-6-one (yakkasterone). The effects on HPV18 expression elicited by TPA and yakkasterone were repressed by a protein kinase inhibitor, staurosporine. Treatment of the cells with cholesterol under serum-free conditions also resulted in an apparent increase of HPV18 expression. PMID- 7841958 TI - High affinity of hybrid liposomes for normal human epidermal keratinocytes in vitro. AB - A high affinity of hybrid liposomes towards normal human epidermal keratinocytes was observed. The fluorescence micrograph showed that hybrid liposomes may be incorporated into the keratinocytes by fusion. PMID- 7841957 TI - The affinity of bopindolol and its two metabolites for a beta 2-adrenoceptor in the bovine mesenteric artery. AB - Bopindolol and its two metabolites (18-502 and 20-785) were examined for their affinity to a beta 2-adrenoceptor in the bovine mesenteric artery using the radioligand binding assay method with [3H]CGP12177 as a radioligand. The Scatchard analysis of the data demonstrated a uniphasic plot with Kd and Bmax values of 0.86 +/- 0.16 nM, and 13.34 +/- 1.11 fmol/mg protein, respectively. The pKi values of bopindolol and its two metabolites for beta 2-adrenoceptors in the bovine mesenteric artery were 7.70 +/- 0.13, 8.07 +/- 0.13, 8.20 +/- 0.24, respectively, with 20-785 showing the highest values among these drugs. The present findings indicate that the bovine mesenteric artery membrane is predominantly beta 2-adrenoceptor tissue, and that bopindolol and its two metabolites were potent for beta 2-adrenoceptors in the bovine mesenteric artery. PMID- 7841959 TI - Local disposition of a new xanthine oxidase/xanthine dehydrogenase inhibitor, BOF 4272, in rat liver. AB - The local hepatic disposition of BOF-4272, a newly developed xanthine oxidase (XO)/xanthine dehydrogenase (XDH) inhibitor, was evaluated in the rat perfusion system following pulse input of the drug into the portal vein. The elution time profiles from the liver into the hepatic vein were analyzed by dispersion models. The disposition of BOF-4272 through the rat liver was represented by a two compartment dispersion model based on the Akaike's Information Criterion (AIC). The area under the concentration time curve (aucH) of BOF-4272 was proportional to the dosing amount, and the mean transit time was constant from 62.5 up to 500 micrograms/liver, which demonstrates that the local hepatic disposition of BOF 4272 is linear in this dosing range. The local disposition parameters were precisely estimated at the dosing amount of 250 micrograms/liver using several rats. These parameters in the dispersion model were correlated to the local moment characteristics. The hepatic recovery ratio (FH) was 22.8 +/- 3.2% and the mean transit time (tH) was 0.112 +/- 0.008 min, which show that the influx of BOF 4272 into the liver is efficiently large. PMID- 7841960 TI - Transport mechanism of anthracycline derivatives in rat polymorphonuclear leukocytes: uptake of pirarubicin, daunorubicin and doxorubicin. AB - We performed experiments on the cis-inhibition and trans-stimulation effect on pirarubicin uptake in order to clarify the involvement of a carrier in the pirarubicin, daunorubicin and/or doxorubicin transport systems in rat polymorphonuclear leukocytes. The uptake of daunorubicin and doxorubicin was a saturable concentration-dependent process. Since the apparent kinetic constants, Michaelis constant (Km) and inhibition constant (Ki), were almost comparable, these drugs presented mutually competitive inhibition. Furthermore, the pirarubicin uptake by polymorphonuclear leukocytes was significantly elevated by increasing the preloaded amount of doxorubicin, indicating that there was a trans stimulation effect on the pirarubicin transport in the leukocytes. These results suggest that carrier-mediated transport might be involved in the uptake of anthracycline derivatives, pirarubicin, daunorubicin and doxorubicin, by rat polymorphonuclear leukocytes. PMID- 7841961 TI - Influence of urethane anesthesia and abdominal surgery on gastrointestinal motility in rats. AB - The influence of various experimental treatments on propulsive gastrointestinal motility was examined in rats, using inulin as a marker. In unanesthetized rats without any surgery, the distribution center of inulin, which was expressed as a dimensionless distance normalized by the length of the small intestine, reached 0.587 down the intestinal tract from the pylorus 60 min after the intragastric administration of inulin. However, the distribution center of inulin moved only 0.061 in 60 min in unanesthetized rats with minimial abdominal surgery for intraduodenal administration of inulin, and did not move in unanesthetized rats with cannulas for perfusion or in the rats anesthetized with urethane and treated with abdominal surgery. In urethane-anesthetized rats without surgery, almost 100% of the inulin was recovered from the stomach 60 min after intragastric administration. These results suggest that gastrointestinal motility is extensively suppressed by minimal abdominal surgery as well as by anesthesia. PMID- 7841962 TI - Enhancement of 12-O-tetradecanoylphorbol-13-acetate-induced tumor necrosis factor alpha production by phenethylphthalimide analogs. AB - Effects of phenyl-, benzyl-, phenethyl-, and phenylpropylphthalimides on 12-O tetradecanoylphorbol-13-acetate (TPA)-induced tumor necrosis factor (TNF)-alpha production by human leukemia cell line HL-60 were examined. Among the four phthalimide derivatives, only phenethylphthalimide showed potent enhancing effect on TNF-alpha production. PMID- 7841963 TI - Health-related quality of life measures for women with urinary incontinence: the Incontinence Impact Questionnaire and the Urogenital Distress Inventory. Continence Program in Women (CPW) Research Group. AB - Urinary incontinence (UI) is a relatively common condition in middle-aged and older women. Traditional measures of symptoms do not adequately capture the impact that UI has on individuals' lives. Further, severe morbidity and mortality are not associated with this condition. Rather, UI's impact is primarily on the health status and health-related quality of life (HRQOL) of women. Generic measures of HRQOL inadequately address the impact of the condition on the day-to day lives of women with UI. The current paper presents data on two new condition specific instruments designed to assess the HRQOL of UI in women: the Urogenital Distress Inventory (UDI) and the Incontinence Impact Questionnaire (IIQ). Used in conjunction with one another, these two measures provide detailed information on how UI affects the lives of women. The measures provide data on the more traditional view of HRQOL by assessing the impact of UI on various activities, roles and emotional states (IIQ), as well as data on the less traditional but critical issue of the degree to which symptoms associated with UI are troubling to women (UDI). Data on the reliability, validity and sensitivity to change of these measures demonstrate that they are psychometrically strong. Further, they have been developed for simple, self-administration. PMID- 7841964 TI - The effects of rG-CSF on health-related quality of life in children with congenital agranulocytosis. AB - A multicentre Phase II clinical trial was recently undertaken to document the value of treatment with recombinant human granulocyte colony-stimulating factor (rG-CSF) in children with congenital agranulocytosis. To assess the impact of such therapy on health-related quality of life (HRQOL), we developed a questionnaire that was administered to the parents of study patients, twice prior to the initiation of treatment, and then monthly thereafter for six months. The questionnaire focused on several aspects of HRQOL that we thought were important in this patient population, including functional status, general health perceptions, activity limitation, disease symptoms, and discomfort associated with therapy. In this paper, we describe the questionnaire that we developed and the process by which it was translated into several languages. We also report on the impact of rG-CSF therapy on HRQOL. A total of 130 questionnaires were administered to the parents of 19 study patients between the ages of four and one half months and 18 years in 11 study centres in four countries. Although our sample size is small, our findings suggest that treatment with rG-CSF may result in significant improvements in general health perceptions, limitations of daily activities, and symptoms of the disease. PMID- 7841965 TI - Measuring change over time: a comparison of results from a global single item of health status and the multi-dimensional SF-36 health status survey questionnaire in patients presenting with menorrhagia. AB - This paper compares the sensitivity to change of a multi-item, multi-dimensional health status measure with a single global health status question, in the assessment of treatment for menorrhagia. A cohort study of patients recruited by general practitioners, was carried out, with a follow up at eighteen months. Questionnaires were administered postally at base-line and follow up. General practices in Berkshire, Buckinghamshire, Northamptonshire and Oxfordshire supplied three hundred and nine women who reported heavy menstrual bleeding, and received either drug treatment alone or both drug and surgical treatment (endometrial resection or hysterectomy) during the eighteen months between the two administrations of the questionnaires. A single global question was given to patients asking them to rate their overall health status as 'excellent', 'very good', 'good', 'fair' or 'poor'. The eight dimensions of the SF-36 health survey questionnaire were also given to patients to complete. The dimensions of the SF 36 indicated only small levels of improvement for patients who received drug treatment. However, on many dimensions of the SF-36, a moderate to large improvement was detected for the surgical group. However, small changes were reported in overall health status, as indicated by the single global question, for both groups. Single item measures of health status may not provide a sufficiently accurate indication of health status to be appropriate for use in longitudinal studies. PMID- 7841966 TI - Spectrum of quality of life impairment in hypothyroidism. AB - The aim of this study is to evaluate the frequency and relative importance of different aspects of health related quality of life (HRQOL) impairment in patients with hypothyroidism. A survey of 200 patients with treated hypothyroidism was undertaken. Patients were identified and questionnaires distributed through family physicians, endocrinologists, and regional branches of the Thyroid Foundation of Canada. Frequency of importance of patients' symptoms attributed to hypothyroidism and resolved or improved with treatment were measured. Establishing the wide variety of patient-specific complaints associated with hypothyroidism provides guidance for clinicians dealing with hypothyroid patients, and investigators interested in HRQOL impairment in these patients. PMID- 7841967 TI - Development of the kidney disease quality of life (KDQOL) instrument. AB - This paper describes the Kidney Disease Quality of Life (KDQOL) Instrument (dialysis version), a self-report measure that includes a 36-item health survey as the generic core, supplemented with multi-item scales targeted at particular concerns of individuals with kidney disease and on dialysis (symptom/problems, effects of kidney disease on daily life, burden of kidney disease, cognitive function, work status, sexual function, quality of social interaction, sleep). Also included were multi-item measures of social support, dialysis staff encouragement and patient satisfaction, and a single-item overall rating of health. The KDQOL was administered to 165 individuals with kidney disease (52% female; 48% male; 47% White; 27% African-American; 11% Hispanic; 8% Asian; 4% Native American; and 3% other ethnicities), sampled from nine different outpatient dialysis centres located in Southern California, the Northwest, and the Midwest. The average age of the sample was 53 years (range from 22 to 87), and 10% were 75 years or older. Internal consistency reliability estimates for the 19 multi-item scales exceeded 0.75 for every measure except one. The mean scores for individuals in this sample on the 36-item health scales were lower than the general population by one-quarter (emotional well-being) to a full standard deviation (physical function, role limitations due to physical health, general health), but similar to scores for dialysis patients in other studies. Correlations of the KDQOL scales with number of hospital days in the last 6 months were statistically significant (p < 0.05) for 14 of the 19 scales and number of medications currently being taken for nine of the scales. Results of this study provide support for the reliability and validity of the KDQOL. PMID- 7841968 TI - Psychometric properties and responsiveness of the EORTC quality of Life Questionnaire (QLQ-C30) in patients with breast, ovarian and lung cancer. AB - The QLQ-C30, a health-related quality of life questionnaire developed for use in patients with cancer, has been previously validated in patients with lung cancer and head and neck cancer. In this study, further validation was carried out for 535 patients, including patients with breast cancer (n = 143) and ovarian cancer (n = 111) for whom there is no previously published validation, as well as patients with lung cancer (n = 160) and a heterogeneous group of other cancers (n = 121). All patients were entered in one of two trials of anti-emetics to prevent chemotherapy-induced emesis. The QLQ-C30 was completed before chemotherapy and on day 8 after chemotherapy. The factor structure in patients with breast and ovarian cancer was similar to that previously described. Interdomain correlations, in the entire group, were strongest for the physical and role function domains and the fatigue, pain and global quality of life domains before and after chemotherapy. In addition, after chemotherapy, social function was also strongly correlated with fatigue and global quality of life. These correlations were not always of equal strength in the breast, ovarian and lung groups, suggesting that there may be differences between these groups. The responsiveness of the QLQ-C30 in the presence of widely metastatic, as compared with locoregional, disease showed changes in the expected directions (i.e., diminished function in physical and social role functions and in global quality of life, with greater fatigue and pain in patients with metastatic disease). Eight days after chemotherapy, decreases were seen in physical, role and social functioning and in global quality of life, and there was greater fatigue, nausea and vomiting compared with before chemotherapy. Patients with breast cancer had better physical, role and social functioning and less fatigue and pain than patients with ovarian cancer. This result is expected, since many of the patients with breast cancer had early stage disease, whereas those with ovarian cancer had advanced stage disease. Mean scores for patients with lung cancer were between the other two groups, in keeping with the mixture of early and advanced stage disease in these patients. There was a strong correlation between ECOG performance status scores and several domains of the QLQ-C30; these were all in the expected directions. The results of this study confirm those in earlier studies on patients with lung cancer, and provide new information on patients with breast and ovarian cancer. In addition, the QLQ-C30 is responsive to the effects of chemotherapy and of metastatic disease. PMID- 7841969 TI - Symbiotic relationships of quality of life, health services research and other health research. AB - Clinical biomedical research, the traditional research orientation of quality of life (QOL) researchers, is chiefly concerned with disease processes and assessing the impact of therapeutic interventions on improving health status and QOL outcomes. This paper suggests, however, that the biomedical paradigm limits utility of QOL research findings in terms of its ability to shape health policy and improve health-related QOL in populations at risk. This paper proposes that health services research (HSR) and other health research paradigms can be used to assess QOL from multiple perspectives. HSR and QOL research can be mutually beneficial. The models for understanding health services utilized in HSR may assist in defining major determinants of QOL and the interaction of QOL with its environment. Conversely, QOL measures may be used to establish the relevance of HSR to people's well-being. The paper first defines the domain of HSR and the domain of quality of life. In order to understand their relationship, we consider what a model or paradigm for each might be, and how they would overlap. Finally, a merging of conceptual frameworks is proposed, linking QOL research to HSR and other health research. Ultimately, expanding the QOL paradigm beyond the biomedical model will promote two objectives. First, it will permit research findings to contribute more fully to shaping national health policy by considering the broader community and the delivery system factors which influence QOL. Second, researchers will be more aware of a broader range of factors affecting patients and will incorporate this in their research. PMID- 7841970 TI - Allergens and other air pollutants. PMID- 7841971 TI - Assessment of emphysema using high resolution CT, CT expiratory density mask, and plain chest films. AB - Pulmonary function tests (diffusing capacity for carbon monoxide of the lungs) and radiological imaging (plain chest film, high resolution computed tomography (CT) and CT expiratory density mask) were compared in the assessment of 29 patients with suspected airways obstruction. Conventional roentgenogram showed a good agreement with the diffusing capacity of the lungs and proved to be useful in predicting the presence of severe emphysema, but the extension of the disease was more precisely assessed by computed tomography. A good agreement was found between high resolution CT and density mask CT, although the "subjective" high resolution identified more patients with mild emphysema than the "automated" density mask. In conclusion, although the plain chest film is useful in the diagnosis of severe emphysema, CT (especially when high resolution is used) is helpful in identifying cases of mild disease and in diagnosing the type of emphysema. PMID- 7841972 TI - Rhodococcus equi infection in HIV-positive patients: report of 5 cases and literature overview. AB - The importance of Rhodococcus equi infection, an uncommon human pathogen that almost exclusively affects immunocompromised hosts, has greatly increased following the advent of acquired immune deficiency syndrome (AIDS) epidemics. Until the present time, 38 cases of R. equi infection have been described in human immunodeficiency virus (HIV)-infected patients; we now report a further five personal cases. R. equi was acquired via respiratory exposure to animals in less than half of the patients, and caused invasive pulmonary infection (91%), bacteraemia and sometimes bloodstream dissemination. R. equi was easily cultured from sputum or blood, but its diagnosis was often difficult due to microbiological and clinical similarities with other pathogens. The persistence of the micro-organism inside macrophages and its high tissular load represent the major limitation to an effective treatment. Several antibiotics are active in vitro, but their efficacy in vivo depends on macrophage uptake and/or bactericidal activity. Treatment should start with at least two intravenous bactericidal antibiotics for 3-4 weeks, and then continue with oral therapy for a period of up to several months with at least two intracellularly active drugs. Surgical resection of the lesions may be beneficial in selected cases. PMID- 7841973 TI - Effects of beta 2-agonists during cardiopulmonary exercise test in COPD patients. AB - The aim of this study was to evaluate endocrine-metabolic, respiratory and cardiovascular effects of two beta 2-sympathomimetic selective agents, such as broxaterol and salbutamol, before and during cardiopulmonary exercise test (CPX). Twelve in-patients with chronic obstructive pulmonary disease (COPD) (with partially reversible airways obstruction) were included. Broxaterol (400 micrograms) and salbutamol (400 micrograms) were administered i.v., according to a double-blind, cross-over study. Before treatment and within 60 min after the administration of each agent, the patients underwent incremental CPX by bicycle ergometer to the maximum tolerable threshold. At these times the following variables were assessed: minute ventilation (VE), oxygen consumption (VO2), carbon dioxide production (VCO2), VE/VO2 ratio and O2 pulse, glycaemia, insulinaemia, plasma norepinephrine (NE) and epinephrine (E), arterial oxygen and carbon dioxide tension (PaO2 and PaCO2), plasma lactates, heart rate (HR), systolic (SBP) and diastolic (DBP) blood pressure. Spirometry was performed before and after the administration of each beta 2-adrenoceptor agonist. CPX brought about a significant increase in VE, VO2, VCO2, and O2 pulse. Broxaterol or salbutamol administration did not significantly modify the increases caused by CPX. At rest, 60 min after treatment, both bronchodilators caused a significant rise in glycaemia. A significant reduction of PaO2 (after broxaterol) and PaCO2 (after salbutamol) was observed at rest. In contrast, both agents caused no modification to potassium and insulin levels.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7841974 TI - Nasal CPAP during wakefulness increases intraocular pressure in glaucoma. AB - Few important side-effects of nasal continuous positive airway pressure (nCPAP) have been reported. No increase of intraocular pressure (IOP) complicating this treatment has previously been described. The goal of our study was to analyse the influence of nCPAP on IOP. We evaluated 18 patients previously diagnosed as having glaucoma and 22 normal subjects. nCPAP was used during wakefulness, at +12 cmH2O for 15 min. The results showed that nCPAP significantly increases IOP in patients with glaucoma (before nCPAP 20.3 +/- 6.3 mmHg) (mean +/- SEM); after nCPAP 22.3 +/- 5.7 mmHg. We believe that nCPAP might be relatively contraindicated in difficult to manage glaucoma patients, if these results are corroborated. PMID- 7841975 TI - Who should prescribe long-term oxygen in patients affected by chronic arterial hypoxaemia? AB - Thirty two patients, 22 males and 10 females, mean age 69 yrs, affected by chronic arterial hypoxaemia due to chronic obstructive pulmonary disease (COPD), were included in a long-term oxygen therapy (LTOT) study. The aim of the study was to retrospectively evaluate the relationship between good education of the patients on long-term oxygen therapy and the different sources of prescription, i.e. general practitioners (GPs), the Departments of Internal Medicine, or our Department of Respiratory Medicine. The results showed that oxygen prescription and instruction in its use were correct more frequently when the recommendations were performed by the Department of Respiratory Medicine, and less frequently when the prescribers were general practitioners or Departments of Internal Medicine. Furthermore, the compliance of the patients to LTOT was significantly related to a specialized prescription, suggesting that oxygen therapy has to be the responsibility of the specialized units. PMID- 7841976 TI - Strongyloides stercoralis infestation masquerading as steroid resistant asthma. AB - A 42 year old man presented with steroid resistant asthma of 6 months duration. Serial chest radiographs showed migrating interstitial shadowing. Electrocardiographs showed decreasing R-wave progression in the precordial leads, and endomyocardial biopsy showed eosinophil infiltration with fibrosis. Bronchoscopy revealed inflammatory changes and lavage showed filariform larvae of Strongyloides stercoralis in the washings. This confirms the diagnosis of parasitic infection with eosinophilic cardiomyopathy. PMID- 7841977 TI - Severe subglottid stenosis, well-tolerated for many years. AB - A 45 year old man was admitted to our hospital due to dyspnoea. At the age of 1 yr, he had undergone orotracheal intubation for croup diphtheria resulting in dysphonia. He was in good health up to the age of 39 yrs when exertional dyspnoea arose. He had had irregular therapy by aerosol without improvement. At admittance, the flow-volume curve indicated an impairment at high flows (peak expiratory flow (PEF) and maximum expiratory flow at 75% (MEF75%)). Fibreoptic bronchoscopy revealed a thin and smooth diaphragm, with a small (7-8 mm) central orifice in the subglottid area. CO2 laser therapy improved symptoms by increasing the cross-sectional area of the diaphragm orifice. PMID- 7841978 TI - Environment and development of respiratory allergy: I. Outdoors. AB - Respiratory allergic diseases appear to be increasing in most countries. In particular, asthma morbidity and mortality have been reported to be increasing despite the availability of effective asthma medications. It has been also observed that subjects living in urban and industrialized areas are more likely to have respiratory allergic symptoms than those living in rural areas. This increase has been linked to air pollution, rather than to a modification of the genome of the patient. The interplay of genetic and environmental factors in the development of allergic disorders remains a subject of investigation. In the outdoor environment, the most important air pollutants are sulphur dioxide, ozone and particulate matter, in particular diesel exhaust emissions. These pollutants, besides acting as irritants, increasing airways hyper-reactivity, are thought to be causal factors which act to modulate the immune response, with an adjuvant activity on immunoglobulin E (IgE) synthesis. In other words, atopic state can be upregulated by environmental influences, and some subjects develop atopic diseases in response to these environmental factors. Since airborne allergens and air pollutants are often both increased in the same areas, potentiation, either in the degree of acquired sensitization or in the degree of the response to allergens, should be considered as an important factor which might help to explain the increasing frequency of allergic respiratory disease. In the light of our present knowledge, it is evident that further investigation in human subjects, aimed at evaluating specific agents, and their concentration in the atmosphere, which can influence pulmonary function, is needed. These studies may help to explain the increasing problem of asthma morbidity and mortality. PMID- 7841979 TI - Environment and development of respiratory allergy. II. Indoors. AB - Even if it is difficult to obtain correct epidemiological evidence, there is a body of evidence which suggests that the frequency of allergic respiratory diseases is increasing. The majority of atopic patients, in particular in childhood and adolescence, develop immunoglobulin E (IgE) antibodies with clinical symptoms to aeroallergens, such as those derived from house dust mites, pollens and pets. Since, in the economically-developed countries individuals spend most of their time indoors (home, school and workplace), indoor pollutants (tobacco smoke etc.) and allergens (house dust mite, cats, etc.) are the most important source of exposure. Indoor allergens are associated with a wide variety of particles in a broad size range, only some of which are microscopically identifiable, culturable, or detectable with existing immunoassay. Evaluation of indoor allergens requires both air and source sampling, and several different analytical techniques. It is likely that the increased prevalence of allergy and asthma may be caused in the indoor environment by the synergistic action of air pollution (in particular derived from tobacco smoking) with allergic sensitization. Passive smoking in infancy has also been involved in the airways allergic sensitization to common aeroallergens. PMID- 7841980 TI - Smoking reduction: an alternative approach for smokers who cannot quit. AB - Cigarette smoking is the foremost cause of death in the United States and is a major health problem worldwide. Clearly, the best way to eliminate the risk of smoking-related diseases, is to quit smoking. Smoking cessation has immediate and long-term benefits and substantially reduces the risk of many smoking-related diseases. Unfortunately, quitting smoking is rarely easy. For those smokers who cannot or do not wish to quit, reduction in their total smoking may represent a potential health benefit. Reduction in total smoking can, theoretically, be achieved by: 1) reducing the number of cigarettes smoked daily; and/or 2) switching to a low tar/low nicotine cigarette. Smokers, however, tend to self adjust nicotine to maintain relatively constant levels. Reduction in tar/nicotine content or number of cigarettes, therefore, may not produce health benefits. Smoking reduction with alternative nicotine delivery, however, may represent an alternative option for smokers who cannot, or do not, wish to quit. PMID- 7841981 TI - Peak expiratory flow monitoring in diagnosis and management of occupational asthma. AB - The role of peak expiratory flow (PEF) monitoring in the diagnosis of occupational asthma has recently been assessed by several studies, which agree that this procedure should always be used to confirm the relationship between symptoms and occupational exposure. Some specific issues should be satisfied: a minimum number of four PEF measurements in a day; several weeks of monitoring in and out of work; and the presence of specific patterns of PEF changes. The sensitivity and specificity of PEF monitoring to detect occupational asthma, in comparison with the specific challenge test in the laboratory (the "gold standard") have been shown to be fairly high, although many authors believe that PEF monitoring cannot substitute for the specific challenge test. Limitations include: the low sensitivity of PEF to detect mild changes in airway calibre with respect to forced expiratory volume in one second (FEV1); the blunting effect of pharmacological treatment; the episodic and irregular exposure to the sensitizer in the workplace; and the compliance and honesty of the subject. Further studies are required to select the best indices of daily and day-to-day variability to be used in the evaluation of PEF changes between work and out-of-work periods. PMID- 7841982 TI - Mycobacterial infections in AIDS: an overview of epidemiology, clinical manifestations, therapy and prophylaxis. AB - One of the most frequent complications of AIDS is Mycobacterial infections. The incidence of tuberculosis has dramatically increased in all countries as a result of the HIV epidemic. Lately, it has been found that the natural history of new Mycobacterium tuberculosis infection is accelerated by HIV disease. In a wide number of cases the emergence of Mycobacterium tuberculosis nosocomial outbreaks of drug-sensitive and drug-resistant strains has been reported in HIV infected patients. The inadequate efforts to provide complete therapy to this kind of patient has caused the emergence of multidrug-resistant tuberculosis, that is responsible for the increased mortality rate in AIDS patients. A renewed interest in mycobacterial infections has also been kindled by the occurrence of Mycobacterium avium infections in patients with acquired immunodeficiency syndrome. The role of Mycobacterium avium as a pathogen is actually confusing and controversial for clinicians who care for AIDS patients. Disseminated Mycobacterium avium infections occur in a high population of HIV infected patients with low CD4+ cell count. Recent studies reported that rifabutin significantly reduced the incidence of Mycobacterium avium bacteremia, although, new macrolides such as clarithromycin and azithromycin are also effective in the treatment of the infection. Therefore, because of the emergence of macrolides resistance, the use of combination therapy is highly recommended in the Mycobacterium avium infection management. PMID- 7841983 TI - Lung volumes and expiratory flow during bronchoconstriction in asthma. AB - Bronchial asthma is characterized by excessive airway narrowing and hyperinflation. In this review, the mechanisms linking the increases of functional residual capacity (FRC) and residual volume (RV) to reduced airway calibre are analysed. The authors have shown that the increase in FRC is closely associated with the occurrence of flow limitation, i.e. the achievement of maximum flow during tidal volume; whereas, the increase in RV can be modulated by the magnitude of the bronchodilator effect of the deep inhalation during induced bronchoconstriction. It can be speculated that flow limitation contributes to the increase in FRC through a reflex mechanism; whereas, the increase in RV depends on the site of airway narrowing, which in turn determines the relationship between airway and parenchymal properties. PMID- 7841984 TI - Clinical usefulness of a new portable oxygen concentrator. AB - Thirty chronic, hypoxaemic patients with a mean arterial oxygen tension (PaO2) of 6.81 kPa (SD 0.56) in air were tested using the Travelair. The study was performed at rest, allowing the patients to breathe in the following conditions: a) compressed air; b) continuous oxygen flow from the concentrator; c) oxygen from the concentrator in demand-valve mode (DV) with an activation time (AT) of 375 ms; d) DV with AT of 750 ms; e) DV with AT of 1,125 ms; f) DV with AT 1,500 ms; and g) continuous oxygen from the hospital outlet at 2 l.min-1. The mean (SD) SaO2% values at each consecutive step were: a) 87.2 (5.0)%; b) 93.0 (3.0)%; c) 93.9 (2.8)%; d) 94.2 (2.5)%; e) 94.0 (2.7)%; f) 94.1 (2.7)%; and g) 94.8 (2.4)%, respectively. Each of the results obtained with DV (b-f) was statistically different from those obtained breathing air (a) or oxygen (g). The mean (SD) respiratory rates at each consecutive step were: a) 21.2 (4.1); b) 21.0 (4.0); c) 21.3 (4.0); d) 21.0 (3.6); e) 20.7 (3.4); f) 21.0 (3.8); and g) 21.2 (3.8) breaths.min-1, respectively. No relationship was found between the mean oxygen saturations and the mean respiratory frequencies of the patients in each condition tested. With the concentrator on demand, the average of the best SaO2% obtained by the patients in whatever of the four DV activation time modes (conditions c-f) was 94.8 (2.4)%, and no statistical difference was detected between this result and the SaO2% obtained with 2 l.min-1 of continuous oxygen. PMID- 7841985 TI - Bronchial provocation test with allergen: comparison between two different techniques. AB - Allergen bronchial provocation tests (BPTs) are often used for assessment of treatment efficacy. Usually, the allergen dose provoking a 20% fall of forced expiratory volume in one second (FEV1) (PD20) is determined on a prestudy day, and this single dose is administered for comparisons on study days. The inhalation of allergen may cause both an isolated early asthmatic response (EAR) or, more frequently, an EAR followed by a late asthmatic response (LAR). Whether the method used to elicit EAR, i.e. the inhalation of cumulative doses up to PD20 or the inhalation of a single predetermined PD20, give comparable results has not been established. We have, therefore, compared the results obtained using the two methods. Twelve patients underwent a first BPT with the increasing doses method and a second BPT with a single dose method. EAR, LAR, and allergen-induced increase of methacholine (MCh) sensitivity were compared. Both methods gave similar EAR's and LAR's although EAR tended to be more severe with the increasing dose method than with the single dose method. The ratio of postallergen/preallergen MCh sensitivity was poorly reproducible. PMID- 7841986 TI - The treatment of patients with cystic fibrosis. PMID- 7841987 TI - Challenging ARDS. PMID- 7841988 TI - Modelling antibodies: approach and perspective. PMID- 7841989 TI - Antiphospholipid syndrome in childhood: the great unknown. PMID- 7841990 TI - Antiphospholipid antibodies, thrombosis and atherosclerosis in systemic lupus erythematosus: a unifying 'membrane stress syndrome' hypothesis. PMID- 7841991 TI - Isolated VH4 heavy chain variable regions bind DNA characterization of a recombinant antibody heavy chain library derived from patient(s) with active SLE. AB - In many autoimmune diseases autoantibodies are intimately involved in disease manifestations. Molecular characterization of these autoantibodies should provide insights into the pathogenesis of these diseases, as well as suggest novel avenues for development of therapeutics. While some prior studies suggest that DNA binding may be a characteristic of individual heavy chain variable regions, the ability of these V regions to bind DNA in isolation has not been investigated. We have utilized a bacterial vector for cloning and expressing isolated antibody heavy chain variable regions. RNA was extracted from peripheral blood mononuclear cells of patients with active SLE, cDNA synthesized and heavy chain V regions amplified with VH specific oligonucleotide primers. The VH fragments were cloned into a bacterial expression plasmid including the pelB leader peptide to direct appropriate expression. Recombinant antibodies were screened for binding to 32P-labeled double-stranded plasmid DNA and later also characterized for binding to single-stranded DNA. Binding was confirmed by standard ELISA methodology. Sequence analysis of seven DNA binding VH fragments revealed that they utilized the VH gene family previously described to be associated with autoimmune responses, with a JH6 segment. On VH sequence analysis only one residue substitution in the consensus sequence is needed to form a VH4 germline gene. Potential contact residues with DNA were delineated by three dimensional structure analysis. We concluded that the DNA binding characteristics of VH regions can be examined in the absence of light chain. DNA binding specificity appears to be a property of the germline VH4 gene. Analysis of such V regions can aid in the identification of hypervariable region contact residues important for DNA binding. PMID- 7841992 TI - HLA antigens in Malay patients with systemic lupus erythematosus. AB - Many studies have shown an association between human leucocyte antigens (HLA) and systemic lupus erythematosus (SLE) in the various study populations. Although SLE is not an uncommon disease in the Malaysian Archipelago, and appears to affect all three major racial groups equally (i.e. Southern Chinese, Malays and Southern Indians), very little information is available on the HLA profiles in the two latter groups. In phase I of our study of the HLA profiles in Malaysian SLE patients, the HLA phenotypes (class I: A, B, C; Class II: DR, DQ) of Malay patients with confirmed SLE and 91 normal Malay controls were determined using the microcytotoxicity assay. The strong association between DR (RR 3.28, P = 0.008) concurs with that reported among Chinese and Japanese populations. Moderate to strong associations with HLA-B 7 (RR 4.99, P = 0.02) and Cw 7 (RR 2.94, P = 0.003) were also found. We believe this is the first report of the association of HLA and SLE in the Malay population. PMID- 7841993 TI - Effect of long-acting thromboxane receptor antagonist (BMS 180,291) on experimental antiphospholipid syndrome. AB - Antiphospholipid syndrome (APS) is characterized by recurrent thromboembolic phenomena, recurrent fetal loss and thrombocytopenia associated with high titers of IgG anticardiolipin antibodies and/or lupus anticoagulant. There is an increased platelet aggregation in these patients and thus aspirin was found to be effective in abrogating some of the clinical findings. The purpose of this study was to employ the experimentally induced APS in mice infused with anticardiolipin antibodies, to study the effect of a thromboxane receptor antagonist (BMS, 180, 291) on the various overt manifestations of APS. Experimental APS was induced in pregnant female mice by iv infusion of a pathogenic anticardiolipin antibody (CAM). The mice were then treated daily with 300 micrograms/mouse of BMS. The study group and the untreated group were killed on day 17 of pregnancy. Live and absorbed fetuses and the mean weight of the placentae, fetuses and platelet counts were recorded. BMS treated mice had a significant reduction in fetal resorption rate from 45% to 19.8% and an increase in mean placental and embryo weights (182 vs 104, 1043 vs 721 mg, respectively). In parallel, an increase in platelet count (from 597,100 to 1075,000 platelets/mm3) and decrease in activated thromboplastin time (95 to 44s) was seen. It seems that thromboxane receptor antagonist may be effective in abrogating the diverse manifestations seen in APLS. Increased platelet aggregation may be one of the pathogenetic mechanisms in APS. PMID- 7841994 TI - An electron microscopic study of muscle capillary wall thickening in systemic lupus erythematosus. AB - Capillary vessel wall thickening may contribute to the muscle fibre atrophy and impaired pulmonary gas transfer notable in SLE/MCTD. Using electron microscopy we measured the thickness of unilaminar capillary basement membranes (CBM) and quantified basement membrane laminae and pericyte layers in the skeletal muscle biopsies of 31 patients with SLE, including 14 with MCTD, and 11 controls. Capillary basement membrane thickness was significantly increased in SLE compared with controls (P < 0.01) and was significantly associated with the level of C3dg (P < 0.01). Patients with MCTD had significantly greater layering of pericytes and laminae compared with patients with SLE alone (P < 0.0001 for both variables). Multiple stepwise regression analysis indicated that ANA titre was a good predictor of pericyte layering (R = 0.63, P = 0.003) and of basement membrane lamination (P < 0.0001), with steroid therapy having a significant negative association with the number of laminae (P < 0.02). A negative association between KCO and the number of layers of basement membrane (R = 0.51, P = 0.01) was documented. However, multiple regression analysis revealed no association between parameters of thickened vessel walls and the presence of muscle fibre atrophy. PMID- 7841995 TI - Kikuchi disease and its association with systemic lupus erythematosus. AB - Histiocytic necrotizing lymphadenitis or Kikuchi disease is a rare entity; furthermore, its association with systemic lupus erythematosus (SLE) was only described in 11 patients in seven reports in the world literature. As the disease affects young women and manifests as a systemic illness associated with lymphadenopathy (usually cervical), the importance of continued follow-up to see whether it remains a self-limiting process or evolves into systemic lupus erythematosus should be emphasized. We present the clinical and histopathological data of eight patients with Kikuchi disease diagnosed in one tertiary care centre, two of whom evolved into SLE. White blood count was normal in all except the two patients who evolved into SLE; erythrocyte sedimentation rate was elevated in all patients tested. Kikuchi disease could be misdiagnosed as non Hodgkin's lymphoma or tuberculous lymphadenitis; furthermore, awareness of its association with SLE is emphasized. PMID- 7841996 TI - Autonomic function in systemic lupus erythematosus. AB - A controlled study with paired analysis of data was performed in 34 patients with systemic lupus erythematosus (SLE) and 34 age and sex-matched healthy controls. Autonomic function was not affected significantly in SLE patients as judged by standardised cardiovascular tests. Pancreatic polypeptide (PP) response to meal stimulation, which is impaired in parasympathetic failure, was for unknown reasons found to be significantly increased in SLE patients both in unstimulated and stimulated states. Neither cardiovascular nor serological tests could thus reveal significant autonomic dysfunction in SLE. Drugs with cardiovascular effects highly influenced autonomic function and could thus be misinterpreted as autonomic dysfunction caused by SLE itself. PMID- 7841997 TI - Deforming arthropathy of the hands in systemic lupus erythematosus is associated with antibodies to SSA/Ro and to SSB/La. AB - Thirteen patients with systemic lupus erythematosus and deforming arthropathy (DA) of the hands were compared with 111 patients with SLE without deforming arthropathy. Clinical features were comparable in the two groups. Patients fulfilling criteria for mixed connective tissue disease (MCTD) were not included in the present study. A higher prevalence of antibodies to SSA/Ro (P < 0.0125) and SSB/La (P < 0.004) were found in the SLE-DA group. The detection of antibodies to SSA/Ro and SSB/La was even more strictly associated with DA in SLE antibodies to SSA/Ro alone (P < 0.002). Regarding the fine specificity of anti SSA/Ro, a prevalent response to the 52 kD protein of the Ro antigen was found. We conclude that patients with SLE developing deformities of the hands belong to a subset of patients with circulating antibodies to SSA/Ro, particularly to the 52 kD component, and to SSB/La. PMID- 7841998 TI - Cytokine gene profile in circulating blood mononuclear cells from patients with systemic lupus erythematosus: increased interleukin-2 but not interleukin-4 mRNA. AB - Cytokines are important in developmental and effector pathways of lymphocyte function. Our objective was to elucidate the profile of cytokines produced by circulating mononuclear cells from patients with systemic lupus erythematosus as estimated from studies of cytokine-gene activation. cDNA prepared by reverse transcription of lymphocyte mRNA was amplified using the polymerase chain reaction and normalized on the basis of beta-actin gene expression. Of 10 cytokines investigated in 16 individuals, differences between SLE and controls were found in only three. IL-2 transcripts were detected in four of six cases of subjects hospitalized for active SLE, but in only one of seven healthy controls, and none of three cases with pulmonary tuberculosis. By contrast, IL-4 transcripts were decreased compared with healthy controls and patients with tuberculosis. Also, TGF beta transcripts appeared to be decreased in SLE. All individuals studied regularly demonstrated high levels of transcripts for IL-1 beta, IL-6 and TNF alpha and transcripts for IFN gamma, TNF beta, IL-5 and IL-10 were variably expressed. In a second group of six SLE patients with less active disease, there was also a decrease in IL-4 expression compared with six healthy controls. Moreover, assays performed on sera from patients with active SLE revealed that IL-4 levels were not increased. Although in mice this cytokine has a well documented role in supporting antibody production, this study provides no evidence that IL-4 is involved in the B cell hyperactivity characteristic of human SLE. PMID- 7841999 TI - Antiphospholipid antibody testing in patients with pregnancy loss. PMID- 7842000 TI - Severe valvular heart disease in a patient with primary antiphospholipid syndrome. AB - Valvular replacement was performed in a patient with primary antiphospholipid syndrome and severe mitral insufficiency. The valvular tissue presented thrombotic phenomena and fibrosis with minimum inflammatory component. PMID- 7842001 TI - Dual pharmacological effect of aminoglutethamide. PMID- 7842002 TI - The glittering prize. PMID- 7842003 TI - Visualizing tumour amplification. PMID- 7842004 TI - On the pulse of genetic cardiology. PMID- 7842005 TI - Exclusion of HRAS from long QT locus. PMID- 7842006 TI - Predicting the total number of human genes. PMID- 7842007 TI - Alzheimer's disease and the family effect. PMID- 7842008 TI - The costs of human inbreeding and their implications for variations at the DNA level. AB - An analysis of the world literature on the children of first cousin marriages reveals that the depression of survival in offspring followed from birth (including late miscarriages; at about six months gestation or later) to a median age of 10 years is constant (4.4% +/- 4.6) across a wide range of values for population prereproductive mortality. There is thus no evidence for the action of conditional lethals. On the basis of these data, it is calculated that the average human is heterozygous for only 1.4 lethal equivalents capable of acting over this portion of the life cycle. The implications of these results are discussed in the context of genetic counseling, and the biomedical significance of variation in DNA. PMID- 7842009 TI - Isolation and characterization of mutations in the human holocarboxylase synthetase cDNA. AB - Holocarboxylase synthetase (HCS) plays an essential role in biotin utilization in eukaryotic cells and its deficiency causes biotin-responsive multiple carboxylase deficiency in humans. We have cloned the human HCS cDNA and show that antiserum against the recombinant protein immunoprecipitates human HCS. A one base deletion resulting in a premature termination and a missense mutation (Leu to Pro) were found in cells from siblings with HCS deficiency. Human HCS shows homology to BirA, which acts as both a biotin-[acetyl-CoA-carboxylase] ligase and a biotin repressor in E. coli, suggesting a functional relationship between the two proteins. The human HCS gene maps to chromosome 21q22.1. PMID- 7842010 TI - Normal long bone growth and development in type X collagen-null mice. AB - To investigate the role of type X collagen in skeletal development, we have generated type X collagen-null mice. Surprisingly, mice without type X collagen were viable and fertile and had no gross abnormalities in long bone growth or development. No differences were detected between the type X collagen-null mice and controls when growth plates of both newborn and 3-week old mice were examined by histology and by immunostaining for extracellular matrix components of bone including osteopontin, osteocalcin and type II collagen. Our results suggest that type X collagen is not required for long bone development. However, mice and humans with dominant acting type X collagen mutations have bone abnormalities, suggesting that only the presence of abnormal type X collagen can modify bone growth and development. PMID- 7842011 TI - Episodic ataxia/myokymia syndrome is associated with point mutations in the human potassium channel gene, KCNA1. AB - Episodic ataxia (EA) is a rare, familial disorder producing attacks of generalized ataxia, with normal or near-normal neurological function between attacks. One type of EA is characterized by brief episodes of ataxia with myokymia (rippling of muscles) evident between attacks. Linkage studies in four such families suggested localization of an EA/myokymia gene near the voltage gated K+ channel gene, KCNA1 (Kv1.1), on chromosome 12p. Mutation analysis of the KCNA1 coding region in these families identified four different missense point mutations present in the heterozygous state, indicating that EA/myokymia can result from mutations in this gene. PMID- 7842012 TI - Two long QT syndrome loci map to chromosomes 3 and 7 with evidence for further heterogeneity. AB - Cardiac arrhythmias cause sudden death in 300,000 United States citizens every year. In this study, we describe two new loci for an inherited cardiac arrhythmia, long QT syndrome (LQT). In 1991 we reported linkage of LQT to chromosome 11p15.5. In this study we demonstrate further linkage to D7S483 in nine families with a combined lod score of 19.41 and to D3S1100 in three families with a combined score of 6.72. These findings localize major LQT genes to chromosomes 7q35-36 and 3p21-24, respectively. Linkage to any known locus was excluded in three families indicating that additional heterogeneity exists. Proteins encoded by different LQT genes may interact to modulate cardiac repolarization and arrhythmia risk. PMID- 7842013 TI - Long-term gene expression and phenotypic correction using adeno-associated virus vectors in the mammalian brain. AB - Adeno-associated viral (AAV) vectors are non-pathogenic, integrating DNA vectors in which all viral genes are removed and helper virus is completely eliminated. To evaluate this system in the post-mitotic cells of the brain, we found that an AAV vector containing the lacZ gene (AAVlac) resulted in expression of beta galactosidase up to three months post-injection in vivo. A second vector expressing human tyrosine hydroxylase (AAVth) was injected into the denervated striatum of unilateral 6-hydroxydopamine-lesioned rats. Tyrosine hydroxylase (TH) immunoreactivity was detectable in striatal neurons and glia for up to four months and we also found significant behavioural recovery in lesioned rats treated with AAVth versus AAVlac controls. Safe and stable TH gene transfer into the denervated striatum may have potential for the genetic therapy of Parkinson's disease. PMID- 7842014 TI - Identification of cryptic sites of DNA sequence amplification in human breast cancer by chromosome microdissection. AB - We have performed microdissection of 16 putative homogeneously staining regions (hsrs) from nine different breast cancer cell lines in order to determine their chromosomal origin and composition. As expected, the most commonly amplified chromosomal band-region was 17q12 (containing ERBB2). However, regions not containing known oncogenes were also identified, including 13q31 (5/9 cases) and 20q12-13.2 (4/9 cases). The chromosomal composition of the integrated amplified DNA within each hsr was determined and in 13/16 cases (81%), hsrs were shown to be composed of two or more chromosomal regions. These studies shed light on the mechanism of formation of hsrs, and identify chromosomal regions likely to harbour genes amplified in breast cancer. PMID- 7842015 TI - Minisatellite mutation rate variation associated with a flanking DNA sequence polymorphism. AB - Human minisatellite mutation in the male germline frequently involves complex interallelic gene conversion events restricted to one end of the tandem repeat array. Some alleles at minisatellite MS32 show reduced variability in human populations and are associated with a G to C transversion upstream of the array. Analysis of single sperm demonstrated a frequently profound reduction in mutation rate at alleles carrying the C variant. This mutation suppression acts in cis, but does not affect the ability of an allele to act as sequence donor during gene conversion. This mutation rate polymorphism provides strong evidence for elements near the minisatellite that regulate tandem repeat instability. PMID- 7842016 TI - Structure and expression of the gene responsible for the triplet repeat disorder, dentatorubral and pallidoluysian atrophy (DRPLA). AB - Dentatorubral and pallidoluysian atrophy is associated with expansion of an unstable CAG repeat on chromosome 12p. We have determined the nucleotide sequences of overlapping cDNA clones and deduced the gene structure. The gene is ubiquitously expressed to form a single 4.5 kb transcript and encoded by an open reading frame of 1184 amino acids (aa), in which a polyglutamine track with variable length starts at aa 484. Although the predicted amino acid sequence does not reveal any function, it does contain several interesting motifs consisting of a simple repeated amino acid sequence, a homo-proline track, two stretches of arginine-glutamic acid dipeptides and a stretch of alternative histidine residues. These results provide clues toward understanding neurodegenerative diseases associated with triplet repeat expansion. PMID- 7842017 TI - Maintenance of an open reading frame as an additional level of scrutiny during splice site selection. AB - Although nonsense mutations have been associated with the skipping of specific constitutively spliced exons in selected genes, notably the fibrillin gene, the basis for this association is unclear. Now, using chimaeric constructs in a model in vivo expression system, premature termination codons are identified as determinants of splice site selection. Nonsense codon recognition prior to RNA splicing necessitates the ability to read the frame of precursor mRNA in the nucleus. We propose that maintenance of an open reading frame can serve as an additional level of scrutiny during exon definition. This process may have pathogenic and evolutionary significance. PMID- 7842018 TI - A locus on chromosome 15q26 (IDDM3) produces susceptibility to insulin-dependent diabetes mellitus. AB - To identify new loci predisposing to insulin-dependent diabetes mellitus (IDDM), we have investigated 250 families with more than one diabetic child. Affected sibling pair linkage analysis revealed strong evidence for an IDDM susceptibility locus near D15S107 on chromosome 15q26 (P = 0.0010) termed IDDM3. Families less predisposed through genes in the HLA region provided most of the evidence for linkage. In these families, discordant sibling pairs also showed linkage (P = 0.0052), and sibling pair disease concordance or discordance was strongly related to the proportion of genes the pair shared at D15S107 (P = 0.0003). Our study also revealed evidence for an IDDM locus on chromosome 11q13 (IDDM4) using affected siblings (P = 0.0043), but no evidence using discordant siblings. PMID- 7842020 TI - No health insurance, no safety net, no letup. PMID- 7842019 TI - Occipital horn syndrome and a mild Menkes phenotype associated with splice site mutations at the MNK locus. AB - We have found mutations in the Menkes disease gene (MNK) which impair, but do not abolish, correct mRNA splicing in patients with less severe clinical phenotypes. In one family, four males aged 2-36 years with a distinctive Menkes variant have a mutation at the +3 position of a splice donor site near the 3' end of the Menkes coding sequence that is associated with exon skipping and a stable mutant transcript. In an unrelated 15-year-old male with typical occipital horn syndrome, a point mutation at the -2 exonic position of a splice donor site in the middle of the gene causes exon-skipping and activation of a cryptic splice acceptor site. In both mutations, maintenance of some normal splicing is demonstrable by RT-PCR, cDNA sequencing and ribonuclease protection. PMID- 7842021 TI - Policy ... tax exempt status. PMID- 7842022 TI - Career advancement ... new benefit plans. PMID- 7842023 TI - Stone age solutions? IS vendors aren't keeping pace with today's delivery needs. AB - Satisfaction is one thing we're all looking for in life and work, but when it comes to information systems, the concept can be elusive. H&HN's exclusive survey of CIOs finds varying levels of current--and anticipated--satisfaction with IS vendors and products. Is codevelopment the answer? PMID- 7842024 TI - The rise of the CIO. AB - If you still think of information management as "the data processing guys down in the basement," it's time to rethink. The CIOs who will lead delivery networks toward successful IS strategies are a new breed, and they're on the move. Exclusive Hay Group data and analysis. PMID- 7842025 TI - CEO summit. The leadership experience--roundtable discussion. AB - All across the country, hospitals, physicians and insurers are sizing each other up as potential strategic partners. But there's much ground to be covered before a final agreement is reached, and not every decision is based on facts and figures. Sometimes it's the personal interaction between CEOs that makes the deal happen--or not. McManis Associates and Hospitals & Health Networks brought together a roundtable of CEOs to talk about the ups and downs and the ins and outs of the leadership experience. Following is a series of first-person accounts by roundtable participants. PMID- 7842027 TI - When the smoke clears ... after sifting through the ashes of a doomed merger, doctors and executives finally learn to work as one. PMID- 7842026 TI - Power notebook. PMID- 7842028 TI - Planning. A strategic kickoff. PMID- 7842029 TI - Integrated care. Wanted: experienced juggling act. PMID- 7842030 TI - Data watch. For our neediest kids, it's not a happy new year. PMID- 7842031 TI - A thumbs-up in Cleveland. PMID- 7842032 TI - Eat to your heart's content. PMID- 7842033 TI - Whose hospital is it anyway? PMID- 7842034 TI - Operation health care. Defense industry peddles its wares to health systems. PMID- 7842035 TI - Closings: the end of the line doesn't mean the end of serving the community. PMID- 7842036 TI - CIOs and the D.R.I.P. (data-rich, information-poor) syndrome. PMID- 7842037 TI - Neural computing in medicine. PMID- 7842038 TI - On the quality of neural net classifiers. AB - This paper describes several concepts and metrics that may be used to assess various aspects of the quality of neural net classifiers. Each concept describes a property that may be taken into account by both designers and users of neural net classifiers when assessing their utility. Besides metrics for assessment of the correctness of classifiers we also introduce metrics that address certain aspects of the misclassifications. We show the applicability of the introduced quality concepts for selection among several neural net classifiers in the domain of thyroid disorders. PMID- 7842039 TI - A neural model of cortical map reorganization following a focal lesion. AB - Neural models based on fairly simple assumptions have been able to account for topographic map formation in sensory cortex and the map reorganization that occurs following repetitive stimulation and deafferentation. The spontaneous reorganization that follows an acute focal cortical lesion, however, has not been modeled successfully. We have developed a computational model of cortex based on the hypothesis that cortical activation is distributed competitively. This model exhibited spontaneous reorganization following a focal cortical lesion and makes a testable prediction about the time course of that reorganization. We describe our model and the hypotheses upon which it is based, and examine some of the factors which influence post-lesion reorganization. We also demonstrate that the extent of post-lesion reorganization can be greatly improved through selective repetitive stimulation, suggesting a clinical rehabilitation technique that can be tried in an experimental setting for patients suffering sensory loss due to focal brain damage. PMID- 7842040 TI - Identifying the measurement noise in glaucomatous testing: an artificial neural network approach. AB - Diagnosis of visual function losses in glaucomatous patients depends to a large extent on the analysis of the data collected from corresponding psychophysical tests. One of the main difficulties in obtaining reliable data from patients in these tests is the measurement noise caused by the learning effect, inattention, failure of fixation, fatigue etc. Using Kohonen's self-organising feature map, we have developed a computational method to distinguish between the noise and true measurement and to provide an instant assessment of reliability of the computer based visual function test. In particular we have experimented with 270 test records from glaucoma patients and glaucoma suspects and found that this method provides a satisfactory way of locating and rejecting noise in the test data, an improvement over conventional statistical methods. This method can also provide doctors with a clear view of the patient's behaviour during the test, thus assisting in their diagnostic decision making process. PMID- 7842041 TI - On using feedforward neural networks for clinical diagnostic tasks. AB - In this paper we present an extensive comparison between several feedforward neural network types in the context of a clinical diagnostic task, namely the detection of coronary artery disease (CAD) using planar thallium-201 dipyridamole stress-redistribution scintigrams. We introduce results from well-known (e.g. multilayer perceptrons or MLPs, and radial basis function networks or RBFNs) as well as novel neural network techniques (e.g. conic section function networks) which demonstrate promising new routes for future applications of neural networks in medicine, and elsewhere. In particular we show that initializations of MLPs and conic section function networks--which can learn to behave more like an MLP or more like an RBFN--can lead to much improved results in rather difficult diagnostic tasks. PMID- 7842042 TI - Removing the assumption of conditional independence from Bayesian decision models by using artificial neural networks: some practical techniques and a case study. AB - The article describes how artificial neural networks with special designs can be applied to approximate a subjective Bayesian decision model without the assumption of conditional independence. New techniques are proposed to resolve some of the practical difficulties during the processes of problem structuring, knowledge elicitation, quantitative modeling, and model interpretation. A Bayesian model considering the conditional dependencies to predict a teenager's marijuana use was constructed by experts using these techniques, and compared to another conventional Bayesian model which assumed conditional independence. The new approach without the assumption of conditional independence had predictive power (r = 0.7) in the test of linearity compared to the conventional approach (r = 0.58) on a data set (n = 129). Its receiver operating characteristic curve dominated the alternative approach within the range (true positive fraction > 0.7) that we were interested in. The interpretations of the possible conditional dependencies provided by the artificial neural network after the training process were consistent with the expert's descriptions. PMID- 7842043 TI - Role of the hippocampus in epilepsy. PMID- 7842044 TI - Hippocampal resections and the use of human tissue in defining temporal lobe epilepsy syndromes. AB - From the clinical perspective, a continued analysis of the hippocampus in animal models of epilepsy as well as in human material will be critical to finally understanding MTLE. Through the continued evolution of surgical feedback to our preoperative localization studies, and from our basic science studies on resected tissue, we propose that 1) the hippocampus is critical to developing medial temporal lobe excitability, and that the inhibitory hilar interneurons which suffer most during developmental injury are likely to be involved in this process; 2) the hippocampus is not the only potentially hyperexcitable medial temporal lobe structure, but seems to function (both normally and pathologically) in a recurrent loop consisting of the entorhinal cortex, amygdala, and temporal neocortices; and 3) hypotheses derived from animal model studies, and data obtained directly from analysis of human tissue can be used to refine epilepsy classifications. PMID- 7842045 TI - On the relationship between neuropathology and pathophysiology in the epileptic hippocampus of humans and experimental animals. PMID- 7842046 TI - Long-term structural and functional alterations induced in the hippocampus by kindling: implications for memory dysfunction and the development of epilepsy. PMID- 7842047 TI - Functional significance of hippocampal plasticity in epileptic brain: electrophysiological changes of the dentate granule cells associated with mossy fiber sprouting. PMID- 7842048 TI - Developmental plasticity and hippocampal epileptogenesis. PMID- 7842049 TI - From seizures to neo-synaptogenesis: intrinsic and extrinsic determinants of mossy fiber sprouting in the adult hippocampus. PMID- 7842051 TI - Seizure circuits in the hippocampus and associated structures. PMID- 7842050 TI - Simulations of epileptiform activity in the hippocampal CA3 region in vitro. PMID- 7842052 TI - Effects of anticonvulsant drugs on hippocampal neurons. PMID- 7842053 TI - Astrocytic dye coupling in rat hippocampus: topography, developmental onset, and modulation by protein kinase C. AB - Previous studies have shown that astrocytes constitute a functional syncytium whereas the cytoplasmata of individual cells are connected via gap junctions. Many studies have used cultured astrocytes and have examined electrical coupling with the help of double electrode techniques. Another approach has been the immunohistochemical detection of gap junction proteins in sections of brain tissue. From the results of these experiments it is difficult to infer the extent of astrocytic coupling in situ. To get an impression of the distribution of coupled astrocytes we took advantage of the hippocampal slice preparation which leaves the topography of neurons and astrocytes intact. We performed injections of low molecular weight dyes into single electrophysiologically identified astrocytes. As these dyes can pass through gap junctions this leads to the staining of all connected cells in a certain area, limited by the diffusional spread of the dye. The results show that there is virtually no border to astrocytic coupling between the diverse hippocampal subdivisions. This widespread coupling could already be detected at postnatal day 4, the earliest age tested. Activation of protein kinase C with phorbol esters showed that it is possible to reduce gap junctional communication by some extent. We conclude that although no compartmentalization was seen with respect to astrocytic coupling, the intercellular communication of these glial cells has the capability of being regulated for example by neuronal signals which activate the phospholipase C pathway in astrocytes. PMID- 7842054 TI - Induction of glial fibrillary acidic protein immunoreactivity in the rat dentate gyrus after adrenalectomy: comparison with neurodegenerative changes using silver impregnation. AB - In the present study we performed a light microscopic anatomical comparison of adrenalectomy (ADX)-induced neurodegeneration using silver impregnation and reaction of astroglial cells using GFAP immunocytochemistry in the hippocampus of the rat. Three survival times following ADX were studied: 24 hours, 3 days, and 3 weeks. Twenty-four hours following ADX we found no degenerative changes or altered GFAP immunostaining. Three days after adrenalectomy, argyrophilic somata appeared in the granular cell layer of the dentate gyrus. Argyrophilic dendrites were seen in the molecular layer of the dentate gyrus and neuritic argyrophilia were seen in the mossy fiber layer. Induction of GFAP immunoreactivity occurred simultaneously with degeneration. Increased GFAP immunoreactivity could be observed 3 days after adrenalectomy in the molecular layer of the dentate gyrus, granular cell layer, sub and supragranular cell layer, and mossy fiber layer. Size and shape of astroglial cells were changed, and their processes in the molecular layer changed from unidirectional to randomly organized. Degeneration and astroglial reaction were more pronounced 3 weeks after adrenalectomy and both were prevented by adding corticosterone to the drinking solution. Animals that did not show degenerative changes showed no increased GFAP immunoreactivity, while both effects were confined to the dentate gyrus and mossy fiber zone. These results show that there is a close relationship between the induction of GFAP immunoreactivity in the hippocampus of the rat and neuronal degeneration in the dentate gyrus following ADX, both in time and space. PMID- 7842055 TI - Effects of medial septal or unilateral hippocampal inactivations on reference and working spatial memory in rats. AB - The memory performances of rats receiving a reversible inactivation of either the medial septum or one side of the ventral hippocampus were compared in a radial arm maze task allowing the assessment of both working and reference memory. After pre-surgery training, rats were chronically equipped with bilateral cannulae into the ventral hippocampus and a single cannula into the medial septum. Following post-surgery retraining, animals received a series of test trials during which they received saline or lidocaine injections in either the medial septum or one side of the ventral hippocampus. Lidocaine injections in either structure resulted in both reference and working memory deficits. However, animals were more impaired after septal injections than after unilateral hippocampal injections. This result suggests that the septo-hippocampal formation acts as a functionally homogeneous structure essential for spatial processing. PMID- 7842056 TI - Synaptic and intrinsic properties of neurons of origin of the perforant path in layer II of the rat entorhinal cortex in vitro. AB - Layer II of the entorhinal cortex (EC) provides the first step in the hippocampal trisynaptic loop via the perforant path projection to the dentate gyrus. While a great deal is known about this projection and the properties of the dentate granule cells, much less information is available concerning the properties of and synaptic inputs to the cells of origin of the pathway in layer II. The present experiments have employed a slice preparation of the rat EC to study the intrinsic membrane properties and synaptic organization of layer II neurons. Two types of neurons could be identified electrophysiologically. The majority were designated type I and displayed a pronounced time-dependent inward rectification in the hyperpolarizing direction. Type II displayed little evidence of this characteristic. However, morphological examination suggested that both types were spiny stellate neurons projecting via the perforant path. Synaptic responses of both types displayed evidence of excitatory inputs mediated by both N-methyl-D aspartate (NMDA) and non-NMDA glutamate receptors. In general, however, at low frequencies the responses were dominated by inhibitory inputs mediated by both GABAA and GABAB receptors. At higher frequencies the bias was shifted much more toward excitation. The contribution of synaptic and intrinsic properties of layer II neurons to the processing capabilities of the EC is discussed. PMID- 7842057 TI - Dopamine D2 receptor expression in hippocampus and parahippocampal cortex of rat, cat, and human in relation to tyrosine hydroxylase-immunoreactive fibers. AB - A detailed study comparing the distribution of D2 receptors and tyrosine hydroxylase-immunoreactive fibers in the hippocampus and parahippocampal cortices of the rat, cat, and human was conducted. The distribution of [125I]epidepride binding to D2 receptors along the transverse and longitudinal axes of the hippocampus and parahippocampus differed among the species. In rat hippocampus, the number of sites was highest in septal portions of lacunosum-moleculare of CA1 and stratum moleculare of the subiculum. Virtually no binding to D2 receptors existed in the temporal hippocampus. For the cat hippocampus, the highest binding existed in the inner one-third of the molecular layer of the dentate gyrus (DG). There were also significant numbers of D2 receptors in strata radiatum and oriens of the CA subfields, with almost undetectable levels in lacunosum moleculare and subiculum. The number of sites was higher in the septal than temporal hippocampus. In the human hippocampus, highest binding was observed in the molecular layer of DG and the subiculum, with lower levels in strata oriens and lacunosum-moleculare of CA3, and very low binding in CA1. The histochemical demonstration of the pattern of mossy fibers revealed an organization complementary to that of D2 receptors in cat and human. In none of the species was there significant expression of D2 receptors in the entorhinal cortex, except in the caudal extreme of this region in the rat. In that region a trilaminar pattern was exhibited that continued into the perirhinal cortex. A trilaminar pattern of D2 receptor expression was observed in the perirhinal cortex of all species, with the highest values in the external and deep laminae and low expression in the middle laminae. The organization of dopamine fibers was assessed by comparing the distribution of tyrosine hydroxylase-positive and dopamine beta-hydroxylase-immunoreactive fibers in these same regions. It revealed consistent mismatches between the pattern of D2 receptor expression and dopaminergic innervation in all three species. The implications for this mismatch are discussed. It is hypothesized that the distribution of D2 receptors, and not of dopamine fibers, determines what neural systems dopamine influences in the hippocampal complex. PMID- 7842058 TI - Computational analysis of the role of the hippocampus in memory. AB - The authors draw together the results of a series of detailed computational studies and show how they are contributing to the development of a theory of hippocampal function. A new part of the theory introduced here is a quantitative analysis of how backprojections from the hippocampus to the neocortex could lead to the recall of recent memories. The theory is then compared with other theories of hippocampal function. First, what is computed by the hippocampus is considered. The hypothesis the authors advocate, on the basis of the effects of damage to the hippocampus and neuronal activity recorded in it, is that it is involved in the formation of new memories by acting as an intermediate-term buffer store for information about episodes, particularly for spatial, but probably also for some nonspatial, information. The authors analyze how the hippocampus could perform this function, by producing a computational theory of how it operates, based on neuroanatomical and neurophysiological information about the different neuronal systems contained within the hippocampus. Key hypotheses are that the CA3 pyramidal cells operate as a single autoassociation network to store new episodic information as it arrives via a number of specialized preprocessing stages from many association areas of the cerebral cortex, and that the dentate granule cell/mossy fiber system is important, particularly during learning, to help to produce a new pattern of firing in the CA3 cells for each episode. The computational analysis shows how many memories could be stored in the hippocampus and how quickly the CA3 autoassociation system would operate during recall. The analysis is then extended to show how the CA3 system could be used to recall a whole episodic memory when only a fragment of it is presented. It is shown how this recall could operate using modified synapses in backprojection pathways from the hippocampus to the cerebral neocortex, resulting in reinstatement of neuronal activity in association areas of the cerebral neocortex similar to that present during the original episode. The recalled information in the cerebral neocortex could then be used by the neocortex in the formation of long-term memories. PMID- 7842059 TI - Development of the AHCPR-sponsored heart failure guideline: methodologic and procedural issues. AB - BACKGROUND: RAND, a nonprofit research and policy organization, served as contractor for the Agency for Health Care Policy and Research (AHCPR)-sponsored guideline on the management of patients with heart failure due to left ventricular systolic dysfunction. PANEL: At meetings of the 16-member panel, discussions concerning practice recommendations were held until a consensus was reached. A draft algorithm was the key tool, serving as a starting point for panel discussion. The algorithm was revised after almost every panel meeting. KEY METHODS AND PROCEDURAL ISSUES: Early decisions included how best to (1) focus the guideline and literature review, (2) rate the strength of evidence underlying practice recommendations, and (3) determine the relationship between strength of evidence and strength of recommendation. In the absence of data, or when panelists did not share a common opinion, the panel attempted to achieve a consensus. An example of this process--when and how patients should be evaluated for possible coronary artery revascularization--is discussed at length. Unlike previous AHCPR guideline panels, this panel solicited opinions of national experts early and often during guideline development. This process helped the panelists arrive at conclusions on certain controversial issues. CONCLUSIONS: The guideline development process was complex and painstaking. The panelists and project staff believe that frequent peer review helped produce a guideline that can be widely accepted across clinical and geographic lines. PMID- 7842060 TI - Making judgements about treatment effectiveness based on health outcomes: theoretical and practical issues. AB - ISSUES: This article considers the problem of deciding which health care outcomes are important and relevant for (1) developing management recommendations for clinical practice guidelines and (2) evaluating patients' responses to treatment. DECISIONS: The Heart Failure Guideline Panel sponsored by the Agency for Health Care Policy and Research (AHCPR) decided that for both purposes the relevant outcomes are those experienced directly by patients: mortality and health-related quality of life (HRQOL). Changes in intermediate outcomes, such as test results of various kinds, were deemed insufficient evidence of effectiveness. CONCLUSIONS: In the context of heart failure, mortality risk (prognosis) can be measured using a variety of biochemical and physiological variables, but changes in these variables do not appear to correspond to changes in prognosis. For this reason, the Heart Failure Guideline Panel recommended that patients' responses to treatment be guided by signs and symptoms, rather than test results (for example, echocardiographic measurement of left-ventricular function or exercise-tolerance testing). HRQOL is best assessed by direct patient self-reports. Although patients may be influenced by a host of other variables (for example, mood, adaptation to chronic disease, placebo effect), self-reports will probably always represent the "gold standard" in assessing HRQOL. The reliability and validity of these reports can be enhanced by using standardized instruments or by incorporating questions from such instruments into the history-taking aspect of patient evaluation and monitoring. Finally, physical examination and submaximal exercise testing can provide additional information that can supplement patient reports. Information from these sources must be evaluated carefully in light of patients' self-reported HRQOL. PMID- 7842061 TI - Combining benchmarking with other quality tools to achieve breakthroughs in admitting. AB - BACKGROUND: A cross-industry benchmarking study in which St Joseph's Regional Health Systems participated recommended that the admissions process (that is, preverifying insurance, obtaining demographic information) be completed before patients arrive at the hospital. To apply this best practice at St Joseph's, management established three team efforts. IMPROVING PREVERIFICATION. One team was assigned to improve the insurance preverification process. After cross training staff to carry out preverification and piloting a electronic, on-line preverification system, the team increased St Joseph's preverification rate from 2% to 70% for scheduled patients. EXPLORING SEAMLESS REGISTRATION: After exploring solutions for an on-line system that will be integrated across the St Joseph system, the team recommended expanding the current computer system to include all entities and to integrate demographic and clinical information. In addition, a subteam reduced the number of registration forms patients must fill out from eight to one. REDESIGNING ADMISSIONS/REGISTRATION. As part of its restructuring effort, St Joseph's is redesigning six core processes, including admissions/registration. This redesign team is currently implementing two recommendations from the benchmarking study: express admitting and centralized scheduling. LESSONS LEARNED: Organizations are advised to understand the process in its current state by collecting data and working toward improvement goals--and to be prepared for changes in job functions and allocation of resources. Other recommendations are offered to organizations attempting to apply best practices from a benchmarking study. PMID- 7842062 TI - Continuous quality improvement and knowledge for improvement applied to asthma care. AB - BACKGROUND: Two key ideas in the practice of continuous quality improvement (CQI) in health care are knowledge for improvement as distinguished from professional knowledge in improving the end results of patient care and the failure of the bad apple theory to explain variation in outcomes. METHODS: As part of their eight week primary care clerkship, medical students at Case Western Reserve University (Cleveland, Ohio) are assigned to more than 20 sites in the greater Cleveland area where they observe and report on the cost and outcome of care for a patient with asthma. (An earlier article presented run charts and fishbone diagrams based on these reports.) In continuing this project, as described in this article, students report on the frequency of causes of variation in costs and outcomes of care. RESULTS: Students are asked to cite the one factor they believe had the most important effect on the cost and clinical outcome of the asthma patient they studied. For cost variation ranked by frequency, disease severity and site of care are reported most frequently, each accounting for 18% of responses. The most frequently reported cause of outcome variation was disease severity. No correlation was found between cost and outcome; higher costs do not produce healthier patients nor are they associated with greater outcome severity. For the nine most frequently used sites of care, the one-way analysis of means for costs shows that average costs for eight of nine sites are well within the expected range. Only one site (G) falls outside the upper boundary. Bringing this one "bad apple" site into conformity would have very little effect on overall costs. The one-way analysis of standard deviations shows that there may be only one case in the site that explains the bad apple outlier. CONCLUSION: Although more than one half of the causes of asthma variation reported in this study fall outside traditional professional knowledge, most of the content of health professions education still falls within the professional realm. Real improvement will require combining traditional professional knowledge with knowledge for improvement. PMID- 7842063 TI - Using pharmacist clinical intervention data for quality improvement of medication use and physician assessment. AB - BACKGROUND: Patient-specific intervention data are often used for drug usage evaluation (DUE), but their use in physician assessment is less often discussed. In response to the quality assurance department's request, the pharmacy department at the Medical College of Georgia (Augusta) developed a database and a reporting system that supports quality assessment of the medical staff, identifies housestaff education needs, and directs efforts for improvement in medication use. THE REPORTING SYSTEM: In 1991 the comprehensive, concurrent screening of drug therapy by pharmacists formed the foundation of the hospital's DUE program. Each month information from the pharmacy database is sorted with use of a spreadsheet software program to generate medical department-level reports and for use in physician reappointment. Identified performance deficiencies can be used to educate individual prescribers and to develop educational programs for the department or specialty areas. Feedback from the medical staff assessment is useful for pharmacist education, such as identifying newly reported indications and dosage regimens. RESULTS: During the first six months after all pharmacists began participating in the reporting program, a mean of 224 interventions were recorded monthly. For the period January through June 1994, 400-550 interventions were recorded monthly. System improvements in medication during the first year of implementation included hospitalwide guidelines for parenteral potassium and phosphate dosing and administration and a renewed focus on patient allergies. CONCLUSION: Emphasis for use of intervention data has shifted from identifying "problem" persons to improving performance by identifying topics for corrective education and redesigning systems to promote positive patient outcomes. PMID- 7842064 TI - Using Hoshin planning in total quality management: an interview with Gerry Kaminski and Casey Collett. Interview by Maggie Kennedy. PMID- 7842065 TI - [Exanthema in infants and in children. Where are we in 1993?]. PMID- 7842066 TI - [Liquid ventilation or back to aquatic life]. PMID- 7842067 TI - [Orbital cellulitis in children]. AB - BACKGROUND: Because the potential for complications is great, orbital cellulitis must be recognized promptly and treated aggressively. POPULATION AND METHODS: The files of 38 children admitted from 1988 to 1993 because of orbital or periorbital cellulitis were retrospectively analyzed. Clinical findings included fever, edema, pain, rhinorrhea, conjunctivitis, limitation of eye movement, loss of vision and ophthalmoplegia. All patients had hemogram, ionogram, blood cultures, search for soluble antigens in blood and/or urine, C-reactive protein measurement; they also had roentgenographic examination of the sinuses, orbital ultrasonography and/or CT scan in patients with retroseptal cellulitis. All patients were given systemic antibiotic therapy. RESULTS: Thirty-five patients had preseptal and three retroseptal cellulitis. Preseptal cellulitis was associated to sinusitis in 17 patients, to ocular infection in 11 (seven conjunctivitis and four dacryocystitis), to an infected wound in six. Seventy three per cent of the patients with ocular infection were less than 2 years of age with a significant preponderance of girls (64%). The three cases of retroseptal cellulitis were associated to sinusitis. Orbital echography was performed in five cases, permitting to recognize the three cases of retroseptal cellulitis that was confirmed by CT scan. Twenty-five of the 38 children were given oral antibiotics during the days preceding admission, explaining the relative rarity of positive bacteriological findings (seven cases). Thirty-five of the 38 children were given IV cefotaxime + fosfomycin, associated to netromycin in 16 cases. Mean duration of treatment was 3 days (range: 1-7). IV antibiotherapy was followed by oral amoxicillin-clavulanic acid administration in 25 patients and pristinamycin in 11. CONCLUSIONS: Orbital cellulitis in children, more frequently preseptal, have a good prognosis under adapted antibiotherapy. A retroseptal cellulitis requires multidisciplinary management because of the risk of extension of infection from the orbit to the eye and/or into the cranial cavity. PMID- 7842068 TI - [Endocrine evaluation and evolution of intrasellar craniopharyngioma (CPIS): study of 8 cases]. AB - BACKGROUND: Craniopharyngiomas generally develop either in the suprasellar region or in both suprasellar and intrasellar regions. Purely intrasellar craniopharyngiomas are rare in children; they have special clinical and radiological features and pose specific therapeutic problems. POPULATION AND METHODS: Eight patients (five girls and three boys), aged 7 to 17 years, were admitted from 1976 to 1992 with a diagnosis of intrasellar craniopharyngioma without extrasellar development. Search for endocrine deficiencies was performed in all these patients as well as radiological investigation (skull X-rays, CT scan and MRI). RESULTS: Persistent delayed growth was the main complaint in seven out of the eight patients. Headache was seen in three patients. The tumor was fortuitously discovered after cranial traumatism in one. Initial endocrine investigations showed growth hormone deficiency in all patients; deficiency in thyrotropin was seen in five, in adenocorticotropin in six. Three patients had moderately increased levels of blood prolactin and four had delayed puberty with gonadotropin deficiency. Only one patient presented with diabetes insipidus. X rays showed enlarged sella turcica in seven of the eight patients with calcifications in three and a cystic lesion in five. Two patients were operated on because of a doubtful diagnosis: their condition is stable 1.5 and 12 year later, respectively. The tumor volume remained stable with a follow-up of 1.5-9 years in five other patients; its volume gradualled increased in another patient requiring surgical removal 18 months after diagnosis. Antehypophysar deficiency generally increased in all patients, operated on or not, and five patients out of six have gonadotropin deficiency. CONCLUSIONS: These intrasellar craniopharyngiomas remain generally stable so that the greatest care must be taken in proposing surgical treatment. PMID- 7842069 TI - [Renal effects of prolonged indomethacin therapy in premature infants]. AB - BACKGROUND: Indomethacin therapy for large patent ductus arterious would be more effective when it is prescribed for 5 or 6 days vs 2 or 3 days. Effects on renal function of such prolonged therapy is still debated. PATIENTS AND METHODS: Seven preterm infants (gestational age: 28.6 +/- 0.9 weeks; birth-weight: 1,169 +/- 267 g) with symptomatic patent ductus arterious were given indomethacin, 0.1 mg/kg/day for 6 days (four patients) and 5 days (three patients). Urinary water excretion, water output/input ratio, creatinine clearance and body weight were measured before and every day during therapy. RESULTS: Urinary water excretion, water output/input ratio and creatinine clearance were significantly decreased after 5 days of treatment, -40 +/- 30%, -42 +/- 27% and -48 +/- 31%, respectively. Creatinemia and body weight were significantly increased, + 34 +/- 36% and + 9 +/- 7%, respectively. Mean sodium plasma level and fractional excretion of sodium, potassium and chloride remained stable. CONCLUSION: Prolonged therapy with indomethacin does not avoid the renal side effects seen with shorter administration. PMID- 7842070 TI - [A rare cause of hyponatremia during introductory treatment of acute lymphoblastic leukemia in an infant: inappropriate secretion of atrial natriuretic factor?]. AB - BACKGROUND: --Hyponatremia is frequently seen during the treatment of acute lymphoblastic leukemia: its causes are numerous. This work aims to present a case in whom hyponatremia was possibly due to an increased secretion of atrial natriuretic factor. CASE REPORT: --A 3 week-old baby was admitted because of malignant hemopathy. A diagnosis of acute lymphoblastic leukemia was rapidly made and the patient was firstly given alkaline diuresis, urate-oxidase and corticosteroids. Vincristine and daunorubicin were associated one week later. Insertion of a central intravenous line in the right subclavicular artery failed so that this catheter was finally inserted into the left jugular vein. Natremia was 126 mmol/l at that time and dramatically decreased within 24 hours to 109 mmol/l without net changes in water and electrolytic input. At that time, sodium urinary excretion was 6 mmol/kg/day (diuresis: 420 mlF/day). There was no hemodynamic changes, nor digestive or cardiac manifestations. Ultrasonography showed that the left superior cava vein drained into the right cardiac atrium. The catheter was withdrawn and the patient was given sodium supplementation permitting complete and definitive cure of hyponatremia within 2 days. CONCLUSIONS: --All usual causes of hyponatremia having been ruled out in this patient, we postulate that hyponatremia was due to direct stimulation of atrial natriuretic peptide through an increase in atrial pressure secondary to the catheter insertion near the cardiac atrium. PMID- 7842071 TI - [How to manage a symptomatic ovarian follicular cyst in a female child?]. AB - BACKGROUND: --Ovarian cysts are common in childhood but most are non functioning. Treatment of those follicular cysts that develop in young children may be difficult. CASE REPORTS: Case no. 1.--A 1 1/2 month-old baby was admitted because of an acute abdominal syndrome. Ultrasonography showed a pelvic, heterogeneous mass without calcifications. Laparotomy showed right ovarian torsion with necrosis of a cyst requiring ovariectomy. At that time, there was an isolated increase in FSH after LHRH stimulation. A transitory premature thelarche without pubertal type response to LHRH was seen at the age of 3 months. Clinical and ultrasonographic controls remain normal with a follow-up of 1 year. Case no. 2.- A 4 yr 10 m-old girl was admitted because of an acute abdominal syndrome. Ovariectomy was necessary because laparotomy showed right ovarian torsion with necrosis of a cyst. Recurrent abdominal pain, 4 months later, was associated with an enlarged left ovary without sexual precocity. Gonadotropin were slightly increased after LHRH stimulation and the patient was given LHRH agonist that suppressed endogenous LHRH within 3 months. Clinical and ultrasonographic controls remain normal 1 year after cessation of treatment. Case no. 3.--A 19 month-old girl was admitted because of a genital hemorrhage with recent development of secondary sexual characteristics. Skeletal age was 2 yrs. Ultrasonography showed an enlarged uterus and a left ovarian cyst, heterogenous with calcifications. Plasma levels of estradiol were increased but gonadotropin were normal. Ovariectomy was performed, followed by disappearance of secondary sexual characteristics. However, the patient was given LHRH agonist at the age of 2 yr 7 mo because of recurrent pubertal activity. CONCLUSIONS: --These cases underline the difficulty in treating follicular cysts in young girls. The possibility of cyst recurrence with manifestations of pubertal activity after ovariectomy lead to discuss indication of LHRH agonists for an undetermined duration. PMID- 7842072 TI - [Homozygote CB deficiency revealed by recurrent Neisseria meningitidis infections in an adolescent]. AB - BACKGROUND: Meningococcal infections associated with late complement component deficiency are rarely severe and usually occur during adolescence and adulthood. We report severe manifestations in a boy in whom the first episode appeared early. CASE REPORT: A 14 year-old gypsy boy was admitted because of a febrile meningococcal meningitis that was complicated by a rapidly extensive and necrotic purpura, obnubilation and clotting abnormalities without hemodynamic anomalies. The patient was given symptomatic therapy and a 12-day course of antibiotics that resulted in rapid and complete recovery. Medical history of this patient showed that he had been admitted at the age of 3 years for a severe febrile purpura with septic shock and clotting abnormalities followed by rapid and complete recovery after symptomatic and antibiotic therapy. No germ had been then isolated. The complement system was studied 3 weeks after the second hospitalization: total hemolytic complement activity could not be detected and C2, C3 and C4 were normal. Examination of the terminal pathway-revealed total C8 deficiency. The patient received meningococcal vaccine and was discharged on oral penicillin prophylaxis. He remained healthy during the ensuing 4 years. CONCLUSIONS: Meningococcal infections associated with late complement component deficiency are generally uncomplicated but they remain potentially severe. Early screening for this late complement component deficiency should be considered after severe clinical manifestations. PMID- 7842073 TI - [Congenital fibrolipoma of the mesencephalic protuberation area]. AB - BACKGROUND: Congenital origin of brain fibrolipoma is still debated. A case of such a tumor is presented. CASE REPORT: A female newborn presented with severe hypotonia and macrocephaly that were seen since birth. She died at the age of 2 days. Post-mortem examination showed hydrocephaly due to a tumor located in the mesencephalo-protuberantial region. Histological features of this tumor were those of a fibrolipoma. CONCLUSION: The presence of this brainstem tumor at birth confirms its congenital origin. PMID- 7842074 TI - [Gitelman syndrome in children: true hypokalemia but false Bartter syndrome]. AB - BACKGROUND: Gitelman's syndrome or familial hypokalemia-hypomagnesemia and Bartter syndrome share some common features but their prognosis is quite different. CASE REPORT: Four unrelated children, aged 5 to 12 years, were studied because they suffered from muscle cramps and/or abdominal pain. Supportive findings included: hypokalemia (2.1 to 2.9 mmol/l), metabolic alkalosis (31 to 34 mmol/l), hyperkaliuresis (5.8 to 7.1 mmol/kg/day), hypomagnesemia (0.58 to 0.64 mmol/l), hypermagnesuria (0.19 to 0.23 mmol/kg/day), hypocalciuria (0.012 to 0.021 mmol/kg/day). Blood pressure contrasting with high renin activity (19.04 to 20.03 ng/ml/hr) was normal. Chloride fractional excretion after oral water supplementation was only slighty decreased and hypercalciuric response to furosemide administration was not observed. Supplementation with magnesium chloride failed to correct hypomagnesemia while potassium chloride improved hypokalemia. CONCLUSIONS: Age of onset, tetany manifestations, absence of growth retardation, hypermagnesuria despite, hypomagnesemia, hypocalciuria not improved by furosemide favor the diagnosis of Gitelman's syndrome rather than that of Bartter syndrome initially considered. PMID- 7842075 TI - [Pneumothorax revealing pneumoblastoma in an infant]. AB - BACKGROUND: Pulmonary blastoma is a tumor with bad prognosis that is exceptionally seen before the age of 2 years. CASE REPORT: A 3 1/2 month-old infant was admitted because she suffered from tachypnea. A left pneumothorax with shift of the mediastinum was recognized that required insertion of a chest tube followed by ventilation and pleural drainage. X rays and CT scan showed a round bullous lesion in the left lung that persisted at the age of 5 months. At that time, clinical deterioration led to thoracotomy allowing excision of a bullous tumor; histological examination showed that this tumor was a pulmonary blastoma. Recurrence of this tumor, 16 months later, required chemotherapy and surgical excision. The patient is normal at the age of 4 years. CONCLUSION: Pulmonary blastoma is exceptional in infancy; it may be revealed by pneumothorax. Its bad prognosis requires aggressive therapy. PMID- 7842076 TI - [Acquired and constitutional neutropenia in children]. AB - The evaluation of a neutropenia first must document its etiology. Besides the particular etiological aspects in the newborn, neutropenia in a child may be 1) acquired, 2) constitutional, part of a complex genetic disease, 3) constitutional, isolated. Primary acquired neutropenia, also called benign chronic neutropenia, is the most frequent cause of chronic neutropenia in children; it is usually well tolerated and has a frequent favorable outcome in 12 14 months. Many complex genetic diseases include a neutropenia, among which several immunologic disorders that must be ruled out before considering the diagnosis of isolated constitutional neutropenia. Infantile agranulocytosis is the main primary constitutional neutropenia. It may be sporadic or hereditary (autosomal recessive or dominant inheritance) and is present at birth. It is profound, usually < 0.5 G/l (< 500/mm3) and exposes to severe pyogenic and fungal infections. In the neonatal period neutropenia must primarily suggest a bacterial infection, although other etiologies have to be known, particularly neonatal neutropenia caused by passive transfer of maternal antibodies and neutropenia related to gravidic maternal hypertension. The treatment of severe chronic neutropenia is directed towards the prevention of infections. It includes prophylactic antibiotherapy, the most commonly used one being the trimetroprim sulfamethoxazole association, and granulocyte colony stimulating factor (G-CSF). G-CSF has considerably improved the condition of patients; it is usually well tolerated, but secondary effects have been reported (hypersplenism, glomerulonephritis, osteoporosis, vasculitis), and a potential leukemogenic risk has been evoked. PMID- 7842077 TI - [Early pediatric-psychiatric management of suicide attempts in adolescents]. AB - The authors describe an experience of early intervention by child psychiatrists in adolescents attending an emergency care pediatrics unit for suicide attempts. The two main aspects of this intervention are: 1) a former interview between the child psychiatrist and the suicidal adolescent taking place within the emergency care pediatrics unit; 2) a systematic few days hospitalization of the suicidal adolescent in a child-adolescent psychiatric unit allowing early therapy for both the adolescent and his/her parents. Based on preliminary results the authors believe that early child psychiatrist intervention provides an improvement in the care of suicidal adolescents, especially to prevent recurrent suicide attempts, as compared with conventional care with delayed child psychiatrist participation. PMID- 7842078 TI - [Rubella vaccine coverage and seroprotection in 11-year-old children in the Indre et-Loire department]. AB - To determine the current rates of vaccination and seroprotection against rubella of French preadolescents, a survey was conducted among children in their first year of junior schools of the department of Indre-et-Loire (prefecture: Tours). The rate of vaccination against rubella during infancy or childhood was 58.8% for the girls and 9.4% for the boys, as compared with 99.5% for both sexes for the vaccination against diphteria, tetanus and poliomyelitis. An effective seroprotection against rubella was found more frequently in girls than in boys (90.4% vs 78%), and was also more frequent among vaccinated than non vaccinated preadolescents (98% vs 77%). From these data the authors recommend that a stronger policy of vaccination against rubella should be be adopted, ie. order to obtain the eradication of rubella in France. PMID- 7842079 TI - [Rapid desensitization for anaphylactoid reactions to desferrioxamine]. PMID- 7842080 TI - [Acute mastoiditis in children: is there a current outbreak?]. PMID- 7842081 TI - [Study of the correlation between folatemia and degree of mucosal damage in children]. PMID- 7842082 TI - [Burns caused by a pulse oximeter]. PMID- 7842083 TI - [Asthma mortality in children]. PMID- 7842084 TI - [Treatment of severe asthmatic attacks]. PMID- 7842085 TI - [Asthma in children: whom to hospitalize and where?]. PMID- 7842086 TI - [Acute severe asthma in pediatric resuscitation. The French Study Group on Pediatric Resuscitation]. PMID- 7842087 TI - [The severe asthmatic attack...and after]. PMID- 7842088 TI - [Statural growth in growth hormone treatment during puberty in irradiated children, from the data of France Hypophyse]. PMID- 7842089 TI - [Final height in Turner syndrome treated with growth hormone]. PMID- 7842090 TI - [Final height in 69 patients with congenital adrenal hyperplasia due to 21 hydroxylase deficiency]. PMID- 7842091 TI - [Final height in precocious puberty patients]. PMID- 7842092 TI - [Bradycardia in the newborn: definitions]. PMID- 7842093 TI - [Bradycardia physiopathology in the newborn]. PMID- 7842094 TI - [Detection of bradycardia episodes in the "convalescent" newborn]. PMID- 7842095 TI - [Recessive polycystic kidneys]. PMID- 7842096 TI - [Other chronic nephropathies with liver involvement]. PMID- 7842097 TI - [Renal involvement in the Alagille syndrome]. PMID- 7842098 TI - [Hepatorenal glycogenoses]. PMID- 7842099 TI - [Renal involvement in type I tyrosinemia]. PMID- 7842100 TI - [Pregnancy in women who underwent organ transplantation]. PMID- 7842102 TI - [Use of recombinant growth hormone in children with kidney failure]. PMID- 7842101 TI - [What is the future for pediatrics in the coming years?]. PMID- 7842103 TI - [Has the use of indomethacin during pregnancy consequences in newborn infants? Prospective study of 83 pregnant women and 115 newborn infants]. AB - BACKGROUND: Prolonged exposure of pregnant women to indomethacin for tocolysis may have significant effects on the fetus or neonate, but their incidence is still debated. POPULATION AND METHODS: From January 1990 to July 1991, 83 pregnant women were prospectively given indomethacin for treatment of premature labor, after ineffective course of salbutamol. The initial dose of indomethacin was 100 mg, then the daily dose was 50 mg while salbutamol was continued. Indomethacin was discontinued beyond the 33rd week of gestational age. Efficacy of indomethacin was judged upon the disappearance of uterine contractions and the increased duration of pregnancy from the onset of treatment until delivery. Adverse effects of treatment were evaluated in the neonates. RESULTS: The mean duration of indomethacin administration was 16 days (range: 1-62 days); the mean total dose was 900 mg (range: 100-4500 mg). The reason for discontinuation of the treatment was its efficacy (41 patients), a gestational age of 33 weeks (12 patients), oligoamnios (21 patients), demonstration of fetal abnormalities (two patients). The mean interval between discontinuation of treatment and delivery was 5 weeks. Fourty three of the 58 patients who were given indomethacin before the 30rd week were delivered after the 33rd week. There was no adverse effect in the women and babies; all oligoamnios were spontaneously reversible. One hundred and fifteen babies were born including 12 who died during the first post-natal days. The rate of admission in an intensive care unit was similar to that of untreated pregnancies. CONCLUSIONS: Indomethacin can be safely used for treatment of premature labor provided that its administration is carefully monitored. PMID- 7842104 TI - [Treatment with recombinant human growth hormone (rhGH) in children with chronic kidney failure or renal transplantation]. AB - BACKGROUND: Administration of recombinant human growth hormone (rhGH) to children with chronic renal failure (CRF), on conservative treatment or kidney transplanted, may induce acceleration of growth. We report our experience of the first 3 years of treatment in such children. PATIENTS AND METHODS: Eight children with CRF on conservative treatment and six kidney transplanted children were included in a European multicentric trial. All children were given rhGH, 30 Ul/m2 body surface area/week, as daily subcutaneous injections, for 12-36 months. RESULTS: The mean growth velocity in children with CRF increased from 3.8 +/- 0.4 cm/yr before treatment to 9.0 +/- 0.4 (P < 0.001), 6.5 +/- 0.3 (P < 0.002) and 5.4 +/- 0.5 cm/yr, after 12, 24 and 36 months of treatment, respectively. The height gain after 2 years of treatment was 1.2 SD (P < 0.001) with bone age advancement not greater than the increase in chronological age. There was a significant decrease in the inulin clearance after 1 year of treatment. In transplanted children, the mean height gain was less important, increasing from 3.2 +/- 0.4 cm/yr before treatment to 6.2 +/- 0.6 cm/yr after 12 months of treatment (P < 0.001). There was no significant decrease in the mean inulin clearance, but two patients experienced rejection crisis. CONCLUSIONS: A short term rhGH treatment may improve growth velocity of CRF or transplanted children. The possible role of GH on decrease in glomerular filtration in CRF and on incidence of acute kidney rejection after transplantation remains to be evaluated in a large cohort of patients. PMID- 7842105 TI - [Eruptive fever of rare cause: familial hemophagocytic lymphohistiocytosis]. AB - BACKGROUND: Clinical onset of familial lymphohistiocytosis is non-specific so that the diagnosis of this rare and severe disease is difficult. CASE REPORT: An 8 week-old girl was admitted suffering from fever and rash. She had hepatosplenomegaly. She developed pancytopenia (Hb: 6.6 g/100 ml; WBC: 4500/mm3; platelets: 25,000/mm3) impaired liver function tests (prothrombin: 15%, blood bilirubin: 40 mg/l; SGOT: 160 mU/ml) and hypofibrinogenemia (0.3 g/l) within a few days. Bone marrow examination showed diffuse histiocytic infiltration and erythrophagocytosis, suggesting a syndrome of inappropriate macrophage activation. The age of the patient, parental consanguinity and absence of specific infection led to diagnosis of familial erythrophagocytic lymphohistiocytosis. The patient died 18 days after clinical onset. CONCLUSION: The diagnosis of this unusual syndrome in infants is strongly supported by parental consanguinity as seen in our case or a positive family history. In this condition, erythrophagocytosis is often a marked feature. PMID- 7842106 TI - [Turner syndrome and insulin-dependent diabetes mellitus]. AB - BACKGROUND: Cases of diabetes mellitus associated with Turner syndrome are noninsulin-dependent. We report a case of insulin-dependent diabetes mellitus (IDDM) with Turner syndrome. CASE REPORT: An 11 year-old girl with Turner syndrome was investigated for glucose tolerance that was normal with glycosylated hemoglobin at 5.1%. The patient was then given growth hormone plus oxandrolone until the age of 15 yr 3 mo; estrogen replacement was initiated at 15 yr 9 mo and progesterone 6 months later. At the age of 16.5 yrs, the patient developed manifestations of diabetes mellitus with polyuria, polydipsia, weight loss. Blood glucose concentration was 415 mg/dl with ketoacidosis. She was given insulin; at that time, blood insulin level was 7 mU/ml, C-peptide 0.8 ng/ml and glycosylated hemoglobin Alc 8.2%. Islet cell auto-antibodies were positive (1/80) and histocompatibility antigens were A1, A2, B14, B18, CW7, DR7, DR11, DQ7. After 6 months of treatment, blood insulin and C-peptide after IV glucagon were nil. There was no familial case of IDDM. CONCLUSIONS: This case of IDDM seems to be the first reported in Turner syndrome. This IDDM could be a manifestation of autoimmunity. PMID- 7842107 TI - [Mid-term outcome of 2 cases with maple syrup urine disease: role of liver transplantation in the treatment]. AB - BACKGROUND: Dietary treatment of maple syrup urine disease remains difficult; chronic nutritional support in the child does not always avoid acute crises so that liver transplantation may represent an alternate choice in some cases. CASE REPORTS: Two gypsy cousins were born by an interval of 4 days; both had maple syrup urine disease and were similarly treated from the first days of life. They were given exchange transfusions followed by diet restricted in the branched chain amino acids, maintaining normal growth and plasma leucine concentrations under 7 mg/100 ml. Laura, at 10 years, was retarded at school. Compliance to school attendance was limited by her diet problems. Helen suffered at 7 yr 3 mo from liver failure due to hepatitis A virus infection which required liver transplantation. Protein intake was normal 1 week later. At 10 years, she presented with the same degree of school retardation as her cousin, and was placed in the same class. CONCLUSION: Liver transplantation may be effective for treating metabolic problems in MSVD without significative difference between outcome post classic treatment or post liver transplantation. PMID- 7842108 TI - [Brachial plexus neuropathy following pyogenic cervical adenophlegmon]. AB - BACKGROUND: Brachial plexopathy is rare in children; it may follow a non-specific respiratory infection or occur after a specific viral disease or immunization. CASE REPORT: An 8 year-old girl was admitted suffering from presuppurative acute cervical adenitis. She was given penicillin V, netilmicin and corticosteroids. The adenitis gradually resolved over a period of ten days. There was no evidence of a specific bacterial infection. The patient suffered from pain localized to her right shoulder 15 days after admission; this pain was resolved within 3-4 days but was followed by paralysis affecting the upper brachial roots without sensory signs. EMG performed 15 days later showed signs of denervation. Amyotrophy set in rapidly but recovery under physiotherapy was complete 5 months later. CONCLUSION: This plexopathy resembling the Parsonage-Turner syndrome could be allergic in pathogenesis although similar cases after bacterial, possibly streptococcal, infection remain to be confirmed. PMID- 7842109 TI - [Respiratory syncytial virus infections in children]. AB - Respiratory syncytial virus (RSV) is the most frequently isolated agent in acute lower respiratory tract infections in children. It is responsible for severe disease in young infants and patients with immune deficiencies or congenital heart disease, and appears to be involved in sudden death in infancy. There is also some evidence for its involvement in the development of asthma following bronchiolitis. Despite encouraging new therapies (ribavirin, immune globulin, recombinant interferon alfa), treatment remains mainly symptomatic. Hopefully the better understanding of the immune response during VRS infection will allow the development of an effective vaccine in the coming years. PMID- 7842111 TI - [Radiological case of the month. McCune-Albright syndrome]. PMID- 7842110 TI - [Generalized idiopathic epilepsy in older children and adolescents]. AB - Generalized idiopathic epilepsies starting between 12 and 18 years of age are mostly represented by juvenile myoclonic epilepsy, juvenile absence epilepsy and grand-mal on awakening. The EEG and clinical description of the seizures, the different epileptic syndromes with their therapeutics, the prognosis and the familial forms with the molecular genetic aspects are studied. The importance of the history for the positive diagnosis is emphasized, in order to display the often overlooked myoclonies occurring in the morning. Differential diagnosis concerns mostly absences which are sometimes difficult to separate from frontal seizures, and in the case of first generalized tonico-clonic seizure, partial epilepsy which needs further investigations, and the exceptional progressive myoclonic epilepsy which begins the same way, but has a totally different prognosis. Psycho-social difficulties due to epilepsy and lack of therapeutic compliance are frequent. The therapeutic results are generally good but there is a high rate of relapse after medication withdrawal. PMID- 7842112 TI - [Reliability of conjugated bilirubin determination in the neonatal period]. PMID- 7842113 TI - [Neonatal hemolytic and uremic syndrome, methylmalonic aciduria and homocystinuria due to intracellular vitamin B12 deficiency]. PMID- 7842114 TI - [Survey of the prevalence of parvovirus in children]. PMID- 7842115 TI - [Risks of severe quinine poisoning]. PMID- 7842116 TI - [One day as the others at the "Enfants-Malades"]. PMID- 7842117 TI - [Specificity of the epidemiology of burns in children]. PMID- 7842118 TI - [Tuberculosis in children: vigilance must be increased]. PMID- 7842119 TI - [Pulmonary tuberculosis in infants. Apropos of 6 cases]. AB - BACKGROUND: The present increased incidence of tuberculosis in children can be explained by contacts with infected adults and/or late BCG vaccination. PATIENTS: Six infants, 3 to 18 months-old (mean: 8 months), were admitted from November 1990 to May 1992 for various reasons; only two were admitted with a diagnosis of tuberculosis based on tuberculin test and only one was given a BCG vaccine. The disease produced a broad range of symptoms. Diagnosis was based on tuberculin test and radiographic examination showing lymph node enlargement of mediastinum and segmental consolidation lesions. Mycobacterium tuberculosis was found in two cases. The patients were given isoniazid, rifampin, ethambutol and/or pyrazinamide; corticosteroids were added in five patients. Each patient received four or three drugs for 2-4 months and two drugs (isoniazid plus rifampin) beyond, for a mean total duration of 13 months (range: 9-17 months). Repeated CT scan of thorax was performed to evaluate the efficacy of treatment. Tuberculosis was diagnosed in 11 subjects in contact with these children. CONCLUSION: Tuberculosis in children is not rare, and BCG vaccination of neonates should be seriously considered. PMID- 7842120 TI - [Prenatal diagnosis of congenital cystic adenomatoid malformation of lung: perinatal management. Apropos of 4 cases]. AB - BACKGROUND: Cystic adenomatoid malformation of the lung can be seen by ultrasonography during pregnancy. Surgical excision of the affected lobe is indicated during the first days of life. CASES REPORT: Four neonates were admitted to an intensive care unit from March 1988 to February 1992, due to cystic adenomatoid malformation of the lung, that had been diagnosed by ultrasonography at 19, 22, 34 and 37 weeks of gestational age, respectively. These malformations were not associated with other abnormalities and were type I (three cases) and II (one case) according to Stocker's classification. Only one patient became symptomatic, requiring intubation by 72 hours of age. Surgical excision of the affected lobe was performed in three patients at 4 hours, 2 and 7 days of life, respectively, with a normal long-term survival. A segmental resection was performed at 5 days of life in the remaining symptomatic patient but persistence of cystic lesions required lobectomy at 10 months. CONCLUSIONS: Early perinatal management of cystic adenomatoid malformations of the lung is necessary as surgical excision is indicated as soon as possible, even in asymptomatic patients. PMID- 7842121 TI - [Brief antiseptic application of iodine in neonatal intensive care units: effects on thyroid function]. AB - BACKGROUND: Transient thyroid dysfunction with its adverse effects of diminished levels of thyroid hormone on mental development has been reported in neonates whose skin has been cleaned with iodine-containing substances. We report the results of thyroid screening in iodine-exposed neonates and controls. POPULATION AND METHODS: Thirty seven neonates admitted to an intensive care unit from 1990 to 1992 and whose medical condition required umbilical catheterization were included in the study. There were 21 neonates (six term and 15 preterm) for whom the area around the umbilicus was cleansed with iodine antiseptic and 16 controls (four term and 12 preterm) for whom the antiseptic used did not contain iodine. Levels of serum free T3 and T4, and TSH were determined by 7 days after catheterization as did urinary iodine and creatinine concentrations. RESULTS: Iodine-exposed neonates had significant high levels of TSH (P < 0.01) and low free T3 (P < 0.05); levels of free T4 were lower than in controls but not significantly. Urinary iodine excretion was significantly increased. The increase in TSH disappeared between 15 and 30 days after iodine application. CONCLUSION: Application of iodine antiseptics may cause transient thyroid dysfunction in neonates leading to propose the use of non iodinated substances with similar antibacterial efficacy. PMID- 7842122 TI - [Epilepsy and accidents: what is the risk in children?]. AB - BACKGROUND: Constant distress and overprotection of parents result from the apprehension and misinformation received, regarding epilepsy of their children and the risk of accidents occurring due to a seizure. Large retrospective studies show that the epileptic children are not more often concerned than the general population. CASE REPORTS: One hundred and ninety-eight epileptic children without permanent motor or mental handicap were followed between 1971 and 1981, covering 1056 years of child's life. They were compared to 3822 injured children admitted to the surgical pediatric emergency unit between 1983 and 1992. RESULTS: Only six accidents occurred because of a seizure in the first group of epileptic children. There were neither deaths nor sequelae. Four of these six accidents revealed an unknown epilepsy. Among the 3,822 injured children, 19 were epileptic but only four of these 19 accidents were caused by a seizure. There were no sequelae. CONCLUSION: The majority of epileptic children without associated handicap are able to have all the normal activities of healthy children. Only severe epilepsies with frequent refractory seizures, some reflex epilepsies and some cases before the seizures are under control require constant supervision. PMID- 7842123 TI - [Two-year follow-up cohort studies on triplets: development of children and mother-child relationship]. AB - BACKGROUND: The number of triplets births has increased during the last 15 years. The psychomotor development of triplets, problems concerning long-term relationships between the mother and her children and between the children themselves are still incompletely studied. PATIENTS AND METHODS: Eleven families with triplets, consecutively born at the Clinique Baudelocque, were assessed at home for 2 years by the same psychologist. IQ was measured in each child at the age of 2 years using the Brunet-Lezine test. At this age, all mothers completed the Symptom-Check List allowing to assess eventual relationship difficulties between the mother and their children. RESULTS: The psychomotor development of the children (IQ = 100) was similar to the mean score in the general population. The mother reported great physical fatigue during the first year after birth and psychological difficulties during the second year. They mentioned behavioral problems and difficult relationships among the triplets. They complained of not being able to fulfill the children's demands. In four families, more severe difficulties, potentially damaging the psychological well-being of the children, required an intervention during the survey. CONCLUSIONS: Improved and prolonged help to families with triplets is necessary, requiring the participation of pediatricians, nurses, psychologists, social workers and specialized people. PMID- 7842124 TI - [Stomatococcus mucilaginosus meningitis in immunocompromised child]. AB - BACKGROUND: Opportunistic infections are responsible for significant morbidity and mortality in patients with malignancy developing granulocytopenia as a result of therapy. A case of Stomatococcus mucilaginosus meningitis is reported. CASE REPORT: A 2 year-old boy was admitted because he had developed fever and neutropenia during chemotherapy given for neuroectodermal tumor. He was previously treated for a Stomatococcus mucilaginosus septicemia with vancomycin given for 15 days through an intravenous catheter which has subsequently been left in place. At admission, fever was associated with severe degree of aplasia (70 WBC/mm3). The patient was given IV ceftazidime plus amikacin. Two days later, the boy developed acute meningitis due to Stomatococcus mucilaginosus; he was then given IV vancomycin (40 mg/kg/d) and imipenem (100 mg/kg/d). Persistence of abnormal clinical and bacteriological findings required subsequent intrathecal administration of vancomycin (1.5 mg/d) for 5 days. CSF cultures were negative 2 days later, leading to stop IV antibiotics after 3 weeks. The catheter was removed 1 week later. CONCLUSION: This patient represents the third reported case of Stomatococcus mucilaginosus meningitis. Combined intrathecal and systemic administration of vancomycin seems to have been useful in our case. PMID- 7842125 TI - [Status epilepticus in an asthmatic child]. AB - BACKGROUND: Chronic administration of theophylline can be used for treating asthma; it may represent a severe risk when some other drugs are prescribed by unaware physicians. CASE REPORT: A 4 yr-8-mo-old boy was admitted suffering from status epilepticus which occurred 3 hours after vomiting. This patient had asthma and was given sustained-release formulation of theophylline and, independently by another physician, two anti-H1 drugs: ketotifen and mequitazine. Serum theophylline concentration measured 9 hours after the onset of vomiting was 28 micrograms/ml; the calculated concentrations were 45.3 +/- 4, 40.2 +/- 4 and 33.4 +/- 4 micrograms/ml after the last administration of theophylline, the onset of vomiting and the onset of seizures, respectively. The patient was given IV fluids plus clonazepam and recovered completely. CONCLUSION: Severe poisoning can be seen with moderately increased blood levels of theophylline when this drug is chronically administered. Association of other drugs such as anti-H1 could represent an additional risk. PMID- 7842126 TI - [Hyperglycemia revealing neonatal infection]. AB - BACKGROUND: Hyperglycemia as the first manifestation of neonatal sepsis is rare. CASE REPORT: A breast-fed neonate was admitted at the age of 6 days because of vomiting. Group B streptococci had been isolated in secretions of the ear at birth but the neonate had not been treated. At admission, physical examination was normal but glucosuria, without ketonuria, and hyperglycemia (9.7 mmol/l) were noted. Because hyperglycemia was not explained by usual causes, the baby was systemically given antibiotics. The next day, blood, spinal fluid and urine cultures taken on admission were positive for group B streptococci while blood fibrinogen and C-reactive protein were increased. Hyperglycemia and glycosuria were normal after 24 hours of antibiotic therapy and follow-up was uneventful. Subsequently, the same bacteria was isolated from the mother's milk. CONCLUSION: Isolated hyperglycemia may reveal an infection; therefore its discovery might contribute to early diagnosis and treatment. PMID- 7842127 TI - [Neonatal herpes simplex hepatitis with favorable outcome after treatment with acyclovir]. AB - BACKGROUND: Herpes simplex virus (HSV) may cause severe disease in the neonate with high mortality and devastating sequellae. This infection presents exceptionally as isolated fulminant hepatitis. CASE REPORT: An 8 day-old baby was admitted because of seizures, fever and vomiting. Initial investigations including CSF analysis were negative and the patient was given ampicillin plus netilmicin. Two skin vesicles were seen 5 days later containing HSV. A second CSF analysis was negative as was the brain scan. At that time, liver involvement was evident: ASAT 3700 IU/l; ALAT 1035 IU/l; prothrombin 37%; fibrinogen 1 g/l. Hemogram showed WBC: 2,500/mm3 and PNN: 702/mm3. The patient was given acyclovir 40 mg/kg/day IV. Blood and CSF culture remained negative; CSF interferon concentration was 4 IU/ml. Serologic investigations in both parents were inconclusive. The disease worsened rapidly with consumption coagulopathy requiring ventilation support. The dose of acyclovir was increased to 60 mg/kg/day, 9 days after admission. Improvement was noted on the 10th day and acyclovir was administered orally on the 21st day. The condition was completely normal 6 months later. CONCLUSION: Early administration of acyclovir may favor complete recovery of neonatal HSV hepatitis. PMID- 7842128 TI - [Physiology of muscular exercise in children]. AB - When compared to adults, muscle mass in children is lower and the relative development of aerobic and anaerobic pathways is different. The main consequences are the following: 1) The aerobic metabolism, evaluated by measurement of maximal oxygen uptake (VO2max), is either the same as in adults or more developed when VO2 max is related to body mass or lean body mass. 2) The maximal anaerobic power developed during force-velocity test and Wingate test is lower than in adults even if it is expressed by total or lean body mass unit. Blood lactate concentration is also lower. This immaturity of the anaerobic metabolism, especially the "lactic pathway" may result from lower anaerobic enzyme activities (lactico-dehydrogenase, phosphofructokinase, etc) and glycogen content. During puberty, "lactic metabolism" starts to develop significantly, simultaneously with muscle mass. It has been suggested that sexual hormones (testosterone in boys, oestrogens in girls) and other factors, such as growth factors, are implicated in this phenomenon. During this period, the aerobic metabolism remains unchanged. In prepubertal children there is neither aerobic nor anaerobic specialization: the highest anaerobic performance is associated with the highest VO2 max. Moreover, it seems that before puberty, bioenergetic profile is not modified by training. 3) Despite a high VO2 max, performance in endurance events is not as high in children as in adults because of a lower running economy. Cardiovascular responses are characterized by higher maximal and infra-maximal heart rates, and lower systolic stroke volume and arterial blood pressures than in adults. During prolonged exercise, the hormonal adaptations for energy substrate utilization is quite different from adults: a lower decrease in insulin and increase in catecholamines and glucagon in response to exercise could be responsible for a less effective regulation of glycemia with a risk of hypoglycemia. Therefore, an adequate carbohydrate intake is recommended. PMID- 7842129 TI - [Diagnosis of metabolic coma in children]. AB - This article describes the metabolic investigations to be applied in any clinical situation consistent with a late acute form of inborn error of metabolism: unexplained coma with or without focal neurological manifestations, recurrent vomiting with lethargy, episodes of ataxia with or without behaviour disorder, fits of psychiatric troubles. In each of these situations, careful medical history is of major importance searching for previous clinical manifestations such as episodes of coma, ataxia or vomiting, anorexia, failure to thrive, developmental delay, all very suggestive of metabolic disorder. The association of neurological symptoms and abnormal hepatic tests is also of great value and must not lead to the diagnosis of Reye's syndrome without considering a metabolic defect of fatty acid oxidation, urea cycle, respiratory chain, or Wilson's disease. When looking for an etiological origin, it is mandatory to collect all the biological information at the same time, also knowing that metabolic abnormalities may be mild and transitory, and that many of them are non specific (metabolic acidosis, hyperlactacidemia, hyperammonemia, hepatic tests disturbances) being encountered in collapsus, shock and multiple organ failure syndrome. PMID- 7842130 TI - [Radiological case of the month. Neonatal gastric volvulus]. PMID- 7842131 TI - [Vitamin D. Let us practice supplementation]. PMID- 7842132 TI - [Announcement of diagnosis of 21-trisomy and abandonment]. PMID- 7842133 TI - [A new case of nephrotic syndrome and kala azar association]. PMID- 7842134 TI - [Treatment of cystic lymphangioma]. PMID- 7842135 TI - [Biological modifications of CSF in hemiplegic migraine]. PMID- 7842136 TI - Homocysteine induces iron-catalyzed lipid peroxidation of low-density lipoprotein that is prevented by alpha-tocopherol. AB - Homocystinuria is an inborn error of methionine metabolism that is characterized by the premature development of arteriosclerosis. As one of the major factors in the pathogenesis of arteriosclerosis, modification of low-density lipoprotein (LDL) has received widespread attention by many investigators. In this study, to elucidate the relationship between elevated homocysteine levels and premature arteriosclerosis, we investigated the role of homocysteine in the iron-catalyzed oxidative modification of LDL. When LDL isolated from a healthy subject was incubated with homocysteine and ferric ion, a gradual decrease of polyunsaturated fatty acids (PUFA), formation of thiobarbituric acid-reactive substances (TBARS) and fluorescent substances, and the fragmentation of apoprotein B (apoB) were observed. The extent of oxidative modification was dependent on the concentration of homocysteine. Modification of LDL was suppressed until the remaining alpha tocopherol concentration reached a critical level. When the alpha-tocopherol content of LDL was increased by 2.6-fold, both the formation of TBARS and the fragmentation of apoB were suppressed. These results suggest that homocysteine might promote iron-catalyzed oxidation of LDL and imply its role for the development of premature arteriosclerosis. PMID- 7842137 TI - Electrochemical studies of tirapazamine: generation of the one-electron reduction product. AB - The electrochemical properties of the benzotriazine di-N-oxide, tirapazamine (SR4233), and the mono- and zero-N-oxides, SR4317 and SR4330 respectively, have been investigated in dimethylformamide and acetonitrile. The voltammetry of tirapazamine is complicated, with up to 6 reduction steps being identified, depending on the solvent. Both SR4317 and SR4330 show two reduction steps. The first reduction of all three compounds is a reversible or quasi-reversible step, which is assigned to a 1-electron addition. Cyclic voltammetric studies show that the anion radical product is stable, although the tirapazamine 1-electron addition product shows a tendency to participate in a chemical following reaction. Subsequent reduction steps are all highly irreversible in nature. The 2nd electron transfer of SR4317 results in the formation of the free base, SR4330, which is identified voltammetrically. Comparison is made with the voltammetric behaviour of quinoline and quinoline-oxide. PMID- 7842138 TI - Developmental aspects of detoxifying enzymes in fish (Salmo iridaeus). AB - The activities of superoxide dismutase, catalase, glutathione reductase, glutathione peroxidase, glutathione transferase and glyoxalase I have been studied during the embryologic development of rainbow trout (Salmo iridaeus) and in several other trout tissues to investigate the protective development metabolism. A gradual increase of superoxide dismutase, catalase, glutathione reductase, glyoxalase I and glutathione transferase activities was noted throughout embryo development. In all trout tissues investigated glutathione peroxidase was found to be extremely low compared to catalase activity. The highest activity of superoxide dismutase, glyoxalase I and glutathione reductase was found in liver followed by kidney. No change in the number of GST subunits was noted with the transition from the embryonic to the adult stages of life according to the SDS/PAGE and HPLC analyses performed on the GSH-affinity purified fractions. PMID- 7842139 TI - Human (THP-1) macrophages oxidize LDL by a thiol-dependent mechanism. AB - The oxidative modification of low-density lipoprotein by macrophages may be an important mechanism in the pathogenesis of atherosclerosis. The human monocytic leukaemia cell line THP-1, when stimulated with phorbol ester, shares many properties with human monocyte-derived macrophages. Oxidation of LDL by these cells was characterised by depletion of alpha-tocopherol, increases in thiobarbituric acid reactive substances and increases in electrophoretic mobility. The LDL particles were also converted to a form which increased accumulation of cholesteryl esters within macrophages. The oxidative mechanism appeared to be dependent upon the presence of thiols in the cellular medium. Oxidation of LDL by THP-1 macrophages, and production of thiols by these cells, were dependent upon the presence of L-cystine in the medium. Furthermore, cellular oxidation of LDL could be partially mimicked by the addition of cysteine to Hams F10 medium. Macrophage-independent oxidation of LDL, mediated by the addition of copper ions, was inhibited by cystine and cysteine in phosphate buffered saline, but not in Hams F10 medium. The glutathione content of THP-1 macrophages was also dependent upon the presence of cysteine or cystine in the medium, but inhibition of glutathione synthesis by buthionine sulfoximine did not prevent the production of thiols or the oxidation of LDL by THP-1 macrophages. PMID- 7842140 TI - Quinolinic aminoxyl protects albumin against peroxyl radical mediated damage. AB - A study of peroxyl radical-mediated bovine serum albumin oxidation in the presence of the quinolinic aminoxyl 1,2-dihydro-2,2-diphenyl-4-ethoxy-quinoline-1 oxyl (QAO) was carried out in order to test its efficiency as a protein antioxidant. Albumin oxidation was induced by the tert-butylhydroperoxide/PbO2 system. The extent of protein oxidation, measured by monitoring the formation of carbonyl groups, was considerably reduced in the presence of QAO. ESR measurements were carried out to confirm the consumption of the nitroxide during oxidation and its incorporation in the protein. The data obtained indicate that the quinolinic aminoxyl function can be used as an effective antioxidant in biological systems. PMID- 7842141 TI - Low mitochondrial free radical production per unit O2 consumption can explain the simultaneous presence of high longevity and high aerobic metabolic rate in birds. AB - Birds are unique since they can combine a high rate of oxygen consumption at rest with a high maximum life span (MLSP). The reasons for this capacity are unknown. A similar situation is present in primates including humans which show MLSPs higher than predicted from their rates of O2 consumption. In this work rates of oxygen radical production and O2 consumption by mitochondria were compared between adult male rats (MLSP = 4 years) and adult pigeons (MLSP = 35 years), animals of similar body size. Both the O2 consumption of the whole animal at rest and the O2 consumption of brain, lung and liver mitochondria were higher in the pigeon than in the rat. Nevertheless, mitochondrial free radical production was 2 4 times lower in pigeon than in rat tissues. This is possible because pigeon mitochondria show a rate of free radical production per unit O2 consumed one order of magnitude lower than rat mitochondria: bird mitochondria show a lower free radical leak at the respiratory chain. This result, described here for the first time, can possibly explain the capacity of birds to simultaneously increase maximum longevity and basal metabolic rate. It also suggests that the main factor relating oxidative stress to aging and longevity is not the rate of oxygen consumption but the rate of oxygen radical production. Previous inconsistencies of the rate of living theory of aging can be explained by a free radical theory of aging which focuses on the rate of oxygen radical production and on local damage to targets relevant for aging situated near the places where free radicals are continuously generated. PMID- 7842142 TI - Characterization of large unilamellar vesicles as models for studies of lipid peroxidation initiated by azocompounds. AB - The aim of this work was to characterize large unilamellar vesicles (LUVETs) prepared by a hand-driven extrusion device in order to use them for studies of lipid peroxidation and antioxidant activity. Vesicle structure and size were examined by electron microscopy. Lipid and antioxidant content was determined before and after the extrusion procedure. Then LUVETs were subjected to autoxidation initiated by both the lipid-soluble 2,2'-azobis(2,4 dimethylvaleronitrile) and the water-soluble 2,2'-azobis(2-amidinopropane hydrochloride) azocompounds. The results demonstrated that: i) LUVETs prepared with lipid concentrations ranging between 25 and 150 mM were essentially unilamellar and reasonably homogeneous, with an average diameter of 90 nm; ii) the phospholipid, cholesterol and antioxidant amounts retained by filters were about 10-15%; iii) LUVETs were suitable for autoxidation studies initiated by the water-soluble azocompound both in the absence and presence of antioxidants. The lipid-soluble azocompound could be used only at low concentrations and its vesicle content had to be determined since part of the initiator was not incorporated into the lipid bilayer. These data suggest that LUVETs seem to be recommended for studies of lipid peroxidation and antioxidant activity. PMID- 7842143 TI - Appearance of ESR signals by the reaction of 3,5-dibromo-4 nitrosobenzenesulfonate (DBNBS) and non-radical biological components. AB - The reaction of 3,5-dibromo-4-nitrosobenzenesulfonate (DBNBS) with non-radical biological components produced spin adducts with ESR signals. The reactions of DBNBS with Trp, Gly-Trp, Trp-Gly, Pro, Cys and glutathione at pH 7.5 and room temperature for more than 1 hour gave the nitroxyl free radicals with ESR signals, whereas the reactions with other amino acids and bovine serum albumin did not. Among the amino acids and the peptides, Trp and Trp-containing peptides gave the most intense signals. The reactions of DBNBS with unsaturated fatty acids, i.e., linoleic acid and oleic acid, gave weak ESR signals, whereas the reaction with stearic acid did not. While DBNBS gave no ESR signals by the reactions with DNA, nucleosides and nucleobases, it caused strand breaking in supercoiled DNA. DBNBS also gave ESR signals by the reaction with human plasma similar to those from the reaction with Trp. It was suggested that the nitroxyl free radicals were produced by the addition of DBNBS to the amino acids and unsaturated fatty acids followed by oxidation in the presence of DBNBS. Hence, the use of DBNBS spin trap to detect free radicals in systems containing these biological components after long incubation may give misleading results. PMID- 7842145 TI - Preparative separation of stereoisomeric 1-methyl-4 methoxymethylcyclohexanecarboxylic acids by pH-zone-refining counter-current chromatography. AB - The application of pH-zone-refining counter-current chromatography (CCC) to the preparative separation of stereoisomeric acids is described. The separation was accomplished on the basis of the difference in acidity of the two stereoisomers. pH-Zone-refining CCC of 400 mg of a crude synthetic mixture of stereoisomeric 1 methyl-4-methoxymethylcyclohexanecarboxylic acids yielded 49.5 and 40 mg of the pure Z- and E-stereoisomers respectively. The two-phase solvent system consisted of hexane-ethyl acetate-methanol-water (1:1:1:1). Trifluoro acetic and octanoic acids were used as retainer acids. The eluent base was aqueous ammonia. The eluted fraction were monitored by gas chromatography-mass spectrometry. PMID- 7842144 TI - Resolution of proteins on a phenyl-Superose HR5/5 column and its application to examining the conformation homogeneity of refolded recombinant staphylococcal nuclease. AB - In order to examine the effect of amino acid substitutions on protein retention in hydrophobic interaction chromatography and the resolution of a phenyl-Superose HR5/5 column, two groups of staphylococcal nucleases, named Y113/W140 (wild type), Y113W/W140 and Y113/W140F, Y113W/W140F, were produced by substituting tryptophan (W) for tyrosine (Y) at residue 113 and phenylalanine (F) for tryptophan (W) at residue 140. For each group, the proteins have the same amino acid at residue 140, but a different amino acid at residue 113. The solvent perturbation of nuclease fluorescence and 1,8-anilinoaphthalene-8-sulfonate binding studies showed that the substitutions do not change the side-chain positions of amino acids at residues 113 and 140. Chromatography of the proteins on the Phenyl-Superose HR5/5 column showed that the proteins with tryptophan at residue 113 have longer retention times than the proteins having tyrosine at residue 113; the proteins with the same amino acid at residue 113 have almost the same retention time regardless of substituting phenylalanine for tryptophan at residue 140. The studies clearly indicate that not all amino acid substitutions have an effect on protein retention; the contribution to retention of a given amino acid substitution depends on its position in a protein. Single amino acid substitutions at the exterior surface of a protein, which change the strength of hydrophobic interaction, can affect the protein retention in hydrophobic interaction chromatography. Staphylococcal nuclease and its mutants with only one amino acid difference on their surfaces can be discriminated by the phenyl Superose column.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7842146 TI - Separation of alkaloids by pH-zone-refining counter-current chromatography. AB - pH-Zone-refining counter-current chromatography was applied to the separation of alkaloids from a crude extract of Crinum moorei using a multilayer coil planet centrifuge. After methyl tert.-butyl ether and water were equilibrated, triethylamine (5-10 mM) was added to the organic phase and hydrochloric acid (5 10 mM) to the aqueous phase. The separation was performed by eluting the column with either the organic phase (displacement mode) or the aqueous phase (reverse displacement mode) while the other phase was used as the stationary phase. From 3 g of the extract, crinine, powelline and crinamidine were separated in 2.5-7 h with minimum overlapping. PMID- 7842147 TI - Applicability of clinical pharmacotherapy guidelines for major depression in primary care settings. AB - OBJECTIVE: To determine whether guidelines established for pharmacologic treatment of major depression are feasible in primary care. DESIGN: Prospective cohort study. SETTING: Ambulatory family health centers and internal medicine clinics. PATIENTS: Ninety-one primary care patients meeting criteria within the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition for a current major depression randomized to receive antidepressant medication after being judged by a psychiatrist as clinically eligible for pharmacotherapy in an ambulatory setting. INTERVENTION: Nortriptyline hydrochloride prescribed by primary care physicians trained in clinical guidelines specifying dosage schedules, durations, and procedures resembling those recommended by the AHCPR (Agency for Health Care Policy and Research) Depression Guideline Panel. MAIN OUTCOME MEASURES: Patient participation and continuation in medication treatment. RESULTS: Fifty-five percent of patients completed the acute phase of treatment after a mean of 6.9 visits extending over a mean of 8.1 weeks. Of those patients entering the continuation phase, 60% completed the follow-up visits for 6 months. Taken together, only 33% of patients assigned to receive antidepressant medication completed the full regimen recommended by the AHCPR guidelines. CONCLUSIONS: The treatment of depressed primary care patients within AHCPR guidelines for antidepressant medication is feasible but complex. Although primary care physicians ably adhere to these guidelines, keeping patients in treatment is difficult and possibly requires greater flexibility in treatment regimens. PMID- 7842148 TI - Domestic violence in a primary care setting. Patterns and prevalence. AB - OBJECTIVES: To determine the prevalence of domestic violence among women patients in a primary care setting, the types of violence experienced by each woman, and the reasons for their visit to the family physician. DESIGN AND SAMPLE: Structured interviews with all consecutive, consenting women patients scheduled for morning appointments between July 26 and August 13, 1993. SETTING: A community-based family practice residency outpatient clinic in a midwestern city with a population of 85,000. RESULTS: Of the 42 women interviewed, 45% reported experiencing physical, social, and/or emotional violence in their relationships. Thirty-six percent reported being physically battered during their lifetimes; 12% reported being currently involved in a battering relationship. Relationships and patterns between various types of violence were evident. Sixty-two percent of the women who had experienced slapping and hitting (moderate abuse) also experienced punching and kicking (severe violence), some of which included sexual violence and weapon use. Women who were sexually abused were also likely to be emotionally abused (r = .66; P < .001), and women who were socially abused were also likely to be severely battered (r = .60; P < .005). None of the currently battered women was being seen for routine health maintenance reasons, but presented instead with specific complaints such as neck stiffness and migraine headache. CONCLUSIONS: Domestic violence is very prevalent among women patients in primary care settings and involves predictable patterns of injury. Physicians should routinely assess for violence at all types of visits, educate patients about violence, and work to prevent the violence that occurs in abusive relationships. PMID- 7842149 TI - Is smoking an indication for prenatal ultrasonography? RADIUS Study Group. AB - OBJECTIVE: To evaluate whether ultrasound screening during pregnancy decreases the frequency of smoking in women who present with a history of smoking. DESIGN: The Routine Antenatal Diagnostic Imaging with Ultrasound Study was a multicenter, randomized clinical trial of ultrasound screening during pregnancy. We obtained information on smoking habits during pregnancy from birth certificate records for the subset of women who were delivered of a neonate in Missouri hospitals, and determined the effect of ultrasound screening on smoking habits during pregnancy. SETTING: The study was conducted in multiple practices in six states. PARTICIPANTS: Women who registered for prenatal care at participating practices. INTERVENTION: Women in the screened group were routinely scheduled for ultrasound screening at 16 to 22 weeks' gestation and at 31 to 35 weeks' gestation. Those in the control group received ultrasound screening only for medical indications, as determined by their physicians. MAIN OUTCOME MEASURE: Smoking habits were measured by the number of cigarettes smoked per day. RESULTS: There was no difference in the rates of smoking cessation between the screened group and the control group. For those who continued smoking, the mean number of cigarettes smoked per day, as reported at the time of delivery, was slightly higher in the screened group. CONCLUSION: Ultrasound screening does not reduce the frequency of smoking during pregnancy. PMID- 7842150 TI - Practicing with the urban underserved. A qualitative analysis of motivations, incentives, and disincentives. AB - OBJECTIVE: To investigate the personal characteristics and professional experiences of medical providers working with medically underserved urban populations. DESIGN: Focus groups of primary care providers. SETTING: Public and private clinics in Salt Lake City, Utah, in which the providers had ongoing relationships with medically underserved patients. PARTICIPANTS: Twenty-four providers (11 men and 13 women), including 12 physicians (three family physicians, seven pediatricians, and two psychiatrists), one dentist, three physician assistants, and eight nurse practitioners participated in three focus groups. MAIN OUTCOME MEASURE: Interpretative analysis of verbatim quotations regarding personal beliefs, feelings, and practice experiences. RESULTS: Participants revealed a strong sense of service to humanity and pride in making a difference. They thrive on the challenge of creatively dealing with their patients' complex human needs with limited health care resources. Factors critical to survival in an urban underserved setting include a hardy personality style, flexible but controllable work schedule, and multidisciplinary practice team. The camaraderie and synergy of teams generate personal support and opportunities for continuing professional development. CONCLUSIONS: Increasing the numbers of health care professionals wanting to work with the medically underserved may be facilitated through refining admissions criteria to schools for health care professionals to include values and personality characteristics, emphasizing within curricula the important skills and practice styles necessary to work with underserved patients, and ensuring that underserved practice environments provide support through multidisciplinary teams and structured work hours. These potentially effective approaches could increase success in recruiting and retaining health care professionals to work with medically underserved patients. PMID- 7842151 TI - Primary care physicians' response to dissemination of practice guidelines. AB - BACKGROUND: Much effort has gone into producing clinical practice guidelines, but relatively few studies address dissemination issues. Unless guidelines are used, little is gained. This study evaluates the effect of three methods to disseminate asthma guidelines on physicians' behavior and attitudes toward education strategies. METHODS: Asthma guidelines were mailed to 60 physicians in three Area Health Education Centers in Arkansas. Dissemination efforts at one site featured a short summary, telephone calls by "detailing" physicians, and a continuing medical education conference. Computer strategies were used at the second site, and a multimedia approach with facsimile messages, posters, videocassettes, audiocassettes, and a continuing medical education conference was used at the third site. A fourth site with 22 participants served as a comparison. Data were collected by mailed questionnaires, outpatient chart reviews, and physician interviews. Changes between baseline and posttest assessments following a 4-month intervention were calculated for medication use, and peak flow monitoring use was compared with the control group (general linear model). Regression analyses were used to identify physician and practice factors associated with particular education techniques. RESULTS: Each site improved in the use of medications or peak flow monitoring, but none improved in all areas. The multimedia, continual reminder approach was well accepted but there was little support for the computer strategies. CONCLUSIONS: Further efforts to disseminate clinical guidelines should include a variety of formats with an emphasis on short, concise summaries and frequent reminders. Social influence appears to play a role and will be a fruitful area for further research. PMID- 7842152 TI - Understanding knowledge and attitudes about breast cancer. A cultural analysis. AB - OBJECTIVE: To evaluate knowledge and attitudes about breast cancer risk factors among Latinas, Anglo-American women, and physicians. DESIGN: Ethnographic interviews employing systematic data collection methods. PARTICIPANTS: Twenty eight Salvadoran immigrants, 39 Mexican immigrants, 27 Chicanas, and 27 Anglo American women selected through an organization-based network sampling and a convenience sample of 30 primary care physicians in Orange County, Calif. MAIN OUTCOME MEASURES AND RESULTS: Data analysis using qualitative content analysis and quantitative cultural consensus analysis, a mathematical technique that determines the degree of shared knowledge within groups and estimates "culturally correct" answers (cultural models), was employed. The content analysis revealed different beliefs about breast cancer risk factors, particularly between the Latinas and the physicians. The cultural consensus analysis found two broad cultural models (defined as groups with ratios between the first and second eigenvalues of > or = 3 and no negative competency scores). A Latina model (ratio = 3.4), formed by the Salvadorans, Mexicans, and Chicanas, emphasized breast trauma and "bad" behaviors, including drinking alcohol and using illegal drugs as risk factors. A biomedical model (ratio = 3.0), embraced by physicians and Anglo American women, emphasized risk factors described in the medical literature, such as family history and age. Within these broad models, each group of respondents also differed enough in their beliefs to form their own, often stronger, cultural models. CONCLUSIONS: Ethnography can provide important insights about culturally based knowledge and attitudes about disease. An understanding of the distinctive cultural models regarding breast cancer risk factors will aid future cancer control interventions. PMID- 7842153 TI - Factors that facilitate compliance to lower fat intake. AB - The success of dietary interventions that are prescribed to reduce the risk of heart disease depends on the degree to which patients actually change their diets. A review of research trials using different diets and various means of fostering dietary change to reduce cardiac risk factors identified specific factors that are associated with a greater degree of dietary change. Contrary to the common conception that strict diets are unacceptable to patients, those research studies that set stricter limits on fat intake achieved a greater degree of dietary change than did studies with more modest goals. Additional factors used by studies that achieved a lower fat intake include monitoring dietary intake at least monthly, family involvement, group support, provision of food, initial residential treatment, the use of vegetarian diets, and symptomatic subjects. These factors may be useful to researchers and to clinicians seeking to improve dietary compliance in patients. PMID- 7842154 TI - Cross-cultural considerations in clinical ethics consultations. AB - Cross-cultural encounters between patients and physicians are now commonplace. Although increasing attention has been given to cultural issues in clinical medicine, there has been little discussion of cultural differences presenting as ethical dilemmas. We report four cases in which such differences led to requests for ethics consultations. In analyzing these cases, we identify four elements that are essential for successful resolution of such dilemmas: (1) an ability to communicate effectively with patients and their families; (2) a sufficient understanding of the patient's cultural background; (3) identification of culturally relevant value conflicts; and (4) a willingness to pursue discussion of the ethical dilemma until a compromise is reached or an otherwise satisfactory resolution of the problem is achieved. We conclude with several practical guidelines for clinicians facing ethical dilemmas in cross-cultural interactions with patients. PMID- 7842155 TI - Improving physicians' preventive health care behavior through peer review and financial incentives. AB - We assessed improvement of preventive health care behaviors by physicians in an independent practice association-health maintenance organization. A before-after, 3-year study of a defined cohort measured changes through chart audit, accompanied by peer review, feedback, and financial incentives. Outcome measures consisted of rates of mump-measles-rubella (MMR) immunization, screening for cholesterol levels, and charting adequacy. Offices meeting MMR vaccination standards over 3 years increased from 78% to 96% (P < .05); those meeting standards for screening for cholesterol levels, from 92% to 95%. The average scores for charting adequacy rose from 87% to 92% (P < .05). The percentage of practices not in compliance with a standard of 90% decreased as follows: for MMR vaccination, from 57% to 12%; for screening for cholesterol levels, from 21% to 11%; and for charting adequacy, from 53% to 29% (P < .05). PMID- 7842156 TI - A stitch in time. PMID- 7842157 TI - The blues: now and forever more? PMID- 7842158 TI - Childhood immunization availability in primary care practices. PMID- 7842159 TI - Striae gravidarum: folklore and fact. PMID- 7842160 TI - Recognition, management, and outcomes of depression in primary care. AB - OBJECTIVE: To evaluate the recognition, management, and outcomes of depressed patients presenting in primary care. DESIGN: Epidemiologic survey with 12-month follow-up. SETTING: Primary care clinics of a staff-model health maintenance organization. PATIENTS AND MAIN OUTCOME MEASURES: Consecutive primary care attenders aged 18 to 65 years (n = 1952) were screened using the 12-item General Health Questionnaire (GHQ-12), and a stratified random sample (n = 373) completed a psychiatric assessment, including the Composite International Diagnostic Interview (CIDI), the 28-item GHQ, and a brief self-rated disability questionnaire (BDQ). Three-month follow-up assessment (n = 347) repeated the GHQ 28 and BDQ, and 12-month follow-up (n = 308) repeated the CIDI, GHQ-28, and BDQ. Use of psychotropic drugs and mental health services was assessed using computerized pharmacy and visit registration records. RESULTS: Structured interviews found 64 cases of current major depression (weighted prevalence, 6.6%) and 58 cases of current subthreshold depression (weighted prevalence, 8.8%). Of those with major depression, 64% (n = 41) were recognized as psychologically distressed by the primary care physician, 56% (n = 36) filled at least one antidepressant prescription during the next 3 months, and 39% (n = 25) made at least one specialty mental health visit. Compared with recognized cases, those with unrecognized major depression were less symptomatic at baseline (GHQ-28 score, 15.31 vs 11.07; P = .006) but showed a similar rate of improvement over 12 months (F test for difference in slopes, P = .93). CONCLUSIONS: While many depressed primary care patients may go unrecognized and untreated, this group appears to have milder and more self-limited depression. A narrow focus on increased recognition may not improve overall outcomes. Treatment resources might be best directed toward more intensive follow-up and relapse prevention among those now treated. PMID- 7842161 TI - Establishment and characteristics of an interleukin-2-dependent STLV-1-producing lymphoid cell line, SPH-7(T), obtained from Papio hamadryas with malignant lymphoma. PMID- 7842162 TI - Culture model for primary hepatocytes. PMID- 7842163 TI - Matrix components and behavior of human adenocarcinoma cells. PMID- 7842164 TI - B16 melanoma cell spreading on activated endothelial cells. PMID- 7842165 TI - Fibroblast chemotaxis in response to dexamethasone. PMID- 7842166 TI - Failure of insulin cells to develop in cultured embryonic chick pancreas: a model system for the detection of factors supporting insulin cell differentiation. AB - Little being known about factors necessary for insulin cell differentiation, we tested the chance observation that these cells were virtually absent from collagen gel cultures of embryonic avian pancreas in which the other pancreatic endocrine cells were numerous. Five-day dorsal buds stripped of their enveloping mesenchyme were embedded in gel and overlaid by a defined medium containing serum, then cultured for 7 days. Immunocytochemical evaluation showed a very low proportion of insulin cells. Substitution of the gel by a polyamino acid coating slightly increased the proportion. In an attempt to test for ability of insulin cell formation to recover, we transferred explants first cultured in collagen gel to polyamino-acid-coated dishes for a further 7 days. No improvement resulted. In controls grown for 14 days on a polyamino acid coating, insulin cells disappeared completely. We conclude that collagen gel does not support survival and differentiation of chick embryonic insulin cells and that the medium used is lacking in some essential factor(s). Determination of their identity should prove possible by exploitation of this model. PMID- 7842167 TI - Regulation of TGF beta 3 gene expression in embryonic palatal tissue. AB - The TGF beta family of genes has been shown to play an important role in regulating various aspects of development, although the mechanisms by which TGF beta exerts its effects have not yet been clarified. Growth and differentiation of both murine embryonic palate mesenchymal (MEPM) cells and palatal epithelium can be regulated by the TGF beta s. We therefore examined the expression of mRNAs encoding TGF beta 1, TGF beta 2, and TGF beta 3 in developing embryonic palatal tissue as well as factors that modulate their levels of expression. Northern blot analysis of RNA isolated from murine embryonic palatal tissue on gestational days (GD) 12, 13, and 14 demonstrated the presence of one mRNA transcript for TGF beta 1 (2.5 kb), two transcripts for TGF beta 2 (4.4 kb, 6.0 kb), and one transcript for TGF beta 3 (3.5 kb). Although steady-state levels of TGF beta 1 mRNA showed no changes during development of the palate, TGF beta 2 mRNA levels were maximal on both GD13 and GD14 and TGF beta 3 mRNA levels transiently increased on GD 13. In addition, levels of TGF beta 3 mRNA seemed much higher than either TGF beta 1 or TGF beta 2. both TGF beta 1 and TGF beta 2 were able to increase, in a dose related manner, the expression of TGF beta 3 mRNA in murine embryonic palate mesenchymal cells in vitro. In contrast, epidermal growth factor (EGF) down regulated the expression of TGF beta 3 mRNA even in the presence of TGF beta 1 or TGF beta 2.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7842168 TI - Endogenous butyrylcholinesterase in SV40 transformed cell lines: COS-1, COS-7, MRC-5 SV40, and WI-38 VA13. AB - Comparison of proteins expressed by SV40 transformed cell lines and untransformed cell lines is of interest because SV40 transformed cells are immortal, whereas untransformed cells senesce after about 50 doublings. In MRC-5 SV40 cells, only seven proteins have previously been reported to shift from undetectable to detectable after transformation by SV40 virus. We report that butyrylcholinesterase is an 8th protein in this category. Butyrylcholinesterase activity in transformed MRC-5 SV40 cells increased at least 150-fold over its undetectable level in MRC-5 parental cells. Other SV40 transformed cell lines, including COS-1, COS-7, and WI-38 VA13, also expressed endogenous butyrylcholinesterase, whereas the parental, untransformed cell lines, CV-1 and WI-38, had no detectable butyrylcholinesterase activity or mRNA. Infection of CV 1 cells by SV40 virus did not result in expression of butyrylcholinesterase, showing that the butyrylcholinesterase promoter was not activated by the large T antigen of SV40. We conclude that butyrylcholinesterase expression resulted from events related to cell immortalization and did not result from activation by the large T antigen. PMID- 7842169 TI - Cytolytic differences among lepidopteran cell lines exposed to toxins of Bacillus thuringiensis subsp. kurstaki (HD-263) and aizawai (HD-112): effect of aminosugars and N-glycosylation. AB - Comparison of lytic-dose response behavior of seven lepidopteran cell lines to the activated delta-endotoxin polypeptides of Bacillus thuringiensis subspecies kurstaki (HD-263) and aizawai (HD-112) indicated distinct differences among the lines. The lines derived from Spodoptera species S. exigua (URC-SE-1A) and S. littoralis (UIV-SL-575) were more susceptible to lysis by aizawai toxin (Bta) than kurstaki toxin (Btk) as were cells from the Lymantria dispar line (IPLB LD652Y). However, the concentrations of Bta required for lysis of 50% of URC-SE 1A and IPLB-LD652Y cells (LC50) were 0.2 to 0.8 micrograms/ml compared to 5 to 9 micrograms/ml for UIV-SL-575 cells. In comparison, Btk LC50 concentrations for the three lines were similar (14 to 19 micrograms/ml). Cells from S. frugiperda (IPLB-SF-21AE) and Trichoplusia ni (TN368) were similar in their response to Bta (LC50 = 2.5 to 3.7 micrograms/ml) and Btk (LC50 = 1.0 to 2.8 micrograms/ml) whereas the lines derived from Heliothis spp. were the least susceptible to both toxins. The LC50 concentrations for Bta with the H. zea line (IPLB-HA-1075) and H. virescens line (BCIRL-HV-AM1) were > 50 micrograms/ml and for Btk were > 50 micrograms/ml and 42 to 50 micrograms/ml, respectively, yet for both lines Btk was the more cytolytic. Cytolysis of TN368 cells could be inhibited to varying extents by preincubation of the toxins with the aminosugars of galactose, mannose, and glucose and their N-acetyl derivatives. The unsubstituted hexoses were not inhibitory.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7842170 TI - Site of synthesis and phylogenetic distribution of a hemolymph trophic factor of the tobacco hornworm, Manduca sexta. AB - Identification of fifth instar larval Manduca sexta fat body and epidermis as sites of synthesis of a hemolymph protein (hemolymph trophic factor or HTF) was achieved using in vitro 3H-leucine incorporation into protein and subsequent immunoprecipitation of tissue homogenates. Fat body is the primary site of HTF synthesis with a maximal rate on Day 1; epidermis is a secondary site with peak synthesis on Day 0. In vitro radiolabelling followed by TCA precipitation of general protein of fat body and epidermal homogenates suggest that fat body actively elaborates protein on Days 0-5 with peak rates on Days 1 and 4, while epidermis is active on Days 0-5 with a peak rate on Day 3. Based on Anti-HTF ELISA estimates, HTF [500 to 1000 micrograms/ml] was found in the hemolymph of representatives of the insect orders Blattodea, Hemiptera, Orthoptera, and Lepidoptera and in the class Crustacea, but not in the class Merostomata. These studies suggest a possible fundamental role for HTF among modern arthropods in cuticular deposition involving both epidermis and fat body. The physiological role of HTF is undetermined. PMID- 7842171 TI - Genital tract growth factors from a moth, the tobacco budworm, Heliothis virescens. AB - Development and maturation of the genital tract of the moth, Heliothis virescens, takes place within a few days in the pupal stage. The insect steroid hormone, 20 hydroxyecdysone (20E), essential during this period, stimulated testis sheath and fat body tissue to secrete factors that, in turn, stimulated growth and development of pupal spermducts and genital imaginal discs in vitro. Factors could be extracted in aqueous solution from tissues incubated for 24 h in media containing 1000pg/microliters 20E, and partially purified by chromatography on polyacrylamide gels. Ten active molecular weight fractions were separated from testis sheath extracts, and 9 from fat body extracts. Most fractions were labile to protease, although the activity of six of the fractions was also destroyed by lipase. Testis sheath, fat body tissue, and active fractions, caused partial development of the genital tract in vitro, as well as increased incorporation of [3H]methionine into precipitable protein and [3H]thymidine into nuclear material. PMID- 7842172 TI - Factors that influence the development of cultured neurons from the brain of the moth Manduca sexta. AB - During metamorphic adult development, neurons and glial cells in the developing olfactory (antennal) lobes of the moth undergo characteristic and extensive changes in shape. These changes depend on an interplay among these two cell types and ingrowing sensory axons. All of the direct cellular interactions occur against a background of changing steroid hormone titers. Antennal-lobe (AL) neurons dissociated from stage-5 (of 18 stages) metamorphosing animals survive at least 3 wk in primary cell culture. We describe here the morphological influences on AL neurons of (1) exposure to the steroid hormone 20-hydroxyecdysone, (2) exposure to sensory axons, and (3) interactions among the AL neurons. Cultured AL neurons respond only weakly, if at all, to 20-hydroxyecdysone. They do, however, show greater total outgrowth and branching when they had been exposed in vivo to sensory axons. Because there is no direct contact between some of the neuronal types and the sensory axons at the time of dissociation, the increase in outgrowth must have been mediated via a diffusible factor(s). When AL cells (neurons and glia) are plated at high density in low volumes of medium, or when the cells are plated at low density but in the presence of medium conditioned by high-density cultures, neurite outgrowth and cell survival are increased. Nerve growth factor (NGF), epidermal growth factor (EGF), fibroblast growth factor basic (bFGF), transforming growth factor-beta (TGF beta) and insulin-like growth factor (ILGF) had no obvious effect on neuronal morphology and thus are unlikely to underlie these effects. Our results suggest that the mature shape of AL neurons depends on developmental interactions among a number of diffusible factors. PMID- 7842173 TI - Roles for insulin and ecdysteroids in differentiation of an insect cell line of epidermal origin. AB - During postembryonic development of insects, molting cycles affect epidermal cells with alternate periods of proliferation and differentiation. Cells of the cell line established from imaginal discs of the Indian meal moth (IAL-PID2) differentiate under the action of the molting hormone, 20-hydroxyecdysone, in a manner that is meaningful in terms of the development of the tissue from which they were derived. In particular, the hormone caused an accumulation of the cells in the G2 phase of their cycle and induced the formation of epithelial-like aggregates and the synthesis of specific proteoglycans. Recent discovery of members of the insulin superfamily in insects and the role of growth factors played by this family of molecules in vertebrates led us to check for their potential effects on IAL-PID2 cell cycle regulation. On the one hand, our results showed that insulin was involved in partial resumption of the cell cycle after an arrest caused by serum deprivation, but that other growth factors present in fetal calf serum were needed for full completion of mitosis. On the other hand, the cytostatic effect of 20-hydroxyecdysone was reversible, and, prior exposure of the cells to the hormone allowed the cells to complete one cell cycle in serum free medium. These results suggest that the production of autocrine growth factors induced by ecdysteroids could circumvent the absence of serum. This cell culture model provides potential for further study of interactions between ecdysteroids and growth factor homologs during differentiation of insect epidermal cells. PMID- 7842174 TI - Introduction: the ethics of publishing research sponsored by the tobacco industry in ATS/ALA journals. PMID- 7842175 TI - Pro: the search for untainted money. PMID- 7842176 TI - Con: the smoking lamp should not be lit in ATS/ALA publications. PMID- 7842177 TI - Pulmonary and critical care procedures. Under the spotlight. PMID- 7842178 TI - Pulmonary and critical care training. Role of the ATS. PMID- 7842179 TI - Withholding and withdrawing life-sustaining therapy. All systems are not yet "go". PMID- 7842180 TI - Procedural skills of practicing pulmonologists. A national survey of 1,000 members of the American College of Physicians. AB - We surveyed pulmonologists to determine which procedures they do in practice, where they learned the procedures, and how much training they recommend to attain and maintain clinical competence in each. We mailed a survey to a random sample of 1,000 members of the American College of Physicians who were identified as practicing pulmonologists; 755 (75%) responded. Respondents performed a variety of pulmonary procedures, an average of 17 of the 29 listed. Pulmonologists who were more recent graduates, who worked longer hours, and who were involved in critical care did a greater variety of procedures. Only 26% of practicing pulmonologists currently do all the procedures required for board certification in pulmonary medicine. For each of 13 specific procedures, the number reported done in the past year was generally unrelated to practice factors. Many respondents who learned procedures in practice did so without formal training or supervision. Respondents' recommendations regarding numbers of procedures required to attain or maintain competence did not vary greatly. Pulmonologists vary considerably in the types of procedures they do. Their opinions about the training needed for competence help to better define requirements for training programs. More attention should be focused on training and certifying practicing pulmonologists in procedures learned after formal fellowship training. PMID- 7842181 TI - Decisions to limit or continue life-sustaining treatment by critical care physicians in the United States: conflicts between physicians' practices and patients' wishes. AB - We surveyed a national sample of 879 physicians practicing in adult intensive care units in the United States, in order to determine their practices with regard to limiting life-sustaining medical treatment, and particularly their decisions to continue or forgo life support without the consent or against the wishes of patients or surrogates. Virtually all of the respondents (96%) have withheld and withdrawn life-sustaining medical treatment on the expectation of a patient's death, and most do so frequently in the course of a year. Many physicians continue life-sustaining treatment despite patient or surrogate wishes that it be discontinued (34%), and many unilaterally withhold (83%) or withdraw (82%) life-sustaining treatment that they judge to be futile. Some of these decisions are made without the knowledge or consent of patients or their surrogates, and some are made over their objections. We conclude that physicians do not reflexively accept requests by patients or surrogates to limit or continue life-sustaining treatment, but place these requests alongside a collection of other factors, including assessments of prognosis and perceptions of other ethical, legal, and policy guidelines. While debate continues about the ethical and legal foundations of medical futility, our results suggest that most critical care physicians are incorporating some concept of medical futility into decision making at the bedside. PMID- 7842182 TI - Clinical risks for development of the acute respiratory distress syndrome. AB - To further understanding of the epidemiology of acute respiratory distress syndrome (ARDS), we prospectively identified 695 patients admitted to our intensive care units from 1983 through 1985 meeting criteria for seven clinical risks, and followed them for development of ARDS and eventual outcome. ARDS occurred in 179 of the 695 patients (26%). The highest incidence of ARDS occurred in patients with sepsis syndrome (75 of 176; 43%) and those with multiple emergency transfusions (> or = 15 units in 24 h) (46 of 115; 40%). Of patients with multiple trauma, 69 of 271 (25%) developed ARDS. If any two clinical risks for trauma were present, the incidence of ARDS was 23 of 57, or 40%. During the study period, we identified 48 patients with ARDS who did not have one of the defined clinical risks, yielding a sensitivity of 79% (179 of 227). Secondary factors associated with increased risk for ARDS in clinical risk subgroups include an elevated Acute Physiologic and Chronic Health Evaluation II (APACHE II) score in patients with sepsis and increased APACHE II and Injury Severity Scores (ISS) in trauma victims. Mortality was threefold higher when ARDS was present (62%) than among patients with clinical risks who did not develop ARDS (19%; p < 0.05). The difference in mortality if ARDS developed was particularly striking in patients with trauma (56% versus 13%), but less in those with sepsis (69% versus 49%). The mortality data should be interpreted with caution, since the fatality rate in ARDS patients appears to have decreased in our institution from the time that these data were collected.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7842183 TI - Heliox improves pulsus paradoxus and peak expiratory flow in nonintubated patients with severe asthma. AB - Heliox is a blend of helium and oxygen with a gas density less than that of air that decreases airway resistance (Raw) in patients ventilated for status asthmaticus. We tested whether breathing an 80:20 mixture of helium:oxygen would reduce pulsus paradoxus (PP) and increase peak expiratory flow (PEF) in patients presenting to the emergency room with an exacerbation of asthma. After receiving 30 min of beta-agonist aerosols and intravenously administered methylprednisolone, 27 patients whose PP remained greater than 15 mm Hg and whose PEF remained less than 250 L/min consented to breathe heliox or room air for 15 min. PP decreased and PEF increased with time in control patients, indicating a time-related effect of routine bronchodilator therapy (p < 0.05). PP decreased in 15 of 16 patients during heliox, and the change with heliox was significantly greater than that during air breathing (p < 0.01). PEF measured with a Wright's peak flow meter calibrated for heliox increased in all patients breathing heliox. Again, the increase in PEF during heliox breathing was significantly greater than the corresponding change in control patients breathing air (p < 0.001). To the extent that PP reflects the inspiratory fall in pleural pressure, this reduction in PP indicates a substantial reduction in inspiratory Raw when the less dense gas is inspired through narrowed bronchi having turbulent flow regimes. The 35% increase in PEF while breathing heliox signals a similar reduction in expiratory Raw, which might diminish the hyperinflation often observed during an exacerbation of asthma.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7842184 TI - The effects of intranasal steroids on nasal and pulmonary responses to cat exposure. AB - To test the hypothesis that nasal antiinflammatory treatment can modify both upper and lower airway responses to allergen exposure, 12 cat-allergic subjects underwent 1 h cat exposure challenges at baseline, with nasal occlusion, and after 1 wk of treatment with either intranasal triamcinolone acetonide or placebo in a double-blind crossover trial. Challenges were performed in a room containing two cats with airborne Fel d I levels ranging from 35 to 37,525 ng/m3. Overall, nasal symptoms were moderately reduced by treatment (p = 0.06), with the greatest reduction occurring in the first 15 and 30 min of the challenge (p < 0.01 and p < 0.05, respectively). Mean lower respiratory symptoms were also diminished by treatment (p = 0.02), although those effects were most evident during the last 15 min of the challenge. Maximum changes in FEV1 were slightly reduced by the nasal therapy (p = 0.07), reaching statistical significance only at the 30-min intervals (p < 0.05). There were no significant differences in nasal histamine or TAME esterase levels. When challenges were repeated with nasal occlusion, no significant differences were detected in chest symptoms or FEV1 changes. We conclude that treatment with an intranasal corticosteroid led to significant reductions in both upper and lower airway responses to intense cat exposure. PMID- 7842185 TI - U46619-induced bronchoconstriction in asthmatic subjects is mediated by acetylcholine release. AB - Thromboxane A2 (TxA2) has been implicated in the pathogenesis of airway hyperresponsiveness. U46619 is a chemical that mimics the effects of TxA2. Both TxA2 and U46619 have been demonstrated to act presynaptically to enhance the release of acetylcholine from cholinergic nerves in canine airway smooth muscle. The purpose of this study was to determine whether the bronchoconstriction caused by inhaled U46619 in asthmatic subjects is caused by acetylcholine release. Airway responsiveness to inhaled methacholine and U46619 was measured in eight subjects with mild stable asthma and expressed as the provocation concentration causing a 20% fall in FEV1 (PC20). Subjects were studied on 4 d, each separated by 3 days. On each study day, subjects inhaled a cholinergic antagonist ipratropium bromide (80 micrograms), or placebo, and 1 h later, increasing doubling doses of methacholine or U46619 were inhaled, and a PC20 value was obtained. The mean methacholine PC20 on the placebo day was 1.42 mg/ml (%SEM, 1.47) and after treatment with ipratropium bromide this increased to 127.33 mg/ml (%SEM, 1.29) (p = 0.0001), a mean 89.4-fold (%SEM, 1.19) increase. The mean U46619 PC20 on the placebo day was 2.09 micrograms/ml (%SEM, 1.56) and after treatment with ipratropium bromide this increased to 47.54 micrograms/ml (%SEM, 1.43) (p = 0.0001), a mean 22.8-fold (%SEM, 1.36) increase. The ability of ipratropium bromide to attenuate responsiveness to the noncholinergic mediator histamine was also investigated in six subjects. The mean increase in histamine PC20 was a 3.09-fold (%SEM, 1.17) increase, significantly less than the increase seen for both methacholine and U46619 (p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7842186 TI - Efficacy of Uniphyl, salbutamol, and their combination in asthmatic patients on high-dose inhaled steroids. AB - A group of 32 patients with moderately severe, chronic asthma (mean FEV1 55% of predicted), maintained on moderately high doses of inhaled corticosteroids (mean dose 1,100 micrograms/d), participated in this double-blind, placebo-controlled crossover study. The effect on pulmonary function of adding theophylline (U, once daily Uniphyl), inhaled salbutamol (S, 200 micrograms four times per day), and their combination (C) or placebo (P) was assessed on Day 14 of each treatment phase. Patients recorded peak expiratory flow, asthma symptom severity (morning and evening), and use of rescue salbutamol inhaler in daily diaries. Mean FEV1 between 0730 and 1800 h and maximum FEV1 between 0730 and 1300 h were significantly higher on U, S, and C compared with P (p < 0.006). Morning peak flow and FEV1 (0730 h) were significantly higher on U and C compared with S and P (p < 0.01). Evening peak flow was higher on U than P (p < 0.001), and C was higher than S and P (p < 0.01). Rescue salbutamol inhaler use was significantly higher on P than on U, C, or S (p = 0.0001). Patient rating of asthma symptoms during C was significantly better than on S or P (p < 0.05). Patient rating of asthma control and study phase preference was significantly higher on combination and Uniphyl alone than on placebo, the combination also being superior to salbutamol alone. Addition of Uniphyl or a combination of Uniphyl and salbutamol significantly improves pulmonary function and asthma symptoms in patients treated with high doses of inhaled corticosteroids and as-needed beta agonists.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7842187 TI - Oral and inhaled corticosteroids reduce bone formation as shown by plasma osteocalcin levels. AB - Osteoporosis is a well-known, serious complication of long-term high-dose corticosteroid therapy. This study was performed to determine the effects of commonly used doses of oral and inhaled steroids on biochemical indices of bone formation. Initially we examined the long-term effects of oral steroids. Thirty four outpatients with symptomatic asthma or chronic obstructive airways disease (COAD) receiving long-term oral prednisolone (mean 10.1 mg daily) were compared with 34 control subjects with asthma or COAD matched individually for age, sex, and menopausal status who were not taking oral steroids. Plasma osteocalcin concentrations were significantly lower (patients 6.3 +/- 0.1 ng/ml; control subjects 8.6 +/- 0.5 ng/ml, mean +/- SEM; p < 0.01) in patients on steroids with no difference in alkaline phosphatase. To examine the short-term effects of oral and inhaled corticosteroids, healthy male volunteers were given a 7-d course of either 15 mg oral prednisolone daily (n = 10) or 500 micrograms inhaled beclomethasone twice daily (n = 20). After 1 wk of oral prednisolone, mean plasma osteocalcin decreased from 11.8 +/- 1.1 ng/ml to 6.9 +/- 0.8 ng/ml (p < 0.001). With inhaled beclomethasone mean plasma osteocalcin decreased from 11.6 +/- 0.6 ng/ml to 9.6 +/- 0.6 ng/ml (p < 0.001) with no change in alkaline phosphatase. In doses routinely prescribed for the prophylaxis and treatment of asthma, oral and inhaled steroids suppress osteocalcin levels and may therefore inhibit bone formation. This effect is seen with short courses of steroids and also with chronic administration.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7842188 TI - A comparison of the effects of inhaled furosemide and ethacrynic acid on sodium metabisulfite-induced bronchoconstriction in subjects with asthma. AB - Inhaled furosemide prevents bronchoconstriction induced by a number of challenges in asthma. One approach to determine the mechanism underlying this protection has been to examine the effects of diuretics with different or overlapping pharmacologic effects. We have compared the effects of furosemide on sodium metabisulfite-induced bronchoconstriction with those of equivalent diuretic doses of ethacrynic acid, a loop diuretic that, unlike furosemide, does not interact directly with the membrane Na/K/Cl cotransporter protein or inhibit carbonic anhydrase. Eight subjects with mild asthma were studied on five occasions, receiving nebulized furosemide (20 and 40 mg), ethacrynic acid (25 and 50 mg), or placebo (normal saline) in random order and double-blind 10 min before a cumulative dose challenge with inhaled sodium metabisulfite. After placebo the geometric mean sodium metabisulfite PD20 was 7.9 mumol. Furosemide 20 mg and 40 mg increased the PD20 by a mean 1.1 (95% confidence interval, -0.2-2.4; p > 0.05) and 1.6 (0.4-2.9; p < 0.02) doubling doses to 17.1 and 24.7 mumol, respectively. After inhaled ethacrynic acid 25 mg and 50 mg, the geometric mean PD20 was increased by 0.9 (-0.4-2.2; p > 0.05) and 1.5 (0.2-2.8; p < 0.05) doubling doses to 14.5 and 22.4 mumol, respectively. Thus, equivalent diuretic doses of furosemide and ethacrynic acid have a similar inhibitory effect on sodium metabisulfite-induced bronchoconstriction in asthma. This suggests that interaction with the Na/K/Cl cotransporter protein, or carbonic anhydrase inhibition, is not relevant to the effects of furosemide in asthma. PMID- 7842189 TI - Bronchial inflammation in occupational asthma due to western red cedar. AB - Bronchoalveolar lavage cells and bronchial biopsies were obtained from nine patients with red cedar asthma, six atopic asthmatics and six non-atopic, non asthmatic control subjects. There were similar proportions of neutrophils, mast cells, lymphocytes, and macrophages in BAL samples from all three groups, but eosinophil numbers were elevated in patients with cedar asthma and atopic asthma (3.0 and 2.5% respectively versus 0.5% in control subjects; p < 0.05 for each group). In bronchial mucosal biopsies, mean numbers of T cells were elevated in both asthmatic groups (cedar asthma 9.8 times, and atopic asthma 2.6 times, control values). CD4+ cells accounted for most of the increase in T-cell numbers, while CD8+ cell numbers were elevated in biopsies from a minority of cedar asthma patients. Absolute numbers of CD25+ (IL-2 receptor-bearing) cells were increased in cedar asthma but the proportion of T cells expressing CD25, was similar in all three groups. Activated eosinophils (EG2+) were increased in both asthmatic groups, with mean numbers 2.5 times greater in the cedar asthma biopsies than in atopic asthmatics. Thus both cedar asthma and atopic asthma are associated with increased numbers of T-cells and activated eosinophils in the bronchial mucosa. There was no major histologic difference between atopic asthma and red cedar asthma. PMID- 7842190 TI - Assessment of the severity of asthma by an expert system. Description and evaluation. AB - Asthmaexpert, an expert system (ES), was produced at the special request of several clinicians in order to better understand the medical decisions made clinical experts in managing an asthmatic patient. We describe and evaluate this knowledge base, focusing mainly on assessment of the severity of asthma. After compiling data from a patient, Asthmaexpert assesses the severity of the disease and identifies the trigger factors involved, suggests any further investigations that may be required, and offers a treatment strategy. Implemented with Nexpert and Hypercard, it runs on a MacIntosh personal computer. The validation stage involved eight clinical experts who provided 20 case report forms (CRF) with their conclusions about management of asthma. The CRF were then programmed into the ES, which provided its own conclusions about the same subjects. Afterward, all the experts evaluated the conclusions given by ES or by their colleagues in a double-blind manner. One hundred twenty-seven CRF were available. The reliability of the experts' opinions was good, with a substantial consensus between them when assessing severity scores (kappa = 0.27 to 0.54). There was no difference in concordance of opinions on severity scores either between the experts who designed the system and ES or between the other experts and ES (weighted kappa = 0.72 and 0.69, respectively). Experts judged that the severity scores given by ES were as good as those proposed by their colleagues, and that the overall conclusions given by ES were as good as or better than those given by their colleagues. The conclusions drawn by ES were given a good rating.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7842191 TI - Asthma self-management education program by home monitoring of peak expiratory flow. AB - A prospective controlled trial of home monitoring of peak expiratory flow rate (PEFR) was conducted to determine the usefulness of an objective measure of lung function in association with an education program and a medication self management plan in reducing morbidity in adult patients with asthma. Thirty-five patients managed themselves, using peak flow readings as the basis for the therapeutic plan coupled with educational intervention, whereas 35 control patients used symptoms and spirometric data for following physicians' treatment plans. After a 6-mo study period, patients in the experimental group showed statistically significant improvements in morbidity parameters (days lost from work, acute asthma attacks, days on antibiotic therapy, physician consultations, and emergency room admissions for asthma), increases in FVC, FEV1, and FEV1/FVC, mean PEFR and mean morning PEFR, decrease in percentage of the mean PEFR amplitude, and a reduction in the use of inhaled beta-agonists, oral theophylline, and oral prednisone. Although improvements in some of these parameters were also found in the control group, they did not reach the levels of significance obtained in the experimental group. The personal use of an objective measure of lung function in association with a medication self-management plan leads to improvement in the patient's condition. PMID- 7842193 TI - Survival in relation to lung function and smoking cessation in patients with severe hereditary alpha 1-antitrypsin deficiency. AB - For patients with COPD, FEV1 has been shown to be the single most important factor to influence survival. Patients with alpha 1-antitrypsin deficiency (alpha 1ATD) develop emphysema at a young age, especially if they smoke, and the purpose of this study was to calculate survival with respect to the initial FEV1 and smoking history. For this study, patients with Pi-type ZZ were analyzed. FEV1 was divided in four groups: below 25%, 25 to 49%, 50 to 74%, and more than 75% of predicted. A total of 347 patients with 107 deaths were available for analysis. Three patients were lost to follow-up, and 17 had received a lung transplant. There was no significant difference in survival between males and females. The median survival time for patients with an initial FEV1 below 25% was 6.3 yr (95% CI 5.2-8.0). For the FEV1 groups 25 to 49% and 50 to 74%, median survival times were: 10.5 (9.2-11.9) and 14.2 (12.4-infinity) yr, respectively. The median survival for the above 75% group was not calculable. For patients with an initial FEV1 less than 50%, smokers had a poorer survival rate than patients who quit smoking during the study period (p < 0.01). We conclude that for patients with severe alpha 1ATD, FEV1 is a very strong predictor of survival regardless of sex. Patients who quit smoking had a better survival rate than patients who continued to smoke. PMID- 7842192 TI - Importance of total serum IgE for improvement in airways hyperresponsiveness with inhaled corticosteroids in asthma and chronic obstructive pulmonary disease. The Dutch CNSLD Study Group. AB - Airways hyperresponsiveness is a hallmark of asthma, and many patients with COPD also demonstrate hyperresponsiveness. Inhaled corticosteroids improve hyperresponsiveness, but the extent of improvement may vary considerably between patients. This study was designed to determine which patient characteristics predict these differences in response. Patients with mild to moderately severe obstructive airways disease (asthma and COPD) were selected if PC20 < or = 8 mg/ml and FEV1 < 95% confidence interval of predicted normal. They were followed for 2.5 yr, during which one-third received inhaled corticosteroids. The independent influences of baseline FEV1/IVC, bronchodilator response, PC20, smoking habits, allergy, age, and sex on the improvement in airways hyperresponsiveness with inhaled corticosteroids were analyzed. Total serum IgE was taken as a parameter of allergy, next to specific IgE for house dust mite, skin tests, and blood eosinophils. Total serum IgE was found to be the most important and single independent predictor of change in PC20 with inhaled corticosteroids: patients with a higher IgE had a greater increase in PC20 when administered inhaled corticosteroids than those with lower IgE levels. Alternatively, patients with a higher IgE who did not receive corticosteroids had a decrease in PC20 compared with patients with a lower IgE. This effect was most prominent in asthma but was inconsistent in asthmatic bronchitis and COPD. The level of IgE cannot be used to predict the response to inhaled corticosteroids in individuals accurately. Total serum IgE is the single most important predictor of change in PC20 with and without inhaled corticosteroids.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7842194 TI - Metabolic enzyme activity in the quadriceps femoris muscle in patients with severe chronic obstructive pulmonary disease. AB - Eighteen patients with severe COPD and seven healthy control subjects 64.0 +/- 2.2 and 66.8 +/- 1.4 yr of age, respectively (mean +/- SEM), were investigated. Arterial blood gas analysis, dynamic lung volumes, and muscle biopsy specimens from the quadriceps femoris muscle were performed. The muscle biopsies were analyzed for citrate synthase (CS), succinic acid dehydrogenase (SDH), 3 hydroxyacyl-CoA dehydrogenase (HAD), phosphofructokinase (PFK), and lactate dehydrogenase (LDH) activities and related to protein content. The PFK activity was higher in the COPD group than in the control group (+34%, p < 0.05). CS showed a group difference in the opposite direction (-29%, p < 0.05). LDH activity followed PFK and tended to be higher in the patient group (+27%, NS), whereas SDH (-31%, NS) and HAD (-28%, NS) mirrored the CS results. Muscle protein concentration tended to be lower in the COPD group (-14%, NS). There were no significant changes in enzyme activity after 7 mo of long-term oxygen therapy (n = 6). These results indicate adaptation in the form of augmented glycolysis (PFK), and decreased aerobic metabolism (CS) in the quadriceps femoris muscle in patients with advanced COPD. PMID- 7842195 TI - The effects of oxygen and dopamine on renal and aortic blood flow in chronic obstructive pulmonary disease with hypoxemia and hypercapnia. AB - Renal blood flow is reduced in patients with chronic respiratory failure caused by chronic obstructive pulmonary disease (COPD), and changes in renal hemodynamics are likely to be important in the pathogenesis of the edematous state of cor pulmonale. We therefore examined the hypothesis that this renal vasoconstriction is reversible by comparing the effects of oxygen therapy and the renal vasodilator dopamine on renal hemodynamics in both hypoxemic patients with COPD and those who were also hypercapnic. We assessed renal hemodynamics noninvasively with color-flow Doppler ultrasound. In order to validate the technique we recorded renal hemodynamics in a group of healthy volunteers before and during a dopamine infusion, and in a subgroup we simultaneously measured effective renal plasma flow (ERPF) with para-aminohippurate clearance. In the healthy volunteers there was a 22.5% rise in time-adjusted mean arterial velocity (Tamx) measured by Doppler compared with a 22% rise in ERPF with dopamine. This rise was significant (p < 0.05). In hypoxemic, normocapnic subjects Tamx rose by 25% with oxygen (p < 0.005), 20% with dopamine (p < 0.005), and 24% with both therapies. There was no significant change in aortic flow whether the subjects received air, oxygen, or dopamine (p = 0.77). In the hypercapnic patients there was no significant change in aortic or renal velocities while receiving oxygen or dopamine (p = 0.85 and 0.86). We conclude that color-flow Doppler velocity measurements can accurately detect changes in renal blood flow. Oxygen and dopamine are equipotent renal vasodilators in hypoxic COPD, but the effect is not additive.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7842196 TI - Inhaled nitric oxide as a screening vasodilator agent in primary pulmonary hypertension. A dose-response study and comparison with prostacyclin. AB - To investigate the capacity of the pulmonary vascular bed to acutely vasodilate, we examined in 35 consecutive patients with primary pulmonary hypertension (PPH), the hemodynamic effects of incremental inhalation periods of an air-NO mixture at different concentrations (10, 20, and 40 ppm), and compared them with those of an acute infusion of prostacyclin (PGI2). An individual pulmonary vasodilator response was defined by a fall in total pulmonary resistance (TPR) > or = 30% relative to mean TPR baseline value. Thirteen patients were responders and 22 were nonresponders to both drugs, and they did not significantly differ in overall baseline characteristics except for mean right atrial pressure (p < 0.03). In responders, both drugs produced similar individual vasodilator response. Changes in mean pulmonary arterial pressure and TPR observed during NO and PGI2 were closely correlated (r2 = 0.9, p < 0.001, and r2 = 0.7, p < 0.01, respectively). The vasodilator response to NO was not concentration-related with a maximal effect obtained at 10 ppm. Combination of both drugs did not lead to any additive vasodilator response. Unlike PGI2, NO did not induce any systemic effect, no adverse reaction, but a moderate increase in methemoglobin. Inhaled NO at low dose (10 ppm) appears to be an effective, safe, and reliable substitute for PGI2 in screening for acute pulmonary vasodilator responsiveness during therapeutic assessment of patients with PPH. PMID- 7842197 TI - Rapid decline in FEV1. A new risk factor for coronary heart disease mortality. AB - Coronary heart disease (CHD) is the leading cause of mortality in the United States. The present cohort study was conducted to determine whether rate of FEV1 loss independently predicts CHD mortality in apparently healthy men. White male Baltimore Longitudinal Study of Aging (BLSA) participants without CHD underwent clinical evaluation at 2-yr intervals; 883 had satisfactory pulmonary and lipid studies and returned for a least one visit. Cases were BLSA subjects without CHD on entry who died a "coronary death" (death from acute myocardial infarction, sudden death, or congestive heart failure in the presence of coronary artery disease). Forced expiratory maneuvers followed American Thoracic Society guidelines. Serum cholesterol, blood pressure, cigarette smoking, and body mass index were obtained from the BLSA database. There were 79 CHD deaths and 804 survivors during an average follow-up of 17.4 yr. After adjustment for age, initial FEV1% predicted, smoking status, hypertension, and cholesterol, a time dependent proportional hazards model showed that cardiac mortality, but not all causes of mortality, generally increased with increasing quintile of FEV1 decline for the entire cohort (relative risk [RR] 2.92-5.13) and separately for the subset of never-smokers. Thus, excess CHD mortality follows a large decline in FEV1, independent of the initial FEV1% predicted, cigarette smoking, and other common CHD risk factors. PMID- 7842198 TI - Normal thoracoabdominal motions. Influence of sex, age, posture, and breath size. AB - The purpose of this study was to assess normal values of thoracoabdominal motions (TAM) during spontaneous breathing and vital capacity (VC) maneuvers in relation to sex, age, and body position. For this, 120 healthy subjects from 10 to > 60 yr old were studied using the respiratory inductive plethysmograph (Respitrace). The volume-motion coefficients obtained during quiet breathing for the rib cage (RC) were almost twice those for the abdomen (ABD) and were not influenced by sex or age and also not by posture, except for the increased ABD coefficients in the supine posture (p < 0.05). Under most conditions RC motion predominated over ABD motion, except quiet breathing in the supine position. Sex-related differences in TAM were not found during quiet breathing, yet during VC maneuvers the women were slightly more RC breathing (p < 0.01). Age-related differences were also only significant during VC maneuvers: men of more than 50 yr old especially became less RC breathing. Posture had a very significant effect (p < 0.001) during quiet breathing as well as during VC maneuvers: the RC predominance was greatest in the standing posture and least in the supine posture. During VC maneuvers the subjects became more RC breathers than during quiet breathing (p < 0.001). The X Y coordinates of RC motion (on the Y axis) versus ABD motion (on the X axis) showed under all conditions a counterclockwise looping during the breathing cycle: the looping was elliptic during quiet breathing but was more irregular and variable during VC maneuvers, and this also depended on body position.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7842199 TI - Spirometry in the Lung Health Study: II. Determinants of short-term intraindividual variability. AB - The Lung Health Study (LHS) is a randomized clinical trial designed to determine whether a smoking intervention program and use of an inhaled bronchodilator (BD) can reduce the rate of decline of FEV1 in cigarette smokers with airflow limitation. During recruitment, spirometry was performed at second and third screening visits, a mean of 21 d apart. A total of 5,887 smokers, 35 to 60 yr of age and of whom 63% were men, met the study eligibility requirements. Smokers taking physician-prescribed BDs or with an FEV1 < 50% or > 90% predicted were excluded, as were those whose FEV1/FVC ratio was greater than 70%. Two inhalations of isoproterenol were given to determine BD response during the second visit. A serial dilution methacholine challenge test was done during the third visit to determine nonspecific airway reactivity. Ninety-five percent of the differences between FEV1 measured at the two visits were within 240 ml for women and within 320 ml for men (coefficients of repeatability). The best independent predictors of the mean short-term (between visit) intraindividual FEV1 variability were factors indicating intrinsic airway reactivity of the participants: bronchodilator response, methacholine reactivity, and the presence of wheezing; as well as factors influenced by the quality of spirometry testing: the difference between the highest and second highest FEV1s and peak flows during baseline spirometry, and the time to reach peak flow (PEFT). PMID- 7842200 TI - Blue-collar normative spirometric values for Caucasian and African-American men and women aged 18 to 65. AB - Normative spirometric values were derived from 5,042 white (of mainly European ancestry) and black (of mainly African ancestry) men and women paper plant workers who are never-smokers, with no respiratory symptoms or diagnoses and no history of occupational exposure to fibrogenic dusts or irritant chemicals. This cohort was selected from a much larger population under long-term respiratory surveillance (n > 50,000 at 50 plants). Standardized equipment, procedures, and data reduction methods complied with ATS recommendations. Data were collected by the medical departments of the participating companies as part of their routine health surveillance, and the graphic and numeric test results were transmitted to the Tulane University Section of Environmental Medicine for centralized quality assurance, interpretation, and archiving. The large numbers allow derivation of gender- and race-specific reference values. Lower limits of normal were derived and depend upon residual variation and any changes in variation with age. The results indicate that polynomial regression equations provide a significantly better fit than linear regressions with breakpoints. In addition to being more biologically plausible, the polynomial model more closely matches observed longitudinal changes in lung function with age. The age range of the cohort, 18 to 65, provides a regression that more closely matches the observed values in this range, because it does not include "supernormal" elderly survivors, which can lessen the slope of the regression and artifactually increase the predicted values of 50 to 65 yr olds. The regression equations derived for black men and women do not support the use of a single race adjustment (0.85 or 0.88) for all age, sex, height, and spirometric test parameter combinations. These race- and gender-specific regression equations, with their respective lower limits of normal, should improve the detection and quantification of adverse health effects in working individuals and populations. PMID- 7842201 TI - Acidic particles and lung function in children. A summer camp study in the Austrian Alps. AB - Epidemiological studies have repeatedly demonstrated the effects of acidic particles on lung function. Three consecutive panels of children participating in a summer camp in the Austrian Alps were investigated. On-site pollution assessment consisted of 24-h measurements of particulate matter < 10 microns and the hydrogen, sulfate, and ammonium ion components. The 24-h maximums of ozone and daily pollen counts were also established. For 47, 45, and 41 subjects, daily FEV1, FVC, and peak expiratory flow were recorded. Fifteen percent, 11%, and 5% of participants, respectively, reported current asthma medication, indicating a markedly increased prevalence of respiratory disease. Mean levels of ambient pollutants were approximately 15% higher for the first panel than for the other two panels, but the hydrogen ion (H+) component was twice as high for Panel 1. The maximum H+ exposure during Panel 1 was 84 nmol/m3 (4 micrograms/m3 H2SO4 equivalent). For FEV1 in Panel 1, a significant decrease of -0.99 ml per nmol/m3 H+ (p = 0.01) was observed. For Panel 2, the FEV1/H+ coefficient was found to be similar (-0.74 ml per nmol/m3 H+; p = 0.28), while for Panel 3 it was in the opposite direction (0.10 ml per nmol/m3 H+; p = 0.83). The decrease in FEV1 observed in Panel 1 was more pronounced when the mean exposure during the previous 4 d was considered (-2.99 ml FEV1 per nmol/m3 H+; p = 0.004). We conclude that summer haze acidic particles may be associated with transient decreases in lung function in children. PMID- 7842202 TI - Cigarette smoke, ferritin, and lipid peroxidation. AB - Gas and tar phases of commercially available filter cigarettes were tested for ferritin-iron-releasing effects and polyunsaturated-fatty-acid oxidant capacity in vitro. A vacuum pump-dependent apparatus with Cambridge filters was used to separate gas and tar; the former was directly smoked into reaction mixtures, while the latter was extracted from Cambridge filters in aqueous medium and freshly used at 40 to 80% final concentrations. Both phases induced ferritin iron release, which was not antagonized by superoxide dismutase (SOD). In specific experiments, we have also shown that gas and tar extracts could cross an organic (i.e., chloroform)-phospholipid layer before mobilizing ferritin iron. Once delocalized from ferritin, iron could trigger lipid peroxidation; however, a marked prooxidant effect (inhibited by 20 microM deferoxamine mesylate and significantly decreased by 40 microM vitamin E) was observed only with gas, whereas tar extracts showed antioxidant effects. Accordingly, tar extracts could also antagonize lipid peroxidation driven by non-chelated iron or by peroxyl radicals. In the absence of ferritin, gas-induced lipid peroxidation was very low, and tar extracts were apparently ineffective. Thus, the intrinsic lipoperoxidative capacity of cigarette smoke is low and is due to gas; however, when smoke interacts with ferritin, a marked iron-driven peroxidation becomes manifest essentially with gas, tar components acting as antioxidants. The present data suggest that cigarette-smoke-mediated iron mobilization from ferritin may represent a specific prooxidant mechanism related to cigarette smoking in vivo. PMID- 7842203 TI - Neutrophil elastase associated with alveolar macrophages from older volunteers. AB - We focused on the role of neutrophil elastase (NE) in alveolar macrophages (AMs), and evaluated the esterolytic activity using an NE-sensitive substrate, methoxysuccinyl-alanyl-alanyl-prolyl-valyl paranitroanilide (MEOSAAPVNA) in AMs from 36 older healthy volunteers (61 +/- 2 yr mean age +/- standard error) and examined the relationship to chronic effects of cigarette smoking and also to the presence of low attenuation areas (LAAs) on the computed tomographic (CT) scans. The AMs from the subjects with LAAs showed significantly higher activity than those from the current smokers without LAA (1.16 +/- 0.40 versus 0.34 +/- 0.07 nM, respectively, p < 0.05). Although the study of inhibitory profile revealed that the esterolytic activity could not be attributed to NE alone, the NE activity seemed to dominate in AMs at least from some who had higher esterolytic activity. We then examined the releasability of NE from cultured AMs in 10 subjects. The immunologic NE complex with alpha 1-protease inhibitor (alpha 1-PI) was released significantly higher in the LAA(+) group than in the LAA(-) group (17.4 +/- 6.5 versus 1.8 +/- 0.6 micrograms/L, respectively, p < 0.05). These data suggest that NE in AMs may play a role in the development of emphysematous changes in susceptible smokers. PMID- 7842204 TI - Continuous versus bilevel positive airway pressure for obstructive sleep apnea. AB - Recent objective studies demonstrate relatively low hours of nightly use during nasal continuous positive airway pressure (CPAP) therapy for obstructive sleep apnea (OSA). Patients frequently complain of dyspnea or discomfort during CPAP use, especially during expiration (against the continuous pressure), which may be a reason for the low hours of use. We hypothesized that with decreased expiratory pressure, hours of nightly use would increase. Therefore, we randomized 83 OSA patients to receive either continuous or bilevel positive airway pressure when expiratory pressure is lower. To document objectively the effective use of either therapy, we built and installed elapsed-time and mask pressure sensors in the patients' positive airway pressure units. A total of 62 patients were evaluable and followed for 1 yr. Of these, 26 received bilevel and 36 CPAP pressures. The machine timers measured accumulated "machine-on" time, and the mask pressure sensor recorded the total time in which the mask pressure was within 2 cm H2O of the effective pressure (pressure shown to eliminate 95% of the obstructive apneas during a full night of polysomnography). The mean machine timer hours of CPAP were 5.0 +/- 0.19 SEM and 4.9 +/- 0.23 SEM during bilevel therapy (p NS) over a 12-mo period. The pressures required during CPAP or bilevel therapy were not different between high and low hourly users. Effective use, the percentage of time that the machine was running and the prescribed pressure was being delivered, was 80% in CPAP and 82% in the bilevel users (p NS). Both groups had equal complaints with regard to mask discomfort, machine noise, and nasal stuffiness.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7842205 TI - Triazolam in patients with obstructive sleep apnea. AB - The purpose of this study was to assess the effect of triazolam (0.25 mg) on apnea duration and the arousal response to airway occlusion during sleep in patients with severe obstructive sleep apnea (OSA). Twelve male subjects with a mean (+/- SD) age of 46.6 +/- 14.1 yr and body weight of 260.8 +/- 55.9 lb were studied on two nights separated by a nonstudy night. They ingested triazolam (0.25 mg) or placebo 0.5 h before bedtime in a randomized double-blind crossover manner. In non-rapid-eye-movement (NREM) sleep, the mean (+/- SEM) duration of apnea/hypopnea was slightly increased (26.8 +/- 1.7 versus 23.8 +/- 1.2 s, p < 0.02) and the mean nadir in arterial oxygen saturation lower (80.1 +/- 1.9 versus 84.2 +/- 1.4%, p < 0.001) on triazolam nights. In NREM sleep, the deflections in esophageal pressure prior to apnea termination were higher on triazolam nights (53.3 +/- 5.4 versus 44.5 +/- 4.8 cm H2O, p < 0.001). However, the rate of increase in inspiratory effort (esophageal pressure deflections) during obstructive events was not decreased by triazolam. We conclude that triazolam increases the arousal threshold to airway occlusion, but that this results in only modest prolongation of event duration and increased desaturation at a dose of 0.25 mg in a group of large sleep apnea patients. PMID- 7842206 TI - Hypoglossal nerve stimulation affects the pressure-volume behavior of the upper airway. AB - To determine the effects of electrical hypoglossal nerve and submental stimulation on upper airway collapsibility, we examined the pressure-volume (P-V) relationships during bilateral supramaximal stimulation of the distal cut hypoglossal nerve ends over a range of frequencies from zero to 100 Hz in the sealed upper airway of 10 anesthetized supine dogs. Animals were artificially ventilated with 50% O2 and maintained under relative hyperoxia and hypocapnia during the study to eliminate the ventilatory drive output. Sealed upper airway pressures were obtained during random injections of different volumes of air from zero to 50 ml with and without hypoglossal nerve stimulation, and the upper airway P-V curves were obtained. The characteristics of the P-V curves were as follows: (1) the upper airway compliance defined as the slope of the regression of P-V curves fell from 4.07 +/- 0.33 ml/cm H2O without stimulation to 3.02 +/- 0.30 ml/cm H2O with stimulation at 50 Hz and plateaued at frequencies greater than 50 Hz, and (2) the volume at a given pressure during stimulation was larger than that without stimulation. The effects of submental stimulation on upper airway collapsibility were similar to those of hypoglossal nerve stimulation. These results suggest that the increase of upper airway muscle tone by hypoglossal nerve or submental stimulation stiffens the upper airway and that increases in muscle tone expand the upper airway. PMID- 7842207 TI - Vagal stimulation augments pulmonary anaphylaxis in the guinea pig lung. AB - The effect of bilateral vagal stimulation on aerosolized antigen-induced responses was examined in the sensitized, perfused guinea pig lung. Vagal stimulation in the sensitized, perfused lung resulted in bronchoconstriction (peak response 160 +/- 18% above baseline) that was unaffected by either atropine (1 microM), a muscarinic receptor antagonist, or CP 96,345 (1 microM), a NK-1 receptor antagonist, but was transiently augmented in the presence of physostigmine (1 microM), a cholinesterase inhibitor, through an atropine sensitive mechanism. However, SR 48968 (1 microM), a NK-2 receptor antagonist, and SR 48968 + CP 96,345 reduced by approximately 50 and 90%, respectively, vagally mediated increases in intratracheal pressure in the perfused lung. Simultaneous challenge with vagal stimulation and aerosolized antigen in the sensitized perfused lung resulted in a significant (p < 0.01) increase in intratracheal pressure (Pi), pulmonary arterial pressure (Ppa), and lung weight (LW) compared with either vagal stimulation or aerosolized antigen alone. Increases in Pi, Ppa, and LW in response to vagal stimulation + aerosolized antigen were associated with elevated venous effluent concentrations of thromboxane A2 (TXA2), prostacyclin, leukotriene C4, and histamine. Vagally mediated potentiation of aerosolized antigen-induced increases in Pi, Ppa, and LW was unaffected by atropine or CP 96,345 but was inhibited by the NK-2 receptor antagonist, SR 48968. These data suggest that vagally mediated (predominantly NK 2) potentiation of aerosolized antigen-induced increases in Pi, Ppa, and LW is characterized by elevated venous effluent concentrations of eicosanoids and histamine. PMID- 7842208 TI - Association between late allergic bronchoconstriction in the rat and allergen stimulated lymphocyte proliferation in vitro. AB - T lymphocytes are potentially of importance in determining the inflammatory response in the airways after allergen challenge. We hypothesized that the proliferative response of lymphocytes on exposure to allergen in vitro would be associated with the magnitude of the airway response in vivo after inhalational challenge. We studied Brown Norway rats that were actively sensitized with ovalbumin (OA) in aluminum hydroxide gel using Bordetella pertussis as an adjuvant. Two weeks later, blood mononuclear cells were isolated, and their proliferative response to culture with OA was measured with 3H-thymidine incorporation. Subsequently, the animals were anesthetized and challenged with aerosolized OA. Early allergic response (ER) and late (LR) allergic response were determined from the changes in pulmonary resistance (RL). Both significant ER and LR were observed in sensitized and challenged animals. The LR (measured as the area under the curve of RL against time) had a median value of 15.2 and ranged from 0.1 to 81.1 units. Lymphocyte proliferation occurred on exposure to OA (34,336 +/- 7,447 cpm) but less than after the mitogen Concanavalin A (250,685 +/ 76,676 cpm). The stimulation index (OA-stimulated 3H-thymidine incorporation standardized for baseline incorporation) was positively correlated with the magnitude of the late response. Interleukin-2 was significantly increased in the supernatant of cultured mononuclear cells exposed to OA, confirming T-cell activation. We conclude that the capacity of sensitized peripheral blood lymphocytes to respond to allergens may determine the magnitude of late airway responses. PMID- 7842209 TI - Modulation of airway intraepithelial dendritic cells following exposure to steroids. AB - Recent studies from our laboratory have identified a network of constitutively class II major histocompatibility complex (MHC) (Ia)-bearing dendritic cells (DC) within the epithelium of the conducting airways of laboratory animal species and in humans. These studies have also demonstrated that the density of the DC network increases within the airway epithelium in response to inflammatory challenge. In the present report, we demonstrate that exposure of adult rats to inhaled steroids leads to a rapid but readily reversible decrease both in the number of airway intraepithelial DC, and in their surface Ia expression. Similar changes are also seen in response to high doses of systemic dexamethasone. In addition, we demonstrate that steroid inhalation reduces the rate of postnatal expansion of the airway intraepithelial DC network in rat pups, and prevents the rapid expansion of the DC network in adults which occurs during the acute inflammatory response following inhalation of microbial stimuli. PMID- 7842210 TI - Chronic bronchitis alters the pattern of aerosol deposition in the lung. AB - Knowledge of the local and regional doses of inhaled particulates is crucial for inhalation therapy and for understanding the progression of pulmonary disease. We studied the deposition pattern of radioactively tagged particles in rats with chronic bronchitis. Rats were exposed to sulfur dioxide (SO2; 236 +/- 14 ppm) for 5 h/d, 5 d/wk for 7 wk to produce chronic bronchitis (CB). Control rats were exposed to room air. The control animals gained 85% more weight over the 7-wk period than did the CB rats. Five control and five CB rats were then exposed for 30 min to an insoluble 99mTc-labeled aerosol. The animals were killed within 5 min after the exposure period. The lungs were excised, dried at total lung capacity (TLC), and sliced into 1 mm sections. The distribution of the radiolabeled particles retained in the lungs was determined in two ways. First, autoradiographs were made of the distribution of the radioactivity throughout a lung slice. Autoradiographs were quantified by image analysis to determine the amount of radioactivity (relative density of the film) associated with airway versus parenchyma (ratio of airway to parenchyma density). The lung slices were then dissected into pieces, the weight and radioactivity content of each piece was measured, and its evenness index (EI) was calculated. This type of analysis enables the homogeneity of particle deposition throughout the lungs to be assessed. If deposition were totally uniform, the average EI would be 1.0 with an SD = 0. The total amount of radioactivity retained in the lungs was similar in control and CB rats.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7842212 TI - Lymphocytes migrate from the bronchoalveolar space to regional bronchial lymph nodes. AB - The fate of lymphocytes in the bronchoalveolar tract was studied in normal young pigs. Peripheral blood lymphocytes were labeled with 51chromium or with fluorescein isothiocyanate (FITC) and instilled into a single segmental bronchus. In the first series of experiments, the radioactivity was determined in several different parts of the lungs, individual bronchial lymph nodes and a series of other lymphoid and nonlymphoid organs. About two-thirds of the radioactivity was still in the lung at 1 d. The draining lymph node also contained high amounts of radioactivity. To exclude that this was caused by labeled cell debris, an immunohistologic technique was used to localize the FITC-labeled cells. There were clearly labeled lymphocytes in the sinusoids of the draining nodes. These lymphocytes were characterized by additional surface staining. B, T, TH, and TS lymphocytes were seen much less often than in the inoculum while the null and gamma delta T cells showed a preference. The lymphocytes reached the bronchial lymph nodes via lymphatics. Lymphocytes in the bronchoalveolar space are not effete cells to be destroyed but return to the immune system. These data provide new interest in the immunologic role of lymphocytes in the bronchoalveolar tract and their kinetics. PMID- 7842211 TI - Airway wall remodeling after cessation of exposure to isocyanates in sensitized asthmatic subjects. AB - To determine whether the cessation of exposure to isocyanates is associated with structural changes of the airway wall in sensitized subjects, we studied bronchial biopsies from 10 subjects with occupational asthma induced by toluene diisocyanate (TDI). Bronchial challenges with TDI and methacholine were performed and biopsies were taken on two occasions, at diagnosis and 6 to 21 mo after cessation of exposure to TDI. After bronchoscopy, biopsies were formalin-fixed or snap-frozen in liquid nitrogen and then processed for a quantitative histochemical and immunohistochemical analysis. After cessation of exposure, we observed a significant decrease of the sensitivity to TDI (p < 0.05), of the thickness of subepithelial fibrosis (p < 0.007), and of the numbers of subepithelial fibroblasts (p < 0.05), mast cells (p < 0.02), and lymphocytes (p < 0.03) as compared with values at diagnosis. By contrast, the nonspecific bronchial hyperresponsiveness and the numbers of macrophages and eosinophils did not change. In conclusion, in patients with occupational asthma induced by TDI, the cessation of exposure to the sensitizing agent is associated with a reduced thickness of subepithelial fibrosis and with a reduced number of subepithelial fibroblasts, mast cells, and lymphocytes in the bronchial mucosa, suggesting a remodeling of the airway wall with the avoidance of the specific stimulus. PMID- 7842213 TI - Effects of intrapleural heparin or urokinase on the extent of tetracycline induced pleural disease. AB - Extravascular fibrin deposition is common at sites of pleural injury and has been related to loculation of pleural fluids. Although thrombolytic therapy has been used to treat pleural loculations, it has not been compared with pleural administration of anticoagulant therapy. We therefore tested interventional strategies designed to compare the relative effects of in vivo anticoagulation or supplemented fibrinolysis on pleural injury, and to characterize the local tissue responses to these modalities. Early intrapleural instillation of saline (Group 1), heparin 1,000 IU (Group 2), or urokinase (uPA) 1,500 IU (Group 3) every 12 h for 3 d was used to interrupt pleural adhesion formation and pleural fibrosis induced by tetracycline hydrochloride in rabbits. Procoagulant and fibrinolytic activities were determined in pleural effusion samples obtained serially every 12 h after the last administered intrapleural dose. Pleural fluid procoagulant activity was blocked by intrapleural heparin (p < 0.001), but plasminogen dependent fibrinolytic activity was rarely increased by intrapleural urokinase. Most plasminogen activator activity in the pleural fluids was found at high molecular-weight regions by enzymography, suggesting that it was bound to inhibitor(s). Pathologic analysis at 14 d demonstrated that the number of pleural adhesions in the heparin (8.4 +/- 3.4, mean +/- standard error) and uPA groups (6.1 +/- 2.5) was less than in saline-treated tetracycline controls (20.7 +/- 4.7) (both p < 0.02). Visceral pleural thickness did not differ between groups (p = NS). We conclude that intrapleural heparin or uPA are equally effective in decreasing intrapleural adhesions in tetracycline-induced pleural injury. The data indicate that early anticoagulation or fibrinolytic intervention can attenuate subsequent pleural symphysis in this model. PMID- 7842214 TI - Delivery and distribution of aerosolized cyclosporine in lung allograft recipients. AB - The aim of the present study was to identify factors determining the delivery to and distribution of aerosolized cyclosporine A (CSA) in the lungs of patients with severe pulmonary allograft rejection. Five such patients inhaled a previously characterized radioaerosol consisting of 4 to 6 cc of CSA (50 mg/ml) in ethanol mixed with technetium-99m (99mTc) bound to human serum albumin, generated by an AeroTech II nebulizer. The total dose of CSA depositing in the lungs was determined with a previously described inspiratory/expiratory mass balance filter technique. Regional distribution of drug within the lungs was measured using a gamma camera. In addition, the following physiologic parameters were measured: regional volume and ventilation using xenon-133 (133Xe) equilibrium and 133Xe washout, respectively, and regional perfusion using intravenous 99mTc macroaggregates. The relationships between these parameters and regional drug deposition were assessed using linear regression analysis. The lung dose ranged from 20 to 53 mg (0.097 to 0.175 mg CSA deposited per milligram placed in nebulizer). In recipients of single-lung allografts, preferential drug deposition occurred either in the allograft (two patients) or in the native lung (one patient). Marked nonuniformities in regional distribution were also apparent in two double-lung allograft recipients. There was a weak but statistically significant correlation between regional drug deposition and regional ventilation, as measured by 133Xe washout (r = -0.542, p = 0.014), suggesting that although regional ventilation is important, it is not the only factor determining regional deposition in these patients.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7842215 TI - Tracheobronchial involvement in Wegener's granulomatosis. AB - This study was designed to characterize the clinical spectrum and course of tracheobronchial involvement in Wegener's granulomatosis (WG). Of the 51 patients with biopsy-proven WG who underwent bronchoscopy at least once at our institution between January 1982 and November 1993, 30 (59%) had endobronchial abnormalities due to WG. Initial findings included subglottic stenosis in five (17%), ulcerating tracheobronchitis with or without inflammatory pseudotumors in 18 (60%), tracheal or bronchial stenosis without inflammation in four (13%), and hemorrhage without identifiable source in two (4%) patients. Nine patients with ulcerating tracheobronchitis on initial study had subsequent bronchoscopies for continued symptoms, which in seven cases documented the progression from ulcerating tracheobronchitis to stenosis without inflammation. Bronchoscopic interventions included dilation by rigid bronchoscope in three, YAG-laser treatment in one, and placement of silastic airway stents in three patients. Only the stents provided persistent airway patency. Endobronchial biopsies were performed on 21 occasions in 17 patients. Half of the specimens were helpful in establishing the diagnosis and in all but three in assessing disease activity. While antineutrophil cytoplasmic antibody titers reflect overall disease activity, no correlation with endobronchial inflammatory activity was apparent. PMID- 7842216 TI - Pulmonary lymphangioleiomyomatosis: a report of 46 patients including a clinicopathologic study of prognostic factors. AB - The clinical and pathologic features of 46 patients from Japan, Korea, and Taiwan with pulmonary lymphangioleiomyomatosis (LAM) were studied. Only two (5%) among 40 evaluable treatments were assessed to be effective. Some prognostic factors of LAM were recognized. A reduction of the forced expiratory volume in one second/forced vital capacity (FEV1/FVC) ratio was a poor prognostic factor at 2 yr after the first examination, with a statistically significant difference (p < 0.05). An increase in the percentage of predicted total lung capacity (%TLC) correlated with a poor prognosis at 2, 3, and 5 yr after the first examination, with statistically significant differences (p < 0.05). Histologically, two types of pulmonary lesions were observed; a predominantly cystic type and a predominantly muscular type. Patients with predominantly cystic LAM lesions showed a tendency to a poor prognosis from 2 to 5 yr after the biopsy. Among open lung biopsy findings, higher grades of abnormal areas were unfavorable as a prognostic factor from 2 to 5 yr after the biopsy, with statistically significant differences (p < 0.05). Higher grades of cystic lesions correlated inversely with survival at 2, 4, and 5 yr after the lung biopsy, with statistically significant differences (p < 0.05). PMID- 7842217 TI - Persistent hyperinflation after heart-lung transplantation for cystic fibrosis. AB - We have measured static lung volumes after heart-lung transplantation (HLT) in seven patients with cystic fibrosis (CF) (Group 1), three patients with chronic hyperinflation due to diseases other than CF (Group 2), and six patients with primary pulmonary hypertension (PPH) (Group 3). Total lung capacity was within normal limits at 1 yr after surgery in all patients. Similarly, FRC was within the normal range in Groups 2 and 3. On the other hand, patients with CF showed a persistent increase in FRC; at 1 yr after HLT, FRC averaged 4.13 +/- 0.52 L compared with a predicted value of 3.20 +/- 0.23 L (p < 0.01). The postoperative static pressure-volume curve of the lung in the patients with CF was superimposed on the predicted one, suggesting that the increased FRC originated in the chest wall. Additional studies with computerized tomographic scans demonstrated that the rib cage anteroposterior diameter at FRC averaged 12.1 +/- 1.6 cm in patients with CF, 9.5 +/- 1.2 cm in patients with PPH, and 9.4 +/- 0.7 cm in a group of healthy subjects matched with the patients with CF (p < 0.01). We conclude that after HLT, patients with CF show persistent hyperinflation due to rib cage expansion along the anteroposterior dimension. This shape change may represent a structural adaptation that occurs in response to chronic pulmonary hyperinflation acquired during rib cage growth. PMID- 7842218 TI - A case of acute eosinophilic pneumonia caused by inhalation of Trichosporon terrestre. AB - We present the diagnostically challenging case of an 18-yr-old Japanese woman who presented with fever, nonproductive cough, and acute respiratory distress. Her chest radiograph showed diffuse interstitial infiltrates and bilateral pleural effusions. Eosinophilic pneumonia was diagnosed by bronchoalveolar lavage and transbronchial lung biopsy. She was treated with minocycline, and was discharged in 2 wk. However, within 3 h of returning home, she experienced a recurrence. She showed positive immediate, Arthus, and delayed-type skin reactions and positive lymphocyte stimulation test to an antigen derived from Trichosporon terrestre, which was isolated from dust in her home. In addition, a bronchoprovocation test with the same antigen caused a nonproductive cough with fever, hypoxemia, and peripheral eosinophilia. We concluded that T. terrestre was the causal agent of the acute eosinophilic pneumonia. PMID- 7842219 TI - Pulmonary surfactant maintains patency of conducting airways in the rat. AB - The hypothesis was tested that after extrusion of the liquid columns that often block the lumen of conducting airways, the latter will remain open because of well-functioning pulmonary surfactant preventing the liquid columns from returning. The extirpated lungs of 22 Wistar rats were studied. Via a tracheal tube a very fine catheter (PE 10) was inserted and advanced until it pierced the pleura. It was extracted until only 2 mm remained in the lung parenchyma. A pressure transducer measured the resistance that met a steady flow of air through the series of tubes: the PE 10 tube, the conducting airway of the lung, and the tracheal tube. The airway resistance was studied for 240 s after three airway flushings, two with saline solution and one with calf lung surfactant extract (CLSE), 3 mg/ml. The pressure recording showed that a low pressure, indicating airway patency, occurred for only 31 +/- 8 s (mean +/- SEM) after the first saline flush, and for 26 +/- 8 s after the second. After the CLSE flush the airway remained open for 174 +/- 12 s, which indicated a significantly reduced resistance (p < 0.0001). The results imply that well-functioning pulmonary surfactant is required for a low airway resistance. PMID- 7842220 TI - Tussive effect of capsaicin in patients with gastroesophageal reflux without cough. AB - The aim of this study was to clarify the influence of gastroesophageal reflux (GER) on cough threshold in patients with digestive symptoms but free from respiratory involvement. Of 57 consecutive subjects referred for 24-h esophageal pH monitoring because of digestive reflux symptoms, 29 patients free from respiratory disorders were studied. They underwent esophageal pH monitoring and manometry, upper gastrointestinal endoscopy, pulmonary function tests, and methacholine and capsaicin challenges. The methacholine test was performed by inhalation of increasing doses of methacholine up to 4,000 micrograms; the results were expressed as the dose causing a 20% decrease in FEV1 from baseline (PD20). The capsaicin threshold was evaluated by inhalation of increasing doses of capsaicin from 0.3 up to 9.84 nmol, expressing the results as the dose of capsaicin eliciting five coughs (PD5). Fifteen patients were considered refluxers on the basis of a total esophageal acid exposure time above 4.7%. Esophagitis grade 0 was found in 15 patients, grade 1 in seven patients, grade 2 in seven patients. PD5 was significantly lower in refluxers (median 0.51 micrograms, range 0.22 to 19.8) than in nonrefluxers (19.8 micrograms, range 0.31 to 19.8) (p < 0.001); there was no difference in baseline ventilatory parameters and in airway responsiveness to methacholine between the two groups. All patients with a pathologic acid exposure time but one had a low cough threshold, irrespective of the presence or absence of esophagitis.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7842221 TI - Expiratory muscle activity increases intrinsic positive end-expiratory pressure independently of dynamic hyperinflation in mechanically ventilated patients. AB - Intrinsic positive end-expiratory pressure (PEEPi) has usually been interpreted as suggesting dynamic hyperinflation, but expiratory muscle activity may also increase end-expiratory alveolar pressure without any additional increase in end expiratory lung volume. The aim of this study was to assess the influence of expiratory muscle activity, which increases abdominal pressure during expiration and is followed by a sudden drop at end-expiration, on PEEPi measurement in mechanically ventilated patients. We studied eight tracheally intubated patients breathing in an assisted mode in whom expiratory muscle activity was present. PEEPi was measured from the fluctuations of esophageal pressure (Pes) while continuous recording of gastric pressure (Pga) and of changes in abdominal cross sectional area assessed expiratory muscle activity. PEEPi was also measured by the airway occlusion method in one patient, and diaphragmatic electromyographic activity was recorded to determine the timing of inspiratory muscle activity in two patients. Varying the level of ventilatory support (pressure support level, peak flow rate, or PEEP level) induced increases in measured PEEPi from 6.7 +/- 3.4 to 13.2 +/- 5.9 cm H2O. Concomitantly, the expiratory rise in Pga increased from 3.1 +/- 2.7 to 8.6 +/- 5.0 cm H2O, and the abrupt decay in Pga observed at the end of expiration increased from 4.2 +/- 3.7 to 10.6 +/- 6.1 cm H2O. The drop in Pga and the drop in Pes at end-expiration were synchronous, and these changes, together with electromyographic measurements, were consistent with a concomitant relaxation of the expiratory muscles and activation of the inspiratory muscles.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7842222 TI - Nutritional supplementation in the ICU. How critical is nutrition for the critically ill? PMID- 7842223 TI - Inhaled beta-adrenergic receptor agonists in asthma: more harm than good? PMID- 7842224 TI - Association of Mycoplasma pneumoniae antigen with initial onset of bronchial asthma. PMID- 7842225 TI - The negative tuberculin test: tuberculin, HIV, and anergy panels. PMID- 7842226 TI - Comparative biochemistry & physiology B bibliography. PMID- 7842227 TI - Purification and characterization of a juvenile hormone binding protein from hemolymph of the silkworm, Bombyx mori. AB - A juvenile hormone binding protein (JHBP) has been isolated from Bombyx mori hemolymph by gel filtration, ion-exchange chromatography, chromatofocusing and hydroxyapatite column chromatography. Gel electrophoresis indicates that the isolated protein is homogeneous in the presence or absence of a denaturing agent. The JHBP in question has a relative molecular mass of 32 kDa, determined by denaturing gel electrophoresis. Chromatofocusing analysis indicated that the JHBP is an acidic protein with pI 4.9. The protein exhibits a dissociation constant of 9.0 x 10(-8) M for JH I, 1.14 x 10(-7) M for JH II and 3.9 x 10(-7) M for JH III, and thus its affinity for JH analogues is in the order of JH I > JH II > JH III. Its amino acid composition indicates that the protein consists of 297 residues of 18 kinds of amino acids. The sequence of the N-terminus of the polypeptide chain was determined for 34 of the first 36 residues: Asp-Gln-Asp-Ala-Leu-Leu- Lys-Pro ?-Lys-Leu-Gly-Asp-Met-Gln-Ser-Leu-Ser-Ser-Ala-Thr-Gln-Gln-Phe-Le u-Glu- Lys-Thr Ser-Lys-Gly-Ile-Pro-?-Tyr-His-. PMID- 7842228 TI - The primary structure of an endocuticular protein from two locus species, Locusta migratoria and Schistocerca gregaria, determined by a combination of mass spectrometry and automatic Edman degradation. AB - The complete primary structures of two variants of a protein, Abd-5, isolated from the endocuticles of the migratory locust Locusta migratoria and the desert locust Schistocerca gregaria, have been determined. The proteins from the two species are N-terminally blocked with pyroglutamic acid. Their sequences differed only in two positions. Comparison of the sequences to those of other cuticular proteins shows that moderate homologies exist to 11 other cuticular proteins from insects representing four different orders. Amino acid residues in certain positions appear to be strictly conserved. PMID- 7842229 TI - Purification and characterization of a poly-L-lysine-activated serine endoprotease from Lumbricus rubellus. AB - An endoprotease in earthworm (Lumbricus rubellus) is purified to apparent homogeneity using 125I-lactalbumin as a substrate. The protease has a molecular mass of 27 kDa and is markedly activated by poly-L-lysine or poly-L-arginine. It is a chymotrypsin-like serine protease. Its activity is distributed to coelomic fluid but relatively little to coelomocytes. PMID- 7842231 TI - Differential time course of liver and kidney glucose-6 phosphatase activity during fasting in rats. AB - We have studied the time course of hepatic and renal microsomal glucose-6 phosphatase (Glc-6Pase) during long-term fasting in the rat. Liver microsomal Glc 6Pase increases up to 48 hr and significantly decreases after 48 hr of fasting. The following activities were determined at 0, 24, 48, 72 and 96 hr: 0.31 +/- 0.02; 0.50 +/- 0.02; 0.54 +/- 0.03; 0.44 +/- 0.03; 0.44 +/- 0.01 mumol min-1 mg protein-1, respectively (all values are means +/- SEM, n = 6). Concomitantly, kidney microsomal Glc-6Pase progressively increases throughout the fast (Vm = 0.21 +/- 0.01; 0.26 +/- 0.004; 0.30 +/- 0.01; 0.37 +/- 0.02; 0.40 +/- 0.01 mumol min-1 mg protein-1, from 0 to 96 hr, respectively). These data suggest that the differential expression of Glc-6Pase activity in the liver and the kidney during long-term fasting could have an important role in the shift from a principally hepatic gluconeogenesis to a hepatic and renal gluconeogenesis. PMID- 7842230 TI - Molecular cloning of the common carp (Cyprinus carpio) rhodopsin cDNA. AB - A recombinant phage clone containing a 1584 nucleotides rhodopsin cDNA was screened from a carp retinal cDNA library. The inserted DNA consisting of a single open reading frame of 1062 nucleotides at positions 72 to 1133 encodes a 354 amino acid polypeptide. The deduced amino acid sequence of carp rhodopsin showed 95.7, 85.5 and 74.4% identity with that of goldfish, sand goby and lamprey, respectively. The sites of palmitoylation, glycosylation, disulfide bond formation and Schiff base formation in the putative rhodopsin are all conserved. PMID- 7842232 TI - Cloning and sequencing of a B. subtilis sigmaF dependent gene from B. megaterium. AB - A promoter-monocistronic structural gene complex from genomic DNA of Bacillus megaterium has been isolated and sequenced. The activity of the promoter during sporulation was measured in B. subtilis using a fusion with the xylE gene of Pseudomonas putida which codes for a catechol-2,3-dioxygenase. From the time of activation in sporulating cells and the activity in a set of defined B. subtilis sporulation mutants we conclude that the promoter requires an active sigmaF factor of RNA-polymerase. Since this sigma-factor is active only in forespores and not in the mothercell compartment it is likely that we have identified a forespore specific gene of B. megaterium. Its function is still unknown. PMID- 7842233 TI - Metabolic and compositional changes in Escherichia coli cells starved in seawater. AB - Thirteen Escherichia coli strains of different biotypes isolated from urine and faeces cultures were studied for metabolic and compositional changes during starvation in seawater at different timepoints. Additionally, the antibiotic susceptibility of the starved E. coli cells was evaluated over time on Mueller Hinton agar (Bauer-Kirby method). All starved E. coli cells lost beta galactosidase activity gradually with time and acquired the ability to degrade gelatine. Nine of the E. coli strains lost the ability to decarboxylate lysine and seven to acidify melibiose. C4 esterase, C8 esterase lipase, leucine arylamidase and C14 lipase activity increased during starvation, while alkaline and acid phosphatase and phosphoamidase activity decreased. Most of the E. coli strains underwent alterations in their electrophoretic protein pattern. The traditional Bauer & Kirby method was shown to be inadequate for testing antibiotic susceptibility of starved strains. PMID- 7842234 TI - Ozone disinfection dynamics of enteric viruses provide evidence that infectious titer reduction is triggered by alterations to viral colloidal properties. AB - The inactivation dynamics of three enteric virus species (polio-, rota- and parvovirus) were analysed in different aqueous suspensions by using O3 under continuous flow conditions. A mathematical model for the reaction rate of infectious titer reduction was proposed, based on the thermodynamic principles of phase behaviour of colloids suspended in aqueous environments. Up to a certain threshold dosage of residual ozone (RO), and depending on the type of test virus and the ionic or organic load in the stock suspension, the logarithm of the reaction rate constant of viral inactivation rate was observed to vary in a rather sigmoidal manner with log RO concentration. Data from photon correlation spectroscopy, electron microscopy and tensiometric analysis suggested that below the threshold RO, the pattern of virus inactivation dynamics reflects the varying potential of different-sized viral particles (VPs) to adsorb to the cellular monolayer. There is strong evidence that oxidant-induced surface activity of organic matter causes redistribution of VP infectivity. This hypothesis was statistically corroborated inasmuch as experimental inactivation data proved to be satisfactorily fitted by a logistic equation. It was concluded that viral infection, and thus viral inactivation, is a complex process which is governed largely by the classical laws of colloidal behaviour. The latter is suggested to appreciably determine the capability of inoculated VPs to infect host cultures. This notion may especially be cause for concern when regulatory requirements for virus disinfection are being based on titration results from in vitro testing procedures. PMID- 7842235 TI - The management of health and safety hazards in tourist resorts. World Tourism Organization. AB - The enjoyment of a holiday has to do with landscape, buildings, people, and their activities. For truly sustainable development, these components need to become better integrated. Ways of achieving this were discussed at the IVth World Health Organization International Conference on Tourist Health, Rimini, Italy, in May 1994. It was agreed that attention to the health enhancing aspects of each component in the built environment is essential. Risks to health from man-made hazards in tourist resorts therefore need to be eliminated where possible, or otherwise minimised, contained or controlled. A systematic approach is outlined here in which owners, managers, operators, workers and users all have responsibilities and in which occupational physicians can contribute. PMID- 7842236 TI - The sanitary inspection in the conditions of social and economic transformation in Poland. AB - A great number of small, privately-owned companies appeared in Poland during the last five years as a result of the transformation process of the whole national economy. Continuous economic changes determine new requirements for the occupational hygiene branch of the State Sanitary Inspection which is designated to exercise control and sanitary supervision over working conditions in individual companies. The Sanitary and Epidemiological Stations are not capable now of ensuring permanent monitoring of various harmful agents even at those workposts which create true risk of health impairment. Lack of adequate legal regulations poses a significant problem in preparing a list of companies to be supervised. The majority of newly-formed, privately-owned companies not only fails to be subjected to any working-environment assessment procedures but also to be kept on any file. One of the crucial problems to be solved in the nearest future is to develop the efficient system for the supervision of working conditions and, at the same time, to find the ways how to improve them. Courses to train occupational hygiene specialists and to advance the skills of occupational hygiene workers seem to be equally important. PMID- 7842237 TI - The effect of acute carbon monoxide poisoning on the respiratory system efficiency. I. Values of spirometric parameters in different degrees of poisoning. AB - The examination of 91 patients, performed as soon as possible after CO poisoning, revealed that the values of ventilatory parameters obtained from the flow-volume loop recorded by a computer-aided spirometer were significantly lower then those after treatment. Ventilatory efficiency closely related with the degree of poisoning, was assessed according to age, COHb concentration, blood lactate level, and neurological symptoms. Ventilatory parameters in 48 persons with medium and acute poisoning were significantly lower than in the group of slightly poisoned patients. The strong relationship between the major spirometric parameters, blood lactate level and duration of exposure to carbon monoxide was noted. However, the correlation between ventilatory parameters and the degree of poisoning taken as a total of all mentioned parameters was strongest. PMID- 7842238 TI - The effect of acute carbon monoxide poisoning on the respiratory system efficiency. II. Types of ventilatory disorder and dynamics of changes according to the severity of carbon monoxide poisoning. AB - As a result of acute carbon monoxide poisoning ventilatory disturbances were found in 62.2% of 91 examined persons, who had never before suffered from any respiratory diseases. An obturation of the central and small bronchi and mixed disorders proved to be the most frequent ventilatory disturbance. In a larger group of patients regression of respiratory disorders was observed after treatment. However, in 44% of medium and severe poisoned persons respiratory disorders, mainly small bronchi obturation, persisted after medication. PMID- 7842239 TI - Selected aspects of the population health status in ecological hazard areas in comparison with ecologically "clean" area. I. Methodology for analysing health status based on the routine data collection system. AB - A proposal for an integrated system of analysis of complex health problems in ecological hazard areas in comparison with reference least polluted area is presented. The proposed procedure can be used in identifying priorities in health promotion. PMID- 7842240 TI - Concentration of dopamine in plasma, activity of dopamine beta-hydroxylase in serum and urinary excretion of free catecholamines and vanillylmandelic acid in women chronically exposed to carbon disulphide. AB - The authors studied 140 women, selected at random, aged 22-55, divided into two groups. Group I (control) included 50 women, mean age 40.1 +/- 1.7 years. Group II included 90 women, mean age 39.7 +/- 2.1 years, chronically exposed to 15.6 - 21.84 mg/m3 of carbon disulphide from 0.5 to over 20 years. It was found that women chronically exposed to CS2 showed significantly lower levels of dopamine and lower activities of DBH (p < 0.001), significantly lower urinary excretion of adrenaline (p < 0.001), but insignificantly lower excretion of noradrenaline and vanillylmandelic acid. PMID- 7842241 TI - The effect of combined exposure to lead and cadmium on serum lipids and lipid peroxides level in rats. AB - The aim of the present study was to investigate the impact of the combined exposure to lead and cadmium on serum lipids and lipid peroxides level in rats and to compare the obtained results with the effects of a single metal. Experiments were performed on male Buffalo rats which were intragastrically administered of lead acetate in doses of 70 mg Pb/kg body wt. twice a week and/or cadmium chloride in doses of 20 mg Cd/kg body wt. once a week for a period of seven weeks. One day after the feeding was over, the following parameters were measured: serum lipids, serum lipid peroxides, blood superoxide dismutase activity, and plasma cholesterol-lecithin-acyltransferase activity. Metal content (lead, copper, cadmium and zinc) in blood and liver was determined by means of atomic absorption spectrophotometry. No clinical signs of lead or cadmium toxicity were observed. In comparison to controls, rats poisoned with cadmium and simultaneously with lead and cadmium displayed lower total, free, and HDL cholesterol concentrations in serum. Rats poisoned with lead displayed lower total and HDL cholesterol levels in comparison to controls, but it was associated with increase of free cholesterol concentration and hypertriglyceridemia. Rats poisoned with cadmium displayed decrease of serum lipid peroxides level and increase of blood dismutase activity. It may be a consequence of redistribution of zinc and copper (increase of copper and decrease of zinc concentrations in blood). In rats treated with lead and cadmium jointly serum lipid peroxides level increased and superoxide dysmutase activity decreased.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7842242 TI - Effects of acute combined inhalation exposure to n-butyl alcohol and n-butyl acetate in experimental animals. AB - The effects of combined exposure to n-butyl alcohol and n-butyl acetate on rotarod performance and hot plate behaviour in rats and respiratory rate in mice were investigated in the condition of an acute inhalation experiment. Rotarod performance and hot-plate behaviour were tested in rats exposed to various concentrations of n-butyl alcohol, n-butyl acetate and their mixture consisting of 50 Vol-% n-butyl alcohol and 50 Vol-% n-butyl acetate immediately after termination of a 4-hour exposure period. The respiratory rate in mice was recorded continuously before the exposure to solvents, during 6 min of exposure and 6 min after termination of exposure using whole body plethysmographic method. Mice were exposed to vapours of single solvents and their 50:50 Vol-% mixture. Both solvents and their mixture caused concentration-dependent disturbances of rotarod performance in rat. The medial effective concentration (EC50) for the effect amounted to 7559 ppm, 8339 ppm and 10672 ppm for n-butyl alcohol, n-butyl acetate and their mixture, respectively. Both solvents and their mixture decreased sensitivity to the pain and changes were concentration-dependent. In condition of combined exposure the results obtained in rotarod and hot-plate behaviour test indicate the summation of individual solvent effects. The tested solvents resulted in concentration-dependent decrease in respiratory rate in mice. n-Butyl alcohol produced maximal decrease in respiratory rate in the first minute of exposure whereas n-butyl acetate in the sixth minute.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7842243 TI - Cyanuric chloride has no genotoxic and mutagenic properties in bacteria and bone marrow cells. AB - Three short-term tests were used; Salmonella/microsome assay, in vivo sister chromatid exchange assay (SCE) and micronucleus assay to evaluate mutagenic and genotoxic properties of 2,4,6-trichlorotriazine; cyanuric chloride. Mutagenicity assays were carried out using the standard top agar overplay plate assay described by Maron and Ames (9). Tester strains TA97a, TA98, TA100 and TA102 were used. Compound was dissolved in 0.1 ml of DMSO and doses of 1, 10, 100 and 500 micrograms/plate were tested in the absence and in the presence of the S9-mix. From the results obtained it appeared that incubation of the test substance with the bacteria did not increase the number of His+ revertants with any of the strains of S. typhimurium, either in the absence or in the presence of the S9 mix. At the high dose level used i.e. 100 and 500 micrograms/plate, the test substance appeared to be slightly toxic for strain TA 97a (in the absence of the S9-mix), as was seen from a diminished number of revertant colonies. The SCE test was performed according to the GENE-TOX programme. No significant increase was noted in the incidence of SCE in the groups treated with all tested doses of cyanuric chloride. Thus, in this test cyanuric chloride did not induce chromosomal damage resulting in SCE formation in bone marrow cells of mice. The micronucleus assay in vivo was performed on mice bone marrow cells. The incidence of micronucleated polychromatic erythrocytes after administration of all doses of cyanuric chloride used were not statistically different (p > 0.05) as compared to negative controls.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7842244 TI - The illusion of control and optimism about health: on being less at risk but no more in control than others. AB - If unrealistic optimism is simply a manifestation of the illusion of control (McKenna, 1993), differences in estimates of the likelihood of events for the self and others (comparative optimism) should have concomitant differences in perceived capacity to control these events. This possibility was tested in the domain of health, along with Perloff & Fetzer's (1986) risk-factor version of this downward comparison hypothesis and the hitherto neglected possibility that unrealistic optimism is an artifact of the comparative procedures employed in studies to date. It was found that likelihood judgements for a range of illnesses tended to be significantly lower when made by subjects providing self-ratings than when made by those providing judgements for the 'typical' student and, to a lesser extent, those making judgements for a friend's friend, but not by those doing so for an acquaintance. This comparative optimism was associated with equivalent differences in perceptions of these targets on a selection of relevant risk factors, but not in ratings of their capacity to control these outcomes (for which there was consensus across targets). The data are thus consistent with the risk-factor version of the hypothesis rather than the control version or the artifact explanation. The theoretical implications of these findings are addressed along with their consequences for health promotion. PMID- 7842245 TI - Gloomy but smarter: the academic consequences of attributional style. AB - The social psychological literature concerning the relationship between attribution and performance has documented the detrimental effects of particular types of attributional pattern on performance, expectancies and mood. The present paper reports three studies in which there was a consistent relationship between attributional style and actual performance. Undergraduate students who tended to attribute achievement-orientated failure to stable, and to some extent global, causes actually performed well on subsequent academic and ability tasks. These findings are new and constitute a challenge to the prevailing assumptions in the literature. PMID- 7842246 TI - Prolactin and the immune system. AB - Prolactin (PRL) is involved in a wide range of physiological effects in several species and its immunoregulatory role has already been well documented. The PRL receptor has been cloned from various species. There are at least two receptor isoforms (short and long) in rats and mice, which differ only in their cytoplasmic domains, generated by alternative splicing of a single gene, although in human only the long form exists. Using the reverse transcriptase-polymerase chain reaction (RT-PCR), we detected transcripts encoding both forms of PRL receptor in all lymphoid tissues examined in human, mouse, and rat, but in mouse and rat the ratio between the two forms was variable from animal to animal. Concerning the transcript encoding the PRL itself, a clear signal was always found in human lymphocytes and occasionally in rat thymus. We also developed a quantitative PCR (Q-PCR) in order to measure the absolute number of transcripts in thymus and spleen from rats at two stages of estrous cycle. The level of expression of the two forms was about equal. Finally, we identified the tyrosine kinase JAK2, which is constitutively associated with the PRLR, using the Nb2 rat lymphoma cell line as a model system with which to study the action of PRL on cell mitogenesis. We also showed that, after stimulation by PRL, the dimerization process is a prerequisite step for the phosphorylation of the PRLR and JAK2, which represents the earliest event in the signal transduction pathway. PMID- 7842247 TI - PCR-based cloning, sequencing, and exon mapping of lymphocyte-derived neuroendocrine peptides. AB - In this report a procedure for the analysis of mRNA expression in cells of limited availability by the reverse transcriptase-polymerase chain reaction (RT PCR) method is described. The cells are lysed with Nonidet P-40, and the mRNA in the lysate is used directly as template for the cDNA synthesis reaction. Target cDNA is then amplified by PCR, and the products can be analyzed that same day by agarose gel electrophoresis. The oligonucleotide primers used for amplification are designed to include restriction sites to facilitate cloning for subsequent sequencing. We have demonstrated that luteinizing hormone-releasing hormone mRNA can be amplified from the hypothalamus and thymus of a 7-day rat pup, in which the starting cell number was limited. Furthermore, exon usage by target cDNA in different cell types can be easily determined by amplifying with exon-specific primers. Proopiomelanocortin (POMC) mRNA expressed in the pituitary utilizes all three exons, while a majority of POMC mRNA expressed in lymphocytes lacks exons 1 and 2. Thus, this provides an extremely rapid and sensitive means not only for analyzing mRNA expression but also for differential exon usage. PMID- 7842248 TI - Interleukin-1 receptors in the brain: characterization by quantitative in situ autoradiography. AB - Autoradiography was performed on mouse brain cryosections to localize interleukin 1 (IL-1) receptors in the mouse brain and pituitary gland and to identify the cell types expressing these receptors. Interleukin-1 receptor binding sites were mapped in the mouse central nervous system (CNS) with [125I]IL-1 alpha and [125I]IL-1 beta. IL-1 receptors were detected in high density in the dentate gyrus of the hippocampus, choroid plexus, meninges, and anterior pituitary. IL-1 receptors are also expressed in the frontoparietal cortex at very low density. Both neurons and glial cells were shown to express IL-1 receptors. An intrahippocampal injection of colchicine, a selective neurotoxin, induced the concurrent disappearance of neuronal cells and [125I]IL-1 alpha binding in the hippocampus. This treatment established that IL-1 bound to the neurons of the dentate gyrus. IL-1 receptors on glial cells were not detected in situ in the CNS under basal conditions. However, [125I]IL-1 alpha bound to glial cells at the site of astrogliosis induced by a local mechanical injury. These results suggest that activated astrocytes express IL-1 receptors. Furthermore, the results of histoautoradiography of [125I]IL-1 alpha binding on astrocyte and microglial cultures showed that astrocytes express IL-1 receptors in vitro. The biochemical characterization of IL-1 binding in the dentate gyrus was achieved by quantitative in situ autoradiography. In the dentate gyrus IL-1 bound to a single class of receptor with characteristics similar to those of the receptor expressed on immune cells (Kd = 0.3 +/- 0.2 nM, Bmax = 60 +/- 10 fmol/mg protein). Competition experiments with IL-1 alpha and IL-1 beta showed that the neuronal receptor characteristics were similar to those of the type I IL-1 receptor, which binds the two isoforms of IL-1 with the same affinity. Regulation of IL-1 receptor density in the CNS and pituitary was studied after peripheral injection of LPS. Stimulation of IL-1 synthesis by LPS was shown to induce a major decrease in the number of receptors available for IL-1 binding in the CNS. A decrease of 84 +/- 9% was observed in the dentate gyrus and in the choroid plexus, but no change occurred in the pituitary gland. PMID- 7842249 TI - Prolactin as a second messenger for interleukin 2. AB - The generation of an effective immune response requires the selection and proliferation of antigen-specific lymphocytes. Activation of at least some T lymphocytes involves the sequential stimulation of cell surface receptors, including the T-cell receptor for antigen, the interleukin 2 receptor, and the prolactin receptor. Prolactin signaling in T lymphocytes appears to utilize a classical receptor-mediated kinase cascade and a novel peptide hormone activation pathway involving nuclear translocation. PMID- 7842250 TI - The role of the hypothalamic-pituitary-adrenal axis in susceptibility to autoimmune/inflammatory disease. AB - The central nervous system (CNS) affects the immune system through endocrine, paracrine, and neuronal mechanisms. The immune system in turn communicates with the CNS through many of the same mechanisms. Evidence that this bidirectional communication plays a vital role in susceptibility to inflammatory and infectious disease is derived largely from animal models in which the communication has been interrupted or reconstituted surgically, pharmacologically, or on a preexisting genetic basis. The advantage of animal models for studying the pathophysiologic relevance of such connections is that the systems can be manipulated at several levels and at different times in relation to development of the inflammatory disease and the outcome of the manipulation can be quantified. While in vitro studies may be used to further define the subcellular and molecular mechanisms of these interactions, only an intact organism, in which the central nervous system is connected to the immune system, can be used to fully define the nature of these interconnections. This review describes approaches to studying CNS-immune system interactions, using relatively inflammatory-susceptible and inflammatory resistant Lewis and Fischer rats as models for evaluating the role of the HPA axis in susceptibility to inflammatory disease. PMID- 7842251 TI - Negative regulatory molecules in the neuroendocrine and immune systems: suppressin as an example. AB - The early foundations of both neuroendocrinology and immunology were established by studies that linked the production, secretion, and action of circulating factors to the physiological state of an organism. These studies ultimately identified the cells of the neuroendocrine and immune systems as a rich source of such homeostatic regulatory molecules, and currently they are referred to as neuroendocrine hormones, peptides, and cytokines. More recently, two additional concepts have been added to this model. The first was that immune cells produce neuroendocrine hormones and peptides and that neuroendocrine cells produce cytokines. The second was the notion that both positive and negative factors control a variety of physiological processes. Recently, we have identified a new polypeptide negative regulator of cell proliferation that we have named suppressin (SPN). This negative regulatory molecule is also produced by both neuroendocrine and immune cells. The objective of this article is to provide an example of the biochemical, cellular, and molecular approaches used to characterize SPN and that could be used to characterize similar molecules from neuroendocrine and immune sources. PMID- 7842252 TI - Theoretical and functional aspects of measuring insulin-like growth factor-I mRNA expression in myeloid cells. AB - This article presents a detailed overview of the conceptual and technical considerations involved in the measurement of insulin-like growth factor-I (IGF I) mRNAs in leukocytes. Two different quantitative techniques that take advantage of the in vitro synthesis of antisense and sense synthetic IGF-I RNA, respectively, are described: the ribonuclease protection assay (commonly referred to as solution hybridization) and competitive RT-PCR. We have improved the ribonuclease protection assay by constructing tandem, cassette riboprobes to generate multigene antisense RNAs of varying sizes. This approach permits the simultaneous quantitation of two or more mRNAs in a single RNA sample, one of which can serve as an internal standard for comparison of IGF-I transcripts among various treatments. The second approach of competitive RT-PCR represents an improvement in previous technologies by cloning a competing IGF-I sequence into an RNA expression vector. The resulting synthetic sense competitor IGF-I RNA (1.1 kb) serves as an internal standard during both the reverse transcription and amplification steps. We have used both the ribonuclease protection assay and competitive RT-PCR to define the macrophage as the major cellular source of leukocyte-derived IGF-I and to characterize these macrophage-derived mRNAs as being derived almost exclusively from exon 1. In addition, these techniques have allowed us to study the ontogeny of IGF-I expression in differentiating bone marrow macrophages and show that hematopoietic progenitors are induced to express abundant IGF-I transcripts as they differentiate into macrophages in the presence of CSF-1. These techniques can be readily adapted for measuring steady-state transcripts for a variety of leukocyte-derived hormones. PMID- 7842253 TI - Possible molecular mechanism of loss of homologous and heterologous gap junctional intercellular communication in rat liver epithelial cell lines. AB - We have previously characterized a series of rat liver epithelial cell lines that exhibit levels of gap junctional intercellular communication (GJIC) which are inversely related to their levels of expression of transformed phenotypes. Cells of the non-tumorigenic line do not communicate with their tumorigenic counterparts. We have examined the molecular mechanisms involved in this loss of homologous and heterologous GJIC, employing a non-tumorigenic cell line, IAR 20, and a tumorigenic cell line, IAR 6-1. While both cell lines expressed a transcript coding for the gap junction protein, connexin 43 (cx 43), and similar levels of cx 43 protein, they exhibited different phosphorylation states of this protein, revealed by Western analysis. Immunohistochemical analysis showed that the non-tumorigenic IAR 20 cell line, but not the tumorigenic IAR 6-1 cells, was able to incorporate cx 43 gap junction plaques extensively into their plasma membranes. When IAR 20 and IAR 6-1 cells were co-cultured, cx 43 proteins were abundant in IAR 20 cells but IAR 20/IAR 20 cell boundaries were cx 43-positive, while IAR 20/IAR 6-1 boundaries were negative. The different phosphorylation state of cx 43 may partially explain the low GJIC of the IAR 6-1 cells and inability to communicate with their non-tumorigenic counterparts, but other mechanisms such as cell-cell recognition processes may also be involved. PMID- 7842254 TI - A secondary structure model of the integrin alpha subunit N-terminal domain based on analysis of multiple alignments. AB - The integrins are alpha/beta heterodimeric proteins which mediate cell-matrix and cell-cell interactions. Current data indicate that the N-terminal moiety of the alpha subunit is involved in ligand binding. This region of the receptor is made up of a seven-fold repeated sequence of unknown structure which contains EF-hand like putative divalent cation-binding sites. Recent studies have shown that multiple sequence alignments can be analysed to yield secondary structure predictions. Therefore, to obtain a model structure for the integrin alpha subunit N-terminal domain repeat, a large alignment of the seven repeats from sixteen integrin sequences was generated. Two methods of analysis were used: First, Chou and Fasman and Garnier, Osguthorpe and Robson predictions were carried out for individual sequences and the consensus predictions derived. Consensus hydrophobicity and chain flexibility data were also used to provide additional data. Second, sites of conservation and variation were analysed by a computer program STAMA (STructure After Multiple Alignment) to yield a secondary structure prediction. The two analyses gave essentially the same predicted structure: undefined region, loop, alpha-helix, beta-strand, divalent cation binding loop, beta-strand, putative turn, loop, beta-strand. This is the first model structure to be presented for an integrin domain. Its implications for integrin function are discussed. PMID- 7842255 TI - Differential expression of integrins alpha 6 and alpha 4 determines pathways in human peripheral CD4+ T cell differentiation. AB - Integrins mediate leukocyte adhesion to vascular endothelium and thereby influence leukocyte recirculation. We have explored expression by peripheral blood T cells of beta 1 and beta 7 integrins, particularly alpha 4 beta 1 (VLA-4, CD49d), alpha 4 beta 7 (LPAM-1) and alpha 6 beta 1 (VLA-6, CD49f). Integrin expression differs between CD4+ cells and CD8+ cells in that CD4+ cells 1) are more heterogeneous, particularly for alpha 4; 2) express on the average less alpha 4 and beta 7; and 3) express on the average more alpha 6 and beta 1. 2D gel electrophoretic analysis was combined with flow cytometric analysis to determine which integrin chain pairs are expressed by the CD45RO- (naive) and CD45RO+ (memory) subsets of CD4+ cells. CD45RO- (naive) cells express homogeneously at intermediate levels the three integrin pairs alpha 6 beta 1, alpha 4 beta 1 and alpha 4 beta 7. Although 2D gel analysis suggests similar average integrin chain composition for CD45RO+CD4+ (memory) cells, flow cytometric analysis demonstrates multiple subsets of CD45RO+ cells differing markedly from each other and from naive cells in levels of expression of alpha 6 and alpha 4 integrins. There are a minimum of three CD45RO+ subsets: 1) alpha 4 beta 1hi alpha 6 beta 1hi alpha 4 beta 7neg, which comprises the majority of memory cells; 2) alpha 4 beta 7hi alpha 6 beta 1low presumptive gut-homing memory cells; and 3) alpha 6 beta 1hi alpha 4 beta 7neg alpha 4 beta 1neg, a previously unidentified subset expected to have unique migrational-functional properties. Of particular importance in these results are: the expression by CD4+ naive cells of alpha 6 beta 1, alpha 4 beta 1 and alpha 4 beta 7, the overall prominence and regulation of alpha 6 beta 1 on CD4+ cells, and the selective decreases as well as increases in alpha 4 beta 7 and alpha 4 beta 1 during CD4+ memory specialization. Taken together, these results suggest that differential regulation of expression of alpha 4 and alpha 6 integrin chains that accompany naive-to-memory transition in CD4+ cells are instrumental in generating functional subsets of CD4+ memory cells with specialized recirculation abilities. PMID- 7842256 TI - Evidence for a role of the epithelial glycoprotein 40 (Ep-CAM) in epithelial cell cell adhesion. AB - Recently we have demonstrated that a 40kD human epithelium-specific glycoprotein exhibit the features of a homophilic cell-cell adhesion molecule, when expressed in transfected murine cells. We suggested the name Ep-CAM for this molecule (Litvinov et al., J. Cell Biol., 125: 437-446). Here we investigate the possible biological function of Ep-CAM in its natural environment--cells of epithelial origin. Immunolocalization of Ep-CAM in tissues and in cultures of epithelial/carcinoma cells showed that the majority of the Ep-CAM molecules are localized at cell-cell boundaries, predominantly along the whole lateral domain of polarized cells. In vitro, on single cells in suspension, the Ep-CAM molecules are present on the entire cell surface, and when the single cells grow attached, Ep-CAM is present at their pseudo-apical domain. During formation of intercellular contacts by such single cells, the majority of the Ep-CAM molecules are redistributed from the pseudoapical to the lateral domain of the cell membrane. Attachment of cells to the substrate does not cause redistribution of the molecules to the site of substrate attachment irrespective of the adhesive substrate (fibronectin, collagens, laminin, EHS-matrigel were tested). The monoclonal antibody 323/A3, reactive with the extracellular domain of the Ep-CAM molecule, has a strong negative effect on the aggregating behavior of COV362 ovarian carcinoma cells and RC-6 immortalized mammary epithelial cells. The mAb affected cell aggregation in both cell lines in the presence of Ca++, but with RC 6 cells the effect was more pronounced in low-calcium medium. The effects of the 323/A3 mAb on the already established intercellular contacts was not significant. The data presented demonstrate that the Ep-CAM molecules are functionally active in the epithelial and carcinoma cells tested, are capable of mediating Ca(++) independent intercellular adhesions, and are not likely to be involved in cell substrate adhesion. PMID- 7842259 TI - Clinical nephrology. PMID- 7842257 TI - Neurite outgrowth stimulated by L1 requires calcium influx into neurons but is not associated with changes in steady state levels of calcium in growth cones. AB - L1, NCAM and N-cadherin are cell adhesion molecules (CAMs), present on neuronal growth cones, which promote cell-contact dependent axonal growth by activating a second messenger pathway in neurons that requires calcium influx through L- and N type calcium channels. In the present study we show that two of these CAMs, (L1 and N-cadherin) can stimulate neurite regeneration from axotomised adult dorsal root ganglion (DRG) neurons cultured in vitro and that this response can be fully inhibited by agents that block or negate the effect of calcium influx into the neurons. However although the response required calcium influx into neurons, it was not associated with an increase in the steady state levels of calcium in neuronal growth cones. These results suggest that small localised changes, or increases in the rate of calcium cycling, in growth cones and/or filopodia, are more important for regulating axonal growth than changes in the steady-state level of calcium. PMID- 7842260 TI - Pathophysiology of hypertension. PMID- 7842258 TI - The I domain is essential for echovirus 1 interaction with VLA-2. AB - VLA-2, the alpha 2 beta 1 integrin, mediates cell adhesion to collagen and laminin, and is the receptor for the human pathogen echovirus 1. Because of its similarity to domains present in other proteins that interact with collagen, a 191 amino acid region within the alpha 2 subunit (the I domain) has been proposed as a potential site for ligand interactions. Although the alpha 2 subunits of human and murine VLA-2 are 84% identical, human alpha 2 promotes virus binding whereas murine alpha 2 does not. We used murine/human chimeric alpha 2 molecules to identify regions of the human molecule essential for virus binding. Virus bound efficiently to a chimeric protein in which the human I domain was inserted into murine alpha 2, indicating that the human I domain is responsible for specific virus interactions. Monoclonal antibodies that inhibited virus attachment all recognized epitopes within the human I domain, further suggesting that virus interacts with this portion of the molecule. Similarly, antibodies that prevented VLA-2-mediated cell adhesion to collagen also mapped to the I domain. These results indicate that the I domain plays a role in VLA-2 interactions both with virus and with extracellular matrix ligands. PMID- 7842262 TI - Clinical nephrology. PMID- 7842261 TI - Overcoming tolerance in autoimmune renal disease. PMID- 7842263 TI - Renal involvement in type II diabetes. AB - The incidence and prevalence of renal failure from type II diabetes have been seriously underestimated in the past. Currently, the incidence of uremia in patients with type II diabetes has increased continuously in Europe and the United States, mainly because of better patient survival (ie, they now live until nephropathy develops) and possibly because of a rising prevalence of type II diabetes in the general population (ie, more patients are at risk of developing nephropathy). Generally, renal hemodynamics and glomerular lesions are similar in type I and type II diabetes, but glomerular histology is more diverse in type II diabetes. Given the high prevalence of diabetes and renal failure from various causes in the elderly, coexistence of the two (even in the absence of glomerulosclerosis) occurs in approximately 20% of uremic type II diabetic patients. The development of nephropathy is controlled by strong genetic determinants, but these have not been further characterized. PMID- 7842264 TI - The management of cardiac disease in chronic uremia. AB - The burden of cardiac disease is high in chronic uremia. Cardiomyopathy results from a combination of cardiac disorders, particularly dilated cardiomyopathy, left ventricular hypertrophy with normal systolic function, and ischemic heart disease. The prognosis for these cardiac disorders is poor. Known potentially reversible risk factors include uremia, anemia, hypertension, smoking, coronary artery disease, hyperparathyroidism, hyperlipoproteinemia, and left ventricular hypertrophy. Randomized controlled clinical trials of interventions that may prevent or ameliorate cardiac disease in dialysis patients are required. These interventions include normalization of hematocrit with erythropoietin compared with partial correction of anemia, increased amount of dialysis compared with that provided by a dialysis prescription of KT/V of 1., control of blood pressure using angiotensin-converting enzyme inhibitors compared with other antihypertensive agents, control of hyperlipidemia, and treatment of diabetes with agents that prevent collagen cross-linking. PMID- 7842265 TI - Treatment of idiopathic membranous glomerulopathy. AB - The treatment of membranous nephropathy, the most common form of glomerular diseases causing nephrotic syndrome in adults, is still debated. A considerable percentage of patients have a spontaneous remission of the disease and reduction of urinary protein excretion with time. Studies in the past have indicated that prednisone may have beneficial effects, but this has not been confirmed by more recent investigation. Others have studied the association of methylprednisolone with cyclophosphamide or chlorambucil, but results are conflicting. The main reasons for the conflicting data are the variety of clinical presentations of the disease and the different study populations. Most trials performed so far have not included enough patients in each category to adequately detect differences between treatment groups and placebo groups. Several studies with few numbers of patients reported that cyclosporine effectively reduced proteinuria and may have less long-term toxicity than more conventional immunosuppressants. This finding, however, must be verified by appropriate clinical trials. PMID- 7842266 TI - Hepatitis C virus in renal disease. AB - Hepatitis C virus (HCV) is the most frequent cause of liver disease in dialysis and renal transplant recipients. Approximately 20% to 30% of the dialysis population is infected with HCV. HCV is also recognized as a cause of membranoproliferative and membranous glomerulonephritis. Enzyme immunoassay or recombinant immunoblot assay identify antibodies to multiple HCV antigens and are useful in the diagnosis of HCV infection, including infections in dialysis patients. However, after transplantation, HCV RNA identification by polymerase chain reaction is often required to detect the infection. The natural history of HCV infection using the new viral markers remains to be defined in patients treated for end-stage renal disease. PMID- 7842267 TI - Current status of chronic analgesic and nonsteroidal anti-inflammatory drug nephropathy. AB - The long-term use of analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs) results in distinct renal abnormalities. The principal lesions induced by both groups is a tubulointerstitial nephropathy which, in the case of analgesics, results in renal papillary necrosis and progressive chronic renal failure. The tubulointerstitial nephropathy associated with NSAIDs presents with massive proteinuria and is generally reversible on discontinuation of the inciting NSAID. The scope and magnitude of the renal syndromes associated with these agents and the risk of renal failure associated with their use remains to be clearly defined. This review focuses on the current understanding of the processes involved and the initial defects in renal function that occur, with the goal of early detection and potential prevention. PMID- 7842268 TI - Dietary management of urolithiasis. AB - Within the United States, 5% to 15% of the population will have a symptomatic episode of a stone within the urinary tract by the age of 70. At least 50% of these individuals will have recurrent stone formation if left untreated. The composition of urine from which these stones are formed and in which they grow is, in part, dependent on diet, including fluid intake. The volume of urine is an important determinant of solute concentration. Ionic strength, pH, and the concentration of the major ionic species present in urine determine the level of saturation for any crystal system that could be precipitating. There are many conditions that can be complicated by the formation of calculi within the urinary tract. Identifying the dietary factors that are contributing to the problem and correcting these abnormalities are the foundations for good medical management. This review identifies dietary components that need to be considered in the management of affected patients and considers specific medical problems that may be especially influenced by diet and fluid intake. PMID- 7842269 TI - Antihypertensive therapy in the context of total cardiovascular risk: the rational basis for therapeutic recommendations. PMID- 7842270 TI - Genetic basis of hypertension. AB - Recent advances in the genetics of hypertension include studies on localizations of many loci involved in blood pressure regulation in the rat, elucidation of the molecular mechanisms underlying monogenetic forms of hypertension, and studies of candidate genes in primary hypertension. Evidence that the angiotensinogen gene is involved in primary hypertension has been found by linkage in affected sibling pairs, and by the demonstration of increased risk of disease associated with DNA variants of the gene. Similar evidence of linkage and association has been found in preeclampsia, which suggests that the two diseases share at least one common factor of genetic susceptibility. PMID- 7842271 TI - Hypertension in blacks. AB - In the United States, blacks have higher blood pressure levels than whites at all ages, a finding that cannot be explained solely by differences in body habitus. A European population survey reported similar differences. Several physiologic mechanisms have been evaluated, including sodium sensitivity and insulin resistance. Although it is often stated that blacks show a greater blood pressure reactivity than whites, recent data are conflicting, and such differences may be attributable to family history of hypertension. The physiologic mechanisms underlying any reactivity differences could be structural changes in the resistance vessels. Blacks tend to show smaller falls of nocturnal blood pressure than whites, and this could be related to the observation of a greater degree of left ventricular hypertrophy seen in blacks for a given level of clinic blood pressure. Severe left ventricular hypertrophy may be associated with functional myocardial ischemia, even in the absence of epicardial coronary artery disease. Renal damage is also more pronounced in blacks than in whites. PMID- 7842272 TI - Hypertensive cardiovascular disease and the treatment of hypertension in the elderly. AB - Hypertension affects most elderly Americans. In eight major randomized, controlled trials evaluating the treatment of hypertension in the elderly, drug therapy for high blood pressure (including isolated systolic hypertension) has been shown to prevent fatal and nonfatal strokes and coronary events. The relative reduction in strokes was greater than that seen in coronary events. An analysis of the combined data shows that the treatment of hypertension in the elderly also reduces mortality from stroke, coronary heart disease, and all causes. All of these major clinical trials used primarily diuretics and beta blockers. Low-dose diuretics may be superior to beta-blockers in the elderly; however, reliable comparisons of these and other antihypertensive agents in terms of cardiovascular risk reduction are not yet available. Limited comparisons on the efficacy of blood pressure-lowering and patient tolerance characteristics are reviewed. PMID- 7842273 TI - Role of the tissue renin-angiotensin system in vascular remodeling and smooth muscle cell growth. AB - In recent years numerous data have given evidence that the tissue renin angiotensin system may play an equal or perhaps an even more important role than the circulating renin-angiotensin system in numerous physiologic processes. This was first suggested by the observation that the blood pressure lowering effect of angiotension-converting enzyme (ACE) inhibitors correlates better with tissue ACE activity than with plasma ACE activity. In response to hypertension and arterial injury, vascular smooth muscle cells undergo three responses: hypertrophy, hyperplasia, and remodeling. The end result is a decrease in lumen diameter and an increase in peripheral vascular resistance. Blockade of angiotensin II formation inhibits these smooth muscle responses in a number of animal models. This review discusses the evidence supporting the existence of local tissue renin angiotensin system in the vasculature and its physiologic effects. Inhibition of the vascular renin-angiotensin system may have important implications in the treatment of patients with hypertension, atherosclerosis, and restenosis following balloon coronary angioplasty. PMID- 7842274 TI - Neurologic consequences of hypertension and antihypertensive drug therapy. AB - Untreated essential hypertension leads to cardiovascular and renal disease and stroke, but antihypertensive drug therapy effectively reduces these consequences of hypertension. Several studies indicate that hypertension can negatively impact on cognitive function, especially on learning and memory, but the ability of antihypertensive drugs to ameliorate these cognitive dysfunctions is less clear. None of the recent studies convincingly demonstrates that any of the antihypertensive drugs currently in use has a major deleterious effect on cognition in hypertensive patients, but some of the drugs more reliably benefit cognitive function in the hypertensive patient. As a class, the angiotensin converting enzyme inhibitors most consistently lead to cognitive improvement in the overall hypertensive population, but beta 1-adrenergic receptor blockers and a subset of calcium channel blockers appear to have very similar effects. Animal studies and clinical studies in demented patients suggest that angiotensin converting enzyme in the cerebral cortex plays a role in normal learning and memory, a finding that provides a theoretic foundation to the beneficial actions of this class of drugs on cognitive function in hypertensive individuals. PMID- 7842275 TI - Molecular dynamics, phase diagrams and electronic properties of fullerenes and alkali fullerides: insights from solid-state nuclear magnetic resonance spectroscopy. AB - Solid-state nuclear magnetic resonance (NMR) measurements have made important contributions to the current understanding of the structural, dynamical, and electronic properties of fullerenes (C60 and C70) and the alkali fullerides AxC60 (A = alkali metal). These measurements and their interpretation are reviewed. One and two-dimensional 13C NMR lineshapes and spin-lattice relaxation rates provide evidence for rapid molecular rotations and orientational order-disorder transitions in the fullerenes and alkali fullerides. The kinetics of molecular reorientations are determined from the NMR data. 13C and alkali metal NMR spectra indicate that the alkali fullerides are stoichiometric compounds. Each stable, stoichiometric phase has distinctive NMR signatures. 13C and alkali metal NMR spectra and relaxation measurements provide valuable and unique information about the electronic properties of the metallic, superconducting, and non-metallic phases of the alkali fullerides. PMID- 7842276 TI - 27Al nuclear magnetic resonance study of synthetic and natural corundum (alpha Al2O3). Some experimental aspects of quantitative 27Al nuclear magnetic resonance spectroscopy. AB - The 27Al nuclear magnetic resonance (NMR) response of a series of natural and synthetic corundum (alpha-Al2O3) samples is studied quantitatively by short-pulse excitation and frequency-stepped adiabatic half-passage (FSAHP). Using on- and off-resonance nutation NMR, it was established that the quadrupole coupling parameters of visible Al is identical in all samples. Remarkably, the relaxation behavior for the aluminum is very different in the various samples and has a marked effect on the quantitative response. In natural corundum samples the 27Al spin-lattice relaxation is very efficient as these samples contain paramagnetic impurities. As a result, however, the full signal could not be recovered, which is attributed to relaxation broadening of spins in the vicinity of these impurities. In synthetic samples, containing no impurities, the full signal could be recovered, although the relaxation behaviour appeared to depend strongly on the preparation method. We observed differences in the spin-lattice relaxation by a factor 20; the longest T1 was observed in a crushed single crystal. This implies that alpha-Al2O3 can only be used as a standard in quantitative analyses if it has been characterized thoroughly. Furthermore, the effective relaxation behaviour for different types of excitation is studied. Finally, a method to measure the spin-lattice relaxation of half-integer quadrupole nuclei is introduced, using a frequency-stepped adiabatic passage (FSAP) to invert the spin system. PMID- 7842277 TI - Effects of magic-angle spinning on spin-lattice relaxations in talc. AB - The spin-lattice relaxation times T1 of 1H and 29Si spins in talc have been measured at room temperature with and without magic-angle spinning (MAS) of the sample. Paramagnetic impurities work as relaxation centers. 1H T1 depends on the spinning rate, whereas 29Si T1 is independent of the spinning rate. These facts demonstrate that spin diffusion plays an important role in 1H relaxation but not in 29Si relaxation. 29Si spins relax through dipole-dipole interactions with electron spins directly, which mechanism is not affected by spinning. The relaxation rates have been analyzed theoretically. PMID- 7842278 TI - Observation of spinning sidebands in the 27Al magic-angle spinning nuclear magnetic resonance spectra of FAU and EMT structure-type zeolites. AB - Wide-band (1 MHz) 27Al magic-angle spinning nuclear magnetic resonance (MAS NMR) spectra were recorded for zeolite Y (Si/Al approximately 2.7) and high-silica (Si/Al approximately 3.8) FAU, EMT and mixed FAU-EMT structure-type zeolites synthesized using 15-crown-5 and/or 18-crown-6 ethers as templating agents. Spinning sidebands (related to first-order quadrupolar effects affecting satellite transitions) are observed in the spectra of the four calcined and fully rehydrated samples, reflecting a high symmetry of the framework aluminium atom surrounded by four oxygens. It is shown that the intensity of the spinning sidebands progressively increases after calcination and rehydration of the samples, indicating that the restoration of the high local order around the 27Al nuclei is rather slow. On the other hand, second-order quadrupolar interactions rapidly decrease upon rehydration of the calcined samples which is achieved within one day, as indicated by thermogravimetry. Some hypotheses are proposed to explain such a difference, and the role of water is also discussed. PMID- 7842279 TI - Study of natural diamonds by dynamic nuclear polarization-enhanced 13C nuclear magnetic resonance spectroscopy. AB - The results of a study of two types of natural-diamond crystals by dynamic nuclear polarization (DNP)-enhanced high-resolution solid-state 13C nuclear magnetic resonance (NMR) are reported. The home-built DNP magic-angle spinning (MAS) 13C NMR spectrometer operates at 54 GHz for electrons and 20.2 MHz for carbons. The power of the microwave source was about 30 W and the highest DNP enhancement factor came near to 10(3). It was shown that in the MAS spectra the 13C NMR linewidths of the Ib-type diamond were broader than those of IaB3-type diamond. From the hyperfine structure of the DNP enhancement as a function of frequency, four kinds of nitrogen-centred and one kind of carbon-centred free radicals could be identified in the Ib-type diamond. The hyperfine structures of the DNP enhancement curve that originated from the anisotropic hyperfine interaction between electron and nuclei could be partially averaged out by MAS. The 13C polarization time of DNP was rather long, i.e. 1500 s, and the spin lattice relaxation time (without microwave irradiation) was about 300 s, which was somewhat shorter than anticipated. Discussions on these experimental results have been made in this report. PMID- 7842280 TI - 31P and 15N solid-state nuclear magnetic resonance spectroscopic study of some monophospha-lambda 5-azenes. AB - 31P Cross-polarization magic-angle spinning nuclear magnetic resonance (CP-MAS NMR) spectra of eight monophospha-lambda 5-azenes were measured at room temperature. Three of these compounds, with 2-OH substituents, are in principle capable of taking part in the equilibrium process. However, only the open form, tautomer A, is found in the present study. 15N CP-MAS NMR spectra support the results. The most shielded component of the 31P chemical shift tensor lies in the direction of the P = N bond. PMID- 7842281 TI - The auditory-vocal-respiratory axis in birds. AB - A series of studies is described which in general aim to identify two sets of neural linkages in the brain and spinal cord of songbirds and non-songbirds, these avian types differing along a dimension of 'complexity of vocal communication'. One set of linkages is postulated to link the vocal system with the respiratory system, since birds, like humans, require controlled expiration in order to vocalize normally. The other set is thought to link the auditory system with the vocal system, at least in songbirds, because they are dependent upon auditory feedback for vocal learning. The systems and their linkages can be regarded as forming an 'auditory-vocal-respiratory axis', around which the animal's communication system evolves and revolves. The experimental strategy used was one which began at the periphery (the abdominal expiratory muscles), then progressively identified more central neural structures using retrograde transport methods in partial combination with recordings of single cell activity. The projections delineated by these methods were then defined in detail by anterograde tracing methods. The results of the studies confirmed the expectation that the vocal and respiratory systems have many neural elements in common. They also suggested that songbirds and non-songbirds possess similar neural pathways in the brainstem and spinal cord for the control of both vocalization and respiration but indicated that there may be significant differences between the two types of birds in the degree to which the telencephalon is able to modulate respiratory-vocal activity downstream. Thus, whereas there is a cascade of descending projections terminating upon syringeal and laryngeal motoneurons and expiratory premotor neurons in both songbirds and non-songbirds, the most rostral origin of this cascade is the telencephalic nucleus robustus archistriatalis in (male) songbirds but, apparently, the dorsomedial nucleus of the intercollicular complex of the midbrain (DM) in pigeons. Connectional studies of the auditory system in pigeons delineated a series of projections which originate in Field L2, the primary telencephalic auditory area, and leave the telencephalon via the nucleus archistriatum intermedium, pars medialis (Aivm), after traversing a minimum of three synapses within the telencephalon.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7842282 TI - Functional anatomy of forebrain auditory pathways in the budgerigar (Melopsittacus undulatus). AB - Interconnections of forebrain auditory and vocal control nuclei were mapped in the budgerigar using pathway tracing techniques. The anatomical results indicate four circuits by which auditory information may influence the vocal motor system: (1) direct auditory thalamic projections from nucleus dorsomedialis posterior (DMP) to both the neostriatal higher vocal center (HVC) and robust archistriatal nucleus (RA); (2) direct projections from a neostriatal projection field of DMP (i.e., MAN, the magnocellular nucleus of the neostriatum) to HVC and RA; (3) projections from DMP and other 'accessory' auditory thalamic nuclei to the ventral paleostriatum (VP), which in turn projects to MAN and RA; (4) projections to HVC from the lateral hyperstriatum ventrale (HV), which receives input from nucleus basalis (Bas) as well as from the oval nucleus of the HV (HVo), which receives direct input from RA. Lesion methods were used to evaluate the roles of auditory pathways in call learning and production. The results show that pathways associated with Bas are essential for call production in both adult and unfledged budgerigars, while VP efferents influence vocalization only in young, unfledged budgerigars. Lesions centered in either the primary auditory neostriatum (Field L2a) or the neostriatal area in receipt of Field L input (the ventrolateral neostriatum intermedium or NIVL) did not affect vocalization in juvenile or adult budgerigars. PMID- 7842283 TI - Neurochemical specializations associated with vocal learning and production in songbirds and budgerigars. AB - Specialized neural circuitry has evolved in groups of birds where vocal learning is known to occur, such as in the oscine suborder of the Passeriformes (songbirds) and in the order Psittaciformes (parrots). These specializations are most prominent in the telencephalon, while the midbrain and medullary portions of the vocal control circuit are generally similar in all orders of birds. Specializations in songbirds have at least four components: 1) a set of distinct and interconnected vocal control nuclei in the forebrain; 2) unique connections between the auditory system and these vocal control nuclei; 3) the occurrence of receptors for sex steroid hormones in a subset of the vocal control nuclei; and 4) unique patterns in the distribution of various markers of the major classes of neurotransmitters within the vocal control nuclei. In the order Psittaciformes, as exemplified by budgerigars (Melopsittacus undulatus), it appears that neural specializations generally similar to those described in songbirds have evolved independently. Although anatomical studies have found a system of interconnected forebrain regions in budgerigars that are roughly similar to those described in oscines, detailed connectivity studies of this forebrain system suggest that it is only superficially similar to that of songbirds, and budgerigars also have unique connections between the auditory and motor systems. Also, analyses of the distribution of markers of neurotransmitter function in the budgerigar brain reveal patterns different from those described in songbird vocal control systems. This work suggests that songbirds and parrots have evolved separate neural 'solutions' to solve the problem of vocal plasticity. There are differences between these 'solutions' but also similarities that may be the result of convergent evolution. Although vocal behavior is learned in both songbirds and parrots, it differs in many respects. By taking advantage of this 'natural' experiment one can gain insight into the hormonal and neural events that mediate these different forms of vocal plasticity. PMID- 7842284 TI - Distributed representation in the song system of oscines: evolutionary implications and functional consequences. AB - This paper reviews the organizational principles and implications that have emerged from the analysis of HVc, a forebrain nucleus that is a major site of sensory, motor, and sensorimotor integration in the song control system of oscine passerine birds (songbirds). Anatomical, physiological, and behavioral data support the conclusion that HVc exists within a hierarchically organized system with parallel pathways that converge onto HVc. The organization of HVc is distributed and redundant, and its outputs exhibit broad divergence. A similar pattern of connectivity exists for neostriatum adjacent to HVc. This and other data support the hypothesis that the song system arose from an elaboration or duplication of pathways generally present in all birds. Spontaneous and auditory response activity is strongly correlated throughout HVc, with auditory responses exhibiting strong temporal modulation in a synchronized fashion throughout the nucleus. This suggests that the auditory representation of song is encoded in the synchronized temporal patterns of activation, and that the predominant selectivity for the individual's own song that is observed for HVc neurons results from interactions of auditory input with central pattern generators for song. Most, or all HVc neurons are recruited during singing. The auditory response and motor recruitment properties of individual HVc neurons have no simple relationship, and the spontaneous activity in HVc may build up in the seconds preceding a song. To the extent HVc participates in perceptual phenomena associated with song, production and perception are not tightly linked in adults but may be linked by shared developmental processes during periods of sensorimotor learning. PMID- 7842285 TI - Motor mechanisms relevant to auditory-vocal interactions in songbirds. AB - Vocal learning through imitation underlies both human speech acquisition and song acquisition in oscine birds; both processes depend on auditory information. In songbirds, a specialized forebrain pathway is responsible for producing the learned temporal and acoustic features of vocalizations, and auditory input reaches every level of this pathway. Nucleus robustus archistriatalis (RA) is the source of the final common output from this pathway; RA is topographically organized into subregions that control the syringeal, respiratory and other effectors involved in vocal production. The acoustic features of learned vocalizations are primarily produced by specific patterns and combinations of syringeal muscle activity, while the overall temporal structure is primarily under respiratory control. In RA, and other vocal control structures, the individual bird's own learned song (BOS) is the most effective stimulus for eliciting auditory responses. Some neurons are 'combination-selective' in that they respond maximally to stimuli consisting of sequences of syllables from song. The recording sites that respond selectively to BOS tend to be located in more ventral parts of RA, the subregion that projects to motor neurons controlling syringeal muscles. These observations do not distinguish between motor feedback and perceptual hypotheses about the function of auditory responses in vocal motor pathways but are consistent with the idea that such responses may reflect a specific pattern of interaction between sensory and motor events that reflects vocal learning. PMID- 7842286 TI - An outline of recent advances in birdsong neurobiology. AB - Several landmark discoveries have shaped the recent study of brain substrates for birdsong. The failure of deaf birds to reproduce a song from memory lent support for the concept of a song template. An attempt to test this idea resulted in the discovery of lateralization of song control. Search for the brain sites of lateralization and auditory control of voice led to the discovery of the main song control nuclei. Neurophysiological studies have unequivocally shown that auditory information reaches the song control system, but the exact pathway by which the song control system receives auditory inputs needs further investigation. The finding that lesions of the lateral magnocellular nucleus of the anterior neostriatum or area X affect song development in young birds but not the maintenance of song in adults suggested a role of the anterior forebrain pathway to RA in song learning. Another area of research in which much progress has been made concerns the relationships between the vocal and respiratory systems. The archistriatal and midbrain vocal nuclei innervate some of the respiratory centers in the medulla. The old questions of 'mini-breath' during fast singing and independent control of the two sides of the syrinx have been resolved. Finally, comparisons of the vocal and auditory systems between taxa indicate that different groups may use different neural circuits to achieve similar vocal-auditory behavior. PMID- 7842287 TI - Adenocarcinoma of the small intestine: 21-year review of diagnosis, treatment, and prognosis. AB - BACKGROUND: The purpose of this study was to evaluate the tumor characteristics and treatment associated with an improved overall survival in patients with adenocarcinoma of the small intestine. METHODS: The records of all patients with primary adenocarcinoma of the small bowel seen between January 1971 and December 1991 were reviewed retrospectively. The study comprised 38 patients, 22 (58%) with duodenal tumors, 11 (29%) with jejunal tumors, and five (13%) with ileal tumors. RESULTS: Although not statistically significant, the patients with duodenal adenocarcinoma lived longer than the patients with jejunal or ileal lesions (p = 0.77). The overall survival was 23% and seemed to correlate best with absence of lymph node metastases (p = 0.04) and pancreaticoduodenectomy for localized duodenal tumors (p = 0.04). The patient's age, duration of symptoms, disease-free interval, tumor location, type of recurrence, and histologic grade did not significantly influence survival. CONCLUSIONS: The lethality of small intestinal adenocarcinoma appears to be related to a delay in diagnosis and treatment. When a definitive surgical procedure is performed before lymph node metastases appear, the patient's chance for long-term survival is greatly improved. PMID- 7842288 TI - Effect of perioperative blood transfusion on recurrence and survival in 232 primary high-grade extremity sarcoma patients. AB - BACKGROUND: Allogeneic blood transfusion (BT) has been implicated as an unfavorable factor influencing cancer recurrence and overall survival. METHODS: To investigate this, 232 consecutive localized, high-grade extremity soft tissue sarcoma (STS) patients admitted between January 1, 1983, and December 31, 1989, were analyzed from our prospective database by univariable and Cox multivariable statistical methods. RESULTS: Twenty-eight patients developed a local recurrence (LR). Factors found significantly unfavorable for the rate of developing an LR by uni- and multivariable tests were age > 60 years and positive microscopic margin. Eighty-nine patients developed a distant metastasis (DM) and 72 patients died of their tumor. Median follow-up of survivors was 48 months. Unfavorable factors for DM and tumor mortality (TM) by univariable analysis included large size, deep tumor (that involved or was below the superficial fascia), positive microscopic margin, invasion of a vital structure, operative blood loss, duration of operation, and perioperative BT (whole blood or packed cells -24 to +48 h of curative operation). Multivariable analysis found large size, deep tumor, and positive margin significant independent unfavorable factors for DM and TM. The effect of BT was not a significant independent prognosticator for LR, DM, or TM by multivariable analysis (p = 0.26, 0.56, 0.08, respectively). The only factor that was found to be significant in a multivariable analysis of factors contributing to postmetastasis survival was time < 6 months until metastasis (p = 0.008). BT had no significant impact on postmetastasis survival (p = 0.42). There was a significant association between BT and deep, large tumors. As the size of deep tumors increased from < 5, > or = 5 < 10, > or = 10 < 15, or > or = 15 cm, the amount transfused was 15, 16, 49, and 68% (p < 0.00001). Also, BT was significantly (p < 0.005) associated with low hematocrit at initial diagnosis, blood loss during surgery, and the length of the surgical procedure. CONCLUSIONS: These data emphasize the importance of size, depth, and margin on distant recurrence and death for localized high-grade extremity STS. In the absence of a randomized trial, the impact of allogeneic blood transfusion would appear to be due to its strong association with large size and deep tumor invasion. This study also highlights the importance of a multivariable analysis and long-term follow up to better define this controversial question. PMID- 7842289 TI - Induction of lymphokine-activated killing with reduced secretion of interleukin-1 beta, tumor necrosis factor-alpha, and interferon-gamma by interleukin-2 analogs. AB - BACKGROUND: Interleukin-2 (IL-2)-based immunotherapy has been shown to effect clinical responses in 15-35% of patients with metastatic renal cell carcinoma or melanoma. Despite its clinical efficacy, many clinicians refrain from using IL-2 because of the associated toxicity. This toxicity is believed to be mediated by such secondary cytokines as IL-1, tumor necrosis factor (TNF), and interferon (IFN)-gamma, which are produced by the patient's IL-2-stimulated peripheral blood mononuclear cells (PBMCs). METHODS: Human PBMCs were stimulated with 1 nM wild type recombinant IL-2 (rIL-2) or IL-2 analogs (R38A or F42K) that preferentially bind to the intermediate affinity IL-2 receptor (IL-2R). PBMCs were activated for lymphokine-activated killer (LAK) activity in 4-h 51Cr-release assays, using Daudi target cells. Cytokine content in the culture supernatants was determined by enzyme-linked immunosorbent assay. RESULTS: Both R38A and F42K were capable of generating substantial LAK activity. Maximal specific lysis was 54% for PBMCs activated by R38A and 52% for F42K-stimulated cells, in contrast to 64% for rIL 2. In addition, analog-stimulated PBMCs secreted 59% of the IL-1 beta, 25% of the TNF-alpha, and only 8% of the IFN-gamma produced in response to rIL-2 (all p < 0.01 compared with rIL-2-stimulated secretion; one-way ANOVA). CONCLUSIONS: IL-2 analogs that preferentially bind the intermediate-affinity IL-2R retain the capacity to induce substantial LAK activity despite a greatly reduced secondary cytokine production. Therefore, such IL-2 analogs may provide an effective, yet less toxic means of cancer immunotherapy. PMID- 7842290 TI - Assessing medical students' and surgery residents' clinical competence in problem solving in surgical oncology. AB - BACKGROUND: We sought to determine the competence of medical students and surgery residents in evaluating clinical problems (using both real and simulated patients) in surgical oncology. METHODS: Forty-five third-year medical students, 23 first postgraduate year (PGY-1) residents, and seven second postgraduate year (PGY-2) residents were presented with the same four clinical problems (breast evaluation, prostate nodule, colon cancer, and mole evaluation). The two resident groups were presented with two additional patients (breast cancer options and thyroid mass). RESULTS: Mean performance scores for the problems were generally poor (32-72%); most students and residents failed almost all of the problems. Level of training was of some importance; the overall mean scores of the PGY-2 residents were superior to those of the medical students and the PGY-1 residents (p = 0.049). However, in many areas of information gathering, diagnosis, and management, training level appeared to have no impact. Numerous important performance deficits were identified in all groups. CONCLUSION: Medical students and surgery residents are not receiving adequate training in diagnosing and treating important problems in surgical oncology. PMID- 7842291 TI - Tumor-associated antigens recognized by human monoclonal antibodies. AB - BACKGROUND: Nonhuman monoclonal antibodies (MoAbs) of desired specificities have been studied in cancer treatment and tumor targeting with minimal success. Attempts of using humanized chimeric antibodies have not improved significantly their clinical applications. We have engaged in the development of human MoAbs by incorporating the in vitro immunization protocols to the nodal lymphocytes of cancer patients. Three human MoAbs thus generated were found to be strongly reactive with various human malignancies. The antigens recognized by the three antibodies were selected for immunochemical and biochemical characterizations. METHODS: The antigens investigated were AgSK1, PA 1-2 and PA 3-1. The patterns of each antigen expression in various human cancer cell lines were studied by the immunocytochemical staining technique. The expression of AgSK1 in association with cellular proliferation was examined by the flow cytometry analysis. In studying the biochemical natures of these antigens, their sensitivities toward various chemical and physical treatments were determined. The antigens that were shown to be proteins were subjected to SDS-PAGE and Western blot for estimations of molecular weights. RESULTS: The AgSK1 was detected in 10 human carcinoma cell lines but in none of the melanoma cell lines. This suggests that SK1 may be an epithelial or carcinoma marker. The phenotypic expressions of AgSK1 were shown to be associated with proliferation of carcinoma cells. Biochemically AgSK1 was a sialophycoprotein with an estimated molecular weight of 42-44 kilodaltons (kDa). HuMAb PA1-2 demonstrated a unique staining pattern at both the cytoplasmic and intercellular interface. The stained filamentlike structures extending from cell to cell indicated that Ag PA1-2 might play a role in cellular interactions. Biochemically, Ag PA1-2 appeared to be an asialocarbohydrate. The Ag PA3-1 was a cytoplasmic glycoprotein expressed by all 13 cell lines. The estimated molecular weights of PA3-1 were 164, 104, and 40 kDa. CONCLUSIONS: Tumor-associated antigens recognized by the human MoAbs may be more relevant clinically than those recognized by the mouse immune system. Carcinoma-specific human MoAbs are desirable for cancer treatment and tumor localization. PMID- 7842292 TI - Primary colorectal non-Hodgkin's lymphoma. AB - BACKGROUND: The gastrointestinal tract is the most common site of extranodal involvement in non-Hodgkin's lymphoma (NHL). Primary colorectal NHL comprises 13 18% of all gastrointestinal NHL but is not commonly reported as a separate entity. METHODS: This was a retrospective review of the medical records of 19 patients over a 16-year period to evaluate the clinical features and behavior of colorectal NHL. RESULTS: A pediatric group of seven male patients presented at an early stage with acute symptomatology. The primary tumor was located in the ileocecum in all cases and intussusception was common. An adult group of 12 patients presented at a later stage with chronic symptomatology. Staging study results were positive by bone marrow biopsy in four of 16 patients (25%), by lymph-angiography in six of 11 patients (54.5%), and by gallium scan in eight of 10 patients (80%). Seven patients relapsed a median of 8 months after treatment. Three other patients died during treatment, one died of other causes, and one died without receiving treatment. The remaining seven patients are alive from 41 to 231 months without evidence of disease. Five of these patients are in the pediatric group, where the median survival was > 72 months. The overall median survival was 45 months. CONCLUSION: Colorectal NHL is a disease that affects both the pediatric and adult population. Although pediatric patients have an excellent prognosis with anticipated long-term survival after treatment, long-term survival can be expected in approximately 50% of adult patients. In both groups of patients, multimodality therapy with surgery, chemotherapy, and radiation is the treatment of choice. PMID- 7842293 TI - Human lung tumor cell secretion of interleukin-2 for protection against tumor engraftment. AB - BACKGROUND: Lung cancer continues to claim large numbers of human lives each year despite advances made in conventional therapies. The use of biologic response modifiers to modulate the immune system against human tumors is an alternate form of immunotherapy. Interleukin-2 (IL-2), or T-cell growth factor, is an important modulator of activated T cells. We show here that tumor cells transduced with human IL-2 cDNA provide protective immunity against engraftment of IL-2 secreting, as well as parental non-IL-2-secreting, tumor cells in vivo. METHODS: In an attempt to increase the antigen-induced proliferation and cytotoxicity T cells within the vicinity of tumor antigen, we have transduced human lung tumor cell lines (generated from whole tumor specimens obtained fresh from the operating room) with a vector containing the IL-2 gene. Cell lines secreting 0.5 20 Cetus units/ml of IL-2 were generated. Control cell lines were similarly established using the same retroviral vector containing the gene for adenosine deaminase (ADA). The growth of tumor xenografts of the vector-modified cell lines was observed in severe combined immunodeficient (scid) mice. RESULTS: Using C.B 17 scid mice, we have observed that the local secretion of IL-2 by these human lung tumor cell lines will prevent engraftment of that tumor into scid mice. The parental tumor as well as the tumor containing the ADA gene grow aggressively in the scid mouse. Growth arrest also correlated strongly with the amount of IL-2 secreted by the tumor cells. The local secretion of IL-2 by the transduced cell line will abrogate the tumorigenicity of the parental cell line as well as an allogeneic tumor. The inhibition of growth occurs only when the tumors are placed in close proximity to each other. After gamma irradiation, transduced tumor cells will continue to secrete IL-2. CONCLUSION: These results indicate that (a) human lung tumor cell lines can be transduced with IL-2-containing retroviral vectors; (b) local and sustained release of IL-2 will induce an antitumor response by the host against the IL-2-secreting as well as the control tumor cells; (c) secretion of IL-2 continues after the cells are irradiated. This study suggests that cytokine-secreting human lung tumors may be used in vaccination protocols for cancer patients. PMID- 7842294 TI - Pharmacokinetics and results of dose escalation in cis-platin hyperthermic isolation limb perfusion. AB - BACKGROUND: We analyzed prospectively collected data on 145 cis-platin hyperthermic isolation limb perfusion (HILPs) for melanoma and soft-tissue sarcoma to determine the pharmacokinetics and maximum tolerable dose of cis platin. There were 70 melanoma and 75 sarcoma patients. Dosages ranged from 26 to 265 mg/m2. Perfusate and systemic cis-platin levels were measured in patients perfused at doses of 190-200 mg/m2. Tissue levels were measured in patients perfused at 123-209 mg/m2. METHODS: Cis-platin HILP was well tolerated up to doses of 250 mg/m2 for lower extremities. Higher doses produced toxicities of rhabdomyolysis, myoglobinuria, hyponatremia, and neuropathy. Systemic levels of cis-platin were equivalent to those of routine intravenous administration, while perfusate levels were 33 times higher. Tissue levels of cis-platin were five to six times higher than effective intravenous levels. RESULTS: Six melanoma patients have developed local recurrences. All were perfused at doses < 120 mg/m2. However, regional nodal recurrences have occurred in six other patients perfused at doses < or = 200 mg/m2. Four sarcomas have recurred locally, but three of them were present at the time of perfusion. CONCLUSIONS: We conclude that 250 mg/m2 is the maximum tolerable dose of cis-platin for lower-extremity HILPs. Neoadjuvant cis-platin HILP may improve local control rates for sarcomas. However, no tolerable dose of cis-platin provides control of nodal metastases from melanoma. PMID- 7842295 TI - Effect of gastroduodenal juice and dietary fat on the development of Barrett's esophagus and esophageal neoplasia: an experimental rat model. AB - BACKGROUND: Reflux of duodenal content into the lower esophagus of rats enhances the formation of nitrosamine-induced esophageal cancer and results in the induction of adenocarcinoma. We investigated the extent of the mucosal injury that was produced when the lower esophagus of rats was exposed to the reflux of gastroduodenal juice in the presence or absence of a carcinogen and tested the hypothesis that induction of esophageal cancer in this model would be influenced by the intake of dietary fat. METHODS: Esophagoduodenostomy with gastric preservation was performed in 165 Sprague-Dawley rats in order to expose the lower esophagus to the reflux of gastroduodenal juice. Postoperatively selected groups of rats were treated with the carcinogen methyl-n-amylnitrosamine (MNAN). Subsequently, rats were fed diets of differing fat and calorie content for 20 weeks until they were put to death. RESULTS: Refluxed gastroduodenal juice, in the absence of MNAN, induced esophageal inflammatory changes (diffuse papillomatosis and hyperkeratosis) in 38 of 39 rats (97%), specialized columnar metaplasia (Barrett's esophagus) in four of 39 (10%), dysplasia in three of 39 (8%), and squamous cell carcinoma in one of 39 (3%). Diet did not influence the incidence of neoplasia in the absence of MNAN treatment. In rats treated with MNAN, refluxed gastroduodenal juice induced inflammation in 110 of 111 rats (99%), columnar metaplasia in 14 of 111 (13%), and cancer in 63 of 111 (57%). Fifty-eight percent of esophageal tumors were squamous cell carcinoma and 42% were adenocarcinoma. The highest incidence of tumors was observed in rats fed the semipurified high-fat diet (24 of 29; 83%) compared with rats fed the semipurified control diet (13 of 29; 45%), semipurified, calorie-restricted diet (15 of 27; 55%), and chow diet (11 of 26; 42%), p < 0.05. CONCLUSIONS: Reflux of gastroduodenal content into the lower esophagus of rats can induce both Barrett's metaplasia and neoplasia. Addition of a carcinogen increases the tumor yield and results in a proportion of the lesions being adenocarcinoma. This carcinogenic process is promoted by a diet with a high fat content. PMID- 7842297 TI - Non-haem iron histochemistry of the normal and Alzheimer's disease hippocampus. AB - Increased free radical production may occur in Alzheimer's disease (AD). In view of the central role of iron in free radical reactions we have investigated the distribution of non-haem iron in the hippocampal formation in normal control individuals and in patients with AD. In controls, non-haem iron was principally associated with glial elements and the neuropil, with highest levels in the stratum radiatum/lacunosum, fimbria, alveus and oriens layers. Except for the subiculum, the pyramidal cell layers and the granule cell layer showed little or no non-haem iron staining. Intensity of staining was in the order of subiculum >> CA2 and adjacent regions of CA3 > CA4 > the remainder of CA3 > CA1. In the hippocampus in AD, iron was associated with cells containing neurofibrillary tangles (NFT) and was present in glial cells and neurites of senile plaques (SP). These findings were most pronounced in CA1 pyramidal cell layer and subicular complex although not all NFT or SP were stained. Since the NFT and SP staining for non-haem iron appears to be associated with glial cells, the association of non-haem iron with the pathological stigmata of AD may be a secondary response of glial cells, in particular microglia, to neuronal damage. PMID- 7842296 TI - SSO Clinical Award Lecture. The surgical oncologist as a key translator of basic biology to patients with gastrointestinal cancer: asking the right questions. PMID- 7842298 TI - Iron histochemistry of the substantia nigra in Parkinson's disease. AB - Raised tissue iron levels in the substantia nigra in Parkinson's disease (PD) suggests that altered iron homeostasis may underly the disorder. We have therefore investigated the distribution of non-haem iron in the normal and PD substantia nigra, using a sensitive histochemical procedure, to assess the pathogenic potential of this metal. In control cases non-haem iron staining was highest in the substantia nigra zona reticulata (SNr) and associated with the neuropil, oligodendrocytes, astrocytes and non-pigmented neurones. The substantia nigra zona compacta (SNc) showed lower non-haem iron staining than the SNr, with generalized impregnation of the neuropil and occasional non-haem iron-positive oligodendrocytes and astrocytes. The pigmented dopaminergic neurones were unstained, often present in areas of neuropil with low iron reactivity. In PD the SNc showed increased iron staining of the neuropil with many iron-positive microglial cells associated with extracellular melanin. The remaining dopaminergic neurones were unstained, though many of the non-pigmented neurones of the SNr were iron-positive. PMID- 7842299 TI - Expression of the neural cell adhesion molecule (NCAM) in Alzheimer's disease. AB - Expression of the nerve cell adhesion molecule, NCAM, was examined in post-mortem brain samples from patients with Alzheimer's disease (AD) and from age-matched controls. Four major isoforms of NCAM were identified by Western blot analysis 195, 185, 145 and 120 kDa with no differences being observed in either the intensity of individual band staining or in the expression of the constituent NCAM isoforms in AD when compared with controls. Immunohistochemical staining revealed star-shaped NCAM-positive structures with numerous radiating 'processes' or a more protoplasmic shape with short and thick 'processes'. These structures were not obviously more abundant in AD and there was no NCAM immunoreactivity in neuritic plaques or neurofibrillary tangles. This evidence suggests there is no change in NCAM expression in AD. PMID- 7842300 TI - Topographic investigation of brain atrophy in parkinsonism-dementia complex of Guam: a comparison with Alzheimer's disease and progressive supranuclear palsy. AB - The topographic distribution of brain atrophy in nine patients with parkinsonism dementia complex of Guam (Guam PDC) was evaluated quantitatively, and compared with that in six Japanese patients with Alzheimer's disease or senile dementia of Alzheimer type (AD), five Japanese patients with progressive supranuclear palsy (PSP), and nine Japanese control subjects. Characteristic features of Guam PDC were as follows: (1) severe atrophy of the frontal and temporal cortex with relative preservation of the white matter; (2) atrophy of the tectum, tegmentum and cerebral peduncle of the midbrain, and (3) atrophy of the tegmentum and base of the upper pons. In contrast, sectional areas of the tectum and cerebral peduncle of the midbrain were relatively well preserved in PSP, while in AD there was no significant atrophy in the brain stem. PMID- 7842301 TI - Intrastriatal infusion of lisuride--a potential treatment for Parkinson's disease? Behavioral and autoradiographic studies in 6-OHDA lesioned rats. AB - The present study examined the effect of chronic intrastriatal infusion of the dopamine receptor agonist lisuride on apomorphine-induced rotational behaviour and on D2-dopamine receptors in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal dopaminergic pathway. The completeness of the lesion of the right ascending nigrostriatal dopaminergic pathway was confirmed by apomorphine-induced rotation and [3H]-mazindol autoradiography. The intrastriatal infusion of lisuride (0.5 microgram/h) into the lesioned striatum for 2 weeks induced an immediate but temporary spontaneous contralateral rotation and a reduction of apomorphine-induced rotation of 47.2% relative to pre-lisuride infusion. The density of D2-receptors in the lisuride-infused striatum was significantly decreased by 40% relative to vehicle-infused 6-OHDA lesioned rats. The level of D2-dopamine receptors returned to normal levels 3 weeks after the termination of lisuride infusion. These results show that the intrastriatal infusion of lisuride reverses the behavioural and D2-dopamine receptor changes present in the 6-OHDA lesion rat model of Parkinson's disease. PMID- 7842302 TI - An experimental animal model of aluminium overload. AB - In order that better therapeutic approaches to disorders in man characterized by aluminium (Al) overload might be developed it is essential to have an appropriate animal model. Chronic oral administration of Al citrate to male Wistar rats leads to an Al overload in a relatively short period of time when compared to previous published animal models. Liver and brain Al levels are increased by 25 and 30 fold respectively compared to control rats after 6 months of loading. Al tissue content was significantly greater when the Al citrate was administered in an iron free diet. The distribution of Al in brain was similar to that in the Al encephalopathy of patients with chronic renal failure or Alzheimer's disease and is in accord with observations that areas of brain that accumulate greatest amounts of Al have highest concentrations of transferrin receptors. In the brain, the toxic effect of Al at the cellular level was characterized by an extensive cytoplasmic vacuolation in astrocytes (especially) and neurones. These changes are reminiscent of those observed in certain human neurodegenerative diseases. PMID- 7842303 TI - Clusterin as a marker for ischaemic Purkinje cells in human brain. AB - Clusterin has been implicated in cell death both in peripheral tissues and in the central nervous system. In the present study, expression of clusterin in the cerebellar cortex was examined in two cases with hypoxic brain damage and in one case with cerebellar infarction. Intense staining of Purkinje cells was observed in each case, and these cells showed the shrunken and pyknotic appearance characteristic of irreversible ischaemic damage. In the cerebella of neurologically normal control cases, as well as in those of some other neurodegenerative diseases, no staining or only punctate staining of Purkinje cells was observed. The results provide additional evidence supporting an association of clusterin with dying neurons in human brain. PMID- 7842304 TI - PrP gene dosage determines the timing but not the final intensity or distribution of lesions in scrapie pathology. AB - We have produced by gene targeting a mouse line with an inactive PrP gene. In animals heterozygous for this mutation, PrP mRNA is reduced by approximately 50% throughout the brain compared with wild type mice. The steady-state level of PrPc is also significantly reduced in heterozygotes compared to wild type mice. PrP mRNA and protein are not detected in brains of mice homozygous for the mutation. We have infected wild type mice and mice heterozygous and homozygous for the mutation with the ME7 strain of scrapie. A gene dosage effect can be seen in time of disease onset and period over which the disease symptoms develop. In heterozygotes disease onset occurs around 220 days and terminal stages are reached by 280 days. In wild type mice disease onset occurs around 130 days and the terminal stages by 160 days. The PrP-/- mice are resistant to disease up to 475 days. PrP deposition in heterozygous mice starts in the same brain area as wild type mice and can be detected as early as 50 days. The pattern of PrP deposition in the brain of heterozygotes follows an identical course to that observed in wild type mice and by terminal stages of disease the amount deposited is equivalent to wild type mice. Vacuolation is detected later than PrP deposition and distribution and degree in the terminal stages of disease is similar in wild type and heterozygous mice. These results show that signs of disease, vacuolation and PrP deposition are dependent upon PrPc in a rate dependent manner. PMID- 7842305 TI - HLA antigens in paraneoplastic cerebellar degeneration associated with anti-Yo antibody. PMID- 7842306 TI - Special issue on magnetic resonance. PMID- 7842307 TI - International workshop on standardization in clinical MRS measurements: proceedings and recommendations. PMID- 7842308 TI - Magnetic resonance spectroscopy applied to clinical oncology. AB - Magnetic resonance spectroscopy provides a means of non-invasively measuring the behaviour of a range of compounds of biochemical significance. With the development of a range of spatial localization and mapping techniques, the method has a range of promising applications in oncology. 31P and 1H spectroscopy are of value in observing the metabolism of both tumours and normal tissues. 19F spectroscopy has been used to monitor the metabolism of fluorine containing anticancer drugs, and 13C may find application in this field, particularly in pre clinical studies. In vivo clinical measurements are complemented by pre-clinical studies, high resolution measurements of extracts from tissue samples and also the measurement of biofluids, which can provide additional metabolic and pharmacokinetic information. The application of these techniques to oncology is reviewed, with particular emphasis on their clinical role. PMID- 7842309 TI - Quantitative magnetic resonance imaging of rat brain tumors: in vivo NMR relaxometry for the discrimination of normal and pathological tissues. AB - The in vivo relaxation times T1 and T2 were quantitatively determined in rat brain. Animals with implanted experimental brain tumors were investigated for discrimination of pathological regions from normal brain structures based on relaxation time differences. The different cerebral tumors (glioma, schwannoma, neuroblastoma) showed no difference in relaxation times, but all tumors had T1(1301 +/- 167 ms) and T2(91 +/- 9 ms) times distinctly longer than normal brain (T1: 1057 +/- 77 ms; T2: 77 +/- 6 ms). T1 can be used for distinction of tumor and edema from normal brain, while T2 is the better parameter for discrimination between tumor and edema. Furthermore, the effect of MRI contrast agents (GdDTPA, MnTPPS, GdTPPS) on the relaxation times of these experimental brain tumors was measured. The enhancement of tumors produced by GdDTPA disappeared within ten minutes after i.p. application. At later times, central cysts and peritumoral edema became the most enhanced structures. The enhancement of tumor following MnTPPS application remained unchanged in T1-weighted images during the whole observation period of four days. A significant reduction of enhancement was not observed during this time. The effect of MnTPPS on T2 was weak. Replacement of manganese with gadolinium as the central ion of the porphyrin TPPS led to a contrast agent with enhancement effects on both, T1- and T2-weighted images. PMID- 7842310 TI - Magnetic resonance angiography: methods and its applications to the coronary arteries. AB - The non-invasive visualisation of the coronary arteries with magnetic resonance imaging would be a highly useful tool for the diagnosis of coronary artery disease, with a potential to partly replace current invasive imaging modalities, and would be a step towards more patient comfort. While magnetic resonance (MR) angiography of most larger blood vessels can nowadays be performed routinely, current techniques are inadequate to image the coronary arteries. This paper provides a short overview of the principal techniques for MR angiography. The combination of a multiple-slice MR angiography technique with a simple and easily performed breathhold scheme is described, which allows to image the main branches of the coronary artery tree within one scan of 9 to 12 min duration. For display the coronary vessels are segmented semi-automatically and reconstructed as 3D objects. Results of volunteer scans and examinations of patients with known coronary artery disease show the feasibility of the approach. However, due to the need for a breathhold scheme, patient cooperation is required. PMID- 7842311 TI - Real-time image reconstruction system for interventional magnetic resonance surgery. AB - Interventional surgery techniques under the control of fast acquired magnetic resonance (MR) images may become important in interventional radiology in the near future. One of the components needed for an interventional MR scanner is the real-time reconstruction of the acquired MR images. However up to now no real time reconstruction systems are readily available for MR images. Therefore a reconstruction device was developed, which allows reconstruction and display of MR images with a delay of less than 50 ms. Additional to the high performance, the main characteristics of the presented device are its full compatibility with different MR acquisition techniques and its moderate cost. The device can be operated with most types of commercial scanners. It is especially suited for interventional MR systems but has also applications with conventional MR scanners. PMID- 7842312 TI - [Traumatic rupture of the isthmic aorta: analysis of 22 recent cases]. AB - This study is an analysis of the cases of acute traumatic rupture of the aorta treated in our hospital between 1987 and 1993. Recent progress concern especially the role of computed tomography and transoesophageal echocardiography in the diagnosis and the confirmation of the benefit of mechanical circulatory support in the treatment. Immediate surgery in all the cases is not yet the rule. Delayed surgical repair can be feasible in cases of severe and multiple associated lesions. PMID- 7842313 TI - [Magnetic resonance imaging during the acute phase of severe head injuries]. AB - In 1994, tomodensitometry is indispensable for diagnosis and treatment of acute head trauma. Magnetic resonance imaging (MRI) is more performant but not yet evaluated in this indication. Two homogeneous series of patients allow the authors to discuss interest and feasibility of MRI and to propose a new strategy for reception of acute head trauma. PMID- 7842314 TI - [Social-professional rehabilitation of patients with multiple trauma without brain or spinal cord injuries]. AB - Social and professional rehabilitation was studied in 77 patients who had sustained 1 to 5 years before a polytraumatism without brain or spinal cord injury. 36 patients (46%) remain professionally disabled, most of them manual workers, despite of long-term specific treatments. Only 41 patients (53%) judge their present quality of life good or satisfactory. PMID- 7842315 TI - [Traumatic emergencies and AIDS]. AB - At the reception of traumatic casualties, the medical staff is exposed to a contact with blood and thus to the risk of H.I.V. contamination. The hollow needle used for taking blood simple or doing intravascular injections is the most dangerous instrument, especially in the period next to medical care. The prevention of these accidents, which must be a permanent, systematic concern, does not take any advantage from the knowledge of the serological status of the patients but essentially rests on the care workers continuous education and the use of safety equipment. PMID- 7842316 TI - [Strategy of blood volume expansion for traumatic emergencies in adults]. PMID- 7842317 TI - [Physician involvement in the prevention of trauma. Reflection on 10 years of practice of the REAGIR program]. AB - Physician's implication in road traffic traumatology prevention has been realized for ten years, in "REAGIR" program. This program consists in analysis of the most serious road traffic accidents and proposals of preventive measures, directly to authorities. Results show the efficacy of this program (diminution of mortality and morbidity). Physicians' contribution in prevention is necessary, specific and effective. PMID- 7842318 TI - [Thoracic wounds: emergency management]. PMID- 7842319 TI - [Cardiorespiratory management of severe injured patients in intensive care units]. AB - Late mortality of severely injured patients could be prevented by the quality of early cardiorespiratory management. Indeed traumatized patients with high risk of multiple organ failure (according to age, ISS, amount of blood transfused, and/or metabolic acidosis) need a pulmonary artery catheterization as soon as possible (postdefinitive phase: during the surgical period or at the admission in the ICU). Such a procedure allows the intensivist to determine therapeutic goals in term of O2 delivery (DO2) and O2 uptake (VO2) in front of a frequent increased peripheral O2 demand, These goals (usually DO2 > or = 600 ml.min-1m-2 and VO2 > or = 150 ml.min-1.m-2) may be reached by the combination of prolonged mechanical ventilation (adapted to the pulmonary status), subnormal O2 carrying capacity (hematocrite between 30 and 35% in the absence of persistent bleeding), and increased cardiac output through an additional volume loading (without an excessive positive cumulated fluid balance on the second posttraumatic day) and the early administration of inotropic drugs (dobutamine). Reaching these goals usually permits a 61% reduction in the posttraumatic incidence of organ failure. PMID- 7842320 TI - [Polytraumatised children]. AB - Trauma is the leading cause of mortality in children between the ages of 1 and 14 years. It represents a major health problem in all industrialized countries. A well coordinated organization of the whole chain of cares is essential, from the initial management at the scene of the accident until the long term neurological rehabilitation of the child. During the initial examination, the presence of anoxia, hypovolemia or neurological distress was systematically evaluated. Emergency therapeutic measures should be ensured. At the term of this initial management: if the haemodynamic state is unstable, an emergency operative procedure may be required; if the haemodynamic state remains stable, one can realize a complete clinical and radiological assessment. The clinical and biological supervision must continue during this evaluation while sedation and analgesia are essential to limit an increase in intracranial pressure (ICP). At the term of this complete assessment, if one or several surgical lesions are identified, an operative program with a precise hierarchy is scheduled; if an intensive medical support is required, the child is then transferred to the pediatric intensive care unit. Most often, children with a serious head trauma do not have neurosurgical lesions but a "brain-swelling" or cerebral edema. Elevated ICP is one of the main risk for cerebral ischemia. Therefore, continuous assessment of ICP is essential. Thoracic trauma is most often a closed trauma in the child: pneumothorax and pulmonary contusion are the problems most frequently met. An emergency laparotomy is required if the abdomen volume increases rapidly associated to the persistence of a unstable haemodynamic status despite an important fluid expansion. However, the presence of intraperitoneal blood is no longer a formal indication to surgery. Frequent examination of liver and splenic lesions with abdominal tomodensitometry allows to avoid surgery in more than 90% of cases at the price of a very rigorous haemodynamic supervision. Intestinal perforations are rare and difficult to diagnose: peritoneal dialysis, if it reveals the presence of a leucocytosis greater than 500/mm3 or bacteria justifies the surgery.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7842321 TI - [Bases for drug therapy of spinal cord injuries]. AB - The initial lesion after spinal cord injury is due to two types of lesions: "primary" and "secondary". Aim of drug treatment is the limitation of the secondary lesion to facilitate recovery at the injury site. Mechanisms involved in the secondary lesion are of two types: a "macroscopic" one due to the compression of the cord and the ischemia due to hypoxia and fall of arterial blood pressure, a "microscopic" one due to biochemical and enzymatic phenomena. In those, glutamate liberation, intracellular calcium modifications, free radical synthesis and lipid peroxidation are the more fashionable. Numerous drug treatments are proposed which will never take the place of immediate resuscitation care and cord decompression. PMID- 7842322 TI - [Sedation of patients with head injuries]. AB - In severe head-injured patients, intravenous sedation is an integrant part of therapy. Its main objectives consist in facilitation of ventilation and other therapeutic procedures but also more specifically in the control of intracranial pressure and epileptic seizures. The ideal sedative drug must fulfil a number of criteria regarding pharmacokinetics, cerebral metabolism and hemodynamics. Opioids, midazolam and propofol are the most commonly used sedative drugs. The therapeutic response and the neurological status of the patients are the guidelines for the choice, the duration and the assessment of sedation. PMID- 7842323 TI - [From emergency: some of the thing I know about]. PMID- 7842324 TI - [Restructuring of emergencies: which investment for private hospitals?]. PMID- 7842325 TI - [Multiple trauma in the elderly]. AB - Morbidity and mortality following multiple trauma are high in elderly patients. Head trauma has a particularly poor prognosis. However intensive care may improve the survival rate and the quality of life in survivors, allowing those to return home. PMID- 7842326 TI - [Oxygen supply in war times. Current perspectives]. AB - The authors report their experience of the use of various sources of oxygen feeding in wartime: a classical feeding by liquid oxygen or by extractive oxygen cylinders; a new type of feeding by oxygen condensers or chemical oxygen. According to their practical experience, each source finds its role in wartime, this role being determined by war conditions. PMID- 7842327 TI - [Evaluation of locoregional anesthesia in an emergency-traumatology operating room]. AB - Surgical activities concerning traumatic emergencies have been evaluated during 3.5 months. There has been 371 cases. Most of them concerned hand injuries (48%); others concerned limbs, and 5 multiple injuries, one spinal fracture and 30 various injuries. Loco-regional anesthesia has been preferred in 63% of all cases; 80% of all hand injuries, 100% of all femoral neck fractures. The success rate--no addition of morphinics--has been evaluated at 85%, with use of sedatives in 28%. PMID- 7842328 TI - [Mobile hospitals of army health units]. AB - The author introduces the modernization program for field medical facilities of the French military health service. It depends mainly on the manufacturing of containerized hospitals, the main features of which are: mobility, modularity and fast setup. PMID- 7842329 TI - [Use of laryngeal masks in repeated fibroscopy under general anesthesia in patients undergoing lung transplantation]. PMID- 7842330 TI - [Affective disorder: clinical and basic study]. PMID- 7842331 TI - [Summary of the national workshop on affective disorder]. PMID- 7842332 TI - [The diagnosis and prognosis of depressive disorders in a community clinic]. AB - To understand the prognosis and stability of diagnosis of depressive disorders, a follow-up study was carried out in a community clinic. The sample includes of 90 cases whose original psychiatric diagnosis were 38 depressive disorders (16 depression and 22 depressive neurosis) and 52 non-depressive neurosis. Eight years later, rediagnosis was made by using the same assessment instruments and diagnostic criteria. The results suggest that the diagnosis are quite stable and the Kappa tests show the predictive validity of diagnosis is 0. 73 in depression and 0.84 in depressive neurosis. Besides a few differences both depression and depressive neurosis have similar characteristics in clinical features, prognosis and outcome. PMID- 7842333 TI - [Diagnosis of depressive neurosis]. AB - We studied 97 patients who were diagnosed at the time of discharge having depressive neurosis within the period of 1984-1992. They were rediagnosed according to the diagnostic criteria of CCMD-2, dysthymia and mild degree of depression in ICD-10 and DSM-III-R. Only 23 patients were in accord with diagnostic criteria of CCMD-2 and maintained the diagnosis of depressive neurosis. The other 74 patients were diagnosed as having depression (single or recurrent episode) other types of neurosis, bipolar affective disorders (depressive phase or mixed phase) and schizophrenia. These diagnoses were similar to those in ICD-10 and DSM-III-R. PMID- 7842334 TI - [Ultrasonographic study on primary hyperparathyroidism: evaluation of B-mode and color Doppler ultrasonography in localization]. AB - Seventy six patients with primary hyperparathyroidism were studied systematically by B-mode ultrasonography (BUS) and color Doppler flow imaging (CDFI). The sensitivity to the patients was 72%, specificity 92%, accuracy 87%, positive predictive value 69%, and negative predictive value 92%. The diagnostic efficiency was the highest in the parathyroid adenomas in normal position. By comparing the diagnostic efficiency of BUS with CDFI, we found that the sensitivity was significantly different (P < 0.05) and the accuracy greatly significantly different (P < 0.01). The accuracy of CDFI was higher than that of BUS. We discussed the value of BUS in localization in the parathyroid lesions and discrimination between the various kinds of parathyroid lesions. In addition, ectopic parathyroid lesions, hyperparathyroid crisis, and comparison between various imaging examinations were also studied. It is suggested that the diagnostic level of BUS and CDFI in primary hyperparathyroidism be improved. PMID- 7842335 TI - [Relation of plasma soluble tumor necrosis factor receptor to tumor necrosis factor and clinical features of hepatitis B]. AB - Plasma soluble tumor necrosis factor receptor (sTNFR) was detected by radioimmunoprecipitation-polyethylene glycol assay in 64 patients with viral hepatitis B. The levels of two distinct receptors (sTN-FR1 and sTNFR2) were significantly higher in chronic severe hepatitis (CSH) followed by chronic active hepatitis (CAH), chronic persistent hepatitis (CPH), and acute hepatitis (AH) or controls (P < 0.01). A more markedly increased sTNFR was observed in patients with high SB (> 342 mumol/L), low Pa (< 20%), and secondary infection or fatal outcome. For patients with 20% below of sTNFR levels, the increase of TNF was proportional to that of sTNFR. But, for patients with exceeding 20% of sTNFR, the ratio of TNF/sTNFR became higher. The ratio of TNF to sTNFR may be greatly indicative to determine the clinical severity and outcome. Administration of sTNFR could prevent the adverse pathologic sequence caused by the exaggerated TNF and open a new therapeutical field. PMID- 7842336 TI - [Chinese strain of hepatitis D virus: molecular cloning and sequencing, and the significance of its genome divergence]. AB - The hepatitis D virus (HDV) obtained from a chronic asymptomatic HDV/HBsAg carrier (SZ 93) in Sichuan province was cloned with 1,684 nucleotides in full length genome by reverse transcription-PCR. Comparison of SZ 93 with those obtained from different geographic area: i.e., Italia, United States, British, Nauru, Taiwan, Netherland, showed 81.8%-95.4% homology in nucleotide sequence of whole genome, 88.9%-96.1% homology in nucleotide sequence of HDAg-coding region, and 86.4%-93.0% homology in amino acid sequence of HDAg protein. Also, another isolate (SZ 92) obtained from a chronic severe hepatitis patient in Sichuan was cloned with HDAg-coding region. There were some mutations in SZ 92 compared with SZ 93 as well as the other clones mentioned above. The meaning for the genome divergence of HDV SZ 93 and SZ 92 was discussed. PMID- 7842337 TI - [Ginseng saponin treatment for intrauterine growth retardation]. AB - Twenty eight patients with intrauterine growth retardation (IUGR) in 31-34 gestational weeks were clinically treated with Chang Bai Shan ginseng saponin tablets, while 26 pregnant women with IUGR were nutritionally treated as controls. The results indicated that in the experiment and control groups, the height of fundus and fetal diparietal diameter (BPD) gradually approached to those of the normal pregnancy group. The urinary estrogens/creatinine (E/C) ratio and serum human placental lactogen (hPL) were close to those of the normal pregnancy group (P > 0.05) after 35 gestational weeks. The weight of neonates treated nutritionally and with ginseng saponin approached to that of the normal pregnancy group. There was no significant difference as compared with the normal pregnancy group (P > 0.05). Glucose and albumen levels in blood of neonates were not significantly different between experiment and control groups, but they were higher than those in IUGR group (P < 0.05). The present results suggest that in treating IUGR, ginseng saponin may show the same effect as in the nutritional treatment. PMID- 7842338 TI - [Unstable DNA sequence and methylation in fragile X syndrome]. AB - Fragile X syndrome is characterized as an inherited unstable DNA sequence: the increasement of (CGG)n copy number. It suffered from the inactivation of FMR-1 (fragile X mental retardation 1), which is inhibited by amplification of (CGG)n and methylation of CpG island. The (CGG)n repeat variation in normal Chinese population was detected by PCR with sequencing gel analysis. We also analysed the amplification of (CGG)n and methylation of CpG island at Xq27.3 from 15 individuals in 6 families by Southern hybridization. These results indicate that abnormal methylation of CpG island always occurs in Fra (X) patients together with large amplification of (CGG)n. The (CGG)n could be either stable or amplified in springs of carrier females. These suggest that there would be a new genetic mechanism dynamic mutation. PMID- 7842339 TI - [Acute allograft glomerulopathy and its etiology]. AB - Acute allograft glomerulopathy (AAG) is a distinctive glomerular lesion of renal allografts. Its clinical signs and symptoms, pathology and etiology were studied. The frequency of AAG was 57.6% in renal transplant recipients. The clinical signs and symptoms included urinary protein, cast, WBC and RBC, etc. The pathologic features were diffuse endothelial hypertrophy and necrosis accompanied by accumulation of periodic acid-schiff (PAS) positive material and mononuclear cells that resulted in obliteration of glomerular capillaries, basilar membrane proliferation and immune complexes deposition. To elucidate the pathogenesis of AAG, we diagnosed HCMV infection of renal transplantation recipients by using polymerase chain reaction (PCR) and ELISA. Circulating T cell subsets were detected with APAAP method. OR of AAG occurrence in HCMV infection group was 32.4 times as high as in non-HCMV infection one (P < 0.01). OR of AAG occurrence in CD4/CD8 < 1.5 group was 12 times as high as in CD4/CD8 > 1.5 one (P < 0.01); so AAG was strongly associated with HCMV infection and T cell subsets changes (decreased or inverted CD4/CD8 ratio) induced by HCMV. PMID- 7842340 TI - [Localization of apoptosis-antagonizing bcl-2 translated product in Hodgkin's disease]. AB - We applied more sensitive immunohistochemical method, i.e. multilayered PAP, to investigate the expression and distribution of apoptosis-antagonizing gene bcl-2 in Hodgkin's disease (HD), bcl-2-positive Reed-Sternberg (RS) cells were found in 7 of 21 (33%) of HD, and 2 of 7 (mixed cellularity) accompanied by a lot of reactive lymphoid follicles, the germinal centers of which were also positive for bcl-2. In contrast, in 4 cases of inflammatory lymphoid follicular hyperplasia as positive controls, the mantle zones rich in long-lived B cells were strongly positive stained with bcl-2 antibody, whereas germinal centers were negative. Thus, our data indicate that overexpressed bcl-2 gene-mediated apoptosis impairment is strongly associated with pathogenesis of HD. PMID- 7842341 TI - [In situ hybridization and immunohistochemical detection of bone morphogenetic protein genes in ameloblastomas]. AB - Bone morphogenetic protein (BMP) is related to the formation of bone and dentin. Immunohistochemical study showed that ameloblasts, odontoblasts and dental papilla cells contained much BMP. It is indicated BMP might be associated with the epothelial-mesenchymal interaction of tooth germs. In this study, the expression and distribution of BMP in 40 patients with ameloblastomas were observed by using in situ hybridization and immunohistochemistry. The results showed that all three BMP genes were overexpressed in the epithelial component of ameloblastomas, however, no positive reaction was found in immunohistochemistry. It is indicated that overexpression of BMP genes might be related to the development of ameloblastomas. PMID- 7842342 TI - [Electron microscopic observation of the denervated flap reinnervation after implantation of sensory nerve]. AB - Flap reinnervation was studied by electron microscopy in the rabbit cervico shoulder flap with great auricular nerve implanted. After transferring the flap to the dorsal defect of the rabbit's ear and division of its pedicle, the original nerve fibers of the flap underwent a degenerative process which would persist over 2 months. The great auricular nerve implanted into the flap regenerated axons by entering into old endoneurial rube of the flap and sprouting. The development process of the regenerating nerves showed that the unmyelinated fibers appeared first in the 2nd month, and the myelinated ones in the 4th month. The regenerating nerve fibers had often accompanied by blood vessels. PMID- 7842343 TI - [Protective effects of ginsenoside on myocardiac ischemic and reperfusion injuries]. AB - Thirty mitral valvular surgical patients were randomly divided into three groups for study of protective effects of Ginsenoside on myocardiac ischemic and reperfusion injuries. In GI, 11 patients (controls), no Ginsenoside was used, in GII, 11, Ginsenoside in total was added into the cardioplegic solusion made in our hospital, and in GIII, 8, instead of Ginsenoside in total Ginsenoside Rb was added. During operation comparative studies were made of pre- and postoperative cardiac functions with intraoperative transesophageal echocardiography and ultrastructures of myocardiac cells with electromicroscopy. We conclude that both Ginsenoside in total and Ginsenoside Rb have protective effects on myocardiac ischemic and reperfusion injuries in open heart surgery, and the effect of Ginsenoside in total is even better than that of Ginsenoside Rb. PMID- 7842344 TI - [Morphologic and molecular evidence of apoptosis during reperfusion phase after brief period of renal ischemia]. AB - A multiparametric analysis was made to demonstrate that brief period of ischemia can initiate extensive loss in a rat kidney through the process of apoptosis during early reperfusion. Microscopic examination of mouse renal tissues subject to a 5, 30, or 45 minute period of complete ischemia showed the presence of apoptotic bodies both within and occasionally between renal tubular, appearing as early 6 hours after reperfusion and increasing in numbers at 12 hours. Furthermore, DNA extracted from such reperfusion renal tissue demonstrated the appearance of a distinct "ladder pattern" of DNA fragments after electrophoresis in agarose gels. It was suggested that renal reperfusion injury after ischemia can initiate a form of cell death-apoptosis that is drastically different from cellular necrosis induced by prolonged severe ischemia. PMID- 7842345 TI - [Early diagnosis and treatment of ischemic femur head necrosis in adult]. PMID- 7842346 TI - [The CD2, CD4 and CD8 mRNA expression of T lymphocytes in patients with acromegaly and hyperprolactinemia]. AB - The CD2, CD4 and CD8 mRNA expression of human peripheral blood lymphocytes (HPBL) from 49 female patients with acromegaly and hyperprolactinemia and 15 healthy women were studied by dot blotting assay using corresponding CD2, CD4 and CD8 antisense RNA probes. It was found that CD2 mRNA expression increased in women with growth hormone over-expression and the ratio of CD4 and CD8 mRNA declined significantly in the women with prolactin over-expression. These suggested that the mRNA expression of these cluster differentiation antigens in peripheral T lymphocytes was affected by the pituitary hormones. The significance of these findings relevant to the study of the neuroendocrine and immune network was discussed. PMID- 7842348 TI - [Effects of calcitonin and indomethacin on bone resorption mediated by interleukin-1]. AB - The effects of calcitonin and indomethacin on bone resorption stimulated by interleukin-1 (IL-1) were studied in cultured neonatal mouse calvariae. The results showed that calcium release from cultured calvariae was significantly increased after adding 20 ng/ml IL-1 (P < 0.01). The increase of calcium release stimulated by IL-1 was blocked by both calcitonin at the concentration of 10, 100, 1,000 ng/ml and indomethacin (10(-6), 10(-5) mol/L). The stimulation of calcium release by IL-1 was also blocked even adding 10 mol/L indomethacin 5 hours after adding IL-1 into the culture. These data showed that both calcitonin and indomethacin can inhibit bone resorption stimulated by IL-1. Thus, it is possible that calcitonin and indomethacin may be used as a therapeutic agent to block inflammatory bone resorption mediated by IL-1. PMID- 7842347 TI - [Trabecular connectivity in primary hyperparathyroidism]. AB - By bone histomorphometry, 10 cases of primary hyperparathyroidism (PHPT) were used to study the trabecular connectivity, which in a few literatures was mentioned to be reserved somehow. Our data suggest that in comparison with the normal control (10 subjects) the nodes (N.Nd), the number of terminus (N.Tm), the total strut length (TSL), the length between the nodes (Nd.Nd), trabecular separation (Tb.Sp) and trabecular thickness (Tb.Th) were significantly increased while no significance was found in N.Nd/N.Tm, Tm.Tm and TBV. The correlation analyses indicate that there is no correlation between the variables in the normal controls. In contrast, however, TBV and Tb.Th showed negative correlations with N.Tm and Tm.Tm. Besides these, there were positive correlations between N.Nd/N.Tm and TBV or Tb.Th, and a negative correlation between N.Nd/N.Tm and Tb.Sp. The results suggest that to certain degree the trabecular connectivity in PHPT be destructed while the three dimensional architecture be reserved. Our data seem to be different from those reported previously. It may be due to the severity of PHPT in our patients. PMID- 7842349 TI - [Preparation of monoclonal antibody directed against hepatitis B virus X protein and detection of reactive antigen in hepatocellular carcinoma]. AB - A mouse monoclonal antibody directed against hepatitis B virus (HBV) X protein (HBxAg) was prepared. The antibody was used to screen by immunohistochemistry 50 liver tissue sections from patients with hepatocellular carcinoma (HCC), and 15 patients with chronic active hepatitis (CAH). 28 of 50(56%) samples were HBxAg positive in tumor tissues. The positive rates of HBxAg only in tumor tissues or in adjacent nontumor tissues were 24% and 16%. HBsAg was detected in 16% of cases in tumor tissues and 74% in surrounding nontumor tissues. In CAH samples, the positive rates of HBxAg and HBsAg were 6.6% and 73.3%. HBcAg was only detected in nontumor surrounding liver tissues, the positive rates being 18%. In CAH samples, no HBcAg was detected. The results showed that HBxAg is a common marker in liver tissue from patients with HBV-related HCC. The findings of HBxAg in the absence of detectable HBsAg and HBcAg in the liver tissues suggested that HBxAg could be independent of HBV replication and implied that the synthesis of HBxAg may be directed from integrated HBV DNA templates. It is possible to use antiHBx monoclonal antibody as a carrier for the targeting therapy of HCC. PMID- 7842350 TI - [Amplification of C-erB-2 oncogene in colon carcinomas]. AB - Differential PCR has been used to detect the variance of c-erbB-2 gene copies in 23 colon carcinoma tissues. It was found that amplification of c-erbB-2 gene existed in 7 out of 23 (30%) cases. All of the three high-middle differentiated colon carcinomas had amplification of c-erbB-2 gene in our specimens. It was higher than that of the middle differentiated colon carcinomas (P < 0.05). The rate of amplification of c-erbB-2 gene in patients with positive lymph node was approximately two times as high as that in negative nodo patients, but this difference was not significant (P > 0.20). PMID- 7842351 TI - [Target therapy by monoclonal antibody against ovarian carcinoma conjugated with liposomes and adriamycin]. AB - Conjugates of monoclonal antibody COC166-9 and adriamycin entrapped in liposome (MLA) were prepared in our laboratory. In vitro growth inhibition of SKOV3 ovarian carcinoma cell line was carried out by MLA and controls. Target therapies by MLA, adriamycin, normal mouse IgG instead of MAb, and control were given for 24 nude mice models with subcutaneous human ovarian carcinoma xenografts and 16 ascitic ovarian carcinoma respectively. MLA group showed the best therapeutic effect than all the other groups which gave a helpful clue to clinical use. PMID- 7842352 TI - [Serum apolipoprotein abnormalities in patients with idiopathic nephrotic syndrome]. AB - We measured serum lipid and apolipoprotein (apo) levels in 45 patients with normal renal function at different stages of idiopathic nephrotic syndrome (NS). Wide abnormalities of lipid metabolism were found. The characteristic disorder of serum apos in NS was a decrease in apoAI and AII and a significant increase in apoB, CII, and CIII. Consequently, the ratio of apoAI to apoB was significantly decreased. Some patients with NS in remission had normal serum lipid concentrations, but abnormalities of serum apos were still observed. It is suggested that the nephrotic patients may be at increasing risk for coronary heart disease (CHD), and that apos may be more sensitive predicators of CHD than lipids. PMID- 7842353 TI - [Changes in and significance of atrial natriuretic peptide, angiotensin II after experimental brain injury]. AB - We used the method of RIA determined the contents of atrial natriuretic peptide (ANP), angiotensin II (ANG II) in plasma and brain tissues after brain injury in 70 rats. The results showed that the ANP was significantly decreased in brain tissues on 6, 72 hours after brain injury. At the same time, the plasma and brain tissues ANG II, brain water contents were significantly increased. The results suggested that the unbalance of ANP and ANG II may be related to the pathophysiological process of brain edema. PMID- 7842354 TI - [Reduction of erythrocyte sorbitol by ascorbic acid in patients with diabetes mellitus]. AB - The content of erythrocyte sorbitol could be reduced by ascorbic acid (AA). To confirm the effect of AA on human erythrocyte sorbitol accumulation and explore its mechanism of the action, we studied in vitro the effects of ascorbic acid on the contents of both sorbitol and glucose in human erythrocytes. The effect of AA on the ratio of sorbitol to glucose in erythrocyte (S/EG) which was referred to as a marker of aldose reductase (AR) activity was observed. Both the accumulation of erythrocyte sorbitol and S/EG were reduced by the addition of ascorbic acid (AA) during in vitro incubations. The sorbitol content in the erythrocyte and S/EG were reduced by a maximum of 87.3%, 83.4% and 93.8%, 63.9% when the medium's AA concentration was at its peak in the 5.6 mmol/L and 28 mmol/L glucose concentration of medium respectively. These suggested that the activity of polyol pathway could be inhibited effectively by AA which might directly act on the activity of AR. The results of a double-blind cross-over trial using AA tablets or inert inositol tablets in 8 diabetic patients showed that the supplementation of 1,000 mg AA/day continued for 2 weeks resulted in reductions of 12.2% and 21.8% in both erythrocyte sorbitol and red cell sorbitol: plasma glucose (S/PG) ratio, respectively (P < 0.05). The fasting plasma glucose levels measured coincidently revealed no changes (P > 0.05). This suggests that the supplementation of moderate AA (1,000 mg/day) might provide a simple, safe and effective means of preventing and ameliorating chronic complications of diabetes. PMID- 7842355 TI - [Delayed fluid resuscitation induced bacterial translocation after lethal thermal injury: role of oxygen free radical injury of intestinal mucosa]. AB - The Present investigation was undertaken to examine the effect of delayed fluid resuscitation (DFR), after lethal thermal injury on oxygen free radical (OFR) injury of intestinal mucosa and its relationship to bacterial translocation. Four groups of gnotobiotic rats with 5 strains of bacteria were studied: sham injury group (control) (n = 6): early fluid resuscitation (EFR) group (n = 24) receiving resuscitation (Parkland) immediately after scald (40% TBSA, third degree); DFR group (n = 24) receiving resuscitation 6 hours after scald; treatment group (n = 12), rats with DFR receiving VitE and VitC treatment before resuscitation 12, 24, 48 and 72 hours after injury, animals (n = 6, at each point) were sacrificed. Plasma endotoxin level, mucosal SOD, GSHPx, MDA and diamine oxidase (DAO) of ileum were determined, and cultures of the mesenteric lymph nodes (MLN), liver, spleen, heart, lung, kidney and blood were done. The level of mucosal MDA and plasma endotoxin and the incidence of bacteria translocation (IBT) to tissues were significantly higher and mucosal SOD, GSHPx, DAO activity significantly lower in DFR group as compared with that in EFR group at most of the time points. In DFR group, mucosal MDA content was negatively correlated with mucosal DAO activity, which correlated positively with plasma endotoxin level and IBT. After treatment with VitE and VitC, mucosal MDA content was decreased, plasma endotoxin level and IBT were significantly decreased, and mucosal DAO activity was significantly increased. Our data indicated that DFR in cases of burn shock can result in OFR injury of intestinal mucosa, disrupting mucosal barrier and promoting translocation of intestinal bacteria and endotoxin. PMID- 7842356 TI - [Quantitative study on the osteogenic potential of vascularized iliac periosteal]. AB - The effect of pedical blood supply, recipient environment, blood supply to the osteogenic capacity of iliac periosteal was investigated. An iliac periosteal flap based on the circumflexa femoris lateralis vessels was developed in a canine model. The vascularied iliac periosteal was rotated onto the quadriceps femoris musculus or epigastrica inferior fibrous-connective tissues in one side and the free flap was done in the same way in another side. 2, 2, 4, 6 animals were killed at 2, 4, 8, 12 week after operation and the flaps were studied by new bone Ca, P content, bone dense measure, double tetracycline labeling, bone histomorphometry analysis and light microscopy. The following results were obtained: (1) Iliac periosteal has good osteogenic capacity; (2) The early good blood supply is much more important than the recipient environment blood supply, it make the bone formation speed 2-4 weeks forward. PMID- 7842358 TI - [Advances in the biochemical and molecular biological study on angiotensinogen]. PMID- 7842357 TI - [Transposing the great trochanter bone flap pedicaled with the deep branch of the medial circumflex artery in repair of necrotic femoral head]. AB - The transposition of the greater trochanter bone flap pedicled with the deep branch of the medial circumflex artery was designed as a new therapeutic method for the treatment of early ischemic necrosis of the femoral head in adults. Bone flap was successfully used in 15 limbs of 13 patients. Applied anatomy, operative indications and procedure of the bone flap was introduced. PMID- 7842359 TI - Neural control of rhinitis. PMID- 7842360 TI - Nitric oxide and bronchial reactivity. PMID- 7842361 TI - Allergy during anaesthesia. PMID- 7842362 TI - Influence of prolonged treatment with topical corticosteroid (fluticasone propionate) on early and late phase nasal responses and cellular infiltration in the nasal mucosa after allergen challenge. AB - We have examined the effect of prolonged treatment with topical corticosteroid on allergen-induced early and late nasal responses and the associated inflammatory cell infiltrate in grass pollen sensitive allergic rhinitics. Following a randomized double-blind 6 week treatment period with fluticasone propionate 200 micrograms aqueous nasal spray twice daily or matched placebo spray, nasal provocation was performed using Timothy grass pollen extract. Nasal symptoms were recorded at intervals from 0 to 24 h. Nasal biopsies were performed before treatment and at 24 h after allergen and processed for immunohistology. When corticosteroid-treated patients were compared with the placebo group there was an approximately 50% decrease in the size of the early (0-60 min) response and almost complete inhibition of late (1-24 h) nasal symptoms after allergen challenge. After allergen challenge markedly fewer T lymphocytes and CD25+ (interleukin-2 receptor bearing) cells were observed in both the epithelium and submucosa in fluticasone treated patients compared with the placebo group. Significantly less total and activated eosinophils were observed, particularly within the nasal epithelium. Submucosal mast cell counts were decreased, whereas increased numbers of submucosal neutrophils were observed. These results confirm that topical corticosteroid treatment inhibits allergen-induced early and late nasal responses. This may possibly occur following a decrease in T lymphocytes and/or mast cells and their products and a consequent reduction in tissue eosinophilia. PMID- 7842364 TI - Effect of grain exposure and smoking on the longitudinal changes in immediate skin reactivity. AB - The study was carried out to investigate the effect of occupational exposure and smoking on the longitudinal changes of immediate skin reactivity over 3 years in working populations. A total of 480 grain elevator workers and 707 transit and ferry (control) workers were included because they had allergy skin tests on both surveys. Skin-prick texts using three common allergens and a negative and histamine controls were administered during both surveys. The reaction was considered positive if the mean weal size was 3 mm or greater than that of the negative control. Conversion was defined as a change from the non-atopic state in the initial survey to the atopic state in the follow-up survey. Reversion was defined as a change from the atopic state in the initial survey to the non-atopic state in the follow-up survey. The findings showed that grain workers had two times risk of conversion than control workers. Recent smokers, who changed their habit from non-smoker/ex-smoker to smoker in the follow-up survey, were at a three times risk of conversion than non-smokers. The reversion of skin-test reactivity was not associated with age, smoking habits, or working exposure. When investigating studies of longitudinal changes in immediate skin reactivity, the effects of age, changes in smoking habit and occupational exposure should be considered. PMID- 7842363 TI - Non-invasive assessment of bronchial inflammation in asthma: no correlation between eosinophilia of induced sputum and bronchial responsiveness to inhaled hypertonic saline. AB - Bronchial inflammation in mild asthma has been investigated using bronchoscopical techniques. The safety of bronchoscopy in patients with more severe asthma has been questioned. We have used the non-invasive technique of hypertonic saline (HS) inhalation to induced sputum samples for cellular analysis whilst simultaneously yielding a measure of bronchial responsiveness. Ten normal subjects and a heterogenous group of 24 asthmatic patients (range % predicted FEV1 43.3-111.5) underwent HS challenge. Sputum samples induced were analysed. Total and differential cell counts between the two groups were compared. The association between bronchial responsiveness to HS and sputum cell counts was examined in the asthma group. Mean maximum fall in FEV1 for normal subjects was 4.0 (2.1-5.9, 95% CI)% after saline. Geometric mean PD20HS for asthma patients was 7.7 (range 0.68-40.92)ml. Adequate sputum samples were obtained from 9/10 normals and 23/24 asthmatic patients. Sputum from normal subjects contained a median of 3.8 (2.8-8.1, interquartile range)% eosinophils compared with 17.6 (8.9 34.1)% in sputum from asthma patients (P < 0.001). Sputum from asthma patients contained fewer of all other cell types compared with normals, with the difference in macrophages reaching significance. There was no correlation between PD20HS and cell count for any cell type in asthma subjects. Analysis of induced sputum represents a simple, safe, non-invasive and well-tolerated method of assessment of bronchial inflammation, suitable for use in patients with a range of asthma severity. There was no relationship between inflammation, as assessed by sputum cell counts and a measure of 'indirect' bronchial responsiveness. PMID- 7842365 TI - Comparison of a new antihistaminic and antiallergic compound KW 4679 with terfenadine and placebo on skin and nasal provocation in atopic individuals. AB - The effects of three oral doses of a new compound KW 4679 thought to have both antihistaminic and antiallergic properties were compared with terfenadine and placebo in a double-blind cross-over trial in 15 volunteers with seasonal allergic rhinitis. Comparison of the effect of the treatments with either 2.5, 5 or 10 mg b.i.d. of KW 4679, 60 mg b.i.d. of terfenadine or placebo was made on the response to histamine and grass pollen skin-prick testing. Nasal provocation testing with grass pollen was performed on the eighth day of treatment. Nasal airway resistance (NAR) was measured using active posterior rhinomanometry and the dose of grass pollen which caused a 200% increase in NAR was determined. The number of sneezes in the first 12 min was counted. Compared with placebo all doses of KW 4679 and terfenadine significantly inhibited the skin weal response to histamine and grass pollen (P < 0.001). The inhibitory effect of KW 4679 on both histamine and allergen induced skin weals was significantly greater than that of terfenadine (P = 0.001 and P = 0.049 respectively). The results of nasal challenges with grass pollen showed that all doses of KW 4679 and terfenadine were effective in reducing sneeze counts (P < 0.001), though there were no significant effects on allergen induced increase in NAR. All three doses of KW 4679 were generally well tolerated. Drowsiness was reported by some of the volunteers on KW 4679 and one volunteer reported drowsiness whilst taking placebo. Slight and reversible rises in AST and ALT concentrations were observed; these were not considered clinically significant. PMID- 7842366 TI - Inhibition by a novel peptide leukotriene receptor antagonist ONO-1078 of airway wall thickening and airway hyperresponsiveness to histamine induced by leukotriene C4 or leukotriene D4 in guinea-pigs. AB - We studied the effect of intravenous administration of leukotriene (LT) C4 or LTD4 on airway responsiveness to histamine and airway wall thickening in guinea pigs. Guinea-pigs were killed and the lungs were fixed in formalin. Slides from paraffin-embedded section of the lungs were stained and the airways that were cut in transverse section were measured by tracing enlarged images using a digitizer. Moreover, airway resistance (Raw) was determined by a pulmonary mechanics analyser and we calculated two indices, an index of airway wall thickening and the one of airway hyperresponsiveness to histamine, from changes of baseline-Raw and peak-Raw following intravenous administration of histamine before and after the intravenous administration of LTC4 or LTD4. The infusion of LTC4 or LTD4 induced an increase of the relative thickness of the airway wall in peripheral bronchi demonstrable by the histological examination. In analysis of airway function, intravenous administration of LTC4 or LTD4 induced airway hyperresponsiveness to histamine with airway wall thickening. The LTC4 and LTD4 receptor antagonist ONO-1078 inhibited these effects of LTC4 and LTD4, suggesting LTC4 and LTD4 may induce airway wall thickening and airway hyperresponsiveness through LTC4 and LTD4 receptors in the airways. PMID- 7842367 TI - Out of darkness comes light--and thanks. PMID- 7842368 TI - Women dentists: equal and different. PMID- 7842369 TI - A critical evaluation of diagnostic tests for periodontal disease. PMID- 7842370 TI - Recommendations regarding total daily fluoride intake for Canadians. PMID- 7842371 TI - The state of oral and dental health of the homeless and vagrant population of Montreal. AB - Not much is known about the state of oral and dental health of homeless and vagrant people in Montreal. However, a study conducted during April 1993, in conjunction with dental health month, has made it possible to undertake a better evaluation of their oral health status and to identify ways of making dental treatment available to them. Once the oral health status of this population is known, the official body responsible for homeless and vagrant individuals, the "Regie regionale Montreal-Centre," can be given possible solutions for their treatment and care. Most of the homeless are welfare recipients and have access to some basic benefits from this source. One of these benefits is free access to all assured basic dental services. These services are available after a six-month waiting period, and are provided by a dentist of the homeless person's choice. At the beginning of this study, the authors hypothesized that homeless people would prefer to be treated in the hostels and shelters where they sleep, which is currently the situation in Boston. But in 65 per cent of cases, their responses to a questionnaire administered as part of this study were quite different, and indicated that they would prefer to visit a private dentist of their choice. However, there is another important group (35 per cent) who wish to receive dental treatment in the hostels they presently frequent. Any proposed solution should take into consideration both groups of homeless and vagrant persons. PMID- 7842372 TI - Technology assessment in dentistry. AB - Technology, in the context of dental health care, is a term that can encompass systems such as water fluoridation, clinical procedures such as sealants, or clinical protocols such as antibiotic coverage of patients with a history of heart surgery. Similarly, the term technology assessment (TA) describes a multidisciplinary, scientific process established to guide policy on the adoption and distribution of health technologies. While this process is already well established in medicine, it is just beginning in dentistry. As such, TA is still evolving in dental care in terms of methods and process. TA is required to guide the content of curriculum and standards of practice in a rapidly changing dental environment. It should precede the adoption or deletion of both technologies and of writing practice guidelines. TA makes it possible to shed inappropriate technologies or the inappropriate application of existing technologies, which may free resources to pay for improvements in the dental care we offer. PMID- 7842373 TI - [Cleidocranial dysplasia: review of the literature and presentation of a case]. AB - Cleidocranial Dysplasia, although not frequent, can present to the dentist. In this article, we have reviewed the literature concerning this disease and we present a patient with this condition. An overview of the disease would reveal partial to complete absence of clavicles, delayed closing of cranial fontanels, prolonged retention of deciduous teeth, subsequent delay in eruption of permanent teeth and multiple impactions. PMID- 7842374 TI - A perspective on homelessness in Canada. PMID- 7842375 TI - Evaluating a computer-based experiential learning simulation: a case study using criterion-referenced testing. AB - A case study of a computer-based experiential learning program involving the use of criterion-referenced testing as a quantitative evaluation tool is described. The simulation was designed to introduce nurses to basic computer operations. One hundred and thirty-eight nurses participated in the evaluation using a specially prepared version of the program that recorded the time required to perform actions, the number of unsuccessful attempts to complete instructions, and the number of correct responses to specific questions. The ability of the nurses to "drag and drop" increased significantly from less than 20% to more than 90% (p < .05, Student's t-test). Their knowledge of the definitions of four computer related terms (i.e., trackball, desktop, window, and icon) increased significantly (from 65% to 80%, p < .1). In subjective evaluations, 82% of respondents reported that they enjoyed the lesson and 89% wanted more computer based instructional units to be developed. Use of criterion-referenced testing helped to shed new light on the utility of such computer aided instructional systems. PMID- 7842376 TI - Literature search and retrieval in the workplace. AB - Nurses do not adequately access and use information to enhance knowledge-based practice. A computerized literature search and retrieval system was installed on a selected hospital unit to evaluate its utility in a work setting. Thirty-three nurses were taught how to use six CD-ROM bibliographic and full-text databases, electronically request articles from the librarian, and to critique the literature. The training program was evaluated by questionnaire and subsequent use of the system. Qualitative data regarding the perceived impact were collected using focus groups. The Michigan Organizational Assessment Questionnaire was administered before and after the intervention. Following training, nurses used the system to successfully answer questions related to patient care, general health issues, and education courses. PMID- 7842377 TI - Knowledge engineering of expert systems for nursing. AB - Expert system technology and its derivatives will be core components of future health care information systems. Nursing presently lacks sufficient knowledge engineering resources to develop and implement expert system technology productively. In this article, knowledge engineering and its implications for nursing are described. PMID- 7842378 TI - Applied information technology: a clinical perspective. Feature focus: the continuum of interoperability. PMID- 7842379 TI - Why graduate students should develop computer simulations. PMID- 7842380 TI - Electronic bulletin board systems extend the advantages of telemedicine. PMID- 7842381 TI - Cultured endothelial cells from distinct vascular areas show differential responses to agonists. AB - We compared the ability of cultured endothelial cells isolated from rabbit aorta, vena cava, ventricular chamber, and pulmonary microvasculature to produce relaxing factor(s) in response to acetylcholine (ACh) and bradykinin (BK). Endothelium-denuded rabbit aortic rings were precontracted with 1 microM phenylephrine and superfused at 2 mL/min with Krebs-Henseleit bicarbonate buffer. Rings were exposed to 3-mL bolus control challenges of 1 microM ACh or 1 microM BK. Boluses of ACh or BK were added to dishes of cultured endothelial cells that had been incubated for 45 min in media either with or without 10 microM NG-nitro L-arginine (NNLA). The resulting solution was applied over the rings within 8 s. Only left ventricular endothelial cells stimulated with ACh and BK, and pulmonary microvascular endothelial cells stimulated with BK produced products that relaxed rings by approximately 6 +/- 2%. Incubation with NNLA attenuated these relaxations. Our findings indicate there are differences in the abilities of endothelial cells of different anatomical origins to release nitric oxide derived relaxing factors in response to ACh and BK. PMID- 7842382 TI - Chronic verapamil treatment attenuates the negative inotropic effect of ethanol in diabetic rat myocardium. AB - It is well established that cardiomyopathy is a consistent feature of diabetic myocardium and that alcohol consumption increases the risk of cardiovascular disease among diabetic subjects. The objective of this investigation was to determine whether acute or chronic verapamil treatment attenuates the negative inotropic effect of ethanol (EtOH) in the diabetic rat heart. Wistar rats were made diabetic with streptozotocin (55 mg/kg, iv). Left-ventricular papillary muscles, from normal and diabetic (8 weeks) rats, were superfused with Tyrode's solution at 30 degrees C while driven at 0.5 Hz. A subgroup of diabetic and normal animals received daily injections of verapamil (8 mg/kg, ip; 8 weeks), whereas muscles from untreated animals were exposed to verapamil (2 microM) in vitro. Peak tension developed (PTD), time to peak tension (TPT), time to 90% relaxation (RT90), and the maximum velocities of tension development (+VT) and decay (-VT) were determined in the absence and presence of clinically relevant concentrations of EtOH (80-240 mg/dL, i.e., 17.4-52.1 mM). Ethanol at 80 mg/dL reduced PTD, +VT, and -VT only in preparations from diabetic animals. Higher concentrations of EtOH (120-240 mg/dL) decreased PTD, TPT, +VT, and -VT. The negative inotropic effect of EtOH (240 mg/dL) was attenuated only in diabetic myocardium chronically treated with verapamil, whereas acute verapamil treatment potentiated the negative inotropic effect of EtOH in both normal and diabetic myocardium. Thus, chronic verapamil therapy diminishes the negative inotropic effect of EtOH in diabetic myocardium and acute verapamil treatment exaggerates it.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7842383 TI - Alpha 2-adrenergic mediation of the effects of angiotensin II on rat renal artery in vitro. AB - Angiotensin II (ANG II) is a major influence on renal blood flow, acting directly on the renal vasculature and upon other controllers. In vivo observations suggest that ANG II affects renal artery resistance, although explicit in vitro studies have produced negative results. To resolve this issue, potential interactive effects of ANG II on renal artery in vitro were tested. Renal arteries were harvested from ketamine-anesthetized Sprague-Dawley rats and perfused in vitro at constant flow. Resistance was determined from the axial pressure drop while downstream pressure was held constant at approximately 80 mmHg (1 mmHg = 133.3 Pa). ANG II, per se, had only a trivial effect on arterial diameter (-5.5 +/- 1.5% at 10(-7) M ANG II) and failed to affect resistance at concentrations ranging from 10(-11) to 10(-7) M. Norepinephrine caused strong concentration dependent constriction, increasing resistance from 0.32 +/- 0.04 to 1.86 +/- 0.73 mmHg.mL-1.min at 10(-6) M and 3.27 +/- 0.88 mmHg.mL-1.min at 10(-5) M. In the presence of 10(-8) M ANG II, these responses were significantly increased to 3.31 +/- 1.00 and 5.02 +/- 1.22 mmHg.mL-1.min, respectively. Similarly, in the presence of 10(-6) M norepinephrine, ANG II caused significant, concentration dependent constriction of renal artery. In a separate experiment, 10(-7) M yohimbine, a relatively specific antagonist of alpha 2-adrenergic receptors, reversed the resistance increment due to ANG II, but not that due to norepinephrine. When yohimbine was applied before norepinephrine and ANG II, it did not affect the response to norepinephrine, but again blocked potentiation of the response by ANG II.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7842384 TI - Hyperplastic effects of aerosolized sodium metabisulfite on rat airway mucus secretory epithelial cells. AB - The ability of aerosolized sodium metabisulfite to induce hypertrophic and hyperplastic changes in rat airway secretory epithelial cells was investigated. A 10% solution of sodium metabisulfite was aerosolized into a Plexiglas exposure chamber, using an ultrasonic humidifier. The level of SO2 gas generated by this apparatus was measured to be 500 ppm. Measured levels of neutral and acidic mucous glycoproteins in extracts from tracheal and lung tissue were used as indices of hypertrophic (increases in mucus content per cell) and hyperplastic (increased numbers of cells containing mucus per gram of tissue) changes occurring in mucus-secreting cells of the airways. Exposing rats to sodium metabisulfite for 3 weeks resulted in profound increases in total neutral mucous glycoproteins found in tracheal and lung tissue (6.2-fold and 10.1-fold, respectively), compared with the H2O-treated counterparts. Total acidic mucous glycoproteins were significantly elevated in lung tissue only (13.5-fold). In addition, neutral and acidic mucous glycoproteins were elevated 20-fold and 9 fold, respectively, in bronchoalveolar lavage samples prepared from sodium metabisulfite exposed animals. These results indicate that aerosolized sodium metabisulfite may be a useful agent for developing small animal models of mucus hypersecretion. PMID- 7842385 TI - Cardiovascular and single-unit responses to subfornical organ stimulation are abolished by pentobarbital anesthesia. AB - The nature of reflex cardiovascular responses to electrical stimulation in the central nervous system has been suggested to be influenced by anesthetic. We report here that pressor responses to subfornical organ stimulation observed in urethane-anesthetized rats (n = 4) are absent, or reversed in animals under pentobarbital anesthesia (n = 5; Student's t test, p < 0.01, compared with urethane anesthesia. Single-unit recordings from identified hypothalamic neurons (n = 60) showed that the activation of these cells, by subfornical organ efferents, with systemic angiotensin observed in urethane-anesthetized animals (29 of 39 cells tested), was not observed under pentobarbital anesthesia (2 of 21 cells tested). Bicuculline treatment of pentobarbital-anesthetized rats (n = 5) restores small pressor responses to subfornical organ stimulation (t test, p < 0.05), suggesting that potentiated GABA inhibition underlies this modified state under pentobarbital anesthesia. PMID- 7842386 TI - Brown adipose tissue thermogenesis evoked by medial preoptic stimulation is mediated via the ventromedial hypothalamic nucleus. AB - Experiments were designed to determine if a functional ventromedial hypothalamic nucleus was required for the activation of brown adipose tissue thermogenesis evoked by medial preoptic stimulation. Male, urethane-anesthetized Long--Evans rats, maintained at 37 degrees C, had temperatures (thermistor probes for gastrocnemius, Tm; intrascapular brown adipose tissue, TIBAT; colonic, Tc; and tail, Tt), gastrocnemius electromyogram activity (via stainless steel recording electrodes), and systemic blood pressure and heart rate (via a femoral arterial catheter) measured before and after a series of unilateral medial preoptic electrical stimulations (monophasic 0.5-ms pulses of 300 microA at 50 Hz for 30 s). Measurements were made (i) after an initial control medial preoptic electrical stimulation, (ii) after medial preoptic stimulation was applied 1 min following an intracranial injection of 300 nL of sterile saline or buffered 2% Lidocaine into the ipsilateral posterior hypothalamic nucleus or the ipsilateral ventromedial hypothalamic nucleus, and (iii) after recovery medial preoptic stimulation 45 min after Lidocaine was injected into the ventromedial hypothalamic nucleus. TIBAT and blood pressure rose significantly (p < 0.05) above the corresponding prestimulation control values with all protocols, except when Lidocaine was injected into the ventro-medial hypothalamic nucleus prior to medial preoptic stimulation. Shivering (electromyogram) activity was not evoked following medial preoptic stimulation and Tm and Tt did not significantly change from the corresponding prestimulation values. A recovery medial preoptic stimulation 45 min after Lidocaine treatment of the ventromedial hypothalamic nucleus again evoked significant increases in TIBAT above the core temperature, similar to the rise in TIBAT seen after the first control medial preoptic stimulation.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7842387 TI - Ultrastructure of interstitial cells of Cajal in the canine distal esophagus. AB - The ultrastructure of canine distal esophagus was studied focusing on interstitial cells of Cajal (ICC) and their relationships to nerves and muscle. The distal esophagus consisted of two muscle layers composed of intertwining skeletal and smooth muscle bundles. The ICC formed an interconnecting network and were an integral part of these structures. The ICC communicated with one another and with adjacent smooth muscle cells through numerous gap junctions. The morphology of individual ICC resembled that observed in other gut regions. All interstitial cells were densely innervated. The highest density of ICC, just proximal to the lower esophageal sphincter, coincided with the previously reported highest incidence of occurrence of electrical slow wave type action potentials. Examination of a large number of structural associations of ICC led us to conclude that in the distal esophagus, two networks of ICC and nerves exist, one associated with the inner muscle layer, another associated with the outer muscle layer. These networks are not sheet-like structures, such as the network of ICC in the myenteric plexus or deep muscular plexus of the small intestine, but are three dimensional and are interspersed throughout both muscle layers. The networks do not extend into Auerbach's plexus. The main branches of the networks run along the long axis of the esophagus and seem ideally suited to facilitate communication in this direction. These observations suggest that esophageal interstitial cells are structurally organized in such a manner that they may play a role in pacemaking and neural control of esophageal motility. PMID- 7842388 TI - Signal transduction events involved in bombesin-stimulated gastrin release from human G cells in culture. AB - The mechanism of action of bombesin on human antral gastrin cells in culture was evaluated by modulating internal and external calcium levels and intracellular enzyme activities. Increasing extracellular calcium increased basal gastrin release and had an additive effect on bombesin-stimulated gastrin release. Removing extracellular calcium had no effect on bombesin-stimulated gastrin release. Inhibiting the activities of phospholipase C by neomycin and protein kinase C by staurosporine had no effect on basal release but decreased bombesin stimulated gastrin release by up to 50%. Chelating intracellular calcium with BAPTA-AM also decreased bombesin-stimulated release by up to 50%. Increasing intracellular calcium levels with thapsigargin did not alter basal gastrin release and had no effect on bombesin-stimulated release. The preparation utilized was a mixed, primary cell culture. To demonstrate direct activation of gastrin cells, alterations in internal calcium levels were monitored by dual excitation microfluorometry of fura 2-AM loaded cells. The individual cells were subsequently identified by immunocytochemistry, confirming that bombesin directly increases calcium levels in the G cells. The data indicated that bombesin acting directly on the G cells activated both arms of the phosphoinositol signalling pathway and that both activities were required for optimal gastrin release. PMID- 7842389 TI - A role for thyroid hormones in cold-induced elevation of blood pressure and cardiac hypertrophy. AB - The systolic blood pressures of two groups of rats that were exposed to cold (5 degrees C) for 4 weeks were elevated significantly above that of warm-acclimated controls maintained at 24 degrees C. At this time these groups were given the antithyroid drug aminotriazole in their food at 0.3 g/kg. At the same time, one group was given 15.8 micrograms thyroxine (T4)/kg body mass per day, while the second received 31.6. The doses were chosen as replacement (15.8 micrograms/kg) and twice replacement (31.8 micrograms/kg) for the rats. The results of the study revealed that both groups receiving aminotriazole and T4 had reductions in blood pressure within 1 week of initiation of treatment. Blood pressures reached control level after 5 weeks. Cardiac hypertrophy accompanying cold-induced hypertension was reduced with the lower dose of T4 and prevented with the higher dose. Serum concentrations of T4 and triiodothyronine (T3) in the two treated groups were reduced, while serum thyroid-stimulating hormone concentration and thyroid mass were increased above that of the warm-acclimated control group. This suggests that the rats were hypothyroid relative to the warm-acclimated control group. However, the treated rats grew at the same rate as nontreated, cold exposed controls and had similar food and water intakes, a similar dipsogenic response to acute administration of isoproterenol, and similar colonic temperatures.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7842390 TI - Tyrosine kinase inhibitors and the contractile action of G-protein-linked vascular agonists. AB - In a porcine coronary artery helical strip preparation, the tyrosine kinase inhibitors genistein and tyrphostin (AG82) attenuated the contractile actions of angiotensin II, arginine vasopressin, epidermal growth factor--urogastrone, noradrenaline, and prostaglandin F2 alpha, under conditions where contractions due to acetylcholine and KCl were not affected. Both genistein and tyrphostin also caused a selective inhibition of angiotensin II action in rat aorta helical strips, without affecting KCl-mediated contractions. The IC50 values for the inhibition of contraction in the porcine coronary artery were in the range of 2-5 microM for genistein and 8-15 microM for tyrphostin. Comparable IC50 values were observed for the inhibitory effects of genistein on angiotensin II and prostaglandin F2 alpha action in the rat aorta, whereas much higher tyrphostin concentrations (IC50 > or = 40 microM) were required to block angiotensin II action in this preparation. Angiotensin II caused an elevation of phosphotyrosyl protein (antiphosphotyrosine Western blot) in the porcine coronary artery, which was reversed by genistein. In addition, porcine coronary artery derived membrane and cytosolic fractions exhibited sarcoma virus related tyrosine kinase activity, which was inhibited by both genistein and tyrphostin. Our data (i) document the selective inhibition by genistein and tyrphostin of the contractile action of some, but by no means all, G-protein-linked vascular agonists in porcine and rat arterial preparations, (ii) establish the presence of sarcoma virus related tyrosine kinase activity in the porcine coronary artery, and (iii) demonstrate angiotensin II mediated increases in phosphotyrosyl protein content in porcine coronary artery tissue. These data support the hypothesis that selected G-protein linked contractile vascular agonists may act in part via the stimulation of nonreceptor tyrosine kinases. The data also indicate the complex actions of the tyrosine kinase inhibitors, even for the same agonist acting in vascular preparations obtained from different species. PMID- 7842391 TI - Neurogenically evoked cerebral artery constriction is mediated by neuropeptide Y. AB - We examined the proposal that neuropeptide Y (NPY) released from nerve endings constricts cerebral arteries. Neurogenic vasoconstriction of rabbit basilar arteries is of adrenergic origin but is resistant to blockade by classical alpha adrenoceptor antagonists. Tetrodotoxin-sensitive contractions of the rabbit basilar artery were elicited by transmural stimulation of nerves. The contractions were inhibited by incubation of tissues with an antiserum to NPY (0.32 microL undiluted immune serum/mL); addition of prazosin (0.1 microM) did not further attenuate the nerve-mediated contraction. The antiserum to NPY also antagonized vasoconstriction due to exogenously administered NPY and was without effect on responses due to histamine or angiotensin. Our results indicate that neurogenic vasoconstriction of the rabbit basilar artery is largely due to the release of NPY and that it is unlikely that other vasoconstrictors contribute significantly to the increased tone. PMID- 7842392 TI - Effect of nitroprusside and endothelium-derived products on slow-twitch skeletal muscle function in vitro. AB - We tested the hypothesis that the products of endothelial cells alter the force developed by skeletal muscle. Since these products have a very short half-life and are produced in a low concentration, we developed a superfused muscle preparation in which the mouse soleus (SOL) was superfused at 10.5 mL/min with Krebs-Henseleit buffer (KH) (27 degrees C; pH 7.4), gassed with 95% O2-5% CO2. To evaluate this preparation, we compared the superfused muscles with muscles submerged in a bath. All muscles were stimulated at 50 Hz for 500 ms once every 30 s. Submerged SOL developed 275 +/- 15 mN/mm2, while the superfused muscles developed 271 +/- 15 mN/mm2. Both submerged and superfused SOL consistently increased rest tension to a 3-mL bolus of 25 mM caffeine and decreased developed force when exposed to a 3-mL bolus of 30 mM diprotonated phosphate (pH 6.4). We then exposed superfused SOL to 3 mL bolus injections of KH, 1 microM acetylcholine, 30 mM nitroprusside (a source of nitric oxide), and the supernatant from dishes of cultured endothelial cells from rabbit aorta challenged with acetylcholine. Nitroprusside and the supernatant significantly improved force maintenance, compared with KH and acetylcholine, respectively. Since the supernatant should contain products of endothelial cells, these products appear to have a positive effect on contractile function in slow-twitch skeletal muscle that is similar to the effect of nitric oxide. PMID- 7842393 TI - The basal endothelial inhibitory influence on vascular tone is not affected in nitroglycerin-tolerant rat aorta. AB - Prolonged exposure to nitrovasodilators produces tolerance and dependence. Nitrovasodilators exert their action on vascular smooth muscle cells by activation of guanylyl cyclase. Nitrates share this mechanism with endothelial NO, which exerts a continuous inhibitory influence on vascular tone. Whether the basal inhibitory endothelial influence might be affected in rat aorta exposed in vitro to a tolerance-inducing concentration of nitroglycerin was investigated in this study. It was found that the basal inhibitory influence, assessed as its inhibitory influence on norepinephrine-induced contraction, and as the contractile effect of N-nitro-L-arginine methyl ester or methylene blue, was the same in nitroglycerin-tolerant and control aortic rings. Our results give an indication that changes in basal inhibitory endothelial influence are not involved in the phenomena of nitrate tolerance and nitrate dependence. PMID- 7842394 TI - Barbiturate attenuation of agonist affinity in cerebral arteries correlates with anesthetic potency and lipid solubility. AB - Barbiturates are known to reduce agonist sensitivity (EC50) in vascular smooth muscle; we provide evidence that the reduced agonist sensitivity can be correlated with a reduction in agonist affinity for its receptor. The histamine receptor was chosen since this agonist caused a consistent and maximum contraction of the cerebral artery used in this study. Segments of the basilar artery of white New Zealand male rabbits were set up in a small-vessel myograph in physiological salt solution, kept at 37 degrees C, pH 7.4, and bubbled with a 95% oxygen and 5% carbon dioxide gas mixture. The equilibrium dissociation constant (KA) of histamine for its receptor was calculated according to Furchgott's method by making three concentration-response curves to histamine: control, in the presence of phenoxybenzamine (0.02 microM), and after addition of a barbiturate in concentrations between 0.1 and 1.0 mM. All barbiturates tested, i.e., thiamylal, thiopental, pentobarbital, and phenobarbital, significantly reduced both histamine sensitivity and affinity. There is a significant correlation between histamine sensitivity and receptor affinity for histamine in a series of arterial segments from different animals. The attenuation of both pharmacological properties was consistent with the known rank order of anesthetic potency and with lipophilicity (r = 0.98; p < 0.05). Receptor reserve did not correlate with sensitivity. Thus, most of the change in receptor sensitivity was due to a change in agonist affinity. We suggest that barbiturates alter agonist receptor affinity by causing a perturbation in the membrane lipid environment of the receptor, leading to a conformational change, although alterations in intracellular mechanisms cannot be excluded. PMID- 7842395 TI - Hemin inhibits protein synthesis and degradation in isolated brown adipose tissue mitochondria. AB - The primary objectives of this work were to evaluate the effects of hemin on protein synthesis and degradation in isolated brown adipose tissue (BAT) mitochondria. Exposure of mice to a cold environment (4 degrees C) caused a significant increase in 5'-aminolevulinate synthase (ALV synthase) activity in BAT coincident with an increase in the tissue mitochondrial protein content. Hemin caused significant inhibition of protein synthesis and of ATP-stimulated proteolysis in isolated BAT mitochondria. These effects were specific, as protoporphyrin IX, a precursor of heme, increased protein synthesis and had no effect on ATP-stimulated degradation of mitochondrial translation products. The end products of degradation of proteins synthesized within isolated mitochondria were amino acids released to the outside of the organelles. Hemin appeared to inhibit an early step of the degradation pathway, as it caused a significant reduction in labelled methionine release from the organelles but no accumulation of peptides. Hemin caused significant inhibition of ATP-stimulated hydrolysis of labelled casein by soluble mitochondrial fractions, while addition of protoporphyrin IX was much less effective. In contrast, protease activity associated with mitochondrial membranes was almost equally sensitive to inhibition by hemin and protoporphyrin IX. These results suggest that heme may play a role in BAT mitochondriogenesis by its action on protein synthesis and degradation within the organelles. PMID- 7842396 TI - Reevaluation of the balloon in gastrointestinal manometry. AB - Although the flow-through catheter (FTC) system has been useful and satisfactorily accurate for gastrointestinal manometry, we hypothesized that a cylindrical, liquid-filled balloon would also accurately reflect stress imposed by a sphincter. Latex balloons were fitted over the side ports of a closed-end catheter. The responses of the balloon and FTC system were compared in a cylindrical chamber commonly identified as a Starling resistor. Independent, constant-pressure sources were used to control both the inwardly directed "contact pressure" of the Starling resistor (Ps) and the intraluminal fluid pressure (P(lum)). The balloon transducers responded linearly and accurately (slope = 1) to changes in both Ps and P(lum) within the test range (0-200 mmHg, 0 26.7 kPa). When either P(lum) or Ps was held constant and the other changed, the balloon transducers always accurately measured the higher of the two pressures. Although the performance of the FTC system was improved after the Starling resistor was lubricated, the FTC system sometimes responded inaccurately to changes in Ps. The ability of the balloon transducers to measure the contractions of the lower esophageal sphincter and of the esophagus was demonstrated. We conclude that the balloon transducer can measure sphincter pressure accurately and suggest that, in certain circumstances, it might be advantageous relative to the FTC system. PMID- 7842397 TI - Plasma endothelin-1 response to acute hypotension induced by vasodilating agents. AB - Cyclic GMP (cGMP) dependent vasodilating agents (natriuretic peptides, nitric oxide) inhibit secretion of endothelin-1 (ET-1) in cultured endothelial cells. However, in circulatory conditions associated with acute hypotension, a marked increase in plasma ET-1 has repeatedly been observed. Therefore, after administration of cGMP-dependent agents in hypotensive dose, the net effect of these opposing influences on ET-1 release may shed light on the mechanisms determining circulating levels of this peptide. We have studied the effect of a hypotensive dose of atrial natriuretic peptide (n = 16), 8-Br-cGMP (n = 5), and papaverin (n = 7) on plasma ET-1 in anesthetized dogs. All agents produced marked increases in the peptide level at the end of infusion (178, 280, and 240% of the last preinfusion level, respectively) and a mean arterial blood pressure (MAP) decrease of 19, 18, and 42 mmHg (1 mmHg = 133.3 Pa), respectively. In all three protocols, plasma ET-1 continued to rise when the hypotensive agent was discontinued and remained elevated for 2-3 h postinfusion, even though MAP was normalized. There was a close positive correlation between the maximal increment in plasma ET-1 and the maximal decrease in MAP (r = 0.67, p < 0.001). These results show that acute hypotension due to directly acting vasodilators is a potent stimulus for systemic release of ET-1, even when due to agents known to inhibit ET-1 production in cultured endothelial cells.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7842398 TI - Diminished diabetogenic effect of streptozotocin in adrenodemedullated rats. AB - Although stress is suspected to play a role in the development of diabetes mellitus, no direct experimental evidence for involvement of the adrenal medullae in onset of the disease has yet been found. We recently observed that, in comparison with sham-operated rats, fewer adrenodemedullated rats become diabetic after an i.v. injection of streptozotocin (STZ); thus, the present study examined the role of the adrenal medullae in the development of experimental diabetes. Male Wistar rats were surgically adrenodemedullated (ADM) or sham-operated (SHAM). After a 3-week recovery period, they were injected with 40 mg STZ/kg freshly dissolved in citrate buffer or buffer alone. A 1-mL arterial blood sample was withdrawn 12 days later in previously cannulated animals; then the rats were killed and their pancreas was removed. The plasma glucose levels were lower in ADM rats injected with buffer alone than in their SHAM counterparts (7.7 +/- 0.1 vs. 8.5 +/- 0.1 mmol/L; p < 0.05). The glucose levels were higher (p < 0.001) in both groups of STZ-treated rats, with values 28% lower in ADM than in SHAM rats (14.7 +/- 1.6 vs. 18.8 +/- 1.2 mmol/L; p < 0.03). Whereas plasma insulin levels did not differ between ADM and SHAM rats injected with buffer alone (431 +/- 38 vs. 428 +/- 35 pmol/L; p > 0.05), they were diminished in SHAM animals injected with STZ (292 +/- 37 vs. 428 +/- 35 pmol/L; p < 0.02).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7842399 TI - Sarcoplasmic reticulum Ca-release channel and ATP-synthesis activities are early myocardial markers of heart failure produced by rapid ventricular pacing in dogs. AB - The contraction-relaxation cycle of the heart is dependent on a cycle of ATP production and utilization and a cycle of Ca uptake and Ca release by the sarcoplasmic reticulum (SR). Heart failure (HF) is associated with abnormalities of myocardial Ca and ATP cycling, but the time course of their development is unknown. This study tested the hypothesis that, compared with ATP-utilizing and Ca-uptake activities, decreases in ATP-synthesis and Ca-release activities occurred earlier in the development of HF and persisted longer during recovery from HF. HF was induced by right ventricular pacing of dogs at 250 beats/min. Dogs were studied after 1 week of pacing (n = 8, early HF), at HF (n = 11, severe HF), and 4 weeks after cessation of pacing (n = 9) and were compared with dogs not subjected to pacing. At early HF, there were decreased activities (p < 0.05) of the SR Ca-release channel (rate constant from 199 +/- 36 x 10(-4) to 90 +/- 16 x 10(-4) s-1), mitochondrial ATP synthesis (from 11.2 +/- 2.4 to 7.0 +/- 2.2 international units (IU)/g), and creatine kinase (CK) from 2028 +/- 266 to 1811 +/- 79 IU/g). The decreased Ca-channel activity was due to a 32% decrease in maximal activity (rate constant from 249 +/- 50 x 10(-4) to 170 +/- 29 x 10(-4) s 1) and to a 2-fold increase (from 19.1 +/- 12.4 to 42.0 +/- 14.2%) in inhibition of maximal channel activity (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7842400 TI - The human-genome project and Pandora's box. PMID- 7842401 TI - Higher levels of interleukin-6 in cystic fluids from patients with malignant versus benign ovarian tumors correlate with decreased hemoglobin levels and increased platelet counts. AB - BACKGROUND: Recently, high pretreatment platelet counts and low pretreatment hemoglobin levels were found to be negative prognostic factors in patients with ovarian cancer. Interleukin-6 (IL-6) is a multifunctional cytokine with a diversity of functions leading to the induction of C-reactive protein (CRP), increased platelet counts, and low hemoglobin levels. Different epithelial ovarian cancer cell lines are found to produce varying amounts of IL-6. In this study, a possible relationship between IL-6 levels in cystic fluids of benign and malignant ovarian tumors and pretreatment serum CRP, platelet counts, and hemoglobin levels was evaluated. METHODS: A bioassay and enzyme-linked immunosorbent assay (ELISA) were performed to determine the IL-6 levels in cystic fluids and serum from 42 patients with benign and malignant ovarian tumors. RESULTS: The median IL-6 level was higher in cystic fluids of malignant tumors (n = 21) when compared with cystic fluids of benign tumors (n = 21) (P < 0.01 for bioassay and ELISA). Serum IL-6 levels in patients with malignant tumors were not significantly higher compared with IL-6 levels in patients with benign tumors, whereas CRP levels were higher in patients with malignant tumors (P < 0.01). Cystic fluid IL-6 levels were related to serum CRP levels (r = 0.60, P < 0.01 [bioassay]; r = 0.41, P < 0.01 [ELISA]), and were related inversely to hemoglobin levels (r = -0.57, P < 0.01 [bioassay]; r = 0.54, P < 0.01 [ELISA]). CONCLUSIONS: IL-6 levels are higher in cystic fluids of malignant ovarian tumors compared with benign tumors. The relationship of cystic fluid IL-6 levels with CRP, platelet counts, and hemoglobin levels suggests a possible causative role of tumor-derived IL-6 in the appearance of general side effects of ovarian cancer, which recently have been recognized as prognostic factors. PMID- 7842402 TI - Immunohistochemical study of type I collagen and type I pN-collagen in benign and malignant ovarian neoplasms. AB - BACKGROUND: Type I collagen is a major constituent of the interstitial connective tissue. Although ovarian carcinoma is known to induce the expression of type I collagen in the peritoneal cavity, the distribution and metabolic activity of this collagen in ovarian tumor tissue are not known. METHODS: The distributions and staining intensities of different molecular forms of type I collagen in ovarian neoplasms were studied immunohistochemically with antibodies to the aminoterminal propeptide of type I procollagen (PINP) and the cross-linked carboxyterminal telopeptide of type I collagen (ICTP), reflecting the presence of newly synthesized and old, cross-linked type I collagen, respectively. RESULTS: A regular pattern of moderately staining, relatively uniform fibers was observed in the stroma of benign serous and mucinous cystadenomas, indicating limited participation in tumor growth. The staining was accentuated subepithelially in borderline epithelial neoplasms and in well differentiated cystadenocarcinomas, suggesting induction of the stromal collagen synthesis by the tumor cells. Fewer degraded collagen fibers were found in moderately differentiated carcinomas, most likely because of enzymatic degradation of the stroma surrounding the neoplasms during tumor spread. Strongly staining, irregular collagen fibers occurred closely around islets of tumor cells in undifferentiated malignant neoplasms and in metastases of ovarian carcinomas; also, intracellular staining was present in part of the malignant cells. In most cases, the staining reactions obtained with the two different antibodies were similar, probably indicating rapid processing of the newly synthesized type I collagen (indicated by PINP) to a maturely cross linked form (indicated by ICTP). CONCLUSIONS: Synthetic and degradative processes are typical of the collagenous matrix in malignant ovarian tumors. Aberrant expression of type I collagen may occur in anaplastic ovarian carcinomas. PMID- 7842403 TI - Orchiectomy after chemotherapy in patients with metastatic testicular cancer. Is it indicated? AB - BACKGROUND: A small proportion of patients with testicular germ cell tumors present with widely metastatic disease and are treated initially with chemotherapy. Little is known about the efficacy of systemic chemotherapy in eradicating the primary testicular germ cell cancer; however, there is concern that the testis may act as a sanctuary site for germ cell cancer in these patients, and orchiectomy, is, therefore, recommended after chemotherapy. METHODS: The results from a clinical and pathologic review of 24 patients who underwent delayed orchiectomy after chemotherapy are presented. The testicular pathologic findings are correlated with those in extragonadal masses and also with a blinded review of postchemotherapy testicular ultrasound scans. RESULTS: The most common testicular pathological finding was a dense fibrous scar that was found in all patients. Three patients had persistent testicular germ cell cancer, six had mature teratoma, and one had carcinoma in situ. There was a strong concordance between the major testicular pathologic findings and those in the resected extragonadal masses. All three patients with persistent testicular germ cell cancer subsequently had disease progression in the extragonadal sites. Testicular ultrasound examination did not distinguish accurately between residual tumor or scar in the testis. CONCLUSION: Persistence of the primary testicular germ cell cancer is most likely due to the same heterogeneous response to chemotherapy observed in different metastatic sites. Because current imaging techniques cannot identify accurately those patients with residual testicular germ cell cancer or related testicular abnormalities that may predispose to subsequent relapse, orchiectomy after chemotherapy remains appropriate. PMID- 7842404 TI - Simultaneous radiochemotherapy in the treatment of inoperable, locally advanced head and neck cancers. A single-institution study. AB - BACKGROUND: Patients with advanced, inoperable head and neck cancers have cure rates of approximately 10-15%. In these patients, concomitant chemoradiotherapy seems to improve local control and survival. 5-Fluorouracil (5-FU) administered by continuous infusion and cisplatin plus concomitant conventional radiation therapy may be promising in treating advanced, inoperable head and neck cancers. METHODS: Forty-five evaluable patients with primary nonmetastatic, inoperable head and neck cancers were treated. From January 1987 to April 1988, the patients were treated with cisplatin plus radiation therapy (Group 1) and from May 1988 to November 1990, they were treated with the same combination plus 5-FU, given in continuous infusion (Group 2). Clinical and pathologic responses were assessed after radiation therapy was completed. Patients who relapsed underwent salvage surgery, if possible. The disease free and overall survival rates of the patients were evaluated. RESULTS: The overall response rate (complete and partial response) was 93%, 60% of which comprised complete remissions. Despite the high response rates obtained in the two groups, the time to progression for complete responses and the median survival time were unsatisfactory (13 [Group 1] and 10 months [Group 2] and 17 [Group 1] and 16 months [Group 2], respectively). The toxicity rate from the two treatments was not relevant. A Grade II mucositis, according to the World Health Organization, was found in 25 patients, and the treatment was interrupted for 7-10 days in 5. CONCLUSIONS: In this study, despite an improvement in the number of complete responses, the chemotherapeutic regimen with or without 5-FU did not prolong the overall patient survival significantly. PMID- 7842405 TI - The hematologic toxicity of interleukin-2 in patients with metastatic melanoma and renal cell carcinoma. AB - BACKGROUND: High dose interleukin-2 (IL-2) has been found to produce durable antitumor responses in some patients, benefiting most greatly those patients with melanoma and renal cell carcinoma. In this paper, the hematologic toxicity and changes resulting from high dose IL-2 alone administered by intravenous bolus are discussed. METHODS: One hundred ninety-nine consecutive patients treated with high dose IL-2 alone from January 1, 1988 to December 31, 1992 were included in this study. All patients had a diagnosis of metastatic melanoma or metastatic renal cell carcinoma and were treated at the National Cancer Institute (Bethesda, MD). RESULTS: Anemia, requiring erythrocyte transfusions, occurred in 14% of all treatment courses, with a median of two units of erythrocytes transfused. Severe leukopenia ( < 1,000 leukocytes/mm3) was rare (1.5% of all patients) and was not associated with any infectious complications. Severe thrombocytopenia ( < 30,000 platelets/mm3) occurred in 2.2% of all treatment cycles, with two patients experiencing a grade 3 hemorrhage, defined as gross blood loss, and one patient experiencing a grade 4 hemorrhage, defined as a debilitating blood loss. Defects in the coagulation pathway were common: abnormal partial thromboplastin time and prothrombin time values occurred in 64% and 25% of the treatment cycles, respectively. In addition, a mean clearance of 93% of lymphocytes from the peripheral blood was observed within 24 hours after initiating IL-2 therapy. This was followed by rebound lymphocytosis to a mean of 198% of baseline on posttreatment Day 4. There were no treatment-related deaths. CONCLUSIONS: During IL-2 therapy, adverse sequelae of anemia, thrombocytopenia, coagulopathy, and leukopenia were usually mild, transient and rarely limited therapy. A profound decrease in lymphocytes in the peripheral circulation occurred within 24 hours after initiating therapy, with a rebound occurring after stopping IL-2. No specific hematologic parameter was associated significantly with a patient's increased probability of responding to therapy. PMID- 7842406 TI - A multicenter phase II clinical trial using dacarbazine and continuous infusion interleukin-2 for metastatic melanoma. Clinical data and immunomonitoring. AB - BACKGROUND: Treatment of patients with metastatic melanoma with either dacarbazine or recombinant interleukin-2 (rIL-2) resulted in a response rate of approximately 15%. This study investigates the possible synergism of this chemoimmunotherapy combination. METHODS: Fifty-seven patients with metastatic malignant melanoma received 135 treatment cycles. Treatment consisted of dacarbazine (Days 1-5) at 250 mg/m2 by a 30-minute slow infusion, and interleukin 2 by constant intravenous infusion (Days 21-25 and 28-32) at 18 x 10(6) IU/m2/24 hours. After this treatment cycle, a 1-week rest was scheduled, and in the absence of undue toxicity or tumor progression, patients received a second cycle as described. Maximum treatment consisted of two induction and four maintenance cycles. In a subgroup of patients, immunoparameters were analyzed to identify prognostic factors. Standard supportive care was given. RESULTS: Common toxicities included fever, hypotension, nausea/vomiting, anemia, leukopenia, thrombocytopenia, an increase in serum lactic dehydrogenase levels and diarrhea. The objective response rate was 15.8% (one complete response and eight partial responses). In 14 patients, the disease stabilized. For patients who had an objective response, median response duration was 13.9 months (6.3-39.0+), and median survival was 19.0 months (6.3-39.0+); overall survival was 9.3 months (0.8 39.0+). Immunomonitoring did not reveal any relevant prognostic factors for overall response. CONCLUSIONS: Sequential treatment with dacarbazine and rIL-2 is feasible and produces long-lasting responses in a minority of patients. PMID- 7842407 TI - Survival of infants with malignant astrocytomas. A Report from the Childrens Cancer Group. AB - BACKGROUND: Very young children with central nervous system malignant brain tumors have a poor prognosis. As compared with older children, survival is less likely, and those children who do survive frequently have severe impairment of growth and cognitive abilities, resulting partly from treatment with radiotherapy. Therefore, an intensive chemotherapeutic regimen was used to treat children younger than 2 years of age with a diagnosis of malignant astrocytomas. PATIENTS AND METHODS: Thirty-nine children younger than 24 months of age who were diagnosed with malignant astrocytoma were treated on a Childrens Cancer Group protocol with an eight-drug chemotherapeutic regimen (vincristine, carmustine, procarbazine, hydroxyurea, cisplatin, cytosine arabinoside, prednisone, and dimethyl-triazenoimidazole-carboxamide) after surgery and postoperative staging. Radiation therapy was to be deferred until the completion of chemotherapy. RESULTS: The objective response rate after two cycles of chemotherapy was 24%. Most patients did not receive radiotherapy. Progression-free survival (PFS) and survival at 3 years was 36% (standard error, 8%) and 51% (8%), respectively. The PFS of those children with anaplastic astrocytoma was 44% (11%), significantly better than that of glioblastoma multiforme (GBM) (0%). Extent of resection was not associated significantly with PFS, but tumors within the cerebral hemispheres were associated with a more favorable prognosis. Tumor progression occurred locally in almost all cases and early in treatment (median PFS, 8 months). CONCLUSION: Chemotherapy appears to be effective primary adjuvant treatment for some very young children with anaplastic astrocytomas. Overall, however, survival remains poor, especially for children with GBM. Strategies to improve outcome require early intervention, because tumor progression occurs soon after diagnosis in the majority of patients. PMID- 7842408 TI - Optic pathway and hypothalamic/chiasmatic gliomas in children younger than age 5 years with a 6-year follow-up. AB - BACKGROUND: Gliomas of the hypothalamus and optic pathways (H/OPG) comprise 5% of pediatric intracranial tumors, present most frequently in patients younger than age 5 years, and may have a more aggressive course in younger children. This study examined clinical characteristics and consequences of treatment of young children diagnosed with H/OPG: METHODS: The authors reviewed the course, treatment, and outcomes of 46 children diagnosed with H/OPG younger than age 5 years; the median follow-up was 72 months. The median age at diagnosis was 27 months. RESULTS: Fifteen (33%) of 46 patients had neurofibromatosis-1 (NF-1). Forty children (87%) had tumor progression in the follow-up period, and tumor growth was less common in children with NF-1. Initial therapy was limited to surgical resection in three and radiation in five children. To postpone radiation until after the age of 5 years, initial therapy was limited to chemotherapy in 32 patients. Radiation was not required in 9 of these patients and was postponed for 40 months (mean) in 17. Of the 46 children, 5 died of tumor progression, 4 became blind, and 20 of 34 evaluable patients had endocrine abnormalities. Endocrinopathy did not correlate with therapy. Ten of 17 children evaluated by questionnaire required special education. There was a trend for educational problems to occur in children who were irradiated before the age of 5 years. CONCLUSIONS: Gliomas of the hypothalamus and optic pathways and their treatment cause long term morbidity in young children. Chemotherapy postpones radiation effectively, and this delay may reduce neurologic morbidity; however, 60% of children eventually relapse. By contrast, patients with NF-1 have indolent disease. PMID- 7842409 TI - Chemoimmunotherapy of melanoma. Is it time for phase III trials? PMID- 7842410 TI - Hyperthermia and radiation therapy for inoperable or recurrent parotid carcinoma. A phase I/II study. AB - BACKGROUND: The treatment of advanced, inoperable, or recurrent parotid tumors represents a clinical challenge. The results obtained with conventional radiotherapy are disappointing. To improve the early response and local control of parotid tumors, local microwave hyperthermia was used in combination with ionizing radiation in a biinstitutional Phase I/II study. METHODS: From 1984 to 1991, 13 patients (20 lesions) with advanced (10 lesions) or recurrent (10 lesions) parotid tumors (15 primaries and the remaining 5 nodal metastases), were treated with 300-915 MHz of external hyperthermia after external irradiation. Heat was applied twice weekly at a minimum desired temperature of 42.0 degrees C for 30 minutes at steady state. Ionizing radiation was delivered using photon, electron, or mixed electron-photon beams; the prescribed total dose was 70 Gy and 30 Gy for untreated and previously treated lesions, respectively; the median computed total dose was 66 Gy for previously untreated patients (range, 56-70 Gy) and 30 Gy for previously irradiated patients (range, 28-32 Gy). RESULTS: Acute side effects were limited. Major acute toxicities included three patients (15%) with superficial necrosis, two of three who healed spontaneously in 4 and 6 months. Clinical response evaluated during the third month after the completion of therapy found that 16/20 patients (80%) had a complete response (CR), and 4 (20%) had a partial response. Four out of 16 patients who had CRs (20%) had a local recurrence, resulting in an actuarial local control at 5 years of 62.3 +/- 13.2%. CONCLUSIONS: The combined treatment of local microwave hyperthermia and ionizing radiation proved to be feasible and moderately toxic for patients with advanced, inoperable, or recurrent parotid tumors. Even if clinical result evaluation was not the study endpoint, early response, and 5-year local control rates were encouraging. PMID- 7842411 TI - Flow cytometric analysis of DNA heterogeneity in superficial carcinoma of the esophagus. AB - BACKGROUND: There are few studies of flow cytometric analysis for DNA heterogeneity of patients with superficial carcinoma of the esophagus limited to the epithelium or superficially invading the lamina propria or submucosa. METHODS: Flow cytometric analysis of cellular DNA content was performed on superficial carcinomas of the esophagus using paraffin embedded blocks of the surgically resected specimens from 56 patients. To evaluate the intratumoral DNA heterogeneity, a total of 141 samples of the 56 tumors were analyzed, depending upon the tumor size. RESULTS: One or two of the samples was available from 18 of 19 patients with tumors 2 cm or less in greatest dimension, whereas more than three of the samples were available from 22 of 37 patients with tumors 2.1 cm or greater in dimension (P < 0.003). Of 56 tumors, 40 (71.4%) exhibited DNA aneuploidy; DNA heterogeneity was found in 26 tumors (46.4%). The remaining 16 tumors exhibited DNA diploidy. Two of the five tumors that were limited to the epithelium had DNA heterogeneity. The mean dimension of the tumors with DNA heterogeneity was significantly greater (5.8 +/- 2.8 cm) than those exhibiting DNA diploidy (2.3 +/- 1.1 cm) and DNA aneuploidy without heterogeneity (2.9 +/- 2.4 cm). Recurrences after esophagectomy were detected in 6 of the 56 patients; the DNA ploidy pattern of these six patients exhibited DNA heterogeneity. CONCLUSION: The incidence of DNA heterogeneity increases as tumor size increases and is associated with an increased risk of tumor recurrence after esophagectomy in patients with superficial carcinoma of the esophagus. PMID- 7842412 TI - Comparison of the molecular genetics of c-erb-B2 and p53 expression in stomach cancer in Britain and Japan. AB - BACKGROUND: Differences in the epidemiology and treatment outcome of stomach cancer have led to the suggestion that in Japan, this disease may be biologically less aggressive than that found in the West. The authors compared p53b and c-erb B2 expression, trying to identify genetic differences in Japanese compared with Western stomach cancers. METHODS: Paraffin embedded formalin fixed tissues from 89 British and 89 matched Japanese patients were examined by immunohistochemistry after microwave treatment. Cases were matched for T-stage, year of surgery, and histopathologic grade. RESULTS: Tumors from 48 British and 46 Japanese patients expressed p53, whereas those of 27 British and 28 Japanese patients expressed c erb-B2. No significant difference in the density or distribution of protein expression was found between the two populations. The distribution of expression between diffuse and intestinal types and the proportion of cases expressing both antigens were similar in the two groups. CONCLUSIONS: p53 and c-erb-B2 are expressed in the same way in stomach carcinomas from Japanese and British patients. This study found no evidence of genetic differences in the cancers from the two countries. PMID- 7842413 TI - Metastasizing intramucosal gastric carcinomas. Well differentiated type and proliferative activity using proliferative cell nuclear antigen and Ki-67. AB - BACKGROUND: Recently, endoscopic surgery for small superficial gastric carcinomas has become increasingly more challenging, and the treatment criteria remain controversial. METHODS: To examine the metastatic potential of intramucosal gastric cancers (IMGCs), IMGCs with regional lymph node involvement (NI) were compared with IMGCs without regional lymph NI clinicopathologically. To clarify the metastatic behavior of well differentiated adenocarcinoma (W-type), immunohistochemical staining using Ki-67 and proliferating cell nuclear antigen (PCNA) monoclonal antibodies were performed. RESULTS: Of the 943 lesions with IMGC, 21 (2.2%) were NI on histologic examination. There was no significant difference between the macroscopic classification and the incidence of NI. The sizes of the IMGCs with NI (median, 4.3 cm) were significantly larger than the IMGCs without NI (median, 2.4 cm). Among the histologic grades classified according to the predominant features, the incidence of NI in poorly differentiated adenocarcinoma (P-type) (12/304, 3.9%) was significantly higher than that in well differentiated (W-type) (6/489, 1.2%). Besides the 12 P-type IMGCs, 6 well and moderately differentiated type IMGCs contained some poorly differentiated components, totaling 18 IMGCs (86%) that were either mainly or partially P-type. Among the W-type IMGCs, the mean values of the Ki-67 and PCNA labeling indices (LI) for IMGCs with NI (Ki-67, 47.5%; PCNA, 58.3%) were higher than those of the 25 randomly selected IMGCs without NI (Ki-67, 39.2%; PCNA, 39.9%). CONCLUSIONS: The potential for NI in IMGCs seems to be related closely to tumor size, the presence of poorly differentiated components, and, particularly in the W-type IMGC, the LI that are demonstrated immunohistochemically with Ki-67 and/or PCNA. PMID- 7842414 TI - Rectal cancer after prolonged sulindac chemoprevention. A case report. AB - BACKGROUND: Sulindac is reported to induce regression of colonic adenomas. However, its role as a chemoprophylactic agent for people with familial adenomatous polyposis (FAP) is under consideration. METHODS: This case report describes a patient with FAP in whom rectal adenocarcinoma developed 37 years after prophylactic colectomy and 15 months after beginning a course of sulindac. She received endoscopic follow-ups every 3 months during 15 months of 150-mg twice-daily sulindac administration. At 12 months, an endoscopic examination was unremarkable; at 15 months, endoscopic examination revealed several polyps and a flat ulcerated lesion. RESULTS: Rectal carcinoma developed in a patient 15 months after beginning chemoprophylaxis: there was metastatic adenocarcinoma in 6 of 20 perirectal lymph nodes. In addition to the carcinoma, rectal mucosa contained two adenomas and multiple foci of adenomatous changes in flat mucosa. CONCLUSION: Sulindac may not alter the pathogenesis of FAP. Patients undergoing sulindac chemoprevention must be monitored closely, including endoscopic examination. Endoscopic surveillance should include an aggressive biopsy approach because the absence of polyps does not prove the absence of neoplastic change. PMID- 7842415 TI - Polypoid growth and K-ras codon 12 mutation in colorectal cancer. AB - BACKGROUND: To clarify genetic changes in colorectal tumorigenesis, K-ras codon 12 point mutations were examined in 101 ordinary colorectal carcinomas and 6 that complicated ulcerative colitis (UC) with special attention to growth patterns. METHODS: The depths of invasion of ordinary carcinoma were submucosa (SMCa) in 39 cases, muscularis propria (PMCa) in 33, and far-advanced in 29. Growth patterns of SMCa and PMCa were classified into three types: polypoid-growth type without central depression (Type 1), polypoid-growth type with central depression (Type 2), and nonpolypoid-growth type. DNA samples were extracted from formalin fixed paraffin embedded sections, and K-ras codon 12 mutations were examined by two step polymerase chain reaction-restriction fragment length polymorphism. RESULTS: K-ras mutation frequency was higher in Type 1 SMCa than in nonpolypoid SMCa, 56% (9/16) versus 6% (1/17), respectively, and in PMCa, 78% (7/9) versus 23% (3/13), respectively. In 6 UC carcinomas, a K-ras mutation was detected in only one polypoid carcinoma and none were detected in five nonpolypoid carcinomas. CONCLUSIONS: These results and the authors' previous study suggest that nonpolypoid carcinomas may be derived from flat adenomas, whose K-ras mutation incidence also was low, and this pathway is different from a genetic model based on the ordinary adenoma-carcinoma sequence through polypoid adenomas. PMID- 7842416 TI - The relationship of human papillomavirus to proliferation and ploidy in carcinoma of the anus. AB - BACKGROUND: Human papillomavirus (HPV) infections have been implicated in anogenital neoplasia in both sexes. In this study, the authors postulated that HPV infections induce squamous epithelium to become hyperproliferative and aneuploid. METHODS: To test this hypothesis, formalin fixed, paraffin embedded tissues were analyzed for the presence of HPV by in situ hybridization. S-phase fraction and DNA content were evaluated by flow cytometry. Proliferative indices also were analyzed using an antibody to proliferating cell nuclear antigen (PCNA). RESULTS: Human papillomavirus DNA was present in 48.1% of the carcinomas. All but one HPV-positive tumor contained HPV 16/18 DNA. The remaining tumor contained only HPV 6/11. No correlation was found between HPV status, patient age, or tumor differentiation. Thirty-three percent of tumors were aneuploid. Only two patients had aneuploid tumors that were HPV-negative; these patients received preoperative radiotherapy. The average S-phase fraction was significantly higher (P < 0.01) in HPV-positive versus HPV-negative lesions. The PCNA index for HPV positive tumors was also significantly higher than that observed in negative tumors (p < 0.003). CONCLUSION: The presence of HPV in tumor cells is significantly associated with an increased proliferative rate and aneuploid status of tumors compared with HPV-negative tumors. These findings are consistent with the fact that viral proteins binding to tumor suppressor gene proteins can deregulate the cell cycle and lead to genomic instability. PMID- 7842417 TI - Phase II trial of a 75-mg/m2 dose of docetaxel with prednisone premedication for patients with advanced non-small cell lung cancer. AB - BACKGROUND: A prior Phase II study of a 100-mg/m2 dose of docetaxel conducted at the Memorial Sloan-Kettering Cancer Center (New York, NY) demonstrated a 38% response rate with grade 3 or 4 neutropenia in 76% of the patients and a grade 2 or greater rash or infusion-related reaction in 41% and 34% of the patients, respectively. The current Phase II study sought to determine the activity of a 75 mg/m2 dose of docetaxel to establish whether this lower dose, combined with prednisone, ameliorates toxicity. METHODS: Twenty untreated patients with advanced non-small cell lung cancer (NSCLC) received a 1-hour 75-mg/m2 dose of docetaxel every 21 days. Fifty milligrams of prednisone were administered twice the day before chemotherapy and once each of the next 3 days. Patients' disease related symptoms were assessed prospectively using the Lung Cancer Symptom Scale (LCSS). RESULTS: All patients were assessable for response and toxicity. Five patients had a major objective response (25%; 95% confidence interval, 11-50%). The median duration of response was 9.1 months. The projected 1-year survival was 71%. Grade 3 or 4 neutropenia occurred in 70% of the patients. Grade 2 or greater rash and infusion-related reactions decreased to 25% each. Analysis of the LCSS measurements found that six of nine component symptoms improved on Day 22, and all improved when baseline measurements were compared with the best value for each patient during the study. CONCLUSIONS: Docetaxel administered at a dose of 75 mg/m2 every 21 days shows significant antitumor activity in untreated patients with NSCLC: Neutropenia is comparable with that observed at a 100-mg/m2 dose. The number of infusional reactions and rash decreased when docetaxel at this dose was administered with prednisone. Based on response rates observed in trials using a 100-mg/m2 dose with similar degrees of neutropenia, a 100-mg/m2 dose with steroid pretreatment is recommended future trials. PMID- 7842419 TI - Topodermatographic image analysis for melanoma screening and the quantitative assessment of tumor dimension parameters of the skin. AB - BACKGROUND: The clinical need to identify and evaluate changes of cutaneous lesions in melanoma screening or follow-up of patients with cancer is of paramount importance. Because skin-lesion changes may be small and numerous, clinical assessment alone does not meet the requirements of quantitative assessment. Using the computer as a diagnostic tool for the image analysis of sequentially captured skin surface images has resulted in the technical problem of insufficient registration reproducibility. This paper describes the technical logistics, setup procedure, and clinical evaluation of the novel technique termed "topodermatography," which performs the quantitative videographic image analysis of skin-lesion changes over time. METHODS: Digitized measurements of skin-surface image parameters were performed using a high-speed processor with an onboard coprocessor, a high-resolution video camera, specifically designed image processing software, and a position framework for the adjustment of the patient's standing position. The topodermatographic image analysis was performed on 109 consecutive patients who were at risk for melanoma (N = 98), had lesions from Kaposi's sarcoma (N = 4), had metastatic skin deposits from melanoma (N = 3), and had breast cancer (N = 4). RESULTS: Skin lesion changes over time could be identified reliably within a few millimeters of diametric enlargement. In this series, a 0.51% early melanoma detection rate was assessed in 19 of 98 patients followed for 12 months. By monitoring manifest neoplastic skin lesions, tumor growth kinetics were analyzed quantitatively to determine the total area of skin involvement, thus facilitating precise response assessment. CONCLUSIONS: Topodermatographic image analysis helps to optimize screening and follow-up procedures for patients with melanoma and populations at risk for melanoma. In addition, metastatic tumor lesions on the skin can be monitored dynamically, facilitating the accurate evaluation of the impact of systemic therapy on multiple skin deposits from melanoma and nonmelanoma cancers. PMID- 7842418 TI - Primary lymphoma of bone. Correlation of magnetic resonance imaging features with cytokine production by tumor cells. AB - BACKGROUND: Primary lymphoma of bone is a rare, aggressive neoplasm that can present with a large, soft-tissue mass despite minimal evidence of cortical destruction on plain radiographs. METHODS: High resolution magnetic resonance imaging (MRI) examinations of four patients with primary lymphoma of bone were reviewed retrospectively, and in each case intramedullary tumors demonstrated "penetrating channels" extending through the cortex. The MRI studies were correlated with the histopathologic assessment of the tumor for each patient. Immunohistochemistry was performed for immunophenotyping and for cytokine expression by tumor cells. The cytokines that were investigated were interleukin 1, interleukin-6, and tumor necrosis factor-alpha, molecules known to regulate osteoclastic activity. RESULTS: The linear cortical foci noted on MRI correlated with the histopathologic findings of tumor-associated cutting cones, in proximity to osteoclastic bone resorption. Immunohistochemical stains showed a B-cell phenotype for each tumor and positive immunoreactivity in tumor cells for cytokine mediators that stimulate osteoclastic activation. CONCLUSIONS: These findings indicate that the tumor cells in these cases produce soluble cytokine mediators that may regulate extensive osteoclastic activity. In primary lymphoma of bone, tumor activation of osteoclastic resorption, with production of tumor tunnels through the cortex, may represent one of the mechanisms by which lymphoma escapes the intramedullary space and forms large, soft-tissue masses without extensive cortical destruction. PMID- 7842420 TI - Angiosarcoma in Japan. A review of 99 cases. AB - BACKGROUND: Angiosarcoma is rare, and information about its clinical features are limited. Therefore, a large scale study of angiosarcoma was performed in Japan. METHODS: Through a nationwide Japanese study, 99 cases of angiosarcoma were collected and their clinicopathologic findings were summarized relative to predisposing risk factors. RESULTS: The patient age at diagnosis was 3-92 years, (mean, 62 years), with a two to one male to female ratio. The head and face were the most common primary site (29 cases); other sites were liver (17); trunk (13): pleural cavity (6), chest wall (2), abdominal wall (2), buttock (2), inguinal region (1); heart (12); and extremities (7). The proven predisposing risk factors included chronic pyothorax for angiosarcoma in the pleural cavity (six), thorotrast in the liver (five), radiotherapy to the abdominal wall and buttock (four), and chronic limb edema of the forearm (one). Irrespective of primary sites, the majority of cases had metastases to lung in 72 cases, bone in 42, liver in 36, regional lymph nodes in 30, and adrenal gland in 24. The 2-year survival rate was 17%. CONCLUSIONS: This study describes a different etiology in the development of angiosarcoma in patients from Japan compared with that of patients from Western countries, though the frequency of angiosarcoma among all soft-tissue sarcomas was similar in both areas. In Japan, chronic pyothorax, radiotherapy, and thorotrast proved to be distinctive causative factors of angiosarcoma. PMID- 7842421 TI - The excess of patients with advanced breast cancer in young women screened with mammography in the Canadian National Breast Screening Study. AB - BACKGROUND: An unexpected excess of patients with breast cancer with four or more positive lymph nodes was observed in mammographically screened women who were younger than the age of 50 years at enrollment into the Canadian National Breast Screening Study (NBSS). It has been suggested that this excess is consistent with prior screening trials evaluating mammography. METHODS: A quantitative evaluation of the distribution of patients with breast cancer with four or more positive lymph nodes in the NBSS was undertaken, and the percentages of patients with breast cancer who were at an advanced state at diagnosis in the NBSS and in previous randomized screening trials were compared. The validity of mortality analyses after eliminating advanced cases detected by physical examination at the initial screening visit is examined. RESULTS: The excess of patients with cancer with four or more positive lymph nodes in the 40-49-year mammography age group of the NBSS was statistically significant, even when expressed as a percentage of all invasive cancers diagnosed. Such an excess is inconsistent with published data on extent of disease at diagnosis from previous studies. Analysis of NBSS mortality data after eliminating advanced cases detected by physical examination at the initial visit should result in minimal, if any, bias. CONCLUSIONS: Mortality analyses eliminating advanced cases detected by physical examination at the initial screening visit may be less susceptible to bias caused by possible nonrandom allocation of study participants and should be considered in future evaluations of the NBSS cohort after longer follow-up periods and in meta analyses that may include the NBSS in assessments of the efficacy of mammography. PMID- 7842422 TI - The evolution of pediatric neurosurgery as a speciality. PMID- 7842424 TI - Benign cerebellar astrocytoma in childhood: experience at the Hospital for Sick Children 1980-1992. AB - Between 1 January 1980, and 31 December 1992, 66 patients with cerebellar astrocytoma were diagnosed and treated at The Hospital for Sick Children in Toronto. These patients ranged in age between 1 and 18 years, with a mean age of 7.3 years. Thirty-eight patients were male and 28 were female. Total removal was possible in 61 patients and no recurrence occurred in these 61 patients. In the 5 patients in whom an incomplete resection was carried out, regrowth occurred between 1 and 8 years following resection. PMID- 7842425 TI - Long-term prognosis for children with shunted hydrocephalus. AB - We reviewed the previous medical history and the social status of all patients of Oulu University Central Hospital who had had in the age range 16-26 years shunted hydrocephalus (HC) during childhood. Of 42 patients selected 7 had died and another 5 had been institutionalized for severe mental handicap. Shunts had been changed a total of 103 times in 29 patients still living. The most common reason for a reoperation was blockage. Half of the patients re-examined showed neurological abnormalities or epilepsy. Both the verbal and the nonverbal IQ of the patients remained weak to average. Even though the patients' medical prognosis was fair, their social maturation did not keep up with their physical abilities. One-third were receiving or had received vocational training, but only a few were working. Up to one-quarter of the patients with shunted HC were at home without any meaningful work activities. PMID- 7842426 TI - Pancreatitis associated with remote traumatic brain injury in children. AB - Vomiting, abdominal distension, and feeding intolerance are common findings following brain injury in children, and are usually attributed to the brain injury or to delayed gastric emptying: a specific cause is usually not sought. We report six children who developed mild to moderate pancreatitis at least 7 days following apparently isolated brain injury, a previously unreported association. Five of the six patients received drugs that are known or suspected pancreatotoxins; all recovered without changes in the medications. When children develop feeding intolerance or upper gastrointestinal symptoms following traumatic brain injury pancreatitis should be suspected. PMID- 7842427 TI - Microgyria associated with Sturge-Weber angiomatosis. AB - A case is reported of an infant affected with Sturge-Weber disease who underwent left hemispherectomy due to untreatable seizures when 97 days old. Pathological analysis of the surgical specimens revealed the presence of four-layered microgyric cortex below the angiomatosis, intense gliosis, and the presence of calcifications of both the abnormal cortex and the underlying white matter. These findings suggest that the early infantile form of Sturge-Weber disease is associated with a developmental disorder of the cortical organization. Such abnormalities are consistent with the presence of an epileptogenic condition that is unresponsive to pharmacological treatment. PMID- 7842423 TI - Traumatic intracranial aneurysms in childhood and adolescence. Case reports and review of the literature. AB - We report four pediatric traumatic intracranial aneurysms occurring before the age of 10 years. Two of these aneurysms were the result of closed head injury. The remaining two were iatrogenic aneurysms which occurred in unusual circumstances. These four children represent 33% of the pediatric intracranial aneurysms seen at the Children's Hospital of Eastern Ontario from 1974 to 1992. Diagnosis of traumatic intracranial aneurysms requires a high index of suspicion: any head-injured or postoperative child who experiences delayed neurologic deterioration, or who fails to improve as expected following treatment, should promptly undergo diagnostic intracranial imaging. Documented subarachnoid hemorrhage, intracerebral or intraventricular hemorrhage, or subdural haematoma in this clinical setting should be further investigated by cerebral angiography to exclude a traumatic aneurysm or other vascular lesion. Traumatic aneurysms typically arise at the skull base or from distal anterior or middle cerebral arteries or branches consequent to direct mural injury or to acceleration-induced shear. Reported traumatic aneurysms account for 14%-39% of all pediatric aneurysms. Iatrogenic aneurysms also occur with unexpected frequency during childhood and adolescence. Pediatric traumatic cerebral aneurysms may present early or late. Most present early with intracranial hemorrhage. Late presentation occurs infrequently, typically as an aneurysmal mass. Once diagnosed, these aneurysms should be promptly treated by craniotomy employing routine microsurgical techniques, or in some cases, by endovascular detachable balloon techniques. Delay in operative treatment entails significant risks of repeated hemorrhage and death. Outcome in these children is primarily determined by the extent of traumatic cerebral injury and the preoperative clinical status. The latter directly depends upon diagnosis of the aneurysm prior to either initial or repeated hemorrhage. PMID- 7842428 TI - Non-traumatic atlanto-axial subluxation in an 8-year-old child. AB - An 8-year-old child with a previous history of neonatal retropharyngeal abscess presented with a 6-month history of progressive quadriparesis. Investigations demonstrated atlanto-axial subluxation with anterior displacement of the odontoid peg to a position anterior to the vertebral body of C2. Magnetic resonance imaging confirmed severe neural compression at this level. The child was placed in a halo fixation device and underwent transoral removal of the odontoid peg together with the upper part of the body of C2. At a subsequent procedure a posterior occipito-cervical fusion was performed. The aetiology and management of this case are discussed. PMID- 7842429 TI - Complete migration of peritoneal shunt tubing to the scalp. AB - The entire length of distal tubing from a ventriculoperitoneal shunt was found to have migrated into the subgaleal space, and resulted in a shunt obstruction. Upward migration of distal shunt catheters has rarely been reported, but probably involves patient motion that creates a "windlass" effect. Cephaled migration requires a potential space (subgaleal or ventricular) and no resistance to movement of the tubing. This complication can be prevented by securing the shunt near the site of motion. PMID- 7842430 TI - Familial occurrence of moyamoya disease. Magnetic resonance angiography as a screening test for high-risk subjects. AB - The authors report four cases of familial occurrence of moyamoya disease. Although the pathogenesis of moyamoya disease is not clear, there is extensive evidence that this disease has a tendency to show multifactorial inheritance. Therefore, a screening test for those at high risk, i.e., who have a moyamoya patient among their blood relatives, is clinically important. Magnetic resonance angiography (MRA) successfully revealed abnormal findings specific to moyamoya disease in members of the four probands families. MRA is a powerful and noninvasive way of detecting individuals at high risk of developing moyamoya disease. PMID- 7842431 TI - Early diagnosis of optic glioma in children with neurofibromatosis type 1. AB - Twenty-five asymptomatic patients with neurofibromatosis type 1 (NF 1), aged 6-21 years, underwent the following examinations: intracranial magnetic resonance testing (MRI), visual acuity testing, ophthalmoscopy, and visual field and pattern reversal visual evoked potentials (VEPs). MRI showed enlargement of one or both optic nerves in six children, with bilateral involvement in three. VEPs were normal in all these patients; two of them had abnormalities on other visual examinations, although there were no subjective visual disturbances. These results show that VEPs cannot be considered as a screening test for optic pathway lesions in children with NF 1, as previously stated, and that other types of visual function examination may be more sensitive. These data may contribute to the establishment of more precise guidelines for the evaluation and treatment of children with NF 1. PMID- 7842432 TI - Brain tumors in the first 2 years of life in Saudi Arabia. AB - Thirty-four patients with brain tumors were diagnosed and treated during the first 2 years of life, representing 8% of the 273 children treated for primary brain tumors from 1981 to 1990 inclusive. Large head circumference, vomiting, and altered level of consciousness were the chief findings at the time of presentation. Overall, the tumors were located mainly supratentorially; in patients in the 1st year of life they were equally distributed above and below the tentorium, while two-thirds of the patients presenting in the 2nd year of life had supratentorial tumors. The most common histological types were astrocytomas and medulloblastomas. Treatment methods were ventricular peritoneal shunt, craniotomy with total or partial removal of the tumor, adjuvant radiotherapy, and in a few cases chemotherapy. The 2-month mortality rate was 5.9%. The follow-up period ranged from 3 to 50 months. PMID- 7842433 TI - Follow-up and quality of survival of 67 consecutive children with CNS tumors. AB - We report the findings at follow-up in 67 consecutive children with central nervous system tumors treated over a 5-year-period at a single institution. The diagnoses were supratentorial astrocytoma (n = 12), cerebellar astrocytoma (n = 10), ependymoma (n = 9), medulloblastoma (n = 9), brain stem glioma (n = 6), optic pathway glioma (n = 5), and others (n = 16). The survival rates were 83% for supratentorial astrocytomas at a median of 46.5 months, 90% for cerebellar astrocytomas and 55% for ependymomas at 40 months, respectively, 55% for medulloblastomas at 22 months, 33% for brain stem gliomas at 23 months, and 80% for optic pathway gliomas at 49 months. With regard to neurological sequelae, 13 patients were treated for epilepsy, 13 patients had mild to moderate neurological deficits, and 4 patients were severely disabled. Seventeen of 37 tested patients performed below average on formal neuropsychometric testing, one-fourth attended special education courses, and at least one-fourth suffered from behavioral and adjustment problems. PMID- 7842434 TI - Posterior fossa duraplasty in children: remarks on surgery and clinical and CT follow-up. AB - A series of 314 posterior fossa duraplasties in children were performed at the Department of Neurosurgery, Hradec Kralove, over the past 33 years. Computed tomographic (CT) imaging was used to compare the healing of various kinds of collagenic dural substitutes--allogeneic fascia lata, allogeneic dura mater and xenogeneic pericardium. Early (8 days to 3 months following surgery) and late (1 18 years following surgery) axial CT scans with sagittal reconstruction for duraplasty in 55 children were evaluated. In early postoperative CT scans, epidural collections of cerebrospinal fluid, sanguinolent liquid or haematoma and/or pseudocysts or pseudomeningoceles appeared. In late CT follow-up, calcifications and ossifications in the "suboccipital coverings complex" (SCC) gradually developed and pseudocysts or pseudomeningoceles rarely persisted. It is concluded, on the basis of perioperative, clinical, and CT examinations, that posterior fossa duraplasties in children formed an important anatomical barrier and regardless of the type of graft had a favourable outcome; CT was shown to be a suitable method for the demonstration of dural grafts at the site of craniectomies. PMID- 7842436 TI - Multicenter study of childhood headache. AB - This multicenter study reports the results obtained between 1990 and 1991 by the Study Group for Childhood Headache of the Italian Neuropediatric Society. Standardized computerized case sheets were used in order to increase the number of young patients studied and obtain more homogeneous results. A clinical diagnosis of headache was made in 600 patients (314 female and 286 male) between 4 and 12 years of age, in accordance with the classification set down by the International Headache Society. Clinical symptoms and follow-up were more severe in children with migraine as opposed to headache. No sequence of associated neurological and neurovegetative symptoms was observed at onset of headache, and some (phono-photophobia, pallor, drowsiness, abdominal pains) were much more prevalent than others. Because of the patient's age we studied only the treatment of acute attack and did not take account of chronic treatment. In childhood the clinical course of primary headache tends to improve spontaneously, and we believe that prevention of headache attacks should be carried out only in very rare individual cases. PMID- 7842435 TI - Celiac disease and epilepsy in pediatric patients. AB - Among 783 patients referred to our institute with different types of seizures as presenting symptom, systematic evaluation of antigliadin and antiendomysial antibodies in the serum has identified nine in whom jejunal biopsy has subsequently confirmed the diagnosis of celiac disease (CD). In three of them brain imaging showed the presence of calcified areas in the occipital region. They had complex partial seizures (CPS), associated in two with transient episodes of blindness. In another patient with CPS and generalized tonic-clonic seizures (GTCS) progressive multifocal cerebral calcifications were noted. In the other six patients with CPS and/or GTCS cerebral calcifications were absent. Symptoms of CD in all these cases were either not previously taken into account, or they were very mild or completely absent. In a group of 36 patients with clinically manifest CD, regular follow-up, and good compliance with the dietary regimen, no clinical seizures were reported. The pathogenetic mechanism and the relationship between epilepsy and an early diagnosis and treatment of celiac disease are discussed. PMID- 7842437 TI - Clinical, radiological and histological findings in desmoplastic infantile ganglioglioma. AB - The clinical course and radiological and histological findings in a 30-month-old boy suffering from desmoplastic infantile ganglioglioma are reported. The child's development was normal until a series of complex partial seizures occurred at the age of 7 months. Cranial computed tomography and magnetic resonance imaging revealed a cystic mass with intensive ring-shaped contrast enhancement in the right temporal fossa without shift of intracranial structures. Histologically, the firm, grayish tumor showed an enormous amount of connective tissue, cystic areas, and some mitoses. Glial and neuronal cell lines were identified by immunocytochemical methods. Eighteen months after surgery the boy had developed well without any neurological dysfunction; no radiation or chemotherapy was given. For the first time a synopsis of radiological findings in this rare brain tumor is correlated with the results of multiple histological and immunocytochemical studies. Despite some malignant characteristics, the prognosis of this dysontogenetic brain tumor is good. PMID- 7842438 TI - Total recuperation in a case of sudden total paraplegia due to an aneurysmal bone cyst of the thoracic spine. AB - A 3-year-old girl developed sudden complete paraplegia because of an aneurysmal bone cyst of the fourth thoracic vertebra. We performed a two-step surgical procedure resulting in complete neurological recuperation and no cyst recurrence within 2.5-year follow-up. Although the literature shows the prognosis of such a condition to be poor, this case reveals the positive effect of rapid surgical decompression and of postponing assessment by magnetic resonance imaging until before the second surgical stage. Furthermore, this case is an example of cure with neither interbody fusion nor postoperative radiotherapy, despite the total involvement of the vertebrae by the lesion. PMID- 7842439 TI - Catheterobronchial fistula due to vena cava superior thrombosis as a late complication of ventriculoatrial shunt. AB - A case of a catheterobronchial fistula as a rare late complication of a ventriculoatrial shunt is reported. The ventriculoatrial shunt was implanted in a 4-month-old boy suffering from extreme postinfectious hydrocephalus. During the following years, twelfth nerve palsy on the right, vertebralgias, and salty taste sensations in the mouth associated with intermittent coughing and swelling of the neck and supraclavicular region on the right side developed. Valvography established a diagnosis of fistula 12 years after the implantation of a shunt. Ultrasonography of the neck and mediastinum and contrast-enhanced dynamic computed tomographic scanning demonstrated a catheterobronchial fistula to the subsegmental bronchus of the anterior segment of the right upper lung lobe, a thrombosis of the right internal jugular and both right and left brachiocephalic veins and the superior vena cava, and an extensive collateral venous system mainly draining into the azygos vein. Normalization of cerebrospinal fluid and blood flow and pressure allowed extraction of the "atrial" catheter without complications. One year after surgery the boys is in good health and without signs of shunt dependence. PMID- 7842440 TI - NMR analysis of succinoglycans from different microbial sources: partial assignment of their 1H and 13C NMR spectra and location of the succinate and the acetate groups. AB - In order to obtain information on the location of succinate and acetate groups, comparative NMR analyses were carried out on succinoglycans from different microbial sources by using conventional and advanced NMR techniques. In particular, one-dimensional, 1H and 13C NMR spectra were recorded for qualitative and quantitative analysis on native high-molecular-weight succinoglycans (both in the Na+ salt and free-acid forms) from Pseudomonas sp. NCIB 11592, Agrobacterium radiobacter A201-25, Rhizobium meliloti YE-2, and Rhizobium sp. isolated from Vicia faba and compared with those of the deacylated and deacylated-depyruvated, partially depolymerised exopolysaccharides from Rhizobium meliloti YE-2. Moreover, a series of two-dimensional experiments was performed on all the exopolysaccharides aiming at the partial assignment of the NMR spectra. The NMR data showed that succinate is located on O-6 of either one or both of the two side chain 3-linked beta-D-Glc residues, whereas the acetate (when it is present) is located on one of the O-6 of backbone 4-linked beta-D-Glc units, but the specific site could not be determined. In addition, the spectral features of the succinate substituent were found to be sensitive to pH changes. PMID- 7842441 TI - Induced circular dichroism study of the aqueous solution complexation of cello oligosaccharides and related polysaccharides with aromatic dyes. AB - Acetobacter xylinum, grown in the presence of low levels of the water-soluble dye Calcofluor White ST produces a pellicle of cellulose that has no detectable crystallinity. Biological factors of this sort are probably more important than physical factors in controlling the higher order structures of celluloses. Circular dichroism (CD) is induced by complexes that are formed by specific interactions between chiral oligosaccharides and dye molecules. Using CD, equilibrium constants were measured for the association reactions between various dyes with a series of cello-oligosaccharides (n = 2-6), methylcellulose, hydroxypropylcellulose (HPC), amylose, cyclomalto-oligosaccharides (cyclodextrins), and the linear malto-oligosaccharides (n = 3-7). Possible structural features of the complexes are discussed. Dyes that are capable of binding to the higher cello-oligomers in aqueous solutions are the same dyes that modify the solid structure of bacterial cellulose. An analogy between the binding of water-soluble dyes to cello-oligosaccharides and the binding of the cellulose degrading enzyme, cellobiohydrolase I, to cellulose is discussed. PMID- 7842442 TI - Conformations and structure studies of sugar lactones. Part III. The composition and conformation of D-mannurono-gamma-lactone in solution, and the structural analysis of its beta anomer in the solid state. AB - Complete analyses of the proton and carbon chemical-shift assignments of D mannurono-gamma-lactone (1) have been achieved by 1D and 2D NMR spectral measurements. At equilibrium, the anomeric alpha and beta forms were present in the ratio of 34:66 in D2O and 72:28 in Me2SO-d6. The solution data indicated that the dienvelope conformation 2E:E4 to be the favored conformation of 1 in solution. The crystal structure of 1 was determined, and it showed that the crystalline form is the beta anomer, a bicyclic structure, consisting of fused five-membered furanose and lactone rings, in agreement with an earlier deduction from chemical evidence. In contrast to the solution conformation, the furanose ring adopts a twist conformation lying between the 2(1)T and 1E conformations with phase angle (P) and pseudorotation amplitude (tau m) of -44.23 degrees and 37.9 degrees, respectively, whereas the lactone ring adopts an envelope E5 conformation slightly distorted towards 6T5 with a phase angle (P) of -22.3 degrees and a pseudorotation amplitude (tau m) of 18.4 degrees. The molecules are linked in the crystal through a hydrogen-bonding network that involves all hydroxyl groups as well as the ring oxygen atoms. PMID- 7842443 TI - The configuration and conformation of di-D-fructose anhydride I. The crystal and molecular structure of 3,4,3',4'-tetra-O-acetyl-6,6'-di (triphenylmethyl)-di-D fructose anhydride I. AB - The crystal structure of 3,4,3',4'-tetra-O-acetyl- 6,6'-di(triphenylmethyl)-di-D fructose anhydride I (1) has been determined by single-crystal X-ray diffraction. The crystals are monoclinic, space group P2(1) with a = 16.399(2), b = 9.091(2), c = 17.946(4) A, beta = 103.66(1) degrees, V = 2600(2) A3, and Z = 2. The structure was refined to R = 0.044 and Rw = 0.051 for 4403 observed reflections. The structure analysis of 1 showed that the previously assigned chemical structure of di-D-fructose anhydride I is undoubtedly alpha-D-fructofuranose beta D-fructofuranose 1,2':2,1'-dianhydride. The conformations of the furanose rings are E5 with P = 59.8 and tau m = 43.2 degrees for D-fructose 1, and 2T3 with P = 34.39 degrees and tau m = 39.64 degrees for D-fructose 2. The two furanose fragments are linked by a 1,4-dioxane ring in a spiro arrangement. The 1,4 dioxane ring has a chair conformation with Cremer-Pople puckering parameters Q = 0.527 A, phi = 72.2 degrees and the a = 14.2 degrees. PMID- 7842444 TI - Facile synthesis of the sugar cores from phenylpropanoid glycosides. AB - Allyl 2-O-benzoyl-4,6-O-benzylidene-alpha-D-glucopyranoside (3), obtained by selective benzoylation of allyl 4,6-O-benzylidene-alpha-D-glucopyranoside (2) with benzoyl chloride-imidazole in anhydrous chloroform, reacted with 2, 3, 4-tri O-benzoyl-alpha-L-rhamnopyranosyl bromide to give a disaccharide derivative (4), and an important intermediate (5) was obtained by cleavage of its acetal. Treatment of 5 with a series of glycopyranosyl bromides, protected by acetyl or benzoyl groups in benzene-nitromethane in the presence of Hg(CN)2 as a catalyst afforded four trisaccharides (6-9). The disaccharide (5) and trisaccharides (6-9) constitute the sugar cores of phenylpropanoid glycosides. A new glycosyl anomeric leaving group, trichloroacetoxy, was employed to prepare the disaccharide (4) and trisaccharides residue (8) efficiently and with high stereoselectivity. PMID- 7842445 TI - Difructose dianhydrides from sucrose and fructo-oligosaccharides and their use as building blocks for the preparation of amphiphiles, liquid crystals, and polymers. AB - Controlled selective protonic activation of the fructosyl moiety in sucrose and fructo-oligosaccharides, with pyridinium poly (hydrogen fluoride) at 20 degrees C, yielded either the kinetic product alpha-D-fructofuranose beta-D fructofuranose 1,2':2,1'-dianhydride (1), or its thermodynamically more stable isomer alpha-D-fructofuranose beta-D-fructopyranose 1,2':2,1'-dianhydride (2), depending on the hydrogen fluoride-pyridine ratio. A similar reaction was performed with 6,6'-dichloro-6,6'-dideoxysucrose, or 6,6'-dideoxy-6,6' diiodosucrose, using a slightly higher ratio of HF, resulting in the corresponding 6-deoxy-6-halo-alpha-D-fructofuranose 6'-deoxy-6'-halo-beta-D fructofuranose 1,2':2,1'-dianhydride derivatives. Both 6,6'-dihalides were converted, upon action of the appropriate nucleophile, into the difructofuranose dianhydride derivatives bearing the 6,6'-di-S-heptyl-6,6'-dithio, 6,6'-diazido 6,6'-dideoxy and then 6,6'-diamino-6,6'-dideoxy functionalities. 6-Chloro-6-deoxy and 6-deoxy-6-iodo derivatives of 2 were also prepared by direct halogenation, and further converted into the 6-S-heptyl-6-thio, 6-azido-6-deoxy and then 6 amino-6-deoxy derivatives of 2. Reaction of chloromethyloxirane with 1 or 2 yielded hydrophilic polymers. The 6,6'-di-S-heptyl-6,6'-dithio derivative of 1 displayed liquid crystal properties. The 6,6'-dideoxy-6,6'-diiodosucrose precursor was prepared by the reaction of Garegg's iodine-imidazole triphenylphosphine reagent with sucrose in N,N-dimethylformamide solution. PMID- 7842446 TI - The crystal and molecular structure of 4-cyanophenyl and 4-nitrophenyl beta-D xylopyranosides. PMID- 7842447 TI - Synthesis of 5-fluorouridine 5'-diphosphate galactose from 5-fluorouridine by chemical phosphorylation and microbial uridylyl transfer. PMID- 7842448 TI - NMR spectroscopic investigation of oligoglucuronates prepared by enzymic hydrolysis of a (1-->4)-beta-D-glucuronan. PMID- 7842449 TI - Preparation of 2,3,6,2',3',4',6'-hepta-O-acetyl-maltose/cellobiose by enzymatic hydrolysis of maltose/cellobiose octaacetate. PMID- 7842450 TI - Structure of the exopolysaccharide of Pseudomonas stutzeri strain ATCC 17588. PMID- 7842451 TI - Preparation of N-acetylchitooligosaccharides by hydrolysis of chitosan with chitinase followed by N-acetylation. PMID- 7842452 TI - Role of positron emission tomography in the investigation of human coronary circulatory function. PMID- 7842453 TI - Why are circulating concentrations of endothelin-1 so low? AB - Physiological and pathophysiological roles of endothelins are still unclear. One reason is that circulating endothelin levels in normal and pathological states are much lower than the concentrations necessary to elicit contractions in vitro. It is usually assumed that endothelin accumulates in diseased tissues and that, because of its degradation, only a small fraction of it reaches the systemic circulation. Such a hypothesis does not fit with recent observations showing that low circulating endothelin levels may be active. We show here that most of the current inferences about the actions of endothelin assume that the peptide acts in the vessel wall under conditions known as non-stoichiometric binding conditions, that is, under conditions in which the receptor concentration in tissues ([Ro]) is smaller than the equilibrium dissociation constant of endothelin receptor complexes (Kd). Under stoichiometric binding conditions (defined by the condition [Ro] > Kd), most ligand molecules are bound to receptors and cannot be present in a free form. Estimates of [Ro] and Kd from the literature suggests that in vivo endothelin probably binds stoichiometrically to its receptors. Under this condition, most of tissue endothelin is probably bound to receptors. It is therefore suggested that plasma endothelin levels are low probably because tissue free endothelin levels are low, and this is not inconsistent with the presence of high tissue levels of active (that is, bound) endothelin. When the topology of the vessels with respect to the site of production (or of delivery) of endothelin is considered, stoichiometric binding may also account for the higher sensitivity to Et-1 of in vivo preparations. It also suggests that autocrine and paracrine actions of Et-1 are favoured at low and high secretory rates respectively, thus providing an explanation for the dual (vasodilator and vasoconstricting) actions of endothelin. Finally, the stoichiometric binding model predicts that functional receptors also act as clearance receptors and provides an explanation for the observation that antagonists of endothelin receptors are also clearance antagonists. PMID- 7842454 TI - Angiotensin II receptor binding following myocardial infarction in the rat. AB - OBJECTIVE: The aim was to determine angiotensin II receptor binding and its relationship to angiotensin converting enzyme (ACE) binding and fibrous tissue formation in the rat heart. METHODS: A model of tissue repair (pericardiotomy and myocardial infarction with left coronary artery ligation) was used together with the following: quantitative in vitro autoradiography to determine angiotensin II receptor (125I[Sar1, Ile8]AngII) and ACE (125I-351A) binding densities. Angiotensin II receptor subtype was determined using an AT1 receptor antagonist (DuP753, losartan) and an AT2 receptor antagonist (PD123177). Five groups were studied: age and sex matched controls receiving this operative procedure without subsequent myocardial infarction (sham operated); rats with coronary artery ligation and myocardial infarction; rats with coronary artery ligation and lisinopril (20 mg.kg-1.d-1 in drinking water); sham operated rats receiving lisinopril; and unoperated rats which served as controls to pericardiotomy. Hearts were collected from each group on postoperative day 3 and weeks 1, 2, 4, and 8. RESULTS: There was (1) low angiotensin receptor binding in normal myocardium; (2) markedly increased angiotensin II receptor binding at the site of left ventricular myocardial infarction and endocardial fibrosis of the interventricular septum at day 3 and weeks 1, 2, 4, and 8; (3) high angiotensin II receptor binding in the pericardial fibrosis that followed pericardiotomy, and in the fibrosis that appeared in response to suture insertion around the left coronary artery, in both infarcted and sham operated rats; (4) total displacement of normal and connective tissue angiotensin II receptor binding by DuP753, but not by PD123177; (5) ACE inhibition by lisinopril, but no change in angiotensin II receptor binding, at all sites of fibrosis; and (6) significant attenuation by lisinopril of collagen formation in the visceral pericardium of sham operated controls. CONCLUSIONS: In this model of tissue repair, increased AT1 receptor binding density is associated with ACE binding and fibrillar collagen formation that appears within sites of fibrous tissue formation, including myocardial infarction, endocardial fibrosis, foreign body (silk suture), and pericardiotomy. AT1 receptors may play a role in mediating the fibrogenic response to tissue injury in the rat heart. PMID- 7842455 TI - Electrodiffusive movements of chloride ion in sodium-free solution: a possible calcium activated chloride conductance in cultured heart cells. AB - OBJECTIVE: The aim was to demonstrate that removal of extracellular sodium (Na+o), a manoeuvre known to increase intracellular calcium (Cai2+), can activate a chloride ion conductance in cultured embryonic chick heart cells. METHODS: Intracellular chloride activity (aiCl) and membrane potentials (Em) were simultaneously measured using chloride selective and 3 M KCl filled microelectrodes. RESULTS: In Na+o-free and K+o-free solutions, a frusemide (0.3 mM) resistant decrease in aiCl of 10 mM was recorded within 10 min, along with a 5 mV hyperpolarisation, and the calculated chloride equilibrium potential (ECl) followed the change of Em, suggesting a possibly enhanced chloride conductance. When cells were exposed to Na+o-free solution, the decrease of aiCl by approximately 10 mM was associated with an initial depolarisation, followed by a hyperpolarisation to approximately -60 mV (more negative than ECl). Subsequent removal of K+o depolarised Em to -39 mV (approximately ECl), and no further loss of aiCl occurred. Restoration of K+o caused a hyperpolarisation of Em (more negative than ECl) and a continuing decline of aiCl. Prevention of K+o induced hyperpolarisation by addition of 1 mM Ba2+ stopped the decline of aiCl (Em approximately ECl), suggesting that following Na+o removal, alteration of the driving force for chloride led to a chloride efflux via an enhanced chloride conductance. When Em depolarised to -50 mV after 3 min exposure to 0.1 mM ouabain, removal of [Cl-]o caused a further depolarisation and readdition of [Cl ]o induced an 18 mV hyperpolarisation. This chloride induced hyperpolarisation was blocked by removal of [Ca2+]o (+1 mM EGTA). CONCLUSIONS: The increase in chloride conductance observed under conditions that are known to raise Ca2+i supports the presence of a Ca2+i activated chloride conductance in cultured chick heart cells. PMID- 7842456 TI - Dofetilide reduces the incidence of ventricular fibrillation during acute myocardial ischaemia. A randomised study in pigs. AB - OBJECTIVE: The aim was to investigate whether dofetilide, a new selective cardiac potassium channel blocker, would reduce the incidence of ischaemia induced ventricular fibrillation in closed chest pigs. METHODS: A randomised, blinded, and placebo controlled study was performed in 32 closed chest pigs with a body weight of 70-90 kg. The animals were given a dofetilide/placebo bolus of 25 micrograms.kg-1 over a 10 min period followed by a maintenance dose of 12.5 micrograms.kg-1.h-1 for the next 130 min. Electrocardiograms were recorded during sinus rhythm and during atrial pacing, before (t0) and 20 min (t20) after the beginning of drug treatment. Twenty minutes after the start of drug treatment, acute myocardial ischaemia was induced by inflation of a percutaneous transluminal coronary angioplasty (PTCA) balloon placed in the left anterior descending coronary artery proximal to the first diagonal branch. If ventricular fibrillation occurred during the 2 h ischaemia period the balloon was deflated and defibrillation attempted by dc shocks (360 joules) up to a maximum of 10 shocks. RESULTS: Basal characteristics for the dofetilide group (n = 16) and the placebo group (n = 16) were similar: body weight 76.1(SD 5.4) kg v 75.4(4.4) kg; heart weight 296(29) g v 302(43) g; and heart rate (RR interval) 854(261) ms v 800(307) ms. During atrial pacing 100 beats.min-1 the paced QT interval (QTp) measured at t0 in the dofetilide group and the placebo group were similar, at 335(36) ms v 330(31) ms, respectively. During drug treatment (t20) the QTp interval increased to 412(38) ms in the dofetilide group (p < 0.001) whereas a much smaller increase to 341(32) ms was observed in the placebo group (p < 0.05). The heart rate and ST elevation in the two groups were similar during coronary artery occlusion. During the 2 h ischaemic period, ventricular fibrillation occurred in 6/16 (38%) of the dofetilide treated pigs, and in 13/16 (81%) of the placebo treated pigs (p < 0.01). Defibrillation was successful in 5/6 (83%) and 6/13 (46%) of the animals, respectively (p = 0.3). CONCLUSIONS: Dofetilide significantly reduces the incidence of ischaemia induced ventricular fibrillation in closed chest pigs. PMID- 7842457 TI - Effects of N-methyl hexanoylhydroxamic acid (NMHH) and myoglobin on endothelial damage by hydrogen peroxide. AB - OBJECTIVE: The aim was to investigate the interaction of the novel antioxidant N methyl hexanoylhydroxamic acid (NMHH) with myoglobin in protecting endothelial cells against H2O2 mediated damage. METHODS: Cultured bovine aortic endothelial cells were exposed to 50-100 microM H2O2 for 10-60 min with and without NMHH and/or myoglobin, and immediate or delayed damage was assessed by lactate dehydrogenase release, 3H adenine uptake, a tetrazolium reduction assay, and microscopy. RESULTS: Brief exposure to low concentrations of H2O2 caused cell damage, for which the tetrazolium reduction assay was the most sensitive assay, and inhibited subsequent cell division. NMHH in concentrations from 50 to 200 microM protected against damage provided it was present at the time of adding H2O2, and the effect was markedly potentiated by 10 microM oxymyoglobin, which had little protective effect alone. CONCLUSIONS: NMHH is an effective antioxidant which is markedly potentiated by low concentrations of oxymyoglobin. Oxymyoglobin may potentiate NMHH by scavenging H2O2 through the rapid formation of ferrylmyoglobin, which is then reduced by NMHH. This synergism may be particularly relevant to the protection of myoglobin-rich cells such as myocytes. PMID- 7842458 TI - Effects of oxidants on the sarcoplasmic reticulum of saponin treated rat ventricular trabeculae. AB - OBJECTIVE: The aim was to determine the effects of the superoxide anion, hydrogen peroxide, and hypochlorous acid on in situ cardiac sarcoplasmic reticulum. METHODS: Simultaneous measurement of caffeine induced calcium release from the sarcoplasmic reticulum and subsequent myofilament tension generation was made on saponin permeabilised rat ventricular trabeculae before, during, and after exposure to various reactive oxygen species. The superoxide anion (O2.-) was generated using the xanthine-xanthine oxidase system, hypochlorous acid (HOCl) was prepared from NaOCl, and hydrogen peroxide (H2O2) was added from a 30% stock solution. RESULTS: At [O2.-] sufficient to abolish tension generation by the myofilaments completely, the associated caffeine induced calcium release was unaffected. Both H2O2 and HOCl diminished caffeine induced calcium release but had differential effects on the associated tension response. Exposure to HOCl favoured the occurrence of spontaneous calcium releases from the sarcoplasmic reticulum. CONCLUSIONS: The reactive oxygen species H2O2 and HOCl reduced the amount of calcium release from the sarcoplasmic reticulum while O2.- was without effect. In some preparations it was observed that HOCl favoured spontaneous calcium release which might additionally reduce the calcium content of the sarcoplasmic reticulum. PMID- 7842459 TI - Expression of fibronectin during rat fetal and postnatal development: an in situ hybridisation and immunohistochemical study. AB - OBJECTIVE: Fibronectin is a protein of the extracellular matrix with numerous binding sites to the other elements of the matrix and to the cells. The aim of this study was to determine the relative importance of fibronectin isoform expression (FN-EIIIA, FN-EIIIB) during fetal and postnatal development of the rat heart. METHODS: In situ hybridisation and immunolabelling approaches were used to describe the cellular synthesis of fibronectin and its distribution throughout the rat heart from 11 d postconception until adulthood. The distribution of fibronectin was compared to that of laminin and of alpha type III procollagen. RESULTS: The accumulation and pattern of distribution of the major fibronectin mRNA isoforms were identical, that is, there was a progressive decrease in their accumulation as a function of time after 11 d postconception, resulting in a complete absence in the adult. The distribution of fibronectin and procollagen type III mRNAs were, however, quite distinct. At the protein level the time course of synthesis and secretion of the locally synthesised fibronectin (c-FN) did not follow fibronectin mRNA expression, the accumulation of the protein being rather poor, except just before birth, where it was found mainly in the coronary vessels. CONCLUSIONS: During the development of the fetal rat heart fibronectin gene transcription is active and progressively decreases with age, whereas the translation of the mRNAs into their corresponding proteins is always relatively poor. If fibronectin is involved in fetal and postnatal morphogenesis of the rat myocardium, it is the plasma form (p-FN) that is most probably involved in the process of growth and differentiation of the rat heart. PMID- 7842461 TI - Intravenous administration of the endothelin-1 antagonist BQ-123 does not ameliorate myocardial ischaemic injury following acute coronary artery occlusion in the dog. AB - OBJECTIVE: It has been proposed that myocardial ischaemic injury is modulated in part by the release of endothelin-1 from the coronary endothelium either during ischaemia or following reperfusion. Release of sufficient amounts of endothelin-1 would result in coronary vasoconstriction and could potentiate ischaemic damage. An endothelin-1 antagonist, BQ-123, was given intravenously to evaluate the role of endothelin-1 in postischaemic injury and determine whether blockade of the ETA receptor would afford protection from ischaemia/reperfusion injury. METHODS: Myocardial injury was induced in anaesthetised dogs using 90 min of left circumflex coronary artery occlusion followed by 4 h of reperfusion. Animals treated with a continuous intravenous infusion of BQ-123 (0.1 mg.kg-1.min-1), begun 10 min before ischaemia and continued throughout ischaemia and reperfusion, were compared to saline treated animals. RESULTS: After 4 h of reperfusion the myocardial infarct size measured by triphenyltetrazolium chloride staining was not different between the two groups. Infarct size in the control group was 25.7 (SEM 5.4)% of the area at risk while BQ-123 treatment resulted in an infarct size of 29.2(7.1)% of the area at risk (p = 0.70). Plasma endothelin-1 concentration measured at the coronary sinus was only significantly increased following 5 min of reperfusion. CONCLUSIONS: The intravenous administration of a specific ETA receptor antagonist does not protect against ischaemia/reperfusion injury. These results suggest that endothelin-1 receptor antagonists require access to the area at risk during occlusion to protect the myocardium from ischaemic injury. PMID- 7842460 TI - Myocardial ischaemia induces platelet activation with adverse electrophysiological and arrhythmogenic effects. AB - OBJECTIVE: The aim was to investigate how platelet activation during myocardial ischaemia can induce electrophysiological and arrhythmogenic effects, and examine the involvement of different platelet membrane receptors in producing these effects. METHODS: Transmembrane action potentials and electrograms were recorded from isolated, Langendorff perfused guinea pig hearts during normal perfusion, global myocardial ischaemia, and reperfusion during infusion of human platelets. Platelet reactivity was altered by treating platelets with forskolin, aspirin, the platelet activating factor (PAF) receptor antagonist BN 52021, the thromboxane A2 (TP) receptor antagonist GR 32191B, and the alpha 2 adrenoceptor antagonist yohimbine. Myocardial catecholamine depletion was induced by treatment with 6-hydroxydopamine. RESULTS: Platelet infusion had no electrophysiological effects during normal perfusion, but during ischaemia it enhanced the reduction in action potential duration at 95% repolarisation [APD95, 110(SEM 3) ms v 121(5) ms, p < 0.05, at 15 min] and increased the incidence of ventricular arrhythmias (from 56% to 94%, p = 0.04) compared to hearts receiving buffer but no platelets. The reductions in APD95 and the arrhythmogenic effects were attenuated when forskolin treated, aspirin treated or GR 32191B treated platelets were infused (VF: 50% v 94%, p = 0.03; 50% v 94%, p = 0.02; 22% v 94%, p < 0.001, respectively). Similar results were obtained when normal platelets were infused into catecholamine depleted hearts (VF: 60% v 94%, p = 0.0549). These differences were associated with inhibited aggregatory responses to thrombin (for forskolin treated platelets) and the thromboxane mimetic U44069 (for GR 32191B treated platelets). Yohimbine was antiarrhythmic in the presence and absence of platelets, suggesting direct myocardial effects, but BN 52021 had no antiarrhythmic effects. CONCLUSIONS: Myocardial ischaemia causes platelet activation resulting in electrophysiological and arrhythmogenic effects. PAF receptor antagonism does not prevent these effects, but inhibition of platelet reactivity, platelet thromboxane receptor antagonism, and myocardial catecholamine depletion are effective. These findings suggest that the arrhythmogenic effects of platelet activation during myocardial ischaemia are principally mediated by a thromboxane dependent mechanism, while catecholamine release has a contributory role. PMID- 7842462 TI - Morphological evidence for the antiatherogenic effect of scoparone in hyperlipidaemic diabetic rabbits. AB - OBJECTIVE: Scoparone (6,7-dimethoxycoumarin), a coumarin isolated from a hypolipidaemic Chinese herb Artemisia scoparia, has vasodilator and antiproliferative activities and possesses free radical scavenging properties in vitro. The aim of the study was to investigate the morphological effects of scoparone in the antiatherogenic process in vivo by using hyperlipidaemic diabetic rabbits as an animal model. METHODS: Male New Zealand White rabbits were divided into three groups: control (normal), hyperlipidaemic diabetic, and scoparone treated hyperlipidaemic diabetic. The plasma concentration of total cholesterol and triglycerides were determined. The thickness of the tunica intima was measured on paraffin sections of the aortas stained with Movat's pentachrome. The aortic samples were also processed for scanning and transmission electron microscopy. RESULTS: Neither the lipid profile in the plasma nor the structures of the aortic wall from the control group showed abnormalities. In contrast, the aortas from the hyperlipidaemic diabetic group showed prominent atherosclerotic plaques. Large numbers of monocytes were found adherent to the luminal surface and a markedly thickened intima filled with many lipid laden foam cells was clearly observed. By comparison, the scoparone treated group showed less advanced atherosclerosis with a lower plasma cholesterol. In the scoparone treated rabbits, the proportion of the aortic surface area covered with macroscopic plaques was 30%, and the thickness of the tunica intima 17%, of that of the non scoparone treated hyperlipidaemic diabetic rabbits. CONCLUSIONS: Scoparone has an antiatherogenic action in hyperlipidaemic diabetic rabbits. PMID- 7842463 TI - Influence of heart rate and vasoactive drugs on blood flow patterns at the canine ilio-femoral bifurcation. AB - OBJECTIVE: The aim was to study the effects of altered heart rate and vasoactive drugs on the blood velocity patterns in the region of an arterial bifurcation. METHODS: Blood velocity profiles were measured in an exposed iliofemoral bifurcation of paced dogs using a pulsed Doppler ultrasound velocimeter with high temporal and spatial resolution. RESULTS: Decrease of the heart rate from 120 beats.min-1 (2 Hz) to 60 beats.min-1 (1 Hz) increased the peak forward velocity (30%), the peak reverse velocity (20%), and the duration of reverse flow (25%). Each drug caused qualitatively similar changes in velocity patterns at both heart rates. The systemic administration of angiotensin II reduced peak forward velocity (-26% at 2 Hz and -33% at 1 Hz) and forward flow duration (-15% at 1 Hz), the peak reverse velocity (-30% at 1 Hz), and reverse flow duration (-20% at 2 Hz and -28% at 1 Hz). Glyceryl trinitrate also reduced the peak forward velocity (-19% at both 2 and 1 Hz) but prolonged forward flow duration (28% at 2 Hz and 17% at 1 Hz) and that of reverse flow (45% at 2 Hz and 24% at 1 Hz), and also decreased the degree of oscillation (-16% at 2 Hz). Barnidipine hydrochloride (a calcium channel antagonist) also increased the duration of forward flow (48% at 1 Hz) and of reverse flow (31% at 2 Hz) but reduced the peak reverse velocity (-29% at 1 Hz) and flow oscillation (-22% at 2 Hz and 20% at 1 Hz). CONCLUSIONS: These dramatic changes in the pattern of blood flow, including alterations in the amplitudes and durations of the different phases of the flow cycle, are expected to have important consequences on the shear dependent responses of endothelial cells in the region of the bifurcation. PMID- 7842464 TI - Modulation of myocardial relaxation by basal release of endothelin from endocardial endothelium. AB - OBJECTIVE: The aim was to study the potential role of basal endothelin-1 release from endocardial endothelium in isolated ferret papillary muscle preparations. METHODS: The following interventions were studied: (1) no treatment (time control); (2) endothelin-1 (5 nM); (3) endothelin-1 (5 nM) in the presence of the specific ETA receptor antagonist, BQ123 (10 microM); (4) BQ123 (10 microM) in endocardium-intact muscles; and (5) BQ123 (10 microM) in endocardium-denuded muscles (n = 6 in each group). RESULTS: Untreated muscles remained stable throughout the experiment. BQ123 fully inhibited the positive inotropic effect of exogenous endothelin-1. In endocardium-intact preparations (n = 6), exposure to BQ123 induced a progressively earlier onset and time course of isometric twitch relaxation [time to peak tension -12.3(SEM 1.8)%, relaxation half time 13.3(1.1)%; both p < 0.01], but had no effect on peak tension or on rate of tension development. Selective denudation of endocardial endothelium induced similar relaxant effects, but also significantly reduced peak tension. In endocardial endothelium-denuded preparations (n = 6), addition of BQ123 did not result in further contractile changes. CONCLUSIONS: Endocardial endothelium in situ on papillary muscle preparations tonically releases endothelin, resulting in a significantly delayed onset of isometric twitch relaxation. There is no evidence for basal endothelin-1 release from microvascular endothelial cells in this superfused preparation. A similar release of endothelin-1 from endocardial endothelium in the intact heart could influence myocardial contractile behaviour independently of changes in coronary perfusion. Endothelin-1 may have a physiological role in modulating myocardial relaxation. PMID- 7842465 TI - Preconditioning of isolated rabbit cardiomyocytes: effects of glycolytic blockade, phorbol esters, and ischaemia. AB - OBJECTIVE: The aim was to discriminate among several hypotheses of preconditioning of isolated rabbit cardiomyocytes and to determine if ischaemic preincubation would evoke a protective response. METHODS: Isolated myocytes were subjected to 5 min of preincubation, in the presence or absence of glucose, and incubated in the presence of 1 mM iodoacetic acid during the final sustained ischaemic period. In a second series, the protein kinase C (PKC) activators phorbol 12-myristate 13-acetate (PMA), ingenol 3, 20-dibenzoate, and thymeleatoxin were added during preincubation. In a third series, preincubation periods were substituted by brief ischaemic pelleting of cells. Final prolonged ischaemic pelleting was preceded by a 30 min postincubation period. Rate and extent of injury was determined by sequential sampling and assessment of trypan blue permeability following 85 mOsM swelling. RESULTS: Myocytes were preconditioned by a 5 min glucose-free preincubation. Addition of iodoacetic acid into the final ischaemic pellet increased the rates of rigor contracture and injury, but did not abolish the protective response. Direct protein kinase C activation with PMA, a non-selective phorbol ester, and ingenol, an epsilon, delta-PKC isozyme selective activator, protected cells, but thymeleatoxin, an alpha, beta, gamma-PKC isozyme selective activator, did not. A 10 min ischaemic preincubation preconditioned, but the protection was not enhanced when ischaemia was extended to 30 min, or when PMA was included during the initial ischaemic preincubation. Adenosine partially inhibited the response. CONCLUSIONS: (1) Preconditioning of isolated myocytes is not dependent on glycolysis or glucose transport. (2) Preconditioning appears dependent on activation of the epsilon-PKC isoform. (3) Ischaemia is capable of preconditioning isolated myocytes in vitro, and initiation of this effect is modified by simultaneous additional of adenosine but not by direct protein kinase C activation with PMA. Induction of protection by PMA and ingenol shows that protection requires protein kinase C activation, but direct potassium channel activation by regulatory G proteins is not critical. PMID- 7842466 TI - Orthotopic cardiac transplantation reverses abnormal reflex regulation of the microvasculature in the lower leg. AB - OBJECTIVE: The aim was to investigate the effect of cardiac transplantation on reflex control of lower leg subcutaneous blood flow. METHODS: The reflex regulation of subcutaneous blood flow of the lower leg was studied in 11 patients following orthotopic cardiac transplantation, in 11 patients with severe congestive heart failure (New York Heart Association functional class III or IV), and in 11 healthy subjects. Four patients were studied before and after cardiac transplantation. Cause of heart failure was classified as idiopathic dilated cardiomyopathy in all heart failure patients and in all the cardiac transplant patients before transplantation. Blood flow was measured by the local 133xenon washout method in the supine position and during 45 degrees head up tilt. RESULTS: When performing head up tilt without activation of the local nervous venoarteriolar axon reflex in patients with congestive heart failure, the relative subcutaneous blood flow increased abnormally, by 50(SD 25)%, but in patients after cardiac transplantation a normal decrease was seen [-28(13)%, p < 0.001]. The responses in the transplant group were similar to those observed in normal controls with a decrease in blood flow [-32(15)%; NS]. Head up tilt with simultaneous activation of the local venoarteriolar axon reflex increased blood flow [31(22)%] in patients with heart failure as compared to the decrease in blood flow found in the transplants [-44(17)%, p < 0.001]. The decrease of blood flow was not significantly different between the transplant group and control subjects [-53(19)%; NS]. CONCLUSIONS: These results indicate that abnormal reflex regulation in severe congestive heart failure with peripheral vasodilation of the lower leg during orthostasis is reversed and even normalised after cardiac transplantation. The haemodynamic consequence may be a regaining of an oedema protective mechanism that eliminates the stress (capillary hypertension) on the microcirculation seen in severe heart failure. PMID- 7842467 TI - cAMP concentrations, cAMP dependent protein kinase activity, and phospholamban in non-failing and failing myocardium. AB - OBJECTIVE: Several signal transduction defects such as a reduction of myocardial cAMP formation and an altered intracellular Ca2+ handling have been observed in the failing human myocardium. The aim of the study was to obtain data on changes beyond cAMP formation involving cAMP dependent protein kinase and its substrates. METHODS: cAMP dependent protein kinase activity and cAMP concentrations were measured in the particulate and soluble fraction of failing human hearts (ischaemic, and dilated cardiomyopathy) and non-failing donor hearts. Phospholamban was quantified by cAMP dependent phosphorylation using 32P-ATP as substrate and on western blots using a monoclonal antibody. RESULTS: cAMP concentrations were reduced in the particulate fraction in both ischaemic and dilated cardiomyopathy and in the soluble fraction in dilated cardiomyopathy, but there was no difference in cAMP dependent protein kinase activity. Both phospholamban levels and cAMP dependent phosphorylation of phospholamban were similar in non-failing myocardium and in both ischaemic and dilated cardiomyopathy. CONCLUSIONS: These findings show that the reduction of cAMP formation is the predominant alteration in heart failure, but cAMP dependent protein kinase and phospholamban are evidently unchanged. PMID- 7842469 TI - Anonymity of reviewers. PMID- 7842468 TI - Transient beta adrenergic stimulation can precondition the rat heart against postischaemic contractile dysfunction. AB - OBJECTIVE: The aim was to assess the abilities of exogenous noradrenaline, isoprenaline, and phenylephrine to precondition the isolated rat heart against ischaemic and reperfusion injury. METHODS: The isovolumetric Langendorff rat heart model was used to determine postischaemic recovery of left ventricular function. The hearts were subjected to 30 min of normothermic global ischaemia followed by 30 min reperfusion. Treated hearts were perfused with noradrenaline (10(-7) M), isoprenaline (10(-8) M), or phenylephrine (10(-6) M, 10(-5) M, and 10(-4) M) for 5 min followed by 5 min washout before the 30 min ischaemic period. RESULTS: Control hearts recovered 47.6(SEM 4.3)% of baseline heart rate x developed pressure after 30 min reperfusion, whereas noradrenaline and isoprenaline treated hearts recovered 75.1(4.6) and 76.4(4.6)%, respectively (p < 0.001 v control). Left ventricular end diastolic pressures at the end of reperfusion were 48.8(4.0), 20.0(2.4), and 21.6(2.7)mm Hg for control, noradrenaline treated (p < 0.001 v control), and isoprenaline treated (p < 0.001 v control) hearts respectively. beta Blockade with propranolol during noradrenaline treatment blocked the protective effects. No concentration of phenylephrine used was able to enhance postischaemic heart rate x developed pressure significantly, or result in improved (lower) postischaemic left ventricular end diastolic pressure. During treatment with noradrenaline and phenylephrine (10(-5) M), lactate release was 13.0(1.0) and 11.0(0.9) mumol.5 min 1, respectively (p = NS); these values were significantly (p < 0.001) greater than baseline value of 3.7(0.5) mumol.5 min-1. Immediately before the 30 min ischaemic period, control and phenylephrine treated groups had glycogen levels of 132(14) and 128(5) nmol.mg-1 protein, respectively (p = NS), whereas the glycogen content of the noradrenaline treated group was only 96(5) nmol.mg-1 protein (p < 0.05 v control and phenylephrine treated). CONCLUSIONS: Transient beta adrenergic but not alpha 1 adrenergic stimulation can precondition the isolated perfused rat heart. The mechanism of protection may, at least in part, be due to transient demand ischaemia. Partial depletion of glycogen following treatment may play a role in the observed protective effects. PMID- 7842470 TI - Never say never again. PMID- 7842471 TI - A selective endothelin ETA antagonist, BQ-123, inhibits 125I-endothelin-1 (125I ET-1) binding to human meningiomas and antagonizes ET-1-induced proliferation of meningioma cells. AB - 1. We studied the effects of BQ-123, a selective ETA receptor antagonist, on 125I endothelin-1 (125I-ET-1) binding to cell surface receptors in surgically exercised human meningiomas and on ET-1-induced DNA synthesis in cultured human meningioma cells in vitro, using a quantitative receptor autoradiographic technique with radioluminography and 3H-thymidine incorporation, respectively. 2. All of the human meningiomas expressed high-affinity binding sites for 125I-ET-1, regardless of differences in histological subtypes (Kd = 2.6 +/- 0.2 nM, Bmax = 374 +/- 93 fmol/mg; mean +/- SE; n = 9). 3. BQ-123 competed for 125I-ET-1 binding to sections of meningiomas with IC50S of 3.2 +/- 0.9 x 10(-7) M, and 10(-4) M BQ 123 displaced 80% of the binding. 4. ET-1 significantly stimulated DNA synthesis in cultured human meningioma cells, up to 170% of the basal level in the presence of 10(-9) M ET-1. BQ-123 inhibited ET-1 (10(-9) M)-induced DNA synthesis in meningioma cells, in a dose-dependent manner, and 10(-5) M BQ-123 reduced it to 120% of the basal level. 5. The number of meningioma cells determined after 4 days in culture was dose dependently increased in the presence of ET-1 (10(-9) and 10(-7) M). The growth rate of meningioma cells, incubated with 10(-9) M ET-1, was reduced by 50% in the presence of 10(-7) M BQ-123.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7842472 TI - Lack of correlation between 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and lovastatin resistance in nerve growth factor treated PC-12 cells. AB - 1. The relationships among the mevalonic acid (MVA) forming enzyme, 3-hydroxy-3 methylglutaryl coenzyme A (CoA) reductase, cell growth and differentiation, and the cytotoxic effects of the reductase inhibitor lovastatin were studied in PC-12 cells, exposed to growth factors. 2. When added individually, nerve growth factor (NGF), basic fibroblast growth factor, and epidermal growth factor induce an increase in HMG-CoA reductase activity in cells grown in serum-containing medium. In the presence of serum, the effect of NGF on HMG-CoA reductase is persistent. 3. Short-term serum starvation and long-term NGF treatment, in combination, have an additive effect, resulting in a high reductase activity. 4. Unlike serum and MVA, which downregulate levels of HMG-CoA reductase by accelerating its degradation, NGF upregulates reductase by slowing the rate of its degradation. This mechanism, however, appears to operate only in the presence of serum, as after prolonged growth with NGF in serum-free medium, cells have a low reductase activity. 5. PC-12 cells grown in the absence of NGF are highly sensitive to lovastatin (25 microM) and more than 70% of the cells die after 48 hr. NGF confers lovastatin resistance on cells grown in the presence or in the absence of serum (only 30-40% cell death after 48 hr with lovastatin). 6. NGF-induced resistance on lovastatin develops with time and is apparent only in the well differentiated PC-12 cells whether or not the cells express a high reductase activity.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7842473 TI - Effects of the amphiphilic peptides mastoparan and adenoregulin on receptor binding, G proteins, phosphoinositide breakdown, cyclic AMP generation, and calcium influx. AB - 1. The amphiphilic peptide mastoparan is known to affect phosphoinositide breakdown, calcium influx, and exocytosis of hormones and neurotransmitters and to stimulate the GTPase activity of guanine nucleotide-binding regulatory proteins. Another amphiphilic peptide, adenoregulin was recently identified based on stimulation of agonist binding to A1-adenosine receptors. 2. A comparison of the effects of mastoparan and adenoregulin reveals that these peptides share many properties. Both stimulate binding of agonists to receptors and binding of GTP gamma S to G proteins in brain membranes. The enhanced guanyl nucleotide exchange may be responsible for the complete conversion of receptors to a high-affinity state, complexed with guanyl nucleotide-free G proteins. 3. Both peptides increase phosphoinositide breakdown in NIH 3T3 fibroblasts. Pertussis toxin partially inhibits the phosphoinositide breakdown elicited by mastoparan but has no effect on the response to adenoregulin. N-Ethylmaleimide inhibits the response to both peptides. 4. In permeabilized 3T3 cells, both adenoregulin and mastoparan inhibit GTP gamma S-stimulated phosphoinositide breakdown. Mastoparan slightly increases basal cyclic AMP levels in cultured cells, followed at higher concentrations by an inhibition, while adenoregulin has minimal effects. 5. Both peptides increase calcium influx in cultured cells and release of norepinephrine in pheochromocytoma PC12 cells. The calcium influx elicited by the peptides in 3T3 cells is not markedly altered by N-ethylmaleimide. 6. Multiple sites of action appear likely to underlie the effects of mastoparan/adenoregulin on receptors, G proteins, phospholipase C, and calcium. PMID- 7842474 TI - Human immunodeficiency virus protein gp120 interferes with beta-adrenergic receptor-mediated protein phosphorylation in cultured rat cortical astrocytes. AB - 1. We have previously shown that acute exposure to the HIV coat protein gp120 interferes with the beta-adrenergic regulation of astroglial and microglial cells (Levi et al., 1993). In particular, exposure to 100 pM gp120 for 30 min depressed the phosphorylation of vimentin and glial fibrillary acidic protein (GFAP) induced by isoproterenol in rat cortical astrocyte cultures. In the present study we have extended our analysis on the effects of gp120 on astroglial protein phosphorylation. 2. We found that chronic (3-day) treatment of the cells with 100 pM gp120 before exposure to isoproterenol was substantially more effective than acute treatment in depressing the stimulatory effect of the beta-adrenergic agonist on vimentin and GFAP phosphorylation. 3. Even after chronic treatment with gp120, no differences were found in the levels and solubility of these proteins. 4. Besides stimulating the phosphorylation of intermediate filament proteins, isoproterenol inhibited the incorporation of 32P into a soluble acidic protein of 80,000 M(r), which was only minimally present in Triton X-100 insoluble extracts. 5. Treatment of astrocytes with a phorbol ester or exposure to 3H-myristic acid indicated that the acidic 80,000 M(r) protein is a substrate for protein kinase C (PKC) and is myristoylated, thus suggesting that it is related to the MARCKS family of PKC substrates. 6. Acute (30-min) treatment with 100 pM gp120 totally prevented the inhibitory effect of isoproterenol on the phosphorylation of the 80,000 M(r) MARCKS-like protein. 7. Our studies corroborate the hypothesis that viral components may contribute to the neuropathological changes observed in AIDS through the alteration of signal transduction systems in glial cells. PMID- 7842476 TI - S-(+)-aporphines are not selective for human D3 dopamine receptors. AB - 1. Our aim was to test the hypothesis that selectivity for D3 dopamine (DA) receptors may contribute to limbic anti-DA selectivity of S-(+)-aporphine DA partial agonists. 2. Affinity was tested with 3H-emonapride, using human D3 receptors in mouse fibroblasts and D2 receptors in rat striatal tissue. 3. D3 receptors showed a picomolar affinity for 3H-emonapride, Na+ dependence, and reversible saturability, as well as stereoselectivity. Confirmatory or novel D3/D2 pharmacologic selectivity was found with several benzamides, thioxanthenes, buspirone, GBR-12909, and DA agonists including hydroxyaminotetralins [ADTN, (+) 7-OH-DPAT, (-)-PPHT and its fluorescein derivative], (-)-N-propylnorapomorphine, (-)-3-PPP, (-)-quinpirole, and SDZ-205-502, but neither aminoergoline nor (+) aporphine partial agonists. 4. The results extend pharmacologic characterization of D3-transfected cell membranes but fail to account for the high limbic anti-DA selectivity of S-(+)-aporphines. PMID- 7842475 TI - Inhibition of the calcitonin-induced outward current in identified Aplysia neurons by interleukin-1 and interleukin-2. AB - 1. The effects of bath-applied recombinant human interleukin-1 (rhIL-1) and interleukin-2 (rhIL-2) on the calcitonin (CT)-induced outward current recorded from identified neurons (R9-R12) of Aplysia kurodai were investigated with conventional voltage-clamp and pressure ejection techniques. 2. Micropressure ejection of CT onto the soma of the neuron induced a slow outward current [Io(CT); 4-6 nA in amplitude, 30-40 sec in duration] associated with a decrease in input membrane conductance. 3. Io(CT) was increased by hyperpolarization. 4. The extrapolated reversal potential was +10 mV. Additionally, Io(CT) was sensitive to changes in (Na+)o but not to changes in (K+)o, (Ca2+)o, and (Cl-)o. 5. Micropressure-ejected forskolin produced a slow outward current similar to that induced by CT. 6. Bath-applied rhIL-1 and rhIL-2 (10-40 U/ml) reduced the CT induced current in identified Aplysia neurons without affecting the resting membrane conductance or the holding current. 7. The inhibitory effects of both cytokines on the current were completely reversible. Heat-inactivated rhIL-1 and rhIL-2 were without effect. 8. These results suggest that the immunomodulators, IL-1 and IL-2, can modulate the CT-induced outward current associated with a decrease in Na+ conductance in the nervous system of Aplysia. Therefore, the study suggests that these cytokines may also serve as neuromodulators. PMID- 7842477 TI - Role of 5'-lipoxygenase metabolites in the activation of peritoneal macrophages for tumoricidal function. AB - Metabolites of arachidonic acid have been shown to be potent biological modulators of macrophage function. While the role of cyclooxygenase metabolites of arachidonic acid have been well studied, metabolites of lipoxygenase have not. In this report, we evaluate the role that select 5'-lipoxygenase (5'-LO) products may play in macrophage activation for select tumoricidal functions. When thioglycollate-elicited macrophages were treated with inhibitors of 5'-LO during activation, cytolytic capacity, nitric oxide production, and tumor necrosis factor-alpha production were significantly inhibited. Moreover, both an inhibitor of the 5'-LO-activating protein and an inhibitor of glutathione-s-transferase (GST) significantly decreased macrophage tumoricidal function. The activating agents used were able to stimulate 5'-LO activity which was measured by quantitating secreted LTC4. Increased production of PGE2 by shunting could have been the cause for decreased macrophage tumoricidal function. However, treatment of macrophages with inhibitors of 5'-LO during lipopolysaccharide stimulation did not increase formation of PGE2. When select 5'-LO metabolites were added to cultures during activation and 5'-LO inhibition, tumoricidal activity could not be restored, even when the metabolites were encapsulated in liposomes. These results suggest that the activity of 5'-LO and GST are important for macrophage activation. However, the specific role of 5'-LO metabolites has not been completely established. PMID- 7842479 TI - Nonresponsiveness of AKR.H-2b congenic mice for anti-AKR/Gross MuLV CTL responses: involvement of inhibitory cells as defined by adoptive transfer experiments. AB - AKR.H-2b mice are unable to elicit AKR/Gross murine leukemia virus (MuLV) specific cytolytic T lymphocyte (CTL) responses. The participation of inhibitory cells was addressed through adoptive transfer experiments utilizing young AKR.H 2b:Fv-1b congenic responder mice as the recipients of AKR.H-2b donor cells. The adoptive transfer of unfractionated viable splenocytes led to inhibition of virus specific CTL responsiveness without affecting minor histocompatibility or allogeneic (H-2d)-specific CTL responses. Negative cell selection studies indicated that of the donor AKR.H-2b spleen cells that mediate specific inhibition, B lymphocytes, CD4-CD8+ and CD4+CD8- T lymphocytes, but not macrophages, even though they are viral antigen positive (as are B and T lymphocytes), were the cells responsible for the diminution of the generation of AKR/Gross virus-specific CTL by AKR.H-2b:Fv-1b mice. To evoke maximal inhibition, the adoptive transfer of AKR.H-2b cells had to be performed prior to in vivo priming with viral antigen. Anti-AKR/Gross MuLV nonresponsiveness of AKR.H-2b mice could not be overcome through utilization of exogenous IL-2 at either the priming or in vitro restimulation phases of CTL generation. These results illustrate the complex interaction between retroviruses and lymphocytes and are relevant to understanding how retrovirus-infected cells may not only escape immune surveillance themselves, but also may inhibit the cytolytic T cell response directed at other infected cells, such as tumor cells. PMID- 7842478 TI - Transient dominance of the early primary immune response by a highly conserved B cell clone that is distinguished by its lack of memory, high threshold of activation, and a high affinity. AB - We establish here that the very early primary response to the hapten phthalate (Xmp) is distinguished by a restricted heterogeneity with over 80% of the anti Xmp antibodies expressing a single well-defined cross-reactive idiotype (CRIXmp 1) associated with a previously described highly conserved clonotype that is expressed by most inbred strains of mice and many outbred mouse populations as well. The characteristic early dominance of this one clonotype in the primary response is transient. While the CRIXmp-1 clonotype is present later in the primary and throughout the secondary response, it represents only a very small proportion of the total anti-Xmp antibody population at these times. The early dominance of the single clonotype is rapidly replaced by a heterogeneous population of antibodies. Differential activation thresholds for the primary response clonotype (CRIXmp-1) and secondary response clonotypes, and the failure of the dominant primary response clonotype to expand in the secondary response (i.e., absence of memory) suggest the presence of two distinct B-cell lineages. PMID- 7842480 TI - Apolipoprotein E restricts interleukin-dependent T lymphocyte proliferation at the G1A/G1B boundary. AB - Apolipoprotein E (apoE), a lipid transport protein important in cholesterol homeostasis, inhibits the proliferation of interleukin-dependent lymphocytes. Growth factor-responsive cells are blocked in the G1A phase of the cell cycle. Suppression by apoE is independent of growth factor, as evidenced by the fact that interleukin-2 (IL2)- and IL4-dependent proliferation of HT-2 T lymphocytes is equally inhibited. apoE has no effect on IL2-augmented killing of target cells by cytotoxic T cells, indicating that it has no direct effect on signaling via interleukin receptors. The data are consistent with inhibition by apoE of an event or pathway distal to receptor signaling and required for G1A transition, or G1B entry. PMID- 7842481 TI - Contribution of p56lck to the upregulation of cytokine production and T cell proliferation by IL-2 in human CD3-stimulated T cell clones. AB - Interaction of the interleukin 2 receptor (IL-2R) beta chain with the lymphocyte specific protein tyrosine kinase (PTK), p56lck, has led to the speculation that p56lck participates in growth signal transduction. Although activation of T cells with interleukin 2 (IL-2) results in the activation of p56lck, accumulating data support the notion that Lck does not play an essential role in mitogenic signal delivery from the IL-2R. Since this src-related PTK has been shown to enhance TCR/CD3-mediated T cell responsiveness, here we investigated whether activation of Lck by IL-2 could contribute to enhance TCR/CD3-mediated T cell functions. This was achieved by using human CD4(+)-cloned T cells and comparing the effects of IL-2 on p56lck kinase activation and cytokine production. Results show that p56lck kinase activity increased as early as 1 min, reached a maximum within 5 min and decreased within 60 min after IL-2 stimulation. Such treatment with IL-2 also resulted in enhancing T cell responsiveness to CD3+PMA stimulation, as assessed by IL-2 and IFN-gamma secretion and by T cell proliferation. This increase of T cell functions was correlated with IL-2-induced p56lck activation in both dose-response and time-course experiments. Taken together these results strongly suggest that activation of Lck by IL-2 may play a role in regulating CD3 mediated T cell functions. PMID- 7842482 TI - Murine nursing thymic epithelial cell lines capable of inducing thymocyte apoptosis express the self-superantigen Mls-1a. AB - Two cloned thymic epithelial cell (TEC) lines, D2.TEC-A3 and AKR TEC-K1, were established from minor lymphocyte-stimulating (Mls)-1a-positive normal, 4-week old DBA/2 (H-2d, Mls-1a2a) mice and AKR (H-2k, Mls-1a2b) mice, respectively. Both cell lines were MHC class I and class II (both I-A and I-E) positive without stimulation by interferon-gamma. They were capable of infolding immature thymocytes to form thymic nurse cells (TNC; we call this type of TEC "nursing TEC") and induced apoptosis with DNA fragmentation in immature thymocytes. Using a primary Mls mixed lymphocyte reaction (MLR) we demonstrated that self superantigen Mls-1a was expressed on these cloned nursing TEC lines. D2.TEC-A3 cells stimulated nylon-wool-purified splenic T cells obtained from H-2d compatible BALB/c (Mls-1b2a) and B10.D2 (Mls-1b2b) mice with a maximal response at a stimulator:responder ratio of 1:40 after 4 days of the coculture. AKR TEC-K1 cells also stimulated purified T cells from H-2k-compatible C3H/He mice (Mls 1b2a) in a similar manner. The Mls MLR induced by the nursing TEC lines was completely inhibited in the presence of anti-mouse I-A and anti-mouse I-E monoclonal antibodies. These results suggest that nursing TEC/TNC could be involved in negative selection due to apoptosis. PMID- 7842483 TI - Stimulation of human lymphocytes by cathepsin G. AB - We investigated the effect of cathepsin G, a serine protease in polymorphonuclear granulocytes, on the function of human lymphocytes. Cathepsin G increased the [3H]thymidine incorporation into human lymphocytes. This mitogenic activity was due to the proteolytic activity of cathepsin G. Both B and T cells showed increased [3H]thymidine incorporation, and this effect was more remarkable for T cells than for B cells. Among the T cell subsets, CD4+ T cells showed the increase in DNA synthesis, but CD8+ T cells did not. When human lymphocytes were stimulated with cathepsin G, intracellular free Ca2+ concentration ([Ca2+]i) increased in B and T cells, including CD4+ T cells and CD8+ T cells. The change in intracellular Ca2+ was due to Ca2+ influx and release of intracellular stores. Cathepsin G also induced the production of inositol 1,4,5-trisphosphate (IP3) in B cells, CD4+ T cells, and CD8+ T cells, leading to the release of Ca2+ from intracellular stores. Moreover, the stimulation with cathepsin G resulted in alkalization of the cytosol of B cells, CD4+ T cells, and CD8+ T cells as the result of Na+/H+ antiport activation. The change in intracellular Ca2+, production of IP3, and cytoplasmic alkalization in lymphocytes were due to its proteolytic activity. Cathepsin G released from granulocytes is considered to act on human lymphocytes in vivo and lead to the increase in DNA synthesis of B cells and CD4+ T cells through IP3 production, an increase in [Ca2+]i, and alkalization. However, these second messengers do not lead to the increase in DNA synthesis of CD8+ T cells. PMID- 7842484 TI - Diversity of T cell receptors specific for the VSV antigenic peptide (N52-59) bound by the H-2Kb class I molecule. AB - As an approach to determine the structural basis of interactions between T cell receptors (TCRs) and MHC class I/peptide complexes, the fine specificities of a panel of vesicular stomatitis virus (VSV)-specific CTL clones recognizing the antigenic peptide (nucleoprotein 52-59) and the class I (Kb) molecule were correlated with the TCR primary structure. Each TCR showed a distinct interaction pattern with N52-59 and the Kb molecule. The large majority of the TCRs expressed by the panel of CTL clones used V beta 13 gene segments that had randomly recombined with D beta and J beta gene segments. The alpha chains were from randomly assorted V alpha and J alpha gene segments. Thus, the panel was found to be a highly heterogeneous set of TCRs, each member of which appeared to have an unique surface interface area, the recognition site, that interacted with a complementary surface formed by the single peptide bound in the class I antigenic groove. PMID- 7842485 TI - Steroid sex hormones regulate the release of tumor necrosis factor by macrophages. AB - Generally, females have been found to have a heightened immune response and a concomitantly higher incidence of autoimmune diseases compared to males. We have used male rat peritoneal macrophages (M phi) to study the effect of female sex hormones on tumor necrosis factor (TNF) release. The amount of TNF released by macrophages (M phi) exposed to 10(-2) and 10(-3) ng/ml of 17 beta-estradiol (E2) (35.1 +/- 7.3 and 23.2 +/- 2.5 units/ml, respectively) was significantly (P < 0.05; n = 9) greater than that released by untreated M phi. Progesterone (P) also significantly (P < 0.05; n = 8) stimulated a maximal TNF release (24.4 +/- 2.8 units/ml TNF) at 10(-2) ng/ml. On the other hand, the amount of TNF released by M phi exposed to E2 or P at concentrations greater than 10(-1) or less than 10(-4) ng/ml was significantly (P < 0.05) reduced compared to untreated controls. In contrast, testosterone did not significantly affect TNF release at any concentration. Within the physiological range of E2 and P concentrations, TNF release from M phi is finely regulated and dramatically affected by relatively small changes in hormone concentrations. PMID- 7842486 TI - Staphylococcal enterotoxin B modulates V beta 8+ TcR-associated T-cell memory against conventional antigen. AB - Primary in vivo challenge with the superantigen staphylococcal enterotoxin B (SEB) induces polyclonal proliferation of an unusually large proportion of circulating T-cells that bear the V beta 8-T-cell receptor (TcR) domain. Early and vigorous proliferation of V beta 8+ T-cells precedes their selective deletion, leaving the host unresponsive upon rechallenge with the native immunogen SEB. Nonetheless, this induction of anergy is incompletely understood. Recently we demonstrated that more cells than just V beta 8+ T-cells undergo clonal proliferation after challenge with SEB (Cell. Immunol. 154, 440, 1994). These findings suggested that non-V beta 8+ T-cells may have a role in the induction of superantigen-induced anergy. To further investigate this, we enumerated CD4+ and CD8+ T-cells in lymph nodes and spleens from Balb/c mice at various times after primary and secondary challenge with either a high or a low dose of SEB. Using these kinetic data we investigated whether challenge with SEB would modulate antigen-specific V beta 8-associated T-memory responses. To this end, the V beta 8+ T-cell-associated responses induced by SEB were compared with the V beta 8+ TcR-associated memory responses induced by the nominal antigen sperm whale myoglobin (SWM). Results indicated that challenge of SWM-primed mice with SEB abrogated the V beta 8-associated SWM-specific T-cell memory for an extended but transient period of time. Moreover, prechallenge with SEB blocked the establishment of de novo V beta + T-cell-mediated immunity. These findings suggest that administration of low and controlled doses of microbial superantigen could provide long-term suppression of antigen-specific cell-mediated immunity. PMID- 7842487 TI - GM-CSF is required for the Pseudomonas exotoxin A-induced proliferation of immature T cells in athymic mice. AB - Previous studies have demonstrated that Pseudomonas exotoxin A stimulated the proliferation of immature T lymphocytes within the splenocytes of athymic mice. These studies were performed to determine which lymphokines were involved in the proliferation of the immature T cells. The results of this study indicate that exotoxin A does not induce the production of interleukin-2 or tumor necrosis factor from B cell-depleted splenotypes from athymic mice. However, exotoxin A does induce the production of granulocyte-macrophage colony-stimulating factor (GM-CSF) from B cell-depleted splenocytes. Furthermore, the GM-CSF was shown to be produced by a Thy1+, CD4-, CD8- T lymphocyte. The addition of anti-GM-CSF antibody abrogates the exotoxin A-induced proliferation of B cell-depleted splenocytes from athymic mice. Thus, these data indicate that exotoxin A induces the production of GM-CSF from immature T lymphocytes within the splenocytes of athymic mice and the exotoxin A-induced proliferation of these immature T cells is dependent on the presence of GM-CSF. PMID- 7842488 TI - Plasmodium yoelii in mice: differential induction of cytokine gene expression during hyporesponsiveness induction and restimulation. AB - Acute Plasmodium yoelii murine malaria is associated with a marked depression of splenic T cell responses. The present study was undertaken to address the question if a defect in T cell proliferation results from a relative increase of a non-T cell population in the spleen or real biological changes occurring in T cells of the spleen after infection. When animals were acutely infected, the splenic cells responded poorly to cross-linked anti-CD3 mAb, Con A, and PWM stimulation. At this stage, a very limited array of cytokine was expressed. We failed to detect the transcripts for IL-2R p55, IL-2, IL-6, IL-10, and IFN-gamma in mice with acute P. yoelii malaria irrespective of the number of splenocytes subjected to RT-PCR. In contrast, late in the infection when mice cleared the parasites and became resistant to reinfection, mRNAs for the above cytokines as well as for IL-4, IL-5, GM-CSF, and TNF-alpha were detectable. During this late phase of infection, lymphocytes proliferated vigorously in response to TCR- and T cell mitogen-mediated stimulation. Surprisingly, during an early phase (as early as 3 days postinfection) with low parasitemia, before the establishment of T cell unresponsiveness, a broad array of cytokine expression including IL-2 and IFN gamma expression as well as marked lymphoproliferative response upon T cell mitogen- and TCR-mediated stimulation was observed. When the expression of cytokine gene in freshly isolated (ex vivo) splenocytes from P. yoelii-infected animals was investigated, a similar pattern of cytokine profile was detected. We devised a methodology in which RNA from an increasing number of splenocytes (ranging from 1 to 16 million) was used to compensate for any difference in the frequency of splenic T cells between immune and acutely infected mice and to augment target molecules which could be measured simultaneously by PCR. The data presented in this study led us to speculate that "anergy" or relative increase of a non-T cell population cannot account solely for the T cell unresponsiveness in the acute phase of infection. We suggest that inactivation or/and ablation of reactive T cells may explain T cell hyporesponsiveness during acute malaria. PMID- 7842489 TI - Changes of adhesion molecule (LFA-1, ICAM-1) expression on memory T cells activated with cytomegalovirus antigen. AB - The expression of adhesion molecules (LFA-1, ICAM-1, CD29) on T cells activated with cytomegalovirus (CMV) antigen was investigated by three-color flow cytometry analysis. Peripheral blood mononuclear cells (PBMC) from CMV-seropositive adults were cultured with CMV or control antigen for 6 days. After culture, the expression of LFA-1, ICAM-1, and CD29 on T cells in subpopulations defined as CD45RO+ or CD45RO- was analyzed. The population of cells that expressed LFA-1 at high levels (LFA-1high) among CD4+C-D45RO+ cells increased when cultured with CMV antigen compared to control antigen. The population of cells that expressed LFA 1high cells among CD8+C-D45RO+ cells was down-regulated by culture for 6 days; however, the population of LFA-1high cells among CD8+CD45RO+ cells cultured with CMV antigen was higher than when cultured with control antigen. The population of LFA-1high cells among CD4+CD45RO- and CD8+CD45RO- cells did not change after culture with CMV antigen. The intensity of CD29 and expression of ICAM-1 also increased on both CD4+CD45RO+ and CD8+CD45RO+ cells after culture with the CMV antigen. Up-regulation of adhesion molecules occurred on activated T cells by culture with the CMV antigen. This change was observed mainly on CD45RO+ T memory cells. The results suggested that these changes of adhesion molecules on activated T cells with CMV may contribute to some immune reaction or inflammatory change. PMID- 7842490 TI - Target-induced anergy of natural killer cytotoxic function is restricted to the NK-target conjugate subset. AB - This study examined the characteristics of functional anergy of natural killer cells (NK) following their interaction with target cells. Purified NK cells were cocultured with K562 for 15 min or 4 hr to allow for binding of targets to NK cells. The resulting NK-target conjugates were then dissociated by EDTA, and the unbound NK cells were separated from the targets by flow cytometry and cell sorting. Compared to untreated NK cells, the K562-dissociated NK cells were inhibited for cytotoxic function as assessed by the 51Cr release assay and by the single killer frequency assay and also responded poorly following activation by IL-2 or IFN-alpha. The inactivated NK cells had a diminished ability to reform conjugates with the target cells. Following cell sorting of the NK subsets, the conjugate subset had the least cytotoxic activity when compared to both the free NK subset or the unfractionated NK population. The IL-2 response observed with the unfractionated anergic NK cells was found to be due to the activation of the NK free cell subset while the conjugate subset was poorly responsive to IL-2. The cell surface CD16, CD2, and CD56 antigen expression was downmodulated in the conjugate subset but not in the free cells. However, the CD69 surface expression was significantly upregulated on the surface of the NK conjugate subset and was potentiated following treatment with IFN-alpha and IL-2. These results demonstrate that target-mediated anergy of NK cells is restricted to the NK target conjugate subset while sparing the remaining free cell subset. Further, the findings demonstrate that the anergic NK cells express the phenotype CD16dimCD2dimCD56dimCD69brightCD11bbright. PMID- 7842491 TI - Modulation of topoisomerase activities by tumor necrosis factor. AB - A number of chemotherapeutic agents which inhibit the DNA topoisomerases markedly potentiate cell death mediated by tumor necrosis factor, suggesting a role for these enzymes in the TNF cytotoxic mechanism. To investigate this possibility, topoisomerase I and II activities were assayed following TNF addition to murine L929 cells. Topoisomerase I and II activities increased within 15 min of TNF addition and returned to baseline levels within 1 and 2 hr, respectively. The increases in both topoisomerase activities were blocked by H-7 (but not H-8) and similar increases were seen following PMA addition. However, concentrations of H 7 which blocked the increased topoisomerase activities had no effect on TNF cytotoxicity nor on the enhancement of TNF cytotoxicity by topoisomerase inhibitors. Thus, in these cells topoisomerase activities are directly modified by TNF during the initial phases of a cytotoxic response. However, neither TNF cytotoxicity nor the enhancement of TNF cytotoxicity by topoisomerase inhibitors appears to require the TNF-mediated increases in topoisomerase activities. PMID- 7842492 TI - Differences in motor performances of children attending or not attending nursery school in Senegal. AB - This study reports the results of motor performance measurements of Senegalese children aged 3.5-5.5 years. A total of 69 children were studied, of whom 30 were from a town and were attending a nursery school, while 39 were from rural areas and did not attend school. The tests were administered three times at 6 months intervals. The children were divided into two age groups: younger group (less than 4.5-years-old) and older group (more than 4.5-years-old). They had physical growth inferior to the international reference. In the successive tests carried out over one year, the children showed progress, while the difference in sex was insignificant. The younger group of urban origin performed better than their rural counterparts in tests of imitation, coordination, precision of movements, running, and balancing. There was less difference in older children according to their origin, however, the urban children had better physical growth and developed a stronger hand grip than their rural counterparts. The usefulness of nursery school as a vehicle for nutritional assistance and motor stimulation of underprivileged children has been emphasized. PMID- 7842493 TI - How are children's growth problems diagnosed? AB - Members of the Child Growth Foundation were surveyed to ascertain how children's growth problems were diagnosed. For many (46%) it was the parents who first expressed a concern about the child's growth. Routine height monitoring detected only 8%. Parents consulted a doctor promptly when worried, but there were often delays between the first medical consultation and referral to a hospital consultant. Many parents reported that their concerns were not taken seriously. PMID- 7842494 TI - Sleep problems in pre-school children: a review of the literature. AB - This paper reviews the literature on sleep problems in pre-school children, aiming to raise awareness of the current knowledge in this field. The article begins with a discussion of the prevalence of sleep problems in young children. Disorders of initiating and maintaining sleep are by far the most common type of sleep problem in this age group, and are therefore the focus of this review. The effects of sleep disturbance are examined, focusing on how parents often feel desperate and in need of support outside the family. The causes of sleep problems are considered and the complexity in identifying causal factors is highlighted. The article continues with an exploration of the treatment of sleep problems, suggesting that much of the advice given to parents is contradictory. The literature demonstrates that the use of medication is common, but it appears that this method of treatment is of limited benefit. It seems that behaviour modification or a psychodynamic approach may be much more successful, and the use of self-help manuals/booklets has been shown to be useful by some authors. Finally, preventative strategies are discussed highlighting the need for further research in this area. PMID- 7842495 TI - Children with liver disease: maternal reports of their adjustment and the influence of disease severity on outcomes. AB - Mothers of 45 children with a liver disease (biliary atresia) completed a questionnaire concerned with their child's health status and psychological adjustment. Emotional and behavioural problems were found to be common; 46% of children under 5 and 43% over 5 years of age scored above the cut-off on standardized measures of adjustment. Maternal mental health difficulties were present in 36% of the sample. The study examined factors that predicted child adjustment, results indicating that maternal perceptions of severity accounted for 40% of the variance in children's psychological adjustment. Neither maternal mental health, nor objective parameters of the child's health status contributed significantly to child adjustment. The findings are discussed in terms of Wallander's model of adaptation to chronic disease and the practical implications for clinical practice are discussed. PMID- 7842496 TI - Evaluating therapy in cerebral palsy. AB - The optimal design for most clinical trials of treatment is the randomized controlled group trial. This methodology is not, however, uniformly applicable or appropriate. The evaluation of physiotherapy in the management of cerebral palsy in childhood is a good example of treatment for which modification of this trial design is needed. Some of the problems with eight studies in this field published between 1960 and 1993 are reviewed here and an alternative approach proposed. A representative series of single case studies with individual goal setting and a validated outcome measurement, using randomized treatment, would overcome many of the disadvantages of published studies at a greatly reduced cost. The results would enable more effective group trials to be mounted in due course to evaluate the probable impact of providing treatment to a defined population of subjects. PMID- 7842497 TI - In search of a mechanism for receptor-mediated neurobehavioral teratogenesis by nicotine: catecholamine release by nicotine in immature rat brain regions. AB - Nicotine disrupts central nervous system development through interactions with nicotinic cholinergic receptors found in immature brain, leading to discoordination of target cell replication and differentiation. However, it is unclear whether the net result is achieved by nicotine's actions on its specific target cells, or indirectly through receptor-mediated release of other neurotransmitters, such as catecholamines, that possess neurotrophic properties. In the current study, developing rats (1, 7, 14 and 21 days old) were challenged acutely with nicotine (0.3 mg/kg) and the release of catecholamines was evaluated in vivo (AMPT method) in three brain regions that differ in nicotinic receptor concentrations. Nicotine did not stimulate catecholamine release at birth, but developed the capacity to do so in parallel with the ontogeny of nicotinic cholinergic receptors in the midbrain+brainstem and in the forebrain. In the cerebellum, which remains poor in nicotinic receptors, no response was obtained at any age. Superimposed on this general pattern, changes in sensitivity to nicotine were also seen that corresponded to ontogenetic changes in endogenous cholinergic tone, suggesting that receptor desensitization occurs normally during developmental stages in which neuronal activity is high. The absence of a catecholamine response to nicotine at birth in the rat indicates that neurobehavioral teratology associated with fetal nicotine exposure does not reflect secondary actions mediated through catecholamines. However, because brain development in the neonatal rat corresponds to fetal stages in man, the onset of these mechanisms may be relevant to human fetal exposure. PMID- 7842498 TI - Postnatal development of glial fibrillary acidic protein, vimentin and S100 protein in monkey visual cortex: evidence for a transient reduction of GFAP immunoreactivity. AB - In the cerebral cortex of some species, the gradual appearance of glial fibrillary acidic protein (GFAP) is often interpreted as reflecting the parallel maturation of neuronal connectivity. We studied the postnatal maturation of astrocytes in the primary visual cortex of Callithrix jacchus using antibodies against GFAP, vimentin and S100 protein as immunohistochemical markers. In the cortical grey matter of this species, the overall GFAP-immunoreactivity (IR) as measured by image analysis is high at birth (130% of the adult value), decreases until about 3 months (80%) and increases again towards adult values (100%). Vimentin-IR was high at birth, and declined towards 3 months and later. In contrast, S100-IR augmented postnatally in neuropil, and showed a laminar shift of maximum IR from layer IV to supragranular layers during ontogenesis. The decrease of GFAP-IR is predominantly due to changes in density of GFAP-positive (+) astrocytes within cortical tissue (newborn: 18,600 GFAP+astrocytes/mm3; 1 month: 11,600/mm3; 3 months: 5,700/mm3; adult: 10,200/mm3), while the overall number of astrocytes remained relatively constant as shown by the number of S100 positive astrocytic cell bodies. At times of low GFAP-IR a reduced area density of intermediate filaments was found in astrocytes by electron microscopy. The period of reduced GFAP-expression coincides with the time of prominent synapse remodeling in the visual cortex of marmosets. These data suggest that GFAP expression may depend on functional conditions rather than time-dependent maturation. PMID- 7842499 TI - Ontogeny of neuropeptide FF pharmacology and receptors in mouse brain. AB - The postnatal ontogeny of neuropeptide FF (NPFF) receptors in mouse brain was mapped by quantitative autoradiography using [125I](1DME)Y8Famide as selective radioligand. By day 14, the adult distribution of NPFF sites was established in almost all brain areas. The density of NPFF receptors reached adult levels between 14 and 28 days after birth, earlier than did mu or delta opioid receptors. During ontogeny, morphine analgesia was measured in hindpaw, forepaw and tail immersion tests (57 degrees C). An antinociceptive effect of morphine in the forepaw and tail immersion test was evident in 14-day-old but not in 7-day old mice. In 14 and 21 day-old mice, the influence of (1DME)Y8Famide on morphine analgesia depended on the dose and on the particular test. A low dose of (1DME)Y8Famide inhibited morphine analgesia in the tail or hindpaw test, whereas a higher dose had either no effect (tail test) or increased morphine activity (hindpaw test). In adult mice, only the inhibition of morphine antinociception by (1DME)Y8Famide was observed. These observations revealed the establishment of an equilibrium between NPFF and opioid functions during ontogeny. PMID- 7842500 TI - Radial glia in the neocortex of adult rats: effects of neonatal brain injury. AB - Microgyria can be induced in otherwise normal rat neocortex by a freezing injury to the cortical plate before the completion of neuronal migration. We had previously reported radial glial like-immunoreactive fibers in the area of the microgyria in 32-day-old rats. Here we demonstrate that these glial fibers, which are immunoreactive to Rat-401, vimentin, and glial fibrillary acidic protein (GFAP) antibodies, are seen in adult rats. The appearance of these fibers is hypothesized to result from the release of a trophic factor during the recovery from neonatal injury which acts to either (1) halt the transformation of radial glia to astrocytes and/or dedifferentiate already committed astrocytes, (2) create a hybrid cell, or (3) induce increased proliferation of glia. PMID- 7842501 TI - L-dopa-induced air-stepping in preweanling rats. I. Effects of dose and age. AB - The effects of several doses of L-DOPA (25, 50, 75 and 100 mg/kg) on air-stepping were studied in rats on the day of birth and on 5, 10, 15 and 20 days of age. Occurrence of air-stepping increased and latency to air-stepping generally decreased with dose except at 10 days of age; duration of air-stepping increased with increasing dose of L-DOPA at every age. The occurrence of a variety of air stepping gaits was age-dependent. On the day of birth, air-stepping consisted primarily of episodes of forelimb alternation; on days 5-20, diagonal progression was the predominant gait, but beginning at day 10, episodes of air-swimming, air galloping and other locomotor patterns were interspersed. Not only could the durations of most of these gaits be increased with increasing dose of L-DOPA, but at some ages, increasing the dose of L-DOPA led to gait changes. PMID- 7842502 TI - L-dopa-induced air-stepping in preweanling rats. II. Kinematic analyses. AB - Coordination of air-stepping elicited by subcutaneous injections of L-DOPA (25 100 mg/kg) was studied in rats from the day of birth through 20 days of age. Results revealed a nearly linear increase in the rate of stepping from about 1.5 steps/s at day 0 to about 4.5 steps/s at day 20, independent of the dose of L DOPA. The ontogenetic increase in the rate of stepping was found to result from decreases in the duration of both retraction and protraction phases of the step cycle, but the decrease in the retraction phase was greater. There was an ontogenetic increase in the amplitude of movement at the wrist, knee and ankle joints, a slight decline in the amplitude of movement at the elbow and little change in amplitude at either the shoulder or hip. The relative timing of movements at joints within each limb also changed with age. Forelimb movements were led by the wrist throughout development, followed by the elbow and then the shoulder, which increasingly lagged behind the other two joints of the forelimb. Hindlimb movements were increasingly led by the knee, followed by the ankle and then the hip. Diagonal progression, in which the diagonal limbs moved in phase with each other and in antiphase with the contralateral limb of the same girdle, was seen at all ages. However, other gaits, which resembled galloping (air galloping) and swimming (air-swimming), became more prevalent between 10 and 20 days of age.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7842503 TI - Chronic embryonic MK-801 exposure disrupts the somatotopic organization of cutaneous nerve projections in the chick spinal cord. AB - The effect of altering neural activity on the development of the central projections of cutaneous and muscle sensory neurons was studied in the embryonic chick spinal cord. Animals were treated chronically with MK-801, a non competitive N-methyl-D-aspartate receptor antagonist, during the period when both cutaneous and muscle sensory afferents form connections in the spinal cord. Daily applications of MK-801 began on embryonic day 5, 1 day before sensory collaterals penetrate the spinal cord gray matter, and continued until the animals were analyzed (at embryonic day 14). The patterns of cutaneous and muscle sensory nerve projections were determined by applying fluorescent tracers to individual, identified peripheral nerves. MK-801 treatment did not overtly alter the pattern of muscle afferent projections. However, in the MK-801-treated embryos, the somatotopic organization of cutaneous afferent projections was dramatically altered. Normally, the projections formed by the lateral femoral cutaneous and the medial femoral cutaneous nerves are located immediately adjacent to one another in the lumbar dorsal horn, with little overlap. In the MK-801-treated embryos, the projections from these two cutaneous nerves both expanded significantly within dorsal horn laminae to become almost completely superimposed. These data suggest that MK-801 disrupts the development of the somatotopic organization of cutaneous afferent projections in the spinal cord. PMID- 7842504 TI - Lesion induced expression of low-affinity NGF-binding protein (p75) immunoreactivity after neonatal and adult aspiration lesions of the rat dorsomedial prefrontal cortex. AB - The present study was performed in order to examine whether or not NGF-mediated processes could be involved in the sparing of function observed after neonatal prefrontal cortex lesions. After unilateral neonatal aspiration lesions of the dorsomedial prefrontal cortex, fibers immunoreactive for the low-affinity NGF binding protein (p75) with a deviant morphology were observed in the severed hemisphere only. The morphology of these fibers was characterized by their large caliber, their large, often bulbous varicosities, and their curly appearance. These fibers were present as soon as 24 h after the operation. Between 3 and 5 days after the operation, the greatest abundance of these fibers was found in the ventrorostral areas of the forebrain and along the pathways of cortical projections of the cholinergic cell groups. After 7 days, such fibers were no longer observed. After comparable lesions in adult animals, a similar type of fiber was observed in the lesioned hemisphere. However, in these cases a response comparable to that observed in the neonatal animals was not observed until 5 days after the operation, with fewer fibers. Furthermore, in contrast to what was observed after neonatal lesions, in adult animals no indications of retrograde transport of p75 immunoreactive material towards the cholinergic cells of the basal forebrain nuclei were found. From these findings it was concluded that the prompt upregulation of p75 expression in neonatal animals may contribute to the survival of the cholinergic cells of the basal forebrain, and may therefore be involved in the restoration of function of the medial prefrontal cortex. PMID- 7842505 TI - Luteinizing hormone-releasing hormone (LHRH)-expressing cells in the nasal septum of human fetuses. AB - In 12-19 weeks old human fetuses, LHRH-immunoreactive (LHRH-Ir) cells were detected in the nerve fascicles arising from the vomeronasal organ (VNO), from their origin to their end point at the medial aspect of the olfactory bulb (vomeronasal and/or terminal nerves). In one 22-weeks-old fetus, LHRH-Ir cells were present only in the upper part of the nasal septum, in the nerve fascicles crossing the cribriform plate. No LHRH cells could be detected in two fetuses, 23 and 36 weeks old. Our results are discussed with regard to the migratory hypothesis of LHRH cells from the medial olfactory placode to the brain. PMID- 7842506 TI - Developmental studies of the inferior olivary nucleus in staggerer mutant mice. AB - The neurological mutation, staggerer, causes a severe disruption in the integrity of the olivo-cerebellar circuitry. The primary site of action is the Purkinje cell population which is reduced in cell number, with cells that are atrophic in dendritic structure, small in size and ectopic in position. This primary defect has a cascade effect on the Purkinje cell-afferent populations, leading to the target-related cell death of virtually all of the cerebellar granule cells and the majority of the neurons in the inferior olive. As part of our ongoing study of the cell-cell interactions in the cerebellar circuitry, we have studied the inferior olive of the staggerer mutant from birth to adulthood. We find that the reduction in olive neuron number does not occur until after birth in the mutants. On the day of birth, the number of cells is indistinguishable in mutants and in wild type. Similarly, we find that the four principal subnuclei of the olive are well defined at birth, but regress to a state of poor resolution during the first 3 postnatal weeks. Finally, Golgi impregnations reveal that of the two morphological classes of inferior olive neurons, only one class--the Type II or complex dendritic type survive in the mutant. These results are discussed in terms of their implications for the cell--cell interactions in the developing olivocerebellar circuit. PMID- 7842507 TI - Brainstem auditory evoked response development in preterm and term baboons (Papio hamadryas). AB - Brainstem auditory evoked responses were recorded longitudinally from 11 neonatal baboons (Papio hamadryas), 6 of which were preterm. Recordings were made in unsedated animals from day 161 to day 362 after conception (term = 182 days). The pattern of development of both waveform morphology and of wave latency was consistent with that seen in the human neonate, with a rapid maturation of the response during the perinatal period, and then a slower development to adult values. Brainstem conduction time was measured from the wave I to wave IV interval, and this demonstrated a similar pattern, with a rapid decrease in latency up to term, and then decreasing more slowly to reach adult values by 4 months of age in the baboon. PMID- 7842508 TI - Brain aromatase activity and plasma testosterone levels are elevated in aggressive male mice during early ontogeny. AB - Testosterone (T) and estradiol (E2) are involved in intraspecific aggressive behavior. Both steroids exert their effects on behaviour via the hypothalamus and the amygdala (Am) of the central nervous system (CNS). In these brain areas T is converted to E2, by the enzyme aromatase. Both the levels of brain aromatase activity (AA) and the effects of T and E2 on aggressive behavior in adulthood depend on steroidal organization of the CNS during ontogeny. In this study we measured plasma T and in vitro brain AA of males fetuses and neonates derived from two strains of wild house mice, which had been genetically selected for aggression, based upon attack latency. There were no differences in preoptic area (POA) AA levels between selection lines on either embryonic day (E) 17 or 18, or the day after birth (day 1). In the non-aggressive long attack latency (LAL) males the POA AA increases with age, i.e. was higher on E18 than on E17, which is correlated with brain weight (BrW). This was in contrast to aggressive short attack latency (SAL) fetuses, which only showed a slight, but not significant differences between embryonic days or a correlation with BrW. Neonatally, the POA AA of LAL males tended to decrease in contrast to SAL males. However, SAL neonates had a higher AA in the amygdala (Am) than LAL neonates, whereas no differences exist in the anterior hypothalamus. Thus, a differential brain AA distribution exists in SAL and LAL pups.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7842509 TI - Dorsal root ganglion cell death and surviving cell numbers in relation to the development of sensory innervation in the rat hindlimb. AB - This study correlates the numbers of dying, surviving and proliferating L4 primary afferent neurons with the development of peripheral hindlimb sensory innervation in the rat. Cell death occurs from embryonic day 15 (E15) to just after birth and peaks at E17-E19. Despite this, surviving cell numbers rise steadily to birth indicating that cell death is more than balanced by cell proliferation over this period. GAP-43 immunostaining indicates that the peripheral sensory axons are only in central parts of the hindlimb by E15 and do not finish arriving at their distal peripheral targets until birth so prenatal cell death in the L4 ganglion is not well correlated with the development of the peripheral innervation by these primary sensory axons. Prenatal cell death does, however, correlate well with the innervation of the cord by central sensory axons. In contrast to the steady rise of surviving cell numbers from E15 to birth, cell numbers go down 16% in the period from birth to postnatal day 5. This loss is correlated with the development of the peripheral innervation. We conclude that the bulk of cell death in the rat L4 dorsal root ganglion, which is prenatal, is controlled by local or central factors whereas peripheral target factors may exert their influence postnatally to determine the final numbers of mammalian sensory neurons. The data also suggest that there may be two phases of cell death, an early phase involving large light cells and a late phase involving small dark cells. PMID- 7842510 TI - Effects of neonatal exposure to caffeine on adenosine A1 receptor ontogeny using autoradiography. AB - The ontogeny of adenosine A1 receptor density was assessed via autoradiographical analysis of [3H]cyclohexyladenosine ([3H]CHA) binding in brains of 14-31-day-old rats as a function of exposure to caffeine over postnatal days 2-6. This exposure period was analogous to the period during which human infants are administered caffeine as treatment for apnea of prematurity. [3H]CHA binding was greatest in CA1 and CA3 hippocampus in both caffeine-exposed and control rats across all ages. Within the anterior, ventral, lateral and medial regions of the thalamus of unmanipulated rats, [3H]CHA binding did not change with age. In caffeine-exposed rats, however, [3H]CHA binding increased significantly within these thalamic subregions as the rats aged. In addition, with age in both treatment groups, the molecular and granular layers of the cerebellum and the CA1 and dentate gyrus of the hippocampus displayed increasing [3H]CHA density. Furthermore, regardless of age, [3H]CHA binding was decreased in the molecular layer of neonatally caffeine exposed animals as compared to controls. Thus, limited exposure to caffeine within the first postnatal week altered the subsequent expression of adenosine A1 receptors in most subregions of the thalamus and in the molecular layer of the cerebellum. PMID- 7842511 TI - Distribution of AMPA selective glutamate receptors in the thalamus of adult rats and during postnatal development. A light and ultrastructural immunocytochemical study. AB - The regional, cellular and subcellular distribution of AMPA receptors was demonstrated immunocytochemically within the thalamus of adult and young (from 1 to 20 days postnatal, P1-P20) rats. The antipeptide antibodies used recognize individual subunit proteins of the AMPA-preferring glutamate receptor, i.e., GluR1, GluR2-3 and GluR4. Our results demonstrate that these AMPA receptor subunits are generally not highly expressed in the thalamus, as compared to other brain areas and that they are enriched differentially within different thalamic nuclei. GluR1 is mostly found in intralaminar and midline nuclei throughout life, whereas GluR2-3 is moderately expressed in the thalamus, with no major developmental changes. GluR4 is the predominant subunit expressed in the reticular nucleus in adult rats, but not in young animals, where until P9 it is instead present in the ventrobasal complex. Samples of paraventricular and lateral geniculate nuclei stained with GluR1 and of reticular nucleus as well as ventrobasal complex stained with GluR4 were used for the ultrastructural study. In all the samples, labelling was in the somatic and dendritic cytoplasm, with dense patches of reaction product apposing post-synaptic densities of terminals with round clear vesicles and asymmetric specializations. Glial staining was observed only with the GluR1 antiserum and there was no evidence of labelled synaptic terminals. The differential distribution of GluR subunits in the thalamus suggests that certain subunits may participate more than others in mediating post-synaptic responses in distinct neuronal populations and also that other GluR types may be involved in the thalamic networks. PMID- 7842513 TI - Regional difference in the neurotoxicity of ochratoxin A on the developing cerebral cortex in mice. AB - Pregnant mice were treated intraperitoneally with 3 mg/kg of ochratoxin A on day 10 of gestation. They were allowed to give birth and the offspring were killed at 6 weeks of age for observation. Prenatal exposure to ochratoxin A caused microcephaly in offspring. Their body weight, brain weight, cortical thickness and numerical densities of neurons and synapses in somatosensory and visual cortex were examined. The mice exposed in utero to ochratoxin A showed a significant deficit in brain weight compared to the age-matched control, but there was no significant difference in body weight between these two groups. The cortical thickness showed a significant decrease in both somatosensory and visual cortex. Normal control mice had about 66,000 neurons/mm3, while age-matched ochratoxin A-treated mice had about 91,000 neurons/mm3 in somatosensory cortex. There was a significant increase in OA-treated group. However, there was no significant difference in the numerical density of neurons in visual cortex. On the other hand, there was no significant difference in the numerical density of synapses in both somatosensory and visual cortex. The somatosensory cortex of control mice had about 13,000 synapses per neuron, whereas ochratoxin A-treated mice had about 9,400 synapses per neuron. In the visual cortex, no significant difference was seen in synapse-to-neuron ratios. The discrepancy in the numerical density of neurons and synapse-to-neuron ratios between the somatosensory and visual cortex might derive from a time difference in cortical neurogenesis. PMID- 7842512 TI - Neurotrophic effects of ipsapirone and other 5-HT1A receptor agonists on septal cholinergic neurons in culture. AB - Repeated treatment of primary cultures of fetal rat septal neurons with 5-HT1A receptor agonists (8-OH-DPAT, ipsapirone, gepirone and buspirone) increased choline acetyltransferase activity after 6-7 days in culture. This effect was optimal with ipsapirone (+ 50-80% at 1 microM of the agonist), and could be prevented by potent 5-HT1A receptor antagonists such as (-)-tertatolol and (+) WAY 100135. Under conditions where they completely suppressed the stimulatory effect of NGF on choline acetyltransferase in these cultures, specific anti-NGF antibodies did not alter the stimulatory effect of ipsapirone, suggesting that a possible release of NGF from some septal cells did not account for the effect of 5-HT1A receptor stimulation. Autoradiographic investigations with [3H]8-OH-DPAT as radioligand and immunocytochemistry with specific anti-choline acetyltransferase antibodies and anti-rat 5-HT1A receptor antibodies showed that 5-HT1A receptors were expressed on septal neurons in culture, notably on the cholinergic neurons identified by their positive staining with anti-choline acetyltransferase antibodies. Detailed morphometrical analysis by computer assisted imaging revealed that repeated exposure to ipsapirone (1 microM for 7 days) did not influence the survival of cholinergic as well as non-cholinergic neurons, but specifically altered the neuritic tree (i.e. the total length of neurites and the number of branching points) of cholinergic neurons only. These data suggest that under in vitro conditions ipsapirone and other 5-HT1A receptor agonists may exert a direct trophic action on septal cholinergic neurons. PMID- 7842514 TI - Expression of GAP-43 (neuromodulin) during the development of the rat adrenal gland. AB - The 'growth-associated protein', GAP-43 was originally considered to be a neuron specific protein associated with plasticity. However, we have recently shown that GAP-43 is expressed by noradrenergic, but not by adrenergic chromaffin cells in the adult rat adrenal gland. In this study, we examine the expression of GAP-43 during embryonic and post-natal development of the adrenal gland using immunohistochemical techniques. In parallel, antibodies directed against two neuroendocrine markers, the catecholamine-synthesizing enzymes, tyrosine hydroxylase (TH) and phenylethanolamine N-methyltransferase (PNMT) were employed to permit identification of the developing chromaffin cell phenotypes. At embryonic day 15.5, GAP-43 was predominately localized in sympathoadrenergic precursor cells in the extra-adrenal blastema, and also in nerve fibers within the adrenal gland. At later embryonic stages, GAP-43 was expressed by nearly all intra-adrenal chromoblasts. Two subsets of chromoblasts can be distinguished even at early stages. A strong GAP-43-positive immunoreaction was observed in those chromoblasts organized in a few large compact clusters which weakly expressed TH and did not express PNMT. A generally weaker GAP-43 immunoreaction was observed in a second type of intra-adrenal chromoblasts which were organized in small isolated groups and characterized by a PNMT-positive, and strong TH-positive immunoreactivity. GAP-43 immunoreactivity was still associated with many PNMT positive adrenergic chromoblasts at birth, but decreased to undetectable levels during the first post-natal week. By the second post-natal week, GAP-43 was restricted, as in the adult, to noradrenergic chromaffin cells which expressed TH, but not PNMT, in addition to nerve fibers and their associated glial cells in the gland. An immunoblot analysis confirmed a decrease in GAP-43 protein during the post-natal period. In agreement with these observations, a three-fold decrease in GAP-43 mRNA in the adrenal gland was measured between late embryogenesis and the second post-natal week. During development, the spatiotemporal expression of GAP-43 suggests a possible role in the migration and aggregation of chromaffin cell precursors into the medullary region of the adrenal gland. PMID- 7842515 TI - Transient expression of somatostatin immunoreactivity in the olfactory-forebrain region in the chick embryo. AB - The tissue distribution of somatostatin (SST) immunoreactivity was studied in the nasal and forebrain region in the chick embryo. On embryonic day (ED) 3, SST immunoreactive (ir) cells were first detected in the cells migrating from the olfactory placode. Then, at ED3.5, SST-ir cells and -ir fibers appeared in the olfactory epithelium and olfactory nerve bundles. At ED6-8, one component of the SST-ir fibers was found to separate from the olfactory nerve and it entered the parenchyma of the medial forebrain surface. These SST-ir fibers extended dorsocaudally toward the preseptal area. During this same period, a few SST-ir cells were observed in the medial forebrain adjacent to the SST-ir fibers. SST immunoreactivity in the nasal and forebrain areas was most striking at ED5-8 but a reduction of SST immunoreactivity in the nasal and forebrain areas occurred at ED11 and it virtually disappeared by the day of hatching. These results indicate that the expression of SST in the nasal and forebrain regions is transient in the chick embryo. Since the SST-ir cells did not co-express luteinizing hormone releasing hormone (LHRH), it, thus, appears that these SST-r cells belong to a different cell population from LHRH neurons that are also found in the olfactory forebrain axis during embryonic development [23]. However, a close relationship exists between SST-ir cells and -ir neuronal fibers and LHRH neurons. This may play a role in development of LHRH neurons. PMID- 7842516 TI - Topographical differences in sweetness sensitivity in the peripheral gustatory system of adults and children. AB - The sensitivity of localised areas of the anterior tongue of adults and 8-year old males to the sweetener sucrose was determined, using a two-alternative forced choice psychophysical procedure. Stimulation of 12 areas by 0.2125 M sucrose or water, using a filter paper technique, indicated that the children were significantly more sensitive to the sweetener at eight of the areas. Counts of papillae at each of the 12 areas showed that there were similar numbers for adults and children at eight areas, whilst at three of the areas that exhibited a higher sensitivity to sucrose, children had significantly more papillae. Since 8 year-old males are less sensitive to sucrose when the stimulus is given as a whole-mouth stimulus [12], it is proposed that the children's gustatory system may be unable to integrate the information available at the tongue as efficiently as adults, or that the threshold and stimulus-response functions of receptor cells are different in the two groups. PMID- 7842517 TI - Choline-acetyltransferase-like immunoreactivity in the organ of Corti of the rat during postnatal development. AB - The mammalian cochlea receives efferent innervation from neurons located in the superior olivary complex. This efferent olivocochlear innervation is divided in two separate systems, lateral and medial, which mainly innervate afferent dendrites connected to inner hair cells and the cell body of outer hair cells, respectively. Besides other substances, lateral and medial efferent terminals of the adult cochlea use acetylcholine (ACh) as a neurotransmitter. In this study, we have used immunocytochemistry to detect the presence of choline acetyltransferase (ChAT), the synthesizing enzyme of ACh, in efferent olivocochlear terminals during the development of the rat. The appearance and distribution of immunoreactivity to ChAT has been studied in developing rat cochleas from birth (postnatal day 1, P1) to adulthood. Attention was paid to the temporal relationships between the expression of ChAT, the presence of other putative neuroactive substances, the onset of hearing and other developmental phenomena. Our results indicate that ChAT-like immunoreactivity is already present at birth (P1) in the region of inner hair cells, that it appears at P3 in the outer hair cell area and that it reaches an adult pattern of distribution by P15. ACh may thus be present early in the developing cochlea, before the onset of hearing, as it also occurs with other putative transmitters/modulators such as enkephalins, CGRP or GABA. It is suggested that ACh could be involved in the modulation of sound-evoked potentials as soon as they appear, and in the regulation of other developmental phenomena such as neurite outgrowth or synaptogenesis. PMID- 7842518 TI - Localization of calretinin in cells of layer I (Cajal-Retzius cells) of the developing cortex of the rat. AB - In order to be able to study the still disputed fate and function of the large Cajal-Retzius cells in the marginal zone (prospective layer I) during corticogenesis, it is necessary to have an unambiguous marker for them. We have found that antibodies to the calcium-binding protein calretinin label Cajal Retzius cells in the rat throughout the whole period of corticogenesis into adulthood. Calretinin positive cells were also detected in the subplate, cortical plate and the ventricular zone. Transient expression of calretinin was observed in cells of the infragranular layers of the developing cortex. We conclude that calretinin can be used as a marker protein for Cajal-Retzius cells. PMID- 7842519 TI - Development of muscarinic acetylcholine receptors in the ferret retina. AB - The development of muscarinic acetylcholine receptor protein in the ferret retina was studied using biochemical, autoradiographic, and light and electron microscopic immunohistochemical techniques. The development of retinal muscarinic cholinergic receptor proteins involves transient shifts in their number and distribution, as well as changes in the relative abundance of two molecular weight variants. Receptor binding assays demonstrate changes in the number and affinity of retinal binding sites for the muscarinic cholinergic ligand [3H]quinuclidinylbenzilate ([3H]QNB). Light microscopic immunohistochemical studies reveal the presence of muscarinic acetylcholine receptor-like (mAChR like) immunoreactivity in the adult inner plexiform layer. During development, the mAChR-like immunoreactivity appears in a number of other retinal layers. Electron microscopic immunohistochemical studies indicate that muscarinic acetylcholine receptor-like immunoreactivity is found at amacrine-amacrine cell contacts. Both autoradiographic and gel slice electrophoretic studies were carried out after labeling of developing and adult retinal muscarinic receptors with [3H]propylbenzilylcholine mustard ([3H]propylbenzilylcholine mustard ([3H]PrBCM), which irreversibly labels the muscarinic acetylcholine receptor. Polyacrylamide gel electrophoresis under reducing, denaturing conditions resolved two peaks of radioactivity corresponding to [3H]PrBCM-labeled protein; both were eliminated by pre- and co-incubation of labeled adult retinas with excess atropine. Combined with the results of earlier studies, these observations suggest that the subtypes, number and distribution of muscarinic receptor proteins changes during retinal synaptogenesis. PMID- 7842520 TI - Correlation between content of high-energy phosphates and hypoxic-ischemic damage in immature and mature astrocytes. AB - The effect of 'simulated ischemia', i.e., combined anoxia and substrate deprivation, was studied in 1- and 3-week-old (i.e., immature and mature) primary cultures of mouse astrocytes. Cell survival, as indicated by retention of the high-molecular cytosolic protein lactate dehydrogenase was compared with retained high-energy phosphate compounds (ATP and phosphocreatine). A previously established longer survival of the immature cells during the metabolic insult was confirmed and found to correlate with a more complete maintenance of high-energy phosphates. However, in both the mature and immature cells, no death occurred as long as the ATP content remained at or above 25% of its control value. ATP concentrations below 10% of control were accompanied by almost complete cell death in both age groups. Thus, the better survival of immature astrocytes during simulated ischemia is correlated with better maintenance of the levels of high energy phosphates and, regardless of age, cell death occurs only once a critically 'low' threshold of ATP has been reached. PMID- 7842521 TI - Expression of neuron-specific enolase in the developing rat retina as revealed by immunocytochemistry. AB - Expression of neuron-specific enolase (NSE) in retinal neurons was immunocytochemically investigated during the development of the rat retina. At embryonic day 14 (E14), the first immunoreaction of NSE was identified in the pigment epithelium. NSE-positive ganglion cells occurred at the inner surface of the retina by E15. Horizontal cells and photoreceptor cells became stainable for NSE in the outer portion of the neuroblastic layer as early as E17. At E20, when the majority of ganglion cells were intensely positive for NSE, immunoreactive amacrine cells first appeared at the outer surface of the developing inner plexiform layer. It was not until postnatal day 7 (P7) that NSE-positive bipolar cells occurred in the middle of the inner nuclear layer. At this stage, most of the photoreceptor cells located in the outer nuclear layer were immunolabeled, whereas the ectopic photoreceptor cells in the inner nuclear layer were devoid of immunoreaction. Most identifiable retinal neurons became strongly immunostained for NSE by P14. Our results indicate that the NSE expression of retinal neurons occurs just after their migration to the final location and prior to establishing the synaptic structures. In this paper, the characteristic sequence in which different types of retinal neurons exhibit NSE immunoreaction is discussed in the light of certain autoradiographic data on the sequence of retinal cell genesis. PMID- 7842522 TI - Ontogeny of pituitary adenylate cyclase-activating polypeptide (PACAP) receptors in the rat cerebellum: a quantitative autoradiographic study. AB - Pituitary adenylate cyclase-activating polypeptide and PACAP receptors are both present in the rat cerebellar cortex, suggesting that PACAP may play an important role in the cerebellum. In the present study, the variation of the concentration of PACAP binding sites in the rat cerebellum was investigated during postnatal development by means of quantitative autoradiography, using [125I]PACAP27 as a radioligand. In the external granule cell layer and the medulla, the density of PACAP binding sites was high at birth, markedly decreased from postnatal day 8 (P8) to P25 and finally vanished at the end of the third postnatal week. In the internal granule cell layer and molecular layer, PACAP binding sites were first detected at P8. In the internal granule cell layer, the density of binding sites slightly decreased during development but remained elevated in adults. Conversely, in the molecular layer, PACAP binding sites rapidly decreased during the second and third postnatal weeks and virtually disappeared after P25. In all four layers of the cerebellar cortex, the autoradiographic labeling was displaced by PACAP27 (IC50 close to 10(-8) M), but was not affected by VIP. No significant changes in IC50 and Hill coefficient were noticed in the various layers throughout development. The present study shows that all four layers of the cerebellar cortex express PACAP binding sites during development. The evolution of the receptor concentration exhibited differential profiles in the various layers but the specificity characteristics of the recognition sites were identical in all four structures.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7842523 TI - Estrogen receptor found in the facial nucleus of the newborn rat is suppressed by exogenous estrogen: immuno- and in situ hybridization histochemical studies. AB - Expression of the messenger RNA coding estrogen receptor (ER-mRNA) was detected in the ventromedial subnucleus of the facial nucleus of the newborn rat by in situ hybridization histochemistry (ISHH). The hybridization signal in this subnucleus increased from 1 to 6 days of age, then decreased at 11 days. By immunohistochemistry (IHC) using an antiserum which detects estrogen receptor (ER) specifically, immunopositive signals were also detected in the same subnucleus of the adjacent sections. On the other hand, neither of these signals were encountered in the same subnucleus of the adult rat. Thus, the present result extend our previous work (Yokosuka and Hayashi, 1992) showing that the expression of the ER in the facial nucleus is transient. A sex difference in the expression of ER molecules was not apparent by ISHH and IHC. Moreover, daily injections of estradiol from the day of birth suppressed the expression of ER in the subnucleus at 6 and 11 days of age. Thus, as has been detected in the mediobasal hypothalamus, ER-mRNA was revealed to be down-regulated by estrogen. PMID- 7842524 TI - Postnatal development and laminar distribution of noradrenergic fibers in cat visual cortex. AB - Previous studies have indicated that adrenergic receptors show significant changes either in laminar distribution or in number during the critical period of kitten visual cortex development. In order to further investigate the postnatal development of this neurotransmitter system, especially in relation to the critical period, we used a polyclonal antibody against dopamine-beta-hydroxylase to localize noradrenaline-containing afferents in visual cortex of kittens of various ages from birth to adulthood. In young kittens, less than 2 weeks of age, noradrenergic fibers were sparse, short and randomly oriented, and were concentrated in layer I and in deep cortical layers V and VI. By postnatal day 40, the fibers were present throughout all cortical layers and exhibited higher densities in layers I, II, III, V and VI, with a band of lower staining in layer IV. While tangential fibers predominated in layers I, V and VI, relatively straight radial fibers traversed layers II and III. After postnatal day 40, we did not find major changes in the laminar distribution of adrenergic fibers. This developmental laminar distribution pattern of adrenergic fibers resembles that of the beta-adrenergic receptors that we and others have studied in kitten visual cortex, but differs from that of alpha-adrenergic receptors. PMID- 7842525 TI - The articular cartilage surface as a target organ. PMID- 7842526 TI - Chronic fatigue syndrome: what factors trigger it off? PMID- 7842527 TI - Human adjuvant disease revisited: a review of eleven post-augmentation mammoplasty patients. AB - OBJECTIVES: We have reviewed 11 women post-augmentation mammoplasty who were referred to our clinic with diffuse rheumatic complaints. All patients had undergone mammoplasty with silicone gel-filled implants prior to the onset of their locomotor symptoms (mean latency time 7.8 years). One physician interviewed and examined each of these patients following a standardized format for clinical retrieval. RESULTS: Of the patients reviewed, 6 patients had clinical fibromyalgia based on the ACR criteria, and the remaining 5 patients had symptoms consistent with the "chronic fatigue syndrome." None of our patients were found to have evidence of a defined connective tissue disease. Antinuclear antibodies were detected in 4 (36%) patients and low level titres of extractable nuclear antigens in only 2 (18%). CONCLUSIONS: Previously a causal relationship between the use of silicone gel-filled breast implants and the subsequent development of symptoms referred to as human adjuvant disease (HAD) has been proposed. On the basis of currently accepted criteria we have preferred to diagnose our post mammoplasty patients without specific connective tissue disease, as having chronic fatigue syndrome (CFS), or when tender points are present, as having fibromyalgia (FMS), rather than implying that such cases represent a separate and unique rheumatological disease entity. In the light of our current understanding of CFS and FMS, a relationship between them and the previous silicone mammoplasty seems possible. PMID- 7842528 TI - Increased levels of circulating intercellular adhesion molecule-1 in patients with systemic sclerosis. AB - OBJECTIVE: To determine the value of the circulating intercellular adhesion molecule (cICAM-1) as a marker for the inflammatory and fibrotic processes in systemic sclerosis (SSc). METHODS: We determined serum levels of cICAM-1 and of the soluble interleukin-2 receptor (sIL-2R) by an enzyme-linked immunosorbent assay in 33 patients with SSc. These values were compared to the concentrations of acute phase reactants and to the extent of skin involvement in diffuse and limited scleroderma. RESULTS: cICAM-1 was elevated in patients with diffuse SSc (498 +/- 134 ng/ml) as compared with 82 healthy controls (312 +/- 71 ng/ml) (mean +/- SD, p < 0.0001). The elevation of cICAM-1 did not correlate with the duration of disease, the pattern of organ manifestations or the type of treatment. While the concentrations of acute phase proteins were not elevated in SSc, a significant correlation between increased serum sIL-2R and cICAM-1 was observed. CONCLUSION: Increased levels of cICAM-1 indicate an activation of immune processes in SSc. The clinical value of the cICAM-1 determination in SSc can only be judged in longitudinal studies. PMID- 7842529 TI - Linkage disequilibrium of HLA-DR3 and HLA-DR4 with HLA-B alleles in Mexican patients with rheumatoid arthritis. AB - OBJECTIVE: We studied the gene frequencies of classes I, II and III antigens of the Major Histocompatibility Complex (MHC) in 32 Mexican mestizo patients with rheumatoid arthritis (RA) and compared them with those obtained from 110 of their first degree relatives and 100 Mexican mestizo controls. Furthermore, we analyzed the observed and expected frequencies of the haplotypes and calculated the delta values in the three groups. METHODS: The class I and class II MHC antigens were determined by the microlymphocytotoxicity test; class III MHC antigens were obtained by high voltage agarose gel electrophoresis and immunofixation. The significance of differences among the three groups was tested by chi-square analysis; linkage disequilibrium among the different alleles in each haplotype was estimated by computing the delta values (observed vs expected frequencies). RESULTS: Patients showed a significantly increased frequency of HLA-A1 (corrected p = 10(-5)), DR3 (corrected p = 0.04) and DQ2 (corrected p = 10(-4)) and a decreased frequency of A31 (corrected p = 0.003) as compared to the normal controls. First degree relatives compared to patients and controls showed a decreased frequency of HLA-DR4 (corrected p = 0.02 and 0.008 respectively); consequently, DQ3 was also diminished (corrected p = 10(-4)). Analysis of MHC haplotypes within families revealed in the patients seven MHC haplotypes with significant differences between the observed and expected frequencies (statistically significant delta values). These haplotypes were: [HLA-B8; DR3], [HLAB44; FC31], [HLA-B8; SC42], [HLA-DR4; SC31], [HLA-B35; SC32], [HLA-DR7; FC31] and [HLA-DR2; SC31]. On the other hand, the control haplotypes showed significant delta values in only one of these haplotypes ([HLA-DR4; SC31]), whereas first degree relatives showed none. Analysis of all the class I, II and III alleles, either alone or as part of specific haplotypes, showed two B-DR haplotypes with higher relative risks than their alleles alone. These haplotypes were: [B44; DR4] (RR = 6.0, p = 0.005), and [B8; DR3] (RR = 8.3, p = 0.010). CONCLUSION: The results suggest that a specific combination of antigens in the same haplotype (for instance between HLA-B and HLA-DR) could contribute to increasing the genetic susceptibility to develop RA. PMID- 7842531 TI - Fish-oil fatty acid supplementation in mixed cryoglobulinemia: a preliminary report. AB - OBJECTIVE: Since fish oils seem to play a potential role in the treatment of inflammatory disorders by inhibiting arachidonic acid metabolism, the purpose of this study was to determine their therapeutic efficacy in mixed cryoglobulinemia (MC), an inflammatory condition caused by the deposition of immune complexes in vessel walls. METHODS: In an 8-week double-blind randomized trial, ten MC patients received a daily dietary supplement of 3 gm of eicosapentaenoic acid (EPA) and 2 gm of docosahexenoic acid (DHA), while 10 other MC patients received placebo (olive oil). The severity of purpura, arthralgias, paresthesias, asthenia and Raynaud's phenomenon were monitored daily, and serological assays were performed at the beginning of the study, at the end of the treatment period, and after 4 weeks of wash-out. RESULTS: No significant differences were found between the two groups with regard to the clinical symptoms, although the percentage of patients who reported a clinical improvement was higher in the group treated with fish oils. As for the serological parameters, no variation was found in the placebo group, while in the group receiving fish oils a significant decrease in cryocrit and rheumatoid factor levels was observed, which in the case of rheumatoid factor persisted at the end of the wash-out period. CONCLUSIONS: Under the experimental conditions employed in this study, we could not demonstrate a significant improvement in clinical symptoms in patients with mixed cryoglobulinemia treated with fish oils. However, since our results indicated some improvement in the serological parameters potentially involved in the pathogenesis of the disorder, further studies are warranted to establish the optimal dose and duration of fish oil supplementation in the treatment of MC. PMID- 7842530 TI - Systemic cytokine measurements: their role in monitoring the response to therapy in patients with rheumatoid arthritis. AB - OBJECTIVE: To determine the value of serial measurements of circulating cytokines in patients with rheumatoid arthritis in response to the introduction of disease modifying anti-rheumatic drugs (DMARDs). METHODS: A prospective 12-week study of 98 patients starting second line therapy with serial measurements of IL1 beta, IL2 receptor, IL6, TNF, and urinary neopterins as well as ESR, CRP and rheumatoid factor. RESULTS: The markers of the acute phase response fell significantly with treatment as did the rheumatoid factor. IL-6 fell in certain sub-groups (significantly so after sulphasalazine SZP) of treated patients, but no other consistent change in circulating cytokine levels was demonstrated. Urinary neopterins rose with therapy. CONCLUSIONS: The measurement of circulating cytokine levels in patients with rheumatoid arthritis is of limited benefit; macrophage function (as measured by urinary neopterins) is initially enhanced by DMARDs in patients with rheumatoid arthritis. PMID- 7842532 TI - Esophageal motility disorders in the rheumatic diseases: a review of 150 patients. AB - OBJECTIVE: Rheumatic diseases are a group of systemic disorders that may be concurrent with Raynaud's phenomenon and involvement of the internal organs, in particular the esophagus. Esophageal motor abnormalities have been widely described in systemic sclerosis, but have not frequently been reported in other diseases. In the present study we have examined the prevalence and pattern of esophageal motility disorders in different rheumatic diseases. METHODS: Esophageal manometry was performed on 150 patients, 21 males and 129 females, suffering from different rheumatic diseases (SSc, RA, SLE, MCTD, undifferentiated CTD, or DM/PM) and on 30 healthy controls. RESULTS: Functional involvement of the esophagus was demonstrated in all the rheumatic diseases considered, although at varying percentages. The frequencies of the functional abnormalities differed when each disease was considered separately. In SSc patients abnormalities were found more frequently in the lower esophageal sphincter (81.8%) and in the esophageal body (84.8%); data for the DM/PM and MCTD patients broadly overlapped. On the contrary, in SLE the lower sphincter appeared to be less (or even not at all) impaired, while the most specific disorder was an isolated abnormal peristalsis. RP did not always correlate with manometric changes in all of the groups studied. CONCLUSIONS: Three conclusions derive from our study: i) motor disorders affecting the esophagus were not only found in SSc, but also in all forms of non-lupus CTD; ii) the simultaneous involvement of the esophageal body and the lower esophageal sphincter is discriminant between non-lupus CTD and SLE; and iii) RP may be regarded as a condition pathogenetically unrelated to manometrically detected esophageal motor abnormalities. PMID- 7842533 TI - Comparison of tests for the lupus anticoagulant and antiphospholipid antibodies in systemic lupus erythematosus. AB - A variety of laboratory assays are used to screen for the presence of the lupus anticoagulant. Six commonly used coagulation tests, and the ELISA assay for antiphospholipid antibody using three different substrate phospholipids, have been evaluated in 110 patients with systemic lupus erythematosus or lupus-like disease. One or more coagulation assays was abnormal in 41% (45/110) of the patients. No individual test detected more than 78% of these abnormalities, indicating that a single phospholipid based coagulation test cannot be used to screen for a possible lupus anticoagulant. A combination of Actin FSL, DTTA and DRVVT detected all the abnormalities. The most sensitive two-test combination was Actin FSL and DRVVT. Approximately half (56%) of the patients with a positive clotting test had an abnormal antiphospholipid antibody assay. A similar proportion (58%) of the aPL positive patients had a prolonged coagulation test. The marked discordance between the coagulation assays and a positive antiphospholipid antibody test further complicates the laboratory definition of this abnormality, at least in patients with systemic lupus erythematosus. PMID- 7842534 TI - Anti-platelet antibodies against gpIIb/IIIa in systemic sclerosis. AB - An enzyme-linked immunosorbent assay and western immunoblotting analysis were used to detect anti-platelet antibodies in the sera of 50 patients with systemic sclerosis. Eleven (22%) positive sera were found by ELISA. Serial investigations showed that the presence of these antibodies was often transient. Immunoblotting analysis demonstrated that the antibodies were directed against a 114 kDa antigen. Using monoclonal antibody, anti-platelet antibodies directed against gpIIIa were found in 4 cases. Similar to immune thrombocytopenia and lupus erythematosus, a significant portion of the anti-platelet antibodies were also directed against the glycoprotein complex IIb/IIIa in systemic sclerosis. PMID- 7842535 TI - Recurrent sterile arthritis following primary septic meningococcal arthritis. AB - Primary septic meningococcal arthritis (PSMA) is an unusual manifestation of meningococcal disease. With appropriate antibiotic therapy, complete recovery is the rule. A "postinfectious arthritis" in the previously infected joint may ensue, however. A patient who developed a recurrent sterile arthritis following PSMA, after a symptom-free interval, is described. Possible pathogenetic mechanisms and the clinical implications are discussed. PMID- 7842536 TI - Cutaneous infection with rapidly growing mycobacteria in patients with systemic rheumatic disease. AB - We report two patients with systemic rheumatic disease being treated with steroids whose cases were complicated by subcutaneous nodules. In both, clinical and histological features suggested cutaneous infection and M. chelonae was isolated from skin specimens. Antibiotic therapy in both and surgery in one led to healing after a prolonged course. A review of the literature and our experience with these two patients suggest that rheumatic patients on steroid therapy are at risk of infection with these unusual pathogens. Knowledge of the risk factors and the distinctive picture of cutaneous mycobacteriosis should improve its diagnosis and therapy. PMID- 7842537 TI - Central nervous system involvement in relapsing polychondritis. AB - Central nervous system (CNS) involvement is a rare condition in relapsing polychondritis. We report a case of meningoencephalitis that revealed relapsing polychondritis in a 70-year-old woman. A vasculitic process is presumed. Patient was treated with steroids and dapsone, and no relapse was observed after a follow up of 2 years. PMID- 7842538 TI - IgA in Sjogren's syndrome. AB - Patients with Sjogren's syndrome (SS) display two sets of immunological abnormalities. B cells are oligoclonally activated, resulting in hypergammaglobulinaemia, elevated levels of circulating immune complexes (CIC) and non-organ specific autoantibodies. The cellular arm of the immune response is also involved, as shown by the predominance of activated T cells within the exocrine gland infiltrate. IgA could well bridge the gap between activated B cells and defective T cells and by doing so, play a pivotal role in the pathogenesis of SS. This interpretation is supported by the high proportion of IgA in immunoglobulin(Igl) production at the mucosal level. Additionally, IgA is the Igl class most dependent on T cell help. A number of studies over the past 15 years have reported high levels of serum and secretory IgA, IgA-rheumatoid factor and IgA-containing CIC. A correlation between disease activity and the latter abnormalities has recently been shown. There is, however, a need for longitudinal assessment of total IgA and IgA autoantibodies in order to further evaluate their role in the pathogenesis of the disease. PMID- 7842539 TI - Erosive juvenile arthritis in a patient with common variable hypogammaglobulinemia. PMID- 7842540 TI - Eosinophilic fasciitis associated with a monoclonal immunoglobulin. PMID- 7842541 TI - CD11/CD18 bearing lymphocytes in cerebrospinal fluid from patients with active Behcet's disease. PMID- 7842542 TI - Recombinant human erythropoietin (r-hu-EPO) treatment in patients with rheumatoid arthritis and anaemia of chronic disease (ACD) PMID- 7842543 TI - Streptococcus agalactiae septic arthritis associated with chondrocalcinosis in a patient without predisposing systemic disease. PMID- 7842544 TI - Antineutrophil cytoplasmic antibodies and endocarditis. PMID- 7842546 TI - The role of forceps in modern obstetrics. PMID- 7842545 TI - Rheumatoid arthritis with sensory neuropathy of the right ulnar nerve. PMID- 7842547 TI - The role of vacuum extraction in modern obstetrics. AB - Vacuum extraction can be an effective technique for operative vaginal delivery, and in some circumstances, it may even be a useful aid in abdominal delivery. Specialized equipment is required, but surprisingly little time is necessary to effect delivery in uncomplicated applications. Rigid vacuum extractors are more effective than pliable instruments but are associated with more fetal scalp trauma. Vacuum extraction spares maternal soft tissue trauma compared with forceps but also more often fails to effect delivery. Unfortunately, both failed vacuum extraction and operative success with delivery can be associated with fetal/neonatal morbidity. It may be that vacuum extraction is an easier technique to learn than forceps, but there is indirect evidence that the ease of application may tempt misuse. Clearly, the technique can be misused, and therefore, good judgment and skill of the operator remain as important as they are in any operative procedure. There are some rare circumstances in which the unique properties of the vacuum confer advantages over forceps, but neither these indications nor the advantages are frequent or clear enough to recommend that every obstetric unit have the availability and capability of vacuum extraction instrumentation and expertise. PMID- 7842548 TI - Cesarean section birth and cesarean hysterectomy. PMID- 7842549 TI - Episiotomy and early repair of dehiscence. PMID- 7842550 TI - Postpartum hemorrhage. PMID- 7842551 TI - Cervical incompetence and cerclage: unresolved controversies. PMID- 7842552 TI - Wound complications after cesarean sections. PMID- 7842553 TI - Invasive techniques for fetal evaluation and treatment. PMID- 7842554 TI - The breast: embryology, development, and anatomy. PMID- 7842555 TI - History, physical examination, and education in breast self-examination. PMID- 7842556 TI - Normal lactation and galactorrhea. PMID- 7842557 TI - Other nipple discharge. PMID- 7842558 TI - Fibrocystic change of the breast. PMID- 7842559 TI - Other benign breast problems. PMID- 7842560 TI - The epidemiologic characteristics of breast cancer. PMID- 7842562 TI - Mammography in the obstetrician-gynecologist's office: early detection of breast cancer. PMID- 7842561 TI - Imaging techniques for breast disease. PMID- 7842563 TI - The gynecologist and surgical procedures for breast disease. AB - Patients with a palpable mass often benefit most from aspiration. As the clinician tries to aspirate, fluid may be obtained if the lesion is cystic. A solid lesion can be assessed with FNA biopsy with a very high degree of accuracy. Excisional biopsy should be used when a cystic lesion recurs, the mass does not disappear after the cyst is aspirated, or if the fluid obtained is bloody. A solid lesion may need to be excised if the aspirate is negative. The overall detection rate of breast cancer is approximately 20% for excisional biopsies. Mammographically detected lesions can be evaluated with needle-localization biopsies and stereotactic biopsies. The detection rates for breast carcinoma averages approximately 30%, with at least 20% of these lesions being noninvasive. The role of core needle biopsy of palpable lesions is limited; however, histologic confirmation of positive cytologic results from aspirate is possible with this approach. Stereotactic needle biopsy appears to correlate well with the specimen obtained at incisional biopsy and may decrease the need for needle localized excisional biopsy. PMID- 7842564 TI - Breast cancer. PMID- 7842565 TI - Radiation therapy for primary breast disease. PMID- 7842566 TI - Adjuvant therapy for breast cancer. PMID- 7842567 TI - Carcinoma in situ. PMID- 7842568 TI - Breast cancer in pregnancy. AB - The traditional view that breast cancer during pregnancy is associated with poor prognosis is no longer tenable. The reported poor prognosis usually is the result of late stage of presentation. It is important for physicians to consider breast cancer in the differential diagnosis of a breast problem discovered during pregnancy. When patients are separated into similar stage at presentation with positive or negative lymph nodes, the 5- and 10-year rates of survival for pregnancy-associated or nonpregnancy-associated breast cancer are identical. The breasts should be carefully examined at least during the first prenatal visit and thereafter if signs and symptoms appear. Operable disease in the first and second trimesters should be treated by modified radical mastectomy, and chemotherapy should be considered if indicated during the second and third trimesters. Breast conservation treatment presents special problems, and the risks and benefits should be discussed with the patient. There is no evidence that termination of pregnancy improves survival. PMID- 7842569 TI - Follow-up of patients with breast cancer. AB - Routine, thorough history and physical examinations are the mainstay of follow-up for patients with breast cancer. Yearly mammography of the contralateral breast in all patients is important, as is more frequent radiologic surveys of the ipsilateral breast in patients who had breast-conserving therapy. Frequent chest films and regular bone scans are beneficial only in those patients with advanced disease for improving palliation. In the remaining patients, aggressive attempts at detecting yet asymptomatic metastatic disease through routine bone and liver surveys, sophisticated serum analyses, and serial chest radiographs appears unwarranted. As noted, these measures have not improved disease-free or overall survival compared with that available through treatment of symptomatic metastatic disease. PMID- 7842570 TI - Detection of protein bound vitamin B12 malabsorption. A case report and review of the literature. AB - The Schilling test is used to identify the cause of vitamin B12 malabsorption in patients with low serum vitamin B12 levels. The initial step required for vitamin B12 absorption is a process of separation from the protein complexes of food. The crystalline Co-57 vitamin B12 used in the Schilling test does not reproduce this physiologic process. Thus, a crystalline stage I Schilling test may be normal even in the face of cobalamin malabsorption. An adjunctive stage I Schilling test using Co-57 vitamin B12 bound to protein has been developed. The authors describe a patient with protein-bound vitamin B12 malabsorption whose crystalline Co-57 vitamin B12 stage I Schilling test was normal. A subsequent stage I Schilling test using Co-57 vitamin B12 bound to chicken serum revealed significant cobalamin malabsorption. A review of the history and literature of this diagnostic test using protein bound vitamin B12 is also presented. PMID- 7842571 TI - Detection of recurrent colorectal carcinoma with In-111 CYT-103 scintigraphy in a patient with nondiagnostic MRI and CT. AB - Detection of recurrent colorectal carcinoma can be a diagnostic challenge. The authors report a case of a patient who, after resection of his primary colorectal carcinoma, had a recurrence that was not detected by MRI or serial CT examination, but was clearly demonstrated by In-111 labeled CYT-103 scintigraphy. This case demonstrates the use of CYT-103 scintigraphy in detecting recurrent colorectal cancer in a patient, despite results of nondiagnostic MRI or serial CT examinations. PMID- 7842573 TI - Child abuse. Extraosseous abdominal bone imaging uptake. PMID- 7842574 TI - Scintigraphic evaluation of a patient with lung cavitations. Ga-67 scintigraphy is nondiagnostic. PMID- 7842572 TI - A case of complete Carney's syndrome. AB - The triad of gastric leiomyoblastoma, paraganglioma, and pulmonary chondroma was first described by Carney in 1977. The authors report a case of a patient with gastric leiomyosarcoma, multiple pulmonary chondromata, and paraganglioma. This represents a complete form of Carney's triad. The paraganglioma was identified with I-123 MIBG. PMID- 7842576 TI - Iatrogenic hemobilia and a positive cholescintigram. PMID- 7842575 TI - Comparison of pulmonary Ga-67 and Tc-99m MAA imaging in a patient with primary amyloidosis. PMID- 7842577 TI - Gorham's syndrome. Correlative imaging using nuclear medicine, plain film, and 3 D CT. PMID- 7842578 TI - Progressive accumulation of activity on scrotal scintigraphy in early incarcerated inguinal hernia. PMID- 7842579 TI - Radionuclide visualization of a thoracic renal ectopia. PMID- 7842580 TI - Sympathetic denervation due to neuroblastoma. PMID- 7842581 TI - Increased vascularity in hepatic hemangiomas. Unusual pattern on Tc-99m RBC scintigraphy. PMID- 7842582 TI - Mismatch on Tc-99m DTPA aerosol ventilation-perfusion lung scan caused by achalasia. PMID- 7842583 TI - A pseudopheochromocytoma? Accumulation of I-123 MIBG in the renal pelvis. PMID- 7842584 TI - Tc-99m sestamibi imaging is useful in brain metastases. PMID- 7842585 TI - Provocative red blood cell scintiscan in occult chronic gastrointestinal hemorrhage. AB - A patient with a chronic occult gastrointestinal bleeding site is described. Because an extensive examination failed to locate the site of bleeding, a heparin infusion was used in conjunction with a conventional Tc-99m labeled red cell bleeding study. A mid-jejunal ulcer was safely localized before elective surgery. A protocol for a heparin provocative bleeding study is proposed. PMID- 7842587 TI - The interrenicular septum. A normal anatomical variant seen on DMSA SPECT. AB - SPECT imaging has been shown to identify additional defects when applied to Tc 99m DMSA scintigraphy. However, the nature of these defects is uncertain. They may be because of small scars or anatomical variants. The interrenicular septum (IRS) is a normal finding that may mimic a scar on ultrasound examination or tomography. In this study, it was found that the IRS may be identified on Tc-99m DMSA SPECT and that it was present in 32% of patients. Its characteristic appearance is a linear area of absent tracer uptake extending from the renal hilum into the parenchyma, usually anterosuperiorly. The preservation of renal cortical uptake differentiates it from a scar, which results in a defect in the rim of cortical Tc-99m DMSA accumulation. PMID- 7842586 TI - Clinical value of labeled red blood cell scintigraphy in patients with difficult to diagnose gastrointestinal bleeding. AB - A retrospective study was conducted using 36 patients with gastrointestinal bleeding in whom the diagnosis was not directly apparent from first line diagnostic procedures. Final diagnosis was established by surgery, endoscopy, or postmortem examination in 20 patients. Scintigraphic examination with Tc-99m or In-111 labeled red blood cells yielded 24 positive and 18 negative results. Nine out of 13 positive scans (verified by other diagnostic procedures) accurately identified the site of bleeding. This was considered to be a satisfactory result in this group of difficult to diagnose patients. The lowest success rate was observed in patients taking drugs that interfered with coagulation, or in patients prone to diffuse blood loss because of coagulopathy. Late scans did not offer additional information and the use of In-111 for this purpose was not thought to be of benefit. Although the technique is rather noninvasive and simple, its application should be restricted to selected patients and its interpretation related to the results of other investigations. PMID- 7842588 TI - Reverse redistribution in Tl-201 stress-redistribution myocardial scintigraphy. Effect of rest reinjection. AB - To clarify the clinical significance of Tl-201 reverse redistribution (RR), 33 patients with chronic coronary artery disease (CAD) underwent stress redistribution Tl-201 cardiac imaging with rest reinjection, coronary arteriography, and 2D-echocardiography. Rest Tc-99m MIBI scintigraphy was also performed in 27 of the 33 patients. A total of 495 segments were analyzed for Tl 201 scintigraphy (405 for Tc-99m MIBI). Each segment was assigned to one of the major coronary artery territories. Two patterns of RR were identified; 1) pattern A (RR-A) showed normal Tl-201 uptake on stress images and lower than normal on redistribution images, and 2) pattern B (RR-B) showed lower than normal Tl-201 uptake on stress images with further decrease on redistribution images. The RR phenomenon was found in 46 (9% of the total) segments; 25 with RR-A and 21 with RR-B. Reverse redistribution pattern A segments had lower Tc-99m MIBI uptake (84 +/- 9% versus 92 +/- 10%, P < 0.0001) and a higher percentage of stenosed coronary arteries (80% versus 49%, P < 0.05) compared to normal segments (n = 204, 41% of the total). No difference in wall motion was observed between RR-A and normal segments. Of the 25 segments with RR-A, 14 showed enhanced Tl-201 uptake after reinjection (Re+) and 11 remained unchanged after reinjection (Re-). Segments that were Re- showed significantly (P < 0.05) lower Tc-99m MIBI uptake (79 +/- 9%) compared to Re+ segments (87 +/- 8%) and normal segments (92 +/- 10%).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7842589 TI - Discordance of dual-isotope (hybrid) myocardial perfusion imaging results in patients who have undergone revascularization procedures. AB - Three hundred twenty-one separate acquisition dual-isotope myocardial perfusion scans were reviewed retrospectively. Studies performed in six patients demonstrated a relative improvement in Tc-99m sestamibi uptake during stress in segments that appeared abnormal on rest injected Tl-201 images. All patients who demonstrated this pattern had a prior history of myocardial infarction and interventional revascularization. While many factors may contribute to this appearance, the authors favor the presence of a patent infarct-related artery as being the most significant. PMID- 7842590 TI - Abnormal sympathetic innervation of the heart in a patient with myotonic dystrophy detected with I-123 MIBG cardiac SPECT. AB - Iodine-123 MIBG is a norepinephrine analog which can be used to image the sympathetic innervation of the heart. The authors report a patient with myotonic dystrophy whose I-123 MIBG SPECT revealed accelerated washout of I-123 MIBG from infero-posterior and a part of lateral wall, although Tl-201 SPECT showed no abnormal finding. The authors conclude that I-123 MIBG can be more sensitive in detecting the cardiac abnormality than Tl-201 SPECT in this disease. PMID- 7842591 TI - Induced right-to-left cardiac shunt during pulmonary perfusion imaging. AB - Ventilation-perfusion lung scans are routinely performed using Tc-99m labeled MAA particles administered intravenously which are subsequently trapped in the pulmonary artery capillary bed. In the presence of a right-to-left shunt, activity may be seen in the systemic circulation. Right-to-left shunts may be worsened by inducing hypoxemia which causes pulmonary artery constriction, and also by increasing venous return to the heart. In this case, the authors used various maneuvers to increase right-to-left shunting and thereby demonstrated the presence of fixed pulmonary hypertension. These findings suggested that the patient's dyspnea on exertion was not primarily because of left ventricular dysfunction, and proposed coronary bypass surgery was deferred for medical management. PMID- 7842592 TI - Resting Tl-201 scintigraphy in the evaluation of coronary artery disease in children with Hurler syndrome. AB - Severe coronary artery disease may occur early in the course of mucopolysaccharidosis. The authors present radiologic, scintigraphic, and pathologic findings in five patients with Hurler syndrome. Thallium-201 myocardial scintigraphy and selective coronary angiography obtained within 2 days to 6 months were correlated in five patients. Postmortem examination of the coronary arteries was obtained in one patient within hours of angiography. Interobserver agreement on grading of scintigraphic abnormalities was poor. Nonspecific findings on Tl-201 studies included septal abnormalities in all five patients. Scintigraphic findings were corroborated by angiography and postmortem results in only 3 of 5 patients. Our findings suggest that resting Tl-201 scintigraphy has limited value in the detection of coronary artery disease in patients with Hurler syndrome. PMID- 7842593 TI - Difference between splenic volume measured at necropsy and that measured in vivo by radionuclide tomography. AB - Reference values for splenic volume used in this study are based on necropsy measurements made in 1970. Because the volumes (measured by radionuclide tomography) seemed to be consistently greater than the necropsy values, the splenic volume in 35 healthy male volunteers ranging in age from 18-30 years (median age, 21 years) was studied. Their mean (SD) splenic volume was 281 (73) ml compared with 138 (34) ml in the reference group. The mean splenic volume in healthy volunteers seems to be significantly greater than in cadavers, and these results suggest that reference range for splenic volume in vivo should be revised. PMID- 7842594 TI - Meperidine in conjunction with cholescintigraphy to diagnose acute cholecystitis in a patient allergic to morphine. AB - Cholescintigraphy with morphine augmentation is used routinely to expedite the differential diagnosis of acute from chronic cholecystitis. A patient with hepatic dysfunction and an allergy to morphine received intravenous meperidine in conjunction with cholescintigraphy. The gallbladder was not visualized 30 minutes after administration of the drug. However, the activity accumulated in the initial photon deficient gallbladder at 4 hours after meperidine administration (6.5 hours after radiopharmaceutical administration). These findings may be explained in part by prolongation of meperidine bioavailability because of impairment of hepatic function. PMID- 7842595 TI - Normal cerebellar MIBG localization. Implications in the interpretation of delayed scans. AB - In the I-131 MIBG scans of 14 patients with neuroblastoma (86%) or pheochromocytoma/paraganglioma (14%) that were studied more than 48 hours after administration of the radiopharmaceutical, 12 (86%) had discernible cerebellar MIBG localization. A few had midbrain or diffuse cerebral uptake as well. None of the patients had cerebellar or other central nervous system signs or symptoms, and the localization is consistent with the known distribution density of central nervous system catecholamine receptors. This suggests that cerebellar MIBG localization is normal in delayed scans and that it should not be confused with neuraxial metastasis of adrenergic neuronal neoplasms. PMID- 7842596 TI - SPECT in adult mosaic Down's syndrome with early dementia. AB - A 52-year-old patient with mosaic Down's syndrome exhibiting clinical features of early dementia who underwent high resolution SPECT neuroimaging is reported. While a CT scan of the brain showed no abnormality, cranial SPECT confirmed the presence of marked cortical blood flow deficits. PMID- 7842597 TI - Bone scintigraphy as a prognostic factor in patients with adult T-cell leukemia lymphoma. AB - Bone scintigraphy in 26 patients with adult T-cell leukemia-lymphoma (ATLL) was evaluated. Abnormally high accumulations were observed in 7 of 26 patients (skull, 5; vertebra, 1; rib, 6; bony pelvis, 1; scapula, 2; lower extremities, 1). Serum calcium levels were significantly elevated in patients with abnormally high accumulations on bone scintigraphy. Survival rates of the patients with positive results on bone scintigraphy were significantly lower than were those with negative results on bone scintigraphy (P < 0.05). Survival rates of patients with high serum calcium levels, high WBC counts, and high serum lactate dehydrogenase (LDH) levels were also significantly lower than were those of the negative groups, in this order of significance. Bone scintigraphy was useful for detecting bone marrow involvement in ATLL and it can be one of the better indicators of the prognoses of patients with ATLL. PMID- 7842598 TI - The role of Tc-99m MDP and Ga-67 imaging in the clinical evaluation of malignant fibrous histiocytoma. AB - The purpose of this study was to evaluate the value of bone and Ga-67 imaging in patients with malignant fibrous histiocytoma (MFH). Thirty-four patients with biopsy-proven MFH were studied. Of these patients, 15 underwent Ga-67 imaging, 26 underwent Tc-99m MDP imaging, and 7 underwent both imaging procedures. In evaluation of the primary tumors, intense Ga-67 uptake was observed in 14 of 15 patients with a diagnostic sensitivity of 93.3%. However, positive bone imaging results were observed in only 10 of 26 patients with a diagnostic sensitivity of 38.5%. Most of these were secondary to Tc-99m MDP uptake in adjacent bone invaded by the primary tumor. Only two patients, of the 18 patients without direct bone invasion, had increased radioactivity in the tumors (11.1%). In evaluation of the metastatic lesions, increased Ga-67 uptake was observed in 8 of 8 metastatic sites (100%). However, Tc-99m MDP could only detect 5 of 12 metastatic sites (41.7%), which were all diagnosed to be bone metastases. None of the extraskeletal metastasis could be detected by Tc-99m MDP imaging. Ga-67 scintigraphy appears to be a very useful tool in the evaluation of both primary and metastatic lesions of MFH and is assumed to be useful in the follow-up. However, it is emphasized that bone scintigraphy is useful only when the tumor invades the skeletal system and is of limited value in the evaluation of extraskeletal lesions. PMID- 7842599 TI - The three neurovascular complexes in the posterior fossa and vascular compression syndromes (honored guest lecture). PMID- 7842600 TI - State of the union "the next generation". PMID- 7842601 TI - The road less traveled: transtemporal access to the CPA. PMID- 7842602 TI - Radiosurgery of tumors of the cerebellopontine angle. PMID- 7842603 TI - Surgical approaches to the craniovertebral junction. PMID- 7842604 TI - Anatomic principles of intradural spinal surgery. AB - In summary, the predominate role of surgery as the definitive treatment modality for the vast majority of intradural pathology provides a unique opportunity to improve outcome through continued advances in microsurgery. There is also, however, the added responsibility that comes with the treatment of benign and generally nonlife-threatening pathology, that is, an increasing expectation of cure and anticipation of preserved neurologic function. Successful intervention is maximized by the surgeon who recognizes that microsurgical technique and judgment are learned skills obtained only through experience but developed within a framework of anatomic principles and an understanding of how anatomy is altered by specific pathologic processes. PMID- 7842605 TI - Surgical management of proximal carotid artery aneurysms. PMID- 7842607 TI - Adenovirus-mediated in vivo gene transfer into the central nervous system of a nonhuman primate (resident award paper). PMID- 7842606 TI - The anatomic basis of spinal instability. PMID- 7842608 TI - Anatomic principles guiding surgery of degenerative lumbar spine disease. PMID- 7842609 TI - Anatomical treatment of cervical spondylosis. PMID- 7842610 TI - Anatomic foundations of aneurysm surgery (honored guest lecture). PMID- 7842611 TI - Anterior circulation aneurysms: improvement in outcome in good-grade patients 1983-1993. PMID- 7842612 TI - Surgical techniques for basilar bifurcation aneurysms. AB - In this review our experience and surgical techniques for clipping basilar bifurcation aneurysm are described. A multidirectional approach is proposed for difficult or unusual aneurysms. Some clipping techniques found useful are described. PMID- 7842613 TI - Principles of aneurysm surgery: cerebral ischemic protection, hypothermia, and circulatory arrest. PMID- 7842614 TI - Anatomic principles of cerebrovascular surgery for arteriovenous malformations. PMID- 7842615 TI - The American health care system in the Clinton era. PMID- 7842616 TI - Glomus jugulare tumors. PMID- 7842617 TI - The Canadian health care system in the nineties. PMID- 7842618 TI - Hospital-based neurosurgical systems. PMID- 7842619 TI - Neurosurgical applications of Le Fort I-type osteotomy. PMID- 7842620 TI - Lesions in functional ("eloquent") cortex and subcortical white matter. PMID- 7842621 TI - Graphic-interactive cranial surgery. PMID- 7842622 TI - Lateral approaches to the cerebellopontine angle and petroclival region (honored guest lecture). PMID- 7842623 TI - Ventriculoscopic surgery. PMID- 7842624 TI - Imaging and drug delivery to tumor-infiltrated brain. PMID- 7842625 TI - Petroclival lesions. PMID- 7842626 TI - Management of thalamic-basal ganglia and brain-stem vascular malformations. PMID- 7842627 TI - Bioinformatics and biotechnology information--some moves in Europe. PMID- 7842628 TI - Irregular distortion of the erythrocytes (acanthocytes, spur cells) in senile dementia. AB - An excess of irregularly distorted red cells with spiked forms (acanthocytes, spur cells) has been found in a substantial minority of patients with senile dementia of Alzheimer type (7 of 50 patients, 3 of 21 men and 4 of 29 women). Of 100 control patients, 42 men and 58 women), 5 (3 men and 2 women) showed comparable distortion, but, of these, one man may well have incipient dementia and the others had serious organic diseases which may be associated with comparable erythrocytic changes. The cause of the distortion is not yet clear, but the presence of occasional giant erythrocytes in the absence of general macrocytosis suggests a possible abnormality of cell-membrane synthesis. This distortion may be a useful marker in patients with loss of memory. Whether it is a manifestation of a haemopoietic clone or a constitutional anomaly associated with Alzheimer's disease remains to be seen. PMID- 7842629 TI - The World-Wide Web: an interface between research and teaching in bioinformatics. AB - The rapid expansion occurring in World-Wide Web activity is beginning to make the concepts of 'global hypermedia' and 'universal document readership realistic objectives of the new revolution in information technology. One consequence of this increase in usage is that educators and students are becoming more aware of the diversity of the knowledge base which can be accessed via the Internet. Although computerised databases and information services have long played a key role in bioinformatics these same resources can also be used to provide core materials for teaching and learning. The large datasets and archives that have been compiled for biomedical research can be enhanced with the addition of a variety of multimedia elements (images, digital videos, animation etc.). The use of this digitally stored information in structured and self-directed learning environments is likely to increase as activity across World-Wide Web increases. PMID- 7842630 TI - Effect of interferon-gamma and TNF-alpha on MUC1 mucin expression in ovarian carcinoma cell lines. AB - In view of the potential uses of cell surface tumour associated antigens in novel anticancer treatment, a study was designed to investigate whether the biological response modifiers interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha) could effect the expression of an epitope on the tumour associated MUC1 epithelial mucin. Four ovarian carcinoma cell lines showing high (OAW42 and GG) and low (JAM and PE01) basal expression of MUC1 were treated with 10-1000 U/mL of IFN-gamma or TNF-alpha for one or five days. Changes in MUC1 expression in cells exposed to IFN-gamma or TNF-alpha were monitored using an ELISA technique with the monoclonal antibody BC2 which reacts with a core protein epitope on the MUC1 mucin, and then corrected for the number of viable cells present. TNF-alpha had little effect on MUC1 expression, but one or five days exposure to IFN-gamma significantly increased MUC1 expression (p < 0.01) in all cell lines including the two cell lines that initially showed little or no expression. PMID- 7842631 TI - Prognostic value of a 90kD subunit containing glycoprotein tumor-associated antigen specific immune complexes in lung cancer patients. AB - An ELISA to detect a glycoprotein TAA-specific immune complexe (IC) has been developed utilizing a murine monoclonal antibody, AD1-40F4, that recognizes a 90kD subunit of the antigen. In this study we determined the applicability of the assay to assess the presence of the glycoprotein TAA-IC in lung cancer patients. The incidence of glycoprotein TAA-IC was 63% (33/89), significantly higher (p < 0.05) than normal controls (3.2%; 8/250). Comparative analyses of pre- and post operative sera of non-small cell lung cancer patients revealed that in 30% (20/66) of patients, the ELISA value for the marker did not become negative, i.e., decrease below the cut-off level (0.410 ODnm) after surgical resection of the tumor. It is postulated that these patients either had extensive disease or microscopic metastases that were not resectable. Evaluation of post-operative glycoprotein TAA-IC results in relation to disease recurrence revealed a significant association between the presence of the antigen in serum and disease recurrence. There did not appear to be any association between the glycoprotein TAA-IC and the other conventional marker, CEA; however, using more than one marker increases the incidence of detection of the disease. PMID- 7842632 TI - Screening and monitoring coeliac disease: multicentre trial of a new serum antibody test kit. AB - A multicentre trial was conducted to evaluate a new test for anti-gliadin antibodies (AGA) in serum (Coeliac Screening Kit, CSK, Medical Innovations Limited, Artarmon, NSW, Australia). The test showed excellent reproducibility for both anti-gliadin IgA and IgG detection. The average intraassay coefficient of variation (CV) was 3.0% for IgA and 2.4% for IgG (n = 6), while the average interassay CV was 6.4% for IgA and 4.3% for IgG (n = 3). By defining a positive test as both IgA and IgG elevated, a sensitivity of 93% in untreated coeliacs (n = 75) was observed. The corresponding specificities in healthy adults (n = 130) and healthy children (n = 77) were > 99% and 100% respectively, while in patients with other gastrointestinal disorders (disease controls) the specificity was 94% (n = 129). The test was also useful in monitoring patients, with anti-gliadin IgA and IgG falling for up to a year after commencing a gluten-free diet (GFD) (12 adults). In some patients however, antibody levels did not reach the normal cutpoint after many months on a GFD, which may reflect the patients' poor adherence to their gluten free diet. The test was superior to the Pharmacia anti gliadin ELISA, and should be useful as an aid to the diagnosis of coeliac disease, as well as in the follow-up of treated patients. PMID- 7842633 TI - Conversation, co-ordination and convention: an empirical investigation of how groups establish linguistic conventions. AB - Two experiments are reported which demonstrate the development of co-ordinated description languages in two groups of communicators playing Garrod and Anderson's (1987) maze game. The experiments contrast language co-ordination between speakers who always interact with the same partner (isolated pairs) as compared with speakers who interact with different partners drawn from the same community. Whereas the isolated pairs show higher degrees of inter-speaker convergence than the community pairs at the start of the experiment, the situation reverses by the time they have all played six or more games. The results are discussed at two levels: (1) in terms of Lewis's formal theory of conventions, and (2) in relation to a language processing model which abides by the "output/input co-ordination" principle proposed in Garrod and Anderson (1987). PMID- 7842634 TI - Suppression of valid inferences: syntactic views, mental models, and relative salience. AB - Byrne (1989) has demonstrated that although subjects can make deductively valid inferences of the modus ponens and modus tollens forms, these valid inferences can be suppressed by presenting an appropriate additional premise "If R then Q" with the original conditional "If P then Q". This suppression effect challenges the assumption of all syntactic theories of conditional reasoning that formal rules of inference such as modus ponens is part of mental logic. This paper argues that both the syntactic and the mental model accounts of the suppression effect are inadequate because they fail to give a principled account of the critical interpretive component involved in reasoning. In contrast, the relative salience model proposed in this study emphasized the centrality of the interpretative processes with the critical component being the relative salience of premises as judged by subjects on the basis of their prior knowledge activated in particular problem situations. Using 120 undergraduates and 120 policemen as subjects, predictions from the model were tested and confirmed in a suppression paradigm and evidence of convergent validity for the construct of salience were obtained. The results cannot be reconciled with either the syntactic view or the mental model view that have dominated theories of conditional reasoning. PMID- 7842635 TI - The emergence of events. AB - Although the concept of an event is widely used as the basic unit in the organization of experience, memory and meaning, little attention has been paid to how events emerge or what determines the boundaries of an event. It is usually taken for granted that one knows what an event is or how events are demarcated. In this paper an explanation is offered for the emergence of events, the cut hypothesis, which states: "A sub-sequence of stimuli is cut out of a sequence to become a cognitive entity if it has been experienced many times in different contexts", and three experiments to demonstrate the predictive power of the hypothesis are described. The stimuli in all three experiments were video films, constructed by randomly assembling short excerpts from movies. In the first experiment the cut hypothesis was juxtaposed with the thesis of demarcation at major changes, and it was shown that, after experiencing a certain repeating sequence, subjects hardly considered dividing at an internal point, even if it was a point of maximal change; points of maximal change were determined on the basis of performance by control subjects who did not experience the repeating sequence. In the second experiment the cut hypothesis was juxtaposed with an associationistic explanation; it was shown that subjects who viewed a certain sequence repeating in variable contexts recognized it better than subjects who had viewed the same sequence repeating always in the same context. In the third experiment a prediction of the hypothesis on recall behaviour was tested and it was shown that experience with sequences of stimuli repeating in various contexts results in cohesion of their elements. PMID- 7842637 TI - An experimental model for the assessment of titanium denture casting techniques. AB - In order to establish the most suitable technique for the construction of cast titanium denture frames, an experimental model was developed for the quantification of casting success. A relatively large wax pattern (36 x 29 x 0.9 mm) was prepared from a grid sheet used for the construction of cast cobalt chromium partial denture frames. The pattern consisted of 100 circles and the number of completely cast circles was counted to obtain a percentage success rate. The castings were complete with pure titanium but incomplete (average 54%) with a titanium alloy. For an inspection of internal defects the radiographic conditions were optimised by adopting a relative density of about 2.0. The procedures described will help in establishing the most suitable casting technique for the construction of titanium denture frames for any casting system employed in a laboratory. PMID- 7842636 TI - Effects of lining materials on the composite resins shrinkage stresses. AB - Recently, three types of lining materials have been used in dental clinics, conventional powder-liquid glass ionomer cement, light-cured powder-liquid glass ionomer cement and a light-cured single paste type. This study compared the effects of these lining materials on the shrinkage stress of light-cured composite resins during the early setting stage, when polymerization shrinkage occurs. After the second irradiation, the shrinkage stress of composite resins lined with light-cured powder-liquid type cements was approximately 1.0 to 2.2 MPa when the lining application was 1.5 mm and 0.5 mm thick, respectively, demonstrating that a thicker lining application decreased shrinkage stress. The single paste type was only slightly effective in reducing shrinkage stress in composite resins. Although the sample lined with conventional powder-liquid type showed that stresses were less affected by the thickness of the lining, and had the lowest shrinkage stress of all conditions tested, greater exfoliation from the composite resin or the cavity occurred compared to that occurring with other materials. PMID- 7842638 TI - Contraction stress and marginal adaptation of composite restorations in dentinal cavity. AB - The influence of contraction stress in composite resins on both the shear bond strength to dentin (BS) and marginal adaptation in a standardized dentin cavity was investigated using three restorative resin systems. A teflon ring mold (TF) or copper ring with a roughened inner surface (CP) placed on human tooth dentin was filled with the composite resin, and a shearing test was then performed. ANOVA of BS demonstrated a significant influence from the resin systems and type of molds. BSCP tended to be lower than BSTF in all three systems. This suggested that the inner surface of the CP restricted the flow of resin and then contraction stress occurred at the interface of the bond to the dentin. The system which demonstrated the smallest difference between BSTF and BSCP also showed the best adaptation. This result indicates that contraction stress in the composite resin plays an important role in marginal adaptation. PMID- 7842639 TI - A new porous hydroxyapatite ceramic prepared by cold isostatic pressing and sintering synthesized flaky powder. AB - A new porous hydroxyapatite ceramic was prepared by cold isostatic pressing and sintering of the flaky powder, that was synthesized through two-stage hydrolysis of brushite; (1) a structural change into the apatite structure and (2) a compositional increase in Ca/P ratio, according to the method of Monma and Kamiya. The appearance of the synthesized powder resembled the flaky shape of the starting materials and its average particle size was about 15 microns. This powder consisted of fine needle crystals, which had a tendency to grow into the larger grains, but the powder was highly resistant to sintering under the usual heating conditions at 1200 degrees C. Porous hydroxyapatite blocks and granules were prepared by cold isostatic pressing and sintering a pellet consisting of the hydroxyapatite powder and spherical polymer beads. The product showed a 70% apparent porosity with spherical pores, ranging from 100-200 microns in size, and most pores were interconnected. These properties were ascribed to the effect of cold isostatic pressing on the hydroxyapatite powders with the flaky shape. PMID- 7842640 TI - In vivo wear pattern of experimental composite resins containing different filler components. AB - Using a scanning electron microscope (SEM) and an electron probe surface roughness analyzer (ERA), we conducted the in vivo study of the effect of various filler components on the wear of composite resins. Experimental light-cured composite resins were prepared employing three different filler components; -(1) Silica type, (2) Strontium type, and (3) Barium type. The filler content for all three types was 80 wt%, with the mean particlesize being 2.6 microns in diameter. The resin monomers consisted of 40 wt% Bis-GMA, 40 wt% TEGDMA and 20 wt% UTMA. These materials were placed in 2 mm diameter cylindrical cavities located in the OCA (occlusal contact area) or the CFA (contact free area) of cast crowns temporarily set in a volunteer patient's mouth. The crowns were removed at monthly intervals for longitudinal SEM observation. After two months, worn surfaces were also analyzed by ERA. The result showed that the wear patterns of the composites were characterized by the filler components, especially in the OCA. PMID- 7842641 TI - Effect of crystallization on fracture strength of castable glass-ceramics containing two crystals. AB - The relationship between fracture strength and crystallization in castable glass ceramics was studied using castable glass-ceramics which contained crystalline apatite and magnesium titanate. Bending strength was increased with increases in crystal phases; 90, 124, 122 and 162 MPa were recorded for as-cast specimens and specimens cerammed at temperatures of 905 degrees, 925 degrees and 945 degrees C, respectively. The results of bending tests suggest that the crystallization of magnesium titanate is more effective than that of apatite in increasing the strength of glass-ceramics. Fracture toughness in specimens reheated at 905 degrees C was doubled compared with as-cast specimens. The apatite particles precipitated during ceramming treatment were thought to be an important factor in increasing both the fracture toughness and crack pinning effect. PMID- 7842642 TI - Syntheses of o-methacryloyl-N-acyl tyrosines and their adhesiveness to un-etched human dentin. AB - O-Methacryloyl-N-acyl tyrosines (MAATY) having acyl groups with the various chain length were synthesized and the strength of bonding agents, consisting of MAATY as an adhesive monomer, to unetched human dentin was studied to elucidate the relationship between the molecular structure of MAATY and its adhesive characteristics. Increasing the flexibility of the carboxyl group of tyrosine favors the interaction with the tooth substrate, causing strict bonding. Also, the properties of the neighboring carboxyl group, i. e., steric hindrance and hydrophobicity, hydrophobic-hydrophilic balance in the monomer, and shrinkage of the monomer at copolymerization, are considered important. Especially, steric hindrance of the substituted group neighboring the carboxyl group of tyrosine would play an extremely important role in the adhesion of O-methacryloyl-N octanoyl tyrosine. The maximum tensile bond strength was obtained with a bonding agent consisting of O-methacryloyl-N-hexanoyl tyrosine (15 mol%) and hydroxyethyl methacrylate (85 mol%), and the strength (4.75 MPa) was the maximum in all methacrylates with phenylalanine as a bone structure. PMID- 7842643 TI - Influence of primers containing cupric ion on bonding of dentin treated with phosphoric acid. AB - A primer containing cupric [Cu (II)] ions that promoted the interfacial initiation of polymerization from dentin surfaces was studied. Bovine dentin surfaces were treated with 10% phosphoric acid, then with a Cu primer consisting of aqueous 35% 2-hydroxyethyl methacrylate (HEMA) containing 0.03% cupric salt, and finally bonded with 4-META/MMA-PMMA resin initiated with oxidized tributylborane (TBBO). The use of the Cu primer resulted in a mean bond strength of 12.5 MPa compared with 3.8 MPa without the primer and 6.3 MPa using a 35% HEMA primer without Cu. The Cu primer produced a bond strength of 13.5 MPa even without 4-META in the resin system. Use of the Cu primer should simplify the bonding procedure since enamel and dentin can be etched simultaneously with 10% phosphoric acid. PMID- 7842644 TI - Magnetic resonance imaging artifacts and the magnetic attachment system. AB - The use of a rare earth magnetic attachment system as a means of retaining dentures or maxillofacial prostheses results in artifacts, when magnetic resonance imaging (MRI) is used as a diagnostic tool. In such cases, the artifact is not caused by the magnet itself, but by the ferromagnetic stainless steel keeper that is placed in the body. This report evaluates such ferromagnetic stainless steel devices with respect to magnetic resonance imaging artifacts. A grid phantom and a 0.2 Tesla superconducting system were used to assess the imaging artifacts. The magnetic properties, shape, composition and size of ferromagnetic stainless steel devices were analyzed to study the relation MRI artifacts and ferromagnetic materials. The higher the magnetic permeability was, the greater the artifact produced. The size and volume of the material directly influence the artifact produced. The artifact size can be attenuated by the sequence used to obtain the images. PMID- 7842645 TI - Fluorine uptake and crystallinity of dentin treated with glass ionomer cement containing tannin-fluoride preparation. AB - We investigated the fluorine uptake in various layers of bovine dentin treated with glass ionomer cement (GIC) where a tannin-fluoride preparation (HY agent) was incorporated in the cement powder at ratios of 0% (HY0), 1.5% (HY1.5), 5% (HY5), and 10% (HY10) by weight. The crystallinity of the dentin treated with the HY0 and HY10 cements was also investigated. The higher the ratio of incorporated HY agent, the deeper the penetration of fluorine in the dentin, and the greater the amount of fluorine taken up that bonded with the apatite. Compared with total fluorine uptake, more time is needed for fluorine to form a stable bond with apatite. It is also suggested that the crystallinity of dentin is enhanced when exposed to GIC containing the HY agent. PMID- 7842646 TI - Thermal- and photo-polymerization of (meth) acrylates containing a spiro ortho ester moiety and the properties of poly[(meth)acrylate]s. AB - The syntheses and polymerizations of acrylate (ASOE) and methacrylate (MASOE) containing spiro ortho ester moieties were carried out and the properties of the polymers obtained were investigated. The ring-opening reaction of the spiro ortho ester groups proceeded well during heat polymerization (HC) with the ionic initiators (BSS and HPSS). However, a small amount of unreacted carbon-carbon double bond was observed in the polymers obtained. Not only vinyl polymerization but also a small amount of ring-opening reaction took place during polymerization with radical initiators (BPO, AIBN, DTB and CQ). The poly-(MASOE)s obtained by HC with BSS, BSS/AIBN and BSS/BPO were plastic like polymers. Low volume shrinkage was observed during HC and UVLC of ASOE and MASOE with ionic initiators. These shrinkages were smaller than those of conventional methacrylate. PMID- 7842647 TI - A database schema for public-domain medical software. AB - The quantity of public-domain medical software available is huge, and a classification schema may be therefore helpful. We developed a schema that includes identification data (name of the software, author, etc.), description (hardware and software requirements), classification (software category, application domain, etc.) and evaluation data (external quality and internal quality factors). The schema was tested on the public-domain software available at the SCAMC meetings (about 36 Mb). We also classified the software by employing students from a master course in computer science and medical informatics. We stored the high quantity of information collected in a database we developed using Paradox. PMID- 7842648 TI - Autoregulation in the stenosed coronary circulation. AB - Coronary vessel stenosis increases vascular resistance and limits the dynamic range of autoregulation. In this study, the limitation imposed by stenosed vessels on oxygen delivery to the myocardium was investigated using a theoretical model. For different degrees of stenosis and for different levels of arteriovenous oxygen content difference, the model predicted the limits of the contractility range for which ventricular oxygen balance is positive. The model also predicted the existence of an optimal contractility level which minimizes the cost of arterial pressure generation and provides the largest coronary oxygen reserve. With severe stenosis, myocardial oxygen balance is extremely sensitive to changes in the level of stenosis. The range of contractility in which the coronary circulation can meet the myocardial oxygen needs is dramatically reduced by small increases in stenosis severity or small decreases in arteriovenous oxygen difference. When the optimal contractility level is maintained, the heart can tolerate these detrimental changes to a greater extent. PMID- 7842649 TI - CMATRIX: software for physiologically based pharmacokinetic modeling using a symbolic matrix representation system. AB - Physiologically based pharmacokinetic (PBPK) modeling is based on an understanding of the physical and biological factors governing drug distribution. It is a procedure requiring composition of differential equations describing the distribution of drugs among physiologically defined compartments. CMATRIX is a program that facilitates development of PBPK models. In CMATRIX, the model is represented as a matrix of transfer parameters; the program generates a corresponding system of differential equations, and solves them numerically. This system dramatically improves the ease with which PBPK models can be developed, allowing the freedom to construct subcompartments down to the receptor level. PMID- 7842650 TI - Analysis of thrombin generation in plasma. AB - Thrombin is the central enzyme of haemostasis. Information on the production and inhibition of thrombin in plasma is important for evaluating the state of the coagulation system. Measurement of thrombin generation in plasma using small oligopeptide chromogenic substrates gives rise to a signal that not only reflects the enzymatic activity of free thrombin, but also contains a contribution of the complex of thrombin with one of its inhibitors, alpha 2-macroglobulin. This paper describes a mathematical procedure to extract from the measured curves the signal due to free thrombin only. The time integral of this free thrombin curve, which we call the thrombin potential, is a parameter which condenses much of the information present in such a curve. Thrombin production from prothrombin can be calculated from the concentration of free thrombin, when the rate constants governing the decay of thrombin are known. It is described how this calculation can be performed, accounting for the consumption of some of the inhibitors of thrombin during coagulation. Measurement of the time integral of the thrombin concentration promises clinical applicability of thrombin generation tests. It is based on the continuous registration of conversion of chromogenic substrate by thrombin during coagulation in plasma. It is shown how the curves obtained by this test can be analysed by a procedure which is analogous to the analysis of curves measured by subsampling from clotting plasma. PMID- 7842651 TI - Development of the bi-directional ultrasound system for base of tongue imaging. AB - The use of conventional ultrasound systems to image the upper airway has been limited because ultrasound energy is attenuated by the air column. In an attempt to study upper airway geometry, we developed a computer controlled bi-directional ultrasound system which combines two conventional ultrasound devices with computer image processing to yield images of upper airway structures. Human studies and cadaver studies were performed to evaluate the system. Images acquired by the bi-directional ultrasound system were comparable to images from 3D volume rendered CT scans. This system may provide valuable data in the study of upper airway physiology and pathology. PMID- 7842652 TI - Correcting two-dimensional kinematic errors for chick embryonic movements in ovo. AB - In motor behavior studies of chick embryos in ovo, kinematic recording is limited to a single camera system and produces kinematic data that are distorted if out of-plane movements are not considered. CONVERT is a rule based algorithm designed to calculate 3D limb movements given 2D kinematic data. CONVERT's calculations are based on a stationary reference point, limited translation of the chick embryo's trunk point, a multi-linked model of the body, and approximate limb segment lengths. Simulations indicate CONVERT calculates joint movements from 2D data with a maximum error of 6 degrees compared to a maximum error of 79 degrees if out-of-plane considerations are ignored. The approach used to correct two dimensional kinematic measurement errors can be readily applied to other experimental conditions that restrict video recording to single camera systems. PMID- 7842653 TI - Clinical evaluation of a renal mass diagnostic expert system. AB - In this paper, we describe our clinical evaluation of the diagnostic accuracy of the renal mass diagnostic system (RMDS) and of seven physicians. To investigate the value of intravenous urography (IVU) and/or retrograde urography (RU) in diagnosing renal parenchymal tumors and tumors of the renal pelvis, RMDS and the seven physicians were tested with and without the information regarding IVU/RU at two different times. From this study we believe that RMDS can help residents in making more accurate presurgical renal mass diagnosis, and may eliminate the need for IVU/RU in the diagnosing process for a specific group of patients. PMID- 7842655 TI - Building the library/information center of the future. Proceedings of a symposium. Bethesda, Maryland, April 7-8, 1994. PMID- 7842654 TI - A PC program for classification into one of several groups on the basis of longitudinal data. AB - A stand-alone, menu-driven PC program, ZCLASS, written in GAUSS386i, for classifying subjects into one of several distinct, existing groups on the basis of longitudinal data is described, illustrated, and made available to interested readers. The program accepts data from studies where common times of measurement are planned, but missing data are accommodated in that one or more measurement sequences may be incomplete. PMID- 7842656 TI - Building the library/information center of the future. AB - Changes in the mission, roles, and infrastructure of academic health sciences libraries pose an enormous challenge to those designing and planning new library buildings. The library will be judged by its ability to respond to changing information dissemination patterns, changing missions, technologies not yet contemplated, and curricular trends, notably the rise of informatics and problem based learning. Key questions are posed; the answers will shape library building now and in the future. PMID- 7842657 TI - Tomorrow's library. AB - The buildings in which we house libraries are like other special purpose structures; the needs they fill are significantly influenced by technology. A prime function of the library building is to house collections (of people, material, and systems) as well as collections of collections (networks). Electronic formats for library material offer new approaches to information service delivery. An example, the information access station, typifies how traditional functions can be reconfigured with respect to space. Flexible design can help ensure that tomorrow's libraries meet the users' needs, but we need to question all our assumptions about building design including those driven by our understanding of the browsing process. PMID- 7842658 TI - The evolution of research library buildings. AB - The principles of research library building planning established in the late 1940s emphasized flexibility of design; interspersal of books and readers; collaboration between librarians and architects; and an increased role for the library in education. Planning a medical research library in today's electronic environment requires attention to these principles as well as dealing with new and emerging technologies; economic constrains; new modes of scholarly research and communication; and the convergence of library science and information services on the campus. The social role of the library and the celebration of the book are factors common to both generations. PMID- 7842659 TI - Trends and recent experiments in library design. AB - An architect relates his experiences in designing new and renovated libraries, 'from the inside out'. He raises questions regarding the impact of technology and addresses concerns about collections, but places primary focus on users--why they come into the library and how they use information in and outside the library building. Design projects reviewed include libraries at Yale, Columbia, the University of Southern California, the Medical College of Wisconsin, Emory, George Mason, and Cornell. PMID- 7842660 TI - Library resources for problem-based learning: the program perspective. AB - The impact of a problem based curriculum has been the subject of increasing interest, as evidenced by several recent articles on the subject [1-4]. McMaster was able to design its library to serve a problem-based curriculum, but since there had been no prior experience with such a curriculum, the library was designed to meet needs that could only be guessed at [5]. In addition, the library serves the needs of a research intensive faculty. How the curriculum and the library have interacted over the past 25 years may be helpful to other schools considering problem-based learning. PMID- 7842661 TI - The Briscoe Library, University of Texas Health Science Center. AB - The Briscoe Library at the University of Texas Health Science Center at San Antonio opened in 1983, to replace and expand space for the growing campus. Work on the design phase began in 1979, once the legislature allocated $9.5 million for the new building. Of the 23 design objectives specified in the building program, flexibility to accommodate changing services and technology was given first priority. Details cover layout and technology, as well as changes to the environment and the building since it opened. PMID- 7842662 TI - Designing the smaller library: a hospital looks to the future. AB - Like other libraries, hospital libraries are preparing for a future which will include a mix, as yet undetermined, of print and electronic information. This case study relates how the library at St. Jude Children's Research Hospital was designed to meet the needs of users and staff and to balance them with the need for more sophisticated methods of retrieving, storing, and delivering information. Details are provided on planning process and on design features such as lighting and color. PMID- 7842663 TI - The J. Otto Lottes Health Sciences Library and the Microcomputer Learning Laboratory. AB - Opened in 1985, the J. Otto Lottes Health Sciences Library at the University of Missouri-Columbia has adapted to changes in information technology by installing a fiber optic backbone, establishing local area networks and file servers with databases and software programs, establishing a microcomputer learning laboratory, and responding to the needs of a problem-based learning curriculum. The library works cooperatively with the Medical Informatics Group, which is housed in the library and runs the micro laboratory, to support student and faculty computing. PMID- 7842664 TI - The Lister Hill National Center for Biomedical Communications. AB - On August 3, 1968, the Joint Resolution of the Congress established the program and construction of the Lister Hill National Center for Biomedical Communications. The facility dedicated in 1980 contains the latest in computer and communications technologies. The history, program requirements, construction management, and general planning are discussed including technical issues regarding cabling, systems functions, heating, ventilation, and air conditioning system (HVAC), fire suppression, research and development laboratories, among others. PMID- 7842665 TI - The Annette and Irwin Eskind Biomedical Library at Vanderbilt. AB - Opened in March 1994, the new library at Vanderbilt was planned to be at the intellectual and geographical heart of the medical center. Constructed of white precast blocks with a glass curtain wall, the building cost $12.5 million. Under an integrated advanced information management system (IAIMS) initiative, the building includes a center for biomedical informatics, which serves as the nerve center of the information enterprise at the medical center. Floor by floor descriptions are provided, including such design details as placing workstations directly inside the first floor entrance, a measure thought to contribute to increased use of the medical center network. User reaction to the building was highly positive in the first month of operation. PMID- 7842666 TI - Evaluating library renovation at the University of Rochester Medical Center. AB - In 1987, the Edward G. Miner Library of the University of Rochester Medical Center completed the second major renovation in its 62-year history. The goal of the renovation was to provide additional space for the library's 3 main constituencies: its readers, its collections, and its staff. A case study of the renovation is presented, outlining processes and issues that shaped the final outcome. The success of the renovation is assessed in terms of project goals, design, and functionality. Changes made since 1987 to accommodate automation are also summarized. The conclusion suggests that library renovation be viewed as a continuing process, and proposes that principles of interface design are appropriate guidelines for evaluating library design across time. PMID- 7842667 TI - The Galter Health Sciences Library at Northwestern University: a library for the 21st century. AB - Initiated to increase space, renovation planning for Northwestern University's Galter Health Sciences Library evolved into a process for developing a more technology-centered library. Design focused on correcting structural problems and providing greater access to technology. Space was redesigned for functionality and flexibility. Design features included a new entrance, relocated and expanded learning resource center; certain limitations remained. The planning process involved all major groups on campus; construction will be phased. PMID- 7842668 TI - Planning the health sciences library: a new building for information services. AB - Planning for a new Health Sciences Library at the University of Maryland at Baltimore extended over more than 15 years. The program plan was created through an interactive process with the architects, involving all the staff from the library and computing/communications groups, now together in a umbrella organization known as Information Services. The layout for the new building was developed to promote interactions and to integrate staff and services on each floor. PMID- 7842669 TI - The campus at the University of Maryland at Baltimore. AB - The University of Maryland at Baltimore (UMAB) is an urban professional school campus. Its 36 acres include 39 buildings, both historic and new. The campus fabric is marked by diversity. The new facilities master plan was developed to reflect the strategic planning process for the campus. Design guidelines are intended to create a common theme while still encouraging each building to have a unique identity. The new Health Sciences Library/Information Services building will sit diagonally from Davidge Hall, built in 1812 and the symbolic center of the campus. PMID- 7842670 TI - Fulfilling programmatic needs at the University of Maryland at Baltimore: the reality. AB - This article will focus on the actual needs enumerated in the University of Maryland at Baltimore's Health Sciences Library/Information Services program entitled, Health Sciences Library: A New Building for Information Services Including the Health Sciences Library. These needs fall into one of 3 categories: collection, staff, and users. PMID- 7842671 TI - On the design of the Health Sciences Library/Information Services building at the University of Maryland at Baltimore. AB - The architect provides his perspective on issues in designing a new library building, including: civic and urbanistic purposes of the building; the process of analysis and synthesis; and the place and meaning of 'library' today. Special attention is given to adjacencies, reader services, space devoted to the study of change, administration, and presentation and itinerary. A verbal floor-by-floor tour of the building is provided. PMID- 7842672 TI - Building the library/information center of the future: a resource guide. AB - For use in planning new or renovated library facilities, this list reviews 20 selected journal articles and monographs, dating from 1980 on. Works cited are in the following categories: the planning process, planning for new technology, interior design, planning the move, and special considerations. PMID- 7842673 TI - All these positive tests to thimerosal. AB - By and large, positive patch tests with thimerosal lack clinical relevance and should cause concern neither to the dermatologist nor to the patient. The substance should be retained in standard test series for scientific purposes, but on clinical grounds its inclusion does not seem to be indicated. Nevertheless, the phenomenon is intriguing in its own right. PMID- 7842674 TI - Mercury exanthem. AB - We have observed 9 male patients with a generalized rash following the topical use of an over-the-counter antiparasitic powder (MOM), containing ammoniated (11.2 g%) and metallic (4.2 g%) mercury, to treat phthiriasis (lice infestation). Primary and intensely erythemato-exudative lesions of the pubic region and genitals were associated with inverted erythema of the upper inner thighs and, in severe cases, involvement of the face, neck, trunk and major flexures. Eruptions included exanthematic, papulo-vesicular, purpuric and erythema-multiforme-like clinical pictures. 7 of the 9 cases presented with general malaise and pyrexia. A positive patch test reaction to ammoniated mercury was observed in all cases. There are probably 3 routes of powder exposure behind this type of rash: (i) direct skin contact; (ii) airborne skin contact; (iii) inhalation. PMID- 7842675 TI - Mite-antigen-stimulated cytokine production by peripheral blood mononuclear cells of atopic dermatitis patients with positive mite patch tests. AB - To investigate possible involvement of Th1-type immunoreaction in the development of skin lesions of atopic dermatitis (AD), we measured mite-antigen-stimulated production of IL-2, IL-4 and IFN-gamma, using peripheral blood mononuclear cells (PBMC) obtained from 23 patients with AD who developed positive patch test reactions to house dust mite antigens extracted from Dermatophagoides pteronyssinus (Dp). Incubation of these PBMC with the Dp antigen for 72 h produced marked secretion of IL-2 and IFN-gamma, but not IL-4, indicating that Dp specific T cells were found in these patients' circulating peripheral blood and were capable of producing IL-2 and IFN-gamma, known as major mediators of the delayed-type allergic reaction. Our study suggests that Th1-type cells may be involved in the development of skin lesions of AD patients with positive patch test reactions to house dust mite antigen. PMID- 7842676 TI - The irritant effect of different metalworking fluids. AB - The irritant effect of different water-based cutting fluids (CFs) on the skin was investigated in healthy subjects (n = 10) using 2 non-invasive bioengineering methods. Transepidermal water loss (TEWL) was measured by an evaporimeter EP1 (Servo Med), skin blood flow (SBF) was recorded with a laser Doppler flowmeter (MBF 3D, Moor Instruments England). Additionally all test sites were evaluated by visual scoring before measurement. 3 cutting fluids A, B and C from different manufacturers were tested at use concentrations of 4% or 5%. Single 24-h patch tests and repeated patch tests were performed on the volar side of the right forearm. Measurements were carried out before and after exposure to assess basal values and the skin response to CF. Tests with CFs A and C resulted in significant increase in TEWL after 24 h and after cumulative treatment, compared with controls (p < 0.01). The TEWL values for CF B did not differ from the water probe. An increase in SBF was found only for CFs A and C after cumulative patch testing (p < 0.01). In spite of their similar alkalinity, the 3 CFs showed different irritant skin reactions, due to their chemical components. This was verified particularly by measurement of TEWL. PMID- 7842677 TI - High sensitization rate to emulsifiers in patients with chronic leg ulcers. AB - Emulsifiers are common constituents of most topical preparations. To study the sensitization rate in a population with frequent use of these agents, we selected 47 patients with chronic or recurrent (> 1 year) inflammatory skin disease (leg ulcers, contact dermatitis, atopic dermatitis, psoriasis) for patch testing with the following emulsifiers: Tween 40 (polyoxyethylene sorbitan monopalmitate). Tween 80 (polyoxyethylene sorbitan monooleate), Span 60 (sorbitan monostearate), Span 80 (sorbitan monooelate), Arlacel 83 (sorbitan sesquioleate), Atlas G 2162 (polyoxyethylene oxypropylene stearate), Atlas G 1441 (polyoxyethylene sorbitol lanolin derivative), triethanolamine, Lanette O (cetylstearyl alcohol), Lanette N. 12 patients had at least 1 positive reaction (25.5%) at 3 or 4 days. Among them, 10 had leg ulcers (43.4% of the leg ulcer group), and 2 had contact dermatitis (13.3% of the contact dermatitis group). No positive reaction was observed in the other patients. When the patients were tested with their own topical preparations or wound dressings, 6 of them, all with leg ulcers, had positive reactions. These results show a surprisingly high prevalence of sensitization to emulsifiers in patients with chronic leg ulcers, in contrast to patients with other inflammatory skin diseases. PMID- 7842678 TI - A single accidental exposure may result in a chemical burn, primary sensitization and allergic contact dermatitis. AB - It is known from experimental studies that antigenic potency and the concentration of antigen determine whether exposure to an antigen will result in sensitization. A single accidental exposure to concentrated antigen may therefore induce primary sensitization. The purpose of this report was to collect clinical cases in which a single exposure had resulted in contact dermatitis suspected to be allergic. Only patients without previous relevant skin symptoms were included. Patch testing was used to demonstrate sensitization. 6 patients developed occupational allergic contact dermatitis from accidental exposure. Patch testing revealed allergy to diglycidylether of bisphenol A epoxy resin, polyfunctional aziridine hardener, methyl acrylate, phenol-formaldehyde resin, and methylchloroisothiazolinone/methylisothiazolinone (Kathon LX), respectively. Furthermore, 2 patients developed allergic contact dermatitis from their first exposure to tear gas chemicals, namely omega-chloroacetophenone and ortho chlorobenzylidene malonitrile. A single exposure can therefore induce both sensitization and subsequent allergic contact dermatitis without further exposure. The allergens described must be considered strong allergens. The skin should immediately be cleaned if an accidental splash with such an allergen has taken place. PMID- 7842679 TI - Propylene glycol dermatitis: re-evaluation of an old problem. AB - Evaluation of dermatitis associated with propylene glycol application or ingestion remains a challenge. The research dealing with skin reactions to propylene glycol is revisited and new aspects for future research are outlined. Based on literature review and our own observations, we propose classifying skin reactions to propylene glycol into 4 mechanisms: (a) irritant contact dermatitis, (b) allergic contact dermatitis, (c) non-immunologic contact urticaria, and (d) subjective or sensory irritation. This concept allows a partial explanation of effects observed by different authors. Despite attempts to define objective criteria, biologically, histopathologically, or clinically, the distinction between irritant and allergic reactions remains unclear. Furthermore, the irritation threshold of propylene glycol, and likewise the optimal standard concentration in patch tests, is sub judice. Future studies on propylene glycol dermatitis should include repeated patch tests with serial dose dilutions, repeated open application tests/provocative use tests, oral challenge tests, and biopsies for a more complete evaluation of mechanisms and clinical significance. PMID- 7842680 TI - Occupational allergic contact dermatitis caused by thiourea compounds. AB - Thiourea compounds are mainly used as accelerators in the rubber industry, but also in other industries, e.g., as antioxidants in the graphics industry. Thiourea compounds may provoke allergic contact dermatitis, although the number of reported cases is relatively low. During 1985-1991, we had 5 patients with allergic patch test reactions caused by thiourea compounds. 1 of our patients had to use a knee brace after an occupational accident. He developed allergic contact dermatitis caused by the knee brace, probably because he had become sensitized to diethylthiourea. 2 patients were probably sensitized by diphenylthiourea in neoprene gloves. A florist had an allergic patch test reaction to diphenylthiourea and might have been sensitized by fungicides or pesticides, which break down into thioureas. It is often difficult, however, to detect the source of thiourea compound sensitization. If the patient has contact dermatitis and has been exposed to products that may contain thiourea compounds (or compounds that break down into thiourea compounds), such as rubber, PVC plastic or adhesive, diazo paper, paints or glue remover, anticorrosive agents, fungicides or pesticides, patch testing with a series of thiourea compounds needs to be performed. If patch testing with thiourea compounds is not performed, allergic contact dermatitis caused by thiourea compounds is not likely to be diagnosed. PMID- 7842682 TI - Can cyclosporin A help distinguish allergic from irritant patch test reactions? PMID- 7842681 TI - Nickel release from nickel-plated metals and stainless steels. AB - Nickel release from nickel-plated metals often induces allergic contact dermatitis, but, for nickel-containing stainless steels, the effect is not well known. In this paper, AISI 304, 316L, 303 and 430 type stainless steels, nickel and nickel-plated materials were investigated. 4 tests were performed: patch tests, leaching experiments, dimethylglyoxime (DMG) spot tests and electrochemical tests. Patch tests showed that 96% of the patients were intolerant to Ni-plated samples, and 14% to a high-sulfur stainless steel (303), while nickel-containing stainless steels with a low sulfur content elicited no reactions. Leaching experiments confirmed the patch tests: in acidic artificial sweat, Ni-plated samples released about 100 micrograms/cm2/week of nickel, while low-sulfur stainless steels released less than 0.03 microgram/cm2/week of nickel, and AISI 303 about 1.5 micrograms/cm2/week. Attention is drawn to the irrelevance of the DMG spot test, which reveals Ni present in the metal bulk but not its dissolution rate. Electrochemical experiments showed that 304 and 316 grades remain passive in the environments tested, while Ni-plated steels and AISI 303 can suffer significant cation dissolution. Thus, Ni-containing 304 and 316 steels should not induce contact dermatitis, while 303 should be avoided. A reliable nitric acid spot test is proposed to distinguish this grade from other stainless steels. PMID- 7842683 TI - Skin damage caused by mucilaginous aggregates in the Adriatic sea. PMID- 7842684 TI - Occupational allergic contact dermatitis from intermediate products in famotidine synthesis. PMID- 7842685 TI - Contact dermatitis due to oleyl alcohol. PMID- 7842686 TI - Atopic dermatitis with severe facial lesions exacerbated by contact dermatitis from topical medicaments. PMID- 7842687 TI - Patch test audit: are we doing more than we need to? PMID- 7842688 TI - Contact sensitivity in pruritus vulvae: a common and manageable problem. PMID- 7842689 TI - Contact dermatitis from ketotifen fumarate eyedrops. PMID- 7842690 TI - Hypersensitivity to rubber surgical gloves in healthcare personnel. PMID- 7842691 TI - Where next to look for formaldehyde? PMID- 7842692 TI - Comparative evaluation of comfort among 105 healthcare workers wearing vinyl and latex gloves. PMID- 7842693 TI - Nickel, chromate and cobalt in toilet soaps analysed by inductively coupled plasma mass spectrometry. PMID- 7842694 TI - Occupational contact dermatitis from vitamin B12. PMID- 7842695 TI - Allergic contact dermatitis from fluocortin butylester. PMID- 7842696 TI - Contact urticaria from cinnamic aldehyde and benzaldehyde in a confectioner. PMID- 7842697 TI - Systemic allergic reaction to corticosteroids. PMID- 7842698 TI - Contact allergy to nitrofurazone. PMID- 7842699 TI - Airborne allergic contact dermatitis caused by preservatives in home-decorating paints. PMID- 7842700 TI - Contact hypersensitivity induced by p-tert-butylphenol-formaldehyde resin in an adhesive dressing. PMID- 7842702 TI - Identification and sensitization studies of colophony components. PMID- 7842701 TI - How to do sensitization tests in guinea pigs. PMID- 7842703 TI - Corneal ablations produced by the neodymium doped yttrium-lithium-fluoride picosecond laser. AB - This study examines corneal ablations produced by the neodymium doped yttrium lithium-fluoride (Nd:YLF) picosecond laser. The laser delivers a 1-KHz, 40-ps pulsed, 1,053-nm wavelength beam (with energy measured in microjoules) to a 15 microns diameter spot size. The ablation mechanism is by plasma formation, which generates acoustic shock waves. Using enucleated rabbit (n = 25) and human donor eyes (n = 29), corneas were examined after tissue ablation at energies ranging from 40 to 300 microJ per pulse with various programmed ablation depths and patterns. The histologic data were collected using light microscopy and transmission electron microscopy. The tissue effects and Nd:YLF laser functions studied were ablation thresholds, cutting ability, programmed ablation depth accuracy, and acute endothelial effects. Our study showed histologic ablation thresholds for the following human corneal layers: epithelium = 7.15 +/- 0.05 x 10(11) W/cm2 (34.1 +/- 8.1 J/cm2 per pulse, 50 microJ per pulse); Bowman's layer = 1.33 +/- 0.29 x 10(12) W/cm2 (58.5 +/- 3.3 J/cm2 per pulse, 100-110 microJ per pulse); stroma and endothelium = 7.10 x 10(11) W/cm2 (28.4 J/cm2 per pulse, 50 microJ per pulse). Depth of corneal ablation was found to be directly related to energy and independent of programmed ablation depth. This study shows the endothelial loss in rabbit corneas by energy beams (50 microJ per pulse) focused 100 microns from this layer. PMID- 7842704 TI - The mechanism of ablation of corneal tissue by the neodymium doped yttrium lithium-fluoride picosecond laser. AB - This study examines the structural changes in cornea resulting from plasma formation and propagated acoustic shock waves produced by the neodymium doped yttrium-lithium-fluoride (Nd:YLF) picosecond laser. Human donor eyes and enucleated rabbit eyes were subjected to various ablation patterns at energies ranging from 40 to 300 microJ per pulse. Two distinctly different patterns were produced depending on the location of initial plasma formation. Plasmas initiated at the corneal surface produced smooth, straight-edged ablations of corneal tissue that consisted of collagen fibril fragmentation, fibril organizational disruption, and possible thermal effect observed along the lateral borders and wound apex. The extent of lateral damage was directly related to the energy applied. The range of acute collagen disorganization observed at the ablation edge in rabbit corneas at various pulsed energies was as follows: 50 microJ = 1.0 12 microns, 150 microJ = 3.8-12.5 microns, 250 microJ = 6.2-23.7 microns, and 300 microJ = 7.5-45.0 microns. Plasma formation initiated within the stroma at or above threshold energies (50-150 microJ per pulse) produced an inter- or intralamellar separation effect with little evidence of ablation or collagen fibril fragmentation. Intrastromal plasmas generated from higher energies (200 300 microJ per pulse) produced tissue ablation, along with ablation or disruption of tissue anterior to the intrastromal target area. PMID- 7842705 TI - Immunochemistry with 5-bromo-2-deoxyuridine for visualization of mitotic cells in the corneal epithelium. AB - The purpose of this study was to determine whether the DNA of mitotic cells in the corneal and conjunctival epithelium can be labeled with 5-bromo-2 deoxyuridine (BrdU) immunostaining. Both corneas of four New Zealand white rabbits were deepithelialized in the center and the regenerated epithelium was evaluated for mitosis at 1, 3, 6, and 10 days. Unwounded corneas of three rabbits were labeled for baseline measurements. We administered the marker intravenously to all seven rabbits 15 h before scheduled killing. Immediately after killing, all of the globes were enucleated and histologic sections were prepared. In unwounded corneas, labeled cells were quantitated and the fraction of mitotic cells in the center of the cornea, in the periphery of the cornea, and in the conjunctiva were compared. In deepithelialized corneas, increase in mitosis in the central epithelium was quantitated. All of the unwounded eyes showed mitosis in the basal layer of both the corneal and conjunctival epithelium. In the center of the cornea 4.1 +/- 2.9% of the epithelial cells were labeled, in the corneal periphery 4.3 +/- 1.7% of the cells were labeled, and in the conjunctiva 4.1 +/- 1.9% of the epithelial cells were labeled, with a p value ranging from 0.84 to 0.99. In wounded corneas, when compared with cell counts in unwounded eyes, 52.6% of the epithelial cells were in mitosis on day 3, 13.9% were in mitosis on day 6, and by day 10 baseline values of 4.2% were obtained. We conclude that BrdU immunostaining is a safe, efficient, and less costly alternative to autoradiography for visualization of dividing corneal and conjunctival epithelium. PMID- 7842706 TI - Effects of oxidized glutathione and reduced glutathione on the barrier function of the corneal endothelium. AB - The protective effects of oxidized glutathione (GSSG) and reduced glutathione (GSH) in the irrigating solution based on BSS plus composition (Santen, Osaka, Japan), which is without GSSG (glutathione-free control solution) were compared on rabbit corneal endothelial barrier function. Corneal barrier function was evaluated by determining the effects of GSSG and GSH on carboxyfluorescein permeability (P(ac)). In a solution containing 0.3 mM GSSG (BSS plus), the P(ac) was significantly inferior to that of its paired glutathione-free control solution. With 0.6 mM GSH, the P(ac) was not different from that of its paired glutathione-free control solution. The P(ac) of the endothelium with 0.3 mM GSSG was significantly inferior to that of paired corneas exposed isolated to 0.6 mM GSH. These results show that the barrier function of the rabbit corneal endothelium is better maintained by supplementing the perfusion solution with 0.3 mM GSSG rather than 0.6 mM GSH. PMID- 7842707 TI - Tear concentrations of topically applied ciprofloxacin. AB - An open-label study of 20 normal, healthy volunteers was conducted to determine the tear concentrations after topical ocular application of ciprofloxacin 0.3% ophthalmic solution (Ciloxan). Tear samples were collected on Schirmer tear strips at 30 min, 2, 3, and 4 h, and were analyzed for ciprofloxacin using reverse-phase high-performance liquid chromatography. The results of this study showed the mean concentration, 4 h after dosing of ciprofloxacin, to be 16.0 micrograms/ml with 95% confidence limits of 8.15 and 23.79. It is concluded that concentrations of ciprofloxacin in tears were significantly greater than the minimum inhibitory concentrations for 90% of strains tested commonly reported for a majority of potential pathogens (i.e., < or = 2 micrograms/ml) 4 h after a single application of ciprofloxacin ophthalmic solution 0.3%. PMID- 7842708 TI - Comparison of topical ciprofloxacin to conventional antibiotic therapy in the treatment of experimental Pseudomonas aeruginosa keratitis. AB - We evaluated the efficacy of topical ciprofloxacin (3.0 mg/ml) in the treatment of experimental Pseudomonas aeruginosa keratitis in 60 rabbits. We compared ciprofloxacin treatment with double drug therapy consisting of tobramycin (13.6 mg/ml) plus polymyxin B (25,000 U/ml) or carbenicillin (6 mg/L). Two strains of P. aeruginosa were used. One was a strain well characterized for use in experimental Pseudomonas keratitis (ATCC organism 27853); the second was an organism from a patient with a Pseudomonas corneal ulcer. Rabbits were treated for 16 h, after which the corneas were excised, homogenized, and plated serially for residual colony-forming units. Both organisms responded significantly better to topical off-the-shelf ciprofloxacin than to therapy with two conventional antipseudomonal fortified antibiotic drugs (p < or = 0.0001). PMID- 7842709 TI - Rapid assay of lactoferrin in keratoconjunctivitis sicca. AB - We compared measurement of lactoferrin concentration by the LactoCard solid phase ELISA assay with the LactoPlate radial immunodiffusion assay in tears of normal patients and those with keratoconjunctivitis sicca. The LactoCard, a new lactoferrin assay, allows rapid determination of tear lactoferrin concentration in 10-15 min, a notable improvement over the 3 days required of the LactoPlate. There was no statistically significant difference between the accuracy of the two assays in normal patients nor in those patients with a diagnosis of keratoconjunctivitis sicca. Both assays showed a significant decrease in tear lactoferrin concentration in patients with severe keratoconjunctivitis sicca when compared to normal patients. The LactoCard is a rapid and reliable means of measuring tear lactoferrin concentration in a clinical setting. PMID- 7842710 TI - Multirecurrence of corneal posterior polymorphous dystrophy. An ultrastructural study. AB - Posterior polymorphous corneal dystrophy (PPD) is a rare bilateral, autosomal dominant disease. The presence of the epitheliumlike endothelium and the thickening of Descemet's membrane by the posterior collagenous layer (PCL) has been reported in the majority of published cases. Reepithelialization of the posterior cornea in donor tissue has been reported only once. Therefore, to examine this process we examined, by light and electron microscopy, three corneal buttons (an original and two subsequent keratoplasties after 3 and 4 years, respectively) from the left eye of a patient with bilateral disease. Our study showed a repopulation of the posterior surface of the donor corneas by the host epitheliumlike endothelium, which was of identical morphology in each case. In contrast to the previously published work, a posterior collagenous layer in the failed grafts was absent from the axial cornea, where the epitheliumlike endothelium was in direct contact with donor Descemet's membrane. A PCL at the periphery in the failed transplants was of the fibrocellular type and differed from the fibrillar PCL in the first keratoplasty specimen. The fibroblastlike cells within the fibrocellular PCL were distinct from the underlying epithelial like cells and contained numerous tertiary phagolysosomes. We suggest that the major contributor to the fibrocellular PCL in the repeat keratoplasties was a fibrous ingrowth from the host/graft junction and not the epitheliumlike endothelium. It appears that the synthetic capacity of the epitheliumlike endothelium was similar to that of the normal epithelium and was much lower than that of normal native endothelium. PMID- 7842711 TI - HPMPC, a broad-spectrum topical antiviral agent, inhibits herpes simplex virus type 1 replication and promotes healing of dendritic keratitis in the New Zealand rabbit ocular model. AB - Previously, we demonstrated that HPMPC, a new, broad-spectrum antiviral agent, inhibited adenovirus type 5 in the New Zealand (NZ) rabbit ocular model (Cornea 1992; 11:529-33). Historically, no antiviral agent has been demonstrated to be effective against both herpes simplex virus type 1 (HSV-1) and adenovirus eye infections in an experimental animal model. In this study, we compared topical 0.2% HPMPC to 1% trifluridine and vehicle control in the NZ rabbit HSV-1 keratitis model. Using a double-masked, two-eye design, NZ rabbits were inoculated in both eyes with HSV-1 W strain (10(5) pfu/eye), and dendritic keratitis and HSV-1 ocular titers were measured serially. Compared with the control group, both topical 0.2% HPMPC and 1% trifluridine significantly reduced healing time of HSV-1 dendritic keratitis, lowered HSV-1 ocular titers on days 3 through 11, and shortened duration of HSV-1 shedding in the tear film. For all outcome parameters measured, topical 0.2% HPMPC was as effective as 1% trifluridine. A new concept of a broad-spectrum topical antiviral agent was shown to be effective against HSV-1 in an NZ rabbit keratitis model, and further development toward clinical application appears desirable. PMID- 7842712 TI - Penetrating keratoplasty in infants with congenital glaucoma. AB - The efficacy of corneal transplantation in infants with corneal opacity secondary to congenital glaucoma has not been established. We retrospectively reviewed our results of nine penetrating keratoplasties performed on eight eyes of six infants who had multiple risk factors for poor prognosis: age < 2 years at the time of grafting; uncontrolled glaucoma in four eyes; concurrent lensectomy, retinal, or glaucoma surgery in five eyes; aphakia in five eyes; and an acute perforation in one eye. Six of the nine grafts (67%) remained clear during a mean follow-up of 24 months (30 months in eyes with clear grafts). Development of ambulatory vision or better occurred in six of eight (75%) eyes after corneal transplantation and treatment of refractive errors and amblyopia. Graft failure occurred in three eyes--two from corneal decompensation, and one from homograft rejection. Complications included one total retinal detachment, one case of Streptococcus pneumoniae keratitis, and three cases that lost intraocular pressure control, requiring further glaucoma surgery. We conclude that useful vision can be achieved after penetrating keratoplasty even in some high-risk infants with congenital glaucoma. PMID- 7842713 TI - Penetrating keratoplasty in xeroderma pigmentosum. Case reports and review of the literature. AB - Xeroderma pigmentosum is an uncommon inherited disorder characterized by hypersensitivity to ultraviolet radiation, with defective repair of DNA damage caused by short-wavelength radiation. Corneal complications of this disorder may require penetrating keratoplasty for visual rehabilitation. Surgery is rarely undertaken in these eyes due to multiple associated problems involving the ocular surface and the lids. We report three cases of successful penetrating keratoplasty in xeroderma pigmentosum and review nine cases reported earlier. Successful grafts were achieved in all 12 eyes initially. Persistent superficial punctate keratopathy was observed in one eye and graft rejection episodes in five eyes. However, graft failure occurred due to an untreated rejection episode in only one eye. Another eye was treated by exenteration for recurrent ocular malignancies. This report highlights the encouraging results of penetrating keratoplasty in carefully selected patients of xeroderma pigmentosum with corneal pathology. PMID- 7842714 TI - Keratohematoma leading to acquired posterior keratoconus. AB - We describe a patient with congenital syphilis associated with corneal neovascularization and subsequent intracorneal hemorrhage. Over time, this condition resulted in acquired posterior keratoconus. A review of our clinical case, the literature, and histologic findings is presented. To our knowledge, this is the first reported case of acquired posterior keratoconus associated with corneal vascularization and hemorrhage secondary to congenital syphilis. We also have provided histopathologic evidence for the prescence of an iron ring. PMID- 7842715 TI - Coccidioidomycosis with necrotizing granulomatous conjunctivitis. AB - A patient with a steroid-resistant conjunctival nodule developed severe necrotizing granulomatous conjunctivitis during aggressive treatment with topical, subconjunctival, and systemic steroids. Culture of the tissue yielded Coccidioides immitis. A cavitary lesion was noted on a chest radiograph, and the same organism was recovered from a lung biopsy specimen. The granulomatous conjunctivitis was controlled only after aggressive debridement of the affected area and months of treatment with topical amphotericin B and oral fluconazole. A review of the literature suggests that subclinical ocular involvement from pulmonary coccidioidomycosis may be more common than generally believed. Conditions that blunt the host immune response may lead to a higher incidence of clinically significant ocular involvement. PMID- 7842716 TI - Successful penetrating keratoplasty in a patient with severe atopic keratoconjunctivitis and elevated serum IgE level treated with long-term topical cyclosporin A. PMID- 7842717 TI - Temporary corneal thinning after penetrating keratoplasty. PMID- 7842718 TI - Iridoschisis following penetrating keratoplasty for keratoconus. PMID- 7842719 TI - CD4+V beta 8+ T cells mediate herpes stromal keratitis. AB - T lymphocytes are critical in mediating herpes simplex stromal keratitis (HSK). Using immunohistologic methods, we studied the T cell subsets and the T cell receptor variable region (TCR V beta) repertoire of T cells in the eye after corneal infection with HSV (KOS strain). We investigated the possibility that there might be differential V beta preferential usage in HSK resistant and susceptible BALB/c congenic mice that differ only in a small region associated with the Igh-1 gene locus. The inflamed corneas of HSK susceptible C.AL-20 mice were mainly infiltrated by CD4+ cells and by V beta 8 expressing cells. Such T cells were not seen in the corneas of resistant C.B-17 mice. Our results indicate that CD4+V beta 8+ cells are involved in mediating HSV-1 stromal keratitis. PMID- 7842720 TI - Flicker perimetry using a luminance threshold strategy at frequencies from 5-25 Hz in glaucoma, ocular hypertension and normal controls. AB - A prototype automated flicker perimeter was used to investigate flicker luminance thresholds in glaucoma patients (n = 11), ocular hypertensives (high risk n = 10, low and intermediate risk n = 21) and normal controls (n = 10). Differential light sensitivity was measured for one eye of each subject using a flickering stimulus at frequencies of 5, 10, 15, 20 and 25 Hz at ten test locations of 1 degree in the arcuate and nasal regions of the central 50 degrees of the visual field using a 4-2 dB staircase. The glaucoma patients had significantly reduced sensitivities for all frequencies (p < 0.001) with minimum sensitivity at 15 Hz. The 'high risk' ocular hypertensives had significantly reduced sensitivities at 10 and 15 Hz (p < 0.02). At present the ocular hypertensive patients in this study show no abnormalities demonstrable by conventional automated static perimetry. These findings may represent the earliest of perimetric deficits in patients with glaucomatous optic neuropathy. PMID- 7842721 TI - Histopathologic features of rejecting orthotopic corneal xenografts. AB - Discordant xenogeneic Hartley guinea pig corneal buttons were transplanted orthotopically to either naive or pre-immune Lewis rats. Recipients were sacrificed serially and grafts were immediately frozen and subsequently examined using standard immunohistologic techniques. Corneal xenografts remained clear in naive recipients for 7 days, at which point they rapidly became opaque and edematous. In pre-immunized recipients, corneal xenografts were rejected much more quickly, becoming opaque and edematous by day 3 post-transplantation. Histologic examination of grafts revealed severe stromal edema and diffuse inflammatory cell infiltrates composed of mononuclear cells and neutrophils. Infiltrates were present as early as day 2 in xenografts from both presensitized and naive recipients. The infiltrates were densest in the posterior half of the grafts with fewer cells penetrating into the epithelium. Immunoperoxidase staining confirmed the presence of OX-19+ T cells as well as a substantial infiltrate of OX-42+ neutrophils/macrophages. Additionally, IgG was deposited throughout the grafts in a diffuse manner. Deposition of IgG was accelerated in presensitized recipients, with intense staining of the entire graft detected by day 2. Examination of the rejected grafts suggests that rejection occurs via mechanisms similar to those seen in corneal allografts. This, in turn, implies corneal xenografts may be amenable to standard immunosuppressive regimens. PMID- 7842722 TI - Lenticular changes in rainbow trout following chronic exposure to UV radiation. AB - Rainbow trout (Onchorynchus mykiss) were exposed to broad band ultraviolet irradiation for a period of 205 days with a 12h/12h on/off cycle. Total radiant exposure was 8.279 x 10(3) J cm-2 of UVA and 1.050 x 10(2) J cm-2 of UVB. Control fish were maintained under UVB-free and blue-free conditions. Quantitative and qualitative evaluation of the teleost crystalline lenses involved photo slitlamp biomicroscopy, dark-field stereomicroscopy and automated scanning laser monitoring. More cataractous changes including discrete anterior subcapsular and 'doughnut' opacities, and peri-nuclear haze were recorded in the lenses of the fish that received chronic UV exposure. However, no significant differences were found in focal lengths and scatter within the sensitivity of the instrumentation. These results support the hypothesis that chronic exposure to ambient levels of ultraviolet radiation is cataractogenic. PMID- 7842724 TI - Transforming growth factor-beta 2 levels increase following retinal laser photocoagulation. AB - To determine if the levels of transforming growth factor-beta 2 (TGF-beta 2) in ocular tissues change following laser photocoagulation, pigmented rabbit eyes underwent panretinal photocoagulation using laser indirect ophthalmoscopy. The rabbits were followed for a period of either 2 or 14 days after the procedure. The eyes were then removed and samples of vitreous and aqueous humor were collected. TGF-beta 2 levels were measured using an immunoassay. When compared to control eyes, TGF-beta 2 levels in the vitreous humor of treated eyes at day 2 and day 14 were increased. Changes in TGF-beta 2 levels were also seen in the aqueous humor of the treated eyes, with increased levels seen at day 2 and day 14 compared to control eyes. The increase in both vitreous and aqueous humor in treated eyes compared to control eyes was shown to be statistically significant (p < 0.05). Our results show that intraocular TGF-beta 2 levels increase significantly following laser photocoagulation. This preliminary study suggests that TGF-beta 2 may be involved in the process of chorioretinal wound healing. PMID- 7842723 TI - Cloning and sequencing of heat shock factor (HSF1) cDNA from human retina. AB - Transcription of heat shock genes takes place in response to the exposure of cells to elevated temperatures or other stress conditions. Heat shock transcription factor (HSF) plays an important role in the activation of such transcription. We report here the identification of human heat shock factor from human retina by RT-PCR and cloning studies. Human retinal poly A+ RNA was reverse transcribed and the cDNAs thus obtained were subjected to PCR using a set of primers designed from the reported cDNA sequence for human HSF1. The amplified product showed 100% sequence identity with the appropriate region of HSF1. A human retinal cDNA library was screened to isolate the full length cDNA for heat shock factor, which showed 100% sequence identity to that reported for human HSF1. Northern blot analysis showed the size of human retinal HSF to be approximately 2.4 kb. PMID- 7842726 TI - The effect of raised inspired carbon dioxide on developing rat retinal vasculature exposed to elevated oxygen. AB - Hyperoxia is a risk factor for retinopathy of prematurity (ROP), a blinding disease in infants. However, ROP develops in human infants without raised arterial oxygen levels, such as in cyanotic congenital heart disease. In these infants raised pCO2 may be a risk factor. We investigated the effect of inspired CO2 on oxygen induced retinopathy in the rat. 56 newborn Sprague-Dawley rats were exposed to high cyclical O2 for seven days. In a control group, 27 rats were exposed to negligible CO2 by the use of soda lime. In the high CO2 group, 29 rats were exposed to elevated CO2 by omitting soda lime from their chambers. Rats in both groups had a recovery period of three days in room air following cyclical O2 exposure. On the eleventh day all rats were sacrificed after intracardiac injections of fluorescein under deep anesthesia and the retinae were dissected and flat mounted for fluorescent microscopy. The ratio of vascularized:total retinal area was calculated using computer assisted image analysis. In the high CO2 group 62% +/- 7% SD of the retina was vascularized vs. 81% +/- 7% in low CO2 group (p < 0.001). Elevated inspired CO2 results in pronounced retardation of retinal vascular development in neonatal rats exposed to fluctuating raised oxygen. PMID- 7842727 TI - Cytogenetic characteristics of Chironomus balatonicus Devai, Wulker, Scholl (Diptera, Chironomidae) from the Chernobyl region. AB - A cytogenetic analysis was carried out on a population of Chironomus balatonicus (Chironomidae, Diptera) from Chernobyl, a highly radioactive area of the Kiev region. Several chromosomal aberrations were established unique to a population of Chironomus balatonicus living in an area contaminated by radioactive waste. Five new heterozygous inversions, deficiencies in arms C, D, E, F and chromatid breaks were found in the irradiated population but not in nonirradiated populations. A pericentric inversion in chromosome AB occurred at a relatively high frequency. Genome aberrations expressed by a heterochromatized 'B' chromosome were evident. In the irradiated and nonirradiated populations common inversions occurred showing variation in their frequency depending on specific environmental conditions. The somatic and also the germ cells were characterized by a number of heteropycnotic nuclei and vacuolized chromosomes. Both the somatic and germ cells showed changes in the structural and functional organization of heterochromatin and this was particularly marked in the telomeric sectors of the chromosomes. The heterochromatin which is extremely sensitive to radioactivity appears to protect euchromatin from adverse environmental conditions. PMID- 7842725 TI - Ultrastructural and immunocytochemical studies of iris vessels in rats with experimental autoimmune uveoretinitis. AB - In this study, we describe the ultrastructural and immunocytochemical changes that occur in the iris of rats with experimental autoimmune uveoretinitis (EAU). General changes include perivascular infiltration of inflammatory cells, followed by hemorrhage and extensive tissue destruction. Alterations in the iris epithelium were also noted. A breakdown in the blood-iris barrier was demonstrated in some vessels at the peak of inflammation; peroxidase reaction product was seen in the basement membrane and perivascular spaces. We found that, in inflamed iris vessels, endothelial cells and smooth muscle cells become hypertrophic and show increased amounts of synthetic organelles. This finding is similar to our previous observations on endothelial cells and smooth muscle cells in retinal vessels in EAU. In addition, as was reported in the retinal vascular basement membrane in EAU, there is an increase in immunoreactivity of several extracellular matrix molecules in the iris vascular basement membrane; during inflammation, there is a significant increase in immunoreactivity of collagen types I and III, entactin, fibronectin, and laminin. Activated endothelial cells and smooth muscle cells are likely to be involved in the synthesis of certain of these matrix molecules. PMID- 7842728 TI - Transport of latex microspheres by peripheral nerves of the rat. AB - The usefulness of rhodamine-labelled latex microspheres (RLM) as a marker for studying intracellular transport in peripheral nerves has been investigated in the intercostal and sciatic nerves of the rat. Suspensions of microspheres were injected into peripheral nerves, and after periods of survival ranging from 24 to 240 h, the nerves and dorsal root ganglia were fixed, frozen sections cut, and sections examined by fluorescence microscopy. It was found that RLM were transported in both anterograde and retrograde directions, but that dorsal root ganglion cells were poorly labelled. Horseradish peroxidase histochemistry did not affect the fluorescence of RLM. Features of the uptake and transport of RLM are discussed and possible applications suggested. PMID- 7842729 TI - Ultrastructural changes in the Leydig cell on treatment with vincristine. AB - The effect of vincristine (VCR), an anticancer drug which brings about mitotic arrest by disturbing the microtubules of the spindle fibres, on the Leydig cells was investigated adopting ultrastructural and RIA of hormone techniques. The Leydig cells of VCR treated rats were necrotic and oedematous with severe damage caused to the steroidogenic machinery, viz the mitochondria and smooth endoplasmic reticulum. Such damage was duly reflected in the serum levels of hormones, wherein the androgen level was decreased with compensatory hypersecretion of follicle-stimulating hormone and luteinizing hormone. The results strongly implicate VCR in Leydig cell toxicity, and explain the problems in the reproductive performance faced by cancer patients receiving VCR as one of the drugs, both during treatment and after remission. PMID- 7842730 TI - Report and abstracts of the fifth international workshop on human chromosome 3 mapping 1994. Ann Arbor, Michigan, May 8-9, 1994. PMID- 7842731 TI - Report and abstracts of the second international workshop on human chromosome 8 mapping 1994. Oxford, United Kingdom, September 16-18, 1994. PMID- 7842732 TI - Report and abstracts of the third international workshop on human chromosome 16 mapping 1994. Pittsburgh, Pennsylvania, May 7-9, 1994. PMID- 7842733 TI - Cloning and chromosomal localization of the human and murine genes for the T-cell transcription factors NFATc and NFATp. AB - The nuclear factor of activated T cells (NFAT) is a transcription factor complex involved in the activation of cytokines and cell surface molecules associated with coordinating the actions of different cells required for an immune response. Two different genes have recently been cloned that encode proteins capable of functioning as the pre-existing (p) and cytosolic (c) component of the NFAT transcription complex, NFATc of human and NFATp of murine origin (Northrop et al., 1994; McCaffrey et al., 1993b). We report here the partial cDNA cloning of the murine homolog of NFATc and the human homolog of NFATp, and the chromosomal localization of both genes in both species to conserved syntenic regions. Through the use of mapping panels of human x Chinese hamster and mouse x rodent cells hybrids, the NFATc genes were mapped to human and mouse chromosomes 18. By analyzing a chromosome 18 radiation hybrid panel, the human NFATc gene was localized to the q terminus, closely linked to STS marker D18S497. The murine Nfatc gene was sublocalized to chromosome band 18E4 by FISH. The NFATp genes were mapped by somatic cell hybrid analysis to human chromosome 20 and mouse chromosome 2. Human NFATp was assigned to chromosome region 20q13.2-->q13.3 by FISH. Based on the conserved syntenic region on human chromosome 20 and mouse chromosome 2, murine Nfatp is predicted to reside in the vicinity of a mutant locus wasted. Homozygous wst/wst mice display a phenotype reminiscent of severe combined immune deficiency or ataxia telangiectasia, disorders that could therefore be considered candidates for NFATp mutations. PMID- 7842734 TI - Localization of the human gene for fibulin-1 (FBLN1) to chromosome band 22q13.3. AB - Using fibulin-1 cDNA probes, we performed fluorescence in situ hybridization to map the human chromosomal location of the gene encoding the extracellular matrix and blood glycoprotein, fibulin-1 (FBLN1). The gene for fibulin-1 was mapped to a single site on the long arm of human chromosome 22 (22q13.3). The assignment of the chromosomal map position for the fibulin-1 gene will aid in the evaluation of its potential roles in human connective tissue and blood diseases. PMID- 7842735 TI - Physical linkage of the gene cluster containing the LCAT gene to the DNA marker D16S124 at human chromosome region 16q22.1. AB - Pulsed-field gel electrophoresis has been used to construct a long-range restriction map spanning more than 900 kb in the q22.1 region of human chromosome 16. The gene cluster containing the lecithin:cholesterol acyl transferase (LCAT) gene is located less than 480 kb from the anonymous DNA marker D16S124 in this map. The results suggest three putative CpG islands within 125 kb, in addition to the island previously shown to be located within the gene cluster. This implies a clustering of both genes and CpG islands in this chromosomal region. PMID- 7842736 TI - The development of painting probes for dual-color and multiple chromosome analysis in the mouse. AB - The recent development of mouse chromosome painting probes for fluorescence in situ hybridization has extended the use of this common laboratory mammal in cytogenetics. We now report the development of additional painting probes by degenerate-oligonucleotide-primed PCR on chromosomes from mouse lung fibroblast cultures, each homozygous for a single Robertsonian translocation chromosome. These probes are for Rb(1.2), Rb(1.3), Rb(4.6), and Rb(6.7). Probes were also made for the sex chromosomes by isolating shoulders from larger peaks (X) or small, clearly resolved peaks (Y) in the flow karyotype. Combinations of probes were used to paint four chromosomes simultaneously in a single color. Multicolor painting was achieved with a biotinylated Rb(1.2) probe and a digoxigenin-labeled Rb(2.8) probe. Each of the three different homologous pairs was uniquely colored by avidin-Texas Red, anti-digoxigenin-FITC, or both simultaneously. These results extend the usefulness of the mouse as a model for understanding adverse environmental exposures and genetic diseases in humans. PMID- 7842737 TI - Incidence of low-fluorescence alpha satellite region on chromosome 21 escaping detection of aneuploidy at interphase by FISH. AB - Aneuploidy detection for chromosome 21 by fluorescence in situ hybridization (FISH) to interphase nuclei using a probe specific for the alphoid DNA sequences D21Z1/D13Z1 should be avoided. An extreme heteromorphism, resulting in misdiagnosis if interphase FISH is the only test employed, may be far more frequent (4/101) than expected. PMID- 7842738 TI - Chromosome mapping of 11 human probes in the region 5q2-->q3 by fluorescence in situ hybridization. AB - Using single- and double-color fluorescence in situ hybridization (FISH), 11 probes from the human chromosome region 5q2-->q3 are mapped. The following map order is proposed, from proximal to distal: 5q21.3-->q22: 15A6 (D5S136), YN5.64, CRI-L372 (D5S49), YN5.48 (D5S81): 5q22: EF5.44 (D5S135), APC; 5q22-->q23.1; CI5.23, L5.69 (D5S137), CRI-T39 (D5S64), MC5.61 (D5S84); 5q31.1-->q31.2: CRI L1265 (D5S52). PMID- 7842739 TI - A proposed system for scoring structural aberrations detected by chromosome painting. AB - The advent of chromosome painting has brought the realization that structural aberrations can be far more complicated than previously imagined. Various investigators have devised their own nomenclature systems to deal with this difficulty, with the result that the terminology has become inconsistent and confusing. Recently, an international group of cytogeneticists experienced in chromosome painting gathered to address this issue. Results of the meeting are presented in this report, which provides a nomenclature system capable of describing chromosome aberrations that occur between painted and unpainted chromosomes, as well as aberrations involving only painted chromosomes. The nomenclature is flexible enough to describe accurately even the extensively rearranged chromosomes. As a consequence of this flexibility, the scheme upon which the nomenclature is based differs substantially from other systems of aberration classification. We call this system the Protocol for Aberration Identification and Nomenclature Terminology (PAINT). PMID- 7842740 TI - Physical mapping of 3 candidate tumor suppressor genes relative to Beckwith Wiedemann syndrome associated chromosomal breakpoints at 11p15.3. AB - A physical map encompassing the 3 Mb region containing the breakpoints of two Beckwith-Wiedemann Syndrome patients at chromosome band 11p15.3 is presented. The candidate tumor suppressor genes WEE1, ST5, and rhombotin, are positioned on this map relative to these Beckwith-Wiedemann syndrome translocation and inversion breakpoints. PMID- 7842741 TI - Isolation and mapping of a human gene (MCM2) encoding a product homologous to yeast proteins involved in DNA replication. AB - From a human fetal-lung cDNA library, we isolated a gene, human MCM2, whose nucleotide sequence predicts a protein product homologous to the yeast nuclear proteins MCM2, MCM3, CDC21, and CDC46. Determination of cDNA sequences covering the entire coding region demonstrated an open reading frame of 1,629 nucleotides encoding 543 amino acids. Sequence comparison revealed 30-40% amino acid identity with these four yeast proteins, all of which are considered to play important roles in DNA replication. Analysis by Northern blotting revealed that the human MCM2 gene is expressed ubiquitously in normal tissues. Furthermore, we localized this gene to chromosomal bands 7q21.3-->q22.1 by fluorescence in situ hybridization. PMID- 7842742 TI - The human OTF1 locus which overlaps the CD3Z gene is located at 1q22-->q23. AB - The human OTF1 locus encoding the Oct-1 protein has previously been mapped to chromosome 1 cen-->q32 by analysis of somatic cell hybrids. We report here the regional localization of OTF1 to 1q22-->q23 by fluorescence in situ hybridization. The physical linkage of the CD3Z gene to the OTF1 transcription unit also refines the location of the CD3Z locus to 1q22-->q23. PMID- 7842743 TI - Localization of the undulin gene (UND) to human chromosome band 8q23. AB - Undulin, a large extracellular matrix (ECM) mosaic glycoprotein related to collagen type XIV, is associated with dense collagen matrices in soft tissues and is likely to be involved in the supramolecular organization of interstitial collagens. By fluorescence in situ hybridization (FISH), we have assigned the undulin locus (UND) to band q23 of human chromosome 8. PMID- 7842744 TI - Localization of the human HTF4 transcription factors 4 gene (TCF12) to chromosome 15q21. AB - Identification and localization of genes that encode regulators of transcription could provide landmarks for functional analysis of the human genome. Toward this goal, we examined a panel of somatic cell hybrids and assigned the gene (TCF12) encoding the helix-loop-helix transcription factors 4 (HTF4) to chromosome 15. Fluorescence in situ hybridization further localized TCF12 to chromosome 15q21. Northern analysis revealed that the relative abundance of HTF4 gene transcripts is not constant but varies depending on the human cell-line or tissue examined. PMID- 7842746 TI - Lung reduction surgery. Great expectations and a cautionary note. PMID- 7842747 TI - Sepsis clinical trials. Don Quixote revisited. PMID- 7842745 TI - The genes coding for rat cystatin-related prostate protein (Cstrp) map to chromosome 3q41. AB - Two genes encoding rat cystatin-related prostate protein (Cstrp), previously called CRP (Devos et al., 1993), were mapped to chromosome 3q41 by fluorescent in situ hybridization. The results were confirmed using a panel of mouse-rat hybrids that segregate rat chromosomes. Analysis of genomic DNA indicates that the Cstrp locus comprises probably more than three very similar genes. PMID- 7842748 TI - Examining the pleura. PMID- 7842749 TI - Respiratory consequences of postoperative hyponatremia in young women. PMID- 7842750 TI - Magnitude of usage and cost of home oxygen therapy in the United States. PMID- 7842751 TI - Correction of pectus excavatum with a self-retaining seagull wing prosthesis. Long-term follow-up. AB - Between June 1958 and December 1991, 315 patients (217 male and 98 female, mean age = 17.8 +/- 5.5 years) affected by pectus excavatum (PE) were surgically treated. Most of the patients required operation for aesthetic reasons only (299 patients; 95 percent). The grade of PE (Chin classification) was I in 72 patients, II in 152, and III in the remaining 91. The surgical technique consisted of a double transversal sternotomy at the level of the lowest and highest part of the depression associated with a longitudinal sternotomy. A wedge resection of the ribs was then performed and the sternum was fixed using a stainless steel strut molded into a seagull wing prosthesis. The strut was removed 12 months postoperatively. There were no operative mortalities. Four patients had sternal wound infection that was successfully treated. The mean follow-up was 15.8 years per patient and was 60 percent complete. From the aesthetic point of view, the postoperative results were excellent in 246 patients (78 percent), good in 57 (18 percent), and poor in 12 (4 percent). All subjective symptoms, when present, disappeared after surgery. The seagull wing prosthesis appears to be safe, easy to implant and to remove, and comfortable for the patient. This technique has shown good long-term results independently of type of deformity and patient age. PMID- 7842752 TI - Preservation of adenosine 5'-triphosphate and mitochondrial function during hypercalcemic reperfusion using verapamil cardioplegia. AB - Immediate hypercalcemic reperfusion results in ventricular dysfunction and loss of high-energy stores. The purpose of this study was to evaluate the effect of verapamil cardioplegia on the preservation of myocardial energy stores, mitochondrial ultrastructure, and ventricular dysfunction in the postischemic rat heart during immediate hypercalcemic reperfusion. Rats in the control group were subjected to cardioplegia with potassium, while rats in groups 1 to 3 were subjected to the same with verapamil (0.5 mg/L). The control and group 1 rats underwent normocalcemic reperfusion and groups 2 and 3 rats underwent hypercalcemic reperfusion. Myocardial samples were analyzed for adenosine 5' triphosphate (ATP) content and mitochondrial ultrastructural damage. Hemodynamic parameters of heart rate, aortic flow (AF), and postischemic rate of aortic pressure change (dP/dT) also were evaluated. Data were analyzed using analysis of variance. The ATP stores were preserved at greater than 100% control levels in hearts subjected to verapamil cardioplegia. There was no evidence of irreversible mitochondrial damage. Heart rate, AF, and dP/dT were significantly (p < 0.05) depressed in hearts subjected to verapamil cardioplegia. This study suggests verapamil cardioplegia preserves ATP and mitochondrial function during immediate hypercalcemic reperfusion but does not improve postischemic hemodynamics. PMID- 7842753 TI - Inability to perform bicycle ergometry predicts increased morbidity and mortality after lung resection. AB - The ability to successfully exercise has been used to assess the cardiopulmonary risk of thoracotomy for lung cancer. Because of musculoskeletal, neurologic, peripheral vascular, or behavioral problems, not all patients presenting for pulmonary resection are capable of exercising. Using a multifactorial cardiopulmonary risk index (CPRI) consisting of a cardiac risk index (CRI) and a pulmonary risk index, we studied 74 patients (60 capable of exercising and 14 incapable of exercising) who underwent thoracotomy for lung cancer resection. The groups were similar in reference to history of pulmonary disease, preoperative pulmonary function, and pulmonary risk index score. The no-exercise patients were more likely to have a history of cardiac disease (64 vs 28%; p < 0.01) and had a higher CRI score (2.0 +/- 0.2 vs 1.4 +/- 0.1; p < 0.05). Cardiopulmonary postoperative complications (POCs) and mortality were more likely among those in the no-exercise group vs those in the exercise group (POCs, 79 vs 35%, p < 0.01; mortality, 21 vs 2%, p < 0.05). Among the eight no-exercise patients with a CPRI of 4 or more, all eight suffered a POC (100%) and three died (38%). Using multiple logistic regression analysis, both the CPRI score and the inability to exercise were independently associated with increased risk for POCs. We conclude that patients unable to perform even minimal preoperative exercise are at substantially increased risk for morbidity and mortality after lung resection. This results both from greater identifiable preoperative cardiopulmonary risk factors (as assessed by the CPRI) and from an independent effect related to the inability to exercise. PMID- 7842754 TI - Mitochondrial enzyme deficiency causing exercise limitation in normal-appearing adults. AB - Deficiencies of mitochondrial enzymes cause a number of severe neurologic syndromes in pediatric patients. Isolated myopathy secondary to enzymatic deficiency only rarely has been recognized and reported in adults. Three normal appearing patients with unexplained dyspnea on exertion, tachycardia, and fatigue were studied with progressive incremental and constant load exercise testing with hemodynamic and gas exchange measurements. Subsequently, muscle biopsies were performed and enzymatic profiles determined. Exercise testing suggested altered cellular energy metabolism. Oxygen transport and gas exchange at rest and with exercise were normal. During exercise, ventilation increased excessively for the work performed, but it was appropriate for carbon dioxide production. Cardiac outputs increased significantly (196 to 305%), heart rates reached maximum levels, and lactic acid levels increased (385 to 833%) during exercise at 25 W. Muscle morphology was normal, but mitochondrial enzyme assays demonstrated one or more deficiencies in all three patients. Mitochondrial enzymatic deficiency can be a cause of unexplained exercise symptomatology and limitation in adults. Our experience would suggest the incidence of the disorder may be greater than that previously recognized or expected. Symptoms of exercise limitation associated with dyspnea, tachycardia, or muscle fatigue should alert the clinician to a possible abnormality in cellular energy metabolism. PMID- 7842755 TI - Cardiorespiratory responses to incremental exercise in sarcoidosis patients with normal spirometry. AB - Patients with sarcoidosis are known to have histologic pulmonary abnormalities despite normal lung fields or conventional pulmonary function or both. These patients permit a useful assessment of the alleged greater sensitivity of the various measurements made during incremental cardiorespiratory exercise testing. Abnormal responses on such testing may provide insight into such complaints as dyspnea in these patients. Incremental exercise testing was performed on 30 patients with biopsy-proven sarcoidosis who had normal spirometry; 13 had clear lung fields radiographically. Of these patients, the 21 who had normal single breath diffusing capacity for carbon monoxide (Dsb; [group A]) were compared with the 9 who had decreased Dsb (group B). Half of the group A patients had excessive ventilation and 38% had increased dead space to tidal volume ratio (Vd/Vt), but frequencies of these abnormalities were greater in group B, 89 and 78%, respectively. Ventilatory response, as minute ventilation to oxygen consumption ratios ventilatory equivalents, and deadspace to tidal volume ratio (Vd/Vt) ratios were higher in group B. Widened alveolar-arterial oxygen pressure differences were seen in 7 of 9 group B patients but only 1 of 17 group A patients. This study supports the clinical impression that occult pulmonary impairment may be present in patients (in this case, sarcoidosis patients) with normal pulmonary function, and corroborates the utility of exercise testing in demonstrating such impairment. Reduction in Dsb predicted greater frequency of abnormal exercise responses, especially in oxygenation. PMID- 7842756 TI - Diagnostic and prognostic value of myocardial scintigraphy with thallium-201 and gallium-67 in cardiac sarcoidosis. AB - STUDY OBJECTIVE: To examine the diagnostic and prognostic value of myocardial scintigraphy using thallium-201 and gallium-67 in cardiac sarcoidosis. PATIENTS: Twenty-five patients with sarcoidosis. METHODS: All patients underwent myocardial thallium-201 scintigraphy. Six patients with myocardial thallium-201 defects were classified into group A and another 19 without defects were classified into group B. Between group A and B, we compared the results of other noninvasive examinations, including standard 12-lead ECG, 24 h ambulatory ECG, chest radiography, measurements of serum angiotensin-converting enzyme (ACE) and lysozyme levels, and gallium-67 scintigraphy. RESULTS: Proportions of subjects who had varying degrees of heart block, severe ventricular arrhythmias (more than or equal to third grade of Lown's classification), and high levels of serum ACE and lysozyme levels were not different between these two groups (p > 0.05). Although an enlarged cardiothoracic ratio was more frequent in group A (p < 0.05), bilateral hilar lymphadenopathy was more frequent in group B (p < 0.01). Four patients of group A and 15 of group B underwent gallium-67 scintigraphy. Although no subjects of group B had myocardial uptake of gallium-67, two of four group A patients showed cardiac uptake. These four group A patients were treated with corticosteroids. The therapy provided clinical and scintigraphic improvement in two patients with myocardial gallium-67 uptake, although it did no improvement in the other two patients without gallium-67 uptake. CONCLUSIONS: When cardiac sarcoidosis was diagnosed according to myocardial thallium-201 defects, other noninvasive examinations were not useful to detect this disease. However, gallium 67 uptake may predict the efficacy of corticosteroids. Thus, the combination of thallium-201 and gallium-67 scintigraphy may be useful not only in diagnosis of cardiac sarcoidosis but also in prediction of effects of corticosteroids. PMID- 7842757 TI - Prospective evaluation of viable myocardium by quantitative dipyridamole-thallium 201 scintigraphy and radionuclide ventriculography. AB - Improvement of myocardial function is a major goal of coronary revascularization. Considerable interest remains in the preoperative identification of viable myocardium. We examined 26 consecutive patients with left ventricular dysfunction undergoing coronary artery bypass grafting. Serial dipyridamole-thallium imaging and radionuclide ventriculography was performed preoperatively and postoperatively. The relationship between preoperative and postoperative thallium perfusion and segmental wall motion was analyzed. The mean preoperative ejection fraction was 32 +/- 9 (21 to 51%) and increased to 41 +/- 12 (17 to 67%) postoperatively (p > 0.01). Seventy-seven percent of patients improved their global ejection fraction postoperatively by > 5%. Thallium perfusion improved postoperatively in 84% of reversible defects vs 63% of partially reversible defects and 35% of fixed defects. Segments with either reversible or partially reversible thallium defects showed an improved postoperative wall motion in 71% and 68%, respectively. Postoperative wall motion improved in 43% of fixed defects. Overall, 67% of hypokinetic segments showed improved postoperative wall motion while only 29% of akinetic or dyskinetic segments improved postoperatively. Preoperative thallium redistribution coupled with preserved wall motion was predictive of improvement in wall motion was predictive of improvement in wall motion postoperatively and indirectly indicates myocardial viability. However, 43% of fixed defects also showed improved postoperative wall motion. A significant improvement in global ejection fraction was found and could be predicted by a linear regression analysis utilizing clinical and thallium parameters. PMID- 7842758 TI - Relationship of left ventricular structure to maximal heart rate during exercise. AB - Previous investigators using clinical, hemodynamic, or exercise parameters to predict maximal exercise heart rate (HRmax) have demonstrated age to be the major determinant. Regression coefficients have ranged from -0.3 to -0.6, leaving approximately two thirds of the variance in HRmax unexplained. Because cardiac size and function are directly related to stroke volume and should influence HRmax, we studied 114 male subjects (aged 19 to 73 years) with two-dimensional and M-mode echocardiography who underwent maximal treadmill testing with respiratory gas analysis. Seventy-three were normotensive (diastolic BP < 95 mm Hg) and 41 were hypertensive. As in previous studies, HRmax was inversely related to age (HRmax = 199-0.63[age], r = -0.47, p < 0.001). M-mode left ventricular (LV) diastolic dimension (LVD) added significantly to the explanation of the variance in HRmax (r = -0.57, p < 0.001) (HRmax = 236 - 0.72 [age]-6.8 [LVD]). Thus, the larger the heart, the lower the HRmax. No other echocardiographic measurement or derived parameter added significantly to the explanation of the variance in HRmax. To evaluate the effects of hypertension on HRmax, we studied hypertensives and normotensives separately. Only age was significantly related to HRmax in the normotensives (r = -0.50, p < 0.001). In the hypertensive subjects, however, both age and relative wall thickness (RWT) (which describes LV wall thickness in relation to LV chamber size) were significantly related to HRmax. Age explained 45% of the observed variance in HRmax (r = 0.67, p < 0.001) and RWT added modestly (9%) but significantly to the relationship (HRmax = 173 0.96[age]+94 [RWT], p < 0.001), together explaining 54% of the variance observed in HRmax. Thus, HRmax is inversely related to LVD and patients with larger ventricles achieve lower HRmax. In hypertensives, the amount of LV muscle mass in relation to chamber size is an additional predictor of HRmax. However, despite controlling for age, sex, and cardiovascular disease, and the inclusion of echocardiographic indices of cardiac size and function, a large portion of the variance in HRmax could not be explained. The unexplained variance in HRmax is most likely due to intersubject variability in resting cardiac size, volume, function, and other as yet undefined factors. PMID- 7842759 TI - Pericardial fluid adenosine in ischemic and valvular heart disease. AB - Adenosine released by ischemic myocardial cells stimulates coronary artery vasodilation. Measurement of adenosine concentrations in pericardial fluid in animal models of myocardial ischemia has been used to study the process of adenosine release. To determine whether pericardial fluid adenosine concentrations are increased in human ischemic heart disease, adenosine concentrations were measured in pericardial fluid in 23 subjects undergoing open heart surgery for coronary artery disease. The results were compared with adenosine concentrations measured in pericardial fluid obtained from 20 subjects undergoing surgery for valvular heart disease. Adenosine concentrations also were measured in pleural fluid obtained during internal mammary artery bypass grafting. Adenosine concentrations were significantly increased in subjects with coronary artery disease compared with fluid obtained from subjects with valvular heart disease (2.47 +/- 0.24 vs 1.36 +/- 0.21 [SEM] microM [p = 0.0013]). Adenosine concentrations were higher in pleural fluid than pericardial fluid from the same individuals. Adenosine concentrations were significantly correlated with pericardial fluid cell counts and lactate dehydrogenase concentrations (r = 0.48; p = 0.0012 and r = 0.77, p = 0.0001, respectively). The results are consistent with myocardial release of adenosine in ischemic heart disease. If adenosine concentrations in pericardial fluid approximate those in myocardial interstitial fluid, sufficient adenosine is present to stimulate adenosine receptor activation in coronary artery smooth muscle. PMID- 7842760 TI - The preflight evaluation. A comparison of the hypoxia inhalation test with hypobaric exposure. AB - STUDY OBJECTIVES: We sought to compare arterial oxygen partial pressure (PaO2) relationships between a 15.1% hypoxia inhalation test (HIT) at sea level and a hypobaric chamber exposure equivalent to 2,438 m (8,000 feet) of altitude above sea level in patients with chronic obstructive pulmonary disease (COPD) and healthy subjects. DESIGN: Comparison of physiologic variables before and during intervention. SETTING: A referral-based pulmonary disease clinic at a US Army medical center in a metropolitan area. SUBJECTS: The study included three groups: group 1, 15 patients, 3 women and 12 men, with COPD (forced expiratory volume in the first second [FEV1, mean +/- SD], 41 +/- 14% of predicted); group 2, 9 healthy men; and group 3, 18 men with COPD (FEV1, 31 +/- 10% of predicted) previously reported in detail. INTERVENTIONS: We evaluated each group at sea level followed by one of two different types of hypoxic exposures. Group 1 received exposure to 15.1% oxygen at sea level, the HIT. Groups 2 and 3 received hypobaric chamber exposure equivalent to 2,438 m (8,000 feet) above sea level. MEASUREMENTS AND MAIN RESULTS: For all three groups combined, the arterial oxygen tension at sea level (PaO2SL) explained significant variability in PaO2 during hypoxic exposure according to the following formula: PaO2 during exposure = 0.417 (PaO2SL)] + 17.802 (n = 42; r = 0.756; p < 0.001). Neither the type of hypoxic exposure (HIT vs hypobaric), status as patient vs control, sex, nor age explained significant variability in PaO2 during hypoxia exposure after inclusion of PaO2SL as a covariate in analysis of variance. Subsequent analysis revealed that forced expiratory spirometric variables FEV1 and FEV1 to FVC ratio served as second order covariates with PaO2SL to improve description of PaO2 during hypoxia exposure for the combined samples (n = 42; p < 0.05). Analysis of residuals from regression analysis revealed approximately normal distribution. CONCLUSIONS: The PaO2 relationships did not differ between the 15.1% HIT at sea level and hypobaric exposures of 2,438 m (8,000 feet) above sea level. Normal subjects and patients with COPD formed a single relationship. The present study extends descriptive models to a larger range of subjects. Regression models have definable accuracy in predicting PaO2 during hypoxia exposure that increases with inclusion of spirometric variables. PMID- 7842761 TI - Home oxygen therapy. A comparison of 2- vs 6-month patient reevaluation. AB - STUDY OBJECTIVE: To contrast the effectiveness of 2- vs 6-month reevaluation intervals on both clinical outcome and cost in patients requiring continuous home oxygen therapy (HOT). DESIGN: Prospective, randomized clinical trial. SETTING: The outpatient program of a university-affiliated Veterans Affairs Medical Center (VAMC) Pulmonary Service. PATIENTS: Fifty patients were chosen from among a cohort of 200 patients currently enrolled in our HOT program. All met specific arterial blood gas criteria, were able to give informed consent, had at least 6 months of prior HOT usage, and did not have any illness expected to independently shorten life expectancy. INTERVENTIONS: Baseline resting oxygen flow rates were prescribed based on the results of arterial blood gas measurements so as to attain a PaO2 > 60 mm Hg. Flow rates were adjusted as needed during a 12-min walk to maintain pulse oximetry readings > 90%. No adjustments in baseline flow rates were made during sleep. Identical evaluations were repeated at either 2- or 6 month intervals. MEASUREMENTS AND RESULTS: At 1-year follow-up, there were no significant differences between the 2- and 6-month groups in any of the clinical outcome parameters measured, ie, number of emergency department visits, number of hospitalizations, number of days hospitalized, or mortality. Total costs were not significantly different between the two groups. Evaluation costs were less in the 6-month follow-up group. CONCLUSIONS: After attaining stability following at least 6 months of continuous HOT usage, patients receiving continuous HOT need not be routinely reevaluated more frequently than every 6 months. PMID- 7842762 TI - Body fat distribution and sleep apnea severity in women. AB - The contribution of body fat distribution to sleep-disordered breathing in women has not been examined in detail (to our knowledge). Fifty women under 65 years of age were diagnosed as having obstructive sleep apnea (OSA) by all-night polysomnography in a 6-month period. Twenty-five women underwent body fat measurements of skin folds and circumferences. The 12 premenopausal and 13 postmenopausal women did not differ in regard to apnea hypopnea index (AHI), SaO2 nadir, body mass index (BMI), or anthropometric measurements. The AHI for these 25 patients was related to the severity of obesity assessed by triceps and subscapular skin folds, the sum of the skin folds, waist circumference, and BMI. The SaO2 nadir correlated with triceps and subscapular skin folds, the sum of the skin folds, and neck skin fold. Clinical features of this same group of 25 women were then compared with those of 45 men with OSA previously described by our laboratory. The women, despite similar age, had less severe OSA than the men (AHI of 34.4 +/- 5.4 vs 51.1 +/- 4.9, p < 0.05). Despite similar BMIs and waist circumference, the men had evidence of a greater degree of upper body obesity with a larger subscapular skin fold thickness, waist-hip ratio, and neck circumference. In addition, for a given degree of upper-body obesity, men had more severe sleep apnea. These findings may explain, at least in part, the greater severity of OSA in the men. PMID- 7842763 TI - Nasal continuous positive airway pressure in the perioperative management of patients with obstructive sleep apnea submitted to surgery. AB - Anesthetic, sedative, and analgesic drugs have been shown in animals and humans to selectively impair upper airway muscle activity. In patients with an already compromised upper airway, these drugs may further jeopardize upper airway patency, especially during sleep. Thus, patients with obstructive sleep apnea syndrome (OSAS) are at high risk for surgery because of the use of the aforementioned drugs in the perioperative period. It has been recommended that such drugs should be avoided or used with extreme caution in patients with OSAS submitted to surgery. We report herein on 16 adult patients with documented OSAS undergoing various types of surgical procedures, including coronary artery bypass surgery. Anesthesia was carried on with the usual type of drugs for each type of surgery. Postoperative opioid analgesia and sedation were not restricted. The first patient, whose OSAS was diagnosed but not treated, died after various complications, including a respiratory arrest in the ward. The second patient experienced serious postoperative complications until a treatment for OSAS with nasal continuous positive airway pressure (N-CPAP) was instituted, and thereafter he made an uneventful recovery. The 14 following patients were started on N-CPAP before surgery, were put on N-CPAP as soon as extubated, on a near-continuous basis, for 24 to 48 h and thereafter for all sleep periods. None of them had major complications. The intensive care unit and hospital stays were the normal ones for each type of surgery in our institution. We conclude that N-CPAP started before surgery and resumed immediately after extubation allowed us to safely manage a variety of surgical procedures in patients with OSAS, and to freely use sedative, analgesic, and anesthetic drugs without major complications. Every effort should be made to identify patients with OSAS and institute N-CPAP therapy before surgery. PMID- 7842764 TI - Side effects of nasal continuous positive airway pressure in sleep apnea syndrome. Study of 193 patients in two French sleep centers. AB - Nasal continuous positive airway pressure (N-CPAP) is now the treatment of choice for patients with sleep apnea syndrome (SAS). Side effects and adverse reactions have been described with this device. We have therefore systematically studied side effects of N-CPAP in 193 patients recruited consecutively from two French sleep centers (Lyon and Grenoble). Patients were followed up with repeated polysomnography, clinical assessment, and a formal questionnaire about subjective benefits and side effects of treatment. The patients (mean age, 59 +/- 12 years) were obese (body mass index, 32 +/- 7 kg/m2) and had been using N-CPAP for 19 +/- 17 months for moderate to severe SAS (respiratory disturbance index [RDI] = 53 +/ 25/h). The clinical presentation was the same in the two sleep centers. Fifty percent of the patients complained of at least one side effect due to the nasal mask (allergy to the face, air leaks, abrasions of the ridge of the nose). Using individually molded masks, the patients exhibited fewer abrasions of the bridge of the nose (p < 0.01) and had red eyes every morning in only 9% of cases vs 24% for the patients using industrial silicone nasal masks (p < 0.025). Patients with silicone nasal masks also had more allergic reaction to the face (13% vs 5%), but this difference did not reach significance. Dry nose or mouth in the morning affected 65% of the patients. Sneezing and nasal drip were present in more than 35% of the subjects and nasal congestion in 25%. When the patients were separated in two groups, whether or not using a humidifier, no difference was found for any of the side effects described. The clinical presentation as to the clinical benefits obtained from N-CPAP were different when comparing mild vs moderate-to severe SAS. However, no differences were shown in the two subgroups regarding the side effects due to the nasal mask. The discomfort of the N-CPAP apparatus in terms of noise was described more frequently in the subgroup with mild SAS. We did not observe any correlation between the side effects and the level of pressure used during N-CPAP. The rate of compliance remains high with a daily use of 6.5 +/- 3 h, with 88% of the patients using their device every night. This could be explained by the clinical benefit obtained: only 1% of the patients had no subjective benefit induced by their therapy.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7842765 TI - Nasal intermittent positive pressure ventilation. Analysis of its withdrawal. AB - Nasal intermittent positive pressure ventilation (NIPPV) applied during sleep has been demonstrated to be useful in the treatment of restrictive thoracic diseases (RTD). The purpose of this study was to evaluate the repercussions of a withdrawal period from NIPPV of 15 days. This would be sufficient time for patients to go on trips without the respirator. It was hypothesized that once daytime improvement was achieved and was stable, it could be maintained for this period of time. Five volunteer patients with severe RTD who had been receiving treatment with nocturnal NIPPV for at least 2 months before and who had improved at least 5 mm Hg in daytime PO2 and PCO2 were included in the study. No significant differences were disclosed clinically or with arterial blood gas levels, spirometry results, lung volumes, airway resistances, or maximal muscle pressures 15 days following the withdrawal. However, in the sleep studies, a severe worsening of gas exchange was observed, mainly during rapid eye movement (REM) sleep, as well as a trend toward a more disturbed sleep pattern and more important alterations in cardiac rhythm. Consequently, withdrawing the treatment with nocturnal NIPPV cannot be recommended, at least for this particular removal period. Moreover, alterations in daytime gas exchange were found to originate in those produced during REM sleep through the blunting of the respiratory center to CO2. The NIPPV obstructs this mechanism, preventing the deterioration of gas exchange during sleep. PMID- 7842766 TI - Postnatal maternal smoking increases the prevalence of asthma but not of bronchial hyperresponsiveness or atopy in their children. AB - We have compared the prevalence of asthma, bronchial hyperresponsiveness (BHR), and atopy in relation to parental smoking in children aged 7 to 13 years. Information on the presence of asthma was obtained from a questionnaire, BHR was assessed by a methacholine challenge test, and atopy was defined as a positive response to a skin prick test. A complete history of the parents' smoking habits during their children's life, including prenatal smoking habits, was recorded. The prevalence of maternal smoking increased from 37.9% during pregnancy to 45.3% at the cross-sectional survey. None of the outcomes was significantly related to paternal smoking, whereas postnatal maternal smoking was positively associated with asthma (odds ratio [OR] = 2.8; 95% confidence interval [CI], 1.3 to 6.1). A negative association between prenatal maternal smoking and atopy was found (OR = 0.6; 95% CI, 0.3 to 0.9). We found no significant association between BHR and parental smoking. Our results indicate that postnatal maternal smoking increases the prevalence of asthma in the offspring without inducing BHR. PMID- 7842767 TI - Effect of cigarette smoking on pulmonary function in each phenotype M of alpha-1 protease inhibitor. AB - Human alpha-1-protease inhibitor (alpha-1-Pi) has been known to be a highly polymorphic protein. We hypothesized that antiprotease activity of each phenotype M of alpha 1-protease inhibitor (PiM) might be different among smokers and that a variation of decrease in pulmonary function for a given amount of cigarette smoking might be associated with PiM phenotypes. To test this, we investigated the effect of cigarette smoking on pulmonary function in each PiM phenotype. The serum level of alpha 1-Pi was measured by the turbidimetric immunoassay and the distribution of PiM phenotypes was determined using isoelectric focusing technique in 247 healthy subjects and 20 COPD patients. Serum levels of alpha-1 antitrypsin of healthy and COPD subjects were 205.1 +/- 31.1 and 179.2 +/- 44.4 (+/- SD) mg/dL, respectively (p > 0.01). The frequency of each PiM phenotype in healthy subjects was shown as follows: M1, 0.555; M1M2, 0.328; M2, 0.041; M1M3, 0.057; M2M3, 0.016; M3, 0.004. The difference in the distribution of PiM phenotypes between healthy and COPD subjects was not significant. Single- and multiple-regression analyses showed that the ratio of FEV1 to forced vital capacity (FVC), in which FEV1 is expressed as percentage of FVC, the maximum flow rate at 50% of FVC divided by measured body height (V50/Ht), and the maximum flow rate at 25% of FVC divided by body height (V25/Ht) were closely related to age and that V25/Ht also was related to smoking index. However, PiM phenotype was unrelated to those pulmonary function variables. We conclude that PiM phenotype is not a major determinant of difference in magnitude of pulmonary impairments caused by cigarette smoking in each individual. PMID- 7842768 TI - Bronchodilating effects of combined therapy with clinical dosages of ipratropium bromide and salbutamol for stable COPD: comparison with ipratropium bromide alone. AB - Several studies have suggested that anticholinergics are at least equal to or may be superior to beta agonists in the treatment of stable COPD. However, since most previous studies have been performed to evaluate the bronchodilating effects of these two agents at relatively high doses, the clinical value of combining these two agents still is under debate. The purpose of this study was to determine if combination therapy with ipratropium bromide and salbutamol, in clinically available dosages, is superior in bronchodilation to ipratropium bromide alone. Twenty-six male patients (mean age, 67.5 +/- 5.9 years; FEV1, 0.87 +/- 0.32 L) with stable COPD were studied in randomized, double-blind, placebo-controlled experiments. On five separate days, all the patients received one of the following: (1) 40 micrograms ipratropium bromide, (2) 80 micrograms ipratropium bromide, (3) 40 micrograms ipratropium bromide plus 200 micrograms salbutamol, (4) 80 micrograms ipratropium bromide plus 400 micrograms salbutamol, or (5) placebo, using metered-dose inhalers (MDIs). Spirometry was assessed before and 15, 30, 60, 90, and 120 min after inhalation. Positive FEV1 responses to combined dosages of 80 micrograms ipratropium bromide and 400 micrograms salbutamol were significantly greater than responses to any other treatment regimen. Significantly greater responses also were achieved by combining 200 micrograms salbutamol with 40 micrograms ipratropium bromide compared with 40 micrograms ipratropium bromide alone. Combination therapy with 200 micrograms salbutamol and 40 micrograms ipratropium bromide produced a significantly greater effect on forced vital capacity than therapy with 80 micrograms ipratropium bromide alone. No significant differences were found between the responses induced by therapy with 80 and 40 micrograms ipratropium bromide. No adverse reactions to any regimen were noted throughout the study. In conclusion, combining the standard dosages of ipratropium bromide and salbutamol may provide greater bronchodilation than doubling the standard dosage of ipratropium bromide in patients with COPD. PMID- 7842769 TI - Bambuterol in the treatment of asthma. A placebo-controlled comparison of once daily morning vs evening administration. AB - Once-daily morning (7 AM) vs evening (10 PM) administration of the terbutaline prodrug bambuterol (20-mg tablet dose) was investigated in a double-blind, cross over, randomized, and placebo-controlled study involving 29 diurnally active patients with asthma. Terbutaline plasma concentration, spirometry, and drug tolerance were assessed during 39-h inpatient studies. A 7-day washout period separated each treatment. Mean 24-h plasma concentration was comparable for morning and evening bambuterol (13.2 vs 14.0 nmol/L). The Cmax for evening vs morning dosing was 17.2 vs 15.5 nmol/L (p < 0.02). The 24-h mean FEV1 was greater (p < 0.001) for bambuterol (morning: 3.2 L; evening: 3.4 L) vs placebo (2.9 L) as it was for FVC, FEF25-75%, and peak expiratory flow rate (PEFR), with the maximum effect at 4 AM independent of medication time. Evening dosing, however, resulted in greatest 7 AM (awakening) FEV1, FEV25-75, and PEFR (p < 0.03). With reference to corresponding-in-time placebo values, improvement in FEV1 at the end of the 24 h dosing intervals amounted to 0.34 L (13.5%) (p < 0.0004) and 0.35 L (15.9%) (p < 0.0012) with evening and morning bambuterol dosing, respectively. Side effects were greater for bambuterol than placebo, but not significantly so. Once-daily bambuterol therapy proved to be an effective treatment for asthma, whether administered in the evening or morning. Evening dosing seems best for nocturnal asthma since airway patency overnight and on awakening at 7 AM is most improved. PMID- 7842770 TI - Inhaled diuretics attenuate acid-induced cough in children with asthma. AB - To evaluate the effect of inhaled diuretics, furosemide and amiloride, on cough induced by acid inhalation challenge in asthmatic children, a double-blind, randomized, placebo-controlled study was conducted. On separate days, 12 asthmatic children (10.3 +/- 0.7 [SEM] years) underwent acetic acid (AD) inhalation challenge after inhalation of furosemide (10 mg/m2 of body) amiloride (0.3 mg/m2 of body), or placebo (0.9% saline solution). Bronchoconstriction was not observed after administration of furosemide and amiloride. Both inhaled furosemide and amiloride exerted a protective effect against AA-induced cough in asthmatic children (p < 0.01 and p < 0.05, respectively), while there was little correlation between the individual protective potency of furosemide and amiloride against AA-induced cough (rs = 0.344, p = 0.255). These results demonstrate that both furosemide and amiloride can attenuate AA-induced cough, although, this protective effect of inhaled diuretics may not necessarily be dependent on Na(+) K(+)-Cl- cotransporter or Na+ channel in airway epithelial cells. PMID- 7842771 TI - Peak expiratory flow rate variability in population surveys. Does the number of assessments matter? AB - We investigated the effect of reducing the number of daily peak expiratory flow (PEF) measurements on (1) the amplitude of PEF variability and (2) the relationships of this amplitude to bronchial reactivity to methacholine. One hundred seventeen workers (mean age = 38.7 years +/- 9.5; men = 86.3%) recorded their highest of three PEF measurements, every 3 waking hours, ie, 5 times a day, for 7 days, each using a newly purchased peak flowmeter (Vitalograph), and underwent methacholine challenge tests. The variability of PEF of each subject was expressed using the three sets of indices: amp%mean, ie, highest of the daily measurements considered minus the lowest/mean x 100, averaged over 6 days from the second to the seventh, amp%highest (same as amp%mean, but with the highest daily measurements as denominators) and SD%mean (calculated initially as single measures using the data of the 6 days considered, with standard deviation (SD) of each subject's PEF measurements). For each set, we used the indices constructed with the five daily measurements of each day (gold standard), with the first, third, fourth, and fifth, the first, third, and fourth, the first and third, and the first and fourth. The PEF variability was significantly reduced when reducing the number of daily measurements, only when the amp%mean and the amp%highest sets were used. No decrease was observed with the SD%mean set of indices, and SD%mean constructed with the first, third, fourth, and fifth daily measurement was satisfactory. Whatever the sort of index used, three daily measurements were sufficient to identify the group of subjects with excessive variability in relation to methacholine reactivity. PMID- 7842772 TI - Diagnostic flexible fiberoptic pleuroscopy in suspected malignant pleural effusions. AB - Up to 25% of malignant pleural effusions can remain undiagnosed following history, physical examination, thoracentesis, and percutaneous closed pleural biopsy. The next diagnostic procedure is often rigid thoracoscopy, an invasive procedure requiring an operating suite and usually a postprocedure chest tube. We performed flexible fiberoptic pleuroscopy using a fiberoptic bronchoscope in conjunction with a closed pleural biopsy on 12 patients with exudative pleural effusions that remained undiagnosed despite extensive clinical evaluation. A sterile 4.8-mm outside diameter flexible fiberoptic bronchoscope was placed into the pleural space during the course of a routine closed pleural biopsy. Pneumothorax was induced to allow visualization. Brush or forceps biopsy specimens of suspicious parietal pleural lesions were taken. Eight pleural spaces appeared smooth while four were diffusely studded on the parietal surface. Of these four, three were proven to have diffuse pleural adenocarcinoma using this procedure; the fourth proved ultimately to have pleural mesothelioma. On long term follow-up (mean = 17.7 +/- 11.4 months), no false-negative studies or unexpected morbidity was noted. Flexible fiberoptic pleuroscopy may provide a diagnosis in exudative pleural effusions when other less invasive procedures fail to do so and is well tolerated with minimal discomfort and risk. PMID- 7842773 TI - Complications of fiberoptic bronchoscopy at a university hospital. AB - STUDY OBJECTIVE: To retrospectively review the indications and complications associated with flexible fiberoptic bronchoscopy (FFB) in a university teaching hospital. DESIGN: retrospective review from April 1, 1988 to March 30, 1993. SETTING: Large tertiary care university hospital. PATIENTS OR PARTICIPANTS: We reviewed 4,273 consecutive FFBs, including 2,493 bronchoalveolar lavages and 173 transbronchial biopsy procedures. INTERVENTIONS: None. RESULTS: Most (52%) FFBs were performed for obtaining lower respiratory tract samples for evaluation of suspected infection. An additional 17% were performed to evaluate an abnormality seen on chest radiograph. The most common therapeutic indication was removal of retained secretions in 8% of FFBs. The mortality rate was 0%, and the frequency of major and minor complications was 0.5% and 0.8%, respectively. The incidence of major complications secondary to transbronchial biopsy was 6.8%. CONCLUSIONS: Flexible fiberoptic bronchoscopy can be performed safely in a teaching hospital with appropriate preparation, supervision, and adherence to protocol. PMID- 7842774 TI - Effect of external chest wall oscillation on gas exchange in healthy subjects. AB - Effective gas exchange can be maintained in animals without the need for endotracheal intubation using external chest wall oscillation (ECWO). The clinical application of this technique has been limited by equipment which was either impractical or uncomfortable. We evaluated a prototype of a new oscillator in which an oscillatory profile of negative and positive pressure was imposed on a negative baseline pressure within a cuirass. In seven healthy subjects, we identified an oscillatory cuirass pressure that could effectively ventilate but would not result in severe hypocapnia over 5 min. We then measured the influence of changing the frequency of oscillation (fo) on PaCO2 and spontaneous ventilation. Lastly, we evaluated the capability of this prototype to achieve targeted changes in chamber pressure. Subjects were ventilated with an inspiratory chamber pressure of -20 +/- 4 cm H2O, an expiratory chamber pressure of 5 cm H2O and an inspiratory-expiratory ratio of 1:1 at 9 oscillatory frequencies (fo: 1 to 5 Hz at 0.5-Hz increments). Each subject was ventilated for 5 min with consecutive periods of ECWO being separated from each other by 10 min of unassisted breathing. Oscillatory tidal volume (Vo) was sampled and PaCO2 was determined from the expired carbon dioxide concentration (FECO2) measured at the mouth. The change in PaCO2 (delta PaCO2) was the difference in PaCO2 immediately before and after ECWO. We found that delta PaCO2 and Vo were inversely related to fo. At 1 Hz the delta PaCO2 was -13 +/- 1 mm Hg and Vo was 344 +/- 34 mL in the absence of spontaneous breathing (fb = 0). At 3 Hz and above, at the chamber pressures used, the delta PaCO2 was small (-1 to -2 mm Hg) and the Vo was less than the predicted dead space. Subjects breathed spontaneously but at a frequency below that of their resting fb. With this prototype, chamber pressure changes up to 30 cm H2O could be accurately achieved at 1, 2.5, and 4 Hz. In conclusion, ECWO can provide effective ventilation among healthy adults in the presence or absence of spontaneous breathing, and further studies are warranted to explore its effectiveness in a variety of clinical circumstances. PMID- 7842775 TI - Comparison of thallium-201 and gallium-67 citrate scintigraphy in the diagnosis of pulmonary disease. AB - Gallium is presently used in the diagnosis of inflammatory, granulomatous, and neoplastic lung disease despite its many logistical problems. In contrast, thallium-201 scintigraphy, which was initially developed for myocardial imaging, offers the principal advantage of immediate imaging and diagnosis although it had not been investigated previously for use in pulmonary disease. In this study, thallium and gallium were prospectively compared with each other for the diagnosis of a variety of lung diseases. The overall concordance rate was 75%. Thallium was found to be significantly more sensitive than gallium for the entire group studied (N = 51, p < 0.006). In a subset of patients in whom a firm diagnosis was established, thallium was also found to be more sensitive, 86% vs 64%. The greater sensitivity of thallium-201 and its several inherent advantages suggest that thallium-201 should replace gallium-67 citrate as the radioisotope of choice for nuclear imaging of the chest. PMID- 7842776 TI - Outbreak of tuberculosis in a church. AB - A 48-year-old white man (index case) with an abnormal chest radiograph remained undiagnosed for tuberculosis for 4 years. Investigation by purified protein derivative (PPD) tuberculin test revealed positive tuberculin reactions (> or = 10 mm induration) in seven of eight (88%) initial close contacts, and in 12 of 46 (26%) coworkers. On the suspicion that transmission had also occurred among members of the index case's church congregation, a PPD tuberculin test survey of 184 of 200 of the members revealed 77 (42%) positive reactors. Thirty percent of the members under the age of 35 years were infected, suggesting transmission of infection. Eight cases of active tuberculosis (including the index case) were detected, yielding a high case rate (4.3%) among the parishioners. Three of the cases were confirmed recent PPD converters. Although bacteriologic findings were available in only three of the eight cases, two cases had phage typing of organism identical to the index case; the third had recrudescent tuberculous disease. Of the remaining five cases without bacteriologic confirmation, two had pleural tuberculosis, one child had progressive primary tuberculosis, and two persons had localized pulmonary nodules suggestive of primary infection progressing to disease. Because transmission of tuberculous infection may occur in any closed environment, including a church, physicians must be conversant with tuberculosis control measures and preventive therapy guidelines to preclude unforeseen transmission of disease. PMID- 7842777 TI - Postgastrectomy aspiration pneumonia. AB - One hundred eighty-six patients who had undergone total gastrectomy were analyzed in regard to pulmonary aspiration. Sixteen patients (8.6%) with recurrent respiratory tract inflammation (r-RTI) and 45 patients (24.2%) with sporadic RTI (s-RTI) were observed. The r-RTI group frequently showed symptoms related to esophageal reflux among the many factors affecting the onset of disease. They were also characterized by marked inflammatory responses with various and atypical clinical courses. The swallowing provocation test showed swallowing disturbances (prolonged latency) in patients with r-RTI. We concluded that the aspiration of esophageal reflux contents was the most important risk factor of recurrent pulmonary complications in patients with total gastrectomy. PMID- 7842778 TI - Risk factors for adverse outcome in persons with pneumococcal pneumonia. AB - OBJECTIVE: To identify risk factors for death and respiratory failure in persons with penicillin-sensitive pneumococcal bacteremia and pneumonia from data available at initial clinical evaluation. DESIGN: Retrospective chart review of persons with pneumococcal bacteremia and pneumonia. SETTING: Tertiary care medical center (University of California Davis Medical Center, Sacramento). PATIENTS: One hundred two consecutive adults admitted to the hospital for treatment of pneumococcal pneumonia with bacteremia. RESULTS: Of 102 persons, 25 (25%; 95% confidence interval [CI], 17 to 34%) died and 17 (16%; 95% CI, 10 to 25%) survived mechanical ventilation for respiratory failure. In univariate analyses, persons with preexisting lung disease (relative risk [RR], 2.0; 95% CI, 1.3 to 3.1), initial body temperature < 38 degrees C (RR, 2.1; 95% CI, 1.3 to 3.6), or nosocomial infections (RR, 2.5; 95% CI, 1.8 to 3.6) or who were > or = 48 years old (RR, 2.7; 95% CI, 1.5 to 4.8) were at greater risk for adverse outcomes than persons without these risk factors. Of 25 persons without these risk factors, only one (4%; 95% CI, 0 to 20%) died, and the remaining 24 persons did not require intensive care. Using these risk factors in a multivariate logistic model, death or respiratory failure would have been predicted in 67% of persons and better outcome predicted in 83% of the persons. In multivariate analysis, nosocomial infection was the greatest risk factor (adjusted odds ratio, 17.3; 95% CI, 3.1 to 98). CONCLUSIONS: Risk factors identified at hospital admission can predict the outcome in persons with pneumococcal pneumonia and bacteremia. Identifying these factors may allow earlier use of intensive care or more aggressive treatment. Independent of age, nosocomially acquired infections were the greatest risk factor for death or respiratory failure. PMID- 7842779 TI - The tissue polypeptide antigen serum test in the preoperative evaluation of non small cell lung cancer. Diagnostic yield and comparison with conventional staging methods. AB - Tissue polypeptide antigen (TPA) is a protein produced and released by proliferating cells that has been shown to possess several characteristics for an ideal tumor marker. Our purpose was to determine the yield of TPA in the pretreatment assessment of non-small cell lung cancer (NSCLC), in comparison with a baseline clinical evaluation and multiorgan computed tomography (CT) assumed to be the gold standard for presurgical staging. One hundred four patients with NSCLC underwent thoracotomy, mediastinoscopy, or biopsy of suspected metastatic deposits, in addition to an extensive noninvasive evaluation of their stage of disease. We restaged retrospectively (UICC 1987 classification) these patients, on the basis of the following: (1) clinical history and physical examination, routine laboratory tests, bronchoscopy, chest radiographs, and any other examination as indicated by the prior baseline evaluation (BE stage); (2) the serum level of TPA (TPA stage); (3) the reading of a CT scan of brain, thorax, and abdomen obtained with no limitation to clinical information (CT stage); and (4) pathologic findings (RE stage). The TPA stage was calculated using 20 threshold values ranging from 45 U/L to 450 U/L. On the basis of the RE stage, sensitivity, specificity, accuracy, and predictive capabilities of BE, CT, and TPA were determined for stage I and II (full operability, FO), stage IIIa (possible operability, PO), and stage IIIb and IV (full inoperability, FI). The TPA thresholds were 110 U/L for detecting FO with the highest rate of success, and 160 U/L for detecting FI. Using these thresholds BE, CT, and TPA showed a diagnostic accuracy of, respectively, 75%, 79%, and 68% for FO; 87%, 69%, and 77% for PO; 87%, 77%, and 76% for FI. The accuracy of BE, CT, and TPA for both FO and FI was, respectively, 85%, 69%, and 69%. Of 74 patients classified operable by BE, 6 had a serum concentration of TPA less than 50 U/L and all 6 were confirmed in stage I or II at the subsequent thoracotomy; 15 others, out of 26 patients judged to have inoperable conditions by BE, had a TPA test result above 135 U/L and all 15 were pathologically classified in stage IIIb or IV. Using appropriate threshold values of TPA, it should be possible to predict NSCLC resectability with a diagnostic accuracy similar to that routinely achieved by CT. PMID- 7842780 TI - Asbestos-related rounded atelectasis. Radiologic and mineralogic data in 23 cases. AB - A retrospective study was conducted in 23 subjects with previous occupational exposure to asbestos and exhibiting rounded atelectasis (RA) on high-resolution computed tomography scan (HRCT scan) to evaluate the retention of asbestos bodies (ABs) using light microscopy in the bronchoalveolar lavage (BAL) fluid or lung parenchyma in such patients. A total of 31 RAs were identified, usually located in the lower (25 RAs) and posterior (23 RAs) parts of the lung. Pleural thickening in contact with the RA was observed in 27 RAs and parenchymal bands were detected in 15 cases. Twelve of the 20 patients who underwent BAL or surgery exhibited significant retention of ABs in BAL fluid or lung tissue. Moreover, a significant retention of ABs was observed in five of nine patients with a history of asbestos exposure but no diffuse pleural thickening on chest radiograph or interstitial opacities on HRCT scan. Patients with RAs and coexisting diffuse pleural thickening and/or interstitial fibrosis should be considered at a higher risk for lung cancer in comparison to patients with isolated circumscribed pleural plaques based on increased AB counts. By contrast, the excess risk of lung cancer is more questionable in patients with only RAs and circumscribed pleural plaques as they may have AB counts either above or below that associated with pleural plaques alone. This emphasizes the need for further follow-up studies to define criteria indicating the need for thoracotomy in these subjects. PMID- 7842781 TI - Empiric prednisone therapy for pulmonary toxic reaction after high-dose chemotherapy containing carmustine (BCNU). AB - STUDY OBJECTIVE: To determine pretreatment factors that predict for pulmonary toxic reactions after high-dose chemotherapy containing carmustine (BCNU) and to determine the utility of prednisone in preventing pulmonary toxic reactions. DESIGN: Retrospective review. SETTING: Tertiary care referral center. PATIENTS: Forty-five patients with relapsed or refractory lymphoma and 27 patients with breast cancer with normal cardiopulmonary function were treated with one of two high-dose combination chemotherapeutic regimens containing the same dose of BCNU. MEASUREMENTS: Recorded pretreatment patient characteristics included previous chemotherapy or radiation therapy, history of pulmonary metastases, history of chronic obstructive pulmonary disease, and history of smoking. Spirometry and single-breath carbon monoxide diffusing capacity (DCO) were obtained before and after high-dose chemotherapy. INTERVENTIONS: Patients were treated with prednisone for a 5% or more drop in postchemotherapy DCO whether or not symptoms were present. RESULTS: Fifty-nine patients were evaluable. No pretreatment characteristic predicted for declines in pulmonary function postchemotherapy. The FEV1/FVC ratio did not change significantly after high-dose chemotherapy, but the DCO decreased 12.1% (p < 0.001). Of the 59 evaluable patients, 30 were treated with prednisone for declines in postchemotherapy DCO. Sixteen (53%) of these 30 patients were asymptomatic. The DCO increased 10.3% in patients treated with prednisone compared with a decrease of 2.3% in patients not treated (p = 0.017). There was no statistically significant difference in FEV1/FVC in patients treated with prednisone compared with those not treated. Regression analysis of pretreatment characteristics, type of high-dose chemotherapy received, and treatment with prednisone identified only treatment with prednisone as a significant variable in predicting an increase in DCO (p = 0.03; regression coefficient = +11.5%, SE = +/- 5.2%) after high-dose chemotherapy containing BCNU. CONCLUSIONS: High-dose BCNU-containing chemotherapeutic regimens cause decreases in DCO that are often asymptomatic and likely represent subclinical pulmonary toxic reactions. Pretreatment clinical parameters cannot predict which patients will manifest pulmonary toxic reactions after high-dose chemotherapy. Empiric treatment with prednisone will reverse chemotherapy-induced decreases in DCO. Earlier institution of glucocorticoids for evidence of pulmonary dysfunction is recommended. PMID- 7842782 TI - Incidence of tricuspid regurgitation and vena caval backward flow in mechanically ventilated patients. A color Doppler and contrast echocardiographic study. AB - In 40 patients requiring mechanical ventilation for an episode of respiratory failure of various causes, prevalence of tricuspid regurgitation (TR) or other cause of vena caval backward flow (VCBF) was systematically investigated using transthoracic Doppler echocardiography. Quantification of TR was obtained from planimetry of the regurgitant jet during color Doppler examination. The influence of cyclic mechanical lung inflation was examined by contrast echography of the inferior vena cava and hepatic veins. All the 40 patients studied had TR, which was mild in 21, moderate in 9 and severe in 10. Using a planimetric scale, TR was more marked during mechanical ventilation, when compared with a brief period of spontaneous breathing. Moreover, contrast echocardiography demonstrated that systolic TR reached inferior vena cava and hepatic veins in 16 cases, and also evidenced direct mechanical action of lung inflation producing a pancardiac VCBF in 15 cases. This high incidence of TR and VCBF partially may explain the relatively poor reliability of the thermodilution method for measurement of cardiac output when used in ventilated patients. PMID- 7842783 TI - Outcome of patients cared for in a ventilator-dependent unit in a general hospital. AB - We describe our initial experience with the admission of 129 patients for 132 episodes of ventilator-dependence to a self-contained ventilator-dependent unit (VDU) in a general hospital and present a survival comparison between VDU patients and a historic control population from the same institution. Forty-three patients were screened and denied admission to the VDU because long-term ventilator dependence was not felt to be a probable outcome (56%); they were medically unstable, often requiring electrocardiographic monitoring (19%), they had poor rehabilitation potential because of markedly depressed mental status (13%), or they preferred to be treated closer to their homes (12%). Thirteen (9.8%) of the VDU patients died in the hospital compared to 44 (42%) in the historic control group. After exclusion of patients with multiorgan failure (who made up 26% of the control group) and using a proportional hazard model to adjust for group differences in age and disease class, the difference in hospital mortality remained highly significant (p < or = 0.01). Ninety-one of the 119 VDU patients (77%) were ultimately able to return home; 16 (13%) continued to use a ventilator intermittently at night; 26 patients (22%) were permanently placed in nursing homes, all off of the ventilator. Overall, 88% of the 119 patients discharged had been liberated from mechanical ventilation. Ninety-seven (82%) and 86 (72%) remain alive 1 and 2 years after discharge, respectively. Some of the survival benefits may be directly attributed to the VDU. Others reflect a change in treatment philosophy, which was nevertheless reinforced by our VDU experience. PMID- 7842784 TI - Predictors of weaning after 6 weeks of mechanical ventilation. AB - STUDY OBJECTIVE: To identify variables associated with weaning outcome in long term ventilator-dependent patients. Using those variables, to construct models to predict weaning success and to test the accuracy of those models. DESIGN: Retrospective medical record review. SETTING: Regional weaning center (RWC). PATIENTS: An initial group of 421 and a subsequent group of 170 consecutive patients referred for attempted weaning after 6 weeks of mechanical ventilation. MEASUREMENTS AND RESULTS: Data obtained on admission to our facility were analyzed for correlation with weaning outcome. In the initial patient group, selected variables which correlated with weaning success were alveolar-arterial oxygen pressure difference (P[A-a]O2), BUN, BUN/creatinine ratio (each with p < or = 0.001), and female gender (p = 0.04). We used these variables in logistic regression models to predict weaning success in this population. We then tested the models in the 170-patient validation group using both standard and receiver operating characteristic (ROC) curve analysis. The ROC analysis indicated 59% accuracy using P(A-a)O2 alone and 68% accuracy using all previously mentioned variables. We used data from all 565 patients with known outcome and omitted BUN/creatinine ratio to fashion a simple scoring system to predict weaning success with 70% accuracy using P(A-a)O2, BUN, and Gender--the A+B+G score. CONCLUSION: In patients suffering prolonged mechanical ventilation, models incorporating simple measurements allowed construction of a score to predict weaning success at our RWC. PMID- 7842785 TI - Outcome of intensive care in patients with HIV infection. AB - OBJECTIVES: To examine ICU admission rates and diagnoses of patients with HIV infection and to determine the outcomes of different critical illnesses. DESIGN: Consecutive enrollment of patients admitted to the ICU with confirmed HIV infection or an AIDS-defining diagnosis. SETTING: Medical ICU of an urban teaching hospital. PATIENTS: 65 adult patients with documented HIV infection or AIDS-defining disorder. INTERVENTIONS: Standard care. RESULTS: In 1 year, there were 1,550 hospital admissions for patients with HIV infection, and 65 (4.2%) were admitted to the ICU. The mortality rate of patients admitted to the ICU was 51%; 35 (54%) were admitted with respiratory failure, 22 of whom had Pneumocystis carinii pneumonia (PCP). Sixteen patients with PCP required mechanical ventilation, and 13 (81%) died despite treatment with adjunctive corticosteroids. Other causes of respiratory failure included bacterial pneumonia, pulmonary tuberculosis, adult respiratory distress syndrome, and pulmonary Kaposi's sarcoma. Overall, 22 of 35 (63%) patients with respiratory failure died in the hospital. Thirty patients (46%) were admitted because of sepsis, neurologic disease, congestive heart failure, hypotension, or drug overdose. These patients had a mortality rate of 37%. Prior antiretroviral and anti-Pneumocystis prophylaxis did not influence outcome, but a body weight of 10% or more below ideal at the time of admission predicted poor survival. CONCLUSION: There is a diverse range of indications for critical care in patients with HIV infection. Although respiratory failure due to PCP was the most common reason for admission to the ICU, it accounted for only 34% of the cases. The prognosis of PCP in patients who require mechanical ventilation despite adjunctive corticosteroid treatment is poor. PMID- 7842786 TI - Prognostic factors of pneumonia requiring admission to the intensive care unit. AB - All patients with severe pneumonias (community-acquired and nosocomial) who required treatment in the intensive care unit (ICU) were included in a 3-year prospective study. Predictive factors for a fatal outcome were analyzed in 127 patients. An etiologic diagnosis was made in 70 (55.1%) patients. Culture of sputum or tracheobronchial secretions were used only as criteria for microbiologic diagnosis of Legionella pneumophila. The pathogens most frequently identified were L pneumophila, Streptococcus pneumoniae, and Pseudomonas aeruginosa. Viruses were not detected as causative agents. A total of 54 patients died (mortality rate, 42.5%). The univariate analysis showed the following factors associated with mortality: advanced age (> or = 70 years); presence of septic shock, requirement of mechanical ventilation, and Simplified Acute Physiology Score [SAPS] index > 12 at the time of admission to the ICU or when symptoms appeared in patients already admitted to the ICU; development of any complication during ICU hospitalization; and P aeruginosa as the etiologic agent of the pneumonia. When all variables were introduced by a stepwise method, the final model included advanced age (> or = 70 years), SAPS index > 12, presence of septic shock, requirement of mechanical ventilation, bilateral pulmonary involvement, and P aeruginosa as the etiologic agent of pneumonia as prognostic factors associated with a fatal outcome. PMID- 7842787 TI - Pulmonary complications of hyponatremic encephalopathy. Noncardiogenic pulmonary edema and hypercapnic respiratory failure. AB - OBJECTIVE: To determine the causes of hypoxia in patients with hyponatremic encephalopathy. DESIGN: Retrospective cohort study. SETTING: Consultation and referral service of two university medical centers and community hospitals. PATIENTS: Forty adults with postoperative hyponatremic encephalopathy and hypoxia of whom 30 had noncardiogenic pulmonary edema and 10 had hypercapnic respiratory failure. MAIN MEASUREMENTS: We evaluated the chest radiographs and measured plasma electrolytes, arterial blood gas values, pulmonary artery pressure, pulmonary capillary wedge pressure (PCWP), cardiac output, and net fluid retention. RESULTS: Forty patients with hyponatremic encephalopathy had hypoxia (arterial PO2 below 70 mm Hg), of whom 30 had pulmonary edema and 10 had hypercapnia (PCO2 above 50 mm Hg). Among the 30 patients with pulmonary edema, the serum sodium (+/- SD) was 114 +/- 7 mmol/L, arterial pH was 7.24 +/- 0.16, PCO2 was 45 +/- 15 mm Hg, and PO2 was 42 +/- 16 mm Hg. The cardiac index was 3.6 +/- 0.4 L/min/M2, pulmonary artery pressure was 26/16 mm Hg, and PCWP was 12 +/- 6 mm Hg. There was pulmonary edema, with normal heart size. The hypoxic patients who did not have pulmonary edema had significant hypercapnia (PCO2 = 91 +/- 29 mm Hg, p < 0.001). CONCLUSIONS: Patients with postoperative hyponatremic encephalopathy can develop hypoxia by at least two different mechanisms: noncardiogenic pulmonary edema or hypercapnic respiratory failure. PMID- 7842788 TI - Roundtable Conference on Clinical Trials for the Treatment of Sepsis. Brussels, March 12-14, 1994. PMID- 7842789 TI - Current status of thrombolysis in acute myocardial infarction. Part II. Optimal utilization of thrombolysis in clinical subsets. PMID- 7842790 TI - Clinical implications of gene therapy for alpha 1-antitrypsin deficiency. PMID- 7842791 TI - Comparison of wedge to forceps videothoracoscopic lung biopsy. Gross and histologic findings. AB - BACKGROUND: The decreased morbidity and rapid recovery after thoracoscopic lung biopsy compared with open lung biopsy by thoracotomy is increasingly recognized, as is the ability to obtain satisfactory diagnostic material thoracoscopically. To our knowledge, however, there has been no systematic comparison of specimen quality using different thoracoscopic biopsy techniques. The purpose of this study was to compare histologic features of lung parenchyma obtained by videothoracoscopic forceps and wedge biopsy techniques. METHODS: Five adult swine were anesthetized, intubated, and ventilated. Sequential left and right videothoracoscopies were performed to obtain biopsy specimens of lung parenchyma using 5-mm endoscopic cupped forceps. Specimens were obtained from fully inflated lung and from partially atelectatic (deflated) lung. Electrosurgery was applied during forceps biopsy for airleak closure. Limited wedge biopsy specimens were obtained using an endoscopic stapler. One hundred thirteen forceps biopsy specimens (55 inflated, 58 deflated) and 24 sections from 8 wedge biopsy specimens were examined. Specimens were assessed for overall histologic quality and ease of microscopic interpretation. Specific histologic features were then evaluated including presence of artifact, congestion and hemorrhage, degree of alveolar inflation, and number of bronchioles and vessels per cross-sectional area. Whole lungs from two animals were examined for extent and depth of lung injury at the areas of biopsy. RESULTS: No major differences in overall microscopic specimen quality were detected among the different techniques nor were significant differences noted between lung inflated and lung deflated forceps biopsy technique. Wedge sections contained more vessels per unit area (p < 0.001), perhaps reflecting the more peripheral nature of forceps biopsy. Small amounts of thermal or crush artifact were noted on the surface of forceps biopsy specimens, but did not affect overall specimen quality. CONCLUSIONS: Multiple 5 mm forceps biopsy specimens were of comparable quality to single wedge biopsy specimens obtained by endoscopic stapling. Although greater numbers of vessels were present in endoscopic stapled wedge biopsy specimens, multiple forceps biopsy specimens in fact, contain amply sufficient vessels for histologic analysis. PMID- 7842792 TI - An 83-year-old with subcutaneous emphysema and bilateral pneumothorax. PMID- 7842793 TI - Fever, multiple pulmonary nodules, and ulcerated skin lesions in a patient with AIDS. PMID- 7842794 TI - Bronchoscopic therapy in patients with intraluminal typical bronchial carcinoid. AB - OBJECTIVE: To study the efficacy of bronchoscopic therapy in patients with intraluminal typical bronchial carcinoid. DESIGN: Retrospective analysis of the data of patients with bronchial carcinoid, treated primarily with bronchoscopic techniques such as Nd-YAG laser in various hospitals in the Netherlands. SUBJECTS: Eleven patients with pulmonary complaints, ages 22 to 60 years, who were found to have intraluminal typical bronchial carcinoid. BRONCHOSCOPIC INTERVENTIONS: Six of the 11 patients received Nd-YAG laser treatments, one received Nd-YAG laser plus photodynamic therapy, and the other four had mechanical tumor removal. RESULTS: Six patients were surgically treated after bronchoscopic therapy. The resected specimens showed no residual carcinoid. Median follow-up has been 70 months (range, 9 to 170 months). Five patients were not surgically treated after bronchoscopic therapy. Follow-up has been 27 to 246 months (median, 47 months) without signs of recurrence. CONCLUSIONS: In 11 patients with typical, intraluminal, bronchial carcinoids, bronchoscopic treatment seemed to result in excellent local control, with surgical proof of cure in 6 of 11 patients. Bronchoscopic approach may provide a tissue-sparing alternative for bronchoplastic surgery in a subset of patients with typical intraluminal bronchial carcinoids. PMID- 7842795 TI - Thoracoscopic surgery as a routine procedure for spontaneous pneumothorax. Results from 82 patients. AB - A total of 82 consecutive patients with recurrent or persistent spontaneous pneumothorax were considered for thoracoscopic blebectomy or bullectomy and pleurodesis. The median age was 47 years, and 70% were men. All the patients were successfully treated using a video-assisted thoracoscopic technique. There were no deaths attributable to the procedure. Complications occurred in 6 patients (7.3%). Three patients (4%) with diffuse bullous lung disease had prolonged intubation (9, 11, and 12 days, respectively). Persistent air leaks lasting from 10 to 14 days occurred in 2 patients (3%). One patient had an endoloop slip from the lung parenchyma after a forceful sneeze 2 days after the operation. Air leak subsided after the second operation using a conventional suturing technique. Blebs or bullae were present in 69 patients (83%). These were ablated by endoscopic stapling (37 patients) and through thoracoscopic ligation using an endoloop technique (32 patients). In this group of patients, the median postoperative hospital stay was 5 days. Thirteen patients with air leaks and diffuse bullous lung disease received only talc insufflation thoracoscopically. All of them showed good lung expansion after the operation. There are no recurrences, with a mean follow-up of 22 months. These results suggest that thoracoscopic ablation of blebs or bullae and pleurodesis may be applicable to patients with spontaneous pneumothorax who require surgical intervention. PMID- 7842796 TI - Status asthmaticus with acute decompensation with therapy in a 27-year-old woman. PMID- 7842797 TI - Right ventricular pseudoaneurysm as a complication of endomyocardial biopsy after heart transplantation. AB - A case of right ventricular pseudoaneurysm occurring 8 days after orthotopic heart transplantation as a result of routine right ventricular biopsy is reported herein. To our knowledge, this is the first report of such a complication. PMID- 7842798 TI - Unilateral hyperlucency with left lower lobe mass in a patient with bronchial asthma. AB - Mucoepidermoid tumors are rare bronchial adenomas whose clinical presentation can mimic that of bronchial asthma. Bronchial adenoma should be included in the differential diagnosis of a patient with a persistent radiographic abnormality and clinical features of bronchial asthma. We present an adolescent female with a history suggestive of bronchial asthma and a persistent left lower lobe atelectasis, who later was found to have a low-grade mucoepidermoid tumor. PMID- 7842799 TI - Resolution of obstructive sleep apnea after microvascular brainstem decompression. AB - Lesions of the brainstem have been associated with obstructive sleep apnea in previous reports. We now report a case in which retromastoid craniectomy with microvascular decompression of the medulla and ninth and tenth cranial nerves resulted in the complete resolution of severe obstructive sleep apnea. Possible mechanisms for this observation are discussed. PMID- 7842800 TI - Exercise-associated cardiac asystole in persons without structural heart disease. AB - Exercise-associated cardiac asystole (EACA) in patients without structural heart disease is uncommonly encountered. Two patients who developed prolonged asystolic arrest associated with exercise are described; both demonstrated a positive head up tilt table response, absence of underlying heart disease, and a history of vagotonia. A review of this condition in the literature suggests the occurrence of this syndrome of EACA in young men with atheletic inclination who developed syncope usually after a strenuous exercise at a high heart rate. Although the described patients usually responded by avoiding maximal exercise and the use of beta-blockade, vagolytic agent, and permanent pacing, EACA may be the link for some cases of exercise-related asystolic deaths. PMID- 7842802 TI - The Churg-Strauss syndrome. A case report with angiographically documented coronary involvement and a review of the literature. AB - The Churg-Strauss syndrome (CSS) is an unusual disease that presents as a systemic vasculitis and peripheral eosinophilia in a patient with chronic atopic disease. Although often not prominent on initial presentation, cardiac involvement is a major cause of morbidity and mortality in patients with CSS. We report a case of a young woman with CSS who had a myocardial infarction. Coronary arteriography was performed for recurrent chest pain and demonstrated diffuse vasculopathy consistent with vasculitis in CSS. We have also included a review of the literature on cardiac involvement in CSS. PMID- 7842801 TI - Familial cryptogenic fibrosing pleuritis with Fanconi's syndrome (renal tubular acidosis). A new syndrome. AB - We describe two siblings with a progressive unrelenting and unique syndrome of bilateral fibrosing pleuritis of unknown cause occurring in association with Fanconi's syndrome (renal tubular acidosis). The parents of the siblings were second cousins. Both siblings had identical pleural histologic characteristics and identical urinary metabolic defects. This condition resulted in the development of severe respiratory failure in both patients and ultimately the death of the older sibling at the age of 21 years. PMID- 7842803 TI - More on thoracic neoplasms related to Lucite sphere plombage. PMID- 7842804 TI - Pneumatosis intestinalis and active cytomegaloviral infection after lung transplantation. PMID- 7842805 TI - Describing a pneumothorax. PMID- 7842806 TI - Should supplemental estrogen be used as steroid-sparing agents in women with asthma? PMID- 7842807 TI - Management of obstructive sleep apnea. PMID- 7842808 TI - OSA treatment UPPP vs N-CPAP. PMID- 7842809 TI - N-CPAP in patients with COPD in acute respiratory failure. PMID- 7842810 TI - Efficacy of breathing and coughing exercises in the prevention of pulmonary complications after coronary artery surgery. PMID- 7842811 TI - Pulmonary involvement in patients with HFRS. PMID- 7842812 TI - What causes CD4+ T-lymphocytopenia? PMID- 7842813 TI - You need more than nocturnal NIPPV to manage Duchenne's muscular dystrophy. PMID- 7842814 TI - New therapies for cystic fibrosis. Introduction. PMID- 7842815 TI - Aerosol delivery of antibiotics to the lower airways of patients with cystic fibrosis. AB - Aerosolized tobramycin is well tolerated in children and adults with cystic fibrosis (CF). It represents a potential alternative to intravenous administration of antibiotics to control respiratory infection with Pseudomonas aeruginosa. Although its exact role in acute therapy for a CF exacerbation is not known, it has been shown to improve lung function and reduce the frequency of exacerbations in the chronic stable outpatient. PMID- 7842816 TI - Aerosolized recombinant human DNase I for the treatment of cystic fibrosis. AB - Respiratory symptoms, recurrent infectious exacerbations, and progressive lung destruction in cystic fibrosis can be attributed to bacterial persistence and the accumulation of viscous purulent secretions in the airways. Purulent secretions contain high concentrations of extracellular DNA, a viscous material released by leukocytes. To evaluate the potential clinical utility of recombinant human DNase I (rhDNase or Pulmozyme), the human enzyme was cloned, sequenced, and expressed. In in vitro studies, rhDNase has been shown to reduce the viscoelasticity, reduce the adhesiveness, and improve the mucociliary transportability of cystic fibrosis sputum. In short-term phase 1 and phase 2 clinical trials, rhDNase has been shown to be safely tolerated and to improve the FEV1, FVC, and symptoms of dyspnea. A long-term placebo-controlled phase 3 study was performed in 968 adults and children (> or = 5 years) with cystic fibrosis to determine the effect of rhDNase on the risk of respiratory exacerbations requiring parenteral antibiotics and on the FEV1. Compared with placebo-treated patients, patients treated with rhDNase once daily or twice daily experienced a reduced risk of respiratory exacerbations by 28% (p = 0.04) and 37% (p = 0.01), respectively, and had a mean improvement in FEV1 of 5.8% (p < 0.01) and 5.6% (p < 0.01), respectively. Compared with placebo treated patients, patients treated with rhDNase spent 2.7 fewer days receiving parenteral antibiotics (p = 0.04) and spent 1.3 fewer days in the hospital (p = 0.06) over the 6-month treatment period. Inhalation of rhDNase did not cause anaphylaxis but was associated with upper airway symptoms (ie, voice alteration, hoarseness, pharyngitis) that were generally mild and transient. In conclusion, aerosol administration of rhDNase was safely tolerated, reduced the risk of infectious exacerbations requiring parenteral antibiotics, and improved pulmonary function and patient well-being. PMID- 7842817 TI - Pharmacologic treatment of abnormal ion transport in the airway epithelium in cystic fibrosis. AB - Cystic fibrosis (CF) is a recessive genetic disease reflecting mutations in the gene coding for the CF transmembrane regulator (CFTR) protein, which normally functions as a cyclic adenosine monophosphate (cAMP)-regulated chloride (Cl-) channel. Functional abnormalities include thick airway secretions resulting from defective cAMP-mediated Cl- (liquid) secretion and a related defect, excessive sodium (Na+) (liquid) absorption. Novel pharmacologic agents are being tested as therapy for these ion transport defects. Aerosolized amiloride inhibits excessive Na+ absorption, and pilot studies in adult patients with CF show slowing of the disease-associated decline in lung function. Clinical trials of amiloride are currently underway in adults and adolescents, and short-term safety studies have been initiated in children. Aerosolized uridine triphosphate (UTP) induces Cl- (and liquid) secretion in CF airway epithelia via non-CFTR Cl- channels. Short term aerosolized UTP is well tolerated by normal subjects and patients with CF, and pilot studies in normal subjects show that aerosolized UTP is an effective stimulator of mucociliary clearance. Pharmacotherapy that modifies airway epithelial ion transport may provide new opportunities for treatment of CF lung disease. PMID- 7842818 TI - Gene therapy for cystic fibrosis. AB - Following the cloning of the cystic fibrosis (CF) gene, in vitro studies rapidly established the feasibility of gene therapy for this disease. Unlike ex vivo approaches that have been utilized for other genetic diseases such as adenosine deaminase deficiency, gene therapy for CF will likely require direct in vivo delivery of gene transfer vectors to the airways of patients with CF. Hence, major research efforts have been directed at the development of efficient gene transfer vectors that are safe for use in human subjects. Several vectors have now emerged from the laboratory for evaluation in clinical safety and efficacy trials in the United States and in the United Kingdom. Adenovirus-mediated gene transfer has been utilized for initial clinical safety and efficacy trials in the United States, while liposome-mediated gene transfer has been chosen for initial clinical safety and efficacy trials in the United Kingdom. The rationale and laboratory studies are reviewed leading to initial clinical safety and efficacy trials. Also reviewed are the currently available vectors for potential use in clinical studies, their advantages and disadvantages, and the promises and pitfalls of current gene therapy efforts for CF in the United States focusing on adenovirus vectors in current clinical trials. PMID- 7842819 TI - Hemodialysis removal of norfloxacin. AB - The effect of hemodialysis on norfloxacin removal was evaluated in 7 patients. Single 800-mg doses of the drug were given to the subjects prior to dialysis using cuprophan hollow fiber dialyzers. Arterial and venous sample pairs were obtained at hourly intervals during treatment. Norfloxacin plasma concentrations were determined by HPLC. The mean hemodialysis clearance and extraction ratio were 38.84 +/- 10.92 ml/min and 0.19 +/- 0.06, respectively. Small differences in these parameters were observed between dialyzers with different surface areas (p > 0.05) and also between treatments using different blood flow rates (p > 0.05). Since a relatively small amount of norfloxacin is removed by hemodialysis, dosage adjustment is not necessary to compensate for the extracorporeal removal. PMID- 7842820 TI - Agar disk diffusion (Bauer-Kirby) tests with various fastidious and nonfastidious reference (ATCC) strains: comparison of several agar media. AB - Several agar media (Mueller-Hinton agar, MHA; diagnostic sensitivity test agar, DSTA; Schaedler agar, SchA; Todd-Hewitt agar with added yeast extract, THYA; Wilkins-Chalgren agar, WCA) were compared using the Bauer-Kirby agar disk diffusion test against six nonfastidious quality control strains: Staphylococcus aureus ATCC 25923 and ATCC 29213, Escherichia coli ATCC 25922 and ATCC 35218, Pseudomonas aeruginosa ATCC 27853, and Enterococcus faecalis ATCC 29212. MHA, DSTA, and THYA yielded essentially comparable inhibition zones. However, WCA and SchA antagonized cotrimoxazole and aminoglycoside antibiotics; furthermore, SchA antagonized polymyxin B, and both WCA and SchA antagonized imipenem against the P. aeruginosa strain, but not against the E. coli strains. Sheep blood-MHA (Bl MHA), WCA, THYA, and DSTA were examined with Streptococcus pyogenes ATCC 19615, Streptococcus agalactiae ATCC 13813, and Streptococcus pneumoniae ATCC 6306. In comparison with Bl-MHA, both WCA and THYA yielded comparable inhibition zones against S. pyogenes; DSTA afforded suboptimal growth. DSTA yielded larger inhibition zones with the majority of antimicrobial drugs against S. agalactiae, whereas WCA and THYA enhanced the activity of oxacillin and penicillin G against this strain. S. pneumoniae strain ATCC 6306 grew well on Bl-MHA, yielded suboptimal growth on WCA and faint growth on THYA, and failed to grow on DSTA. Chocolate-supplemented sheep blood-MHA (CHOC-MHA) was compared with Haemophilus test medium (HTM), WCA with added NAD, and THYA with added hematin and NAD against Haemophilus influenzae strains ATCC 35056 and ATCC 49247. The activities of doxycycline and rifampin were enhanced against both strains by HTM, WCA+NAD, and THYA+hematin+NAD. Only WCA+NAD antagonized cotrimoxazole against both H. influenzae strains, an effect due to thymidine; however, HTM antagonized cotrimoxazole against S. aureus ATCC 25923 and E. coli ATCC 25922. It was concluded that Bl-MHA performed best for beta-hemolytic streptococci quality control strains. Likewise, CHOC-MHA was optimal for the two H. influenzae strains used in this comparative agar disk diffusion study. PMID- 7842821 TI - Antibacterial activity of cefepime in vitro. AB - Cefepime is a new parenterally active fourth-generation cephalosporin which is undergoing in vitro and in vivo evaluations. Using the standard agar dilution method we compared the in vitro activity of this drug with other cephalosporins and ciprofloxacin against clinical isolates of Escherichia coli (98 strains), Klebsiella pneumoniae (99 strains), Acinetobacter spp. (24 strains), Pseudomonas aeruginosa (98 strains), Haemophilus influenzae (108 strains), Staphylococcus aureus (100 strains), Enterococcus spp. (45 strains), Streptococcus pneumoniae (10 strains), Streptococcus pyogenes (group A; 19 strains) and Streptococcus agalactiae (group B; 36 strains). Cefepime showed excellent activity against E. coli and K. pneumoniae, inhibiting 90% of these isolates at 0.12 mg/l. The in vitro activity of cefepime was superior to or comparable to the third-generation cephalosporins tested but was inferior to ciprofloxacin against Acinetobacter spp. and P. aeruginosa. Against H. influenzae, whether or not the strains produced beta-lactamase, its activity was similar to comparable drugs. All 84 isolates of methicillin-susceptible S. aureus were inhibited by 8 mg/l of cefepime whereas, like other cephalosporins, it had little activity against methicillin-resistant S. aureus. Of the 45 enterococci isolates tested, 44.4% were inhibited by 8 mg/l of cefepime. Against streptococci, its activity was superior to any drug tested. This in vitro study indicates that cefepime has the potential to be a valuable agent for the treatment of community- and hospital acquired cutaneous, respiratory and urinary tract infections. PMID- 7842822 TI - Comparative antimicrobial activity of FK037, cefpirome, ceftazidime and cefepime against aminoglycoside-sensitive and aminoglycoside-resistant Pseudomonas aeruginosa and Pseudomonas spp. AB - The activities of FK037, cefpirome, ceftazidime and cefepime against 71 aminoglycoside-resistant, 35 aminoglycoside-sensitive, 29 cystic fibrosis Pseudomonas aeruginosa isolates, and 31 Pseudomonas spp. strains were studied using the agar dilution technique (final inoculum 10(4) c.f.u./spot). The MIC90 for aminoglycoside-sensitive P. aeruginosa against FK037, cefpirome, ceftazidime and cefepime was 32, 16, 8 and 16 mg/l, respectively. The MIC90 for P. aeruginosa strains resistant to one or more aminoglycosides was similar for FK037, cefpirome and ceftazidime (128 mg/l) and two dilutions lower for cefepime (32 mg/l). The MIC90 for P. aeruginosa isolates highly resistant to all three aminoglycosides (MIC > or = 128 mg/l) was 64 mg/l for FK037 and cefpirome, and 32 mg/l for ceftazidime and cefepime. The MIC90 for P. aeruginosa from patients with cystic fibrosis was 32 mg/l for all four cephalosporins tested, and 8, 32 and 64 for tobramycin, gentamicin and amikacin, respectively. Xanthomonas maltophilia was resistant to all four cephalosporins and three aminoglycosides. The activity of ceftazidime and cefepime was one to two dilutions greater against P. cepacia and P. picketti than of FK037 and cefpirome. The activity of ceftazidime was two dilutions greater than the other three cephalosporins against P. fluorescens. In kinetic time kill curves against P. aeruginosa, all four cephalosporins demonstrated similar activity at 6 and 24 h when tested at 1 x MIC. At 2 x MIC, regrowth was less at 24 h for cefepime, cefpirome and FK037 than for ceftazidime. In time kill curves for P. aeruginosa, synergy was clearly demonstrated at 1/4 MIC and 1/2 MIC concentrations for FK037 and tobramycin. PMID- 7842823 TI - Susceptibility of clinically significant Haemophilus influenzae strains to oral antimicrobial agents used in Saudi Arabia. AB - The incidence of beta-lactamase production by Haemophilus influenzae strains and their susceptibility to commonly used oral antimicrobial agents were evaluated. From 1990 to 1992, 600 significant isolates of H. influenzae obtained from various hospitals throughout Saudi Arabia were identified, serotyped and tested for beta-lactamase production using cefinase discs and susceptibility to various antibiotics using the agar dilution method. The study revealed that 17% of the strains produced beta-lactamase; 21% of them were type b. The overall level of resistance was 30% to erythromycin, 28% to tetracycline, 14.3% to co-trimoxazole, 6.6% to chloramphenicol, 1.8% to amoxicillin-clavulanate and 1.5% to cefaclor. About 1.3% of the strains that did not produce beta-lactamase were resistant to ampicillin. Resistance of H. influenzae to antibiotics is increasing and in several parts of the world resistance to ampicillin has reached substantial levels particularly in type b strains. Information on resistance is needed for the appropriate selection of initial empiric therapy among patients in whom H. influenzae is a suspected pathogen. PMID- 7842824 TI - Comparative study of the effects of cefodizime and HBW 538 in potentiating the production of reactive oxygen species by human polymorphonuclear leukocytes. AB - The immunomodulatory activity of cefodizime (CDZM), an aminothiazolylcephalosporin, was compared to that of HBW 538, a derivative of the CDZM side chain at position 3 (the mercaptothiazolyl group) in respect to the production of reactive oxygen species (ROS) by human whole blood and polymorphonuclear leukocytes (PMN) in vitro. Ten-fold diluted whole blood and PMN from healthy individuals were incubated with CDZM or HBW 538 alone at the concentrations of 1, 10, or 100 micrograms/ml, or CDZM or HBW 538 at 100 micrograms/ml in combination with tumor necrosis factor-alpha (TNF-alpha) at 100 U/ml or lipopolysaccharide (LPS) at 1 microgram/ml. The production of ROS was measured by a chemiluminescence (CL) assay in which luminol was added to a mixture and after which the PMN or whole blood were stimulated with nonopsonized zymosan or phorbol myristate acetate. The following results were obtained: (1) The CL responses of whole blood and PMN were slightly but not significantly enhanced by CDZM at 100 micrograms/ml, whereas both CL responses were significantly enhanced by exposure to HBW 538 at 10 and 100 micrograms/ml. (2) The enhanced PMN CL response which followed priming with TNF-alpha or LPS was not augmented by CDZM but was significantly augmented by HBW 538. These results indicate that the ability of the HBW 538 molecule to enhance the production of ROS by stimulated PMN and to act agonistically with TNF-alpha or LPS is abrogated when HBW 538 is part of the CDZM molecule.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7842825 TI - Levofloxacin, an optical isomer of ofloxacin, has attenuated epileptogenic activity in mice and inhibitory potency in GABA receptor binding. AB - The combination of some new quinolone antibacterials with 4-biphenylacetic acid (BPAA) functionally inhibits the gamma-amino-butyric acid (GABA) receptors and thereby induces clonic convulsions. We examined the effects of ofloxacin and its optical isomers on this quinolone-induced neurotoxicity. Norfloxacin at 10(-5) M alone or at 10(-7) M in combination with BPAA (10(-4) M) inhibited [3H]muscimol binding to rat brain synaptic membranes. Ofloxacin and its optical isomers did not affect muscimol binding by themselves. While they slightly reduced muscimol binding at 10(-4) M in combination with BPAA, the inhibitory activity of the l isomer levofloxacin (DR-3355) on muscimol binding was slightly, but significantly, weaker than that of the d-isomer DR-3354 and ofloxacin. Intracisternal injection of norfloxacin (5 micrograms), ofloxacin, levofloxacin or DR-3354 (50 micrograms each) induced clonic convulsions in mice. The incidence of these convulsions was enhanced by the combination with BPAA (50 micrograms). The epileptogenic activity of levofloxacin was also weaker than that of DR-3354 or ofloxacin when quinolones were given alone or in combination with BPAA. These results suggest that epileptogenic activity of quinolones is closely related to the inhibitory potency in GABA receptor binding and that levofloxacin may have lower neurotoxicity than ofloxacin and DR-3354. PMID- 7842826 TI - Enhancement of chemosensitivity of quiescent cell populations in murine solid tumors using nicotinamide. AB - Cis-diamminedichloroplatinum(II) (CDDP) was intraperitoneally injected into mice bearing SCC VII or EMT6/KU tumors after 10 administrations of 5-bromo-2' deoxyuridine (BUdR) to label all the proliferating tumor cells. One hour later, the tumors were excised, minced and trypsinized. The tumor cell suspensions were incubated with cytochalasin B (a cytokinesis blocker). The micronucleus (MN) frequency was determined using immunofluorescence staining to BUdR. The cells that were not labeled with BUdR could be regarded as the quiescent cells. The MN frequency in total tumor cells was determined from the tumors that were not pretreated with BUdR. To modify the sensitivity to CDDP, nicotinamide was intraperitoneally injected before CDDP administration. In both tumor system, the MN frequency in quiescent cells was lower than in total cells. Nicotinamide pretreatment increased the MN frequency in total and quiescent cells in both tumor systems, especially in total cells of the SCC VII tumor. The nicotinamide injection increased the uptake of 195mPt-CDDP into the total cells, especially in the SCC VII tumor. Nicotinamide administration before chemotherapy using CDDP was considered to be effective for tumor control, especially in tumors including large acutely hypoxic fractions such as the SCC VII murine tumor. PMID- 7842827 TI - Alterations in erythrocyte membrane structure of breast cancer patients treated with CMF--a lipid profile. AB - Most of the breast cancer patients are treated with CMF which is a combination of three anticancer agents namely cyclophosphamide, methotrexate and 5-fluorouracil. The metabolites of CMF induce the level of lipid peroxides in the system, which are circulated in the blood. The present study reports the effect of CMF on the levels of cholesterol and phospholipids in erythrocytes of breast cancer patients showing a significant increase in the level of phospholipids. As the cholesterol/phospholipid ratio increases, the fluidity of the membrane decreases, thereby altering the architecture of the erythrocyte membrane in the breast cancer patients treated with CMF. PMID- 7842829 TI - Antimicrobial prophylaxis with ceftriaxone in renal transplantation. Prospective study of 170 patients. AB - Due to their uremic state and altered host response induced by immunodepressive therapy, renal transplant recipients are particularly susceptible to infectious complications with high morbidity and mortality. We here report the results of a prospective study with 170 renal transplant patients, undertaken to evaluate the efficacy of ceftriaxone in the prevention of wound and early urinary tract infection. No wound infection was observed, however, 12 patients (7.1%) developed urinary tract infections. On the basis of these data, we recommend ceftriaxone prophylaxis as a safe and effective measure to prevent transplant wound infection and to reduce the incidence of postoperative urinary tract infection. PMID- 7842828 TI - Teicoplanin plus pefloxacine versus teicoplanin plus netilmicin in empiric therapy of febrile patients with cancer and neutropenia. A randomized study of two once daily regimens in patients with previously inserted catheters. AB - In a comparative randomized trial, teicoplanin 5 mg/kg plus either netilmicin 5 mg/kg or pefloxacine 10 mg/kg was administered in a once daily empiric therapy to 40 cancer patients with fever and neutropenia after cytotoxic chemotherapy. Both regimens were analyzed with respect to the localisation of the underlying disease, catheter presence and agents isolated from blood culture. The cure and improvement rate were 80% (teicoplanin plus netilmicin) and 85% (teicoplanin plus pefloxacin), with no statistically significant difference between the groups. Teicoplanin with either an aminoglycoside or a quinolone administered once daily seems to be a suitable approach in empiric therapy for fever in neutropenia and may prevent catheter insertion in cancer patients. PMID- 7842830 TI - An adolescent psychiatric unit for difficult medical patients. AB - While the combined psychiatric and medical treatment of patients is highly desirable, such treatment of more complex medical patients in a psychiatric milieu has been difficult to accomplish. This paper describes the creation of and experience with a psychiatric unit for adolescents with both difficult medical and psychiatric problems. Useful aspects of the structure of such a unit are discussed, and case examples are presented. PMID- 7842831 TI - Family System Test (FAST): are parents' and children's family constructs either different or similar, or both? AB - Perceptions of family cohesion and hierarchy structures were assessed by the Family System Test (FAST), a clinically-derived figure placement technique. Parents (N = 140) and their preadolescent offspring (N = 70) completed typical and conflict representations in individual as well as group settings. Typical representations were characterized by balanced family structures (i.e. cohesive and moderately hierarchical) and those displaying conflict situations showed predominantly unbalanced patterns. FAST portrayals were related to respondent (mother vs. father vs. child). Fathers represented typical family relations as balanced more often than mothers. Regarding conflict representations, children were more likely than fathers to portray the family as unbalanced. However, analyses of representations of the same family (i.e. intra-family comparisons) indicated that all respondents differed in their perceptions and, that fathers' typical portrayals showed most often the same structure as those done by the family members as a group. PMID- 7842832 TI - Encounter with reality: children's reactions on discovering the Santa Claus myth. AB - Fifty-two children who no longer believed in Santa Claus were individually administered a structured interview on their reactions to discovering the truth. Their parents completed a questionnaire assessing their initial encouragement of the child to believe in Santa and rating their child's reactions to discovering the truth as well as their own reactions to the child's discovery. Parental encouragement for the child to believe was very strong. Children generally discovered the truth on their own at age seven. Children reported predominantly positive reactions on learning the truth. Parents, however, described themselves as predominantly sad in reaction to their child's discovery. PMID- 7842833 TI - Can we differentially diagnose an attention deficit disorder without hyperactivity from a central auditory processing problem? AB - This article examines the dilemma involved in properly diagnosing children with Central Auditory Processing Deficits (CAPD) and children with Attention Deficit Disorders (without hyperactivity) (ADD) as they may not be mutually exclusive. With the help of a case illustration, the diagnostic difficulties are highlighted. There is a strong need for professionals in the speech/language and psychiatric communities to communicate to differentially diagnose a child who exhibits characteristics of both CAPD and ADD. PMID- 7842834 TI - Situational and interpersonal correlates of anxiety associated with peer victimisation. AB - In Study One the nature of peer bullying among 353 Australian primary school children from years three to seven was studied with a view to understanding the anxiety generated by victimisation. Over one-third of the sample reported feeling unsafe from bullying at school and over half of the sample believed that the reason children did not ask for help from bullying was that they were too afraid. In Study Two 114 primary school students from a second school were assessed for social-evaluative anxiety associated with peer victimisation at school. The findings indicated that victimisation was associated with fear of negative evaluation amongst males and females and social avoidance amongst females. PMID- 7842836 TI - Arthroplasty in the ankylotic hip. AB - A total of 30 cases submitted to arthroplasty for the treatment of ankylotic hip are reported. The clinical results show that movement improved in 63% of the cases, with recovery of normal joint excursion in 37%. Severe limping consequent to hypotrophy of the gluteal musculature persisted in 62% of the cases, requiring the use of two canes in 17% of the patients. There was pain < or = 3 based on the Merle D'Aubigne and Postel evaluation scale in 13% of the patients, while 87% remained totally asymptomatic. Radiographic results were favorable: the incidence of aseptic loosening 86 months after surgery in 25 cemented prostheses was 20% for the acetabulum and 12% for the stem, while the 5 cementless prostheses were stable an average of 27 months after surgery. The incidence of aseptic loosening was greater in patients < or = 45 years of age (30% vs 10%). Early complications included dislocation (6.6%), caused by hypotrophy of the gluteal musculature secondary to the ankylosis. Leg length discrepancy, which was present preoperatively in 10 cases with an interval ranging from -5 to 6 cm (mean 3 cm), was corrected in 6 cases and reduced by half in the remaining 4 patients. PMID- 7842835 TI - Patellar resurfacing in tumor endoprosthesis: a study in regard to power transmission. AB - Relation between quadriceps muscle mass and knee extension strength was investigated after resection of malignant bone tumor and endoprosthetic replacement of the distal femur in 19 patients with patellar resurfacing (Group A) and 16 patients without resurfacing (Group B). In all cases, a modular cementless, hinged prosthesis had been used. Age and follow-up period were comparable in the 2 groups. Muscle mass was measured ultrasonographically and strength was evaluated isokinetically. All the data on the operated side are given as percentage of the non-operated side. There was a positive correlation between muscle mass and strength in both groups. By linear regression analysis, a slightly lower value of strength was predicted in the unresurfaced group than in the resurfaced group. Analysis of covariance revealed that the influence of patellar resurfacing on strength was significant. This factor should also be considered in making a decision about patellar resurfacing with a tumor endoprosthesis. PMID- 7842837 TI - The Miller-Galante knee prosthesis system: a review of 42 cases. AB - The authors report their experience in 42 total Miller-Galante knee prostheses; 40 of the prostheses have an average follow-up of 25 months (minimum 9, maximum 55). Based on the Hungerford-Kenna clinical evaluation system, 59% of the patients obtained excellent results, 26% good results, 10% fair results, and 5% poor results. Radiographically, there were no cases of loosening of the implant. The joint axis was always well-corrected. A total of 12% of the patients complained of patellar pain (3 cases without either a prosthesis or keiloplasty; 2 cases with a patellar prosthesis). Overall, 85% of the patients obtained excellent or good results. PMID- 7842838 TI - Medial patellar synovial plica syndrome: the influence of associated pathology on long-term results. AB - The results obtained after 4-8 years in 42 patients submitted to arthroscopy for the treatment of medial patellar synovial plica syndrome are analyzed. There was a considerable difference in the values obtained depending on whether the plica was isolated, or associated with meniscal or cartilaginous lesion. In fact, based on the Lysholm score, treatment of isolated plica obtained 17 excellent or good results in 21 patients, while in the 21 cases where the lesion was associated with other pathologies excellent or good results were observed in only 9 subjects. Thus, associated lesions definitely influence long-term results. PMID- 7842839 TI - Acute posterior dislocation of the shoulder: diagnosis. AB - The authors describe the clinical and radiographic findings of posterior dislocation of the shoulder by examining 19 cases observed at the Rizzoli Orthopaedic Institute between 1981 and 1990; of the total number of cases, 16 were acute and 3 inveterate, equal to 1.7%. After analyzing the pathogenesis of the lesion, which was due to direct trauma, indirect trauma, or which occurred during an episode of convulsions, the authors call attention to the rareness of the lesion, and consequently the little amount of knowledge of the clinical and radiographic elements characterizing it. Three varieties are distinguished: subacromial (or retroglenoid), subglenoid, and subspinous. Finally, the results obtained with non-surgical treatment, which always allows for recovery of the joint relationships and complete functional recovery, are reported. PMID- 7842840 TI - A computerized morphometric evaluation of x-ray films for preoperative planning of hip arthroplasty. AB - Methods for measuring metric size on radiograms constitute an instrument of proven utility. For example, when preoperatively evaluating hip arthroplasty the diameter of the medullary canal and the cervicodiaphyseal angle, must be measured in order to determine the center of rotation of the femoral head, and to establish the flare index of the diaphyseal canal. These results may be obtained by using a computer-controlled graphic table to place the coordinates for the areas of greater anatomical and physiological importance on the radiologic image. Thus, a calculation of distances, anatomical axes and angles is obtained immediately, accurately defining the morphometry of the joint. In this study, the anteroposterior preoperative radiographic views of 87 femurs in 84 patients were evaluated by this method. The values provided by the morphometric analysis were then related to sex, age and weight. The diaphyseal canal was classified by typology for the preoperative planning of hip arthroplasty. PMID- 7842841 TI - Register of primary malignant tumors of the bone at the Rizzoli Orthopaedic Institute in Bologna. AB - 2,123 cases of primitive malignant bone tumors were collected from January 1982 to December 1992 at the Registry of Rizzoli Orthopaedic Institute. General data (name, age, gender, site, diagnosis) and histological and imaging documentation for each patient were filed. Considering the incidence of these tumors, we can assume that this registry (with contribution of more than 50 institutions) collect about 50% of italian cases of primitive malignant bone tumors. This registry permits informations regarding epidemiology, diagnosis and therapy of these rare neoplasms. PMID- 7842842 TI - Electromagnetic fields in the treatment of postmenopausal osteoporosis: an experimental study conducted by densitometric, dry ash weight and metabolic analysis of bone tissue. AB - The authors conducted an experimental study on 32 female rats which had been castrated at 10 months of age in order to verify the ability of pulsating electromagnetic fields to prevent osteoporosis induced by surgical menopause. Two different values of intensity of PEMFs were used: 30 G and 70 G. After 4 months of treatment the following testing was done: monophotonic bone densitometry of the lumbar spine, quantitative measurement of the dry ash weight of the femurs, and hematochemical tests to evaluate bone metabolism. The experimental study showed that the PEMFs supplied at 30 Gauss were capable of slowing down the loss of bone mass, while the PEMFs supplied at 70 Gauss obstructed bone decay, providing values for Bone Mineral Density and dry ash weight which were very similar to those observed in the non-castrated control group. Hematochemical tests did not reveal significant variations between the two groups. PMID- 7842843 TI - Lumbosacral monolateral dislocation. AB - The authors describe a case of traumatic monolateral dislocation of L5 on S1. It is a very rare lesion which involves serious diagnostic and therapeutic problems. Surgical treatment constituted by reduction and stabilization alone can obtain stable correction of the deformity and complete functional recovery. PMID- 7842844 TI - Tears of the rotator cuff associated with neurologic disorders: a description of two cases. AB - Based on their clinical experience with the two cases described, the authors analyze the association between surgically treatable tear of the rotator cuff and neurologic pathology. A semeiologic sign is emphasized, which may be of help in differential diagnosis involving isolated lesion of the rotator cuff. Furthermore, after a review of the literature, the authors express doubts as to the type of surgical treatment to be carried out. PMID- 7842845 TI - Spondylometaphyseal dysplasia: description of a case. AB - The authors describe a case of a boy aged 15 who came to their observation for severe valgus of the knee, limping, and deficit in stature. The evaluation carried out led to a diagnosis of Kozlowski-type spondylometaphyseal dysplasia. PMID- 7842846 TI - Surgical technique: dorsal vertebral hemiresection for bone tumors. AB - The authors describe the technique of sagittal vertebral hemiresection used for the treatment of tumors of the thoracic spine involving one or more hemivertebrae. This type of treatment is not frequently indicated because of the rare asymmetrical distribution of vertebral tumors. PMID- 7842847 TI - Caso quiz. Osteoma of the proximal femur. PMID- 7842848 TI - Symposium on the biosynthesis of tetrapyrrole pigments. London, 30 March-1 April 1993. PMID- 7842849 TI - The evidence for a spirocyclic intermediate in the formation of uroporphyrinogen III by cosynthase. AB - In the course of the cyclization of the linear tetrapyrrole hydroxymethylbilane to uroporphyrinogen III, catalysed by uroporphyrinogen III synthase (cosynthase), ring D of the bilane becomes inverted. Many different mechanisms have been proposed for this transformation but the most economical is one involving a spirocyclic pyrrolenine. Synthesis of a spirolactam, and other compounds closely related to the spirocyclic pyrrolenine, has shown that such compounds are not impossibly strained. The spirolactam is a powerful inhibitor of the enzyme, which suggests it does resemble an intermediate in the enzymic process. In the synthetic procedure to make an ester of the spirolactam the two products obtained were initially thought to be conformational isomers. However, molecular mechanics calculations on a model of the spirolactam predicted that several low energy conformations should exist and that the energy barriers for their interconversion are all lower than 32 kJ/mol. Reinvestigation revealed that one of the two products is in fact a macrocyclic dimer with a 28-membered ring. On the basis of the predicted preferred conformations of the spirolactam and of uroporphyrinogen III, a detailed three-dimensional mechanism is proposed, along with a rationalization of how the rearrangement of ring D may be directed by the enzyme. PMID- 7842850 TI - The modification of acetate and propionate side chains during the biosynthesis of haem and chlorophylls: mechanistic and stereochemical studies. AB - In the conversion of uroporphyrinogen III into protoporphyrin IX and thence into chlorophylls, all eight carboxylic side chains, as well as the four meso positions, are modified, and four enzymes are involved. In the uroporphyrinogen decarboxylase-catalysed reaction all four acetate side chains are converted into methyl groups by the same mechanism, to produce coproporphyrinogen III. Both methylene hydrogen atoms remain undisturbed and the reaction occurs with the retention of stereochemistry. Several questions regarding the enzymology of the decarboxylase are posed. Do all the decarboxylations occur at the same active site and, if so, are the four acetate chains handled in a particular sequence? Is the decarboxylation reaction aided by the transient formation of an electron withdrawing functionality in the pyrrole ring? Coproporphyrinogen oxidase converts the two propionate side chains of rings A and B into vinyl groups, with an overall anti-periplanar removal of the carboxyl group and the Hsi from the neighbouring position. Evidence is examined to evaluate whether a hydroxylated compound acts as an intermediate in the oxidative decarboxylation reaction. Protoporphyrinogen oxidase then converts the methylene-interrupted macrocycle of protoporphyrinogen IX into a conjugated system. The conversion has been suggested to involve three consecutive dehydrogenation reactions followed by an isomerization step. The face of the macrocycle from which the three meso hydrogen atoms are removed in the dehydrogenation reaction is thought to be opposite to that from which the fourth meso hydrogen is lost during the prototropic rearrangement. In an investigation of the in vivo mechanism for the esterification of the ring D propionic acid group with a C20 isoprenyl group 5 aminolaevulinic acid was labelled with 13C and 18O at C-1 and incorporated into bacteriochlorophyll a. The 18O-induced shift of the 13C resonance in the NMR spectrum showed that both oxygen atoms of the carboxyl group are retained in the ester bond. This and other results suggest that the reaction occurs by the nucleophilic attack of the ring D carboxylate anion on the activated form of an isoprenyl alcohol. PMID- 7842851 TI - Biosynthesis of open-chain tetrapyrroles in plants, algae, and cyanobacteria. AB - Phycobilins are open-chain tetrapyrroles of plants and algae which act as the chromophores of phycobiliproteins where they function as light energy-harvesting pigments. Phytochromobilin, another open-chain tetrapyrrole, is the chromophore of phytochrome, which functions as a light-sensing pigment in plant development. These open-chain tetrapyrroles are biosynthetically derived from protohaem. Enzyme reactions that convert protohaem to biliverdin IX alpha, and biliverdin IX alpha to phycocyanobilin, have been detected and characterized in extracts of the unicellular rhodophyte Cyanidium caldarium. Algal haem oxygenase and algal biliverdin-IX alpha reductase are both soluble enzymes that use electrons derived from reduced ferredoxin. Biochemical intermediates in the conversion of biliverdin IX alpha to (3E)-phycocyanobilin were identified as 15, 16 dihydrobiliverdin IX alpha, (3Z)-phycoerythrobilin and (3Z)-phycocyanobilin. Separate enzymes catalyse the two two-electron reduction steps in the conversion of biliverdin IX alpha to (3Z)-phycoerythrobilin. Z-to-E isomerization of the phycobilin ethylidine group is catalysed by an enzyme that requires glutathione for activity. Protein-bound phycoerythrobilin can be chemically converted to phytochromobilin which can then be released from the protein by methanolysis. This procedure was used to produce phytochromobilin in quantities sufficient to allow its chemical characterization and use in phytochrome reconstitution experiments. The results indicate that (2R,3E)-phytochromobilin spontaneously condenses with recombinant oat apophytochrome to form photoreversible holoprotein that is spectrally identical to native phytochrome. PMID- 7842852 TI - Chlorophyll a biosynthetic heterogeneity. AB - Chlorophyll a biosynthesis is presently interpreted in terms of two different biochemical pathways. According to one pathway, chlorophyll a is made via a single linear chain of reactions starting with divinylprotoporphyrin IX and ending with monovinylchlorophyll a. The experimental evidence for this pathway is marred by incompletely characterized intermediates that were detected in Chlorella mutants. The second pathway considers chlorophyll a to be made via multiple and parallel biosynthetic routes that result in the formation and accumulation of monovinyl- and divinylchlorophyll a chemical species. Two of these routes, namely the di/monocarboxylic monovinyl and divinyl routes, are responsible for the biosynthesis of most of the chlorophyll a in green plants. The experimental evidence for these two routes consists of: (a) the detection and spectroscopic characterization of intermediates and end products; (b) the demonstration of precursor-product relationships between various intermediates in vivo and in vitro; and (c) the detection of 4-vinylreductases that appear to be mainly responsible for the observed biosynthetic heterogeneity. The biological significance of chlorophyll a biosynthetic heterogeneity is becoming better understood. On the basis of the prevalence of the di/monocarboxylic monovinyl-and divinylchlorophyll a biosynthetic routes, green plants have been classified into three different greening groups. It now appears that the major chlorophylls in the euphotic zone of tropical waters are divinylchlorophyll a and b. It also appears that the di/monocarboxylic monovinyl and divinyl biosynthetic routes lead to the formation of different pigment proteins in different greening groups of plants, and that the more highly evolved monovinylchlorophyll a biosynthetic route is associated with higher field productivity in wheat. PMID- 7842853 TI - Biosynthetic studies on chlorophylls: from protoporphyrin IX to protochlorophyllide. AB - The series of reactions leading from protoporphyrin IX to protochlorophyllide have been studied over the last 15 years in the authors' laboratories at Davis and Clemson. Here, two crucial steps are emphasized, the discovery of the ATP requirement for Mg2+ chelation, and the oxidative cyclization of Mg protoporphyrin IX monomethyl ester to protochlorophyllide. The in vitro systems for the chelation of Mg2+ and for the oxidative cyclization of Mg-protoporphyrin IX monomethyl ester both require membrane-associated and soluble heat-labile components. We speculate about the enzymological mechanisms of these important reactions, their sub-plastidic localization and the relationship of these individual steps to the broader questions of chloroplast and cell development. PMID- 7842854 TI - Biosynthesis of coenzyme F430, a nickel porphinoid involved in methanogenesis. AB - Coenzyme F430 is the prosthetic group of methyl-coenzyme-M reductase, which catalyses the final step of methane formation in methanogenic bacteria. The coenzyme is a nickel-containing macrocyclic tetrapyrrole of unique structure. We describe the biosynthesis of this nickel porphinoid from L-glutamate via 5 aminolaevulinic acid, uroporphyrinogen III and dihydrosirohydrochlorin, the binding of the coenzyme to methyl-coenzyme-M reductase and the regulation of coenzyme F430 biosynthesis. We end with some evolutionary considerations on the biosynthesis of macrocyclic tetrapyrroles and remarks on the degradation of these compounds under anaerobic conditions. PMID- 7842855 TI - Haem d1 and other haem cofactors from bacteria. AB - Several bacterial haem prosthetic groups whose structures deviate significantly from the ubiquitous protohaem (Fe-protoporphyrin) have been discovered recently. These newly discovered pigments contain dramatic modifications in their aromatic core and/or side chains. Examples include the dioxoisobacteriochlorin-type haem d1 and the chlorin-type haem d as well as the haem a-like haem o. Total syntheses of these macrocycles have been accomplished. Synthetic haem d1 and its analogues were used in reconstitution studies with nitrite reductase which revealed the importance of the oxo groups and the acrylate side chain for enzymic activity. The structural features of these porphyrinoids immediately suggest some possible, but as yet unproven, biosynthetic pathways. PMID- 7842856 TI - Genetics and enzymology of the B12 pathway. AB - The chemical complexity of vitamin B12 suggests that its formation may involve a large number of enzymic steps. However, until recently, little was known of the number, mechanism and stereochemical course of the many enzymic interconversions that are essential to vitamin B12 biosynthesis. In response to this the French groups led by Francis Blanche and Joel Crouzet have carried out extensive investigations into the genetic and biochemical organization of this remarkable biosynthetic pathway. Through heterologous complementation studies with cobalamin producing mutants they were able to clone and identify a total of 22 unique cob genes from four genomic regions (A-D) of the Pseudomonas denitrificans chromosome. This was the first report of a genetic analysis of cob genes at the molecular level and provided a suitable genetic model from which biosynthetic investigations could be initiated. The metabolic roles of most of the products of these genes have now been defined and in light of this progress current research concentrates on the development and use of a variety of techniques to investigate the chemistry involved in these individual enzymic steps. Here, my focus is on the recent efforts and successes of the French groups that have led to the elucidation of almost the entire enzymic sequence of events in vitamin B12 biosynthesis. From this perspective, recent developments at Cambridge (UK) regarding the utilization of reconstituted enzymic systems to manufacture substrates as probes for this biosynthetic pathway are illustrated. PMID- 7842857 TI - 5-Aminolaevulinic acid synthase and uroporphyrinogen methylase: two key control enzymes of tetrapyrrole biosynthesis and modification. AB - Two enzymes which play an important role in regulation and flux control through the tetapyrrole biosynthetic pathway are considered. The Rhodobacter sphaeroides 5-aminolaevulinic acid synthase isoenzymes are discussed and the progress being made on their recombinant expression and isolation is reported. The Escherichia coli uroporphyrinogen methylase, which is encoded by the cysG gene, is also examined. In this case evidence is provided which demonstrates that the gene product is responsible for the complete synthesis of sirohaem from uroporphyrinogen III. The enzyme is thus capable of performing two S adenosylmethionine-dependent methylation reactions, an NADP(+)-dependent dehydrogenation and iron chelation. The uroporphyrinogen methylase is thus a small multifunctional enzyme. PMID- 7842858 TI - New intermediates in the B12 pathway. AB - Vitamin B12 has a complex structure which represents one of the most challenging biosynthetic problems in Nature. Exciting progress has been made by combining the techniques, approaches and strengths of chemistry, spectroscopy and biology. Most of the advances until recently came from experiments based either on labelling simpler precursors with radioactive isotopes followed by controlled degradation of the labelled products, or on the use of stable isotopes, 13C in particular, because it can be detected and its environment can be studied by NMR spectroscopy. These experiments imposed heavy demands on synthesis which provided the specifically labelled starting materials. More recently, the powerful methods of genetics and molecular biology have been added to the armoury, leading to another massive surge forward by allowing the preparation, through gene overexpression, of large quantities of the enzymes of the biosynthetic pathway. Equally important has been the generation of mutant forms of B12-producing organisms in which the biosynthetic pathway is blocked at specific points. Here I focus on the latest advances. The structures of the newly discovered intermediates are described and some of the chemistry involved is explored. In conclusion, the presently known pathway to vitamin B12 is reviewed. PMID- 7842859 TI - Recent studies of enzymically controlled steps in B12 biosynthesis. AB - The acquisition and sequencing of the genes encoding the enzymes for vitamin B12 biosynthesis in Salmonella typhimurium and Pseudomonas denitrificans has dramatically altered the direction of research on the pathway from uroporphyrinogen III to the corrinoids. Through a combination of molecular biology, organic chemistry and NMR spectroscopy, logical progression along the sequence is being made. Recent work from our laboratory is focused on the discovery and specificities of the methyltransferases connecting uroporphyrinogen III with cobyrinic acid, the temporal resolution of cobalt insertion and a comparison of the anaerobic pathway in S. typhimurium and the aerobic pathway in Ps. denitrificans. The implication of two parallel routes to corrins in these bacteria is discussed. PMID- 7842860 TI - Enzymic and mechanistic studies on the conversion of glutamate to 5 aminolaevulinate. AB - Higher plants, algae, cyanobacteria and several other photosynthetic and non photosynthetic bacteria synthesize 5-aminolaevulinate by a tRNA(Glu)-mediated pathway. Glutamate is activated at the alpha-carboxyl by ligation to tRNA(Glu) with an aminoacyl-tRNA synthetase. An NADPH-dependent reductase converts glutamyl tRNA(Glu) to glutamate 1-semialdehyde, which is finally converted to 5 aminolaevulinate by an aminotransferase. These components are soluble and in plants and algae are located in the chloroplast stroma. In plants and algae the tRNA(Glu) is encoded in chloroplast DNA whereas the enzymes are encoded in nuclear DNA. The tRNA(Glu) has a hypermodified 5-methylaminomethyl-2-thiouridine pseudouridine-C anticodon and probably plays a role in the light-dark regulation of 5-aminolaevulinate synthesis. Ligation of glutamate to tRNA(Glu) requires ATP and Mg2+ and proceeds via a ternary intermediate. Glutamyl-tRNA(Glu) reduction appears to involve formation of a complex. Glutamate 1-semialdehyde non enzymically synthesized by reductive ozonolysis from gamma-vinyl GABA is used as substrate by the last enzyme. Glutamate-1-semialdehyde aminotransferase contains pyridoxal phosphate as a prosthetic group. The enzyme is converted to spectrally different forms by treatment with 4,5-diaminovalerate or 4,5-dioxovalerate. The pyridoxamine 5'-phosphate form of the enzyme converts (S)-glutamate 1 semialdehyde to 5-aminolaevulinate via 4,5-diaminovalerate through a bi-bi ping pong mechanism. PMID- 7842861 TI - B12: reminiscences and afterthoughts. AB - This paper describes some of the chemistry of synthetic corrinoids and corphinoids carried out at the ETH (Swiss Federal Institute of Technology) after the completion of the non-enzymic synthesis of vitamin B12 and attempts to delineate the interplay between mechanistic hypotheses, model studies and the experimental research in B12 biosynthesis which had spurred this work. The afterthoughts deal with why and how the work on corrinoids eventually led to an experimental involvement in the problem of a chemical aetiology of the structure of natural nucleic acids. PMID- 7842862 TI - 5-Aminolaevulinic acid dehydratase: characterization of the alpha and beta metal binding sites of the Escherichia coli enzyme. AB - The alpha and beta metal-binding sites of 5-aminolaevulinic acid dehydratase (ALAD) (porphobilinogen synthase, EC 4.2.1.24) from Escherichia coli were investigated to determine the function of each metal ion and the role of the reactive cysteines in metal binding. Occupancy of the alpha site by Zn2+ restored virtually all catalytic activity to the inactive metal-depleted ALAD (apoALAD). Occupancy of the alpha site by Co2+ also yielded an active enzyme and resulted in a charge-transfer band indicative of a single cysteine amongst the metal ligands. Subsequent labelling of this cysteine residue with 14C-labelled N-ethylmaleimide, followed by peptide analysis, indicated the involvement of Cys-130. The metal ion at the alpha site is thought to be essential for binding of the second molecule of substrate at the A substrate-binding site that forms the acetic acid side of the product, porphobilinogen. Binding of Zn2+ to the beta site restored little activity if the alpha site was unfilled. Metal ion binding to the beta site could be monitored by following the change in protein fluorescence with Zn2+ titration of apoALAD at pH 6. A conformational change upon beta site occupancy may explain why binding of Mg2+ at the alpha site can occur only if Zn2+ is bound at the beta site. The binding of Co2+ at the beta site produced an inactive enzyme that exhibited a charge-transfer band indicative of at least three cysteine ligands. PMID- 7842863 TI - The biosynthesis of uroporphyrinogen III: mechanism of action of porphobilinogen deaminase. AB - The biosynthesis of the uroporphyrinogen III macrocycle from porphobilinogen requires the sequential participation of two enzymes--porphobilinogen deaminase (1-hydroxymethylbilane synthase, EC 4.3.1.8) and uroporphyrinogen III synthase (cosynthase, EC 4.2.1.75). The product of the deaminase-catalysed reaction is a highly unstable 1-hydroxymethylbilane called preuroporphyrinogen which acts as the substrate for the uroporphyrinogen III synthase, resulting in the exclusive formation of uroporphyrinogen III. In the absence of the synthase, preuroporphyrinogen cyclizes spontaneously to give uroporphyrinogen I. Porphobilinogen deaminase contains a dipyrromethane cofactor that acts as a primer onto which the tetrapyrrole chain is built. The assembly process occurs in stages through enzyme-intermediate complexes, ES, ES2, ES3 and ES4. The negatively charged carboxylates of the cofactor, substrate and intermediate complexes interact with positively charged amino acid side chains in the catalytic cleft. Mutagenesis of conserved arginines has dramatic effects on the assembly of the dipyrromethane cofactor and on the tetrapolymerization process. During the polymerization, the enzyme changes conformation to accommodate the elongating pyrrole chain. The structure of the deaminase from Escherichia coli has been determined by X-ray crystallography at 1.9A resolution and gives important insight into the enzymic mechanism. Aspartate 84 plays a key role in catalysis and its substitution by glutamate reduces kcat by two orders of magnitude. PMID- 7842864 TI - Structural studies on porphobilinogen deaminase. AB - The X-ray crystallographic analysis of porphobilinogen deaminase (hydroxymethylbilane synthase, EC 4.3.1.8) shows the polypeptide chain folded into three domains, (1) N-terminal, (2) central and (3) C-terminal, of approximately equal size. Domains 1 and 2 have a similar overall topology, a modified doubly wound parallel beta-sheet. Domain 3 is an open-faced three stranded antiparallel beta-sheet, with one face covered by three alpha-helices. The active site is located between domains 1 and 2. The dipyrromethane cofactor linked to cysteine 242 protrudes from domain 3 into the mouth of the cleft. Flexible segments between domains 1 and 2 are thought to have a role in a hinge mechanism, facilitating conformational changes. The cleft is lined with positively charged, highly conserved, arginine residues which form ion pairs with the acidic side chains of the cofactor. Aspartic acid 84 has been identified as a critical catalytic residue both by its proximity to the cofactor pyrrole ring nitrogen and by structural and kinetic studies of the Asp-84-->Glu mutant protein. The active site arginine residues have been altered by site-directed mutagenesis to histidine residues. The mutant proteins have been studied crystallographically in order to reconcile the functional changes in the polymerization reaction with structural changes in the enzyme. PMID- 7842865 TI - [Experimental studies on transmission of EHF in rodents]. AB - Studies on the possible routes of transmission of epidemic hemorrhagic fever (EHF) were conducted in experimental animals. Results showed five-ID50/ml of EHF virus (EHFV) suspension could infect rats through their damaged skin. Both gamasid mites and mower's mites collected from epidemic areas could naturally infect and transmit EHFV by biting and stinging, or transmit transovarially. EHFV excreted from the experimentally infected animals could be transmitted to normal ones by aerosol. Experimental rats could be infected with EHFV via damaged mucous membrane of the digestive tract. The above results suggested the main route of transmission of EHFV was via damaged skin. Mite-borne transmission played an important role in perpetuating natural foci of EHF in rats. Respiratory transmission of EHFV via aerosol also was a possible route of transmission under specific conditions. In general, EHFV could hardly be transmitted via digestive tract. All those mentioned above provided an important scientific basis for prevention of EHF. PMID- 7842866 TI - [Phage typing of Salmonella typhimurium in 20 provinces, autonomous regions and municipalities of China]. AB - Thirty strains of Salmonella bacteriophages were isolated from hospital sewage. Eleven strains selected from them, in combination with Felix Salmonella Phage O I, were used as a phage typing set for serotyping Salmonella. Thirty-one identified types and 20 undefined types were detected in 2348 strains of Salmonella typhimurium collected from 20 provinces, autonomous regions and municipalities in China. The nine types with higher frequencies were 7774 (accounted for 48.0%), 0774 (17.1%), 6774 (7.7%), 4774 (7.3%), 5774 (3.3%). 3774 (2.2%), 4000(2.1%), 0000 (1.8%) and 7000 (1.7%). Most outbreaks of nosocomial infection and food poisoning were caused by phage types 7774 and 4774. Phage types of Salmonella typhimurium in domestic ducks, pigs, rats, snails, and in sewages were analyzed, and their significance in epidemics was discussed. PMID- 7842867 TI - [Comprehensive evaluation of inheritance and environmental factors in the etiology of primary liver cancer]. AB - A1:1 matched case-control study was carried out in 152 cases with primary liver cancer (PLC) and 152 controls to identify the risk factors associated with it and its cumulative mortality in their second- and third-degree relatives. Results showed cumulative mortality of PLC in the relatives of the cases (0.46%) was significantly higher than that of controls (0.07%). Cumulative mortality of PLC in consanguineous relatives of the cases (0.55%) was significantly higher than that in non-consanguineous ones (0.08%). Cumulative mortality of PLC decreased regularly with family relation (consanguinity) drifting apart. Genetic factors still played an important role independently in the etiology of PLC with multiple regression and stratification analyses studying genetic and environmental factors as a whole. This laid a theoretical basis to study further the association between genetic factors and PLC incidence. PMID- 7842868 TI - [Whole embryo culture for detecting teratogen]. AB - Whole embryo culture technique was used to study direct effects of Penicillin G, Thiadiazole, Actinomycin D and glucose solution of high concentration on the development and growth of rat embryos, without maternal and placental influence. Nine-and-a-half-day rat embryos were transplanted to culture flasks from the animal's wombs for in vitro culture, and the four chemicals were added to culture medium, respectively. Results showed all those chemicals could cause death and malformation of the embryos and retardation in embryonic development and growth cultured in vitro, with an apparent dose-effect relationship. The embryonic malformations caused by the chemicals were the same both in vitro culture and in vivo. Possible teratogenesis of the chemicals and survival of the malformed embryos were speculated based on the above dose-effect relationship. PMID- 7842869 TI - [Inhibitory effects of fifteen kinds of Chinese herbal drugs, vegetables and chemicals on SOS response]. AB - Effects of 15 kinds of herbal drugs, vegetables and chemicals on lex-dependent sfi-SOS response were determined by micropersistent and/or pulse models induced by 4-Nitroquinoline-N-oxide (4NQO) and Mitomycin C (MMC) in Escherichia coli(E. coli) PQ37 and PQ35, respectively. Results showed the water extract of Rhizoma Polygonati (RP), Fructus Chebulae (FC), Radix Polygoni Multiflori (RPM), Fructus Ligustri Lucidi (FLL), Bulbus Fritillariae Thunbergii (BFT), shell of water chestnut with a pedicle, Chinese chives juice, and solutions of 5-Fluorouracil, Tannic acid and garlicin could inhibit SOS responses with a dose-response relationship and suggested the inhibitory effects took place both inside and outside E. coli cells. Water extract of FC, FLL, BFT, shell of water chestnut with a pedicle, Chinese chives juice and solution of 5-Fluorouracil and Tannic acid could intracellularly inhibit SOS responses induced by MMC in E. coli PQ35, and acetone extract of Grifola Frondosa (GF) could extracellularly inhibit SOS responses in E. coli PQ37 and intracellularly in PQ35 induced by 4NQO or MMC. Water extract of raw hawthorn. Radix Angelicae Duhuricae (RAD), Radix Ophiopogonis (RO), and 5-Fluorodeoxyuridine could extracellularly inhibit SOS responses induced by 4NQO in E coli PQ37. The possible mechanisms of intracellular inhibition and antidamage repair were discussed in the paper. PMID- 7842870 TI - [Deposition of air particles with polycyclic aromatic hydrocarbons (PAH) in human respiratory tract]. AB - Atmospheric concentrations of five sizes of particles with PAH were determined in Taiyuan, and deposition of PAH in human respiratory tract was estimated. Results showed 47%-70% of air PAH concentrated in the particles less than 2 microns in diameter. Total PAH deposition in respiratory tract measured 12. 53 micrograms per day, and 53% of them deposited in nasopharyngeal region, 65% in tracheobronchial region and 32% in alveoli. PMID- 7842871 TI - [Preliminary study on health effects in the residents exposed to liquefied petroleum gas]. AB - Combustion of liquefied petroleum gas (LPG) can cause indoor air pollution with sulfur dioxide, nitrogen dioxide, total suspended particulate (TSP) and total hydrocarbons. Mice exposed to the pollutant air for three months showed lower ANAE, prolonged sleep time, increased PCE micronucleus in bone marrow, high positivity in Ames test for the lung homogenate and deformity of sperm in males, with obvious dose-response relationship. Investigation on a human population exposed to LPG for more than five years revealed irritating symptoms in respiratory tract, nose and eyes, and prevalence of pharyngitis, rhinitis and conjunctivitis increased significantly. Positive Ames test and micronucleus test in peripheral erythrocytes were detected in concentrated urine samples collected from them. It is postulated this may be associated with the mutagenic pollutants contained in the waste gas emitted by combustion of LPG. PMID- 7842872 TI - [Chronic toxic effects of aluminum on nervous system in rabbits]. AB - Twenty-one male rabbits were administered with alum (aluminum potassium sulfate) for 32 weeks to study the accumulative toxic effects of aluminum in food additives on central nervous system. Results showed aluminum levels in blood and brain tissue of the animals increased significantly with intake of alum (P < 0.01). Blood zinc levels, and activities of superoxide dismutase (SOD) and monoamine oxidase B (MAO-B) correlated negatively with aluminum levels in blood and brain, and SOD activity correlated negatively to accumulative aluminum deposit and positively to lipid oxide level in brain. Pathological examinations showed lesions in gyrus centralis anterior, gyrus hippocampi and spinal cord of the animals got more severely and extensively with aluminum intake and brain aluminum content, with disarrangement of neurofilaments and neurotubule, and deformation of synaptic structures. PMID- 7842873 TI - [Effects of exposure to TNT on sex hormones in male workers]. AB - Field investigation on labour hygiene in two plants producing trinitrotoluene (TNT) in Henan Province showed most air TNT levels in the workplace exceeded national maximum allowable concentration (MAC 1 mg/m3) and the skin of the workers exposed to TNT was severely contaminated. Determinations of serum levels of sex hormones showed those of testosterone were lower, but those of interstitial cell-stimulating hormone (ICSH or LH) and follicle stimulating hormone (FSH) were higher in workers exposed to TNT than that in controls with statistical significance (P < 0.01). PMID- 7842874 TI - [Determination of dust content in the lungs of 10 cases with stage I coal workers' pneumoconiosis (CWP)]. AB - Dust deposition in the lung tissue of 10 cases with pathologically diagnosed stage I CWP was determined. The left lung tissue was digested by 37% hydrochloric acid, and its organic composition was removed by chloroform and 50% ethanol. Results showed total dust content averaged 8.64 grams per left lung, with a standard deviation of 5.54 grams. Dust content varied in different parts of the lung, measured the highest in lymph nodes, the upper lobe and pleura the next and the lowest in the lower lobe, with a very significant difference by ANOVA (F = 44.76, P < 0.001). Dust less than 5 microns in diameter accounted for 94.0% of the total content, and that equal to or more than 10 microns only 0.8%. A certain amount of fibrous dust could be found in the lung. Dust deposited in the lung accounted only for 0.64% of that exposed to. PMID- 7842875 TI - [Difficulties in measles elimination and the countermeasures]. PMID- 7842876 TI - [A case-control study on colorectal cancer and dietary fiber and calcium of various sources]. AB - A population-based case-control study was conducted in 726 incident cases with colorectal cancer and 1400 controls matched on age and sex in Shanghai, to explore the possible difference in associations between colorectal cancer and dietary fiber and calcium of various sources. The results showed reverse correlation between intake of vegetable fiber and ascending and descending colon cancer and rectal cancer, and between intake of fruit fiber and ascending colon cancer only. Dietary intake of calcium from animal sources could reduce the relative risk of ascending and descending colon cancer. These associations still existed after adjustment of the effects of the factors such as age, sex, intakes of total calorie, vitamin C, saturated fatty acid, etc. with logistic regression model, which indicated all of those variables were independent of other ones. Intake of dietary fiber from grains and calcium from plant sources had no significant protection from colorectal cancer. This study also showed the protective effects of dietary fiber and calcium on colorectal cancer not only correlated to their intake, but also closely to their sorts and sources. PMID- 7842877 TI - [A comparative study on blood cholesterol and dietary fat intake between Hong Kong and Cantonese children]. AB - Blood cholesterol level in children aged 7 in Hong Kong (4.59mmol/L) was significantly higher than that in Jiangmen City, Guangdong Province (4.16mmol/L). Duplicate meals were collected from 20 children each in Hong Kong and Jiangmen for chemical analysis of fat intake and fatty acid profile. Results showed daily fat intake was 34.7 g for children in Jiangmen, which was about 30% lower than that in Hong Kong (47.6 g). Fatty acid profile in the diet of Jiangmen children showed a significantly higher polyunsaturated fatty acid saturated fatty acid ratio (0.81 vs 0.69) and linoleic acid/myristic acid ratio (20.73 vs 10.91) than that of Hong Kong children. It suggested dietary mode in a society with rapid developing economy and well-to-do life has changed, and it is necessary to prevent from the damage to health, especially the risk of coronary heart disease, caused by over-nutrition, as early as possible. PMID- 7842878 TI - [N-nitroso-compounds of pickles in the areas with high incidence of digestive cancers and their mutagenic effects]. AB - Contents of N-nitroso-compounds and their precursors in pickles preserved by local residents living in the areas with high incidence of digestive cancers in Jiangsu Province, and micronucleus test in animals taking-in pickles were determined. Results showed nitrite was detected in pickles ranging 0.010 to 0.450g/kg, with 37.5% of them exceeding the national hygienic criterium of 0.030 g/kg set for meat products, and N-nitroso-compounds were detected in 95% of the samples ranging 0.02 to 110.50 micrograms/kg. N-nitrosodimethylamine (NDMA) and N nitrosodiethylamine (NDEA) in pickles averaged 31.98 and 34.02 micrograms/kg, respectively. Micronucleus frequencies in bone marrow of mice induced by NDMA and NDEA in pickles were 6.92/1000 and 6.17/1000, respectively, with a significant difference as compared with control animals (F = 34.43, P < 0.01), indicating apparently mutagenic effects. PMID- 7842879 TI - [Quantitative study on DNA-adduct in normal lung tissues of smoking and non smoking lung cancer patients]. AB - Lung tissues from 32 cases of lung cancer with surgical operation, 22 smokers and 10 nonsmokers, were analyzed with P1-mediated modification of 32P-postlabelling technique. The level of lung DNA-adduct in cigarette smokers was higher that in nonsmokers with significant difference (P < 0.001). Autoradiogram showed a diagonal radioactive zone in smokers' lung tissues. Correlation analysis indicated DNA-adduct in lung tissues increased with the number of cigarettes smoked with a regression equation of Y = 0.411 X + 3.52, r = 0.74, P < 0.001. PMID- 7842880 TI - [Case-control study on intrauterine growth retardation and vitamin nutritional status in late pregnancy]. AB - Ninety-seven cases of pregnant women with intrauterine growth retardation (IUGR) and 133 controls were investigated on their dietary intake and blood vitamin levels in late pregnancy. Results showed insufficient calorie and protein intake, deficiency in calcium and vitamin B2, and low intake of vitamins A and B1 in pregnant women with IUGR. Their serum level of vitamin E was only half as that in controls (P < 0.01). Mothers' serum level of vitamin E correlated positively to several indicators reflecting infant growth with multiple stepwise regression analysis. There was no significant difference of activity of erythrocytic transketonas activity (TPP%) and activity coefficient (AC) of glutathione reductase between the two groups. It suggested pregnant women in both groups suffered from deficiency in thiamine and riboflavin (TPP% > 16%, AC > 1.2). PMID- 7842881 TI - [A study on body fat in children aged 7-12]. AB - Three and sixty healthy children aged 7-12 with normal development and better nourishment were selected by stratification according to their height and weight. Body density was measured with hydrostatic weighing technique. Body fat proportion was calculated with Brozek formula. Skinfolds of the four parts of the body (triceps, subscapular, etc.) were measured by Harpenden skinfolds caliper. Results showed body fat proportion in children aged 7-12 averaged 15.12% for male and 17.15% for female, with no significant difference. Body fat proportion was analyzed by stepwise regression on height, weight, skinfolds, and upper arm circumstance. Body fat proportion highly correlated to skinfolds with an r = 0.6664 and P < 0.01. A regression equation of body fat on skinfolds was developed, and laws for the development and changes of body fat discussed in the paper. PMID- 7842882 TI - [Effects of high-level-manganese sewage irrigation on children's neurobehavior]. AB - The neurobehavioral status was tested for 92 matched-pair pupils aged 11-13 in an area with high-level-manganese sewage irrigation and a control area. Results showed there was significant difference in manganese contents of drinking water between the area with sewage irrigation and the control area during 1990-1992, ranged 0.241-0.346 mg/L and 0.030-0.040 mg/L, respectively, with P < 0.01. Hair manganese content of children in the area with sewage irrigation (1.252 micrograms/g) was significantly higher than that in the control area (0.961 micrograms/g) with P < 0.01. Scores in digit span, Santa Ana manual dexterity, digit symbol, Benton visual retention test and pursuit aiming test for children in the area with sewage irrigation were significantly lower than those in the control area (P < 0.01). Hair manganese contents of the children in the area with sewage irrigation correlated negatively with most of those scores. It suggested high level of manganese in drinking water of the area with sewage irrigation might be an important factor affecting children's neurobehavioral changes. PMID- 7842883 TI - [Studies on reproductive toxicity induced by enriched uranium]. AB - Reproductive toxicity induced by body contamination with enriched uranium (235UO2F2) in different levels was studied. Results showed abnormalities dominated with bicaps and non-hock sperms could be induced by 235UO2F2. Chromosome aberration in spermatogonia induced by 235UO2F2 was dominated with chromosome breakage, and caused chromosome fragment, translocation, polyvalent in primary spermatocyte and DNA strand breakage in sperm. The quantity of sperm DNA strand breakage increased with the raise of intake of 235UO2F2. It was noted that enriched uranium could damage genetic materials in rats and cause dominant lethality and skeletal abnormalities in fetal rats. Incidence (B) of the induced skeletal abnormalities correlated positively to the injected dose (I) of 235UO2F2 into their testes with a regression equation of B = 28.84 + 0.86I. PMID- 7842884 TI - [An epidemiological study on clonorchiasis sinensis in Hubei Province]. AB - An epidemiological study on clonorchiasis sinensis was conducted in 62 counties and cities in Hubei Province during 1987-1991, and clonorchis sinensis was identified in 52 counties and cities. Human population studies showed there were patients with clonorchiasis sinensis in 29 of 31 counties and cities investigated, with infection rates of 0.1%-16.2%. There were five species in two families of freshwater spiral shells as first intermediate host of clonorchis sinensis, 31 species in seven families of freshwater fish (with five species of fish newly discovered) and one species of freshwater shrimp as second intermediate host, and six species as reservoir host. Studies revealed holding small fish in the mouth and eating undercooked roasted fish were two major modes of transmission for clonorchiasis sinensis in the province. PMID- 7842885 TI - [Advances in the study of hepatitis E]. PMID- 7842886 TI - [Effects of electromagnetic field emitted by electric blankets on brain catecholamine in fetal mice]. AB - A study of effects of electromagnetic field emitted by electric blankets on brain catecholamine (CA) content in fetal mice under development was carried out, to determine which component of the electromagnetic field, electric field or magnetic field or both, causes the effects, and to improve the design of the electric blankets. Forty-eight NIH pregnant mice were divided into three groups exposed to electric field, magnetic field and electromagnetic field, respectively for five hours daily during mice's whole gestational periods, and one control group. Twelve infant mice in each group were decapitated at the seventh day after delivery, and sagittal sections of the middle part of their brain were prepared for quantitative histofluorescence analysis of CA with a microspectrophotometer. Results showed brain CA content in all the exposed groups was lower than that in controls, with F values of 18.5 and 37.6 in hypothalamus and hippocampus, respectively. Both electric and magnetic fields could decrease brain CA content in mice, but electric fields had greater effects. It suggested the focus in production of electric blankets should be put on reducing electric field, as well as reducing magnetic field by cloth wiring design. Electric field lowered to less than 100 V/m for the electric blankets with such design from 1 kV/m, and magnetic field to less than 0.08 microT from 1 microT. PMID- 7842887 TI - [Effects of sodium fluoride on the activity of Ca2+Mg(2+)-ATPase in synaptic membrane in rat brain]. AB - Effects of sodium fluoride on Ca2+Mg(2+)-ATPase activity of synaptic membrane in rat brain were studied with in vitro or in vivo methods. Concentrations of sodium fluoride of 0.3, 1.6, 8.0, 20.0 and 40.0 mmol/L can significantly inhibit the activity of the enzyme with proportions of 6.6%, 18.0%, 41.0%, 55.5% and 63.1%, respectively, and with a half inhibitory concentration of 14.8 mmol/L reflecting an obvious dose-effect and time effect relationship. Analysis of enzyme substrate kinetics showed the effect that sodium fluoride had was a non competitive inhibition. Activity of Ca2+Mg(2+)-ATPase on synaptic membrane in female rat brain showed a decreasing tendency after feeding with water fluorinated with 5, 15 and 50 mg/L of fluoride during their gestation and lactation for 50 days, and that in their newborn offsprings with 5 and 50 mg/L of fluoride was inhibited by 11.3 and 32.1%, respectively. PMID- 7842888 TI - [Reference values for blood, hair, and organ selenium levels in adults of Beijing]. AB - Two hundred and four blood specimens and 202 hair specimens, and 72 tissue specimens of heart, liver, spleen, lung, kidney, muscle and skeleton from adults living in Beijing suddenly died were collected during 1990-1991. Selenium levels were determined by 2,3-diamine naphthalene fluorescence method with serum, human hair and calf liver as standard references to assure the quality of determination, and their reference values for adults in Beijing were established. Selenium nutritional status of the adults was evaluated preliminarily. Dietary selenium intake was estimated based on serum selenium levels, and the body total selenium content was estimated by biological monitoring. PMID- 7842889 TI - [Studies on generation and inhibition of active oxygen in alveolar macrophage by chrysolite and aluminum citrate]. AB - Chrysolite-induced generation and aluminum citrate-induced inhibition of active oxygen in alveolar macrophage were studied with ESR spin-trapping technique, cytochrome C reduction and phenol red oxidation assays. Results showed, under certain conditions, Mangya and Laiyuan chrysolite fiber could stimulate macrophage to generate OH., O2-. and H2O2 in a dose-dependent manner. But such an induced-generation of active oxygen would be inhibited by the treatment of chrysolite with aluminum citrate solution at room temperature for one hour. PMID- 7842890 TI - [Comparison of sensitivity of six indices indicating genetic damage to human blood lymphocytes by benzo(a)pyrene]. AB - Comparison of sensitivity of six indices, i.e., SCE, MN, CA, FADU, DRSI and UDS, in detection of genetic damage to human peripheral blood lymphocytes caused by benzo(a)pyrene were studied under the same condition for in vitro toxicant treatment and cell culture. Ratio of the slope of regression straight line of concentration-response to the standard deviation of regression staigy line from observed values was used as an indicator reflecting sensitivity of all the above indices. The results showed the order of sensitivities of all the above indices are as follows: SCE > MN > CA > FADU > DRSI > UDS. SCE and MN (cytokinesis block method) should be choice of indices to monitor genetic damage in human population exposed to benzo(a)pyrene. And, it is warranted to use FADU, as a simple, convenient and rapid method, in human population monitoring. PMID- 7842891 TI - [Ribosomal DNA fingerprinting analysis of Enterobacter cloacae isolated from an outbreak of nosocomial infection]. AB - 16s and 23s ribosomal DNA (rDNA) genes were amplified form E. coli, labelled with [alpha- 32P] dATP by nick translation, and applied as conserved gene probes to detecting broad-spectrum rDNA. rDNA fingerprinting analysis of Enterobacter cloacae (E. cloacae) isolated form an outbreak of nosocomial infection and other hospital environmental sources was conducted with digestion by different restrictive endonuclease, such as Hind III, EcoRI, BamHI, Bgl I, et al. Results showed rDNA fingerprinting of E. cloacae strains isolated from 10 patients with nosocomial infection was the same as that from other sources. It suggested E. cloacae causing this outbreak was originated from one genetic clone, and its source of infection was the tubes and humidifying bottles for oxygenation. rDNA fingerprinting technique is accurate, reliable, specific and repeatable, and will plays important roles in identification and classification of bacteria, tracking the source of transmission of nosocomial infection. PMID- 7842892 TI - [Meta-analysis in neurobehavioral toxicological studies]. AB - Meta-analysis was used to deal with the data collected in neurobehavioral toxicological studies to synthesize their findings quantitatively. Results revealed neurotoxic chemicals could cause changes in cognitive abilities, psychomotor function and emotion of persons exposed. However, each toxicant had its distinct effects on neurobehavior, for example, lead mainly impairs touch sense, memory, emotion and cognitive abilities, mercury does intelligence, concentration and motor stability, and carbon disulfide does eye-hand coordination. It suggested meta-analysis could be directive to selecting the best combination of neurobehavioral tests. PMID- 7842893 TI - [Preliminary analysis of factors causing mental retardation in China]. AB - Analysis of the data collected from national sampling survey of the mental retarded in 1987 showed: (1) prevalence of mental retardation in China was 12.68/1,000, (2) its causes mainly included hereditary diseases, cerebral diseases, malnutrition, pregnant infection and birth trauma for children and senile dementia for the elderly aged 60 or over, (3) severe mental retardation was mainly caused by cerebral diseases and developmental deformity in the country, and (4) the causes for 40.1% of the mental retarded persons remained unknown. Based on the researches at home and abroad, a series of major preventive measures for mental retardation have been put forward, they included: (1) to promote better birth and better rearing, vaccination, proper nutrition for pregnant mothers and infants, and safety education as focuses in primary prevention, (2) to detect early and timely treat cerebral diseases and nutritional deficiency, to strengthen antenatal diagnosis and early screening for inborn metabolic diseases as secondary prevention, and (3) to strengthen education, behavioral training and psychological rehabilitation, and to provide community-based rehabilitation service for the mental retarded as tertiary prevention. PMID- 7842894 TI - [A follow-up study on 103 HBsAg carriers during 16-21 years]. AB - One hundred and three HBsAg carriers were followed up for 16-21 years with an average of 18.6 years. Results showed 30 of them recovered from carrier status. 26 became post-hepatitis carriers and 21 asymptomatic carriers, six suffered from acute hepatitis B and seven chronic active hepatitis, and 13 died. Negative conversion rate of HBsAg averaged 33.3% with 13.8% for those aged 30 or less and 42.6% for those over 30. Negative conversion rate of HBsAg and recover rate in carriers with high-titer HBsAg were very significantly lower, and incidence rates of acute hepatitis B and chronic active hepatitis significantly higher than those with low titer. PMID- 7842895 TI - [A study on alcohol drinking pattern in freshmen and sophomores]. AB - Alcohol drinking pattern in 871 freshmen and sophomores of Han nationality was studied. Results showed 92.7% of the male and 72.9% of the female students were alcohol drinkers. There were highly significant differences in alcohol drinking pattern and types of alcoholic beverage they drank between males and females (P < 0.0001), and between students specializing in different subjects (P < 0.01). Alcohol drinking pattern of male students was influenced by their academic concerns and the drinking behavior of their fathers and friends. PMID- 7842896 TI - [Effects of chloroform, chlorobenzene and polychlorinated biphenyls on erythrocyte lipid peroxidation and membrane fluidity in poisoned rabbits]. AB - Effects of three chlorinated compounds, i.e., chloroform, chlorobenzene and Aroclor 1254 (PCBs), on lipid peroxidation and membrane fluidity of erythrocytes in poisoned rabbits were studied. Results revealed daily intraperitoneal injection of peanut oil containing chlorinated compounds into rabbits showed nonenzymic promotion effects on its erythrocyte lipid peroxidation in varying degrees, but different effects on erythrocyte membrane fluidity, promoting by chloroform and inhibiting by Aroclor 1254. It suggested the constitutional characteristics of toxicant molecules also had effects on membrane fluidity. In addition, it was found there existed potential relationship between maintenance of cell morphology and membrane fluidity. PMID- 7842897 TI - [Vaccination--past, present and future]. PMID- 7842898 TI - [Experimental study and clinical application of endothelium seeded vena caval prostheses]. AB - One hundred and eleven mongrel dogs were used for this study. Endothelial cells were harvested from jugular vein or omentum with methods of collagenase digestion and density gradient separation. Animal model of prosthetic interposition into the inferior vena cava with or without distal arteriovenous fistula was established. The complete endothelialization was established 5 to 10 days following a high density seeding. The neointimal hyperplasia was inhibited. A 100 day 100% patency of prosthesis was reached. The seeded endothelium secreted higher level of PGI2 than normal control and lower level of TXB2, hence the positive effect of distal AVF functioning for a week on the patency was demonstrated. This method used in 10 cases with Budd-Chiari syndrome resulting in good outcome after 3 to 5 years follow-up. We conclude that the endothelial seeding technique has a promising future using in the venous circuit. PMID- 7842899 TI - [Dacron grafts transplanted to abdominal aorta of dogs in different stages: histomorphological study]. AB - After dacron vessel transplantation in 10 dogs, we analysed the middle-bore Chinese dacron grafts transplanted to the abdominal aorta of dogs and observed histomorphologically changes of the grafts in different stages within 12 weeks. 2cm-long dacron artificial vessel transplantation to the abdominal aorta took 4 weeks for the new endothelial membrane, which mainly comes from the proliferation of the contiguous arterial endothelial smooth muscle fibers, to cover the inner wall of the grafts. More time was needed for endothelial cells than the self vessels to cover the dacron grafts the dacron grafts endothelial membrane was not intact and stable in 7 weeks after operation. The autoclaving dacron grafts should not be used repeatedly. PMID- 7842900 TI - [Study on correlation of valvular function of deep vein and clinical symptoms]. AB - The material consists of 291 cases (299 limbs) in which all limbs have varicosity of superficial vein. Routine conventional venographic examinations were performed. Valsalva's test was adauted to observe the valvular function of the deep vein. The statistics showed close corelationship between valvular functional state and clinic manifestations (P < 0.005). In maintenance of the normal function of the vein in lower extremities, the valvular function of femoral vein together with that of the popliteal vein is better than each alone. The valvular function of the femoral vein is more efficient than that of popliteal vein. PMID- 7842901 TI - [Evolution of biomechanical changes and microstructural components in autogenous vein grafts]. AB - We evaluated the compliance characteristics of autogenous vein grafts clinically and experimentally. The image analysis instrument was applied in measuring the relative contents of elastin and collagen of the grafts. The results showed the consistent compliance mismatch between the vein graft and the host artery, but no definitive bearing on abnormal blood flow velocity waveform by the compliance mismatch. The compliance characteristics of the vein graft resembled these of the vein rather than those of the artery. The relative contents of elastin and collagen within the graft wall and the ratio of collagen to elastin (C/E) did not change significantly as a function of time. The vein graft and vein had the similar value of C/E, which was lower than that of the artery. PMID- 7842902 TI - [SEM image analysis of endothelial cells of autogenous vein grafts]. AB - The autogenous veins of 17 dogs were distended with 40kPa, 80kPa and 120kPa pressure prior to grafting to femoral arteries respectively. The sections were harvested immediately, and after 1 week, 4 and 16 weeks and inspected with SEM. The endothelial cells of grafted veins were studied with an image analysis system. The results showed that the desquamation extent of intimal layer correlated positively with pressure. 80 and 120kPa caused relatively severe damage to the endothelium, which was significantly different from that of control group (P < 0.05). We conclude that preimplantation distention of vein grafts should be employed with less than 80kPa pressure, and 120kPa can never be used in clinic, as it adversely affects the course of reendotheli alization. The distention did not make a notable impact to graft patency rate as demonstrated in this experiment. PMID- 7842903 TI - [Surgical treatment of atherosclerotic occlusion of lower extremities]. AB - 27 patients with atherosclerotic occlusion of lower extremities were admitted from January 1988 to December 1992. Those patients underwent various kinds of bypass operations, with an effective rate of 86.8%. Some factors influencing the operative effect are discussed. PMID- 7842904 TI - [Treatment of middle stage arterial embolism through both Fogarty catheter embolectomy and directly pouring thrombolytic agents into artery]. AB - We treated successfully 9 patients with middle stage arterial embolism through both Fogarty catheter embolectomy and directly pouring thrombolytic agents into artery. In all patients the extremities were salvaged and symptoms disappeared. The patients were operated upon 15, 30, 60 hours and 3, 5, 8, 30, 39, 40 days respectively after onset of the disease. The indications for this treatment are dependent on how many hours last between onset and treatment and whether the extremity is gangrened. The main embolus in the greater artery can be removed by Fogarty catheter, while the thrombosis in smaller artery can be resolved by directly arterial luminal pouring thrombolytic agents, so the result is better if the two methods are combined. PMID- 7842905 TI - [Subclavian steal syndrome: a report of 25 cases]. AB - From 1982 to 1992, 25 patients with subclavian steal syndrome (SSS) were admitted with 20 undergoing surgery. Etiology included atherosclerosis 56% (14/25), Takayasu's disease 36% (9/25), 14 of them were smokers. Stenosis or occlusion of the left subclavian artery were found in 14, the right in 7, and bilateral in 4. 14 cases had vertigo symptoms, 24 cases had claudication of the arm, 9 of them complained transient ischemic attack (TIA). Carotid to subclavian bypass were performed for 15 cases. Two patients underwent axilloaxillary bypass with evidence of both clinical and laboratory improvement. Aorta-Carotid graft bypass was done in 2 cases with good result in one. PTA was done for a girl with innominate severe stenosis but symptom recurred three months later. Symptoms of the upper extremity ischemia were relieved in 75% of the patients, and of the cerebrovascular ischemia in 50%. Our conclusion is that surgical therapy remains the treatment of choice in symptomatic patients. PMID- 7842906 TI - [Noninvasive diagnosis of thoracic outlet syndrome]. AB - Doppler ultrasound and photoplethysmography for the diagnosis of thoracic outlet syndrome was described in this article. There were 14 cases clinically confirmed, 16 cases highly suspected, and 10 cases of normal control. The positive rates were 92% (13/14), 50% (8/16) and 0% (0/10) respectively. The results showed remarkably consistent with the clinical diagnosis. This method has provided a reliable objective evidence for the clinical diagnosis and treatment of this condition. PMID- 7842907 TI - [Intraoperative radiotherapy of unresectable pancreatic carcinoma]. AB - During the period from 1986 to 1991, 33 patients with unresectable carcinoma of the pancreas received intraoperative radiotherapy (IORT). Abdominal and back pain which tormented all patients before IORT totally disappeared in 18 patients (54%) and was allevrited in 13 patients (40%). The average survival time of 6.5 months for patients treated with IORT was not statistically different from that of 30 patients with resectable pancreatic cancers undergoing resection. IORT hence is a good palliative therapy for unresectable carcinoma of the pancreas. PMID- 7842908 TI - [Experience in the surgical treatment of hepatic hydatidosis]. AB - Of 1290 cases of hydatidosis hospitalized, 907 (70.3%) cases of hepatic hydatid cyst (HHC) were treated surgically (1954-1990). Of the 907 cases, 484 (53.3%) were males and 423 (46.7%) females. Hepatic hydatid cysts were single in 54%, multiple in 21.2% and complicated with hydatid cysts of other organs in 24.8%. 67.5% of the cysts were in the right lobe of the liver, 15.6% in the left lobe, 16.9% in both lobes. 79.0% were situated in the right lower part of the liver, 21.0% on the dome of the liver. Rupture of the cysts into biliary system, peritoneal cavity, the thorax (pulmonary-bronchial tree) and the pericardial sac were 35 (30%), 50 (42.6%), 31 (26.5%) and 1 case (0.9%) respectively. There were 5 deaths. Our experiences include: (1) routine intravenous drip of corticosteroids to alleviate the possible occurrence of allergic reaction during the operation and postoperative hyperpyrexia. (2) mebendazole or albendazole (ABZ) 20 mg/kg/d for one week before operation and 1-2 courses (1 course = 30 days) after operation to destroy the protoscoleces left in the body during operation. (3) antibiotics administration in complicated cases. (4) closure of intrahepatic biliary fistula. PMID- 7842909 TI - [Failure of unicompartmental tibiofemoral prosthesis in treatment of arthrosis: clinical study of 34 cases]. AB - We studied retrospectively and prospectively 34 cases of failed knee arthroplasty. The failure was mostly due to contralateral progressive arthrosis in the tibiofemoral joint (15 cases, 44.1%). Instabilization of the knee joint and abnormal ranked prosthesis second (9 cases, 26.5%), and loosening third (7 cases, 20.6%). Infections were noted only in 3 cases (8.8%). This prosthesis demands meticulous surgical techniques and strict indications because of its geometric characteristics and stabilization. Contralateral progressive arthrosis and abnormal prosthesis accounted for 70.0% in all, and were resulted from poor surgical technique and improper indications. PMID- 7842910 TI - [Correction of tetralogy of Fallot in patients with a single pulmonary artery]. AB - 2249 patients underwent correction of tetralogy of fallot in our department. 23 of them were with unilateral absence of pulmonary artery, 19 absence of the left pulmonary artery, 4 absence of the right pulmonary artery. The age at operation ranged from 4 to 21 years. Valve-containing conduits were used in 9 patients and right ventricular outflow patch in 14 patients. There were two operative death who both had hypoplasia of the left ventricle. All survivors had good early and late results. Outflow patch with a single valve should be used in tetralogy of fallot with a single pulmonary artery and pulmonary valve ring stenosis. Aorticvalved homograft conduit is suit for the patient with anomalous coronary or pulmonary atresia. PMID- 7842911 TI - [Clinical study on the use of multiglycosides of Tripterygium wilfordii after cadaveric kidney transplantation]. AB - Based on the animal experiments, we first used the multiglycosides of Tripterygium wilfordii (GTW) as a main immunosuppressive agent to treat the patients with cadaveric kidney transplantation instead of Azathioprine (Aza) from 1990. By clinical observation and 3-year follow-up, the result showed the GTW having a satisfactory immunosuppressive effect. In this study, there were 85 cases in control group (Aza+CSA+Pred) and 87 cases in therapeutic group (GTW+CSA+Pred). The normalizing times of graft function after transplantation taked 18.17 +/- 1.61 days in control group and 10.9 +/- 0.18 days in therapeutic group respectively. The 1-, and 2-year graft survival rates were 89.3 +/- 0.3% and 87.0 +/- 0.3% in control group, 96.1 +/- 0.2% and 90.4 +/- 0.6% in therapeutic group respectively. The difference of the normalization times of graft function and graft survival rates between the two groups had statistically significant (P < 0.01). The incidence of complication such as infection, liver function damaging, etc, in therapeutic group was lower than in control group. PMID- 7842912 TI - [Flow cytometry in diagnosis and treatment of bladder tumor]. AB - The cellular DNA contents of 139 bladder irrigations from 52 cases of bladder tumors were determined by flow cytometry. The results were compared with those of pathological grading and exfoliative cytology. It is suggested that cytological results were less accurate than DNA contents. High aneuploid DNA contents in tumor cells were marked by low grade and deep penetration of the bladder tumor. Total cystectomy was needed for bladder tumor with high aneuploid DNA, and partial cystectomy and TURBT for that tumor showed high recurrence with instillation of BCG. The results showed that DNA content of tumor is correlated with the nuclear grade, especially in poorly differentiated neoplasms, but flow cytometry can not replace cystoscopy examination. PMID- 7842913 TI - [Treatment of the lesions at anterolateral area of the brain stem via far-lateral approaches]. AB - Based on our 12 cases of lesions located at anterolateral area of brain stem which were successful operated upon via far-lateral approaches, the study and progress of the far-lateral approaches were reviewed. In our cases, there were 4 intramedullary lesions including 3 vascular malformations, and 1 glioma. The other 8 lesions were located at extramedullary anterolateral area of brain stem including 2 large acoustic neuromas, 2 meningiomas at clivus and 2 neurofibromas at anterolateral areas of the medulla oblongata and upper spinal cord, 1 teratoma at the anterolateral area of pone-medulla and 1 large aneurysm at the junction of vertebrobasilar artery. During the operations, 8 lesions were totally removed. 1 meningioma was subtotally removed. 2 (1 vascular malformation and 1 glioma) were subtotally removed too, the aneurysm was only given a decompression of increased intracranial pressure, because the patient's interrupted respiration during the operation. There were nooperative mortality and morbidity and good results were obtained in this group. The details of our modified far-lateral approach was also described in this paper. PMID- 7842914 TI - [Severe burn injury: glucose absorption and early enteral nutrition]. AB - We investigated the changes of glucose absorption and the effect of early enteral nutrition after severe burn injury. A new animal model was developed with a specially bred miniswine (Gui Zhou species) to which multiple catheterizations were applied for sampling different blood from the portal, inferior mesenteric as well as jugular (central) veins. The animals were sustained with 30% III burns of TBSA 7 days after the catheterizations and divided randomly into early feeding (EF) group, given a complete diet beginning from 2 hours postburn, and delayed feeding (DF) group, given the same diet on 4 days postburn. After burn injury, glucose absorption was significantly decreased, but the absorption was much lower in group DF than that in group EF. However, the intestinal ability of absorbing nutrients was not attenuated greatly, and the reduction of portal blood flow was attributed to the decrease of absorption of nutrients. Early enteral feeding can increase portal blood flow obviously. PMID- 7842915 TI - [Laser ablation of intervertebral disc: animal experiment]. AB - The lumbar intervertebral discs (L3-6) were ablated through a transperitoneal approach in 12 adult dogs by using Nd: YAG laser (1.06 microns) with a 600 microns quartz fiber. The status of limbs motion and sphincter (bladder, bowel) was observed for evaluating the safety of laser irradiation. After irradiation, the animals were sacrificed at prescribed intervals of up to 40 weeks (2, 4, 8, 12 and 40 weeks after operation). The lumbar intervertebral discs were harvested and subjected to light microscopic observation. No dog had suffered from neurogenic dysfunction of limb motion and sphincter. Histological findings immediately after the irradiation showed the disc was vaporized and a cavity was made. After 2 and 4 weeks, fibrous tissues began to proliferate, but cartilaginous tissues replaced the fibrous tissues 12 weeks after the laser irradiation. No new bone formation was found within 40 weeks after operation. On the basis of this study and our previous cadaveric study, percutaneous laser disc decompression (PLDD) was applied in clinical practice in march of 1993. 10 patients underwent PLDD utilizing the same laser equipment. The average follow-up was 3 months. According to the Macnab's criteria, there was an excellent response in 7 patients and a good response in 3. PMID- 7842916 TI - [Osteogenesis role played by dermal fibroblasts cultured in vitro]. AB - Fibroblasts were harvested by in vitro culture of split-thickness skin of New Zealand rabbit. Some opaque bone nodules were formed in the culture flasks when the fibroblasts underwent subculture for 8 days. Some of the nodules might enlarge, extend and form trabecula-like or flake-like structures, when the fibroblasts underwent subculture for 37 days. The above mentioned structures revealed golden-yellow fluorescence under the blue-violet light fluorescence microscope when the specimens were labeled with Tetracycline intravitally, denoting that they were newly formed bone tissues. In these structures, the calcium salt staining and collagen staining also showed positive reaction, fully reflecting the calcium and collagen composition. Osteogenesis caused by dermal fibroblast cultured in vitro was thus verified. There were evenly scattered oval spots in the osteogenic areas, after the specimens were treated with Alcina Blue Sirius Red stain. Their diameter was about 10 microns, and they stained yellow color by Picric Acid. Therefore, these spots colored yellow with Picric Acid might be the dermal epithelia (and/or endothelia), which induced the fibroblasts to form the bone tissues. PMID- 7842917 TI - [Injury severity score (ISS) in evaluation of patients with multiple injuries]. AB - Since there are short comings in injury severity score (ISS) for evaluation of multiple injuries. We modified it 482 cases by expanding the 3 injury sites of 3 main areas of ISS to 7 injury sites in 4 areas. Comparison of the two scores showed that in ISS, only 72.84% of the injuries were shown and in the modified about 97.56%. Statistical analysis and clinical observations indicated that that RISS is accurate in evaluating patients with multiple injuries. PMID- 7842918 TI - [The operative treatment of hip fracture in patient over 80 years old: report of 81 cases]. AB - The treatment of hip fracture in 81 cases of elderly (age ranged from 80 to 95) were reviewed. 13 of them were over 90 years old and 42 (52%) were accompanied with more than three preexistent diseases, mainly cardiovascular and cerebrovascular diseases. The femoral neck fracture (31 cases) were treated by Smith-Petersen nail or femoral head prosthesis replacement, the intertrochanteric fracture of femur (50 cases) were treated by McLaughlin or Richard nail. 24 cases (29.6%) had post-operative complications, e.g. pneumonia in 9 cases, cerebrovascular disease in 7 cases, cardio-vascular disease in 5 cases. Most of them recovered promptly after appropriate treatment. 5 patients died of pneumonia, the mortality is 6%. Internal fixation of hip fractures in elderly is one of very important methods of relieving pain, lowering morbidity and mortality, and early recovery of motion and normal daily life. It is believed that the proper evaluation of patient's general condition, appropriate treatment of preexistent disease, smooth anesthesia, skillful technique and intensive nursing care are needed for getting good results. The large majority of them will tolerate the operation nicely, even in high risk. PMID- 7842919 TI - [Clinical analysis of femoral neck fracture in 188 adult cases]. AB - There were 188 cases of femoral neck fracture of adult below the age of fifty five years old admitted to our hospital from 1974 to 1989, including 152 cases of fresh fracture, 36 old fracture. The rate of femoral head necrosis after fracture was 11.8 percent in the group of patients under fifty years of age, and 9.8 percent in patients between fifty-one and fifty five years old. The operation adopted in our series was mainly the percutaneous screw-thread pinning for internal fixation. Bone graft transplantation with the pedicle of quadratus femoris muscle was simultaneously performed in some cases, 26.7 percent in patients between the age of fifteen and twenty, along with the increase of age the patient number for transplantation decreased, only 7.8 percent in patients between the age of fifty-one and fifty-five. The author suggests that in treatment of femoral neck fracture of adult generally should not consider the use of artificial prosthesis replacement. We should decide according to the patients general and local status as the basis for the choice of a reasonable internal fixation, and consider whether an operation should be performed to further improve blood circulation of the femoral head. PMID- 7842920 TI - [Treatment of femoral trochanteric fracture with intramedullary interlocking nailing: a report of 32 cases]. AB - We improved and made the intramedullary interlocking nail and it's instrument for surgical operation in December 1989 by consulting the reported material of the gamma locking nail. 32 cases of the femoral trochanteric fracture were treated by using this fixation system. The results were satisfactory. The patients could stand up and move about beginning from 6th to 13th day after operation. No mechanical failure of implant, infection and other complications occurred in our series. 29 cases were followed-up for 5 to 19 months and showed all of the fractures were healed. Their hip functions were completely or basically recovered. Coxa vara deformity occurred in two cases and one had a 2.5 cm shortening of the lower limb. We consider that the intramedullary interlocking nail conforms to the principle of human biomechanics and it may be used as an effective surgical treatment with the fracture fixation of superior strength and stability for every type of femoral trochanteric fractures. PMID- 7842921 TI - [The treatment of severe talus fracture-dislocations and peritalus dislocations]. AB - Twenty-eight cases with severe talus fracture-dislocation and 17 cases with peritalus dislocations were treated and were followed up with an average of 7 years and 2 years plus 5 months for these two groups respectively. Comparison of the results of treatment in the cases with severe talus fracture-dislocations with 3 different methods (reduction and immobilization, total talus resection and arthrodesis) was made. Satisfactory result was obtained only in cases treated with arthrodesis, therefore, this method should be considered at first in the treatment of severe talus fracture-dislocations. Impaction of intraarticular fragments and soft tissues are usually the indications of open reduction for peritalus dislocations. Severity of injury accompanied with intraarticular fractures, and open injury are the factors influencing the prognosis. Different from severe talus fracture-dislocations, talus avascular necrosis did not occur in cases with peritalus dislocations. PMID- 7842922 TI - [Experimental study of fracture healing promotion with mechanical vibration in rabbits]. AB - Under aseptic operation, a 0.3mm defect each was resected in the middle shaft of both radii in 54 rabbits. One of 4 groups was subjected to vibration along the long axis of right radius in each healing stage. The feature of fracture healing was evaluated with X-ray film, pathological examinations and measurement of maximum resistance to bending force and pressing stress. The authors came to these preliminary results: (1) The vibration (12.5 approximately 200 Hz) promoted fracture healing; (2) A significant acceleration of fracture healing was seen at the vibrated radius in 3 approximately 4 weeks. PMID- 7842923 TI - [The effects of frequency of mechanical vibration on experimental fracture healing]. AB - Mechanical vibration was performed with 5 different frequencies after radius fracture of 76 rabbits. The vibration effects were evaluate by means of X-ray film and bio-mechanical and pathological examinations. Our results suggests: (1) Vibration promotes the fracture healing in rabbits regardless of the frequency. Both bone strength and speed of fracture healing are better than those of the controls. (2) Bone strength is elevated by 20% approximately 30% by the best stimulation of stress. (3) The best frequencies are 25Hz and 50Hz, second best, 12.5 and 100Hz and then, 200Hz. PMID- 7842924 TI - [Clinical and experimental studies of the dynamic changes in neuropeptides after trauma]. AB - Dynamic changes of contents of beta-endorphin, leu-enkephalin and oxytocin in plasma were determined in seventeen fracture patients with shock, fascial space syndromes, or infection postoperation. There was significant rise of contents in beta-endorphin and leu-enkephalin but not in oxytocin after trauma, Of those accompanied by infection postoperation, beta-endorphin and oxytocin remained high. The contents of beta-endorphin and enkephalin decreased gradually in non infectious group, but were still higher than normal. The most obvious change was seen in beta-endorphin, suggesting that beta-endorphin plays a more important role in trauma. This was also confirmed in rat injury model. PMID- 7842925 TI - [Clinical study on the type of operation in the treatment of acute necrotizing pancreatitis]. AB - The type of operation in the treatment of acute necrotizing pancreatitis (ANP) is still controversial. Seventy-two surgical cases of ANP by using three different approaches since 1985 were analyzed retrospectively. The total mortality rate was 25%. The sump drainage was used in 28 cases, marsupialization in 11 cases and retroperitoneal drainage in 33 cases. The mortality rates were 25%, 36.4% and 21% respectively. The selection of approaches should be determined by clinical pathological types and by whether or not there is a retroperitoneal invasion. Sump drainage is a simple approach for ANP and is preferable in cases of sporadic focal necrosis. For extensive fusional pancreatic necrosis not complicated with retroperitoneal invasion, marsupialization is used, and in those with the invasion retroperitoneal drainage is the procedure of choice. PMID- 7842926 TI - [Laparoscopic cholecystectomy performed in 235 cases of cholecystitis with impacted gallstones]. AB - During the past 2 years, 235 cases of cholecystitis with impacted gallstones were treated with laparoscopic technique. There were 221 chronic cases and 14 acute cases accounting altogether for 15.19% of a total of 1475 patients undergoing laparoscopic cholecystectomy during the same period. As a result, 9 of these patients were converted to open surgery. Severe adhesion around the gallbladder or/and in the Calot triangle in 7, acute impacted gallstone, gallbladder necrosis along with obscure anatomy in the calot triangle in 1, and gallstone impacted at the junction of the common hepatic and cystic duct in 1 were observed. Conversion rate was 3.8%. Postoperative bile leakage developed in 2 cases and healed spontaneously. There were no intraperitoneal sepsis and perioperative death in our patients. The diagnosis, classification, and management for acute or chronic impacted gallstone are discussed. PMID- 7842927 TI - [Effects of different lymph node clearances on long-term survival in patients with gastric carcinoma]. AB - From 1980 to 1987, radical gastrectomy plus R2 or R3 lymph node clearance was performed in 309 cases of gastric carcinoma of which 179 were with R2 and 130 with R3. The 1, 3, 5 years survival rate of R3 was statistically higher than that of R2. The 5 years survival rate of R2 was nearly the same as R3 in patients at stage I (I a, I b) and borrmann type I and II, While R3 yields better results than R2 at stage II and III a, it was even 25.5% higher by R3 than by R2 at II b and IV. R3 still benefits patients at stage II with serosa infiltration, R3 should also be performed in advanced cases with poorly biologic behavior, such as diffuse growth pattern; undifferentiated cancer and lymphatic cancerous embosis. The recovery time, complications and mortalities of patients with R2 or R3 were mainly related to the model of gastrectomy not to the extent of lymph node clearance. PMID- 7842928 TI - [The diagnosis and surgical treatment of Leriches syndrome: an analysis of 16 cases]. AB - The authors report 16 cases of atherosclerotic obliteration of the terminal abdominal aorta seen in the period of 1987-1991. Early diagnosis can be made by using color doppler, and angiography and DSA are very important to determinate the clinical patterns and occlusive locations. A/B Index is also valuable in the diagnosis and treatment. Clinically, it should be differentiated from orthopedic, neurologic and urologic diseases, surgical procedure varies with occlusive location, clinical patterns, general status, and conditions of the affected blood vessels. Follow-up found that Y type aorto-femoral bypass get the best result with one-year unobstructed rate of 100% in all cases, and five-year cumulative unobstructed rate of 75%. The outcome of auxiliary-femoral bypass grafts were the least satisfactory, with the five-year cumulative unobstructed rate of only 34%. Comprehensive therapy should be adopted to improve the long-term cumulative unobstructed rate. PMID- 7842929 TI - [Staged surgery in the treatment of Budd-Chiari's syndrome of mixed type]. AB - 9 patients with Budd-Chiari's syndrome of mixed type were operated upon. Among them 3 cases were treated by percutaneous transluminal angioplasty using balloon catheters, and 1 to 2 weeks after followed by Hassab's procedure and Linton's procedure. Two cases were treated by incision and plasty of IVC, and 1 month after followed by Hassab's procedure and Linton's procedure. The remaining 4 were treated by prehepatic cavoatrial shunt, succeeded by Hassab's procedure and Linton's procedure one month after. 6 to 24 months' follow up of the 9 cases revealed satisfactory results. PMID- 7842931 TI - [Preliminary experience of use of ultrasonic surgical aspirator for lung limited resection]. AB - The authors reported 8 cases undergone lung limited resections (11 operations) by cavitron ultrasonic surgical aspirator (CUSA). There were 3 cases (6 operations) with multiple metastases in lung, 1 case with single metastasis in lung, 1 case with peripheric lung cancer, 1 case with nodule of tuberculosis in lung, 1 case with lung abscess and 1 case with lung cyst. All the patients recovered well postoperatively. Until now 4 cases with lung metastatic tumors have living well for 3.5, 1, 0.5, and 0.3 years. Ultrasonic Aspiration is very beneficial for lung limited resection: Less blood lose; Simple surgical techniques; and to be able to resect the deep lesions in lung and multiple lung lesions, and avoid lobectomy or pneumonectomy for more preserving lung tissue. PMID- 7842932 TI - [Methicillin-resistant Staphylococcus aureus infection and its treatment in burned patients]. AB - Burn wound and systemic infections caused by methicillin-resistant Staphylococcus aureus (MRSA) were analysed in 95 patients. Results showed that both 95 (92.2%) out of 103 strains of Staphylococcus aureus isolated from burn wound and all 17 strains from blood were MRSA. Wound MRSA infection could be found in patients with variety of severity and in any kind of wound, while systemic MRSA infection was often occurred in extensive burn patients. The isolated MRSA were most resistant to cephalosporins and sensitive to vancomycin. In order to control wound MRSA infection, Lysostaphin which is active against these organisms could be used as a topical antimicrobial. PMID- 7842930 TI - [Diagnosis and management of pericardial cysts and diverticulum]. AB - Eleven cases of pericardial cysts and 3 cases of pericardial diverticulum were reported. The prominent X-ray manifestations were a round or oval shape shadow with homogeneous density and smooth border in the mediastinum. In this series, the sizes of the lesions were 5-22 cm in diameter with averaged 9.9 cm. In the cases of pericardial diverticulum with a large base, fluoroscopic examination usually revealed that variation in contour of diventiculums during respiration and changing in position of the patients. Some aspects on the operation for pericardial cysts with secondary infection or adhering to the cardiac muscles were suggested in this paper. PMID- 7842933 TI - [Biomechanical study on bone healing in experimental limb lengthening]. AB - In this experiment, 32 goats were performed osteotomy limb lengthening by tibial upper metaphyseal. The strength, stiffness and energy absorption of the lengthened bone had been measured in different period after the lengthening ceased. The results demonstrated that during the lengthened bone healing process, the recovery of bone mechanical properties is compatible with its histological changes; and the healing process of lengthened bone can be roughly divided into three biomechanical stages: (1) Low strength and low stiffness stage; (2) Low strength and high stiffness stage; (3) High strength and high stiffness stage. PMID- 7842934 TI - [Culture of cartilaginoid tissue reconstituted by chondrocytes embedded within collagen gels]. AB - Chondrocytes from the sterna of embryonal chicken were dissociated by enzymatic digestion. Dissociated cells were cultured within collagen gels for 8 days. The cells increased 3 fold in 8 days. The gels gradually became white cartilaginoid tissue in appearance. Morphologic study showed that cells lied in lacunae and maintained the differentiated characteristics of cartilage. Extracellular matrix produced by cells deposited on exogenous collagen. Biochemical analysis showed that the collagen newly synthesised by the cells was type II collagen. This experiment demonstrates that collagen gels provide a suitable environment for chondrocyte growth, proliferation and differentiation, and chondrocytes embedded within collagen gels reconstitute cartilaginoid tissue. PMID- 7842935 TI - [The contrast enhanced ultrasonography of hepatic vessels]. PMID- 7842936 TI - [Preoperative evaluation of resectability of hilar bile duct carcinoma by color Doppler flow imaging and duplex Doppler]. AB - Color flow images of hilar bile duct carcinoma and the relationship between tumors and hilar important blood vessals were observed in 22 patients with hilar bile duct carcinoma by color Doppler flow imaging (CDFI) and Duplex Doppler. It was found that most of bile duct carcinoma were of oligovascularity. Accurate rate were 81.82% and 77.28% respectively by preoperative ultrasound evaluation of the relationship between the tumor and the portal vein, and the tumor and the hepatic artery. CDFI and Duplex Doppler are sensitive, convenient and noninvasive methods for preoperative evaluation of resectability of hilar bile duct carcinoma and provide important information for surgery. PMID- 7842937 TI - [The diagnosis and surgical treatment of cholelithiasis of the caudal lobe of the liver]. AB - From June 1983 to Feb. 1993, a total of 528 patients with hepatobiliary stones were surgically treated by hepatoenterostomy with a basin-typed plasty at the stump of hilar bile duct. Among them there were 220 cases suffering from cholelithiasis in the caudal lobe, with an average age of 39.1 years. Preoperative sonography, PTC, ERCP, and CT all failed to find stones in this particular location. In the 220 cases, simple caudal lobe stones accounted for 14.5%, caudal lobe stones with bile duct abnormality accounted for 46.8%, and stones with stricture of the duct for 46.4%. Surgical treatment included bile duct dilatation, cholangiotomy, and cholangioplasty and direct chilangiotomy in the caudal lobe. PMID- 7842938 TI - [Surgical treatment for hilar bile duct stricture]. AB - 474 patients suffering from hilar bile duct strictures were treated from 1975 to 1992. 74.7% of the patients had a history of biliary surgery for 1-5 times. Causes of strictures were of iatrogenic in 10.9%, of primary in 71.7%, and of suppurative in 7.1%. Site of strictures: LHD in 37.6%, LHD+RHD+CHD in 17.4%, RHD in 9.6%, CHD in 14.7%, and LHD+RHD in 11.5%. The inferior end of the CBD were of spasmodic or flaccid in 23.6% and 48.3%, respectively. Treatment included cholangioplasty in 56.5%, dilatation and stent in 15.2%, lobectomy and segmetectomy of involued liver in 48%, repairing in 11.4%, bilio-enterostomy in 60.7%, and portal vein decompression in 6.3%. PMID- 7842939 TI - [Cholangioplasty by using a patch of bovine pericardium in the treatment of stricture of extrahepatic bile duct]. AB - From Sept. 1989 to Jan. 1994, processed fresh bovine pericardium was used for the repairment of stricture of extrahepatic bile duct in 6 cases (7 times). All patients have been followed up for 8 approximately 52 months (average 24 months). One case reoperated on for recurrent jaundice on 26th month postoperation. All cases are alive and in good health, without any clinical symptom. PMID- 7842940 TI - [Isolation, purification and the characteristics of 70 KD pronucleation glycoprotein in the bile]. AB - In recent years, the great achievement in the etiology of cholelithiasis is the discovery of pro- and anti-nucleating factors in human bile. Using Con-A affinity chromatography combined with Sephadex G-200 molecular sieve technique, we have isolated and purified a strong pronucleating glycoprotein in gallbladder bile. Its molecular weight is 70KD, the quantity ratio of neutral hexose to protein in this glycoprotein is 15.88%. One molecule has about 640 amino acid residues. Its N-terminal amino acid sequence is N-Ser-His-Gly-Met-Arg-Gln-Tyr-Tyr-Met-Lys. The pathogenic and biological significance of this glycoprotein in the pathogenesis of gallstone were discussed. PMID- 7842941 TI - [Study on motor function of the esophagus by SG-II computer manometer]. AB - The manometric studies of esophageal motility were performed on 30 normal subjects. Pressures were detected with a 3-microtransducer catheter following wet swallow. The measure, record and data processing were performed with the computer. The values obtained by us were compared with those reported by other laboratories. We consider that this method is simple, quick and accurate. PMID- 7842942 TI - [Study on surgical resection length of esophageal carcinoma: an analysis of 2325 cases of the resected samples with esophageal carcinoma]. AB - The paper studied the relationship between the resected length above and below the esophageal carcinoma and positive rate of the residual carcinoma in the resected rims. The positive rates of the carcinoma were 65.0%, 17.2%, 12.3%, 10.6%, 6.7%, 5.8%, 4.0%, 3.1%, 2.0%, 0.9% and 0% respectively while the length of the resected esophagus above and below the carcinoma was 1-10 cm and 10 cm respectively. The results shown that it would be the best for all patients with esophaged carcinoma to resect esophagus more than 10 cm in length above and below the carcinoma respectively. PMID- 7842943 TI - [Evaluation of MRI of knee by arthroscopy]. AB - Between August 1989 and April 1993, 61 patients (68 knees) suspected of having intraarticular knee pathology underwent magnetic resonance imaging (MRI) before arthroscopy. In order to evaluate the diagnostic value of the MRI of knee joints, a retrospective study was undertaken. The analysis of the correlation between the arthroscopic findings and the results of MRI indicated the high sensitivity and specificity of MRI in diagnosing disorders of the knee joint. Also the characteristics of MRI of knee and the affecting factors have been discussed in this paper. PMID- 7842945 TI - [Evaluation of multiple prognostic factors in colorectal cancer]. AB - A multivariate stepwise discriminant analysis was performed to evaluate the prognostic value of DI, PI, AgNOR, p21D, CEAD and several clinicopathological features (age, sex, tumor location, histological grading, typing and staging) in 83 patients with colorectal cancer who underwent radical surgery. A fisher's discriminant function was established by using 6 selected items (staging, grading, DI, PI, AgNOR and p21D). It's efficiency, sensitivity and specificity were 91.28%, 87.18%, and 95.45% respectively. Correlative studies on DI, PI, AgNOR and p21D indicated that they are independent factors influencing prognosis. Therefore, in addition to Dukes's classification and histopathological grading of the tumor, these molecular biological factors can be considered as a new clue to evaluation of patients prognosis. PMID- 7842944 TI - [Comparative study on MRI and arthroscopic findings of knee joint]. AB - A retrospective analysis of MRI results of knee joints of 40 patients with routine arthroscopic operation was performed by the authors. The results showed the accuracy rate of MRI for diagnosis of internal and external meniscus injury was 84.25% and 87.5%, and that for anterior and posterior cruciate ligament was 90.25% and 100.00%, respectively. Although MRI possessed good resolving capacity for soft tissue, the authors stress the attention should be paid to clinical data collection. PMID- 7842946 TI - [Study and application of dual interventional embolization in patients with acute gastroesophageal variceal bleeding]. AB - From Nov. 1991 to Nov. 1992, twelve cases of acute massive gastro-esophageal variceal bleeding with liver function grading III had been treated with dual interventional embolization (DIE). Hemostasis were successful in all patients during the acute phase. Ten partial splenic embolization (PSE) cases with their hypersplenism cured or improved. The liver function in survived cases were improved with various degree after DIE. The mechanism of DIE in the treatment of acute gastro-esophageal variceal bleeding had been discussed and the alterations in portal pressure, the histopathology of the spleen, the peripheral hematologic changes as well as the complications after DIE were analysed and discussed. The authors claimed that DIE is an alternative method in treating the advanced cirrhosis complicating massive variceal bleeding. PMID- 7842947 TI - [Diagnostic value of imaging in localizing primary aldosteronism]. AB - From May 1985 to March 1993, 159 patients with primary aldosteronism were treated surgically. The results of localization of aldosteronomas by B-type ultrasonography, CT and scintigraphy in 103 were compared with pathological results. The accurate rate of the modalities was 80.6%, 75.8% and 67.4% respectively. As a routine, we usually employ sonography and CT for localizing aldosteronomas. Only when difficulty was encountered with these two methods, scintigraphy was added. In our series, an accurate rate of 96.1% was obtained in surgical explorations with these imaging examinations with a consideration of clinical data. PMID- 7842948 TI - [Urogenital rhabdomyosarcoma in children: analysis of 39 cases]. AB - From 1967 to 1992, 39 patients with urogenital rhabdomyosarcoma were admitted to our hospital. Of them 30 were male and 8 female and their age ranged from 4 months to 14 years (32 were less than 5 years). Primary tumor was located in bladder or/and prostate in 26, paratesticule 9, vagina 3, and penis 1. Among the 31 patients receiving treatment, 23 were followed up. There were 15 (65%) survivors, including 13 who were free from tumor for over 4 years. The eldest two patients were 20 and 21 years of age. Two patients with vaginal tumor and 4 with bladder tumor preserved their organs with normal function. Biopsy were done only in 8 patients. In recent years, conservative surgery combined with chemotherapy for urogenital rhabdomyosarcoma has been justified. PMID- 7842949 TI - [Long-term results of meniscectomy]. AB - The long-term results after total meniscectomy in 60 patients have been reviewed with an average follow-up period of 16.1 years (10 to 33 years) and 58.3% excellent and good results were demonstrated. Statistical analysis showed that the late results were related to the time of follow-up and not associated with the length of history before operation. Radiological degeneration of the knee was seen in 87.5% of the patients, while no relationship between the degeneration and the clinical results was found. It is indicated from this retrospective study that the menisci are of so great importance in biomechanics that total meniscectomy should be as far as possible avoided. PMID- 7842950 TI - [Experimental study of myocardium protection with warm blood cardioplegia]. AB - The present paper has shown the effects of myocardial protection of isolated rat heart which were infused with different kinds of cardioplegia, and made to be arrested in the state of ischemia and absence of oxygen for 120 min. The heart rate, left ventricular constraction pressure and cardiac output volume, the myocardium water content and calcium content and pathological examination of myocardium were observed. The isolated rabbit heart under the circumstances of ischemia and absence of oxygen at 37 degrees C for 20 min Observations of the different kinds of cardioplegia. was observed that the different pH and oxygen content between artery and vein of the heart during the infusion of cardioplegia, the value of left ventricular constraction pressure multiplied by heart rates after reperfusion with autologous artery blood for 20 min. The values of CPK and MDA in right atrial blood, the ATP and CP volume of myocardium and pathologic study of myocardium were carried out. The results demonstrated that the warm blood cardioplegia had a better myocardial protection effect in supplying sufficient oxygen to myocardium during heart arrest, preserving and increasing energy store; controlling reperfusion in jury after ischemia, buffering acidosis and preserving heart status function. Therefore it has great value for improving the safety of the patients with complex and high risk heart diseases in perioperation. PMID- 7842951 TI - [The roles of macrophage in immune dysfunction following severe thermal injury]. AB - This experimental study in serious scald mice showed that the cytosolic free calcium ion concentration and the capacity of secreting TNF-alpha of macrophage (M phi) were obviously increased while the secretion of IL-1 was significantly decreased, and accompanied with simultaneous apparent rising of serum TNF-alpha in early postburn period. These indicate that M phi have been highly or even over activated after burn. But the ability of antigen presentation of M phi during this period was deeply suppressed rendering the obvious declination of activity and proliferation response of antigen pulsed lymphocytes. It might be concluded that the defective antigen presentation of M phi played a critical role in early immune dysfunction of severe scald mice, and the highly activated or even overactivated M phi by excessive secretion of TNF-alpha were the molecular basis of the alterations of M phi function. PMID- 7842952 TI - [BMP1 fusion protein expressed in E. coli]. AB - The expression plasmid pMS32C/BMP1 was constructed successfully by using recombinant DNA techniques. The validity of the reconstructed plasmid was confirmed by restriction map of PMS32C/BMP1 plasmid. Then the 66KD BMP1 fusion protein was highly expressed in E. coli, which accounting for 20% of total bacterial proteins. The expressed protein was purified by means of SDS-PAGE. The antiserum of BMP1 fusion protein was prepared by immunization of mice. The antisera immunoprecipitated with fusion protein and specifically bound to BMPs purified from human bone with high titer in immuno-dot assay. It is indicated that the BMP1 fusion protein contains human BMP moiety. PMID- 7842953 TI - [Surgical treatment of combined valvular disease in 680 patients]. AB - Between 1982 and May 1993, we operated on 680 patients with combined valvular disease. Previous operations were including closed mitral commissurotomy in 87, and bioprosthetic valve replacement in mitral position in 15. The types of combined valve disease included mitral valve disease combined with functional tricuspid regurgitation (FTR) (245), with organic tricuspid disease (OTD) (10); mitral and aortic disease (258), combined with FTR (128), and with OTD (39). The early mortality was 4.7% in total 2.4% and 6.1% respectively in MVR or DVR plus tricuspid procedures. The main cause of early death was low cardiac output syndrome. The late mortality was 2.6% pt-yr, congestive heart failure and coagulant-related hemorrhage were the predominant causes of late death. We considered that FTR is the outcome of right ventricle decompensation, while tricuspid valve must be actively inspected intraoperatively, and must be corrected completely. OTD can be successfully repaired in most patients. Myocardial protection should be emphasized, and continuous perfusion of cold blood cardioplegia and controlled reperfusion of warm blood contained mannitol have marked effect. PMID- 7842954 TI - [Clinical and morphologic classification of valve replacement with giant heart]. AB - From Apr. 1977 to Dec. 1992, 285 patients with giant heart (CTR > 0.70) underwent valve replacement. According to the index of cardiac chamber enlargement, the patients were clinically and morphologically classified in to four types. Type of left atrium (153 cases, 56.3%) is most common and has good surgical result. The operative mortality was reduced from 11.1% to 1.3%. Type of left ventricle (42, 15.2%) was high risk for surgical treatment, the operative mortality was 33.3%. Type of right cardiac enlargement (17 cases) is less common than other types, and is mainly for tricuspid valve incompetence. Type of total cardiac enlargement was found in 60 cases (22.1%), it was conventionally complicated with the disfunction of other organs with a higher operative mortality of 23.3%. We conclude that this classification represents the degree of cardiac chamber enlargement and the severity of heart disfunction, and has good coincidence with surgical result. It is helpful to identifying operative candidate for valve replacement with giant heart. PMID- 7842955 TI - [Pathological classification and clinical implications on rheumatic heart disease with giant heart]. AB - Between Jan. 1982 and July, 1993, 102 patients with rheumatic giant heart disease (cardio-thoracic ratio > or = 0.8) underwent valve replacement. Heart functional class III was in 54 patients, and class IV in 48. Early mortality was 8.8%, late mortality 3.6%. We classified the patients into five types, based on the valvular lesions, dilated degree of each atrial and ventricular chamber: Type I, giant left atrium (LA); Type II, obvious enlargement of LA and left ventricle (LV); Type III; obvious enlargement of LA, right atrium and ventricule (RA and RV); Type IV; all chambers obviously dilated; Type V, giant LA and RA. Clinical results showed that this kind of classification can reflect kinds of diseased valves, pathophysiological changes and clinical characteristics, and postoperative early and late outcomes, also can offer useful suggestions to operative method selection, and has great clinical significance for perioperative management. PMID- 7842956 TI - [Double valve replacement in 400 cases]. AB - From 1985 to 1992, 400 patients received mitral and aortic double valve replacement. Of the patients, 218 were male and 187 female. In early operative days, 6.25% of the patients died. Follow-up study showed that 91.3% of the patients are alive. Perioperative management and improvement of operative technics are detailed. PMID- 7842957 TI - [Treatment of MSOF after heart valve replacement: an analysis of 53 cases]. AB - We treated 53 patients with multiple system organ failure (MSOF) following heart valve replacement. MVR was performed in 20 cases, AVR in 6 and DVR in 27. Before operation, NYHA functional class II was in 5, III in 17, and IV in 31. MSOF of all 53 patients occurred within 2-7 days after operation, and failing organs involved heart, lungs, kidneys, brain, gastrointestinal and blood coagulation system. The patients with the maximum organ failure had 6 failing organs, 36 of the 53 patients were living and 17 (32.1%) died. The mortality correlated positively with the number of failing organs. The results of MSOF which occurred sequentially were better compared with those occurred simultaneously. The death rate in patients with class IV was higher than that in those class II, III. The type of operation (MVR, AVR, DVR) did not effect the result of MSOF. The causes and management of MSOF after heart valve replacement were discussed. PMID- 7842958 TI - [Laparoscopic resection of the adrenal tumor]. AB - Laparoscopic resection of the adrenal tumor was carried out in 8 patients since January 1993. The age of the patients was 22 to 45 years, 6 with aldosteronism and 2 with Cushing's syndrome. The tumors were located in righ adrenal in 5 cases and left adrenal in 3. The tumor size was 1.0-3.6 cm. All laparoscopic procedures were performed under general edothacheal anesthesia. The operative time ranged from 90 minutes to 4 hours. Bleeding volume during the operation was 20-90 ml. We developed a reliable technique for adrenal tumor using a laparoscopic approach. The anatomy of adrenal glands, operative indications and complications are discussed. Laparoscopic resection of the adrenal tecmos is a valuable method. PMID- 7842959 TI - [Treatment of refractory acute rejection after renal transplantation with lymphogloline]. AB - 156 patients received renal transplantation in the Nanfang Hospital from October 1992 to December 1993. 27 patients developed refractory acute rejection (RAR). Of them, rejection was reversed completely with lymphogloline (ATG) in 22 patients and reversed with OKT3 in 4. One patient died of cerebral hemorrhage after removal of the donor's kidney. The results suggest that ATG is safe, effective, highly specific, sensitive, and of less side-effect. The pathogenesis, diagnosis of RAR and cautions for ATG are discussed. PMID- 7842960 TI - [Surgical management of hepatic trauma]. AB - In the past 37 years, 207 patients with hepatic injuries were managed in our hospital. Of them, 5 patients died during the preparation for emergency laparotomy. 191 patients were surgically treated, with 11 (5.8%) postoperative deaths, while all 11 patients treated nonsurgically were cured. Finally, we discussed operative methods of hepatic injuries and indications for conservative therapy. PMID- 7842961 TI - [Adenomyomatosis of the gallbladder: report of 42 cases]. AB - This article reported 42 cases of adenomyomatosis of the gallbladder diagnosed by postoperative pathology. Since adenomyomatosis is often asymptomatic and accompanied by cholecystitis and gallstone, it is difficult to diagnose correctly before operation. Seven cases out of this group (16.7%) was diagnosed preoperatively. Correct diagnosis is based on alertness to this disease and cholecystogram. Cholecystectomy is the effective treatment. The relationship between the pathological types and Cholecystogram are discussed. PMID- 7842962 TI - [Diagnosis and treatment of presacral tumors: report of 28 cases]. AB - Tumors in presacral space are uncommon. From 1980-1991, 28 patients with presacral tumors underwent surgical operation at PUMC Hospital. Most tumors are of the congenital type (epidermoid, teratoma and chordoma). 9 patients had no symptoms and their tumors were found on routine anal examination. Ultrasound and CT scans had been proved valuable in the diagnosis of presacral tumors. The tumor was completely resected in 23, incompletely resected in 2 without operative mortality. The diagnosis and surgical management of presacral tumors were discussed. PMID- 7842963 TI - [The clinical significance of nuclear DNA content measurements in pancreatic neoplasms and their Kaplan-Meier survival analysis]. AB - Between 1979 and 1991, 48 cases of pancreatic paraffin-embedded specimens, ie 32 carcinomas and 16 islet cell tumors, confirmed by operative and pathological examination, were studied by flow cytometric nuclear DNA content measurements. 10 specimens taken from the normal pancreatic tissue nearby the tumor transection margin and another 8 specimens in pancreatitis were compared as controls. The results demonstrated that the aneuploid rate and DNA index in pancreatic carcinoma was obviously higher than that of non-pancreatic tumor (P < 0.01). In the field of pancreatic carcinoma, the S-phase fraction was much higher in aneuploid specimens (P < 0.05). Then the nuclear DNA content was a relatively independent factor to evaluate the cancerous biological behavior. The surgical resectability of pancreatic tumors with diploid DNA was significantly higher than aneuploid ones (P < 0.05), and the later carried a shorter survival time proved by Kaplan-Meier survival analysis (P < 0.05). Finally, the clinical significance of DNA content measurements in islet cell tumor was also discussed. PMID- 7842964 TI - [Flow cytometric analysis of DNA in giant cell tumor of bone]. AB - The DNA content of 44 giant cell tumors (GCTs) was determined by flow cytometry and simultaneous analysis of cell surface antigens and cellular DNA was performed in two of these GCTs. Two grade III GCTs, one with lung metastases, were all aneuploid. Out of 42 grades I and II GCTs, 16 were aneuploid, statistically, there was no difference in proliferative activity and rate of aneuploidy between grade I and grade II GCTs, but significant difference between primary and local recurrent GCTs existed. After 5 passages in culture the proliferative rate of cells in 13 GCTs increased significantly, the rate of cells bearing GCT associated antigen stepped up and in 2 GCTs tested specially. All these findings demonstrate: (1) the morphological difference of these tumors was not remarkable (2) DNA determinations as an adjunct to conventional histopathologic assessment may provide objective clinically relevant information for prognosis, (3) tumor and non-tumor cells co-exist in GCTs and only tumor cells could survive in long term culture in vitro. PMID- 7842965 TI - [The experimental study of the canine auxiliary partial liver transplantation for the liver failure]. AB - A model of hepatic failure was established by injection of galactosamine in CCL4 induced liver cirrhosis. Auxiliary partial liver transplantation (APLT) was carried out to treat those dogs. The survival rate, biochemical change patterns, and histologic changes were investigated in both APLT group and control group. The survival rate in APLT and control group was 59.1% and 7.1% respectively, (P < 0.01). Fair supporting graft function was demonstrated by uptake and excretion of 99mTC-HIDA and 99mTC-DIASA at cholescintigraphy, ammonia aetoxification, synthesis of clotting factors and glucohomeostasis. The results indicate that auxiliary transplantation of a partial liver proviae metabolic support and improve survival in animals with hepatic failure. The character of the model, the advantages and the disadvantages of the APLT, were also discussed. PMID- 7842966 TI - [Distal blood pressure changes after ligation of the femoral artery or vein in the rat]. AB - In the rat, immediately after ligation of the femoral artery below the profundus branch, the intraluminal pressure at the distal part dropped from 15.80kPa to 4.82kPa, and continued to decrease even after seven days. For the femoral vein, the distal intraluminal pressure rose from 0.67kPa to 3.91kPa in one minute. After one hour it dropped slowly and reached 1.25kPa after 24 hours. After seven days it was 0.74kPa. The author consider that it is unsuitable for the distal cut end of an artery or a vein to be used as the feeding vessel in microvascular free tissue transfer, because lowered blood pressure might result in inadequate tissue perfusion. When a big artery of limb was injured, it should be repaired no matter whether the collateral branch can maintain the distal circulation of the limb or not. PMID- 7842967 TI - [Superficial femoral vein valvuloplasty under direct angioscopic vision]. AB - Superficial femoral vein valvuloplasty (SFV) under direct angioscopic vision without venotomy was designed and performed in 18 patients (20 limbs), suffering from primary SFV valve incompetence and the primary popliteal vein valve insufficiency. The indication of the operation is that the valves developed completely inborn, but with the effects of postnatal pathogenic factors, the leaflets prolapsed and became redundant, irregular diastema between leaflets emerged and the valve-ring dilated. The operation has several advantages: (1) Angioscopy confirms primary venous valve incompetence. (2) The technique precludes venotomy and valve exposure, reducing the rate of postoperative venous thrombosis. (3) The operation eliminates the blindness of kistner's external surgical technique, overcoming its empiricism. The initial clinic use of the technique has shown that it is of excellent short-term effect without complications. PMID- 7842968 TI - [The modern conception of primary hyperthyroidism]. PMID- 7842969 TI - [Topography of intraabdominal supra and infra-hepatic IVC and its application in hepatectomy]. AB - Topographic study of infra-diaphragmatic and supra-hepatic IVC (ISIVC) was made in 16 fresh adult cadavers. The diameter and length of ISIVC averaged 35.94 +/- 5.68 mm and 16.87 +/- 5.14 mm respectively, hence making band-blockade of the ISIVC is practical. In clinical application, 21 cases of liver cancer involving the second or third hepatic hilus underwent lobectomy or segmentectomy with temporary band-blocking of the ISIVC, the infrahepatic IVC and the first hepatic hilus to prevent or to treat massive bleeding. In 3 of the 21 cases, the middle hepatic vein was inadvertently torn and was successfully suture repaired with this way. PMID- 7842970 TI - [An experimental study on bloodless hepatic resection under vascular exclusion with atrioportacaval shunt (HVE-APCS)]. AB - We developed a new technique--atrioportacaval shunt (APCS) both to increase the blood-return volume and to decompress the portal system and the inferior vena cava below the occlusion during hepatic vascular exclusion (HVE) in canine. A balloon catheter with a hole on its side was inserted up into inferior vena cava (IVC) through a venotomy just above the confluence of the bilateral renal veins, until the tip with the balloon was at the level of diaphragm. The caudal outside IVC was passed into portal vein. HVE-APCS was performed with clamping hepatic pedicle, tightening an umbilical tape around IVC immediately above the confluence of bilateral suprarenal veins, and finally inflating the balloon. Blood of the portal system and IVC below the occlusion was allowed to return to the right atrium through the catheter. The experimental results showed that HVE-APCS is characteristic of simplicity and safety, and of less harmful effect on the systemic hemodynamics. Because of the portal decompression, the recirculation injury to the ischemic liver was mild. It is concluded that HVE-APCS is an ideal method to control the bleeding from the major hepatic veins and retrohepatic vena cava. PMID- 7842971 TI - [Alveolar hydatid disease: report of 90 cases]. AB - From 1960 through 1992, 2750 cases of hydatid disease disease were admitted to our hospital, among them there were 90 cases of alveolar hydatid disease proved by laparotomy, biopsy, or autopsy. The preoperative misdiagnosis rate in this series was 24.3% owing mainly to the difficulty of differentiating from multilocular echinococcosis and liver cancer. Basing on clinical and pathological features, the authors proposed its diagnostic and staging principles, and therapeutic approaches to improve the prognosis of this disease. PMID- 7842972 TI - [Diagnostic value of heart-liver nuclein ratio in cirrhotic portal hypertension]. AB - A new method for evaluating portal systemic collaterals with administering 99mTc MIBI per rectum was described in 80 cases. The heart to liver uptake ratio (H/L) in 15 healthy subjects was 0.267 +/- 0.1, slightly increased (0.455 +/- 0.13) in 8 patients with viral hepatitis and significantly increased in 68 cirrhotics. There was a good correlation between H/L ratio and the Child-Pugh classification with the ratio in Child A group of 0.57 +/- 0.12, in Child B group of 1.0 +/- 0.19, and in Child C group of 1.19 +/- 0.25 respectively (P < 0.01). For the diagnosis of portal hypertension, tentatively taking the ratio of > or = 0.62 as positive the sensitivity was 96%, specificity 89%, and accuracy 94%. The authors believe that 99mTc-MIBI imaging is a noninvasive method very useful in evaluating porta-systemic shunts. PMID- 7842973 TI - [Anastomotic coarctation in the treatment of serious encephalopathy following splenosystemic shunt]. AB - In this study, 11 cases of serious encephalopathy following splenorenal or splenocaval shunt were treated by anastomotic coarctation, in 4 of the 11 cases, portoazygos disconnection was added. All symptoms and signs disappeared soon after the procedure. The portal hepatopetal blood flow increased. Liver function improved. Blood ammonia concentration decreased. Follow-up of 6 to 48 months found, no recurrent encephalopathy or variceal bleeding. Anastomotic coarctation is effective method to treat serious post-splenosystemic shunt encephalopathy. PMID- 7842974 TI - [Adenoma of the gallbladder and its canceration: an analysis of 88 cases]. AB - In this report, 88 cases of gallbladder adenoma collected from Chinese medical literature including the author's own 12 cases were analysed. Canceration was found in 17 (19.3%) cases. Risk factors included multiple and sessile adenoma, tubular adenoma, adenoma of more than 1 cm in diameter, and adenoma coexistent with gallstones. It is the authors' believe that any polypoid neoplasms of the gallbladder of more than 0.5 cm in diameter found by B-mode ultrasonography justify surgical exploration in order not to overlook a possible canceration. PMID- 7842976 TI - [Villous tumor of the duodenum]. AB - 8 cases of duodenal villous tumor were reported. A total of 11 tumors, with 2 in the bulb and 9 in the descending part, were excised. Malignant change was found in 4 cases (50%). Diagnosis could be made by using hypotonic duodenography and fibroscopy. The integral tumor should be examined by frozen section during operation, so as to determining the appropriate operation for satisfactory result. Postoperative follow up should be done periodically because of the possibility of recurrence after local excision. PMID- 7842975 TI - [Preoperative selective intraarterial chemotherapy combined with gastrectomy in the treatment of gastric carcinoma]. AB - In this study, 19 cases of gastric carcinoma were treated by selective intraarterial chemotherapy before surgical resection. Pathological examination of the resected specimen found that the effective rate of this selective chemotherapy was 89%. The survival rate of 6 months, 1 year, 2 years, and 3 years was 100%, 90%, 87%, and 83%, respectively. PMID- 7842977 TI - [Myelographic diagnosis and treatment of lumbosacral nerve root anomalies]. AB - Altogether 480 patients were examined with myelography in the study from 1987 to 1992 and 28 cases having anomalous lumbosacral nerve roots with other concomitant diseases were found. The anomalies were classified three types based on myelographic findings. Type 1, root sleeve displacement; Type 2, a, roots through one foramen; b, roots through two foramina; c, roots through three foramina; Type 3, double roots through one foramen. All patients were proved and treated during operation. The results of treatment were good (92.8%). We considered that most lumbosacral nerve roots anomalies were asymptomatic, however, when they were compressed by degenerative canal tissue, classic nerve root pain appeared eventually. Myelography is helpful to its diagnosis and treatment. PMID- 7842978 TI - [Histological investigation of the ligamentum flavum]. AB - The micro- and ultrastructures of the human ligamentum flavum were investigated. It was found that the ligamentum flavum is made of chiefly of elastic fibers. This kind of structure provides a basis for the important physiological functions of the ligamentum flavum. So the load is transmitted between the vertebrae and spinal stability is maintained by means of this ligament. Then clinical relevance was discussed. PMID- 7842979 TI - [p53 antioncogene abnormal in osteosarcoma]. AB - Immunohistochemical evaluation of 24 osteosarcoma using an anti-p53 protein monoclonal antibody (Moab p53-12) showed strong positive reaction in the nuclei of tumor cells in 14 osteosarcoma (58.3%). Many studies have proved that this overexpression of p53 protein in tumor cells is associated with mutation of the p53 gene. Contrast study with DNA flow cytometry made on osteosarcoma showed that most of the p53 strongly positive tumors have higher DNA Index value than negative or slightly positive ones, though no statistically difference existed between two groups. Southern blot hybridization of p53 gene was also made in osteosarcomas. 5 of 20 cases (20%) had the structural changes of p53 gene. 3 of them were part or whole deletion of the gene. 2 of them had the extra-band, indicating the rearrangement of the gene. PMID- 7842980 TI - [Discussion of the role of fiberoptic bronchoscopy examination in the choosing the type of operation for centre type lung cancer]. AB - This paper summarized the clinical data of the 112 cases centre type lung cancer examined by the X-ray films or/and CT scan and fiberopiticbronchoscopy (FOB) from Oct. 1984 to Aug. 1993 and discussed the role of FOB examination playing in the surgical treatment of centre type lung cancer. The authors thinks the FOB examination should be one of the necessary means of routine pre-operation checking, because it takes an important part in finding area of bronchus infiltrated by the cancer and choosing the type of operation. PMID- 7842981 TI - [Pulmonary resection by dealing with pulmonary vessels inside pericardium: report of 104 cases]. AB - During 1985-1993, the writer had performed 104 pulmonary resections, which was 10% of the same time pulmonary resections, to treat type III center lung carcinoma by dealing with pulmonary vessels inside pericardium. The results demonstrated: one-year survival rate was 35%, while three year survival rate was 10%. The writer also found that this kind of operative mode can raise the pulmonary resection rate by 8.75%, and reduce the exploratory thoracotomy rate by 33% compared with the traditionary pulmonary resection. PMID- 7842982 TI - [Long-term result of surgical management of metastatic neoplasms to the lungs]. AB - We reviewed the role of pulmonary resection for metastatic pulmonary lesions in our hospital. Over a 25 year period, 58 patients underwent 61 thoracotomies. Pulmonary resections were done in 56 patients. Two were done by explorations and one of them was only for diagnostic purpose. The operative mortality was 6.6% (< 30 days). Long-term follow-up in 45 patients whose primary tumor was controlled and secondary tumor was resected revealed 1, 3, and 5 year accumulative survival rates of 76.8%, 37.9% and 18.0% respectively. Patients with multiple pulmonary metastases resulted in lower survival rates than solitary lesions (P < 0.05). Postoperative survival rates were also found to be affected by the tumor doubling time (r = 0.8460). The surgical indications for secondary lung tumor were discussed. PMID- 7842983 TI - [Follow-up study of porcine bioprosthetic valve replacement in 15 children]. AB - GD-I porcine bioprosthetic valve replacement were performed in 15 cases from Jul. 1978 to Nov. 1982. Pathology: RHD 11, CHD 4, 13 with MVR, 1 AVR, 1 TVR. One patient died during operation (operative mortality 6.7%). 13 cases were followed up for 3-10 years: in the early years the symptoms and cardiac function were greatly improved and the size reduced. However dysfunction of bioprosthetic valve was detected 2-8 years after operation in 12 patients (19.37%/patient year). The main cause of damage and dysfunction of porcine valve is calcification of the leaflet. As compared with the adult group(dysfunction rate 3.6%/patient year) in this institute, more calcification of the porcine valve in children is considered because of: (1) stronger metabolism of calcium in children, (2) less mobility of the leaflet due to lower cardiac output in children, and (3) stronger immunoreaction to porcine valve in children. PMID- 7842984 TI - [Experiment and clinical significances of papillary myotomy's and septal valvotomy's resuture in the right ventricle]. AB - In this paper, the results of the papillary myotomy and septal tricuspid valvotomy were studied. The 19 dogs were randomly divided into four groups so as to observe the blood supply, healing course, strength and functions of the anterior papillary muscle. It was confirmed that the traumatic rupture of the papillary muscle should be repaired early. In the clinic 31 patients of ventricular septal defect with tricuspid valve pouch were treated by the approach with septal valvotomy and cone papillary myotomy of tricuspid valve. The successful rate of VSD repair was up to 100%. Therefore, this approach is worthy to be used clinically. PMID- 7842985 TI - [Prophylactic effects of zhuling and BCG on postoperative recurrence of bladder cancer]. AB - The prophylactic effects of Chinese herbal medicine Zhuling (Grifola umbellata pilat) and BCG on bladder cancer after TURBT and partial cystectomy were evaluated. 146 patients with bladder cancer were divided into 3 groups, Zhuling, BCG, and control group. Follow-up for 48-124 months (average 70.8 months) showed that the tumor recurrence rate was 33.3%, 34.3% and 65.1%, respectively. Compared to the control group, the recurrence rate of Zhuling group and BCG group was significantly decreased (P < 0.01). The effect of Zhuling was similar to that intravesical BCG. Zhuling was cheaper and convenient in usage, and no side effects. PMID- 7842986 TI - [Ondansetron on postoperative nausea and vomiting]. AB - The efficacy and safety of prophylactic intravenous ondansetron on prevention of postoperative nausea and vomiting were investigated in 65 ASA grades I-III patients undergoing elective abdominal surgery and receiving general anesthesia. Patients received ondansetron 4mg i.v. prior to a standardized technique for induction and intubation. Anesthesia was maintained with N2O-O2 and enflurane. The results showed that, by ondansetron 4mg, nausea and emesis could be significantly decreased. The effect lasted around 24h postoperatively without sedation. No one developed vomiting and only 9 patients developed nausea. No changes on laboratory parameters as well as vital signs were observed. No side effects related to ondansetron were found. In prophylaxis of postoperative nausea and vomiting, ondansetron is effective and safe. PMID- 7842987 TI - [Study on preserving intestinal function and the possible mechanism of hypermetabolic response following severe burn injury]. AB - In order to approach the mechanism of hypermetabolic response following severe burn injury, a new animal model was developed with a specially bred miniswine (Guizhou species). Multiple catheterizations were applied for sampling different blood from portal, inferior mesenteric as will as jugular (central) veins. The animals were sustained with 30% III burn of TB-SA and divided randomly into early feeding group, given a complete diet beginning from 2 hours postburn (N = 6), and delayed feeding group, given the same diet initiating on 4 day postburn (N = 6). The results showed that compared with delayed feeding, early enteral feeding could strengthen the barrier function, decline the rate of translocation of bacteria and endotoxin from the gut to portal vein, reduce obviously blood TNF, CRP and catabolic-hormones, and significantly decrease REE (resting energy expenditure) and urinary 3-Mehis excretion. During the hypermetabolism (PBD7-10), the metabolic response mediated by "intestinal way" was at least 35%. The way of "intestinal tract--macrophages in liver--Hypermetabolism" is a possible mechanism of hypermetabolic response following severe burn injury, and the bacteria and endotoxin translocated from the gut, the active products (IL-1, TNF, etc) released by Kupffer's cells might be the mediating factors of the mechanism. PMID- 7842988 TI - [Osteogenic potential of rabbit dermal fibroblasts cultured in vitro: a histochemical and scanning electron microscopic study]. AB - Split-thickness rabbit skin was processed into small chips that were cultured in vitro and subjected to inverted phase contrast microscopic and scanning electron microscopic observation. The fibroblasts swam out of the skin chips and they increased in number rapidly and became confluenced. The cells exhibited squamous configuration, possessing arboreal bifurcations and forming multi-layer structure. The fibroblasts then excreted numerous minute granules, heaping up on and around the cells. Henceforth emerged on the cell surface fine needle-like crystals, that agglomerated with the granules to form nodules. The fibroblasts orientated themselves in a radiating pattern around the large nodules. Neighbouring nodules could be linked up into trabecular structure. Histochemical study of both the nodules and the trabecular structure with specific new bone labeller (Tetracycline and Alizarin red S) revealed positive reaction, denoting that the nodules and the trabecular structure produced by the fibroblasts were bone tissues. These results pointed out clearly to the osteogenic potential of the dermal fibroblasts. PMID- 7842989 TI - [Small incision extra-capsular cataract extraction with a manual nucleus division technique and intraocular lens implantation]. AB - A 6mm incision extra-capsular cataract extraction (ECCE) with a manual nucleus division technique and intraocular lens implantation was performed on 70 eyes of 66 patients with senile or complicated cataracts. Post-operatively, the visual acuities were 0.5 or better in 76.6% at one week and in 96.4% at three months. The mean post-operative astigmatism was 1.96 +/- 1.08D at one week and 0.92 +/- 0.68D at three months which was less than that in the control group, large incision (10-12mm) ECCE performed in the same period and compared at the same times, respectively (P < 0.001). The technique and instruments of this procedure were described, and its key steps and complications discussed. PMID- 7842990 TI - [Congenital cataract extraction with primary posterior chamber IOL implantation]. AB - Congenital cataracts in 41 eyes were extracted with primary implantation of posterior chamber IOLs, of which 35 were the one-piece PMMA variety. The patients were followed up 3-28 months, averaging 9.5 months. Corrected visual acuities of 1.0-1.5 were achieved in 29.3% and 0.5 or better in 85.4% of the eyes. Postoperative complications were few. Among 34 eyes of preoperative low vision, visual acuities of 0.3 or over were restored to 31 eyes (91.2%) immediately after the operation. PMID- 7842991 TI - [Factors affecting the visual prognosis after extraction of congenital cataract with IOL implantation]. AB - Multivariated analysis of corrected visual acuities after extraction of congenital cataract with IOL implantation in 24 patients (41 eyes), including 14 children (22 eyes) under 12 years of age, revealed that 6 factors significantly affected the postoperative results, namely, the pattern of lenticular opacity, monocularity, strabismus, nystagmus, after-cataract formation and its time of onset. Therefore, operation as early as possible is recommended for cases with these factors and IOL implantation considered, with discretion, in children for whom other forms of visual aids are not available. PMID- 7842992 TI - [Management of posterior capsule rupture and vitreous loss during IOL implantation]. AB - Among 331 cataract extractions with IOL implantation performed May 1988-Jan. 1992, 33 (10%) were complicated with posterior capsule rupture and vitreous loss occurred in 16 eyes (4.8%). After vitrectomy with scissors and sponge, in-the-bag implantation was performed in 3 eyes, sulcus-fixed lenses in 24 eyes, and anterior chamber lenses in 6 eyes. 32 eyes (97%) gained visual acuity of 0.5 or better during follow-ups of 5 months to 4 years, indicating that with careful anterior vitrectomy and proper modality of IOL implantation, good visual results could be achieved. PMID- 7842993 TI - [Management of dislocated or subluxated posterior chamber intraocular lens]. AB - The experiences of the management of 20 cases (20 eyes) of intraocular lens (IOL) dislocation or subluxation were summarized in this report. All the patients underwent primary extracapsular cataract extraction with posterior chamber IOL implantation. The dislocation or subluxation occurred in 2 eyes intraoperatively and 18 eyes in 1 day to 3 years, post-operatively. The IOLs were captured at pupils in 12 eyes, dislocated into the vitreous in 4 eyes, represented as in westeast syndrome in 2 eyes and sunset and sunrise syndrome in 1 eye and 1 eye, respectively. Of the 20 eyes, 1 eye with mild sunset syndrome was treated with a miotic, 2 eyes with IOL pupillary capture were treated successfully by conservative therapy and the rest, by surgeries. In cases treated by operations, the IOLs were removed from original incisions in 3 eyes, by vitrectomies in 5 eyes and surgical reposition of IOLs were undertaken in 9 eyes with IOL pupillary capture of which 7 eyes were successful and in 2 eyes recurrence took place shortly after reposition. The causes and management of IOL dislocation or subluxation were discussed. PMID- 7842994 TI - [Experimental study of the 50% damage threshold of Nd:YAG laser on IOL]. AB - The 50% damage threshold (DT50) of Nd:YAG laser was determined for IOLs of PMMA (lathed or molded), silicone and glass. The laser resistances in increasing order were silicone 79.22 gW/cm2, glass 100.82 gW/cm2, lathed PMMA 115.23 gW/cm2 and molded PMMA 142.49 gW/cm2. The authors recommended that only dosages below the DT50 be used in posterior capsulotomy to minimize the risk of IOL damage. The various laser damage patterns on IOL were studied by scanning electron microscopy. PMID- 7842995 TI - [Laser Raman spectrometry study on experimental galactose-induced cataract]. AB - In order to observe the dynamic changes of hydration in galactose induced cataract, laser Raman spectrometry was used to study the water-content of lens nuclear of Wistar rats after fed them on galactose by 3, 7, 9, 11 and 17 days. The results showed that, (1) during the formation of cataract, the ratio of I3390/I2935 increased from 0.31 (3 days) to 2.26 (17 days). The water content in the nuclear was significantly increased. (2) the hydration of lens nuclear could be divided into two phases. The ratio of I3390/I2935 was increased slowly and steadily by 11 days after galactose feeding. Then, the ratio turned to increase quite fast till 17 days. It indicates that the hydration of nuclear is changed simultaneously with the formation of cataract. PMID- 7842996 TI - [Changes in water-soluble, urea-soluble and membrane intrinsic proteins in human senile cataract]. AB - Gel filtration of water-soluble protein shows a substantial increase in HM+ alpha crystallin and a marked decrease in beta- and gamma-crystallins in cortical cataract. A decrease in beta 1-crystallin in cortical punctate opaque lenses is also striking. In nuclear cataractous lenses HM+ alpha- and beta-crystallin increase, while gamma-crystallin decreases. The urea-soluble protein from clear lenses contains mainly of alpha beta chain, whereas in cataractous lenses the relative amounts of the 28 and 23ku polypeptides (the components of beta crystallin) increased markedly. In cataractous lenses the relative amount of membrane intrinsic proteins decreases slightly and it has little statistical meaning. PMID- 7842997 TI - [Corneal topography of keratoconus]. AB - A computerized video keratoscope (TMS-1) was used to determine the topographic findings of 6 eyes of 4 patients with keratoconus and they were compared with those of 18 normal eyes. The results show that in keratoconus the central corneal refractive power is greater, the difference between the refractive powers of the bilateral central corneas of a case is larger and the inferior cornea is steeper than the superior cornea. The above topographic findings are possibly the characteristics of the corneal topography of keratoconus. PMID- 7842998 TI - [Topical clonidine in prevention of intra-ocular hypertension after Nd: YAG laser therapy]. AB - We evaluated the prophylactic effect of 0.25% Clonidine HCl on the increase of intraocular pressure after Nd: YAG laser therapy. IOP of 150 eyes using Clonidine and 119 eyes without Clonidine were measured before and 0.5, 1, 2, 24 hours after Nd: YAG application. Various stages of angle-closure glaucoma and after cataract were both included in the treated and control groups and were compared respectively. Overall, the incidence of increase of IOP in the Clonidine-treated group was significantly less (9.3%) than the group without Clonidine (63.0%); the incidence of marked increase (> 1.06kPa) was also significantly less (2.0%) than those without Clonidine (18.5%). The peak value of IOP after laser therapy in the treated group did not exceed 3.06 kPa. Therefore, topical Clonidine is recommended as an effective and safe procedure to prevent the intraocular hypertension in Nd: YAG laser therapy. PMID- 7842999 TI - [An analytic study of metastatic carcinoma to the uvea]. AB - The authors analyzed 107 cases of metastatic carcinoma to the uvea, 21 cases from their hospital and 86 cases from Chinese literature, to find no predilection for either eye and that the tumor originated from the lung in 45 cases (42.1%) and from the breast in 14 cases (13.1%). Among 43 cases of lung cancer with records, 33 cases reported visual symptoms as their first complaints while none of the 14 cases of breast cancer so did. This could have been due to the higher incidence of lung carcinoma which was also less readily detected. PMID- 7843000 TI - [Trans-corneal trabeculectomy]. AB - One of the main causes in failure of fistulizing operations for glaucoma is related to conjunctival and subconjunctival cicatrization. Trans-corneal trabeculectomy is different from conventional fistulizing operations and the conjunctival incision is avoided. Passing through the cornea, partial thickness sclera and trabecula are removed. The conjunctiva is least violated during the procedures. Trans-corneal trabeculectomy was completed in 15 eyes with glaucoma. Most of filtering blebs revealed diffuse. The conjunctival inflammatory reaction was minimal with only mild hyperemia even at the first postoperative day. Intraocular pressure of 14 eyes was normal without any medication postoperatively. PMID- 7843001 TI - [Application of silicone oil in management of complicated retinal detachment surgery]. AB - 60 eyes of 60 cases with complicated retinal detachment were treated by vitrectomy combined with silicone oil tamponade, including grade D of proliferative vitreoretinopathy (PVR) in 27, giant retinal tears with posterior flaps folded up in 15, posterior polar or macular holes in 13 and traumatic PVR in 5 eyes. After 3-24 months of follow-up, it is shown that 48 eyes obtained anatomic reattachment, the success rate being 80%, and the post-operative visual acuities improved in 43 eyes of which 32 eyes achieved > 0.05. The authors consider that vitrectomy and membrane peeling create a situation for silicone oil tamponade to play its role fully, vitrectomy is perfected by the combination of silicone oil tamponade and the rate of success of the retinal detachment operation is increased. The theory, indications, advantages and disadvantages of silicone oil tamponade were briefly discussed. PMID- 7843002 TI - [Treatment of macular hole retinal detachment with vitrectomy]. AB - Pars plana vitrectomies were performed on 64 eyes with macular hole retinal detachment of which 20 with severe proliferative vitreoretinopathy (PVR C-D) and 18 with definite vitreoretinal traction on the maculae were found. Retinal reattachment occurred in 57 eyes in the follow-up (89.1%) of which the visual acuities improved in 43 (74.5%), unchanged in 13 and decreased in 1. The points for attention in the operation were discussed. The key factors influencing the success of the operation are severe PVR, the course of the retinal detachment. PMID- 7843003 TI - [Effects of contact lens wear on the corneal endothelium and sensitivity]. AB - The corneal endothelium of 38 contact lens wearers (74 eyes) and 74 normal eyes for control was photographed and analyzed with specular microscopy and the graphic processing system. The central corneal sensitivity and thickness were also measured. The results showed that the frequency rate of hexagonal cells that reflected the changes in endothelial cell morphology and size, the coefficient of variation of cell area, and the ratio of largest to smallest cell areas differed significantly from those of the control eyes comparable in age and sex distribution. The central corneal sensitivity declined while the corneal thickness was not affected. The causes and clinical significance of endothelial changes were discussed. PMID- 7843004 TI - [The immunophenotypic lymphocyte analysis of orbital lymphadenosis and its significance]. AB - An immunophenotypic lymphocyte analysis of 56 cases of orbital lymphadenosis was performed with a panel of 10 monoclonal antibodies against the lymphocyte differentiation antigen by the streptavidin-peroxidase conjugate method to reveal that (1) all 15 cases of inflammatory pseudotumor and 32 of 33 cases of reactive lymphocyte hyperplasia manifested polyclonality of the constituent cells; (2) the immunophenotype of cells was monoclonal in 2 of 3 cases of atypical lymphocyte hyperplasia and diagnosis of malignant lymphoma (ML) were established; and (3) among 5 cases of ML, the cells were shown to be B-cells in 4 cases and T-cells in 1 case. These results suggested that immunophenotyping could be useful in differentiating the benign from the malignant orbital lymphadenosis and the histologic types of ML. The relationship between pathologic and immunologic classifications of orbital lymphadenosis was also discussed. PMID- 7843005 TI - [Retinoblastoma: cell origin and differentiation]. AB - 50 retinoblastoma paraffin blocks were studied immunohistochemically (NSE, GFAP) and histochemically (colloidal-iron, RNA), and 13 cases by EM. The Rb cells demonstrated varying degrees of positive or negative reaction to NSE, most F-W and H-W rosettes being positive and the fleuretes weakly positive or negative. The GFAP positive cells were mainly found in the periphery of the tumor mass and around the blood vessels, and sparsely among the NSE positive cells. Fleuretes were clearly shown by RNA-Brachet staining. F-W rosettes and fleuretes showed similar ultrastructures as the photoreceptor of normal retina. The results confirmed that retinoblastoma originates from the retinoblast with potential of differentiation into photoreceptors and neurons. The glial components pertained to reactive gliosis, however, the rare possibility of forming a small portion of the tumor could not be ruled out. PMID- 7843006 TI - [An immunohistochemical study of cornea and adjacent bulbar conjunctiva in Mooren's ulcer]. AB - The specimens of the corneal lesions and their adjacent bulbar conjunctivas taken from 14 cases with Mooren's ulcers were studied by immunohistochemical techniques to investigate the expression of HLA-DR antigen and the subgroups of lymphocytes. It is discovered that there is an aberrant expression of HLA-DR antigen in a large amount of keratoconjunctival epithelial cells and stromal keratocytes and simultaneously, the CD4/CD8 ratio is significantly higher than that of the normal control group. The results suggest that the aberrant expression of MHC-II antigen in the resident cells at the peripheral cornea and its adjacent conjunctiva and a raised local TH/TS ratio leading to an excessive autoimmune reactivity be possibly the direct cause of the pathogenesis of the Mooren's ulcer. PMID- 7843007 TI - [In vivo observations and electron microscopy in the treatment of experimental HSV keratitis with monoclonal antibodies]. AB - In vivo observations and electron microscopy showed that topical use of anti-HSV monoclonal glycoprotein antibodies produced marked antiviral effects in inhibiting the development of experimental herpetic keratitis in rabbits and in protecting the susceptible corneal cells. As a new biological product, the anti HSV monoclonal antibodies may provide a new approach to the treatment of HSV keratitis. PMID- 7843008 TI - [An epidemiologic survey on lens opacities in Doumen County]. AB - Age-related lens opacity is the main cause of vision disability in elderly all over the world. A longitudinal study was designed to investigate the prevalence of lens opacity. 1,817 eyes of 932 adults over 45 year-old were sampled randomly. The lens opacities were graded according to a standardized photo of the Lens Opacities Classification System II (LOCS-II). The prevalence of lens opacities in nuclear color, nuclear opacity, cortical opacity and subcapsular opacity was 16.1%, 28.6%, 30.3% and 8.7% respectively. The frequency of all four types of opacities increased with age. The prevalence of lens opacities in four types were higher in female than that in male. The color of nuclear was related to the degree of myopia, the deeper the higher. These results are important information in eye care project. PMID- 7843009 TI - [Characteristics of reversed optic cupping in glaucoma after reduction of intraocular pressure]. AB - Quigley's hypothesis indicates that the dense connective tissue is the least and the pores of the lamina cribrosa are the largest at the superior and inferior poles of the lamina cribrosa, therefore they are the most vulnerable locations to be involved by the characteristic glaucomatous optic nerve damage. To get clinical evidences of the hypothesis, the reversal or contraction of glaucomatous optic cup after reduction of intraocular pressure (IOP) was examined (The change is primarily caused by intraocular hypertension--induced distortion and posterior ectasia of the lamina cribrosa which moves forward reversely, leading to dilated optic cup contraction.). The method of examination was a stereoscopic flicker comparison with a computerized image system, alternatively displaying superposed 2 serial stereo pairs rapidly and the changing part presenting jumping appearance. Under stereoscopic observations, the changes of 3-dimension optic cup end be seen and the false positive phenomena caused by photographic angle variation, vascular pulsation, etc. can be differentiated from the characteristic changes of the cup. Stereo fundus photographs were taken from 31 eyes with high intraocular pressures before and after treatment for reduction of IOPs which was either diamox administration or trabeculectomy. The results show that the reversal of optic cups after reduction of IOPs are mostly asymmetrical, especially at the superior and/or inferior poles. By multiple stepwise regression, it is known that the amount of the change is only correlated with the initial IOP.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843010 TI - [Laser suture lysis following trabeculectomy]. AB - Trabeculectomies with tightly sutured scleral flap was performed on 49 eyes of 45 patients with angle closure or open angle glaucomas, the experimental group, of which 41 eyes underwent laser suture lysis subsequently. After a mean period of follow-up 14.7 months (12-36 months), the average intraocular pressure was decreased from pre-operative 5.93 kPa (44.5 mmHg) to post-operative 1.96 kPa (14.7mmHg). The experimental group of patients was compared with the control group, 41 eyes of 39 cases at the same period randomly undergoing trabeculectomy without laser suture lysis. The control rate of intraocular pressure is higher (89.8%:73.2%) and the incidence of ocular complications (such as, shallow anterior chamber, choroid detachment, hyphema, lens opacity) is significantly lower in the former group, showing that trabeculectomy with following laser suture lysis is a safe and effective anti-glaucoma surgery. The advantages, points for attention and experiences of laser suture lysis have been introduced in the paper. PMID- 7843011 TI - [External trabeculotomy in the treatment of developmental glaucoma: a clinical report on 140 eyes of 88 cases]. AB - 140 eyes of 88 cases with developmental glaucoma including 128 eyes of 80 cases with infantile glaucoma and 12 eyes of 8 cases with juvenile glaucoma were treated by external trabeculotomy. The success rate of the operation is 73.9% and by addition of small amount of topical antiglaucoma agent the rate of glaucomatous control reaches to 86.4%, the average period of follow-up being 15.2 months. The complications of the operation are few and mild in degree. The important steps of the operative procedure and the critical points of the post operative management were described, the therapeutic effect of the operation was evaluated and the factors which possibly can affect the prognosis of the operation were analyzed. It is recognized that the operation is better than goniotomy. We recommend external trabeculotomy for treatment of developmental glaucoma which is especially suitable for primary infantile glaucoma. PMID- 7843012 TI - [Releasable sutures for scleral flap in trabeculectomy]. AB - Releasable sutures for scleral flaps in trabeculectomies were performed on 20 eyes of 15 patients. The sutures were removed on the 3rd to 14th post-operative days. The anterior chambers of 19 eyes (95%) were reformed within 24 hours, post operatively, the mean remote intraocular pressure (IOP) was 1.71 +/- 0.38 kPa and 17 eyes (85%) had functional conjunctival blebs of filtration. In comparison with the control group, there are very significant differences in the duration for reformation of anterior chamber and remote level of IOP (P < 0.005, < 0.001). The procedure has the advantages of maintaining a deep anterior chamber during the early postoperative period and of facilitating long-term functional filtration. PMID- 7843013 TI - [A pathological analysis of the causes of failure of filtration operation in 25 glaucomatous eyes]. AB - Histopathological investigations were carried out in 25 glaucomatous eyes of 25 cases which had been enucleated because of the failure of the filtration operations. Among them, 3 cases with malignant melanoma of either choroid or anterior uvea were misdiagnosed pre-operatively, post-operative rupture of filtering blebs leading to acute suppurative endophthalmitis or chronic endophthalmitis occurred in 5 cases and fibrous proliferation or incarcerations of iris, ciliary body or lens material were found in the filtration incisions in some cases. The causes of the failure of the filtration operations in these cases were discussed. PMID- 7843014 TI - [Histopathologic and ultrastructural studies of the iris in acute angle-closure glaucoma]. AB - By light and transmission electron microscopy, iris specimens from 40 eyes of 24 patients with acute angle-closure glaucoma were investigated and compared with those of healthy eyes in the same patients. During an acute attack, the anterior border layer of the iris became thickened, and stromal cells and collagen fibrils greatly proliferated. The endothelial cells swelled and muscle fibers showed vacuolization, depigmentation or atrophy. During the stage of remission, the iris was structurally disrupted and the stromal cells degenerated markedly. In the absolute stage, the stromal cells were atrophic and the fibers resolved, while the mast cells increased in large numbers. The significance of these findings were discussed. PMID- 7843015 TI - [Experimental studies on changes in retinal enzyme activities under acute ocular hypertension in cat eyes]. AB - The changes of 10 enzymatic activities of cat retinas and their blood vessels under acute ocular hypertension were systematically observed by enzyme histochemical methods. These changes were induced by the damage caused by retinal ischemia-reperfusion. The activities of the free radical scavengers, catalase and hydrogen peroxidase, were decreased, demonstrating that the excess of free radicals is one of the essential causes of the injury. The principles of treatment are besides lowering of intraocular hypertension, during retinal ischemic stage, oxygen and nutrients needed urgently should be supplied through extra-vascular route and during reperfusion stage, free radical scavengers ought to be given. PMID- 7843016 TI - [Pars plana lensectomy and anterior vitrectomy for the treatment of congenital subluxated lenses]. AB - The conventional surgical management of congenital subluxated lenses is frequently associated with a high incidence of complications leading to poor visual prognosis. Lensectomy through the pars plana with modern techniques of microsurgery and automated suction-cutting devices was performed on 11 patients (18 eyes) whose pre-operative visual acuities with the best optical correction ranged from 0.05-0.3, which were improved postoperatively to 0.5-1.0 during a follow-up of 3 to 60 months with an average of 36 months. The complications were accidental small cuts at the pupillary borders of 3 eyes, indicating that pars plana lensectomy is a safe procedure for the treatment of congenital subluxated lenses. PMID- 7843017 TI - [Treatment of ocular injury with lensectomy and closed vitrectomy]. AB - The authors reviewed 104 consecutive cases of ocular injury treated with lensectomy and closed vitrectomy including anterior segment resection in 80 cases and posterior segment, in 24 cases. The curative rate was 80.8%. Post operatively, 44 eyes (47.8%) gained visual acuities of 0.025-0.6 and 68 eyes (65.4%) obtained visual improvement. 29 eyes were followed up 1-38 months, averaging 22.5 months, to find long-term therapeutic effects in 23 eyes (79.3%). The authors believe that lensectomy with closed vitrectomy is a useful modality in treatment of ocular injury. PMID- 7843018 TI - [Factors of graft failure after chemical corneal injury]. AB - 83 cases (97 eyes) of keratoplasty after chemical corneal injury were followed up for a mean 14 months with the results that 21 (21.6%) grafts were transparent and 76 (78.4%) opaque or semitransparent. The success rate depended on the severity of the chemical injury; it was 87.5% for type A corneal scarring and 15.7% for type B. The causes of graft failure were postoperative epithelial erosion (70.7%) and corneal rejection (28.0%). Most patients with epithelial erosion had problems of insufficient tear secretion and tear-film defects. The prevention and management of graft failure were discussed. PMID- 7843019 TI - [Vitrectomy under temporary keratoprosthesis]. AB - In vitreoretinal disorders complicated by corneal opacity, a temporary keratoprosthesis device is placed into a trephined opening in the cornea to provide a clear stable view which permits the performance of pars plana vitrectomy and immediately following the vitrectomy, the keratoprosthesis is replaced by a corneal graft. Using this technique, we have saved blind eyes with corneal and vitreoretinal disorders in one surgical procedure, being a new approach for rehabilitation of eye sight. Since 1990, the operation has been performed on 10 patients of whom 9 obtained satisfactory results. They were the patients who had been impossible to be saved by other methods and had been abandoned. The patient with the best result had been followed for 15 months and his visual acuity achieved and maintained 0.3. In six cases, the operation was combined with multiple procedures in the vitreous, such as gas fluid exchange, internal drainage of subretinal fluid, injection of silicone oil, etc. to facilitate the reattachment of the complicated retinal detachment. PMID- 7843020 TI - [Prediction of curative effect of amblyopia by laser interference fringe visual acuity]. AB - Laser interference fringe visual acuities (IVAs) and E visual acuities (EVAs) of 116 cases 171 amblyopic eyes were examined. All cases were treated by various therapies and the average follow-up was 2.5 years. Before treatment, the IVAs of 86.5% eyes were better than their EVAs and the IVAs of 13.5% eyes were equal to their EVAs. After treatment, the EVAs of all the eyes were raised to their IVA levels (P < 0.0001, r = 0.8218). The results show that the IVA examination can predict the curative effect and monitor the treatment of amblyopia. The relationships between the IVA and the character of visual fixation, the type and degree of amblyopia, elder child and adult amblyopia, etc. were discussed. PMID- 7843021 TI - [Stereoscopic visual evoked potential elicited by static random dot stereogram]. AB - Using 16.56' visual disparity stimulation produced by television random dot stereogram (TVRDS), we recorded visual evoked potentials (VEPs) elicited from 35 normal subjects with and without breaking their stereopsis and 28 stereoblind subjects. The results showed that a constant negative-positive wave complex was observed in 33 of 35 normal subjects; this negative-positive wave-complex disappeared when the stereopsis was artificially inhibited by a prism and in the stereoblind group, and no VEP wave was elicited in all of the stereoblind patients except in one with paralytic strabismus. The results revealed that under this condition the VEPs elicited by TVRDS were specific VEPs related to visual disparity stimulation and were stereoscopic ones. The TVRDS is an effective electro-physiological means to examine the stereopsis objectively and a new way to approach the occurrence and development of stereopsis. PMID- 7843022 TI - [Evaluation of application of transparent keratoscope in ocular microsurgery]. AB - The clinical effects of application of a transparent keratoscope in cataract extraction and intraocular lens implantation were reported. The patients were divided into 2 groups: 1 group without and the other group with the application of a transparent keratoscope to control the corneal curvature by regulating the strength of the continuous suture during the microsurgery. The pre-operative and the post-operative corneal curvatures of patients in both groups were measured and the results were compared. The comparison shows that the clinical effect in regard to the corneal curvature is better in the group with the application of a transparent keratoscope. In this group, 63% of the post-operative corneal astigmatism is less than 2D, 91% less than 3D and none more than 4D. PMID- 7843023 TI - [Bilateral progressive obliterative retinal vasculitis]. AB - 10 cases were reported with a special type of retinal vasculitis which was characterized by progressive obliteration of retinal blood vessels from peripheral retinas to the posterior poles in both eyes. In the late stage of the disease, it was complicated by vitreous hemorrhage in 5 eyes, neovascular glaucoma in 5 eyes, etc. The visual acuities of 10 eyes (50%) were < or = 0.05. It seems that argon laser photocoagulation can delay its natural course. Its fundus changes, fluorescein angiographic findings, differential diagnosis and treatment were discussed. PMID- 7843024 TI - [Pathological and ultrastructural changes in conjunctival malignant melanoma treated by cryotherapy]. AB - The liquid nitrogen cryotherapy was used to treat conjunctival malignant melanoma. Light and transmission electron microscopic examinations were carried out before, during and after the treatment. It was discovered that the tumor cells died within a few minutes after the cryoapplication. Under transmission electron microscope, marked necrosis of tumor cells was seen 10-14 days after the treatment and a large amount of collagenous fibers and fibroblast hyperplasia were seen in the tumor in 3-4 weeks following the application, while the tumor cells were seldom found. Under light microscope, as significant necrosis of the malignant melanoma occurred, the surface conjunctival epithelium gradually grew and covered the defect of the conjunctiva, showing that the malignant melanoma cells are much more sensitive to the cryoapplication than the normal conjunctival epithelial cells. PMID- 7843025 TI - [Application of polymerase chain reaction for quick assay of herpes simplex viral acute ocular infection and ganglionic latent infection]. AB - Polymerase chain reaction (PCR) was applied as a quick assay for herpes simplex virus-I (HSV-I) ocular infection and trigeminal ganglionic latent infection. A pair of primers derived from the sequence of HSV-I latency associated transcript (LAT) gene were designed and synthesized to detect HSV-I DNA, the gene fragment increased being 452bp. The primers were used for the assays of 30 corneal swabs taken from experimental rabbits with herpes simplex keratitis (HSK), 28 ocular swabs from 23 patients with HSK and from 5 with HSV lid infection and 8 trigeminal ganglionic specimens from experimental rabbits with quiet HSK. Simultaneously, the tissue cultures of all the same above specimens were made. The results of PCR were compared with those of the tissue culture. The comparison indicates that PCR is specific and sensitive. It not only can be used as a quick assay and an objective criterion for clinical diagnosis of HSK, but also can be applied as a powerful weapon for investigation of HSV-I latent infection. PMID- 7843026 TI - [Morphological and functional studies on nerve regeneration after corneal nerve injuries]. AB - Using gold chloride impregnation of nerves and horse-radish peroxidase (HRP) axoplasma retrograde tracing technique, we monitored nerve regeneration over a period of 6 months following penetrating perilimbal incisions and penetrating keratoplasties (PKP) in rabbits. Post-operatively, at 1 month after a 180 degrees perilimbal incision, loose unconnected subepithelial plexus were present in the limbus, at 2 months 1-2 bundles of deep stromal nerve were seen in the stroma and by 6 months only a few stromal nerves regenerated. There was no difference in nerve regeneration between post-operative autograft and allograft PKP. By 6 months, the quantity of HRP-labelled cells in the trigeminal ganglia was less than the normal level. The results indicated that nerve regeneration by 6 months after corneal nerve injuries was inadequate to restore a normal corneal nerve extent and function. PMID- 7843027 TI - [An ultrastructure and proteoglycan study of experimental alkali burned cornea of the rabbit]. AB - A rabbit model of alkali burned cornea was made with 1 mol/L NaOH. On days 1, 3, 7 and 14 after the burn, changes in ultrastructure and the ruthenium red (RR) proteoglycan granules were as follows: (1) The epithelium and endothelium peeled off within day 1. In lightly burned cases, the epithelium regenerated on days 3 7; (2) The collagen fibers of corneal stroma became loose and irregular after the burn and began to recover with recovery of the cornea; (3) The RR proteoglycan granules decreased markedly after the burn, in light cases they increased on day 7 and gradually exceeded the normal amount, and then they reapproached the normal when the cornea was essentially recovered. PMID- 7843028 TI - Outpatient management of the depressed patient. AB - Major depression is a serious, potentially life-threatening illness that can cause significant pain and suffering. It afflicts up to 50% of patients who are seen in the primary care setting. However, it is a remarkably treatable disorder, once it is recognized. The mainstay of treatment is education about the illness, brief supportive counseling, and antidepressant medication. This monograph is a synopsis of a book, Outpatient Management of the Depressed Patient, recently published on this subject. We focus on how to diagnose and treat major depression in the primary care setting, in which the vast majority of patients with this condition are seen. We review the condition itself, how to establish the diagnosis, what education and brief supportive counseling are needed and how to provide them, how to select an antidepressant, and how to use the drug to induce and maintain remission. PMID- 7843029 TI - [Constancy of the nCPAP pressure values in the long-term monitoring of patients with obstructive sleep apnea]. AB - A retrospective study was undertaken to discover how often mask pressures had to be adjusted over time in patients treated for sleep apnoea by continuous positive airway pressure (nCPAP). Data were analysed on 106 such patients (95 men, 11 women; mean age 55.6 [33-74] years). Their body-mass index was 31.5 +/- 5.5 kg/m2, the apnoea hypopnea index before adjustment 7.6 +/- 2.2 mbar. At the first control, after a median of 7.5 months, the pressure had to be adjusted in 55% of patients, by an average of 8.3 +/- 2.4 mbar (P < 0.001). At the second and third follow-ups (after 19.5 and 31.5 months, respectively), no further significant adjustment in mean pressure was necessary, while changes had to be made in 34.0% and 17.9%, respectively. Changes in body weight correlated with changes in pressure level (r = 0.4614 for difference between initial setting and first control; r = 0.6708 for first and second controls; r = 0.7013 for second and third controls). 61% of patients in whom mask pressure had to be altered had symptoms. Of those in whom the pressure had to be increased 82% had symptoms. Only 17% of patients requiring no change had symptoms. These findings indicate that patients on nCPAP must be monitored by polysomnography about 6 months after the initial setting, and further tests should be performed about a year apart. If body weight and feeling of well being are maintained, non-laboratory monitoring should be adequate. PMID- 7843030 TI - [Bowenoid papulosis, Bowen's disease and squamous cell carcinoma of the anus and vulva in congenital intestinal lymphangiectasis]. AB - A 32-year-old woman with congenital intestinal lymphangiectasia (CIL) and warts (condylomata acuminata) was found to have bowenoid papulosis, Bowen's disease and squamous-cell carcinoma, at first in the anus, later also in the vulva. Limited surgical measures and laser vaporization with systemic and topical administration of interferon controlled the tumour development for some time. But after 7 years the squamous-cell carcinoma recurred with infiltration of the outer anogenital region. The patient then had an episode of thrombotic cerebral ischemia, which prevented a planned abdominoperineal resection with radical vulvectomy. Instead she received chemotherapy with bleomycin, mitomycin and cisplatin. But she died 8 weeks later, from tumour cachexia. Occurrence of a squamous-cell carcinoma of the anus and vulva in this young patient suggests a high oncogenic potential of the papilloma virus (HPV) infection. The latent period was probably shortened by a cellular immune deficiency as part of CIL. Treatment of the various carcinomatous manifestations should as long as possible be by local measures and interferon administration. PMID- 7843031 TI - [Tuberculous spondylitis--a forgotten differential diagnosis in backache]. AB - A four-year-old boy had been complaining for one year of backache when sitting or bending. Radiological changes in the lumbar spine were at first interpreted as due to an old vertebral fracture. Half a year after the onset of the symptoms his sister was found to have open pulmonary tuberculosis, but a positive Tine test (he had not received BCG vaccination) was without any consequences. He was finally hospitalized five months later because the backache persisted and he now also had impaired movement of the left hip-joint. Physical examination revealed a 10 x 15 cm firm mass in the abdomen. Imaging demonstrated destruction of the 4th and 5th lumbar vertebrae and a large abscess. Acid-fast bacteria were found in gastric juice. Tuberculostatic treatment was started with isoniazid (10 mg/kg), rifampicin (10 mg/kg) and pyrazinamide (30 mg/kg). Two weeks later spondylectomy was performed, the defect being bridged with bone chips from the iliac crest. Four months after the operation, tuberculostatic treatment now being only isoniazid and rifampicin, he was able to partake fully in all activities of his age group. PMID- 7843032 TI - [Cardiac manifestations of terminal kidney insufficiency. Current characterization of uremic cardiomyopathy]. PMID- 7843033 TI - [Percutaneous transluminal coronary rotation ablation. Technique, results, complications]. PMID- 7843034 TI - [Timeliness of patient information in ambulatory surgery. Decision by the BGH (Federal High Court) of 6-14-1994]. PMID- 7843035 TI - [Prevention of infection in indwelling catheters]. PMID- 7843036 TI - [Leg amputation and infrarenal abdominal aortic aneurysm]. PMID- 7843037 TI - [Interferon therapy of chronic hepatitis C in hemophilia]. PMID- 7843038 TI - [Sudden greying or whitening of the scalp hair]. PMID- 7843039 TI - [Prognosis of vertically infected children with HIV]. PMID- 7843040 TI - Long-term developmental outcomes of method of delivery. AB - OBJECTIVE: In the general framework of relating birthing events to later mental development, this study addresses the hypothesis that uneventful non-vertex delivery is associated with higher intelligence than uneventful vertex delivery. STUDY DESIGN: In the course of a developmental obstetrical survey, data was gathered prospectively on families having a non-vertex birth at Huron Road Hospital during the 1950s and early 1960s. The intelligence quotient (IQ) scores and school success ratings for the cohort of 658 children who had been delivered uneventfully by specific non-vertex methods of birth (viz. elective section, breech and internal podalic version) are compared with those of 1151 of their own siblings and peers delivered by cephalic presentation without complication. Intrafamily comparisons allow the control of genetic and socioeconomic factors. RESULTS: The one-sided 95% confidence intervals (using the t-statistic) for mean values do not overlap. They are: IQ > 112.1 (non-vertex) vs. < 110.1 (vertex) and school success scores > 2.64 (non-vertex) vs. < 2.54 (vertex). These findings are confirmed for IQ when the analysis is restricted to only those 434 children in the families allowing intrafamily comparisons (i.e. comparable siblings born by both non-vertex and vertex deliveries). The one-sided 95% confidence intervals for mean values do not overlap. They are: IQ > 112.89 (non-vertex) vs. < 112.86 (vertex). CONCLUSIONS: Speculation is given as to the reasons for this phenomenon. It is unclear whether these differences are due to physical phenomena related to delivery or to effects due to differing levels of anesthesia-analgesia or whether these differences in intellectual potential are associated with the cause of obstetrical difficulties. PMID- 7843041 TI - Ductus venosus velocity waveforms in appropriate and small for gestational age fetuses. AB - The objective of this study was to evaluate differences in ductus venosus velocity waveforms between appropriate and small for gestational age fetuses by using a new index based on the ratio between systolic and atrial peak velocities. Ductus venosus velocity waveforms were cross-sectionally recorded in 164 appropriate for gestational age fetuses at 16-42 weeks of gestation and in 97 small for gestational age fetuses free from structural and chromosomal abnormalities between 24-36 weeks of gestation. Small for gestational age fetuses were divided according to the Doppler findings in arterial peripheral vessels: group A (n = 33), normal ratio between umbilical artery and middle cerebral artery Pulsatility Indices; group B (n = 41), umbilical artery/middle cerebral artery ratio > 95th centile but presence of end diastolic flow in umbilical artery; group C (n = 23), umbilical artery/middle cerebral artery ratio > 95th centile and absence of end diastolic flow in umbilical artery. Eighteen small for gestational age fetuses (10 from group B and 8 from group C) were also serially studied until delivery due to fetal distress. Ductus venosus velocity waveforms were recorded at the level of its origin from umbilical vein and the ratio between systolic and atrial peak velocities (systolic/atrial ratio) calculated. In appropriate for gestational age fetuses, systolic/atrial ratio values significantly decrease with gestation. No significant differences were found in systolic/atrial ratio between appropriate for gestational age fetuses and group A small for gestational age fetuses while, after correction for gestational age, significantly higher values were found in group B (P < or = 0.01) and group C (P < or = 0.001) fetuses. Among these fetuses, those with systolic/atrial ratio above the 95th confidence interval showed a poorer perinatal outcome. No relationships were found between systolic/atrial ratio and Pulsatility Index values from fetal arterial peripheral vessels, while a positive relationship was found with the percentage reverse flow in inferior vena cava. In fetuses serially followed, the systolic/atrial ratio progressively increased approaching the onset of abnormal fetal heart rate patterns. The systolic/atrial ratio allows the evaluation of ductus venosus hemodynamics in small for gestational age fetuses and this index may be useful in the monitoring of such fetuses. PMID- 7843042 TI - Nutrient balance, metabolic response, and bone growth in VLBW infants fed fortified human milk. AB - The effects of fortification of preterm human milk were evaluated by comparing two groups of very low birth weight infants (birth weight < or = 1300 g, gestational age < or = 30 weeks): six fed preterm human milk fortified with a commercially available protein-mineral supplement (protein 0.7 g/dl, calcium 90 mg/dl, phosphorus 45 mg/dl) and seven fed unfortified preterm human milk. Nitrogen and energy balance studies were performed at an average age of 56 postnatal days. Nitrogen retention in the fortified group (348.2 +/- 70.5 mg/kg/day) was significantly greater than that in the unfortified group (196.0 +/ 50.0 mg/kg/day) and similar to that of fetuses of comparable gestational age. Energy stored by the two groups did not differ. At age 8 weeks, the infants in the fortified group had higher serum protein, higher serum albumin, and better mineral status (higher serum calcium and phosphorus and lower alkaline phosphatase and renal tubular reabsorption of phosphate). The bone density and width of the distal third radius, as measured by X-ray microdensitometry, were greater in the fortified group than in the unfortified group 12 weeks after birth. These results suggest that the supplement corrects any nutritional inadequacies of preterm human milk for very low birth weight infants. PMID- 7843043 TI - What is the minimum number of heart rates necessary to evaluate fetal conditions at different gestational ages? AB - Our objective was to determine the minimum number of fetal heart rates (FHRs) needed to assess various fetal conditions adequately, focusing on FHR changes in relation to gestational age. We used probability distribution matrices previously derived from 10,934,604 FHRs of 743 uncomplicated fetuses. These matrices were made at nine consecutive 2-week intervals between 23 and 40 weeks' gestation, from which samples were taken after assigning random numbers to FHRs in sequence. As a variable, the difference rate (%) between the sample probability distribution matrix and its corresponding age-group probability distribution matrix was calculated. Scattergrams of difference rates vs. a given number of FHR samplings were analyzed using piecewise linear regression. One critical point per age-group emerged, ranging between 9000 and 10,000 beats, for all age-groups. A linear decrease in the difference rate was noted with a step-by-step increase in random sampling size of FHRs until reaching the critical point, beyond which the difference rate remained constant between 25-33%. The critical points indicate that the minimum number of FHRs for assessment of the fetus at 23-40 weeks' gestation is almost the same, between 9000 and 10,000, with 67-75% baseline variability (so called beat-to-beat variability) and 25-33% long-term variability regardless of advance in gestation. PMID- 7843044 TI - Doppler colour flow imaging of fetal intracerebral arteries relative to fetal behavioural states in normal pregnancy. AB - In 14 normally developing term fetuses, the relationship between the blood flow velocity waveforms at cerebral arterial level (internal carotid artery, anterior, middle and posterior cerebral artery) and fetal behavioural states was studied using Doppler colour flow imaging. Behavioural state dependent changes in absolute flow velocities occurred in all vessels, except for the middle cerebral artery. These changes suggest preferential blood flow to the left heart resulting in increased flow to the cerebrum during fetal behavioural state 2F (active sleep) when compared with fetal behavioural state 1F (quiet sleep). The middle cerebral artery supplies the neocerebrum. This developing part of the cerebrum does not seem to take part in the regulation of fetal behaviour. In the internal carotid artery, an inverse relationship between peak systolic velocity and fetal heart rate could be established, which can be explained by a shorter rapid filling phase at raised fetal heart rate according to the Frank-Starling Law. PMID- 7843045 TI - The development of the human lateral pterygoid muscle and the temporomandibular joint and related structures: a three-dimensional approach. AB - The development of the human fetal temporomandibular joint and surrounding structures was investigated in 11 specimens on the basis of histologic examination and three-dimensional reconstructions. Until the 10th week, there were no signs of the disc, joint spaces and capsule formation of the temporomandibular joint (TMJ). Apart from Meckel's cartilage, all the temporomandibular joint and related structures attained their adult shape at 14 weeks. Throughout the embryologic and fetal development, the relative positions of the branches of the mandibular nerve remained unchanged. From 11-12 weeks onwards, the lateral pterygoid muscle became a complex structure which was segmented by aponeuroses dividing the muscle into three main parts: superior, infero-medial and infero-anterior parts. The superior segment was attached to the TMJ disc superiorly and medially. The infero-medial segment was inserted onto the antero-medial aspect of the TMJ condyle and disc. The infero-anterior portion was attached to the anterior aspect of the condyle. PMID- 7843046 TI - Connection between skin arteriovenous shunt flow fluctuations and heart rate variability in infants. AB - Large, spontaneous fluctuations in blood flow to acral skin, caused by synchronous opening and closing of arteriovenous anastomoses (AVAs), have been demonstrated in adults in a thermoneutral environment. Individual AVA constrictions were accompanied by a diphasic heart rate (HR) response, indicating the presence of an autonomic rhythm which affected both skin AVA activity and heart rate variability. In the present study, 24 neonates were examined on day 2 (range 1-3 days) and re-examined at 14 weeks (11-17 weeks). The presence of rhythmic, synchronous fluctuations in laser Doppler flux in the palm of the hand and sole of the foot in 20 of 24 neonates strongly indicated the presence of functional skin AVA at birth. Both neonates and 3-month-old infants showed a diphasic HR response in association with cutaneous AVA constrictions. The infant response differed from the adult response mainly by the longer duration of the secondary bradycardia. This may reflect different properties of the baroreceptor reflex in infants and adults. PMID- 7843047 TI - [The concepts of asthenia and fatigue]. AB - Fatigue is one of the most common complaint of medicine and a very usual manner of communication between people. We must avoid to offer any reductionism. Fatigue is often related with physical and psychological symptoms. The inquiry is always difficult. Asthenia is a fatigue without or before effort. The world of the patient is subverted and we have to try to discover the meaning of this strange situation. PMID- 7843048 TI - [Fatigue syndromes, neurasthenia, psychasthenia, thymasthenia, dysthymia. Proceedings of a symposium. Bordeaux, France, October 23, 1993]. PMID- 7843049 TI - [Neurasthenia, yesterday and today]. AB - Neurasthenia was described and explained in very mechanistic terms, at the end of the 19th century, by G.M. Beard to account for physical and mental exhaustion and for varied somatic troubles imputed to failure of too much solicited nervous resources. This concept was then universally adopted and gave rise to diverse interpretations, among which was the Freud's one. Later, in Occident, came a deterioration, the diagnostic of neurasthenia giving way to those of anxious or affective disorders. In the same time, at least for ideological and cultural reasons, the concept remained lively in Russia and in Asia. During the last decade the western psychiatry has been led to accept that there are clinical situations focussed on fatigue and fatigability, even if it coined for them new terminologies (post-infectious fatigue, chronic fatigue syndrome, etc.) and while DSMs keep on ignoring neurasthenia, the ICD 10 gives it an important place. PMID- 7843050 TI - [Psychasthenia: history and evolution of the P. Janet concept]. AB - Description of psychasthenia by P. Janet (1903) sets up at the end of a double reflection, with on the one hand a theorization of asthenia, the notion of which already occupied the medical concepts of the 18th and 19th centuries, and on the other hand a progressive attribution of neurosis to the psychiatric field. Its clinical characteristics (feelings of non-fulfillment in action and emotion, experiences of oddness and depersonalization, obsessions, phobias...) makes psychasthenia a fully-fledged illness, the psychopathological organization of which results from a decrease of psychological tension and from a loss of reality function. Since P. Janet, the term of psychasthenia has not ceased to be used, although its etiopathological references blurred behind the psychoanalytic work, and it is usually synonymous with obsessional neurosis, even with obsessional personality. Description of psychasthenia appears in these rubrics of the DSM III, even though the term itself is ignored. PMID- 7843051 TI - [Neurasthenia and thymasthenia]. AB - The term of depression applies to two syndromes at least; one is associated with a reduction in interests, activities and with a withdrawal; the other consists of a moral pain, a pessimism, a guilty feeling, an irritability. In each case the depressive mood corresponds to the subjective state. A first survey concerning 3,000 outpatients in general practice allowed us to identify 16.5 of depressed subjects, with 3% showing a pure painful syndrome, 7% showing a syndrome that we described as thymasthenia, and 6% showing the two syndromes (this last group consists probably of major depressive states). This new study, organized by the WHO and concerning 2,000 consecutive patients in primary care, permitted to precise the definition of thymasthenic subjects. The prevalence of current major depressive states is 13.7% and that of dysthymic disorders is 3.6%. Thymasthenia is observed in 9.2% of patients (mean age: 38 years; 60% of women). Among them, 62% show major depressive states, 18% dysthymic disorders, 16% panic disorders, and 11% pure thymasthenia, corresponding to a prevalence of 1%. It should be noted that the prevalence of neurasthenia (according to the definition given by IDC-10) is of 2.9% and that 36% of thymasthenic subjects show also neurasthenia (according to IDC-10). The qualitative content of these two syndromes will be compared. PMID- 7843052 TI - [Dysthymia: a model of the interaction between personality traits and psychopathologic state?]. AB - The subtlety and complexity of the relationships between biology and psychology are nowhere more important than in the study of personality and dysthymic states. The study of personality and affective illness can aid in understanding the relationship between temperamental factors and personality, delineating the role of mood in personality development and expression, generating theories about the impact of personality structure on the clinical presentation of symptoms and identifying personality predictors on treatment responsiveness and compliance. PMID- 7843053 TI - [Depressive states and chronic asthenic syndromes in general practice]. AB - It has been shown in Great Britain that general practitioners fail to recognize as many as 50% of the cases of depressive illness that present to them. The diagnosis is missed particularly when it is the physical type of symptom, such as asthenia, that is prominent. The Royal College of Psychiatrists, in association with the Royal College of General Practitioners, has launched the "Defeat Depression" campaign which includes amongst its aims the intention to provide up to-date educational materials to family doctors on the recognition and treatment of depression. We have held two consensus meetings jointly with psychiatrists and primary care physicians and the results have been published in the British Medical Journal (2). One of our key recommendations is that, when medication is used to treat depressive illness in general practice, the antidepressants should be continued for six months after full remission has taken place. At present patients in general practice take their drugs for a total of three or four weeks. One of the reasons for patients abandoning their medication prematurely has been revealed by surveys that we have carried out on the general public. The lay person has little confidence in the efficacy of antidepressants and, perhaps more importantly, believes that they are addictive. It is therefore no surprise, then, that patients are keen to stop their antidepressants before they become dependent on them.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843054 TI - [Epidemiologic study of chronic fatigue in primary care (general practice)]. AB - The results of a cross sectional study of fatigue in two large samples of patients attending primary care physicians are reported. The level of complaint of fatigue was higher in the prospective sample, which consisted of patients who had been diagnosed as suffering from a viral infection six months earlier. Duration and frequency of experience of fatigue correlated with severity in both samples. Severity, duration and frequency were continuously distributed in these populations. Attribution of fatigue in these two samples was mixed: social stresses, current physical illness and psychological problems all being offered as explanations. 11% of the cross sectional sample and 17% of the prospective sample met study operational criteria for a possible chronic fatigue state. These patients were assessed in greater detail. The majority had a diagnosable psychiatric disorder, predominantly depression. Physical illnesses were not adequate to explain these fatigue states. These studies in primary care do not support a clinical entity of a "chronic fatigue syndrome". Some patients in primary care settings have complaints of fatigue that are both disabling and long lasting, but they do not form a distinct group although the majority are likely however to be suffering from a concurrent psychiatric disorder. In contrast to similar patients with chronic fatigue syndromes attending hospital clinics, primary care patients with complaints of fatigue are much more varied in their ideas of causation with considerable less evidence of disease conviction. PMID- 7843055 TI - [Chronic fatigue syndrome. Clinical, social psychological problems and management]. AB - Fatigue chronic syndrome (SFC) is the heir-at-law of neurasthenia. Both are seen like physical diseases and share certain therapeutic measures, such as sleep; they have the same symbolic function and enable patients as well as doctors reluctant to psychological dimensions of pathology, to get and express sympathy and attention. A strong controversy developed these last years concerning the SFC physiopathology particularly concerning the responsibility of viral infectious agents or psychiatric troubles. The SFC fatigue is unlikely hysterical or neuromuscular but it probably depends on several associated factors; cerebral neurobiochemistry anomalies (possibly induced by an infection or immune reactions), effort perception trouble, affective trouble, lack of physical activity. The handicap seems to be worse on account of unsuitable care and inefficacious treatment. Especially sleep, which is often beneficial in a short term, is source of ulterior chronicisation. Antidepressants are the only justified pharmacological treatment for SFC at the moment. Referring to the existence and the nature of cognitive distortions, the author suggests a cognitivo-behavioural therapy, whose aim is a progressive activity resumption. PMID- 7843056 TI - [Current studies on the neurobiology of chronic fatigue syndrome]. AB - Cytokines are soluble mediators which are released by activated immune cells during infection and inflammation. The possibility that fatigue is mediated by the effects of cytokines on the central nervous system is supported by several converging lines of evidence: 1) infusions of cytokines to immunocompromised patients induce flu-like symptoms including fatigue and malaise; 2) peripheral and central injection of cytokines to laboratory rodents induce sickness behaviour; 3) symptoms of sickness behaviour occurring during experimental infections can be abrogated by administration of anti-cytokine treatments; 4) although many pitfalls in the detection of cytokines still exist, patients afflicted with the chronic fatigue syndrome have been found in some studies to display instances of excessive production of cytokines. Experimental studies have confirmed that cytokines are interpreted by the brain as internal signals for sickness. Furthermore, there is evidence that sickness is a motivation which reorganizes the organism's priorities in face of this particular threat which is represented by infectious pathogens. The elucidation of the mechanisms that are involved in these effects and in particular, the role of the cytokines which are produced in the brain in response to peripheral immune stimuli and to stressors, should give new insight on the way sickness and recovery processes are organized in the brain. PMID- 7843057 TI - [Epidemiology of fatigue in general practice]. AB - The epidemiology of fatigue is not well known in France, and this study reports on factors associated with fatigue in a sample of 3,784 general practice patients. Prevalence rates according to several definitions of fatigue are presented and factors are examined that have been reported to be associated with fatigue. Although 41.2% of the sample report having experienced symptoms of fatigue for at least three days, only 7.6% declare fatigue as a reason for consulting a doctor. Women report more symptoms of fatigue, but they do not consult more often than men for this reason. Age is strongly correlated with fatigue, but this is found only for men. Socioprofessional category bears no relationship to fatigue as a reason for consultation, however, the diagnosis of fatigue is more often attributed to professionals and upper management than it is to office staff or skilled and unskilled workers. We do find a strong relationship between depressive symptomatology as measured by the Center for Epidemiologic Studies (CES-D) and fatigue; nonetheless, fatigue is neither sensitive nor specific to the diagnosis of depression. PMID- 7843058 TI - [Fatigue and signs of depressive symptoms in general practice in Aquitaine]. AB - An epidemiologic study of patients consulting General Practitioners (GPs) was conducted among GPs who usually collaborate on Aquitaine Sentinel Network, supported by the Department of Medical Informatics of the University of Bordeaux II. One day in June and one day in December 1992, each GP who participated in this investigation had to collect age, sex and reason for consulting about every patient who took medical advice. For every patient over 15 year old, on the day of the consultation or the previous week, the GP had to collect signs of depression, dysphoria, loss of interest or pleasure in the daily-living activities, insomnia, fatigue, inappropriate guilt, diminished ability to think or indecisiveness, recurrent thoughts of death... RESULTS: In June, 79 GPs collected data on 1,500 patients and in December 80 GPs interviewed 1,400 patients. The main sign was fatigue (35%). Then, in frequency order, sleep disorders (26.5%), appetite and weight disorders (22.7%), dysphoria (18.7%) and loss of interest or pleasure for daily-living activities (16.7%) have been found. Among patients who present at least one of the signs of depression (more than 50% of the sample), half had associated handicap in every-day life activities. Major depression prevalence rate was respectively 5% in June and 6.3% in December whereas dysthymia was 4.3%. PMID- 7843059 TI - [Research about fatigue in France over the past 20 years]. AB - The author reported the works of the "Fatigue Studies Group" founded 20 years ago to explore the different dimensions of "fatigue" complaint. The emphasis is placed on the asthenic syndromes evaluation instrument created by the group, which takes into account the socio-demographic data of the patient, clinical signs and their severity as well as the potential etiological factors. Its first version (GEF-3) enabled to isolate 4 groups of asthenia (overworking, somatic, psychosomatic and psychic), each of them requesting a specific treatment. An ulterior version (GEF-4) has been elaborated to describe better the psychiatric semeiology. Finally, a simplified version (GEF-10) was used as an evaluation instrument in different therapeutic researches. At the same time, the group continued its researches on the fatigue psychosocial dimensions and its nosographic status, especially in comparison with dysthymic disorders. PMID- 7843060 TI - Inflammation and dental pain in man. AB - In the present article special interest has been focused on indicators of latent and manifest pulpal inflammation studied by psychophysical and electrophysiological techniques. Intradental A-delta nerve activity was recorded from two electrodes placed in the dentin on the labial tooth surface. The psychophysical measures were obtained by means of direct scaling methods in combination with sensory verbal descriptors. For stimulation cooling (ethyl chloride) and heating (hot guttapercha) of the tooth surface were employed. In addition, potentially algogenic substances, bradykinin and histamine, were administered on partly exposed pulps. Hot guttapercha induced a more complex neural response pattern than ethyl chloride. In all the recordings the responses evoked by heat showed a characteristic pattern consisting of three phases: an initial phase of short duration (i) followed by a depression in activity relative to the baseline (ii) and a slow spontaneously emerging activity in the absence of a physical stimulus (iii). The latter neutral event (iii) passed unnoticed by all the subjects. In the light of earlier experiments on feline pulp it was hypothesized that this third phase of the neural response was an indication of hyperexcitability in dental pulps and thus inflammation. Those subjects who experienced pulsating, dull, lingering pain (clinically diagnosed as pulpitis) showed a poor correlation between magnitude estimates of their mixed pain percepts and the total flux of A-delta nerve activity. Bradykinin and histamine evoked dull pain in the majority of cases probably caused by excitation of pulpal C fibers. In one experiment A-delta neural discharge of short duration could also be triggered by histamine.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843061 TI - Effect of fluoride on root resorption caused by mechanical injuries of the periodontal soft tissues in rats. AB - The present study was carried out to investigate histologically and histometrically the effect of fluoride on root resorption induced by mechanical injuries of the periodontal soft tissues in rats. Resorption lacuna in the root surface of the molar in animals given both mechanical injuries and fluoride administration was significantly smaller in length and area than that in animals given only mechanical injuries. Moreover, resorption lacuna in the former animals contained fewer odontoclasts than that in the latter. The results of the present study might suggest that the administration of fluoride suppressed root resorption induced by mechanical injuries of the periodontal soft tissues. PMID- 7843062 TI - Effectiveness of two different methods for preparing curved root canals. AB - In this study, the effect of using two different methods for preparing curved root canals of extracted, single-rooted teeth were analyzed with the scanning electron microscope. The instrumentation systems tested were the Canal Master and a standard circumferential filing technique in which conventional K-files were used. Shaping effectiveness was qualitatively evaluated in terms of respect for conservation of the apical constriction and the presence or absence of ledging, specially in the apical third of the root canals. As a result of our observations, it appeared that the Canal Master instrumentation technique provided well-centered and tapered preparations. Conversely, the use of conventional K-files with a standard circumferential filing technique resulted in frequent alterations of the initial pattern of the root canals, showing transportation of the apical foramen and ledge formation. PMID- 7843063 TI - In vitro evaluation of an audiometric device in locating the apical foramen of teeth. AB - A new audiometric device to determine the location of the apical foramen of teeth undergoing endodontic treatment according to "the relative value method" was tested in in vitro experiments. In 96.5% of the 350 human teeth used in the experiment, the location of the apical foramen was determined within acceptable limits (0-0.5 mm). In 60 teeth, where the measurements were based on an intermittent audio signal, a point about 1 mm short of the apical foramen was located. The results were considered promising and a clinical evaluation of the device will be carried out. PMID- 7843064 TI - Dental trauma in children and adolescents in Valparaiso, Chile. AB - This study analyzed traumatic injuries in the primary and permanent dentition in children treated from 1990 to 1992 at the Children's Dental Traumatology Service in Valparaiso, Chile. A total of 227 records from patients 2 to 21 years old was studied with regard to the cause of injury, location of injury, time elapsed before treatment, history of previous trauma, type of injury, number of injured teeth, and how patients seek treatment. A total of 73 patients had injuries to the primary dentition (pD) and 154 to the permanent dentition (PD) with a total of 357 injured teeth (115 primary, 242 permanent). Ten to 12-year-old children had the highest number of injuries (33%). Falling was the most common cause of injury in both groups (82% pD, 58% PD), followed by striking against objects (13% pD, 19% PD) and bicycle accidents (9% PD). Most injuries in children with primary dentition (68%) occurred at home, while children with permanent dentition had most accidents at school (38%). Most children (61%) sought treatment after 24 h (52% pD, 65% PD), 61 children had suffered previous trauma (36% pD, 23% PD). The most common injuries in primary teeth were luxation (26%), intrusion (21%) and subluxation (18%). Uncomplicated crown fracture (34%), followed by complicated crown fracture (21%), were the main injuries in permanent teeth. There was no difference in the number of teeth involved for either dentition. A single tooth injury was found in 54%. Two teeth were involved in 35%, and three or more teeth in 11%.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843065 TI - Biological properties of IRM with the addition of hydroxyapatite as a retrograde root filling material. AB - The effect of adding 10% & 20% hydroxyapatite (HAP) on the antibacterial activity and cytotoxicity of IRM (Intermediate Restorative Material) when used as a retrograde root filling was compared with amalgam, a commonly used material. The antibacterial activity was assessed using the agar diffusion inhibitory test. Forty standardized pellets of each material were produced. Fresh materials, and materials aged for 1 week in sterile distilled water, were placed on blood agar plates inoculated with Streptococcus anginosus (milleri) or Enterococcus faecalis. The presence and diameter of zones of inhibition were recorded at intervals of 3, 7 and 10 days. There was no statistically significant overall difference in the response of the two bacteria tested. However, there were statistically significant overall differences in diameters of the zones of inhibition related to different materials, period of exposure and ageing of materials (P < 0.001). The diameter of the zones of inhibition increased with time for all materials, fresh and aged. IRM and both the HAP-modified forms produced large zones of inhibition. Amalgam produced no measureable zones of inhibition whether aged or fresh, regardless of period of exposure and was different from the other materials (P < 0.001). The cytotoxicity was assessed using the Millipore filter method. Ten standardized pellets of each material were produced and aged by storage in sterile distilled water for 72 h. Ten filters were included as controls. Amalgam produced a consistent cytotoxic score of 1, and the difference between amalgam and the other materials was statistically significant (P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843066 TI - Reaction of inflamed periapical tissue to intracanal medicaments and root canal sealers. AB - The effects of different intracanal medicaments and zinc oxide-eugenol based root canal sealers on an experimentally induced apical periodontitis were studied histologically in mesial roots of lower molars of Wistar rats. After root canal instrumentation each canal was filled either with an intracanal medicament twice for 3 days each time or with a sealer for 21 days. The intracanal medicament chlorophenol caused periapical tissue damage. P-chloroxylenol-camphor lead to periapical improvement as did 5% sodium-hypochlorite. 12% sodium-hypochlorite gave tissue damage. After intracanal medication with an aqueous suspension of calcium hydroxide periapical repair was clearly visible. A combination of a corticoid and an antibiotic appeared to induce damage of the periapical tissues. The root canal sealers Endomethasone and N2 essentially impaired periapical repair. The results were acceptable for Aptal-Zink-Harz root canal fillings after 21 days as well as after 56 days. PMID- 7843067 TI - Evaluation of calcium hydroxide-containing root canal sealers with an improved rabbit ear chamber. AB - An improved rabbit ear chamber was used to evaluate calcium hydroxide-containing root canal sealers on their potential to induce dystrophic calcification in connective tissue. Four sealers and two control materials were introduced into the chambers and the effects of these materials on the living vascular tissue were observed continuously under a biomicroscope up to 9 weeks. Conventional histopathological investigation and examinations with a scanning electron microscope and an X-ray microanalyzer were done to supplement the results. Sealapex and Calvital (Ca(OH)2 + iodoform) revealed almost the same tissue reaction as calcium hydroxide-saline paste; they rapidly made a precipitate barrier of calcium phosphate in the connective tissue, inducing calcification. However, Dentalis KEZ (ZnO-Ca(OH)2 + eugenol) caused mild disorders of microcirculation without calcification, as well as Canals (ZnO + eugenol). New A (Ca(OH)2 + fatty acid) had good compatibility with microvessels as well as New B (ZnO + fatty acid), however they induced no calcification and disintegrated rapidly in the tissue. These sealers were reclassified according to what they actually bring about in the tissue, not according to what they include. PMID- 7843068 TI - Growth hormone and the heart. AB - GH exerts direct effects on myocardial growth and function. Evidence from laboratory models shows that GH (or IGF-I) induces mRNA expression for specific contractile proteins and myocyte hypertrophy. Furthermore, GH increases the force of contraction and determines myosin phenoconversion toward the low ATPase activity V3 isoform. These data provide plausible explanations for the cardiac abnormalities observed in clinical settings of excessive or defective GH production. In acromegaly, the functional consequences of GH excess initially prevail (hyperkinetic syndrome), followed by alterations of cardiac function when myocardial hypertrophy develops. This involves both ventricles and is purposeless because it occurs without increased wall stress. Hypertrophy also entails proliferation of the myocardial fibrous tissue that leads to interstitial remodeling. The functional consequence is an impaired ventricular relaxation that causes a diastolic dysfunction, followed by impairment of systolic function. In untreated disease, cardiac performance slowly but inexorably deteriorates and heart failure eventually develops. Several lines of evidence support the specificity of heart disease in acromegaly. Particularly demonstrative are the recent studies in which GH production was suppressed by octreotide, with a consequent significant regression of hypertrophy and improvement of cardiac dysfunction. It is not yet established whether full recovery of normal cardiac morphology and function is possible after correction of GH excess. The point is not a minor one since the possibility to revert, albeit partially, myocardial fibrosis is of great relevance to the control of cardiac hypertrophy in general. GHD leads to a reduced mass of both ventricles and to impaired cardiac performance with low heart rate (hypokinetic syndrome). These alterations are particularly evident during physical exercise and might provide an important contribution to the reduced exercise capacity of GHD patients, in addition to the reduced muscle mass and strength. The data also support a role of GH in the maintenance of a normal cardiac structure and performance. The hypokinetic syndrome is well documented in young patients in whom GHD began very early in their childhood. In contrast, the data in adult-onset GHD are less consistent. This suggests that the consequences of GHD are more relevant if the disorder starts during early heart development. As observed with other abnormalities associated with GHD, cardiac dysfunction is also susceptible to marked improvement by hrGH. This observation lends further support to the proposal to treat these patients with replacement therapy. PMID- 7843069 TI - Leydig cells: endocrine, paracrine, and autocrine regulation. PMID- 7843070 TI - Transcriptional regulation by the helix bundle peptide hormones: growth hormone, prolactin, and hematopoietic cytokines. PMID- 7843071 TI - Recent advances in the chemistry and immunochemistry of human chorionic gonadotropin: impact on clinical measurements. PMID- 7843072 TI - Pregnancy maintenance and parturition: the role of prostaglandin in manipulating the immune and inflammatory response. PMID- 7843073 TI - Respiratory effects of coal dust exposure: clinical effects and diagnosis. AB - During the past two decades, growing evidence has been reported on the role of respirable inorganic dust in the development of airflow obstruction, impaired diffusion capacity, chronic bronchitis, and emphysema, irrespective of the extent of possible pneumoconiotic abnormalities. These nonpneumoconiotic effects associated with dust exposure in miners and the relationship between dust exposure and mortality are reviewed. When pneumoconiotic changes can be visualized by different radiologic techniques, including computed tomography (CT) and high-resolution CT, assessment of the respiratory impairment in coal workers at present requires evaluation of the ventilatory and gas exchange capacity. PMID- 7843074 TI - Recognition and progression of coal workers' pneumoconiosis in the collieries of northern France. AB - In France, both active and retired coal miners take part in medical surveillance programs. Those compensated for pneumoconiosis are registered and receive annual chest X-rays and regular lung function assessments. A longitudinal study was done among 2719 pneumoconiotics from the Nord-Pas de Calais region Compensation Register, who received first compensation between 1942 and 1987 to study progression of CSWP. Chest radiographs taken at time of compensation and in 1987 were examined by three independent readers. There was a change over time in the characteristics of pneumoconiosis at the time of first compensation toward a low profusion of irregular opacities. In the period from 1982 to 1987, 645 pneumoconiotics developed progressive massive fibrosis (PMF). The occurrence of PMF was related to the date of compensation and the profusion of small opacities at detection (after controlling for time to follow-up). Two profiles for changes in coal workers' simple pneumoconiosis (CWSP) were observed: the first in the group of subjects with mild pneumoconiosis at compensation, who did not reach category 2 at follow-up and had a low attack rate of PMF; and the second in the group of those compensated for category 1/2 pneumoconiosis or higher, who reached severe CWSP and had a twofold attack rate for PMF at follow-up. The changes observed in the characteristics of pneumoconiosis at first compensation between 1942 and 1987 suggest a lessening of disease severity. PMID- 7843075 TI - High-resolution computed tomography of the lungs in coal miners with a normal chest radiograph. AB - Nowadays, there is a tendency to carry out high-resolution computed tomography (HCRT) in diagnosis of interstitial disease in former coal miners, but the validity and consequences in terms of compensation have not been validated. This study was designed to investigate HRCT outcome (visual and densitometric) and lung function in a group of ex-coal miners with a normal (ILO < or = 0/1) chest radiograph. In more than half of the coal miners HRCT assessed nodules visually, indicative of coal workers' pneumoconiosis (CWP). This finding was strengthened by densitometric data. With increment of cumulative dust exposure a trend was observed toward a higher mean coal workers' pneumoconiosis (MCWP) score and a higher mean lung density value. No relation was observed between the pulmonary function tests and the MCWP score or the mean lung density. In conclusion, visual assessment of HRCT slices is more sensitive than chest radiographs to detect CWP. Application of densitometric analysis to the individual coal miners with early disease seems limited because of the variability in lung density among normals. PMID- 7843076 TI - Airflow obstruction and monocyte TNF release in coal workers. AB - Respiratory health of 102 retired coal miners was assessed by chest radiographs, lung function measurements, and questionnaires, and related to tumor necrosis factor-alpha (TNF-alpha) production by blood monocytes upon priming with different stimuli. The objective was to assess a possible relationship between airflow obstruction and TNF-alpha production in retired coal workers. No significant differences in lung function were observed between cases of coal workers' pneumoconiosis (CWP) (n = 27; > %) and references (n = 75; = > %), nor was the effect of cumulative exposure on flow volume or impedance parameters significant. TNF-alpha release upon stimulation of blood monocytes with coal mine dust was significantly increased in cases with International Labour Organisation (ILO) score 0/1 (doubtful cases) compared to references and cases with a higher ILO score. Airflow limitation defined either as a FEV1 < 80% (N = 10; 5 cases of CWP) or as a resonance frequency > 15 Hz accompanied by a negative frequency dependence of resistance (N = 9; 4 cases of CWP) was significantly related to high levels of TNF-alpha release upon stimulation with endotoxin and silica, with silica showing the strongest relation. These data suggest that in this group airflow limitation is associated with an increased expression of inflammatory mediators indifferent of the presence of pneumoconiosis. PMID- 7843077 TI - Evaluation of tumor necrosis factor-alpha (TNF) as an exposure or risk marker in three French coal mining regions. AB - Several studies have shown the crucial role of the tumor necrosis factor-alpha (TNF) in the fibrosis induced by dusts containing silica and its role in the transition from simple pneumoconiosis (CWSP) to progressive massive fibrosis (PMF). To evaluate the nocivity of dust exposure among coal miners (n = 474) from different mining regions in France (e.g., Nord-Pas de Calais, Lorraine, and Provence), spontaneous and LPS or silica-induced TNF released by peripheral blood monocytes was quantified. The primary aim of this effort was to study the link between the prevalence of coal workers pneumoconiosis (CWP) and TNF release. TNF levels were significantly different between active miners from the three regions. However, after correction for age and region, TNF was found not to be related to dust exposure. Interestingly, a very low, homogeneous expression of TNF was observed in the group from Provence. These results are probably related to the absence of pneumoconiosis in this area. A positive relation between profusion and TNF release was found for all stimulants among retired miners with PMF. Although in retired miners TNF release was consistently higher, the design of the study does not allow this effect to be separated from that of age. Both silica and nonstimulated TNF release were found to increase with increasing radiological symptoms; the opposite was found for LPS-induced release. PMID- 7843078 TI - Serum procollagen type III peptide in coal workers' pneumoconiosis: a five-year follow-up study. AB - Several studies have suggested the use of serum type III procollagen peptide (PIIIP) as a marker in fibrotic lung disease. To test serum PIIIP as a biomarker for progression of coal workers' pneumoconiosis (CWP), a follow-up study was conducted among 156 coal miners. A five-year progression of simple CWP was determined from paired chest X-ray readings and related to serum PIIIP measured in 1987 (n = 73) and in 1992 (n = 104). Although in eight subjects CWP had progressed, none of these subjects had abnormal levels of serum PIIIP, nor were they different from nonprogressed miners with regard to exposure, age, or smoking habits. The results suggest that the use of serum PIIIP as a biomarker to screen for coal workers' pneumoconiosis is limited. PMID- 7843079 TI - Biological markers and occupational lung disease: mineral dust-induced respiratory disorders. AB - There is a need for methods to monitor early adverse effects, exposure, and/or susceptibility of individual subjects due to occupational and environmental causes. This paper discusses the experimental origin, value, and validity of several biological indicators, termed biomarkers, that were used to study coal dust-induced respiratory disorders. The findings are presented in a framework to visualize problems and challenges when developing biomarkers. Taking the framework of mineral dust-induced lung disorders as an example, it is demonstrated how carefully designed follow-up studies are a prerequisite to test the validity and use of events often put forward as biomarkers. It is concluded from the data that serum type III procollagen is neither an exposure nor an (early) effect marker, antioxidant enzyme expression is related to the early inflammatory response after mineral dust inhalation, while the evidence is accumulating that tumor necrosis factor-alpha is a susceptibility marker for progression in mineral dust-induced lung fibrosis. PMID- 7843080 TI - Differential cytotoxic effects of arsenic on human and animal cells. AB - Human fibroblasts (HFW) were 10-fold more susceptible than Chinese hamster ovary (CHO-K1) cells to sodium arsenite. Comparison of cellular antioxidant enzyme activities showed that CHO-K1 cells contained 3- and 8-fold more glutathione peroxidase and catalase activities, respectively, than HFW cells. Since vitamin E, methylamine, and benzyl alcohol could prevent, in part, the arsenite-induced killing of HFW cells, we suggest that arsenite can induce oxidative damage in HFW cells. We have also established arsenic-resistant cells, SA7 and CL3R, from CHO cells and from a human lung adenocarcinoma cell line (CL3), respectively. The arsenic resistance of SA7 cells was attributed mainly to elevation of glutathione S-transferase pi levels, and that of CL3R cells was possibly due to an increase in heme oxygenase activity. Since induction of heme oxygenase is a general response to oxidative stress, we suspect that the differential toxicity of arsenic to human and animal cells could be due to arsenic's more efficient induction of oxidative damage in human cells. PMID- 7843081 TI - Newer systems for bacterial resistances to toxic heavy metals. AB - Bacterial plasmids contain specific genes for resistances to toxic heavy metal ions including Ag+, AsO2-, AsO4(3-), Cd2+, Co2+, CrO4(2-), Cu2+, Hg2+, Ni2+, Pb2+, Sb3+, and Zn2+. Recent progress with plasmid copper-resistance systems in Escherichia coli and Pseudomonas syringae show a system of four gene products, an inner membrane protein (PcoD), an outer membrane protein (PcoB), and two periplasmic Cu(2+)-binding proteins (PcoA and PcoC). Synthesis of this system is governed by two regulatory proteins (the membrane sensor PcoS and the soluble responder PcoR, probably a DNA-binding protein), homologous to other bacterial two-component regulatory systems. Chromosomally encoded Cu2+ P-type ATPases have recently been recognized in Enterococcus hirae and these are closely homologous to the bacterial cadmium efflux ATPase and the human copper-deficiency disease Menkes gene product. The Cd(2+)-efflux ATPase of gram-positive bacteria is a large P-type ATPase, homologous to the muscle Ca2+ ATPase and the Na+/K+ ATPases of animals. The arsenic-resistance system of gram-negative bacteria functions as an oxyanion efflux ATPase for arsenite and presumably antimonite. However, the structure of the arsenic ATPase is fundamentally different from that of P-type ATPases. The absence of the arsA gene (for the ATPase subunit) in gram-positive bacteria raises questions of energy-coupling for arsenite efflux. The ArsC protein product of the arsenic-resistance operons of both gram-positive and gram negative bacteria is an intracellular enzyme that reduces arsenate [As(V)] to arsenite [As(III)], the substrate for the transport pump. Newly studied cation efflux systems for Cd2+, Zn2+, and Co2+ (Czc) or Co2+ and Ni2+ resistance (Cnr) lack ATPase motifs in their predicted polypeptide sequences. Therefore, not all plasmid-resistance systems that function through toxic ion efflux are ATPases. The first well-defined bacterial metallothionein was found in the cyanobacterium Synechococcus. Bacterial metallothionein is encoded by the smtA gene and contains 56 amino acids, including nine cysteine residues (fewer than animal metallothioneins). The synthesis of Synechococcus metallothionein is regulated by a repressor protein, the product of the adjacent but separately transcribed smtB gene. Regulation of metallothionein synthesis occurs at different levels; quickly by derepression of repressor activity, or over a longer time by deletion of the repressor gene at fixed positions and by amplification of the metallothionein DNA region leading to multiple copies of the gene. PMID- 7843082 TI - Oxidizing intermediates generated in the Fenton reagent: kinetic arguments against the intermediacy of the hydroxyl radical. AB - It has long been recognized that the aqueous mixture of hydrogen peroxide and ferrous ion, known as the Fenton reagent, generates powerful oxidants. Furthermore, the chemical intermediates and reaction pathways of the type generated by this reagent have been implicated in oxidative damage in biological systems. Although the subject continues to be debated, the hydroxyl radical (.OH) is generally invoked as the predominant oxidizing intermediate formed by the Fenton reagent. However, recent results from this laboratory have demonstrated that the principal pathway for the Fenton-mediated oxidation of N nitrosodimethylamine does not involve .OH, but instead must involve the intermediacy of another strongly oxidizing species. This conclusion was based on stopped-flow spectrophotometric observation of a transient, A, believed to be an iron(II) nitrosyl adduct, which was formed at a rate five-fold faster than that predicted for formation of .OH. Subsequent experiments have shown that methanol and other organic compounds can quench the formation of A. This quenching procedure provides a unique spectrophotometric probe with which to examine the relative reactivities of putative Fenton-type oxidizing intermediates toward organic substrates. Presented here are the results of several such quenching studies, plus an overview of our mechanistic investigations of the Fenton reaction. PMID- 7843083 TI - Role of lead-binding proteins in renal cancer. AB - High-dose lead exposure in rodents has been shown to produce pathognomonic lead intranuclear inclusion bodies and to result in an increased incidence of renal adenocarcinomas. Studies from this laboratory and others have demonstrated the presence of high-affinity renal lead-binding proteins in rat kidneys which act as tissue sinks for lead at low dose levels. Cell-free nuclear translocation studies have shown that these molecules are capable of facilitating the intranuclear movement of lead and that they are associated with chromatin. These data suggest that renal lead-binding proteins may play a role in mediating known alterations in renal gene expression associated with formation of intranuclear inclusion bodies. More recent studies from this laboratory have demonstrated the presence of chemically similar lead-binding proteins in kidneys of both monkeys and humans. Such observations suggest that a similar mechanism may be operating in primates since lead intranuclear inclusion bodies are also observed in these species. These data provide a testable mechanistic approach for assessing the possible role(s) of lead-binding proteins in mediating the intranuclear movement of lead and lead-induced renal cancer in primate species. PMID- 7843084 TI - Nickel-induced alterations in human renal epithelial cells. AB - Cellular progression to malignancy appears to require a number of distinct steps in which genetic damage in key regulatory genes accumulates. Immortalization, or escape from senescence, is considered to be one of the first phenotypic changes. Ni2+ treatment of normal human kidney epithelial (NHKE) cells in vitro resulted in immortalization of the cells IHKE cells). The combined action of Ni2+ and v-Ha ras oncogene fully transformed the cells to tumorigenicity in athymic nude mice. Sequence analysis of DNA from IHKE cells revealed point mutation in the p53 gene at codon 238 with T-->C transition. These findings suggest that Ni-induced mutation in the p53 gene can be involved in the immortalization of the NHKE cells. The results also show that changes in the responses to EGF and TGF beta and in the expression of their receptors occur during malignant progression in vitro. PMID- 7843085 TI - Molecular mechanisms of transformation of C3H/10T1/2 C1 8 mouse embryo cells and diploid human fibroblasts by carcinogenic metal compounds. AB - Carcinogenic arsenic, nickel, and chromium compounds induced morphological and neoplastic transformation but no mutation to ouabain resistance in 10T1/2 mouse embryo cells; lead chromate also did not induce mutation to ouabain or 6 thioguanine resistance in Chinese hamster ovary cells. The mechanism of metal induced morphological transformation was likely not due to the specific base substitution mutations measured in ouabain resistance mutation assays, and for lead chromate, likely not due to this type of base substitution mutation or to frameshift mutations. Preliminary data indicate increases in steady-state levels of c-myc RNA in arsenic-, nickel-, and chromium-transformed cell lines. We also showed that carcinogenic nickel, chromium, and arsenic compounds and N-methyl-N nitro-N-nitrosoguanidine (MNNG) induced stable anchorage independence (Al) in diploid human fibroblasts (DHF) but no focus formation or immortality. Nickel subsulfide and lead chromate induced Al but not mutation to 6-thioguanine resistance. The mechanism of induction of Al by metal salts in DHF was likely not by the type of base substitution or frameshift mutations measured in these assays. MNNG induced Al, mutation to 6-thioguanine resistance, and mutation to ouabain resistance, and might induce Al by base substitution or frameshift mutations. Dexamethasone, aspirin, and salicylic acid inhibited nickel subsulfide, MNNG, and 12-O-tetrade-canoylphorbol-13-acetate (TPA)-induced Al in DHF, suggesting that arachidonic acid metabolism and oxygen radical generation play a role in induction of Al. We propose that nickel compounds stimulate arachidonic acid metabolism, consequent oxygen radical generation, and oxygen radical attack upon DNA.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843086 TI - Molecular mechanisms of nickel carcinogenesis. AB - Carcinogenic, water-insoluble Ni compounds are phagocytized by cells; and the particles undergo dissolution inside the cell, releasing Ni ions that interact with chromatin. Ni produces highly selective damage to heterochromatin. The longest contiguous region of heterochromatin in the Chinese hamster genome is found on the q arm of the X chromosome, and this region is selectively damaged by Ni. More than half of the male mice in which there were Ni-induced transformations of Chinese hamster cells exhibited complete deletion of the long arm of the X chromosome. The introduction of a normal X chromosome into these cells resulted in cellular senescence, suggesting that the Ni interacted with Chinese hamster genome to inactivate a senescence gene. Investigations were conducted into the mechanisms by which Ni produced damage to chromatin. Ni ions have a much higher affinity for proteins and amino acids than for DNA (by five to seven orders of magnitude). Therefore, Ni interacted with chromatin because of the protein present, not because of its reactivity for DNA. Studies have shown that Ni produced an increase in oxidative products in cells as indicated by oxidation of the fluorescent dye dichlorofluorescein; Ni has also been shown to produce oxidation of proteins in cells, as measured by carbonyl formation. Ni cross-linked certain amino acids and proteins to DNA. These covalent cross-links were not dissociated by EDTA and are inconsistent with direct Ni involvement, but they are consistent with Ni acting catalytically. Using subtractive hybridization, we have isolated a number of clones that are expressed in normal but not in Ni-transformed cells.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843087 TI - The significance of the nuclear and cytoplasmic localization of metallothionein in human liver and tumor cells. AB - Metallothioneins are a group of low-molecular-weight intracellular proteins present in high levels in fetal mammalian livers, bound to zinc and copper. They are also present in two major isoforms in low basal levels in various organs of adults in several species. Although a number of functions have been proposed for metallothioneins, their major biological roles may be in the storage of zinc and copper during rapid growth and development, and also in the detoxification of certain toxic metals. In adult liver, metallothionein is mainly localized in the cytoplasm, it is localized also in the hepatocyte nuclei in human fetal liver and fetal and neonatal rat liver, as determined by immunohistochemical staining with a specific metallothionein antibody. Because of its high expression in fetal development, the potential role of metallothioneins in human tumors was investigated. The cellular localization of metallothionein was demonstrated in various human tumors such as thyroid tumors, testicular germ cell carcinoma, bladder transitional cell carcinomas, and salivary gland tumors. In most of these tumor tissues, metallothioneins were found in high levels in nucleus and cytoplasm in both benign and malignant tumors, although the proliferating edge of the malignant tumors showed most intense metallothionein staining. The expression of metallothionein is not universal to all tumor growth; its presence may depend on various factors, such as the type of tumor, cellular origin, morphological heterogeneity, or stage of growth. Human testicular seminomas, which are well differentiated, showed little expression of metallothionein irrespective of the staging, as compared to less well-differentiated embryonal carcinomas.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843088 TI - Apparent quiescence of the metallothionein gene in the rat ventral prostate: association with cadmium-induced prostate tumors in rats. AB - Several chronic studies in rats indicating that cadmium exposure can induce tumors of the ventral prostate have recently been completed in our laboratory. In one such study, a single dose of cadmium, s.c., increased prostatic tumor incidence only at doses below 5.0 mumol/kg, the approximate threshold for cadmium induced testicular damage. In a further study, prostatic tumors were elevated with higher doses of cadmium (30 mumol/kg, s.c.) if testicular damage was prevented by zinc pretreatment. Most recently, we found that dietary cadmium (25 to 200 micrograms/g) also can increase prostatic neoplastic lesions, but these were reduced by zinc-deficient diets. Thus it appears that cadmium produces prostatic tumors only if testicular function is maintained. Furthermore, we find that metallothionein (MT), a protein associated with cadmium tolerance, may be deficient in the rat prostate, and the prostatic MT gene, at least in the ventral lobe, is unresponsive to metal stimuli. In liver, MT gene expression, as assessed by MT-1 mRNA, was quite apparent in control tissue and was induced in a dose dependent manner 24 hr following cadmium exposure (1 to 10 mumol/kg, s.c.). However, in the ventral prostate very low constitutive levels of MT-1 mRNA were detected and increases did not occur with cadmium exposure. Cadmium concentrations in the ventral prostate were in excess of those that cause significant induction in the liver. In sharp contrast to the gene in the ventral prostate, in the dorsal prostate the MT gene was quite active. The dorsal prostate is not susceptible to cadmium carcinogenesis.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843090 TI - Monitoring metal concentrations in tissues and single cells using ultramicrosensors. AB - Intercellular and extracellular metal concentrations were measured using carbon fiber ultramicrosensors plated with mercury or with polymeric porphyrinic p-type semiconductors. Concentrations of unbound nickel and lead ions were studied within individual BC3H-1 myocytes, and H4-11-C3 rat hepatoma cells. Unbound ions are predominantly solvated inorganic ions not coordinated to biological cellular components. Fabrication of ultramicrosensors appropriate for the cells under investigation is described, including procedures for sharpening and waxing the microsensors in order to control the shape, area, and dimensions of the electroactive surface. Metal ion movement through cell membranes and intracellular ion diffusion in aorta tissue were studied. PMID- 7843089 TI - In vitro and in vivo studies on the degradation of metallothionein. AB - Degradation of metallothionein (MT) from rat liver was examined. Degradation of apo-MT by liver homogenate was greater than that by cytosol. At pH 5.5, degradation by homogenate was more than that at pH 7.2. These findings suggest that proteases that function at acidic pH are probably involved in MT degradation. Because lysosomes are the principal subcellular organelles that contain acid proteases (cathepsins), we compared the degradation of apo-MT by lysosomes and cytosol. Apo-MT was degraded about 400 times faster by lysosomal fraction than by cytosolic fraction. To determine the relative importance of different cathepsins, we used different inhibitors. Leupeptin, which inhibits cathepsins B and L, inhibited the degradation of apo-MT by 80%, implying that cathepsins B and/or L might be very important in the intracellular turnover of MT. Cathepsin D appeared to be the least significant, because apo-MT degradation was reduced by about 20% by inhibiting cathepsin D. When we extended this study with purified cathepsins, we obtained the same answer, i.e., the ability of different cathepsins to degrade apo-MT was in the following order: cathepsin B >> cathepsin C > cathepsin D. While apo-MT was susceptible to degradation, ZnMT and CdMT were highly resistant to degradation. Coincubation of ZnMT or CdMT with either lysosomal extract or purified cathepsins did not result in any appreciable degradation even after 16 hr. However, longer incubations did result in some degradation, especially by purified cathepsin B. Interestingly, CdMT degraded little faster than ZnMT by both lysosomal extract as well as purified cathepsin B.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843091 TI - Induction of internucleosomal DNA fragmentation by carcinogenic chromate: relationship to DNA damage, genotoxicity, and inhibition of macromolecular synthesis. AB - Hexavalent chromium (Cr) compounds are respiratory carcinogens in humans and animals. Treatment of Chinese hamster ovary cells with 150 and 300 microM sodium chromate (Na2CrO4) for 2 hr decreased colony-forming efficiency by 46 and 92%, respectively. These treatments induced dose-dependent internucleosomal fragmentation of cellular DNA beyond 24 hr after chromate treatment. This fragmentation pattern is characteristic of apoptosis as a mechanism of cell death. These treatments also induced an immediate inhibition of macromolecular synthesis and delayed progression of cells through S-phase of the cell cycle. Cell growth (as evidenced by DNA synthesis) was inhibited for at least 4 days and transcription remained suppressed for at least 32 hr. Many of the cells that did progress to metaphase exhibited chromosome damage. Chromate caused the dose dependent formation of DNA single-strand breaks and DNA-protein cross-links, but these were repaired 8 and 24 hr after removal of the treatment, respectively. In contrast, Cr-DNA adducts (up to 1/100 base-pairs) were extremely resistant to repair and were still detectable even 5 days after treatment. Compared with other regions of the genome, DNA-protein cross-links and Cr adducts were preferentially associated with the nuclear matrix DNA of treated cells, which was 4.5-fold enriched in actively transcribed genes. Chromium adducts, formed on DNA in vitro at a similar level to that detected in nuclear matrix DNA, arrested the progression of a DNA polymerase in a sequence-specific manner, possibly through the formation of DNA-DNA cross-links.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843092 TI - In vivo effects of chromium. AB - The production of reactive oxygen species on addition of hexavalent chromium (potassium dichromate, K2Cr2O7) to lung cells in culture was studied using flow cytometer analysis. A Coulter Epics Profile II flow cytometer was used to detect the formation of reactive oxygen species after K2Cr2O7 was added to A549 cells grown to confluence. The cells were loaded with the dye, 2',7' dichlorofluorescein diacetate, after which cellular esterases removed the acetate groups and the dye was trapped intracellularly. Reactive oxygen species oxidized the dye, with resultant fluorescence. Increased doses of Cr(VI) caused increasing fluorescence (10-fold higher than background at 200 microM). Addition of Cr(III) compounds, as the picolinate or chloride, caused no increased fluorescence. Electron paramagnetic resonance (EPR) spectroscopic studies indicated that three (as yet unidentified) spectral "signals" of the free radical type were formed on addition of 20, 50, 100, and 200 microM Cr(VI) to the A549 cells in suspension. Two other EPR "signals" with the characteristics of Cr(V) entities were seen at field values lower than the standard free radical value. Liver microsomes from male Sprague-Dawley rats treated intraperitoneally with K2Cr2O7 (130 mumole/kg every 48 hr for six treatments) had decreased activity of cytochromes P4503A1 and/or 3A2, and 2C11. Hepatic microsomes from treated female Sprague-Dawley rats, in contrast, had increased activities of these isozymes. Lung microsomes from male Sprague-Dawley rats had increased activity of P4502C11. PMID- 7843093 TI - Active oxygen species in DNA damage induced by carcinogenic metal compounds. AB - Some carcinogenic metal compounds [chromate(VI), Fe(III) nitrilotriacetate, cobalt(II), and nickel(II)[ induced formation of various oxygen radical species in the presence of hydrogen peroxide. These oxygen radicals were suggested to give different kinds of site-specific DNA damage; 8-hydroxyl-2'-deoxyguanosine formation is included in the DNA damage. Using pulsed-field gel electrophoresis, nickel sulfide was shown to induce oxidative DNA cleavage in cultured cells. On the basis of these findings, we have emphasized the role of oxygen radicals in metal carcinogenesis. PMID- 7843094 TI - Effects of cadmium on nuclear protein kinase C. AB - Cadmium is a carcinogen whose genotoxicity is only weak. Besides its tumor initiating capacity, cadmium may be tumor-promoting, since it interferes with several steps of cellular signal transduction. We have investigated effects of cadmium(II) on protein kinase C (PKC), which is a key enzyme in the control of cellular growth and differentiation. Tumor-promoting phorbol esters cause an activation and translocation of PKC from the cytosol to the plasma membrane and to the nucleus of mammalian cells. In mouse 3T3/10 T 1/2 fibroblasts, cadmium(II) potentiated the effect of phorbol ester on nuclear binding and activation of PKC. Furthermore, in a reconstituted system consisting of rat liver nuclei and rat brain PKC, cadmium stimulated the binding of the enzyme to a 105-kDa protein. We propose a model in which cadmium(II) substitutes for zinc(II) in the regulatory domain of PKC, thus rendering the putative protein-protein binding site exposed. Further work is required to elucidate the potential role of the nuclear PKC binding protein(s) in the control of cell proliferation. PMID- 7843095 TI - Transmembrane signals and protooncogene induction evoked by carcinogenic metals and prevented by zinc. AB - Cd2+ provokes an immediate production of inositol trisphosphate and the release of Ca2+ from internal stores in human fibroblasts and some other mammalian cells. Ni2+, Co2+, Fe2+, and Mn2+ evoke the release of stored Ca2+, but are less potent than Cd2+ (apparent K0.5 = 40 nM). Zn2+ and Cu2+ competitively inhibit Ca2+ release evoked by Cd2+ without affecting Ca2+ release by hormones such as bradykinin. Zn2+ has the same apparent Ki value (80-90 nM) towards the five agonist metals, which suggests that the metals interact with the same site. Many other divalent cations neither released stored Ca2+ nor affected Cd(2+)-evoked Ca2+ release. The agonist metals appear to activate phospholipase C via a G protein rather than a tyrosine kinase. The production of reactive oxygen species is probably not involved in Ca2+ release by the metals. Cd2+ and other stimuli that raise cytosolic-free Ca2+ induce cyclic (AMP) production, apparently by activating a calmodulin-dependent adenylyl cyclase. We suggest that an orphan receptor mediates the hormonelike responses to Cd2+ and the other agonist metals. The receptor is referred to as an orphan because its physiological stimulus is unknown. Growth of the fibroblasts in high Zn2+ desensitizes them to the five agonist metals without affecting Ca2+ release by bradykinin or histamine. A several hour incubation in culture medium with normal Zn2+ fully restores responsiveness to the five active metals. Growth in high Zn2+ appears to repress the synthesis of the putative orphan receptor because inhibitors of RNA or protein synthesis, or asparagine-linked glycosylation, prevented the restoration of metal responsiveness.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843096 TI - Subcellular targets of cadmium nephrotoxicity: cadmium binding to renal membrane proteins in animals with or without protective metallothionein synthesis. AB - Nephrotoxic effects of cadmium exposure are well established in humans and experimental animals. An early manifestation of such toxicity is calciuria a few hours after injection of CdMT in rats. Protection against calciuria and other adverse effects such as proteinuria (occurring later) is offered by pretreatment with Cd, which effectively induces metallothionein synthesis. In the present experiment, one group of animals was given pretreatment with CdCl2 to induce metallothionein synthesis. The comparison group was left without pretreatment. The distribution of Cd from a normally nephrotoxic dose of 109CdMT was studied by gel chromatography in subcellular fractions of kidney cortex in both groups. In the pretreated animals, 109Cd in the plasma membrane and microsome fractions of renal cortical cells was mainly bound to metallothionein and other low molecular weight proteins at 4 hr. In nonpretreated animals the major part of 109Cd was bound to high molecular weight proteins. These findings indicate that membrane proteins may be important targets for Cd when inducing nephrotoxicity and that sequestering of Cd by metallothionein (and other low molecular weight proteins) may be a mechanism of protection. PMID- 7843097 TI - Metal replacement in "zinc finger" and its effect on DNA binding. AB - Metal replacement studies were used to investigate the metal requirement of a bacterially expressed polypeptide encoding the zinc finger DNA binding domain of the estrogen receptor. Apopolypeptide was generated by dialysis of native polypeptide against low-pH buffer under reducing conditions. Specific DNA binding can be restored by refolding the apopolypeptide in the presence of ionic zinc, cadmium, or cobalt. However, refolding in the presence of copper or nickel fails to regenerate DNA binding activity. While cobalt-reconstituted polypeptide has a reduced affinity for its AGGTCA-binding site compared to zinc- or cadmium polypeptide, it has the surprising property of increased cooperative DNA binding. Our work indicates that metal substitution results in a range of effects upon DNA binding in vitro. The potential biological significance of metal substitution in vivo is discussed. PMID- 7843098 TI - Experimental localization of intestinal uptake sites for metals (Cd, Hg, Zn, Se) in vivo in mice. AB - The intestinal uptake process consists of two separable steps: transport over the luminal membrane into epithelial cytoplasm and transport over the basolateral membrane into serosal fluid. A compound's residence time in mucosal epithelial cytoplasm depends on rates of the two transport processes and, if the rate of the second step is low, on the rate of mucosal sloughing. Using gamma-emitting metal isotopes, in vivo labeling profiles of the intestinal tract were obtained from mice eating their normal diet. The results pertain to processes in the functioning, undisturbed intestinal tract. Single-dose chase experiments indicated that intestinal uptake processes were in fact studied. The labeling profiles varied considerably for different metals. Thus, Cd++ was absorbed mainly in duodenum and early jejunum, while Zn++ was taken up in jejunum and ileum. The uptake profile of Hg++ indicated most rapid uptake in proximal jejunum. Selenomethionine labeled the entire intestinal tract, most rapidly the duodenum, the following intestinal segments were labeled with falling rate. This experimental method is rapid and simple. Further studies aim at developing a quantitative model suited for studying interactions between essential and toxic metals at the level of intestinal metabolism. PMID- 7843099 TI - Iron and aluminum homeostasis in neural disorders. AB - The brain is the most compartmentalized organ. It is also highly aerobic. Because nerve cells grow but do not regenerate, the brain is the organ best suited for the accumulation of metabolic errors colocalized in specific areas of the brain over an extended period. Alzheimer's disease (AD) is primarily a neurological disorder of the elderly. It is suggested that this disorder results from the accumulation of such errors, and that AD onset aluminum and iron contribute to but do not necessarily initiate the onset of the disease. In vitro and in vivo evidence summarized here suggests that this is effected by interfering in the utilization of glucose and glucose-6-phosphate, and sequestration of iron by ferritin. beta-amyloid precusor proteins (beta-APPs) are normal components of the human brain and some other tissues. Proteolysis of these, presumably by serine proteases, generates a 39 to 42 amino acid long peptide, the alpha-amyloid (beta AP). In AD brains, beta-AP aggregates into plaque, the hallmark of AD brains. Some of the alpha-APPs also contain a 56 amino acid long segment which inhibits serine proteases. We show that in vitro, at pH 6.5, aluminum activates beta chymotrypsin 2-fold and makes it dramatically resistant to protease inhibitors such as bovine pancreatic trypsin inhibitor (bPTI) or its mimic present in the beta-amyloid precursor proteins (beta-APPs). Iron and oxygen are reported to favor cross-linking of beta-AP in vitro.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843100 TI - Chromium(VI) reduction by ascorbate: role of reactive intermediates in DNA damage in vitro. AB - Reaction of chromium(VI) with one equivalent of ascorbate was studied by electron paramagnetic resonance spectroscopy in the presence of 0.10 M 5,5-dimethyl-1 pyrroline-1-oxide (DMPO) at room temperature in 0.10 M (N-[2 hydroxyethyl]piperazine-N'-[2-ethanesulfonic acid]) (HEPES) and 0.05 M tris(hydroxymethyl)aminomethane hydrochloride (Tris-HCl) buffers (pH 7.0 room temperature). Chromium(V), ascorbyl radical, and carbon-based DMPO-radical adducts were observed. A higher level of Cr(V) was observed in HEPES buffer and a higher level of the DMPO-radical adducts was observed in Tris-HCl buffer. Chromium-DNA binding studies were carried out in vitro for calf thymus DNA incubated with Cr(VI) and ascorbate in both buffers at 37 degrees C. Higher Cr DNA binding was observed in HEPES buffer. DNA strand-break studies were carried out in vitro on pBR322 DNA incubated with Cr(VI) and ascorbate in both buffers at 37 degrees C. Higher percent nicking was observed in Tris-HCl buffer. Addition of DMPO decreased nicking levels in Tris-HCl buffer. These results suggest that free radicals are more reactive than Cr(V) in producing DNA strand breaks and that Cr(V) will react with DNA to produce Cr-DNA adducts. The fact that buffer affects the nature of the reactive intermediates produced upon reduction of Cr(VI) may be related to differences in intracellular metabolism of Cr(VI) and resulting DNA damage observed in various cell culture systems and animal tissues in vivo. PMID- 7843101 TI - Influence of the common human delta-aminolevulinate dehydratase polymorphism on lead body burden. AB - delta-Aminolevulinate dehydratase (ALAD) is the second enzyme in the heme biosynthesis pathway. ALAD is a zinc metalloenzyme, and its inhibition by lead substitution for zinc is one of the most sensitive indicators of blood-lead accumulation, a measure of recent lead exposure. Stoichiometry calculations indicate that a significant portion of blood lead is stored in ALAD. Human ALAD exhibits a charge polymorphism, with about 20% of Caucasians expressing the rarer ALAD2 allele. Human ALAD1 and ALAD2 cDNAs and the 16-kb ALAD gene have been cloned and sequenced. A simple polymerase chain reaction test has been established and validated for determining ALAD genotypes. Two population studies have indicated that lead-exposed individuals with the ALAD2 allele have blood lead levels about 10 micrograms/dl greater than similarly exposed individuals carrying only the ALAD1 allele. Ongoing work is directed toward determining the biochemistry underlying the allele-specific accumulation of blood lead, and toward determining the contribution of human ALAD genotype to lead accumulation in other tissues in transgenic mouse models and to final lead deposition in bone in both mouse and man. PMID- 7843102 TI - Occupational exposures to Cd, Ni, and Cr modulate titers of antioxidized DNA base autoantibodies. AB - This study was undertaken to establish whether occupational exposures to derivatives of carcinogenic metals evoke inflammatory immune responses, as determined by the presence of elevated titers of antibodies (Ab) that recognize oxidized DNA bases. Sera obtained from the blood of steel welders (Delaware) and from workers of the Centra Ni-Cd Battery Factory (Poznan, Poland) were analyzed by the enzyme-linked immunosorbent assay. To determine specific and nonspecific binding, an oxidized thymidine [5-hydroxymethyl-2'-deoxyuridine (HMdU)] coupled to bovine serum albumin (HMdU-BSA) as well as mock-coupled BSA (M-BSA) were used as antigens for coating the wells of microtiter plates. Titers of anti-HMdU Ab were significantly elevated in the high Cd and Ni exposure groups (18.3 +/- 3.2 vs 10.8 +/- 2.1 A492/microliters; p < 0.05). The sera of the groups with low exposures to Cd and Ni also had enhanced titers of those Ab but those increases were not statistically significant. Interestingly, the Ab titers present in the sera of controls for Cd and Ni exposures appear to be constant regardless of the protein content. In contrast, both lightly and heavily exposed subjects exhibited Ab titers that increased with increasing protein content. When 12 randomly selected workers (4 from each of the control, lightly, and heavily exposed groups) were outfitted with personal monitors, anti-HMdU Ab titers of those workers showed a significant difference between the groups with light (< 100 micrograms/m3) and heavy (> 200 micrograms/m3) exposures to Cd (9.8 +/- 3.7 vs 22.1 +/- 3.7 A492/microliters; p < 0.01) and Ni (11.7 +/- 1.4 vs 31.0 +/- 1.8; p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843103 TI - Use of denaturing-gradient gel electrophoresis to study chromium-induced point mutations in human cells. AB - A large number of hprt-mutants were obtained by treating human lymphoblast cells (TK6) with 5 microM K2Cr2O7 for 5 hr and selecting by growth in 6-thioguanine. A combination of high fidelity polymerase chain reaction (PCR) and denaturing gradient gel electrophoresis (DGGE) allowed us to measure mutant frequencies as a function of DNA sequence. Chromium(VI) induced four hotspots in a 104 bp domain of hprt exon 3. Substitutions at G:C base pairs were the predominant mutations. One of the chromium-induced hotspots was located at the same position as previously determined hydrogen peroxide and benzo(a)pyrene diol epoxide hotspots. PMID- 7843104 TI - Generation of hydroxyl radical by chromate in biologically relevant systems: role of Cr(V) complexes versus tetraperoxochromate(V). AB - While Cr(V) species and .OH radicals have been suggested to play significant roles in the mechanism of chromate-related carcinogenesis, controversy still exists regarding the identity of the Cr(V) species and their role in the generation of .OH radicals. Some recent studies have suggested that the primary Cr(V) species involved is the tetraperoxochromate(V) (CrO8(3-)) ion, which produces .OH radical either on decomposition or by reaction with H2O2. The present study utilized ESR and spin trapping techniques to probe this mechanism. The results obtained show that (i) CrO8(3-) is not formed in any significant quantity in the reaction of chromate with biologically relevant reductants such as glutathione, glutathione reductase, NAD(P)H, ascorbate, vitamin B2, etc. (ii) Decomposition of CrO8(3-), or its reaction with H2O2 does not generate any significant amount of .OH radicals. (iii) The major Cr(V) species formed are complexes of Cr(V) with reductant moieties as ligands. (iv) These Cr(V) complexes generate .OH radicals from H2O2 via Fenton-like reaction. The present study thus disagrees with the recently proposed "tetraperoxochromate(V) theory of carcinogenesis from chromate." Instead, it suggests an alternative mechanism, which might be labeled as "the Cr(V)-complexation-Fenton reaction model of carcinogenesis from chromate. PMID- 7843105 TI - The generation of DNA single-strand breaks during the reduction of chromate by ascorbic acid and/or glutathione in vitro. AB - The potential role of iron and copper and the involvement of hydroxyl radicals in the DNA cleavage caused by chromate and glutathione (GSH) has been investigated. We have also studied the ability of chromate, on reaction with ascorbate as well as in mixed solutions of ascorbate and GSH, to cause DNA strand breaks. In both fully demetalated and conventional (i.e., metal contaminated) systems, chromate and GSH induced similar numbers of DNA strand breaks. This observation suggests that traces of iron or copper contaminating the reaction mixtures do not play a major role in the DNA cleavage caused by chromate and GSH. A series of hydroxyl radical scavengers exhibited a protective influence on the induction of DNA strand breaks. However, glucose and sucrose, both strong hydroxyl radical scavengers, showed no concentration-dependent inhibition of DNA cleavage. Competition kinetics studies yielded apparent rate constants that were not consistent with hydroxyl radicals being the species responsible for DNA strand breaks. Ascorbate in combination with chromate was also found to induce strand breaks in DNA; this damage could be attributed to reactive intermediates generated during the reduction. When mixed systems of ascorbate and GSH in the presence of chromate were investigated, there were clearly interactions between the two reductants. PMID- 7843106 TI - Reactive oxygen species produced from chromate pigments and ascorbate. AB - The reactions of various chromate pigments and ascorbate were investigated by an ESR spin trapping technique. Production of Cr(V) was detected directly and productions of very electrophilic reactive oxygen species (ROS) was detected via the oxidation of formate. We demonstrated previously that both dissolved oxygen and Cr (V) were essential in the production of ROS in this system, and that ROS production was inhibited by catalase. We studied here the effect of solubility of different chromate pigments: sodium, calcium, strontium, basic zinc, basic lead supported on silica, and lead and barium chromates on the production of ROS in buffered medium and cell culture medium (Dublecco's Modified Eagle medium + fetal calf serum). Sodium, calcium, basic zinc, and basic lead chromates were active in the production of ROS in presence of cell culture medium, whereas lead and barium chromates were inactive. PMID- 7843107 TI - Protective effects of thiol compounds on chromate-induced toxicity in vitro and in vivo. AB - The effects of thiol compounds (L-cysteine ethyl ester, 2,3-dimercaptosuccinic acid, or 2,3-dimercapto-1-propanesulfonic acid) on the toxicity induced by chromate (potassium dichromate) were investigated in HeLa cells and mice. Chromate-induced cytotoxicity evaluated by inhibition of cell growth and chromium content of the cells was diminished by all of the thiol compounds tested when the cells were incubated in the medium with both chromate and one of the thiol compounds. In mice injected ip with a thiol compound immediately after injection of chromate, mortality, ornithine carbamyl transferase activity in the serum, and chromium content in the liver were diminished remarkably compared with mice injected with chromate alone. These thiol compounds also caused an increase of urinary chromium excretion. These results suggest that the thiol compounds tested are useful for treating chromate-induced toxicity when they are given immediately after intake of the metal. PMID- 7843108 TI - Complexing of amino acids to DNA by chromate in intact cells. AB - Using o-pthaldialdehyde (OPT) fluorescence, the amino acids associated with DNA were studied following exposure of intact Chinese hamster ovary cells to chromate. Rigorous extraction with EDTA, acid, or base was required to release the amino acids cross-linked to the DNA isolated from control or chromate-treated cells by standard procedures (i.e., proteinase K, phenol, etc.). Amino acids resisting extraction from DNA were not studied since analysis was limited to those that could be released by these procedures. There was a chromate dose dependent increase in amino acids complexed with the DNA that could be released by EDTA, acid, and base, and these amino acids were separated by HPLC and identified. Substantial increases in cysteine, glutamine, glutamic acid, histidine, threonine, and tyrosine were found as a function of increasing concentrations of chromate. There was also a time-dependent increase in complexing of these amino acids to the DNA by chromate. The amino acids found complexed to DNA in intact cells by chromate were thought to originate from reactions of free amino acids or small peptides with the DNA rather than being proteolytic products derived from larger proteins that were cross-linked to the DNA. This was supported by a number of experiments: a) free amino acids or bovine serum albumin (BSA) were cross-linked by chromium to DNA in vitro and the DNA was isolated by standard procedures.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843109 TI - Correlation between cadmium-induced pulmonary carcinogenicity, metallothionein expression, and inflammatory processes: a species comparison. AB - There is sufficient evidence for pulmonary carcinogenicity of inhaled Cd compounds in rats whereas no such evidence was found in mice and hamsters; the evidence in humans has been termed limited, indicating significant species differences in pulmonary response to inhaled Cd. We hypothesized that expression of metallothionein (MT) protein in the lung after inhalation of Cd differs between species thereby providing different degrees of sequestration of Cd and protection from its effects. Rats and mice were exposed to 100 micrograms CdCl2 aerosols/m3 for 4 weeks, and the presence of MT was determined in lung and free lung cell homogenates as well as by immunocytochemistry in lung sections up to 28 days postexposure. In addition, pulmonary inflammatory, and cell proliferative responses were determined. Cd exposure significantly increased MT in homogenates of total lung in both species; however, no significant increase of MT in rat lung tissue after removal of free lung cells by lavage was found whereas MT was still significantly increased in lavaged mouse lung tissue throughout the postexposure time. In contrast, exposed rats showed significant increases in MT in the lavageable lung cells and mice did not. Histochemical analysis of lung sections revealed that mainly the epithelial cells of the bronchi, bronchioli, and alveoli of Cd-exposed mice expressed MT. Mice also exhibited a marked and sustained pulmonary inflammatory and cell proliferative response upon CdCl2 exposure which was not observed in rats. The retained Cd dose per gram lung was about 2-fold greater in mice, which is consistent with a greater deposition efficiency of inhaled Cd-aerosols in mice.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843110 TI - Interference of cadmium with ATP-stimulated nuclear calcium uptake. AB - The spatial and temporal regulation of intracellular free Ca2+ serves as a modulator of signal transduction pathways involved in cell growth and differentiation. Thus, interference of metals with intracellular Ca2+ homeostasis has been considered as a target of toxic action. We used the fluorescence indicator fura-2 to monitor the level of free Ca2+ in isolated bovine liver nuclei. Nuclei accumulated Ca2+ by an ATP-stimulated Ca2+ uptake system, which is sensitive to inhibition by thapsigargin, a specific inhibitor of intracellular Ca(2+)-ATPases. Preincubation of nuclei with nanomolar concentrations of free Cd2+ resulted in a dose-dependent inhibition of ATP-dependent nuclear Ca2+ uptake. We conclude that impairment of nuclear Ca2+ regulation caused by Cd2+ provokes alterations in nuclear events related to gene expression and cell proliferation. PMID- 7843111 TI - Effects of zinc and cadmium on apoptotic DNA fragmentation in isolated bovine liver nuclei. AB - Isolated nuclei from mammalian cells contain a calcium-dependent endonuclease. The produced DNA fragmentation is a necessary step in the sequence of events resulting in apoptosis (programmed cell death). We report here that zinc and cadmium inhibit the calcium-dependent endonuclease. The essential metal ion zinc may counterbalance the calcium-mediated apoptosis. In contrast to zinc, cadmium alone stimulates the endonuclease by replacing calcium. Thus cadmium exerts a dual effect: micromolar concentrations inhibit the apoptotic endonuclease in the presence but activate the enzyme in the absence of calcium. PMID- 7843112 TI - Evidence for radical species as intermediates in cadmium/zinc-metallothionein dependent DNA damage in vitro. AB - Toxicologic data on cadmium (Cd) indicate that intracellular metallothionein (MT) is protective for Cd exposure, whereas extracellular Cd-containing MT might be toxic. Moreover, Cd is suspected to be a carcinogen though the underlying mechanism is not known. Here we report on the genotoxic activity of cadmium/zinc metallothionein (Cd/Zn-MT) in a cell-free test system: a concentration-dependent increase in DNA strand breaks was detected with increasing doses of Cd/Zn-MT, whereas no DNA strand breaks were observed in the presence of heat-denatured MT or Cd or Zn ions alone. Modifications of native Cd/Zn-MT by the metal ion chelating agent EDTA or the sulfhydryl group alkylating agents N-ethylmaleimide and iodoacetamide suggest that the various cysteine residues of MT, together with the attached heavy metal ions, may be involved in the DNA cleavage reaction. Furthermore, DNA strand breaks caused by Cd/Zn-MT seem more likely to be random than sequence- or base-specific. Results from experiments with radical scavengers and electron spin resonance spectroscopy point to radical species formed by Cd/Zn MT as mediators of the DNA damage. Thus, the actual activity of Cd/Zn-MT--whether protective or damaging--appears to depend on various parameters governed by the extra- and intracellular environment. PMID- 7843113 TI - Effect of cadmium on liver regeneration after partial hepatectomy in rats. AB - Cadmium is a nonabundant element that is widely distributed throughout the biosphere and its toxic effects are becoming potentially more serious due to industrialization. It has been reported that cadmium might interact with nucleic acid biosynthesis. In this study we examined the effect of cadmium administration, either 24 hr before or simultaneously to partial hepatectomy, on the liver regenerative process in rats, at different time intervals. The rate of DNA synthesis was suppressed markedly in the cadmium pretreated group and the first peak of liver regeneration was delayed, compared to the simply partially hepatectomized one. The administration of cadmium simultaneously to partial hepatectomy, caused a marked decrease of the rate of DNA biosynthesis, compared to the pretreatment. The rate-determining enzyme thymidine kinase was suppressed in the liver of both cadmium-treated groups. Biochemical parameters and histological findings were also coestimated. The above data suggest that either pre- or simultaneous administration of cadmium, suppressed the liver regenerative process, probably due to the inhibition of thymidine kinase. PMID- 7843114 TI - Effect of progesterone pretreatment on cadmium toxicity in male Fischer (F344/NCr) and Wistar (WF/NCr) rats. AB - A previous report indicated that progesterone pretreatment can markedly reduce cadmium (Cd) toxicity in male NAW mice. Therefore we examined the effects of progesterone pretreatment on Cd toxicity in male Fischer (F344) and Wistar (WF) rats. A single subcutaneous injection of 10 or 30 mumole (CdCl2)/kg proved nonlethal over 24 hr but caused the typical spectrum of testicular lesions in these rats. Moreover, when F344 rats were pretreated with progesterone (100 mg/kg, sc, at -48, -24, and 0 hr) and then given cadmium (20 mumole CdCl2/kg, 0 hr), this dose of cadmium proved very toxic, unexpectedly causing 53% mortality. Progesterone pretreatment had no effect on cadmium-induced lethality in WF rats or on testicular lesions in either strain. Significant elevations in serum lactate dehydrogenase (LDH) activity, indicative of hepatotoxicity, were also observed in progesterone-pretreated F344 rats given cadmium as compared to rats given Cd alone. Progesterone did not induce increases in hepatic or renal metallothionein (MT) and hepatic or testicular MT-I mRNA levels in F344 rats. In contrast, levels of the testicular cadmium-binding protein (TCBP) in progesterone pretreated F344 rats were doubled. This increase in TCBP provided no protection against cadmium toxicity in the testes. These results indicate that, in contrast to previously reported data for mice, progesterone pretreatment increased the lethality of cadmium in male F344 rats and had no effect on cadmium-induced testicular toxicity in F344 and WF rats. PMID- 7843115 TI - The role of nickel and nickel-mediated reactive oxygen species in the mechanism of nickel carcinogenesis. AB - Increasing evidence demonstrates the reactive oxygen species (ROS) are implicated in metal carcinogenesis. Exposure of cultured Chinese hamster ovary (CHO) cells to several nickel compounds, i.e. NiS, Ni3S2, NiO (black and green), and NiCl2 has been shown to increase oxidation of 2',7-dichlorofluorescein to the fluorescent 2',7-dichlorofluorescein (DCF), suggesting that nickel compounds increased the concentration of oxidants in CHO cells. This fluorescence can be attenuated by addition of exogenous catalase to the extracellular media, indicating that H2O2 is one of the formed oxidants in this system. Fluorimetric measurements of chromogens following thiobarbituric acid reaction showed that nickel compounds also induce lipid peroxidation with a decreasing potency NiS, Ni3S2 > black NiO > green NiO > NiCl2. These results suggest that lipid hydroperoxides may also be produced through the action of nickel in intact cells. MgCl2, an antagonist of Ni-induced DNA strand breaks and cell transformation, has no effect on the formation of DCF fluorescence induced in CHO cells by nickel. The results suggest that nickel is an active inducer of ROS in intact mammalian cells and that the molecular mechanism of nickel carcinogenesis may involve multiple steps of nickel-mediated ROS. PMID- 7843116 TI - DNA damage induced in cultured human alveolar (L-132) cells by exposure to dimethylarsinic acid. AB - Gene damage in cultured human alveolar (L-132) cells induced by exposure to dimethylarsinic acid (DMAA), a major metabolite of inorganic arsenics in mammals, was studied. DNA single-strand breaks and DNA-protein cross-links were induced by the treatment of L-132 cells with 10 mM DMAA. These kinds of damage appeared at 8 hr after start of exposure to DMAA. As regards DNA-protein cross-links, the DNA was found to bind not only to core histone proteins but also linker histone (H1) and nonhistone proteins. Furthermore, the cross-links were formed by the binding to serine or threonine residues of H1 or nonhistone proteins through phosphate moieties of the DNA. The induction of the alkali-labile sites in DNA in DMAA treated L-132 cells was observed prior to that of DNA single-strand breaks and DNA-protein cross-links. As one of the alkali-labile sites in DNA, we estimated apurinic/apyrimidinic (AP) sites in DNA. The present study suggests that the DNA single-strand breaks and DNA-protein cross-links induced by the treatment of L 132 cells with DMAA occurred via the formation of AP sites in the DNA and that the DNA-protein cross-links were produced by a Schiff-base reaction between amino groups of nuclear proteins and aldehyde groups of AP sites in the DNA and the DNA single-strand breaks, by a beta-elimination reaction on AP sites in the DNA. PMID- 7843117 TI - Transformation of human osteoblasts to anchorage-independent growth by insoluble nickel particles. AB - Nickel compounds are well established by epidemiologic studies as human carcinogens. Although the carcinogenicity of nickel compounds has been studied in experimental animals and in a variety of cultured mammalian cells, there are only sporadic reports of nickel-induced transformation of human cells. In attempts to study the mechanisms of nickel-induced carcinogenesis in human cells, an immortalized human osteoblastic cell line (HOS) that could not grow in soft agar or form tumors in athymic nude mouse was repeatedly treated with a water-soluble nickel compound (NiCl2) or a less water-soluble nickel compound crystalline (NiS). After three rounds of NiS treatment, there was an increase in anchorage independent (AI) colony formation. This was not found in untreated or NiCl2 treated cells. Ten AI colonies obtained from NiS-treated cells were isolated. All of these clones showed changes in cell morphology, including the appearance of uniform polygon shape, growth in multilayers, and heavy staining with Giemsa. Most of these clones were retested for their ability to grow in soft agar and showed growth efficiencies of 5 to 50%. It has been shown by other investigators that aggregate growth is well correlated with tumorigenic potential in viral or chemical transformants of HOS cells. Four of seven tested NiS-transformed clones were able to form large aggregates compared to their untransformed counterparts, and continued to proliferate in aggregate form when they were plated on 0.9% agar. Current investigations focus on the molecular and genetic changes induced by nickel compounds in these human cells. PMID- 7843118 TI - Glutathione transferases in the urine: sensitive methods for detection of kidney damage induced by nephrotoxic agents in humans. AB - With the aid of immunohistochemical methods the localization of the various isoenzymes of glutathione S-transferase was investigated. The alpha isoenzyme was present solely in the proximal tubular cells of the human kidney, while the pi form was restricted to the distal convoluted tubules, the thin loop of Henle, and the collecting ducts. Damage to the epithelial cell membranes results in the increased excretion of these enzymes with the urine. The alpha and pi isoenzymes have been isolated in a highly purified form and used for the production of polyclonal antisera. Subsequently, radioimmunological and ELISA techniques were developed for quantitation of these proteins in the urine; the methods exhibited a high specificity and were sufficiently sensitive to determine nanogram quantities or less. Disease affecting tubular function, cyclosporine A treatment, administration of nephrotoxic antibiotics, and exposure to cadmium all resulted in characteristic changes in the pattern of the glutathione transferase isoenzymes present in urine. Such effects were seen also in patients who had previously been exposed to nephrotoxic agents, but in whom conventional tests for kidney function were apparently normal. Thus, it appears that radioimmunologic or immunochemical quantitation of alpha and pi forms of the enzyme can be used as sensitive and relatively simple markers for the early detection of toxic effects with respect to the renal tubuli. PMID- 7843119 TI - Antagonistic effect of nickel on the fermentative growth of Escherichia coli K-12 and comparison of nickel and cobalt toxicity on the aerobic and anaerobic growth. AB - The facultative anaerobic enterobacterium Escherichia coli requires the activity of nickel-containing hydrogenase for its anaerobic growth. Deficiency of the specific nickel transport system led to a hydrogenase-minus phenotype and slowed down the fermentative growth in the nik mutant. Addition of 300 microM nickel to the growth medium could restore the hydrogenase activity. This restoration resulted in the recovery of anaerobic growth. A further increase of nickel concentration inhibited growth. Thus nickel shows an antagonistic effect on the anaerobic growth of E. coli. To study the mechanism of nickel toxicity, two classes of nickel-resistant mutants were isolated. The nkr mutant was obtained by selecting colonies grown on nickel-containing minimal plate. It acquired simultaneously the resistance to cobalt. A nonspecific magnesium transport mutant corA was isolated on cobalt-containing plate. The corA mutant was also resistant to nickel. When analyzing the influence of nickel and cobalt on the bacterial growth, we obtained two interesting observations. First, anaerobic growth was less sensitive than aerobic growth to cobalt toxicity. In contrast, nickel toxicity did not vary from the growth conditions. Second, cobalt seems to abolish the growth, while nickel appears to slow down the growth rate under the condition used. PMID- 7843120 TI - Chemical models important in understanding the ways in which chromate can damage DNA. AB - Chromate is an established human carcinogen. There have been many studies of the reactivity of chromate aimed at improving understanding of chromate toxicity. In the present paper a number of conclusions of these studies are reviewed and considered in the light of new results obtained in our laboratories. A number of hypotheses are considered; it is concluded, however, that it is impossible to reconcile the generation of strand breaks by chromate during its reduction by glutathione with any simple mechanism involving the generation of DNA lesions by free hydroxyl radicals. Kinetic, spin-trapping, and competition kinetic studies, based on a strand-breaking assay, are reported in support of this conclusion. PMID- 7843121 TI - Development of an 125I-postlabeling assay as a simple, rapid, and sensitive index of DNA-protein cross-links. AB - A rapid, simple, and sensitive 125I-postlabeling technique has been developed to allow detection of DNA-protein cross-links induced by environmental contaminants and carcinogens. This method is based on specific incorporation of 125I into tyrosine residues associated with DNA. Cultured Chinese hamster ovary cells were exposed to various crosslinking agents, e.g., UV light, K2CrO4, or NiCl2. DNA was isolated by proteinase K/phenol/chloroform. The residual peptides cross-linked to DNA were radioiodinated with Na125I and chloramine T. After repeated precipitation with ethanol, the radioactivity was determined. The 125I method was compared with a 3[H]-tyrosine prelabeling method and found to be of similar sensitivity. PMID- 7843122 TI - Inorganic mercury exposure, mercury-copper interaction, and DMPS treatment in rats. AB - The aim of this study was to evaluate the efficiency of oral treatment with sodium 2,3-dimercaptopropane-1-sulfonate (DMPS) on reducing mercury deposits in rat kidney after chronic exposure to inorganic mercury. The effect on kidney copper levels was also evaluated. The results showed that after two months of exposure to 50 ppm of mercury (as mercuric chloride) the concentration of mercury in the kidney was 124 micrograms/g wet tissue. At the same time copper concentration rose from 11 to 77 micrograms/g. DMPS treatment caused 2- and almost 4-fold reduction of mercury and copper, respectively. This study demonstrates that chronic exposure to inorganic mercury may alter metabolism of copper and that DMPS is an effective means for reduction of both mercury and copper. PMID- 7843123 TI - Monoisoamyl meso-2,3-dimercaptosuccinate as a delayed treatment for mercury removal in rats. AB - Monoisoamyl meso-2,3-dimercaptosuccinate (Mi-ADMS) was found to be superior to meso-2,3-dimercaptosuccinic acid (DMSA) in decreasing the body burden of 203Hg in rats under conditions of early treatment. In this experiment Mi-ADMS was used as late treatment for mercury removal. Albino rats aged 6 weeks and 7-day-old sucklings received a single intraperitoneal injection of 203Hg (as nitrate). Two weeks later they were treated with DMSA or Mi-ADMS (0.25 mmole/kg bw) on two consecutive days. The radioactivity in the carcass (whole body after removal of the gastrointestinal tract), liver, kidneys and brain was determined by solid crystal gamma scintillation counting six days after chelation therapy administration (3 weeks after 203Hg application). Both chelators reduced the body burden of mercury compared to controls. The effect of Mi-ADMS was superior to DMSA treatment in older rats for decreasing carcass and kidney retention, and in suckling rats for decreasing carcass, liver, and kidney retention. They were equally effective in decreasing brain retention in older rats and had no effect on brain retention in sucklings. The efficiency of Mi-ADMS in reducing the body burden of mercury was generally higher than the efficiency of the DMSA treatment. Therefore, Mi-ADMS deserves further attention as a late treatment for mercury removal. PMID- 7843124 TI - Role of paramagnetic chromium in chromium(VI)-induced damage in cultured mammalian cells. AB - Chromium(VI) compounds are known to be potent toxic and carcinogenic agents. Because chromium(VI) is easily taken up by cells and is subsequently reduced to chromium(III), the formation of paramagnetic chromium such as chromium(V) and chromium(III) is believed to play a role in the adverse biological effects of chromium(VI) compounds. The present report, uses electron spin resonance (ESR) spectroscopy; the importance of the role of paramagnetic chromium in chromium(VI) induced damage in intact cultured cells is discussed, based upon our studies with antioxidants including vitamin E (alpha-tocopherol), B2 (riboflavin), C (ascorbic acid), and so on. These studies appear to confirm the participation of paramagnetic Cr such as chromium(V) and Chromium(III) in chromium(VI)-induced cellular damage. PMID- 7843125 TI - Establishment and characterization of methylmercury-resistant PC12 cell line. AB - Methylmercury (MeHg)-resistant sublines of rat pheochromocytoma (PC12) cells were isolated by repeated exposure to stepwise increased concentrations of MeHg. One of the sublines (PC12/TM) showed an 8- to 10-fold increase in resistance to MeHg compared with parent PC12 cells on the basis of the concentration required for 50% inhibition (IC50) of growth. PC12/TM cells accumulated smaller amounts of MeHg than parent PC12 cells. This reduction in MeHg accumulation in PC12/TM cells resulted from slow uptake and rapid efflux. The intracellular glutathione (GSH) level in PC12/TM cells was four times higher than that of PC12 cells. Pretreatment of PC12/TM cells with buthionine sulfoximine, which decreased the GSH level to that of the parent PC12 cells, increased the sensitivity of PC12/TM cells to MeHg. A close correlation between the MeHg accumulation and MeHg sensitivity was found among seven sublines of PC12 cells and parent PC12 cell line. The GSH level in PC12 sublines was also correlated with their sensitivity to MeHg. PMID- 7843126 TI - Dose and time relations in Hg(++)-induced tubular necrosis and regeneration. AB - Mercuric chloride is a well-known human and animal nephrotoxicant. Previous studies have demonstrated an inverse relationship between dose size and relative whole-body retention of mercury after oral administration of mercuric chloride to mice. The present study indicates that this inverse relationship is caused by a dose-related induction of kidney damage leading to increasing leakage of mercury through the kidneys. Histopathologic investigation revealed extensive necrosis of the proximal tubules in kidneys from mice exposed to 100 mumole HgCl2/kg or higher doses. Moreover, maximum renal damage occurred between days 2 and 3 after administration. The renal damage was followed by regeneration, which was observed between days 3 and 7 at increasing dose levels up to 100 mumole HgCl2/kg. The amount of glutathione and the glutathione peroxidase activity in kidney decreased with increasing doses of mercuric chloride. The reduced glutathione peroxidase activity was due to a reduction in selenium-dependent glutathione peroxidase activity. The level of lipid peroxidation was not changed by increasing doses of mercuric chloride, and hence was not a primary toxic mechanism in acute nephrotoxicity induced by mercuric chloride. PMID- 7843127 TI - Effects of simultaneous low-level dietary supplementation with inorganic and organic selenium on whole-body, blood, and organ levels of toxic metals in mice. AB - Classical experiments have demonstrated that Se compounds protect against the toxicity of several toxic metals in acute experiments with simultaneous parenteral administration of high doses of Se and the toxic metal. Blood and organ levels of the toxic metals were increased, conceivably due to formation of inert Se complexes. Less is known about effects of long-term Se status on the toxicokinetics of toxic metals. Possible Se interactions in toxic metal biokinetics should therefore be studied at Se levels ranging from those just sufficient to avoid Se deficiency and up to those believed to be optimum in relation to antioxidative and other beneficial effects of Se. The toxic-metal exposure levels investigated should be similar to those occurring in human populations that are not occupationally exposed. To study interactions between Se and toxic metals at ultralow exposure levels, mice were fed semisynthetic diets containing different levels of Se. The mice were given ultralow doses of metal salts either as a single oral dose by stomach tube or as prolonged exposure in the drinking water. Diets with high or normal Se levels slightly, but nonsignificantly increased the whole-body retention (WBR) of Hg++ and CH3Hg+ compared to a diet low in Se. The dietary Se level was, however, without effect on the WBR of Cd2+ and Ag2+ in single-dose experiments. During prolonged exposure, the diets fortified with Se increased the WBR of Ag2+, had no effect on WBR of Hg2+, and reduced the WBR of CH3Hg+ and Cd2+. During prolonged exposure, the diets fortified with Se reduced blood Hg++ while organ levels were unaltered.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843128 TI - Effects of organometals on cellular signaling. I. Influence of metabolic inhibitors on metal-induced arachidonic acid liberation. AB - Organic lead and tin compounds stimulate an increase of free arachidonic acid (AA) in HL-60 cells. This fatty acid is involved in numerous health problems and physiological mechanisms. Three major pathways result in a liberation of AA from membrane phospholipids and there is evidence that G-proteins serve as couplers within all three pathways. Therefore we investigated the influence of pertussis toxin (PT) on the organometallic-induced AA liberation. The effect of all studied compounds (organotin and organo-lead) was diminished by PT. We conclude that the organometals activate PLA2 to some extent via a PT-sensitive pathway. The ionophor A 23187 (1-10 microM) led to an increase of free AA by raising the intracellular Ca2+ level. One of the postulated ways of AA release is via Ca2+ channel activation; phospholipases are Ca2+ dependent. Thus, we examined the necessity of free intracellular Ca2+ for the organometallic effect. The Ca2+ chelator EGTA inhibited the increase of free AA induced by organometals. This is true also for verapamil, a Ca2+ channel blocker. Quinacrine, which is thought to be an inhibitor of phospholipase A2 (PLA2), prevented the AA liberation from membrane phospholipids induced by organometals. This could be due to the inhibition of PLA2, but it could also be the result of an inhibited Ca2+ influx. PMID- 7843129 TI - Effects of organometals on cellular signaling. II. Inhibition of reincorporation of free arachidonic acid and influence on paf-acether synthesis by triethyllead. AB - Organometal compounds affect many enzymes, especially those containing SH-groups as acyl- and acetyltransferases involved in lysophospholipid reacylation. In HL 60 cells, organotin and -lead compounds stimulate phospholipase A2 activity, contributing thus to increase the level of lysophospholipids. In the present study, we have tested whether paf-acether (paf) biosynthesis was affected by treatment with triethyllead (Et3PbCl) in HL-60 cells. Et3PbCl inhibits the incorporation of exogenous arachidonic acid in the presence of high (> or = 50 microM) but not low concentrations (< or = 1 microM). High concentrations of the lead compound are unable to induce paf formation by itself, however, lower concentrations (< or = 10 microM) acted synergistically with TPA or fMLP to stimulate paf formation. Whereas unstimulated cells produced 0.4 pmole paf/2 x 10(6) cells, the stimulation with low fMLP (0.1 microM) resulted in the synthesis of 1.7 pmole and with low TPA (2 ng/ml) in 0.5 pmole paf. Preincubation of the cells with 10 microM Et3PbCl for 20 to 30 min increased the amount of paf formed by these cells to 3.3 pmole after treatment with 0.1 microM fMLP and 1.5 pmole after TPA. Furthermore, the results showed an inhibition of acetyltransferase (the key enzyme of paf synthesis) by the high and not by low concentrations of the lead compound. We conclude that low concentrations of Et3PbCl (< or = 10 microM) may act as a synergistic inducer of paf synthesis initiated via a receptor-coupled stimulation. PMID- 7843130 TI - Bioavailability of biologically detoxified lead: risks arising from consumption of polluted mussels. AB - The possible risk for human health arising from consumption of lead-polluted shellfish was suggested by experiments on the bioavailability for mice of a "biologically detoxified" form of the metal. In this work, young mice were fed with a mixed diet including mussels collected in a Pb-polluted area. Metal concentrations in blood, kidney, liver, urine, and feces and the activity of erythrocytic delta-aminolevulinic acid dehydratase were determined after 1, 2, and 4 weeks. Comparisons were made with mice treated with balanced diet, mixed diet including control mussels, and drinking water with lead dissolved as acetate. In mice fed polluted mussels, lead concentrations increased in blood, kidney, and liver, whereas no significant accumulation was observed in urine. Different responses in mice treated with Pb(CH3COO)2 in drinking water are probably due to the diversity of lead chemical form in the two treatments. Our results demonstrate the bioavailability of biologically detoxified lead that can be transferred to a consumer with possible consequences also for human health. PMID- 7843132 TI - DNA single-strand breaks and cytotoxicity induced by chromate(VI), cadmium(II), and mercury(II) in hydrogen peroxide-resistant cell lines. AB - The induction of cytotoxicity and DNA single-strand breaks by chromium(VI), cadmium(II), and mercury(II) were compared in H2O2-resistant Chinese hamster ovary (CHO(R)) cells and parental (CHO(P)) cells. Using a colony-forming assay, CHO(R) cells were found to be significantly more resistant than CHO(P) cells to the cytotoxicity caused by CdCl2 and HgCl2, but not to that caused by Na2CrO4. However, the DNA single-strand breaks produced by each of these metals were significantly lower in the CHO(R) cells. With respect to chromium reduction, the level of chromium(V) in CHO(R) cells was decreased. The role of intracellular active oxygen in the heavy metal-induced DNA damage and cytotoxicity is discussed. PMID- 7843133 TI - Vanadium distribution in rats and DNA cleavage by vanadyl complex: implication for vanadium toxicity and biological effects. AB - Vanadium ion is toxic to animals. However, vanadium is also an agent used for chemoprotection against cancers in animals. To understand both the toxic and beneficial effects we studied vanadium distribution in rats. Accumulation of vanadium in the liver nuclei of rats given low doses of compounds in the +4 or +5 oxidation state was greater than in the liver nuclei of rats given high doses of vanadium compounds or the vanadate (+5 oxidation state) compound. Vanadium was incorporated exclusively in the vanadyl (+4 oxidation state) form. We also investigated the reactions of vanadyl ion and found that incubation of DNA with vanadyl ion and hydrogen peroxide (H2O2) led to intense DNA cleavage. ESR spin trapping demonstrated that hydroxyl radicals are generated during the reactions of vanadyl ion and H2O2. Thus, we propose that the mechanism for vanadium dependent toxicity and antineoplastic action is due to DNA cleavage by hydroxyl radicals generated in living systems. PMID- 7843134 TI - Induction of lung-specific DNA damage by metabolically methylated arsenics via the production of free radicals. AB - To clarify the genotoxicity of inorganic arsenics, we focused on the genotoxic effect of metabolically methylated arsenics in mammals. Oral administration to mice of dimethylarsinic acid (DMAA), a major metabolite of inorganic arsenics, induced lung-specific DNA damage, i.e., DNA single-strand breaks and the clumping of heterochromatin. The lung-specific strand breaks were not caused by DMAA itself, but by dimethylarsine, a further metabolite of DMAA. An in vitro experiment indicated that DNA single-strand breaks by dimethylarsine were suppressed by the presence of superoxide dismutase and catalase, suggesting that the strand breaks were induced via the production of free-radical species including active oxygens. Dimethylarsenic peroxyl radical [(CH3)2AsOO.] and superoxide anion radical produced from the reaction between molecular oxygen and dimethylarsine were detected by electron-spin resonance analysis using a spin trapping agent and the cytochrome-c method, respectively. Of these two radicals, the dimethylarsenic peroxyl radical rather than the superoxide anion radical is assumed to play the dominant role in causing the DNA damage, at least for DNA single-strand breaks. PMID- 7843131 TI - Respiratory toxicity of copper. AB - Respiratory toxicity of copper was tested in Wistar rats by spraying copper sulfate (330 g/l spray) for daily periods of 1 hr in a self-contained chamber for up to 10 days. The respiratory toxicity was compared with that from intraperitoneal administration of 1 mg Cu/mg body weight and with adequate control rats. Analysis of tissue Cu and Zn was done in lung, liver, kidney, and plasma by using atomic absorption spectrophotometry. Similar organ and subcellular distribution of both elements were found between the two treated groups, and only statistically significant higher levels of Cu were found in plasma and liver. After exposure, Cu and Zn were basically associated with a low molecular-weight component, which eluted as metallothionein in the postmicrosomal fractions. PMID- 7843135 TI - Effects of chromium on DNA replication in vitro. AB - Chromium is an environmentally significant human carcinogen with complicated metabolism and an unknown mechanism of mutagenesis. Chromium(VI) is taken up by cells as the chromate anion and is reduced intracellularly via reactive intermediates to stable Cr(III) species. Chromium(III) forms tight complexes with biological ligands, such as DNA and proteins, which are slow to exchange. In vitro, CrCl3.6H2O primarily interacts with DNA to form outer shell charge complexes with the DNA phosphates. However, at micromolar concentrations, the Cr(III) binds to a low number of saturable tight binding sites on single-stranded M13 DNA. Additional chromium interacts in a nonspecific manner with the DNA and can form intermolecular DNA cross-links. Although high concentrations of Cr(III) inhibit DNA replication, micromolar concentrations of Cr(III) can substitute for Mg2+, weakly activate the Klenow fragment of E. coli DNA polymerase I (Pol I-KF), and act as an enhancer of nucleotide incorporation. Alterations in enzyme kinetics induced by Cr(III) increase DNA polymerase processivity and the rate of polymerase bypass of DNA lesions. This results in an increased rate of spontaneous mutagenesis during DNA replication both in vitro and in vivo. Our results indicate that chromium(III) may contribute to chromate-induced mutagenesis and may be a factor in the initiation of chromium carcinogenesis. PMID- 7843137 TI - Effects of metal treatment on DNA repair in polyamine-depleted HeLa cells with special reference to nickel. AB - Human cells depleted of the naturally occurring polyamines putrescine, spermidine, and spermine exhibit altered chromatin structure and marked deficiencies in DNA replicative and repair processes. Similar effects have been observed following treatment of normal mammalian cells with various heavy metal salts. In an attempt to better understand how metals interfere with normal DNA metabolic processes, a series of studies was carried out in which the toxicity and repair-inhibitory properties of various metals were evaluated in polyamine depleted HeLa cells. Cytotoxicity of copper, zinc, magnesium, and cadmium was not altered in cells carrying lower polyamine pools. However, the sensitivity to nickel was markedly increased upon polyamine depletion, a condition that was readily reversed by polyamine supplementation. Nucleoid sedimentation analysis indicated that a greater amount of nickel-induced DNA damage occurred in polyamine-depleted cells than in normal cells, possibly serving as the basis for the increased sensitivity. Both polyamine depletion and nickel treatment result in decreased repair of DNA strand breaks and decreased cloning efficiency following X-ray and ultraviolet irradiation. Nickel treatment of polyamine depleted cells resulted in synergistic sensitivity to both radiation treatments. None of the other metals tested enhanced X-ray or ultraviolet sensitivity of polyamine-depleted cells. Analysis of retarded repair sites following ultraviolet irradiation indicated those sites to be nonligatable in polyamine-depleted and nickel-treated cells, suggesting a block in the normal gap-sealing process. PMID- 7843136 TI - Role of DNA repair inhibition in lead- and cadmium-induced genotoxicity: a review. AB - Compounds of lead and cadmium have been shown to be carcinogenic to humans and experimental animals. However, the underlying mechanisms are still not understood. In mammalian cells in culture, lead(II) is weakly mutagenic after long incubation times and generates DNA strand breaks only after treatment with high, toxic doses. Cadmium(II) induces DNA strand breaks and chromosomal aberrations, but its mutagenic potential is rather weak. However, both metals exert pronounced indirect genotoxic effects. Lead(II) is comutagenic towards UV and N-methyl-N-nitro-N-nitrosoguanidine (MNNG) and enhances the number of UV induced sister chromatid exchanges in V79 Chinese hamster cells. With regard to DNA repair, lead(II) causes an accumulation of DNA strand breaks after UV irradiation in HeLa cells, indicating an interference with the polymerization or ligation step in excision repair. Cadmium(II) enhances the mutagenicity of UV light in V79 Chinese hamster cells and an increased sensitivity toward UV light is observed in various rodent and human cell lines. Furthermore, an inhibition of unscheduled DNA synthesis after UV-irradiation and a partial inhibition of the removal of UV-induced DNA lesions has been shown. For both metals, the indirect genotoxic effects are observed at low, nontoxic concentrations, suggesting that an interference with DNA repair processes may be predominant at biologically relevant concentrations. This might also explain the conflicting results of epidemiological studies obtained for both metals. Possible mechanisms of repair inhibition are discussed. PMID- 7843139 TI - Metal mutagenesis in transgenic Chinese hamster cell lines. AB - Metals are toxic agents for which genotoxic effects are often difficult to demonstrate. To study metal mutagenesis, we have used two stable hprt/gpt+ transgenic cell lines that were derived from Chinese hamster V79 cells. Both the G12 and G10 cell lines are known to be very sensitive to clastogens such as X rays and bleomycin, with the mutagenic response of the integrated xanthine guanine phosphoribosyl transferase (gpt) gene in G10 usually exceeding that of the same gene in the transgenic G12 cells. In studies with carcinogenic insoluble nickel compounds, a high level of mutagenesis was found at the gpt locus of G12 cells but not at the endogenous hypoxanthine phosphoribosyl transferase (hprt) locus of V79 cells. We have since demonstrated the similar recovery of a high frequency of viable G12 mutants with other insoluble nickel salts including nickel oxides (black and green). The relative mutant yield for the insoluble nickel compounds (G12 > G10) is the opposite of that obtained with nonmetal clastogens (G10 > G12). In the G12 cells, nickel mutagenesis may be related to the integration of the gpt sequence into a heterochromatic region of the genome. For some of the insoluble nickel compounds, significant inhibition of both cytotoxicity and mutant yield resulted when the G12 cells were pretreated with vitamin E. In comparison with the nickel studies, the mutagenic responses to chromium compounds in these cell lines were not as dramatic. Mutagenesis of the gpt target could not be demonstrated with other metals such as mercury or vanadium. PMID- 7843138 TI - Mutagenesis by metal-induced oxygen radicals. AB - To assess the contribution of reactive oxygen species (ROS) to metal-induced mutagenesis, we have determined the spectrum of mutations in the lacZ alpha gene after exposure of M13mp2 DNA to Fe2+, Cu2+, and Ni2+. With iron and copper ions, mutations are clustered and are predominantly single-base substitutions. Fe, Cu, and phorbol ester-stimulated neutrophils also produced tandem double CC-->TT mutations. This mutation may provide a marker for the role of oxidative damage in carcinogenesis. Mutagenesis by Ni2+ required the complexing of the metal to a tripeptide and the addition of H2O2. To assess the contribution of ROS in mammalian cells, we determined the spectrum of mutations produced when purified DNA polymerases-alpha and -beta synthesized DNA using a template that had been damaged by ROS. The mutation spectra produced by the two polymerases indicates that these enzymes substitute different nucleotides opposite the same lesions. PMID- 7843140 TI - Toxicity, uptake, and mutagenicity of particulate and soluble nickel compounds. AB - Toxicity testing in AS52 cells (24-hr exposures) gave LC50 values of 2 to 130 micrograms Ni/ml for particulate nickel compounds and 45 to 60 micrograms Ni/ml for water-soluble salts (NiCl2, NiSO4, Ni(CH3COO)2). The Ni(OH)2, NiCO3, and sulfides (Ni3S2, Ni7S6, "amorphous NiS") exhibited similar toxicities (LC50's of 2 to 8 micrograms Ni/ml), while three nickel oxides were more variable and less toxic (LC50's of 18 to 130 micrograms Ni/ml). Most compounds displayed nuclear to cytoplasmic nickel ratios of approximately 1:1.5 to 1:5 (except approximately 1:20 for nickel salts). At the LC50's, a 75-fold range in exposure levels occurred compared to a 10-fold range in cytoplasmic and nuclear nickel concentrations, [Ni]. Cellular nickel distribution indicated three groupings: inert compounds (green NiO, lithium nickel oxide, relatively low nuclear and cytosolic [Ni]); water-soluble salts (very low nuclear [Ni]; high cytosolic [Ni]), and slightly soluble compounds (relatively high cytosolic and nuclear [Ni]). Nickel compounds are considered to be only weak or equivocal mutagens. In this study, a low but significant increase in mutation rate at the gpt locus was shown. Although the results would not be sufficient to deem nickel compounds mutagenic by traditional criteria, characterization by PCR analysis indicated that the spontaneous and nickel-induced mutants exhibited different and compound specific mutational spectra (thus confirming nickel compound involvement). The results reported illustrate some of the methodologic problems involved in testing "weak" mutagens and indicate that alternative approaches may be necessary in classifying the mutagenicity of nickel and other compounds. PMID- 7843141 TI - The role of mutagenic metal ions in mediating in vitro mispairing by alkylpyrimidines. AB - A variety of alkylating mutagens and carcinogens produce pyrimidine adducts in DNA that block DNA synthesis in vitro. Since DNA synthesis past the lesion is a necessary step to produce mutations, we investigated the role of the mutagenic metal ion Mn++ in facilitating DNA synthesis past alkylpyrimidines. In the presence of the natural metal activator Mg++, N3-ethyldeoxythymidine (N3-Et-dT) and O2-ethyldeoxythymidine (O2-Et-dT), present at a single site in DNA, blocked in vitro DNA synthesis 3' to the lesion and after incorporating dA opposite each lesion. The presence of Mn++ permitted postlesion synthesis with dT misincorporated opposite N3-Et-dT and O2-Et-dT, implicating these lesions in A.T- >T.A transversion mutagenesis. The DNA synthesis block by O4-ethyldeoxythymidine (O4-Et-dT) in the presence of Mg++ was partial and was also removed by Mn++. Consistent with in vivo studies, dG was incorporated opposite O4-Et-dT during postlesion synthesis, leading to A.T-->G.C transition mutagenesis. We also have discovered a new class of DNA adducts, N3-hydroxyalkyldeoxyuridine (3-HA-dU) lesions, which are produced by mutagenic and carcinogenic aliphatic epoxides. 3 HA-dU is formed after initial alkylation at the N3 position of dC followed by a rapid hydrolytic deamination. As observed with the analogous mutagenic N3-Et-dT, the ethylene oxide-induced 3-hydroxyethyldeoxyuridine (3-HE-dU) blocked in vitro DNA synthesis, which could be by-passed in the presence of Mn++. The nucleotide incorporated opposite 3-HE-dU during postlesion synthesis is being identified. These studies suggest a role for Mn++ in mediating mutagenic and carcinogenic effects of environmentally important ethylating agents and aliphatic epoxides. PMID- 7843144 TI - The functional significance of low body mass index (BMI). Proceedings of an IDECG workshop. Rome, Italy, 4-6 November 1992. PMID- 7843142 TI - Enhanced generation of hydroxyl radical and sulfur trioxide anion radical from oxidation of sodium sulfite, nickel(II) sulfite, and nickel subsulfide in the presence of nickel(II) complexes. AB - Electron spin resonance (ESR) spin trapping was utilized to investigate the generation of free radicals from oxidation of sodium sulfite, nickel(II) sulfite, and nickel subsulfide (Ni3S2) by ambient oxygen or H2O2 at pH 7.4. The spin trap used was 5,5-dimethyl-1-pyrroline-N-oxide (DMPO). Under ambient oxygen, a solution of sodium sulfite alone generated predominantly sulfur trioxide anion radical (.SO3-) due to the autoxidation of sulfite. Addition of nickel(II) chloride [Ni(II)] enhanced the .SO3- yield about 4-fold. Incubation of sulfite with Ni(II) in the presence of chelators such as tetraglycine, histidine, beta alanyl-3-methyl-L-histidine (anserine), beta--L-histidine (carnosine), gamma aminobutyryl-L-histidine (homocarnosine), glutathione, and penicillamine did not have any significant effect on that enhancement. In contrast, albumin, and especially glycylglycylhistidine (GlyGlyHis), augmented the enhancing effect of Ni(II) by factors of 1.4 and 4, respectively. Computer simulation analysis of the spin-adduct spectrum and formate scavenging experiment showed that the mixture of sodium sulfite, Ni(II), and GlyGlyHis generated both hydroxyl (.OH) radical and .SO3- radical, in the ratio of approximately 1:2. The free-radical spin adduct intensity reached its saturation level in about 5 min. The yield of the radical adducts could be slightly reduced by deferoxamine and very strongly reduced by diethylenetriaminepentaacetic acid (DTPA). Aqueous suspensions of sparingly soluble nickel(II) sulfite in the presence of air and GlyGlyHis generated surface located .SO3- and .OH radicals. The same radicals were generated in Ni3S2 suspension in the presence of GlyGlyHis and H2O2, indicating sulfite production by oxidation of the sulfide moiety of this compound.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843143 TI - Induction of arsenite tolerance and thermotolerance by arsenite occur by different mechanisms. AB - Both V79 and As/R28A cells (an arsenite-resistant Chinese hamster V79 cell variant) show increased resistance to toxic concentrations of arsenite after pretreatment with a nontoxic concentration. The induced tolerance can be completely inhibited by actinomycin D or cycloheximide. Pretreatment with a nontoxic heat shock (45 degrees C, 10 min) resulted in a clear increased thermotolerance in both cell lines but failed to induce arsenite tolerance in either cell line. Pretreatment with arsenite induced a thermotolerance in V79 cells but not in As/R28A cells. These results are consistent with a model whereby the signal for induction of arsenite tolerance involves binding of arsenite to a protein effector which is amplified in the As/R28A line, thereby preventing action of arsenite in the regulation of heat shock factor which induces the heat shock response. PMID- 7843145 TI - Introduction: the challenge of adult chronic energy deficiency. AB - In Guatemala, in 1987, the term 'chronic energy deficiency' (CED) was being used as a term to indicate an inadequate household food supply. Since then, attempts to define, measure and assess CED have evolved, using the body mass index (BMI or weight/height) of individuals as the index of CED. An estimate of food intake or physical activity was incorporated into the early analyses, but has since been discarded as difficult and unnecessary because so many people of normal BMI were found to be inactive. Provisional cut-off points for low BMI were developed to define grades of CED in the same way as Garrow used higher levels of BMI to define different grades of obesity. The same BMI cut-off points were proposed for men and women in the absence of suitable data for proposing sex-specific cut-off points. Since then, we have been collecting and sifting worldwide data to test the validity of BMI as a measure of CED. FAO has helped in making data available with extensive information being obtained from China, India, Ethiopia and Zimbabwe. There is now clear evidence that those with a low BMI have more sickness, a lower work capacity, limited social activity, and a lower income. Mothers with a low BMI also have a greater proportion of low birth weight babies compared with those of normal BMI. Three challenges remain before confirming the use of BMI as the key to specifying a state of CED: Is it valid? Does it apply to individuals as well as populations? What are the causes of CED?(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843146 TI - Population differences in body composition in relation to the body mass index. AB - This paper examines the relationships between body mass index (BMI) and body composition in different population groups where low BMIs might be expected to occur and assesses the extent to which BMIs are influenced by size and shape. The relationship between BMI and fat as a percentage of body weight is approximately linear although theoretically a curvilinear relationship is to be expected. However, by allowing for a variable composition of weight differences, an approximately linear theoretical relationship is obtained. There are few direct data (e.g. from densitometry, hydrometry etc.) on body composition in the groups in question and to examine the relationships indirect data were used. The regression coefficients of fat-free mass on BMI for 285 samples of Africans, people of Asian origin, Indo-Mediterraneans and Pacific people were not significantly different in the various groups of each sex; % fat on BMI was similarly related in four groups of women. Intercept terms were all significantly different. Using the sitting height-to-stature ratio (SH/S) as an index of body shape in 158 groups, the regression coefficient of BMI on SH/S was 0.90 kg/m2 per 0.01 SH/S. Mean SH/S lies between 0.50 and 0.55 in most populations so that shape could affect BMI by 5 kg/m2 and influence markedly the interpretation of BMI. However, allowing for SH/S is not straightforward as there is as much variation within as between groups. In conclusion, low BMI approximates to low weight, fat mass and fat-free mass. There are differences in the relationships of BMI to body composition but over the range 20-25 kg/m2 these may not be important in epidemiological studies. To interpret BMI in terms of body composition in more detail it is necessary to take into account sex, age, shape and ethnicity. PMID- 7843147 TI - An assessment of nutritional factors affecting the BMI of a population. AB - This paper assesses some of the environmental factors relating to BMI in a very large and comprehensive household survey conducted in 1974 in Brazil and involving about 51,000 households in all parts of the country. In this study not only were the children and adults in all households weighed and measured but the household diet, socio-economic status and a variety of issues relating to household practices were assessed as part of a major national economic survey conducted by the Brazilian Institute of Geography and Statistics with technical support from FAO. One of the authors (P.F.) was the principal collaborator from FAO. PMID- 7843148 TI - Body mass index: its relationship with food consumption and socioeconomic variables in Brazil. PMID- 7843149 TI - Use of body mass index in the assessment of adult nutritional status in Vietnam. AB - The authors have used body mass index (BMI: kg/m2) to assess the Vietnamese adult nutritional status and classified the population into different grades of chronic energy deficiency (CED). CED is prevalent in Vietnamese adults (average 40%). The mean value of BMI of the age group 26-40 years is 19.7 but it decreases thereafter except in urban areas. The BMI curve of distribution is different between adults living in rural, urban and mountainous areas. There seems to be a relation between BMI of mothers and the nutritional status of their < 5-year-old children. The survey also revealed a relation between maternal BMI and birth weight, and between CED and the health status of the population. PMID- 7843150 TI - Body mass index: a measure of the nutritional status in Indian populations. AB - Anthropometric data available through National Nutrition Monitoring Bureau surveys/studies conducted by the National Institute for Nutrition were analysed to study body mass index (BMI:kg/m2) profiles of adults and relate them to various parameters such as the nutritional status of preschool children, socio economic status, low birth weight and mortality. The results show that nearly one half (49%) of adult Indian rural population is suffering from some grade of chronic energy deficiency (CED). The adults' household BMI and child's nutritional status are associated. Mean BMI values were lower in landless agricultural occupational groups and in low per capita income group households compared with cultivators, artisan and higher income groups. Mean birth weights showed definite differences between BMI classes (2500 g in grade III CED and 2800 g in the normal BMI group). The odds ratio for low birth weight (LBW) was found to be three times more in severe CED groups compared to normal BMI groups of mothers. The influence of BMI on the incidence of LBW was evident despite the confounding factors of parity and maternal age. The frequency distribution of BMI values of adults who had been malnourished at the age of 5 years was distinctly different from that of the well-nourished group. The mean BMI of the group who were malnourished as children was 16, while those who had been well nourished was now 21 on average. Data from affluent and well-grown Indians suggests that a cut off point of 18 rather than 18.5 would be more appropriate to distinguish the nutritionally normal groups from the energy deficient group (CED). PMID- 7843151 TI - Is body mass index sensitively related to socio-economic status and to economic adjustment? A case study from the Congo. AB - Several nutritional surveys based on representative samples from various urban and rural situations show that the Congo presents a situation of nutritional transition. There is a large prevalence of low body mass index (BMI) in adults from rural zones and this increases with age. There is, however, a large prevalence of high BMI in urban populations despite the persistence of some degree of chronic energy deficiency (CED), particularly at younger ages. Correspondence analysis and logistic regression were used to construct a socio economic index and measure adjusted risk factors for CED. In rural areas, the major risk factors were old age, sex (women) and the absence of schooling; low economic status, a commonly shared factor, did not differentiate between households for CED. In Brazzaville, CED was linked to a young age (< 30 years) and, clearly, to poverty. The change in the prevalence of CED in mothers from the capital city during a period of economic adjustment showed an increased incidence in young mothers, and also showed that the disparity between low and high economic levels regarding CED had grown. Finally, there was a high level of correspondence between the mean values for the weight-for-height of children and the BMI categories of the mothers. There is a parallel evolution during the period of economic adjustment between the increase of wasting in infants and the increase of CED in mothers. Therefore BMI appears to be a potential core indicator for use in nutritional surveillance in the Congo. PMID- 7843153 TI - Body mass index values in the Cuban adult population. AB - An anthropometric study was carried out on 31,662 male and female adults from 20 to 60 years of age, living in Cuba's 14 provinces. Measurements were taken utilizing the methods and equipment recommended by the UN International Biological Programme. Weight/height, body mass index (BMI), Rohrer, Sheldon, Ponderal and Benn indices were registered as well as their correlation with height, weight and fat folds in order to obtain the suitable index for nutritional evaluation. The BMI was selected as the most appropriate and its values were recorded by sex, age, dwelling, educational level and type of occupation. The cut-off points of 'normal' BMI values were determined. Their range, based exclusively on anthropometric data, in general coincided with those defined by international actuarial data. The distribution of BMI values was very similar to that of developed countries with more overweight than underweight individuals, particularly in females. Rural populations were lighter than those in urban communities and had more underweight subjects. Lower educational levels were directly related to higher percentages of chronic energy deficiency (CED) in women; in men, there was no defined trend. On the contrary, in men CED was slightly more related to jobs that required light effort; in women there was no defined trend. Finally, a model of action against malnutrition is proposed. PMID- 7843152 TI - The body mass index of Chinese adults in the 1980s. AB - Patterns and trends in the body composition of Chinese adults are studied with data from the 1982 China Nationwide Nutrition Survey (CNS-82) and the 1989 China Health and Nutrition Survey (CHNS-89). The CNS-82 showed rural inhabitants were approximately 3 kg lighter than urban residents and approximately 2.2 cm shorter. Males were heavier (55.2 +/- 7.4 vs 50.7 +/- 8.0 kg) and taller (165.3 +/- 7.3 and 153.5 +/- 6.3 cm). Using a cut-off for underweight of a body mass index (BMI: kg/m2) < 18.5 and for obesity of > 25, 11.6% and 12.9% of the urban and rural sample were underweight and 9.8% and 6.9% respectively were overweight. The CHNS 89 surveyed 5138 adults aged 20-45 in eight selected provinces. The proportion of underweight in both urban and rural samples declined slightly (approximately 1.3%) but the proportion of obesity increased considerably (4.8% for the urban sample and 2% for the rural one). Increased income was significantly associated with reduced low body mass index (BMI: kg/m2) in the urban sample while, for the rural and overall samples, the opposite was found for obesity. Provincial patterns in energy intake were not associated with the distribution of BMI while occupation was. In particular, government officials and housewives were much more likely to be obese as also were subpopulation groups consuming greater proportions of energy from animal sources. Over 80% of the population fell in the normal BMI range (18.5-25). This may relate to the relatively even distribution of food in China during the past several decades. PMID- 7843154 TI - Body mass index defines the risk of seasonal energy stress in the Third World. AB - A method has been devised to quantify the effect of seasonal environmental stress on nutritional well-being and to estimate the proportion of Third World populations at risk of functional deterioration. An Index of Agro-Climatic Seasonality, IACS--a measure of potential agricultural biomass availability--has been developed from agro-climatic data. IACS was found to be highly correlated with the seasonal weight loss of adults in rural Third World communities. This relationship was then used to predict the existence and severity of seasonal energy stress incurred by the adult population of Third World countries at any given body mass index (BMI). The average weight loss recorded in all seasonality studies was calculated; this value was used to specify, in combination with BMI, a condition of moderate seasonal energy stress. This grade of energy stress involved a loss of about 2% fat-free mass. The risk of greater energy stress, with larger losses of lean tissue, was specified as severe when predicted weight changes exceeded the maximum losses of weight recorded--at any given BMI--in Third World rural communities. The global dimensions of seasonality were then calculated by enumerating the individuals who--by the combined criteria of the BMI and the IACS of the habitat--fell into the categories of moderate and severe seasonality risk. On this basis, 65% of the rural adult population in the Third World run the risk of at least moderate seasonal energy stress, while 45% fall into the severe stress category. Of these 25% qualify as true seasonal 'casualties' because their body weight loss shifts their BMI from the normal range of nutritional status into the category of chronic energy deficiency. PMID- 7843155 TI - The choice of cut-off point for distinguishing normal body weights from underweight or 'chronic energy deficiency' in adults. PMID- 7843156 TI - Use of BMI for monitoring and surveillance. Practical issues. PMID- 7843157 TI - Analysing cross-sectional anthropometric data. AB - This paper provides a detailed account, with examples, of the types of statistical analyses which can be carried out on cross-sectional anthropometric data. For continuous characters the analyses described cover t-tests, one-way analysis of variance, more complex analysis of variance with covariates; testing for curvilinearity; regression analysis and multiple regression analysis. For discrete characters the analyses include chi-square, odds ratios, sensitivity and specificity, logistic regression and discriminant analyses. PMID- 7843158 TI - Body mass index: its relationship to basal metabolic rates and energy requirements. PMID- 7843159 TI - Low body mass index, physical work capacity and physical activity levels. AB - In a normal population the distribution of body mass index (BMI) is such that a certain proportion of the population is likely to be at low values without necessarily being malnourished. However, although they may have low BMIs without being malnourished, they could certainly be physiologically and physically disadvantaged. An attempt is made to dissect out the probability of work capacity and physical activity being influenced by changes occurring in the human body with diminishing BMI. The conclusion reached is therefore that before physical activity is affected, the BMI would probably have to be 17 or less, although it is possible that work capacity might be reduced before this level is reached. In any case, work requiring the use of the body mass - such as carrying loads, digging or shovelling earth or coal, pulling or cycling a rickshaw, stone splitting etc.- would impose a greater stress on people of low BMI. PMID- 7843160 TI - Body mass index and economic productivity. AB - The paper reviews the evidence to date on the nutritional links with productivity and then goes on to provide results from a multi-country study on the effects of increasing body mass index (BMI) on productivity. The research relating nutritional status to work capacity is more consistent than the research linking nutritional status to productivity. None of the studies to date elucidate the pathways through which improved nutrition improves economic productivity. In addition, many of the studies that have been conducted on the nutrition/wage links have been based on samples that contained a disproportionate number of male subjects. The few studies that have disaggregated data by gender report different results for men and women. Research conducted at IFPRI is presented to examine the trends in BMI for men and women across countries and for Kenya to examine the relationships between various measures of nutritional status--BMI and height--and energy expenditures in women. BMIs of men show a more consistent relationship with increasing household income than do the BMIs of women. In the case of the Gambia and Kenya, the mean BMI of women decreases with increasing household income. One reason for the apparently low response of BMI to increasing household income in Kenya is the time allocation patterns of women. Women in the Kenya sample spend the largest proportion of their day in home production activities which are energy intensive. In examining the relationship between nutritional indicators and the time devoted to work, the results suggest a significant, positive association between both BMI and height and the amount of time devoted to work. In the models presented, both BMI and height appear to increase the capacity to carry out work. It is difficult to value much of this work time since a disproportionate share is devoted to home production activities. Some of the more classic methods of measuring economic productivity, such as measuring wage rates, are not relevant for women in this setting. The data from Kenya suggest that more appropriate measures for specifying the value of women's work need to be developed in order to capture some of the nutrition/productivity links which may exist. PMID- 7843161 TI - Maternal body mass index: the functional significance during reproduction. PMID- 7843162 TI - Maternal body mass index and pregnancy outcome in the Nutrition Collaborative Research Support Program. AB - This paper uses data from the Nutrition CRSP in Egypt, Mexico and Kenya to examine relationships between maternal BMI and pregnancy outcome. Women were studied from the periconceptional period up to 6 months of lactation. No women in Egypt or Mexico, and only two in Kenya where periods of food shortage occurred, had a BMI < 18 at conception. Women with a lower BMI in Mexico and Kenya gained more weight and fat in pregnancy and lost more weight and fat during lactation. These counter-intuitive relationships affect the interpretation of weight and body composition measures used to assess energy adequacy during pregnancy and lactation. Lower pre-pregnancy BMI predicted lower infant weights at birth and was a risk factor for low birthweight in Kenya. At 3-6 months post partum, maternal BMI was less strongly related to infant size, and the lean body mass component of BMI appeared to be a more important predictor than fatness. PMID- 7843163 TI - Body mass index and lactation performance. AB - Data from the world literature have been analysed in order to test whether low body mass index (BMI: kg/m2) is a useful indicator of functional impairment of lactation performance. Forty-one databases containing 1726 measurements have been identified as having reliable estimates of breast-milk quantity and/or quality. There is no detectable relationship between maternal BMI and the volume of milk produced by mothers when analysed according to the mean BMI of different populations, or of different subgroups stratified by BMI within populations. This conclusion holds even at BMIs < 18.5. The most remarkable feature of the data is the very high milk volumes produced by very thin mothers. It is accepted that the composition of breast milk is relatively unaffected by general undernutrition of the type that would be indicated by a low BMI with the possible exception of milk fat levels and hence the energy content. Analysis of the available data reveals studies in which there are weak, but significant, correlations between maternal BMI and milk fat. However, other studies show no association or even a negative relationship. Inter-country analysis fails to reveal any detectable association between BMI and milk energy. Milk energy levels seem adequate even at BMIs < 18.5. It is concluded that human lactation performance is extremely robust and that BMI does not provide a useful indicator of function at the levels studied so far. Lactation performance must become compromised when undernutrition is sufficiently severe, but it appears that this must occur only in famine or near famine conditions. PMID- 7843164 TI - Assessing the linkages between low body mass index and morbidity in adults: evidence from four developing countries. AB - The study explores the relationship between low BMI and illness patterns in four developing countries. Using probit analysis, the study finds small but statistically significant effect of low BMI on proneness to morbidity in Pakistan and Kenya but none in the Philippines and Ghana. The circularity of causation between low BMI and illness was addressed by using the instrumental variable approach. The study also finds that the threshold at which morbidity begins to rise is not consistent with the suggested cut-off of BMI 18.5 kg/m2. The cut-offs were meaningful only in the case of Pakistan, but even here, the sizes of relationships are quite small although statistically significant. PMID- 7843165 TI - Body mass index and illness in rural Sarawak. AB - This paper reports findings of a cross-sectional anthropometric survey of 447 men and 564 women aged > 18 years of the Iban tribe in rural Sarawak. The percentage of each approximately 10 year cohort with body mass index (BMI: kg/m2) < 18.5 increased progressively with age > 40 years in both sexes. BMI and arm-muscle plus bone cross-sectional area (AMBA) were influenced significantly by reported single symptoms in men and two concurrent symptoms in women. Sensitivity of BMI < 18.5 for identifying those reporting symptoms of illness was 21% in men and 29% in women. Independently of illness effects, values of stature, BMI and AMBA in men, and stature alone in women, were significantly greater in those farming plots with the shortest time left fallow, suggesting their comparative success. The BMI of men may reflect primarily their economic activities, while that of women their experience of illness; the AMBA may also be a better overall index of health than BMI in this population. PMID- 7843166 TI - Clinical implications of generalized electrographic status epilepticus. AB - We reviewed clinical features of 48 patients without prior epilepsy who had generalized electrographic status epilepticus (ESE) identified from EEG readings. Clinical status epilepticus (SE) had occurred in 40%, but most were thought to have stopped seizing. Overall, ESE was unsuspected in 81% of patients. Many types of seizures were present before the EEG, but clinical seizures recurred in only 17 patients after diagnosis, and 18 patients (38%) never had clinical evidence of seizures. Most patients (60%) were comatose. The cause of ESE often remained uncertain though many patients had serious medical illnesses. Eighty-eight percent died, and a poor outcome was predicted by coma at the time of diagnosis (29 of 29), anoxia (15 of 15), an invariantly discharging, low-voltage background EEG (15 of 16), and refractory electrographic or clinical seizures (29 of 31). Seizure type did not predict outcome, and mortality was as high for patients without clinical evidence of seizures (89%) as for the series as a whole. ESE is often unanticipated and signifies neurologic disease with a prognosis worse than convulsive SE or the typical nonconvulsive SE; the absence of clinical seizures confers no advantage. PMID- 7843167 TI - Long-term observations on the clinical use of lamotrigine as add-on drug in patients with epilepsy. AB - We report open-label clinical observations of additional lamotrigine (LTG) in 16 adult patients with refractory epilepsy, aimed to assess the long-term efficacy and safety of LTG in clinical use. LTG was added to the current antiepileptic drug (AED) regimen at a daily dosage of 200-400 mg depending on the concomitant treatment. Ten patients completed one year's treatment and were followed up to an overall exposure ranging 15-38 months. Six patients (38% of the initial group) had a reduction of seizure frequency greater than 50% of pre-treatment baseline after one year; the further follow-up indicated some efficacy decline, since the percentage of improved patients dropped to 19% after 2 years and 13% after 3 years. The dropouts during the first year were due to seizure breakthrough (two patients), Steven-Johnson-like syndrome (one patient) and reasons unrelated to treatment (three patients); in one patient LTG treatment was stopped due to macrocytic anemia after 23 months. Other reported adverse events were dizziness, mild ataxia, diplopia and localized purpura. No other hematological or biochemical changes were noted. LTG was not associated with any significant changes in plasma concentrations of concomitant AEDs. These findings confirm the moderate efficacy and low toxicity of long-term LTG in severe epilepsy. PMID- 7843168 TI - Traumatic compared to non-traumatic clinical-pathologic associations in temporal lobe epilepsy. AB - This study determined differences in clinical-pathologic characteristics of intractable temporal lobe epilepsy (TLE) patients whose mechanism of cerebral injury and chronic seizures involved a prior history of cerebral trauma compared to those with non-traumatic initial injuries. TLE patients (n = 120) from a single epilepsy center were retrospectively and blindly catalogued into pathogenic groups (independent variables) based on if there was a significant Birth injury (n = 11) or Cerebral trauma (n = 26). These two 'trauma' categories were compared to TLE patients with non-seizure non-trauma histories (Non-Sz/Non Trauma; n = 17), or a first Prolonged seizure (n = 66). The four groups were compared for differences in the time course of their clinical injuries and seizures, quantified hippocampal neuron counts, other temporal neocortical pathologies, and seizure outcomes (dependent variables). Between group statistically significant (at least P < 0.05) results showed: (1) In Birth injury, 33% had Ammon's Horn (AH) neuron loss under 50%, 54% had other temporal neocortical pathologies, they showed the most CA4 neuron loss, and the worse seizure outcomes. (2) Cerebral trauma were older when injured, 29% had AH loss under 50%, 50% showed other pathologies, and they had the best seizure outcomes. (3) Non-Sz/Non-Trauma showed the least AH and CA4 neuron losses, only 12% had other temporal pathologies, and they had seizure outcomes that were intermediate. (4) Prolonged seizure showed the youngest age of habitual TLE onsets, the greatest AH, CA1, and prosubiculum neuron loss, only 11% had other temporal pathologies, and their seizure outcomes were excellent. These results indicate that in intractable surgically treated TLE, a history of cerebral trauma or birth injury as the pathogenic mechanism of their seizures show different clinical pathologic features and seizure outcomes compared to non-trauma patients. This supports the notion that in TLE there are different pathogenic mechanisms associated with different types of initial injuries and that patients will have different responses to surgical therapy. PMID- 7843169 TI - Withdrawal of antiepileptic medication in children. Correlation of cognitive function and plasma concentration--the multicentre 'Holmfrid' study. AB - Eighty-three patients with epilepsy and 83 matched controls completed 12 computerized cognitive tests while on antiepileptic drugs and six months later when they had been medication-free for three to four months. All patients had been seizure-free for more than one year and were on monotherapy with carbamazepine (CBZ, n = 56), valproate (VPA, n = 17), or phenytoin (PHT, n = 10). The tests and plasma concentration collection were done at noon. The mean peak plasma concentrations in the CBZ patients were as follows: 31% below 30 mumol/l, 48% between 30 and 42 mumol/l and 21% above 42 mumol/l. No difference in performance could be detected between the groups. One significant correlation between plasma concentration and test results was found. The mean VPA concentration was 625 mumol/l (S.D. 189). A tendency towards a weak negative correlation between test results and plasma concentration was present. The PHT patients' therapeutic range had a mean concentration of 32.0 mumol/l (S.D. 18.5). One significant correlation between a memory test and plasma concentration could be detected. Overall, the patients in the different antiepileptic groups performed less good than the control group and in a few cases the differences were statistically significant when compared either before or after withdrawal. A comparison of the changes after withdrawal showed improvement in the majority of tests, but these changes were also present in the matched control group. PMID- 7843170 TI - Do dichotic word listening asymmetries predict side of temporal lobe seizure onset? AB - Dichotic word listening asymmetries are thought to be useful in predicting side of temporal lobe dysfunction. However, little direct evidence exists to support this assumption in practice, especially in patients with subtle epileptogenic lesions. To determine if word listening ear asymmetries are valid predictors of side of temporal lobe seizure onset, we examined the preoperative dichotic word listening performance of 80 patients with either left (N = 41) or right (N = 39) temporal lobe (TL) seizure foci. On a group level, patients showed a statistically significant 'lesion effect' as evidenced by a relative deficit in the ear contralateral to the side of lesion. Prediction of side of seizure focus in individual cases, however, was poor: depending upon the criteria used, 61% to 80% of epileptics with unilateral temporal lobe foci did not show the expected contralateral ear deficit. Results suggest that caution be exercised when inferring side of temporal lobe seizure focus through dichotic word listening asymmetries in individual temporal lobe epilepsy cases. PMID- 7843171 TI - Altered patterns of catecholaminergic fibers in focal cortical dysplasia in two patients with partial seizures. AB - We present the histologic study of two patients who underwent cerebral cortex resection for partial seizures linked with cortical dysplasia. The distinction of areas of seizure origin from areas of seizure propagation was made according to stereoelectroencephalographic criteria. Samples of epileptogenic tissue were studied by using cytoarchitectonic and immunohistochemical stainings. We mapped the catecholaminergic afferents by employing antisera directed against tyrosine hydroxylase and dopamine-beta-hydroxylase enzymes. The epileptic activity was correlated with the underlying patterns of cytoarchitectonic and immunohistochemical changes. The neuropathological features were focal and consisted of large neurons dispersed through all but the first cortical layer (associated in one case to giant glial cells), of variable disturbance of lamination, of neuronal ectopia in the white matter and of moderate proliferation of small glial cells. Areas of seizure onset coincided with that of dysplastic zones. Both laminar distribution and density of catecholaminergic fibers were altered in the dysplastic cortices (area of seizure onset) and there was an increase in the density of tyrosine hydroxylase-immunoreactive fibers in the surrounding areas of seizure propagation. Our results indicate that these developmental epileptogenic lesions were associated with abnormal neuronal circuitry. They provide evidence at the structural level of the increase in tyrosine hydroxylase activity previously reported in spiking areas of human epileptogenic cerebral cortex and they suggest that catecholamines may contribute toward limiting seizure activity propagation. PMID- 7843172 TI - Bromide, in the therapeutic concentration, enhances GABA-activated currents in cultured neurons of rat cerebral cortex. AB - We investigated the effect of bromide on gamma-aminobutyric acid (GABA)-activated currents in cultured cerebral neurons of the rat, employing whole-cell voltage- and current-clamp techniques. Application of 100 microM GABA elicited currents whose reversal potential was 0 mV with equal concentrations of chloride in both pipette and bath solutions and more negative than -60 mV with 159 mM chloride extracellularly and 4 mM chloride inside. Bicuculline blocked the currents. These findings showed that the currents were composed of chloride flux through GABAA receptor-coupled channels. Reversal potential revealed a permeability ratio of bromide with respect to chloride (PBr/PCl) of 1.51. When 100 microM GABA was applied with the extracellular solution containing 140 mM bromide and 19 mM chloride, the currents were enhanced 2.00- and 1.91-fold at the holding potentials of -20 mV and 0 mV, respectively. Extracellular solutions containing various concentrations of bromide substituted for the same amount of chloride were applied with 100 microM GABA. The therapeutic concentration of 10 mM and 20 mM bromide enhanced the currents 1.28- and 1.36-fold of the control currents at the holding potential of -20 mV, respectively. Under current-clamp recording, a larger hyperpolarization was obtained by the application of GABA with a 140 mM bromide-containing solution. These findings suggest that bromide potentiated GABA activated currents at the therapeutic concentrations ranging from 10 mM to 20 mM, causing the larger GABA-induced hyperpolarization. It is postulated that the antiepileptic effect of bromide might occur through the potentiation of inhibitory postsynaptic potentials elicited by GABA. PMID- 7843173 TI - Antiepileptic drug pharmacokinetics and neuropharmacokinetics in individual rats by repetitive withdrawal of blood and cerebrospinal fluid: phenytoin. AB - The temporal pharmacokinetic (blood) and neuropharmacokinetic (cerebrospinal fluid, CSF) interrelationship of phenytoin was studied after acute and during chronic (up to 5 days) intraperitoneal administration of phenytoin (30, 50 or 100 mg/kg) using a new freely behaving rat model. After administration, phenytoin rapidly appeared in both serum (Tmax mean range 0.15-0.38 h) and CSF (Tmax mean range 0.9-1.4 h), suggesting ready penetration of the blood-brain barrier. However, transport across the blood-brain barrier may be rate limiting since whilst phenytoin concentrations rose dose dependently in serum, CSF concentrations did not. Further, the divergence between the blood and CSF compartments increased with chronic dosing. Cmax, AUC and t1/2 values for serum increased non-linearly, suggestive of accumulation kinetics. Based on these data, high initial phenytoin blood concentrations are essential if phenytoin entry into the brain is to be facilitated, and this may be important in studies of phenytoin in animal models of status epilepticus. PMID- 7843174 TI - Use of teicoplanin in community medicine. AB - Administration of parenteral antibiotics to outpatients is increasingly used to reduce hospital costs, to reduce loss of earnings for the patient and to improve the quality of life in patients requiring prolonged antibiotic treatment. The glycopeptides are required for treatment of infections caused by methicillin resistant staphylococci and some enterococci, or for treatment of patients allergic to beta-lactam agents. For home therapy, teicoplanin has some advantages over vancomycin in that it requires only once-daily bolus administration, does not necessitate monitoring of serum concentrations and offers the choice of intravenous or intramuscular administration. Teicoplanin has been used to complete treatment of endocarditis at home in selected patients, streptococcal disease being the most suitable form of endocarditis for this treatment. In open trials, teicoplanin has been found effective in home therapy of osteomyelitis but, as with other agents, prolonged dosage can be associated with adverse effects. It has also been used for home treatment of infections of the respiratory tract, intravascular catheters and soft tissue. Despite its higher acquisition costs, teicoplanin is to be preferred over vancomycin because of the reduced administration and assay costs and fewer adverse effects. PMID- 7843175 TI - Relationship between fluconazole sensitivity of Candida albicans isolates from HIV positive patients and serotype, adherence and CD4+ lymphocyte count. AB - The sensitivity of fluconazole, serotype and adherence to buccal epithelial cells of 46 Candida albicans isolates was studied in vitro. Strains were isolated from 18 HIV-positive patients with variable CD4+ lymphocyte counts who were receiving long-term fluconazole therapy. Results showed that sensitivity to fluconazole correlated with serotype. Of the sensitive isolates 81.5% were serotype A and 18.5% serotype B, whereas of the resistant isolates 37.5% were serotype A and 62.5% serotype B. Sensitivity to fluconazole also correlated with adherence capacity, resistant isolates showing slightly less adherence to buccal epithelial cells than sensitive isolates. Weakly adherent isolates represented 87% of resistant isolates and only 63% of sensitive isolates. Resistant strains were isolated in highly immunocompromised patients. All strains isolated in patients with CD4+ lymphocyte counts above 200 lymphocytes/microliters were sensitive, whereas intermediate and resistant strains were isolated in patients with counts below 200 lymphocytes/microliters. Statistical analyses showed no correlation between adherence of isolates to buccal epithelial cells and CD4+ lymphocyte counts. PMID- 7843176 TI - Faster identification of mycobacteria using gas liquid and thin layer chromatography. AB - Gas liquid chromatography (GLC) and thin layer chromatography (TLC) analysis of cell wall content was used for identification of mycobacteria isolated in primary cultures. GLC permitted determination of the fatty acid and alcohol profiles of Mycobacterium simiae and Mycobacterium marinum and detection of a peak in Mycobacterium ulcerans formerly described for Mycobacterium malmoense. Using the data obtained to fill some of the gaps in the dichotomic trees of Tisdall et al. and Jantzen et al., GLC analysis allowed full identification of 8 of 22 mycobacterial species after 24 hours. The other 14 species could be divided into four groups on the basis of similar findings on GLC. TLC was used for full identification of three species. The identification results of conventional methods were concordant with those of GLC and TLC in 161 of 169 strains (93%) representing 21 different species. Using primarily chromatography for analysis of cell wall content, and in the case of some species complementary biochemical tests, the identification procedure could be shortened to a maximum of three days after primary culture. PMID- 7843177 TI - Detection of amplified Chlamydia trachomatis DNA using a microtiter plate-based enzyme immunoassay. AB - A microtiter plate-based method to detect amplified DNA was developed. The method uses on biotin-labeled primer in the polymerase chain reaction (PCR) mixture. The labeled amplicon is bound to streptavidin-coated microtiter plates, denatured and hybridized to a digoxigenin-labeled probe. The specificity of the hybridization reaction was optimized by varying the temperature of the subsequent washing step and adding urea to the washing buffer. The digoxigenin label was detected using an enzyme immunoassay (EIA). This PCR-EIA was compared with a standard PCR assay that uses gel electrophoresis, blotting and hybridization to detect the amplicon, with isolation in cell culture, and with an antigen detection EIA (Chlamydiazyme) in the diagnosis of Chlamydia trachomatis infection in 309 female patients attending a sexually transmitted diseases outpatient clinic. The prevalence of Chlamydia trachomatis infection as determined by isolation in cell culture, EIA, PCR-EIA and standard PCR assay was 9.1%, 8.7%, 12.3%, and 12.9%, respectively. Compared with results of a reference set of confirmed-positive cases (defined by a positive result in two or more independent assay after analysis of discrepancies), the sensitivity and specificity was 71.1% and 99.6% for cell culture, 65.8% and 99.3% for the EIA, 92.1% and 98.9% for the PCR-EIA, and 97.4% and 98.9% for the standard PCR assay. It is concluded that the PCR-EIA described is a fast, sensitive and specific method for detecting Chlamydia trachomatis in clinical specimens. PMID- 7843178 TI - In vitro development and stability of tolerance to cloxacillin and vancomycin in Staphylococcus aureus. AB - The stability of tolerance of Staphylococcus aureus during subculturing at 37 degrees C and development of this property after repeated exposure to cloxacillin or vancomycin were investigated in vitro. Four of five tolerant strains lost this property during repeated subculturing at 37 degrees C for 50 days. Conversely, tolerance emerged in two of four nontolerant strains after repeated cycles of exposure to 25 micrograms of cloxacillin/ml or 10 micrograms of vancomycin/ml alternating with growth in antibiotic-free medium. Previous in vivo exposure to cloxacillin did not enhance the development of tolerance in vitro. MICs of both cloxacillin and vancomycin did not change significantly during this procedure. Whether the conversion of nontolerant strains to the tolerant state can also occur during antibiotic exposure in treatment of patients remains to be determined. PMID- 7843179 TI - Bronchopneumonia caused by Propionibacterium acnes. AB - Propionibacterium acnes was identified as the pathogen in a case of subacute lung infection by examination of an open lung biopsy specimen. The patient was a 65 year-old male with exacerbation of chronic lung disease. The organism was isolated in pure culture and was present in large numbers on Gram stain. Histological examination demonstrated active interstitial fibrosis; macrophages laden with Propionibacterium acnes antigen were revealed using a peroxidase antiperoxidase stain. This is the first report of subacute infection of pulmonary tissue due to this organism. PMID- 7843180 TI - Invasive pulmonary pseudallescheriasis with direct invasion of the thoracic spine in an immunocompetent patient. AB - Most invasive pseudallescheriasis infections have occurred in immunocompromised patients. The case of an immunocompetent patient with invasive pulmonary pseudallescheriasis and subsequent contiguous extension to the ribs and spine is reported. Aspergillosis was mistakenly diagnosed on histopathologic examination of the debrided tissue. Culture of the debrided tissue yielded Pseudallescheria boydii. PMID- 7843181 TI - Value of antigen and antibody detection in the serological diagnosis of invasive aspergillosis in patients with hematological malignancies. AB - In a study to determine the value of antigen and antibody detection in the serological diagnosis of invasive aspergillosis in patients with hematological malignancies, 436 sequential serum samples from 79 neutropenic patients were tested. Circulating galactomannan antigen was detected with a latex agglutination method (Pastorex Aspergillus) and antibody to Aspergillus fumigatus with an immunodiffusion test on agar gel. Among the 79 patients 18 cases of invasive aspergillosis were detected (4 proven, 6 highly probable, 3 probable, 5 suspected). Antigen was detected in 7 of these 18 patients. The sensitivity of the antigen test was 38.8% and the specificity 95%. The antibody test showed 55.5% sensitivity and 100% specificity. In this study the antigen test was less sensitive than previously reported but highly specific and might serve as a supplementary diagnostic test. PMID- 7843182 TI - Beta-lactam resistance in aerobic faecal flora from general practice patients in the UK. AB - One hundred faecal specimens submitted to a diagnostic laboratory in Edinburgh and found to be negative for gastrointestinal pathogens were examined for the presence of antibiotic-resistant bacteria. The results were compared with findings in the healthy population in the same area. The highest incidence of resistance was observed to cefuroxime (65%) and ampicillin (60%). Of the ampicillin-resistant isolates, 62% could transfer their resistance determinants to a standard Escherichia coli host strain. In 100% of these transconjugants ampicillin resistance was shown to result from the presence of the TEM-1 beta lactamase which was identified in a heterogeneity of plasmid profiles. These plasmids commonly mediated resistance to streptomycin and tetracycline in addition to ampicillin. PMID- 7843183 TI - Dissemination of cephalosporin-resistant Serratia marcescens strains producing a plasmidic SHV type beta-lactamase in Greek hospitals. AB - The resistance to third generation cephalosporins in nine Serratia marcescens strains isolated in Greek hospitals was studied. Eight of the strains transferred resistance to Escherichia coli by means of large plasmids that encoded for an extended-spectrum beta-lactamase. Hybridization, isoelectric focusing and hydrolysis studies showed that the enzyme resembled the SHV-5 beta-lactamase. In the eight isolates that possessed the SHV type enzyme, cephalosporinase expression was inducible, whereas the remaining strain was a cephalosporinase hyperproducing strain. Introduction of a plasmid coding for the regulatory ampD gene in the latter strain eliminated beta-lactamase production and rendered the strain susceptible to cephalosporins. PMID- 7843184 TI - Pharmacokinetics and suction blister fluid penetration of a semisynthetic injectable streptogramin RP 59500 (RP 57669/ RP 54476). AB - RP 59500 is a new semisynthetic injectable streptogramin with excellent activity against most gram-positive bacteria. In order to assess its potential for the treatment of tissue infections, the pharmacokinetics and penetration into suction blister fluid were studied in a pilot phase I study in six male volunteers following a single infusion of 12 mg/kg over 1 h. Plasma and suction blister fluid concentrations were determined by microbiological assay. The mean peak concentration in plasma was 8.65 mg/l at the end of infusion. The mean plasma elimination half-life was 1.48 h. The mean peak concentration in interstitial fluid was 2.41 mg/l and was reached after 1 h in two volunteers and after 2 h in the other four. The mean percentage penetration for the interval 0-6 h was 82.5%. RP 59500 was still detectable in interstitial fluid at 6 h at a mean concentration of 0.92 +/- 0.25 mg/l. The data of this pilot study demonstrate good penetration of RP 59500 into non-inflammatory interstitial fluid. PMID- 7843185 TI - Fatal meningitis due to catheter-related Staphylococcus epidermidis bacteraemia in a granulocytopenic patient without predisposing trauma. PMID- 7843186 TI - Oral source of Staphylococcus epidermidis septicemia in a neutropenic patient. PMID- 7843187 TI - Vertebral osteomyelitis with Stomatococcus mucilaginosus. PMID- 7843188 TI - Streptococcus intermedius spondylodiskitis. PMID- 7843189 TI - Research and treatment in cystic fibrosis (in honour of the work of Harry Shwachman). PMID- 7843191 TI - Adenosine-tri-phosphate treatment for supraventricular tachycardia in infants. AB - Adenosine is an endogenous nucleoside acting on coronary perfusion and myocardial conduction. Although the anti-arrhythmic effects of adenosine have been known for decades, interest in the use of adenosine or adenosine-triphosphate (ATP) (a precursor of adenosine) in termination of supraventricular tachycardia (SVT) has been renewed. We studied the use of striadyne (ATP and a mixture of other nucleosides including adenosine) in 22 infants younger than 6 months in order to evaluate efficiency and safety of the drug in this particular age group. Striadyne stopped SVT in 17 cases and was diagnostic in another 4 cases. Ten out of 17 successfully converted infants showed one or more reinitiations of SVT, which were easily controlled. The results support the efficiency of ATP for the termination of re-entry types of tachycardia, as well as its diagnostic value and its lack of serious side-effects. PMID- 7843190 TI - Paraneoplastic manifestations in children. AB - Paraneoplastic manifestations are signs and symptoms observed in patients with cancer, distant from the tumour or its metastases and not caused by invasion, obstruction or bulk mass. In children with cancer, paraneoplastic manifestations are rare and distinct from those observed in adults. Knowledge about paraneoplastic manifestations can be of great clinical importance because they may be the presenting sign of a tumour or its recurrence and hence facilitate early diagnosis. In contrast, they sometimes mask the symptoms of a tumour and cause diagnostic delay. In this review, paraneoplastic manifestations in children are described, including hypercalcaemia, Cushing syndrome, precocious puberty, opsoclonus/myoclonus, acquired von Willebrand disease, watery diarrhoea syndrome, and hypertension. The mechanisms causing these manifestations are also discussed. PMID- 7843192 TI - Impact of different doses of ethinyl oestradiol on reduction of final height in constitutionally tall girls. AB - Fifty-two tall girls were treated for constitutionally tall stature with different ethinyl oestradiol (EE) dosages. They were divided into three different treatment groups: group B (100 micrograms EE/day; n = 11); group C (300 micrograms; n = 25) and group D (500 micrograms; n = 16) and compared with an untreated group A (n = 21) matched for age, height, bone age (BA) and height prediction. Using the height prediction method TW II, EE treatment reduced final height compared with the untreated girls in a weak dose-dependent manner, 2.3 cm (100 micrograms/day), 3.0 cm (300 micrograms/day), and 3.8 cm (500 micrograms/day). Such a dose dependency was not found on applying the Bayley Pineau height prediction method (100 micrograms/day; 4.1 cm; 300 micrograms/day: 4.2 cm; 500 micrograms/day: 4.5 cm). However, there was a striking inverse correlation of the BA at the onset of treatment with the height reduction achieved using the TW II method (r: -0.43; P < 0.001). Importantly, girls with a BA below 12 years at the onset of treatment experienced a height reduction of more than 6 cm. CONCLUSION The EE dose used in the range of 100-500 micrograms/day is not crucial for the amount of height reduction in tall girls. In general high dose EE treatment should be given restrictively, and especially so in girls with a BA (TW2 RUS-ZH) above 12.0 years. PMID- 7843193 TI - Hyperintense lesions of the globus pallidus on MRI in children with chronic liver disease. AB - In three children with chronic liver disease of different aetiology without obvious hepatic encephalopathy, bilateral and symmetrical hyperintensity of the globus pallidus in T1-weighted images was found on cranial MRI. Reversibility was shown in one child with autoimmune hepatitis after normalisation of liver function tests under immunosuppressive therapy. CONCLUSION: As central nervous system involvement in liver disease is only partially understood, brain imaging by MRI offers a potential additional tool to further elucidate the incidence and time course of previously undetected brain alterations. PMID- 7843194 TI - Total body mineral mass measured with dual photon absorptiometry in healthy children. AB - Using dual photon absorptiometry, bone mineral content (BMC) and bone mineral density (BMD) of the total body and the lumbar spine were assessed in 97 healthy, Caucasian children aged 3-14 years. Excellent correlations were found between BMC and BMD on the one hand and age, body height and body weight on the other. No differences were found between boys and girls. There was a strong correlation between lumbar spine measurement as compared to those of the total body. Regression equations for total body and the different parts of the skeleton were calculated with either BMC or BMD as the dependent variable, and age, body height and body weight as independent variables. High variation coefficients were obtained in these multiple regressions, except for the head. For total body BMC and total body BMD, growth charts were constructed using Tanner and Whitehouse data on body height and body height and body weight. Conclusions. The increase in total body mineral content is an important feature of normal growth. Normal data for BMC and BMD in childhood are essential for bone mineralisation abnormalities in paediatric patients. PMID- 7843195 TI - Clinical and molecular study of DiGeorge sequence. AB - DiGeorge sequence (DGS) is a developmental field defect of the third and fourth pharyngeal pouches. The cardinal features of the syndrome are hypo- or aplasia of the thymus and parathyroids, congenital heart defect of the conotruncal type and characteristic facial dysmorphism. Such a pattern of malformations has been associated with various conditions but it is now well established that most cases of DGS are due to haplo-insufficiency of the chromosome 22q11 region. We report here a series of 16 patients, including a familial case. Minimal criteria for inclusion in this series were two or more of the following features: conotruncal heart defect, hypocalcaemia, hypoplastic/absent thymus and typical facial dysmorphism. Molecular analysis with specific probes of the 22q11 region was conducted in all patients according to two methods, fluorescent in situ hybridization and DNA dosage analysis. A deletion was found at the molecular level in all patients. We emphasize the fact that clinical analysis remains an important step of the diagnosis. The implication of these molecular techniques on diagnosis, prognosis and genetic counselling of DGS are discussed. PMID- 7843196 TI - Mortality from group C meningococcal disease: a case for a conjugate vaccine? AB - This 17-year retrospective review of children with meningococcal disease (MCD) has determined the mortality due to serogroup C, in order to assess the potential impact of a group C conjugate vaccine. Four hundred and forty-nine cases of MCD were admitted to our hospitals during 1977-1993; 78 due to group C, 11 of whom died. There was a significant increase in the proportion of cases due to group C from 1986 onwards (10% vs 21%), and an increase in the total number of cases of MCD (151 vs 298). The currently available group C polysaccharide vaccine has low efficacy below 2 years of age and could not have prevented 54 cases of group C disease. A conjugate group C vaccine administered between 2 and 4 months of age could have prevented 68 cases, including all fatal cases. The recent increase in MCD is partly due to an increase in group C disease. A meningococcal group C conjugate vaccine could prevent most cases of infection due to group C, and decrease the mortality from MCD by up to 30%. PMID- 7843197 TI - Chloride deficiency as a presentation or complication of cystic fibrosis. AB - Thirteen children with cystic fibrosis (CF), aged 1.5 months-15 years, had 18 episodes of hypochloraemia and metabolic alkalosis over the period 1983-1991. Five patients were not known to have CF prior to developing these electrolyte disturbances. There were two distinct clinical presentations: 5 patients had an acute isolated picture of heat exhaustion while 8 patients (all infants) had a more chronic course associated with failure to thrive. Many episodes were not associated with particularly high environmental temperatures, although most occurred during the summer and early autumn months. Serum electrolytes should be assessed regularly in children with CF, and this diagnosis should be considered in any infant presenting with unexplained hypochloraemic metabolic alkalosis. PMID- 7843198 TI - Sodium chloride deficiency in cystic fibrosis patients. AB - Sodium chloride deficiency (SCD) was observed within the 1st year of life in 12 of 46 cystic fibrosis (CF) patients between July 1989 and September 1992. All patients showed sweating, loss of appetite, fever, vomiting, irritation, dehydration, weakness, and cyanosis during an attack. Mean plasma sodium, potassium and chloride levels were 122.9 (range 106-135), 2.5 (range 1.6-3.5), and 73.3 (range 60-90) mEq/l respectively. Alkalosis and elevated plasma renin activity were detected in all patients. Of the patients, 50% showed microscopic haematuria, and hypercalciuria was detected in two out of four patients. Low urinary sodium and high urinary potassium were observed in the four examined patients. Increased creatinine, BUN and uric acid values returned to normal with treatment. All the patients were treated initially with intravenous fluids and electrolyte solutions. All patients were less than 7 months of age during the first attack, five received only breast milk and the others breast milk with formula milk. Their oral salt supplement was 2-4 mEq/kg per day, which is recommended for CF patients, but could be deficient in excessively sweating infants. The genotype of these patients might be cause of high salt losses. F508 is the most common mutation with the frequency of 38% in our CF patients with SCD, but the frequency of unknown mutations is high (54%). PMID- 7843199 TI - Phenylketonuria and some aspects of emotional development. AB - Early dietary treatment of phenylketonuria (PKU) prevents intellectual retardation and gross neurological impairment although not all neuropsychological problems. This study investigates to what extent the illness and its treatment imposes a burden on emotional development of early-treated PKU patients and on rearing practices of their parents. It is concluded that in early-treated PKU it is particularly difficult to find constructive ways to adapt to the situation for children as well as for parents. As coping with PKU and its treatment is so complicated, paediatric control should be combined with psychocounselling. PMID- 7843200 TI - Elevated arterial blood pressure is associated with peri-intraventricular haemorrhage. AB - In a prospective study, brain ultrasound scans were performed in 42 newborns (median birth weight 1700 g, range 1020-3720 g; gestational age 32 weeks, 26-36) to reveal peri-intraventricular haemorrhage (PIVH) (grades I-IV) as well as echodensities (ED) and/or periventricular leucomalacia (PVL). ECG and arterial blood pressure were recorded on magnetic tape at 8-h intervals during the first 24 h of life for further computer analysis. Heart rate (HR) and its variability (HRV) indices RMSM (long-term variability) and RMSSD (short-term variability), together with their coefficients of variation, were computed. Systolic (SBP), diastolic (DBP), and mean blood pressures (MBP) were detected as average values for 2-min stationary segments together with the respective minima and maxima. The indices of variability and their coefficients of variation were computed for the arterial pressure. PIVH was found in 12 newborns and ED in 8 (of whom two developed PVL). The remaining 22 served as controls. Neither HR, HRV nor BP variability differed between the groups. DBP was higher in the group with PIVH (39 mmHg) when compared to both the controls (33 mmHg, P < 0.05) and the ED group (32 mmHg, P < 0.01). MBP behaved respectively (45 mmHg, 38 mmHg, 37 mmHg, P < 0.01). SBP behaved also similarly when gestational age and birth weight were used as covariates (57 mmHg, 48 mmHg, 47 mmHg, P < 0.01). CONCLUSION: Our results suggest that elevated diastolic, mean and systolic blood pressure are significantly associated with peri-intraventricular haemorrhage in preterm newborn infants. PMID- 7843201 TI - Intracerebral haemorrhages in surfactant treated neonates with severe respiratory distress syndrome: age at diagnosis, severity and risk factors. AB - Within a randomized European multicentre trial the time of onset, severity and progression of intracerebral haemorrhages (ICH) were investigated prospectively by serial cranial ultrasonography in 343 ventilated infants with severe respiratory distress syndrome (RDS) following instillation of single or multiple doses of a natural porcine surfactant (Curosurf). In 148/343 infants (43%) ICH was diagnosed (grade I or II: 22%, grade III or IV: 21%). In 26 cases (8%) ICH was present on the ultrasound scan prior to surfactant instillation at a median age of 6 h. Incidence and severity of ICH was similar after single- or multiple dose surfactant treatment. Using a logistic regression model the following risk factors predictive of ICH were defined: low birth weight, allocation to certain hospitals, vaginal delivery, Apgar score < or = 6, rectal temperature on admission < or = 36 degrees C, primary anaemia, acidosis prior to treatment, RDS grade IV in pre-treatment chest films and poor response to surfactant treatment. CONCLUSION: Our study provides supportive evidence that multiple doses of Curosurf do not increase the risk for ICH as compared to single-dose administration. PMID- 7843202 TI - Pharmacokinetics of recombinant human erythropoietin in children treated with continuous ambulatory peritoneal dialysis. AB - In children treated by continuous ambulatory peritoneal dialysis (CAPD) renal anaemia is preferably treated by intraperitoneal administration of erythropoietin, since subcutaneous administration is painful and frightening for the child. Pharmacokinetics of erythropoietin were studied in three groups of children treated by CAPD. In group subcutaneous (SC) (n = 5) erythropoietin was administered subcutaneously, whereas in group intraperitoneal 1 (IP1) (n = 8) and intraperitoneal 2 (IP2) (n = 8) erythropoietin was given intraperitoneally during a 12-h dwell. Group IP1 received erythropoietin in 20 ml/kg of dialysis fluid, while in group IP2 the hormone was added to only 50 ml of dialysate, irrespective of body weight. The median area under the curve (AUC) was 4064 mU.h/ml (range 2647-24357) in group SC, 1698 (570-5514) in group IP1 and 3577 (1225-6555) in group IP2. In comparison to group SC the AUC was significantly lower in group IP1 (Wilcoxon: P = 0.02). The difference between group SC and group IP2 was not statistically significant. CONCLUSION: In children on CAPD the resorption of erythropoietin after intraperitoneal administration, measured as AUC, is similar to subcutaneous administration, when erythropoietin is administered in 50 ml of dialysate. The dose needed to treat renal anaemia with erythropoietin administered intraperitoneally this way will have to be established in a therapeutic study. PMID- 7843203 TI - Renal tubular dysfunction following treatment with anti-epileptic drugs. AB - To evaluate renal side-effects of anti-epileptic medication in children, we performed a cross-sectional study of various aspects of renal function. We studied 59 patients from our outpatient clinic. They had been on anti-epileptic monotherapy for at least 3 months. None had a history of renal disease. Twenty three healthy children of the same age group served as controls. After collecting 24-h urine samples, glomerular function was derived from creatinine clearance and from the excretion of albumin. Proximal tubular function was investigated by the urinary excretion of alpha 1-microglobulin and of the tubular enzymes N-acetyl beta-D-glucosaminidase, alanine-amino-peptidase and fructose-1,6-di-phosphatase. Distal tubular function was examined by the 24-h excretion of Tamm-Horsfall protein. On treatment with carbamazepine (n = 27) and phenytoin (n = 8), the excretion of alpha 1-microglobulin was significantly increased, as compared with the healthy controls. On valproate (n = 20), ethosuximide (n = 9) and phenytoin (n = 8), therapies significantly increased excretion of N-acetyl-beta-D glucosaminidase. This must be interpreted as an indication of a functional disturbance of the proximal tubulus. The other parameters, indicating function of the glomerulus, loop of Henle and distal tubules did not differ from normal. CONCLUSION: Patients on anti-epileptic treatment with therapeutic drug levels may demonstrate minor signs of tubular dysfunction. These are probably insignificant from a clinical standpoint, but they should be considered in drug overdose. PMID- 7843204 TI - Normalisation of severe cranial CT scan abnormalities after biotin in a case of biotinidase deficiency. PMID- 7843205 TI - Rapid intravenous immunoglobulin infusions in children with idiopathic thrombocytopenic purpura. PMID- 7843206 TI - Intracardiac thrombosis associated with acquired protein C deficiency. PMID- 7843207 TI - Dexamethasone in meconium aspiration. PMID- 7843208 TI - Periureteral pheochromocytoma in a child. PMID- 7843209 TI - Do endomysial antibodies in connection with selenium deficiency contribute to pericardial effusions in coeliac disease? PMID- 7843210 TI - Hypothyroidism phenocopy in glycanosis CDG (carbohydrate-deficient glycoprotein syndrome) PMID- 7843211 TI - Age-related differences in basic cognitive processes: implications for work. AB - Negative relationships between age and proficiency in many basic cognitive processes have been well documented in the research literature, and there is also evidence that work performance is positively related to the efficiency of basic cognitive processes. It does not necessarily follow, however, that increased age is a handicap in most occupational situations, because experience may play an important role in moderating the influence of age on work performance. The relationships among age, experience, and performance both in basic cognitive tasks and in more complex work environments are briefly discussed. PMID- 7843212 TI - Career development: a life span issue. AB - One of the challenges for individuals pursuing a career throughout their life span is how to maintain a high level of professional competence. As the composition of the workforce changes, and new technologies are developed, workers are faced with changing job demands and pressures. A major issue for the 1990s is how long a worker's skills will remain current. With rapid technological changes, workers may find it necessary to update continually their knowledge, skills, and abilities or risk becoming obsolete. Factors such as individuals' motivation and attitudes and organizational climate can contribute to choices regarding career development. Current research on the factors that contribute to career development activities is reviewed, along with the impact of multiple career transitions throughout the life span. Interventions such as retraining and outplacement, which allow individuals in later life to continue work, change jobs, and further develop their careers, are also discussed. PMID- 7843213 TI - Employment opportunities for older adults: engineering design and research issues. AB - A challenge facing the engineering community is to find ways to integrate older people into the labor force. Despite laws regarding age discrimination and compulsory retirement, older people's participation in the labor force is declining. Unless strategies are developed to keep older people in the workforce, the issues of economic dependency and intergenerational equity are likely to become formidable in the near future. There are a number of areas where engineering applications can enhance older adults' employment opportunities. These include training, workplace and equipment design, and job design. An overview of current knowledge regarding aging and work is provided. Gaps in the knowledge base are identified as areas for research. Examples of how engineering can contribute to the integration of older people into work settings are presented. PMID- 7843214 TI - Heat tolerance and aging. AB - Work-heat tolerance has been reported to be generally lower in middle-aged and elderly men and women than in younger men and women. Some authors have suggested that physically fit older men have fewer decrements in performance during work heat stress than do less fit men of the same age. However, none of the studies matched older and younger individuals on any pertinent physiological or morphological variables. Recently, four different researchers have reported results of studies in which men or women differed in average age by 25 to 36 years but were matched for body weight, surface area, surface area: body weight ratio, percentage of body fat, and maximal aerobic power. Evidence from three of these studies indicated little impairment of the thermoregulatory system during acute work-heat stress or heat acclimation in these men and women, at least through the seventh decade of life. One of the four studies did indicate higher core temperatures and lower sweating rates in middle-aged women than in younger women after heat acclimation; however, the length of time the heat could be tolerated did not differ between these matched groups. These observations generally support the importance of aerobic fitness and other morphological factors to middle-aged and elderly individuals working or performing recreational activities in hot environments. PMID- 7843215 TI - The potential environment: home, technology, and future aging. AB - Two issues of technology and aging that need to be resolved before potential residential environments for older adults become habitable are (a) the extent to which technological advances that would support habitability are user-friendly to this population and (b) the extent to which retrofits or inclusions in new architecture are affordable. The notion that older people are uncomfortable with new technologies or unable to adapt to them does not seem credible, considering that all manner of electronic devices have been adopted by this cohort. Engineers wishing to apply new technologies to housing must consider the future needs of individual households. To the extent that most Americans will continue to prefer to age in place, methods of centralizing information systems must be developed, so that a wide range of services can be locally delivered. If electronic communication and control systems are to function on behalf of the elderly or disabled within the home, single-call backup and repair services, at a local level, must also be immediately available. Older people's priorities in daily living dictate what they need in terms of new technologies. PMID- 7843216 TI - Technology for seniors' living environment: directions for product development. AB - In May 1991, approximately 40 world experts on technology and aging were invited to Directions '91 in Winnipeg, Canada. The focus of the 3-day seminar was on living environments for seniors and on the research and development of products to meet the needs of an aging society. The built environment--furnishings and appliances, self-care, and leisure and recreation--was targeted in both plenary and breakout sessions. This article highlights the key concerns and recommendations developed at Directions '91. The "universal design" concept is stressed, particularly as it relates to our need to rethink the design of the built environment and the products that are currently being used by seniors seeking independence and dignity in their daily living. Consideration is also given to the physiological changes that occur in the natural process of aging and how these changes need to be accommodated in products designed for the living environment. PMID- 7843217 TI - Recommendations for environmental design research correlating falls and the physical environment. AB - The risk of falls by aging individuals (55 years or older) is increased by physical elements within the built environment. Many environmental factors are considered high-risk hazards that can lead to serious injuries such as hip fractures. This article lists the design features most often mentioned in the literature as possible contributing factors to falls that result in injury. In addition, recommendations for research to assist designers, architects, planners, facilities management teams, and health care providers in designing physical environments that meet the specific requirements of individual users are offered. With concrete empirical research, the risk of falls and consequent injuries can be reduced, making the built environment safer and more user-friendly. PMID- 7843218 TI - Interleukin-12 production by human polymorphonuclear leukocytes. AB - Human polymorphonuclear leukocytes (PMN) stimulated by lipopolysaccharide (LPS) produce interleukin-12 (IL-12). Both the free IL-12 p40 chain and minute amounts of the biologically active IL-12 p70 heterodimers are produced by PMN. Interferon gamma (IFN-gamma) enhanced the LPS-induced secretion of both the free IL-12 p40 chain and the p70 heterodimer by approximately fivefold. As observed for other IL 12-producing cell types, the ratio of free p40 chain to p70 heterodimer secreted by LPS-stimulated PMN was approximately 20:1. LPS induced a 100-fold increase of IL-12 p40 mRNA, but had minimal effect on p35 mRNA accumulation. IFN-gamma enhanced the LPS-induced accumulation of p40 mRNA and directly induced a several fold increase in the accumulation of p35 mRNA. Therefore, the combined effect of LPS and IFN-gamma induced sufficient expression of both p40 and p35 to attain production of the biologically active p70 heterodimer at physiologically relevant concentrations. The ratio between p40 and p35 mRNA abundance in PMN stimulated with both LPS and IFN-gamma was approximately 200:1, explaining the secretion of the free p40 chain in much higher concentrations than the p70 heterodimer. IL-10, an inhibitor of the production of various cytokines in PMN, also suppressed IL-12 mRNA accumulation and secretion by PMN. Because of the important immunoregulatory function of IL-12, in particular induction of IFN-gamma production and facilitation of T helper cell type 1 response, the ability of PMN to produce IL 12 suggests that neutrophils may play an active role in the regulatory interaction between innate resistance and adaptive immunity. PMID- 7843219 TI - Clearance of Sendai virus by CD8+ T cells requires direct targeting to virus infected epithelium. AB - Minimal numbers of CD8+ T cells are found in bronchoalveolar lavage (BAL) populations recovered from Sendai virus-infected mice that are homozygous (-/-) for a beta 2-microglobulin (beta 2-m) gene disruption. The prevalence of the CD8+ set was substantially increased in the pneumonic lungs of 8-12-week radiation chimeras made using substantially class I major histocompatibility complex (MHC) glycoprotein-negative beta 2-m (-/-) recipients and normal beta 2-m (+/+) bone marrow. Even so, the CD8+ (but not the CD4+) lymphocyte counts were still much lower than in the (+/+)-->(+/+) controls. The (+/+)-->(+/+) and (+/+)-->(-/-) chimeras cleared Sendai virus and potent virus-immune CD8+ cytotoxic T lymphocytes (CTL) specific for H-2Kb+viral nucleoprotein peptide were found in the BAL from both groups. However, following in vivo depletion of the CD4+ population, only the (+/+)-->(+/+) mice were able to deal with the infection. Similarly, adoptively transferred, H-2Kb-restricted CD8+ T cells from previously primed (+/+) mice also failed to clear virus from the lungs of (+/+)-->(-/-) chimeras infected within 2 weeks of reconstitution with bone marrow, though they were effective in the (+/+)-->(+/+) controls. Sendai virus-immune CD8+ T cells are thus unable to eliminate virus-infected beta 2-m (-/-) lung epithelial cells that might be thought to be expressing very small amounts of either isolated class I heavy chain, or class I MHC glycoprotein that has bound beta 2-m derived from beta 2-m (+/+) T cells or macrophages present in the pneumonic lung. Furthermore, the CD8+ CTL that are being exposed to beta 2-m (+/+) stimulators in the BAL population cannot operate in some bystander mode to clear virus from respiratory epithelium. PMID- 7843220 TI - Human eosinophils express a receptor for secretory component. Role in secretory IgA-dependent activation. AB - The existence of a functional receptor for secretory component (SC) on the eosinophil membrane might explain the preferential degranulation induced by secretory IgA (sIgA) when compared to serum IgA. Indeed, flow cytometry analysis revealed that purified human SC could bind to a subpopulation (4-59%) of blood eosinophils purified from 19 patients with eosinophilia. Binding of radiolabeled human SC could be competitively inhibited using unlabeled SC or secretory IgA but not with serum IgA or IgG. Immunoprecipitation and immunosorbent chromatography using human SC revealed the presence of a major component at 15 kDa in eosinophil extracts as well as in culture supernatants but not in neutrophils. The 15-kDa protein eluted from the human SC immunosorbent was able to bind to SC or to sIgA but not to serum IgA. Eosinophils preincubated with human SC or sIgA released eosinophil cationic protein (ECP) and eosinophil peroxidase (EPO) after addition of anti-SC or anti-IgA monoclonal antibody as respective cross-linking reagents. These results indicated that binding of free or complexed SC to human eosinophils could induce eosinophil degranulation. Furthermore, the dose-dependent inhibition by SC of mediator release induced by sIgA but not by serum IgA, suggested that the receptor for SC could be involved in the preferential degranulation mediated by sIgA. These results indicate a novel pathway of eosinophil activation and its potential involvement in mucosal immunity, particularly in inflammatory diseases associated with infiltration of eosinophils and the enhanced production of sIgA. PMID- 7843221 TI - Involvement of the interleukin-2 receptor gamma subunit in interleukin-4 dependent activation of mouse hematopoietic cells and splenic B cells. AB - Interleukin-4 (IL-4) has various activities on B cells and on hematopoietic cells. We previously reported that TUGm2, a monoclonal antibody to the gamma subunit of the IL-2 receptor (IL-2R gamma), inhibited IL-4-dependent proliferation of CTLL2, a cytotoxic T cell line. We proposed that IL-2R gamma is required for the functional IL-4 receptor (IL-4R) in T cells. In the present work, we further examined whether or not IL-2R gamma is involved in IL-4R function in mouse myeloid cell lines and splenic B cells. TUGm2 suppressed the IL 4-induced proliferation of BA/F3 or IC2 cells, as well as of purified splenic B cells. TUGm2 partially suppressed proliferation of B cells induced by the combination of IL-4 and anti-immunoglobulin M (IgM) antibody. In contrast, TUGm2 had no effect on proliferation of B cells induced by anti-IgM antibody alone or lipopolysaccharide (LPS). TUGm2 also inhibited IgE production induced by IL-4 of LPS-stimulated B cells. The induction of major histocompatibility complex class II molecules or CD23 by IL-4 was virtually unaffected by TUGm2 antibody. These results indicate that IL-2R gamma is differentially involved in various IL-4 dependent reactions. PMID- 7843222 TI - Regulation of non-classical protein kinase C isoenzymes in a human T cell line. AB - We have examined the expression and responses to activation, of novel/atypical protein kinase C (PKC) isoforms epsilon, zeta, and delta in the T cell lymphoma cell line K-4. The effects of 1-h phorbol 12-myristate 13-acetate (PMA) and OKT3 activation of K-4 cells on PKC isoform distribution were examined. In addition, the effects of PMA-mediated down-regulation on the expression of PKC epsilon and zeta were determined using high concentrations of PMA over 24- and 48-h time periods in these cells. PKC zeta expression was not altered by incubation of K-4 cells with up to 200 ng/ml PMA over a 24- or 48-h period. PKC epsilon was down regulated in a concentration-dependent manner by PMA after both 24- and 48-h of activation. Expression of PKC epsilon was not completely depressed, however, even at the highest concentration of the phorbol ester after 48-h incubation with PMA. The presence of PKC epsilon, zeta, and delta was confirmed by immunohistochemistry with distinct patterns of expression observed. PMA-induced PKC activation for a 1-h period resulted in a translocation of PKC delta from resting cytoplasmic/nuclear staining to a cytoplasmic aggregate. Following 1-h activation through the T cell receptor-associated complex CD3, PKC delta translocated from a peri-nuclear/cytoplasmic compartment to a putative cytoskeletal location in K-4 cells. This translocation was time dependent and redistributed to a cytoplasmic aggregate prior to the cytoskeleton. Similarly, following 1-h activation through the T cell receptor, PKC zeta redistributed directly to what is possibly a cytoskeletal cell compartment. The cytoplasmic distribution of PKC zeta was unaltered following activation with PMA over a 1-h time period. There was no apparent redistribution of PKC epsilon cytoplasmic staining pattern following a 1-h direct or indirect activation. These results underline the differences in individual PKC isoform distribution, and responses to different stimuli, thereby providing additional evidence for the use of discrete PKC isoform signaling pathways in T cells. Furthermore, this data underlines the differences in PMA-mediated PKC activation and activation through the T cell receptor. PMID- 7843223 TI - T helper subset involvement in two high antibody responder lines of mice (Biozzi mice): HI (susceptible) and HII (resistant) to collagen-induced arthritis. AB - CD4+ T helper cells play a critical role in the chronicity of collagen-induced arthritis (CIA) in mice. The present results focus on the involvement of Th1 and Th2 subsets at the initial stage of the experimental disease in two lines of mice selected for high antibody production: HI that is susceptible, and HII that is resistant to CIA. Both lines are known to be H-2q, display an identical full set of V-beta genes, and mount similar antibody responses to both heterologous and autologous CII. The kinetic analysis of local T cell and anti-bovine CII antibody responses was followed by Elispot assays, the production of interferon-gamma (IFN gamma) and IgG2a being considered indicative of a Th1 profile, and interleukin-5 (IL-5) as well as IgG1-IgE, of a Th2 profile. The number of IL-5 Elispots is constantly higher in susceptible than in resistant mice. The IFN-gamma production is rather low in HI compared to HII, and besides, preferential help is observed for the Th2-dependent IgG1-IgE isotype-producing B cells in HI, while a switch over toward IgG2a anti-CII isotype is found in HII. These results suggest that a Th1 preeminence at the onset of the anti-CII response is decisive in the resistance to CIA. PMID- 7843224 TI - CD4 T cells inhibit in vivo the CD8-mediated immune response against murine colon carcinoma cells transduced with interleukin-12 genes. AB - Retroviral-mediated cytokine gene transfer into tumor cells is a highly effective way of inducing tumor inhibition and immunity. We analyzed the tumorigenicity of C-26 murine colon carcinoma cells transduced with genes encoding the two subunits of murine interleukin-12 (IL-12) in a polycistronic retroviral vector and selected for resistance to G418 and for IL-12 production (30-80 pg/ml). BALB/c mice injected s.c., i.v. and intrasplenically with C-26/IL-12 cells from three different IL-12-producing clones showed delayed tumor onset as compared with mice injected with control NeoR-transduced or parental tumor cells. Although C-26/IL 12 tumor-bearing mice eventually died of lung metastasis, their survival time was twice as long as that of mice injected with control cells. In experiments with mice selectively depleted of natural killer (NK) cells before tumor cell injection, the time of tumor onset and survival of mice injected with C-26/IL-12 s.c. and i.v., respectively, was reduced. CD8+ T cell depletion had no effect on latency or survival, whereas removal of CD4+ T cells led to C-26/IL-12 tumor regression in about 40% of mice. Histological and immunocytochemical characterization of leukocytes infiltrating C-26/IL-12 tumors showed only slight infiltration with few T cells in non-depleted mice but abundant infiltration by CD8+ T cells and asialo-GM1+ NK cells in tumors of mice depleted of CD4+ T cells. The lack of CD8+ T cell infiltration is not due to a CD4-mediated suppression of their activation because irradiated C-26/IL-12 cells primed for the induction of a strong cytotoxic T lymphocyte response against C-26 parental cells and induced CD8+ effector cells that protected against C-26/IL-12 in a Winn assay. Rather, the results suggest that, although C-26/IL-12 cells injected in vivo stimulate both NK and CD8+ T cells, tumor infiltration by the latter is inhibited by CD4+ T cells. PMID- 7843225 TI - Enhanced tumor necrosis factor suppression and cyclic adenosine monophosphate accumulation by combination of phosphodiesterase inhibitors and prostanoids. AB - We investigated cooperative effects of phosphodiesterase (PDE) inhibitors and prostanoids on cyclic adenosine monophosphate (cAMP) accumulation and tumor necrosis factor (TNF)-alpha synthesis in human peripheral blood mononuclear cells (PBMC). PDE inhibitors alone induced only a small increase in cAMP levels in lipopolysaccharide (LPS)-stimulated PBMC. Cicaprost (a stable analogue of prostacyclin) and pentoxifylline added simultaneously to LPS-stimulated PBMC (2.0 x 10(6)/ml) induced a rapid increase of cAMP to a level of 100 nM that peaked within 10 min and remained at a plateau for up to 4 h. Thus combined prostanoids and PDE inhibitors enhanced cAMP accumulation. TNF-alpha suppression in the presence of pentoxifylline and prostanoids exceeded that of either drug alone. The potency of different PDE inhibitors (theophylline, pentoxifylline, penthydroxifylline, albifylline, torbafylline, A 80 2715, amrinone and rolipram) to increase cAMP levels in combination with cicaprost was evaluated after 1 h of incubation. The dose-dependent increase of cAMP for all PDE inhibitors tested in this combined stimulation provided a useful tool for evaluating the potency of PDE inhibitors on cAMP accumulation. The effective concentration of PDE inhibitors, which raised cAMP levels to 300% of control, (EC300), correlated with the IC50 for TNF-alpha suppression (r = 0.930, p = 0.007, with theophylline excluded from the analysis). Interestingly, by contrast, the specific type IV PDE inhibitor rolipram caused only a moderate rise of accumulated cAMP in the same cells. Our data support cAMP as an essential mediator for TNF-alpha suppression by PDE inhibitors. Furthermore, an enhanced inhibiting effect on TNF-alpha production may prove therapeutically advantageous. It may occur in inflammatory and infectious diseases in vivo, since high levels of endogenous prostaglandins are liberated in these conditions. PMID- 7843226 TI - Co-ligation of ICAM-1 (CD54) and membrane IgM negatively affects B cell receptor signaling. AB - A possible role of intercellular adhesion molecule 1 (ICAM-1, CD54) in transmembrane signaling was investigated in B cells from the Burkitt lymphoma cell line MTLM4. Cross-linking of membrane IgM (mIgM) induced an increase in intracellular free Ca2+ as a result of the release from intracellular stores and an influx of extracellular Ca2+. When the B cells were incubated with limiting concentrations of anti-IgM, co-ligation of mIgM and CD54, but not CD19, resulted in an inhibition of the Ca2+ response. Separate cross-linking of mIgM and CD54 under these conditions, using isotype mismatched monoclonal antibodies (mAb), did not affect the mobilization of Ca2+. The CD54-mediated inhibition of the Ca2+ response was also observed in the absence of extracellular Ca2+. All CD54 mAb tested (F10.2, F10.3 and F7.11) interfered with mIgM signaling. The results presented in this report imply that CD54 is linked to intracellular signaling pathways and, via co-ligation with mIgM, interferes in the release of Ca2+ from intracellular stores. PMID- 7843227 TI - Hydrogen peroxide as a potent activator of T lymphocyte functions. AB - During inflammatory processes infiltrating cells produce large amounts of reactive oxygen intermediates (ROI). Increasing evidence suggests that ROI besides being cytotoxic may act as important mediators influencing various cellular and immunological processes. In this study, we have investigated the effects of hydrogen peroxide on several aspects of lymphocyte activation. In ESb L T lymphoma cells, micromolar concentrations of hydrogen peroxide rapidly induced activation of the transcription factor NF-kappa B, whereas DNA-binding activity of the transcription factor AP-1 was virtually not affected. In addition, hydrogen peroxide induced early gene expression of interleukin-2 (IL-2) and the IL-2 receptor alpha chain. The stimulation of IL-2 expression was found to be conferred by a kappa B-like cis-regulatory region within the IL-2 gene promoter. In contrast to these activating effects, addition of hydrogen peroxide was largely inhibitory on cell proliferation which is consistent with a general requirement of thiol compounds for lymphocyte proliferation. However, hydrogen peroxide significantly increased T cell proliferation when applied for a short period under reducing conditions. These data indicate that ROI may act as an important competence signal in T lymphocytes inducing early gene expression as well as cell proliferation. PMID- 7843228 TI - Selective enhancing effect of the Yaa gene on immune responses against self and foreign antigens. AB - The BXSB Y chromosome-linked mutant gene, Yaa, accelerates the progression of a lupus-like autoimmune syndrome only in mice that are predisposed to autoimmune diseases. Unlike the lpr gene, which causes the defects in the Fas antigen mediating apoptosis, the autoimmune enhancing activity of the Yaa gene is selective, depending on autoantigens, and varies among lupus-prone mice. To obtain a better definition of the role of the Yaa gene in the acceleration of autoimmune disease, we have investigated immune responses to several foreign antigens to determine whether the Yaa gene is able to potentiate immune responses to foreign antigens in a selective manner. We report here that the Yaa gene potentiated immune responses against foreign antigens only in mice which are genetically (H-2-linked) low responding, but not high or non-responding. Moreover, studies on Yaa(+)-Yaa- double bone marrow chimeric mice revealed that B cells from Yaa+ mice were selectively stimulated to produce antibodies to low responding antigen, human IgG, while both B cell populations similarly responded to high-responding antigen, ovalbumin. Our results suggest that first, the selective immune enhancing activity of the Yaa gene may be related to differences in the capacity of T helper cells specific for given self or foreign antigens; and second, a specific cognate interaction of T helper cells with Yaa+ B cells is apparently responsible for the selective enhancement of immune responses to antigens, to which mice are genetically low responding. PMID- 7843229 TI - Differential reactivity of residual CD8+ T lymphocytes in TAP1 and beta 2 microglobulin mutant mice. AB - TAP1 -/- and beta 2-microglobulin (beta 2m) -/- mice (H-2b background) express very low levels of major histocompatibility complex (MHC) class I molecules on the cell surface. Consequently these mice have low numbers of mature CD8+ T lymphocytes. However, TAP1 -/- mice have significantly higher numbers of CD8+ T cells than beta 2m -/- mice. Alloreactive CD8+ cytotoxic T lymphocyte (CTL) responses were also stronger in TAP1 -/- mice than in beta 2m -/- mice. Alloreactive CTL generated in TAP1 -/- and beta 2m -/- mice cross-react with H-2b expressing cells. Surprisingly, such cross-reactivity was stronger with alloreactive CTL from beta 2m -/- mice than with similar cells from TAP1 -/- mice. The beta 2m -/- mice also responded more strongly when primed with and tested against cells expressing normal levels of H-2b MHC class I molecules. Such H-2b-reactive CD8+ CTL from beta 2m -/- mice but not from TAP1 -/- mice also reacted with TAP1 -/- and TAP2-deficient RMA-S cells. In contrast, H-2b-reactive CD8+ CTL from neither beta 2m -/- mice nor TAP1 -/- mice killed beta 2m -/- cells. In line with these results, beta 2m -/- mice also responded when primed and tested against TAP1 -/- cells. We conclude that the reactivity of residual CD8+ T cells differs between TAP1 -/- and beta 2m -/- mice. The MHC class I deficient phenotype of TAP1 -/- and beta 2m -/- mice is not equivalent: class I expression differs between the two mouse lines with regard to quality as well as quantity. We propose that the differences observed in numbers of CD8+ T cells, their ability to react with alloantigens and their cross-reactivity with normal H 2b class I are caused by differences in the expression of MHC class I ligands on selecting cells in the thymus. PMID- 7843230 TI - Biphasic control of nuclear factor-kappa B activation by the T cell receptor complex: role of tumor necrosis factor alpha. AB - The regulation of nuclear factor (NF)-kappa B activation by the T cell receptor (TcR)/CD3 complex in primary human T cells has been studied at various times after activation. Only p50 NF-kappa B protein bound the kappa B element of interleukin-2 receptor (IL-2R) alpha chain promoter on resting T cells. However, immediately after TcR/CD3 cross-linking (after approximately 1 h; immediate) binding of p50.p65 heterodimers was observed. p50.c-rel heterodimers were also detected bound to this sequence at early time points (7-16 h; early), and both remained active at later time points (40 h; late) after activation. This regulation takes place mainly at the level of nuclear translocation of p65 and c rel, at immediate and early time points. Activation also induced c-rel and p105/p50 mRNA synthesis, but not p65 mRNA whose expression was constitutive. Interestingly, all those early and late events, but not the immediate ones, were inhibited by a neutralizing anti-tumor necrosis factor alpha (TNF-alpha) monoclonal antibody. Similarly, cycloheximide prevented the p65 and c-rel translocation and consequent formation of active binding heterodimers, at early and late times. Cyclosporin A impaired not only early and late, but also immediate events; however, addition of TNF-alpha prevented all inhibition. These results indicate that the regulation of NF-kappa B activation during T cell activation by TcR/CD3 signals is biphasic: TcR/CD3 triggers its immediate translocation, which is transient if no TNF-alpha is present. TNF-alpha, therefore, emerges as the main factor responsible for a second phase of NF-kappa B regulation, controlling both translocation of p65 and c-rel, and new mRNA synthesis for c-rel and p105/p50. PMID- 7843231 TI - Isotype exclusion in lambda 1 transgenic mice depends on transgene copy number and diminishes with down-regulation of transgene transcripts. AB - We have compared expression of the endogenous kappa and transgenic lambda 1 light chains in three lines of mice carrying one, four and eight copies of a lambda 1 transgene. We have found that in very young mice, even a single rearranged transgenic lambda allele excludes expression of the endogenous kappa loci. As the lambda 1 transgenic mice age, the proportion of lambda-positive cells decreases, as has been reported by others (Neuberger et al., Nature 1989, 338:350; Pettersson et al., Nature 1990. 344:165; Hagman et al., J. Exp. Med. 1989. 169:1911; Bogen and Weiss, Eur. J. Immunol. 1991. 21:2391). The decrease in lambda-positive B cells is accompanied by an increase in kappa-positive cells. We show that the decrease in B cells bearing surface lambda immunoglobulin depends on transgene copy number and occurs most rapidly in lower copy number lines. The decrease in surface lambda expression correlates with a dramatic decrease in the level of lambda mRNA in splenic B cells. Transgene down-regulation cannot be alleviated by stimulation of splenocytes with the mitogen lipopolysaccharide. These are the first data to establish that a single copy transgene can effect isotype exclusion. In addition, these results provide strong evidence that down regulation of transgene expression is controlled at the level of transcription, and that it is the level of expressed light chain that regulates isotype exclusion. PMID- 7843232 TI - Mouse interleukin-12 (IL-12) p40 homodimer: a potent IL-12 antagonist. AB - Interleukin-12 (IL-12) is a cytokine that has regulatory effects on T and natural killer (NK) cells and is composed of two disulfide-bonded subunits, p40 and p35. It was recently reported that supernatants from cultures of mouse IL-12 (moIL-12) p40-transfected COS cells could inhibit IL-12-dependent responses in vitro (Mattner, F., et al., Eur. J. Immunol. 1993. 23: 2202). We have further characterized the nature of the inhibitory substance. Purified mouse p40 produced in a baculovirus expression system was found to consist of two species: the p40 monomer and a disulfide-linked p40 dimer [(p40)2]. The (p40)2 was 25- to 50-fold more active than the p40 monomer in causing specific, dose-dependent inhibition of IL-12-induced mouse concanavalin A (Con A) blast proliferation and could also inhibit IL-12-induced interferon-gamma (IFN-gamma) secretion by mouse splenocytes and IL-12-dependent activation of mouse NK cells. Competitive binding studies on mouse Con A blasts showed that (p40)2 was equally effective as moIL-12 in competing with 125I-labeled moIL-12 ([125I]moIL-12) for binding to mouse Con A blasts. However, in contrast to moIL-12, mouse (p40)2 displayed little ability to compete with 125I-labeled human IL-12 (huIL-12) for binding to high-affinity IL 12 receptors (IL-12R) on human phytohemagglutinin (PHA) blasts and caused little or no inhibition of huIL-12-induced human PHA blast proliferation. Nonetheless, mouse (p40)2 was equally effective as moIL-12 in competing with [125I] huIL-12 for binding to COS cells transfected with the human IL-12R beta subunit and expressing low-affinity IL-12 binding sites. These results suggest that (i) the majority of the structural determinants required for binding of IL-12 to its receptor are contained within the p40 subunit, but p35 is required for signaling, (ii) the p40 subunit of IL-12 interacts with the beta subunit of IL-12R, and (iii) (p40)2 may be a suitable IL-12 antagonist for studying the role of IL-12 in various immune responses in vivo as well as in vitro. Further studies are required to determine whether or not (p40)2 is produced by normal lymphoid cells and is a physiologic regulator of IL-12 activity. PMID- 7843233 TI - Spleen cells from antigen-minimized mice are superior to spleen cells from germ free and conventional mice in the stimulation of primary in vitro proliferative responses to nominal antigens. AB - T lymphocytes from mice reared under conditions of differential exposure to food, environmental and microbial antigens were compared for phenotypic shifts that may be associated with prior exposure to antigens as well as functional variations in the ability to respond to antigens de novo. While the intra-epithelial CD8 T cell compartment was found to differ significantly in the type of T cell receptor predominantly expressed, CD4 T cells from various lymphoid organs of conventionally reared specific pathogen-free (CL-SPF) mice showed only subtle phenotypic differences from cells obtained from antigen-minimized germ-free (AF) and germ-free (GF) mice. Cells derived from mice exposed to a reduced antigen load exhibited primary in vitro proliferative responses to antigens such as dinitrophenyl-keyhole limpet hemocyanin which were significantly enhanced when compared with similar responses of cells from conventional mice. In cell mixing experiments, differences in the reactivity of T cells from the spleens of AF, GF and CL-SPF mice were dependent on the source of the spleen cells employed as antigen-presenting cells (APC). Experiments in which the T cell population was held constant revealed that, as APC, spleen cells from AF mice were most often superior to spleen cells from GF mice which were in turn considerably better than a similar population from SPF mice. We conclude that the enhanced primary reactivity of spleen cells from AF mice to nominal antigen in vitro is likely to be the result of a difference in the function and/or regulatory activities of the cell population employed as APC in this investigation. PMID- 7843234 TI - Insertion of a short human immunodeficiency virus (HIV)-2 gp36 sequence into an HIV-1 p24 recombinant protein results in a polypeptide with potent and TCRBV restricted T cell triggering activity. AB - In the present work we investigate whether artificial alterations of the structure of an inactive retrovirus-encoded protein could transform it in a superantigen. As a model system we used a recombinant human immunodeficiency virus (HIV)-1 p24 protein and two of its variants in which a short peptide corresponding to sequences of gp41 of HIV-1 (HIV-1 p24*) or gp36 of HIV-2 (HIV-1 2 p24*) has been inserted nearby the carboxy-terminal end of HIV-1 p24. As expected both HIV-1 p24 and HIV-1 p24* were inactive, while HIV-1-2 p24* was a potent inducer of human, but not murine, T cell proliferation. The possibility that the observed activity was due to contaminants was ruled out since the proliferative response could be specifically inhibited by a monoclonal anti-p24 antibody and by a peptide encompassing the area of HIV-1 p24/HIV-2 gp36 junction. Furthermore, the data exclude the possibility that the gp36 insertion is per se responsible for the observed proliferative activity. The analysis of the functional, phenotypic and molecular properties of the responding cells demonstrated that the response was class II dependent and that the activated cells were predominantly CD4+CD8- expressing a strongly biased repertoire of TCRBV segments. Collectively, these data strongly suggest that the HIV-1-2 p24* fusion protein shares common functional properties typical of superantigen molecules. Thus, our demonstration that a viral protein can be transformed into a superantigen simply by the insertion of a short peptide at the carboxy-terminal end has important implications for understanding the mode of action of retrovirus encoded superantigens. PMID- 7843235 TI - Effect of anti-V3 antibodies on cell-free and cell-to-cell human immunodeficiency virus transmission. AB - The present study was undertaken to compare the effects of a type-specific (HIV-1 MN) anti-V3 antibody on in vitro human immunodeficiency virus (HIV) infection of peripheral blood mononuclear cells in systems of cell-free versus cell-to-cell transmission of virus. Anti-V3 antibody completely prevented HIV-1 infection when cell-free virus was the sole mechanism of infection. A significant reduction of the neutralizing activity of the anti-V3 antibody was observed when infectivity was dependent on both cell-free and cell-to-cell mechanisms of infection. Furthermore, when cell-to-cell transfer of virions was the primary mechanism of HIV-1 infection, inhibition of HIV-1 infection was not observed. Therefore, a potent neutralizing antibody with a single epitope specificity failed to effectively control dissemination of a persistent HIV-1 infection in a system characterized predominantly by cell-to-cell transfer of virus. PMID- 7843237 TI - Macrophage inflammatory protein-1 alpha influences eosinophil recruitment in antigen-specific airway inflammation. AB - Allergic airway inflammation is characterized by peribronchial eosinophil accumulation within the submucosa of the airway of the lung. In the present study we have utilized a model of airway inflammation induced by intratracheal challenge with parasite (Schistosoma mansoni) egg antigen (SEA) in presensitized mice. The recruitment of neutrophils and eosinophils into the airway was found to be maximal at 8 and 48 h post challenge, respectively. Since macrophage inflammatory protein-1 alpha (MIP-1 alpha) has previously been found to be chemotactic for eosinophils, in vitro, we postulated that MIP-1 alpha was involved in the airway inflammation and more specifically in eosinophil recruitment into the airway. Initial studies demonstrated an increase in MIP-1 alpha mRNA expression at 8 h post-SEA challenge, as compared to vehicle-treated control mice. We next demonstrated a significant increase in MIP-1 alpha protein in the lungs of SEA-challenged mice at 8 h compared to control challenged mice, correlating to the mRNA data. Immunohistochemical staining of lungs from SEA challenged mice demonstrated MIP-1 alpha protein expression in airway epithelial cells, alveolar macrophages and in recruited mononuclear cell populations. Immunolocalization of MIP-1 alpha to cells within the bronchoalveolar lavage fluid demonstrated that macrophages and eosinophils stained positive for the protein. To determine the contribution of MIP-1 alpha expression to eosinophil accumulation, SEA-challenged mice were passively immunized with either neutralizing MIP-1 alpha antibodies or normal rabbit IgG, 3-4 h prior to the intratracheal SEA challenge. These studies demonstrated a > 50% decrease in eosinophil recruitment to the lungs and airway in animals receiving neutralizing MIP-1 alpha antibodies with no effect on early neutrophil recruitment. These results suggest that the production of MIP-1 alpha, induced by an antigen specific response, plays an important role in recruitment of eosinophils in this airway model of inflammation. PMID- 7843236 TI - Organ-specific autoimmunity induced by adult thymectomy and cyclophosphamide induced lymphopenia. AB - Autoimmune gastritis, a CD4+ T cell-mediated organ-specific autoimmune disease, can be induced by thymectomy of neonatal, but not of older, BALB/c mice. Here we have shown that autoimmune gastritis can also be induced in 6-8-week-old BALB/c mice by thymectomy combined with a single dose of cyclophosphamide (300 mg/kg). This treatment reduced the numbers of splenic T and B cells approximately 25 fold. However, by 8 days after treatment, the number of splenic lymphocytes had returned to normal adult levels. Approximately 50% of treated mice developed autoimmune gastritis after 10-12 weeks. These mice had mononuclear cellular infiltrates within the gastric mucosa and serum autoantibodies to the alpha and beta subunits of the gastric H+/K+ ATPase. Transgenic mice, expressing the gastric H+/K+ ATPase beta-subunit in the thymus (Alderuccio, F., Toh, B. H., Tan, S. S., Gleeson, P. A. and van Driel, I. R., J. Exp. Med. 1993. 178: 419), did not develop autoimmune gastritis after the adult thymectomy/cyclophosphamide treatment. Thus a T cell response to the H+/K+ ATPase beta-subunit is likely to be required for the onset of gastritis. These observations suggest that pathogenic autoreactive T cells exist in the periphery of normal adult mice and that autoimmunity can be induced by the activation of these autoreactive T cells following transient lymphopenia. Cyclophosphamide-treatment of adult mice without thymectomy did not induce autoimmune gastritis, suggesting thymic regulation of these pathogenic T cells. PMID- 7843238 TI - Anti-acetylcholinesterase antibodies display cholinesterase-like activity. AB - A monoclonal antibody (mAb) raised against human acetylcholinesterase (AChE) was found to have catalytic activity. A similar phenomenon was observed in a polyclonal antibody raised against the same antigen. The antibodies were demonstrated to be pure, and no contamination with either AChE or butyrylcholinesterase was found. Both antibodies hydrolyzed acetylthiocholine, an AChE substrate, and the mAb followed Michaelis-Menten kinetics. Six other mAb and one other polyclonal antibody showed no evidence of catalytic activity. This development of cholinesterase-like behavior by certain anti-AChE antibodies may have arisen by stable complexation of the enzyme with a substrate or inhibitor during antigen presentation. This phenomenon may have implications for the diagnostic measurement of AChE activity as well as in assessing the immunological reasons for the markedly raised AChE level in developmental conditions such as Hirschsprung's disease. PMID- 7843239 TI - Fibronectin induces phosphorylation of a 120-kDa protein and synergizes with the T cell receptor to activate cytotoxic T cell clones. AB - Fibronectin (FN) has been shown to act as a costimulator in both CD4+ and CD8+ T cell activation through the T cell receptor (TcR). Consistent with previous studies, we found that FN is able to both enhance the maximal amount of TcR triggered degranulation and lower the threshold for activation. The density of immobilized anti-CD3 or anti-TcR required to induce degranulation and tyrosine phosphorylation of cellular proteins by several cytotoxic T lymphocyte clones is quantitatively about tenfold lower in the presence of FN. We further demonstrate that FN alone stimulates transient tyrosine phosphorylation of a 120-kDa protein (pp120) in CD8+ T cells and when FN is coimmobilized with substimulatory amounts of anti-CD3 or anti-TcR there is a synergistic response, resulting in prolonged and enhanced phosphorylation of pp120. To determine if FN acts as a costimulator in CD8+ cells solely through mediating adhesion events or if it also transduces signals in T cells we conducted remote stimulation experiments. Degranulation was induced when FN and sub-stimulatory anti-CD3 were presented on separate surfaces, indicating that FN induces independent transmembrane signals capable of augmenting TcR-induced signals resulting in a functional response. Both FN plus TcR-induced tyrosine phosphorylation of pp120 and degranulation are inhibited by RGD-containing peptides, implying that an RGD-dependent FN receptor is mediating phosphorylation of pp120 and enhancing TcR-mediated degranulation. PMID- 7843240 TI - Immunoglobulin heavy chain germ-line JH-C mu transcription in human precursor B lymphocytes initiates in a unique region upstream of DQ52. AB - From human precursor B cells which had both immunoglobulin (Ig) heavy (H) chain loci in germ-line configuration, various IgH chain germ-line transcripts were isolated and sequenced. These transcripts were shown to contain sequences derived from the JH region, the IgH chain enhancer element or the Ig switch region. A number of isolated cDNA clones contained sequences at their 5' end that were derived from a single exon located just upstream of DQ52, designated the mu o' element. Sequence analysis of a 920-bp genomic DNA segment, containing the mu o' exon and its 5' flanking region, revealed the presence of various conserved motifs for DNA-binding proteins, such as E2A, Ets, NF-kappa B and AP-2, which have previously been found in the IgH and L chain enhancers. We propose that the activity of the mu o' element, resulting in germ-line transcription of the DQ52 JH gene segment, is required to generate full accessibility for the V(D)J recombinase. PMID- 7843241 TI - The alternative splicing of human Fc gamma RII mRNA is regulated by activation of B cells with mIgM cross-linking, interleukin-4, or phorbolester. AB - The human type two IgG binding receptors (Fc gamma RII) are encoded by three genes (Fc gamma RIIA, -B and C) resulting in at least six protein isoforms generated by alternative mRNA splicing. Surface expression of Fc gamma RII has been shown to be modulated during B cell activation, although data characterizing the isoform(s) expressed are not available. The extracellular as well as the transmembrane domains of various Fc gamma RII are highly homologous. Only the intracellular domains vary between the different Fc gamma RII isoforms, suggesting differences in signal transduction. Using reverse transcriptase and polymerase chain reaction of mRNA obtained from resting tonsil B cells, we show that the majority of Fc gamma RII mRNA species to be of b2 type, although b1 type and a low level of Fc gamma RIIa type are also present. Culturing the cells for 18 h in the presence of 2.5 U/ml interleukin-4 or 10 micrograms/ml affinity purified anti-IgM F(ab')2 fragments induced a switch in alternative splicing, resulting in a significant increase of Fc gamma RIIb1 mRNA expression, while the synthesis of Fc gamma RIIb2 mRNA was down-regulated. Stimulation of B cells with 100 ng/ml phorbol 12-myristate 13-acetate induced similar alteration, although only after 48-h treatment. The accumulation of Fc gamma RIIb1 and the reduction of both Fc gamma RIIb2 and Fc gamma RIIa mRNA in activated cells is accompanied by the enhanced expression of Fc gamma RII on the cell surface, representing most probably the Fc gamma RIIb1 isoform. Heat-aggregated IgG inhibited the anti-IgM induced proliferation of resting but not that of activated B cells, suggesting that aggregation of Fc gamma RIIb2 constitutively expressed on resting B cells might be responsible for the prevention of inadequate activation of resting B cells. PMID- 7843242 TI - Evolution of specific antigen recognition: size reduction and restricted length distribution of the CDRH3 regions in the rainbow trout. AB - The immunoglobulin heavy chain repertoire in fish was investigated by cloning a total of 88 rearranged VDJ junctions from the head kidney B cell mRNA of a salmonid, the rainbow trout (Oncorhynchus mykiss). Trout DH segments are short and cannot be classified into independent DH families. Several of the ten identified putative DH segments had stretches of nucleotide sequence identity with mouse (DQ52, DFL 16.2 and Dsp 2.1), human (DM1) and chicken (DH4) DH. There was a clear preference for one or two of the three putative DH reading frames and a stop codon is often present in the less used reading frame. Four of the six JH segments are preferentially used, and analysis of the VH-DH and DH-JH junctions suggest the presence of N-nucleotides. The absolute size and size heterogeneity of the rainbow trout CDRH3 are smaller than those of the Xenopus, mouse and human CDRH3. About 75% of the 84 in-frame trout CDRH3 have 8, 9 or 10 residues and none of them have more than 11 residues. This homogeneization of the CDRH3 loop size may partly explain the restricted antibody diversity in lower vertebrates. PMID- 7843243 TI - Lymphocytic CD43 and CD45 bear sulfate residues potentially implicated in cell to cell interactions. AB - CD43 is a major heavily glycosylated lymphocyte surface molecule. It has been shown to play an important role in lymphocyte activation and cell-cell interactions. Here we demonstrate that in human activated lymphocytes and CEM T cells, CD43 is a sulfated molecule. We also observed that CD45, another lymphocyte surface glycoprotein, is a sulfated molecule. 35SO4(2-) incorporation would thus appear to be an appropriate labeling method for CD43 and CD45 visualization. Moreover, we show that the level of cell surface protein sulfation can modulate CD43-mediated homotypic aggregation induced by CD43 monoclonal antibodies. It is well known that glycoprotein sulfation is required for various recognition phenomena. Since there are numerous potential sulfation sites on CD43 and CD45, these residues could play an important role in regulating cell-cell interactions. PMID- 7843244 TI - The effect of VH residues 6 and 23 on IgG3 cryoprecipitation and glomerular deposition. AB - MRL/lpr mice spontaneously develop a lupus-like autoimmune syndrome characterized by immunopathologic manifestations such as necrotizing vasculitis of the skin and glomerulonephritis. A feature of this autoimmune syndrome is the production of extremely large amounts of monoclonal IgG3 cryoglobulins. The structural basis of IgG3 cryoprecipitation is not well understood. Although the IgG3 isotype is necessary for cryoprecipitation, not all IgG3 antibodies cryoprecipitate. It has been postulated that electrostatic charge may be influential in cryoprecipitation. To investigate this problem, the VH and VL sequences of a panel of IgG3 cryoglobulins and non-cryoglobulins were compared, with particular attention to charged amino acid differences. At VH residues 6 and 23 the cryoglobulins were more positively charged than their non-cryoglobulin counterparts. To analyze further the effect of charge on cryoprecipitation, the sequence of an IgG3 monoclonal cryoprecipitating rheumatoid factor was modified by site-directed mutagenesis. The more positive residues at VH 6 and 23 present in some of the cryoglobulin antibodies were mutated to the more negative residues found in the non-cryoglobulins. The results show that VH residue 6 affects cryoprecipitation while residue 23 does not. When injected into normal BALB/c mice, the unmutated antibody produced glomerular immune deposits and focal glomerulonephritis, whereas loss of cryoprecipitability by mutating residue 6 completely abrogated glomerular immune deposition and glomerular injury. In contrast, the mutation at residue 23 which retains cryoprecipitability reduced glomerular immune deposition and prevented glomerular injury. PMID- 7843245 TI - Expression of interleukin-2 receptor gamma on human monocytes: characterization of lineage specific post-translational modifications. AB - Functional interleukin-2 receptors (IL-2R) on lymphocytes contain both IL-2R beta and gamma chains. Whereas constitutive expression of IL-2R beta has been found on monocytes, the expression of IL-2R gamma on these phagocytes has not been examined. We performed reverse-transcription-polymerase chain reaction with Southern blot analysis on RNA derived from purified human monocytes and discovered that they constitutively produce IL-2R gamma mRNA. Western immunoblotting revealed 58- and 64-kDa forms of IL-2R gamma on YT-1 and human monocytes, whereas 58-, 64-, and 69-kDa bands were detected using peripheral blood mononuclear cells and non-adherent lymphocytes. These different forms resulted from variable N-linked glycosylation since culture of the cells in tunicamycin resulted in detection of a single 39-kDa band which corresponds to the molecular weight predicted from the deduced amino acid sequence. By co immunoprecipitation, the IL-2R beta subunit associates with only the 64-kDa IL-2R gamma protein band in monocytes. PMID- 7843246 TI - The cytoplasmic tail of the T cell receptor zeta chain is required for signaling via CD26. AB - The protease dipeptidylpeptidase IV (CD26) provides an alternative activation pathway for T lymphocytes and is involved in several aspects of T cell function. Activation via CD26 requires the expression of the T cell receptor (TcR)/CD3 complex. Here we have investigated the role of the TcR zeta chain for T cell activation via CD26. T cell hybridomas expressing TcR with various deletions in the CD3 zeta chain were transfected with a CD26 cDNA and the response of the transfected cells to anti-CD26 monoclonal antibodies was tested. Our data show that the zeta chain is essential and that at least one YXXL motif in the cytoplasmic tail of the zeta chain is required for CD26-mediated signaling. Other TcR components do not replace the zeta chain. PMID- 7843247 TI - Stimulation of kappa transcription by a decamer-dependent, synergistic mechanism. AB - The intact SP6 kappa promoter stimulated transcription 30 times more efficiently than did a control promoter consisting of a TATA motif as the only promoter element. Mutation of the SP6 kappa promoter decamer in two positions reduced the transcriptional stimulation activity by over 90%. Promoters containing the SP6 kappa promoter octamer or a consensus octamer in front of a TATA box were ineffective immunoglobulin promoters and stimulated at the most 15% of maximal transcription. Identical results were obtained after transfection of untransformed mouse splenic B cells stimulated by lipopolysaccharide, that express high levels of Oct2A, or of S194 cells that express negligible levels of Oct2A. Selective mutations in the penta-decamer (pd), kappa Y or early B cell factor (EBF) elements of the promoter reduced transcriptional stimulation by 20 30% in untransformed B cells. In S194 plasmacytoma cells the EBF mutation was functionally silent while the kappa Y and pd mutations reduced transcriptional activation by 60-70% in this cell line. A mutation in a TATA-proximal E-box motif did not alter the functional activity of the promoter in either cell population. It can be concluded that kappa promoter function is highly dependent on complex interactions between individual promoter elements and that the decamer motif is pivotal for these interactions. The relative functional activity of a given promoter varied according to the target cell population used for the functional assay. PMID- 7843248 TI - Antigen-processing organelles from DRB1*1101 and DRB1*1104 B cell lines display a differential degradation activity. AB - We have developed an in vitro assay for tetanus toxin (tt) C fragment (C-fr) degradation. Purified endosomes (abbreviated endosomes 1101 or 1104) and lysosomes (abbreviated lysosomes 1101 or 1104) from the DRB1*1101 (Gly 86) and DRB1*1104 (Val 86) B cell lines were used to degrade 125I-labeled C-fr in vitro. Using three distinct methods of analysis, we show that the capacity of endosomes and lysosomes to degrade the tt C-fr or tt synthetic Y-P30 peptide differed. Using sodium dodecylsulfate-polyacrylamide gel electrophoresis, 125I-labeled C-fr degradation patterns observed either with endosomes 1101/1104 or lysosomes 1101/1104 are distinct both in terms of the number of fragments and the kinetics of generation of the fragments. These results were confirmed by high-performance liquid chromatography analysis, where we observed that the elution profiles of the 125I-labeled Y-P30 peptide digested by endosomes 1101/1104 were different compared to those obtained with lysosomes 1101/1104. Furthermore, the kinetics of degradation of 125I-labeled Y-P30 were faster with lysosomes 1104 than with lysosomes 1101. This difference in activity of the 1101 and 1104 organelles was also found in a functional assay where we showed that the activation capacity of the P30 peptide was diminished when digested by lysosome 1104, regardless of the antigen-presenting cell (APC) used, whereas endosomes 1101 or lysosomes 1101 modified P30 peptide in a form that discriminated between presentation by 1101 or 1104 APC. Taken together, these results suggest that the differential processing and presentation displayed by the DRB1*1101 and DRB1*1104 APC is due partly to a different enzymatic content and partly to the dimorphism at position DR beta 86. PMID- 7843249 TI - Differential effects of gangliosides on human IgE and IgG4 production. AB - The effects of gangliosides on human IgE and IgG4 production were studied. Of the various gangliosides tested, only GM2 and GM3 inhibited the IgE and IgG4 production induced by interleukin (IL)-4 plus hydrocortisone (HC), or that induced by IL-13 plus HC, in human surface IgE- and IgG4-negative (sIgE-, sIgG4-) B cells without affecting the production of IgG1, IgG2, IgG3, IgM, IgA1 or IgA2. In contrast, GM1, GD1a, GD1b, GD3, GT1b and GQ1b were without effects. The GM2- and GM3-mediated inhibition was specific, since each was blocked by a corresponding antibody. Of the various factors tested. IL-6, IL-10, and tumor necrosis factor (TNF)-alpha enhanced the IgE and IgG4 production induced by IL-4 plus HC or by IL-13 plus HC, while IL-8 and transforming growth factor (TGF)-beta inhibited these responses. However, only TNF-alpha counteracted the GM2- and GM3 mediated inhibition of IgE and IgG4 production, while IL-6, IL-10, anti-IL-8 monoclonal antibody and anti-TGF-beta antibody failed to do so. Anti-TNF-alpha monoclonal antibody, but not control IgG1, not only inhibited IgE and IgG4 production in the absence of TNF-alpha but also blocked the counteraction of inhibition by TNF-alpha. In cultures containing IL-4 plus HC or IL-13 plus HC. GM2 and GM3 specifically inhibited TNF-alpha production without affecting TNF alpha receptors, IL-6 production or IL-6 receptors. These results indicate that GM2 and GM3 inhibit IgE and IgG4 production by inhibiting endogenous TNF-alpha production. PMID- 7843250 TI - Activated T cells enhance nitric oxide production by murine splenic macrophages through gp39 and LFA-1. AB - Macrophages can be stimulated to produce a relatively large amount of nitric oxide, which is an important component in macrophage-mediated defense mechanisms and regulation of T cell activities. It has been known that T helper (Th) cell activation requires intimate physical interaction between T helper cells and macrophages and that cytokines from activated Th cells regulate macrophage activities including nitric oxide production. The current study indicates that surface molecules on activated Th cells also can synergize with cytokines to substantially enhance nitric oxide production by macrophages through cell-cell contact. The CD40 ligand (gp39) and LFA-1 appear to be two major contributors for T cell dependent nitric oxide production. PMID- 7843251 TI - Protein kinase C is not a downstream effector of p21ras in activated T cells. AB - The aim of this present study was to investigate the role of protein kinase C (PKC), downstream of p21ras, in activating interleukin-2 (IL-2) gene expression. It has been reported that PKC is an effector of p21ras in T cells. Data is presented, using the potent and selective PKC inhibitor Ro 31-8425 and transient expression of a constitutively active ras mutant, which clearly shows that PKC is not downstream of p21ras in the induction of NF-AT and AP-1 transcriptional activity and in the expression of IL-2 in human Jurkat T cells. Reporter gene experiments demonstrated that NF-kappa B transcriptional activity is not affected by expression of activated p21ras. The signaling pathways involving PKC activation, calcium mobilization and ras activation combine to provide the necessary components for production of IL-2 during T cell activation. PMID- 7843252 TI - Poor loading of major histocompatibility complex class II molecules with endogenously synthesized short peptides in the absence of invariant chain. AB - In normal antigen-presenting cells, newly synthesized major histocompatibility complex (MHC) class II molecules associate with the invariant chain (Ii) glycoprotein in the endoplasmic reticulum (ER). They are loaded with peptides only after proteolytic removal of the Ii in post-Golgi endocytic vesicles. Since the Ii inhibits peptide binding to MHC class II molecules, this association could protect MHC class II molecules from being loaded with endogenous peptides early after biosynthesis. If this were an important function of the Ii in vivo, MHC class II molecules synthesized in cells lacking the Ii should be loaded efficiently with short endogenous peptides in the ER; such peptides are known to be present there due to TAP-mediated import from the cytosol. To examine this possibility, we have studied peptide loading in HeLa transfectants expressing murine H-2Ak MHC class II molecules either alone or together with an excess of Ii. Endogenous peptides could readily be extracted from conformationally intact Ak alpha beta dimers of biosynthetically labeled Ii+ cells, whereas peptide loading was greatly (> 95%) diminished in the absence of Ii. Significant amounts of sodium dodecyl sulfate-(SDS) stable 55-kDa peptide: Ak complexes were only found in the Ii+ transfectants. In the absence of Ii, the MHC class II molecules instead formed stable complexes with long (20 and 50 kDa) polypeptides. Known Ak binding peptides bound stably to Ak molecules on Ii- cells, could be co-purified with them, and were resistant to release in SDS, suggesting that poor recovery of endogenous peptides was not due to decreased stability of Ak:peptide complexes in the absence of Ii. We conclude that protection of MHC class II molecules from endogenous short peptides does not appear to be a quantitatively important function of the Ii molecule, because peptide loading is inefficient in its absence. PMID- 7843253 TI - The influence of positive selection on RAG expression in thymocytes. AB - The expression of recombination activating gene (RAG) products, responsible for T cell receptor (TcR) gene rearrangement, is shut off during positive selection of thymocytes. The precise stage at which this down-regulation occurs remains somewhat controversial. We have analyzed RAG-1 expression in thymocytes of TcR transgenic mice carried on selecting versus non-selecting genetic backgrounds, both by in situ hybridization on thymus sections and by polymerase chain reaction amplification of RNA from sorted cells. The data from several transgenic lines indicate that RAG expression is already reduced in immature, cortical, CD4+CD8+ cells in the presence of positively selecting major histocompatibility complex molecules, although complete shut-off is not achieved until the mature, medullary, single-positive stage. This finding has practical and theoretical significance for studies on the mechanism of positive selection. PMID- 7843254 TI - Differential modulation of T helper type 1 (Th1) and T helper type 2 (Th2) cytokine secretion by prostaglandin E2 critically depends on interleukin-2. AB - Prostaglandin E2 (PGE2) favors T helper type 2 (Th2)-like cytokine secretion profiles in murine and human CD4+ T cells by inhibiting the production of the Th1 associated cytokines interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) and up regulating the production of the Th2-associated cytokines IL-4 and IL-5 in a dose dependent way. However, the potent inhibition of IL-2 production by PGE2 seems to be in contrast with the simultaneous up-regulation of IL-4 and IL-5 production, because the induction of these cytokines requires IL-2. We, therefore, investigated to which extent the net modulatory effect of PGE2 is determined by the availability of IL-2. To this aim, we examined the effects of PGE2 on the cytokine secretion profiles of a panel of human Th0 clones upon stimulation via different activation pathways, resulting either in high or low IL-2 production. The differential modulation of Th1 and Th2 cytokines by PGE2 was observed only upon modes of stimulation resulting in high IL-2 production. When IL-2 production was low, PGE2 inhibited the secretion of all four cytokines. These different modulation patterns were directly related to the IL-2 availability, because (i) neutralizing antibody to IL-2 abrogated the up-regulatory effect of PGE2 on IL-4 and IL-5 secretion in experiments with high endogenous IL-2 levels, (ii) lack of differential cytokine modulation by PGE2 in conditions with low levels of endogenous IL-2 could be restored with exogenous IL-2, and (iii) cell viability was comparable in all conditions. These results demonstrate that the net modulatory effect of PGE2 on the cytokine secretion profile of T cells critically depends on the availability of IL-2. Since this parameter varies with the experimental conditions and the T cell population studied, this finding may explain why certain immune responses may be either up- or down-regulated by PGE2 under different conditions. PMID- 7843256 TI - Distinct splicing of CD45 mRNA in activated rat gamma delta cytotoxic T lymphocytes. AB - Previous studies have demonstrated tumor- and allo-specific cytotoxic gamma delta T lymphocytes in rats. In this report we define the surface phenotype of these T cell receptor (TCR) gamma delta+ T cells and demonstrate distinct CD45 mRNA splicing in activated gamma delta cytotoxic T lymphocytes (CTL). gamma delta T lymphocytes in the blood and the peritoneal cavity were TCR alpha beta-CD3+CD8 alpha+CD45RC+ but expressed variable levels of LFA-1 molecules. Normal peritoneal gamma delta T lymphocytes, peritoneal gamma delta T cells from rats injected with the bacterial superantigen staphylococcal enterotoxin A (SEA) as well as gamma delta T lymphocytes in peripheral blood were all LFA-1low. Peritoneal gamma delta T cells from tumor-, and allo-sensitized rats were either LFA-1low or LFA-1high and specific cytotoxicity was highly enriched in the LFA-1high subset. No cytolytic activity against SEA-presenting cells was recorded in gamma delta T cells from SEA-injected rats. Different isoforms of CD45 in T cells are generated by alternative mRNA splicing of exons 4, 5, 6 (or A, B and C, respectively) and the recently described alternate exon 7. CD45 splicing in sorted gamma delta T cells was evaluated utilizing reverse transcription polymerase chain reaction. Normal peritoneal gamma delta T cells expressed exon(578), exon(678), exon(78) and the extensively spliced exon(8) variant. Peritoneal gamma delta T cells from rats sensitized with irradiated syngeneic tumor cells, allogeneic cells or bacterial superantigen SEA as well as gamma delta T lymphocytes in peripheral blood contained the full-length exon(45678), as well as the exon(5678), exon(578), exon(678) and exon(78) splicing products. Notably, the exon(8) variant was also seen in peritoneal gamma delta T cells of SEA-sensitized rats. Sorted tumor-specific LFA-1high gamma delta CTL expressed exon(45678), exon(5678), exon(578), exon(678) and exon(78) CD45 splicing products whereas the non cytolytic LFA-1low gamma delta T cell subset also contained exon(8) variant. In summary, it is concluded that antigen-specific TCR gamma delta+ CTL express high levels of LFA-1 and that the splicing machinery in these cytolytic cells favors expression of the exon(45678) and exon(5678) CD45 splicing products whereas the exon(8) variant is lost. TCR alpha beta+ CTL express high levels of LFA-1 but are devoid of the full-length exon(45678) splicing product. The different CD45 splicing patterns found in alpha beta CTL and gamma delta CTL indicate different molecular requirements in respect to CD45 during activation and differentiation of these T lymphocyte subsets. PMID- 7843255 TI - Experimental therapy of systemic lupus erythematosus: the treatment of NZB/W mice with mouse soluble interferon-gamma receptor inhibits the onset of glomerulonephritis. AB - Female NZB/W F1 mice develop an autoimmune disease similar to human systemic lupus erythematosus (SLE), and ultimately die of glomerulonephritis. Starting at the age of 16 weeks NZB/W F1 mice were treated for a period of 19 weeks with soluble interferon-gamma receptor (sIFN-gamma R), anti-IFN-gamma monoclonal antibody (mAb) or IFN-gamma. All mice treated with sIFN-gamma R or anti-IFN-gamma mAb were alive 4 weeks after the treatment was discontinued, whereas 50% of mice died in the placebo groups and 78% of the mice died in the IFN-gamma-treated group. Histologically, there was severe membrano-proliferative glomerulonephritis in IFN-gamma- and placebo-treated mice, and minimal or no mesangioproliferative disease in mice receiving sIFN-gamma R or anti-IFN-gamma mAb. The renal mononuclear infiltrate (T lymphocytes and monocytes), expression of major histocompatibility complex class II antigen and glomerular immunoglobulin and complement deposition were reduced in those mice. These data suggest that an IFN gamma inhibitor, such as the soluble IFN-gamma R, can be used for SLE therapy in the early stages of the disease. PMID- 7843257 TI - Host intestinal intraepithelial gamma delta T lymphocytes present during acute graft-versus-host disease in mice may contribute to the development of enteropathy. AB - We reported that T cell receptor (TcR) gamma delta intestinal intraepithelial lymphocytes (i-IEL) of host origin increased transiently, then decreased drastically at the early stage of non-irradiated acute graft-versus-host disease (GVHD) in mice. We investigated the role of the TcR gamma delta i-IEL of host origin in the pathogenesis of the intestinal lesions that occur during acute GVHD. The acute GVHD was induced in mice which had been depleted of TcR gamma delta by in vivo administration of hamster monoclonal antibody (mAb) against TcR gamma delta. Although the degree of splenomegaly after the induction of acute GVHD in mice treated with anti-TcR gamma delta mAb was similar to that in control mice treated with hamster anti-2,4,6-trinitrophenyl mAb, infiltration of donor derived T cells into the epithelium, and mitosis and apoptosis of crypt cells in the intestinal mucosa were dramatically suppressed in these mice. This suggest that host TcR gamma delta T cells in i-IEL contribute to the development of enteropathy in acute GVHD in mice. PMID- 7843258 TI - Cross-reactive trinitrophenylated peptides as antigens for class II major histocompatibility complex-restricted T cells and inducers of contact sensitivity in mice. Limited T cell receptor repertoire. AB - The induction of contact sensitivity in mice by hapten reagents such as trinitrochlorobenzene (TNCB) involves the activation of class II major histocompatibility complex (MHC)-restricted, hapten-specific, CD4+ T cells. Reports from different laboratories have indicated that the relevant antigenic epitopes in such reactions might include hapten-conjugated, MHC class II associated peptides. This study for the first time directly demonstrates that hapten-peptides account for the majority of determinants recognized by trinitrophenyl (TNP)-specific CD4+ T lymphocytes. The sequences of those TNP carrier peptides do not have to be related to mouse proteins. Thus, we show that TNP-modified peptides derived from mouse IgG, pigeon cytochrome c or staphylococcal nuclease known to bind to I-Ab or from lambda repressor with specificity to I-Ad as well as TNP-proteins such as bovine serum albumin, ovalbumin or keyhole limpet hemocyanin all create class II-restricted hapten determinants for a number of TNP-specific T cell clones and hybridomas. All of these cells were induced with cells modified by trinitrobenzene sulfonic acid (TNBS). In addition, we present arguments indicating that individual TNP-specific helper T cells may cross-react with different TNP-peptides bound to identical class II molecules. Chemical treatment of antigen-presenting cells with TNCB or TNBS may thus result in a limited number of particularly repetitive immunodominant hapten epitopes. Immunodominant epitopes were also indicated by an overrepresentation of the TCR elements V beta 2 and V alpha 10 in I-Ab/TNP specific T cells. Most importantly, however, we demonstrate that TNP attached to lysine 97 in the staphylococcal nuclease peptide 93-105 (i.e. a clearly "non self" sequence) is able to prime mice for subsequent elicitation of contact sensitivity by TNCB in the absence of foreign protein. We take this to indicate that those TNP-peptide determinants defined by us as immuno-dominant are responsible for the induction of contact sensitivity to haptens. PMID- 7843259 TI - Atypical beta-adrenoceptor in bovine adrenal medulla. AB - Bovine adrenal medullary membranes were incubated with [125I]cyanopindolol to assess beta-adrenoceptor binding. Binding was saturable and specific; a single low affinity site (Kd = 750 pM) was identified. [125I]Cyanopindolol binding was displaced by micromolar concentrations of classic beta-adrenoceptor antagonists and by sodium-4-[-2-[2-hydroxy-2-(-3-chloro-phenyl) ethylamino] propyl] phenoxyacetate. These data are similar to reported binding of beta 3 adrenoceptors and may explain beta-adrenoceptor agonist modulation of chromaffin cell degranulation in this catecholamine rich environment. PMID- 7843261 TI - Effect of cimetidine and omeprazole on gastric ulcer healing of rats with limited food intake time. AB - The effects of cimetidine, omeprazole and atropine sulfate on the healing of acetic acid-induced gastric ulcers in rats with limited food intake time (9:00 10:00 a.m. and 5:00-6:00 p.m.) were evaluated 15 days after the acid injection. Oral repeated administration of cimetidine (25-100 mg/kg twice daily) or omeprazole (10-50 mg/kg once daily) dose dependently accelerated ulcer healing. Atropine sulfate (10 mg/kg twice daily, p.o.) was ineffective. A single oral administration of omeprazole (50 mg/kg) or cimetidine (100 mg/kg) resulted in potent and long-lasting anti-acid secretory and gastrin-releasing actions. The degree and duration of anti-acid secretion by atropine sulfate were equal to those of cimetidine, but the elevation of gastrin release by atropine sulfate was weak and temporary. These results indicate that the gastric ulcers of rats with a limited food intake time are useful for evaluating the healing effects of cimetidine and omeprazole on gastric ulcers. In addition, the effects of both drugs may be related to the increased gastrin release rather than to the reduced acid secretion. PMID- 7843262 TI - Cimetidine and omeprazole accelerate gastric ulcer healing by an increase in gastrin secretion. AB - Daily oral administration of cimetidine or omeprazole markedly accelerated the healing of acetic acid-induced gastric ulcers in rats with a limited food intake time. The increased gastric acid secretion induced by daily treatment with histamine affected neither the spontaneous healing of the ulcers nor the healing promoting actions of both agents. Pretreatment of rats with ulcers with 6 hydroxydopamine significantly inhibited the increase in the antrum gastrin cells, serum gastrin levels and corpus mucosal thickness elicited by repeated administration of cimetidine or omeprazole. Pretreatment with 6-hydroxydopamine did not affect the inhibitory actions of cimetidine and omeprazole on acid secretion, but completely abolished the ulcer healing-promoting actions of both drugs. Daily intraperitoneal administration of pentagastrin accelerated ulcer healing. These results suggest that cimetidine and omeprazole mainly accelerate the healing of gastric ulcers by the trophic action of gastrin via the increase in gastrin secretion, while the inhibition of acid secretion may play a minor role in ulcer healing. PMID- 7843260 TI - Behavioral and neurochemical data suggest functional differences between dopamine D2 and D3 receptors. AB - In an in vitro model for mitogenic activity in cloned Chinese hamster ovary (CHO) cells expressing rat dopamine D2 or D3 receptors, the EC50D2/EC50D3 ratios for the agonists, apomorphine, (+)-3-hydroxy-N-n-propyl-phenylpiperidine ((+)-3-PPP), quinpirole, R-(+)-7-hydroxy-2-(di-n-propylamino)tetralin (R-(+)-7-OH-DPAT) and pramipexole (SND919) were found to be 0.36, 0.41, 1.3, 3.7 and 7.0, respectively. In locomotor activity experiments with actively exploring rats, the more dopamine D3 preferring agonists, R-(+)-7-OH-DPAT and pramipexole, were most efficacious to reduce locomotion. The hypoactivity was also observed at doses that did not affect brain dopamine synthesis rate (DOPA accumulation) or release (measured in in vivo dialysis experiments). In contrast, for apomorphine, (+)-3-PPP and quinpirole there was a closer correlation between doses that reduced exploratory activity and doses that reduced brain dopamine release and synthesis. The present data support the hypothesis that the functional dopamine D3 receptor is a postsynaptic receptor inhibitory on rat locomotion. PMID- 7843263 TI - Adenosine A1 and A2 receptor agonists alter cardiac functions and prostacyclin release in the isolated guinea-pig heart. AB - The actions of the adenosine A1 receptor agonist CCPA (2-chloro-N6 cyclopentyladenosine) and the adenosine A2 receptor agonist CGS 21680 (2-[p-(2 carboxyethyl(phenethylamino]-5'-N- ethylcarboxamidoadenosine) on myocardial functions and prostacyclin release were studied in Langendorff-perfused guinea pig hearts. In spontaneously beating hearts, perfused at constant pressure, CCPA reduced heart rate and left ventricular actively developed pressure with EC50 values of 54.4 +/- 8.7 nM and 81 +/- 6.2 nM, respectively. The adenosine A1 receptor antagonist PACPX (1,3-dipropyl-8-(2-amino-4-chloro)phenylxanthine, 1 microM) antagonized the effects of CCPA on heart rate and left ventricular actively developed pressure and increased the EC50 values 11-fold and 8-fold, respectively. CGS 21680 caused vasodilatation and doubled the coronary flow rate (EC50 of 5.77 +/- 3 nM). The potent but non-selective adenosine receptor antagonist CGS 15943A (9-chloro-2-(2-furanyl)-5,6-dihydro-1,2,4-triazolo(1,5 c)quinazolin++ +-5-imine, 0.1 microM) caused a shift to the right of the concentration-response curve of CGS 21680 for coronary flow rate and increased the EC50 value 52-fold. In electrically paced hearts, perfused at constant flow rate, CCPA (1-100 nM) and CGS 21680 (10-1000 nM) increased the 6-oxo prostaglandin F1 alpha release (stable non-enzymatic hydrolysis product of prostacyclin) into the cardiac effluent to a maximum of 170 +/- 16% and 184 +/- 6%, respectively. The effects of CCPA and CGS 21680 on cardiac functions indicate a high selectivity of both agonists for adenosine A1 and A2 receptor subtypes of the isolated guinea-pig heart, respectively. The elevation of 6-oxo-prostaglandin F1 alpha in the effluent of guinea-pig hearts by CCPA and CGS 21680 is possibly independent of stimulation of adenosine receptors on the vascular endothelium. PMID- 7843264 TI - Chronic haloperidol, but not clozapine, produces altered oral movements and increased extracellular glutamate in rats. AB - Rats administered chronic haloperidol or clozapine in their drinking water for 6 months were monitored for changes in oral movements using a computerized video analysis system. Haloperidol-treated animals exhibited late onset increases in small amplitude oral movements and an increase in the percentage of oral movements in the 1-2 Hz range, accompanied by a decrease in oral movements in the higher frequency range (> 6 Hz) as determined by fast fourier analysis. In contrast, clozapine-treated rats showed a decrease in medium-sized amplitude oral movements, but did not demonstrate significant changes in the distribution of oral movements across frequencies. Extracellular concentrations of gamma aminobutyric acid (GABA) and glutamate in the ventrolateral striatum were then assessed by intracranial microdialysis during oral drug administration and 3 days after drug withdrawal. Extracellular GABA and glutamate levels were not significantly different between groups during drug administration. However, 3 days after drug withdrawal, there was a significant increase in glutamate in the haloperidol-treated rats. No changes were noted for glutamate levels in clozapine treated rats or for GABA levels in either group following withdrawal. These results confirm the atypical profile of clozapine in an animal model of tardive dyskinesia and suggest that alterations in striatal glutamatergic function follow typical, but not atypical, antipsychotic drug administration. PMID- 7843266 TI - Dopamine depletion attenuates amphetamine-induced increases of cortical acetylcholine release. AB - The extent to which the d-amphetamine (2.0 mg/kg)-induced increase in cortical acetylcholine release is mediated by dopamine and/or noradrenaline was assessed using in vivo microdialysis in freely moving rats. Unilateral 6-hydroxydopamine lesions of the mesotelencephalic dopaminergic system, which depleted forebrain dopamine by 99% on the lesioned side, significantly attenuated the effect of d amphetamine on cortical acetylcholine release compared to a surgical control group (160% baseline vs. 270%), suggesting that dopamine at least in part mediates this effect of d-amphetamine. In contrast, bilateral 6-hydroxydopamine lesions of the dorsal noradrenergic bundle which depleted forebrain noradrenaline by at least 95% had no effect on d-amphetamine-stimulated cortical acetylcholine release. These results point to an important role for forebrain dopamine in the regulation of cortically projecting cholinergic neurons and fail to support the hypothesis that the ascending noradrenergic projections of the locus coeruleus are significantly involved. PMID- 7843265 TI - Differential relationships among dopamine transporter affinities and stimulant potencies of various uptake inhibitors. AB - Binding to the dopamine transporter and inhibiting dopamine reuptake are considered important factors in regulating behavioral effects of cocaine. One prominent behavioral effect of cocaine and other dopamine uptake inhibitors is the stimulation of locomotor activity. To examine the relationship between action at the dopamine transporter and behavior, the displacement of [3H]WIN 35,428 (CFT naphthalene sulfate; 2-beta-carbomethoxy-3-beta-(4-fluorophenyl)tropane-1,5 naphthalene disulfonate) binding in rat caudate putamen by cocaine and other uptake inhibitors was compared with stimulation of mouse locomotor activity. There was a significant correlation among affinities for binding and potencies for stimulating activity for cocaine and structurally similar compounds. For structurally dissimilar uptake inhibitors, however, there was no significant correlation among potencies for stimulation of activity and affinity for displacement of [3H]WIN 35,428 binding. These findings provide evidence that cocaine analogs may bind to the dopamine transporter in a manner that is fundamentally different from that for structurally dissimilar uptake inhibitors. PMID- 7843267 TI - Spermidine potentiates dizocilpine-induced impairment of learning performance by rats in a 14-unit T-maze. AB - The NMDA receptor, a ligand-gated ion channel complex, has been reported to be involved in memory processes. Learning is impaired following administration of dizocilpine, a non-competitive antagonist of the NMDA receptor. Polyamines, such as spermine and spermidine, interact with the NMDA receptor to enhance binding of dizocilpine, which blocks the ion channel. The present study assessed action of polyamines as modulators of learning via NMDA receptor activation. Dizocilpine (0.05 mg/kg) was given i.p. before maze learning, at a dose that produced a slight, nonsignificant impairment of maze learning. Pretreatment with 80 mg/kg but not 15 or 40 mg/kg spermidine (i.p.) before dizocilpine impaired maze learning compared to saline controls. Administration of 80 mg/kg spermidine without dizocilpine did not impair maze learning. The results are consistent with the view that systemic injection of a polyamine can modulate learning processes involving the NMDA receptor. PMID- 7843268 TI - Estimates of antagonist affinities at P2X purinoceptors in rat vas deferens. AB - In functional studies pyridoxalphosphate-6-azophenyl-2',5'-disulphonic acid (iso PPADS), suramin, GR200282 (4,4'-[carbonyl-bis(imino-3- benzoylimino)]-bis[5 hydroxy-naphthalene-2,7-disulfonic acid] tetrapotassium salt), cibacron blue, trypan blue and congo red, each produced specific antagonism of the contractile responses of isolated rat vas deferens, induced by alpha,beta-methylene ATP (alpha,beta-meATP), with antagonist pKB estimates of 6.6 +/- 0.3, 5.5 +/- 0.2, 5.1 +/- 0.3, 5.8 +/- 0.2, 4.7 +/- 0.2 and 4.6 +/- 0.2, respectively. In radioligand binding studies, iso-PPADS, suramin, cibacron blue, GR200282, trypan blue and congo red competed for the high affinity [3H]alpha,beta-meATP binding sites in rat vas deferens membranes with pKi estimates of 5.6 +/- 0.04, 5.5 +/- 0.08, 5.6 +/- 0.15, 5.6 +/- 0.04, 4.3 +/- 0.06 and 4.9 +/- 0.10, respectively. Comparison of pKB and pKi estimates revealed a good agreement between the two approaches for estimating measures of affinity for the putative antagonists, except in the case of iso-PPADS. However, we found that two populations of [3H]alpha,beta-meATP binding sites can be identified by iso-PPADS, 26.4% of these having low affinity (pKi of 4.4 +/- 0.2), and 73.6% having high affinity (pKi of 6.5 +/- 0.02) for iso-PPADS. The pKi of 6.5 obtained at the high affinity sites identified by iso-PPADS was close to the equivalent pKB value of 6.6 from functional studies. These studies therefore show a good agreement between pKB and pKi estimates for several antagonists, and suggest that the high affinity binding sites labelled with [3H]alpha,beta-meATP in rat vas deferens represents binding to functional P2X purinoceptors. PMID- 7843270 TI - Role of dorsal and median raphe nuclei in lower lip retraction in rats. AB - Induction of lower lip retraction after local infusion of the selective 5-HT1A receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) in the dorsal and median raphe nuclei was measured. Infusion of 8-OH-DPAT (2.5, 5 and 10 micrograms/rat) into the median raphe nucleus caused an immediate and dose dependent lower lip retraction. After infusion into the dorsal raphe nucleus a higher dose was needed. The lowest dose of 8-OH-DPAT that induced lower lip retraction was 10 micrograms/rat. Infusion of 8-OH-DPAT (10 micrograms/rat) into the pontine reticular nucleus induced the same degree of lower lip retraction as seen after infusion of the compound into the dorsal raphe nucleus. 8-OH-DPAT induced lower lip retraction was attenuated by s.c. injection of the preferential 5-HT2C receptor agonist m-chlorophenyl-piperazine. The results suggest that lower lip retraction is mediated by 5-HT1A receptors in the median rather than in the dorsal raphe nucleus. PMID- 7843269 TI - Characterization of the GABA autoreceptor in human neocortex as a pharmacological subtype of the GABAB receptor. AB - Release-regulating gamma-aminobutyric acidB (GABAB) autoreceptors were studied in synaptosomes from fresh specimens of human cerebral cortex. The K+ (12 mM)-evoked overflow of [3H]GABA was inhibited by the GABAB receptor agonists (-)-baclofen (EC50 = 1.48 microM) and 3-aminopropylphosphinic acid (3-APPA; EC50 = 0.034 microM). The effect of 10 microM (-)-baclofen was differentially reduced by the three GABAB receptor antagonists CGP 52432 ([3-[[(3,4 dichlorophenyl)methyl)amino]propyl]-(diethoxymethyl)- phosphinic acid), phaclofen and CGP 35348 (3-aminopropyl-(diethoxymethyl)- phosphinic acid). CGP 52432 was by far the most potent antagonist (IC50 = 0.09 microM). Phaclofen was about 700-fold less potent than CGP 52432 (IC50 = 70.0 microM) while CGP 35348 was ineffective up to 100 microM. The present results suggest that human and rat GABAB neocortical autoreceptors have similar pharmacological characteristics. PMID- 7843271 TI - Correlation of neuroendocrine and anti-edema activities of alanine-corticotropin releasing factor analogs. AB - Thirty-three ovine corticotropin-releasing factor (CRF) analogs, systematically substituted with alanine (Ala) residues, were tested for inhibitory activity on edema induced in the pentobarbital-anesthetized rat paw by heat (immersion in 58 degrees C water for 1 min). The activity of each analog, administered 0.1 mg/kg i.v. 10 min before heat, was compared to the rank order of the analog's potency in stimulating adrenocorticotropin (ACTH) release from cultured rat pituicytes. A strong positive rank correlation was found between the anti-edema and neuroendocrine activities of these analogs. PMID- 7843272 TI - Catching RNA polymerase I in Flagranti: ribosomal genes are transcribed in the dense fibrillar component of the nucleolus. PMID- 7843273 TI - Involvement of early and late lysosomes in the degradation of mannosylated ligands by rat liver endothelial cells. AB - The intracellular transport and degradation of endocytosed mannosylated albumin (Man-BSA) was studied in cell cultures of rat liver endothelial cells by subcellular fractionation, fluorescence microscopy, and electron microscopy. The ligand used for subcellular fractionation experiments was labeled with 125I labeled tyramine cellobiose or 131I-labeled tyramine cellobiose. The labeled degradation products are trapped in the degradative compartments and may therefore serve as markers for these compartments. Cell fractionation was performed using Nycodenz gradients. The cell fractionation experiments demonstrated that the ligand sequentially occupied three compartments of increasing density. After 15 min it was mainly found in large cisternal organelles that banded in the gradient at about 1.09 g/ml. These organelles were rab5 positive and showed a peripher distribution in the fluorescence microscope. Degradation of ligand started after 30-60 min and this coincided with its transfer to a electron lucent vesicle with a density of 1.12 g/ml. After > 1 h, degradation products started to accumulate in perinuclear, electron-dense lysosomes that banded in the gradient at 1.15 g/ml. The density distribution of lysosomal beta-acetylglucosaminidase coincided with the densest organelle. The results obtained show that the degradation of ligand takes place sequentially in two types of lysosomes. The early lysosome is an electronlucent vesicle of low density, whereas the terminal lysosome is an electron-dense organelle with higher density and a more perinuclear distribution. The main degradation of the ligand takes place in the early lysosome. The transfer of ligand and degradation products from the early to the late lysosome is slow. Texas red-labeled ovalbumin (OVA) coincided with lysosomes labeled with OVA-Bodipy 24 h in advance only after 4-6 h. PMID- 7843274 TI - Fibronectin receptor internalization and AP-2 complex reorganization in potassium depleted fibroblasts. AB - Potassium-depleted fibroblasts are unable to develop polarized morphology and lack coated pits. Experiments were carried out to measure internalization of fibronectin receptors (FNR) in potassium-depleted cells and possible association of FNR with AP-2 complexes after adding potassium back to the cells, which restores cell polarization. AP-2 complexes are the cell surface component of coated pits that contain both clathrin and membrane receptor binding domains. Potassium-depleted fibroblasts endocytosed antibody-tagged FNR and also internalized fluorescent fibronectin that previously had been adsorbed to the substratum. During cell polarization, antibody-tagged FNR reorganized into fibrillar structures along stress fibers beginning from nucleation sites at cell margins. Plasma membrane AP-2 complexes, which were undetectable in potassium depleted cells, reappeared at the cell surface above the nucleus and then spread toward the cell margins. The results show that endocytosis of FNR can occur at least partially by a coated pit-independent mechanism. PMID- 7843275 TI - Insulin and insulin-like growth factor I prevent the mitogenic response of chick limb bud mesoderm cells to platelet-derived growth factor-AA. AB - Platelet-derived growth factor AA (PDGF-AA) increases DNA synthesis by chicken limb bud mesoderm in culture. Preincubation of either mesoderm from whole limb buds (stage 24-25) or mesoderm from the distal tip of the bud (stage 25) in insulin or insulin-like growth factor type I (IGF-I) resulted in increased DNA synthesis compared to control levels in two different types of medium. However, no further increase in DNA synthesis was then induced by PDGF-AA. This was found even when the level of DNA synthesis in IGF-I or insulin-containing medium was below that seen in cells treated only with PDGF. The response to PDGF was not dependent on the presence of serum in the medium. Insulin and IGF-I inhibited expression of the PDGF alpha receptor in mesoderm from whole limb buds. However, this was detected at times after the increase in DNA synthesis in response to PDGF was normally seen. IGF-I did not inhibit expression of the PDGF alpha receptor in mesoderm from distal limb bud tips. Thus, IGF-I and insulin modify the response of limb bud mesoderm to PDGF. The effects of IGF-I and insulin on receptor expression may be dependent on the cell populations present but do not appear to account for modulation of the PDGF-induced mitogenic response. PMID- 7843276 TI - Developmental expression of D-galactoside-binding lectin in sea urchin (Anthocidaris crassispina) eggs. AB - The spatial and temporal expression of a sea urchin (Anthocidaris crassispina) egg lectin (SUEL) during early embryogenesis was studied using antiserum raised against SUEL. Western blotting analysis revealed the presence of SUEL in all stages so far examined, from unfertilized eggs to gastrula stage embryos. Immunofluorescence and immunoelectron microscopic observation showed that SUEL was stored in small electron-dense granules which migrated to the cortex within 10 min after fertilization. SUEL was localized in the cortical cytoplasm of the blastomere during cleavage stages and subsequently migrated to the outer surface of the embryo, including the invaginated portion of the gastrula. Immunoelectron microscopic study indicated that SUEL was deposited in the hyaline layer at least at the mid gastrula stage. Migration of SUEL to the cortex was significantly reduced by treatment with cytochalasin B, suggesting that actin filaments play an important role in this translocation. Exogenously added SUEL was adsorbed at the surface of unfertilized eggs and hatched embryos, but not to embryos with fertilization membrane. Lactose inhibited this adsorption, suggesting the presence of an endogenous glycoligand(s) specific for SUEL on the surface of unfertilized eggs and in the hyaline layer. We conclude that SUEL is secreted at a certain stage of embryogenesis and specifically adsorbed to the hyaline layer. Temporal changes in extraembryonic matrices caused by SUEL seem to play an important role in developmental morphogenesis. PMID- 7843277 TI - The time course of basic fibroblast growth factor expression in crush-injured skeletal muscles of SJL/J and BALB/c mice. AB - Staining for basic fibroblast growth factor (bFGF), a potent mitogen, was examined in muscle recovering from a crush injury and compared between two mouse strains with distinctly different capacities for muscle regeneration to determine if bFGF staining and the steps and outcome of repair were related. Immunofluorescence studies on intact and crushed tibialis anterior muscle were carried out at 0, 1, 3, 6, and 12 h postcrush in SJL/J mice, and at 1, 2, 3, 5, 7, and 11 days after injury in both SJL/J and BALB/c mice (n = 2-4). Disrupted fibers showed increased sarcoplasmic staining for bFGF as little as 3-6 h after injury prior to infiltration with intensely fluorescent mononuclear cells (at 12 24 h). Fiber bFGF was maintained in SJL/J muscles for 2 days, but was lower in most damaged fibers of BALB/c muscles at the same time. Surviving stumps of crushed fibers, once sealed, exhibited sarcoplasmic extensions, some of which stained intensely for bFGF. These processes appeared to connect adjacent fiber stumps, and many were noted in association with aligned mononuclear cells (presumptive myoblasts) at the site of new myotube formation. In representative sections there were more bFGF-positive mononuclear cells present in SJL/J than BALB/c muscles. Intense bFGF localization marked newly regenerating myotubes in both SJL/J and BALB/c muscles, and such myotubes were more frequent and larger in SJL/J muscles. More bFGF was present in regenerating muscles of SJL/J compared with BALB/c mice (with respect to damaged myofibers, mononuclear cells, and myotubes) and this correlates with the superior new muscle formation seen in SJL/J mice. These studies support the idea of a positive relation between bFGF in damaged fibers, the bFGF-positive mononuclear cells, and the speed and success of muscle regeneration. PMID- 7843278 TI - Enhanced expression of alpha v integrin subunit and osteopontin during differentiation of HL-60 cells along the monocytic pathway. AB - HL-60 cells, a promyelocytic leukemic cell line, provide a good model for studying the role of adhesion molecules and associated receptors involved in cell differentiation. When exposed to factors such as phorbol esters, these cells grown in suspension differentiate into monocytes and adhere to tissue culture dishes. In this study we showed that HL-60 cells exposed to phorbol esters express osteopontin (OPN), a cell adhesion molecule linked with osteoclast function. Moreover, the timed expression of OPN, in phorbol ester treated cells, was linked to increased cell adhesion. Subsequent to the expression of OPN, an increase in mRNA levels for alpha v integrin subunit was observed. The alpha v beta 3 integrin, a cell surface receptor found in high concentrations in osteoclasts, is considered to be a receptor for OPN. Furthermore, during differentiation we detected an increase in two cell surface markers specific for osteoclasts, 75B and 121F. This is the first report to demonstrate expression of OPN during differentiation of HL-60 cells, indicating that HL-60 cells can be used as a tool to enhance our understanding as to the role of OPN in cell differentiation. PMID- 7843279 TI - Differential aldehyde sensitivity of newly replicated chromatin from Drosophila melanogaster embryos. AB - By using a series of formalin concentrations we have found that high aldehyde levels in the fixation buffer of Miller spreads are correlated with the appearance of nonnucleosomal stretches in newly replicated chromatin of embryos from Drosophila melanogaster. These nucleosome-free gaps are found 0-500 nm behind the replication fork and do not correspond to naked DNA. The analysis of the distribution of nucleosome-free gaps on newly replicated DNA has revealed some structural details about the maturation of nucleosomes and provides direct evidence that parental nucleosomes have an altered structure at the replication fork. Finally, these stretches of nonnucleosomal chromatin are located in a trans disposition inside the active replicon, although there exists a considerable variability. PMID- 7843280 TI - Transcription factors and aldolase B gene expression in microdissected renal proximal tubules and derived cell lines. AB - Renal expression of the aldolase B isoenzyme and transcription factors previously shown to regulate the aldolase B gene promoter in the liver were analyzed in whole kidney, microdissected tubules, and the two PKSV-PCT and PKSV-PR proximal tubule cell lines derived from transgenic mice. Aldolase B gene expression appeared restricted to the proximal tubule, the site where HNF1 alpha, HNF1 beta, C/EBP alpha, and DBP transcripts were also abundant. Compared to the liver, another organ synthesizing aldolase B, proximal tubules from the kidney were characterized by the absence of HNF3 and the presence of higher ratio of HNF1 beta/HNF1 alpha transcripts. The same features were conserved in both PKSV-PCT and PKSV-PR proximal tubule cell lines. Transactivation experiments in PKSV-PCT cultured cells showed that HNF1 alpha, C/EBP alpha, and DBP behave as transactivators of the 190-bp aldolase B gene promoter, and that HNF1 beta had a low transactivating efficiency. HNF1 beta, as well as HNF3, antagonized the HNF1 alpha-dependent transactivation of the aldolase B promoter. The fact that both HNF1 beta and HNF3 factors play similar negative roles by competitively binding close to or on the HNF1 site could suggest that, in proximal tubule renal cells, HNF1 beta has the same attenuator effect on the aldolase B gene promoter as HNF3 in hepatocytes. Thus, these results indicate that such models of established renal tubule cell lines, which have conserved the same features of parental cells, represent valuable tools for studies of the regulation of genes expressed in proximal tubules of the kidney. PMID- 7843281 TI - Thrombin and phorbol ester induce internalization of thrombin receptor of human mesangial cells through different pathways. AB - Thrombin is a potent activator of human mesangial cells probably by activation of its functional receptor. Northern blot analysis demonstrates the presence of mRNA encoding the functional thrombin receptor in mesangial cells, and surface expression of thrombin receptor antigen has been confirmed by immunocytochemistry. Using 125I-labeled ATAP2, a monoclonal antibody against the functional thrombin receptor, we found that thrombin and thrombin receptor agonist peptide (TRAP) induce homologous internalization of thrombin receptor in a dose-dependent manner. Redistribution of thrombin receptor from the cell surface to vesicular structures in the cytoplasm has been followed by immunocytochemistry. Additionally, a dose-dependent loss of cell surface thrombin receptor is induced by phorbol 12-myristate 13-acetate (PMA), suggesting that thrombin receptor undergoes heterologous internalization in response to PMA. The time course of thrombin-induced receptor internalization is different from that observed with TRAP and PMA. Protein kinase C inhibitors, staurosporine and GF 109 203 X, do not affect thrombin receptor internalization induced by thrombin and TRAP but block receptor internalization stimulated by PMA. These data suggest that heterologous thrombin receptor internalization induced by PMA is mediated by protein kinase C. However, activation of protein kinase C is not responsible for homologous thrombin receptor internalization caused by thrombin and TRAP. PMID- 7843282 TI - An adherent cell model to study different stages of apoptosis. AB - Apoptosis in the classical thymocyte model occurs very rapidly making it difficult to study the intermediate steps in the process. An alternative adherent cell model is characterized and proposed in this paper. HT29 cells treated with a teniposide were collected at various times for morphological and biochemical assessments. Large DNA breaks (450-500, 350-400, 100-200 kb) were observed in these cells between 6 and 24 h. The larger DNA breaks appeared initially and in progression such that the smaller DNA break of 100-200 kb became apparent by 24 h. These changes in DNA corresponded with an increase in cell diameter and a gradual rounding and detaching of cells from each other but not from the tissue culture plates. The smallest DNA break of 23-50 kb appeared at 48 h and persisted throughout the 96 h of incubation. DNA ladders of 180- to 200-bp oligomers were also observed between 48 and 96 h and these coincided with the presence of small floating cells. Changes in cell adherence after teniposide treatment have permitted the consistent isolation of cells in four distinct morphological and biochemical stages of apoptosis: (1) "preapoptotic," (2) "swelling," (3) "rounding," and (4) "floating." The main advantages of this adherent cell model are: (1) apoptosis occurs very slowly (minimum of 48 h) permitting the observation of progressive changes; (2) cells from four stages of apoptosis can be used to study the sequence of events of other biochemical and genetic factors involved in the process; and (3) extracellular matrix proteins are present in this model so their participation in apoptosis, if any, can be determined. PMID- 7843283 TI - Induction, effects, and quantification of sublethal oxidative stress by hydrogen peroxide on cultured human fibroblasts. AB - Conditions to induce and parameters to evaluate sublethal oxidative stress of cultured human fibroblasts have been investigated in the attempt to identify markers for a more accurate quantification of cell injury. Sublethal oxidative stress was obtained by treating fibroblasts with 0.5 mM H2O2 in DMEM plus 5% FCS for times not exceeding 60 min. Under these conditions cells remained viable throughout long-term incubation, showing no appreciable release of cytosolic enzymes into the medium. On the contrary, exposures of fibroblasts to 0.5 mM H2O2 for times > 60 min induced a lethal cell injury which was fully expressed 2 days later by massive monolayer wasting and leakage of cytosolic components. Early metabolic effects of sublethal stress consisted of a rapid and significant fall of both ATP and NAD+ pools. Concomitantly, there was a moderate increase (about threefold) in both ADP-ribosyl transferase activity and free [Ca2+]i, while the specific activity of glyceraldehyde-3-phosphate dehydrogenase was partially decreased upon treatment. Oxidative injury also caused delayed effects consisting of a large depression of both protein and DNA synthesis. However, while the former was partially restored within 10 days of incubation, the latter remained severely impaired, as encountered in a growth-arrested population. Microfilaments of H2O2-treated cells appeared to be morphologically altered due to partial fragmentation of cytoskeleton actin which, however, was still maintained in the polymerized form as F-actin. Moreover, sublethally injured fibroblasts exhibited a reduced adhesiveness to plastic once they were detached and reseeded into new dishes. Relative adhesion efficiencies (number of adherent cells at 16 h as a percentage of seeded cells) were found to correlate inversely with times of exposure to H2O2. This finding allowed the identification of a biological parameter which showed itself to be very sensitive to oxidative stress and was also useful for developing an assay to grade sublethal injury to fibroblasts. PMID- 7843284 TI - Structure and growth-dependent regulation of the human cyclin B1 promoter. AB - As a step toward defining the signals important for the regulation of cyclin B1 expression, we cloned, sequenced, and partially characterized a 1012-bp genomic fragment encompassing the human cyclin B1 promoter. By transient expression experiments, we found that promoter activity resides within a -150/+182-bp DNA fragment. The activity of this promoter fragment was high in asynchronous NIH-3T3 cells, but dramatically decreased in quiescent cells. Time-course experiments, using stable transfectants expressing the CAT gene under the control of this fragment, were performed after releasing the cells from serum starvation. The results showed that the promoter becomes active at the end of the S phase and its activity increases during the cell cycle. Similar experiments performed with a shorter promoter region (-58/+182) showed that this 5' deletion mutant is active throughout the cell cycle. In good agreement with promoter activity, Northern analysis indicated that the endogenous gene is negatively regulated in quiescent murine NIH-3T3 cells. The data presented here demonstrate that in NIH-3T3 cells the cyclin B1 promoter is growth regulated, and important regulatory elements must exist in the region spanning -150 to -58 bp. PMID- 7843285 TI - Dimethyl sulfoxide suppresses apoptosis in Burkitt's lymphoma cells. AB - Previous reports have suggested that dimethyl sulfoxide (DMSO) may be a useful reversible G1 arresting agent for synchronizing Raji Burkitt's lymphoma cells (K. Takase et al. (1992) Cell Growth Differ. 3, 515-521; M. Sawai et al. (1990) Exp. Cell Res. 187, 4-10). We have therefore critically evaluated several aspects of DMSO's effects using Daudi and Ramos Burkitt's lymphoma (BL) cells. In BL cells starved in the presence or absence of DMSO for 4 to 6 days (approximately four to six doubling times), the following observations were noted: (A) Both Daudi and Ramos cells show increased cell synchrony accompanied by apoptosis when starved in RPMI 1640 supplemented with 10% fetal calf serum (FCS). Inclusion of 1.5% DMSO causes a diminution in apoptosis with minimal effects on synchrony. (B) Lowering the FCS concentration to 5% induces apoptosis. DMSO-mediated protection from apoptosis is observed in Daudi but not in Ramos. (C) When human serum (10%) is used instead of FCS, Daudi cells show no apoptosis and DMSO is without effect on cell cycle distribution. By contrast, Ramos cells show significant apoptosis, which is prevented by the inclusion of DMSO. (D) When starved in a chemically defined medium (AIM-V), both Daudi and Ramos cells show significant apoptosis. DMSO protects Ramos from apoptosis under these conditions. (E) Upon removal of DMSO, both Daudi and Ramos cells reenter the cell cycle but with significant apoptosis. (F) The protective effect of DMSO from apoptosis is observed in a narrow range of concentration between 1 and 2%. At higher concentration, DMSO itself induces apoptosis. These results suggest that DMSO itself prevents apoptosis, an effect which may present as an apparent effect on cell synchrony. PMID- 7843286 TI - Differences in dispersion of influenza virus lipids and proteins during fusion. AB - Digitally enhanced low-light-level fluorescence video microscopy and immunochemical staining were used to examine influenza virus envelope lipid and protein redistribution during pH-induced fusion. Video microscopy was performed using viruses labeled with either the lipid analogue octadecylrhodamine B (R18) or fluorescein isothiocyanate (FITC) covalently linked to envelope proteins. Viruses were bound to human red blood cells, and the pattern and intensity of fluorescence were monitored for 30 min while cell-virus complexes were perfused with pH 7.4 or 4.8 media at temperatures either above or below 20 degrees C. R18 showed complete redistribution and dequenching by 30 min at all incubation temperatures, confirming reports that viral fusion occurs at subphysiological temperatures. FITC-labeled protein showed spatial redistribution at 28 degrees C but no change at low temperature. Electron microscopy observations of immunochemical staining of viral proteins confirmed both that protein redistribution at 37 degrees C was slower than R18 and the failure of movement within 30 min at 16 degrees C. Video microscopy monitoring of RNA staining by acridine orange of virus-cell complexes showed redistribution to the RBCs at all temperatures but only after low pH-induced fusion. The results are consistent with differential dispersion of viral components into the RBC and the existence of relatively long-lived barriers to diffusion subsequent to fusion pore formation. PMID- 7843287 TI - Down-regulation of the cyclin A promoter in differentiating human embryonal carcinoma cells is mediated by depletion of ATF-1 and ATF-2 in the complex at the ATF/CRE site. AB - The human embryonal carcinoma cell line NEC14 can be induced to differentiate by the addition of N,N'-hexamethylene-bis-acetamide (HMBA). After treatment with HMBA, the level of cyclin A transcript decreased steeply, reaching less than one tenth of the original level by 48 h. The promoter elements concerned with this down-regulation were studied by using reporter genes and by analyzing DNA-protein complexes. The deletion of the sequence between -608 and -259 containing three GC boxes decreased the promoter activity to about a half, and further deletion up to -194, eliminating the ATF/CRE site, resulted in a decrease to about a tenth of the original level in undifferentiated NEC14 cells. These sequences were involved in down-regulation of the promoter activity in differentiation-induced NEC14 cells. DNA-protein complexes formed at the ATF/CRE site with extracts prepared from undifferentiated and differentiation-induced cells gave the same footprint, but showed different electrophoretic mobilities. The supershift assay with specific antibodies against ATF-1 and ATF-2 indicated that both factors were depleted in the complex after induction of NEC14 cell differentiation. Both the ATF/CRE site and GC boxes seemed to be also involved in up-regulation of the cyclin A promoter in growth-stimulated human fibroblasts at the G1/S boundary. PMID- 7843288 TI - Differences in the developmental fate of cultured and noncultured myoblasts when transplanted into embryonic limbs. AB - Myoblasts from embryonic, fetal, and adult quail and chick muscles were transplanted into limb buds of chick embryos to determine if myoblasts can form muscle fibers in heterochronic limbs and to define the conditions that affect the ability of transplanted cells to populate newly developing limb musculature. Myoblasts from each developmental stage were either freshly isolated and transplanted or were cultured prior to transplantation into limb buds of 4- to 5 day (ED4-5) chick embryos. Transplanted myoblasts, regardless of the age of the donor from which they were derived, formed muscle fibers within embryonic limb muscles. Transplanted cloned myoblasts formed muscle fibers, although there was little evidence that the number of transplanted myoblasts significantly increased following transplantation or that they migrated any distance from the site of injection. The fibers that formed from transplanted clonal myoblasts often did not persist in the host limb muscles until ED10. Diminished fiber formation from myoblasts transplanted into host limbs was observed whether myoblasts were cloned or cultured at high density. However, when freshly isolated myoblasts were transplanted, the fibers they formed were numerous, widely dispersed within the limb musculature, and persisted in the muscles until at least ED10. These results indicate that transplanted myoblasts of embryonic, fetal, and adult origin are capable of forming fibers during early limb muscle formation. They also indicate that even in an embryonic chick limb where proliferation of endogenous myoblasts and muscle fiber formation is rapidly progressing, myoblasts that are cultured in vitro do not substantially contribute to long-term muscle fiber formation after they are transplanted into developing limbs. However, when the same myoblasts are freshly isolated and transplanted without prior cell culture, substantial numbers of fibers form and persist after transplantation into developing limbs. Thus, these studies demonstrate that the extent to which transplanted myoblasts fuse to form fibers which persist in host musculature depends upon whether donor myoblasts are freshly isolated or maintained in vitro prior to injection. PMID- 7843289 TI - Estrogen reduces the excitability of the female rat medial amygdala afferents from the medial preoptic area but not those from the lateral septum. AB - Electrical stimulation of the medial amygdala (AMY) elicited antidromic action potentials in neurons in the preoptic area (POA) and the lateral septum (LS) of 36 urethane-anesthetized ovariectomized female rats, which were either treated with estrogen o not treated. The extracellular potentials from the two sites showed similar characteristics, with the exception of the sensitivity to estrogen: they had latencies between 3 and 35 ms. Thresholds were as low as 100 microA. The mean relative refractory period was 2.2 ms. The peak-to-peak amplitudes of the positive-negative biphasic potential ranged from 1.0 mV to 12.0 mV. Estrogen had site-specific effects on parameters of antidromic activation in the POA. Estrogen-treated rats had a significantly higher threshold (937 vs 664 microA) and a longer refractory period (2.5 vs 2.1 ms) than the ovariectomized rats (P < 0.05 for each). The effects were absent in the LS. Selective cutting of the stria terminalis diminished the AMY-induced antidromic responses in the POA and LS. Electrical stimulation of the stria blocked the AMY-induced antidromic potentials by collision. Thus, estrogen-sensitive POA efferents as well as non estrogen-sensitive LS efferents project to the AMY via the stria terminalis. Reductions in axonal excitability would inhibit neural conduction and transmission. Estrogen may therefore reduce the AMY inputs from the POA, without affecting those from the LS. Such alterations in the neural impulse flow may underlie estrogen-dependent neuroendocrine or behavioral regulation. PMID- 7843290 TI - The fixation area of the cat superior colliculus: effects of electrical stimulation and direct connection with brainstem omnipause neurons. AB - The superior colliculus has long been recognized as an important structure in the generation of saccadic displacements of the visual axis. Neurons with presaccadic activity encoding saccade vectors are topographically organized and form a "motor map." Recently, neurons with fixation-related activity have been recorded at the collicular rostral pole, at the area centralis representation or fixation area. Another collicular function which deals with the maintenance of fixation behavior by means of active inhibition of orientation commands was then suggested. We tested that hypothesis as it relates to the suppression of gaze saccades (gaze = eye in space = eye in head + head in space) in the head-free cat by increasing the activity of the fixation cells at the rostral pole with electrical microstimulation. Long stimulation trains applied before gaze saccades delayed their initiation. Short stimuli, delivered during the gaze saccades, transiently interrupted both eye and head components. These results provide further support for a role in fixation behavior for collicular fixation neurons. Brainstem omnipause neurons also exhibit fixation-related activity and have been shown to receive a direct excitatory input from the superior colliculus. To determine whether the collicular projection to omnipause neurons arises from the fixation area, the deep layers of the superior colliculus were electrically stimulated either at the rostral pole including the fixation area or in more caudal regions where stimulation evokes orienting responses. Forty-nine neurons were examined in three cats. 61% of the neurons were found to be orthodromically excited by single pulse stimulation of the rostral pole, whereas only 29% responded to caudal stimulation. In addition, stimuli delivered to the rostral pole activated, on average, omnipause neurons at shorter latencies and with lower currents than those applied in caudal regions. These results suggest that excitatory inputs to omnipause neurons from the superior colliculus are principally provided by the fixation area, via which the superior colliculus could play a role in suppression of gaze shifts. PMID- 7843292 TI - The interactive contribution of neck muscle proprioception and vestibular stimulation to subjective "straight ahead" orientation in man. AB - Seventeen normal subjects were asked to direct a laser point to the position they felt to lie exactly straight ahead of their body. Subjects were seated in complete darkness in an approximately spherical cabin in an upright position with the orientation of the trunk and head aligned. For both the horizontal and vertical plane, "straight ahead" judgements were closely scattered around the objective straight ahead body position. Posterior neck muscle vibration as well as caloric vestibular stimulation with ice water led to (1) an apparent motion and horizontal displacement of a stationary visual target to the side opposite to stimulation and (2) a horizontal deviation of subjective "straight ahead" perception toward the side of stimulation. Only those subjects who experienced an illusion of target motion also showed a deviation of their subjective body orientation. No systematic effect of a displacement of subjective body orientation in the vertical plane was detected. When vestibular stimulation and neck muscle vibration were combined their effects were additive, i.e. the horizontal deviation of subjective body orientation observed when either type of stimulation was applied in isolation, was linearly combined either by summation or by cancellation. The present results clearly support the assumption that afferent visual, vestibular and proprioceptive input converge to the neural generation of an egocentric, body-centred coordinate system that allows us to determine our body position with respect to visual space. PMID- 7843291 TI - Gaze shifts evoked by stimulation of the superior colliculus in the head-free cat conform to the motor map but also depend on stimulus strength and fixation activity. AB - In our previous paper we demonstrated that electrical microstimulation of the fixation area at the rostral pole of the cat superior colliculus (SC) elicits no gaze movement but, rather, transiently suppresses eye-head gaze saccades. In this paper, we investigated the more caudal region of the SC and its interaction with the fixation area. In the alert head-free cat, suprathreshold stimulation in the anterior portion of the SC but outside the fixation area evoked small saccadic shifts of gaze consisting mainly of an eye movement, the head's contribution being small. Stimulating more posteriorly elicited large gaze saccades consisting of an ocular saccade combined with a rapid head movement. At these latter stimulation sites, craniocentric (goal-directed) eye movements were evoked when the cat's head was restrained. The amplitude of eye-head gaze saccades elicited at a particular stimulation site increased with stimulus duration, current strength, and pulse rate, until a constant or "unit" value was reached. The peak velocity of gaze shifts depended on both pulse rate and current strength. The movement direction was not affected by stimulus parameters. The unit gaze vector evoked, in the head-free condition, by stimulating one collicular site was similar to that coded by efferent neurons recorded at that site, thereby indicating a retinotopically coded gaze error representation on the collicular motor map which is not revealed by stimulating the head-fixed animal. Evoked gaze saccades were found to be influenced by fixation behavior. The amplitude of evoked gaze shifts was reduced if stimulation occurred when the hungry animal fixated a food target. Electrical activation of the collicular fixation area was found to mimic well the effects of natural fixation on evoked gaze shifts. Taken together, our results support the view that the overall distribution and level of collicular activity contributes to the encoding of the metrics of gaze saccades. We suggest that the combined levels of activity at the site being stimulated and at the fixation area influence the amplitude of evoked gaze saccades through competition. When stimulation is at low intensities, fixation-related activity reduces the amplitude of evoked gaze saccades. At high activation levels, the site being stimulated dominates and the gaze vector is specified only by that site's collicular output neurons, from which arises the close correspondence between the unit-evoked gaze saccades and the neurally coded gaze vector at that site. PMID- 7843293 TI - Arthrokinetic and vestibular information enhance smooth ocular tracking during linear (self-)motion. AB - We studied the gain of smooth ocular tracking for visual, vestibular and arthrokinetic cues, in combination as well as separately, in order to examine how these multisensory cues influence tracking performance. By use of motion along a linear track (besides the self-evident visual influence) evidence was found for arthrokinetic and vestibular enhancement of smooth ocular tracking. These results were in close correspondence with the results of our former study about arthrokinetic influence on linear self-motion perception. Therefore, we conclude that information from the limbs about linear (self-)movement has analogous characteristics and generates analogous responses to the information about angular (self-)movement. PMID- 7843294 TI - Quantification of D- and I-wave effects evoked by transcranial magnetic brain stimulation on the tibialis anterior motoneuron pool in man. AB - Transcranial stimulation in man evokes multiple descending volleys in the spinal cord giving rise to multiple subpeaks in a peri-stimulus-time histogram (PSTH) obtained from a cross-correlation of motor unit discharges with transcranial stimuli. The first volley is termed the D wave, as it is assumed to be evoked by direct excitation of pyramidal tract neurons, whereas the subsequent I waves appear to be generated by indirect excitation of the pyramidal tract neurons via cortical interneurons. It was the aim of this study to obtain an estimate of the effect induced by multiple volleys evoked by transcranial magnetic stimulation on the entire motoneuron pool of the tibialis anterior in awake subjects. A considerable part of a particular motoneuron pool was investigated by sampling responses of a large number (at least 19) from each muscle investigated. In total, three tibialis anterior muscles from three normal volunteers were studied. From each of the 63 units included in this study, a PSTH to 100 transcranial magnetic stimuli and a PSTH to 100 electrical stimuli given to the peroneal nerve were compiled. From the motor unit response to the peripheral nerve stimulation, the latency of the single-unit H reflex peak was obtained. This yielded, the timing of the subpeaks in response to the magnetic stimulation relative to the timing of the H reflex of the same unit, thus eliminating the influence of the peripheral conduction time from the motoneuron to the recording electrode. It was found that 50 (79%) of the motor units exhibited at least two subpeaks in response to the cortical stimulus.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843295 TI - The importance of somatosensory information in triggering and scaling automatic postural responses in humans. AB - To clarify the role of somatosensory information from the lower limbs of humans in triggering and scaling the magnitude of automatic postural responses, patients with diabetic peripheral neuropathy and age-matched normal controls were exposed to posterior horizontal translations of their support surface. Translation velocity and amplitude were varied to test the patients' ability to scale their postural responses to the magnitude of the translation. Postural response timing was quantified by measuring the onset latencies of three shank, thigh, and trunk muscles and response magnitude was quantified by measuring torque at the support surface. Neuropathy patients showed the same distal-to-proximal muscle activation pattern as normal subjects, but the electromyogram (EMG) onsets in patients were delayed by 20-30 ms at all segments, suggesting an important role for somatosensory information from the lower limb in triggering centrally organized postural synergies. Patients showed an impaired ability to scale torque magnitude to both the velocity and amplitude of surface translations, suggesting that somatosensory information from the legs may be utilized for both direct sensory feedback and use of prior experience in scaling the magnitude of automatic postural responses. PMID- 7843296 TI - The role of the right medial temporal lobe in the control of memory-guided saccades. AB - The role of the hippocampal formation in the control of memory-guided saccades is unclear. We tested two types of memory-guided saccades with short memorization delay in three patients with a lesion affecting the right medial temporal lobe and involving the hippocampal formation. In single memory-guided saccades, testing spatial working memory, the gain of the patient group did not differ from that of an age-matched control group. In contrast, in sequences of memory-guided saccades, testing chronological working memory, there was a marked and significant increase in the percentage of erroneous sequences in patients, compared to controls. These results suggest an important role of the hippocampal formation in the memorization of the chronological order of saccade sequences. In contrast, this structure does not appear to be crucial for spatial working memory, used in single memory-guided saccades. PMID- 7843297 TI - Vergence can be controlled by audio feedback, and induces downward ocular deviation. AB - We measured horizontal and vertical eye positions, using binocular search coils, in three humans. Subjects could maintain vergence by means of audio biofeedback. Feedback consisted of a pair of audio tones, one variable and one fixed at a reference frequency. The variable tone was controlled by instantaneous vergence and provided immediate feedback on the vergence state. The reference frequency, which they attempted to match, was set to correspond to a target distance of either 0.34 m or 0.14 m. Subjects could maintain vergence consistently, even while undergoing lateral motions at 0.5 Hz and 0.2 g peak acceleration in darkness. There was also a consistent tendency for the eyes to deviate downward during near vergence. The results may be useful in experiments in which one wishes to control vergence without providing a visual reference which might inhibit conjugate eye movements. PMID- 7843298 TI - Very short-term potentiation of climbing fiber effects on deep cerebellar nuclei neurons by conditioning stimulation of mossy fiber afferents. AB - Field potentials induced in deep cerebellar nuclei by the electrical stimulation of contralateral red, pontine and reticularis tegmenti pontis oralis nuclei, the restiform body and the inferior olive were recorded in the alert cat. Recording sites in interpositus and fastigial nuclei were selected with the aid of antidromic field potentials induced by red nucleus and restiform body stimulation, respectively. Pontine and reticularis tegmenti pontis oralis nuclei stimulation induced small, but constant amplitude, field potentials consisting of one or two negative waves. Control field potentials induced by inferior olive stimulation consisted of a negative wave at 2-3 ms followed by a late (4-6 ms) positivity. Conditioning stimuli applied to the pontine and reticularis tegmenti pontis oralis nuclei greatly enhanced the amplitude of the inferior olive-evoked synaptic field potential for a time window of about 40 ms. In contrast, inferior olive conditioning stimulation failed to modify the field potentials induced by pontine nuclei stimulation. These facilitatory effects on field potential amplitude showed no long-lasting modifications. The transient modification of inferior olive-induced field potentials could be related to attentional movements made by the animal to natural or electrically-induced sensory cues. PMID- 7843299 TI - Head-direction cells in the rat posterior cortex. II. Contributions of visual and ideothetic information to the directional firing. AB - This study investigated the effects of visual and ideothetic cues on the spatial tuning of head-direction (HD) cells recorded in the rat posterior cortices. Extracellular, single unit responses were recorded from animals performing each of two different tasks, a spatial working memory task on a radial-arm maze and a passive rotation task on a modified "lazy Susan" platform. The influence of visual cues was assessed by manipulating the position of one white and three black cue-cards placed around the maze. We found three major categories of HD cells based on their response to cue manipulations in the maze tasks. Type A cells (10/41) rotated their preferred directions along with the rotation of the cues. The majority (type B, 25/41) of the HD cells were unaffected by the rotation of visual cues, maintaining their established preferred direction. Type C cells (6/41) showed complex responses to cue rotation, with the preferred direction reflecting either a combination of both type A and type B responses or an unpredictable response. The results indicate that the internal representation of directionality can be calibrated by visual cues and that some mnemonic processes may have been involved in the registration of the previous cue locations. Eleven cells were tested in both the maze task and the passive rotation task. Most (9/11) showed a significant directionality in the former task, but showed either no or weak directionality in the latter task, suggesting that movement-related ideothetic cues may be used in supporting the directional firing of these cells. Only two cells showed significant directionality in both tasks. Their established preferred directions did not rotate along with the cues in the maze task, but did rotate with the cues in the passive rotation task. We conclude that the dynamic aspect of the directional tuning in these cortical HD cells may represent on-line calibration of an angular coordinate representation. PMID- 7843300 TI - Serotonin reveals ineffective spinal pathways to contralateral phrenic motoneurons in spinally hemisected rats. AB - Serotonin reveals ineffective (subthreshold) pathways from the C2 lateral funiculus to ipsilateral phrenic motoneurons in spinalized rats. The objective of the present study was to investigate serotonergic modulation of crossed-spinal pathways to contralateral phrenic motoneurons. Rats (n = 10) were anesthetized (urethane), paralyzed, vagotomized, and artificially ventilated. The spinal cord was hemisected at C1-C2 and, on the intact side, a tungsten stimulating electrode was placed ventral to the C2 dorsal root entry zone in the dorsolateral (approximately 1.1 mm) or the ventrolateral funiculus (approximately 2.2 mm depth). Single shocks (100-750 microA, 0.1-0.5 ms, 2 Hz) elicited a short-latency (approximately 1.0 ms to peak) excitation in the ipsilateral phrenic nerve, but usually evoked little or no response in the contralateral phrenic nerve at either stimulus site. Following systemic injection of the monoamine oxidase inhibitor pargyline (25 mg/kg) and the serotonin precursor 5-hydroxytryptophan (5-10 mg/kg), complex responses were revealed in the contralateral phrenic nerve, including: (1) spontaneous tonic activity; (2) a short-latency (approximately 1.0 ms to peak) evoked excitation; and (3) two long-latency (approximately 2.2 and 7.8 ms to peak) evoked excitations. The longest latency excitation was expressed only when the stimulating electrode was positioned in the dorsolateral funiculus. Contralateral evoked responses were blocked by systemic methysergide (2-6 mg/kg), a broad-spectrum serotonin receptor antagonist. These results indicate that serotonin converts ineffective crossed phrenic pathways in the spinal cord to effective pathways. It remains to be determined whether serotonin is both necessary and sufficient in this modulatory process, or if it is a nonspecific result of increased phrenic motoneuron excitability. PMID- 7843301 TI - Lowering of extracellular pH suppresses low-Mg(2+)-induces seizures in combined entorhinal cortex-hippocampal slices. AB - Lowering [Mg2+]o induces epileptiform bursting in hippocampus and entorhinal cortex (EC), presumably by activation of N-methyl-D-aspartate (NMDA) receptors. Since increasing [H+]o has been shown to reduce NMDA receptor activation, we hypothesized that this could contribute to anticonvulsant actions of acidic pH. To test this, we studied the effects of raising extracellular PCO2 (20.6%, pH = 6.7) or lowering extracellular pH (6.7 or 6.2) on low-Mg(2+)-induced epileptiform discharges. Lowering the pH to 6.7 by either means increased the interval between seizure-like events (SLEs), decreased the maximal amplitude of SLEs, and if the site of seizure generation was at a distance from the recording site, acidification slowed the rate of seizure propagation. In contrast, the duration of SLEs was unaffected by acidic pH or high PCO2. Raising PCO2 or lowering pH to 6.7 also blocked early (8-10 min) but not late (> 20 min) phases of status-like discharges. All effects of the extracellular pH changes were fully reversible. Further lowering of extracellular pH to 6.2 completely and reversibly blocked both SLEs and status-like discharges. Our data show that the effects of high PCO2 and low pH on seizures in the EC in vitro may be dose-dependent and consistent with induction by proton blockade of NMDA receptors. Thus, blockade of NMDA currents by protons may be an important component of the anticonvulsant action of extracellular acidosis. The results also suggest that acidosis may be a desirable property for new antiepileptic treatments. PMID- 7843302 TI - Bilateral phasic increases in dorsal root ganglia nerve growth factor synthesis after unilateral sciatic nerve crush. AB - The amount of nerve growth factor (NGF) in the L5, L6, and cervical dorsal root ganglia of rats was examined from 1 to 30 days after a unilateral crush lesion of the sciatic nerve and adjacent branches of the lumbar plexus at the level of the sciatic notch. Unilateral nerve crush produced increases in NGF content of lumbar ganglia at 1, 4, and 7-8 days after injury, with increased NGF mRNA at 4 and 7-8 days. Increases in NGF at 1 and 4 days were most pronounced on the unlesioned side while increases at days 7 and 8 were most pronounced on the lesioned side. NGF content increased in cervical ganglia of nerve-lesioned animals at 3 and 7 days after injury and in lumbar and cervical ganglia of sham-operated animals 3-5 days after surgery, with no comparable changes in NGF mRNA. Elevations of ganglionic NGF coincide temporally with some of the alterations in metabolism and morphology which occur in dorsal root ganglion neurons after sciatic nerve crush. However, the bilateral nature of increases in NGF demonstrates that the factor(s) producing the response is not restricted to ganglia axotomized by the injury. The data suggest that ganglionic NGF may be regulated by systemic factors, produced during stress or trauma, as well as by factors from the denervated target tissue and/or regenerating axons. PMID- 7843303 TI - Phosphinic acid derivatives as baclofen agonists and antagonists in the mammalian spinal cord: an in vivo study. AB - The actions of a series of derivatives of 3-aminopropyl-phosphinic acid as baclofen agonists and antagonists have been examined on the synaptic excitation of neurones by impulses in primary afferent fibres in the lumbar spinal cords of pentobarbitone-anaesthetised cats and rats. Both the pre- and postsynaptic inhibitory actions of microelectrophoretic (-)-baclofen were reduced by similarly administered CGP 35,348, 36,742, 46,381, 52,432, 54,626 and 55,845, the latter being the most potent antagonist. None of these antagonists either decreased or increased the excitability of spinal neurones, and the inhibitory action of GABA was reduced only by local concentrations of antagonists which also reduced the action of piperidine-4-sulphonic acid, a GABAA agonist. Although the weak inhibitory effect of 3-aminopropylphosphinic acid in both the rat and the cat was not reduced by these baclofen antagonists, the pre- and postsynaptic inhibitory effects of 3-aminopropyl-methyl-phosphinic acid (CGP 35,024), which was more potent than (-)-baclofen, were reduced by the antagonists. Like (-)-baclofen, CGP 35,024 was relatively ineffective in reducing transmitter release in the cord from the terminals of excitatory spinal interneurones, the terminals of excitatory tracts in the dorsolateral funiculus and the cholinergic terminals of motor axon collaterals. In both rat and cat cords, receptors for (-)-baclofen could not be demonstrated to be activated by microelectrophoretic GABA, possibly because of the predominantly dendritic location of GABAB receptors. Spinal pre- and postsynaptic baclofen receptors appeared to be pharmacologically similar but differed from those in the higher central nervous system of the rat, where 3 aminopropylphosphinic acid has been reported to be an effective baclofen agonist. The compounds tested, particularly CGP 55,845 and 46,381, will be of use in further investigations of the physiological relevance of baclofen receptors at central synapses where GABA may be the transmitter. PMID- 7843305 TI - Head-direction cells in the rat posterior cortex. I. Anatomical distribution and behavioral modulation. AB - We examined the behavioral modulation of head-directional information processing in neurons of the rat posterior cortices, including the medial prestriate (area Oc2M) and retrosplenial cortex (areas RSA and RSG). Single neurons were recorded in freely moving rats which were trained to perform a spatial working memory task on a radial-arm maze in a cue-controlled room. A dual-light-emitting diode (dual LED) recording headstage, mounted on the animals' heads, was used to track head position and orientation. Planar modes of motion, such as turns, straight motion, and nonlocomotive states, were categorized using an objective scheme based upon the differential contributions of movement parameters, including linear and angular velocity of the head. Of 662 neurons recorded from the posterior cortices, 41 head-direction (HD) cells were identified based on the criterion of maintained directional bias in the absence of visual cues or in the dark. HD cells constituted 7 of 257 (2.7%) cells recorded in Oc2M, 26 of 311 (8.4%) cells in RSA, and 8 of 94 (8.5%) cells in RSG. Spatial tuning of HD cell firing was modulated by the animal's behaviors in some neurons. The behavioral modulation occurred either at the preferred direction or at all directions. Moreover, the behavioral selectivity was more robust for turns than straight motions, suggesting that the angular movements may significantly contribute to the head directional processing. These behaviorally selective HD cells were observed most frequently in Oc2M (4/7, 57%), as only 5 of 26 (19%) of RSA cells and none of the RSG cells showed behavioral modulation. These data, taken together with the anatomical evidence for a cascade of projections from Oc2M to RSA and thence to RSG, suggest that there may be a simple association between movement and head directionality that serves to transform the egocentric movement representation in the neocortex into an allocentric directional representation in the periallocortex. PMID- 7843304 TI - Re-initiated growth from mature ventral mesencephalon: an in oculo transplant study of nigrostriatal co-grafts. AB - The ability of mature dopaminergic neurons derived from ventral mesencephalon to re-initiate growth after making contact with a non-innervated target was studied using the intra-ocular grafting model. Foetal ventral mesencephalic tissue or brain stem including the locus coeruleus area was grafted to the anterior chamber of the eye. Two weeks, 6 weeks or 1 year after the first implantation, foetal striatal tissue was placed in contact with the nigral graft or grafted alone. The size of the transplants was measured through the cornea. The final size of the striatal grafts was significantly larger when placed alone than when co-grafted with 1-year-old or 6-week-old dopaminergic grafts. Striatum grafted together with 2-week-old nigra was larger than when grafted adjacent to mature substantia nigra, but not significantly so. Nerve fibre outgrowth into the iris from the nigral transplants did not increase after maturation, but the re-innervated area of the host iris progressively increased around the locus coeruleus grafts. Ingrowth of tyrosine hydroxylase (TH) immunoreactive nerve fibres into the striatal grafts was studied 6 weeks after the second implantation. TH immunohistochemistry revealed innervation of the striatal piece in all cases, except for the group where striatum alone was grafted. With the short survival time for co-grafts of 6 weeks, TH-positive nerve fibres innervated a larger volume, had a patchy appearance and the density was higher in striatum grafted to 2 week-old nigral transplants than that seen in striatal transplants grafted to mature nigral grafts. The patchy pattern of TH-immunoreactive nerve terminals was also seen in striatum co-grafted with 6-week-old or 1-year-old nigral transplants. No difference in striatal innervation volume was detected between those latter two groups. When striatum was implanted adjacent to mature ventral mesencephalon and grown together for 6 months--the longer survival time--the same dense TH-positive innervation as seen in striatum co-grafted with immature nigral tissue at the shorter survival time was found. Additionally, the nigral part of the co-grafts showed increased TH-immunoreactive nerve fibre density. In conclusion, dopaminergic neurites from mature ventral mesencephalic transplants can re-initiate growth if placed in contact with non-innervated striatal tissue. The nigral grafts do not progressively re-innervate the host iris, while locus coeruleus grafts do. The intra-ocular grafting model can be used to study the in vivo effects of trophic factors on mature dopaminergic neurons. PMID- 7843306 TI - Locus coeruleus neuronal activity in awake monkeys: relationship to auditory P300 like potentials and spontaneous EEG. AB - These experiments were designed to test the hypothesis that novel auditory stimuli lead to phasic and/or tonic increases in locus coeruleus (LC) cell firing, which may be a necessary condition for the occurrence of P300 potentials. Event-related potentials (ERPs) and LC unit activity were simultaneously recorded from three awake macaque monkeys exposed to an auditory "oddball" paradigm. Oddball stimuli resulted in probability-sensitive potentials resembling the human P3a component. Twenty-five percent (3/12) of LC units showed small phasic enhancements of LC firing after infrequent but not frequent tones. A comparison between histograms elicited by the two types of stimuli revealed significant effects of stimulus sequence. This pattern suggested a slight activation by rare tones, followed by a brief inhibition of firing in the subsequent trial. These data suggest that changes in LC activity during oddball paradigms are subtle, heterogeneous, and influenced by the subject's level of arousal and vigilance. PMID- 7843307 TI - Projections from the presubiculum and the parasubiculum to morphologically characterized entorhinal-hippocampal projection neurons in the rat. AB - The relations between the inputs from the presubiculum and the parasubiculum and the cells in the entorhinal cortex that give rise to the perforant pathway have been studied in the rat at the light microscopical level. Projections from the presubiculum and the parasubiculum were labeled anterogradely, and, in the same animal, cells in the entorhinal cortex that project to the hippocampal formation were labeled by retrograde tracing and subsequent intracellular filling with Lucifer Yellow. The distribution and the number of appositions between the afferent fibers and hippocampal-projection neurons in the various layers of the entorhinal cortex were analyzed. The results show that layers I-IV of the entorhinal cortex contain neurons that give rise to projections to the hippocampal formation. The morphology of these projection neurons is highly variable and afferents from the presubiculum and the parasubiculum do not show a preference for any specific morphological cell type. Both inputs preferentially innervate the dendrites of their target cells. However, presubicular and parasubicular projections differ with respect to the layer of entorhinal cortex they project to. The number of appositions of presubicular afferents with cells that have their cell bodies in layer III of the entorhinal cortex is 2-3 times higher than with cells in layer II. In contrast, afferents from the parasubiculum form at least 2-3 times as many synapses on the dendrites of cells located in layer II than on neurons that have their cell bodies in layer III. Cells in layers I and IV of the entorhinal cortex receive weak inputs from the presubiculum and parasubiculum. Not only is the presubiculum different from the parasubiculum with respect to the distribution of projections to the entorhinal cortex, they also differ in their afferent and efferent connections. In turn, cells in layer II of the entorhinal cortex differ in their electrophysiological characteristics from those in layer III. Moreover, layer II neurons give rise to the projections to the dentate gyrus and field CA3/CA2 of the hippocampus proper, and cells in layer III project to field CA1 and the subiculum. Therefore, we propose that the interactions of the entorhinal-hippocampal network with the presubiculum are different from those with the parasubiculum. PMID- 7843308 TI - Functional properties of rotation-sensitive neurons in the posterior parietal association cortex of the monkey. AB - We studied the functional properties of rotation-sensitive (RS) neurons of the posterior parietal association cortex in detail. We classified 58 neurons as RS neurons on the basis of statistical analysis, to indicate that their responses to rotary movement were significantly greater (P < 0.01) than those to linear movement of the same stimulus. We calculated rotation index, 1-(L/R), in 82 cells, where L/R is the ratio of net response to linear movement to that to rotary movement. All the RS neurons had rotation index greater than or equal to 0.3. The recording site of these RS neurons was localized in the posterolateral part of area PG (area 7a of Vogt), on the anterior bank of the caudal superior temporal sulcus (STS), in the region partly overlapping the medial superior temporal (MST) area. We compared the response of RS neurons to rotation with that to shearing movement as well as to linear movement. In the majority of RS neurons the ratio of shearing response to rotation response (S/R) was smaller than the ratio of linear response to rotation response (L/R), indicating that the response to rotation was not due to a simple combination of linear movements in the opposite direction. Most of the RS neurons responded to the rotary movement of a single spot as well as that of a slit, although the response was smaller (average 70%) for the former. Most of the RS neurons had large receptive fields (60-180 degrees in diameter) and their responses were independent of the position within the receptive field. The responses of most RS neurons increased monotonically with the increase in angular velocity and were also dependent on the size of the stimulus, although the rate of increase was small when the length was more than 10 degrees. The majority of RS neurons (37/58) responded better to rotation in depth than to that in the frontoparallel plane. Some of them (12/37) responded to diagonal rotation rather than to sagittal or horizontal rotation. We found that some depth RS neurons showed reversal in the preferred direction when we used a trapezoidal window-like plate as the rotating stimulus in the monocular viewing condition, just as occurs in the case of the Ames window illusion. The response of some RS neurons (5/7) was enhanced by tracking eye movement.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7843309 TI - Early morphological changes of primary afferent neurons and their processes in newborn mice after treatment with capsaicin. AB - Degenerating figures of dorsal root ganglion (DRG) neurons and their central and peripheral processes (dorsal root and saphenous nerve) and terminals (central terminals in the superficial dorsal horn and cutaneous nerve of the hind paw dorsal skin) of neonatal mice were examined 30 min, 1, 2 and 5 h, and 2, 3, 5, and 10 days after subcutaneous injection of capsaicin on post-natal day 2. Many small DRG neurons showed degeneration 1 h after treatment. Scarcely any features of degeneration were seen in the DRG and dorsal root 10 days after treatment. The degenerating aspects of terminal axons in the marginal layer of the superficial dorsal horn were characterized by enlarged round axons with closely packed osmiophilic materials, lamellar bodies, and loss of axoplasmic organelles. Two types of central terminals (C-terminals) showed degeneration in the substantia gelatinosa from 30 min after treatment onward. One type consisted of small, round, sinuous or slender dark terminals (CI-terminals), and the other of large, pale, round or angular terminals (CII-terminals). Those that degenerated markedly had homogeneously electron-dense axoplasm with dilated synaptic vesicles and inclusion bodies. Extensive degeneration of terminal axons in the marginal layer occurred 5 h after treatment, whereas conspicuous degeneration of C-terminals occurred from 30 min to 10 days after treatment in the substantia gelatinosa. CI terminals showed marked degeneration during the first 3 days, whereas marked degeneration of CII-terminals occurred between 5 and 10 days after treatment. This time difference between the peaks of degeneration of CI- and CII-terminals indicates an important difference in the origins of these two types of capsaicin sensitive, nociceptive fibers in the superficial dorsal horn; CI-terminals are derived from small DRG cells, whereas CII-terminals are derived from larger DRG cells. Unmyelinated axons in the dorsal root, saphenous nerve, and dorsal skin of the hind paw showed similar degeneration patterns 2 h after treatment to those of terminal axons in the marginal layer. Thus, the degenerating profiles in the marginal layer suggest that these axons arose from collaterals of unmyelinated primary axons descending or ascending within the marginal layer. Numerous enlarged degenerating axons showing vacuolation were conspicuous in the dorsal skin 3 days after treatment. The synchronous degeneration of the smaller DRG neurons, their central and peripheral processes, and their CI-terminals in the substantia gelatinosa supports the idea that the smaller DRG neurons are directly influenced by capsaicin, and that their degeneration is followed by centrifugal degeneration. PMID- 7843310 TI - The cisternal organelle as a Ca(2+)-storing compartment associated with GABAergic synapses in the axon initial segment of hippocampal pyramidal neurones. AB - The axon initial segment of cortical principal neurones contains an organelle consisting of two to four stacks of flat, membrane-delineated cisternae alternating with electron-dense, fibrillar material. These cisternal organelles are situated predominantly close to the synaptic junctions of GABAergic axo axonic cell terminals. To examine the possibility that the cisternal organelle is involved in Ca2+ sequestration, we tested for the presence of Ca(2+)-ATPase in the cisternal organelles of pyramidal cell axons in the CA1 and CA3 regions of the hippocampus. Electron microscopic immunocytochemistry using antibodies to muscle sarcoplasmic reticulum ATPase revealed immunoreactivity associated with cisternal organelle membranes. The localisation of Ca(2+)-ATPase in cisternal organelles was also confirmed by enzyme cytochemistry, which produced reaction product in the lumen of the cisternae. These experiments provide evidence for the presence of a Ca2+ pump in the cisternal organelle membrane, which may play a role in the sequestration and release of Ca2+. Cisternal organelles are very closely aligned to the axolemma and the outermost cisternal membrane is connected to the plasma membrane by periodic electron-dense bridges as detected in electron micrographs. It is suggested that the interface acts as a voltage sensor, releasing Ca2+ from cisternal organelles upon depolarisation of the axon initial segment, in a manner similar to the sarcoplasmic reticulum of skeletal muscle. The increase in intra-axonal Ca2+ may regulate the GABAA receptors associated with the axo-axonic cell synapses, and could affect the excitability of pyramidal cells. PMID- 7843311 TI - Morphometric studies demonstrate that aromatase-immunoreactive cells are the main target of androgens and estrogens in the quail medial preoptic nucleus. AB - The volume and cytoarchitectonic organization of the sexually dimorphic medial preoptic nucleus (POM) of the quail are sensitive to plasma levels of testosterone (T). We previously showed that, in castrated quail, T or its estrogenic metabolite, estradiol (E2), increases the size of the large neurons located in the lateral part of POM. Embryonic treatments with estrogens are also known to affect permanently the size of these large neurons. Since the lateral POM also contains a dense population of aromatase-immunoreactive (ARO-ir) cells, and these are known to be a target for steroids, we hypothesized that the effects of steroids identified in previous experiments were primarily directed to these ARO-ir cells. This idea was tested in two experiments in which the size of these cells was measured in male quail under various endocrine conditions. In experiment 1, a detailed analysis of ARO-ir and of non-immunoreactive cells in the POM of adult, sexually mature males revealed that the immunoreactive perikarya are larger than the non-immunoreactive cells and that they constitute the vast majority of the large cells (area > 50 microns 2) in the POM. In experiment 2, it was shown that T and E2 actually increase the size of ARO-ir cells in the POM while the androgenic metabolite of T, dihydrotestosterone has no effect at this level. Taken together, these data suggest that the sex differences and the steroid-induced changes in cell size previously described in the study of POM sections stained for Nissl material largely concern aromatase-containing cells. Since aromatization of T plays a limiting role in the activation of male copulatory behavior, these changes may represent the morphological signature of the mechanisms causally involved in the control of this behavior. PMID- 7843312 TI - Influence of acid-base changes on the intracellular calcium concentration of neurons in primary culture. AB - The influence of changes in intra- and extracellular pH (pHi and pHe, respectively) on the cytosolic, free calcium concentration ([Ca2+]i) of neocortical neurons was studied by microspectrofluorometric techniques and the fluorophore fura-2. When, at constant pHe, pHi was lowered with the NH4Cl prepulse technique, or by a transient increase in CO2 tension, [Ca2+]i invariably increased, the magnitude of the rise being proportional to delta pHi. Since similar results were obtained in Ca(2+)-free solutions, the results suggest that the rise in [Ca2+]i was due to calcium release from intracellular stores. The initial alkaline transient during NH4Cl exposure was associated with a rise in [Ca2+]i. However, this rise seemed to reflect influx of Ca2+ from the external solution. Thus, in Ca(2+)-free solution NH4Cl exposure led to a decrease in [Ca2+]i. This result and others suggest that, at constant pHe, intracellular alkalosis reduces [Ca2+]i, probably by enhancing sequestration of calcium. When cells were exposed to a CO2 transient at reduced pHe, Ca2+ rose initially but then fell, often below basal values. Similar results were obtained when extracellular HCO3- concentration was reduced at constant CO2 tension. Unexpectedly, such results were obtained only in Ca(2+)-containing solutions. In Ca(2+)-free solutions, acidosis always raised [Ca2+]i. It is suggested that a lowering of pHe stimulates extrusion of Ca2+ by ATP-driven Ca2+/2H+ antiport. PMID- 7843313 TI - A comparison of paired-pulsed facilitation of AMPA and NMDA receptor-mediated excitatory postsynaptic currents in the hippocampus. AB - Paired-pulse facilitation of excitatory synaptic transmission was investigated in the CA1 region of rat hippocampal slices using whole-cell patch-clamp recording. To optimise the measurement of excitatory synaptic transmission, gamma-amino butyric acid (GABA)-mediated synaptic inhibition was eliminated using both GABAA and GABAB antagonists. Pure alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) or N-methyl-D-aspartate (NMDA) receptor-mediated excitatory postsynaptic currents (EPSCs) were then isolated pharmacologically. Paired-pulse facilitation of either AMPA or NMDA receptor-mediated EPSCs (EPSCA and EPSCN, respectively) was investigated using two stimuli of identical strength delivered at intervals of between 25 and 1000 ms. The paired-pulse facilitation profiles of both EPSCA and EPSCN were similar. Paired-pulse facilitation of EPSCA was independent of holding potential. In contrast paired-pulse facilitation of EPSCN was markedly voltage-dependent; maximum facilitation was recorded at hyperpolarised membrane potentials. At positive membrane potentials there was little or no paired-pulse facilitation and, in most neurones, paired-pulse depression was observed. Voltage-dependence of paired-pulse facilitation of EPSCN was similar in the presence of nominal absence of Mg2+ in the bathing medium, and was unaffected by extensive dialysis of neurones with 1,2-bis(2 aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA). These data are consistent with a presynaptic locus for paired-pulse facilitation of EPSCA. However, paired pulse facilitation of EPSCN involves postsynaptic factors. PMID- 7843314 TI - Coordination between head and hindlimb motions during the cat scratch response. AB - Coordination between motions of the head and the hindlimb paw ipsilateral to the stimulated pinna were assessed during the scratch cycle in freely moving cats. Motor patterns were determined by electromyographic (EMG) recordings made from epimysial-patch electrodes surgically implanted on the biventer cervicis (BC), complexus (CM), obliquus capitis inferior (OC), and splenius (SP) muscles and by fine-wire EMG electrodes implanted in two ankle muscles, medial gastrocnemius (MG), and tibialis anterior (TA). To assess head motions during the three phases of the scratch cycle (precontact, contact, postcontact), several responses were filmed, and in some cats an in vivo force transducer was implanted on an ankle extensor muscle (MG or plantaris, PL) to determine the tension profile during the scratch cycle. During the scratch cycle, the head's trajectory was usually characterized by a small oscillation in which the head was pushed away during paw contact (as hindlimb joints extended) and then repositioned during the noncontact phases (as hindlimb joints flexed). Neck muscle activity did not occur during all responses or during all cycles of a single multicycle scratch response, and when it occurred, neck muscle EMG was characterized as phasic (a single burst during the cycle) or tonic (low-level activity during the entire cycle). Neck muscles ipsilateral (i) to the scratching limb exhibited phasic bursts more than contralateral (c) muscles, and phasic activity was most frequently observed in the iBC, iSP, iOC, and cOC muscles. The cOC was reciprocally active with the ipsilateral muscles, and its burst coincided with the postcontact phase and the ankle flexor (TA) burst. The ipsilateral muscles (iOC, iSP, iBC) were active during paw contact, and the termination of all three bursts occurred synchronously just after peak tension of the ankle extensor was reached. The iBC was active before the onset of paw contact and may have been responsible for repositioning the head, along with the cOC, during the precontact phase. The iOC became active after the onset of paw contact (22 ms) and was recruited more often when the peak extensor tendon force was high (10-16 N). The iSP, in contrast, was active during the contact phase of most scratch cycles examined and its recruitment appeared to be unrelated to tendon forces. Our data suggest that phasic neck muscle activity is not obligatory during the cat scratch response, but is related to certain conditions such as a higher than average tendon force of an ankle extensor during contact and the need to reposition the head during the noncontact phases of the cycle.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7843315 TI - Platelet-derived growth factor exerts trophic effects on rat striatal DARPP-32 containing neurons in culture. AB - The objective of the present study was to determine if either of the two isoforms of platelet-derived growth factor (PDGF), PDGF-AA and PDGF-BB, exerts trophic effects in vitro on developing rat strial neurons. Striatal neurons were identified using immunocytochemistry for dopamine- and adenosine 3':5' monophosphate-regulated phosphoprotein with a molecular weight of 32 kilodalton (DARPP-32). In control cultures without PDGF, the mean number of DARPP-32 positive neurons decreased by 47% at days 3 to 5 in vitro. PDGF-BB, but not PDGF AA, significantly increased the number of DARPP-32-positive neurons both at day 3 (by 42%) and day 5 (by 149%). Total cell number was similar in control and PDGF BB-treated cultures, suggesting that, in striatal cultures, the action of PDGF-BB is relatively specific for DARPP-32-positive neurons. The DARPP-32-positive neurons in PDGF-BB-treated cultures had longer neurites and larger soma areas than those in control and in PDGF-AA-treated cultures. Our data provide evidence that PDGF-BB exerts a trophic action on striatal DARPP-32-positive neurons in vitro by promoting cell survival and morphological differentiation, although a stimulatory effect on intraneuronal DARPP-32 levels also is possible. The findings raise the possibility that PDGF-BB might also be involved in the development and maintenance of striatal neurons in vivo, and could be used to counteract striatal degeneration in models of Huntington's disease. PMID- 7843316 TI - Sex differences in GABA/benzodiazepine receptor changes and corticosterone release after acute stress in rats. AB - Since many hormonal indices of stress responsiveness are sexually dimorphic in rats, we examined sex differences and the effects of gonadectomy on the stress related changes in GABAA/benzodiazepine receptors in rats. Intact or ovariectomized female rats displayed a markedly greater corticosterone response and a more pronounced increase in benzodiazepine receptors than males (intact or orchidectomized) after acute handling or swim stress. Swim stress increased benzodiazepine receptor density without modifying affinity in cortex, hippocampus, and hypothalamus. Corticosterone treatment induced benzodiazepine receptor levels comparable to those seen after swim stress in all hormone groups. Handling stress also enhanced cortical low-affinity GABAA receptor levels in males and ovariectomized females. Both GABA and benzodiazepine receptor levels were positively correlated with circulating corticosterone levels in female, but not male groups. GABA/benzodiazepine coupling was unaffected by stress or hormonal status. These sexual dimorphisms in hormonal responses to stress may help elucidate the causes and consequences of stress-induced changes in the GABAA/benzodiazepine receptor complex. PMID- 7843317 TI - Visual classification of X and Y perigeniculate neurons of the cat. AB - The spike activity of perigeniculate cells evoked by small light spots flashing along the axes of their receptive fields was recorded and presented in response planes. This method allowed the investigated neurons to be grouped into two classes characterized by (1) large receptive fields and phasic-like responses and (2) small fields and tonic responses. The latency measurements for stimulation of the optic chiasma and visual cortex revealed that the cells from the first group are excited by fast, Y fibers and the second by slow, X axons. The spatial tuning curves of the second harmonic component, as measured from the responses of the cells from the two groups for slowly moving square gratings, are also different. We conclude that the X and Y systems of the visual pathway are segregated at the level of the perigeniculate nucleus. PMID- 7843318 TI - The control and coordination of one-handed catching: the effect of temporal constraints. AB - The aim of the experiment was to identify the control mechanisms involved in a goal-directed task by manipulating the temporal constraints. Subjects were required to catch, with one hand, table tennis balls projected by a ball projection machine under five temporal conditions (ball speed ranged from 5.7 to 9 m/s, giving rise to flight times of 550-350 ms). By means of three-dimensional kinematics analysis the following results were obtained, which are some spatio temporal adaptations of the catching movement to the increase of temporal constraints: (1) a decrease in movement time, (2) an increase in the straightness of the trajectory of the wrist, and (3) a shift backwards of the place of ball hand contact while (4) the grasping time was kept constant. Moreover, as a result of increasing temporal constraints, the acceleration phase of the transportation component was kept constant while the deceleration phase was progressively decreased and nearly suppressed. Further, an increased correlation of the initial direction of the transportation component with the initial direction of the ball path was found. These findings show some spatio-temporal adaptations of the catching movement when the time available is manipulated. They also support the contention of a shift in the control mechanisms involved in one-handed catching facing different temporal constraints. PMID- 7843319 TI - The effect of viewing the static hand prior to movement onset on pointing kinematics and variability. AB - Pointing accuracy and arm movement kinematics of six human subjects were measured in three conditions where the hand was never visible during the ongoing movement: (1) in the dark; (2) the static hand was seen in peripheral vision prior to target presentation, but not during the reaction time (H-T); (3) the static hand was seen in peripheral vision until movement onset (H+T). It was shown that: (1) viewing the hand prior to movement decreased pointing variability as compared to the dark condition. (2) Viewing simultaneously hand and target (H+T) and further decreased pointing variability as compared to the H-T condition. This effect was proportional to the reaction time. (3) A lengthening of the deceleration phase was observed for movements performed in the H+T condition, as compared to the other two conditions. (4) A negative correlation between variability and the first part of the deceleration phase was observed in the H+T condition, but neither in the H-T condition nor in the dark. These results suggest that the decrease in pointing variability observed in the H+T condition is due to a feedback based on kinesthetic reafference. Better encoding of the initial position of the hand relative to the target (as in H+T) would allow a calibration of arm position sense, which is used to drive the hand toward the target during the deceleration phase. PMID- 7843320 TI - A three-dimensional analysis of vergence movements at various levels of elevation. AB - Earlier studies have shown that eye positions, recorded in subjects scanning a distant visual scene with the head in a stable position, have only two degrees of freedom (Listing's law). Due to cyclovergence, this law is modified in near vision. Two previous quantitative studies have documented that the sign of the torsional vergence component depends systematically on elevation: when fixating a nearby target, the eyes show intorsion in up gaze, extorsion in down gaze and no cyclotorsion at some intermediate elevation level (to be denoted as the null elevation). Both studies found a linear cyclovergence/elevation relation, but disagreed on the amount of cyclotorsion. A further uncertainty is how this phenomenon develops dynamically when the binocular fixation point shifts from a far to a near position. Therefore, we have investigated the dynamic coupling between the horizontal and torsional components of vergence in human subjects who were instructed to refixate a light target after it stepped in depth. The target steps were presented at various vertical and horizontal directions relative to the straight-ahead axis of the cyclopean eye. We found that the quantitative relations among horizontal vergence, torsional vergence and elevation were intermediate between those found in the two earlier near-vision studies and that they correspond reasonably to the predictions of a model by Mok and co-workers. The cyclotorsion vergence component had about the same latency and dynamics as the horizontal component. When refixations were studied at different elevations, the torsional vergence component changed from incyclotorsion in up gaze to excyclotorsion in down gaze. In agreement with expectations derived from two quantitative models, the null elevation of cyclovergence was near the binocular primary position. Furthermore, we found no consistent additional dependence on the horizontal direction of the refixation trajectory relative to the midsaggital plane. Other experiments showed that the cyclotorsional changes accompanying convergence were not critically dependent upon the visual conditions. Quantitatively similar similar cyclotorsional components were found even in convergent refixations executed in full darkness towards the location of a remembered (flashed) target. We conclude that visual feedback is unlikely to be very important in controlling cyclovergence in these various conditions. PMID- 7843322 TI - Ethical principles and guidelines for experiments on animals. Swiss Academy of Medical Sciences. PMID- 7843321 TI - Scaling of joint torque during planar arm movements. AB - The present study scrutinized the "Motor Program" concept for aimed arm movements. Human subjects pointed at visual targets in a horizontal plane, with movements of varying starting positions, amplitudes and directions. We recorded movement kinematics and subsequently calculated the shoulder and elbow joint torque profiles. Our results indicate that the shape of torque profiles is rather uniform across movements and joints. We defined the size of those profiles by six "landmark variables", which could be subsequently reduced to three factors using factor analysis: one factor represented torque magnitude and two represented different aspects of torque timing. Additional analyses indicated that total torque duration is an important controlled signal. Our findings conform with the view that movements are executed by playing back scaled versions of prototypical joint torque profiles. PMID- 7843323 TI - Estradiol binding to synaptosomal plasma membranes of rat brain regions. AB - The equilibrium parameters (Bmax and Km) of estradiol binding to synaptosomal plasma membranes prepared from brain regions of adult female rats were examined. Michaelis-Menten plots of the specific binding in samples prepared from the telencephalon and mesencephalic reticular formation showed only one saturation plateau, indicating the presence of a single population of synaptosomal membrane binding sites for estradiol. According to Bmax and Km values, the binding sites appeared to be similar in the two regions. On the other hand, two distinct populations, one with high capacity and lower affinity and another with low capacity and higher affinity, were detected in samples prepared from the nucleus caudatus, brain stem and hippocampus, as shown by two saturation plateaus on corresponding Michaelis-Menten graphs. The equilibrium parameters of the two populations were different in the three regions. The shapes of the Michaelis Menten plots were substantially the same for intact and for ovariectomized animals. Scatchard and Hill plots revealed cooperativity for estradiol binding in all the regions investigated. These results suggest that central non-genomic effects of estradiol are mediated via multiple types of neuronal membrane binding sites, which appear not to be under ovarian control. PMID- 7843324 TI - Increased beta-endorphin but not Leu-enkephalin in plasma due to preoperative stress. AB - The levels of beta-endorphin and Leu-enkephalin were measured in the plasma of 23 children (16 male, 7 female) who were admitted to the Children's Hospital for elective (non-emergency) surgery, adenoidectomy and/or tonsillectomy. Two blood samples were obtained preoperatively. The first sample was taken during admission to the hospital; the second on 24 h later and just 5 min before the operation, without pre-medication or narcosis. beta-endorphin and Leu-enkephalin levels were measured using a RIA method after solid phase extraction of the samples. Mean beta-endorphin concentrations during admission to the hospital were 11.77 +/- 9.36 pg/ml. Twenty four hours later, and just 5 min before surgery, the mean levels of beta-endorphin were increased to 27.45 +/- 16.66 pg/ml. A statistically significant increase (t-value = -5.42) was found for beta-endorphin levels 5 min before the operation compared with 24 h earlier (2-tail probability p < 0.0001). The Wilcoxon matched-pairs signed-ranks-test also showed p < 0.0001 (Z = -4.197). In contrast, Leu-enkephalin levels remained unchanged. The mean values were 11.44 +/- 1.49 pg/ml on the day of admission, and 12.11 +/- 2.08 pg/ml 5 min before the operation. We did not find statistically significant differences between the paired samples (t-value = -1.53, 2-tail probability p = 0.139). The increase in beta-endorphin could be the result of preoperative anxiety about the narcosis and surgery. PMID- 7843326 TI - Comparison of three different methods for determining yeast killer toxin K1 activity and standardisation of units. AB - A new rapid assay of the yeast killer toxin K1 activity in Saccharomyces cerevisiae, the BCP (bromocresol purple) fluorescence test, was compared with two standard methods, the plating test and the well test. The BCP test is as precise as the plating test and more sensitive than the well test. Under suitable conditions, the test is universally applicable for determining the proportion of cells with a damaged plasma membrane in a population. A procedure was developed for calculating the results of all three tests in terms of a single well-defined unit (lethal or killer unit, LU). PMID- 7843325 TI - Production of mouse immunoglobulin G by a hybrid plant derived from tobacco-mouse cell fusions. AB - Mouse-tobacco hybrid calli, and complete plants producing mouse gamma-3 heavy and lambda light chains, have been generated by somatic cell fusions of mouse spleen cells and tobacco mesophyll protoplasts. Both gamma 3 and lambda chains were detected in hybrid calli and complete plants by enzyme-linked immunosorbent assay, immunofluorescent staining, and Western blotting. When cellular DNA from hybrid tobacco mesophyll protoplasts was amplified by the polymerase chain reaction (PCR) using two pairs of gamma 3 chain DNA primers and one pair of lambda chain DNA primers, the PCR products contained gamma 3 and lambda chain DNAs, which could be detected by southern blotting and DNA hybridization, using specific synthetic oligonucleotide probes for gamma 3 and lambda respectively. In situ hybridization of hybrid tobacco mesophyll protoplasts with specific recombinant DNA probes of gamma 3 and lambda chains showed the presence of gamma 3 and lambda chain DNAs in the hybrid protoplasts. PMID- 7843327 TI - Protection against alloxan-induced diabetes by various dialkyldithiocarbamates. AB - Dialkyldithiocarbamates injected into mice 0.5 h prior to alloxan protected dose dependently against the diabetogenic action of alloxan, and increased blood glucose levels at the time of alloxan injection. Furthermore, they exhibited anti oxidative properties in vitro such as inhibition of lipid peroxidation, removal of hydrogen peroxide and reduction of the stable free radical, 1, 1-diphenyl-2 picrylhydrazyl (DPPH). These results suggest that dialkyldithiocarbamates protect against the development of alloxan-induced diabetes by the indirect mechanism of producing hyperglycemia at the time of alloxan injection and possibly by their anti-oxidative effects as well. PMID- 7843328 TI - 'Waste waters' from olive oil production are rich in natural antioxidants. AB - Milling of olive paste during olive oil production is accompanied by continuous washing with water, i.e. malaxation. The resulting 'waste-water' is currently discarded. Since olives and olive oil are rich in natural antioxidants, we hypothesized that some of these might be extracted from the olive paste during malaxation. Interest in natural antioxidants is increasing because of the growing body of evidence indicating the involvement of oxygen-derived free radicals in several pathological processes, such as cancer and atherosclerosis. A waste-water extract was characterized by HPLC and tested in a model of lipid peroxidation, copper sulphate-induced oxidation of low density lipoproteins. The results demonstrate that waste-water extracts have powerful antioxidant activity and might therefore represent a cheap, as yet unused, source of natural antioxidants. PMID- 7843330 TI - Proteinaceous precursors of human axillary odor: isolation of two novel odor binding proteins. AB - The characteristic odor which arises in the human axillary region consists of volatile C6-C11 acids with the most abundant being (E)-3-methyl-2-hexenoic acid (E-3M2H). This acid, as well as several other components of the characteristic axillary odor, can be liberated from the odorless, aqueous soluble components of apocrine secretion by either saponification or bacteriolysis. It is therefore likely that a major characteristic odor is being carried to the skin surface bound to a water soluble precursor where it is liberated by axillary bacteria. The individual proteins found in apocrine secretions were separated, isolated and hydrolyzed with the resultant hydrolyzates analyzed by gas chromatography/mass spectrometry. These studies demonstrated that 3M2H was liberated from 2 proteins with apparent molecular mass of 26 and 45 kilodaltons: Apocrine Secretion Odor Binding Protein 1 and 2, respectively (ASOB1 and ASOB2). Antisera to these proteins were prepared and used to examine a variety of other body fluids. Several fluids contained an immunoreactive protein with the same electropheretic migration pattern as the 45 KDa protein. Three of these body fluids (tears, nasal secretions and saliva) were separated into aqueous and organic soluble fractions and hydrolyzed to demonstrate that 3M2H could be liberated from the aqueous soluble materials. These results suggest interesting parallels between non-human mammalian odors used as chemical signals and human axillary odor. Previous studies have suggested the axillae as a source of human primer-type pheromones; consequently, if the odors which characterize the underarm are responsible for the pheromonal activity, then the chemistry involved may be similar to that in other mammalian chemical communication systems where proteins act as carriers of one or more chemical signals. PMID- 7843329 TI - Biological activity of secondary metabolites from Bupleurum salicifolium (Umbelliferae). AB - Secondary metabolites from Bupleurum salicifolium were tested against viruses, Gram-positive and Gram-negative bacteria, the yeast Candida albicans, the nematodes Globodera pallida and G. rostochiensis, the insect Spodoptera littoralis and the crustacean Artemia salina. These compounds were also tested against tumoral and non-tumoral cell lines. The polyacetylene 8S-heptadeca-2(Z) 9(Z)-diene-4,6-diyne-1,8-diol exhibited toxicity for A. salina and specific antibiotic activity against Gram-positive bacteria. Nine of the lignans and one coumarin showed toxicity for A. salina, and the lignans bursehernin and matairesinol inhibited the hatching of the two nematode species. These are the first lignans that have been reported as affecting phytoparasitic nematodes, and the first natural products known to have an effect on the hatching of G. pallida. Lignans may play a role in the defence mechanisms of potato plants, as allelopathic substances acting against cyst-forming nematodes. PMID- 7843331 TI - Preload recruitable stroke work in the presence of intact cardiovascular reflexes in rats fed a diet high in unsaturated fats. AB - A decreased inotropic effect of myocardial beta receptor agonists in animals receiving diets high in unsaturated fats (UNSAT) has been demonstrated. The effect of an UNSAT diet on myocardial systolic performance under different loading conditions, in the presence of intact cardiovascular reflexes, has not been examined. We investigated the effect of an UNSAT diet on preload recruitable stroke work (SW) in the anaesthetised, open chest, ventilated rat. A control (CONTROL, 11% by energy), a high saturated fat (SAT, 37% by energy) and a high UNSAT (37% by energy) diet were fed to three groups of rats. At three months, systolic myocardial performance (stroke work: SW) at increasing left ventricular end diastolic pressures (LVEDP) was measured within a physiological preload range. There were no significant differences in either the slope or the intercept of the LVEDP/SW relation were found between the three diet groups. Systemic vascular resistance and heart rate decreased to the same extent in the three diet groups over the range of preloads examined. This occurred as a consequence of intact baroreceptor reflexes. Hence dietary modulation of unsaturated fats does not influence myocardial contraction over a wide range of physiological preloads in the presence of intact baroreceptor reflexes. PMID- 7843332 TI - 2-Methoxybenzoyl phosphate: a new substrate for continuous fluorimetric and spectrophotometric acyl phosphatase assays. AB - A new aromatic acyl phosphate, 2-methoxybenzoyl phosphate, has been synthesized. The compound shows an intrinsic fluorescence; it displays an intense emission band at 390 nm upon excitation in the near UV region. This band practically disappears after hydrolysis of the product. On the other hand, the product displays differences in the near UV absorption spectra measured before and after hydrolysis. The delta epsilon at 301 nm is 2720 M-1 cm-1, a value that is 4.3 fold higher than that of benzoyl phosphate (the usual substrate for acylphosphatase assay) at 283 nm. The main kinetic parameters of three different acylphosphatase molecular forms (the muscular isoenzyme and two subtypes of the organ common isoenzyme) were determined using both benzoyl phosphate and 2 methoxybenzoyl phosphate as substrates, and then compared. These kinetic data and the UV absorption and fluorescence properties of 2-methoxybenzoyl phosphate suggest that this compound has better substrate features than benzoyl phosphate, and can be used for both high sensitivity continuous fluorimetric and UV absorption spectrophotometric assays of acylphosphatase. PMID- 7843333 TI - Powerful hepatoprotective and hepatotoxic plant oligostilbenes, isolated from the Oriental medicinal plant Vitis coignetiae (Vitaceae). AB - The methanol extract of the Oriental medicinal plant Vitis coignetiae (Vitaceae) showed hepatoprotective activity in the in vitro assay method using primary cultured rat hepatocytes. Activity-guided fractionation of the extract afforded epsilon-viniferin as an active principle. The protective effect of epsilon viniferin against mice carbon tetrachloride-induced hepatic injury in mice was shown by serum enzyme assay as well as by pathological examination. In addition to epsilon-viniferin, plant oligostilbenes, ampelopsins A, C, F and the mixture of vitisin A and cis-vitisin A were also present in the extract. Among them, ampelopsin C and the mixture of vitisin A and cis-vitisin A were found to be powerful hepatotoxins. PMID- 7843334 TI - Genotoxic evaluation of ten carcinogens in the Drosophila melanogaster wing spot test. AB - To provide further background data on the wing spot somatic mutation and recombination assay, 10 selected carcinogens (acetamide, acrylamide, benzo(a)pyrene, cyclophosphamide, diethylstilbestrol, 4-nitroquinoline N-oxide, propyleneimine, safrole, thiourea, and o-toluidine) were tested in this assay. 72 h-old third-instar larvae, trans-heterozygous for 2 recessive wing cell markers: multiple wing hairs (mwh) and flare3 (flr3) were fed with 3 concentrations of each carcinogen during the rest of their development until pupation, and the genotoxic effects were measured as significant increases in the appearance of visible mutant hair clones on the adult wing blade. Our results show that 6 of the carcinogens tested produce significant increases in wing spot frequency, at least at one of the concentrations assayed. Benzo(a)pyrene, diethylstilbestrol, safrole and thiourea were the compounds that did not increase the incidence of mutant clones. PMID- 7843335 TI - Selection of biting sites on man by two malaria mosquito species. AB - While searching for blood, female mosquitoes pass through a behavioural process involving responses to visual, physical and chemical properties of the host. Temperature and humidity are thought to dominate mosquito orientation near the host. We observed that biting of two malaria mosquito species, i.e. Anopheles atroparvus (van Thiel) and Anopheles gambiae s.s. (Giles) preferentially occurs on different body regions of a naked motionless human host. Their preference for the head and foot regions respectively correlated with particular combinations of skin temperature and eccrine sweat gland density. Subsequent modification of the host's odour profile by removing exhaled breath and washing feet results in significant changes of these preferences. PMID- 7843336 TI - Expression pattern of uricase II gene during root nodule development in Phaseolus vulgaris. AB - A Phaseolus vulgaris uricase II cDNA clone has been isolated and sequenced. Comparison on the nucleotide level between this clone and the soybean uricase II clone revealed 88.8% identity. The in situ hybridization technique was used to follow the expression pattern in developing root nodules of Phaseolus vulgaris. The uricase II transcripts were localized only in the uninfected cells of the central tissue and mainly in the periphery of the cell. Uricase II mRNA is first detected in nodules 12 days after infection. A maximum level of transcripts is reached in 21-day-old nodules, followed by a considerable reduction in 28-day-old nodules. PMID- 7843337 TI - Cigarette smoking and acute myocardial infarction. A case-control study from the GISSI-2 trial. GISSI-EFRIM Investigators. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto--Epidemiologia dei Fattori di Rischio dell'infarto Miocardioco. AB - To make a further quantitative assessment of the relationship between cigarette smoking and the risk of myocardial infarction, a multicentric case-control study was conducted in Italy between September 1988 and June 1989 within the framework of the GISSI-2 trial. Ninety hospitals in various Italian Regions participated. 916 cases of acute myocardial infarction with no history of ischaemic heart disease and 1106 controls admitted to hospital for acute conditions not related to known or suspected risk factors for ischaemic heart disease were studied. Relative risks (RR) and 95% confidence intervals (CI) of myocardial infarction according to various measures of tobacco smoking, were adjusted for identified potential confounding factors using multiple logistic regression. Compared to lifelong non-smokers, the RR was 1.3 (95% CI 1.0 to 1.9) for ex-smokers, 2.0 (95% CI 1.4 to 2.9) for current smokers of less than 15 cigarettes per day, 3.1 (95% CI 2.2 to 4.2) for 15-24 cigarettes per day and 4.9 (95% CI 3.4 to 7.1) for 25 or more cigarettes per day. No trend in risk was evident for the duration, the RR being around 3 for subsequent categories. There was a significant interaction between smoking and age. Below the age 45, smokers of 25 or more cigarettes per day had a 33 times higher risk than non-smokers, compared to 7.5 at in the age group 45-54, 4.4 between the ages 55-64 and 2.5 at the age of 65 or over. The risk estimates were higher in women (RR for > or = 25 cigarettes per day = 10.1), in subjects in the lowest cholesterol tertile (RR = 11.9), with no history of diabetes (RR = 6.8), hypertension (RR = 9.5), no family history ischaemic heart disease (RR = 9.1) and low body mass index (RR = 9.3). The importance of smoking is confirmed as a cause of acute myocardial infarction: about 50% of all nonfatal infarctions in this Italian population could be attributable to cigarette smoking.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843338 TI - Salmonella typhimurium and Salmonella enteritidis: changing epidemiology from 1973 until 1992. AB - A retrospective analysis, covering a period of 20 years, of 2049 primo-isolates of Salmonella typhimurium and 343 primo-isolates of Salmonella enteritidis was performed at our laboratory. In 1991, S. enteritidis (43.8%) outnumbered S. typhimurium (32.1%) as the most frequently isolated Salmonella. The age group distribution of S. enteritidis yielded peaks in the under-five and above-60 year age groups, whereas S. typhimurium only peaked in the under-five age group. S. enteritidis appeared to be twice as invasive as S. typhimurium. Both serotypes were more invasive in middle and older age groups than in under-fives. PMID- 7843339 TI - Impact of sexual habits on the clinical evaluation of male HPV infection. AB - A series of 199 male regular sexual partners of women attending an STD clinic for the examination and treatment of HPV-associated diseases was examined by peniscopy, surgical biopsy and nucleic acid hybridization for the presence of clinical, histological and molecular markers pathognomic of HPV infection. There was a 100% correlation between condylomata acuminata and detection of HPV type 6 or 11 DNA. Papillary lesions displayed neither histological signs of HPV infection, nor did they harbor HPV DNA (viral types 6, 11, 16, 18, 33) while 44.9% (22/49) of acetowhite epithelia showed HPV-suggestive histological changes. Of the 19 analysed for HPV DNA, 15.8% (3/19) harbored HPV 6/11 and 16 DNA. Regular male and female sexual partners did not always harbor the same HPV types, showing that latent or occult infection and the sexual habits of each individual play an important role in the clinical manifestations of HPV infection observed in sexual couples. The present data show that: i) the likelihood of developing a clinical HPV lesion was affected, to a large extent, by the previous sexual history and habits in the partners of women with flat condylomata, while partners of women with condylomata acuminata or CINs displayed a higher correlation with the current state of infection in their regular partner; ii) despite the assessed infective state of their consorts, men with a low lifetime number of sexual partners seldom displayed HPV-associated acetowhitening.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843340 TI - Blood lead levels in shopkeepers and car traffic pollution in Liguria, Italy. AB - A study was conducted into the exposure to atmospheric pollution caused by car traffic by measuring blood lead (PbB) levels in a sample of 657 adult individuals (shopkeepers) all living in Liguria. The mean level of blood lead in all examined individuals was 9.39 micrograms dl-1 (0.45 mumol per liter; C.I. 95%: 9.06-9.75 micrograms dl-1; 0.44-0.47 mumol per liter) with a range between 2.0 and 46.03 micrograms dl-1 (0.10-2.22 mumol per liter). The average Pb values in individuals working in streets with high and very high traffic was 8.30 micrograms dl-1 (0.40 mumol per liter; C.I. 95%: 7.41-9.31 micrograms dl-1; 0.36-0.45 mumol per liter) and 9.98 micrograms dl-1 (0.48 mumol per liter; C.I. 95%: 9.62-10.37 micrograms dl-1; 0.46-0.50 mumol per liter), respectively. These average blood lead levels were statistically greater than the average PbB values of those working in low traffic streets (7.06 micrograms dl-1; 0.34 mumol per liter; C.I. 95%: 6.22-7.94 micrograms dl-1; 0.30-0.38 mumol per liter). The percentile distribution (50th, 90th and 98th P) for all subgroups surveyed has always proved to be below the maximum limits specified by EC Directive No. 77/312. PMID- 7843341 TI - Mobility of Scottish injecting drug users and risk of HIV infection. AB - Nine hundred and nineteen injecting drug users (IDUs) were interviewed in Glasgow, Scotland during 1990 and 1991, as part of a wider study of HIV risk behaviour, about their injecting and sexual behaviour outside the city in the previous two years. Forty-five percent of respondents injected outside Glasgow, 6% shared needles and syringes (n/s) and 20% had sexual intercourse. Much activity occurred outside Scotland but mainly within the UK, particularly London. Predictors of n/s sharing outside Glasgow during the previous two years included current injecting with and passing on of used n/s and sexual intercourse with casual partners. Predictors of sexual behaviour outside Glasgow included passing on used n/s, having sexual intercourse with casual partners and, for females, engaging in prostitution. Glasgow IDUs are a highly mobile group and although HIV prevalence remains low within this population, considerable potential for importation/exportation of HIV and other bloodborne and sexually transmitted infections exists. Further work is required to establish why IDUs travel to, and engage in high-risk activities in locations outside their home environment, and detailed data about activities such as frequency of condom usage and n/s cleaning practices need to obtained. While there is a widespread network of services for IDUs in the UK, information provided usually relates to local services and may not fully address the needs of this mobile population. Therefore, we recommend that IDUs be provided with details of facilities such as n/s exchange schemes and drug-treatment establishments in centres to where they most commonly travel. PMID- 7843342 TI - Construction of plasmids useful for production of the B subunit of cholera toxin from Vibrio cholerae or a heat-labile enterotoxin from enterotoxigenic Escherichia coli. AB - A simple method to construct the plasmids producing the B subunit of porcine or human heatlabile enterotoxin or cholera toxin was developed, and the B subunits produced by the resulting plasmids were purified. The gene of LTp from pEWD 299 was ligated to pHSG 396 or pBluescript SK(+)-1 and the vector carrying one Xbal and EcoR1 site in the LTp-A gene was constructed. The Xbal-EcoR1 fragment of LTp A gene was exchanged for the multicloning site of pHSG 396 containing Xbal, BamH1, Cla 1, Kpn1, Sac1 and EcoR1 sites. This plasmid (pTSU28) produced the LTp B subunit. Moreover, the fragment of the LTp-B gene of pTSU 28 was exchanged by the EcoR1-HindIII fragment of LTh-B from E. coli H10407 strain (pTSU 35) or by the Cla 1-Hind III fragment of CT-B gene amplified by the PCR procedure with the chromosomal DNA of V. cholerae 86KT25 (pTSU 32). The DNA sequence of the CT-B subunit amplified by PCR procedure was compared and found identical to that cited in the literature [11]. After these plasmids were transformed into E. coli MV 1184 strain, the toxins produced by them were purified using a Bio-Gel A 5m affinity column for both LT-Bs and an immunobilized D-galactose affinity column for CT-B. Though both columns absorbed only the B subunit, the eluates contained a single protein corresponding to the B subunit, suggesting that each mutant produces only the B subunit. PMID- 7843343 TI - Malaria epidemiological trends in Italy. AB - Based on the official reports received from local health laboratories, an epidemiological analysis of malaria cases reported in Italy from 1989 to 1992 is presented. A total of 1,941 cases were reported, 1,287 among Italians and 654 among foreigners. The incidence of cases was on average 500 per year with a maximum in 1990. A slight, but constant decrease of incidence of malaria cases was recorded in this period among Italian citizens (-21.5%), while the incidence among foreigners increased (+80%). Plasmodium falciparum accounted for 74.2% of total infections, followed by P. vivax (19%). The highest number of cases was imported from Africa (86.5%), followed by Asia, South America, and Oceania. 11 cases were contracted in Europe (transfusion, airport and cryptic malaria). 26 people died from malaria during the four years, with a fatality rate of 2.3% among Italians. Other epidemiological features concerning incidence in the different categories of travellers, countries of infection, clinical and therapeutic aspects of cases, are also discussed. PMID- 7843344 TI - Drug data coding and analysis in epidemiologic studies. AB - In epidemiologic studies that collect comprehensive information on medication use, the complexity of dealing with a large number of trade and generic names may limit the utilization of these data bases. This paper shows the specific advantage of using two coding systems, one to maximize efficiency of data entry, and the other to facilitate analysis by organizing the drug ingredients into hierarchical categories. The approach used by two large surveys, one in the USA and one in Italy, is described: the Established Populations for Epidemiologic Studies of the Elderly (EPESE) and the 'Gruppo Italiano di Farmacovigilanza nell' Anziano' (GIFA). To enter the medications into a computerized database, codes matching the drug product names are needed. In the EPESE the prescription and over the counter drug products are coded with the Drug Products Information Coding System (DPICS) and the Iowa Nonprescription Drug Products Information Coding System (INDPICS), respectively. The GIFA study uses the coding system of the Italian Ministry of Health (MINSAN), with a unique numeric code for each drug product available in Italy. To simplify the analytical process the drug entry codes are converted into hierarchical coding systems with unique codes for specific drug ingredients, chemical and therapeutic categories. The EPESE and GIFA drug data are coded with the Iowa Drug Information System (IDIS) ingredient codes, and the Anatomical Therapeutic and chemical (ATC) codes, respectively. Examples are provided that show coding of diuretics in these two studies and demonstrate the analytic advantages of these systems. PMID- 7843346 TI - Is plasmid based differentiation of Coxiella burnetii in 'acute' and 'chronic' isolates still valid? AB - Ten human Coxiella burnetii isolates from french patients with acute hepatitis or chronic endocarditis were characterized according to their polymorphism in DNA restriction patterns and differentiated by plasmid-specific PCR. The aim of this investigation was to clarify if the present classification of so called 'acute' and 'chronic' Coxiella burnetii isolates--based on plasmid profile of a so far limited number of partly ancient isolates--could be confirmed with lately isolated organisms of this agent. The data obtained in this investigation indicate that this classification based on C. burnetii plasmid content is no longer justified. PMID- 7843345 TI - Analysis of the entire nucleotide sequence of the cryptic plasmid QpH1 from Coxiella burnetti. AB - The complete plasmid QpH1 from Coxiella burnetti, isolate 'Nine Mile', phase I, was cloned as NotI fragment with a size of 37329 bp. The entire plasmid was sequenced by the chain termination method after EcoRI subcloning. 37 open reading frames coding for polypeptides larger than 100 amino acid residues were determined. The predicted polypeptide products of the open reading frames were compared by computer analysis with reported protein sequences. Homologies of predicted polypeptide products to analogous proteins are described. PMID- 7843347 TI - Histoplasmosis capsulati in Italy: autochthonous or imported? AB - Reports of a few apparently autochthonous cases of human histoplasmosis and results of epidemiological research suggested the autochthonous presence of the disease in Italy. Identifying two new histologically documented cases of Italian patients, who had never been abroad, and, the positive results of a histoplasmin reactivity survey carried out in the Province of Cremona, Italy confirmed this possibility. PMID- 7843348 TI - Falls, hip fractures and the weather. AB - The time of fall for 429 patients with a hip fracture was correlated with the prevailing weather conditions. Results show that other than for ground frost, there was no significant association between the prevailing weather conditions and no seasonal variance in the incidence of hip fractures. PMID- 7843349 TI - Steady HIV prevalence among pregnant women in Marseille, France. PMID- 7843351 TI - 7th European Meeting of Influenza and Its Prevention. Berlin, 22-24 September 1993. PMID- 7843350 TI - A double malarial infection in a soldier returning from Somalia. PMID- 7843352 TI - Europe preparing to face an influenza pandemic. PMID- 7843353 TI - Introduction to pandemic influenza through history. AB - For the past 400 years, epidemics resembling influenza have been recorded in many countries. Epidemics from as early as the 16th Century in England and the 18th Century in the USA are recognizable as influenza, even in the absences of precise knowledge of their causative agents. PMID- 7843354 TI - Source for influenza pandemics. AB - There are three ways how influenza A viruses can escape the immune response in the human population: (1) By antigenic drift. This means by mutation and selection of variants under the selection pressure of the immune system. These variants have amino acid replacements mainly in the epitopes of the hemagglutinin. (2) By antigenic shift. This means replacement of at least the hemagglutinin gene of the prevailing human strain by the allelic gene of an avian influenza virus by reassortment. (3) As a rare event, direct or indirect introduction of an avian influenza virus in toto into the human population. A prior introduction of an avian virus into pigs and an adaptation to the new host might be a presupposition for its final passage to humans. In this sense the nowadays situation is reminiscent to that of about 100 years ago, when an avian virus was presumably first introduced into pigs, and from there into humans. Immediately or some time thereafter the disastrous Spanish Flu in 1918/19 had killed at least 20,000,000 people in one winter. Pandemic strains can be created by all three means, however the most common way is by reassortment. In order to recognize a pandemic strain as soon as possible a worldwide surveillance system and collaborating laboratories equipped with corresponding modern technologies are required. PMID- 7843355 TI - Role of international networks for the surveillance of influenza. PMID- 7843356 TI - Identification of pandemic viral strains. Role of the national reference centre. AB - The identification of a pandemic viral strain will be performed by the National Reference Centres. The well established sentinels network collecting respiratory samples is able to work not only during the winter season but also a part from it and to allow the early detection of new variants. It also supplies pertinent clinical and epidemiological data in order to correlate a new strain with authentic pathogenic and epidemiologic potential. Based on the previous pandemics experiences, and on the current circulating Influenza strains in humans and animals, a limited number of H and N antigens could be expected as component of a new pandemic strain. The recent rapid tests for the detection and the isolation of influenza viruses permit the diagnosis of a new strain within a few days or weeks. Rapid exchanges of data, strains and reagents under the WHO authority would help in a rapid prediction of a pandemic risk. PMID- 7843357 TI - Antigenic and genetic characterization of current influenza strains. AB - Annually the influenza centre receives more than 1000 virus isolates from around the world to monitor the changing pattern of viruses causing influenza throughout the year. These are characterized antigenically using both polyclonal and monoclonal antibodies and selected viruses are subjected to closer scrutiny by nucleotide sequence analyses of their HA genes. This information is used in making the annual recommendation of vaccine composition. As in the last 15 years, influenza A viruses of both H3N2 and H1N1 subtypes and influenza B viruses have been isolated during the recent influenza season. Outbreaks in the northern hemisphere were largely caused by influenza B viruses which are similar to the B/Panama/45/90 reference strain. The proportion of influenza A increased later in the season and was predominantly of the H3N2 subtype, viruses similar to the recent A/Beijing/32/92 variant being most prevalent. The observed changes taking place will be discussed in the context of recent trends. PMID- 7843358 TI - Influenza: global surveillance for epidemic and pandemic variants. AB - Influenza viruses, unlike other viruses for which vaccines have been developed, undergo rapid and unpredictable antigenic variation in the hemagglutinin (HA), the surface glycoprotein primarily responsible for eliciting neutralizing antibodies during infection. Because of this antigenic variability and its consequences, the World Health Organization (WHO) in 1947 established an international network of collaborating laboratories to monitor the emergence and spread of new epidemic and pandemic strains of influenza. This network now includes three international WHO collaborating centers and over 100 WHO national collaborating laboratories. The primary purpose of this network is to detect, through laboratory surveillance, the emergence and spread of antigenic variants of influenza that may signal a need to update the formulation of the influenza vaccine. This laboratory surveillance network has provided the strains needed to update the vaccine as well as a repository of influenza viruses useful for studying the antigenic and genetic evolution of this virus. Knowledge gained from molecular studies on the evolution of drift variants and on the emergence of pandemic strains has made influenza a useful model for understanding the potential threat of other emerging or reemerging microbial diseases. PMID- 7843359 TI - A mathematical model for the European spread of influenza. AB - Following a study modelling the geographical spread of influenza in France, on the basis of population movements through the use of railroad data, we applied the same methodology on a European scale. We simulated an epidemic within a network of 9 European cities (Amsterdam, Berlin, Budapest, Copenhagen, London, Madrid, Milano, Paris, Stockholm), only taking into account regular between cities air transport. Transportation data were obtained from the International Civil Aviation Organization (1991). The theoretical results show that the time lag for action is probably short (less than one month) after the first detection of an epidemic focus. PMID- 7843360 TI - When is the epidemic warning cut-off point exceeded? PMID- 7843361 TI - Constitution and monitoring of an epidemiological surveillance network with sentinel general practitioners. AB - The Reseau National Tele-informatique de surveillance et d'information sur les Maladies Transmissibles (RNTMT) (French communicable diseases computerised surveillance network) comprises a network of sentinel general practitioners (SGP). These benevolent volunteers are responsible for the weekly epidemiological surveillance. Since its creation, 1,700 SGPs have participated in the RNTMT, representing a total of more than 120,000 connections to the RNTMT telematic service center. The principal motivation of these benevolent SGPs was to 'actively participate in public health', although only a minority of them (17.6%) had any training in this field. Such a system, based on the benevolent and voluntary activity of SGPs, requires a good understanding of SGPs' attitudes towards epidemiological surveillance in general and the tool used, in order to quantitatively and qualitatively follow their participation and to provide regular and useful feedback to the surveillance actors. PMID- 7843362 TI - The prediction of epidemics of respiratory infection. AB - Experience from 25 years of clinical monitoring of influenza and related illnesses has been considered in relation to the prediction of epidemics of influenza. The monitoring has taken place in a network of sentinel practices in England and Wales who report new episodes of illness weekly as they occur. The practice data are aggregated at the Birmingham Research Unit of the Royal College of General Practitioners and weekly rates per 100,000 population are published in age-specific groups. Major epidemics of respiratory infection are heralded by an increase in the weekly rates for influenza and influenza-like illness of 30 per 100,000 and by increase in the rate for all acute respiratory illness of 150 per 100,000. Increases of this magnitude have been consistently associated with major epidemics of respiratory illness which in turn cause substantial increases in deaths. When epidemics occur around the turn of the year, respiratory syncytial virus has to be considered as a possible cause but otherwise epidemics of this magnitude are invariably due to infection by Influenza A virus. PMID- 7843363 TI - Influenza vaccines: a main problem in control of pandemics. AB - The optimal strategy for control of pandemic influenza is early vaccination with influenza vaccine produced from influenza pandemic strains. However, for pandemic control, vaccine improvements are essential and should include quicker ways of manufacturing and testing of vaccine as well as flexibility on the part of licensing bodies. The production of mass doses of monovalent vaccine in a short time can be more realistic if egg independent production technology can be adopted. In this respect production of an influenza vaccine on a stable cell line can solve many of the problems in increased production of influenza vaccine. But the difficulty with influenza vaccines is that the yield of human influenza viruses on tissue culture is much lower than in embryonated eggs. A new high yield donor is needed for construction of recombinants with a new pandemic strain, which can replicate in a stable cell line with high titre. The live influenza vaccine may be the most appropriate for prophylaxis of influenza pandemic, as the implementation of this vaccine for mass vaccination is simpler than of inactivated influenza vaccine, and this vaccine, after one immunization of unprime persons, induces local mucocosa immunity which plays an important role in the protection against influenza. PMID- 7843364 TI - Vaccine manufacture at the time of a pandemic influenza. AB - In the event of a major influenza epidemic, the availability of a potent and safe vaccine would be a major concern. The following presentation describes the main features of a flu vaccine manufacturing campaign: beginning with the supply of embryonated eggs, in which the flu viruses are cultivated, through the different steps of vaccine production - egg harvest, purification, inactivation, splitting down to the final vaccine formulation and aseptic filling in the appropriate containers. In usual times, such a production cycle takes over 70 weeks. In an emergency situation, the manufacturers and the authorities would have to take innovative approaches to minimize such delays. This will inevitably translate into an enormous strain on all the players in such a project, from the egg suppliers to the organisers of the vaccine dispatching and administration. It will result in suboptimal yields and costs. However, facing a massive and urgent need of vaccine, both the authorities and the vaccine manufacturers must work together to supply the necessary doses in time. PMID- 7843365 TI - Therapeutic approaches of clinicians to influenza pandemic. AB - In the event of influenza pandemic, clinicians have to be sure that vaccination has been correctly performed in all patients in whom it is usually recommended. Pregnant women should probably be vaccinated. Vaccination of health personnel is recommended to limit transmission of nosocomial influenza to high-risk persons, and to decrease the risk of absenteeism related to influenza. Chemoprophylaxis is effective in preventing influenza A, and is indicated in high-risk persons with major contraindication or impaired response to vaccination or who have not yet been vaccinated. PMID- 7843366 TI - Surveillance of influenza in the United Kingdom. Pandemic and interpandemic period. AB - In the United Kingdom the morbidity surveillance is carried out by the General Practitioner Spotter Practice Schemes (RCGP), the Medical Officers of Schools Association (MOSA) and the Emergency Bed Service. Mortality data is provided weekly by the Office of Population and Censuses and Surveys (OPCS). PHLS Communicable Disease Surveillance Centre (CDSC) collects all information and publishes the findings weekly in the Communicable Disease Report (CDR). There are 53 Public Health Laboratories situated in all parts of England and Wales. Most of these laboratories provide diagnostic services for influenza, together with many National Health and academic laboratories. A similar service is also available in Scotland. PMID- 7843367 TI - The PHLS response to a pandemic of influenza. An action plan. PHLS Influenza Subcommittee. AB - This document sets out the Public Health Laboratory Service (PHLS) action plan for responding to an influenza pandemic. The plan entails, in phase 0, interpandemic surveillance by the Communicable Disease Surveillance Centre (CDSC) and the Enteric & Respiratory Virus Laboratory (ERVL) of the Central Public Health Laboratory (CPHL), as well as maintenance by Area & Regional (A & R) Public Health Laboratories of updated diagnostic techniques for influenza. In phase 1 (the emergence of a 'shifted' influenza virus strain) a Pandemic Working Group will be convened to consider what action by PHLS is necessary. In phase 2 (pandemic influenza outside UK) the pre-defined roles for PHLS laboratories and CDSC will be adopted. When a pandemic is imminent in the United Kingdom (phase 3) the Working Group will coordinate PHLS activities and the Director of the Service will assess what special studies should be implemented. In phase 4, when the pandemic has reached the UK, the action plan sets out comprehensive measures that will be taken by CDSC, ERVL and A & R Laboratories to gather and collate information, provide DoH with weekly surveillance data and develop recommendations for prophylaxis, clinical management and treatment. When influenza activity has returned to background levels (phase 5) a report will be drafted by the Working Group prior to it being stood down by the Director of the Service. The response is summarised in tabular form in Table 1. PMID- 7843368 TI - Pandemic planning in Canada. AB - A Canadian plan for pandemic influenza was completed by the National Advisory Committee on Immunization in 1988. Its development took several years and involved consultation with provincial public health and laboratory authorities, the licensing body, manufacturers of influenza vaccine and antiviral agents, and representatives in the USA and UK. Key decisions in creating the pandemic plan include: (1) aiming for federal-provincial consensus on use of vaccine and antiviral drugs, (2) a selective vaccination approach (high-risk persons plus essential workers), (3) bulk purchasing and distribution of vaccine through the public sector, (4) leaving antiviral drugs on the open market, (5) careful planning of the communications strategy, and (6) increasing inter-pandemic use of flu vaccine in target groups. The plan addresses recognition of a pandemic; activation of a Pandemic Influenza Committee whose membership and responsibilities are spelled out; the federal-provincial decision making process; influenza vaccine considerations; amantadine and other antiviral agents; estimates of target group size, vaccine uptake, manufacturing capabilities and time frames; and communication considerations. Since 1988, influenza vaccine use has increased considerably in Canada and experience has been gained with amantadine. Manufacturing capability within Canada for influenza vaccine has also been enhanced. It is now time to update the plan, especially the targets, and to make sure that everyone involved remains aware of the assigned roles. PMID- 7843369 TI - Role of the French drug licensing authority in the prevention of influenza pandemics. AB - The French Drug Agency is responsible for the control and delivery of batch release certificates. In the case of an influenza pandemic, the use of inactivated vaccines, produced according to well-established procedures and controlled according to the European Pharmacopea and FDA requirements, will be strictly dependent on the necessary delays for production and controls. Mutual recognition between the National Control Laboratories in Europe might help in shortening the delays. If new, inactivated vaccines are produced either on cell cultures or by using genetically modified organisms, and if live attenuated vaccines are needed, it would be suitable to organize ad hoc working groups and international collaborative studies in fields of both research and regulation. PMID- 7843370 TI - Attitude of the French Armed Forces Health Service to the risk of influenza pandemic. PMID- 7843371 TI - Populations of persons who must be vaccinated with priority. AB - During a major pandemic of influenza, it would be impossible to vaccinate the entire population. Thus, it is necessary to determine which groups of individuals must be immunized with priority, considering the additional constraints related to the actual situation: to seek to reduce transmission of the virus and to maintain the activity of the community, especially those involved in public services. Another unavoidable factor must also be taken into consideration: the capacity for manufacturing and distributing the vaccine on an emergency basis. Lastly, contingency and planning measures must be made to avoid having to improvise. PMID- 7843372 TI - Licensing and control authority batch release of influenza vaccine in Germany in accordance with EEC regulations. AB - The epidemiological situation calls for almost yearly changes in the antigenic composition of influenza vaccine, thus necessitating fresh licensing procedures. Since the time for bringing a new vaccine onto the market should be relatively short, the following work of all parties involved must be done expeditiously: 1) WHO recommendations on new virus strains and their subsequent adaptation by the EEC (February/March); 2) Distribution of the new virus strains to the International Reference Centers for Influenza in the UK and USA (February/March); the centers later issue reference materials for the determination of the haemagglutinin antigen concentration (April/May); 3) Production and testing of seed virus by manufacturers, as well as validation of the producer's inactivation process for the new virus strains (May/June); 4) Licensing of the vaccines by the National Control Authority (Paul-Ehrlich-Institute) (June/July); in the case of previously licensed products, the procedure is limited essentially to the approval of the detailed protocol of production and tests on the new virus strains, clinical studies not being required before licensing because of a lack of time; 5) Paul-Ehrlich-Institute's test for batch release, according to Directive 89/342/EEC, besides protocol approval, conducts material testing of the endotoxin and antigen content of each vaccine lot; the assay for the antigen quantification is especially laborious and sometimes must be repeated because of test invalidity. PMID- 7843373 TI - Crisis communication in the event of a flu pandemic. AB - When we talk about planning we cannot avoid discussing information, prevention and reaction, three notions that underlie communication in times of emergency. From a management point of view, emergency information in the event of an influenza pandemic comes under two headings: preventive information and reactive information. An example of preventive information provided by GEIG has aimed to sensitize public opinion about the phenomenon of influenza, correcting various preconceived ideas about the illness and reinforcing faith in the influenza vaccine. The strategy adopted by GEIG is founded on a few simple rules: (1) One message/one voice, GEIG unites its areas of competence by relying on a Scientific Council that guarantees the legitimacy of its influenza information, (2) the collection and coordination of information, (3) the identification and prioritisation of target groups, (4) an understanding of the media based on working relationships, making GEIG a reference when it comes to opinion, (5) the conception of information packs adapted to different categories of the public (press packs, documents for health professionals, leaflets for the general public, etc.), and (6) side-by-side with its role as broadcaster, the GEIG has set up a mechanism for listening and for evaluation (public opinion surveys, special enquiries, etc.). These are reliable monitoring tools allowing constant updating of our information policy. Emergency strategy: reactive information. An influenza pandemic is a special kind of crisis, since it is a crisis of collective responsibility, requiring a rapid deployment of adapted communication techniques.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843374 TI - Norway: problems which a small and sparsely populated European country without a national vaccine production would face during a pandemic. AB - Since Norway at present has no national influenza vaccine production, there is some concern that during a pandemic influenza situation it would be difficult to secure even a limited quantity of appropriate influenza vaccine. It is conceivable that national emergency directives declared in the manufacturing countries would ban or severely hinder export of a life-saving commodity such as influenza vaccine. Most probably, this would be the situation for all European countries without a national influenza vaccine production. To ensure vaccine availability for the purchasing country even under a national influenza emergency situation declared in the manufacturing country such agreements must be safe against unilateral cancellation. PMID- 7843375 TI - Political fiction or a future scenario for a pandemic of influenza? PMID- 7843376 TI - Recommendations of the 7th European Meeting of Influenza and Its Prevention. PMID- 7843377 TI - Preliminary report of molecular detection of retinoblastoma gene mutations. AB - To develop gene diagnosis for retinoblastoma predisposition, it is necessary to disclose the retinoblastoma gene mutations or deletions in detail. Genomic DNA from tumor and peripheral white blood cells in 33 patients with retinoblastoma was detected with 3.8kb probe derived from 3' end of retinoblastoma gene cDNA. The gene abnormalities, including deletion, partial deletion and rearrangement, were found in 18 patients. Further research will be aimed at microdeletions or mutations for those patients without detectable variations in Southern hybridization. PMID- 7843378 TI - The study on improved cryopreservation technique of the ultrastructure of corneal endothelial cells. AB - The traditional corneal cryopreservation technique was improved. We carried out an experimental study that rabbit corneas were cryopreserved by using polyvinylpyrolidone (PVP) as cryoprotective agent and dimethylsulfoxide (DMSO) as the control. The endothelia of cryopreserved corneas were evaluated by scanning and transmission electron microscopy and vital staining. The study shows that PVP is an excellent extracellular cryoprotective agent and has the characteristic of low toxicity or not toxicity to corneal endothelia. PVP is able to enhance the cryoprotective action of DMSO when combined with DMSO. The changes of the ultrastructure of endothelial cells are able to reflect the endothelial viability. PMID- 7843379 TI - Assessment of sulfhydryl group in individual rat lens protein subunits during galactose cataract development. AB - A specific reagent DACM [N-(7-Dimethylamino-4-methyl-3-coumarinyl)maleimide] is used to study the -SH groups in lens proteins of normal and galactose cataractous rats. DACM when reacts readily with -SH groups form strong fluorescent adducts. The two -dimensional electrophoresis with DACM pre-labeled proteins is a simple and sensitive method for detecting -SH groups of protein subunit. In the present study, based on IEF/SDS-PAGE electrophoretically characterized soluble crystallins, describes specific changes in -SH groups of protein subunit during the development of galactose cataract. The contents of -SH groups of crystallins are progressively decreased in cataractous (5+) lens, the reduction of -SH content in alpha- and beta- crystallin protein subunits of the normal and cataractous lens proteins is also noticeable. PMID- 7843380 TI - The biological study of the cultured human lens epithelial cells in vitro. AB - The human lens epithelial cells (HLE) cultured in vitro was established in normal and cataractous lenses. The biological feature, histological characteristics and the ultrastructure of the cultured HLE cells were investigated. The results reveal that the proliferative capacity of the cultured HLE cells is reversely proportional to the donor age; the cultured HLE cells has the limited proliferative capacity in vitro. The relieve of the contact inhibition is the effective trigger of the HLE cell proliferation. This research work is possible to make a basis for the further study of the regeneration of the lens and the roles of the lens epithelial cells in the development of the cataract. PMID- 7843381 TI - The comprehensive control of astigmatism during and following intraocular lens implantation. AB - The operating corneoloscope and Terry operative keratometer were used respectively in 29 and 34 eyes during the intraocular lens implantation to measure the corneal astigmatism qualitatively or quantitatively, so that the tension of incision closure could be adjusted. The surgically induced astigmatism in qualitative group two weeks after the operation was 3.5 +/- 1.70 D and that in quantitative group was 2.56 +/- 1.60 D. There were 55.17% and 38.24% of the eyes with over 2.00 D corneal astigmatism in qualitative and quantitative group two months after the surgery. The astigmatism of both groups at the early stage after the operation was significantly lower than that of the control group (p < 0.05). Argon laser, Nd:YAG laser or razor-blade were used to cut 1 to 3 limbal sutures in 64 eyes with over with-the-rule astigmatism 2.25 D at the early stage (2 months) after the operation. One hour after suture cutting, the with-the-rule corneal astigmatism reduced significantly with an average of 2.61 D. The astigmatism continued to reduce and stabilized one month after the suture cutting. The arcuate keratotomy was performed in 21 eyes, of which the postoperative astigmatism was over 2.25 D (with the average of 3.34 D) more than 6 months after IOL implantation. The mean astigmatism was 0.82 and 1.18 D one day and 6 months after the keratotomy respectively. The uncorrected visual acuity improved significantly after the keratotomy. These results indicate that applying corneoloscope or Terry keratometer to adjust the tension of incision closure during operations, selected suture cutting at the early postoperative stage, and performing arcuate keratotomy at the late postoperative stage be the effective methods to reduce surgically induced corneal astigmatism. PMID- 7843382 TI - PVEP in patients with different types of congenital cataract. AB - The preoperative and postoperative PVEP in 79 eyes of 45 patients with three types of congenital namely lamellar cataract, nuclear cataract and total cataract was studied. The results showed that visual acuity of patients who could be cooperatively examined was improved significantly after operation. The examination of PVEP revealed that more abnormal waveforms were found in total cataract group before operation. P1 latencies of low and medium spatial frequencies (140', 70', and 35') became much longer in total cataract group than those in lamellar and nuclear cataract groups. The abnormal changes of P1 latency of high spatial frequency (17.5') showed similar in three groups. It is suggested that time for surgery should be based on visual function in the different types of congenital cataract. The total congenital cataract and unilateral cataract should be extracted as early as possible. PMID- 7843383 TI - Delayed hyphema after posterior chamber intraocular lens implantation. PMID- 7843384 TI - Ultrastructural observations of the anterior chamber angle tissues in congenital glaucoma. AB - Eighteen trabeculectomy specimens of congenital glaucoma were examined by light and transmission electron microscopy. The results showed that the primary anomalies in congenital glaucoma included the developmental defects of trabecular meshwork, excessive collagen fibrils in the trabecular matrix, shifting forward of ciliary muscle fibres and persistent mesenchymal tissues in the anterior chamber angle. The authors also pointed out the importance of the secondary lesions of the trabecular meshwork in the pathogenesis of congenital glaucoma. PMID- 7843385 TI - The clinical analysis of secondary glaucoma following posterior chamber intraocular lens implantation. AB - We present 14 patients with secondary glaucoma following the implantation of a posterior chamber intraocular lens (IOLs). All patients were unilateral glaucoma, which developed within 1 month following the IOL implantation in 10 cases, and from 1 to 3 years in 4 cases. The angle of anterior chamber was open in 8 patients, and close in 6 ones. Seven patients required treatment of antiglaucomatous medicine; 4 patients underwent laser iridectomy and 3 patients required antiglaucoma surgery. The results showed that the corrected visual acuity was more than 0.5 in 28% of the patients before antiglaucoma treatment and in 50% of the patients after treatment. The main cause of poor vision is glaucomatous optic nerve atrophy. It suggests that it is important to find glaucoma early. PMID- 7843386 TI - Eleven-year experience with radial keratotomy. AB - 1,900 consecutive eyes that underwent radial keratotomy by the senior author were evaluated retrospectively. 3 months after surgery, minimum reduction in mean spherical equivalent of 0.67D was achieved with 1 incision and maximum 7.25D with 24 incisions. Uncorrected visual acuity of 20/40 or better was obtained in 99.4% of eyes with low myopia, 64.2% with moderate myopia and 32.4% with high myopia. For anisometropia, bilateral RK reduced refractive error from -12. 12D to -5. 22D in more myopic eyes and -8. 18D to -3. 4D in less myopic eyes and unilateral surgeries reduced refractive error from -9. 45D to -3. 85D. Anisometropia after surgery became clinically and physically acceptable and aniseikonia was significantly improved. No vision threatening complications occurred. Our results indicate that radial keratotomy is a relatively safe and effective surgical procedure for myopia. PMID- 7843387 TI - Electro-oculogram of retinal vein occlusion. AB - Twenty five cases, including 26 eyes with retinal vein occlusion (RVO) were examined by means of the electro-oculogram. The results showed that 23 of the 26 eyes suffering from RVO exhibited abnormalities of the electro-oculogram (EOG). The potential difference and Arden ratio in the RVO eyes were lower than those in the normal eyes (P < 0.01). The more the visual acuity of ill eyes was decreased, the higher the abnormal rate of EOG in ill eyes was. 14 eyes had the visual acuity less than 0.1, whose EOGs were abnormal. Six eyes had the visual acuity from 0.2 to 0.4, in which the EOGs of 5 eyes were abnormal. Six eyes had the visual acuity more than 0.5, among which the EOGs of 4 eyes were abnormal. Based on the above observations, it may be considered that the circulatory disturbance resulting from RVO damages not only the internal layer but also the external layer of the retina. We suggest that EOG is a useful method for distinguishing lesions caused by RVO and may reflect the functional condition of the outer layer of the retina. PMID- 7843388 TI - [Glucocorticoid cataract and intraocular lens implantation]. AB - 13 cases (21 eyes) of patients with glucocorticoid cataract due to topical or systemical administration of dexamethasone or prednisone were reported. The patients comprised 10 men and 3 women, averaging 34 years of age (ranged from 11 to 64 years). Average time of administrating glucocorticoid was 7.1 years (ranged from 6 months to thirty years). The clinical type was posterior subcapsular cataract (PSC). After the treatment of discontinuation of the glucocorticoid drugs, cataract was not improved. 7 cases (11 eyes) of the patients underwent extracapsular cataract extraction and posterior chamber intraocular lens implantation. In 91.1% of the eyes, the postoperative corrected visual acuity achieved 0.5 or better, and 88.9% of the ECCE eyes achieved the same level. There were no significant differences between them. The study shows that posterior chamber intraocular lens implantation is an effective way for glucocorticoid cataract. PMID- 7843389 TI - [The treatment of lenticular magnetic foreign body using tri-combined operation]. AB - Fourteen patients with lenticular magnetic foreign bodies are reported. All received magnetoperation extraction of foreign bodies combined with extracapsular cataract extraction and primary posterior chamber IOL implantation. Of them, 3 patients underwent a suture fixation of haptic in ciliary sulcus during operation due to tear of posterior capsule of lens. The operation we performed can effectively resolve the problems of the wounders' monocular blindness caused by lenticular foreign bodies and recover their binocular vision simultaneously. The results indicate that this method is good for lenticular foreign bodies. The operative method, opportunity, complication and its management are also discussed. PMID- 7843391 TI - [Clinical observation and management of the filtration bleb after trabeculectomy]. AB - The author reports 42 patients (56 eyes) of glaucoma performed trabeculectomy under operating microscope from August 1991 to April 1993. After operation the conjunctival filtration blebs were observed in details. The formation rate of ideal blebs was 80.3%. The success rate of operation was 87.5%. The author discusses the mechanisms of lowered intraocular pressure in trabeculectomy and the relation between the type of filtration bleb and intraocular pressure. The author believes that the formation of functional subconjunctival filtration blebs is the key to successful operation. The management of non-functional filtration blebs is presented in this paper. PMID- 7843390 TI - [A comparative study of homoharringtonine with 5-fluorouracil in filtering surgery]. AB - With a prospective, randomized and double-masked control method, homoharringtonine(H.H) and 5-Fluorouracil (5-FU) were used in filtering surgery. We compared the effect and side effect of H.H with those of 5-FU. 24 eyes were in H.H group and 23 eyes in 5-FU group. An average follow-up of 18 months revealed: (1) the cumulative percentage of functioning bleb in H.H group (84.9%) was significantly higher than that in 5-FU group (62.2%) (P < 0.05); (2) the cumulative surgical success rate in H.H group (85.7%) was significantly higher than that in 5-FU group (61.1%) (P < 0.05); (3) the rate of corneal erosion in H.H group (20.8%) was significantly lower than that in 5-FU group (52.2%) (P < 0.05), the difference of other complications between H.H group and 5-FU group was not significant. PMID- 7843392 TI - [Analysis on refraction status of eyes with normal vision]. AB - Refractive status of 1,324 eyes with normal vision of the juvenile students in four grades was analysed. It was raised that the meaning of refractive status was different between the medical physiological optics and the physical or geometrical optics. "Emmetropia" did not really mean "the normal eye" in refraction as viewed from normal physiology, and the problem about the physiological refractive status of eyes in the juvenile was discussed preliminarily. PMID- 7843393 TI - [A preliminary study on the relation of myopia to the development and nutrition of primary and middle school]. AB - Myopia is the major cause for hypopsia of primary and middle school students. The height, weight and vision of 3,884 students were measured. It is concluded from their statistical analysis that vision and weight are positively interrelated whereas there is no interrelation found between vision and height. It is also pointed out that one of the key factors affecting vision is weight, which will be affected by irrational food structure, food preference and hypotrophy. The heavy study load of primary and middle school students is also one of the numerous causes for the increasing incidence of myopia. PMID- 7843394 TI - [Clinicopathological analysis of rhabdomyosarcoma of the ocular adenexa]. AB - 12 cases including 11 males and 1 female of rhabdomyosarcoma of ocular adenexa were analysed. The average age of the patients was 4.2 years. 9 cases of lesion were located in the orbit, 2 in the eyelid and 1 in conjunctiva. Pathologically 8 cases were embryonal forms, 2 alveolar, 2 polymorphic. Immunohistochemical studies were performed in 8 cases, which showed desmin positive. Myoglobin presented strong or weak positive in 5 cases, suspicious positive in 3 cases. The clinical manifestation, prognosis and treatment were briefly discussed. PMID- 7843395 TI - [An experimental study on cultivation of human trigeminal ganglionic cell in vitro and its sensitivity to infection of herpes simplex virus type 1]. AB - We firstly report an experimental study on the sensitivity of primary cultural human trigeminal ganglionic cells infected by herpes simplex virus type 1 (HSV-1) in different time-points. The results indicate that the neuron of human trigeminal ganglia is the most sensitive cell type, the antigen of HSV-1 replicates rapidly within the cytoplasm and cell nucleus, the fibroblasts and glia cells are infected partly by the virus. Therefore, perhaps the neuron is the main harboring cell type. PMID- 7843396 TI - [The follow-up survey of results of radial keratotomy]. AB - We reviewed 119 cases of consecutive radial keratotomies of 67 patients who were followed up for three years to evaluate the stability and safety of the surgery. The average change of overall refraction was -0.12D between one year and three years after the surgery, which was statistically insignificant. Stable refractive results were achieved in 72.3% of the eyes. 16.8% of the eyes experienced an increase from -1.00D to 2.50D, and 10.9% displayed a decrease from 1.00D to 3.50D. Eyes with preoperative high myopia were more likely to cause significant postoperative refractive change. In three years, 8.5% of the eyes gained the best corrected visual acuity of two to four lines. 2.6% of the eyes lost two lines because of macular disorders. Specular microscopy indicated that there was no significant change in corneal endothelial cell density following radial keratotomy. PMID- 7843397 TI - [A clinic report of 54 cases of reconstruction for the anterior segment of eye]. AB - 54 cases (54 eyes) of severe injury in the anterior segment of eye with little light perception were treated by reconstruction for the anterior segment of eye. The results showed that the eyeballs in 48 cases (88.9%) were survived successfully, and 28 cases (51.9%) of the grafts were clear. The procedures included keratoplasty, iridectomy, lensectomy, anterior vitrectomy, and reconstruction of the anterior chamber to restore the cosmetic shape of the eyeball. The indications, complications of the operation, and the surgical technique are discussed. PMID- 7843398 TI - [Corneal topography of patients with unsatisfactory visual acuity after epikeratophakia for aphakia]. AB - Corneal topographic characteristics of 5 patients who obtained unsatisfactory vision after aphakic epikeratophakia, with at least nine months follow-up, were reported. All grafts were apparently decentered relative to visual axis. The contour of cornea showed highly irregular pattern of power distribution. These findings suggest that to mark visual axis before surgery, lathe corneal lenses carefully and do standard operation should be the basis of successful epikeratophakia. PMID- 7843399 TI - [Comparison of corneal topography and keratometer in patients with cataract preoperatively and postoperatively]. AB - The comparison of corneal topography with keratometer in 200 patients (278 eyes) was made. The results revealed that Sim K values of corneal topography were 44.22D and 44.26D, mean diopters of keratometer were 44.16D and 44.23D in 150 eyes of 116 patients with cataract preoperatively. There was no significant difference between Sim K values of topography and diopters of keratometer (P > 0.05). The Sim K values of the topography were 46.37D and 43.06D and diopters of keratometer were 46.09D and 42.88D in 90 eyes of 67 patients who received cataract extraction with IOL implantation or second IOL implantation. No significance was found in results between Sim K values and diopters of keratometer in patients postoperatively (P > 0.05). Our investigation demonstrated that Sim K values of corneal topography were in agreements with diopters of keratometer in patients with cataracts preoperatively or postoperatively. However, corneal topography has great values in diagnosis of corneal diseases, traumatic astigmatism, severe non-rule stigmatisms, in which keratometer is often useless. PMID- 7843400 TI - [Auto-analysis of corneal endothelium with photoelectrical scans and computer]. AB - A quantitative analysis of corneal endothelial cells was made with photoelectrical scans and computer in 67 eyes. No difference was found as regards to the mean cell area and density between the endothelial analysis system and routine square counting. On the other hand, we analyzed corneal endothelial cells between 30 eyes wearing hard contact lens and 30 eyes of age- and sex-matched nonwearing control. The parameters, including cell density individual cell area, area, mean cell area, standard deviation, coefficient of variation of cell size (CV), maximum cell, minimum cell, the ratio of the maximum to minimum cell, and percentage of the hexagoal cells, were automatically displayed. The cell density and mean cell area also showed no significant difference (P > 0.05) between the wearers and nonwearing control, but the CV and the frequency of the hexagonal cells showed significant difference (P < 0.01). The ratio of maximum to minimum cell, the polymegethism and pleomorphism were obviously increased in the wearers. It is highly suggested that computer analysis system is of great value in evaluating corneal endothelial cells. PMID- 7843401 TI - [Cyclocryotherapy for refractory glaucoma after penetrating keratoplasty]. AB - Twenty-eight patients (28 eyes) with secondary glaucoma following penetrating keratoplasty and failed to respond to anti-glaucoma drugs and routine filtering procedures were performed with cyclocryotherapy by nitrogen monoxide. All patients were followed up for more than one year. The results showed intraocular pressure was well controlled in 89% of the eyes, graft remained clear in 85%, and visual functions are preserved in 82% of the patients. Our study suggests that precisely controlled temperature, time, and extent of cryotherapy, and post operative anti-rejection agents be the key factor to success. Over-treatment, which may lead to atrophy of the eye, must be avoided. It should not be given up flowing under-treatment in the initial procedure. PMID- 7843402 TI - [Restrictive fragment length polymorphism analysis of gamma-crystallin in congenital cataract families]. AB - Using gamma-crystallin gene probe P5G1, we investigated the RFLP in two large families of congenital cataracts and normal people, calculated the allelic gene frequency and defined the haplotypes by genetic linkage analysis. In accordance with foreign reports, TaqI/p5G1 detected 3 polymorphic sites, and the allelic gene frequency was close to that in foreign reports. However, foreign reports claimed that the haplotype P was linked to Coppock cataracts, but we did not find such linkage by haplotype analysis. The result suggests that not all the inherited cataracts are linked to gamma-crystallin gene, and the haplotype P should not be simply regarded as genetic marker in prenatal diagnosis. PMID- 7843403 TI - Curcacycline A--a novel cyclic octapeptide isolated from the latex of Jatropha curcas L. AB - From the latex of Jatropha curcas L. (Euphorbiaceae) a novel cyclic octapeptide was isolated, which we named curcacycline A. The compound was found to contain one threonine, one valine, two glycine, and four leucine residues. By two dimensional 1H-NMR spectroscopy (HOHAHA and ROESY), its sequence was determined to be Gly1-Leu2-Leu3-Gly4-Thr5-Val6-Leu7-Leu8-Gly1+ ++. Curcacycline A displays a moderate inhibition of (i) classical pathway activity of human complement and (ii) proliferation of human T-cells. PMID- 7843404 TI - Tissue-specific expression of the human receptor for glucagon-like peptide-I: brain, heart and pancreatic forms have the same deduced amino acid sequences. AB - Glucagon-like peptide-I(GLP-I), encoded by the glucagon gene and released from the gut in response to nutrients, is a potent stimulator of glucose-induced insulin secretion. In human subjects GLP-I exerts its physiological effect as an incretin. The incretin effect of GLP-I is preserved in patients with Type II diabetes mellitus (NIDDM), suggesting that GLP-I receptor agonist can be used therapeutically in this group of patients. In these studies we addressed the question of whether GLP-I has broader actions in human physiology. To investigate this issue we examined the tissue distribution of GLP-I receptor using RNAse protection assay in order to avoid the cross-reactivities with structurally related receptors and to increase the sensitivity of detection. The riboprobe was synthesized from the human pancreatic GLP-I receptor cDNA and used in hybridization experiments with total RNA isolated from different human tissues. In addition to the pancreas, we found expression of GLP-I receptor mRNA in lung, brain, kidney, stomach and heart. Peripheral tissues which are the major sites of glucose turnover, such as liver, skeletal muscle and adipose did not express the pancreatic form of the GLP-I receptor. We also cloned and sequenced GLP-I receptor cDNA from human brain and heart. The deduced amino acid sequences are the same as the sequence found in the pancreas. These results indicate that GLP-I might have effects beyond the pancreas, including the cardiovascular and central nervous systems where a receptor with the same ligand binding specificity is found. PMID- 7843405 TI - Possible involvement of the transcription factor ISGF3 gamma in virus-induced expression of the IFN-beta gene. AB - Two virus-inducible transcription factors, IRF-1 and IRF-2 have been identified as an activator and a repressor, respectively, of the type I interferon (IFN) genes. Recent studies with mice carrying null mutations for the IRF-1 or IRF-2 alleles have revealed the existence of IRF-1-dependent and -independent pathways mediating IFN-beta gene induction. Here we report that the expression of an IRF family member ISGF3 gamma is induced upon viral infection in IRF-1-/-, IRF-2-/- embryonic fibroblasts. Furthermore, ISGF3 gamma can bind to a virus-inducible promoter element in the IFN-beta gene. These results suggest that ISGF3 gamma or complex containing ISGF3 gamma is involved in the IRF-1-independent pathway mediating IFN-beta gene regulation. PMID- 7843406 TI - Estimation of dolichol and cholesterol synthesis in microsomes and peroxisomes isolated from rat liver. AB - The participation of peroxisomal and microsomal fractions from rat liver in dolichol and cholesterol synthesis was investigated using marker enzymes. Recovery was 8% for peroxisomes and 33% for microsomes, with virtually no cross contamination between these fractions. Using these data, it was calculated that the peroxisomal branch-point enzyme activities for dolichol and cholesterol biosynthesis, i.e. cis-prenyltransferase and squalene synthase, were 25% and 12%, respectively, of the total homogenate activity. Treatment with mevinolin increased the peroxisomal contribution in the case of both enzymes, to levels almost equal to that of their microsomal counterparts. These results indicate that peroxisomes play a role in the biosynthesis of isoprenoid lipids and that the extent of this participation is increased extensively when peroxisomes are induced by various treatments. PMID- 7843407 TI - Characterization of a protein tyrosine phosphatase (RIP) expressed at a very early stage of differentiation in both mouse erythroleukemia and embryonal carcinoma cells. AB - From our previous studies, several protein tyrosine phosphatases (PTPase) are implicated in the early events leading to in vitro differentiation of both mouse erythroleukemia (MEL) and embryonal carcinoma (F9) cells. Among the PTPases, recent experiments suggest that a new PTPase (RIP) plays a critical role in differentiation processes, particularly at their early stages. We isolated cDNA clones for RIP from a RNA preparation isolated from differentiating MEL cells, and determined the total 7932 bp base sequence for RIP cDNA. The cDNA codes for a putative 269.8 kDa (2450 amino acids) protein with a PTPase catalytic domain. We have demonstrated that the transcripts exist in multiple forms, and among mouse tissues they were found predominantly in kidney and, to a lesser extent, in lung, heart, brain and testis. The RIP gene was mapped between D5Mit90 and D5Mit25 on mouse chromosome 5. PMID- 7843408 TI - Specificity of the purified inositol (1,3,4,5) tetrakisphosphate-binding protein from porcine platelets. AB - The specificity of the inositol 1,3,4,5-tetrakisphosphate binding protein purified from porcine platelets [Cullen et al. (1995) Biochem. J. 305, 139-143] was examined using all the isomers of myo-inositol tetrakisphosphate. From the relative potencies of these compounds it appears that phosphorylation of the 1, 3 and 5 positions is essential for high affinity binding, that there is some tolerance of phosphorylation of the 6-hydroxyl, but none of a phosphate in the 2 position, and that phosphorylation of the 4-hydroxyl has very little influence. The binding of Ins(1,3,4,5)P4 was not appreciably altered by physiological Mg2+ concentrations, and the pH dependence of binding under physiological conditions showed a decline from pH 5.5 to pH 9.0. PMID- 7843409 TI - Wortmannin inhibits carcinogen-stimulated phosphorylation of ethanolamine and choline. AB - We have previously reported that in C3H/10T1/2 fibroblasts the environmental carcinogen 7,12-dimethyl-benz[a]anthracene (DMBA) stimulated phosphorylation of ethanolamine (Etn). Here we show that in these fibroblasts DMBA also stimulates phosphorylation of choline (Cho). Wortmannin (50-200 nM), an established inhibitor of phosphatidylinositol-3-kinase (PI3K), significantly inhibited DMBA induced phosphorylation of both Etn and Cho. Wortmannin also inhibited the effect of insulin, a major activator of PI3K, on DNA synthesis. However, insulin had no effect on the phosphorylation of Etn and Cho. These data suggest that a carcinogen-induced kinase phosphorylates both Etn and Cho, and that the inhibitory effect of wortmannin on Etn/Cho kinase activity may be unrelated to its inhibitory effect on PI3K activity. PMID- 7843410 TI - Cold denaturation of yeast phosphoglycerate kinase: which domain is more stable? AB - Under destabilising conditions both heat and cold denaturation of yeast phosphoglycerate kinase (PGK) can be observed. According to previous interpretation of experimental data and theoretical calculations, the C-terminal domain should be more stable than the N-terminal domain at all temperatures. We report on thermal unfolding experiments with PGK and its isolated domains, which give rise to a revision of this view. While the C-terminal domain is indeed the more stable one on heating, it reveals lower stability in the cold. These findings are of importance, because PGK has been frequently used as a model for protein folding and mutual domain interactions. PMID- 7843411 TI - SecA restricts, in a nucleotide-dependent manner, acyl chain mobility up to the center of a phospholipid bilayer. AB - The effects of SecA-lipid interactions on lipid mobility were studied by electron spin resonance (ESR) spectroscopy in bilayer systems containing phospholipids spin-labeled at different positions along the acyl chain. The SecA protein, which functions in protein translocation at the cytosolic side of the E. coli inner membrane, was found to decrease the mobility of the lipids upon its interaction with the membrane. The restriction of lipid motion, at all chain positions measured, reflects the ability of SecA to penetrate the membrane. At a 49:1 lipid/protein molar ratio, a second, motionally more restricted component is observed in ESR spectra of phospholipids spin-labeled close to the methyl ends of the chains (12th and 14th positions). Furthermore, SecA was found to eliminate the order-to-disorder phase transition of 1,2-dimyristoyl-sn-glycero-3 phosphoglycerol bilayers. A remarkably strong reduction in the ability of SecA to penetrate the membrane was found when the nucleotides ATP and ADP+P(i) were present. The presence of the non-hydrolyzable analogue AMP-PNP had no effect. These results clearly demonstrate that SecA perturbs, in a nucleotide dependent manner, lipid mobility upon insertion into the bilayer. The implications of these findings for translocation of precursor proteins across the E. coli inner membrane are discussed. PMID- 7843412 TI - Multi-step DNA cleavage in rat liver nuclei is inhibited by thiol reactive agents. AB - DNA fragmentation in isolated rat liver nuclei is a Mg(2+)-dependent, multi-step process which is potentiated by Ca2+ and cleaves the DNA into > or = 700, 200-300 and 30-50 kilobase pair (kbp) fragments, prior to internucleosomal cleavage by Ca2+/Mg(2+)-dependent endonuclease(s). We now show that Cd2+, Hg2+, dichloroisocoumarin (DCI, a serine protease inhibitor) and N-ethylmaleimide (NEM) block both Mg2+ and Ca2+/Mg(2+)-dependent processes. Inhibition of DNA cleavage produced an increase in the size of the DNA fragments, from mono /oligonucleosomes to 30-50, 200-300, > or = 700 kbp and finally to intact DNA. NEM and DCI inhibition was blocked by dithiothreitol, and it is proposed that a critical thiol(s) is involved in the DNA cleavage reactions which are a feature of the apoptotic process. PMID- 7843413 TI - Full-length and short forms of utrophin, the dystrophin-related protein. AB - All previous studies of the localization of utrophin (the dystrophin-related protein) in muscle and other tissues have been performed only with antibodies against the C-terminal region of the protein. Since several short forms of dystrophin, the apo-dystrophins, are produced from the 3' end of the dystrophin gene, there is a possibility that similar short forms of utrophin exist and that these could be responsible for some of the many different localizations of 'utrophin' in muscle. We have produced a new panel of 15 mAbs against the N terminal region of utrophin and we have used it together with mAbs against the C terminal region to show that full-length utrophin is present at neuromuscular junctions, in nerves, blood vessels and capillaries in normal muscle and in the sarcolemma of patients with muscular dystrophy and dermatomyositis. However, two of the 15 mAbs also recognised rat/mouse utrophin and both of these detected an additional 62 kDa protein on Western blots of rat C6 glioma cells. This potential 62 kDa 'apo-utrophin' was not detected in human cerebral cortex, in rat Schwannoma cells nor in any of the non-nerve cells and tissues tested. PMID- 7843414 TI - Prohibitin, an antiproliferative protein, is localized to mitochondria. AB - Prohibitin is a ubiquitously expressed protein with antiproliferative properties. When rat prohibitin tagged with a carboxy-terminal c-Myc epitope was expressed in baby hamster kidney cells the protein was targeted to mitochondria. In immunofluorescence microscopy prohibitin colocalized with a mitochondrial marker E3. Immunoelectron microscopy revealed that prohibitin was associated with the periphery of mitochondria. The amino-terminus of prohibitin shares characteristics of the known mitochondrial import signals, and positioning of the tag at the N-terminus causes accumulation of the protein in the cytoplasm. These findings help to direct functional studies on prohibitin and suggest that a mitochondrial protein may act as a tumor suppressor. PMID- 7843415 TI - Zinc co-ordination in the DNA-binding domain of the yeast transcriptional activator PPR1. AB - The structure of the native zinc form of the DNA binding domain in the yeast transcriptional activator PPR1 was investigated by extended X-ray absorption fine structure (EXAFS). By carrying out the EXAFS measurements at 11k we were able to demonstrate explicitly the proximity of the two zinc ions (Zn-Zn distance = 3.16 +/- 0.03 A) and the presence of bridging cysteine ligands. The results show that the six cysteine residues co-ordinate two zinc ions in a two-metal ion cluster. PPR1 is the first member of this class of protein for which such information has been obtained. PMID- 7843416 TI - The protein fold of the von Willebrand factor type A domain is predicted to be similar to the open twisted beta-sheet flanked by alpha-helices found in human ras-p21. AB - The von Willebrand Factor type A domain is the prototype for a protein superfamily. It possesses no significant sequence similarity to any known protein structure. Secondary structure predictions indicate a largely alternating pattern of six alpha-helices and six beta-strands. A protein fold for this domain is proposed to correspond to a doubly-wound open twisted beta-sheet structure flanked by alpha-helices. Close agreement was found with the GTP-binding domain of human ras-p21, provided that an extra alpha-helix was inserted. The structure of the predicted fold showed high compatibility with the proximate location of two Mg(2+)-binding Asp residues, two disulphide-bridged Cys residues, and other known functional attributes of this domain. PMID- 7843418 TI - Increased rates of tRNA charging through modification of the enzyme-aminoacyl adenylate complex of phenylalanyl-tRNA synthetase. AB - The transfer of amino acid to tRNA by Escherichia coli phenylalanyl-tRNA synthetase (PheRS) was studied using replacements of Ala294 in the alpha subunit previously shown to have modified amino acid specificity. Steady-state analysis of tRNA charging showed little difference between wild-type and mutants, whereas pre-steady-state analysis revealed higher rates of tRNA charging by both the A294S PheRS-phenylalanyl adenylate and the A294G PheRS-p-Cl-phenylalanyl adenylate. The decrease in energy required for the formation of the transition state of amino acid transfer in these mutants could be related to a weaker binding of the amino acid in the aminoacyl adenylate complex. Thus a compromise appears to exist between amino acid activation and tRNA charging, because slowing down the first step increases the rate of the second step, possibly as a result of decreased stability of the PheRS.amino acid-AMP complex. PMID- 7843417 TI - An SH3 domain is required for the mitogenic activity of microinjected phospholipase C-gamma 1. AB - Phospholipase activity is elevated in dividing cells. In response to growth factor stimulation, phospholipase C-gamma (PLC-gamma) binds to activated tyrosine kinase receptors via SH2 binding domains, resulting in phosphorylation of PLC gamma and activation of its enzyme activity. These observations suggest that PLC gamma participates in the signal transduction pathway employed by growth factors to promote mitogenesis. Consistent with this hypothesis, microinjection of purified bovine PLC-gamma into quiescent fibroblasts has been previously reported to initiate a mitogenic response [Smith et al. (1989) Proc. Natl. Acad. Sci. 86, 3659]. We have reproduced this result using recombinant rat PLC-gamma protein. Surprisingly, however, a catalytically inactive mutant of PLC-gamma, H335Q, also elicited a full mitogenic response. The capacity to induce mitogenesis by microinjection of PLC-gamma was mapped to the 'Z' domain of the protein, which contains PLC-gamma's SH2 and SH3 motifs. Inactivation of the phosphorylated tyrosine binding properties of both SH2 domains had no effect on the mitogenic activity of the Z-domain peptide. However, deletion of the SH3 domain resulted in a complete loss of activity. These results suggest that PLC-gamma's mitogenic properties do not require the enzyme's phospholipase activity, but are instead mediated by a novel pathway for mitogenic stimulation which is dependent upon an intact SH3 domain. PMID- 7843419 TI - Molecular cloning and functional expression in yeast of a human cAMP-specific phosphodiesterase subtype (PDE IV-C). AB - We have recently reported increased survival of dopaminergic substantia nigra neurons by inhibition of phosphodiesterase type IV enzymes. As a first step to unravel the involvement of PDE IV subtypes in this process, we isolated phosphodiesterase type IV cDNAs from human substantia nigra. One isolated partial cDNA clone was most homologous to the partially cloned rat and human PDE IV-C isogene. Distribution analysis revealed that the enzyme is expressed in various tissues but not in cells of the immune system. Isolation of the full-length human PDE IV-C isogene cDNA and expression in a PDE-deficient yeast strain resulted in functional complementation of the yeast heat shock response. Inhibition of the enzymatic activity by rolipram characterized this enzyme as a typical type IV phosphodiesterase. PMID- 7843421 TI - Purification and characterization of leukotriene A4 hydrolase from human epidermis. AB - The leukotriene A4 hydrolase is a central enzyme in leukotriene B4 formation. Unlike 5-lipoxygenase, leukotriene A4 hydrolase activity is present in normal human epidermis, where it is likely to be involved in transcellular leukotriene formation. In this study the leukotriene A4 hydrolase was purified from human epidermis and human cultured keratinocytes and compared with leukotriene A4 hydrolase from human neutrophils. To purify leukotriene A4 hydrolase from human epidermis a new non-specific affinity chromatography column, with the leukotriene A4 hydrolase inhibitor bestatin coupled to AH-Sepharose, was introduced. The epidermal leukotriene A4 hydrolase was purified to apparent homogeneity and the molecular weight was determined to be approximately 70,000 Da by SDS-PAGE. The pI was 5.1-5.4 for the epidermal as well as the keratinocyte and neutrophil leukotriene A4 hydrolase, as determined by chromatofocusing. Only minor differences in the amino acid composition were seen between the three enzyme sources. The optimal pH for the hydrolase activity was 7.5-8.5 for the epidermal and neutrophil leukotriene A4 hydrolases. Finally, it was also shown that the epidermal leukotriene A4 hydrolase undergoes suicide inactivation when transforming leukotriene A4 into leukotriene B4. It was concluded that there is a close resemblance between the epidermal leukotriene A4 hydrolase and the hydrolase found in other cell types. Therefore, the human epidermis may be a good model for the in vivo study of transcellular leukotriene formation. PMID- 7843422 TI - Analysis of the N-linked oligosaccharides of human C1s using electrospray ionisation mass spectrometry. AB - Information on the structures of the oligosaccharides linked to Asn residues 159 and 391 of the human complement protease C1s was obtained using mass spectrometric and monosaccharide analyses. Asn159 is linked to a complex-type biantennary, bisialylated oligosaccharide NeuAc2 Gal2 GlcNAc4 Man3 (molecular mass = 2206 +/- 1). Asn391 is occupied by either a biantennary, bisialylated oligosaccharide, or a triantennary, trisialylated species NeuAc3 Gal3 GlcNAc5 Man3 (molecular mass = 2861 +/- 1), or a fucosylated triatennary, trisialylated species NeuAc3 Gal3 GlcNAc5 Man3 Fuc1 (molecular mass = 3007 +/- 1), in relative proportions of approximately 1:1:1. The carbohydrate heterogeneity at Asn391 gives rise to three major types of C1s molecules of molecular masses 79,318 +/- 8 (A), 79,971 +/- 8 (B), and 80,131 +/- 8 (C), with an average mass of 79,807 +/- 8. A minor modification, yielding an extra mass of 132 +/- 2, is also detected within positions 1-153. PMID- 7843420 TI - Hypoxia and platelet-derived growth factor-BB synergistically upregulate the expression of vascular endothelial growth factor in vascular smooth muscle cells. AB - Vascular endothelial growth factor (VEGF) mRNA expression was analysed in rabbit vascular smooth muscle cells following exposure to hypoxia and platelet-derived growth factor-BB (PDGF-BB). Hypoxia potently upregulated VEGF mRNA steady-state levels in a time- and concentration-dependent manner reaching a maximum level (approximately 30-fold increase) after 12-24 h at 0% 0(2). In contrast, PDGF-BB caused a modest increase in VEGF expression. However, the combination of PDGF-BB and a threshold hypoxic stimulus (2.5% O2 for 4 h) had a marked synergistic effect. Synergy between hypoxia and PDGF-BB was selective for VEGF expression as hypoxia had no effect on the PDGF-induced upregulation of the proto-oncogene c myc. These results raise the possibility that hypoxia and PDGF-BB may act in concert to induce VEGF expression in the arterial wall during the development of atherosclerosis. PMID- 7843423 TI - Operative laparoscopy: surgical modalities. AB - OBJECTIVE: To review basic physics of different surgical modalities and their clinical applications and outcomes. DESIGN: The relevant literature and personal experience were used to prepare the manuscript. RESULTS: Operative laparoscopy is safe and effective whether using sharp dissection, electrosurgical, or laser energy. The newer surgical modalities, including the vibrating ultrasound scalpel and argon beam coagulator, need further evaluation. CONCLUSIONS: The results of laparoscopic surgery are independent of the surgical modality used. The surgeon's skill and experience, his or her preference of the technique, and proper patient selection play a more important role. PMID- 7843424 TI - Should male infertility patients be tested for leukocytospermia? PMID- 7843425 TI - The use of progestins for programming assisted reproductive cycles and gonadotropin-releasing hormone agonist flare-up protocols in older patients. AB - OBJECTIVES: To determine if the use of norethisterone acetate (NET) in the previous cycle affects the ovarian response to GnRH agonist (GnRH-a) in flare-up protocols and controlled ovarian hyperstimulation in older patients. DESIGN: Retrospective analysis of the outcome of the assisted reproductive technology (ART) cycle. PATIENTS: Eighty women > 37 years old undergoing controlled ovarian hyperstimulation (COH) for a ART cycle (GIFT, IVF, zygote intrafallopian transfer). Forty received NET during the luteal phase of the previous cycle for programming the procedure and 40 did not receive NET (control group). Gonadotropin-releasing hormone agonist in follicular phase (flare-up) protocols were administered to all the patients. MAIN OUTCOME MEASURES: Cycle outcome: amount of gonadotropins used, oocyte production and quality, fertilization, and pregnancy rates. Estradiol, FSH, and LH levels the first 3 days of COH in eight patients. RESULTS: There were no differences between both groups in the cycle outcome. Estradiol levels during the first 3 days of COH were higher in the patients that did not receive NET in the previous cycle. Follicle-stimulating hormone and LH levels were similar in both groups. CONCLUSIONS: The administration of NET in the previous cycle in patients > 37 years old does not affect the ovarian response to the combination of follicular phase GnRH-a and gonadotropins for COH. PMID- 7843426 TI - Outcome of triplet pregnancies after assisted reproductive techniques: how frequent are the vanishing embryos? AB - OBJECTIVE: To assess the incidence of spontaneous embryo reduction as well as the obstetric and neonatal outcome of triplet gestations after assisted reproductive techniques (ART). METHODS: We analyzed the spontaneous outcome of 38 pregnancies in which three gestational sacs were identified with vaginal ultrasound between 21 and 28 days after ART. Weekly follow-up visits were scheduled during the first trimester until referral to a high-risk obstetrician. After delivery, each patient was interviewed individually and, if necessary, the obstetrician was contacted. RESULTS: The triplets delivery rate was 47.4%, whereas 31.6% delivered twins, 18.4% delivered singletons, and only one patient miscarried all three cases (2.6%). Finding three fetal heart beats was associated with a triplet delivery rate of 69.2%, a twin incidence of 19.2%, and a singleton birth rate of 11.6%. Embryo resorptions were observed mainly during the first 7 weeks of gestation and did not occur beyond the 14th week. The mean gestational age at delivery and neonatal birth weight were significantly lower among triplets (32.8 weeks and 1,740 g versus 35.3 weeks and 2,352 g in twins and 39.1 weeks and 3,122 g for singletons). Triplets had a 100% prematurity and cesarean section rate compared with 67% and 75% in twins and 0% and 43% in singletons, respectively. Hospitalization at the Neonatal Intensive Care Unit was required in 83% of newborn triplets, 29% of twins, and 0% of singletons, with a mean stay of 34 and 21 days for triplets and twins, respectively. One stillbirth and no neonatal deaths were reported, with an overall perinatal mortality rate of 11.9 per 1,000. CONCLUSIONS: Spontaneously, approximately 50% of triplet pregnancies will experience at least one embryo resorption. The ongoing triplets demand a complex and more expensive perinatal management, a strong argument to consider limiting the number of oocytes-embryos transferred in ART. PMID- 7843427 TI - Pregnancies in postmenopausal women over 50 years old in an oocyte donation program. AB - OBJECTIVE: To determine the potential of the aging uterus in terms of pregnancy, implantation, and abortion rates, and obstetric complications in postmenopausal women age 50 and over, receiving oocyte donation. DESIGN: Retrospective data analysis. SETTING: A tertiary infertility center. PATIENTS: Thirty-four postmenopausal women (50 to 62 years of age) undergoing a total of 61 cycles of oocyte donation. INTERVENTIONS: Hormone replacement therapy (HRT) was given using increasing doses of 17 beta-E2 (2, 4, and 6 mg) and 100 mg of P in oil. MAIN OUTCOME MEASURES: Pregnancy, abortion, and implantation rates, and pregnancy outcome. RESULTS: There were 34 patients treated through 61 cycles. Fifty-five transfer cycles were performed. A total of 18 clinical pregnancies were achieved with a pregnancy rate per transfer of 32.7% and per patient of 52.9%. There was one abortion, resulting in an abortion rate of 5.5%. Twenty-one of the 116 transferred embryos implanted, resulting in an implantation rate of 18%. No statistically different rates were found in oocytes donors. CONCLUSION: Women over the age of 50 and up to 62 can become pregnant using donated oocytes. The aging uterus after HRT allows implantation as well as in young women, and it is able to carry pregnancy to term apparently without any problems. PMID- 7843428 TI - Successful implantation of frozen sibling embryos is influenced by the outcome of the cycle from which they were derived. AB - OBJECTIVES: To determine if the success of frozen embryos obtained from assisted reproductive technology (ART) cycles is dependent upon the outcome of the ART cycle from which they were derived and to determine if the length of time in cryostorage affects pregnancy rates (PRs). DESIGN: Retrospective analysis of pregnancy outcome of consecutive frozen ETs compared with their corresponding "'fresh" cycles. SETTING: University-affiliated private ART program. PATIENTS: Between July 1986 and December 1992, 375 oocyte retrieval cycles had at least one subsequent frozen ET for comparison. Of the 375 patients, 94 achieved a clinical pregnancy during their fresh cycle (group A) and 281 patients did not (group B). INTERVENTIONS: Frozen ETs were performed using either natural (unstimulated) cycles (n = 79) or artificial cycles (n = 296). Transfers during natural cycles were timed with a combination of serum LH levels and ultrasound (US). These transfers were performed 2 days after ovulation. Ovarian suppression with leuprolide acetate followed by sequential estrogen and P replacement were used in the artificial cycles. These transfers were performed on the 3rd day of P administration. Clinical pregnancies were defined as the presence of a gestational sac on transvaginal US. MAIN OUTCOME MEASURES: Patients were compared based on the pregnancy outcome of their frozen ET cycle and fresh ART cycle. chi 2 analysis and Student's-tests were used to test for statistical significance. RESULTS: Twenty-three patients (24.1%) from group A achieved a pregnancy from their frozen transfers compared with only 24 patients (8.5%) in group B who achieved a pregnancy from their frozen cycle. PRs did not differ based on the method of follicle aspiration, laparoscopy versus transvaginal US retrieval. Significantly lower PRs were noted in frozen ETs done within the first 10 months after cryopreservation compared with fresh cycle PRs. CONCLUSIONS: Sibling embryos from a prior successful ART cycle are more likely to initiate a frozen pregnancy and prolonged cryostorage did not affect PRs. This higher PR probably reflects better quality in both fresh and frozen embryos. Therefore, the outcome of the initial cycle can be used to predict the success or failure of subsequent frozen transfers and oocyte-embryo quality appears to be key. PMID- 7843429 TI - Increased capillary permeability induced by human follicular fluid: a hypothesis for an ovarian origin of the hyperstimulation syndrome. AB - OBJECTIVE: To examine the effect of follicular fluid (FF) and peritoneal fluid (PF) from patients undergoing assisted reproductive technology procedures on endothelial barrier function. This was determined in vitro by measuring the permeability of filter-grown bovine aortic endothelial cell monolayers to a permeability marker. DESIGN: Endothelial cells obtained from bovine thoracic arotas were treated with collagenase solution and plated on millicell filters, on which they formed confluent monolayers. Flux rate was determined at 60 minutes by measuring the radioactive tracer (3H mannitol) permeating from the apical to the basolateral part of the filter. Fifty-eight samples of FF and PF, both from stimulated and natural cycles were analyzed and grouped according to the number of eggs retrieved. Follicular fluid and PF samples from natural cycles were used as controls. RESULTS: There was an augmentation in the permeability rate of both FF and PF from patients undergoing controlled ovarian hyperstimulation (COH) who responded with an increasing number of eggs compared with controls (51% and 39%, respectively). When analyzing samples from patients who responded with a low number of oocytes, no significant increase was observed. CONCLUSIONS: It is known that in OHSS, the increase in capillary permeability is related to the administration of gonadotropins, and is believed to be mediated by a vasoactive substance of ovarian origin. In this study, FF and PF from patients undergoing COH showed a significant increase in the permeability rate through endothelial cells in vitro. Based on these findings, it could be hypothesized that if the same events took place in vivo, the isolation of this factor from ovarian source could be of significant importance to elucidate the pathogenesis of OHSS. PMID- 7843430 TI - Gonadotropin requirements of the developing follicle. AB - OBJECTIVE: To evaluate follicular FSH and LH requirements during suppression of endogenous gonadotropins with the GnRH antagonist Nal-Glu and whether LH-like activity could be supplied by administering subcutaneous hCG. DESIGN: Randomized clinical trial. PARTICIPANTS: Thirty-two normally cycling females in the late follicular phase (dominant follicle mean diameter > or = 14 mm). INTERVENTION: Twelve normal women were randomized to receive 150 IU IM FSH with or without 75 IU SC hCG; 11 subjects were randomized to receive 225 IU FSH with or without 50 IU SC hCG; 9 women received 150 or 225 IU IM hMG. Subjects returned the next day for repeat blood sample and ultrasound. RESULTS: Continued follicular maturation, as evidenced by rising E2 levels, correlated with serum immunoactive and bioactive FSH levels and was unrelated to bioactive LH-hCG. Two hundred twenty five international units of exogenous FSH consistently supported follicular maturation. There was a similar increase in mean follicular diameter in women with an E2 rise versus those with a plateau or fall. In subjects receiving SC mini-dose hCG, serum bioactive LH-hCG levels were increased significantly and were similar to levels before Nal-Glu. CONCLUSIONS: During administration of a GnRH-a, the maturing follicle appears to require only FSH support. In markedly hypogonadotropic women, mini-dose hCG may be a more practical alternative to recombinant LH to promote normal follicle maturation. PMID- 7843431 TI - Presence of thyroid antibodies in early reproductive failure: biochemical versus clinical pregnancies. AB - OBJECTIVE: To evaluate the clinical usefulness of thyroid antibodies in determining early pregnancy outcome. SETTING: University-based facility at the Center for Reproductive Health, University of California, Irvine. PATIENTS: Four hundred eighty-seven infertile patients that successfully conceived with assisted reproductive techniques from January 1991 to December 1992. INTERVENTIONS: An enzyme immunoassay for semiquantification of thyroglobulin (TG) and thyroid peroxidase antibodies used to determine antibody status from stored serum of these patients. MAIN OUTCOME MEASURE: Thyroid antibody status in early pregnancy. RESULTS: Of the 487 patients studied, there were 106 women who were antibody positive for anti-TG, antithyroid peroxidase, or both, and 381 who were negative. The overall incidence of positivity was 22%. In the antibody-positive group there was a 32% clinical miscarriage rate in comparison to 16% in the antibody-negative group. This did reach statistical significance. There was no significant difference between the two groups in the incidence of biochemical or ectopic pregnancies. There also was no significant difference between the groups in age, gravidity, or number of prior pregnancy losses. CONCLUSION: In our patient population, thyroid antibodies proved to be a useful marker for identifying women at risk for clinical miscarriage but they appear not to have an association with biochemical pregnancies. PMID- 7843432 TI - Inhibition of growth of human ovarian cancer in nude mice by luteinizing hormone releasing hormone antagonist Cetrorelix (SB-75). AB - OBJECTIVE: To report on the in vitro and in vivo inhibitory effects of LH releasing hormone (LH-RH) antagonist Cetrorelix (SB-75; Asta Medica, Frankfurt Main, Germany) against a panel of human ovarian carcinomas. INTERVENTIONS: IN VITRO STUDIES: the effect of SB-75 was measured using a standardized chemosensitivity assay in the following ovarian cancer cell lines: UCI 101; UCI 107; PA-1; NIH: OVCAR 3; UCLA: 222; A2780, parental; A2780-CR, cisplatin resistant; A2780-DR, doxorubicin resistant; and the human breast cancer cell line, MCF-7. Results were expressed as percent growth inhibition determined by crystal violet photometric analysis. In vivo studies: the antiproliferative effect of this agent was examined using UCI-107, a primary epithelial ovarian carcinoma cell line, in a nude mouse model. On day 0, 10 x 10(6) UCI 107 cells were implanted subcutaneously into 20 intact female athymic nude mice (5 to 6 weeks old). On day 8, the mice were randomly divided into two groups of 10; control mice were implanted with miniosmotic pumps filled with a vehicle solution consisting of 5.2% mannitol in saline; and treated animals received pumps filled to deliver continuous administration of SB-75 at 60 micrograms per mouse per day. RESULTS: IN VITRO STUDIES: direct inhibition of cell proliferation by SB-75 was not observed at concentrations ranging from 1 nM to 100 microM (exposure lasting three to four cell doublings) with the exception of MCF-7, which demonstrated a 33% inhibition at the latter concentration. In vivo studies: on day 16, caliper measurements were taken from subcutaneous tumor nodules in SB-75-treated and untreated mice and a significant difference of 270% in mean tumor volume was observed. End point was determined, on day 30, when control tumor volume approached 10,000 mm3. At that time the difference in mean tumor volumes increased to 600%, indicating a substantial antiproliferative effect had been achieved in the SB-75-treated group. CONCLUSION: Our in vitro findings show direct inhibition by SB-75 on proliferation of human breast cancer cells. This direct inhibition in vitro was not observed in our ovarian cancer cell lines. However, in vivo SB-75 caused a significant inhibition of growth of human epithelial ovarian cancer. This may be a result of inhibition of the pituitary gonadal axis and gonadotropin secretion. Our results warrant further investigation. PMID- 7843433 TI - Physiological characterization of blastocyst hatching mechanisms by use of a mouse antihatching model. AB - OBJECTIVES: To use the protein-free medium blastocyst antihatching model to characterize physiological events that mediate hatching. DESIGN: In a series of four prospective experiments, our aims were to [1] test the efficacy of the antihatching model and assisted hatching; [2] exam the influence of initial in vivo developmental stage and late serum supplementation on hatching inhibition; [3] discount the role of zona hardness and physical expansion directly affecting hatching; and [4] provide evidence that the trophectoderm is directly responsible for secreting a zona lysin. SETTING: University-based research laboratory. RESULTS: Culturing two- to eight-cell mouse embryos in serum-free human tubal fluid (HTF) medium significantly reduced hatching levels to < or = 2%, however, hatching increased to 10.7% when initially culturing morula-stage embryos. Hatching was effectively rescued to control levels when embryos were placed in HTF with serum at the early blastocyst stage. There was no difference in blastocyst total cell numbers or zona pellucida digestion intervals between culture treatments. Finally, we showed that trophectodermal vesicles, devoid of inner cell mass, are capable of hatching under control conditions. CONCLUSIONS: The primary mechanism of blastocyst hatching is not physical expansion and abnormal zona hardness is not responsible for hatching inhibition. Certain extracellular precursors found in serum (e.g., amino acids) are required in culture medium upon cellular determination of trophectoderm (i.e., morula to blastocyst stage) to facilitate the intrinsic secretion of an undefined hatching factor. PMID- 7843434 TI - Does intrauterine insemination offer an advantage to cervical cap insemination in a donor insemination program? AB - OBJECTIVE: To compare pregnancy outcome after IUI versus cervical cap insemination in a donor insemination program. DESIGN: A randomized prospective clinical trial in which patients were alternately inseminated with cryopreserved human semen using either IUI or cervical cap insemination methods. SETTING: The donor insemination program at Washington University School of Medicine. PATIENTS: Forty-two women with either isolated male factor or male factor plus corrected ovulatory dysfunction using clomiphene citrate underwent 141 cycles of donor insemination. MAIN OUTCOME MEASURES: Clinical pregnancy rates (PRs) defined as a viable intrauterine gestation > 12 weeks or delivered were compared between groups using the chi 2 test. RESULTS: Clinical PRs were significantly higher in the IUI group (16.4%) compared with the cervical cap insemination group (5.9%). The spontaneous abortion rates were similar between the IUI (1.4%) and cervical cap insemination groups (4.4%). CONCLUSIONS: These findings suggest an advantage to IUI over cervical cap insemination in a donor insemination program. PMID- 7843435 TI - Unexpected pregnancies after tubal recanalization failure with selective catheterization. AB - OBJECTIVE: To evaluate selective salpingography sensitivity. DESIGN: Retrospective study. SETTING: Obstetrics and Gynecology Department, University of Genoa, Italy. PATIENTS: One hundred seventeen patients previously submitted to selective salpingography because of unilateral or bilateral proximal tubal injection failure. RESULTS: Seven pregnancies, one of which was ectopic, were obtained in 17 patients who had only recanalized tubes available for conception; 15 pregnancies were obtained in 39 patients who had one tube recanalized and one already patent; 3 tubal pregnancies were obtained in 12 patients who had only one tube already patent; 4 pregnancies, one of which was ectopic, were obtained in 19 patients who had neither patent nor recanalized tubes. CONCLUSIONS: Selective salpingography can give false-positive results; therefore, it is possible to obtain a pregnancy even after selective salpingography failure. PMID- 7843436 TI - Prognostic role of laparoscopic salpingoscopy of the only remaining tube after contralateral ectopic pregnancy. AB - OBJECTIVE: To evaluate the prognostic value of laparoscopic salpingoscopy in detecting patients who are at increased risk for a repeat ectopic pregnancy (EP). DESIGN: Patients with secondary infertility after a previous contralateral salpingectomy for EP were evaluated by laparoscopy with tubal perfusion and salpingoscopy of the only remaining tube. Subsequent reproductive outcome was evaluated and correlated to laparoscopic and salpingoscopic findings. SETTING: Department of Obstetrics and Gynecology of the Catholic University, a tertiary care university center in Rome, Italy. PATIENTS: Eighteen patients submitted to laparoscopy and salpingoscopy after a previous salpingectomy for EP. INTERVENTION: A two- to three-puncture laparoscopy with tubal perfusion and salpingoscopy. MAIN OUTCOME MEASURE: Reproductive outcome after a mean follow-up of 42.6 months. RESULTS: Salpingoscopy revealed a normal tubal mucosa in 13 patients (72%) and intra-ampullary adhesions in 5 patients (28%). Eight of the 13 patients with a normal mucosa conceived an intrauterine pregnancy. In the 5 patients with intra-ampullary adhesions, there were 3 repeat EPs, with one patient having first a term pregnancy and then a repeat EP. The presence of peritubal adhesions at laparoscopy was not of prognostic significance. CONCLUSION: Direct visualization of the ampullary mucosa by salpingoscopy can allow the detection of intraluminal adhesions that put the patient at increased risk for a repeat EP. PMID- 7843438 TI - Secretion of monocyte chemotactic protein-1 by cytokine-stimulated endometrial cells of women with endometriosis. Le groupe d'investigation en gynecologie. AB - OBJECTIVE: To evaluate in vitro the production of monocyte chemotactic protein-1 (MCP-1) by endometrial cells of patients with and without endometriosis. DESIGN: Primary cultures of stromal and epithelial cells isolated from human endometrium were exposed during 24 hours to different cytokines. Monocyte chemotactic protein 1 secretion was analyzed in the culture medium. SETTING: Gynecology clinic and laboratories of endocrinology of reproduction and immunology. PATIENTS: Women presenting for infertility or pelvic pain in which endometriosis was diagnosed at laparoscopy (n = 6) and women presenting for tubal ligation without laparoscopic evidence of the disease (n = 6). INTERVENTIONS: None. MAIN OUTCOME MEASURES: De novo secretion of MCP-1 in the culture supernatant by immunoprecipitation and sodium dodecyl sulfate-polyacrylamide gel electrophoresis after metabolic labeling with 35S-cysteine. RESULTS: The incubation of endometrial epithelial cells of endometriosis women with either interleukin-1 beta or tumor necrosis factor-alpha resulted in the appearance of at least two and sometimes three bands having approximately 15, 13, and 9 kd molecular weights. These bands were identified as three distinct species of MCP-1 as their immunoprecipitation was prevented effectively in presence of an excess of cold MCP-1. In contrast, the endometrial epithelial cells of only one of six normal women produce significant levels of MCP-1 under the same stimulation conditions. The stromal cells of both groups of subjects do not secrete appreciable amounts of MCP-1 or only small quantities in two cases of endometriosis. CONCLUSIONS: Monocyte chemotactic protein-1 secretion is upregulated in cytokine-stimulated endometrial epithelial cells of women having endometriosis as compared with normal women without evidence of the disease. Such a difference at the level of eutopic endometrial cell may have a significance in the physiopathology of endometriosis. PMID- 7843437 TI - Total renin after gonadotropin stimulation in polycystic ovarian disease. AB - OBJECTIVE: To examine the influence of polycystic ovarian disease (PCOD) on the levels of total renin in plasma and follicular fluid (FF) after stimulation with hMG. DESIGN: Comparative study of the plasma and FF concentrations of total renin in women with and without PCOD after stimulation with hMG. SETTING: In vitro fertilization-embryo transfer program at the Department of Obstetrics and Gynecology, the University Central Hospital of Turku, Finland. PATIENTS: Thirty six women undergoing IVF-ET for infertility with (n = 10) or without (n = 26) ultrasonographically diagnosed PCOD. Of the latter group, 15 women had tubal infertility, and the rest suffered from an anovulatory infertility and reacted with PCO-like ovarian response to stimulation. MAIN OUTCOME MEASURES: The concentrations of total renin in plasma and FF, serum E2, and protein in FF. RESULTS: The concentrations of plasma total renin after the gonadotropin stimulation were significantly higher in the PCOD and PCO-like groups when compared with the tubal group. The concentration of total renin in FF and the ratio of total renin per protein in FF were higher in the PCOD and PCO-like groups than in the tubal group, but the differences did not reach statistical significance. Positive correlations were found between the plasma total renin and serum E2 concentrations in the PCO-like and in the tubal group and between plasma total renin concentrations and the number of mature follicles in all groups. Follicular fluid total renin did not correlate with FF protein in any group. All findings were independent of the total hMG dosage used and the body mass index of the patients. CONCLUSIONS: In the present study the concentrations of total renin in plasma were enhanced markedly after gonadotropin stimulation in women with PCOD compared with women having tubal infertility. The pattern of the hormonal secretions revealed a group of infertile patients reacting biochemically like women with PCOD. PMID- 7843439 TI - Metabolic approaches to the subclassification of polycystic ovary syndrome. AB - OBJECTIVES: To examine the relationship between various hormonal and metabolic variables in a large group of women with unequivocal evidence of polycystic ovarian syndrome (PCOS) to dissect out the metabolic heterogeneity of this condition. DESIGN: Cross-sectional observational study of PCOS (n = 122) and non PCOS (n = 26) subjects. SETTING: Reproductive medicine unit in a tertiary teaching hospital. PATIENTS: Subjects with presumed PCOS were recruited from the Reproductive Medicine and Gynaecological Clinics and later confirmed as PCOS with recognized criteria. Several other subjects were identified through recruiting reference subjects. The PCOS population consisted of 122 patients. Reference subjects were recruited from partners of male factor infertility patients in the clinics and from the general population (n = 27). INTERVENTIONS: A 75 g 2-hour oral glucose tolerance test was performed on all subjects in their midluteal phase. Blood was taken at fasting and at 30, 60, 90, and 120 minutes. MAIN OUTCOME MEASURES: Age, body mass index (BMI), waist to hip ratio, levels of integrated glucose and insulin, concentrations of maximum insulin, sex hormone binding globulin, T, triglyceride, apolipoproteins (Apo A1, B), high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol (LDLC). RESULTS: Five clusters could be identified. They are characterized as a nonobese group, a moderately obese group, and three very obese groups. The nonobese group (n = 41, BMI = 24.1) exhibited the lowest level of integrated insulin (236.4 mIU/L or microU/mL) and concentration of serum T (5.5 nmol/L). The moderately obese group had the second lowest level of integrated insulin (497.1 mIU/L) whereas the three very obese groups (n = 15, 13, and 5, respectively) had significantly higher but different levels of integrated insulin (group 3: 850.8 mIU/L; group 4: 1,131.5 mIU/L; and group 5: 1,531.9 mIU/L), triglyceride (group 3: 1.39 mmol/L; group 4: 1.76 mmol/L; and group 5: 2.78 mmol/L [1 mmol/L = 88mg/mL]), Apo B (group 3: 1.18 g/L; group 4: 1.08 g/L; and group 5: 1.55 g/L) and LDLC (group 3: 3.81 mmol/L; group 4: 3.05 mmol/L; and group 5: 5.06 mmol/L [1 mmol/L = 38.6 mg/100 mL]). CONCLUSIONS: The metabolic heterogeneity of the PCOS population is reflected at least partly in patients' levels of insulin, lipids, and lipoproteins, dependent and independent of BMI. PMID- 7843440 TI - Intrauterine and subdermal progestin administration in postmenopausal hormone replacement therapy. AB - OBJECTIVE: To compare the effects of intrauterine and subdermal administration of levonorgestrel on control of bleeding and on the endometrium in postmenopausal hormone replacement therapy. INTERVENTIONS: Nineteen women started continuous oral E2 valerate therapy (2 mg daily) together with continuous parenteral progestin therapy. The subjects randomly received either a subdermal levonorgestrel-releasing implant (n = 9) or an intrauterine device (IUD) releasing levonorgestrel (n = 10). MAIN OUTCOME MEASURES: Serum concentrations of estrone, E2, FSH, sex hormone-binding globulin (SHBG) and levonorgestrel were followed. Endometrial biopsies and transvaginal ultrasonography were used to evaluate the endometrium. The subjects kept daily records of bleeding. The observation time was 1 year. RESULTS: Serum concentrations of the hormones mentioned above and SHBG were similar in both groups during the observation time, but the patterns of bleeding differed. In the IUD group there were 0.9 days (mean, range 0 to 4 days) of spotting and no days of bleeding during the last month of the follow-up year. In the implant group there were 8 days (mean, range 0 to 25 days) of spotting and 3.4 days (mean, range 0 to 14 days) of bleeding. In histological examination there was uniform atrophy in the endometrial samples from the IUD group, and a weak or absent progestin effect in the implant group. CONCLUSIONS: In spite of similar serum levonorgestrel concentrations, local intrauterine administration of levonorgestrel resulted in better control of bleeding and in more effective endometrial suppression than subdermal administration. PMID- 7843441 TI - More than 90% fertilization rates after intracytoplasmic sperm injection and artificial induction of oocyte activation with calcium ionophore. AB - OBJECTIVE: To examine whether fertilization rates after intracytoplasmic sperm injection can be increased by artificial oocyte activation. DESIGN: Oocytes that failed to fertilize spontaneously by 24 hours after intracytoplasmic sperm injection were treated either with calcium ionophore to induce activation or with solvent only to serve as control. The ability of ionophore-treated and control oocytes to achieve delayed fertilization was compared. SETTING: Private hospital and public research center. PATIENTS: Infertile couples treated by intracytoplasmic sperm injection. INTERVENTIONS: Intracytoplasmic sperm injection. MAIN OUTCOME MEASURES: Fertilization and cleavage rates. RESULTS: The mean rate of spontaneous fertilization after intracytoplasmic sperm injection was 32%, but 88% of the oocytes that failed to fertilize spontaneously did so after subsequent exposure to calcium ionophore. Most of these oocytes underwent at least one apparently normal cleavage division. In contrast, delayed fertilization of oocytes not treated with ionophore was an exceptional finding. If only oocytes remaining intact after intracytoplasmic sperm injection are taken into account, the mean global fertilization rate of ionophore-enhanced intracytoplasmic sperm injection was 91%. CONCLUSIONS: These results show that the failure of oocyte activation is the main cause of fertilization failure after intracytoplasmic sperm injection. If an appropriate, clinically applicable treatment is found to overcome this problem, intracytoplasmic sperm injection can be expected to yield fertilization rates far exceeding those of standard IVF with normal spermatozoa. PMID- 7843442 TI - The predictive value of discriminatory human chorionic gonadotropin levels in the diagnosis of implantation outcome in in vitro fertilization cycles. AB - OBJECTIVE: To determine if early serum hCG levels are predictive of implantation outcome in patients undergoing IVF-ET. DESIGN: Retrospective study of IVF cycles using receiver operator characteristic curve (ROC) analysis. SETTING: Tertiary care, university hospital-affiliated IVF program. PATIENTS: Three hundred fifty one conception cycles were studied. INTERVENTIONS: None. MAIN OUTCOME MEASURE: Implantation failure, defined as chemical pregnancies, ectopic gestations, and first trimester abortions, or implantation success, defined as delivered singleton and multiple pregnancies, and second trimester abortions. RESULTS: For each post-ET day 14 to 20, mean hCG levels of the implantation success group were significantly greater than implantation failure outcomes (P < 0.0001). Using ROC curve analysis, hCG cutoff values for each post-ET day were calculated for optimal discrimination of implantation failure from implantation success cycles. A patient with an hCG measurement greater than the calculated cutoff value had a > or = 90% chance of having an implantation success after IVF-ET. CONCLUSION: Discriminatory hCG cutoff values may be useful in predicting implantation outcome in IVF-ET cycles and may guide clinicians in identifying those pregnancies at risk for adverse outcomes and instituting more intensive surveillance in this population. This information also may be useful in providing counseling to IVF patients regarding pregnancy prognosis and result in cost savings. PMID- 7843443 TI - In vitro fertilization for women with pure tubal occlusion: the impact of short gonadotropin-releasing hormone agonist treatment. AB - OBJECTIVE: To evaluate the impact of a short GnRH agonist (GnRH-a) protocol on follicular and luteal characteristics and treatment outcome in women undergoing IVF for isolated pure tubal occlusion. DESIGN: A prospective randomized study. PATIENTS: Eighty patients with pure tubal occlusion undergoing IVF for the first time. INTERVENTIONS: Patients in group 1 (control group) were administered hMG from day 3 of the menstrual cycle. Patients in group 2 were administered 900 micrograms/d buserelin acetate intranasally from day 1 of the menstrual cycle, followed by hMG administration from day 3. Buserelin acetate was discontinued on the day of hCG administration. MAIN OUTCOME MEASURES: Information collected included E2 levels and follicular growth throughout cycle, amount of hMG required for stimulation, number of oocytes retrieved, fertilization, pregnancy, and cancellation rates. RESULTS: The short GnRH-a protocol resulted in significantly higher E2 levels and required less hMG for stimulation. However, the number of follicles aspirated, number of oocytes retrieved, fertilization rate, number of embryos transferred, pregnancy rate, and cancellation rate in both groups were comparable. CONCLUSIONS: The findings suggest that administration of a short protocol of GnRH-a to patients with pure tubal occlusion has no obvious superiority in comparison with hMG alone, except for the lower amount of hMG required for ovarian stimulation. PMID- 7843444 TI - The abnormally large follicle during controlled ovarian hyperstimulation: management and outcome of the cycle. AB - OBJECTIVE: To investigate if the presence of an abnormally large follicle during controlled ovarian hyperstimulation (COH) under pituitary suppression has any effect on the outcome of the cycle. DESIGN: Prospective, observational. SETTING: The reproductive endocrinology unit of a university hospital. PATIENTS: One hundred fifty patients undergoing COH for assisted reproductive techniques during a 6-month period (August 1990 to January 1991). INTERVENTIONS: Transvaginal follicular aspiration and IVF-uterine ET. RESULTS: A total of 19 cycles had abnormally large follicles identified on day 8 of the stimulation cycle after normal baseline ultrasound. Gonadotropins were continued and hCG injection was indicated when two or more follicles of the main cohort achieved a diameter of 20 to 22 mm. Twenty preovulatory oocytes were retrieved from 22 large follicles. Two were transferred for GIFT and 18 were inseminated in vitro, resulting in a 72.0% fertilization rate. The mean number of oocytes retrieved per patient was 10.9, 71.4% of which were mature with a fertilization rate of 67.7%. All these figures were comparable with the results obtained in the 131 patients of the control group undergoing IVF. No evidence of premature luteinization was observed in the study group, based on plasma P levels (x 0.83 ng/mL [conversion factor to SI unit, 3.180], range 0.31 to 1.40 ng/mL). The clinical pregnancy rate for the group with abnormally large follicles did not differ from the control group (27.8% versus 28.2%, respectively). CONCLUSIONS: The presence of an abnormally large follicle during COH under pituitary suppression does not affect the outcome of the cycle. Moreover, under these conditions, continuous gonadotropin stimulation of a follicle to diameters considerably larger than the standard ones does not have a detrimental effect on the oocyte contained in it, suggesting that oocyte aging is an independent process from follicular growth once LH surge is prevented. PMID- 7843445 TI - Air in the uterine cavity after embryo transfer. AB - OBJECTIVE: To examine the effect on the pregnancy rate (PR) caused by air bubbles loaded into the transfer catheter to bracket the embryo-containing medium. DESIGN: Prospective, randomized study. SETTING: One hundred ninety-six consecutive ETs in the Institute of Sterility Treatment. INTERVENTIONS: Air bubbles were loaded into the transfer catheter concomitantly with the medium in group I (n = 98), whereas in group II (n = 98) no air bubbles were used. RESULTS: The PR of group I equals that of group II. CONCLUSIONS: Bracketing the embryo containing medium by air bubbles offers several advantages, especially the possibility of tracking the air on the ultrasound monitor to localize the embryos after the ET. For these reasons we recommend using the proven method. PMID- 7843446 TI - Effects of induced hyperprolactinemia on in vitro fertilization cycles. AB - OBJECTIVE: To investigate the effect of induced endogenous hyperprolactinemia on the luteinization process, as expressed by the shift in the P:E2 ratio after hCG injection in IVF cycles. PATIENTS AND INTERVENTIONS: Serum PRL, E2, and P levels were measured in 49 IVF patients (leuprolide acetate and hMG protocol) on the day of hCG injection. Estradiol and P also were measured on the day after hCG. Serum P:E2 ratios were calculated for two groups of patients; group I (control): PRL < or = 20 ng/mL (conversion factor to SI unit, 1.00); group II (hyperprolactinemia): PRL > 20 ng/mL. Estradiol and P also were measured in follicular fluid (FF) and the gamete performance was compared between groups. RESULTS: Data analysis showed no significant differences in the mean +/- SD serum peak E2 (pg/mL; conversion factor to SI unit, 3.671) between groups: group I, 1,769 +/- 843; group II, 2,333 +/- 1,194; the mean FF E2 (pg/mL) group I, 351 +/- 221; group II, 370 +/- 186; or the mean FF P (ng/mL; conversion factor to SI unit, 3.180) group I, 8,357 +/- 3,127; group II, 11,354 +/- 12,888. No significant differences were found between groups in the P:E2 ratios on days 1 or 2: group I, 78 +/- 48 and 209 +/- 137; group II, 70 +/- 47 and 224 +/- 197, respectively. The magnitude of the P shift also showed no significant difference between the two groups; the mean +/- SD shift in the P level was 2.9 +/- 2.2 for group I, and 4.3 +/- 5.1 for group II. The serum PRL level had no effect on the fertilization rate (60% for group I and 70% for group II) or on the pregnancy rate (17% for group I and 23% for group II). CONCLUSION: These findings suggest that mild endogenous hyperprolactinemia induced by ovarian stimulation does not affect granulosa cell luteinization and gamete performance in humans. PMID- 7843447 TI - Occupationally related magnetic field exposure and male subfertility. AB - OBJECTIVE: To determine whether there is an association between occupationally related magnetic field exposure, as estimated in milligauss (mG), and male subfertility. DESIGN: Nested case-control study using three defined case groups and one standard control group. SETTING: Yale New Haven Hospital Infertility Clinic, New Haven, Connecticut. PATIENTS, INTERVENTIONS: Male partners of couples seeking diagnosis and care at the infertility clinic. Men included in the analysis had complete first semen analysis and interview information. Subjects for this investigation consisted of case groups for motility (n = 177), morphology (n = 135), and concentration (n = 172); controls included men normal on all three parameters (n = 304). MAIN OUTCOME MEASURES: Laboratory confirmation in semen analysis of poor morphology, inadequate motility, and low concentration. Comparisons of occupational magnetic field exposure categories are made between case groups and controls. RESULTS: The odds of high job exposure category to magnetic fields (> 3 mG [> 0.3 muT]) for morphology cases were odds ratio (OR) = 0.6, for motility cases OR = 1.1, and concentration cases OR = 1.0 as compared with controls. No significant association was demonstrated for medium exposure (> 2 to 3 mG) among all case groups. Multivariate adjustment for selected risk factors did not substantially change estimates of risk. CONCLUSIONS: A lack of association between occupationally related categories of magnetic field exposure and male subfertility, as evaluated by morphology, motility, and concentration, has been demonstrated. These findings do not substantiate theories of deleterious effects to male reproductive health from magnetic fields. PMID- 7843448 TI - Effectiveness of crossover transseptal vasoepididymostomy in treating complex obstructive azoospermia. AB - OBJECTIVE: To review the indications, surgical technique, and results of crossover transseptal vasoepididymostomies for treatment of complex obstructive azoospermia and oligospermia. DESIGN: Retrospective review of our experience with crossover transseptal end-to-side vasoepididymostomies in 10 men. INTERVENTIONS: Ten men underwent crossover transseptal end-to-side vasoepididymostomies. Nine men had primary and one had secondary infertility. Seven men were azoospermic, and the remaining 3 had severe oligospermia (sperm density < 1 x 10(6)/mL). All had a combination of irreparable ipsilateral ductal obstruction or agenesis with a normal testis and a poorly functional or absent contralateral testis. Contralateral testicular atrophy was associated with a prior hernia repair in 3 men, varicocele-induced atrophy in 2, and severe orchitis in 2. Cryptorchidism, testicular torsion, and one unknown cause were reported for three others. Congenital absence of the vas deferens caused the ipsilateral ductal pathology in 5 men. Three men had a vas injury from pediatric inguinal surgery, and 2 had an idiopathic vas obstruction. RESULTS: Twelve microsurgical crossover transseptal vasoepididymostomies were performed (2 men had repeat procedures). Anastomosis was performed to the caput in five men, the corpus in two, and the cauda in three men. Eight of nine men followed for 6 months or more had sperm in their ejaculate. Two of seven couples have established pregnancies. Total sperm counts ranged from 18 to 201 x 10(6) (mean, 98.1 x 10(6)) with motility of 5% to 37% (mean, 13%). Men with congenital absence of the vas deferens had significantly lower postoperative total sperm counts than men with all other causes of ductal pathology: 37.8 x 10(6) versus 135 x 10(6). No other characteristics (type of infertility, preop semen analysis, cause of testicular pathology, site of epididymal anastomosis) were useful predictors of postoperative sperm counts. CONCLUSIONS: If there is a solitary functioning testis with irreparable excurrent ductal obstruction or agenesis, a crossover transseptal vasoepididymostomy can restore patency in most men. PMID- 7843449 TI - Comparison of the effectiveness of placebo and alpha-blocker therapy for the treatment of idiopathic oligozoospermia. AB - OBJECTIVE: To determine whether alpha-blocker (bunazosin) improves fertility and/or semen parameters DESIGN: Placebo-controlled, double-blind clinical study. SETTING: Nagoya University Hospital Andrology Clinic, Nagoya, Japan. PATIENTS: Thirty-four men with sperm density between 5 and 20 x 10(6) sperm/mL, normal serum gonadotropins and T, and a fertile partner were enrolled in this study. INTERVENTIONS: After a 3-month control period, patients randomly were prescribed bunazosin 2 mg/d or a placebo, two tablets per day, for 6 months. Semen and blood samples were collected before and after therapy. Semen parameters, serum gonadotropins, T, PRL, and E2 were evaluated before and after therapy. RESULTS: The pregnancy rate (PR) in the alpha-blocker group was 25%, compared with 6.7% in the placebo group. There was no statistical difference in the PR between groups. The alpha-blocker group had significantly higher levels of sperm density and total motile sperm count. There were no differences between the placebo and alpha blocker groups in seminal volume, the percentage of motile sperm, and normal morphology or hormone levels. CONCLUSIONS: The authors conclude that alpha blocker is a useful drug in the treatment of idiopathic moderate oligozoospermic men. PMID- 7843450 TI - Pregnancy after zona drilling of cryopreserved thawed embryos: case report. AB - OBJECTIVE: To confirm successful implantation of IVF, cryopreserved human embryos after assisted hatching with acidic Tyrode's solution. DESIGN: Case report. SETTING: In vitro fertilization-ET facility of a university-based practice. PATIENT: A 28-year-old female with nonoperable bilateral tubal occlusion and > 1 1/2 years of primary infertility. INTERVENTIONS: The patient was stimulated for egg retrieval after an hMG-controlled ovarian hyperstimulation regime. Luteal phase leuprolide acetate (1 mg) was administered SC for 10 days. The dose was then reduced to 0.5 mg, and she was given hMG and FSH IM twice daily until two lead follicles reached 20 mm average diameter. The patient was administered 10,000 IU hCG 36 hours before retrieval. MAIN OUTCOME MEASURES: Viable pregnancy documented by ultrasound (US). RESULTS: After the transfer of five cryopreserved thawed human embryos that were subjected to assisted hatching using acidic Tyrode's solution, the patient established a triplet gestation as documented by US. CONCLUSION: This case report demonstrates that zona drilling can be successfully applied to frozen-thawed pronuclear stage embryos that were cultured to 72 hours without damaging them, as evidenced by continued cleavage and resulting implantation. PMID- 7843451 TI - The relationship between size and maturation in vitro in the unstimulated human oocyte. AB - OBJECTIVE: To determine if the size of human oocytes at collection from unstimulated ovaries is related to their ability to resume meiosis and undergo maturation in vitro. DESIGN: A comparative study of oocyte diameter at collection. SETTING: Department of Obstetrics and Gynecology, Northwestern University Medical School. PATIENTS: Women age 25 to 39 years of age undergoing gynecological procedures yielding oophorectomy specimens. INTERVENTION: Oocytes obtained from ovarian tissue were cultured in Ham's F-10 and fetal bovine serum for 72 hours and observed two times per day. MAIN OUTCOME MEASURE: The oocytes ability to resume meiosis and complete maturation based on their diameter at collection. RESULTS: Chi-squared analysis revealed a significant difference in oocytes measuring 86 to 105 microns versus those measuring 106 to 125 microns. CONCLUSION: The unstimulated human oocyte appears to have a size-dependent ability to resume meiosis and complete maturation. PMID- 7843452 TI - Amplification of exon 11 of the gene for the alpha-chain of beta-N acetylhexosaminidase in single human blastomeres. AB - OBJECTIVE: To evaluate the possibility of using polymerase chain reaction (PCR) technology for preimplantation diagnosis for Tay-Sachs disease. DESIGN: Polymerase chain reaction on single human blastomeres. SETTING: Bad quality embryos from IVF analyzed in an academic research genetics lab. INTERVENTIONS: Patients underwent standard IVF procedures as infertility treatment. RESULTS: Amplification was seen in 89.5% of the blastomeres; only one blank was contaminated. CONCLUSION: The technique of PCR on single blastomeres is ready to be used in clinical preimplantation diagnosis for Tay-Sachs disease. PMID- 7843453 TI - Preoperative sonographic measurement of endometrial pattern predicts outcome of surgical repair in patients with severe Asherman's syndrome. AB - OBJECTIVE: To assess the predictive value of preoperative endometrial sonography in the diagnosis and surgical treatment of women with amenorrhea due to severe Asherman's syndrome. DESIGN: Patient series. SETTING: Academic clinical practice. PATIENTS: Seven women with severe Asherman's syndrome characterized by amenorrhea despite normal ovulatory function and complete obstruction of the uterine cavity at the level of the cervix or lower uterine segment at hysterosalpingogram. MAIN OUTCOME: Ability of vaginal sonography to predict successful hysteroscopic treatment as assessed by resumption of menstrual cyclicity and normalization of the uterine cavity. RESULTS: Transvaginal sonography demonstrated a well developed endometrial stripe in three of seven women, while three others had virtually no endometrium seen. All women with well-developed endometrium were found to have adhesions occluding the lower uterine segment and had resumption of normal menses and normalization of the cavity after hysteroscopy. The women with minimal endometrium had no cavity identified and derived no benefit from surgery. A seventh woman with endometrium seen only on one side of the cavity had patency successfully established only on that side. CONCLUSION: The endometrial pattern seen with transvaginal sonography is highly predictive of surgical and clinical outcome in women with severe Asherman's syndrome characterized by complete obstruction of the cavity at hysterosalpingogram. PMID- 7843454 TI - The use of topical anesthesia in diagnostic hysteroscopy and endometrial biopsy. AB - OBJECTIVE: To show that intrauterine anesthesia is a reliable method for reducing pain associated with endocavitary procedures. DESIGN: A prospective, randomized, double-blind study. SETTING: The Department of Obstetrics and Gynecology, Tor Vergata University of Rome, Rome, Italy. PATIENTS: Forty-five patients undergoing diagnostic hysteroscopy (n = 27) or hysteroscopy and endometrial biopsy (n = 18). INTERVENTIONS: Five milliliters of 2% mepivacaine or saline solution were injected transcervically into the uterine cavity before performing the procedures. MAIN OUTCOME MEASURES: Evaluation of pain reduction on a visual analogue scale. RESULTS: Pain expectation and pain reported were reduced during and after the procedures. CONCLUSION: Topical anesthesia effectively reduces pain during hysteroscopy and endometrial biopsy. PMID- 7843455 TI - Fluorescent in situ hybridization evaluation of human Y-bearing spermatozoa separated by albumin density gradients. AB - OBJECTIVE: Fluorescent in situ hybridization of decondensed sperm nuclei was employed to evaluate the effectiveness of the Ericsson albumin gradient enrichment technique of Y-bearing sperm. DESIGN: Mature human spermatozoa were separated from donor- and randomly selected patient semen using three different albumin density layers. Sperm nuclei, in the albumin layer with highest density, were decondensed and the percentage Y-bearing sperm was determined by fluorescent in situ hybridization. RESULTS: A slight, although statistically significant, increase in percentage Y-bearing sperm was observed. CONCLUSION: Although statistically significant, the clinical relevance of the small increase in Y bearing sperm remains uncertain. A randomized controlled clinical study should help to clarify the above laboratory results. PMID- 7843456 TI - Determination of a maximum number of artificial inseminations by donor children per sperm donor. AB - OBJECTIVE: To determine a safe maximum number of artificial insemination (donor insemination [DI]) children per anonymous sperm donor. DESIGN: Multiparameter calculation model of contribution of DI to inbreeding. SETTING: Data of the collaborative DI centers and demographic population data of The Netherlands. INTERVENTIONS: Calculations of the contribution of DI to inbreeding were made, taking into account all possible unintentional consanguineous matings and consanguineous inseminations with a coefficient of inbreeding (F) of > or = 1/16 for the offspring. MAIN OUTCOME MEASURE: Coefficient of inbreeding (F). RESULTS: The contribution of DI to inbreeding was estimated to be 46.6 x 10(-6) + k (1.66 x 10(-6)) (k = number of DI children per donor). When only half-sibling matings were considered, the kmax was 32. When all possible consanguineous matings and inseminations were taken into account, kmax decreased with 28% to 25 children. CONCLUSION: Calculations of a maximum number of DI children per sperm donor, based on possible enhancement of inbreeding and given the Dutch population and DI setting, show that 25 children per DI donor is a safe threshold for clinical practice. PMID- 7843457 TI - Tissue actions of bipolar scissors compared with monopolar devices. AB - OBJECTIVES: To establish whether bipolar scissors offer equivalent cutting performance compared with monopolar scissors and to compare extent of thermal coagulation injury using two electrosurgical generators. DESIGN: Eighteen female rabbits' uterine horns were cut using controlled velocity at several different wattages with either bipolar or monopolar scissors. The specimens were examined microscopically and zones of thermal necrosis were measured using a stage micrometer against a 1 mm standard. RESULTS: Bipolar scissors cut equally well compared with monopolar scissors and showed significantly less thermal injury. When coupled to a constant voltage generator both the bipolar and monopolar scissors performed better. CONCLUSION: Bipolar scissors offer the surgeon significant safety advantages and equivalent or better performance compared with monopolar scissors when used for laparoscopic surgery. PMID- 7843458 TI - Diagnosis and origins of endometriomas. PMID- 7843459 TI - "When you have the real thing". PMID- 7843460 TI - Analysis of the cell death in the mucoid epithelium of mouse stomach. AB - The death and phagocytosis of the stomach mucoid epithelium cells in 2-8 day old mice were investigated in relation to the state of cell differentiation and the cell age. The autoradiographic determination of 3H-thymidine and cytochemical demonstration of neutral mucosubstances in secretory granules (TA-UA and PA-TCH SP methods) were used. During the migration from the proliferation centers to the surface of the mucoid epithelium the cell death occurs in two different ways: by apoptosis and by necrosis. Necrosis is limited to superficial, fully differentiated mucoid cells, which--after the cell death has occurred--are desquamated into the lumen as fragments of irregular shape. The apoptosis is very common and takes place in all the regions: from the proliferation nests up to the surface. It does not depend on the step of differentiation or the age of the cells. In the phagocytosis of apoptotic bodies are included neighbouring mucoid cells. The general occurrence of the apoptosis indicates the important role of this process in the regulation of the cell population during the morphogenesis of the stomach epithelium. PMID- 7843461 TI - Cytochemical localization of monoamine oxidase in the pig pineal gland. AB - Monoamine oxidase plays an important role in the regulation of monoamine levels in the pineal gland by oxidative deamination of serotonin to 5-hydroxyindole acetic acid. The ultrastructural sites of this process are still not well known. In the present study the pig pineal glands were examined by using two cytochemical methods for demonstration of MAO activity at the ultrastructural level. The use of selective inhibitors of MAO-A (clorgyline and amiflamine) and MAO-B (deprenyl) showed that MAO-A was localized predominantly in noradrenergic nerve terminals as well as in the cell membrane of endothelial cells. MAO-B activity was localized in pinealocytes. However, in the outer membranes of cytoplasmic dense bodies, which are characteristic cytoplasmic structures of pig pinealocyte, we noticed the activity of both MAO-A and MAO-B enzymes. The MAO-A was localized exclusively in dense bodies within bulbous ending of pinealocyte processes present in the perivascular space. Our results show that in pig pineal gland there are two forms of MAO localized in different compartments of the pineal tissue. The most important result of our study is the presence of MAO in cytoplasmic dense bodies, which points to these bodies as to the sites of oxidative deamination and confirms their participation in the secretory process in pig pineal gland. PMID- 7843462 TI - Localization of S-100 protein in pig ovarian structures. AB - Distribution of S-100 protein in porcine ovaries was revealed by an application of polyclonal antibodies against S-100 protein and PAP universal kit to formalin fixed, paraffin-embedded tissues. The presence of S-100 protein was demonstrated in follicular cells of all ovarian follicles (including their atretic forms), with a decrease in intensity of the reaction parallel to an increase in follicle size. No reaction was found in oocytes, regardless of the developmental stage of the follicle. Weak expression of S-100 protein was observed in theca interna cells of mature follicles and in the youngest generation of theca-lutein cells of the corpus luteum. A distinctly positive reaction was also observed in groups of cells resembling hilus cells as well as in endothelia of arteries and some capillaries. Results are compared with data concerning the localization of S-100 protein in human and bovine ovaries. Possible relationship between the presence of S-100 protein and the level of cellular differentiation is discussed. PMID- 7843463 TI - Immunocytochemical studies on pancreatic endocrine cells at early stages of development of the pig. AB - The studies were performed on pig embryos between 23rd and 31st day of intrauterine life. Immunocytochemical markers of neuroendocrine cells, i.e. neuron-specific enolase, chromogranin and synaptophysin as well as basal hormones, i.e. insulin, glucagon, somatostatin, pancreatic polypeptide and, additionally, serotonin and gastrin were detected in serial sections. Our studies indicate that differentiation of pancreatic endocrine cells does not take place unitemporally. At the first stage, the cells acquire the traits of neuroendocrine cells and secrete more than one hormone while final specialization toward cells secreting individual hormones take places at a later stage. PMID- 7843464 TI - Influence of brain hypoxia on megakaryocytic emperipolesis in rats. AB - An evaluation of frequency and intensity of the megakaryocytic emperipolesis in the rat bone marrow after unilateral carotid artery occlusion was performed. The results were compared with those obtained in the group undergoing a blood loss and the group not subjected to surgical procedures. A significant increase in the frequency of emperipolesis was found in the bled rats following a carotid artery cannulation, but also in animals exposed to the carotid artery occlusion only. In most cases the cytoplasm of megakaryocytes contained granulocytes and erythroblasts. The observed emperipolesis phenomenon is likely to be a result of brain hypoxia and a secondary neurogenic stimulation of the bone marrow activity. PMID- 7843465 TI - Evidence for inhibition of steroid hormone secretion by arginine vasotocin (AVT) in tissue culture of isolated ovarian follicular cells. AB - Two follicular compartments, granulosa (G) and theca interna (T) cells isolated from porcine ovaries were cultured alone or in co-culture (GT). Cells were grown as monolayers in a control medium without hormone and in a media supplemented with arginine-vasotocin (AVT) at a concentration of either 10(-7)M or 2 x 10( 7)M. Progesterone (P4), estrogen (E2) and androgen (A) concentrations in the culture media were taken as measures of the effect of AVT on the function of follicular cells. Steroids were analysed by radioimmunoassay. AVT action in this culture system was expressed as a decrease in progesterone secretion by cultures of granulosa cells alone, and especially as a change in the pattern of estradiol and androgen secretion by co-cultures. Control T and G cells cultured alone secreted small amounts of A (238.0pg/10(5) cells, 27.3pg/10(5) cells, respectively), and E2 (272.5pg/10(5) cells, 10.6pg/10(5) cells, respectively) while in co-culture these two cell types interacted and the result of this positive interaction was a significant increase in secretion of these two steroids (941.0pg/10(5) cells androgen secretion and 854.1pg/10(5) cells estradiol secretion). This phenomenon is similar to that observed in the intact follicle in vivo. AVT introduced to the culture medium impaired the effect of this positive interaction of mixed G and T cells on the production of high levels of E2 and A by untreated co-cultures. PMID- 7843466 TI - Glycosaminoglycans of umbilical cord arteries and their alterations in EPH gestosis. AB - It was found that the umbilical cord arteries (UCAs) contained several types of glycosaminoglycans (GAGs), including hyaluronic acid and sulphated glycosaminoglycans. EPH-gestosis is accompanied by significant changes in the composition of extracellular matrix of the UCAs. Significant increase in collagen content was found. Total amount of GAGs did not change much but the quantitative ratio between various GAGs distinctly altered. A decrease in hyaluronic acid content and an increase in the amount of sulphated GAGs as well as a diminution of GAGs/collagen ratio were observed. These observations were confirmed by histochemical methods. The significance of these phenomena for collagen fibrillogenesis in the arterial wall is discussed. PMID- 7843467 TI - In situ hybridization of two nodule-specific gene products from yellow lupin. AB - We have applied in situ hybridization technique to examine the expression of two tissue-specific plant genes represented by cDNA clones: pLN-13 and pLN-50 during the symbiosis of Lupinus luteus with Bradyrhizobium lupini. Both genes are expressed in root nodules and their transcripts are restricted to the infected zone of the nodule as revealed with 35S-or 3H-labelled antisense RNA probes. The number of grains over bacteroid-containing cells after hybridization with 3H labelled probes differed during three tested phases of nodule development: at the 14th, 21st and 28th day after the infection with B. lupini. As control, apical root meristems and segments of root hair zones of uninfected plants were used for incubation with RNA of either sense or antisense orientation preceded by RNAse A digestion. The data obtained confirm that both genes are organ-specific and reveal their developmentally regulated expression pattern during the course of root nodule morphogenesis. PMID- 7843468 TI - Characteristics and location of Hae III repetitive sequences family in Haemanthus (Scadoxus) katharinae (Amaryllidaceae). AB - A dispersed repetitive Hae III-family sequences in Haemanthus katharinae, a monocotyledonous diploid species with very large genome (2C DNA = 117 +/- 2.24 pg) were characterized. The restriction pattern is similar in different tissues and organs (root meristems, leaves and endosperm). This Hae III-family is represented by population of highly reiterated fragments whose average sizes were estimated to be: p6-167 bp, p7-183 bp, p39-400 bp and p44-501 bp. The above fragments constitute: p6 and p7 together 0.56% (3.26 x 10(5) copies), p39 1.62% (8.42 x 10(5) copies) and p44 0.28% (4.06 x 10(4) copies) of the haploid genome. There is no distinct homology among these fragments. p39 and p44 fragments are characterized by high AT content: 68.0% and 64.3%, respectively, while in p6 it reaches 51.5% and 52.4% in p7. Internal sequence organization in p39 fragment revealed a number of short direct repeats. p44 homologous sequences are located uniformly over the mitotic chromosomes and interphase nuclei. PMID- 7843469 TI - Metabolic complications of visceral obesity: contribution to the aetiology of type 2 diabetes and implications for prevention and treatment. PMID- 7843470 TI - One year comparative trial of metformin and glipizide in type 2 diabetes mellitus. AB - Forty-eight diabetic subjects with diet-failed Type 2 mellitus, aged 40-69 years, were randomised to metformin (24 patients) or glipizide (24 patients) therapy, and followed prospectively for 12 months. Most subjects were obese. Metformin gave better fasting plasma glucose control compared to glipizide at 24 (p < 0.01), 36 (p < 0.05) and 52 weeks (p < 0.05) with a lower HbA1 concentration at 52 weeks (p < 0.05). Metformin treated patients lost weight whereas glipizide treated subjects gained weight. The weight change between the treatment groups reached significance at 4 weeks (p < 0.05) and was highly significant (p < 0.001) at 8, 12, 24, 36 and 52 weeks. There were no significant changes in either fasting plasma lipid or blood lactate levels in either the metformin or glipizide treated groups. Both drugs caused a similar reduction in albumin excretion rates. In conclusion, metformin gave better glycaemic control than glipizide, with weight loss rather than weight gain in obese Type 2 patients. PMID- 7843471 TI - Relationship between hemorheological and microcirculatory abnormalities in diabetes mellitus. AB - From numerous studies, it is now well known that diabetes mellitus is usually accompanied by miscellaneous hemorheological disturbances. These may alter the microcirculatory flow and lead ultimately to tissue chronic hypoxia. In this report, red blood cell aggregation characteristics and transcutaneous oxygen pressure (TcPO2) have been evaluated in diabetic patients without any sign of angiopathy. Results showed a tendency towards erythrocyte hyperaggregation in diabetic patients, even when under good glycaemic control. TcPO2 measurements, were found to be significantly lower in diabetic patients than in control subjects. Furthermore, the TcPO2 values were related with the aggregation parameters, confirming thereby the existence of an inter-relationship and thus the possible role played by hemorheological parameters in oxygen transport to tissues and hence in the pathogenesis of microangiopathy at the functional level. PMID- 7843472 TI - [Diabetes and road safety]. AB - The purpose of this study is to analyse the driving habits of a group of diabetic individuals, insulin and noninsulin treated, compared with the driving habits of an equivalent group of individuals in good health. Specific attention is given to the evaluation and management of stress related to driving. The analysis relies mainly upon the answers of 307 persons of both sex on a questionnaire regarding their driving habits and concerning twenty more or less risky behaviors. The diabetic subjects were sampled among the patients of an endocrinology clinic, and the pilot group (in good health) was gathered among the patients from the clinic of a general practitioner. The subjects were aged between 25 and 65. All were in possession of a driving licence and had a driving experience of over two years. The results show, on one hand, that the evaluation of stress related to a risky behavior is associated to the taking of risk at the wheel, and on the other hand, that compared with the other subjects in the study the diabetic subjects had a lesser tendency to taking risks in driving. The subjects avoided the behaviors they judged risky. Beside avoiding dangerous road behaviors, the latter brought special attention to food and relaxation needs and they showed a great alertness towards climatic and road conditions. Finally, they are especially careful in preventing and curing hypoglycaemic states. PMID- 7843474 TI - [Dyschromatopsia: manifestation or epiphenomenon in the course of diabetic neuropathy]. AB - We performed a study in 92 diabetic patients (76 Type 1 and 16 Type 2) without retinopathy to determine the relation between diabetic dyschromatopsia and neuropathy, which has been evoked in previous studies. Color vision was explored with Lanthony's desaturated D 15 panel. Peripheral nervous function was explored with an electrophysiological score which has been beforehand validated. Moreover evoked visual potentials were performed in 38 diabetic subjects in order to determine whether dyschromatopsia was related to an impairment of central optic pathways. Fifty-one among the 92 diabetic subjects had a blue-yellow dyschromatopsia. Among the recorded parameters, only peripheral nervous impairment was significantly more frequent in the group with dyschromatopsia than in the group without. Ten among 38 diabetics had impairment of the evoked visual potentials. Frequency of alteration of evoked visual potentials was not different between the group with and the group without dyschromatopsia. Our results confirm the relationship between dyschromatopsia and the alteration of the nervous function in diabetic subjects. In return, lack of significant modification of evoked visual potentials among diabetic patients with dyschromatopsia and the blue-yellow axis of dyschromatopsia are in opposition with a direct neurological origin of dyschromatopsia. We therefore evoke a common process in the beginning of the diabetic dyschromatopsia and of peripheral neuropathy. PMID- 7843473 TI - Diabetic patient's compliance with bespoke footwear after healing of neuropathic foot ulcers. AB - OBJECTIVES: To define personal attributes and factors associated with compliance to wearing protective footwear in severely neuropathic diabetic patients with a history of foot ulceration. DESIGN: Case-control study. SETTING: Diabetic foot clinic. SUBJECTS: 85 patients regularly attending the foot clinic were assessed after healing of neuropathic foot ulceration. INTERVENTION: Recommendation of wearing cushioned bespoke shoes instead of normal shoes, prescription of up to 2 pairs of bespoke shoes on request. MAIN OUTCOME MEASURES: Clinical characteristics and attitudes of compliant patients wearing bespoke shoes (cases) versus non-compliant control patients wearing normal shoes on a random day. RESULTS: The 51 case patients were significantly older and more often amputated than the 34 controls; they more frequently rated their feets' sickness and their overall health status as less favourable than did controls (p < 0.05). The controls, however, were more often on renal replacement therapy. Although the appearance of bespoke shoes was disliked by all of the patients, and 47% of the cases and 100% of the controls would favour normal shoes for cosmetic reasons, all case patients wore their bespoke shoes according to the physicians recommendation, as compared to 26% of the controls (p < 0.01). CONCLUSION: Differences in age, perception of foot abnormalities and health status, and other distressing medical conditions (i.e. renal replacement therapy, previous minor amputations) in addition to cosmetic reasons may affect the patients' compliance with bespoke protective footwear. PMID- 7843475 TI - Measurement of insulin sensitivity by the minimal model method using a simplified intravenous glucose tolerance test: validity and reproducibility. AB - This study aimed at testing whether 12 rather than 26 plasma glucose and insulin determinations can be used to calculate the indices of insulin sensitivity and of glucose effectiveness using Bergman's minimal model during a simple intravenous glucose tolerance test performed without tolbutamide injection. Two intravenous glucose tolerance tests (separated by 1 week) were performed in 7 lean normal subjects and a single test was performed in 9 severely obese non-diabetic subjects. Intra-subject reproducibility of insulin sensitivity was not significantly different when 26 or 12 time-points were analyzed (CV = 16.8 +/- 3.4 versus 18.9 +/- 3.8% respectively). Compared with the insulin sensitivity of the lean subjects, that of obese subjects was significantly (P < 0.001) and similarly reduced when using 12 (2.14 +/- 0.34 versus 7.97 +/- 1.29 10(-4)min 1/mU.1-1) rather than 26 determinations (2.13 +/- 0.42 versus 6.95 +/- 1.12 10( 4) min-1/mU.1-1) respectively. Glucose effectiveness was less reproducible than insulin sensitivity and was slightly diminished by the reduction of blood samples (relative error: -9.7 +/- 4.4%; P < 0.05). Finally, glucose effectiveness tended to be slightly lower in the morbidly obese subjects than in the lean controls with both modes of calculation. In conclusion, in non-diabetic subjects, the insulin sensitivity index can be accurately measured during a simple intravenous glucose tolerance test, without tolbutamide injection and with only 12 blood samples. The possibility of performing a simplified test should contribute to increase the use of the minimal model method for estimating insulin sensitivity in clinical practice. PMID- 7843476 TI - [Cardiac autonomic neuropathy. Current realities and future outlook]. AB - Cardiac autonomic neuropathy frequently affects Type 1 and Type 2 diabetic patients. This disease is distinguished by visible clinical consequences which can be tragic. It can also worsen a number of degenerative complications. Therefore, cardiac autonomic neuropathy seems to play a deciding role in silent ischaemia and in dysregulations of blood pressure. Clinical explorations continue to be based on the tests validated by Ewing, but the development of simple and reliable techniques seems to be an objective the interest of which cannot escape any clinician. PMID- 7843477 TI - [Sports activities and type 1 diabetes]. PMID- 7843478 TI - Worldwide survey of assisted vaginal delivery. AB - OBJECTIVES: To ascertain which instruments are most commonly used for assisted vaginal delivery. METHODS: A postal survey in which 1411 questionnaires were sent to major obstetric centers worldwide. RESULTS: Over 60% (305/508) of the respondents indicated willingness to participate in a multicenter randomized controlled trial between the two instruments. CONCLUSIONS: The forceps remained popular in most of the 'English-speaking' countries, as well as in Eastern Europe and South America. The ventouse was most popular in Africa, Asia and Northern Europe. PMID- 7843479 TI - Prevention of preeclampsia with calcium supplementation and vitamin D3 in an antenatal protocol. AB - OBJECTIVES: Using an angiotensin sensitivity test we carried out a prospective study in an attempt to predict the possible onset of preeclampsia and to prevent it by calcium supplementation (elemental calcium 156 or 312 mg/day per os) and treatment with vitamin D3 (0.5 micrograms/3 day per os). METHOD: We used a study design in which 666 singleton pregnant women were managed with conventional antenatal care and 210 singleton pregnant women were managed with a protocol, together with conventional antenatal care. RESULT: Of the 666 women managed conventionally, 113 (16.9%) developed preeclampsia. However, the incidence of preeclampsia in the 210 women managed on the protocol was lower, at 10.9%. CONCLUSION: Our findings indicate that this protocol for the prediction and prevention of preeclampsia is useful for pregnant women at high risk of developing preeclampsia. PMID- 7843480 TI - Thromboembolic prophylaxis with low molecular weight heparin during pregnancy. AB - OBJECTIVE: The objective of this study was to show that low molecular weight heparin (LMWH) can be used in preventing veno-pulmonary thromboembolic diseases in pregnancy. METHODS: Twenty-four women carrying 27 pregnancies with known risk of veno-pulmonary thromboembolic diseases in pregnancy were prophylactically treated with LMWH (dalteparin) during part of their pregnancy. Our therapeutic target was a plasma concentration of 0.20-0.50 anti-Xa U/ml measured 2-6 h after subcutaneous administration of LMWH into the abdominal wall. To obtain this anti Xa activity the patients were given total doses of 2500-10,000 anti-Xa U daily. Monitoring of anti-Xa activity in patients receiving < or = 5000 U/day was not necessary. RESULTS: Twelve out of the 24 women received LMWH at the time of delivery. Our biochemical assay could not show the presence of anti-Xa activity in the blood samples from the babies although it was possible to show anti-Xa activity in their mothers. In three out of 24 women, blood samples showed activation of coagulation. These patients were changed to the vitamin K antagonist phenindione. CONCLUSIONS: None of the treated women showed any clinical or paraclinical signs of thromboembolic diseases during pregnancy or 6 weeks postpartum. All the babies were born healthy. None of the women had any side effects due to the treatment. PMID- 7843481 TI - A retrospective analysis of pathological placental implantation--site and penetration. AB - OBJECTIVES: To determine the incidence of pathologically implanted placenta, i.e. placenta previa and accreta, at the Maternity Hospital of Kuwait. In addition the study aimed to identify the risk factors for such conditions, and test the hypothesis that previous cesarean section increases the likelihood of abnormal placentation. METHODS: Analysis of all deliveries in the Maternity Hospital of Kuwait with identification of cases of placenta previa, placenta accreta, previous cesarean section and manual removal of placenta. Information was obtained from the medical records of the hospital between 1981 and 1992 except for the period 1990-1991 due to incomplete information as a consequence of the Iraqi invasion. The incidences of these conditions were calculated followed by identification of risk factors for placenta accreta and previa. RESULTS: The incidence of placenta previa was 0.5% and that of placenta accreta 9.5 per 100,000 deliveries. Placenta previa and previous cesarean section were found to be significant predisposing factors for placenta accreta. The increased risk for placenta accreta in the presence of these factors was much less than that reported in the international literature. Abnormal placentation was responsible for 34% of peripartum hysterectomies. CONCLUSIONS: Placenta accreta and previa are major causes of massive obstetric hemorrhage. They are interrelated with a common predisposing factor, cesarean section. Even though the rate of cesarean section and placenta previa is increasing, the incidence of placenta accreta remains stable in Kuwait. PMID- 7843482 TI - Transcervical endometrial cryoablation (ECA) for menorrhagia. AB - OBJECTIVE: To evaluate endometrial cryoablation (ECA) as a treatment for menorrhagia. METHOD: Prospective study of 67 women. ECA uses the Joule Thompson principle of expanding gases. The ECA probe has a channel to inject saline solution into the uterine cavity. The probe is introduced into the uterine cavity, which is distended with 5 ml saline solution. The device is activated for two freeze-thaw cycles. The saline solution forms an ice mold of the uterine cavity which can be observed by ultrasound scan. RESULTS: No surgical or long term complications were observed. Two-thirds of patients followed up for > 3 months were completely satisfied. CONCLUSIONS: ECA is technically very easy, can be learned quickly, is free of complications and led to improvement of menstrual symptoms in 63% of patients followed up for 3-18 months. The device is virtually maintenance-free and requires only a small initial investment, while running costs are negligible. PMID- 7843483 TI - Transvaginal sonography in patients with pathological cervical exfoliative cytology or histologically verified cervical carcinoma. AB - OBJECTIVE: The aim of the study was to evaluate whether detection of cervical carcinoma or cervical dysplasia is possible with the use of transvaginal sonography (TVS). METHODS: TVS was performed in 215 patients with pathological cervical cytology (PAP III-V), suspicious clinical findings or histologically verified carcinoma of the cervix. RESULTS: Cone biopsy in 54 patients with suspicious cytology and normal cervical features revealed 26 cases of cervical intraepithelial neoplasia (CIN) 0-II and 19 cases of carcinoma in situ. Sonography failed to detect cervical carcinoma in only nine cases (stages Ia, Ib and IIa). False-positive results of TVS were associated in no cases with CIN 0. In 161 cases with suspicious cervical lesions, 133 invasive cancers and 23 carcinomas in situ were detected. The most striking cytological finding was that 92% of patients with PAP III/IIID and abnormal sonographic signs, and 7% with normal sonographic results and suspicious PAP, had cancer of the cervix uteri. CONCLUSION: We conclude that TVS could be usefully applied to the routine pretreatment evaluation of patients with cervical carcinoma. PMID- 7843484 TI - Preoperative sonographic evaluation of patients with endometrial carcinoma. AB - OBJECTIVE: The aim of the study was to evaluate the possibilities of endovaginal ultrasound in the preoperative clinical assessment of patients with endometrial carcinoma. METHOD: Sixty-four postmenopausal women with a diagnosis of endometrial carcinoma after dilatation and curettage were scanned before operation with a 7.5-MHz endovaginal probe. RESULTS: The location of the process and depth of myometrial invasion were estimated correctly in the vast majority of patients. Spread beyond the uterus and distance from the serosa could not be estimated precisely. CONCLUSION: Preoperative evaluation and staging of endometrial carcinoma are possible and useful for gynecologists, as they provide information on tumor location, depth of myometrial invasion, and involvement, if present, of the lower uterine segment or cervix. PMID- 7843485 TI - Effect of hormone replacement therapy on bone and lipid metabolism in women oophorectomized for the treatment of gynecologic malignancies. AB - OBJECTIVE: Our purpose was to evaluate the effects of hormone replacement therapy (HRT) on bone and lipid metabolism in women oophorectomized for the treatment of gynecologic malignancies. METHODS: Bone mineral density (BMD), bone metabolic markers, sex hormones and lipoproteins were measured in three groups of age- and body mass-matched subjects. The subjects consisted of HRT(+) patients, i.e. those given HRT after oophorectomy (n = 39), HRT(-) patients, who received no HRT (n = 15), and controls comprising premenopausal women with no history of oophorectomy (n = 36). RESULTS: BMD decreased significantly in the HRT(-) patients, but no decrease in BMD was observed in the controls or HRT(+) patients. HRT was effective in preventing bone loss by reducing high-turnover osteopenia. HRT reversed the negative trends in lipoprotein profiles by lowering low-density lipoprotein cholesterol and increasing high-density lipoprotein cholesterol. There were no serious side effects or recurrences among the HRT(+) patients. CONCLUSION: HRT appeared to have beneficial effects on bone and lipid metabolism in oophorectomized patients treated for gynecologic malignancies. PMID- 7843486 TI - Termination of pathological pregnancy in second and early third trimesters with extraamniotic instillation of 16-phenoxy-omega-tetranor prostaglandin E2 methylsulfonylamide. AB - OBJECTIVES: To evaluate the efficacy, safety and influence on subsequent fertility of sulprostone, a prostaglandin E2 analog, in terminating pathological pregnancies via the extraamniotic route. METHODS: Forty pregnant women with intrauterine fetal death or major congenital anomalies were enrolled. Sulprostone was instilled into the extraamniotic space through a silicon Foley catheter. The instillation rate was 0.5-1 microgram/min. Instillation was discontinued when the catheter was expelled or when rupture of the membranes occurred. The duration of instillation and the time interval to completion of abortion was recorded. Information about subsequent fertility was collected by telephone or at outpatient clinic visits. RESULTS: The mean duration of instillation was 7.0 h and the mean dose of sulprostone was 314.8 micrograms. The mean induction-to abortion interval (IAI) was 17.0 h. In two of the 40 patients, the cervix was not adequately ripened after 48 h and these pregnancies were ultimately terminated by alternative methods. The success rate of termination in 48 h was 92.5% (37/40). No severe side effects were encountered. CONCLUSION: To the best of our knowledge, this is the first report in the English literature of administration of sulprostone by extraamniotic instillation for termination of pathological pregnancies. The method is effective and safe and has an insignificant influence on subsequent fertility. PMID- 7843487 TI - Cesarean scar endometriosis. AB - A mass located in a scar area during examination is an infrequent phenomenon. Such a mass can be associated with keloid, hematoma, granuloma, hernia or neoplasm. Two cases of scar endometriosis are reported. The late onset of symptoms after surgery (average 4.5 years) is the usual reason for misdiagnosis. Awareness of this infrequent and late postoperative complication would increase the detection rate. Surgical excision remains the treatment of choice and should be accomplished without complications. PMID- 7843488 TI - Low rate of histological confirmation of macroscopic endometriotic lesions. PMID- 7843489 TI - Vaginal rhabdomyomas. PMID- 7843490 TI - Ultrasonographic appearance of cystic uterine leiomyoma. PMID- 7843491 TI - Gastrocolic fistula due to a metastatic marginal ulcer from carcinoma of the cervix. PMID- 7843492 TI - Segmental absence of the fallopian tube--a rare anomaly. PMID- 7843493 TI - The effect of respiratory physiotherapy on the pulmonary function of women following cesarean section under general anesthesia. PMID- 7843494 TI - Operative vaginal delivery. ACOG Technical Bulletin Number 196-- August 1994 (replaces No. 152, February 1991). AB - The scope of operative vaginal delivery as described in this bulletin includes the use of forceps and vacuum extraction as well as the management of shoulder dystocia and internal podalic version. While knowledge of the material presented is necessary to perform operative vaginal deliveries, it alone is not sufficient to achieve optimal maternal and perinatal outcome. Technical skill should be taught during residency training and maintained through use in clinical practice. PMID- 7843495 TI - Down syndrome screening. ACOG Committee Opinion: Committee on Obstetric Practice. Number 141--August 1994 (replaces No. 76, December 1989). PMID- 7843496 TI - Effectiveness of infertility treatments: choice and comparative analysis. AB - Choice of infertility treatments usually depends on a balance of the chances of conceiving with or without treatment, and with more or less complex and costly treatments, and on other factors such as duration of infertility and the woman's age. Pregnancies often occur independent of treatment and prospective controlled trials are needed. Comparability between reported results requires pregnancy and birth rates to be calculated in a time-specific or cycle-specific way. Cumulative rates are preferable to account for the usual tendency of fecundity to fall progressively. This review focuses on such published data in order to assess the relative effectiveness of treatments, both conventional and assisted conception methods. The main conclusions are: (1) The only treatments that can achieve a normal chance of pregnancy are the ovulation induction methods in cases of oligomenorrhea/amenorrhea, and the assisted conception methods for other female causes and unexplained infertility. (2) Tubal/pelvic infective damage and endometriosis require new severity classifications which are sensitive to functional potential before and after surgery, and in vitro fertilization (IVF) would often be indicated as the primary choice. (3) Duration of unexplained infertility determines the need and therefore benefit of any of the treatments used, of which the assisted conception methods are by far the most effective. (4) Interpretation of reported results of treatments for 'male factor' infertility is critically affected by the diagnostic accuracy of defining sperm dysfunction. (5) In cases of well-defined sperm dysfunction there is little or no therapeutic benefit to the chance of natural conception, nor by intrauterine insemination; there is moderate success by IVF, but no proven benefit over standard IVF by any micromanipulative method except probably intracytoplasmic sperm injection. PMID- 7843497 TI - Maternal sensitivity as an external organizer for biobehavioral regulation in infancy. AB - Recent findings from both animal and human research have clearly demonstrated connections between behavioral coping mechanisms and adrenocortical function. The aim of this study was to address the role of maternal sensitivity as an external organizer of psychobiological function in infants during the first year of life. Forty-one infants and their mothers were observed during play at 3, 6, and 9 months of age. Age-specific patterns of relation between maternal sensitivity and infant behavioral organization were found indicating contextual dependence of infant behavior at 3 months and experience-related behavioral function at 9 months. An affect of maternal sensitivity on adrenocortical function during the free play was demonstrated at 3 and 6 months, because an increase in cortisol was most frequently observed in infants of highly insensitive mothers. The findings indicate the importance of maternal behavior for infant biobehavioral organization. PMID- 7843498 TI - Separation and depression in infant gorillas. AB - Three 27-month-old infant gorillas living with their mothers and a silverbacked male were separated to a cage for 24 weeks. The infants initially showed threat responses and increased locomotion, characteristic of the protest stage of anaclitic depression in children. Within several days, these were replaced by dorso-ventral contact among the infants as well as self-holding and fetal positioning. Additionally, social and solitary play and object examination occurred at lower levels through separation than in the pre-separation condition. These changes were characteristic of the despair stage of separation. There was a substantial recovery of many infant nonsocial and social behaviors in the later months of the separation. Upon reunion, the infants did not immediately engage in attachment behaviors with their mothers, and spent more time in contact with each other than with their mothers for the first several days, indicating detachment. Following this, there was an increase in mother-infant attachment behaviors. PMID- 7843499 TI - Vagal tone during quiet sleep in normal human term fetuses. AB - The purpose of this paper was to calculate vagal tone (V) for 17 normal human fetuses in quiet sleep (QS) between 36 and 40 weeks gestation. The fetal cardiac electrical signal was captured transabdominally in 3-min blocks at a rate of 833 times per second and fetal R-waves were extracted using adaptive signal processing techniques. Fetal R-wave interbeat intervals were converted to equally spaced, time-based data, and the low-frequency component was removed using a 21 point third-order moving polynomial. The parameter V was calculated by taking the natural logarithm of the sum of the power densities between 0.3 Hz and 1.3 Hz. We found that fetal breathing was associated with an approximately 25% increase in V as compared to nonbreathing, 3.33 +/- 0.48 versus 2.57 +/- 0.47, p < 0.0001. Furthermore, there was a significant linear relationship between the mean single fetus V during spontaneous respiration and the mean single-fetus V during normally occurring apneic periods, r = 0.772, p < 0.002. We conclude that respiratory activity is associated with a significant increase in vagal tone for normal human fetuses in QS. PMID- 7843500 TI - Brain and behavioral effects of dietary n-3 deficiency in mice: a three generational study. AB - Feeding mice a diet deficient in n-3 fatty acids for three generations resulted in a 53% decrease in docosahexaenoic acid (DHA, 22:6n-3) in the brain. Maternal pup retrieval and social learning of a food preference are both tasks based on olfactory function. All dams made contact more readily with pups of their own dietary group, and animals of both dietary groups demonstrated the ability to learn a food preference through exposure to a conspecific that had previously eaten the food. Both groups showed similar ability to learn the location of the hidden platform in the Morris water maze, while the n-3 deficient animals were marginally faster in locating the platform on the cued trial. They were also more active when tested in the open field. While they did not differ in their duration of immobility in a forced swimming test, the deficient animals did have longer paw-lick latencies on a hot plate. Thus, in this study a significant reduction in brain n-3 fatty acid composition, while associated with some indications of change in emotional reactivity, did not impair olfactory function or learning of either a latent or spatial nature. PMID- 7843501 TI - Publication productivity ranking questioned. PMID- 7843502 TI - The balancing act: should we perfect our juggling? PMID- 7843503 TI - Latino health in California, 1985-1990: implications for family practice. AB - Family practice, especially when applied to the Community-oriented Primary Care model, needs to incorporate the epidemiological profile and health care needs of a particular community. The rapidly growing Latino population is creating a great number of largely Latino communities. While they tend to have high poverty rates and low education rates, their family and health profiles contradict many assumptions made about poor, underserved minority groups. Data for the 29.8 million California residents, including 7.7 million Latinos, show a strong Latino health profile. Compared to Anglos and blacks, Latinos have high complete nuclear family rates and low non-family rates. They have low rates of low birth weight babies and low infant mortality, about equal to the rate among Anglos and Asians. Latinos also have lower age-adjusted death rates due to heart disease, strokes, and cancers, again, about equal to Asians. Latinos do, however, have higher death rates due to motor vehicle accidents and cirrhosis than Anglos, blacks, or Asians and a diabetes death rate higher than Anglos or Asians. Surprisingly, Latinos have lower age-adjusted death rates due to drug-related causes and weapons related causes than Anglos or blacks, but substantially higher than Asians. It is suggested that, much against the stereotype, Latinos should be considered a high level wellness population for whom family practice, based on prevention and primary care, would be an ideal match. PMID- 7843505 TI - Peer coaching in clinical teaching: a case report. AB - Peer coaching is a method for improving teaching skills that was developed for use in general educational classroom settings. Key elements of peer coaching include the identification of specific goals for improving teaching skills, focused observation of teaching by colleagues, and the provision of feedback, analysis, and support. As part of a faculty development project, we adapted peer coaching methodology to the clinical teaching setting. This report describes the experiences of two family physicians who have served as peer coaches for each other over the past 2 years. The participating physicians report enthusiastically about their experiences with peer coaching as a method for personalized faculty development. They report more self-awareness of their clinical teaching behaviors, the ability to improve specific teaching skills, and the rewards of a collaborative relationship between colleagues. PMID- 7843504 TI - Increasing the production of generalists: a computer simulation. AB - BACKGROUND & OBJECTIVES: The Association of American Medical Colleges set a goal for US medical schools to produce 50% of their graduates as generalists. Methods for achieving this goal have not been established. METHODS: We developed a computer simulation to gauge the effect of interventions that could occur at five different points during medical school education. Each intervention would improve by 10% the proportion of trainees choosing a generalist career. RESULTS: Our model predicts that 24.1% of 1992 medical school graduates will ultimately become generalists. Any of the interventions we evaluated increased generalist production to the 25%-26.5% range. If class size is held constant and if a 10% annual improvement occurred in all of the other intervention points for 3 years, our model still predicts only 44.8% generalists. CONCLUSIONS: Computerized "what if" analysis can effectively project specialty outcomes after various interventions. The best intervention increased generalist production 2.6 times more than did less effective interventions. The loss of primary care residents into subspecialty fellowships is substantial. Even if 100% of current medical graduates could be directed into family practice, internal medicine, and pediatric residencies in their current proportions, only a 43.7% generalist outcome would be achieved because of attrition of internists and pediatricians into subspecialties. Family practice is the most efficient producer of generalists but currently lacks either the capacity or the marketability to be the nation's sole supplier. More effective interventions are needed to achieve a 50% generalist outcome. PMID- 7843506 TI - Christian mission hospitals as family practice educational resources. AB - With the worldwide family practice movement, a need has arisen to develop new residency training programs in economically developing countries. Christian mission hospitals exist in many areas where there is a need for more family physicians. These hospitals have been providing service and education, and some are now becoming training sites for family physicians. Currently, seven such institutions have operational family practice residency programs, all of which welcome personnel exchanges with faculty or residents in North American training programs. Christian mission hospitals with family practice residency programs exist in South America, Asia, and Africa. PMID- 7843507 TI - Physical therapy education in family practice residency programs. AB - BACKGROUND: This study investigated the role and extent of physical therapy education in family practice residency programs. Physical therapy is not specifically included in graduate curricula guidelines, and the literature contains little information on its involvement in programs. METHODS: A questionnaire was developed to determine how physical therapy education is taught in family practice residencies. The questionnaire was mailed to all (391) directors of US-accredited family practice residency programs. RESULTS: A total of 256 directors (65.5%) responded. The majority of directors (67%) stated that there was a significant need for the physical therapy component. Only 52% (133/256), however, included physical therapy in their curricula. Physical therapy education was most frequently (67.6%, 92/136) included in required rotations (eg, orthopedics) and taught mostly by hospital-based physical therapists (77.0%, 104/135) or subspecialists (55.6%, 75/135). CONCLUSION: This study shows that physical therapy education offers a potentially relevant and important element of family practice residency training, but it has been underemphasized. PMID- 7843508 TI - Family practice residents' attitudes toward their academic projects. AB - BACKGROUND AND OBJECTIVES: As research has become an increasingly important activity in family medicine, so the teaching of research skills has become an important part of family practice residents' training. The purpose of the study was to determine the attitudes toward research and related topics of a family practice program's graduates who had participated in a required academic project during their residency training. METHODS: A questionnaire using Dillman methodology was mailed to graduates of the University of Toronto family practice program. Graduating years surveyed were 1987-1992. RESULTS: There were 321 (78%) responses from the 427 graduates. Most projects completed during residency had been literature reviews. Ninety percent of respondents felt that critical appraisal skills were important to them as practicing physicians, but only 39% felt they had been sufficiently educated about these skills. Other research related skills (writing, presenting, data analysis) were learned more thoroughly. The majority (58%) felt neutral or negative about their projects, and 79% would not have done a project if it had been optional. CONCLUSIONS: This cohort of family practice graduates felt negatively about the teaching of research skills during residency. Providing more support and developing a curriculum may improve resident satisfaction. PMID- 7843509 TI - Physician and staff acceptance of continuous quality improvement. AB - BACKGROUND: Increasing numbers of health care organizations are adopting Continuous Quality Improvement (CQI) principles. This study's objective was to evaluate the attitudes toward and acceptance of CQI by a family practice residency program's providers and staff after 3 years' experience with the process. METHODS: Our CQI project groups examine selected problems and develop system-based solutions. We surveyed staff, residents, and faculty to determine their awareness of the CQI projects, the perceived usefulness of the projects and results, how well they were informed of the results, and whether they believe CQI is a useful tool in our clinic. RESULTS: Of 19 clinical and/or administrative projects we implemented, 75% of the faculty, 55% of the residents, and 71% of the staff perceived the projects to be useful. Eighty-eight percent of the faculty, 64% of the residents, and 82% of the staff believe CQI to be useful tool in our clinic. However, only 50% of faculty, 36% of residents, and 24% of staff felt they were well informed of the project results. The time involved in CQI and the need to improve communication among personnel on CQI processes were identified as important concerns about CQI. CONCLUSION: Faculty, resident, and staff members accept the CQI process and perceive it to be a useful tool in clinical practice. CQI requires attention to the time involved and communication about CQI projects and results. PMID- 7843510 TI - A comparison of primary versus secondary cardiovascular disease prevention in an academic family practice. AB - BACKGROUND: The risk of mortality from cardiovascular disease (CVD) is much higher in those with preexisting CVD than in those without it. Risk factor modification can reduce these risks. This study was designed to determine whether physicians manage risk factors differently in patients with and without overt CVD. METHODS: Risk factor identification and management strategies after the diagnosis of CVD (secondary prevention) were analyzed by chart audit for 61 patients with premature CVD and 61 age-matched patients free of CVD (primary prevention). All of these patients had entered an academic family practice within 1 year of each other and had at least two physician visits between 1982-1992. RESULTS: In the majority of patients, risk factors for CVD were identified by family physicians. Few differences in counseling and management of risk factors were noted between patients with premature CVD and those free of CVD. Management of hypertension was performed with behavioral and pharmacologic therapy; more than 94% of the patients had at least one posttreatment blood pressure below 140/90. Lipid disorders, however, were managed primarily by diet; only 20% of cases with hyperlipidemia and premature CVD received pharmacologic therapy, and only 2.5% had a controlled blood cholesterol level (below 200 mg/dl). CONCLUSIONS: In an academic family practice, CVD risk factor identification was high but recommended management practices in the secondary prevention of CVD were suboptimal. Management of CVD risk factors was not more aggressive among secondary prevention cases compared to primary prevention controls. PMID- 7843511 TI - Myths and misconceptions: Latino health in California. PMID- 7843512 TI - Understanding randomized controlled trials: explanatory or pragmatic? PMID- 7843513 TI - 'Baby Check' in the inner city--use and value to parents. AB - 'Baby Check', an information booklet designed to aid assessment of acutely ill babies, was given to a group of socioeconomically disadvantaged families from one inner city general practice. Parents' perceptions and use of the booklet were explored in a qualitative study based on audiotaped interviews with 42 parents of 34 babies under 6 months old. Most families (26) used Baby Check spontaneously. Parents found that Baby Check was helpful, reduced anxiety and increased confidence coping with illness, seeking medical advice and communicating with doctors. Parents experienced some difficulties, e.g. they had concerns about a check for rectal temperature and they sought more information and advice about common illnesses. Parents valued and were empowered by access to 'medical' information. Further evaluation and consultation with parents is required to ensure that information is relevant to their needs. PMID- 7843514 TI - Screening, detection and management of depression in elderly primary care attenders. I: The acceptability and performance of the 15 item Geriatric Depression Scale (GDS15) and the development of short versions. AB - One-hundred and ninety-eight elderly subjects attending their general practitioners (GPs) were asked to complete the 15 item Geriatric Depression Scale (GDS15). Analysable results were obtained from 194 (98%). Of these, 67 (34%) scored above the GDS15 cut-off (4/5) for significant depressive symptomatology. 87.6% found the questionnaire to be acceptable and only 3.6% found it very difficult or very stressful. The GDS15 had a high level of internal consistency (Cronbach's alpha = 0.80). All the individual items of the GDS15 associated significantly (P < 0.01) with total score and 'caseness'. A single question "do you feel that your life is empty?" identified 84% of 'cases'. In an attempt to devise short scales to screen elderly primary care patients for depression, the data were subjected to logistic regression analysis. Ten (GDS10), four (GDS4) and on (GDS1) item versions were generated. Agreement between these short scales and the GDS15 in the original sample was 95, 91 and 79% respectively. Cronbach's alpha was 0.72 for the GDS10 and 0.55 for the GDS4. The short scales were then validated in an independent sample of 120 patients in whom both GDS data and the results of a detailed psychiatric interview (the Geriatric Mental Status Schedule, GMS) were available. The sensitivity and specificity of the GDS10 against GMS caseness were 87 and 77% (cut-off 3/4); those of the GDS4 were 89 and 65% (cut-off 0/1) and 61 and 81% (cut-off 1/2). Sensitivity and specificity for the GDS1 were 59 and 75%. It is concluded that these short scales may be useful in helping GPs and practice staff to identify elderly patients with significant depressive symptoms. PMID- 7843515 TI - Screening, detection and management of depression in elderly primary care attenders. II: Detection and fitness for treatment: a case record study. AB - Case note data were obtained for 186 elderly primary care attenders who also completed the 15 item Geriatric Depression Scale (GDS15). The presence or absence in the case notes of a current or past diagnosis of depression, of current treatment of depression, and of a number of clinical features of depression were noted. Case notes were also rated for the presence or absence of contraindications to the use of tricyclic antidepressants (TCAs) and to serotonin specific reuptake inhibitors (SSRIs). Whereas 65 (35%) patients were rated as 'cases' of depression on the GDS15, only 28 (15%) had a current case note diagnosis of depression and 37 (20%) had one or more current symptoms of depression recorded in the case notes. Patients rated by their GP as having one or more current symptoms of depression scored higher on the GDS15 (P < 0.05) and were more likely to be categorized as a GDS case (P = 0.05). There was no significant relationship between GDS caseness and a current case note diagnosis of depression. Seventy-three patients (39%) had a past history of depression and 53 (28.5%) patients had previously been treated with antidepressants. The former was significantly associated with GDS caseness (P < 0.05). Twenty-four patients (13%) were currently on antidepressants, 19 of them receiving adequate doses (equivalent to at least 75 mg of amitriptyline). Current antidepressant treatment was not associated with GDS 'caseness'.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843516 TI - Risk factors in otitis media with effusion. A 1 year case control study in 5-7 year old children. AB - What are the associations and risk factors for otitis media with effusion (glue ear)? A 1 year case control study in 5-7 year old children from four south-west Hampshire schools examined some of the factors highlighted by the literature. A history of frequent ear problems over the previous year, a history of earache at any time in the child's life, bottle feeding, a red drum at otoscopy and the new finding of night cough all carried an increased relative risk. PMID- 7843517 TI - Care for the imminent miscarriage by midwives and GPs. AB - A postal questionnaire was sent to a random sample of 495 Dutch general practitioners (GPs) and 278 midwives to evaluate the use of the 'imminent miscarriage' standard used by the Dutch College of General Practitioners. The response rates were 63 and 87% respectively. The first questions asked related to the respondents' routine management of an imminent miscarriage. The second part of the questionnaire addressed the respondents' attitude to the 17 most important guidelines in the standard. Finally, the respondents were invited to describe problems arising in adhering to the standard. Midwives and GPs differed in their management of an imminent miscarriage. Midwives used more 'technology' such as ultrasound scans or a doptone to trace complications or see if the fetus was still viable, whereas the GPs more often carried out vaginal and speculum examinations. Midwives also paid more attention to care following a miscarriage. The guidelines that many respondents did not adhere to involved the period of 10 days for the follow-up appointment and counselling after 6 weeks. Guidelines restricting ultrasound scans and the decision only to refer the patients to an obstetrician after three consecutive miscarriages were also not accepted by all respondents. Respondents mentioned several practical problems or obstacles in adhering to the standard, including women's requests for ultrasound scans or referrals and also the attitude of obstetricians who sometimes simply assumed control. The results will serve as a starting point for updating the standard. PMID- 7843518 TI - Antibiotics prescription in primary care: a 5-year follow-up of an educational programme. AB - An educational programme on the use of antibiotics for respiratory tract infections (RTIs) in primary care, initiated among district physicians at the Community Health Centre of Hoor, Sweden in 1985, resulted in an overall reduction in prescriptions for antibiotics, particularly broad-spectrum antibiotics. The aim of the present study was to evaluate the long-term effects of the programme on antibiotic prescription patterns at the centre. Since 1985, computerized records have been kept of every consultation at the centre, including details of the attending physician, the patient, diagnosis and type of antibiotic prescribed. Moreover, during a 3-month period in 1991, each pharmacy in the region recorded details of all prescriptions for antibiotics dispensed. Estimated immediately after the programme, the proportion of RTI patients prescribed antibiotics had fallen to 44%, a figure virtually unchanged 5 years later. During the subsequent five-year period, antibiotics dispensed at the pharmacy in Hoor were further reduced from 14.1 to 13.2 defined daily doses 1000 inhabitants-1 day 1. As compared with district physicians at other community health centres in the region, those at Hoor prescribed more penicillin V (80% of all antibiotic prescriptions) and less broad-spectrum antibiotics. The educational programme, combined with an active interest among district physicians at Hoor in current research into antibiotic usage, has thus wrought enduring changes in the pattern of antibiotic prescription. A probable contributory factor was the district physicians' awareness that the computerized registration of diagnosis and treatment enables prescription patterns to be audited at an individual level. PMID- 7843519 TI - Measuring patient satisfaction in primary care: a joint project of community representatives, clinic staff members and a social scientist. AB - We describe the process of planning and developing a questionnaire and conducting a patient satisfaction survey in a neighbourhood clinic in Beer-Sheva, Israel. The project was conducted by the clinic staff members, patient representatives and a medical sociologist. The satisfaction survey was conducted in patients' homes, with a 67% response rate. General satisfaction and satisfaction with specific components of service are described. Patient satisfaction was higher among men than among women, and negatively correlated with family size. The strongest predictor of general satisfaction was satisfaction with physicians' services. Implications of the survey results were decided upon by active collaboration between the clinic staff and the patient representatives. The inferences drawn from the patients' replies and the changes introduced as a result of them, are discussed. Health care consumers should be active participants in carrying out surveys of satisfaction on a regular basis. PMID- 7843520 TI - The effectiveness of waiting room notice-boards as a vehicle for health education. AB - To determine whether patients read and remembered health promotion messages displayed in waiting rooms, 600 patients in a UK general practice were given a self-complete questionnaire. Two notice-boards carried between 1 to 4 topics over four study periods. Three-hundred and twenty-seven (55%) of subjects responded. Twenty-two per cent recalled at least one topic. Increasing the number of topics did not increase the overall impact of the notice-boards. The numbers of patients recalling a topic remained constant, but increasing the number of topics reduced the number remembering each individual topic. Patients aged over 60 years were less likely to recall topics, but waiting time, gender and health professional seen had no effect on results. Very few patients (< 10%) read or took health promotion leaflets. These results suggest that the role of waiting room notice boards should be reassessed. More modern methods of communication such as electronic notice-boards or videos could be used. However, the waiting room might best function not as an area where a captive audience can be bombarded with health promotion messages, but rather as a place for relaxation before consulting a health professional, making patients more receptive to health advice in the consultation. PMID- 7843521 TI - Is the potential of teenage consultations being missed?: a study of consultation times in primary care. AB - There is a paucity of knowledge regarding teenage health even though it features as one of the priority areas in the government's health plans. There have been few reports of adolescent contacts with primary care teams, although there are impressions of a suboptimal service. As a prelude to understanding more about communication between general practitioners and teenage patients, this study aimed to look at the time spent on teenage consultations, which can be used as one method of describing the quality of care provided to teenage patients. Nine hundred consultations involving six doctors in one surgery were timed over a 3 month period by one observer using a validated method. One-hundred and nineteen consultations with patients aged 11-19 were compared with the 781 consultations for other age groups and showed a statistically significant mean shortfall of nearly 2 minutes (23%). This trend was confirmed for all six doctors, despite a broad range of average consulting times. The study also demonstrated some other characteristics of teenage consultations. Several implications of these results are discussed as well as possible reasons for these findings. The study emphasizes the need for further research in this area. PMID- 7843522 TI - Job satisfaction, mental health and job stress among general practitioners before and after the new contract--a comparative study. AB - In order to compare measures of job satisfaction, mental health and job stress among general practitioners (GPs), the results of a 1993 survey were compared with that obtained in the previous study in 1987. Eight-hundred and fifty GPs were selected at random by seven Family Health Service Authorities in England, 380 of whom returned questionnaires suitable for statistical analysis. There were significant differences between the 1987 and 1993 surveys. GPs experienced less job satisfaction, poorer mental health and more stress in 1993 than in 1987. These changes may have occurred as a result of the introduction of the new contract. PMID- 7843523 TI - Primary care, financing and gatekeeping in western Europe. AB - Primary care in western Europe is delivered by general practitioners (GPs) but their role within the overall health system is poorly understood. The aim of this article is to present an overview of the characteristics of general practice in the context of health systems and to describe their variability and interrelationships. Data were obtained from two main sources: publications of official organizations and EC research projects. The characteristics of general practice are described and analysed with regard to three features: mode of payment, gatekeeper function and practice organization and workload. Despite their focus on general practice as the cornerstone of the health system, western European countries differ considerably in the major characteristics of primary care. There is variability in the ratio of GPs to population and in the extent to which patients relate to individual physicians. Although all countries have universal health insurance, the mode of payment of GPs differs. In some countries, the gatekeeper function of general practice is more highly developed and the use of specialist services varies accordingly. Practice characteristics such as workload, length of consultation, ordering of tests and reappointments also vary with differences in payment and gatekeeping arrangements. In particular, fee-for-service was associated with weaker physician-patient relationships, reduced attractiveness of general practice, more home visiting and longer consultations. Strong gatekeeping arrangements are not incompatible with high public satisfaction and are associated with lower visit rates. However, strong gatekeeping is not characteristic of fee-for-service arrangements. These findings suggest a need for more concerted research that could inform policy decisions concerning primary care in the USA as well as in Europe. PMID- 7843524 TI - Latino health in Los Angeles: family medicine in a changing minority context. AB - The inner city population of the Los Angeles county has rapidly become largely Latino. The 3.3 million Latinos living in the county in 1990 had much higher poverty rates and lower educational attainment rates than Anglo (non-Hispanic white) or blacks. The health indicators of the three groups are compared for 1990. In birth outcome, although Latinos were the least likely to receive care in the first trimester, Latinos and Anglos had identical rates of low birth weight babies, and lower rates than blacks. Latino infant mortality was the lowest of the three. The age-adjusted death rates showed that Latinos have a lower overall death rate than Anglos or blacks, and lower specific rates for heart disease, cancer, AIDS and stroke. Latinos did have higher death rates than Anglos for accidents, homicides, cirrhosis and diabetes. Latinos had incidence rates of gonorrhoea and syphilis similar to Anglos and lower than blacks. The communicable disease rates for Latinos was many times higher than Anglos or blacks, including those for measles, shigellosis, giardiasis and hepatitis A. Implications for family medicine are discussed. PMID- 7843525 TI - Focus groups: a method for developing consensus guidelines in general practice. AB - The measurement of quality in any clinical discipline depends, in part, on a comparison with an accepted standard. Currently, such standards do not exist for the management of many common clinical situations in Australian general practice. As part of the General Practice Evaluation Programme, a group of Illawarra general practitioners (GPs) selected 'GP management of the menopause and asthma' for in-depth study, and were able to arrive at a consensus on 'principles of practice' and 'minimal acceptable care' for these conditions through a series of focus (research) group meetings. However, the process by which these standards were derived was felt, of itself, to be a valuable means of: (i) reducing professional isolation; (ii) promoting quality assurance; (iii) introducing peer review; (iv) introducing clinical audit; and (v) providing meaningful and targeted continuing medical education appropriate to Australian general practice. This paper describes the focus group methodology used in this process. PMID- 7843526 TI - Research in general practice: Dutch problems, European solutions? PMID- 7843527 TI - Selections from current literature: screening for colorectal cancer. AB - Of the five modalities currently used to screen for colorectal cancer, the DRE is the least useful as a solitary screening tool. Also, while FOBT is widely used, its high false positive rate and uncertain cost benefit ratio make it less than ideal as a screening tool. Flexible sigmoidoscopy in a well defined regimen, has been shown to result in a decrease in CRC mortality. Paramedical personnel with a moderate amount of training have been shown to be able to safely and efficiently perform screening sigmoidoscopy. This has the potential to make it widely available at an affordable cost to the general population; however, its limitations, namely its ability to detect only lesions found in the distal colon, need to be kept in mind. With all limitations in the above mentioned screening modalities, colonoscopy may be the best tool to detect colorectal cancers. It has a significant advantage over DCBE of being both a diagnostic and therapeutic tool; however, it is imperative that a randomized controlled trial be performed to fully document its potential efficacy, advantages and disadvantages. Finally while genetic testing looms on the horizon as a promising new tool for CRC screening, at this time there are still too many unanswered questions and dilemmas, ethical as well as others, to warrant its use in the general clinical setting. However, maybe in the future, CRC screening will involve a simple blood test performed at birth, or perhaps even prenatally. PMID- 7843528 TI - Bacterial flora in patients with sore throats. PMID- 7843529 TI - [Systems analysis of functionally determined variability in the fine structure of the EEG field]. PMID- 7843530 TI - [Omega-potential dynamics during lateralized transcranial electric stimulation]. PMID- 7843531 TI - [Materials for detailed study of the fine structure of human brain biopotentials]. PMID- 7843532 TI - [Systems analysis of bioelectric activity in the human brain at rest and when concentrating attention]. PMID- 7843533 TI - [Reorganization of the spatio-temporal structure of the electric field of the human brain as a results of psychotraining]. PMID- 7843534 TI - [Methods of study of acoustic anisotropy of human skin]. PMID- 7843535 TI - [Nonlinear components of respiratory arrhythmia and methods for their detection]. PMID- 7843536 TI - [A comprehensive psychophysiologic evaluation of health and professional development in people engaged in mental work]. PMID- 7843537 TI - [Spatial organization of brain bioelectric activity in children with learning problems]. PMID- 7843538 TI - [Effect of climatic factors in the Kol'skii peninsula on the physiologic state of adolescents at the time of the expedition]. PMID- 7843539 TI - [Effect of model disorders of binocular vision on automobile driving]. PMID- 7843540 TI - [Effect of light stimulation of the retina on super-weak luminescence of the contralateral eye in man]. PMID- 7843541 TI - [Vascular prostacyclin reaction and thrombocyte disaggregation at varying levels of arterial pressure in mountain shepherd populations]. PMID- 7843542 TI - [Biochemical blood parameters in women during menstrual cycle dynamics]. PMID- 7843543 TI - [Debatable problems in clinical neurophysiology]. PMID- 7843544 TI - [Genetic correlations of human psychophysiologic characteristics. I. Evoked potentials]. PMID- 7843545 TI - [Features of brain electric activity in people from various biogeochemical regions]. PMID- 7843546 TI - [Diagnostics of brain functional state in young school children with learning problems]. PMID- 7843547 TI - [Individual functional features of young school children as a function of the harmony of their physical development]. PMID- 7843548 TI - [Effect of lateralized presentation of visual information on the organization of probability-prognostic activity]. PMID- 7843549 TI - [Features of an unpracticed form of word writing (interpretation of N.A. Bernstein's theory of movements]. PMID- 7843550 TI - [Switching of the tonic vibration reflex in the shoulder muscles]. PMID- 7843551 TI - [Age-related dynamics of effectors of the arterial basin system in people with deviations in the activity of the cardiovascular system of the ischemic type]. PMID- 7843552 TI - [Correlation between body mass and specific oxygen consumption in healthy people and patients with heart disease]. PMID- 7843553 TI - [Adaptive reactions of the body to muscle loads and cold during hypo- and hyperthyroidism]. PMID- 7843554 TI - [Physiologic mechanisms of adaptation during work under conditions of exposure to increased radiant and convective heat]. PMID- 7843555 TI - [Shifts in the human immune system in various disorders as a result of use of immunomodulators]. PMID- 7843556 TI - [Criteria for the strictness of scientific publications]. PMID- 7843557 TI - Presence of angiotensin II immunoreactivity in the ovary of the rainbow trout, Oncorhynchus mykiss. AB - Renin-angiotensin system is present in mammalian ovarian follicular fluid and follicles. The demonstration of specific binding sites for angiotensin II in the follicular structures of rats suggests that angiotensin II may be related to the regulation of steroid biosynthesis in the mammalian ovary. Little is known about the presence and the action of angiotensin II in nonmammalian ovaries. An immunocytochemical investigation of angiotensin II in developing ovarian follicles of trout has been carried out. The specific antiserum was raised against (Val5)-angiotensin II of the trout. There was strong immunoreactivity in the ooplasm of endogenous vitellogenic follicles. Angiotensin II immunoreactive material was present in the follicular cells, but not within oocytes at the end of vitellogenesis. Immunocytochemically angiotensin II-like material in the ovary of rainbow trout fluctuates during the cycle of development. PMID- 7843558 TI - Regulation of aldosteronogenesis in domestic turkey (Meleagris gallopavo) adrenal steroidogenic cells. AB - The hormonal and cationic regulation of aldosterone production by freshly isolated turkey (Meleagris gallopavo) adrenal steroidogenic cells was investigated. Angiotensin II (AII), ACTH [human ACTH-(1-39)], and K+ stimulated aldosterone production in a concentration-dependent manner albeit these agents exhibited considerable differences in lag time for the significant stimulation of aldosterone production over basal production. By contrast, Ca2+ was without effect except at a high concentration (10 mM). Although ACTH was more efficacious than AII, it had about one-third the potency of AII for stimulating aldosterone production. However, ACTH potentiated the maximal aldosterone response to AII [maximal enhancement (+499%) at 3 x 10(-10) M ACTH]. Extracellular K+ was an absolute requirement for AII-induced aldosterone production (threshold concentration = 3 mM), and maximal enhancement (+200%) occurred with 5 mM (a physiological concentration). Although extracellular Ca2+ was not an absolute requirement for inducible aldosterone production, it enhanced AII-induced aldosterone production in a concentration-dependent manner [maximal enhancement (+727%) at 3 mM], albeit it did not alter the half-maximal steroidogenic concentration (EC50) of AII. Ca2+ also enhanced maximal ACTH-induced aldosterone production but to a lesser extent (+96% with 1 mM Ca2+). However, Ca2+ dramatically enhanced ACTH potency (ED50) (nearly 100 times at 1 mM Ca2+). The acute augmentation of AII-induced aldosterone production by ACTH, K+, and Ca2+ was not accompanied by increases in the cellular concentration and affinity of AII receptors, suggesting that the agents acted at intracellular loci distal to the AII receptor. Several aspects of the present study with isolated turkey adrenal steroidogenic cells differ markedly from those of studies with isolated chicken (Gallus gallus domesticus) adrenal steroidogenic cells and mammalian zona glomerulosa cells, thus suggesting interclass and intraclass differences in homeothermic vertebrate adrenal steroidogenic regulation. PMID- 7843559 TI - Dietary vitamin D dependence of cat and dog due to inadequate cutaneous synthesis of vitamin D. AB - As in herbivores and omnivores, the biosynthesis of vitamin D3 in the skin exposed to ultraviolet (uv) light is generally expected to also occur in the dog and the cat. The purpose of this in vitro study was to measure the concentrations of vitamin D3 and its precursor 7-dehydrocholesterol (7DHC) in dog and cat skin before and after a quantitatively and qualitatively standardized exposure to uv light. The results are compared to those obtained by the same method in the skin of the rat. The efficiency of extracting 7DHC and vitamin D3 from skin was 72 +/- 8% and 67 +/- 3%, respectively. In dog and cat skin the concentrations of nonesterified 7DHC were below the detection limit of the HPLC system. Therefore, skin extracts were saponified and total 7DHC and vitamin D3 concentrations were measured by normal-phase HPLC. Before irradiation with uv-B light the total concentrations of 7DHC were 1858 +/- 183, 1958 +/- 204, and 17,620 +/- 2345 ng/cm2 skin (mean +/- SEM; n = 5) for the dog, the cat, and the rat, respectively. The corresponding concentrations of vitamin D3 were 211 +/- 44, 193 +/- 18, and 161 +/- 32 ng/cm2 skin for the dog, the cat, and the rat, respectively. Irradiation of standard solutions of 7DHC with 0.15 J uv-B light/min resulted in a time-dependent decrease in 7DHC and a concomitant increase in previtamin D3.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843560 TI - Extended production of the mullerian duct regressor in the American alligator. AB - Regression of the mullerian ducts in mammals and birds is caused by the testicular hormone, mullerian inhibiting substance (MIS), which is produced for an extended period of time after testicular differentiation. Because it is present long after the ducts regress, it has been proposed to have additional effects other than inducing Mullerian duct regression. A testicular substance also appears to be responsible for mullerian duct regression in the alligator based on studies in which testicular grafts from hatchling males caused regression when implanted into castrated hatchling females. In this study, the approximate ontogeny of the regressor in the alligator was investigated by implanting testicular grafts from both hatchling and yearling males into castrated female hatchlings. Histological quantification of the ducts revealed that regression in both treatment groups was not significantly different indicating that the mullerian duct regressor in the alligator is produced for at least a year after hatching and may have additional nonregressive functions in the alligator as has been proposed for mammals and birds. PMID- 7843561 TI - Increased substrate concentration causes a shift from production of 11-oxygenated androgens to 17,20-dihydroxyprogestogens during the in vitro metabolism of 17 hydroxyprogesterone by goldfish testes. AB - Goldfish testes were incubated with [3H]17-hydroxyprogesterone in the presence of 0 to 100 micrograms/ml of unlabeled substrate and metabolites examined by thin layer and high performance liquid chromatography. Conjugated steroids, predominantly sulfates, accounted for 50% of recovered activity with radiolabeled substrate alone, but percentage yields decreased to very low levels with substrate concentrations of 1 micrograms/ml and above. The 11-oxygenated androgens, androstenetrione and 11-ketotestosterone, were the major products with 0 to 0.1 micrograms/ml substrate, but at concentrations of 1 to 100 micrograms/ml the major products were 17,20 alpha-dihydroxy-4-pregnen-3-one (30% of recovered activity) with smaller amounts of the 20 beta-epimer. 11-Deoxycortisol was a minor product at all substrate concentrations. Production of 11-oxygenated androgens in the medium reached a maximum value of 40 ng/100 mg tissue/3 hr with 2 micrograms substrate, but progestogen production continued to increase up to the maximum substrate used (30 micrograms at 200 micrograms substrate). The results demonstrate a clear switch from production of 11-oxygenated androgens to that of 20-reduced progestogens with increased substrate concentration. This switch shows similarities to that observed for in vivo plasma steroid concentrations during the prespawning period of many male teleosts and it is suggested that this, at least in part, may be due to increased substrate availability resulting from elevated gonadotropin secretion. PMID- 7843562 TI - Kinetic parameters of plasma thyroid hormone and thyroid hormone receptors in a dwarf and control line of chicken. AB - Sex-linked dwarf chickens have in plasma low triiodothyronine (T3) levels and slightly raised thyroxine (T4) concentrations and are functional hypothyroid. The kinetic parameters of T4 and T3 were investigated using 125I-labeled hormones. In addition the nuclear T3-receptors in the liver were examined using a radioreceptorassay and Scatchard analysis. Four-week-old dwarf (dw) and normal (Dw) chickens were injected with 125I-labeled T3 or T4 and blood samples taken 60, 120, 180, and 300 min after 125I-T3 injection and 120, 240, 360, and 480 minutes after 125I-T4 treatment. Labeled T4 and T3 and the degradation products were separated by paper chromatography. After the paper strips were dried, the iodinated compounds were visualized and counted in the gamma counter. The kinetic parameters, the half-life time (T1/2), the apparent distribution volume (Vd) and the metabolic clearance rate (MCR) were calculated using the natural base logarithm values of the measured radioactivity plotted against time and used for linear regression. T4 was cleared from circulation more slowly in dwarf than in control chicks and reflected a longer T1/2 (21.8%) and a reduced MCR (45%). The Vd tended to be lower (34.7%) in dwarfs. While the T1/2 of T3 was longer (28.1%) in dwarf chickens than in control animals, the MCR for T3 was considerably increased (31.8%). This results from an increased Vd (63.1%) in the dwarf chicks. The T3-receptor study in the liver of dwarf and non-dwarf chickens from Week 1 to Week 4 posthatching revealed that the total capacity and the affinity constant of the binding sites were comparable in dwarf and normal chickens. However, the occupancy of the receptors was higher in the dwarf animals. PMID- 7843563 TI - Development of a homologous radioimmunoassay for coho salmon insulin-like growth factor-I. AB - A specific homologous radioimmunoassay (RIA) for measurement of insulin-like growth factor-I (IGF-I) in plasma of salmonid and a few non-salmonid fish species was developed using recombinant coho salmon IGF-I (rsIGF-I) as tracer and standard, and antiserum against this peptide raised in rabbits. The minimum detection level of IGF-I was 1.5 ng/ml and linearity was obtained in a range from 1.5 to 23 ng/ml. No cross-reaction was detected in the salmon IGF-I RIA with mammalian growth factors, salmon pituitary hormones, salmon or mammalian insulin, or any peptide in rat plasma. Although salmon IGF-I has high sequence similarity to mammalian IGF-I, it did not cross-react with anti-human IGF-I serum in human RIA and serial dilutions of plasma from salmon were not parallel to the human IGF I standards in this assay system. In contrast, dilution curves for plasma of salmonids, such as coho (Oncorhynchus kisutch), Atlantic (Salmo salar), and sockeye (O. nerka) salmon, rainbow trout (O. mykiss), some other teleost fish, such as tilapia (Oreochromis mossabmica), carp (Cyprus carpio), eel (Anguilla rostrata), Atlantic halibut (Hippoglossus hippoglossus), and agnathan, the sea lamprey (Petromyzon marinus), assessed in salmon IGF-I RIA were parallel to the rsIGF-I standards. Acid-ethanol extraction of plasma samples altered the molecular weight, but not the quantity, of immunoreactive IGF-I, implying that IGF-I binding proteins in salmon plasma do not affect the performance of the salmon IGF-I RIA. Gel filtration of nonacidified plasma on a Sephadex G-75 superfine column produced two immunoreactive IGF-I peaks of molecular weights of approximately > 70 k and 7 kDa, whereas acidification of plasma increased the relative amount of the 7-kDa peak (IGF-I) and the > 70-kDa peak disappeared. The recoveries of rsIGF-I added to extracted or nonextracted plasma were 97.4 and 94.9%, respectively. Inter- and intraassay coefficients of variation were 3.6 and 3.3%, respectively. Plasma IGF-I levels in coho salmon smolts were 117.4 +/- 19.1 ng/ml as compared to IGF-I levels in parr (45.3 +/- 2.5 ng/ml) or in adult fish (45.2 +/- 5.4 ng/ml) measured in the same assay. Injection of salmon growth hormone, but not prolactin or somatolactin, caused a significant and dose dependent elevation of plasma IGF-I levels, while either fasting or injection of streptozotocin led to a significant decline in systemic IGF-I.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7843564 TI - Central melatonin binding sites in rainbow trout (Onchorhynchus mykiss). AB - A combination of in vitro autoradiography and membrane homogenate receptor assays has been used to localize and characterized 2-[125I]iodomelatonin binding sites in the brain of the rainbow trout (Onchorhynchus mykiss). Specific 2 [125I]iodomelatonin binding, defined as that displaced by 1 microM melatonin, increased linearly with increasing protein concentration in membrane homogenates of whole trout brain. Specific binding was both time and temperature dependent and reversible in the presence of 1 microM melatonin. Binding was saturable at between 100-150 pM 2-[125I]iodomelatonin and Scatchard analysis of saturation isotherms revealed a dissociation constant (Kd) of 15.00 +/- 0.95 pM and a maximum receptor number (Bmax) of 42.35 +/- 2.70 fm/mg protein (n = 16). Addition of 10(-4) M GTP gamma S (an analogue of guanosine triphosphate) to saturation isotherms apparently reduced the Bmax by 75% on average with no apparent change in the affinity of the binding. Scatchard analysis of saturation isotherms generated from whole brain membrane homogenates of trout kept on long days (15 hr light:9 hr dark) and killed either during the midlight or middark phase showed no significant differences in either the Kd or the Bmax of 2-[125I]iodomelatonin binding, although a robust rhythm in melatonin concentration was confirmed in these fish. Displacement of 2-[125I]iodomelatonin binding with increasing concentrations of competing ligands gave an order of potency of 2-iodomelatonin > melatonin >> 5-HT. Localization of specific central 2-[125I]iodomelatonin binding in the rainbow trout showed high levels of binding associated with neuronal areas involved in the processing of visual signals, particularly the optic tectum and nucleus rotundus.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843565 TI - Neurosecretory cells expressing the gene for common precursor for diapause hormone and pheromone biosynthesis-activating neuropeptide in the suboesophageal ganglion of the silkworm, Bombyx mori. AB - Diapause hormone (DH) is a neurohormone which is secreted from suboesophageal ganglion (SG) and responsible for induction of embryonic diapause in the silkworm, Bombyx mori. DH is generated along with four other functionally different neuropeptides including pheromone biosynthesis-activating neuropeptide from the common polyprotein precursor, DH-PBAN (DHP), which is translated by a single species of mRNA. In this paper, the site of the gene expression was determined by reverse transcription-polymerase chain reaction and in situ hybridization using cDNA probe. The transcript of the DHP gene was found in SG of pupae and pharate adults, but no positive sign was detected in other tissues such as brain, thoracic ganglia, abdominal ganglia, and midgut. In situ hybridization with the cDNA clearly stained 12 cells near the ventral midline of SG which were aggregated into three clusters. The clusters were respectively localized in the mandibular, maximally, and labial neuromere of SG. The similar staining profile was observed in the SG cells at the larval, pupal, and adult stages, indicating that the DHP gene is expressed in the same set of cells throughout the postembryonic development. PMID- 7843566 TI - Characterization of insulin receptors in chicken kidneys: effect of nutritional status. AB - In chickens, the kidneys actively contribute to gluconeogenesis. A cytosolic form of phosphoenolpyruvate carboxykinase (PEPCK) is present in this tissue but is absent in liver. Cytosolic renal PEPCK is nutritionally and hormonally controlled which indicates a likely contribution of insulin in the control of this enzyme (and other renal functions). The present studies characterize renal insulin receptors in the chicken. The effects of the following nutritional conditions were examined: fed, 48 hr fasted, and 24 hr refed following a 48-hr fast. PEPCK activity was increased by the 48-hr fast and returned to normal after refeeding. Specific binding of 125I-insulin to renal membranes was time-, temperature-, and protein-dependent. Unlabeled insulin was more potent than IGF-1 in inhibiting 125I-insulin binding; the ratio of potencies for insulin and IGF-1, however, was dependent upon the nutritional state. Insulin binding was significantly higher (P < 0.05) following 48 hr fasting and lower (P < 0.05) following refeeding compared to ad libitum feeding. Receptor affinity was similar irrespective of the nutritional state. Solubilized and wheat germ agglutinin purified renal insulin receptors were devoid of ATPase activity in contrast to hepatic receptors. The sizes of alpha- and beta-subunits of renal receptors were similar to those of hepatic receptors: 135 and 95 kDa, respectively. Insulin-stimulated autophosphorylation of the beta-subunit was decreased, although not significantly, by prolonged fasting. Phosphorylation of artificial substrate: poly(Glu-Tyr) 4:1 was significantly decreased by the 48-hr fast at high insulin concentrations (10 and 100 nM). Kinase activities of renal insulin receptors from fed or refed chickens were very similar. In conclusion, typical insulin receptors are present in chicken kidneys. These receptors exhibit a regulation at the level of their number and kinase activity in a fashion similar to that found for hepatic receptors. The present results suggest a role for insulin in chicken renal function. PMID- 7843567 TI - Photoperiodically induced changes in glutamatergic stimulation of LH secretion in male Syrian hamsters: role of circulating testosterone and endogenous opioids. AB - In seasonally breeding mammals, the sensitivity of LH secretion to stimulation by the glutamate agonist N-methyl-D-aspartic acid (NMDA) is lower in the sexually active condition than in animals with testicular regression. One experiment determined if this increased sensitivity to NMDA in the reproductively inactive animal reflects reduced circulating testosterone. Responses to NMDA were determined during long days (LD) and short days (SD) in castrated hamsters bearing silastic testosterone implants, designed to maintain constant serum testosterone concentrations throughout a photoperiodically induced seasonal cycle. As expected, no significant effect of NMDA (50 mg/kg BW, sc) on secretion of LH occurred in testosterone-implanted castrate or intact control hamsters when challenged in LD. In contrast, both groups of hamsters responded to this dose of NMDA after 8 weeks exposure to SD, despite the maintenance of high serum testosterone concentrations in the castrate group. Moreover, the increased response to NMDA was not a reflection of lower LH concentrations associated with this photoperiod, because a response to NMDA persisted after removal of implants when endogenous secretion of LH had increased. Thus, the low circulating concentrations of testosterone in male hamsters exposed to an inhibitory SD photoperiod cannot explain the increased response to glutamatergic stimulation in the sexually inactive state. Photoperiod, acting centrally, is the major determinant of the response to activation of NMDA receptors. Other experiments investigated whether the lack of response to glutamatergic stimulation in the LD sexually active state results from endogenous opioid (EOP) tone that inhibits further increases in LH secretion at this stage of the reproductive cycle. If this is so, then pretreatment with an opioid antagonist would reveal or increase the stimulatory effect of NMDA on secretion of LH. Hamsters in LD were pretreated with the opioid antagonist naloxone (NAL; 5 mg/kg BW sc) before NMDA treatment (50 mg/kg BW sc), and blood samples collected 15 min later. Compared with controls, serum LH was significantly elevated in hamsters pretreated with NAL, but NMDA alone did not elevate LH. Surprisingly, LH concentrations in hamsters pretreated with NAL and then injected with NMDA were significantly lower than in hamsters receiving NAL only. Treatment with a submaximal dose of NAL (0.1 mg/kg) did not increase serum LH, nor did it reveal a stimulatory effect of subsequent NMDA treatment. The results demonstrate that the decreased sensitivity to glutamatergic agonists in the sexually active state is not a reflection of masking by inhibitory EOP mechanisms.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7843568 TI - Seasonal variations in the daily rhythm of melatonin and NAT activity in the Harderian gland, retina, pineal gland, and serum of the green frog, Rana esculenta. AB - Day-night variations of melatonin content and N-acetyltransferase (NAT) activity were studied in the Harderian gland (HG), retina, pineal gland, and serum of the green frog Rana esculenta. Throughout the year the retinal melatonin content was correlated with retinal NAT activity and was always higher than those in the pineal gland and HG. On the other hand, in these structures diurnal fluctuations in NAT activity were observed. There were clear seasonal differences in the magnitude of the nocturnal increase of retinal melatonin levels as well as in the nocturnal pattern of retinal NAT activity. In summer day-night variations of melatonin and NAT are absent. The prevailing photoperiod seems to affect melatonin and NAT circadian rhythms in R. esculenta. PMID- 7843569 TI - Photostimulation changes the pattern of luteinizing hormone secretion in turkey hens. AB - Changes in the secretory pattern of luteinizing hormone (LH) were determined in turkey hens during initiation of reproduction. Photosensitive hens were switched from a short day photoschedule of 6L:18D (light:dark) to 14L:10D and serially bled six times during the next 6 weeks of photostimulation and early after ovulatory cycles had begun. The pattern of LH secretion at 0-1 day of photostimulation was characterized by a low baseline concentration of LH with numerous low frequency, high amplitude pulses. This pattern changed at Days 4-5 and 11-12 of photostimulation (hens photostimulated but not yet laying) to a pattern characterized by a high baseline with few ill defined pulses of very short duration. Once the hens had initiated egg production, ovulatory surges of LH (duration of 358 +/- 104 min) were superimposed on the basic pattern seen during photostimulation. The ascending limb of the ovulatory surge was much shorter in duration than the descending limb. No diurnal variation was detected in baseline concentration before or during photostimulation or after egg production had begun. It was concluded that photosensitive turkey hens secrete LH in low frequency; high amplitude pulses superimposed on a low baseline. During photostimulation, this pattern changes to one characterized by a high baseline with few pulses of low amplitude and short duration. This pattern of secretion is stimulatory to the ovary and continues until egg laying begins when it is modified by ovulatory surges of LH, characterized by short duration ascending limbs and longer duration descending limbs, which are superimposed on the high baseline pattern noted during photostimulation. PMID- 7843570 TI - The effects of cortisol on hepatocyte metabolism in rainbow trout: a study using the steroid analogue RU486. AB - The objective of this study was to examine if RU486, a corticosteroid antagonist, modified hepatocyte metabolism and blocked the metabolic effects of exogenously administered cortisol in rainbow trout (Oncorhynchus mykiss). The fish were given a single intraperitoneal implant of either coconut oil alone or coconut oil containing RU486 (100 mg.kg-1), cortisol (100 mg.kg-1), or a combination of RU486 and cortisol and were sampled 7 days postimplantation. The RU486 implants had no effect on plasma cortisol and glucose concentrations, hepatocyte glycogen content, and total glucose production, but increased in vitro hepatocyte glycogen breakdown. Cortisol implantation had no effect on plasma glucose concentration, hepatocyte glycogen content, glycogen breakdown, or total glucose production, while it significantly increased alanine oxidation and gluconeogenesis in rainbow trout hepatocytes. Hepatocyte responsiveness to epinephrine and glucagon stimulation of total glucose production was not modified by either RU486 or cortisol treatment, whereas the insulin response on total glucose production was decreased with cortisol. RU486 treatment modified hepatocyte glycogen metabolism and blocked the cortisol-induced increases in alanine gluconeogenesis and glycogen mobilization for endogenous use by the hepatocytes. These results indicate that cortisol enhances the metabolic potential of hepatocytes, thereby adapting the fish to cope with stress. This study provides further validation of RU486 as a tool for studying metabolic actions of cortisol in fish. PMID- 7843571 TI - Peptide hormones influence in vitro interrenal secretion of cortisol in the trout, Oncorhynchus mykiss. AB - Adrenocorticotrophic hormone (ACTH), angiotensin II (AII), and the urophysial peptides, urotensins I and II (UI and UII), stimulate cortisol secretion by interrenal preparations of seawater (SW) and freshwater (FW) adapted trout. Steroid secretion was not disturbed in sham-treated control groups. The increased cortisol secretion following perifusion of tissue with 10(-7) M ACTH in combination with 10(-7) M AII, 10(-7) M UI, or 10(-7) M UII was greater than after separate administration of ACTH, AII, UI, or UII. These responses were no greater than the summation of the separate effects of ACTH, AII, or UII in SW and FW derived tissue or of ACTH and UI in FW derived tissue. However, the increased cortisol secretion (600-700%) after UI and ACTH in combination in SW adapted fish was significantly higher than the summated responses (100-200%) to UI and ACTH when administered separately. These results suggest that in SW fish interrenal UI enhances the steroidogenic action of ACTH, a potentially important response in SW teleost fish. PMID- 7843572 TI - Properties of angiotensin II receptors of domestic turkey (Meleagris gallopavo) adrenal steroidogenic cells. AB - In the present study, the properties of angiotensin II (AII) receptors of intact domestic turkey adrenal steroidogenic cells were characterized. AII (but not ACTH) induced an immediate and sustained increase in intracellular Ca2+. In addition, dithiothreitol inhibition of maximal AII-induced aldosterone production was closely correlated with its inhibition of binding suggesting that these receptors are type 1-like and operate through a non-"spare" receptor mode. Equilibrium-binding analysis revealed a single class of binding sites at a concentration of 63,500 sites/cell and having an apparent dissociation constant (Kd) of 1.21 nM. However, the Kd derived from kinetic analyses, 0.27 nM, was lower. Both empirically determined and model-based calculated distributions of bound hormone indicated that at equilibrium, about 30% of hormone-receptor complexes were internalized whereas 70% remained on the surface. This distribution contrasts sharply with that reported for mammalian (rat) adrenocortical cells. In keeping with recent cloning studies, these avian AII receptors of intact adrenal steroidogenic cells discriminated angiotensins and mammalian peptidic and nonpeptidic antagonists differently from mammalian adrenocortical and duck adrenal receptor preparations. Importantly, turkey adrenal steroidogenic cell AII receptors poorly discriminated the nonpeptide antagonists, losartan (DuP 753) (type-1 specific) and PD123177 (type-2 specific). Thus, AII receptors of freshly isolated, intact turkey adrenal steroidogenic cells are pharmacologically distinct from mammalian adrenocortical type-1 receptors. PMID- 7843573 TI - Somatization disorder: the need for effective intervention studies. PMID- 7843575 TI - Screening for depression in medical patients. Is the focus too narrow? AB - There is growing consensus that depression is a major public health problem causing significant psychosocial morbidity and mortality which should be addressed by case-finding effects in primary care settings. A large amount of literature has examined the ability of self-report questionnaires to detect depression in medical patients and the results have been encouraging. However, studies of general population and psychiatric patient samples indicate that depression is frequently comorbid with other psychiatric disorders, and that psychiatric disorders other than depression are also associated with significant morbidity and mortality. Consequently, we believe that psychiatric screening in primary care should be broad based. We administered a newly developed, multidimensional questionnaire (the SCREENER), that simultaneously screens for a range of DSM-III-R psychiatric disorders, to 508 medical outpatients attending a VA general medical clinic. Compared with nondepressed cases, the depressed patients significantly more often reported all of the nondepressive symptoms. Nine of the ten nondepressive disorders screened for by the SCREENER were significantly more frequent in the depressed group. Most patients who screened positive for depression also screened positive for at least one nondepressive disorder. Compared with patients who only screened positive for depression, those who screened positive for both depression and a nondepressive disorder rated their physical and emotional health more poorly and made more visits to the doctor. Compared with patients who did not screen positive for any disorder, those who only screened positive for a nondepressive disorder rated their physical and emotional health more poorly, and more frequently had a history of mental health treatment.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843574 TI - Effectiveness of psychiatric intervention with somatization disorder patients: improved outcomes at reduced costs. AB - In order to determine the health effects of an intervention that reduces the cost of care for somatization disorder (SD) patients, 59 primary care physicians were randomized to receive a psychiatric consultation letter providing treatment recommendations for 73 patients either at baseline or the end of the year-long study. Seventy of these patients (96%) were followed every 4 months for 1 year by a research assistant blind to randomization. A year following the intervention, patients of experimental physicians reported greater physical capacity than patients of control physicians (mean difference = 17.9, 95% CI 1.0-34.9) with a $466 reduction (95% CI $132-$699) in health care charges. In addition to a net 21% reduction in health care charges for the typical SD patient, the consultation letter improved physical functioning in a group of highly impaired subjects. PMID- 7843576 TI - A review of delirium assessment instruments. AB - This paper reviews various types of assessment instruments for delirium, including nursing screening scales, symptom checklists, an analog scale, an interview schedule, and symptom rating scales. Their structures and applicability to the clinical and research assessment of delirium are described. Despite the seeming plethora of assessment methods, only a few are suitable for use by researchers. PMID- 7843577 TI - Alcohol drinking in pregnancy. AB - Our study attempted to determine the prevalence of regular drinking during the second half of pregnancy among prenatal patients; the characteristics that differentiate drinkers from nondrinkers; and characteristics that differentiate prenatal patients who drink 7 or fewer standard drinks per week and those who drink more than 7. In our survey of consecutive English-speaking prenatal patients over 20 weeks' gestation, women self-reported on health habits from a study questionnaire and completed the General Health Questionnaire and Fetal Health Locus of Control. Eighty-three percent (466 of 561) of women provided data on alcohol intake during the second half of pregnancy: 106 (22.7%) reported regular weekly drinking in pregnancy, and the mean number of standard drinks was 1.97 (SD 9.78, range 0.5-184) per week. Thirty-eight (8.2%) women reported drinking more than seven standard drinks, and 14 (3.0%) reported more than 14 standard drinks per week. Women who drank more than seven standard drinks per week were significantly more likely to be under 21 years of age, poorly educated, unemployed, unmarried, to have unplanned pregnancies, emotional problems, eat unhealthy diets, smoke, use illicit drugs, and be physically abused. They also were more likely to meet psychiatric case status on the General Health Questionnaire (t = 3.85, p = 0.0001) and to believe that "chance" (t = 3.41, p = 0.001) rather than "internal control" (t = -3.54, p = 0.001) affected the health of their fetuses as measured by the Fetal Health Locus of Control. We concluded that pregnant women who drink alcohol often have other health risk factors.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843578 TI - Psychological distress in female cancer patients with Holocaust experience. AB - This study examined whether severe emotional and physical trauma in the past affects the psychological condition of female patients currently afflicted with cancer. Using the Brief Symptom Inventory (BSI), 41 women with cancer, who had sustained extreme trauma during the Nazi Holocaust of the midcentury, were compared with three different groups: a matched group of cancer patients without Holocaust experience, a physically healthy group of female Holocaust survivors, and healthy women without a Holocaust past. Although psychological distress was comparable in the two healthy groups, it was far higher in Holocaust cancer patients than in either their non-Holocaust counterparts or in the group of healthy Holocaust survivors. These results may suggest that the severe trauma of the Holocaust could be responsible for markedly diminished psychological response when such patients are confronted with new stress. PMID- 7843580 TI - Depression, HIV dementia, delirium, posttraumatic stress disorder (or all of the above) AB - A 29-year-old single Puerto Rican woman with AIDS was admitted to the Medical Service for pneumonia, seen by the Psychiatric Consultation Service, an eventually transferred to the Inpatient Psychiatric Unit with several possible psychiatric diagnoses including major depression, HIV dementia, delirium, and posttraumatic stress disorder. These possibly coexisting and interacting syndromes are discussed by three psychiatrists, one of whom is also a board certified neurologist. This case illustrates the combined contribution of organic and psychological factor to complex behavioral disorders, which are increasingly common in HIV infection. PMID- 7843579 TI - Hypnotic efficacy and safety of triazolam administered during the postoperative period. AB - This study examined the hypnotic efficacy and safety of short-term use of triazolam following elective surgery. One hundred women (ages 26-69) who had received 0.125 mg of traizalam the evening before breast cancer surgery were enrolled in a randomized, double-blind study comparing triazolam to placebo. Study medication was begun on the first or second evening following surgery, depending on the patient's level of postoperative alterness, and was administered in the hospital for three consecutive evenings. The starting dose of triazolam was 0.125 mg, with the option of increasing the dose to 0.25 mg on subsequent nights if sleep response was inadequate. Relative to patients in the placebo group, patients in the triazolam group reported significantly (p < 0.05) less difficulty falling asleep, fewer nightime awakenings, better overall sleep quality, and a greater sense of restfulness. No clinically significant adverse reactions were encountered and no adverse reactions occurred more frequently in the triazolam group than in the placebo group. Results indicate that administration of traizalam is a safe and effective method of improving sleep in patients recovering from surgery. PMID- 7843581 TI - [Paracelsus in opinions of the 18th century]. AB - Paracelsus was a topic of intense discussion during the eighteenth century in the encyclopedias, works of philosophy, natural science and medicine of this time. His contributions to chemistry and the chemical foundation of medicine were acknowledge as well as his fight against the ancient humoral pathology and specific achievements in surgery and drug therapy. In contrast, his concept of science and use of language were rejected. The gap between his expressed moral standards and his own behavior was criticized. The contemporary circumstances must be taken into consideration. PMID- 7843582 TI - [Birth of the German clinic]. AB - The aim of this article is to show that, in the case of Germany, the birth of the clinic not only represents a change in the medical outlook, as described by Foucault, but should also be analyzed as the result of a complex interplay of political, economic, and social forces and as a conjunction of various demands which do not merely emanate from the university and scientific institutions. PMID- 7843583 TI - [Scientific theoretical founding of medicine as a natural science by Hermann von Helmholtz (1821-1894)]. AB - In this study an attempt will be made to discuss the epistemological problems in the theory and practice of modern technical medicine in the writings of Hermann von Helmholz. An inquiry into the relationship between von Helmholtz' thinking and the critical philosophy of Immanuel Kant is followed by the characteristics of von Helmholtz' philosophy of science which he himself called "empirical theory". The question of medicine as a science finally leads to the main problem of medical epistemology, viz., the relationship between theoretical knowledge and practice in medicine. In this context the anthropological dimension is brought into consideration. PMID- 7843584 TI - [Historical geographical epidemiology of poliomyelitis]. AB - Poliomyelitis was considered a rare disease before it terrified Europe and North America with large-scale epidemics during the first half of the 20th century. In Africa and Asia the number of reported cases increased remarkably only after World War II. A theory which is widely accepted today assumes that infection with poliovirus 1, 2 and 3 has always been globally endemic, but that the proportion of cases with residual paralysis has increased only since 1900 as a consequence of the rise of the mean age at infection. Sabin, however, initially was convinced that virus strains with enhanced neurotropism had caused the dramatic increase in paralytic poliomyelitis. Epidemic outbreaks in anglo-american troops in Malta and in the Far East during the war played a crucial role in the discussion. Later, also Sabin sustained the theory mentioned first, which gradually assumed the position of a dogma. The present paper deals with the question of how this dogma became dominant, in spite of the weakness of its epidemiological and virological foundation. PMID- 7843585 TI - [History of founding the Swiss Cancer League]. AB - The Swiss Cancer League was founded in 1910 under the name of "Schweizerisches Komitee fur Krebsforschung". It was initiated by the first director of the Swiss Federal Health Office, Dr. Friedrich Schmid. Schmid received most impulses from the Genevan "Societe de la lutte contre le cancer", founded in 1907 in Geneva. Its mentor, Dr. Robert Odier, had struggled for federal support and for membership in the International Organisation for Cancer Research (founded in 1908 in Berlin). The main purpose of the "Schweizerisches Komitee fur Krebsforschung" was to start a national cancer research program. For this reason, another society was founded, the "Schweizerische Vereinigung fur Krebsforschung". It had to procure money and provide information of lay people and physicians as well. During and after World War I activities stagnated and reorganisation became necessary. Changes of personnel, new activities and topics and opening membership to non-medical persons initiated a new phase of modernization. PMID- 7843586 TI - [A document. Manuscript of a 1873 obituary for the Swiss medical historian Conrad Meyer-Ahrens]. AB - In 1991 the Medical History Institute and Museum of the University of Zurich received a significant portrait and biographical collection from the private estate of the physician family Meyer "zum Felsenegg". Of particular interest is the handwritten obituary notice for the distinguished Swiss medical historian, Conrad Meyer-Ahrens. Written by his personal friend and professional colleague, Conrad Meyer-Hofmeister, this obituary was read to the Society of the Zurich Masonic Lodge "Modestia cum Libertate" on January 25, 1873. PMID- 7843587 TI - The first epidemic of cerebrospinal meningitis. PMID- 7843588 TI - Cell death and disposal in retinoblastoma: an electron microscopic study. AB - BACKGROUND: Tumor necrosis and cell death are common features of retinoblastoma. In non-malignant retinal cells after ischemia, as well as in many non-retinal tumors, cell death occurs in at least two ways. We investigated whether similar patterns of cell death could be demonstrated in retinoblastoma cells. METHODS: Nine globes with retinoblastoma from eight patients were studied. Paraffin sections stained with HE or the Feulgen method were examined by light microscopy. Several samples from each tumor were selected for electron microscopic study. RESULTS: Ultrastructurally, two main types of cell death were identified. Type I was characterized by progressive lysis of the cytoplasm and karyoplasm. Nuclear chromatin either dissolved or was transformed into compact clumps becoming extracellular dense bodies. Phagocytosis of cell remnants by neighboring tumor cells, or occasional macrophages, was common. Type II was characterized by progressive condensation and shrinkage of the cytoplasm and nucleus. Type II was subdivided in two forms distinguished mainly by characteristic patchy vs crescentic chromatin condensation. Small parts of condensed cytoplasm were engulfed by neighboring tumor cells. Compact cell remnants then underwent either phagocytosis by neighboring retinoblastoma cells or progressive intercellular disaggregation. CONCLUSION: Retinoblastoma cells may undergo at least two types of cell death. Type I fits the definition of necrosis, while both forms of type II exhibited several features consistent with apoptosis. The types of cell death observed in retinoblastoma exhibited similarities to patterns observed in ischemic retina, as well as in other malignant tumors. Type II cell death (apoptosis) may play a role in limiting tumor growth. PMID- 7843589 TI - Expression of mRNA coding for TNF alpha, IL-1 beta and IL-6 by cells infiltrating retinal membranes. AB - BACKGROUND: Cellular mechanisms of inflammation are thought to be involved in the pathogenesis of proliferative vitreoretinopathy, and cytokines, which are products of cell activation, are known to play an important role in the development and maintainance of inflammatory reactions. It was the aim of this work to investigate the presence of cells expressing cytokine mRNA within retinal membranes. METHODS: The presence of mRNA coding for the cytokines interleukin 1 beta (IL-1 beta), interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF alpha) was investigated in 19 epiretinal membranes obtained from eyes undergoing vitrectomy for the treatment of retinal detachment complicated by proliferative vitreoretinopathy. RESULTS: Cells expressing mRNA for IL-1 beta were observed in 7 membranes, cells positive for IL-6 mRNA were seen in 12 membranes, and cells exhibiting mRNA for TNF alpha were present in 9 specimens. Only three membranes contained cells expressing mRNA for all the cytokines investigated. Four membranes possessed positive cells for IL-6 and TNF alpha, two contained cells expressing mRNA for IL-6 and IL-1 beta, and two others exhibited cells expressing mRNA for TNF alpha and IL-1 beta. Five membranes contained IL-6 mRNA-positive cells only, whilst two exhibited cells expressing mRNA for IL-1 beta or TNF alpha only. CONCLUSION: The present findings indicate that cellular activation may occur during the development of PVR, and suggest that these cytokines may be locally produced by cells infiltrating epiretinal membranes. The presence of IL-1 beta, IL-6 and TNF alpha mRNA-positive cells within retinal membranes provides further evidence of a pathogenic role of these cytokines in proliferative vitreoretinopathy. PMID- 7843590 TI - Increased lipid peroxide level and myeloperoxidase activity in the vitreous of patients suffering from proliferative vitreoretinopathy. AB - BACKGROUND: Retinal pigment epithelium cells and activated phagocytes are believed to be involved in the pathogenesis of proliferative vitreoretinopathy (PVR). Both cell types are capable of producing oxygen free radicals and other molecules with a high oxidative potential which can lead to a propagation of oxidative damage. It was the aim of this study to investigate whether products of oxidative reactions are detectable in the vitreous body of patients suffering from PVR. METHODS: In vitreous aspirates of patients vitrectomized because of PVR (n = 27), macular pucker (n = 9), or other reasons (controls, n = 31), the following parameters were determined: lipid peroxides (LPO), determined as malondialdehyde-like substances (MDA) and as thiobarbituric acid-reactive substances (TBARS), and myeloperoxidase activity (MPO). RESULTS: Compared with the controls, both LPO levels and MPO activities were significantly elevated in the vitreous of patients suffering from PVR. Vitreous of patients with macular pucker did not reveal any significant differences from controls in the parameters analyzed. CONCLUSION: Our results suggest that both oxygen free radicals and inflammation-related reactions participate in the process of PVR. Oxidative tissue damage is obviously not involved in the pathogenesis of macular pucker. PMID- 7843591 TI - Ocular blood flow velocity reduction after buckling surgery. AB - BACKGROUND: It has been reported that scleral buckling reduces the blood flow velocity in retinal vessels. Blood flow changes may also appear in other ocular and extraocular vessels. This study describes the blood flow velocity changes in the ophthalmic artery (OA) after performing this procedure. METHODS: The study was carried out in 12 patients (12 eyes) with rhegmatogenous retinal detachment. Color Doppler imaging was used to measure the peak and average blood flow velocity in the OA. Measurements were taken 1 day before and 2 days after scleral buckling surgery was performed. Intraocular pressure (IOP) was measured prior to each ultrasound study. RESULTS: We found that statistically significant reductions in the peak flow velocity (33%) and average flow velocity (31%) occur in the OA after scleral buckling. All patients showed an increase in IOP after surgery. CONCLUSION: Buckling surgery reduces the blood flow velocity in the OA. Since the OA is the origin of the arterial branches that supply blood to the eye, our results suggest that scleral buckling may decrease not only retinal but also choroidal blood perfusion. Some extraocular structures might also be affected. PMID- 7843592 TI - The efficacy of the combination of l-moprolol and dipivefrin in reducing the intraocular pressure in primary open-angle glaucoma or in ocular hypertension. AB - BACKGROUND: In this double-blind prospective trial the efficacy of lowering the intraocular pressure of l-moprolol given alone and in combination with dipivefrin was tested. METHODS: Twenty-seven patients with primary open-angle glaucoma or ocular hypertension were randomly assigned to receive twice-daily l-moprolol eye drops or dipivefrin eye drops for 4 weeks; in a second phase of the trial, the combination of the two drugs was administered for 4 weeks. RESULTS: The results of this study indicated that l-moprolol and dipivefrin had an equivalent effect in lowering the intraocular pressure. The association of the two drugs caused a further reduction of intraocular pressure which was significant only in the group previously treated with dipivefrin alone. CONCLUSION: This trial demonstrated that the combination of l-moprolol and dipivefrin is an effective and safe treatment for elevated intraocular pressure. PMID- 7843593 TI - Diurnal and nocturnal blood pressure drops in patients with focal ischemic glaucoma. AB - BACKGROUND: The purpose of this study was to assess the role of arterial hypotension in the pathogenesis of certain types of glaucoma. METHODS: We compared diurnal and nocturnal fluctuations in blood pressure by using an ambulatory recording over a 24-h period in two different groups of patients: one of 16 patients with focal ischemic glaucoma (FIG) and another of 16 patients with primary open angle glaucoma (POAG). RESULTS: In patients with FIG, compared to those with POAG, we found: lower diastolic blood pressure (BP; 75.7 vs 82.5 mmHg, P < 0.05), systolic BP (121.7 vs 131.2 mmHg, P < 0.05) and mean BP (90.5 vs 101.5 mmHg, P < 0.05) over 24 h; lower diurnal diastolic BP (78.1 vs 85.5 mmHg, P < 0.05), and systolic BP (124.6 vs 134.2 mmHg, P < 0.05); greater nocturnal systolic BP variability (8.2% vs 6.2%, P < 0.05); and a greater percentage of diurnal low readings (14.53% vs 2.8%, P < 0.05), compared with the literature limits (101/61 mmHg). However, the number of nocturnal low readings was not different for either group. CONCLUSION: It is important to detect arterial hypotension - one of the components of the vascular factor - during examination of a patient with normal-pressure glaucoma. This is one element in preserving the best possible perfusion of the optic nerve. PMID- 7843594 TI - Application of eye drops to the medial canthus. AB - BACKGROUND: Our purpose was to investigate the efficacy of instillation of eye drops in the medial canthus with the lids closed at the time of application. METHODS: The pupils of 50 healthy volunteers were dilated with tropicamide 0.125%. The effect of the drug on pupillary dilatation when instilled in one eye with the lids closed was compared to its effect when instilled in the conventional mode in the other eye. RESULTS: Maximal mydriasis achieved was 2.75 +/- 0.76 mm in the eye with closed lids and 2.8 +/- 0.77 mm in the eye in which eye drops were instilled in the conventional mode. CONCLUSION: Eye drop instillation in the medial canthus with the lids closed at the time of application seems to be an effective means of ophthalmic drug delivery. PMID- 7843596 TI - Extraocular muscle surgery in a rabbit model: site of reattachment following hang back and conventional recession. AB - To determine the precise site of reattachment of recessed muscles, 4-mm conventional and hang-back recessions of the inferior rectus muscle were performed in 18 albino rabbits. Six weeks later, the distance from the anterior border of the reattached muscle to the insertion was measured both grossly and microscopically. In all cases the operated muscles had advanced minimally from the site of surgical placement. Gross observation showed that the mean forward creep was significantly greater for those rabbits which underwent hang-back recession (1.81 +/- 0.67 mm) than for those that were submitted to the conventional technique (0.83 +/- 0.38 mm). Measurements done on histological sections revealed that the mean distance of the anterior border of the muscle fiber from the reference suture was larger for conventional recession (2.73 +/- 0.75 mm) than for hang-back recession (1.91 +/- 0.72 mm). PMID- 7843595 TI - Hamster Greene melanoma in the rabbit eye: immunosuppressive treatment to improve this tumor model. AB - BACKGROUND: The hamster Greene melanoma (HGM) implanted in the anterior chamber of the rabbit eye has been used to study experimental therapies for human uveal melanoma. However, the occurrence of spontaneous necrosis limits the value of this model for long-term evaluation of experimental treatments. In the present study we tested the hypothesis that an immune response is the cause of this necrosis and that prevention of the immune response can prolong the experimentation time METHODS: HGM was implanted in the anterior chamber of control, presensitized and immunosuppressed rabbits. The effects of sensitization and immunosuppression were assessed by clinical and histological observation RESULTS: Sensitization led to a significant slowing down of tumor growth, but not to a difference in necrosis. Immunosuppressive treatment with cyclosporin A improved the success rate of implantation and decreased the amount of necrosis in the tumor CONCLUSION: The immune response plays a role in the occurrence of necrosis. However, although immunosuppressive treatment with cyclosporin A decreased the amount of necrosis, significant necrosis still occurred, suggesting that other factors like angiogenesis play a part as well and still limit the usefulness of this model in the long-term evaluation of experimental therapies. PMID- 7843597 TI - Public policies on aging: reconsidering old-age eligibility. PMID- 7843598 TI - Changing criteria in old-age programs: the introduction of economic status and need for services. AB - For more than a decade, incremental changes have gradually eroded the traditional approach in many policies that have relied primarily on specific old-age categories to determine eligibility for public benefits and the amount of those benefits. These changes, and other recent policy proposals, have introduced need based criteria as well as the principle of asking wealthier older persons to pay greater taxes or share more heavily in financing services and benefits than those older people who have less income and accumulated wealth. This discussion of such modifications in policies on aging begins with a depiction of the political context in which they have emerged. It then reviews the emergence of the new approaches, and concludes with commentary on the political viability of these and other possible changes in the mixture of criteria used in old-age benefit programs. PMID- 7843599 TI - "Equivalent retirement ages" and their implications for Social Security and Medicare financing. AB - The projected implications of population aging, especially the attendant costs of income support and health care, are based on a definition of normal retirement age as age 65, although the retirement age for full Social Security benefits will be raised gradually to age 67 by the year 2027. Should the retirement age be increased beyond what is now scheduled in the 1983 law? This article discusses the concept of "equivalent retirement ages" as a method for determining an appropriate age for normal retirement, and points out the usefulness and limitations of raising normal retirement age as a policy instrument. PMID- 7843600 TI - Testing the boundaries of universality: what's mean? What's not? AB - This article explores the relationship between recent policy reforms, targeting proposals, and a universal Social Security program. It explores principles that inform Social Security, concluding that treating benefits as taxable income and raising the "normal" retirement age push at the boundaries of universality without violating the fundamental precepts of a social insurance program. Universal eligibility to Social Security is assessed as an essential feature of a public pension program and especially beneficial to low- and moderate-income populations. Introduction of a means test is assessed as potentially undermining political support for the program, the economic well-being of low-income elders, and retirement savings efforts. Greater targeting of benefits and financing is possible within the context of the existing Social Security program. Further targeting in Social Security and improvements in selective programs such as SSI do not contradict and may enhance a public retirement income strategy which is built upon social insurance principles. PMID- 7843601 TI - A contingency-based approach for assessing policies on aging. AB - This article assesses the demographic and ideological shifts reshaping aging policy and proposes an approach to rethinking the bases of aging-based and aging related policy. This approach takes into account new and multiple patterns of need and well-being among the old and, as such, holds the promise of providing both a defense of and a rationale for a range of age-related benefits. As well, it opens the possibility of shifting responsibilities for well-being in old age among government, the private sector, and individuals themselves. PMID- 7843602 TI - Mainstreaming gerontology in the policy arena. AB - Aging has come of age and is now one of the important domestic issues facing the United States. What we do or don't do in the 1990s will determine what type of aging society we will have in the next century. The challenge we face as gerontologists is to think about new ways to help broaden the debate about preparing for an aging society in a comprehensive manner that takes into account the diverse disciplines and interest groups that will increasingly shape aging related issues. Those who have labored in the field of aging when it was a relatively cloistered profession should delight in the new-found respect and recognition of their work by the larger society. On the other hand, this mainstreaming of aging will create new challenges and opportunities, as we look ahead to the new aging. PMID- 7843603 TI - Revisiting the Kansas City study of adult life: roots of the disengagement model in social gerontology. PMID- 7843604 TI - Re-engaging the disengagement theory of aging: on the history and assessment of theory development in gerontology. AB - While "disengagement theory" is today largely discounted, it has an important place in the history of gerontological explanation. First we analyze the historical context of this theory. Second, we examine its long-term contributions and deficiencies in terms of finer criteria--standards which we suggest should be used in evaluating current, and future, theories in social gerontology. PMID- 7843605 TI - Lives through the years revisited. AB - Williams and Wirths' distinctly sociological study of older adults provides a useful insight into the theory and methods of early interdisciplinary research on social aspects of adulthood and aging in the United States. The Kansas City Study of Adult Life, particularly the concept of disengagement developed there, figured prominently for two decades in theoretical discussions of development in later life. In this sociological presentation, Parsonian action theory is used to develop a framework for assessing the structured interaction of persons and social context, and the autonomy and persistence of life styles which provide a basis for predicting successful aging. PMID- 7843606 TI - Sociology, psychology, and the theoretical legacy of the Kansas City studies. AB - The theoretical impact of the Kansas City Studies stems from issues ignored as much as from those addressed. The largest concerted gerontological investigation of its day had a profound influence on the field through publications and through students trained through the studies. The studies advanced the search for "normal" aging but did not initially adequately address diversity. However, over time, investigators were forced to recognize diversity in their data. They contributed to viewing aging in a life course perspective, an advance over previous emphases on "the aged." The studies adopted and furthered a highly individualistic understanding of aging, while the sociological analyses from the studies lacked an adequate conceptualization of social structure. PMID- 7843607 TI - Do for-profit and not-for-profit nursing homes behave differently? AB - The purpose of this study was to examine behavioral differences between for profit (FP) and not-for-profit (NFP) nursing homes. Previous studies have failed to establish consistent behavioral differences. This study uses a simultaneous equation model to control for potential endogeneity among system variables, with model parameters estimated using 3SLS. The study provides evidence that NFPs provide significantly higher quality of care to Medicaid beneficiaries and to self-pay residents than do FPs, as evidenced by better staffing and better outcomes among nursing homes with residents at higher risk for adverse outcomes. PMID- 7843608 TI - A comparison of the effect of regulation on health care for the older American: a tale of two states. AB - The enactment of changes in health care policy necessitates monitoring industry practice to assure a response in line with intent. Theory predicts that tightly controlled organizations produce too few services to meet needs. Those under milder restrictions produce too many services to compensate for perceived losses in revenue. This study explores the relationship, if any, between level of regulatory intensity upon, and subsequent service delivery within, the hospital industry. Some service retrenchment may be desirable, particularly if fewer iatrogenic events occur. Too few services proffered are harmful. A look at prior efforts may prove beneficial before the United States initiates overall health care reform. PMID- 7843609 TI - Cardiopulmonary resuscitation and older adults' expectations. AB - The purpose of this study was to determine the knowledge, attitudes, and opinions of older adults about cardiopulmonary resuscitation (CPR). Sixty hospitalized/institutionalized older adults were interviewed. Most had little or no accurate knowledge of CPR. However, many stated that they would wish to receive CPR and would want to be involved in the CPR decision-making process. The knowledge deficits and misconceptions of older adults should be addressed in order that they may become informed and active participants in the CPR decision making process. PMID- 7843610 TI - Housing quality of U.S. elderly households: does aging in place matter? AB - This article investigates whether older people who have lived longer in their dwellings are more likely to occupy physically deficient accommodations. It analyzes data from the 1987 American Housing Survey describing the housing conditions of 12,859 aged 60-and-older households. A multiple regression analysis assessed whether length of residential occupancy significantly influenced housing quality after controlling for other likely influences such as building age, chronological age, household composition, race/ethnicity, socioeconomic status, and location. Overall, length of residence was a relatively poor predictor of housing quality, and only certain subgroups of longtime owners and renters were more likely to occupy physically deficient dwellings. PMID- 7843611 TI - Aspects of eldercare that place employees at risk. AB - Through multiple regression analyses, this study examined the contribution of seven different aspects of eldercare to the prediction of several work and personal outcome among employees of eight organizations. The analyses were restricted to the 1,302 (25.4%) employees over the age of 35 who provided assistance to an elderly relative by helping them with either at least one Activity of Daily Living (ADL) or with at least two Instrumental Activities of Daily Living (IADL). The results revealed that assistance with ADLs, eldercare management activities, and the number of eldercare crises to which the employee responded, each placed respondents at risk of more family interference with work, more stress, and more personal and job costs. PMID- 7843612 TI - Taking next steps: gerontological education, research, and the literary imagination. AB - This article interprets two literary works--both about old women who have suffered strokes and are near death--and argues that literature can make essential contributions to gerontological research and education by developing sensitivity to theory, empathic understanding, and self-awareness. This article examines these fictional accounts against two theoretical perspectives--the political economy of aging and theories of personal meaning--and encourages epistemological experimentation. PMID- 7843613 TI - The establishment of clinical cutoffs in measuring caregiver burden in dementia. AB - Although several scales have been developed to assess burden, their clinical utility has been limited by the absence of relevant cutoff points. Clinical data from 140 primary caregivers seeking a dementia evaluation for a family member were analyzed to establish the psychometric properties of a caregiver burden screen. Results indicate that the cutoff values were both sensitive and specific to negative caregiving outcomes. These findings suggest that use of a burden screen may assist clinicians when assessing the adequacy of caregiving arrangements in dementia. PMID- 7843614 TI - Interdisciplinary team training in geriatrics: reaching out to small and medium size communities. AB - Since 1989, six teams in the state of Michigan have been involved in a team training program designed to promote the development of geriatric services in small to medium-size communities. The program was enthusiastically received by participants, but after 18 months, only half of the teams had implemented clinical services for older adults. Monitoring the progress of the teams over 18 months and analyzing the activities of two teams revealed that financially stable and supportive sponsoring agencies and the community were critical factors in the implementation of interdisciplinary clinical services in geriatrics. Future team training programs trying to promote the development of geriatric services in small to medium-size communities should try to address these issues through community organization interventions. PMID- 7843615 TI - An evaluation of a gerontological training program for nursing assistants. AB - A gerontological training program for nursing assistants has been developed by the New England Gerontology Academy to (1) improve the quality of care delivered to the institutionalized elderly, and (2) provide training and assistance on a gerontology career ladder to displaced homemakers, AFDC (Aid to Families with Dependent Children) recipients, unemployed immigrants, and other disadvantaged groups. The program successfully produced a cadre of committed paraprofessionals but was not suited for those whose removal from the labor market had been long term. PMID- 7843616 TI - [Critical observations on unconventional methods in gynecology and obstetrics]. PMID- 7843617 TI - [Acupuncture in gynecology and obstetrics]. PMID- 7843618 TI - [Therapeutic procedures in the Lukas Clinic, Arlsheim, Switzerland]. PMID- 7843619 TI - [Natural substances in gynecologic oncology]. PMID- 7843620 TI - [Unconventional methods in managing breech presentation]. PMID- 7843621 TI - [Gynecology in Chinese medicine]. PMID- 7843622 TI - [Unconventional treatment of viral papilloma?]. PMID- 7843623 TI - [Chronic recurrent colpitis after abortion in adenosis vaginae]. PMID- 7843624 TI - The end of a long search: at last thrombopoietin. PMID- 7843625 TI - Molecular heterogeneity of hereditary elliptocytosis in Italy. AB - BACKGROUND: Common HE is the most prevalent clinical form of hereditary elliptocytosis; its clinical findings vary considerably, ranging from an asymptomatic carrier state to a severe, even life-threatening hemolytic disorder. Structural modification and reduction of 4.1 protein, or abnormalities at the spectrin self-association site could lead to elliptocytes. METHODS: Sixty-one Italian HE patients belonging to 28 families were studied. Analysis of red blood cell cytoskeleton was performed by means of SDS-PAGE, and spectrin dimer percentage was assessed by non denaturing polyacrylamide gel electrophoresis. Limited tryptic digestion of spectrin was employed in patients showing an abnormal dimer increase, and the amount of abnormal alpha I peptide was estimated. Molecular defects were detected by means of PCR of alpha and beta spectrin genes and direct sequencing of genomic DNA. RESULTS: We found a very heterogeneous spectrum of cytoskeletal alterations: 18 (29%) subjects showed partial protein 4.1 deficiency, whereas 31 (51%) displayed an increased amount of spectrin dimers; we were not able to detect any alteration in 12 (20%) HE patients. Patients enrolled in this study were widely distributed throughout Italy. CONCLUSIONS: The subgroup of HE patients related to 4.1 deficiency is homogeneously asymptomatic, whereas forms due to disruption of the spectrin tetramerization site are very heterogeneous, and clinical severity appears to be related to spectrin dimers and especially to spectrin content. These two parameters in turn are related to the presence of a low expression alpha allele in trans and to the degree of disruption of head-to-head contact between alpha and beta chains. PMID- 7843626 TI - Serum levels of cytokines and soluble antigens in polytransfused patients with beta-thalassemia major: relationship to immune status. AB - BACKGROUND: A series of immunological abnormalities has been described in patients with beta-thalassemia. The aim of this study was to investigate whether the measurement of serum levels of selected cytokines and soluble molecules (deriving from cell membrane antigens) involved in the immune response could be useful for a better definition of such alterations. PATIENTS AND METHODS: Serum levels of interleukin-2 (IL-2), IL-6, tumor necrosis factor (TNF), soluble (s) CD4, sCD8, sCD23 and sCD25 were measured using immunoenzymatic assays in 45 transfusion-dependent patients affected by beta-thalassemia major and correlated to conventional immunological indexes, such as peripheral lymphocyte subpopulations and circulating immunoglobulins. RESULTS: Patients with beta thalassemia major showed increased TNF, sCD8, sCD23 and sCD25 and lower sCD4 values compared to normal controls. IL-2 and IL-6 were found to be undetectable or within the normal range in all patients. Splenectomized patients presented lower levels of sCD8 and sCD23 than those observed in unsplenectomized ones. A series of correlations involving TNF, sCD8, sCD23, sCD25, serum immunoglobulins and some lymphocyte subpopulations was observed. In addition, serum markers of immune activation (TNF, sCD23, sCD25) correlated directly with the annual blood transfusion requirement. Despite this series of immunological anomalies, no patient had a history of repeated infectious episodes. CONCLUSIONS: Polytransfused beta-thalassemic patients are characterized by a partial functional immunodeficiency determined by increased activity of CD8+ suppressor/cytotoxic lymphocytes and possibly reduced activity of the CD4+ helper/inducer subset. B-lymphocytes also appear highly activated. The allo antigenic stimulation of transfusions seems to play a major role in the determination of these defects; however, this functional immunological imbalance does not seem to have any clinical relevance. PMID- 7843627 TI - Soluble forms of p55-IL-2R alpha, CD8, and CD30 molecules as markers of lymphoid cell activation in infectious mononucleosis. AB - BACKGROUND: Epstein-Barr virus (EBV) infection in infectious mononucleosis (IM) is associated with lymphocyte activation leading to the expansion of cells expressing activation-associated antigens. Most of these antigens are released as soluble molecules in vitro and in vivo. METHODS: We investigated the serum levels of the soluble forms of the CD8 (sCD8), p55-IL-2R alpha (sIL-2R alpha), and CD30 (sCD30) molecules in 55 patients following primary EBV infection. These data were compared with the phenotypic pattern of circulating lymphoid subsets. RESULTS: In all cases at presentation, lymphocytosis, mainly characterized by the expansion of a CD8+, HLA-DR+, p75-IL-2R beta+, p55-IL-2R alpha- population, was associated with high levels of the investigated soluble molecules. Their mean values (+/- SD) were: 17,172 +/- 12,885 U/mL for sCD8 (vs 334 +/- 95 in controls), 2,922 +/- 2,813 U/mL for sIL-2R alpha (vs 331 +/- 115 in controls), and 477 +/- 451 U/mL for sCD30 (vs 4.9 +/- 6.4 in controls). Follow-up study (15 cases, up to 60 days) showed a progressive decline of all soluble molecules, associated with a reduction of activated CD8+/HLA-DR+/p75-IL-2R beta+ T-cells. By the 30th day, values of sIL-2R alpha and sCD30 (729 +/- 333 U/mL and 20 +/- 21 U/mL, respectively) were only slightly higher than in normal controls, whereas sCD8 levels remained consistently higher (1,777 +/- 1,385 U/mL, p < .001). CONCLUSIONS: sCD8, sIL-2Ra and sCD30 serum levels in IM reflect the total bulk and/or the activation-related events of infected and reactive cells. The variations in these soluble molecules during the follow-up provide useful information on the in vivo biological modifications occurring after EBV infection. PMID- 7843629 TI - Intravenous prostacyclin (as epoprostenol) infusion in thrombotic thrombocytopenic purpura. Four case reports and review of the literature. Italian Cooperative Group for Thrombotic Thrombocytopenic Purpura. AB - BACKGROUND: The enhanced platelet aggregation which is observed in TTP, was suggested to be due to an imbalance between unknown agents insulting endothelial wall and defense factors, such as prostacyclin (PGI2). Several reports suggested an aberration of PGI2 activity as a critical step in the pathogenesis of TTP. Therefore, PGI2 was proposed as an alternative treatment for TTP patients. METHODS: We report the results obtained with increasing doses (from 2 ng/Kg/min to 10 ng/Kg/min in 5 days) of PGI2-as epoprostenol-in 4 TTP patients from the retrospective series of the Italian Cooperative Group who were considered resistant to conventional plasma-exchange (PE)-based treatments. RESULTS: Despite PGI2 infusion, 2 patients died, while the extant 2 achieved stable complete remission. Notably, the only patient whose PE was administered with adequate frequency and for an adequate period of time, and thus the only unquestionably PE resistant patient, was also resistant to PGI2 infusion. Major side-effects were few and observed at the highest doses. CONCLUSIONS: In our experience and from the analysis of the literature, which, as far as we know, includes only 23 patients treated with PGI2-like substances, the role of PGI2 in the treatment of TTP appears to be modest. Maybe the identification of subgroups of TTP patients exhibiting some defects in PGI2 metabolism, together with the use of more manageable PGI2 analogs, such as iloprost, could revive interest in these molecules in the future. PMID- 7843628 TI - Diagnosis of acute myeloid leukemia and system Coulter VCS. AB - BACKGROUND: The aim of this study was to evaluate the possible contribution VCS could make in a hematological laboratory for the diagnosis of acute myeloid leukemia (AML). MATERIALS AND METHODS: Peripheral blood samples from 42 AML patients and 58 normal donors were analyzed by flow cytometry with the VCS. Normal and leukemic peripheral blood samples were tested to establish a correlation between VCS data and the reference manual method. We evaluated the sensitivity threshold of the VCS for blast cell detection in progressively diluted samples. We looked at a correlation between different scatterplots and flags and the FAB classification of acute myeloid leukemia in order to identify a characteristic VCS image for each subtype. Thirty-four bone marrow samples (18 normal donors and 16 leukemic patients) were analyzed by the VCS system to demonstrate a characteristic scattergram distribution. Further, we tried to compare scatterplots to the flags of leukemic bone marrow samples and, finally, we compared VCS scatterplots with aberrant antigen expression in AML cases. RESULTS AND CONCLUSIONS: Overall VCS specificity was 93.1% (54/58) in peripheral blood samples; sensitivity was 100% (42/42) and VCS efficiency was 96%. In AML the characteristic X6 flag was observed in 95.23% of the cases (40/42). In peripheral samples discrimination was made between AML M1 with agranular blasts > 50% of the non erythroid cells (NEC), M4, M5 on the one hand, and AML M1 with granular blasts > 50% of NEC, M2, M3 on the other: the X5 flag was often present in the second group because of the different localization of the cells (p = 0.001). In all normal bone marrow samples we observed granuloblasts in different maturation stages in the neutrophil region of the DF1 VCS scatterplot corresponding to the X5X6 flags or, rarely, to the X5X6X1, because of the presence of immature erythroid cells. This association X5X6 was never observed alone in patients affected by AML. In our study, it was difficult to identify peculiar scatterplots and alarms for each FAB class of AML. Nevertheless, we observed that in all M4 and M5 FAB cases the blastic cells both in the peripheral blood and in the bone marrow samples were located in the monocyte region, with the frequent presence of the X3 flag often associated with the X6 flag. Eight out of the 16 AML bone marrow samples (1 FAB M0, 1 M2, 1 M3, 2 M4, 3 M5) showed the X2 flag and partial localization of blasts in the lymphoid region. In all these cases the presence of some small blastic cells with agranular cytoplasm was confirmed by morphological observation and cytochemical stainings. PMID- 7843630 TI - Guidelines for the treatment of severe aplastic anemia. Working Party on Severe Aplastic Anemia (WPSAA) of the European Group of Bone Marrow Transplantation (EBMT). PMID- 7843631 TI - Soluble transferrin receptor following bone marrow transplantation from donors heterozygous for beta thalassemia. AB - This study analyzes the serum transferrin receptor (sTfR) levels in a series of 184 ex-thalassemic patients with a follow-up of 1 to 9 years after bone marrow transplantation (BMT) for homozygous beta thalassemia. A significant inverse correlation between sTfR and Hb levels was observed (r = -0.36, p < 0.001). Patients who received the marrow from an HLA-identical sibling donor heterozygous for beta thalassemia displayed significantly higher levels of sTfR than patients transplanted from a normal sibling donor (p < 0.001). A cut-off value of 2600 ng/mL of sTfR was established. Only 3 out of 56 (5%) patients who received the marrow from a normal sibling, reached a sTfR value above the cut-off level, while 64 out of 128 (50%) patients transplanted from a heterozygous sibling donor showed sTfR values > 2600 ng/mL (p < 0.001). These results suggest that the level of sTfR helps to identify ex-thalassemic patients with enhanced or normal erythropoietic activity among those transplanted from HLA-identical sibling donors heterozygous for beta thalassemia. The physiologic and clinical significance of different patterns of sTfR levels in ex-thalassemic patients with beta thalassemia trait deserves to be investigated. PMID- 7843632 TI - CD11c expression in B-cell chronic lymphocytic leukemia. A comparison of results obtained with different monoclonal antibodies. AB - In order to obtain more information on the pattern of CD11c-positivity in otherwise typical B-cell chronic lymphocytic leukemia (CLL), we analyzed immunological and clinico-pathological features of 99 such patients studied with two different monoclonal antibodies (MoAbs). Fifty-two out of 70 (74.2%) patients stained with IOM-11C MoAb and 3 out of 29 (10.3%) patients stained with Leu-M5 MoAb had more than 30% CD11c positive cells (P < 0.0002). The two groups were similar with regard to the expression of B-cell CLL-related antigens (CD5, CD20, CD23), as well as clinico-pathological features (i.e. Binet clinical stage and pattern of bone marrow involvement), thus suggesting that differences in CD11c expression were due to different reactivity patterns of the MoAbs utilized. In our experience, the use of different reagents may affect immunophenotyping results, thus providing conflicting data at times. PMID- 7843633 TI - Pure red cell aplasia following peripheral stem cell transplantation: complete response to a short course of high-dose recombinant human erythropoietin. AB - We studied a patient who developed pure red cell aplasia (PRCA) following peripheral stem cell transplantation for non-Hodgkin lymphoma. Serum erythropoietin was appropriate for the degree of anemia. Corticosteroid treatment was ineffective. Four months after transplantation rHuEpo was administered subcutaneously at a dose of 150 U/Kg per day, five days a week for 8 weeks. Treatment induced an erythropoietic response and corrected anemia. Response was maintained following discontinuation of rHuEpo. This study and previous reports indicate that high doses of rHuEpo given over a short time can resolve PRCA following autologous or allogeneic stem cell transplantation. PMID- 7843634 TI - Platelet support of patients with hematological malignancies. AB - The most significant advances in platelet transfusion therapy for oncology hematology patients can be summarized as follows: 1) prophylaxis versus treatment of hemorrhage. Usual practice is based on hemorrhage prophylaxis. Debate is still open on the transfusion trigger, which is traditionally set at 20 x 10(9)/L platelets: some authors suggest it could safely be decreased in stable patients to 10 or 5 x 10(9)/L platelets; 2) preparation of platelet concentrates. Platelets prepared from platelet-rich plasma or buffy-coats obtained from multiple bag donations should be used as the first-choice for all patients, while apheresis platelets, which have a significantly higher cost of production, should be reserved for patients refractory to random donor support. The final choice, however, of a prudent strategy must also consider logistic aspects, such as product availability, distance from site of production to site of use, etc; 3) leukocyte reduction. Filtration is the method of choice to prepare leukocyte reduced platelets. Leukocyte-reduced platelets can be used to prevent transmission of CMV in selected patient groups for whom this is indicated. When leukocyte reduction is used for the prevention of NHFTR, it should be performed with fresh platelets and reserved for patients developing more than 1 reaction. Routine leukocyte reduction for all oncology-hematology patients cannot be recommended at this time, in the absence of definitive information on the cost effectiveness of this approach; 4) quality control. Studies are under way to check whether evaluation of the swirling phenomenon, that is produced by good quality platelets when inspected with the naked eye against a strong light source is a useful and inexpensive test for quality control; 5) correction of refractoriness to random donor platelet support. Effective platelets for refractory patients can be obtained through HLA typing and/or platelet cross matching. Although HLA typing can be very effective, cross-matching seems to be equally effective, simpler and less expensive. PMID- 7843635 TI - Current concepts in coronary thrombolysis. AB - Thrombolytic therapy has become standard care in treating acute myocardial infarction. Fibrinolytic drugs such as streptokinase, APSAC and urokinase are non fibrin specific, and induce systemic activation of the fibrinolytic process, while t-PA and prourokinase are fibrin specific since they are able to activate mainly fibrin bound plasminogen. Both groups of thrombolytics exert different and opposing effects on the hemostatic balance: indeed, they have antithrombotic as well as prothrombotic properties, and this may be important for explaining therapeutic failures or reocclusions. New strategies have been considered or are under investigation for further improving the already excellent efficacy of thrombolytic treatment in myocardial infarction: combined administration of fibrinolytic agents, thrombus-targeted thrombolytic drugs, association with other drugs both effective and ineffective on the hemostatic process. At present, however, the first priority still seems to be a continuing effort to increase the percentage of patients treated with thrombolytics, since the benefits of this therapy have already been clearly demonstrated. PMID- 7843636 TI - Morphological pictures of peripheral blood during a full-blown malaria case. PMID- 7843637 TI - Pathogenesis and classification of von Willebrand disease. AB - Von Willebrand disease, the most common congenital bleeding disorder in humans, is the consequence of quantitative and/or qualitative defects of von Willebrand factor, a protein necessary for platelet adhesion and thrombus formation at sites of vascular injury. Distinct molecular defects of von Willebrand factor are responsible for the heterogeneity of von Willebrand disease subtypes. A classification in four main groups, each characterized by distinctive pathogenetic features, represents the basis for a correct therapeutic approach to bleeding episodes in these patients. PMID- 7843638 TI - Response to 1-deamino-8-D-arginine vasopressin in von Willebrand disease. AB - The synthetic agent, 1-deamino-8-D-arginine vasopressin (DDAVP), is generally regarded to be the treatment of choice for persons with type I von Willebrand disease (vWD), and may be useful in type IIA vWD as well. Several formulations of the drug are available, including a highly concentrated intranasal spray formulation which is ideal for home use. The degree of F VIII and vWF response to DDAVP varies among individuals, but is generally consistent in individual patients over time. Some have tachyphylaxis while others do not. While side effects are uncommon, DDAVP is a potent antidiuretic agent. Thus one should be aware of the possibility of hyponatremia and water intoxication if certain precautions are not observed. PMID- 7843639 TI - Biochemical characteristics of therapeutic plasma concentrates used in the treatment of von Willebrand disease. AB - Therapeutic plasma concentrates containing von Willebrand factor (vWF) lack the largest, most hemostatically active multimers. In order to evaluate whether this abnormality results from proteolysis during manufacturing, we have analyzed the subunit structure of vWF in 21 commercial products and found a marked reduction in the relative content of intact 225 kD subunit, paralleled by an increase in the proteolytic fragments normally present in plasma, particularly that of 176 kD. There was no heightened vWF fragmentation in blood-bank cryoprecipitate prepared from platelet-poor, single-donor plasma; in contrast, there was a marked degree of fragmentation in cryoprecipitate prepared from pooled plasmapheresis plasma representing the starting fraction for the production of commercial concentrates. In cryoprecipitate prepared experimentally from plasma containing varying numbers of platelets, the degradation of vWF was proportional to the platelet count but was greatly diminished by adding protease inhibitors to plasma. On the basis of these findings, we postulate that the loss of the largest vWF multimers in commercial concentrates results from the use of poorly centrifuged plasmapheresis plasma containing an excessive number of residual platelets and leukocytes. PMID- 7843640 TI - Plasma product treatment in various types of von Willebrand's disease. AB - Four different virus-inactivated factor VIII concentrates (Haemate P, Behring; Profilate, Alpha, FVIII-VHP-vWF, CRTS), near-pure von Willebrand factor (Facteur Willebrand, CRTS) or one recombinant FVIII preparation (Recombinate, Baxter) were given to one or more patients with different forms of von Willebrand's disease. Duke bleeding time, VIII:C, vWF:Ag, RC of activity, and the multimeric pattern of plasma vWF were monitored. Both Duke bleeding time and the multimeric pattern were normalized after treatment with Haemate P, FVIII-VHP-vWF, or Facteur Willebrand, and to a lesser extent after Profilate. Except in one case, the reduction in bleeding time lasted longer after Haemate P than after the other concentrates. Recombinate had no effect on primary hemostasis, and the half-life of VIII:C was very short. If prompt hemostasis is required, and when pharmacological correction of the defect is impossible, we recommend a concentrate containing both FVIII and the full complement of vWF multimers, but for prophylactic treatment pure von Willebrand factor may be used. PMID- 7843641 TI - Experience with Haemate P in von Willebrand's disease in adults. AB - The virally inactivated pasteurized FVIII concentrate Haemate P contains nearly intact vWF multimers. It is currently the treatment of choice to achieve satisfactory hemostasis for moderate to severe vWD and for patients with variants of vWD that cannot be adequately treated with DDAVP or for whom DDAVP is contraindicated. Therefore, we treated patients with type Ia, type IIa, type IIb and type III vWD with Haemate P. A correction of the hemostatic defect was seen in all patients. The type of bleeding events included 24 gastrointestinal, 18 other mucosal, 5 central nervous system, 15 orthopedic and 4 other. 28 dental surgical procedures, 9 operative deliveries, 5 tonsillectomies, 17 orthopedic and 11 miscellaneous surgeries were performed under the cover of Haemate P. PMID- 7843642 TI - Haemate P in children with von Willebrand's disease. AB - In our center, 289 children with von Willebrand's disease (vWD) have been diagnosed since 1982. The majority of cases (n = 198) were congenital vWD whereas 91 patients suffered from vWD induced by valproate (VPA). We overview bleeding episodes in 45 children and 64 operative procedures requiring therapeutic intervention. The aim of therapeutic and prophylactic procedures in vWD is correcting the hemostatic disorder and normalization of bleeding time. This can be achieved by application of Haemate P leading to an elevation of plasma levels of von Willebrand parameters together with normalization of bleeding time. In patients with vWD type I, DDAVP will be preferred if contraindications can be excluded and efficacy has been shown. Severe bleeding complications could be prevented in a total of 50 surgical procedures in children with vWD type I by prophylactic treatment with DDAVP or Haemate P. Two children initially treated with DDAVP had to be substituted with Haemate P in the follow-up because of continuous bleeding. In type IIa and type III vWD as well as in VPA-induced vWD, the use of Haemate P was essential for sufficient hemostasis in all bleeding and operations. We conclude that Haemate P provides effective bleeding prophylaxis and treatment in all types of vWD except platelet-type. PMID- 7843643 TI - Safety of plasma derivatives. AB - In clinical treatment practice of substitution therapy involving a plasma component, numerous aspects related to recipient's safety are relevant to the physician. Since viral contaminants may be present in the donor blood, safety begins in the institution collecting raw plasma where donors are inquired about any unusual behavior that may potentially threaten safety. Other measures that could lead to exclusion of a donation are positive serological tests for HIV and hepatitis B and C. In this context, meticulously accurate logistics are mandatory. During the course of manufacture of plasma products, viral inactivation procedures have been adopted based on chemical and physical principles. The distinct effects of these depend on methodology and the types of virus in question. An important safety measure relates to establishing that the label value of content corresponds to the in vivo recovery of the reconstituted plasma derivative and, by inference, the clinical efficacy of the product. In patients deficient in plasma coagulation factors, treatment may trigger the development of functionally inhibiting alloantibodies against the factor needed for substitution which is a significant clinical complication. The reported incidences of such inhibitors have varied greatly. No clear relationship between their frequency and the type of concentrate used have been established. However, recent experience has shown an unexpected increase in inhibitors in a regional subset of previously stable patients when shifted from a dry-heat-inactivated concentrate to a pasteurized version of the same concentrate. Hence, the possible introduction of neoantigens is important. In the early era of concentrate use, side effects to treatment were often observed like alloimmune hemolytic anemia and various degrees of anaphylactoid reactions. With the appearance of concentrates of increased purity that contain less unwarranted proteins, side effects of this kind have been rare. In conclusion, safety of plasma derivatives by today's standards is not a single entity, but a long chain of interdependent issues, each of which needs full attention to protect patients from mild and serious treatment complications. PMID- 7843644 TI - The quick machine--a mathematical model for the extrinsic activation of coagulation. AB - The present paper describes a mathematical model of the kinetics of the extrinsic coagulation cascade in vitro. The coagulation factors FI, FII, FV, FVII, FX, heparin and antithrombin III (ATIII) as well as soluble fibrin polymers are considered. The effect of single-factor deficiencies of the factors II, V, VII and X, diseases like hypo- and dysfibrinogenaemia, hepatic insufficiency, inhibited polymerisation by degradation products, heparin therapy with and without ATIII deficiency and coumarin therapy on prothrombin time can be portrayed. Physiology of coagulation is represented in a dynamic mathematical model as a differential equation system. The model is based on three reaction types: enzymatic cleavage, complex formation and polymerisation. The model was implemented in a continuous simulation program on a personal computer using the Pascal programming language. Unknown rate constants were estimated by chi 2 fit. Prothrombin time calculated by the model was compared to the training set of 20 plasma samples. In most but not all cases the model harmonized quite well with the coagulometric data. PMID- 7843645 TI - Effects of recombinant hirudin on D dimer levels before and after experimental venous thrombosis. AB - In a randomized, blind study, the effect of saline, a low-molecular-weight heparin (Fragmin), and a recombinant hirudin (CGP 39393) on thrombin-antithrombin (TAT) complexes and D dimer (DD) levels were studied in 60 rabbits. The drugs were always injected subcutaneously 2 h before the induction of thrombosis in the jugular vein by a combination of endothelial damage and flow reduction. A sample of blood was obtained just before surgery, and a further sample was obtained 10 min after thrombus formation. No significant differences were found in TAT plasma levels between the different study agents, either before or after thrombus development. However, 2 h after drug administration DD values were significantly lower in hirudin-treated animals (292 +/- 69 vs. 372 +/- 138 ng/ml; p < 0.05). Then, after thrombus formation, DD levels significantly increased in all three groups of animals, as compared to baseline levels. But the increase was significantly higher in hirudin-treated rabbits; DD levels after thrombus development were significantly higher in this group as compared to placebo (779 +/- 188 vs. 664 +/- 152 ng/ml; p < 0.05). There are no previous reports in the literature about the effect of hirudin on DD levels. Our hypothesis is that the effect of hirudin on DD may be the result of its ability to inhibit the thrombin induced thrombus growth. If the thrombus is not allowed to grow then it will lyse more quickly, producing more DD and the process will not be impaired by the constant deposition of fibrin.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843646 TI - D-dimer and thrombin/antithrombin III complex--diagnostic tools in deep venous thrombosis? AB - In order to evaluate the usefulness of determining D-dimer and thrombin antithrombin III complex (TAT) in the diagnosis of deep venous thrombosis (DVT), three D-dimer assays were tried: one ELISA and one latex test from Diagnostica Stago and one new latex method from Biopool. TAT was assessed using an ELISA (Behringwerke). We studied 96 consecutive outpatients with suspected DVT, of whom 36 had phlebographically confirmed DVT. Statistical calculations showed high sensitivity and a negative predictive value for the D-dimer ELISA (97% for both), confirming the results obtained by others. The new latex method (Biopool) showed similar figures (96% for both). The latex method from Diagnostica Stago and TAT showed lower sensitivity and negative predictive values. No differences in the D dimer results were found with or without antifibrinolytics in the tubes for blood sampling. Our data suggest that negative results when using the new simple and cheap latex method (Biopool) may reduce the number of phlebographic examinations. PMID- 7843647 TI - Preventive effect of argatroban on ellagic acid-induced cerebral thromboembolism in rats. AB - The preventive effect of argatroban, a synthetic thrombin inhibitor, on cerebral infarction was evaluated with ellagic acid (EA)-induced cerebral thromboembolism in rats. Platelet-rich thrombi containing fibrin and EA crystal were formed in the microarteries in the affected hemisphere by the injection of EA suspension into the cerebral arteries. The mortality in saline control was over 80% 6 h after the EA injection. Argatroban decreased the mortality to 0% at a dose of 3 mg/kg/h, and significantly reduced the ischemic area in the affected cerebral hemisphere. Heparin also decreased the mortality to 30% at a dose of 600 U/kg/h, but marked bleeding was observed at the incised wound. These findings suggest that argatroban is a more effective and safer anticoagulant than heparin for the prevention of ischemic damage on cerebral thrombosis. PMID- 7843648 TI - The influence of heparin and protamine sulfate on platelet ADP and platelet factor 4 release and the expression of glycoprotein IIb/IIIa. AB - We present results concerning the pathogenic mechanism of heparin-induced thrombocytopenia type I. An ELISA was developed for directly measuring the expression of glycoprotein IIb/IIIa (GPIIb/IIIa) on platelets in the presence and absence of ADP and under the influence of various heparins. In addition, the release of ADP and platelet factor 4 (PF4) was measured in platelet-rich plasma. Heparin also induced the expression of GPIIb/IIIa without prior stimulation with ADP. On the other hand we could demonstrate that the addition of heparins and protamine sulfate to platelets resulted in a significant release of intracellularly stored ADP and PF4. These results suggested that heparin(oid)s modulate the expression of GPIIb/IIIa with ADP as a mediator, and that protamine sulfate is contraindicated as an antidote in heparin-induced thrombocytopenia. PMID- 7843649 TI - Differences in plasminogen activator inhibitor 1 activity between blacks and whites may be diet related. AB - Two matched groups of healthy non-smoking male volunteers between 18 and 23 years old and with a body mass index of 19-24 kg/m2 were selected from urban whites (n = 15) and from rural Vendas (blacks; n = 17). Fasting venous blood samples were collected between 07.00 and 10.00 h, and a validated food frequency questionnaire was administered. The results showed highly significant differences in dietary patterns. Significant differences were observed with regard to serum cholesterol (p < 0.02), percentage high-density lipoprotein cholesterol (p < 0.02), calculated insulin sensitivity index (p < 0.04), and plasma fibrinogen levels (p < 0.03). Tissue plasminogen activator antigen did not differ significantly. The plasminogen activator inhibitor 1 activity was significantly lower (p < 0.0001) in the Vendas than in the whites. It is concluded that diet may be an important determinant of plasminogen activator inhibitor 1 activity. PMID- 7843650 TI - [Thyroid dysfunction and goiter among immigrants from Ethiopia]. AB - 1131 immigrants from Gonder, Ethiopia were surveyed a year after arrival in Israel. The overall prevalence of goiter was 46.1%; the lowest rates (6.7%) were in infants (aged 1-2 years) and the peak prevalence in males was 56.7% (in those aged 12-14 years) and in females, 77.7% (in those aged 35-40). A significant decrease in goiter prevalence was observed after the age of 60 for both men (7.2%) and women (35%). The prevalence of hypothyroidism was 1.1%, 2% in children and 0.2% in adults. That of hyperthyroidism was 1.7%, 0.8% in children and 2.4% in adults. The high prevalence of goiter and hyperthyroidism with low prevalence of hypothyroidism probably resulted from the combined effects of food goitrogens and iodine deficiency in Ethiopia, with the latter playing only a minor role. Neither factor was in effect after arrival in Israel. Genetic and hormonal factors may contribute to the low prevalence of both goiter and hypothyroidism in the adult males. In view of the high prevalence of hyperthyroidism, iodine enrichment is not recommended for Ethiopian immigrants. PMID- 7843651 TI - [AIDS-related dementia]. AB - Dementia is a common process in which there is gradual decrease in mental function due to disease of either cortical or subcortical structures. The numerous causes of dementia can be divided into those in which dementia is the primary manifestation, as in Alzheimer's disease, or secondary to chronic disease, neoplasms, endocrine and metabolic disorders and chronic infections. The dementia in AIDS is usually part of the syndrome of acquired immunodeficiency and may be its first manifestation. PMID- 7843652 TI - [Facial injury by fishing harpoons]. AB - The methods of removing penetrating fish-hooks or harpoons are unique and require understanding of the structures of these instruments and their mechanisms, and methods of neutralization. We describe 2 cases of penetrating spear-gun fishing harpoon to the face and the recommended clinical management. PMID- 7843653 TI - [Congenital urethral strictures]. AB - We present 12 patients with presumed congenital urethral stricture (mean age at diagnosis 20 years). They complained of various urological symptoms, including dysuria, transient urinary retention, urgency and reduced flow. The time from onset of symptoms to diagnosis averaged 18 months. The strictures were presumed congenital because no patient had a history of urethral infection or of instrumentation, and all the strictures were at the proximal bulbar urethra, as has been described for congenital, bulbar, urethral stricture. We treated 5 patients initially by internal urethrotomy, of whom 2 required transurethral dilatation at follow-up. 7 others were treated initially by transurethral dilatation, 4 of whom required more than 1 treatment. Follow-up has averaged 21 months. In 8 of 10 patients the maximal urinary flow at latest follow-up is greater than 20 ml/sec. PMID- 7843654 TI - [Hyperbaric oxygen for hydrogen sulfide poisoning]. AB - Hydrogen sulfide (H2S) is a toxic gas produced in decaying substances containing organic sulfur. Exposure to the gas causes severe disturbances in the central nervous and respiratory systems. The mechanism of toxicity is disruption of the electron transport chain in mitochondria, resulting in intracellular hypoxia. Treatment of H2S poisoning includes mechanical ventilation with 100% oxygen and immediate administration of sodium nitrate. Treatment with hyperbaric oxygen (HBO) has been studied in animal models, and has also been used in a number of patients. However, the clinical effectiveness of this mode of therapy has not been clearly proven. Having recently treated a case of H2S poisoning, we suggest HBO to reduce mortality. PMID- 7843655 TI - [Porokeratosis of the skin in an immunosuppressed patient]. AB - Porokeratosis is a chronic, progressive disease of hereditary origin, characterized by the formation of annular, flat lesions with elevated scaly borders. It appears as a few clinical variants that differ mainly in the mode of spread of the lesions and age of onset. In recent years immunosuppression has been found to initiate appearance of the disease or cause its exacerbation. We present a 39-year-old man who developed porokeratosis a year after commencing immunosuppressive treatment following a heart transplantation. There is a relationship between the immune system, malignant transformation and porokeratosis. PMID- 7843656 TI - [Severe neuropathy in a young diabetic]. AB - A 19-year-old woman with insulin-dependent diabetes mellitus (IDDM) of 3.5 years duration had been suffering from recurrent episodes of diabetic ketoacidosis (DKA), dizziness, and weight loss (16 kg, 29%) for 6 months. History and physical examination gave evidence of severe peripheral and autonomic neuropathy. Radionuclide retention on gastric emptying test at 60 min was greater than 90% (normal < 60%). On autonomic cardiovascular testing there was evidence of both parasympathetic and sympathetic damage. There was no evidence of nephropathy or retinopathy. Optimal diabetic control using 4 insulin injections (2 u/kg/day) and high-dose cisapride terminated the vomiting, and she regained the weight lost within 5 months. This case is unique in that severe diabetic neuropathy followed relatively soon after onset of disease, without other microvascular complications. The correct diagnosis of gastroparesis as the cause of the recurrent DKA and weight loss, and the specific prokinetic therapy and nearly normoglycemic control of the diabetes led to dramatic clinical and functional improvement. Specific prokinetic therapy and the nearly normoglycemic control of the diabetes led to dramatic clinical and functional improvement. Gastroparesis can cause recurrent DKA even in young patients with IDDM of short duration. PMID- 7843657 TI - [Thou shalt not take the name of research in vain]. PMID- 7843658 TI - [Mathematical predictive models for physiological responses under exercise heat stress]. PMID- 7843659 TI - [Treatment of male infertility--light at the end of the tunnel]. PMID- 7843660 TI - [Troponins T and I--new markers for cardiac damage]. PMID- 7843661 TI - [Surgery for peptic ulcer disease--what is the procedure of choice? Part II: Emergency surgery]. PMID- 7843662 TI - [Evaluation of functional status in primary care--use of WONCA/COOP charts]. PMID- 7843663 TI - [Neonatal seizures--new aspects]. PMID- 7843664 TI - [Delusions of parasitosis]. PMID- 7843665 TI - [Nifedipine as a tocolytic drug]. PMID- 7843666 TI - [Consensus: diagnostic criteria for Sjogren's syndrome]. PMID- 7843667 TI - [Microsatellite sequences--from genetic linkage to cancer research]. PMID- 7843668 TI - [Measurement of medical results based on patients preference. An indicator for evaluation of a new therapeutic program]. PMID- 7843669 TI - [Sensitization without manifest allergy. Immune disease is rather the exception]. PMID- 7843670 TI - [Small cell prostatic carcinoma. Presentation of diagnosis, therapy and prognosis based on a case report]. AB - On the basis of a case report, the particular features of the rare small-cell carcinoma of the prostate, which has much in common with, for example, small-cell lung cancer, are discussed. Diagnosis, treatment and course of the disease are presented. The primary therapeutic mode is not surgical removal but cytostatic chemotherapy. The results of large retrospective studies of case material are discussed. PMID- 7843671 TI - [Mechanical lesions of the peripheral nervous system. Possible damage at work and leisure]. AB - For the most part, mechanical injuries to peripheral nerves occurring at work or at play as a result of closed traumatization, are caused by compressive, stretching/shearing or vibrational forces. In a patient in whom various compression lesions of peripheral nerves recur, the possible presence of a predisposing hereditary neuropathy must be considered. Modern magnetic resonance imaging is capable of clarifying the causes and conditions of compression injuries, in particular in the region of the tunnel: presence of osteophytes, other space-consuming processes or anatomical narrowing of the tunnel. Injury sequelae, for example in the case of carpal tunnel syndrome affecting the median nerve, or tendinopathies, can also be visualized. A number of lesions and their triggering mechanisms that occur during work or leisure are described. PMID- 7843672 TI - [Diagnosis and therapy of tumor pain. 4: Adjuvant treatment--neuroablative and neurolytic procedures]. PMID- 7843673 TI - [Respiratory tract infections: how frequent is antibiotic resistance? In vitro activity of older and recent antibiotics against the significant pathogens]. AB - Presumably influenced by the new cost-saving health care regulations, more of the long-established antibiotics are now being prescribed. This fact prompted the present study on the current resistance profiles of such antibiotics used to treat major pathogens responsible for airway infections. A total of 202 strains of Streptococcus pneumoniae, Streptococcus pyogenes, Moraxella catarrhalis and Haemophilus influenzae were investigated. Sensitivity was determined using the agar dilution test for doxycycline, erythromycin, penicillin G, amoxicillin clavulanic acid and cefpodoxime. In the case of such older antibiotics as doxycycline, erythromycin and amoxicillin, certain shortcomings in their efficacy against these common pathogens were found, while the bacteria were all sensitive to a combination of amoxicillin and clavulanic acid and to the oral cephalosporin, cefodoxime. In order to avoid the risk of ineffectivity in the treatment of infection of the airways, it is recommended that in Germany a new oral cephalosporin or a combination of an aminopenicillin and a beta-lactamase inhibitor be used. PMID- 7843674 TI - [Asthenozoospermia--a multifactorial symptom]. AB - For the clarification of sperm motility disorders, changes in the flagella must be differentiated from influences exerted by the seminal fluid and extrinsic factors. The disorders of the flagella may be testicular or epididymal in origin. Only by taking account of these aspects of etiology and pathogenesis, will a rational therapeutic approach be possible. PMID- 7843675 TI - [Epididymal maturation of human spermatozoa]. AB - The role of the human epididymis in spermatozoa maturation is demonstrated by means of several sperm function tests, with the aid of which, the various stages in the fertilization process can be mimicked. Accordingly, as they pass through the epididymis, spermatozoa become progressively more motile--which can be enhanced by the addition of phosphatidylcholine--inducibility of the acrosome reaction increases, and chromatin condensation is completed. Capability of fusing with the ovum is observed for spermatozoa from the epididymis, but not for those from the caput epididymis, while the spermatozoa from the latter already have normal acrosine activity. Ability to bind to the zona pellucida has not been adequately clarified. These results demonstrate the significance of the human epididymis for sperm maturation, even though a small percentage seem to reach adequate maturity in the caput epididymis. PMID- 7843677 TI - [Differential hepatitis A, B, C, D and E diagnosis. Clinical, biochemical and viral serologic criteria. 1: Stepwise diagnosis--status of clinical findings]. PMID- 7843676 TI - [Andrology--historical retrospect and future development]. AB - Andrology is an interdisciplinary medical speciality that deals mainly with disturbances of potentia generandi and coeundi in the male. In German-speaking countries it developed from dermatology/venerology, but in its modern form has also been influenced by urology, gynecology and endocrinology. This has resulted in the establishment of centers of reproductive medicine at various universities. The historical development of andrology in the hospital and in private practice is analysed, and future areas of focus in diagnosis and therapy are discussed. PMID- 7843678 TI - [Is differentiation of ACE inhibitors based on their effects on the brain possible?]. PMID- 7843679 TI - [Legal problems in ambulatory surgery. How legal difficulties can be avoided]. PMID- 7843680 TI - [Pioneers with "many enemies, much honor". Medicine in Frankfurt am Main--the tradition extends far beyond the 80th faculty anniversary]. PMID- 7843681 TI - [Increased autoaggression caused by cholesterol lowering drugs?]. PMID- 7843682 TI - [Treatment of hypertension--the value of non-drug measures]. AB - METHOD: To investigate the usefulness of non-pharmacological measures in the treatment of essential hypertension, 91 subjects comprising patients attending a physical-medical department and the inhabitants of an old people's home, were asked to complete a questionnaire. RESULTS: Almost all patients were receiving drug therapy (n = 89); in two-thirds treatment had been initiated when the diagnosis was first established. Although two-thirds were well informed about non pharmacological measures (physical exercise, sodium restricted diet, reduced caloric intake, changes in dietary habits), more than one-half of the patients had neither been informed about, nor instructed in the use of, any of these alternatives by their general practitioners. Some 40% were aware of the benefit of relaxation techniques, but only one in six practiced them. CONCLUSIONS: Although this study revealed a high level of knowledge of non-pharmacological anti-hypertensive therapy, the care-providing doctors clearly attach more importance to prescribing drugs. In view of the potential value of alternative forms of treatment, greater consideration of this point by the physician would be desirable. PMID- 7843683 TI - [MALT lymphoma, stomach carcinoma--role of Helicobacter pylori. Are chances for prevention on the horizon?]. AB - The pathogenesis of gastric carcinoma developing after infection with Helicobacter pylori now seems to be clear. The release of urease, alcohol dehydrogenase, enzymes and cytotoxin on the one hand, and chemotactic factors, PAF and heat-shock proteins on the other trigger chronic inflammation and epithelial metaplasia and dysplasia in the stomach. Under the influence of additional carcinogens, the epithelial changes progress to severe dysplasia and finally carcinoma. As a result of chronic inflammation, MALT lymphomas can also be induced. These can be made to regress by eradicating Hp. The possibility of being able to prevent up to 80% of the carcinomas of the stomach by eradicating Hp holds out good prospects, over the long-term, for the prevention of these tumors. Accurate identification of the patient groups carrying a high risk is now necessary. PMID- 7843684 TI - [Development of a vaccine against solid tumors. Reinjection of genetically modified, IL 2 and interferon producing tumor cells]. PMID- 7843685 TI - [Differential diagnosis of hepatitis A, B, C, D and E. Clinical, biochemical and viral serologic criteria. 2: Biochemical pathology--serology--hepatitis A]. PMID- 7843686 TI - [Early diagnosis of diabetes mellitus with the anti-GAD test]. PMID- 7843687 TI - [Prehospital thrombolytic therapy of acute myocardial infarct]. AB - The extent of myocardial damage occurring during acute myocardial infarction is time dependent, and there is abundant evidence from most clinical trials that mortality reduction is greatest in patients treated early with thrombolytic agents, although beneficial effects have been shown with treatment initiated up to 12 hours after onset of symptoms. This temporal dependence of benefit was most clearly seen with the 47% mortality reduction obtained with streptokinase given within the first hour in the GISSI-1 trial (Table 1). The process of infarction may be completely aborted if reperfusion is initiated within 30 minutes after symptom onset. Current approaches designed to reduce the time delay between onset of symptoms and the initiation of thrombolytic treatment include increasing public awareness of the need to seek prompt medical attention in the event of chest pain, reducing in-hospital delays in initiation of thrombolytic therapy, and administration of thrombolytic agents in the prehospital setting. Since the first paper on prehospital thrombolysis by Koren et al. in 1985 there have been numerous studies published, including several randomized trials comparing prehospital and in-hospital initiation of thrombolytic therapy (Table 2). In randomized studies patients received in the pre-hospital phase either a bolus or infusion with the thrombolytic agent followed by placebo after hospital admission, or placebo when first seen outside the hospital, followed by the thrombolytic agent after arrival at the hospital. This was performed in a double blind fashion in some of the trials. Some of the studies on prehospital thrombolysis have focused only on feasibility and safety, others on time gain, differences in ejection fraction and mortality benefit. Almost all have conclusively shown the practicability and safety of patient selection and administration of the thrombolytic agent. This positive result was observed in different organizational types of the emergency system: In the Myocardial Infarction Triage and Intervention trial (MITI) patients with chest pain were screened by paramedics using a checklist of clinical inclusion and exclusion criteria. The paramedics then obtained a computer-interpreted ECG which was transmitted to the emergency department in the hospital where a physician made the decision on the form of treatment. The thrombolytic agent was then administered by the paramedic. In the European Myocardial Infarction Project (EMIP) an emergency physician was personally present and responsible in the prehospital setting, whereas in the Grampian Region Early Anistreplase Trial (GREAT) general practitioners made the decision for enrolling the patient. PMID- 7843688 TI - [Development of new thrombolytic substances]. AB - Early treatment with thrombolytic drugs has been shown to reduce mortality in patients with acute myocardial infarction. Thrombolytic therapy with early, complete and sustained patency of the infarct related artery is associated with a low inhospital mortality of 3 to 4% (Figure 1). Even with the most effective thrombolytic regimens this aim at present is achieved in only about 50% of the patients. The optimal thrombolytic drug should be effective (rapid, complete and sustained recanalization of the infarct related artery), safe (low incidence of severe bleedings), easy to administer (e.g. bolus application) and cost effective. Attempts to improve thrombolytic treatment include the search for better fibrinolytic agents and more effective adjunctive therapies. In the field of adjunctive therapy new more specific thrombininhibitors appear promising and are currently under investigation. In dose-finding studies recombinant hirudin reduced reocclusions and reinfarctions after t-PA thrombolysis. There are several approaches for the improvement of plasminogen activation (Table 1). While new improved dose regimens (e.g. "front-loaded" t-PA) and combination therapies are not subject of this article, it will deal with the recombinant production of naturally occurring plasminogen activators and the development of "designer drugs", which were created in the laboratory by altering the natural occurring molecules t-PA and scu-PA. t-PA contains four domains with different functional properties (Figure 3). Of a variety of mutants and variants of t-PA with altered fibrin-affinity half-life or fibrin specificity one recombinant plasminogen activator (r-PA) is under clinical investigation. r-PA, a deletion mutant of t-PA consisting of the kringle-2 and protease domains, in a dose escalation study (GRECO) showed high early patency rates (Table 2), while there was a trend to a higher incidence of very early reocclusions. In a randomised trial (RAPID), comparing three different r-PA regimens with standard t-PA (100 mg/3 h) a double bolus of 10 MU+ 10 MU r-PA was most effective with regard to early patency (Table 3). Chimeric plasminogen activators (Figure 4) consisting of parts of t-PA and the single-chain urokinase-type plasminogen activator (scu-PA) did not significantly improve at the same time fibrin specificity and thrombolytic potency of the natural occurring molecules. Complexes of plasminogen activators and monoclonal antibodies against platelets or fibrin improve the specificity and thrombolytic activity of the plasminogen activators (Figure 5). However, these molecules are potentially antigenic, costly and not in clinical use yet. Recombinant production of naturally occurring plasminogen activators seems at least as promising as the production of the above mentioned socalled designer drugs.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7843689 TI - [Pro-urokinase for infarct therapy]. AB - The development of new thrombolytic agents is concentrating on substances which are more effective and more fibrin specific than streptokinase. Prourokinase is a single chain urokinase-type plasminogen activator (scu-PA). The recombinant unglycosylated prourokinase (saruplase) is synthesized in transformed E coli bacteria. The dominant half life is 9 minutes. With the standard dosage regimen about 28% of saruplase is converted into two chain urokinase-type plasminogen activator (tcu-PA), which is rapidly inactivated by plasma inhibitors whereas saruplase is not. Saruplase is fibrin-specific since it predominantly activates plasminogen bound to fibrin. Even without measurable conversion to tcu-PA, saruplase appears able to activate fibrin. The fibrin specific action is dose dependent and correlates inversely with the rate of saruplase converted to tcu PA. Dose finding studies have shown that a 20 mg bolus followed by 60 mg given intravenously over 60 minutes is an effective thrombolytic regimen. In the PASS study 1,698 patients were treated with saruplase. The results of the PASS-study (Table 1) confirmed the efficacy and safety of the 20/60 mg dosage. This standard dosage has been compared with streptokinase, urokinase and alteplase in randomized multicenter-studies. The systemic fibrinolytic activity is less in comparison to streptokinase but higher than the systemic fibrinolytic activity of alteplase. In the PRIM1-study the early patency (60: minutes) was significantly higher with saruplase in comparison to streptokinase (Figure 1). Patency after 90 minutes and 24 to 36 hours did not differ significantly between both substances. Bleeding complications were less frequent with saruplase. Urokinase was compared with saruplase in the SUTA-MI-study. The patency rates (TIMI-flow 2 and 3) at 24 to 72 hours were similar in both groups (saruplase 75.4%, urokinase 74.2%). Hospital mortality was higher in the urokinase group (8.1% vs 4.4%), but this difference was not significant. The efficacy and safety of saruplase (80 mg, 1 hour) was compared with alteplase (100 mg, 3 hours) in the SESAM-study. There was a non significant trend towards earlier patency with saruplase at 45 min (Figure 2). Complication rates and hospital mortality were similar in both groups. The importance of heparin comedication was investigated in the LIMITS-study.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7843690 TI - [t-PA in thrombolytic therapy of acute myocardial infarct]. AB - In the past decade, thrombolytic therapy has become standard treatment of acute myocardial infarction. When the importance of thrombosis in the pathogenesis of acute infarction was fully recognised, several plasminogen activators were developed, streptokinase, urokinase, recombinant tissue-type plasminogen activator (t-PA, alteplase), anistreplase and saruplase (prourokinase). Thrombolytic agents are plasminogen activators which possess as a common characteristic the ability to activate plasminogen to plasmin, and result in fibrinolysis and varying degrees of depletion of circulating fibrinogen, factor V and factor VIII. A lot of animal experiments provided the basis for the rationale that recanalisation and reperfusion early in the course of myocardial infarction would limit myocardial necrosis, improve left ventricular function, and improve patient outcome. Native tissue plasminogen activator is normally secreted by vascular endothelium and the most important property of the drug is its relative fibrin specificity. Fibrin strikingly increases the rate of conversion of plasminogen to plasmin by t-PA. The isolation of the complementary DNA coding for t-PA, its insertion into the genome of Chinese hamster ovary cells, and its expression in suspension cultures of these cells have facilitated the large-scale production of t-PA, making it available as a drug for the treatment of acute myocardial infarction. A variety of dosage schemes have been used for alteplase, the standard schedule has been 100 mg given over 3 hours. Higher doses and faster administration (accelerated, front-loaded) are associated with higher patency rates. Alteplase has generally but not always been shown to have higher reocclusion rates than the non-fibrin-specific plasminogen activators. Reocclusion has been shown to be associated with adverse clinical outcome. Therefore, the rate of reocclusion is considered an important measure in evaluating thrombolytic regimens. The combination of alteplase with either urokinase or streptokinase has resulted in early patency rates comparable to alteplase alone, and low rates of reocclusion. Large, randomised clinical trials have demonstrated that thrombolytic therapy reduces mortality significantly in patients with ST elevation treated within the first 6 to 12 hours of acute myocardial infarction. As compared to an overall reduction of mortality with thrombolytic treatment, neither the GISSI-2/international trial nor the Third International Study of Infarct Survival (ISIS-3) trial of more than 60,000 patients found a difference in associated mortality between the use of streptokinase and the use of t-PA, or between the use of these agents and that of anistreplase. The addition of subcutaneous heparin to the regimens did not significantly reduce mortality as compared with no use of heparin.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7843691 TI - [Significance of coronary perfusion for therapeutic success in myocardial infarct]. AB - Survival in acute myocardial infarction is dependent on several parameters. Some of them act by limiting the infarct size, others improve the prognosis independent of the final infarct size. Determinants of infarct size are time of vessel occlusion, degree of collaterals and area at risk. The latter two determinants do not offer a therapeutic approach in acute myocardial infarction. The most important therapeutic intervention remains the restoration of blood flow in the area at risk by either thrombolysis or PTCA. Reperfusion within 60 to 120 minutes significantly reduces mortality and infarct size. Within this time frame, changes in left ventricular function correlate with the survival rate. If reperfusion occurs later, the correlation between changes in left ventricular function and survival is poor or absent in some studies, despite a persistent survival benefit. After 4 bis 6 hours reperfusion is no longer able to limit infarct size significantly. However, this time frame is variable since there are wide variations in the degree of collaterals. With increasing occlusion time of the infarct related coronary artery, mechanisms independent of the limitation of infarct size will determine the prognosis. Late reperfusion has a beneficial effect on survival and on left ventricular function in certain cases. Left ventricular re-modeling and the incidence of severe ventricular arrhythmias can be reduced by delayed reperfusion. Reactivation of hibernating myocardium following reperfusion therapy may improve global left ventricular function. We analysed the importance of the infarct artery perfusion grade (TIMI flow) in 156 consecutive patients treated with infarct-PTCA. The most frequent indications for infarct-PTCA were failed thrombolysis and cardiogenic shock (Table 1).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843692 TI - [Therapy of cardiogenic shock in acute myocardial infarct]. AB - Cardiogenic shock in acute myocardial infarction patients is the most common cause of in-hospital death. Various studies showed, that 60 to 100% of patients in cardiogenic shock will die, if no early reperfusion of their coronary artery could be established. The incidence of cardiogenic shock has decreased during the last years, most likely due to early thrombolytic therapy and administration of nitroglycerin. Reasons for cardiogenic shock are either necrosis of 40% or more of the left ventricular wall, right heart infarction, or complications which can be treated by the surgeon, like papillary muscle rupture, ventricular septal defect or rupture of the free ventricular wall. Diagnosis is based on clinical criteria, echocardiography, and on hemodynamic monitoring. The hemodynamic criteria for cardiogenic shock are a cardiac index of < 2.2/l, and an increased wedge pressure of > 18 mm Hg; additionally, diuresis is usually < 20 ml/h. Therapy can be divided into the following categories: a) pharmaceutical interventions to increase cardiac output like vasodilators or positive inotrope drugs; b) mechanical support systems; c) acute interventions with the aim of reperfusion; d) acute surgical interventions addressing complications like papillary muscle rupture, ventricular septal defect or rupture of the free ventricular wall. While steps a) and b) are able to stabilize the hemodynamical situation in patients with cardiogenic shock, they are rarely the definitive treatment. Point c), reperfusion of the coronary artery, can be divided in thrombolysis or acute PTCA. Thrombolysis failed to show a beneficial effect in most studies, either after intravenous or intracoronary application. On contrast, acute PTCA showed to be of great benefit in various studies with a technical success rate of 54 to 100% and a survival rate of patients from 58 to 100%. Thus, emergency PTCA is the treatment of choice in cardiogenic shock. Point d), surgical interventions can be divided in acute bypass grafting, which should be reserved for patients with severe multivessel disease, left main involvement, or failed PTCA. Furthermore, acute heart transplantation is effective, but will be possible in a minority of patients only. The last part of surgically manageable complications are surgery of papillary muscle rupture and ventricular septal defect. Results of early surgery in papillary muscle rupture or ventricular septal defects are much better than delayed interventions. Rupture of the free wall is usually a fatal event. In summary, the most successful therapy of cardiogenic shock is early emergency PTCA.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7843693 TI - A unique insertion in the S gene of surface antigen--negative hepatitis B virus Chinese carriers. AB - The presence of unique hepatitis B virus (HBV) variants has been investigated in two Chinese patients with chronic liver disease, whose sera were positive for HBV DNA by dot blot hybridization or polymerase chain reaction (PCR) but hepatitis B surface antigen (HBsAg)-negative by conventional polyclonal antibody based immunoassays. PCR amplification of HBV-DNA followed by direct sequencing showed an insertion of six nucleotides, which introduced two additional amino acids between codons 122 and 123 in one patient (Isolate 1), whereas a nine nucleotide insertion in the other patient (Isolate 2) gave rise to three amino-acids between codons 123 and 124 immediately upstream from the 'a' determinant in the S gene. These insertions have not been described previously in any published sequences of the known subtypes and were absent from sequences of 30 HBsAg-positive Chinese patients from the same region. In the cases under study, the insertion is associated with four consecutive adenine molecules from nucleotides 516 to 519. It seems likely that this area is a hot spot for insertions in HBV. We found none of the previously described amino-acid deletions or substitutions in the pre-S1, pre-S2 and S genes, which are involved in unusual antigenic profiles. This finding suggests that genetic mutations in the S gene outside the 'a' determinant may be responsible for failure to detect HBsAg in some Chinese patients with chronic hepatitis caused by HBV infection. PMID- 7843694 TI - Porphyria cutanea tarda and hepatitis C and B viruses infection: a retrospective study. AB - Based on the knowledge that patients with porphyria cutanea tarda (PCT) usually have chronic liver disease, several authors studied a possible relationship to hepatotropic virus infections. However, the prevalence of hepatitis B virus (HBV) DNA by polymerase chain reaction (PCR) in serum of these patients, as well as the presence of hepatitis C virus (HCV)-RNA in paired liver, peripheral blood mononuclear cells (PBMCs), and serum samples in these patients has not been reported. We have studied 34 patients with sporadic PCT. Antibodies against HBV were detected in 91% of the patients, but in only 41% of the patients against HBV (P < .01). Viral genomes of HCV and HBV were detected in 65% and 40% of our patients, respectively (P < .05). Genomic and antigenomic HCV strands were found in liver biopsy specimens (100% and 54%), mononuclear cells (100% and 54%), and serum (45% and 0%) from 11 patients. Twelve patients were retrospectively studied, and no correlation was observed between the appearance or disappearance of viral genomes and the simultaneous presence of both genomes with the course of porphyria. In our patients with PCT, detection of viral genomes did not correlate with phlebotomy or length of time since PCT was diagnosed. Our findings demonstrate that HCV infection may be underestimated when detection is performed only in serum of PCT patients, and that HBV infection might also be increased in PCT. PMID- 7843695 TI - Differential distribution of hepatitis C virus genotypes in patients with and without liver function abnormalities. AB - Hepatitis C virus (HCV) infection persists for an indefinite length of time in a major proportion of patients, inducing chronic liver lesions that evolve to cirrhosis and hepatocellular carcinoma (HCC) in approximately 20% of cases. We studied HCV viremia and genotypes by reverse transcription-polymerase chain reaction (RT-PCR) in 341 consecutive anti-HCV-positive patients. Of these, 167 patients had persistently normal or near normal alanine aminotransferase (ALT) levels (fluctuations < or = 5 IU above the upper limit of normal); the remaining 174 patients presented with elevated ALT and histological evidence of chronic liver disease. Seventy percent of patients with normal ALT values had circulating HCV RNA despite the absence of biochemical indicators of liver damage and mild histological forms of chronic hepatitis were detected in most patients who underwent liver biopsy. Isolated genotype III infection was significantly more prevalent in this patient group with respect to control patients with abnormal ALT values (70% vs. 39%; P < .001). Conversely, isolated genotype II was more frequently found in patients with elevated ALT values and evidence of chronic liver disease (45% vs. 23%; P < .01) and it was progressively more represented in advanced liver disease, such as cirrhosis and HCC. Virological features of HCV infection might be associated with different clinical manifestations, suggesting a potential prognostic significance on disease outcome. PMID- 7843696 TI - Ability of prolonged interferon treatment to suppress relapse after cessation of therapy in patients with chronic hepatitis C: a multicenter randomized controlled trial. AB - The aim of this study was to determine whether 12 months course of interferon alfa (IFN-alpha) therapy could improve the beneficial effect of IFN in chronic hepatitis C. Eighty-eight patients were treated with natural IFN-alpha for either 28 weeks (45 cases) or 52 weeks (43 cases). Sustained response was achieved in 15 (33.3%) of 45 cases treated for 28 weeks and in 23 (53.5%) of 43 cases treated for 52 weeks. Transient response with relapse of alanine transaminase (ALT) after completion of therapy was observed in 13 cases (28.9%) treated for 28 weeks and in 4 cases (9.3%) treated for 52 weeks. Thus, ALT relapse was suppressed by prolonged IFN treatment. No response was found in 17 cases (37.8%) treated for 28 weeks and in 16 cases (37.2%) treated for 52 weeks, indicating that approximately 38% of the patients with chronic hepatitis C were resistant to IFN therapy even with prolonged treatment. The rate of sustained response was significantly higher in patients with type 2a or 2b than in those with type 1b. Even in type 1b cases, it was higher in the 52-week treatment group than in the 28-week treatment group, and the rate of transient response was lower in the 52-week treatment group, indicating that relapse in type 1b cases was suppressed by prolonged IFN therapy. IFN therapy was not effective for patients with advanced liver fibrosis.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843697 TI - Quantitative analysis of transforming growth factor beta 1 messenger RNA in the liver of patients with chronic hepatitis C: absence of correlation between high levels and severity of disease. AB - Transforming growth factor beta 1 (TGF beta 1) is a cytokine involved in liver fibrogenesis. Previous semiquantitative studies of patients with chronic viral hepatitis showed that liver TGF beta 1 messenger RNA (mRNA) was increased, compared with normal controls and with patients with chronic hepatitis C virus (HCV) infection who responded favorably to interferon alfa (IFN alpha) treatment. To evaluate its potential prognostic significance, we measured liver TGF beta 1 mRNA, using a new competitive reverse gene amplification assay, in a total of 35 patients with chronic HCV. This technique was reproducible and sensitive; we could measure as few as 5,000 molecules of TGF beta 1 mRNA per microgram of total liver RNA. In patients with chronic HCV, the mean level of TGF beta 1 mRNA was 200-fold higher than in controls. However, no correlation could be found between TGF beta 1 mRNA and either the biological (serum amino-terminal peptide of type III procollagen) and histological (Knodell scores) indices of liver fibrosis or a favorable response to IFN alpha therapy. In 9 patients, second liver specimens were obtained after treatment; in most cases, TGF beta 1 mRNA levels and hepatic histological findings varied in parallel. These data are consistent with the hypothesis that TGF beta 1 plays a role in stimulating liver fibrogenesis during chronic HCV, despite the lack of prognostic value of TGF beta 1 mRNA levels measured before treatment.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843698 TI - Localization of hepatitis C virus antigens in liver and skin tissues of chronic hepatitis C virus-infected patients with mixed cryoglobulinemia. AB - Skin and/or liver biopsy specimens were obtained from the following patients: 15 anti-hepatitis C virus (HCV), HCV RNA-positive patients and 3 anti-HCV, HCV RNA negative patients with type II mixed cryoglobulinemia (MC); 7 anti-HCV, HCV RNA positive patients with chronic active liver disease (CALD); 5 anti-HCV, HCV RNA negative patients with noncryoglobulinemic vasculitis; and 7 anti-HCV, HCV RNA negative patients with lichen ruber planus. A pool of murine monoclonal antibodies (MAbs) developed against c22-3, c33c, and c100-3 proteins was used to detect HCV-related antigens (Ags) by indirect immunohistochemistry. Acid electroelution (AEE) of tissue sections was performed to enhance the sensitivity of the immunohistochemical method. In anti-HCV-positive MC patients, specific HCV related Ags were detected in the small vessels of the skin and in the cytoplasm of hepatocytes. Prior AEE of biopsy sections allowed detection of HCV Ags in 6 of 15 (40%) skin biopsy and in 9 of 14 (64.3%) liver biopsy specimens. HCV immunoreactive deposits in the skin displayed two immunohistochemical patterns: (1) coarse intraluminal material associated with dermal inflammatory infiltrates and intravascular deposition of eosinophilic hyaline material; and (2) reactivity confined to the vessel wall in the context of an apparently normal tissue. Immunoglobulin (Ig) G and IgM deposition in the skin showed immunohistochemical features comparable with those found for HCV Ag deposits.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843699 TI - Selective accumulation of the X transcript of hepatitis B virus in patients negative for hepatitis B surface antigen with hepatocellular carcinoma. AB - In HBsAg-negative patients with hepatocellular carcinoma (HCC), hepatitis B virus (HBV) genomes are present at a low copy number per cell, and the role of HBV in liver transformation is still unclear. We have mapped by polymerase chain reaction (PCR) the HBV genome in 19 HBsAg-negative tumorous and 9 corresponding nontumorous tissues and evaluated, by RT-PCR, the presence of HBV S, X, and C transcripts in the tumorous and nontumorous tissue of nine HBsAg-negative and, for comparison, six HBsAg-positive patients. Disrupted, presumably integrated, HBV genomes were detected by PCR in 10 of 19 tumorous tissues and in only one of nine nontumorous tissues. Significant accumulation of viral RNAs containing X but not C or S sequences was shown in 7/9 tumors and 7/8 nontumorous tissues from HBsAg-negative patients. In contrast, viral RNAs revealed by X-as well as by S- and C-specific primers were detected in five of six tumors and in six of six nontumorous tissues from HBsAg-positive patients. In conclusion, our results suggest the frequent integration of the HBV genome and the accumulation of X related RNAs in HCCs developing in HBsAg-negative patients. This finding is consistent with a role, in these cases, for the potentially transforming X protein. PMID- 7843700 TI - Interferon and ursodeoxycholic acid combined therapy in the treatment of chronic viral C hepatitis: results from a controlled randomized trial in 80 patients. AB - Because 70% to 75% of patients with chronic hepatitis C either do not respond to or relapse after interferon (IFN) therapy, and because ursodeoxycholic acid (UDCA) has been shown to reduce aminotransferase levels in patients with chronic hepatitis, we undertook a prospective controlled randomized trial of IFN (group I) versus IFN plus UDCA (group II) in 80 patients with chronic hepatitis C. IFN was administered in both groups for 6 months (3 to 5 million units [MU] three times a week), and in group II UDCA (10 mg/kg/d) was administered with IFN and then alone for 3 additional months. Response to therapy was defined as the normalization of alanine transaminase (ALT) levels. The results showed that 6 months after cessation of IFN, 59% of responders had relapsed in group I but only 27% had relapsed in group II (P = .03). There was no difference between the two groups for the initial (month 6) and the late (months 15 and 18) response rates to IFN. There was no virological effect or significant histological improvement attributable to the addition of UDCA to IFN treatment. In conclusion, the results of this study show that the addition of UDCA to IFN therapy significantly prolongs the period for which serum ALT remain, within the normal range after discontinuation of IFN. Further studies would be required to determine whether UDCA has any potential for long-term amelioration of the histological severity of liver disease caused by hepatitis C virus (HCV) infection, and, therefore, whether it could be advocated as an adjunct to antiviral therapy. PMID- 7843701 TI - Human immunodeficiency virus infection as risk factor for mother-to-child hepatitis C virus transmission; persistence of anti-hepatitis C virus in children is associated with the mother's anti-hepatitis C virus immunoblotting pattern. AB - To determine the rate of vertical transmission of hepatitis C virus (HCV), we prospectively studied 45 babies born to anti-HCV-positive women with or without concomitant infection with the human immunodeficiency virus (HIV). We performed a second-generation recombinant immunoblotting assay, alanine transaminase (ALT) evaluation, and HCV-RNA testing on sera from 27 infants of HCV+, HIV- mothers and 18 babies of HCV+, HIV+ women, at birth and thereafter. After birth, HCV antibodies progressively disappeared within 12 months in all children but one, whose mother was HCV+, HIV+; this child was the only one who showed detectable levels of HCV-RNA and abnormal ALT values throughout the follow-up (range, 12 to 27 months). Viremia was persistently negative, and ALT levels were continuously normal in the remaining infants, showing that "seronegative" infection with HCV was absent in both groups. Clearance of passively acquired anti-HCV antibodies was found to be slower among babies born to HIV+ mothers (22.3% vs. 3.8% at 12 months, P = .03) and children whose mothers showed three or four anti-HCV reactivities by immunoblotting maintained anti-HCV for longer periods compared with babies born to mothers with one or two anti-HCV reactivities (P = .0001). Seventeen of 27 babies born to HCV+, HIV- mothers were breast-fed, and none of them was infected, confirming the apparent safety for HCV of breast milk. In summary, according to our study, vertical transmission of HCV is an infrequent event, and the presence of HIV in the mother is not an important co-factor for transmission of HCV infection. PMID- 7843702 TI - Long-term clinical and virological outcome after liver transplantation for cirrhosis caused by chronic delta hepatitis. AB - Liver transplantation for liver diseases related to hepatitis B virus (HBV) and hepatitis delta virus (HDV) remains problematic because of the risk of viral recurrence. We report here the long-term virological outcome of patients transplanted for HDV-related liver cirrhosis (HDV cirrhosis). From December 1984 to December 1990, 76 patients with HDV cirrhosis underwent liver transplantation. Before transplantation, all the patients were HBsAg-positive/anti-HDV positive, and all but one were HBV DNA-negative by dot blot hybridization. HDV RNA was detected by HDV RT-PCR and liver HDAg by fluorescent HDV Ab. After transplantation, all the patients except four received continuous long-term anti HBs passive immunoprophylaxis. The actuarial 5-year survival was 88%. All patients who did not receive anti-HBs immunoprophylaxis remained HBsAg-positive and developed hepatitis. Among the 68 patients receiving antiHBs immunoprophylaxis with a minimum follow-up of 2 months, HBsAg reappeared in 7 (10.3%) after a mean of 17 months. These seven patients developed hepatitis, with simultaneous HBV and HDV replication; and four cleared later HBsAg. Patients without HBV reinfection were studied for HDV reinfection: liver HD Ag or serum HDV RNA were present in 88% of the patients during the first year, without developing hepatitis; however, they were no longer detectable after 2 years in 95% of the patients. In conclusion, liver transplantation for HDV cirrhosis gives good results, with a 5-year actuarial survival of 88%.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843703 TI - Spontaneous bacterial peritonitis in cirrhotic patients treated using paracentesis or diuretics: results of a randomized study. AB - Diuretic treatment in cirrhotic patients with ascites increases ascitic fluid concentration of total protein and complement components, and opsonic activity. These changes are not observed in patients treated with paracentesis. Based on these data it has been suggested that therapeutic paracentesis may be associated with an increased risk of spontaneous bacterial peritonitis (SBP) development. To assess this possibility, 80 cirrhotic patients with tense ascites were randomly allocated in two therapeutic groups: group 1 (40 patients) was treated with total paracentesis associated with plasma volume expansion and group 2 was treated with diuretics. After mobilization of ascites, patients from both groups received diuretics to avoid reaccumulation of ascites; cases that developed tense ascites during follow-up (mean follow-up period, 60 +/- 6 and 55 +/- 4 weeks, respectively) were treated according to initial randomization. Patients from both groups had similar results regarding baseline clinical and standard laboratory data, ascitic fluid concentration of total protein, complement components, and opsonic activity. Sixteen patients (7 from group 1 and 9 from group 2) developed SBP during the study period. The 4-week and 1-year probability of SBP occurrence were 2.5% and 18.6%, respectively, in group 1 patients, and 11.9% and 24%, respectively, in group 2 patients. Therefore, our study indicates that therapeutic paracentesis does not increase the early- and long-term risk of SBP development in cirrhotic patients with tense ascites. PMID- 7843704 TI - Histopathological heterogeneity in fulminant hepatic failure. AB - The clinicopathological features of 38 patients admitted consecutively for fulminant hepatic failure were studied. Histopathological material was reviewed in all patients. Both percutaneous and whole livers (either explanted or autopsy specimens) were available in 16 patients: whole livers only in 12 patients and biopsy specimens only in 10 patients. All patients were negative for antibodies to hepatitis C, whereas 24% had hepatitis B infection and 10% had adverse drug reactions. Livers from 75% of patients showed confluent hepatic necrosis. However, there was considerable variability in the extent of necrosis, and biopsy specimens from about 50% of the most severely affected livers showed only minimal bridging necrosis. In patients with massive hepatic necrosis, percutaneous liver biopsy specimens were frequently misleading because of regional inhomogeneities. Interestingly, five patients (13%) had established cirrhosis at the time of diagnosis. The best clinical predictors of survival were age and the maximal grade of encephalopathy. By contrast, neither the severity of confluent hepatic necrosis nor the etiology predicted the decision to transplant or the outcome. There were no differences in the histopathology corresponding to different etiologies. In summary, the approach to the patient with fulminant hepatic failure should be guided principally on clinical grounds, and further classification should be based on pathological and etiologic considerations. However, histological classification and prognosis based on percutaneous biopsy specimens alone may be misleading. PMID- 7843705 TI - Whole-body and segmental bioelectrical parameters in chronic liver disease: effect of gender and disease stages. AB - The aim of this study was to examine and compare whole-body and segmental impedance measurements in control subjects and patients with progression of liver disease and to investigate whole-body and segmental bioelectrical changes occurring during dehydration therapy or paracentesis. Males have lower resistance (R) and reactance (Xc) values than females in measurements both of the whole body and of the arm, leg, and trunk. This is not true in patients. In the three groups of patients, whole-body R and Xc were lower in each increased disease stage, suggesting that stage has a significant main effect on impedance measurements. The lower extremities were the segment most influenced by the progression of liver disease. The sum of the arm and leg R was only slightly lower than the value of whole-body resistance. The trunk has a meager influence on this parameter, as is clearly shown by the absence of variations before and immediately after paracentesis. In edematous cirrhotic patients without ascites treated with diuretics, our data also showed a significant correlation (r = .81; SEE = 1.2) between changes in body weight (BW) and in the bioelectrical evaluation of total body water (TBW). The association of a prevalent increment of Xc (approximately 40%) with a reduction of extracellular water is the most significant bioelectrical event during dehydration therapy. All these findings show that impedance measurements have a low sensitivity in detecting the volume of ascites in cirrhotic patients, whereas Xc has a clinical use in monitoring changes in extracellular water (EW). PMID- 7843706 TI - Single photon emission computed tomography to determine effective hepatic blood flow and intrahepatic shunting. AB - The noninvasive determination of effective hepatic blood flow, intrahepatic shunted blood flow, intrahepatic shunt index, and total hepatic blood flow was investigated by using the sequential single photon emission computed tomography. This method was performed for a period of 10 minutes following an intravenous injection of 99mTc-(Sn)-N-pyridoxyl-5-methyltryptophan and a venous blood sampling. This study comprised 8 healthy volunteers, 16 patients with chronic hepatitis, and 33 patients with liver cirrhosis. The intrahepatic shunt index measured with this method coincided with the intrahepatic shunt index determined by catheterization, indicating the high reliability of this procedure. The effective hepatic blood flow in patients with liver cirrhosis was significantly lower than that in the healthy controls and the chronic hepatitis group. The intrahepatic shunted blood flow was significantly higher in patients with liver cirrhosis compared with the flow in healthy controls. The intrahepatic shunt index was also significantly higher in patients with liver cirrhosis compared with the index of healthy controls and those with chronic hepatitis. No substantial differences were noted in the total hepatic blood flow among the three groups. The effective hepatic blood flow, the intrahepatic shunted blood flow, and the intrahepatic shunt index, correlated with the serum albumin concentration, the serum cholinesterase level, and the plasma indocyanine green attenuation rate. From these results, it was concluded that the present procedure constitutes a reliable and effective method for the noninvasive determination of hepatic blood flows. Consequently, it will be of high clinical value for assessing the functional and the pathological alterations of the liver. PMID- 7843707 TI - A double-blind, randomized, placebo-controlled trial of prostaglandin E1 in liver transplantation. AB - A double-blind placebo-controlled trial of intravenous prostaglandin PGE1 (40 micrograms/h) was conducted in adult orthotopic liver transplant recipients. Infusion was started intraoperatively and continued for up to 21 days. Patients were followed up for 180 days postoperatively. Among 172 patients eligible for treatment in the study, 160 could be evaluated (78 PGE1; 82 placebo). Patient and graft survival were similar (PGE1: 16 deaths, 9 retransplantations [7 survivors]; controls: 15 deaths, 6 retransplantations [3 survivors]). In patients with surviving grafts, however, PGE1 administration resulted in a 23% shorter mean duration of hospitalization following transplantation (PGE1: 24.4 days; controls: 31.8 days; P = .02) and a 40% shorter length of time postoperatively in the intensive care unit (PGE1: 8.2 days; controls 13.7 days; P = .05). Reduced needs for renal support (P = .03) or surgical intervention other than retransplantation (P = .02) were also noted with PGE1 use. Further, PGE1 administration resulted in a trend toward improved survival rates in patients with mild renal impairment (preoperative serum creatinine 1.5 mg percent or greater; P = .08). Neither the incidence of acute cellular rejection nor of primary nonfunction was significantly different in the two groups. Phlebitis was the only complication that was more common during PGE1 administration, (PGE1: 9; controls: 4). These results suggest that PGE1 use in hepatic allograft recipients reduces morbidity and may result in sizable cost reductions. PMID- 7843708 TI - Bilirubin conjugate changes in the bile of gallbladders containing gallstones. AB - Gallbladder bile was obtained at laparoscopic cholecystectomy from 31 patients with gallstones, and duodenal aspirates from 18 normal controls. Bile pigments (9 conjugates and unconjugated bilirubin) were analyzed by high-performance liquid chromatography. The average proportional composition of the bile pigments from the patients with gallstones was characteristically different from the controls. Whereas the average values for the principal conjugates in the controls were bilirubin diglucuronide 83.4%, bilirubin monoglucuronide 10.1%, bilirubin monoglucuronide monoglucoside 4.5%, and bilirubin monoglucuronide monoxyloside 1.0%, the corresponding values in the biles from the patients with gallstones were 66.3%, 20.6%, 6.5%, and 2.8%, respectively. Values from the more minor conjugates and unconjugated bilirubin were less than 2% in either data set. In samples obtained in 9 of the gallstone patients early and late in the procedure, no significant change was found. Over the spectrum of findings in the gallstone patients, as the proportion of bilirubin diglucuronide became smaller, that of bilirubin monoglucuronide increased substantially, whereas those of bilirubin monoglucuronide monoglucoside and bilirubin monoglucuronide monoxyloside increased to a small extent. The findings suggest that bilirubin diglucuronide hydrolysis occurs in the gallbladder bile of gallstone patients, with the production of bilirubin monoglucuronide, and that if further hydrolysis of bilirubin monoglucuronide occurs with the formation of unconjugated bilirubin, the latter does not ordinarily increase because it is being absorbed. Stasis with increased gallbladder residence time was likely present in some of the patients.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843709 TI - Detection and quantification of soluble asialoglycoprotein receptor in human serum. AB - We describe the first evidence that soluble asialoglycoprotein receptors (AGPR) are present in human serum and that they are quantifiable by an enzyme-linked immunosorbent assay (ELISA). An affinity chromatography gel immobilized with monoclonal antibodies (McAbs) against human liver AGPR was mixed with normal sera, and the bound fraction was analyzed both by sodium dodecyl sulfate polyacrylamide gel electrophoresis and by Western blot analysis. Immunoreactive bands corresponding to 35 to 40 kd were obtained, which were lower than those of liver AGPR (41 kd and 46 kd). Soluble AGPR in human serum was able to bind to D galactose-immobilized beads, indicating that the soluble AGPR remained ligand binding activity. In order to quantify soluble AGPR, we established an ELISA using a monoclonal antibody (30220 McAb)-immobilized microplate and horseradish peroxidase-labeled F(ab')2 of another monoclonal antibody (30201 McAb). Reproducibility of intra- and interassay of the ELISA were 4% to 14% and 7% to 14%, respectively. Analytical recoveries ranged from 93% to 99%. The detection limit was estimated to be 0.1 micrograms/L. By nonparametolic analysis, a median and a 90% tile of serum AGPR level obtained from 283 normal volunteers were 0.4 micrograms/L and 2.4 micrograms/L, respectively. PMID- 7843710 TI - Bone disease in primary biliary cirrhosis: does ursodeoxycholic acid make a difference? AB - Ursodeoxycholic acid (UDCA) has been proposed as beneficial therapy for patients with primary biliary cirrhosis (PBC). The effects of UDCA on metabolic bone disease, a major source of morbidity in patients with PBC, are essentially unknown. Preliminary information suggests that UDCA may improve biochemical indices of bone disease, although information about the effects of UDCA on bone density is lacking. In this study, we describe the effects of UDCA on lumbar spine bone mineral densities over a 3-year period during which patients were enrolled in a randomized, double-blind, therapeutic trial of UDCA for the treatment of PBC. Lumbar spine dual-photon densitometry was measured at entry and annually. Eighty-eight patients, 50 in the UDCA group and 38 in the placebo group, had serial measurements available for up to 3 years. There was no statistical difference between the two treatment groups at entry with respect to histological stage, total bilirubin, age, use of calcium supplement, vitamin D levels, or estrogen. After 3 years of treatment, there was no significant difference in the lumbar spine bone densitometry measurements between the UDCA treated and placebo groups. We conclude that, after 3 years of treatment, UDCA is not associated with statistically significant differences in the rate of bone loss from the lumbar spine in patients when compared with placebo despite beneficial effects of treatment on the underlying liver disease. Further efforts to define effective treatments for the bone disease need to be pursued. PMID- 7843711 TI - Prognostic significance of nucleolar organizer regions in hepatocellular carcinoma. AB - It has been suggested that the number of argyrophilic nucleolar organizer regions (AgNORs) correlates with cellular activity and the aggressiveness of malignancy. The mean number of AgNORs per nucleus may, therefore, be a prognostic factor for hepatocellular carcinoma (HCC). The purpose of this study was to evaluate the prognostic significance of the number of AgNORs in HCC. The silver-staining technique was applied to surgically resected specimens to indicate AgNORs. Eighty nine of the specimens were of HCC, 23 were of normal liver adjacent to HCC, and 32 were of cirrhotic liver adjacent to HCC. The number of AgNORs of HCC (mean +/- SD, 3.26 +/- 1.23) was significantly higher than those of normal liver (1.37 +/- 0.13) and cirrhotic liver (1.49 +/- 0.14). The number of AgNORs was significantly correlated with serum alpha-fetoprotein level, tumor size, portal vein invasion, and Edmondson-Steiner histological grade. In patients undergoing curative resection, the survival rate of those with a high number (> 3.04) of AgNORs was significantly worse than that of those with a low number (< or = 3.04) of AgNORs. Multivariate analysis showed that the number of AgNORs was a significant prognostic indicator in patients without portal vein invasion, and portal vein invasion was the only significant variable when all patients undergoing curative resection were assessed together. The results of this study suggest that the number of AgNORs is useful as an indicator of the grade of malignancy and as a predictor of the prognosis of patients with HCC who do not have portal vein involvement. PMID- 7843712 TI - Association of primary biliary cirrhosis with the allele HLA-DPB1*0301 in a German population. AB - The major histocompatibility complex class II alleles at the HLA-DPB1 locus were investigated in 32 German Caucasoid patients with primary biliary cirrhosis (PBC) and compared with those from 47 normal control patients using molecular genotyping techniques. The second exon of the HLA-DPB1 gene was amplified by polymerase chain reaction (PCR) and hybridized with 25 sequence-specific oligonucleotides (SSOs) to assign the HLA-DPB1 alleles on the basis of known sequence variations, according to the protocols of the Eleventh International Histocompatibility Workshop. A strong association of PBC was found with the allele HLA-DPB1*0301. The allele HLA DPB1*0301 was present in 50% (16 of 32) of the patients with PBC compared with 13% (6 of 47) of normal controls (P corrected < .015), whereas the other HLA-DPB1 alleles showed no significant differences in both groups. The relative risk (RR) estimate for the allele HLA-DPB1*0301 was 6.8 (95% confidence limits: 2.27 to 20.57). In summary, this study clearly demonstrates an association of PBC with the HLA-DPB1*0301 allele in German Caucasoids and may add new data to the immunogenetic background of PBC, suggesting a contribution of the HLA-DPB1 gene to the genetic susceptibility of the disease. PMID- 7843713 TI - Detection of liver cells in peripheral blood of patients with advanced-stage hepatocellular carcinoma. AB - A large percentage of patients with advanced-stage hepatocellular carcinoma (HCC) have a recurrence of tumor in the liver or lung after primary resection and even after orthotopic liver transplantation. One reason for this may be the presence of small numbers of tumor cells circulating in the blood before surgery or the liberation of tumor cells into circulation during surgical manipulation. We tested this hypothesis by measuring messenger RNA (mRNA) for human albumin gene as a liver cell marker with the highly sensitive reverse transcriptase polymerase chain reaction (RT-PCR) technique. Albumin mRNA was not found in peripheral blood from normal humans (0 of 6), from patients with liver cirrhosis (0 of 10), from other tumors metastatic to liver (0 of 10), or during liver transplant surgery for cirrhosis (0 of 10). In patients with advanced-stage HCC (TNM stages III and IV), albumin mRNA was detected (16 of 17) in peripheral blood. After liver transplantation in the HCC patients, the level of mRNA decreased below the detectable limit (0 of 9). Three of these patients again had detectable mRNA levels when they had recurrence of HCC after liver transplantation. Patients with stage I HCC did not have detectable expression. These results suggest that circulating tumor cells are present in patients with advanced-stage HCC, which may be one of the reasons why these patients have a high incidence of tumor recurrence after apparently definitive surgical resection and even after liver transplantation. PMID- 7843714 TI - Reliability and predictive value of the National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database nomenclature and grading system for cellular rejection of liver allografts. AB - Pathologists participating in the National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplant Database (LTD) created a histopathological grading system for acute liver allograft rejection, and tested it first for inter and intra-rater reliability among a group of five pathologists experienced in liver and transplantation pathology. Specimens from post-transplantation biopsies from 48 patients with rejection, hepatitis, or other diagnosis(es) were reviewed. There was moderate to good (kappa = 0.40 to 0.55) inter-rater and good (kappa = 0.55 to 0.58) intrarater agreement for the diagnosis and exact grading of mild, moderate, or severe acute rejection, which improved when a short clinical history was provided. Thus, the scheme was reproducible, and few of the disagreements among the pathologists would have affected treatment decisions. Secondly, the ability of the grading system to predict an unfavorable short- or long-term outcome from the initial histopathological diagnosis of cellular rejection was tested on groups of 168 and 133 patients, respectively, from the three LTD clinical centers, who were followed up for at least 6 months after the first onset of rejection. This analysis showed that a higher histopathological grade of acute rejection on first biopsy diagnosis was significantly associated (P < or = .006) with both an unfavorable short-term outcome, defined by failure of the episode to resolve within 21 days or the need for aggressive immunosuppressive treatment, and a long-term outcome defined by death or retransplantation from rejection within 6 months of onset. Lastly, an analysis was performed to determine whether subjective rejection grading by the pathologist or certain "objective" histopathological features identified by logistic regression modeling were more accurate in predicting an unfavorable outcome.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843715 TI - Effect of functional grade and etiology on in vivo hepatic phosphorus-31 magnetic resonance spectroscopy in cirrhosis: biochemical basis of spectral appearances. AB - Hepatic phosphorus-31 magnetic resonance spectroscopy (31P MRS) was undertaken in 85 patients with histologically proven cirrhosis of varying etiologies and functional severity. Reference data were acquired from 16 healthy volunteers who had no history or evidence of liver disease or alcohol abuse. In vivo hepatic 31P MR spectra were acquired with pulse angle 45 degrees and repetition times (TR) of 5 and 0.5 seconds. Peak area ratios of phosphomonoesters (PME), inorganic phosphate (Pi), and phosphodiesters (PDE) relative to beta ATP, and of PME relative to PDE were calculated from spectra acquired at TR 5 seconds. Estimates of saturation effects for individual resonances were obtained by dividing the peak height at TR 5 seconds by that at TR 0.5 seconds to yield a T1-related signal height ratio (SHR). When compared with reference values, the patients with liver disease showed a significantly higher PME/ATP (P < .0001), PME/PDE (P < .0001), PME SHR (P < .001), and Pi SHR (P < .02), and a lower PDE/ATP (P < .001) and PDE SHR (P < .001). The magnitude of these changes increased significantly and progressively with increasing functional impairment. In patients with compensated cirrhosis spectral appearances varied with etiology; thus, patients with postviral cirrhosis showed a significantly higher Pi/ATP; those with alcoholic cirrhosis, a significantly lower PDE/ATP; and those with cirrhosis secondary to primary sclerosing cholangitis, a significantly lower Pi/ATP than the healthy volunteers or other etiological groups. However, spectral appearances did not vary with etiology in patients with decompensated disease. In vitro 31P MRS of perchloric extracts of samples of liver tissue obtained from 10 patients with cirrhosis at transplant hepatectomy showed increases in levels of the soluble PME metabolites, phosphorylcholine and phosphorylethanolamine, and reductions in the levels of the soluble PDE metabolites, glycerophosphorylcholine and glycerophosphorylethanolamine. These changes suggest regenerative activity in cirrhotic livers. The increases in soluble phosphomonoesters in the aqueous extracts accounted for the increased PME/ATP ratio seen in the in vivo spectra, and might account for the increase in PME SHR. The reduction in soluble phosphodiesters in the aqueous extracts did not entirely account for the reduction PDE/ATP ratio seen in vivo.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7843716 TI - Interobserver and interequipment variability of echo-Doppler examination of the portal vein: effect of a cooperative training program. AB - The aim of this study was to assess the interobserver, interequipment, and time dependent variabilities of echo-Doppler measurements of portal blood flow velocity (PBV), portal vein diameters (PVDs) and their derived parameters, portal blood flow (PBF), and congestion index (CI) in cirrhotic patients. The influence of a cooperative training program of the operators on the reproductibility of the results was also investigated. The echo-Doppler parameters were independently measured in 15 patients by four skilled operators, using four echo-Doppler machines (Acuson, ATL, Hitachi-Esaote, Toshiba. Eight of the 15 patients were restudied after 15 days by the same operators using only one machine. Significantly different values of PBV, PBF, and CI were obtained. PBV variance was equipment-related (32%) and operator-related in a smaller portion (5%). No systematic effect related to the time of investigation was found. After training to define a precise protocol, new measurements were performed by four operators on 8 different patients. No significant differences were found among the operators for any of the parameters and the 95% confidence limits (CL) and coefficients of variation (CV) of PBV showed a marked decrease (CL from +/- 26.4% to +/- 15.6%). These results indicate that (1) a significant systematic variability exists between Doppler measurements with different equipment; (2) there is no significant time-dependent systematic variability of Doppler measurements; and (3) a cooperative training program reduces the interobserver variability for direct measurements, such as PBV. PMID- 7843717 TI - Changes in hepatic lobe volume in biliary tract cancer patients after right portal vein embolization. AB - Changes in lobar volume of the liver and in total hepatic function were studied in 19 patients with biliary tract cancer who underwent right portal vein embolization as preoperative management for extensive liver resection. Computed tomography (CT) was performed to estimate liver volume before and approximately 11 days after embolization. An indocyanine green (ICG) test was performed before and 11 to 13 days after embolization. The calculated volume of the right lobe decreased from 761 +/- 181 cm3 to 625 +/- 110 cm3 11 days after embolization (P < .0001), whereas the volume of the left lobe increased from 420 +/- 94 cm3 to 555 +/- 110 cm3 (P < .0001). Thus, portal embolization produced a gain in left lobe volume of 136 +/- 62 cm3 and an almost equivalent loss in right lobe volume. The hypertrophy ratio of the left lobe, expressed as percentage of postembolization volume of the left lobe to preembolization size, of the 5 patients with diabetes mellitus (DM) was lower than that of the 14 patients without diabetes (116.7 +/- 6.3% vs. 140.4 +/- 18.4%; P < .005). The ICG disappearance rate in 16 patients improved from 0.163 +/- 0.034 to 0.177 +/- 0.027 (P < .05). The improvement was especially evident in 9 of 14 post-jaundice patients, although the rate decreased slightly in 2 patients without jaundice. We conclude that right portal vein embolization can produce a compensatory hypertrophy of the left lobe within 11 days without seriously affecting hepatic function. In diabetic patients, however, a longer interval between embolization and operation may be needed to achieve sufficient hypertrophy of the left lobe. PMID- 7843718 TI - Increased signals seen in globus pallidus in T1-weighted magnetic resonance imaging in cirrhotics are not suggestive of chronic hepatic encephalopathy. AB - Increased, symmetrical signals of varying intensity in the globus pallidi on T1 weighted (T1W) images, without corresponding signals on T2-weighted (T2W) images, have been reported previously in chronic hepatic failure. It has been suggested that these signals are characteristic of chronic hepatic encephalopathy. To test this hypothesis, we evaluated the relationship of magnetic resonance imaging (MRI) abnormalities with ammonia, albumin, bilirubin, prothrombin time, ascites, clinical encephalopathy, and neuropsychological tests in 46 patients (16 with alcohol-induced cirrhosis and 30 with non-alcohol-induced cirrhosis). T1W signal and cortical atrophy were graded by a neuroradiologist in a blinded fashion. Eleven patients had no T1W signal, 18 had minimal T1W signal, and 17 had high T1W signal. Twenty-five patients had no cortical atrophy, 14 had mild atrophy, and 7 had moderate atrophy. Cortical atrophy was noted more commonly in patients with alcohol-induced liver disease. The neuropsychological tests correlated significantly with albumin, prothrombin time, Child-Pugh's score, clinical encephalopathy, and ammonia. T1W signal and cortical atrophy did not correlate with the neuropsychological tests, clinical encephalopathy, ascites, albumin, prothrombin time, ammonia, or Child-Pugh's score. Patients with high T1W signal showed significant correlation with bilirubin (P < .005). This study suggests that globus pallidus signal in T1W images observed in liver disease are not indicators of chronic hepatic encephalopathy as previously assumed. PMID- 7843719 TI - 31P magnetic resonance spectroscopy of the liver: correlation with standardized serum, clinical, and histological changes in diffuse liver disease. AB - The goal of this study was to analyze the possibilities of 31P MR spectroscopy to detect abnormal hepatic histological changes in patients with diffuse liver disease. 31P MR spectroscopy was performed, on a 1.5 T whole-body spectrometer using an image guided localization technique (ISIS), on 38 patients with various diffuse liver diseases, who all underwent histological and serum analysis, and 22 healthy volunteers. Phosphomonoester expressed as a fraction of total phosphorus (PME/P) showed a correlation with abnormal serum aspartate transaminase (AST), histological intralobular degeneration/focal necrosis, portal inflammation, and piecemeal necrosis. We found a lower correlation for PME/P with fibrosis. It was not possible to differentiate between fibrosis and cirrhosis. In summary, 31P MR spectroscopy is a technique to detect intralobular degeneration, inflammation and necrosis and to a less extent fibrosis. No diagnostic value was found with respect to steatosis and cholangitis. Furthermore, 31P MR spectroscopy is a poor method for classifying patients into diagnostic categories. PMID- 7843720 TI - Effect of Brefeldin A on transcytotic vesicular pathway and bile secretion: a study on the isolated perfused rat liver and isolated rat hepatocyte couplets. AB - This study investigated the effect of Brefeldin A (BFA) on the transcytotic vesicular pathway labeled with horseradish peroxidase (HRP) in both isolated rat hepatocyte couplets (IRHC) and the isolated perfused rat liver (IPRL). To evaluate the role of the transcytotic vesicular pathway on bile secretion, the effect of BFA on bile secretion in the IPRL was then investigated. In the basolateral area of IRHC, BFA showed no effect on the density and percentage of area of HRP-labeled vesicles. However, HRP-labeled vesicles tended to accumulate in the juxtanuclear area of BFA-treated hepatocytes (P < .001 vs. controls). In the pericanalicular area, on the other hand, HRP-labeled vesicles were depleted compared with controls (P < .001). In keeping with these findings, although the early peak remained unchanged, BFA inhibited as much as 50% of the late peak of HRP excretion in bile, after a pulse load of HRP in the IPRL. Bile flow and the biliary secretion of bile salts (BS) and phospholipids were not modified by BFA in isolated livers perfused without BS in the perfusate or with 1 mumol/min taurocholate (TCA). In BFA-treated livers, peak bile flow and BS output decreased by 20% (P < .05 vs. controls) only when a 5 mumol TCA bolus was administered. In conclusion, this study demonstrates that BFA inhibits the transcytotic vesicular pathway in the liver. However, BFA has no significant effect on bile secretion either in basal conditions or during perfusion with physiological amounts of BS. BFA slightly decreases bile flow and BS output only after an overload of BS, providing evidence against the physiological relevance of the transcytotic vesicular pathway in the process of bile formation. PMID- 7843721 TI - In vivo evaluation of a hollow fiber liver assist device. AB - Orthotopic liver transplantation is the only effective form of therapy currently available for patients with fulminant hepatic failure (FHF). The use of an extracorporeal (EC) liver assist device (LAD) may result in improved presurgical clinical management. Alternatively, patients treated with LADs could avoid the transplantation procedure if they are able to regenerate a critical mass of hepatocytes that will sustain functional viability. In this study, the efficacy of a prototype hollow fiber LAD seeded with rabbit hepatocytes was assessed in vivo by the use of two different animal models: (1) normal rabbits injected with diazepam or lidocaine, and (2) a galactosamine (Gal)-intoxicated rabbit model of FHF. The EC LAD clearly decreased the blood levels of the two drugs and significantly generated diazepam and lidocaine metabolites indicating the maintenance of active P450 forms in the cellular component of the devices. A 6 hour EC treatment significantly increased the survival time and delayed the onset of hepatic encephalopathy (HE) in the Gal-intoxicated rabbits. Histological evaluations of postmortem livers showed greater hepatocyte regenerative activity in the animals treated with hepatocyte-seeded LADs than in the two control groups, e.g., rabbits not treated or treated with unseeded devices. These findings support the concept that a microporous hollow fiber LAD seeded with rabbit hepatocytes is able to sustain drug detoxification in vivo as well as to modify the course of FHF in a well-characterized animal model. PMID- 7843722 TI - Stimulated hepatic tissue repair underlies heteroprotection by thioacetamide against acetaminophen-induced lethality. AB - Acetaminophen (APAP) is a widely used analgesic and antipyretic drug that causes massive centrilobular hepatic necrosis at high doses, leading to death. The objectives of this study were to test our working hypothesis that preplaced cell division and hepatic tissue repair by prior thioacetamide (TA) administration provides protection against APAP-induced lethality and to investigate the underlying mechanism. Male Sprague-Dawley rats were treated with a low dose of TA (50 mg/kg, intraperitoneally [i.p.]) before challenge with a 90% lethal dose (1,800 mg/kg, i.p.) of APAP. This protocol resulted in a 100% protection against the lethal effect of APAP. Because TA caused a 23% decrease of hepatic microsomal cytochromes P-450, the possibility that TA protection may be caused by decreased bioactivation of APAP was examined. A 30% decrease in cytochromes P-450 induced by cobalt chloride failed to provide protection against APAP lethality. Time course of serum enzyme elevations (alanine aminotransferase, aspartate aminotransferase, and sorbitol dehydrogenase) indicated that actual infliction of liver injury by APAP peaked between 12 to 24 hours after the administration of APAP, whereas the ultimate outcome of that injury depended on the biological events thereafter. Although liver injury progressed in rats receiving only APAP, it regressed in rats pretreated with TA. Acetaminophen t1/2 was not altered in TA treated rats, indicating that significant changes in APAP disposition and bioactivation are unlikely. Moreover, hepatic glutathione was decreased to a similar extent regardless of TA pretreatment, suggesting that decreased bioactivation of APAP is unlikely to be the mechanism underlying TA protection. [3H]Thymidine incorporation studies confirmed the expected stimulation of S-phase synthesis, and proliferating cell nuclear antigen studies showed a corresponding stimulation of cell division through accelerated cell cycle progression. Intervention with TA-induced cell division by colchicine antimitosis ended the TA protection in the absence of significant changes in the time course of serum enzyme elevations during the inflictive phase of APAP hepatotoxicity. These studies suggest that hepatocyte division and tissue repair induced by TA facilitate sustained hepatic tissue repair after subsequent APAP-induced liver injury, producing recovery from liver injury and protection against APAP lethality. PMID- 7843723 TI - In vivo microscopy of hepatic metastases: dynamic observation of tumor cell invasion and interaction with Kupffer cells. AB - In vivo microscopy was used in the study of the biological behavior of tumor cells and of the activity of Kupffer cells in hepatic tumors in situ. Three tumor models, Friend erythroleukemia inoculated into Dilute Brown Aguti (DBA)/2 mice, murine colon adenocarcinoma (CT)-26 in Bagg Albino inbred albino (BALB)/c mice, and mammary cancer 13762 NF in Fischer rats, were investigated. Tumor cells showed a strong tendency to adhere to the sinusoidal endothelium, most frequently in the sinusoids near the tumors. Mechanical trapping of tumor cells in the narrow portion of hepatic sinusoids, a phenomenon suggested by previous investigators as a predominant pattern for tumor cells to arrest in the liver, was not confirmed. Our study documented that in tumor-bearing livers, as compared with normal control livers, the population size and the phagocytic capacity of Kupffer cells are increased in nontumorous areas but are significantly decreased inside the tumors. In vivo microscopic images showed that Kupffer cells are not only attracted to tumor cells in the hepatic circulation but also have the ability to phagocytose those tumor cells. In vivo microscopy has been shown to be a useful tool for dynamic studies in tumor biology, pathology, and pharmacology. PMID- 7843724 TI - Insulin suppresses bile acid synthesis in cultured rat hepatocytes by down regulation of cholesterol 7 alpha-hydroxylase and sterol 27-hydroxylase gene transcription. AB - Evidence from in vivo studies indicates that the bile acid pool and bile acid excretion are increased in humans with diabetes mellitus and in experimental diabetic animals, and that both parameters return to normal levels after administration of insulin. To investigate the biochemical background of these changes, the effects of insulin on bile acid synthesis and cholesterol 7 alpha hydroxylase and sterol 27-hydroxylase, two key enzymes in routing of cholesterol toward bile acids, were studied in cultured rat hepatocytes. Mass production of bile acids was dose dependently diminished, showing significant reduction (-33% to -53%) at physiological concentrations of the hormone (1.4 to 14 nmol/L) and a maximal decrease at 140 nmol/L (-65%). The decrease of bile acid synthesis correlated well with the suppression of cholesterol 7 alpha-hydroxylase and sterol 27-hydroxylase activity. The enzyme activity for cholesterol 7 alpha hydroxylase, examined in more detail, was dose dependently diminished on incubation of hepatocytes with various concentrations of insulin, reaching maximal reduction at 14 nmol/L of insulin. Maximal decrease of the enzyme activity was seen after 8 hours of incubation (-70%). Insulin strongly reduced the rise in cholesterol 7 alpha-hydroxylase activity induced by incubation with dexamethasone. Sterol 27-hydroxylase activity was inhibited up to -58% after 24 hours of incubation with 140 nmol/L insulin. To study the mechanism of suppression of cholesterol 7 alpha-hydroxylase and sterol 27-hydroxylase activity, the effects of insulin on their respective levels of messenger RNA (mRNA) and gene transcription were assessed. The decrease in enzyme activities could be explained by a concomitant reduction in the cholesterol 7 alpha hydroxylase (-76%) and sterol 27-hydroxylase (-62%) mRNA level. Transcriptional activity, as assessed by nuclear runoff assays, was decreased to the same extent, i.e., -60% for cholesterol 7 alpha-hydroxylase and -75% for sterol 27 hydroxylase. Transient expression experiments using a construct containing the proximal 348 basepairs of the cholesterol 7 alpha-hydroxylase promoter fused to the chloramphenicol acetyltransferase (CAT) gene (-348Rcat) showed a significant reduction of transcriptional activity (-64%) with insulin, indicating that a sequence important for an insulin-induced transcriptional response is located within the first 348 basepairs, preceding the transcription start of the cholesterol 7 alpha-hydroxylase promoter.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7843725 TI - Glutamine transport in isolated human hepatocytes and transformed liver cells. AB - The transport of L-glutamine was examined in isolated adult and fetal human hepatocytes as well as in the human hepatoma cell lines HepG2 and SK-Hep. In all cells studied, glutamine uptake was at least 85% Na(+)-dependent. Kinetic analysis of the Na(+)-dependent component indicated mediation by a single transporter in three human hepatocyte preparations and in SK-Hep cells, whereas two transporters appeared to be responsible for glutamine uptake in HepG2 cells and in hepatocytes from the liver of one male patient. Amino acid inhibition analysis showed primary mediation by System N in fetal and adult hepatocytes, whereas System ASC was principally responsible for glutamine uptake in transformed cells. Similar to the rat transporter, human System N was pH sensitive, stereospecific, and responsive to treatment with steroid hormones. Although the human carrier was less tolerant of Li(+)- for Na+ substitution, glutamine transport in primary human hepatocytes was stimulated by treatment with hypotonic buffer (cell swelling), as reported in rat parenchymal cells. In contrast, glutamine transport in hepatoma cells was relatively insensitive to changes in extracellular pH and failed to show enhanced activity in response to hypoosmotic challenge. Collectively, the data suggest that markedly distinct plasma membrane transporters mediate the concentrative uptake of glutamine in normal and transformed human hepatocytes, and that the salient properties of System N have been largely conserved from rat to man. PMID- 7843726 TI - The effects of dietary iron on initiation and promotion in chemical hepatocarcinogenesis. AB - The aim of this study was to evaluate the effects of dietary iron on hepatocarcinogenesis in an animal model mimicking noncirrhotic genetic hemochromatosis. Iron overload may lead to liver cirrhosis and an increased risk of developing primary hepatocellular carcinoma. It is unknown if iron is of pathogenic importance for the carcinogenic process, or whether the increased cancer risk results solely from the cirrhotic process. We investigated the initiating, promoting, and mitogenic properties of carbonyl iron in the Solt Farber model of chemical hepatocarcinogenesis. A diet supplemented with 2.5% to 3.0% carbonyl iron was either added to, or replaced, the initiating and promoting events in the model. None of the animals developed hepatic fibrosis. Hepatic iron was increased 6- to 13-fold in iron-treated animals, and predominantly located in periportal hepatocytes. Iron as an initiator did not increase the number of glutathione-S-transferase-Yp-positive foci. Iron reduced the number of foci when added to low-dose diethylnitrosamine plus partial hepatectomy, which may be explained by a delayed hepatic regeneration in iron-loaded liver. As a promoter, iron did not selectively induce proliferation of initiated cells. Added to a complete promotive regimen, iron decreased the volume density of preneoplastic nodules, possibly because of a mitostimulatory effect of iron on normal hepatocytes surrounding the nodules. Iron increased the hepatocyte labeling index and counteracted the mitoinhibitory effect of 2-acetylaminofluorene on regenerating liver.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843727 TI - Deoxycholate and cholate modulate the source of cholesterol substrate for bile acid synthesis in the rat. AB - In the current study, the role of the supply of preformed and newly synthesized cholesterol for the feedback control of the synthesis of different bile acids and the secretion of biliary cholesterol was investigated. To define these cholesterol fluxes and the possibility of a different modulation by bile acids with different suppressive capacities, a continuous labeling with tritiated water was used in rats with an extracorporeal bile duct receiving intraduodenal infusions of taurocholate or taurocholate plus deoxycholate. After bile acid pool depletion (6 to 9 hours) total muricholate, cholate, and chenodeoxycholate synthesis was variably increased (24% to 93%) during an infusion of 304 mumol taurocholate/kg per hour. The increase in bile acid synthesis and biliary cholesterol output was predominantly due to the utilization of preformed (unlabeled) cholesterol. The addition of 52 mumol/kg per hour of deoxycholate to 258 mumol/kg per hour of taurocholate had a comparable effect. In the late period (30 to 54 hours), the taurocholate infusion had little impact on total muricholate and chenodeoxycholate synthesis but caused by a significant increase of the proportion from performed cholesterol. Both total cholate production and its synthesis from de novo (labeled) cholesterol was inhibited by 30% (P < .05) and 64% (P < .01), respectively. The secretion rate of total and de novo biliary cholesterol was higher (65% and 72%; P < .01) compared with controls. In comparison, the combined bile acid infusion led to a further increase of total muricholate synthesis (P < .05), which was again due to an enhanced synthesis from performed cholesterol (P < .001). Similar changes were observed in chenodeoxycholate. The more pronounced suppression of total cholate synthesis by 81% (P < .05) was due to a diminished cholate synthesis from both de novo cholesterol by 72% (P < .001) and preformed cholesterol by 91% (P > .05). We conclude that the modulation of the synthesis of the various primary bile acids in the rat differs and feedback regulation of cholate synthesis by taurocholate and deoxycholate is mediated by different mechanisms of control, including inhibition of cholesterol 7 alpha-hydroxylase, HMG-CoA reductase, and uptake of lipoprotein cholesterol. PMID- 7843728 TI - Increased sinusoidal wall permeability and liver fatty change after two-thirds hepatectomy: an ultrastructural study in the rat. AB - Accumulation of lipids in the hepatocyte cytoplasm after partial hepatectomy (PH) has long been recognized, but the mechanism behind this phenomenon is still poorly understood. In this study, rats subjected to a standard two-thirds PH showed early and marked increase in portal venous pressure (P < .01). On scanning electron microscopy, the regenerating liver fixed by portal perfusion under hemodynamic conditions identical to that found in vivo during the first 24 hours showed a significant (P < .01) 10-fold increase in the sinusoidal wall porosity (percentage open area by fenestrations). This was paralleled by the disappearance of the sieve-plate arrangement of small fenestrations and by a significant decrease in the number of fenestrations per micrometers squared of sinusoidal surface at 6 (P < .01) and 12 hours (P < .05). In addition, there were major changes in the frequency and distribution of all three classes of fenestrations. At 6 and 12 hours, there was a marked decrease of small class 1 fenestrations and a marked increase of intermediate class 2 fenestrations and large class 3 fenestrations (P < .0001). A concurrent accumulation of lipid droplets in the hepatocyte cytoplasm produced a 20-fold increase in the hepatocyte total lipid volume. A statistically significant linear correlation (r = 0.907; P < .01) was found between the amount of intracellular lipids and the data quantitating the changes in porosity of liver sinusoids at 24 hours. It is concluded that an increased sinusoidal wall permeability to lipids may be the primum moves in the pathogenesis of transient liver fatty change after PH in the rat. PMID- 7843729 TI - Endothelin stimulates platelet-activating factor synthesis by cultured rat Kupffer cells. AB - Endothelins are potent peptide mediators that elicit glycogenolytic and vasoconstrictor actions in the liver. Endothelins were found to stimulate the synthesis and release of the lipid mediator platelet-activating factor in cultured rat Kupffer cells. Endothelin-mediated synthesis of platelet-activating factor required extracellular calcium in that the calcium chelator, EGTA and nifedipine, a calcium ion channel blocker, inhibited platelet-activating factor synthesis. The phospholipase A2 inhibitor, 4-bromophenacyl bromide, strongly inhibited endothelin-induced platelet activating factor synthesis. Endothelin stimulated platelet activating factor synthesis was inhibited after treatment of Kupffer cells with cholera toxin, whereas pertussis toxin inhibited only this response to endothelin-1. Agents that elevate intracellular cyclic AMP levels were found to inhibit endothelin-induced platelet-activating factor synthesis in Kupffer cells. Staurosporine, a protein kinase C inhibitor minimized endothelin induced platelet-activating factor synthesis but phorbol myristate acetate, an activator of protein kinase C, did not affect endothelin-induced platelet activating factor synthesis. Thus, the current study demonstrates that activation of an endothelin receptor in cultured rat Kupffer cells results in the synthesis and release of platelet-activating factor. The importance of endothelin-mediated platelet-activating factor synthesis relates to the mechanism of intercellular signaling occurring between endothelial cells (i.e., the site of endothelin synthesis) and Kupffer cells (i.e., the site of formation of secondary mediators such as platelet-activating factor and eicosanoids) within the rat liver exposed to various types of pathophysiological episodes. PMID- 7843730 TI - Nitric oxide production in arterial vessels of cirrhotic rats. AB - Indirect evidence exists implicating vascular nitric oxide in the pathogenesis of arterial vasodilation in cirrhosis. In the current study, a coincubation assay to estimate the vascular nitric oxide production was developed and the nitric oxide production by arterial segments of cirrhotic and control rats was assessed. In the assay, measurement of reporter monolayer cell-associated cGMP levels allows the influence of nitric oxide released by arterial segments to be determined. RFL 6 cells served as reporter cells. Nitric oxide production was determined in thoracic aorta and mesenteric arteries of 22 control rats, 10 cirrhotic rats without ascites, and 12 cirrhotic rats with ascites. Basal and bradykinin stimulated (10(-6) mol/L) intracellular content of nitric oxide-dependent cGMP was significantly higher in RFL-6 cells coincubated with aortic segments of cirrhotic rats with (21.3 +/- 3.6 pmol/10(5) cells, P < .05 and 44.7 +/- 7.0 pmol/10(5) cells, P < .025) and without ascites (15.3 +/- 3.0 pmol/10(5) cells, P < .05 and 43.2 +/- 7.6 pmol/10(5) cells, P < .05) than in those incubated with aortic segments of control rats (9.7 +/- 1.3 and 19.5 +/- 2.5 pmol/10(5) cells). RFL-6 cells exposed to bradykinin-stimulated mesenteric arterial segments of cirrhotic rats also showed increased cGMP content (ascitic: 2.73 +/- 0.31 pmol/10(5) cells, P < .005; nonascitic: 2.58 +/- 0.51 pmol/10(5) cells, P < .025) compared with cells exposed to control mesenteric arterial segments (1.28 +/- 0.15 pmol/10(5) cells). No differences between cirrhotic and control vessels were observed after endothelium denudation.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843731 TI - Pathogenesis of diquat-induced liver necrosis in selenium-deficient rats: assessment of the roles of lipid peroxidation and selenoprotein P. AB - A dose of diquat below the amount injurious to selenium-replete animals causes lipid peroxidation and massive liver necrosis in selenium-deficient rats. The current study was undertaken to characterize the lipid peroxidation with respect to the liver injury and to correlate the presence of several selenoproteins with the protective effect of selenium. Lipid peroxidation was assessed by measurement of F2 isoprostanes. Diquat caused an increase in liver and plasma F2 isoprotanes. A gradient of these compounds was detected across the liver in some animals, indicating that this organ was a source of some of the plasma F2 isoprostanes. A time-course experiment showed that liver F2 isoprostane concentration increased before plasma alanine transaminase (ALT) levels rose. Selenium-deficient rats were injected with selenium doses from 2 to 50 micrograms/kg and studied 12 hours later. A dose of 10 micrograms/kg or more prevented diquat-induced lipid peroxidation and liver injury. This dose increased plasma selenoprotein P substantially, and a dose-response was present. Liver cellular and plasma glutathione peroxidase activities remained below 2% of their values in control rats for all selenium doses. In selenium-deficient rats given diquat, hepatic lipid peroxidation precedes hepatic necrosis and could therefore be an important mechanism of the necrosis. Selenoprotein P levels were increased by selenium injections, which protected against diquat injury, but glutathione peroxidase activity was not increased. This is consistent with selenoprotein P being the mediator of the selenium effect. PMID- 7843732 TI - Unexplained Budd-Chiari syndrome in a young man. PMID- 7843733 TI - Ischemic-type biliary strictures in liver allografts: the Achilles heel revisited? PMID- 7843734 TI - Prostaglandins in liver transplantation. PMID- 7843735 TI - Putting the freeze on hepatitis C virus-associated mixed cryoglobulinemia. PMID- 7843736 TI - p53 mutations and hepatitis B virus: cofactors in hepatocellular carcinoma. PMID- 7843737 TI - p53 mutations in nonmalignant human liver: fingerprints of aflatoxins? PMID- 7843738 TI - Detection of benzodiazepine in hepatic encephalopathy. PMID- 7843739 TI - 2nd Annual Congress of the British Society for Immunology, Harrogate, United Kingdom, 5-7 December 1994. Abstracts. PMID- 7843740 TI - Beta-adrenergic receptors and angiotensinogen gene expression in mouse hepatoma cells in vitro. AB - We have previously reported that addition of 8-bromocyclic AMP enhances the stimulatory effect of dexamethasone on the expression of the angiotensinogen gene in mouse hepatoma cells in vitro. Isoproterenol is known to stimulate the synthesis of hepatic intracellular cyclic AMP via beta-adrenergic receptors. To study the possible effect of beta-adrenergic receptors on the expression of the angiotensinogen gene in mouse hepatoma cells, we transiently transfected them with a fusion gene with the 5'-flanking region of the angiotensinogen gene linked to a bacterial chloramphenicol acetyltransferase coding sequence as a reporter, pOCAT (ANG N-1498/+18). The addition of isoproterenol (10(-9) to 10(-5) mol/L) alone had no stimulatory effect on the expression of pOCAT (ANG N-1498/+18). In the presence of dexamethasone (10(-6) mol/L), however, isoproterenol enhanced the stimulatory effect on the dexamethasone on the expression of pOCAT (ANG N 1498/+18). The enhancing effect of isoproterenol was inhibited by the presence of propranolol (beta 1- and beta 2-adrenergic receptor antagonist) and ICI 118,551 (beta 2-adrenergic receptor antagonist) but not by the presence of atenolol (beta 1-adrenergic receptor antagonist). Furthermore, the addition of Rp-cAMP (an inhibitor of protein kinase A I and II) blocked the enhancing effect of isoproterenol. These studies demonstrated that isoproterenol enhances the stimulatory effect of dexamethasone on the expression of the angiotensinogen gene in mouse hepatoma cells via beta 2-adrenergic receptor and cyclic AMP-dependent protein kinase pathways. Our data may be important in understanding the molecular mechanism(s) of the stimulatory effect of catecholamines/glucocorticoid-induced expression of the angiotensinogen gene in the liver. PMID- 7843741 TI - Myofilament calcium sensitivity of normotensive and hypertensive resistance arteries. AB - We measured intracellular Ca2+ and isometric force simultaneously in endothelium denuded mesenteric resistance arteries of 12- to 15-week-old male spontaneously hypertensive rats (SHR). Wistar-Kyoto (WKY) rats, and Wistar rats. Basal Ca2+ did not differ among vessels of these strains (SHR, 86.6 +/- 4.5 nmol/L; WKY, 78.5 +/ 4.7 nmol/L; Wistar, 83.1 +/- 3.9 nmol/L). Myofilament Ca2+ sensitivity was determined by measuring the intracellular Ca2+ and force responses to cumulative addition of extracellular Ca2+ (0.025 to 2.5 mmol/L) in the presence of 100 mmol/L K+ or 10 mumol/L norepinephrine after depletion of releasable intracellular Ca2+ stores. With 100 mmol/L K+, no between-strain differences in active stress, intracellular Ca2+, or myofilament Ca2+ sensitivity were observed. With 10 mumol/L norepinephrine, the active stress response of SHR vessels to 0.025 and 0.05 mmol/L Ca2+ was increased compared with both normotensive strains. The intracellular Ca2+ response was not different in vessels of SHR and WKY rats but was depressed in Wistar vessels. Myofilament Ca2+ sensitivity of SHR was elevated compared with both WKY and Wistar rats (P < .05) (ED25 for SHR, 74.4 +/- 5.1 nmol/L; WKY, 89.8 +/- 5.5 nmol/L; Wistar, 86.9 +/- 3.4 nmol/L). No strain differences in intracellular Ca2+ or active stress responses of SHR and WKY vessels were detected during cumulative addition of norepinephrine with constant extracellular Ca2+ (1.5 mmol/L). These results indicate that no hypertension associated defect in vascular Ca2+ handling exists in mesenteric arteries of the SHR.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843742 TI - Rapid effects of aldosterone on sodium transport in vascular smooth muscle cells. AB - Increasing evidence has accumulated for rapid nongenomic steroid actions in various cell systems and, more recently, for rapid aldosterone effects on the Na(+)-H+ antiport in human mononuclear leukocytes. The aim of the present study was to demonstrate a rapid, nongenomic aldosterone action in rat vascular smooth muscle cells as a key effector cell in cardiovascular regulation. Basal 22Na+ influx in quiescent vascular smooth muscle cells was 22.1 +/- 1.9 nmol/mg protein per minute (mean +/- SEM, n = 9). Aldosterone (1 nmol/L) stimulated influx to 28.6 +/- 1.5 nmol/mg protein per minute after 4 minutes (n = 9, P < .05), with a half-maximal effect between 0.1 and 0.5 nmol/L; the effects were inhibited by ethylisopropylamiloride, the specific inhibitor of the Na(+)-H+ exchanger, demonstrating the involvement of this transport system in rapid effects of aldosterone. Hydrocortisone (1 mumol/L) was ineffective, and fludrocortisone and deoxycorticosterone increased influx with half-maximal effects at approximately 0.5 nmol/L. Canrenone, a classic antagonist of aldosterone action, did not inhibit stimulation by aldosterone at a 1000-fold excess concentration. Aldosterone significantly stimulated intracellular inositol 1,4,5-trisphosphate levels (P < .05) after 30 seconds; the inhibitors of phospholipase C, neomycin and U-73122, inhibited aldosterone-stimulated Na+ influx and increase of intracellular inositol 1,4,5-trisphosphate. The rapid stimulation of sodium transport in vascular smooth muscle cells and the pharmacological characteristics of this effect are clearly incompatible with the classic, genomic pathway of steroid action and represent further evidence for nongenomic effects of aldosterone. PMID- 7843743 TI - Hypertrophy and hyperplasia of smooth muscle cells of small intramyocardial arteries in spontaneously hypertensive rats. AB - Hearts of stroke-prone spontaneously hypertensive rats (SHR) were investigated by means of stereology and were compared with those of normotensive. Wistar-Kyoto controls. At the age of 9 months, hypertensive rats showed cardiac hypertrophy, marked myocardial fibrosis, activation of nonvascular interstitium, focal myocytial degeneration, reduction of capillarization, and microarteriopathy of small intramyocardial arteries. Stereologically, a significant increase in the total left ventricular arterial wall volume (+180% versus controls) was found in SHR hearts. By using new stereological techniques, the orientator and the nucleator, we investigated whether this significant increase in total left ventricular arterial wall volume was due to hyperplasia of smooth muscle cells in addition to the process of vascular smooth muscle cell hypertrophy that is common in SHR. Additionally, the nuclear size and ratio of cell volume to nuclear volume were determined using another new stereological technique, the selector. The stereological data indicate a significant increase in mean cell and nuclear volumes as well as in the total number of left ventricular arterial smooth muscle cells of SHR. Additionally, the total length of intramyocardial arteries was also significantly increased in hypertensive rats. The volume and number of arterial smooth muscle cells per arterial length were significantly (P < .001 and P < .05, respectively) higher in SHR than in normotensive controls. Thus, we conclude that hypertrophy and hyperplasia of smooth muscle cells are involved in intramyocardial arterial growth processes in hypertensive heart remodeling.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843744 TI - Monocyte infiltration and c-fms expression in hearts of spontaneously hypertensive rats. AB - To elucidate mechanisms of myocardial hypertrophy in spontaneously hypertensive rats (SHR), we examined by Northern blotting the expression of the proto oncogenes c-myc, c-fos, c-sis, and c-fms in the hearts of 4- and 14-week-old SHR and normotensive Wistar-Kyoto (WKY) rats. No difference in c-myc or c-fos expression could be found between SHR and WKY rats. In SHR, c-sis gave a weak and c-fms a very strong signal at 14 weeks, whereas no signal for these oncogenes was found in either WKY rats or Sprague-Dawley controls. Since c-fms codes for the receptor of monocyte colony-stimulating factor, we next used in situ hybridization to localize the presence of c-fms in hearts of SHR at 14 weeks. We found strong signals for c-fms around small blood vessels and between cardiac myocytes in 14-week-old SHR but none in WKY rats. Immunohistochemical staining corroborated the presence of clusters of monocyte infiltration at these same perivascular sites in significantly greater numbers in SHR than in WKY rats. We conclude that c-fms expression and macrophage infiltration are increased in the perivascular space of hypertrophied hearts from SHR. We suggest that mononuclear cell recruitment and induction of c-fms may play a role in the development of hypertension-associated myocardial hypertrophy. PMID- 7843745 TI - Sustained hypertension in Dahl rats. Negative correlation of agonist response to blood pressure. AB - The perfused mesenteric vasculature of Dahl salt-sensitive rats on a high salt diet for 5 days (prehypertensive or early hypertensive) is selectively supersensitive to norepinephrine. The present goal was to determine whether that supersensitivity was maintained as hypertension developed. Littermates of salt sensitive and salt-resistant rats (Dahl Brookhaven strain) were followed on low or high salt for up to 6 weeks. Systolic blood pressure was elevated in the salt sensitive, high salt rats after 3 or 6 weeks but not after 5 days of the diet. The perfused mesenteric vascular beds from salt-sensitive rats were supersensitive to norepinephrine and nerve stimulation but not to potassium chloride when the rats had been maintained for 5 days or 3 weeks on the high salt diet. However, responses to norepinephrine declined after 6 weeks of the high salt diet. To determine whether sustained high blood pressure has a negative effect on mesenteric vascular responses, we conducted additional experiments with perfused mesenteric vascular beds from salt-sensitive Brookhaven (high salt, 5 weeks) and Rapp (high salt, 6 weeks) animals. Both groups exhibited significant negative correlations between in vivo systolic pressure and maximal responses of mesenteric vessels to norepinephrine and potassium chloride. We suggest that sustained hypertension in Dahl rats has a negative effect on the contractility of the mesenteric arterial system that, by 5 to 6 weeks, masks the initial supersensitivity to norepinephrine. No effects of any diet on the dilating responses of the mesenteric vessels to acetylcholine were observed in any group. PMID- 7843746 TI - Characterization of the angiotensin II receptor antagonist TCV-116 in healthy volunteers. AB - The purpose of this study was to assess the inhibitory effect of TCV-116, an orally active angiotensin II (Ang II) antagonist, on the pressor action of exogenous Ang II and to determine the compensatory rise in plasma renin activity and Ang II levels. Twenty-three male volunteers were treated for 8 days in a double-blind fashion with either placebo or TCV-116 (1, 2, or 4 mg PO daily) and challenged on the first, fourth, and eighth days with repeated bolus injections of Ang II. An additional 4 subjects received 8 mg PO daily in a single-blind fashion. The inhibitory effect on the systolic blood pressure response to Ang II was long lasting and clearly dose related. Six hours after 4 mg TCV-116, the systolic blood pressure response to a given dose of Ang II was reduced to 40 +/- 4% and 35 +/- 8% of baseline value on days 1 and 8, respectively. TCV-116 induced a dose-related increase in plasma renin activity and Ang II levels that was more pronounced on the eighth than on the first day of drug administration. Despite this compensatory mechanism, the relation between the time-integrated systolic blood pressure response to Ang II and the time-integrated CV-11974 levels, the active metabolite of TCV-116, was not different between days 1 and 8. In conclusion, TCV-116 appears to be a well-tolerated, orally active, potent, and long-lasting antagonist of Ang II in men. PMID- 7843747 TI - Wistar fatty rat is obese and spontaneously hypertensive. AB - The purpose of this study was to determine whether genetically obese Wistar fatty rats have higher blood pressure than their lean littermates and if so to elucidate the mechanism of this obesity-related hypertension. We measured blood glucose and plasma insulin levels, blood pressure, and catecholamine and sodium excretions in age-matched female Wistar fatty and lean rats. After 12 weeks of age, the body weight of Wistar fatty rats was significantly greater than that of their lean counterparts. Fasting blood glucose and plasma insulin concentrations were higher in the fatty than the lean rats throughout the observation period (8 to 24 weeks of age). Systolic blood pressure of fatty rats measured by the tail cuff method was similar to that of lean rats at 8 weeks of age (135 +/- 2 [mean +/- SEM] versus 134 +/- 3 mm Hg) but significantly higher at 16 (158 +/- 2 versus 136 +/- 3 mm Hg, P < .01) and 24 (166 +/- 5 versus 142 +/- 2 mm Hg, P < .01) weeks of age. Urinary norepinephrine excretion was significantly increased in the fatty rats at both 16 (1755 +/- 173 versus 977 +/- 128 ng/24 h, P < .05) and 24 (1907 +/- 283 versus 737 +/- 173 ng/24 h, P < .01) weeks of age. The ratio of urinary norepinephrine excretion to body weight was also significantly increased in the fatty rats. These results show that with increasing body weight Wistar fatty rats develop hypertension, which may be attributable to an increased sympathetic nerve activity.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843748 TI - Hypertensive microalbuminuria. PMID- 7843749 TI - Hemodynamic and biochemical effects of the AT1 receptor antagonist irbesartan in hypertension. AB - We studied the hemodynamic, neurohumoral, and biochemical effects of the novel angiotensin type 1 (AT1) receptor antagonist irbesartan in 86 untreated patients with essential hypertension on a normal sodium diet. According to a double-blind parallel group trial, patients were randomized to a once-daily oral dose of the AT1 receptor antagonist (1, 25, or 100 mg) or placebo after a placebo run-in period of 3 weeks. Randomization medication was given for 1 week. Compared with placebo, 24-hour ambulatory blood pressure did not change with the 1-mg dose, and it fell (mean and 95% confidence interval) by 7.0 (4.2-9.8)/6.1 (3.9-8.1) mm Hg with the 25-mg dose and by 12.1 (8.1-16.2)/7.2 (4.9-9.4) mm Hg with the 100-mg dose. Heart rate did not change during either dose. With the 25-mg dose, the antihypertensive effect was attenuated during the second half of the recording, and with the 100-mg dose, it was maintained for 24 hours. Baseline values of renin and the antihypertensive response to the 25- and 100-mg doses were well correlated (r = .68, P < .01). Renin did not change with the 1-mg dose, but it rose threefold to fourfold with the 25-mg dose and fourfold to fivefold with the 100-mg dose 4 to 6 hours after administration. With the 100-mg dose, renin was still elevated twofold 24 hours after dosing. The changes in renin induced by the AT1 receptor antagonist were associated with parallel increments in angiotensin I and angiotensin II. Aldosterone, despite AT1 receptor blockade, did not fall.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843750 TI - Relationships among plasma aldosterone, high-density lipoprotein cholesterol, and insulin in humans. AB - To investigate the pathogenesis of hypertension in patients with obesity and insulin resistance and to explore the role of plasma lipids, we studied 30 subjects at the end of 7 days of low (20 mEq/d) then high (200 mEq/d) sodium diets. Glucose and insulin tolerance tests were performed at the end of each week and blood and urine collected for measurements of plasma aldosterone, renin activity, electrolytes, insulin, and lipoproteins. There was a strong negative correlation between plasma aldosterone and high-density lipoprotein cholesterol during both diets. There were weaker positive correlations between plasma aldosterone and insulin or triglycerides. When the aldosterone-renin ratio was the dependent variable and the correlation controlled for serum potassium, the inverse relationship with high-density lipoprotein cholesterol and the positive correlation with insulin remained, but only during the high salt diet. Subjects were divided into three groups based on high-density lipoprotein cholesterol. Subjects with the lowest high-density lipoprotein cholesterol levels showed the highest aldosterone, plasma triglycerides, body mass index, and waist-to-hip ratio. Those subjects also demonstrated the greatest resistance to insulin action on glucose and plasma unesterified fatty acids. There was a weak direct correlation between plasma aldosterone and systolic blood pressure during the high salt diet. These data suggest that high aldosterone levels may be a link between dyslipidemia, insulin resistance, and hypertension, a relationship made more evident by high salt intake. PMID- 7843751 TI - Biochemical effects of losartan, a nonpeptide angiotensin II receptor antagonist, on the renin-angiotensin-aldosterone system in hypertensive patients. AB - We investigated the effects of angiotensin II (Ang II) type 1 receptor blockade with losartan on the renin-angiotensin-aldosterone system in hypertensive patients (supine diastolic blood pressure, 95 to 110 mm Hg). Qualifying patients (n = 51) were allocated to placebo, 25 or 100 mg losartan, or 20 mg enalapril. Blood pressure, plasma drug concentrations, and renin-angiotensin-aldosterone system mediators were measured on 4 inpatient days: end of placebo run-in, after first dose, and 2 and 6 weeks of treatment. Plasma drug concentrations were similar after the first and last doses of losartan. At 6 weeks, 100 mg losartan and 20 mg enalapril showed comparable antihypertensive activity. Four hours after dosing, compared with the run-in day, 100 mg losartan increased plasma renin activity 1.7-fold and Ang II 2.5-fold, whereas enalapril increased plasma renin activity 2.8-fold and decreased Ang II 77%. Both drugs decreased plasma aldosterone concentration. For losartan, plasma renin activity and Ang II increases were greater at 2 than at 6 weeks. Effects of losartan were dose related. After the last dose of losartan, plasma renin activity and Ang II changes were similar to placebo changes by 36 hours. These results indicate that long-term blockade of the feedback Ang II receptor in hypertensive patients produces modest increases of plasma renin activity and Ang II that do not appear to affect the antihypertensive response to the antagonist. PMID- 7843752 TI - Antihypertensive therapy in dyslipidemic men. Effects on coronary heart disease incidence and total mortality. AB - To investigate the influence of antihypertensive therapy and the success of blood pressure control on coronary heart disease incidence and total mortality, we studied dyslipidemic middle-aged men participating in the placebo arm of the Helsinki Heart Study, a randomized coronary primary prevention trial with gemfibrozil. Based on blood pressure level and the presence of antihypertensive therapy at study entry, the participants were classified into four categories. Relative risks of coronary heart disease (nonfatal myocardial infarction or cardiac death) and total mortality during the 5-year trial period were calculated using Cox proportional hazards models. With subjects who were not using antihypertensive drugs and who had normal blood pressure (category I) as reference, the relative risks of coronary heart disease during the trial period were 2.1 (95% confidence interval [CI], 1.3 to 3.3) in untreated hypertensive subjects (category II), 0.9 (95% CI, 0.2 to 3.8) in subjects with successful antihypertensive therapy (category III), and 2.0 (95% CI, 1.0 to 4.1) in subjects who remained hypertensive despite drug therapy (category IV). The relative risks of death were 1.9 (95% CI, 0.9 to 3.9) in category II and 1.0 (95% CI, 0.1 to 7.3) in category III; in category IV subjects, those with unsuccessful antihypertensive therapy, the relative risk was 4.4 (95% CI, 2.0 to 9.6). The excess mortality in this category was due to cardiovascular causes and was clustered in subjects with multiple drug therapy for hypertension control. We conclude that successful antihypertensive therapy in dyslipidemic men reduced coronary heart disease incidence despite its adverse effects on high-density lipoprotein cholesterol and triglycerides.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843753 TI - Increased prevalence of hypertension and long-term arsenic exposure. AB - To examine the association between long-term exposure to inorganic arsenic and the prevalence of hypertension, we studied a total of 382 men and 516 women residing in villages where arseniasis was hyperendemic. Hypertension was defined as a systolic blood pressure of 160 mm Hg or greater, a diastolic blood pressure of 95 mm Hg or greater, or a history of hypertension treated regularly with antihypertensive drugs. The long-term arsenic exposure was calculated from the history of artesian well water consumption obtained through standardized interviews based on a structured questionnaire and the measured arsenic concentration in well water. Residents in villages where long-term arseniasis was hyperendemic had a 1.5-fold increase in age- and sex-adjusted prevalence of hypertension compared with residents in nonendemic areas. Duration of artesian well water consumption, average arsenic concentration in drinking water, and cumulative arsenic exposure were all significantly associated with hypertension prevalence. The higher the cumulative arsenic exposure, the higher the prevalence of hypertension. This dose-response relation remained significant after adjustment for age, sex, diabetes mellitus, proteinuria, body mass index, and serum triglyceride level. The results suggest that long-term arsenic exposure may induce hypertension in humans. PMID- 7843754 TI - Evaluation of the SA locus in human hypertension. AB - The SA gene is expressed at 10-fold greater levels in the kidney of the spontaneously hypertensive rat compared with the normotensive Wistar-Kyoto rat. The gene is linked to blood pressure levels in a number of crosses involving the spontaneously hypertensive rat and other strains of genetically hypertensive rats. To assess its role in human hypertension, a human SA cDNA was cloned from a liver library. The cDNA was 1513 bp in length and exhibited a high identity with the published rat SA cDNA sequence in the coding region. A microsatellite marker was developed from a yeast artificial chromosome clone containing SA and mapped by linkage to human chromosome 16p13.11-12.3. Polymerase chain reaction amplification of human genomic DNA revealed two introns located in the SA gene, one of which contains a frequent polymorphism due to a single nucleotide substitution (cytosine to thymidine at residue 79 of the intron). Association and linkage studies in a large sample of hypertensive patients, normotensive control subjects, and multiplex sibships with these markers and other microsatellites in close proximity to SA revealed no evidence favoring involvement of the gene in the disease in humans. The methodology used in this study can be applied to the evaluation of other novel candidate genes obtained from investigations of experimental models of hereditary hypertension. PMID- 7843755 TI - Renal effects of acute amino acid infusion in hypertension induced by chronic nitric oxide blockade. AB - L-Arginine is the physiological substrate of nitric oxide, a vasodilator that controls blood pressure and renal hemodynamics in the basal state. In the present studies, we produced chronic nitric oxide blockade by oral administration of the L-arginine analogue NG-nitro-L-arginine methyl ester, which produced sustained hypertension and increased renal vascular resistance in conscious rats. Acute excess L-arginine had little effect on blood pressure but completely normalized renal vascular resistance and increased renal plasma flow in chronically nitric oxide-blocked hypertensive rats. In contrast to L-arginine, D-arginine had no renal hemodynamic effects in either normal or chronically nitric oxide-blocked rats. Acutely administered glycine was ineffective in vasodilating the chronically nitric oxide-blocked rat kidney, in a dose that produced renal vasodilation in normal rats. These findings indicate the following: (1) Hypertension induced by chronic nitric oxide blockade due to substituted L arginine analogue cannot be acutely reversed with excess L-arginine, suggesting that the maintenance of the hypertension is not solely caused by competitive inhibition of nitric oxide production; (2) in contrast, the kidney remains responsive to L-arginine whereas the renal vasodilator response to glycine is abolished in this model of hypertension. PMID- 7843756 TI - Evidence of coexisting changes in 11 beta-hydroxysteroid dehydrogenase and 5 beta reductase activity in subjects with untreated essential hypertension. AB - We compared corticosteroid metabolite excretion rates and patterns in a group of 68 subjects with untreated essential hypertension and a matched group of 48 normotensive control subjects. The ratio of tetrahydrocortisol plus allotetrahydrocortisol to tetrahydrocortisone and the ratio of allotetrahydrocortisol to tetrahydrocortisol were significantly higher in the hypertensive group. This is qualitatively similar to the situation found in patients with the syndrome of apparent mineralocorticoid excess or subjects treated with licorice or carbenoxolone where hypertension is known to arise from deficiencies of 11 beta-hydroxysteroid dehydrogenase and 5 beta-reductase activities. The equivalent ratios for corticosterone metabolites were not different between groups, but total corticosterone metabolite excretion was higher in the hypertensive group. Plasma cortisol levels were lower in hypertensive than in control subjects, but corticosterone levels were higher. This evidence supports a previous suggestion that the activities of these two enzymes may be reduced in essential hypertension, but the contribution of these changes to hypertension is not known. PMID- 7843757 TI - Relation between cold pressor test and development of hypertension based on 28 year follow-up. AB - The present study examined the relation between blood pressure reactivity to cold stimulus and the subsequent development of hypertension based on a follow-up study from 1960 through 1988 of 824 normotensive participants (mean age, 35.8 +/- 10.8 years) in the Adult Health Study in Nagasaki, Japan. Hypertension developed in 343 individuals during the 28 years of follow-up, with a mean incidence rate of 24.6 per 10(3) person-years. Confounding variables, including attained age, resting systolic and diastolic blood pressures, and body mass index at baseline, were adjusted using a Poisson regression model. Systolic response was found to be an independent and significant predictor. The relative risk of hypertension for systolic hyperreactors was 1.37, with a 95% confidence interval of 1.10 to 1.71. Diastolic response was significant only when resting diastolic blood pressure was also considered. The cold pressor test appears to be useful if performed on middle-aged subjects older than 40 years at the time of examination, when hypertension is more prevalent. The current results support the hypothesis that hyperreactivity is a predictor of the development of hypertension. PMID- 7843758 TI - Hypertension after renal transplantation. Calcium channel or converting enzyme blockade? AB - We compared the effects of 4 weeks of calcium channel blockade (amlodipine) or converting enzyme inhibition (lisinopril) on blood pressure and renal hemodynamics in a double-blind crossover trial in a group of 20 hypertensive cyclosporine-treated renal transplant patients. Amlodipine (10 mg) was more effective than the same dose of lisinopril in controlling hypertension (mean 24 hour arterial pressure, 111 +/- 9 and 115 +/- 9 mm Hg, respectively; P < .05). Blood pressure during both treatments was lower than during placebo (124 +/- 12 mm Hg, P < .05). Compared with placebo, amlodipine treatment was associated with a significant increase in glomerular filtration rate (10 +/- 20%, P < .05) and effective renal plasma flow (27 +/- 20%, P < .01) and a decrease in renal vascular resistance (23 +/- 18%, P < .01). Renal hemodynamics did not change during lisinopril. Neither drug had an effect on proteinuria. The data indicate that amlodipine is more effective than lisinopril in controlling hypertension in cyclosporine-treated patients and that treatment with amlodipine but not with lisinopril is accompanied by an increase in glomerular filtration rate and effective renal plasma flow and a decrease in renal vascular resistance. The data suggest that the renin-angiotensin system does not play a main role in determining cyclosporine-associated changes in renal hemodynamics and has a limited role in determining cyclosporine-associated hypertension. PMID- 7843759 TI - Blood pressure after captopril withdrawal from spontaneously hypertensive rats. AB - The purpose of the present study was to compare the effect of chronic captopril treatment on blood pressure in young and adult spontaneously hypertensive rats (SHR) and to assess the time course for development of hypertension after captopril withdrawal. SHR received drinking water or captopril solution from 4 weeks of age and were instrumented with radiotelemetry devices at 18 weeks of age to allow continuous monitoring of blood pressure. At 23 weeks of age, mean blood pressure in the captopril group was 100 +/- 1 mm Hg compared with 157 +/- 3 mm Hg in the water group. Pulse pressure also was significantly reduced in the captopril-treated rats. Infusion of angiotensin II into a subset of captopril treated rats increased pulse pressure and restored blood pressure to levels of water-treated rats. Captopril treatment for 6 weeks in adult, 24-week-old SHR did not reduce blood pressure to the level of rats treated from 4 weeks of age. Ten weeks after cessation of captopril, blood pressure was 125 +/- 4 and 144 +/- 4 mm Hg in SHR treated with captopril from 4 to 30 and from 24 to 30 weeks of age, respectively, compared with control hypertensive rats with mean blood pressure of 160 +/- 6 mm Hg. Results from this radiotelemetry study confirm previous findings that captopril treatment prevents the development of hypertension and produces a persistent reduction of blood pressure after treatment in young SHR. Captopril treatment produced a persistent reduction of blood pressure after discontinuation in adult rats; however, the effect was less than that observed with captopril initiated in young rats. PMID- 7843760 TI - Racial differences in epinephrine and beta 2-adrenergic receptors. AB - This study examined the effects of ethnicity and hypertension on beta 2 adrenergic receptors and on plasma catecholamines in a group of 77 unmedicated mildly hypertensive and normotensive men. Black hypertensive subjects had the most sensitive and white hypertensive subjects the least sensitive beta-receptors (as assessed by isoproterenol-stimulated cyclic AMP in lymphocytes [P = .02]). In contrast, postreceptor adenylate cyclase activation (as assessed by forskolin stimulation) was similar among groups. As with beta-receptor sensitivity, black hypertensive subjects had the highest beta-receptor density and white hypertensive subjects the lowest (P = .03). Blacks demonstrated lower plasma epinephrine values compared with whites (P = .03). Across all subjects, plasma epinephrine was negatively correlated with beta-receptor density (r = -.26, P < .05) and sensitivity (r = -.25, P < .05). There were no group differences in binding affinity to the beta-antagonist iodopindolol. The findings support the notion of increased beta-adrenergic receptors in hypertension in blacks. PMID- 7843761 TI - Ramipril-induced regression of left ventricular hypertrophy in treated hypertensive individuals. HYCAR Study Group. AB - The objective of this trial was to assess the effects of 6-month daily treatment with two doses of ramipril on left ventricular mass and the dependence of this on blood pressure changes in hypertensive patients with left ventricular hypertrophy. After a selection phase of 4 to 6 weeks with patients under antihypertensive therapy with 20 mg furosemide daily, 115 patients with either controlled or uncontrolled hypertension and left ventricular hypertrophy were randomized in a double-blind manner to receive either placebo (n = 40), 1.25 mg (low dose, n = 38), or 5 mg (regular dose, n = 37) ramipril daily for 6 months. Treatment with furosemide was continued unchanged during this phase. The main outcome measured was left ventricular hypertrophy regression as assessed from central blind reading of echocardiograms recorded at randomization and after 6 months. No significant differences were observed for changes in casual or ambulatory blood pressure between the three groups. Left ventricular mass index was found to be significantly reduced in patients receiving 5 mg ramipril compared with those receiving placebo (-10.8 +/- 3.7 versus +4.1 +/- 4.0 g/m2, P = .008); in patients receiving 1.25 mg ramipril, the difference was close to borderline significance compared with placebo (-7.0 +/- 4.3 g/m2, P = .06). Similar results were observed for changes in left ventricular mass (-20.3 +/- 6.6 and -13.0 +/- 7.8 g in the 5- and 1.25-mg ramipril groups, respectively, versus +9.1 +/- 7.2 g in the placebo group; P = .004 and .04, respectively).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843762 TI - Myocardial remodeling in hypertensive Ren-2 transgenic rats. AB - Rats harboring the mouse Ren-2 transgene develop hypertension despite low levels of plasma renin. We determined the extent of left ventricular remodeling present in Ren-2 rats at 16 weeks of age by measuring blood pressure, ratio of heart weight to body weight, left ventricular wall thickness, passive (diastolic) left ventricular compliance, and left ventricular collagen content using hydroxyproline and collagen area fraction. Changes in perivascular fibronectin and collagen type I and III were examined with immunohistochemistry. Blood pressure values at time of death were 244 +/- 15 mm Hg for Ren-2 rats (mean +/- SD, n = 5). Ratios of heart weight to body weight (grams per kilogram) for Ren-2 animals were 4.1 +/- 0.2 versus 3.1 +/- 0.1 for controls (n = 6, P < .001). Wall thickness values for control animals were 2.6 +/- 0.1 versus 4.1 +/- 0.4 mm for Ren-2 animals (P < .001). Left ventricular Ren-2 hydroxyproline measurements were significantly decreased (3.4 +/- 0.2 versus 4.7 +/- 0.9 mg/g dry wt for controls). Significant decreases of approximately 30% were also observed in collagen area fraction in Ren-2 rats. Immunohistochemical and picrosirius red staining indicated increased amounts of perivascular fibrosis in all Ren-2 animals (when compared with controls) with enhanced levels of perivascular fibronectin and type I and type III collagen proteins. Left ventricular compliance measurements indicated a decrease in left ventricular volume for all left ventricular pressures (P = .07).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843763 TI - Theodore Cooper Memorial Lecture. Hypertension and the pathogenesis of atherosclerosis. Oxidative stress and the mediation of arterial inflammatory response: a new perspective. AB - Hypertension is a risk factor for the development of atherosclerosis, although the mechanisms have not been well elucidated. As the cellular and molecular mechanisms of the pathogenesis of atherosclerosis and the effects of hypertension are being more clearly defined, it becomes apparent that the two processes have certain common mechanisms. The endothelium is a likely central focus for the effect of both diseases. There is increasing evidence that atherosclerosis should be viewed fundamentally as an inflammatory disease. Atherogenic stimuli such as hyperlipidemia appear to active the inflammatory response by causing expression of mononuclear leukocyte recruiting mechanisms. The gene for one of these, the vascular cell adhesion molecule-1, is controlled at least in part by transcriptional factors regulated by oxidative stress, which modifies the redox state of the endothelial cell. Alterations in the redox state of the arterial wall also may contribute to vascular smooth muscle cell growth. In a somewhat parallel fashion, there is evidence that hypertension may also exert oxidative stress on the arterial wall. This article reviews evidence that leads to the postulate that hypertension predisposes to and accelerates atherosclerosis at least in part because of synergy between elevated blood pressure and other atherogenic stimuli to induce oxidative stress on the arterial wall. PMID- 7843764 TI - Resetting blood pressure in spontaneously hypertensive rats. The role of bradykinin. AB - Brief angiotensin-converting enzyme (ACE) inhibition in young spontaneously hypertensive rats (SHR) causes a persistent reduction in blood pressure. Bradykinin accumulation may contribute to these long-term effects, and to test this hypothesis we studied the consequences of bradykinin B2 receptor antagonism during ACE inhibitor treatment in young SHR. Male SHR were treated from 6 to 10 weeks of age with water, ramipril (1 mg/kg per day), Hoe 140 (0.5 mg/kg per day), or both ramipril and Hoe 140. Systolic blood pressure and body weight were measured each week from 6 to 20 weeks of age. During treatment, Hoe 140 treatment resulted in lower blood pressures than in controls. Rampiril caused a larger fall in blood pressure over the same period. The ramipril plus Hoe 140 group had the lowest blood pressures of any group during treatment. After treatment, the blood pressure of Hoe 140-treated SHR was similar to that of untreated SHR. After ramipril, blood pressure rose but plateaued significantly below values in controls. In contrast, withdrawal of combined ramipril and Hoe 140 treatment caused a rapid rise of systolic blood pressure to levels significantly higher than in ramipril-treated SHR but less than in controls. The antihypertensive effects of Hoe 140 during the development of genetic hypertension may represent a direct effect of the drug or some alteration in the normal relation between bradykinin and blood pressure. The antagonism by Hoe 140 of the long-term blood pressure reduction after ramipril withdrawal indicates that the persistent effects of ACE inhibitors may in part be due to the accumulation of bradykinin during a critical stage of development. PMID- 7843765 TI - A heme oxygenase product, presumably carbon monoxide, mediates a vasodepressor function in rats. AB - Heme oxygenase is a mammalian enzyme that converts heme to biliverdin and carbon monoxide. Carbon monoxide activates soluble guanylate cyclase and relaxes vascular smooth muscle, and it has been implicated as a potential neuromessenger. The regulatory functions of endogenous carbon monoxide on hemodynamics are not known. Zinc deuteroporphyrin 2,4-bis glycol (ZnDPBG) inhibits heme oxygenase in rats and thus permits assessment of the hemodynamic response to inhibition of endogenous carbon monoxide synthesis. In chronically instrumented, awake male Sprague-Dawley rats, ZnDPBG (45 mumol/kg IP) increased mean arterial pressure (19 +/- 2%, P < .05) and total peripheral resistance (47 +/- 4%, P < .05), decreased cardiac output (-16 +/- 2%, P < .05), but did not affect heart rate. Another heme oxygenase inhibitor, zinc protoporphyrin IX (45 mumol/kg IP), also increased arterial pressure (17 +/- 5%, P < .05), with no effect on heart rate. In contrast, neither the nonmetallic deuteroporphyrin 2,4-bis glycol (45 mumol/kg IP) nor bilverdin (45 mumol/kg IP) had any effect on blood pressure or heart rate. These findings suggest that ZnDPBG and zinc protoporphyrin IX increase arterial pressure by inhibiting heme oxygenase activity. After pretreatment with chlorisondamine (5 mg/kg IP) or prazosin (5 mg/kg IP) to inhibit autonomic ganglionic or alpha 1-adrenoceptor functions, respectively, ZnDPBG did not affect arterial pressure or heart rate. This suggests that ZnDPBG-induced increases in blood pressure rely on autonomic nervous function. We conclude that the pressor response to heme oxygenase inhibitors results from withdrawal of the inhibitory influence of endogenous carbon monoxide on a pressor mechanism mediated by the autonomic nervous system. PMID- 7843766 TI - Production of aldosterone in isolated rat blood vessels. AB - Angiotensin I (Ang I), Ang II, angiotensinogen, and renin are formed locally in the vasculature. We undertook this study to determine whether the rat mesenteric artery produces aldosterone and to investigate the effects of adrenalectomy, an angiotensin-converting enzyme inhibitor, Ang II, or potassium on aldosterone production in vascular tissue. Isolated rat mesenteric arteries were perfused with Krebs-Ringer solution for 4 hours. The perfusate was collected and chromatographed in a reversed-phase high-performance liquid chromatographic (HPLC) system. The fraction corresponding to synthetic aldosterone was collected and analyzed by mass spectrometry. The aldosterone concentration in the perfusate from the adrenalectomized rats and rats treated with an angiotensin-converting enzyme inhibitor was measured using radioimmunoassay after HPLC separation. The mass spectra of synthetic aldosterone and aldosterone isolated from the perfusate of rat mesenteric arteries were identical. Aldosterone production in the mesenteric arteries of adrenalectomized rats was increased and of rats treated with an angiotensin-converting enzyme inhibitor was reduced compared with that of controls. Ang II (1.9 x 10(10) mol/L) and potassium (6.0 mmol/L) increased aldosterone production in mesenteric arteries. This study shows that the rat mesenteric artery produces aldosterone and that the intravascular renin angiotensin-aldosterone system may contribute to vascular tone. PMID- 7843767 TI - Nitric oxide synthesis inhibition blocks reversal of two-kidney, one clip renovascular hypertension after unclipping. AB - It is well established that two-kidney, one clip renovascular hypertension can be rapidly reversed by unclipping. We hypothesized that rapid renal reperfusion and the subsequent fall in blood pressure are mediated in part by nitric oxide, the endothelium-derived relaxing factor. We tested whether the hypotensive response to unclipping could be blocked by nitric oxide synthesis inhibition using a bolus of 10 mg/kg body wt N omega-nitro-L-arginine methyl ester. Rats were made hypertensive by placing a silver clip on the left renal artery. After 4 weeks, they were anesthetized and either not treated (controls) or had nitric oxide synthesis blockade. After 10 minutes, the clip was removed and blood pressure monitored over 60 minutes. Initial pressure in controls was 157 +/- 8 mm Hg, and heart rate was 310 +/- 21 beats per minute. Unclipping resulted in pressure falling to 125 +/- 6 mm Hg within 45 minutes (P < .005). Heart rate was unchanged (312 +/- 9 beats per minute). In contrast, nitric oxide synthesis inhibition increased blood pressure from 149 +/- 6 to 174 +/- 9 mm Hg (P < .001). Unclipping did not change blood pressure, which was 167 +/- 8 mm Hg after 60 minutes (P < .005 versus controls), and heart rate remained unchanged (282 +/- 13 versus 276 +/- 16 beats per minute). We determined the blood flow to the clipped kidneys using radioactive microspheres. Unclipping untreated hypertensive rats resulted in a 10-fold increase in renal blood flow (P < .001), concomitant with a decrease in blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843768 TI - Role of nitric oxide in the regulation of coronary vascular tone in hearts from hypertensive rats. Maintenance of nitric oxide-forming capacity and increased basal production of nitric oxide. AB - In arterial hypertension, coronary flow reserve, expressed by the difference between autoregulated and maximal coronary flow, is frequently impaired. Previous experimental and clinical investigations using acetylcholine as a stimulus for the production of endothelium-derived relaxing factor suggested that an impaired endothelium-dependent vasodilation, presumably caused by a decreased formation of nitric oxide (NO), may account for this microvascular dysfunction. However, so far no study has been performed that quantifies the formation of NO within the coronary circulation of hypertensive hearts to assess its role in setting coronary vascular tone in the hypertensive heart. We therefore quantified NO formation within the coronary circulation of constant flow-perfused, isolated hearts from spontaneously hypertensive rats (SHR, 16th to 26th week), as a model for hypertensive heart disease, and from the normotensive control strain (Wistar Kyoto, WKY) using the oxyhemoglobin technique. Coronary perfusion pressure and vascular resistance were almost 30% higher in SHR compared with WKY hearts. Intracoronarily applied NO decreased coronary vascular resistance by maximally 45% of resting values in a concentration-dependent manner in both groups. The bradykinin-induced decrease in coronary vascular resistance and the parallel increase in NO release were comparable in SHR and WKY hearts and fell within the vasodilator range of exogenously applied NO. Moreover, basal release of NO normalized to heart wet weight was 50% higher in SHR compared with WKY hearts. Rates of basal NO release were correlated inversely with changes in coronary perfusion pressure and vascular resistance in both groups (r = -.85 and -.84, respectively, P < .05).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843769 TI - Different mechanisms of endothelial dysfunction with aging and hypertension in rat aorta. AB - We analyzed the effects and mechanisms of aging in aortic endothelium and vascular smooth muscle of 12-week-old (adult) and 72-week-old (senescent) normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Aortas were suspended in organ chambers filled with physiological salt solution (95% O2/5% CO2; 37 degrees C), and isometric tension was measured. In WKY, endothelium-dependent relaxations to acetylcholine were diminished with aging (P < .05); in SHR, they were reduced compared with WKY (P < .05) but unchanged with aging. The thromboxane/endoperoxide receptor antagonist SQ 30741 increased relaxations only in adult SHR. Relaxations to sodium nitroprusside were slightly enhanced with age in WKY and SHR (P < .05). Endothelium-dependent contractions to acetylcholine were unmasked by NG-nitro-L-arginine methyl ester (P < .05) and prevented by SQ 30741 or endothelium removal. In WKY, contractions increased with age. In adult SHR, marked endothelium-dependent contractions occurred (P < .05 versus WKY), which diminished with age (P = NS versus senescent WKY). The thromboxane analogue U46619 elicited similar contractions in adult and senescent WKY and adult SHR, whereas responses in senescent SHR were weaker (P < .05). In WKY and SHR, contractions to norepinephrine were similar and unaltered by aging. In WKY, contractions to endothelin-1 remained unaffected by aging. Adult SHR exhibited contractions to endothelin-1 comparable to those in WKY, whereas senescent SHR contracted less (P < .05). Bosentan, a combined endothelin A/endothelin-B receptor antagonist, inhibited endothelin-1 markedly, especially in SHR (P < .05).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843770 TI - Glomerular dynamics and morphology of aged spontaneously hypertensive rats. Effects of angiotensin-converting enzyme inhibition. AB - Relationships between glomerular dynamics and renal injury, micropuncture and histological studies were assessed in 73 week-old normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats divided into untreated and angiotension converting enzyme inhibitor-treated (quinapril; 3 mg/kg/day; for 3 weeks) groups. Urinary protein excretion (UPE) and histologic arteriolar (AIS) and glomerular (GIS) injury scores were determined. Mean arterial pressure (MAP) of untreated SHR was increased compared with WKY (200 +/- 6 vs 119 +/- 4 mm Hg; P < 0.01), effective renal plasma flow (ERPF) was reduced (1.47 +/- 0.21 vs 3.06 +/- 0.26 ml/min/per g; P > 0.01), and filtration fraction (FF) and total renal vascular resistance (RVR) of SHR were increased (P < 0.01). Single-nephron plasma flow (SNPF) of untreated SHR was decreased (174 +/- 17 vs 80 +/- 9 ml/min; P < 0.01), and single-nephron filtration fraction and afferent arteriolar resistance (RA) were increased (19.4 +/- 1.8 vs 30.0 +/- 2.5% and 1.90 +/- 0.25 vs 9.05 +/- 1.35 U, respectively; both P < 0.01). Despite reduced SNPF, glomerular capillary pressure (PG) increased (49.7 +/- 0.7 vs 53.8 +/- 1.3 mm Hg; P < 0.05), the result of efferent arteriolar constriction (1.15 +/- 0.18 vs 2.84 +/- 0.36 U; P < 0.01). Untreated SHR had higher UPE (13.9 +/- 1.5 vs 42.8 +/- 3.2; mg/100 g per day; P < 0.01) and GIS and AIS scores than WKY (4.3 +/- 1.1 vs 64.3 +/- 8.4 and 16.6 +/- 3.1 vs 96.3 +/- 14.4; both P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843771 TI - Insulin and forearm vasodilation in hypertension-prone men. AB - Insulin-stimulated peripheral glucose uptake and insulin-mediated forearm vasodilation were investigated in 38 normotensive men with a family history of hypertension (relatives) compared with 27 age- and body mass index-matched normotensive men with no family history of hypertension (control subjects). The euglycemic hyperinsulinemic clamp technique was used to measure peripheral glucose uptake (insulin sensitivity index) and the metabolic clearance rate of insulin. Intra-arterial blood pressure and forearm blood flow were determined simultaneously, and forearm vascular resistance was calculated. The insulin sensitivity index was lower in relatives than in control subjects. The metabolic clearance rate of insulin was reduced and did not correlate to glucose disposal in the relatives as opposed to the control subjects. Forearm blood flow increased and forearm vascular resistance decreased to a similar extent in the two groups during the clamp. The vasodilator response was positively correlated to glucose disposal only in the relatives. In conclusion, impaired insulin-stimulated peripheral glucose uptake in normotensive sons from hypertensive families was accompanied by retained insulin-mediated forearm vasodilation. Thus, skeletal muscle blood flow supply does not seem to be the major determinant for glucose disposal. On the other hand, the positive correlation between glucose disposal and decrease in forearm vascular resistance in the relatives suggests that insulin-mediated vasodilation may be a limiting factor for peripheral glucose uptake in insulin-resistant individuals. PMID- 7843772 TI - Natriuretic peptides inhibit DNA synthesis in cardiac fibroblasts. AB - We have examined the effects of the natriuretic peptides on DNA synthesis in primary cultures of neonatal rat cardiac fibroblasts. Binding analysis using 125I labeled atrial natriuretic peptide identified a single class of high-affinity binding sites (Kd = 0.03 +/- 0.01 nmol/L) in these cells. Of these sites, 80% appear to be of the natriuretic peptide C receptor subtype, with the remainder being A and B receptor subtypes. Northern blot analysis confirmed the presence of all three natriuretic peptide receptors in these cells. Atrial natriuretic peptide (10(-7) mol/L) effected a modest but consistent reduction in both agonist and stretch-stimulated [3H]thymidine incorporation (17% to 41%). Moreover, brain natriuretic peptide (10(-7) mol/L), C-type natriuretic peptide (10(-7) mol/L), and des-[Gln18,Ser19,Gly20,Leu21,Gly22]-ANF 4-23-NH2 (10(-7) to 10(-6) mol/L) all proved capable of antagonizing growth factor-dependent [3H]thymidine incorporation (the inhibition ranged from 14% to 28%) and cell proliferation, suggesting that all three natriuretic peptide receptor subtypes are involved in the regulation of mitogenesis in these cultures. The inhibition by atrial natriuretic peptide was amplified by cotreatment with phosphodiesterase inhibitors. Similar reduction in [3H]thymidine incorporation was seen after treatment with 8-bromo-cGMP (10(-4) to 10(-3) mol/L) or nitroprusside (10(-4) to 10(-3) mol/L). These results suggest an important paracrine role for the natriuretic peptides in regulating fibroblast growth during cardiac hypertrophy. PMID- 7843773 TI - Cardiac glucose and fatty acid oxidation in the streptozotocin-induced diabetic spontaneously hypertensive rat. AB - Hypertension intensifies the cardiac dysfunction of diabetes. We investigated the possible role of altered exogenous fuel oxidation in this phenomenon. Diabetes was induced by streptozotocin in spontaneously hypertensive rats and normotensive Sprague-Dawley rats. Two weeks later, mechanical performance and the oxidation of glucose and palmitate were quantified in working hearts ex vivo at intermediate and high workloads. The results showed that the nondiabetic spontaneously hypertensive rat hearts, compared with those of the normotensive controls, oxidized glucose at a higher rate but oxidized palmitate at a much lower rate, as reported previously. The effects of diabetes in the hypertensive rats, compared with its effects in the normotensive strain, were characterized by (1) a more pronounced decrease in heart performance, (2) either a similar or a less marked reduction in the rate of glucose oxidation, depending on the workload, and (3) a relatively greater increase in palmitate oxidation, particularly at the higher workload. These findings suggest that the exaggerated stimulation of fatty acid oxidation by diabetes in the hypertrophic left ventricle may be a more important contributor to the premature mechanical dysfunction than the inhibition of glucose oxidation. Possible mechanisms include antagonism of energetically favorable shifts in fuel oxidation or inhibition of accelerated membrane lipid biosynthesis in left ventricular hypertrophy. PMID- 7843774 TI - Gender differences and the electrocardiogram in left ventricular hypertrophy. AB - We examined the relations of gender differences in electrocardiographic (ECG) voltages and QRS duration to differences in cardiac dimensions and body size between men and women and gender differences in test performance of ECG criteria for the detection of echocardiographic left ventricular hypertrophy in 389 subjects (112 women and 277 men). ECG voltage-duration products were calculated as the product of QRS duration and voltages. Among subjects with normal left ventricular mass and also among subjects with left ventricular hypertrophy, men had longer QRS duration, higher Cornell voltage, higher 12-lead sum of QRS voltage, and higher Cornell and 12-lead voltage-duration products than did women. Significant gender differences in QRS duration, Cornell voltage, the 12-lead sum of voltage and their voltage-duration products remained after adjusting for the greater left ventricular mass, height, and weight in men than women. Comparison of areas under receiver operating characteristic curves using gender-specific criteria demonstrated higher performance of QRS duration, Cornell voltage, the 12 lead sum of QRS voltage, and the respective voltage-duration products for the identification of left ventricular hypertrophy in men than women. Thus, gender differences in body size and left ventricular mass do not completely account for gender differences in QRS duration and voltage measurements, and ECG criteria for left ventricular hypertrophy have lower accuracy in women even when gender differences in partition value selection are taken into account.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843775 TI - Blockade of the renin-angiotensin system in cardiac pressure-overload hypertrophy in rats. AB - Left ventricular hypertrophy in response to pressure overload may be modified by neurohumoral activation. To investigate the contribution of the renin-angiotensin system, we studied rats after banding of the ascending aorta that developed severe left ventricular hypertrophy associated with normal plasma renin but elevated cardiac angiotensin-converting enzyme (ACE) levels. Rats were treated with vehicle, ACE inhibitor (ramipril), angiotensin II type 1 receptor antagonist (losartan), or vasodilator (hydralazine) during weeks 7 through 12 after aortic banding. A significant regression of left ventricular mass index as determined by serial echocardiography was observed in ramipril- and losartan-treated groups during weeks 9 through 12 after banding, whereas hypertrophy further increased in vehicle- and hydralazine-treated groups. Twelve weeks after banding, relative left ventricular weights and myocyte widths were markedly increased in vehicle- and hydralazine-treated groups, whereas ramipril and losartan significantly reduced these parameters. In addition, molecular adaptations in left ventricular hypertrophy, such as upregulation of left ventricular atrial natriuretic peptide and downregulation of sarcoplasmic reticulum Ca(2+)-ATPase mRNA levels, were blunted by ramipril or losartan treatment. Hypertrophic regression was associated with reduced mortality in rats treated with ramipril (11%) and losartan (13%) versus hydralazine (20%) and vehicle (31%). Thus, the renin-angiotensin system may be involved in the maintenance of chronic left ventricular hypertrophy. Blockade of the system may result in regression of the hypertrophic phenotype and improve survival in rats despite persistent pressure overload. PMID- 7843776 TI - Different flow regulation mechanisms between celiac and mesenteric vascular beds in conscious rats. AB - The aims of this study were to elucidate the vasoconstrictor mechanism that mediates the changes in celiac and mesenteric vascular resistances during vasoconstriction and hypertension induced by ganglionic blockade and to explore the preferential mechanism that contributes to the elevation of arterial pressure in conscious spontaneously hypertensive rats (SHR). In conscious SHR and normotensive control rats, blood flow and arterial pressure were measured with an implanted electromagnetic flow probe and an indwelling arterial catheter. Peripheral vascular resistance was calculated as arterial pressure divided by regional flow. Celiac contribution to the hypertension in SHR was below average for the entire body and was smaller than that from the superior mesenteric bed. The increase of mesenteric resistance with arterial pressure elevation after ganglionic blockade suggests that mesenteric blood flow is regulated by a stretch dependent myogenic mechanism, whereas celiac blood flow is regulated preferentially by the sympathetic neural mechanism. It is speculated that the flow superregulation in the mesenteric bed in SHR is due to the enhanced myogenic response and contributes to the early stage of hypertension. PMID- 7843777 TI - Blood pressure response to the Valsalva maneuver in pheochromocytoma and pseudopheochromocytoma. AB - To elucidate whether a difference in blood pressure reactivity exists between patients with pheochromocytoma (n = 8) and pseudopheochromocytoma (n = 22), we evaluated blood pressure changes during a Valsalva maneuver and baroreceptor reflex sensitivity. We also examined the effects of propranolol and prazosin on blood pressure reactivity during a Valsalva maneuver in patients with pseudopheochromocytoma. Pseudopheochromocytoma was defined as a paroxysmal rise in blood pressure accompanying pheochromocytoma-like symptoms and normal catecholamine values. The difference in systolic blood pressure between phase IV of the Valsalva maneuver and baseline (delta SBP) was markedly smaller in the pheochromocytoma patients (8.4 +/- 18.4 mm Hg) than in the essential hypertension patients (n = 30, 30.9 +/- 19.4 mm Hg) and normotensive control subjects (n = 10, 31.3 +/- 11.4 mm Hg), whereas delta SBP in the pseudopheochromocytoma patients (77.8 +/- 11.2 mm Hg) was markedly greater than in the other three groups. delta SBP was markedly suppressed by the administration of both propranolol and prazosin. Baroreceptor reflex sensitivity index was lower in the pheochromocytoma group than in the other three groups. In conclusion, blood pressure reactivity responses to a Valsalva maneuver are disparate between pheochromocytoma and pseudopheochromocytoma. The high blood pressure reactivity to a Valsalva maneuver in pseudopheochromocytoma is due to hyperactivity in both beta- and alpha 1 adrenergic receptor functions, and the low blood pressure reactivity to a Valsalva maneuver in pheochromocytoma seems to be mainly due to the desensitization of both adrenergic systems associated with chronic catecholamine excess. In addition, the impaired baroreceptor function in pheochromocytoma is partially responsible for it. PMID- 7843779 TI - Attenuated cardiovascular response to adenosine in the brain stem nuclei of spontaneously hypertensive rats. AB - We previously reported that adenosine has significant depressor effects in the nucleus tractus solitarii and area postrema of the rat. The purpose of this study was to determine whether the spontaneously hypertensive rat (SHR) has abnormalities in medullary sensitivity to adenosine. Male SHR and Wistar-Kyoto (WKY) rats (aged 12 to 15 weeks) were anesthetized with urethane, and blood pressure was monitored intraarterially. Stereotaxic microinjection (60 nL) of adenosine was made into the nucleus tractus solitarii and the area postrema and was confirmed histologically. Dose-related decreases in mean blood pressure and heart rate occurred in both strains tested, and this effect was completely abolished by 1,3-dipropyl- 8-p-sulfophenylxanthine (0.92 nmol), a potent adenosine receptor antagonist. However, there were significant differences between SHR and WKY rats in the magnitude of blood pressure and heart rate depression. A similar pattern of response was found in the area postrema. Thus, adenosine is a potent depressor agent in the nucleus tractus solitarii and area postrema of rats, and adenosine has significantly fewer depressor effects in SHR. These data suggest that alterations in purinergic mechanisms of central cardiovascular control exist in the SHR model. PMID- 7843778 TI - Carotid artery mechanical properties of Dahl salt-sensitive rats. AB - We evaluated the mechanical properties of the carotid artery in anesthetized Dahl rats with or without long-term treatment with the diuretic compound indapamide. The mechanical properties of the carotid artery were evaluated by establishing pressure-volume curves in situ in vivo before and after total relaxation of arterial smooth muscle by potassium cyanide. Dahl salt-sensitive and salt resistant rats were fed either a low (0.4%) or high (7%) NaCl diet for 5 weeks. In each group, half the rats received for the same period of time oral treatment with indapamide (3 mg/kg per day). Blood pressure, heart rate, and pressure volume curves were studied at the end of the 5-week period. In untreated Dahl salt-sensitive rats, the pressure-volume curve of the carotid artery was shifted to the right compared with that in untreated Dahl salt-resistant rats. The finding was observed even after potassium cyanide and regardless of the NaCl diet (P < .01 between Dahl salt-sensitive and -resistant rats). Indapamide was able to prevent the development of hypertension in Dahl salt-sensitive rats receiving a high NaCl diet (185 +/- 7 versus 146 +/- 8 mm Hg in untreated and treated Dahl salt-sensitive rats with a high NaCl diet, P < .0005). In the other groups, indapamide had no effect on blood pressure. Indapamide treatment increased carotid arterial static compliance in Dahl salt-sensitive rats with a high or low NaCl diet and to a lesser extent in Dahl salt-resistant rats. The increase was observed even after total relaxation of carotid arterial smooth muscle by potassium cyanide.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843780 TI - Effect of EXP 3174 on blood pressure of normoreninemic renal hypertensive rats. AB - This study examined the effect on mean blood pressure of a new orally active nonpeptide angiotensin II (Ang II) receptor antagonist, EXP 3174, in doses that completely block exogenous Ang II action. Anesthetized and conscious two-kidney, two clip chronic renovascular hypertensive rats and sham-operated animals were used. In anesthetized hypertensive rats, intracerebroventricular administration of the inhibitor had no effect on blood pressure, whereas blood pressure was normalized by intravenous injection of the antagonist (163 +/- 12 to 110 +/- 9 mm Hg, P < .05). In sham anesthetized rats, intravenous injection of EXP 3174 also lowered blood pressure (112 +/- 6 to 96 +/- 6mm Hg, P < .05). In conscious rats, intravenous EXP 3174 induced a fall in pressure that was larger in hypertensive (156 +/- 9 to 132 +/- 5 mm Hg, P < .05) than in sham (104 +/- 3 to 94 +/- 4 mm Hg, P < .05) rats. Plasma renin activity was very high in anesthetized animals (hypertensive versus sham, 87.8 +/- 8.3 versus 95.7 +/- 10.2 ng Ang I/mL per hour); differences were not significant either between anesthetized hypertensive and sham or in conscious animals (hypertensive versus sham, 9.42 +/- 1.58 versus 6.74 +/- 2.32 ng Ang I/mL per hour). Angiotensinogen concentration was higher in cerebrospinal fluid in anesthetized hypertensive rats (36.4 +/- 3.0 versus 26.0 +/- 2.4 ng Ang I/mL, P < .05) and in the artery wall of hypertensive conscious rats (103.1 +/- 10.3 versus 75.2 +/- 7.8 ng Ang I/g, P < .05).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843781 TI - Enhanced slow pressor effect of angiotensin II in two-kidney, one clip rats. AB - Phase II of two-kidney, one clip (2K1C) Goldblatt hypertension in the rat is characterized by elevated blood pressure and near-normal plasma concentrations of angiotensin II (Ang II) but is reversed by inhibition of the renin-angiotensin system. We hypothesized that this angiotensin dependence is due to enhanced responsiveness to the slow pressor effect of Ang II caused by renal artery stenosis. To test this idea, we submitted rats to either renal artery clipping or sham operation. These groups were immediately subdivided; some animals received enalapril in their drinking water (508 mumol/L), and the rest drank distilled water only. After 10 to 14 days, catheters were inserted into the aorta and vena cava, and the rats were housed in metabolism cages. After 3 control days of measurement of mean arterial pressure and other variables, the enalapril-treated groups received an intravenous infusion of Ang II at a dose of 3.8 pmol/min (4 ng/min) for 14 days. Rats not drinking enalapril received only saline vehicle (2 mmol Na+ per day). After 3 days of Ang II infusion, the enalapril-treated 2K1C rats had attained a significantly higher level of mean arterial pressure than the enalapril-treated sham rats. At the end of the Ang II infusion, mean arterial pressure in enalapril-treated 2K1C rats was 151 +/- 6 mm Hg versus 107 +/- 7 mm Hg in enalapril-treated sham rats. Mean arterial pressure in the enalapril treated sham rats after Ang II infusion was not significantly different from that of untreated sham rats (109 +/- 2 mm Hg).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843782 TI - Feasibility study of N-of-1 trials with blood pressure self-monitoring in hypertension. AB - The objective of this study was to assess individual responses to antihypertensive treatment by N-of-1 trials using blood pressure self-monitoring in 79 patients of both sexes referred to a hypertension clinic. Thirty-five patients who remained untreated (study 1) and 44 N-of-1 trial participants (study 2) were consecutively selected if their clinic blood pressure was between 160/95 and 220/115 mm Hg and there were no hypertensive complications. Blood pressure was measured daily at home for 21 days (three consecutive measures, morning and evening). Each N-of-1 trial was a single-blind treatment consisting of two successive 10-day treatment pairs, each pair comprising 5 days of placebo followed by 5 days of 20 mg enalapril once daily in the morning. Study 1 showed no significant blood pressure regression toward the mean over 20 days and justified the choice of 5-day treatment periods in study 2. In study 2, blood pressure fell significantly 12 hours after the first administration of enalapril and rose within 24 hours of the end of the 5-day active treatment period. Using evening blood pressure values (12 hours after enalapril intake) from the first treatment pair, 33 patients were classified as responders (diastolic blood pressure fall > or = mm Hg). In 16 of these 33 patients, the fall in blood pressure above 6 mm Hg was not maintained in the morning, 24 hours after drug intake. Response reproducibility was tested by comparison with the second treatment pair: the observed agreement was only 0.71 (chance-corrected agreement: 0.34) when defined according to both evening and morning values.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843783 TI - Axons regulate the expression of Shaker-like potassium channel genes in Schwann cells in peripheral nerve. AB - We examined potassium channel gene expression of two members of the Shaker subfamily, MK1 and MK2, in sciatic nerves from rats and mice. In Northern blot analysis, MK1 and MK2 probes detected single transcripts of approximately 8 kb and approximately 9.5 kb, respectively, in sciatic nerve and brain from both species. Polymerase chain reaction amplification of a cDNA library of cultured rat Schwann cells using MK1- and MK2- specific primers produced DNA fragments that were highly homologous to MK1 and MK2. To determine whether these channel genes were axonally regulated, we performed Northern blot analysis of developing, permanently transected, and crushed rat sciatic nerves. The mRNA levels for both MK1 and MK2 increased from P1 to P15 and then declined modestly. Permanent nerve transection in adult animals resulted in a dramatic and permanent reduction in the mRNA levels for both MK1 and MK2, whereas normal levels of MK1 and MK2 were restored when regeneration was allowed to occur following crush injury. In all cases, MK1 and MK2 mRNA levels paralleled that of the myelin gene P0. Elevating the cAMP in cultured Schwann cells by forskolin, which mimics axonal contact but not myelination, did not induce detectable levels of MK1 and MK2 mRNA by Northern blot analysis. Further, the level of MK1 mRNA in the vagus nerve, which contains relatively fewer myelinating Schwann cells and relatively more non-myelinating Schwann cells than the sciatic nerve, is reduced relative to the sciatic nerve. In conclusion, we have identified two Shaker-like potassium channel genes in sciatic nerves whose expressions are regulated by axons. We suggest that MK1 and MK2 mRNA are expressed in high levels only in myelinating Schwann cells and that these Shaker-like potassium channel genes have specialized roles in these cells. PMID- 7843784 TI - Postmitotic oligodendrocytes generated during postnatal cerebral development are derived from proliferation of immature oligodendrocytes. AB - The phenotype of proliferating glia is examined during postnatal rodent development by combining immunocytochemistry (ICC) with 3H-thymidine autoradiography (ARG) to identify cells in the S phase of the cell cycle. Antibodies (ABs) which are specific for cells in the oligodendrocyte (OL) lineage were utilized, with emphasis placed upon the proliferation of OLs as it remains unclear whether this cell type divides in situ. The results show that proliferating cells stain with ABs which are specific for OLs and myelin glycolipids. The proliferating OLs (oligodendroblasts), although they do not appear to have formed myelin sheaths, have quite elaborate and distinctive morphologies. These oligodendroblasts give rise to very long, thin processes which in turn have additional branches. Their cytoarchitecture corresponds closely to cells described as oligodendroblasts with electron microscopy and whose processes often appear to be in the initial phase of myelination (Skoff et al: J. Comp. Neurol. 169:291-312, 1976a). These proliferating OLs are still quite immature because the expression of myelin specific proteins is only occasionally observed in 3H-thymidine labeled cells. The phenotype of the oligodendroblasts is quite different from that of proliferating astrocytes (astroblasts). As shown in previous studies (Skoff; Dev. Biol. 139:149-163, 1990), the astroblasts, which are identified by the presence of glial fibrillary acidic protein (GFAP), usually have thick, stubby processes, and both their nucleus and cytoplasm are larger and of lighter density than those found in oligodendroblasts. In early myelinating regions of the cerebrum, glycolipid positive cells account for the majority of the 3H-thymidine labeled cells. This data, when combined with the quantification of proliferating astrocytes (ASs) from previous immunocytochemical and electron microscopic studies, indicate that oligodendroblasts and astroblasts constitute the vast majority of the proliferating glia in the brain and in optic nerve at times when ASs and OLs are being generated. In normal postnatal cerebral development, the immature ASs and OLs which proliferate are the direct, immediate precursors for most postmitotic ASs and OLs. PMID- 7843785 TI - Cortical type 2 astrocytes are not dye coupled nor do they express the major gap junction genes found in the central nervous system. AB - The O-2A progenitor cell first described from the rat optic nerve is a bipotential precursor of oligodendrocytes and type 2 astrocytes. Each cell expresses specific markers that distinguish them as unique cell types. O-2A progenitors cultured in high serum preferentially differentiate into type 2 astrocytes and when exposed to defined medium or low serum develop along the oligodendrocyte lineage. We analyzed the gap junction gene expression of type 2 astrocytes to determine if they are coupled to form a syncytium, like their type 1 astrocyte counterparts. Dye coupling experiments demonstrated that cortical type 2 astrocytes are not coupled, while type 1 astrocytes in the same culture dish are highly coupled. Immunocytochemistry revealed the presence of Cx43 in type 1 astrocytes but we could not detect Cx26, 32, or 43 protein in type 2 astrocytes. In situ hybridization did not detect mRNA for any of the three connexin genes in type 2 astrocytes. These data demonstrate that type 2 astrocytes do not express the major gap junction genes found in the central nervous system. The precise function of type 2 astrocytes is not known but the lack of gap junction genes expression suggests that their functions are different from the spatial buffering capacity of type 1 astrocytes. PMID- 7843786 TI - A comparative Mac-1 immunocytochemical and lectin histochemical study of microglial cells in the normal and athymic mice. AB - The number of microglial cells in the supraventricular part of the corpus callosum stained with Mac-1 antibody (against CR3 antigens) and the intensity of staining were studied in both the homozygous athymic nude mouse (nu/nu) and normal BALB/c mouse (+/+). For quantitative analysis, the mean microglial cell counts (expressed in terms of packing density) from 40 microns thick immunostained sections were obtained and tested by analysis of variance. The Mac 1 positive cells in neonatal nude mice were slightly less intensely stained than those of their normal littermates. Such was not noticeable in the 13-week- and 1 year-old animals. The mean number of immunopositive microglial cells per 0.0324 mm2 was significantly less in the 5-day-old (P < 0.001) and 13-week-old (P < 0.05) nude mice when compared to normal mice of corresponding ages. The difference was insignificant in the 1-year-old nude and normal mice. The distribution of Mac-1 labelled microglia in different areas of the brain of the postnatal nude and normal mouse was also examined. In the brain areas examined, e.g., the olfactory bulb, cerebral and cerebellar cortex, the number of microglia in the nude mouse was considerably reduced. The study of lectin labelled sections also showed a much smaller number of labelled microglial cells in the athymic mouse. This was especially obvious in the 5-day-old nude mouse when compared to the normal BALB/c mouse (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843787 TI - Transitory disappearance of microglia during the regeneration of the lizard medial cortex. AB - In normal lizards, microglial cells populate the medial cortex (a zone homologous to the hippocampal fascia dentata), with a preferential distribution along the border between the granular cell layer and the plexiform layers. Intraperitoneal injection of the neurotoxin 3-acetylpyridine (3AP) induces a selective lesion in the medial cortex with a rapid degeneration of the granular layer and its zinc enriched axonal projection. Within 6-8 weeks, the granular layer is, however, repopulated by a new set of neurons generated in the subjacent ependyma and the cell debris is removed. The aim of this study was to determine to what extent microglia were involved in the scavenging processes during the regeneration process. To this end we studied the brains of regenerating lizards at different times after 3AP lesion, visualising microglial cells by the nucleoside diphosphatase (NDPase) histochemical reaction. Surprisingly, we found that stained microglial cells disappeared 6-8 hours after 3AP injection and remained absent until 10-15 days after injection. One month postlesion an increased population of microglial cells was found scattered throughout all plexiform layers of the cortex. Thorough examination of semithin and ultrathin sections confirmed the absence of microglia in the medial cortex of recent lesioned animals but the presence of an exuberant population after 1 month postlesion. In the tissue, phagocytotic scavenging was carried out by radial ependymocytes, not by microglia. PMID- 7843788 TI - Immunocytochemical demonstration of glycogen phosphorylase in Muller (glial) cells of the mammalian retina. AB - Glycogen phosphorylase (GP) was immunocytochemically detected in Muller cells of the rabbit and rat retina using a monoclonal antibody raised against bovine brain GP. Immunofluorescence and immunoenzymatic procedure were applied on isolated, Muller cells and sections of paraformaldehyde-fixed, paraffin-embedded retinas. All methods used revealed positive immunostaining. GP immunoreactivity was most intense in the Muller cell endfeet and the pericarya, corresponding to the nerve fibre layer and the inner nuclear layer in the retina. The presence of GP in Muller cells stresses the important role of these glial cells in the energy metabolism of the mammalian retina. PMID- 7843789 TI - Evidence for an NGF-induced autocrine neurotrophic potential of glial cells in nervous system development. AB - NGF receptor bearing peripheral glial cells, purified from chicken embryo dorsal root ganglia, were found to secrete neurite growth promoting activity (NGPA) but no NGF (detection limit 1 pM). If, however, minute concentrations of NGF (2 pM) were added to the glial cultures, an autocrine response was observed. Levels of NGF-like activity in the medium rose up to 50-fold. Induction of this autocrine response occured within a narrow range of NGF concentrations. NGPA production was not affected by addition of NGF. Coculture with neurons influenced the neurotrophic factor production. The data suggest that glial cells can "sense" traces of NGF and regulate its availability during neural development. PMID- 7843790 TI - Induction of neutrophil Mac-1 integrin expression and superoxide production by the medicinal plant extract gossypol. AB - Gossypol is present in antiinflammatory poultices made from the medicinal tree Thespesia populnea. Isolated human neutrophils exposed to 3-20 microM gossypol for 15-90 min were assayed in vitro for superoxide production and surface expression of Mac-1 (CD11b/CD18). Gossypol increased superoxide production in a time- and concentration-dependent fashion consistent with a moderate, delayed respiratory burst. Surface Mac-1 expression was increased within 15 min by 3-5 microM gossypol, resulting in a 14-fold increase over controls and a threefold greater increase over that produced by PMA. Staurosporine failed to block gossypol induction of superoxide and Mac-1, while EDTA inhibited induction of Mac 1 only, implicating a calcium-dependent mechanism. Gossypol increased intracellular calcium to peak levels, but in a delayed fashion as compared to FMLP. These findings demonstrate that gossypol is a highly potent stimulant of Mac-1 expression and suggest at least two protein kinase C-independent pathways of neutrophil activation. The resultant exhaustion of neutrophils may account for the antiinflammatory properties of plants containing gossypol. PMID- 7843791 TI - NADPH-oxidase activity of stimulated neutrophils is markedly increased by serum. AB - In this study we have investigated the effects of serum (10, 20, and 40% final concentrations) on the activity of NADPH-oxidase and energy metabolism of activated human neutrophils in vitro. Neutrophils were stimulated with FMLP, PMA, or opsonized zymosan in the presence and absence of serum, and generation of reactive oxidants by intact cells was measured using lucigenin-enhanced chemiluminescence (LECL). This method was also used to measure NADPH-oxidase activity in purified membrane preparations from neutrophils activated with PMA in the presence or absence of serum. Cellular ATP levels and activities of the various glycolytic enzymes were assayed using CL and spectrophotometric procedures, respectively. Inclusion of serum with neutrophils during exposure to the various stimuli of membrane-associated oxidative metabolism caused significant enhancement of the LECL responses of intact cells as well as of the activity of NADPH-oxidase in purified membranes prepared from PMA-activated neutrophils. In the absence of serum, the ATP levels and activity of glyceraldehyde-3-phosphate dehydrogenase (G3PDH), but not the other glycolytic enzymes, were decreased in activated neutrophils, while inclusion of serum preserved neutrophil ATP levels and activity of G3PDH. Serum supplementation of the cell-suspending medium appears to promote optimum activity of NADPH-oxidase in stimulated neutrophils by preventing premature, oxidative inactivation of cellular energy metabolism. PMID- 7843792 TI - Prostanoid generation in early stages of acute pancreatitis: a role for nitric oxide. AB - The role of nitric oxide in eicosanoid and oxygen-free radical production in the early stages of sodium taurocholate-induced acute necrotizing pancreatitis has been studied. Male Wistar rats were divided into three groups: group I: control group, a volume of 0.1 ml/100 g body wt saline solution was injected at low pressure in the pancreatic duct; group II: acute pancreatitis was induced by administration of 3.5% sodium taurocholate; and group III: intravenous administration of NG-nitro-L-arginine methyl esther (a nitric oxide synthase inhibitor) 5 min before induction of acute pancreatitis as stated for group II. At 5 and 60 min after induction of pancreatitis, blood and pancreas tissue samples were taken for assays. Increases in 6-keto PGF1 alpha, TXB2, PGE2, PGF2 alpha, and 12-HETE were observed in the pancreatic tissue. Lipoperoxidation was also enhanced and remained unaltered after nitric oxide inhibition. The fact that nitric oxide synthase inhibition could only reverse the increases in 6-keto PGF1 alpha and TXB2 levels indicates that in acute pancreatitis endothelial and platelet eicosanoid generation is mediated through an nitric oxide-dependent mechanism. In contrast, nitric oxide appears to be not related with oxygen free radical damage associated with acute pancreatitis. PMID- 7843793 TI - Stimulation of protein kinase C activity may increase microvascular permeability to colloidal carbon via alpha-isoenzyme. AB - The vasculature of the isolated mesentery and small intestine was perfused with a gelatin-containing physiological salt solution in vitro. Various phorbol-related compounds that are known to have different affinities for the protein kinase C (PKC) isoenzymes, and bradykinin (BK), were tested for their ability to cause the microvascular endothelium to become permeable to injected colloidal carbon (CC). Phorbol 12,13-dibutyrate (PDB), 12-deoxyphorbol 13-phenylacetate (DOPPA), thymeleatoxin (TMX), and resiniferatoxin (RFX), each at a concentration of 1 microM, were found to increase permeability. Pretreatment with the PKC inhibitor Ro 31-8220 (1 microM) significantly reduced the response to all of these compounds. Indomethacin (1 microM), on the other hand, reduced only the effect of RFX. 12-Deoxyphorbol 13-phenylacetate 20-acetate (DOPPAA) (1 microM) and BK (10 microM) did not increase CC leakage. These results suggest that the Ca(2+) dependent PKC alpha-isoenzyme was involved in the increase in endothelial permeability. BK does not appear to stimulate PKC activity in this experimental situation. PMID- 7843794 TI - Suppression by isoproterenol of endothelial cell morphology and barrier function changes induced by platelet-activating factor. AB - Using a model to study vascular permeability on hydrostatically perfused bovine pulmonary artery endothelial cell (EC) monolayers and software to analyze cell morphological parameters automatically in a computer image workstation, we studied the effects of isoproterenol (IPN) on platelet-activating factor (PAF) induced changes in EC monolayer permeability and cell morphological parameters. Albumin has fortifying effects on endothelial barrier function. As albumin concentration in the perfusate increased (0, 1, 5, 10, 20 mg/ml), EC monolayer hydraulic conductivity (Lp) decreased gradually while Lp of the filter membranes did not change. After treatment of the EC monolayer with PAF 10(-8) mol/liter for 30 min, transmonolayer fluid flow, protein clearance rate, and Lp value increased noticeably. At the same time, cell area decreased and intercellular distance and percentage of intercellular space area in total cell monolayer increased. Pretreatment with 10(-4) mol/liter IPN blocked PAF-induced EC permeability and morphological changes, suggesting that EC contraction and intercellular gap formation are important mechanisms for PAF-induced high vascular permeability. IPN inhibits the effects of PAF via stabilization of EC morphology, protection of intercellular junction, and blockade of intercellular gap formation. PMID- 7843795 TI - Administration of large doses of vitamin C does not decrease oxidant-induced lung lipid peroxidation caused by bacterial-independent acute peritonitis. AB - Acute zymosan-induced peritonitis in rats produces lung inflammation and lipid peroxidation. The effect of this process on plasma and lung tissue ascorbic acid was determined, as was the effect of infusing 150 mg/kg of ascorbic acid immediately after zymosan on the degree of lung insult. Ascorbic acid levels were significantly decreased in plasma and lung tissue at 24 h after zymosan, and lung tissue conjugated diene and neutrophil content was also significantly increased. Vitamin C infusion increased postzymosan plasma levels by 50% over normal control levels. However, lung tissue ascorbic acid was still decreased, and no decrease in the lung injury process was noted. Added ascorbic acid also did not prevent a decrease in plasma vitamin E with the peritonitis. We conclude that the amount of ascorbic acid given in this study did not diminish the lung oxidant inflammatory changes. An insufficient dose or inadequate time for plasma ascorbic acid to equilibrate with the lung cytosol are possible explanations for the lack of attenuation of lung oxidant stress. PMID- 7843796 TI - Heterogeneity of Kupffer cells and splenic, alveolar, and peritoneal macrophages for the production of TNF, IL-1, and IL-6. AB - Kupffer cells and alveolar, splenic, and peritoneal macrophages from normal rats were incubated for various periods of time in the presence of LPS, and the culture supernatants were analyzed for IL-6, IL-1, and TNF. There was very little difference in the amounts of the cytokines produced by the macrophages when stimulated with 0.01-10 micrograms/ml of LPS. The shapes of the time course curves for the production of the cytokines by the different types of macrophages were generally similar, although only Kupffer cells continued to produce IL-6 throughout the entire incubation period and splenic macrophages showed a lag period in the production of IL-1. Kupffer cells produced more IL-6 than that produced by the other populations of macrophages, and alveolar macrophages produced more IL-1 compared to that produced by splenic cells. Kupffer cells and peritoneal macrophages produced more IL-6 in 24 h than in 6 h of culture, and splenic macrophages produced more IL-1 in 24 compared to 6 h of culture. Alveolar macrophages produced more TNF than that produced by the other populations of cells but only when integrated over the entire incubation period. These results confirm and extend the observed functional heterogeneity of macrophages obtained from different tissues of the same animal. This study and future studies will lead to a better understanding of the role of cytokines in the inflammatory response. PMID- 7843797 TI - Inhibition of neutrophil activation by fibrinogen. AB - Physiological levels of human fibrinogen markedly inhibited the chemotactic activity of human neutrophils triggered by zymosan-activated serum (ZAS), C5a, or IL-8 in a Boyden chamber assay. Fibrinogen also slightly inhibited the N-formyl methionyl leucyl-phenylalanine (FMLP)-induced migration of human neutrophils. Albumin was devoid of the inhibitory activities displayed by fibrinogen in this system. The inhibition of chemotaxis by fibrinogen was dose-dependent and saturable. Fibrinogen placed in the upper compartment of the Boyden chamber produced a larger inhibition than that obtained with fibrinogen placed in the lower compartment. Lysine as well as the lysine analog 6-aminohexanoic acid (AHA) decreased the inhibitory capacity of fibrinogen. In contrast, both arginine and glutamine failed to suppress the fibrinogen-mediated inhibition of neutrophil chemotaxis. AHA counteracts the inhibition of ZAS-induced chemotaxis by anti-CD18 monoclonal antibody, suggesting that lysine binding sites are required for integrin function in chemotaxis. Fibrinogen also inhibited, in a dose-dependent manner, the oxygen consumption of neutrophils activated by opsonized zymosan. Taken together, the present results indicate that fibrinogen modulates neutrophil functions and suggest that in addition to its role in blood coagulation, circulating fibrinogen may be involved in regulation of the inflammatory response. PMID- 7843798 TI - Interleukin-1 treatment increases neutrophils but not antioxidant enzyme activity or resistance to ischemia-reperfusion injury in rat kidneys. AB - Hearts from rats treated with interleukin-1 (IL-1) intraperitoneally developed a rapid (6 h after IL-1), transient increase in neutrophils, tissue hydrogen peroxide (H2O2), and oxidized glutathione (GSSG) levels, and a subsequent (36 h after IL-1) increase in myocardial glucose-6-phosphate dehydrogenase (G6PD) activity and tolerance to ischemia-reperfusion. In the present investigation, we found that rats treated similarly with IL-1 had increased numbers of neutrophils in their kidneys, which were comparable to myocardial neutrophil increases, but did not develop increased renal tissue H2O2 or GSSG levels acutely (6 h after IL 1) or increased G6PD activity or resistance to ischemia-reperfusion injury later (36 h after IL-1). Our findings indicate that IL-1 treatment increased neutrophil accumulation in rat kidneys but did not increase oxidative stress, antioxidant enzyme activity, or resistance to ischemia-reperfusion injury. We conclude that organ-to-organ differences exist with respect to IL-1-induced tolerance. PMID- 7843799 TI - Sawdust-induced inflammatory changes in rat lung: effects on alveolar and interstitial cells in relation to time. AB - Exposure to sawdust and its contaminants, e.g., terpenes, may cause respiratory tract and lung parenchymal inflammation. To monitor these changes over time. Sprague-Dawley rats were exposed at one occasion to 2.5 mg sawdust or saline by intratracheal instillation. Flow cytometry analyses were done on bronchoalveolar lavage (BAL) cells. Lung tissue specimens were analyzed histologically and immunohistochemically. After one week, the number of BAL polymorphonuclear leukocytes was increased (P < 0.05, N = 8), followed at six weeks by increases of macrophages and lymphocytes (both P < 0.01, N = 8). Enhanced expressions of class II antigens and complement receptors on macrophages after one week were even more pronounced at six weeks, indicating cellular activation. The BAL findings, also including increased (P < 0.001, N = 8) concentrations of hyaluronan with progressing changes over time, confirmed the signs of inflammation, as did the histological analysis of the lung tissue specimens with an accumulation of polymorphonuclears, macrophages, and hyaluronan in the interstitium. PMID- 7843800 TI - Retinoic acid modulation of mucin mRNA in rat tracheal explants: response to actinomycin D, cycloheximide, signal transduction effectors and antisense oligodeoxynucleotide. AB - Factors affecting the retinoic acid modulated expression of mucin mRNA in rat tracheal cultures were studied. Actinomycin D had no effect on mucin mRNA in cultures grown with retinoic acid (RA+). The usual precipitous drop in mucin mRNA in cultures lacking retinoic acid (RA-) was prevented by actinomycin D. Cycloheximide also had no effect on mucin mRNA in RA+ cultures, but, like actinomycin D, it prevented the precipitous drop in mucin mRNA in RA- cultures. cAMP agonists had some marginal effects on the mucin mRNA, but none as dramatic as those noted by actinomycin D and cycloheximide in the RA- cultures. An antisense oligomer (18 bases) to rat mucin cDNA inhibited the mucin mRNA expression in RA+ cultures. PMID- 7843802 TI - Immunohistochemical demonstration of bikunin, a light chain of inter-alpha trypsin inhibitor, in human brain tumors. AB - The presence and localization of bikunin (HI-30, or acid-stable protease inhibitor), a light chain of inter-alpha-trypsin inhibitor, was examined in 30 brain tumors employing immunohistochemical methods. The brain tumors involved 13 kinds of histological diagnosis. Bikunin immunoreactivity was detected in all of the brain tumors examined. Fibrillary staining of the glial processes was observed in astrocytoma, oligodendroglioma, and schwannoma. Intracytoplasmic staining in the interstitial cells, reactive astrocytes, and macrophages was noted in medulloblastoma, ependymoma, and meningioma. Metastatic tumors demonstrated intense immunoreactivity in the tissues surrounding the tumor cells. Neuronal cells revealed no bikunin immunoreactivity. There was no correlation between the intensity of staining and histologic type or grading of malignancy. In view of our earlier report that bikunin was present in the connective tissues around the site of cancer invasion, the above findings suggest that bikunin may play an important role in defense or repair at the tissue destruction and degeneration site. PMID- 7843801 TI - Studies of skin-window exudate human neutrophils: complex patterns of adherence to serum-coated surfaces in dependence on FMLP doses. AB - Human neutrophils were isolated both from peripheral blood (PB) and from aseptic inflammatory exudates obtained by the Senn's skin-window (SW) technique. The respiratory burst (O2- release) and the adherence to serum-coated wells of culture microplates was investigated using a simultaneous assay. Unstimulated PB resting neutrophils did not produce a significant amount of O2- and were incapable of adhering to serum-coated plastic surfaces, while unstimulated SW neutrophils showed augmented adhesion to serum-coated culture wells. SW neutrophils were primed to enhanced FMLP-dependent O2- release in response to n formyl-methionyl-leucylphenylalanine (FMLP). Adhesion of SW neutrophils was significantly decreased by addition of low doses (10(-10)-10(-8) M) of FMLP (from 17.1% to 8.4%, P < 0.01, N = 12), while fully activating doses (> 5 x 10(-8) M) of FMLP induced a marked increase of the cell adhesion, more pronounced in SW (39.2%) than in PB cells (27.2%). Low (5 x 10(-9) M) and high (5 x 10(-7) M) FMLP doses induced morphological changes (polarization) and actin polymerization in the neutrophils from both sources. Biphasic dose-response curves of SW neutrophil adherence were observed using FMLP, but not using concanavalin A or phorbol myristate acetate as stimulatory agents. Therefore, the adherence of SW cells appears to be regulated in a complex fashion, nonlinearly dependent on the chemotactic peptide doses and specifically regulated according to the receptors involved. PMID- 7843803 TI - Effects of allopurinol on in vivo suppression of arthritis in mice and ex vivo modulation of phagocytic production of oxygen radicals in whole human blood. AB - Recently, we demonstrated elevated levels of xanthine oxidase in serum of patients with various inflammatory and autoimmune rheumatic diseases. The present study reports the antiarthritic efficacy of the xanthine oxidase inhibitor and immunosuppressant allopurinol in DBA/1xB10A(4r) mice suffering from peroxochromate-induced arthritis. A profound dose-dependent suppression of arthritis was noted (P < 0.001). The ED50 was 80 +/- 14 mumol/kg/day. The arthritis index correlated positively to the phagocytic production of oxygen radicals (r2 > 0.672) and negatively to the concentrations of allopurinol (r2 = 0.915). Ex vivo, allopurinol and various conventional antirheumatic drugs were screened for the inhibition of 12-O-tetradecanoylphorbol-13-acetate-stimulated whole human blood chemiluminescence. The concentrations of antirheumatic drugs required to inhibit the chemiluminescence by 50% were compared to the therapeutic doses administered to rheumatic patients. While D-penicillamine and cis platinum(II) increased the phagocytic generation of superoxide, nonsteroidal antiinflammatory drugs (NSAIDs), steroids, and slow-acting antirheumatic drugs (SAARDs) inhibited the whole blood chemiluminescence in a dose-dependent manner. Therapeutic doses of NSAIDs, SAARDs, or steroids inhibited the phagocytic generation of reactive oxygen species by 10-50%. In addition to well-known mechanisms of action of NSAIDs and SAARDs, our results support the hypothesis that most common anti-rheumatic drugs act also by modulating the levels of reactive oxygen species, which serve important mediator and signal transduction functions in inflammatory and autoimmune diseases. Pharmacologically safe antioxidants like allopurinol, which simultaneously modify the oxidative burst of phagocytes, inhibit xanthine oxidase, and display immunosuppressive effects may well be suited to control the consequences of chronic phagocytic hyperreactivity in rheumatic patients. PMID- 7843804 TI - Role of oxygen radicals and IL-6 in IL-1-dependent cartilage matrix degradation. AB - It has been suggested that IL-1 produces cartilage matrix degradation by metalloproteinases such as collagenase and that such degradation is regulated by metalloproteinase inhibitors. In the present study, the effects of IL-6 and oxygen radical scavengers on cartilage matrix degradation were studied. Superoxide dismutase, catalase, or methionine all significantly inhibited cartilage matrix degradation both in IL-1 beta-stimulated and unstimulated experimental conditions. Both 10 mM EDTA and 100 nM tissue inhibitor of metalloproteinase (TIMP) significantly inhibited cartilage matrix degradation. The addition of methionine significantly inhibited collagenase activity produced in the culture supernatants of chondrocytes stimulated with IL-1 beta. IL-6 significantly suppressed cartilage matrix degradation produced spontaneously or by IL-1 beta stimulation in chondrocytes. IL-6 inhibited superoxide production by chondrocytes both in IL-1 beta-stimulated or unstimulated conditions. These results suggest that oxygen radicals are involved in cartilage matrix degradation mediated by both paracrine and autocrine IL-1 mechanisms and that oxygen radical mediated activation of collagenase in chondrocytes may explain the mechanisms of how oxygen radicals are involved in cartilage matrix degradation. IL-6 inhibited superoxide production in chondrocytes and thus inhibited cartilage matrix degradation. PMID- 7843805 TI - S-nitroso-N-acetylpenicillamine reduces leukocyte adhesion to type I collagen. AB - The initial step in the migration of neutrophils to the extravascular space is adhesion to the endothelium. We examined the effect of nitric oxide on this process by treating human neutrophils with S-nitroso-N-acetylpenicillamine (SNAP), a NO-producing compound. Since NO has been shown to increase the level of cGMP in other cell types, we used 8-Br-cGMP in order to mimic the effects of NO. Indeed, both these treatments resulted in a reduced adhesion of neutrophils to type I collagen coated surfaces. After a prolonged incubation with SNAP, the adhesion was the same as for untreated cells. SNAP incubation reduced the F-actin content in the cells whereas 8-Br-cGMP increased it, demonstrating different mechanisms of action on F-actin. These data suggest that endothelium-derived nitric oxide is an important endogenous modulator of neutrophil adhesion, but the effect is not mediated by a cGMP-dependent regulation of F-actin levels. PMID- 7843806 TI - Effects of endothelin receptor antagonists on bradykinin-induced increases in macromolecular efflux. AB - The goal of this study was to determine the effects of endothelin receptor antagonists on agonist-induced increases in macromolecular extravasation in the hamster cheek pouch in vivo. We used intravital fluorescent microscopy and fluorescein isothiocyanate dextran (FITC-dextran; mol wt = 70 K) to examine extravasation from postcapillary venules in response to bradykinin and endothelin before and following application of inhibitors of endothelin receptors (ETAB and ETA). Increases in extravasation of macromolecules were quantitated by counting the number of venular leaky sites. Bradykinin (0.5 and 1.0 microM) and endothelin 1 (0.01 and 0.1 nM) produced a dose-related increase in the number of venular leaky sites and superfusion of PD 142893 (ETAB antagonist), and PD 147953 and BQ 123 (ETA antagonists) significantly decreased bradykinin- and endothelin-induced responses. Addition of calcium to the superfusate restored bradykinin-induced increases in venular leaky sites in the presence of endothelin receptor antagonism. Thus, the findings of the present study suggest that endothelin receptor antagonists abrogate bradykinin- and endothelin-induced increases in macromolecular efflux from postcapillary venules. The mechanism for the effects of endothelin receptor antagonists appears to be related to inhibition of the ETA receptor which, in turn, alters the mobilization of calcium across venular endothelium. PMID- 7843807 TI - Reversibility of tachyphylaxis to C5A in guinea pig tissues, perfused human placental lobule, and umbilical artery. AB - The spasmogenic effect of C5a is mediated by histamine and/or eicosanoids. Tachyphylaxis to this effect of C5a occurs rapidly, but the spasmogenic effects of C5a on a guinea pig lung parenchymal strips, field-stimulated ventricular papillary muscle, and human umbilical artery were completely restored by a 1-h period of drug-free rest, whereas that of guinea pig ileum was not. Perfusion of the isolated human placental lobule with C5a caused a transient pressor response that was largely abolished by indomethacin (5 microM), indicating mediation by cyclooxygenase metabolites. This pressor response to C5a was also completely restored following a 1-h rest period. The results show that tissue rest reverses tachyphylaxis to the spasmogenic effects of C5a in tissues where the response is mediated by cyclooxygenase metabolites. Where the response is mediated by histamine released by mast cells, restoration does not occur, presumably because of the catastrophic nature of mast cell degranulation. Histamine released in guinea pig papillary muscle by C5a may be from non-mast-cell sources. PMID- 7843808 TI - Response of soluble IL-2 receptor, interleukin-2 and interleukin-6 in patients with positive and negative Borrelia burgdorferi serology. AB - This study was designed to investigate serum soluble interleukin-2 receptor (S-IL 2R), interleukin-2 (IL-2) and interleukin-6 levels (IL-6) in patients with either a positive or negative Borrelia burgdorferi serology. Serum samples from 101 individuals, divided in to five groups according to clinical symptoms and outcome of serology were analysed. Samples of cerebrospinal fluid (CSF) from nine of the individuals were also studied. The highest average serum S-IL-2R levels (1,180 +/ 1,140 U/ml) were found in patients with erythema migrans, the hallmark of Lyme borreliosis, followed by patients with symptoms closely related to Borrelia infection (900 +/- 1,200 U/ml) and with a strong positive serology. In two patients with central nervous system (CNS) involvement, increased levels of S-IL 2R of 920 and 620 U/ml respectively (normal value < 50 U/ml) were detected in the CSF. No statistically significant relationship between IgG or IgM antibody activity and serum S-IL-2R levels was found. Detectable levels of IL-2 were only found in three patients. Increased levels of IL-6 were found in sera from 14 patients. The highest concentration, 90 pg/ml (normal value < 10 pg/ml), was measured in a patient presenting with vasculitis. In conclusion, B. burgdorferi infection causes a moderate increase of serum S-IL-2R levels, although there is no relationship between the severity of the infection, as estimated by the antibody concentration or to serum IL-2 or IL-6 levels. Secondary complications of the infection, such as vasculitis, may cause an increased level of serum IL 6.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843809 TI - Acute non-A, non-B hepatitis in Italy: a 16-year prospective epidemiological study. The possible role of hepatitis C virus. AB - During a survey of acute symptomatic viral hepatitis conducted in Padua over the last 16 years, 404 (20%) cases of non-A, non-B hepatitis were observed, including 55% with overt parenteral exposure (35% drug abusers) and 45% with unknown exposure. Between 1978 and 1982 the attack rate of the disease increased significantly (p < 0.01) in males, (from 3.8 to 17.3/10(5) inhabitants), in adolescents and in youths. The prevalence of drug abusers rose up to 58% in 1982 suggesting the occurrence of an outbreak in this risk group. In subsequent years the attack rate returned to initial levels in males, although drug abuse still remains the single most important route of infection, and declined in females, especially after the disappearance of post-transfusion hepatitis since 1991. Retrospective anti-HCV testing of patients seen up to 1990 and prospective investigation of patients hospitalized later have shown an antibody prevalence of 88% among parenterally transmitted cases, and of 29% in the other patients, without significant differences between the prospective and the retrospective study. These findings suggest that an outbreak of hepatitis C occurred in our area in the early eighties and that drug abuse is still the most important mode of transmission of acute hepatitis C. PMID- 7843811 TI - Treatment of chronic replicative hepatitis B virus infection with short-term continuous infusion of foscarnet. AB - Three patients with chronic replicative hepatitis B virus infection were treated for 7 days with a continuous intravenous infusion of foscarnet (trisodium phosphonoformate) after an initial bolus dose of 20 mg/kg body weight. Although the dose was calculated from a nomogram, approximately only half the intended plasma concentration (500 microM/l = 150 micrograms/l) was achieved. The levels of s-ALAT, HBV-DNA and DNA-polymerase changed only marginally during the treatment and 24-week follow-up period. All three patients remained HBsAg and HBeAg positive during treatment and follow-up. There were no severe side-effects. We conclude that foscarnet treatment with the dose regimen given in this study had no or only a minor antiviral effect in patients with chronic replicative HBV infection. It remains to be explored if higher doses, longer treatment periods or the use of foscarnet in combination regimen are more effective. PMID- 7843810 TI - Release of TNF alpha and IL6 from human monocytes infected with Mycobacterium kansasii: a comparison to Mycobacterium avium. AB - Tumor necrosis factor alpha (TNF alpha) and interleukin 6 (IL6) are cytokines with a varied spectrum of inflammatory and immunological activities, for example modulation of acute phase proteins, fever and stimulation of B-lymphocytes. Mycobacterium avium has been shown to stimulate the release of TNF alpha and IL6 from cultured human monocytes and macrophages into the cell supernatant. Cultured human monocytes were infected with Mycobacterium kansasii and M. avium. The concentrations of TNF alpha and IL6 were measured in the supernatant. Monocytes infected with M. kansasii produced significantly lower amounts of TNF alpha (34.8 +/- 20.3 pg/ml) and IL6 (12.0 +/- 8.9 pg/ml) compared to monocytes infected with M. avium (198.3 +/- 171.7 pg/ml and 63.2 +/- 37.6 pg/ml respectively). The extent of cytokine production might be relevant for the clinical manifestation of mycobacterial disease. PMID- 7843812 TI - Enhanced killing of methicillin-resistant Staphylococcus aureus in human macrophages by liposome-entrapped vancomycin and teicoplanin. AB - The antibacterial effects of liposomal vancomycin and teicoplanin against intracellular methicillin-resistant Staphylococcus aureus (MRSA) were evaluated using a macrophage infection model. Human blood-derived monocytes were cultured for 7 days to obtain adherent macrophages. Uptake of each drug by macrophages was markedly enhanced by liposomal encapsulation. Following phagocytosis and removal of residual extracellular MRSA, the infected macrophages were exposed to clinically achievable concentrations of teicoplanin and vancomycin. The free (untrapped) and liposome-entrapped forms of each drug were used at the same concentration. The number of intracellular surviving bacteria was determined by colony counts after lysis of the macrophages at different time intervals following drug treatment. Intracellular antimicrobial effect of each drug was significantly (p < 0.001) increased by entrapment in liposomes. Also, the efficacies of the free and liposomal forms of both drugs were correspondingly comparable (p > 0.05). It is, therefore, concluded that liposomal encapsulation of vancomycin and teicoplanin results in an increased availability of the antibiotics for efficient elimination of intracellular MRSA infection. PMID- 7843813 TI - Penetration of ciprofloxacin into the human pancreas. AB - The aim of this study was to determine the concentrations of ciprofloxacin in human pancreatic tissue and juice. Concentrations were measured by high-pressure liquid chromatography (HPLC). Two hundred mg of ciprofloxacin were administered as a short i.v. infusion (30 min). The median ciprofloxacin concentrations 140 min (median) after the start of infusion in pancreatic tissue as well as in pancreatic juice were 0.9 mg/kg (mg/l). The penetration ratio was 1.0 for pancreatic tissue and 0.83 for pancreatic juice. With regard to the minimal inhibitory concentrations (MIC) for the respective bacteria, ciprofloxacin seems to be an appropriate drug for the treatment of septic complications in necrotizing pancreatitis. Future clinical trials are necessary to prove this assumption. PMID- 7843814 TI - The use of ceftriaxone in the prevention of urinary tract infection in patients undergoing transurethral resection of the prostate (TUR-P). AB - We evaluated 101 patients undergoing transurethral resection of the prostate in this open randomized study in which 51 received antibiotic prophylaxis and 50 did not (control group). In those patients receiving antibiotics, ceftriaxone 1 g was administered intravenously within 1 h before transurethral prostatectomy and a second dose was given 3-4 days postoperatively, within 1 h before the suprapubic catheter was removed. The groups had similar clinical and demographic characteristics. During the 28-day study period, bacteriuria appeared in six ceftriaxone-treated patients and in 20 control patients (p < 0.005). On days 3-4 after the resection, only two patients who had received ceftriaxone had bacteriuria compared with 14 in the control group (p < 0.005). In addition, the incidence and duration of fever and length of hospitalization were shorter in the patients treated with ceftriaxone. In conclusion, these results support the use of prophylactic antibiotics in transurethral prostatectomy, even in patients at low risk of developing bacteriuria. PMID- 7843815 TI - An unusual case of hip septic arthritis due to Bacteroides fragilis in an alcoholic patient. AB - We describe a 53-year-old alcoholic man who presented with hip septic arthritis due to Bacteroides fragilis. This arthritis involved a severe destruction of the femoral head, which was completely devitalized. Recovery was achieved after 4 months of antimicrobial therapy with imipenem/cilastatin plus metronidazole, surgical debridement of the necrotic tissues and four sessions of hyperbaric oxygen. PMID- 7843816 TI - Parvovirus B19 infection in HIV-1 infected patients with anemia. AB - Serum samples were analysed for IgM and IgG antibodies to parvovirus by ELISA and for parvovirus B19 DNA by polymerase chain reaction (PCR) in 69 HIV-1 infected Swedish patients with anemia and in 37 HIV-1 infected subjects without anemia. In 5/69 anemic patients, parvovirus B19 DNA was detected despite the lack of IgM antibody activity to the virus. The detection of parvovirus B19 DNA was significantly correlated to the degree of anemia in the anemic patients. In two patients who had a chronic anemia, a persistent parvovirus infection was detected by PCR, but not by serology, for 1 and 1.5 years, respectively. The results suggest that persistent parvovirus infection is a rare cause of anemia, but important to identify, since the infection is potentially treatable with intravenous immunoglobulin. PMID- 7843817 TI - An intramedullary dermoid cyst abscess due to Brucella abortus biotype 3 at T11 L2 spinal levels. AB - A 17-year-old boy was admitted to hospital with a history of backache, weakness of the lower extremities and fever. While the diagnosis of brucellosis was made his clinical course worsened. Acute medulla spinalis mass effect and signs of meningitis predominated. It was shown that he had a dermoid cyst infected with Brucella abortus biotype 3 which was the same strain growing in his blood cultures. PMID- 7843818 TI - Re: G. E. Schutze et al.: Resistant pneumococcus: a worldwide problem (Infection 22 [1994] 233-237) PMID- 7843820 TI - Toxic epidermal necrolysis in a patient suffering from acquired immune deficiency syndrome. PMID- 7843819 TI - A retrospective study of Nocardia infections associated with the acquired immune deficiency syndrome (AIDS) PMID- 7843821 TI - Prevalence of HIV infection among hemodialysis patients in Turkey. PMID- 7843822 TI - First case of tick-borne encephalitis (TBE) in the Saarland. PMID- 7843823 TI - In vitro activity of cefpodoxime in comparison with other oral beta-lactam antibiotics. AB - The aim of our study was to re-evaluate the in vitro activity of cefpodoxime in comparison with other oral beta-lactam antibiotics against bacteria causing respiratory tract infections. The study drugs were cefpodoxime, cefaclor, cefixime, cefuroxime, cefetamet, cefprozil, and the combination of amoxicillin and clavulanic acid (= augmentin). In addition, cefotaxime as the standard agent of parenteral third generation cephalosporins was examined. The organisms tested were Staphylococcus aureus, Streptococcus pyogenes, Streptococcus agalactiae, streptococci of serogroups C and G, Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae and Proteus mirabilis. Minimal inhibitory concentrations of the antimicrobials were determined with the agar dilution procedure. Cefpodoxime showed the broadest spectrum and generally also the highest activity of the oral beta-lactam antibiotics examined. The drug was equally active against the major groups of beta-lactamase negative and positive bacteria causing respiratory tract infections. Against penicillin-resistant pneumococci, all beta-lactam agents exhibited reduced activity comparable to the reduced activity of penicillin. PMID- 7843824 TI - The antimicrobial activity of cefotaxime: comparative multinational hospital isolate surveys covering 15 years. AB - The "third-generation" cephalosporins (3GC) have emerged as one of the most significant therapeutic entities in the last 15 years. These 3GC compounds (using cefotaxime as a model) have generally maintained their potency and spectrum of activity against important pathogens. However, the continuing popularity of this class associated with local, regional, or national-level use or abuse has led to efficacy reduction against some organism populations associated with selection of Class I cephalosporinase, stably derepressed mutants predominantly among Citrobacter and Enterobacter spp.; emergence of extended-spectrum beta-lactamase producing Enterobacteriaceae (usually Klebsiella spp.), as well as some isolates mimicking Class I-type resistance patterns; and lastly, altered PBP-mediated resistances among pneumococci, Haemophilus influenzae and pathogenic Neisseria spp. Some of these resistance patterns had been present prior to the clinical introduction of 3GCs and have only significantly threatened their use in the last 5 years. Prudent application of these 3GC drugs should be the goal for this decade as follows: 1) use as monotherapy at appropriate doses and frequencies only for organisms with low potential for mutational events; 2) use combination therapy routinely for organisms such as Citrobacter, Enterobacter, some indole positive protease and Pseudomonas aeruginosa, to minimize emerging resistance clones; 3) use conservatively in high risk patients to minimize "super colonization" by emerging problem bacteria (e.g. vancomycin-resistant enterococci, Xanthomonas maltophilia etc.); 4) use only those agents among 3GCs that have documented safety, broad clinical applications to all age groups, acceptable pharmacokinetic features and clear cost-saving potential; and 5) use in prophylaxis (surgical procedure, selective decontamination), should be focused toward single-dose or short-course regimens to reduce total hospital-wide exposure to broad-spectrum beta-lactam drugs.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843825 TI - Treatment of severe infections caused by penicillin-resistant pneumococci. Role of third generation cephalosporins. AB - Penicillin resistance occurred soon after the discovery of penicillin, first in the test tube and subsequently in patients. The prevalence of invasive pneumococcal disease has been estimated to be as high as 15-18/100,000 in the elderly population and even higher in AIDS patients, children and the very old. While prevention with pneumococcal vaccine seems the most reasonable solution, under-utilization of the vaccine and an increase in the number of immuno compromised individuals has limited the success of this approach. Streptococcus pneumoniae is conventionally classified as penicillin-susceptible (MIC < 0.125 mg/l), penicillin-intermediate (MIC 0.125-1.0 mg/l) and penicillin-resistant (MIC > or = 2 mg/l). In many countries, penicillin resistance in pneumococci is on the increase and in some areas penicillin intermediate and resistant isolates reach 60%. As a consequence, a switch of therapy from penicillin to other agents is mandatory in infections caused by penicillin-resistant strains. Benzyl penicillin, however, can be used for most infections caused by penicillin intermediate and all infections caused by penicillin-sensitive strains. Third generation cephalosporins, and in particular cefotaxime, are an optional alternative, particularly in view of their low MICs against penicillin susceptible and -intermediate and some penicillin-resistant strains, and the easily achievable therapeutic concentrations in serum, pulmonary tissues and other compartments in which pneumococcal infections occur. Third generation cephalosporins have a high safety record and can be administered to children, pregnant women and the elderly.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843826 TI - Spontaneous bacterial peritonitis in liver cirrhosis: treatment and prophylaxis. AB - Spontaneous bacterial peritonitis in liver cirrhosis is due to the passage of intestinal bacteria into intestinal lymph vessels, systemic circulation and ascitic fluid. It may occur in patients with severe portal hypertension and hepatic failure, impaired reticuloendothelial phagocytic activity and low ascitic fluid opsonic activity. Spontaneous bacterial peritonitis is a monomicrobial infection usually caused by gram-negative bacteria. The treatment of choice of spontaneous bacterial peritonitis is cefotaxime. Several subgroups of cirrhotic patients have been shown to be predisposed to develop spontaneous bacterial peritonitis, including cases with gastrointestinal hemorrhage, patients with high serum bilirubin and low ascitic fluid protein concentration (< 1 g/dl), and patients who had recovered from an episode of spontaneous bacterial peritonitis. Since spontaneous bacterial peritonitis is associated with a relatively high in hospital mortality rate (20-40%), prophylactic measures to prevent this infection are required. Short-term and long-term selective intestinal decontamination with oral norfloxacin has proved highly effective in preventing bacterial infection and spontaneous bacterial peritonitis in bleeding cirrhotic patients as well as recurrence of spontaneous bacterial peritonitis. PMID- 7843827 TI - Antimicrobial drug utilisation in hospitals in Italy and other European countries. AB - Antibiotic prescribing patterns in hospitals are analysed in this review of three drug utilisation studies conducted in six European countries, with special emphasis to the third-generation cephalosporins. A great variability in the use of antimicrobial drugs is evident, both between countries and between hospitals in the same country. This variability is found also between patients with the same infectious disease. The possible reasons for these differences are discussed and a strategy to modify the hospital drugs prescribing is suggested. PMID- 7843828 TI - The injectable cephalosporins in the treatment of serious infections. PMID- 7843829 TI - Multiple chemical sensitivities. Is there a scientific basis? PMID- 7843830 TI - Respiratory effects and serum type III procollagen in potato sorters exposed to diatomaceous earth. AB - Exposure to diatomaceous earth with low crystalline silica content (< 1%) is rarely reported to cause pneumoconiotic disease, whereas airway obstruction and bronchitis are more frequently reported. We investigated the occurrence of pneumoconiosis and airflow limitation in 172 male workers from 5 potato sorting plants (55 controls, 29 salesmen, 72 currently exposed, and 16 retired exposed) exposed to inorganic dust from former sea terraces (7.7-15.4 mg/m3), high in diatomaceous earth. The presence of fibrosis was evaluated by chest radiographs (exposed only) and serum levels of type III procollagen (P-III-P) were measured as an estimate of fibrogenetic activity. Lung function was assessed by flow volume curves and impedance measurements. A validated questionnaire was used to record respiratory symptoms. No pneumoconiotic abnormalities were demonstrated by chest radiographs. In line with this finding, serum P-III-P levels were not elevated in exposed workers as compared to controls, suggesting no differences in fibrogenetic activity. In fact, serum P-III-P levels decreased significantly (P < 0.03) with increasing cumulative exposure. Flow volume parameters indicated airflow obstruction, dose-related to (cumulative) dust exposure; the annual decline in forced expiratory flow volume (FEV1) was estimated at 10.5 ml/year (P < 0.05). Airway obstruction was confirmed by impedance analysis: In the retired group impedance changes were compatible with airway obstruction extending into the peripheral airways. We conclude that this exposure to quartz during potato sorting does not result in an increased risk for pneumoconiosis, but that (prolonged) surveillance in this group is desirable in order to detect early indications of airflow obstruction. PMID- 7843831 TI - Lead exposure in starter battery production: investigation of the correlation between air lead and blood lead levels. AB - The threshold limit value (TLV) for lead (in Germany, the MAK value) is based on a certain blood lead concentration (in Germany BAT value = biological tolerance value for working materials) that is not to be exceeded; thereby a statistically significant association between air lead (PbA) and blood lead (PbB) is assumed. On the basis of a 10-year period of (1982-1991) biological and ambient monitoring of 134 battery factory staff and their workplaces, a PbA/PbB correlation with the regression equation PbB = 62.183 + 21.242 x Log 10 (PbA) (n = 1089, r = 0.274, P < 0.001) was calculated. These results are in line with those of several other investigations. The shape of the regression curve and the wide scattering of values led to the assumption that PbA values above the MAK value (0.1 mg/m3) do not necessarily result in increased PbB values. Similarly, PbA values lower than the MAK value do not guarantee PbB levels below the BAT value in every case. These observations are influenced by numerous confounders and intervening variables. It is concluded that lowering MAK values as a consequence of lowering BAT values is not mandatory. PMID- 7843832 TI - Effect of occupational exposure to aldrin on urinary D-glucaric acid, plasma dieldrin, and lymphocyte sister chromatid exchange. AB - The effects of exposure to the chlorinated cyclodiene termiticide aldrin was evaluated in pest control workers potentially exposed to this material. Sister chromatid exchange (SCE) frequencies were not elevated in workers handling aldrin. This is consistent with the fact that chlorinated cyclodienes are not genotoxic. Plasma dieldrin concentrations (up to 250 ng/ml) confirmed exposure in workers actively performing termiticide treatments and in maintenance and store workers, when compared with unexposed control workers (median concentration, 4.8 ng/ml). Urinary D-glucaric acid (DGA), an index of hepatic enzyme activity, was elevated in pesticide-exposed groups but urinary DGA was poorly correlated with plasma dieldrin level. This indicates that concurrent exposures of these groups to other pesticides may have influenced mixed-function oxidase metabolic activity. PMID- 7843833 TI - Work in operating rooms and pregnancy outcome among nurses. AB - The aim of this study was to analyse the relationship between work in an operating room and pregnancy outcome, as described by the rates of spontaneous abortion and of birth defects. The population comprised the female nurses of 17 hospitals in Paris, interviewed in 1987-1989. An exposed group included all operating room nurses, and a control group was composed of female nurses in other departments matched by hospital, age and duration of service. Each woman described all prior pregnancies. In total, 776 pregnancies were described by 418 nurses who were first pregnant in 1970 or thereafter; ectopic pregnancies, those terminated by voluntary induced abortion and those leading to multiple births were excluded. The rate of spontaneous abortion was significantly higher for pregnancies during which women worked in an operating room than for the other pregnancies. Birth defects were not significantly related to work in an operating room during pregnancy. These results are in agreement with others showing a significant relationship between occupational exposure to operating rooms and spontaneous abortion, although identification of the responsible factor remains difficult. They suggest that effective ventilating systems should be installed in all operating rooms and that special preventive measures must be taken for women of childbearing age. PMID- 7843834 TI - Internal lead and cadmium exposure in 6-year-old children from western and eastern Germany. AB - Lead and cadmium levels in blood and deciduous teeth (shed incisors only) of 6 year-old German children were determined in 1991 in a large epidemiological study carried out in rural and urban areas of western Germany (Duisburg, Essen, Gelsenkirchen, Dortmund, Borken) and eastern Germany (Leipzig, Halle, Magdeburg, Osterburg, Gardelelegen, Salzwedel). In total, blood lead and cadmium levels of 2311 German children and tooth lead and cadmium levels of 790 German children were analyzed. Blood lead levels were generally low in all study areas with geometric means between 39.3 micrograms/l and 50.8 micrograms/l in the western German and between 42.3 micrograms/l and 68.1 micrograms/l in the eastern German study areas. The mean blood lead level of Turkish children (n = 213) living in the western German study areas was 50.1 micrograms/l and thus 5.6 micrograms/l higher than the overall geometric mean of the western German children. The higher exposure may be explained by a higher oral uptake from food and different living conditions. These children were excluded from multiple regression analysis because they were all living in the western study areas. The mean tooth lead levels ranged between 1.50 and 1.74 micrograms/g in the western and between 1.51 micrograms/g and 2.72 micrograms/g in the eastern study areas. Thus, they show a distribution pattern similar to blood. Blood and tooth lead levels were higher in urban than in rural areas and higher in the eastern German than in the western German study areas. With regard to the blood and tooth cadmium concentrations, no significant differences between the study areas could be found.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843835 TI - Gaschromatographic determination of butoxyacetic acid after hydrolysis of conjugated metabolites in urine from workers exposed to 2-butoxyethanol. AB - For the gaschromatographic determination of total butoxyacetic acid (BAA), i.e., free plus conjugated BAA in urine, we studied the acid hydrolysis condition to cleave the conjugate. The optimum condition for hydrolysis was chosen to be 60 min boiling of the mixture of 1 ml twofold diluted urine and 1.2 ml hydrochloric acid. For the biological monitoring of workers exposed to 2-butoxyethanol (BE), we applied our acid hydrolysis method to the urine from 6 workers exposed to the solvent for 7 days and determined total BAA as well as free BAA and conjugated BAA, which was calculated as the difference between the concentrations of free and conjugated BAA. The percentages of conjugated BAA vs. total BAA varied from 44.4% to 92.2% (mean value 71.1%) among 6 individual workers over 7 days and decreased gradually over the consecutive work days. In the latter half of the work week, free BAA comparatively accounted for the larger portion of urinary BAA. Significant correlations were found between urinary BAA concentrations and BE levels in the breathing-zone air (TWA). The correlation coefficients of urinary concentrations of total or conjugated BAA vs. BE levels was higher than that of free BAA concentrations vs. BE levels. Hence, the determination of total BAA in urine is a suitable test for the biological monitoring of BE exposure, because of the simplicity in procedures and the good agreement with BE exposure levels. PMID- 7843836 TI - Blood lead levels in the general population of Taiwan, Republic of China. AB - The purpose of this study was to investigate the environmental lead exposure of the general population in Taiwan. A total of 2919 residents of Taiwan were selected by multistage sampling methods. The participants were characterized by questionnaires and 10 ml venous blood was collected for blood lead measurement. A quality assurance/quality control program was designed during the analysis of blood lead levels. The mean blood lead level of 2719 residents without occupational lead exposure was 8.29 +/- 5.92 micrograms/dl. After adjustment for age and sex distribution to the Taiwan general population, the mean blood lead level was 8.10 micrograms/dl. Adjusted for an 11% underestimation of blood lead levels among the six laboratories, the mean blood lead level was estimated to be 8.99 micrograms/dl. This study also found that blood lead levels were associated with personal characteristics, i.e., gender, ethnic group, education level; lifestyle factors, i.e., smoking, alcohol consumption, sources of drinking water; and residential location, i.e., levels of urbanization, distance of house from the road. However, age, floor of residence, milk consumption, betel nut consumption, and Chinese herbal drug consumption were not found to be associated with blood lead levels. These results show that blood lead levels in Taiwan residents were not higher than in most developed and developing countries. Environmental lead pollution does not seem to be a serious problem in Taiwan. PMID- 7843837 TI - Occupational exposure to water-based paints and self-reported asthma, lower airway symptoms, bronchial hyperresponsiveness, and lung function. AB - The associations between occupational exposure to water-based paints and the prevalence of self-reported asthma, other lower airway symptoms, bronchial hyperresponsiveness (BHR), and lung function were studied in house painters. Symptom prevalences were obtained from a self-administered questionnaire sent to 415 male painters during 1989-1992. Clinical investigations were carried out in three selected groups: 23 painters with asthmatic symptoms, nine painters with other lower airway symptoms, and 12 painters without airway symptoms. The clinical studies included lung function test, methacholine provocation test, and occurrence of atopy, confirmed by skin prick test to common allergens. In addition, a group of 18 young male painters with no occupational exposure to solvent-based paints were followed with dynamic spirometry before and after a workshift, when only water-based paints were used. The prevalence of self reported asthma (7%) was somewhat, but not statistically, increased compared to an industrial population without exposure to water-based paints or other airway irritants. A decrease in FEV1 and FVC during the workday was observed in the young painters. In the clinical studies the painters exhibited increased BHR compared to the referents and a decreased FEV1. The number of years working as a painter was related to a decrease in FEV1, which was most pronounced in subjects with atopy who also reported lower airway symptoms in relation to the degree of work with water-based paints, but not to the degree of use of solvent-based paints. Our results indicate that house painters have an increased risk of airway problems.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843838 TI - Passive smoking in the workplace: classical and Bayesian meta-analyses. AB - There are currently several classical and Bayesian methods of meta-analysis available for combining epidemiological results. We describe and compare these in a consistent framework, and apply them to published studies of the relative risk of lung cancer associated with exposure to environmental tobacco smoke in the workplace. We find that although all methods give reasonably similar combined estimates of relative risk of lung cancer associated with this exposure (none of which is significantly raised above unity, in either a frequentist or a Bayesian sense), the approximations arising from classical methods appear to be nonconservative and should be used with caution. The Bayesian methods, which account more explicitly for possible inhomogeneity in studies, give slightly lower estimates again of relative risk and wider posterior credible intervals, indicating that inference from the non-Bayesian approaches might be optimistic. PMID- 7843839 TI - Factors affecting long-term sick leave in an industrial population. AB - Factors affecting long-term absenteeism for non-accident-related sickness leave in a large, remotely located factory (Dead Sea Industry, Israel) were evaluated. About 10% (89 persons) of the workers were found to be on sick leave for more than 20 days/year. This group was designated as high absence workers (HAW). Most of the sickness absence were for repeated short-term leaves due to intercurrent diseases, rather than for continuous periods related to a major or single illness. Average cumulative duration of sick leave in this group was 54 days/year. The average number of spells was 11 per year (4.9 days/spell). There were significantly more HAW among skilled (relative risk, R.R. = 1.6) workers or shift workers (R.R. = 1.3), compared to white collar workers. There were significantly fewer HAW among workers 35-49 years of age (7.6%) than among younger (12.5%) or older workers (13.8%). Except for possible hearing loss in one worker, no occupationally related illness was identified. Sixty-six percent of the HAW took many sick leaves, over 20 days during the year following the study year, and 52% of this group took over 20 days in the preceding year (usually for minor diseases or complaints). This pattern of long-term sickness absence indicates that various socio-economic factors determine HAW to a greater extent than immediate occupational risks or health problems. PMID- 7843840 TI - Nitro musk. AB - The detection of nitro musk compounds in breast milk and in human adipose tissue is mainly due to the use of such substances as perfume in detergents from which they enter the sewage and finally the whole freshwater system. Due to their low degradability and a high biological concentration factor, they enter the food chain without the toxicological investigations to date allowing any certain conclusions on the effect of such accumulation in the human organism or on the effect of accumulation in ecological systems. PMID- 7843841 TI - Where is here and when is now? The adaptational challenge of mental health reform for group psychotherapy. AB - The structure of health care delivery is in a period of rapid change. An understanding of psychotherapy service use patterns indicates the importance of time categories as well as the relevance of group techniques. Traditional interpersonal and psychodynamic group techniques may be modified for time-limited use without sacrificing basic values and with demonstrated effectiveness. Adapting to a more fiscally stringent practice environment requires the clinician to undertake a difficult process of transition. As professionals our task is to prepare ourselves for this challenge and to let the health care system know that proper practice guidelines are necessary to achieve effective treatment for our patients. PMID- 7843842 TI - Here is now. AB - This article responds to K. Roy MacKenzie's Presidential Address, which concerns the challenge of mental health reform as it effects group psychotherapy. Issues of the time-effective use of groups for specific patient populations are explored. The need for practice guidelines that benefit from outcome studies is emphasized. In addition, the efforts of the National Registry of Certified Group Psychotherapists to support group therapy within the current managed care environment are explicated. PMID- 7843843 TI - Managed care cost effectiveness: fantasy or reality? AB - This article reviews some of the health care issues raised by K. Roy MacKenzie. The author identifies additional contributors to spiralling costs and offers a slightly different perspective on the issue of the efficacy of short-term time limited psychotherapy. In particular, the author raises questions regarding the cost-driven aspect of today's health care delivery system versus quality of care. He also challenges some of the research findings used in support of MacKenzie's argument that short-term time-limited group therapy is as cost-effective as long term individual psychotherapy. More specifically, he considers how resistance and the sense of hopefulness might influence the favorable outcomes of the studies cited in MacKenzie's article. In addition, the relationship between short-term psychotherapy and managed care abuse is addressed and a partial solution to preventing such abuse by legislating public accountability is offered. PMID- 7843844 TI - Resolving shame in group psychotherapy. AB - This article addresses shame and the defenses against shame in group psychotherapy. The experience of shame involves the activation of devalued and devaluing introjects, either of which can be externalized through projection or projective identification resulting in the manifestation of contempt and envy. This article will examine ways to identify, understand, and manage these defenses in order to help resolve shame. The resolution of shame involves experiencing and verbalizing the profound sense of inadequacy associated with shame without resorting to splitting or receiving the anticipated rejection and condemnation from self and others. PMID- 7843846 TI - Treating wife abuse: an integrated model. AB - Group treatment of wife abusers has largely focused on time-limited, structured treatment models. Drawing on a range of theories, a developmental model is presented that provides abusing men with affective education, helps them to resolve their childhood traumas, provides a therapeutic group environment for learning new problem-solving skills, and above all, emphasizes their ending violent and controlling behavior. PMID- 7843845 TI - Group psychotherapy for depressed adolescents: a critical review. AB - The usefulness and efficacy of group psychotherapy with a variety of adolescent problems has been well documented. Far less has been reported with respect to group treatment approaches for youthful depressives, however. Currently available treatments lack specificity, making replication difficult. Additionally, they often focus on a narrow range of deficit areas rather than addressing the multifaceted range of dysfunction characteristic of depression in adolescents. This paper critically reviews the available literature on group treatments with depressed adolescents, explores some of the shortcomings inherent in these reports, and suggests alternatives for future group protocols. It is proposed that subsequent interventions be manualized and that they target affective, behavioral, and cognitive aspects of adolescent depression. Such an approach would be more amenable to scientific investigation, replication, and comparison with alternative approaches. PMID- 7843847 TI - Characteristics of patients who choose between two types of group psychotherapy. AB - Patient selection or matching to group psychotherapy is usually done by therapists. An alternative is to allow patients to "sample" and then select from different group therapies. In the current study characteristics of patients (N = 20) who selected from two types of group psychotherapy in a day-treatment program were examined. Patients were assessed on measures of current psychiatric symptomatology (Symptom Checklist 90-Revised [SCL-90R]; Derogatis, Rickles & Rock, 1976), psychological mindedness (McCallum & Piper, 1990) and psychological defenses Mechanisms Inventory (Ihilevich & Gleser, 1986). The two groups did not differ with regard to symptomatology or psychological mindedness. It was found that patients who chose a verbal and process-oriented psychotherapy tended to have externalizing defenses (turning anger against others and projection), however. These defenses appear to be congruent with this more emotionally expressive therapy. Patients who chose a structured and activity-oriented group psychotherapy tended to have internalizing defenses (repression/denial and intellectualization). These defenses seem consistent with this group therapy, which emphasized less emotional expressiveness. The implications of patient choice for group therapy and patient selection practices are discussed. PMID- 7843848 TI - Response to HarPaz, Weiner, and Leszcz. PMID- 7843849 TI - Response to Scheidlinger. PMID- 7843850 TI - Predominant suppression of anti-TNP IgE response in mice by monoclonal anti-TNP IgG1 antibody: characterization of its mode of action by in vitro and in vivo studies. AB - It was found that an antigen-specific IgE response both in vitro and in vivo was strongly suppressed in the presence of IgG1 monoclonal antibody (mAb) against the antigen. Anti-trinitrophenyl (TNP) IgE response was elicited by the co-culture of C3H B-cells and a conalbumin (CA)-specific helper T-cell clone, D10.G4.1, in the presence of 0.1 microgram/ml TNP-CA. Addition of anti-TNP IgG1 monoclonal antibody (mAb) at 1 microgram/ml to the culture resulted in a marked (> 90%) suppression of anti-TNP IgE formation, while anti-TNP IgG1 and IgM responses were affected to a lesser extent (50-60% suppression). Similar observations were made in in vivo experiments. When 100-200 micrograms of anti-TNP IgG1 mAb was injected i.p. into BDF1 mice prior to immunization with TNP-CA, the anti-hapten (TNP) IgE response as well as the IgE response to the carrier (CA) was suppressed by 80 90%, while anti-TNP IgM production was inhibited by less than 50%. Injection of anti-TNP IgM or IgA mAb showed only marginal effects on anti-TNP IgE production. Spleen cells from anti-TNP IgG1 mAb-treated mice cultured in vitro secreted much lower levels of anti-TNP IgE spontaneously than those from untreated mice. In in vitro and in vivo experiments using the F(ab')2 of anti-TNP IgG1 mAb, an IgG1 mAb with an irrelevant specificity and mAb directed to Fc gamma RII, it was shown that the binding of the IgG1 mAb with the antigen and the interaction of its Fc portion with Fc gamma RII are required for the suppressive effects to be exerted. PMID- 7843851 TI - Pyridinyl imidazoles inhibit the inflammatory phase of delayed type hypersensitivity reactions without affecting T-dependent immune responses. AB - The effects of pyridinyl imidazoles, specifically SK&F 105809 and its metabolite, on normal T-cell and B-cell mediated immune responses were examined and compared to the fungal macrolide immunosuppressives, cyclosporin A, FK506 and rapamycin and to the corticosteroid, dexamethasone. The orally active prodrug SK&F 105809 [2-(4-methylsulfinylphenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo [1,2-a] imidazole[ and its metabolite, SK&F 105561 [2-(4-methylthiophenyl)-3-(4-pyridyl) 6,7-dihydro-[5H]-pyrrolo[1,2 -a] imidazole] are dual 5-lipoxygenase (5-LO) and cycloxygenase (CO) inhibitors with potent anti-inflammatory and cytokine (IL 1/TNF) suppressive activities. The anti-inflammatory activity of SK&F 105809 and its metabolite were evaluated in an antigen-specific murine model of delayed type hypersensitivity (DTH) response, where they were found to affect only the inflammatory and not the induction phase of this response. In contrast, these compounds and other pyridinyl imidazoles (SK&F 86002 and its analog, SK&F 104351) exhibited no immunosuppressive activity under conditions where the macrolide rapamycin and the corticosteroid dexamethasone abrogated both the cellular and humoral immune responses. Thus, the ability of pyridinyl imidazoles to attenuate independently the inflammatory components of the disease without causing generalized immunosuppression enhances their profile as candidates for therapy of chronic inflammatory diseases, specifically those mediated by cytokines (e.g. IL 1, TNF) and eicosanoids. PMID- 7843852 TI - Characterization of cAMP-dependent inhibition of LPS-induced TNF alpha production by rolipram, a specific phosphodiesterase IV (PDE IV) inhibitor. AB - Bacterial endotoxins (lipopolysaccharide or LPS) provoke shock and tissue injury by eliciting the release of toxic factors from reticuloendothelial cells. One of the principal endogenous factors involved in this process is tumor necrosis factor alpha (TNF alpha). In this study, inhibitors selective for different classes of phosphodiesterases (PDE), were examined for their effects on LPS induced TNF alpha production by human monocytes. The selective cAMP-PDE IV inhibitors, rolipram and RO-20-1724 were capable of inhibiting LPS-induced TNF alpha production by human monocytes in a concentration-dependent manner. Rolipram was used to examine further the cellular pharmacology of PDE IV inhibitors on cytokine production. The IC50 for inhibition of LPS-induced TNF alpha production by rolipram was 0.1 microM, whereas production of IL-1 beta or IL-6 was unaffected. Furthermore, rolipram was equally effective in inhibiting TNF alpha production by a number of other stimuli. Inhibition of TNF alpha production by rolipram was associated with an elevation of intracellular cAMP, consistent with a mechanism involving phosphodiesterase inhibition. Rolipram was efficacious in suppressing LPS-induced TNF alpha mRNA expression, and at the protein level was also active when added to cultures post-stimulated with LPS. This indicates that rolipram may act at both the transcriptional and translational levels. Rolipram inhibited TNF alpha production in vivo in a rat endotoxemia model. Collectively, these data suggest that the prototypic inhibitor of PDE IV isozyme, rolipram, can effectively and selectively inhibit LPS-induced TNF alpha production through elevation of intracellular cAMP. PMID- 7843853 TI - Lymphocyte activation by liposome-trapped streptozotocin in murine popliteal lymph node (PLN) test. AB - The lymphoproliferative potential of liposome-trapped streptoztocin (STZ) was compared to the effect of saline-dissolved STZ injected locally into the foot pad of CD-1 mice. Popliteal lymph node (PLN) enlargement and early cell activation of lymphocyte subsets were monitored during the onset of STZ-induced autoimmune-like reaction. Injection of the optimal STZ dose, 0.5 mg/foot pad, markedly increased the absolute PLN cell number as well as specific T-helper (CD4+), T suppressor/cytotoxic (CD8+), and B-(Ig+) cell subsets stained with fluorescent monoclonal antibodies. Furthermore, there was a marked increase in the number of large/activated CD4+ and CD8+ cells and subsets bearing specific markers of early activation. These included cells stained with fluorescein-conjugated monoclonal antibodies against interleukin-2 receptor (CD25+) and early activation marker (EAM+) (CD69+), and with fluorescein-conjugated peanut agglutinin (PNA+). Surprisingly, the injection of liposome-trapped STZ, at a 1/10 of the optimal dose only, induced a marked PLN enlargement comparable to the effect of optimal STZ dose. The effect of liposome-STZ could be dissociated from the non-drug containing MLV-related lymphocyte activation. The data suggest several possible advantages from the introduction of chemicals by the liposome route and the subsequent PLN test for chemical-induced autoimmunity. Toxicological advantages could involve better control of chemical exposure, controlled exposure to the water-insoluble substances, drastic reduction of xenobiotic dose, a stronger, clear PLN response and possible elimination or at least restriction of false negative results, due to the liposome adjuvancity. Overall, application of liposomes as an exposure route potentialized the STZ-induced early lymphocyte activation. PMID- 7843854 TI - Partial characterization of the enhanced survival of female NZB/W mice treated with lithium chloride. AB - Previous investigations have indicated that initiation of LiCl treatment (4 mg/day) of female NZB/W mice at 10 weeks of age led to enhanced survival of 50% of the mice to > 11 months of age (Lithium, 3, 61-67, 1992). The present results indicate that this enhancement of survival is dose dependent in that 2 mg 7LiCl/day was less effective than 4 mg 7LiCl/day. Daily treatment of groups of mice with 2 or 4 mg LiCl per day starting at 8 weeks of age led to the survival of 40% and 70%, respectively, of the mice at 40 weeks of age, a time when only 10% of the untreated mice remained alive. Initiation of treatment with 2 mg 7LiCl/day after the disease process was evident (24 weeks of age) led to diminished effectiveness. Parallel experiments with mice treated with 4 mg 7LiCl/day revealed 60% long-term survivors in the early treatment groups and 33% in the delayed treatment groups. Cessation of treatment in both groups led to some additional deaths, but 20-27% of the mice remained alive at 60 weeks of age, even though animals had detectable levels of anti-ssDNA antibodies in their serum. Additional experiments with 2 and 4 mg 7LiCl/day in NZB/W mice pretreated with C. parvum-PER, a treatment previously shown to enhance survival (Int. J. Immunopharmac., 14, 35-41, 1992), indicated that the effect of the two modalities was not additive. The results presented indicate that treatment of NZB/W mice with LiCl leads to very effective prolongation of survival by unique mechanisms, possibly involving alteration of the effector phase of autoimmune damage to the kidney or the susceptibility of kidney elements to immune-mediated damage leading to renal failure. PMID- 7843855 TI - OHM3295: a fentanyl-related 4-heteroanilido piperidine with analgesic effects but not suppressive effects on splenic NK activity in mice. AB - The immunoregulatory effects of fentanyl and a fentanyl-related compound, OHM3295, were studied in mice. Male CD1 mice treated with a range of fentanyl doses (0.1-1.0 mg/kg, subcutaneously) showed suppression of splenic natural killer (NK) activity following 0.25-0.50 mg/kg fentanyl dose but not higher (0.75 1.0 mg/kg) or lower (0.1 mg/kg) doses. Fentanyl (0.01-32.0 mg/kg) also induced dose-related analgesia as measured by an increase in tail flick latency; these analgesic effects were antagonized by naltrexone (1.0-10.0 mg/kg). Pretreatment with naltrexone (1.0-3.2 mg/kg) resulted in significant suppression of splenic NK activity following fentanyl (10.0-32.0 mg/kg) administration. In comparison to fentanyl, OHM3295 (3.2-25.0 mg/kg) augmented splenic NK activity in a naltrexone reversible manner. Similar to fentanyl, OHM3295 (1.0-32.0 mg/kg) also induced a naltrexone-sensitive, dose-related analgesia as measured by an increase in tail flick latency. These results with OHM3295 demonstrate a novel profile of effects which includes naltrexone-sensitive analgesic effects in the absence of immunosuppressive effects. In addition, this is the first reported case in which a compound with opioid analgesic effects has been shown to potentiate natural killer cytolytic activity following in vivo administration. PMID- 7843856 TI - Combined treatment of autoimmune MRL/MP-lpr/lpr mice with a herbal medicine, Ren shen-yang-rong-tang (Japanese name: Ninjin-youei-to) plus suboptimal dosage of prednisolone. AB - Therapeutic effects of combined treatment with a Chinese medicine prescription, Ren-shen-yang-rong-tang (Japanese name: Ninjin-youei-to, NYT) and suboptimal doses of prednisolone (PSL) on pathological findings of autoimmune-prone MRL/lpr mice were examined. Six-week-old MRL/lpr mice were treated orally with 1000 mg/kg of NYT, 0.5 or 2 mg/kg of PSL, 1000 mg/kg of NYT plus 0.5 or 2 mg/kg of PSL (combined treatment) or solvent only (control) six times per week. The rates of signs and symptoms of autoimmune disease (lymphadenopathy, proteinuria, dermatitis, loss of hair) were suppressed significantly in groups given PSL (2 mg/kg) alone, NYT alone and combined treatment with PSL (2 mg/kg) plus NYT (1000 mg/kg) compared with control, respectively, whereas treatment with PSL (0.5 mg/kg) alone did not inhibit their occurrence. ConA response and IL-2 production were also improved significantly in lymphocytes of mice given the combined treatment. Interestingly, treatment with NYT alone enhanced further the augmented IFN-gamma production in MRL/lpr mice but the combined treatment suppressed such an augmented production. The combined treatment dramatically reduced the level of anti-DNA antibodies in serum of MRL/lpr mice. By contrast, NYT alone treatment had no effect on autoantibodies production. These results suggest that combined treatment with NYT plus a suboptimal dose of PSL could be effective for systemic lupus erythematosus without severe side-effects. PMID- 7843857 TI - Effects of a traditional Chinese herbal medicine, Kanzo-bushi-to, on the resistance of thermally injured mice infected with herpes simplex virus type 1. AB - The protective effect of Kanzo-bushi-to (TJS-038) was investigated on the opportunistic infection of herpes simplex virus type 1 (HSV) in thermally injured mice (TI-Mice). We have previously reported that TI-Mice were approximately 100 times more susceptible to HSV infection than normal mice (N-Mice) and that CD8+ suppressor T (ST)-cells induced by burn injury were involved in causing this increased susceptibility of TI-Mice. Increased susceptibility of TI-Mice to the infection was reversed to the levels observed in N-Mice when TI-Mice were treated intraperitoneally with TJS-038 at a dose of 5 mg/kg 1 and 4 days after thermal injury. The activity of ST-cells was greatly decreased in TI-Mice treated with TJS-038. The generation of Vicia villosa lectin-adherent CD4+ CD28+ TCR alpha/beta+ contrasuppressor T (Contra-ST)-cells associated with the appearance of ST-cells was expanded and occurred earlier in spleens of TJS-038-treated TI Mice as compared with that of untreated TI-Mice. The improved resistance of TJS 038-treated TI-Mice to the infection was transferred to untreated TI-Mice by adoptive transfer of Contra-ST-cells prepared from TJS-038-treated TI-Mice. These results suggest that TJS-038 may restore the resistance of TI-Mice to the HSV infection through the expanded generation of Contra-ST-cells. PMID- 7843858 TI - The influence of amino acids on mitogen-activated proliferation of human lymphocytes in vitro. AB - Recurrent infections are common features in patients affected by various aminoacidopathies. Since these disorders are biochemically characterized by tissue accumulation of amino acids, it is possible that these compounds may act as immunosuppressants. We therefore investigated the influence of 21 amino acids on in vitro cellular growth of lymphocytes stimulated with phytohaemagglutinin (PHA), concanavalin A (Con A) and pokeweed mitogen (PWM), a recognized test of cellular immunocompetence. Human peripheral lymphocytes were cultured in flat bottomed 96-well microplates at 37 degrees C for 96 (PHA and Con A) or 144 h (PWM) in the presence of one mitogen at different concentrations and of one amino acid added at doses of 2, 4 or 8 mM. Cell reactivity was measured by the incorporation of tritiated thymidine into cellular DNA and compared to that of identical cultures with no amino acids added (controls). We found that among the 21 amino acids tested, cysteine stimulated lymphocyte growth, whereas glutamate, tryptophan, phenylalanine and glutamine caused significant inhibition. These results may reflect an immunomodulatory role for some amino acids. PMID- 7843859 TI - Detection and localization of 3,3',4,4'-tetrachlorobiphenyl-induced P4501A protein in avian primary immune tissues. AB - P4501A can be detected in thymic and bursal microsomes from chickens pretreated with 3,3',4,4'-tetrachlorobiphenyl (TCB) using a polyclonal antibody against purified P4501A from 3-methylcholanthrene (3-MC)-induced chicken embryo liver. A dose-response for induction by TCB of P4501A protein was detected by Western blotting in both bursal and thymic microsomes. Ethoxyresorufin-O-deethylase (EROD), a specific catalytic activity of P4501A, was also induced in a dose response fashion. More TCB-induced P4501A was detected in thymus than bursa by both methods. No EROD was detected in bursal or thymic microsomes from untreated chickens, although P4501A protein was detected at very low levels in thymic microsomes from untreated chickens. P4501A was detected by immunohistochemistry in scattered patches of non-lymphocytic cells residing in medullary regions of the TCB-induced thymus but was not detected in lymphocytes. This result supports previous work demonstrating that TCB-inducible EROD is much higher in the supporting tissue cell fractions than in lymphocyte fractions of the primary immune tissues. Although EROD was induced by TCB in the late stage embryo after 20 h exposure, no effect of TCB on the cell cycle in thymic or bursal lymphocytes was observed over the same period. The same TCB exposure resulted in bursal but not thymic cellular depletion. Thymic and bursal supporting tissue cells may be primary sites of immunosuppression within these organs by P4501A inducers or substrates whether immunosuppression occurs subsequent to metabolism or through interaction with Ah receptors. PMID- 7843860 TI - Assessing the relationship between a multidimensional psychological "control profile" and cardiovascular risk. AB - This article begins by citing apparently conflicting sets of literature regarding the association between control and cardiovascular risk. Each set of findings is based on a unidimensional understanding of control. To gain more precise information, a multidimensional control inventory, the Shapiro Control Inventory (SCI), was given to twenty individuals at the time of their yearly physical. Results showed that low perceived control on the domain specific control scale was associated with higher cardiovascular risk. Further, several findings between specific risk parameters--smoking, calories from fat, blood pressure, and cholesterol level (HDL)--were significantly associated with different dimensions of the control profile. Case study data from the two individuals at highest risk suggest that different control profiles may be associated with cardiovascular risk. Guidelines and suggestions for future research are offered. PMID- 7843861 TI - Relaxed exercise. PMID- 7843862 TI - An emancipating orientation to biofeedback; an implication for psychotherapy. AB - This article contrasts controlling and emancipating orientations to biofeedback. An emiprical study which the investigator did, its methodology and findings are described. The study supports both the meanings of ttiis differentiation and the implications this distinction has for psychotherapy. PMID- 7843863 TI - The dichotomy of alexithymia and panic disorder. AB - This manuscript presents a novel model of psychophysiologic markers for the stress response. The hypothesis describes what we believe is a human analogue of the physiologic changes described in animal models of inescapable shock. This is bolstered by laboratory and clinical data derived from patients with stress related functional gastrointestinal disorders. The idea explains the clinical findings of simultaneous analgesia and somatization in alexithymics. The implications for understanding the physiologic relationship between panic disorder and functional bowel disorders in the context of the stress response is discussed along with novel treatment strategies for these disabling conditions. PMID- 7843864 TI - Life events and stress reactivity as predictors of cancer, coronary heart disease and anxiety disorders. AB - The topic relative to the differential psychobiological mechanisms between cancer and coronary illness has been showing for the last years. In this sense, some theoretical models which have been formulated by relevant authors have suggested the possibility of differentiating cancer and cardiovascular disease, both the onset and the progression, from coping strategies, personality variables and affective states, as well as the different categories of psychosocial stress. Likewise, the implication of psychological distress, such as anxiety, anger and depression for the occurrence of somatic disease has been reported frequently. This research was designed to analyze the psychosocial patterns which could explain the incidence of heart disease, cancer and anxiety based disorders. Measures of life events and stress reactivity were obtained from a total of 109 patients diagnosed as having breast cancer (37), infarct (37), and anxiety (35), and from 72 normal control subjects. Our data tend to show that the cancer group was strongly predicted by lost and illness events, while the coronary group was more associated with work events. The anxiety disorders group lacked a life events dimension, but shared the same category of the infarct group. We also found a strong relationship between depressive reactions and cancer in contrast to the anxiety-anger variable that was more relevant in the infarct patients. The interaction between internal and external stress factors in the etiology of disease is also discussed. PMID- 7843865 TI - A rationale for a multilevel model of relaxation. AB - A Three dimensional evolutionary leveled model of the main states of consciousness is offered as a rationale for relaxation. "Relaxing states" and "relaxation response states--Differentiated Waking States of Consciousness" are distinguish on the horizontal plane according to the integrated model of the main states of consciousness. It is proposed that states of consciousness in relaxation could be considered also on vertical evolutionary dimension described according to neo-Jacksonian theory in terms of the metabolism of information. The model opens perspectives for the description of dynamic fluctuations of states of consciousness during relaxation in terms of the main states of consciousness, i.e., REM-sleep, NREM-sleep, Ordinary Waking States of Consciousness, Differentiated Waking States of Consciousness, as well as in terms of dissolution (regression) and evolution on the vertical developmental dimension. It is illustrated by the discussion on meditation and hyponosis. PMID- 7843866 TI - The reliability of EMG muscle scanning. AB - The reliability of a surface EMG scanning procedure was investigated for the right and left aspects of 10 muscle sites using a large clinical sample of 102 chronic pain patients. Two neutral postures (sitting/standing) were systematically studied on three occasions approximately one hour apart on the same day. The multivariate analysis of RMS microvolts indicated no significant effects for Age, Gender, Muscle site, Aspect or Period. The range of the Pearson correlations was 0.41 to 0.94 when all muscle sites, aspects, postures, and periods were considered. The median correlation was found to be 0.64. The pattern of reliability was seen to be slightly higher in the upper back while sitting, and slightly higher in the lower back while standing. The results indicate that with adequate attention to skin preparation, EMG sensors held in place by hand with a light pressure produce reliable results. PMID- 7843867 TI - Physiological and psychological effects of Hatha-Yoga exercise in healthy women. AB - Hatha-Yoga has become increasingly popular in western countries as a method for coping with stress. However, little is known about the physiological and psychological effects of yoga practice. We measured heart rate, blood pressure, the hormones cortisol, prolactin and growth hormone and certain psychological parameters in a yoga practicing group and a control group of young female volunteers reading in a comfortable position during the experimental period. There were no substantial differences between the groups concerning endocrine parameters and blood pressure. The course of heart rate was significantly different, the yoga group had a decrease during the yoga practice. Significant differences between both groups were found in psychological parameters. In the personality inventory the yoga group showed markedly higher scores in life satisfaction and lower scores in excitability, aggressiveness, openness, emotionality and somatic complaints. Significant differences could also be observed concerning coping with stress and the mood at the end of the experiment. The yoga group had significant higher scores in high spirits and extravertedness. PMID- 7843868 TI - Biofeedback treatments for premenstrual and premenstrual affective syndromes. PMID- 7843869 TI - Complementary healing therapies. AB - The effect of non-contact therapeutic touch (NCTT) in isolation and in combination with Reiki, LeShan, and Intercessory Prayer on the healing rate of full thickness human dermal wounds was examined utilizing a randomized, double blind, within subject, crossover design. The protocol incorporated an integral biofeedback, guided imagery, and visualization/relaxation component in order to assess the influence of psychophysiological factors on the healing process. Biopsies were performed on the lateral deltoid in healthy subjects and assessed by two independent physicians for the rate of reepithelialization at day 5 and day 10. Subjects met as a group on odd numbered days for a one hour visualization/relaxation session which incorporated guided imagery with either a specific intent to heal their biopsy wound or a specific intent to relax. Treatment intervention included two NCTT healers or two mimic practitioners who worked in-person for a duration of 6 minutes per subject. LeShan and Intercessory Prayer healers worked at a distance and a Reiki healer worked in-person with the NCTT healers. On even numbered days, subjects were trained in hand temperature biofeedback with either a specific intent to heal or a specific intent to relax. Results showed significance for the treated versus the control group but in the opposite direction from that expected. Several factors could have contributed to the nonsignificance obtained including: (a) the natural healing ability of the two mimic practitioners; (b) the subjects' increased proficiency with the self regulatory techniques; and (c) a carryover effect from the two NCTT healers and/or the Reiki, LeShan, or Intercessory Prayer healers. PMID- 7843870 TI - The psychophysiology of nontraditional prayer. AB - This study was a replication and extension of previous research which indicated that Non-Contact Therapeutic Touch had a significant effect in normalizing the activity of the "end organ" for the central nervous system (CNS). The study utilized a randomized double-blind within subject crossover methodological design to examine the effect of nontraditional distant prayer upon autonomic and CNS parameters. The impact of complementary healing was assessed utilizing multi-site surface electromyographic (sEMG) recordings located at the frontalis, Cervical 4 paraspinals, Thoracic 6 paraspinals, and Lumbosacral 3 paraspinals. The autonomic indicators of physiological activity included hand temperature, heart rate, skin conductance levels (SCL), and blood volume pulse (BVP). Twenty-one subjects were randomly assigned to treatment and control conditions for two thirty minute evaluation sessions for a total of forty-two psychophysiological monitoring periods. All participants were blinded to the true nature of the experimental protocol as well as the fact that a healing study was being conducted in order to control for suggestion, expectation of healing, and the placebo effect. The analysis of autonomic indicators demonstrated a slight decrease in BVP and heart rate, coupled with a minor increase in SCL suggesting a mild "anticipatory effect" arousal trend. The data also showed that two of the four muscle regions monitored-T6 and L3 paraspinals-indicated a significant reduction in electromagnetic energy during and following the distant healing treatment intervention for a majority of the subjects. For example, the T6 SEMG showed significance at the p < .0002 level, while the L3 SEMG indicated significance at the p < .001 level.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843871 TI - Alleviating dental phobia with the neuro-associative conditioning model. AB - Robbins' Neuro-Associative Conditioning (NAC) model is described and its value in providing a structure for therapeutic work outlined. The applicability of the model is illustrated through a single-session treatment of dental phobia which makes use of: (i) case taking by means of a problem solving model to identify patient needs, (ii) interruption of an old behavior/emotional pattern through use of Bandler's (1) Theatre technique, and (iii) installation of new behavior through success imagery. PMID- 7843872 TI - Postmodern and cross-cultural perspectives on mind and body. AB - New conceptualizations of the so-called "mind/body problem" have resulted from research findings in psychoneuroimmunology, from theoretical speculations of the postmodernists, and from an examination of other cultural perspectives on "mind" and "body". The interaction between the two may lead to a wholistic perspective not unlike the one proposed by humanistic psychologists and appearing in their journals, their conferences, and their clinical practice. PMID- 7843873 TI - Addiction: a Russian perspective. PMID- 7843874 TI - Psychotherapeutic application of group hypnosis. AB - This clinical observational study examined the effects of group hypnosis on psychosomatic disorders. A psychotherapist conducted hypnotic sessions with a single group of 306 people on four consecutive days. Our follow-up studies indicated that group hypnosis can have strong positive effects on many types of disorders. The depth of hypnosis was not related to the level of improvement. The results suggest that the human body has considerable potential for psychophysiological regulation. PMID- 7843875 TI - Presumed paranormal linkage of rings. AB - Examples are presented in the SORRAT experiments of: (1) presumed paranormally linked human aortic rings and their teleportation into a sealed, glass globe; (2) videographed experiments with Joe Nuzum, paragnost, while in a trancelike state, accomplishing linkage of a class ring on his finger to one key of several held in a researcher's hand; and (3) in a different experiment linking two rubber bands of several which were held in a researcher's hand. X-ray and MRI studies tend to confirm the genuineness of these mind-over-matter psychosomatic effects. Further linkage experiments are described including videographed linking and delinking of rubber bands, and a videographed linking and delinking of a gold seamless ring and brass nut. It is speculated that these experiments illustrate some degree of conscious, volititional control and might have analogous and overlooked aspects and possibilities in human biology and nature, and that these are overripe areas for intensive parapsychiatric investigation. PMID- 7843876 TI - Genetic technology in health care. A global view. AB - Clinical genetics services have become an integrated part of health care in nearly all European countries. The emphasis has been on postnatal cytogenetic, biochemical, and DNA diagnosis of congenital disorders, carrier detection, genetic counseling, and prenatal diagnosis. Use has been satisfactory, and very few ethical problems have arisen, apart from moral objections against abortion by minority groups. The progress of human gene mapping is associated with new perspectives in clinical genetics and will enable the identification of people at risk of major adult diseases. This prospect has caused some concern about psychosocial and ethical issues that are being dealt with in different ways in various postindustrial societies. In future decades, however, 95% of the world's population increase will occur in developing countries. In most of these countries, a low per capita income, female illiteracy, low rates of contraceptive use, teenage pregnancy, and religious and traditional cultural factors are major complications of implementing genetic services at a global level. There are, however, some exceptions, which are discussed. PMID- 7843877 TI - Reflections on the cost consequences of the new gene technology for health policy. AB - This article presents a preliminary and necessarily tentative and subjective assessment of the impact of new gene technology on health care costs. In the short term, diagnosis and treatment of genetic disease are likely to increase costs. Treatment with nongene therapy will continue to be far less expensive than gene therapy where it is available. Research developments to monitor as indicators of forthcoming cost reductions in genetic therapy are set forth. Some forms of genetic screening may soon reduce health care costs, and an example is provided. Genetically engineered pharmaceuticals are described and their impact on costs reviewed. Conditions under which they are likely to reduce health care costs are indicated. PMID- 7843878 TI - Discovery, transfer, and diffusion of technologies for the detection of genetic disorders. Policy implications. AB - Much of the current interest in genetics stems from the Human Genome Project. Although the project will accelerate the identification of disease-related genes, as currently formulated it may retard discovery of gene function and effective treatments, thereby prolonging the stage in which people at risk of genetic diseases can be identified but not treated. This stage is fraught with ethical problems. The project's goal of sequencing the entire human genome could also detract from basic biological research, as could the growing interest of universities in biotechnology transfer to the commercial sector. PMID- 7843879 TI - Assessing genetic technologies. Two ethical issues. AB - Assessment of the impact of genetic technologies requires an understanding of the ethical issues that such technologies raise, which in turn requires an understanding of the social context of genetics. This article discusses 10 factors that characterize the social context of contemporary genetics, and considers two presumptions that usually are unquestioned--first, that more choice is always better; second, that what can be improved should be improved. Recent experience with genetic screening and testing to increase reproductive choice indicates that it is sometimes an ambiguous good. Prenatal testing, which has been guided by an ideology of nondirective counseling, will become increasingly problematic as the menu of possible genetic tests grows longer, because nondirectiveness offers no way to distinguish between significant disease and parental whim. In the realm of reproduction, more choice may also come to mean increasing parental responsibility to have genetically "healthy" offspring. Technologies intended to improve health outcomes may also be used for non-health related goals--such as to increase athletic performance or to capitalize on social prejudices. Genetic technologies increasingly will challenge the troubled distinction between therapy and enhancement. PMID- 7843880 TI - DNA technology and vaccines. AB - It has been 20 years since the concepts that are now embraced in the term recombinant DNA technology were first described. The technology has been used to design new vaccines, and one product--that for hepatitis B--has been in widespread use for almost a decade. Several other engineered vaccines have shown considerable promise in laboratory trials. Nevertheless, the potential of the approach is still to be realized. This article describes the principles that are involved in the design of these new vaccines, focusing on those for hepatitis B and rabies. PMID- 7843881 TI - Perspectives in genetic screening. Principles and implications. AB - Recent advances in genetic identification and characterization of a number or hereditary disorders have led to increased possibilities for genetic testing and screening. The context and methods of screening are important given that identification of otherwise healthy persons as being presymptomatic or at increased risk for genetic diseases may have serious consequences for their future lifestyle, employment, and insurability. This article examines general principles for genetic screening, including goals, delivery issues, and professional and lay responses to screening and counseling, and recommends areas in which social psychological research on screening is needed. PMID- 7843882 TI - Techniques in current use in prenatal diagnosis. AB - Prenatal diagnosis is now offered to the majority of pregnant women in Europe and the United States. Advances in obstetric and laboratory techniques mean that increasing numbers of conditions can be diagnosed prenatally; indeed, gene carriers can be identified before pregnancy in some cases. Current obstetric and laboratory techniques for prenatal screening and diagnosis of genetic disorders are discussed. PMID- 7843883 TI - DNA diagnosis in monogenic diseases. AB - Several routine procedures are available for diagnosis of diseases caused by an alteration in a single gene. These techniques include Southern analysis, the polymerase chain reaction, allele-specific oligonucleotide screening, automated DNA nucleotide sequencing, and linkage analysis. DNA testing procedures can be used for diagnosis of disease, determination of carrier status in affected families, or general screening of the population. Some of the more commonly used techniques and their applications are described in this article. PMID- 7843884 TI - DNA diagnosis in oncology. AB - Our understanding of the genetic changes that transform normal cells into malignant cells is increasing at a remarkable pace. Some of the changes involve detectable cytogenetic aberrations, whereas others are identifiable only at the molecular level. Many of the structural cytogenetic changes have also been defined molecularly because the genes involved have been cloned. Thus, we are approaching the stage in which the DNA obtained from tumor tissue can be analyzed to detect the presence of a series of chromosomal and molecular alterations. These studies provide important information regarding the precise diagnosis of the tumor type as well as prognostic information about the likely response to therapy and survival. PMID- 7843885 TI - Gene therapy. Molecular medicine of the 1990s. AB - In less than four years, the techniques of gene transfer have been taken from the laboratory and translated into numerous clinical trials. Although gene therapy was initially designed for the molecular repair of monogenic deficiency diseases, most of the current studies of gene therapy are targeting cancer. PMID- 7843886 TI - Physicians' influence on the decision to acquire magnetic resonance imagers in acute care hospitals. AB - The influences of four principal types of decision makers on the acquisition of magnetic resonance imagers were measured in hospitals in Southern California, Oregon, and Washington. We propose that of the decision makers assessed, physicians had the most influence on the acquisition of magnetic resonance imagers. PMID- 7843887 TI - The concept of cost in the economic evaluation of health care. A theoretical inquiry. AB - The costs included in economic evaluations of health care vary from study to study. Based on the theory of cost-benefit analysis, the costs that should be included in an economic evaluation are those not already included in the measurement of willingness to pay (net willingness to pay above any treatment costs paid by the individual) in a cost-benefit analysis or in the measurement of effectiveness in a cost-effectiveness analysis. These costs can be defined as the consumption externality of the treatment (the change in production minus consumption for those included in the treatment program). For a full economic evaluation, the consequences for those included in the treatment program and a caring externality (altruism) should also be added. PMID- 7843888 TI - The economic costs of acute myeloid leukemia in Sweden. AB - The direct and indirect costs of acute myeloid leukemia were estimated for Sweden in 1989. The calculated total cost was SEK 460 million. Nearly half of the costs, or 1.7 million per patient diagnosed, were indirect costs due to premature mortality. Direct costs of relapses and indirect costs of mortality represent costs due to the absence of completely curable therapy. They also represent potential cost savings that could be obtained after introduction of new treatment options in the future. PMID- 7843889 TI - The effect of allowing clinical discretion in ordering biochemical tests. Evaluation by complementary methods. AB - We describe the effects on costs, working patterns, and clinical behavior of installing a DAX "discretionary" biochemistry analyzer. Use of the new analyzer encouraged doctors to be more specific in requesting biochemical tests, which substantially reduced the number of tests requested and slightly reduced overall costs. Doctors preferred being able to order tests in this more specific way. PMID- 7843890 TI - Individual perception of education and treatment versus actual outcome. A theoretical model exemplified by an interventional study on patients with insulin dependent diabetes mellitus. AB - An educational model is presented that stresses the importance of the interaction between individual characteristics and intentional educational influences on outcome variation. This model is exemplified by an interventional study of patients with insulin-dependent diabetes mellitus who, despite long-term conventional medical treatment, had been unable to achieve satisfactory hemoglobin Alc levels. Treatment modes and their importance for understanding variations in outcomes are discussed from the interactional perspective suggested in the model. PMID- 7843891 TI - Report from the Argentinian Association for Health Research and Development (ACINDES). Socioeconomic analysis of hormone replacement therapy: impact of consumer satisfaction on the outcomes of therapy. PMID- 7843892 TI - Report from the Canadian Coordinating Office for Health Technology Assessment (CCOHTA). Photodynamic therapy. PMID- 7843893 TI - Report from the Conseil D'Evaluation des Technologies de la Sante du Quebec (CETS). The costs of conventional cholecystectomy, laparoscopic cholecystectomy, and biliary lithotripsy. PMID- 7843894 TI - Report from the Swedish Council on Technology Assessment in Health Care (SBU). Literature searching and evidence interpretation for assessing health care practices. PMID- 7843895 TI - Independent observation in the review of sequential days clustered by stay. PMID- 7843896 TI - Donor age and corneal endothelial cell density. PMID- 7843897 TI - Introduction of Debora B Farber 1994 corecipient of the Proctor Award. PMID- 7843898 TI - From mice to men: the cyclic GMP phosphodiesterase gene in vision and disease. The Proctor Lecture. PMID- 7843899 TI - Serum carotenoids and tocopherols and severity of nuclear and cortical opacities. AB - PURPOSE: To determine whether higher levels of individual carotenoids and tocopherols in the serum are related to less severe nuclear and cortical opacities within the general population. METHODS: Levels of individual carotenoids and tocopherols in the serum were determined in 400 randomly selected persons aged 50 to 84 years participating in the Nutritional Factors in Eye Disease Study of Beaver Dam, Wisconsin. Severity of nuclear and cortical opacities was assessed from lens slit lamp and retroillumination photographs taken at the same time. Relationships between serum levels of nutrients and prevalence of these opacities were evaluated using logistic regression analysis accounting for known possible confounders. RESULTS: Higher levels of individual or total carotenoids or alpha-tocopherol in the serum were not associated with less severe nuclear or cortical opacities overall. However, associations differed between men and women and within specific population subgroups. A significant trend for lower odds for either type of opacity with increasing levels of beta carotene in the serum was observed in men. For nuclear sclerosis, this protective association with beta-carotene was found in younger but not older men. Higher levels of three other carotenoids (alpha-carotene, beta-cryptoxanthin, and lutein) in serum were significantly related to lower odds for nuclear sclerosis only in men who smoked. In contrast to these inverse associations observed in some subgroups, higher levels of some carotenoids and alpha-tocopherol often were directly associated with nuclear sclerosis, particularly in women. CONCLUSIONS: Higher levels of carotenoids and tocopherols are not consistently associated with less severe opacities in the general population. PMID- 7843900 TI - Hydrogen peroxide affects specific epithelial subpopulations in cultured rabbit lenses. AB - PURPOSE: To investigate the effect of hydrogen peroxide on the epithelial cells of cultured rabbit lenses. METHODS: Lenses were cultured in minimum essential medium containing a single dose of 0.03, 0.1, or 0.2 mM H2O2. Three hours later the medium was replaced with peroxide-free minimum essential medium. Lenses were also treated with 0.5 mM 1,3-bis(2-chloroethyl)-1 nitrosourea (BCNU) to lower the activity of glutathione reductase and then exposed to 0.03 mM H2O2 maintained nearly constant by glucose oxidase. After H2O2 treatment, lenses were fixed and whole mounts of the epithelium were prepared or lenses were processed for electron microscopy. RESULTS: Cells exposed to a single dose of 0.03 mM H2O2 appeared normal; 0.1 mM H2O2 was not cytotoxic. Exposure to 0.2 mM H2O2 elicited swelling in cells in the pre-equatorial region (30 minutes) followed by the formation of islands of cells in the pre-equatorial region at 1 hour. Central epithelial cells appeared normal at 1 hour, were swollen at 3 hours and dead at 24 hours. By 48 hours, dead cells were found in the pre-equatorial and central regions. Cells in the peripheral region of the epithelium did not exhibit cytotoxicity. If lenses were pretreated with BCNU and then challenged with a maintained level of 0.03 mM H2O2, cytotoxicity was induced in the central and pre equatorial regions. Cells in the peripheral region survived BCNU-H2O2 treatment. CONCLUSIONS: Cells in the peripheral region of cultured lenses were more resistant to H2O2 cytotoxicity than cells in the central and pre-equatorial regions. The antioxidant defense or repair systems for H2O2-induced damage do not appear to be uniformly distributed in subpopulations of the lens epithelium. PMID- 7843901 TI - Neonatal lensectomy and intraocular lens implantation: effects in rhesus monkeys. AB - PURPOSE: To compare the effects of a lensectomy with and without intraocular lens (IOL) implantation on a neonatal rhesus monkey eye. METHODS: A lensectomy and anterior vitrectomy was performed on 75 monkeys during the first 16 days of life; 21 of these monkeys also had an IOL implanted into the posterior chamber. The eyes were examined at regular intervals using biomicroscopy, applanation tonometry, and ophthalmoscopy. RESULTS: The pseudophakic monkeys were studied until they were 92.5 +/- 5.8 weeks of age and the aphakic monkeys until they were 80.4 +/- 5.7 weeks of age. Pupillary membranes (100% versus 55.5%; P < 0.01) and lens regeneration into the pupillary aperture (28.6% versus 5.6%; P = 0.02) occurred more often in the pseudophakic than the aphakic eyes. As a result, the pseudophakic eyes required more reoperations than the aphakic eyes to keep the visual axis clear (P < 0.01). There was not a significant difference in the incidence of ocular hypertension between the pseudophakic and aphakic eyes (9.5% versus 12.7%; P = 0.34). Pupillary capture of the IOL optic occurred in 52% and haptic breakage in 33% of the pseudophakic eyes. All of the eyes with broken haptics had a prominent Soemmerring's ring varying in maximum thickness from 0.6 to 2 mm. Nine of the haptics from the seven eyes with broken IOLs had eroded into the iris, two into the ciliary body, and one into the anterior chamber. CONCLUSIONS: Implanting an IOL into a neonatal monkey eye after a lensectomy and anterior vitrectomy increases the likelihood of a reoperation being necessary. Haptics frequently erode into the iris and ciliary body and may break because of stress placed on the optic-haptic junction by forward movement of the IOL. PMID- 7843902 TI - Alpha-crystallin can act as a chaperone under conditions of oxidative stress. AB - PURPOSE: Previous studies have shown that alpha-crystallin, a major lens protein, acts as a chaperone preventing the thermal denaturation of other lens crystallins. However, there has not been an examination of the alpha-crystallin chaperone ability with respect to the types of insult thought to cause human cataract. Therefore, an examination of the chaperone potential of alpha crystallin under conditions of oxidative stress was undertaken. METHODS: Oxidation of alpha-, beta low (beta L)-, and gamma-crystallins was performed with an ascorbate FeCl3-EDTA-H2O2 system. Thermal denaturation was carried out by heating preparations at 62 degrees C or 72 degrees C. After protein denaturation, 360 nm scatter was measured. Protein-complex formation was measured with a TSK gel G4000 SW 600 x 7.5 mm exclusion column. RESULTS: This study indicates that: (1) alpha-crystallin markedly reduces the 360-nm light scatter of gamma crystallin caused by oxidation at 37 degrees C. (2) alpha-crystallin appears to protect the gamma-crystallin thiol groups from extensive oxidation. (3) Oxidation of alpha-crystallin causes only a small change in its ability to prevent heat induced scattering of either gamma- or beta L-crystallin. (4) Oxidation of both alpha- and gamma-crystallin does not significantly affect the ability of alpha crystallin to inhibit 360-nm light scattering of gamma-crystallin at 72 degrees C. (5) Oxidation of beta L-crystallin decreases its susceptibility to thermally induced scattering, but, conversely, oxidation of gamma-crystallin increases such susceptibility. (6) Oxidation of beta L-crystallin at 37 degrees C produces only a slight increase in light scatter, in contrast to observations obtained with gamma-crystallin. (7) alpha-crystallin provides long-term protection against thermally induced scatter of beta L-crystallin but not of gamma-crystallin. High performance liquid chromatography (HPLC) analysis suggests that the alpha-gamma crystallin complex gradually becomes insoluble at 72 degrees C, in contrast to the alpha-beta L-crystallin complex. Differing from thermal insult, alpha crystallin causes a marked decrease in gamma-crystallin light scattering under long-term oxidation. (8) The alpha-gamma-crystallin complex that results from oxidation represents a weak interaction because it cannot be isolated with procedures used to obtain the thermally induced complex. (9) This work confirms a previous study demonstrating that each alpha monomer (alpha m) contains a binding site for a partially denatured crystallin. CONCLUSIONS: The overall results indicate that alpha-crystallin can act as a chaperone under conditions of oxidative stress, decreasing the light scatter and thiol oxidation of other crystallins. Because oxidative stress is thought to be present under normal physiological conditions, it is probable that alpha-crystallin contributes to the mechanisms that maintain the lens in a transparent state. PMID- 7843903 TI - Relationship between spectral transmittance and slit lamp color of human lenses. AB - PURPOSE: To study the relationship between subjective lens color as observed with slit lamp biomicroscopy and spectral transmittance of the lens. To propose a model for this relationship to derive quantitative information on lens pigmentation from slit lamp observation. METHODS: Twenty-nine normal lenses, from donors aged 14 to 86 years, were used. The fraction of light transmitted from a narrow beam was measured as function of wavelength. The spectra were fitted with the one-parameter TL model of Pokorny et al. The relationship between this parameter and the color grading from Chylack et al. (lens opacity classification system III nuclear color score) was established. RESULTS: After slight adaptation of the TL model, the shapes of the transmittance spectra corresponded closely to the TL model (average residual error 0.05 log units). Log transmittance and lens opacity classification system nuclear color score were closely related (r = 0.90, 0.77, and 0.55 for 400, 500, and 602 nm, respectively). CONCLUSIONS: A mathematical relationship between TL parameter and lens opacity classification system nuclear color score could be established to predict lens transmittance from lens opacity classification system nuclear color score. This relationship was successful in predicting the correction for lens absorption needed in blue-on yellow perimetry. PMID- 7843904 TI - Differences in interleukin-6 gene expression between cultured human corneal epithelial cells and keratocytes. AB - PURPOSE: To determine whether interleukin-6 (IL-6) can be synthesized by human corneal keratocytes and epithelial cells. METHODS: Epithelial cells and keratocytes isolated from the same donor corneas were grown in vitro. After 2 to 3 passages, the cultures were exposed to varying concentrations of recombinant human interleukin-1 (IL-1 alpha) or tumor necrosis factor (TNF-alpha). Culture supernatants subsequently underwent enzyme-linked immunosorbent assays for cytokine content. The levels of cytokine mRNA in cell lysates were monitored by the reverse transcription-polymerase chain reaction. RESULTS: Cultured human keratocytes stimulated with 100 U/ml IL-1 alpha for 18 hours produced more than 160 ng IL-6 per 10(6) cells. Under the same conditions 500 U/ml TNF-alpha induced approximately 5 ng IL-6. IL-6 mRNA, evident by 3 hours after exposure to either cytokine, accumulated and persisted through 18 hours. Exposure of epithelial cells to IL-1 alpha or TNF-alpha induced minimal and transient expression of IL-6 mRNA and < 0.5 ng protein product per 10(6) cells. The poor production of IL-6 did not reflect an inability of epithelial cells to respond to IL-1 alpha and TNF alpha because both cytokines induced these cells to make copious amounts of IL-8. CONCLUSIONS: These results demonstrate that both IL-1 alpha and TNF-alpha could induce keratocytes to produce nanogram levels of IL-6 but IL-1 alpha was a 30 fold more effective inducer. In contrast, neither cytokine could stimulate epithelial cells to make more than picogram quantities of IL-6. The abundant IL-6 synthesized by keratocytes may promote various activities including specific immune responses in surrounding lymphoid tissues. PMID- 7843905 TI - Platelet-activating factor induces the expression of metalloproteinases-1 and -9, but not -2 or -3, in the corneal epithelium. AB - PURPOSE: The inflammatory mediator platelet-activating factor (PAF) induces the expression of interstitial collagenase (metalloproteinase-1) messenger RNA in rabbit corneal epithelium. In this study, the authors investigated the effect of PAF on gene expression and protein activity of other matrix metalloproteinases (MMPs) in the cornea. METHODS: Rabbit corneas were incubated in an organ culture with 100 nM of cPAF (a nonhydrolyzable PAF analog), PAF, or lyso-PAF, an inactive metabolite of PAF. In some experiments, the corneas were preincubated for 1 hour with 10 microM BN50730, a PAF antagonist, before cPAF was added to the medium. Corneal epithelial cells and/or conditioned medium were collected at different times for analysis. Also, in vivo experiments were done by injecting 2 micrograms of cPAF intrastromally into rabbit eyes and collecting the epithelium 8 hours later for study. Northern blot analysis and zymography were performed to determine the mRNA abundance and/or enzyme activity of 92 kd gelatinase (MMP-9), 72 kd gelatinase (MMP-2), and stromelysin (MMP-3). The activity of MMP-1 was tested by collagenase assays. RESULTS: cPAF induced the expression of MMP-9 mRNA, but not MMP-3 mRNA. The message was induced at 4 hours and remained elevated at 48 hours, with a peak at 36 hours. In corneas preincubated with BN50730, MMP-9 mRNA activation by cPAF was inhibited. In vivo injection of cPAF also induced the expression of MMP-9. Furthermore, cPAF increased MMP-9 activity in the epithelial cells and in the conditioned media. The effect was blocked by BM50730. cPAF did not affect MMP-2 activity. Finally, cPAF also increased MMP-1 collagenolytic activity of the corneal epithelium, which was blocked by the PAF antagonist. CONCLUSION: These results suggest a novel mechanism by which PAF activates MMPs. The lipid mediator selectively enhances the expression of MMP-1 and MMP-9 in rabbit corneal epithelium. This activation by PAF may be involved in the remodeling mechanisms of the cornea after injury and, when overexpressed, may lead to the formation of corneal ulcers. Specific PAF antagonists could therapeutically deter corneal ulcer formation and facilitate corneal wound healing. PMID- 7843906 TI - Cell surface glycoproteins of corneal epithelium. AB - PURPOSE: To identify those plasma membrane glycoproteins of corneal epithelial cells that are synthesized in a higher amount or are downregulated during cell migration. METHODS: Primary cell cultures of rabbit corneal epithelium were used. Sialic acid and terminal galactose/N-acetylgalactosamine residues of plasma membrane glycoproteins of migrating and nonmigrating corneal epithelial cells were labeled using two well-characterized cell surface carbohydrate labeling techniques. The labeled glycoproteins were extracted in phosphate-buffered saline containing nonionic detergents and various protease inhibitors, and then they were analyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis and fluorography. RESULTS: At least 12 to 13 radiolabeled components (molecular weight, 240 kd to 21 kd) were detected in the fluorographs of both sialic acid and galactose-labeled cells. Regardless of the labeling technique used, one sialoglycoprotein (GP1, 240 kd) was found in a higher amount in the extracts of nonmigrating cells than in migrating cells, and another glycoprotein (GP12, 28 kd) was present in a higher amount in migrating than in nonmigrating cells. Furthermore, one sialoglycoprotein (GP13, 21 kd) was detected only in migrating cells, and two glycoproteins (GP10, 42 kd; GP11, 32 kd) with terminal galactose/N acetylgalactosamine residues were present in a higher amount in migrating than in nonmigrating cells. CONCLUSIONS: This study has demonstrated that during corneal epithelial cell migration, the level of one membrane glycoprotein is markedly reduced, and the levels of four membrane glycoproteins are elevated. Further characterization of these glycoproteins should contribute to a better understanding of the mechanisms that modulate corneal epithelial sheet migration and wound healing. PMID- 7843907 TI - Involvement of integrins with adhesion-promoting, heparin-binding peptides of type IV collagen in cultured human corneal epithelial cells. AB - PURPOSE: The aim of this work was to identify the integrin subunits present on the cell surface of human corneal epithelial cells. The authors determined to show whether type IV collagen, heparin-binding peptides of type IV collagen (Hep I, Hep-II, and Hep-III), fibronectin, and GRGDSP promote cell adhesion of human corneal epithelial cells. Type IV collagen and heparin-binding peptides of type IV collagen may be important in corneal epithelial cell adhesion in normal and pathologic conditions and reepithelialization. The authors assess the role of cell surface integrins in mediating cell adhesion to these proteins and peptides. METHODS: Fluorescence-activated cell sorter (FACS) analysis was used to determine the integrin subunits expressed at the cell surface of the cultured human corneal epithelial cells. Cell adhesion was assessed with type IV collagen, heparin binding peptides of type IV collagen, fibronectin, and GRGDSP: Antibodies to the integrin subunits were used to determine the potential role of integrins in cell adhesion to the above proteins and peptides. RESULTS: FACS analysis identified the beta 1, beta 4, alpha 2, alpha 3, alpha 5, alpha 6, and alpha v integrin subunits on human corneal epithelial cells grown as primary cultures. The anti beta 1 antibody inhibited cell adhesion to heparin-binding peptides of type IV collagen, type IV collagen, fibronectin, and GRGDSP: Antibodies to the alpha 2 integrin subunit inhibited cell adhesion to the heparin-binding peptides of type IV collagen and slightly inhibited cell adhesion to intact type IV. Antibodies to the alpha 3 integrin subunit exhibited a somewhat lesser effect compared to the anti-alpha 2 integrin antibody. CONCLUSIONS: These data show that the alpha 2 beta 1 integrin of human corneal epithelial cells recognize heparin-binding peptide sequences derived from human type IV collagen. It seems likely that these sequences play an important role in integrin-mediated corneal epithelial cell adhesion. In addition, the alpha 3 beta 1 integrin may mediate similar events. PMID- 7843908 TI - Dihydropyridine-sensitive calcium currents in freshly isolated human and monkey retinal pigment epithelial cells. AB - PURPOSE: The authors previously reported that rat retinal pigment epithelial (RPE) cells exhibit an ionic current through voltage-operated calcium channels that is dihydropyridine sensitive. They attempted to record the same current from freshly isolated fetal or adult primate RPE cells, as well as from cultured cells. METHODS: The whole-cell version of the patch-clamp technique was applied to RPE cells freshly isolated by enzymatic dissociation from fetal human and adult human and monkey eyes, as well as cultured fetal and adult human RPE cells. The cells were loaded with cesium to minimize potassium-related current and were bathed in an extracellular solution containing 40 mM barium to intensify the calcium currents. RESULTS: Freshly isolated cells, both fetal and adult, showed sustained and inward-going barium current through voltage-operated calcium channels with membrane depolarizations from a high holding voltage of -60 mV. This current was affected by dihydropyridine compounds. Cultured human RPE cells showed no sign of a calcium current of this type. CONCLUSIONS: Freshly isolated fetal and adult human RPE cells, as well as adult monkey, exhibit calcium current through voltage-operated, dihydropyridine-sensitive channels, similar to the neuronal L-type, just as in rat RPE cells. PMID- 7843909 TI - Patch transplants of human fetal retinal pigment epithelium in rabbit and monkey retina. AB - PURPOSE: To transplant human fetal retinal pigment epithelium (RPE) into the subretinal space of rabbits and monkeys as an organized monolayer without artificial support. METHODS: The method involves dissecting small patches of cultured RPE monolayers in sheets (1 to 5 mm2), sucking them into a glass pipette and injecting them into the subretinal space after producing a bleb detachment of the neural retina. RESULTS: These patches unfold and survive as a quasi-monolayer under the reattached neural retina intimately associated with the host photoreceptors and phagocytizing host outer segment material. Graft rejection is observed in most rabbits at 1 month but not in monkeys at 3 months after transplantation. CONCLUSIONS: Monolayer patches of cultured human fetal RPE can be transplanted to the subretinal space, where they survive in contiguity with healthy host outer segments. In primates, but not in rabbits, host-graft rejection does not occur for at least 2 to 3 months. PMID- 7843910 TI - Accommodation-convergence relationships and age. AB - PURPOSE: The objective of this study was to determine if there are differences in accommodative-convergence/accommodation (AC/A) and convergence accommodation/convergence (CA/C) ratios in subjects with increasing age. The authors aimed to relate the findings to the present theories of the development of presbyopia. METHODS: Using a Canon AutoRef R-1 to measure accommodation and an IRIS eye movement monitor to measure eye movements, the authors determined objective AC/A and CA/C ratios for 23 subjects between 17 and 42 years of age with normal binocular vision. Changes in accommodation and convergence responses were stimulated by lenses (-1.00 DS and -2.00 DS) and prisms (4 and 8 prism diopters), respectively. Measures were made at two visits on consecutive days. RESULTS: A moderate linear relationship was found between AC/A ratio and age (P < .002), and a strong linear relationship was found between CA/C ratio and age (P < .0001). The decrease in CA/C ratio with age was due to a decreased accommodative response to prisms (P = .0001). Measurements were reliable, with 95% confidence intervals at +/- 1.28 delta/D and +/- 0.02 D/delta for AC/A and CA/C ratios, respectively. A reciprocal relationship existed between the AC/A and CA/C ratios. CONCLUSION: The AC/A ratio increases, and the CA/C ratio decreases, in persons between 20 and 40 years of age. This may be because increasing ciliary muscle contraction is required to produce a given change in accommodation with increasing age or because of changes in the adaptability of the tonic accommodation and vergence systems with age. PMID- 7843911 TI - Characterization of cell-mediated immune responses elicited by orthotopic corneal allografts in mice. AB - PURPOSE: Corneal allografts placed orthotopically induce a unique and unusual response in recipient mice. More orthotopic corneal allografts are accepted indefinitely than similar skin allografts. Of the rejected corneal grafts, class I major histocompatibility complex (MHC)-incompatible grafts are rejected less frequently than grafts that express only minor histocompatibility complex (minor H) or MHC plus minor H alloantigens. To describe the spectrum of T cells activated (or not) by orthotpic corneal grafts, the authors examined the development of delayed hypersensitivity (DH) to donor-specific alloantigens. METHODS: Recipient BALB/c mice received orthotopic corneal allografts from donor mice that were MHC incompatible at MHC loci only, multiple minor H loci only, or MHC plus multiple minor H loci. These groups of mice were examined to determine when alloantigen-specific DH developed. RESULTS: The authors report that all mice, whether they accept or reject grafts, acquire donor-specific DH within 4 weeks of engraftment. This reactivity is primarily directed at minor H, rather than MHC-encoded, alloantigens. Through time, spontaneous DH reactivity disappears in all mice, and thereafter, donor-specific DH can be induced by cognate immunization only in mice that have rejected their cornea grafts. CONCLUSIONS: These results can be explained in the context of "direct" and "indirect" pathways of allorecognition. Because normal corneas lack passenger leukocytes, the potential for direct recognition of alloantigens on orthotopic corneal grafts is small. Therefore, T cells activated by orthotopic corneal allografts must recognize donor-derived antigens primarily on recipient antigen presenting cells, that is, through the indirect pathway of allorecognition. Because minor H antigens are the dominant cellular proteins in grafts, it is proposed that minor H determinants are the most immunogenic alloantigens in orthotopic corneal grafts because they are the major source of peptides that will be loaded onto recipient class II molecules for T-cell recognition. We further predict that long-term acceptance of corneal allografts is promoted when recipient mice acquire anterior chamber associated immune deviation (impaired and suppressed DH) directed at minor H alloantigens of the grafts. PMID- 7843912 TI - Relationship between natural killer cell susceptibility and metastasis of human uveal melanoma cells in a murine model. AB - PURPOSE: The purpose of this study was to determine the susceptibility of human uveal melanoma cells to in vitro and in vivo natural killer (NK) cell-mediated cytolysis and to determine if NK cells influence metastasis from the eye. METHODS: Four human uveal melanoma cell lines and one melanoma cell line derived from a metastatic lesion from a patient with uveal melanoma were tested for in vitro and in vivo NK cell-mediated lysis in a mouse model. Major histocompatibility complex (MHC) class I antigen expression was evaluated by flow cytometry. The role of NK cells in controlling the metastasis of uveal melanoma cells from the eye to the liver was examined in nude mice. RESULTS: Sensitivity to in vitro and in vivo lysis by human and murine NK cells was correlated with reduced expression of MHC class I antigens. Uveal melanoma lines expressing normal MHC class I antigen expression were insensitive to NK cell-mediated lysis, both in vitro and in vivo. Metastasis of uveal melanoma cells was inhibited by NK cell activity because disruption of in vivo NK function produced a sharp increase in the spontaneous metastasis of intraocular melanomas in nude mice. CONCLUSIONS: There is considerable variation in the susceptibility of human uveal melanomas to NK cell-mediated cytolysis. Susceptibility is closely correlated with reduced expression of MHC class I antigen expression. Disruption of NK cell function significantly increases the development of hepatic metastases from human uveal melanoma cells. PMID- 7843913 TI - Intravitreal sustained-release dexamethasone device in the treatment of experimental uveitis. AB - PURPOSE: Uveitis often runs a chronic course requiring long-term therapy. Topical treatment results in poor intravitreal penetration, and systemic therapy is associated with significant side effects. The authors investigated whether an intravitreal sustained-release dexamethasone device was effective in the treatment of severe panuveitis in a rabbit model. METHODS: Twenty New Zealand white rabbits were immunized twice subcutaneously with 10 mg of Mycobacterium tuberculosis H37Ra antigen. Twelve days later, sustained-release dexamethasone devices were implanted into the vitreous of the right eye of 10 rabbits. Ten control rabbits received a sham device. One day later, rabbits were challenged with an intravitreal injection of 33 micrograms of antigen. Three animals in each group were sacrificed on post-challenge days 7 and 13 for aqueous white blood cell (WBC) count, protein determination, and histologic examination. To simulate chronic inflammation with exacerbations, the eight remaining eyes were rechallenged with intravitreal antigen on day 15 and were observed for 3 1/2 months. Inflammation was graded clinically by two masked observers. Retinal function was evaluated by electroretinography (ERG). Light microscopy was used to evaluate the eyes histopathologically. The amount of residual drug in the devices was measured on day 13 and at the end of the experiment. RESULTS: By all clinical criteria measured--anterior chamber cells, flare, and vitreous opacity--treated eyes had significantly less inflammation than untreated eyes (P < 0.05). Clinical examination correlated well with objective data. Both protein concentration (P < 0.05) and aqueous WBCs (P < 0.02) were approximately 10-fold higher, and ERGs were significantly depressed (P < 0.05) in untreated eyes compared to treated eyes. Histopathologic examination showed marked inflammation and tissue disorganization in the untreated compared to the treated eyes. After antigen rechallenge, inflammation in experimental eyes was still less than in control eyes. Late complications such as corneal neovascularization, cataract, and hypotony were also less in the treated eyes than in the untreated eyes. At the end of the experiment (99 days after device implantation), approximately 30% of drug remained in the devices. CONCLUSIONS: The intravitreal sustained-release dexamethasone device is highly effective in suppressing inflammation and preventing complications after two episodes of experimental uveitis in a rabbit model for at least 3 1/2 months. This device may be useful in the management of patients with severe chronic posterior uveitis who cannot tolerate systemic or periocular therapy. PMID- 7843914 TI - Spontaneous development of corneal crystalline deposits in MRL/Mp mice. AB - PURPOSE: The presence of corneal opacities associated with dacryoadenitis and lacrimal gland destruction has led investigators to consider MRL/Mp mice as models for band keratopathy and Sjogren syndrome. In this study, the authors examined the time course of the corneal opacification and investigated whether the opacities were associated with altered serum levels of parathyroid hormone, calcium, and phosphorus, as well as quantitative and qualitative differences in tear production. METHODS: Corneas were analyzed microscopically and tear fluid production was measured by a modified Schirmer test. RESULTS: Corneal lesions were observed as early as the fifth week after birth. The lesions consisted of calcium phosphate and appeared as punctate, crystalline opacities located subeithelially. Lesions were present in 72% (56 of 78) of the MRL/Mp mice, with no significant difference in incidence between MRL/Mp +/+ and MRL/Mp lpr/lpr mice. Corneal calcification was occasionally associated with a self-limiting keratitis and neovascularization. In control mice, corneal opacities were not observed before the animals were 6 months of age. Levels of circulating parathyroid hormone decreased significantly during the first 16 weeks of age in MRL/Mp mice. In addition, MRL/Mp mice of both sexes had a significantly lower tear fluid production as compared to BALB/c mice of the same age. CONCLUSION: Because corneal lesions start to develop in 5-week-old MRL/Mp mice, thereby preceding the clinical signs of systemic autoimmune disease, and may develop in 6 month-old nonautoimmune-prone mice, it is suggested that calcification develops independent of the systemic autoimmune disease and might be restricted to the cornea. PMID- 7843915 TI - mdxCv3 mouse is a model for electroretinography of Duchenne/Becker muscular dystrophy. AB - PURPOSE: To identify an animal model for the abnormal scotopic electroretinogram found in a majority of Duchenne and Becker muscular dystrophy patients. METHODS: Ganzfeld electroretinograms were recorded in dark-adapted normal C57BL/6 mice, and two strains of mice with different X-linked muscular dystrophy mutations (mdx and mdxCv3). Responses for the right eye were averaged and the amplitudes and implicit times of the a-wave and b-wave were measured. The electroretinogram was digitally filtered to extract the oscillatory potentials. Statistical analyses included one-way analysis of variance and the Scheffe S test. RESULTS: While the electroretinogram in mdx was normal, in mdxCv3 the scotopic b-wave was markedly reduced and the oscillatory potentials were delayed, similar to changes observed in Duchenne and Becker muscular dystrophy patients. Some of the mdxCv3 animals demonstrated negative configuration electroretinograms, with the b-wave amplitude reduced compared to that of the a-wave. CONCLUSIONS: Abnormalities found in the electroretinograms of Duchenne and Becker muscular dystrophy patients led to the identification of dystrophin in human retina and the discovery that dystrophin is required for normal retinal electrophysiology. These results indicate that mdxCv3 is a model for elucidating the role of dystrophin in retina and suggest that dystrophin isoforms, consisting of only the C-terminal domains of the full-length protein, may be important to the development of normal retinal electrical potentials. PMID- 7843916 TI - Dexamethasone-induced ocular hypertension in perfusion-cultured human eyes. AB - PURPOSE: Glucocorticoid administration can lead to the development of ocular hypertension and corticosteroid glaucoma in a subset of the population through a decrease in the aqueous humor outflow facility. The purpose of this study was to determine whether glucocorticoid treatment can directly affect the outflow facility of isolated, perfusion-cultured human eyes. METHODS: The anterior segments of human donor eyes from regional eye banks were placed in a constant flow, variable pressure perfusion culture system. Paired eyes were perfused in serum-free media with or without 10(-7) M dexamethasone for 12 days. Intraocular pressure was monitored daily. After incubation, the eyes were morphologically characterized by light microscopy, transmission and scanning electron microscopy, and scanning laser confocal microscopy. RESULTS: A significant increase in intraocular pressure developed in 13 of the 44 pairs of eyes perfused with dexamethasone with an average pressure rise of 17.5 +/- 3.8 mm Hg after 12 days of dexamethasone exposure. The contralateral control eyes, which did not receive dexamethasone, maintained a stable intraocular pressure during the same period. The outflow pathway of the untreated eyes appeared morphologically normal. In contrast, the dexamethasone-treated hypertensive eyes had thickened trabecular beams, decreased intertrabecular spaces, thickened juxtacanalicular tissue, activated trabecular meshwork cells, and increased amounts of amorphogranular extracellular material, especially in the juxtacanalicular tissue and beneath the endothelial lining of the canal of Schlemm. The dexamethasone-treated nonresponder eyes appeared to be morphologically similar to the untreated eyes, although several subtle dexamethasone-induced morphologic changes were evident. CONCLUSION: Dexamethasone treatment of isolated, perfusion-cultured human eyes led to the generation of ocular hypertension in approximately 30% of the dexamethasone-treated eyes. Steroid treatment resulted in morphologic changes in the trabecular meshwork similar to those reported for corticosteroid glaucoma and open angle glaucoma. This system may provide an acute model in which to study the pathogenic mechanisms involved in steroid glaucoma and primary open angle glaucoma. PMID- 7843917 TI - Galactose-induced retinal microangiopathy in rats. AB - PURPOSE: The suitability of the galactose-fed rat as a model of diabetic retinopathy was examined in nondiabetic rats fed diets enriched with either 30% or 50% galactose for up to 2 years. METHODS: Retinal capillaries were examined by light and electron microscopy, and the prevalence or severity of diabetic-like lesions was quantitated. RESULTS: Histologic evaluation of trypsin digests of retina revealed significantly greater than normal frequencies of pericyte ghosts and acellular capillaries at both 15 and 23 months receiving a 50% galactose diet. Similar lesions were observed in rats receiving a 30% galactose diet for 23 months. Capillary basement membrane thickening, dilated hypercellular capillaries (or intra-retinal microvascular abnormalities), and foci of vascular cells appeared in rats fed 50% galactose, but saccular microaneurysms characteristic of retinopathy in diabetic patients, diabetic dogs, and experimentally galactosemic dogs were not observed. Administration of the aldose reductase inhibitor, Sorbinil, to rats fed 50% galactose resulted in a significant inhibition of cataract and of galactitol accumulation in nerve and blood (by more that 90%) and retina (by 62%), but did not inhibit development of the retinal microvascular lesions. CONCLUSIONS: Two years of galactosemia in rats seems to reproduce only a portion of the lesions characteristic of diabetic retinopathy in patients or dogs. Nevertheless, lesions characteristic of at least the early stages of retinopathy clearly do develop in this galactosemic rat model, and are not restrained by inhibition of retinal polyol accumulation by 62%. PMID- 7843918 TI - Variability of contact transscleral neodymium:YAG cyclophotocoagulation. AB - PURPOSE: To study the variability of ciliary body lesions created by contact Nd:YAG cyclophotocoagulation and to evaluate modifications in probe design to reduce this variability. METHODS: Contact transscleral Nd:YAG cyclophotocoagulation was performed on fresh, enucleated porcine eyes in three ways: using a standard, handheld fiber-optic probe (98 eyes); using the same probe with an adjunctive contact lens guide to control for probe pressure, angle, and position (69 eyes); and using a spring-loaded handpiece to control for probe pressure (148 eyes). Four laser lesions were created in each eye and were rated for size and severity of tissue response. RESULTS: For the three groups of eyes, the mean for size differences (largest lesion minus smallest lesion in millimeters for each eye) was 2.53, 1.65, and 2.36, respectively. The mean for severity differences (most severe lesions minus least severe lesion for each eye, based on a four-part subjective rating) was 1.9, 1.1, and 1.7, respectively. These measures of size difference and severity difference were significantly lower with the lens guide than with the other two systems (P = 0.022 and P = 0.020, respectively). CONCLUSIONS: These findings indicate that contact transscleral cyclophotocoagulation can be associated with considerable variation in the size and severity of the ciliary body reaction. This variation has a significant dependence on probe pressure and orientation against the eye and can be reduced by modification in probe design. PMID- 7843919 TI - Crystallin degradation and insolubilization in regions of young rat lens with calcium ionophore cataract. AB - PURPOSE: To determine if the susceptibility of rat lenses to cataract formation in culture changes with increasing age and to investigate the regional differences in crystallin degradation and insolubilization during the formation of cataracts in cultured lenses. METHODS: Lenses from 4-week-old (young group) and 12-week-old (adult group) rats were divided into four subgroups: noncultured control, cultured control, cultured in calcium ionophore A23187, and cultured in ionophore plus calpain inhibitor E64. Lenses were cultured for 7 days, and the cortex and nucleus were homogenized and separated into water-soluble and water insoluble fractions. Two-dimensional electrophoresis and N-terminal sequencing were then performed. RESULTS: Young lenses treated with ionophore produced thin cortical and dense nuclear opacities. Adult lenses treated with ionophore also developed thin cortical opacity, but no nuclear opacity was observed, even though a large increase in the concentration of insoluble protein occurred. Two dimensional electrophoresis and sequencing suggested that calpain caused protein degradation in the cortex region. However, unlike nuclear opacity, the formation of opacity in the cortex was not inhibited by E64 in young or adult lenses. CONCLUSIONS: Calpain was activated, and crystallins were proteolyzed in the cortex of ionophore-treated lenses. However, cortical opacity was not the result of proteolysis by calpain. Maturation also decreased the susceptibility of rat lens nucleus to calcium ionophore cataract. PMID- 7843921 TI - Masking potency and whiteness of noise at various noise check sizes. AB - PURPOSE: The masking effect of spatial noise can be increased by increasing either the rms contrast or check size of noise. In this study, the authors investigated the largest noise check size that still mimics the effect of white noise in grating detection and how it depends on the bandwidth and spatial frequency of a grating. METHODS: The authors measured contrast energy thresholds, E, for vertical cosine gratings at various spatial frequencies and bandwidths. Gratings were embedded in two-dimensional spatial noise. The side length of the square noise checks was varied in the experiments. The spectral density, N(0,0), of white spatial noise at zero frequency was calculated by multiplying the noise check area by the rms contrast of noise squared. RESULTS: The physical signal-to noise ratio at threshold [E/N(0,0)]0.5 was initially constant but then started to decrease. The largest noise check that still produced a constant physical signal to-noise ratio at threshold was directly proportional to the spatial frequency. When expressed as a fraction of grating cycle, the largest noise check size depended only on stimulus bandwidth. The smallest number of noise checks per grating cycle needed to mimic the effect of white noise decreased from 4.2 to 2.6 when the number of grating cycles increased from 1 to 64. CONCLUSION: Spatial noise can be regarded as white in grating detection if there are at least four square noise checks per grating cycle at all spatial frequencies. PMID- 7843920 TI - Establishment of epithelial lines from cryopreserved lenses and capsule epithelial preparations. AB - PURPOSE: To determine if lens epithelial lines can be established from cryopreserved whole rabbit lenses and from cryopreserved capsule-epithelial preparations (CEPs). METHODS: Lenses or freshly isolated CEPs were cryopreserved and subsequently thawed. Thawed whole lenses were cultured for 48 hours in growth medium and fixed, and whole mounts were examined for mitosis. In addition, CEPs were peeled from cryopreserved lenses and placed in tissue culture. Viability of cryopreserved cells was assessed measuring attachment efficiency and growth. RESULTS: Whole mounts from cryopreserved lenses that were thawed and placed in organ culture in a serum-containing medium exhibited numerous mitotic figures. Freshly isolated CEPs that were cryopreserved and CEPs from cryopreserved lenses generated cell lines. Attachment efficiency was 90% within 3 hours of plating. When 50,000 cells from cryopreserved CEPs were cultured in growth medium, 10(6) cells were noted after 7 days of culture. The cells completed 27 population doublings and showed no sign of senescence. CONCLUSIONS: Rabbit lens epithelial cell lines can be initiated from cryopreserved lenses or CEPs. PMID- 7843922 TI - Optimal LT4 dosage in primary hypothyroidism. PMID- 7843923 TI - Conflict of interest in CME. PMID- 7843924 TI - Papillomaviruses. PMID- 7843925 TI - Anatomy, taxonomy and evolution of papillomaviruses. PMID- 7843926 TI - Papillomavirus DNA replication. PMID- 7843927 TI - Transcription of papillomavirus genomes. PMID- 7843928 TI - Transforming proteins of the papillomaviruses. PMID- 7843929 TI - Intra- and extracellular control mechanisms of human papillomavirus infection. PMID- 7843930 TI - Animal models of human-papillomavirus-associated oncogenesis. PMID- 7843931 TI - Natural history of genital papillomavirus infections. PMID- 7843932 TI - Epidemiology: a tool for the study of human papillomavirus-related carcinogenesis. PMID- 7843933 TI - Treatment of papillomavirus infections: recent practice and future approaches. PMID- 7843935 TI - "Dysmotility syndromes: what can be defined?". PMID- 7843934 TI - Current concepts of the pathogenesis of inflammatory bowel disease. AB - Although the cause of inflammatory bowel disease is not known, the pathogenesis involves an immune-mediated tissue damage that is the result of an interaction among genetic predisposing factors, exogenous triggers and endogenous modifying influences. Multiple genes are involved and operate at the level of the immune response and at the target organ. Exogenous triggers include the enteric microflora which might stimulate the mucosal immune system in genetically predisposed individuals. Endogenous modifying factors such as the psychoneuroendocrine system have regulatory effects on the immune system and the inflammatory response, and may influence the course of the disease. While autoimmune phenomena do occur, particularly in ulcerative colitis, there is no evidence that they are directly responsible for the tissue damage. It appears more likely, particularly in Crohn's disease, that tissue injury may occur as an indirect or "bystander" effect of mucosal T-cell hyperactivation, perhaps in response to a normal enteric microbial antigen. Most of the immunologic and histologic features of Crohn's disease can be explained by the effects of T-cell derived and other cytokines on the epithelium, the local immune system, the microvasculature, and the recruitment of auxiliary effector cells such as neutrophils. PMID- 7843936 TI - Oesophageal dysmotility. PMID- 7843937 TI - Intestinal dysmotility and the irritable bowel syndrome. PMID- 7843938 TI - The afferent side of the story: the role of sensation and perception in gut dysfunction. PMID- 7843939 TI - Psychiatric dysfunction and dysmotility. PMID- 7843940 TI - Oro-anal dyspepsia: doctor or patient related? PMID- 7843941 TI - A review of the management of iatrogenic bile duct injuries. AB - Injuries to the extrahepatic biliary tree occurring during cholecystectomy or other upper gastrointestinal surgical procedures are not uncommon. The consequences are often catastrophic. We report the results of a personal series of bile duct repairs from a tertiary referral centre over a twenty-one year period. A total of 33 patients were referred. Percutaneous transhepatic cholangiography was the radiological investigation of choice to outline the biliary system. Percutaneous transhepatic dilatation was performed in six patients and 22 patients had either primary surgical repair, or reconstruction of their biliary tree performed by hepaticojejunostomy with an 80 cm Roux-en-Y limb. Of these only two have required revision surgery. We recommend early referral of patients with recognised iatrogenic injuries to specialist hepatobiliary units with no attempt at repair prior to referral. PMID- 7843942 TI - Brachial plexus injuries. Guidelines for management: our experience. AB - In spite of the progress made by microneurosurgery, the treatment of brachial plexus injuries still remains a great challenge. This personal series of 49 patients with brachial plexus injuries (excluding tumours and thoracic outlet syndromes) is peculiar because the cases arose after the introduction in Italy of the law requiring all motorcyclists to wear a safety helmet. Our experience confirms that there has been a 32% increase in very severe almost irreparable injuries of the plexus in comparison with previous data reported in the literature. This is probably due to the higher rate of survival among severely injured patients, although the possibility of a direct effect of the helmet on the plexus cannot be completely discarded. Our results confirm the good prognosis of the microsurgical repair of C5-C6 stretch injuries and infraclavicular lesions. PMID- 7843944 TI - Neuroleptic malignant syndrome in an AIDS patient: clinical and pathological findings. AB - Neuroleptic malignant syndrome (NMS) has been recently described following therapy with non strictly neuroleptic drugs that alter dopaminergic function, such as sulpiride and metoclopramide, and might occur more easily in patients with functional or organic brain disorders. We observed an AIDS patient who suffered from NMS following treatment with clotiapine for insomnia and agitation. Two months later, he presented with a similar syndrome following antiemetic treatment with alizapride. On both occasions, the symptoms completely regressed after the administration of dopaminergic and muscle relaxant drugs. The patient died of pneumonia one month after the last episode. The present paper describes the clinical and pathological findings. PMID- 7843943 TI - Paramedian diencephalic syndrome. AB - The clinical characteristics of paramedian diencephalic syndrome (PDS) are described on the basis of two recently observed cases: one with paramedian thalamic infarct, the other with paramedian thalamopeduncular infarct. Analysis of the clinical symptoms and the results of CBF study show that PDS is a complex neurological syndrome characterized by symptoms due to both anatomical lesions and functional disconnections. PMID- 7843945 TI - Primary antiphospholipid syndrome (PAPS) and isolated partial seizures in adolescence. A case report. AB - The case of a young male patient presenting isolated clustered partial seizures is reported. Despite the normality of the neurological features, as well as of ictal and interictal EEG, the MRI (performed three days after the symptoms) disclosed bilateral signal alterations in the parietal cortical region. These abnormalities disappeared at the MRI control examination performed one month later. The finding of positive anticardiolipine antibodies made possible the diagnosis of partial epileptic seizures symptomatic of a vascular disorder ascribed to a Primary antiphospholipid Syndrome (PAPS). PMID- 7843946 TI - Crohn's disease and multiple sclerosis: a single case report. AB - A case of the association of multiple sclerosis and Crohn's disease in a 47 year old patient is reported. A possible relationship between these two diseases has been widely documented, both sporadically and at a familial level. Albeit in the absence of precise experimental data, it is legitimate to presume that the two diseases share common pathogenetic traits. PMID- 7843947 TI - Association of neuromyotonia with peripheral neuropathy, myasthenia gravis and thymoma: a case report. AB - A case of neuromuscular hyperactivity syndrome associated with a thymoma, high serum titres of anti-acetylcholine receptor and anti-DNA antibodies is reported. The study of peripheral nerve conduction revealed a peripheral neuropathy. Repetitive stimulation showed a decrease in the fifth M response. Myasthenic symptoms were anamnestically reported but were absent at clinical observation. The clinical picture and EMG examination improved after phenytoin administration. PMID- 7843948 TI - Sumatriptan in acute migraine using a novel cartridge system self-injector. United Kingdom Study Group. AB - This double-blind, randomized, placebo-controlled, parallel-group, multicenter study assessed the efficacy, acceptability, safety, and tolerability of subcutaneous sumatriptan 6 mg administered using a novel cartridge system self injector for the acute treatment of migraine. Eighty-six patients treated one migraine attack at home with sumatriptan or placebo. A second identical injection was available after 1 hour for inadequate relief or if the headache recurred. Rescue medication was available 1 hour later. The primary end point was headache relief (improvement in headache from moderate or severe to mild or no pain) within 60 minutes of the first injection. Secondary end points included the acceptability of the self-injector, requirement for and efficacy of a second dose, relief of nonheadache symptoms, use of rescue medication, and adverse events. Significantly more patients taking sumatriptan than placebo reported headache relief 1 hour after the first injection (88% vs 11%, P < 0.001). The device was well accepted by patients; about 90% found it easy to use and wanted to take further medication using it. Significantly fewer patients taking sumatriptan than placebo required a second injection (33% vs 92%, P < 0.001) or rescue medication after the second injection (35% vs 67% P < 0.05). Significantly more patients taking sumatriptan than placebo reported headache relief after the second injection (83% vs 32%, P < 0.01), and resolution of nonheadache migraine symptoms (54% vs 23%, P < 0.01). Sumatriptan was generally well tolerated. Subcutaneous sumatriptan 6 mg self-administered using the novel self-injector is an effective, well accepted, and well tolerated acute treatment of migraine. PMID- 7843949 TI - Paper-pencil tests for retrospective and prospective evaluation of primary headaches on the basis of the IHS criteria. PMID- 7843950 TI - The effect of verapamil calcium antagonist on autonomic imbalance in migraine: evaluation by spectral analysis of beat-to-beat heart rate fluctuations. AB - Abnormalities in autonomic control have been documented in migraine even during the headache-free interval. It has long been recognized that spectral analysis of heart rate (HR) fluctuations can reflect the autonomic function, especially the sympathetic to parasympathetic balance. This technique is the basis for a quantitative approach to the investigation of migraine applied in the present study. A 24-hour Holter ECG recording was performed for each subject in a group of five migraine patients during the interheadache period. In addition, shorter 5 minute-long recordings of blood flow (BF) and blood pressure (BP) were made in these patients in both supine and standing positions. Short, 256-second subtraces were taken every 30 minutes along the 24-hour ECG signal and were submitted, as well as the BF and BP traces, to A/D conversion and computation of the power spectrum of fluctuations in HR, BF, and BP. Spectral analysis of fluctuations in these hemodynamic parameters was performed in the migraine patients before and during the treatment with verapamil and compared to that of a healthy control group. This procedure enabled us to assess the autonomic function, the sympathetic vs parasympathetic balance, and their response to a change in position, before and during calcium blockade. A characteristic autonomic abnormality is revealed in the group of untreated migraine patients in supine position: enhanced low frequency (LF) fluctuations reflecting increased sympathetic sensitivity during the inter-headache phase. An exaggerated sympathetic response is measured in the migraine patients during the transition from supine to standing position with a concomitant nonsignificant decrease in parasympathetic response.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7843951 TI - Treatment of childhood headache with dihydroergotamine mesylate. AB - This study was undertaken to determine whether pediatric patients with migraine without aura who have failed standard outpatient regimens including intravenous dihydroergotamine mesylate (DHE) in conjunction with oral metoclopramide would respond to an inpatient treatment protocol of intravenous DHE and oral metoclopramide. Thirty patients were evaluated in this study which was an open label, retrospective review of treatment. Independent of the duration of the refractory migraine, 80% of the patients responded to the protocol with only minimal side effect. The dose of DHE mesylate ranged from 0.1 to 0.5 mg. The dose of DHE is lower than is typically utilized in standard adult protocols. The patients received an average of five doses of DHE. PMID- 7843952 TI - Treatment of juvenile migraine with subcutaneous sumatriptan. AB - An open, prospective study was undertaken to assess the efficacy and safety of subcutaneous sumatriptan in 17 children, ages 6 to 16 years, with severe, recurrent migraine. A 6-mg dose was used in 15 patients and relieved headache within 1 hour in six and by 2 hours in five others. Two smaller children received a 3-mg dose and both were headache-free within 2 hours. Most also reported marked improvement in associated symptoms such as nausea and photophobia. Four subjects had no clinical improvement after a 6-mg dose. Side effects, such as neck pressure, were brief and mild. These findings suggest that subcutaneous sumatriptan can be both effective and safe as an abortive agent in juvenile migraine, but the appropriate dose in smaller children will need further investigation. PMID- 7843953 TI - Empty sella and headache. AB - Empty sella is an anatomical condition caused by herniation of the subarachnoid space into the pituitary fossa through an incompetent sellar diaphragm. Headache seems to be one of the most frequently reported symptoms. We studied 13 headache patients (12 females, 1 male) presenting with primary empty sella (PES) on CT scan. The characteristics of the headache were analyzed and plasma levels of pituitary hormones or cortisol assessed. We confirmed the nonspecific nature of the headache in PES even though the majority of our patients complained of daily headache, mostly localized anteriorly. Hormone plasma levels were within normal range in all the patients assessed. However, four patients reported earlier endocrine disorders and more than half of the patients presented with obesity. In our opinion, PES should be suspected in middle-aged overweight women with daily headache even in the absence of endocrine symptomatology. PMID- 7843955 TI - Alleviation of migraines with therapeutic vitamin D and calcium. AB - Two postmenopausal migraineurs who developed frequent and excruciating migraine headaches (one following estrogen replacement therapy and the other following a stroke) were treated with combination vitamin D and calcium. Therapeutic replacement with vitamin D and calcium resulted in a dramatic reduction in the frequency and duration of their migraine headaches. PMID- 7843954 TI - Paroxetine in the treatment of chronic daily headache. AB - Forty-eight patients with chronic daily headache, unresponsive to several combinations of pharmacological treatments, were selected for an open-label study using paroxetine. Patients were given 10 mg to 50 mg of paroxetine for a period of 3 to 9 months. Ninety-two percent of the patients improved significantly, based on the patients' percent of the reduction in number of headache days per month. The common side effects were fatigue, insomnia, and urogenital disturbances. The possible mechanism of action of paroxetine in the treatment of chronic daily headache is discussed. Paroxetine appears to be effective in the treatment of chronic daily headache; however, double blind studies are needed to confirm these preliminary findings. PMID- 7843956 TI - Transcranial Doppler monitoring of a migraine with aura attack from the prodromal phase to the end. AB - Transcranial Doppler sonography (TCD) was performed in a case of migraine with aura during the different phases of the attack. In the prodromic period our patient showed a slight central deficit of the seventh right cranial nerve and hypesthesia in her right arm. TCD indicated a remarkable decrease of the mean flow velocity (MFV) of the left middle cerebral artery (MCA). During the headache phase and when the signs and symptoms subsided, TCD showed an increase in MFV of both middle cerebral arteries with normal symmetry. An electroencephalogram (EEG) demonstrated a left temporal disorder. A month later a cranial CT scan, an EEG, and TCD were normal. In our opinion all these findings suggest a focal reduction in cerebral blood flow in the prodromic phase. PMID- 7843957 TI - Acetazolamide for the treatment of chronic paroxysmal hemicrania. AB - A 25-year-old patient presented with clinical characteristics of chronic paroxysmal hemicrania which failed to respond to indomethacin 300 mg daily. Total relief of headaches was obtained with acetazolamide 250 mg t.i.d. PMID- 7843958 TI - Does chronic use of sumatriptan induce dependence? PMID- 7843959 TI - Denial of hospitalization by insurers for inpatient treatment of medication rebound headaches. AB - Inpatient treatment with intravenous dihydroergotamine has been remarkably successful in managing chronic daily headaches due to excessive use of analgesics or ergotamine tartrate. Recently we have been denied authorization in appropriate patients for this procedure by third party payers on the grounds that it was "not medically necessary," "based on anecdotal information," or is "an outpatient procedure." Three cases are described in which the insurer's decision was either contested as an issue of substandard care, or the patient elected to pay for the procedure. The outcome in two cases was dramatically favorable, at least from the patient's and the physician's point of view. The third case is currently being appealed. Time and energy spent on combating the position of the third party payer on issues of standards of specialist care should be unnecessary. Publication of standards of care by specialists, and a requirement that these care standards must be provided by third party payers are needed in order that quality medical care can continue in this society. PMID- 7843960 TI - Reversal of symptomatic orthostatic hypotension in migraine by metoclopramide. PMID- 7843961 TI - [Paraneoplastic pemphigus. Induction of autoantibodies against structural proteins in the skin]. AB - Paraneoplastic pemphigus (PP) is a newly reported autoimmune disease, which is always associated with an underlying neoplasia. It is characterized by painful mucosal erosions and ulcerations, and by polymorphous skin lesions reminiscent of erythema multiforme, pemphigus vulgaris and lichen planus pemphigoides. These patients have autoantibodies that bind to a distinct complex of epidermal proteins, including desmoplakin I (250 kD), major bullous pemphigoid antigen (230 kD), desmoplakin II (210 kD) and a 190-kD and a 170-kD protein, neither of which has yet been further characterized. Histological findings include acantholysis, epidermal cell necrosis, vacuolar interface changes and, sometimes, lichenoid infiltrates of the upper dermis. Direct immunofluorescence shows an intercellular deposition of immunoreactants in the epidermis and granular deposits at the dermal-epidermal junction. Indirect immunofluorescence with rodent bladder as substrate shows an intercellular pattern. This method is the most convenient and cost-effective method of screening for PP, since antigens of both pemphigus vulgaris and pemphigus foliaceus are not expressed in this tissue. PMID- 7843962 TI - [Contact allergies in medical occupations]. AB - Based on reports in the literature, data from the information network of German dermatology centres (Informationsverbund Dermatologischer Kliniken) and the authors own findings, a review is presented on prevalence, clinical picture and causative agents of contact allergic dermatoses in health care professions. In 1991 the proportion of suspected occupational diseases in the health care professions (including hairdressers) represented by cases of dermatitis, as reported to the responsible insurance institution, reached 72% of the total for the year (7287 out of 10127). Every 20th to 40th case was recognized as an occupational dermatosis according to German law. Accurate figures on incidence are scarce; for dentists an incidence of 0.11% has been calculated. The risk of developing occupational hand eczema has been shown to be at least three times higher for nurses than for other so-called dry professions. For persons engaged in the personal care of the ill and the elderly, relevant occupational allergens were found to be benzalkonium chloride and aldehydes in disinfectants, as well as rubber accelerators such as thiuram mix. Latex contact urticaria has increasing significance for medical personnel, with prevalence rates of sensitization between 4.5% and 10.7%. Among physicians, contact allergies to thiuram mix were found to be dominant (12.9%). For surgeons and orthopaedic surgeons, methyl methacrylate as a constituent of bone cement is of great importance. Various esters of acrylic acid and methacrylic acid are important sensitizers in the dental professions, particularly in heavily exposed dental laboratory technicians. Only a few gloves protect against these types of sensitizers. Sensitizations by medicaments can be avoided in most cases by reducing direct skin contact, as practiced with penicillin or ispaghula powder. Strategies of prevention include information of atopics regarding the increase in occupational dermatitis, the regular use of barrier creams, intensive skin care after work and avoidance of irritants and allergens wherever possible. PMID- 7843963 TI - [Clinical aspects and therapy of early lepromatous leprosy with a case example]. AB - Taking into account the increase in worldwide human migration, leprosy is of growing importance in the differential diagnosis of dermatological diseases encountered in Central Europe. We report on the case of a young man from Ghana who developed hypopigmented maculae and plaques on his trunk and proximal limbs. The diagnosis of lepromatous leprosy could be made in consideration of the histological pattern of infiltrating leucocytes and detection of numerous acid fast mycobacteria on skin biopsy. The results of the physical examination as well as routine laboratory and immunological parameters were consistent with this form of leprosy. Due to glucose-6-phosphate-dehydrogenase deficiency, treatment with dapsone was contraindicated. With high-dose rifampicin and clofazimine therapy, the skin changes cleared over the course of 11 months following a leprosy reaction type II (erythema nodosum leprosum) that developed during a phase of discontinued therapy due to low patient compliance. PMID- 7843964 TI - [Photo-brine therapy in patients with psoriasis and neurodermatitis atopica]. AB - The effectiveness of salt water baths and subsequent selective ultraviolet phototherapy (SUP) was investigated in a prospective study on 40 patients with psoriasis vulgaris and atopic dermatitis. There were two groups with 20 patients each. The first group was treated with salt water (15%) that contained synthetic Dead Seas salt called "Psorisal"; the patients in the second group had a bath in a 3% NaCl solution. After 4 weeks of daily treatment, we found that 80% of the patients in the group treated with "Psorisal" had significantly better results than the second group. The subjective feeling of being ill had decreased significantly in both groups by the end of the study. The only side effect we found was the occurrence of sunburn in few cases, but this occurred significantly less in the "Psorisal" group. Both groups generally accepted the balneophototherapy, so it can easily be employed on an outpatient basis. PMID- 7843965 TI - [High dosage intravenous gamma globulin therapy in juvenile dermatomyositis]. AB - In the last few years high-dose intravenous therapy with gammaglobulin in juvenile dermatomyositis with steroid resistant myopathy has been discussed as an alternative to cytostatic therapy. The 12-year-old Filipinogirl suffered from dermatomyositis with pronounced weakness of the limbs and masticatory muscles; creatinine-kinase was increased 22-fold. After 5 weeks of therapy with prednisolone (1.5 mg/kg body/weight/daily), the creatinine kinase decreased to sixfold of its standard value; the muscular weakness, however, progressed to almost complete paralysis of the scapular abductors and rotators and the coxofemoral flectors and rotators. Additional therapy with gammaglobulin at a dose of 1 g/kg body weight on two consecutive days at 4-week intervals led to complete restoration of muscular strength, normalization of muscle enzymes, and stabilization of these results after 12 courses of gammaglobulin and discontinuation of the steroid medication after 8 courses. This observation suggests that high-dose intravenous application of gammaglobulin represents an efficient therapy with minimal side effects in steroid-resistant juvenile dermatomyositis. PMID- 7843966 TI - [Localized Sweet syndrome]. AB - A 73-year-old women developed an inflammatory tumor on her right cheek within 3 weeks. The lesion measured more than 7 cm in diameter, contained a central crateriform depression and was studded with several sterile pustules. Histology showed a dense dermal infiltration of neutrophils, but no leukocytoclasia or destruction of dermal tissue. There was no associated leukocytosis or fever, but the patient suffered from recurrent chronic bronchitis. Because the acute inflammation was progressive under treatment with antibiotics, high-dose corticosteroids were given systemically. The tumor regressed quickly and resolved without scarring. Although this localized Sweet's syndrome is unusual, it fulfills several major and minor criteria of Sweet's syndrome and thus represents a rare form of this disease. PMID- 7843967 TI - ["Granulomatous slack skin"--cutaneous elastolytic lymphoma]. AB - The term "granulomatous slack skin" (GSS) was introduced by Ackerman for a disease first described by Convit et al. in 1973. GSS represents a rare cutaneous lymphoma characterized by localized elastolytic lesions with a granulomatous infiltrate. We recently observed two male patients with the characteristic features of this disease. Both patients responded well to therapy with interferon alpha 2b. In one patient clinical remission was stable under long-term treatment with clofazimine. We report on common features of these two patients and give a review of the cases published in the literature. PMID- 7843968 TI - [Idiopathic clubbing of the fingers. Pathogenetic mechanisms and differential etiologic diagnosis]. AB - We report on a patient with marked clubbing of the fingers and toes with watch glass deformity of the nails, diagnosed as idiopathic clubbing. New findings on the pathogenesis of clubbing provide evidence for the important role of cytokines, especially platelet-derived growth factor and tumor necrosis factor alpha. The differential diagnosis includes, besides rare primary forms, clubbing in malignant neoplasias and chronic inflammatory diseases of the heart, the lung, the upper gastrointestinal tract and the liver. Clubbing can precede other symptoms of neoplasias by mouths and could be dependent on a genetic predisposition. PMID- 7843969 TI - [Urticaria-vasculitis syndrome in metastatic malignant testicular teratoma]. AB - We report on the case history of a 30-year-old man with chronic, therapy resistant urticarial vasculitis for more than 1 year. On clinical examination a metastasizing malignant teratoma of the testes was diagnosed. For surgical management and oncological therapy the patient was referred to appropriate clinical units. After the treatment there urticarial vasculitis also disappeared without any specific therapy, but the persisting metastases in the lungs caused early reappearance of the urticarial vasculitis. Chemotherapy led to partial remission of metastases, and in fact also to an improvement in the urticarial alterations of the skin. Two months after the last cycle of chemotherapy metastases of the brain were discovered and at the same time the urticarial vasculitis was found to be present again in full-blown form. PMID- 7843970 TI - [Contact allergy to gold alloys]. PMID- 7843971 TI - [Side effects caused by thiomersal and ovalbumin in vaccinations]. PMID- 7843972 TI - [Grunewald nevus]. AB - An accurate and complete depiction of the halo naevus has been left by Matthias Grunewald in his painting "The Temptation of St. Anthony", which is part of the Isenheim altar piece (1512-1516), which is now exhibited in Colmar, Alsace. In contrast, Sutton in 1916 only described a "leucoderma acquisitum centrifugum", leaving the nature of the central lesion in the dark. The term Sutton naevus therefore appears less appropriate than the alternative eponymic designation "Grunewald naevus". PMID- 7843973 TI - [Meeting report of the 4th Pecs Scientific Session of the Hungarian Dermatologic Society 14-16 October 1993]. PMID- 7843975 TI - Health care problems in America. PMID- 7843974 TI - [Scabies]. PMID- 7843976 TI - Perceptions of innovations as predictors of implementation levels: the diffusion of a nationwide health education campaign. PMID- 7843977 TI - The importance of social interaction: a new perspective on social epidemiology, social risk factors, and health. AB - Social epidemiology research has provided persuasive evidence of the link between the social environment--especially socioeconomic status--and health outcomes, but has failed to identify underlying mechanisms that might account for the association. The research may have been limited to date by its reliance on traditional epidemiological methods that emphasize a search for specific causal factor-disease relationships. It is time to take the research evidence and recast it to find practical solutions. We argue that the human development perspective supplies a framework for understanding the critical interaction between elements of social environment and health: Analyzing the social epidemiological research from this perspective can help to explain why and how the most potent factor, socioeconomic status, affects health outcomes. Equally important, this alternative perspective also presents health education practice implications. PMID- 7843978 TI - The transtheoretical model of change and HIV prevention: a review. AB - The transtheoretical model of health behavior change is described and supporting empirical work is presented that reviews the central constructs of the model: the stages of change, processes of change, decisional balance, confidence, and temptation. Model-based applications to a broad range of problem behaviors are summarized. Applications to human immunodeficiency virus (HIV) prevention behavior changes are highlighted for each variable. Finally, several questions about the area of sexual behavior change to reduce risk of HIV exposure are explored and future research ideas are described within the context of this model. PMID- 7843979 TI - Using the health belief model to predict safer sex intentions of incarcerated youth. AB - The purpose of this study was to test constructs of an enhanced version of the health belief model (HBM) in predicting juvenile delinquents' safer sex intentions. An accessible sample (n = 452) of incarcerated youth between the ages of 13-18 years from a midwestern state were subjects. HBM constructs were measured with an instrument tested for face, content, and construct validity as well as internal reliability. HBM constructs accounted for 28% of the variance in safer sex intentions. The results of this study support the use of the HBM in understanding human immunodeficiency virus (HIV) risk behavior in this population. The implications of these results for theory-based HIV prevention among incarcerated youth are presented. PMID- 7843980 TI - Stages of change in adopting healthy diets: fat, fiber, and correlates of nutrient intake. AB - The stages of change construct, which addresses the readiness to change, has only recently been applied to dietary behavior, such as fat consumption. This article describes the application of the stages of change construct to dietary fat and fiber consumption and examines the association of dietary stages to eating practices and related demographic and psychosocial factors in a large, geographically diverse population of workers. We present results from the baseline survey of 17,121 employees in the Working Well Trial. We assessed stage from an algorithm based on seven items and measured dietary intake with an 88 item food frequency questionnaire. Findings indicated that a greater proportion of the population has actively tried to reduce fat intake than to consume more fiber. Stage of change was associated with fat, fiber, and fruit and vegetable intake in a stepwise manner, as predicted. In multivariate analyses that controlled for demographic characteristics, stage of change predicted between 8 and 13% of the variance in dietary intake, and more than demographic variables. These findings have implications for the design of nutrition interventions and for the evaluation of intermediate outcomes. PMID- 7843981 TI - Health education interventions among Native Americans: a review and analysis. AB - Relatively few health education interventions directed at preventive health behaviors and management of chronic illness among Native Americans have been reported in the literature. This article provides a selective review of health education interventions among Native Americans that address the prevention and management of chronic illnesses/conditions as well as preventive health behaviors. For each intervention included in the review, a description of its cultural relevance, sample, design, and evaluation is provided. Limitations are noted, as well as implications for research and practice. PMID- 7843982 TI - Deconvolution in 3-D optical microscopy. AB - Fluorescent probes are becoming ever more widely used in the study of subcellular structure, and determination of their three-dimensional distributions has become very important. Confocal microscopy is now a common technique for overcoming the problem of out-of-focus flare in fluorescence imaging, but an alternative method uses digital image processing of conventional fluorescence images--a technique often termed 'deconvolution' or 'restoration'. This review attempts to explain image deconvolution in a non-technical manner. It is also applicable to 3-D confocal images, and can provide a further significant improvement in clarity and interpretability of such images. Some examples of the application of image deconvolution to both conventional and confocal fluorescence images are shown. PMID- 7843983 TI - Localization of the expression of type I, II and III collagen genes in human normal and hypochondrogenesis cartilage canals. AB - The expression of type I, II and III collagens genes was examined in human normal and hypochondrogenesis cartilage canals employing electrophoretic analysis, immunohistochemistry and in situ hybridization techniques. In normal cartilage, collagens type I and III were present in perichondrium, in the connective tissue surrounding the vessels of cartilage canals and in the dense fibrous tissue. However, types I and III procollagen mRNAs were detected only in fibroblasts of the perichondrium and of the canals, but not in the polymorphic cells. Type II collagen was present in the cartilage matrix and in the dense fibrous tissue, in good accordance with the localization of type II procollagen mRNAs detected in the chondrocytes and in the polymorphic cells. These data suggest that there are no transitional cells expressing type I, II and III collagen genes and that polymorphic cells are of chondrocytic origin. In the case of hypochondrogenesis, type II collagen was less abundant than in normal cartilage, whereas the corresponding mRNA level was equivalent. That suggests that a postranscriptional regulation of this protein is involved in the decrease of type II collagen production. Type I collagen, unexpectedly detected in the cartilage matrix, was synthesized by chondrocytes and polymorphic cells, suggesting a replacement of type II by type I collagen. The canal hypertrophy observed in this pathological case could thus be due to a modification in the regulation of the growth of cartilage canals caused by a defective cartilage matrix. PMID- 7843984 TI - Distribution patterns in glycoconjugate expression during the development of the rat palate. AB - The distribution of complex carbohydrate structures during the embryonic development of the rat palate was analysed by examining lectin-binding patterns in serial paraffin and cryostat sections. With few exceptions, the binding patterns showed a general increase in lectin receptors in the more developed stages of palatogenesis. High mannose oligosaccharides were especially amplified during development. Terminal fucose molecules were not expressed. In contrast, terminal sialic acid molecules were ubiquitously distributed in epithelial and mesenchymal tissues. Non-sialylated terminal N-acetylglucosamine was specifically restricted to evolving bone matrix. Before palatal fusion, quantitative but not qualitative differences were detected between oral, nasal, and medial-edge epithelial surfaces. The only exception was LCA, which specifically marked epithelial cells at the tip of palatal shelves. A very selective affinity for Jacalin was demonstrated in the oral epithelium of the palate after day 16, suggesting the presence of sialylated terminal galactose-(beta-1,3)-N acetylgalactosamine. PNA specifically marked the basal lamina of the oral side of palatal processes. The binding patterns of DBA, GSL IA, SBA, and VVA indicated that the epithelium of the tongue is characterized by terminal alpha- and beta galactose residues, whereas palatine cells possess only molecules with beta anomery. During palatogenesis, glycosaminoglycans patterns were significantly modified. Our data suggest that alteration of complex carbohydrate structures may play a central role in modulating cell-cell and cell-matrix interactions. The significance of these findings, however, remains to be elucidated. PMID- 7843985 TI - Immunolocalization of antioxidant enzymes in adult hamster kidney. AB - Immunoperoxidase and immunogold techniques were used to localize the following antioxidant enzyme systems in the adult hamster kidney at the light and ultrastructural levels: superoxide dismutases, catalases, peroxidases and glutathione S-transferases. Each cell type in the kidney showed specific patterns of labelling of these enzymes. For example, proximal and distal tubular and transitional epithelial cells showed significant staining for all of these enzymes, while glomerular cells and cells of the thin loop of Henle did not show significant staining at the light microscope level. In addition, high levels of glutathione peroxidase were found in smooth muscle cells of renal arteries. At the ultrastructural level, each enzyme was found in a specific subcellular location. Manganese superoxide dismutase was found in mitochondria, catalase was localized in peroxisomes, while copper, zinc superoxide dismutase and glutathione S-transferase (liver and placental forms) were found in both the nucleus and cytoplasm. Glutathione peroxidase was found to have a broad intracellular distribution, with localization in mitochondria, peroxisomes, nucleus, and cytoplasm. Microvilli of tubular cells were labelled by antibodies to catalase, copper, zinc superoxide dismutase, glutathione peroxidase, and glutathione S transferases. Cell types that were negative by light microscopy immunoperoxidase studies showed definite labelling with immunogold post-embedding ultrastructural techniques (glomerular cells and cells of the loop of Henle), demonstrating the greater sensitivity of the latter technique. These observations demonstrate that there are large variations in the levels of antioxidant enzymes in different cell types, and that even within a distinct cell type, the levels of these enzymes vary in different subcellular locations. Our results demonstrate for the first time the overall antioxidant enzyme status of individual kidney cell types, thereby explaining why different cell types have differing susceptibilities to oxidant stress. Possible physiological and pathological consequences of these findings are discussed. PMID- 7843986 TI - Nuclear pores in the apoptotic cell. AB - During apoptosis, nuclear pores undergo strong modifications, which are described here in five different apoptotic models. Conventional electron microscopy, supported by freeze-fracture analysis, showed a constant migration of nuclear pores towards the diffuse chromatin areas. In contrast, dense chromatin areas appear pore-free and are frequently surrounded by strongly dilated cisternae. A possible functional significance of this pore behaviour during apoptosis is discussed. PMID- 7843987 TI - Localization of osteopontin in resorption lacunae formed by osteoclast-like cells: a study by a novel monoclonal antibody which recognizes rat osteopontin. AB - The characteristics of a monoclonal antibody produced against osteoclast-like multinucleated cells (MNCs) formed in rat bone marrow cultures were examined immunohistochemically and biochemically. The in vitro immunization was performed using as immunogen the MNCs from rat bone marrow cell culture, which revealed many characteristics of osteoclasts. After screening and cloning of hybridomas, the monoclonal antibody HOK 1 was obtained. This antibody reacted weakly with stromal cells and intensely with both MNCs and their putative migratory traces on culture dishes. Immunofluorescent examination of paraffin sections revealed intense reactivity on the epithelium of the choroid plexus, the ileum and the proximal-convoluted tubules of the kidney, and also on bone cells such as osteocytes, osteoblasts, and osteoclasts. Western blotting using purified rat osteopontin verified that the antigen recognized by HOK 1 was osteopontin. Positive HOK 1 immunoreactivity was further observed in the resorption lacunae formed by a culture of MNCs on human tooth slices and on the surface of osteoclasts. The present data suggested that osteopontin is preferentially present on the resorption lacunae in resorbing calcified matrices and that osteoclasts under a specific state might trap this protein on their cell surface. PMID- 7843988 TI - Basolateral localization of anion exchanger 2 (AE2) and actin in acid-secreting (parietal) cells of the human stomach. AB - Basolateral uptake of chloride by the HCl-secreting parietal cells of the gastric (oxyntic) glands is most likely mediated by a HCO3-/Cl- anion exchange mechanism. Circumstantial evidence indicates that in rodents the anion exchange proceeds through an anion exchanger 2(AE2)-like membrane protein. In the present study, we raised antibodies against a bacterial fusion protein expressing a approximately 26-kDa portion of the human AE2 sequence. These antibodies were used to identify and localize AE2 in the human stomach. Here we report that the mucosa of the human stomach expresses an approximately 160-kDa immunoreactive form of AE2 containing the AE2-specific exoplasmic domain (Z-loop) as identified by polymerase chain reaction. Immunostaining specific for AE2 was restricted to the basolateral membrane domain of parietal cells and was also detected in small epithelial cells localized in the glandular isthmus region. The latter cells most likely represent pre-parietal cells. Parietal cells were identified by simultaneous and sequential labelling with antibodies against the gastric H+,K(+) ATPase and actin, respectively. Both actin and the H+,K(+)-ATPase were localized along the apical membrane of parietal cells and the membrane of their secretory intracellular canaliculi. In addition, actin was shown to be colocalized with AE2 along the basolateral cell surface. Discontinuous staining for AE2 coincided with infoldings of the basolateral plasma membrane labelled by the actin antibody. These observations indicate that AE2 might be placed at specialized (folded) microdomains of the basolateral cell surface by linkage to the actin-based cytoskeleton. PMID- 7843989 TI - Ultrastructural distribution of growth hormone and prolactin mRNAs in normal rat pituitary cells: a comparison between preembedding and postembedding methods. AB - In situ hybridization (ISH) at the electron microscopic level is essential for elucidating the intracellular distribution and role of mRNA in protein synthesis. We describe our electron microscopic ISH method using biotinylated oligonucleotide probes for rat growth hormone and prolactin mRNAs and compare the preembedding method with the postembedding method. Preembedding electron microscopic ISH localized rat growth hormone and prolactin mRNAs on the polysomes of the rough endoplasmic reticulum (RER). Rat growth hormone mRNA was distributed diffusely on the RER, whereas rat prolactin mRNA was scattered and distributed focally. Thus there might be a specific translational site for prolactin mRNA on the RER. Rat growth hormone mRNA signals were also recognized on the polysomes of the RER, using the postembedding method with streptavidin gold conjugate. The hybridization signal intensity using the postembedding method was lower, and non specific signals were more frequent, in comparison with the preembedding method. The preembedding method thus appears to be easier and better than the postembedding method from the viewpoint of utility and preservation of mRNA. Electron microscopic ISH is considered to be an important tool for evaluating the intracellular localization of mRNA and the site of specific hormone synthesis on the RER. PMID- 7843990 TI - Localization of carbonic anhydrase in the salivary glands of the cockroach, Periplaneta americana. AB - Carbonic anhydrase (CA) activity was localized in the salivery glands of the cockroach, Periplaneta americana, by (1) Hansson's histochemical technique, and (2) the use of the fluorescent sulphonamide, 5-dimethyl-amino-naphthalene-1 sulphonamide (DNSA). Both techniques reveal the same distribution pattern of CA in the four morphologically different cell types of the glands: peripheral cells, central cells, inner acinar duct cells, and distal duct cells. Positive reactions with Hansson's cobalt/phosphate technique were found in the apical regions of the peripheral cells and the distal duct cells, and were inhibited by 10(-5) M acetazolamide in control experiments. No staining could be detected in the central cells and the inner acinar duct cells. The fluorescent CA inhibitor DNSA (10(-4)M) specifically stained the peripheral cells and the distal duct cells in methanol-fixed cryostat sections, whereas the central cells and the inner acinar duct cells remained unstained. The role of CA in the peripheral cells is not clear. CA activity in the distal duct cells may provide the protons needed to run the vacuolar-type H(+)-ATPase on the apical infoldings of the cells. This ATPase may be involved in modification of the primary saliva. PMID- 7843991 TI - The mammosomatotroph: a transitional cell between growth hormone and prolactin producing cells? An immunocytochemical study. AB - In this report the occurrence of mammosomatotroph (MS) cells was correlated with changes in the somatotroph population of adult rat pituitary gland submitted to various experimental conditions (ovariectomized, orchidectomized and intact males, and after treatment with oestradiol benzoate). Cell and volume density of somatotrophs were assessed in sections stained with the immunogold-silver enhancement technique. Mammosomatotrophs were identified by double immunogold labelling at the electron microscopic level. Colocalization of prolactin (PRL) and growth hormone (GH) in the same cell was rarely observed. Only a few MS cells (0.1-0.2% of all parenchymal cells) were found in some experimental models. Oestrogen treatment decreased both cell and volume density of somatotrophs in ovariectomized rats. In this model, serum GH increased significantly but no changes in the pituitary content of the hormone were observed. Our results demonstrate that MS cells are an uncommon cell type in the pituitary of adult ovariectomized, orchidectomized and intact male rats. The oestrogen treatment, which is well known to induce proliferation of lactotrophs, has no effects on the MS population. Data presented in this report do not support the suggested role for mammosomatotrophs as transitional cells in the presumptive interconversion of PRL and GH producing cells. PMID- 7843992 TI - Immunocytochemical localization of glucocorticoid receptor in rat skin. AB - The aim of the present study was to map immunohistochemically the distribution of the glucocorticoid receptor (GR) in rat skin. Nuclear GR-like immunoreactivity (LI) was found in both epidermis and dermis. In the epidermis, the basal cell layer showed an intense immunoreaction; the lower part of the spinous layer was also labelled. In the dermis, the fibroblasts as well as the sweat glands, sebocytes and adipocytes were GR-immunoreactive (IR). In the root sheath of the hair follicle the staining was most intensive in the outer layer. The endothelial cells comprising the smooth muscle cells of the blood vessels, as well as the arrector pili muscle, showed GR-LI. In the peripheral nerves, the immunoreaction was localized to the nuclei of the Schwann cells and in the perineurial fibroblasts. Mast cells did not show nuclear GR-LI. Based on our immunocytochemical findings that several cell types of the skin are GR-IR, the variable physiological and pharmacological effects of glucocorticoids are easier to understand. PMID- 7843993 TI - Protein kinase C modulation in apoptotic rat thymocytes: an ultrastructural analysis. AB - Numerous events in the cell, such as gene expression, cell growth and metabolism are regulated by signal transduction pathways involving protein kinase C (PKC). Recent data indicate that a PKC-dependent mechanism also underlies the apoptotic death of cells induced by glucocorticoid hormones. In this report we have analysed the changes of PKC during dexamethasone-induced apoptosis in thymocytes by means of immunocytochemical and immunochemical analysis. The data obtained show an increase and intracellular movement of protein kinase C, which is translocated to the nucleus and linked to the nuclear matrix during the apoptotic process. PMID- 7843994 TI - Intercellular adhesion molecule-1 (ICAM-1) expression in the islets of the non obese diabetic and low-dose streptozocin-treated mouse. AB - The expression of intercellular adhesion molecule-1 (ICAM-1) was studied in 8 week-old non-obese diabetic (NOD) mice and low-dose streptozocin-treated (LDS) mice. ICAM-1 expression in NOD mice was observed at the islet periphery, corresponding to the peri-islet venular network, within the islet and on scattered elements along septa of the exocrine portion of the pancreas. Image analysis demonstrated that LDS-treated animals had less ICAM-1 immunoreactivity within and around the islets compared to NOD mice. At the ultrastructural level the peri-islet vessels were found to be filled with mononuclear elements. Moreover, endothelial cells showed signs of activation, and margination of monocytes and polymorphonuclear leukocytes was observed. PMID- 7843995 TI - Hybridocytochemical and immuno-ultrastructural study of calcitonin gene expression in cultured medullary carcinoma cells. AB - The study was aimed at a morphological demonstration of calcitonin (CT) gene expression in cultured TT cells, or, more specifically, hybridocytochemical detection of CT mRNA and calcitonin gene-related peptide (CGRP) mRNA and ultrastructural localization of the two hormones. The TT cells originated from medullary carcinoma of human thyroid gland. Ultrastructural studies of TT cells demonstrated a well-developed rough endoplasmic reticulum, large Golgi apparatus and low number of secretory granules. Hybridocytochemical studies showed the presence of mRNAs for CT and CGRP in all TT cells. At the ultrastructural level, double immunolabelling demonstrated that the two hormones were always expressed together in the same secretory granules. Our results provide a significant addition to the biochemical studies performed up to now and indicate that all TT cells produce both mRNAs and both hormones in parallel. PMID- 7843996 TI - [Human papillomaviruses (HPV) and its association with tumors of the ENT area]. PMID- 7843997 TI - [Clinical experiences with local capsaicin treatment of chronic rhinopathy]. AB - Eighty-four patients with clinical findings of hyperactive rhinopathy and no significant septal deviations were treated for 4 weeks with topical applications of capsaicin, which is the pungent substance in hot peppers. A neutral solution of low-dose capsaicin allowed patients to administer self-therapy without the need for local anesthesia. The majority of the patients showed a marked reduction in symptoms without significant side effects. Patients with (additional) allergic or medication-related rhinopathy seemed to show fewer therapeutic effects when compared to patients with only hyperactive rhinopathy. PMID- 7843998 TI - [Inverted papilloma and its association with human papillomavirus (HPV). A study with polymerase chain reaction (PCR)]. AB - Nasal inverted papilloma is usually a benign tumor but is associated with squamous cell carcinoma in about 10% of cases. To determine the etiological role of human papillomavirus (HPV) in inverted papilloma and to clarify the relationship between the different types of human papillomavirus and malignant transformation, we analyzed retrospectively a series of 29 formalin - fixed, paraffin-embedded cases, 3 of which had squamous cell carcinoma. A highly sensitive and specific modification of the polymerase chain reaction (PCR) was used to detect the E6 gene sequences of HPV 6/11, 16 and 18. HPV was present in 20 of the cases (69%), HPV 6/11 in 14 (48%), HPV 16 in 19 (65%) and both HPV 6/11 and 16 in 13 of the specimens (45%). HPV 18 was not identified in any specimen. In all three of the squamous cell carcinomas based on inverted papillomas, HPV 6/11 and 16 were detected. These results were in agreement with other studies. While HPV is related etiologically to inverted papilloma, we suggest that HPV 16 may be involved in its malignant transformation. PMID- 7843999 TI - [The lidocaine test in tinnitus. Determination of its current status]. AB - Intravenous administration of high doses of lidocaine has been used as a treatment modality for tinnitus. From 1991 to 1992 we treated 108 patients with high-dose lidocaine and had each patient complete a special tinnitus questionnaire. The effects of therapy were estimated on patients' subjective responses concerning loudness, suppression, stress relationships and mastering of tinnitus. These parameters were recorded before and after 5 days of lidocaine therapy. Quantification of tinnitus in acute and chronic disease showed significant temporary diminution of tinnitus in all patients. Complete alleviation of tinnitus was so impressive that personal attitudes concerning tinnitus were changed. These findings demonstrated that lidocaine was a useful strategy for significant relief of symptoms due to tinnitus. PMID- 7844000 TI - [Detailed results of orbital and optic nerve decompression]. AB - Orbital complications of various pathogenesis include impairment or loss of vision inhibition of globe motility and exophthalmos, and are treated best by an interdisciplinary team. Preoperative strategy should include information about underlying diseases, since success of treatment is related to diagnosis. To analyse our postoperative results we examined four groups of cases: injuries, tumors, infections and mucoceles. Diseases were located in the orbit or paranasal sinuses and produced similar symptoms. But prognosis and results of surgical treatment produced significant differences. The best improvement in vision was seen after treatment of inflammatory processes or after post-traumatic optic nerve decompression. An 88% improvement in globe motility and diplopia was seen in patients undergoing treatment for mucoceles, while a 95% improvement was found following transethmoidal surgery for inflammations of the paranasal sinuses. Overall results represent current trends for indications for surgical techniques employed to treat orbital and paranasal sinus disease. PMID- 7844001 TI - [Hearing capacity and speech production in 417 children with facial cleft abnormalities]. AB - Children with cleft palates often suffer from chronic conductive hearing losses, delayed language acquisition and speech disorders. This study presents results of speech and language outcomes in relation to hearing function and types of palatal malformations found. 417 children with cleft palates were examined during followup evaluations that extended over several years. Disorders were studied as they affected the ears, nose and throat, audiometry and speech and language pathology. Children with isolated cleft lips were excluded. Among the total group, 8% had normal speech and language development while 92% had speech or language disorders. 80% of these latter children had hearing problems that predominantly consisted of fluctuating conductive hearing losses caused by otitis media with effusion. 5% had sensorineural hearing losses. Fifty-eight children (14%) with rhinolalia aperta were not improved by speech therapy and required velopharyngoplasties, using a cranial-based pharyngeal flap. Language skills did not depend on the type of cleft palate presents but on the frequency and amount of hearing loss found. Otomicroscopy and audiometric follow-ups with insertions of ventilation tubes were considered to be most important for language development in those children with repeated middle ear infections. Speech or language therapy was necessary in 49% of the children. PMID- 7844002 TI - [Necrotizing sialometaplasia of the nasal cavity]. AB - In the present paper we report two cases of "necrotizing sialometaplasia" in uncommon locations. The relevant literature is reviewed. Necrotizing sialometaplasia is self-limiting and is characterized by necrosis and squamous pseudohypertrophy. Typically occurring in the minor salivary glands of the oral mucosa, our cases appear to be the sixth and seventh cases of involvement of the nasal cavity reported in the literature. Owing to the similarity of histological findings, the term "sialometaplasia" is also used for this disorder. This rare disease is a benign process but may be misdiagnosed as mucoepidermoid or squamous cell carcinoma. Therefore, the possibility of this disease in the nose should again be presented. Both of our cases show that with a histological examination considering defined morphological findings, the diagnosis of necrotizing sialometaplasia can be verified and a diagnosis of a carcinoma can be excluded. Especially with regard to radical and possibly unnecessary invasive therapeutic procedures we emphasize the importance of considering "necrotizing sialometaplasia" as part of the differential diagnosis of nasal lesions. PMID- 7844003 TI - [Surgical treatment of chronic otitis media. III: Middle ear reconstruction]. PMID- 7844004 TI - [Expert assessment in ENT practice regarding the severe handicap regulation]. PMID- 7844005 TI - [Principles of rhinoplasty. THe "Indian" and "Italian" method]. AB - Enumeration of individual methods of rhinoplasty for total reconstruction of the nose does not lay claim to completeness. It is the sole purpose of this review to show that the development of rhinoplasty received its definitive origins about 600 BC ("Indian" method) and in the 15th century AD ("Italian" method). As a result of the need to reconstruct the external nose after its destruction from infectious diseases, injuries or tumors, various methods of rhinoplasty have evolved. As such, the history of reconstructive rhinoplasty is almost identical with that of plastic surgery. Since their introduction, adjacent flaps (Indian method) and distant flaps (Italian method) are still in use at the present time. Although India should be considered the cradle of rhinoplasty, further refinements must be credited to Italian surgeons who undoubtedly knew about the Indian method for rebuilding the nose. PMID- 7844006 TI - [Obliteration of the maxillary sinuses with ionomer cement in the rabbit]. AB - Ionogran is both a solid and porous bone substitute. It is based on ionomer cement, a material obtained by a neutralization reaction between a glass powder and a polymaleic acid. This material has already been used for reconstruction of large bony defects following tumor surgery. In an experimental study, the maxillary sinuses in 12 rabbits were obliterated using the ionomer-based microimplant. This granulate was placed on the intact mucosa or immediately on bone after removal of the mucoperiostal lining. After its application to intact sinus mucosa no bone regeneration was detected. In contrast, after application to exposed bone osteoneogenesis was observed 28 days later, starting from the bony sinus wall. After periods of 56-84 days, a continued increase in new bone was seen inside the obliterated cavity. These results indicate that Ionogran is suitable for obliteration of the paranasal sinuses after complete removal of the mucosal lining. PMID- 7844007 TI - [Maturation of postsynaptic acetylcholine receptors in cochlear outer hair cells]. AB - Sound transduction in the inner ear is controlled by olivocochlear efferents terminating predominantly at outer hair cells (OHC). Development of efferent fibers and thereby of postsynaptic OHC receptors was studied immunohistochemically in 13 cochleae from fetal guinea pigs. The gestational ages of the animals ranged from gestational day (GD) 35 to GD 56. To visualize nicotinic acetylcholine receptors (nAChR), sera were used from myasthenia gravis patients with confirmed nAChR antibodies. At GD 53 no staining was observed, whereas at GD 58 a striking nAChR-immunoreactivity was found. In cochleae from adult animals postsynaptic receptors were visualized at the bases of all three rows of OHCs. The region of the inner hair cells (IHC) was not stained. The present results indicate that nAChRs in guinea pig cochleae develop between GD 53 and GD 58. Maturation of the postsynaptic nAChRs coincides with development of OHC motile properties. PMID- 7844008 TI - [Localized amyloidosis in the area of the head-neck. A retrospective study]. AB - Localized amyloidosis is a benign rare process in the head and neck. From 1972 to 1992, 12 patients with amyloid deposits of the head and neck were treated at the ENT Department of the University of Erlangen-Nurnberg. Negative congo red staining of rectal biopsy specimens established that the amyloidosis was not systemic. Localized amyloidosis appeared as a diffuse grey-to-yellow mass in the nose (n = 1) or larynx (n = 11). In 10 of the 12 cases excision of amyloid was possible with preservation of adjacent functional structures. Two patients refused surgery and underwent only symptomatic treatment with clinical followup investigations. Amyloid deposits completely excised did not recur during a mean postoperative period of 10 years. When not operated, the amyloid tumors showed a slowly progressive growth pattern. PMID- 7844009 TI - [Localized amyloidosis of the ENT area]. AB - Although amyloidosis is in general a systemic disorder, it may occur as an isolated lesion, especially in the head and neck. The actual classification of amyloidosis is dependent on the biochemical nature of its protein deposits. In the present report, the symptoms and diagnosis of localized amyloidosis are discussed with special regard to histological findings. PMID- 7844010 TI - [Calculated displacements of the middle ear ossicles in static load]. AB - To investigate the dynamic properties of human hearing, experiments in vivo and with cadaver specimens can be carried out. Furthermore, electrical or mechanical models can also be used to study specific phenomena and parameter sensitivities. Present electrical and mechanical models are often based on crude structural and kinematic simplifications in which testing is restricted to static loading or simplified investigations. To investigate both static and dynamic behavior of normal and pathological ears spatial mechanical models have to be established. The different parts of sound transmission--i.e., airborne sound, elastic membranes, fluids, and ossicles have to be represented by different mechanical systems. In this investigations, a rigid body model of the middle ear was investigated. For verification, simulation results with respect to static loads were compared with measurements reported previously by Huttenbrink. In further investigations, the dynamic behavior of the model will be evaluated. Models for the tympanic membrane and inner ear will also be formulated in order to create a compositive model that describes the whole hearing process. By so doing the successful development of prostheses as well as diagnostic methods will be supported. PMID- 7844011 TI - [Treatment of lagophthalmos with adhesive eyelid weights (reversible lid loading)]. AB - BACKGROUND: In facial palsies with lagophthalmic keratopathy, an hour-glass dressing is indicated. This dressing has the disadvantage of a moisture chamber, visual impairment occurs by steaming up. After weeks of placement dermal irritations are possible. An alternative is gravity-dependent lid-loading, using gold implantation in cases of irreversible lagophthalmos. METHODS AND PATIENTS: Lead weights of 0.8 to 2.0 g are glued to the upper lid with an adhesive layer that is well-tolerated by the skin (Combihesive*) or by a simple foil that is glued on both sides (Tesafix). This results in a lid closure without impairment of lid opening. After tests on 10 normal persons lid-loading implants were placed on 22 patients with lagophthalmos and compared with hour-glass dressing. The new method was also applied to 26 additional patients. RESULTS: The dynamic lead weight was effective and well-tolerated. It was more accepted eosine tically, especially during the day because of its better cosmetic appearance and better visual function than was the hour-glass dressing. These latter dressings are still important for use in serious cases during the night. CONCLUSION: Lid loading with lead weights that are glued by an adhesive layer to the upper lid can be recommended as a useful method in cases of reversible lagophthalmos or as a preparatory step before gold implantation. PMID- 7844012 TI - [Risk of hearing loss caused by listening to music with head phones]. AB - Sound levels of music played from mini-cassette players via headphones were measured in a nonrepresentative group of 681 pupils whose ages were between 10 to 19 years. Each pupil completed a questionnaire giving the total time spent listening to music each day. The pupils set the music levels (free field corrected short time Leq) between 60 dB(A) and 110 dB(A). In the age group from 12-16 years, 10% chose 110 dB(A). Nearly 50% of the total group usually listened to music less than one hour per day, and just less than 10% listened for four or more hours. The energy equivalent of continuous sound pressure level for an exposure time of 8 h per day was for 55% Leq 8 h < 66 dB(A) and for 7% Leq 8 h > 95 dB(A) while 4% had an Leq 8 h > 105 dB(A). Estimation of the expected hearing losses (HL) were based on ISO 1999: about 10% of the total group were predicted to have a HL > 10 dB at 4 kHz after 5 years. After listening to sound in this manner 0.3% were expected to develop hearing losses at age 25 years that would be severe enough to substantially impair speech intelligibility. PMID- 7844014 TI - [Corrective interventions after rhinoplasty]. PMID- 7844013 TI - [Unusual, biphasic differentiated mesenchyma tumor of the frontal sinus. Benign fibromyxo-osteoma]. AB - Myxomas, and especially fibromyxomas of the head and neck are rare but when occurring are usually located in the mandible. Here we present the case of a 24 year old man with an unusual mesenchymal tumor in the frontal sinus. Microscopic and histomorphological aspects demonstrated a benign tumor with biphasic differentiation (a myxoid and an osteoid part). The tumor was therefore classified as fibromyxo-osteoma. The association of two different tumors is not probable because of the extremely narrow topographic link between soft tissue and osteoid tumor parts. Other arguments against a perifocal myxoid reaction of the osteoma are that myxoid degeneration of osteomas is unknown and that appropriate immunohistochemical methods were able to show a relatively high proliferation activity of the spindle-shaped cells in the myxoid tissue. Therapy consisted of complete resection of the well-delimited tumor. The patient has remained free of any recurrence 2 years after primary therapy. PMID- 7844015 TI - [Information by the Deafness Group for physician counseling of hearing aid wearers. Even the best technical hearing aid is only as good as user comprehension of proper use]. PMID- 7844016 TI - Ambivalences among Freudians and feminists. PMID- 7844017 TI - On corruption. AB - This paper begins with the premise that in most individuals and in most cultures there is an inevitable force that presses toward the production of corruption as time passes, a force that requires vigilant resistance. Corruption is here defined as a falling away from the ego ideal of the individual or the ideals of the culture, which results in certain unfortunate and maladaptive changes in attitude and behavior of both the group and the individual. Support is given to the premise by a brief review of the work of Robert Hutchins and of Oswald Spengler, both of whom were eloquent and learned advocates of the premise, although, perhaps for personal reasons, they were too pessimistic. There follows a discussion of the metapsychology of corruption both in individuals and in cultures, both from an ego psychology point of view and from a self psychology point of view. Freud's paper on narcissism and Kohut's "psychology of the self in the narrow sense" are taken as starting points. Using the terms of the former, a divestment of the ego ideal of narcissistic libido is described, along the lines of, and somewhat parallel to, Freud's concept of secondary narcissism. Using Kohut's early concept of a separate line of development for narcissism, it is suggested that a similar separate line of development can exist for "corruption" in both individuals and cultures. At the root of this development are the repeated narcissistic wounds inevitable in the course of individual life and in the life of a culture as it tries to live up to its ideals. Resistance to the demoralizing effects of the vicissitudes of life is an important function of the ego, and depends on the strength of the ego, of the cohesiveness of the sense of self, and of a conscious awareness of the dangerous pressures toward corruption that pervade our civilization and resolve not to be swept up by these pressures. This leads to the main point of the paper, focus on the status of the ego ideal of the psychoanalyst or, conversely, his or her level of "corruption," whether conscious or unconscious. It is maintained that this level and the particular value system of the analyst, as well as the level of energy invested in living up to his or her value system, is communicated subtly to both one's students and patients, and has a vital role in the treatment process.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7844018 TI - The negative therapeutic reaction in severe characterological depression. PMID- 7844020 TI - Shame: contemporary psychoanalytic perspectives. PMID- 7844019 TI - Can the impossible profession help the impossible patient--is Freud relevant in the south Bronx? PMID- 7844021 TI - The masked superhero. PMID- 7844022 TI - The relevance of attachment research to psychoanalysis and analytic social psychology. AB - The extensive empirical research generated by attachment theory is briefly reviewed, with special reference to transgenerational transmission of attachment patterns, internal working models, cross-cultural, and longitudinal studies. It is claimed that attachment theory and research support the alternative psychoanalytic approach initiated by Ferenczi, especially as regards the re evaluation of real-life traumatic events, the occurrence of personality splits after childhood trauma, and the aggravation of trauma due to its denial by adults. The concepts of transgenerational transmission and of alternative developmental pathways are further contributions to an alternative psychoanalytic framework. Finally, attention is called to the relevance of the cross-cultural studies to Fromm's analytic social psychology. PMID- 7844023 TI - Psychoanalysis and women's experiences of "coming-out": the necessity of becoming a "bee charmer". PMID- 7844024 TI - The crucial and difficult role of the psychotherapist in the treatment of the HIV positive patient. PMID- 7844025 TI - The eroticized transference: a tool for the reconstruction of childhood sexual trauma. AB - In this paper the eroticized transference is seen as a tool to reconstruct the childhood trauma through the patient's material and the corresponding countertransference in the therapist. The theses is presented that the eroticized transference is an indicator of the existence in the life of the patient of childhood sexual trauma, often unbeknownst to him or her and that it can be of great value in the reconstruction of the experience. The reason it has not been used may lie in our tendency to deny the reality of incest and in the propensity of the analyst for counterresistance in response to these patients. Between avoidance and acting out lies the opportunity to use the countertransference response of the analyst as a catalyst and to reconstruct the traumatic events through the patient's material and the corresponding response in the analyst. Two cases, a male and a female, exemplify the use of transference and countertransference for recollection and reconstruction of the traumatic childhood experience. PMID- 7844026 TI - Changes in the treatment of abused children: a retrospective review of a practice. AB - Using the population of sexually abused children from three periods of my practice, I have described changes in my practice of play therapy over the past 30 years. These changes have come about in part due to the pioneering work of psychiatrists specializing in studies of development in children not designated as emotionally disturbed or mentally ill (Chess and Thomas, 1986; Greenspan, 1981; Winnicott, 1953, 1965, 1971) as well those who have described treatment techniques and theoretical constructs of the experience of traumatized children (Finkelhor and Browne, 1985; Terr, 1991). Because of these convincing works, I have been able to shorten treatment, and shift my goals from direct efforts at unconscious conflict resolution to the more indirect but more effective method of re-establishing maturational tracks through involvement of families, dialogue with children in multiple play techniques as well as words, and to plan ahead for these traumatized children. It remains to be seen what the eventual outcome of this change in treatment will be. Although I always ask families and children to keep in touch even by postcard, only about 20% of them do. Naturally, these are families that are doing well. I am not sure that this necessarily means the other 80% are not doing well but I simply do not know. Because all of these patients are known to one authority or another (police, Rape Centers, courts and Department of Welfare) it should be possible to plan long-term studies of treatment outcome at the time of the initial contact. It seems important enough to me to do this because betrayed trust has a very long lag time before its full effects may be seen in the adults these children become. Because there are so many cases of child abuse, defining the relative effectiveness and efficacy of different kinds of treatment could be useful in managing what is, in effect, a public health problem. PMID- 7844027 TI - Woody Allen's "The purple rose of Cairo": a psychoanalytic allegory. PMID- 7844028 TI - The loss of my dad: an adult developmental issue. AB - The death of a parent as an adult can be viewed as a developmental issue. The trauma of death can allow for the positive reorganization of life experiences. PMID- 7844029 TI - FR901451, a novel inhibitor of human leukocyte elastase from Flexibacter sp. I. Producing organism, fermentation, isolation, physico-chemical and biological properties. AB - A novel human leukocyte elastase (HLE) inhibitor, FR901451 was discovered in the fermentation broth of a bacteria. The bacteria was identified as Flexibacter sp. No. 758. FR901451 has a molecular weight of 1269 and a molecular formula of C60H79N13O18. The mode of inhibition against HLE is competitive, with a Ki value of 9.8 x 10(-9) M. PMID- 7844031 TI - Panclicins, novel pancreatic lipase inhibitors. I. Taxonomy, fermentation, isolation and biological activity. AB - Panclicins A, B, C, D, and E are novel pancreatic lipase inhibitors isolated from Streptomyces sp. NR 0619. Structurally, panclicins A, B, C, D, and E are analogues of tetrahydrolipstatin (THL), which contains a beta-lactone and a N formyl leucine ester, and the IC50s of panclicins A, B, C, D, and E for porcine pancreatic lipase are 2.9, 2.6, 0.62, 0.66, and 0.89 microM, respectively. The potency of the inhibitory activity of each compound is attributed to the amino acid moiety of each structure. The panclicins are either glycine-type compounds such as panclicins C, D, E, which are two to threefold more potent than THL, or they are alanine-type compounds such as panclicins A and B, which are less potent than the glycine compounds. The inhibitory profiles of the panclicins for other lipases such as post-heparin plasma lipases and bacterial lipases are similar to those for pancreatic lipase. Panclicins A, B, C, D, and E, in a manner similar to THL, irreversibly inhibit pancreatic lipase. However, the compounds don't irreversibly inhibit the enzyme as strongly as THL does. PMID- 7844030 TI - FR901451, a novel inhibitor of human leukocyte elastase from Flexibacter sp. II. Pharmacological effect of FR901451. AB - Intratracheal (i.t.) or intravenous (i.v.) administration of FR901451, a potent inhibitor of human leukocyte elastase (HLE) prevented HLE-induced lung hemorrhage in hamsters with ED50 values of 10.5 micrograms/site and 8.1 mg/kg, respectively. alpha 1-Antitrypsin (alpha 1-AT) also showed inhibitory effect in this model. However, the ED50 value by i.t. injection of FR901451 was 20-fold lower than that of alpha 1-AT. Moreover, FR901451 i.t. significantly modulated porcine pancreas elastase (PPE)-induced changes of the respiratory mechanics in hamsters. The ED50 values were 529 micrograms/site and 244 micrograms/site, which were expressed by static lung compliance (Cst) and vital capacity (VC) of the lungs, respectively. These results suggest that FR901451 could be clinically useful agent for the treatment of the destructive lung disease such as pulmonary emphysema. PMID- 7844032 TI - Panclicins, novel pancreatic lipase inhibitors. II. Structural elucidation. AB - Panclicins A-E are novel and potent pancreatic lipase inhibitors produced by Streptomyces sp. NR 0619. Their structures have been elucidated based on NMR and FAB-MS experiments. The relative configurations have also been determined by NMR experiments. The absolute stereochemistry has been determined by the chiral HPLC analysis of the hydrolysates of panclicins A and B and by modified Mosher's method on a derivative of panclicin A. They are structurally related to beta lactone esterase inhibitors of microbial origin, lipstatin, valilactone, ebelactones and esterastin. Panclicins also contain a beta-lactone structure with two alkyl chains, one of which has an N-formylalanyloxy or N-formylglycyloxy substituent. PMID- 7844033 TI - Novel antibiotics SF2738A, B and C, and their analogs produced by Streptomyces sp. AB - Three new antibiotics SF2738A, B and C, and their analogs were isolated from the culture broth of Streptomyces sp. The antibiotics are active against Gram positive bacteria, Gram-negative bacteria and fungi, and exhibited cytotoxic activity against P388 murine leukemia cells with IC50 values of 0.08, 0.25 and 7.5 micrograms/ml, respectively. Their structures were determined by spectral analyses and chemical conversion. Especially, the structure of SF2738A was confirmed to be (E)-((4-methoxy-5-methylthio-2-(2-pyridyl)pyridin-6 yl)methylene)azan ol by X-ray crystallographic analysis. PMID- 7844034 TI - Isolation and characterization of a new 12-membered macrolide FD-895. AB - During the course of our screening program for natural product drugs effective against multidrug resistant cells by using adriamycin resistant HL-60 cells, we have discovered a new 12 membered macrolide FD-895 in the fermentation broth of Streptomyces hygroscopicus A-9561 isolated from a soil sample collected at Iriomote Island, Okinawa prefecture, Japan. FD-895 showed stronger cytocidal activities against in vitro tumor cell lines than adriamycin. FD-895 had the same IC50 values against parent and adriamycin resistant HL-60 cells. PMID- 7844035 TI - Bioxalomycins, new antibiotics produced by the marine Streptomyces sp. LL-31F508: taxonomy and fermentation. AB - An actinomycete strain designated LL-31F508 was isolated from an intertidal sediment sample collected in Key West, Florida. Culture LL-31F508 was assigned to the Streptomyces genus based on the presence of LL-diaminopimelic acid (DAP) in the cell wall and observations of spiny spores using scanning electron microscopy (SEM). Excellent antimicrobial activity against Staphylococcus and Enterococcus spp. were detected in both the supernatant and cell extract samples from fermentations of culture LL-31F508. Production of antibiotic activity peaked at 48-50 hours and closely paralleled cell growth, during which time glucose was more rapidly assimilated than dextrin. A series of new antibiotics called the bioxalomycins was identified as the antibacterial products from fermentations of this culture. Fermentation conditions for production of bioxalomycin alpha differed substantially from those required for production of a related compound, naphthyridinomycin, by the reference culture Streptomyces lusitanus NRRL 8034. PMID- 7844036 TI - Spectomycins, new antibacterial compounds produced by Streptomyces spectabilis: isolation, structures, and biosynthesis. AB - Three new tetrahydroanthracene antibiotics have been isolated from modified culture broths of Streptomyces spectabilis. The new compounds, spectomycins A1, A2 and B1, exist as monomeric (C20H20O7, A1; C19H18O7, A2) and as symmetrical dimeric (C38H34O14; B1) forms. Only spectomycin B1 has moderate activity against Gram-positive microorganisms. We report here the structure elucidation and biosynthetic origin of these compounds. PMID- 7844037 TI - Martinomycin, a new polyether antibiotic produced by Streptomyces salvialis. I. Taxonomy, fermentation and biological activity. AB - Actinomycete culture LL-D37187 has been found to produce the new polyether antibiotic martinomycin. Taxonomic studies, including morphological, physiological, and cell wall chemistry analyses, revealed that culture LL-D37187 is a novel streptomycete species, and the proposed name is Streptomyces salvialis. Martinomycin exhibits activity against the Southern Army Worm (Spodoptera eridania) and Gram-positive bacteria. PMID- 7844038 TI - Physiological studies on gentamicin: phosphate repression of antibiotic formation. AB - The effect of inorganic phosphate on the fermentative production of gentamicin by Micromonospora purpurea has been studied using a chemically defined medium. Phosphate concentrations higher than 5.75 mM (1 g/liter-1) did not inhibit growth but specifically prevented antibiotic formation. Changes in the pH medium and carbon or nitrogen depletion were excluded as the cause of antibiotic underproduction. The use of a phosphate analogue, a protein synthesis inhibitor and the profiles of differential rate of antibiotic production suggested that phosphate itself transiently repressed gentamicin formation. Phosphate affected the formation of 2-deoxystreptamine from 2-deoxyinosose, a none phosphorylated substrate. PMID- 7844039 TI - Isolation and characterization of linear plasmids from lankacidin-producing Streptomyces species. AB - Streptomyces rochei 7434AN4, a producer of lankacidin and lankamycin contains three large linear plasmids, pSLA2-L (200 kb), M (100 kb), and S (17 kb). Studies on the mutants of 7434AN4 having a different plasmid profile showed a parallel relationship between the presence of pSLA2-L and the production of both lankacidin and lankamycin. When pSLA2-L was transferred by protoplast fusion to S. rochei 2-39, a non-antibiotic-producing mutant of 7434AN4 which contained no detectable plasmid, the fusants gained the capacity to produce both antibiotics. From the physical maps of pSLA2-L and pSLA2-L1, a deletion plasmid (160 kb) of pSLA2-L, the latter plasmid was determined to contain a symmetrical linear repeat composed of the right 80-kb part of pSLA2-L. Four other lankacidin-producing Streptomyces strains were also found to have distinctive large linear plasmids which hybridized with the pSLA2-L probe. These results support the involvement of pSLA2-L in the production of lankacidin and lankamycin in S. rochei 7434AN4. PMID- 7844040 TI - Directed biosynthesis of 5"-fluoropactamycin in Streptomyces pactum. AB - A new pactamycin analogue, 5"-fluoropactamycin, was prepared by directed biosynthesis. Supplementation of the fermentation medium of Streptomyces pactum, var. pactum with 3-amino-5-fluorobenzoic acid, an analogue of 3-aminobenzoic acid, an advanced precursor in pactamycin biosynthesis, resulted in co-production of pactamycin and the new pactamycin analogue. A similar feeding experiment with 3-amino-5-methylbenzoic acid did not result in formation of the corresponding methylated pactamycin analogue, but only in inhibition of pactamycin production. Comparison of antimicrobial and cytotoxic activities of pactamycin and 5" fluoropactamycin showed no significant differences. PMID- 7844041 TI - Berninamycins B, C, and D, minor metabolites from Streptomyces bernensis. AB - Berninamycins B, C, and D were isolated from fermentation of Streptomyces bernensis and their structures were studied with 13C NMR and FAB mass spectrometry. Berninamycin B has a valine unit in its cyclic peptide loop instead of the beta-hydroxyvaline unit found in berninamycin A. Berninamycin D has two fewer dehydroalanine units attached to the carboxyl carbon of the pyridine ring. Based on FAB-MS results, berninamycin C is postulated to have only one dehydroalanine unit attached to the carboxyl carbon of pyridine. The biogenesis of berninamycins B, C, and D is discussed. PMID- 7844042 TI - Matlystatins, new inhibitors of type IV collagenases from Actinomadura atramentaria. III. Structure elucidation of matlystatins A to F. AB - The structures of matlystatins, novel type IV collagenase inhibitors isolated from Actinomadura atramentaria, have been determined by a systematic application of homo- and heteronuclear 2D NMR and FAB-MS/MS techniques. Their structures were characterized by the presence of piperazic acid and hydroxamic acid moieties, structural motifs often seen in protease inhibitors. PMID- 7844043 TI - Matlystatins, new inhibitors of type IV collagenases from Actinomadura atramentaria. IV. Synthesis and structure-activity relationships of matlystatin B and its stereoisomers. AB - The first total synthesis of matlystatin B (1a), a low molecular weight inhibitor of type IV collagenases, was accomplished, and its absolute configuration was unambiguously determined. Furthermore, ten stereoisomers of 1a were synthesized, and the inhibition of the 92 kDa type IV collagenase and of other metalloproteinases by each stereoisomer was investigated. PMID- 7844044 TI - Amides of de-acetylglucosaminyl-deoxy teicoplanin active against highly glycopeptide-resistant enterococci. Synthesis and antibacterial activity. AB - Removal, by selective reduction, of the acetylglucosamine from teicoplanin A2-2 (CTA/2) produced the 34-de(acetylglucosaminyl)-34-deoxy pseudoaglycone (II). This compound was more active in vitro than CTA/2 against coagulase-negative staphylococci (CNS). Amide derivatives obtained by condensation of the carboxyl group of II with primary amines were particularly active against Streptococcus pyogenes and had some in vitro activity against VanA enterococci highly resistant to both teicoplanin and vancomycin. Among them, a carboxamide (VII) with a branched tetramine also had better activity than the corresponding amide of teicoplanin against CNS. In contrast, the dimethylamide (VIII) of II had little activity against VanA enterococci. While the overall structure of the heptapeptide backbone of the secondary carboxamides of II is the same as in CTA/2 and its amide derivatives, in deoxy pseudoaglycone II and its tertiary amide VIII the 51,52-peptide bond undergoes a conformational change from the original cisoid to the transoid orientation. This difference between the secondary amides of II and dimethylamide VIII is reflected in their different antibacterial spectrum. The direct synthesis of the amides of deoxy pseudoaglycone II from parent CTA/2 amides by reaction with sodium borohydride is also described. PMID- 7844045 TI - Studies on orally active cephalosporins. I. Synthesis and structure-activity relationships of new 3-substituted carbamoyloxymethyl cephalosporins. AB - The synthesis and antibacterial activities of 7 beta-[2-(2-aminothiazol-4-yl)-2 hydroxyiminoacetamido]-3-N,N - dimethylcarbamoyloxymethyl-3-cephem-4-carboxylic acid (E1100) and its analogs are described, as well as oral absorbability and in vivo activities of the 1-(isopropoxycarbonyloxy)ethyl ester (E1101) and its analogous esters. The introduction of acyclic and cyclic lower alkyl groups at the N-position of 3-carbamoyloxymethyl cephems influences antibacterial activities, especially against H. influenzae, and oral absorbability of their prodrug esters. The structure-activity relationships are also discussed. PMID- 7844046 TI - Studies on orally active cephalosporins. II. Synthesis and structure-activity relations of new [(E) or (Z) 3-substituted carbamoyloxy]-1-propenyl cephalosporins. AB - In an effort to find a new oral cephalosporin with well-balanced antibacterial spectrum, good oral absorbability and long plasma half-life, a series of oxyimino aminothiazolyl 3-[(E)- or (Z)-N-substituted carbamoyloxy]propenyl cephems was synthesized and evaluated for antibacterial activity and oral absorbability. The substituents of the carbamoyloxy group affected their in vitro activity and bioavailability after oral administration of their pivaloyloxymethyl esters at the C-4 position. The compound possessing an N,N-dimethylcarbamoyloxy moiety at the C-3 position showed good oral absorption and well-balanced antibacterial activity. In this report, the structure-activity relationships and the structure oral absorbability relationships of 3-(N-substituted carbamoyloxy)-propenyl cephems are described. PMID- 7844047 TI - Microbial metabolites with tipA promoter inducing activity. III. Thioxamycin and its novel derivative, thioactin, two thiopeptides produced by Streptomyces sp. DP94. PMID- 7844048 TI - NK372135s, novel antifungal agents produced by Neosartoria fischeri. PMID- 7844049 TI - Martinomycin, a new polyether antibiotic produced by Streptomyces salvialis. II. Isolation and structure determination. PMID- 7844050 TI - Reversible isomerization of rapamycin demonstrated by liquid chromatography. PMID- 7844051 TI - The affinity of cyclodepsipeptides to the brain chloride channel domain of the GABAA receptor in vitro. PMID- 7844052 TI - Antitumor activity of heptelidic acid chlorohydrin. PMID- 7844053 TI - Revised structure of the antibiotic GE 2270A. PMID- 7844054 TI - Assessing influential dimensions of reinforcers on choice in students with serious emotional disturbance. AB - We examined how reinforcer rate, quality, delay, and response effort combined to influence the choices of 6 youths with learning and behavior difficulties, and the viability of an assessment methodology derived from matching theory for determining differential responsiveness to those reinforcer and response dimensions. The students were given two concurrent sets of math problems that were equal on two dimensions but competed on two other dimensions (e.g., one set yielded higher rate and lower quality reinforcement than the other). Competing dimensions were counterbalanced across the six conditions of the initial assessment phase, permitting assessment of each dimension on time allocation. The conditions resulting in the most and least time allocated to one problem set alternative relative to the other were then replicated. Time allocated to each of the problems within sets was differentially affected by the reinforcer and/or response dimensions, with allocation patterns varying across students. The results are discussed in the context of implications for the design of treatments and extrapolations from basic research on matching and behavioral economics. PMID- 7844055 TI - Effects of high-probability requests on the social interactions of young children with severe disabilities. AB - High-probability requests were used to increase social interactions in 3 young boys with severe disabilities who had been identified as severely socially withdrawn. A multiple baseline design across participants was used to evaluate the effects of high-probability request intervention on (a) social initiations, (b) social responses, (c) continued interactions, and (d) performance of high- and low-probability requests. The students were observed in a second setting to examine generalization effects across peers who did not participate in the training sequence and settings. The results demonstrated that the high probability requests increased the students' responsiveness to low-probability requests to initiate social behavior. Increases were also found in (a) unprompted initiations and extended interactions to the training peers, (b) unprompted initiations and extended interactions to peers who were not involved in the training procedure, and (c) generalized unprompted initiations and interactions in a second nontraining setting. The students maintained increased levels of initiations and interactions after all prompts were removed from both the training and nontraining settings. PMID- 7844056 TI - Momentum and extinction effects on self-injurious escape behavior and noncompliance. AB - Previous research on applications of behavioral momentum has indicated that a high-probability (high-p) instructional sequence, in which a series of instructions for which there is a high probability of compliance is presented immediately before an instruction for which there is a low probability of compliance, is an effective method for increasing compliance. It is not clear, however, whether the procedure is effective when individuals actively attempt to escape from the instructional situation. In this study, we examined the effects of the high-p sequence, when implemented first alone and then later with an extinction component, as treatment for the self-injurious escape behavior of 2 individuals. Results showed that when the instructional sequence was implemented without extinction, rates of self-injury increased and percentage of compliance decreased. In addition, the percentage of trials occasioning escape behavior increased for both high- and low-probability instructions. When an extinction component was added to the high-p sequence, rates of self-injury and the percentage of trials containing self-injury decreased, and compliance increased. These findings suggest that extinction may be an important component of treatment when escape behavior such as self-injury accompanies noncompliance in instructional contexts and competes with compliant behavior. PMID- 7844057 TI - Generalized imitation and response-class formation in children with autism. AB - An experimental analysis of imitation was conducted to examine the influence of response topography on generalization of imitation across three response types. Four children with autism were presented with both reinforced training trials and nonreinforced probe trials of models from vocal, toy-play, and pantomime response types. The probe trials were used to examine generalization within each response type. A multiple baseline design was used to analyze percentage of matching and nonmatching responses to models across response types. This study, the first to analyze imitative response classes in children with autism, showed that imitation generalized from reinforced training models to nonreinforced probe models within a response type, but it did not generalize across response types. Thus, functional response classes determined by topographical boundaries were exhibited within generalized imitation. PMID- 7844058 TI - A note on transfer of stimulus control in the delayed-cue procedure: facilitation by an overt differential response. AB - This case study describes initially unsuccessful attempts to use the delayed-cue procedure to teach conditional discriminations to an individual with moderate mental retardation. The task was matching printed-word comparison stimuli to dictated-name sample stimuli. In three experiments, the subject typically waited for the delayed cue unless differential responses to the dictated samples (repeating the sample names) were required. Hence, the study provides an example of a way to make the delayed-cue method more effective. The stimulus control bases for the results are discussed. PMID- 7844059 TI - Assessment of stereotypic and self-injurious behavior as adjunctive responses. AB - Certain responses of both humans and nonhumans appear to be maintained indirectly by intermittent reinforcement schedules and have been referred to collectively as adjunctive behavior. Although basic research has examined adjunctive behavior extensively, relatively few studies have been conducted with humans, particularly those with developmental disabilities who often engage in frequent and varied stereotypic behavior. This study assessed possible adjunctive characteristics of self-injurious and stereotypic behaviors using a multielement design containing two types of control conditions. Four subjects who engaged in both self-injurious behavior and stereotypy participated after variables maintaining their self injury were identified via functional analyses. Each day, subjects were exposed to three 15-min sessions in random order: (a) noncontingent presentation of food on a fixed-time schedule (e.g., FT 30 s), (b) a massed-reinforcement (food) control, and (c) a no-reinforcement control. A variety of fixed-time schedules were examined during different experimental phases. Results of this preliminary study suggested that self-injury was not induced by intermittent reinforcement schedules, whereas the stereotypic behavior of some individuals showed characteristics of adjunctive behavior. The importance of research on adjunctive behavior and suggestions for future studies are discussed. PMID- 7844060 TI - Overcoming an autistic child's failure to acquire a tact repertoire. AB - A 6-year-old nonvocal autistic girl who had acquired over 30 signs as mands (requests), simple intraverbals (English-sign translations), and imitative responses repeatedly failed to acquire a tact (labeling) repertoire. It was speculated that the verbal stimulus "What is that?" blocked the establishment of stimulus control by nonverbal stimuli. When procedures to transfer stimulus control from verbal to nonverbal stimuli were implemented, the subject quickly learned to tact all 18 target stimuli. PMID- 7844061 TI - On the beta-glucuronidase binding protein (BGBP) of microorganisms. Its purification, the antiserum preparation against that and its localization in leproma and the other infectious lesions shown by immunohistologic method. AB - Our previous studies suggested that M. leprae (ML) grow in peripheral nerves and lepra cells because ML metabolize hyaluronic acid (HA), and use its component for their growth by the aid of host enzyme combined to the bacilli derived beta glucuronidase binding protein (BGBP). In this study, therefore, we examined the method to purify BGBP from a mycobacterium HI-75 originally separated from a leproma and cultured by modified Ogawa's medium containing split products of HA (glucuronic acid and N-acetylglucosamine). The distribution of BGBP in leproma and the other lesions consisting of hepatitis B virus infected liver and M. avium intracellulare infected lung tissue were also immunohistologically examined. As the result, the best method to get BGBP was preparatory electrophoresis in the final step of the purification and not the molecular sieving. The BGBP was actually proven in leproma and the other infected tissues as described, indicating the abilities of these microorganisms to utilize the metabolic machinery of the host with the similar ways to that of ML. PMID- 7844062 TI - [Elimination of contaminants in a homogenate of nude-mouse footpad experimentally infected with Mycobacterium leprae]. AB - For elimination of contaminants in a homogenate of nude-mouse footpad infected with M.leprae, the pretreatment with trypsin was tested. The results obtained indicated that the final sterile product was satisfactorily obtained, if the pretreatment with trypsin 0.05%, 37 degrees C, 60min to the homogenate was carried out before the treatment with sodium hydroxide 1%, 37 degrees C, 15min. This procedure might contribute to make a suspension of partially purified M.leprae from the infected tissues, because both the treatments with trypsin and sodium hydroxide could eliminate the infected tissues surrounding M.leprae as well as any contaminants, except other mycobacteria, present in a tissue homogenate. PMID- 7844063 TI - [Is a false image of the senile plaque in elderly Japanese with leprosy?- pathological findings on the immunohistology]. AB - By the advance of chemotherapy and aging of the inpatients with leprosy (mean age: 75.7 years), geriatric disease are becoming major problems in Japanese National Leprosarium. Dementia is not diagnosed inpatient with leprosy. After autopsy Alzheimer fibrillary tangle and senile plaques in the brain of aged leprosy is not easy demonstrated by routine stains. However, these is easy demonstrable a different senile plaque with accretion to the Alzheimer fibrillary tangle, if it employed the specific immunohistochemical method on these brain. We employed both tau protein and the divided beta protein, and each of protein is able to divide dementia and non-dementia into aged groups in leprosy. Low prevalence in Japanese leprosy patients is demonstrable in dementia of what happened was accurate in alzheimer disease with subtype of senile plaque. PMID- 7844064 TI - [A device for prevention of the wound caused by leprosy patient's living environment--apply the thermosplint to the wound]. AB - We tried to apply the use of thermosplint to prevent or protect leprosy patient's wound from risky factors in their living environment. Among 40 patients of the use of thermosplint, 27 cases wore it on some places in their hands, and 17 cases did in feet. We observed that 31 cases of the wear of thermosplint had effect on prevention or improvement in their wound, but 3 cases did not. Particularly good effect was obtained in 23 cases of the wear in their hand and 8 cases in foot. In 10 cases, however, we had to stop wearing it because of another damage or patient's uneasy. We found it difficult to apply the use of thermosplint to the plantar ulcer. Some factors such as histological and anatomical ones should be considered in more detail. Several problems of hindrances or inconveniences for daily life in wearing the thermosplint should be solved by further studies including devices for better application of the technique to the leprosy patients. At any rate it should be stressed that both patients and nurses had taken interest in the cause of the injury and could had positively come to grips with prevent of it through this study. PMID- 7844065 TI - Infection determinants at extremes of age. AB - The immune defence of the full-term neonate is compromised in several ways. Although adequate numbers of B lymphocytes are present, antibody production may be delayed compared with the adult. Decreased levels of complement components contribute to the impaired opsonization potential of newborn sera and in turn, to impaired chemotactic responses of neonatal polymorphonuclear leucocytes (PMN). Multiple abnormalities in neonatal PMN function, coupled with deficient bone marrow supplies during stress, contribute greatly to the increased vulnerability to infection of neonates. Infection is a major problem for infants born before 28 weeks. Their serum IgG antibody levels are extremely low and the deficiencies in complement levels and PMN chemotatic responses noted in full-term neonates are even more marked and persist for longer. Opsonic activity decreases with decreasing gestational age and septicaemic pre-term infants are liable to develop neutrophil storage pool exhaustion. In contrast to neonates, the effect of ageing on the immune response is more variable but the changes in cell-mediated immunity have the greatest clinical impact. This decline in T cell function alters the balance between the immune system and intracellular organisms and leads to reactivation of previously controlled infections. Impaired function of immunoregulatory cells contributes to the poor and unsustained antibody responses of the elderly to primary and booster immunizations. Immunosenescence contributes to the morbidity and mortality of old age by several mechanisms, but mainly through an increased susceptibility to infection. PMID- 7844066 TI - Septicaemia in the newborn and elderly. AB - Analysis of 5304 episodes of septicaemia at St Thomas' Hospital showed that both the elderly (> 65 years) and neonates accounted for increasing proportions between 1969 and 1992. In particular the increase was greatest for patients aged over 84 years who accounted for 3% of episodes in adults with community-acquired septicaemia in the 1970s compared with 13% in the 1990s. The change may be explained partly by demographic factors. The majority (85-90%) of elderly patients presented with fever, or leucocytosis or both. The urinary and gastrointestinal tracts were the most common foci for the elderly and they were less likely than other adults to have iv access associated sepsis. Among neonates Escherichia coli septicaemia became less common whereas there was little changes in the incidence of group B streptococcal septicaemia; coagulase-negative staphylococcal infection became more common. Overall mortality declined for both neonates and elderly patients. Poor outcome appeared related to the focus of infection, febrile response and age in the elderly and to the time of onset and organism in neonates. PMID- 7844067 TI - Antibiotics at the extremes of age: choices and constraints. AB - Infection is a frequent cause of morbidity and mortality at the extremes of life. Its treatment is complicated by a lack of specificity in the clinical findings and wider range of pathogens than in other patients. For these reasons empirical therapy must cover a wide range of pathogens and yet, because the clinical findings may not even be due to infection, it should be as non-toxic as possible. It is also essential to investigate intensely before therapy so as to stand the best chance of making an aetiological diagnosis and possibly allowing a change to more directed therapy. Neonates in particular, but also the elderly, are susceptible to age-associated antibiotic toxicities, such as those from tetracyclines and chloramphenicol. Polypharmacy in the elderly renders them particularly liable to drug interactions. Both age groups have altered pharmacokinetics of antibiotics, including differences in absorption, distribution and elimination compared with healthy adults, and therapeutic drug monitoring may be needed more frequently as a result. PMID- 7844068 TI - Immunoprophylaxis at extremes of age. AB - Many infections that occur at the extremes of age are preventable by active or passive immunization. The immune response to vaccines in neonates and the elderly may be diminished when compared with other age groups, however this is usually outweighed by the benefits of providing protection at the age when the need is greatest. Immunoprophylactic agents used at birth include BCG vaccine, oral polio vaccine, varicella-zoster immunoglobulin and hepatitis B vaccine and immunoglobulin. In the elderly, influenza, pneumococcal and tetanus vaccines are often indicated, although the uptake in this age group is poor in comparison with neonates. PMID- 7844069 TI - Economics of infection at the extremes of age. AB - People are more vulnerable to infection at the extremes of age for a variety of reasons, the most important being that they are more likely to be in hospital in a crowded ward environment and to be at risk from hospital acquired infection. Recognition of this increased vulnerability to infection should be accompanied by equal emphasis on their increased susceptibility to nosocomial disease arising from the diagnosis or treatment of infection. An economic evaluation of infection at the extremes of age should include an assessment of need made in terms of the capacity of patients to benefit from investigation or treatment. Benefits should not be confused with treatment effects such as reduction in pyrexia or correction of other physiological abnormalities. Ideally benefits should be quantified in a manner which allows comparison with the cost-effectiveness of other uses of health care resources. In order to achieve this aim clinicians must understand the economic terms opportunity cost and marginal cost-effectiveness. These terms are defined in general terms and then applied to examples of investigation, prevention and treatment of infection at the extremes of age. PMID- 7844070 TI - Pharmacokinetics in children. AB - The first year of life is associated with major changes in the processes affecting the absorption, distribution, metabolism and excretion of drugs. Drug absorption by the oral route is affected by reduced gastric emptying so that this route is unreliable in the neonate. The intramuscular route is also unreliable but transdermal absorption is often greater, with risks of toxicity. The volume of distribution of many drugs is often markedly increased in the neonate, partly because of reduced plasma protein binding (both to albumin and to alpha-1-acid glycoprotein) but also because of an increased volume of extracellular fluid relative to total body water. These factors both result in increased half-life of elimination of drugs. Metabolic processes are often immature at birth and this results in reduced clearance rates and prolonged half-life of elimination of those drugs for which metabolism is a significant mechanism for elimination. Renal excretion in the newborn is reduced although glomerular filtration rate (a passive process) and active tubular secretory rate increase relatively rapidly during infancy. Since these processes tend to be the most important drug elimination mechanism for antibiotics, dose adjustment is particularly important; methods using calculated glomerular filtration rate and the role of therapeutic drug monitoring are described. Finally, the pharmacokinetic processes develop at different rates during the first year of life and an understanding of these factors can help in the safe and effective prescribing of antibiotics. PMID- 7844071 TI - Pharmacokinetics and prescribing in the elderly. AB - The use of prescribed medication in general is higher in the elderly than in the young and it is possible that existing patterns of antimicrobial agent prescribing may predispose to suboptimal response, certain adverse drug reactions (ADR) and the emergence of resistant strains of organisms. Age is an important variable affecting the pharmacokinetics of drugs, including many antimicrobials. Changes which may affect Cmax/MIC ratios and/or the time above MIC include reduced first-pass metabolism, altered distribution volume, reduced binding to albumin, reduced metabolic biotransformation and reduced renal elimination. Application of a knowledge of antimicrobial agent pharmacokinetic changes with age and their implications for response may enable more precise determination of dose regimens for older patients, which is probably desirable for the prevention of both ADR and bacterial resistance. PMID- 7844072 TI - Biopharmaceutical aspects of anti-infective therapy at the extremes of age. AB - Optimal anti-infective therapy at the extremes of age can be supported by the development of appropriate dosage forms. With regard to neonates, infants and children an oral liquid formulation appears to be superior compared with standard formulations such as tablets and capsules, since individualized dosing by body weight or body surface area is more easily achieved. Reformulation of marketed dosage forms, such as crunched tablets or opened capsules, by the hospital pharmacist may result in stability and bioavailability problems and therapeutic failures may be the consequence. With regard to the elderly a reduction in dosing frequency and individualized dosing are important in order to increase compliance. A reduction of dosing frequency can be achieved by oral controlled release dosage forms, which are designed to release the drug in small amounts at predefined rates. However, to permit ease of swallowing they require a relative small daily dose together with excipients. In addition absorption must occur throughout the entire gastrointestinal tract; this is not the case for several antibiotics. Various advantages and disadvantages of oral liquid and oral controlled-release dosage forms are discussed. In the development of an oral formulation, in addition to a standard tablet a variety of information, such as physico-chemical characteristics, pharmacokinetics and pharmacodynamics must be available. Physico-chemical disadvantages can largely be solved by advanced pharmaceutical concepts, such as the pro-drug approach, complex formation or coprecipitation, which are discussed. Using ciprofloxacin with its long lasting and extremely bitter taste as an example, the pharmaceutical development of an oral liquid formulation and the pharmacokinetic investigations in healthy volunteers are described. PMID- 7844073 TI - Epidemiology of neonatal infections. AB - Neonatal infections can be considered in three groups, those acquired antenatally, perinatally and nosocomially. For many years it has been recognized that antenatal infections may cause death or serious fetal damage, but only recently have the more subtle features of antenatal infection been recognized. These include particularly the ability of some (such as toxoplasmosis) to produce disease many years later. Perinatal infection is often the result of maternal carriage of organisms, usually asymptomatically, and a variety of treatment approaches including immunotherapy (for hepatitis B) and antibacterial prophylaxis (for chlamydia) are being used to reduce the short- and long-term morbidity associated with this route of neonatal infection. Nosocomial infection in the neonatal nursery, and particularly in the neonatal intensive care unit may again lead to longer term problems in the infant, and organisms such as staphylococci or salmonella acquired during neonatal life may cause invasive disease weeks or even months later. The prevention of nosocomial infection will depend on the synthesis of a variety of approaches to reduce the number and spread of organisms in the environment of the vulnerable neonate. PMID- 7844074 TI - Urinary tract infection in early childhood. AB - The infantile kidney is most vulnerable to damage from vesicoureteric reflux combined with urinary tract infection. A UTI, as well as giving rise to significant morbidity, may provide the clue to an underlying congenital abnormality such as obstructive uropathy. Urinary tract infection is less prevalent in circumcised boys and infants who are breastfed. Often the diagnosis of UTI is not thought of because of the non-specific nature of the symptoms in this age group and the difficulties of obtaining and interpreting urine cultures. Too little use and attention is paid to proper collecting bags and clean catch specimens. Suprapubic aspiration should always be considered in the septicaemic infant where UTI is high on the list of differential diagnoses. Escherichia coli is responsible for most UTIs although in very young infants, kidneys may be involved secondary to septicaemic infection. Antibiotic therapy should be prompt and investigations comprehensive in young infants. Most children with vesicoureteric reflux are managed conservatively with long term prophylactic antibiotics. PMID- 7844075 TI - Acute bacterial meningitis in the newborn. AB - Acute bacterial meningitis is more common during the neonatal period than at any other time of life and is accompanied by a high incidence of mortality and long term significant sequelae. The incidence of neonatal meningitis is variously calculated at between 0.25 and 0.32 per 1000 live births depending on the inclusion criteria. There is no evidence that the incidence has changed during the last 25 years although during this time there have been dramatic changes in the neonatal population. The pathogenesis of neonatal meningitis is complex and not fully understood. The range of bacteria involved is wider than in paediatric meningitis. Mortality rates are highest following infection with enteric Gram negative bacilli, and still exceed 30%, lower with the Lancefield group B streptococcus and lower still with other Gram-positive bacteria. The predisposing factors to neonatal meningitis are few with the exception of maternal infection or pyrexia at the time of delivery. Any association between meningitis and other possible predisposing factors has not been reliably established. There is evidence to suggest that meningitis in premature low birth weight and sickly babies is caused by organisms, usually from the maternal genital tract, which do not have recognized pathogenicity factors. In contrast, late onset infection is associated with organisms with recognized virulence and pathogenicity factors, many of which have a predisposition to the central nervous system. The clinical presentation of neonatal meningitis is non-specific and meningitic babies cannot be easily distinguished from those with other septic foci or sick uninfected babies. In consequence appropriate antibiotic therapy must be initiated as soon as meningitis is suspected. It is currently recommended that neonatal meningitis is treated with a third-generation cephalosporin, cefotaxime or ceftriaxone, with or without an aminoglycoside, usually gentamicin or amikacin. If there is a significant risk of infection with listeria or enterococci then ampicillin should also be given until CSF culture results are available. While steroids are extensively used for the treatment of paediatric meningitis there is no evidence to support their use in the treatment of neonatal infection. New therapeutic regimens are being developed which are intended to alleviate the pathophysiological consequences of endotoxin release which follows the administration of antibiotics.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7844076 TI - Hydrocephalus shunt infections. AB - Hydrocephalus is most commonly diagnosed in the first few months of life, though cases also arise in later life. Cerebrospinal fluid shunts used to control the condition are prone to colonization particularly by Staphylococcus epidermidis. The incidence is very much higher in infancy than in older age groups, and this is probably due to prolonged hospital stay as a result of the underlying pathology, combined with the propensity for a high skin bacterial density with more adherent strains, rather than to any immune immaturity. Diagnosis of shunt colonization is often very difficult and serological tests have an important role to play even in infancy. There are several pitfalls in diagnosis, particularly in the elderly. Treatment of shunt infections should include removal of the colonized shunt, though regimens to avoid this are currently being investigated. Intraventricular therapy with vancomycin along with intravenous rifampicin offers the best changes of success at the first attempt. Shunted patients who contract purulent bacterial meningitis should not have their shunts removed but should be treated in the same way as those without shunts. PMID- 7844077 TI - Pneumonia in the elderly. AB - However it is assessed, pneumonia is more important in the elderly than in any other age group. For community acquired or nosocomial pneumonia elderly adults far exceed any other age group with 97% of all pneumonia deaths occurring in this age group. Increasingly pneumonia in the immunocompromised elderly is also being seen. The factors which determine the increased frequency of pneumonia in the elderly include social effects, immune changes and physiological changes in the lungs. These are compounded by the effects of the high frequency of chronic disease in this group. The clinical presentation of pneumonia is slightly different in the elderly and this, together with the presence of underlying disease, may make diagnosis difficult; however, focal signs in the chest are nearly always present. Streptococcus pneumoniae is the most important cause of community acquired pneumonia in the elderly followed by Haemophilus influenzae and the influenza viruses. In contrast to younger adults Mycoplasma pneumoniae infection is rarely identified. The role of Gram-negative enterobacteria is unclear, with some studies suggesting that this is the most frequent pathogen, others finding no cases at all. The pathogens causing nosocomial pneumonia are similar to those in younger adults. Management is more difficult because of the effects of underlying diseases, altered drug pharmacokinetics and drug interactions and the outcome is significantly worse with 25% of adults with community acquired pneumonia dying in recent prospective studies. PMID- 7844078 TI - Tuberculosis in the elderly. AB - Although the cause of the steady increase in tuberculosis (TB) notifications in England and Wales since 1987 is multifactorial, the elderly have made an appreciable contribution. From 1987-1989 the increase was 6% for all ages combined, but 13% in females and 16% in males over the age of 75. Tuberculosis in the elderly therefore remains an appreciable problem. Although the characteristic presentation of chronic cough, malaise and weight loss, with cavitatory changes in the upper lobes still predominates in the elderly, there has been an increased incidence of cryptic miliary disease in which the onset is insidious and chest X ray often normal. The diagnosis must often be made on suspicion and treatment started before a positive diagnosis is obtained. The elderly are more likely to suffer adverse effects from the anti-tuberculous chemotherapy than the younger population and greater care must be taken. Drug resistance is uncommon in the elderly in the UK. Isoniazid, rifampicin and pyrazinamide are appropriate for the initial two months of treatment. Rifampicin and isoniazid should be continued for a further four months for disease at virtually any site, with the exception of TB meningitis, when a further 10 months therapy should be given. In the UK, preventative therapy in the form of isoniazid or rifampicin and isoniazid probably has no place in disease control in an elderly population; tuberculin tests are frequently negative, even in the presence of active disease, as elderly patients are often anergic. PMID- 7844079 TI - Information highway travelling back to our roots. PMID- 7844080 TI - Survival and morbidity rates for very low birthweight infants in Arkansas. PMID- 7844081 TI - Surgical treatment of intractable epilepsy. PMID- 7844082 TI - Results of temporal lobectomy for the treatment of partial complex epilepsy. AB - Epilepsy is the third most common cause of neurologic disability. The disease carries a 15 prevalence and a 3.5% lifetime risk. Seventy percent of patients can achieve good seizure control with medication. The remaining 30%, some 360,000 people across the United States, have intractable epilepsy and would benefit from evaluation at an epilepsy specialty center where surgical intervention is an option. The following report reviews a series of 50 patients referred to the Arkansas Comprehensive Epilepsy Program for treatment of intractable complex partial epilepsy. In this series, we evaluate results of temporal lobectomy, commenting upon factors in the patients' histories which may influence their outcomes. PMID- 7844084 TI - Acute exacerbation of asthma in children: a role for prevention and education. PMID- 7844083 TI - Radiological case of the month. Wilson's disease. PMID- 7844085 TI - A double-blind, cross-over study using salbutamol, beclomethasone, and a combination of both in bronchial asthma. AB - A double-blind, cross-over protocol was applied to 22 asthmatic patients who were previously subjected to provocation tests with methacholine. The baseline FEV1 for mild asthma was 89.6 +/- 13.6% while for moderate asthma it was 73 +/- 6%. The initial provocation tests with methacholine revealed that the mild asthma group needed a greater accumulated dose of methacholine than that required by the moderate asthma group to lower the FEV1 by 20%, stressing the enhanced bronchial hyperreactivity present in the latter group. Significant differences in the PD20 values were obtained in both groups of patients using the combination of salbutamol plus beclomethasone. Salbutamol alone was ineffective to change the PD20 values in mild asthma while beclomethasone alone was able to change significantly the PD20 values in these patients, stressing the importance of the inflammatory component in the pathogenesis of stable asthma. Furthermore, the combination of both drugs was also more effective in the moderate asthma group than either medication alone, confirming the pharmacological control of the obstructive and inflammatory changes that are already established in patients with moderate asthma. PMID- 7844086 TI - Decreased production of endothelin-1 in asthmatic children after immunotherapy. AB - Endothelin-1 (ET-1) is an endothelium-derived peptide that may be the most potent vasoconstrictor and bronchoconstrictor yet known. To investigate the role of ET-1 in the pathogenesis of bronchial asthma and the effect of immunotherapy (IT) on endothelin production, we measured the in vivo and in vitro production of ET-1 in 24 asthmatic children before and after specific allergen IT for 2 years as well as in age-matched healthy controls. Our results showed that both the plasma concentrations and in vitro production of ET-1 from the supernatants of cultured mononuclear cells (MNCs) were significantly higher in asthmatic children than in control subjects. The mean plasma levels of ET-1 in asthmatic children before or after IT were significantly higher than in controls (49.4 +/- 26.5 and 30.6 +/- 20.7 ng/L vs. 13.2 +/- 8.5 ng/L, p < 0.05 and p < 0.01, respectively). When stimulated with phytohemagglutin (PHA) (1 microgram/ml) or mite extract (10 micrograms/ml) for 3 days, mononuclear cell from asthmatic children before IT produced significantly higher ET-1 than did those after IT (31.8 +/- 23.0 vs. 18.0 +/- 15.7 ng/L, stimulated with mite, and 67.9 +/- 22.4 vs. 25.0 +/- 13.3 ng/L, stimulated with PHA). The decreased production of ET-1 in MNCs culture supernatant of asthmatic children after IT indicated that immunotherapy may result in an immune nonresponsive state, which may reverse the abnormal secretory pattern of ET-1 production in asthmatic children and partly account for its clinical effectiveness in treating atopic patients. PMID- 7844087 TI - Eosinophil accumulation and activation in antigen-induced late asthmatic response in guinea pigs. AB - The purpose of this study was to investigate the participation of airway eosinophils in the antigen-induced late asthmatic response (LAR) and increased airway responsiveness in the guinea pig model of asthma. After antigen challenge, guinea pigs sensitized with aerosolized ovalbumin showed a late-phase decrease in specific airway conductance, which was accompanied by airway hyperresponsiveness to histamine, eosinophilia in the bronchoalveolar lavage fluid (BALF), decreased BALF eosinophil density, and increased generation of superoxide anions from purified BALF eosinophils. We demonstrated an association of the LAR with eosinophil accumulation and activation in the airway. PMID- 7844088 TI - Do both paternal and maternal smoking influence the prevalence of childhood asthma? A study into the prevalence of asthma in children and the effects of parental smoking. AB - Asthma is one of the commonest of chronic illnesses affecting children. Parental smoking has been considered to have an effect on this. In an attempt to clarify the relationship between parental smoking and the prevalence of childhood asthma we interviewed parents of 97.5% of the children aged 3-11 years registered with a large urban British general practice. We found a lifetime prevalence of asthma of 19.6%, 23.2% of boys and 15.9% of girls. Asthma was more common, 37.6%, in children who also had eczema. Parental smoking appeared to increase the prevalence of asthma. This was more marked when both parents smoked. PMID- 7844089 TI - Outpatient management of acute exacerbations of asthma in children. PMID- 7844090 TI - No association found between Strongyloides infestation and asthma. AB - It has been postulated that infestation with Strongyloides stercoralis is associated with asthma. We conducted a case-control study to determine whether the presence of parasites is associated with asthma. We undertook a retrospective analysis of 15,856 stool specimens received by our Parasitology Laboratory from January 1989 to December 1992. The diagnosis of asthma was secured by a chart review or a review of the computer diagnosis coding system. An association between asthma and Strongyloides was tested by calculating an odds ratio, as well as a Fisher's Exact Test to estimate the strength of the relationship. We also prospectively collected stool specimens for Strongyloides in asthmatics hospitalized for acute exacerbations of asthma from January 1992 to January 1993. Of 60 subjects with evidence of Strongyloides in a stool specimen, 6 were asthmatic. Of 203 stool-negative controls matched for age, sex, and ethnicity, 13 were asthmatic (odds ratio, 1:62; 95% confidence interval, 0.6-4.4; Fisher's Exact two-tailed, p = 0.39). Of 443 subjects admitted for acute exacerbations of asthma, stool specimens were analyzed for the presence of Strongyloides from 161, of which two were parasitized. These data suggest no statistically significant difference in prevalence of asthma among patients with Strongyloides infestation compared to those without parasitic infection. These results do not support the hypothesis that there is an association, either causal or protective, between Strongyloides infestation and asthma. PMID- 7844091 TI - Lack of significant bronchial reactivity to inhaled normal saline in subjects with a positive methacholine challenge test. AB - Patients with symptoms suggestive of asthma often have normal resting pulmonary function. In these patients, a determination of airway responsiveness by bronchial challenge is useful in demonstrating bronchial hyperreactivity (BHR), a defining feature of asthma. In the methacholine (Mch) challenge, it is recommended that following a baseline measurement of FEV1, the patient inhale the normal saline (NS) diluent and FEV1 be repeated to assess for nonspecific BHR to NS. It is also recommended that post-NS inhalation FEV1 should be used as the control value from which decrement in FEV1 is compared following Mch challenge. Mch testing was performed in 44 patients with symptoms suggestive of asthma (cough, chest tightness, dyspnea) and normal resting pulmonary function. Baseline spirometry was obtained and repeated after inhalation of NS and after five breaths each of Mch at the following concentrations: 0.025 mg/ml, 0.25 mg/ml, 2.5 mg/ml, 10 mg/ml, and 25 mg/ml. The procedure was terminated when FEV1 decreased to at least 80% of the post-NS value or if the maximal concentration of Mch had been reached. The post-NS FEV1 value was > or = 91% of the pre-NS value in all the subjects range 91-105%). Using the post-NS FEV1 as the recommended control value, 20 patients (45%) had a positive Mch challenge and 24 patients (55%) had a negative Mch challenge. Had we used the pre-NS FEV1 as a control value, only 2 patients would have been reclassified, and when these 2 cases are carefully examined, there would have been no significant change in the clinical interpretation of the MCh test.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7844092 TI - Subjective sleep quality and mental fitness in asthmatic patients. AB - Asthmatic patients from our outpatient pulmonary clinic were asked to fill out a questionnaire about their sleep and daytime fitness. Seventy-eight responded. Sixty-five healthy persons served as a control group. Patients reported decreased sleep quality, decreased daytime mental fitness, and increased daytime somnolence. There was no relation between these features and lung function, bronchial hyperreactivity, or nocturnal asthma. We conclude that these asthmatic patients reported more sleep disturbances and daytime somnolence than healthy control persons. PMID- 7844093 TI - Tuberculosis simulating asthma in an infant. PMID- 7844094 TI - Compliance with parental prohibition in autistic children. AB - In a controlled observational study of young autistic children ages 3 to 5, responses to parental prohibition were compared to those of mental-age-matched mentally retarded and normal children. The children were prohibited from eating a candy offered to them by the experimenter. Behavioral response, affect, and gaze patterns were compared across the three groups. Autistic children exhibited significantly less compliant behavior than did children in the two control groups; this behavior correlated with chronological age, not with mental age, language development, or parental behavior. Although affect and gaze patterns of the autistic children were different from the controls, these patterns were not correlated with compliant behavior. In conclusion, when compared to mental-age matched control groups, autistic children are significantly less compliant to parental prohibition and they show different gaze and affect patterns. PMID- 7844095 TI - Parent and teacher agreement in the assessment of pervasive developmental disorders. AB - Although it is well known that informants often disagree about the degree of psychopathology in children, this issue has not been systematically evaluated in children with autism. The objective of this paper is to estimate the extent of agreement between parents and teachers on the assessment of autistic symptoms and adaptive behavior skills. We assessed 83 children, 4-6 years of age, with a diagnosis of pervasive developmental disorder (PDD), using the Autism Behavior Checklist (ABC) and the Vineland Adaptive Behavior Scales (VABS). Parents and teachers rated each child on each measure. While there was good agreement between informants on the VABS, teachers tended to rate the PDD children higher than parents. In contrast, there was virtually no agreement on the ABC. High levels of stress experienced by parents appeared to be associated with parents reporting more autistic behaviors and less adaptive skills than teachers. As with other child psychiatric disorders, caution must be exercised in combining information from several informants. PMID- 7844096 TI - Effects of high and low constraint utterances on the production of immediate and delayed echolalia in young children with autism. AB - This study examined the effects of adult antecedent utterances on the occurrence and use of echolalia in children with autism during a free play setting. Adult antecedent utterances were differentiated into two types, high and low constraint, based on the degree of linguistic constraint inherent in the adult utterance and social-communicative control exerted on the child's social and verbal interaction. Results of this study identified a variety of patterns of echolalia usage following adult high and low constraint utterances. Overall results found that a majority of immediate echoes followed high constraint utterances and were primarily used as responsives, organizational devices, and cognitives. The majority of delayed echoes followed low constraint utterances and were primarily used as requestives, assertives, and cognitives. Delayed echoes were more likely than immediate echoes to be produced with evidence of comprehension, but there were no differences in comprehension within the two categories of echolalia following high and low constraint utterances. Educational implications are discussed. PMID- 7844097 TI - Abnormal classical eye-blink conditioning in autism. AB - Cerebellar and limbic system pathologies have been reported in persons with autism. Because these brain areas are involved centrally in the acquisition and performance in classical eye-blink conditioning, this study evaluated conditioning in 11 persons with autism. Compared to matched controls, persons with autism learned the task faster but performed short-latency, high-amplitude conditioned responses. In addition, differences in learning the extinction rates systematically varied with age thus suggesting a developmental conditioning abnormality in autism. The observed pattern of eye-blink conditioning may indicate that persons with autism have the ability to rapidly associate paired stimuli but, depending on processing of certain contextual information, have impairments in modulating the timing and topography of the learned responses. This abnormality may relate to deviant cerebellar-hippocampal interactions. The classical eye-blink conditioning paradigm may provide a useful model for understanding the biological and behavioral bases of autism. PMID- 7844098 TI - Matching to complex samples and stimulus class formation in adults with autism and young children. AB - Adults with autism and young children first learned to match one-element comparison stimuli to two-element sample stimuli. Test conditions then examined whether each of the individual sample elements (a) controlled selections of the comparison stimuli to which they were related during training, (b) were interchangeable with one another as either sample or comparison stimuli, and (c) were interchangeable with the original comparison stimuli. Test data were positive and suggested the formation of three-member stimulus classes. Subsequent experiments demonstrated the formation of four-member classes by (a) adding novel stimuli by training outside the original context; (b) adding novel stimulus elements to the two-element samples used during baseline training; and (c) training with three-element rather than two-element sample stimuli from the outset. Results suggest that acquisition of stimulus classes may be one of the benefits of broad rather than restricted attention to the components of complex stimuli. PMID- 7844099 TI - The effects of subject-performed tasks on the memory performance of verbal autistic children. PMID- 7844100 TI - Autism and the chemical connection. PMID- 7844101 TI - Management of comorbid anxiety and depression. AB - The coexistence of anxiety and depression is common and frequently poses diagnostic and treatment challenges in the clinical setting. Although precise diagnosis is important for treatment selection, it is often complicated by the shortcomings of the current classification system. Whereas some patients present with symptoms that meet the diagnostic criteria for both an anxiety disorder and major depression, others may present with "subsyndromal" symptoms of depression and/or anxiety. Epidemiologic data and a rational treatment approach to the patient with mixed anxiety and depression, depressive symptoms coexistent with "syndromal" and "subsyndromal" symptoms of generalized anxiety disorder, panic disorder, obsessive compulsive disorder, and social phobia are discussed, as well as areas of future research to examine coexisting anxiety and depression. PMID- 7844102 TI - A combined treatment approach to anxiety in the medically ill. AB - Anxiety occurs frequently in patients who are medically ill. A proper search for the underlying cause of the anxiety is essential if the clinician is to make a correct diagnosis and initiate appropriate treatment. Two aspects of the patient's history are particularly important during assessment: the duration and severity of medical illness (and treatments) and the duration and severity of anxiety symptoms. When acute anxiety is encountered, the clinician must rule out a rapidly worsening medical condition, substance-induced anxiety (toxicity or withdrawal), and a psychological reaction to stressors associated with the medical illness. During evaluation of medically ill individuals with chronic anxiety, the clinician must rule out medical disorders that can mimic anxiety disorders, psychiatric disorders associated with anxiety symptoms, and poor adjustment to the medical illness. It is also worth remembering that anxiety disorders occur at an increased frequency in individuals who have chronic medical illness. PMID- 7844103 TI - The management of depression and anxiety in the elderly. AB - The most common psychiatric disorders in later life, with the exception of dementia, are depression and anxiety. Often underdiagnosed or simply accepted with resignation as an inevitable part of aging or as an unavoidable complication of other constitutional illnesses, these disorders contribute to excess disability in older patients and further compromise their quality of life. This report discusses depression and anxiety in the growing elderly population--its prevalence, detection methods, diagnostic considerations, and present interventions. PMID- 7844104 TI - Treating anxiety in patients with alcoholism. AB - The clinical management of patients who present with anxiety syndromes combined with alcohol abuse or dependence is reviewed. A critical step is to make the differential diagnosis between alcohol-induced anxiety (principally alcohol withdrawal) and anxiety disorders per se. Interview and examination techniques useful in making this differential are presented. Clinical management of and pharmacotherapy for alcohol withdrawal are outlined. Anxiety disorders that can be comorbid with alcoholism include panic disorder, social phobia, obsessive compulsive disorder, generalized anxiety disorder, and posttraumatic stress disorder. Psychotherapeutic and pharmacotherapeutic measures for each of these in the setting of alcoholism are suggested, and various possible interrelationships between anxiety disorders and alcoholism are considered. Although anxiety disorders may contribute to the underlying etiology of alcoholism in some cases, alcohol abuse tends to take on a life of its own. Treatment of an anxiety disorder can rarely, if ever, be expected to cure alcoholism. Therefore, the need to institute simultaneous treatment aimed at establishing and maintaining sobriety is emphasized. Research on anxiety disorders and alcoholism is as yet inadequate to fully answer many clinical questions about their relationship and their appropriate diagnosis and management. More research is needed in this area. PMID- 7844105 TI - New strategies in the treatment of depression in women. AB - It is well documented that women are twice as likely as men to be diagnosed with depression, but recent data suggest that gender differences also must be considered in the treatment of depressed patients. Specifically, depression in women may have a different longitudinal course and has been associated with a less successful treatment outcome. Several possible explanations are explored here. First, there appear to be gender differences in pharmacokinetics and responsiveness to medication. Second, depressed women have higher rates of psychiatric and medical comorbidity than depressed men. Third, normal hormonal changes may serve as triggers for psychiatric illness in genetically vulnerable women. Finally, women are subject to unique psychosocial stressors that can impede recovery if not addressed. These data indicate that our approaches to treating women with depression need to be modified. This report concludes with a list of integrated strategies designed to meet the treatment needs of these patients. PMID- 7844106 TI - Serotonergic mechanisms and current and future psychiatric practice. AB - The participation of serotonin (5-HT) in the regulation of diverse biological and psychological functions makes it possible for medications acting on 5-HT subsystems to play a role in the treatment of a growing number of psychiatric and medical disorders. The actions of new medications on the 5-HT reuptake mechanism are complemented by actions on the 5-HT receptors and on other neurotransmitter systems that may be effective in complex and treatment-resistant syndromes. New drugs acting on one or more of the seven major 5-HT receptor classes that have been identified thus far appear to be promising for the treatment of specific subtypes of psychiatric syndromes, from depression to anxiety to schizophrenia. A given serotonergic medication may be useful for more than one disorder because it acts on specific dimensions of psychobiological malfunction that characterize more than one disorder, dimensions that are mediated by more than one receptor. PMID- 7844107 TI - Minimizing and managing antidepressant side effects. AB - Side effects often complicate the use of antidepressants for treatment of patients with major depression. Aggressive minimization and management of antidepressant side effects may relieve discomfort and distress, improve quality of life, enable clinicians to use appropriate medications at therapeutic doses, improve compliance, and thus enhance overall outcome. In this article we present recommendations for the management of side effects associated with antidepressant medications. Specifically, strategies are provided for the management of anticholinergic, cardiovascular, sedative, and activating side effects. Strategies for the management of antidepressant-associated insomnia, hypomania and mania, sexual dysfunction, appetite stimulation and weight gain, cognitive impairment, and parathesias are also discussed. PMID- 7844108 TI - Treatment of sleep disturbances in depressed patients. AB - Sleep is disturbed in 90% of patients with major depression. Disordered sleep physiology may persist after clinical remission of depression, suggesting either that sleep disruption is a trait characteristic of recurrent depression or that depressed patients acquire new habits that perpetuate sleep-related problems. This article reviews the data suggesting a common pathophysiology between sleep and depression. It then focuses on a strategy for evaluating and treating sleep disruption in depressed patients. Treatment must have a conservative goal of restoring sleep quality to the pre-episode level. The treatment of sleep disruption relies primarily on optimal treatment of the depression itself. This includes evaluation and treatment of comorbid medical disorders, substance use (e.g., caffeine, alcohol), and sleep disorders (e.g., nocturnal myoclonus, sleep apnea). The effects of the different classes of antidepressant medications on sleep architecture are presented. Nonpharmacologic strategies for improving sleep, such as behavior modification, relaxation, and phototherapy, are discussed. Finally, the risks and benefits of hypnotic use in the depressed patient and a treatment algorithm for the acute and chronic use of hypnotics are considered. PMID- 7844109 TI - The role of ascorbate in antioxidant protection of biomembranes: interaction with vitamin E and coenzyme Q. AB - One of the vital roles of ascorbic acid (vitamin C) is to act as an antioxidant to protect cellular components from free radical damage. Ascorbic acid has been shown to scavenge free radicals directly in the aqueous phases of cells and the circulatory system. Ascorbic acid has also been proven to protect membrane and other hydrophobic compartments from such damage by regenerating the antioxidant form of vitamin E. In addition, reduced coenzyme Q, also a resident of hydrophobic compartments, interacts with vitamin E to regenerate its antioxidant form. The mechanism of vitamin C antioxidant function, the myriad of pathologies resulting from its clinical deficiency, and the many health benefits it provides, are reviewed. PMID- 7844110 TI - Transport of vitamin C in animal and human cells. AB - The transport systems of animal and human tissues for vitamin C are reviewed with respect to their properties. It emerges that pure diffusion plays only a very minor role while a variety of more or less specific transporters is found on cellular membranes. Although most tissues prefer the reduced ascorbate over the oxidized dehydroascorbic acid and have high-affinity transporters for it, there are several examples for the reversed situation. Special attention is given to similarity or identity with glucose transporters, especially the GLUT-1 and the sodium-dependent intestinal and renal transporters, and to the very widespread dependence of ascorbate transport on sodium ions. The significance of ascorbate transport for vitamin C-requiring and nonrequiring species as well as alterations in states of disease can be seen from ample experimental evidence. PMID- 7844111 TI - Dehydroascorbate reduction. AB - Dehydroascorbic acid is generated in plants and animal cells by oxidation of ascorbic acid. The reaction is believed to occur by the one-electron oxidation of ascorbic acid to semidehydroascorbate radical followed by disproportionation to dehydroascorbic acid and ascorbic acid. Semidehydroascorbic acid may recycle to ascorbic acid catalyzed by membrane-bound NADH-semidehydroscorbate reductase. However, disproportionation of the free radical occurs at a rapid rate, 10(5) M-1 s-1, accounting for measurable cellular levels of dehydroascorbate. Dehydroascorbate reductase, studied earlier and more extensively in plants, is now recognized as the intrinsic activity of thioltransferases (glutaredoxins) and protein disulfide isomerase in animal cells. These enzymes catalyze the glutathione-dependent two-electron regeneration of ascorbic acid. The importance of the latter route of ascorbic acid renewal was seen in studies of GSH-deficient rodents (Meister, A. (1992) Biochem. Pharmacol. 44, 1905-1915). GSH deficiency in newborn animals resulted in decreased tissue ascorbic acid and increased dehydroascorbate-to-ascorbate ratios. Administration of ascorbic acid daily to GSH-deficient animals decreased animal mortality and cell damage from oxygen stress. A cellular role is proposed for dehydroascorbate in the oxidation of nascent protein dithiols to disulfides catalyzed in the endoplasmic reticulum compartment by protein disulfide isomerase. PMID- 7844112 TI - Extracellular ascorbate stabilization: enzymatic or chemical process? AB - Ascorbate is stabilized in the presence of HL-60 cells. This stabilization has been questioned as a simple chemical effect. Further properties and controls about the enzymatic nature of this stabilization are described and discussed. Our results showed that cAMP derivatives and cAMP-increasing agents stimulated the ability of HL-60 cells to stabilize ascorbate. On the other hand, tunicamycin, a glycosylation-interfering agent, inhibited this ability. These data, together with hormonal regulation, support the hypothesis of an enzymatic redox system located at the plasma membrane as being responsible for the extracellular ascorbate stabilization by HL-60 cells. PMID- 7844113 TI - The action of ascorbate in vesicular systems. AB - Many effects of ascorbate center on its interactions with membranes from plant and animal cells. These actions can be studied using vesicles produced from phospholipid components (liposomes), by isolating naturally occurring vesicles, or by purifying particular membranes that form vesicles during the extraction process. Liposomes have provided information concerning the anti- and prooxidant properties of ascorbate and about how the water-soluble vitamin can have effects within the phospholipid bilayer. The involvement of ascorbate in transmembrane electron transport has been characterized in vesicles normally found in certain cells, such as, chromaffin granules, synaptosomes, glyoxisomes, peroxisomes, and clathrin-coated vesicles. Redox activity using reducing power associated with ascorbate/ascorbate free radical (AFR) has been characterized in some of these vesicles and it appears to be mediated by a b-type cytochrome. Ascorbate also participates in the reduction of iron within clathrin-coated vesicles. Vesicles appearing during purification of plasma membranes have transmembrane electron transport, oxidoreductase activity with ascorbate/AFR as redox agents, and an ascorbate-reducible b-type cytochrome. It is also possible that ascorbate-related redox activity exists at the tonoplast of plant cells. PMID- 7844114 TI - Ascorbate on cell growth and differentiation. AB - Ascorbate, an essential nutrient in humans, primates, and guinea pig, is involved in many cellular functions. Ascorbate also modulates cell growth and differentiation. Ascorbate can reduce or stimulate the growth of tumor cells, depending on the cell type. The inhibitory effect is not specific for the biological active isomer L-ascorbate, and isoascorbate and D-ascorbate are more effective in reducing cell growth than L-ascorbate. These results indicate that ascorbate has a cytotoxic effect by killing cells directly, rather a cytostatic one. However, only L-ascorbate is able to stimulate cell growth, but the mechanism of this stimulation is still unknown. L-Ascorbate stimulates the in vitro differentiation of several mesenchyme-derived cell types by altering the expression of multiple genes as the cell progresses through specific differentiation programs. Stimulation of collagen matrix at gene transcription, mRNA stabilization, hydroxylation, and secretion is a key role for L-ascorbate. L Ascorbate also prevents cell transformation by stabilization of the differentiated state and cooperates with other agents to induce differentiation in a leukemia cell line. PMID- 7844115 TI - Ascorbate and plant cell growth. AB - Ascorbate and related enzymes are involved in the control of several plant growth processes. Ascorbate modulates cell growth by controlling (i) the biosynthesis of hydroxyproline-rich proteins required for the progression of G1 and G2 phases of the cell cycle, (ii) the cross-linking of cell wall glycoproteins and other polymers, and (iii) redox reactions at the plasma membrane involved in elongation mechanisms. The effect of ascorbate on onion root elongation is reviewed here. The ascorbate free radical induces a high vacuolization responsible for elongation. This effect may be dependent on the activity of the redox system linked to the plasma membrane. Current data are discussed on the basis of the modulation of the plasma membrane energetic state derived from the ascorbate induced hyperpolarization and the activity of an intrinsic transplasmalemma ascorbate-regenerating enzyme. PMID- 7844116 TI - Ascorbate system in plant development. AB - By using lycorine, a specific inhibitor of ascorbate biosynthesis, it was possible to demonstrate that plant cells consume a high quantity of ascorbate (AA). The in vivo metabolic reactions utilizing ascorbate are the elimination of H2O2 by ascorbate peroxidase and the hydroxylation of proline residues present in the polypeptide chains by means of peptidyl-proline hydroxylase. Ascorbate acts in the cell metabolism as an electron donor, and consequently ascorbate free radical (AFR) is continuously produced. AFR can be reconverted to AA by means of AFR reductase or can undergo spontaneous disproportion, thus generating dehydroascorbic acid (DHA). During cell division and cell expansion ascorbate consumption is more or less the same; however, the AA/DHA ratio is 6-10 during cell division and 1-3 during cell expansion. This ratio depends essentially on the different AFR reductase activity in these cells. In meristematic cells AFR reductase is very high, and consequently a large amount of AFR is reduced to AA and a small amount of AFR undergoes disproportionation; in expanding cells the AFR reductase activity is lower, and therefore AFR is massively disproportionated, thus generating a large quantity of DHA. Since the transition from cell division to cell expansion is marked by a large drop of AFR reductase activity in the ER, it is suggested here that AFR formed in this compartment may be involved in the enlargement of the ER membranes and provacuole acidification. DHA is a toxic compound for the cell metabolism and as such the cell has various strategies to counteract its effects: (i) meristematic cells, having an elevated AFR reductase, prevent large DHA production, limiting the quantity of AFR undergoing disproportionation (ii) Expanding cells, which contain a lower AFR reductase, are, however, provided with a developed vacuolar system and segregate the toxic DHA in the vacuole. (iii) Chloroplast strategy against DHA toxicity is efficient DHA reduction to AA using GSH as electron donor. This strategy is usually poorly utilized by the surrounding cytoplasm. DHA reduction does play an important role at one point in the life of the plant, that is, during the early stage of seed germination. The dry seed does not store ascorbate, but contains DHA, and several DHA-reducing proteins are detectable. In this condition, DHA reduction is necessary to form a limited AA pool in the seed for the metabolic requirements of the beginning of germination. After 30-40 h ascorbate ex novo synthesis starts, DHA reduction declines until a single isoform remains, as is typical in the roots, stem, and leaves of seedlings.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7844117 TI - Hormone- and growth factor-stimulated NADH oxidase. AB - An NADH oxidase activity of animal and plant plasma membrane is described that is stimulated by hormones and growth factors. In plasma membranes of cancer cells and tissues, the activity appears to be constitutively activated and no longer hormone responsive. With drugs that inhibit the activity, cells are unable to grow although growth inhibition may be more related to a failure of the cells to enlarge than to a direct inhibition of mitosis. The hormone-stimulated activity in plasma membranes of plants and the constitutively activated NADH oxidase in tumor cell plasma membranes is inhibited by thiol reagents whereas the basal activity is not. These findings point to a thiol involvement in the action of the activated form of the oxidase. NADH oxidase oxidation by Golgi apparatus of rat liver is inhibited by brefeldin A plus GDP. Brefeldin A is a macrolide antibiotic inhibitor of membrane trafficking. A model is presented where the NADH oxidase functions as a thiol-disulfide oxidoreductase activity involved in the formation and breakage of disulfide bonds. The thiol-disulfide interchange is postulated as being associated with physical membrane displacement as encountered in cell enlargement or in vesicle budding. The model, although speculative, does provide a basis for further experimentation to probe a potential function for this enzyme system which, under certain conditions, exhibits a hormone- and growth factor stimulated oxidation of NADH. PMID- 7844118 TI - Energy-transducing nicotinamide nucleotide transhydrogenase: nucleotide sequences of the genes and predicted amino acid sequences of the subunits of the enzyme from Rhodospirillum rubrum. AB - Based on the amino acid sequence of the N-terminus of the soluble subunit of the Rhodospirillum rubrum nicotinamide nucleotide transhydrogenase, two oligonucleotide primers were synthesized and used to amplify the corresponding DNA segment (110 base pairs) by the polymerase chain reaction. Using this PCR product as a probe, one clone with the insert of 6.4 kbp was isolated from a genomic library of R. rubrum and sequenced. This sequence contained three open reading frames, constituting the genes nntA1, nntA2, and nntB of the R. rubrum transhydrogenase operon. The polypeptides encoded by these genes were designated alpha 1, alpha 2, and beta, respectively, and are considered to be the subunits of the R. rubrum transhydrogenase. The predicted amino acid sequence of the alpha 1 subunit (384 residues; molecular weight 40276) has considerable sequence similarity to the alpha subunit of the Escherichia coli and the N-terminal 43-kDa segment of the bovine transhydrogenases. Like the latter, it has a beta alpha beta fold in the corresponding region, and the purified, soluble alpha 1 subunit cross-reacts with antibody to the bovine N-terminal 43-kDa fragment. The predicted amino acid sequence of the beta subunit of the R. rubrum transhydrogenase (464 residues; molecular weight 47808) has extensive sequence identity with the beta subunit of the E. coli and the corresponding C-terminal sequence of the bovine transhydrogenases. The chromatophores of R. rubrum contain a 48-kDa polypeptide, which cross-reacts with antibody to the C-terminal 20-kDa fragment of the bovine transhydrogenase. The predicted amino acid sequence of the alpha 2 subunit of the R. rubrum enzyme (139 residues; molecular weight 14888) has considerable sequence identity in its C-terminal half to the corresponding segments of the bovine and the alpha subunit of the E. coli transhydrogenases. PMID- 7844119 TI - Preparation of highly phosphorylating mitochondria from the yeast Schizosaccharomyces pombe. AB - Schizosaccharomyces pombe yeast cells grown on either fermentable or respiratory media were efficiently converted to stable spheroplasts by the alpha-(1-->3) glucanase Novozym 234 in the presence of 1.2 M sorbitol. Lysis of spheroplasts by gentle homogenization in dilute sorbitol resulted in the preparation of mitochondria with a structure similar to that observed within the starting yeast cells. The isolated mitochondria exhibited high oxidation rates with various respiratory substrates, NADH being the most efficient. The mitochondria appeared well coupled since the second State 4 rate observed after ADP consumption was identical to the initial one. The State 3 rate in the presence of ADP was completely inhibited by low oligomycin concentrations, similarly to the concomitant ATP synthesis of 900 nmol/min x mg protein. These NADH oxidation and dependent ATP-synthesis activities are much higher than those previously described for mitochondria isolated from Schizosaccharomyces pombe, and similar to the highest values reported for Saccharomyces cerevisiae. PMID- 7844120 TI - Triphenyltin as inductor of mitochondrial membrane permeability transition. AB - The effect of triphenyltin on mitochondrial Ca2+ content was studied. It was found that this trialkyltin compound induces an increase in membrane permeability that leads to Ca2+ release, drop of the transmembrane potential, and efflux of matrix proteins. Interestingly, cyclosporin A was unable to inhibit triphenyltin induced Ca2+ release. Based on these results it is proposed that the hyperpermeable state is produced by modification of 2.25 nmol of membrane thiol groups. PMID- 7844121 TI - Excision of hemivertebrae and wedge resection in the treatment of congenital scoliosis. AB - The results of anterior and posterior excision or wedge resection of a hemivertebra and arthrodesis of the spine were reviewed retrospectively for thirty-seven patients. The degree of correction that was obtained and maintained, the balance and alignment of the trunk, changes in pelvic obliquity, and associated complications were evaluated. The average age at the time of the operation was twelve years (range, six months to forty-two years). The average duration of follow-up was six years (range, two to nineteen years). The resection was at the mid-thoracic level in six patients, at the thoracolumbar level in nine, at the mid-lumbar level in seven, and at the lumbosacral level in seventeen. (Two patients had an excision of a hemivertebra at two levels.) Instrumentation was used in twenty-eight patients. Postoperatively, all patients were managed with a body cast, with a unilateral or bilateral pantaloon extension, for four to six months. The instrumentation allowed early walking and the use of a unilateral rather than a bilateral pantaloon extension. The index curve (the curve containing the hemivertebra) averaged 54 degrees (range, 18 to 132 degrees) preoperatively, 33 degrees (range, 0 to 105 degrees) postoperatively, and 35 degrees (range, 0 to 110 degrees) at the most recent follow-up evaluation. A measurable improvement in balance was achieved and maintained in nineteen patients. Pelvic obliquity did not change appreciably, as it was related primarily to limb-length inequality in this series. Complications included a temporary nerve-root lesion in seven patients, a permanent neurological deficit involving the first sacral nerve root in one patient, a pseudarthrosis in three patients, and a wound infection in three patients. Six patients had extension of the arthrodesis to include additional vertebrae. PMID- 7844122 TI - Posterior interbody arthrodesis with a fibular strut graft in spondylolisthesis. AB - We reviewed the results of posterior interbody arthrodesis of the fifth lumbar and first sacral vertebrae with the use of a fibular strut graft in nine patients who had had a grade-III, IV, or V spondylolisthesis. The average age of the patients at the time of the operation was twenty-seven years (range, seventeen to thirty-two years). The average duration of the symptoms preoperatively was three years (range, nine months to eleven years), and the average duration of follow-up was three years (range, two to five years). The most common preoperative symptom was back pain, which was rated an average of 8.3 points (7, 8, or 9 points) on a visual-analog scale of 1 to 10 points. The average angle of the slip was 45 degrees (range, 15 to 70 degrees). Four of the slips were grade III, four were grade IV, and one was grade V. Postoperatively, the average pain score was 1.4 points (1, 2, or 3 points). This improvement was significant (p < 0.05, Student t test). All nine patients had roentgenographic evidence of osseous fusion at the one-year follow-up examination. Complications included a dural tear in one patient, a superficial wound infection in two patients, temporary weakness of the evertors of the foot in six patients, and transient decreased sensation along the dorsum of the foot of the donor leg in two patients. PMID- 7844123 TI - The anatomy of the pelvis in the exstrophy complex. AB - We compared computerized tomography scans of the pelvis of twenty-four patients who had exstrophy of the bladder with scans of age-matched controls in order to analyze the pelvic deformity that accompanies the variably severe manifestations of this condition. The patients who had classic exstrophy of the bladder were found to have a mean of 12 degrees of external rotation of the posterior aspect of the pelvis on each side, retroversion of the acetabula, a mean additional 18 degrees of external rotation and 30 per cent shortening of the pubic rami, and progressive diastasis of the symphysis pubis. The foot-progression angle demonstrated 20 to 30 degrees of external rotation beyond the normal limits seen in early childhood, but this improved with age. The patients who had exstrophy of the cloaca and the bladder not only had all of these pelvic deformities to a greater degree but also had asymmetry of measured parameters between the right and left sides of the pelvis, malformation of the sacro-iliac joints, and occasional dislocation of the hip. An understanding of the pelvic anatomy that accompanies exstrophy is essential when corrective approaches are planned. Such an understanding will improve the rate of success of both closure of the bladder and control of urinary continence postoperatively. PMID- 7844124 TI - Acute spondylolytic spondylolisthesis. Risk of progression and neurological complications. AB - Acute spondylolytic spondylolisthesis was diagnosed after major trauma in five patients. The level of injury was between the third and fourth lumbar vertebrae in one patient and between the fifth lumbar and first sacral vertebrae in four. The initial spondylolisthesis was grade I in four patients and grade III in one. Four of the patients were initially managed non-operatively. The deformity did not progress in a five-year-old boy with grade-I spondylolisthesis who had been managed with immobilization in a body cast. The deformity progressed in two of the adolescents who had been managed non-operatively; the progression was from grade I to grade III in one of these patients and from grade III to grade V (spondyloptosis) in the other, in whom a cauda equina syndrome also developed. The latter patient was subsequently managed with posterior reduction and arthrodesis followed by an anterior arthrodesis, and the neurological deficits resolved. The deformity also progressed, from grade I to grade II over three years, in a fifty-seven-year-old woman who had been managed non-operatively. One patient who had a grade-I deformity was managed with immediate operative stabilization followed by immobilization in a thoracolumbosacral orthosis; the deformity did not progress. Although minor or repetitive trauma is often associated with spondylolysis, high-energy trauma may produce a more severe form of spondylolysis with spondylolisthesis. These deformities are more unstable, with instability similar to that of a fracture-dislocation, and they have a greater propensity to progress than the usual form of spondylolytic spondylolisthesis.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7844125 TI - The effect of chevron osteotomy with lateral capsular release on the blood supply to the first metatarsal head. AB - The chevron osteotomy is one of the most widely used distal metatarsal osteotomies for the treatment of hallux valgus in adults. Because the osteotomy interrupts the intraosseous blood supply to the metatarsal head, there has always been a concern that the operation could produce osteonecrosis of the metatarsal head, particularly if the important extraosseous blood supply was also damaged. We used latex injection and a modified Spalteholz technique in cadaveric specimens to demonstrate the effect of the chevron osteotomy, with and without lateral capsular release, on the vascular supply to the first metatarsal head. We found an extensive network of extraosseous vasculature to the metatarsal head both proximal and distal to the site of the osteotomy. Both of these vascular networks were preserved when the osteotomy was done properly. Also, an extensive plantar and plantar lateral network of vessels provided circulation to the head. Potential technical flaws in the performance of the osteotomy included cutting of the first dorsal metatarsal artery by overpenetration of the saw blade and incorrect placement of the proximal arms of the osteotomy inside the joint capsule. These technical errors, alone or in conjunction with extensive capsular stripping, can result in damage to the vessels that supply the metatarsal head. PMID- 7844126 TI - Radiographic analysis of hallux valgus. A two-dimensional coordinate system. AB - A new method was devised for the evaluation of medial and lateral splaying of the foot on dorsoplantar radiographs made while the patient is bearing weight. This method involves use of a two-dimensional coordinate system; the axis of the shaft of the second metatarsal is the x axis, the intersection of the x axis with the proximal end of the second metatarsal is the point of origin, and the perpendicular to the x axis that passes through the point of origin is the y axis. This method was used to study the radiographs of 177 feet of 112 female patients who had symptomatic hallux valgus and those of ninety-four normal feet of sixty-four female subjects. The site of origin of metatarsus primus varus in the patients who had hallux valgus was the first metatarsocuneiform joint. The great toe and first metatarsal of the patients who had hallux valgus were longer, on the average, than those of the normal subjects. However, the x coordinates at the tip of the great toe and at the end of the first metatarsal were larger only in the patients who were less than twenty years old, because of the progression of angulation of the great toe and of the first metatarsal in the older patients. PMID- 7844128 TI - The effect of warfarin on the attachment of bone to hydroxyapatite-coated and uncoated porous implants. AB - The attachment of bone to hydroxyapatite-coated and uncoated porous implants made of cobalt-chromium-molybdenum alloy was investigated with and without postoperative administration of warfarin sodium. The implants were placed transcortically in the femoral diaphysis of adult female goats and were evaluated after three, six, and twelve weeks in situ. Mechanical push-out testing and histological evaluation revealed that the attachment strength and the ingrowth of bone at the bone-implant interface increased with time in situ for both the hydroxyapatite-coated and the uncoated implants. The administration of warfarin significantly impaired both the attachment strength and the ingrowth of bone at twelve weeks. At twelve weeks, the attachment strength and bone ingrowth of the hydroxyapatite-coated implants in the animals that had received warfarin were statistically equal to those of the uncoated implants in the control animals. PMID- 7844127 TI - Transmission of the hepatitis-C virus by tissue transplantation. AB - The hepatitis-C virus has been the most prevalent cause of chronic hepatitis in both blood and organ recipients. The introduction of a second-generation immunoassay for antibodies to the hepatitis-C virus (HCV 2.0) provided the opportunity to determine if the hepatitis-C virus can be transmitted through tissue transplantation. Banked sera from tissue donors that had previously been found to be non-reactive to the first-generation hepatitis-C virus antibody assay (HCV 1.0) and non-reactive for antibodies to hepatitis-B core antigen were retested with HCV 2.0. The sera from two donors were reactive; the transplant records of recipients of tissues from these donors were reviewed, and the surgeons or hospitals were contacted. The tissue recipients were tested with HCV 2.0, and positive sera were tested for hepatitis-C virus RNA by polymerase chain reaction. Viral nucleic acids isolated from viremic donors and recipients were analyzed for identity by sequencing of the hepatitis-C virus envelope gene (E2) hypervariable region. There were twenty-one grafts, which had been treated with gamma radiation, from one donor; thirteen had been transplanted to twelve recipients. Serum samples from six of the recipients were tested; one was reactive. This patient had other risk factors for infection with the hepatitis-C virus, and sequence analysis demonstrated non-identity between the donor and recipient hepatitis-C virus isolates. Nine of twelve grafts from a second donor had been transplanted in nine recipients. Serum samples from five patients were tested with HCV 2.0; four were reactive. In three of the four patients, the sera were determined to be positive for the hepatitis-C virus by polymerase chain reaction. E2 sequence analyses of hepatitis-C virus RNA isolates from two of these recipients demonstrated sequence identity with the donor isolate. The results of the present report demonstrate that the hepatitis-C virus can be transmitted by bone, ligament, and tendon allografts. They also support the need for testing of all tissue donors for antibodies to the hepatitis-C virus before the tissue is released for transplantation. The results also suggest that seventeen kilo-gray of gamma radiation may inactivate the hepatitis-C virus in tissue. PMID- 7844129 TI - Atrophy of the proximal part of the femur after total hip arthroplasty without cement. A quantitative comparison of cobalt-chromium and titanium femoral stems with use of dual x-ray absorptiometry. AB - The purpose of this study was to compare the density of periprosthetic bone about titanium and cobalt-chromium stems that had been inserted without cement. The analysis was done, three to four years after a total hip arthroplasty, in a retrospectively matched cohort of thirty patients. Fifteen patients had a stem that was collarless, proximally coated, and made of titanium; the other fifteen had a stem of similar design that was made of cobalt-chromium. The criteria for selection in the study included an excellent clinical and radiographic result and separately calculated modified Harris and Mayo hip scores of more than 94 points. All stems had radiographic evidence of osseous ingrowth. A comparison of the bone mineral density about the two different types of stem with dual-energy x-ray absorptiometry revealed a significant difference only along the calcar of the femur. There was no significant difference about the remaining, preponderant portion of the proximal part of the femur. Our data suggest that the difference in the modulus of elasticity between the two types of stem had little effect on the loss of bone-mineral density in most of the proximal part of the femur after arthroplasty without cement. PMID- 7844130 TI - Oblique osteotomy for the correction of tibial malunion. AB - Fifteen patients had an oblique osteotomy of the tibia for the correction of a multiplanar deformity between January 1989 and March 1991; twelve were followed for an average of twenty-five months (range, twelve to forty-two months). Preoperatively, the average deformity in the coronal plane was 14 degrees (range, 30 degrees of valgus to 25 degrees of varus) and the average deformity in the sagittal plane was 13 degrees (range, 40 degrees of recurvatum to 23 degrees of procurvatum [angulation convex anteriorly]). The average leg-length discrepancy was 2.2 centimeters (range, one to six centimeters). No patient had a rotational deformity. After careful preoperative planning, all patients had an oblique osteotomy and placement of a lag screw and a neutralization plate. Somatosensory evoked potentials were monitored during any axial lengthening. A fibular osteotomy and lengthening of the Achilles tendon were performed as needed. Full weight-bearing on the extremity was prohibited until radiographic and clinical examination indicated that union had occurred, which was at an average of 4.5 months (range, three to six months). At the most recent follow-up examination, ten patients had an excellent result. The average correction in the coronal plane was to within 1 degree (range, 0 to 3 degrees) of normal and the average alignment in the sagittal plane was to within 2 degrees (range, 0 to 12 degrees) of normal. An average of 1.3 centimeters (range, 0.5 to 2.5 centimeters) of lengthening was obtained.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7844131 TI - The effect of lengthening of the femur on the extensors of the knee. An electromyographic study. AB - Surface electromyography of the quadriceps femoris muscle was performed in seven patients in order to determine the effect of extensive lengthening of the femur on the muscles that extend the knee. Electromyograms were made during sustained (thirty-second) isometric extension of the knee, at an angle of flexion of the knee of 30 degrees, while a load equal to 15 per cent of body weight was applied to the leg just proximal to the ankle. The average circumference of the thigh was smaller, the motor-unit recruitment of the muscles was slower, and the fatigability was greater on the involved side compared with the uninvolved side. The vastus medialis exhibited greater fatigability and slower motor-unit recruitment than the rectus femoris or the vastus lateralis. The atrophy index of the involved muscles correlated well with the muscle fatigability, the preoperative limb-length discrepancy, the percentage of lengthening, and the motor-unit recruitment. Analysis also revealed a correlation between muscle fatigability and the percentage of lengthening of the bone and between muscle fatigability and the preoperative limb-length discrepancy. The percentage of lengthening correlated with the extent of motor-unit recruitment. The results of this study suggest that the amount of damage to neuromuscular tissue varies according to the extent of the lengthening of the femur. Of all of the knee extensors, the vastus medialis was affected the most. PMID- 7844132 TI - The orthopaedic manifestations of prune-belly (Eagle-Barrett) syndrome. AB - Forty children were managed for prune-belly syndrome between 1979 and 1989, and twenty-five of them had musculoskeletal abnormalities. The musculoskeletal abnormalities were primary in twenty-two children, secondary to renal osteodystrophy in one, and both primary and secondary to renal osteodystrophy in two. Thirteen children had marked abnormality of the hip, and congenital dislocation was typically resistant to conventional treatment. Scoliosis was seen in seven patients. Pectus excavatum (a chest-wall deformity) was seen in eleven patients, including five of the six who had an idiopathic-like curve. Although prune-belly syndrome is uncommon, the diagnosis necessitates a thorough orthopaedic evaluation because of the high prevalence of associated musculoskeletal abnormalities. PMID- 7844133 TI - Evaluation of treatment modalities for septic arthritis with histological grading and analysis of levels of uronic acid, neutral protease, and interleukin-1. AB - We compared the effectiveness of antibiotics alone and in combination with arthroscopy, arthroscopy with debridement, arthrotomy, or needle aspiration for the treatment of septic arthritis. Each modality has its proponents, but, to our knowledge, no comparative studies have been conducted in animals. We used biochemical and histological analysis to compare these methods of treatment in an experimental model. The right hind knee of thirty goats was injected with 1 x 10(5) Staphylococcus aureus bacilli. The left hind knee was not inoculated and served as the normal control. Seventy-two hours after inoculation, a two-week course of treatment with intramuscular administration of cefuroxime sodium, either alone or in combination with another mode of treatment, was initiated in each of five groups. The cartilage was evaluated histologically with biochemical, enzymatic, and interleukin-1 analyses. Despite the early therapeutic intervention, on the average, there was a 25 per cent loss of uronic acid (t test, p < 0.001) and a 43 per cent increase in neutral protease activity (signed rank test, p = 0.003) in the treatment groups. There were no significant intergroup differences with regard to the histochemical-histological rating or the levels of uronic acid, neutral protease, or interleukin-1. PMID- 7844134 TI - Augmentation of a total knee arthroplasty with a modular metal wedge. A case report. PMID- 7844135 TI - Extensive growth of an osteochondroma in a skeletally mature patient. A case report. PMID- 7844136 TI - Compression of the cervical cord due to alcaptonuric arthropathy of the atlanto axial joint. A case report. PMID- 7844137 TI - Unicompartmental osteoarthrosis of the knee. PMID- 7844138 TI - Magnetic resonance-imaging scans in discitis. Sequential studies in a child who needed operative drainage: a case report. PMID- 7844139 TI - Magnetic-resonance-imaging scans in discitis. Sequential studies in a child who needed operative drainage: a case report. PMID- 7844140 TI - Cytological diagnosis of vertebral tuberculosis with fine-needle aspiration biopsy. PMID- 7844142 TI - The beta subunit of the signal recognition particle receptor is a transmembrane GTPase that anchors the alpha subunit, a peripheral membrane GTPase, to the endoplasmic reticulum membrane. AB - The signal recognition particle receptor (SR) is required for the cotranslational targeting of both secretory and membrane proteins to the endoplasmic reticulum (ER) membrane. During targeting, the SR interacts with the signal recognition particle (SRP) which is bound to the signal sequence of the nascent protein chain. This interaction catalyzes the GTP-dependent transfer of the nascent chain from SRP to the protein translocation apparatus in the ER membrane. The SR is a heterodimeric protein comprised of a 69-kD subunit (SR alpha) and a 30-kD subunit (SR beta) which are associated with the ER membrane in an unknown manner. SR alpha and the 54-kD subunits of SRP (SRP54) each contain related GTPase domains which are required for SR and SRP function. Molecular cloning and sequencing of a cDNA encoding SR beta revealed that SR beta is a transmembrane protein and, like SR alpha and SRP54, is a member of the GTPase superfamily. Although SR beta defines its own GTPase subfamily, it is distantly related to ARF and Sar1. Using UV cross-linking, we confirm that SR beta binds GTP specifically. Proteolytic digestion experiments show that SR alpha is required for the interaction of SRP with SR. SR alpha appears to be peripherally associated with the ER membrane, and we suggest that SR beta, as an integral membrane protein, mediates the membrane association of SR alpha. The discovery of its guanine nucleotide-binding domain, however, makes it likely that its role is more complex than that of a passive anchor for SR alpha. These findings suggest that a cascade of three directly interacting GTPases functions during protein targeting to the ER membrane. PMID- 7844141 TI - PICK1: a perinuclear binding protein and substrate for protein kinase C isolated by the yeast two-hybrid system. AB - Protein kinase C (PKC) plays a central role in the control of proliferation and differentiation of a wide range of cell types by mediating the signal transduction response to hormones and growth factors. Upon activation by diacylglycerol, PKC translocates to different subcellular sites where it phosphorylates numerous proteins, most of which are unidentified. We used the yeast two-hybrid system to identify proteins that interact with activated PKC alpha. Using the catalytic region of PKC fused to the DNA binding domain of yeast GAL4 as "bait" to screen a mouse T cell cDNA library in which cDNA was fused to the GAL4 activation domain, we cloned several novel proteins that interact with C kinase (PICKs). One of these proteins, designated PICK1, interacts specifically with the catalytic domain of PKC and is an efficient substrate for phosphorylation by PKC in vitro and in vivo. PICK1 is localized to the perinuclear region and is phosphorylated in response to PKC activation. PICK1 and other PICKs may play important roles in mediating the actions of PKC. PMID- 7844143 TI - The oligomerization reaction of the Semliki Forest virus membrane protein subunits. AB - The Semliki Forest virus (SFV) spike is composed of three copies of a membrane protein heterodimer. The two subunits of this heterodimer (p62 and E1) are synthesized sequentially from a common mRNA together with the capsid (C) in the order C-p62-E1. In this work heterodimerization of the spike proteins has been studied in BHK 21 cells. The results indicate that: (a) the polyprotein is cotranslationally cleaved into individual chains; (b) the two membrane protein subunits are initially not associated with each other in the endoplasmic reticulum (ER); (c) heterodimerization occurs predominantly between subunits that originate from the same translation product (heterodimerization in cis); (d) the kinetics of subunit association are very fast (t1/2 = 4 min); and (e) this heterodimerization is highly efficient. To explain the cis-directed heterodimerization reaction we suggest that the p62 protein, which is made before E1 during 26S mRNA translation, is retained at its translocation site until also the E1 chain has been synthesized and translocated at this same site. The mechanism for p62 retention could either be that the p62 anchor sequence cannot diffuse out from an "active" translocation site or that the p62 protein is complexed with a protein folding facilitating machinery that is physically linked to the translocation apparatus. PMID- 7844144 TI - Kinesin is the motor for microtubule-mediated Golgi-to-ER membrane traffic. AB - The distribution and dynamics of both the ER and Golgi complex in animal cells are known to be dependent on microtubules; in many cell types the ER extends toward the plus ends of microtubules at the cell periphery and the Golgi clusters at the minus ends of microtubules near the centrosome. In this study we provide evidence that the microtubule motor, kinesin, is present on membranes cycling between the ER and Golgi and powers peripherally directed movements of membrane within this system. Immunolocalization of kinesin at both the light and electron microscopy levels in NRK cells using the H1 monoclonal antibody to kinesin heavy chain, revealed kinesin to be associated with all membranes of the ER/Golgi system. At steady-state at 37 degrees C, however, kinesin was most concentrated on peripherally distributed, pre-Golgi structures containing beta COP and vesicular stomatitis virus glycoprotein newly released from the ER. Upon temperature reduction or nocodazole treatment, kinesin's distribution shifted onto the Golgi, while with brefeldin A (BFA)-treatment, kinesin could be found in both Golgi-derived tubules and in the ER. This suggested that kinesin associates with membranes that constitutively cycle between the ER and Golgi. Kinesin's role on these membranes was examined by microinjecting kinesin antibody. Golgi-to-ER but not ER-to-Golgi membrane transport was found to be inhibited by the microinjected anti-kinesin, suggesting kinesin powers the microtubule plus end directed recycling of membrane to the ER, and remains inactive on pre-Golgi intermediates that move toward the Golgi complex. PMID- 7844145 TI - The Hansenula polymorpha PER8 gene encodes a novel peroxisomal integral membrane protein involved in proliferation. AB - We previously described the isolation of mutants of the methylotrophic yeast Hansenula polymorpha that are defective in peroxisome biogenesis. Here, we describe the characterization of one of these mutants, per8, and the cloning of the PER8 gene. In either methanol or methylamine medium, conditions that normally induce the organelles, per8 cells contain no peroxisome-like structures and peroxisomal enzymes are located in the cytosol. The sequence of PER8 predicts that its product (Per8p) is a novel polypeptide of 34 kD, and antibodies against Per8p recognize a protein of 31 kD. Analysis of the primary sequence of Per8p revealed a 39-amino-acid cysteine-rich segment with similarity to the C3HC4 family of zinc-finger motifs. Overexpression of PER8 results in a markedly enhanced increase in peroxisome numbers. We show that Per8p is an integral membrane protein of the peroxisome and that it is concentrated in the membranes of newly formed organelles. We propose that Per8p is a component of the molecular machinery that controls the proliferation of this organelle. PMID- 7844146 TI - Cytoplasmic determinants involved in direct lysosomal sorting, endocytosis, and basolateral targeting of rat lgp120 (lamp-I) in MDCK cells. AB - Rat lysosomal glycoprotein 120 (lgp120; lamp-I) is a transmembrane protein that is directly delivered from the trans-Golgi network (TGN) to the endosomal/lysosomal system without prior appearance on the cell surface. Its short cytosolic domain of 11 residues encodes determinants for direct lysosomal sorting, endocytosis and, in polarized cells, basolateral targeting. We now characterize the structural requirements in the cytosolic domain required for sorting of lgp120 into the different pathways. Our results show that the cytoplasmic tail is sufficient to mediate direct transport from the trans-Golgi network (TGN) to lysosomes and that a G7-Y8-X-X-I11 motif is crucial for this sorting event. While G7 is only critical for direct lysosomal sorting in the TGN, Y8 and I11 are equally important for lysosomal sorting, endocytosis, and basolateral targeting. Thus, a small motif of five amino acids in the cytoplasmic tail of lgp120 can be recognized by the sorting machinery at several cellular locations and direct the protein into a variety of intracellular pathways. PMID- 7844147 TI - Glycosyl phosphatidylinositol-dependent cross-linking of alpha-agglutinin and beta 1,6-glucan in the Saccharomyces cerevisiae cell wall. AB - The cell adhesion protein alpha-agglutinin is bound to the outer surface of the Saccharomyces cerevisiae cell wall and mediates cell-cell contact in mating. alpha-Agglutinin is modified by addition of a glycosyl phosphatidylinositol (GPI) anchor as it traverses the secretory pathway. The presence of a GPI anchor is essential for cross-linking into the wall, but the fatty acid and inositol components of the anchor are lost before cell wall association (Lu, C.-F., J. Kurjan, and P. N. Lipke, 1994. A pathway for cell wall anchorage of Saccharomyces cerevisiae alpha-agglutinin. Mol. Cell. Biol. 14:4825-4833). Cell wall association of alpha-agglutinin was accompanied by an increase in size and a gain in reactivity to antibodies directed against beta 1,6-glucan. Several kre mutants, which have defects in synthesis of cell wall beta 1,6-glucan, had reduced molecular size of cell wall alpha-agglutinin. These findings demonstrate that the cell wall form of alpha-agglutinin is covalently associated with beta 1,6-glucan. The alpha-agglutinin biosynthetic precursors did not react with antibody to beta 1,6-glucan, and the sizes of these forms were unaffected in kre mutants. A COOH-terminal truncated form of alpha-agglutinin, which is not GPI anchored and is secreted into the medium, did not react with the anti-beta 1,6 glucan. We propose that extracellular cross-linkage to beta 1,6-glucan mediates covalent association of alpha-agglutinin with the cell wall in a manner that is dependent on prior addition of a GPI anchor to alpha-agglutinin. PMID- 7844148 TI - Differential localization and functional role of calsequestrin in growing and differentiated myoblasts. AB - Calsequestrin (CSQ) is the low affinity, high capacity Ca(2+)-binding protein concentrated within specialized areas of the muscle fiber sarcoplasmic reticulum (a part of the ER) where it is believed to buffer large amounts of Ca2+. Upon activation of intracellular channels this Ca2+ pool is released, giving rise to the [Ca2+]i increases that sustain contraction. In order to investigate the ER retention and the functional role of the protein, L6 rat myoblasts were infected with a viral vector with or without the cDNA of chicken CSQ, and stable clones were investigated before and after differentiation to myotubes. In the undifferentiated L6 cells, expression of considerable amounts of heterologous CSQ occurred with no major changes of other ER components. Ca2+ release from the ER, induced by the peptide hormone vasopressin, remained however unchanged, and the same occurred when other treatments were given in sequence to deplete the ER and other intracellular stores: with the Ca2+ pump blocker, thapsigargin; and with the Ca2+ ionophore, ionomycin, followed by the Na+/H+ ionophore, monensin. The lack of effect of CSQ expression on the vasopressin-induced [Ca2+]i responses was explained by immunocytochemistry showing the heterologous protein to be localized not in the ER but in large vacuoles of acidic content, positive also for the lysosomal enzyme, cathepsin D, corresponding to a lysosomal subpopulation. After differentiation, all L6 cells expressed small amounts of homologous CSQ. In the infected cells the heterologous protein progressively decreased, yet the [Ca2+]i responses to vasopressin were now larger with respect to both control and undifferentiated cells. This change correlated with the drop of the vacuoles and with the accumulation of CSQ within the ER lumen, where a clustered distribution was observed as recently shown in developing muscle fibers. These results provide direct evidence for the contribution of CSQ, when appropriately retained, to the Ca2+ capacity of the rapidly exchanging, ER-located Ca2+ stores; and for the existence of specific mechanism(s) (that in L6 cells develop in the course of differentiation) for the ER retention of the protein. In the growing L6 myoblasts the Ca(2+)-binding protein appears in contrast to travel along the exocytic pathway, down to post-Golgi, lysosome-related vacuoles which, based on the lack of [Ca2+]i response to ionomycin-monensin, appear to be incompetent for Ca2+ accumulation. PMID- 7844149 TI - Mechanical function of dystrophin in muscle cells. AB - We have directly measured the contribution of dystrophin to the cortical stiffness of living muscle cells and have demonstrated that lack of dystrophin causes a substantial reduction in stiffness. The inferred molecular structure of dystrophin, its preferential localization underlying the cell surface, and the apparent fragility of muscle cells which lack this protein suggest that dystrophin stabilizes the sarcolemma and protects the myofiber from disruption during contraction. Lacking dystrophin, the muscle cells of persons with Duchenne muscular dystrophy (DMD) are abnormally vulnerable. These facts suggest that muscle cells with dystrophin should be stiffer than similar cells which lack this protein. We have tested this hypothesis by measuring the local stiffness of the membrane skeleton of myotubes cultured from mdx mice and normal controls. Like humans with DMD mdx mice lack dystrophin due to an x-linked mutation and provide a good model for the human disease. Deformability was measured as the resistance to indentation of a small area of the cell surface (to a depth of 1 micron) by a glass probe 1 micron in radius. The stiffness of the membrane skeleton was evaluated as the increment of force (mdyne) per micron of indentation. Normal myotubes with an average stiffness value of 1.23 +/- 0.04 (SE) mdyne/micron were about fourfold stiffer than myotubes cultured from mdx mice (0.34 +/- 0.014 mdyne/micron). We verified by immunofluorescence that both normal and mdx myotubes, which were at a similar developmental stage, expressed sarcomeric myosin, and that dystrophin was detected, diffusely distributed, only in normal, not in mdx myotubes. These results confirm that dystrophin and its associated proteins can reinforce the myotube membrane skeleton by increasing its stiffness and that dystrophin function and, therefore, the efficiency of therapeutic restoration of dystrophin can be assayed through its mechanical effects on muscle cells. PMID- 7844150 TI - Syntrophin binds to an alternatively spliced exon of dystrophin. AB - Dystrophin, the protein product of the Duchenne muscular dystrophy locus, is a protein of the membrane cytoskeleton that associates with a complex of integral and membrane-associated proteins. Of these, the 58-kD intracellular membrane associated protein, syntrophin, was recently shown to consist of a family of three related but distinct genes. We expressed the cDNA of human beta 1 syntrophin and the COOH terminus of human dystrophin in reticulocyte lysates using an in vitro transcription/translation system. Using antibodies to dystrophin we immunoprecipitated these two interacting proteins in a variety of salt and detergent conditions. We demonstrate that the 53 amino acids encoded on exon 74 of dystrophin, an alternatively spliced exon, are necessary and sufficient for interaction with translated beta 1-syntrophin in our assay. On the basis of its alternative splicing, dystrophin may thus be present in two functionally distinct populations. In this recombinant expression system, the dystrophin relatives, human dystrophin related protein (DRP or utrophin) and the 87K postsynaptic protein from Torpedo electric organ, also bind to translated beta 1-syntrophin. We have found a COOH-terminal 37-kD fragment of beta 1 syntrophin sufficient to interact with translated dystrophin and its homologues, suggesting that the dystrophin binding site on beta 1-syntrophin occurs on a region that is conserved among the three syntrophin homologues. PMID- 7844151 TI - Mammalian alpha 1- and beta 1-syntrophin bind to the alternative splice-prone region of the dystrophin COOH terminus. AB - The carboxy-terminal region of dystrophin has been suggested to be crucially important for its function to prevent muscle degeneration. We have previously shown that this region is the locus that interacts with the sarcolemmal glycoprotein complex, which mediates membrane anchoring of dystrophin, as well as with the cytoplasmic peripheral membrane protein, A0 and beta 1-syntrophin (Suzuki, A., M. Yoshida, K. Hayashi, Y. Mizuno, Y. Hagiwara, and E. Ozawa. 1994. Eur. J. Biochem. 220:283-292). In this work, by using the overlay assay technique developed previously, we further analyzed the dystrophin-syntrophin/A0 interaction. Two forms of mammalian syntrophin, alpha 1- and beta 1-syntrophin, were found to bind to very close but discrete regions on the dystrophin molecule. Their binding sites are located at the vicinity of the glycoprotein-binding site, and correspond to the amino acid residues encoded by exons 73-74 which are alternatively spliced out in some isoforms. This suggests that the function of syntrophin is tightly linked to the functional diversity among dystrophin isoforms. Pathologically, it is important that the binding site for alpha 1 syntrophin, which is predominantly expressed in skeletal muscle, coincides with the region whose deletion was suggested to result in a severe phenotype. In addition, A0, a minor component of dystrophin-associated proteins with a molecular mass of 94 kD which is immunochemically related to syntrophin, binds to the same site as beta 1-syntrophin. Finally, based on our accumulated evidence, we propose a revised model of the domain organization of dystrophin from the view point of protein-protein interactions. PMID- 7844152 TI - Tropomyosin is essential in yeast, yet the TPM1 and TPM2 products perform distinct functions. AB - Sequence analysis of chromosome IX of Saccharomyces cerevisiae revealed an open reading frame of 166 residues, designated TPM2, having 64.5% sequence identity to TPM1, that encodes the major form of tropomyosin in yeast. Purification and characterization of Tpm2p revealed a protein with the characteristics of a bona fide tropomyosin; it is present in vivo at about one sixth the abundance of Tpm1p. Biochemical and sequence analysis indicates that Tpm2p spans four actin monomers along a filament, whereas Tpmlp spans five. Despite its shorter length, Tpm2p can compete with Tpm1p for binding to F-actin. Over-expression of Tpm2p in vivo alters the axial budding of haploids to a bipolar pattern, and this can be partially suppressed by co-over-expression of Tpm1p. This suggests distinct functions for the two tropomyosins, and indicates that the ratio between them is important for correct morphogenesis. Loss of Tpm2p has no detectable phenotype in otherwise wild type cells, but is lethal in combination with tpm1 delta. Over expression of Tpm2p does not suppress the growth or cell surface targeting defects associated with tpm1 delta, so the two tropomyosins must perform an essential function, yet are not functionally interchangeable. S. cerevisiae therefore provides a simple system for the study of two tropomyosins having distinct yet overlapping functions. PMID- 7844153 TI - Both synchronous and asynchronous muscle isoforms of projectin (the Drosophila bent locus product) contain functional kinase domains. AB - In Drosophila, the large muscle protein, projectin, has very different localizations in synchronous and asynchronous muscles, suggesting that projectin has different functions in different muscle types. The multiple projectin isoforms are encoded by a single gene; however they differ significantly in size (as detected by gel mobility) and show differences in some peptide fragments, presumably indicating alternative splicing or termination. We now report additional sequence of the projectin gene, showing a kinase domain and flanking regions highly similar to equivalent regions of twitchin, including a possible autoinhibitory region. In spite of apparent differences in function, all isoforms of projectin have the kinase domain and all are capable of autophosphorylation in vitro. The projectin gene is in polytene region 102C/D where the bentD phenotype maps. The recessive lethality of bentD is associated with a breakpoint that removes sequence of the projectin kinase domain. We find that different alleles of the highly mutable recessive lethal complementation group, l(4)2, also have defects in different parts of the projectin sequence, both NH2-terminal and COOH terminal to the bentD breakpoint. These alleles are therefore renamed as alleles of the bent locus. Adults heterozygous for projectin mutations show little, if any, effect of one defective gene copy, but homozygosity for any of the defects is lethal. The times of death can vary with allele. Some alleles kill the embryos, others are larval lethal. These molecular studies begin to explain why genetic studies suggested that l(4)2 was a complex (or pseudoallelic) locus. PMID- 7844154 TI - A MAP kinase necessary for receptor-mediated activation of adenylyl cyclase in Dictyostelium. AB - Analysis of a developmental mutant in Dictyostelium discoideum which is unable to initiate morphogenesis has shown that a protein kinase of the MAP kinase/ERK family affects relay of the cAMP chemotactic signal and cell differentiation. Strains in which the locus encoding ERK2 is disrupted respond to a pulse of cAMP by synthesizing cGMP normally but show little synthesis of cAMP. Since mutant cells lacking ERK2 contain normal levels of both the cytosolic regulator of adenylyl cyclase (CRAC) and manganese-activatable adenylyl cyclase, it appears that this kinase is important for receptor-mediated activation of adenylyl cyclase. PMID- 7844155 TI - LAR tyrosine phosphatase receptor: alternative splicing is preferential to the nervous system, coordinated with cell growth and generates novel isoforms containing extensive CAG repeats. AB - Receptor-linked tyrosine phosphatases regulate cell growth by dephosphorylating proteins involved in tyrosine kinase signal transduction. The leukocyte common antigen-related (LAR) tyrosine phosphatase receptor has sequence similarity to the neural cell adhesion molecule N-CAM and is located in a chromosomal region (1p32-33) frequently altered in neuroectodermal tumors. To understand the function of receptor-linked tyrosine phosphatases in neural development, we sought to identify LAR isoforms preferentially expressed in the nervous system and cellular processes regulating LAR alternative splicing. We report here the isolation of a series of rat LAR cDNA clones arising from complex combinatorial alternative splicing, not previously demonstrated for the tyrosine phosphatase receptor gene family in general. Isoforms included: (a) deletions of the fourth, sixth and seventh fibronectin type III-like domains; (b) an alternatively spliced novel cassette exon in the fifth fibronectin type III-like domain; (c) two alternatively spliced novel cassette exons in the juxtamembrane region; (d) a retained intron in the extracellular region with in-frame stop codons predicting a secreted LAR isoform; and (e) an LAR transcript including an alternative 3' untranslated region containing multiple stretches of tandem CAG repeats up to 21 repeats in length. This number of repeats was in the range found in normal alleles of genes in which expansions of repeats are associated with neurodegenerative disease and the genetic phenomenon of anticipation. RT-PCR and Northern analysis demonstrated that LAR alternative splicing occurred preferentially in neuromuscular tissue in vivo and in neurons compared to astrocytes in vitro and was developmentally regulated. Alternative splicing was also regulated in PC12 cells by NGF, in 3T3 fibroblasts by cell confluence and in sciatic nerve and muscle subsequent to nerve transection. Western blot analysis demonstrated that alternatively spliced cassette exons result in the presence of corresponding amino acid segments of LAR protein in vivo. These studies suggest specialized functions of LAR isoforms in the nervous system and support our hypothesis that LAR-like tyrosine phosphatase receptors play a role in neural development and regeneration. PMID- 7844156 TI - Transforming growth factor-alpha and beta-amyloid precursor protein share a secretory mechanism. AB - Cleavage and release of membrane protein ectodomains, a regulated process that affects many cell surface proteins, remains largely uncharacterized. To investigate whether cell surface proteins are cleaved through a shared mechanism or through multiple independent mechanisms, we mutagenized Chinese hamster ovary (CHO) cells and selected clones that were unable to cleave membrane-anchored transforming growth factor alpha (TGF-alpha). The defect in TGF-alpha cleavage in these clones is most apparent upon cell treatment with the protein kinase C (PKC) activator PMA, which stimulates TGF-alpha cleavage in wild-type cells. The mutant clones do not have defects in TFG-alpha expression, transport to the cell surface or turnover. Concomitant with the loss of TGF-alpha cleavage, these clones have lost the ability to cleave many structurally unrelated membrane proteins in response to PMA. These proteins include beta-amyloid precursor protein (beta APP), whose cleavage into a secreted form avoids conversion into the amyloidogenic peptide A beta, and a group of cell surface proteins whose release into the medium is stimulated by PMA in wild type CHO cells but not in mutants. The mutations prevent cleavage by PKC-dependent as well as PKC-independent mechanisms, and thus affect an essential component that functions downstream of these various signaling mechanisms. We propose that regulated cleavage and secretion of membrane protein ectodomains is mediated by a common system whose components respond to multiple activators and act on susceptible proteins of diverse structure and function. PMID- 7844157 TI - Cell growth-promoting activity of tissue inhibitor of metalloproteinases-2 (TIMP 2). AB - Human tissue inhibitor of metalloproteinases-2 (TIMP-2) has a potent growth promoting activity for wide range of human, bovine and mouse cells, having an optimal concentration (10 ng/ml, 0.46 nM) that is ten-times lower than that of TIMP-1 (Hayakawa et al. (1992) FEBS Lett. 298, 29). Neither TIMP-1 complexed with progelatinase B nor TIMP-2 complexed with progelatinase A, both of which have full inhibitory activity against active forms of matrix metalloproteinases (MMPs), showed any cell growth-promoting activity. On the contrary, both reductively alkylated TIMPs had no MMP inhibitory activity, but significantly stimulated cell proliferation. These facts clearly indicate that the cell proliferation. These facts clearly indicate that the cell-proliferating activity of TIMPs is independent of MMP inhibitory activity. We also demonstrated that [3H]thymidine was significantly incorporated into Raji cells, a Burkitt lymphoma cell line, in the presence of either 4 ng/ml of TIMP-1 or 0.1 ng/ml of TIMP-2. Under steady-state conditions at 4 degrees C, high-(Kd = 0.15 nM) and low-(35 nM) affinity binding sites for TIMP-2 were identified on Raji cells with 20,000 and 1.4 x 10(5) sites/cell, respectively. Both high- and low-affinity binding of 125I TIMP-2 to Raji cells were competitively inhibited by unlabeled TIMP-2 but not by unlabeled TIMP-1, suggesting the presence of receptors for TIMP-2 independent from those for TIMP-1. TIMP-2 seems to be another new TIMP cell-growth factor in serum, besides TIMP-1. PMID- 7844158 TI - Characterization of very acidic phagosomes in breast cancer cells and their association with invasion. AB - Human metastatic breast cancer cells in culture contain large acidic vesicles (diameter 5-10 microns) in which endocytosed extracellular matrix can be digested by activated lysosomal proteinases such as cathepsin D (P. Montcourrier et al. (1990). Cancer Res. 50, 6045-6054). We examined these large compartments by transmission electron microscopy, measured their pH by video-enhanced epifluorescence using FITC-dextran, and studied their functional significance. Their presence in metastatic MDA-MB231 cells was found to be correlated with an increased ability of cells to migrate through Matrigel and a high cathepsin D concentration. These cells were able to phagocytose 1.24 microns diameter latex beads and fluorescence Matrigel and incorporate this extracellular material into large acidic vesicles. This indicated that large acidic vesicles were associated with both phagocytosis and invasion, and are heterophagolysosomes rather than autophagosomes. Large acidic vesicles were actively acidified with a H(+)-ATPase vacuolar pump specifically inhibited by bafilomycin A1, and reached pH values (< 4), lower than the lysosomal value (pH approximately 5) in the same cells and in specialized phagocytotic cells such as macrophages. We conclude that the phagocytotic activity of breast cancer cells, associated with high cathepsin D expression, and high acidification potential, characterize cancer cells that have migrated through Matrigel. PMID- 7844159 TI - Association of the Dictyostelium 30 kDa actin bundling protein with contact regions. AB - 'Contact regions' are plasma membrane domains derived from areas of intercellular contact between aggregating Dictyostelium amebae (H.M. Ingalls et al. (1986). Proc. Nat. Acad. Sci. USA 83, 4779). Purified contact regions contain a prominent actin-binding protein with an M(r) of 34,000. Immunoblotting with monoclonal antibodies identifies this polypeptide as a 34,000 M(r) actin-bundling protein (known as 30 kDa protein), previously shown to be enriched in filopodia (M. Fechheimer (1987). J. Cell Biol. 104, 1539). About four times more 30 kDa protein by mass is associated with contact regions than is found in total plasma membranes isolated from aggregating cells. In agreement with these observations, immunostaining of the 30 kDa protein in aggregating cells reveals a prominent localization along the plasma membrane at sites of intercellular contact. By contrast, alpha-actinin does not appear to be significantly enriched at sites of cell to cell contact. Binding experiments using purified plasma membranes, actin and 30 kDa protein indicate that the 30 kDa protein is associated with the plasma membrane primarily through interactions with actin filaments. Calcium ions are known to decrease the interaction of actin with 30 kDa protein in solution. Surprisingly, membrane-associated complexes of actin and the 30 kDa protein are much less sensitive to dissociation by micromolar levels of free calcium ions than are complexes in solutions lacking membranes.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7844160 TI - NSP-encoded reticulons, neuroendocrine proteins of a novel gene family associated with membranes of the endoplasmic reticulum. AB - The novel NSP gene was previously shown to encode, among a variety of neuroendocrine cell types, two 3'-overlapping transcripts, a 3.4 kb one for NSP-A (776 amino acids) and a 1.8 kb one for NSP-C (208 amino acids). The deduced proteins, which were predicted to possess distinct amino-terminal regions, appeared to exhibit some architectural resemblance to known neuroendocrine proteins. In this paper the biochemical characterization and subcellular localization of the two proteins is addressed. In vitro translation of NSP-A and C RNA produced proteins of about 135 and 23 kDa, respectively. Proteins of similar molecular mass were also detected in immunoprecipitation and western blot analyses of neural and endocrine cells using specific anti-NSP-A or -C antisera; some heterogeneity of NSP-A was observed. NSP-A, but not NSP-C, appeared to be highly phosphorylated and preferentially on serine residues. In immunocytochemical studies, we demonstrated that NSP-A and -C are associated with the endoplasmic reticulum; NSP-A was found to co-localize with SERCA2b, a membrane-associated Ca(2+)-ATPase of the endoplasmic reticulum. In Purkinje cells, we found NSP-immunostaining in the perikaryon, the extensive dendritic tree and the axon, also suggesting association with the smooth endoplasmic reticulum. Biochemical studies of NSP-A provided evidence that NSP-A is strongly associated with microsomal membranes and analysis of deletion mutants of NSP-A revealed that the hydrophobic carboxy-terminal portion of the protein, which is also present in NSP-C, is critical for membrane binding. Through database searches, finally, we found two different NSP-related sequences, one in a sequenced region of human chromosome 19, and the second in a human, pancreatic islet-derived partial cDNA, suggesting that the NSP gene is the prototype of a larger gene family. The results of our studies seem to indicate that the NSP encoded proteins are novel, membrane-anchored components of the endoplasmic reticulum for which we propose the name reticulons. PMID- 7844161 TI - Association of kinesin with the Golgi apparatus in rat hepatocytes. AB - The Golgi apparatus is a dynamic membranous structure, which has been observed to alter its location and morphology during the cell cycle and after microtubule disruption. These dynamics are believed to be supported by a close structural interaction of the Golgi with the microtubule cytoskeleton and associated motor enzymes. One microtubule-dependent motor enzyme, kinesin, has been implicated in Golgi movement and function although direct evidence supporting this interaction is lacking. In this study, we utilized two well-characterized kinesin antibodies in conjunction with subcellular fractionation techniques, immunoblot analysis and immunofluorescence microscopy to conduct a detailed study on the association of kinesin with the Golgi and other membranous organelles in a polarized epithelial cell, the primary rat hepatocyte. We found that kinesin represents approximately 0.3% of total protein in rat liver homogenates, with approximately 30% membrane associated and the remainder in the cytosol. Among membrane fractions, kinesin was concentrated markedly in Golgi-enriched fractions, which were prepared using two independent techniques. Kinesin was also abundant in fractions enriched in transcytotic carriers and secretory vesicles, with lower levels detected on fractions enriched in endosomes, endoplasmic reticulum, lysosomes and mitochondria. Immunofluorescence microscopy showed that kinesin is concentrated on Golgi-like structures in both primary cultured hepatocytes and rat hepatocyte derived clone 9 cells. Double-label immunofluorescence demonstrated that kinesin staining colocalizes with the Golgi marker, alpha-mannosidase II, in both cell types. These results provide compelling evidence showing that kinesin is associated with the Golgi complex in cells and implicate this motor enzyme in Golgi structure, function and dynamics. PMID- 7844162 TI - Imaging subcellular structures of rat mammary carcinoma cells by scanning force microscopy. AB - Scanning force microscopy (SFM) was used for imaging subcellular structures of cultured rat mammary carcinoma cells dried in air. Identification of cellular substructures was achieved by immunofluorescence and specific fluorescence probes. Cells grown attached to a glass support exhibited submicrometer thickness in the dried state. Inside the nuclear domain the nucleoli appeared as prominent conical protrusions. Membrane extensions, microspikes and microvilli were well preserved at the cell periphery after fixation in glutaraldehyde vapor and air drying and were distinguishable either as isolated elements or intercellular communications. The plasma membrane and soluble proteins were selectively removed with nonionic detergent in a buffer system. The mitochondria were concentrated primarily in the perinuclear space and exhibited a well defined filamentous shape. Their identity was confirmed by specific fluorescence staining with rhodamine 123. In the membrane-free system achieved by dry-cleaving of the sample surface, the cytoskeletal network was resolved as a complex mesh of actin containing fiber bundles interwoven with a filigree arrangement of thinner filaments. The smallest fibrous substructures revealed by SFM with the scanning tips used to date were approximately 8 to 10 nm in height and 80 nm in width. PMID- 7844163 TI - Platelet-derived growth factor is an autocrine growth stimulator in retinal pigmented epithelial cells. AB - The retinal pigmented epithelium (RPE) plays a major role in normal and exaggerated retinal wound repair; the latter can result in epiretinal membrane formation and loss of vision. The RPE forms a stable monolayer of highly differentiated cells that proliferates only during wound repair. The mechanism underlying the change to the proliferating phenotype is unknown. When grown on a plastic substratum, cultured RPE cells mimic the proliferating phenotype in situ; they escape density arrest and proliferate in serum-free medium. In this study, we have demonstrated that a platelet-derived growth factor (PDGF) autocrine loop is involved in RPE growth in serum-free medium, because: (1) RPE cells secrete PDGF into their media and express PDGF receptors; (2) the PDGF receptors on RPE cells are autophosphorylated in serum-free medium and suramin, an agent that displaces PDGF and other growth factors from their receptors, blocks the autophosphorylation; and (3) a neutralizing antibody to PDGF significantly decreases RPE growth in serum-free medium. When a linear scrape is made in an RPE monolayer, the cells migrate and proliferate to fill in the gap mimicking wound repair in situ. Cells along the edge of the scrape show increased expression of PDGF and PDGF-beta receptors, and increased staining for proliferating cell nuclear antigen. Immunohistochemistry and in situ hybridization demonstrate expression of PDGF in ganglion cells and cells of retinal blood vessels. PDGF is not detected in the outer retina or RPE in untreated eyes, but is detected in RPE participating in wound repair, either adjacent to laser burns or underlying retinal detachment. PDGF and PDGF receptors are also expressed in RPE in epiretinal membranes removed during vitreous surgery. These data suggest that PDGF is an autocrine stimulator of growth in RPE that plays a role in retinal wound repair and epiretinal membrane formation. PMID- 7844164 TI - Surface antigens of Leishmania mexicana amastigotes: characterization of glycoinositol phospholipids and a macrophage-derived glycosphingolipid. AB - Amastigotes of the protozoan parasite Leishmania proliferate in phagolysosomes of macrophages. They abundantly express glycoinositol phospholipids (GIPLs), which are considered necessary for parasite survival by providing a shield at the surface against lysosomal hydrolases and by serving as receptors for the interaction with host cells. The structures of four GIPLs of L. mexicana amastigotes were characterized by a combination of gas-liquid chromatography-mass spectrometry, methylation linkage analysis and enzymatic treatments. They contain the glycan structures Man alpha 1-3Man alpha 1-4GlcN (iM2), Man alpha 1-6(Man alpha 1-3)Man alpha 1-4GlcN (iM3), Man alpha 1-2Man alpha 1-6(Man alpha 1-3)-Man alpha 1-4GlcN (iM4) and (NH2-CH2CH2-PO4)Man alpha 1-6(Man alpha 1-3)Man alpha 1 4GlcN (EPiM3), which are linked to alkylacyl-phosphatidylinositol. The predominant amastigote GIPL, EPiM3 (approximately 2 x 10(7) molecules/cell), is located at the parasite cell surface, in the flagellar pocket and in lysosomal membranes, but not on host cell structures as shown by immunofluorescence and immunoelectron microscopy. In addition, amastigotes in infected Balb/c mice contain a glycolipid with similar distribution as EPiM3, which has the same characteristics as the Forssman antigen of mammalian cells. In contrast to EPiM3, there is strong evidence that this glycosphingolipid is not synthesized by amastigotes but by macrophages in the lesion. This suggests a mechanism of lipid transfer from the macrophage to the parasite. PMID- 7844165 TI - Formation of high molecular mass DNA fragments is a marker of apoptosis in the human leukaemic cell line, U937. AB - Inhibitors of macromolecular synthesis and topoisomerases induce apoptosis in the human leukaemic cell line, U937. In this study, U937 cells were treated with the RNA synthesis inhibitor, actinomycin D (1 microM), the protein synthesis inhibitors, emetine (1 microM) and cycloheximide (100 microM), the topoisomerase II inhibitor, teniposide (5 microM), or the topoisomerase I inhibitor, camptothecin (1 microM). Apoptotic cell death was assessed both by flow cytometry and agarose gel electrophoresis, and was correlated to the appearance of large (20 to > or = 580 kilobase pairs) DNA fragments, as assessed by field inversion gel electrophoresis. In all cases, the appearance of DNA fragments of 20-50 kilobase pairs accompanied the appearance of an apoptotic population and of internucleosomal cleavage. However, teniposide additionally induced a marked increase in fragmentation to > or = 580 kilobase pairs. The cotreatment of cells with zinc (1 mM) inhibited the formation of all large DNA fragments, internucleosomal cleavage and the appearance of an apoptotic population. We conclude that the generation of large DNA fragments is characteristic of apoptosis induced by various stimuli in U937, as has been found previously in rat thymocytes. However, unlike what occurs in rat thymocytes, zinc treatment does not dissociate the formation of large fragments from conventional markers of apoptosis. PMID- 7844166 TI - Ca2+ signaling in the Chlamydomonas flagellar regeneration system: cellular and molecular responses. AB - In response to certain extracellular stimuli, Chlamydomonas reinhardtii cells excise their flagella, induce expression of more than 200 different flagellar mRNAs, and assemble a new flagellar pair. Normally, flagellar excision, gene induction and outgrowth are tightly coupled temporally. Our previous studies showed that uncoupling the cellular response of flagellar excision from flagellar outgrowth resulted in submaximal flagellar gene induction, and led us to propose that normal flagellar gene induction is a composite response. The present study extends these observations by measuring flagellar gene induction in Chlamydomonas cells stimulated under conditions where both flagellar excision and flagellar outgrowth are blocked. We find that the flagellar genes are induced in a Ca(2+) dependent manner in response to stimulation in the absence of flagellar excision and outgrowth. Flagellar gene induction is therefore independent of flagellar excision and outgrowth but sensitive to extracellular Ca2+ levels. Thus, flagellar excision, flagellar outgrowth and flagellar gene induction are three responses to a common stimulus that are related by their requirement for extracellular Ca2+. PMID- 7844167 TI - Astrocytes modulate retinal vasculogenesis: effects on fibronectin expression. AB - Vasculogenesis is the formation of blood-vessels by differentiation of vascular precursor cells. Experiments using retinal models were designed to test the hypothesis that astrocytes influence this process by effects on the composition of the extracellular matrix. Retinal vasculogenesis was studied in relation to the migration of astrocytes and expression of the extracellular matrix proteins laminin and fibronectin by in vivo experiments in neonatal rats. The results show that astrocytes spread into the retina just ahead of the newly formed vessels, where they probably initiate vasculogenesis. They also establish that fibronectin, but not laminin, is expressed in the zone of vasculogenesis immediately prior to vessel formation. Increased amounts of fibronectin mRNA indicate that fibronectin is synthesized by cells within this same region during this same time period. Later, as the new vessels form, differentiation of endothelial cells is correlated with the appearance of pericytes in the vessel wall and laminin in the vascular basement membrane. In vitro experiments using conditioned medium approaches showed that astrocytes stimulate endothelial cell fibronectin expression. Taken together with the in vivo observations these in vitro results suggest that fibronectin expression is an essential component in the initiation of retinal vasculogenesis. This study is the first indication that astrocytes influence the fibronectin component of the extracellular matrix during retinal vasculogenesis and that expression of fibronectin precedes that of laminin in this process. PMID- 7844168 TI - Ezrin has properties to self-associate at the plasma membrane. AB - Ezrin, a member of a family of proteins involved in the interaction of the microfilament cytoskeleton with the plasma membrane, plays a role in membrane translocation in gastric parietal cells (Hanzel, D., Reggio, H., Bretscher, A., Forte, J. G. and Mangeat, P. (1991). EMBO J. 10, 2363-2373). Human ezrin was expressed in and purified from Escherichia coli. It possesses all the major biophysical, immunological and physiological properties of natural ezrin. Upon microinjection in live gastric HGT-1 cells, ezrin was incorporated into the dorsal microvilli, a site where the endogeneous protein is localized. By coimmunoprecipitation and ezrin-affinity assays, two HGT-1 cell proteins of 77 and 72 kDa behaved as ezrin-binding proteins. In enriched gastric apical membranes, 125I-ezrin labelled proteins of 80, 77 and 72 kDa by overlay assay. The 80 kDa protein was identified as ezrin and the 77 and 72 kDa proteins as gastric forms of proteins structurally related to ezrin, such as radixin and moesin. In insect cells infected with a recombinant baculovirus, one-third of over-expressed ezrin accumulated at the plasma membrane. Ezrin bound a 77 kDa endogenous peripheral membrane protein, behaving as an insect counterpart of the mammalian ezrin family. In addition to the respective role of the amino- and carboxyl-terminal domains of ezrin in linking the membrane and the cytoskeleton (Algrain, M., Turunen, O., Vaheri, A., Louvard, D. and Arpin, M. (1993). J. Cell Biol. 120, 129-139), both domains interacted synergistically in a salt-dependent manner to trigger self-association of ezrin. Ezrin's self-association properties could represent another way of regulating the number of ezrin molecules bound at specific membrane sites. PMID- 7844169 TI - Control of stable lamellipodia formation by expression of cell surface beta 1,4 galactosyltransferase cytoplasmic domains. AB - Mesenchymal cell migration on basal lamina is mediated, in part, by the binding of cell surface beta 1,4-galactosyltransferase (GalTase) to specific N-linked oligosaccharides in the E8 domain of laminin. On migrating cells, surface GalTase is anchored to the cytoskeleton; when GalTase is prevented from associating with the cytoskeleton, lamellipodia formation and subsequent migration are inhibited. To define better the involvement of GalTase-cytoskeleton interactions in cell motility, we examined the lamellipodia formation, polarity and migratory behavior of stably transfected 3T3 fibroblasts expressing increased or decreased levels of GalTase capable of interacting with the cytoskeleton. Initially, the motile behavior of individual cells was quantified in the absence of exogenous stimuli. Cells that overexpress GalTase binding sites for the cytoskeleton changed their polarity more frequently and translocated more erratically than did control cells when assayed on laminin substrata. These differences were not observed, however, when cells were plated on fibronectin, which does not contain binding sites for surface GalTase. GalTase-transfected cells were also assayed for their ability to polarize in response to a specific stimulus. In this case, the ability of a cell to reorient towards a gradient of platelet-derived growth factor was found to be directly proportional to the amount of GalTase associated with the cytoskeleton. Differences in response to platelet-derived growth factor were not due to differences in growth factor binding. Indirect immunofluorescence showed that altering the level of GalTase did not affect the ventrally distributed pool of GalTase stably associated with the cytoskeleton; however, stress fiber formation was inhibited. Thus, increasing surface GalTase binding sites for the cytoskeleton leads to erratic, multipolar behavior in the absence of any vectorial stimulus, but the ability to form a functional lamellipodium in response to a stimulus is dependent upon the amount of surface GalTase associated with the cytoskeleton. Apparently, cells are able to regulate cytoskeletal assembly and lamellipodial stability by altering the expression and/or affinity of appropriate matrix receptors, such as GalTase, and their corresponding binding sites in the cytoskeleton. PMID- 7844170 TI - Inhibition of apical but not basolateral endocytosis of ricin and folate in Caco 2 cells by cytochalasin D. AB - Apical and basolateral endocytic pathways in polarised Caco-2 cells were investigated by following the uptake, recycling and transcytosis of the galactose binding protein toxin ricin, as a membrane marker. Differences in the extent and kinetics of lectin uptake, recycling and transcytosis were observed at the apical and basolateral domains and altered with the age of the cell monolayer. Treatment of polarised Caco-2 cells with cytochalasin D showed a domain-specific, concentration-dependent inhibition of apical endocytosis of ricin. Inhibition of apical endocytosis by cytochalasin D was not due to a gross change in brush border morphology, although actin stress fibres within the cell body were disrupted. It is not clear whether inhibition of apical endocytosis in polarized epithelial cells by cytochalasin D is caused simply by disruption of a mechanochemical motor involving microvillar actin filaments. The cytochalasin D effect was also observed when measuring uptake of folate, suggesting apical domain-specific inhibition of caveolar, as well as clathrin-mediated, endocytic routes. PMID- 7844171 TI - LFA-1 integrin redistribution during T-cell hybridoma invasion of hepatocyte cultures and manganese-induced adhesion to ICAM-1. AB - We have reported previously that the integrin LFA-1 is essential for metastasis of T-cell hybridomas to the liver. We show here that hepatocytes isolated from normal non-inflamed rat liver express intercellular adhesion molecule-1 (ICAM-1) at the dorsal surface and more prominently at the lateral and substratum-adherent surfaces. Anti-rat ICAM-1 mAb inhibited adhesion of TAM8C4 T-cell hybridoma cells to hepatocytes. Invasion between hepatocytes was not affected, but this is probably due to lack of penetration of the mAb between the hepatocytes. In all hepatocyte-adherent TAM8C4 cells, LFA-1 was concentrated at the adhesion site. Redistribution of ICAM-1 to the interacting hepatocyte membrane was also seen, but only for part of the adherent TAM8C4 cells. LFA-1 was highly concentrated on pseudopods of invading TAM8C4 cells inserted between hepatocytes, and on the upper surface of invaded TAM8C4 cells located under the hepatocytes. ICAM-1 was concentrated in the hepatocyte membrane overlying TAM8C4 cells located underneath the monolayer. These results suggests that ICAM-1 is of major importance for liver invasion by these lymphoma cells. For optimal adhesion to ICAM-1, LFA-1 on T-cell hybridomas requires activation, which apparently occurs upon contact with cell layers that are invaded (G. La Riviere et al., J. Cell Sci. 107, 551-559, 1994). LFA-1 can be activated artificially by Mn2+. To study LFA-1 redistribution upon ICAM-1 interaction with higher resolution, we performed immuno-EM on cells before and after Mn(2+)-induced adhesion and spreading on immobilized ICAM-1. By immune fluorescence, LFA-1 was observed to redistribute to the ICAM-1-adherent surface, and to be concentrated in lamellipodia of spreading TAM8C4 cells. By immuno-EM, LFA-1 was localized in microclusters of approximately 10 gold particles. This was seen in cells fixed in suspension, and the size of these clusters did not change upon adhesion to ICAM-1. LFA-1 was present at high density in thin filopodia, but again in microclusters of similar size. Comparable results were obtained with a cytotoxic T-cell clone. We conclude that Mn(2+) induced activation of LFA-1 is not associated with the formation or enlargement of LFA-1 clusters. PMID- 7844172 TI - The PsB glycoprotein complex is secreted as a preassembled precursor of the spore coat in Dictyostelium discoideum. AB - The PsB glycoprotein in Dictyostelium discoideum is one of a diverse group of developmentally regulated, prespore-cell-specific proteins, that contain a common O-linked oligosaccharide. This post-translational modification is dependent on the wild-type modB allele. The PsB protein exists as part of a multiprotein complex of six different proteins, which have different post-translational modifications and are held together by both covalent and non-covalent interactions (Watson et al. (1993). J. Biol. Chem. 268, 22634-22641). In this study we have used microscopic and biochemical analyses to examine the cellular localization and function of the PsB complex during development. We found that the PsB complex first accumulates in prespore vesicles in slug cells and is secreted later during culmination and becomes localized to both the extracellular matrix of the apical spore mass of mature fruiting bodies and to the inner layer of the spore coat. The PsB associated with the spore coat is covalently bound by disulfide bridges. The PsB protein always exists in a multiprotein complex, but the composition of the PsB complex changes during secretion and spore maturation. Some of the PsB complex proteins have been identified as spore coat proteins. These data demonstrate that some of the proteins that form the spore coat exist as a preassembled precursor complex. The PsB complex is secreted in a developmentally regulated manner during the process of spore differentiation, at which time proteins of the complex, as well as additional spore coat proteins, become covalently associated in at least two forms of extracellular matrix: the interspore matrix and the spore coat. These and other studies show that proteins with modB dependent O-linked oligosaccharides are involved in a wide variety of processes underlying morphogenesis in this organism. These developmental processes are the direct result of cellular mechanisms regulating protein targeting, assembly and secretion, and the assembly of specific extracellular matrices. PMID- 7844173 TI - The heparin-binding domain of heparin-binding EGF-like growth factor can target Pseudomonas exotoxin to kill cells exclusively through heparan sulfate proteoglycans. AB - Heparin-binding EGF-like growth factor (HB-EGF) is a smooth muscle cell mitogen composed of both EGF receptor and heparin-binding domains. To better understand the function of its domains, intact HB-EGF or its heparin-binding (HB) domain (amino acids 1-45) were fused to a mutant Pseudomonas exotoxin with an inactivated cell-binding domain. The resulting chimeric toxins, HB-EGF-PE* and HB PE*, were tested on tumor cells, proliferating smooth muscle cells and a mutant Chinese hamster ovary cell line deficient in heparan sulfate proteoglycans (HSPGs). Two targets were found for HB-EGF-PE*. Cells were killed mainly through EGF receptors, but the HB domain was responsible for killing via HSPGs. HB-PE* did not bind to the EGF receptor and thus was cytotoxic by interacting exclusively with HSPGs. We conclude that the HB domain of HB-EGF is able to mediate internalization through HSPGs, without requiring the EGF receptor. PMID- 7844174 TI - Drosophila mutants in the 55 kDa regulatory subunit of protein phosphatase 2A show strongly reduced ability to dephosphorylate substrates of p34cdc2. AB - The 55 kDa regulatory subunit of Drosophila protein phosphatase 2A is located in the cytoplasm at all cell cycle stages, by the criterion of immunofluorescence. We are unable to detect significant change in protein phosphatase activity during the nuclear division cycle of syncytial embryos. However, cell cycle function of the enzyme is suggested by the mitotic defects exhibited by two Drosophila mutants, aar1 and twinsP, defective in the gene encoding the 55 kDa subunit. The reduced levels of the 55 kDa subunit correlate with the loss of protein phosphatase 2A-like, okadaic acid-sensitive phosphatase activity of brain extracts against caldesmon and histone H1 phosphorylated by p34cdc2/cyclin B kinase, but not against phosphorylase a. Thus the mitotic defects of aar1 and twinsP are likely to result from the lack of dephosphorylation of specific substrates by protein phosphatase 2A. PMID- 7844175 TI - Yeast homolog of mammalian mitogen-activated protein kinase, FUS3/DAC2 kinase, is required both for cell fusion and for G1 arrest of the cell cycle and morphological changes by the cdc37 mutation. AB - Saccharomyces cerevisiae FUS3/DAC2 protein kinase, a homolog of mammalian mitogen activated protein (MAP) kinase, inactivates a G1 cyclin encoded by the CLN3 gene to arrest cell division in the G1 phase and activates a transcriptional factor STE12 in response to mating pheromone during sexual conjugation. To elucidate the role of the FUS3/DAC2 gene product in the mating process, I constructed and characterized dac2 cln3 double mutants. Here, I show that FUS3/DAC2 is required for completion of cell fusion even in the dac2 cln3 double mutants in which the pheromone response is restored, suggesting that FUS3/DAC2 plays a positive role in cell fusion during conjugation. In addition, the cdc dac2 and cdc37 ste double mutants were constructed and investigated for their phenotypes to clarify the relationship between FUS3/DAC2, STE7 or STE11 and CDC gene products (CDC28, 36, 37 and 39). The results indicate that FUS3/DAC2 may act upstream of CDC28 and provide evidence that the G1 arrest and morphological changes conferred by the cdc37 mutation may require FUS3/DAC2 (MAP kinase), STE7(MEK) and STE11 (MEK kinase). PMID- 7844176 TI - Elastin exhibits a distinctive temporal and spatial pattern of distribution in the developing chick limb in association with the establishment of the cartilaginous skeleton. AB - In this work we have analyzed the presence of elastic components in the extracellular matrices of the developing chick leg bud. The distributions of elastin and fibrillin were studied immunohistochemically in whole-mount preparations using confocal laser microscopy. The association of these constituents of the elastic matrix with other components of the extracellular matrix was also studied, using several additional antibodies. Our results reveal the transient presence of an elastin-rich scaffold of extracellular matrix fibrillar material in association with the establishment of the cartilaginous skeleton of the leg bud. The scaffold consisted of elastin-positive fibers extending from the ectodermal surface of the limb to the central cartilage forming regions and between adjacent cartilages. Fibrillin immunolabeling was negative in this fibrillar scaffold while other components of the extracellular matrix including: tenascin, laminin and collagens type I, type III and type VI; appeared codistributed with elastin in some regions of the scaffold. Progressive changes in the spatial pattern of distribution of the elastin-positive scaffold were detected in explant cultures in which one expects a modification in the mechanical stresses of the tissues related to growth. A scaffold of elastin comparable to that found in vivo was also observed in high-density micromass cultures of isolated limb mesodermal cells. In this case the elastic fibers are observed filling the spaces located between the cartilaginous nodules. The fibers become reoriented and attach to the ectodermal basal surface when an ectodermal fragment is located at the top of the growing micromass. Our results suggest that the formation of the cartilaginous skeleton of the limb involves the segregation of the undifferentiated limb mesenchyme into chondrogenic and elastogenic cell lineages. Further, a role for the elastic fiber scaffold in coordinating the size and the spatial location of the cartilaginous skeletal elements within the limb bud is also suggested from our observations. PMID- 7844178 TI - The effects of diazepam on mitosis and the microtubule cytoskeleton. I. Observations on the diatoms Hantzschia amphioxys and Surirella robusta. AB - The effects of diazepam (DZP) on mitosis and the microtubule (MT) cytoskeleton in the live diatoms Hantzschia amphioxys and Surirella robusta were followed using time-lapse video microscopy. Similarly treated cells were fixed and later examined for immunoflouresence staining of MTs or for transmission electron microscopy. DZP treatment (250 microM) had no effect on interphase cells but affected mitosis, resulting in the majority of prometaphase and metaphase chromosomes releasing from one or both spindle poles and collecting irregularly along the central spindle. Chromosomes remaining attached to one pole continued to display slight prometaphase oscillations; however, this activity was never observed in metaphase spindles. Following removal of DZP, some chromosomes still bipolarly attached, immediately released elastically from one pole. Within the first 2 minutes of recovery, all chromosomes recommenced spindle attachment, exhibiting normal prometaphase oscillations and proceeded through mitosis. DZP treatment during anaphase had no detectable effect on chromosome motion or cell cleavage. These results suggest that DZP acts as an anti-MT agent, selectively affecting polar MTs at prophase, prometaphase and metaphase, and thereby weakening kinetochore connection to the poles. From these and other results (unpublished), its mode of action is different to that of most anti-MT agents. PMID- 7844177 TI - The regulated degradation of a 3-hydroxy-3-methylglutaryl-coenzyme A reductase reporter construct occurs in the endoplasmic reticulum. AB - The rate-limiting enzyme in cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, is regulated at a number of levels. One important mechanism is regulation of the half-life of the protein by a controlled proteolytic system. This comes about in response to downstream products of the sterol biosynthetic pathway. Little is known about this system, including where in the cell this regulated degradation occurs. HMG CoA reductase resides in the endoplasmic reticulum. To localize the site of regulated degradation of HMG CoA reductase, we used a construct that fuses the N-terminal membrane-anchoring domain of HMG CoA reductase in-frame with beta-galactosidase as a reporter domain (HM-Gal). HM-Gal has previously been shown to reproduce faithfully the degradative properties of native HMG CoA reductase (Chun et al. (1990) J. Biol. Chem. 265, 22004-22010). CHO cells transfected with DNA encoding HM-Gal were exposed to mevalonic acid, which enhances the rate of HMG CoA reductase degradation several fold, and leads to the reduction of the steady state levels of HM-Gal by 80-90%. To accumulate HMG CoA reductase at the site of degradation, cells were simultaneously treated with N-acetyl-leucyl-leucyl-norleucinal (ALLN), which inhibits the protease responsible for reductase degradation. HM-Gal was localized morphologically by immunofluorescence and biochemically by measuring beta-galactosidase activity in Percoll gradients of cellular homogenates. Using either technique HM-Gal localization was indistinguishable from that of ER markers in both control cells and in cells treated to accumulate HMG CoA reductase at the site of degradation.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7844179 TI - [Obstruction of the small intestine caused by bridles and adherences. Analysis of 157 operated cases]. AB - We retrospectively studied a series of 157 patients who were operated for post operative occlusion of the small bowel. Our aim was to analyze the clinical and operative aspects with particular emphasis of the factors predicting intestinal necrosis. We also reviewed the literature. There were 103 females and 54 males with a mean age of 61 and 51 years respectively (p < 0.01). Patients with neoplasia, hernia or irradiated bowel syndrome were excluded. Perioperative variables were analyzed and compared with the incidence of intestinal necrosis and post-operative morbidity and mortality. Data were compared with the chi 2 test. The most frequent prior surgery was appendectomy (33%) and pelvic operations (25%). The mean latency period was 15 years and 5 patients (3%) developed immediate post-operative occlusion (mean 7 days). The preoperative interval was 24 hours on the average. The pathologies involved were: bridles 48%, bridles + adherences 35%, adherences 17%. No clinical sign could distinguish between these three categories, but strangulation was more frequent in patients with bridles (p < 0.003). The following factors were significantly related to intestinal necrosis: signs of abdominal defence (p < 0.0002), white-cell-count > 16000 (p < 0.002), systolic hypotension (p < 10(-7)) and the lack of a history of occlusion (p < 0.04). Mortality was 6% (all at age > 70 years). Age was the only factor significantly related to morbidity-mortality. Emergency surgery shoulder be performed for patients at risk of intestinal necrosis, especially elderly patients. PMID- 7844180 TI - [Results of vascular repairs in trauma of the femoral veins, iliac veins and the inferior vena cava]. AB - We examined the records of 12 patients operated for lesions of the inferior vena cava, the iliac vein, or the common femoral vein were examined. The results of venous grafts, treatment of the lesions of the posterior inferior vena cava or the supra hepatic vena cava and the permeability after repair of these large vessels was studied. Treatment included simple suture (n = 9), venous patch (lateral iliac vein, n = 1), and venous autografts (common femoral veins, n = 2). For 3 lesions of the posterior or supra-hepatic inferior vena cava, haemostasis was obtain by double clamping (n = 2) or four-way clamping (n = 1) with right hepatectomy. In 9 cases, the patients were followed-up for a mean of 59 months. Morphologic exploration with phlebography (n = 1) or echo-Doppler examination (n = 7) was performed during the follow-up period. There were no post-operative deaths. There were no functional sequellae affecting the lower limbs. In one case, the echo-Doppler examination revealed repermeabilization of a thrombosed lateral iliac vein after simple suture. Lesion repair of large diameter veins with autografts using the internal jugular or internal saphenous vein gave good results. Haemostais of posterior or supra-hepatic lesions to the inferior vena cava was obtained with clamping. In cases with associated hepatic involvement, haemostasis was controlled with a four-way clamp and trans-hepatic access or digitoclasty. Long-term permeability of venous repair was good. PMID- 7844181 TI - [Hepatic tumoral form of bacterial infections. Diagnostic and therapeutic considerations apropos of 3 cases]. AB - When the clinical picture and complementary tests reveal a tumoural formation in the liver suggesting cancer, it is often difficult to diagnose such formations resulting from bacterial infection without surgical exploration. The diagnosis is particularly difficult since exclusive hepatic formations are extremely rare, the latency period is often long and specific markers are often lacking. We observed 3 such cases with local hepatic tumour-like formations due to tuberculosis, brucellosis and actinomycosis. Pathology examination of a liver biopsy can contribute to the diagnosis and avoid unnecessary exploratory laparotomy allowing successful medical treatment. PMID- 7844182 TI - [Incidental discovery of a pseudocyst of the spleen. Possible role of previous pregnancy]. AB - Non-parasite pseudo cysts of the spleen are rarely observed and most often are related to trauma. They can be differentiated from true cysts due to the lack of a true capsule. We incidentally observed a pseudocyst of the spleen which may have been related to pregnancy two years earlier. PMID- 7844183 TI - [Retroperitoneal perforations of the colon. Apropos of 2 cases]. AB - The retroperitoneal perforation of the colon is rare and our observations illustrate its two modes of revelation: a retroperitoneal suppuration; it must be traited quickly in order to decrease the mortality. Note that the abscess of the thigh is exceptional. Retroperitoneal perforations during colonoscopy whose treatment (initially medical) become surgical if there is no clinical improvement. PMID- 7844184 TI - [Appendiceal mucoceles. Pathophysiology and therapeutic indications]. AB - Appendiceal mucoceles (AM) are rare lesions of the appendix, characterized by an accumulation of mucus. Two main pathogenic mechanisms may be invoked to explain their development. Firstly, AM are secondary to an obstruction of the appendiceal lumen for a wide variety of reasons. Secondly, they may be due to tumours of the appendix, whether malignant (cystadenocarcinomas) or benign (cystadenomas), responsible for a hypersecretion of mucus. Intraperitoneal mucinous effusion (IME) develops when appendiceal perforation occurs, especially with malignant AM. We found 13 retention AM and in most a definite obstructive lesion was present. There were 3 malignant AM, all associated with a neoplastic IME. While they are frequently described in the literature, no cystadenoma was observed in these series. Clinical symptoms are often confusing, but paraclinical investigations may lead to preoperative diagnosis. Appendectomy is the treatment of retention AM and cystadenoma. Their prognosis is related to other associated diseases, namely ovarian and colorectal tumours, but is otherwise good. Cystadenocarcinomas require a right hemicolectomy with evacuation of IME but their prognosis is poor. PMID- 7844185 TI - [Perforation of the small intestine caused by endometriosis]. AB - Endometriosis is rarely located on the small bowel. A case of small bowel perforation resulting from a stenosis due to endometriosis is reported. Pre operative diagnosis of this type of lesion is most difficult in genetically active women since the clinical picture is a mixture of gynaecological and digestive disturbances. The treatment is surgical resection. PMID- 7844186 TI - [Benign giant epignathic teratoma in the newborn. Apropos of an unusual clinical case]. AB - A rare case of giant epignathus teratoma with intracranial extension is reported in a male newborn. Pre-operative diagnosis of teratoma was made or suspected on radiological evidence of calcification within the tumor and increased level of alpha-foetoprotein. Optimal treatment consisted in complete surgical resection. The literature is revisited and surgical indications are discussed. PMID- 7844187 TI - [Protruding dermatofibrosarcoma. An unusual cutaneous tumor]. AB - Local reoccurrence of protuberant dermatofibrosarcoma was seen in a female patient 3 years after exeresis. We reviewed the data in the literature on the physical examination, outcome, histology and therapeutic approach. The Darier and Ferrand dermatofibroma is a very unusual skin tumour which develops in the dermal layer. Diagnosis can only be confirmed by histologicaal examination of the specimen. Wide surgical exeresis is required to avoid local relapse. Despite the high risk of reoccurrence, the prognosis is excellent. PMID- 7844188 TI - [Origins, obligations and future in war surgery]. PMID- 7844189 TI - [A case of biliary ileus of the colon]. PMID- 7844190 TI - [Laparoscopic surgery of inguinal hernias. The extraperitoneal route]. AB - Laparoscopic techniques for treating inguinal hernia have been well defined. Complete pre-peritoneal route, described here, is based on the well established Stoppa procedure. The different operative times are given in detail, including positioning the split windowed unfixed polypropylene prosthesis. The limitations of the procedure, the complications and its relative role among other modern laparoscopic and conventional treatments of inguinal hernias are discussed here. The pre-peritoneal route described is perfectly reproductable. Early results of reported cases are discussed and have been quite favourable. PMID- 7844191 TI - [Treatment of urinary incontinence by vaginal approach]. AB - The vaginal route is routinely used for surgical cure of exersion-induced urinary incontinence. This technique has the advantage of being rapid and easily performed during a short hospital stay. Long-term results however, have been debated. Certain factors have been identified in the literature which would affect long-term failure. These factors indicate that the "ideal" vaginal route should be based on the Burch operation starting at the upper portion and working downwardly. Finally, sphincter failure or detrusor instability must be eliminated before an operation for exertion-induced incontinence can be indicated since such a combination would modify the procedure. PMID- 7844192 TI - [Practical approach to tumoral perforations of cancers of the colon. Apropos of 7 cases]. AB - In 4 to 5% of cases, the cancer of large bowel is presented with a perforation in situ. The mortality rate in these conditions is high, and it is evaluated in the literature between 40 to 50% of cases. The authors present their experience with 7 consecutive patients, operated for this complication. In all cases, the tumour is excised: in 6 patients, terminal colostomy is realised while one patient only had a direct resection anastomosis. No per-operative mortality, was noted, and in four patients retauration of intestinal tract is realised, within 3 to 6 months latter. In our experience, the perforated tumour does not appear as a factor of immediate gravity. PMID- 7844193 TI - [Treatment of large abdominal eventrations with an intraperitoneal stapled plate. Apropos of a series of 27 patients]. AB - Treatment of 27 large abdominal eventrations by intra-peritoneal prothesis fixed by staples is reported. Only one recurrence (3.5%) in the post-operative period, the good results observed, absence of grave complication, and great simplicity of this procedure lead the authors to recommend the use of intraperitoneal prosthesis in the treatment of post-operative eventration with major loss of parietal substance. PMID- 7844194 TI - [Neurosarcoma of the Treitz fossa. Apropos of a case]. AB - A unique neurosarcoma was observed located in the Treitz' fossa. Such tumours are usually occur in Rechlinghausent's disease and are exception in isolated situations. Diagnosis is difficult and requires a small bowel study. Surgical exeresis is the only treatment. PMID- 7844195 TI - [Long-term result of surgical treatment of epicondylitis. Apropos of 26 cases]. AB - Results obtained after surgical deinsertion of the second radial and arthrotomy of the hundred-radial joint in 26 cases of epicondylitis were evaluated after a mean follow-up of 5 years range (3-9 years). The surgical technique, operative findings, early and long-term results were described. Long-term results were excellent or good in 85% of the cases and remained unchanged over time with no morbidity. The results of this series were similar to those obtained in other published series reporting several surgical techniques based on different pathophysiological theories. It is concluded that surgery can be an effective treatment for epicondylitis and can be proposed early when medical treatment does not give lasting improvement. The surgical technique should be as simple as possible. PMID- 7844196 TI - [Surgical treatment of ruptures of hydatid cysts of the liver]. AB - During the last 20 years (1972-1992), 421 patients underwent surgery for hydatid disease of the liver. 96 out of 421 patients had a rupture such as, intrabiliary rupture 49 patients, intrathoracic rupture 43 patients and free rupture in the peritoneal cavity 4 patients. The surgical treatment required a variety of procedures: 1) Prolonged tube drainage of the residual cavity and exploration of the common bile duct followed by either T tube drainage or sphincteroplasty or choledocho-duedonostomy if it was necessary, for intrabiliary rupture. 2) Lung resection if it was necessary, and evacuation plus drainage and the hepatic cavity followed by suture of the diaphragmatic rupture of closure of the bronchial opening if present for intrathoracic rupture. 3) Lavage and prolonged tube drainage of the hepatic cavity for free rupture in the peritoneal cavity. Five patients died in the postoperative period one from suppurative cholagitis, one from pulmonary embolism and 3 from M.O.F. PMID- 7844197 TI - [Spontaneous rupture of the spleen under ticlopidine. Apropos of two cases]. AB - We observed two cases of spontaneous rupture of an apparently healthy spleen in two patients who were taking ticlopidine as anti-platelet aggregation treatment. The notion that the spleen was apparently healthy was based on well-defined criteria, essential for the imputability of the spontaneous lesions. In general drug-induced spontaneous ruptures of the spleen have been reported for anticoagulants but no case due to antiplatelet aggregation has been reported to our knowledge. The analysis of these two cases and a review of the recent literature suggests that ticlopidine was the causal agent in these two cases of splenic rupture. PMID- 7844198 TI - [Penetrating injuries of the abdomen. Results of two classical and selective attitudes in the management of 249 wounds]. AB - The systematic surgical exploration of each abdominal penetrating wound allows an exact out-come of lesions and an adequate treatment without delay. But these advantages are made upon a possibly 30% negative laparotomy. The selective attitude in the management of these abdominal's wounds has permitted to decrease this rate to 5% with a risk of secondary operation for non primary detected lesions in 5%. Our attitude toward 249 penetrative abdominal's wounds was classic and selectable respectively from 86 to 89 and 90 to 93. The results has confirmed the literature's date and especially has shown no significant difference between the two attitude concerning the morbidity and the mortality. PMID- 7844199 TI - [Local resection of cancers of the rectal ampulla. Indications and results]. PMID- 7844200 TI - [An unusual "incidentaloma": adrenal leiomyoma]. PMID- 7844201 TI - Sex selection via albumin columns: 20 years of results. PMID- 7844202 TI - Separation of X- and Y-bearing human spermatozoa using albumin gradients. PMID- 7844203 TI - Human sex pre-selection by sperm manipulation. PMID- 7844204 TI - Vertical transfer of prion disease. PMID- 7844205 TI - A simple and inexpensive treatment of menopause: prophylaxis of postmenopausal bone loss. AB - Relatively few women elect to receive classical hormone replacement therapy (HRT), and others discontinue treatment because of side-effects or fear of complications. This report presents the results of a long-term study of a low dose step-down HRT protocol and discusses its potential benefits. PMID- 7844206 TI - Comparison between prolactin, gonadotrophins and steroid hormones in serum and follicular fluid after stimulation with gonadotrophin-releasing hormone agonists and human menopausal gonadotrophin for an in-vitro fertilization programme. AB - The inter-relationship between serum and follicular fluid prolactin, oestradiol, progesterone, follicle stimulating hormone (FSH), and luteinizing hormone (LH) in two groups of women was investigated. In group 1, 32 women were treated with gonadotrophin-releasing hormone agonist (GnRH-a) in a long term protocol and subsequently stimulated with human menopausal gonadotrophin (HMG). In group 2, 25 women were simultaneously stimulated with GnRH-a in a short protocol with HMG. Follicular fluid was collected from 54 follicles in group 1 and 47 follicles in group 2. Serum was obtained on the day of human chorionic gonadotrophin (HCG) administration. Serum prolactin and oestradiol concentrations were significantly higher (P < 0.025 and P < 0.01, respectively) in group 1 than in group 2. Serum LH (P < 0.005), FSH (P < 0.01) and progesterone (P < 0.025) were significantly lower in group 1 than in group 2. Follicular fluid prolactin was significantly higher (P < 0.005) in group 1. No differences were found in follicular fluid progesterone and oestradiol. Follicular fluid LH was significantly lower (P < 0.05) in group 1. Serum prolactin correlated positively with oestradiol in both groups (P < 0.005 group 1; P < 0.02 group 2). No significant correlation was found between serum prolactin and LH in group 1. We conclude that prolactin secretion is independent from LH secretion. Hyperprolactinaemia, which is observed in women stimulated with GnRH-a and HMG, is positively associated with increased oestradiol. PMID- 7844207 TI - Evidence suggesting an additional control mechanism regulating episodic secretion of luteinizing hormone and follicle stimulating hormone in pre-pubertal children and post-menopausal women. AB - The possible differential regulation of pulsatile follicle stimulating hormone (FSH) and luteinizing hormone (LH) secretion in pre-pubertal children and in post menopausal women was investigated. Children were studied for 4 h and post menopausal women for 6 h; blood samples were taken every 10 min. Post-menopausal women were studied before and 21 days after administration of a single i.m. dose of gonadotrophin-releasing hormone (GnRH) analogue. Eight post-menopausal women and 18 children (nine boys and nine girls) were enrolled. The children were divided into two groups: A, at Tanner stages 0-1 (four boys and three girls); B, at Tanner stage 2-3 (five boys and six girls). Plasma LH and FSH concentrations were determined using an immunofluorimetric assay. Time series were analysed and the specific concordance (SC) index was computed to determine the degree of concordance between episodes of LH and FSH secretion. While children of group A had LH concentrations below the minimal detectable dose of 0.1 IU/l, group B showed measurable LH plasma concentrations (1.4 +/- 0.3 IU/l, mean +/- SEM). Plasma FSH concentrations were detectable in both groups. Group A showed FSH plasma concentrations significantly lower than those of group B (0.75 +/- 0.2 and 1.95 +/- 0.4 IU/l respectively; P < 0.05), but FSH pulse frequency was higher in group A (P < 0.05). Children of group B showed significant concomitance of LH and FSH secretory events at time 0 (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7844208 TI - A comparison between a standard and reduced dose of D-Trp-6-luteinizing hormone releasing hormone administered after pituitary suppression for in-vitro fertilization. AB - A randomized prospective study was undertaken to compare low and standard luteinizing hormone-releasing hormone agonist (LHRHa) dosage used in combination with gonadotrophins in ovarian stimulation for in-vitro fertilization (IVF). A total of 42 ovulatory patients with mechanical infertility were administered 0.5 mg/day LHRHa (Decapeptyl) from day 21 of their cycles for 14 days. Following down regulation, patients were randomly allocated to continue with the same dose of LHRHa (22 patients, group A) or to receive a lower dose of 0.1 mg/day LHRHa (20 patients, group B) during folliculogenesis. Luteal phase was supported by daily i.m. progesterone (50 mg) injections and human chorionic gonadotrophin (HCG; 1500 IU) every 4 days. Ovarian response, human menopausal gonadotrophin (HMG) dosage used for induction of ovulation, evidence of premature luteinization, and clinical and laboratory IVF outcome, were compared between groups A and B. The two groups were comparable in respect of: age (32.6 +/- 0.7 and 33.0 +/- 0.9 years), HMG dosage (33.0 +/- 1.6 and 36.0 +/- 2.5 ampoules), day of HCG (11.2 +/- 0.3 and 12.2 +/- 0.4), oocytes/patient (13.3 +/- 1.0 and 12.9 +/- 1.3), fertilization rate (68.5 and 65.2%), cleavage rate (95% for both), pregnancy/embryo transfer (32 and 35%) and implantation rate (10.8 and 10.5%), for groups A and B respectively. There was no evidence of premature luteinization or luteolysis in either group. It was concluded that lowering the dose of LHRHa to 0.1 mg/day during folliculogenesis had no adverse effect on ovarian response or clinical results. However, it had no advantage in reducing the HMG dose used for ovulation induction. PMID- 7844209 TI - Contraception with NORPLANT implants. AB - NORPLANT progestogen-only implant contraception provides several years of effective protection against pregnancy following a single application. It is reversible whenever desired, with return to normal fertility. Drug release and concentrations are maximal in the first month of use, when a set of six capsules releases approximately 85 micrograms/day of levonorgestrel. Release is 25-30 micrograms/day at 60 months. Circulating drug concentrations and pregnancy rates vary inversely with body weight at placement, but even among heavier women, failure rates are below those of oral contraceptives in the general population. Side-effects are most marked at the initiation of use. Disruption of normal menstrual patterns occurs in 70-80% of recipients initially. Menstrual blood loss is decreased, however, and most women experience modest increases in haemoglobin. Headache, acne, other skin or hair problems, changes of weight and of mood and abdominal pain, are the most common side-effects attributed to NORPLANT contraception. The frequency of occurrence of side-effects diminishes with increased duration of use. The comparative paucity of major side-effects, coupled with the method's convenience and effectiveness and its very long action have made NORPLANT implants highly acceptable in both developing and developed countries. PMID- 7844210 TI - Assessment of the relevance of zona pellucida antibodies in follicular fluid of in-vitro fertilization (IVF) patients. AB - The presence of anti-zona pellucida antibodies in the follicular fluid of 11 women who underwent in-vitro fertilization (IVF) and embryo transfer was analysed. Only infertile couples with tubal or unexplained pathologies were included in our study, which was aimed at investigating the relationship between anti-zona pellucida antibodies in follicular fluid and failed fertilization. Whether or not these antibodies were present in some or all follicles in the same patient was also investigated. Out of 55 follicular fluids analysed, 36.3% were positive to the test and no fertilization was observed in oocytes from these follicles, while 63.6% were negative, and the oocyte fertilization rate associated with these was 51.4%. The presence of anti-zona pellucida antibodies was positively correlated with the degree of fertilization failure (P < 0.001 chi 2 test). PMID- 7844211 TI - Immunosuppression by corticosteroid has no effect on the pregnancy rate in routine in-vitro fertilization/embryo transfer patients. AB - Immunosuppression by exogenous corticosteroids has been used to improve the rates of embryo implantation and pregnancy in in-vitro fertilization (IVF) patients who have micromanipulated embryos replaced. The present study was conducted, in a prospective design, to evaluate effects of corticosteroid on the pregnancy rate in IVF/embryo transfer patients who have non-micromanipulated embryos replaced. Infertile women < 40 years old with tubal factor were included in this study. Patients were grouped according to the different follicle stimulation protocols, and received various doses of 16 beta-methylprednisolone (0, 16 or 60 mg/day) for 4 days from the day of oocyte retrieval. The mean age, duration of infertility, length of folliculogenesis and serum oestradiol concentrations at the time of human chorionic gonadotrophin (HCG) injection were not significantly different between control and corticosteroid-treated groups of patients. Short-term immunosuppression by 16 beta-methylprednisolone administration did not show any effects on the pregnancy and miscarriage rates in IVF/embryo transfer patients. Also, immunosuppression showed no dose effects in any groups. There was no relationship between the types of follicle stimulation protocols and the effect of 16 beta-methylprednisolone. Therefore, we concluded that short-term immunosuppression by exogenous corticosteroids in IVF/embryo transfer patients who have embryos with intact zona pellucida replaced has neither positive nor negative effects on pregnancy rates. PMID- 7844212 TI - AJ-FS9 monoclonal antibody detects masked antigens within the human sperm tail fibrous sheath. AB - AJ-FS9 is one of a new series of monoclonal antibodies (mAbs) raised by immunizing mice with isolated human sperm tail fibrous sheath (FS). Using indirect immunofluorescence (IIF) of human spermatozoa dried onto slides, the AJ FS9 mAb reacted with the principal piece of occasional spermatozoa. Following their enzymatic treatment with trypsin, dispase or collagenase, but not sulphatase, all the spermatozoa were stained at their principal piece. The ultrastructural localization of the antigens to the FS was established by immunogold electron microscopy, which showed the distribution of gold particles on the FS outer surface of spermatozoa sequentially treated with 1% Triton and dispase; spermatozoa demembranated by Triton alone showed no reaction. For biochemical characterization, spermatozoa were lysed with 1% Triton, and the sperm pellet was run through a reducing sodium dodecyl sulphate-polyacrylamide gel electrophoresis, Western blotted and immunostained with AJ-FS9. The results showed the reaction of the antibody with three protein bands with molecular masses ranging between 46 and 56 kDa. IIF screening of human testicular cryostat sections with AJ-FS9 mAb showed its reactivity with occasional sperm tails; but following their dispase treatment, all spermatozoa were stained. The restricted staining of the assembled FS of maturing sperm tails indicated the late appearance of the antigens during spermatogenesis. The antibody did not react with sperm cell precursors or other cell types within/without the seminiferous tubules. Untreated and dispase-treated frozen sections of skin, oesophagus, tongue, liver, kidney, stomach, ileum or their blood vessels showed no reaction.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7844213 TI - Allergenic potential of gonadotrophic preparations in experimental animals: relevance of purity. AB - Local reactions have been frequently reported following repeated injections of human menopausal gonadotrophins (HMG) for the treatment of infertility. Also immunoglobulin (Ig) E-mediated systemic reactions have sporadically been observed. Since most HMG preparations contain significant amounts of non-hormonal urine-derived proteins, it was suggested that these contaminating proteins are responsible for the various allergic reactions. In order to verify this hypothesis, different human follicle stimulating hormone (HFSH) and HMG preparations (Metrodin and Pergonal from Ares-Serono, and Humegon from Organon), were compared with a highly purified preparation (Metrodin HP from Ares-Serono) for the frequency and severity of allergic reactions induced in laboratory animals. The occurrence of anaphylactic shock or related symptoms was studied in sensitized guinea-pigs. The production of specific IgE was evaluated in serum from mice sensitized with the test drugs by the induction of passive cutaneous anaphylaxis in rats. In both models, two different schedules of sensitization were used. Severe allergic reactions were found in 20 of 7% of the guinea-pigs receiving highly purified FSH (Metrodin HP) in the two schedules, respectively, compared to 90 and 88% with the other preparations. Similarly significantly lower IgE titres were induced by highly purified FSH in respect to the other preparations. It can be concluded that the elimination of contaminating proteins significantly reduces the allergenicity of urine-derived HFSH preparations. PMID- 7844214 TI - beta 2-Glycoprotein I-dependent and -independent anticardiolipin antibodies in healthy pregnant women. AB - The purpose of this study was to determine the association between beta 2 glycoprotein I (beta 2GPI)-dependent anticardiolipin antibodies (aCL) and beta 2GPI-independent aCL and their respective relevance to adverse pregnancy outcomes. Therefore, we prospectively studied 210 normal pregnant women, utilizing a modified enzyme-linked immunosorbent assay method for beta 2GPI dependent and -independent aCL. Seven of the 210 pregnant women (3.3%) demonstrated evidence for beta 2GPI-independent immunoglobulin G (IgG)-aCL. Two patients, who also appeared positive for beta 2GPI-dependent IgG-aCL, were proven to be false positives. Amongst the 210 patients, not one was thus positive for beta 2GPI-dependent aCL. Women with beta 2GPI-independent aCL demonstrated no adverse pregnancy outcomes. These results suggest that the presence of beta 2GPI independent aCL is not associated with the presence of beta 2GPI-dependent aCL, though it may give rise to false positive results. Since the presence of beta 2GPI-independent aCL does not appear to be associated with adverse pregnancy outcomes, beta 2GPI-dependent assays may represent better markers of miscarriage risk. PMID- 7844215 TI - Spontaneous ovulatory cycle donor insemination programme: prognostic indicators of a successful pregnancy. AB - The effects of female and male infertility factors as well as the insemination regime on the outcome of donor insemination (DI) during 1001 spontaneous ovulatory cycles were assessed. Overall, the average monthly fecundability was 4.4% and the cumulative conception rate after nine cycles was 45%. Female DI recipients' age, nulligravidity or the presence of other infertility factors were associated with a significantly lower pregnancy rate. DI recipients of azoospermic partners had a significantly higher pregnancy rate. The likelihood of a successful pregnancy was higher when more frequent (> or = 1) inseminations were used or in association with higher cervical score and larger follicle diameter at the time of insemination. We suggest that female recipients of DI should be fully investigated before commencing DI treatment. Early resort to other methods of assisted reproduction should be considered in DI recipients aged > or = 35 years, or in younger women if they fail to conceive after nine cycles of DI. More frequent and better timing of inseminations is expected to improve the fecundability rate during spontaneous ovulatory DI cycles. PMID- 7844216 TI - Evaluation of transvaginal sonography combined with a urinary luteinizing hormone monitor in timing donor insemination. AB - There remains controversy as to the most accurate method of predicting ovulation for the timing of donor insemination. In a prospective study based at a tertiary referral donor insemination clinic we have assessed the ability of a urinary luteinizing hormone (LH) kit combined with vaginal ultrasonography to predict ovulation for donor insemination. A total of 25 natural cycles were monitored from the first day of the LH surge (detected by the urinary kit). Daily transvaginal sonographic measurement of follicular size and endometrial thickness were used to predict ovulation; monitoring continued until post-ovulatory changes were seen. Transvaginal sonography combined with a urinary LH kit successfully predicted all those women who ovulated (20/25) and detected unfavourable conditions for insemination in the remaining 20% (5/25). In conclusion, where available transvaginal sonography combined with a urinary LH kit should be the method of choice for timing donor insemination. PMID- 7844217 TI - Late low-dose pure follicle stimulating hormone for ovarian stimulation in intra uterine insemination cycles. AB - At present, there is general agreement that ovarian stimulation improves pregnancy rates after intra-uterine insemination (IUI). Also, ovulation induction with gonadotrophins is associated with higher success rates than clomiphene citrate in IUI cycles. However, the drawbacks to the use of gonadotrophin stimulation before IUI include the risks of ovarian hyperstimulation and multiple gestation, and the relative cost of a treatment cycle in a view of the medication costs and the need for increased monitoring by hormone assays and ultrasonographic measurements. In the present prospective randomized trial, the efficacy and safety of ovarian stimulation with clomiphene citrate (50 mg/day for 5 days) and IUI (clomiphene/IUI group) were compared with those of late low-dose pure follicle stimulating hormone (FSH, 75 IU/day from day cycle 7 until the leading follicle reached > 17 mm in diameter) and IUI (FSH/IUI group) in ovulatory women who were infertile because of unexplained infertility (n = 40) or male subfertility (n = 60). The mean length of treatment in the FSH group was 6.4 +/- 2.5 days. Multiple follicular development was seen in 25% of clomiphene stimulated cycles but only in 8% of those treated with FSH. Pregnancy rate per cycle in clomiphene/IUI and FSH/IUI groups was 4% (4/98) and 13% (12/94) respectively (P = 0.02). All pregnancies obtained were singleton. There were two and one clinical abortions in the clomiphene/IUI (50%) and FSH/IUI (8%) groups respectively. No patient developed ovarian hyperstimulation syndrome. Use of our therapeutic scheme, which proved to be efficacious, safe and economic for ovarian stimulation in IUI cycles, is advocated before the institution of in-vitro fertilization (IVF) or gamete intra-Fallopian transfer (GIFT) therapy in infertile patients with patient Fallopian tubes. This late low-dose technique of administering pure FSH is suitable for use in offices without immediate access to oestradiol results. PMID- 7844218 TI - Analysis of the extent to which sperm movement can predict the results of ionophore-enhanced functional assays of the acrosome reaction and sperm-oocyte fusion. AB - This study has examined the extent to which the information generated by ionophore-enhanced bioassays of the acrosome reaction and sperm-oocyte fusion might be predicted from the computer-aided analysis of sperm motility. Strong correlations (r approximately 0.7) were observed between specific components of sperm movement in semen and the potential for A23187-induced sperm-oocyte fusion, generating a stepwise regression coefficient of R = 0.663 on the bais of two criteria, percentage progressive motility and amplitude of sperm lateral head displacement (ALH). The movement characteristics of the spermatozoa recovered from the Percoll gradients gave an even higher R value of 0.838 on the basis of four variables (percentage rapid, average path velocity, straightness and ALH). In contrast, the ability of human spermatozoa to undergo acrosome reaction in response to A23187 exhibited a limited correlation with sperm movement, whether these measurements were made in the original semen sample or following Percoll purification (R approximately 0.4). These results have diagnostic implications, since sperm-oocyte fusion and the acrosome reaction clearly differ in their relative dependence on sperm motility. In practical terms, it should be noted that the computer-aided analysis of sperm movement was shown to provide up to 70% of the information generated by the more laboured assessment of sperm-oocyte fusion. PMID- 7844219 TI - Characterization and frequency distribution of sperm acrosome reaction among normal and infertile men. AB - We studied the acrosome reaction (AR) in human spermatozoa from 58 normal fertile men and 232 infertile patients. The median AR in the normal population was 17%; AR was > 9% in 83% of the subjects studied and only 2% of fertile individuals had a failed AR (< 5%). We calculated the within person variability using multiple specimens from each subject; the 95% confidence interval for each subject was 4 AR units above and 4 AR units below his mean value. In contrast, the median AR for the infertile population was 3%. AR values were below the normal range (< 5%) in 60% of the patients and only 26% of the patients had AR values > 9%. Because patients entered the study sequentially, without regard to the aetiology of infertility, the patient population comprised a wide variety of subjects ranging from individuals with good to extremely poor semen quality. There was a progressively greater number of individuals with a failed AR as semen quality deteriorated (P < 0.01). However, among patients with good count, motility and morphology, 20% unexpectedly had a failed AR, and among patients with severely impaired semen quality, 29% had a positive AR. We also analysed the relationship of AR values with other semen measurements. The frequency of acrosomal reactions was significantly correlated (Spearman, P < 0.001) with morphology (r = 0.509), concentration (r = 0.524), progression (r = 0.416) and percentage motility (r = 0.356), but not with the percentage of sperm moving at a curvilinear velocity of < or = 40 microns/s.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7844220 TI - Acrosome reaction inducibility predicts fertilization success at in-vitro fertilization. AB - We prospectively studied the ability of acrosome reaction (AR) inducibility to predict fertilization success in a group of 232 infertile patients presenting sequentially for in-vitro fertilization (IVF). The median percentage of eggs fertilized for the overall patient population was 25% (interquartile range 5 58%), with one to 29 oocytes available for insemination (median, five oocytes). The median percentage of eggs fertilized at IVF increased as the percentage of spermatozoa able to undergo AR became greater: spermatozoa with a failed AR (< or = 5%) fertilized only 12% of eggs, while spermatozoa with AR values > 9% fertilized 50% of eggs. The assay had a specificity of 0.75, a sensitivity of 0.55 and an odds ratio of 2.9; thus, AR-positive patients are 2.9 times more likely to achieve fertilization than patients with a failed AR. Receiver operator characteristic (ROC) curves were constructed for AR, sperm concentration and percentage of normal forms in semen. All three parameters proved to be potentially useful in predicting the occurrence of fertilization, although AR and morphology appeared to be better than sperm concentration by ROC analysis. Patients were divided into four clearly defined subgroups according to their traditional semen characteristics, including morphology. The median percentage of eggs fertilized decreased as traditional semen characteristics deteriorated, from a median of 46% for patients with excellent sperm concentration, motility and morphology, to a median of 29% for patients with suboptimal semen quality and a median of 0% for patients with severely impaired semen.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7844221 TI - Which semen parameters have a predictive value for pregnancy in infertile couples? AB - A prospective study was carried out in 156 couples attending an infertility clinic. To assess the predictive value of semen parameters in relation to pregnancy, we defined a group of 16 couples (group II) in whom the female became pregnant by intra-uterine insemination (IUI), and therefore in whom a female factor could be ruled out. Studies of semen parameters before and after capacitation were carried out in the first trimester of pregnancy (< 12 weeks). The same studies were done in the remaining 140 men (group III) with primary infertility and then all results were compared with a control group of 27 healthy, fertile men (group I), with normal semen parameters. Our results showed that progressive motility and straight line velocity were significantly lower in group III compared with group II: 33.4 and 45.2% respectively (P < 0.001) for progressive motility, and 25.7 and 32.8% respectively (P < 0.005) for straight line velocity. Acrosome alterations, on the other hand, were significantly more frequent in group III compared with group II: 21.4 +/- 0.7 and 5.9 +/- 1.7 respectively (P < 0.003). After capacitation, the recovery in terms of numbers of motile spermatozoa, spermatozoa with normal morphology and acrosome-reacted spermatozoa could be a predictive parameter of fertilization, because all were significantly decreased in group III compared with group II (P < 0.01). PMID- 7844222 TI - Seventeen live births after the use of an erbium-yytrium aluminum garnet laser in the treatment of male factor infertility. AB - Mechanical partial zonal dissection (PZD) is one of the microinsemination techniques developed to improve the chances of fertilization by in-vitro insemination in subfertile males. We developed a new and safe laser method (erbium laser ablation) for PZD, with the aim of producing a precise opening as well as ablation of some layers of the zona pellucida. From February 1992 to March 1993, 104 couples suffering from male factor infertility were treated in our centre. All patients were affected by severe oligoasthenozoospermia and had previously undergone one failed in-vitro fertilization attempt each. Photoablation of the zona pellucida was induced in 512 oocytes by exposure to an erbium--yytrium aluminium garnet (Yag) laser. The openings obtained were approximately 14 microns in diameter. Of the laser-treated oocytes, 158 (30%) fertilized and 139 (88%) cleaved. Nineteen (18.3%) clinical pregnancies resulted and produced 17 newborns, all in good health. In our series there were four miscarriages, 23 damaged oocytes (4.4%) and 13 with three or more pronuclei (2.5%). Considering that the incidence of damaged oocytes and polyspermy is low, it seems that in some cases of male factor infertility erbium-Yag laser photoablation of the oocyte zona pellucida can be considered a procedure which is effective in enhancing fertilization and which is safe, allowing normal embryo development. PMID- 7844224 TI - The effect of pentoxifylline on mouse in-vitro fertilization and early embryonic development. AB - This study was designed to assess the effect of pentoxifylline (PTX) on fertilization and early embryonic development in the mouse. Oocytes from superovulated B6CBA female mice were inseminated in vitro with spermatozoa from B6CBA males incubated with PTX according to different protocols, i.e. (i) 3.6 and 7.2 mM PTX washed out prior to insemination, (ii) 3.6 and 7.2 mM PTX diluted six times in the insemination medium and (iii) PTX present at 3.6 and 7.2 mM in the insemination medium. After insemination and washing, fertilization was assessed by the presence of 2-cell stage embryos. These were further cultured up to the blastocyst or egg-cylinder stage to assess embryonic development. Parthenogenetic activation was evaluated by exposing post-ovulatory oocytes to 3.6 and 7.2 mM PTX. If spermatozoa were washed free from PTX before insemination, no effect on either fertilization or subsequent development was found. If PTX was not washed out, fertilization was reduced significantly, yet development of fertilized oocytes was unaffected. If insemination was performed in the presence of PTX both fertilization and development were impaired. Parthenogenetic activation was not increased by PTX exposure. We conclude that if used in in-vitro fertilization, exposure of oocytes and/or zygotes to PTX has to be avoided by washing out the compound thoroughly to prevent adverse effects on early embryonic development. PMID- 7844223 TI - Progesterone-induced acrosome reaction: potential role for sperm acrosome antigen 1 in fertilization. AB - We have established a monoclonal antibody (mAb) AG7 defining a sperm acrosome antigen-1 (SAA-1) on spermatozoa from the human and several mammalian species. MAb AG7 inhibits fertilization of mouse eggs in vitro and in vivo. An important characteristic of mAb AG7 is its inhibition of the rise in intracellular calcium induced by progesterone in human spermatozoa. Here we show that, following the acrosome reaction, SAA-1 is lost from the cap of human spermatozoa but remains detectable in the equatorial region. Acrosome reaction assays demonstrated a clear difference between progesterone- and A23187-induced acrosome reactions. For induction of the acrosome reaction with progesterone, a minimum capacitation time of 6 h was required. A23187 induced the acrosome reaction regardless of capacitation time. MAb AG7 completely inhibited the progesterone-induced acrosome reaction, but not the A23187-induced acrosome reaction in human spermatozoa. Differences in the pattern of calcium flux induced by the two agents might account for this phenomenon. The inhibition of the progesterone-induced acrosome reaction by mAb AG7 implies a regulatory function of SAA-1 during the human sperm acrosome reaction. PMID- 7844225 TI - Embryonic human chorionic gonadotropin secretion and hatching: poor correlation with cleavage rate and morphological assessment during preimplantation development in vitro. AB - Of 593 bipronucleate eggs allowed to develop in vitro, 275 (46%) achieved the blastocyst stage and beyond, 124 (21%) initiated hatching, but only 49 (8%) fully hatched. About half of the pre-embryos (48%) which developed to these more advanced stages were incapable of secreting significant amounts (> 200 microIU) of cumulative human chorionic gonadotropin (HCG) up to day 14. HCG production does not appear to begin until the expanded stage and is independent of hatching. Assessing cleavage rate through successive stages and morphological grades up to the 8-cell stage had little bearing on the ability of a pre-embryo to hatch or secrete HCG. Progression through the stages of preimplantation development in vitro does not always appear to be accompanied by the necessary biochemical stages. If only 46% of pre-embryos with two pronuclei are capable of achieving the blastocyst stage, and of these only 52% are capable of secreting HCG, then it follows that only 24% of the original bipronucleate pre-embryos in vitro can be considered anatomically and biochemically competent. However, this is only applicable for pre-embryos not transferred or frozen, and is thus subject to a selection bias. Inability to detect HCG in vitro is not conclusive proof that a pre-embryo is developmentally incompetent. Similarly failure to hatch in vitro may not be taken as definitive evidence that hatching would have failed had fertilization and development been completed in vivo. Nevertheless, if pre embryonic development in vitro is similar to that in vivo, this may be a contributory factor in the low pregnancy rates following in-vitro fertilization treatment. PMID- 7844226 TI - Controlled comparison of Earle's balanced salt solution with Menezo B2 medium for human in-vitro fertilization performance. AB - In order to optimize the in-vitro fertilization (IVF) procedure and to avoid the batch-to-batch fluctuations of in-house culture medium, we investigated the use of a commercially available medium. In our human IVF programme, a controlled comparison was performed from July 1991 to February 1992 between in-house Earle's medium and commercially available Menezo B2 medium. The major difference between the two tested media is the additional presence of amino acids and water-soluble vitamins in Menezo B2 and the different origins of the proteins source, i.e. bovine serum albumin (BSA) in Menezo B2 and human serum albumin (HSA) in Earle's medium. In the first, auto-controlled study, sibling oocytes cultured in Menezo B2 showed a significantly higher fertilization rate than those cultured in Earle's medium: 58.1 +/- 37.2% and 52.1 +/- 36.9% respectively. After further culture of the fertilized oocytes, there was no difference in the morphological characteristics of the embryos cultured in the different media, although the rate of development was different. In Menezo B2 medium, a higher proportion of the embryos had reached at least the 4-cell stage at transfer. In the second, randomized study, effects on the pregnancy and implantation rates of both media were analysed. In the group of oocytes cultured in B2, more excellent or good quality embryos were available for transfer at a more advanced stage of development. No significant difference in pregnancy rate was observed: 39.1% per transfer in Earle's medium versus 40.5% per transfer in Menezo B2.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7844227 TI - Established cell lines and their conditioned media support bovine embryo development during in-vitro culture. AB - These experiments were conducted to evaluate the ability of different somatic cell monolayers or conditioned medium from somatic cells for supporting bovine embryo development in vitro. In the first experiment, bovine embryos (2- to 4 cells) were allocated randomly to a control (medium 199 with 10% fetal bovine serum and antibiotics) group or co-cultured with bovine oviduct epithelial (BOEC), buffalo rat liver (BRL), Madin Darby bovine kidney (MDBK) or African green monkey kidney (Vero) cells. In the second experiment, bovine embryos (1 cell) were allocated randomly to the following groups: control medium or conditioned medium from BOEC, BRL, MDBK and Vero monolayers. In both experiments, development to the blastocyst stage was assessed after 8 days of incubation at 39 degrees C and 5% CO2. In Experiment 1, coculture improved development to the blastocyst stage compared with control medium alone, and the highest development was observed after co-culture with BOEC. In Experiment 2, conditioned medium enhanced development to morulae and blastocysts compared with the control medium; however, no differences were detected among different cell supports. These results indicate that both co-culture and conditioned medium from different cell monolayers supported development to the blastocyst stage at a higher efficiency than control medium alone. PMID- 7844228 TI - The prognostic value of successful in-vitro fertilization in subsequent trials. AB - A retrospective study comparing in-vitro fertilization (IVF) results in patients with previous successful trials versus new IVF patients was designed with the objective of evaluating the prognosis in both groups. Patients were divided into two groups: group A, 22 patients with previous conception in IVF trials; and group B, 235 new IVF patients. All patients had tubal factor as the only cause of infertility and were stimulated by a standard protocol of gonadotrophin-releasing hormone agonist and human menopausal gonadotrophin. The pregnancy rate in group A (64%) was significantly higher than in group B (19%). In group A, 77% of the patients had three or more grade 1 embryos per transfer as compared with 16% in group B. In group A, 95.5% of patients had easy embryo transfer as compared with 61.2% in group B. The results of the study demonstrated that patients with previous IVF pregnancies have a significantly higher pregnancy rate compared with the control group. The improved pregnancy rate is due to the higher quality of embryos and the higher percentage of easy embryo transfers. PMID- 7844229 TI - Low implantation rate after in-vitro fertilization in patients with hydrosalpinges diagnosed by ultrasonography. AB - The purpose of this study was to assess whether patients with tubal infertility and a hydrosalpinx have a reduced implantation rate after in-vitro fertilization. The study included 741 patients who had 1190 consecutive oocyte aspirations. The presence or absence of hydrosalpinges was assessed by transvaginal ultrasonography on day 2 of all cycles. In 62 patients treated in 104 cycles a hydrosalpinx was diagnosed, whereas 493 patients treated in 813 cycles had no hydrosalpinx and eight patients treated in 16 cycles had uncertain hydrosalpinx. The results show that the presence of a hydrosalpinx is associated with a reduced pregnancy rate per aspiration (19.2 versus 32.6%; P < 0.01), reduced implantation rate (2.9 versus 10.3%, P < 0.0005), reduced delivery rate per aspiration (5.8 versus 20.9%, P < 0.0005), reduced delivery rate per embryo transfer (6.6 versus 22.8%, P < 0.0005) and increased early pregnancy loss (70 versus 36%, P < 0.005). Among 178 patients with unexplained infertility or other infertility factors treated with 257 aspirations the results were similar to those in patients with tubal infertility without a hydrosalpinx. In conclusion, the presence of a hydrosalpinx does not impair the number of embryos transferred but seems to impair the implantation process. We hypothesize that this may be due to leakage of fluid into the uterine cavity which may disturb the receptivity of the endometrium and/or the developing embryos. PMID- 7844230 TI - Atrial natriuretic peptide antagonizes the contractile effect of angiotensin II in the human uterine artery. AB - The regulatory peptides angiotensin II (Ang II) and atrial natriuretic peptide (ANP) are believed to play important roles in the pathogenesis of pre-eclampsia. The interactions between Ang II, ANP and noradrenaline (NA) were studied in vitro on the human uterine artery. Both Ang II and NA contracted the isolated vessel in a concentration-dependent way. At high doses a decrease in the contractile force induced by Ang II but not NA was encountered. ANP inhibited the smooth muscle activity elicited by Ang II, resulting in a dextroshift of the concentration response curve, and a decrease in both Emax (the maximum contractile response) and pD2 (the negative logarithm of the agonist concentration inducing 50% of the Emax) for Ang II. The results might indicate a specific antagonism between Ang II and ANP, probably at the post-receptor level. ANP did not induce any significant change in pD2 of the concentration-response curve for NA. Only at the highest dose of ANP (10(-7) M) was Emax depressed. Thus, the results only indicate a weak antagonistic relationship between NA and ANP in the human uterine artery. PMID- 7844231 TI - Intrafollicular concentrations of free cortisol close to follicular rupture. AB - Concentrations of total and free, non-protein-bound cortisol were determined in serum and pre-ovulatory follicular fluid sampled from 14 women who underwent in vitro fertilization (IVF) embryo transfer treatment. Seven of the women became pregnant and seven did not. In the pregnant group the number of pre-embryos transferred was equal to the number of implantations, identifying the follicles which contained an oocyte that resulted in a clinical pregnancy after IVF. The concentrations of free and total cortisol in follicular fluid were associated with oocyte cleavage and the establishment of pregnancies. Follicular fluid concentrations of total cortisol averaged 78% of that found in serum (244 versus 312 nM), whereas the concentration of free biologically active cortisol was nearly 10 times higher in follicular fluid than in serum (54 versus 6 nM). In serum > 94% of the cortisol was bound to cortisol binding protein (CBP) and 2.1% was free. In contrast, follicular fluid contained 22% free cortisol and only 48% bound to CBP. Follicles associated with pregnancy contained similar amounts of both free and total cortisol compared with follicles in which the oocyte failed to implant or did not cleave in vitro. It is suggested that the high concentrations of free cortisol in pre-ovulatory follicular fluid may confine and reduce some of the inflammatory-like reactions which take place close to follicular rupture. This study does not support the current concept of cortisol playing a role in follicular development of large antral follicles and oocyte maturation during the follicular phase. PMID- 7844232 TI - Alcohol and risk of spontaneous abortion. AB - The objective of this study was to assess the association between alcohol drinking before and during pregnancy and the risk of spontaneous abortion using data from a case-control study conducted in Milan, Italy. A total of 462 women (median age 30 years) were admitted for spontaneous abortion (within the 12th week of gestation) to a network of obstetrics departments in the greater Milan area. Of these, 148 (32%) were between the fourth and the eighth week of gestation and 314 (68%) between the ninth and the 12th week. A control group was made up of 814 women (median age 29 years) who gave birth at term (> 37 weeks gestation) to healthy infants (Apgar 5th minute > or = 8, weight > or = 3000 g) on randomly selected days at the same hospitals where cases had been identified. A total of 212 cases (46%) and 355 controls (47%) reported alcohol drinking before conception. Considering non-drinkers as the reference category, the relative risks (RR) of spontaneous abortion were 1.2 [95% confidence interval (CI), 0.9-1.6] and 0.8 (95% CI, 0.6-1.1), respectively, in drinkers of one to seven and more than seven drinks per week before conception. No association emerged between the duration of alcohol drinking and the risk of spontaneous abortion. A total of 166 cases (35.9%) and 263 (32.3%) controls reported any alcohol drinking during the first trimester of pregnancy. The corresponding relative risk was 1.1 (95% CI, 0.9-1.4) and no relationship emerged between the number of drinks per week and the risk of abortion.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7844233 TI - The benefits of low-dose aspirin therapy in women with impaired uterine perfusion during assisted conception. AB - The objective of this long-running study was to determine whether the addition of low-dose aspirin to a standard hormone replacement therapy (HRT) protocol improved uterine perfusion during assisted conception. A total of 99 women scheduled for frozen embryo replacement were studied. Endometrial preparation was with a standard buserelin/HRT protocol. Uterine perfusion was assessed by Doppler ultrasound and classified as impaired or normal. In their first attempts, those with impaired perfusion (group I, n = 37) received low doses of aspirin [150 mg (n = 26) or 300 mg daily (n = 11)], starting from day 13 of HRT. Women with normal perfusion (group II) did not receive aspirin. In subsequent attempts, those from group I were arbitrarily allocated to start aspirin on day 1 or day 13 of HRT, and 10 women from group II were arbitrarily selected to receive aspirin from day 1 of HRT. In group I, the cancellation (46 versus 36%) and pregnancy rates (15 versus 25%) in those who received 150 or 300 mg aspirin daily were similar. In those with cancelled first attempts, good perfusion was achieved in 82 versus 20% (P < 0.02) of subsequent attempts using aspirin from day 1 versus day 13 of HRT. Higher pregnancy rates (47 versus 17%) were achieved in those taking aspirin from day 1 of HRT. In group II, pregnancy rates were not statistically different in those who did or did not receive aspirin during their subsequent attempts (10 versus 35%). The addition of low-dose aspirin to a standard HRT protocol in women with impaired uterine perfusion is associated with improved blood flow and satisfactory pregnancy rates. PMID- 7844234 TI - The vascular architecture of human fetal oviduct: a scanning electron microscopic study of corrosion casts. AB - Vascular architecture was investigated, in 18-21 week old human fetuses, for the first time with the use of corrosion casting and scanning electron microscopy, which offer high resolution and three-dimensional images of the vascular networks. The general arrangement of large vessels was similar to that described for the mature oviduct; however, the intramural vasculature of the muscular layer and mucosal folds consisted predominantly of capillary and sinusoidal networks. A characteristic feature of the fetal oviduct was a prominent sub-serosal venous plexus, which was most extensive in the isthmic segment. The relatively low degree of differentiation found in the fetal oviduct vasculature seems to reflect its functional immaturity. PMID- 7844235 TI - Transfusion-dependent homozygous beta-thalassaemia major: successful twin pregnancy following in-vitro fertilization and tubal embryo transfer. AB - Homozygous beta-thalassaemia (thalassaemia major) is a severe, transfusion dependent anaemia that also causes infertility due to endocrine impairment. Very few pregnancies are reported among such patients and there is only one report in the literature referring to a pregnancy achieved with ovulation induction and intra-uterine insemination. We report here the first successful twin pregnancy following in-vitro fertilization and tubal embryo transfer in a transfusion dependent homozygous beta-thalassaemic woman with an oligoasthenozoospermic partner. Prior to ovarian stimulation, desferrioxamine was discontinued due to potential fetotoxicity. Pre-gestational transfusional and chelating therapies were resumed after delivery. In such patients, ovulation induction and assisted reproductive techniques appear crucial in achieving pregnancy with concurrent haematological balance without desferrioxamine administration. PMID- 7844236 TI - Heterotopic pregnancy obtained after in-vitro fertilization and embryo transfer following bilateral total salpingectomy: case report. AB - Heterotopic (coexistent ectopic and intra-uterine) pregnancy is common following in-vitro fertilization and multiple embryo transfer. Total bilateral salpingectomy is generally considered to eliminate the risk of ectopic, and hence heterotopic pregnancy. This is, however, not strictly correct as it does not eliminate the risk of interstitial tubal pregnancy. This is the first reported case of a heterotopic pregnancy following total bilateral salpingectomy. The diagnostic pitfalls and a suggested method of avoiding them are discussed. PMID- 7844237 TI - Seasonality in ectopic pregnancy? PMID- 7844238 TI - Visual function testing: clinical correlations. AB - Visual function tests provide criteria to determine the extent and type of retinal malfunction in patients with retinal disease. This chapter provides an overview of some selected measures of retinal function that are useful as aids in diagnosis of retinal diseases, particularly those that involve the cone and rod photoreceptors. PMID- 7844239 TI - Anatomy and physiology of the visual system. AB - This article reviews the anatomy and physiology of the visual system. The physical stimulus is coded by several separate and parallel pathways at multiple sites in the nervous system. We outline the major parallel pathways of the system, from their beginning in the retina, to the multiple cortical areas that receive visual input. Emphasis has been placed on the functional properties of the neurons of these pathways and the various cortical processing areas as they are currently known. Clinical syndromes as a result of damage to specific visual cortical areas are also described. PMID- 7844240 TI - Visual evoked potentials. AB - The recording of visual evoked potentials (VEPs) is an important means of obtaining reproducible, quantitative data on the function of the anterior visual pathways. In this review, the technical aspects of recording VEPs are briefly discussed, components of the VEPs are described, and the clinical uses of VEPs are considered. It is concluded that VEPs are useful in providing information concerning the functional integrity of the anterior visual pathways. They are especially useful in evaluating patients with visual symptoms but no objective findings on examination and in patients without visual symptoms but with diseases that are known to involve the visual pathways commonly and subclinically. Lastly, the utility and limitations of VEPs in various neurological disorders are summarized, bearing in mind the widespread availability of advanced neuroimaging techniques. PMID- 7844241 TI - Neuroradiologic investigation of the visual system using magnetic resonance imaging. AB - The aim of this review is to give highlights about technical imaging aspects with which researchers in the neuro-ophthalmologic fields ought to be familiar. After a short overview of history of anatomy of the visual system, a review of the main anatomic details and their corresponding MRI aspects concerning the visual pathways is proposed. Reference lines suitable for MR imaging of the visual system in normal and in diseased states are proposed to orient the neuroradio ophthalmologic investigations. Brain, cutaneous, and bony landmarks are given to help multimodality imaging approaches, indispensable for anatomofunctional correlations. The neuro-ocular plane is used as the reference for the screening of the visual pathway in its entirety and retained as the orientation of choice for studying orbital optic nerves and eyes. Two other reference lines primarily devoted to temporal lobe imaging, are proposed for the study of the intracranial optic path: the chiasmatocommissural line and the commissural-obex, brainstem axis reference line. Based on brain commissural landmarks present in all vertebrates, these two lines are also helpful in comparative brain anatomic and physiologic studies in vivo as well as in vitro. PMID- 7844242 TI - Sympathetic skin response. AB - The sympathetic skin response (SSR) is the potential generated by sweat in response to different stimuli. This potential has a waveform that habituates with closely repeated stimuli and a latency of 1.3-1.5 s at the hand and 1.9-2.1 s at the foot. It has been used to study the peripheral sympathetic system in peripheral nerve diseases. The response is absent in many cases of peripheral neuropathy, often in the presence of autonomic symptoms. SSR has also been used to study a few diseases that may affect the central sympathetic system. This review outlines the history, physiopathogenesis, and analysis of SSR as well as general techniques used in its study. The reported association of SSR with peripheral and central nervous system diseases is also presented. PMID- 7844243 TI - Technology and equipment review. Audiometers. PMID- 7844244 TI - Promoting the health of aging adults in the community. PMID- 7844246 TI - Increased cholecystectomy rates among Medicare patients after the introduction of laparoscopic cholecystectomy. AB - A study was undertaken of Medicare claims coded for cholecystectomy and those coded for laparoscopic cholecystectomy for the four year period 1990-1993 in New York State. During this time period there was a 28.12% increase in total cholecystectomies performed and an increase in the proportion of laparoscopic cholecystectomies from 15.86% to 50.0%. The increase in total cholecystectomies appears to be driven by a dramatic increase in laparoscopic procedures. Possible reasons for this increase include the performance of laparoscopy on patients previously assessed as too risky to undergo the conventional procedure, laparoscopy on mildly symptomatic patients who had previously put off a perceived higher risk open procedure and a possible broadening of indications for gallbladder surgery. The dramatic increase in the numbers of cholecystectomies performed in the early 1990s may be due in part to procedures performed on a large pool of procrastinating mildly symptomatic patients. If this is the case, then these increased rates should decline to baseline levels as soon as this pool of patients is exhausted. However, if surgeons are performing laparoscopy on asymptomatic patients with gallstones, then these rates may well be sustained. Such a broadening of indications for gallbladder surgery is of concern to many and has prompted the issuance of guidelines concerning the treatment of gallstones. Any broadening of indications for gallbladder surgery also has significant implications for health care costs and the use of health care resources. PMID- 7844245 TI - Condom use relative to knowledge of sexually transmitted disease prevention, method of birth control, and past or present infection. AB - The purpose of this study was to assess knowledge regarding STD spread and prevention, and to assess motivational and behavioral factors that influence the use of condoms to prevent STD acquisition among inner-city women at high risk for STD infection. In addition, the effect of past and/or current STD infection on a woman's knowledge of the mechanism of STD acquisition and subsequent use of a condom to prevent STD infection was explored. We utilized three inner-city clinics offering family planning or gynecologic care located in Brooklyn, New York. Our study linked clinical findings regarding current infection with chlamydia or Trichomonas vaginalis. One thousand four hundred and four sexually active black and Hispanic women participated in the study. A past history of STD (37%) or current infection (29%) was recorded for 54% of the study population (12% were positive for both past and current infection). On average, only 60% of women who reported prior treatment for STD infection reported receiving any information regarding prevention of re-infection during the course of treatment. Depending on the specific STD, from 6.8% to 42.9% of women reporting prior treatment for an STD did not know the disease they were being treated for was sexually transmitted. Condom use for disease prevention was more frequently reported by women who had previously been treated for an STD (OR = 1.62, 95% CI 1.23-2.13). However, condom use for contraception was a stronger predictor of use for STD prevention. Women who relied on condoms for contraception were almost 10 times more likely to also report condom use for STD prevention relative to women who did not use condoms for contraceptive purposes (OR = 9.71, 95% CI 7.0-13.5). In addition, condom use was associated with the perceived attitude of their sexual partner toward such use. Condom use to prevent STD acquisition was more than twice as frequently reported when a favorable attitude was perceived by a male sexual partner (OR = 2.30, 95% CI 1.54-3.43). Our findings suggest that prevention of unplanned pregnancy was a stronger motivator for condom use than disease prevention among the women comprising our study group. The findings also indicate the need for more extensive information regarding STD prevention among women at high risk for STD acquisition.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7844247 TI - AIDS in Thailand: a medical student's perspective. AB - Acquired Immunodeficiency Syndrome (AIDS) has become the biggest problem facing the health profession of Thailand today. The Ministry of Public Health reports that there are 400,000 individuals in Thailand already infected with the Human Immunodeficiency Virus (HIV) and is predicting that 4 million will be infected by the year 2000. This explosive epidemic first occurred among intravenous drug abusers (IVDAs) and subsequently spread to other high risk groups, especially prostitutes. The heterosexual population was next affected. The AIDS problem in Thailand was seen close-up by this writer, then a fourth year medical student, studying during an international health elective. At all three hospitals where I worked, I encountered large numbers of AIDS related admissions. Ten percent of medical beds at a Bangkok hospital were occupied by patients with AIDS related problems. In comparison, two hospitals located in the northern province of Chiang Mai had 15-20% and 30-40% of their beds occupied by patients with AIDS complications. Opportunistic infections were the primary reason for admissions. This paper describes the current AIDS epidemic in Thailand and the preventive measures being undertaken to combat it. Strategies to combat AIDS focus on preventive measures. The current program in Thailand emphasizes AIDS education and awareness, the promotion of condom usage, decreasing needle sharing, the screening of donated blood, and the development of the GP160 vaccine. The program, however, has been undermined by the country's well organized sex industry. Without a clear commitment from the Thai government, Thailand faces serious health and economic consequences from this epidemic in the coming decade. PMID- 7844248 TI - Breast self-examination: knowledge and practices of Hispanic women in two southwestern metropolitan areas. AB - The breast self-examination (BSE) practices of 1,453 Hispanic women in Phoenix, Arizona and San Diego, California were the focus of this study. Variables proposed as factors that influence the frequency and proficiency of BSE were demographic variables, particularly language and level of acculturation, having been taught BSE by a health professional, and experience with the disease. Results indicate that even though the majority of the women at both the Phoenix (78.1%) and San Diego (83.7%) sites had been taught BSE by a professional and most women in Phoenix (62.5%) and San Diego (63.4%) reported performing BSE within the past month, only 0.7% of the women at both sites were found to be proficient in the technique of BSE. Further, results indicate that language and acculturation were correlated with whether or not a woman performed BSE. These findings suggest that BSE education classes must provide information and techniques that promote proficiency in BSE, and must be designed to meet the unique needs of Hispanic women, particularly those of low acculturation levels. PMID- 7844249 TI - Selected health and behavioral effects related to the use of caffeine. AB - This paper reviews the research literature concerning health and selected behavioral effects of caffeine. Epidemiological and laboratory findings are reviewed to determine the health risks associated with both acute and chronic caffeine exposure. Common sources of caffeine, its properties, and physiological effects are considered. The relationships between caffeine and various health conditions are examined including caffeine's association with heart disease, cancer, and benign breast disease. Caffeine's possible contribution to enhanced exercise performance is discussed along with a brief overview of caffeine's effects on mental and emotional health. Over 100 references cited in this review were part of a more extensive literature base obtained from several on-line services including MEDLINE and LEXIS/NEXIS medical data bases. Other sources of relevant literature included manual searches of research journals and the use of selected references from appropriate articles. The relationship between caffeine consumption and various illnesses such as cardiovascular disease and cancer remains equivocal. Prudence might dictate that pregnant women and chronically ill individuals exercise restraint in their use of caffeine, although research suggests relatively low or nonexistent levels of risk associated with moderate caffeine consumption. PMID- 7844250 TI - Loneliness, emotional repression, marital quality, and major life events in women who develop breast cancer. AB - Women awaiting mammograms at a breast clinic were given questionnaires to investigate the role of psychosocial variables in the development of breast cancer while controlling for established breast cancer risk factors. Questionnaires to determine loneliness, emotional repression, marital quality, and major life changes were completed by 826 female volunteers who were later classified into groups according to their diagnoses. The total emotional repression score showed a hierarchy of most repression to least repression for the most-diseased to the most-healthy subjects. A breakdown of the emotional repression scale revealed that each group was significantly different from the other in suppression of anger and unhappiness. Women in the new cancer group showed significantly more loneliness than the women in the fibrocystic and normal groups. The newly diagnosed cancer group also had a higher proportion of women who experienced the death of a spouse or close family member within the past two years compared to the other groups. PMID- 7844251 TI - Relationship of thalamic basal forebrain projection neurons to the peptidergic innervation of the midline thalamus. AB - To better understand the input-output organization of the midline thalamus, we compared the distribution of its peptidergic and monoaminergic afferents, which were visualized by using immunocytochemistry, with the distribution of neurons projecting to different basal forebrain structures, which were mapped using retrograde fluorescent tracers. Serotonin and most of the peptides were found throughout paraventricular thalamic nucleus (PV) and in other midline and intralaminar nuclei (type 1 pattern). Neuropeptide Y, alpha MSH and the catecholamine synthetic enzymes were largely restricted to dorsolateral PV (type 2 pattern). Vasopressin was found in dorsomedial PV and intermediodorsal nucleus in a pattern complementary to the type 2 distribution (type 3 pattern). Neurons projecting to accumbens core were present in paraventricular, intermediodorsal, and other midline nuclei. Neurons projecting to accumbens shell and to central amygdaloid nucleus were found in dorsal PV. The peptidergic zones were only loosely correlated with the distribution of different classes of projection neurons. The type 2 pattern overlapped best with neurons projecting to accumbens shell, and to a lesser extent to central amygdaloid nucleus, while the type 3 pattern overlapped best with neurons projecting to core of accumbens. This partial overlap suggests that some brainstem and hypothalamic nuclei preferentially affect different basal forebrain targets through the midline thalamus, and may allow, for example, information about stress to specifically influence accumbens shell and central amygdaloid nucleus. Nevertheless, most of the peptidergic afferents (type 1 pattern) to midline thalamus cover neurons projecting throughout the basal forebrain, which suggests that all of these neurons receive a variety of brainstem and hypothalamic inputs. PMID- 7844252 TI - Undernutrition during early life does not affect the number of granule cells in the rat olfactory bulb. AB - Undernutrition during early life causes deficits and distortions of brain structure. However, whether or not this includes a diminution of the total numbers of neurones remains uncertain. Recent advances in stereological techniques have made it possible to obtain unbiased estimates of total numbers of cells in well-defined biological structures. Rats were undernourished from conception to 90 postnatal days of age by standardised procedures. Groups of well fed control and undernourished rats were anaesthetised and killed by intracardiac perfusion with fixatives at 30 and 90 days of age. Each olfactory bulb was serially sectioned at a nominal thickness of 100 microns on a vibratome. These sections were analysed by the Cavalieri principle to obtain estimates of the total volume of the olfactory bulb as well as the volume of its granule cell layer. The physical "disector" method was later used on serial 1-micron-thick toluidine-blue-stained sections to estimate the numerical density of granule cell neurones in the olfactory granule cell layer. These values were used to compute estimates of the total number of olfactory granule cell neurones for each animal. Thirty-day-old control and undernourished rats had between 2.6 and 3 million granule cell neurones in the olfactory bulb. By 90 days of age the number of granule cells had increased in both groups of animals to between about 4.2 and 5.2 million cells. Analysis of variance tests showed a significant main effect of age but not nutrition in these estimates. Although the interaction term did reach statistical significance, post hoc analysis did not reveal any differential effect of undernutrition between the two age groups examined.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7844253 TI - Ultrastructural and morphometric features of the acetylcholine innervation in adult rat parietal cortex: an electron microscopic study in serial sections. AB - This study was aimed at characterizing the ultrastructural morphology of the normal acetylcholine (ACh) innervation in adult rat parietal cortex. After immunostaining with a monoclonal antibody against purified rat brain choline acetyltransferase (ChAT), more than 100 immunoreactive axonal varicosities (terminals) from each layer of the Par 1 area were photographed and examined in serial thin sections across their entire volume. These varicosities were relatively small, averaging 0.6 micron in diameter, 1.6 microns 2 in surface, and 0.12 micron 3 in volume. In every layer, a relatively low proportion exhibited a synaptic membrane differentiation (10% in layer I, 14% in II-III, 11% in IV, 21% in V, 14% in VI), for a I-VI average of 14%. These synaptic junctions were usually single, symmetrical (> 99%), and occupied a small portion of the surface of varicosities (< 3%). A majority were found on dendritic branches (76%), some on spines (24%), and none on cell bodies. On the whole, the ACh junctional varicosities were significantly larger than their nonjunctional counterparts, and both synaptic and nonsynaptic varicosities could be observed on the same fiber. A subsample of randomized single thin sections from these whole varicosities yielded similar values for size and synaptic frequency as the result of a stereological extrapolation. Also analyzed in single sections, the microenvironment of the ChAT-immunostained varicosities appeared markedly different from that of unlabeled varicosity profiles randomly selected from their vicinity, mainly due to a lower incidence of synaptically targeted dendritic spines. Thus, the normal ACh innervation of adult rat parietal cortex is predominantly nonjunctional (> 85% of its varicosities), and the composition of the microenvironment of its varicosities suggests some randomness in their distribution at the microscopic level. It is unlikely that these ultrastructural characteristics are exclusive to the parietal region. Among other functional implications, they suggest that this system depends predominantly on volume transmission to exert its modulatory effects on cortical activity. PMID- 7844255 TI - GABAergic terminals in nucleus magnocellularis and laminaris originate from the superior olivary nucleus. AB - The auditory brainstem nuclei, angularis (NA), magnocellularis (NM), and laminaris (NL) of the chicken, Gallus, contain terminals that stain for antibodies against the inhibitory neurotransmitter, gamma-aminobutyric acid (GABA). Some of these terminals originate from cells surrounding nucleus magnocellularis. Results from this study indicate that the majority of the GABAergic terminals found in NA, NM and NL originate from the superior olivary nucleus (SON). Injections of cholera toxin and horseradish peroxidase show that superior olivary nucleus (SON) neurons, which respond to pure tones, project bilaterally to NA, NM, and NL. NA and NL are reciprocally connected with the SON. More NA cells project to the SON than NL cells. While SON neurons project to NM, NM neurons do not project axons back to the SON. The configuration of SON terminals in NA, NM and NL matches the pattern of GABA-immunoreactive puncta seen in these three nuclei: they surround individual NM cells, congregate in the dendritic neuropil of NL, and blanket the NA. The data indicate that NA, NM and NL may be affected by two different inhibitory cell types: local interneurons and SON neurons. Patterns of connectivity described in this report suggest that the activity of NA cells could influence NM and NL cell physiology. Specifically, increases in NA cell activity could augment the effects of GABAergic SON neurons on NM and NL. Hence, binaural perception in the chicken may be more dependent upon changes in intensity cues than previously believed. PMID- 7844254 TI - Connectivity of the lobus parolfactorius of the domestic chicken (Gallus domesticus): an anterograde and retrograde pathway tracing study. AB - In 1-week-old domestic chicks, the connectivity of the lobus parolfactorius (LPO), part of the avian basal ganglia, was investigated using Phaseolus vulgaris leucoagglutinin and horseradish peroxidase for anterograde and retrograde pathway tracing, respectively. Tyrosine hydroxylase immunocytochemistry was applied in combination with Phaseolus lectin to assess the overlap between LPO efferents and diencephalic and mesencephalic catecholamine centres. Anterograde projections from LPO were detected in the hyperstriatum, neostriatum, and paleostriatum. Intranuclear connections were also apparent within the LPO. Descending LPO efferents innervated the lateral mammillary and intramedial nuclei and the dorsomedial thalamic complex. Fibres from LPO were observed in the tectal gray, substantia nigra, area ventralis tegmentalis of Tsai, and the adjacent nucleus mesencephalicus profundus. Further caudally, projections from LPO reached the nucleus papillioformis, locus coeruleus, and subcoeruleus ventralis. LPO efferents were coextensive with tyrosine hydroxylase-positive cells in the nuclei mamillaris lateralis and intramedialis of the hypothalamus, area ventralis tegmentalis, substantia nigra, locus coeruleus, and subcoeruleus ventralis of mesencephalic and pontine tegmentum. Close contacts between LPO fibres and catecholamine cells were visible in the nigra and the area ventralis tegmentalis. Retrograde labelling from LPO was found in the archistriatum, dorsomedial thalamic complex, nuclei lateralis anterior and superficialis parvicellularis thalami, substantia nigra, central gray, area ventralis tegmentalis of Tsai, and locus coeruleus and in cells dorsal to the decussation of brachium conjunctivum. Reciprocal connections were verified between the LPO and the following areas: dorsomedial thalamic complex, central gray, substantia nigra, area ventralis of Tsai, and locus coeruleus. PMID- 7844256 TI - Distribution of preproenkephalin mRNA in the chicken and pigeon telencephalon. AB - Bioassay and immunological studies have detected the presence of opioid peptides in the nervous system of representatives of all classes of vertebrates. The present study evaluates the expression and localization of preproenkephalin (PPE) mRNA to determine the sites of synthesis of the enkephalin peptides in the adult chicken and pigeon telencephalon using in situ hybridization histochemistry. We used a 500-base-pair chicken RNA probe corresponding to chicken PPE cDNA. In both the chicken and the pigeon telencephalon, the highest concentration of PPE mRNA containing cells was observed in the lobus parolfactorius, paleostriatum augmentatum, nucleus accumbens, and septum. Distinct populations of labeled cells were also detected in the hyperstriatum accessorium, hippocampus, area parahippocampalis, nucleus of the diagonal band, cortex dorsolateralis, and cortex piriformis. Differences in PPE mRNA expression between chicken and pigeon were observed in several telencephalic regions. For instance, the bulbus olfactorius was heavily labeled in the pigeon, but was not labeled in the chicken, and numerous PPE mRNA-containing cells were present in the area parahippocampalis of pigeons but not of chickens. In contrast, in the hyperstriatum dorsale and hyperstriatum ventrale, numerous PPE mRNA-expressing cells were detected in the chicken but not in the pigeon. Overall, PPE mRNA expressing cells were more numerous than enkephalin-immunoreactive cells described in previous studies. In addition, our results suggest that the general pattern of enkephalin expression in the avian telencephalon is similar to that found in other vertebrates. Finally, the results of the present study illustrate some differences in the pattern of PPE mRNA distribution between closely related species, indicating the existence of species-specific neurochemical pathways, which may influence and perhaps mediate different behaviors characteristics of these species. PMID- 7844257 TI - Spatially and temporally differentiated patterns of c-fos expression in brainstem catecholaminergic cell groups induced by cardiovascular challenges in the rat. AB - Brainstem catecholaminergic neurons have been implicated as mediating adaptive autonomic and neuroendocrine responses to cardiovascular challenges. To clarify the nature of this involvement, immuno- and hybridization histochemical methods were used to follow c-fos expression in these neurons in response to acute stimuli that differentially affect blood pressure and volume. From low basal levels, hypotensive hemorrhage (15%) provoked a progressive increase in the number and distribution of Fos-immunoreactive (ir) nuclei in the nucleus of the solitary tract (NTS), the A1 and C1 cell groups of the ventrolateral medulla, and in the pontine A5, locus coeruleus, and lateral parabrachial cell groups peaking at 2.0-2.5 hours after the challenge. Fos-ir ventrolateral medullary neurons, subsets of which were identified as projecting to the paraventricular hypothalamic nucleus or spinal cord, were predominantly aminergic, whereas most of those in the NTS were not. Infusion of an angiotensin II antagonist blunted hemorrhage-induced Fos expression in the area postrema, and attenuated that seen elsewhere in the medulla and pons. Nitroprusside-induced isovolemic hypotension yielded a pattern of c-fos induction similar to that seen following hemorrhage, except in the area postrema and the A1 cell group, where the response was muted or lacking. Phenylephrine-induced hypertension stimulated a restricted pattern of c-fos expression, largely limited to induced hypertension stimulated a restricted pattern of c-fos expression, largely limited to non-aminergic neurons, whose distribution in the NTS conformed to the termination patterns of primary baroreceptor afferents, and in the ventrolateral medulla overlapped in part with those of vagal cardiomotor and depressor neurons. These findings underscore the importance of brainstem catecholaminergic neurons in effecting integrated homeostatic responses to cardiovascular challenges and their ability to responding strategically to specific modalities of cardiovascular information. They also foster testable predictions as to effector neuron populations that might be recruited to respond to perturbations in individual circulatory parameters. PMID- 7844258 TI - Dynamics of retinotectal synaptogenesis in normal and 3-eyed frogs: evidence for the postsynaptic regulation of synapse number. AB - Quantitative stereological methods were used to determine if the number, density, and types of synaptic connections formed during development are regulated by presynaptic input or by postsynaptic target cells in the optic tectum of normal and 3-eyed Rana pipiens tadpoles and frogs. Our analysis indicates that the number and size of synapses is approximately the same in both tecta of 3-eyed tadpoles and frogs, even though one tectal lobe is receiving input from twice the normal complement of retinal ganglion cells. Moreover, the number and size of synapses in the tectal lobes of 3-eyed animals did not differ significantly from values determined for normal tadpoles and frogs of the same developmental stage. These data suggest strongly that developing tectal cells regulate the number of synaptic contacts they will form. Differences in several morphological features between singly and doubly innervated tecta, however, including synapse density, distribution and complexity, amount of extracellular space, and number of myelin figures, suggest that the presence of supernumerary input retards tectal maturation. We propose that the noncorrelated activity of retinal ganglion cell terminals in the doubly innervated tectum results in fewer stabilized synapses per unit volume of neuropil and in the delayed maturation of the tectal neuropil. Taken together, our data suggest a complex dynamic interaction between retina and tectum during development. PMID- 7844259 TI - Pharmacological control of periodontal disease. I. Antiplaque agents. AB - Inhibition of the development of dental plaque remains one of the primary aims of periodontal care. Many patients, however, are unable to master completely the mechanical methods of plaque control and for this reason, considerable research efforts have been directed towards the development and use of chemical agents to inhibit the growth of plaque. This first of two articles, therefore, examines the pharmacological properties and efficacy of commercially available antiplaque agents. We have also summarized the findings of some of the major clinical trials that have provided the scientific basis for the introduction of these agents for the management of gingival inflammation. PMID- 7844260 TI - Analgesic agents and strategies in the dental pain model. AB - Pain following removal of impacted third molar teeth has proven to be a useful clinical model for evaluating oral analgesics. Moreover, as the underlying pathophysiology becomes elucidated the model serves as a tool for monitoring the relative contributions of different pain events, including peripheral and central sensitization. Non-steroidal anti-inflammatory drugs (NSAIDs) demonstrate high potency in this model, reflecting the large contribution that peripheral prostaglandins may make to the pathophysiology of postoperative pain. However, other analgesic agents, with weak activity against peripheral prostaglandin synthesis (e.g. paracetamol, opioid analgesics), may also provide pain relief in the dental pain model. The activity of these agents is dependent on the time and method of administration, and may be related to more centrally located analgesic activity, or to peripheral actions other than inhibition of prostaglandin synthesis. In single dose studies it is possible to enhance pain relief by combining analgesic agents of different activities, e.g. ibuprofen 400 mg and codeine 20 mg. Such enhanced activity is also demonstrated by higher doses of certain NSAIDs, e.g. ketoprofen 100 mg. This may reflect the existence of complimentary analgesic activities within a single therapeutic agent. As a clinical research tool the dental pain model has several attributes which suggest that it will continue to be of value in identifying potentially improved analgesic strategies for postoperative pain. PMID- 7844261 TI - Clinical performance of porcelain laminate veneers without incisal overlapping: 3 year results. AB - The aim of this clinical trial was to evaluate the performance of 135 porcelain laminate veneers placed on anterior teeth without incisal preparation. Only 0.3 0.5 mm of the facial enamel was removed using a tapered round-ended diamond bur. The veneers were fabricated from a sintered feldspathic porcelain, etched and silanized and then bonded with a light-cured composite lute. The veneers were yearly examined clinically for debonding, chipping, marginal integrity and staining. After 3 years of service all veneers were retained. Incisal chipping occurred in seven veneered teeth. Wear and staining were negligible. It was concluded that this minimal porcelain veneer restoration with no incisal overlapping was conservative, predictable and successful. PMID- 7844262 TI - Clinical performance of machined titanium restorations. AB - In 37 patients 88 titanium restorations were placed during a 1-year period 1990 91. The 69 crowns and 19 fixed partial dentures comprised 147 prosthodontic units. All restorations were fabricated by duplication milling and electrical discharge machining of pure titanium (Procera Technology, Nobelpharma, Gothenburg, Sweden). Based on the results of clinical follow-up, Kaplan-Meier survivor functions were calculated. The survivor rate of 40 metal crowns and pontics was 100%. In 107 porcelain-fused-to-metal units the 3-year survivor rate concerning removal was 95%. When relating the survival to an intact ceramic veneer, the 3-year survivor rate of porcelain-fused-to-metal units was 84%. The quality of the restorations evaluated by the rating system of the California Dental Association was found to be satisfactory in the vast majority of cases. It can be concluded that machined titanium restorations are suitable for clinical use, although not all problems, especially in the field of metal-ceramics have yet been completely solved. PMID- 7844263 TI - Factors affecting the role of dental surgery assistants in cross-infection control in dental practice. AB - A study of cross-infection control in general dental practices in the North Western Health Region of England suggested that much of its quality might lie in the hands of dental surgery assistants (S. Doohan, 1991, personal communication). The present paper describes part of a programme of work intended to improve cross infection control in general dental practices and to discover any factors which might affect this control. A qualitative study of dental surgery assistants' behaviour was used to devise an interview schedule for making quantitative assessments; these were made in visits to 82 general dental practices. A high proportion of DSAs were aware that they are failing to carry out cross-infection control procedures and were worried by this. PMID- 7844264 TI - Effect of food and oral simulating fluids on dentine bond and composite strength. AB - The effect of up to 30 days' immersion in 75% ethanol solution and in an artificial saliva (Moi-Stir) on the dentine shear bond strength (SBS) of three adhesive/composite systems (Tenure/Marathon One, Scotchbond Multi-Purpose/Z100 and Optibond/Herculite XRV) was evaluated. Two control series were stored either in 100% humidity or in air. Diametral tensile specimens (DTS) of the composites studied were stored in 75% ethanol for up to 30 days. The fracture mode and morphology of the failure interface were examined by scanning electron microscopy (SEM). Data were analysed using ANOVA and the Tukey LSD test. The SBS for all systems stored in Moi-Stir (24.8 +/- 3.0 MPa) and air (28.3 +/- 3.0 MPa) was not influenced by length of storage. Microscopic (SEM) examination of the debonded air, and Moi-Stir stored specimens showed that failure had primarily occurred through the dentine. Significant decreases (30-50%) in the SBS of all systems occurred after immersion in 75% ethanol. There was no significant difference among brands. The DTS of the composites showed significant decreases as a function of ethanol exposure. Marathon One and Herculite XRV showed significantly lower DTS after 14 days' storage while Z100 showed no reduction in DTS until after 30 days. The decrease in both SBS and DTS after storage in ethanol was a function of the square root of time (P < 0.001) and followed Fick's laws of diffusion. Ethanol diffusivity was approximated as 1.8 x 10(-6) cm2 s-1 for both SBS and DTS specimens, suggesting that alcohol attack in SBS specimens occurred primarily in the composite system.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7844265 TI - Effect of radiant heat on the surface hardness of glass polyalkenoate (ionomer) cement. AB - The use of heat to improve mechanical properties of materials is a widely accepted phenomenon. It has been studied in dentistry with a view to improving the properties of resin composite. Dental cements may benefit by the application of heat, in particular with regard to their early surface properties. This study was carried out to examine the effect of the application of radiant heat to the surface hardness of one type of glass polyalkenoate cement. It was found that raising the temperature of the surface of the cement to a maximum of 60 degrees C significantly improved the early surface hardness of the material. The application of a high level of heat also improved the surface hardness of the cement after 24 h compared to cement which had not been heat treated. The use of heat would appear to accelerate the matrix-forming reaction of the material and although further work is necessary this technique may have clinical application. PMID- 7844266 TI - Strength-probability-time (SPT) diagram--an adjunct to the assessment of dental materials? AB - This investigation sought to construct and compare strength-probability-time (S-P T) diagrams for four dental materials. Three of these were resin composites and one was dental plaster. In the case of dental plaster a total of 90 compressive specimens as fabricated whereas for each of the other materials a total of 75 specimens was prepared. The compressive strength of equal sized groups of each material was then determined at the crosshead (XHD) speeds of 1, 5 and 10 mm min 1 respectively. The data was subjected to Weibull analysis to relate the probability of failure to the applied stress. Where strong correlations were found between the (i) mean compressive strength and crosshead speed, (ii) individual compressive strengths and failure times, the data was used to determine the crack velocity exponent (n) and produce a S-P-T diagram. Although only one of the materials (P-50) evaluated fulfilled all the necessary criteria and yielded a value of n = 16.13 (7.22), it is suggested that this method may enable comparisons to be made amongst other materials satisfying the required conditions. As such diagrams are based upon a crack growth law they may be of value in assessing the likely clinical wear resistance of new formulations. Consideration, however, should always be given to what levels are deemed acceptable for the intended clinical application of the material. Thus, before this technique can be employed fully, to the evaluation of new restorative materials, further work is necessary to determine appropriate design criteria. PMID- 7844267 TI - Three-dimensional reconstruction of microleakage pattern using a sequential grinding technique. AB - Dye penetration tests are very commonly used to detect the absence of a fluid seal at the tooth-restoration interface. Airlocks in the marginal gap, leaching of water-soluble tracers during processing, and the failure of only a few sections to allow interpretation of the full pattern, limit these tests to low reproducibility and precision. The purpose of this present study was to generate high-resolution three-dimensional images of waterfast tracer patterns. Cylindrical class V (3 mm diameter, 2 mm deep) dentine-bonded resin composite restorations in buccal coronal dentine were thermally cycled (1000 x, 8 degrees C, 55 degrees C, 30 s dwell at each temperature) and then silver stained using an initial vacuum (100 mmHg pressure). Each restoration was sequentially abraded from the free surface on wet 180 grit silicon carbide paper, producing up to 30 parallel surfaces at approximately 0.15 mm separation through the restoration down to the pulp. Images of the ground surfaces were captured, and assembled by a computer image analyser program to give a three-dimensional model of the tracer pattern. The maximum depths of tracer penetration below the reference surfaces were 3.00 mm, 2.09 mm, 3.16 mm and > 2.29 mm for the four specimens. Projections of the models were viewed from several directions with sections in various locations to allow investigation of the full tracer pattern. This method allows the creation of high-resolution three-dimensional tracer patterns. PMID- 7844268 TI - Effect of air inlet ring opening on sonic handpiece performance. AB - This study investigated the effect of air inlet ring opening on the oscillatory pattern of the MM 1500 sonic handpiece and files. The oscillatory pattern of the driver head and files in air and under load was determined microscopically. The results showed that a critical opening of the air inlet ring was necessary to elicit oscillation of the driver head and sonic file. The driver oscillated in an elliptical manner, the displacement of which varied with air inlet ring opening. When operated in air the file exhibited an elliptical movement which was influenced by different design, length and thickness. This action was constrained under load and replaced by a longitudinal action of the same dimension for all files which appeared to have an efficient cutting action. This work shows that air inlet ring opening increases oscillation of the driver head once a critical opening has been reached and that clinical loading does not constrain the cutting action of the file. PMID- 7844269 TI - Screening tests for systemic effects of dental materials. AB - Due to the minimal release of compounds from most materials, systemic toxicity effects caused by dental materials have been considered to occur very seldomly or not at all. Screening tests for systemic toxicity are therefore justified only with certain body contact for long periods of time with a dental product. The international standardization on biological evaluation of medical devices has demonstrated a need for improved screening tests and continuous revision of the standards for testing. It is obvious that certain published studies on systemic effects of dental materials and some proposed test methods do not reflect today's demand for toxicokinetic and organ effect studies. PMID- 7844270 TI - Screening tests for sensitization potential of dental materials. PMID- 7844271 TI - Animal tests for biocompatibility of dental materials--relevance, advantages and limitations. AB - Biocompatibility refers to the ability of a material to perform with an appropriate host response, in a specific application. Usage tests have been developed specifically for the evaluation of the biocompatibility of dental materials. The pulp and dentine test, the pulpotomy test and the endodontic usage test are widely recognized. The relevance, advantages and limitations of these tests are discussed with particular reference to the pulp and dentine usage test. Controversies remain in the understanding of the role of several variables in determining the outcome of this test. These are highlighted by reference to the significance of the residual dentine thickness, the smear layer and microbial microleakage at the material-cavity wall interface. Limitations in the relevance of these animal models to man due to species variations in the structure and composition of the dental tissues and their oral environment may be more perceived than real. The nature of an appropriate host response may be different in the consideration of different dental materials, for example lining materials and filling materials, and there is a need for these criteria to be reviewed. PMID- 7844272 TI - Clinical testing of dental materials--histological considerations. AB - In order to assess the biocompatibility of dental materials, clinical studies, as well as in vitro studies, are needed. Although no bacteria were detected inside tubules, pulp reactions were observed when either adhesives of the last generation aiming to create an hybrid layer were used or restorative materials controlling the interface between the biomaterial and dental tissues. However, the reactions were feeble to moderate. Reparative dentine seldom appeared after such treatments. Differences between odontoblast and pulp cells, the nature of the lesion (necrosis or apoptosis), and differences between sound experimental and carious teeth seen in the real clinical situation are discussed in the context of in vivo human studies. PMID- 7844273 TI - Clinical testing of dental materials--general clinical aspects. PMID- 7844274 TI - Biological assessment of dental materials in Europe 1993--recommendations and regulations. AB - The requirements for biological testing in Europe have evolved over the last 30 years. A milestone was passed when the EEC Directive concerning Medical Devices was published on 1 February, 1993. It included the essential requirements for medical devices used in dentistry. Many administrative problems have to be resolved in the following two years until the requirements outlined become mandatory. The certification of medical devices used in dentistry will be based on European standards which are identical or similar to international (ISO) standards. PMID- 7844275 TI - Use of cell cultures for toxicity testing of dental materials--advantages and limitations. PMID- 7844276 TI - Dean-bashing. PMID- 7844277 TI - Peer review. AB - All research agencies and prestigious journals insist they are rewarding excellence, that they have a merit-based system, and that their system serves their mission well--all part of the ideology of the infallibility of peer review. There have been, and continue to be, criticism about the peer review system and several alternatives to peer review have been posed. A discussion of peer review is intended to allow the reader to evaluate approaches to the peer review system. PMID- 7844278 TI - Clinical scholarship. AB - Clinical research in nursing is well known and well described. Clinical scholarship is an alternative, but not a substitutable, form of nursing's intellectual activity. Clinical scholarship is described with examples. It is argued that for some kinds of nursing work, clinical scholarship is the appropriate method. PMID- 7844279 TI - Nursing's international agenda: what are the WHO collaborating centers and whom do they serve? PMID- 7844280 TI - Academic and scientific misconduct: issues for nursing educators. AB - The public attention to issues of academic and research misconduct requires that all faculty and students become familiar with the policy and procedural areas and roles of various officials in handling allegations of misconduct. Although the incidence of such misconduct seems to be small, issues of reporting, adjudication, rehabilitation, and deterrence are important to all with concern about the integrity of academic processes. Many issues concerning the management of allegations of academic or research misconduct remain unresolved. Examples include the definition of misconduct, provision for (or lack of) anonymity, the role of the whistleblower, the burden of proof, the statute of limitations, the nature and application of sanctions, and the processes of rehabilitation. PMID- 7844281 TI - Is campus drinking an antecedent to professional impairment? PMID- 7844282 TI - The case study approach to teaching scientific integrity in nursing and the biomedical sciences. AB - Scientific integrity courses for graduate trainees are emerging at many institutions. The content of such courses varies and is evolving as faculty strive to meet the needs of their specific student audiences. Typical course subject matters include responsible authorship, conflict of interest, handling of scientific misconduct, data management, and the use of humans and animals in biomedical experimentation. These and other topic areas are amenable to teaching methods that use the case study approach. In this article we discuss our experiences in teaching scientific integrity using the case study approach. Issues covered include underlying philosophy of the approach, preparation and use of cases, desired inclass preparation and teaching. Examples of short cases are presented and, where appropriate, discussed in the context of these issues. PMID- 7844283 TI - The ethics of qualitative nursing research. AB - Nurse researchers conducting qualitative studies need to be acutely aware of the unique ways ethics, both nursing and research ethics, affect all phases of the qualitative research process. Decisions about what to study, which persons will be asked to participate, what methodology will be used, how to achieve truly informed consent, when to terminate or interrupt interviews, when to probe deeply, when therapy or nursing care supersedes research, and what and how case studies should be documented in the published results are all matters for ethical deliberation. This article seeks to examine some of the less obvious, yet very important, ethical concerns that nurses face throughout the research process and build a common core of values that can lead to meaningful process and socially responsible research results. PMID- 7844284 TI - Information-seeking, research utilization, and barriers to research utilization of pediatric nurse educators. AB - This study used Roger's diffusion of innovations model to examine information seeking, research utilization, and perceived barriers to research utilization of pediatric nurse educators in National League for Nursing accredited baccalaureate degree nursing (BSN) programs. A four instrument survey was mailed to 409 pediatric nurse educators. The response rate was 52 per cent. The most frequently selected sources of information for updating instruction of BSN students were nursing journals, educational activities by specialty groups, and nursing texts. The level of research utilization was estimated using the Nursing Practice Questionnaire-Education (NPQ-E). The level of research utilization for the eight nursing practices related to pediatric pain assessment and management was at the implementation stage. The highest perceived barriers to research utilization in clinical settings using the Barriers instrument were characteristics of the nurse followed by characteristics of the setting, the presentation, and the research. Pediatric nurse educators who selected nursing journals among their top three sources of information had significantly higher research utilization scores than those who did not select nursing journals among their top three sources of information. PMID- 7844285 TI - The value of women and children. PMID- 7844286 TI - Cyclical evolution of nursing education and profession in Iran: religious, cultural, and political influences. AB - This article was written to gain some insight into the underlying social and/or cultural forces that have, over the centuries, influenced the development of nursing education and the nursing profession in Iran, one of the most ancient civilizations of the world. As a native of Iran deeply involved in the nursing profession and in many aspects of nursing education, I decided to review my many years of experience and observations in these fields in Iran to better understand how the noble profession evolved as it did in my native country. For the years following the Islamic Revolution of 1977 to 1979, I was forced to rely on information gathered from my professional colleagues. An extensive search of the literature yielded a better understanding of the very early years. Analysis of this data seemingly produced a potpourri of such basic issues as modes of education, cultural/religious states of consciousness, and the rights of women. These are not factors generally considered germane to the development of the nursing profession and nursing education, although the latter two have proven to be crucial issues in understanding the development and current status of nursing education and the nursing profession in Iran. PMID- 7844287 TI - Entrepreneurial ethics: a contextual perspective. PMID- 7844289 TI - Dentistry has been good to me. PMID- 7844288 TI - Conflict resolution: critical to productive schools of nursing. AB - Conflict, a normal component of university life, is enhanced in today's schools of nursing because of declining resources and increased expectations of faculty. Management of conflict for positive change and increased productivity is essential for academic leaders. A variety of strategies to diagnose, confront, and resolve conflict are important resources to facilitate change and allow faculty and administrators to respond to new opportunities and challenges. Collaboration and win/win strategies are ideal, but not always possible. Alternative approaches to confront destructive conflict, yet present options that benefit individuals as well as schools are also essential. PMID- 7844290 TI - On implants and dentures. PMID- 7844291 TI - Implants and O-rings. PMID- 7844292 TI - A social responsibility. PMID- 7844293 TI - Cancer screening. PMID- 7844294 TI - A failure of vigilance. PMID- 7844295 TI - Oral ulcers remedy gets FDA clearance. PMID- 7844296 TI - Spotlight on today's major issues. Five share their views. PMID- 7844297 TI - The effects of bleaching application time on the dental pulp. AB - This study evaluated and compared pulpal responses of teeth exposed to a 10 percent carbamide peroxide bleaching gel using short and extended application times. Of 28 subjects, four discontinued use because of thermal sensitivity. For the remaining participants, there was no difference between the pulpal readings recorded before the use of the gel or at any point during the study. PMID- 7844298 TI - Using a fluoride-releasing resin to reduce cervical sensitivity. AB - Significant research indicates that dental hypersensitivity is caused by open dentinal tubules. A review of such research is presented as well as results of a study using fluoride resin in a composite restoration to reduce sensitivity. PMID- 7844299 TI - Nature vs. nurture in dental caries. AB - Why are some people more resistant to dental caries than others? Certainly diet plays a part, but are there hereditary factors that affect caries development? This report explores genetic components that appear related to caries resistance and susceptibility. PMID- 7844300 TI - Pain response after psychological preparation for repeated periodontal surgery. AB - The effects of pre-surgery intervention messages on postsurgical pain and recovery in 42 female patients were compared. Each participant was scheduled for at least two periodontal surgeries and exposed to one of four messages before each surgery. Auditory and visual messages classified as "control enhancement" were associated with reduction of pain after the second surgery with no effect after the first surgery. PMID- 7844301 TI - Identifying true lidocaine allergy. AB - Allergies to local anesthetics are rare. More often, the allergic response is caused by a metabolite, preservative or unrelated substance. At times, an apparent allergic reaction can be brought on by anxiety. An idiopathic reaction to lidocaine is described, and allergy testing is discussed. PMID- 7844302 TI - Coronal leakage: bacterial penetration through obturated canals following post preparation. AB - Coronal leakage of bacteria from saliva into root canal filling materials is a potential cause of failure. This problem may be more pronounced when only a small volume of obturating material remains in the canal, such as after post preparation. In this study, coronal leakage of bacteria through unsealed, apically obturated canals was investigated using a new in vitro model system. PMID- 7844303 TI - Managing dental patients with joint prostheses. AB - A literature review explored the possible association of late infections of major joint prostheses and dental bacteremias. The review showed transient dental bacteremias had little or no role in causing late infections of prosthetic joint replacements. However, patients with certain systemic conditions or complications with their prostheses may be at greater risk for infection after transient dental bacteremias. PMID- 7844304 TI - Should you and can you afford to bond amalgams? PMID- 7844305 TI - Dental malpractice liability insurance market: surveys of insurers and insurance commissioners. AB - Surveys of malpractice insurers and state insurance commissioners in 1992 show a highly concentrated market with opportunities for greater competition. Fewer than 50 firms write coverage nationally. Weighted premiums for $1 million/$3 million coverage vary across U.S. census divisions from $1,700 in the South to $3,000 in the Northeast. These data may be of interest to practitioners who purchase insurance and will aid dental associations in effectively participating in revisions of malpractice liability statutes as part of overall health care reform. PMID- 7844306 TI - Building the relationship between general practice and specialty dentists. AB - Consultation is the cornerstone on which a strong referral relationship is built. Too often, general dentists and specialists underestimate the expertise of the primary practitioner. The importance of each professional is considered and situations are used to illustrate how the patient can be shortchanged when the two don't work as a team. PMID- 7844307 TI - The proof is in the patient. PMID- 7844308 TI - Parvocellular neurons of the paraventricular nucleus are involved in the reduction in renal nerve discharge during isotonic volume expansion. AB - The parvocellular neurons of the paraventricular nucleus (PVN) of the hypothalamus are known to be involved in the control of central autonomic outflow. While the PVN is also known to be involved in the control of fluid balance, most of the studies examining this nucleus have emphasized the magnocellular neurons, which are involved in the humoral control of fluid-balance and related hemodynamics. The present study took advantage of the differential sensitivity of these two cell types to kainic acid as a means of investigating the role of the parvocellular neurons in the reflex reduction of renal sympathetic nerve discharge (RSND) during acute isotonic volume expansion. Kainic acid (18 pmol), which destroys parvocellular but not magnocellular neurons in the PVN, was microinjected (20 nl) bilaterally at sites in and adjacent to the PVN 3 4 days prior to acute isotonic volume expansion. In anesthetized rats RSND decreased by 59% at the completion of acute isotonic volume expansion (10% of body weight) in the vehicle-injected control group; on the other hand, it decreased by 33% in the kainic acid-treated group. The effect of destruction of the parvocellular neurons on the baroreceptor reflex was also examined. Neither the renal nerve component (delta %RSND/delta AP), nor the heart rate component (delta HR/delta AP), of the baroreceptor reflex were different in the kainic acid treated group (3.1 +/- 0.4, and 1.1 +/- 0.1, respectively) than in the vehicle injected control group (2.9 +/- 0.7, and 0.8 +/- 0.1, respectively). We conclude that the parvocellular neurons of the PVN are an important synaptic relay site in the reflex are that is activated during isotonic volume expansion, but not in the baroreceptor reflex. PMID- 7844309 TI - Excitatory amino acid projections to the nucleus of the solitary tract in the rat: a retrograde transport study utilizing D-[3H]aspartate and [3H]GABA. AB - Afferents to the nucleus tractus solitarius utilizing excitatory amino acid transmitters were described in rat brain by autoradiography following microinfusion and retrograde transport of D-[3H]aspartate. Parallel experiments with the injection of [3H]GABA were employed to establish the transmitter selective nature of the retrograde labelling found with D-[3H]aspartate. Following infusion of D-[3H]aspartate, perikaryal labelling was heaviest in myencephalon, where at least 16 discrete nuclei were labelled. Heaviest labelling was localized bilaterally in the trigeminal nucleus with cells extending through its subdivisions and the entire rostrocaudal axis. Intense labelling was also obtained in the inferior olive, predominantly contralaterally, and non-perikaryal labelling noted. Vestibular, reticular and raphe nuclei contained heavily labelled perikarya. In cervical spinal cord, a moderate density of labelled cells was found in dorsal horn, adjoining the central canal (lamina X) and in the central cervical nucleus, along with appreciable labelling of processes and non perikaryal labelling. The relative density of labelled perikarya in mesencephalic nuclei was much lower than found in myencephalon, although D-[3H]aspartate produced topographic and precise labelling of a small number of cells in the periaqueductal gray, medial parabrachial nucleus and Koelliker-Fuse nucleus. Only weak labelling was found in cortex and hypothalamus. Labelled cells were not consistently observed in other regions (stria terminalis, amygdala, fastigial nucleus, locus coeruleus and rostral ventrolateral medulla) known to innervate the nucleus tractus solitarius. Lower densities of labelled perikarya were found after the microinjection of [3H]GABA, and the only regions in which a small number of cells were labelled by both D-[3H]aspartate and [3H]GABA were trigeminal nucleus, reticular nuclei and raphe obscurus. An exception was the ventrolateral medulla, where [3H]GABA produced precise labelling in the nucleus ambiguus and facial nucleus consistent with previous evidence for a GABAergic pathway from this area to the nucleus tractus solitarius. Our findings confirm the selectivity of the retrograde transport of D-[3H]aspartate and [3H]GABA. Overall, the transport of D-[3H]aspartate revealed a complex topographic and convergent network of afferent pathways to the nucleus tractus solitarius likely to utilize an excitatory amino acid transmitter. PMID- 7844310 TI - Cardiovascular effects of microinjection of atrial natriuretic factor (ANF) in the nucleus tractus solitarii of spontaneously hypertensive rats. AB - The effects on mean arterial pressure (MAP) and heart rate (HR) of unilateral microinjections of atrial natriuretic factor (ANF) into discrete sites of the nucleus tractus solitarii (NTS) of spontaneously hypertensive rats (SHR) were compared with those observed in normotensive Wistar-Kyoto rats (WKY). NTS sites were identified to be involved in cardiovascular control on the basis of the bradycardia and hypotension elicited by microinjections of 20 nl of 0.1 M L glutamate. Microinjection of 20 nl of 10(-7) M ANF into 38 NTS 'cardiovascular sites' in rats of the SHR strain decreased MAP (-8.7 +/- 1.8 mmHg) and HR (-7.8 +/- 1.9 bpm) in 9 sites (24%), but caused no changes in the remaining 29 sites (76%). In WKY rats 35 cardiovascular sites within the NTS were studied. In 18 sites (51%) ANF microinjections induced a decrease in MAP (-15.1 +/- 1.9 mmHg) and in HR (-18.1 +/- 3.9 bpm), whereas the remaining 17 sites (49%) were unaffected. The decreased responsiveness of the NTS to ANF in the SHR animals could play a role in the development and/or maintenance of the elevated arterial blood pressure in genetically hypertensive rats. PMID- 7844311 TI - The role of GABA in the central regulation of AVP and ANP release and blood pressure due to angiotensin and carbachol, and central GABA release due to blood pressure changes. AB - To assess whether GABA given intracerebroventricularly (i.c.v.) affects vasopressin (AVP) and atrial natriuretic peptide (ANP) release and changes in blood pressure in response to i.c.v. angiotensin (AT II) and carbachol (CB), or whether changes in blood pressure affect GABA release in the brain, experiments were carried out. In experiment I (Ex I), GABA (100 micrograms) with AT II (50 ng) or CB (25 ng) was i.c.v. administered in conscious rats (n = 12). The same dose of AT II or CB alone also was administered without GABA (n = 12). In experiment II (Ex II), AT II (100 ng/kg per min) or nitropuruside (NP, 10 micrograms/kg per min) was intravenously (i.v.) infused and GABA release in the area adjacent to the paraventricular nucleus was determined, using the microdialysis method, in conscious rats (n = 12). In the experiments, mean arterial blood pressure (MABP), heart rate (HR), plasma AVP and/or ANP and plasma Na+ and K+ levels were measured. In Ex I, i.c.v. AT II increased plasma AVP and MABP without changes in HR and plasma ANP, but i.c.v. GABA never affected these responses. Icv CB also increased plasma AVP and MABP with decreased HR, but did not affect plasma ANP. Icv GABA abolished bradycardiac responses, but did not affect the others. In Ex II, the pressor response to i.v. AT II increased GABA release without apparent decreases in plasma AVP. However, the depressor response to NP produced decreases in GABA release with increased plasma AVP. These results shows that i.c.v. GABA did not affect AVP and pressor responses to i.c.v. AT II and CB, but changes in blood pressure modulates GABA release in the brain with changes in plasma AVP. PMID- 7844312 TI - Neuronal expression of Fos protein in the rat brain after baroreceptor stimulation. AB - The purpose of this study was to identify the CNS neurons that express Fos protein after repeated activation of the baroreceptor reflex. This was done in Wistar rats anesthetized with urethane and alpha-chloralose with careful physiological controls. The intact control rat showed few Fos-immunoreactive (ir) neurons, whereas the anesthetized control rat showed many Fos-ir neurons in the CNS from the medulla oblongata to the forebrain. After repeated stimulation of baroreceptors by pressor responses to phenylephrine (dose), we counted the amounts of Fos-ir neurons (response). The correlation coefficient of the dose response relationship was high, and significant only in the medial part of the nucleus tractus solitarii (NTS) in the medulla and periaqueductal gray (PAG) in the midbrain, whereas it was comparatively high but insignificant in the commissure and lateral parts of the NTS, caudal and rostral ventrolateral medulla, periambiguus nucleus, dorsal and ventral medullary reticular nuclei, lateral parabrachial nucleus, paraventricular nucleus thalamus, and dorsomedial nucleus hypothalamus. No significant correlation was found in the humoral control nuclei in the preoptico-hypothalamic structure. Fos expression was never detected in the sensory neurons in the ganglia petrosum and nodosum, and in the sympathetic preganglionic neurons in the intermediolateral nucleus of the thoracic spinal cord. This study shows that Fos expression in the CNS neurons is induced not only by baroreceptor stimulation but also by anesthesia and/or sham operation, and that Fos expression in the NTSm and PAG neurons faithfully responds to baroreceptor stimulation. PMID- 7844313 TI - A unique receptor-mediated mechanism in vagal chemoreception of somatostatin in the hepatoportal area. AB - Our previous results have indicated that the hepatic vagus is receptive to intraportal appearance of somatostatin-14 (SS), a gastroenteropancreatic peptide hormone, in rat. To examine the actual involvement of the SS receptor mechanism in the neural reception, the receptor function was modified with monoclonal antibody against rat neural SS receptor. Our monoclonal antibody of IgG1(kappa) isotype bound to the SS binding site of the receptor in competition with the ligand. Intraportal SS injection at a physiological dose (3.05 pmol) significantly facilitated the afferent firing discharge rate of the hepatic vagus in rats anesthetized with urethane and chloralose. The antibody ascites, but not the control ascites, administered intraportally 5 min prior to the SS injection abolished completely the SS-induced increase in discharge rate. However, when the antibody was administered more than 15 min after the SS injection, the SS-induced increase in discharge rate did appear, implying an unique post-receptor mechanism in reception. The present results indicate that the SS receptor mechanism operates in the neurochemoreception of SS, suggesting the existence of a hepatic vagal, receptor-mediated system for monitoring the hormone secreted from the splanchnic organs. PMID- 7844314 TI - Lack of long-term potentiation, non-cholinergic transmission and muscarinic inhibition in cat superior cervical ganglia innervated by nodose ganglion cells. AB - In anesthetized cats, in which a nodose-superior cervical ganglion (SCG) anastomosis had been performed 6-9 months earlier, the nictitating membrane contraction evoked by electrical stimulation of the cervical vagus nerve ipsilateral to the anastomosis was recorded. The competence of nodose neurons in regulation the multiple synaptic mechanisms of the sympathetic ganglion was tested by comparing this response with the responses to stimulation of (self reinnervated SCG). The response of the nictitating membrane ipsilateral to the anastomosis was smaller and had a lower EC50 for hexamethonium (C6) than the responses of the nictitating membrane ipsilateral to the intact or sutured CST. A 40 Hz 10s stimulus train to the intact or sutured CST produced potentiation of ganglionic transmission lasting 1 hour or longer, while a similar stimulus train to the anastomosed cervical vagus nerve produced no potentiation. During block of ganglionic nicotinic transmission with C6, CST or vagus nerve stimulation evoked responses which increased in amplitude with increasing stimulus frequency and were blocked by the selective muscarinic receptor antagonist pirenzepine. When the anticholinesterase eserine was added, the responses evoked by preganglionic stimulation decreased in amplitude in the intact SCG, as previously shown [7], and in the self-reinnervated SCG. This effect, which is due to inhibition mediated by muscarinic receptors selectively blocked by AF-DX116, was absent in the anastomosed SCG. During block of ganglionic transmission with C6 and atropine, a 40 Hz stimulus train to the intact or to the sutured CST evoked a slow, small amplitude contraction that was enhanced by naloxone. This response, most likely mediated by peptides [6], was absent in the anastomosed SCG.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7844315 TI - Effect of chromogranin A on central autonomic control of blood pressure. AB - We investigated the effect of exogenous chromogranin A (CgA) on central autonomic structures involved in the control of blood pressure. Actions of CgA were assessed on neurons in the rostral ventrolateral medulla, the most important brain area for cardiovascular control and for generation of sympathetic activity. Changes in renal sympathetic nerve activity, arterial pressure, heart rate, and somato-sympathetic reflexes were measured after microinjections of chromogranin A into the rostral ventrolateral medulla of anesthetized rats. The sites of microinjection of chromogranin A were determined from well known sympathetic and cardiovascular responses to microinjection of the inhibitory amino acid glycine. Significant decreases in renal nerve activity and arterial blood pressure began 10 min after microinjection of chromogranin A into the rostral ventrolateral medulla, and the maximum effect was observed at 20 min. Moreover, the bulbar component of somato-sympathetic reflexes was depressed 20 min after microinjections of chromogranin A. Our results indicate that chromogranin A can modify the activity of neurons within rostral ventrolateral medulla involved in regulation of cardiovascular autonomic control. PMID- 7844316 TI - Participation of nitric oxide in the nicotine-induced relaxation of the cat lower esophageal sphincter. AB - The participation of nitric oxide in the relaxation of the cat lower esophageal sphincter muscle strip in response to electrical field stimulation or administration of nicotine was studied. The nicotine-induced relaxation was mediated via a neuronal pathway, since it was inhibited by administration of hexamethonium or tetrodotoxin. Inhibition of nitric oxide biosynthesis by N-nitro L-arginine decreased the relaxation induced by nicotine (50 microM) or field stimulation. With the maximal concentration of N-nitro-L-arginine (1 mM) electrical field stimulation-induced relaxation was abolished, while nicotine induced relaxation decreased by 70%. L-Arginine (1 mM) partly restored this relaxation. Desensitization of P2x receptors by alpha, beta methylene-adenosine 5 triphosphate (alpha, beta-m-ATP) did not change the relaxation induced by either electrical field stimulation or administration of nicotine. It is therefore suggested that the field stimulation-induced relaxation is mediated by the release of nitric oxide, but in the nicotine-produced relaxation is only partly due to nitric oxide, other factor(s) might be also be involved. PMID- 7844318 TI - Changes in neuronal contribution to contractile responses of vas deferens of young and adult guinea pigs. AB - The response characteristics of vas deferens to electrical hypogastric nerve stimulation at various frequencies was studied in guinea pigs of 2 to 15 weeks old. In 2-week-old guinea pigs the stimulation induced monophasic contraction, some of which remained after blocking alpha 1-adrenoceptor and desensitizing P2 purinoceptors with prazosin and alpha, beta-methylene ATP, respectively. In guinea pigs of 10 to 15 weeks old stimulation induced biphasic contraction, which was almost completely inhibited by both blockers. These results suggest that some unknown component other than ATP and norepinephrine is involved in the transmission at 2 weeks, and that its relative significance changes during development. PMID- 7844317 TI - Role of nitric oxide in the peripheral vessels of patients with familial amyloidotic polyneuropathy (FAP) type I. AB - In order to establish the generation of endothelial derived relaxating factor (EDRF) in patients with familial amyloidotic polyneuropathy (FAP) type I, the muscle temperature of the lower limb was measured with a deep portion thermometer. The temperature of the gastrocunemius muscle in FAP patients was significantly decreased compared with control subjects. In order to investigate the generation of EDRF in FAP patients, we administered NG-monomethyl-L-arginine (L-NMMA), specific inhibitor of nitric oxide, from the brachial artery and measured the changes in blood flow. Although 61.7 +/- 18.2% of the blood flow was transiently decreased after administration of L-NMMA in control subjects, FAP patients showed poor responses. In contrast, in the same way as in control subjects, significant vasodilatation was seen in FAP patients after administration of L-arginine. The urinary secreted NO2-/NO3- levels per day, which reflect the synthesis of nitric oxide in the systemic circulation, was a great deal lower in FAP patients than in control subjects. These results suggest that, although peripheral vessels can be dilated when a large amount of the substrate for NO synthase, L-arginine, is supplied, production of nitric oxide may be suppressed, and, as the result of this phenomenon, blood flow is decreased in the peripheral tissues of FAP patients in a static state. PMID- 7844319 TI - The neuronal and extraneuronal origins of plasma 3-methoxy-4-hydroxyphenylglycol in rats. AB - 3-Methoxy-4-hydroxyphenylglycol (MHPG) is formed by the sequential actions of monoamine oxidase (MAO) and catechol-O-methyltransferase on norepinephrine within extraneuronal tissues or by extraneuronal O-methylation of 3,4 dihydroxyphenylglycol (DHPG) produced intraneuronally from norepinephrine. This study examined the contributions of neuronal and extraneuronal norepinephrine metabolism to formation of MHPG in rats. Spillover of MHPG into plasma (605 +/- 28 pmol/kg per min) was higher than spillover of DHPG (463 +/- 15 pmol/kg per min), norepinephrine (165 +/- 9 pmol/kg per min) and normetanephrine (56 +/- 4 pmol/kg per min). Comparison of MHPG spillover with the increment in normetanephrine spillover after MAO inhibition (81 pmol/kg per min) combined with the spillover of MHPG derived from circulating normetanephrine (21 pmol/kg per min) indicated that only 17% of plasma MHPG is derived from the extraneuronal deamination and O-methylation of norepinephrine; the remaining 83% is from DHPG produced by deamination of norepinephrine within neurons. The production of MHPG from infused DHPG indicated that 30% of the MHPG in plasma is produced by O methylation of DHPG after entry of DHPG into the bloodstream and 53% (83-30) from metabolism of DHPG before its entry into the bloodstream. Metabolism of circulating norepinephrine made a minor (1-3%) contribution to plasma concentrations of DHPG and MHPG, but a much larger (46%) contribution to plasma normetanephrine. The results provide a comprehensive examination of norepinephrine metabolism by O-methylation and deamination pathways. Since MHPG is the principal norepinephrine metabolite excreted in the rat, the findings also show that total body turnover of norepinephrine is dependent mainly on neuronal metabolism of the transmitter; at rest extraneuronal pathways contribute as little as 15% to norepinephrine turnover. PMID- 7844321 TI - Redistributing health care resources without redistributing income. PMID- 7844320 TI - Understanding the choices in health care reform. The Health Care Study Group. AB - This commentary is the joint product of a group of concerned scholars, many of them long associated with this journal. It assesses the debate over health care reform with the goal of minimizing the many myths and misunderstandings that exist. We address eight issues most likely to engender confusion: (1) the question whether cost control and universal coverage are contradictory goals, (2) the definition of universal coverage, (3) sources of bureaucracy in a reformed health care system, (4) the meanings of "competition" and "regulation," (5) the difference between short- and long-term measures to control costs, (6) subsidization of universal health care, (7) the role of medical care professionals in decision making about the delivery of services, and (8) the meaning of "choice" for patients and caregivers. PMID- 7844322 TI - Market competition and the quality of nursing home care. AB - This article identifies factors influencing the degree of competition in the nursing home market. Using data obtained from the 1987 Medicare and Medicaid Automated Certification Survey, the relationship between competition and structural and process measures of quality (registered nurse staffing and resident care management practices) is estimated by weighted two-stage least squares regression. Results suggest that the quality effects of indicators of competition vary and that market concentration may not diminish quality-based competition. Proposals for nursing home reimbursement reform are evaluated with respect to their incentives for enhancing quality, particularly in the Medicaid market segment. PMID- 7844323 TI - Access to long-term care: race as a barrier. AB - Race continues to impede access to health services, for acute as well as long term care. Whites, for example, use disproportionately more days of nursing home care than nonwhites, not simply because they are more likely to be private payers and, therefore, are preferred over nonwhites: the difference in utilization persists even among those whose nursing home stays are covered by Medicare. Using data from a study of patients awaiting alternative placement in North Carolina acute care general hospitals in 1991, this article examines racial differences in discharge delay, that is, in the time between when a patient is medically ready for discharge to another form of care and when he or she actually is discharged. Logistic regression and ordinary least squares are used heuristically to identify patient characteristics associated with delay, and two-way analyses of variance are used to document the independent effect of race. The results indicate that race has substantial independent explanatory power. This finding is reinforced by the analysis of variance with controls for the patient's payment source for long term care, chronic condition or special care requirements, demographic attributes, family cooperativeness, whether the patient had a behavior problem that impeded the discharge planning process, and whether there was a financial problem in arranging for the patient's discharge. The inescapable conclusion is that nursing homes discriminate on the basis of race in admitting patients. This practice is patently objectionable; it also is costly to hospitals, thus to society, since hospitals bear the direct costs of delayed discharges and hospitals do not keep costs to themselves. While research is needed to determine whether the North Carolina findings are replicable in other states, past research suggests that the problem is not confined to this state. PMID- 7844324 TI - Nursing studies laid end to end form a circle. AB - As early as 1915, leaders in the nursing profession were concerned with the "image problem of nurses," which they saw as needing improvement. Since then, countless studies, reports, and commissions have attempted to explain and solve perceived shortages of registered nurses, which have occurred regularly after brief periods of quiescence or oversupply. Usually, their recommendations have hinged on nurses changing their image. In fact, few of these studies have dealt with the real issues of nursing work, which are a narrow pay range, little extra pay for working on undesirable shifts, disincentives for full-time work, pay unrelated to education, and education unconnected to job level. The multiple studies and commissions do nothing more than recycle data and in the process obscure fundamental problems. Educational funding has been no more successful. Their ineffectiveness suggests the need for less "image enhancement" and more support from physicians and employers to bring about systemic reform. This includes licensing nurses according to their education, assigning them according to their competencies and education, and paying accordingly. These measures, and only these, will eventually curtail the cycles of nursing "shortages." PMID- 7844325 TI - Notes from the insurance underground: how the chronically ill cope. AB - This report from the field is an account of the experience of individuals with multiple sclerosis (MS) in Indiana in getting and keeping private health insurance. The report presents the findings of a telephone survey of individuals with MS in Indiana. While survey respondents were generally able to obtain health insurance through the Medicare program or employer-based private health insurance plans, many experienced formidable barriers to adequate and affordable health insurance, such as preexisting exclusions, cancellations, high premiums, and coinsurance. Respondents adopted a variety of strategies to keep private health insurance, including selectivity in submitting claims, which worked to reduce their health insurance coverage. Our findings raise two crucial questions: (1) to what extent are the chronically ill forced to take extraordinary measures to get and keep health insurance? and (2) to what extent do insurer practices in pricing insurance and determining coverage of benefits actually make health insurance even more inadequate and unaffordable for the chronically ill? These two questions are critical in understanding the full dimensions of the health insurance crisis in the United States today. PMID- 7844326 TI - Measuring health care: political fate and technocratic reform. PMID- 7844327 TI - Relationship of financial strain and psychosocial resources to alcohol use and abuse: the mediating role of negative affect and drinking motives. AB - Limited research has examined the relationship between financial strain and alcohol use and abuse. Building on affect regulation theory and recent research in the stress and alcohol literatures, this study developed and tested a model relating financial strain, social resources, personal resources, depression, and drinking to cope to alcohol use and abuse. Data were obtained from a random sample of 1,424 adults who indicated that they had drunk alcohol in the previous year. We tested and then revised our model using structural equation modeling analysis. Results supported the affect regulation model of financial strain and alcohol use and abuse. Generally, depression mediated the relationship between financial strain and drinking to cope, and drinking to cope mediated the relationship between depression and alcohol use and abuse. In addition, both gender and race moderated six of the relationships in our revised model. PMID- 7844328 TI - Race, gender, and housing inequality: an exploration of the correlates of low quality housing among clients diagnosed with severe and persistent mental illness. AB - This paper explores the relationship of race and gender to housing quality among clients diagnosed with severe mental illness. More specifically, it asks: "How do a client's race and gender affect her/his odds of living in a "low-quality" housing arrangement?" A low-quality arrangement is defined as one which is time limited and/or physically unsafe. The analysis draws upon clinical, demographic, and housing data for 517 African American and White consumers of publicly-funded mental health services in King County, Washington. Multivariate logistic regression is the primary analytic strategy used. Controlling for certain clinical/behavioral and economic/ecological factors, race/gender category is found to affect significantly the odds of experiencing low-quality housing. PMID- 7844329 TI - Narratives of aging and social problems in medical encounters with older persons. AB - This study asks: How do older patients and their doctors deal with social problems in the discourse of routine medical encounters? Our research has been influenced by a growing recognition of narratives as an important analytic focus in the study of patient-doctor communication. We attempted to advance theoretical knowledge by emphasizing elements of sociocultural context, ideology, social control, underlying structure, and features of discourse that appear marginal to medicine's technical tasks. Based on a critical review of both quantitative and qualitative techniques in research on patient-doctor communication, we tried to move methodologically beyond prior work by developing a new interpretive method with systematic criteria to guide the sampling of encounters, transcription of recordings, interpretation of transcripts, and presentation of findings. We applied the interpretive method to 50 encounters selected randomly from a stratified random sample of 336 audiotaped encounters involving patients and primary care internists. As shown by illustrative encounters, a characteristic narrative structure and sequencing emerge, which tend to marginalize contextual problems, to leave them incompletely expressed, and to reinforce ideologies of stoicism and individualism. PMID- 7844330 TI - Institutional environments and organizational responses to AIDS. AB - Drawing from theory on institutionalized organizational environments, this paper analyzes the actions of community-based service programs providing care for people with AIDS. The focus is on the interorganizational relations developed by the lead agencies in demonstration projects attempting to coordinate services in three communities. The paper identifies differential styles of organizational response to developmental and operational issues. These differences are related to the conceptual distinction between organizational responses to technical environments and those to normative, or "institutional," environmental features. Various factors are identified that appear to promote a higher degree of institutionalization in interorganizational relations. Coordination as a reform strategy is seen to have become, in itself, an institutionalized myth to which organizations must subscribe in order to gain legitimacy. PMID- 7844331 TI - Health care utilization, family context, and adaptation among immigrants to the United States. AB - We use the 1990 National Health Interview Survey supplement on Family Resources to examine the health care utilization patterns of immigrant and native-born adults in the United States. We modify a standard health care utilization framework by including duration of residence in the United States and measures of immigrant adaptation and family health context to model both the probability and number of physician contacts in the previous year. We find that duration of residence has a strong effect. Recently-arrived immigrants are much less likely to have had a contact in the previous year and had fewer contacts than either native-born or longer-term immigrant adults. Once the measures of adaptation--age at immigration and language of survey interview--are included, immigrants who have been in the United States for 10 years or more are not statistically different from the native-born. Family characteristics, including measures of exposure to the formal health care system, slightly reduce the size of the effects but do not alter the basic relationship between duration of residence and health care utilization. These results suggest that, net of socioeconomic characteristics, access to health insurance, and differences in morbidity, recent immigrants are much less likely than both the native-born and those immigrants of longer duration, to receive timely health care. PMID- 7844332 TI - Nongenetic familial transmission of psychiatric disorders? Evidence from children of Holocaust survivors. AB - There is considerable evidence that psychiatric disorders aggregate in families, a phenomenon for which both genetic and nongenetic explanations have been proposed. However, since genetic and social inheritance usually co-occur, it is difficult to separate out their effects. In this paper, we argue that examining the rates of disorder among children of Holocaust survivors provides a special situation where genetic and nongenetic factors in familial transmission can be separated, and where specific nongenetic mechanisms can be tested. We specify competing hypotheses, and test their viability using data from an epidemiological study of psychiatric disorders conducted in Israel. We find no evidence of higher symptom scale scores or higher rates of current psychiatric disorders for the children of Holocaust survivors. However, they did have higher rates of past disorders. PMID- 7844333 TI - HIV screening for healthcare providers: can we provide sense and sensibility without pride or prejudice? PMID- 7844335 TI - Methicillin-resistant Staphylococcus aureus in tertiary care institutions on the Canadian prairies 1990-1992. AB - OBJECTIVE: To review experience with methicillin-resistant Staphylococcus aureus (MRSA) in tertiary acute-care teaching hospitals on the Canadian prairies. DESIGN: Retrospective review for a 36-month period, 1990 through 1992. SETTING: Five tertiary acute-care teaching hospitals in three Canadian prairie provinces. METHODS: MRSA isolates and susceptibility were identified through the clinical microbiology laboratory at each institution. For each patient, data collected included duration of institutional residence prior to isolation, patient ethnic background, age, sex, and antimicrobial susceptibility. Epidemiologic typing of strains used restriction fragment length polymorphism analysis by pulsed-field gel electrophoresis. RESULTS: Two hundred fifty-nine MRSA isolates were identified in 135 patients during the 36 months, with substantial institutional variation in number of isolates. No consistent increase in yearly numbers of isolates was apparent. Patients usually had MRSA identified at admission (62%); only one of five centers had the majority of isolates acquired nosocomially. Patients with MRSA present at admission were more frequently of aboriginal (First Nations) ethnicity (62% compared with 14% of nosocomial; P < 0.001). Pulsed-field gel electrophoresis of 167 isolates from 135 patients revealed 46 different strains with little interprovincial or interinstitutional identity of strains. CONCLUSIONS: MRSA isolated in patients in tertiary care institutions in these three Canadian provinces usually is acquired prior to admission. A disproportionate number of isolates are identified in aboriginal Canadians. Epidemiologic typing was consistent with a polyclonal origin of MRSA in this geographic area. PMID- 7844334 TI - HIV screening of surgeons and dentists: a cost-effectiveness analysis. AB - OBJECTIVE: To assess the cost-effectiveness of human immunodeficiency virus (HIV) screening strategies of surgeons and dentists. DESIGN: We constructed a model to project costs and HIV transmissions prevented over 15 years for four screening scenarios: 1) one-time voluntary screening, 2) one-time mandatory screening, 3) annual voluntary screening, and 4) annual mandatory screening. One-time screening occurs only in the first year of the program; annual screening occurs once each year. Under mandatory screening, all practitioners are tested and risks of practitioner-to-patient transmission are eliminated for all practitioners testing positive. Voluntary screening assumes 90% of HIV-positive and 50% of HIV-negative practitioners are tested, and risks of transmission in the clinical setting are eliminated for 90% of HIV-positive surgeons and dentists. All costs and benefits are discounted at 5% per annum over 15 years. RESULTS: Using "best-case" scenario assumptions, we find for surgeons that a one-time voluntary screening program would be most cost-effective, at $899,336 for every HIV transmission prevented. For dentists, the one-time voluntary program also is the most cost-effective, at $139,571 per transmission prevented. Annual mandatory programs were least cost effective for both surgeons and dentists, at $63.3 million and $2.2 million per transmission prevented, respectively. CONCLUSIONS: HIV screening of surgeons and dentists ranks among the more expensive medical lifesaving programs, even using liberal assumptions about program effectiveness. Frequency of screening and whether testing is mandatory or voluntary dramatically affect cost per transmission prevented; these features should be considered carefully in designing specific HIV screening programs. PMID- 7844336 TI - Investigation of a pseudo-outbreak of orthopedic infections caused by Pseudomonas aeruginosa. AB - OBJECTIVE: To report a pseudoepidemic of Pseudomonas aeruginosa infections discovered during an investigation of postoperative joint infections. DESIGN: A retrospective review of case patients' hospital charts, operative reports, and laboratory data, as well as environmental culturing, polymerase chain reaction (PCR) ribotyping of outbreak isolates, and in vitro analysis of P aeruginosa growth characteristics. SETTING: A 510-bed, university-affiliated adult tertiary care hospital. RESULTS: Between October 1 and December 1, 1992, seven postsurgical joint infections were diagnosed, including four caused by P aeruginosa. A bottle of "sterile" saline used to process tissue specimens was found to be contaminated with P aeruginosa. Further investigation revealed that P aeruginosa had grown from seven additional tissue cultures, all of which had been processed with the contaminated saline. PCR ribotypes of the contaminant matched those of the clinical isolates. In vitro, P aeruginosa strains were viable in commercial nonbacteriostatic saline, but never caused visible turbidity. Six patients received antibiotics for their presumed infections; four patients had peripherally inserted central catheters placed, and one experienced severe anaphylactic reactions to several antibiotics. CONCLUSIONS: Pseudoepidemics due to common organisms are often difficult to detect, and delayed recognition can result in substantial morbidity. This outbreak investigation illustrates the potential for contamination of diluents in the microbiology laboratory and emphasizes the need for meticulous quality control. PMID- 7844337 TI - Relatedness of coagulase-negative staphylococci causing bacteremia in low birthweight infants. AB - OBJECTIVE: To investigate coagulase-negative staphylococcus (CONS) causing bacteremia in a neonatal intensive care unit (NICU). DESIGN: A 14-month retrospective review of 47 infants in the NICU with CONS bacteremia was undertaken to determine CONS glycocalyx production, plasmid pattern, total DNA restriction fragment polymorphism, and clinical risk factors. RESULTS: The isolates included 32 Staphylococcus epidermidis, six Staphylococcus haemolyticus, four Staphylococcus warneri, four Staphylococcus saprophyticus, and one Staphylococcus hominis. Sixty-five percent of S epidermidis produced glycocalyx; other species did not. Oxacillin resistance (52%) and the antibiograms of the CONS were consistent with other units in the hospital. Five similar CONS plasmid patterns were found among 16 isolates; 31 isolates had unique patterns. Extractions of total DNA from these isolates were digested using HindIII, HaeIII, and BstEII. Those with similar restriction fragment length patterns could not linked as nosocomially transmitted among infants with bacteremia. CONCLUSION: Our observations suggest that multiple strains of CONS infect infants in the NICU who have similar risk factors. Although current infection control practices limit transmission of a pathogen, they do not prevent CONS bacteremias. PMID- 7844338 TI - Airborne nosocomial infection: a contemporary perspective. AB - The history of airborne nosocomial infections is reviewed, and current beliefs about such infections are placed into their historical context. Possible sources, both animate and inanimate, of airborne nosocomial infections in the hospital environment are identified. Viruses, bacteria, and fungi that have been important causes of airborne nosocomial infections in the past are discussed, and examples of key studies that have confirmed an airborne route of transmission are presented. Where relevant, measures that have been used to control airborne transmission of nosocomial pathogens are discussed. Although outbreaks of airborne nosocomial infection have been uncommon, airborne transmission appears to account for about 10% of all endemic nosocomial infections. PMID- 7844339 TI - The Lone Ranger rides again, this time followed by a federal posse. AB - The Centers for Disease Control and Prevention proposed guidelines regarding the high-efficiency particulate air-filtered respirator have raised many questions that the healthcare worker has found difficult to answer. This product commentary addresses questions related to material that the respiratory protection program should include; provides information related to the physical exam before the use of the respirator; and explains the types of respirators. Cost issues also are discussed. PMID- 7844340 TI - Osler's clinical clerkship: origins and interpretations. PMID- 7844341 TI - John Hunter and the Natural History of the Human Teeth: dentistry, digestion, and the living principle. PMID- 7844342 TI - Plague of Athens--fungal poison? PMID- 7844343 TI - Ramon y Cajal and his school: personal recollections. PMID- 7844344 TI - An outbreak of Candida parapsilosis prosthetic valve endocarditis following cardiac surgery. AB - Five of 34 (15%) patients who received prosthetic cardiac valves between May and August 1982 at the Victoria General Hospital in Halifax, Nova Scotia, developed Candida parapsilosis prosthetic valve endocarditis. The clustering of these cases pointed to a common source outbreak. In a retrospective cohort study, no significant differences were found between infected and uninfected patients in terms of pre-, intra-, and postoperative risk factors. Environmental investigations suggested intraoperative contamination through the cardiac bypass equipment as the source of infection but a causal relationship could not be established. The outcome for the cases was uniformly fatal, emphasizing the need for prevention of such serious nosocomial infections. PMID- 7844345 TI - Characterization of two different clusters of clonally related methicillin resistant Staphylococcus aureus strains by conventional and molecular typing. AB - The DNA fragments of 28 distinct isolates of methicillin-resistant Staphylococcus aureus (MRSA) originating from different hospitals in Warsaw and Lodz, were studied. They were obtained by cleavage with restriction endonuclease SmaI and subsequently analysed by pulsed-field electrophoresis. Sixteen different patterns were seen and clusters of related strains were clearly distinguishable. Minor differences in fragment patterns within these clusters and among epidemiologically related strains, revealed genomic rearrangements in the course of clonal dissemination of particular strains. The isolates were also checked for the expression of methicillin resistance. Isolates with heterogenous and homogeneous phenotypes, fell into clearly distinct clusters and thus formed two clonally related MRSA strains. Differences were also seen with phage and biochemical typing, and antimicrobial resistance patterns. PMID- 7844346 TI - Clinical practice and the perceived importance of identifying high risk patients. AB - The Royal Free NHS Trust is implementing a Universal Precautions policy for blood and body fluids. Anticipating the introduction of this policy, a questionnaire was sent to a sample of staff and students who work with patients or clinical specimens. The questionnaire covered: views about identifying 'high risk' patients and specimens; perceived risks of human immunodeficiency virus (HIV) and hepatitis B infection from blood exposures; and current practices to avoid exposure to blood. Over half the respondents thought it important to identify high risk patients and specimens. Such respondents were more likely to overestimate the risks of HIV and hepatitis B virus transmission after blood exposures, they were less likely to wear gloves and more likely to resheathe needles. Although two-thirds of respondents thought Universal Precautions would reduce their risk of blood-borne infections, they identified a number of reasons why it would be difficult for them to practice it. Those who thought it important to identify high risk patients gave more reasons than other respondents. This survey indicates that many staff believe it is important to identify high risk patients and this belief seems to influence clinical practice. In order to implement a policy of Universal Precautions successfully, it is necessary to address underlying beliefs as well as giving staff information and training. PMID- 7844347 TI - Inactivation of human immunodeficiency virus type 1 by alcohols. AB - Alcohols are commonly used as disinfectants for skin, surfaces and immersion of some medical instruments. Measurements of the activity of alcohols against human immunodeficiency virus type 1 (HIV-1) must take account of the compatibility of neutralizers used to stop the disinfectant reaction, and of toxicity to the cell line used to detect residual virus. We have developed protocols to measure the efficacy of alcohols against HIV in suspension and dried onto surfaces in the presence of high and low protein concentrations. High titres of HIV in suspension were rapidly inactivated by 70% ethanol, independent of the protein load. When virus was dried onto a glass surface, the rate of inactivation decreased when high levels of protein were present. Due to its rapid evaporation, a spray or a wipe with alcohol cannot be guaranteed to disinfect a surface contaminated with blood or other body fluids without preliminary cleaning. PMID- 7844348 TI - Lucilia sericata (Diptera: Calliphoridae) causing hospital-acquired myiasis of a traumatic wound. AB - A case of traumatic nosocomial myiasis caused by the green bottle fly Lucilia sericata (Meigen, 1826) occurred in a patient hospitalized following a serious road traffic accident. The patient had suffered extensive polytrauma particularly in the facial area of the skull. A total of 50 larvae was discovered in the oral cavity, nose, paranasal sinuses and enucleated eye-socket. Projected timing indicated that the eggs were laid while the patient was hospitalized. The development of myiasis was facilitated by the mental and physical debility and dependency of the patient, numerous and deep facial necrotic wounds and a lengthy period of hot weather which led to prolonged open window ventilation of his room. PMID- 7844349 TI - A study of wound infections following inguinal hernia repair. AB - A prospective study was carried out to determine the incidence of wound infection following surgery for inguinal hernia repair in a day surgery unit. The study incorporated surveillance for 1 month postoperatively. All patients were contacted by telephone, and reports of possible wound infection investigated via their General Practitioners. Ninety-seven patients were included in the study and the infection rate was 4%. PMID- 7844350 TI - Irradiation and reuse of 'Grippers' shoes. PMID- 7844351 TI - Outbreak screening for penicillin-resistant pneumococci. PMID- 7844352 TI - Leonard Colebrook and his family. PMID- 7844353 TI - Intravascular device-associated systemic infections: a 2 year analysis of cases in a district general hospital. AB - The increasing use of intravascular devices (IVDs) throughout medicine has been accompanied by significant morbidity and mortality associated with catheter related sepsis (CRS). Within the South Buckinghamshire district, 330 episodes of bacteraemia/fungaemia were recorded over the 2 year period 1992-1993. Thirty-nine episodes (12%), occurring in 37 patients, were associated with IVDs and these were divided into three groups according to the type and site of device. Six patients died with CRS contributing to mortality whilst one patient suffered serious morbidity, in the form of vertebral osteomyelitis. This analysis highlighted deficiencies in the management of IVDs which are likely to be found in similar district general hospitals in the UK. There is an urgent need for national guidelines on IVD care together with recommendations for the optimal treatment of IVD-associated infection. PMID- 7844354 TI - Physical efficiency of Bengali farmers in response to change in environmental factors. AB - The present study was conducted on young farmers, selected randomly from a village of West Bengal. Their pre-exercise heart rate (HR), blood pressure (BP), mean arterial pressure (MAP), and other physical parameters were recorded. They were asked to perform standard step test at four different times of a day when environmental factors were recorded. Recorded environmental factors were maximum ambient temperature (Tmax), and minimum ambient temperature (Tmin) for the whole day, ambient temperature (Ta), relative humidity (RH), air velocity (AV), and globe temperature (Tg). The barometric pressure (P) was noted to be constant throughout the experiment. Post-exercise HR and MAP were also recorded. Our observations showed that environmental factors changed as the day progressed from the morning to noon and from noon to night; the physiological parameters of the farmers also changed. HR was lowest in the morning and night but highest in the evening while MAP was highest at midday and gradually returned to the pre exercise level by the evening. The determined Physical Fitness Index (PFI) of the farmers was noted to be lowest at midday but highest at night. Our studies indicate that environmental factors have a role on the physical efficiency of farmers. Ta, RH and Tg appear to be primarily responsible for the alterations in the physiological functions and PFI. PMID- 7844355 TI - The influence of long-term visual near-work on accommodation and vergence: a field study. AB - A study of the influence of sustained, visual near-work upon a set of oculomotor functions (ZCSV i.e. Zone of Clear Single Vision) was carried out on a randomly drawn group (N = 43) of young, female, healthy and experienced accountants (mean age 24.6 years) who were daily engaged in full-time interactive VDT work. PRA (Positive Relative Accommodation), NRA (Negative Relative Accommodation), PRC (Positive Relative Convergence) and NRC (Negative Relative Convergence) was measured twice: 1) in the morning before the subjects started work and 2) at the end of the working day. Results showed significant reductions in the four ZCSV components over the working day. Vergence reductions accounted for over 60% of the ZCSV changes. PMID- 7844356 TI - Study of forward sloping seats for VDT workstations. AB - The main focus of this study was to identify and evaluate various forward seat inclinations (5, 10, 15 degrees) for Video Display Terminal workstation type seating by constructing a fixture to be fitted to a test chair to achieve various seat angles. The discomfort in critical areas i.e. neck and lower back were evaluated by 25 male university students (avg. age 22 years) with no history of musculoskeletal disorders on a subjective scale for comfort. The comfortable or uncomfortable seat inclinations were identified after a statistical analysis. The heart rate and blood pressure were observed every 5 min for validation purposes. It was recommended that, to avoid neck problems, a chair with a forward incline greater than 5 degrees should not be used and to avoid lower back problems a chair with a seat angle of approximately 10 degrees be used. On the overall comfort criteria it is recommended to use a chair with a seat pan which inclines to approximately 15 degrees (forward). The findings and recommendations from this study can enhance the safety and productivity of the people whose jobs require continuous forward bending in a sitting task involving VDT workstations. PMID- 7844357 TI - Interrelation of one mile running time and HST score among rural school boys. AB - Peak physiological capabilities are necessary for top level performance in sports, although skills and motivation play an important role. Laboratory assessments often give us valuable insights concerning the physiological factors underlying athletic performance. The Physical Fitness Index (PFI) determined by the Harvard Step Test (HST) is one of the most important indexes which predicts the physical abilities of athletes. HST, Cooper's 12-min run-walk test and one mile run are good measures of cardiorespiratory fitness. In the present study, we have attempted to determine the relationship between HST and the one-mile run in an open field on 31 school boys of a rural village, 14-15 years of age, who were in early puberty. The mean HST score was 90 +/- 7.07, and one-mile running time was 443.45 +/- 29.82 s. There is a good correlation between HST and running time (r = 0.94). Probable running time for one-mile may be determined from the HST score by using the regression equation: Running time in s = 783 - 4* HST +/- 0.13 (SE of estimate). PMID- 7844358 TI - Anthropometric evaluation of agricultural laborers in selected parts of Thailand. AB - For the design of farm machinery, body dimension data is essential. There are little such anthropometric data available on agricultural laborers from developing countries. This research, therefore, aimed to collect anthropometric data of agricultural laborers in selected parts of Thailand. Forty-four physical dimensions of both 50 men and 50 women agricultural laborers were measured. These laborers were selected randomly from two provinces in the central plains of Thailand. The average body dimensions, standard deviation and 5th, 10th, 50th, 90th, and 95th percentiles were determined. No significant difference was observed in most of the body dimensions of men and women laborers in different age groups used in this study. Body dimensions of length were in constant proportion to stature. The body dimensions of Thai laborers obtained in this study were also compared with the data of body dimensions from some Asian as well as Western countries. PMID- 7844359 TI - A model of ergonomics intervention in industry: case study in Japan. AB - This paper presents the results of an ergonomics survey in four different Japanese work places. The survey consisted of two parts. In the first part, the physical and psycho-social problems of the female workers were investigated. Questionnaire techniques were used to assess musculoskeletal disorders in various parts of the body and of psycho-social stress at work as well as in the daily life situation. Furthermore, work posture analysis, task analysis, simple clinical tests and flexibility tests were conducted. In the second part, the ergonomics intervention practices in different types of Japanese work places were examined. Three different questionnaires were developed and used to collect information from representatives of employees, management and responsible governmental agents of the Department of Industrial Safety and Health, Ministry of Labor, with regard to ergonomic interventions at work places. Management, employees, and government representatives expressed desire for cooperation and participation for arrangement of the ergonomics intervention program. A model for appropriate ergonomics intervention in industry is developed with regard to physical and psycho-social problems at work. Factors influencing worker participation and the establishment of a dynamic system of ergonomics intervention at work places are discussed. Practical ways for improving the working conditions of female workers are: (i) cooperation between managers, workers, and government officers is regarded as vital for the ergonomics intervention program, (ii) worker participation, (iii) appropriate training course with regard to ergonomics education, and (iv) managerial support. PMID- 7844360 TI - Anthropometrical data of middle-aged Japanese women for industrial design applications. AB - Despite the growing importance of human interface design, and despite the growing number of working women, no considerations have been given to women's working spaces and tools. Their designs are based on men's anthropometrical data, and this does not assure safety and amenity of women's working environments. Moreover, few data on women's body measurements are available. The Research Institute of Human Engineering for Quality Life is carrying out an ergonomic anthropometrical study on a large number of Japanese people to create a database for industrial use. The fee for the use of these data is, however, making it very difficult to profit from their acquisition. Therefore, we conducted an anthropometrical study for industrial design use on middle-aged female subjects, who are in the most difficult age group to access. This report should be useful in designing working spaces and tools for women as laborers as well as users. PMID- 7844361 TI - Bidirectional transmission of infectious cytomegalovirus between monocytes and vascular endothelial cells: an in vitro model. AB - Cytomegalovirus (CMV) infects multiple tissues and organs; however, mechanisms of dissemination remain elusive. Although hematogenous spread has been implicated, in vitro studies have generally indicated that peripheral blood mononuclear cells (PBMC) do not support the complete viral reproductive cycle. Since CMV infects endothelial cells (EC), the hypothesis that PBMC can be productively infected by contact with CMV-infected EC was tested by coculturing PBMC with CMV-infected endothelial monolayers. Dual immunohistochemical staining for mononuclear cell markers and CMV-specific antigens demonstrated infection of up to 30% of monocytes adhering to EC. To determine if infected monocytes could transmit infectious virus, they were separated from EC, replated in culture wells, and then overlaid with fresh EC. The subsequent appearance of CMV-positive cytopathic foci within the overlaid monolayers indicated that these monocytes were capable of transmitting infectious virus. Thus, these results support an interactive role for the endothelium and circulating monocytes in the dissemination of this clinically problematic virus. PMID- 7844362 TI - Detection of human herpesvirus 6 in plasma of children with primary infection and immunosuppressed patients by polymerase chain reaction. AB - A sensitive and specific polymerase chain reaction method for the detection of human herpesvirus 6 (HHV-6) DNA in serum or plasma has been developed. In total, 157 human serum or plasma samples were studied. HHV-6 DNA was detected in 6 (85.7%) of 7 children with exanthem subitum, 3 (23.1%) of 13 bone marrow transplant (BMT) recipients, 4 (22.2%) of 18 human immunodeficiency virus (HIV) infected patients, 1 (2.6%) of 39 patients with chronic fatigue syndrome, and none of 37 healthy adults. In the HHV-6-positive BMT recipients, HHV-6 plasma DNA was transiently detected during episodes of fever and respiratory infection. In children with exanthem subitum and in 1 HIV-infected patient, the HHV-6 strains were characterized as variant B, whereas variant A was detected in all other patients. Detection of viral DNA in serum or plasma is a marker of active infection that can be used to investigate the role of HHV-6 in human disease. PMID- 7844363 TI - Application of six hepatitis C virus genotyping systems to sera from chronic hepatitis C patients in the United States. AB - Serum samples from 139 US patients with chronic hepatitis C virus (HCV) infection were studied using six different genotyping systems, including both molecular and serologic methods, to determine the applicability of these approaches and the prevalence of various HCV subtypes. The concordance of genotyping results based on the various systems (except for core polymerase chain reaction genotyping) was good (93.5%). Subtypes 1a and 1b were prevalent (37.4%). Subtypes 2a (2.2%), 2b (8.6%), and 3a (5.8%) were less common. HCV genotypes could not be determined in 3.4%-16.5% of samples depending on the method used. HCV type 2 was associated with greater histologic activity but lower serum HCV RNA levels (P < .05), whereas type 3 was associated with lower serum alanine aminotransferase levels (P < .05). These data demonstrate a high concordance between HCV genotyping systems and provide a foundation for comparison of genotyping data between studies using different systems. HCV types 1a and 1b are both prevalent in the United States. PMID- 7844364 TI - Lombok Hepatitis B Model Immunization Project: toward universal infant hepatitis B immunization in Indonesia. AB - The Lombok Hepatitis B (HB) Model Immunization Project was the first mass infant HB immunization project in Indonesia. Key aspects were the procurement of low cost HB vaccine, integration into routine infant immunization services, and delivery of the first dose in the home within 1 week of birth. The project achieved > 90% coverage with 3 doses of vaccine. The prevalence of HB surface antigen was 1.4% in infants who received 3 doses (with the first dose within 7 days of birth) and 3.0% in those who received the first dose > 7 days after birth, compared with a baseline prevalence of 6.2% (P < .001 in each case). Most vaccine failures occurred in children born to HBe antigen-positive mothers. Antibody prevalence and titers did not correlate with protection. HB vaccine can be successfully integrated into the Expanded Programme on Immunization (EPI), strengthening the EPI and significantly reducing chronic HB infection. PMID- 7844365 TI - Human immunodeficiency virus type 1 quantitative cell microculture as a measure of antiviral efficacy in a multicenter clinical trial. AB - A quantitative cell microculture assay (QMC) was used to measure the human immunodeficiency virus type 1 (HIV-1) peripheral blood mononuclear cell (PBMC) associated titer in 109 subjects rolled in an open-label phase I/II study of didanosine monotherapy or combination therapy with zidovudine. The titer was inversely correlated with CD4+ cell count at baseline (r = .37, P = .001). After 12 weeks of therapy, subjects showed a significant decreases in virus titer and those with the highest baseline virus titers had the greatest increase in CD4+ cell number (r = .430, P = .002). The QMC assay was more sensitive (98%) for assessing the antiretroviral effect of therapy than was immune complex dissociated HIV p24 antigen (32%) or plasma culture (3.4%). Estimated sample sizes for phase I/II clinical trials were derived using the within-subject QMC SD of .72 log10 infectious units per 10(6) PMBC. PMID- 7844366 TI - Association between anti-CD4 antibodies and a decline in CD4+ lymphocytes in human immunodeficiency virus type 1 seroconverters. AB - Serum specimens (n = 161) from 31 persons before and after human immunodeficiency virus type 1 (HIV-1) seroconversion were tested for anti-CD4 antibodies. These antibodies were detected by both ELISA and Western blot in 55% (17/31) of subjects when HIV-1 seroconversion was detected and in 26% (8/31) from sera obtained 6-24 months earlier. A decrease in CD4+ cell number was associated more with development of anti-CD4 antibodies or peak anti-CD4 antibody activity than with development of anti-HIV-1 antibodies. Quantitative DNA polymerase chain reaction assay of peripheral blood mononuclear cells from 7 seroconverters showed evidence of HIV-1 infection in 4 of 4 specimens obtained after HIV-1 seroconversion but was nonreactive for 12 of 12 specimens obtained before HIV-1 seroconversion, including 4 specimens positive for anti-CD4 antibodies by ELISA and Western blot. Therefore, anti-CD4 antibodies are frequently present in the sera of HIV-1-infected persons before and at the time HIV-1 seroconversion is detectable and are associated with a decline in CD4+ cell counts, but they are not a marker for HIV-1 infection in seronegative persons. PMID- 7844367 TI - Macrophages from human immunodeficiency virus-positive persons are defective in host defense against Histoplasma capsulatum. AB - The phagocytic and fungistatic activity of monocyte-derived macrophages from human immunodeficiency virus (HIV)-positive persons against Histoplasma capsulatum yeasts was determined. Macrophages from HIV-positive patients were profoundly deficient in their capacity to recognize and bind H. capsulatum, but ingestion of bound yeasts was normal. The binding of H. capsulatum by patient macrophages tended to decrease with a decrease in CD4+ T lymphocyte counts. Another major defect was that patient macrophages were more permissive for the intracellular growth of H. capsulatum. Macrophages from 22 of 58 patients showed a > or = 2-fold increase in intracellular growth compared with control macrophages. Thus, in addition to defects in cell-mediated immunity caused by a loss of CD4+ T cells, macrophages from HIV-positive patients exhibit intrinsic defects in macrophage function against H. capsulatum that may contribute to the increased susceptibility of HIV-positive patients to disseminated histoplasmosis. PMID- 7844368 TI - Depressed CD4+ T lymphocyte proliferative response and enhanced antibody response to viral antigen in chronic lentivirus-induced arthritis. AB - The proliferative response of peripheral blood mononuclear cells (PBMC) stimulated with caprine arthritis-encephalitis virus (CAEV) surface glycoprotein (SU) was depressed 4- to 20-fold in Saanen goats with chronic CAEV-induced arthritis compared with asymptomatic goats. Phytohemagglutinin-stimulated responses were not depressed. Complement depletion of PBMC with anti-CD4 or anti CD8 monoclonal antibodies identified CD4+ T lymphocytes as the antigen-responsive cells in both high-responder asymptomatic goats and low-responder arthritic goats. Serum antibody titers to CAEV SU were 8- to 32-fold higher in goats with chronic arthritis. Increased anti-CAEV SU titers as early as 3 months after infection predicted the eventual development of clinical arthritis. Thus, CAEV induced arthritis is associated with chronic B cell activation resulting from dominant type 2 immune responses to viral antigen. The clinical outcome of CAEV infection may be determined by differential activation of type 1 or 2 T lymphocyte phenotypes at or near the time of initial exposure to CAEV. PMID- 7844369 TI - Interactions of surfactant protein A with influenza A viruses: binding and neutralization. AB - The interaction of pulmonary surfactant protein A (SP-A) with influenza A H1N1 and H3N2 viruses was investigated. SP-A is a sialated C type lectin with affinity for mannose residues. Flow cytometry showed that binding of fluorescein isothiocyanate (FITC)-labeled SP-A to H3N2 virus-infected cells was specific and time- and concentration-dependent. Oligosaccharides did not affect the binding of FITC-SP-A to the infected cells. Preincubation of H1N1 and H3N2 with SP-A resulted in a dose-dependent reduction of the infectivity of the viruses to cells. Removal of the carbohydrate moiety of SP-A by N-glycosidase F or cleavage of its sialic acid residues by neuraminidase prevented the interactions of SP-A with the viruses. It is concluded that SP-A binds to influenza A viruses via its sialic acid residues and, thereby, neutralizes the virus. PMID- 7844370 TI - Hematogenous bacterial meningitis in an intercellular adhesion molecule-1 deficient infant mouse model. AB - Mice genetically deficient in the gene encoding for intercellular adhesion molecule-1 (ICAM-1) production were compared with wild-type mice after injection with Haemophilus influenzae type b (Hib) or Streptococcus pneumoniae. The incidence of Hib bacteremia was greater in the ICAM-1-deficient mice than wild type mice (P = .007), but mortality was greater for wild-type mice at 24 h (P = .03). In contrast, the incidence of S. pneumoniae bacteremia was equivalent but mortality was greater in ICAM-1-deficient mice at 24 h (P = .0003). More ICAM-1 deficient mice had cerebrospinal fluid cultures (CSF) positive for Hib (P = .04), whereas all animals at sacrifice had CSF cultures positive for S. pneumoniae. CSF white blood cell counts and histology of the meninges and cochlea were no different between groups for either organism. ICAM-1 deficiency may be protective early in Hib infection but has a detrimental effect in S. pneumoniae infection. PMID- 7844371 TI - Phagocytosis of Streptococcus pneumoniae measured in vitro and in vivo in a rat model of carbon tetrachloride-induced liver cirrhosis. AB - Both humans and rats with liver cirrhosis have increased morbidity and mortality from pneumococcal pneumonia. By use of a rat model of carbon tetrachloride induced liver cirrhosis, uptake of fluorochrome-labeled Streptococcus pneumoniae by polymorphonuclear leukocytes (PMNL) and alveolar macrophages (AM) was examined by flow cytometry. Peripheral blood PMNL from cirrhotic rats showed no defect in phagocytic or bactericidal capacity for type 10A S. pneumoniae in vitro. However, in vivo, fewer type 3 S. pneumoniae were engulfed by PMNL in the lungs of cirrhotic rats with a concomitant increase in the number of organisms taken up by their AM in comparison with controls. These studies indicate the importance of using more relevant in vivo methodologies for assessing bacterial phagocytosis. In addition, the reduction in uptake of type 3 pneumococci by PMNL within the microenvironment of the cirrhotic rat lung could help to explain the increased susceptibility of cirrhotic rats to pneumococcal pneumonia. PMID- 7844372 TI - Biliary complications in the treatment of unsubstantiated Lyme disease. AB - Treatment of unsubstantiated Lyme disease has led to serious complications in some cases. Two case-control studies, based on information in clinical records of patients discharged with a diagnosis of Lyme disease during 1990-1992, were conducted at a central New Jersey hospital. Twenty-five patients with biliary disease were identified, and 52 controls were selected from 1352 patients with suspected Lyme disease. Only 3% of 71 evaluatable subjects met the study criteria for disseminated Lyme disease. Patients with biliary disease were more likely than were antibiotic controls to have received ceftriaxone and more likely than ceftriaxone controls to have received a daily ceftriaxone dose > or = 40 mg/kg and to be < or = 18 years old. Fourteen of 25 biliary case-patients underwent cholecystectomy; all had histopathologic evidence of cholecystitis and 12 had gallstones. Thus, treatment of unsubstantiated diagnoses of Lyme disease is associated with biliary complications. PMID- 7844373 TI - Early murine Lyme carditis has a macrophage predominance and is independent of major histocompatibility complex class II-CD4+ T cell interactions. AB - To compare the role of macrophages and CD4+ T lymphocytes in early Lyme carditis, immunohistochemical techniques were used to analyze cardiac infiltrates in immunocompetent mice infected with Borrelia burgdorferi spirochetes. Macrophages predominated in the infiltrate during the first 4 weeks after infection. CD4+ and CD8+ lymphocytes each constituted < 5% of the infiltrate; B lymphocytes were rare. Infected mice deficient in class II major histocompatibility complex (MHC) antigen and depleted of CD4+ lymphocytes developed similar infiltrates, suggesting that class II MHC-CD4+ lymphocyte interactions do not play a critical role in disease initiation. Expression of mRNA encoding JE within areas of cardiac inflammation implicates this chemokine in the recruitment and activation of macrophages in this disease. These data demonstrate that early murine Lyme carditis requires neither class II antigen expression nor presentation of antigen to CD4+ T lymphocytes and suggest a direct response of macrophages to cardiac tissue invasion by B. burgdorferi. PMID- 7844374 TI - Antimicrobial-resistant epidemic Shigella dysenteriae type 1 in Zambia: modes of transmission. AB - To determine the modes of transmission of an epidemic caused by Shigella dysenteriae type I (Sd1) in Zambia, a case-control study was conducted. Case patients were more likely to have recent contact with a person with dysentery (P = .03) and to have a family member with preceding dysentery (P = .01). Case households were more likely to share their latrine (P = .06). Stored drinking water was obtained by hand-dipping a cup into wide-mouthed vessels or by pouring from narrow-mouthed vessels; case households were more likely to obtain drinking water only by hand-dipping (P = .03). Case-patients were more likely to have eaten relish (a cooked meat or vegetable dish; P = .03) purchased from a vendor. Evidence from this study suggests that Sd1 was transmitted by person-to-person spread, by water stored in vessels that permitted hand-dipping, and by prepared foods sold by vendors. Preventive measures should be directed at these risk factors. PMID- 7844375 TI - Modulation of nonspecific antimicrobial resistance of mice to Klebsiella pneumoniae septicemia by liposome-encapsulated muramyl tripeptide phosphatidylethanolamine and interferon-gamma alone or combined. AB - Activation of the host defense system in a nonspecific way might provide tools to support failing antibiotic treatment in certain infectious diseases. The antimicrobial effect was investigated of liposome-encapsulated muramyl tripeptide phosphatidylethanolamine (MTPPE) and interferon (IFN)-gamma and liposome coencapsulated MTPPE and IFN-gamma on Klebsiella pneumoniae septicemia in mice. Prophylactic treatment of mice with five doses of liposomal MTPPE or IFN-gamma increased survival from 0 to 65%. Administration of MTPPE and IFN-gamma coencapsulated in liposome resulted in 100% survival. In vitro, peritoneal macrophages by themselves were stimulated by these agents but were unable to kill K. pneumoniae. However, production of both oxygen and nitrogen intermediates increased when immunomodulators were added to macrophages. These results indicate that effective prophylactic treatment of septicemia due to K. pneumoniae with coencapsulated MTPPE and IFN-gamma is not solely due to activation of the resident macrophages. PMID- 7844376 TI - Pharmacologic inhibitors of tumor necrosis factor production exert differential effects in lethal endotoxemia and in infection with live microorganisms in mice. AB - Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) are principal mediators of septic shock; inhibition of TNF-alpha production may ameliorate outcome in severe infections. Pentoxifylline, chlorpromazine, and thalidomide inhibit TNF-alpha production. Their effects were tested in lethal endotoxemia in sensitized mice. Only chlorpromazine significantly improved survival. Chlorpromazine and pentoxifylline significantly reduced postendotoxin circulating TNF-alpha, by 89% and 76%, respectively. Chlorpromazine also significantly reduced IL-1 beta and soluble TNF receptor-P75. No drug improved survival in Klebsiella pneumoniae-infected mice despite significantly lower circulating TNF-alpha concentrations in chlorpromazine- or pentoxifylline-treated animals. The three compounds decreased circulating TNF-alpha in Candida albicans infected mice, but survival was not influenced. In neutropenic mice, chlorpromazine had no influence on candida in organs, but in normal mice, Candida counts in kidneys were higher in chlorpromazine-treated mice. Thus, inhibition of TNF-alpha production was of no benefit in K. pneumoniae infection and worsened outcome in C. albicans infection. PMID- 7844377 TI - Exacerbation of acute and chronic murine tuberculosis by administration of a tumor necrosis factor receptor-expressing adenovirus. AB - Tumor necrosis factor (TNF) plays a pivotal role in inflammatory phenomena that culminate in either pathogenesis or resistance in mycobacterial disease. The regulatory role of TNF in murine tuberculosis was examined by administering a recombinant adenovirus encoding a fusion protein consisting of the human 55-kDa TNF receptor extracellular domain and the mouse IgG heavy chain domain (AdTNFR). During acute infections with Mycobacterium tuberculosis, AdTNFR pretreatment induced elevated mycobacterial burdens of 1 log10 in the tissues of H37Ra infected mice and 2 log10 (spleen and liver) and 4 log10 (lungs) in H37Rv infected mice. In mice infected chronically with H37Rv, AdTNFR treatment induced a 3-log10 increase of M. tuberculosis in the lungs, in which a tuberculous bronchopneumonia developed with numerous acid-fast bacilli visible in alveoli and bronchi. Administration of AdTNFR may serve as a useful model for studying the pathogenesis and chemotherapy of progressive primary tuberculosis. PMID- 7844378 TI - Fluconazole and amphotericin B antifungal therapies do not negate the protective effect of endogenous tumor necrosis factor in a murine model of fatal disseminated candidiasis. AB - In systemic candidiasis, endogenously produced tumor necrosis factor (TNF)-alpha prolongs survival of the infected host. To determine whether endogenously produced TNF-alpha has a beneficial effect beyond that provided by antifungal therapy, survival was assessed in infected mice that received fluconazole or amphotericin B alone and in combination with anti-TNF-alpha antibody. Neutralization of serum TNF-alpha did not affect survival in fluconazole recipients; however, for amphotericin B recipients, it significantly shortened mean survival. For both fluconazole and amphotericin B recipients, colony counts in organs were significantly higher in animals that also received anti-TNF-alpha antibody. Administration of anti-TNF-alpha antibody with amphotericin B or fluconazole did not affect the morphology of fungi or the inflammatory response in kidneys. This study suggests that exogenous TNF-alpha and drugs that increase the endogenous production of TNF-alpha by the host may be useful adjuncts to fluconazole and amphotericin B for the treatment of systemic candidiasis. PMID- 7844380 TI - Lyme disease: primum non nocere. PMID- 7844379 TI - Preferential recognition by human IgE and IgG4 of a species-specific Schistosoma haematobium serine protease inhibitor. AB - IgE induction in schistosomiasis is an important human response to infection, yet few specific parasite allergens have been characterized. One allergen of Schistosoma haematobium was found to be a species-specific surface antigen and a member of the serine protease inhibitor gene family (SH serpin). The purified recombinant SH serpin protein was used to characterize human isotypic responses to this antigen. Quantitative ELISA based on the recombinant antigen revealed marked IgG4 and IgE responses and a high degree of species specificity (IgG = 96%, IgG4 = 66%, and IgE = 95%) in sera from S. haematobium-infected persons. In contrast, ELISA based on soluble adult worm or egg antigens could not discriminate between species. There was no correlation between serpin-specific IgE and IgG4 levels in 41 infected persons. Further, serpin-induced antibody production in vitro indicated that IgE and IgG4 responses are not coordinately regulated. PMID- 7844381 TI - Rare association of human papillomavirus DNA with esophageal cancer in Japan. AB - To examine whether human papillomavirus (HPV) DNA is associated with esophageal cancer, frozen and paraffin-embedded neoplasms of the upper aerodigestive tract, including esophageal cancer, were investigated. DNA obtained from frozen specimens and cell lines were analyzed by both polymerase chain reaction (PCR) and Southern blot hybridization. DNA from paraffin-embedded samples were analyzed strictly by PCR. DNA of HPV types 6 and 11 was detected in papillomas of the upper respiratory tract at > 50%. However, HPV DNA was infrequently detected in specimens from the upper digestive tract (31 esophageal cancers and 2 esophageal carcinoma--derived cell lines), even by PCR at a sensitivity of 0.1 copy number per cell. These results suggest that the etiologic significance of HPV infection in esophageal cancer is negligible. PMID- 7844382 TI - Genital human papillomavirus infection among male and female sex partners: prevalence and type-specific concordance. AB - Penile, cervical, and vulvovaginal samples from 50 couples attending a sexually transmitted disease clinic and perianal samples from women only were tested for human papillomavirus (HPV) DNA by dot filter hybridization (DFH) and polymerase chain reaction (PCR). Only 18% of women and 4% of men were HPV-positive by DFH, but 72% of women and 63% of men were HPV-positive by PCR. HPV type-specific concordance between partners was more common than predicted by chance (P = .01) and was associated with detection of HPV DNA by DFH in either partner. Thus, genital HPV infection in this population is common in both men and women, and the HPV type-specific concordance in sex partners is consistent with sexual transmission. Higher levels of genital or perianal HPV, as reflected by detection of HPV DNA with the less-sensitive DFH method, may promote sexual transmission. PMID- 7844383 TI - Human cytomegalovirus DNA is present in CD45+ cells in semen from human immunodeficiency virus-infected patients. AB - Human cytomegalovirus (CMV) DNA was detected and quantitated in both blood and semen cells from human immunodeficiency virus (HIV)-infected men with 100-800 CD4 cell counts/mm3. None of the 35 patients studied had demonstrable CMV DNA in mononuclear cells isolated from blood. Blood samples from 8 of these patients were cultured for CMV and found to be negative. About 30% of HIV-seropositive patients in the study group had > 100 copies of CMV in semen (range, > 100 to >10(6); mean, approximately 100,000). Persistent CMV infection was detected for > 8 months in some patients with no obvious signs or symptoms of CMV disease. The CMV-infected cell in semen CD45+ and probably had Fc receptors. Mature spermatozoa were not a major reservoir of CMV infection. PMID- 7844384 TI - Immunization of chimpanzees with recombinant gp160, but not infection with human immunodeficiency virus type 1, induces envelope-specific Th1 memory cells. AB - The human immunodeficiency virus (HIV) type 1 envelope protein (recombinant [r] gp160)-induced T cell lymphokine release pattern of chimpanzees immunized with HIVIIIB rpg160 tested and compared with rpg160-induced lymphokine releases of T cells from unimmunized, HIV-1-infected chimpanzees. The results showed that infection of chimpanzees with HIV-1 did not induce rgp160-specific memory T cells (as evidenced by the lack of Th1 and 2 type lymphokine releases after rgp160 stimulation). In contrast, T cells of rgp160-immunized chimpanzees released Th1 type lymphokines upon stimulation with rgp160 of HIVIIIB, HIVMN, and HIVRF. release was comparable whether chimpanzees were immunized with rgp160 only or also challenged with HIV-1 and protected or not protected. Thus, rgp160 immunization leads to generation of Th1 type memory cells. Whether Th1 type responses contribute to protection against HIV-1 infection has yet to be clarified. PMID- 7844385 TI - Systemic immunoprophylaxis of nasal respiratory syncytial virus infection in cotton rats. AB - The cotton rat model was used to test whether systemically administered immunoglobulin could protect nasal tissues against low challenge doses of respiratory syncytial virus (RSV). Animals were pretreated by intraperitoneal injection of human immunoglobulin with moderate (1:2226) or high (1:15,000) neutralizing antibody titers to RSV (day 0), challenged intranasally with RSV Long at doses ranging from 10(1) to 10(5) pfu (day 1), and sacrificed for virus titration (day 5). Pretreatment with moderate-titer immunoglobulin effected complete or near complete nasal protection against low to moderate (10(1)-10(3) pfu) RSV challenge doses and a significant reduction in nasal RSV titers at high (10(4)-10(5) pfu) challenge doses. Pretreatment with high-titer immunoglobulin effected near complete nasal protection at an RSV challenge dose of 10(3) pfu and highly significant and significant reductions in nasal RSV titers at challenge doses of 10(4) and 10(5) pfu, respectively. Immunoprophylaxis effected complete or near complete pulmonary protection at all RSV challenge doses. PMID- 7844386 TI - Quantitative branched DNA assay and genotyping for hepatitis C virus RNA in Chinese patients with acute and chronic hepatitis C. AB - To determine the value of a quantitative branched DNA (bDNA) assay for detection of hepatitis C virus (HCV) RNA, 309 serum specimens were collected from 100 patients with acute or chronic hepatitis C for detection of HCV RNA by bDNA assay and reverse transcription-polymerase chain reaction (RT-PCR) assay. There were 256 samples positive by RT-PCR; 199 (78%) were also positive by bDNA assay. All but 1 of the remaining 53 samples negative by RT-PCR were also negative by bDNA assay. Combination of the two methods clearly demonstrated changes in HCV RNA titers during and after interferon (IFN) treatment. The most common genotype of HCV infection was Okamoto type II (Simmonds type 1b, 60.0%), followed by type III (type 2a, 16.5%) and type IV (type 2b, 8.2%); mixed or underdetermined types were noted in 15.3%. Patients with chronic type II HCV infection tended to have higher HCV RNA titers. These findings suggest that the bDNA assay is a reliable test for HCV RNA. PMID- 7844387 TI - Age-specific prevalence of antibodies to hepatitis A and E viruses in Pune, India, 1982 and 1992. AB - The age-specific seroprevalence of antibody to hepatitis A virus (HAV) and antibody to hepatitis E virus (HEV) were studied in persons in Pune, India, where both viruses are endemic. The data showed that HAV infected the majority of persons by age 3 years and virtually 100% by late childhood. In contrast, infection with HEV was rare in children and did not reach peak prevalence (33% 40%) until early adulthood. The reason for the differences in infection rates between HAV and HEV is not known. Age-specific antibody patterns in serum samples obtained 10 years apart show that neither HAV nor HEV has diminished in medical importance in this Indian community. PMID- 7844388 TI - Sexually transmitted diseases and human immunodeficiency virus control in Malawi: a field study of genital ulcer disease. AB - Men with genital ulcer disease (GUD) attending a clinic in Malawi were evaluated and treated with one of five drug regimens. Haemophilus ducreyi was isolated from 204 (26.2%) of 778 patients. Of 677 men, 198 (29.2%) had treponemes detected in ulcer material by direct immunofluorescence or had rapid plasma reagin reactivity of > or = 1:8. Human immunodeficiency virus type 1 (HIV-1) seroprevalence was 58.9% overall and 75.8% among patients reporting a history of GUD (P < .001). By logistic regression analysis, HIV-1 seropositivity was shown to impair ulcer healing (P = .003). Treatment failure rates for culture-proven chancroid were 19% for trimethoprim-sulfamethoxazole, 12.9% and 7.4%, respectively, for low- and high-dose erythromycin regimens, and 8.3% and 0, respectively, for low- and high dose ciprofloxacin regimens. Herpes antigen was detected by EIA in 6 (23.1%) of 26 nonhealing ulcers. In Malawi, GUD should be managed as a syndrome to assure treatment of both syphilis and chancroid. PMID- 7844389 TI - Pulsed-field gel electrophoresis for genomic analysis of Neisseria gonorrhoeae. AB - Pulsed-field gel electrophoresis (PFGE) is a technique for analyzing large DNA fragments. PFGE was compared to auxotyping and Por serovar (A/S) classification to determine its utility in the study of gonococcal infection, subtyping A/S classes, and clone identification. PFGE patterns were stable in vitro after 2 isolates were passaged 50 times, and those from sex partners were indistinguishable with both enzymes. Fourteen proline-requiring IA-6 isolates from Kenya produced 8 NheI and 7 XbaI patterns; these included 6 Tet M-carrying isolates, all producing the same NheI pattern. PFGE patterns of 14 arginine-, hypoxanthine-, and uracil-requiring IA-1,2 isolates, from the US Pacific Northwest and Hawaii in 1993, were less diverse with both enzymes. PFGE analysis represents a potentially useful addition to the current gonococcal classification system. PMID- 7844390 TI - Virulence of coccoid and bacillary forms of Helicobacter pylori in gnotobiotic piglets. AB - This study sought to determine if coccoid forms of Helicobacter pylori are virulent for gnotobiotic piglets. Coccoid forms were generated by maintaining broth cultures of H. pylori under microaerobic conditions for 16 days. The resulting cultures contained bacteria with a coccoid morphology that could not be cultured in vitro. Coccoid H. pylori did not colonize any of 6 gnotobiotic piglets that were inoculated, whereas bacillary H. pylori colonized 6 of 6 inoculated piglets. Piglets colonized by bacillary H. pylori developed lymphocytic gastritis, but no gastritis developed in piglets inoculated with coccoid H. pylori, and coccoid-inoculated piglets were sero-negative for H. pylori-specific antibody. Thus, coccoid H. pylori appears to be a degenerate nonviable morphologic phase. PMID- 7844391 TI - Induction of urinary tract infection by intraurethral inoculation with Escherichia coli: refining the murine model. AB - Murine models are important for studying the induction and pathophysiology of ascending urinary tract infections (UTI). However, when vesicoureteral reflux occurs during intravesical inoculation of mice with bacterial suspensions, it is difficult to distinguish between naturally ascending infections and those resulting from the inoculation procedure. The current study investigated whether introducing a bacterial suspension into the urethra rather than into the bladder could minimize or eliminate this complication. There were no differences in the intensity or time course of bladder infections induced by intraurethral or intravesical inoculation. In contrast, the prevalence of kidney infections was < 7% in mice given 10 microliters of intraurethral inoculations versus nearly 60% in animals inoculated intravesically with 100 microliters. There were equivalent numbers of bacteria in the kidneys after inoculation by either route. Thus, intraurethral inoculation of female mice with a small volume of bacteria appears to simulate most closely the pathophysiology of ascending UTIs in humans. PMID- 7844392 TI - Heterogeneity of enteroaggregative Escherichia coli virulence demonstrated in volunteers. AB - Enteroaggregative Escherichia coli (EAggEC) are diarrheal pathogens defined by aggregative adherence to HEp-2 cells. In an effort to identify pathogenic EAggEC isolates, four groups of 5 volunteers were fed 1 of 4 different EAggEC strains, each at a dose of 10(10) cfu. Strain 042 caused diarrhea in 3 of 5 adults; 3 other EAggEC isolates (17-2, 34b, and JM221) failed to elicit diarrhea. A gene encoding enterotoxin EAST1 was found in strains 042 and 17-2 but not 34b or JM221; a 108-kDa cytotoxin was expressed in all 4 isolates. All 4 isolates showed a modest degree of gentamicin protection in HEp-2 cells. 17-2, 34b, and JM221 expressed the fimbrial antigen AAF/I; 042 did not express this fimbria as determined by immunogold electron microscopy and genetic probe hybridization. PMID- 7844393 TI - Interleukin-10 and the monocyte/macrophage-induced inflammatory response in septic shock. AB - Interleukin (IL)-10 is a potent immunosuppressant of monocyte/macrophage function and may help control the inflammatory response induced by bacterial infection. To analyze whether IL-10 is detectable in plasma of patients with septic shock and to evaluate its relationship with endotoxin (lipopolysaccharide [LPS])-induced and monocyte/macrophage-induced inflammatory response, plasma IL-10, tumor necrosis factor (TNF)-alpha, IL-1 beta, IL-6, IL-8, LPS, and neopterin were studied in 24 patients with septic shock and in 12 critically ill patients. Eighty-three percent of patients with septic shock and 25% of critically ill patients had detectable levels of IL-10 (P < .001). There was a significant correlation between plasma IL-10, neopterin (r = .72), TNF-alpha (r = .76), IL-6 (r = .68), and IL-8 (r = .61) levels in patients with septic shock. Monocyte/macrophage activation leads to massive secretion of IL-10, which, however, seems to be unable to control the increased production of proinflammatory mediators during septic shock. PMID- 7844394 TI - Nondifferentiation between Lyme disease spirochetes from vector ticks and human cerebrospinal fluid. AB - To determine whether Lyme disease neuropathogenesis may result from infection by a particular segment of the locally extant population of spirochetes, genetic markers of spirochetes found in cerebrospinal fluid (CSF) of 12 pediatric patients were compared with those in spirochetes from 40 vector ticks sampled in the vicinity of their homes. The primary structure of the outer surface protein A served as the marker of variation; a fragment of the corresponding gene was amplified by nested polymerase chain reaction and the products sequenced. Tick derived variants clustered in seven distinct categories, of which four were present in CSF. One of the CSF variants differed from any found in ticks. Coinfection by different spirochete variants was infrequent in ticks and absent in human samples. Spirochetal neuropathology in children in our study site does not correlate with a particular segment of the tickborne pathogens present in nature. PMID- 7844395 TI - Diagnosis of bacteremic pneumococcal pneumonia by amplification of pneumolysin gene fragment in serum. AB - A polymerase chain reaction (PCR) assay based on the amplification of pneumolysin gene fragments in patient sera was developed for the etiologic diagnosis of acute pneumococcal pneumonia. Two pairs of oligonucleotide primers were designed to amplify a 348-bp and a 208-bp fragment of the pneumolysin gene. Amplified products were analyzed by agarose gel electrophoresis and hybridization using a 24-mer probe internal to the amplified DNA. The nested PCR could detect 10 organisms as determined by serial dilutions of DNA from Streptococcus pneumoniae. All 20 serum samples from patients with acute pneumococcal pneumonia (confirmed by blood culture) were positive. Among 100 serum samples from healthy elderly controls, 94 were negative and 6 were positive by PCR. Thus, PCR may be a novel diagnostic method for pneumococcal pneumonia. PMID- 7844397 TI - Divergent effects of zinc on different bacterial pathogenic agents. AB - Zinc is essential for immunologic function; therefore, it has been postulated that elevated serum levels of zinc might lead to improved immune responses. However, it is not known whether or how serum zinc levels contribute to a clinically relevant mechanism of immunologic activation. In our studies with human peripheral blood mononuclear cells and whole blood, the zinc level selectively enhanced the biologic activity of endotoxin. The combination of nonstimulatory doses of lipopolysaccharide (LPS) and nonstimulatory concentrations of zinc led to the secretion of large amounts of interleukin (IL) 1 beta. In contrast, zinc levels specifically down-regulated monocyte activation caused by some superantigens, staphylococcal enterotoxin A and E and Mycoplasma arthritidis--derived superantigen, but not toxic shock syndrome toxin-1. This demonstrates that zinc levels control IL-1 beta secretion after both LPS and superantigen challenge within a clinically relevant range of concentrations. Our data suggest that the indications and contraindications for clinical zinc supplementation should be reconsidered. PMID- 7844396 TI - In vitro activity of subinhibitory concentrations of quinolones on urea-splitting bacteria: effect on urease activity and on cell surface hydrophobicity. AB - The effect of subinhibitory concentrations of ciprofloxacin, lomefloxacin, norfloxacin, ofloxacin, and sparfloxacin on urease activity and on cell surface hydrophobicity of urea-splitting bacteria was examined. Quinolones at 0.5 MICs demonstrated variable effects on bacterial-urease activity. Norfloxacin inhibited enzyme activity in Proteus vulgaris and Proteus mirabilis, while other quinolones had no effects. In Morganella morganii, sparfloxacin and ciprofloxacin enhanced urease activity, particularly at the initial phase of growth. All quinolones tested showed no marked effect on urease activity by Providencia rettgeri. Quinolones at the same concentrations induced an increase in the cell surface hydrophobicity, which was strain-dependent. There was no correlation between urease inhibition and cell surface hydrophobicity. Inhibition of urease activity by quinolones, in addition to their antibacterial activities, may prevent the progression of urinary tissue damage and stone formation. PMID- 7844398 TI - Malaria in east African refugees resettling to the United States: development of strategies to reduce the risk of imported malaria. AB - Resettlement to the United States of malaria-infected refugees can pose problems for both the refugees and their resettlement communities. To formulate malaria management strategies for East African refugees before resettlement to the United States, epidemiologic data were reviewed and malaria prevalence surveys were conducted among refugees awaiting resettlement in Mombasa, Kenya, and Khartoum, Sudan, in 1993. Overall, 279 Somali (Mombasa) and 127 Ethiopian (Khartoum) refugees were surveyed. Malaria contributed significantly to morbidity in Mombasa: 15% (43/279) of Somalis were parasitemic; 39 infections (91%) were due to Plasmodium falciparum. Sulfadoxine-pyrimethamine was effective treatment. In Khartoum, only 0.8% (1/127) were parasitemic; recent fever or antimalarial use were uncommon. Presumptive sulfadoxine-pyrimethamine treatment before departure was recommended for all resettling refugees from Mombasa; in Khartoum, individual assessment of febrile illness was recommended. Prevention of malaria parasitemia by mass drug administration or individual therapy can minimize the burden of malarial illness to refugees and their resettlement communities. PMID- 7844400 TI - Soluble receptors for tumor necrosis factor as markers of disease activity in visceral leishmaniasis. AB - Serum concentrations of soluble receptors for tumor necrosis factor (sTNFRs) were measured before and after antimony therapy in 25 Sudanese patients with active visceral leishmaniasis (VL). Both sTNFR types I and II were significantly elevated in patients with VL compared with healthy controls from the same region and from the Netherlands (P < .01). In all 23 patients who initially responded to therapy, both sTNFR types decreased sharply, reaching and remaining at levels similar to those found in normal controls; 2 relapsed after an initial response to therapy, and their sTNFR concentrations had increased at the time of relapse. The 2 patients who did not respond to therapy had persistently elevated sTNFR levels. Tumor necrosis factor was detectable in only 16% of patients with VL. Hence, the serum concentrations of sTNFRs may be useful for monitoring therapeutic efficacy in patients with VL. PMID- 7844399 TI - Trypanosoma cruzi induces endothelin release from endothelial cells. AB - The potential role of endothelin-1 (ET-1) in the pathogenesis of focal microvascular spasm, previously implicated in the etiology of Chagas' cardiomyopathy, was investigated. There was an increase in ET-1 in the supernatants of Trypanosoma cruzi--infected human umbilical vein endothelial cells (HUVEC). Infection of HUVEC and vascular smooth muscle cells had no effect on the synthesis of transforming growth factor-beta, which induces ET-1 synthesis. Bioassay studies of isolated rat aortic rings revealed that the increases in ET-1 production were associated with augmented contractile responses, which were significantly attenuated by preincubation with the ETA receptor antagonist, BQ-123. When big ET was incubated with the parasite, there was no conversion of the precursor to the active hormone (ET-1), demonstrating that the parasite did not possess the necessary converting enzyme. These observations suggest the potential importance of ET-1 in the etiology of the microvascular spasm associated with Chagas' disease. PMID- 7844401 TI - Infection with human immunodeficiency virus type 1 among leprosy patients in Zaire. PMID- 7844402 TI - The predictive value of a serologic test for the detection of Babesia microti antibody. PMID- 7844403 TI - No evidence of long-term immunosuppression after high-titer Edmonstron-Zagreb measles vaccination in Senegal. PMID- 7844404 TI - Disseminated acyclovir-resistant herpes simplex virus type 2 treated successfully with foscarnet. PMID- 7844405 TI - Human immunodeficiency virus type 1-infected patients with no disease progression display high-avidity antibody production to autologous V3 sequences. PMID- 7844406 TI - International inter- and intrahospital patient spread of a multiple antibiotic resistant strain of Klebsiella pneumoniae. PMID- 7844407 TI - Emergence of serotype V group B streptococcal infection among infants and adults. PMID- 7844408 TI - Human microsporidiosis in African AIDS patients with chronic diarrhea. PMID- 7844409 TI - Human astrocytes inhibit intracellular multiplication of Toxoplasma gondii by a nitric oxide-mediated mechanism. PMID- 7844410 TI - Evaluation of specific Fasciola antigen in the immunodiagnosis of human fascioliasis in Egypt. AB - Enzyme-linked immunosorbent assay (ELISA) and enzyme linked immunoelectrotransfer blot technique (EITB) were employed for the detection of circulating Fasciola antibodies in infected human sera using a specific Fasciola antigen, prepared by immunoaffinity purification of homogenates of Fasciola hepatica adult worms. Ninety two individuals diagnosed clinically and parasitologically were classified into: Fascioliasis group (21 patients), schistosomiasis group (21 patients) and subjects harbouring other parasitic infections (50 patients). Eighteen healthy individuals served as normal controls. ELISA was 100% sensitive and 93% specific with 96.5% diagnostic efficacy, whereas EITB was 100% sensitive and specific with 100% diagnostic efficacy. Our data revealed that ELISA can be used as a good screening test while EITB can serve as a confirmatory test for immunodiagnosis of fascioliasis. PMID- 7844411 TI - Molecular weight determination of Fasciola antigens specific for diagnosis of acute fascioliasis. AB - Acute human fascioliasis depends in its diagnosis on detecting specific antibodies in the sera of patients. It was observed that both somatic fraction I and crude E/S products of adult Fasciola gigantica worm gave sensitive and specific results. Using IgM ELISA, the cut off O.D was 0.6 and 0.3 nm. and the accuracy was 93% and 98% for the two antigens respectively. Determination of the molecular weight of these two antigens was undertaken by SDS-PAGE. The molecular weight of the somatic fraction I ranged from 17.5 to 43.9 kd, that of the crude E/S products ranged from 12.5 to 14.7 kd. These results were compored with those of previous works performed on antigens of F. hepatica. PMID- 7844412 TI - Schistosoma mansoni: a comparative study on two cercarial transformation methods. AB - An agar: gelatin plate method, incorporating varying concentrations of linoleate was devised to measure cercarial penetration and transformation in vitro. Schistosoma mansoni cercariae were stimulated over a wide range of linoleate concentrations, while the transformation process occurred over a narrow range. Penetration rates rose gradually until at linoleate concentrations of 0.3 mM and greater, where penetration approached 100% while transformation just started to occur. The latter then reached maximum (90%) at 3 mM. This optimal concentration of linoleate leading to maximal transformation was then compared with a mechanical transformation method in relation to proteolytic activity and nuclear content. It was found that, proteolytic activity was higher by the chemical than by the mechanical transformation method. The nuclear content decreased by both techniques. This decrease was greater when the mechanical transformation method was applied. PMID- 7844413 TI - Treatment of schistosomiasis with praziquantel among school children. AB - This study, as a part of the drug resistance project, one of the activities of the schistosomiasis research project, was carried out in 3 villages in lower Egypt. Its main objective is to assess the praziquantel cure rate and to identify infected persons not responding to praziquantel treatment. Among the studied population, the prevalence of S. mansoni among school children (age 6 to 18 years) was 21.8%, 32.7% and 32.4% in the 3 villages respectively. Those who were found infected were treated with praziquantel (40 mg/kg body weight). The cure rate after six weeks was 75.8%, 83.9% and 72.7% among school children respectively. This cure rate among school children was less than that of adults by 5-10%. Compared with that of preschool age, it showed variable results. A second dose after 6-8 weeks was given to those who were still infected. Those who remained infected even after this second treatment, received a third dose of 60 mg/kg body weight. After the third treatment, only 5 patients of school age remained infected compared to one among adults and one among preschool age. The failure rate was found to be 50%, 18.5% and 12.5% among preschool, school children and adults respectively after the third treatment regimen. PMID- 7844414 TI - Immunoglobulins in patients with atopic dermatitis due to mites infestation in Qualyobia Governorate, Egypt. AB - Atopic dermatitis (A.D.) is a hereditary and distinct form of eczema which may be associated with other atopic manifestations. The aetiopothogenesis of A.D. is unknown and it is widely accepted that both intrinsic and extrinsic factors are involved. House dust mites (HDM) are of great medical importance in causing allergic manifestations in human being. In the present work, a total of 30 A.D. patients with different ages of both sexes were examined for the immunoglobulins level as compared to control group. The IgG, IgM, IgA & IgE were higher in the patients than in the controls. These differences were highly significant in the IgE. On the other hand, IgA showed no significant increase. PMID- 7844415 TI - Human resistance to reinfection with schistosomes. II. Specific IgA titres before & 3 months after praziquantel treatment. AB - Specific IgA assays by ELISA technique for schistosomal cases of school age children (12-14 years), were performed before and 3 months after praziquantel treatment. Sera of the resistant cases (non-reinfected after chemotherapeutic cure) showed a significant higher titres of anti-soluble egg antigen (anti-SEA) and anti-soluble worm antigen preparation (anti-SWAP) IgA antibodies than that of reinfected schistosomal cases before and 3 months after treatment. Praziquantel therapy insignificantly (P > 0.05) increased anti-SEA and anti-SWAP IgA antibodies in the sera of schistosomal cases and 3 months after treatment. Anti SEA IgA & IgE anti-SWAP IgA & IgE were correlated positively with each other among schistosomal cases either resistant or reinfected while anti-SEA and anti SWAP IgA antibody levels of schistosomal cases with eosinophilia were significantly higher than that with normal eosinophilic counts. Anti-SEA IgA antibody titres of schistosomal cases were correlated negatively, before treatment, with intensity of infection but anti-SWAP IgA titres were not, which might indicates that anti-SEA IgA antibodies inhibit schistosomes for egg laying and subsequently pathological complications due to granuloma formation. The higher titres of specific IgA antibody of resistant cases, its positive correlation with IgE and its negative correlation with intensity of infection might support the role of IgA as an essential component of acquired (resistance) immunity to share with IgE in protection of cured schistosomal cases against reinfection. PMID- 7844416 TI - The effect of Ambrosia maritima (Damsissa) on the viability of Lymnaea cailliaudi; an experimental study. AB - The present work aimed at studying the effect of Ambrosia maritima (Damsissa) on the viability of Lymnaea snails. Lymnaea snails used in these trials were acclimatized to laboratory conditions before use in the toxicity test. The snails were exposed to various concentrations (100-3000 mg/l) of dry powdered Damsissa, Ambrosia maritima was lethal to Lymnaea snails at concentration of 3000 mg/L after one day and at 100 mg/l after 14 days. PMID- 7844418 TI - Two new species of Eumegacetes Looss, 1900 (Digenea: Eumegacetidae) from Egyptian birds. AB - Two new species of the genus Eumegacetes Looss, 1900 are described from avian hosts in Sharkia province, Egypt and these include Eumegacetes (Anterovitellum) pycnonotus n. sp. from the bulbul, Pycnonotus barbatus, and E. (Posthovitellum) hirundus n. sp. from the barn swallow Hirundo rustica saviginii. The descriptions are based primarily on differences in the shape and elevation of the intestinal caeca, the position of the genital opening and the shape and distribution of the vitelline follicles, testes, ovary and uterine loops. PMID- 7844417 TI - Tumour necrosis factor (TNF-alpha) in zoonotic cutaneous leishmaniasis. AB - Generally speaking, the cell mediated immunity plays a pivotal role in the host resistance against the protozoal parasite Leishmania species. On the other hand, TNF-a (Cachectin) is a protein produced mainly by macrophages, with wide range of biological activities and may be important in inflammatory processes. Also, it plays the important role in some infectious diseases. In the present study, TNF alpha was measured in the sera of 30 parasitologically proved zoonotic cutaneous leishmaniasis (ZCL). Serum TNF-alpha was elevated in 4/30 (13.3%) of the patients. However, it was not elevated in 26/30 of the patients as well as in 15 normal control. It was concluded that the TNF-alpha did not correlate with the number, site and/or duration of the lesion (s), but with high serum level of indirect haemagglutination tests associated with the severity of ZCL. PMID- 7844419 TI - Schistosoma mansoni: IgG reactivity to soluble adult worm antigen preparation (SWAP) in sera of immunized mice with irradiated attenuated and virulent cercariae. AB - The aim of this work was to identify the antigens, that elicit a greater or unique immune response in the immunized host against Schistosoma mansoni (Egyptian strain) infection. Moreover the difference in immune response to this antigen between mice immunized with radiation-attenuated cercariae or immunized with virulent cercariae were investigated. Immunobloting technique was used to monitor the fine specificity of host IgG to SDS-PAGE separated SWAP in the sera of different test groups immunized with either radiation-attenuated cercariae or low doses of virulent cercariae compared to non-immunized group. Data from this study showed that groups immunized with virulent and irradiated-attenuated cercariae showed 74.7% and 68.3% reduction in worm burden respectively. Differences of humoral immune response of sera of different tested groups against SWAP proteins were definite. Sera of non-immunized mice precipitated non immunogenic proteins of 87 and 83 KD. SWAP proteins of 106 and 97 KD were identified only by the sera of vaccinated animals with irradiated attenuated cercariae whether challenged or not. Resistant sera from animals immunized by either irradiated-attenuated cercariae or virulent cercariae recognized low molecular weight antigens that ranged from 34 to 52 KD in addition to 57 KD. This indicated that the 106 and 97KD may be the target antigens for protection by radiation-attenuated larvae, while the marker of resistance induced by attenuated or virulent larvae may be 34-52 and 75 KD antigens. PMID- 7844420 TI - Endothelial tissue pathological alterations demonstrated in mice naturally infected with Sarcocystis. AB - Comparative electron microscopical study showed a spectrum of cytopathological changes ranging from exudative to obstructive inflammation of the vascular endothelium in mice naturally infected with Sarcocystis. The endothelial cells changes were characteristic of necrotizing vasculitis and ischaemic injury indicating loss of metabolic integrity and impaired perfusion. Signs of chronic inflammation and reflecting macrophage-lymphocyte interaction were also evident. The fact that the endothelial affection was not a consistent feature in all infected mice, indicates that such cytopathological alterations may often be temporary and repairable or more likely they are genetically predisposed. PMID- 7844421 TI - Description of Hastospiculum bipinnatum (Linstow 1899) Chandler, 1929 (Nematoda: Diplotriaenoidea) from Egyptian Varanus griseus. AB - Hastospiculum bipinnatum worms were recovered from the thoracic cavity of the lizard Varanus griseus from Egypt. Both adult worms and their larvae were described and compared with the related species. The present is the first record of this parasite from Egypt. PMID- 7844422 TI - Scanning electron microscope observations on Parapharyngodon bulbosus (Linstow, 1899) (Nematoda: Pharyngodonidae) from Egyptian Chalcides ocellatus. AB - The oxyurid nematode Parapharyngodon bulbosus was collected from the lizard Chalcides ocellatus from Egypt. Male and female worms were described by light and scanning electron microscopes. The specific characteristics of the worms were defined, including; mouth opening, cuticular surface of the body, genital cone and genital papillae in the male. PMID- 7844423 TI - Time factor and eosinophil count in relation to experimental Schistosoma mansoni infection. AB - The effects of diurnal variations of eosinophils on hostparasite relationship was studied in mice primarily exposed to S. mansoni infection. The eosinophil counts of 20 control normal mice showed different variations at different hours of the day with maximum level at midday and the minimum level at midnight. At these times, 2 groups of mice, each consists of 30 mice, were infected by about 100 S. mansoni cercariae. The infected mice in both groups showed more or less the same results as regards the worm burden, egg counts in tissues and histopathological changes in livers. Both infected groups showed marked eosinophil elevation versus normal control group yet the difference in-between them was insignificant. This means that the normal physiological variation in eosinophils in normal mice is useless in protection against infection. Complete ablation of eosinophils from animal using antieosinophilic sera, is essential for any study on eosinophils in relation to infection. PMID- 7844424 TI - Parasitic infections in primary and secondary schools in Giza Governorate, Egypt. AB - Four primary and two secondary schools at Kafr Hakeem, El-Mansuria and Berkash villages in Imbaba district were surveyed. Urine and stool specimens of 791 students were examined. Results revealed amoebiasis (22.4%); hymenolepiasis nana (6.2%); ancylostomiasis doudenale (5.7%); ascariasis (1.5%) and enterobiasis (1.1%). Parasites transmitted by autoinfection represented 15.9% of the total infected subjects; those transmitted by the skin penetration 27.2% and by contaminated food 56.9%. There was no statistical difference between primary and secondary school students as regards the rate of infection. PMID- 7844425 TI - Evaluation of urinalysis reagent strips versus microscopical examination of urine for Schistosoma haematobium. AB - This study deals with the effectivecess of chemical reagent strips for detection of haematuria and proteinuria in selecting S. haematobium egg positive subjects as compared to microscopical examination of urine. Out of 222 students from primary and secondary rural schools, 191 were S. haematobium and 59 were parasitologically negative. 135 students had a count of less than 50 eggs/10 ml. urine and 56 had more than 50 eggs/10ml. The sensitivity of reagent strips in detecting haematuria was 10% and 36% for the groups with less than and more than 50 eggs/10 ml. of urine respectively. The correspondant microscope figures were 42% and 93% respectively. Proteinuria was detected in 11% and 29% of urines from the groups with less than and more than 50 eggs/10 ml. respectively. The specificity of strips and microscopical examination in detection of haematuria was 100%, while that for proteinuria was 97% as detected by strips. These results show that urinalysis strips cannot be used as an alternative to microscopic examination of urine for the presence of S. haematobium eggs. PMID- 7844426 TI - Evaluation of two cultural media (CPLM & TYM) for isolation and maintenance of Trichomonas vaginalis stocks in the laboratory. AB - Five hundreds vaginal discharge specimens were inoculated simultaneously in 2 axenic culture media (CPLM & TYM), in order to compare their ability to isolate and to maintain the growth of T. vaginalis in the laboratory. While both media were found to be equally good in detecting the organisms in vaginal discharges, yet, T. vaginalis stocks were maintained for a longer time in TYM medium (one year), than in the CPLM medium (2 weeks). The yields of the parasites with different inocula subcultured and after different incubation periods were counted in the TYM medium. PMID- 7844427 TI - Trichomoniasis in non-gonococcic urethritis among male patients. AB - Urethral discharge of 415 male patients, age 18-50, were examined for Trichomonas vaginalis by direct examination of fresh and Giemsa-stained slides and cultivation in CPLM media. In this study, 85 (20.7%) specimens out of 415, were found to be positive for trichomoniasis. Three groups consisting of 30, 29 and 26 patients each was treated with secnidazole, metronidazole and ornidazole respectively. In the follow up controls, all patients were found to be negative for trichomoniasis and all complaints were disappeared totally without a significant difference between all groups. PMID- 7844428 TI - Effect of praziquantel on sex hormone levels in murine schistosomiasis mansoni. AB - Changes in sex hormonal levels were studied in Schistosoma mansoni infected and praziquantel treated mice (400 x 2 mg/Kg), drug control and in normal control groups. It was observed that schistosomiasis lead to increase in the level of testosterone, progesterone and 17B-esteradiol, 60 and 70 days postinfection in male and female mice, respectively. In praziquantel treated group the level of testosterone was lowered 10, 20 & 30 days post treatment, progesterone and 17 beta-estradiol fell 30 days post treatment after primary rise. The mechanism of recorded changes will be discussed in details. PMID- 7844429 TI - Cytophotometric estimation of hepatocytes DNA in chronic liver diseases including schistosomiasis for detection of early preneoplastic changes. AB - No doubt chronic liver diseases due to schistosomiasis and other causes as virus hepatitis are not uncommon among Egyptian patients. Besides, neoplastic changes in such patients are always seen. So, the aim of this work was to evaluate the estimation of hepatocytes DNA in chronic liver diseases as a diagnostic feature for early preneoplastic changes in different groups of patients. These groups included (a) chronic persistent hepatitis, (b) chronic active hepatitis, (c) liver cirrhosis due to schistosomiasis and other causes & (d) hepatocellular carcinoma. The results were evaluated histochemically and histopathologically. It was concluded that the cytophotometic evidence of hepatocytes DNA in chronic liver diseases is a promising mean in detecting early preneoplastic changes. PMID- 7844430 TI - Congenital toxoplasmosis among premature infants with different clinical pictures in Saudi Arabia. AB - No doubt, toxoplasmosis is a prevalent infection in all the Arab countries. However, the incidence differs from one country to another and even within the same country. Congenital toxoplasmosis is the most important form of the infection. In the present study, some 78 premature infants with different clinical pictures were examined for Toxoplasma IgG (by IHAT and ELISA) and Toxoplasma IgM (by ELISA). The results showed Toxoplasma IgG ranging between 32.1% (IHAT) and 46.2% (ELISA) while IgM (ELISA) was 23.1%. The highest positivity rate was among those suffering jaundice and the lowest was among those suffering fever of unknown origin. Protection of women particularly pregnant ones, from Toxoplasma infection is a must. PMID- 7844431 TI - Frequency of Entamoeba gingivalis among periodontal and patients under chemotherapy. AB - This study was carried out to investigate the frequency of E. gingivalis in the gingival crevices of patients with periodontitis compared to normal subjects. Flagyl therapy was tried in cases with periodontitis. Also the frequency of this amoeba was investigated in patients receiving chemotherapy to be compared to normal subjects. The results revealed that higher frequency was observed in patients with periodontitis and flagyl therapy reduced this frequency. Cases under chemotherapy showed higher frequency than the normal control. Histopathological sections from the gingiva of periodontitis patients did not show any amoeba invading the tissue. PMID- 7844432 TI - Use of Kato and nucleopore techniques for qualitative diagnosis of schistosomiasis. AB - A comparison on qualitative basis, is attempted between merthiolate-iodine formaldehyde concentration (MIFC) and Kato thick smear techniques for diagnosis of schistosome eggs in stools. As well, the centrifugation-sedimentation method was compared with the Nucleopore filtration technique for schistosome eggs in urine. Using MIFC and Kato techniques, 149 out of 185 subjects were found to have Schistosoma mansoni infection, 41 of them were diagnosed by Kato alone, while no case was solely MIFC positive. The sensitivity of MIFC compared to kato was 72.3% and both techniques were 100% specific. For diagnosis of S. haematobium infection, 78 out of 103 subjects were positive by centrifugation- sedimentation and/or Nucleopore techniques. 42 of them were diagnosed by Nucleopore alone and none was positive by centrifugation- sedimentation only. The sensitivity of the latter technique was 46.2% and both techniques were 100% specific. The study demonstrates that Kato thick smear and Nucleopore filtration are highly sensitive techniques that can be used for routine qualitative diagnosis of schistosomiasis. Under field conditions, they are qualitatively and quantitatively useful. The Kato technique besides its high sensitivity is very cheap. The only limitation for the Nucleopore technique is its relative high expenses. PMID- 7844433 TI - Scaning electron microscopy of Capillaria muris sylvatici from Clethrionomys glareolus with reference to the zoonotic species. AB - Species of the genus Capillaria are numerous. Many of them are parasites of different species of vertebrates, including man, causing various pathological manifestations. The taxonomy of the capillariids is a complicated one. In the present study, light and scanning electron microscopes were used to illustrate and clarify the taxonomic features of Capillaria muris sylvatici. This capillus or hair nematode was recovered from the vole Clethrionomys glareolus. The results were discussed with reference to the species encountered in the medical and veterinary fields. PMID- 7844435 TI - Laboratory induced resistance to praziquantel in experimental schistosomiasis. AB - To study the effect of praziquantel (PZQ) on successive generations of S. mansoni worms, infected mice were treated 6 weeks after infection with different doses of PZQ (300, 500 mg/kg.), the schistosome strain was originally obtained from an infected Egyptian patient. The eggs subsequently produced by worms that had survived the PZQ treatment were used to infect snails and mice of the following generations. The results were expressed as average number of worms and cure rates in comparison with control groups. It was found that the use of PZQ., especially in low subcurative dose may lead to the development of resistance to therapeutic dose of the drug in following generations. PMID- 7844434 TI - Effect of immunomodulation on the course of experimental toxocariasis in mice. AB - Immunosuppressed groups treated with cortisone showed fulmination of Toxocara canis infection in terms of significant increase in brain parasitism, total larval count and significant decrease in the percentage reduction of the total count. Suppression of the host inflammatory responses was detected in the liver, lungs, brain and muscles. Accelerated transit of larvae through the liver was observed when cortisone was given before infection. Whether BCG was given before or after infection, it showed no significant changes regarding all criteria compared to the control group. Induction of diabetes, whether before or after infection, led to persistence of larvae in the liver, insignificant increase in brain and total larval parasitism and insignificant decrease in the percentage reduction of the total count. PMID- 7844436 TI - Aberrant fascioliasis: ectopic focus in peritoneal cavity. PMID- 7844437 TI - [Effect of hormone replacement therapy on lipid metabolism in patients with premature ovarian failure and Turner's syndrome]. AB - Premature ovarian failure (POF) and Turner's syndrome patients who are also hypoestrogenomic, like postmenopausal women, are considered to be a high risk group for hyperlipemia. Our long-term study was conducted to evaluate the effect of hormone replacement therapy (HRT) on lipid metabolism in 16 POF and 10 Turner's syndrome women. 1. The initial average total cholesterol (TC) of the untreated and treated POF patients (209, 196mg/dl) and that of untreated and treated Turner's syndrome patients (213, 240mg/dl) were significantly higher than those in the control group (175mg/dl) except treated POF patients. LDL cholesterol (LDL-C) of the untreated and treated POF patients (135, 113mg/dl) and that of untreated and treated Turner's syndrome patients (142, 144mg/dl) were significantly higher than those in the control group (108mg/dl) except treated POF patients. In comparison to healthy women of a similar age, POF and Turner's syndrome patients were at high risk of hyperlipemia because of higher serum TC and LDL-C levels. 2. After HRT for 2 years, LDL-C decreased by 18% and 13%, and HDL cholesterol increased by 38% and 41% in POF and Turner's syndrome patients, respectively. Hence AI decreased by 40% and 50% respectively. The younger the hyperlipemic patients are, the higher the relative risk for atherosclerosis is. The results of this study suggest that, because of the beneficial effects of HRT on serum lipid metabolism, it can help to prevent the development of coronary heart disease. PMID- 7844438 TI - [Effect of autoantibodies on women with infertility]. AB - The present study was conducted to elucidate the clinical significance of autoantibodies in infertility. Among 203 cases of infertility, 27 cases (A group) were positive for antinuclear antibodies (ANA), and 18 cases (B group) were positive for antiphospholipid antibodies (APA) regardless of the presence of ANA. The progress of pregnancy over time in the study period was clarified in 13 cases in A group and 12 cases in B group. Although only luteal support was given to the A group, appropriate for gestational age babies were obtained in all cases except 3 cases in which there occurred early abortion. In B group, babies were obtained successfully in 8 cases by steroid-aspirin therapy, but intrauterine fetal death occurred in the second trimester in 2 cases, and in the other 2 cases early abortion occurred. In cases positive for the antibody (beta 2(-)ACA) to cardiolipin, fetal distress did not occur in any of the 3 cases. On the other hand, in cases positive for the antibody (beta 2(+)ACA) to the cardiolipin-beta 2 glycoprotein I complex and/or lupus anticoagulant (LA), marked fetal distress occurred in all except one of the 7 cases. In conclusion, there was little correlation between ANA, beta 2(-)ACA and infertility, suggesting that the cause of infertility is the induction of placental circulating disorder by beta 2(+)ACA and LA. PMID- 7844439 TI - [Clinical study of autologous blood transfusion in pregnant women]. AB - The effect of autologous blood donation during the third trimester of pregnancy on the maternal circulation, the properties of blood collected in a phosplatebuffered citrate anticoagulant solution, and the clinical outcome of autologous blood donation and transfusion for pregnant women were investigated in this study. Thirty-four pregnant women with placenta previa or previous cesarean delivery underwent phlebotomies in an autologous transfusion program. Three hundred ml of blood was collected under the observation of fetal heart rate patterns and uterine contractions from 3 weeks prior to the planned date of cesarean section and a total of 900 ml of blood was stored. Electronic fetal monitoring tracings were all normal and changes in blood pressure and pulse rates were minimal during the blood donation. The decrease in hemoglobin after the removal of 900 ml of blood was only 0.6g/dl on average during the 3 weeks, since the concentration of erythropoietin in serum and the counts of reticlocyte increased in a few days after blood removal. But there were no significant changes in TAT levels in serum. Twelve out of 34 pregnant women received the autologous blood transfusion during or after cesarean delivery and the homologous transfusions were avoided. The results of this study suggested that autologous blood transfusion for pregnant women with a high incidence of blood loss at delivery, such as placenta previa or previous cesarean delivery was safe and advantageous in avoiding homologous blood transfusion. PMID- 7844440 TI - [Antenatal screening for fetal well being by pulsed Doppler velocimetry]. AB - A pulsed Doppler screening study was performed on pregnant women to investigate the ability of the test to detect adverse pregnancy outcome by following two methods. The waveforms were analyzed by calculating the resistance index (RI). Method 1.: longitudinal study: Blood flow velocity in the umbilical artery (UA) was recorded at 23, 28, 32, and 35 weeks' gestation in 726 pregnancies. Method 2.: cross-sectional study with FAS: Blood flow velocity in the UA and fetal middle cerebral artery (MCA) was recorded before and after fetal acoustic stimulation (FAS) at 35 weeks' gestation in 525 pregnancies. Result 1.: As UA-RI decreases continuously with gestational age, there was a linear correlation between them. The 726 cases were classified into three groups according to the UA RI value. The UA-RI of the control group (n = 698) never reached mean + 2SD. The UA-RI of the +2.5D group (n = 4) increased with gestational age and was over mean +2.5SD at the last measurement. The +2SD group (n = 24) remained. There was a significant adverse pregnancy outcome in the +2.5SD group as judged by intrauterine growth retardation (SGA) (+2.5SD; 75%, +2SD; 17%, control; 10%), fetal distress (+2.5SD; 75%, +2SD; 5%; control; 9%) and pregnancy induced hypertension (+2.5SD; 75%, +2SD; 23%, control; 8%). Result 2.: The normal ranges of UA-RI and MCA-RI were calculated at 35 weeks' gestation, both before and after FAS, and women with UA-RI > +2SD or MCA-RI < -2SD were considered as abnormal.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7844441 TI - [Mass-screening for ovarian cancer by transvaginal ultrasonography--study on ultrasonographic findings]. AB - Mass-screening for ovarian cancer by means of transvaginal ultrasonography has been performed in Aomori Prefecture since 1989. To select appropriate candidates to receive the second screening, the findings in 614 ultrasonic pictures of pelvic tumors over 30mm recorded on a VTR were studied. The results were as follows: 1) At the first screening, the rate of solid tumors was similar in each age group, but that of mixed tumors was higher in the thirties. 2) When ultrasonic findings at the first screening with that of the second screening were compared, (1) Twenty to thirty per cent of all tumors detected in the first screening had disappeared or had become under 30mm in size at the second screening. (2) About 20% of solid tumors detected in the first screening were not ovarian tumors (uterine myomas or others) in the second screening, regardless of the tumor size. (3) The rate which decided the course of therapy or follow up at the time of the second screening was not related to the ultrasonic findings for tumors smaller than 50mm. At the present time, classification of transvaginal ultrasonic findings is insufficient, and so it is difficult to use it to select appropriate candidates to receive the second screening. But the ultrasonic findings are very important in deciding on the course of therapy and follow up. PMID- 7844442 TI - [Characteristic of cystic glandular hyperplasia as a precursor of endometrial carcinoma]. AB - The natural history and biological behavior of cystic glandular hyperplasia (CGH), which has been considered to be a precursor of endometrial carcinoma, still remain unclear. The present prospective study included 52 patients with CGH, who were followed up for 6 months to 5 years with occasional curettage, surgical procedures or hormonal therapy. The lesion disappeared in 35 cases (67.3%), persisted in 12 cases (23.1%) and became more serious in 5 cases (9.6%). Of these 5 cases, one case was found to have endometrial carcinoma during her follow-up. Nuclear DNA analysis was performed by Flow cytometry in 8 CGH cases. Eighty four point nine % of the cells from these 8 cases were in G0+1 phase, 8.3% in S phase and 7.4% in G2 + M phase. The proliferation index for CGH was 15.7%. Proliferative and mitotic activities of CGH were found to be similar to those of adenomatous hyperplasia, and the levels of these activities were between those of normal endometrium and atypical hyperplasia.G1. PMID- 7844443 TI - [Mass-screening for ovarian cancer by transvaginal ultrasonography--study on tumor markers at the second screening]. AB - Examination of tumor markers (CAMPAS) at the second screening in our mass screening for ovarian cancer was evaluated. CAMPAS has been performed in 866 women with enlarged ovaries over 30mm in size among 20,242 who received the first screening by transvaginal ultrasonography. In those with semi-malignant and malignant ovarian tumor (ovarian cancer), their serum levels of CA125, CEA, CA19 9, AFP and L-LDH were also measured (Combination Assay) and CA125, CEA, CA19-9, AFP, CA602, CA54 and CA61 antigens in removed tumor tissues were studied by immunoperoxidase staining (Tumor Assay). The results were as follows: 1) Ten of the 866 women were positive for CAMPAS, however, only one of them was found to have ovarian cancer. 2) Of the 20,242 women, six were found to have ovarian cancer: all in stage I and all detected among these 866 women. 3) Of the 6 women with ovarian cancer, three had high serum levels in the Combination Assay, and 4 had positive finding in the Tumor Assay, but of the 4 women with a positive Tumor Assay, one had different kinds of tumor markers in serum and one did not have a high serum level. Thus, CAMPAS was not useful as the second screening method in our mass-screening system for ovarian cancer. PMID- 7844444 TI - [Evaluation of adequate number of transferred embryos to prevent supertwin pregnancies in IVF-ET programs]. PMID- 7844445 TI - [A case of polyhydramnios treated with indomethacin under measurement of hourly fetal urine production rate (HFUPR) as an indicator]. PMID- 7844446 TI - [A case of pregnancy complicated with congenital left lung agenesis]. PMID- 7844447 TI - [A study on the mechanism of thrombosis in ovarian hyperstimulation syndrome (OHSS)]. AB - The purpose of this study was to investigate whether endothelial cell procoagulant activity (PCA), which triggers the extrinsic coagulation pathway, is involved in thrombosis in patients with ovarian hyperstimulation syndrome (OHSS). PCA in OHSS sera was measured by an activation of tissue factor expression on cultured human umbilical vein endothelial cells (HUVEC). The substance responsible for the expression of PCA in sera was partially purified and characterized. The results obtained were as follows. (1) OHSS sera contained significantly (p < 0.05) higher PCA than in controlled women (during the follicular phase). Fetal cord sera contained very strong PCA. (2) There was no correlation between PCA and the level of either estradiol (E2) or progesterone (P4) in OHSS sera. (3) The substance that expresses PCA in fetal cord sera was heat-labile with high affinity for heparin sulfate and had a molecular weight of approximately 100,000. These results support these conclusion: (1) PCA is involved in thrombosis in patients with OHSS and (2) neither the serum level of E2 nor that of P4 is associated with PCA. PMID- 7844448 TI - [Clinical study on total omentumectomy for ovarian cancer]. AB - Omentumectomy as a basic surgical method at the site of metastasis of ovarian cancer was examined, and the importance of total omentumectomy was evaluated. Nineteen patients who underwent initial laparotomy and did not receive preoperative chemotherapy were examined histopathologically. 1. Omental metastasis was found in 9 of 19 patients (47%). 2. No significant correlation was seen between the maximum tumor diameter and omental metastasis. 3. No significant correlation was seen between the amount of ascites and omental metastasis. 4. Cytodiagnosis of the ascites and intraperitoneal lavage fluid showed significantly more omental metastasis in patients who tested positive. 5. Omentum in the upward direction from the teniae of the transverese colon showed a high incidence of metastasis. 6. Postoperative disturbances associated with total omentumectomy were mild. These results indicated that the omentum is the principle site of metastasis of ovarian cancer, and omentumectomy should be performed as total resection whenever possible since metastasis occurs in the upward direction because partial resection is not significant and postoperative disturbance is mild but there is the need for requiring further examination in the case of Ia stage. PMID- 7844449 TI - [Circumvention of cisplatin resistant ovarian cancer cells by antiestrogens]. AB - Antiestrogens (AEs) have been considered to elicit antitumor effects via estrogen receptor. However, recent reports have demonstrated that AEs had an antitumor effect even in cases without estrogen receptor, and that AEs caused various kinds of biological behavior such as a chemosensitizing effect. We therefore investigated the possibility of circumvention of cisplatin (CDDP) resistance due to the chemosensitizing effect of AEs by using 5 ovarian cancer cell lines. They were named KF, MH, KK, KFra and KFrb cell lines. KF and MH were derived from serous cystadenocarcinomas, and KK from a clear cell carcinoma. KFra and KFrb were CDDP-resistant cell lines developed from the KF cell line. MCF-7 cell line derived from breast cancer was used as a control. The study of a 50% inhibitory concentration (IC50) revealed that clomiphene (CLO) had the most potent antiproliferative effect among the AEs used, and was followed by tamoxifen (TAM) and toremifene (TOR) with a similar effect. On the whole, the degree of CDDP sensitivity was not correlated with the degree of AE sensitivity. KFra cell line which had the highest CDDP-resistance among the 5 ovarian cancer cell lines used was the most sensitive to AEs, especially to CLO. In the study on the combined administration of CDDP and AEs, 1 microM of CLO significantly reduced the IC50 of CDDP to KFrb, KK and MCF-7 cell lines. Similarly, 1 microM of TAM significantly reduced the IC50 of CDDP to KF, KFra and MCF-7 cell lines, and 1 microM of TOR significantly reduced it to KFra, KK and MCF-7 cell lines.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7844450 TI - [Normal-sized ovary carcinoma syndrome: histopathological analysis of 14 cases]. AB - Fourteen cases of "normal-sized ovary carcinoma syndrome" (diffuse metastatic malignant disease of the abdominal cavity of the female, with normal-sized ovaries, with no origin assigned definitively by intraoperative or preoperative evaluation, Feuer et al., 1989) were analyzed histologically, histochemically, immunohistochemically and ultrastructurally. Through these studies, 14 cases were divided into 11 primary peritoneal tumors (4 diffuse malignant mesotheliomas and 7 serous surface papillary carcinomas) and 3 metastatic peritoneal tumors (2 ovarian tumors and 1 appendicular tumor). To distinguish serous surface papillary carcinomas from epithelioid diffuse malignant mesotheliomas, examinations such as hyaluronidase digestion test, electron microscopy, and immunohistochemical studies using antibodies for Ber-EP4 and Vimentin were found to be useful. In order to achieve an accurate prognosis of normal-sized ovary carcinoma syndrome, it seems necessary for us to accumulate more information on this syndrome. PMID- 7844451 TI - [Clinical usefulness of GnRH agonist therapy for premenopausal women with uterine leiomyoma]. AB - The purpose of this study was to evaluate the tumor volume reducing effect and the frequency with which menopause is induced in premenopausal women with leiomyoma uteri treated with GnRHa buserelin, 900 micrograms/day for 24 weeks. Twenty-six women, whose average age was 49.7 +/- 2.1 years (Mean +/- SD), were enrolled in this study. Uterine and myoma volume were measured by computed tomography (CT) and transvaginal sonography, respectively. Mean uterine and myoma volume had decreased by 33.7% and 39.9%, respectively at 24 weeks of GnRHa therapy. Nine patients were brought to menopause following the treatment. This rate (34.6%) is significantly higher than that of the age matched control group (11.8%), at eighteen months' observation without GnRHa treatment. We conclude that GnRHa treatment for premenopausal women with uterine leiomyoma causes not only temporary ovarian suppression but also has a strong tendency to induce menopause. PMID- 7844453 TI - [Evaluation of the peripheral skin sympathetic function by cooling thermography in women with climacteric complaints]. AB - To evaluate the peripheral skin sympathetic function, cooling thermography was performed on women with climacteric complaints (CG) and without them (NG). Both hands were immersed into 4 degree C water for 1 minute ant the nail temperature of the right second finger was measured before and after the stress every 1 minute for 7 minutes. And the recovery rate was calculated. By dividing the CG groups by the 5 minute recovery rate minus the 2SD of the NG groups, there was seen to be a significant difference between the recovery patterns. One is a good recovery group (GR, N = 26) and the other is a poor recovery group (PR, N = 28). The significant difference between GR and PR groups was only recognized in the pre-cooling nail temperature. No significant difference was seen in age, Body Mass Index, Kupperman Index, symptoms, serum estradiol or serum testosterone levels. These results indicate that in about half of women with climacteric symptoms, peripheral skin sympathetic nerve function is continuously hypertensioned and the response to cooling stress is decreased. Although the reason for these results is not clear, sympathetic nerve dysfunction is supposed to be the main cause. This test is useful for evaluating peripheral skin sympathetic function. PMID- 7844452 TI - [Time course changes in bone metabolic markers after menopause--a cross-sectional study]. AB - To clarify the clinical significance of the measurement of bone metabolic markers in postmenopausal subjects, a cross-sectional study of 546 healthy women (215 premenopausal, 164 bilateral oophorectomized and 167 natural menopausal) was conducted. All the subjects had their lumbar bone (L2-4 mineral density measured by means of DEXA. Bone metabolic markers (bone formation markers: serum alkaline phosphatase, osteocalcin and intact osteocalcin; bone resorption markers: urine excretion of hydroxyproline, pyridinoline and deoxypyridinoline) were also evaluated. After dividing the subjects according to the length of time after menopause, the time course changes in the Z-score values for bone metabolic markers were calculated. A triphasic pattern of lumbar bone loss was seen: there was a rapid phase in the first 5 years after menopause, a plateau phase in the second 5 years and a slow phase beginning 10 years menopause. The changes in bone metabolic markers coincided closely with the rapid phase of bone loss. In the plateau and slow phases, there were no markers which significant changed greatly. One possible clinical application of bone metabolic markers is in assessing the results of treatment for postmenopausal osteoporosis. PMID- 7844454 TI - [Correlation of bone mineral density with lumbago and vertebral fracture in climacteric women]. AB - Lumbago is considered to be an important clinical symptom of involutional osteoporosis, and is designated by the Ministry of Health and Welfare of Japan as one of the principal symptoms included in the criteria for the diagnosis of that condition. A study was designed to investigate the relationship between bone mineral density (BMD) and lumbago, as well as between BMD and vertebral compressive fractures in climacteric women. The study included a total of 400 outpatients (aged 49.2 +/- 0.4 years) visiting our department. The degree of lumbago was evaluated on the basis of an oral questionnaire. BMD was measured simultaneously by X-ray of the thoracic and lumbar vertebrae, the MD/MS and DXA. The presence or absence of vertebral fracture was judged on the X-ray image. As a result, there was seen to be no relation between lumbago and BMD. BMD was found to be significantly (p < 0.01) lower in 15 subjects with compressive fracture at thoracic and/or lumbar levels as judged on X-ray image than in subjects without fractures (n = 328). The above results suggested that, rather than considering lumbago as an important clinical symptom, the exact measurement of BMD and assessment of fracture in accordance with the definition of osteoporosis is the first step in diagnosing this disease. The upper limit of the fracture threshold determined from L2-4 BMD in these 15 subjects was 0.982 g/cm2. Of the subjects without fractures, 48.3% were found to have L2-4 BMD values at this level or lower, suggesting that they are at high risk of future fracture.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7844455 TI - [A case of uterine epithelioid leiomyosarcoma with hypoglycemia]. PMID- 7844456 TI - [A case of endometrial cancer detected at 2 years after childbirth]. PMID- 7844457 TI - [The mechanism of beta-receptor desensitization in human myometrial culture cell]. AB - Beta-adrenoceptor desensitization is considered to be primarily due to phosphorylation of receptors by protein kinase A (PKA) and beta-adrenaline receptor kinase (beta-ARK) and sequestration of receptors themselves. But in the human uterine muscle, the desensitization mechanism has been evaluated only as a phenomenon, and there are few studies on its mechanism. We evaluated cAMP production by beta-agonist and changes in the number of beta-receptors in cultured human myometrial cells. Uterine muscle cell were obtained from patients with benign disease before menopause and cultured. 1) At the confluent stage, dl Isoproterenol Hydrochloride (ISP) was added under various conditions, and the intracellular cAMP concentration was determined by EIA. 2) After the addition of ISP (10(-6) M), plates were incubated at 37 degrees C, and beta-AR on the cell membrane surface (S beta-AR) and total beta-AR (T beta-AR) was measured in a binding assay with 125I-pindolol. The production of cAMP dose-dependently increased 30 minutes after the addition of ISP at 10(-6) M or higher, but rapidly decreased thereafter. T beta-AR was similar in the cells treated with ISP (10(-6) M) and the untreated cells. On the other hand, S beta-AR decreased by about 50% in the ISP treated cells. These result suggest the desensitization of beta-AR in human uterine muscle, and the involvement of the sequestration mechanism as its cause. PMID- 7844458 TI - [A case of meningeal carcinomatosis which occurred after treatment for recurrence of the cervical carcinoma]. PMID- 7844459 TI - [Endometrial carcinoma occurred after irradiation therapy for squamous cell carcinoma of the uterine cervix]. PMID- 7844460 TI - ECG of the month. Permutations. Atrial premature impulses. PMID- 7844461 TI - Meniere's disease. AB - Meniere's disease is the most common cause of true vertigo and it affects about 2.4 million Americans. Episodic tinnitus, hearing loss, vertigo, and aural fullness are the classic findings. The symptom which is most debilitating and which causes most people to seek treatment is vertigo. Most patients respond extremely well to medical management and only rarely is surgery necessary. This paper discusses the symptoms, diagnosis, and clinical course of Meniere's disease. Medical and surgical therapeutic options are discussed. PMID- 7844462 TI - A 57-year-old man with bruising and joint pain. AB - The differential diagnosis for a 57-year-old man with joint pain, bruising, and diarrhea is discussed in the setting of a Clinical Pathological Conference at Louisiana State University Medical Center in Shreveport, La. The pathophysiology and etiology of malabsorptive states are presented. PMID- 7844463 TI - Inter-observer variability in ultrasonic evaluation of abdominal aortic aneurysms. AB - This study was undertaken to assess the consistency in 16 independent observations of the diameters of abdominal aortic aneurysms by diagnostic ultrasound. Confidence intervals were developed for the anterior-posterior dimension and the transverse dimension. Clinical treatment decisions should be made with appreciation that measurements of diameter increases greater than 0.21 cm in the anterior-posterior dimension and 0.31 cm in the transverse dimension are significant and are not a result of inter-observer variation. PMID- 7844464 TI - Recognizing genetic hemochromatosis. AB - This article reviews the disease process hemochromatosis, which is now recognized as one of the most common genetic disorders. Hemochromatosis is transmitted as autosomal recessive, and occurs in 3% of persons of Anglo-Saxon descent. It is caused by an inappropriate increase in intestinal iron absorption resulting in deposition of excess iron in tissues. Hemochromatosis usually presents in males in their 40s, and females much later. The most frequent initial symptoms are weakness, lassitude, weight loss, and symptoms related to the onset of diabetes mellitus. The classical triad of cirrhosis, diabetes mellitus, and skin pigmentation occurs late in the disease. There is debate over the value of mass screening for the disorder; however, it is recommended that once a case has been identified family members at risk should be screened. Therapy is directed at removing excess iron by phlebotomy. By instituting early therapy, many of the long-term complications, including cirrhosis and hepatoma, can be prevented. It is imperative that physicians learn to recognize early signs and symptoms of hemochromatosis so that treated patients can expect a normal life span with minimal medical intervention. PMID- 7844465 TI - Regressing malignant melanoma. AB - Malignant melanoma may undergo spontaneous regression. This phenomenon may cause difficulty in clinical or pathologic diagnosis. The cases reported in the literature as complete spontaneous regression of primary malignant melanomas have been diagnosed only in retrospect, after the patient presented with metastatic malignant melanoma. Two cases of malignant melanoma with partial regression are reported. In these cases the areas of complete regression cannot be recognized as malignant melanoma. The definitive diagnosis of malignant melanoma can be made only in the areas with at least two of three characteristic features of melanoma, (1) melanocytic cells with atypical nuclei and prominent nucleoli, (2) mitoses in melanocytic cells, and (3) invasion of the epidermis by atypical melanocytic cells. Clinical features suggesting regressing malignant melanoma include changes in color, especially areas of depigmentation, variations in color in different areas of a pigmented mole, and decrease in size of a mole. Histopathologic features of regression include loss of melanin pigment from the epidermis, melanophages in the dermis, telangiectasia of capillaries in the dermis, and lymphocytic infiltration in the dermis in a band-like or perivascular pattern. These histologic findings may also be found in inflammatory lesions such as lichen planus and in regressing benign melanocytic nevi. PMID- 7844466 TI - The lymphocyte chemoattractant factor. AB - The LCF is a unique interleukin without significant homology to other interleukins or chemokines. It is a chemoattractant factor for all CD4+ cells and either uses CD4 as its receptor or utilizes a cell surface complex of molecules for which there is an absolute requirement for the presence of CD4. In addition to its chemoattractant activity, it is a growth factor for CD4+ T cells, inducing resting cells to enter G1, as evidenced by the expression of MHC II molecules and IL-2R. Once induced by LCF to express IL-2R, CD4+ T cells become competent to respond to LCF and progress through the cell cycle to proliferation. LCF's activity on CD4 cells defines a role for CD4 on the eosinophil and monocyte and broadens the scope of functions of CD4 on the T cell. In this regard it may have importance in human disease states that are characterized by increased numbers of activated CD4+ cells, such as sarcoidosis, rheumatoid arthritis, or asthma. Likewise, it may play a key role in monocyte and eosinophil chemotaxis into tissues, being important in the latter in concert with hematopoietic factors that increase the available eosinophil pool. PMID- 7844467 TI - Escherichia coli heat-stable enterotoxins, guanylins, and their receptors: what are they and what do they do? AB - STa represents a family of homologous heat-stable peptide toxins that are elaborated by a variety of bacteria capable of causing enteric disease in human beings. All these peptides have a tertiary structure, maintained by disulfide bridges, which is required for receptor occupancy and biologic activity. The toxins have highly homologous carboxy-terminal domains and variable differences at the amino-terminal domain. The amino-terminal domain of these various peptides is not required for biologic activity. Recently an endogenous ligand called guanylin has been extracted from mammalian intestine and shown to bind the STa receptor. A similar peptide, called uroguanylin, has been found in human and animal urine. It is likely that guanylin and uroguanylin are indeed endogenous ligands for the STa receptor and may be modulators of Cl- secretion in the intestine, kidney, and perhaps in other organs. The STa-guanylin receptors are located on enterocytes, colonocytes, and various extraintestinal tissues. These receptors are one of a family of transmembrane guanylate cyclases that have homologous intracytoplasmic domains but divergent extracellular domains. It is likely that the extracellular domains of these various receptor cyclases confer specificity for ligand binding. Although GC-C, the STa receptor, may also be a receptor for guanylin, other receptors may exist that may be more specific for guanylin.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7844468 TI - Impaired rodent vagal nerve sodium-potassium-ATPase activity in streptozotocin diabetes. AB - Experimental diabetes in rodents is associated with diminished activity of sodium potassium-adenosine triphosphatase (Na+ -K+ -ATPase) in the sciatic nerve, an abnormality that has been invoked as being factorial in the genesis of diabetic peripheral neuropathy. Whether a parallel metabolic abnormality occurs in the autonomic vagus nerve is unknown. To answer this question, adult male rats made diabetic with streptozotocin (45 mg/kg) and age-matched nondiabetic controls were killed at 1 and 3 months after induction of diabetes. The cervical vagi and sciatic nerves were excised, weighed, and homogenized, and Na+ -K+ -ATPase activities were determined. After 1 month, the diabetic animals showed a significantly reduced sciatic nerve Na+ -K+ -ATPase activity as compared with respective controls, whether expressed in micromoles per gram wet weight per hour (20.5 +/- 4.9 [mean +/- SEM] vs 61.6 +/- 13.0) or micromoles per milligram of protein per hour (0.77 +/- 0.21 vs 2.48 +/- 0.57, p < 0.05, diabetic vs control, respectively). Diabetic vagus nerve Na+ -K+ -ATPase activity was also diminished (40.6 +/- 6.9 mumol/gm wet weight per hour vs 63.2 +/- 9.7 mumol/gm wet weight per hour and 3.83 +/- 0.81 mumol/mg protein per hour vs 5.86 +/- 0.73 mumol/mg protein per hour), but the results did not reach statistical significance. After 3 months, diabetic sciatic nerve Na+ -K+ -ATPase activity was still significantly less than the control group value (16.89 +/- 3.91 mumol/mg wet weight per hour vs 38.9 +/- 4.24 mumol/gm wet weight per hour and 0.48 +/- 0.11 mumol/mg protein per hour vs 1.04 +/- 0.14 mumol/mg protein per hour; p < 0.05, diabetic vs control, respectively).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7844469 TI - Molecular correlation between in vitro and in vivo activity of beta-lactam and beta-lactamase inhibitor combinations against methicillin-resistant Staphylococcus aureus. AB - Beta-Lactam resistance in Staphylococcus aureus is associated with beta-lactamase production, with the presence of a new penicillin binding protein (PBP) called PBP2a, with reduced affinity for beta-lactam antibiotics, and with modifications of normal PBPs. We have studied these mechanisms of resistance, in vivo and in vitro, for several beta-lactam antibiotics against both beta-lactamase-producing and non-producing methicillin-resistant S. aureus organisms (MRSA). Our results showed that all tested agents inhibited binding of labeled penicillin G to many PBPs. The combination of cefoperazone and sulbactam was the best combination, and it inhibited radiolabeled penicillin G binding to PBP2a at a lower concentration than that needed for cefoperazone alone. In vivo, the regimen of cefoperazone plus sulbactam was also more effective than cefoperazone alone. For beta lactamase-negative strains this correlated with an increased binding affinity of cefoperazone plus sulbactam to PBP2a and PBP4. The improved efficacy of cefoperazone plus sulbactam versus cefoperazone with a beta-lactamase producing strain was closely related to cefoperazone hydrolysis by beta-lactamase that was inhibited by sulbactam. This study demonstrates that there is more than one effect of beta-lactamase inhibitors when they are combined with beta-lactam antimicrobial agents, and also that there may be a role for these agents in therapy for MRSA infections. PMID- 7844470 TI - The effect of cyclosporine and methylprednisolone on plasma lipoprotein levels in rats. AB - The aim of this study was to evaluate in rats the effects of cyclosporine, methylprednisolone, and the combination of both (CyP) on plasma lipids and lipoproteins levels. Three groups received a low doses of cyclosporine, methylprednisolone, and CyP (cyclosporine, 15 mg/kg/day; methylprednisolone, 1 mg/kg/day; and CyP, 15 plus 1 mg/kg/day of cyclosporine and methylprednisolone, respectively). Three additional groups received high doses (cyclosporine, 30 mg/kg/day; methylprednisolone, 2 mg/kg/day; and CyP, 30 plus 2 mg/kg/day of cyclosporine and methyprednisolone, respectively). The administration of cyclosporine produced an increase in plasma levels of triglycerides, very low density lipoprotein (VLDL) triglycerides, low-density lipoprotein (LDL) cholesterol and in total cholesterol/HDL cholesterol and LDL cholesterol/high density lipoprotein (HDL) cholesterol ratios. In addition, cyclosporine decreased plasma HDL cholesterol and HDL2 cholesterol levels. The administration of methylprednisolone produced an increase in triglycerides and VLDL triglycerides and a decrease in HDL cholesterol and HDL2 cholesterol levels. Total cholesterol/HDL cholesterol and LDL cholesterol/HDL cholesterol ratios did not change after administration of methylprednisolone. The association of both drugs resulted in a greater increase in triglycerides and VLDL triglycerides than the separated administration of either cyclosporine or methylprednisolone alone. In rats receiving cyclosporine the increase in triglycerides and VLDL triglycerides may be due to a significant decrease in plasma lipoprotein lipase activity.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7844471 TI - Comparison of neutrophil chemotactic factor release by human and rabbit alveolar macrophages in response to tannin exposure. AB - It is essential to determine whether the results obtained from animal models actually reflect human disease processes. Tannin is a component of cotton dust that acts as a polyclonal cell activator in vitro. Most of the effects of tannin on alveolar macrophages (AM phi) have been studied in rabbit AM phi. Therefore, we compared tannin-mediated in vitro neutrophil chemotactic factor (NCF) secretion from normal human and rabbit AM phi. For both species the NCF secretion from AM phi was dependent on tannin dose and time of exposure. The NCF released was a lipid with a molecular weight of less than 800 daltons, suggesting that it may be a metabolite of arachidonic acid. Tannin stimulation of both human and rabbit AM phi resulted in the release of 90% unmetabolized arachidonic acid derived from both phosphatidyl choline and phosphatidyl inositol membrane lipids. The NCF secreted was not leukotriene B4 or platelet-activating factor. In conclusion, tannin mediates the release of a so far undescribed NCF from resident AM phi in rabbits and human subjects that may contribute to the pathogenesis of the acute neutrophilic alveolitis associated with cotton dust inhalation. The similarity of results obtained from human and rabbit cells supports the pertinence of using rabbit cells to study tannin-mediated effects. PMID- 7844472 TI - Inhibition of expression of monocyte interleukin-1 by inhibitors of Hageman factor (factor XII). AB - In an earlier study, activated species of Hageman factor (factor XII) induced elaboration of interleukin-1 by human monocytes. These observations did not address whether Hageman factor participated in endotoxin-induced release of interleukin-1. To examine this question, the release of interleukin-1 by endotoxin-stimulated human mononuclear cells was measured in the presence of popcorn inhibitor, a specific inhibitor of Hageman factor. In the experiments herein described, popcorn inhibitor sharply decreased the release of interleukin 1 by human mononuclear cells that were incubated with endotoxin. This observation suggests that Hageman factor may play a role in the elaboration of interleukin-1 by human mononuclear cells. Conforming with this view, the addition of antiserum directed against Hageman factor inhibited the release of interleukin-1 from endotoxin-stimulated mononuclear cells. PMID- 7844473 TI - Inhibitory action of amyloid precursor protein against human Hageman factor (factor XII). AB - Amyloid precursor protein forms that contain Kunitz protease inhibitor domains are released from activated platelets, T-lymphocytes, and leukocytes and inhibit trypsin, plasmin, and activated factor XI. We investigated the effects of amyloid precursor protein isoforms on activated Hageman factor (factor XII), activated factor X (Stuart factor), and thrombin. Recombinant amyloid precursor proteins with or without the Kunitz domain, 770 and 695 amino acids, respectively, were produced in insect cells by Baculovirus expression (BAC770 and BAC695). Neither BAC695 nor BAC770 inhibited human alpha-thrombin or activated factor X. The partial thromboplastin time was prolonged by both amyloid precursor proteins, only one of which, BAC770, contains the Kunitz protease inhibitor domain. Both forms of amyloid precursor proteins inhibited ellagic acid-induced activation of Hageman factor but did not inhibit activated Hageman factor. Bismuth subgallate, which is an insoluble analog of ellagic acid, lost its ability to activate Hageman factor on being exposed to BAC770. Inhibition of ellagic acid-induced activation of Hageman factor by both forms of amyloid precursor protein was enhanced by heparin. These findings suggested that the heparin-binding domain of amyloid precursor proteins is not in the Kunitz domain. This heparin-binding domain may block the activation of Hageman factor by negatively charged agents. Thus, amyloid precursor proteins may be involved in the control of hemostasis, properties not all dependent on the Kunitz domain. PMID- 7844474 TI - Intravenous eugenol causes hemorrhagic lung edema in rats: proposed oxidant mechanisms. AB - Although eugenol, the active phenolic constituent of oil of cloves, has been implicated as a cause of noncardiogenic pulmonary edema, the mechanism of lung injury is unknown. We studied the effects of intravenous infusion of eugenol in rats and found that 4 microliters and 8 microliters of eugenol (6.52 mol/L) caused acute respiratory distress with hemorrhagic pulmonary edema. Histologic features included perivascular, interstitial, and alveolar edema with extravasation of red blood cells and neutrophils into the alveolar space and alveolar capillary trapping of neutrophils. In addition, lungs treated with eugenol had increased bronchoalveolar lavage fluid (BALF) protein content, and lung wet-to-dry weight ratios were increased in animals treated with 8 microliters eugenol. Pretreatment with intravenous superoxide dismutase (SOD) or catalase but not dimethylthiourea (DMTU) decreased BALF protein content after infusion of 4 microliters and 8 microliters of eugenol. SOD and catalase but not DMTU decreased lung wet-to-dry weight ratios in animals infused with 8 microliters of eugenol. We conclude that intravenous infusion of eugenol causes hemorrhagic pulmonary edema with intrapulmonary sequestration of neutrophils and suggest that the injury may be at least partly oxidant mediated. PMID- 7844475 TI - Active pancreatic digestive enzymes show striking differences in their potential to damage isolated rat pancreatic acinar cells. AB - Active digestive enzymes are involved in the pathophysiology of acute pancreatitis. Previous studies have mainly focused on the role of trypsin in the autodigestive process. The present study compares the noxious potential of different pancreatic enzymes to damage acinar cells. Acinar cells were isolated from rat pancreas by collagenase digestion. Cell viability was studied by (1) exclusion of trypan blue, (2) release of lactate dehydrogenase, and (3) release of newly synthesized proteins identified with methionine labeled with sulfur 35. Cells were then incubated in oxygenated N-2-hydroxyethylpiperazine-N-'-2 ethanesulfonic acid-Ringer solution containing different concentrations of various active digestive enzymes. Uptake of trypan blue was the most sensitive and reliable test of cell damage when compared with release of lactate dehydrogenase or radiolabeled newly synthesized proteins. All active digestive enzymes studied caused dose-dependent cell damage. The noxious potential, however, was strikingly different for the various enzymes. Pancreatic elastase in nanomolar concentrations caused marked cell damage after 45 to 90 minutes of incubation. Lipase and chymotrypsin caused a similar damage only at micromolar concentrations, whereas even millimolar concentrations of trypsin failed to cause significant damage. The present results confirmed recent work showing that lipase and phospholipase A2 probably cause cell damage through release of free fatty acids and lysolecithin. Although activation of trypsin might be the trigger to start the activation cascade in acute pancreatitis, trypsin itself is markedly less noxious to acinar cells when compared with other digestive enzymes. Elastase by far had the greatest noxious potential of all enzymes evaluated. Studies analyzing therapeutic effects of protease inhibitors should evaluate not only the inhibitory potential against trypsin but also that against other digestive enzymes, particularly elastase. PMID- 7844476 TI - Incidence of Haemophilus influenzae type b disease in Kentucky. Relationship to immunization, 1988 through 1993. PMID- 7844477 TI - Places of change: special education's power and identity in an era of educational reform. AB - Special education is in danger of disintegration due to (a) justified criticisms of implementational failures, and (b) unjustified criticisms from reformers and detractors, mostly having to do with its conceptualization and the separate placement of some students with disabilities. Needed reforms in special education include (a) constructing defensible rival philosophies, (b) improving the preparation and support of special education teachers, and (c) putting educational methods on a sound scientific footing. PMID- 7844478 TI - EEG power spectra of children with dyslexia, slow learners, and normally reading children with ADD during verbal processing. AB - EEG power spectra were studied in two poor reader groups (with dyslexia and slow learning) and a normally reading clinic control group (with attention deficit disorder) as the children viewed strings of words and letters (seven categories). The children ranged in age from 7.5 to 12 years; 33 were girls, 86 were boys. Bilateral temporal and parietal sites and four midline sites were used. The major difference between groups was in the low beta band, where the ADD group had greater power at the parietal and midline sites. Also, the slow learner group had marginally greater low beta at the left than right temporal site, with the opposite trend found for the dyslexic and ADD groups. Across groups, power was greater at the right than at the left parietal site in the delta and alpha bands and at the right than at the left temporal site in the low beta band. Stimulus category effects were modest, with some alpha suppression to word strings, relative to letter strings, found in the poor readers. In correlational analyses, the combination of greater low beta and less theta power significantly predicted better reading and spelling. Results indicate that the adequate readers more actively processed the stimuli than did the poor readers. PMID- 7844479 TI - Practices and attitudes of postsecondary LD service providers in North America. AB - A nationwide survey of 510 postsecondary LD service providers was conducted to determine (a) the types of interventions utilized by service providers, and (b) their attitudes toward the needs of adults with learning disabilities. The results of this study revealed that an educationally diverse group of professionals have been given the responsibility of developing programs and providing direct instruction to individuals with LD. The proliferation of services found in this survey is analogous to a "menu" of options, with little or no philosophical base. Findings suggest that service providers should be encouraged to utilize interventions that lead to self-determination and independence for adults with LD. PMID- 7844480 TI - Naming speed in children with dyslexia. AB - A series of tests of naming speed in discrete reaction time format were undertaken by seven groups of children: three groups with dyslexia with mean ages 8, 13, and 17 years; three groups of normally achieving children matched for age and IQ with the dyslexic groups; and a group of 10-year-old children with mild learning difficulties (slow learners) matched for reading age with the youngest dyslexic group. The children with dyslexia were significantly slower than even their chronological age-matched controls, and equivalent to their reading age matched controls, on naming colors, digits, and letters, and significantly slower than even their reading age-matched controls on naming pictures of common objects. Overall, performance of the 17-year-old children with dyslexia was closest to that of the 8-year-old controls. Performance of the slow learners was equivalent to that of the youngest children with dyslexia. The results show that children with dyslexia have persistent-and unexpectedly severe-problems in naming speed for all stimuli, regardless of whether or not the stimulus requires grapheme-phoneme decoding. PMID- 7844481 TI - Early identification and remediation of phonological-processing deficits in first grade children at risk for reading disabilities. AB - The present study assessed 486 first-quarter first graders on their reading and phonological-processing skills and intelligence. Based on this assessment, and using the classification data from Hurford et al.'s (1993) study, 99 children were identified as being at risk for reading difficulties: 53 children at risk for reading disabilities (RD) and 46 children at risk for becoming "garden variety" poor readers (GV). Half of the RD and GV groups received the phonological-processing intervention. Posttraining assessment indicated that the training procedure not only was effective in increasing the phonological processing skills of the trained participants, but also increased their reading ability. Both of the RD and GV trained groups benefited from the training. Analyses also indicated that the initial screening device was somewhat less accurate in the present study in identifying at-risk children than in our previous studies (85% vs. approximately 98%, respectively). The results of the present study indicate that it is possible to identify children at risk for reading difficulties and to significantly improve their phonological-processing and reading abilities. PMID- 7844482 TI - Testing the automatization deficit hypothesis of dyslexia via a dual-task paradigm. AB - Fourteen children with dyslexia were compared with controls matched for age and reading age on automatic processing under a dual-task paradigm. The primary task was a motor balance one, and the secondary task was an auditory-choice task. Main results show that the dyslexic group was more impaired in the dual-task condition compared to the single-task condition. The findings support the automatization deficit hypothesis of dyslexia. PMID- 7844484 TI - Hemisphere-specific treatment of dyslexia subtypes: better reading with anxiety laden words? AB - Twenty children (12 boys, 8 girls; mean age = 10.4 years) with P-type dyslexia (accurate but slow and fragmented reading) and 20 children (12 boys, 8 girls; mean age = 10.3 years) with L-type dyslexia (hurried, inaccurate reading) were treated with visual hemisphere-specific stimulation employing the HEMSTIM computer program. Stimulation was produced by presenting words to the left (L dyslexia) or to the right (P-dyslexia) visual field. Children in the control condition received treatment with neutral words, whereas children in the experimental condition received treatment with anxiety-laden words. After treatment, the children with L-dyslexia in the experimental group made fewer substantive errors and more fragmentations on a text-reading task than did the children with L-dyslexia in the control group. The results are explained as being the consequence of additional activation of the right hemisphere caused by the anxiety-laden words. It is concluded that children with L-dyslexia can benefit from the use of such words in the HEMSTIM program. PMID- 7844483 TI - An analysis of two discrepancy-based models and a processing-deficit approach in identifying learning disabilities. AB - The incidence of learning disabilities (LD) in a research center sample of 107 boys and 103 girls between 6 and 12 years of age was calculated using Wechsler IQ and Woodcock-Johnson cluster scores in a regression model (REG) and a reliability model (REL). The REL method identified LD three times more often than the REG method, and all those identified by REG were also identified by REL. When stratified by IQ, REG and REL identified similar percentages in the lowest IQ group; however, REG identified at a lower rate as IQ increased. All 87 children identified with reading disabilities (both REL-RD and REG-RD) were weak to a similar extent on phonemic awareness. Comorbid elevated attention ratings were found in 62% of children with RD; 26% had elevated attention ratings but no linguistic processing deficits, and 21% had at least one linguistic processing deficit but no attentionally suspect rating. PMID- 7844485 TI - Academic achievement and attention-deficit/hyperactivity disorder in children with left- or right-hemisphere dysfunction. AB - The neuropsychological investigation of learning disabilities has contributed much toward a more complete understanding of how the hemispheres are functionally organized and how differences in this functional organization may affect differential patterns of learning and behavior. It has been suggested that right hemisphere dysfunction increases the likelihood of difficulty with attention/concentration and of overactive behavior, and interferes with arithmetic calculation more readily than reading and spelling. The present study examined the influence of right-versus left-hemisphere neuropsychological dysfunction on academic achievement and attention using two groups of children with learning disabilities and a group of nondisabled children. Results provide limited support for the hypothesis that the right hemisphere subserves attention and concentration. No support was found for the hypothesis that right-hemisphere deficits are more frequently associated with deficient arithmetic calculation, as opposed to reading and spelling performance. Results are discussed in the context of previous research on right-hemisphere dysfunction and learning disabilities. PMID- 7844486 TI - How to achieve academic and creative success in spite of the inflexible, unresponsive higher education system. PMID- 7844487 TI - Teachers' ratings of the social competence and school adjustment of students with LD in elementary and junior high school. AB - The purpose of this study was to examine whether teachers' judgments of students' social competence and school adjustment differentiated students with learning disabilities (LD) (n = 30; boys = 19, girls = 11) from low-achieving (LA) students (n = 29; boys = 17, girls = 12) and average-achieving (AA) students (n = 33; boys = 18, girls = 15) at two grade levels: third/fourth (mean age = 9.97, SD = 1.09) and seventh/eighth (mean age = 13.63, SD = .65). Teachers completed the Walker-McConnell Scale of Social Competence and School Adjustment for each student. They rated younger students with LD and LA students as having significantly lower social competence and school adjustment than their AA peers. In addition, the results supported the use of teacher ratings for initial screening and identification of elementary students at high risk for social behavioral problems. However, teachers' ratings did not discriminate LD, LA, and AA students at the older grade levels. The discussion focuses on the utility of teachers' identification of social problems at different grade levels. PMID- 7844488 TI - Calculation abilities in young children with different patterns of cognitive functioning. AB - This study examined the arithmetic calculation abilities of kindergarten and first-grade children with different patterns of cognitive functioning: children with low language but adequate spatial abilities (Low Language; n = 33, male = 42%); children with low spatial but adequate language abilities (Low Spatial; n = 21, male = 42%); children with general delays (Delayed; n = 21, male = 48%); and children with no language or spatial impairments (Nonimpaired; n = 33, male = 48%). Each child was given a series of addition and subtraction calculations presented as nonverbal problems, story problems, and number-fact problems. Story problems and number-fact problems require mastery of conventional verbal symbols, whereas nonverbal problems do not. The findings show that nonverbal, story, and number-fact problem formats are differentially sensitive to variation in cognitive ability. The Low Language group performed significantly worse than the Nonimpaired group on story problems but not on nonverbal problems or number-fact problems. The Delayed group performed significantly worse than the Nonimpaired group on nonverbal problems as well as on story problems but not on number-fact problems. The Low Spatial group did not differ significantly from the Nonimpaired group on any of the three problem types, although the overall performance of these children was weaker. When we adjusted for finger use on number-fact problems, the Nonimpaired group outperformed both the Low Language and the Delayed groups but not the Low Spatial group. Thus, the finding that the Low Language and Delayed groups perform as well as the Nonimpaired group on number fact problems is attributable to their greater finger use. PMID- 7844489 TI - The bidirectional relationship between achievement and externalizing behavior problems of students with learning disabilities. AB - The current study examined the bidirectional relationship between academic achievement and externalizing behavior problems of adolescents with learning disabilities. Forty-three students attending a residential school were assessed for externalizing behavior problems via parent and teacher reports on the Child Behavior Checklist and the Children's Attention and Adjustment Survey. The Wide Range Achievement Test-Revised was used to estimate academic achievement in reading, spelling, and arithmetic. Achievement measures did not predict externalizing behavior problems 1 to 2 years later, although verbal IQ predicted parent reports. Teacher reports of externalizing behavior problems predicted reading and spelling achievement scores 1 year later, and parent reports of externalizing behavior problems predicted changes in reading achievement. There was evidence that attentional problems were the component of externalizing behavior accounting for these relations, consistent with the explanation that inattentive students have difficulty achieving in an intensive learning environment. PMID- 7844490 TI - Bacterial pneumonia in the elderly. AB - Five hundred and twenty-six cases of bacterial pneumonia in adults admitted to Chulalongkorn Hospital during the period January 1987 to December 1991 were studied, comparing the elderly aged > or = 60 years (241 cases) with the nonelderly < 60 years of age (285 cases). The study indicates that there was a significantly increased number of community and hospital-acquired pneumonia in the elderly than previously reported. Pneumonia in the elderly might present with no fever, no cough no signs of parenchymal infiltration, but significant mental changes. There was a higher incidence of pleural involvement, but lower incidence of septic shock in the non-elderly than the elderly, which suggests that the nonelderly had better systemic resistance against bacterial infection than the elderly. There was no significant difference in complete blood count between the two groups. However, sputum specimens to be collected through endotracheal tube and Gram-negative bacilli on Gram stain were found more in the elderly than the non-elderly. The elderly had more respiratory failure requiring mechanical ventilation, septic shock, and had higher mortality than the non-elderly. They also required longer duration of treatment and hospitalization. There were parameters which indicated the high-risk factors for mortality among the elderly. These included hospital-acquired pneumonia, bronchopneumonia, Gram-negative pneumonia, abnormal status of host, sputum specimens requiring collection by suction, respiratory failure and septic shock. PMID- 7844491 TI - Non-invasive hormonal analysis for ovulation detection. AB - The present study suggested that measurement of LH, E2 and P in blood may be replaced by non-invasive measurements of E2 and P in saliva and by assays of LH, E1-3G and P2-3G in urine. These alternative methods for determination of reproductive hormones in saliva and in urine provide similar and reliable information of endocrine status in both normal and abnormal reproductive functions. The advantages of these non-invasive methods should be brought into consideration whenever the physiological assessments or clinical investigations of ovarian functions are required. PMID- 7844492 TI - Precancerous lesion and early carcinoma of the pyriform sinus. AB - Thirty-five specimens from total laryngopharyngectomy clinically diagnosed as squamous cell carcinoma of the pyriform sinus were studied. Patients receiving chemotherapy or radiotherapy were excluded. Pathological examinations revealed 26 (74.3%) precancerous lesions and early carcinoma of the pyriform sinus. Eight out of 26 cases were detected by gross examination. Most pathological findings were carcinoma in situ (CIS). Epithelial changes of the pyriform sinus were not similar to those of the uterine cervix. They usually showed abrupt change, frequently from normal to CIS, mild dysplasia to invasive carcinoma and these lesions can be detected early by physical examination. Because of multifoci of carcinoma, the concept of "multicentric origin" is proposed. PMID- 7844493 TI - A simple tunneler for extra-anatomical bypass grafts and interposition arteriovenous hemodialysis fistulas. AB - A simple and inexpensive tunneler has been employed in arterial grafting encompassing femoropopliteal, aortofemoral, axillo femoral bypass and vascular access procedures. This is fashioned from a disposable Argyle thoracostomy tube. This technique is recommended because of its simplicity, ready availability, lack of expense, and relative safety. PMID- 7844494 TI - Ondansetron: prevention of nausea & vomiting in cisplatin based chemotherapy. AB - Ondansetron in the prophylaxis of Cisplatin-induced emesis and nausea. The 5-HT3 antagonist ondansetron clearly offers a new approach to the control of Cisplatin induced emesis and has been evaluated in Thailand. To evaluate anti-emetic efficacy of ondansetron in the prevention of nausea and vomiting induced by Cisplatin containing cancer chemotherapy regimen, we carried out an open multicentre study from January 1991 to December 1992. In this study, patients receiving Cisplatin based chemotherapy received ondansetron 32 mg as a single intravenous dose over 15 minutes prior to the administration of Cisplatin. This was followed by oral ondansetron 8 mg three times a day, preferably one hour before each meal for 5 days. All patients were chemotherapy naive in-patients and were at least 18 years or older with Karnofsky performance status of at least 60 per cent. The number of emetic episodes, nausea and food intake were recorded during the 24 hours following Cisplatin administration. A total of 103 patients were recruited with 84 (81.6%) evaluable patients (48 men and 36 women) scheduled to receive cisplatin chemotherapy at dose 60 mg/m2 or more (60-100 mg/m2), either as single agent or combination therapy. Complete response (complete control of emesis) was achieved in 60 per cent; major response (1-2 emetic episodes) was 13 per cent; minor response (3-5 emetic episodes) was 13 per cent; and failure (5+ emetic episodes) was 10 per cent. Side effects were very mild and not significant. We conclude that ondansetron is efficacious in protecting patients from Cisplatin induced emesis and nausea. PMID- 7844495 TI - Reconstruction of bone and skin defect using the osteocutaneous free fibular graft. AB - The attempt to use an osteocutaneous free fibular graft (OCFFG) to reconstruct composite bone and skin defects of the extremities following trauma was carried out in eighteen cases. Ten of seventeen cases were successful with the method without surgical complications and bony union occurred after 3 to 6 months (average 5.2 months). Three cases had skin flap necrosis (2 partial and 1 total) and required further skin grafting or skin coverage. Four cases failed due to thrombosis of the vascular anastomosis. The procedure was abandoned in one case because of failure to identify a reliable septocutaneous vessel to the skin flap. PMID- 7844496 TI - Management of HIV infected pregnant women in Chonburi Hospital. AB - This study on birth control methods used, and HIV infection protection of the HIV infected pregnant women in the obstetrics-gynecology department of Chonburi Hospital from 1 January 1990 to 31 December 1993 revealed that there were 27 HIV infected women with less than 24 weeks gestational age, using birth control methods as such 12 women (44.44%) had tubal resection after abortion, 8 women (29.62%) oral contraceptive pills, 5 women (15.51%) injectable contraception, and 2 women (7.40%) norplants. The 106 HIV infected women with more than 24 weeks gestational age were allowed to deliver. The birth control methods were as follows: 19 women (17.92%) tubal resection, 38 women (35.84%) oral contraceptive pills, 49 women (46.22%) injectable contraception. They were all encouraged to use a condom while having sexual intercourse. Only 40 women of this group are still seen in the follow-up clinic and all are found to be healthy, the birth control is effective and HIV infection is in the early stage. The new born babies were not allowed to be breast fed and were followed-up periodically to 18 months old. Twenty five babies received HIV blood test; 7 babies (28%) were found to be HIV infected. The birth control and HIV infection protection used in this study demonstrate no adverse effects on the disease, and the unexpected problems of these women, as well as the health personnel concerned are reduced both economically and socially. This study provides the guidelines of good care for HIV infected pregnant women. PMID- 7844497 TI - Laryngotracheoesophageal cleft. AB - Laryngotracheosophageal (LTE) cleft is a rare congenital anomaly which results from failure of cephalad advancement of the tracheoesophageal septum and fusion of cricoid cartilage. Four cases of LTE cleft from Children's Hospital are reported. Most of them presented with aspiration after feedings that mimic T-E fistula. Three cases had other associated anomalies. Non-ionic water soluble esophagography showed proximal leakage of contrast media at cricopharyngeal region. The definitive diagnosis was made by direct laryngoscopy. Three cases died from their complications in spite of surgical repair. So, LTE cleft should be considered as one of the causes of aspiration in the newborn. PMID- 7844498 TI - Effects of television content on physical risk-taking in children. AB - This study is an investigation of effects of risk-taking by characters in television programs on children's self-reported willingness to take physical risks. Twenty-four boys and 26 girls, ages 6 to 9 years, were assigned to view TV stimulus programs with infrequent physical risk-taking. TV stimulus programs with frequent risk-taking, or no TV stimuli. A self-report measure was used to assess children's willingness to take physical risks in several common injury-relevant situations. Five of the items were administered as a pretest before children watched the stimulus programs and five items were used as a post-test after they viewed the programs. A validation assessment on an independent sample of children indicated that the risk-taking measure was positively correlated with other measures of risk-taking as well as physical injuries. Results indicated that children who viewed the high-risk TV programs increased their self-reported risk taking significantly more than children in the low-risk TV and no-TV control conditions. Findings are discussed within a theoretical context of observational learning processes, with implications for childhood injury. PMID- 7844499 TI - Decision-making in young adolescents and adults. AB - In two experiments, 13-year-olds and college students were asked to make "risky" decisions in a game format. Analyses focused on whether adolescents and adults (a) used similar strategies for evaluating their options, (b) were equally optimistic, (c) held similar beliefs about their ability to produce outcomes, (d) were equally likely to choose the best options, and (e) had equally accurate memories of their performance. Results showed that age differences emerged along each of these dimensions, especially when the game was made more complex. PMID- 7844500 TI - Generalized imitation in preschool boys. AB - The purpose of the present study was to determine the extent to which the generalized motor imitation paradigm developed by Baer and Deguchi (1985) applies to the vocal imitation of preschool boys. Five normally developing male preschool children between 3 and 5 years of age served as subjects. We presented the children with four choices: Matching, Nonmatching, Listening, and Waiting. Once we established a baseline preference measure, we introduced reinforcement of imitation for a different vocal response (color naming). The effect of this manipulation was to increase the preference for matching for three of the five children. The results are consistent with the conditioned-reinforcement hypothesis regarding generalized imitation. They are also consistent with previous research showing that not all children prefer to imitate following direct reinforcement of other imitative behavior. PMID- 7844501 TI - Development of exclusivity in perceptually based categories of young infants. AB - The exclusivity of perceptually defined categorical representations for natural animal categories in young infants was investigated. Previously, as well as in Experiment 1, evidence was obtained for a categorical representation for cats in 3- and 4-month-old infants that excluded dogs but included perceptually similar female lions after a number of different familiarization procedures. However, in Experiment 2 both dogs and female lions were found to be excluded when the initial familiarization with cats alone was followed by six pairings of familiar cats and novel lions intermingled with two added pairings of familiar cats. The present results indicate that a categorical representation can attain a high level of exclusivity during early infancy as a consequence of experience with exemplars of the contrasting categories that accents the perceptual similarities among members of a category and the perceptual differences among exemplars from different categories. PMID- 7844502 TI - The effect of body orientation to gravity on early infant reaching. AB - The purpose of the study was to examine the effect of body orientation with respect to gravity on infant's reaching quantity and quality. Two groups, 12- to 19-week-old and 20- to 27-week-old infants, were seated in three positions: vertical (90 degrees from horizontal), recline (60 degrees), and supine (0 degrees). Nine balls on a black board were presented. Video recordings were used to measure quantity of reaching (number and duration of reaches) and quality of reaching (open or closed hand, starting position of the arm, and position of touched and grasped balls). On the quantity measure there was a significant age x body position interaction that indicated that the 12- to 19-week-olds showed reaching behavior in the vertical position equal to that of 20- to 27-week-old infants in all positions. A similar tendency, although not significant, was found for the quality measurements. These findings indicate that the development of reaching does not just reflect maturation of the central nervous system, but a changing interaction between organismic and environmental constraints. PMID- 7844503 TI - Further evidence for hierarchical chunking in rat spatial memory. AB - In Experiment 1, rats were given a test to determine the order of preference among 3 types of food. Two groups of rats then were trained on a 12-arm radial maze in Experiment 2, with the 3 foods placed in fixed-arm locations for 1 group and in locations that varied randomly across sessions for the other group. The results replicated those of Dallal and Meck (1990) by showing faster learning and more clustering of arm choices by food type in the fixed-locations group than in the random-locations group. Two further experiments were performed to test the chunking hypothesis. Observations of working memory in Experiment 3 and the reorganization of reference memory in Experiment 4 both supported the chunking hypothesis by showing superior spatial memory and arm chunking by food type when chunk integrity was maintained than when it was compromised. PMID- 7844504 TI - Simultaneous timing of multiple intervals: implications of the scalar property. AB - Three experiments with pigeons are reported in which the scalar property in simultaneous timing tasks was studied. According to scalar expectancy theory, the scalar property should be maintained in simultaneous timing, but the behavioral theory of timing predicts that the scalar property should be evident only in independent timing. Experiment 1 showed that the appearance of distinct peaks at reinforcement times required about a 4:1 ratio between intervals. Experiment 2 (2 interval timing task) and Experiment 3 (3-interval timing task) used an individual trial analysis technique to examine high-rate responding segments bracketing the times of reinforcement. The standard deviations of the starting and stopping times of high-rate segments were linearly related to their means and to reinforcement time, supporting the scalar property in simultaneous timing. PMID- 7844505 TI - Classification of frequencies into ranges by songbirds and humans. AB - We trained songbirds and humans in go/no-go discriminations among 27 tones. In the compact discrimination, S + s formed a contiguous middle range (3080-4040 Hz), and S-s formed contiguous lower (2000-2960 Hz) and upper (4160-5120 Hz) ranges. In the distributed discrimination, S + s were spread across all 3 ranges. Songbirds acquired the compact discrimination more quickly and with higher accuracy than humans. Songbirds acquired the distributed discrimination only after much extended training; humans did not acquire the distributed discrimination. Compact groups (birds and humans) accurately classified test tones spaced 60 Hz from the training tones, but the distributed groups did not. A single reversal in discrimination between tones on the boundary between the lower S- and middle S + ranges did not propagate to all the tones in either range. A neural network model provided an account of the classification of tones in songbirds and humans. PMID- 7844506 TI - Categorical scaling of time: implications for clock-counter models. AB - Pigeons partitioned time into three intervals. Responses to one key could be reinforced after a short time, to a second key after an intermediate time, and to a third key after a long time. The values of the short, intermediate, and long times and the proportion of trials ending with reinforcement were varied. Absolute and relative response rates on each key were an orderly function of time and showed approximately proportional changes with changes in the interval values, consistent with Weber's law, Gibbon's (1977) scalar expectancy theory, and Killeen and Fetterman's (1988) behavioral theory of timing (BeT). Standard deviations of the times at which subjects switched between successive keys increased more slowly within a condition than across conditions, as predicted by BeT. Increases and decreases in reinforcement probability produced both transient and longer lasting changes in timing behavior, once again, in accord with predictions of BeT. PMID- 7844507 TI - Sensitivity to violations of "run" and "trill" structures in rat serial-pattern learning. AB - Rats learned serial patterns composed of either "run" chunks (e.g., 123 234 ...) or "trill" chunks (e.g., 121 232 ...). For each type of pattern, 1 group of rats encountered an element at the end of the pattern that violated the run or trill structure. In both run and trill patterns, violations were unusually difficult for rats to learn, whereas corresponding elements in "perfect" patterns that did not violate pattern structure were easy. Additionally, rats' errors on violation elements conformed to the structure of the patterns in which they were embedded. Thus, rats were sensitive to the run or trill organization of their patterns and mastered the rules governing the pattern before learning "exceptions to the rule." PMID- 7844508 TI - Responses to quantity: perceptual versus cognitive mechanisms in chimpanzees (Pan troglodytes). AB - Two chimpanzees were trained to select among 2 different amounts of candy (1-6 items). The task was designed so that selection of either array by the active (selector) chimpanzee resulted in that array being given to the passive (observer) animal, with the remaining (nonselected) array going to the selector. Neither animal was able to select consistently the smaller array, which would reap the larger reward. Rather, both animals preferentially selected the larger array, thereby receiving the smaller number of reinforcers. When Arabic numerals were substituted for the food arrays, however, the selector animal evidenced more optimal performance, immediately selecting the smaller numeral and thus receiving the larger reward. These findings suggest that a basic predisposition to respond to the perceptual-motivational features of incentive stimuli can interfere with task performance and that this interference can be overridden when abstract symbols serve as choice stimuli. PMID- 7844509 TI - Visual, orthographic, phonological, and lexical influences in reading. AB - The fuzzy logical model of perception (FLMP), used as a framework to analyze phenomena in reading, asserts that there are multiple influences on reading performance. Experiments on the dynamic interaction of letter information and orthographic context are presented. Previous results have supported the FLMP over a variety of interactive activation models. These findings indicated that lateral masking and the time course of processing must be accounted for in the theoretical prediction of letter and word recognition. A new finding is that the word superiority effect is not influenced by the nature of the backward masking stimulus, nor is it diminished with letter and word masks, contrary to the predictions of several extant explanations. The FLMP is extended to account for reaction time in reading. Perceptual recognition, naming, and lexical decision tasks reflect the influence of multiple sources of information. These include orthographic structure, spelling-to-speech correspondences, and word frequency. Reading can be productively analyzed as a prototypical pattern recognition situation in which the reader exploits multiple sources of information in perception and action. PMID- 7844510 TI - Nonword pronunciation and models of word recognition. AB - Nonword pronunciation is a form of generalization behavior that has been at the center of debates about models of word recognition, the role of rules in explaining behavior, and the adequacy of the parallel distributed processing approach. An experiment yielded data concerning the pronunciation of a large corpus of nonwords. The data were then used to assess 2 models of naming: a model developed by D. C. Plaut and J. L. McClelland (1993), which is similar to the one described by M. S. Seidenberg and J. L. McClelland (1989) but uses improved orthographic and phonological representations, and the grapheme-phoneme correspondence rules of M. Coltheart, B. Curtis, P. Atkins, and M. Haller's (1993) dual-route model. Both models generate plausible nonword pronunciations and match subjects' responses accurately. The dual-route model does so by using rules that generate correct output for most words but mispronounce a significant number of exceptions. The parallel distributed processing model does so by finding a set of weights that allow it to generate correct output for both "rule governed" items and exceptions. Some ways in which the two approaches differ and other issues facing them are also discussed. PMID- 7844511 TI - Building a resonance framework for word recognition using design and system principles. AB - Basic elements of a principle-based approach to model development are presented. The approach is needed to understand the operation of models capable of complex behavior. The use of principles facilitates both assignment of explanatory credit and blame when testing models and guides refinement of models when they fail. Two types of principles are distinguished: design and system. Design principles relate model behavior to observable human behavior. System principles relate model behavior to assumptions about a model's formal structure (architectural axioms). The use of, and relationship between, such principles is illustrated by building the theoretical framework of resonance (S. Grossberg & G. O. Stone, 1986) through the successive addition of principles. PMID- 7844512 TI - Interdependence of form and function in cognitive systems explains perception of printed words. AB - Perception is described within a complex systems framework that includes several constructs: resonance, attractors, subsymbols, and design principles. This framework was anticipated in J. J. Gibson's ecological approach (M. T. Turvey & C. Carello, 1981), but it is extended to cognitive phenomena by assuming experiential realism instead of ecological realism. The framework is applied in this article to explain phonologic mediation in reading and a complex array of published naming and lexical decision data. The full account requires only two design principles: covariant learning and self-consistency. Nonetheless, it organizes and explains a vast empirical literature on printed word perception. PMID- 7844513 TI - Computational modeling and elementary process analysis in visual word recognition. AB - An attempt is made to isolate the assumptions that make a connectionist approach to visual word recognition distinctive. These include the commitment to distributed representations, the claim that there is no distinction between lexical and nonlexical systems in the naming task, and the claim that it is possible to map from orthography to meaning without using localized representations. It is argued that merely demonstrating that a network model can perform these tasks is not sufficient and that a detailed theory of how the network performs its tasks must accompany the simulation, because a simulation is not equivalent to an explanation. It is argued that further progress requires detailed modeling and experimental study of the elementary processes assumed to be involved in networks and that it is premature to dismiss alternative models of lexical access such as serial search models. PMID- 7844514 TI - The fatalities of the Intifada (uprising): the first five years. AB - The uprising of the Palestinian population (Intifada) against the Israeli occupation of the Gaza Strip and the West Bank, which erupted in December 1987, has resulted in the deaths of hundreds of Israeli citizens and Palestinian residents. The data on dead victims, as reported by two civil rights organizations of opposite political orientation and by the official military authority, are analyzed and compared with the information obtained from post mortem examinations of some 65% of the victims carried out over the period 1987 to 1992. The agencies' reports were found to differ, sometimes markedly, from the official autopsy data in respect of number of deaths, their cause and manner. The study indicates a generally downward trend in the number of Palestinians killed by the Israeli Defence Forces, which could be the result of the wider use of rubber and plastic bullets, and a steady continuous increase in Israeli victims killed by the Palestinians, possibly accounted for by a shift from the use of "cold weapons" in favour of firearms, and an escalation in violence. It is suggested that the post-mortem examination should be an essential tool for the detection and documentation of possible abuse and bodily harm. PMID- 7844515 TI - Extraction of high quality genomic DNA from microsamples of human blood. AB - A simple and efficient method for extracting human genomic DNA from microsamples of blood has been developed. This method used sodium perchlorate, chloroform, polymerised silica gel and a dumbbell-shape tube, instead of proteinase K and phenol. The entire process took less than two hours, and high molecular weight DNA, in high yield and purity, was obtained from a few microlitres of human blood. DNA prepared in this way can be easily digested with restriction endonucleases and has been employed for DNA profiling and the polymerase chain reaction. PMID- 7844516 TI - An autopsy evaluation of defence wounds in 195 homicidal deaths due to stabbing. AB - Defence wounds may be of value in differentiating between homicide, suicide and accidental death. A study of 3183 forensic autopsies in Istanbul between 1988 and 1989 showed that 195 deaths (6.1%) were due to stab wounds, and that defence wounds were found in 38.5% of the victims. Defence wounds were seen on 35.2% of males, and 54.5% of females; 39.7% of defence wounds were classified as 'active' and 60.3% as 'passive'; 40.5% were seen on the right hand and forearm, and 59.5% on the left side. There was no connection in this study between the occurrence of defence wounds and the consumption of alcohol by the victim before the stabbing. PMID- 7844517 TI - Identification of polydimethylsiloxane lubricant traces from latex condoms in cases of sexual assault. AB - A polydimethylsiloxane (PDMS) liquid is used as a lubricant by many condom manufacturers. Because the use of condoms in sex crimes is likely to increase, a protocol was developed that could extract PDMS and the spermicide nonoxynol-9 from evidence items and separately identify them by Fourier transform infrared spectroscopy. Additionally, at least some discrimination was provided by microscopically identifying insoluble lubricants such as corn starch, lycopodium, silica, and talc which are added to some brands. Desorption chemical ionization mass spectrometry was used to compare the PDMS used by different manufacturers and to detect as little as 20 ng. The protocol was successfully used in two actual cases, one in which the assailant wore a lubricated condom, and a second in which he did not, but claimed to have done so. PMID- 7844518 TI - Recent advances in the molecular biology of entomopoxviruses. PMID- 7844519 TI - Brefeldin A inhibits vaccinia virus envelopment but does not prevent normal processing and localization of the putative envelopment receptor P37. AB - The fungal metabolite Brefeldin A was found to inhibit the production of the infectious enveloped form of vaccinia virus, although production of the infectious intracellular form was not affected. Electron microscopic analysis and caesium chloride density centrifugation of progeny virions indicates that the drug block is not due to retention and accumulation of enveloped virions within the cell. Biochemical analysis of the candidate envelopment receptor for vaccinia virus, viral protein P37, shows that the drug has no discernible effect on palmitylation of this protein and does not prevent or alter its association with intracellular membranes. This suggests that P37 may not in fact be the receptor on intracellular membranes for vaccinia virus envelopment, and leaves open the question of what function this molecule performs in the envelopment process. 24AI 20563 PMID- 7844520 TI - Constitutive expression of human cytomegalovirus glycoprotein B (gpUL55) with mutagenized carboxy-terminal hydrophobic domains. AB - Stable transfectants were selected from human astrocytoma cells (U373) after transfection with recombinant expression vectors carrying the human cytomegalovirus (HCMV) glycoprotein B (gB; gpUL55) gene with alternative deletions of hydrophobic domain segment 1 (hd1) or segment 2 (hd2) of the carboxy terminal potential bipartite membrane anchor domain. Comparative analysis of HCMV gB forms from cell lines gB(Mhd1) and gB(Mhd2), expressing mutagenized gB, and those from cells expressing authentic gB showed that deletion of hd1, but not that of hd2, interfered with efficient proteolytic cleavage of the gB precursor. Both mutagenized gB forms exhibited correct transport to the cell surface. Deletion of hd2, but not that of hd1, caused loss of membrane anchoring of the gB molecule, resulting in secretion of the respective gB form into the culture medium. The carboxy-terminal cleavage product of the soluble gB molecule, which migrated more slowly than its authentic counterpart, was modified by complex carbohydrate side chains and formed disulphide-linked complexes. Our observations indicate that hd2 is essential as well as sufficient for membrane anchoring of the HCMV gB molecule. For hd1, a potential fusogenic role is suggested by the conserved positional pattern of glycine residues, which is comparable to that of known fusion peptides of other viruses. PMID- 7844521 TI - Identification and characterization of the major proteins of malignant catarrhal fever virus. AB - Malignant catarrhal fever virus (MCFV), a gamma-herpesvirus, causes a severe inflammatory and lymphoproliferative disease of cattle and other susceptible ruminants. Polyclonal antisera and monoclonal antibodies (MAbs) to the Minnesota isolate of MCFV were produced and used to examine the characteristics of the viral proteins. Immunoprecipitation of antigens of the Minnesota isolate of MCFV with polyclonal antisera revealed at least 11 proteins with molecular masses ranging from 17 kDa to 145 kDa. Among 279 candidate anti-MCFV hybridomas, 14 were selected and clustered into six groups on the basis of the patterns of reactivity to viral proteins in immunoprecipitation and immunoblot. The group I MAbs exhibited strong neutralizing activity and recognized a glycosylation-dependent conformational epitope on a 110 kDa protein. The MAbs in group II bound a non neutralizing conformational epitope on a 130 kDa non-glycosylated protein. A glycosylated protein complex of 115/110/105/78/45 kDa moieties was identified by the MAbs in group III. The MAbs in groups IV, V and VI reacted with non glycosylated proteins of 36/34 kDa, 24 kDa and 17 kDa, respectively. Comparison of three MCFV isolates [the Minnesota isolate, the Austrian isolate (Au-732) and the African prototype isolate (WC-11)] revealed no apparent differences in immunoprecipitation patterns with the single exception that the 110 kDa protein of WC-11 was slightly smaller than its counterpart in the Minnesota isolate. PMID- 7844522 TI - Coupled transcription of Epstein-Barr virus latent membrane protein (LMP)-1 and LMP-2B genes in nasopharyngeal carcinomas. AB - The presence of transcripts of the Epstein-Barr virus genes for Epstein-Barr nuclear antigen (EBNA)-1 and EBNA-2 and for latent membrane protein (LMP)-1, LMP 2A and LMP-2B was investigated in 24 nasopharyngeal carcinoma (NPC) biopsies of Chinese origin and two NPC-derived solid tumour lines, CAO and C15, of Chinese and north African origin respectively, propagated by serial transplantation in nude mice. Transcripts were detected by PCR amplification of cDNA. EBNA-1 transcripts were present in all biopsies tested and originated exclusively from the FQ promoter while the C and W promoters were inactive. Using nested primers, LMP-1 and LMP-2B RNAs were found to be co-ordinately expressed in 22 of the 24 biopsies, while the two remaining tumours were negative for both. LMP-2A transcription was detected in 17 of the 22 LMP-1-positive biopsies. In summary, the following patterns of viral gene expression were observed in the tumour biopsies: (i) LMP-1-LMP-2B and LMP-2A positive (17 biopsies); (ii) LMP-1-LMP-2B positive but LMP-2A negative (five biopsies); (iii) no viral gene other than EBNA 1 expressed (two biopsies). PMID- 7844523 TI - Sequence polymorphism in the Epstein-Barr virus latent membrane protein (LMP)-2 gene. AB - Latent membrane protein 2A (LMP-2A) is expressed in Epstein-Barr virus transformed B lymphocytes in vitro and has been detected in various types of EBV associated malignancies. LMP-2A interferes with membrane signal transduction through phosphorylation of its hydrophilic N-terminal domain and binding of the cellular tyrosine kinases encoded by fyn and lyn. In vitro, the domain can block calcium influx and participate in signal transduction inducing cytokine production. These two activities are differently affected by site-directed mutagenesis of potentially phosphorylated amino acid residues. Several potential tyrosine protein kinase recognition motifs have been identified including an antigen recognition motif (ARAM). ARAMs are activated by tyrosine phosphorylation that enables binding of tyrosine protein kinases such as lyn and fyn. To assess the importance of potential sequence variation in natural EBV infection and in tumourigenesis, the sequence of the LMP-2A N-terminal domain was determined in 28 EBV isolates, including 14 fresh tumour isolates. Comparison of the corresponding sequences with the prototype B95 strain indicates that LMP-2 is generally conserved with a few base pair changes resulting in conservative amino acid changes in an occasional isolate. However, five single-base loci were frequently mutated, resulting in three patterns of sequence polymorphism in exon 1 of LMP 2A. The patterns did not segregate with EBV Type 1 or Type 2 and were detected in both lymphoid and epithelial tissues. Four of the most frequent mutations at loci 166627, 166750, 166796 and 166805 (codons 23, 63, 79 and 82) could potentially affect tyrosine protein kinase binding motifs. The pivotal tyrosines (codons 74 and 85) and leucines (codons 77 and 88) of the LMP-2 ARAM were not affected in any of the isolates, suggesting that ARAM function is important for EBV infection in vivo. However, the inter-spacing positions 79 and 82 were distinct in more than 50% of the isolates. These prevalent polymorphisms could influence interaction of the LMP-2 cytoplasmic domain with specific cellular ligand proteins. PMID- 7844524 TI - Human herpesvirus 6 (strain U1102) encodes homologues of the conserved herpesvirus glycoprotein gM and the alphaherpesvirus origin-binding protein. AB - The nucleotide sequence of 3,134 bp from the genome of human herpesvirus 6 (HHV 6) strain U1102 was determined. The sequence overlaps and is contiguous with the 21,858 bp nucleotide sequence published by us previously. The sequence reported here encodes two open reading frames, named 18L and 19R. The protein encoded by 18L shares amino acid sequence similarity with the multiply hydrophobic glycoprotein M conserved in the genomes of all herpesviruses sequenced to date. ORF 19R encodes a protein which shares a significant degree of amino acid sequence conservation with the origin-binding protein homologues encoded by members of the alphaherpesvirus subgroup, but does not share detectable amino acid sequence homology with positionally analogous open reading frames present in the genomes of other betaherpesviruses or in the genomes of gammaherpesviruses. PMID- 7844525 TI - Genetic modification of an entomopoxvirus: deletion of the spheroidin gene does not affect virus replication in vitro. AB - In the late stages of an entomopoxvirus infection, virions become embedded within a crystalline occlusion body or spheroid. Spheroids are composed primarily of a single polypeptide, spheroidin. We describe the construction of a genetically modified Amsacta moorei entomopoxvirus (AmEPV) in which the spheroidin gene coding sequences are deleted and replaced with those of a heterologous reporter gene encoding chloramphenicol acetyltransferase (CAT). A transfer vector, pAmCP1, was prepared containing a unique BamHI site in lieu of the spheroidin gene coding region, together with 1 kbp of upstream and downstream DNA sequence that flanks the spheroidin gene. The flanking sequences provide the transcriptional control signals and also guide homologous recombination so that the spheroidin gene coding region can be replaced with that of the foreign gene. The transfer vector was designed so that the translational start codon of the introduced foreign gene would be utilized. A recombinant virus, AmEPV.CAT, was produced by transfecting AmEPV-infected cells with the transfer vector encoding the CAT gene. The recombinant virus was isolated from wild-type virus by identifying plaques with a spheroidin-negative phenotype. Light microscopy and SDS-PAGE analysis demonstrated that no spheroids or spheroidin protein were produced in the recombinant virus-infected cells. The recombinant virus was able to replicate to high titres (10(7) p.f.u./ml) in insect cells indicating that the spheroidin gene is non-essential for AmEPV replication in vitro. Moderate levels of CAT were synthesized in recombinant virus-infected cells and temporal analyses indicated that CAT synthesis followed the pattern of spheroidin production suggesting that the spheroidin gene promoter was functioning under normal regulatory control in the genetically modified virus. PMID- 7844526 TI - Comparative analysis of fourteen individual human cytomegalovirus proteins for helper T cell response. AB - The potential of selected proteins of human cytomegalovirus (HCMV) to induce a helper T (Th) cell immune response was investigated in healthy HCMV-seropositive donors. Recombinant derived glycoproteins B (gpUL55), H (gpUL75), integral membrane protein (pUL100), the US6-US11 glycoprotein family (pUS6-US11), the matrix proteins pp65 (ppUL83), pp28 (ppUL99) and the immediate early proteins IE1 (pUL123), IE2 (pUL122) and UL69 (pUL69) were used as stimulating antigens in a lymphocyte proliferation assay. The antigen-specific proliferative response was measured in HCMV-specific T cell lines (phenotype CD4+ CD8-) generated from five donors by stimulation of peripheral blood mononuclear cells with purified HCMV or HCMV-infected fibroblasts. A proliferative T cell response was induced by pp65, gB, gH, IE1, IE2 and UL69, with a dominant response to pp65 in all donors. Three T cell lines responded to gB and gH, respectively. For IE1, IE2 and UL69 a T cell stimulation could be demonstrated in single cell lines generated with lysate of HCMV-infected fibroblasts. PMID- 7844527 TI - Early and late pre-mRNA processing of budgerigar fledgling disease virus 1: identification of viral RNA 5' and 3' ends and internal splice junctions. AB - Budgerigar fledgling disease virus 1 (BFDV-1) is the first avian polyomavirus to be identified, and it possesses uncommon structural and biological properties. Here we present an analysis of the processed viral RNAs in infected chicken embryo fibroblast cells. Two early and 18 late BFDV-1 mRNAs were defined according to their 5' ends and internal splice patterns. In the early region of the genome an incomplete splice reaction covering 195 nt is responsible for creating two mRNAs that could encode small t and large T antigens, which would be initiated from a hypothetical early promoter, PE. The late mRNA 5' ends define two putative promoter regions (PL1 and PL2), 111 nt apart in the BFDV-1 genome non-coding region. The overall splicing pattern of the late mRNAs is further complicated by an alternative splice reaction of intron 2 (deletion of either 64 nt in intron 2a or of 256 nt in intron 2b) and a splice removing intron 3 (870 nt), resulting in deletion of most of the VP2-VP3 coding region. The positions of the late mRNA 5' ends and the splicing pattern indicate the existence of two open reading frames, putatively encoding two pairs of agnoproteins, in the 5' region of several late mRNAs. These mRNAs appear to be bicistronic and to encode one of the agnoproteins together with one of the viral coat proteins. PMID- 7844528 TI - Cell-mediated transmission of human T cell lymphotropic virus type I to human malignant trophoblastic cells results in long-term persistent infection. AB - We investigated permissiveness of the malignantly transformed trophoblast (choriocarcinoma) cell lines JAR, BeWo and JEG-3 to the human T cell lymphotropic virus type I (HTLV-I). After co-culture with the productively infected cell line MT-2 the choriocarcinoma cell lines were analysed for infection over a period of three months. The presence of HTLV-I viral DNA was examined by PCR using primers targeting the gag, pol, env and pX specific sequences. All amplified segments were found consistently in the cell cultures throughout the period of study. Further analysis that aimed to characterize the size variation of the integrated proviral DNA by Southern blotting revealed the presence of integrated proviral sequences which consisted, for the most part, of incomplete genomes. The presence of the full-length HTLV-I genome, however, was unequivocally confirmed in clonally expanded cell cultures derived from the originally infected parental cells. In order to analyse virus expression at the transcriptional level, we used reverse transcriptase (RT)-mediated PCR that was targeted at intra-exon regions (gag, pol, env and pX), and the splicing sites of the env and pX-tax/rex mRNAs. When compared with MT-2 cells, substantially lower levels of all transcripts were found in all the cell lines analysed. We were unsuccessful in attempts to detect viral protein expression using polyvalent or Tax- and Gag-specific monoclonal antibodies by Western blot analysis or immunoprecipitation, and we could not detect any RT activity released into the supernatant of the infected cells either. Collectively, these data suggest that the trophoblastic cells may become persistently but essentially non-productively infected with HTLV-I. PMID- 7844529 TI - Differences in human immunodeficiency virus type 1 V3 sequences from patients with and without AIDS dementia complex. AB - Paired serum and cerebrospinal fluid (CSF) samples from 10 AIDS patients with and 10 without AIDS dementia complex (ADC) were studied, in an attempt to uncover ADC associated variation in V3 sequences. Sequences were obtained from four of the patients with and eight of those without ADC. Comparison of the sequences using a resampling technique revealed a significant ADC-associated difference occurring at several amino acid positions. Results from serum and CSF sequences were comparable. These differences may indicate that the virus found in ADC and that in non-ADC patients have different biological properties. Comparison of serum versus CSF sequences within samples from both ADC and non-ADC patients, using the same resampling technique, revealed no clear distinctions. In some patients, the sequence populations in serum and CSF were completely distinct, while in others, there was no difference in distribution. These patterns were not associated with ADC. PMID- 7844530 TI - Sequence of host-range determinants in the env gene of a full-length, infectious proviral clone of exogenous avian leukosis virus HPRS-103 confirms that it represents a new subgroup (designated J). AB - A genomic DNA library was constructed, in a bacteriophage lambda vector, from line 0 chick embryo fibroblasts (CEFs) infected with HPRS-103, an exogenous avian leukosis virus (ALV; envelope subgroup J) recently isolated from meat-type chickens. The library was screened at high stringency using a full length RAV-1 (subgroup A) proviral probe. From 10(6) plaques, two clones which hybridized strongly to the RAV-1 probe were isolated; one contained a full-length copy of the proviral genome of HPRS-103 and the other contained a copy lacking the 5' long terminal repeat (LTR) and part of gag. The relative strength of hybridization of RAV-1 and HPRS-103 clones, to RAV-1 probes representing different parts of the proviral genome, indicated that the gag and pol genes of HPRS-103 share a high level of identity with those of RAV-1 but that the env gene and the LTRs are considerably less well conserved. Infectious virus was recovered from CEFs transfected with the full-length clone, as detected by ELISA. The recovered virus appeared to be identical to HPRS-103 by electron microscopy and by Southern blotting of proviral DNA. The recovered virus was shown to be of the same subgroup as HPRS-103 by serum neutralization and receptor interference assays. Sequence analysis of the env gene of HPRS-103 shows that it differs considerably from the env genes of other ALV subgroups, particularly in the host range determinants, consistent with the finding that HPRS-103 represents a new subgroup (designated J). PMID- 7844531 TI - Genomic sequence analysis identifies Jembrana disease virus as a new bovine lentivirus. AB - Jembrana disease virus, the cause of an acute, severe disease in Bali (Bos javanicus) cattle in Indonesia was recently identified as a retrovirus, and possibly a lentivirus. We have produced sequence data representing 598 bp of the pol gene, amplified by PCR from viral cDNA using broadly reactive universal primers for retroviruses and more specific genus-reactive primers for lentiviruses. When the sequence data were compared with that of known lentiviruses and other bovine retroviruses, the closest alignment was with bovine immunodeficiency-like lentivirus (BIV), showing 74% nucleotide sequence identity. This confirmed that JDV is a lentivirus and that it is distinguishable from BIV. The pathogenesis of Jembrana disease is most unusual for a lentivirus infection and differs markedly from that reported for BIV infection. PMID- 7844532 TI - Nucleotide sequence analysis of the non-structural NS1 (1C) and NS2 (1B) protein genes of bovine respiratory syncytial virus. AB - The nucleotide and deduced amino acid sequences of the non-structural (NS) protein genes of bovine respiratory syncytial virus (BRSV) strain A51908 were determined. The NS1 and NS2 genes were 524 and 489 nucleotides long with single open reading frames, encoding polypeptides of 136 and 124 amino acids, respectively. Comparison of the NS1 gene of BRSV with the corresponding sequences of ovine respiratory syncytial virus (ORSV) and human respiratory syncytial virus (HRSV) subgroups A and B revealed 82, 67 and 65% identity at the nucleotide level, and 89, 69 and 68% identity at the amino acid level, respectively. The nucleotide identity of the NS2 gene of BRSV to those of ORSV and HRSV subgroups A and B was 80, 69 and 67% and the predicted amino acid identity was 87, 84 and 83%, respectively. The intergenic sequences of the NS1-NS2 and NS2-N gene junctions of BRSV were determined and found to be 13 nucleotides shorter and 29 nucleotides longer, respectively, than the corresponding regions of HRSV. PMID- 7844533 TI - The appearance of H3 influenza viruses in seals. AB - Surveillance for influenza A virus infection of seals has continued following the association of influenza A virus with epizootics of pneumonia in seals off the New England coast in 1979-1980 and 1982-1983. In January 1991 and January to February 1992, influenza A viruses were isolated from seals that died of pneumonia along the Cape Cod peninsula of Massachusetts. Antigenic characterization identified two H4N6 and three H3N3 viruses. This was the first isolation of H3 influenza viruses from seals, although this subtype is frequently detected in birds, pigs, horses and humans. Haemagglutination inhibition assays of the H3 isolates showed two distinct antigenic reactivity patterns: one more similar to an avian reference virus (A/Duck/Ukraine/1/63) and one more similar to a human virus (A/Aichi/2/68). The haemagglutinin (HA) genes from two of the H3 seal viruses showing different antigenic reactivity (A/Seal/MA/3911/92 and A/Seal/MA/3984/92) were 99.7% identical, with four nucleotide differences accounting for four amino acid differences. Phylogenetic analysis demonstrated that both of these sequences were closely related to the sequence from the avian H3 virus, A/Mallard/New York/6874/78. This indicates that influenza A viruses of apparent avian origin, including the H3 subtype viruses, continue to infect seals. PMID- 7844534 TI - Evolution of the HA1 domain of human influenza A (H1N1) virus: loss of glycosylation sites and occurrence of herald and conserved strains. AB - Thirty-one strains of human influenza A (H1N1) viruses isolated in Europe, mostly in Finland, from 1978-1992 were compared with respect to their nucleotide sequences coding for the HA1 portion of haemagglutinin. In 1984, at least two sublineages of H1N1 subtype viruses co-circulated in Finland. The viruses isolated after 1986 formed three sequential phylogenetic clusters. Loss of glycosylation sites, on the globular head of the HA1 portion suggests that oligosaccharides at these sites are not necessarily advantageous for the human virus. Isolation of a herald strain in Finland in June 1988 raised the question as to whether the virus was able to survive in Europe throughout the non-epidemic summer period. Demonstration of highly conserved strains, found over two continents in 1988, is further evidence of the existence of infection chains whose viruses have not been subjected to random sampling or selection events. PMID- 7844535 TI - Prevalence of hepatitis C virus sequence variants in South-East Asia. AB - The nature and distribution of hepatitis C virus (HCV) genotypic variants present in south-east Asia have not been extensively investigated. We analysed HCV RNA obtained from 67 clinical serum samples from Singapore, Thailand, Indonesia, the Philippines and South Korea. All samples were amplified by semi-nested RT-PCR and the nucleotide sequence determined for four regions within the E1, E2/NS1, NS4 and NS5 genes. Each isolate had a unique nucleotide and deduced amino acid sequence, consistent with the genetic heterogeneity of this virus. There was remarkably little amino acid sequence variation between isolates of the same genotype, apart from variable domains within putative envelope glycoproteins that are likely to be under immune pressure. All isolates could be classified according to the currently recognized genotypes of HCV, with the exception of one Singapore isolate that defined a new group 3 subtype. The 1b genotype, which predominates in Japan, was the most widely distributed genotype and accounted for 58% of all isolates sequenced. Regional variations in HCV genotype distribution were observed, with type 3a being found almost exclusively in Thailand. By contrast, the 1a genotype, which predominates in the USA was the most prevalent genotype in the Philippines. Genotype 1a was found less commonly among the Thai isolates, presumably having been introduced from the West in stored blood products or by sporadic transmission. The significant prevalence of HCV types 2 and 3 restates the need for variant genotypes to be included in immunodiagnostic and vaccine development strategies. This study reveals that the 1b genotype of HCV, previously found to be the major variant present in east Asia, also predominantes in the south-east Asian region, and may be the major HCV type found worldwide. PMID- 7844536 TI - Neutralizing F(ab')2 fragments of protective monoclonal antibodies to yellow fever virus (YF) envelope protein fail to protect mice against lethal YF encephalitis. AB - Monoclonal antibodies (MAbs) prepared against the yellow fever virus (YF) vaccine strain 17D (17D YF) envelope E protein were used to investigate Fc piece involvement in antibody-mediated protection against YF encephalitis in mice 17D YF passaged either in Vero cells or in mouse brain (P-YF) to increase neurovirulence was used. To avoid uncertainty concerning antibody clearance and blood-brain barrier penetration, and to directly compare protective activity with neutralization in vitro, pre-formed antibody-virus complexes were injected intracerebrally or assayed for plaque formation in parallel. F(ab')2 fragments of an IgG2a MAb that strongly neutralized both YF strains retained molar equivalent neutralizing activity in vitro, but did not protect. However, further incubation of such F(ab')2-virus antibody complexes with rabbit IgG, but not F(ab')2 anti mouse IgG resulted in protection. To unambiguously test for Fc piece involvement in this model we derived an IgG2a isotype switch variant from a protective IgG1 MAb-secreting hybridoma and prepared F(ab')2 fragments of the derivative. Intact and fragmented antibodies exhibited weak neutralizing activity. The variant antibody failed to protect against P-YF, but against considerably less neurovirulent 17D YF its protective capacity was 10-fold higher than that of its IgG1 parent. F(ab')2 fragments of the variant did not protect. Together, these results provide strong evidence of an in vivo protective function for the anti virion antibody Fc piece and indicate that in vitro neutralizing activity as a predictor of antibody protective capacity is dependent on Fc piece integrity and isotype. PMID- 7844537 TI - VP6 from porcine rotavirus strain CN86: amino acid sequence divergence with conservation of subgroup II specificity. AB - A porcine rotavirus strain, CN86, originally isolated from rotavirus-infected piglets in Argentina, has been shown to possess unique characteristics. It was the first animal strain described to be antigenically related to human serotype G1 and the standard counterpart of another porcine strain showing rearrangement of genome segment 11. Owing to these features, molecular characterization of this virus seemed relevant. The gene encoding the major inner capsid protein, VP6, was cloned and its nucleotide sequence was determined. Comparative analysis of the deduced amino acid sequence of CN86 VP6 with those representing the four different subgroups showed that it is more closely related to subgroup II human Wa and porcine Gottfried strains, albeit to a lesser extent than they are to each other. Despite exhibiting sequence divergence, CN86 VP6 has 12 out of the 14 residues expected to be conserved in strains bearing subgroup II specificity. Interestingly, CN86 VP6 shows a high degree of homology with VP6 of porcine strain YM rotavirus which, although being closely related to subgroup II strains, has been serologically characterized as subgroup I. Subgroup II reactivity of CN86 strain, predicted by sequence analysis, was confirmed by ELISA with subgroup specific monoclonal antibodies. Taken together, our results provide evidence for the existence of a human-pig lineage for rotavirus gene 6. PMID- 7844538 TI - Several symptom-modulating mutations in the coat protein of turnip crinkle carmovirus result in particles with aberrant conformational properties. AB - Particles of several symptom-modulating TCV coat protein (CP) mutants were pretreated at pH 5.5, 7.5 or 8.5 and their conformations compared by agarose gel electrophoresis to those of wild-type particles. Particles of two mutants were swollen under conditions in which wild-type particles remained contracted; particles of one mutant were contracted under conditions in which wild-type particles were swollen; a portion of the particles of one mutant was contracted and another portion swollen under conditions in which wild-type particles remained contracted; and particles of one mutant, that elicited wild-type symptoms, comigrated with wild-type particles under all conditions tested. The results of in vitro translation experiments with mutant particles were essentially similar to those with wild-type particles, despite conformational differences at pH 5.5 and 8.5. These results suggest that more than the swollen conformation is required for in vitro translation, and that particle conformation may play a role in symptom elicitation. PMID- 7844539 TI - Tomato leaf curl geminivirus from India has a bipartite genome and coat protein is not essential for infectivity. AB - Genomes of two isolates of tomato leaf curl geminivirus from India (ToLCV-India) have been sequenced. ToLCV-India contains A and B components, both of which are required for systemic movement and symptom development. The two isolates have 94% sequence identify but one isolate gave mild symptoms in Nicotiana benthamiana and tomato. The genome organization of ToLCV-India is similar to other whitefly transmitted geminiviruses (WTGs) with bipartite genomes. However, it contains an additional ORF, AV3, that has not been reported for other WTGs. Its coat protein (CP) sequence is highly homologous to that of Indian cassava mosaic virus (90%). Two mutations that truncated the CP after amino acids 65 or 172 did not affect systemic movement and symptom development in either N. benthamiana or tomato. However, the symptoms caused by mutant viruses were different from those in plants infected with unmodified viruses, and plants infected with the mutants had markedly reduced amounts of single-stranded viral DNA. Comparison of sequences and other biological features of ToLCV-India with other geminiviruses showed that ToLCV-India is a distinct virus and is related to the WTGs from the Old World. It is similar to African cassava mosaic virus in its requirement for B component and dispensability of coat protein for symptom development, unlike other geminiviruses that infect tomato in the Old World. It is proposed that ToLCV India evolved more recently as compared to other geminiviruses that infect tomato in the Old World. PMID- 7844540 TI - Characterization of the P1 protein and coding region of the zucchini yellow mosaic virus. AB - The nucleotide sequence of the 5'-terminal P1 coding region of an aphid transmissible isolate of zucchini yellow mosaic virus (ZYMV; strain FL/AT), a mild isolate (strain MD) and a severe isolate (strain SV), all from Florida, were compared with two other ZYMV isolates. The ZYMV MD and SV isolates and an isolate from California (ZYMV CA) had 95-98% sequence similarities to FL/AT, whereas an isolate from Reunion Island (ZYMV RU) had a 60% sequence similarity to FL/AT. ZYMV MD had an 18 nucleotide insert following the start codon of the P1 coding region. The P1 proteins of all ZYMV isolates shared conserved amino acids in areas of the C terminus similar to those reported for other potyviruses. Polyclonal antisera were prepared to the P1 proteins of ZYMV FL/AT and RU expressed in Escherichia coli. The FL/AT and RU P1 antisera showed varying degrees of reactivity in Western blots with extracts of pumpkin (Cucurbita pepo L.) singly infected with a number of distinct ZYMV isolates. The reaction of the FL/AT P1 antiserum with isolate RU-infected tissue extracts was very weak compared to the homologous reaction. Neither antiserum reacted with extracts from plants singly infected with three other potyviruses, a potexvirus, or a cucumovirus. The P1 proteins of ZYMV isolates ranged in molecular mass from 33 kDa to 35 kDa. The P1 protein of strain MD was larger (35 kDa) than that of FL/AT (34 kDa). Indirect immunofluorescence tests with FL/AT P1 antiserum indicated that the P1 protein aggregates in ZYMV-infected tissues. The antisera to the ZYMV P1 proteins have potential as serological probes for identifying ZYMV and for distinguishing ZYMV isolates by immunoblotting. PMID- 7844541 TI - The Semliki Forest virus E2 gene as a virulence determinant. AB - We have determined the nucleotide sequences of the capsid, E3, E2 and 6K genes of the avirulent Semliki Forest virus variant A774 (SFV A7). The sequence analysis revealed a nucleotide identity of 98% for capsid, 98% for E3, 97% for E2 and 98% for 6K genes, as compared with the prototype SFV strain L10. At the protein level, the capsid and E3 polypeptides of SFV A7 both exhibited two amino acid substitutions, whereas point mutations in the 6K gene did not alter the amino acid sequence. In the E2 gene of SFV A7, seven of the 34 point mutations led to an amino acid difference as compared with the L10 strain. Replacement of the E2 glycoprotein gene of the virulent SFV4 clone with the corresponding region of SFV A7 resulted in a new plasmid construct, pME2, that gave rise to infectious virus CME2. CME2 and SFV4 replicated similarly in an immortalized mouse brain cell line (MBA 13). Intraperitoneal injection of 10(6) p.f.u. of CME2 into 4- to 6-week-old BALB/c mice caused mild clinical signs in some mice, whereas the majority of the infected animals remained asymptomatic, similar to infection with the avirulent SFV A7. In contrast, infection with the parental SFV4, a derivative of the virulent L10 strain, was lethal in 80% of mice. Virus titres in blood and brain tissue specimens of BALB/c mice were similar after infection with CME2 or A7 viruses. The results suggest that amino acid differences in the E2 glycoprotein individually or in concert cause the attenuation of CME2. PMID- 7844542 TI - Nuclear localization of the truncated hepatitis C virus core protein with its hydrophobic C terminus deleted. AB - The core protein of hepatitis C virus (HCV) is considered to be cleaved from the N terminus of the large precursor polyprotein by cellular signalase. The HCV cDNA encoding the core protein was expressed (i) in monkey COS cells by a plasmid expression vector driven by the SR alpha promoter, and (ii) in insect cells by a recombinant baculovirus. The expressed product had an M(r) of 22,000 and was located in the cytoplasm. When the C-terminal hydrophobic domains were deleted, however, the truncated core proteins were translocated into the nucleus. The truncated core proteins were located in the nucleus even when they were expressed as a fusion protein with E. coli beta-galactosidase, which is essentially localized in the cytoplasm. Plasmids containing HCV cDNAs with a deletion in one of the regions encoding clusters of basic amino acids were expressed in COS cells and the localization of the core protein was examined. The residues PRRGPR were suggested to play an important role in nuclear localization. HCV is an RNA virus and its life cycle was originally considered to be confined to the cytoplasm; the present study, however, suggests that the HCV core protein can translocate into the nucleus under certain circumstances. PMID- 7844543 TI - Poliovirus subviral particles associated with progeny RNA in the replication complex. AB - The poliovirus replication complex (RC), the site of genomic 36S RNA synthesis, was previously shown to contain subviral particles of 5S protomer and 14S pentamer antigenicity. The present investigation demonstrates that 5S/14S antigenic subviral particles can be cross-linked to viral RNA by UV irradiation of a subcellular fraction containing the poliovirus RC. Each capsid protein of the subviral particles, i.e. VP0, VP1 and VP3, was cross-linked to viral RNA. SDS PAGE analysis of the cross-linked capsid proteins revealed a bandshift for VP1, whereas VP0 migrated in several bands, which were interpreted to be multimers of VP0 linked by short stretches of RNA. It was found that 36S RNA rather than replicative intermediate RNA was cross-linked to capsid proteins. Our results indicate that encapsidation of poliovirus RNA starts in the RC and is initiated by 14S pentamers. PMID- 7844544 TI - Molecular epidemiology of rabies virus in South Africa: evidence for two distinct virus groups. AB - In order to derive phylogenetic relationships between rabies virus isolates from different geographical locations and host species in South Africa, two genome regions of the virus, viz. the cytoplasmic domain of the glycoprotein and the G-L intergenic region (pseudogene), were sequenced. A high level of nucleic acid sequence conservation indicated a close phylogenetic relationship between virus isolates from domestic dogs, jackals and bat-eared foxes, i.e. Canidae. These isolates appeared to be distinct from but closely related to European strains of rabies virus. However, a phylogenetically distinguishable and distant group, which contained isolates from mongooses (i.e. Viverridae) was identifiable. The latter group appears to be distantly related to European and vaccine strains of rabies virus and may have evolved uniquely on the central plateau of South Africa. Our data also indicate that spillover from mongooses (or other viverrids) to canid hosts occurs occasionally. PMID- 7844545 TI - Expression of human polyomavirus JC T antigen by an adenovirus hybrid vector and its binding to DNA sequences encompassing the JC virus origin of DNA replication. AB - In the search for factors that influence the outcome of human polyomavirus JC (JCV) infection, the roles not only of host-related immunological control but also of virus-dependent regulatory steps have to be taken into account. Besides cell-specific control of early expression of the multifunctional virus protein large tumour antigen (T Ag), control mechanisms involve individual steps of the DNA replication process. For the analysis of T Ag DNA binding, the protein was expressed by an adenovirus hybrid vector in the 293 cell line to provide saturating amounts of JCV T Ag. After determination of the size and immunoreactivity, functional activity was analysed by specific DNA binding. To avoid the interference of cellular proteins, T Ag was immunoprecipitated prior to the reaction. Binding to T Ag-binding sites I and II within a 141 bp DNA segment in the control region was analysed using deletion mutants of a JCV subtype from brain tissue of a patient with fatal central nervous system disease. The specificity of the binding was confirmed by recombinant T Ag binding to origin of DNA replication (ori) sequences of wild-type JCV genomes. These data document that recombinant T Ag overexpressed by the adenovirus vector in eukaryotic cells was JCV-specific, had the expected length and exhibited specific ori-binding activity, thus providing the essential tool for future analysis of virus-host interactions at the level of viral DNA replication. PMID- 7844546 TI - Development of a bovine adenovirus type 3-based expression vector. AB - We constructed a non-defective bovine adenovirus type 3 recombinant (BAd3-Luc) containing the firefly luciferase gene inserted in the early region 3 (E3) of the BAd3 genome. Deletion of a 696 bp XhoI-NcoI E3 segment and insertion of the luciferase gene in E3 was confirmed by Southern blot analyses. Luciferase was expressed in Madin-Darby bovine kidney cells infected with BAd3-Luc as measured by enzymic assays and Western blotting. Analyses of luciferase expression in the presence or absence of 1-beta-D-arabinofuranosylcytosine indicated that approximately 70-75% of luciferase expression was dependent on viral DNA replication, suggesting that transcription of the gene was at least partially under the control of a late promoter. Although yields of infectious virus for BAd3-Luc were approximately 10-fold lower than for wild-type virus, replication of the vector was still relatively efficient. In a Western blot experiment, anti luciferase antibody reacted with a 62 kDa protein which is of the same molecular mass as the purified firefly luciferase polypeptide. Luciferase was also expressed in the 293 cell line infected with BAd3-Luc for at least 6 days post infection as monitored by luciferase assays. Based on these observations we suggest that BAd-based expression vectors should have excellent potential for the development of recombinant vaccines for cattle and may also be suitable as vectors for gene transfer into human cells. PMID- 7844547 TI - The remarkable variety of plant RNA virus genomes. PMID- 7844548 TI - Classification and identification of geminiviruses using sequence comparisons. AB - The genomes and ORFs of 36 geminiviruses were compared to obtain phylogenetic trees and frequency distributions of all possible pairwise comparisons with an objective to classify geminiviruses. Such comparisons show that geminiviruses form two distinct clusters of leafhopper-transmitted viruses that infect monocots (subgroup I) and whitefly-transmitted viruses that infect dicots (subgroup III), irrespective of the part of the genome considered. Of the two leafhopper transmitted viruses that infect dicots, tobacco yellow dwarf virus has a sequence most similar to subgroup I viruses, and that of beet curly top virus differed depending upon the ORF considered. The distributions of identities within subgroups are significantly different suggesting that the taxonomic status of a particular isolate within a subgroup can be quantified. All the recognized strains of any one virus have greater than 90% sequence identity. It was observed that the 200 nucleotide intercistronic regions of geminiviruses are more variable than the remainder of the genome. The amino acid sequences of the coat protein (CP) of subgroup III viruses are more conserved than the remainder of the genome. However, a short N-terminal region (60-70 amino acids) of the CP is more variable than the rest of the CP sequence and is a close representation of the genome. PCR primers based on conserved sequences can be used to clone and sequence the N terminal sequences of the CP of the geminiviruses; this sequence is sufficient to classify a virus isolate. A possible taxonomic structure for geminiviruses is proposed after considering the sequence comparisons and biological properties. PMID- 7844549 TI - Mutational analysis of the coat protein N-terminal amino acids involved in potyvirus transmission by aphids. AB - The nature of the amino acids in the N-terminal 'DAGX' motif of the coat protein of tobacco vein mottling virus (TVMV) that have a direct effect on aphid transmissibility of the virion were further defined by site-directed mutagenesis. In the first position of the DAGX motif, Asp or Asn are required for aphid transmissibility. In the second position, the nonpolar residue Ala, but not the nonpolar Gly or Val or the polar Thr and Ser, is compatible with transmissibility. In the third position, the small, neutral, nonpolar Gly appears to be critical; even substitution of Ala, with a minimal side-chain, drastically reduces transmissibility. Although the amino acid following the DAG sequence is not highly conserved among potyviruses, the presence of an acidic Glu or Asp residue at this position in the TVMV coat protein drastically reduces or abolishes aphid transmissibility. An attempt was made to test the hypothesis that trypsin cleavage of the N terminus is involved in the aphid inoculation process by destroying a trypsin cleavage site downstream from the DAGX motif. While the predicted decrease in transmission occurred from infected plants, there was no effect on the transmission of purified virus. Of the 23 mutations in the DAGX region of TVMV reported here and previously, only two, substitutions of Lys and Arg for Asp, had a detectable adverse effect other than on aphid transmissibility. These, and perhaps other, residues near the N terminus function in some phase of the TVMV life cycle, in addition to aphid transmission. PMID- 7844550 TI - Microplitis demolitor polydnavirus induces apoptosis of a specific haemocyte morphotype in Pseudoplusia includens. AB - Microplitis demolitor polydnavirus (MdPDV) is associated with Microplitis demolitor, a parasitic wasp that attacks the larval stage of the lepidopteran Pseudoplusia includens. Previously, we observed that MdPDV induced several alterations in the granular cells and plasmatocytes of P. includens, the primary haemocytes involved in regulating the cellular immune response toward M. demolitor and other parasites. In examining the mechanisms underlying immunosuppression of this host, we found that MdPDV induced apoptosis of granular cells. Granular cells underwent apoptosis both when virus was injected into the haemocoel of P. includens larvae and after infection with MdPDV in vitro. Characteristics of MdPDV-induced apoptosis included condensation of chromatin, cell surface blebbing and fragmentation of DNA into a 200 bp ladder. Although MdPDV induced changes in the ability of plasmatocytes to adhere to foreign surfaces, apoptosis of this morphotype was not observed. Examples from the literature suggest that some viruses promote their own survival by suppressing apoptosis of host cells. However, since polydnaviruses are likely to be transmitted vertically, we suggest that MdPDV promotes its own survival by inducing apoptosis of host immune cells which would otherwise kill the developing M. demolitor egg. PMID- 7844551 TI - Serological and molecular evidence of rhesus papillomavirus type 1 infections in tissues from geographically distinct institutions. AB - We have previously demonstrated the presence of rhesus monkey papillomavirus type 1 (RhPV-1), from molecular and pathological evidence, in a mating group within a single institution. We have now also obtained a number of fresh or archival tissues of rhesus monkeys from other geographically distinct institutions. Using PCR amplification, we observed two animals from one of these institutions and five animals from another which demonstrated RhPV-1 DNA sequences. In addition we molecularly cloned the E7, E2, E4, L2 and L1 genes of RhPV-1 into bacterial expression vectors. The fusion gene products were used to test for serological response to RhPV-1 antigens by Western blot analysis. Responses were observed in up to 52% of the animals tested. While some serologically positive animals were also RhPV-1 DNA-positive, most were not. PMID- 7844552 TI - Phospholipid interactions of the putative fusion peptide of hepatitis B virus surface antigen S protein. AB - One of the first steps in the infective cycle of an enveloped virus consists of the fusion of the viral and cellular membranes. This process is usually achieved as a result of membrane destabilization brought about by a viral fusion peptide located at the amino terminus of one of the viral envelope glycoproteins. Previous sequence similarity studies by Rodriguez-Crespo et al. (Journal of General Virology 75, 637-639, 1994) have shown that a hydrophobic stretch in the amino-terminal sequence of the S protein of hepatitis B virus shares several characteristics with fusion peptides of retroviruses and paramyxoviruses. A 16 residue peptide with this sequence was synthesized and its interaction with liposomes characterized. This peptide was able to mediate vesicle aggregation, lipid mixing and liposome leakage in a pH dependent manner at concentrations ranging from 3.5 to 52.0 microM. These effects were specific for negatively charged phospholipid vesicles. The peptide was also able to haemolyse erythrocytes. This study supports the notion that the sequence might be important in the initial infective steps of this virus, interacting with the target membranes and bringing about their subsequent destabilization. PMID- 7844553 TI - Longitudinal analysis of cytomegalovirus load in renal transplant recipients using a quantitative polymerase chain reaction: correlation with disease. AB - Serial surveillance samples of urine collected from 103 renal transplant recipients were analysed by polymerase chain reaction (PCR) for the presence of human cytomegalovirus (HCMV) DNA. The PCR results were consistently negative in 70 patients, none of whom developed HCMV disease, and PCR positive in 33 patients of whom 10 developed HCMV disease (P < 0.001). In 12 patients, PCR results were positive in three or more consecutive samples indicating extensive HCMV replication. HCMV load in 104 samples from these patients was analysed using a quantitative co-amplification PCR system. The maximal viral burden in the symptomatic patients ranged from 10(5.9) to 10(7.12) genomes/ml urine (median 10(6.5)) and in the asymptomatic patients from 10(4) to 10(5.7) genomes/ml urine (median 10(5.2)). The 10(1.3) difference between these median values was significant (P < 0.01). Individual kinetic profiles of viral burden showed that high levels of HCMV correlated with clinically apparent disease. In the majority of the asymptomatic individuals HCMV load remained between 10(4) and 10(5.1) genomes/ml urine; however, in two patients fluctuations in viral load were observed involving higher viral levels (up to 10(5.7) genomes/ml urine) suggesting that immune responses able to modulate viral replication could be studied in individual patients. Analysis of the temporal appearance and quantity of HCMV in the urine with alterations in white cell numbers showed that leukopenia occurred following the appearance of HCMV in the urine of symptomatic patients but preceded HCMV in the urine of asymptomatic patients (P = 0.01). Overall, these results show that longitudinal analysis using fully quantitative PCR methods for HCMV can provide insight into the natural history of HCMV disease in renal transplant recipients. PMID- 7844554 TI - Replication, establishment of latent infection, expression of the latency associated transcripts and explant reactivation of herpes simplex virus type 1 gamma 34.5 mutants in a mouse eye model. AB - The herpes simplex virus type 1 (HSV-1) gamma 34.5 gene is located within a region that is transcriptionally active during latent HSV-1 infection. To determine whether the gamma 34.5 gene deletion affects latency-associated transcript (LAT) gene expression or latent HSV-1 infection, a gamma 34.5 gene deletion mutant, 1716, and a stop codon insertion mutant, 1771, were studied in the mouse eye model. Although the gamma 34.5 gene is not essential, 1716 and 1771 replicated poorly in mouse eyes and trigeminal ganglia (TG). When mice were inoculated with 1716, infectious virus was detected in eyes only on the first day post-infection (p.i.), and was not detected at any time point in TG. Following inoculation with 1771, a small amount of virus was detected in the eyes on days 2 and 4 p.i., and in the TG of one animal on day 2 p.i. Reactivation of virus from mice latently infected with 1716 (0/30 TG) and 1771 (1/20 TG) was extremely low compared with the parental strain, 17+, and appropriate rescuants (80 to 100% reactivation), even though latent 1716 DNA was detected by PCR in 50% of TG. These results differ from those obtained following footpad inoculation; in the footpad there was limited 1716 replication and reactivatable latent infection was established in some dorsal root ganglia. The data support the hypothesis that the role of gamma 34.5 may be tissue and/or cell type specific. The synthesis, processing, and stability of the 2.0 kb LAT during 1716 and 1771 replication was not affected by these mutations in the gamma 34.5 gene. However, during latent infection of 1716 in mice the LATs were not detectable in TG by Northern blot, and were present in reduced amounts (approximately 10-fold less) during 1771 latency. The LATs from 1716 were barely detectable in a few neurons by in situ hybridization. Therefore, the gamma 34.5 gene might (i) affect replication in the eye, and reduce the amount of virus available to establish latent infection, be directly involved in (ii) establishment of latency, and/or (iii) the reactivation process. PMID- 7844555 TI - Leukaemogenesis by the delta Mo + SV Moloney murine leukaemia virus (M-MuLV) variant in E mu pim-1 transgenic mice: high frequency of recombination with a solo endogenous M-MuLV LTR in vivo. AB - We previously described an enhancer variant of Moloney murine leukaemia virus (M MuLV), delta Mo + SV M-MuLV, in which the enhancers of MuLV have been deleted and replaced with the enhancers of the simian virus 40 (SV40). When this virus is injected into neonatal NIH Swiss mice, pre-B and B-lymphoblastic lymphomas develop with a latency of 17 months. Van Lohuizen et al. (1989) described a line of transgenic mice that carry an activated pim-1 proto-oncogene transgene (E mu pim-1). They also reported that E mu pim-1 transgenic mice show greatly accelerated lymphoma development when infected with wild-type M-MuLV at birth. In these experiments, neonatal E mu pim-1 transgenic mice were infected intraperitoneally with delta Mo + SV M-MuLV. Marked acceleration of T-lymphoid leukaemia was seen. However, 10 of the 11 tumours analysed were found to be negative for the SV40 enhancers, but they still contained M-MuLV DNA as measured by Southern blot analysis. The LTRs on viruses cloned from two such tumours (as well as on virus recovered by infection onto NIH 3T3 cells) were characterized by PCR amplification, molecular cloning and sequence analysis. The LTR's from the two tumours were identical to each other and were distinct from both the delta Mo + SV M-MuLV and wild-type M-MuLV LTRs. However, they were identical to a rearranged solo M-MuLV LTR present in the E mu pim-1 transgene. These results indicate that the recombination in vivo between delta Mo + SV M-MuLV and the E mu pim-1 transgene yielded a replication-competent and pathogenic virus at high efficiency. This is the first report of in vivo recombination between an exogenous MuLV and a solo endogenous LTR. PMID- 7844556 TI - Casein kinase II is the P protein phosphorylating cellular kinase associated with the ribonucleoprotein complex of purified vesicular stomatitis virus. AB - Protein kinase activities associated with a highly purified transcriptionally active ribonucleoprotein complex from the virions of vesicular stomatitis virus (VSV) were isolated and characterized. Based upon several biochemical and immunological criteria, the protein kinase activity, which phosphorylated the bacterially expressed unphosphorylated (Po) protein, was shown to be cellular casein kinase II (CKII). These studies included inhibition of the protein kinase by specific inhibitors, phosphorylation of mutant phosphoproteins (P), immunoprecipitation by CKII antibody and Western blot analyses, and finally its ability to activate Po to synthesize RNA in a transcription-reconstitution reaction. The P protein is phosphorylated intracellularly by cellular CKII. The present study demonstrates that VSV specifically packages CKII which remains strongly associated with the ribonucleoprotein complex during morphogenesis. PMID- 7844557 TI - A 2',5'-oligoadenylate analogue inhibits murine hepatitis virus strain 3 (MHV-3) replication in vitro but does not reduce MHV-3-related mortality or induction of procoagulant activity in susceptible mice. AB - Exposure of inbred mice to murine hepatitis virus strain 3 (MHV-3) causes a strain dependent spectrum of disease symptoms which correlates with induction of procoagulant activity (PCA) by macrophages. Previous studies have demonstrated a role for interferons in resistance to MHV-3 infection. These cytokines have both antiviral and immunoregulatory effects which may be crucial for MHV-3 resistance. One of their antiviral effects is the ability to induce 2',5'-oligoadenylate (2 5A) synthetase leading to activation of the latent endoribonuclease RNase L. Once activated, RNase L degrades ssRNA thereby inhibiting viral-induced protein synthesis. These studies were undertaken to determine the effects of Oragen 0004 (Oragen), an RNase L activating 2-5A analogue, on MHV-3 replication and induction of PCA in vitro and on the course of MHV-3 infection in susceptible BALB/cJ mice in vivo. Oragen inhibited MHV-3 replication in peritoneal macrophages derived from resistant A/J and susceptible BALB/cJ mice in a dose-dependent fashion. Concentrations of Oragen greater than 110 micrograms/2 x 10(6) macrophages decreased viral replication by greater than 89% in peritoneal macrophages in vitro obtained from both BALB/cJ and A/J mice and by 86% in livers from MHV-3 infected mice in vivo. However, Oragen failed to inhibit induction of PCA following in vitro exposure of BALB/cJ mice-derived peritoneal macrophages to MHV 3 and failed to prevent the development of fulminant hepatitis in BALB/cJ mice in vivo. Thus, these studies demonstrate clearly that induction of 2-5A synthase and inhibition of viral replication is not sufficient to prevent MHV-3-related hepatocellular injury, and these data further support the role of PCA in the pathogenesis of MHV-3 infection. PMID- 7844558 TI - The asialoglycoprotein receptor is a potential liver-specific receptor for Marburg virus. AB - The liver is one of the main target organs of Marburg virus (MBG), a filovirus causing severe haemorrhagic fever with a high fatality rate in humans and non human primates. MBG grown in certain cells does not contain neuraminic acid, but has terminal galactose on its surface glycoprotein. This observation indicated that the asialoglycoprotein receptor (ASGP-R) of hepatocytes may serve as a receptor for MBG in the liver. Binding studies revealed that the attachment of MBG to ASGP-R-expressing HepG2 cells, but not to ASGP-R-negative E6 Vero cells, has the characteristics of ligand binding to the ASGP-R: binding is dependent on calcium and is inhibited by excess asialofetuin and by anti-ASGP-R antiserum. Asialofetuin and the specific antiserum also inhibited MBG infection of HepG2 cells. In addition, it was shown that expression of ASGP-R cDNA in NIH 3T3 cells enhanced the susceptibility of these cells to MBG infection 4.5-fold. Interaction of MBG with the hepatic ASGP-R could thus explain the marked hepatotropism of the virus. PMID- 7844559 TI - Nucleotide and deduced amino acid sequence of the structural protein genes of Japanese encephalitis viruses from different geographical locations. AB - Strain variation among Japanese encephalitis (JE) virus isolates has been previously demonstrated by many workers using different methods. We report the nucleotide sequence of the 5' non-coding region and the nucleotide and deduced amino acid sequences of structural protein genes for eight wild-type JE virus strain isolated from different Asian countries (Vietnam, Nepal, Indonesia, Thailand, India, Japan and China). We compare these with five other published wild-type JE virus strains isolated from Japan and the mainland of China. No strain variation could be related to geographical location on the basis of the wild-type JE virus strains studied. The viruses differed from each other by between 21 (0.9%) and 111 (4.6%) nucleotides and by between 3 (0.4%) and 31 (4.2%) amino acids over the 2434 nucleotides examined. The amino acid divergence of the envelope (E) protein gene of the viruses was 4.2% or less among the 13 strains compared. Thus there is little genetic divergence in the strains studied. However, four variable E protein amino acids (E-51, E-209, E-244 and E-366) were identified. Residue positions E-51, E-244 and E-366 are found in peptides with functional T helper cell epitopes in two other flaviviruses. Therefore, these amino acids may be important in defining the various immunotypes of JE virus identified by antibody reactivity patterns. PMID- 7844560 TI - Molecular basis of attenuation of neurovirulence of wild-type Japanese encephalitis virus strain SA14. AB - To identify the molecular determinants for attenuation of wild-type Japanese encephalitis (JE) virus strain SA14, the RNA genome of wild-type strain SA14 and its attenuated vaccine virus SA14-2-8 were reverse transcribed, amplified by PCR and sequenced. Comparison of the nucleotide sequence of SA14-2-8 vaccine virus with virulent parent SA14 virus and with two other attenuated vaccine viruses derived from SA14 virus (SA14-14-2/PHK and SA14-14-2/PDK) revealed only seven amino acids in the virulent parent SA14 had been substituted in all three attenuated vaccines. Four were in the envelope (E) protein (E-138, E-176, E-315 and E-439), one in non-structural protein 2B (NS2B-63), one in NS3 (NS3-105), and one in NS4B (NS4B-106). The substitutions at E-315 and E-439 arose due to correction of the SA14/CDC sequence published previously by Nitayaphan et al. (Virology 177, 541-552, 1990). The mutations in NS2B and NS3 are in functional domains of the trypsin-like serine protease. Attenuation of SA14 virus may therefore, in part, be due to alterations in viral protease activity, which could affect replication of the virus. PMID- 7844561 TI - Sequence of non-structural regions 3 and 5 of hepatitis C virus genomes from Spanish patients: existence of a predominant variant related to type 1b. AB - Several hepatitis C viruses (HCV) have been described. In this study, the prevalence of HCV subtypes 1a, 1b, 2a and 2b has been studied by means of specific PCR in 93 serum samples of Spanish patients. Among these, the HCV-1b subtype was the most frequently detected (62%). Complementary DNA fragments from non-structural region 3 (NS3) and 5 (NS5), obtained from serum samples of three Spanish patients, were amplified by PCR and the products were cloned and sequenced. Comparison of the sequence obtained with those previously published shows the highest homology (91.7% in NS3 and 91.8% in NS5) with the HCV-1b subtype. The incidence of the local variant was analysed among the HCV-1b infected patients. In order to distinguish between the local and HCV-1b prototype subtype, a new specific PCR assay was designed using primers from NS5. In the majority of the 76 HCV-1b-infected patients, the local variant was the only subtype detected (53%). These findings support the existence of a local variant, belonging to the HCV-1b subtype. PMID- 7844562 TI - Protection of hamsters against experimental mumps virus (MuV) infection by antibodies raised against the MuV surface glycoproteins expressed from recombinant vaccinia virus vectors. AB - The fusion (F) and haemagglutinin-neuraminidase (HN) glycoproteins of mumps virus (MuV) have been produced in CV1 cells via vaccinia virus recombinants. Recombinant proteins accumulated in infected cells and were glycosylated. Upon reduction, the F protein product was completely converted into its subunits. Hamsters infected with vaccinia recombinants expressing either the F or HN proteins produced antibodies recognizing MuV antigens and neutralizing MuV infectivity in vitro. These antibodies provided protection against MuV-induced encephalitis in newborn hamsters. PMID- 7844563 TI - C-terminal phosphorylation of human respiratory syncytial virus P protein occurs mainly at serine residue 232. AB - To determine which human respiratory syncytial virus (HRSV) P protein serine residues are modified by cellular protein kinase(s), several mutated versions of P protein were expressed in the absence of other viral proteins. Mutations at serines 232 or 232 and 237 drastically reduced the extent of phosphorylation P protein in vivo. Serine 232 is the main site of modification and is also essential for in vitro phosphorylation by casein kinase II. Additional in vivo phosphorylation was also detected in the region containing serines 116, 117 and 119. PMID- 7844564 TI - Sequence and expression of the ns2 protein gene of human coronavirus OC43. AB - The complete nucleotide sequence of the ns2 gene of human coronavirus OC43 (HCV OC43) was determined. Sequence analysis revealed an open reading frame that could encode a protein of 278 amino acids, with an estimated molecular mass of 32.2 kDa. Six potential phosphorylation sites are present but no sites of N glycosylation were found. The amino acid sequence of the HCV-OC43 ns2 protein shows 92% identity with that of the Mebus strain of bovine coronavirus (BCV). However, a stretch of nine consecutive amino acids near the C terminus is completely different, causing it to be very hydrophilic, which contrasts with the hydrophobic nature of this region in BCV. As shown by immunofluorescence with a monospecific antiserum, the ns2 protein was expressed in the cytoplasm of HCV OC43-infected HRT-18 cells. PMID- 7844565 TI - Identification of a novel viral protein in infectious bursal disease virus infected cells. AB - Infectious bursal disease virus (IBDV), a member of the Birnaviridae, specifies two genomic double-stranded RNAs, segment A and segment B. Segment A encodes a 110 kDa polyprotein which is processed into virus proteins VP2, VP3 and VP4. A second open reading frame (ORF), designated ORF A-2, immediately preceding and partially overlapping the 110 kDa protein gene has also been described. After prokaryotic expression of this ORF and immunization of rabbits with the expressed protein we obtained reagents that allowed the identification of the ORF A-2 gene product in IBDV-infected cells. The ORF A-2 protein exhibits an apparent molecular mass of 21 kDa which is larger than the size of 16.5 kDa calculated from the deduced amino acid sequence. Immunofluorescence studies demonstrated the presence of the ORF A-2 protein in bursa samples from IBDV-infected chicken. In summary, the IBDV ORF A-2 product represents the fifth IBDV protein described. Therefore, we propose to designate it as IBDV VP5. PMID- 7844566 TI - Interferon-beta strong cytopathic effect on human papillomavirus type 16 immortalized HPK-IA cell line, unexpectedly not shared by interferon-alpha. AB - We report a novel, unusually severe cytopathic effect of interferon-beta (IFN beta). Data concerning antibody neutralization, induction and recovery time course, CPE50 dose, impact on oxidative metabolic activity and 1D SDS-PAGE total cellular protein analysis are provided for preliminary characterization. This cytopathic effect appears to be linked to human papillomavirus type 16 (HPV-16) genome presence as it is markedly evident in the HPV-16-immortalized HPK-IA cell line, but is not induced in diploid keratinocytes. It is also not induced in highly malignant SiHa cells suggesting that it also requires a fairly conserved phenotype. This effect is unexpectedly not shared by IFN-alpha pointing to a discrimination between IFN-alpha and -beta signal despite the well-known sharing of a common receptor. It remains to be clarified whether this divergence, undetectable in other cellular systems, represents a direct effect of viral presence or a non-specific consequence of cellular homoeostatic disregulation induced by the papillomavirus genome. PMID- 7844567 TI - Characterization of human telomeric repeat sequences from human herpesvirus 6 and relationship to replication. AB - Here we examine by polymerase chain reaction amplification followed by cloning and sequence analyses selected regions of the human herpesvirus 6 (HHV-6) genome which contain human telomeric repeats (TTA-GGG). We determine the relative number, arrangement and orientation of the repeats in the unit length genome, in concatemeric replicative intermediates and in heterogeneous (het) regions. We also examine distribution of the repeats in the entire genome (159 kb) and their orientation relative to DNA packaging motifs and the origin of lytic replication. In the prototype orientation the HHV-6 repeat is the related complement, TAACCC. We show that tandem arrays of this repeat are present in the right and left long direct repeats (DRL and DRR, 8 kb each) which bound the long unique sequence (UL, 143 kb). Within each DR there is a left terminal imperfect tandem array and a right terminal perfect tandem array (58 copies). In DR they are each adjacent to DNA packaging motifs, pac1 and pac2, described for herpes simplex virus and human cytomegalovirus, in the arrangement pac1-imperfect repeat-7.2 kb-perfect repeat pac2. Five independent clones were isolated and sequence determined from junctions of concatemeric replicative intermediates which showed adjacent pac2 and pac1 motifs surrounded by telomeric repeats. Favoured cleavage sites for unit length genomes were indicated which avoided cleavage within the repeats. Analyses of the complete genome showed no tandem repeats within UL but did show a polar distribution of monomeric copies and related sequences around the origin of replication, with an effect on the overall base composition. The implications for virus replication are discussed. PMID- 7844568 TI - Efficient infection from cDNA clones of cucumber mosaic cucumovirus RNAs in a new plasmid vector. AB - Full-length cucumber mosaic cucumovirus (CMV) cDNAs were cloned into a new plasmid vector containing a modified plant virus promoter designed to transcribe the inserted sequence from its first nucleotide. cDNA copies of CMV strain Q (Q CMV) genomic RNAs 1, 2 and 3 cloned into this vector were infectious when inoculated together, producing symptoms indistinguishable from those caused by wildtype Q-CMV infection. The infectivity of the clones could be substantially increased by excision of the viral insert together with the transcriptional promoter and terminator prior to inoculation. A diagnostic but silent mutation was introduced into the RNA 2 cDNA and found to be stably maintained in viral infection, allowing distinction of the recombinant virus from native contaminants. The infectious cDNA clones supported the replication of CMV satellite RNA when co-inoculated with biologically active Q-CMV satellite RNA transcripts. Using the infectious cDNAs described, it was found that a newly identified overlapping gene (2b) encoded by Q-CMV RNA 2 was not essential for either systemic viral infection of Nicotiana glutinosa or replication of the satellite RNAs. PMID- 7844569 TI - Nucleotide sequence of tomato ringspot virus RNA1. AB - The nucleotide sequence of tomato ringspot nepovirus (TomRSV) RNA1 has been determined. TomRSV RNA1 is 8214 nucleotides in length, excluding the 3' poly(A) tail, and contains a single long open reading frame (ORF) of 6591 nucleotides beginning at the first AUG codon at nucleotide position 78. This ORF accounts for 80% of the RNA1 sequence and would give rise to a polyprotein with a predicted molecular mass of 244 kDa. Amino acid sequence comparisons between portions of the TomRSV RNA1-encoded polyprotein and proteins encoded by several members of the picornavirus superfamily have provided information concerning the genomic organization and putative functions of TomRSV-encoded proteins. The putative TomRSV protease retains a conserved histidine residue present in the proteases encoded by members of the como-, poty- and poliovirus groups which is thought to be involved in dipeptide cleavage site recognition. Interestingly, this histidine residue is replaced by a leucine in the proteases of other sequenced nepoviruses. This suggests that the TomRSV protease shares dipeptide cleavage site specificity with that of como-, poty- and picornaviruses rather than the other nepoviruses. PMID- 7844570 TI - Sequence analysis of a faba bean necrotic yellows virus DNA component containing a putative replicase gene. AB - Faba bean necrotic yellows virus (FBNYV) has a circular ssDNA genome possibly consisting of several components of about 1 kb each. The complete nucleotide sequence of one component of FBNYV (FBNYV DNA 1) containing a putative replicase gene is presented. This component consists of 1002 nucleotides and, in the virion orientation, contains one large open reading frame (ORF1) potentially encoding a 32.3 kDa replicase with the NTP-binding motif GGEGKS. No obvious functions could be assigned to two smaller ORFs (7.4 and 9.3 kDa) occurring in the complementary orientation. Amino acid sequence comparisons of the putative replicase of FBNYV with that of other similar ssDNA viruses yielded higher homologies to subterranean clover stunt virus than to banana bunchy top and coconut foliar decay viruses. A potential stem-loop structure and a TATA box were identified within the noncoding region. Two oligonucleotides derived from FBNYV DNA 1 were used for direct sequencing of the virion ssDNA to determine its virion polarity and for amplifying part of this component by immunocapture PCR in extracts from from FBNYV-infected plants. PMID- 7844572 TI - Partial posttraumatic stress disorder (PTSD): the issue of psychological scars and the occurrence of PTSD symptoms. PMID- 7844571 TI - Work rehabilitation and improvements in insight in schizophrenia. AB - Research has suggested that impaired insight in patients with schizophrenia is associated with poorer treatment compliance and outcome. Little is known about what forms of treatment can lead to improvements in insight. Research has found that impairments in insight remain stable despite participation in standard treatments. This study examined changes in insight in a sample of 44 subjects with impaired insight who were enrolled in a vocational rehabilitation program. Significant improvements in insight rating were observed for the sample, with a total of 61% of subjects (N = 27) improving. Multiple regression analysis revealed that measures of cognitive impairment (Digit Symbol Subtest Test, Slosson IQ Test, Wisconsin Card Sorting Test) predicted improvement in insight (R2 = .33), with greater levels of cognitive impairments predicting lesser improvement. Psychosocial variables, including concurrent measurements of positive and negative symptoms, were not significant predictors of improvement. These results suggest that vocational rehabilitation can favorably affect insight, particularly for subjects with less severe cognitive deficits. PMID- 7844573 TI - Civil unrest and exacerbation of psychiatric symptoms: a case series. PMID- 7844574 TI - Psychiatric diagnoses of adult male victims of childhood sexual abuse. PMID- 7844575 TI - Generalized dystonia and obsessive-compulsive disorder associated with bilateral circumscribed magnetic resonance signal changes in the putamen. PMID- 7844576 TI - Pseudopregnancy, prenatal, and postpartum psychosis: a case study. PMID- 7844577 TI - Spontaneous seizure after concurrent use of methohexital anesthesia for electroconvulsive therapy and paroxetine: a case report. PMID- 7844578 TI - Acute disseminated encephalomyelitis presenting as an acute psychotic state. PMID- 7844579 TI - The contributions of S. Weir Mitchell (1829-1914): the 100th anniversary of his 1894 address to American psychiatry. PMID- 7844580 TI - Active dependency. AB - Although dependency has long been associated with passivity, weakness, and submissiveness, a review of the empirical literature reveals that, in certain situations and settings, dependent persons actually exhibit a variety of active, assertive behaviors. In this article, I: a) trace the historical roots of the dependency-passivity link; b) review empirical studies from developmental, social, and clinical psychology which indicate that, in certain circumstances, dependency is associated with active, assertive behavior on the part of the dependent person; c) offer an alternative conceptual model of dependency that accounts for the entire range of behaviors-both passive and active-that are exhibited by the dependent person; and d) discuss the diagnostic and therapeutic implications of this alternative conceptual model of dependency. PMID- 7844581 TI - The relationship among stress, depression, locus of control, irrational beliefs, social support, and health in Alzheimer's disease caregivers. AB - This study evaluated the hypothesis that Alzheimer's disease caregivers and control subjects who experienced stressful life events, held the belief that external factors control one's destiny, endorsed irrational beliefs, and had decreased social support would experience more depression and poor health than less stressed individuals who were more internal, had less rigid cognitive beliefs, and had better support. A battery of psychosocial and health measures were administered at baseline and 6 months later. The results suggest that, overall, the experience of marked adversity, increased externality, and the endorsement of irrational beliefs were related to depression and poor health. While diminished social support was not associated with poor health in this study, satisfaction with social support and diminished adherence to irrational beliefs were related to improved ratings of subjective health over time. These findings indicate that psychosocial interventions designed to modify cognitive reactions to stress might improve the quality of life and the physical well being of a population at risk for poor health as a result of their age and life circumstances. PMID- 7844582 TI - Coping styles differ between recovered and nonrecovered women with bulimia nervosa, but not between recovered women and non-eating-disordered control subjects. AB - We examined potential differences in dispositional coping styles among women who had recovered from DSM-III-R bulimia nervosa (RBN; N = 40), women actively suffering from the disorder (N = 40), and women with no history of eating disturbance (control; N = 40). Using a 60-item self-report measure, we found that women with active bulimia nervosa were less likely than the other two groups to utilize active coping, planning, and seeking emotional support, and less likely than the recovering bulimia nervosa group to focus on and vent emotions. They were more likely than control subjects to use behavioral disengagement. On none of the scales did recovered women differ significantly from control subjects. Our findings suggest that the characteristic coping styles of women who have recovered from bulimia nervosa are as adaptive as those with no history of eating disorder, whereas women who are actively bulimic manifest fewer adaptive and more maladaptive coping behaviors. PMID- 7844583 TI - Predictors of depression among male cancer patients. AB - The diagnosis of cancer is often associated with a host of negative emotional responses, including depressed mood. Social support and quality of life were used to predict depression in a sample of older male cancer patients. Depression was found to be a common, but not universal, reaction to the diagnosis and treatment of cancer. Almost 40% of subjects reported symptoms of moderate depression and nearly one fifth produced scores indicative of clinical depression. A stepwise multiple regression analysis revealed that our social support and quality of life measures accounted for 31.5% of the variance in total Beck Depression Inventory scores. Quality of life accounted for more of the variance in depression than did social support. PMID- 7844584 TI - Age-related differences in the symptomatic expression of major depression. AB - Hamilton Rating Scale for Depression and Beck Depression Inventory results were examined in a consecutive series of 174 female and 83 male patients, ranging in age from 18 to 81 years, admitted to a psychiatric hospital with a diagnosis of major depression. Items on the two scales were examined to determine the relationship between age and the symptomatic expression of major depression. Overall scores on the Hamilton scale revealed no relationship with age, but scores for males on the Beck Depression Inventory were negatively associated with age. In addition, the most prevalent types of depressive symptoms showed significant correlations with age. Items related to low self-esteem, such as guilt, sense of failure, self-accusations, and thoughts of suicide, showed a negative relationship with age for both males and females. It is possible that psychological maturation or other age-related factors reduce vulnerability to low self-esteem during episodes of clinical depression; however, selection bias or a cohort effect cannot be ruled out with the current methodology. PMID- 7844585 TI - Comparison of human oxyhemoglobin in lyophilized form, red blood cells, and concentrated solution: the features of Mossbauer spectra and heme iron stereochemistry. AB - Mossbauer spectra of human oxyhemoglobin in red blood cells, concentrated solution, and lyophilized form were measured at 87 K. Additionally, Mossbauer spectra of lyophilized oxyhemoglobin were measured at 295 K. The values of quadrupole splitting appeared to be the same for oxyhemoglobin in red blood cells and concentrated solution and slightly lower than those of oxyhemoglobin in lyophilized form. The asymmetry of the Mossbauer absorption line shapes previously observed for oxyhemoglobin in red blood cells was also found for oxyhemoglobin in concentrated solution. These Mossbauer spectra were better fitted using two quadrupole split doublets with almost equal areas. In contrast, Mossbauer spectra of lyophilized oxyhemoglobin were symmetrical and satisfactorily fitted with one quadrupole split doublet. However, these spectra were also fitted with two quadrupole split doublets with equal areas. The variations of the absorption line shapes and parameters of oxyhemoglobin Mossbauer spectra were analyzed in terms of stereochemical differences of the heme iron and Fe(II)-O2 bond in alpha- and beta-subunits of tetrameric oxyhemoglobin. PMID- 7844586 TI - Synthesis, crystal structure, and biological activity of a Pt-dipyridamole salt. AB - In the present paper we present data on the synthesis, crystal structure and biological activity of bis(dipyridamole) tetrachloroplatinate(II).dipyridamole.dihydrate, [dpmH]2 PtCl4.dpm.2H2O. The crystals are Triclinic P1 with a = 11.490(2) A, b = 13.630(2) A, c = 15.81(1) A, a = 100.97(2) degrees, beta = 100.89(3) degrees, gamma = 112.35(1) degrees, Z = 1, M = 1885.9, Dx = 1.46 g/cm3, MoK alpha (lambda = 0.71069 A), mu = 0.0184 mm-1, R = 4.4%, Rw = 5.0%, 3231 (1 > 2 sigma (I)). The structure is stabilized by a hydrogen-bonding network. It was observed that although dpm alone is not able to alter the electrophoretic mobility of pUC8 DNA forms, the synthesized Pt-dpm compound substantially modifies the DNA conformation since it significantly alters the electrophoretic mobility of nicked and closed circular forms of pUC8 DNA. However, the alteration in mobility of pUC8 DNA induced by this compound upon binding is lower than that induced by cis-DDP. The analysis of the antiproliferative activity of the Pt-dpm salt against MDA-MB 468 (breast carcinoma) and HL-60 (leukemia) human cancer cells showed that this compound has ID50 values of 0.87 microM and 0.65 microM, respectively. Interestingly, it was found out that although the dpm molecule does not present any significant antiproliferative activity, the ID50 values of Pt-dpm are about 3-fold and 7-fold lower than those of cis-DDP and K2PtCl4, respectively. Altogether the biological data suggest that in Pt-dpm a synergic effect between cation and anion is produced. PMID- 7844587 TI - Complexes of azathioprine, a biologically active mercaptopurine derivative, with Pt(II), Pd(II), Rh(III), Ru(III) and Ag(I). AB - In order to possibly elucidate the prevailing factors determining the binding sites in the interactions of azathioprine (AZAH), a biologically active 6 mercaptopurine derivative, with the platinum group and other heavy metals, we probed the binding sites of AZAH with Pt(II), Pd(II), Rh(III), Ru(III), and Ag(I) by using 1H and 195Pt NMR, ESR, and IR spectroscopic techniques as well as magnetic susceptibility measurements and mass spectrometry. The altered coordination behavior of AZAH with respect to the parent 6-mercaptopurine, with sulfur no longer being the primary binding site, was ascertained. In the Pt(II), Rh(III), and Ru(III) complexes, 1H NMR data imply coordination of the metal through the N(3) and N(9) positions of the purine ring, while in the case of the Pt(II) compound, 195Pt NMR data further ascertain AZAH binding in a bridging mode through ring nitrogens. As opposed to the aforementioned metals, in the Pd(II) and Ag(I) compounds, 1H NMR data suggest binding via the N(9) position of deprotonated AZAH. Conductivity measurements for all compounds, except for that of Pt(II), showed a nonelectrolyte behavior in solution; the presence of ionic nitrate in the Pt(II) compound was further ascertained by IR spectroscopy. The coordination sphere of the metal in the cases of the Pt(II) and Pd(II) compounds is completed by ammonia and water molecules, respectively, while in those of the Rh(III) and Ru(III) compounds is completed by chloride bridge. For the Ru(III) compound, the latter is confirmed by magnetic susceptibility measurements. PMID- 7844588 TI - The interaction of colloidal metals with erythrocytes. AB - The interactions of citrate reduced colloids (Ag, Au, and Bi) with intact erythrocytes and erythrocyte lysate have been studied by 1H spin echo NMR. Silver colloid is observed to induce cellular depletion of cytosolic glutathione and bismuth colloid induces cytosolic glutathione oxidation in the intact cell. In comparison, there is no detectable effect with gold colloid. With red cell lysate the three colloids all remove glutathione from the spectrum. The metal salts AgNO3 and NaAuCl4 both oxidize intracellular glutathione to diglutathione whereas BiO(NO3) has no effect. Thus colloidal preparations have a different reactivity to their parent metal salts. The differences observed between the three types of colloids (silver, gold, and bismuth) are unique to the colloids studied. None of the colloids studied were biologically inert in the erythrocyte model used. PMID- 7844589 TI - 26th Meeting of the American Society for Neurochemistry. Santa Monica, California, March 5-9, 1995. Abstracts. PMID- 7844590 TI - Ifosfamide: should the honeymoon be over? PMID- 7844591 TI - CNS leukemia: problem of diagnosis, treatment, and outcome. PMID- 7844592 TI - Docetaxel is a major cytotoxic drug for the treatment of advanced breast cancer: a phase II trial of the Clinical Screening Cooperative Group of the European Organization for Research and Treatment of Cancer. AB - PURPOSE: This trial investigated the toxicity and efficacy of docetaxel as first line chemotherapy in women with heavily pretreated advanced breast cancer. PATIENTS AND METHODS: From April 1992 to August 1992, 35 patients with advanced breast cancer from 29 to 65 years of age with a performance status of 0 to 2 were entered onto the study. Docetaxel 100 mg/m2 was administered every 3 weeks as a 1 hour infusion on day 1 without routine premedication for hypersensitivity reactions. Thirty-one patients were assessable for response. Previous adjuvant chemotherapy had been given to 11 patients. RESULTS: Five complete responses (CRs) and 16 partial responses (PRs) were observed, for an overall response rate of 67.7% (95% confidence interval, 49% to 83%). A CR occurred at 13 of 45 assessable sites (four liver, two lung, three breast, three lymph node, and one skin). The median duration of response was 44+ weeks, the median time to disease progression 37+ weeks, and the median overall survival time 16+ months. Among 34 patients assessable for toxicity (177 cycles; median, five cycles per patient), the following side effects were reported: nadir neutropenia grade 3 (three patients); grade 4 (31 patients); no grade 3 to 4 infection, acute hypersensitivity-like reaction (10 patients); grade 2 to 3 alopecia (all patients); and grade 2 to 3 nausea and vomiting (six patients). Fluid retention occurred in 26 patients and consisted of weight gain, edema alone (15 patients), or edema associated with serous effusion (11 patients). This side effect led to treatment discontinuation in 16 of 21 responding patients after a median of five cycles and a median cumulative dose of docetaxel of 574 mg/m2. CONCLUSION: Our data suggest that docetaxel has major antitumor activity when used as a single cytotoxic agent as first-line chemotherapy in advanced breast cancer. PMID- 7844593 TI - Maximum-tolerated doses of ifosfamide, carboplatin, and etoposide given over 6 days followed by autologous stem-cell rescue: toxicity profile. AB - PURPOSE: A phase I dose-escalation study of ifosfamide, carboplatin, and etoposide (ICE) with autologous stem-cell rescue (ASCR) was conducted to determine the maximum-tolerated dose (MTD) of ICE given over 6 days. PATIENTS AND METHODS: One hundred fifty-four patients with a variety of poor-prognosis malignancies received escalating doses of ifosfamide 6,000 to 24,000 mg/m2, carboplatin 1,200 to 2,100 mg/m2, and etoposide 1,800 to 3,000 mg/m2 divided over 6 days. Mesna was administered in a dose equal to ifosfamide. ASCR was performed 48 hours after the completion of ICE. The source of stem cells was bone marrow (BM) in patients without BM micrometastases and peripheral-blood stem cells (PBSC) in patients with BM micrometastases. Patients were evaluated for hematologic and nonhematologic toxicities, as well as response to therapy. RESULTS: The MTD of the ICE regimen is 20,100 mg/m2 of ifosfamide, 1,800 mg/m2 of carboplatin, and 3,000 mg/m2 of etoposide. The dose-limiting toxicities of ICE were CNS toxicity and acute renal failure. Additionally, reversible elevations of serum creatinine levels were noted in 29% of patients treated at the upper dose levels. Forty-six patients were treated at the MTD. Severe, reversible mucositis and enteritis were the major nonhematologic toxicities seen at the MTD (78% and 33%, respectively). The overall mortality rate was 8% for all dose levels (4% at the MTD). At the MTD, the median times to an absolute neutrophil count > or = 0.5 x 10(9)/L, to a platelet count > or = 20 x 10(9)/L, and to discharge were 18, 22, and 24 days, respectively. The overall response rate was 40% for 77 patients with assessable disease at the time of treatment. CONCLUSION: ICE is well tolerated, with acceptable hematopoietic side effects and predictable organ toxicity. PMID- 7844594 TI - An intensive re-treatment protocol for children with an isolated CNS relapse of acute lymphoblastic leukemia. AB - PURPOSE: To assess the salvage rate and long-term complications among children treated with an intensive regimen for isolated CNS relapse during first remission of acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Twelve boys and eight girls, diagnosed at a median age of 4 years, had CNS relapse at a median age of 7 years. Five had CNS leukemia at presentation, while five completed treatment before relapse. First complete remission lasted a median of 22.5 months. Ten patients had received cranial irradiation plus intrathecal (IT) therapy, and the remainder had received high-dose intravenous and/or IT methotrexate (MTX) as CNS-directed treatment. Retrieval therapy consisted of a five-agent intensive reinduction regimen followed by continuation therapy with four rotating drug pairs. Triple-IT therapy was administered weekly for 4 to 5 weeks, then every 6 weeks until craniospinal radiation (cranium, 24 Gy; spine, 15 Gy; both sites, 1.5 Gy per fraction) was administered. RESULTS: All 20 children achieved a second complete remission. The 5-year estimate of disease-free survival (mean +/- SE) was 70% +/- 11%. Thirteen patients remain in remission at 71+ to 126+ months (median, 104+), and 10 of 13 patients tested have normal IQ scores. Four patients have had a second relapse (one CNS and three non-CNS), and three have developed other malignancies. Prior cranial irradiation was associated with subsequent failure; only three of 10 patients who previously received radiotherapy, compared with all of the other 10 patients, remained in second remission. CONCLUSION: This intensive retrieval therapy is effective and well tolerated by children with an isolated CNS relapse of ALL, especially those who have not received prior cranial irradiation. Most patients have no significant neuropsychologic impairment. PMID- 7844595 TI - Levels of L-asparagine in CSF after intramuscular administration of asparaginase from Erwinia in children with acute lymphoblastic leukemia. AB - PURPOSE: As part of a study on the pharmacokinetics associated with the administration of asparaginase (ASNase) from Erwinia to the CNS, we determined the levels of asparagine in the CSF of children with acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Twenty children received eight standard doses of intramuscular ASNase (10,000 IU/m2) every 3 days as part of induction therapy. In the postremission phase of therapy, the children were randomized to receive either 20 courses of high-dose intramuscular ASNase (25,000 IU/m2) weekly (n = 8) or four courses of standard-dose intramuscular ASNase (10,000 IU/m2) every 3 days (n = 12). RESULTS: All patients had detectable levels of L-asparagine in the CSF at the time of diagnosis. The levels of L-asparagine in CSF were undetectable in 15 of 20 (75%) and in seven of 19 (36.8%) children 3 and 5 days, respectively, after administration of standard-dose ASNase. After administration of high-dose ASNase, the levels of L-asparagine in the CSF were undetectable in five (62.5%) and two (25%) of eight children after 3 and 5 days, respectively. CONCLUSION: In this study 60% to 70% and 25% to 35% of children had complete depletion of L asparagine from the CSF after 3 and 5 days, respectively, after administration of both schedules of ASNase from Erwinia. In the remaining patients, administration of ASNase may have resulted in a suboptimal antileukemic effect at the CNS level. PMID- 7844596 TI - Treatment of childhood acute lymphoblastic leukemia in second remission with allogeneic bone marrow transplantation and chemotherapy: ten-year experience of the Italian Bone Marrow Transplantation Group and the Italian Pediatric Hematology Oncology Association. AB - PURPOSE: To compare the results of allogeneic bone marrow transplantation (AlloBMT) with those obtained with chemotherapy (CHEMO) in children with acute lymphoblastic leukemia (ALL) in second complete remission (CR) after a marrow relapse. The experience of the Italian Bone Marrow Transplantation Group and the Italian Pediatric Hematology Oncology Association is summarized. PATIENTS AND METHODS: All children who had a relapse in the period 1980 to 1989 in 27 centers in Italy were eligible for the study. Of 287 eligible patients, 230 were treated with CHEMO, most of them (93%) according to a standard multiple-drug relapse protocol. The remaining 57 children underwent AlloBMT. Preparative regimens included total-body irradiation and chemotherapy (n = 51) or chemotherapy alone (n = 6). Statistical analysis was performed with a Cox regression model adjusting for waiting time to transplant and prognostic factors. RESULTS: In the whole series, minimum and median follow-up after second CR were 3 and 6.2 years, respectively; at 8 years from second CR, disease-free survival (DFS) was 20.0% (SE 2.5) and survival was 26.4% (SE 2.9). In the group of patients with an early first relapse, DFS was significantly longer after AlloBMT than after CHEMO (relative risk [RR] = 0.45, P = .002). No significant advantage of AlloBMT over CHEMO was found for patients with a late relapse (> 30 months since diagnosis). Duration of first CR significantly influenced prognosis in the CHEMO group (RR = 0.32, P = .0001 for patients with late first relapse versus patients with early first relapse). CONCLUSION: Results suggest an advantage in DFS of AlloBMT over CHEMO in ALL patients who experienced an early first medullary relapse. Prospective trials are needed to address efficacy of AlloBMT versus CHEMO in patients with late bone marrow relapse. PMID- 7844597 TI - Non-Hodgkin's lymphomas of childhood and adolescence: results of a treatment stratified for biologic subtypes and stage--a report of the Berlin-Frankfurt Munster Group. AB - PURPOSE: To prove the efficacy of a treatment stratified according to histology for children with non-Hodgkin's lymphoma (NHL), including acute B-cell leukemia (B-ALL). PATIENTS AND METHODS: From October 1986 to March 1990, 302 assessable patients, 0.6 to 17.8 years of age, with newly diagnosed NHL were enrolled onto study ALL/NHL-BFM 86. Fifty percent of patients had Burkitt-type lymphomas, including B-ALL; 24% had lymphoblastic lymphoma; 18% had diffuse large-cell lymphoma; and 8% had an NHL not further classified. Therapy group B included Burkitt's-type lymphomas, B-ALL, and most large-cell lymphomas including Ki-1 anaplastic large-cell lymphoma. Patients with stage I and II disease resected received three, while all others received six, 5-day therapy courses (dexamethasone, methotrexate [MTX] 0.5 g/m2 [5 g/m2 for stage IV and B-ALL], and intrathecal [IT] therapy in each course, plus ifosfamide, cytarabine, and etoposide alternating with cyclophosphamide and doxorubicin). Therapy for group non-B patients (lymphoblastic lymphoma and pleomorphic T-cell lymphoma [PTCL]) consisted of a Berlin-Frankfurt-Munster (BFM) acute lymphoblastic leukemia protocol, including cranial irradiation for advanced stage. Local therapy was restricted to patients with incomplete tumor regression. RESULTS: The probabilities of event-free survival (pEFS) at 7 years were 80% +/- 2% for the whole group, 81% +/- 3% for group B (n = 225), and 78% +/- 5% for group non-B (n = 77) with a follow-up duration of 3.6 to 7 years (median 5 years). Treatment results were comparable between NHL subtypes, except for PTCL, in which three of four patients suffered from relapse. Local disease manifestations were the most frequent site of failure. CONCLUSION: This therapy strategy provided patients of all NHL subtypes with an equally high chance to survive event-free, except patients with PTCL. With reduced systemic failure, local tumor control may become more important. PMID- 7844598 TI - CD30 (Ki-1)-positive anaplastic large-cell lymphomas in 13 patients with and 27 patients without human immunodeficiency virus infection: the first comparative clinicopathologic study from a single institution that also includes 80 patients with other human immunodeficiency virus-related systemic lymphomas. AB - PURPOSE: CD30 (Ki-1)-positive anaplastic large-cell lymphoma (Ki-1 ALCL) rarely has been described in patients with human immunodeficiency virus (HIV) infection. The purpose of this study was to characterize further the clinicopathologic features of Ki-1 ALCL in patients with HIV infection and, for the first time, to make a comparison with Ki-1 ALCL in patients without HIV infection. PATIENTS AND METHODS: From September 1987 to April 1993, 93 patients with HIV infection and systemic non-Hodgkin's lymphoma (NHL) were treated at the Cancer Center of Aviano, Italy; in 13 (14%), the diagnosis was of Ki-1 ALCL subtype. This group of patients was compared with the remaining 80 patients who had other HIV-related NHL and with another group of 27 patients with Ki-1 ALCL who were without a diagnosis of HIV infection. RESULTS: There was no case of a T-cell phenotype in the 13 HIV-positive Ki-1 ALCL patients, whereas there was such a phenotype in six of 27 (22%) HIV-negative Ki-1 ALCL patients. In regard to the general characteristics of the two groups with Ki-1 ALCL, more patients with stage IV, two or more extranodal sites at presentation, treatment-related leukopenia, and opportunistic infections as the cause of death were observed in the HIV-positive Ki-1 ALCL group. When these variables were compared with those of the other HIV related NHL group, such differences were not present. CONCLUSION: Ki-1 ALCL is not a rare clinicopathologic entity among NHL in patients with HIV infection. The differences observed within the two Ki-1 ALCL groups of patients may be because of factors related to the HIV infection alone. PMID- 7844599 TI - Evaluation of the efficacy of the VEEP regimen in adult Hodgkin's disease with assessment of gonadal and cardiac toxicity. AB - PURPOSE: The aim of this phase II study was to investigate the potential of the vincristine, epirubicin, etoposide, and prednisolone (VEEP) regimen to reduce the risks of long-term sequelae of chemotherapy such as sterility, cardiopulmonary damage, and second malignancies, while maintaining efficacy in terms of response and survival. PATIENTS AND METHODS: Eighty-five adult patients with newly diagnosed and previously untreated stage II to IV Hodgkin's disease (HD) were entered and monitored for a minimum of 1 year. Patients were treated to maximum response plus two further courses, and if they had not attained a complete response (CR) or CR-unconfirmed/uncertain [CR(u)] were changed to second-line chemotherapy. Adjuvant radiotherapy was administered to patients with bulky disease and those with postchemotherapy residual masses. Measurements of left ventricular ejection fraction (LVEF), gonadotropins in females, and sperm count in males were taken both before and after treatment with VEEP. RESULTS: The maximum rates of response were as follows: CR, 32%; CR(u), 47%; and PR, 21% [CR + CR(u), 79%]. The median follow-up duration is 45 months, with a 5-year overall survival (OS) rate of 89% and failure-free survival (FFS) rate of 62%. Patients in CR at the end of chemotherapy had a higher FFS at 5 years compared with patients in CR(u) (88% v 56%). Acute toxicity was mild, with no pulmonary toxicity or treatment-related deaths. The median LVEF was 62% before VEEP and 57% after VEEP. Gonadal function tests following treatment were normal in 92% of males and 100% of females. No second malignancies have been observed. CONCLUSION: VEEP is an active combination with tolerable acute toxicity that preserves fertility and cardiopulmonary function. The efficacy of VEEP is comparable to that of established regimens, but a definitive evaluation of its potential to reduce second malignancies will require a longer follow-up duration. PMID- 7844600 TI - Mini-BEAM as salvage therapy for relapsed or refractory Hodgkin's disease before intensive therapy and autologous bone marrow transplantation. AB - PURPOSE: To evaluate the efficacy of carmustine (BCNU), etoposide, cytarabine (Ara-C), and melphalan (mini-BEAM) as salvage therapy in patients with relapsed or refractory Hodgkin's disease who were potentially eligible to undergo intensive therapy and autologous bone marrow transplantation (ABMT). PATIENTS AND METHODS: Forty-four patients with refractory or relapsed Hodgkin's disease after front-line combination chemotherapy referred for consideration of ABMT were treated with mini-BEAM (BCNU 60 mg/m2 on day 1, etoposide 75 mg/m2 on days 2 to 5, Ara-C 100 mg/m2 twice per day on days 2 to 5, and melphalan 30 mg/m2 on day 6) to maximum response. Eleven patients were refractory to primary chemotherapy. Twenty-three patients were treated in first relapse and 10 in second or subsequent relapse; 21 received mini-BEAM as their first salvage regimen. Patients were restaged to determine disease status immediately before intensive therapy and transplant. RESULTS: The overall response rate was 84% (exact 95% confidence interval [CI], 70% to 92%), with a complete response (CR) rate of 32% (95% CI, 20% to 47%) and a partial response (PR) rate of 52%. No treatment related deaths were observed. Myelosuppression was the major toxicity. Almost all patients required platelet transfusions. Eighty-four percent were given RBC transfusions, and 54% required intravenous antibiotics for fever while neutropenic. CONCLUSION: Mini-BEAM is a safe and effective regimen for treatment of refractory or relapsed Hodgkin's disease. Further studies are required to determine if responding patients have improved disease-free survival (DFS) after intensive therapy and ABMT. PMID- 7844601 TI - Bone marrow involvement in Hodgkin's disease: an analysis of 135 consecutive cases. German Hodgkin's Lymphoma Study Group. AB - PURPOSE: To describe the incidence of primary bone marrow involvement (BMI) in Hodgkin's disease (HD) and its correlation with clinical and laboratory features present at diagnosis, and to evaluate the prognostic relevance of BMI. PATIENTS AND METHODS: Between 1983 and 1991, 2,307 patients with HD were treated according to two trial generations (HD1-3 and HD4-6) of the German Hodgkin's Lymphoma Study Group (GHSG). RESULTS: One hundred thirty-five cases of primary BMI were observed. The incidence of BMI was 4.8% in the HD4-6 study generation, which included all stages. Among stage IV patients, 32% had BMI. Among those with BMI, other organs were also involved in 33%. Among all patients, the presence of BMI was significantly associated with B symptoms, lymph nodes on both sides of the diaphragm, mixed cellularity histologic subtype, leukocytopenia, anemia, thrombocytopenia, lactate dehydrogenase (LDH) level more than 400 U/L, and erythrocyte sedimentation rate (ESR) more than 40 mm/h. BMI was negatively correlated with a large mediastinal tumor (3.7% v 20.0% in non-BMI cases). Eighty seven of 108 (81%) assessable patients with BMI achieved a complete remission (CR). This compares favorably with the overall CR rate in all stage IIIB/IV patients. Among stage IV patients, BMI has no prognostic relevance with regard to freedom from treatment failure and overall survival. Twenty-one patients with BMI relapsed after having achieved a CR. Only five of these (24%) again had a positive bone marrow biopsy. CONCLUSION: The prognosis of patients with BMI is not worse than the prognosis of other advanced-stage HD patients. BMI alone does not define a special high-risk group in which a different treatment approach is indicated. PMID- 7844603 TI - Rapid in vitro assay for predicting response to fluorouracil in patients with metastatic breast cancer. AB - PURPOSE: To determine if a rapid 3H-uridine uptake assay using breast tumor cells from biopsy specimens could predict clinical response to fluorouracil (5FU) in patients with metastatic breast cancer. PATIENTS AND METHODS: A double-blind prospective study was conducted of 60 patients with measurable, metastatic breast cancer who had failed to respond to at least one prior chemotherapy regimen. Patients received 5FU 300 mg/m2/d by continuous infusion and were monitored for response. Tumor cells from biopsy specimens were grown in microwells and exposed for 3 days to 0.1, 1.0, 10.0, and 100.00 micrograms/mL of 5FU on strips coated with drug and extracellular matrix. Cells were pulsed with 3H-uridine overnight. Incorporated radioactivity was compared for wells with and without drug. Results were available 4 days from specimen submission. RESULTS: Of 45 eligible patients, 11 (24%) were not assessable in vitro. Nine patients were assessable in vitro, but not clinically. Of the remaining 25 patients, who were assessable both clinically and in vitro, there was one complete response (CR), five partial responses (PRs), five cases of stable disease, and 14 cases of progressive disease, for an objective response rate of 24%. Response in vitro was significantly correlated with clinical response (P = .002). Of six clinical responders, five also responded in vitro, for an assay sensitivity of 83%. Of 19 nonresponders, 17 were nonresponders in vitro, for a specificity of 89%. The positive predictive value of the test was 71% (five of seven), and the negative predictive value was 94% (17 of 18). CONCLUSION: Results of an in vitro assay were significantly correlated with clinical response in patients with metastatic breast cancer treated with continuous infusion 5FU. PMID- 7844602 TI - Clinical application of retroviral gene transfer in oncology: results of a French study with tumor-infiltrating lymphocytes transduced with the gene of resistance to neomycin. AB - PURPOSE: Adoptive immunotherapy with tumor-infiltrating lymphocytes (TIL) and interleukin-2 (IL-2) has been reported to mediate tumor regression in some human cancers. To define better the biologic characteristics of TIL, especially survival and distribution in vivo, we performed a gene-marker study in patients with advanced malignancies. PATIENTS AND METHODS: We treated five patients with metastatic melanoma or renal cell carcinoma with adoptive immunotherapy. TIL were genetically modified, before their infusion, using a recombinant retroviral vector that contained the marker gene coding for resistance to neomycin (NeoR). RESULTS: All of the patients tolerated the treatment well and none of the theoretic safety hazards due to the retroviral gene transduction was observed. The presence of the NeoR gene in TIL was detected by Southern blot analysis, with an efficiency of transduction that ranged from 1% to 26%. With polymerase chain reaction (PCR) analysis, we demonstrated that gene-modified TIL can survive for several months after reinjection, since positive blood samples were observed up to day 260 following reinjection. Eight malignant biopsy specimens were obtained from three patients after cell infusion. TIL were detected in only four of these eight tumor deposits on days 7 and 260. CONCLUSION: These results confirm the feasibility and safety of using in vitro retroviral gene transduction in human lymphocytes to analyze their in vivo distribution for further therapeutic applications. However, a selective and prolonged retention of TIL at the tumor site was not found in this study. PMID- 7844604 TI - High complete remission rates with primary neoadjuvant infusional chemotherapy for large early breast cancer. AB - PURPOSE: To investigate the efficacy of continuous infusion fluorouracil (5FU) with every-3-week epirubicin and cisplatin (ECF) as primary chemotherapy instead of immediate mastectomy for patients with large, potentially operable, breast cancer. PATIENTS AND METHODS: Fifty patients with large operable breast cancer, median tumor diameter 6 cm (range, 3 to 12), were treated with 5FU 200 mg/m2/d via a Hickman line using an ambulatory pump for 6 months with epirubicin 50 mg/m2 intravenously (IV) and cisplatin 60 mg/m2 IV every 3 weeks for eight courses. Subsequent surgery and/or radiotherapy was determined by clinical response. RESULTS: Forty-nine patients achieved an overall response (98%; 95% confidence interval [CI], 94% to 100%), including 33 complete clinical remissions (CRs) (66%; 95% CI, 53% to 79%). Only three patients (6%) still required mastectomy. Tumor cellularity was markedly reduced on repeat needle biopsy following 3 weeks of treatment in 81% of patients versus only 36% in similar patients after conventional chemotherapy (P < .002). Severe (World Health Organization [WHO] grade 3 to 4) toxicity was rare, with nausea/vomiting being the most common, occurring in 20% of patients. CONCLUSION: Primary infusional ECF appears to be more active on clinical and histopathologic grounds than conventional chemotherapy for large operable breast cancer and is well tolerated. This approach now merits randomized comparison to determine if high CR rates may translate into improved survival. PMID- 7844605 TI - Influence of prior and subsequent pregnancy on breast cancer prognosis. AB - PURPOSE AND METHODS: The prognostic influence of pregnancies 5 years before (n = 173) and after (n = 50) breast cancer diagnosis was investigated in 2,119 women less than 50 years of age with a primary operable breast cancer. The main end point was distant metastasis. Univariate and multivariate analyses were performed using the Cox proportional hazards model. In the analyses of the effect of pregnancy after diagnosis of breast cancer, a Cox model with a time-dependent covariate was applied. RESULTS: Women with a pregnancy before diagnosis had slightly larger tumors than the control group. However, they did not differ with respect to nodal status and estrogen receptor (ER) status. There was no evidence that women with a pregnancy during the 5-year period preceding breast cancer diagnosis had a worse prognosis compared with women without pregnancy during the same period. Similarly, there was no evidence that women with a pregnancy after breast cancer diagnosis had a worse prognosis. CONCLUSION: The hormonal changes associated with pregnancy thus seem to have little, if any, influence on the prognosis of breast cancer. In the present study, at least, there was no indication of a worse prognosis. In fact, the relative hazard for women who became pregnant after diagnosis of breast cancer in comparison with women without a subsequent pregnancy was 0.48 (P = .14), which suggested a possible decreased risk of distant dissemination. PMID- 7844606 TI - Combined chemotherapy and radiotherapy for patients with breast cancer and extensive nodal involvement. AB - PURPOSE: This retrospective review examines local control, freedom from distant failure, and survival for patients with nonmetastatic breast cancer with extensive nodal disease (> 10 nodes, 45 patients; or > or = 70% involved nodes, if < 10 nodes found, 19 patients). All patients received chemotherapy and radiotherapy following mastectomy. PATIENTS AND METHODS: Sixty-four patients were treated between January 1980 and December 1988 at Westmead Hospital, Westmead, NSW Australia. The median follow-up duration for surviving patients was 91.5 months (range, 56 to 121). The median age was 51 years, and the median number of positive nodes was 11. Four successive protocols evolved, each with three phases, as follows: induction chemotherapy (doxorubicin or mitoxantrone, plus cyclophosphamide; three cycles), radiotherapy (50 Gy in 25 fractions to chest wall and regional nodes), then chemotherapy (cyclophosphamide, methotrexate, and fluorouracil [CMF]) of progressively shorter duration. Radiotherapy and chemotherapy were concurrent in the fourth regimen. RESULTS: One patient (1.5%) developed local recurrence before distant relapse, and seven patients (11%) developed local and/or regional recurrence simultaneously or after distant relapse. The 5-year actuarial freedom from distant relapse and overall survival rates were 45% and 65%, respectively. Overall survival did not vary significantly by menopausal status, nodal subgroup, or dose-intensity. There were no treatment related deaths. CONCLUSION: Combined chemotherapy and radiotherapy in standard dosage is an acceptable approach following mastectomy for patients with extensive nodal involvement at high risk for local recurrence and distant relapse. This approach should be considered standard best therapy for any randomized trials that examine high-dose chemotherapy or bone marrow transplantation for this subgroup of patients. PMID- 7844607 TI - Randomized trial of epirubicin and cisplatin chemotherapy followed by pelvic radiation in locally advanced cervical cancer. Cervical Cancer Study Group of the Asian Oceanian Clinical Oncology Association. AB - PURPOSE: Pelvic radiation is standard treatment for women with stage IIb to IVa cervical cancer, but treatment results are disappointing, particularly for women with bulky tumors. We investigated the role of primary chemotherapy followed by pelvic radiotherapy in a randomized trial. PATIENTS AND METHODS: Two hundred sixty patients with stage IIb and IVa cervical cancer received either standard pelvic radiotherapy or primary chemotherapy with cisplatin 60 mg/m2 and epirubicin 110 mg/m2 administered at 3-week intervals for three cycles, followed by pelvic radiotherapy. RESULTS: Ninety-nine patients have relapsed with a median follow-up duration of 1.3 years; in 62 patients, the first site of progressive disease was the pelvis. Patients who received primary chemotherapy had a significantly higher pelvic failure rate than those who received radiotherapy alone (P < .003). Seventy-six patients have died, and those who received primary chemotherapy had significantly inferior survival compared with those who received radiotherapy alone (P = .02). Tumor response following chemotherapy was observed in 63%. After radiotherapy, tumor response occurred in 72% of those who received combined modality treatment, compared with 92% of those who received radiotherapy alone. CONCLUSION: Primary chemotherapy with epirubicin and cisplatin, although resulting in tumor response in a significant proportion of patients, is accompanied by an inferior local control rate and survival compared with standard pelvic radiotherapy alone. PMID- 7844608 TI - Randomized trial of hyperfractionated radiation therapy with or without concurrent chemotherapy for stage III non-small-cell lung cancer. AB - PURPOSE: To investigate the efficacy of combined hyperfractionated radiation therapy (HFX RT) and concurrent chemotherapy (CHT) in stage IIIA or IIIB non small-cell lung cancer (NSCLC) compared with that of HFX RT alone. PATIENTS AND METHODS: Between January 1988 and December 1989, 169 patients were divided randomly into the following groups: group I, HFX RT with 1.2 Gy twice daily to a total dose of 64.8 Gy (n = 61); group II, same HFX RT with CHT consisting of 100 mg of carboplatin (CBDCA) on days 1 and 2 and 100 mg of etoposide (VP-16) on days 1 to 3 of each week during the RT course (n = 52); and group III, same HFX RT with CHT consisting of 200 mg of CBDCA on days 1 and 2 and 100 mg of VP-16 on days 1 to 5 of the first, third, and fifth weeks of the RT course (n = 56). RESULTS: The median survival time (MST) was 8 months for group I, 18 months for group II, and 13 months for group III. The 3-year survival rates were 6.6%, 23%, and 16%, respectively. There was a significant difference in the survival rate between groups I and II (P = .0027, log-rank test), but not between groups I and III (P = .17) or between groups II and III (P = .14). The relapse-free survival rate in group II was also higher than that in group I (P = .0024), which was largely due to improved local control in group II patients. Patients in groups II and III showed a higher incidence of acute and/or late high-grade toxicity compared with group I patients, but no patient died of treatment-related toxicity. CONCLUSION: The combination of HFX RT and continuous CBDCA/VP-16 CHT was tolerable and substantially increased the survival rate. PMID- 7844609 TI - Phase I trial of escalating doses of interleukin-1 beta in combination with a fixed dose of interleukin-2. AB - PURPOSE: Interleukin-1 (IL-1) and IL-2 have synergistic antitumor and myelostimulatory activities. We investigated the clinical and biologic effects of IL-1/IL-2 therapy. PATIENTS AND METHODS: Twenty patients with metastatic cancer, divided into five cohorts, were treated with escalating doses of IL-1 beta (0.005 to 0.2 micrograms/kg/d) administered as a 30-minute intravenous (IV) infusion on days 1 to 4, combined with a fixed dose of IL-2 (0.1 mg/m2/d) administered by continuous IV infusion on days 1 to 4. The 4-day cycles were repeated weekly for up to 8 weeks in the absence of toxicity and/or progressive disease. RESULTS: Patients tolerated up to 0.2 microgram/kg/d of IL-1 beta in combination with IL-2 without severe adverse effects. Peripheral-blood CD4-to-CD8 ratios and lymphokine activated killer (LAK) activity were higher at the lower doses (0.005 to 0.05 microgram/kg/d) of IL-1 beta and higher than that of a cohort of patients treated with IL-2 alone. WBC counts, primarily neutrophils, increased significantly with higher doses of IL-1 beta (0.1 to 0.2 microgram/kg/d). Platelet counts were not significantly altered. Increases in serum IL-6, interferon gamma (IFN-gamma), and soluble IL-2 receptor levels were observed, but did not vary with IL-1 beta dose. Tumor regressions were observed in patients with colorectal cancer, melanoma, and renal cell carcinoma. CONCLUSION: IL-1 beta cancer be administered in combination with IL-2 with acceptable toxicity. Our results suggest that the addition of even low-dose IL-1 beta to IL-2 may be associated with potentially beneficial biologic activity; higher doses of IL-1 beta (0.1 to 0.2 microgram/kg/d) may add potentially beneficial hematologic activity. PMID- 7844610 TI - Randomized placebo-controlled multicenter evaluation of diethyldithiocarbamate for chemoprotection against cisplatin-induced toxicities. AB - PURPOSE: Diethyldithiocarbamate (DDTC) blocks cisplatin-induced toxicities in animal models without inhibiting antitumor effects. DDTC chemoprotection was tested in a randomized, multicenter, double-blind comparison versus placebo (PB) in patients with lung or ovarian cancer. Primary end points were nephrotoxicity, ototoxicity, neuropathy, and completion of therapy. PATIENTS AND METHODS: Between April 1990 and February 1992, 221 patients were registered with small-cell lung cancer (SCLC), non-small-cell lung cancer (NSCLC), or ovarian cancer. Cisplatin (100 mg/m2) and cyclophosphamide (in ovarian cancer) or etoposide (in lung cancer) were administered with either DDTC (1.6 g/m2 over 4 hours) or PB intravenously, every 4 weeks for a planned six cycles. RESULTS: At an interim safety analysis, data were available for 195 patients from the combined lung and ovarian cancer populations (PB, 99 patients; DDTC, 96 patients). Withdrawal for chemotherapy-induced toxicities occurred in 9% of PB-treated patients and 23% of DDTC-treated patients (P = .008). The mean cisplatin delivered dose-intensity (DDI) was 23 mg/m2/wk on both arms. However, the mean cisplatin cumulative dose delivered (CDD) was 379 mg/m2 on the PB arm, compared with 247 mg/m2 on the DDTC arm (P = .0001). At the time of interim analysis, 28% of PB-treated patients had completed all six cycles of therapy, compared with only 6% of DDTC-treated patients (P < .001). Although, clinical hearing loss, neuropathy, emesis, and myelosuppression were equivalent in the two treatment arms, DDTC-treated patients had more nephrotoxicity as determined by changes in serum creatinine concentration. Toxicities related to DDTC infusion included transient hypertension, flushing, and hyperglycemia. DDTC did not compromise response rates in either tumor type. CONCLUSION: This study did not demonstrate a significant chemoprotective effect against cisplatin-induced toxicities with the DDTC dose schedule tested. Patients who received DDTC received lower cumulative doses of cisplatin, but were more likely to be withdrawn from treatment early due to chemotherapy-related toxicities. PMID- 7844611 TI - Multiinstitutional home-therapy trial of recombinant human interleukin-2 and interferon alfa-2 in progressive metastatic renal cell carcinoma. AB - PURPOSE: In a phase II multiinstitutional outpatient trial, patients with progressive metastatic renal cell carcinoma were treated with a combination of subcutaneous (SC) recombinant interleukin-2 (rIL-2) and recombinant interferon alfa-2 (rIFN alpha 2). PATIENTS AND METHODS: One hundred fifty-two patients with metastatic renal cell carcinoma were treated. Treatment courses consisted of SC rIL-2 at 20 x 10(6) IU/m2 three times per week in weeks 1 and 4, and at 5 x 10(6) IU/m2 three times per week in weeks 2, 3, 5, and 6. Additionally, patients received SC rIFN alpha 2 6 x 10(6) U/m2 once per week in weeks 1 and 4, and three times per week in weeks 2, 3, 5, and 6. RESULTS: There were nine (6%) complete responses (CRs) and 29 (19%) partial responses (PRs), for an overall response rate of 25% (95% confidence interval, 19% to 32%). The median duration of responses for CRs and PRs was 16+ and 9 months, respectively. Additionally, 55 patients (36%) had stable disease (SD). Fifty-nine patients (39%) had continued disease progression (PD) despite treatment, or went off study after less than 4 weeks of therapy. The majority of patients treated experienced fever, chills, malaise, nausea, vomiting, and anorexia, side effects that were mostly limited to World Health Organization (WHO) grade 1 and 2. However, one patient developed grade 4 CNS toxicity with extended somnolence. On cessation of therapy, the neurologic symptoms in this patient were fully reversible, with no neurologic deficiency. CONCLUSION: In summary, this multiinstitutional home-therapy setting of SC rIL-2 and SC rIFN alpha 2 in patients with progressive metastatic renal cell carcinoma demonstrated drastically reduced systemic toxicity, while it confirmed the therapeutic efficacy of the low-dose SC immunotherapy combination schedule. PMID- 7844612 TI - The practice guidelines development cycle: a conceptual tool for practice guidelines development and implementation. AB - PURPOSE: To develop a conceptual tool for the systematic development of cancer treatment practice guidelines. MATERIALS AND METHODS: The guidelines development tool, the Practice Guidelines Development Cycle, was derived from observing an evidence-based practice guidelines initiative at a comprehensive cancer center in Ontario, Canada, and from a literature review that uncovered barriers to guidelines development and implementation. Based on the literature findings and direct observations of how clinicians struggled with evidence-based guidelines development, we evolved a framework to incorporate clinical and administrative factors (eg, costs) into evidence-based guidelines. Use of the Practice Guidelines Development Cycle is illustrated with a clinical example (the use of adjuvant systemic therapy in good-risk, node-negative premenopausal breast cancer patients). RESULTS: The result is the Practice Guidelines Development Cycle, which consists of eight sequential steps, from topic selection to policy formulation. Independent validation of guidelines is included. The cycle products are the evidence-based recommendation, the practice guideline, and the practice policy. The main features of the cycle are emphasis on scientific evidence, acknowledgment of the roles of clinical experience and nonclinical (administrative) factors through consensus, and explicit separation of clinical and cost considerations in guidelines development. Twenty guidelines are currently in development. CONCLUSION: Attention to the barriers of guidelines development and the sociocultural nature of clinical practice, and respect for clinical experience, can lead to improved strategies for guidelines development. PMID- 7844613 TI - Use of tamoxifen for breast cancer: twenty-eight years later. AB - PURPOSE: The mechanisms of antitumor activity, clinical pharmacology, toxicity, and efficacy of tamoxifen in women with early and advanced breast cancer and the drug's potential role in prevention of breast cancer were reviewed. DESIGN: A comprehensive review of the literature from 1966 to 1994 was conducted; reports were identified using the Cancerline and Medline data bases. RESULTS: The cellular actions of tamoxifen are not completely understood, but it appears that the drug's antiproliferative effects are mediated primarily by inhibition of the activities of estrogen through binding to estrogen receptors (ERs). Disease-free and overall survival rates have been increased in postmenopausal women with ER positive tumors when tamoxifen has been used as adjuvant therapy (irrespective of nodal status). In premenopausal women, adjuvant therapy with tamoxifen has been associated with prolongation of disease-free survival, but its impact on survival remains to be defined. Tamoxifen is the initial hormonal treatment of choice in both premenopausal and postmenopausal women with ER-positive metastatic disease. Retrospective review of adjuvant therapy studies showed an approximately 39% reduction in the incidence of contralateral primary breast carcinoma in tamoxifen treated women, which indicates that tamoxifen could have a role in breast cancer prevention. CONCLUSION: The use of tamoxifen has resulted in a substantial modification of breast cancer's natural history, particularly in postmenopausal women. Ongoing clinical trials will examine the effects of tamoxifen therapy on lipids, coagulation proteins, bone, and endometrium, and its effectiveness as an agent in the prevention of breast cancer. PMID- 7844614 TI - Paclitaxel-induced "recall" soft tissue injury. PMID- 7844615 TI - Myocardial ischemia and infarction associated with vinorelbine. PMID- 7844616 TI - Leiomyosarcoma of the urinary bladder after cyclophosphamide. PMID- 7844617 TI - Second malignancies after testicular cancer. PMID- 7844618 TI - Pneumonitis related to treatment with paclitaxel. PMID- 7844619 TI - Advances in treatment of tumors of the cranial base. Advances in imaging. AB - Imaging has facilitated aggressive skull base surgery by allowing precise preoperative delineation of the extent of lesions. Continued advances providing even better resolution on imaging studies may in turn facilitate the development of new surgical approaches to the skull base. PMID- 7844621 TI - Cytogenetics of cranial base tumors. AB - Many different tumor types can arise in or invade the skull base. The more common tumors include, but are not limited to, angiofibromas, chondrosarcomas, chordomas, hemangiopericytomas, meningiomas, carcinomas, olfactory neuroblastomas, paragangliomas, pituitary adenomas, and rhabdomyosarcomas. Several of these tumors, including meningiomas, hemangiopericytomas, and rhabdomyosarcomas are characterized by nonrandom cytogenetic abnormalities. In this paper, we review the recognized chromosomal aberrations in cranial base tumors and illustrate the insights that can be gained into the genetic basis of tumor formation using karyotypes from skull base tumors that we have examined. As in tumors in other locations, chromosomal findings may be of diagnostic and prognostic value in cranial base tumors. PMID- 7844620 TI - The biology and pathology of selected skull base tumors. AB - This paper describes the pathobiology of some of the more common skull base tumors. In addition to clinicopathologic features, emphasis is placed upon methods of diagnosis utilizing immunoperoxidase stains and molecular markers that may or may not impact upon prognosis. PMID- 7844622 TI - Meningiomas of the cranial base. AB - Treatment objectives for meningiomas of the cranial base include relief of neurologic disability and prevention of clinical progression or recurrence with the least morbidity. Recent advances in skull base surgical techniques, through an appreciation of skull base anatomy and institutional specialization, have contributed major improvements to the outlook for patients with these tumors, and previously inoperable cases may now often be removed completely with acceptable risk. Since significant morbidity may be incurred during surgical resection of these difficult lesions, especially in terms of cranial nerve dysfunction, the value of aggressive surgical resection must be weighted against the often indolent natural history of these lesions, and must be individualized in each patient. Completeness of resection is the major prognostic factor determining the outcome of patients with typical benign meningiomas in terms of length of survival, risk of recurrence, and neurological disability. Various means of prognosticating the growth potential of a given tumor are being investigated, though none have yet been confirmed for their predictive value in typical, histologically benign meningiomas. The role of external beam radiotherapy has not been subjected to adequately controlled, prospective studies, and there is currently insufficient followup to assess the risks and benefits of stereotactic radiosurgery. Advances in the clinical management of tumors of the skull base has had perhaps the greatest impact for patients with meningiomas who constitute a large portion of tumors seen in these locations. Although the majority have benign histological features, skull base meningiomas can present a formidable challenge due to their proximity to vital structures, surgical inaccessibility, and occasional aggressive features. The combination in recent years of advances in skull base surgical techniques, adjuvant therapy, and rehabilitation methods have dramatically improved the outcome for these tumors. PMID- 7844624 TI - Neurophysiologic monitoring during cranial base surgery. AB - The last decade has seen a rapid growth in surgical techniques directed at resection of skull base tumors. Lesions that were previously inoperable can now be resected either partially or in some cases completely. The morbidity in these procedures has diminished with increased surgical experience. Additional aids to successful surgical resection include intraoperative neurophysiologic monitoring techniques. The following text outlines methods of monitoring cranial nerve and brain function in a manner that is directly relevant to cranial base surgery in which so many structures are potentially at risk. These techniques permit the identification of nerves obscured by tumor before they may be inadvertently damaged, the repeated confirmation during tumor resection that a nerve is still functional, and infer the state of brain and brainstem function during the course of long surgical procedures to help signal vascular compromise, or the effects of brain retraction. These techniques can only help to enhance the safety of the long and complex procedures required for successful resection of tumors of the cranial base. PMID- 7844623 TI - Review of skull base surgery approaches: with special reference to pediatric patients. AB - The techniques of skull base surgery attempt to maximize the exposure of a cranial base lesion while using the least amount of brain retraction. Cranial base surgery is not a 'new' area of neurosurgical or otolaryngologic interest, but instead represents a resurgence of efforts to treat difficult lesions involving the cranial base. This resurgence of interest and effort is a product of recent advances in microanatomical knowledge of the cranial base, advances in microsurgical technique, improved neurophysiologic monitoring, and improved collaborative relationships between neurosurgery, otolaryngology and plastic surgery. Furthermore, improved neuroanesthetic techniques allow the surgeon to proceed with surgery without undue concern about time, and improved neuroimaging techniques provide the surgeon with detailed knowledge of the three dimensional characteristics of the tumor and surrounding structures. This review will focus on the surgical management of cranial base tumors primarily affecting the pediatric population. Little has been written on the techniques of skull base surgery as they apply to the pediatric population, since cranially-based tumors are a relatively rare occurrence in this patient population. In most instances, however, many of the 'standard' skull base approaches can be applied to the pediatric patient with few modifications, and in our experience, the pediatric patients have tolerated these approaches as well as their adult counterparts. PMID- 7844625 TI - Chemotherapy for cranial base tumors. AB - The tumors I will discuss in this chapter on chemotherapy will be ethesioneuroblastoma, salivary gland tumors, chordoma and nasopharyngeal carcinoma. Due basically to the rarity of these lesions, with the exception of nasopharyngeal carcinoma, there have been no multi-institutional studies of chemotherapy use reported in the literature. As a result, there is no clear-cut consensus on the standard of care as it relates to chemotherapy for these tumors. As with most authors who have previously reviewed these tumor types, I believe it is important for us to propose protocols of therapy and test these in arenas where we can accumulate enough patients for meaningful results. In this way, we can test the apparently active agents and combinations in relapsed or extensive disease. We might also begin to explore concurrent therapy (i.e., concurrent radiation and chemotherapy after the surgical procedure, for example). PMID- 7844627 TI - Faxes, modems, and fax/modems. AB - Although the use of computers for word processing and spreadsheet analysis is widespread, other less well-known uses can also increase efficiency and productivity. In this bimonthly column, Dr. Nicoll discusses a variety of computer applications to help the nurse executive catch up, keep up, and get ahead. PMID- 7844626 TI - Evolution and advances of the lateral surgical approaches to cranial base neoplasms. AB - The evolution and advances of the lateral surgical approaches used for neoplasms of the cranial base involving the middle and posterior cranial fossa are reviewed. The lateral approaches available for access to the cranial base are diverse and are often used in combination. Approaches for tumors that are completely extradural, usually involving the temporal bone or infratemporal fossa, include the infratemporal fossa approach described by Fisch and the preauricular subtemporal-infratemporal fossa approach. Lateral approaches used to provide exposure of intradural tumors involving the clivus and traversing the middle and posterior cranial fossa are based on the following approaches: the frontotemporal orbitozygomatic, subtemporal/middle fossa, transpetrosal, lateral suboccipital, and transcondylar approaches. The great strides that have been made in the safe and effective surgical treatment of cranial base neoplasms are due, in part, to the availability of multiple surgical approaches and the ability to tailor the planned operative procedure to the precise location and extent of the cranial base tumor. PMID- 7844628 TI - The effect of ambulatory oncology nursing practice models on health resource utilization. Part 2, Different practice models--different use of health resources? AB - The continuous rise in healthcare expenditures concerns providers, recipients, and payers alike, all of whom seek to explain, justify, or contain these costs. Although nurses are major healthcare providers in ambulatory oncology settings, the efficiency or productivity of nursing, expressed as frequency and cost of services (resource utilization), has not been addressed. Part 1 presented findings from a retrospective comparative study that delineated two different models of oncology nursing practice, the Nurse Complement Model and the Nurse Substitute Model of practice. Part 2 discusses these differences in the economic effectiveness of ambulatory oncology nursing in terms of health resource utilization. PMID- 7844629 TI - The learning network. Leadership development for the next millennium. AB - The complex process of creating a learning organization demands new methods for development and learning. Individuals need to find new ways of working together by increasing self-knowledge and changing their behavior. Learning networks, a simple but profound approach to learning, offer participants an opportunity to exchange experiences in a safe and supportive environment. Participants review their most important and difficult work and develop their interpersonal skills and self-awareness to new heights. In the spirit of empowerment and creating a learning culture, colleagues learn to listen and observe as well as ask helpful questions and offer alternative perspectives and practical ideas. They also give and receive feedback. The author explores the concepts, experiences, structures, and results of learning networks that allow readers the opportunity to contemplate a new form of development for themselves and their staffs. PMID- 7844630 TI - Managing with precision. A budgetary decision support model. AB - In this era of intense competition for restrained healthcare resources, a sound financial system can provide the foundation for evaluating care requirements while balancing allocation and deployment of resources. The authors describe one nursing division's comprehensive budgetary decision support model. This model has enabled achievement of rigorous budgetary goals while maintaining high standards of quality. The budgetary decision support model was internally created; however, it is applicable and easily adaptable to any healthcare organization. PMID- 7844631 TI - Decision support systems. Using computers to help manage. AB - Nurse executives often are encouraged to work smarter, not harder. Decision support systems offer methods for refining the decision-making process. The authors review the types of decisions that managers make and the ways that decision support systems can help nurse executives work smarter. PMID- 7844632 TI - The changing world of nurse administrative practice. AB - The American Organization of Nurse Executives (AONE) is the national organization of nurse executives and nurse managers. AONE provides leadership, professional development, advocacy, and research to advance nursing practice and patient care, promote nursing leadership excellence, and shape healthcare public policy. This column, written by officers and executive staff members of AONE, raises issues and discusses trends of importance to nursing administrators. PMID- 7844633 TI - Acuity classification in the urgent care setting. AB - Efforts to control costs but provide accessible services have led to the development of urgent care centers. Viable urgent care centers must provide cost effective care while maintaining quality. This requires staff allocation appropriate to patient needs as well as volume. Few articles have been written on patient acuity systems that permit optimal urgent care center staffing. Sharp Rees-Stealy Medical Centers have developed an acuity system for use in the urgent care center. PMID- 7844634 TI - "We don't make widgets here". Voices of chief nurse executives. AB - In a rapidly changing healthcare environment, the leadership behavior of chief nurse executives is essential to the organizations they manage. The author describes the leadership behavior of a group of female nurse executives who share perspectives on their life/career development. Themes discussed are progressive leadership and power, transformational leadership, cyclic mentorship, macro organizational perspective, and competition and achievement. PMID- 7844635 TI - Care of patients. AB - Hospital accreditation standards have changed from focusing on capability to actual performance and outcomes. This shift in emphasis requires organization leaders and staff members to make significant paradigm shifts. In this series of articles, the authors will discuss the functional standards for 1994-1995 and their implications. PMID- 7844636 TI - Specificity of riboflavin molecular groups for riboflavin binding to rat small intestinal brush border membrane. AB - The binding of riboflavin to rat small intestinal brush border membrane at equilibrium was formerly shown to have a saturable, specific component, prevailing at the intraluminal physiological concentrations of the vitamin. In this study, the specificity of riboflavin binding to rat small intestinal brush border vesicles was further investigated using structural analogues of riboflavin. The vesicles, prepared by Ca(2+)-precipitation, were incubated at 25 degrees C, for 20 min, in the presence of [3H]-riboflavin at physiological intraluminal concentrations for rat, and each analogue, at appropriate concentrations. Three groups of analogues were used, that were derived from the riboflavin molecule by modifying one of the following positions: the ribityl side chain, position 3, and position 8 of the isoalloxazine moiety. Group specificity was assessed by determining the inhibition potency of each analogue on the saturable component of riboflavin binding to the vesicles. Inhibition constants were calculated, according to Dixon, for lumiflavin, lumichrome, and for analogues substituted at position 8. Specific riboflavin binding was inhibited competitively by most of the analogues used. Substitutions at the ribityl side chain or at position 3 of the isoalloxazine moiety reduced the inhibition power. Substitutions at position 8 enhanced the inhibition power in direct proportion to the bulk of the substituents. We conclude that the ribityl side-chain and the NH group at position 3 are essential for recognition by the specific binding sites, whereas the methyl group at position 8 is important but not essential. The analogues that bind to specific membrane sites for riboflavin share specificity requirements with many riboflavin binding proteins, and are also good substrates for the intracellular phosphorylating enzyme flavokinase. Thus, the riboflavin binding component in the membrane is likely to be a protein with high specificity. Cellular internalization of the membrane bound vitamin is probably achieved by phosphorylation of the vitamin bound to the inner side of the membrane. PMID- 7844637 TI - The effect of natural carotenoid (palm fruit carotene) intake on skin lipid peroxidation in hairless mice. AB - To study the effect of palm fruit carotene intake on skin lipid peroxidation, hairless mice were given ad libitum palm fruit carotene, beta-carotene, or vehicle emulsions for 15 weeks in which the carotene (0.005%, w/w) was suspended in drinking water, and then their dorsal skin was exposed to ultraviolet ray (UV). The carotene content of the skin was increased by the oral intake of palm fruit carotene or beta-carotene. In carotene-drinking mice, before the UV irradiation, the amount of thiobarbituric acid-reacting substances (TBARS) in the skin was lower than that of control (carotene untreated) mice. The skin TBARS immediately after the UV irradiation was lower in carotene-treated mice than in control mice. At 24 h after irradiation, the skin TBARS of mice that orally received palm fruit carotene was lower than that of beta-carotene mice. Immediately after the UV irradiation, the skin carotene content transiently decreased but gradual recovery was observed at 48 h. In palm fruit carotene treated mice, the rate of carotene recovery after UV irradiation was higher than in beta-carotene-treated mice. Retinol found in the skin had also decreased after UV irradiation, and recovered gradually in both carotene-drinking groups within 48 h. These results suggested that the carotene intake, especially palm fruit carotene, prevented skin lipid peroxidation in hairless mice. PMID- 7844638 TI - The antioxidant effect of palm fruit carotene on skin lipid peroxidation in guinea pigs as estimated by chemiluminescence-HPLC method. AB - To study the antioxidant effect of palm fruit carotene on skin lipid peroxidation, the guinea pigs were orally fed ad libitum palm fruit carotene, beta-carotene, or vehicle emulsions, in which carotene (0.05%, w/w) was suspended in drinking water. After treatment of carotene for 12 weeks, animals were exposed to ultraviolet ray (UV), and squalene monohydroperoxide (SqOOH)/squalene (Sq) ratios in the skin lipid were analyzed using the chemiluminescence-HPLC method. Carotene accumulation was found in the skin of guinea pigs that were orally administered palm fruit carotene or beta-carotene. After UV irradiation, especially immediately after, the rise in the SqOOH/Sq ratio was effectively suppressed in both carotene-drinking groups in contrast with the control (carotene-untreated) group. An inverse correlation between the carotene content and the SqOOH/Sq ratio in the skin was also observed. The results suggested that palm fruit carotene intake prevents skin lipid peroxidation caused by UV irradiation. PMID- 7844639 TI - Effects of dietary short-necked clam, Tapes japonica, on serum and liver cholesterol levels in mice. AB - Male mice were fed cholesterol-supplemented diets containing short-necked clams or defatted short-necked clams for 2 weeks under the dietary regimen of the same dietary level of protein (20%), fat (5%), and cholesterol (0.5%). Casein was used as a control protein. Similar results were obtained in two separate experiments with either boiled (Exp. 1) or steamed (Exp. 2) short-necked clams. The concentration of serum cholesterol in mice fed a clam diet was lower than in those fed control and defatted clam diets. Delipidation of clam raised the concentration of serum triglyceride. Both clams and defatted clams markedly reduced the concentration of hepatic cholesterol. Fecal excretion of neutral steroids was significantly increased by clam but not defatted clam, whereas the excretion of acidic steroids was stimulated by both specimens, in particular defatted clam. The results suggest that the hypocholesterolemic effect of short necked clams is attributed to its lipid fraction, whereas non-lipid components contribute to the reduction of hepatic cholesterol and increased fecal excretion of bile acids. PMID- 7844640 TI - Alteration of beta-D-glucan from edible mushroom after injection into mouse peritoneal cavity. AB - Tritium-labeled antitumor beta-D-glucan derivative (T-labeled glucan) was prepared from the branched beta-1,3-D-glucan of an edible mushroom, Volvariella volvacea, by its periodate oxidation followed by reduction with NaBT4. Twenty three hours after T-labeled glucan had been injected into the mouse peritoneal cavity, about 3% of the total radioactivity injected was found in the mouse serum. In spite of the fact that T-labeled glucan had no affinity to the anion exchange column before injection, about 50% of the labeled beta-D-glucan in the serum thus obtained was adsorbed onto the column. The labeled beta-D-glucan fraction eluted from the column by salt gradient showed antitumor activity in vivo. PMID- 7844641 TI - Bile diversion lowers apolipoprotein A-I and A-IV mRNA levels in rat ileum. AB - We recently reported that cholestyramine (a bile acid sequestrant) lowered ileal apolipoprotein A-I mRNA level in rats. To obtain further information about this phenomenon, in this study, we investigated whether bile diversion lowers apolipoprotein A-I mRNA level in the ileum of rats. Bile-diverted rats were fed a diet with no added Na taurocholate (control diet) or with 0.4% Na taurocholate for 7 days. Sham-operated rats were also fed the control diet for the same period. Northern blot analysis revealed that the relative concentrations of jejunal apolipoprotein A-I and A-IV mRNA at the end of experimental period did not differ between groups while ileal apolipoprotein A-I and A-IV mRNA concentrations were significantly lower in bile-diverted rats fed the control and Na taurocholate-containing diets than in sham-operated rats. Plasma total and HDL cholesterol concentrations were the same in all groups. Relative concentration of apolipoprotein A-I in plasma also did not change. These results suggest that the bile plays an important role in ileal apolipoprotein gene expression at the pretranslational stage, but it is still unclear whether the effector is the bile acid or not. The unchanged concentration of plasma apolipoprotein A-I may have resulted from the constant secretion independent of synthesis in the intestine or the larger contribution from the liver which is another principal site for apolipoprotein A-I expression. PMID- 7844642 TI - Effects of dietary casein and soy-protein on metabolic conversion of eicosapentaenoic acid to docosahexaenoic acid in the liver of rat. AB - The differential effects of dietary proteins on the metabolic process of eicosapentaenoic acid (EPA, 20:5n-3) via docosapentaenoic acid (DPA, 22:5n-3) to docosahexaenoic acid (DHA, 22:6n-3) were studied using parameters calculated from the proportion of n-3 polyenoic acid in liver phospholipid (PL) of rats. Rats were given casein or soy-protein isolate (SPI) diet containing 3% EPA with or without methionine (Met) supplementation for 3 weeks. The (22:5 + 22:6)/20:5 and 22:5/20:5 ratios of the PL fractions in the liver of rats given SPI were evidently elevated compared with those given casein. These ratios were also elevated when linoleic acid (LA, 18:2n-6) was added to the diet. There were no significant differences in the 22:6/22:5 ratio of the same PL fractions between the casein and SPI groups without the addition of LA, but the ratio was lowered by the addition of LA. It was found that these parameters for metabolic conversion were not affected by supplementation of Met or by a decrease in body weight. The above results suggest that the elongation step from EPA to DPA is affected by the type of protein, i.e., it is accelerated by SPI and is not affected by the presence of LA, while the metabolic process from DPA to DHA is not affected by the type of proteins without the addition of LA but is suppressed when LA is added. PMID- 7844643 TI - Food deprivation increases apoptotic cell counts induced by 1,2-dimethylhydrazine in rat descending colonic and rectal crypts. AB - The frequency of apoptosis after treatment with 1,2-dimethylhydrazine (DMH) was counted in the descending colonic and rectal crypts of food-deprived and fed rats. Food-deprived or fed rats were subcutaneously injected with DMH (100 mg/kg body weight). Six hours after the injection, apoptotic cells were observed in crypt regions by light microscopy. The incidence of DMH-induced apoptosis in food deprived rats was significantly higher than in fed rats. The incidence appeared to be higher in descending colon than in rectum. PAS staining revealed that DMH treatment lowered mucin secretion in crypts, which was substantially lowered by food deprivation. The effect of food deprivation on apoptosis induced by DMH may be due to the decrease in mucus barrier against DMH. PMID- 7844644 TI - Ethical issues near the end of life: a physician's perspective on caring for persons with AIDS. PMID- 7844645 TI - Ethical issues in bone marrow transplantation: a nursing perspective. AB - It is clear that there are many challenges facing health professionals who care for this patient population. The close collaboration with the physicians on our team ensures that patients and nurses receive clear communication about the goals of the treatment plan. It is our hope that by sharing these insights we challenge other health care teams to provide patient and family-centred care which is compassionate towards the needs of those who depend so greatly on us. PMID- 7844646 TI - Dyspnea: ethical concerns. PMID- 7844647 TI - The management of dehydration in terminally ill patients. PMID- 7844648 TI - Ethical issues in pain management at home. AB - This review of several studies from the authors' program of research supports the notion that the experience of pain, particularly in the home, has a profound effect not only on the patient, but on family and health care providers as well. Family caregivers revealed their private grief and burden when describing the physical suffering they witnessed. They faced the daily responsibility of making decisions regarding a loved one's pain, and the decisions often resulted in ethical conflicts. Caregivers generally felt ill-prepared for the administration of pain medication. They struggled to balance the need for medications to relieve pain against the perceived unwanted side effects and fear of addiction. These studies also demonstrate that a concerted effort must be made by health care providers to support the pain management role of family caregivers. By listening, being available, making pain management a priority, and reinforcing appropriate pain management principles, health care professionals help sustain family caregivers in carrying out their anguishing and unrelenting task. PMID- 7844649 TI - I would never do that! PMID- 7844650 TI - Making a bridge: the moral work with patients we do not like. PMID- 7844651 TI - How much should I say to whom? AB - During the past several decades, attitudes in North America have shifted with regards to disclosing information to patients about their own diagnosis. There is still debate, however, about the extent of the information that should be shared regarding treatment and prognosis. Families have their own set of needs in the face of coping with life-threatening illness and supporting the patient. Receiving clear honest information about the patient's condition, prognosis, and comfort are important to family caregivers. Resolving the issue of disclosing patient information to families demands that health care professionals engage in sensitive communication and achieve a delicate balance between the patient's right to confidentiality and meeting the family members' needs for information. PMID- 7844652 TI - High-risk behaviors for HIV: a comparison between crack-abusing and opioid abusing African-American women. AB - High rates of unprotected sexual behaviors and the exchange of sex for crack have been reported among female crack cocaine users. This subpopulation of drug users is at significant risk for contracting and transmitting HIV and AIDS. To date, there has been no research comparing crack- and opioid-abusing women, particularly regarding their involvement in high-risk behaviors and other key background indicators for different subgroups of drug-abusing women. Sixty-one crack-abusing African-American women who recently entered an intensive outpatient treatment program were compared to 64 matched women whose primary drug of abuse was heroin. The opioid subgroup represented both those who were involved in methadone maintenance and those who were out of treatment. Higher rates of high risk sexual behaviors were reported by the crack subgroup, including prostitution, number of sexual partners, and infrequency of condom use. As expected, i.v. drug use and high-risk behaviors associated with needle use were much higher among the opioid subgroup. Other significant differences were found between the two groups across key indicators. Individuals in the crack subgroup were younger, cared for more children, were less employable, were less likely to be married, and had more extensive lifetime substance abuse. Quantitative and qualitative background and clinical data are also presented. The nature of crack versus heroin abuse is also discussed, particularly in relation to high-risk sexual behaviors. Finally, the impact of the findings on developing appropriate treatment interventions for both groups is addressed. PMID- 7844653 TI - African-American women who smoke crack cocaine: sexual trauma and the mother daughter relationship. AB - This study evolved from previous writings that linked sexual abuse to the quality of the mother-daughter relationship. The purpose of this investigation was to examine the mother-daughter relationship among African-American women who abuse crack cocaine by comparing three different groups: women who have not experienced incest but have experienced sexual abuse; women who have experienced incest; and women who have not experienced sexual abuse. A convenience sample of 64 African American women was used, 35 of whom were in drug abuse treatment and 29 of whom were abusing crack cocaine. Using analysis of variance studies, significant differences were found between the three groups in terms of the mother-daughter relationship. Differences were also found between the group that experienced incest and the group that experienced nonincestuous sexual abuse in terms of the amount of abuse and first age of abuse. This preliminary investigation indicates the need for further study of specific populations in this area--most notably, African-American women who abuse crack cocaine. PMID- 7844654 TI - Effectiveness of a specialized intervention for women in a methadone program. AB - Over the past 20 years, specialized programming for chemically dependent women has been recommended for improving psychosocial functioning and retention in treatment. This study examined the impact of a structured, six-week assertiveness and sexuality workshop for women at three community-based methadone maintenance programs. Results indicated that women who participated frequently in the women's groups (four to six sessions) showed greater increases in self-esteem and knowledge compared to women who participated infrequently (one to three sessions). In addition, level of participation was positively associated with length of stay in the treatment program after completing the workshop. PMID- 7844655 TI - Are "traditional" sex differences less conspicuous in young cannabis users than in other young people? AB - Recent research has revealed conspicuously few distinctions between young males and females who use cannabis. Such findings may reflect the general slackening of the sex-role pattern in the younger generations. Alternatively, they may reflect distinctive characteristics of the cannabis culture. Using data from a nationwide representative sample (n = 1,478) of young Norwegians (21-24 years old), this study explores whether "traditional" sex differences in respect to mental health and alcohol use are less conspicuous among users than among nonusers of cannabis. The respondents' sex-role-related values and preferences were also studied. Results indicate that the sex differences in mental health did not vary between users and nonusers of cannabis; however, female cannabis users were disproportionately young when they experienced their first intoxication by alcohol. Their level of drinking was also disproportionately high. This implied that the sex difference in alcohol use was smaller among users than among nonusers: male users of cannabis consumed 2.8 times more alcohol than their female counterparts, whereas the corresponding male to female ratio was 3:2 in the nonusers. The extensive use of alcohol in female cannabis users did not reflect mental health problems or a rejection of traditional sex-role characteristics. Cannabis-using males were less typically masculine in their values and preferences than other males, but not more feminine. The measures for sex-role-related preferences did not discriminate between female users and female nonusers of cannabis. PMID- 7844656 TI - Injection drug users in the Midwest: an epidemiologic comparison of drug use patterns in four Ohio cities. AB - Variations in the drug use patterns of injection drug users (IDUs) can have important implications for public health efforts aimed at reducing drug abuse and the transmission of the human immunodeficiency virus. This article describes and compares the characteristics of IDUs living in four Ohio cities and compares African-American and White IDUs at a statewide level. Data from 2,001 IDUs who were recruited for the National AIDS Demonstration Research project between 1989 and 1991 in Columbus, Cleveland, Cincinnati, and Dayton were compared on a number of variables by city and by ethnicity using descriptive statistics and ANCOVA analysis. Significant differences among IDUs in the four cities exist for the use of alcohol, marijuana, cocaine, crack, heroin, speedball, other opioids, shooting gallery use, "safer" needle practices, treatment history, and self-help participation. Differences by ethnicity emerged on all variables except marijuana use, overall injection frequency, and incarceration experience. The results suggest that dramatic differences exist between African-American and White IDUs, and among IDUs in cities relatively close together, regardless of ethnicity. These findings should be considered when developing policy and programs for prevention and treatment activities targeting IDUs. PMID- 7844657 TI - Salvia divinorum and the unique diterpene hallucinogen, Salvinorin (divinorin) A. AB - Salvia divinorum is a vision-inducing mint used by the Mazatec people of Oaxaca, Mexico. It is grown in California and other parts of the United States where it is employed as a legal hallucinogen. Traditional opinion has been that the plant has mild psychotropic activity, at best. However, when ingested in the correct manner, it is quite powerful. The fresh leaves are chewed as a quid and kept in the mouth. They may also be eaten raw or prepared as an aqueous infusion. When dried, they are smoked in the manner of marijuana. The neoclerodane diterpene, salvinorin A (also known as divinorin A), has been demonstrated in animals and humans to be its major active ingredient. Essentially inactive if taken orally, the compound is effective in doses of 200 to 500 mcg when smoked in a manner similar to cocaine free base. This makes salvinorin A the first documented diterpene hallucinogen and the most potent naturally occurring hallucinogen thus far isolated. This is somewhat remarkable, since the compound is not an alkaloid. This article reviews the use of S. divinorum and its chemistry. In addition, it discusses the effects of the plant and salvinorin A in animals and humans, as well as their potential to become drugs of abuse. PMID- 7844658 TI - Possible role of marijuana smoking as a carcinogen in the development of lung cancer at a young age. PMID- 7844659 TI - Common themes in a group for female i.v. drug users who are HIV positive. PMID- 7844660 TI - Allergic colitis in infants. PMID- 7844661 TI - Enhanced adrenomedullary response and increased susceptibility to neuroglycopenia: mechanisms underlying the adverse effects of sugar ingestion in healthy children. AB - OBJECTIVE: Eating simple sugars has been suggested as having adverse behavioral and cognitive effects in children, but a physiologic mechanism has not been established. This study was performed to address this issue. DESIGN: Metabolic, hormonal, and symptomatic responses to a standard oral glucose load (1.75 gm/kg; maximum, 120 gm) were compared in 25 healthy children and 23 young adults, and the hypoglycemic clamp, together with measurements of P300 auditory evoked potentials, was used to assess whether children are more vulnerable than adults to neuroglycopenia. SETTING: Children's Clinical Research Center, Yale University School of Medicine. RESULTS: Baseline and oral glucose-stimulated plasma glucose and insulin levels were similar in both groups, including the nadir glucose level 3 to 5 hours after oral administration of glucose (3.4 +/- 0.1 mmol/L (61 +/- 1.8 mg/dl) in children and 3.5 +/- 0.1 mmol/L (63 +/- 1.8 mg/dl) in adults). The late glucose decrease stimulated a rise in plasma epinephrine levels that was twofold higher in children than in adults (2260 +/- 289 vs 1031 +/- 147 pmol/L (407 +/- 52 vs 186 +/- 26 pg/ml), p < 0.01) and a significant increase in hypoglycemic symptom scores in children (p < 0.01), but not in adults. During control experiments, in which six of the healthy children ingested a sugar-free drink, there were no significant changes in plasma glucose levels, hormone concentrations, or hypoglycemic symptom scores. During the hypoglycemic clamp, P300 potentials did not change in any of eight adult subjects until the plasma glucose concentration was lowered to 3.0 mmol/L (54 mg/dl), whereas similar changes in P300 potentials were observed in six of seven children at glucose levels 3.6 to 4.2 mmol/L (65 to 75 mg/dl). CONCLUSION: Enhanced adrenomedullary responses to modest reductions in plasma glucose concentration and increased susceptibility to neuroglycopenia may be important contributing factors to adverse behavioral and cognitive effects after sugar ingestion in healthy children. PMID- 7844662 TI - Effects of acute hyperglycemia on mental efficiency and counterregulatory hormones in adolescents with insulin-dependent diabetes mellitus. AB - OBJECTIVE: To determine whether acute hyperglycemia adversely affects mental efficiency to the same extent as acute mild hypoglycemia. STUDY DESIGN: We administered a battery of cognitive tests to adolescents studied at hyperglycemic (20 mmol/L (360 mg/dl)), hypoglycemic (3.3 mmol/L (60 mg/dl)), or euglycemic (5.5 mmol/L (100 mg/dl)) targets, which were maintained by an insulin-glucose clamp. The study included 36 children, 9 to 19 years of age (mean = 14.7 years), with diabetes duration more than 2 years (mean = 6.9 years). RESULTS: Cognitive test performance did not deteriorate during hyperglycemia. In contrast, there was a significant decline in performance on all cognitive tests during mild hypoglycemia. Autonomic symptoms did not change significantly during hyperglycemia or during the rapid return from hyperglycemia to euglycemia. Although significant increments in epinephrine and pancreatic polypeptide levels occurred during mild hypoglycemia, no changes in counterregulatory hormones occurred during hyperglycemia. An exploratory regression analysis demonstrated that changes in mental efficiency were best predicted by increases in pancreatic polypeptide, a marker of autonomic activation. CONCLUSION: These results confirm our previous finding that mild hypoglycemia causes transient decrements in cognitive function. In contrast, neither hyperglycemia, nor the rapid drop from acute hyperglycemia to euglycemia, affected symptoms, cognitive function, or counterregulatory hormone secretion. PMID- 7844663 TI - Subsequent insect stings in children with hypersensitivity to Hymenoptera. AB - To investigate the risk of life-threatening reactions to future stings, we sequentially challenged 113 children (aged 2 to 17 years) allergic to insect stings with a sting by the relevant insect. The time interval between the challenges varied from 2 to 6 weeks. The history of the index stings was a large local reaction (LR) in 16% and a systemic reaction (SR) in 84% of the test subjects. On the first challenge, 76% had a normal LR, 11% a large LR, and 13% an SR. On the second challenge, 78% of the children had a normal LR, 5% a large LR, and 17% an SR. Thirty-nine of the untreated children were exposed to a field sting during the subsequent 3-year follow-up period. In comparison with other diagnostic evaluations such as skin-prick tests, determinations of specific IgE and IgG antibodies, and single-sting exposure, the dual sting challenge scheme appears to be the best predictor of reactions to subsequent stings. It also appears to be helpful in selecting patients with an uncertain sensitization status for venom immunotherapy. PMID- 7844664 TI - Relation between infant feeding and infections during the first six months of life. AB - We assessed the effect of the method of feeding on respiratory and gastrointestinal illnesses during the first 6 months of life among 776 infants born in New Brunswick, Canada. During a 1-year period, these infants were drawn from the offspring of a population of primiparous women in the province who, after at least 36 weeks of pregnancy, gave birth to one normal infant weighing 2500 gm or more. Data were collected by means of a self-administered standardized questionnaire mailed to every mother a week before her infant reached 6 months of age. The crude incidence density ratio (IDR) revealed a protective effect of breast-feeding on respiratory illnesses (IDR = 0.66; 95% confidence interval (CI), 0.52 to 0.83), on gastrointestinal illnesses (IDR = 0.53; 95% CI, 0.27 to 1.04) and on all illnesses (IDR = 0.67; 95% CI, 0.54 to 0.82). The protective effect of breast-feeding on respiratory illnesses persisted even after adjustment for age of the infant, socioeconomic class, maternal age, and cigarette consumption (adjusted IDR = 0.78; 95% CI, 0.61 to 1.00). Moreover, if we distinguished ear infection from other respiratory illnesses, we observed a separate protective effect for these two types of events. The results of this retrospective cohort study suggest a protective effect of breast-feeding in our population during the first 6 months of life. PMID- 7844665 TI - Effect of neonatal immunization with diphtheria and tetanus toxoids on antibody responses to Haemophilus influenzae type b conjugate vaccines. AB - We randomly assigned 150 newborn infants to receive diphtheria and tetanus toxoids (DT) or Hib oligosaccharide conjugate (HbOC) at birth to determine whether exposure to the Haemophilus influenzae type b (Hib) conjugate vaccines' carrier proteins would enhance immune responses to subsequent administrations of HbOC or PRP-tetanus toxoid conjugate (PRP-T) at 2, 4, and 6 months of age. Their antibody responses were compared with those of 100 children immunized with HbOC or PRP-T beginning at 2 months of age. No serious adverse reactions were associated with neonatal vaccination. Administration of HbOC at birth did not lead to earlier or higher antibody levels. Newborn immunization with DT did not prime children for enhanced antibody responses. Moreover, Hib antibody levels were lower in DT-primed children than in children immunized beginning at 2 months of age. Diphtheria antibody levels, but not tetanus antibody levels, were also lower in children immunized with DT at birth. We conclude that neonatal immunization with Hib conjugate vaccines is not a means to provide earlier protection against invasive Hib disease. Newborn DT administration does not enhance subsequent antibody responses to Hib conjugate vaccines, and may lead to suppression of Hib and diphtheria antibody responses. PMID- 7844666 TI - Enhanced antibody responses in infants given different sequences of heterogeneous Haemophilus influenzae type b conjugate vaccines. AB - To evaluate the safety and immunogenicity of differing sequences of heterogeneous Haemophilus influenzae type b (Hib) conjugate vaccines, we randomly assigned 300 infants to one of six vaccination schedules. At 2, 4, and 6 months of age, subjects were given single or heterogeneous vaccines: Hib polysaccharide (PRP) conjugated to mutant diphtheria toxin (HbOC), PRP conjugated to outer-membrane protein of Neisseria meningitidis (PRP-OMP), or PRP conjugated to tetanus toxoid (PRP-T). No serious reactions were attributable to immunization with heterogeneous vaccines, and there were few significant differences in the rates of minor adverse reactions among groups. PRP-OMP was the only vaccine that induced an antibody response after the first dose, but significant booster responses were not seen after the second and third doses. Subjects given PRP-T vaccine responded well after two doses, but three doses of HbOC vaccine were needed for an equivalent antibody response. All the Hib vaccine schedules evaluated were immunogenic, and schedules initiated by PRP-OMP vaccine at 2 months of age, followed by two doses of either HbOC or PRP-T vaccine at 4 and 6 months of age, induced the highest antibody levels after each dose. Such schedules may be the best for protecting infants and children who are at greatest risk of having invasive Hib disease, such as American Indian children. PMID- 7844667 TI - Pediatric Investigators Collaborative Network on Infections in Canada (PICNIC) prospective study of risk factors and outcomes in patients hospitalized with respiratory syncytial viral lower respiratory tract infection. AB - OBJECTIVE: To provide information on disease attributable to respiratory syncytial viral lower respiratory tract infection (RSV LRI) and to quantify the morbidity associated with various risk factors. DESIGN: Prospective cohort study. SUBJECTS: Patients hospitalized with RSV LRIs at seven centers were eligible for study if they were younger than 2 years of age, or hospitalized patients of any age if they had underlying cardiac or pulmonary disease or immunosuppression. MEASUREMENTS AND RESULTS: Enrolled (n = 689) and eligible but not enrolled (n = 191) patients were similar in age, duration of illness and proportion with underlying illness, use of intensive care, and ventilation. Of the enrolled patients, 156 had underlying illness. The isolates from 353 patients were typeable: 102 isolates were subgroup A, 250 were subgroup B, and one isolated grouped with both antisera. The mean hospital stay attributable to respiratory syncytial virus (RSV) was 7 days; 110 patients were admitted to intensive care units, 63 were supported by mechanical ventilation, and 6 patients died. Regression models were developed for the prediction of three outcomes: RSV associated hospital duration, intensive care unit admission, and ventilation treatment. In addition to previously described risk factors for an increased morbidity, such as underlying illness, hypoxia, prematurity and young age, three other factors were found to be significantly associated with complicated hospitalization: aboriginal race (defined by maternal race), a history of apnea or respiratory arrest during the acute illness before hospitalization, and pulmonary consolidation as shown on the chest radiograph obtained at admission. The RSV subgroup, family income, and day care attendance were not significantly associated with these outcomes. CONCLUSIONS: Hypoxia on admission, a history of apnea or respiratory arrest, and pulmonary consolidation should be considered in the management of children with RSV LRIs. Vaccine trials should target patients with underlying heart or lung disease or of aboriginal race. PMID- 7844668 TI - Hospitalization for lower respiratory tract illness in infants: variation in rates among counties in New York State and areas within Monroe County. AB - OBJECTIVE: Lower respiratory tract illness (LRI) is the most common serious illness in childhood and the most common reason for hospitalization of infants beyond the neonatal period. This study assessed the potential for cost savings from reduction in hospitalization for LRI. SETTING AND SAMPLE: LRI hospitalization rates for children in the first 2 years of life (infants) were studied for the 62 counties of New York State and six socioeconomic areas within Monroe County (Rochester) for the years 1985 through 1991. DESIGN: Analysis of small area variations. RESULTS: LRI accounted for 51.2% of infant hospitalizations in New York State. The overall LRI hospitalization rate for New York's 62 counties was 27.0 per 1000 child-years and ranged, among the 18 most populous counties, from 10.7 for Monroe County to 39.3 for the Bronx. Unemployment rate was the strongest predictor of LRI hospitalization rates for counties, explaining 29% of the variance in multiple regression analysis. Within Monroe County, LRI hospitalization rates followed a geographic gradient from the inner city (22.5) to the rest of the city (12.2), and to the suburbs (7.3). Deaths from LRI were uncommon (0.36% of state LRI hospitalizations) and varied little between inner city (0.42%) and suburbs (0.51%). If LRI hospitalization rates for Monroe County suburban children prevailed for the entire state, 10,439 hospitalizations and $32,916,000 would be saved annually. CONCLUSIONS: A large portion of the increased cost of health care for children living in poverty is attributable to hospitalization for LRI in infants. Physician discretion in decision making and factors associated with socioeconomic status are probably major determinants of variation. Well-coordinated follow-up of acute illness visits, home monitoring by visiting nurses, and empirically based clinical guidelines for management of LRI might yield both substantial cost savings and better service to families. PMID- 7844669 TI - Expanded spectrum of herpes simplex encephalitis in childhood. AB - We designed a polymerase chain reaction method to detect herpes simplex virus (HSV) DNA in spinal fluid from patients with encephalitis. The polymerase chain reaction amplified a 211 base-pair segment of the HSV DNA polymerase gene. Applying this method, we diagnosed HSV type 1 infection in three young children, aged 7 to 13 months, who had atypical forms of the illness. On the basis of magnetic resonance imaging, their disease was diffuse or multifocal in two cases and, in all three, lacked the temporal lobe involvement considered characteristic of HSV encephalitis beyond the neonatal period. Most of the diffuse or multifocal abnormalities detected by magnetic resonance imaging were not apparent by computed tomography. Restriction enzyme analysis of the polymerase chain reaction products from all three patients indicated that their disease was caused by HSV type 1. We conclude that in preschool-age children beyond the neonatal period, the spectrum of HSV encephalitis includes multifocal or diffuse involvement of the brain, which may be detected most efficiently by magnetic resonance imaging. The polymerase chain reaction method has the potential for providing an early diagnosis, but further studies are required to define the sensitivity and specificity of the polymerase chain reaction before it can be used for routine clinical decision making. PMID- 7844670 TI - Lipid abnormalities in Turner syndrome. AB - Turner syndrome is associated with insulin resistance, increased incidence of type II diabetes, and hypertension, all of which are cardiovascular risk factors. The purpose of this study was to evaluate the lipid profile of girls with untreated Turner syndrome, (aged 5 to 14 years; 68% 45,XO) and age-matched, normal girls. A total of 137 girls with Turner syndrome and 70 normal girls had lipid profile measurements, including cholesterol, high-density lipoprotein cholesterol, and triglycerides. Older girls with Turner syndrome (> 11.0 years) had increased cholesterol levels (p < 0.01), compared with control values (190 +/ 38 vs 165 +/- 26 mg/dl). Cholesterol levels were elevated in older subjects with Turner syndrome versus normal subjects, after adjustment for age, karyotype, and body mass index z score effects (p = 0.01). In the subjects with Turner syndrome but not the normal subjects, serum cholesterol values correlated with age, weight, and body mass index z score (p < 0.02). We conclude that adolescent girls with untreated Turner syndrome have significantly increased cholesterol levels, independent of age, body mass index z score, or karyotype, and that these precede any treatment with exogenous estrogen or growth hormone. PMID- 7844671 TI - Lysinuric protein intolerance characterized by bone marrow abnormalities and severe clinical course. AB - STUDY OBJECTIVE: To evaluate phenotypic variability of lysinuric protein intolerance in a cohort of nine Italian patients. DESIGN: Retrospective analysis of patient records. SUBJECTS: Nine Italian patients (seven independent families), all originating from southern Italy, observed during the last 14 years. RESULTS: Some of the patients had unique clinical features, including bone marrow abnormalities featuring erythroblastophagocytosis (five patients) and clinical course and the outcome of the disease, have also been observed: respiratory involvement was present in five cases, with a lethal picture of "alveolar proteinosis" in one. Severe kidney involvement, with both glomerular and tubular damage and rapidly progressing to chronic renal failure, has been observed in one case. CONCLUSION: Lysinuric protein intolerance may cause severe multisystem involvement, which requires early and careful monitoring. Some peculiar clinical findings observed in Italian patients point to a genetic heterogeneity of lysinuric protein intolerance. PMID- 7844672 TI - Long-term reduction in bone mass after severe burn injury in children. AB - OBJECTIVE: Because burn victims are at risk of having bone loss, a cross sectional study was undertaken to determine whether severe burn injury had acute and long-term effects on bone mass or on the incidence of fractures in children. METHODS: Dual-energy x-ray absorptiometry of the lumbar portion of the spine was performed on 68 children: 16 moderately burned (15% to 36% of total body surface area) and 52 age-matched severely burned (> or = 40% of total body surface area). Twenty-two severely burned children were hospitalized and studied within 8 weeks of their burn, and 30 others were studied approximately 5 years after discharge. In the severely burned group, both hospitalized and discharged, serum and urine were analyzed for calcium, phosphorus, intact parathyroid hormone, osteocalcin, and type I collagen telopeptide. RESULTS: Sixty percent of severely burned patients had age-related z scores for bone density less than -1, and 27% of severely burned patients had age-related z scores for bone density less than -2 (p < 0.005, for each). In the moderately burned group, 31% of patients had z scores less than -1 (p < 0.005 vs normal distribution), but only 6% had z scores less than -2 (p value not significant). There was evidence of increased incidence of fractures after discharge in the severely burned patients. Biochemical studies were compatible with a reduction in bone formation and an increase in resorption initially, and with a long-term persistence of low formation. CONCLUSION: We conclude that acute burn injury leads to profound and long-term bone loss, which may adversely affect peak bone mass accumulation. PMID- 7844673 TI - Venom immunotherapy: who should receive it? PMID- 7844674 TI - Critical illness neuromuscular disease in children manifested as ventilatory dependence. AB - Four children with prolonged dependency on a ventilator were found to have reversible quadriparesis, muscle wasting, and hyporeflexia after 8 to 20 days of assisted ventilation for life-threatening sepsis or respiratory failure. Critical illness neuromuscular disease, which was recently recognized as a distinct clinical syndrome in adults, may also be manifested in children by prolonged ventilatory dependency. PMID- 7844675 TI - Transient elevation of sweat chloride concentration in a malnourished girl with the Mauriac syndrome. AB - Elevated sweat chloride concentration in a patient with Mauriac syndrome has been reported only once. The authors of that report regarded their patient's underlying malnutrition, and not Mauriac syndrome per se, as the cause of the elevated sweat chloride concentration. We describe a second example of transient elevation of sweat chloride concentration, which confirms that the malnutrition intrinsic to Mauriac syndrome, rather than the syndrome itself, was the probable cause of elevated sweat chloride values. PMID- 7844676 TI - Painful keratoderma and photophobia: hallmarks of tyrosinemia type II. AB - Tyrosinemia type II (Richner-Hanhart syndrome), which is caused by a deficiency of hepatic tyrosine aminotransferase, results in elevated plasma and urinary tyrosine concentrations. We describe a young boy who was seen at 6 months of age with red eyes, photophobia, and eye pain that were not suspected to be caused by tyrosinemia II until painful plantar keratoderma developed at 2 1/2 years of age. Treatment with a diet low in tyrosine and phenylalanine reversed the manifestations of the disease. PMID- 7844677 TI - Loss of detectable antibody to hepatitis B surface antigen in immunized patients with hemophilia but without human immunodeficiency virus infection. AB - We investigated the loss of detectable antibody directed against the hepatitis B surface antigen after immunization with hepatitis B vaccine in 55 patients who were seronegative for the human immunodeficiency virus and had hemophilia. Twenty percent of patients lost detectable antibody at a mean of 4.6 years after completion of immunization. Monitoring of hepatitis B serostatus or routine revaccination may be necessary. PMID- 7844678 TI - Effect of maternal glucocorticoid exposure on risk of severe intraventricular hemorrhage in surfactant-treated preterm infants. AB - OBJECTIVE: To determine whether the reduced risk of severe intraventricular hemorrhage (SIVH) that follows antenatal maternal glucocorticoid (AMG) receipt is mediated by an AMG effect on blood pressure or improved respiratory function in infants who receive artificial surfactant as rescue therapy. DESIGN: Retrospective cohort study. SETTING: Two level III neonatal intensive care units, Boston, Mass. PARTICIPANTS: Two hundred twenty-five infants < or = 32 weeks of gestational age and < or = 1.7 kg birth weight, treated with surfactant. MAIN FINDINGS: SIVH occurred in 10% (10/102) of infants who were exposed to AMG, compared with 23% (25/111) of infants not exposed (odds ratio, 0.4; 95% confidence interval, 0.2 to 0.8). Hypotension and need for colloid or dopamine were associated with both SIVH and the absence of AMG exposure (p < or = 0.03). Logistic regression models of SIVH risk and AMG exposure, with adjustment for antenatal potential confounders, were altered by the addition of measures of hypotension. Most clinical measures of pulmonary function, both before and after surfactant receipt, were not associated with reduced risk of SIVH and did not appear to account for the increased risk of SIVH in babies not exposed to AMG. CONCLUSION: The reduced risk of SIVH in preterm newborn infants whose mothers received AMG was associated with normal blood pressures. The association between AMG and SIVH was not consistently enhanced by respiratory function improvement after surfactant therapy. PMID- 7844679 TI - Reducing blood donor exposures in low birth weight infants by the use of older, unwashed packed red blood cells. AB - We performed a prospective, randomized masked trial to determine whether the use of dedicated units of packed red blood cells equipped with seven satellite bags would reduce donor exposures in infants with birth weights < 1500 gm. We also examined the use of unwashed and older red blood cells. Red blood cells given to the study group were used without washing and until their expiration date (35 to 42 days). Changes in blood pH, potassium, ionized calcium, and hemoglobin were determined with each transfusion and compared with data collected from a control group that received washed, younger red blood cells. There was a 64% reduction in donor exposures in the study group. Changes in infants' blood pH and calcium levels with transfusion were the same in the two groups. There was a clinically unimportant difference in potassium levels. A greater rise in hemoglobin values occurred when washed cells were used. There was no correlation between changes in the blood levels measured and the age of unwashed cells infused. We conclude that the use of red blood cells from satellite bag-equipped dedicated units decreases donor exposures, and that the practices of using only younger red blood cells and of saline washing of red blood cells before infusion, are unwarranted. PMID- 7844680 TI - Effects of parenteral L-carnitine supplementation on fat metabolism and nutrition in premature neonates. AB - The effects of parenteral L-carnitine supplementation on fat metabolism, nutrient intake, and plasma and erythrocyte carnitine concentrations were studied in 43 very low birth weight infants. Infants were randomly assigned to control or carnitine-supplemented (50 mumol/kg per day) groups within two weight categories: group 1, 750 to 1000 gm, and group 2, 1001 to 1500 gm. Plasma total, free, and acyl carnitine levels, erythrocyte carnitine levels, serum beta-hydroxybutyrate and triglyceride levels, and total fat intake were monitored weekly until 50% of total caloric intake was met enterally. Neonates receiving carnitine had higher plasma carnitine levels than control groups (total carnitine: group 1, 75.2 +/- 22.9 vs 9.6 +/- 2.7 mmol/ml; group 2, 61.6 +/- 31.2 vs 13.0 +/- 9.2 nmol/ml). Levels of beta-OH-butyrate decreased from baseline in control neonates (group 1, 0.12 +/- 0.06 to 0.03 +/- 0.02 mmol/L; group 2, 0.11 +/- 0.03 to 0.05 +/- 0.02 mmol/L); they remained unchanged in supplemented groups. Thus ketogenesis appeared less impaired in infants receiving supplements. Supplemented group 2 tolerated more fat than control group 2; triglyceride levels remained acceptable in all groups. Carnitine group 2 had greater weight gain than control group 2 during the first 2 weeks of life. We conclude that very low birth weight infants requiring prolonged parenteral nutrition have carnitine deficiency with impaired ketogenesis. Parenteral administration of carnitine appears to alleviate this metabolic disturbance. PMID- 7844681 TI - Congenital cytomegalovirus infection as a result of nonprimary cytomegalovirus disease in a mother with acquired immunodeficiency syndrome. AB - A pregnant woman with acquired immunodeficiency syndrome had nonprimary cytomegalovirus (CMV) viremia and died of complications from Pneumocystis carinii pneumonia and CMV sinusitis and pneumonitis. A boy was delivered by cesarean section at 34 weeks of gestation as the mother's health deteriorated and fetal distress developed. The infant died soon after delivery of interstitial pneumonitis and hyaline membrane disease with invasive CMV disease that affected the kidneys, adrenal glands, and placenta; the CMV strains from the mother and neonate were identical. PMID- 7844682 TI - Growth and the growth hormone axis in prepubertal children with asthma. AB - To determine the influence of asthma and its treatment with inhaled corticosteroids on growth, linear growth velocity, and the growth hormone axis in prepubertal children, we performed a longitudinal study for 12 months in 56 children with asthma, aged between 4.4 and 11.7 years. Height, weight, skin-fold thickness, and lung function were measured every 3 months and bone age at entry to and exit from the study. A 24-hour serum growth hormone concentration profile and fasting insulin-like growth factor I levels were measured halfway through the year. Seventy-four percent of boys and 62% of girls had heights below the 50th percentile. Growth velocity in the nonsteroid-treated control group (n = 13) was normal; 10 of 20 children taking beclomethasone grew slowly (14/20 used a dry powder device), and 4 of 19 children taking budesonide grew slowly (15/19 used a spacer). Three of four children using inhaled steroids and prednisolone grew slowly. In none of the treatment groups were measures of growth hormone secretion or levels of radioimmunoassayable serum insulin-like growth factor I affected. We conclude that slow growth in steroid-treated children with asthma does not appear to be associated with major perturbations in the growth hormone axis. PMID- 7844683 TI - Corticosteroid therapy for ventricular tachycardia in children with silent lymphocytic myocarditis. AB - OBJECTIVE: The objective of our study was to describe the efficacy of corticosteroids for ventricular tachycardia in four children with structurally normal hearts in whom endomyocardial biopsy revealed histologic changes of lymphocytic myocarditis. PATIENTS: The four patients had unexplained ventricular tachycardia. Three dysrhythmias were sustained, and one was inducible by exercise. Patient ages ranged from 4 months to 12 years. Three of the four patients had no symptoms. In two of them, ventricular tachycardia was identified by mass screening for heart disease. Two patients received oral steroids and two received pulse steroid therapy. RESULTS: In all four patients, significant underlying diseases were not found by noninvasive evaluation. Right ventricular endomyocardial biopsy revealed abnormal histologic findings of chronic lymphocytic myocarditis in all patients. Steroid therapy was effective in all four patients, two of whom received methylprednisolone pulse therapy. CONCLUSIONS: We conclude that unexplained ventricular tachycardia may be the only manifestation of clinically silent myocarditis. Steroid therapy should therefore be considered if conventional antiarrhythmic medication is not effective and histologic findings confirm the presence of lymphocytic myocarditis. PMID- 7844684 TI - A randomized comparison of intravenously administered granisetron versus chlorpromazine plus dexamethasone in the prevention of ifosfamide-induced emesis in children. AB - PURPOSE: To compare the efficacy and safety of intravenously administered granisetron with those of chlorpromazine plus dexamethosone in the prevention of ifosmamide-induced emesis in children with malignant disease. PATIENTS AND METHODS: Eighty-eight children, aged 2 to 17 years, were scheduled for ifosfamide therapy (> or = 3 gm/m2) for 2 or 3 consecutive days. On each day, children received granisetron, 20 microgram/kg intravenously, before ifosfamide therapy, plus up to two more doses within 24 hours if required, or chlorpromazine, 0.3 to 0.5 mg/kg intravenously, every 4 to 6 hours, plus dexamethasone, 2 mg/m2 intravenously every 8 hours. RESULTS: During the initial 24 hours, significantly fewer episodes of vomiting were recorded after granisetron administration (median number, 1.5 vs 7.0; p = 0.001), and the percentages of children having no more than one vomiting episode (51% granisetron vs 21% chlorpromazine-dexamethasone) and no worse than mild nausea (67% granisetron vs 38% chlorpromazine dexamethasone) were lower after granisetron therapy (p < 0.01). Fewer children had sedation with granisetron (2 vs 19; p < 0.001); there were no extrapyramidal reactions during granisetron therapy compared with two during control therapy. CONCLUSION: Granisetron was superior to chlorpromazine-dexamethasone antiemetic therapy for children receiving ifosfamide therapy and deserves further study during other chemotherapy regimens. PMID- 7844685 TI - Short-term use of amoxicillin-clavulanate during upper respiratory tract infection for prevention of acute otitis media. AB - We performed a randomized, double-blind, placebo-controlled study to determine whether acute otitis media could be prevented by antibiotic therapy initiated promptly after the appearance of symptoms of upper respiratory tract infection. One hundred four children aged 1 to 4 years received a 7-day course of either amoxicillin-clavulanate or placebo. Acute otitis media developed in 9 (18%) of the 50 children receiving amoxicillin clavulanate and in 12 (22%) of the 54 children receiving placebo (p = 0.59). PMID- 7844686 TI - Antenatal corticosteroid therapy to prevent respiratory distress syndrome. AB - The recent National Institutes of Health Consensus Development Conference on ANS was strongly supportive of the use of ANS, even for 24 hours but, if possible, for 48 hours, in all fetuses between 24 and 34 weeks of gestation and at risk of preterm delivery regardless of race, gender, or the availability of surfactant replacement. For preterm rupture of membranes at less than 30 to 32 weeks, the use of ANS was also recommended in the absence of amnionitis, and patients eligible for tocolytic therapy were also deemed eligible for ANS. Thus the currently available literature indicates that pediatricians should encourage obstetricians to provide ANS in high-risk pregnancies, as outlined in the proposed National Institutes of Health guidelines. Even if a full 48-hour course of ANS cannot be achieved, ANS given less than 24 hours before delivery is associated with a decreased incidence of intraventricular hemorrhage and periventricular leukomalacia. In addition, we propose that investigators, reviewers, and editors ensure uniformly high maternal ANS exposure, consistent with the realities of clinical practice, when designing, evaluating, and publishing clinical trials with outcomes (e.g., RDS, intraventricular hemorrhage, periventricular leukomalacia, bronchopulmonary dysplasia, and death) that can be significantly affected by ANS. Otherwise, studies will continue to be performed on infants who, as fetuses, were deprived of treatment that may have prevented or ameliorated the disorder being assessed. Studies with an infrequent use of ANS may not be applicable or generalizable to an era when the use of ANS is an essential part of perinatal practice. Future trials should document both ANS use and the reasons for failure to achieve an acceptable level of such treatment. PMID- 7844687 TI - Usefulness of cerebrospinal fluid bacterial antigen tests. PMID- 7844688 TI - Infectious hazards of immune globulin. PMID- 7844689 TI - Differences in clinical significance of maternal-infant blood group incompatibility in mothers with blood type O, A, or B. PMID- 7844690 TI - Screening neonates for intrauterine cocaine exposure. PMID- 7844691 TI - Accuracy of aural infrared temperature device. PMID- 7844692 TI - The relationship between drug and alcohol use and peer group associations of college freshmen as they transition from high school. AB - College freshmen responded to a drug and alcohol questionnaire. For drugs other than alcohol and marijuana, the best predictor of drug use at the beginning of college is drug use during a typical month of the senior year of high school. College freshmen, however, use marijuana less frequently than they did in high school and the use of alcoholic beverages increases early in college. While the frequency of alcohol use increases considerably, college freshmen do not increase the number of times they got drunk. It has been hypothesized that the likely change in peer relations between high school and college would alter subsequent rates of drug and alcohol use. However, the data shows that college and high school drug use are very similar and entering freshmen found new friends much like their high school friends to use drugs with and get drunk. Therefore, alcohol and drug use may be important determining factors in the choice of new college friends. PMID- 7844693 TI - Identifying the outcomes of prevention: results of a longitudinal study in a small city school district. AB - This article reports on the results of three successive surveys of fifth through twelfth grade students conducted over a five year period, 1986 through 1991. During the time covered by the surveys, these adolescents were exposed to an eclectic variety of both school and community-based prevention and intervention programs. The surveys indicate that younger students have increasingly delayed their entry into use of alcohol and other drugs; older students also show some declines in use, comparable to those reported nationally, but heavy, regular use of both marijuana and alcohol persists as well among a substantial minority. The article concludes with consideration of the perceived effectiveness of the community's prevention efforts, the justifications for these judgments, and the implications of these for further programming efforts. PMID- 7844694 TI - Drug attitude factors: comparisons of samples from 1985 and 1992. AB - The Stanislaus Chemical Effects Survey, which contains the names of twenty-four substances and asks subjects to rate the relative harm and benefit of each to society, was given to male and female undergraduates in 1985 and 1992. Factor analysis of the responses from each sample were done separately and then a comparison was made of the resulting factors. Fifteen of the twenty-four drugs retained their approximate same position in the structure of drug attitudes between the two samples. Attitudes about three substances, tobacco, oral contraceptives, and PCP, notably appeared to have undergone significant shifts. Discriminant analysis revealed significant differences between the two samples, between males and females regardless of year, and an interaction between year and gender. Findings suggest that attitudes remain conservative about drugs in general and that public policies may be contributing to the shifts in attitudes seen. PMID- 7844695 TI - A substance use profile of delinquent and homeless youths. AB - The overall health status of delinquent and homeless youths is of increasing concern. These high-risk youth populations have a variety of health problems, including relatively high levels of substance abuse. This study provides empirical data on the substance use behaviors of a sample of delinquent and homeless youths in San Francisco, California. The data, secured within the context of medical examinations, indicate that both samples use tobacco, alcohol, and illicit drugs at higher rates than the general adolescent population. The study concludes that drug education and prevention programs must be tailored to fit the needs and lifestyles of these two populations, and that the programs should be provided within the broader context of adolescent health care. PMID- 7844696 TI - Antecedents of substance use among Mexican American school-age children. AB - This article describes a study designed to examine the association of demographic, psychological, and environmental characteristics of a sample of low socioeconomic status, Mexican American students in elementary and middle school and their reported use of nine substances. Students in grades four, five, and six (N = 2295; males 52% and females 48%) located in a metropolitan school district in South Texas were surveyed in order to ascertain information pertaining to the initiation and/or ongoing use of substances. Regression analyses were employed to determine the relative contribution of variables measured to lifetime use of both minor and major substances. Results indicate that a specific combination of variables were predictive of both minor and major substance use for the subjects surveyed. Implications for future research and substance intervention are included. PMID- 7844697 TI - The social stress model of substance abuse among childbearing-age women: a review of the literature. AB - The Social Stress Model of Substance Abuse has been derived from numerous psychosocial theories and models. This model suggests that the likelihood of an individual engaging in drug abuse is influenced by the stress level and the extent to which it is offset by stress modifiers such as social networks, social competence and resources. This article synthesizes current empirical evidence for this model. Thirteen primary research studies of women are synthesized and described, with special attention to the four key constructs inherent in the model: stress, social networks, social competencies, and resources. Consistencies and inconsistencies in the findings, a critique of key methodological issues, implications for future research, and implications for clinical policy and practice are provided. PMID- 7844698 TI - Process evaluation of Nebraska's Team Training Project. AB - BACKGROUND: A process evaluation of the Nebraska Drug Free School/Community Residential Team Training Project is described. This training project utilizes a "system approach" in the formation and implementation of localized strategic (action) plans targeting alcohol and other drug (AOD) abuse prevention. METHODS: In June of 1990, training participants completed a pre-post survey in conjunction with the four-day training. The majority of the participants (51.2%) were teachers, 19.2 percent were parents, 13.6 percent administrators, and 9.6 percent were counselors. RESULTS: Although the overall attitudes of the participants (N = 125) were positive initially, they became even more so by the end of the training (N = 121). Prior to training participants felt they could have a significant impact on their local AOD abuse problem, and this attitude became more positive by the completion of training (p < 0.05). CONCLUSIONS: The Nebraska team training process immerses team members in an active planning process allowing teams to develop a plan of action for their school and community. During this process, participants experience a positive growth in attitudes reflecting not only the training experience itself, but even more importantly their ability to meaningfully affect AOD abuse and related destructive behaviors in their homes, schools, and community. PMID- 7844699 TI - Phylogeny of dermatophytes and dimorphic fungi based on large subunit ribosomal RNA sequence comparisons. AB - The phylogeny of dermatophytes and dimorphic fungi was considered using the large subunit of ribosomal RNA (25S rRNA). Aligned sequences of 595 nucleotides covering the two most divergent domains D1 and D2, permitted a comparison of phylogenetic relationships at different levels. The dimorphic species (Onygenaceae) were significantly separated from dermatophytes (Arthrodermataceae) and from a third group including geophilic or very weakly pathogenic species (Onygenaceae and Gymnoascaceae). On a species level, the varietal status of Histoplasma duboisii and Histoplasma farciminosum, as close relations of Histoplasma capsulatum, was confirmed. The dimorphic fungus Emmonsia parva, in spite of a completely different parasitic form (adiaspores instead of yeast-like cells), clustered with Blastomyces dermatitidis which has a perfect form resembling that of H. capsulatum. From our data, teleomorphs of E. parva, Paracoccidioides brasiliensis and H. farciminosum, three dimorphic fungi known only under their anamorphic states, should belong to the family of Onygenaceae and the genus Ajellomyces. Among Arthrodermataceae, and family containing the most keratinophilic species, it was not possible to establish a clear hierarchy of species. Only Ctenomyces serratus, the species adapted to degrade keratin of feathers, Trichophyton ajelloi and Trichophyton terrestre were significantly separated. The speciation of true dermatophytes resulted most likely from a very recent evolution by adaptation to parasitism. Among species used as outgroups, the two emerging pathogens Pseudallescheria boydii (Scedosporium apiospermum) and Scedosporium prolificans (Scedosporium inflatum) were shown to be closely related to each other. PMID- 7844700 TI - A preliminary study on the ultrastructure of Actinomadura pelletieri and its host tissue reaction. AB - This is the first report on the fine structure of Actinomadura pelletieri. The in vitro ultrastructure of the organism and that of the grain in vivo were similar. The grain consisted of packed filaments with a faintly electron-dense matrix in between. The individual filament was septate, the cytoplasm was either vacuolated or contained intracellular organelles and the cytoplasmic membrane was adherent to the filamentous wall, which has three electron-dense and two electron-lucent layers. The absence of cement substance around the grain may partially explain the aggressive and destructive behaviour of this organism and may probably also explain its good response to medical treatment. The inflammatory host reaction was similar to that seen with all mycetoma organisms except that there was a massive neutrophil reaction. This was confirmed by electron microscopy. PMID- 7844701 TI - A novel model of cutaneous candidiasis produced in prednisolone-treated guinea pigs. AB - In an attempt to develop an animal model of cutaneous candidiasis useful for the pre-clinical evaluation of antifungal drugs, experimental cutaneous Candida albicans infections were produced in mature and immature guinea-pigs treated with prednisolone. The morbidity of this model in terms of the extent and the duration of the superficial infection was compared with that of two other reported models: those produced by alloxan treatment, or the use of occlusive dressings. Infected animals were also included which received neither of these treatments. The Candida infection continued steadily for 14 days or more in both mature and immature animal groups treated subcutaneously with prednisolone and appeared to be more suitable than that produced with alloxan treatment or under occlusive dressings. In prednisolone-induced infection, most of the micro-organisms were confined to the epidermis and there was no evidence of their dermal penetration during the 14 day experimental period. In view of these facts, we attempted a more quantitative method by counting viable Candida in order to evaluate antimycotics in a shorter therapy period during which animals would receive less exposure to the vehicle. These findings appear to indicate that the experimental model of cutaneous C. albicans infection produced in prednisolone-treated mature and immature guinea-pigs would be useful for studies on the therapeutic efficacy of antifungal agents against cutaneous candidiasis. PMID- 7844702 TI - Exophiala jeanselmei var. lecanii-corni, an aetiologic agent of human phaeohyphomycosis, with report of a case. AB - Characters of morphology and nutritional physiology of Exophiala jeanselmei var. lecanii-corni are described. The taxon was proven to be distinct from the var. jeanselmei and from Exophiala dermatitidis by physiology, which is supported by molecular characters. A case of cutaneous phaeohyphomycosis caused by var. lecanii-corni is reported. PMID- 7844703 TI - Production and regeneration of protoplasts from the Y-phase of the human pathogenic fungus Paracoccidioides brasiliensis. AB - Protoplasts of Y-cells and partially converted M-cells from several human isolates of Paracoccidioides brasiliensis were obtained with a combined enzyme system containing Novozym 234 and a chitinase. A laboratory made extract from Trichoderma harzianum CBS-345-33 supplemented with chitinase induced the release of protoplasts from partially converted M-cells but not from established Y-cells. A similar yield of protoplasts (1-2 x 10(5) ml-1 after 16 h) was produced by using either enzymatic system. Protoplasts regenerated on nutrient gelatin at 23 degrees C at a frequency of 0.1%. PMID- 7844704 TI - Efficacy of oral amphotericin B in AIDS patients with thrush clinically resistant to fluconazole. AB - Reports of thrush clinically refractory to azoles in AIDS patients are increasing with the more widespread use of these agents. We studied our own oral preparation of amphotericin B in the treatment of two AIDS patients who developed oral thrush due to Candida glabrata after prolonged fluconazole use. Improvement occurred in both in less than 1 week, with eventual clearing and absence of side effects. Oral amphotericin B may have advantages over alternatives for this increasing problem. PMID- 7844705 TI - Systemic fungal infections in Thailand. AB - Between January 1988 and December 1993, 254 cases of systemic mycoses were recorded in Thailand. Between 1988 and 1991, the common mycoses were aspergillosis, candidosis and cryptococcosis. In 1992, cryptococcosis increased to 30 cases with 27 being AIDS related. In 1993, cryptococcosis increased dramatically to 57 cases with 49 AIDS related. Eight cases of penicillosis marneffei occurred in AIDS patients in 1993. Skin manifestations of penicillosis marneffei and histoplasmosis in AIDS usually manifested as molluscum contagiosum like papulonecrotic lesions. Clinical signs and symptoms could not be differentiated from each other. PMID- 7844706 TI - Strains of Cryptococcus neoformans with defined capsular phenotypes. AB - The polysaccharide capsule is a virulence factor in the opportunistic yeast pathogen, Cryptococcus neoformans. We describe a collection of strains which were isolated or constructed to exhibit defined capsular phenotypes. The collection includes strains with wild-type, acapsular and hypercapsular traits. PMID- 7844707 TI - Platelet-derived growth factor induces fetal wound fibrosis. AB - The fetal response to cutaneous injury differs markedly from that of the adult, proceeding with only minimal inflammation, minimal fibroblast proliferation, and only essential collagen deposition. Although the sequence of events in adult wound healing is well defined and thought to be controlled in part by potent polypeptide cytokines, relatively sparse information exists regarding growth factor involvement in fetal wound repair. Thus, the authors sought to examine the effect of platelet-derived growth factor (PDGF), a putative adult wound healing regulator, on the cellular and extracellular matrix events at a fetal wound site. SILASTIC wound implants containing 0, 1.0, 5.0, or 10.0 ng of human PDGF were placed subcutaneously on the backs of 24-day-gestation fetal rabbits (full term, 31 days) and then harvested after either 1, 3, or 5 days in utero. The specimens underwent standard histological processing and were evaluated in a blinded fashion. Compared with controls, PDGF-treated implants had a marked increase in acute inflammation, fibroblast recruitment, and collagen and hyaluronic acid deposition; these differences appeared to be largely time- and PDGF dose dependent. Thus, the fetal system is responsive to an adult wound healing mediator, and these data suggest that fetal repair proceeds in the absence of PDGF. PMID- 7844708 TI - Predictive factors of the outcome of traumatic cervical spine fracture in children. AB - The uncommon traumatic cervical spine fractures and dislocations were studied in 227 consecutively treated children (1 to 17 years of age). Lower cervical spine injuries (C-3 to C-7) affected 73% of our patients. However, among the 38 patients younger than 8 years of age, 87% had an injury at the C-3 level or higher (P < .0001). There were 19 fatalities (8.4%), all of which were associated with injuries at the C-4 level or higher. Of the 11 patients with atlanto-axial fracture or dislocation, all died soon after the injury. All had an unstable fracture and cord transection that resulted in cardiorespiratory collapse. Injuries at the vertebral levels C-1, C-2, C-3, and C-4 were associated with fatality rates of 17%, 9%, 4.3%, and 3.7%, respectively. No fatalities were encountered among patients with lesions lower than C-4. The authors conclude that the younger the age, the higher the cervical spine injury, and that the fatality rate correlates directly with the level of cervical spine fracture. PMID- 7844709 TI - Umbilical preservation in omphalocele repair. AB - A newborn with a large omphalocele is presented. A new technique of umbilical preservation is introduced. The cosmetic result was excellent, and the method is suitable for both primary and staged omphalocele repairs. PMID- 7844710 TI - Necrotizing fasciitis: a serious complication of omphalitis in neonates. AB - Necrotizing fasciitis occurs when the inflammation (cellulitis) spreads beyond the umbilicus to include the subcutaneous tissue and underlying fascia. Presently, omphalitis is relatively uncommon because of aseptic delivery techniques and antimicrobial therapy. One hundred three neonates aged 7 to 28 days, with varying degrees of omphalitis, were treated on an outpatient or inpatient basis between 1989 and mid-1993. The neonates were full-term and weighed at least 2.5 kg. Patients with necrotizing fasciitis initially appear deceptively well, which results in less-than-optimum treatment at the outset, followed by a rapid and fulminating downhill course, in turn resulting in death within 24 to 72 hours. Early recognition of the condition, with aggressive resuscitation, appropriate antibiotics, and early surgery are necessary to salvage this high-risk group. The risk factors that may predict the development of necrotizing fasciitis and its early detection are discussed. PMID- 7844711 TI - Separation of ischiopagus tripus conjoined twins. AB - The authors report on their second experience of a successful separation of ischiopagus tripus conjoined twins. Particular emphasis is placed on the painful decision of sacrificing the only available leg to cover the infected wound after an unexpected complication in twin A. The twins' preoperative evaluation, separation surgery, and subsequent 16-month course are described. PMID- 7844712 TI - Percutaneous dilational tracheostomy in children and teenagers. AB - Percutaneous dilational tracheostomy (PDT) is a new technique that has been successfully performed in adult patients who required long-term mechanical ventilation, but it has not been used in children. The authors report their initial experience with PDT in 11 children and teenagers. The procedure is as follows. Using Seldinger's technique, the trachea is cannulated with a guide wire. It is then progressively dilated, to an appropriately sized tract, with dilators from a commercially available kit. Then, a tracheostomy tube can be inserted into the trachea, loaded over a dilator. Eleven children, aged 10 to 20 years, underwent PDT in an average of 20 minutes. In eight cases, PDT was performed at the bedside. One intraoperative and one postoperative complication developed in the same patient; both complications were easily recognized and treated. Tracheal stenosis has not developed in eight decannulated patients at an average of 43 +/- 30 weeks after decannulation. PDT appears to be a safe, potentially cost-effective alternative to open tracheostomy in young patients. PMID- 7844713 TI - Effects of estradiol and progesterone on the synthesis of collagen in corrosive esophageal burns in rats. AB - The effects of sex hormones on the synthesis of collagen were investigated in rats with alkali-induced corrosive esophageal burns. In 75 rats, a standard esophageal burn was produced as described by Gehanno. The animals were then grouped as follows: controls (group A), animals with pure esophageal burns (group B), and animals with esophageal burns treated with estradiol and progesterone (group C). All animals were killed on the 28th day of the experiment. Hydroxyproline levels were determined, and histopathologic evaluation was performed for each group. The hydroxyproline levels were significantly lower in the rats treated with estradiol and progesterone. Histopathologically, collagen deposition in the submucosa and tunica muscularis was lower in the estradiol/progesterone group than in the group with pure esophageal burns. Based on the results, the authors believe that estradiol and progesterone inhibited new collagen synthesis, and therefore, alkali-induced esophageal stricture formation. PMID- 7844714 TI - Long-term results after nonshunt operations for esophageal varices in children. AB - The clinical results of nonshunt operations for esophageal varices in 15 children were evaluated. The varices were caused by congenital extrahepatic portal obstruction (EHPO) in 10, liver cirrhosis or fibrosis (C/F) in 3, and idiopathic portal hypertension (IPH) in 2. The operative procedures were transthoracic esophageal transection with paraesophageal devascularization (TR) for 2 EHPO patients under 5 years of age, TR combined with splenectomy and paragastric devascularization (Sugiura procedure) for 11 (8 EHPO, 3 C/F), and splenectomy with devascularization (SP) or splenectomy for the 2 IPH patients. In the EHPO patient under 5 years of age, TR is associated with a likelihood of gastric or esophageal hemorrhage resulting from hypersplenism, gastric congestion, or persistent distal esophageal varices, which can be treated with partial splenic arterial embolization (PSE), endosclerotherapy, or an additional abdominal procedure. The Sugiura procedure has provided satisfactory long-term results, without rebleeding from esophageal varices, in patients with EHPO and C/F for 1 to 20 years. But EHPO patients who undergo the Sugiura procedure before age 6 can have gastric hemorrhage, because of mucosal congestion, for more than 10 years after the procedure, and selective gastric arterial embolization (GAE) might be necessary. In some EHPO patients, especially young ones who have variceal bleeding, a significant increase in hepatopetal portal flow may not develop, but hepatofugal natural shunts may progress. Therefore we recommend direct operative procedures, ie, TR for patients < or = 6 years of age and a one- or two-stage Sugiura procedure for those over 7 years old.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7844715 TI - Esophagocoloplasty in children: surgical technique, with emphasis on the double blood supply to the interposed colon, and results. AB - The description of certain surgical technical modifications of pediatric esophagocoloplasty and their impact on morbidity and mortality rates are presented. Seventy children, aged 12 to 120 months (mean, 52.3 +/- 39.5), were divided in two groups. Group 1 (40 patients), which represents a historical group, underwent esophagocoloplasty by the conventional technique. Group 2 (30 patients) had the following modifications to the operation: (1) preservation of the double blood supply to the interposed colon, based on the left colic vessels and left paracolic arcade, via the sigmoid vessels; (2) low cologastric anastomosis, performed at the lowest level of the anterior antrum; (3) in cases of retrosternal transposition (25 patients), fixation of the inferior border of the liver to the diaphragm and anterior abdominal wall; and (4) complete section of the left anterior muscles, behind the colon. Five patients in group 2 were supposed to undergo surgical correction of a congenital cardiac anomaly and had the colon transposed through the posterior mediastinum, on the original esophageal bed. The incidence of graft necrosis, gastrocolic reflux, esophagocolic anastomotic leak, and dysphagia are compared between the groups; the survival rates also were compared. Statistical analysis was performed using the Fisher-Yates' test, with significance set at .05. Groups 1 and 2 had the following complication rates, respectively: graft necrosis, 12.5% and 0% (P < .05); gastrocolic reflux, 20.0% and 0% (P < .05); dysphagia, 9.5% and 0% (P < .05); and esophagocolic anastomosis leak, 28.5% and 33.3% (not significant). The mortality rate was 17.5% for group 1 and 3.5% for group 2 (P < .05).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7844716 TI - Diaphragmatic agenesis as a distinct clinical entity. AB - Anatomically, diaphragmatic agenesis (DA) represents the most extreme form of congenital diaphragmatic defects, but clinically it has not been defined separately from Bochalek's hernia (BH). Between 1986 and 1992, the authors treated 55 neonates who had diaphragmatic defects. Forty-eight of them presented within 24 hours of birth and comprised the study group. Seventeen neonates (35.4%) were found to have DA; the other 31 (64.6%) had BH. There were no differences in the maternal age, gestation course, gender ratio, birth weight, or incidence of co-existing congenital anomalies between the two groups. However, there were significant differences with respect to the incidence of antenatal diagnosis (76.4% for DA patients v 12.5% for BH patients; P = .0004), mean (+/- SD) Apgar scores at 1 (4.1 +/- 2.0 v 5.7 +/- 2.3; P = .034) and 5 minutes (5.5 +/ 2.7 v 7.6 +/- 2.2; P = .016), mean duration of preoperative stabilization (2.8 +/- 2.0 v 2.1 +/- 1.9 days; P = .044) and mean duration of postoperative respiratory support (27.7 +/- 13.6 v 9.3 +/- 8.0 days; P = .002). Complications occurred in all seven survivors of DA and in only four (19.0%) of 21 survivors of BH (P = .0008). The neonates with DA had a significantly poorer long-term survival rates (29.4% v 64.5%; P = .04). Diaphragmatic agenesis is a distinct clinical entity; its unique short-term and long-term problems require careful management. PMID- 7844717 TI - Predictors of survival for infants with congenital diaphragmatic hernia. AB - Over the past decade, the survival rate of infants with congenital diaphragmatic hernia (CDH) treated in the intensive care unit of the Royal Children's Hospital, Melbourne, has remained unchanged at 56% +/- 6%. Newer forms of treatment, such as extracorporeal membrane oxygenation (ECMO), high-frequency oscillation, and surfactant and nitric oxide therapy, are now available. The exact role of these therapies in the management of infants with CDH has not been determined. This study examines five clinical parameters derived from an infant's best preoperative ventilatory and blood gas data in the first 24 hours of life. One hundred twenty-five CDH infants were admitted to the intensive care unit between January 1, 1981 and December 31, 1991. Criteria for inclusion in the study were (1) CDH diagnosed within 6 hours of delivery, (2) ventilation before repair, and (3) no associated lethal congenital abnormality. Of the 90 cases studied in detail, there were 38 deaths (42% mortality rate). All five parameters were analyzed by receiver operating curve analysis to determine the optimum value of each parameter in predicting survival. An oxygenation index (MAP x FIO2/PaO2) of less than 0.08 predicted a 94% chance of survival, with a sensitivity of 96% and a specificity of 95%. Similarly, a modified ventilation index (PIP x RR x CO2/1,000) of less than 40 predicted a 91% chance of survival, with a sensitivity of 94% and a specificity of 86%. By stratifying each criterion according to outcome, three groups of infants were identified according to their response to conventional therapy.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7844718 TI - Gastroesophageal reflux occurring after repair of congenital diaphragmatic hernia. AB - Over the past 2 decades, 110 patients with congenital diaphragmatic hernia (CDH) were treated in the authors' hospital. Eighty-six survived; of these, 10 patients (11.6%) had gastroesophageal reflux (GER) after repair of CDH. Seven occurred in the past 5 years, during which time advanced intensive care including extracorporeal membrane oxygenation (ECMO) was used. Vomiting started within 4 weeks after repair of CDH in eight cases, and hiatal hernia was demonstrated in six cases. Three patients responded to conservative therapy; the other seven required antireflux surgery. Several factors are believed to be possible causes of the development of GER in CDH cases. Among them, slow pulmonary expansion of the affected side was thought to be the most important. Namely, in a case of CDH associated with severe hypoplastic lung, the esophagus may be deviated to the affected side before the lung is expanded. After expansion, the abdominal esophagus shortens, and GER or a hiatal hernia can occur in severe cases. There were seven such patients in our series of 10. With the increase in the survival rate of CDH cases associated with severe hypoplastic lung, the number of such patients also may increase. Therefore, some additional procedure to prevent the lower esophagus from sliding will be necessary in the repair of diaphragmatic hernia. PMID- 7844719 TI - Nutritional management of dumping syndrome associated with antireflux surgery. AB - Eight children were identified as having dumping syndrome by a glucose tolerance test and evidence of rapid gastric emptying. All had undergone a fundoplication with concomitant feeding gastrostomy placement at 18.4 +/- 17.4 months of age (range, 3 to 54 months). Symptoms suggestive of dumping syndrome occurred 1 to 4 months after surgery. There was considerable delay in diagnosis (3 to 8 months). These children were successfully managed with nutritional manipulation alone, using a combination of a complex carbohydrate and a fat emulsion. Complete resolution of symptoms and normoglycemia was achieved in all the children, without any complications. PMID- 7844720 TI - Docosahexaenoic acid status of patients with extrahepatic biliary atresia. AB - Docosahexaenoic acid (DHA) is believed to be an important long-chain polyunsaturated fatty acid (LCPUFA), which may be essential for neurofunction in infants. Patients with extrahepatic biliary atresia (EBA) may have DHA deficiency secondary to fat malabsorption. The authors investigated DHA and other LCPUFA levels in plasma and red blood cell (RBC) phospholipids of patients after the Kasai portoenterostomy and after supplementation with essential fatty acids. Ten children aged 8 to 17 months (mean, 12.6 months) comprised the study group. Five were jaundiced and five had a normal bilirubin level. The patients received 1 mL/kg of fat emulsions (10% Intralipid, containing 50% linoleic acid and 9% alpha linolenic acid) in addition to an age-appropriate diet. Additional supplements were ursodeoxycholic acid (UDCA) (15 mg/kg/d) and taurine (100 mg/kg/d). The percentages of DHA in both plasma and RBC phospholipids of patients in the jaundiced group were significantly lower than those of normal children. Patients in the jaundice-free group had significantly lower levels of DHA and higher levels of linoleic acid in both plasma and RBC phospholipids in comparison to the normal group. This study shows that postoperative EBA patient become DHA deficient even when supplemented with fat emulsions (largely composed of linoleic acid) that contain DHA's precursor, alpha-linolenic acid. This demonstrates a deficiency in the long-chain acid desaturase activity of these patients. It is recommended that excessive/linoleic acid intake be avoided and that all EBA patients have small amounts of DHA added to their lipid supplementation. PMID- 7844721 TI - Does the morphology of the extrahepatic biliary remnants in biliary atresia influence survival? A review of 205 cases. AB - Resected extrahepatic remnants taken at the time of portoenterostomy were examined in a single-center review of 205 cases of biliary atresia. The morphological features of the size and number of residual ducts at the porta hepatis and the degree of inflammation at the porta hepatis were analyzed using a semiquantitative scoring system. The morphology of the common hepatic and common bile duct was classified into seven types. These features were then related to age at time of initial surgery and to survival. This showed that few or absent ductal remnants at the porta hepatis and absence of portal inflammation were predictors of poor prognosis. These histological features may represent the "burnt out" end result of the disease process. There was no correlation between age at time of portoenterostomy and either portal duct patency or portal inflammation. The common hepatic and common bile duct were variably involved in the sclerosing process, but the patterns of obliteration were not indicative of prognosis. The severity of intrahepatic biliary cholangiopathy and the extent of liver damage may ultimately be more important to survival in the long term. PMID- 7844722 TI - Hepatocellular carcinoma and liver cell dysplasia in children with chronic liver disease. AB - The histology of 72 livers from 72 children who underwent liver transplantation was reviewed. Nine children (12.5%) had hepatocellular carcinoma (HCC) and/or liver cell dysplasia (LCD) in their native livers. Ages at the time of transplantation ranged from 2 months to 11 years. Primary liver diseases included tyrosinemia (3), biliary atresia (2), chronic active hepatitis B (1), chronic active non-A non-B non-C hepatitis (1), idiopathic neonatal hepatitis (1), and neonatal iron storage disease (1). Explanted livers showed large multifocal HCC in two cases, incidental HCC in three, and dysplastic nodules in four. LCD also was present in three cases in conjunction with HCC. All patients had cirrhosis. Alpha-fetoprotein was measured in six children and was elevated in all six (range, 300 to 1,770,000 ng/mL; normal, 0 to 15 ng/mL). Abdominal computed tomography, ultrasonography, and/or magnetic resonance imaging showed large masses in two cases, but did not detect the tumors of less than 2 cm or the dysplastic nodules in the other seven children. After a follow-up period of 2 months to 3 years (mean, 19.8 +/- 12.1 months), eight children are alive and have no evidence of recurrence. The patient with neonatal iron storage disease died 2 months after transplantation, without evidence of tumor recurrence. The authors conclude that children with end-stage liver disease of diverse causes referred for liver transplantation may have LCD and/or HCC. Serial determination of alpha fetoprotein and images studies may detect early lesions curable by liver transplantation. PMID- 7844723 TI - Abdominal expansion as a bridging technique in stage IV-S neuroblastoma with massive hepatomegaly. AB - Stage IV-S neuroblastoma has a relatively favorable outcome. However, urgent surgical treatment may be necessary for management of life-threatening complications related to massive hepatomegaly caused by metastatic tumor infiltration. The enlarged liver often becomes of primary concern because diaphragmatic elevation results in life-threatening respiratory embarrassment. An external SILAS-TIC dome has been used as a temporizing procedure to decrease the intraabdominal pressure. The authors developed a modification of this approach using an internal polytetrafluoroethylene patch to create a ventral hernia. This technique decreases the potential complications of prosthetic material use, namely, risk of infection. The graft may be left in place for an extended period and removed in staged operations as the bulk of the metastatic tumor regresses. PMID- 7844724 TI - Necrotizing enterocolitis: laboratory indicators of surgical disease. AB - The timely distinction between infants with necrotizing enterocolitis (NEC) who need surgery and those who are likely to recover with medical management is important, but it may be difficult clinically. Because pneumoperitoneum is not always present, additional markers of bowel gangrene are needed. Among 73 babies managed for NEC over the study period, 49 (67%) met the study criteria of Bell's stage > 1, and their records were reviewed to determine the usefulness of common laboratory tests in predicting outcome. The patients were divided into three groups based on management. Group 1 (7 patients) required surgery at the time of initial presentation because of pneumoperitoneum. The remaining 42 patients were initially managed medically, 19 of whom (group 2) recovered successfully; the other 23 (group 3) required surgery. The combination of certain laboratory tests, ie, white blood cell count (WBC), immature:total neutrophil ratio (I:T), platelet count (PLT), and base excess (BE), was of significance in distinguishing between infants who would need surgery and those who would recover with medical therapy (group 3 v group 2) 4 to 12 hours or 12 to 24 hours after the diagnosis of NEC was established. A scoring scale was developed, with a point for each of the following: WBC < 9,000/mm3, I:T > .5, PLT < 200,000/mm3, and BE < or = -2. A score of > or = 3 during 4 to 12 hours after diagnosis of NEC strongly predicted the presence of surgical disease (positive predictive value, 100%; negative predictive value, 76%; specificity, 100%; sensitivity, 64%).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7844725 TI - Absent intestinal musculature: anatomic evidence of an embryonic origin of the lesion. AB - Absent intestinal musculature is a rare entity of uncertain etiology. The diagnosis is confirmed histologically by segmental absence of the intestinal muscularis. The remaining layers of the bowel wall are completely intact, and notably absent are significant inflammation and hemorrhage. The authors report two cases of segmental absence of intestinal musculature presenting as perforations. There was gross or microscopic evidence of diverticula formation at sites of perforation and absent muscle. Based on the anatomic evidence in these specimens and a review of the surgical literature, we propose that the etiology is based on embryologic diverticuli. PMID- 7844726 TI - Two-dimensional demonstration of myenteric nerve plexus: application for pseudo Hirschsprung's disease. AB - The use of two-dimensional demonstration of myenteric nerve plexus for the morphological estimation of pseudo-Hirschsprung's disease is introduced. By fluorescent immunohistochemistry for S-100 protein on flat-mounted frozen sections, a decrease in the amount of ganglionic plexuses in the small intestinal segments in cases of pseudo-Hirschsprung's disease was able to be distinguished from normoganglionic plexuses in control cases. Moreover, a morphological difference between the two types of cases was clearly demonstrated. This method may be an indispensable tool in the reliable diagnosis of pseudo-Hirschsprung's disease. PMID- 7844727 TI - Repositioning the misplaced colostomy for high imperforate anus: report of a new technique. AB - The case of a 2-year-old boy with high imperforate anus and an incorrectly positioned colostomy (in the left upper quadrant of the abdomen) is presented. To relieve the resulting tension on the distal rectosigmoid colon and to allow for its use in a combined pull-through and posterior sagittal anorectoplasty, the colostomy was moved to the subumbilical area. PMID- 7844728 TI - Sacroperineal anorectoplasty using intraoperative ultrasonography: evaluation by computed tomography. AB - A new operative technique that uses ultrasonography during sacroperineal or sacroabdominoperineal anorectoplasty was performed on seven patients with an intermediate or high anorectal malformation. Ultrasonography was used for the purpose of making a pull-through tunnel under visual guidance. The results of this technique were evaluated by computed tomography scanning to find the anatomic position of the pulled-through rectum in relation to the anal sphincter muscle. Postoperative computed tomography scans showed that the rectum was correctly placed in the center of the sphincter muscle in all patients. PMID- 7844729 TI - In utero defecation of the nondistressed fetus: a roentgen study in the goat. AB - An experimental study was performed to investigate gastrointestinal motility and meconium passage, with simultaneous blood gas measurements, in the fetuses of eight pregnant goats at 110 to 114 days' gestation (full term, 147 to 155 days). With the goats under halothane anesthesia, a nasogastric tube and a heparinized central venous catheter were inserted into the fetuses. 24 hours after surgery, 10 mL of gastric juice from the fetus was replaced with a nonhydrosoluble contrast medium, and serial roentgenograms and blood samples (for pH, PO2, and PCO2 measurement) were taken every 4 hours. All fetuses began to pass the contrast medium into the amniotic cavity within 16 to 22 hours, and central venous blood gas values were normal. The results of this study suggest that the fetus, which urinates routinely, also defecates routinely into the amniotic cavity, even in the absence of distress. The increased incidence of meconium staining in fetal distress conditions may be indicative of impaired clearance of amniotic fluid. PMID- 7844730 TI - Hemodialysis via the Scribner shunt in childhood: a surgical evaluation. AB - From 1973 to 1988, 105 children with renal failure (average age, 6.5 years; range, 5 days to 16.2 years) were treated with hemodialysis via surgically implanted Scribner shunts (n = 120). The average duration of dialysis was 16 days (range, 1 to 194 days). Twenty-three patients died during treatment or during the hospital stay because of the underlying disease; no patient died because of shunt complications. The treatment was initially successful for 82 children, but 14 of them died within several months of discharge. Among the initially surviving 82 patients, the shunt was the only means of access for dialysis in 52. In the other 30, the primary Scribner shunt was unsuccessful; it required replacement, or the type of dialysis had to be changed. The shunts were implanted in the forearm in 23%, the groin in 40%, and the ankle in 37%. Early complications were local bleeding (17%) after an average of 37.3 days, shunt occlusion (34%) after an average of 47.3 days, infections (9.3%) after an average of 43.9 days, and decreased blood flow (8.5%) after an average of 47.7 days. Vessels were reconstructed after discontinuation of dialysis in 28 cases, in which the Scribner shunt had been implanted in the groin. No patient experienced immediate ischemic problems. Long-term follow up results were obtained for 60% (n = 40) of the surviving 68 children after an average of 7 years (range, 2.1 to 15.2 years). We found no evidence of arterial or venous complications at the former shunt site.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7844731 TI - Inguinal herniotomy in young infants, with emphasis on premature neonates. AB - Over a period of 6 years, 251 infants under 6 months of age underwent repair of inguinal hernias (IH; n = 311). There were 241 males and 10 females. Incarceration occurred in 59 infants (24%), one of whom had bilateral incarceration. As a result of the authors' policy to operate on infantile IH within 7 days of diagnosis, only 6% of the incarcerations occurred in already diagnosed cases. Sedation and taxis did not reduce the hernia in 22 cases (38%); transperitoneal closure of the internal ring was performed in 14 of these. Eighty nine infants (36%) were born premature; thirty-nine (41%) of these had been ventilated before, a possible cause of the hernia. Bilateral presentation was more common in the premature infants (35% v 17%); surprisingly, incarceration was less common (13% v 24%). Hence, the policy of delaying herniotomy until discharge from the neonatal unit was justified. During follow-up, six recurrences were noted and two cases of testicular atrophy. PMID- 7844732 TI - Single incision for bilateral inguinal herniorrhaphies in female children. AB - One hundred eight consecutive bilateral inguinal herniorrhaphies were performed in female infants and children over the past 56 months. A technique that uses a single suprapubic incision is described. The average age was 29.8 months. The operative time was decreased by 5.6 minutes, and the final results were excellent. PMID- 7844733 TI - Distal spinal cord pathology in the VATER association. AB - Herein the authors report the pathology of six cases of VATER association and tethered spinal cord that underwent operative intervention for removal of lipomas of the conusfilum terminale and/or release of the tethered cord. In five of the six patients, the excised filum terminale consistently showed excessive mature adipose tissue, normal blood vessels, small myelinated nerve fibers, and fibrous connective tissue. One patient had mature lobulated adipose tissue and vessels only. It is concluded that patients with the VATER association who present with distal spinal cord pathology consistently have abnormal involution of the filum terminale, the hallmark being an abnormal collection of mature fat, thickening of the filum, and extension of the fat into the conus medullaris. PMID- 7844734 TI - Personality variables and self-medication in substance abuse. AB - Khantzian (1985) has proposed a model of substance abuse that asserts that some drug-dependent individuals select a drug of choice to provide relief from specific painful affective states. This study was undertaken to examine the self medication hypothesis in four groups of substance abusers defined by their use of specific drugs. The Personality Assessment Inventory (Morey, 1991), an inventory characterized by scales of homogeneous clinical content, was used to examine group differences in symptomatology and personality traits. Results suggest that there are traits or symptoms that separate various groups of drug-dependent patients, but not in concordance with the self-medication hypothesis. PMID- 7844735 TI - The MCMI-II diagnosis of schizophrenia: operating characteristics and profile analysis. AB - The Millon Clinical Multiaxial Inventory-II (MCMI-II) scores of 35 schizophrenic inpatients were compared with scores from a matched group of 35 psychiatric inpatients with no thought disorder. The operating characteristics of the Thought Disorder (SS) scale in overlapping and nonoverlapping form were determined using various cutoff points defined by Base Rate (BR) scores or the numbers of prototypic items endorsed by the subject. The Thought Disorder scale was found to perform poorly--no better than chance (Prevalence = 50%)--at correctly classifying patients as schizophrenic or nonschizophrenic, regardless of the type of cutoff lines used. A profile analysis was performed on six schizophrenia relevant scales in search of a distinguishing schizophrenia profile. Results indicated that the schizophrenic group produced no distinct profile. Results are discussed in terms of their relevance for clinicians and further research. PMID- 7844736 TI - Depressive personality styles and the five-factor model of personality. AB - The depressive personality constructs described by Blatt (1990; Dependency and Self-Criticism) and Beck (1983; Sociotropy and Autonomy) were examined in relation to the five-factor model of personality. Male (N = 91) and female (N = 81) undergraduates completed the Depressive Experiences Questionnaire (Blatt, D'Afflitti, & Quinlan, 1976), the Personal Style Inventory (Robins et al., 1993), and the NEO Personality Inventory (NEO-PI; Costa & McCrae, 1985). Friends of the subjects completed a peer-report version of the NEO-PI. Dependency and Sociotropy were positively correlated with Neuroticism and with Agreeableness in both men and women. In women, Self-Criticism and Autonomy were positively correlated with Neuroticism and negatively correlated with Agreeableness. In men, Self-Criticism was positively correlated with Neuroticism, but Autonomy was negatively correlated with Agreeableness and Openness. Similarities and differences between Blatt and Beck's constructs were discussed. Research addressing vulnerability to depression may be able to profit from work on the five-factor model of personality. PMID- 7844737 TI - The relation between socialization and antisocial behavior, substance use, and family conflict in college students. AB - Gough's (1960) Socialization (So) scale has been widely used as a measure of the extent to which societal values are internalized. It is well documented that antisocial individuals evidence low So scores but less clear that low So scores predict antisocial behavior in nonclinical samples. Two studies conducted at different universities in different geographical regions and different decades provided evidence consistent with this hypothesis. Results from Study 1 revealed that self-reports of several types of antisocial behavior and substance use were significantly more common among Low-So than High-So undergraduate men and women. Study 2 replicated principal findings for both men and women using correlational analyses. In addition, Study 2 yielded a significant relation between low So scores and greater family conflict as well as several gender differences reflecting stronger correlations in men than in women. These findings indicate substantial generality for the relations between socialization and antisocial behavior, especially in men, and are consistent with the use of the So scale to identify subjects who share important characteristics with criminal or psychopathic groups. PMID- 7844738 TI - Mini-markers: a brief version of Goldberg's unipolar big-five markers. AB - Goldberg (1992) developed a robust set of 100 adjective markers for the Big-Five factor structure found in phenotypic personality description. Because and even briefer marker set might be advantageous under certain assessment conditions, the performance of these 100 markers in 12 data sets was scrutinized, leading to the selection of an optimally robust subset of only 40 adjectives. This "Mini-Marker" subset demonstrated unusually impressive features for an abbreviated inventory, consisting of five scales that show, in comparison to the original scales, less use of difficult items, lower interscale correlations, and somewhat higher mean inter-item correlations; alpha reliabilities are somewhat lower. A format for administering this briefer inventory is appended. PMID- 7844739 TI - Form C of the MHLC scales: a condition-specific measure of locus of control. AB - Form C of the Multidimensional Health Locus of Control (MHLC) scales is an 18 item, general purpose, condition-specific locus of control scale that could easily be adapted for use with any medical or health-related condition. Data from 588 patients with one of four conditions--rheumatoid arthritis, chronic pain, diabetes, or cancer--were utilized to establish the factor structure of Form C and to establish the reliability and validity of the resultant four subscales: Internality; Chance; Doctors; and Other (powerful) People. The alpha reliabilities of the subscales are adequate for research purposes. Data from the arthritis and chronic pain subjects established that the Form C subscales were moderately stable over time and possessed considerable concurrent and construct validity. Some discriminant validity of Form C with Form B of the MHLC was also demonstrated. PMID- 7844740 TI - Frequencies of MMPI-168 code types among asymptomatic and symptomatic HIV-1 seropositive gay men. AB - Welsh codes of Minnesota Multiphasic Personality Inventory-168 (MMPI-168) profiles were calculated for 151 HIV-1 seropositive gay men and 27 gay seronegative controls. Although 99% of seropositives' profiles were clinically elevated, the profile configurations among subjects were varied. These data document the presence of considerable emotional distress among HIV-infected individuals, yet the heterogeneity of codes encountered argues against generalizations of seropositive subjects based upon mean MMPI profiles. PMID- 7844741 TI - [Na+/K+/Cl- cotransport in the cell membrane]. PMID- 7844742 TI - A comparison of the color stability of conventional and titanium dental porcelain. AB - Simulation of naturally appearing enamel in fixed prosthodontics is best achieved with porcelain. This study investigated the color stability of two different dental porcelains, Ceramco and Procera, after they were exposed to 900 hours of accelerated aging. Twenty titanium plates provided the substrate to which the Procera porcelain samples in shades A3, A3.5, C3, and D3 were fired, five in each shade. An equal number of metal-ceramic alloy (Olympia) plates were cast to the same dimensions to form the 20 substrates to which Ceramco porcelain was fired. The four shades of porcelain were again added to each of the samples. Commission International de l'Eclairage L a b readings were recorded with a Minolta Chroma Meter II before and after exposure to 900 hours of accelerated aging simulation. After the aging process the color differences between the pretest and posttest condition were calculated. Although statistical comparisons demonstrated a difference in color change (p < or = 0.05) between Ceramco and Procera porcelain in three of the shades tested, critical remarks of color refer to both types having "slight" color change. In terms of color stability, neither porcelain had "noticeable" changes after 900 hours of accelerated aging. PMID- 7844743 TI - Comparison of shear bond strengths of two resin luting systems for a base and a high noble metal alloy bonded to enamel. AB - Researchers are investigating the use of noble metals for the fabrication of resin-bonded prostheses because of concerns about health hazards of nickel and beryllium in base metal alloys. Tin-plating has been advocated to improve the bond of resin luting agents to noble metal alloys. Some manufacturers have suggested that tin-plating is unnecessary to bond noble metal alloys to etched enamel with their products. In this study, Rexillium base metal and Olympia noble metal alloy specimens were bonded to extracted human teeth with the use of two resin luting agents (F21 and Panavia OP). One third of the noble metal specimens were tin-plated, one third were oxidized, and one third were oxidized and sandblasted. Each of the bonded specimens were thermocycled and subjected to a shear force until bond failure. The base metal specimens bonded with Panavia OP luting agent exhibited the greatest mean shear bond strengths. The tin-plating surface treatment significantly increased the mean shear bond strengths of Olympia noble metal specimens. PMID- 7844744 TI - Repair of denture base resins using visible light-cured materials. AB - Specimens of denture base resins were repaired with autopolymerizing and visible light-cured (VLC) repair materials. Flexural properties were measured and revealed that the highest strength and toughness of joint are obtained by the autopolymerizing repair material and are independent on the base resin. The VLC materials exhibited a lower repair strength (22% to 58%) and toughness (9% to 33%) than those of the autopolymerizing resin. No interaction between base and repair material was detected, which was attributed to poor adhesive bonding created at the interface. PMID- 7844745 TI - The current status of maxillofacial prosthetic training programs in the United States. AB - A survey was conducted to examine the current status of maxillofacial prosthetics programs. Their relationship to private practice, compared curriculums, patients, and other recent changes of merit were evaluated, and the results of the survey are presented. PMID- 7844746 TI - Disclusion time measurement studies: a comparison of disclusion time between chronic myofascial pain dysfunction patients and nonpatients: a population analysis. AB - From a pool of 89 patients, 49 patients were classified as having chronic myofascial pain dysfunction syndrome (MPDS), and 40 were classified as asymptomatic or non-MPDS patients designated as the control group for the study. To achieve balanced sample size in both groups, 40 patients were arbitrarily selected from the MPDS group. All patients from each of the two primary groups were then categorized and assigned to one or more subgroups according to the following criteria: (1) jaw classification, (2) open occlusion, (3) previous orthodontic therapy, or (4) no previous orthodontic therapy. A fifth subgroup composed of only MPDS patients and equally divided into those who had or had not experienced orthodontic therapy was established to determine whether mean disclusion time differences occur between orthodontic and nonorthodontic MPDS patients. All 80 patients were evaluated for disclusion time of their right and left mandibular excursions to determine statistical population comparisons. Statistical assessment of right and left disclusion times for women and men in the MPDS and non-MPDS groups was performed separately for each of the five subgroups. Analysis of the comparisons revealed that in all except two of the subgroups, mean disclusion time was significantly longer in the MPDS patient group than in the non-MPDS group. The two subgroups in which this was not apparent were those with open occlusion and orthodontic patients compared with nonorthodontic patients. These findings suggest that lengthy posterior disclusion time may be of diagnostic importance when the differing etiologic factors of chronic MPDS patients are evaluated. PMID- 7844747 TI - A comparison of the diametral tensile strength, the flexural strength, and the compressive strength of two new core materials to a silver alloy-reinforced glass ionomer material. AB - This study compared three mechanical properties of two recently introduced core materials, a light-activated glass ionomer cement (VariGlass VLC) and a fluoride release dual cure composite resin (FluoroCore), with those of a conventional silver-reinforced glass-ionomer cement (Miracle Mix). Seventy-two samples (eight per product for each property) were prepared for testing diametral tensile strength, flexural strength, and compressive strength. The specimens were cured, stored for 24 hours at 37 degrees C in 100% humidity, and tested with the use of an Instron universal testing machine. The results of this study indicate that the diametral tensile strength, flexural strength, and compressive strength of the FluoroCore and VariGlass VLC materials were significantly higher than those of the conventional Miracle Mix. The values obtained with FluoroCore material were consistently higher than those obtained with VariGlass VLC material. PMID- 7844749 TI - Prosthodontic Treatment for the Geriatric Patient. Proceedings of the Toronto Symposium. Toronto, Ontario, December 1993. PMID- 7844748 TI - Prosthodontic treatment for the geriatric patient. PMID- 7844750 TI - Clinical epidemiologic concerns and the geriatric prosthodontic patient. AB - Investigations of the oral health of the elderly leave little doubt that disease and dysfunction are plentiful, although there is some debate on how the clinical observations translate into treatment needs. The problems appear to be greatest among the disabled and the institutionalized, whereas dentists generally show little enthusiasm for offering their services outside the confines of the traditional dental practice. Consequently the oral health concerns in the older population, and especially as they relate to prosthodontic treatment, remain substantially unanswered. PMID- 7844751 TI - Managing the medically compromised geriatric patient. AB - Demographic trends indicate that dentists will be treating more dentate geriatric patients, many of whom will be medically compromised. This article emphasizes the effect advancing age may have on the identification and management of common medical problems. In particular, cardiovascular disease, (ischemic heart disease, hypertension, prevention of infective endocarditis), diabetes, and arthritis (prosthetic joints) were reviewed. The prevalence of all these diseases increases with age and many geriatric patients have undiagnosed cardiac disease or diabetes. Knowledge of the pathophysiology of these common systemic diseases will be increasingly important to dentists in the future. PMID- 7844752 TI - Periodontal care for community-dwelling older adults. AB - The prevalence and severity of periodontitis increases with age. Epidemiologic studies have identified several risk variables associated with advancing periodontitis in older adults: namely tobacco smoking, frequency of dental appointments, infection with anaerobic bacteria considered periodontal pathogens, plaque and calculus accumulation, and some socioeconomic variables. Future morbidity from periodontitis might be reduced by minimizing the impact of these risk-associated variables at younger ages. Treatment of periodontal disease in community-dwelling older adults should be aimed at (1) targeting care to their overall health, functional, and esthetic needs; (2) strategic planning for maximal health and patient satisfaction; (3) documentation of past susceptibility and current risk; (4) control of principal risk factors; (4) investing time in patient education and informed consent; and (5) planning ahead for a potentially catastrophic decline in health. Periodontal treatment needs should be met in an integrated treatment plan that considers the overall prognosis for the dentition and individual teeth and the most efficacious prosthodontic options. Frequent recall for supportive periodontal care is essential. Several medical, physical, and societal impediments to provision of optimal care for older adults should be sought and minimized by the practitioner. Population dynamics and health-oriented activism among older adults are increasing the demand for essential and elective periodontal and prosthodontic services, which are met by implant-supported prostheses. Over the next few decades, as the incidence of tooth loss declines and our knowledge of the pathogenesis of periodontitis and biology of tissue regeneration increases, there will likely be a renewed emphasis on the preservation of the natural periodontium. PMID- 7844753 TI - Temporomandibular disorders in the geriatric population. AB - Contrary to popular assumptions that temporomandibular disorders may become more prevalent with increasing age, a review of the literature shows that this is clearly not the case. Instead, it seems that most objective "signs" of temporomandibular disorders, namely clicking, tender joints and muscles, crooked opening, limited movement, and so forth, are found either less often in the elderly or at approximately the same rate in all adult age groups. Subjective complaints, however, decrease as populations get older, and the demand for treatment declines accordingly. PMID- 7844754 TI - Dental management considerations for institutionalized geriatric patients. AB - The elderly in general and the residents of nursing home facilities in particular are increasingly frail, old, and dentate. Dentists should be prepared to manage the oral health needs of elderly clients who are afflicted with complex medical, functional, and dental disabilities. Proper dental management requires a commitment to provide treatment of quality despite myriad obstacles. From the outset of evaluation, there must be recognition of the likelihood of compromised self-care and the development of proactive strategies to address dependence in oral care. PMID- 7844755 TI - Operative dentistry considerations for the elderly. AB - As the mean age of an older dentate population increases, so does the incidence of dental caries in its primary and secondary forms. Primary and secondary root decay gingival to existing restorations are significant operative problems prevalent in the elderly. Treated root decay is prone to recurrence if the etiology is ignored. Effective, customized prevention must parallel operative intervention. The dentist today has a wider selection of techniques and materials than ever before to treat the elderly patients. Use of preventive restorative materials such as conventional and hybrid glass ionomer materials for the treatment of root decay are discussed. PMID- 7844756 TI - Fixed prosthodontics and esthetic considerations for the older adult. AB - A new generation of older adults, who are more educated, health-conscious, and economically independent than their predecessors is bringing a fresh perspective and poses unique opportunities and challenges to fixed prosthodontics. Subtle differences in technique, attention to detail, and innovative application of materials and procedures are the main ingredients of successful fixed prosthodontic care for seniors. The goals of fixed prosthodontics for the older adult are fundamentally different from those for a younger population. A practice that enhances the integrity of residual tooth structure while simultaneously creating an environment less prone to dental disease and disability should be emphasized. PMID- 7844757 TI - Removable partial prostheses for the elderly. AB - Elderly partially edentulous patients can have teeth replaced with removable or fixed prostheses supported by mucosa, teeth, or implants. Age per se does not influence which option is best. Instead, the relative health of the patient, dental tissues, and the patient's finances determine treatment. A three-level index of these factors, the PTF index, is proposed to assist in the decision making for treatment. Removable partial prostheses (RPPs) can be indicated for all patients because RPPs offer esthetic, versatile, noninvasive, and reversible features. They are particularly indicated when remaining teeth are questionable. If teeth are lost, they can be more easily added to existing RPPs compared with fixed prostheses. Six changes to ideal designs are illustrated in this article for prostheses with a compromised dentition, to make continued prosthetic service simpler. PMID- 7844758 TI - A review of traditional therapies in complete dentures. AB - The number of persons in the United States and Canada over 65 years of age who are edentulous and in need of complete dentures appears to be decreasing as a percent of the total population (by the year 2030), but the total number of patients needing these services will be almost the same as it is today. Administering complete denture prosthodontics to geriatric patients will continue to be a formidable part of the general dentistry practice well into the next century despite changing demographics. Careful dental evaluation of the patient through a well-structured examination and care based on sound principles and concepts continues to be the standard that must be provided. A lifetime commitment by the patient to a program of recall and maintenance for continuous monitoring of the dentures and the oral tissues is essential for older adult edentulous patients. We should periodically review these traditional therapies to improve our knowledge. PMID- 7844759 TI - Overdentures with roots or implants for elderly patients: a comparison. AB - Roots maintained under the denture base preserve the alveolar ridge, provide sensory feedback and improve the stability of the dentures. Furthermore, with the use of copings and precision attachments, retention of the denture is provided. Overdentures are a favored treatment modality for elderly patients with few remaining teeth because adaptation to wearing dentures is facilitated. Recently, overdenture treatment with the use of implants has become popular for edentulous elderly patients who are maladaptive to complete dentures. Although the biologic basis of implants installed in the bone is different from roots surrounded by a periodontal membrane, the prosthetic concept is similar. Tactile sensibility is reduced because of the absence of periodontal receptors. However, oral function with overdentures supported by roots or implants is comparable and does not seem to depend on the presence of a periodontal membrane. Comparison of studies demonstrates a higher tendency for success when overdentures are supported by implants than by roots. This is particularly true for mandibular overdentures, whereas for maxillary implants, more frequent failures are observed with low bone quality and short implants. This study discusses results and special applications with regard to an elderly population who will profit from the benefit of overdenture therapy. PMID- 7844760 TI - Preprosthetic surgery in the elderly. AB - Preprosthetic surgery is an aspect of dentistry that has a close relationship to prosthodontics and oral and maxillofacial surgery. The main functions of preprosthetic surgery are elimination of pathology in the denture-bearing soft and hard tissues, and ridge improvement. Limited vestibuloplasty is still considered a predictable and cost-effective procedure for patients who are well adapted to removable dentures. The excellent documentation of osseointegrated implants as supportive and retentive devices for prostheses has reduced the need for major ridge-improving surgery. Many clinical conditions, especially in the maxilla, cannot be managed solely with implants. The combination of preprosthetic surgery and implants may solve problems that neither discipline can solve alone. PMID- 7844761 TI - Osseointegration for elderly patients: the Toronto study. AB - Successful osseointegration promises a virtual panacea for the edentulous predicament. However, the impact of this technique on specific age groups is far from clear. In an attempt to determine the efficacy and effectiveness of implant supported prostheses in geriatric patients, the treatment outcomes of elderly patients already included in ongoing clinical trials were assessed. The following preliminary observations were made: (1) being elderly is not a contraindication to long-term implant survival; (2) successful osseointegration can be maintained irrespective of a patient's oral hygiene performance; and (3) diverse prosthesis designs appear feasible. PMID- 7844762 TI - Making a custom tray for elastomeric impression materials without a primary cast. AB - The custom tray is recommended for impressions in which it is desirable to establish precise borders, such as Kennedy class I maxillary partial dentures, where an accurate postpalatal seal is a requirement. The peripheries, including the postpalatal seal, can be established with a high degree of accuracy with a custom tray. A procedure is described that does not require a primary impression or a primary cast to make a custom tray for elastomeric impression materials. PMID- 7844763 TI - Custom impression trays with a new hypoallergenic material. PMID- 7844764 TI - Schizophrenia family work: mental health nurses delivering an innovative service. AB - 1. Mental Health Nurses (MHNs) have an unique role in providing care to the mentally ill. The Thorn Nurse Initiative designed to prepare and evaluate the work of MHNs has been successful in providing nurses with the skills of Family Work for Schizophrenia. 2. The effectiveness of family work in improving MHNs' knowledge of and attitudes about schizophrenia has been demonstrated, and there is increasing evidence of the efficacy of MNHs in delivering family work. 3. The impact of schizophrenia on families tends to go unrecognized, and there is an urgent need to train nurses in family work to help families cope with this illness. 4. Families are extremely valuable and a positive resource for clients. The emphasis of family work is to promote and support all families in improving their knowledge of schizophrenia, and its effects, and in developing their coping skills. PMID- 7844765 TI - Collaboration between families and university faculty: a partnership in education. AB - 1. Collaboration between nursing faculty and family members of persons with mental illness can help nursing students form a positive view of the family as a resource to treatment and as a source of support for the client. 2. Faculty and family collaboration may result in a program of home visiting, which can augment the psychiatric nursing practicum and increase nursing student empathy and sensitivity to the family burden of mental illness. 3. Nursing students use of CAMI instructional resources has accelerated the incorporation of biological perspectives of mental illness into the nursing curriculum. PMID- 7844766 TI - Beyond discharge: telephone follow-up and aftercare. AB - 1. Decreased length of stay, inadequate aftercare service, and insufficient attention on the part of professionals to the immediate difficulties of postdischarge adjustment have made the transition from psychiatric hospital back to the community more difficult. 2. Telephone follow-up and aftercare groups ease the patient's transition from hospital to community, help to prevent rapid readmission, and provide a feedback loop to the staff on discharge planning. 3. Little is known about the immediate postdischarge experience for patients and its effects on long-term adjustment. Extended contact with the discharged patient is an ideal way to begin to collect such data. PMID- 7844767 TI - Projective drawings: helping adult survivors of childhood abuse recognize boundaries. AB - 1. Boundary issues for adult childhood trauma survivors are complex, problematic, difficult to resolve, and occur on a level of unawareness. 2. Boundary concepts can be found in all types of projective drawings. 3. Projective drawings can facilitate awareness and understanding of boundary problems experienced by adult childhood trauma survivors. PMID- 7844768 TI - Patients with disordered water balance. Innovative psychiatric nursing intervention strategies. AB - 1. Patients with disordered water balance (DWB) have difficulty with fluid intake/output and osmoregulation. These difficulties are characterized by polydipsia, polyuria, significant variation in pattern of excretion, abnormal diurnal weight gain, and behavioral changes. 2. Therapeutic milieu-management strategies for patients experiencing acute and chronic phases of DWB are the cornerstone of long-term management of these patients. 3. Implementation of the intervention and milieu-management strategies described in this article resulted in a reduction of patients requiring acute medical treatment subsequent to an acute phase of DWB. PMID- 7844769 TI - Ill health in spouses of psychiatric patients: cause or consequence? AB - 1. In the literature on the marital relationship of psychiatric patients it often has been reported that the healthy spouses may show a considerable degree of psychological distress. 2. A correlation of psychiatric disorders in married couples commonly has been interpreted according to two models: assortative mating and pathogenic interaction, neither of which can sufficiently explain the spousal psychiatric illness correlation. 3. The issue of psychiatric illness in the spouses of patients merits more attention from both researchers and clinicians. A psychiatric illness in one spouse must be understood within the ongoing interaction of the marital relationship. PMID- 7844770 TI - Solution-focused therapy and inpatient psychiatric nursing. AB - 1. Creative ways must be found to deliver high quality nursing care--with fewer nurse-patient interactions--to patients experiencing more severe problems. 2. Solution-focused therapy underscores the positive attributes of the patient; facilitates the development of a working partnership between the nurse and patient; helps the patient develop future-oriented goals; and identifies actions necessary for reaching those goals. 3. As a result of incorporating solution focused therapy at the institution highlighted in this article, the quality of patient care, as well as effectiveness and cohesiveness of the nursing staff, improved. PMID- 7844771 TI - Methadone anonymous: a 12-step program. Reducing the stigma of methadone use. AB - 1. Methadone is a synthetic narcotic that relieves the craving for heroin. Methadone enables the former heroin addict to feel well and unimpaired by side effects, and be free of heroin hunger. 2. Methadone Anonymous (MA) is a 12-step program (similar to Alcoholics Anonymous and Narcotics Anonymous) for individuals with addictions who are in methadone treatment programs. 3. The MA program at our facility in New York has been extremely successful. Patients carry the message to new sites and leave information for potential groups. Requests for information are received weekly, both from neighboring states and even abroad. PMID- 7844772 TI - Do you go to hell if you commit suicide? PMID- 7844773 TI - [What is the dose?]. PMID- 7844774 TI - [Management of accidental internal exposure]. AB - Radionucleides can penetrate into the body via the lung, the digestive tract, wounds and sometimes through healthy skin. Once they have penetrated the body, they can either remain localized at the site of entry or be rapidly metabolized. The risk is late effects. Radioelements must be eliminated as rapidly as possible decreasing the exposure proportionally. The effectiveness of the treatment depends on early institution. Nevertheless, emergency intensive care or surgery may be required. As soon as possible, explorations must be carried out to evaluate the level of contamination (human spectrometry, radiotoxicological examinations) and to start treatment. Modalities include non-specific techniques (lavage, insolubilization, laxatives) and specific techniques such as complexation or isotopic dilution (iodine for iodine, Prussian blue for cesium, DTPA for plutonium, Diamox or sodium bicarbonate for uranium). Surgical cleaning of wounds and burns is an excellent means of decontamination. External contamination is often associated. Further contamination must be prevented immediately. PMID- 7844775 TI - [Magnetic resonance imaging and x-ray computed tomography in advanced cancer of the oral cavity. A comparative clinical, radiological and morphological study]. AB - The objective of this prospective study is to assess the impact of magnetic resonance imaging (MRI) and computed tomography (CT) as compared to physical examination in the choice of type of surgery for advanced intraoral cancers (with or without resection of the mandibula). From 1990 to 1993, we operated on 21 intraoral malignant tumors with segmental resection of the mandibula followed by a histological examination. The preoperative evaluation consisted of an MRI (n = 8), a CT (n = 8) or both (n = 5). MRI suspected an infiltration of the bone in 9 cases, CT in 4 and physical examination in 16. This was histologically confirmed in 6 of the 21 patients only. MRI and CT both have a high sensitivity, as does physical examination, but neither have a good specificity (physical examination: 5 true positive, 4 true negative, 11 false positive, 1 false negative; MRI: 4 true positive, 4 true negative, 5 false positive, 0 false negative; CT: 3 true positive, 7 true negative, 3 false positive, 0 false negative). In conclusion, the decision of a mandibular resection can only be taken after a careful physical examination, including palpation under general anesthesia in a fully relaxed patient. This is best accomplished during the pretherapy bronchoesophagoscopy, routinely performed for the detection of synchronous second primary tumors using toluidin blue as a vital staining method. If this initial evaluation gives a suspicion of a massive infiltration of the mandible, an MRI, rather than a CT, should be performed to determine the extent of the resection because of a high rate of artefacts with CT. PMID- 7844776 TI - [Imaging protocol in salivary pathology]. AB - Numerous techniques have been used for imaging salivary glands including standard radiography, scintigraphy, sialography, echography, computed tomography and finally NMI. These different techniques each have their own indications or complementary role. We therefore developed a protocol for using the different imaging techniques according to the different salivary pathologies encountered. This protocol is given as an examination flow chart to be used in light of clinical findings. A large number of images selected by P. Laudenbach illustrate the typical pathologies encountered. Special emphasis is placed on sialography, an important imaging technique, unfortunately somewhat neglected. PMID- 7844777 TI - [Triple and quadruple images in scan of fractures of the articular processes of the lower cervical spine]. AB - The authors describe the triple and quadruple image aspects of the articular pillar, which are encountered respectively in one-sided uni- and biarticular fractures of the lower cervical spine, and they have analysed these images' specificity from a retrospective study. This study concerned 52 cases out of a group of 220 patients hospitalised between 1979 and 1992, with an injury of the lower cervical spine and who underwent a CT-scan examination in addition to the conventional radiographic check-up. Among a total of 70 lesions, 14 uniarticular and 4 biarticular one-sided fractures were recorded. All presented these characteristic aspects, formed by the separated fragment of the articular process; the unseparated component of the process and, concerning the triple image the intact process, or concerning the quadruple image the fragments of the second fractured process. An only case of a transisthmian fracture associated with a fracture of the lower articular process showed a similar aspect, which underlines the high specificity of these images. PMID- 7844778 TI - [Value and results of radioguided deep spinal biopsy]. AB - MATERIAL AND METHODS. 76 percutaneous vertebral biopsies were performed with fluoroscopic guidance at the Radiology B Service, Hopital Cochin in Paris, from November 1991 to March 1994. There were 12 cervical, 23 thoracic, 45 lumbar and sacral biopsies. There were 71 patients (28 women and 43 men), aged 22 to 88 years old (mean age 55.9). The needle used was either a trophine needle (Mazabraud) or a cutting needle (Surcut) or both. We have been doing vertebral percutaneous biopsies for 20 years in our radiology Service, and we published a review of 100 cases in 1983. The aim of this second review is to actualize the technique and the results. RESULTS. An accurate diagnosis was made in 80% of all cases. Diagnosis were: malignancy (34 cases), infection (21 cases), benign compression fracture (10 cases), miscellaneous (11 cases). There were two complications, one at the cervical spine (aggravation of a cervical cord compression) and one at the thoracic spine (pneumothorax). CONCLUSION. Percutaneous vertebral biopsy under fluoroscopic guidance is a safe and reliable method of obtaining a diagnosis in different spine lesions, avoiding thus, in most cases, a surgical procedure. PMID- 7844779 TI - [Coraco-trochineal conflict or anteromedial conflict of the shoulder. Contribution of arthroscanners]. AB - Like the anterosuperior subracromial conflict, the coracotrochineal or anteromedial conflict of the shoulder is a groove pathology. In a series of 340 patients who had an arthroscan of the shoulder, including 245 with a conflict syndrome (70%), we observed an anteromedial conflict in 12 cases (8.5%) of the 140 patients with an intact cuff and 52 cases (50%) in 102 patients with an injured cuff. The frequency of the anteromedial conflict appears to be proportional to the degree of cuff injury. We described the signs of the trochin suggesting the anterior musculotendinous structures (subscapsular tendon and/or long biceps tendon) are involved and conclude that the anteromedial conflict is often misdiagnosed. It would appear to be a frequent complication of cuff injury (mechanical theory) which the surgeon should take into consideration when repairing cuff injury. PMID- 7844780 TI - [Responses of medical imaging in battered children. The Silverman-Ambroise Tardieu syndrome]. AB - Imaging procedures offer an important contribution to the syndrome of the abused child that F.N. Silverman himself proposes to call the Ambroise Tardieu syndrome. First they disclose and analyse the lesions which may involve bones, encephalon or spinal cord, viscera, soft tissues. Then they must answer four questions: Traumatic lesion or normal variant? If traumatic, are there arguments pointing to abuse, for instance multiple bone lesions of different ages and more specifically fractures of ribs, clavicle, spine, pelvis, phalanxes? Is there a possibility of a general disease explaining such traumatic lesions? Etiologies are revised including sensibility deficits. Finally are the bad treatments inflicted with an intention of hurting, injuring or destroying? The answer results of a discussion with clinicians and social interveners but some lesions, as phalanx fractures, may be determining. In this situation that involves the vital prognosis and may induce severe sequellae the imaging strategy, fully described, is of paramount importance. PMID- 7844781 TI - [Ultrasonography in the diagnosis and treatment of psoas abscess. Apropos of a study with 30 patients]. AB - The abscess of psoas are more often secondary to a loco-regional cause. The authors report a series of 42 abscess of psoas in 30 patients during 3 years. It concerns 16 men and 14 women witch a mean age of 35 years. The abscess was secondary to a spondylodiscis in 25 patients and primary in 5 patients. The size of the abscess was upper 5 cm with a variable ultrasound structure: liquid in 33 cases, hypoechogenic in 9 cases. All patients underwent a percutaneous treatment guided by ultrasonography. A single or multiple evacuation puncture with 16 Gauge needle were performed for 40 abscess. Complementary percutaneous drainage with 14 french drain was used in 3 cases. In 2 other cases, the percutaneous drainage was used firstly. The bacteriological study of puncture liquid isolated the germ in 8 cases. Evaluation has been assessed in only 29 cases. The recovery was reached in 12 abscess on 15 which were treated by a single puncture. In 10 abscess on 13 treated by multiple puncture; and in 4 abscess an 5 managed by drainage. The results demonstrate the accuracy of single or multiple drainage puncture associated with adapted antibiotherapy in the management of abscess. PMID- 7844782 TI - [History of diagnostic radiology at the Mayo Clinic]. PMID- 7844783 TI - [Aneurysmal bone cysts]. PMID- 7844784 TI - Post primary school teachers' view point on reproductive health and contraceptive practice among schoolgirls in Port Harcourt, Nigeria. AB - The view point of secondary school teachers on reproductive health, specifically, their attitude towards contraceptive practice among sexually active schoolgirls and general opinion on teenage pregnancy was examined. A sample survey of teachers was conducted in all the registered girls and mixed post primary schools in Port Harcourt. A substantial proportion of teachers were of the opinion that sexually active schoolgirls should not be encouraged to use contraceptives because they damage reproductive organs. A greater proportion (33.8%) of teachers was also of the opinion that schoolgirls should abstain from sex until they are married. This was closely followed by the suggestion that sexually active girls should use contraceptives (20.8%). The majority (48.3%) of teachers, however, advocated a sex education programme in the schools in order to prevent unwanted pregnancy. PMID- 7844785 TI - Pregnancy experience, knowledge of pregnancy, childbirth and infant care and sources of information among obstetric patients at King Khalid Hospital, Riyadh. AB - One hundred obstetrics patients were interviewed at King Khalid Hospital (Saudi Arabia) concerning their current pregnancy experience, knowledge of pregnancy and child care and sources of information on these topics. Interviews were conducted and a short knowledge test given to nulliparous, primaparous and multiparous patients. The overall mean score of respondents was 50.4%. Significant information deficits existed in: the implications of prescription drugs and dental care during pregnancy; time of conception; when to contact a physician for personal care. Nulliparous patients scored lower, and information deficits appeared in: when to call a physician for infant care, immunization for newborns and events during pregnancy. Respondents did not perceive physicians and nurses as significant sources of information when compared with alternative sources. PMID- 7844786 TI - Lead poisoning from paint--still a potential problem. AB - Regulations were introduced in the UK in the 1970s to limit the lead content of paints. This has greatly reduced the number of children poisoned by ingesting leaded paint. However, it is argued that old paintwork is still a lead poisoning hazard in some older UK properties. Paint collected from a children's nursery classroom in a London school included samples with lead concentrations exceeding suggested safety levels. Lead poisoning from paint is a problem which should not be forgotten in the UK, and may be a more serious problem in countries with less stringent lead in paint regulations. PMID- 7844787 TI - Using soft systems methodology to develop a simulation of out-patient services. AB - Discrete event simulation is an approach to modelling a system in the form of a set of mathematical equations and logical relationships, usually used for complex problems, which are difficult to address by using analytical or numerical methods. Managing out-patient services is such a problem. However, simulation is not in itself a systemic approach, in that it provides no methodology by which system boundaries and system activities may be identified. The investigation considers the use of soft systems methodology as an aid to drawing system boundaries and identifying system activities, for the purpose of simulating the outpatients' department at a local hospital. The long term aims are to examine the effects that the participative nature of soft systems methodology has on the acceptability of the simulation model, and to provide analysts and managers with a process that may assist in planning strategies for health care. PMID- 7844788 TI - Clinica Tibas: an experimental response to health system challenges in Costa Rica. AB - Several experiments in health services delivery featuring contractual arrangements between government and the private sector have been initiated in Costa Rica. This report describes a public-private partnership serving a community of 50,000. A 'cooperative' of providers stands to gain financially if it succeeds in providing clinic services in an efficacious and efficient manner. This experimental approach retains elements of the existing public system for health promotion and disease prevention while introducing innovations for increased organizational efficiency and client satisfaction. The clinic provides easier access to better care, including ambulatory surgery, pharmacy service, and home visits, and at a lower cost to government than that budgeted under pre existing arrangements. Inappropriate usage of area hospitals has been reduced; and a commitment to community participation and organized programming permit greater responsiveness to community needs. Those served by the clinic report satisfaction. Personnel also report satisfaction and enthusiasm for their work. Issues concerning extension of this model are considered. PMID- 7844789 TI - Whistle while you work in the health-related professions? AB - The spate of correspondence and publicity, following the disciplining, and subsequent settlement in his favour, at an Industrial Tribunal, of Stockport Health Authority Charge Nurse Graham Pink, suggested that the urge to blow the whistle was at almost epidemic proportions in the NHS. It might have been surmised that the only device which kept this under control was the fear of discipline and perhaps dismissal. This fear has been increased by the contracts of employment of the NHS Trusts which have outlawed acts of whistleblowing. There are similar pressures for those working in other health-related professions, and in health and safety, and environmental protection. It is important to question whether such severe strictures are in the public interest, or whether they are there to make the life of senior managers easier, or to make it possible to ensure that doctors, nurses, and other caring professionals and support staff, conform to budgetary constraints without resort to campaigning. PMID- 7844790 TI - Due diligence and food hygiene. PMID- 7844791 TI - Smokers have less dense bones and fewer teeth. AB - Women and men who smoke are more slender than their non-smoking counterparts and have a bone density appropriate to their degree of slenderness. As a result, they are more likely to sustain a fracture than their non-smoking counterparts. The lower bone density found in smokers may arise because of less stress and strain imposed on the skeleton by a slim physique. Smokers have poorer oral hygiene and less teeth than their non-smoking counterparts. The relationship between smoking and tooth pathology remains unclear: smoking may either act via a direct mechanism based on the toxicity of tobacco smoke or indirectly through body weight (ie the effect on teeth is part of a wider effect on bone structure). PMID- 7844793 TI - Health aspects of housing estates--the pharmacists' perspective. PMID- 7844792 TI - Polarisation and residualisation--producing unhealthy communities. PMID- 7844794 TI - Public health in the United States. PMID- 7844795 TI - Global surveillance network. PMID- 7844796 TI - The health of the nation: strategy for action for cancer prevention. PMID- 7844797 TI - Vaccine for hepatitis B. PMID- 7844798 TI - Can a low fat diet reduce atherosclerosis? PMID- 7844799 TI - Drug to combat ovarian cancer. PMID- 7844800 TI - The enemy within. PMID- 7844801 TI - Breast-feeding in Egypt. AB - Planning, implementation and evaluation of programmes to promote appropriate infant feeding practices require detailed, current information about these practices in the target populations. To estimate the prevalences and identify the correlates of overall breast-feeding and of exclusive breast-feeding in different age periods during infancy, a cohort of 152 apparently healthy neonates and their mothers were followed during October 1987 through April 1989 in rural Bilbeis, Sharqiya Governorate, Egypt. Feeding data were collected through twice weekly home visits thus reducing the potential for bias in our findings due to respondent recall errors. The prevalence of overall breastfeeding in the infants declined from 100% in age period 0-11 weeks to 89% in age period 36-47 weeks. Mothers with previous living children were associated with significantly higher (odds ratio [OR]: 6.53, 95% confidence interval [CI]: 1.33-32.09) and ownership of refrigerators was associated with significantly lower (OR: 0.18, 95% CI: 0.05 0.67) overall breast-feeding prevalences in age periods 24-35 and 36-47 weeks, respectively. The prevalence of exclusive breast-feeding in breast-fed infants dropped from 20% in age period 0-11 weeks to 0% in age period 36-47 weeks. After multivariate adjustment, prelacteal feeding was significantly negatively (OR: 0.12, 95% CI: 0.04-0.37) associated with exclusive breast-feeding in age period 0 11 weeks. Nearly 90% of Bilbeis infants were breast-fed at age 47 weeks, but the initiation of supplementation at 0-11 weeks in 80% of breast-fed infants is contrary to current recommendations.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7844802 TI - Casualty risk reduction from safety seat belts in a desert country. AB - A prospective study was carried out between December 1991 and October 1992 to assess the knowledge, attitudes and practices of hospitalized drivers regarding seat belt usage in United Arab Emirates (UAE). During this period, a total of 800 vehicle drivers were seen and treated in the Accident and Emergency Departments of two general hospitals. A total of 706 (88%) drivers gave consent for the study. The study showed that the rate of constant seat belt usage among drivers was 10.5%, and the rate of frequent seat belt usage was 5.8%. There was a statistically significant difference between seat belting and age groups (p = 0.0051). However, there were no significant statistical differences between seat belt usage versus non usage by sex, nationality and marital status. There were statistically significant differences between user and non-users of seat belts concerning their educational level and occupation. The results showed a reduction in the number of injuries due to usage of seat belts. Those patients who were not wearing seat belts were at risk twice as often as drivers who were restrained by belts. There was a statistically significant difference between the number of persons injured wearing and not wearing seat belts, (p = 0.032). It was observed that the majority of patients stated that seat belts are the best protective measure against all injuries (62.1%) and severe injuries (29.1%) of road traffic accidents. Also, there was strong support for the mandatory use of safety seat belts (56%). We may conclude that these data are encouraging, and would suggest general acceptance of seat belt legislation in the United Arab Emirates. PMID- 7844803 TI - Rat infestations in urban and rural areas in Nigeria: public health implications. PMID- 7844804 TI - Fire and disabled people in buildings. PMID- 7844805 TI - Pollution and health in the Katowice province of Poland. PMID- 7844806 TI - An innovative strategy to promote oral health in schoolchildren. AB - It is believed that the single most important factor affecting the incidence of dental caries in children is the frequency of exposure of teeth to non-milk extrinsic sugars, particularly sucrose, in the diet. Restricting consumption of sugar-containing snacks and drinks to mealtimes makes a significant contribution to the reduction of dental caries in children and consequent improvement in oral health. Many schools offer children sugar-containing drinks and snacks at break times although they may give children the option of healthy food choices at mealtimes. Attempts by dentists to persuade schools to change their break-time food and drink policies may be met with moderate success, especially with respect to drinks. Recently a sugar-free cup drink has been made available to schools in an attractive package and at an attractive price. An innovative campaign to promote sugar-free cup drinks in schools is described. By this campaign a reduction of dental caries' experience in schoolchildren may be achieved. Proposals are made for sugar-free cup drinks to be recognised as a safe confectionery and to be endorsed with the 'Tooth-friendly Sweets' logo. PMID- 7844807 TI - Plague in India: is a future 'crisis' preventable? PMID- 7844808 TI - Smoking and chronic inflammatory bowel disease. PMID- 7844809 TI - Leisure, later life and care in homes. PMID- 7844810 TI - Recreation in old age: an opportunity. PMID- 7844811 TI - Public health in the United States. PMID- 7844812 TI - The transcriptional activator protein FIS: DNA interactions and cooperative interactions with RNA polymerase at the Escherichia coli rrnB P1 promoter. AB - The E. coli rrnB P1 promoter owes its strength, in part, to the transcriptional activator protein FIS. FIS binds to three sites upstream of the RNA polymerase (RNAP) binding site and increases transcription in vivo four to ten-fold. In this report, hydroxyl radical and DMS footprinting analyses show that FIS binds to its three sites along one side of the DNA helix, and that FIS bound at the promoter proximal site (site I) and RNAP bound at the promoter are in close proximity. The binding of FIS at site I and RNAP at the promoter are mutually cooperative. These observations support a model for direct interaction between the FIS protein bound at site I and RNAP in transcription activation at rrnB P1. We also find that FIS does not bind cooperatively to its three sites upstream of rrnB P1, and that the relatively small activation associated with FIS bound at sites II and III does not result indirectly by facilitation of binding of FIS to site I. PMID- 7844813 TI - Site-specific recombination at res sites containing DNA-binding sequences for both Tn21 and Tn3 resolvases. AB - Tn3 and gamma delta resolvases catalyse site-specific recombination at res sites from Tn3 but not at Tn21 res sites. Tn21 resolvase has no activity at Tn3 sites and acts only at Tn21 sites. In both Tn3 and Tn21, res had three binding sites for the cognate resolvases; the cross-over site, I; and the accessory sites II and III, from which the bound proteins may stabilize the synaptic complex by protein-protein interactions. In this study hybrid res sites were made by replacing either II or III in the Tn21 res site with the equivalent sequence from Tn3. Plasmids containing either a hybrid and a wild-type Tn21 res site, or two hybrid sites, were tested for recombination. Relative to the reaction with two wild-type sites, recombination by Tn21 resolvase was reduced by replacing II at one res site and it was reduced further by replacing II at both loci but, in both cases, Tn21 recombination was enhanced by Tn3 or gamma delta resolvases. Very few of the amino acid on the external surface of gamma delta resolvases are conserved in Tn21. Moreover, mutants of gamma delta resolvase with defective protein protein interactions also enhanced Tn21 recombination at this hybrid site. The resolvase at II thus seems not to be involved in protein-protein interactions and its main role may be to bend the DNA to the required structure. The replacement of III in the Tn21 site with Tn3 sequence also reduced recombination by Tn21 resolvase, especially when both loci carried the alteration but, in contrast to before, Tn3 or gamma delta resolvases now inhibited the Tn21 reaction. Recombination thus seems to require identical proteins at I and III, perhaps to allow for protein-protein interactions. PMID- 7844814 TI - Site-specific recombination at res sites containing DNA-binding sequences for both Tn21 resolvase and CAP. AB - The res sites, the loci for site-specific recombination by resolvase, contain three binding sites for the protein; the cross-over site, I, and accessory sites II and III. The role of DNA bending by resolvase was examined by replacing either II or III in the res site from Tn21 with the recognition sequence for a heterologous DNA-bending protein, CAP (the catabolite-gene activator protein from Escherichia coli). The CAP sequence was placed at either the same position as the target sequence for Tn21 resolvase or a different position along the DNA. The activity of Tn21 resolvase for recombination between each hybrid and a wild-type res site was measured in the presence of CAP and cyclic AMP. When III was substituted, CAP inhibited Tn21 recombination, except when the CAP sequence was placed sufficiently far away from site II to allow resolvase to bind non specifically to the DNA between II and the CAP site. With the substitutions at II, the extent of Tn21 recombination in the presence of CAP varied with the position of the CAP sequence: more recombination was observed when it superimposed the target sequence for resolvase than when it was displaced by five base-pairs. Efficient recombination by Tn21 resolvase thus seems to demand the cognate protein at site III in res, presumably for protein-protein interactions in the synaptic complex, while the function of resolvase at site II can be fulfilled, at least in part, by a heterologous DNA bend. PMID- 7844815 TI - CRP-DNA complexes: inducing the A-like form in the binding sites with an extended central spacer. AB - The consensus DNA sequence for binding of the Escherichia coli cyclic AMP receptor protein (CRP) has two symmetrically related inverted recognition elements TGTGA:TCACA, separated by a variable spacer, normally 6 bp long. We have shown that the CRP-cAMP complex, when bound to synthetic binding sites with an extended 8 bp spacer segment, induces an increase in the DNA circular dichroism (CD). The CD change at lambda > 275 nm agrees with the shift of approximately one helical turn of DNA into A-like form. The B-conformation is preserved for CRP binding sites similar to that in the lac and uxaCA promoters with 6 bp spacers. Another effect accompanying DNA binding is a dramatic increase of the negative CD magnitude in the spectral region of the ligand cAMP, at lambda < 272 nm. This effect is observed when CRP binds to specific sites with 6 or 8 bp spacers as well as to non-specific DNA. We reason that the A-like form arises by compressing and unwinding the DNA in CRP-DNA complexes having 8 bp central spacers. This serves to maintain a fixed length and twisting angle and is controlled by the protein's relatively rigid frame. This model is consistent with the observation that some binding sites with 6 bp spacers may also show the CD increase inherent to the sites with the extended 8 bp spacers. These 6 bp spacers are characterized by an increased twisting angle that requires their unwinding to bind to CRP. We propose that a mutual adaptation between CRP and binding sites by local untwisting and a B-->A-like transition in the DNA is of general importance and may occur in other protein-DNA complexes, such as the complex of RNA polymerase with promoter DNA. PMID- 7844816 TI - Structural characterization of two variants of fibulin-1 that differ in nidogen affinity. AB - Two C-terminal variants C and D of mouse fibulin-1 were purified from the culture medium of stably transfected human kidney cell clones. They showed, after rotary shadowing, a dumbbell-like structure of about 33 nm in length. Pepsin digestion demonstrated stability of the disulfide-bonded domains 1 (anaphylatoxin-like) and II (multiple EGF-like motifs) but not for domain III which is different in the variants. A close similarity of the variants was observed in immunochemical assays indicating that domain III epitopes are not very antigenic. Binding analysis in solid phase assays demonstrated for variant C a 100-fold stronger binding to the basement membrane protein nidogen than for variant D. Both interactions were sensitive to EDTA. Surface plasmon resonance assays confirmed this difference and showed KD = 60 nM for variant C and KD > 1 microM for variant D. Lower binding activities and smaller differences between both variants were observed for the calcium-dependent binding to fibronectin, laminin-1 and collagen IV. Self aggregation into nest-like oligomers was observed at high concentrations of fibulin-1 which was not sensitive to EDTA. PMID- 7844817 TI - Elucidating the folding problem of helical peptides using empirical parameters. II. Helix macrodipole effects and rational modification of the helical content of natural peptides. AB - Explaining the helical behaviour of amino acid sequences in solution could be one of the first steps in solving the protein folding problem in a rational way. The information about the conformational behaviour of helical peptides in solution, as well as the alpha-helix stability in proteins, has been utilised to derive a database with the energy contributions for various interaction taking place in an alpha-helix: intrinsic helical propensities, side-chain to side-chain interactions, main-chain to main-chain hydrogen bonds, and capping effects. This database was implemented in a algorithm based on the helix-coil transition theory (AGADIR). Here, the effects on helix stability due to interactions between charged groups and the helix macrodipole are described, quantified and implemented in AGADIR. The algorithm correctly calculates the average helical behaviour in solution of 423 peptides analysed by circular dichroism and it describes the helicity at a residue level, as found when comparing the prediction for each amino acid residue with the data derived from nuclear magnetic resonance studies. Using AGADIR we have done a rational modification of peptides corresponding to protein secondary structure elements in order to increase their helical content. The circular dichroism analysis of the mutant peptides showed a very good agreement between the experimental and calculated helical content. Moreover, in certain specific cases in which strong tertiary contacts in folded proteins do not exist, the algorithm successfully predicts the length of mutagenised alpha-helices. It is interesting to note that the final values of the parameters used do not significantly differ in absolute terms from those extracted from mutagenesis studies in proteins. This indicates that the same physico-chemical principles stand for both systems. PMID- 7844818 TI - Elucidating the folding problem of helical peptides using empirical parameters. III. Temperature and pH dependence. AB - Explaining the helical behaviour of amino acid sequences without tertiary interactions, in aqueous solution, could be considered one of the first steps to solve the protein folding problem in a rational way. In the accompanying paper the information about the conformational behaviour of helical peptides in solution, as well as the studies on alpha-helix stability in proteins has been utilised to derive a database of energy interactions. This database, when implemented in an algorithm based on the helix-coil transition theory (AGADIR), correctly calculates the average helical behaviour in solution of 423 peptides analysed by circular dichroism. The majority of these peptides have been studied at low temperatures (0 to 10 degrees C), and neutral pH. However, in vivo, proteins fold at higher temperatures and in some cases low or high pH values. To understand protein folding it is necessary to calculate the helical behaviour of linear peptides under very different temperature and pH experimental conditions. We have included the temperature and pH effects on the helical behaviour of peptides by means of generally accepted assumptions and simplifications. The inclusion of these terms allow us to calculate the helical behaviour of polyalanine-based peptides, as well as of complex natural sequences, under different experimental conditions. PMID- 7844819 TI - Three-dimensional reconstruction of mammalian 40 S ribosomal subunit embedded in ice. AB - A platform-like structure, which appears equivalent to the platform or lobe structure of the 30 S subunit of the eubacterial ribosome, is observed in the reconstruction of the small 40 S ribosomal subunit from images of ice-embedded particles. This cup-shaped structure, 15.0 nm in side length and 13.5 nm wide at its rim, extends obliquely upward on the back of the subunit. Other previously characterized features of the 40 S subunit can readily be identified: the head with its prominent beak structure, the body with its two back lobes expressed as relatively small-scale features, and the two widely separated feet that comprise the base of the subunit. PMID- 7844820 TI - Consecutive low-usage leucine codons block translation only when near the 5' end of a message in Escherichia coli. AB - Insertion of nine consecutive low-usage CUA leucine codons after codon 13 of a 313-codon test mRNA strongly inhibited its translation without apparent effect on translation of other mRNAs containing CUA codons. In contrast, nine consecutive high-usage CUG leucine codons at the same position had no apparent effect, and neither low- nor high-usage codons affected translation when inserted after codon 223 or 307. Additional experiments indicated that the strong positional effect of the low-usage codons could not be accounted for by differences in stability of the mRNAs or in stringency of selection of the correct tRNA. The positional effect could be explained if translation complexes are less stable near the beginning of a message: slow translation through low-usage codons early in the message may allow most translation complexes to dissociate before they read through. PMID- 7844821 TI - Role of NusA in L4-mediated attenuation control of the S10 r-protein operon of Escherichia coli. AB - The transcription of the 11 gene S10 operon of Escherichia coli is autogenously regulated by one of the operon's products, ribosomal protein L4. This protein stimulates termination of transcription in vivo at a specific site within the S10 leader. The in vivo effect can be reproduced in a purified transcription system but requires an additional factor, NusA. Our earlier in vitro studies showed that NusA is required for RNA polymerase pausing at the termination site; such paused complexes are further stabilized by L4, which presumably accounts for L4's stimulation of termination in vivo. Here we show that NusA is not absolutely required for RNA polymerase to recognize the attenuation site: at low (5 microM) UTP concentration, RNA polymerase pauses at the site, although the paused transcription complex formed in the absence of NusA can be further stabilized by subsequent addition of the protein. Furthermore, RNA polymerase pausing at the attenuation site is not sufficient for the L4 effect, since L4 cannot stabilize a transcription complex paused at the attenuation site in the absence of NusA. We have been able to isolate paused complexes formed without NusA and/or L4; such complexes are active upon re-addition of NTPs, and respond as expected to the addition of L4 or NusA. Our experiments are consistent with the notion that L4 is a stable component of a paused transcription complex. PMID- 7844822 TI - An intramolecular triplex structure from non-mirror repeated sequence containing both Py:Pu.Py and Pu:Pu.Py triads. AB - A plasmid insert containing the (TA)7GATC(TA)7 inverted repeat and an adjacent (AG)7 tract adopts a cruciform structure at neutral pH. However, under acidic conditions the cruciform becomes readily disrupted in favor of a triplex. The (AG)7.(CT)7 duplex and one strand of the (TA)7GATC(TA)7 element are engaged in the three-stranded DNA formation, as determined using single-stranded DNA specific probes. The structure extrudes by displacing the (TA)7 strand adjacent to the (AG)7, and folding it back into the major groove of the (AG)7.(CT)7 duplex. This new variant of H-DNA is supercoil and pH dependent, requiring pH 6.1 or lower to form. The triplex is stabilized by T:A.T and A+:G.C triads. This unusual triad composition (50% of T:A.T and 50% of A+:G>C), that has not previously been observed in intramolecular triplexes, violates both the widely accepted division of triplexes into Py:Pu.Py or Pu:Pu.Py types and the requirement for mirror repeat symmetry. PMID- 7844823 TI - The mitochondrial DNA of the amoeboid protozoon, Acanthamoeba castellanii: complete sequence, gene content and genome organization. AB - In phylogenetic trees based on comparison of nuclear small subunit rRNA sequences, Acanthamoeba castellanii (an amoeboid protozoon) is positioned near the base of the radiation leading to the animals, fungi and plants. However, the specific affiliation of this protist with the major multicellular lineages of eukaryotes is currently uncertain. To further explore the evolutionary position of A. castellanii, we have determined the complete primary sequence of its mitochondrial genome. We find that the circular mtDNA (41,591 bp; 70.6% A+T) encodes two rRNAs (small subunit and large subunit), 16 tRNAs and 33 proteins (17 subunits of the respiratory chain and 16 ribosomal proteins). As well, this genome contains eight open reading frames (ORFs) larger than 60 codons and of undefined function. Two of these ORFs (orf124 and orf142) have homologs in other mtDNAs ("orf25" and "orfB", respectively), three are unique to A. castellanii mtDNA (orf83, orf115 and orf349), and three are intronic ORFs. Among notable features of A. castellanii mtDNA are the following: (1) Genes and ORFs are all encoded on the same strand and are tightly packed, with only 6.8% of the total sequence not having an evident coding function and intergenic spacer sequences ranging from only 1 to 616 bp (average 64 bp). Ten pairs of protein-coding genes overlap by up to 38 bp and two subunits of cytochrome oxidase (COX1 and COX2) are specified by a single continuous ORF. (2) Only three introns, all group I and each containing a free-standing ORF, are present; these are localized in the 3' half of the large subunit rRNA gene. (3) The genome encodes fewer than the minimal number of tRNA species required to support mitochondrial protein synthesis, suggesting that additional tRNAs are imported from the cytosol into A. castellanii mitochondria. Of the 16 tRNAs specified by A. castellanii mtDNA (one with an 8-nucleotide anticodon loop), 13 have been shown or are predicted to undergo a novel form of RNA editing within the acceptor stem. (4) A modified genetic code is used in which UGA specifies tryptophan. (5) Repeated sequences and obvious small sequence motifs that might represent regulatory elements are absent. In overall size, gene content and organizational pattern, A. castellanii mtDNA most closely resembles the mtDNA of the chlorophycean alga Prototheca wickerhamii (55,326 bp; 74.2% A+T), but is quite different in these respects from the mtDNA of Chlamydomonas reinhardtii (15,758 bp; 54.8% A+T), another chlorophycean alga, as well from characterized animal and fungal mitochondrial genomes.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7844824 TI - Proximity probing of Tet repressor to tet operator by dimethylsulfate reveals protected and accessible functions for each recognized base-pair in the major groove. AB - We have tracked the path of Tet repressor across the major groove in the complex with tet operator. This was done by a methylation protection analysis of nine tet operator mutants containing replacements by a G residue of each nucleotide in base-pairs important for Tet repressor recognition. We demonstrated sequence specific binding of Tet repressor to these operator mutants using DNA retardation assays and the protection of the wild-type +2G residue from methylation. Hydroxyl radical cleavage protection analysis of the Tet repressor-tet operator complexes indicated identical, or at least very similar, locations of the DNA reading head across the major groove of wild-type and mutant operator DNA. Methylation protection occurred at the G residues in positions +3, +4, -5 and -6, whereas the G residues in the respective opposite strands showed enhanced methylation. These results show that most amino acid side-chains of Tet repressor are in close proximity to only one base of each base-pair in the major groove of tet operator. The Tet repressor mutant PS39 gave a changed methylation protection pattern at base-pair four of tet operator indicating that the residue at this position can contact either base at this base-pair depending on the amino acid side-chain present. Tet repressor mutants QA38 and TA40 with a loss of specificity phenotype gave the same methylation protection profile as wild-type TetR confirming that this experiment scores proximity rather than chemical interaction. The excellent agreement of these results with those obtained in genetic analyses demonstrates that this method yields a high-resolution proximity pattern of Tet repressor with tet operator and that it may be generally applicable for the analysis of protein DNA complexes. PMID- 7844825 TI - Characterization of the 5 S RNA binding activity of Xenopus zinc finger protein p43. AB - One major component of the Xenopus 42 S ribonucleoprotein (RNP) storage particle is the p43 protein. The 5 S RNA binding protein is structurally similar to TFIIIA, containing nine zinc finger domains. The RNA binding properties of recombinant p43 were characterized using a nitrocellulose filter binding assay. The experimental conditions necessary for in vitro p43-5 S RNA complex formation include: pH 7.5, 0.1 M KCl and incubation at 22 degrees C. Under these conditions, the protein binds to Xenopus oocyte 5 S RNA with an apparent association constant of 1.61(+/- 0.12) x 10(9) M-1. A series of mutations in 5 S RNA were used to determine which sequence and structural features of the 5 S RNA are required for high affinity binding of p43. The primary contact points for p43 include the sequences and structures of stems II, V and loop D of the 5 S RNA. Although p43 and TFIIIA are structurally similar and are both relatively insensitive to mutations in the 5 S RNA, they do require different features of the 5 S RNA molecule for high affinity binding. PMID- 7844826 TI - Poly(dA).poly(dT) forms very stable nucleosomes at higher temperatures. AB - The synthetic polymer poly(dA).poly(dT) was long thought to be refractory to nucleosome formation. Several years ago our laboratory demonstrated that the polymer could be mixed with authentic nucleosomes in a low-salt exchange procedure to form a nucleoprotein complex that behaved in a manner identical with that of nucleosomes. Competitive exchange assays at 37 degrees C showed that the homopolymer reconstituted about as well as heterogenous-sequence DNA. However, studies by other laboratories have shown that the conformation of poly(dA).poly(dT) depends on temperature; the polymer converts from its well known, atypical structure, found at ambient temperature, to a conformation more closely resembling a canonical B form as temperature is increased. We have measured the ability of the homopurine.homopyrimidine to form nucleosomes as a function of temperature. It is seen that poly(dA).poly(dT) forms nucleosomes more strongly as the temperature of the exchange mixture is increased, so that poly(dA).(dT) outcompetes heterogeneous-sequence DNA for histones at elevated temperatures. PMID- 7844827 TI - Tyrosine phosphorylation of the tetragonal paracrystalline array of Aeromonas hydrophila: molecular cloning and high-level expression of the S-layer protein gene. AB - High virulence strains of the fish pathogenic bacterium Aeromonas hydrophila produce a tetragonally arranged paracrystalline surface protein array (S-layer). The gene (ahsA) encoding the S-protein subunit of A. hydrophila TF7 was cloned into lambda EMBL 3, and sub-cloned into pUC 18. Transformation into Escherichia coli led to stable high-level expression of full-size S-protein under the control of its native promoter. The DNA sequence revealed a 1406 base-pair open reading frame encoding a protein consisting of a 19 amino acid residue signal peptide, and a 448 residue 45,400 Da molecular mass mature protein with a predicted isoelectric point (pI) of 6.72 compared with the measured M(r) of 52,000 and pI of 4.6. This suggested that the S-protein was post-translationally modified and in vivo cell labelling with [32P]orthophosphate, acid phosphatase digestion of S protein, ascending thin-layer chromatography of partially acid hydrolysed S protein and Western blot analysis with monoclonal anti-phosphotyrosine antibody showed that the S-protein of strain TF7 contained phosphotyrosine. S-proteins produced by the other strains of motile aeromonads tested also reacted with this anti-phosphotyrosine antibody. Cell fractionation studies employing plasmid encoded ahsA showed that in A. hydrophila the S-protein subunits were secreted across the outer membrane by the native S-protein secretion pathway, while in E. coli and A. salmonicida the cloned A. hydrophila S-protein inserted into the outer membrane of the foreign host. These findings indicate that the process employed to translocate Aeromonas S-proteins across the outer membrane is highly specific. PMID- 7844828 TI - Structural dynamics of F-actin: I. Changes in the C terminus. AB - The biochemical properties of G-actin, and the kinetics of polymerization of G actin into F-actin, are dependent upon whether Mg2+ or Ca2+ is bound at the high affinity metal-binding site in actin. Three-dimensional reconstructions from electron micrographs show that a bridge of density, that we interpret as arising from a major shift of the C terminus, exists between the two strands of the filament in Ca(2+)-actin that is absent in Mg(2+)-actin. This bridge is also absent in models of F-actin built from an atomic structure of G-Ca(2+)-actin. The cleavage of the DNase I-binding loop in actin between residues 42 and 43, with the non-covalent association of the 42 cleaved residues with the remainder of the actin, induces an even larger bridge of density between the two strands. When the bridge is absent, the two C-terminal residues in F-actin are easily cleaved by trypsin, while these residues become increasingly resistant to tryptic cleavage as the bridge becomes more prominent. Conversely, cleavage of the two C-terminal residues leads to a conformational change in the DNase I-binding loop. Since both the DNase I-binding loop and the metal-binding site are quite distant from the C terminus, large allosteric effects must exist in F-actin. The conformational change in F-actin that results from the creation of this bridge may be induced by myosin binding, since this movement generates changes in actin's diffraction that are very similar to the changes in the muscle X-ray pattern during activation that are associated with the binding of myosin to the thin filament. PMID- 7844829 TI - Structural dynamics of F-actin: II. Cooperativity in structural transitions. AB - A large body of biochemical evidence suggests that the F-actin filament can have internal cooperativity. We have observed large cooperative effects on the low resolution structure of actin filaments under three very different conditions. First, when G-Ca(2+)-actin is polymerized by both Mg2+ and KCl, filaments may be found in two different populations, with two discrete positions seen for subdomain 2. When G-Ca2+ actin is polymerized by only Mg2+, a single F-Mg(2+) actin population is seen. The structural data suggest that an entire filament exists with subdomain 2 in one state or the other when there is a heterogenous mixture of Mg2+ and Ca(2+)-actin. Second, when actin filaments are nucleated from gelsolin there is a conformational change that can be observed throughout the filament that is consistent with a large shift in the actin C terminus. There must be a large cooperative propagation of this effect throughout the filament from the nucleation point. Third, we have used phalloidin to stabilize F-actin in which two C-terminal residues have been proteolytically removed by trypsin. It has been shown biochemically that this stabilization occurs at substoichiometric amounts of phalloidin. Phalloidin, at either a 1:1 or a 1:20 molar ratio with actin, restores the connectivity between the long-pitch helical strands. F actin's internal cooperativity will have large implications in vivo, particularly in muscle. PMID- 7844830 TI - Involvement of a stem-loop structure in the location of junction sites in viral RNA recombination. AB - Recombination between RNAs associated with turnip crinkle virus is thought to occur during plus-strand synthesis at motifs resembling the 5'-ends of genomic, subgenomic and satellite RNAs. Common structural regions encompassing the motifs have been found for major crossover sites on two different minus-strand templates, with junctions preferentially located in a single-stranded region at the 3' base of a hairpin. Base changes, deletions and compensatory alteration constructed in and around the hairpin in the region of the turnip crinkle virus genomic RNA involved in recombination support the importance of the hairpin for normal crossover site selection. This region of the genomic RNA is also important for replication of the viral genomic RNA in plants and protoplasts, suggesting a common link between sequences required for recombination and viral replication. PMID- 7844831 TI - A sialic acid-derived phosphonate analog inhibits different strains of influenza virus neuraminidase with different efficiencies. AB - A phosphonate analog of N-acetyl neuraminic acid (PANA) has been designed as a potential neuraminidase (NA) inhibitor and synthesized as both the alpha (ePANA) and beta (aPANA) anomers. Inhibition of type A (N2) and type B NA activity by ePANA was approximately a 100-fold better than by sialic acid, but inhibition of type A (N9) NA was only ten-fold better than by sialic acid. The aPANA compound was not a strong inhibitor for any of the NA strains tested. The crystal structures at 2.4 A resolution of ePANA complexed to type A (N2) NA, type A (N9) NA and type B NA and aPANA complexed to type A (N2) NA showed that neither of the PANA compounds distorted the NA active site upon binding. No significant differences in the NA-ePANA complex structures were found to explain the anomalous inhibition of N9 neuraminidase by ePANA. We put forward the hypothesis that an increase in the ePANA inhibition compared to that caused by sialic acid is due to (1) a stronger electrostatic interaction between the inhibitor phosphonyl group and the active site arginine pocket and (2) a lower distortion energy requirement for binding of ePANA. PMID- 7844832 TI - Structural and functional domains of the large subunit of the bacteriophage T3 DNA packaging enzyme: importance of the C-terminal region in prohead binding. AB - During head assembly of phage T3, DNA is packaged into a preformed protein shell, called the prohead, with the aid of non-capsid packaging proteins, the products of genes 18 and 19 (gp18 and gp19). We have developed a defined system, composed of purified gp18,gp19 and proheads for in vitro packaging of T3 DNA. Our previous results using the defined in vitro system indicate the sequential events in DNA packaging: the packaging proteins, gp18 and gp19, bind DNA and proheads, respectively. These complexes associate to form a direct precursor complexes for DNA translocation into the head. The formation of the precursor complexes requires ATP as an allosteric effector. Subsequent DNA translocation is driven by ATP hydrolysis. gp19 is an ATP binding protein that plays multiple roles in DNA packaging through interaction with ATP. gp19 changes its conformation by binding to ATP, as judged from the analysis of limited proteolysis. Sites cleaved by limited proteolysis were determined and mapped on the gp19 polypeptide (586 amino acid residues) to image the conformational change of gp19 induced by ATP. C Terminal fragments generated by trypsin digestion bound the prohead and inhibited DNA packaging by intact gp19 in a competitive manner. On the other hand, N terminal fragments did not bind the prohead nor did they inhibit DNA packaging. These results define a prohead binding domain at the C terminus of gp19. To identify the prohead binding domain more precisely, deletion mutants lacking the last 10 and 15 amino acids (gp19-delta C10 and gp19-delta C15, respectively) of the extreme C terminus of gp19 were constructed. Limited tryptic digestion patterns of these mutant proteins in the presence or absence of ATP were basically the same as those of gp19-wt, indicating that the conformation and its ATP response were not changed by these deletions. gp19-delta C15 lacked prohead binding activity and, therefore, DNA packaging activity. gp19-delta C10 had significant DNA packaging activity although it was reduced to one-tenth of that of gp19-wt. These results indicate that a C-terminal region of residues L571 to D576 of gp19 is crucial for prohead binding and that the last ten residues D577 to W586 of the C terminus seems to be important in stable binding of gp19 to the prohead. PMID- 7844833 TI - Calculation of protein structures with ambiguous distance restraints. Automated assignment of ambiguous NOE crosspeaks and disulphide connectivities. AB - The distances derived from nuclear Overhauser effect (NOE) spectra are usually converted into three-dimensional structures by computer algorithms loosely termed distance geometry. To a varying degree, these methods require that the distance data is unambiguously assigned to pairs of atoms. Typically, however, there are many NOE crosspeaks that cannot be assigned without some knowledge of the structure. These crosspeaks have to be assigned in an iterative manner, using preliminary structures calculated from the unambiguous crosspeaks. In this paper, I present an alternative to this iterative approach. The ambiguity of an NOE crosspeak is correctly described in terms of the distances between all pairs of protons that may be involved. A simple restraining term is defined in terms of "ambiguous" distance restraints that can allow all possible assignments. A new minimization procedure based on simulated annealing is described that is capable of using highly ambiguous data for ab initio structure calculations. In particular, it is feasible to specify the restraint list directly in terms of the proton chemical shift assignment and the NOE peak table, without having assigned NOE crosspeaks to proton pairs. While the primary aim of this paper is determining the global fold of proteins from NMR data, similar strategies can be used for other types of ambiguous distance data. The application to one example, disulphide bridges with unknown connectivity, is described. Model NOE data were generated from the X-ray crystal structure of a small protein with known chemical shift assignments. Varying degrees of ambiguity in the data were assumed. The method obtained the correct polypeptide fold even when all distance restraints were ambiguous. Thus, the new approach may facilitate structure calculations with data derived from very overlapped spectra. It is also a step towards automating the calculation of structures from NMR data. This could prove especially valuable for data derived from three- and four-dimensional experiments. The approach may also prove useful for model building studies and tertiary structure prediction. PMID- 7844834 TI - Structure and dynamics of ferrocytochrome c553 from Desulfovibrio vulgaris studied by NMR spectroscopy and restrained molecular dynamics. AB - The solution structure of Desulfovibrio vulgaris Hildenborough (DvH) ferrocytochrome c553 has been determined by nuclear magnetic resonance spectroscopy and combined simulated annealing/high temperature restrained molecular dynamics calculations. This three-stage protocol consists of an initial determination of overall fold from randomised co-ordinates, followed by a 20 picosecond exploratory stage, during which the non-bonded terms are simplified to facilitate as broad a sampling of conformational space as possible, and a 26 picosecond refinement stage, using the full AMBER force field. This latter stage systematically improved the energetic and convergence characteristics of the ensemble, while still satisfying the experimental restraints. Forty structures have been obtained from a total of 875 distance constraints for this protein of 79 amino acid residues. The root-mean-square deviation over all residues with respect to the mean is 0.70(+/- 0.12)A for the backbone (N, C alpha and C') atoms. Two conformations of the turn motif at the solvent/heme cleft interface have been identified, both fulfilling the experimental data and having equally viable energetic characteristics. The stability of the ensemble and the dynamic characteristics have been further investigated by subjecting ten of the structures to constraint-free molecular dynamics calculations (130 picoseconds) in vacuo. The structures were found to be stable to within 1.5 A of the initial backbone conformation. Comparison with the dynamic behaviour of the restrained molecular dynamics calculations has been used to identify regions of inherent flexibility in the molecule. PMID- 7844835 TI - Nucleation, fiber growth and melting, and domain formation and structure in sickle cell hemoglobin gels. AB - Pathogenesis in sickle cell disease depends on polymerization and gelation of deoxyhemoglobin S. Under the double nucleation model, polymerization is initiated by homogeneous nucleation, followed by heterogeneous nucleation on pre-existing fibers. Fibers grow by non-cooperative addition of hemoglobin. The model derives from macroscopic results rather than direct observation of individual events. We observe individual events and structures by differential interference contrast (DIC) microscopy to show consistency with the model, to define structure and development of gel domains and their relation to kinetics, and to demonstrate the mechanism of fiber melting. Kinetics were controlled by producing deoxyhemoglobin by photolysis of CO hemoglobin under DIC observation. The first visible polymers appeared randomly and were usually linear aggregates less than 1 micron long, consistent with homogeneous nucleation and immediate post-nucleation aggregates. Aggregates then branched extensively, consistent with heterogeneous nucleation. This branching of new fibers was also induced at countable rates on isolated single fibers. Branching and fiber growth rapidly produced dense domains. Changes in photolytic intensity altered domain growth rates and domain structure. At low intensity and slow growth, fibers grew radially without branching. Domains lacked cross-links and polymer density was low. High intensity produced faster growth, much heterogeneous nucleation and highly cross-linked, dense, domains. At still higher intensity, homogeneous nucleation was very rapid, producing many small domains. These results show a hierarchy of processes: as deoxyhemoglobin concentration increases, growth occurs without observable nucleations, and then heterogeneous and finally homogeneous nucleation become dominant. This is consistent with the double nucleation model under which the concentration dependence of growth is low, and that of heterogeneous and homogeneous nucleation successively higher. Under decreased photolysis, fiber ends melted continuously without fiber breakage; increased photolysis reversed this, producing growth. Isolated fibers melted and grew at both ends. The results are consistent with a fiber melting mechanism that is the reverse of growth. PMID- 7844836 TI - Dengue vector control: present status and future prospects. AB - Dengue Fever (DF) and Dengue Haemorrhagic Fever (DHF) have been the most common urban diseases in Southeast Asia since the 1950s. More recently, the diseases have spread to Central and South America and are now considered as worldwide diseases. Both Aedes aegypti and Aedes albopictus are involved in the transmission of DF/DHF in Southeast Asian region. The paper discusses the present status and future prospects of Aedes control with reference to the Malaysian experience. Vector control approaches which include source reduction and environmental management, larviciding with the use of chemicals (synthetic insecticides and insect growth regulators and microbial insecticide), and adulticiding which include personal protection measures (household insecticide products and repellents) for long-term control and space spray (both thermal fogging and ultra low volume sprays) as short-term epidemic measures are discussed. The potential incorporation of IGRs and Bacillus thuringiensis-14 (Bti) as larvicides in addition to insecticides (temephos) is discussed. The advantages of using water-based spray over the oil-based (diesel) spray and the use of spray formulation which provide both larvicidal and adulticidal effects that would consequently have greater impact on the overall vector and disease control in DF/DHF are highlighted. PMID- 7844837 TI - The epidemiology, prevention and control of dengue hemorrhagic fever in Indonesia. PMID- 7844838 TI - Dengue control programme in Malaysia. PMID- 7844839 TI - Research on dengue vectors. PMID- 7844840 TI - National dengue prevention and control program in the Philippines. PMID- 7844841 TI - Dengue vector control in Thailand: development towards environmental protection. PMID- 7844842 TI - Dengue/dengue hemorrhagic fever situation in Vietnam. PMID- 7844843 TI - Dengue fever in the Taiwan area. PMID- 7844844 TI - Perspectives on the prevention and control of dengue hemorrhagic fever. AB - The global geographic expansion and increased incidence of dengue/dengue hemorrhagic fever in the past 15 years has made dengue one of the most important emergent diseases of tropical urban centers worldwide. This paper discusses the urgent need to develop more effective prevention and control strategies, and for public health officials to coordinate these efforts with urban planning and environmental health specialists. PMID- 7844845 TI - Education and employment of medical entomologists in Aedes aegypti control programmes. AB - Most dengue/DHF endemic countries have facilities for the training of entomologists. However, experience has shown that many of the graduates of such courses remain in the area of research and relatively few are employed in Aedes aegypti vector-control programmes. Few university courses in medical entomology provide specific training in vector control including such subjects as the organization and administration of vector control programmes and vector-control methods; chemical, biological and environmental control; evaluation of control activities and the epidemiology of the vector-borne diseases. Governments and municipalities are often unaware of the complexities of an efficient control programme and the importance of employing well trained entomologists to plan and implement them. Inadequately organized and poorly supervised vector-control programmes are often the reason for failure to interrupt transmission of the disease. The type of training required and the necessity for providing adequate career structures for vector control personnel and adequate funding for the control programmes is discussed. PMID- 7844846 TI - Dengue in the health transition. AB - The "Health Transition" describes the medical consequences which accompany the demographic transition and development. In many Asian countries, as the infectious diseases of infancy decline, such as diarrhea, acute respiratory disease, measles and malaria, so too, do infant mortality rates. As a consequence of falling infant mortality rates and declines in fertility, the age pyramid has become more rectangular. No longer is nearly half of the population under the age of 15 years. Diseases of adults are beginning to become predominant: trauma, heart disease, cancer, stroke and diabetes. Life expectancy has increased along with costs of the health care system. As a fraction of per capita gross domestic product, health care is beginning to become a major national expense. It is ironic that the one vector-borne infectious disease likely to bridge the health transition in tropical countries is dengue. As evidenced by the experience of Singapore and Taiwan, modern housing and commercial development provide more, rather than fewer breeding places for Aedes aegypti. Greater affluence often means less compliance with mosquito control programs. Meanwhile, the dengue viruses, heeding some unknown genetic imperative, cause ever more severe disease. Modern Asian societies must count dengue as a real and enduring threat. To prevent costly hospitalizations and a sense of social disorder, effective measures must be adopted to achieve a significant reduction of Aedes aegypti populations. Sustained dengue control requires source reduction which, in turn depends upon imaginative leadership, skilled man power, legislative authority, an authentic national research program and intersectoral cooperation. A leadership role beckons for new actors in the control of Aedes aegypti: large municipalities, environmental agencies and the private sector. PMID- 7844847 TI - Dengue vector control in the urban environment of Taiwan. AB - An epidemic of dengue occurred in southern Taiwan in 1987, and by the end of 1988 there were 10,420 reported cases, of which 60.5% were from Kaohsiung Municipality. The urbanization and industrialization of the municipality have resulted in a vast increase in the breeding habitats of the dengue vector, Aedes aegypti. In the early stage of the epidemic, only space spraying with insecticides was undertaken, but the Aedes density gradually increased and reached its peak in the third quarter of 1988. Through a great effort in the promotion of extensive and systematic community-based source reduction started in December 1988, the Aedes density and number of dengue cases dropped significantly. Excellent results were thus achieved and no more indigenous cases occurred in 1990. PMID- 7844848 TI - Control of dengue vectors in Singapore. AB - Singapore has a well-established system for the surveillance, research and control of Aedes aegypti and Aedes albopictus. Control of these vectors comes under the jurisdiction of the Environmental Public Health Division of the Ministry of the Environment. The strategy for Aedes control is an integrated approach incorporating case detection, source reduction, health education and law enforcement. This is done through the Quarantine & Epidemiology Department (dengue surveillance and research), Vector Control & Research Department (Aedes surveillance, control and research), Environmental Health Department (environmental sanitation and hygiene) and Public Education Department (health education on dengue prevention and control). Despite its success in reducing the Aedes population to a house index of around 1%, the incidence of dengue fever/dengue haemorrhagic fever has increased sharply during the last 5 years. The Ministry realises that the dengue problem can only be tackled on a regional basis and it is with this objective in mind that the Institute of Environmental Epidemiology has been formed to collaborate with other international agencies in operational research and training projects. PMID- 7844849 TI - Urban planning and vector control in Southeast Asian cities. AB - A large and growing proportion of the population in many Southeast Asian cities live in slums and squatter settlements and they suffer from excessive exposure to insect and rodent vectors which transmit disease from one host to another. In such settlements, the quality of life, which is poor anyway, is made even worse by the high incidence of vector-borne diseases. Vector proliferation in high density, low-income urban settlements is the consequence of a number of factors, such as lack of adequate housing, water supply, sanitation, drainage, and solid waste management facilities. There is an urgent need to rethink intersectoral and integrated approaches to the design and planning of healthy urban environments, covering such matters as basic infrastructure and services, urban land use planning and waste management, health-promoting housing and architecture, and the control of all other factors that determine human health and well-being. With cooperation between and among the communities, local governments, and nongovernmental organizations as the basis, the installation of low-cost sanitation and drainage systems, the organization of collection services for the disposal of garbage, the provision of house screening and other protective measures, and the removal of breeding sites can greatly reduce the threat of most urban vectors. PMID- 7844850 TI - Recovery and disposal of discarded tires in the Taiwan area. AB - Urbanization and industrialization has resulted in a vast amount of artificial water containers in Taiwan, especially discarded automobile tires. 3.5 million automobile tires and several million motorcycle tires are discarded annually. The discarded tires contaminate the environment and also become a substantial number of breeding sites for the dengue vector mosquitoes. In order to establish a sound system for the recovery and disposal of discarded tires and to control dengue fever through source reduction, it has been emphasized that users must pay for their waste. It is necessary to recover and properly dispose of these discarded tired. The commercial firms which sell or manufacture tires are therefore advised to cooperate with the Environmental Protection Administration of the Executive Yuan, R.O.C. and follow the "Regulations of Recovery and Disposal of Discarded Tires". They are requested to establish foundations for the recovery of discarded tires. Those who are willing to join should prepay a deposit or related charge by the size of tire, which is imported or locally manufactured. The foundation utilizes the deposits for the recovery and disposal of discarded tires. From 1991 to 1993 the commercial tire firms had already achieved the 80% recovery rates declared by the authorities concerned. Some of the tires, after having been recovered, were recycled in the original form and the rest were cut into small pieces for recycling after physical treatment. It should be mentioned that the Department of Environmental Protection of Kaohsiung City has collected 80 thousand discarded automobile tires to be used as ocean jetty.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7844851 TI - Intersectoral approaches to dengue vector control. AB - Medical entomology in the context of urban vector control, especially for dengue, can be likened to the tail of a dog. Vertically structured Aedes aegypti campaigns such as run by Gorgas and Soper earlier this century relied on sufficient legislative backing for vector control to ensure that the tail was capable of wagging the dog. Under these conditions, especially where individual rights do not intrude, vertical programs will be successful. The global expansion of dengue, dengue hemorrhagic fever and its vectors, plus growing trends towards urban/periurban living indicate a more serious scenario than at present. In 1987, the Brundtland Report: "Our Common Future" decried sectoralism in problem solving. Following the United Nations Conference on Environment and Development (UNCED) in 1992, the resulting Commission on Sustainable Development has promoted the intersectoral message of health, environment and development. The WHO/FAO/UNEP/UNCHS Panel of Experts on Environmental Management for Vector Control has promoted this for some time and is attempting to build multidisciplinary projects against urban vector borne disease. Adequate solid waste management and recycling will reduce numbers of water bearing containers infested with Aedes aegypti and provision of reliable piped water supplies will impact heavily on infested water storage containers. Both should be encouraged as viable control options. For much of the world, vertical programs have been reported as prohibitively expensive, and unacceptable intrusion on human rights and thus unsustainable in the modern economic context. However there are successful modern examples.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7844852 TI - Pest control industry and vector control activities in Taiwan. AB - At the end of 1993, there were 117 private pest control companies in Taiwan, with 438 technical managers and 274 technicians. Their business includes the control of mosquitoes, cockroaches, fleas, rodents, termites, houseflies, etc. Pyrethroids and some organophosphates are employed. At present, no applications of insect growth regulators or microbial agents are used by private pest control operators. During dengue epidemics they assist the government in space spraying with insecticides. The Environmental Protection Administration, Executive Yuan, R.O.C., is responsible for the training and management of pest control operators. In addition, the Administration is also in charge of affairs concerning the manufacture, import, registration and sale of environmental pesticides and microbial agents. It establishes protocols for testing the efficacy of insecticides and promotes pest control on the community level. PMID- 7844853 TI - Mosquito abatement district programs in the United States. AB - Mosquito abatement districts and vector control districts in the United States offer a wide variety of programs with emphasis on local problems. Management of these programs is the important factor. The various program elements, program administration, organizational structure, staffing, funding, public education, program evaluation, training, technical guidance, and preventive planning are discussed. PMID- 7844854 TI - Privatization of mosquito control services in urban areas. PMID- 7844855 TI - Ecology and control of dengue vector mosquitoes in Taiwan. AB - Due to rapid urbanization, industrialization and social changes in recent years, the use of packing materials and tires has dramatically increased in the Taiwan area. What is more is that some parts of southern Taiwan are short of water resources and water preservation with huge containers becomes part of custom in those areas. Storage water containers, waste vessels and tires are good habitats for Aedes. Meanwhile, some persons traveling to dengue endemic countries bring the dengue disease back to Taiwan. Surveys taken since 1988 show that dengue occurs mainly in the urban and coastal areas where Aedes aegypti is prevalent. This species is the most important, if not the only, vector of dengue in Taiwan. It appears that the types of Aedes breeding have changed quickly. In dengue fever epidemic areas, the most popular breeding sites are ornamental containers (38.8%), storage water containers (30.1%), discarded containers (25.4%), receptacles (3.3%) and water collection in the basement (2.2%). In dengue fever epidemic areas, those building basements, huge water containers, waste vessels and waste tires in open fields are most difficult to clean up and manage and become the most popular Aedes habitats. We established a waste recycling system and promoted a breeding site reduction campaign for waste management, including the application of Temephos in containers to kill larvae. For the drinking water management, fish were released in water containers to prevent larval breeding. It should be mentioned that with the integrated pest control and regular inspections of Aedes larvae in Taiwan the density figures 1, 2-5, and 6 or above for Aedes aegypti were 38.7%, 42.9%, and 18.4%, respectively, in 1988, and in 1993 were 90.8%, 9.2% and 0%. The incidence of dengue fever cases has 98% decreased since 1988. In 1990 and 1993, there was no indigenous cases. We have concluded that integrated pest control is the best and most effective method for dengue fever control, including solid waste and drinking water management. PMID- 7844856 TI - Surveillance and control of Aedes aegypti in epidemic areas of Taiwan. AB - Aedes aegypti is the main, if not the only, vector of dengue fever in Taiwan. The dengue epidemics that have occurred in Taiwan correlate with the distribution of Aedes aegypti which is limited to south of the Tropic of Cancer. During the 1987 outbreak of dengue fever in Taiwan, the average larval density for the months July-December in the five cities and counties of southern Taiwan was 2,284 larvae per 100 households. After control measures were taken, the average annual larval density in the years from 1988 to 1993 declined to 1,580, 671, 442, 178, 110, and 88 larvae per 100 households, respectively. During 1987-1988, the number of confirmed cases and the Breteau index of Aedes aegypti showed an obvious positive relationship (r = 0.74) in the most heavily infected 25 cities and towns. Our Institute has conducted eight training courses since 1989 for 176 health workers who serve in their respective areas as local scouts for monitoring Aedes larval density. The number of cities and towns surveyed by them in the years 1990-1993 was 116, 149, 254, and 156, respectively. The number of households covered by space spraying with permethrin was 43, 183 in 1991, 11,186 in 1992 and 4,856 in 1993. Residual spraying with alphacypermethrin was applied to houses in areas where the Breteau index was above 35. The number of houses treated in the years 1990-1993 was 4,735, 32,279, 33,726 and 17,848, respectively.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7844857 TI - Framework for application of geographic information system to the monitoring of dengue vectors. AB - In a successful management program of dengue vectors, not only health education, source reduction or insecticide application should be conducted, but all basic information should also be manipulated properly and efficiently. This information includes the surveys of species, dispersal and dynamics of vectors, as well as the detection of breeding sources, and the records of dengue cases and epidemic periods. Most of the above information expressed as regionalized variables always varies spatially and/or temporally. However, due to the deficiency of topological information, the conventional database management system cannot efficiently analyze those dengue related data. Thus, we have applied the geographic information system (GIS) to the monitoring of dengue vectors. The purpose of this report is to introduce the basic concepts of GIS, to describe the framework of the prototype dengue vector monitoring system which was built using data collected from the Sanmin area, Kaoshiung city, Taiwan, and to indicate the possibility of using this system to manipulate spatially correlated data and support decision making in the control of dengue disease. PMID- 7844858 TI - Growing use of medicinal botanicals forces assessment by drug regulators. PMID- 7844859 TI - Judge rules diversion of antismoking money illegal, victory for California Tobacco Control Program. PMID- 7844860 TI - Trial halted as sickle cell treatment proves itself. PMID- 7844861 TI - From the Food and Drug Administration. PMID- 7844862 TI - From the Centers for Disease Control. State-specific trends among women who did not receive prenatal care--United States, 1980-1992. PMID- 7844863 TI - Performance on the NBME Part I examination. PMID- 7844864 TI - Performance on the NBME Part I examination. PMID- 7844865 TI - Doxycycline treatment and Desert Storm. PMID- 7844866 TI - Estrogen replacement therapy in breast cancer survivors. PMID- 7844867 TI - Estrogen replacement therapy in breast cancer survivors. PMID- 7844868 TI - Estrogen replacement therapy in breast cancer survivors. PMID- 7844869 TI - Estrogen replacement therapy in breast cancer survivors. PMID- 7844870 TI - Diagnostic delays with bacterial meningitis. PMID- 7844871 TI - A piece of my mind. Shreds of a flowered shirt. PMID- 7844872 TI - Optic nerve decompression surgery for nonarteritic anterior ischemic optic neuropathy (NAION) is not effective and may be harmful. The Ischemic Optic Neuropathy Decompression Trial Research Group. AB - OBJECTIVE: To assess the safety and efficacy of optic nerve decompression surgery compared with careful follow-up alone in patients with nonarteritic anterior ischemic optic neuropathy (NAION). DESIGN: The Ischemic Optic Neuropathy Decompression Trial (IONDT) is a randomized, single-masked, multicenter trial. SETTING: Twenty-five US clinical centers. PARTICIPANTS: The IONDT ceased recruitment on October 20, 1994, on the recommendation of its Data and Safety Monitoring Committee. The preliminary results presented herein are based on data as of September 8, 1994, from 244 patients with NAION and visual acuity of 20/64 or worse. One hundred twenty-five patients had been randomized to careful follow up, and 119 had been randomized to surgery, with 91 and 95, respectively, having completed 6 months of follow-up. INTERVENTION: Patients in the surgery group received optic nerve decompression surgery and follow-up ophthalmologic examinations; those in the careful follow-up group received ophthalmologic examinations at the same times as the surgery group. MAIN OUTCOME MEASURES: Gain or loss of three or more lines of visual acuity on the New York Lighthouse chart at 6 months after randomization, as measured by a technician masked to treatment assignment. RESULTS: Patients assigned to surgery did no better when compared with patients assigned to careful follow-up regarding improved visual acuity of three or more lines at 6 months: 32.6% of the surgery group improved compared with 42.7% of the careful follow-up group. The odds ratio (OR) for three or more lines better, adjusted for baseline visual acuity and diabetes, was 0.74 (95% confidence interval [CI], 0.39 to 1.38). Patients receiving surgery had a significantly greater risk of losing three or more lines of vision at 6 months: 23.9% in the surgery group worsened compared with 12.4% in the careful follow-up group. The 6-month adjusted OR for three or more lines worse was 1.96 (95% CI, 0.87 to 4.41). No difference in treatment effect was observed between patients with progressive NAION and all others. CONCLUSION: Results from the IONDT indicate that optic nerve decompression surgery for NAION is not effective, may be harmful, and should be abandoned. The spontaneous improvement rate is better than previously reported. PMID- 7844873 TI - Outcome of treatment for childhood cancer in black as compared with white children. The St Jude Children's Research Hospital experience, 1962 through 1992. AB - OBJECTIVE: To determine whether there is a racial difference in prognosis among childhood cancers. DESIGN: An overall (30-year) survival analysis by race was followed by separate studies for "early" and "recent" treatment eras, defined by time points at which significantly improved outcome was demonstrated for specific tumor types. Stratified analyses were performed to adjust for recognized prognostic features. SETTING: Pediatric oncology research and treatment center. PATIENTS: The study included 798 black and 4507 white children with newly diagnosed malignancies treated from January 1962 through June 1992. These patients were accepted for treatment regardless of their financial status and were enrolled on disease-specific protocols. RESULTS: Across the 30-year study period, black children had a significantly poorer rate of survival than white children (P < .001, log-rank test). In the early treatment era, a significant difference was seen for all forms of cancer combined (P < .001), with 10-year Kaplan-Meier estimates (+/- SE) of 37% +/- 3% for black children and 50% +/- 1% for white children. This difference largely reflected the poorer prognosis of black children with the most common childhood cancer, acute lymphoblastic leukemia. In the recent treatment era, there were no significant differences in treatment outcome by race for specific disease categories or for all forms of cancer combined. Ten-year survival rates were 67% +/- 6% for black children and 66% +/- 3% for white children, indicating a significantly greater improvement in the former group. CONCLUSION: With equal access to effective contemporary treatment, black children with cancer fare as well as white children when treated with protocol-based therapy at a pediatric oncology research center. PMID- 7844874 TI - Acute renutrition by cyclic enteral nutrition in elderly and younger patients. AB - OBJECTIVE: To evaluate the efficacy and tolerance of cyclic enteral nutrition (CyEN) in elderly compared with younger patients. DESIGN: Prospective case series. SETTING: University hospital nutritional support unit. PATIENTS: A total of 51 patients younger than 65 years (mean age, 45 years) and 46 patients 65 years of age and older (mean age, 77 years) referred for refeeding after having lost at least 20% of their body weight or at least 10% in 3 months. All patients were severely undernourished but were ambulatory. INTERVENTION: Cyclic enteral nutrition was administered via a nasogastric tube during the night; in the daytime patients were allowed to eat normally. MEASUREMENTS: Ten biological and anthropometric nutritional parameters and a global nutritional deficiency (GND) were measured at day 0, at day 15, and at the end of CyEN. RESULTS: Total energy intakes were 288% and 282% of resting energy expenditure in groups 1 and 2, respectively, and duration of CyEN was a mean of 27 days in both groups. Tolerance was generally good, although one patient in each group discontinued refeeding because of aspiration pneumonia. In both groups, seven nutritional parameters and the GND improved significantly; six parameters improved significantly more in younger than in elderly patients: body weight, serum albumin, serum prealbumin, serum transferrin, 24-hour urinary creatinine, and the GND (44.7% vs 35.4%; P = .006). After 1 year, the probability to be alive without relapse was 62% in the elderly and 76% in the younger patients (P = .18). CONCLUSIONS: Cyclic enteral nutrition appears to be a well-tolerated and effective treatment of undernutrition in older malnourished ambulatory patients, although their response to CyEN was somewhat less than in younger patients. PMID- 7844875 TI - Customized probability models for early severe sepsis in adult intensive care patients. Intensive Care Unit Scoring Group. AB - OBJECTIVE: To develop customized versions of the Simplified Acute Physiology Score II (SAPS II) and the 24-hour Mortality Probability Model II (MPM II) to estimate the probability of mortality for intensive care unit patients with early severe sepsis. DESIGN AND SETTING: Logistic regression models developed for patients with severe sepsis in a database of adult medical and surgical intensive care units in 12 countries. PATIENTS: Of 11,458 patients in the intensive care unit for at least 24 hours, 1130 had severe sepsis based on criteria of the American College of Chest Physicians and the Society of Critical Care Medicine (systemic inflammatory response syndrome in response to infection, plus hypotension, hypoperfusion, or multiple organ dysfunction). RESULTS: In patients with severe sepsis, mortality was higher (48.0% vs 19.6% among other patients) and 28-day survival was lower. The customized SAPS II was well calibrated (P = .92 for the goodness-of-fit test) and discriminated well (area under the receiver operating characteristic [ROC] curve, 0.78). Performance in the validation sample was equally good (P = .85 for the goodness-of-fit test; area under the ROC curve, 0.79). The customized MPM II was well calibrated (P = .92 for the goodness-of-fit test) and discriminated well (area under the ROC curve, 0.79). Performance in the validation sample was equally good (P = .52 for the goodness-of-fit test; area under the ROC curve, 0.75). The models are independent of each other; either can be used alone to estimate the probability of mortality of patients with severe sepsis. CONCLUSIONS: Customization provides a simple technique to apply existing models to a subgroup of patients. Accurately assessing the probability of hospital mortality is a useful adjunct for clinical trials. PMID- 7844876 TI - The future of the Department of Veterans Affairs health care system. PMID- 7844877 TI - Estimating health expenditure growth under managed competition. Science, simulations, and scenarios. AB - The estimated impact of health system reform proposals on health expenditures influences the health system reform debate. Health expenditure growth rate (HEGR) estimates are particularly critical because small differences in rates over time create large differences in health expenditures. There currently is no hard scientific basis for estimating the impact of managed care/managed competition legislation and market developments on the HEGR. For the 1994 health system reform debate, the two leading nonpartisan modelers developed qualitative scenarios about future health system developments in which managed care/managed competition would have little or no impact on the HEGR. We conclude that there are alternative plausible scenarios, based on current health system changes interacting with potential legislation, in which managed care/managed competition will substantially lower the HEGR. We recommend that simulation models should provide a range of estimates that better reflect both market trends and the profound uncertainty about the effects of health system reform. PMID- 7844878 TI - The clinical utility of the perinatal autopsy. AB - OBJECTIVE: To evaluate the clinical utility of the perinatal autopsy in determining the cause of a perinatal death. DESIGN: Retrospective observational survey. SETTING: University-affiliated, private, tertiary care hospital, limited to obstetrics, gynecology, and neonatology. SUBJECTS: All fetal deaths and neonatal deaths from 1990 and 1991 at Women and Infants Hospital, Providence, RI, were reviewed. Fetal deaths with a gestational age of less than 20 weeks and neonatal deaths occurring more than 48 hours after birth were excluded. MAIN OUTCOME MEASURES: A clinical medical record review assessed the clinical diagnosis. Pathology records were reviewed independently. The clinical and autopsy diagnoses were compared and categorized as follows: (1) confirm (clinical and autopsy diagnoses concordant); (2) change (clinical and autopsy diagnoses discordant); (3) add (significant unexpected findings noted on the autopsy although the clinical diagnosis was not altered); (4) autopsy inconclusive; (5) autopsy not done or not available. RESULTS: Of 168 perinatal deaths, an autopsy was not obtained in 26.2% and was inconclusive in 24.2% of cases with an autopsy. Of 94 patients with conclusive autopsies, in 55.3%, the pathologic diagnosis confirmed the clinical diagnosis, and in 44.7%, it changed or significantly added to the clinical diagnosis. CONCLUSIONS: These findings support the clinical relevance of the perinatal autopsy. As few published reports directly address the specific yield of the autopsy among fetal and neonatal deaths, these results may be useful in counseling patients who are considering a perinatal autopsy. PMID- 7844879 TI - Clarifying the treatment of nonarteritic anterior ischemic optic neuropathy. PMID- 7844880 TI - The future of the VA. Centralization, costs, politics, and presentism. PMID- 7844881 TI - Health care policy implications of the 1994 congressional elections. PMID- 7844882 TI - [Surveillance of multidrug-resistant environmental bacteria]. AB - The multidrug-resistance of Staphylococcus epidermidis and Pseudomonas aeruginosa was surveyed. The multidrug-resistant S.epidermidis isolated accounted for 18% of the total S.epidermidis (1991.4 to 1992.3) and were frequently isolated from specimens of the urine and respiratory system. The polymerase chain reaction revealed the existence of the mec A gene in S.epidermidis showing various degree of antibiotic resistance, suggesting that S.epidermidis is in the process of achieving multidrug resistance. The multidrug-resistant P.aeruginosa were isolated from 14.6% of the total P.aeruginosa (1993.5 to 1993.8) and were most frequently isolated from the urine. Most of the multidrug resistant P.aeruginosa showed serotype E, suggesting the relationship between serotype and acquirement of drug resistance. Pulsefield electrophoresis of SpeI digested P.aeruginosa genomic DNA showed a characteristic pattern and the genome pattern should be applicable for the epidemiology. PMID- 7844883 TI - [Role of lipoprotein(a) in the progression of atherosclerosis: implication of localization in atherosclerotic lesions and clinical usefulness of serum level determination]. AB - Lipoprotein(a) (Lp(a)) is generally regarded as an atherogenic lipoprotein because so much previous cross-sectional research has shown a tight connection between its plasma level and development of atherosclerosis. Previous studies on Lp(a) concerning its localization in atherosclerotic lesions and the clinical usefulness of serum level determination were reviewed, and the role of Lp(a) in the progression of atherosclerosis was discussed. In addition to its experimental and biophysiological relevance, clinicoepidemiological and socioeconomical consideration is becoming necessary for the clinicopathologist to evaluate the usefulness of blood Lp(a) measurement. In the clinicopathological field, much interest has been concentrated on the standardization of Lp(a) measurement because many methods have previously been applied to measure the blood Lp(a) concentration, and many problems concerning Lp(a) measurement have been raised. Future results from randomized or cohort studies in Japanese populations on Lp(a) will provide firmer evidence for the clinical usefulness of Lp(a) measurement. PMID- 7844884 TI - [Effect of shear stress on hemostatic regulation in endothelium]. AB - The vascular endothelium plays a pivotal role in regulating the hemostatic system. Various cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor (TNF) are known to perturb endothelial cells to reduce antithrombogenicity. On the other hand, blood flow has been shown to affect the endothelium to maintain its antithrombogenicity under some levels of shear stress in the laminar flow system. We examined the role of hemodynamic forces on the vascular system under cytokine stimulation using a cone-plate type viscometer. Treatment of endothelial cells with either IL-1 beta or TNF-alpha under static conditions increased PAI-1, vWF and prostacyclin release, while t-PA secretion was unchanged. When cells were exposed to steady shear stress of 0, 6, 12, 18 and 24 dyne/cm2, the release of t PA, t-PA-PAI complex and prostacyclin elevated with the increase of shear stress intensity, while a gradual decrease of total PAI-1 secretion was observed and vWF secretion was unchanged. On the contrary, active PAI-1 secretion was significantly decreased under the shear stress of over 18 dyne/cm2. Interestingly, cytokines, which did not affect t-PA secretion of resting cells, increased the t-PA secretion and had an additive effect on prostacyclin secretion with shear stress under the shear stress of over 18 dyne/cm2. PAI-1 elevation induced by cytokines was markedly abolished under the same shear forces. No additive effect was observed in the secretion of vWF. Thus, shear stress attenuates the alteration of the balance in the fibrinolytic and coagulation system induced by cytokines. These findings clearly indicate that hemodynamic forces play a crucial role in regulating the hemostatic activity in vivo. PMID- 7844885 TI - [Genetic analysis and a new therapy for a hereditary disease: familial amyloid polyneuropathy]. AB - Familial amyloid polyneuropathy (FAP) is a hereditary disorder with autosomal dominant trait and is characterized by the accumulation of transthyretin at the nervous systems. The disorder mostly becomes overt in the fourth decade of life among affected individuals. Treatment of FAP has been directed toward the relief of symptoms and not intended to eliminate the yet unknown cause of this disorder. Recently, Val30 to Met substitution in the transthyretin gene was found among the patients with typical FAP. This enabled us to genotype affected individuals by PCR-RFLP and paved the way to the treatments directed to lower the levels of abnormal transthyretin in patients. In 1990, a Swedish group successfully performed liver transplantation to patients with FAP. This report was followed by more than 60 cases of liver transplantation to FAP patients in the Western hemisphere. Herein, I describe the first case of living-related liver transplantation to an FAP patient at Shinshu University Hospital. The patient was a 31-year-old female, whose father and aunt died of typical FAP in their fifth decade. She was suffering from severe pains in her lower extremities and nausea and vomiting. PCR-RFLP of her transthyretin gene revealed that she was heterozygous for Val to Met substitution at codon 30. In 1993, she was transplanted the left lobe of liver from her elder sister, who was genetically free of the disorder. Two weeks after the transplantation, serum Met30 transthyretin levels fell below 5% of the initial level. Symptoms due to peripheral nervous system and gastrointestinal tract were relieved after the transplantation.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7844886 TI - [Suppression of myoclonus associated with intermittent photic stimulation (IPS) in a case of Creutzfeldt-Jacob disease: with special reference to the specificity of IPS frequency]. AB - The present study deals with electrophysiological findings 3 months after the patient fell into an apallic state during the course of Creutzfeldt-Jacob disease (CJD), when periodic limb myoclonus synchronizing with periodic synchronous discharge (PSD) began to diminish. The findings were as follows: On 2 Hz intermittent photic stimulation (IPS), myoclonus and the diffuse bisynchronous high amplitude sharp wave showed dissociation; the myoclonus was completely suppressed, while the high amplitude sharp wave was elicited. On 3 Hz IPS, myoclonus was incompletely suppressed, corresponding to every other high amplitude sharp waves which were induced synchronous to IPS. On 1 Hz IPS, the high amplitude sharp waves were scarcely induced while neither PSD nor the myoclonus were suppressed. The frequency of the PSD was about 1.2 Hz. Based on these findings, we propose that in addition to the cortical refractory period after PSD or the giant response to photic stimulation, there must be another refractory period in the distal impulse pathway longer than the cortical one. Although the exact electrophysiological mechanism involved in the present findings remains unknown, the possible mechanism responsible for the suppression of myoclonus by IPS and the specificity of IPS frequency in the suppression could be due to competitive suppression of the impulse between periodic myoclonus and the cortical reflex myoclonus through the interaction of the two independent refractory periods in the transmission pathway of the impulse. PMID- 7844887 TI - [Genetic diagnosis of phenylketonuria. III. Mutations of phenylalanine hydroxylase gene in Orientals]. AB - Phenylketonuria (PKU) is an autosomal recessive disorder caused by lesions in the phenylalanine hydroxylase (PAH) gene. The recent studies on PAH mutations show the genetic drift of PKU alleles among some Oriental populations. Therefore, we searched for PKU mutations among Japanese, Chinese and Taiwanese. Direct sequencing was conducted on DNA fragments amplified by the polymerase chain reaction, using solid-phase technology involving the biotin-streptavidin system. Two new mutations (R241C and G247V) and two of the known mutant alleles (Y204C and R243Q) were found in two Taiwanese and two Chinese PKU patients, and three known mutations (R111X, Y204C and R413P) were recognized in three Japanese; two new mutations were identified in exon 7 of the PAH gene at codon 241 and codon 247, where the single base changes from C to T and from G to T substituted cysteine for arginine and valine for glycine, respectively. Further all the PAH mutations detected are common in Oriental populations as they have been thus far unreported among Caucasians. From these data as well as the clinical phenotype of the patients, we suggest that the R241C and G247V substitutions may interfere with proper enzyme function, although we have not yet performed functional studies. More detailed studies would be needed to clarify the regional distribution of mutant chromosomes in Oriental populations and other unidentified mutations. PMID- 7844888 TI - [Genetic diagnosis of phenylketonuria. IV. Mutations of phenylalanine hydroxylase gene in Caucasian and Gypsy populations in Czech and Slovakia Republics]. AB - Direct sequencing was conducted on the regions of the exon 7 and 12 in the phenylalanine hydroxylase (PAH) gene amplified by the polymerase chain reaction, using solid-phase technology involving the biotin streptavidin system. A novel mutation and seven previously known mutations were identified in the PAH genes among 15 Caucasians and 10 Gypsies in the Czech and Slovakia republics, affected with classical phenylketonuria (PKU). Two of these substitutions (R243X and G272X) resulted in the generation of a premature stop codon, and a single base transition of G to A at codon 261 resulted in the substitution of Arg for Gln (R261Q). These three mutations together accounted for 16.7% of PKU alleles among 15 Caucasians. The R252W mutation was detected in these two groups: two Caucasians were compound heterozygous for the P281L or R408W mutations (6.7% of all mutant alleles). However, all 10 Gypsy PKU patients were homozygous for the R252W transition. The R408W mutation accounted for 43% of PKU alleles in 15 Caucasian PKU patients. A novel heterozygous C-to-G transversion at the third base of codon 263 in the exon 7, resulting in the substitution of Phe for Leu (F263L), was detected in a Caucasian PKU patient (3.3% of all mutant alleles). In this study, we revealed a novel PKU mutation of the F263L in Caucasian populations and a high-risk PKU mutation of the R252W in Gypsy populations. PMID- 7844889 TI - [A study of low density lipoprotein in a patient with hyper-high density lipoprotein cholesterolemia with normal cholesterolester transfer protein]. AB - We examined a patient with hyper-cholesterolemia with a high level of HDL2 and LDL-cholesterol in serum. The metabolism of lipoproteins in this case was different from that in well-known hyper-high density lipoproteinemia or hyper-low density lipoproteinemia, because the patient had normal levels of cholesterolester transfer protein, lipoprotein lipase and hepatic triglyceride lipase activity. This study describes the characterization of LDL obtained from the patient's serum. LDL from the patient was separated by ultracentrifuge, and analyzed by gradient PAGE. The molecular weight of two LDL from the patient have been estimated to be approximately 1250 and 1450kDa by polyacrylamide gel electrophoresis, and were larger than those of normal individuals and patients with typical hypercholesterolemia (approximately 1150kDa in molecular weight). The LDL from the patient was separated into three fractions by HPLC, and their lipid composition was not significantly different from that of normal LDL. The high level and large size of LDL from the patient may be caused by a reduction in the transfer of cholesterol from LDL to HDL2, or an equilibrium of cholesterol with the increased HDL2. PMID- 7844890 TI - [Distribution of glutathione peroxidase in the glomeruli of IgA nephropathy]. AB - To study the role of reactive oxygen species in chronic renal disease, we studied the location of Glutathione peroxidase (GSH-Px) in glomeruli of patients with IgA nephropathy. In normal kidney, GSH-Px was localized in tubular cells, and not in glomeruli. In the kidney with IgA nephropathy, GSH-Px was detected in glomerular cells in addition to the tubular cells. As for the relation between the extent of GSH-Px and clinical findings, the following results were obtained. When GSH-Px are strongly stained in glomeruli, histological change of glomeruli was milder. Concerning the renal function, when GSH-Px was stained weakly, Ccr reduced significantly one year after the renal biopsy. Thus, when this enzyme are present in glomeruli, renal function appeared to be more preserved. These results suggest that this enzyme have the beneficial action for renal function as antioxidative factors in IgA nephropathy. PMID- 7844891 TI - [Detection of methicillin-resistant Staphylococcus aureus using PCR and non radioactive DNA probes: IV. Mutational sequences in the region upstream of the mec A gene in clinical staphylococcal strains]. AB - Expression of mec A is regulated by two regulatory genes (mecR1 and mecI); the intact regulatory genes exist in the N315 strain of methicillin-sensitive S. aureus, whereas the repressor gene (mecI) is deleted in the MR108 strain of methicillin-resistant S. aureus (MRSA). However, our previous findings that clinical strains of N315 type were methicillin-resistant suggest possible mutations within the operator region, by which the inhibitory effect of MecI is released to induce the constitutive expression of mec A. Therefore, we analyzed nucleotide sequences in the region upstream of the mec A gene and in the regulatory genes, by using PCR-direct sequencing and ASO probes. Analysis of selected clinical strains by ASO probes revealed that 74% of MRSA and 36% of MRSE (methicillin-resistant S. epidermidis) lacked the mecI gene whereas 26% of MRSA and 64% of MRSE possessed the intact regulatory genes. Furthermore, PCR-direct sequencing identified four different mutations in the operator nucleotide sequence and one mutation in Shine-Dalgarno sequence. Additionally, these mutations were shown to occur in the strains of N315 type with higher probability rather than in those of MR108 type. The data suggest that one or more of these mutational sequences at least may have some influence on the expression of methicillin-resistance in clinical staphylococcal strains. PMID- 7844892 TI - [An enzyme-linked immunosorbent assay for the detection of IgG antibodies against urease of Helicobacter pylori]. AB - We have developed an enzyme-linked immunosorbent assay (ELISA) for the detection of IgG antibodies against Helicobacter pylori (HP) using purified HP urease as an antigen. The urease was purified from ultrasonicated extract of HP by NaCl linear gradient system on DEAE-Sepharose 4B chromatography. Two molecular weight bands, 65kD and 27kD were observed on a SDS-PAGE gel in the purified urease sample. The urease antigen did not crossreact to rabbit antibodies prepared against Campylobacter coli and Campylobacter jejuni. Out of 93 gastric biopsy patients, sixty nine patients (74.2%) were positive in HP culture test. Serum HP antibody titers (AU: arbitrary unit) of HP culture positive and negative patients were 42.9 +/- 47.4 and 16.7 +/- 25.7 (mean +/- SD), respectively (p < 0.05). The ELISA system have sensitivity of 72.5% and specificity of 70.8%. We believe that the ELISA system is useful for diagnosis and monitoring of HP infection. PMID- 7844894 TI - [SGOMSEC and international cooperation]. PMID- 7844893 TI - [A trial of setting of the reference intervals of thrombin antithrombin III complex and fibrin.fibrinogen degradation products in pregnant women]. AB - Activity of coagulation and fibrinolysis during pregnancy differed greatly from that during a nonpregnant period. We examined the reference intervals by mean +/- 2 standard deviations for thrombin antithrombin III complex (TAT), total FDP (T FDP), FDP-E, D-dimer before and after delivery. The reference intervals obtained were as follows: TAT (micrograms/l): 1.0-4.8 for 1st trimester, 2.0-10.2 for 2nd trimester, 2.8-14.2 for 3rd trimester, 2.6-16.3 for full term pregnancy, 0-10.5 for post partum. T-FDP (micrograms/ml): 1.5-4.2 for 1st trimester, 1.8-5.6 for 2nd trimester, 1.9-8.5 for 3rd trimester, 2.9-9.7 for full term pregnancy, 2.4 9.0 for post partum. FDP-E(ng/ml): 26.4-98.0 for 1st trimester, 42.4-176.7 for 2nd trimester, 53.1-222.5 for 3rd trimester, 82.4-297.9 for full term pregnancy, 56.9-240.6 for post partum. D-dimer (micrograms/ml): 0.2-2.0 for 1st trimester, 0.6-3.8 for 2nd trimester, 0.6-4.3 for 3rd trimester, 0.7-6.8 for full term pregnancy, 0.6-5.7 for post partum. Further studies are needed to determine the borderline values to determine the clinical abnormality, with a comparison of the reference intervals with the pathologic laboratory data. PMID- 7844895 TI - Quantitative assessment of stressors and stress reaction: a review. AB - To survey methods for assessing stress and to examine the relationship of stress to health and the factors of lifestyle, we reviewed the literature on stressors and stress reactions. Firstly, we reviewed the representative methods for assessing stressors. Secondly, self-report questionnaires based on a theoretical model of occupational stressors were surveyed and factors in work stress were listed. Then, we reviewed stress reactions including physiological, psychological and behavioral reactions. Finally, we examined the relationship of perceived stress measured by a single question to mental health status determined by the General Health Questionnaire (GHQ-28), lifestyles and personality based on the Egogram in Transactional Analysis. It is suggested that we need to assess subjective aspects as well as using objective indices such as data from physical examinations, to evaluate the level of stress and to promote mental health. PMID- 7844896 TI - A simple apparatus using inclinometer for monitoring working postures. AB - A new apparatus was developed for evaluating a load on the low back caused by working postures by measuring upper body inclination. This apparatus consists of an inclinometer and a portable unit. The inclinometer that uses a magnetic resistance sensor is attached to the upper body of the subject. The portable unit, controlled by a one-chip CPU, is enclosed in a cloth case and carried by the subject on his waist belt. The inclination is measured at a certain interval and recorded in the memory of the portable unit. All the recorded data are later transferred to a host computer and then analyzed. According to the theoretical analysis by using a simple mathematical model, upper body inclination changes according to the height of work places, and one cm difference in height causes more than one degree of upper body inclination. A model work of material handling was carried out to collect sample data. Two male subjects lifted ten boxes onto a platform from a stand in several heights. Both stooped and squat lifting methods were used as the lifting protocol. The mean and standard deviation (SD) of the upper body inclination during work decreased according to the lift distance only in stooped lifting. As a practical application, working postures during the task of changing diapers for handicapped people were analyzed with out apparatus. A female subject changed diapers eight times at different height of beds. The mean value of inclination decreased according to the height of the beds.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7844897 TI - Analysis of toxic gas produced by heating tar epoxy resin paint to assess work atmosphere. AB - Two male workers were acutely intoxicated with gas produced by heating tar epoxy resin paint, and developed peripheral neuropathy. To assess the work atmosphere, we analyzed the degradation products by GC-MS. The major toxic products emitted by heating tar epoxy resin were hydrogen cyanide, phenol, and benzene, as well as naphthalene. From 1 m2 of the surface of steel plates painted with tar epoxy resin, 2.4 g of hydrogen cyanide, 9.6 g of benzene, and 1.2 g of nephthalene were produced by heating at 1000 degrees C, At 700 degrees C, the amounts of phenol and p-isopropylphenol produced were 3.7 g and 0.57 g, respectively. Based on these results and the area of steel surface burned, the concentration of hydrogen cyanide, benzene, and phenol in the atmosphere of work environment was estimated to be 16, 64 and 24 mg/m3, respectively. Some of the symptoms of the workers including peripheral neuropathy might be related to the sole or cooperative action of the foregoing toxic chemicals mentioned above. PMID- 7844898 TI - [Analysis of acute toxicity (LD50-value) or organic chemicals to mammals by solubility parameter (delta) (2). Acute oral toxicity to mice]. AB - Acute oral toxicity (LD50-value) of organic chemicals to mice was analyzed by using solubility parameter (delta c), a thermodynamic parameter, of the chemicals. As it was observed in the previous study with rats, parabolic correlations were established between logarithm of LD50-value (mmol/kg body weight, mice) and delta c of all the collected chemicals (n = 85, R = 0.626), alcohols (n = 10, R = 0.683), ketones (n = 7, R = 0.631) and aromatics (n = 62, R = 0.645). Introducing molar volume (Vc) to the above equations did not improve the correlations. Although statistically significant correlations were not found in alcohols and ketones with mice, we successfully assured the theoretical equation regardless of species difference by establishing significant correlations with all the collected chemicals and aromatics. By analysis, we could determine the solubility parameter of 2.27 x 10(4) (J/m3)1/2 for the biological membrane (absorption site) of mice. As the delta c-values which dip the LD50-values are approximately the same for mice and rats, common deleterious effects and mechanism may be working at common target sites. In addition, no species difference in sensitivity (toxicity) was found for the aromatics. For comparison, log P was used to describe LD50 of all the collected chemicals, but no correlation was established (R = 0.004-0.418). PMID- 7844899 TI - [Analysis of acute toxicity (LD50-value) of organic chemicals to mammals by solubility parameter (delta) (3). Acute dermal toxicity to rabbits]. AB - Acute dermal toxicity (LD50-value) of organic chemicals to rabbits was analyzed by using solubility parameter (delta c), a thermodynamic parameter, of the chemicals. As it was observed in the previous studies with rats and mice, parabolic correlations were also established between logarithm of LD50-value (mmol/kg body weight, rabbits) and delta c of all the collected chemicals (n = 56, R = 0.498), alcohols (n = 19, R = 0.857), ketones (n = 7, R = 0.711), aldehydes (n = 7, R = 0.633) and aromatics (n = 20, R = 0.613). Introduction of molar volume (Vc) to the above equations did not improve the correlations. In the study, we assumed that chemicals absorbed dermally by the mammals similarly disturb the homeostasis, as in acute oral toxicities of organic chemicals to rats and mice. We successfully confirmed the theoretical equation regardless of species and routes of administration by establishing statistically significant correlations with all the collected chemicals, alcohols and aromatics. By analysis, we could determine the solubility parameter of 2.24 x 10(4) (J/m3)1/2 for the biological membrane (absorption site) of rabbits. As the dermal delta c values which dip the LD50-values for rabbits are approximately the same as in acute oral toxicities with rats and mice, common deleterious effects and mechanism may be working at the common target sites. The regression curves of LD50-values of rabbits, however, are slightly higher than those of rats and mice, which may reflect the difference in amounts of the chemicals absorbed by the body.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7844900 TI - [The frequency of glutathione-S-transferase M1 (GSTM1) gene deletion in patients with lung and oral cancer]. AB - A homozygous gene deletion at the glutathione-S-transferase (GST) M1 locus of genomic DNA isolated from the peripheral blood was investigated for its relationship with lung and oral cancer using the polymerase chain reaction (RCR) technique. DNA samples were prepared from 91 healthy controls, 53 lung cancer patients and 48 oral cancer patients. As for the genotype, 38 of 91 healthy controls (41.7%), 27 of 53 lung cancer patients (50.9% [p > 0.05], odds ratio 1.45, 95% confidence interval 0.73-2.86) and 26 of 48 oral cancer patients (54.2% [p > 0.05], odds ratio 1.65, 95% confidence interval 0.82-3.32) were GSTM1 deletion types. When male-smoker patients and healthy controls were analyzed, the frequency of GSTM1 deletion genotype was 41.6% in the healthy controls and 52.2% (p > 0.05, odds ratio 1.53, 95% confidence interval 0.58-4.14), 54.5% (p > 0.05, odds ratio 1.68, 95% confidence interval 0.45-6.26), and 50.0% (p > 0.05, odds ratio 1.40, 95% confidence interval 0.55-3.60) in pulmonary squamous cell carcinoma, small cell carcinoma, intraoral squamous cell carcinoma patients, respectively. Thus, the GSTM1 deletion genotype as a host factor predisposing to lung and oral cancer could not be confirmed in this study. PMID- 7844901 TI - [Exercise-induced ST segment change and coronary risk factors in apparently healthy men]. AB - Exercise stress test is useful for the early detection of coronary artery disease and is recommended as a medical clearance test before the initiation of exercise training. However, when applied to apparently healthy people, there are many false positive results. It is therefore necessary to determine indications for stress testing, but few data are available in Japan. In this study, we performed exercise stress test in apparently healthy men to investigate the incidence of exercise-induced ST segment changes and their relationship to coronary risk factors. The subjects were 2,187 men who underwent symptom-limited exercise stress test at a health-promotion center in Tokyo. Those with a history of cardiovascular disease were excluded. They underwent symptom-limited exercise stress test on a treadmill with a modified Bruce protocol or on a cycle ergometer with a ramp protocol (20 watts per minute). Twelve-lead electrocardiogram was recorded every 3 min. Cardiologists evaluated the exercise ECG responses, and advised those with abnormal ST segment changes (Group A) to undergo further examinations at a cardiovascular hospital. The results of further examination such as exercise scintigraphy and/or coronary angiography were obtained. Twice the number of subjects with normal exercise responses were selected as age matched controls (Group N) to compare the coronary risk factors between the two groups. Twenty-nine subjects had abnormal ST segment changes (1.33% of the total subjects) (Group A). Their mean age was 57 years (38 to 76). Among these, 27 had ST segment depression and 2 had ST elevation.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7844902 TI - [Significance of 1,5-anhydro-D-glucitol in diabetes mellitus management]. PMID- 7844903 TI - [One opinion on the handling of problem drinkers within corporations--based on three actual cases]. PMID- 7844904 TI - [A case of asbestosis with long survival by artificial ventilation]. AB - We treated a 63-year-old man in whom asbestosis developed after he had sprayed asbestos for 24 years. He was admitted with the chief complaint of dyspnea and was managed for 4 years with artificial ventilation. We believe that he survived for this long because he was free of severe pneumonia and because the lower lung, which is primarily affected by asbestos, was relatively intact so his pulmonary function did not deteriorate rapidly. Pathological findings included plate-like atelectasis in both upper lung fields and marked thickening of the pleura. Lung fibrosis was centrilobular but showed no honeycombing. The lung tissue contained 265 X 10(6) asbestos particles and 910 X 10(6) asbestos fibers per gram (dry weight), and the pleura also had 805 asbestos particles and 3,035 asbestos fibers. Most of these asbestos fibers were 20 microns or longer and were crocidolite. PMID- 7844905 TI - [A case of bilateral coronary-pulmonary artery fistula with multicystic saccular aneurysms]. AB - A 71-year-old woman was admitted to our hospital for evaluation of a chest X-ray abnormality. Heart murmur was not heard. Chest X-ray showed a bulge with calcification at left third arch. Chest computed tomography revealed contrast enhancement of masses, which appeared to originate from the vascular system. Coronary angiography demonstrated multicystic aneurysmal dilatation of a coronary artery fistula originating from the proximal left descending and right coronary artery. Electrocardiography showed no remarkable findings and a treadmill exercise test showed no significant ST-T change. The size of the mass of 3 cm in diameter on chest X-ray remained the same for two years. We concluded that surgery was not necessary immediately. In Japan, nineteen cases of coronary pulmonary artery fistula with multicystic saccular aneurysms have been reported in the literature, including our case. The majority of these cases are elderly women from fifty to sixty years old. PMID- 7844906 TI - [A case of multiple nodular pulmonary amyloidosis associated with Sjogren's syndrome]. AB - A 58-year-old female, who had complained of dryness of the conjunctiva and mouth for nine years, was admitted to our hospital because chest X-ray films revealed increases in both the size and the number of pulmonary nodules in comparison to four years earlier. Histological findings of the salivary gland biopsy confirmed a diagnosis of Sjogren's syndrome. An open lung biopsy was performed. Histologically, the pulmonary nodules consisted of homogeneous, acellular eosinophilic materials, which were identified as amyloid by Congo red staining. Immunohistochemical examination showed the amyloid to be composed of AA protein. There were no deposits in other organs. Peribronchial lymphocytic infiltration associated with Sjogren's syndrome was present. Nodular pulmonary amyloidosis with Sjogren's syndrome is very rare condition. To our knowledge, this case is only the ninth to be reported in the literature. PMID- 7844907 TI - [A case of esophageal cyst resected by thoracoscopic surgery]. AB - A 59-year-old woman was admitted with back pain and an abnormal chest shadow in the left hilar region. Her chest CT scan showed a posterior mediastinal mass surrounding the descending aorta. By transesophageal ultrasonography, a diagnosis of mediastinal cyst was made. She underwent thoracoscopic resection under general anesthesia with new endoscopic devices including endo-scissors, endoscopic hemoclips and electrocautery. Pathologically, the tumor was an esophageal cyst lined by ciliated columnar and squamous epithelium overlying smooth muscle layers. She made an uneventful recovery. Her back pain subsided following the operation. Thoracoscopic resection is a useful technique for patients with mediastinal cystic tumor. PMID- 7844908 TI - [A case of idiopathic pulmonary fibrosis associated with bilateral pulmonary arterial thrombosis found at autopsy]. AB - A 73-year-old woman admitted to the hospital with dyspnea on exertion. Chest radiography revealed a diffuse interstitial shadow; PaO2 was 72 Torr, and PaCO2 was 41 Torr. Laboratory examination results were compatible with idiopathic pulmonary fibrosis (IPF). Prednisolone relieved the dyspnea, but tapering of the drug led to a recurrence of this symptom. Pulse therapy was started and azathioprine was added to the corticosteroid. Over the course of 6 months of treatment, the patient's respiratory function remained fairly stable. Then respiratory distress was induced by an attack of atrial fibrillation, with relief provided by anti-arrhythmic drugs and large doses of corticosteroids. The patient died suddenly 3 weeks later. An autopsy revealed large thrombi in both pulmonary arteries with 90% stenosis. Parts of the thrombi were organized, which suggests that 2-3 weeks had elapsed since initial thrombus formation. Histological examination of lung tissue showed usual interstitial pneumonia. Pulmonary thromboembolism should be considered in patients with IPF if respiratory distress suddenly and unexpectedly worsens. PMID- 7844909 TI - [Two cases of invasive pulmonary aspergillosis in non-immunocompromised hosts]. AB - Invasive pulmonary aspergillosis generally occurs in immunocompromised hosts such as patients with leukemia, and other malignancies, who are receiving anti-cancer chemotherapy. In this report, two non-immunocompromised patients who developed invasive pulmonary aspergillosis are presented. Case 1: A 63-year-old man complained of productive cough and fever. He received antibiotic therapy from his personal physician. This symptoms did not respond, however, and dyspnea developed. He was then transferred to our hospital, about one month after the onset. The chest X-ray showed a meniscus shadow suggesting an aspergilloma in the right upper lung field and an infiltrative shadow in the remaining right lung field. Case 2: A 78-year-old man was admitted because of dyspnea, productive cough and appetite loss over the previous three months. The chest X-ray showed a meniscus shadow in the left upper field, an infiltrative shadow in the left lower field and a right pleural effusion sign was also observed. Both cases were diagnosed as having aspergillosis, early in their illness, by the detection of aspergillus antigen in their sera and histopathological and cultural studies of specimens obtained by TBLB. Both improved with intravenous amphotericin B (30 mg/day) and intravenous ulinastatin (200000 IU/day) administration. On the examinations conducted during hospitalization, there was no evidence of any immunosuppressive diseases or immunoincompetent conditions such as leukemia, and other malignancies human immunodeficiency virus infection, diabetes or alcoholism. PMID- 7844910 TI - [Cyst puncture and injection of contrast medium for diagnosis and treatment of pericardial cyst]. AB - We present two cases of pericardial cyst diagnosed by cyst puncture and the injection of contrast medium. The first patient was a 48-year-old man. He was admitted for the evaluation of an abnormal chest X-ray which demonstrated a mass lesion inseparable from the right heart border. CT scan confirmed the mass in the anterior cardiophrenic angle. The mass was quite homogeneous, with an attenuation value of -0.3 HU. Under CT guidance a 21-G needle was inserted into the cyst and 3 ml of clear fluid was obtained, and then contrast medium was injected. A thin smooth walled cyst was outlined by the CT scan. A presumptive diagnosis of pericardial cyst was made. Surgery was performed and the diagnosis was confirmed. The second patient was a 24-year-old woman. An abnormal shadow was noted at annual check up. CT scan confirmed the mass in the anterior cardiophrenic angle. The mass was quite homogeneous, with an attenuation value of +10.4 HY. We made the diagnosis of pericardial cyst by cyst puncture and injection of contrast medium. The CT scan after three months showed no recurrence of the pericardial cyst. We consider that pericardial cyst can be diagnosed clearly by cyst puncture and the injection of contrast medium, and only percutaneous aspiration of the cyst fluid may be sufficient for the treatment. PMID- 7844911 TI - [Lymphocyte phenotype and cytokine mRNA expression of steady-state asthma BALF cells]. AB - Recently, the roles of inflammatory processes in the pathogenesis of asthma have been emphasized. To elucidate the roles of T lymphocytes in local inflammatory sites in asthma, we examined T cell phenotypes with flow cytometry and carried out cytokine message amplification phenotyping (MAPPing) of bronchoalveolar lavage (BAL) cells taken from patients with steady-state asthma (n = 11). The percentage of CD4+ T cells in total lymphocytes correlated significantly (r = 0.784, p < 0.005) with that of lymphocytes in total CD45+ BAL cells. The positivities of T cell activation markers (CD25, HLA-DR) in CD4+ T cells were inversely correlated with the ratio of CD3+ T cells to total CD45+ BAL cells (CD25, r = 0.648, p = -0.059, HLA-DR, r = -0.741, p < 0.05). Most CD4+ T cells were of the CD45 RO+ "memory" phenotype. With cytokine MAPPing, IL-2 or IFN gamma were detected in only 2 of 11 patients, but IL4 or IL-5 were detected in 8 patients. These results suggest that non-activated TH2 type memory CD4+ T cells accumulate in local inflammatory sites of the bronchi of patients with steady state asthma, and that these cells releases cytokines (IL-4, IL-5) when activated by some stimuli, which can lead to an asthma attack. PMID- 7844912 TI - [Evaluation of serum thrombomodulin in patients with interstitial pneumonia]. AB - We encountered a 63-year-old man whose dry cough due to interstitial pneumonia had been successfully with an anti-thrombin drug, argatroban, which was given to treat exacerbated Buerger's disease. We therefore prospectively evaluated fibrinogen, fibrin-degradating product D-dimer, thrombin anti-thrombin III complex, and plasmin anti-plasmin complex in patients with interstitisal lung diseases. In a preliminary study, we found that some patients actually had elevated levels of these markers. These findings suggested that increased coagulability was involved in the pathophysiology of interstitial pneumonia. In this study, we measured the levels of serum-soluble thrombomodulin as a marker of endothelial cell damages that lead to hemostasis. We found that serum levels of thrombomodulin were high in about 35% of patients with sarcoidosis, interstitial pneumonia associated with collagen diseases, or idiopathic interstitial pneumonia. Furthermore, these levels decreased as the patients' conditions improved. Although further evaluation is needed, these results suggest that endothelial cell damage and hemostasis are involved in the pathophysiology of interstitial pneumonia. PMID- 7844913 TI - [Effect of E. coli endotoxin and D-galactosamine on pathophysiology in rat lungs]. AB - The effects of repeated intravenous injection of E. coli endotoxin (ETX) and intraperitoneal injection of D-galactosamine (GAL), which decreases the circulating level of alpha 1-antitrypsin, on the pathophysiology of chronic lung injury was studied in rats. Four groups were prepared as follows for 8 weeks. Group 1 (control): Intravenous injection of saline. Group 2: Intravenous injection of ETX (2 mg/kg) once a week. Group 3: Intraperitoneal injection of GAL (200 mg/kg), 2 times daily on 3 consecutive days each week. Group 4: Injection of both ETX and GAL, at the same dosages as used in groups 2 and 3. Total lung capacity and static lung compliance divided by weight were high in the ETX group and the ETX + GAL group, comparative when compared with those in the control and GAL groups, even though weight gain rates in the ETX + GAL group was less than in other groups. Mean linear intercept of rats in the ETX + GAL group was significantly greater than in other groups. These results suggest that ETX + GAL treated rats have more emphysematous changes in pulmonary function and structure. PMID- 7844914 TI - [Detection of intratumoral DNA heterogeneity in primary lung cancer using a multiple sampling method]. AB - The nuclear DNA contents of 18 freshly resected specimens of primary lung cancer tissue were determined by flow cytometry with a multiple sampling method. A DNA aneuploidy pattern was observed in all cases. In three cases, a diploid DNA pattern was observed along with abnormal DNA stem lines. Twelve cases (66%) had two or more abnormal DNA stem lines, and were classified as DNA multiploidy. The frequencies of DNA aneuploidy and DNA multiploidy were higher than in previously reported studies. Intratumoral DNA heterogeneity was observed in 10 cases (55%). Three of these were a mixture of DNA diploidy and DNA aneuploidy, and the other seven were a mixture of DNA aneuploidy and DNA multiploidy. If multiple sampling had not been performed in these cases, their ploidy patterns would have been misinterpreted. We conclude that multiple sampling is important in determining the precise DNA ploidy patterns of primary lung cancers. PMID- 7844915 TI - [Effects on bone metabolism of asthma treatment with beclomethasone dipropionate (BDP) inhalation and short term burst of oral steroids]. AB - Inhaled steroids are currently the first-line treatment of chronic asthma. Because each metered dose of beclomethasone dipropionate (BDP) is small (50 micrograms), short term burst or continuous use of oral steroids are combined in moderately to severely asthmatic patients. The effect of these treatments on bone metabolism remains unclear. Bone mineral density (BMD), osteoclacin (OC), PTH, Ca, and ALP were assessed in 130 asthmatic patients. There were 3 groups: the first group [B+R] consisted of 17 patients taking BDP (1190 +/- 536 micrograms/day) and also taking oral steroids (8.0 +/- 3.8 mg/day, 8.11 +/- 5.52 years), the second group [B+S] had 35 patients taking BDP (885 +/- 320 +/- g/day) and short-term bursts of oral steroids (PSL 20-40 mg/day, 3-7 days/course, 7.51 +/- 4.54 courses/year) and the third group [B alone] consisted of patients who were taking BDP (480 +/- 260 micrograms/day) alone. BMD was measured by dual energy X-ray absorptiometry (DEXA). In the [B+R], [B+S], and [B alone] groups, the BMD of vertebra (L1-4) was 0.75, 0.86, and 0.90 g/cm2, respectively. The percentages of predicted values based on age and sex were 92.0, 102.7, and 106.9% respectively. BMD and percent decrease were significantly lower in the [B+R] group than in the [B+S] or [B alone] group. It is likely that this phenomenon is caused by long-term use of oral steroids rather than by BDP inhalation but there is no significant difference between the [B+S] and the [B alone] groups. Daily BDP dose did not correlate with BMD by multiple regression analysis.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7844916 TI - [A case of sarcoidosis with middle lobe atelectasis]. AB - We report a case of sarcoidosis complicated by middle lobe atelectasis. A chest radiograph and a chest CT film on admission revealed middle lobe atelectasis and mediastinal lymphadenopathy. Bronchofiberscopic findings showed slit-like stenosis and reddish, edematous mucosal change of the middle lobe orifice. On admission, the serum angiotensin-converting enzyme (ACE) level was within the normal range. However, the ACE level had increased beyond the normal range by 2 months later, histological examination of a specimen from a transbronchial lung biopsy (TBLB) of the middle lobe revealed noncaseating epithelioid cell granulomas. We diagnosed sarcoidosis because of the histological findings from the TBLB and serum ACE elevation. Treatment with predonisolone resulted in remarkable alleviation of middle lobe atelectasis and mediastinal lymphadenopathy. Cases of sarcoidosis with middle lobe atelectasis are rare in Japan. PMID- 7844917 TI - [Idiopathic interstitial pneumonia that responded to intermittent intravenous administration of high-dose cyclophosphamide]. AB - A 78-year-old man was admitted to the hospital with exertional dyspnea and fever. Chronic idiopathic interstitial pneumonia (IIP) had been diagnosed a year before. Follow-up chest X-ray examination showed diffuse reticular shadows and progressive shrinkage of both lower lobes. Chest CT scan revealed honeycomb appearance of both lower lung fields. Moderate hypoxemia was found by arterial blood gas analysis. The patient responded to an orally administered corticosteroid. Because tapering of the medicine caused exacerbation of the hypoxemia, methylprednisolone pulse therapy was given with poor response. Then high-dose (750 mg) of cyclophosphamide (CPM) were given intravenously 6 times, every 3 or 4 weeks. After the second administration of CPM, decreases in hypoxemia and in blood LDH levels were observed. This treatment allowed as to taper the dose of oral corticosteroid from 60 mg/day to 15 mg/day. This case suggests that intravenous administration of high-dose CPM may be effective against IIP. PMID- 7844918 TI - [A case of unilateral brain-stem tumor and impaired ventilatory response]. AB - A 44-year-old man with a unilateral brain-stem tumor (ganglioglioma) presented with marked hypoventilation and irregular breathing. His respiratory muscle strength was impaired slightly, and his ventilatory responses to chemical stimuli were markedly diminished. Magnetic resonance imaging of the brainstem revealed that the tumor was located in the left superior cerebellar peduncle and the medulla, and involved the left lateral portion of the medullary reticular formation, ambiguous nucleus, and solitary nuclear complex. From these findings, we conclude that the abnormality of ventilatory control may have been caused by damage to both the unilateral respiratory neuron group in the medulla and the afferent pathway to the respiratory motor unit on the opposite side. PMID- 7844919 TI - [A case of subcutaneous sarcoid nodules induced by interferon-alpha]. AB - A 57-year-old woman came to our hospital complaining of multiple subcutaneous nodules that developed while she received corticosteroid therapy for pulmonary sarcoidosis. She was treated with interferon-alpha (IFN-alpha) at another hospital for C-type chronic hepatitis and she noticed these nodules with tenderness two months after treatment began. A biopsy specimen of the nodule revealed subcutaneous sarcoid granuloma. Her abnormally high serum-ACE value and subcutaneous nodules resolved after the dose of IFN-alpha was gradually reduced. IFN therapy should be used with care in cases of sarcoidosis in which IFN-gamma and T-lymphocytes are mainly involved. PMID- 7844920 TI - Labeling for physicians? PMID- 7844921 TI - Health care reform: dead in the water, or just biding its time? PMID- 7844922 TI - The health care stabilization fund after eighteen years. PMID- 7844923 TI - Dementia and the quality of life. PMID- 7844924 TI - The medical information superhighway. PMID- 7844925 TI - Effects of antipsychotic withdrawal in elderly nursing home residents. PMID- 7844926 TI - Occupational injuries: the need for preventive strategies. PMID- 7844927 TI - Healthy Kansans 2000 health objectives. PMID- 7844928 TI - Malaria in Kansas, 1988-1993. PMID- 7844929 TI - Is "routine" right heart catheterization OK? PMID- 7844930 TI - [Tubercle bacilli and the defence factors for infection in sputum and bronchoalveolar lavage fluid]. AB - The defence factors against infection in sputum and bronchoalveolar lavage fluid (BALF) of patients with pulmonary tuberculosis were measured. As the defence factors, lactoferrin, lysozyme and secretory IgA (sIgA) in sputum or BALF of patients with bacilli (+) or (-) tuberculosis were measured and compared. Lactoferrin in sputum was significantly higher in patients with sputum smear positive tuberculosis compared with patients with smear and culture negative tuberculosis. SIgA in sputum was significantly higher in smear negative and culture positive cases compared with culture negative cases. As to the lysozyme in sputum, significant difference was not proved between each group. The level of these factors in BALF did not show significant difference between bacilli (+) and (-) cases. Neither significant correlation was observed among the level of three defence factors in sputum or BALF, nor between the number of leucocyte and tubercle bacilli in sputum. In tubercle bacilli positive group, however, significant positive correlation between the number of leucocyte and lactoferrin in sputum was found. In vitro experiments, high concentration of lactoferrin or lysozyme inhibited the growth of standard strain of tubercle bacilli (H37Rv) and BCG. The results suggest that the measurement of lactoferrin, lysozyme and sIgA in sputum or BALF is useful to determine the clinical activity of tuberculosis. PMID- 7844931 TI - [A study on drug resistance of newly admitted pulmonary tuberculosis patients with special reference to the resistance to SM, INH, EB and RFP]. AB - Previously untreated 347 tuberculosis patients newly admitted to our hospital from 1980 to 1991 with positive bacilli and the full record of the drug sensitivity tests were analysed in this study. Among them, 49 cases showed primary resistance to either of major 4 anti-tuberculosis drugs (SM, INH, EB, RFP). The results obtained were as follows: 1. The number of patients with positive bacilli increased with age. The rate of primary drug resistance in patients of age group below 49 were significantly higher than that of age group over 50. 2. The rate of resistance was 8.6% to SM, 4.0% to INH, 1.4% to RFP and 0.6% to EB. These results are consistent with the results of studies of the Tuberculosis Research Committee, Ryoken. EB was frequently substituted to resistant drugs. 3. There was no significant difference between a group with primary resistance and a sensitive group in the various risk and intractable factors, laboratory data as a indicator of risk factors, and in the results of tuberculin skin test. There was also no significant difference in the rate of culture negative conversion of tubercle bacilli and the improvement in radiological findings. 4. We could rarely find the source of infection in 49 cases with primary resistance. In only 5 cases, family contacts were suspected and in another 1 case, the contact in a work place was suspected. PMID- 7844932 TI - [Analysis of tuberculosis cases among students reported from Osaka prefectural high schools and counter--measures for tuberculosis]. AB - The number of newly registered cases of tuberculosis has been increasing in the age group 15-19 year-old and over. To investigate the prevention of tuberculosis among young people under 20 years old, a survey was conducted on reported cases of tuberculosis among Osaka Prefectural high school students during the period from April, 1989 to May, 1994. Altogether 67 cases were reported from their schools during this period. Although there was a decrease in the total number of students since 1990, there was no corresponding decrease in the number of cases of tuberculosis. Of the total number of cases among high school students registered at public health centers in Osaka, only 23% were reported from the high schools. Cases confirmed bacteriologically positive consisted 13% of all cases. Male students accounted for 61% of reported cases. The methods of detection included medical consultation due to symptoms (75%), mass radiography (18%) and pre-employment health checkup (7%). 46% of cases reported during the first school year were discovered by mass radiography. While 24% of all cases were detected in April, no less than 46% of cases among those in the first school year were detected in April. Compared with those detected in any other school years, cases detected in the first school year showed some characteristic differences with regards to detection and bacteriological results. There has been one tuberculosis epidemic which accounted for six cases during the past five years.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7844933 TI - [Rapid identification of mycobacteria by combined method of polymerase chain reaction and the gen-probe DNA hybridization system]. AB - We developed the rapid detection and identification method of mycobacteria, involving amplification of mycobacterial 16S rRNA gene by nested PCR and identification of M. tuberculosis complex or M. avium-intracellulare complex (MAC) by hybridization protection assay (HPA) using the acridinium-ester (AE) labeled DNA probe. The specificity of the nested PCR combined with DNA probe test was excellent in terms of detection of mycobacterial organisms and identification of M. tuberculosis or MAC. The detection limits of the present method were 10 fg DNA for M. tuberculosis, and 100 fg DNA for MAC, respectively. We further investigated on the optimum temperature for hybridization in HPA with AE labeled DNA probe because there was the difference in the mode of DNA-RNA hybridization from that of DNA-DNA hybridization. In our method, the optimum temperature of hybridization was estimated as 55 +/- 1 degrees C. In preliminary experiments on two clinical cases, we practically detected and identified M. tuberculosis and MAC in clinical specimens, such as sputa, by using this newly devised method. We concluded that this method is useful for rapid detection and identification of M. tuberculosis and MAC in clinical specimens. PMID- 7844934 TI - [Evaluation for rapid detection of rifampicin-resistant mycobacterium tuberculosis by polymerase chain reaction-single strand conformation polymorphism]. AB - We evaluated usefulness of the rapid diagnostic method for detection of rifampicin (RFP)-resistant Mycobacterium tuberculosis, which was based on polymerase chain reaction. The MICs of RFP were measured for 38 clinical isolates of Mycobacterium tuberculosis which were suspected to be RFP-resistant organisms, and 12 strains were found to be resistant to RFP. The PCR primers used were the same as those reported by Telenti et al, which were targeting the RNA polymerase beta subunit gene (rpoB). We confirmed that this gene was possessed by all the strains tested. Eight strains out of the 12 strains with RFP-resistant phenotype were demonstrated to have a point mutation or some alterationin the rpoB gene on the basis of PCR-single strand conformation polymorphism (SSCP). Thus, the sensitivity of our method was calculated as 67%. In addition, we could not detect any alterations in the rpoB gene by all RFP-susceptible strains. These results indicated that rapid detection of the RFP-resistant Mycobacterium tuberculosis was possible directly from clinical specimens by using PCR-SSCP technique. PMID- 7844935 TI - [Identification of Mycobacterium avium and Mycobacterium intracellulare using DNA probe test, and their ratio in Niigata area]. AB - Using Gen-Probe test, both the Mycobacterium avium and Mycobacterium intracellulare strains were identified in the 76 disease-associated Mycobacterium avium complex (MAC) strains isolated in the NIIGATA area. The following results were obtained: 1) Fifty-four MAC strains (71.1%) reacted with M. avium-probe and 22 strains (28.9%) reacted with M. intracellulare-probe. 2) There were no significant differences between the ratio of two strains before and after 1991. 3) The ratio of female cases with M. avium was significantly higher (22/32) in the later period (after 1991) than in the former period (9/22). PMID- 7844936 TI - [The history of research in color perception as a key to understanding various forms of congenital defects in red-green perception]. AB - It is accurate to date the first scientific report about colour-deficiencies on 1777. Earlier descriptions may be followed up to the end of the 17th century. But usually it is only mentioned, that mistakes had happened. Huddart 1777, however, reported for the first time, that more than one person was involved in a family and that demonstrations of coloured ribbons helped to find out which colours became confounded. The famous self-observation of Dalton contains the assortment of individually combined silk-threads, which is an anticipation of subsequent arrangement-tests. Goethe developed a systematic arrangement-test of self-made small coloured targets with colours out of his own colour-wheel. A. Seebeck was the first who--using the spectrum for examination--found out that a special group of subjects showed a shortening of the spectrum at the red end. From this result Helmholtz concluded the existence of two types of red-green blindness. This new argument for the trichromatic organisation of our colourvision was the basis for the statement of the three types: protanopia, deuteranopia and tritanopia (v. Kries, A. Konig). Rayleigh later on succeeded in finding out anomalous trichromats following preparatory examinations of Maxwell. Nagel has the merit to have analysed protanomaly and deuteranomaly using the anomaloscope constructed by himself. Side by side with the spectral colour-tests pseudoisochromatic plates were developed for diagnostic purposes, at first thought out and introduced by Stilling and in the meantime used in many variations. PMID- 7844937 TI - [Lens surgery: yesterday, today and tomorrow]. AB - Short review of the evolution of lens surgery since the beginning of our century up to the present time: from extracapsular to intracapsular extraction and back again to the modern version of extracapsular extraction. From the beginning of intraocular lens implantation to modern intraocular lenses and, finally, a focus on the future toward the possibilities of "restoration" of the lens to recuperate not only visual acuity but also accommodation. PMID- 7844938 TI - Treatment of low, moderate, and high myopia with the 193-nm excimer laser. AB - PATIENTS AND METHODS: Photorefractive keratectomy using the VISX 2015 193-nm excimer laser was performed on 134 consecutive eyes of 97 myopic patients by the two authors. Preoperative refractive errors (spherical equivalent) ranged from 1.63 to -14.25 diopters (D) (mean, -5.76 +/- 2.40 D). Follow-up of 6 months was available on 110 eyes. At six months, the average residual refractive error was +0.16 +/- 1.13 D (range -2.88 to +3.38). Correction within 1 D of that attempted was obtained in 77 eyes (70%). Uncorrected visual acuity of 20/40 or better was achieved in 89 eyes (81%), and 20/25 or better in 54 eyes (49%). RESULTS: At one year, follow up was available on 57 eyes. The average residual refractive error was -0.22 +/- 0.87 D (range -3.00 to +2.00 D). Correction within 1 D was achieved in 47 eyes (82%). Visual acuity was 20/40 or better uncorrected in 50 eyes (88%), and 20/25 or better in 35 eyes (61%). One patient lost three lines of best corrected visual acuity and 4 patients lost 2 lines of best corrected visual acuity from corneal haze or irregular astigmatism, while all other patients returned to best corrected visual acuity within one line of their preoperative best corrected visual acuity. CONCLUSION: Photorefractive keratectomy with the 193-nm excimer laser appears to be a useful treatment modality for the reduction of low to moderate myopia. PMID- 7844939 TI - Manual ECCE, the present state of the art. AB - BACKGROUND: Manual ECCE has proved to be safe surgery compatible with small incision, no stitches, possible topical anesthesia, very cost effective and quick rehabilitation. The technique has a learning curve and needs experience. "Mini nuc" stands for mini nucleus. This surgery can be achieved only if performed under positive intraocular pressure (IOP). METHODS: A BSS bottle is connected to the eye by an anterior chamber maintainer (ACM). The height of the BSS bottle controls the IOP during the surgery. Controlled IOP is a principle suggested for all kinds of cataract surgery. It creates continuous flow which washes out of the eye cortex debris, blood, pigment, etc. The BSS contains antibiotics and adrenalin, it creates low turbulence due to the small amount of BSS used per case, 30-50 cc. A round capsulorhexis is essential. A special way of hydrodissection creates a very small hard core nucleus delivered to the anterior chamber and is extracted out through a sclero-corneal tunnel using a glide introduced under the nucleus to guide the nucleus out. RESULTS: Positive IOP during all stages of surgery creates the best operative conditions for controlled surgery throughout all manipulations. This technique is a very cost effective system and at the same time provides a high quality procedure. PMID- 7844940 TI - The Australian Corneal Graft Registry (ACGR). AB - The value of a register of corneal grafts is that it can provide new data about the long-term outcome of corneal transplantation and may allow a more reasoned distribution of scarce donor corneas. The large numbers of cases and events can accommodate wide variations in practice patterns without losing statistical power. The Australian Corneal Graft Register follows over 6000 cases; univariate and multivariate analyses are performed every two years. Amongst the interesting recent findings of the analyses are that a past history of elevated intraocular pressure and early graft suture removal are associated with graft failure, as are the more well-established factors of inflammation, neovascularization, formation of synechiae and recurrence of herpetic eye disease. Donor corneas harvested from relatively elderly donors, however, do not appear to be associated with graft failure. Best-corrected visual acuity achieved post-operatively is very variable, but depends to some extent on the original indication for graft. PMID- 7844941 TI - [Pseudoexfoliation syndrome--a risk factor in modern cataract surgery?]. AB - BACKGROUND: The pseudoexfoliation (PEX) syndrome has been described in the ophthalmic literature as a major risk factor of cataract surgery. Most of the authors have reported extracapsular cataract extraction (ECCE) complication rates of more than 10% for zonular dialysis, capsular rupture, and vitreous loss. However, Osher et al. (1993) found that these complications from in situ phacoemulsification (PE) cataract surgery were less than 1%. We compared ECCE with PE by using the same surgeons for both procedures and evaluated retrospectively the complications for each in our patients. PATIENTS AND METHODS: Of 10,450 patients who underwent cataract surgery from 1986 to 1993, 102 PEX cases (0.98%) occurred. ECCE was performed on 34 of these patients, PE on 68 of the 102 patients. The average age of the PEX patients was 78 years. Miosis of 4 mm or less occurred in 19 eyes. To dilate the pupils, sphincterectomies were performed and iris retraction hooks were applied to the iris in the last two years. Eight surgeons (four with long-term experience and the remainder in training) performed the operations. RESULTS: The complication rates were 16.6% altogether for zonular dialysis, capsular rupture and vitreous loss, 26.47% for ECCE, and 11.76% for PE (p = 0.0664), in contrast to 1.3% for uncomplicated age related cataract operations. However, these complications occurred in 14.28% of the ECCE patients and 9.09% of the PE patients with more or less normal dilation of the pupil. Still PE with miosis had fewer complications (23.07%) and was, thus, significantly safer (p = 0.0022) than ECCE (83.33%). Slight phakodonesis, observed during capsulorhexis, and an additional diagnosis of chronic open-angle glaucoma did not provide significant differences between the two surgical methods resulting in PEX. CONCLUSION: Miosis is beside phacodonesis the primary risk factor of PEX associated with cataract surgery. Compared with ECCE, PE had significantly fewer complications from PEX with miosis, not from PEX with phacodonesis. Applying the small iris retraction hooks appeared to decrease the complication risks stemming from miosis. PMID- 7844942 TI - Large corneal transplants in corneal destructive disease. AB - PATIENTS AND METHODS: Forty nine keratoplasties were performed in 18 eyes of 17 patients with severe corneal destructive disease. RESULTS: One eye became phthisical and 5 others lost useful visual acuity but retained a satisfactory cosmetic result. No eyes were enucleated. Recurrence of the host disease in the graft was the largest cause of visual failure. Primary allograft rejection was rare in spite of the large size of the grafts and their proximity to the limbus and new vessels. CONCLUSION: For these grafts to succeed it is essential to bring the underlying systemic disease under control by intensive systemic immunosuppressive therapy before, during and for many months after surgery. It was found that those with Mooren's ulcer had the worst prognosis for the retention of vision. PMID- 7844943 TI - [Regulating intraoperative pressure in filtering glaucoma operations with a sterilizable tonometer]. AB - BACKGROUND: Hypotony with shallow or flat chamber and hypertony without filtration are important short-term complications of filtering procedures in glaucoma. Both reflect the difficulty to adjust the tension of the scleral flap in a way that the artificial valve opens at pressures within the therapeutic range. Our aim was to avoid these complications by improving the filling test. PATIENTS AND METHOD: 22 eyes of 21 patients with chronic glaucoma of different etiology underwent a trabeculectomy. After preliminarily fixing the sutures, the anterior chamber was filled until fluid appeared at the rim of the scleral flap. Then, the pressure was measured using a newly developed, sterilizable applanation tonometer. By tightening or loosening the sutures the opening pressure was adjusted to values between 5 and 20 mm Hg. RESULTS: The IOP at the first postoperative day correlated well with the intraoperative flap opening pressure (correlation coefficient 0.771), but was 20% lower at the average. All cases had a sufficient filtering zone and IOP below 20 mm Hg. At the first day, all chambers were deep. After 2 to 9 days, 4 eyes developed temporarily a shallow chamber (minimum depth: 1 1/2 times corneal thickness). This complication occurred only in eyes with intraoperative pressures of 5 to 10 mm Hg. CONCLUSION: Intraoperative pressure control during trabeculectomy allows a fairly good determination of the postoperative IOP. Choosing a suitable pressure level (15 to 20 mm Hg), hypotony and shallow chambers should be avoided. Hypertony can be hindered, as well. PMID- 7844944 TI - [Theoretical and clinical image properties of refractive 3-zone multifocal lenses with different distribution of far and near focus]. AB - BACKGROUND: The optic of common multifocal IOLs (MIOLs) is effecting an even light distribution to far and near focus. New MIOL designs were developed by Jacobi to improve distance or near contrast, by favouring the far or near focus with 60-70% of the light energy. For binocular implantation, an "asymmetrical" MIOL-combination is possible with accentuation of distance focus in one eye and near focus in the other eye. METHODS: By means of an optical system described by Jacobi and Reiner "artificial eyes" with the new MIOLs were implanted in 7 young healthy subjects and contrast sensitivity was measured for distance and near. Clinical implantation was performed in 46 patients and visual acuity, contrast sensitivity, depth of focus and binocular functions were determined after 6 months. RESULTS: MIOL designs with accentuation of distance vision did not show a significant reduction of distance contrast compared with a monofocal IOL. Asymmetrical binocular implantation of the new lenses resulted in a better distance and near contrast sensitivity than implantation of MIOLs with an even light distribution. Binocular functions were not impaired. CONCLUSION: Asymmetrical implantation of the new MIOLs with uneven light distribution to far and near focus enables distance vision comparable to monofocal IOLs, but with the advantage of an increased depth of focus. PMID- 7844945 TI - [Pathogenesis of secondary glaucoma after intraocular silicone oil administration]. AB - BACKGROUND: There are various causes of increasing ocular tension after vitrectomy and intraocular silicone oil filling; it is reported on a new type of postoperative secondary glaucoma. MATERIALS AND METHODS: A 56-year-old man with flat anterior chamber and secondary glaucoma after vitrectomy and intraocular silicone oil filling was examined; only the transpupillary inspection of the posterior surface of the iris with the three mirror contact glass yielded the decisive reference to the pathogenesis of the glaucoma. RESULTS: The secondary glaucoma was caused by small perfluoroctane bubbles blocking up Ando's peripheral iris coloboma. CONCLUSIONS: In case of an unclear pathogenesis of secondary glaucoma after vitrectomy and fluid/perfluoroctane/silicone oil exchange among others a blockade of Ando's peripheral coloboma by small perfluoroctane bubbles should be considered as a cause of increased intraocular tension. PMID- 7844946 TI - Green cataract. AB - BACKGROUND: The term "green cataract" appears in the literature of the 16th century and at the same time it was mentioned that couching a green cataract would not restore the vision. PATIENTS: The cases of a 54-year-old women and a 74 year-old man with green cataract and the diagnosis of vitreous hemorrhage and end stage rubeosis iridis with absolute glaucoma and no light perception is recorded. In the second case an enucleation was performed. An iron stain of the lens revealed heavy accumulation of iron in the lens epithelium. CONCLUSION: Green cataract is a distinct entity. It is due to the presence of blood pigments from the breakdown of intraocular hemorrhage. It is usually accompanied by rubeosis irides and an absolute glaucoma. The observation, that surgery of these cataracts will not restore light, is also correct. PMID- 7844947 TI - [Lamellar horseshoe sclerokeratoplasty and thermoplasty in keratoconus with peripheral ectasia of the cornea]. AB - PURPOSE: Peripheral ectasia of the cornea is a rare, but rather complicated form of keratoconus, which in its severest form cannot be corrected by glasses or contact lenses. Penetrating corneal grafts must be positioned directly at the limbus. Such transplants mostly fail because of a high risk of immune reactions which can only be circumvented by systemic Ciclosporin A. To avoid the potential risks of such a systemic immunomodulation we performed instead of a penetrating keratoplasty a special lamellar procedure which restored the normal configuration of the cornea. PATIENT: The 35-year-old man presented with best corrected visual acuity of 0.1 in both eyes. Contact lenses were not tolerated any longer. RESULT: After lamellar dissection, thermoplasty and lamellar horse-shoe sclerokeratoplasty the patient now wears well-fitting contact lenses and has a visual acuity of 0.8 with his right and 0.5 with his left eye after a follow-up period of 25 and 14 months respectively. There were no postoperative complications. CONCLUSION: Lamellar horse-shoe sclerokeratoplasty preceded by lamellar corneal dissection and thermoplasty is a technically difficult, but efficient surgical measure to restore the normal corneal curvature in patients with advanced peripheral ectasia of the cornea. PMID- 7844948 TI - [Metastasis of differentiated follicular thyroid carcinoma to the ciliary body]. AB - A girl aged 20 years was suffering from a slowly growing tumor of the ciliary body of her left eye. The tumor was excised with iridocyclectomy supposed to be a melanoma. The histologic examination showed a well-differentiated follicular carcinoma of the thyroid gland. The primary tumor had been excised 16 years before, the diagnosis at that time was benign thyroid adenoma. After the successful removal of the ciliary body a follicular carcinoma of the thyroid gland was finally diagnosed and treated by total thyroidectomy and systemic 131I therapy. PMID- 7844949 TI - [Prenatal eyelid development in the hl-mouse--a hairless mutant of the colored wild mouse]. AB - BACKGROUND: A decisive condition for the clarification of malformations and degenerations is knowledge of the pre- and postnatal development. Therefore investigations were undertaken to determine the plan and lay-out of the eye-lids in an hairloss mutant of mouse. MATERIALS AND METHODS: Biomicroscopical and histological investigations were carried out in 51 hl-mice from the 10th day of gestation unto the birth. This particular mouse is a spontaneous hairloss mutant, in which corneal degenerations also occur. RESULTS: On the 11th day of gestation the ectodermal dips may be distinguished, as well as the shoe-lace-like furrows around the eye-ball, which indicate the development of the eyelids. The upper and lower lid are formed by proliferation. The fusion of the eyelids is completed around the 16th day of gestation. DISCUSSION: The eyelid development starts in mice between the 11th and 14th day of gestation. The fusion is completed on day 15-17. The morphogenesis of the eyelid development will be discussed. PMID- 7844950 TI - Techniques of experimental animal radiotherapy. AB - Animal research is a crucial component of the generation of new knowledge in human and veterinary medicine. Total body irradiation, whole brain irradiation, total lymphoid irradiation, and local field irradiation of experimental animals are powerful tools for immunology, oncology, studies of normal tissue radiation tolerance, and medical physics. Animal radiotherapy requires specialized techniques. Because of necessarily smaller field sizes, beam localization must be particularly precise. Care must be taken to obtain optimum and accurate dose distribution. This requires consultation with a medical physicist. Optimum dose distribution may be obtained, depending upon the circumstance, by use of either a single beam or two parallel opposed beams with or without bolus. To ensure a proper dose to the animal target volume, care must be paid to the selection of beam energy and the use of radiation attenuators. Beams may be shaped by custom made lead alloy blocks. Radiation dose rate may be modified by changing the linear accelerator output or the distance from the beam source to the animal, or by attenuating the beam. Reliable targeting of animals requires, for fields other than total body irradiation, anesthesia-utilizing agents such as ether, ketamine, and pentobarbital. The objective of this report is to review the techniques of experimental animal radiotherapy. PMID- 7844952 TI - Hemodynamic, renal, and hormonal effects of rapid ventricular pacing in conscious dogs. AB - The interactions of the systemic adaptations during and after rapid ventricular pacing, a model of heart failure, were assessed in conscious, unstressed dogs. One week of ventricular tachycardia (260 beats/min) significantly reduced mean +/ SEM cardiac output (2.3 +/- 0.1 to 1.2 +/- 0.1 liter/min), mean arterial pressure (119 +/- 3 to 93 +/- 3 mm Hg), renal blood flow (168 +/- 19 to 96 +/- 9 ml/min), sodium excretion (36 +/- 5 to 10 +/- 4 mEq/d), increased left and right atrial pressures (8 +/- 1 to 21 +/- 1 and 4 +/- 0 to 11 +/- 1 mm Hg, respectively), plasma atrial natriuretic peptide concentration (24 +/- 4 to 141 +/- 38 fmol/ml), plasma cyclic GMP concentration (9 +/- 1 to 16 +/- 4 pmol/ml), and urinary cyclic GMP excretion (0.77 +/- 0.05 to 2.18 +/- 0.34 nmol/min). These changes persisted throughout 3 weeks of pacing. Gradual increases in systemic and renal vascular resistances (to 122 +/- 17 and 1.30 +/- 0.22 mm Hg/liter/min, respectively) and reductions in glomerular filtration rate (65 +/- 6 to 44 +/- 4 ml/min) reached significance during the third week. Resumption of sinus rhythm stimulated a brisk natriuresis and a return of cardiac output, systemic vascular resistance, and hormone concentrations to control values within 7 days. However, increases of left and right atrial pressures (14 +/- 2 and 8 +/- 1 mm Hg, respectively) were still present after 2 months of recovery. In conclusion, persistent increases in cardiac filling pressures were induced by rapid ventricular pacing in conscious, unstressed dogs, whereas the systemic hemodynamic, renal, and hormonal responses were largely reversible during recovery.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7844951 TI - Experimentally induced intravaginal Tritrichomonas foetus infection in the estrogenized mouse. AB - Studies were initiated to establish and maintain intravaginal Tritrichomonas foetus infections in female BALB/c mice as a model for elucidation of parasite and host factors that affect the course of vaginal protozoan infections. Results of these studies indicated that T. foetus infections could only be established in mice in which estrus was induced and maintained. Over a period of several weeks, mice induced to estrus by weekly administration of estradiol cypionate exhibited purulent vaginal discharge and perivulvar abscesses. Implantation of silastic tubing containing 15 micrograms of estradiol-17 beta proved effective in induction and maintenance of estrus and avoided the animal health problems associated with estradiol cypionate treatment. Results of quantitative experiments indicated that the duration of trichomonad infection was influenced by initial colonization of the vagina, i.e., mice with high numbers of vaginal trichomonads at 7 days after infection maintained infections longer than did mice with lower numbers of vaginal parasites. Weekly administration of either 2 or 4 mg of methylprednisolone acetate to estrogenized mice did not extend the duration of T. foetus infections, thereby suggesting that the immune response did not limit the establishment and maintenance of primary vaginal trichomonad infections. Study of estrogenized BALB/c nu/nu mice supported these observations in that establishment of T. foetus infections was difficult in nu/nu mice and that, in most nu/nu mice (76%), the course of infection was not lengthened (mean, 1.9 weeks). When examined by electron microscopy, the earliest lesions were characterized by degeneration and necrosis of chondrocytes, along with degradation of cartilage matrix. These findings confirm that quinolone arthropathy develops in juvenile rabbits and is similar to quinolone arthropathy in other laboratory animals.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7844953 TI - Myocardial effects of repetitive episodes of rapid ventricular pacing in conscious dogs: surgical creation, echocardiographic evaluation, and morphometric analysis. AB - The interactions of the systemic and myocardial adaptations during and after rapid ventricular pacing, a model of heart failure, were assessed in conscious, unstressed dogs. Ultrasonic probes and vascular catheters were surgically implanted into dogs for measurements of blood flows and pressures during 3 weeks of pacing and after 2 months of recovery. Three weeks of tachycardia (260 beats/min) resulted in a marked reduction in hemodynamic parameters and left ventricular dilatation, with caudal wall thinning throughout the pacing period and 1 week of recovery. Sinus rhythm resumed after the pacer was turned off, with return toward normal in hemodynamic parameters; however, left ventricular dilatation and ventricular remodeling, with significant fibrosis, loss of myocytes, and hypertrophy of the surviving cells were still present after 2 months of recovery. In conclusion, even though hemodynamic parameters normalized during recovery, adaptive myocardial remodeling caused permanent ventricular fibrosis, hypertrophy, and increased cardiac filling pressures. PMID- 7844954 TI - Characterization of new inbred strains of Dahl-Iwai salt-sensitive and salt resistant rats. AB - Dahl-Iwai salt-sensitive (S) and salt-resistant (R) rat strains were newly established as inbred strains. To characterize the strains, the Dahl-Iwai S and R rats were fed low-salt (0.3% NaCl) and high-salt (8.0% NaCl) diets from 5 weeks after birth, and systolic blood pressure and pathologic findings were examined at intervals. The distributions of alleles at 19 biochemical and immunologic loci also were examined in the aforementioned strains, together with those for the inbred SS/Sea and SR/Sea strains, which were derived from inbred SS/Jr and SR/Jr strains, respectively. The Dahl-Iwai S rats were hypertensive after 3 weeks of consuming the 8.0% NaCl diet and died from 6 to 10 weeks after the diet was initiated. Renal lesions developed after 4 weeks' consumption of the high-salt diet. The Dahl-Iwai S rats were not hypertensive until at least the age of 21 weeks while they consumed the 0.3% NaCl diet, whereas it was reported that the SS/Jr rats became hypertensive at about 20 weeks of age when they consumed the low-salt diet. The Dahl-Iwai R rats were normotensive whether fed the 0.3 or 8.0% NaCl diet. Hydronephrosis was not observed in the Dahl-Iwai R rats, though it develops in SR/Jr rats with high frequency. Different distributions were detected for kidney alkaline phosphatase-1 (Akp-1) and amylase-1 (Amy-1) alleles between the Dahl-Iwai S and SS/Sea strains, and for esterase-14 (Es-14) and seminal vesicle protein-1 (Svp-1) alleles between the Dahl-Iwai R and SR/Sea strains. The phenotypic differences between the substrains of inbred Dahl rats could be ascribed to different genetic backgrounds. PMID- 7844955 TI - Gastric acid secretion in the cynomolgus monkey. AB - Gastric acid secretion was measured in male and female cynomolgus monkeys under basal conditions and in response to intravenous administration of pentagastrin (PG). There were no statistically significant differences between males and females in either basal or PG-stimulated gastric acid output. Neither were differences between males and females statistically significant when adjusted according to body weight. For both sexes combined, basal acid output was 17 +/- 20 muEq/h. Intravenous infusion of PG stimulated gastric acid secretion at dose rates of 1 micrograms/kg/h and greater. Maximal stimulation occurred at dose rates of 10 and 100 micrograms/kg/h, indicating gastric acid secretion plateaus above PG doses of 10 micrograms/kg. Acid secretion values in response to 100 micrograms of PG/kg/h for both sexes combined were 571 +/- 132 and 400 +/- 135 muEq/kg/h for peak acid output and maximum acid output, respectively. These data suggest that the cynomolgus monkey may be a useful model for gastric physiology studies of relevance to human beings. PMID- 7844956 TI - Evaluation of detomidine anesthetic combinations in the rabbit. AB - Detomidine, a potent alpha 2-adrenergic receptor agonist, was chosen for study alone and in combination with ketamine with or without diazepam. Four regimens were evaluated: detomidine (150 micrograms/kg of body weight) alone (D); ketamine (35 mg/kg) and detomidine (150 micrograms/kg) (KD); ketamine (35 mg/kg) and high dose detomidine (300 micrograms/kg) (KDh); and ketamine (35 mg/kg), diazepam (1 mg/kg), and detomidine (150 micrograms/kg) (KDD). The same six rabbits were anesthetized with each combination at weekly intervals. Atropine (0.04 mg/kg) was administered as a preanesthetic 5 min prior to test substance administration. All agents were administered IM, except for diazepam, which was administered IV. Heart and respiratory rates, mean arterial blood pressure, and arterial blood gas tensions were measured. Pedal, palpebral, and righting reflexes also were evaluated. Cardiopulmonary depression, as indicated by decrease in heart and respiratory rates, blood pH, PO2, and increase in PCO2, was observed in all groups. With the exception of heart rate, detomidine used alone caused the least depression of these parameters. Reflexes were consistently lost only after KDh and KDD administrations. The pedal reflex, used as an index of anesthetic depth, was lost in response to KDh and KDD for 56.7 +/- 11.6 and 43.8 +/- 7.4 min, respectively (mean +/- SEM). Three of the six rabbits were anorectic after KDh administration. Necropsy and histologic evaluation revealed myocardial necrosis and fibrosis in five animals. Due to the inconsistent reflex loss in response to KD and D and inappetance associated with KDh, these combinations were not considered safe or reliable.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7844957 TI - A comparison of two surgical techniques for preparation of rats with chronic bile duct cannulae for the investigation of enterohepatic circulation. AB - Two surgical biliary cannulation procedures for study of enterohepatic circulation in chronically cannulated rats were compared in a randomized study. Control rats (group A) had only a jugular vein cannula and no laparotomy, whereas experimental group-B rats additionally had the bile duct cannulated at two locations, one for collecting bile from the liver and the other for returning bile into the duodenum. Experimental group-C rats had the jugular vein cannula as well as the bile duct cannula for collecting bile, but the duodenal wall was cannulated for returning bile to the intestine. Several physiologic and biochemical indicators were monitored daily after surgery, including body weight, bile flow rate, and plasma concentrations of bilirubin and creatinine, and activities of glutamate-pyruvate transaminase (GPT) and lipase. Overall duration of survival of group-B rats was shorter than that of group-A rats (P < 0.05), whereas no difference was found between groups A and C. Group-B rats had higher bilirubin concentration than did controls (P < 0.05), whereas group-C rats did not. Group-B rats had higher plasma lipase activity than did rats of the other two groups, and this analyte was more variable in group-B rats. Rats of groups B and C had high GPT activity after surgery (P < 0.05). A statistically significant loss of body weight was associated with group-B rats over 8 days after surgery and for group-C rats over 2 days after surgery, after which body weight stabilized in group-C rats.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7844958 TI - Epidural catheter placement for testing of obstetrical analgesics in female guinea pigs. AB - The pregnant guinea pig may be a useful model for the study of drug effects in the newborn. A reliable technique for epidural catheterization in the guinea pig was developed to allow use of this model to evaluate the effects of epidural labor analgesics on neonates. Catheters were implanted in two open pilot animals and 19 time-dated pregnant animals on days 59 to 62 of gestation. After establishing a surgical plane of isoflurane-induced anesthesia, an incision was made over the dorsal lumbar part of the spine. The L3-4 intervertebral space was exposed to allow introduction of a caudally directed 27-gauge catheter into the epidural space. The catheter was capped and implanted subcutaneously, then the animal was allowed to recover from anesthesia. Catheter placement was evaluated, using a bupivacaine test dose in 17 animals and postmortem histologic examination in 20 animals. One animal died immediately after surgery. Epidural placement was confirmed histologically in 15 of 20 animals. Failed catheters were either subdural, with one catheter found to be penetrating the spinal cord (intraspinal), or intramuscular. Response to epidurally administered bupivacaine was variable but was typically characterized by normal alertness and ability to use the forelimbs; depression of the panniculus reflex in the dorsal lumbar region; and hind limb motor impairment, with ataxia, loss of the placing reflex, and a tendency to drag the hind limbs. Subdural placement was associated with CNS depression, recumbency, shallow breathing, and sensory block ascending to the level of the ears.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7844959 TI - Use of subcutaneous vascular access ports in rhesus monkeys. AB - To investigate new approaches for treatment of drug abuse, subcutaneous vascular ports were implanted in rhesus monkeys (Macaca mulatta) for use in drug self administration studies. Internal or external jugular veins were cannulated, and the catheter was attached to a subcutaneous port that was positioned on the back between the shoulder blades. This port/catheter system allowed easy serial blood sampling and intravenous drug administration. Daily use of the ports in awake monkeys was simple, effective, and caused no apparent stress over a 2-h experimental session. At the time of submission, the mean functional lifetime of the port/catheter system in 20 monkeys implanted longer than 6 months was 243.61 days, with the upper range being 540 days. Several complications developed with this system, and solutions to these problems are described. With proper aseptic use, the subcutaneous vascular port system provided a safe and enduring method for daily access for intravenous sampling and/or drug delivery. The duration of the preparation is a considerable improvement compared with exteriorized catheterization. PMID- 7844961 TI - Pharmacokinetic properties of methadone hydrochloride after single intramuscular administration in adult dairy goats. AB - Pharmacokinetic parameters of methadone were studied in adult dairy goats. Five goats were each given methadone hydrochloride as a single 0.2 mg/kg of body weight dosage by intramuscular (IM) administration. Plasma methadone concentrations were determined for 96 h after dosing. Plasma methadone concentrations after IM administration were best described by an open one compartment model. Overall elimination half-life (t1/2) was 1.38 h. Peak plasma concentrations were reached 0.25 h after dosing, and the actual plasma concentration averaged 37.8 ng/ml (SD = 12.76) at that time. The data obtained from this study suggest that plasma concentrations, similar to those that are analgesic in humans, can be achieved after IM administration of methadone at a dose rate of 0.2 mg/kg of body weight. In addition, these plasma concentrations can be maintained for up to 3 h after a single injection and, therefore, may provide satisfactory analgesia for such period. PMID- 7844960 TI - Premortem biodistribution of radioactivity in the rat: measurement of blood and tissue activity of tracers used in clinical imaging studies. AB - Radioactive tracers are used in nuclear medicine imaging studies to detect sites of human disease. Use of animal models helps to establish tracer biodistribution kinetics and, thus, is critical to the early testing of radiopharmaceuticals. We developed a method to characterize the premortem temporal, spatial, and compartmental biodistribution of tracer molecules in the rat and used this method to study three tracers of potential value in detecting thromboembolic disease. Dynamic gamma scintigraphy was used to determine the spatial and temporal distribution of 99mTc-labeled IgG antifibrin antibody, Fab' fragment of antifibrin, and oxidized human serum albumin (OHSA). The blood pool compartment within each tissue was determined from the biodistribution of 131I-labeled bovine serum albumin injected prior to termination. The biodistribution of the blood compartment was maintained by immediately freezing the rat carcass in isotonic saline. Three-dimensional maps of tracer distribution in the tissue and blood compartments were then constructed from cross sections of the frozen tissue. These maps were used to relate necropsy tissue counts to premortem scintigraphic images. Over a 60-min interval after administration of tracer via a tail vein, significant differences in biodistribution were evident. The IgG remained within the blood pool, but there was rapid blood clearance of the OHSA molecules by the kidney and liver. The Fab' molecules were cleared more slowly by the kidney; Fab' molecules were found in the extravascular spaces, whereas IgG and OHSA were not found. The kinetics of OHSA and Fab' in organ regions paralleled changes in the blood compartment.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7844962 TI - Experimental allergic encephalomyelitis (EAE) in nonhuman primates: a model of multiple sclerosis. PMID- 7844963 TI - Diagnostic exercise: hemolytic anemia in several sheep. PMID- 7844964 TI - Eradication of pinworms (Syphacia obvelata) from a large mouse breeding colony by combination oral anthelmintic therapy. PMID- 7844966 TI - Primary Herpesvirus simiae (B-virus) infection in infant macaques. PMID- 7844965 TI - Respiratory disease in a rat colony: identification of CAR bacillus without other respiratory pathogens by standard diagnostic screening methods. PMID- 7844967 TI - Spontaneous osteosarcoma in a C57BL/6J mouse. PMID- 7844968 TI - Calcium carbonate urolithiasis in a rabbit. PMID- 7844969 TI - Glass wool column filtration: effects on motility, viability, and fertilizing ability of epididymal spermatozoa from mice. PMID- 7844970 TI - Modification of the cannulation for the dorsal aorta of Atlantic salmon (Salmo salar). PMID- 7844971 TI - A primer on school violence prevention. AB - Violence has reached epidemic proportions in the United States with particularly serious health implications for school-age children and adolescents. Schools that experience the daily threat of potential student violence have their primary mission of education eroded at great cost to students. This article reviews the problem of violence in public schools and summarizes existing knowledge on school violence prevention. Violence prevention programs that use educational, regulatory, technological, or combined approaches are reviewed. Recommendations are presented addressing both policy and program needs related to control of violence in public schools. School health professionals should be active participants in violence prevention efforts. A critical need exists to carefully evaluate any planned prevention program so future efforts can be built on methods proven successful. PMID- 7844972 TI - A national survey of public support for restrictions on youth access to tobacco. AB - A national telephone survey was conducted to measure public support for seven proposals to restrict youth access to tobacco products, including increases in the cigarette excise tax. A random digit dialing survey, using computer-assisted telephone interviews and a two-stage Mitofsky-Waksberg design, was used to generate and replace telephone numbers and to select individuals from within households. More than 94% of respondents believed cigarette smoking by children and adolescents to be a "very serious" or "somewhat serious" problem. Most respondents expressed support for all the proposed measures to restrict youth access to tobacco products (fines for sellers, fines for youthful violators, licensing of all tobacco vendors, restrictions on cigarette vending machines, ban on sponsorship of youth-oriented events, and ban on all tobacco advertising), and for increases in the cigarette excise tax. PMID- 7844974 TI - Understanding ethnicity, identity formation, and risk behavior among adolescents of Mexican descent. AB - The population of adolescents of Mexican descent is growing rapidly in the United States. However, the health needs of this group are not being adequately addressed by the health care system. Understanding the factors contributing to risk behavior in adolescents of Mexican descent may help improve service delivery and use. This article presents a sociodemographic profile of this group as well as a description of how one's degree of ethnic identification, acculturation, and other risk factors may contribute to problem behavior. Recommendations are provided to increase culturally appropriate prevention programs for youth of Mexican descent. PMID- 7844973 TI - Peer participation in Project Northland: a community-wide alcohol use prevention project. AB - This paper describes the rationale, conceptual framework, and program components of a peer participation program for prevention of alcohol use among young adolescents. The peer participation program was one component of Project Northland, a community-wide program that seeks to prevent or delay onset of alcohol use among a cohort of young adolescents. The peer participation program, implemented in 20 northeastern Minnesota schools when students were in seventh grade, consisted of student groups who planned supervised, alcohol-free activities for themselves and their classmates. Program goals included 1) providing peer leadership and social support for non-use of alcohol, 2) creating opportunities for alternative behaviors to alcohol use, thereby 3) creating a norm of non-use among young adolescents. PMID- 7844975 TI - Evaluation of sex education curricula: measuring up to the SIECUS guidelines. Sex Information and Education Council of the U.S. AB - Most sexuality education curricula developed the past 20 years were not thoroughly evaluated. This study provides results from a content analysis of 10 sexuality education curricula for junior and senior high school students. Nine nationally available sexuality education curricula and one curriculum guide comprised the sample. The basis for analysis was the Guidelines for Comprehensive Sexuality Education, developed by the Sex Information and Education Council of the U.S. (SIECUS) and an instrument developed to measure bias in the curricula. Trained coders found that Sex Respect and Teen Aid addressed less than half the topics suggested by the SIECUS guidelines. Several of the curricula contained gender and sexual orientation bias. Certain key concepts such as "Sexual Behavior" and "Society and Culture" were not adequately addressed by most of the curricula. Findings indicate that of 10 curricula, only six are considered acceptable for educating junior and senior high school students. PMID- 7844977 TI - Emergency care training for school nurses in Fairbanks, Alaska. PMID- 7844976 TI - The effect of two types of teacher training on implementation of Smart Choices: a tobacco prevention curriculum. AB - This study examined the implementation phase of a four-year research project to test the effectiveness of strategies to increase diffusion of Smart Choices, a school-based tobacco prevention program. The impact on curriculum implementation of two approaches to teacher training are compared. School districts were randomly assigned to a live workshop training or video training condition. The outcome of the evaluation was teachers' implementation of Smart Choices. Results show a lower proportion of video-trained teachers implemented the curriculum, but overall completeness and fidelity of implementation for those teachers who did teach the curriculum were comparable for the two groups. Video-trained teachers, however, were less likely to use brainstorming and student presentations/role plays, two of the methods prescribed by the curriculum. Implications of the results for teacher training are discussed. PMID- 7844978 TI - Effects of doxorubicin on cancer cells after two-thirds hepatectomy in rats. AB - A rat model of liver metastases generated by intraportal injection of syngeneic tumor cells after two-thirds hepatectomy was used to determine the optimal regional chemotherapeutic modality for early hepatic metastases. WKA rats had viable tumor cells injected directly into the portal vein after two-thirds hepatectomy. Ten rats were used as a control; the remaining groups were given doxorubicin (4/3 mg/kg) injected directly into the hepatic artery at 24 hr, 72 hr, and 7 days (after liver regeneration) postoperatively. The mean survival period in each group was 21.0, 20.0, 20.5, and 20.7 days, respectively, compared with those treated with doxorubicin (4 mg/kg) injection at 24 hr, 72 hr, and 7 days postoperatively, with a mean survival period in each group of 20.0, 21.6, and 25.6 days, respectively. When a comparison was made with regard to the doses of doxorubicin administered, statistically significant differences in survival rates were recognized between the rats that had doxorubicin (4 mg/kg) injection 7 days postoperatively and the others (P < 0.01). Based on these findings, we believe that appropriate adjuvant chemotherapy should be given after the liver regeneration phase. PMID- 7844979 TI - Pancreatic cancer treatment in the U.S. veteran from 1987 to 1991: effect of tumor stage on survival. AB - To assess the outcomes after pancreatic cancer treatment in a nationwide hospital system, patients treated in Department of Veterans Affairs (DVA) hospitals from 1987 to 1991 were studied by tumor stage, the most significant reported influence on survival. Tumor registrars from DVA hospitals provided information that allowed TNM staging in 598 patients, and duration of survival from treatment to death was known in 96+% of cases. Survival was 9 months longer after 64 resections for stage I-II (localized) pancreatic cancer than after 149 other treatments (P < 0.05, ANOVA), but resection did not increase mean survival in 49 patients with stage III (lymph node metastases) disease. Twenty-one patients with ampullary, duodenal, bile duct, or cystic cancers had a significantly increased survival at any stage, but this may be due to the selection of sicker patients for nonoperative therapies. PMID- 7844980 TI - Clinicopathologic study of patients with Borrmann type IV gastric carcinoma. AB - Between 1979 and 1993, 665 Japanese patients with advanced gastric cancer underwent surgery at our hospital. These patients were divided into two groups, consisting of 102 patients with Borrmann type IV carcinoma, and the remaining 563 patients with all other types of gastric carcinoma, which were then compared clinicopathologically. In the patients with Borrmann type IV carcinoma, 77.4% of the lesions demonstrated poorly differentiated adenocarcinoma, and 99 patients were classified as Stage III or IV. The resection rate was 87.2% (89/102) with only 39 curative operations despite the fact that 70 total gastrectomies were performed. The incidence of peritoneal dissemination (29.4%) and serosal invasion (97.0%) was significantly higher in these patients. Microscopic lymph node metastasis was positive in 86.5%. The 5-year survival rate was 23.4% in the patients with a curative operation and 5.0% in those with a noncurative operation (p < 0.01). Peritoneal dissemination was most frequently noted in the recurrence patterns. We conclude that early detection and a curative operation are both essential to improve the prognosis of patients with Borrmann type IV gastric cancer. The addition of a potent postoperative chemotherapy regimen is also recommended. PMID- 7844981 TI - Malignant melanoma of the anorectal region. AB - The charts of 15 patients with malignant melanoma of the anorectal region treated at Roswell Park Cancer Institute in the period 1975-1991 were reviewed. All the lesions except one developed at the pectinate line, in the area of transitional mucosa. Two of the patients at the time of initial presentation had distant metastases. Of the remaining 13, 8 were treated with abdominoperineal resection (APR) and 5 with local excision (LE). The incidence of local recurrence was 50% in the LE group and 22% in the APR group. Patients treated with APR had a 25%, 5 year survival rate compared with 0% for those treated with LE, although one of the latter group died 55 months following LE due to unrelated causes without recurrence. The median survival of those with LE was 15.7 months and of those with APR 13.7 months. PMID- 7844982 TI - Treatment of pseudomyxoma peritonei in a geriatric patient population. AB - Pseudomyxoma peritonei of appendiceal origin is a disease characterized by the progressive accumulation of mucus ascites within the abdomen and pelvis. Metastatic disease outside the peritoneal cavity is unusual. Gastrointestinal function is lost from external compression of stomach, small bowel, and large bowel. New surgical and regional chemotherapy treatments were used to provide palliation of two patients aged 88 and 85 years. The selection criteria and methodologies for treatment of geriatric patients with pseudomyxoma peritonei are presented. PMID- 7844983 TI - Immunohistochemical analysis of p53 in colorectal cancer regarding clinicopathological correlation and prognostic significance. AB - The overexpression of the tumor suppressor gene p53 was investigated immunohistochemically in 144 cases of primary colorectal cancer and in 8 cases with cancer in the corresponding metastatic lymph nodes. Abnormalities in p53 expression were found in 36 cases (25%) of the 144 primary cancer cases. In addition, p53-positive tumors were found to metastasize frequently to the lymph nodes, as compared to p53-negative tumors (61.1% vs. 41.7%, P = 0.0428). p53 staining was identical in 7 of 8 (87.5%) cases in primary and metastatic lesions. When the DNA content of the tumor was determined by flow cytometry, the DNA index (mean +/- SD) was significantly higher in p53-positive tumors than in p53 negative tumors (1.57 +/- 0.38 vs. 1.39 +/- 0.37, P = 0.012). Therefore, the immunohistochemical data of p53 in colorectal cancer may help in potentially predicting metastatic spread to the lymph nodes. PMID- 7844984 TI - Effect of dibutyryl cyclic AMP on the cell cycle of human pancreatic cancer inoculated in nude mice. AB - The prognosis of pancreatic cancer is very poor because of its high malignant potential. To improve the prognosis of pancreatic cancer, a decrease in the grade of malignancy by dibutyryl cyclic AMP (db-cAMP), a differentiation inducer, was attempted using human pancreatic cancer cell line inoculated to nude mice. In this study, 0.1 or 5.0 mumol/animal/day of db-cAMP was administered for 7 consecutive days in short-term group animals and for 28 consecutive days in long term group animals. Animals in both groups are sacrificed 28 days after first administration of db-cAMP, and tumor size, histology, and cell cycle analysis using flow cytometry (FCM) were studied. Tumor size and histology showed no significant changes by db-cAMP. However, in cell cycle analysis, 5.0 mumol/animal/day of db-cAMP brought significant block of the cell cycle phases between G1 and S in the short-term group and the phase between S and G2/M in the long-term group, indicating a decrease in cell cycle speed and, consequently, a decrease in the proliferation of tumor cell. The results show that db-cAMP may be useful in decreasing the grade of malignancy of pancreatic cancer. PMID- 7844985 TI - Comparison of nephrectomy and/or doxorubicin treatment in rabbit renal VX-2 carcinoma. AB - To compare survival after local intra-arterial and intravenous administration of doxorubicin, VX-2 carcinoma was implanted in one kidney of 48 rabbits. Treatments were given 9-14 days after tumor implantation. Survival after doxorubicin was significantly longer than the controls, whereas no difference was established between intra-arterial or intravenous treatment. Overall only 9 of 32 doxorubicin treated rabbits were cured at autopsy after 18 months. It was assumed that circulating tumor cells from tumor implantation resulted in "primary" lung metastases. To kill circulating tumor cells intravenous doxorubicin was given immediately before implantation in 40 rabbits, followed by combinations of nephrectomy and doxorubicin. Doxorubicin without nephrectomy cured 8 of 16 rabbits, whereas doxorubicin combined with nephrectomy cured 4 of 16. Doxorubicin improved survival in responders, but likelihood of response was limited. Nephrectomy did not improve survival, most likely due to metastatic seeding at implantation. Intravenous doxorubicin immediately before did not prevent metastatic spread in connection with tumor implantation. PMID- 7844986 TI - Bladder resection during radical hysterectomy following pelvic irradiation. PMID- 7844987 TI - Cytokine-mediated alterations in host metabolism prevent nutritional repletion in cachectic cancer patients. AB - The clinical syndrome of cachexia is characterized by anorexia, continued losses of lean body mass, and altered carbohydrate and lipid metabolism. As early as the 1930s, this "chronic wasting" syndrome had been identified as the most frequent immediate cause of death in patients with cancer [Warren: Am J Med Sci 184:610 619, 1932]. At present, controversy remains as to the benefit of supplemental parenteral or enteral feedings in the nutritional repletion of cachectic cancer patients, since only selected patient groups have demonstrated clear benefit from their administration [Copeland et al.: Cancer 43:2108-2116, 1979; Copeland et al.: Cancer Res 37:2451-2456, 1977; Terepka and Waterhouse: Am J Med 20:225-238, 1956]. Despite having these advanced nutritional modalities firmly in our therapeutic armamentarium, the progression of cachexia in the nutritionally depleted cancer patient often continues unabated, and our ability to intervene successfully remains limited. This review proposes that host: tumor interactions lead to a nonspecific inflammatory response mediated in part by the chronic production and release of proinflammatory cytokines, including interleukin-1, tumor necrosis factor alpha, interleukin-6 and interferon-gamma, which antagonize the anabolic signals associated with enteral and parenteral nutrition support. Cytokine-mediated alterations can explain the inability of adequate dietary nitrogen and calories to result in lean tissue repletion. Based on this proposal, interrupting proinflammatory cytokine production or target organ action may be an appropriate therapeutic objective to improve nutrient utilization in patients with tumors. PMID- 7844988 TI - Aneuploidy of tumor cells in cases of gastric cancer with esophageal invasion: another indicator of poor prognosis. AB - The prognosis of patients with gastric cancer with esophageal invasion is extremely poor. To evaluate factors related to this poor prognosis, we analyzed 200 patients with gastric cancer located in the upper third of the stomach. These patients underwent gastrectomy and were divided into two groups in terms of the presence (E[+] group; n = 62) or absence (E[-] group; n = 138) of histological evidence of esophageal invasion. Even when apparently curative surgery was performed, the 5-year survival rate of patients with E[+] gastric cancer (45.8%) was significantly lower than of patients with E[-] gastric cancer (71.6%). In the E[+] group, the 5-year survival rate of patients who had tumors with infiltrative growth and DNA aneuploidy was only 10.0%. These patients had a high frequency of peritoneal metastasis at operation (5/16; 31.3%); even when apparently curative operations were performed, 50% of these patients died from peritoneal metastatic recurrence within 2 years after surgery. Gastric adenocarcinoma with esophageal invasion accompanied by infiltrative growth and DNA aneuploidy had a high potential for peritoneal metastasis. This combination is associated with the most pessimistic prognosis for patients with gastric cancer with esophageal invasion. PMID- 7844989 TI - Incidence and management of major urinary complications after pelvic exenteration for gynecological malignancies. AB - Urinary fistulae and obstruction following pelvic exenteration are frequent and life-threatening complications. They increase the mortality and morbidity rates of large exereses performed during pelvic exenteration for gynecological cancers. From a series of 97 patients who underwent pelvic exenteration for gynecological cancers we report the incidence, risk factors, and management of major urinary complications. Eighty patients had had previous surgery and/or pelvic radiation therapy at the time of pelvic exenteration. A urinary diversion was performed in 63 patients. Major early urinary complications were: urinary fistula in seven patients and ureteral obstruction in four patients (11.3% of the patients). Ten patients had a late urinary complication: stenosis of the cutaneous ureteral meatus (five), stenosis of the ureteroileal anastomosis following ileal loop (two), and urinary fistulae (three). Cancer recurrence was found in 4 of these 10 cases. Major early urinary complications were significantly increased in patients who had received previous pelvic radiation therapy (P < 0.05) and in patients who had had an intestinal conduit for urinary diversion (P < 0.05). Reoperation was done in six of seven cases of early urinary fistula (urinary undiversion four, nephrectomy one, ureteral reimplantation one). Three of four ureteral obstructions were managed with percutaneous nephrostomy and ureteral stent. We recommend the use of nonirradiated bowel segment for urinary diversion as transverse colon or jejunal conduit in patients who have received previous high doses of pelvic radiotherapy. For the management of urinary complications post pelvic exenteration, reoperation is required for most urinary fistula but ureteral obstructions can be managed with percutaneous nephrostomy and ureteral stent. PMID- 7844990 TI - Neural cell adhesion molecule and perineural invasion in gallbladder cancer. AB - To clarify the role of neural cell adhesion molecule (NCAM) in perineural invasion, NCAM expression was studied by immunohistochemical staining in 26 cases with gallbladder cancer. In gallbladder cancer, the incidence of perineural invasion and that of positive NCAM expression was 42% and 31%, respectively, which are less frequent than those of bile duct cancer in our previous report. Perineural invasion was observed in 88% of the patients with positive expression of NCAM and in 22% of those with negative expression. The former is similar to that of bile duct cancer but the latter is significantly lower. Eighty percent of the cancer cells that invaded the perineural space were positive for NCAM, when the primary tumor was positive for NCAM expression. Therefore, in gallbladder cancer, positive cells in NCAM expression likely invade the perineural spaces. However, the perineural invasion of negative cells in NCAM expression is not likely to occur as compared to bile duct cancer. In conclusion, perineural invasion in gallbladder cancer is not as common as in bile duct cancer, but the role of NCAM in perineural invasion is more important in gallbladder cancer than in bile duct cancer. PMID- 7844991 TI - Mind as a force field: comments on a new interactionistic hypothesis. AB - The survival and development of consciousness in biological evolution call for an explanation. An interactionistic mind-brain theory seems to have the greatest explanatory value in this context. An interpretation of an interactionistic hypothesis, recently proposed by Karl Popper, is discussed both theoretically and based on recent experimental data. In the interpretation, the distinction between the conscious mind and the brain is seen as a division into what is subjective and what is objective, and not as an ontological distinction between something immaterial and something material. The interactionistic hypothesis is based on similarities between minds and physical forces. The conscious mind is understood to interact with randomly spontaneous spatio-temporal patterns of action potentials through an electromagnetic field. Consequences and suggestions for future studies are discussed. PMID- 7844992 TI - Neural networks and chaos. PMID- 7844993 TI - Obstacles on the road towards a neuroscientific theory of mind. AB - In the efforts to establish neuroscientific theories of the mind, one should distinguish between conceptual and scientific obstacles. The conceptual obstacles comprise, for example, various dualist-materialist philosophical positions, emergentism, failure to distinguish between models and non-models, lack of ontological commitment, and the constraints of language. The scientific obstacles comprise, for example, the lack of methods to describe the behaviour of neuron networks and their properties, the difficulties of establishing transition rules between micro-networks and macro-networks, the difficulties in working with non Pavlovian paradigms and imposing information processing constraints and informational requirements on brain processes. PMID- 7844994 TI - Will neuroscience explain consciousness? AB - This paper is a defence of a pragmatic version of mind-brain reductionism from a neuroscientist's point of view. It is claimed that there are good reasons to believe that future neuroscience will be able to explain (in a weak and pragmatic sense) the puzzling aspects of mind and consciousness. Opposition to reductionism comes from both philosophical and empirical quarters. It is argued here that philosophical arguments, such as semantic problems with the concept of identity, are unconvincing and should be regarded with the greatest suspicion. The most influential empirical result that has been claimed to constitute a problem for reductionism is the temporal delay and mental antedating of consciousness found by Benjamin Libet. It is argued that these results, far from being a problem for reductionism, constitute evidence for a particular view of the physiological origins of consciousness. Finally, it is argued that many subjective aspects of experience can already be given satisfactory scientific explanations and that scientific progress is likely to rob the mind and subjective experience of their mystery. PMID- 7844995 TI - Computer models of the brain--how far can they take us? AB - The recent developments in computer capacity and algorithms, together with a tremendous growth of data in neuroscience have dramatically improved the possibilities of modeling and simulating certain brain structures and activities with a considerable degree of realism. Although there is still a long way to go, some claim that we will one day be able to create artificial "brains" with similar capacity to the human brain, perhaps even surpassing it. Here we focus on these perspectives, discussing the potentials and limitations of today's computer models, and how far they might be able to take us. PMID- 7844996 TI - The will of the brain: cerebral correlates of willful acts. AB - Current imaging techniques can depict physiological events in the brain which accompany sensory perception and motor activity, as well as cognition and speech. "Pure" mental events unaccompanied by sensory input or motor/behavioral output also induces cerebral functional changes which apparently are related to inner representations of thoughts, ideas, visions, inner speech and so forth. Cerebral events during cognition, mental effort, imagined volitional acts, augment the activity in the prefrontal cortex. An augmentation in the cerebellum is also recorded. It is known that temporally organized (sequential) neuronal activity takes place in these structures. The prefrontal activation accompanying volitional acts most likely corresponds to a willful mobilization of inner representations of future events. These representations serve as action programs for the achievement of the goal. Phylogenetically older parts of the cerebral cortex close to the midline (the cingulate gyrus) participate in willful acts. They are possibly involved in emotional/motivational ("value") aspects of volition. Abnormal volition ("sick will") is encountered in organic dementia, Parkinson's disease, depression, and schizophrenia. Such disorders are characterized by inactivity, lack of ambitions, and a reduced motor and verbal output. Patients in these groups often show a decreased activity in prefrontal regions. Individuals with supraorbital and mesial frontal lesions may develop a so-called psychopathic behavior including abnormalities of volition with lack of impulse control, boredom susceptibility, sensation-seeking behavior, and abnormal risk taking. Knowledge about cerebral events coupled to willful acts may shed some light on the "collective will" expressed by groups of individuals and organizations. PMID- 7844997 TI - Mechanism of control of erythrocyte shape: a possible relationship to band 3. AB - A mechanism of control of erythrocyte shape, differing significantly from those previously proposed, is hypothesized. It was inferred from previous observations on the states of association of Band 3, the anion exchange protein. Its salient points are as follows. (i) The membrane skeleton is a pliable protein meshwork structure used to generate different erythrocyte shapes. (ii) Band 3 is a dodecamer bound by one of its subunits to ankyrin which is itself bound to the mid region of filamentous spectrin. (iii) Spectrin, by virtue of its high flexibility, folds and unfolds and its folding links the two actin protofilaments bound at its ends to Band 3 through the intermediary of Band 4.1 and glycophorin A. (iv) The alternate influx and efflux of anions mediated by Band 3 respectively folds and unfolds spectrin. (v) The ratio of Band 3 molecules with outward-facing conformation to those with inward-facing conformation controls the extents of folding of the skeleton spectrin molecules. This ratio is governed by the Gibbs Donnan equilibrium ratio of anions and protons and by the Band 3 anion affinities and exchange rates. PMID- 7844998 TI - A suggested mechanism for aluminum biotoxicity. AB - Following earlier work on the relevance of silica (SiO2) and fluoride (F) to the biotoxicity of aluminum (Al), it is shown that relatively high risks of a measure of mental impairment are frequently associated with relatively low SiO2 and F in the drinking water available in different parts of Ontario. Also, because of a negative association between SiO2 and F concentrations in the treated water available in different municipalities, a low SiO2 concentration can account for the observed association involving high F concentrations, and low F concentrations can similarly account for associations involving high SiO2 concentrations. In the light of these observations, the biotoxic effects at low Al concentrations can be explained by assuming that interactions occur with membranes. Such interactions may be less likely at higher SiO2 and F concentrations, because at these concentrations, interactions between Al-, SiO2- and F-containing species are more important. Generally, the various associations with a measure of mental impairment can be explained on the assumption that F exerts a protective effect against the biotoxic effects of Al, as does SiO2 under certain conditions, but the effects of SiO2 only become important at higher SiO2 concentrations. The results from this and other studies suggest that the neurotoxic effects of Al depend on other water constituents. The results also indicate that absorption through the lung or skin, rather than through the stomach or the bowel, can better explain the reported associations. PMID- 7844999 TI - Third codon G + C periodicity as a possible signal for an "internal" selective constraint. AB - Quasi-local analysis methods, such as window Fast Fourier Transform and an information theoretical quantity known as mutual information, have allowed us to gain some further insights on the importance and the contextual dependence of a pattern found in DNA sequences showing a periodicity of three with a G or C base in the third position. We have screened for such a periodicity, in terms of the alternative "strong" (S = C or G) versus "weak" (W = A or T) base, a large sample of DNA coding and non-coding sequences from both prokaryotes and eukaryotes, with the aim of testing whether this pattern could be considered as a significant signal for past or present constraints regarding DNA organization and/or function. This periodicity was indeed found in a number of sequences always associated with open reading frames, generally confined in prokaryotes living in extreme environments or in highly conserved eukaryotic genes. Moreover, codon usage was found to be very similar even in genes coding for very different functions. The data are discussed in view of their possible implications for an adaptive value of such a periodicity, in terms of more accurate translation processing and better overall stability. PMID- 7845000 TI - On the interspike intervals calculated from diffusion approximations of Stein's neuronal model with reversal potentials. AB - In this paper we compare a discontinuous model with two diffusion models of a simulated neuron. The mean and coefficient of variation of the interspike intervals were calculated for these three models. The means were found to be shorter for the diffusion approximations than for the discontinuous model for all values of parameters. By increasing the excitation, the difference between firing frequencies generated by the models became smaller. The coefficient of variation (CV) exhibited a relatively close agreement for all three models. The firing patterns for both diffusion models were similar to each other. PMID- 7845001 TI - Specific thrombopoietin cloned and sequenced--with personal retrospect and clinical prospects. AB - Description of some properties, and nomination of human thrombopoietin (TP) had already occurred in Hungary, in 1958. In 1994 five laboratories (three in USA, one in France and one in Japan) independently published clonal purification, sequencing, and chromosomal localization of TP. This breakthrough now approaches therapeutic use in humans. PMID- 7845002 TI - Dicentric (9;12) in acute lymphocytic leukemia and other hematological malignancies: report from a dic(9;12) study group. AB - Fourteen cases of dic(9;12)(p11-13;p11-12) in early B-lineage acute lymphoblastic leukemia (ALL) and other hematological malignancies are reported with a review of the literature. Altogether 36 cases were collected for analysis: ALL at diagnosis (31 cases) or in relapse (one case), chronic myeloid leukemia in lymphoid blast crisis (two cases), T-cell lymphoblastic lymphoma (one case) and T-cell non Hodgkin's lymphoma (one case). We report the first cases of dic(9;12) with a T cell phenotype. Dic(9;12) occurs predominantly in B-progenitor ALL of childhood and young adults (age range, 1-47 years, median 12 years) but not of infancy. One or more adverse clinical features, age > 10 years, WBC > 100 x 10(9)/l, pre-B immunophenotype, platelets < 100 x 10(9)/l, were found in over 90% of cases. Additional structural chromosomal changes or trisomy 8 were frequently present. Nevertheless with a median follow-up of 5 years, 29/31 cases (94%) remain in first remission conferring an excellent prognosis to this leukemia. Additional cases are being sought to confirm the prognostic value of this cytogenetic aberration in various hematological malignancies. PMID- 7845003 TI - FISH diagnosis of t(8;21) in a myelodysplasia secondary to Hodgkin lymphoma. AB - A t(8;21)(q22;q22) translocation without blood and bone marrow invasion by immature myeloid precursors was suspected in a conventional karyotype and confirmed by fluorescence in situ hybridization (FISH) with chromosome 8 and 21 painting in a patient previously treated for Hodgkin's lymphoma. Six weeks later, the diagnosis was confirmed by the onset of acute myeloid leukemia (AML) M2 with a t(8;21) in the bone marrow. PMID- 7845004 TI - Cytogenetic clonality in chronic myelomonocytic leukemia studied with fluorescence in situ hybridization. AB - Chronic myelomonocytic leukemia (CMML) is a myelodysplastic syndrome (MDS) subtype, characterized by monocytosis, dysgranulocytosis and a low number of blast cells in the peripheral blood (PB). The clonal nature of MDS has been demonstrated by various techniques: the stem cell involved initially is capable of myeloid and lymphoid differentiation. Fluorescent in situ hybridization (FISH) is a technique which can be utilized without any pretreatment on whole interphase cells. In this study leukocytes of PB Wright-stained smears from four CMML patients with trisomy 8 (three cases) and 9 (one case) have been analyzed by FISH. Utilizing a probe for the centromere of chromosome 8 and for the heterochromatic region of chromosome 9, we observed the cells involved by trisomy. In each of the four cases neutrophils, eosinophils, basophils and monocytes may show trisomy 8 or 9, whereas lymphocytes resulted disomic. The comparison between leukocytes morphology and genotype suggests that the supernumerary chromosome does not influence cellular differentiation and maturation. We conclude that FISH analysis of PB leukocytes of patients with CMML is informative when studying the clonality of the disease. Chromosomal abnormalities seem to involve a hematopoietic cell committed to myeloid but not lymphoid differentiation. Trisomies 8 and 9 seem to confer some proliferative advantage without influencing the morphologic characteristics of leukocytes. Other causes will be investigated to explain dysmorphisms of neutrophils and monocytes typical of this disease. PMID- 7845005 TI - Clinical and prognostic significance of trisomy 21 in adult patients with acute myelogenous leukemia and myelodysplastic syndromes. AB - Trisomy 21 is the second most common trisomy in patients with acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS). However, its clinical and prognostic significance is not known. We analyzed the records of 1187 consecutive patients with untreated AML or MDS. Thirty-seven (3.3%) had trisomy 21: four (0.3%) as the only cytogenetic abnormality and 33 (2.7%) with other cytogenetic abnormalities (-5 and/or -7 in 15, +8 in nine, t(15;17) in three, inv(16) in three, t(8;21) in one, and hyperdiploid with several other additional chromosomes in two). Twenty-eight patients had AML and nine MDS. No patients had megakaryocytic phenotype (M7), common in patients with constitutional trisomy 21 (Down's syndrome) and AML. Overall, 57% achieved complete remission (CR), with median CR duration of 39 weeks, and median survival of 31 weeks. When patients with additional cytogenetic abnormalities were compared to patients with similar abnormalities but no trisomy 21, their clinical features as well as their CR rate, CR duration and survival were similar, with or without trisomy 21. We conclude that trisomy 21 in AML typically presents in conjunction with other cytogenetic abnormalities, especially -5/-7 and +8 whose presence rather than the presence of +21 dictates the clinical outcome. PMID- 7845006 TI - Phosphorothioate BCR-ABL antisense oligonucleotides induce cell death, but fail to reduce cellular bcr-abl protein levels. AB - The bcr-abl oncogene is a fusion gene resulting from a reciprocal translocation which forms the hallmark of chronic myeloid leukemia (CML). Antisense oligonucleotides complementary to the two possible mRNA breakpoints were found to inhibit cell growth of CML patient cells and cell lines, but doubt exists about their specificity. In order to test the specificity, phosphorothioate and 3' phosphorothioate capped antisense BCR-ABL oligonucleotides of different length were used. Stability, cellular uptake of oligonucleotides and effect on cell growth were studied in two CML cell lines, BV173 and LAMA-84. Phosphorothioate antisense BCR-ABL oligonucleotides were most stable, showed the highest uptake and induced cell death in BV173 but not in LAMA-84 cells. We selected the most effective antisense oligonucleotide for further analysis. The BV173 and LAMA-84 cell lines do not express the normal c-abl protein, we therefore used a c-abl specific monoclonal antibody for the detection of p210bcr-abl expression by flow cytometry. Dead cells found after treatment were gated out of analysis. Although BCR-ABL antisense oligonucleotides can induce apoptosis, no reduction of p210bcr abl levels could be detected in living cells after treatment with antisense oligonucleotides. We conclude that antisense mediated inhibition of translation of mRNA into p210bcr-abl is not the mechanism responsible for the induction of apoptosis in cell line BV173. PMID- 7845007 TI - Inhibition of bcl-2 with antisense oligonucleotides induces apoptosis and increases the sensitivity of AML blasts to Ara-C. AB - We have previously shown that blasts from acute myeloid leukaemia (AML) patients which grow autonomously in culture have high bcl-2 expression which in turn has been linked to a poor clinical response to chemotherapy. The bcl-2 protein promotes cell survival by preventing the onset of apoptosis or programmed cell death following growth-factor deprivation. Bcl-2 has also been shown to be responsible for chemo-resistance in human leukaemic cell lines. Here we have investigated the role of bcl-2 expression in mediating resistance to apoptosis induced by cytosine arabinoside in vitro. The blasts from 17 AML patients exhibiting autonomous growth in a blast cell colony assay and expressing high levels of bcl-2 protein were studied. Incubation of the blasts with antisense oligonucleotides directed against bcl-2 mRNA resulted in a significant decrease in expression of the bcl-2 protein in seven of the 17 samples. In these seven cases the decreased expression of bcl-2 was accompanied by increased apoptosis and the susceptibility of the blasts to apoptosis induced by Ara-C was increased in the presence of bcl-2 antisense. As a high level of bcl-2 defines a group of AML patients who exhibit a poor response to chemotherapy, the demonstration that chemosensitivity of a significant proportion of these patients can be increased by bcl-2 antisense suggests this approach may have clinical potential. PMID- 7845008 TI - Differential uptake of all-trans retinoic acid by acute promyelocytic leukemic cells: evidence for its role in retinoic acid efficacy. AB - All-trans retinoic acid (ATRA) has been demonstrated to be an efficient alternative to chemotherapy in the treatment of acute promyelocytic leukemia (APL or AML3). Complete remission is obtained by inducing granulocytic differentiation of the leukemic cells. To date, the exact mechanism through which ATRA exerts its differentiating effect is not known. The present investigation was initiated to characterize ATRA intracellular concentrations achieved in human myeloid leukemic cells in relation to their different sensitivity to ATRA differentiating effect. During the first 24 h of incubation, a significant decrease of ATRA in the culture medium and a marked increase in the intracellular concentrations were observed. Maximal uptake by the leukemic cells was reached within minutes, with levels between 20 and 260 pmol/10(6) cells (median = 100). Interestingly, a correlation between ATRA-induced differentiation and the intracellular ATRA concentration achieved was observed. In fact, patients with intracellular levels below 60 pmol/10(6) cells defined slow uptakers, never exceeded 40% differentiated cells at day 3. On the other hand, cells with 2-4-fold higher concentration (100-250 pmol/10(6) cells) achieved 100% differentiated cells at day 3. This report suggests that intracellular ATRA concentration is a key pharmacological parameter that should be taken into account to gain further insights into ATRA sensitivity in APL patients. PMID- 7845009 TI - DMSO-like rapid decrease in c-myc and c-myb mRNA levels and induction of differentiation in HL-60 cells by the anthracycline antitumor antibiotic aclarubicin. AB - The anthracycline antitumor antibiotic aclarubicin is known to induce granulocytic differentiation in the human myeloid leukemia cell line HL-60. We investigated whether this effect is accompanied by changes in the expression of the protooncogenes c-myc and c-myb. Treatment of HL-60 cells with aclarubicin, 50 nM, caused a rapid decrease in c-myc and c-myb mRNA levels within 1 h and 2 h, respectively. In parallel, we demonstrated a strong induction of superoxide-anion production on day 8 of treatment. The kinetics of the effect of aclarubicin on c myc and c-myb expression were comparable to those associated with the dimethylsulfoxide-induced granulocytic differentiation in this cell line, or to those observed following a chase with actinomycin D, 4 microM. Since aclarubicin partially inhibited total- and poly(A)(+)-RNA synthesis, this macromolecular synthesis inhibition may be causally related to the decrease in c-myc and c-myb mRNA levels. In contrast, the conventional anthracycline doxorubicin, which did not initiate differentiation, failed to affect c-myc or c-myb mRNA levels even in high cytotoxic concentrations, indicating that the suppression of c-myc and c-myb mRNA levels may be an early differentiation-related effect of aclarubicin. On the other hand, actinomycin D, 12.5 nM, and novobiocin, 300 microM, two other known inducers of granulocytic differentiation in HL-60 cells, did not induce an early decrease in c-myb or c-myc expression. Therefore, the immediate suppression of c myc and c-myb mRNA levels, apparently, is not an obligatory step in chemically induced myeloid differentiation in HL-60 cells, but the common phenomenon in DMSO and aclarubicin-induced differentiation. PMID- 7845010 TI - Pilot study of all-trans retinoic acid as post-remission therapy in patients with acute promyelocytic leukemia. AB - Chemotherapy may decrease relapses of acute promyelocytic leukemia (APL) following induction with all-trans retinoic acid (ATRA), however the optimal timing of these two modalities remains to be determined. We treated eight patients with morphologic evidence of APL with intensive induction chemotherapy followed by ATRA (45 mg/m2/d for 10 weeks). All eight patients achieved a complete remission following chemotherapy. After a median follow-up of 29.0 months, seven patients remain in complete remission; one patient relapsed at 26.9 months. RT-PCR analysis for the PML/RAR alpha rearrangement was performed to monitor patients for evidence of minimal residual disease. Both of the patients with persistence of this rearrangement after induction chemotherapy converted to negative following ATRA. Toxicity of ATRA given in the post-remission setting was mild and consisted of headache, dry skin, and elevations of triglycerides and transaminases. No patient developed evidence of the retinoic acid syndrome. The administration of ATRA after intensive induction chemotherapy is associated with durable remissions and minimal toxicity in patients with APL. Disappearance of the PML/RAR alpha rearrangement after ATRA suggests that ATRA is effective against minimal residual disease. PMID- 7845011 TI - A C-terminal FMS mutation in a patient with B-cell malignancy. AB - The FMS proto-oncogene encodes a polypeptide growth factor receptor expressed on the cell surface of monocytes and B lymphocytes within the haematological system. Mutations of the FMS gene at codons 301 and 969 have been detected in a number of haematological disorders. Mutations at these codons are thought to be important in the pathogenesis of leukaemia in cells expressing a mutant receptor. Following our finding that the colony stimulating factor-1 receptor (CSF-1R) was expressed on B cells, we have assessed DNA from 17 patients with B-cell chronic lymphocytic leukaemia (CLL), 15 with acute lymphoblastic leukaemias (ALL), two samples from patients with B-cell non-Hodgkin's lymphoma (B-NHL), and 20 haematologically normal individuals for the presence of C-terminal mutations of the FMS gene. Using single stranded conformational polymorphism analysis (SSCP), a single band shift was detected resulting from a nucleotide insertion at codon 965 in the DNA isolated from a patient with B-NHL. These results indicate that mutations of the FMS gene in this region are rare in B-cell malignancy but may contribute to the pathogenesis of leukaemias and lymphomas in a small subset of patients. However, the presence of other mutations not detected using this type of analysis cannot be excluded. PMID- 7845012 TI - Lysozyme in human neutrophils and plasma. A parameter of myelopoietic activity. AB - Lysozyme was found to be present in all three types of human neutrophil granules (azurophil-, specific- and gelatinase granules) as determined by subcellular fractionation, employing a three-layer Percoll gradient and measurement of lysozyme by a novel ELISA. The content of lysozyme was also measured in plasma. In contrast to other neutrophil granule proteins (lactoferrin, NGAL, and gelatinase), plasma lysozyme was unaffected by increase in the number of circulating neutrophils induced by intravenous administration of methylprednisolone to healthy individuals. Also in contrast to lactoferrin, NGAL, and gelatinase, plasma lysozyme was found to rise 1 week prior to detectable increases in the number of circulating neutrophils in patients undergoing allogeneic bone marrow transplantation. We conclude that plasma lysozyme is a parameter of myelopoietic activity and may be useful as a marker for bone marrow repopulation after transplantation. PMID- 7845013 TI - Increased detection of specific tyrosine phosphoproteins correlates with tumor progression of Abelson virus-infected lymphocytes. AB - Leukemias induced with the v-abl or BCR/ABL oncogene undergo a process of tumor progression which suggests that the ABL oncogene is required but not sufficient for full transformation. In order to identify cellular changes that correlate with progression to full transformation in v-abl transformed lymphoblasts Abelson virus (A-MuLV)-infected murine bone marrow was plated over a pre-established stromal feeder layer. Shortly after A-MuLV infection, transformed lymphoblasts were poorly oncogenic, but over time, progressed in a stepwide manner to a more oncogenic state. The transformants first acquired the ability to grow efficiently in agar, but only over the feeder layer. They next progressed to efficient feeder independent growth in liquid culture, and then to efficient feeder-independent growth in soft agar. Cell lines that reached the advanced stage of feeder independent agar growth showed increased detection by antiphosphotyrosine Western blot of the GAP-associated p62 phosphoprotein as well as of a 55 kDa phosphoprotein while detection of the P160 v-abl phosphoprotein remained constant throughout all stages of progression. Although the identity of the p55 phosphoprotein and the mechanism by which detection of p55 and p62 phosphoproteins change on the Western blots during tumor progression are unknown, the data demonstrate that these changes strongly correlate with the stage of progression of v-abl-transformed cells and raise the possibility that these changes may play a role in tumor progression in this model. PMID- 7845014 TI - Tumor formation by a human pre-B leukemia cell line in scid mice is enhanced by matrigel and is associated with induction of CD10 expression. AB - We have previously demonstrated the engraftment of human pre-B acute lymphoblastic leukemia (ALL) cells injected intravenously into irradiated scid mice. We now report on the ability of the reconstituted extracellular matrix, Matrigel, to promote the formation of subcutaneous tumors in non-irradiated scid mice by a CD10- pre-B ALL cell line termed G2. Lymphatic tumors infiltrating the dermis were seen in all eight mice sacrificed 10-13 weeks after the co-injection of G2 cells and Matrigel but in only 2/8 mice injected with leukemic cells alone. Infiltration of bone marrow, spleen, thymus, lung and liver was observed earlier and was more extensive in the Matrigel-treated group. The tumor cells derived from Matrigel-treated mice could be passaged in vitro and their colony-forming ability was higher than that of the original G2 line. When re-injected intravenously into non-irradiated scid mice, the tumor cells invaded the thymus earlier than did the G2 cells. The expression of CD10/neutral endopeptidase was induced at high levels in all tumors, in Matrigel or non Matrigel-treated animals. This up-regulation was transient as the tumor variants grown in vitro or in vivo lost expression of CD10. However, 6-8 weeks later, induction of CD10 was observed on both tumor variants and parental G2 cells growing in the thymus and at a lower level on cells in bone marrow and spleen. Culturing G2 cells in vitro at high density or in the presence of documented growth-promoting cytokines such as IL-3, IL-6, IL-7, and GM-CSF did not stimulate the expression of CD10 mRNA. The induction of this surface endopeptidase was thus associated with growth of leukemic cells in the specific microenvironments provided by the lymphoid tumors and the thymus in scid mice. The function of CD10 might be related to the hydrolysis of peptides which are critical in regulating interactions between adjacent pre-B cells, the stromal microenvironment and the transduction of growth and/or differentiation signals. PMID- 7845015 TI - Absence of point mutations in the extracellular domain of the alpha subunit of the GM-CSF receptor in a series of patients with acute myeloid leukemia (AML). AB - The GM-CSF receptor belongs to the cytokine receptor superfamily. The high affinity receptors of this class are lacking intrinsic tyrosine kinase domains. The GM-CSF receptor consists of alpha and beta subunits. The beta subunit is shared with the receptors of IL-3 and IL-5. In addition to the membrane bound forms the receptors have been found to possess soluble isoforms. Since retroviral infection of the human GM-CSF dependent cell line, TF-1, leads to factor independent growth by increased expression of the GM-CSF receptor alpha chain in a subgroup of infected clones, we were interested in studying the role of this chain in human AML. Further considering that a point mutation in the extracellular domain of the erythropoietin receptor, also a member of the cytokine receptor superfamily, resulted in constitutive activation of a murine cell line, we investigated the possibility that a point mutation of the GM-CSF receptor was responsible for autonomous growth of AML cells. We sequenced a segment of the receptor coding for the extracellular domain of the alpha subunit. cDNA was prepared from peripheral blood or bone marrow cells from 24 patients with AML, from four patients with MDS and from three human myeloid cell lines. The region of interest was amplified with two rounds of PCR reactions with nested primers, covering five overlapping fragments, and directly sequenced using a non radioactive technique. No point mutations were found in the investigated samples. Thus, point mutations in this segment of the GM-CSF receptor gene do not seem to play an important role in the transformation process of human acute leukemia. PMID- 7845016 TI - Ethnic differences in the lymphoid malignancies of children in the United Arab Emirates. A clue to aetiology? AB - Tawam Hospital is the major paediatric oncology referral centre in the UAE. During the past 11 years, 352 patients (0-12 years of age) were diagnosed to have a childhood malignancy. Leukaemia and lymphoma accounted for 62.7% of all tumours. Stage distribution for Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) showed a relatively high proportion of advanced stage disease. Histological analysis demonstrated a preponderance of lymphocyte predominance and mixed cellularity cases in Hodgkin's disease, and 2/3 of the NHL patients had small, non-cleaved cell lymphoma. Children fell into three main ethnic groups based on the origin/nationality of their parents: Group 1: UAE nationals and Omanis; Group 2: other Arabs; Group 3: Indian/Pakistani (subcontinental) origin. When compared for the relative proportion of leukaemia/lymphoma/other tumours, children of subcontinental origin had significantly more acute lymphoblastic leukaemia (ALL) and less lymphoma than the other two ethnic groups. This is probably due to the higher level of education and smaller family size in group 3 and lends support to the proposed infectious aetiology in ALL. PMID- 7845017 TI - Molecular epidemiology of acute lymphoblastic leukemia in Egypt. AB - We have characterized immunophenotypically defined acute lymphoblastic leukemia (ALL) in Egypt for rearrangements of the antigen receptor genes, and correlated this with rearrangements of ALL-1 and the presence of p53 mutations. Thirty-nine cases were analyzed for rearrangements of the immunoglobulin (Ig) and T-cell receptor (TCR) genes. All precursor B-cell ALLs (12 cases) contained rearranged Ig heavy-chain (JH) region which was biallelic in 92% of these tumors. In addition to JH rearrangements, TCR delta, beta and gamma rearrangements were observed in 80, 40 and 30% of these cases, respectively. TCR genes were invariably rearranged in T-cell ALLs (11 cases). A small fraction (2/11) of T cell ALL showed concurrent IgJH rearrangement which was monoallelic. Simultaneous rearrangement of IgJH and TCR genes was also observed in both cases of biphenotypic ALL (coexpressing B and T markers). We observed marked heterogeneity in the pattern of rearrangement of antigen receptor genes in mixed-lineage leukemias (ALL coexpressing myeloid-associated markers), including the retention of germline configuration in two cases. Rearrangements of the ALL-1 gene were confined to the leukemias that demonstrated lineage infidelity. Mutations in p53 were infrequent and were present in only three of 47 ALL cases (6%) analyzed; two of these were mixed-lineage leukemias. These results suggest that mixed-lineage and biphenotypic leukemias accumulate pathogenetic lesions that are distinct from B- and T-cell ALL, and that ALL in developing countries includes molecular entities similar to those in developed countries. PMID- 7845018 TI - Expression of the Evi-1 gene in myelodysplastic syndromes. AB - Increased expression of the proto-oncogene Evi-1 has been shown to block the in vitro granulocytic differentiation of myeloid cells in response to granulocytic colony-stimulating factor and to interfere with the proliferation of erythroid cells in response to erythropoietin. We determined the frequency of Evi-1 expression in myelodysplastic syndromes (MDS), a disorder with altered proliferation and differentiation in the erythroid and myeloid lineages. Twenty one patients were studied. Abnormal expression was found in 1/9 patients with refractory anemia and in 7/12 patients with refractory anemia with excess of blasts (RAEB) or in transformation (RAEBt). No correlation could be found between expression of Evi-1 and age, sex, hemoglobin level and percentage of bone marrow blasts or erythroblasts. This result suggests that the high incidence of Evi-1 expression which remains at low levels in RAEB and RAEBt is not a major determinant of ineffective erythropoiesis and myelopoiesis in MDS. PMID- 7845019 TI - Purification of lysozyme from human neutrophils, and development of an ELISA for quantification in cells and plasma. AB - Lysozyme was purified from exocytosed granule material from PMA-stimulated human neutrophils by polyethyleneglycol precipitation, cation exchange chromatography and molecular sieve chromatography. Rabbit antibodies were biotinylated and affinity purified on a lysozyme column, for subsequent development of a novel ELISA. This ELISA for lysozyme is sensitive and accurate, and applicable to determination of lysozyme in neutrophils and plasma. PMID- 7845020 TI - Detection of four different 11q23 chromosomal abnormalities by multiplex-PCR and fluorescence-based automatic DNA-fragment analysis. AB - A nested polymerase chain reaction (PCR) protocol was developed for rapid detection of four different 11q23 abnormalities by a single PCR assay. During each of the two PCR rounds a sense primer located within exon 5 of the MLL gene at 11q23 was combined with four different antisense primers, each located within possible translocation partner genes at chromosomes 4, 6, 9, and 19, respectively. Except for the MLL primer all primers used during the second round of nested-PCR carried a characteristic fluorescence label at their 5'-end. Agarose gel analysis of the PCR products was sufficient to discriminate between the absence of any of the four MLL rearrangements and the presence of at least one of them. Discrimination of the four different MLL translocation partner genes was not possible by agarose gel analysis due to a molecular heterogeneity of the 11q23 breakpoints resulting in PCR products of variable size. For this reason, automatic fluorescence-based DNA-fragment analysis was used to exactly define the MLL translocation partner genes if a positive result had been obtained by agarose gel analysis. In patients with leukemia, this assay may enable a fast and highly sensitive detection of different 11q23 abnormalities, which usually correlate with poor clinical prognosis. PMID- 7845021 TI - IgH/TCR delta PCR oligonucleotide liquid hybridization, a fast and sensitive assay for monitoring minimal residual disease in childhood B-precursor ALL. AB - The detection of minimal residual disease (MRD) in childhood B-precursor acute lymphoblastic leukemia (ALL) by polymerase chain reaction (PCR) may turn out to be a powerful tool in the evaluation and guidance of therapy. Most previously described techniques are highly sensitive but also too laborious for application in a routine setting. Here we describe a technique based on the determination of IgH VHDJH and TCR V delta 2D delta 3 junctional regions by PCR/cycle sequencing analysis and hybridization of junctional region oligonucleotide probes in a standard liquid hybridization (LH) assay. We systematically analyzed the applicability of this simplified approach for the monitoring of MRD in a large patient group. IgH VHDJH and TCR V delta 2D delta 3 junctional regions were amplified from presentation bone marrow samples obtained from 53 childhood B precursor ALL patients. The combined approach allowed the identification of at least one tumor marker for 49/53 (92.5%) of patients. A total of 75 oligonucleotide probes (54 DJH, 21 V delta 2D delta 3) was tested in the LH assay. Sensitivity range was 10(-2)-10(-5) and 10(-4)-10(-5) for DJH and V delta 2D delta 3 junctional region probes, respectively. A sensitivity of at least one malignant cell in 10(4) normal cells was obtained for 84.8% of evaluable patients, applying on average 1.1 IgH and 0.47 TCR delta probes per patient. Comparison to a method based on the use of initial PCR product as clone-specific probe showed that oligonucleotide LH was one log more sensitive in six of nine patients tested. The presented technique allows the monitoring of MRD with acceptable sensitivities in over 90% of childhood B-precursor ALL patients. Moreover, the technique is suitable for prospective patient studies in a routine setting as it is fast, reproducible and makes use of a standard hybridization protocol for different oligonucleotide probes. PMID- 7845022 TI - Basophilia, t(15;17) translocation and atypical AML. PMID- 7845023 TI - ORTHO Permeafix fixation is not suitable for the flow cytometric detection of nuclear terminal transferase in acute myloid leukemia cells. PMID- 7845024 TI - Polymorphism in the RAG-1 gene identified by SSCP. PMID- 7845025 TI - Effects of interferon-alpha on L-BCGF- and TNF-alpha-induced proliferation of hairy cell leukemia in Japan. AB - Interferon-alpha (IFN-alpha) is very effective in patients with hairy cell leukemia (HCL), although its mechanism of action is still unknown. To investigate this issue, we studied the in vitro response to IFN-alpha of a variant type of HCL, recently reported by us as the Japanese variant. Their clinical response to IFN-alpha (remission rate 35.7% in the multicenter study in Japan) was inferior to that of typical HCL (remission rate 80%; mean of previous reports). We found that both low molecular weight B-cell growth factor (L-BCGF) and tumor necrosis factor-alpha (TNF-alpha) induced the proliferation of HC from patients with the Japanese variant, as well as those with typical HCL. While, in typical HCL, IFN alpha strongly inhibited the in vitro proliferation of HC induced by L-BCGF and TNF-alpha, the inhibitory effect of IFN-alpha on L-BCGF and TNF-alpha-induced proliferation was low in most Japanese variant patients. These in vitro findings may be related to the extent of clinical efficacy of IFN-alpha in the Japanese variant, obtained in the multicenter study. Since the degree of inhibition was parallel in L-BCGF- and TNF-alpha-induced proliferation in three patients examined simultaneously, it appeared that the antiproliferative effect of IFN alpha is not specific to individual growth factors. Rather, IFN-alpha might affect fundamental growth mechanisms triggered by these factors. PMID- 7845026 TI - GM-CSF in a double-blind randomized, placebo controlled trial in therapy of adult patients with de novo acute myeloid leukemia (AML). AB - We investigated whether GM-CSF given concomitantly with chemotherapy (CT) and thereafter, improves the outcome of adults with de novo AML by increasing the efficacy of CT and reducing infections. CT included Ara-C, daunorubicin and etoposide (DAV) for induction and early consolidation therapy and one cycle with high-dose (patients aged < or = 50 years) or intermediate dose Ara-C (patients aged > 50 years)/daunorubicin for late consolidation therapy. Eight patients were randomized after DAVI to receive either GM-CSF (E. coli, 250 micrograms/m2/day, s.c.) or placebo starting 48 h prior to DAVII and the subsequent courses and given throughout CT until the absolute neutrophil count had recovered to > 500/microliters. The CR rate was 81% in the GM-CSF and 79% in the placebo group (p = 0.57; Fisher's exact test). The probability of relapse-free survival at 41 months after a median follow-up of 35 months was 42% in the GM-CSF and 41% in the placebo group (p = 0.89; log rank test). GM-CSF did not shorten the period of neutropenia < or = 500/microliters, while it prolonged the duration of thrombocytopenia < or = 25,000/microliters. The incidence and severity of infections as well as the non-hematological toxicity were similar in both groups. In summary, in this randomized trial GM-CSF as an adjunct to AML therapy was feasible. For the present GM-CSF does not have a significant effect on treatment outcome. PMID- 7845027 TI - Primary extra-thoracic T-cell non-Hodgkin's lymphoma of childhood. The United Kingdom Children's Cancer Study Group. AB - Between 60-80% of non-Hodgkin's lymphoma (NHL) of T-cell lineage in children, present with primary mediastinal disease. On current therapy, this and nodal low stage disease are associated with a relatively favourable outcome. In order to evaluate whether the primary site of disease is a prognostic factor, we examined the clinical characteristics and outcome of 36 children with primary extrathoracic T-cell NHL diagnosed during a 7-year period by the United Kingdom Children's Cancer Study Group. Eight, eight, 11 and nine children had stage I, II, III and IV disease, respectively. The primary site of disease was nodal in 22, skin and subcutaneous tissue in five, abdominal in three, bone in three and at other sites in three. Eighteen (50%) had lymphoblastic, ten (28%) large cell anaplastic (LCA) and seven (19%) pleomorphic large or medium cell (PLC) tumours. In one child the histology was inconclusive. All children with lymphoblastic, three with LCA, three with PLC disease and one with unknown histology were treated on intensive, sustained and continuous leukaemia protocols. Ten, seven with LCA and three with PLC, were treated on regimens of short duration pulsed therapy and one child with PLC with radiotherapy only. The three-year event-free survival (EFS) was 78% for the group as a whole. Those with stage IV lymphoblastic disease had a significantly worse prognosis (p < 0.0005). Primary site of disease, gender, therapeutic regimen and histology were not predictive for survival. In primary extrathoracic T-cell NHL with lymphoblastic histology, leukaemia-like therapy is recommended. For non-lymphoblastic disease, in particular the Ki-1 positive tumours, evidence suggests that short duration pulsed therapy may be optimal. PMID- 7845028 TI - Frequent expression of CD3 epsilon in CD3 (Leu 4)-negative nasal T-cell lymphomas. AB - Adult natural killer (NK) cells had not generally been thought to express CD3 proteins other than zeta; however they were recently demonstrated to express CD3 epsilon in an activated condition. This prompted us to investigate the tumor tissues from 17 patients with Leu4-negative peripheral T-cell lymphoma, including eight with nasal T-cell lymphoma (NTCL), for the expression of CD3 epsilon. The tissues were immunohistologically stained with rabbit anti-human CD3 epsilon antibody. The expression of CD3 epsilon was more frequent in the tissues of nasal lymphoma than in the non-nasal lymphoma tissues: specimens from six of eight of the NTCL patients expressed CD3 epsilon, while only one of nine of the non-NTCL patients did so. The NTCL patients presented clinically with lethal midline granuloma, had histologic findings of tumor necrosis and angioinvasion, and had a peculiar CD2+, Leu4-, CD3 epsilon+, CD5-, CD7+, CD45RO+, CD4-, CD8-, beta F1-, T cell receptor (TRC) delta 1-, CD56+ phenotype. This peculiar phenotype seems to be closely associated with NTCL. No clonal rearrangement of the TCR genes was detected in three NTCL patients examined. The NK cell origin of NTCL has been suggested by previous investigators. The phenotypic correspondence of our nasal tumors to adult activated NK cells supports this possibility, together with their lack of clonal rearrangement of the TCR genes. PMID- 7845029 TI - 2',3'-Dideoxyadenosine killing of TdT-positive cells is due to a trace contaminant. AB - We have previously reported that the chain-terminating nucleoside analogue 2',3' dideoxyadenosine (ddA) is specifically cytotoxic for TdT-positive cells in the co presence of the adenosine deaminase (ADA) inhibitor coformycin (CF). Further studies with ddA/CF revealed that cytotoxicity occurs only if ddA is supplied from the Calbiochem or Fluka companies. ddA supplied from other commercial sources (Pharmacia, Sigma) or the NCI Pharmaceutical Resources Branch is non cytotoxic. To explore the basis for this difference, ddA from various sources was subjected to reverse-phase high-pressure liquid chromatography (HPLC) analysis. The Calbiochem and Fluka ddA had a unique HPLC peak, with a retention time of 12.8 min, representing a contaminant of less than 0.1% of the bulk material applied to the C-18 HPLC column. Study of all HPLC peaks resolved from the bulk material showed cytotoxic activity in only the 12.8 min peak. To identify the nature of the unknown compound, we compared HPLC characteristics of the synthetic intermediates and byproducts of ddA synthesis to the peak eluting at 12.8 min. Of these, only 3'-deoxyadenosine (cordycepin) had similar HPLC characteristics. In addition, in the co-presence of CF, cordycepin was specifically cytotoxic (IC50 < 0.5 microM) for all TdT-positive cell lines tested. Cytotoxicity was seen in TdT negative cells only at concentrations 10-100-fold higher. We conclude that our previous report on ddA/CF as a TdT-specific cytotoxic combination was due to contamination of the ddA supplied by Calbiochem by cordycepin. ddA itself is non cytotoxic for TdT-positive cells. Cordycepin in the co-presence of an ADA inhibitor may be effective in the treatment of TdT-positive hematological malignancies. PMID- 7845030 TI - Flow cytometric analysis of intercellular adhesion between B-cell precursor acute lymphoblastic leukemic cells and bone marrow stromal cells. AB - The growth of B-cell precursor acute lymphoblastic leukemic (BCP ALL) cells in vitro is dependent on interactions with bone marrow (BM) stromal cells. We have recently demonstrated that the rate of cell division of BCP ALL cells increases when cultured in direct contact with BM stromal cells. In this study we describe a new method for examining the direct binding of BM stromal cells and BCP ALL cells at a cellular level. For this binding assay, BCP ALL cells from six patient samples were first stained with the lipophilic fluorescent probe PKH 26 GL and mixed with BM stromal cells in suspension. In all cases, aggregates between BCP ALL and BM stromal cells were identified by flow cytometry and isolated. Using this assay we have examined some of the mechanisms involved in this binding process. The pattern of aggregate formation at various leukemic/stromal cell ratios showed that the aggregate formation increased by increasing the number of either cell type and that the binding could not be saturated. This suggests that the interaction between these cells is an equilibrium reaction. Functional studies showed that the majority of BCP ALL-BM stromal cell binding is dependent on the presence of divalent cations and requires active cellular metabolism. Finally, by use of inhibitory monoclonal antibodies (moAbs) directed against cell adhesion molecules including anti-CD29, VCAM and CD18, we have demonstrated that the involvement of these molecules in the direct cellular interactions could be detected by this method. However, the maximum inhibition observed was 36% which suggests either that the avidity is low or that other adhesion molecules are involved. The data show that the use of flow cytometric analysis of aggregate formation (rather than cell binding to intact cell layers) allows the study of cell interactions at the individual cell level which can reveal additional cellular adhesion mechanisms. PMID- 7845031 TI - Overexpression of C-FMS in the myeloid cell line FDC-P1 induces transformation that dissociates M-CSF-induced proliferation and differentiation. AB - Hemopoietic growth factors have been implicated in the pathogenesis of some myeloid leukemias when the cells acquire the autocrine capacity to produce a relevant growth factor. We report transformation of the immortalized cell line FDC-P1 by overexpression of murine c-fms, the receptor for macrophage colony stimulating factor (M-CSF). Three types of cell lines were obtained following expression of c-fms in FDC-P1 cells. The first type of cell line (FD-c-fms) was dependent on stimulation by M-CSF to induce cell proliferation and also underwent limited monocytic/macrophage differentiation in response to M-CSF. The second type of cell line (FD-c-fmsi) was able to proliferate in serum-containing cultures without stimulation by exogenous hemopoietic regulators. Stimulation of the FD-c-fmsi cell lines with M-CSF suppressed proliferation compared to cultures of unstimulated cells and induced monocytic/macrophage differentiation. The third type of cell line (FD-c-fms) was autonomous, failed to differentiate in response to M-CSF and secreted M-CSF into the culture medium, suggesting an autocrine mechanism of transformation. All three types of cell lines demonstrated varying degrees of suppression of cell proliferation when stimulated by the combination of M-CSF and GM-CSF. The data indicate that transformation of c-fms expressing cells results in a variety of phenotypes with dissociation of M-CSF induced proliferation and differentiation in different cell lines. PMID- 7845032 TI - Expression of basic fibroblast growth factor (bFGF) and FGF-receptors in human leukemic cells. AB - Recent reports have suggested that basic fibroblast growth factor (bFGF) could play a permissive role in hematopoiesis, in combination with specific colony stimulating factors. We investigated the expression of bFGF and FGF-receptors (FGF-Rs) in leukemic cell lines of various hematopoietic lineages. Three protein isoforms of bFGF of approximately 18, 22 and 24 kDa were detected in the myeloid cell line K562, but not in myelomonocytic or lymphoid (T or B) cell lines. In vitro-induced differentiation of K562 cells did not change the pattern of expression of the different bFGF isoforms. Accordingly, the mRNA of bFGF was found expressed in K562, but not in other leukemic lines tested, as assayed by reverse transcript amplification (RT-PCR). Using the same technique, we searched for the presence of high affinity FGF-Rs on these cells: in eight out of ten cell lines tested, mRNA for at least one FGF-R among FGF-R1, FGF-R3 or FGF-R4 was expressed, whereas FGF-R2 was never detected. We found that two cell lines were responsive to bFGF in different biological assays: (i) in K562 myeloid cells induced to differentiate by hemin, preincubation with bFGF and heparin increased cell viability and decreased hemin-induced DNA fragmentation, without affecting erythroid differentiation; and (ii) in U937 monocytic cells, the production of plasminogen activator was increased by bFGF or aFGF in combination with heparin. Binding experiments with 125I-bFGF (up to 200 pM) in the presence of heparin revealed high affinity receptors on the K562 and U937 cell lines (1177 +/- 440 and 392 +/- 184 sites/cell, Kd = 61.7 +/- 8.6 and 43.1 +/- 13.5 pM, respectively). Thus our results strongly suggest that cells of hematopoietic origin could express functional FGF-receptors. PMID- 7845033 TI - Autocrine loop of tumor necrosis factor induced by interferon-alpha in tumor cells from hairy cell leukemia. AB - Interferon-alpha (IFN-alpha) is successfully used in the therapy of hairy cell leukemia (HCL). We previously reported that IFN-alpha administered to HCL patients stimulated the levels of tumor necrosis factor (TNF) receptors on hairy cells. Here, we investigated the interactions between IFN-alpha and TNF, using the HCL cell line Eskol as a model. We showed that increased levels of TNF receptors (TNFR) induced by IFN-alpha treatment were associated with stimulation of high M(r) TNFR. Low M(r) TNFR were not detected on Eskol cells or hairy cells, either before or after IFN-alpha treatment. Furthermore, the expression of TNF mRNA increased in Eskol cells treated with IFN-alpha for 1-4 h as compared to control cells. In vivo experiments showed that IFN-alpha given to HCL patients induced both TNF mRNA expression in hairy cells and secretion of active TNF protein in patients' serum. These results provide evidence that IFN-alpha may induce an autocrine loop of TNF in HCL. PMID- 7845034 TI - Clinical and prognostic significance of chromosomal abnormalities in childhood acute myeloid leukemia de novo. AB - We report on the chromosomal pattern of 120 patients with childhood AML de novo. One hundred and fifteen patients (96%) had adequate samples for analysis; 98 (85%) of these showed clonal karyotypic abnormalities. They were classified into cytogenetic subgroups which were closely correlated with FAB subtypes: t(8;21) and M2 (n = 9); t(15;17) and M3 (n = 12); inv(16) and M4Eo (n = 9); t(9;11) and M5a (n = 10); t(11q23) other than t(9;11) and M4-M5 (n = 11); and t(1;22) and M7 (n = 4). In patients with -7/del(7q) (n = 6), leukemia was preceded by MDS in half of the cases, although they had diverse FAB subtypes. Thirty-seven patients had miscellaneous abnormalities. Despite a high CR rate, patients with t(8;21) had a very poor survival: only one child was event-free at 3 years from diagnosis. One third of patients with t(15;17) died during induction. Those eight who achieved CR fared well: only two relapsed, and six were event-free survivors. Patients with inv(16) had a high remission rate and a long survival: five children were in CR 20 to 136 months. Both groups with t(9;11) and t(11q23) had a high remission rate: however, outcome was superior for the t(9;11) group when compared to either the t(11q23) group (EFS at 3 years +/- SE, 56 +/- 17% vs. 11 +/- 10%, p = 0.07) or to the remaining patients (p = 0.06). Both -7/del(7q) and t(1;22) groups had low CR rates (50%) and poor survival. Cytogenetic analysis identifies clinically distinct subsets of childhood AML and is useful in tailoring treatment for these patients. Favorable cytogenetic groups (t(15;17), inv(16), and t(9;11)) may do well with current therapy protocols, whereas unfavorable groups (t(11q23), t(8;21), -7/del(7q), and t(1;22)) require more effective therapies. PMID- 7845035 TI - Scintigraphy of the whole gut: clinical evaluation of transit disorders. AB - OBJECTIVE: To describe an initial clinical experience with a noninvasive scintigraphic technique for assessing gastrointestinal motility. DESIGN: We studied gastric, small bowel, and colonic transit in 109 unselected patients encountered between June and December 1992 at the Mayo Clinic. MATERIAL AND METHODS: The study patients were categorized on the basis of major complaint (constipation in 46, upper gastrointestinal symptoms in 45, and diarrhea in 18) and presence or absence of an underlying organic disease. Radioscintigraphy was used to analyze various regions of the gastrointestinal tract; scans were obtained at 2, 4, 6, and 24 hours after ingestion of a radiolabeled test meal. RESULTS: Overall, patients with a main complaint of constipation usually had slow or normal gastric, small bowel, and colonic transit, whereas those with diarrhea as the major symptom usually had normal or fast results of these studies. In the 65 patients with no underlying organic disease, inconsistent patterns of gastric emptying and small bowel and colonic transit were noted. CONCLUSION: Our results suggest that this 24-hour scintigraphic test may be clinically useful in screening for dysmotility syndromes in patients with nausea, vomiting, diarrhea, or constipation. PMID- 7845036 TI - Clinical and radiologic features of cerebral edema in fulminant hepatic failure. AB - OBJECTIVE: To describe a series of consecutive patients with fulminant hepatic failure (FHF) and to present a new classification system for brain edema, an important cause of mortality in such patients. DESIGN: We reviewed 22 computed tomographic (CT) scans of the brain in 12 patients with FHF and classified the severity of cerebral edema by using predefined criteria. RESULTS: No cerebral edema was detected on CT scans in four patients with stage 1 or 2 hepatic encephalopathy at the time of admission, but it was noted in seven of eight patients with stage 3 or 4 hepatic encephalopathy. The severity of brain edema on CT scans was significantly correlated (P < 0.001) with the stage of hepatic encephalopathy. Three of the four patients who had stage 1 or 2 hepatic encephalopathy at the time of initial assessment ultimately had a good outcome. Of seven patients with stage 3 encephalopathy, two had rapid deterioration to brain death, three died of nonneurologic causes, and two had a good outcome after liver transplantation. One patient with stage 4 hepatic encephalopathy died, and autopsy showed cerebral edema. CONCLUSION: Stage 3 or 4 hepatic encephalopathy is associated with cerebral edema that can be detected on CT scans. The clinical and radiologic signs of cerebral edema in patients who have progression to stage 3 hepatic encephalopathy can be reversed with conventional treatment of increased intracranial pressure. Whether early recognition and treatment of cerebral edema result in increased survival of patients with FHF remains to be determined. PMID- 7845037 TI - Increase in total plasma homocysteine concentration after cardiac transplantation. AB - OBJECTIVE: To determine whether plasma homocysteine concentrations are increased in patients after cardiac transplantation. DESIGN: Total plasma homocysteine concentration was measured in 44 consecutive patients before and at 3, 6, and 12 months after orthotopic heart transplantation between June 1, 1988, and Oct. 15, 1992, and the data were analyzed statistically. RESULTS: Mean homocysteine concentrations (normal range, 4 to 17 mumol/L) increased 70% from 12.5 mumol/L before cardiac transplantation to 21.2 mumol/L (P < 0.002) 3 months after transplantation, at which time the concentrations were above normal in 14 of 26 patients (54%). Homocysteine concentrations remained elevated 6 and 12 months after transplantation (20.4 and 22.6 mumol/L, respectively) but did not increase further. Mean concentrations of plasma folic acid and vitamin B12, cofactors in homocysteine metabolism, decreased 20% and 49%, respectively, within 3 months after transplantation (11.6 to 9.3 micrograms/L [P = 0.04] and 584 to 295 ng/L [P = 0.01]). The mean glomerular filtration rate decreased 25% during this same interval (81 to 61 mL/min; P = 0.0001). Linear regression analysis revealed an association between the increase in homocysteine concentration and the folic acid concentration that approached statistical significance (P = 0.07); we found no statistically significant correlates of the increase in homocysteine concentration. CONCLUSION: The homocysteine concentration increases in most patients within 3 months after cardiac transplantation to levels previously associated with premature atherosclerotic coronary artery disease, and it remains increased for at least 1 year. Further investigation into the mechanism for the increase in homocysteine concentration and the relationship between homocysteine and coronary artery disease after transplantation is warranted. PMID- 7845038 TI - Failure of signal-averaged electrocardiography with use of time-domain variables to predict inducible ventricular tachycardia in patients with conduction defects. AB - OBJECTIVE: To extend the application of signal-averaged electrocardiography (SAECG) to patients with ventricular conduction defects by analysis of electrocardiographic (ECG) time-domain variables. MATERIAL AND METHODS: In 123 consecutive patients with a QRS duration of 118 ms or more on a resting ECG and without evidence of an accessory pathway, SAECG was done at the time of electrophysiologic (EP) study. For EP testing, up to three stimuli were delivered during two paced drives from two right ventricular sites. A "positive" EP result was defined as monomorphic ventricular tachycardia that lasted for more than 30 seconds or necessitated intervention. Data were obtained for four time-domain variables. All variables were analyzed for differences between patients with EP positive and those with EP-negative results. RESULTS: Unfiltered QRS duration was the only time-domain ECG variable that was statistically different (P = 0.02) between patients with EP-positive and those with EP-negative results (141.3 and 147.8 ms, respectively); this difference persisted when patients with right bundle branch block were excluded from analysis. This finding is the opposite of previously reported observations. When only patients with ischemic heart disease were analyzed, no SAECG variables were significantly different between patients with inducible ventricular tachycardia and those without it. CONCLUSION: High resolution ECG time-domain variables cannot be used to predict inducibility of ventricular tachycardia during EP testing in patients with conduction defects. PMID- 7845039 TI - Sir John Eccles--prize-winning neurophysiologist. PMID- 7845040 TI - Management of prenatally detected fetal hydronephrosis. AB - The increased frequency of prenatal ultrasonography has resulted in an increase in the detection of fetal genitourinary abnormalities, many of which are of minimal clinical significance. Severe fetal urinary tract obstruction with associated oligohydramnios results in a recognizable constellation of physical findings, including renal dysplasia, pulmonary hypoplasia, and perinatal death. In selected cases, prenatal intervention to decompress urinary tract obstruction may reestablish amniotic fluid volume, prevent renal damage, and allow normal pulmonary development. After severe renal injury has occurred, intervention is unlikely to improve the prognosis of the affected fetus. Renal function may be analyzed prenatally by ultrasound examination and determination of chemical composition of fetal urine in order to identify fetuses in whom kidney development has not yet been irrevocably damaged and those likely to benefit from prenatal intervention. Postnatal renal evaluation with ultrasonography, voiding cystourethrography, and radionuclide imaging facilitates further characterization of the abnormality detected on prenatal ultrasound examination. PMID- 7845041 TI - Medical and surgical management of intracranial aneurysms. AB - OBJECTIVE: To examine the medical and surgical aspects of intracranial aneurysms, including the pathogenesis, clinical manifestations, management of subarachnoid hemorrhage (SAH), and indications for surgical intervention. DESIGN: This review presents the classification of intracranial aneurysms, defines specific aneurysms, and analyzes the Mayo Clinic experience with surgical treatment of cerebral aneurysms. MATERIAL AND METHODS: Intracranial aneurysms are classified by cause, size, site, and shape. The clinical grading systems for SAH, the most common manifestation, are as follows: modified Botterell, Hunt and Hess, and World Federation of Neurological Surgeons. Surgical options are direct clipping, interventional neuroradiologic treatment, proximal ligation or trapping of aneurysms, and wrapping or coating of aneurysms. Although the timing of surgical intervention after SAH is controversial, it should be based on the clinical grade, site of the aneurysm, and patient's medical condition. RESULTS: The frequency of intracranial aneurysms is estimated to be 1 to 8% in the general population, and 90% of patients have SAH. After SAH, 8 to 60% of patients die before they get to a hospital. After hospitalization, the mortality rate is 37%, severe disability is 17%, and outcome is favorable in 47%. The current trend for surgical treatment is early after SAH. The Mayo Clinic experience with 1,947 patients who underwent surgical treatment because of aneurysmal SAH or for aneurysmal repair between 1969 and 1990 is as follows: 1,445 had an excellent outcome, 231 had a good outcome, 171 had a poor outcome, and 100 died. CONCLUSION: Aggressive management can be beneficial for many patients with severe neurologic injury after SAH by preventing rerupture of the aneurysm, attenuating the severity and sequelae of vasospasm, and decreasing the surgical complications. PMID- 7845042 TI - Pulmonary artery sarcoma: diagnosis and postoperative follow-up with gadolinium diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging. AB - Pulmonary artery sarcomas are infrequently encountered and are often misdiagnosed before surgical exploration or autopsy. On clinical examination and conventional imaging studies, they are frequently mistaken for pulmonary emboli. To our knowledge, this case report is the first to describe the postoperative magnetic resonance imaging (MRI) appearance of residual disease of a pulmonary artery sarcoma and to assess the potential usefulness of MRI for monitoring such lesions postoperatively. Contrast-enhanced MRI, a relatively noninvasive method, seems well suited for postsurgical follow-up of pulmonary artery sarcomas. PMID- 7845043 TI - Sarcoidosis. AB - Sarcoidosis is a systemic granulomatous process of unknown cause. Pathologically, it is characterized by noncaseous granuloma, and in more than 90% of patients, the lung or intrathoracic lymph nodes are affected. A roentgenographic staging system (stages I, II, and III), based on the appearance of the plain chest roentgenogram, conveys important information about prognosis, degree of symptoms, and pulmonary function abnormalities. The diagnosis should be confirmed by histopathologic examination and exclusion of known causes for the noncaseous granulomatous reaction. When indicated, treatment with alternate-day regimens of prednisone is highly effective. Serial chest roentgenography, pulmonary function studies, and the serum angiotensin-converting enzyme level are useful for monitoring the course of the disease. PMID- 7845044 TI - Cascade testing for autoantibodies in connective tissue diseases. PMID- 7845045 TI - 27-year-old woman with pancytopenia. PMID- 7845046 TI - Euthanasia and assisted suicide. PMID- 7845047 TI - Measurement of whole-gut transit: a new test comes of age? PMID- 7845048 TI - Neurologic consequences of fulminant hepatic failure. PMID- 7845049 TI - Additional causes of torsades de pointes. PMID- 7845050 TI - Methemoglobinemia and oxyhemoglobin concentration. PMID- 7845051 TI - Distinction between acute myopathy syndrome and critical illness polyneuropathy. PMID- 7845052 TI - Effect of age on adherence and chemotaxis capacities of peritoneal macrophages. Influence of physical activity stress. AB - The aim of the present research was to study the effects of age on the adherence and chemotaxis capacities of macrophages. Macrophages were obtained from the peritoneum of young and old mice (young, 12 +/- 4 weeks; old, 68 +/- 6 weeks) and young and mature guinea pigs (young, 12 +/- 1 weeks; mature, 108 +/- 2 weeks). Adherence of macrophages was evaluated with a plastic adherence technique, and chemotaxis in a Boyden chamber. The macrophages from old animals showed a higher adherence capacity (studied at 10, 40 and 60 min of incubation), and lower chemotaxis capacity in both mice and guinea pigs. The effect of physical activity stress (swimming until exhaustion) was also studied, both with and without a previous training program, on the adherence and chemotaxis of macrophages from young and old mice. While the physical activity stress (detected by the increase of the serum corticosterone concentration) did not induce changes in adherence or chemotaxis of peritoneal macrophages from young mice, in the old mice, there was a decrease in adherence and an increase in chemotaxis. PMID- 7845053 TI - Influence of aging and endurance training on lactate dehydrogenase in liver and skeletal muscle. AB - The purpose of this investigation was to determine the effects of aging and endurance training on lactate dehydrogenase (LDH) activity and isozyme pattern in liver and skeletal muscle. Male Fischer 344 rats (n = 30) of three different age groups (young, 4 months; middle-aged, 12 months and old, 22 months) were trained on a treadmill at 75% running capacity for 1 h/day, five times per week for 10 weeks. Age-matched sedentary controls (n = 36) were used for comparison. Total LDH enzyme activity was measured spectrophotometrically; LDH isozymes were separated by native 5.5% polyacrylamide gel electrophoresis and quantified densitometrically. With increasing age, hepatic LDH activity decreased 28%. Old sedentary animals displayed significantly less (22%) hepatic LDH 5 than young and middle-aged animals, and significantly more (40%) hepatic LDH 4 than middle-aged animals. Training resulted in a significant decrease (38%) in total hepatic LDH activity in young rats only. Young animals displayed a significant increase in hepatic LDH 3 (28%), whereas middle-aged animals exhibited a significant decrease in hepatic LDH 3 (40%) with training. No change in total hepatic LDH activity was exhibited in middle-aged or old rats with training. Neither aging or training had a significant effect on LDH activity or isozyme pattern in extensor digitorum longus (EDL). Similarly, LDH activity was maintained in soleus with age, and isozyme pattern was only negligibly affected. We conclude that with age there is a decline in hepatic LDH activity and a decrease in the LDH 5 isozyme. Endurance training induced significant decreases in hepatic LDH activity of young animals. However, these decreases were not a result of shifts in isozymal pattern. Further, LDH activity was maintained in EDL and soleus muscle with age. Finally, endurance training did not have a significant effect on LDH activity or isozymal pattern of EDL or soleus. PMID- 7845054 TI - A theory that may explain the Hayflick limit--a means to delete one copy of a repeating sequence during each cell cycle in certain human cells such as fibroblasts. AB - A model that may explain the limited division potential of certain cells such as human fibroblasts in culture is presented. The central postulate of this theory is that there exists, prior to certain key exons that code for materials needed for cell division, a unique sequence of specific repeating segments of DNA. One copy of such repeating segments is deleted during each cell cycle in cells that are not protected from such deletion through methylation of their cytosine residues. According to this theory, the means through which such repeated sequences are removed, one per cycle, is through the sequential action of enzymes that act much as bacterial restriction enzymes do--namely to produce scissions in both strands of DNA in areas that correspond to the DNA base sequence recognition specificities of such enzymes. After the first scission early in a replicative cycle, that enzyme becomes inhibited, but the cleavage of the first site exposes the closest site in the repetitive element to the action of a second restriction enzyme after which that enzyme also becomes inhibited. Then repair occurs, regenerating the original first site. Through this sequential activation and inhibition of two different restriction enzymes, only one copy of the repeating sequence is deleted during each cell cycle. In effect, the repeating sequence operates as a precise counter of the numbers of cell doubling that have occurred since the cells involved differentiated during development. PMID- 7845055 TI - Effects of stimulated growth hormone secretion on age-related changes in plasma cholesterol and hepatic low density lipoprotein messenger RNA concentrations. AB - Growth hormone (GH) secretion declines during aging. Since GH alters plasma cholesterol (PC) concentrations, it was of interest to determine how GH secretagogues affect age-related hypercholesterolemia. Fischer 344 rats (3 and 14 months old) were co-administered (s.c.) GH releasing hormone (3 micrograms/kg; GHRH) and GH releasing hexapeptide (100 micrograms/kg; GHRP) for 120 consecutive days. Aging was associated with a progressive increase in PC, which was reduced in rats administered GHRH and GHRP compared to those administered vehicle, i.e. changes in PC during the study were 26.5 +/- 1.2 mg/dl vs. 40.1 +/- 0.9 mg/dl (P < 0.05) in the younger rats and 17.6 +/- 2.3 mg/dl vs. 31.6 +/- 5.3 mg/dl (P < 0.05) in the older rats, respectively. The lower concentrations of PC in GH secretagogue-treated older rats were associated with higher mean concentrations of hepatic LDL receptor mRNA (1.27 +/- 0.4 vs. 0.4 +/- 0.1; P < 0.05) but not cholesterol 7-alpha hydroxylase mRNA. Although GH secretagogue treatment was also associated with lower plasma cholesterol in the younger rats, it was not accompanied by quantitative changes in mean group concentrations of hepatic LDL receptor mRNA. Instead, daily administration of GHRH and GHRP in the younger rats correlated with a significant reciprocal relationship (P < 0.05) between PC and hepatic LDL receptor mRNA for individual group members. The results of this study suggest that reduced GH secretion during aging contributes, at least in part, to a progressive increase in plasma cholesterol that can be partially prevented with GH secretagogues. Furthermore, the effects on PC may result from GH-mediated, qualitative and quantitative changes in hepatic LDL receptor mRNA that increase receptor-mediated cholesterol clearance. PMID- 7845056 TI - Age-related changes in the induction of tyrosine aminotransferase by dexamethasone: correlation with the low-affinity glucocorticoid binding sites. AB - Rat liver membranes contain Low-affinity glucocorticoid binding sites (LAGS), capable of binding with low affinity (Kd approximately 100 nM) endogenous glucocorticoids. Unlike the glucocorticoid receptor (GR), the LAGS level undergoes abrupt changes throughout life. The investigation of these changes may be useful in determining whether the LAGS are involved in the cellular response to glucocorticoids. For this purpose, we have studied glucocorticoid induction of tyrosine aminotransferase (TAT), and its relationship with the LAGS level in adrenalectomized and fasted rats of different ages. No significant differences in the GR level, or in its Kd and activation, were observed among rats of 1, 3, and 12 months of age. On the other hand, the LAGS level showed an important variation with age, from almost undetectable in 1-month-old rats, to a maximum value in 3 month-old rats. With respect to TAT activity, an increase with age in the threshold of response to dexamethasone (DEX) administration was observed. The smallest dose of DEX capable of provoking a significant TAT induction rose from 0.1 microgram/kg body wt. in 1-month-old rats to 10 micrograms/kg body wt. in 12 month-old rats. However, the smallest dose of DEX able to elicit the maximal response was 10 micrograms/kg body wt. in all the assayed ages. This dose provoked a 40% decrease in the GR level, but did not significantly modify the LAGS content. From these results, we conclude that there is an age-related change in the threshold of response to DEX that cannot be explained by the GR glucocorticoid interaction. The possibility that the LAGS modulate the cell response to glucocorticoids arises from the coincidence of this change with that observed in the LAGS concentration throughout life. PMID- 7845057 TI - Temporal and substrate-dependent patterns of stress protein expression in the hypothalamus of caloric restricted rats. AB - Stress proteins (sps) 27, 34, 70 and 90 (Mr x 10(3)) were induced in the hypothalamus of caloric restricted (CR) rats by feeding stress. A definite time pattern for sps synthesis was observed when their induction was examined at several time points after the rats were fed, and the level of sps expression was found to vary significantly at different times of the day. The same group of proteins was induced in ad libitum fed rats when they were subjected to food deprivation for 48 h. Stress protein 34 expression in the hypothalamus of old caloric restricted rats was found to be dependent on blood glucose levels, and was substantially reduced when insulin was added to the glucose infusion. The expression of sps 27, 70 and 90, however, was little changed with glucose and/or insulin infusion. PMID- 7845058 TI - Chronic caloric restriction induces stress proteins in the hypothalamus of rats. AB - The induction of stress proteins (sps) in the hypothalamus of female Fischer 344 rats in response to caloric restriction (CR) and to heat stress was investigated. Caloric restriction was found to elicit sps 27, 34, 70, and 90 in the hypothalamus of both young and old rats while none was found in the hypothalamus of ad libitum (AL) fed controls. Heat stress initiated heat shock proteins (hsps/sps) 27, 70, and 90 in the hypothalamus of the young (AL) fed animals, the same proteins evoked by feeding stress. The same sps were induced in the old (AL) rats although the expression showed substantial decline with age. This reduction was less marked, however, with the old CR rats. Stress protein 34, an infrequently reported protein, was related to feeding and was not induced by heat shock. Recent reports point to the important role sps play in the cellular reaction to stress, as well as their involvement in the higher functions. The findings reported here suggest that sps are involved in the regulatory mechanisms allowing CR animals to tolerate stress related to metabolic substrate deprivation. PMID- 7845059 TI - Life-span of Drosophila melanogaster in highly oxygenated atmospheres. AB - The life-span of Drosophila melanogaster males kept for their entire life in atmospheres of differing O2 concentration (21%, 30%, 40%) was measured. The life span decreased linearly with the increase in O2 proportion. In order to test the rate of living and the threshold theories of ageing, Drosophila melanogaster males were kept for 15 days in a given atmosphere and from day 16 on in another one. The life-spans observed in these alternate conditions were very close to the values predicted by the rate of living theory and are thus not compatible with the threshold theory. PMID- 7845060 TI - Effect of aging on autoimmune response to rat male accessory glands: young, but not aged, antigen-presenting cells efficiently induce suppression in aged rats. AB - The present report analyzes the suppressor cell system of aged rats in an experimental model of autoimmunity to rat male accessory glands (RAG). A state of specific suppression to RAG was induced when young rats are pretreated with peritoneal cells (PC) obtained from syngeneic young rats i.p. injected 2 h previously with chromatographic fraction I (Sephadex G-100) (FI) of RAG (yFI-PC). Although the yFI-PC injection diminished the DTH in aged rats the autoimmune response remained positive. Peritoneal cells obtained from aged rats injected with FI of RAG (oFI-PC) did not suppress the DTH response in either aged or young rats. In both young and aged, pretreatment with yFI-PC stimulates spleen cells capable of inducing suppression (inductor-phase suppressor cells) when they are transferred to young recipients. However, the spleen inductor-phase suppressor cells of 12-month-old rats are unable to suppress the autoimmune response in their own aged environment. To obtain effective suppression in 12-month-old rats, the injection of yFI-PC was necessary prior to and subsequent to immunization. In this work we observe that 12-month-old rats could efficiently induce inducer phase and effector-phase suppressor cells when the adequate young antigen presenting cells were present to stimulate them. PMID- 7845061 TI - Dietary butylated hydroxytoluene counteracts with paraquat to reduce the rate of hepatic DNA single strand breaks in senescence-accelerated mice. AB - The present study was designed to assess the age-related changes of DNA single strand breaks (SSB) in the liver of senescence-resistant and senescence-prone mice, SAMR1/Fky and SAMP1@Fky. In the first series of experiments, the animals were fed a commercial diet for 12-18 months. The mice were killed and the livers were excised at 3- or 6-month intervals for the analysis of the rate of DNA SSB by the ethidium bromide fluorescence method. With advancing age, the rate of DNA SSB was increased in both strains of mice but the increase was significantly higher in SAMP1@Fky than in SAMR1/Fky. In the second series of experiments, the mice were fed one of the following diets for 12 weeks: 20% casein diet (basal diet), basal diet with 300 ppm butylated hydroxytoluene (BHT) added, basal diet with 200 ppm paraquat (PQ) added, and basal diet with 200 ppm PQ plus 300 ppm BHT added. Added dietary PQ increased the rate of DNA SSB in both SAMP1@Fky and SAMR1/Fky. The increases were offset by co-administration of BHT. Dietary BHT, therefore, may suppress the oxidative stress developed by paraquat administration. PMID- 7845062 TI - Muscarinic cholinergic receptors in the hippocampus of aged rats: influence of choline alphoscerate treatment. AB - The present study was designed to investigate age-dependent changes of muscarcinic M1 and M2 cholinergic receptors in the rat hippocampus using radioreceptor assay and autoradiographic techniques with [3H]pirenzepine and [3H]AF-DX 116 as ligands. The analysis was performed on 2-, 12- and 27-month-old male Wistar rats, considered young, adult and old, respectively. Moreover, the influence of a 6-month treatment with choline alphoscerate on the density and pattern of M1 and M2 cholinergic receptors was assessed. Choline alphoscerate (L alpha-glyceryl phosphorylcholine) is a precursor in the biosynthesis of several brain phospholipids which increases the availability of acetylcholine in various tissues. Muscarinic M1 cholinergic receptors were significantly decreased with increasing age whereas M2 cholinergic receptors did not show changes. Choline alphoscerate treatment countered, in part, the loss of muscarinic M1 receptor sites in old rats. Light microscope autoradiography revealed a loss of silver grains developed after exposure of sections of hippocampus to [3H]pirenzepine in the stratum oriens of CA1 and CA3 fields in rats of 12 and 27 months in comparison with young animals. Choline alphoscerate restored, in part, the decrease of silver grains noted in old rats. Quantitative analysis of the density of silver grains developed in the cell body of pyramidal neurons of CA1 and CA3 fields processed for the demonstration of muscarinic M1 receptor sites revealed a decrease of these grains in rats of 27 months in comparison with younger cohorts. These findings suggest that the reduction in muscarinic M1 sites noticeable between 2- and 12-month rats is probably dependent on the loss of nerve cells and/or terminals in these hippocampal fields rather than to a reduction of their density per neuron. Treatment with choline alphoscerate increased the expression of muscarinic M1 cholinergic receptors within the cell body of pyramidal neurons of CA1 and CA3 fields compared to age-matched control old rats. Consistent with radioreceptor assay data, no changes in the density of muscarinic M2 cholinergic receptors in the animal groups examined were demonstrated by light microscope autoradiography. The possible pharmacological relevance of the increased expression of muscarinic M1 cholinergic receptors elicited by choline alphoscerate in the hippocampus of aged rats is discussed. PMID- 7845063 TI - Thermal method for continuous measurement of cerebral perfusion. AB - A new thermal system using constant heating power for continuous measurement of cerebral perfusion is presented. It is designed and implemented for optimal perfusion sensitivity and dynamic response based on heat-transfer analysis of perfused brain tissue with thermistors on the cortical surface. Two matched thermistors are used, one to serve as a perfusion sensor and the other to compensate for the base-line temperature changes. To improve the signal-to-noise ratio of the measurement system, lock-in amplifiers are used to minimise long term drift and low-frequency noise. Errors in the measurement caused by electrical and thermal fluctuations are tested and analysed. In vitro tests show that the measurement accuracy of temperature change is better than 10(-3) degrees C, and the temperature resolution is even greater. In vivo evaluation confirms that the system is responsive to cerebral perfusion changes associated with sudden changes in mean arterial blood pressure caused by bolus injection of norepinephrine, blood withdrawal and blood infusion. The dynamic response of the system is sufficient to detect the autoregulatory perfusion changes in response to arterial blood pressure alteration and the oscillations of cerebral blood flow. PMID- 7845064 TI - Bilateral asymmetry of respiratory acoustic transmission. AB - Sonic noise transmission from the mouth to six sites on the posterior chest wall is measured in 11 healthy adult male subjects at resting lung volume. The measurement sites are over the upper, middle and lower lung fields and are symmetric about the spine. The ratios of transmitted sound power to analogous sites over the right (R) and left (L) lung fields are estimated over three frequency bands: 100-600 Hz (low), 600-1100 Hz (mid) and 1100-1600 Hz (high). A R L dominance in transmission is measured at low frequencies, with a statistically significant difference observed at the upper site. No significant asymmetry is observed in any measurement site at mid or high frequencies. A theoretical model of sound transmission that includes the asymmetrical anatomy of the mediastinal structures is in agreement with the observed asymmetry at low frequencies. These findings suggest that the pathway of the majority of sound transmission from the trachea to the chest wall changes from a more radial to airway-borne route over the measured frequency range. PMID- 7845065 TI - Non-invasive conductivity technique to detect changes in haematocrit: in vitro validation. AB - An on-line haematocrit measurement in extracorporeal circuits might be useful under some clinical circumstances (e.g. haemodialysis or cardiac surgery). As no such measurement exists, a device has been developed that makes it possible to detect haematocrit (Ht) continuously without a loss of blood. It is a multi frequency system for the detection of electrical conductivities. The aim of this study was to investigate whether this device can measure Ht alterations properly. Ht alterations were induced by adding pure mannitol and 20% mannitol to fresh human blood. Furthermore, the effect of both mannitol substances on the intracellular ion content, intracellular conductivity and Ht were investigated. Alternations in Ht were established by the addition of 1000, 800, 600, 400, 200 and 0 mg of pure mannitol to 10 ml of fresh human blood, and 3.0, 2.5, 2.0, 2.0, 1.5, 1.0, 0.5 and 0 ml of 20% mannitol to fresh human blood until a total volume of 10 ml was achieved. Although their effects were significantly different, pure mannitol and 20% mannitol both caused a reduction in mean cellular volume, and thus in Ht. A highly significant correlation was found between Ht and intracellular conductivity (r = 0.90, p < 0.001). In addition to these effects, addition of pure mannitol and 20% mannitol had different effects on the intracellular ion content. Pure mannitol caused an increase in intracellular ion content due to a transcellular ion shift, whereas 20% mannitol induced a decrease. From this study, it can be concluded that the multi-frequency conductivity method observes changes in Ht (and intracellular fluid volume) in an accurate manner.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845066 TI - Comparison of two methods for correcting ocular artefacts in EEGs. AB - A major problem in the study of brain potentials is the occurrence of ocular artefacts in electro-encephalograms. OAs can be monitored by placing electrodes near the eyes and recording electro-oculograms. In the paper, two OA correction methods based on simulations are compared; the Jervis method and the vandenBerg method. In most simulations, the residual (the difference between the original EEG and the EEG after correction) is smaller in amplitude and variance for the vandenBerg method than for the Jervis method. When eye movements and blinks are given different factors, the blinks are not removed completely. For both methods, the residual of the blinks increases with the differences between the model parameters for the blinks and for eye movements. The occurrence of a slow negative wave greatly disturbs the estimated parameters and thus the residuals of the Jervis method. For the vandenBerg method, there is only a very small effect. The conclusion from correcting a recorded data set, which does not contain a slow negative wave, is that, for these data, there is no evidence that one method is better than the other. PMID- 7845067 TI - Intracranial pressure dynamics in clinical practice: online PC-based ICP monitoring system. AB - Correct patient management involves determining the exact point on the intracranial pressure/volume (P/V) curve that corresponds to the patient; this requires calculating intracranial elastance (IE). Intracranial pressure (ICP) monitoring systems should provide the necessary information for this purpose. An ICP monitoring unit is presented that acquires ICP, systemic arterial pressure (SAP) and airway pressure (AWP). The cerebral perfusion pressure (CPP) and the mean values and the peak-to-peak values of the two of them (ICPmean, SAPmean, ICPp-p, SAPp-p,) are calculated. Graphs display the temporal evolution (TE) of the ICP and SAP, as well as histograms of the ICP (%) and intracranial pulse amplitude (ICPAmP) with respect to the ICP or CPP during the preceding 3, 6, 12 or 24 h of monitoring. By digital filtering the ICP respiratory and cardiac components (RCICP, CCICP) are calculated. Finally, the pulse amplitudes (AmP) of the ICP, CCICP and RCICP are computed, as well as the average pulses per minute of SAP, CCICP, AWP and RCICP. Two off-line pulse-amplitude and pulse-morphology oriented toolkits display the afore-mentioned curves, histograms and average pulses per minute, and other additional ones, in order to achieve a deeper patient monitoring study. PMID- 7845068 TI - Analogue and digital instruments for non-invasive estimation of muscle fibre conduction velocity. AB - Analogue and digital instruments for non-invasive on-line measurement of muscle fibre conduction velocity (CV) have been designed, built and compared using test signals and real myo-electric signals. Their inputs consist of two single differential or double-differential myo-electric signals, obtained using a three- or four-contact surface electrode system. The analogue device computes CV by tracking the lag of the zero-crossing of the cross-correlation between the first signal and the derivative of the second. The digital device computes the peak of the cross-correlation function between the two signals by sampling them at 50 KHz for 20 ms (or longer, up to 320 ms), computing CV in about 30 ms (or longer, up to about 670 ms) and resuming sampling. Both devices allow estimation of CV during either voluntary or electrically elicited contractions and include a stimulation stage and a signal conditioner with artefact suppression features. Both devices provide analogue and numerical outputs and allow interfacing with analogue and digital instrumentation. They can be used in clinical or in research environments for easy and quick identification of appropriate electrode locations and/or for monitoring CV during sustained voluntary or electrically elicited contractions. The digital version is more versatile and requires no adjustments; it provides an estimate based on intermittent reading of the signals and is more sensitive to noise and momentary CV fluctuations. PMID- 7845069 TI - Finite-element method in electrical impedance tomography. AB - In electrical impedance tomography (EIT), current patterns are injected into a subject and boundary voltages are measured to reconstruct a cross-sectional image of resistivity distribution. Static EIT image reconstruction requires a computer model of a subject, an efficient data-collection method and robust and fast reconstruction algorithms. The finite-element method is used as the computer model. The paper describes the finite-element analysis software package developed, including an interactive graphical mesh generator and fast algorithms for solving linear systems of equations using sparse-matrix and vector techniques. Various models of irregularly shaped subjects are developed using mesh-design tools, including automatic mesh generation and optimisation using the Delaunay algorithm. Even though the software package is customised for use in electrical impedance tomography, it can be used for other biomedical research areas, such as impedance cardiography, cardiac defibrillation and impedance pneumography. PMID- 7845070 TI - Elastic porous tube model of reactive hyperaemia. AB - Reactive hyperaemia is the term given to the temporary increase in blood flow that follows release of an occlusion of the arterial supply. Measurement of reactive hyperaemia in the leg below the knee is useful in assessment of the vascular system, as resting flows remain unaffected even in the presence of quite severe occlusive arterial disease. An elastic porous tube representation of the vascular system is used to develop equations for the variation of the mean pressure, flow and vessel calibre in the vascular system. The tube represents the arteries and large arterioles, which respond passively to changes in pressure. Leakage through the tube walls represents flow into the small arterioles, which respond actively to the rise in pressure following release of the occlusion by constricting (the myogenic response). The capillaries are represented by rigid tubes, and the venous system is represented by a single compliant vessel. The model predicts variations in the flow, pressure and vessel calibre that are in agreement with experimental observations, and identifies that the pressure gradient is important in determining the initial transient increase in the flow following release of the occlusion. The subsequent development in the flow is governed by the small arteriolar flow, which is determined by the magnitude and duration of the myogenic response. PMID- 7845071 TI - Unsupervised clustering of evoked potentials by waveform. AB - A procedure for clustering evoked potentials (EPs) according to their waveforms is presented. Clustering is performed without a priori selection of basis waveforms, the number of basis waveforms or the number of clusters. The method uses the principal-component-analysis coefficients of EP records as features for unsupervised optimal fuzzy clustering (UOFC) of the records. The validity of the procedure is demonstrated in two instances: visual evoked potentials (VEPs) and cognitive event-related potentials (ERPs) from humans in a memory-scanning task. In the clustering of VEPs, the procedure differentiates between waveforms judged to be clinically normal and abnormal. In the clustering of ERPs, the procedure correctly differentiates between waveforms evoked by the same stimuli which differ in their context to the performance of a memory-scanning task (memorised items against probes). Within this classification, the procedure detects two subgroups to probe-evoked waveforms, which are not obvious from visual inspection of the waveforms. The advantage of the procedure, which conducts clustering by UOFC, is the adaptive and machine-learning nature of its operation. PMID- 7845073 TI - New technique for assessment of velopharyngeal function. PMID- 7845074 TI - Digital demodulation in bio-impedance measurement. PMID- 7845075 TI - Classification of non-averaged EEG data by learning vector quantisation and the influence of signal preprocessing. PMID- 7845072 TI - Radio-immunotherapy dosimetry with special emphasis on SPECT quantification and extracorporeal immuno-adsorption. AB - Results from therapeutic trials with radiolabelled monoclonal antibodies are difficult to compare, because of lack of accurate macroscopic and microscopic dosimetry for both tumours and normal tissues. Requirements for such a dosimetry are covered in the paper. Accurate in vivo dosimetric measurement techniques for verification of calculated absorbed doses are also needed to verify treatment planning. In the review, important topics related to dosimetry in therapeutic trials in RIT are covered, such as, absorbed-dose calculations and activity quantification techniques for planar imaging and SPECT. The latter is particularly discussed, including a summary of different correction techniques. Absorbed-dose calculations and treatment-planning techniques are also discussed. Possible ways of enhancing the therapeutic ratio are reviewed, especially the novel technique with extracorporeal immuno-adsorption. The review could form the basis of the development of future treatment-planning protocols and for dosimetry calculations in radio-immunotherapy, considering some of the most important parameters for approaching an accurate in vivo dosimetry. PMID- 7845076 TI - Microfabricated printed circuit for measuring oxygen in vitro. PMID- 7845077 TI - Performance characteristics of a pulsed plasma cathode X-ray source operated without diode closure. PMID- 7845078 TI - Tracking jaw movement. PMID- 7845079 TI - Computerised semiconductor probe-based system for in vivo dosimetry of patients undergoing high-energy radiotherapy. PMID- 7845080 TI - System based on a digital signal processor for real-time cross-correlation of neural signals. PMID- 7845081 TI - Development system for pulse oximetry. PMID- 7845083 TI - [Help for physicians with problems!]. PMID- 7845082 TI - Standard algorithm of blood-pressure measurement by the oscillometric method. PMID- 7845084 TI - [Scandinavians in London may receive care at the Swedish Harley Street Centre]. PMID- 7845085 TI - [Changing primary health care--which direction this time?]. PMID- 7845086 TI - [It could have been better now!]. PMID- 7845087 TI - [Progress in carotid surgery]. PMID- 7845088 TI - [Good results of the "Strimman Patientkontakt" in Linkoping]. PMID- 7845089 TI - [Reform the law on involuntary commitment!]. PMID- 7845090 TI - [Cholesterol level and women]. PMID- 7845091 TI - [The Nobel Prize in medicine]. PMID- 7845092 TI - [It is a waste not to introduce computerization into health care!]. PMID- 7845093 TI - [A revolution stopped short. Will the visions of the the nineties on gene therapy be realized?]. PMID- 7845094 TI - [Inhalation steroids in pseudocroup. Good results in Canada, Swedish application is delayed]. PMID- 7845095 TI - [The first breast cancer gene isolated. Safer risk assessment for affected families]. PMID- 7845096 TI - [Concealed multiple abuse with codeine preparations. Combination with alcohol is life-threatening]. PMID- 7845097 TI - [Orbital panorama. A 20-year perspective]. PMID- 7845098 TI - [Poisonings in Sweden 1990. Deliberate drug overdosage dominates]. PMID- 7845099 TI - [Enterococci as a new nosocomial problem. A Vancomycin-resistant strain was isolated in Sweden]. PMID- 7845100 TI - [Treating substance abuse in physicians. Good possibilities of positive results]. PMID- 7845101 TI - [Food additives in the EEC-perspective. National law is valid while waiting for the EEC rules]. PMID- 7845102 TI - [Sulfite in food--a risk to health? Hypersensitivity was noticed in patients with asthma]. PMID- 7845103 TI - [Hypersensitivity to azo coloring agents. Tartrazine in food may cause rash and asthma]. PMID- 7845104 TI - [The Uppsala profile in medical education. A combination of knowledge of human nature and biology]. PMID- 7845105 TI - [Stress fractures of the pelvis. Report of three cases]. PMID- 7845106 TI - [Syndromes with tics are worth to be noticed. They may add to the knowledge about mental disorders]. PMID- 7845108 TI - [An industrial model misunderstood in the debate on health care management]. PMID- 7845107 TI - [Technical aids, injections, implants. Is it possible to cure impotence?]. PMID- 7845109 TI - Canada's threatened healthcare system. PMID- 7845110 TI - World summit on social development. PMID- 7845111 TI - Do cell membrane dynamics participate in insulin resistance? PMID- 7845112 TI - Temperature and cardiovascular mortality. PMID- 7845113 TI - Antipyretics in severe sepsis. PMID- 7845114 TI - Effects of pulsed beta-stimulant therapy on beta-adrenoceptors and chronotropic responsiveness in chronic heart failure. AB - In animals, intermittent sympathomimetic stimulation with dobutamine produces benefits analogous to those of physical conditioning. Longer intermittent or continuous beta-stimulant therapies have not, however, been successful in managing patients with chronic heart failure. We have investigated the role of beta-receptor stimulants in patients with severe chronic heart failure by changing the method of administration to intermittent, very short-duration pulsed intrope therapy (PIT). We studied 10 patients (mean age 64 [SE 2] years) with stable moderate to severe chronic heart failure (ejection fraction 23 [3]%) who received PIT, and 10 control patients matched for age and severity. We infused sufficient dobutamine to raise heart rate to 70-80% maximum for 30 min per day, 4 days per week for 3 weeks. PIT increased exercise tolerance (from 10.4 [1.2] min at baseline to 13.0 [1.5] min at 3 weeks; p < 0.001, 95% CI for difference 1.6 to 3.9) and lowered peripheral vascular resistance (19.8 [3.1] to 17.7 [2.4] mm Hg.min.L-1; p < 0.05, -4.1 to -0.1). PIT produced significant increases in lymphocyte beta-receptor density (502 [110] to 1200 [219] per cell, p < 0.02, 258 to 1138) and chronotropic responsiveness to exercise (change in heart rest to peak exercise 51.0 [3.2] to 57.5 [3.9] beats per min; p < 0.01, 2.9-10.1). Plasma noradrenaline concentrations (2.39 [0.28] to 1.65 [0.19] nmol/L, p < 0.05) were reduced. The patients' symptoms were also improved. By contrast, no change in autonomic function or exercise capacity was seen in the control group. Short duration PIT induces pharmacological conditioning with improved symptoms, autonomic balance, exercise tolerance, beta-receptor up-regulation, and enhanced chronotropic responsiveness in chronic heart failure. PMID- 7845116 TI - Temperature extremes and mortality from coronary heart disease and cerebral infarction in elderly Chinese. AB - We studied the relation between outdoor temperature and mortality rates from cardiovascular disease in Taiwan from 1981 to 1991. In 11 years, there were 30,085, 21,750, and 39,818 deaths from coronary artery disease, cerebral infarction, and cerebral haemorrhage, respectively, among 7.6 million residents aged 25 and over in selected areas where climate was recorded. A temperature mortality relation was especially apparent in the elderly. A U-shaped relation was observed between temperature and mortality from coronary artery disease and cerebral infarction. The range corresponding to least deaths from coronary artery disease (26-29 degrees C) and cerebral infarction (27-29 degrees C) was higher than that in countries with colder climates. In the elderly, the risk of cerebral infarction at 32 degrees C was 66% higher than that at 27-29 degrees C; the risk increased by 3.0% per 1 degree C reduction from 27-29 degrees C. The risk of coronary artery disease at 32 degrees C was 22% higher than that at 26-29 degrees C; below 26-29 degrees C, the risk increased by 2.8% per 1 degree C reduction. Mortality from cerebral haemorrhage decreased with increasing temperature at a rate of 3.3% per 1 degree C. These results imply a pathophysiological difference between thromboembolic and haemorrhagic cardiovascular diseases. Poor thermoregulation in older people may precipitate cardiovascular disease events. PMID- 7845115 TI - Long-term results of single course of adjuvant intraportal chemotherapy for colorectal cancer. Swiss Group for Clinical Cancer Research (SAKK) AB - The efficacy of adjuvant chemotherapy after surgery for colorectal cancer remains unproven. We have investigated the efficacy of a perioperative intraportal cytotoxic regimen in a randomised trial of 533 patients with operable colorectal carcinoma. Patients were randomly assigned either a single course of portal infusion with mitomycin (10 mg/m2, one dose) plus fluorouracil (500 mg/m2 per 24 h for 7 days) starting immediately after surgery, or no adjuvant treatment. 505 (94%) were evaluable. At median follow-up of 8 years, adjuvant therapy reduced the risk of recurrence by 21% (hazard ratio 0.79 [95% CI 0.62-1.00], p = 0.051) and the risk of death by 26% (0.74 [0.57-0.97], p = 0.026). The lower risk of relapse was observed in all subgroups based on node status or localisation of the tumour; the risk reduction was greatest in patients with tumour-involved lymph nodes (Dukes' C; 0.67 [0.45-0.99], p = 0.045) and for those with colon cancer (0.78 [0.56-1.09], p = 0.151). Most of the difference in overall and disease-free survival could be attributed to a consistent reduction of all kinds of tumour recurrences (local relapses, liver metastases, and other distant metastases) in the treated group, rather than to a reduction of liver relapses only. We conclude that part of the benefit obtained with a single course of adjuvant chemotherapy via the portal vein for patients with operable colorectal carcinoma might be due to the systemic effects of the portal chemotherapy. PMID- 7845117 TI - Hepatitis B virus infection without immunological markers after open-heart surgery. AB - Post-transfusion hepatitis is still an important problem, despite the screening of blood donors for hepatitis B (HBV) and C virus infections. We assessed whether HBV DNA might be detected by PCR in prospectively collected serum samples of patients with unexplained post-transfusion hepatitis but no immunological HBV markers. We found HBV DNA in 4 (20%) of 20 patients with unexplained post transfusion hepatitis and in 5 patients with mildly increased aminotransferases. The clinical course of these HBV infections was usually mild and self-limiting. Thus we found that low-titre, immunologically negative HBV infections do exist and might represent a significant cause of post-transfusion hepatitis. PMID- 7845118 TI - Cell membrane dynamics and insulin resistance in non-insulin-dependent diabetes mellitus. AB - Insulin resistance in non-insulin-dependent diabetes mellitus (NIDDM) could be related to changes in cell membrane properties. We measured insulin sensitivity and mononuclear leucocyte membrane fluidity by fluorescence polarisation in fifteen NIDDM patients and twenty-one normal subjects. Core-region anisotropy was significantly lower in leucocytes from diabetic subjects (mean 0.164 vs 0.174, p < 0.001). Insulin sensitivity was positively correlated with such anisotropy before and after acute in-vitro insulin treatment. There was no difference in superficial membrane anisotropy. This study suggests that altered membrane dynamics in NIDDM may contribute to insulin resistance. PMID- 7845119 TI - Hyperlipidaemia, hypertension, and coronary heart disease. PMID- 7845120 TI - Subcutaneous immunoglobulin replacement in patients with primary antibody deficiencies: safety and costs. AB - Immunoglobulins (IgG) as replacement therapy in primary antibody deficiencies can be given as intramuscular injections, or as intravenous or subcutaneous infusions. Our aims were to obtain information on the frequency of adverse systemic reactions during subcutaneous therapy, the occurrence and intensity of tissue reactions at the infusion sites, and serum IgG changes. Furthermore, we compared costs between the different replacement regimes. Our study included 165 patients (69 women, 96 men, aged 13-76 years) with primary hypogammaglobulinaemia or IgG-subclass deficiencies. Data were compiled from questionnaires filled in by the patients and from their medical records. 33,168 subcutaneous infusions (27,030 in home therapy) had been given. 106 (of which 16 were at home) adverse systemic reactions (100 mild, 6 moderate) were recorded in 28 patients (17%). No severe or anaphylactoid reactions occurred. Despite large immunoglobulin volumes given during 434 patient years (28,480 infusions), no signs have been found that indicate the transmission of hepatitis virus. Transient tissue reactions occurred at the infusion sites but were not troublesome to most patients and we found significant increases in mean serum IgG. The use of subcutaneous instead of intravenous infusions at home would reduce the yearly cost per patient for the health-care sector by US $10,100 in Sweden alone. We conclude that subcutaneous administration of IgG is a safe and convenient method of providing immunoglobulins. We were able to reach serum IgG concentrations similar to those by the intravenous therapy and we found that the method could also be used successfully in patients with previous severe or anaphylactoid reactions to intramuscular injections. PMID- 7845121 TI - The new politics of risk assessment. PMID- 7845122 TI - Cautious optimism over new anti-HIV agents. PMID- 7845123 TI - Conflicting views on alleged plagiarism. PMID- 7845124 TI - Travellers' diarrhoea and use of single-dose ciprofloxacin. PMID- 7845125 TI - Travellers' diarrhoea and use of single-dose ciprofloxacin. PMID- 7845126 TI - Topical treatment for Dupuytren's contracture. PMID- 7845127 TI - Travellers' diarrhoea and use of single-dose ciprofloxacin. PMID- 7845128 TI - Travellers' diarrhoea and use of single-dose ciprofloxacin. PMID- 7845129 TI - End of New Zealand asthma epidemic. PMID- 7845130 TI - Cardiovascular disease in the tropics, ethics, and need for action. PMID- 7845131 TI - End of New Zealand asthma epidemic. PMID- 7845132 TI - Outcome in offspring of women with mild hyperphenylalaninaemia. PMID- 7845133 TI - Sudden infant death syndrome and volatile antimony compounds. PMID- 7845134 TI - Unnecessary D & Cs. PMID- 7845135 TI - Shifting indications for hysterectomy. PMID- 7845136 TI - Shifting indications for hysterectomy. PMID- 7845137 TI - Shifting indications for hysterectomy. PMID- 7845138 TI - Folic acid in prevention of neural tube defects. PMID- 7845139 TI - Is contrast enhancement in cranial computed tomography necessary? PMID- 7845140 TI - Folic acid in prevention of neural tube defects. PMID- 7845141 TI - HIV testing in prison. PMID- 7845142 TI - Nitric oxide production and heart failure. PMID- 7845143 TI - Superoxide dismutase and amyotrophic lateral sclerosis. PMID- 7845144 TI - Parental influence on inheritance of familial amyotrophic lateral sclerosis. PMID- 7845145 TI - Involvement of macrophages in lethal forms of graft-versus-host disease. PMID- 7845146 TI - Breastfeeding and neurological status. PMID- 7845147 TI - Migration of Echinococcus granulosus via lymphatics. PMID- 7845148 TI - Lack of effect of nedocromil sodium in ACE-inhibitor-induced cough. PMID- 7845149 TI - When practice makes perfect. PMID- 7845150 TI - Hepatitis B vaccine boosting among young healthy adults. PMID- 7845151 TI - Efficacy of lamivudine on replication of hepatitis B virus in HIV-infected patients. PMID- 7845152 TI - Vertical transmission of hepatitis A virus. PMID- 7845153 TI - Risk factors in melanoma. PMID- 7845154 TI - Delay in onset of malaria with mefloquine prophylaxis. PMID- 7845155 TI - Subacute cutaneous lupus erythematosus associated with cilazapril. PMID- 7845156 TI - [Surgical therapy of liver metastases. Therapeutic procedures, results and prognostic factors]. AB - In a period of 7 years, 151 patients were treated by resection and/or regional chemotherapy after liver metastases from various primary tumours. The subgroup of patients with colorectal liver metastases was evaluated separately from the heterogeneous group with any other primaries. Radical resection of colorectal liver metastases was followed by a 5-year survival of 17%. The time from resection of the primary to development of the metastatic lesions was shown by univariate and multivariate analysis to be the most important prognostic factor. Adjuvant regional chemotherapy failed to improve outcome after curative resection of liver metastases. Neither palliative regional chemotherapy in cases of diffuse hepatic metastases nor the combination of palliative resection with regional or systemic chemotherapy significantly prolonged survival. PMID- 7845157 TI - [Addition of an osmotic agent to liver preservative solutions in a model of in vitro preservation of hepatocytes]. AB - To avoid hypoxic cell swelling during liver preservation followed by reduced perfusion in the reoxygenation period, osmotic substances such as mannitol, sucrose and raffinose, and the impermeant anion lactobionate are used in established liver preservation solutions. The various osmotic agents were investigated at concentrations of 60, 140, 260 and 300 mM, the solutions being kept isotonic by substitution with sodium and potassium chloride to 300 mosmol/l. Cultures of adherent pig hepatocytes were incubated in an in vitro model of cold hypoxia (4 degrees C, PO2 < 0.1 mmHg) for 24 h and reoxygenated with standard culture medium for 3 h. After each incubation period, light microscopy was performed to estimate cell viability and detachment rate. LDH and GOT liberation were also measured. To estimate the change in cell volume, isolated hepatocytes were incubated in suspension for 24 h of cold hypoxia. The cell volumes were compared after centrifugation and measurement of the pellet and the solute levels. Rising concentrations of osmotic substances resulted in increasing liberation of LDH and GOT. The levels of LDH and GOT release from cultures incubated with 60 mmol/l sucrose or raffinose were comparable to those in a preservation solution of "extracellular" ion composition. Addition of mannitol to the preservation solution resulted in cell damage. At high concentrations, sucrose did not affect the hepatocytes as much as raffinose. While mannitol can permeate the hepatocytes and lead to cell swelling, a cell-shrinking effect was observed when sucrose was used, and even more pronounced cell shrinking was seen with raffinose, to which the hepatocyte membrane is known to be permeable.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845159 TI - [Preoperative risk assessment in elective visceral surgery. Study design--results -perspectives]. AB - Since 1988 we have been analysing all our patients undergoing elective general surgery with general or spinal anaesthesia in a prospective study, with the aim of identifying and weighing up risk factors. The risk factors have been divided into the following groups: environment, surgeon, anaesthesia, operative intervention, disease and patient, regardless of the current illness. In 1990 a total of 682 patients (mean age 51.6 years, range 14-90), 365 male and 317 female, entered on study. General complications have been recorded in 63 patients (9.2%), whereas local complications occurred in 73 patients (10.7%). The following parameters were identified as risk factors for general complications: age > or = 70 years, hypertensive blood pressure level, haematocrit < 40% (male patients), operative procedure for malignancies, reduced physical capacity, pathologic cardiac or lung history, pathologic ECG, excessive alcohol consumption, hepatosplenomegaly, foreign origin, carotid artery bruit. Five patients died within 30 days following surgery for a malignant disease. This ongoing prospective study is a valuable instrument for the definition of preoperative risk factors in elective general surgery with the objective of eliminating mortality by the end of the century. PMID- 7845158 TI - [Ultrasound diagnosis of appendicitis by surgeons--a matter of experience? A prospective study]. AB - A number of studies have shown that ultrasound has an advantage over physical examination in the diagnosis of acute appendicitis. Most of these studies were conducted by experts in the field of ultrasonography. In this study the influence of experience on the results of the sonography of acute appendicitis were evaluated. All 203 patients admitted to our unit between December 1990 and December 1992 were examined physically and sonographically by a team of surgeons consisting of one experienced sonographer and six inexperienced surgical trainees. Laparotomy was performed in 136 patients (46%). Appendicitis was demonstrated histologically in 119 cases (39.4%). Initial clinical findings were positive in 87 (28.8%). Sonography was positive in 119 patients (39.4%). The 163 patients not operated on demonstrated other pathology on ultrasound in 60 cases (19.9%). The rate of negative laparotomies amounted to 7.2% in our study. Sensitivity and specificity for the sonographic diagnosis were 92% and 95%, respectively. They were only 81% and 80% for physical examination. Overall accuracy was 92% for sonography. Sensitivity and specificity for the inexperienced surgeons were 87% and 93%, respectively, while the experienced surgeon reached values of 97% and 98%, respectively. The results of both groups are comparable with values in the literature, suggesting that ultrasound evaluation of appendicitis is not a diagnostic tool limited to a few experienced sonographers. PMID- 7845160 TI - [Prognostic scores in peritonitis: the Mannheim Peritonitis Index or APACHE II?]. AB - Scoring systems are mandatory to quantify the severity of abdominal sepsis on the basis of objective criteria. The Mannheim Peritonitis Index (MPI) is a disease specific score based on easy to handle clinical parameters. APACHE II is a large scale general scoring system with acute physiological and chronic health parameters. To evaluate the prognostic value of both systems 108 patients with severe abdominal infection managed by open treatment entered a prospective study. 32 patients (29.6%) died, 23 of them due to sepsis and 9 from other causes. Both MPI and APACHE II scores correlated closely with mortality, with three and two significantly different classes, respectively. Statistical validation showed a sensitivity of 93% and a specificity of 16% for MPI, and 89% and 25% for the APACHE II. ROC curves were nearly parallel for both scores. In conclusion there was no significant difference in prognostic value between the scoring systems. PMID- 7845161 TI - [Developments up to now and current status of adjuvant chemo- and radiotherapy in colonic and rectal carcinoma]. AB - A review is given of the historical and current concepts of adjuvant chemo- and radiotherapy of colorectal cancer. Early studies analyzing the use of single drug regimens were followed by a second study generation investigating adjuvant chemotherapeutic combinations. 5-FU proved to be the most efficient single drug investigated and 5-FU/MeCCNU/vincristin the most efficient chemotherapeutic combination, but no significant improvement in 5-year survival rates was achieved. Clear progress was noted with the introduction of levamisol (LEV) for modulation of 5-FU. A 33% improval in the 5-year survival rate in patients with stage III colon carcinoma was documented. It was therefore recommended (NIH consensus conference 1990) that all patients with stage III colon carcinoma be treated with this regimen unless admitted to other trials of adjuvant therapy. Preoperative radiotherapy with a dosage of 35-45 Gy can lead to downstaging of rectal cancer. Nevertheless, significant improvement in patient survival has not been proved convincingly using either isolated pre- or postoperative adjuvant radiotherapy. However, combined radiochemotherapy has been shown to improve both patient survival and local tumor control compared to surgical resection alone. It is therefore recommended that all stage II and III rectal cancer patients be treated with adjuvant combined radiochemotherapy. 5-FU/MeCCNU is currently expected to be the most efficient chemotherapy in combination with radiotherapy. Early data point out that MeCCNU could possibly be omitted. Intraoperative radiotherapy (IORT) allows further dosage escalation in order to improve local tumor control without affecting radiosensitive structures. Available data are still sparse and mostly based on the treatment of advanced carcinoma. A general validation of IORT is not yet possible, but current data are promising. PMID- 7845162 TI - [Jejunal small intestine duplication]. AB - Duplications of the alimentary tract are rare. Most of them are diagnosed during infancy or childhood, when they become symptomatic and a palpable mass is found. Major complications are bleeding, perforation, ileus and pancreatitis. In the majority of cases the gastro-intestinal duplication is localized in the small bowel. Correct preoperative diagnosis by means of imaging techniques is rare. Because there is no malignancy surgery is only necessary in symptomatic cases. PMID- 7845163 TI - [An intestinal neosphincter attained by circumscribed muscle proliferation. Technical development and functional evaluation in the dog]. AB - In an experimental study an intestinal neosphincter (INS) was constructed by modifying the principle of the ileocolic nipple-valve anastomosis by means of ultrasonic tissue fragmentation of the contacting serosa of the ileum and the corresponding mucosa of the ileum and colon. The healing of the muscle layers was studied histologically. The function of the INS was investigated in six dogs and compared intraindividually with that of the ileocecal valve and conventional end to-end anastomosis. Morphologically the neospincters healed within 3 months without major fibrosis. The reference values of the aerobic and anaerobic bacterial counts in the terminal ileum were more than 2 logs lower than in the colon with the normal ileocecal valve, and after ileo-colonic end-to-end anastomosis bacterial colonization of the terminal ileum was found both qualitatively and quantitatively. Subsequent interposition of the INS led to bacterial clearance of the terminal ileum. The median aerobic bacterial counts were lower by six logs and the an aerobic bacterial counts by 3 logs than in the colon. However, differences were not statistically significant owing to the wide variation in the individual values. Nevertheless, the demonstrable clearance of the terminal ileum could be explained by the orthograde passage with absolutely no stagnation and the relative competence of the INS in resisting retrograde pressure competence. In conclusion, ultrasonic fragmentation of the serosa and mucosa of the bowel allows construction of an INS from three muscle layers, which acts as a bacteriological barrier. Before it is introduced into the clinical setting its integration into the intestinal motility should be evaluated by further studies. PMID- 7845164 TI - [Primary sarcoma of the liver in adults]. AB - Eleven adult patients with primary sarcoma of the liver underwent surgery at the University Hospital of Hamburg-Eppendorf between 1985 and January 1994. In 8 cases it was possible to resect the tumor with wide margins (R0), in 1 of these in the course of orthotopic liver transplantation. Three patients had primarily marginal resection (R1). By the end of the study period 7 of the patients who underwent initial R0 resection are tumor-free, with a mean survival time of 57 (5 104) months. The patient with orthotopic liver transplantation developed metastases 31 months after primary surgery. At 7 months after initial R1 resection, 1 patient is alive with no evidence of disease while 2 others died after 30 and 35 months, respectively. Patients with non-metastasized, primary sarcomas of the liver can expect long-term survival if the tumor is resected with wide margins in an anatomical hepatectomy. In the case of multifocal growth in the liver transplantation can be considered. PMID- 7845166 TI - [Gastrointestinal tumors: standards and perspectives]. PMID- 7845165 TI - Fungal infections in liver transplant recipients. AB - A retrospective analysis of 462 consecutive orthotopic liver transplantations was undertaken to evaluate incidence, risk factors, clinical course, and outcome of fungal infections. Infections involving Aspergillus (6 cases), Candida (5 cases), Mucor (1 case), and Cryptococcus (1 case) were observed in 2.8% (13/462) of our patients. Twelve of the 13 episodes developed during the first 2 postoperative months. None of the potential risk factors for fungal infections described by other authors (i.e., age, rejection treatment, dialysis, mechanical ventilation, graft failure, long operation time, second transplant, serious non-fungal infection) correlated significantly with the episodes in our patients. However, in patients who exhibited three or more of these potential risk factors the incidence of fungal infections was elevated (P < 0.001). Six of seven exogenous infections (Aspergillus, Mucor) began before July 1991 when our department moved from Charlottenburg to Wedding, thus indicating that the incidence of these infections is highly influenced by exposure (P = 0.01). Exposure prophylaxis should therefore by meticulously followed, particularly when severely compromised patients are involved, in order to prevent exogenous infections (i.e., Aspergillus/Mucor). Infections involving such patients are combined with a very high mortality (57%). We observed Candida infection as a pathological overgrowth of physiological oropharynx flora into the esophagus and/or trachea in five patients. In each case treatment led to full recovery. PMID- 7845167 TI - [Helicobacter pylori eradication therapy with omeprazole and amoxicillin: current status]. AB - Combined therapy with the proton pump inhibitor omeprazole and amoxicillin has become an important alternative in the treatment of ulcer disease associated with Helicobacter pylori infection. Due to the high efficacy in eradicating H.pylori, missing resistance of H.pylori against amoxicillin and high tolerability and digestibility this regimen may be recommended for widespread routine use. In a randomized, double-blind multicenter trial an H.pylori eradication rate of over 90% has been achieved for the first time by dual therapy using a daily omeprazole dose of 120 mg (3x40 mg) in combination with 3 x 750 mg amoxicillin for 14 days, which is comparable with classical triple therapy containing bismuth and two antibiotics. On the basis of an "intention-to-treat-analysis" dual therapy of omeprazole 3x40 mg + 3x750 mg amoxicillin is considered at present to be the most effective regimen for the treatment of H.pylori-associated diseases. PMID- 7845168 TI - [Surgical therapy of chronic pancreatitis: index-assisted evaluation of therapeutic success]. AB - Surgery for chronic pancreatitis is criticized as being too risky to treat an allegedly self-limiting disease. Therefore, analysis of treatment results after surgery is necessary. Relevant parameters are--besides late surgical complications--pain, exocrine and endocrine insufficiency, weight loss, regular medications, general fitness and ability to work, all of which have to be accounted for pre and postoperatively. All parameters were integrated into an outcome score. 64 patients were studied 3.5 years (median) after different surgical procedures for proven chronic pancreatitis. Efficient pain control was achieved with every procedure. Resection caused more often functional deficiencies. However, these patients felt generally fitter after surgery and more often worked full-time. The outcome score demonstrated different results for the various procedures. Especially the risk-benefit ratio of cystoenterostomies can probably be improved by percutaneous drainage techniques. PMID- 7845169 TI - [Mechanisms for cell damage in acute pancreatitis using isolated acinar cells]. AB - Due to the complexity of interacting organ systems, in vivo the interpretation of results obtained from whole-animal experiments of acute pancreatitis remains difficult. To enlighten cause-and-effect-relationships, functional isolated parts of the pancreas are applied increasingly in research into the pathogenesis of the disease, therefore. By means of a collagenase digestion technique, intact acinar cells from normal as well as from pretreated rat pancreas could reproducibly be obtained in high yield. Animals were pretreated in situ by induction of either mesenteric ischemia/reperfusion, juice edema, or acute pancreatitis (AP). Pancreatic acinar cells isolated from these pretreated rats consumed oxygen at comparable rates under resting conditions throughout all experimental groups. A reduced stress capacity of cell respiration as well as a preterm decline in short term culture was observed in the cells of the AP group, however. These results demonstrate that the induction of AP has found its reflection within the acinar cells themselves. Interestingly, these effects were not clouded by the isolation procedure. The manner of in-situ pretreatment of the respective animal proved to be decisive for later viability of isolated acinar cells in short-term culture. Uncoupling of oxidative phosphorylation by 2,4-dinitrophenol (DNP) lead to an accelerated decline of the acinar cells in all groups. The intactness of cellular energy metabolism seems to play a crucial role in maintaining cellular integrity, therefore. In additional experiments in vitro, the intracellularly mediated cell damage by DNP was compared with one induced from the extracellular environment of isolated cells by antibodies directed against cell surface antigens plus complement.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845170 TI - [Cost-benefit analysis of conservative therapy of gastritis and ulcer disease]. PMID- 7845171 TI - Alcohol and motor vehicle accidents in the National Capital District of Papua New Guinea. AB - Alcohol consumption is a major cause of motor vehicle accidents worldwide. This study was undertaken to determine the magnitude of alcohol related accidents in Port Moresby, the capital of Papua New Guinea. A total of 104 motor vehicle accidents occurred in a nine-month period involving 188 people. More alcohol related accidents occurred at night and on weekends, particularly pay weekends. There is a need to carry out an awareness campaign about drinking and driving in the community and to establish random alcohol testing for drivers. PMID- 7845172 TI - The anatomy of violence. AB - The aim of this article is to analyse the causes and background of violence in the light of the increasing incidence internationally of both group and interpersonal violence. The author classifies violence according to types and causes. Comparative statistics are quoted to illustrate the incidence of violence in the author's experience and in some other countries. Indications are that violence is multifactorial in aetiology and suggestions are made how the incidence of violence may be reduced. PMID- 7845173 TI - Behaviour modification by genetic intervention--the law's response. AB - The Human Genome Initiative has stimulated research worldwide into mankind's genetic structure. It has led to identifying and understanding the function of many genes which cause illnesses, deformities, organ malfunctions and, more recently, behavioural aberrations. The science of gene therapy has developed in tandem and has initiated therapeutic treatment by the replacement of defective genes in humans. In the legal sphere guidelines for the application of gene therapy have been recommended by the Council of Europe, the United Kingdom, France, Denmark and the United States amongst others. South Africa has adopted the guidelines of the American National Institutes of Health. It is however submitted that third world countries such as South Africa have many other more basic health care problems on which to spend their limited resources despite having the technology to practise gene therapy. PMID- 7845174 TI - The role of legislation in health services development (with particular reference to China and Australia). AB - The World Health Organization has supported initiatives in many countries including China to improve the effectiveness and quality of legislation as a form of technical support to help achieve and consolidate the global strategy of health for all by the year 2000. These initiatives are reviewed. Traditionally China did not rely much on legislation as a technique to underpin and implement the organization and delivery of health services, but it appears that more use will be made of it in the future for a number of reasons, including the implementation of the momentous decision of the National People's Congress in October 1992 to move towards a 'socialist market economy'. PMID- 7845175 TI - The application of the forensic sciences to human rights investigations. AB - Prior to the mid-1980's, human rights abuses were documented almost entirely through witness and victim testimony. In 1984-85, forensic scientists from the United States, working under the auspices of the American Association for the Advancement of Science, exhumed skeletal remains of disappeared persons in Argentina. They provided physical evidence for the trial of members of the deposed military junta and trained an Argentine forensic anthropology team. It became apparent that medical and forensic verification of torture and extrajudicial executions could provide irrefutable evidence that such activities had, in fact, taken place. Requests for assistance came from human rights groups throughout the world, and led to the development of an international protocol for the investigation of government sponsored murders. The United States based Physicians for Human Rights has now conducted missions to nearly 30 countries. The recent documentation of mass graves in El Salvador, Guatemala, Iraqi Kurdistan and the former Yugoslavia demonstrates how forensic scientists expose such crimes to international scrutiny, and the necessity of scientific evidence when confronting human rights violations. PMID- 7845176 TI - Medicolegal problems associated with do not resuscitate orders. AB - The use and potential abuse of the do not resuscitate (DNR) order has wide ranging ethical, legal and economic implications. A DNR order is essential for clear communication between health care professionals, but the order itself may affect the care that patients subsequently receive. In addition, the DNR order may be a crucial therapeutic decision point in the care of the critically ill. Although general guidelines exist for withholding resuscitative measures from the terminally ill and general principles have been established, Spanish legislation is ambiguous on a number of points, forcing medical professionals to make difficult choices. This has led to the systematic, indiscriminate application of resuscitative measures, motivated in many cases by the desire to avoid a possible future lawsuit. We believe clearer and more precise legislation should be developed to bring Spanish criteria into line with those of international organizations that provide a common set of guidelines on important issues relating to the right to life and the right to refuse treatment. PMID- 7845177 TI - Informed consent: information about the physician. AB - Does the doctrine of 'informed consent' require disclosure about the physician? Recent developments indicate that the doctrine requires information not only about the treatment but also about the physician. There is also modification in the requirement of proof of a causal nexus between the lack of informed consent and injury. PMID- 7845178 TI - Preparing a child witness in sex abuse cases: the destruction and re-creation of testimony. AB - Although dominant wisdom concerning child witnesses would have us believe that a child is not as competent as an adult in the exercise of memory and recall functions, recent research has shown the opposite to be true. However, it has also been shown that children do not process information in the same way as adults. This does not make them less reliable witnesses. It simply means that children who testify should be treated differently from adults. If a child's evidence is elicited in a correct and suitable manner, its testimony will be as competent as an in certain respects superior to an adult's. The South African Law Commission recognized the need for child witnesses to be protected from what is often a harsh and unsympathetic judicial system, and its recommendations resulted in the Criminal Law Amendment Act 135 of 1991 which became effective on 30 July 1993. The act introduced two novel concepts to the South African law of evidence: the closed-circuit video-link which enables a child to testify in a room removed from the courtroom, and the appointment of a suitably qualified person to act as an intermediary between the court and the child. It is submitted that the commission should have used the opportunity to modify the existing law concerning the admissibility of videotaped statements further, and perhaps more importantly, to formulate a code of practice to be incorporated into the act to regulate the substantive and technical content of videotaped interviews with child victims, thereby ensuring the rights of both the accused and the child victim. PMID- 7845179 TI - Removal of life support in intensive care units. AB - Advancements in techniques of medical technology have made it possible to postpone death, which, in many situations, amounts to nothing more than a protracted process of dying rather than a prolonging of life. This, together with the fact that these techniques are prohibitively expensive has brought to the fore difficult and extremely uncomfortable problems in medical ethics, especially with regard to who should have and who should not have high technology medical treatment. The principles of autonomy and informed consent, in the context of a shared resource such as intensive care, are particularly thorny issues. Normally it is imperative that individuals make their own autonomous decisions in respect of medical treatment but there are times when consent is of secondary importance and when autonomy must of necessity be limited. However, information concerning medical decisions in intensive care should always be freely available to patients and their surrogates. PMID- 7845180 TI - 'Necklace murders': a review of a series of cases examined in a Port Elizabeth mortuary. AB - This article reviews a series of 135 murders labelled 'necklace murders'. The period under review is that from 1 January 1985 to 31 December 1987. An attempt was made to look at the sociopolitical and historical factors which contributed to this phenomenon. Finally, a case report illustrating the value of a 'team approach' to the performance of autopsies on these victims is presented. PMID- 7845181 TI - Cases of death caused by gas or warning firearms. AB - Five cases of lethal injuries caused by gas or warning firearms are discussed. In one suicide case a modified weapon (elongated barrel) and steel bullets were used to fire a shot into the head, the bullets lodged in the skull and lethal bleeding resulted. In the other cases conventional gas weapons without evidence of alteration were used for contact shots; injuries were caused by the effect of propelling powder gases. Two of these cases were suicides (temporal contact shot and back of the neck contact shot), one was an accident (inguinal contact shot with lethal bleeding), and one was an attack by another person with a contact shot against the neck with bilateral tears of the hypopharynx. After successful surgery, a delayed death occurred 12 days later caused by bleeding into the airways from the ruptured external carotid artery. PMID- 7845182 TI - Forensic pathology--a different perspective: investigative medicolegal systems in the United States. AB - The author's experience and impressions of the proceedings of the Office of the Medical Examiner, Cook County, Chicago, Illinois, United States of America are discussed. This experience demonstrates the limitations of the South African medicolegal system, particularly its lack of credibility among the greater proportion of the community. The medical examiner's office in the United States, being independent, enjoys credibility and the confidence of the community at large and of the courts, without alienating the police or other law enforcement agencies. These organizations feature in the medical examiner system by courtesy of the chief medical examiner. In the United States two types of investigative medicolegal systems coexist, sometimes in the same state or adjacent country: the coroner system (unlike the English coroner system) and the medical examiner system. Of the two, the coroner system is the older, is not always headed by a medically trained person, and is a political appointment. This system has been accused of lacking autonomy and scientific objectivity. PMID- 7845183 TI - Human communication is an essential tool in legal and ethical issues concerning doctor and nurse relationships. PMID- 7845184 TI - Nurses and the management of death, dying and euthanasia. AB - This article is one of two which report findings of research which examined the attitudes and practices of health professionals in South Australia towards the management of death, dying and euthanasia. The focus in this article is on findings related to nurses. Conducted in August 1991, mail-back, self administered questionnaires were posted to a sample of 500 nurses on the general nurses register held by the Nurses Board of South Australia. A total response rate of 57.8% was obtained, and 55% (278) were usable returns. The survey found that 47% of the respondents had received requests from patients to hasten their deaths by withdrawing treatment, and 30% had received request from patients for active euthanasia. 'Persistent and irrelievable pain' was the main reason for such requests. The majority either would or did discuss such requests with relatives, other medical practitioners and nursing staff. Nineteen per cent had taken active steps which had brought about the death of a patient. Eighty-two per cent thought that guidelines for withholding and withdrawal of treatment should be established. Sixty per cent were in favour of legalization of active euthanasia under certain circumstances. PMID- 7845185 TI - The delusion based will: the question of validity. AB - The psychiatric evaluation of the testamentary capacities of a delusional person may be hindered by (a) the cognitive, emotional and situational factors affecting the evaluator during the execution of her or his task, and (b) the sometimes very difficult challenge of proving testament invalidity due to the presence of delusions. As an illustration, this article presents a specific case which was recently brought to court in Israel. PMID- 7845186 TI - Goals of institutional therapy of sexual delinquents. AB - Sexology departments in Czech psychiatric institutions have been established, mainly to protect society from delinquent sexual deviants. The methods used to attain this therapeutic goal are discussed. The author concludes that sexology departments have been relatively successful. PMID- 7845187 TI - Antioxidants and disease prevention. PMID- 7845188 TI - Prelamination: defining the prefabricated flap--a case report and review. AB - Modification of flaps prior to local or distant transfer has gained wide acceptance. The term prefabricated has been used to describe all possible modifications. In this article we introduce the term prelamination to refer to the implantation of tissue or other devices into a flap prior to transfer and suggest that prefabrication be restricted to the implantation of vascular pedicles. A case is presented illustrating these concepts. PMID- 7845189 TI - Manipulating prefabricated flaps: an experimental study examining flap viability. AB - As flap prefabrication becomes a more commonly used clinical tool, it is necessary to investigate the limitations of this technique. Reconstructive procedures of the face often require "custom fitted" flaps to satisfy esthetic demands. This study examines and compares the safety of manipulating thin prefabricated skin flaps versus established axial pattern skin flaps. Twenty seven New Zealand white rabbits were used to determine if prefabricated flaps can be folded 180 degrees around the edge of the rabbits' ears. The survival of these folded prefabricated flaps was compared with the survival of axial pattern flaps sutured into an identically recipient site. In addition, flaps prefabricated in the same manner were sutured onto a straight recipient bed to evaluate the viability of the newly vascularized tissue. The folded prefabricated flaps had reduced survival (56%) compared to equivalent folded axial pattern flaps (85%), P < 0.005. The nonmanipulated prefabricated flaps and axial pattern flaps survived completely. PMID- 7845190 TI - Current status of topical antithrombotic agents in microvascular surgery. AB - Several technical advances over the years have allowed microsurgery to be successful. However, thrombosis, particularly at the anastomosis site, remains a complication of microvascular surgery. Various preventive measures, including drugs, have been used to improve microvascular surgical anastomotic patency rates. The purpose of this article is to review the literature and the current status of topical antithrombotic agents. From this review along with laboratory investigations it is concluded that a combination of topical as well as systemic agents offers the best patency rates. However, the "ideal" antithrombotic agent is yet to be discovered and investigations need to be continued in order to improve or eliminate the complication of microvascular thrombosis. But the importance of atraumatic technique cannot be overemphasized. PMID- 7845191 TI - Reconstruction of refractory defect of scalp and skull using microsurgical free flap transfer. AB - Ten patients--six with acute burns, two with old accident or surgical trauma, and two with cranial carcinoma--experienced extensive full-thickness necrosis of the scalp and necrosis or defect of underlying skull bone. Microsurgical free flaps were used for the repair. Four latissimus dorsi, two rectus abdominis, one greater omentum, one prefabricated omentum-cutaneous flap, and two vascularized outer-table of the cranial bone flaps were used with complete survival. The heat devitalized cranial bone covered by living tissue flaps healed well and substantial "regeneration" of previously necrosed bone was shown by roentgenogram, bone scan, and histopathological examination in the postoperative follow-up. Choosing an artery with high perfusion, bypassing from the carotid artery to support a massive free flap, is recommended. PMID- 7845192 TI - Microvascular replantation of a completely avulsed scalp. AB - Total scalp avulsion is an unusual injury. To obtain good functional and cosmetic results, immediate revascularization using microsurgical techniques and replacement of the scalp in the correct anatomical position is the procedure of choice. This article describes a case report of successful replantation of a totally avulsed scalp from a 26-year-old male. Bilateral superficial temporal vessel anastomoses were performed using reversed autologous long saphenous vein grafts on the right side and direct repair on the left. Points of technique are discussed and the literature is reviewed. PMID- 7845193 TI - Digital reconstruction by free microvascular transfer of two fingers as a unit from the contralateral paralyzed hand. AB - The ideal reconstruction for damaged or missing fingers has yet to be achieved. While toe transfer offers an excellent option for reconstruction of the thumb, this type of reconstruction often falls short in replacement of other digits of the hand. Microsurgical transfer of a finger or fingers from the opposite hand offers an option, but is rarely performed due to the morbidity in the donor hand. The case of a patient with a paralyzed, but otherwise normal, opposite hand presents a unique opportunity to repair the contralateral damaged but innervated hand. This case report deals with such a patient in whom two fingers were moved from a paralyzed hand to replace two traumatically missing digits in his previously normal hand. Technical considerations will be discussed and the result at 33 months will be presented. PMID- 7845194 TI - Effects of combined cold and hyperbaric oxygen storage on free flap survival. AB - We have previously reported that hyberbaric oxygen (HBO) improved the survival rate of experimental free flaps. The purpose of this study was to evaluate the effects of combined hypothermia and HBO administered during storage on free flaps and on the xanthine oxidase system in rats. Epigastric skin flaps were stored cold for 48 and 72 hours either in room air or under HBO (2.9 atmospheres absolute, 100% oxygen) before free flap transfer. The success rates of free flaps were 80% (8/10) after 48 hours and 20% (2/10) after 72 hours of cold storage in room air. HBO produced no effect after 48 hours but significantly increased the success rate to 70% (7/10) after 72 hours of cold storage. Tissue hypoxanthine (plus xanthine) levels increased to 210% of normal after 48 hours of cold storage in room air and to 176% in HBO. Elevated hypoxanthine levels returned toward normal by 72 hours of cold storage in room air, while the increased levels remained under HBO. Xanthine oxidase activities significantly increased by 60 to 80% during 72 hours of room air storage. HBO treatment inhibited xanthine oxidase activity to 48% of normal by 72 hours of storage. Free flaps exhibited no significant alterations in GR and G6PDH activity after 48 hours of cold storage in room air or HBO. After 72 hours of cold storage, the room air control displayed a trend of decreasing GR activity and a significant 20% decrease in G6PDH activity, while HBO groups showed no significant alterations in both GR and G6PDH activity compared to normal. Protection of the antioxidative enzymes by hypothermia and inhibition of the xanthine oxidase activity by HBO appear to be one of the mechanisms of improved skin flap survival in free flaps. PMID- 7845195 TI - Age and tolerance to secondary ischemia in rat epigastric flaps. AB - The use of microvascular procedures is increasing as the population continues to age. The purpose of this study was to observe the survival of skin flaps after ischemic injury. Skin flaps (n = 50) underwent either 3 hours of primary (1 degree) or secondary (2 degrees) venous occlusion in young (2-3 mo) and old (18 22 mo) rats. Skin flap survival was assessed on postoperative day 7. Survival rates for young and old after 3 hours of 1 degree ischemia was 100% and 90% (ns). Survival rats for young and old after 2 degrees ischemia were 67% and 47% (ns). PMID- 7845196 TI - Microsurgical model of ischemia reperfusion in rat muscle: evidence of free radical formation by spin trapping. AB - The purpose of developing the experimental model described in this study was to verify the hypothesis that free radicals are formed during ischemia-reperfusion of skeletal muscle. Spin trapping technique, along with electron spin resonance spectroscopy (ESR), directly indicates the presence of reactive radicals, which are widely considered to be important in tissue injury. The experimental model was a rat pedicled rectus femoris muscle flap. The femoral artery and vein were cannulated to inject the "spin trap" and collect the effluent flow. The spin trap agent was phenyl-t-butyl nitrone (PBN) and Hank's balanced salt solution. Three injections and collections were made: a) before ischemia; b) after ischemia of 15, 30, 60, 120, and 180 minutes, but before blood flow had been restored; and c) after blood flow had been restored. No ESR signal was detected either before the ischemic period or after only 15 minutes of ischemia. PBN radical adducts were detected after 30, 60, 120, and 180 minutes of ischemia. A similar signal was detected when PBN was injected during reperfusion 10 minutes after the ischemic periods. The study demonstrated the presence of free radicals in an in vivo intact skeletal muscle ischemia-reperfusion model. PMID- 7845197 TI - Free prepared composite forearm flap transfer for ear reconstruction: three case reports. PMID- 7845199 TI - Classification of peptidases. PMID- 7845198 TI - Experimental study on vascularized bone allografts for reconstruction of massive bone defects. AB - To study the healing mechanism of vascularized bone allografts under short-term as well as long-term immunosuppression with cyclosporin A, experimental vascularized intercalary bone allograft transplantation was carried out between inbred rats using the tibiofibula graft model. Bone scintigram and radiographs were used as an indicator for early detection of rejection after transplantation and bone union. In vascularized bone allografts under long-term immunosuppression with cyclosporin A, early bone union and continuous incorporation were similar to that observed in vascularized bone autograft transplantation. When administration of cyclosporin A was discontinued before completion of bone union, the graft was rejected and bone union was delayed. Apparent swelling on the operated limb associated with a decrease in bone scintigram uptake suggested the occurrence of rejection of the allograft. Vascularized bone allograft transplantation is useful for reconstruction of massive bone defects only if immunosuppressants are used and maintained at least until bone union is obtained. PMID- 7845200 TI - Hepsin. PMID- 7845201 TI - Glutamyl endopeptidases. PMID- 7845202 TI - Lysyl endopeptidase of Achromobacter lyticus. PMID- 7845203 TI - IgA-specific prolyl endopeptidases: serine type. PMID- 7845204 TI - Biochemical and genetic methods for analyzing specificity and activity of a precursor-processing enzyme: yeast Kex2 protease, kexin. PMID- 7845205 TI - Purification of recombinant soluble forms of furin produced in Chinese hamster ovary cells. PMID- 7845206 TI - Pro-protein convertases of subtilisin/kexin family. PMID- 7845207 TI - Prolyl oligopeptidases. PMID- 7845208 TI - Families of serine peptidases. PMID- 7845209 TI - Oligopeptidase B: protease II from Escherichia coli. PMID- 7845210 TI - Dipeptidyl-peptidase IV from rat liver. PMID- 7845211 TI - Acylaminoacyl-peptidase. PMID- 7845212 TI - Carboxypeptidases C and D. PMID- 7845213 TI - Serine-type D-Ala-D-Ala peptidases and penicillin-binding proteins. PMID- 7845214 TI - Cleavage of LexA repressor. PMID- 7845215 TI - Bacterial leader peptidase 1. PMID- 7845216 TI - Eukaryote microsomal signal peptidases. PMID- 7845217 TI - Endopeptidase Clp: ATP-dependent Clp protease from Escherichia coli. PMID- 7845218 TI - Multicatalytic endopeptidase complex: proteasome. PMID- 7845219 TI - ATP-dependent protease La (lon) from Escherichia coli. PMID- 7845220 TI - Mitochondrial ATP-dependent protease from rat liver and yeast. PMID- 7845221 TI - Omptin: an Escherichia coli outer membrane proteinase that activates plasminogen. PMID- 7845222 TI - Transient transfection assay of the herpesvirus maturational proteinase, assemblin. PMID- 7845223 TI - Purification and kinetic characterization of human cytomegalovirus assemblin. PMID- 7845224 TI - Amino acid and peptide phosphonate derivatives as specific inhibitors of serine peptidases. PMID- 7845225 TI - Isocoumarin inhibitors of serine peptidases. PMID- 7845226 TI - Families of cysteine peptidases. PMID- 7845227 TI - Catalytic mechanism in papain family of cysteine peptidases. PMID- 7845228 TI - Cathepsin S and related lysosomal endopeptidases. PMID- 7845229 TI - Cysteine endopeptidases of Entamoeba histolytica. PMID- 7845230 TI - Cysteine endopeptidases of parasitic protozoa. PMID- 7845231 TI - Glycyl endopeptidase. PMID- 7845232 TI - Pineapple cysteine endopeptidases. PMID- 7845233 TI - Cancer procoagulant. AB - Cancer procoagulant is a unique cysteine proteinase. The enzyme has been purified by several procedures and many of its characteristics and enzymatic properties have been determined. Several sensitive and reproducible assays are now available. Many proteinase inhibitors have been evaluated for their effect on CP; most low molecular weight inhibitors work well in a reduced environment. In the foreseeable future, protein and gene sequence information, expression vectors, molecular probes, and highly specific antibodies and inhibitors should provide the research tools to delineate a functional understanding of CP at the molecular and cellular level. PMID- 7845234 TI - Picornains 2A and 3C. PMID- 7845235 TI - Adenovirus endopeptidases. PMID- 7845236 TI - Legumain: asparaginyl endopeptidase. PMID- 7845237 TI - Myeloblastin: leukocyte proteinase 3. PMID- 7845238 TI - Interleukin-1 beta converting enzyme. PMID- 7845239 TI - Isoprenylated protein endopeptidase. PMID- 7845240 TI - Affinity chromatography of cysteine peptidases. PMID- 7845241 TI - Peptidyl diazomethanes as inhibitors of cysteine and serine proteinases. PMID- 7845242 TI - Peptidyl (acyloxy)methanes as quiescent affinity labels for cysteine proteinases. PMID- 7845243 TI - N,O-diacyl hydroxamates as selective and irreversible inhibitors of cysteine proteinases. PMID- 7845244 TI - Granzyme A. PMID- 7845245 TI - Cystatins. PMID- 7845246 TI - Granzyme B. PMID- 7845247 TI - Tryptase: a mast cell serine protease. PMID- 7845248 TI - [Reactivation of UV inactivated Escherichia coli cell extracts of propionic acid bacteria: fractionation of the extract]. AB - Cell free extract from Propionibacterium shermanii VKM-101 partially reactivates Escherichia coli AB 1157 irradiated by UV light. Fractionation of extract followed by the estimation of protective effect of fractions showed that this effect is linked to two fractions of soluble proteins. The fraction of cell walls, ribosomes and nucleic acids were poorly effective. Two active protein fractions (I-20-40% (NH4)SO4 and II-60-80% (NH4)2SO4) were separated by HPLC chromatography into 7 and 8 subfractions respectively. The activity was localised in subfraction N4 (fraction I) and N5.6 (fraction II). PMID- 7845249 TI - [Regulation of microbiologic processes in the rumen of ruminants by bacteriophages of Streptococcus bovis]. AB - Influence of bacteriophages of Streptococcus bovis on microbial activity in the rumen was investigated in experiments on cows. Main elements of the mechanism of bacteriophage action on the microflora have been detected. The daily feeding with bacteriophages results in productive infection of sensitive to them rumen bacteria and is associated with increasing bacteriophage concentration in the rumen contents, lower number and activity of amylolytic bacteria, higher cellolytic activity and increased number of bacteria utilizing xylan, cellobiose and xylose. The fermentation is usually shifted to a higher production of propionate and butyrate at the expense of lower acetate. The regulating action of a single bacteriophage feeding on the rumen microflora and its metabolic activity stops on the fifth day. Daily introduction of bacteriophages into the ration of cows under moderate or high levels of feed increases the milk fat by 0.1-0.3%. PMID- 7845250 TI - [Sulfurococcus yellowstonii sp. nov/--a new species of iron- and sulfur-oxidizing thermoacidophilic Archaeobacterium]. AB - A spheric thermoacidophilic sulphur-oxidizing archaebacterium (strain Str6kar) has been isolated from the hydrotherm of the Yellowstone National Park (USA). The isolate is a facultative autotroph. The strain Str6kar oxidizes elemental sulfur, ferrous sulfate and sulphide minerals, it is capable of using some organic compounds. The isolate grows at the temperature of 40-80 degrees. The content of GC-pairs in the DNA of the bacterium is 44.6 mol%. The level of homology of the isolates DNA for the Str6kar and Sulfurococcus mirabilis is 12-15%, for Str6kar and Metallosphaera sedula-0.7-7%. According to the structure of the 5s rRNA, the described bacteria are similar to S. mirabilis. Basing on morphological, physiological and molecular-genetical features, this archaeobacterium can be presented as a new species of the genus of Sulfurococcus-S. yellowstonii sp. nov. PMID- 7845251 TI - Continuing medical education in Europe: a survey. AB - The Continuing Medical Education (CME) in Europe Project is conducted by the World Federation for Medical Education, in conjunction with the Association for Medical Education in Europe, the Association for Medical Deans in Europe, and the European Office of the World Health Organization, with Upjohn Medical Sciences Liaison Division. The aim of the Project is to promote the development of CME in all European countries. It also has global relevance: all six Regions participated in initiating the Project, and its progress and outcomes will be generalized to the other five Regions. This Project coordinates information about the important developments in CME in all countries of Europe. In addition to this coordinating function, the Project has a dissemination function, promoting knowledge about good examples and CME experience (demonstration projects) in the countries of Europe. A survey was made of the methods of CME in each country, the informants being the members of the Project's CME Task Force. It consists of nominated representatives from the National Associations for Medical Education of countries in the European Region. PMID- 7845252 TI - Linking the university with the community and its health system. AB - Over many years Latin American universities have operated 'extension projects' in their surrounding communities. These projects, in health professions schools, frequently involved the establishment of community-based health centres operated by the university. Since the early 1970s, a large number of health professions schools entered into agreements with local or regional health systems for the operation of projects of 'articulation of teaching and services' in well-defined geographic areas. The primary health care strategy emphasized by WHO and actively promoted by national governments since the Alma Ata Declaration of 1978 led to a worldwide movement toward effective 'community participation' in each own local health system. An assessment of these initiatives, involving three types of paired relationships (university-community; university-local health system; local health system-community) provided the idea and the experiential basis for an innovative programme bringing the three partners together in a joint effort. Program UNT was set up and now includes 23 projects which are partially supported by the Kellogg Foundation. They all share a common set of ideas and ideals, emanating from the Alma Ata and Edinburgh Declarations, and are currently being implemented in 11 countries of Latin America. PMID- 7845253 TI - Medical education change: a detailed study of six medical schools. AB - This article reports a comparative case study of six selected USA medical schools, undertaken to identify factors that facilitate or obstruct innovation in medical education. The findings suggest that the culture of each medical school results from a combination of intra-institutional and external factors. Together these forces influence substantially the fate of educational innovations. The institutional culture influences critical elements such as educational philosophy, leadership and resources provided in support of innovation. Equally important, the culture shapes the level and type of change a school considers and implements. The findings also suggest that the availability of resources and the creative impetus present in schools giving priority to research can benefit the educational goals and facilitate educational change. PMID- 7845254 TI - Determinants of career choices among women and men medical students and interns. AB - Women continue to be poorly represented in medical specialties other than general practice. A cross-sectional design was used to explore the development of career plans as medical training progressed; men and women students were compared in their first (n = 316), final (n = 295) and intern (n = 292) years. Women at each stage of training were significantly more likely to choose general practice as the field in which they were most likely to practise. There was little evidence that these differences were influenced by experience during training: women were as likely to choose general practice in first year as in the intern year. The most important determinant of career choice appeared to be the flexibility of training and of practice of medicine: variables such as the opportunity for part time training, flexible working hours and part-time practice were important determinants of career choice and were of more importance to women than to men. The study also found high rates of discrimination or harassment reported by women medical students and interns. The results indicate the need for continued debate about these issues within medicine and the development of more flexible styles of medical training and practice. PMID- 7845255 TI - What drives the student in problem-based learning? AB - In problem-based learning, the development of self-directed learning skills is encouraged through confronting students with (professional) problems. However, several other elements of a problem-based curriculum, such as general teaching objectives, lectures and tutors, may have an impact on students' actual learning activities. The present study focuses on the extent to which various elements of a problem-based curriculum influence students' decisions on what to study. First, interviews were conducted to obtain qualitative data about what actually takes place when students initiate learning activities during self-study. Based on the findings of these interviews, a questionnaire was developed, consisting of statements describing elements of the learning process and their influence on student learning. Elements included in the questionnaire were: the discussion in the tutorial group, content tested, course objectives, lectures, the tutor and reference literature. The students reported that all these elements may have an impact on decisions on what to study. Moreover, first-year students tend to rely more on the literature cited in the references list and content covered in lectures and tests than students in the other three curriculum years. In general, the influence of these elements showed a decrease over the four curriculum years. The influence of the discussion in the tutorial group, on the contrary, tended to increase over the four curriculum years. These findings suggest that students in a problem-based curriculum become more accomplished self-directed learners over the four curriculum years, even although they are provided with many clues which may play a role in their decisions on what to study. PMID- 7845256 TI - Computer skills and attitudes to computer-aided learning among medical students. AB - One hundred and forty-four third-year medical students at the University of Edinburgh were surveyed as to levels of computing skills and confidence in carrying out computing tasks. Attitudes to computer-aided learning for clinical teaching were also measured. Thirty-one per cent of students had not used a computer in the previous year and 38% had not used a computer outside supervised laboratory work. Twenty-two per cent had never used the university library computerized catalogue and 43% had never carried out a medline search using the library CD-ROM. Students were not confident of their ability to carry out simple computing tasks. Fifty-four per cent said they would need support or instruction in printing out a document, 69% were not confident they could copy a file onto a disk and 74% did not believe they could independently create a graph in a document. Students who had completed an intercalated honours year were significantly more skilled and confident in computing tasks. Attitudes to computer-aided learning were related to computing confidence. Medical students who have not acquired basic computer information technology (IT) skills by the third year of undergraduate training are unlikely to do so in the final hospital based years. Undergraduate curricula for medical students must incorporate specific computer (IT) training. PMID- 7845257 TI - Teaching disability and rehabilitation to medical students. Steering Group on Medical Education and Disability. AB - A survey of UK medical schools was undertaken to determine the teaching that was being offered on disability and rehabilitation. In general, teaching on this topic appeared fragmented and inadequate but a number of interesting innovations were identified. These included: a drama workshop run by a group whose members mainly have learning disabilities at St George's Medical School, student-directed learning at the University of Dundee and structured teaching programmes at the Universities of Leeds and Edinburgh. The General Medical Council Education Committee's 1991 discussion document on the undergraduate curriculum specifically mentions disability as an important topic. A number of schools mentioned that they were in the process of revising their curriculum as a consequence. Recommendations arising from the findings of the survey include integration of disability and rehabilitation into clinical teaching, focus of teaching on those types of disability which are common in the community, greater emphasis on functional assessment in teaching the physical examination, and the wider use of standard assessment instruments, for example for activities of daily living, cognitive impairment and locomotor disability. There is a need for improved communication between medical schools to facilitate the spread of educational activities on this topic. PMID- 7845259 TI - Evaluating and improving multiple choice papers: true-false questions in public health medicine. AB - The quality of a multiple true-false (MTF) examination paper in public health medicine for 149 clinical medical students was evaluated using predefined performance criteria to offer guidelines for improvement of such a paper. There were 35 questions, each with five true-false branches, and the performance of the overall best 25% of candidates was compared for individual items with that of the overall worst 25%. To improve discrimination between best and worst candidates, 60% of items needed changes, and several indicators were used to identify how, usually because the branch was too easy (26%), unpopular (16%) or too hard (10%). A number of guidelines for writing good MTF questions and for improving them are suggested. The inequity is illustrated of marking systems which do not allocate a negative mark for incorrect answers equal in size to the positive mark for correct ones, with zero for unanswered questions or 'don't know' answers. PMID- 7845258 TI - Formative assessment: a student perspective. AB - An educator's view would be that formative assessment has an important role in the learning process. This study was carried out to obtain a student perspective of the place of formative assessment in the curriculum. Final-year medical students at Royal Prince Alfred Hospital took part in four teaching sessions, each structured to integrate teaching with assessment. Three assessment methods were used; the group objective structured clinical examination (G-OSCE), structured short answer (SSA) questions and a pre/post-test multiple choice questionnaire (MCQ). Teaching sessions were conducted on the subject areas of traumatology, the 'acute abdomen', arterial disorders and cancer. Fifty-five students, representing 83% of those who took part in the programme, responded to a questionnaire where they were asked to rate (on a 5-point Likert scale) their response to general questions about formative assessment and 13 specific questions concerning the comparative value of the three assessment modalities. Eighty-nine per cent of respondents felt that formative assessment should be incorporated into the teaching process. The SSA assessment was regarded as the preferred modality to reinforce previous teaching and test problem-solving skills. The MCQ was the least favoured assessment method. The effect size variable between the total scores for the SSA and MCQ was 0.64. The variable between G-OSCE and SSA/MCQ was 0.26 and 0.33 respectively. Formative assessment is a potentially powerful method to direct learning behaviour. Students should have input into the methods used. PMID- 7845260 TI - Multiple choice question tests in physiology: a preliminary attempt to apply the minimum pass level. AB - At the mid-term test in Part I Physiology at the University of Zagreb the students (n = 280) were graded by our standard pass level (SPL) arbitrarily set at 54% correct answers (SPL = 0.54). The test consisted of 50 items of the one best answer type. Items were selected from the pool by one examiner to conform, by his judgement, to the predetermined SPL. Post hoc the minimum pass level (MPL) was assessed independently by eight examiners and an MPL value of 0.60 for the whole test was obtained. The original Nedelsky scale was used in assessment of MPL but for statistical analysis the data was expressed as log(1/MPL) to linearize the scale of measurements and to reduce the variances. The data showed a large difference between examiners in their assessment of MPL. Nevertheless, the average log(1/MPL) value of individual items showed a significant negative linear relationship with the item difficulty indices as calculated from student's answers, indicating that despite the large heterogenity in assessment the average item log(1/MPL) may be acceptable as a reasonable prediction of item difficulty. Finally, 'subtests' were formed from the whole test by grouping items according to their log(1/MPL) value. The passing rate at these subtests was found to be identical despite the fact that they considerably differed in their MPL values. Therefore, the MPL value seems to be useful in setting objective standards for the decision of pass or fail, even when the MPL was assessed in a very heterogenous way. PMID- 7845261 TI - Medical graduates evaluate the effectiveness of their education. AB - In response to the General Medical Council's 1991 Consultative Document proposing changes to medical curricula, the King's College School of Medicine and Dentistry, London, established a steering group to plan a new curriculum. As part of this process a postal survey was undertaken of five cohorts of King's graduates to ascertain how well the medical course they had undertaken had equipped them for practice. The questionnaire explored the level of factual content, the adequacy of their skills training, and the development of personal attributes during the course. A total of 371 graduates replied, a response rate of 78%. Over 70% indicated that their education had satisfactorily equipped them for their medical practice. Significant differences were found, however, between those now practising in primary care and those in hospital medicine regarding the importance attached to different subjects within the curriculum, and also with respect to the personal attributes the graduates felt they had acquired. Both groups identified deficiencies in virtually all aspects of their skills training: clinical, analytical, communication, management and technical. This feedback from some of the 'consumers' of medical education is now being used to assist the planning of the new King's curriculum. PMID- 7845262 TI - Assessing the competence of general practitioners in diagnosing generalized anxiety disorder using standardized patients. AB - The competence of general practitioners (GPs) in diagnosing anxiety neurosis was assessed using standardized patients (SPs) unknown to the doctors. Out of a computer-generated random sample of 100 general practitioners in Kuala Lumpur, 42 volunteered to participate in the study. The results showed that the GPs can be divided into three groups: group A made the correct diagnosis and informed the SPs about their condition (11.9%); group B prescribed tranquillizers and did not inform the SPs of the actual diagnosis but instead said that they were either normal or were suffering from some stress (28.6%); and group C made various diagnoses of physical disorder or did not detect any abnormality at all (59.5%). Thus about 40% of the doctors considered an emotion-related disorder and only 12% of the doctors were confident enough to make and inform the patient of the actual diagnosis. Group A significantly (P < 0.001) asked higher numbers of relevant questions in the signs and symptoms section of the history than the other two groups. No differences between the three groups were observed in the other two sections of history-taking (personality, family, social and precipitating factors), in the general and specific physical examination and interpersonal skills. Generally, with the exception of the interpersonal skills section, the doctors performed less than 40% of the expected tasks in every section. The study highlighted the lack of competence in making a definite diagnosis of anxiety disorder. Among those who apparently made the diagnosis (group B) or made the diagnosis with certainty (group A), there was no demonstration of appropriate treatment behaviour with respect to pharmacological intervention.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845263 TI - Selecting medical students. PMID- 7845264 TI - Sociocultural influences on disease perception. PMID- 7845265 TI - Radiology in Malaya in the 1920s. PMID- 7845266 TI - Disease and risk factor perception among patients with coronary artery disease in Kuala Terengganu. AB - One hundred consecutive patients with coronary heart disease attending the Physician Clinic, Kuala Terengganu General Hospital self-completed a questionnaire on their awareness of the coronary risk factors and their perception of their disease. Seventy-one subjects were males. Twenty-seven subjects had never had formal education and only 6 had completed tertiary education. Whilst 52% considered themselves as having less than 25% knowledge about their disease, many were aware of hypercholesterolaemia, emotional stress, inadequate exercise and smoking as risk factors for coronary heart disease. Diabetes and family history were less known as coronary risk factors. Despite their awareness of the risk factors, though, the subjects failed to control these. For example, smoking was prevalent and their awareness of the harmful effects of smoking did not seem to deter them from this habit. Further, formal education did not seem to influence positive health behaviour. In terms of disease perception, the subjects tended to believe that their illness could be cured. Eighty subjects expected a cure from their doctors. Sixty-three subjects wanted more explanation of their illness from their doctors. These findings suggest that efforts should be made to translate patients' awareness of their illness to appropriate health behaviour, and perhaps doctors could achieve this by spending more time explaining to the patients, and educating them. PMID- 7845267 TI - Descriptive terms used by Malay patients for exertional angina pectoris. AB - Description of the chest pain of angina pectoris by patients is commonly used in the diagnosis, evaluation and monitoring of ischaemic heart disease. Whilst certain descriptive terms have been identified as describing angina and not other causes of chest pain, these terms have not been systematically evaluated among local Malaysian patients. Reliance on a translation of the description used by Western patients may not be totally correct in the local context. Seventy-one Malay patients with documented ischaemic heart disease were asked, by questionnaire and by interview, to identify the descriptive terms they used for their angina pectoris. Common terms used by these patients were sempit (constrictive) [56.3%], mencuck (pricking) [54.9%], berat (heavy) [53.5%], panas (burning) [50.7%], menekan (pressing) [46.4%], and pedih (smarting) [43.7%]. Other less common descriptions used were tajam (sharp), mencengkam (strangulating), hempap (compressive), ngilu, hiris (knife-like), lengoh (aching). Two-thirds of the patients used more than three terms to describe their angina pectoris. Direct translation of the description of angina may not only be inaccurate but could also be misleading. It is suggested that the actual words used by the patients in Bahasa Malaysia be recorded in the patient's notes rather than a translation of these. More studies are required to determine whether the terms used by the patients in this study are related to local dialect (in this case Terengganu) or are actually common in Malaysia. Further, similar studies among Chinese and Indian patients are also required. PMID- 7845268 TI - Hepatitis delta virus in intravenous drug users in Kuala Lumpur. AB - The hepatitis delta virus (HDV) is an RNA containing virus that requires hepatitis B virus (HBV) to supply the envelope proteins. HDV only infect man in the presence of HBV, either as a coinfection or as superinfection in HBV carriers. In the presence of hepatitis B infection, the HDV may cause more severe liver damage than that caused by the hepatitis B virus alone. HDV infection was studied in 44 HBsAg positive serum samples collected from male intravenous drug users sent for screening to the Blood Services Centre (BSC), Hospital Kuala Lumpur (HKL) between 1990 and 1992. The majority (39) were in the 20 to 39 age group. The youngest was 19 years old and the oldest was 61 years old. There were 25 Malays, 13 Chinese, five Indians and one Albanian. Anti hepatitis delta antibody (Anti-HDV) was detected in 15 out of 44 (34%) of the drug addicts. These results shows an increased in delta infection in HBsAg positive intravenous drug addicts compared to the surveillance results in 1985 when no delta antibodies were detected, and the 1986 and 1989 surveillance which showed 17.8% and 20% delta antibody positivity respectively. PMID- 7845269 TI - Incidence of Listeria spp. in vegetables in Kuala Lumpur. AB - From April 1992 to September 1992, 280 samples of 10 different fresh vegetables, bought from four different market outlets in Kuala Lumpur were examined for the presence of Listeria spp. Most of the market produce were locally grown with the exception of carrots. The isolation procedure was based on the Food & Drug Administration method (modified) used for the detection of Listeria spp. Isolation media used were Listeria Selective medium and LiCl- phenylethanol Moxalactam agars. The identification of isolates was by means of conventional biochemical tests and API Listeria identification system. Five out of the 280 samples showed Listeria contamination, Listeria monocytogenes was isolated in lettuce, sengkuang (Pachyrrhizus erosus) and selom Oenanthe javanica) and Listeria innocua was isolated from sengkuang (Pachyrrhizus erosus) and pegaga (Hydrocotyle asiatica). PMID- 7845270 TI - Case-finding for pulmonary tuberculosis in Penang. AB - The process of case-finding was studied in 100 consecutive patients with pulmonary tuberculosis treated by the Chest Clinic, Penang Hospital. The median time from the onset of the illness until the initial medical consultation was two weeks (patient's delay). This delay was longer in males, patients with lower than secondary education and drug abusers. Only 47% of patients were put on treatment with a correct diagnosis within one month of the first consultation (doctor's delay). Almost all patients had at least one symptom suggestive of tuberculosis at presentation and the mean number of consultations before diagnosis was three. Patients who first visited government medical facilities had shorter doctor's delay than those who first saw private practitioners, and patients who first consulted a private practitioner were the least likely to be appropriately investigated by sputum examination and chest radiography. The median total delay was three months and at the time of diagnosis, 95% of patients had moderate or far advanced disease radiologically. In order to shorten doctor's delay, all medical practitioners, especially those in the private sector, should be made aware of the importance of early diagnosis and the proper management of tuberculosis. Health education campaigns for the public should also be undertaken to shorten patient's delay. PMID- 7845272 TI - Patterns of superficial veins of the cubital fossa in Malays. AB - Patterns of superficial veins of the cubital fossa were studied in 170 male and 96 female Malays. Six venous patterns were observed. The less commonly known but clinically important patterns observed included absence of communication between basilic and cephalic veins (in 7.3% females and 8.8% males); an arched median cubital vein (in 2.0% females and 6.5% males); absence of the cephalic vein (in 1.0% females and 2.9% males) and two median cubital veins (in 1 male only). Awareness of these uncommon cubital venous patterns and their approximate incidence would be very useful for those performing venepuncture or venesection in Malays, especially under emergency conditions. PMID- 7845271 TI - Ondansetron against metoclopramide/dexamethasone--a comparative study. AB - This trial was carried out in Hospital Kuala Lumpur. Fifty-two patients who were scheduled to receive their first or subsequent courses of cancer chemotherapy with single dose cisplatinum containing chemotherapy regimens were evaluated. Thirty-four patients were given ondansetron in one group while 18 in the other group received metoclopramide with dexamethasone. The response to treatment was categorised as complete (0 emetic episode), major (1 or 2 emetic episodes), minor (3 to 5 emetic episodes) or failure (> 5 emetic episodes or rescue medication). Among the 52 patients, a complete or major control (0 to 2 emetic episodes) was achieved in 23/34 patients (68%) from the ondansetron group and in 3/18 patients (17%) from the metoclopramide with dexamethasone group (p < 0.002) on day 1. Similarly, the control of nausea was greater in the ondansetron group compared with the metoclopramide with dexamethasone group (p < 0.0009) on day 1. Two patients were excluded (dropped out) after day one from each of the two study groups due to excessive vomiting subsequent to cisplatinum therapy. From days 2 to 6, there was a trend in favour of ondansetron. Both treatments were well tolerated. The results of this trial show that in the prophylaxis of nausea and vomiting induced by cisplatinum containing chemotherapy, the efficacy of ondansetron is superior to that of a standard anti-emetic combination, metoclopramide with dexamethasone. PMID- 7845273 TI - Psychiatric morbidity in an urban general practice. AB - Two hundred and six patients attending an urban general practice were surveyed using a self-rating questionnaire, the 30-item version of the General Health Questionnaire. At a cut-off score of 6/7, 34.5% of the respondents were found to be high-scorers which gives a corrected estimate of psychiatric morbidity of 29.9% in this clinic. Among those who presented with general complaints, such as aches and pains for which no organic cause was found, a significant proportion (70%) were high-scorers. There were no significant differences in the sex and age distribution of the high-scorers. However the mean score of Malays was significantly higher than that of Chinese. PMID- 7845274 TI - Family characteristics of suicides in Cameron Highlands: a controlled study. AB - Cameron Highlands has one of the highest suicide rates in the world, especially among Indians. Forty Indian families (19 suicides; 21 controls) were studied to compare family characteristics such as income, overcrowding, birth order of index cases of suicide, family history of suicidal behaviour or mental illness, marital disharmony, presence of alcohol abuse, availability of, and knowledge about, weedicides/insecticides, talk/threat of suicide among family members and experience of significant losses in the past year. Controls were matched for age, sex and educational level with the index cases of suicide. A significant difference was only found for one of the above factors, namely increased experience of significant losses in the past year in the family of index cases of suicide. More than 75% in both groups had alcohol related problems. About equal proportions in each group had a family history of suicidal behaviour and mental illness. There was more marital disharmony in families of suicides but this failed to reach significance. These results and methodological limitations of this study are discussed. PMID- 7845275 TI - All elevated creatine kinase is not neuroleptic malignant syndrome. AB - Creatine kinase (CK) is an enzyme that is found widely in muscle tissues. Raised levels would occur when there is muscle damage. Raised levels are used as one of the diagnostic criteria for Neuroleptic Malignant Syndrome (NMS). This study looks at CK levels in 30 psychotic inpatients without NMS and compares them with 10 patients with NMS. It was found that 67% of the patients without NMS had raised CK levels, 20% of whom had levels in excess of 1000 IU/L. The rest had a two to five-fold increase over normal limits. Raised levels were associated with the use of intramuscular injections and physical restraints, situations which are well known to result in muscle injury. All the NMS patients had raised CK levels but 40% had levels below 1000 IU/L. Our findings support the idea that CK levels, though helpful, should be interpreted with care as raised levels are nonspecific. PMID- 7845276 TI - Protection by tocotrienols against hypercholesterolaemia and atheroma. AB - Antioxidants such as tocotrienols may protect against atherosclerosis since tissue injury from free radicals is a final common pathway of damage in arterial disease. In this study, the effects of tocotrienols on serum cholesterol, lipid peroxides, and aorta atheroma were assessed in rabbits fed an atherogenic diet for 12 weeks. Tocotrienols were more effective than tocopherols in preventing increases in serum LDL (p = 0.03) and total cholesterol (p = 0.008) levels in the cholesterol-fed rabbits. Elevation of serum lipid peroxides was effectively suppressed by tocotrienols (p = 0.01). Both tocopherols and tocotrienols offered significant protection against atheroma in the rabbit aorta, but tocotrienols had a stronger hypolipidaemic effect. PMID- 7845277 TI - Parents' views of lumbar puncture in children with febrile seizures. AB - A study was carried out to ascertain the views of parents regarding the performance of lumbar punctures on their children admitted for febrile seizures. One hundred and seventeen (117) children with febrile seizures were recruited over nine months. Either one of the parents was interviewed a day after admission. In most cases, this was usually the mother. The ethnic groups of the patients were Malays (62.4%), Indians (26.5%), Chinese (8.5%) and others (2.6%). Lumbar punctures were requested by the doctor in attendance in only 28 (23.9%) patients This showed that the rate of request for lumbar punctures in febrile seizures was low. Parents of eight of them refused. The main reasons for the refusal were: fears that the child might be paralysed, advice from relatives and fear that the child might die from the procedure, or might find it too painful. All the parents who refused were Malays. A lumbar puncture was also more likely to be refused in a girl. Those who consented to lumbar puncture did so because they wanted the doctor to get to the diagnosis. Another reason given was that it might be therapeutic. Parents whose children did not require a lumbar puncture also thought that lumbar puncture may cause paralysis. The main sources of information on lumbar punctures for the parents were their relatives and/or friends. In only 85% of the cases were the reasons for the lumbar puncture explained to the parent. In 71.4% of the time the explanation was done by the medical officer, and in only 4.8% of the time was the consultant involved.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845278 TI - Epidural anaesthesia for caesarean section: a comparison of 0.5% bupivacaine plain, 0.5% bupivacaine plus 100 micrograms fentanyl and 0.5% bupivacaine plus 50 micrograms fentanyl. AB - Thirty-one healthy women who underwent Caesarean section were studied in a double blind trial to compare the effectiveness of epidural 0.5% bupivacaine plain, 0.5% bupivacaine plus 100 micrograms fentanyl and 0.5% bupivacaine plus 50 micrograms fentanyl in the prevention of intraoperative pain. There was no difference in the quality of analgesia between the three groups. The incidence of complications was significantly higher in the 0.5% bupivacaine plus 100 micrograms fentanyl group compared with the other two groups. PMID- 7845279 TI - The problem student on clinical rotations: a comparison of Malaysian and North American views. AB - The purpose of this study is to explore the types of problem students that clinical teachers encounter in clinical settings. A questionnaire developed by the Association of American Medical Colleges that lists a variety of types of problem students was completed by 466 clinicians at the University of Washington School of Medicine (UWSOM) and 98 Malaysian clinicians from Universiti Kebangsaan Malaysia (UKM) and Universiti Sains Malaysia (USM). In addition, 120 medical students from UKM completed a slightly modified version of this questionnaire. Both the faculty and student questionnaires asked the respondent to identify the frequency of a given problem type. The faculty was also asked to estimate how difficult it was to evaluate a specific problem. In general, there was strong agreement among the North American and Malaysian faculty on the frequency and difficulty of the 24 types of problem students listed. There were some notable differences, such as Malaysian teachers perceiving the "shy" student more frequently than their North American counterparts who rated the student with deficits in knowledge more frequently. However, the overall similarity in the rankings suggest that clinical teachers face similar types of problems, independent of cultural differences and institutional differences. PMID- 7845280 TI - Transarticular spread of the sacroiliac joint in a chondrosarcoma. AB - Primary bone tumours, even in very advanced stages, rarely exhibit transarticular spread. We present a case of chondrosarcoma of the ilium with destruction of the sacroiliac joint, the ipsilateral sacral ala and with sacral nerve involvement. PMID- 7845281 TI - Idiopathic oedema: a lesson in differential diagnosis. AB - This paper outlines our approach to the diagnosis of Idiopathic Oedema. The patient presented illustrates some of the pertinent clinical and laboratory pointers one has to take into consideration before labelling a person as suffering from idiopathic oedema. The discussion also includes a brief review of the literature on the patho-physiology and management of this benign disorder. PMID- 7845282 TI - Primary non-Hodgkin's lymphoma of the pelvic bone in a child. PMID- 7845283 TI - Post traumatic stress disorder following an electric shock. AB - Post Traumatic Stress Disorder (PTSD) is still a diagnosis which is frequently missed even by psychiatric professionals. Each doctor needs to maintain a high level of awareness that patients may have experienced trauma; that PTSD can often occur for a variety of common symptoms; and that it may also be at the root of a persisting treatment-resistant depressive or anxiety state. This case demonstrates that occupational accidents may result in this condition. PMID- 7845284 TI - A case of torsion of the spleen presenting as an acute abdomen. AB - A middle-aged man presented with acute abdomen was found to have torsion of the spleen on laparotomy with the spleen lying in an abnormal position. Wandering spleen is an unusual entity, with torsion being a common complication. PMID- 7845285 TI - Huntington disease: report of first case documented in Malaysia. AB - Huntington disease has not previously been recorded in Malaysia. We report the first case in a local patient with a positive family history. The implications of diagnosing this disease will be discussed. PMID- 7845286 TI - Primary hyperparathyroidism with carcinoma of the right breast--a case report. AB - A patient with carcinoma of the right breast and coincidental primary hyperparathyroidism is presented. The distinction between hypercalcemia of malignant and hyperparathyroid origins is based on biochemical analysis and localisation of parathyroid adenoma on a computer tomogram of the neck. PMID- 7845287 TI - Massive ovarian cysts--successful management of two cases. AB - Massive ovarian cysts are not commonly encountered. They frequently present a challenge to the gynaecologist who is faced with them. Two cases of successful removal of massive ovarian cysts are presented. Successful management would involve recognition of complications which occur at various steps in the treatment. PMID- 7845288 TI - The role of abdominal angiography in difficult gastrointestinal bleeding. AB - Two cases of leiomyomas of the jejunum presenting with gastrointestinal bleeding of uncertain origin are described. Diagnosis was finally established by selective angiography. Laparotomy and resection of the tumour were successfully performed. The approach and management of this rare tumour are outlined. PMID- 7845289 TI - Continent pouch ileostomy. AB - Continent pouch ileostomy is fashioned for patients who need a proctocolectomy. It is usually indicated for cases of ulcerative colitis and familial adenomatous polyposis where the anal sphincter can no longer maintain normal function or has to be removed. A case of familial adenomatous polyposis with features of Gardner's syndrome is reported. The patient presented with carcinoma of the rectum. Abdominoperineal resection followed by completion pancolectomy was performed. A continent pouch ileostomy was fashioned for him. He resumed work as a labourer within six months. The pouch was troublefree, needed to emptied four to six times a day and was fully continent of fluid, flatus and faeces until his demise three years later from liver secondaries. Continent pouch ileostomy is a better alternative than permanent end ileostomy. All care should be taken to rule out the existence of Crohn's disease. It is proposed that continent pouch ileostomy should be offered to patients needing permanent ileostomy if the expertise is available. PMID- 7845290 TI - Mutation analysis of Western Australian families affected by cystic fibrosis. AB - OBJECTIVE: To document the results of mutation analysis on 160 individuals with cystic fibrosis and 31 obligate carriers of the cystic fibrosis gene in 191 Western Australian families to facilitate accurate genetic counselling. METHODS: We tested for 17 mutations of the cystic fibrosis gene by either a variation of the polymerase chain reaction amplification refractory mutation system (PCR-ARMS) or with a series of restriction enzyme cuts and dot blots using chemiluminescent probes. RESULTS: At least one of the two intragenic mutations causing cystic fibrosis was identified in 98% of affected individuals and both were detected in 68%. The delta F508 deletion occurred in 89.8% of patients: 51% were homozygous for this defect. In carriers, 85% of the mutations were detected with a panel of 16 probes, identifying 17 intragenic defects: the delta F508 deletion occurred in 72.4%. Both cystic fibrosis mutations were detected in 68% of cystic fibrosis families. CONCLUSIONS: By analysis with 16 intragenic cystic fibrosis genomic probes, we have documented the frequencies of various mutations in the Western Australian population. These data will be useful in accurate genetic counselling for affected families and carrier screening for the general population. PMID- 7845291 TI - Depression of plasma glutamine concentration after exercise stress and its possible influence on the immune system. AB - OBJECTIVE: To determine whether plasma glutamine levels can be used as an indicator of exercise-induced stress, and to consider the possible effects of low plasma glutamine concentrations on the immune system. METHODS: We used two exercise regimens: in Trial 1 seven male subjects were randomly stressed on a treadmill at 0, 30%, 60%, 90% and 120% of their maximal oxygen uptake (VO2max); in Trial 2 five highly trained male subjects underwent intensive interval training sessions twice daily for ten days, followed by a six-day recovery period. RESULTS: Plasma glutamine concentrations decreased significantly from an average of 1244 +/- 121 mumol/L to 702 +/- 101 mumol/L after acute exercise at 90% VO2max (P < 0.05) and to 560 +/- 79 mumol/L at 120% VO2max (P < 0.001). Four of the five subjects showed reduced plasma glutamine concentrations by Day 6 of the overload training trial, with all subjects displaying significantly lower glutamine levels by Day 11. However, glutamine levels showed a variable rate of recovery over the six-day recovery period, with two subjects' levels remaining low by Day 16. CONCLUSIONS: Reduced plasma glutamine concentrations may provide a good indication of severe exercise stress. PMID- 7845292 TI - Laparoscopic Burch colposuspension for stress incontinence: preliminary results. AB - OBJECTIVE: To assess the safety, effectiveness and potential benefits of laparoscopic Burch colposuspension. DESIGN: Non-randomised prospective study. SUBJECTS: Fifteen women, presenting consecutively with urodynamically confirmed urinary stress incontinence. RESULTS: The operation was successfully completed with no perioperative morbidity in 14 women. One woman subsequently underwent laparotomy after injury to the inferior epigastric artery. The average duration of surgery was 110 minutes, postoperative catheterisation 30 hours, and hospital stay 2.3 days. There was little postoperative discomfort. Most women were able to return to normal activities within one to two weeks. At follow-up (6 weeks-9 months) all the women were continent. CONCLUSION: Laparoscopic Burch colposuspension is a safe and feasible alternative to the open technique. Early results show the benefits of easy access to the cave of Retzius, a clear view of the operating field, minimal intraoperative blood loss, shortened postoperative catheterisation and hospitalisation times, little postoperative pain and early return to normal lifestyle. PMID- 7845293 TI - Insomnia in the elderly: its prevalence and correlates in the general population. AB - OBJECTIVE: To estimate the prevalence of persistent insomnia and its correlates in samples of people living in the community and in institutional settings. METHODS: Respondents were interviewed in their place of residence by trained interviewers using the Canberra Interview for the Elderly, a structured psychiatric examination. RESULTS: Information about sleeping habits was obtained from 874 community and 59 institutional residents. Insomnia was persistent in 16% of the community-dwelling population and 12% of the institutional residents, with 15% and 40%, respectively, regularly taking a hypnotic. Of those without insomnia, 10% in the community but over a third in institutions were using a hypnotic. Insomnia was associated with depression, pain and poor physical health. CONCLUSIONS: Persistent insomnia in the elderly, as in other age groups, is strongly associated with depressed mood, as well as with physical disease. Because of this, insomnia should not be dismissed as a normal part of ageing, and therefore ignored as a significant symptom. Continued surveillance is needed in general practice, geriatric services and nursing homes of the routine use of hypnotics by the elderly. PMID- 7845294 TI - Trends in prognostic factors of melanoma in South Australia, 1981-1992: implications for health promotion. AB - OBJECTIVE: To analyse trends in prognostic factors at diagnosis of melanoma to indicate targets for health promotion. METHODS: Cases of melanoma notified to the South Australian Cancer Registry during 1981-1992 (1361 in situ and 4509 invasive) were analysed by tumour site, histological type, stage, thickness, period of diagnosis and sociodemographic characteristics of the patient. RESULTS: The relative probability of being diagnosed with an in-situ, rather than a thin invasive, lesion increased progressively between 1984-1986 and 1990-1992. The relative probability of having an in-situ melanoma diagnosed was: lower among those aged 80 years or more; higher among patients residing in the upper socioeconomic areas of Adelaide; high for lesions on the face; and high for lentigo maligna as opposed to superficial spreading lesions. The relative probability of invasive lesions being diagnosed when more than 1.5 mm thick decreased progressively between the 1981-1983 and 1990-1992 diagnosis periods. The relative probability of thick lesions being diagnosed was higher among older patients and for nodular lesions compared with superficial spreading or lentigo maligna lesions. Facial lesions and those in males tended to be thicker. CONCLUSIONS: There are favourable trends towards earlier detection of melanomas in South Australia, probably reflecting the effect of skin-cancer awareness campaigns. Further campaigns should emphasise early detection in people aged 60 years and over, males and residents of less affluent areas. Early detection of nodular melanomas and invasive lesions of the face also warrants special attention. PMID- 7845295 TI - Cerebral venous sinus thrombosis associated with the primary antiphospholipid syndrome. Resolution with local thrombolytic therapy. PMID- 7845297 TI - Health outcomes: of means and ends. PMID- 7845296 TI - Attendance patterns in general practice. AB - OBJECTIVE: To determine the completeness of data acquired previously on the attendance patterns of patients visiting three general practices and the exclusivity of attendance at these practices. DESIGN: A retrospective comparison of attendance data with data extracted from the Health Insurance Commission database. Three study practices were investigated to give a rough cross-section of general practice in Western Australia. RESULTS: Eighty-nine per cent of patients and 92% of services recorded in our earlier study were also recorded by the HIC, with 31% of patients also attending another general practice during the six months, mostly only once or twice. However, there was considerable variation between practices in data match and attendance at other practices. CONCLUSIONS: We found a high level of completeness of data. Sixty-nine per cent of patients attended no other practice during the six months, indicating that doctors in the study practices have some opportunity to provide continuity of care to their patients. The implications for patients' needs and doctors' resources of variations in attendance patterns need to be examined further. PMID- 7845298 TI - Pharmacology of asthma treatment: an overview. AB - The major advance in the last decade in treating asthma is the realisation that it is primarily an inflammatory process in the airways and not a bronchial smooth muscle disease. Accordingly, much more emphasis is being placed on the early introduction of regular anti-inflammatory therapy, greatly facilitated by the development of inhaled steroid products. Despite this, inhaled beta 2-agonists remain the other major therapy in modern asthma treatment because of their ability to provide rapid relief from potentially life-threatening bronchoconstriction. At present, there is a tendency to avoid regular daily use of beta 2-agonists alone for persistent symptoms. Theophylline is still used, despite concern about its toxicity. However, it does have pharmacological effects in addition to bronchodilatation that may give it an additional therapeutic role in asthma therapy. It seems unlikely that the search for new single-mediator antagonists or synthesis inhibitors will result in the development of a new, effective asthma treatment. PMID- 7845299 TI - Congestive cardiac failure and arrhythmias. PMID- 7845300 TI - Treatment of primary breast cancer--lessons from a screening program? PMID- 7845301 TI - Treatment of primary breast cancer--lessons from a screening program? PMID- 7845302 TI - The Buteyko asthma breathing technique. PMID- 7845303 TI - The human toxicity of marijuana. PMID- 7845304 TI - Cell-mediated immunity in combat veterans with post-traumatic stress disorder. PMID- 7845305 TI - An outbreak of typhoid associated with a "lafet" in Vanuatu. PMID- 7845306 TI - Diagnostic imaging: reversing the focus. PMID- 7845307 TI - Fixed dilated pupil in the long distance traveller. PMID- 7845308 TI - The laryngeal mask airway for helicopter transportation of neonates. PMID- 7845309 TI - When all else fails, read the instructions. PMID- 7845310 TI - Interferon alfa for chronic active hepatitis B. Long term follow-up of 62 patients: outcomes and predictors of response. AB - OBJECTIVE: To evaluate the response to treatment with interferon alfa and the long term outcome of patients with chronic active hepatitis B. METHODS: Sixty-two patients with chronic active hepatitis B (43 males, 19 females; age range, 10-67 years) who were treated with interferon alfa at Westmead Hospital between 1984 and 1992 were followed up (mean period of follow-up, 44 months). Thirty-nine patients were treated with interferon alfa-2a and 23 with interferon alfa-2b for a mean of 22.5 weeks. Interferon was given three times a week with a dose range of 3-21 million U. We evaluated pretreatment predictors of response (patient's age, sex, ethnic origin, presence of cirrhosis, serum levels of alanine aminotransferase [ALT] and hepatitis B virus DNA [HBV-DNA]) and the effect of dose and type of interferon. RESULTS: Nine patients had a complete response to treatment with interferon alfa (loss of hepatitis B surface antigen), 26 had a partial response (permanently HBV-DNA negative, hepatitis B e antigen to anti hepatitis Be seroconversion), eight had a transient response and 19 had no response. All patients with a complete response had normal ALT levels at last follow-up. Histological evidence of hepatic inflammation was significantly reduced in responders. A high pretreatment ALT level and a low HBV-DNA titre were both positive predictors of a favourable response. We found no significant difference in the response to different types of interferon or to high or low dose regimens, or in the responses of patients with cirrhosis. CONCLUSION: Treatment with interferon alfa was associated with prolonged suppression of HBV replication in over half these patients and 14% appear to have been cured of the infection. Suppression of HBV replication is associated with sustained abatement of liver disease. PMID- 7845311 TI - Blood and blunder. PMID- 7845312 TI - Whose child is it anyway? PMID- 7845314 TI - Fluvoxamine for obsessive-compulsive disorder. PMID- 7845315 TI - Aspirin for prevention of myocardial infarction. PMID- 7845317 TI - Cytomegalovirus in liver biopsies of marrow transplant recipients: detection methods, clinical, histological and immunohistological features. AB - In a retrospective analysis liver biopsy specimens obtained from 44 marrow transplant recipients were studied to evaluate the frequency of local presence of human cytomegalovirus (CMV) and graft-versus-host disease (GvHD)-like histological and immunohistological alterations in patients with and without liver dysfunction following bone marrow transplantation (BMT). In 22 of 28 patients with marked liver dysfunction after BMT and histopathological alterations described as typical for acute GvHD CMV could be detected in the liver biopsy specimen. The polymerase chain reaction (PCR) technique revealed the highest sensitivity for CMV detection in liver biopsy samples, but in 20 of 22 PCR-positive specimens CMV infection could be confirmed by at least one additional technique. All the liver biopsies obtained from 16 patients with normal liver function lacking histopathological signs of GvHD were CMV negative. In all 3 patients with CMV-positive liver biopsy started on antiviral therapy liver function improved and no generalized CMV disease occurred. All the 4 patients without local presence of CMV started on severe immunosuppressive therapy showed an improvement of liver dysfunction without occurrence of CMV infection. Local CMV infection of the liver could not be differentiated from hepatic GvHD by clinical and histopathological features, nor by immunohistological analysis of the bile duct epithelium. In contrast, only in liver biopsy with local viral presence could an increase in HLA class II- and ICAM-1 expression be demonstrated on hepatocytes. Thus, especially the high negative predictive value of the PCR technique helps to manage the patient with liver dysfunction after BMT. PMID- 7845316 TI - The gag proteins of human immunodeficiency virus type 1: mechanisms of virus assembly and possibilities for interference. PMID- 7845318 TI - Characterization of different oligomeric species of the Yersinia enterocolitica outer membrane protein YadA. AB - The oligomeric structure of the plasmid-encoded outer membrane protein YadA of Yersinia enterocolitica was studied by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and sucrose gradient sedimentation, respectively. The apparent molecular weight (M(r)) of the oligomeric 200-kDa YadA species detected by SDS-PAGE varied from 152,000 to 240,000 depending on the respective acrylamide concentration. The atypical electrophoretic behavior of the 200-kDa YadA species results form an exceptionally high relative free mobility as revealed by the Ferguson plot. In contrast, the apparent M(r) of 53,000 of the YadA monomer was independent of the acrylamide concentration. An additional oligomeric 116-kDa YadA species was detected by SDS-PAGE when membrane preparations of Y. enterocolitica were solubilized in SDS at 37 degrees C. The gel-purified 116-kDa YadA species was completely converted to the 200-kDa species by heating at 100 degrees C and to the monomeric form (M(r) 53,000) by heating in the presence of 10 M urea without reducing agents, respectively. This suggests that the 116-kDa YadA species represents the native oligomeric form of YadA, whereas the 200-kDa species is only generated from native YadA during denaturation in SDS. The significance of the 116-kDa YadA species is also supported by the rather slow sedimentation at about 6 S of detergent-solubilized YadA in sucrose gradients, which probably contains only two or three monomers. PMID- 7845319 TI - The pathology of nephrotoxic injury: a reappraisal. AB - The class of nephrotoxins which are directly tubulotoxic in animal studies (cis platinum, gentamicin, and cephaloridine) produce minimal histological changes in the human kidney. Such alterations do not correlate with the degree of organ dysfunction and fall into the broad category of what has been called 'acute tubular necrosis'. Some nephrotoxins (cyclosporine and amphotericin), acutely and chronically diminish renal perfusion, causing injury to renal parenchymal zones known to have limited oxygen a availability (medullary ray and inner stripe). In cyclosporine toxicity, the human and animal models appear equivalent. This is less clear with amphotericin where there appears to be a tubulotoxic component. Other nephrotoxic substances (contrast, nonsteroidal anti-inflammatory drugs) acutely alter renal perfusion, particularly affecting the medulla. In animal models of renal failure induced by these substances, there is an excellent correlation between medullary thick ascending limb injury and renal failure. Documentation of this phenomenon in human biopsies/autopsies is lacking, probably because of the lack of biopsy material and problems in defining medullary injury. Finally, in toxicological screening programs for nephrotoxic substances, there are groups of reactions which cannot be predicted and are thought to be mediated by immune mechanisms, i.e., immune complex glomerular disease, nil disease and interstitial nephritis. PMID- 7845320 TI - Urinary biomarkers and nephrotoxicity. AB - Biomarkers represent measurable changes in biologic systems or samples which correlate with an organism's altered biochemical or cellular function. For the kidney urine is the usual body fluid sampled. The principle processes which are evaluated are filtration/elimination and reabsorption/secretion. Proteins, either abnormal in type or amount, and enzymes have dominated interest in this field for many years. However, application of monoclonal antibody techniques, along with an understanding of the role of cytokiness, growth factors, collagen matrix and lipid mediators have rapidly expanded the field of new candidates for urinary biomarkers. PMID- 7845321 TI - Nephrotoxicity of nonsteroidal anti-inflammatory drugs. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) are important therapeutic agents in the management of rheumatologic disorders and other pain syndromes. Over the counter availability of the drugs has expanded the usage of the drugs. This article reviews the nephrotoxicity of these drugs, with some emphasis on NSAID related proteinuria. Although reversibility of renal involvement upon drug discontinuance is the rule, progression to end-stage renal disease has occurred. A proposed guideline for monitoring renal impairment in low- and high-risk patients is also presented. PMID- 7845322 TI - Renal insufficiency due to angiotensin-converting enzyme inhibitors. AB - Angiotensin-converting enzyme (ACE) inhibitors represent a major therapeutic breakthrough for treatment of hypertension, congestive heart failure and various chronic renal diseases. They are effective generally well tolerated and safe for most patients. However, acute renal insufficiency or overt renal failure occurs in some patients with underlying critical renal artery stenosis (RAS), hypertensive nephrosclerosis, autosomal dominant polycystic kidney disease, diabetes mellitus, and chronic congestive heart failure. Diuretic-induced sodium depletion and underlying chronic renal insufficiency are the major predisposing factors for renal insufficiency in all of these patient populations. Renal insufficiency is usually asymptomatic, nonoliguric, associated with hyperkalemia, and in nearly every case completely reversible after discontinuation of the offending agent. Moreover, it can usually be managed in the outpatient setting by discontinuation of the ACE inhibitor, concomitant diuretic or both. An asymptomatic increase in serum creatinine in patients administered ACE inhibitors should raise the possibility of RAS; however, more common renal diseases should be considered. The decision to pursue testing for RAS should be done on an individual basis; moreover, it is imperative that patient willingness to undergo invasive procedures including angioplasty and/or surgery should be determined prospectively. PMID- 7845324 TI - Renal tubular transport and nephrotoxicity of beta lactam antibiotics: structure activity relationships. AB - Several of the cephalosporin and carbapenem antibiotics produce acute renal failure when given in large single doses. Antibiotic concentrations in the tubular cell, determined by the net effects of contraluminal secretory transport and subsequent movement across the luminal membrane, make the proximal tubule the sole target of injury, and are important determinants of the nephrotoxic potentials of different beta-lactams in different animal species. At least three molecular mechanisms of injury have been shown with cephaloridine, the most widely studied nephrotoxic beta-lactam: (1) lipid peroxidation, (2) competitive inhibition of mitochondrial carnitine (zwitterionic) transport and fatty acid oxidation, and (3) acylation and inactivation of tubular cell proteins, most thoroughly evaluated with mitochondrial anionic substrate transporters. The first two of these injuries are dependent upon one or both of cephaloridine's side group substituents, which are not present on the other nephrotoxic cephalosporins or carbapenems. It is not surprising, therefore, that only toxicity to mitochondrial anionic substrate carriers has been found in studies of the other beta-lactams. However, the several effects of cephaloridine on the tubular cell indicate a potential for different mechanisms of attack on different molecular targets. Continuing studies of the effects of existing and newly developed beta lactams are likely to identify further nephrotoxic mechanisms of this complex and rapidly growing group of antimicrobials. PMID- 7845323 TI - Cisplatin nephrotoxicity. AB - Cisplatin treatment causes tubulointerstitial injury to the kidneys. Common clinical syndromes associated with its use include acute renal failure and a magnesium wasting state. Routine fluid infusion therapy has markedly reduced the incidence of acute renal failure. However, methodologic limitations of most recent studies preclude confident conclusions regarding long-term effects of cisplatin treatment on renal function. Experimental and clinical evidence suggests that sulfhydryl metabolism and oxidative stress are central to cisplatin renal injury. Both in animals and humans, a variety of agents appear to alter renal uptale of cisplatin and its hemodynamic consequences, thus modulating nephrotoxicity. Thiosulfates and related agents have received most study. Other agents examined have included calcium channel blockers, bismuth, selenium, glycine, cimetidine, and probenecid. PMID- 7845325 TI - Contrast-associated nephropathy: presentation, pathophysiology and management. AB - Contrast-associated nephropathy, a significant rise in serum creatinine 1-5 days following intervascular contrast injection, remains one of the most serious complications of contrast imaging. The reported incidence varies widely; in consecutive random cases ranges from 2 to 7%, but it can increase 5- to 10-fold in high risk patients with serum creatinine > 1.5 mg/dl. Postulated mechanisms of renal damage include vasoconstriction and direct tubular cell injury. The usual clinical presentation is an asymptomatic increase in serum creatinine without oliguria. Residual loss of renal function occurs in principle in patients with preexisting renal impairment. Aggressive prestudy hydration along with selective use of low osmolar contrast media can significantly reduce the risk of contrast nephropathy for patients with either chronic renal failure or diabetic nephropathy. PMID- 7845326 TI - Thermoregulation in laboratory mammals and humans exposed to anticholinesterase agents. AB - The regulation of body temperature is one of many homeostatic functions affected by exposure to anticholinesterase (antiChE) pesticides, and related compounds. In the study of antiChE neurotoxicity, thermoregulatory variables are often used as sensitive physiological indices. Hence, a review on the thermoregulatory aspects of antiChE agents would be useful to researchers in a variety of fields. A reduction in body temperature is a commonly used indicator of antiChE poisoning in laboratory rodents. On the other hand, humans and some other species often shown an elevation in body temperature when exposed to antiChE agents. Hyperthermia has also been noted in animals treated with either low levels of antiChEs or during recovery from high doses of antiChEs. In this review, the literature dealing with the central and peripheral effects of cholinergic agonists and antagonists is reassessed because the thermoregulatory effects of antiChEs are thought to be linked to the activation of cholinergic pathways. This is followed by a thorough review of the studies reporting thermoregulatory responses in laboratory rodents and humans exposed to low and high doses of a variety of antiChE agents, including the organophosphate- (OP) and carbamate- (CB) based pesticides and related drugs. Attention is given to the possible mechanism of action of OPs on thermoregulation in the laboratory rodent including the involvement of behavioral and autonomic processes. The incidence of antiChE induced hyperthermia (fever) in humans exposed to antiChEs is also addressed. Other topics of antiChE-induced thermoregulatory dysfunction discussed in this review include the role of exercise, heat, and cold stress, tolerance to antiChE agents, and genetic variability. Overall, the mechanism of antiChE-induced changes in body temperature cannot always be explained solely by the immediate consequences of ChE inhibition. PMID- 7845327 TI - Lead exposure potentiates the effects of NMDA on repeated learning. AB - Several studies now suggest that Pb exposure disrupts NMDA receptor complex function, findings which may have implications for understanding the basis of Pb induced learning impairments. To further evaluate this possibility, the behavioral properties of the glutamate agonist NMDA were compared in rats that had been chronically exposed to 0, 50, or 250 ppm Pb acetate in drinking water from weaning. Acute administration of NMDA (20-50 mg/kg IP) decreased accuracy in both the repeated acquisition (RA) and performance (P) components of this multiple schedule with a selective effect on the learning component in the second half of the session. Analyses of error patterns revealed that the disruption of RA accuracy derived from initial perseverative errors followed by errors of skipping forward and backwards in the 3-member response sequence. Response rates in both RA and P were suppressed by NMDA. Pb-exposure potentiated the accuracy impairing effects of NMDA by further increasing the frequencies of these error classes, and likewise potentiated the rate-suppressing effects of NMDA. These findings add further support to the possible involvement of Pb with the NMDA receptor complex. PMID- 7845328 TI - Long-term behavioral effects of prenatal alcohol exposure in rats. AB - Two studies were conducted to examine the effects of prenatal alcohol exposure on ambulation and head-dipping behavior of rats. The apparatus was a modified "open field" that contained holes in the floor where an animal could "dip" its head. Animals were tested under conditions in which another animal was present in the adjacent box, or the adjacent box was empty. In the first study, 18-month-old rats, prenatally exposed to alcohol, ambulated more and made more head dips than controls when tested with an empty adjacent test box; when there was another animal in the adjacent box, animals prenatally exposed to alcohol did not differ from controls. In the second study, all rats were tested with the adjacent box empty. In this study, 8-month-old rats, prenatally exposed to alcohol, did not ambulate significantly more but did make significantly more head dips than controls. These results indicate that prenatal alcohol exposure has long-term effects on behavior and that some tests (head-dipping) are affected more reliably than others (ambulation). The results also suggest that test conditions may mask these differences. PMID- 7845329 TI - Reversal learning tasks may provide rapid determination of cognitive deficits in lead-exposed children. AB - An historical cohort study of twins, aged 6 to 15 years, found reduced cognitive performance related to subclinical exposure to lead (Pb) much earlier in life. Pairs of twins discordant for blood Pb (low-Pb twins ranged from 30-50 micrograms/dl and high-Pb twins ranged from 43-80 micrograms/dl) exhibited reduced learning of a computer-administered visual discrimination and reversal by the twin having the higher exposure. There was no evidence that sensory or motor impairment contributed to the cognitive deficit. Performance of a reference group indicated that test's validity for age-related cognitive development and the method's suitability for children of varying socio-economic or racial status. Because the reversal learning approach required only one 20-min test session and was powerful enough to document Pb-related deficits in a small sample (n = 8), it may indicate a practical method for obtaining early evidence of environmentally induced developmental delays. An advantage of the test is that it can be used with both humans and animals. Tests capable of direct comparison of behavioral data from humans and animals can guide the search for behavioral and biological mechanisms in experiments that can be done only with animals. They also can augment the clinical procedures currently used. PMID- 7845330 TI - Multiple risk factors do not identify cocaine use in rural obstetrical patients. AB - This nonconcurrent, cohort study of consecutive admissions to one of three hospital units: labor and delivery (n = 474), well-born nursery (n = 100), and the neonatal intensive care unit (n = 100), was designed to determine the prevalence of cocaine exposure in a rural obstetrical sample and to determine the relationship between exposure and perinatal variables. Urines were analyzed for benzoylecgonine, and the Obstetrical Complications Scale was completed for each mother-infant pair. Elementary comparisons were made using chi 2 analyses and Student's t test. Stepwise discriminant and discriminant function analyses were performed. The prevalence of exposure in the three groups of subjects ranged from 5%-7%. No significant differences in perinatal variables were found between users and nonusers in either of the newborn samples. In the maternal sample the groups differed on twelve mother or infant factors. However, no single variable or set of variables predicted use versus nonuse in any of the groups. PMID- 7845331 TI - Neurobehavioral testing and hazardous chemical sites. AB - The Agency for Toxic Substances and Disease Registry (ATSDR) has focused its health assessment efforts on seven priority health conditions, including neurotoxic disorders, and has begun to select tests and associated measurement tools that can detect those health effects. The evaluation of community-level exposures has introduced new challenges beyond the earlier testing models based on occupational exposures. Community populations are far more diverse than those found in workplace settings, including children, elderly persons, and the infirm, and the neurotoxic agents present at most hazardous waste sites usually are incompletely characterized and commonly are found in complex mixtures. This article describes the background to the four following articles reporting on a 3 day national workshop convened to assist ATSDR in developing standardized neurobehavioral test batteries for studies of adverse health outcomes in communities. PMID- 7845332 TI - Neurobehavioral test methods for environmental health studies of adults. AB - The Agency for Toxic Substances and Disease Registry convened a workshop in Atlanta, GA, that evaluated approaches and methods to ascertain whether there are neurobehavioral sequelae to children and adults exposed to hazardous substances in the environment. This article, developed from that Workshop, recommends testing methods [to identify neurotoxic insult] for immediate use in environmental health field studies of adults. A list of broad functional domains or modalities affected by chemicals was identified from the occupational and related literature (learning and memory, coding, sustained attention, higher intellectual function, strength, coordination, speed, vision, somatosensory, and affect). A core set of tests was selected that should assess those functions with the greatest demonstrated sensitivity to established neurotoxic chemicals, and a secondary set was selected to assess a broader group of functions. The core tests should be used in all investigations where neurotoxic effects would be targeted for identification; secondary tests would be used where suggested by questionnaire or symptom data or by knowledge of the effects of chemicals at the hazardous waste site. PMID- 7845333 TI - Neurobehavioral test strategies for environmental exposures in pediatric populations. AB - The Agency for Toxic Substances and Disease Registry convened a workshop in Atlanta, GA, that evaluated approaches and methods to ascertain whether there are neurobehavioral sequelae to children and adults exposed to hazardous substances in the environment. This article, developed from that workshop, addresses the feasibility of employing extant neurobehavioral tests to screen pediatric populations. A matrix lists basic functions to be assessed during eight developmental periods ranging from birth to high school. The best of these neurobehavioral tests for pediatric populations and the types of assessment tools that are still needed are discussed. We make 10 specific recommendations to establish a hazardous substances neurobehavioral screen for pediatric populations, including appointing a review panel, developing a structured questionnaire, convening a conference on design and analysis, addressing minority and socially disadvantaged populations, coordinating adult and child assessment methods, information sharing among Federal agencies, baseline data, methodology research, research associated with hazardous worksites, and establishment of a pediatric databank. PMID- 7845334 TI - Criteria for progressive modification of neurobehavioral batteries. AB - Six specific issues affecting the progressive modification of neurobehavioral test batteries used in field studies of populations exposed to neurotoxicants are discussed and test review recommendations are provided addressing each issue. The issues include: (a) general test review standards, (b) comprehensive assessment, (c) tailored batteries, (d) incorporation of new tests and techniques, (e) personnel and mechanisms for review, and (f) development of a battery assessing peripheral nervous system function. PMID- 7845335 TI - Adoption of an adult environmental neurobehavioral test battery. AB - Nationally recognized experts participated in a 3-day workshop to discuss the complex issues associated with neurobehavioral testing in environmental health settings, and to propose basic and focused test batteries for use in evaluating populations living near hazardous chemical sites. The Adult Environmental Neurobehavioral Test Battery (AENTB), which evaluates major neurobehavioral domains and functions, was adopted by the Agency for Toxic Substances and Disease Registry (ATSDR) for use as a basic screening panel in field studies. Pilot testing of the AENTB demonstrated an examiner training requirement of 3-6 practice sessions, a mean total testing time of 58.0 min (SD = 9.6), and, for 9 of the component tests, a sample size requirement of fewer than 140 (alpha = 0.05, 95% power) to detect a 20% difference between study groups. ATSDR administered the AENTB to 467 persons, selected randomly from 1,382 participants in field study sites in three states. Total testing time varied noticeably by participant age and study site, suggesting an ongoing need for site-specific controls in each field study using the AENTB. Also planned is adoption of a pediatric test battery to evaluate the domains and functions most relevant at major stages of child development. PMID- 7845336 TI - Atypical inheritance: new horizons for neurology. AB - Rediscovery of Mendel's laws produced an enthusiastic new discipline at the turn of this century. The eugenics movement had many disciples in the United States, and it should be noted that the term "final solution" was first used by the National Association of Charities and Corrections in the 1920s. American advocates of eugenics accomplished mass sterilization of retarded individuals and the prohibition of Jewish immigration from Germany during World War II. It is interesting that the close of this century has produced a similar revolution in genetics. These newer genetic mechanisms expose the major fallacy of eugenics: traits may be genetic without showing obvious familial transmission. Sanctions against reproduction or immigration thus will have little effect on the gene pool. The clinical implications of atypical inheritance are enormous. Almost every medical disorder must be reinvestigated for evidence of subtle chromosome changes, for worsening in progressive generations, and for influence of parental origin. The classical Mendelian model taught that extreme and rare phenotypes shed light on more frequent ones, hence the definition of genes responsible for hypercholesterolemia, for Alzheimer disease, and for amyotrophic lateral sclerosis. Atypical inheritance mechanisms further enhance this approach, bringing all of neurology under the light of genetic technology. The lure for the practitioner, then, is not the hyperbole of molecular biology; it is the need for a seasoned hand so emphasized by Huntington's disease and the duty to protect the next century from disasters of the current one. PMID- 7845337 TI - Genetic anticipation. Expanding tandem repeats. AB - The recent discovery that expanding trinucleotide repeats are a form of mutation is a radical departure from the traditional genetic principles of inheritance based on the stable transmission of DNA sequences. The concept that a gene may be altered from tissue to tissue in a single individual or from one generation to the next and that it may confer increasing mutability on itself has provided some insight into the phenomenon of anticipation as manifested by increasing severity, declining age of onset, and increasing penetrance in several inherited disorders. This concept raises the question of how common this mutational mechanism may be in the causes of genetic disease. For example, expansions of trinucleotide repeats may be the underlying mechanism for other disorders that show features suggestive of anticipation such as schizophrenia, bipolar affective disorder, autism and other hereditary ataxias. Expressed genes with trinucleotide repeats have been observed in fetal and adult brains. A recent approach to identifying expanded repeats may simplify the process of finding candidate genes. It is intriguing to speculate how often observations such as intrafamilial variation and even new mutations may be due to such a mechanism. Systematic studies of families with disorders found to be associated with such repeats will be necessary. The implications in genetic counseling for prediction of postnatal outcome as well as risks of recurrence are truly staggering. Meanwhile, the immediate benefit of the knowledge of trinucleotide repeat expansions concerning the six disorders discussed will be the application of direct methods of diagnosis avoiding linkage analysis. The long-term benefits may very well be the discovery of more effective treatment modalities based on correction of the gene defects. Exciting times for human genetics appear to be at hand. PMID- 7845339 TI - Peroxisomal disorders. AB - Disorders of peroxisome function result in severe and progressive neurologic deficits. Knowledge of these disorders and their role in neurodegenerative disorders has been growing rapidly over the last 40 years. Noninvasive diagnostic tests can identify all of the peroxisomal disorders, many of them prenatally. The genetic basis of some of these peroxisomal disorders is being established, which will advance understanding of their pathobiology and provide clues for therapeutic interventions. PMID- 7845338 TI - Molecular diagnosis and modern management of Duchenne muscular dystrophy. AB - The increased understanding of the genetic basis for DMD and the pathophysiology of the disease have produced improved techniques of patient and carrier diagnosis, genetic counseling, and new approaches to searching for a treatment. The present level of experimentation with both myoblast implantation and gene therapy may make treatment of this inherited, relentlessly progressive muscle disease possible within the next several years. PMID- 7845340 TI - Biochemical and molecular teratology of fetal hydantoin syndrome. AB - Animal and human research has clearly shown that anticonvulsants are teratogens and pose a risk for fetal malformations. In the case of dilantin it appears that fetal susceptibility correlates with the fetal level of the microsomal detoxifying enzyme epoxide hydrolase. The genetics of seizures in the parents does not predict the risk for fetal teratogenesis. The clinician must work with a mother who has seizures prior to conception to achieve the best control of seizures with a single anticonvulsant at the lowest effective dose to minimize the teratogenic potential, but even if this is done there is still a risk of fetal malformations and developmental delays. Each pregnancy in a woman on anticonvulsants is at risk, and appropriate counseling should be accomplished before conception so the family can make an informed decision. The exact risk of teratogenesis is lower than previously recorded. Dilantin poses approximately a 10% risk, tegretol less than 10%, and valproic acid causes a threefold increase in the risk of neural tube defects as well as an increased risk of other malformations. The positive aspect is that with good medical management and good prenatal care approximately 90% of infants exposed to anticonvulsants in utero will not show evidence of teratogenesis. Finally, it is important to stress that all pregnancies carry a 3% risk for a major birth defect independent of any exposures or genetic history. PMID- 7845341 TI - Pregnancy, teratogenesis, and epilepsy. AB - Women with epilepsy who are of childbearing age need to understand what the risks of pregnancy are. These women have a 33% risk of increased seizures, a twofold increase in risk of hemorrhage, eclampsia, premature labor, and an increased need for cesarean sections. Babies born to women with epilepsy face a higher risk of miscarriage, stillbirth, prematurity, developmental delay, and major malformations. Seizure control should be obtained without clinical toxicity. Monotherapy reduces the risk of adverse outcomes. PMID- 7845342 TI - Cerebral dysgenesis. An overview. AB - A significant portion of patients with neurodevelopmental abnormalities (mental retardation, learning disabilities, and so forth) have no definable cause for these problems. Mounting evidence suggests a substantial number of these idiopathic conditions have subtle abnormalities of brain development (cerebral dysgenesis) as the inherent pathophysiologic event. In this article the authors summarize normal and abnormal brain development, the diagnostic approach to idiopathic neurodevelopmental anomalies, and the new molecular genetic insights into the underlying causes of brain malformations. PMID- 7845343 TI - Morphometric studies using neuroimaging. AB - The contemporary revolution in computerized information processing has enabled the development of methods to quantitate brain morphology in vivo, especially through the analysis of MR imaging. The first brain morphometric studies employed a planimetric approach, usually assessing the cross-sectional areas of midline structures such as the corpus callosum. Subsequently, computer-assisted methods have been developed to quantitate brain volumes, and to segment the white and gray matter and cerebrospinal fluid compartments of the brain. Studies of Tourette, Turner, Down, and Williams syndromes also demonstrate methods that have been used for the morphometry of specific regions within the cerebrum and cerebellum. Although there remain some important issues regarding the interpretation of morphometric results, technological progress will continue to advance the power and availability of brain morphometry. Morphometric data may soon provide useful diagnostic and prognostic information for the practice of pediatric neurogenetics. PMID- 7845344 TI - Indicators of nicotine addiction among women--United States, 1991-1992. AB - An estimated 22 million U.S. women were current smokers in 1993; of these, 73% wanted to quit smoking (1). However, attempts to quit smoking and to remain abstinent are hindered by nicotine addiction and by the subsequent effects of nicotine withdrawal (2). To assess the prevalence of selected indicators of nicotine addiction among U.S. women, CDC analyzed data from the National Household Survey on Drug Abuse (NHSDA) in 1991 and 1992 (3). This report presents the findings of the analysis.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845345 TI - Prevalence of recommended levels of physical activity among women--Behavioral Risk Factor Surveillance System, 1992. AB - Regular physical activity provides important health benefits for women, including lower risks for coronary heart disease, some cancers, osteoporosis, and other leading causes of death and disability (1-3). Despite such benefits, the proportion of women in the United States reporting regular physical activity has been low (4). Because even moderately intense physical activity has substantial health benefits, public health recommendations for physical activity have been expanded to a broader spectrum of activity, including gardening, walking, and housework in addition to more vigorous aerobic exercise (e.g., jogging) (5,6). To improve estimates of the prevalence of participation in physical activity at levels associated with health benefits among adult women, data about leisure-time physical activity were analyzed from the 1992 Behavioral Risk Factor Surveillance System (BRFSS). This report summarizes the results of these analyses.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845346 TI - Smokeless tobacco use among American Indian women--southeastern North Carolina, 1991. AB - Rates of smokeless tobacco use among U.S. adults are highest for young males, American Indians/Alaskan Natives, persons residing in the South or rural areas of the country, and those of low socioeconomic status (1). In addition, the prevalence of smokeless tobacco use has been reported to be high in tobacco producing regions, including rural North Carolina and Kentucky (2,3). In southeastern North Carolina, reports from physicians and dentists suggested a high prevalence of smokeless tobacco use in the local American Indian population, the Lumbee--particularly among women and children. In response to these reports, the Department of Family and Community Medicine at the Bowman Gray School of Medicine of Wake Forest University analyzed data from a National Cancer Institute sponsored cervical cancer prevention program to estimate the prevalence of smokeless tobacco use during 1991 among Lumbee women aged > or = 18 years residing in Robeson County, North Carolina (1990 population: 105,179).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845347 TI - Update: dracunculiasis eradication--Pakistan, 1994. AB - Dracunculiasis (Guinea worm disease)--a disabling infection that affects persons in 16 African and three Asian countries--has been targeted by the World Health Organization (WHO) for global eradication by the end of 1995. A total of 221,055 cases were reported to WHO for 1993 (1). Efforts to eradicate dracunculiasis in each of the 19 affected countries are focused on interrupting all transmission. This report summarizes the impact of Pakistan's Guinea Worm Eradication Program (GWEP).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845348 TI - Serogroup B meningococcal disease--Oregon, 1994. AB - In Oregon, the incidence of meningococcal disease has increased substantially, more than doubling from 2.2 cases per 100,000 persons in 1992 to 4.6 per 100,000 in 1994--the highest incidence in Oregon since 1943. This incidence was almost fivefold higher than recent estimates for the United States during 1989-1991 (approximately one case per 100,000 persons annually) (1). This report describes meningococcal disease surveillance data from 1994 and summarizes epidemiologic and laboratory data on serogroup B meningococcal disease in Oregon during 1987 1994. PMID- 7845349 TI - Trends in sexual risk behavior among high school students--United States, 1990, 1991, and 1993. AB - Since the early 1980s, adolescents in the United States have experienced high rates of unintended pregnancies (1) and sexually transmitted diseases (STDs) (2), including HIV infection (3). Since 1990, CDC's Youth Risk Behavior Surveillance System has enabled measurement of priority health-risk behaviors among high school students at the national, state, and local levels (4). This report examines data from the 1990, 1991, and 1993 national Youth Risk Behavior Survey (YRBS)* to describe trends in selected self-reported sexual risk behaviors among U.S. high school students. PMID- 7845350 TI - Update: influenza activity--New York and United States, 1994-95 season. AB - Influenza activity in the United States during the current influenza season began in the Northeast, and during late January, spread to other regions of the country. This report describes influenza outbreaks in nursing homes in New York and summarizes national influenza surveillance data from October 2, 1994, through February 11, 1995. PMID- 7845351 TI - NPK15, a tobacco protein-serine/threonine kinase with a single hydrophobic region near the amino-terminus. AB - A cDNA clone (cNPK15) was isolated from tobacco cells in suspension culture, which encodes a predicted protein kinase of 422 amino acids. The predicted NPK15 protein consists of a hydrophobic region near the amino-terminus, a linker domain and the catalytic domain of a protein-serine/threonine kinase in the carboxyl half. NPK15 was not found to be closely related to any reported protein, but its putative catalytic domain shares some structural similarity with those of receptor-like protein kinases of plants, such as ZmPK1 from Zea mays and TMK1 from Arabidopsis, even though no receptor-like domain is found in NPK15. Recombinant NPK15 expressed in Escherichia coli as a fusion protein was found capable of autophosphorylation and of phosphorylation of the histone H1 protein on both serine and threonine residues. Upon overexpression of cNPK15 under control of the promoter of cauliflower mosaic virus 35S RNA in tobacco cells, into which it had been introduced by Agrobacterium-mediated transformation, the NPK15 gene acted as a "suicide" gene and blocked proliferation of the host cells. By contrast, such a suicide effect was not observed with the gene for a kinase negative mutant protein in which the nucleotide sequence for the ATP-binding site had been mutated or with a mutant derivative encoding a protein in which the hydrophobic region had been deleted. Thus, the protein kinase activity of NPK15 and the hydrophobic region of the protein are responsible for the suicide effect. The NPK15 protein kinase seems to be associated with specific cellular functions. Southern blot analysis with cNPK15 as the probe detected several fragments in restriction digests of genomic DNAs from both tobacco and other members of the Solanaceae. This results suggests that NPK15-related genes constitute a small gene family in the genomes of Solanaceae. PMID- 7845352 TI - A new yeast gene, HTR1, required for growth at high temperature, is needed for recovery from mating pheromone-induced G1 arrest. AB - A new temperature-sensitive mutant of Saccharomyces cerevisiae was isolated. Arrested cells grown at the nonpermissive temperature were of dumb-bell shape and contained large vacuoles. A DNA fragment was cloned based on its ability to complement this temperature sensitivity. The HTR1 gene encodes a putative protein of 93 kDa without significant homology to any known proteins. The gene was mapped between ade5 and lys5 on the left arm of chromosome VII. The phenotype of the gene disruptant appeared to be strain-specific; disruption of the gene in strain W303 caused the cells to become temperature sensitive. The arrested phenotype here was similar to that of the original ts mutant and cells in G2/M phase predominated at high temperature. Another disruptant in a strain YPH background grew slowly at high temperature due to slow progression through G2/M phase, and morphologically abnormal (elongated) cells accumulated. A single-copy suppressor that alleviated the temperature-sensitive defects in both strains was identified as MCS1/SSD1. The wild-type strains W303 and YPH are known to carry defective MCS1/SSD1 alleles; hence HTR1 may function redundantly with MCS1/SSD1 to suppress the temperature-sensitive phenotypes. In addition, based on a halo bioassay, the disruptant strains appeared to be defective in recovery from, or adaptive response to G1 arrest mediated by mating pheromone, even at the permissive temperature. Thus the gene has at least two functions and is designated HTR1 (required for high temperature growth and recovery from G1 arrest induced by mating pheromone). PMID- 7845354 TI - Promoter analysis and transcriptional regulation of Lactobacillus pentosus genes involved in xylose catabolism. AB - The xyl genes in Lactobacillus pentosus are induced by xylose and repressed by glucose, ribose, and arabinose. Northern blot analysis showed that regulation is mediated at the transcriptional level. Under inducing conditions, two xylA transcripts were detected, a major transcript of 1.5 kb and a minor transcript of 3 kb. The 3 kb transcript also comprises sequences from xylB, suggesting that xylA and xylB are transcribed together. A 1.2 kb xylR transcript was found under inducing and non-inducing conditions. In the presence of xylose, a second xylR transcript (> 7 kb) was detected, which includes sequences from two upstream genes, xylQ and xylP. The transcription start sites for xylA and xylR were mapped by primer extension and S1 nuclease experiments at 42 and 83 nucleotides, respectively upstream of the translation start sites. Induction by xylose of the chloramphenicol acetyltransferase (CAT) gene under control of the xylA promoter, on a multicopy plasmid, was 60 to 80-fold, but only 3 to 10-fold in the presence of glucose and xylose. Expression of CAT under control of the xylR promoter was constitutive at a level tenfold less than that observed under control of the xylA promoter. Sequence analysis suggests the presence of two operator-like elements, one overlapping with the promoter -35 region of xylA and controlling the expression of xylA by binding factors involved in catabolite repression, and a second operator downstream of the promoter -10 region of xylA, which may bind the product of xylR, the repressor.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845353 TI - Molecular and genetic characterization of the rhizopine catabolism (mocABRC) genes of Rhizobium meliloti L5-30. AB - Rhizopine (L-3-O-methyl-scyllo-inosamine, 3-O-MSI) is a symbiosis-specific compound, which is synthesized in nitrogen-fixing nodules of Medicago sativa induced by Rhizobium meliloti strain L5-30. 3-O-MSI is thought to function as an unusual growth substrate for R. meliloti L5-30, which carries a locus (mos) responsible for its synthesis closely linked to a locus (moc) responsible for its degradation. Here, the essential moc genes were delimited by Tn5 mutagenesis and shown to be organized into two regions, separated by 3 kb of DNA. The DNA sequence of a 9-kb fragment spanning the two moc regions was determined, and four genes were identified that play an essential role in rhizopine catabolism (mocABC and mocR). The analysis of the DNA sequence and the amino acid sequence of the deduced protein products revealed that MocA resembles NADH-dependent dehydrogenases. MocB exhibits characteristic features of periplasmic-binding proteins that are components of high-affinity transport systems. MocC does not share significant homology with any protein in the database. MocR shows homology with the GntR class of bacterial regulator proteins. These results suggest that the mocABC genes are involved in the uptake and subsequent degradation of rhizopine, whereas mocR is likely to play a regulatory role. PMID- 7845356 TI - Glutathione transferase gene family from the housefly Musca domestica. AB - Three new glutathione transferase (GST) genes from the housefly Musca domestica are described. These genes, identified as MdGST-2, -3, and -4, were from cDNA clones obtained from a cDNA bank in phage lambda. The bank was prepared using poly(A)+ RNA from a housefly that is highly resistant to organophosphate insecticides because of enhanced expression of multiple members of the glutathione transferase gene family. The DNA sequence of each is reported and has a complete open reading frame that specified an amino acid sequence similar to other dipteran glutathione transferases. Based on phylogenetic analysis, we can conclude that the insect glutathione transferase gene family falls into two groups, each of which evolves at a different rate, presumably due to differences in functional constraints. We show that MdGST-1 (and their homologues from Drosophila and Lucilia) evolve at a significantly slower rate than the other members of the gene family. Each housefly GST cDNA was inserted into a bacterial plasmid expression system and a glutathione transferase activity was expressed in Escherichia coli. The transcription pattern of each of these glutathione transferases was examined in a variety of different housefly strains that are known to differ in their resistance to organophosphate insecticides due to different patterns of glutathione transferase expression. We found that the level of transcription for two of our clones was positively correlated with the level of organophosphate resistance. PMID- 7845355 TI - Amplification of the groESL operon in Pseudomonas putida increases siderophore gene promoter activity. AB - Pseudobactin 358 is the yellow-green fluorescent siderophore [microbial iron(III) transport agent] produced by Pseudomonas putida WCS358 under iron-limiting conditions. The genes encoding pseudobactin 358 biosynthesis are iron-regulated at the level of transcription. In this study, the molecular characterization is reported of a cosmid clone of WCS358 DNA that can stimulate, in an iron-dependent manner, the activity of a WCS358 siderophore gene promoter in the heterologous Pseudomonas strain A225. The functional region in the clone was identified by subcloning, transposon mutagenesis and DNA sequencing as the groESL operon of strain WCS358. This increase in promoter activity was not observed when the groESL genes of strain WCS358 were integrated via a transposon vector into the genome of Pseudomonas A225, indicating that multiple copies of the operon are necessary for the increase in siderophore gene promoter activity. Amplification of the Escherichia coli and WCS358 groESL genes also increased iron-regulated promoter activity in the parent strain WCS358. The groESL operon codes for the chaperone proteins GroES and GroEL, which are responsible for mediating the folding and assembly of many proteins. PMID- 7845358 TI - A mating-type factors of Coprinus cinereus have variable numbers of specificity genes encoding two classes of homeodomain proteins. AB - We have identified the seven genes that constitute the A43 mating-type factor of Coprinus cinereus and compare the organisation of A43 with the previously characterised A42 factor. In both, the genes that trigger clamp cell development, the so-called specificity genes, are separated into alpha and beta loci by 7 kb of noncoding sequence and are flanked by homologous genes alpha-fg and beta-fg. The specificity genes are known to encode two classes of dissimilar homeodomain (HD1 and HD2) proteins and have different allelic forms which show little or no cross-hybridisation. By partial sequencing we identified a divergently transcribed HD1 (a1-2) and HD2 (a2-2) gene in the A43 alpha locus. a2-2 failed to elicit clamp cell development in three different hosts, suggesting that it is non functional. a1-2 elicited clamp cells in an A42 host that has only an HD2 gene (a2-1) in its alpha locus, thus demonstrating that the compatible A alpha mating interaction is between an HD1 and an HD2 protein. The A43 beta locus contains three specificity genes, the divergently transcribed HD1 and HD2 genes b1-2 and b2-2 and a third HD1 gene (d1-1) that was shown by hybridisation and transformation analyses to be functionally equivalent to d1-1 in A42. An untranscribed footprint of a third A42 HD1 gene, c1-1, was detected between the A43 b2-2 and d1-1 genes by Southern hybridisation. PMID- 7845357 TI - Site-directed mutagenesis of the yeast PRP20/SRM1 gene reveals distinct activity domains in the protein product. AB - Prp20/Srm1, a homolog of the mammalian protein RCC1 in Saccharomyces cerevisiae, binds to double-stranded DNA (dsDNA) through a multicomponent complex in vitro. This dsDNA-binding capability of the Prp20 complex has been shown to be cell cycle dependent; affinity for dsDNA is lost during DNA replication. By analyzing a number of temperature sensitive (ts) prp20 alleles produced in vivo and in vitro, as well as site-directed mutations in highly conserved positions in the imperfect repeats that make up the protein, we have determined a relationship between the residues at these positions, cell viability, and the dsDNA-binding abilities of the Prp20 complex. These data reveal that the essential residues for Prp20 function are located mainly in the second and the third repeats at the amino-terminus and the last two repeats, the seventh and eighth, at the carboxyl terminus of Prp20. Carboxyl-terminal mutations in Prp20 differ from amino terminal mutations in showing loss of dsDNA binding: their conditional lethal phenotype and the loss of dsDNA binding affinity are both suppressible by overproduction of Gsp1, a GTP-binding constituent of the Prp20 complex, homologous to the mammalian protein TC4/Ran. Although wild-type Prp20 does not bind to dsDNA on its own, two mutations in conserved residues were found that caused the isolated protein to bind dsDNA. These data imply that, in situ, the other components of the Prp20 complex regulate the conformation of Prp20 and thus its affinity for dsDNA. Gsp1 not only influences the dsDNA-binding ability of Prp20 but it also regulates other essential function(s) of the Prp20 complex. Overproduction of Gsp1 also suppresses the lethality of two conditional mutations in the penultimate carboxyl-terminal repeat of Prp20, even though these mutations do not eliminate the dsDNA binding activity of the Prp20 complex. Other site directed mutants reveal that internal and carboxyl-terminal regions of Prp20 that lack homology to RCC1 are dispensable for dsDNA binding and growth. PMID- 7845359 TI - Mutational spectrum induced in Saccharomyces cerevisiae by the carcinogen N-2 acetylaminofluorene. AB - The spectrum of mutations induced by the carcinogen N-2-acetylaminofluorene (AAF) was analysed in Saccharomyces cerevisiae using a forward mutation assay, namely the inactivation of the URA3 gene. The URA3 gene, carried on a yeast/bacterial shuttle vector, was randomly modified in vitro using N-acetoxy-N-2 acetylaminofluorene (N-AcO-AAF) as a model reactive metabolite of the carcinogen AAF. The binding spectrum of AAF to the URA3 gene was determined and found to be essentially random, as all guanine residues reacted about equally well with N-AcO AAF. Independent Ura- mutants were selected in vivo after transformation of the modified plasmid into a ura3 delta yeast strain. Plasmid survival decreased as a function of AAF modification, leading to one lethal hit (37% relative survival) for an average of approximately 50 AAF adducts per plasmid molecule. At this level of modification the mutation frequency was equal to approximately 70 x 10( 4), i.e. approximately 50-fold above the background mutation frequency. UV irradiation of the yeast cells did not further stimulate the mutagenic response, indicating the lack of an SOS-like mutagenic response in yeast. Sequence analysis of the URA3 mutants revealed approximately 48% frameshifts, approximately 44% base substitutions and approximately 8% complex events. While most base substitutions (74%) were found to be targeted at G residues where AAF is known to form covalent C8 adducts, frameshift mutations were observed at GC base pairs in only approximately 24% of cases.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845360 TI - Sequencing of genes within the vir regulon of Streptococcus pyogenes type M15--an opacity factor-positive serotype with low opacity factor expression. AB - Major virulence determinants of group A streptococci, such as M-protein, immunoglobulin Fc-receptors (FcRA, EmmL) and C5a peptidase, appear to be genetically co-regulated, their genes being located within a vir regulon. We studied the organization of these genes in a group A, type M15 strain of Streptococcus pyogenes, previously defined as OF-, by hybridization analysis of chromosomal DNA and of an S. pyogenes gene library in Escherichia coli, and by gene sequencing. Within the vir regulon, in addition to the virR and scpA genes, three so-called emm-related genes were found: fcrA, emmL and enn. Whereas IgG Fc binding proteins were encoded by fcrA and emmL, the product of enn was not identified. The presence of three emm-related genes in this region is reminescent of vir regulon organization in OF+ rather than OF- strains as earlier defined by others. Furthermore, analysis of the deduced product of the emmL gene showed deletions and amino acid substitutions within the PGTS-rich domain and membrane anchor, which thus resembles corresponding products of OF+ rather than OF- strains. In view of these findings, the opacity factor (OF) activity of the strain was tested using growth supernatant, with negative outcome. However, a concentrated SDS cell extract revealed definite OF activity. One of two other type M15 reference strains also showed definite OF activity in SDS extracts. We therefore propose that type M15 strains belong to the OF+ category but often show low levels of expression of OF. PMID- 7845361 TI - Ethanol-hypersensitive and ethanol-dependent cdc- mutants in Schizosaccharomyces pombe. AB - Ethanol-hypersensitive strains (ets mutants), unable to grow on media containing 6% ethanol, were isolated from a sample of mutagenized Schizosaccharomyces pombe wild-type cells. Genetic analysis of these ets strains demonstrated that the ets phenotype is associated with mutations in a large set of genes, including cell division cycle (cdc) genes, largely non-overlapping with the set represented by the temperature conditional method; accordingly, we isolated some ets non-ts cdc- mutants, which may identify novel essential genes required for regulation of the S. pombe cell cycle. Conversely, seven well characterized ts cdc- mutants were tested for their ethanol sensitivity; among them, cdc1-7 and cdc13-117 exhibited a tight ets phenotype. Ethanol sensitivity was also tested in strains bearing different alleles of the cdc2 gene, and we found that some of them were ets, but others were non-ets; thus, ethanol hypersensitivity is an allele-specific phenotype. Based on the single base changes found in each particular allele of the cdc2 gene, it is shown that a single amino acid substitution in the p34cdc2 gene product can produce this ets phenotype, and that ethanol hypersensitivity is probably due to the influence of this alcohol on the secondary and/or tertiary structure of the target protein. Ethanol-dependent (etd) mutants were also identified as mutants that can only be propagated on ethanol-containing media. This novel type of conditional phenotype also covers many unrelated genes. One of these etd mutants, etd1-1, was further characterized because of the lethal cdc- phenotype of the mutant cells under restrictive conditions (absence of ethanol). The isolation of extragenic suppressors of etd1-1, and the complementation cloning of a DNA fragment encompassing the etd1+ wild-type gene (or an extragenic multicopy suppressor) demonstrate that current genetic techniques may be applied to mutants isolated by using ethanol as a selective agent. PMID- 7845362 TI - Sequence of the HAP3 transcription factor of Kluyveromyces lactis predicts the presence of a novel 4-cysteine zinc-finger motif. AB - The Kluyveromyces lactis homologue of the Saccharomyces cerevisiae HAP3 gene was isolated by functional complementation of the respiratory-deficient phenotype of the S. cerevisiae hap3::HIS4 strain SHY40. The KlHAP3 gene encodes a protein of 205 amino acids, of which the central B-domain of 90 residues is highly homologous to HAP3 counterparts of S. cerevisiae and higher eukaryotes. The protein contains a novel 4-cysteine zinc-finger motif and we propose by analogy that all other homologous HAP3 proteins contain the same motif, with the position containing the third cysteine being occupied by a serine residue. In contrast to the situation in S. cerevisiae, disruption of the KlHAP3 gene in K. lactis does not result in a respiratory-deficient phenotype and the growth of the null strain is indistinguishable from wild type. There is also no effect on the expression of the carbon source-regulated KlCYC1 gene, suggesting either a different role for the HAP2/3/4 complex, or the existence of a different mechanism of carbon source regulation. Sequence verification of the S. cerevisiae HAP3 locus reveals that, just as in K. lactis, a long open reading frame (ORF) is present upstream of the HAP3 gene. These highly homologous ORFs are predicted to have at least eight membrane-spanning fragments, but do not show significant homology to any known sequence present in databases. The ScORFX gene is transcribed in the opposite direction to ScHAP3, but, in contrast to an earlier report by Hahn et al. (1988), the transcripts of the two genes do not overlap. The model proposed by these authors, in which the ScHAP3 gene is regulated by an anti-sense non-coding mRNA, is therefore not correct. PMID- 7845363 TI - Domoic acid inhibits adenylate cyclase activity in rat brain membranes. AB - Adenylate cyclase activity measured by the formation of cyclic AMP in rat brain membranes was inhibited by a shellfish toxin, domoic acid (DOM). The inhibition of enzyme was dependent on DOM concentration, but about 50% of enzyme activity was resistant to DOM-induced inhibition. Rat brain supernatant resulting from 105,000 x g centrifugation for 60 min, stimulated adenylate cyclase activity in membranes. Domoic acid abolished the supernatant-stimulated adenylate cyclase activity. The brain supernatant contains factors which modulate adenylate cyclase activity in membranes. The stimulatory factors include calcium, calmodulin, and GTP. In view of these findings, we examined the role of calcium and calmodulin in DOM-induced inhibition of adenylate cyclase in brain membranes. Calcium stimulated adenylate cyclase activity in membranes, and further addition of calmodulin potentiated calcium-stimulated enzyme activity in a concentration dependent manner. Calmodulin also stimulated adenylate cyclase activity, but further addition of calcium did not potentiate calmodulin-stimulated enzyme activity. These results show that the rat brain membranes contain endogenous calcium and calmodulin which stimulate adenylate cyclase activity. However, calmodulin appears to be present in membranes in sub-optimal concentration for adenylate cyclase activation, whereas calcium is present at saturating concentration. Adenylate cyclase activity diminished as DOM concentration was increased, reaching a nadir at about 1 mM. Addition of calcium restored DOM inhibited adenylate cyclase activity to the control level. Similarly, EGTA also inhibited adenylate cyclase activity in brain membranes in a concentration dependent manner, and addition of calcium restored EGTA-inhibited enzyme activity to above control level.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845364 TI - Conformationally altered aortic myosin light chains. AB - Aorta smooth myosin contains two types of light chain, LC20 and LC17, which fold together with the N-terminal region of each heavy chain to form the globular head region of myosin. We demonstrate an altered conformation of LC20 after its separation from heavy chain by high concentrations of urea, on the basis of the following evidence: 1) A polyclonal antibody against LC20 was not able to recognize this conformationally altered form; 2) Myosin reconstituted from heavy chains and urea-dissociated light chains exhibited extremely low ATPase activity. Circular dichroism unfolding profiles showed that light chains dissociated from heavy chains by SDS appeared to be more stable than those generated by urea dissociation. PMID- 7845365 TI - Protective effects of lazaroids against oxygen-free radicals induced lysosomal damage. AB - Lipid peroxidation of membranes by oxygen free radicals has been implicated in various disease states. Different antioxidants and iron chelators have been used to reduce lipid peroxidation. Lazaroids have been used for the acute treatment of central nervous system disorders such as trauma and ischemia wherein lipid peroxidative processes take place. In this study we evaluated the effect of lazaroids (U-78518F and U-74389F) on the release of acid phosphatase activity and formation of malondialdehyde (MDA) in rat liver lyosomes subjected to exogenously generated oxygen free radicals. There was a significant increase in the acid phosphatase release and MDA formation in the presence of oxygen free radicals. This was prevented by both the lazaroids. In a separate study the effect of lazaroid U-74389F was seen on the zymosan-stimulated polymorphonuclear (PMN) leukocyte-derived chemiluminescence. The PMN leukocyte chemiluminescent activity was attenuated by the lazaroid in a dose-dependent manner. These studies suggest that lazaroids may inhibit lipid peroxidation and stabilize the membrane. PMID- 7845367 TI - Hydroxyl radical-scavenging property of indomethacin. AB - The ability of indomethacin to scavenge hydroxyl radical (.OH) using high pressure liquid chromatography (HPLC) was investigated. .OH radical was generated by photolysis of H2O2 (1.5-10 mmoles/L) with UV light and was trapped with salicyclic acid (500 nmoles). H2O2 produced .OH in a concentration-dependent manner as estimated by .OH adduct products 2,3- and 2,5-dihydroxybenzoic acid (DHBA). Indomethacin in increasing concentrations (5-600 mumoles/L) produced increasing inhibition of generation of 2,3-DHBA (7-67%) and of 2,5-DHBA (7-77%). The results indicate that indomethacin scavenges .OH in a concentration-dependent manner. PMID- 7845366 TI - Acetoacetate metabolism in AS-30D hepatoma cells. AB - Metabolic characteristics of experimental hepatoma cells include elevated rates of glycolysis and lipid synthesis. However, pyruvate derived from glucose is not redily oxidized, and the source of acetyl CoA for lipid synthesis in As-39D cells has not been characterized. In this study ketone bodies were examined as a possible source of acetyl CoA in AS-30D hepatoma cells. The major findings were: 1. Acetoacetate was utilized by AS-30D cells, with 14C-lipid and 14CO2 as major products of [3-14C] acetoacetate. 2. Lipid synthesis from acetoacetate was dependent on the presence of glucose in the medium. 3. Acetoacetate supported rapid respiration by AS-30D mitochondria in the presence of 0.1 mM malate. 4. Succinyl CoA acetoacetyl CoA transferase activity in AS-30D mitochondria was approximately 40 fold greater than that found in rat liver mitochondria. 5. Addition of acetoacetate, but not beta-hydroxybutyrate decreased conversion of [1 14C] acetate to 14CO2, presumably by diluting the specific radioactivity of the acetyl CoA derived from the acetate tracer. 6. In the presence of glucose, approximately one fourth of acetoacetate utilized was converted to lipid. This result is consistent with elevated lipogenesis postulated by the truncated TCA cycle hypothesis.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845368 TI - Demonstration of argininosuccinate synthetase activity associated with mitochondrial membrane: characterization and hormonal regulation. AB - Argininosuccinate synthetase (AS) is the third enzyme in ureogenesis, it catalyses the reaction of condensation of citrulline and aspartate into argininosuccinate. In the present report, we described the first characterization of AS within the outer membrane of rat liver mitochondria. Mitochondria associated AS displayed the same kinetic characteristics as the cytoplasmic enzyme, but was found to be thermostable while cytoplasmic AS was not. The evolution of the co-location of AS was analyzed during ontogenesis. Total AS activity increased throughout rat fetal development. Simultaneously, the subcellular distribution of the enzyme has changed. AS activity was mainly mitochondrial in fetal and new-born liver liver and cytoplasmic in adult rat liver. The variation in subcellular distribution of AS may be due to the dramatic changes in hormonal levels that occur during this period. The role of corticosteroid and pancreatic hormones was studied. During fetal period, corticosteroid hormones induced an increase in mitochondria-associated AS activity. This was prevented by insulin. Glucagon did not modify total AS activity but reduced mitochondrial AS activity, meanwhile, a comparable increase in cytoplasmic AS activity was observed. One may hypothesize that glucagon may participate in the transfer of mitochondrial enzyme into the cytosol. PMID- 7845369 TI - Regulation of the phosphorylation of calpain II and its inhibitor. AB - Phosphorylation of calpain II (or its inhibitor) by the catalytic subunit of cyclic AMP-dependent protein kinase (A-PK), cyclic GMP-dependent protein kinase (G-PK), and protein kinase C (PK-C) was analyzed by SDS-polyacrylamide gel electrophoresis and autoradiography. Among these protein kinases, the catalytic subunit of A-PK exhibited the strongest phosphorylations of both calpain II and its inhibitor. Arachidonic acid and staurosporine effectively inhibited phosphorylation regardless the type of kinase tested. Despite its lack of effect on the phosphorylation of calpain II by the catalytic subunit of A-PK, sphingosine moderately enhanced the phosphorylation of calpain II by G-PK. Other agents, including phosphatidylethanolamine, phosphatidylinositol and 1, 2 dioleoyl-sn-glycerol, had no significant effect. PMID- 7845370 TI - Effect of beta-alanyl-L-histidinato zinc on protein components in osteoblastic MC3T3-El cells: increase in osteocalcin, insulin-like growth factor-I and transforming growth factor-beta. AB - The effect of beta-alanyl-L-histidinato zinc (AHZ) on protein components in osteoblastic MC3T3-E1 cells was investigated. Cells were cultured for 3 days at 37 degrees C in CO2 incubator in plastic dishes containing alpha-modified minimum essential medium supplemented with 10% fetal bovine serum. After the cultures, the medium was exchanged for that containing 0.1% bovine serum albumin plus various concentrations of AHZ or other reagents, and the cells were cultured further 3 or 6 days. The homgenate of cells was analyzed with SDS-polyacrylamide gel electrophoresis (SDS-PAGE). The presence of AHZ (10(-7) to 10(-5) M) caused an appreciable increase of many protein components in cells. Especially, the 67 killo-dalton (kDa) and 44 kDa proteins which are the major components from control cells were clearly increased by the presence of AHZ. Furthermore, the concentrations of osteocalcin, insulin-like growth factor-I and transforming growth factor-beta in the culture medium secreted from osteoblastic cells were markedly increased by the presence of AHZ (10(-6) and 10(-5) M). The effect of AHZ was a greater than that of zinc sulfate (10(-6) and 10(-5) M). The present findings suggest that AHZ can increase many proteins which are involved in the stimulation of bone formation and cell proliferation in osteoblastic cells. PMID- 7845372 TI - Nicotine regulates collagen gene expression, collagenase activity, and DNA synthesis in cultured cardiac fibroblasts. AB - Cardiac fibroblasts that reside in the interstitium are the cellular origin of collagen and other proteins of the extracellular matrix in the heart. We have previously shown that in vitro gene expression, proliferation and even phenotypic features of cardiac fibroblasts are subject to regulation by biological factors such as hormones, growth factors and neurotransmitters. The influence of nicotine, the active ingredient of tobacco, on risk factors for cardiac diseases is well known. In vivo adverse effects of nicotine are as the result of its direct and indirect effects. The cellular and molecular mechanisms of direct effects of nicotine in the heart are widely unknown. The objective of this study was to investigate if nicotine has direct influence on cardiac fibroblasts. To this end, we studied the effects of nicotine on cultured cardiac fibroblasts. Northern hybridization analysis of RNA extracted from cardiac fibroblasts, enzymography of conditioned medium of cardiac fibroblasts and [3H]-thymidine incorporation into DNA of cardiac fibroblasts were used to examine the effects of nicotine on collagen gene expression, collagenase activity and DNA synthesis respectively. Treatment of cardiac fibroblasts with nicotine (10 micrograms/ml) led to a 31% (P < 0.05) decrease in the abundance of mRNA for pro alpha 1(I) but not pro alpha 2(I) collagen compared with control untreated cells. Nicotine treatment of cardiac fibroblasts also led to decreased collagenase activity (62%, P < 0.001) in the conditioned medium of those cells in culture. Studies with [3H] thymidine incorporation into DNA of cardiac fibroblasts showed a nicotine-induced decrease (39%, P < 0.001) in DNA synthesis in those cells.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845373 TI - Studies on the inhibitory effects of curcumin and eugenol on the formation of reactive oxygen species and the oxidation of ferrous iron. AB - The spice principles curcumin (from turmeric) and eugenol (from cloves) are good inhibitors of lipid peroxidation. Lipid peroxidation is known to be initiated by reactive oxygen species. The effect of curcumin and eugenol on the generation of reactive oxygen species in model systems were investigated. Both curcumin and eugenol inhibited superoxide anion generation in xanthine-xanthine oxidase system to an extent of 40% and 50% at concentrations of 75 microM and 250 microM respectively. Curcumin and eugenol also inhibited the generation of hydroxyl radicals (.OH) to an extent of 76% and 70% as measured by deoxyribose degradation. The .OH-radical formation measured by the hydroxylation of salicylate to 2,3-dihydroxy benzoate was inhibited to an extent of 66% and 46%, respectively, by curcumin and eugenol at 50 microM and 250 microM. These spice principles also prevented the oxidation of Fe2+ in Fentons reaction which generates .OH radicals. PMID- 7845371 TI - More to learn from gene knockouts. AB - Gene targeting by homologous recombination in mouse embryonic stem cells is a powerful technique to determine the physiological function of any gene product in embryonic and postnatal development and in molecular pathogenesis. Although the technique is very demanding and still in its developing stage several knockout mice carrying disrupted genes, which were once thought important for the development or molecular pathogenesis of certain tissues, have given unexpected results. A gene/function redundancy or superfluous and on-functional theory has been advanced by many investigators to explain the unexpected results. These surprising results may teach us a new lesson and lead to a revision of the strongly held view that highly conserved and abundantly expressed genes have a prominent role and function in cell physiology and development. Additional, they may also support the notion that molecular cross-talk among the genes may play an important role in determining the minimal phenotype. PMID- 7845374 TI - Improved postischemic ventricular functional recovery by amphetamine is linked with its ability to induce heat shock. AB - Heat shock has been shown to increase the cellular tolerances to ischemic injury. In this study, we examined the effects of heat shock induced by amphetamine on postischemic myocardial functional recovery in a setting of coronary revascularization for acute myocardial infarction. Intramuscular injection of amphetamine (3 mg/kg, i.m.) to pigs increased the body temperature to 42.5 degrees C within 1 h, and maintained this temperature for an additional 2 h. Fourty h after the amphetamine injection, the pigs were placed on by cardiopulmonary bypass and then isolated, in situ heart preparations were subjected to 1 h of global hypothermic cardioplegic arrest and 1 h of normothermic reperfusion. Postischemic myocardial performance was monitored by measuring left ventricular (LV) pressure, its dp/dt, myocardial segmental shortening (%SS), and coronary blood flow. Cellular injury was examined by measuring creatine kinase (CK) release. Biochemical measurements included quantification of plasma catecholamines and study of the induction of heat shock gene expression and antioxidative enzymes in the heart tissue. The results of this study indicated significantly greater recovery of LV contractile functions by amphetamine as demonstrated by improved recovery of LVDP (61% vs 52%), dp/dtmax (52% vs 44%), and segmental shortening (46.2% vs 10%). Myocardial CK release was significantly reduced in the amphetamine group. Furthermore, amphetamine pretreatment was associated with the induction of heat shock protein (HSP) 27 mRNA and stimulated Cu/Zn-superoxide dismutase and catalase levels, suggesting that amphetamine mediated improved postischemic ventricular recovery might be linked with its ability to induce heat shock and stimulate antioxidant enzymes. PMID- 7845375 TI - Expression of glycosphingolipids in serum-free primary cultures of mouse kidney cells: male-female differences and androgen sensitivity. AB - The expression of neutral glycosphingolipids was examined in primary kidney cell cultures derived from adult male and female beige mutant mice (C57BL/6J;bgj/bgj) with enrichment for proximal tubule cells during preparation of explants and using defined serum-free medium for the culture conditions. Cells proliferated for 7 days in vitro to provide confluent or nearly confluent monolayers of epithelial-type growth indicative of proximal tubule cells. The male vs female differences in neutral glycosphingolipids seen in the kidney in vivo were retained in these 7 day cultures. Cultures derived from males contained galacto- and digalactosylceramides whereas those from females did not express these types of glycolipids. Also, male cells had higher ratios of sphingosine: phytosphingosine containing species in Nfa (non-hydroxy fatty acid) globotriaosylceramide and in glucosylceramide than females. The shift in sphingosine: phytosphingosine to male ratios in Nfa globotriaosylceramide and in glucosylceramide could be stimulated in female kidney cells by treatment with 10( 5) M testosterone or 5 alpha-dihydrotestosterone. The male-specific expression of neutral glycosphingolipids, then, appears to be stable character of male-type differentiation in mouse kidney that is passed on during proliferation in culture. Female kidney cells retain an ability to respond to androgens with specific changes in neutral glycosphingolipid expression during 7 days of growth in vitro in serum-free conditions, but do not respond with the induction of the male-specific glycolipids galacto- and digalactosylceramides as seen in vivo. PMID- 7845376 TI - Human HE2 (microB) and microA motifs show the same function as whole IgH intronic enhancer in transgenic mice. AB - In the murine IgH gene intronic enhancer (ENHiH), two major functional domains were reported. One is the E4/octomer region and another includes the microA and microB motifs. In the human ENHiH, it was reported that the HE2, which corresponds to the murine microB, and E6 motifs play an important role in an enhancer activity and a tissue-specificity at cellular level. Here we examined the in vivo function of the E6, microA and HE2 motifs within the human ENHiH by using the transgenic mice technique. The microA and HE2 motifs together revealed almost the same enhancer function as the whole human ENHiH, but the E6 motif had lesser enhancer activity and tissue-specificity. PMID- 7845378 TI - Effect of aluminium (Al) on brain mitochondrial monoamine oxidase-A (MAO-A) activity--an in vitro kinetic study. AB - Effect of aluminium (Al) on rat brain mitochondrial monoamine oxidase-A (MAO-A) was studied in vitro at three different pH (4.0, 7.4 and 9.0) values. The results have shown that Al is a non-competitive inhibitor for MAO-A. The data also showed that MAO-A inhibition by Al varies with free Al3+ concentration and different forms of Al under different pH conditions. Al altered the maximum velocity (Vmax) of MAO-A but did not affect substrate-enzyme affinity (Km). Al formed a strong chelation with the substrate (Kynuramine) (1:1). PMID- 7845379 TI - The characterization of aluminium--alanine complex. AB - The potentiometric titration curves and computer modelling studies indicated that aluminium complexes with alanine at -C00- moiety and also altered the proton affinity at +NH3 and -CH3 moiety. 27Al NMR spectra broadening also confirmed the interaction. PMID- 7845377 TI - Structure, biosynthesis, and function of salivary mucins. AB - The glandular secretions of the oral cavity lining the underlying buccal mucosa are highly specialized fluids which provide lubrication, prevent mechanical damage, protect efficiently against viral and bacterial infections, and promote the clearance of external pollutants. This mucus blanket contains large glycoproteins termed mucins which contribute greatly to the viscoelastic nature of saliva and affect its complex physiological activity. The protein core of mucins consists of repetitive sequences, rich in O-glycosylated serine and threonine, and containing many helix-breaking proline residues. These features account for the extended, somewhat rigid structure of the molecule, a high hydrodynamic volume, its high buoyant density, and high viscosity. The oligosaccharide moiety of salivary mucins accounts for up to 85% of their weight. The oligosaccharide side chains exhibit an astonishing structural diversity. The isolation, composition, structure, molecular characteristics, and functional relevance of salivary mucins and their constituents is discussed in relation to recent advancements in biochemistry and molecular biology. PMID- 7845380 TI - Deoxyribose degradation catalyzed by Fe(III)-EDTA: kinetic aspects and potential usefulness for submicromolar iron measurements. AB - Iron ions play a central role in .OH radicals formation and induction of oxidative stress in living organisms. Iron-catalyzed .OH radical formation degrades deoxyribose to thiobarbituric acid reactive substances (TBA-RS). This paper analyzes kinetic properties of the Fe(III)-EDTA-catalyzed deoxyribose degradation in the presence of ascorbate. The yield of TBA-RS formation in the presence of EDTA was 4-fold higher than in its absence, contrasting with results reported elsewhere, Cu(II)-EDTA and Fe(III)-citrate were unable to catalyze deoxyribose degradation. The dependence on deoxyribose concentration was fitted to a Lineweaver Burk-like plot and it was calculated that approximately 4.5 mM deoxyribose scavenged half of the .OH radicals formed. The data for Fe(III)-EDTA concentration dependence could also be fitted to a rectangular hyperbolic function. This function was linear up to 1 microM added FeCl3 and this property could be utilized as an assay for the estimation of submicromolar iron concentrations. Submicromolar concentrations of iron could induce measurable yields of TBA-RS. Differences of as little as 0.1 microM Fe(III)-EDTA could be reproducibly detected under optimum experimental conditions, above a consistent background absorbance that was equivalent to 0.35 +/- 0.05 microM Fe(III)-EDTA and represented contaminating iron in the reactants that could not be removed with Chelex-100. The low method determination limit makes the deoxyribose degradation reaction potentially useful as a new, highly sensitive and cost effective assay for iron quantification. PMID- 7845381 TI - Studies on the iodination of a ras protein and the detection of ras polymers. AB - Several methods for the iodination of recombinant v-H-ras protein were compared. The Iodobead method gave greatest incorporation of radioactivity with minimal modification of the ras protein. Upon treatment of the ras protein with [125I] Nal and an Iodobead, radioactivity was initially incorporated into a 22 kDa species with a pl of 5.2, then predominantly into a 23 kDa species with a pl of 5.4. The specific activity of [125I]ras was 6 x 10(6) cpm/pmol total ras protein. Iondination did not alter the biological activity of the ras protein as judged by its ability to bind GTP gamma S and induce maturation of Xenopus laevis oocytes. It is concluded that while iodination alters the apparent molecular weight and pI of ras, presumably by the oxidation of one or more classes of amino acids, this does not affect the biological function of the protein. The ras protein, radioactively-labelled with iodine using the Iodobead method, should be suitable for studies of protein-protein interactions involving ras. Treatment of iodinated ras with the chemical cross-linking agent disuccinimidyl suberate revealed the presence of several minor high molecular weight protein species. This result shows that, in a dilute solution of purified ras protein, the monomeric form is in equilibrium with small amounts of polymeric forms. PMID- 7845382 TI - Role of delta 9 desaturase activity in the maintenance of high levels of monoenoic fatty acids in hepatoma cultured cells. AB - The incorporation and delta 9 desaturation of exogenous [14C]stearic acid were studied in HTC 7288c cells in suspension. We examined the uptake of the acid over a wide range of concentrations (0-160 microM) after incubating the cells for 6 h in a chemically-defined medium. Under this experimental condition, the uptake of the labeled acid was more extensive than that obtained from static cultures or from monolayer of isolated hepatocytes of rats. At an external concentration of 160 microM ca. 52 nmoles of acid per mg of cellular protein was taken up. The production of oleic acid from [14C]stearate (delta 9 desaturation) correlated well with the uptake curve between 0-80 microM concentration. For higher stearate concentrations, the biosynthesis of oleic acid declined substantially and a plateau of 22 nmoles/mg cellular protein was reached. The incorporation and desaturation of an initial exogeneous concentration of [14C]stearic acid (80 microM) was also studied from 0-6 h. The results obtained demonstrated that the uptake of the substrate into cellular lipids was fast and non saturable. Quantitative gas-liquid chromatography of total cellular lipids under the different experimental conditions demonstrated a negative correlation between the decrease in the palmitic and palmitoleic acids and the increase in the intracellular levels of stearic and oleic acids. These analytical modifications took place with no changes in the saturated/monoenoic fatty acid ratio. This work also demonstrated a significant contribution of the stearoyl-CoA desaturase system to the high levels of oleic acid present in this kind of hepatoma cells. PMID- 7845383 TI - Biochemical mechanism of irreversible cell injury caused by free radical initiated reactions. AB - Effects of oxidative stress on isolated rat ventricular myocytes were studied. Myocyte viability was determined by the ability of these cells to retain rod shaped morphology and to exclude trypan blue. The mean life time of myocytes was quantitated using the Weibull distribution function. Superfusion with 200 microM tert-butyl hydroperoxide (t-BHP) led to a time-dependent loss of cell viability, generation of the products of lipid peroxidation, oxidation of protein and non protein thiols, a decrease in [ATP]i and in the cellular energy charge. Dithiothreitol (DTT, 5 mM) prolonged survival of myocytes exposed to t-BHP, attenuated oxidation of protein and non-protein thiols, and preserved the energy charge. Exposure to DTT did not affect the concentration of t-BHP-generated lipid peroxidation products. Promethazine (1 microM) prevented t-BHP-induced increase in the concentration of lipid peroxidation products, but did not prevent either loss of thiols or loss of cell viability. Superfusion with N-ethylmaleimide (NEM, 5 microM) also led to loss of cell viability, with accompanying decreases in protein and non-protein thiols, ATP and energy charge without the accumulation of the products of lipid peroxidation. Superfusion with FeSO4 (400 microM) and ascorbate (1 mM), (Fe-Asc) did not result in loss of cell viability or a decrease protein thiols or the energy charge. Superfusion with Fe-Asc, did, however, lead to a slight decrease in the concentration of non-protein thiols and ATP and a large increase in the concentration of lipid peroxidation products. Accumulation of lipid peroxidation products induced by Fe-Asc was prevented by promethazine.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845384 TI - Effect of retinol deficiency and curcumin or turmeric feeding on brain Na(+)-K+ adenosine triphosphatase activity. AB - The effect of retinol deficiency and curcumin and turmeric feeding on brain microsomal Na(+)-K(+)ATPase activity was investigated. The brain Na(+)-K(+)ATPase activity registered an increase of 148.5% as compared to the control group. Upon treating retinol deficient rats with curcumin or turmeric, the abnormally elevated activity showed a decrease of 36.9 and 47.1%, respectively, when compared to the retinol deficient group. An increase in Vmax by 67% and Km by 66% for ATP was observed in the retinol deficient group. Curcumin or turmeric fed retinol-deficient groups reduced the Vmax by 25 and 33%, while Km was reduced by 25 and 31%, respectively, compared to the retinol deficient group. Arrhenius plot of Na(+)-K(+) ATPase showed a typical bi-phasic pattern in all the groups. Cholesterol:Phospholipid ratio showed a decrease in the retinol-deficient group by 67.8%, which showed a marked increase in curcumin or turmeric treated groups. Detergents could increase the Na(+)-K(+) ATPase activity more in the control group than in the retinol deficient groups. Curcumin or turmeric improved the detergent action on the enzyme. Subsequent freezing and thawing over a period of 30 min decreased the enzyme activity by 22.8% in the retinol deficient group compared to 15.9% decrease in the control group. Curcumin or turmeric treated groups showed a decrease in the enzyme activity by 22.0 and 19.2%, respectively, when compared to the zero time in each group. In the presence of concanavalin-A (Con-A) there was only 52.4% stimulation in the enzyme activity in retinol deficient groups, compared to 108.0% in the control group.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845385 TI - Purification and characterization of a deoxy-ribonuclease acting on native and UV irradiated DNA from young and aging rat brain. AB - A deoxyribonuclease has been purified to electrophoretic homogeneity from young and old rat brain. The enzyme is an endonuclease, with an optimum pH 5.0. Divalent cations are not needed for the activity. The DNase showed highest activity towards Native DNA either as such or UV irradiated with little activity on denatured DNA, apurinic DNA or DNA pretreated with mitomycin C or actinomycin D. The enzyme hydrolyzes double stranded poly (dA-dT).(dA-dT) but not other homologous or heterologous synthetic polynucleotides. The enzyme does not excise pyrimidine dimers preferentially but acts at a site away from the dimer. The DNase was partially purified from nuclei also and both the nuclear and extra nuclear enzymes showed similar properties. The specific activity of brain DNase decreases markedly with age. DNase preparations from both young and old rats showed similar apparent molecular weight (62KD) and many other properties like elution profiles and the N-terminal amino acid. However the old enzyme was more susceptible to temperature and proteolytic digestion. These results are taken to indicate a possible role for this enzyme in recognizing conformational distortions in DNA and that altered molecules of this enzyme accumulate in aging brain. PMID- 7845386 TI - Metabolic adaptation of renal carbohydrate metabolism. V. In vivo response of rat renal-tubule gluconeogenesis to different diuretics. AB - We have studied the effects of the diuretics mersalyl, furosemide and ethacrynic acid on renal gluconeogenesis is isolated rat-kidney tubules and on the activities of the most important gluconeogenic and glycolytic enzymes in both fed and fasted rats. Mersalyl (15 mg.kg-1 animal weight) significantly decreased the rate of gluconeogenesis in well-fed rats (68%) as well as in 24 and 48-h fasted ones (33 and 37% respectively). This inhibition occurred when lactate, pyruvate, glycerol or fructose were used as substrates. Ethacrynic acid at a dose of 50 mg.kg-1 animal weight provoked a transient inhibition of renal glucose production by almost 20% but only in fed rats with lactate as substrate, whereas the same dose of furosemide did not affect this metabolic pathway. Parallel to these changes, mersalyl caused a significant inhibition in the maximum activity of the most important gluconeogenic enzymes, phosphoenolpyruvate carboxykinase, fructose 1,6-bisphosphatase and glucose 6-phosphatase, in both fed and fasted rats. Neither ethacrynic acid nor furosemide produced any variations in the activities of these enzymes. The activity of the glycolytic enzymes phosphofructokinase and pyruvate kinase was not modified by these diuretics. Nevertheless, the activity of the thiol-enzyme glyceraldehyde 3-phosphate dehydrogenase was severely inhibited by mersalyl and to a lesser extent by the other diuretics. This inhibition was higher in fasted than fed rats. Hence, we conclude that the inhibitory effect of mersalyl on renal gluconeogenesis is due, at least partly, to a decrease in the flux through the gluconeogenic enzymes.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845387 TI - Interaction of rat liver microsomes containing saturated or unsaturated fatty acids with fatty acid binding protein: peroxidation effect. AB - In the studies described here rat liver microsomes containing labeled palmitic, stearic, oleic or linoleic acids were incubated with fatty acid binding protein (FABP) and the rate of removal of 14C-labeled fatty acids from the membrane by the soluble protein was measured using a model system. More unsaturated than saturated fatty acids were removed from native liver mircrosomes incubated with similar amounts of FABP. The in vitro peroxidation of microsomal membranes mediated by ascorbate-Fe++, modified its fatty acid composition with a considerable decrease of the peroxidizability index. These changes in the microsomes facilitated the removal of oleic and linoeic acids by FABP, but the removal of palmitic and stearic acids was not modified. This effect is proposed to result from a perturbation of membrane structure following peroxidation with release of free fatty acids from susceptible domains. PMID- 7845388 TI - Mechanism of quercetin-induced suppression and delay of heat shock gene expression and thermotolerance development in HT-29 cells. AB - Previous studies have shown that a combination of low pH and quercetin (QCT) treatment following heat shock markedly suppresses and delays the expression of heat shock protein genes, particularly the HSP70 gene (Lee et al., Biochem. Biophys. Res. Commun., 186:1121-1128, 1992). The possible mechanism for alteration of gene expression by treatment with QCT at low pH was investigated in human colon carcinoma cells. Cells were heated at 45 degrees C for 15 min and then incubated at 37 degrees C for various times (0-12 h) with QCT (0.05-0.2 mM) at pH 7.4 or 6.5. Gel mobility-shift analysis of whole cell extracts from heated cells showed the formation of the heat shock transcription factor (HSF)-heat shock element (HSE) complex. Dissociation of HSF from the HSE of the human HSP70 promotor occurred within 4 h under both pH conditions. The kinetics of recovery were not affected by treatment with 0.1% dimethyl sulfoxide (DMSO). However, the dissociation of HSF-HSE complex was markedly delayed during treatment with a combination of low pH and QCT. In addition, in vitro transcription assays showed a suppression of initiation and elongation of HSP70 mRNA. These results may explain why the combination of low pH and QCT treatment suppresses and delays the HSP70 gene expression as well as thermotolerance development. PMID- 7845389 TI - Regulation of HSP70 and HSP28 gene expression: absence of compensatory interactions. AB - We have previously reported the lack of HSP28 gene expression during acute and chronic thermotolerance development in L929 cells (J Cell Physiol 152: 118-125, 1992; Cancer Res 52: 5787, 1992). In contrast to HSP28, an extremely high level of inducible HSP70 synthesis was observed. These results led us to investigate the possibility of compensatory interactions between HSP70 and HSP28. To test the hypothesis, L929 cells were transfected with the human HSP28 gene contained in plasmid pCMV27. Data from Western blot and two-dimensional gel electrophoresis of [3H] leucine and [32P] orthophosphate-labeled proteins showed the synthesis and phosphorylation of HSP28 in transfected cells after heating at 45 degrees C for 10 min. However, the expression of constitutive and inducible HSP70 genes, along with the synthesis of their proteins, was not decreased after heat shock. These results suggest an independent regulation of HSP28 and HSP70 gene expression. PMID- 7845391 TI - Cloning and functional expression of the bovine natriuretic peptide receptor-B (natriuretic factor R1c subtype. AB - We describe the isolation of a 3,276 base pair cDNA for the bovine natriuretic peptide receptor-B (NPR-B). Expression of this clone in Cos-P cells demonstrates that it encodes an agonist-dependent guanylyl cyclase. Porcine CNP stimulates the activity of this receptor up to 200-fold with an ED50 of 12 +/- 2 nM, whereas brain natriuretic peptide C-type natriuretic peptide (CNP) and atrial natriuretic factor (ANF) are less efficacious. In addition, ligand binding studies indicate that this receptor exhibits the pharmacology appropriate for the bovine NPR-B. CNP binds to Cos-P cell membranes expressing this clone with a Kd of 13 +/- 1 pM, and natriuretic peptides compete for [125I]-CNP binding with a rank order of pCNP > pBNP > rANF. Thus, the expressed receptor-guanylyl cyclase exhibits the expected pharmacological profile for ligand binding and cyclase activation of the bovine NPR-B receptor. PMID- 7845390 TI - Ontogeny of the ryanodine receptor in rabbit urinary bladder smooth muscle. AB - Bladder smooth muscle contraction is mediated by both direct calcium entry through the cell membrane, and by calcium induced calcium release (CICR) from the sarcoplasmic reticulum (SR) storage sites. Ryanodine is a neutral plant alkaloid which binds to an ion channel located on the SR membrane. Its effects in cardiac skeletal muscle are well characterized where it inhibits the efflux of intracellular calcium stores, and thus it serves as a negative inotrope. It has also been shown that in the developing rabbit myocardium, there is a gradual increase in the expression of this ion channel. Little has been written about the expression and function of the ryanodine sensitive ion channel in smooth muscle. Recently we have shown that neonatal rabbit bladder smooth muscle is not very sensitive to ryanodine, while that from mature rabbits is extremely sensitive. This leads us to quantify the expression of the ryanodine sensitive ion channel. In this paper we demonstrate that the Kd values do not change to any significant degree with normal rabbit bladder development. However the Bmax values for 3 day, 2, 4, 6, and 8 week rabbit bladder smooth muscle are 7, 10, 15, 29, and 44 fmol specifically bound ryanodine/mg protein. The differences between the neonatal groups and the mature groups are significant (P < 0.5). This increase in ryanodine sensitive ion channel expression with normal growth would suggest that with normal maturation, the bladder smooth muscle cell acquires an increased pool of sequestered intracellular calcium. This would follow a similar pattern of development that has already been described in rabbit myocardium. PMID- 7845392 TI - Carbohydrate-binding profile of a pregnancy-associated rat uterine glycoprotein. AB - Sugar-binding proteins obtained from the peri-implantation uterine tissue have been thought in recent years to have significant roles in embryo implantation, where carbohydrate moieties of the protein are actively involved. Based on this rationale a mannose-containing glycoprotein/lectin (named uterine agglutinin or UA) was purified by Concanavalin A (Con A) affinity chromatography in a previous study. A modification of the original purification procedure to include a 33% ammonium sulfate fractionation improves the yield of the protein significantly. An alternative purification procedure by Mannan affinity matrix, indicates that apart from containing mannose, UA possesses mannose-binding properties as well. In this paper, we report some of the biochemical and more specifically, the carbohydrate-binding characteristics of UA. The protein is seen to contain mannose-6-phosphate (M-6-P)-binding sites, which is of importance since M-6-P receptors have a large number of biologically significant roles, including that of binding to growth factors. SDS-PAGE, gel filtration chromatography and alkaline PAGE indicate the homogenous nature of the protein with subunit molecular weights of 36 kDa and 19 kDa, and a native size of 64 kDa. Amino acid analysis shows glycine, glutamic acid and aspartic acid to be the major constituents. UA is a glycoprotein and shows presence of N-acetyl glucosamine and galactose, apart from mannose. De nove synthesis studies in the presence of tunicamycin show that the carbohydrate moiety of the glycoprotein is attached by N-linkage to the protein. Binding characteristics of the protein is studied quantitatively in which (125I)-labelled lectin is bound to Mannan-Sepharose affinity matrix.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845393 TI - Alterations in histones of the liver and oviduct of Japanese quail during aging. AB - Age-related changes occur in histones of the liver and oviduct of the female quail. In the liver an extra histone band, named HCX, between H2A and H4, is observed that increases with age. In the oviduct, a large complex of histones is seen which is tissue-specific. This complex declines with increasing age. The changes in the histones of the oviduct of adult and old birds in response to estradiol and progesterone are age-related. In the adult, the histone-complex increases after administration of either one of the hormones. In old birds, however, it is seen only after progesterone administration. Thus, the alterations in histones in the birds are not only tissue- and age-related, but also vary in response to steroid hormones. PMID- 7845394 TI - Mice lacking Snrpn expression show normal regulation of neuronal alternative splicing events. AB - The SmN protein is closely related to the constitutively expressed RNA splicing protein SmB but is expressed only in brain and heart tissue. Mice which lack expression of SmN die shortly after birth suggesting a critical role for this protein possibly in the regulation of neuronal-specific alternative splicing events. We show here however that the neuronal-specific alternative splicing of the RNAs encoding several different classes of protein proceeds normally in mice lacking SmN expression. The potential role of SmN and the reasons for the lethal effect observed in non-expressing mice are discussed. PMID- 7845395 TI - Dynamics of telomere turnover in Plasmodium berghei. AB - Non-uniform composition in telomeric repeats at the extremities of Plasmodium chromosomes was exploited in order to obtain data on intraclonal diversification of telomeric sequences, relevant for the study of telomere regeneration dynamics. Families of sibling telomeric clones were obtained from several chromosomal ends of Plasmodium berghei, and analysed so as to determine the exact points from which individual clones start to diverge. As much as 90% of the telomeric tract appears to be subject to events causing abrupt changes in the sequence of telomeric repeats. The results are compatible with the hypothesis that breakpoint probability is a continuously increasing function over the entire telomeric tract. PMID- 7845396 TI - Transfer RNA analysis during the reproductive cycle of a freshwater teleost, H. fossilis. AB - Transfer RNA was analyzed qualitatively as well as quantitatively from ovaries of the fresh water teleost Heteropneustes fossilis for twelve months. The tRNA samples were found to be pure and devoid of any high molecular weight RNA or DNA contaminations. The quantity of tRNA as well as its biological activity, assayed by in vitro aminoacylation using homologous aminoacyl tRNA synthetases, were found to be higher during resting and preparatory (pre-vitellogenic) phases, i.e. from November to March, as compared to vitellogenic and spawning phases of the fish, i.e. from April to October. The highest tRNA pool and its activity was found in the month of February, which coincides with the early preparatory phase. The results indicate that the accumulation of active tRNA starts in the resting phase. Such an accumulation of tRNA may be a part of the enrichment of mature eggs with complete translational machinery before ovulation in order to cope with the high rate of protein synthesis after fertilization. PMID- 7845397 TI - Factors influencing the amplitude and frequency of essential tremor. AB - Quantitative electromyography (EMG) and triaxial accelerometry were used to measure hand tremor, finger tremor, and forearm motor unit activity in 36 men and 23 women with essential tremor. Hand tremor was studied with and without 300-g mass loading. Tremor and EMG were recorded twice, with a 3-min rest interval, to assess the spontaneous intertrial variability in tremor amplitude, frequency, and motor unit entrainment. In general, the minimum detectable differences in tremor amplitude, frequency, and motor unit entrainment were roughly 30%, 5%, and 10% of the initial sample means, respectively, assuming a sample size of 30 patients, a statistical power of 0.9, and a significance level of 0.05. Linear regression analyses were performed to test the hypotheses that (a) there is an age associated decrease in tremor frequency that is independent of symptom duration and (b) tremor frequency and motor unit entrainment make independent contributions to tremor amplitude. Our data supported both hypotheses. PMID- 7845398 TI - Respiratory chain and mitochondrial deoxyribonucleic acid in blood cells from patients with focal and generalized dystonia. AB - An increasing number of neurodegenerative diseases seem to be associated with or even due to disturbances of cerebral energy metabolism. One generally accepted example is complex I deficiency in substantia nigra from patients with Parkinson's disease. Reports on a complex I defect in platelets from patients with dystonia led us to check for disturbances of the respiratory chain or of the mitochondrial genome in isolated mitochondria from patients with focal or generalized dystonia. We could not confirm the idea of mitochondrial disturbance in platelets from patients with dystonia because we did not find abnormal enzyme activities or any deletions of the mitochondrial genome. Thus, we do not think that blood cells such as platelets can serve as markers for neurodegenerative disorders such as dystonia. PMID- 7845399 TI - Botulinum toxin A injections for the treatment of hand tremors. AB - We conducted an open-label study to determine the utility of treating severe hand tremors with intramuscular injections of botulinum toxin (BTX) in forearm and arm muscles in 26 patients, 12 with Parkinson's disease (PD) and 14 with essential tremor (ET). The effect after 6 weeks for each patient was evaluated using two clinical rating scales, subjective evaluations of functional improvement and global disability, measures of weakness, and computer-assisted quantitative assessments of tremor. Although none of the clinical scores averaged > 3/4 point change, statistical significance was found on comparison of pre- and postinjection scores in the Webster Tremor and Global Disability Scales in the ET patients. Similarly, although average tremor amplitudes decreased by no more than 25% by quantitative analysis, amplitude decrease significantly correlated with patient subjective assessment in ET. In only two of 12 PD (17%) and three of 14 ET patients (21%) were major quantitative changes in tremor amplitude (> 50% reduction) found after BTX injections. Nevertheless, 10 patients (38%; five PD and five ET) reported moderate to marked subjective improvement in functional benefit after BTX. These findings suggest that although there were no major changes in clinical ratings or objective measurements, BTX injections may subjectively improve tremor in some patients, particularly those with ET. PMID- 7845400 TI - "Apraxia of lid opening," a focal eyelid dystonia: clinical study of 32 patients. AB - We have seen 32 patients with "apraxia of lid opening" (ALO) in the following clinical settings: as an isolated condition (3 patients), idiopathic blepharospasm (BSP, 20 patients, including 4 familial cases), progressive supranuclear palsy (PSP, 7 patients), and dystonic parkinsonian syndrome (2 patients). Twenty-nine patients treated with botulinum toxin into the orbicularis oculi muscle were rated before and after treatment and 83% of the patients improved on a clinical scale. Best results were obtained with injections directed toward the junction of the preseptal and pretarsal parts of the palpebral orbicularis oculi. Several patients also improved on anticholinergic drugs. Besides medical treatment, lid crutches, in conjunction with botulinum toxin injections, were useful in some patients. ALO is not a true apraxia; it constitutes an eyelid dystonia as shown by its clinical and electrophysiological features as well as pharmacological reactions and is encountered in a clinical spectrum ranging from an isolated form to predominant BSP. It was an important cause of treatment failures in botulinum toxin-treated BSP but by modifying our injection strategy and by adding anticholinergic drugs and also lid crutches, we obtained a good functional benefit. PMID- 7845401 TI - Reliability among neurologists in the severity assessment of blepharospasm and oromandibular dystonia: a multicenter study. AB - The reliability of a scale of 0 to 4 (where 0 is normal) in rating the severity of blepharospasm (BS) and oromandibular dystonia (OMD) was evaluated by the concordance among six neurologists from different neurological institutions. As expressed by k index, interobserver agreement was moderate either for BS or for OMD according to the Landis classification. Neurologists showed different rating attitude toward BS and OMD. In fact, the category analysis showed that raters were inclined to overestimate BS and to underestimate OMD. The familiarity with dystonia influenced reliability more than the length of professional experience in neurology. In fact, when examiners were subdivided into subgroups (each of three raters) according to the former criteria, the level of interobserver agreement increased significantly. Almost perfect agreement was obtained in intrarater comparisons. These results may be of value with regard to the conduct of multicenter epidemiologic and clinical studies on focal dystonias. PMID- 7845402 TI - Coprolalia in younger patients with Gilles de la Tourette syndrome. AB - The objective of this study was to determine the frequency of coprolalia in younger patients with Gilles de la Tourette syndrome (GTS). Coprolalia, which is the least understood and perhaps most unusual symptom of GTS, is reported to occur in 4-60% of all patients with GTS. Most reports indicate a prevalence > 30%. The widely varying prevalence figures for coprolalia may reflect cultural differences, severity of disease, and the age of the population surveyed. This study is a chart review of 112 patients seen in a pediatric neurology clinic in South Florida who met the Diagnostic and Statistical Manual of Mental Disorder (3rd ed., revised) criteria for GTS. Only 8% of the patients in the study exhibited coprolalia. This unusually low frequency of coprolalia suggests that coprolalia may be rarer than previously believed in younger patients. It may also better reflect the frequency of coprolalia in a community-based pediatric neurology practice. PMID- 7845403 TI - Exclusion of the DYT1 locus in a non-Jewish family with early-onset dystonia. AB - The DYT1 gene on chromosome 9q34 underlies idiopathic torsion dystonia (ITD) in Jewish and non-Jewish families with childhood and adolescent-onset dystonia that usually starts in a limb, spreads to other limbs, and uncommonly involves cranial muscles. We examined 39 members of a Mennonite family of German ancestry in which seven were affected with ITD. Age at onset was 14.7 years (range 5-34 years) and symptoms began in a limb in four. The remaining three had onset in the neck, face, and larynx. Dystonia progressed to involve at least one arm and one leg in all seven and there was cranial involvement in six. Five of these six had moderate or severe speech impairment. Linkage analysis with 9q34 markers excluded the region containing the DYT1 locus in this family. This study suggests that a gene other than DYT1 underlies some cases of early limb-onset ITD. The clinical features of prominent cranial involvement and impaired speech distinguish this "non-DYT1" early-onset ITD family from the typical DYT1 phenotype. PMID- 7845404 TI - Cortical myoclonus in Huntington's disease. AB - We describe three patients with Huntington's disease, from two families, in whom myoclonus was the predominant clinical feature. The diagnosis was confirmed at autopsy in two cases and by DNA analysis in all three. These patients all presented before the age of 30 years and were the offspring of affected fathers. Neurophysiological studies documented generalised and multifocal action myoclonus of cortical origin that was strikingly stimulus sensitive, without enlargement of the cortical somatosensory evoked potential. The myoclonus improved with piracetam therapy in one patient and a combination of sodium valproate and clonazepam in the other two. Cortical reflex myoclonus is a rare but disabling component of the complex movement disorder of Huntington's disease, which may lead to substantial diagnostic difficulties. PMID- 7845405 TI - Dystonia as the major manifestation of Leigh's syndrome. AB - We report eight patients who had a progressive illness dominated by generalised dystonia and who had clinical and imaging features suggestive of Leigh's syndrome (LS). Six of the eight cases were male. Early development was usually normal but three cases exhibited impaired mental and/or motor development, and three others had a history of an earlier unexplained encephalopathy or febrile illness. The onset of the dystonia occurred at a mean age of 3 years (range 2 months-7 years). All had abnormalities in the basal ganglia on brain imaging; symmetrical bilateral lucencies or calcification were seen in the basal ganglia on computed tomography scan in five cases, and high signal lesions were evident in these regions on T2-weighted magnetic resonance imaging sequences in seven cases. Other causes of such changes in the basal ganglia were excluded by appropriate investigations. Raised blood lactate levels were found in four of the eight patients. Muscle biopsies were done in seven patients but histology and histochemistry were normal. The common mitochondrial DNA mutations associated with LS in mitochondrial encephalopathies were not found in the six cases examined. LS presenting as a pure dystonic syndrome is uncommon, but should be considered in the differential diagnosis of symptomatic dystonia presenting in childhood. PMID- 7845406 TI - Perturbation of precision grip in Friedreich's ataxia and late-onset cerebellar ataxia. AB - Perturbations of precision grip were tested in 7 patients with Friedreich's ataxia (FA) and 11 patients with late-onset cerebellar ataxia (CA). Subjects were instructed to hold a small compressible manipulandum between thumb and index finger and to resist any perturbation of maintained finger position. A sudden increase of load induced a displacement of fingers until this was stopped by subjects' active intervention. The amount of initial displacement emerged as a highly sensitive parameter to differentiate the clinical subgroups: Responses in FA patients were missing or massively delayed, whereas displacements in CA patients were normal or only moderately abnormal. This discrimination of impaired hand function in FA and CA patients has not been possible by using only tasks of isometric grip force control. We concluded that our task relies more on intact sensory afferents, which are known to be impaired in FA, than on cerebellar function. In a second task the stiffness of the maintained grip was determined. On the average, preresponse stiffness was lower in FA patients as compared with CA patients and normal controls. However, stiffness appeared to be an independent parameter that did not influence the amount of displacement in the perturbation task. PMID- 7845407 TI - Anorectal manometry in the assessment of anorectal function in Parkinson's disease: a comparison with chronic idiopathic constipation. AB - We investigated the role of anorectal manometry in evaluating constipation and anorectal function in 15 patients with Parkinson's disease (PD) and compared results with those of 9 patients with idiopathic constipation (IC) and 8 control (C) subjects. Anal sphincter pressures on voluntary squeeze were lower in the PD patients. Sustained squeeze pressures (mm Hg C versus IC versus PD: 46.8 +/- 5.2 versus 31.2 +/- 3.6 versus 26.6 +/- 3.9; p < 0.05 PD versus C), squeeze duration (seconds: 53.6 +/- 2.5 versus 48.5 +/- 4.1 versus 33.6 +/- 9; p < 0.05 PD versus C) and squeeze index (area under the squeeze curve: 44.0 +/- 2.9 versus 34.5 +/- 3.3 versus 21.4 +/- 2.9; p < 0.001 PD versus C) were significantly lower in the PD group in comparison to the control group. In contrast, none of the parameters of anorectal manometry differed between controls and patients with idiopathic constipation. Some Parkinson's disease patients demonstrated an abnormal, hypercontractile response on testing of the rectoanal inhibitory reflex. Anal sphincter length, basal sphincter pressures, maximal squeeze pressures, extent of relaxation on rectoanal inhibitory reflex and threshold volume for rectal sensation were similar in the three groups. We conclude that an impaired squeeze response is a specific feature of anorectal function in Parkinson's disease. This may indicate direct involvement of the pelvic floor musculature by the parkinsonian disease process. PMID- 7845408 TI - The dopamine D1 agonist SKF 81297 and the dopamine D2 agonist LY 171555 act synergistically to stimulate motor behavior of 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-lesioned parkinsonian rhesus monkeys. AB - At present, the pharmacotherapy of Parkinson's disease (PD) consists mainly of L dihydroxyphenylalanine (L-DOPA) and/or dopamine D2 receptor agonists. However, in general the clinical efficacy of D2 agonists is less than that of L-DOPA. Therefore, attention is being focussed on the role of the D1 receptor as a target for therapeutic intervention in PD. Recently, we reported that SKF 81297 is a selective D1 agonist that stimulates motor behavior of unilaterally MPTP (1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-lesioned rhesus monkeys. Presently, we studied the effect of coadministration of SKF 81297 and the D2 agonist LY 171555 using the same model of PD. Coadministration of behaviorally active doses of SKF 81297 (0.3 mg/kg) and LY 171555 (0.01 mg/kg) resulted in a prolongation of the motor stimulation induced by either of the drugs alone. Neither administration of SKF 81297, in a dose of 0.03 mg/kg, nor of LY 171555, in a dose of 0.003 mg/kg, were behaviorally active, whereas the combined administration of these compounds induced a significant stimulation of motor behavior. These data suggest that (a) D1 receptor stimulation will prove to be useful in the treatment of PD and (b) better therapeutic results will be obtained by simultaneous stimulation of D1 and D2 receptors as compared with stimulation of both receptors alone. PMID- 7845409 TI - Familial levodopa-responsive parkinsonian-pyramidal syndrome. AB - We present four patients--two pairs of siblings--followed for many years, with pyramidal and parkinsonian features, who responded consistently to levodopa therapy. The patients belong to two unrelated consanguineous families, suggesting that this condition is genetically determined and recessively inherited. PMID- 7845410 TI - Symptomatic and essential palatal tremor. 2. Differences of palatal movements. AB - Palatal tremor, a rhythmic movement disorder of the soft palate, may be described as two separate entities: symptomatic palatal tremor (SPT) and essential palatal tremor (EPT). The symptomatic form is associated with brain stem or cerebellar disease, whereas the essential form has no known etiology. A cardinal symptom of EPT is the presence of ear clicks, which do not occur in SPT. Visual observation of the movements in the two disorders suggests that the difference in symptoms is due to the activation of different palatal muscles, the levator veli palatini in SPT and the tensor veli palatini in EPT. Electromyographic recording from the levator veli palatini muscle showed abnormal bursting activity time locked to the palatal movements in patients with SPT, but not in those with EPT. Because the two palatal muscles are innervated by different cranial nerves, SPT and EPT are likely to have separate origins. PMID- 7845411 TI - Case 2, 1994: parkinsonism and cognitive impairment. PMID- 7845412 TI - Anticholinergics and dyskinesia. PMID- 7845413 TI - Variability in early communicative development. AB - Data from parent reports on 1,803 children--derived from a normative study of the MacArthur Communicative Development Inventories (CDIs)--are used to describe the typical course and the extent of variability in major features of communicative development between 8 and 30 months of age. The two instruments, one designed for 8-16-month-old infants, the other for 16-30-month-old toddlers, are both reliable and valid, confirming the value of parent reports that are based on contemporary behavior and a recognition format. Growth trends are described for children scoring at the 10th-, 25th-, 50th-, 75th-, and 90th-percentile levels on receptive and expressive vocabulary, actions and gestures, and a number of aspects of morphology and syntax. Extensive variability exists in the rate of lexical, gestural, and grammatical development. The wide variability across children in the time of onset and course of acquisition of these skills challenges the meaningfulness of the concept of the modal child. At the same time, moderate to high intercorrelations are found among the different skills both concurrently and predictively (across a 6-month period). Sex differences consistently favor females; however, these are very small, typically accounting for 1%-2% of the variance. The effects of SES and birth order are even smaller within this age range. The inventories offer objective criteria for defining typicality and exceptionality, and their cost effectiveness facilitates the aggregation of large data sets needed to address many issues of contemporary theoretical interest. The present data also offer unusually detailed information on the course of development of individual lexical, gestural, and grammatical items and features. Adaptations of the CDIs to other languages have opened new possibilities for cross-linguistic explorations of sequence, rate, and variability of communicative development. PMID- 7845414 TI - Pathogenicity of yeasts and algae isolated from bovine mastitis secretions in a murine model. AB - The pathogenicity of strains of yeasts and algae isolated from bovine mastitis secretions was evaluated in immunosuppressed mice. Strains of Candida tropicalis (n = 3) were the most pathogenic, but all strains of Geotrichum capitatum (n = 5) and the colourless alga Prototheca zopfii (n = 5) were also lethal to mice at the highest dose of 1 x 10(7) CFU per mouse. Reisolation of the inoculated micro organisms and the occurrence of histopathological lesions within organs of mice challenged with 1 x 10(3) to 1 x 10(7) CFU per animal revealed strains of C. krusei (n = 17), C. kefyr (n = 6) and C. rugosa (n = 6) to have a moderate pathogenicity, whereas strains of C. valida (n = 1) and C. catenulata (n = 2) were weakly pathogenic and non-pathogenic respectively. PMID- 7845415 TI - Invasive Trichosporon beigelii infection in immunosuppressed rats. AB - Fulminant systemic mycoses were seen as complications in rats undergoing drug trials for the treatment of Pneumocystis carinii pneumonia. Rats were immunosuppressed with corticosteroids and by feeding with a low-protein diet. Homogenized pulmonary tissue from a rat with pneumocystosis was inoculated transtracheally. Secondary invasive mycosis was found in 56 of 59 rats examined. Trichosporon beigelii was identified as the causative agent in the majority of cases. After examining possible sources of infection, a Pneumocystis inoculum contaminated with fungi was found to be the obvious source. T. beigelii infections are becoming increasingly significant in immunocompromised human patients. The need for suitable and reproducible animal models is therefore also increasing. Observations described in this paper may help in the further development of such models. PMID- 7845416 TI - Experimental aspergillosis in guinea pigs: influence of itraconazole on fungaemia and invasive fungal growth. AB - The guinea pig model of experimental aspergillosis was used to evaluate the efficacy of itraconazole 2.5 and 5 mg kg-1 in preventing the invasive phase of the disease when animals were already loaded with Aspergillus conidia. Evaluations were made by recording the survival rates, culturing fragments of nine organs, examining seven organs by means of histochemistry and immunohistochemistry (mAb EB-A1 to Aspergillus galactomannan) and by serological titration of galactomannan. The data indicate that itraconazole is highly effective in preventing true invasive aspergillosis. Serological evaluations of antigenaemia suggest that low titres may only reflect fungaemia, while titres of 1:8 and above are suggestive of invasive disease. PMID- 7845417 TI - Successful treatment of cerebral aspergillosis by stereotactic operation and antifungal therapy. AB - The following is a case report of a cerebral Aspergillus abscess in a male patient predisposed to this disease on account of many years of alcohol abuse. After timely identification of the pathogenic organism, the patient was cured by stereotactic operation in conjunction with antifungal therapy using amphotericin B and 5-fluorocytosine. The origin and the starting point of the infection remain obscure. PMID- 7845418 TI - Bioavailability of fluconazole in the skin after oral medication. AB - Fluconazole is an antimycotic drug which until now has been used mostly in the systemic therapy of yeast infections. We have now demonstrated the presence of this drug in various skin structures. After administration of 50 mg of fluconazole per day for 12 days to healthy volunteers, the following mean drug concentrations were measured: serum 1.81 micrograms ml-1, sweat 4.58 micrograms ml-1, dermis-epidermis (without stratum corneum) 2.77 micrograms g-1 and stratum corneum 73 micrograms g-1. Thus, 4 h after the last dose the antimycotic attains a 40-fold higher concentration in the stratum corneum than in serum. One week after ending the oral treatment, 5.8 micrograms g-1 fluconazole was present in stratum corneum. After daily ingestion of 200 mg of fluconazole for 5 days there was a further increase in the mean concentration of fluconazole in stratum corneum, to 127 micrograms g-1. Even 4-5 months after completing the oral treatment, fluconazole was detectable in the head hair and toenails of healthy volunteers. Fluconazole is eliminated from the stratum corneum about 2-3 times more slowly than from serum or plasma. After oral administration fluconazole evidently accumulated rapidly and intensively into the stratum corneum. The concentrations then attained or exceeded the in vitro minimal inhibitory concentrations of fluconazole for most of the dermatophytes and yeasts which are involved in cutaneous mycoses. PMID- 7845419 TI - A miconazole lacquer in the treatment of Candida-associated denture stomatitis. AB - An open randomized controlled study involving two parallel treatment groups comprising 50 patients with Candida-associated denture stomatitis was performed to evaluate the efficacy and safety of one application of 1 g of miconazole 55 mg/g denture lacquer in comparison with that of a commercially available miconazole 2% gel applied four times daily for 2 weeks. The results showed a pronounced reduction in the yeast scores and a reduction in the palatal erythema in both treatment groups, but there was no apparent difference between the efficacy of the two treatments. The results indicate that a single application of the denture lacquer (55 mg of miconazole) is safe and almost as effective as administration of gel four times a day for 2 weeks (3000 mg of miconazole). PMID- 7845420 TI - Podopompholyx due to pemphigus vulgaris and Trichophyton rubrum infection. Report of an unusual case. AB - We report the case of a 48-year old man who after a disease-free interval of 7 years developed a relapse of pemphigus vulgaris (PV) presenting as pompholyx of the left foot. The patient was first thought to suffer from a dyshidrosic form of tinea pedis due to Trichophyton rubrum. Although the concomitant occurrence of a dermatomycosis and PV has been described previously, our case illustrates an unusual and misleading presentation of PV, which may delay the correct diagnosis. PMID- 7845421 TI - Microsporum canis infection in a 5-year-old boy: transmission from the interior of a second-hand car. AB - Microsporum canis is one of the most common zoophilic dermatophytes. If transmitted to humans, inflammatory lesions may develop, e.g. on the scalp. M. canis was isolated from a 5-year-old boy living in a suburban area who suffered from a long-standing, mildly inflammatory lesion on the scalp that had been treated for several months with anti-eczematous regimens. There had been no contact with animals, e.g. cats or dogs, in the previous months, but the lesions had developed a few weeks after the family had bought a used car from a dog owner. Indeed, M. canis could be grown on contact plates from the car's interior. This case illustrates that attention should be paid to the often neglected diagnosis of M. canis-induced tinea capitis and to unusual routes of infection. PMID- 7845422 TI - False-positive reaction of a Cryptococcus antigen test owing to Pseudallescheria mycosis. PMID- 7845423 TI - Ecology and physiology of the emerging opportunistic fungi Pseudallescheria boydii and Scedosporium prolificans. AB - Nutritionally physiological patterns of Pseudallescheria boydii (Microascaceae) and the related species Scedosporium prolificans were established. Differences between the two species were found in assimilation of sucrose, ribitol, xylitol and L-arabinitol. In contrast, no physiological distinction could be made between the three intraspecific variants of P. boydii which have been recognized on the basis of nDNA/DNA homology data and of morphological and clinical differences. Some potential virulence factors were studied in the fungi mentioned above and in some related anamorphs. All species were capable of anaerobic growth, but differed in their temperature relations. PMID- 7845424 TI - Polymerase chain reaction-based detection of dermatophyte DNA with a fungus specific primer system. AB - There is significant clinical interest in primers which are specific for fungi and do not hybridize to DNA of other eukaryotes or prokaryotes. Such primers would allow specific amplification of fungal DNA from human tissue samples containing fungi. Fungal identification to the species level could follow by direct sequencing or restriction analysis. Several previously described primer systems cross-react with DNA of plants and animals. We have designed a primer system that amplifies a fragment of the gene coding for the small ribosomal subunit 18S rRNA. Database searches and sequence analyses were performed using the HUSAR (Heidelberg Unix Sequence Analysis Resources) computer system at the German Cancer Research Centre, Heidelberg, Germany. Primers TR1 (5' GTTTCTAGGACCGCCGTA) and TR2 (5'-CTCAAACTTCCATCGACTTG) bind to sequences which are homologous within the fungi, but differ from corresponding DNA fragments of plants and animals. The amplified fragment is 581 base pairs in length and contains variable, and therefore species-specific, regions. The DNA of Trichophyton rubrum, Trichophyton mentagrophytes, Trichophyton verrucosum, Trichophyton terrestre, Microsporum canis, Microsporum gypseum and Epidermophyton floccosum and of several yeast species was amplified by the primers, but not the DNA from 42 normal human skin samples. Furthermore, other DNA preparations from plants and animals, including those from radish, cabbage, wheat and mouse, did not show amplification reactions. PMID- 7845425 TI - Partial purification and characterization of a 235,000M(r) extracellular proteinase from Trichophyton rubrum. AB - An extracellular proteinase has been partially purified from culture filtrates of Trichophyton rubrum by ultrafiltration, isoelectric focusing and gel filtration chromatography. The enzyme has a non-reduced molecular weight of 235,000 by substrate SDS-PAGE. It has a pH optimum of 8.5 using azocasein and azoalbumin as substrates and a pI of 3.6-3.8. The metalloproteinase inhibitors EDTA and 1,10 phenanthroline, together with the chymotrypsin inhibitor chymostatin, strongly inhibited its activity. The serine proteinase inhibitors phenylmethanesulphonyl fluoride and diisopropylfluorophosphate showed weak inhibitory activity. The proteinase exhibited broad substrate activity against azocoll, azoalbumin, azocasein, laminin and fibronectin. It exhibited weak activity against elastin and keratin. Observations on the occurrence of this proteinase together with previously described lower molecular weight proteinases suggests that the former is the first to appear in minimal medium cultures. Freeze/thaw cycling of the partially purified 235,000 M(r) proteinase was found to generate low molecular weight proteinases, particularly at 53,000, 27,000 and 25,000 M(r), indicating that the latter may originate from the larger molecule. PMID- 7845426 TI - The effect of debulking surgery after induction chemotherapy on the prognosis in advanced epithelial ovarian cancer. Gynecological Cancer Cooperative Group of the European Organization for Research and Treatment of Cancer. AB - BACKGROUND: Although the value of primary cytoreductive surgery for epithelial ovarian cancer is beyond doubt, the value of debulking surgery after induction chemotherapy has not yet been defined. In this randomized study we investigated the effect on survival of debulking surgery. METHODS: Eligible patients had residual lesions measuring more than 1 cm in diameter after primary surgery. After three cycles of cyclophosphamide and cisplatin, these patients were randomly assigned to undergo either debulking surgery or no surgery, followed by further cycles of cyclophosphamide and cisplatin. The study end points were progression-free and overall survival. At surgery 65 percent of the patients had lesions measuring more than 1 cm. In 45 percent of this group, the lesions were reduced surgically to less than 1 cm. RESULTS: Of the 319 patients who underwent randomization, 278 could be evaluated (140 patients who underwent surgery and 138 patients who did not). Progression-free and overall survival were both significantly longer in the group that underwent surgery (P = 0.01). The difference in median survival was six months. The survival rate at two years was 56 percent for the group that underwent surgery and 46 percent for the group that did not. In the multivariate analysis, debulking surgery was an independent prognostic factor (P = 0.012). Overall, after adjustment for all other prognostic factors, surgery reduced the risk of death by 33 percent (95 percent confidence interval, 10 to 50 percent; P = 0.008). Surgery was not associated with death or severe morbidity. CONCLUSIONS: Debulking surgery significantly lengthened progression-free and overall survival. The risk of death was reduced by one third, after adjustment for a variety of prognostic factors. PMID- 7845428 TI - Brief report: treatment of severe colchicine overdose with colchicine-specific Fab fragments. PMID- 7845427 TI - Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. AB - BACKGROUND: Increased levels of certain hemostatic factors may play a part in the development of acute coronary syndromes and may be associated with an increased risk of coronary events in patients with angina pectoris. METHODS: We conducted a prospective multicenter study of 3043 patients with angina pectoris who underwent coronary angiography and were followed for two years. Base-line measurements included the concentrations of selected hemostatic factors indicative of a thrombophilic state or endothelial injury. The results were analyzed in relation to the subsequent incidence of myocardial infarction or sudden coronary death. RESULTS: After adjustment for the extent of coronary artery disease and other risk factors, an increased incidence of myocardial infarction or sudden death was associated with higher base-line concentrations of fibrinogen (mean +/- SD, 3.28 +/- 0.74 g per liter in patients who subsequently had coronary events, as compared with 3.00 +/- 0.71 g per liter in those who did not; P = 0.01), von Willebrand factor antigen (138 +/- 49 percent vs. 125 +/- 49 percent, P = 0.05), and tissue plasminogen activator (t-PA) antigen (11.9 +/- 4.7 ng per milliliter vs. 10.0 +/- 4.2 ng per milliliter, P = 0.02). The concentration of C-reactive protein was also directly correlated with the incidence of coronary events (P = 0.05), except when we adjusted for the fibrinogen concentration. In patients with high serum cholesterol levels, the risk of coronary events rose with increasing levels of fibrinogen and C-reactive protein, but the risk remained low even given high serum cholesterol levels in the presence of low fibrinogen concentrations. CONCLUSIONS: In patients with angina pectoris, the levels of fibrinogen, von Willebrand factor antigen, and t-PA antigen are independent predictors of subsequent acute coronary syndromes. In addition, low fibrinogen concentrations characterize patients at low risk for coronary events despite increased serum cholesterol levels. Our data are consistent with a pathogenetic role of impaired fibrinolysis, endothelial-cell injury, and inflammatory activity in the progression of coronary artery disease. PMID- 7845429 TI - Images in clinical medicine. Tophaceous gout. PMID- 7845430 TI - Hypoxia of the renal medulla--its implications for disease. PMID- 7845431 TI - Melanoma in children. PMID- 7845432 TI - Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 7-1995. A 58-year-old man with common variable immunodeficiency, splenomegaly, and hemolytic anemia. PMID- 7845433 TI - Beyond overeating. PMID- 7845434 TI - Interval debulking of ovarian cancer--an interim measure. PMID- 7845435 TI - Hemostatic function and coronary artery disease. PMID- 7845436 TI - Finding an obesity gene--a tale of mice and man. PMID- 7845437 TI - Immediate versus delayed fluid resuscitation in patients with trauma. PMID- 7845438 TI - Immediate versus delayed fluid resuscitation in patients with trauma. PMID- 7845439 TI - Inhaled budesonide for mild asthma. PMID- 7845440 TI - Inhaled budesonide for mild asthma. PMID- 7845441 TI - Children with very low birth weights. PMID- 7845442 TI - Chronic idiopathic thrombocytopenic purpura. PMID- 7845443 TI - Chronic idiopathic thrombocytopenic purpura. PMID- 7845444 TI - Hyperkalemia due to nafamostat mesylate. PMID- 7845445 TI - Amebiasis from the "miraculous water of Tlacote". PMID- 7845446 TI - Is plagiarism OK? PMID- 7845447 TI - NIH: in line with expectations. PMID- 7845448 TI - Gene therapy trial passed in Japan. PMID- 7845449 TI - University challenges plagiarism judgement. PMID- 7845450 TI - Europe dilutes draft bioethics convention. PMID- 7845451 TI - MRC concordat 'under threat', say Lords. PMID- 7845452 TI - Revolutionary birthdays. PMID- 7845453 TI - Planetary science. How special is Jupiter? PMID- 7845454 TI - Palaeoanthropology. Homo at the gates of Europe. PMID- 7845455 TI - Alzheimer's disease. Mouse model made. PMID- 7845456 TI - Protein-tyrosine kinases. Getting down to specifics. PMID- 7845457 TI - A tombstone in Alzheimer's? PMID- 7845458 TI - Calcium entry signal? PMID- 7845459 TI - The structural basis of specific base-excision repair by uracil-DNA glycosylase. AB - The 1.75-A crystal structure of the uracil-DNA glycosylase from herpes simplex virus type-1 reveals a new fold, distantly related to dinucleotide-binding proteins. Complexes with a trideoxynucleotide, and with uracil, define the DNA binding site and allow a detailed understanding of the exquisitely specific recognition of uracil in DNA. The overall structure suggests binding models for elongated single- and double-stranded DNA substrates. Conserved residues close to the uracil-binding site suggest a catalytic mechanism for hydrolytic base excision. PMID- 7845460 TI - Inhibition of giant-planet formation by rapid gas depletion around young stars. AB - Although stars form from clouds of gas and dust, there are insignificant amounts of gas around ordinary (Sun-like) stars. This suggests that hydrogen and helium, the primary constituents of planets such as Jupiter and Saturn, are not easily retained in orbit as a star matures. The gas-giant planets in the Solar System must therefore have formed rapidly. Models of their formation generally suggest that a solid core formed in < or = 10(6) yr, followed by the accretion of the massive gaseous envelope in approximately 10(7) yr (refs 1-5). But how and when the gas of the solar nebula dissipated, and how this compares with the predicted timescale of gas-giant formation, remains unclear, in part because direct observations of circumstellar gas have been made only for stars either younger or older than the critical range of 10(6)-10(7) yr (refs 8-15). Here we report observations of the molecular gas surrounding 20 stars whose ages are likely to be in this range. The gas dissipates rapidly; after a few million years the mass remaining is typically much less than the mass of Jupiter. Thus, if gas-giant planets are common in the Galaxy, they must form even more quickly than present models suggest. PMID- 7845461 TI - A Plio-Pleistocene hominid from Dmanisi, East Georgia, Caucasus. AB - Archaeological excavations at the mediaeval site of Dmanisi (East Georgia) revealed that the town was built on a series of deposits yielding Late Villafranchian mammalian fossils and led to the discovery in late 1991 of a well preserved early human mandible. Dmanisi, where excavations are being carried out by a joint expedition of the Archaeological Research Centre of the Georgian Academy of Sciences and the Romisch-Germanisches Zentralmuseum (Mainz, Germany), is located southwest of Tbilisi, at about 44 degrees 20'N, 41 degrees 20'E (Fig. 1). The fossils date to the latest Pliocene (or perhaps to the earliest Pleistocene), probably between 1.8 and 1.6 million years ago (Myr). Here we identify the mandible as belonging to the species Homo erectus, of which it is the earliest known representative in western Eurasia. It shows a number of similarities to the African and Chinese representatives of this species. PMID- 7845462 TI - Dynamics of neuronal interactions in monkey cortex in relation to behavioural events. AB - It is possible that brain cortical function is mediated by dynamic modulation of coherent firing in groups of neurons. Indeed, a correlation of firing between cortical neurons, seen following sensory stimuli or during motor behaviour, has been described. However, the time course of modifications of correlation in relation to behaviour was not evaluated systematically. Here we show that correlated firing between single neurons, recorded simultaneously in the frontal cortex of monkeys performing a behavioural task, evolves within a fraction of a second, and in systematic relation to behavioural events. Moreover, the dynamic patterns of correlation depend on the distance between neurons, and can emerge even without modulation of the firing rates. These findings support the notion that neurons can associate rapidly into a functional group in order to perform a computational task, at the same time becoming dissociated from concurrently activated competing groups. Thus, they call for a revision of prevailing models of neural coding that rely solely on single neuron firing rates. PMID- 7845463 TI - Neuronal correlates of inferred motion in primate posterior parietal cortex. AB - For many types of behaviours, it is necessary to monitor the position or movement of objects that are temporarily occluded. The primate posterior parietal cortex contains neurons that are active during visual guidance tasks: in some cases, even if the visual target disappears transiently. It has been proposed that activity of this sort could be related to current or planned eye movements, but it might also provide a more generalized abstract representation of the spatial disposition of targets, even when they are not visible. We have recorded from monkey posterior parietal cortex while the animal viewed a visual stimulus that disappeared, and then, depending on experimental context, could be inferred to be either moving or stationary. During this temporary absence of the stimulus, about half of the neurons were found to be significantly more active on those trials in which the stimulus could be presumed to be moving rather than stationary. The activity was thus present in the absence of either sensory input or motor output, suggesting that it may indeed constitute a generalized representation of target motion. PMID- 7845464 TI - Seeing the forest but only half the trees? AB - In visuo-spatial neglect after right hemisphere damage, patients fail overtly to notice and respond to stimuli on the side of space contralateral to lesion. Nonetheless, these neglected stimuli may covertly influence their performance in other tasks less direct than overt detection or identification. We report here a new type of dissociation between two forms of conscious perceptual awareness in a patient with left neglect. J.R. was shown hierarchical drawings in which a larger (global) form, such as a geometric figure or an alphabetic letter, is composed of smaller (local) forms (dots, circles, or letters). She gave accurate verbal reports of the global structure of these stimuli (Navon figures), yet when required to cross out the smaller subfigures, she only cancelled those on the right of each global figure. Conscious perception of the whole does not automatically lead to visual awareness of all the parts thereof. PMID- 7845465 TI - Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta amyloid precursor protein. AB - Alzheimer's disease (AD) is the most common cause of progressive intellectual failure in aged humans. AD brains contain numerous amyloid plaques surrounded by dystrophic neurites, and show profound synaptic loss, neurofibrillary tangle formation and gliosis. The amyloid plaques are composed of amyloid beta-peptide (A beta), a 40-42-amino-acid fragment of the beta-amyloid precursor protein (APP). A primary pathogenic role for APP/A beta is suggested by missense mutations in APP that are tightly linked to autosomal dominant forms of AD. A major obstacle to elucidating and treating AD has been the lack of an animal model. Animals transgenic for APP have previously failed to show extensive AD type neuropathology, but we now report the production of transgenic mice that express high levels of human mutant APP (with valine at residue 717 substituted by phenylalanine) and which progressively develop many of the pathological hallmarks of AD, including numerous extracellular thioflavin S-positive A beta deposits, neuritic plaques, synaptic loss, astrocytosis and microgliosis. These mice support a primary role for APP/A beta in the genesis of AD and could provide a preclinical model for testing therapeutic drugs. PMID- 7845466 TI - Gating of the voltage-dependent chloride channel CIC-0 by the permeant anion. AB - Chloride channels of the ClC family are important for the control of membrane excitability, cell volume regulation, and possibly transepithelial transport. Although lacking the typical voltage-sensor found in cation channels, gating of ClC channels is clearly voltage-dependent. For the prototype Torpedo channel ClC 0 (refs 11-15) we now show that channel opening is strongly facilitated by external chloride. Other less permeable anions can substitute for chloride with less efficiency. ClC-0 conductance shows an anomalous mole fraction behaviour with Cl-/NO3- mixtures, suggesting a multi-ion pore. Gating shows a similar anomalous behaviour, tightly linking permeation to gating. Eliminating a positive charge at the cytoplasmic end of domain D12 changes kinetics, concentration dependence and halide selectivity of gating, and alters pore properties such as ion selectivity, single-channel conductance and rectification. Taken together, our results strongly suggest that in these channels voltage-dependent gating is conferred by the permeating ion itself, acting as the gating charge. PMID- 7845467 TI - Expression of relB is required for the development of thymic medulla and dendritic cells. AB - Dendritic cells (DC) derived from bone marrow are critical in the function of the immune system, for they are the primary antigen-presenting cells in the activation of T-lymphocyte response. Their differentiation from precursor cells has not been defined at a molecular level, but recent studies have shown an association between expression of the relB subunit of the NF-kappa B complex and the presence of DC in specific regions of normal unstimulated lymphoid tissues. Here we show that relB expression also correlates with differentiation of DC in autoimmune infiltrates in situ, and that a mutation disrupting the relB gene results in mice with impaired antigen-presenting cell function, and a syndrome of excess production of granulocytes and macrophages. Thymic UEA-1+ medullary epithelial cells from normal mice show striking similarities to DC and, interestingly, these cells are also absent in relB mutant mice. Taken together, these results suggest that relB is critical in the coordinated activation of genes necessary for the differentiation of two unrelated but phenotypically similar cells (DC and thymic UEA-1+ medullary epithelial cells) and is therefore a candidate for a gene determining lineage commitment in the immune system. PMID- 7845468 TI - Catalytic specificity of protein-tyrosine kinases is critical for selective signalling. AB - How do distinct protein-tyrosine kinases activate specific down-stream events? Src-homology-2 (SH2) domains on tyrosine kinases or targets of tyrosine kinases recognize phosphotyrosine in a specific sequence context and thereby provide some specificity. The role of the catalytic site of tyrosine kinases in determining target specificity has not been fully investigated. Here we use a degenerate peptide library to show that each of nine tyrosine kinases investigated has a unique optimal peptide substrate. We find that the cytosolic tyrosine kinases preferentially phosphorylate peptides recognized by their own SH2 domains or closely related SH2 domains (group I; ref. 3), whereas receptor tyrosine kinases preferentially phosphorylate peptides recognized by subsets of group III SH2 domains. The importance of these findings for human disease is underscored by our observation that a point mutation in the RET receptor-type tyrosine kinase, which causes multiple endocrine neoplasia type 2B, results in a shift in peptide substrate specificity. PMID- 7845471 TI - Activation of dopamine D1 receptors or alpha 1 adrenoceptors is not involved in the EEG effect of nicotine in rats. AB - Based on previous own EEG-studies and behavioural studies of other authors, it has been claimed recently that D1 receptors are involved in addictive properties of drugs. It seemed, therefore, of interest to study whether nicotine produces D1 characteristic EEG alterations in rats. EEG was recorded in non-anesthetized, freely moving rats, transmitted telemetrically and underwent power spectral analysis. Nicotine (0.1, 0.2, 0.4 mg/kg s.c.) produced a desynchronization in the EEG and a decrease of power in all of the frequency bands (delta, theta, alpha 1, alpha 2, beta 1) except in beta 2. With regard to behaviour, an increase of locomotor activity and some discontinuous sniffing was manifest. The effect of nicotine (0.2 mg/kg) was not antagonized by blockade of dopamine D1 receptors by SCH 23390 (0.1 mg/kg s.c., 30 min before nicotine), although this drug by itself increased the power in most of the frequency bands. Prazosine (0.2 mg/kg i.p.), a selective antagonist at alpha 1 adrenoceptors, by itself increased the power in all of the frequency bands, but also failed to antagonize the effects of nicotine (0.2 mg/kg). In contrast, the blocker of nicotinic cholinoceptors mecamylamine (1 mg/kg i.p.) was effective in antagonizing the action of nicotine on the EEG. The results suggest that in nicotine-mediated desynchronization and decrease of power in the EEG, the activation of dopamine D1 or alpha 1 adrenoceptors is not involved. PMID- 7845469 TI - Complex information processing by the transmembrane signaling system involving G proteins. AB - Much of the information cells receive is transduced by a membranous signaling system that uses heterotrimeric guanine nucleotide binding proteins (G proteins) to functionally couple cell surface receptors to a variety of effectors. During recent years it has been shown that receptors, G protein alpha, beta and gamma subunits as well as effectors involved in this signaling system exhibit a remarkable structural diversity and that the interactions of these components display a bewildering complexity. Even though many questions remain to be answered, it is becoming obvious that G proteins form the basis of a complex membranous signaling network which allows the cell to coordinate and to process incoming signals already on the level of the plasma membrane. PMID- 7845470 TI - In vivo release of catecholamines in the locus coeruleus. AB - To investigate the release of endogenous dopamine, noradrenaline and adrenaline in the locus coeruleus, this brain area was superfused with artificial cerebrospinal fluid (CSF) through push-pull cannulae and the release of catecholamines was determined in the superfusate radioenzymatically. Collection of superfusates in time periods of 10 min revealed that release rates of the three catecholamines fluctuated, thus pointing to the existence of ultradian rhythms with following mean periods (minutes per cycle): noradrenaline 52 +/- 4, dopamine 37 +/- 2, adrenaline 36 +/- 2. The rhythm frequency of noradrenaline was significantly lower than the frequencies of dopamine and adrenaline. When the locus coeruleus was superfused with neuroactive drugs, superfusates were collected in time periods of 3 min. Superfusion with tetrodotoxin (1 mumol l-1) for 12 min elicited a prompt and sustained decrease (-70%) in the release rates of dopamine and adrenaline. The release rate of noradrenaline was also reduced, although to a lesser extent (-40%). Superfusion with veratridine (50 mumol l-1) led to an immediate and very pronounced enhancement in the release rates of dopamine, noradrenaline and adrenaline. The veratridine-induced increase in catecholamine outflow was decreased strongly by simultaneous superfusion with tetrodotoxin. The findings suggest that the release of endogenous catecholamines in the locus coeruleus fluctuates according to ultradian rhythms. Changes in the release on superfusion with veratridine and tetrodotoxin demonstrate the neuronal origin of the three catecholamines. The observed differences in the release characteristics between noradrenaline on the one hand and dopamine and adrenaline on the other might indicate that noradrenaline is partly released from somatodendritic sites of the noradrenergic cell bodies in the locus coeruleus. PMID- 7845472 TI - Effects of 6-hydroxydopamine on noradrenaline metabolism linked to neuronal uptake1 and extraneuronal uptake1 in dental pulp in vitro. AB - The study was undertaken to determine the relative roles of neuronal and extraneuronal uptake1 in the metabolism of 3H-noradrenaline in human dental pulp. Rabbit dental pulp was used as a reference since it was already known that normetanephrine (NMN) formation in this tissue utilised extraneuronal uptake1. Slices of pulp were preincubated in the absence and presence of 6-hydroxydopamine (1.6 mmol/l, for 10 or 20 min at pH 4.5) and subsequently incubated with 3H noradrenaline (0.18 mumol/l for 30 min at pH 7.4). The principal metabolites formed were normetanephrine in rabbit pulp and deaminated catechols (dihydroxymandelic acid and dihydroxyphenylglycol) in human pulp. In both tissues 6-hydroxydopamine strongly inhibited formation of the deaminated catechols, but was without effect on normetanephrine formation. It is concluded that: i) in vitro 6-hydroxydopamine does not influence the metabolic process which is dependent on extraneuronal uptake1, namely normetanephrine formation in rabbit dental pulp, and ii) the deaminated catechols are largely neuronal in origin in human pulp. Attention is drawn to an unusual feature of the neuronal metabolism in human pulp, namely the appearance of dihydroxymandelic acid as the principal metabolite. PMID- 7845473 TI - 5-Hydroxytryptamine receptors with a 5-HT6 receptor-like profile stimulating adenylyl cyclase activity in pig caudate membranes. AB - This study deals with the characterization of 5-hydroxytryptamine (5-HT, serotonin) receptors positively linked to adenylyl cyclase in membranes from pig brain caudate. 5-HT and related agonists induced a concentration-dependent stimulation of adenylyl cyclase activity in pig caudate membranes, with the following rank order of potency (mean pEC50 values): 5-HT (7.1) > or = 5 methoxytryptamine (6.9) > 5-carboxamidotryptamine (5.6) > sumatriptan (< 5). Maximal stimulation by 5-HT averaged 35 pmol cyclic AMP/min/mg protein over a basal activity of 159 pmol cyclic AMP/min/mg protein. 5-Methoxytryptamine and 5 carboxamidotryptamine had similar efficacies to that of 5-HT, whereas sumatriptan was about half efficacious. Other compounds known as agonists at some 5-HT receptors were weakly potent (mean pEC50 values < 5). They include the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH DPAT), the 5-HT4 receptor agonist, renzapride and the 5-HT2 receptor agonist, (1 (2,5-dimethoxy-4-iodophenyl)-2 aminopropane) (DOI). In antagonist studies, methiothepin (0.1 and 1 mumol/l) shifted the 5-HT curve to the right with no depression of the Emax, yielding pKB values of 7.4-8.0. Clozapine (1 mumol/l) also produced surmountable antagonism of 5-HT-induced effects (pKB 6.9). Ketanserin (10 mumol/l) weakly antagonized 5-HT (pKB 5.0). The 5-HT4 receptor antagonists, tropisetron (ICS 205-930) and SDZ 205-557 (2-methoxy-4-amino-5 chloro-benzoic acid 2-(diethylamino) ethyl ester), each at 1 mumol/l, did not significantly alter the concentration-response curve of 5-HT.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845474 TI - Lack of prophylactic or therapeutic efficacy of 5-HT2A receptor antagonists in halothane-induced porcine malignant hyperthermia. AB - During halothane-induced malignant hyperthermia (MH), plasma levels of serotonin (5-hydroxytryptamine, 5-HT) increase in pigs. Administration of 5-HT agonists which stimulate the 5-HT2A subreceptor triggers MH in susceptible pigs. A possible link between MH induced by 5-HT2A receptor agonists and halothane could be an increase of second messengers such as phosphoinositides (inositol polyphosphates), which have recently been implicated in the abnormal regulation of skeletal muscle calcium release in MH. If so, antagonists of 5-HT2A receptors which are linked to phosphoinositide turnover should be capable of preventing, retarding or attenuating halothane-induced MH. This possibility was investigated in the present study in MH susceptible pigs, using dantrolene for comparison, Development of MH triggered by a halothane challenge (inhalation of 3% halothane for 15 min) was completely prevented by dantrolene, 3.5 mg/i.v., whereas the 5 HT2A receptor antagonists ritanserin (0.5-10 mg/kg i.v.) or ketanserin (0.5-10 mg/kg i.v.) exerted no prophylactic effect. In pigs in which dantrolene, ritanserin or ketanserin where given in combination with hyperventilation after development of MH, dantrolene exerted therapeutic efficacy, whereas neither ritanserin nor ketanserin were effective treatments. The data indicate that 5-HT is not critically involved in the mechanisms of halothane-induced MH, at least under the conditions of the present experimental study. PMID- 7845475 TI - Convulsant action of a benzodiazepine receptor agonist/inverse agonist Ro 19-4603 in developing rats. AB - An inverse benzodiazepine receptor agonist Ro 19-4603, administered intraperitoneally, was found to induce two types of motor seizures, i.e. minimal, predominantly clonic and major, generalized tonic-clonic, in rats at all developmental stages studied (7, 12, 18 and 25 days old). The developmental profile of the two types of seizure was different. Minimal seizures could be induced easily in the two youngest groups, whereas there were no marked differences in the induction of major seizures between the age groups. A lethal outcome was more common in 18- and 25-day-old rats than in younger animals. The convulsant action of the benzodiazepine agonist/inverse agonist Ro 19-4603 shows only quantitative changes during post-natal development in the rat. PMID- 7845476 TI - The role of extracellular Ca2+ in carbachol-induced tonic contraction of the pig detrusor smooth muscle. AB - The role of extracellular Ca2+ in the tonic-contractile response to muscarinic receptor stimulation was investigated in isolated detrusor smooth muscle from the pig urinary bladder. Carbachol (10(-8)-10(-5) M) produced a concentration dependent contractile response in isolated pig detrusor smooth muscle strips consisting of an initial phasic component followed by a tonic component. During the plateau of the tonic contractions induced by carbachol at the submaximal concentration of 10(-6) M, the inhibiting effects of atropine, EGTA, nifedipine (a voltage-dependent calcium channel antagonist), H-7 [a protein kinase C (PKC) inhibitor] and YM934 (a potassium channel opener) on the contractions were evaluated. Atropine (10(-10)-3 x 10(-8) M) concentration-dependently inhibited the tonic contractions induced by carbachol. In the same experimental conditions, EGTA (4 mM) and nifedipine (10(-9)-3 x 10(-7) M) depressed the tonic contractions in a concentration-dependent manner as did H-7 (10(-5)-3 x 10(-5) M) and YM934 (10(-8)-10(-6) M). However, H-7 (10(-5)-3 x 10(-5) M) and YM934 (10(-6) M) were very weak in inhibiting the contractions induced by KCl (50 mM) in isolated pig detrusor smooth muscle strips. These results suggest that the tonic-contractile response induced by carbachol in pig detrusor smooth muscle strips is dependent mainly on depolarization of the cell membranes and an influx of extracellular Ca2+, and also suggest that this depolarizing response may be due to inactivation of ATP-sensitive potassium channels through muscarinic activation of PKC. PMID- 7845477 TI - Neurogenic chloride secretion induced by scorpion venom and veratrine in rabbit colon. AB - In earlier reconstitution experiments the venom of the scorpion Leiurus quinquestriatus, LQV, was shown to block Ca(2+)-activated high-conductance K+ channels from the basolateral cell membrane of rabbit colonocytes (Turnheim K, Costantin J, Chan S, Schultz SG (1989) J Membrane Biol 112:247-254). These LQV sensitive K+ channels do not seem to be involved in active Na+ transport across rabbit colon, as absorptive Na+ fluxes were not significantly affected by serosal addition of LQV to isolated epithelia of rabbit descending colon. While Na+ absorption was not changed, LQV and veratrine caused electrogenic Cl- secretion in this tissue by a neural (tetrodotoxin sensitive) mechanism. The secretory effect of LQV was partly inhibited by atropine, suggesting the involvement of m cholinoceptors, and by a VIP-antagonist. In contrast to the neurogenic secretion in the small intestine of guinea pig, rat and cat, 5-hydroxytryptamine (5-HT) does not seem to be involved in neurogenic secretion in rabbit colon, as 1) several 5-HT receptor antagonists did not inhibit the LQV effect with the exception of high concentrations of tropisetron, 2) exogenous 5-HT had no secretory effect, and 3) there was no significant release of 5-HT from the tissue during neurogenic secretion. The inhibitory effect of tropisetron on intestinal Cl- secretion seems to be unrelated to its property as a 5-HT3 receptor antagonist. PMID- 7845480 TI - The inotropic agents DPI 201-106 and BDF 9148 differentially affect potassium currents of guinea-pig ventricular myocytes. AB - The inotropic agents DPI 201-106 and BDF 9148 increase action potential duration (APD) of heart muscle. This effect can be explained by inhibition of inactivation of sodium current, which is affected by both agents to a similar extent (Ravens et al. 1991, Br J Pharmacol 104:1019-1023). However, as DPI 201-106 prolongs APD of guinea-pig ventricle to a larger extent than BDF 9148, other currents may also be involved. The aim of the present study was to measure the effects of DPI 201 106 and BDF 9148 on the inward rectifier IK1, and the two components of the delayed rectifier, IKs and IKr. The methyl-for-carbonitrile-substituted derivative BDF 8784 was included to study structure-activity relationships. Single-electrode whole-cell voltage-clamp technique was used to measure membrane currents of guinea-pig ventricular myocytes. Only DPI 201-106 reduced IK1 at potentials both negative and positive to the reversal potential. Three microM of DPI 201-106 reduced IKs, whereas 1 microM of BDF 9148 had no effect on this current. These concentrations were equieffective with respect to positive inotropic action (Ravens et al. 1991, Br J Pharmacol 104:1019-1023). BDF 9148 did however block IKs at higher concentrations, as did BDF 8784. It is concluded that block of outward current by DPI 201-106, but insignificant effects of BDF 9148, are responsible for the differential effects of these compounds on APD at equieffective concentrations with respect to inotropy. PMID- 7845478 TI - Endothelins induce prostacyclin release in both vascular and non-vascular tissue. AB - The effects of an i.v. administration of endothelin-1, -2 and -3 (0.25-3 nmol kg 1) or their corresponding proendothelins (1-20 nmol kg-1) on blood pressure and 6 keto-prostaglandin F1 alpha (6 keto-PGF1 alpha) release in the anaesthetized ganglion-blocked rat were evaluated. The same peptides were tested for their ability to release 6 keto-PGF1 alpha from the rat vas deferens in vitro. Endothelins and proendothelins showed a transient hypotensive effect followed by a potent, long lasting vasopressor response. Blood pressure increase induced by endothelins was found to be dose-dependently correlated with 6 keto-PGF1 alpha plasma level increases. On the other hand proendothelins produced similar pressor responses, but their effect on 6 keto-PGF1 alpha plasma levels was much less intense at equipressor doses. The effects of endothelins on arterial pressure and 6 keto-PGF1 alpha release were phosphoramidon-insensitive, while the activities of proendothelins were reduced by phosphoramidon (10 mg kg-1 i.v.). Both endothelins (5-15 nmol/l) and proendothelins (100-300 nmol/l) were able to increase to a similar extent 6 keto-PGF1 alpha levels in the rat vas deferens incubation buffer. The releasing activity of endothelins was not modified by the pretreatment with phosphoramidon (50 mumol/l). This pretreatment strongly inhibited proendothelin-1 and -2 effects, but not that of proendothelin-3. PMID- 7845479 TI - Effects of enalapril and hydrochlorothiazide on the salt-induced cardiac and renal hypertrophy in normotensive rats. AB - Recent studies have shown that, not only in hypertensive animals but even in normotensive rats, dietary salt (sodium chloride) produces a dose-related increase in the left ventricular and renal mass. In the present study the effects of the angiotensin converting enzyme inhibitor (ACEI) enalapril and the thiazide type diuretic, hydrochlorothiazide, on the development of the salt-induced left ventricular and kidney hypertrophy were examined in normotensive Wistar-Kyoto and Wistar rats. A high intake of sodium chloride (6% of the dry weight of the chow to mimic the level found in many human food items) during eight weeks produced a marked increase in the mass of the left ventricle and the kidneys in both rat strains with little or no effect on blood pressure. The cardiac hypertrophy correlated strongly with the renal hypertrophy. These salt-induced changes in the heart and in the kidneys were completely blocked by hydrochlorothiazide, while enalapril was devoid of any significant effects during the high-salt diet. However, during a low-salt diet enalapril, but not hydrochlorothiazide, effectively lowered the blood pressure and decreased the left ventricular mass of the normotensive rats. There was a 3- to 4-fold increase in the urinary excretion of calcium during the high intake of sodium chloride. Hydrochlorothiazide decreased the urinary excretion of calcium even during the low salt diet, and it completely blocked the salt-induced hypercalciuria. Enalapril had no significant effect on the urinary calcium excretion. During the low-salt diet hydrochlorothiazide increased the calcium and decreased the potassium concentration in the heart while enalapril increased the phosphorus concentration. In conclusion, a high intake of sodium chloride produced hypertrophy both in the heart and in the kidneys, even in the absence of a rise in blood pressure. Salt also remarkably increased the urinary calcium excretion. These harmful effects of salt were blocked by the thiazide diuretic hydrochlorothiazide but not by the ACEI enalapril. However, this study does not allow to make any direct comparison between the effects of enalapril and hydrochlorothiazide. PMID- 7845481 TI - A missense mutation in exon 6 of the CYP2D6 gene leading to a histidine 324 to proline exchange is associated with the poor metabolizer phenotype of sparteine. AB - The sparteine/debrisoquine polymorphism is a clinically important genetic deficiency of cytochrome P4502D6-catalyzed oxidative drug metabolism. 5-10% of Caucasians designated as poor metabolizers have a severely impaired capacity to metabolize more than 30 therapeutically used drugs. Genotyping of a random Caucasian population for the known cytochrome P4502D6 mutations A, B and D which are associated with the poor metabolizer phenotype has revealed a substantial number of misclassified poor metabolizers indicating the existence of one or more unknown mutations which cannot be identified with the currently available genotyping assays. Therefore we have cloned and sequenced one nonfunctional cytochrome P4502D6 allele of a misclassified poor metabolizer and could identify a single missense mutation designated E mutation at position 3023(A-C) in exon 6. Direct sequencing analysis, FokI restriction analysis and a newly developed allele-specific polymerase chain reaction assay were applied to analyze for this mutation in a population study. Three out of 97 randomly selected Caucasians were carriers of this mutation and thus the E allele has a frequency of 1.5% (confidence interval95% = 0.33 - 4.54%). Since only 2 out of 4 misclassified poor metabolizers carried the E mutation, additional unknown mutant alleles must exist. Computer modelling suggests that the E mutation, which results in a histidine to proline exchange in position 324 of the protein, may cause an alteration of the 3D structure of CYP2D6 in close vicinity to the active site thereby leading to total loss of enzyme function. PMID- 7845482 TI - [Acute arthritis or post-Streptococcus-reactive arthritis; an unexpected reactivation in The Netherlands]. PMID- 7845483 TI - [The changed role of the pathologist in medical care. I. Increasingly more possibilities with increasingly less material]. PMID- 7845484 TI - [The changed role of the pathologist in medical care. II. What should and what should not go to the pathologist?]. PMID- 7845485 TI - [The changed role of the pathologist in medical care. III. From epilogue to prologue]. PMID- 7845486 TI - [Post-streptococcal diseases, especially in children]. PMID- 7845487 TI - [Excessive crying in babies: literature review and practical recommendations]. PMID- 7845488 TI - [Characteristics of patients during their stay in a nursing home and at discharge]. AB - OBJECTIVE: To determine the characteristics of patients during stay in nursing homes, and at the moment of discharge or death. DESIGN: Cross-sectional study. METHOD: Data were collected concerning September 30th 1991 using the National Nursing Home Registration System SIVIS, in which over 80% of the nursing homes participate. There were 45,471 patients (23,395 somatic and 22,076 psychogeriatric patients). RESULTS: Frequent morbidity consisted of stroke, neurological disorders, locomotor disorders and dementia. There was a high degree of disability regarding the activities of daily life and mobility. The average length of stay for somatic patients was just over one year, that for psychogeriatric patients almost two and a half years. After rehabilitation, one third of the patients could be discharged to their homes or to a home for the aged. (Most of the remaining patients eventually died in the nursing home.) CONCLUSION: Residing nursing home patients are mainly characterised by chronic disorders. Consequently, disabilities and handicaps occur in many areas, such as self-care, mobility and psychological functioning. For a number of patients the distinction between somatic or psychogeriatric nursing becomes irrelevant. For all categories of patients the utilisation of care resources is increasing. PMID- 7845489 TI - [Diagnosis of pneumothorax not improved by additional roentgen pictures of the thorax in the expiration phase]. AB - OBJECTIVE: To evaluate whether an expiratory chest roentgenogram adds anything to the results obtained by a standard inspiratory chest roentgenogram in patients with a pneumothorax. DESIGN: Retrospective analysis and blinded re-evaluation of the radiographs. SETTING: Free University Hospital, Amsterdam. METHOD: Of 59 patients with a proven pneumothorax the chest roentgenograms at the time of the pneumothorax (54 inspiratory and 46 expiratory roentgenograms) were evaluated independently by 4 investigators in random order, as were 28 roentgenograms of the same patients made on different occasions. RESULTS: On all expiratory chest roentgenograms the pneumothorax was seen, of the 54 inspiratory ones two investigators missed one very small apical pneumothorax. All 28 control roentgenograms were scored correctly. No reliable additional information was obtained from the expiratory X-rays with regard to the cause of the pneumothorax. CONCLUSION: Expiratory chest roentgenograms are not indicated as a routine investigation for patients in whom pneumothorax is suspected. PMID- 7845490 TI - [Acute rheumatic fever in a 33-year-old man]. AB - In a 33-year-old man with an abnormal ECG three weeks after an episode of a sore throat, laboratory investigations revealed signs of a recent streptococcal infection. Mitral valvular and aortic valvular regurgitation were confirmed by echocardiography. The diagnosis of acute rheumatic fever was established according to the Jones criteria. PMID- 7845491 TI - [Issuing of rules in plastic surgery; suitable or unsuitable restrictions?]. PMID- 7845492 TI - [Budd-Chiari syndrome]. PMID- 7845493 TI - [Relationship between depression and personality]. PMID- 7845494 TI - [Budd-Chiari syndrome: current aspects and developments]. PMID- 7845495 TI - [Suspicion of pulmonary plague following return to The Netherlands from an epidemic area: real or not?]. PMID- 7845496 TI - [Farmacotherapeutisch Kompas 1995]. PMID- 7845497 TI - [Use of the pill by adolescents for contraception or as therapy]. AB - OBJECTIVE: To describe frequency of oral contraceptive (OAC) use, indications for OAC use and influence of calender age, gynaecological age (age minus age at menarche) and level of education on OAC use among ninth grade secondary school girls. SETTING: Secondary schools in Amstelland-de Meerlanden, a combined urban and rural region to the south of Amsterdam. METHOD: By questionnaire and individual interview on menstrual cycle pattern and OAC use, school girls were asked about duration and reasons for OAC use and what preparation they used. RESULTS: The response to the questionnaire was 92%, that to the interview 83%. Of the 2248 responders 248 (11%; mean age 15.3 years (SD: 0.6)) used OAC: 74% used low dose 'sub 50' preparations, 3% pills with 50 micrograms oestrogen, 3% 3-phase preparations and 17% pills with antiandrogens. Of girls aged 14, 15 and 16 years 4%, 12% and 28%, respectively, used OAC. Of the 15-year-olds 36% mentioned contraception as most important reason, 20% menstrual cycle irregularity, 28% dysmenorrhoea, 12% acne and 5% other reasons. With multiple logistic regression analysis age, gynaecological age and level of education were independent variables for OAC use in general and for OAC use for contraception or dysmenorrhoea, but less so for OAC use for menstrual cycle irregularity or acne. CONCLUSION: During adolescence low dose OACs are frequently used. Of adolescent OAC users 36% mentioned contraception as most important reason. OAC use in the Netherlands among girls aged 15 and 16 years doubled in comparison with 1982. Gynaecological age and calender age (determinants of biological maturation), and level of education (a determinant of life style) were associated with OAC use. PMID- 7845498 TI - [Patients in the Groningen lung transplantation program, 1990-1993; preliminary results of the medical technology assessment]. AB - OBJECTIVE: Medical technology assessment of lung transplant programme in Groningen, the Netherlands. DESIGN: Descriptive evaluation study. SETTING: University Hospital Groningen. METHOD: Description of the patient route through the treatment process of the transplantation programme. RESULTS: From mid-1990 to 1-1-1994, 257 patients (M/F ratio approximately 1, median age 43 years) were evaluated. The most frequent diagnoses were: COPD/emphysema, cystic fibrosis, pulmonary hypertension and lung fibrosis. In 1991 relatively more patients came from the northern provinces, but in 1993 there was no difference from the rest of the Netherlands. Until 1-1-1994, 116 patients were excluded from the programme: 58 patients were denied transplantation in the early phase of the programme, 47 died, 6 withdrew and 5 were lost in follow-up. Until 1-1-94, 77 patients were placed on a waiting list and 35 of these underwent unilateral (n = 12) or bilateral transplantation (n = 23). One patient had a retransplantation. The 1 year survival rate was 84%. The mean time between admission and transplantation was 15 months. CONCLUSION: The results of the lung transplantation programme in Groningen are promising. PMID- 7845499 TI - [HIV infection in the Rijnmond area, 1985-1993: more transmission via heterosexual contact and drug use, and more female patients]. AB - OBJECTIVE: To evaluate the characteristics of HIV infected patients in the Rijnmond region during 1985-1993. DESIGN: Descriptive. SETTING: University Hospital Rotterdam-Dijkzigt (AZR). METHOD: Data of medical records of all HIV infected patients in AZR were prospectively collected from 1988 on and retrospectively for 1985-1987. RESULTS: During the period 1985-1993 510 HIV positive patients consulted an internist at AZR (eight were infected with HIV-2). During the study 255 patients developed AIDS. Since 1991 fewer than 50% of the new HIV infected individuals belonged to the risk group of homosexual and bisexual men. The majority was infected by intravenous drug abuse or by heterosexual intercourse. Half the population infected by heterosexual transmission came from HIV endemic areas. The increasing number of HIV infection among heterosexuals was associated with an increasing number of HIV infected women. CONCLUSION: The Rijnmond region showed a noticeable shift of risk groups with HIV infection: heterosexual transmission and intravenous drug abuse were the cause of HIV infection in more than half of the HIV infections at AZR in 1992 and 1993. Counselling, health care and treatment should take account of the diversity of cultural backgrounds of the patient groups. PMID- 7845500 TI - [Erythema ab igne]. AB - A 47-year-old woman suffering from chronic abdominal pain developed erythema ab igne (reticular hyperpigmentation of the skin caused by exposure to heat). Histological examination revealed premalignant changes in two specimens of affected skin. The incidence of erythema ab igne is declining since fewer people use open fires for heating. Nowadays it is found mostly in patients suffering from chronic pain using hot water bottles, infrared lamps or heating pads. The disease is an important clinical indication for underlying chronic diseases. The affected skin runs a higher risk of development of actinic keratoses. Bowen's disease and squamous cell carcinomas. Dysplastic features of keratinocytes can be found histologically in lesions which are clinically not under suspicion. PMID- 7845501 TI - [From the library of the Nederlands Tijdschrift voor Geneeskunde: a hygienist's pearl, the manual of Ali Cohen (1872)]. PMID- 7845502 TI - [Mild exertional dyspnea is sometimes a serious symptom]. PMID- 7845503 TI - [No positive effect of preoperative exercise therapy and instruction in patients about to undergo hip arthroplasty]. PMID- 7845504 TI - [Gene therapy for brain tumors: gene therapy for malignant brain tumors using prodrug-sensitivity genes (series 4)]. PMID- 7845505 TI - [Surgical approaches to the tumors in and around the jugular foramen]. PMID- 7845506 TI - [Rebleeding of ruptured intracranial aneurysms in the acute stage]. AB - Among the cases of ruptured aneurysms we have handled, some patients have rebled before surgery was performed. In this study, we examine the factors that contribute to the rerupture of cerebral aneurysms in the acute stage and suggest measures to prevent rerupture prior to surgery. We have encountered 32 cases of rebleeding prior to surgery. The rebleeding occurred within six hours of the initial subarachnoid hemorrhage (SAH) in 26 patients, among whom 21 rebled within three hours. Thirteen patients rebled during bed rest, 10 patients during angiography, 4 patients during CT scan and 5 patients in various other circumstances. Nine of the 10 patients who rebled during angiography had undergone the procedure within three hours of the initial SAH. Overall, the patients' condition deteriorated substantially after rebleeding. Considering these circumstances surrounding aneurysmal rerupture, we suggest the following measures for the prevention of preoperative rerupture in the acute stage: 1) maintenance of lowered blood pressure during the risky period; 2) intentional delay of performance of angiography until at least hours after the initial rupture, and 3) performance of surgery on an emergency basis. PMID- 7845507 TI - [Diaschisis in right putaminal hemorrhage: correlation with motor function]. AB - Local cerebral lesions may cause depression of function in remote areas of the brain presumably by a transneural mechanism; it has been called "diaschisis". In the present study, to investigate the relationship between motor function and "diaschisis" regional brain blood flow in hypertensive right putaminal hemorrhage was studied in 33 patients (mean age, 55 years; 22 men, 11 women). The hematoma was treated conservatively in 8 patients, aspirated stereotaxically in 9 patients, and evacuated through a craniotomy in 16 patients. The regional blood flow in the right motor cortex and the left cerebellar hemisphere was measured by a single photon emission CT with N-isopropyl-p- (123 I) iodo-amphetamine intravenous injection method, and was evaluated by the RI count on early image/the decay-corrected RI count on delayed image (E/D) value. The time during which regional brain blood flow was measured ranged from 29 to 35 days from the onset. There was a positive correlation between the grade in the motor function in the subacute stage and the regional blood flow in the right motor cortex and the left cerebellar hemisphere. There was also a positive correlation between the Barthel index in the chronic stage (mean follow-up periods: 40 months) and the regional blood flow in the right motor cortex and the left cerebellar hemisphere. The results of the present study suggest that in right putaminal hemorrhage the flow reduction in areas remote from the primary lesion, i.e., "diaschisis", may reflect not only the degree of functional abnormalities of the internal capsule, but also the possibility of functional recovery. PMID- 7845508 TI - ["Skip lesions" in neurological deficits caused by tethered cord syndrome]. AB - The neurological deficits caused by tethered cord syndrome do not necessarily follow a dermatomal pattern of the affected spinal cord from caudal to cephalic fashion. The authors defined these neurological deficits as "skip lesions", and reviewed the neurological deficits in tethered cord syndrome. Among 29 cases, inconsecutive segmental motor weakness in 3 cases, inconsecutive segmental sensory impairment in 6 cases, positive Babinski reflex in 8 cases, supranuclear neurogenic bladder in 3 cases and lumbago or leg pain in 4 cases were observed and they were thought to be compatible with the neurological deficits called "skip lesions". The basic mechanism of this sign is that the cephalic portion of the spinal cord is functionally impaired during flexion of the lumbosacral spine, while the caudal spinal cord with decreased visco-elasticity dose not elongate. Inconsecutive motor-sensory disturbance, accelerated deep tendon reflexes in the lower extremities, positive Babinski or other pathological reflexes in the lower extremities, uninhibited neurogenic bladder, lumbago and pain in the legs were considered to belong to the category of "skip lesions" and they can be treated by the untethering procedure. The authors concluded that preoperative careful insight into the mechanism of "skip lesions" revealed surgical efficacy for the reversible neurological deficits by the untethering procedure, or the efficacy of decompression of the lipoma or neurolysis around the involved spinal nerve roots. PMID- 7845509 TI - [Outcome evaluation in putaminal hemorrhage by multiple regression analysis]. AB - The aim of this study was to determine the factors that influence the prognosis of hypertensive putaminal hemorrhage. We investigated the outcome of the activity of daily living (ADL 1: full recovery at social life, 2: self cared, 3: required partial care at home, 4: remained bedridden, 5: vegetative state, 6: dead) one year after the onset of putaminal hemorrhage in comparison with initial data obtained on the day when it occurred. The following parameters were assessed: sex, age, side of hematoma, classification of computed tomography (CT) findings, neurological grade, degree of muscle power, hematoma volume, treatment, past history of cerebrovascular disease, and laboratory data. In 67 patients with putaminal hemorrhage, the relationships among these parameters were examined using Spearman's rank correlation analysis. Additionally, in 55 patients (24 male and 31 female) with complete data from the day of onset, multiple regression analysis was performed. The data of muscle power were handled by the quantification method. The result of Spearman's rank correlation coefficient indicated that the outcome had a positive correlation with age (correlation coefficient = 0.375), CT classification (0.595), neurological grade (0.714), hematoma volume (0.689), a past history of cerebrovascular disease (0.475), the white blood cell count (0.541), and the lactate dehydrogenase level (0.347). The outcome had a negative correlation with muscle power (-0.579) and the cholinesterase (-0.340).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845510 TI - [Suprasellar ectopic pituitary adenoma: report of a case]. AB - An extremely rare case of an ectopic pituitary adenoma in the suprasellar region is reported. A 57-year-old man was referred to us in March, 1993, because of bitemporal hemianopsia. Magnetic resonance imaging (MRI) and computed tomography (CT) revealed a well-circumscribed enhancing mass in the suprasellar region. Sagittal tomography of the skull showed normal-sized sella turcica. Endocrinological tests were almost within normal range. The tumor was totally removed by combined right subfrontal and interhemispheric approach. At the time of the operation, we confirmed that the tumor did not continue to the pituitary gland and that the diaphragma sellae was intact. Histological diagnosis of the tumor specimen was pituitary adenoma. Post-operative MRI showed a normal pituitary gland, thus supporting the diagnosis of ectopic pituitary adenoma. To our knowledge, only ten cases of suprasellar ectopic pituitary adenoma have been reported, including our case. Pathogenesis of ectopic pituitary adenoma was briefly discussed. PMID- 7845511 TI - [Deep sylvian meningioma: a case report of a child]. AB - A case of deep sylvian meningioma without dural attachment in a 12-year-old boy was reported. He had been suffering from severe headache for a month. Neurological examination was normal. CT scan and MR images showed a well-enhanced 7 cm mass lesion with small cysts, located in the left sylvian fissure. Peritumoral edema was slight and the midline structures were minimally shifted in spite of its large size. A fronto-temporal craniotomy was made and the tumor was grossly totally removed. The tumor had no dural attachment and existed in the left sylvian fissure, involving the middle cerebral artery and its branches. The histological diagnosis was transitional meningioma without malignancy. The postoperative course was uneventful except for transient mild left oculomotor palsy for several days. He is doing well now one year after the surgery and follow-up MR images showed no recurrence. Intracranial meningioma is rare in children. According to the literature, meningioma in children is slightly more frequent in males. There is a higher incidence of lack of dural attachment and cystic tumors than in adults. Deep sylvian meningioma without dural attachment is also very rare. Including our case, 13 cases of deep sylvian meningioma were reported in the literature. Four of them were under 20 years old. We report this case in detail with other cases reported previously. PMID- 7845512 TI - [Evaluation of cerebro-vascular diseases with persistent carotid-basilar anastomosis]. AB - Five cases of cerebro-vascular diseases with carotid-basilar anastomosis were evaluated. Case 1: a 73-year-old female was diagnosed as having subarachnoid hemorrhage due to a ruptured aneurysm of the right internal carotid artery posterior communicating artery bifurcation and demonstrated that a left proatlantal intersegmental artery. Case 2: a 38-year-old female showed intraventricle hemorrhage due to arteriovenous malformation and showed left primitive hypoglossal artery. Case 3: 73-year-old female was diagnosed as having subarachnoid hemorrhage due to a ruptured basilar top aneurysm and demonstrated that a right primitive hypoglossal artery. Case 4: a 29-year-old male with unruptured aneurysm of the left internal carotid artery-posterior communicating artery bifurcation, and right trigeminal artery was detected incidentally by magnetic resonance angiography (MRA). Furthermore, right proatlantal intersegmental artery was detected by conventional angiography. Case 5: a 76-year old male was diagnosed as having subarachnoid hemorrhage due to a ruptured aneurysm of the anterior communicating artery. MRA showed the aneurysm and a primitive trigeminal artery. No clinical symptom related with carotid-basilar anastomosis was detected. Magnetic resonance angiography (MRA) was useful for diagnosis of asymptomatic carotid-basilar anastomosis. Especially, axial view of MRA by time of flight method detected two cases of a primitive trigeminal artery. And coronal view of MRA by phase contrast method is useful for diagnosis of primitive proatlantal intersegmental artery. More asymptomatic persistent carotid basilar anastomosis may be detected by MRA. PMID- 7845513 TI - [A case of hemifacial spasm associated with a cerebellar hematoma]. AB - This is a report of a hemifacial spasm associated with a cerebellar hematoma. A 60 year-old female was admitted to our hospital due to severe vertigo and nausea. On admission, the neurological examination showed drowsy conscious level, cerebellar sign dominant on the left side, and left hemifacial spasm. CT scans disclosed a large hematoma in the left cerebellar hemisphere. An angiography revealed a dominant left PICA, but showed neither vascular malformation nor aneurysm. An emergency removal of the hematoma was carried out by using suboccipital craniectomy. Three days after the surgery, the patient's left hemifacial spasm disappeared completely. She had never suffered from left hemifacial spasm prior to this cerebellar bleeding. The hemifacial spasm was thought to be due to either the compression of the left facial nerve by the PICA which had been displaced by the cerebellar hematoma, or to the fact that the nucleus of the left facial nerve might have been stimulated by the hematoma, and the hemifacial spasm might have been caused as a result of the stimulation. The total removal of the hematoma and the postoperative CSF leakage might have decompressed the facial nerve. It was considered that this might be similar to microvascular decompression. PMID- 7845514 TI - [Double-loculated chronic subdural hematoma in a patient on hemodialysis: case report]. AB - A 61-year-old male who had been regularly hemodialyzed for a year and 8 months developed a double-loculated chronic subdural hematoma (CSDH). Computed tomography (CT) revealed a heterogenous-density hematoma at the right fronto parietal convexity. After a burr hole aspiration and irrigation, CT disclosed a residual hematoma and a septum separating the hematoma cavities. The hematoma and the septum were removed by right frontal craniotomy. At surgery, it was found that the thick septum completely separated the hematoma cavities and the outside hematoma was made up of coagula containing trabecula-like structures, and the inside hematoma consisted of old bloody fluid. Histological examination showed that the outer membrane and the septum were both thick because of the invasion by numerous lymphocytes which suggested that the intramembraneous bleeding from sinusoids split the outer membrane of an old CSDH. Double or multi-loculated CSDH should be considered in a case which is slow in recovery or aggravated after a burr hole aspiration and irrigation. PMID- 7845515 TI - [An adult case of lumbar intradural lipoma]. AB - A 42-year-old female with intradural lipoma at the level of L1 is reported. She was admitted with a history of 32 months of lumbago, 25 months of pain of the left leg, and 12 months of motor weakness in the left leg. Neurologically, sensory impairment below the L1 dermatome of the left leg, and motor weakness of bilateral legs were noted on admission. CT demonstrated a low density mass with no contrast enhanced effect at the level of L1. MRI showed a mass with high signal intensity on the T1-weighted image, and low signal intensity on the T2. L1 laminectomy, and additional Th12 and L2 partial laminectomy were performed and the tumor was partially removed. The tumor was completely in the intradural space. Pathologically, the tumor consisted of mature adipose cells with normal vessels. Postoperatively, the epidural effusion at the operative area caused sensory impairment and motor weakness of the right leg. Finally, the patient came to be neurologically free of defects except for slight sensory diminution of the L4 dermatome of the left leg. In this case, total removal of the tumor was difficult because of adhesion between the tumor, the cauda equina and the conus medullaris. Postoperatively, neurological findings showed a marked improvement. The preoperative neurological deterioration in this case seemed to be associated with simple compression exerted on the nerves. PMID- 7845516 TI - [Carotid endarterectomy: its controversial point]. PMID- 7845517 TI - [Identification of motor area by transcranial magnetic stimulation using an "eight-figure" coil in patients with motor paralysis]. AB - In patients with motor paralysis, we tried to identify the functional motor area by transcranial magnetic stimulation using an "eight-figure" coil designed by Ueno. Motor evoked potentials (MEPs) were recorded in 7 patients from 50 to 64 years old, and in 5 normal volunteers 26 to 45 years old. They were stimulated at 49 points over an unilateral hand motor area, and at 21 points over a foot motor area, and surface MEPs were recorded on their contralateral thenar muscle and abductor hallucis brevis muscle. In normal volunteers, the optimal eddy current for stimulating the hand motor area was directed anteriorly parallel to the midline, and for stimulating the foot motor area, it was postero-laterally directed with an angle of 45 degrees towards the midline. MEPs could be induced at their muscle contractions during which their thumbs and middle fingers softly touched each other, and their halluxes slightly flexed. In five patients two kinds of amplitude mappings reconstructed from MEPs were obtained at rest or at muscle contraction. A line connecting these two peaks on an amplitude mapping was regarded as an "MEP-motor area". A geographical difference between the MEP-motor area and MRI-motor area (identified by an MRI surface image) was studied at muscle contraction and at rest. In normal subjects the sites of the MEP-motor area and of the MRI-motor area coincided, whereas, in patients with space occupying lesions near the central sulcus, the MEP-motor areas were located 1 to 2cm posterior to MRI-motor areas.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845518 TI - [Aneurysm surgery using temporary occlusion under SEP monitoring]. AB - Premature rupture of a cerebral aneurysm during operation is a serious hazard. Temporary occlusion of intracranial arteries has emerged as a valuable technical adjunct in the management of intracranial aneurysms. Twenty-five patients (from a group of 43 consecutive aneurysm patients treated during a 13-month period) underwent elective temporary arterial occlusion under somatosensory evoked potential (SEP) monitoring. Median nerve SEPs were used during 19 ICA and MCA aneurysm operations, while posterior tibial SEPs only were used in 7 patients with aneurysm of the ACA. Amplitude of the N20 or P40 was evaluated. A decrease in amplitude more than 50% when compared to baseline value was defined as a significant SEP change. In 11 patients of the 25 cases, SEP changes were observed. Temporary occlusion was applied to the proximal portion of the internal carotid artery 10 times, to the M1 portion of the middle cerebral artery 5 times, to the M1-M2 complex 5 times, to the A1 portion of the anterior cerebral artery 9 times, and to the A2 - A3 once. Of the 26 clipping (25 patients), 12 had SEP alterations, 14 had no SEP changes. Temporary occlusion was released within 3 minutes after disappearance of N20 (or P40) in all the patients with SEP changes except one. Nine of these 11 patients showed complete recovery of SEP and two showed partial recovery. Patients with partial recovery of SEP were associated with postoperative new neurological deficit, which was transient in one of them. There was a correlation between changes in SEP and post operative outcome.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845519 TI - [Surgical decompression for massive cerebellar infarction]. AB - The authors report 10 patients with progressive neurological deterioration due to massive cerebellar infarctions. Computerized tomography scans confirmed obstructive hydrocephalus and brain stem compression. All 10 patients (seven men, three women; mean age, 59 years) were treated by external ventricular drainage and decompressive suboccipital craniectomy. After discharge from the hospital, they were followed up (23-101 months) and their functional independence was evaluated by the Barthel Index. The condition of three patients with brain-stem infarction had deteriorated despite decompressive surgery. Two of these died during the acute stage and one because severely disabled. The remaining seven patients showed neurological improvement during the postoperative period. Four patients with preoperative Japan Coma Scale of 100 returned to their previous jobs within the follow-up period and three patients with preoperative Japan Coma Scale of 200 required some assistance in daily activities. It is suggested that decompressive surgery may be beneficial for massive cerebellar infarction. The postoperative prognosis depends mainly on the presence or absence of coexisting brain-stem infarction. It is possible that, without brain-stem infarction, patients who remained in a "dependent" state may have recovered better if they had been operated on earlier. PMID- 7845520 TI - [Chronic subdural hematoma with bleeding tendency; clinical analysis of 11 surgical cases]. AB - Eleven patients with chronic subdural hematoma (CSDH) with bleeding tendency (BT) were surgically treated in the last 12 years. To study the clinical problem of CSDH with BT, 11 surgical cases were divided into 3 groups, Group A; CSDH with primary BT (1 case of hemophilia A), Group B; CSDH with BT secondary to a basic disease (3 cases of leukemia, 2 cases of malignant tumor with DIC, 1 case of chronic renal failure and 1 case of liver cirrhosis), Group C; CSDH with BT by anticoagulants (warfarin) (2 cases of replacement of mitral valve, 1 case of A-C bypass). Evacuation of the hematoma was performed by means of one or two burr holes with irrigation of the hematoma cavity and a drainage tube was placed in the subdural space. The outcome was excellent in Groups A and C. In Group B, two patients with DIC due to gastric cancer and prostatic cancer died, and 3 patients with leukemia recovered dramatically from CSDH, but the poor course of the disease itself resulted in death. The outcome of other patients in Group B was excellent. Since CSDH with BT is often fatal, those patient had usually been treated conservatively. However, from this analysis, we stress that CSDH with BT should be surgically treated after checking the blood conditions carefully to determine whether or not the patient has need for surgery. PMID- 7845521 TI - [Tension pneumocephalus in association with ventriculoperitoneal shunt and congenital bony defect in the mastoid tegmen]. AB - The authors report a case of tension pneumocephalus in association with a congenital bony defect at the mastoid tegmen, and a ventriculoperitoneal (V-P) shunt for obstructive hydrocephalus, due to the presence of a posterior fossa meningioma. After multiple diagnosis and surgical procedures, congenital bony defect at the right mastoid tegmen demonstrated by a middle ear cavity computerized tomography (CT) scan, was identified as the source of entry of the air. The air must have penetrated the lateral ventricle through a porencephalic cyst in the right temporal lobe. Reconstruction of the bony defect in the mastoid tegmen successfully prevented further recurrence of tension pneumocephalus. We discussed the possible pathogenic mechanisms involved in this kind of tension pneumocephalus, and suggested that a middle ear cavity CT scan should be performed for tension pneumocephalus that has developed after V-P shunt. PMID- 7845522 TI - [Magnetic resonance imaging of supratentorial and parafalcial empyema]. AB - The authors report the MR imaging of two patients with multiple subdural empyemas, including one in the interhemispheric fissure. MRI demonstrated convexity and interhemispheric collections which were mild hyperintense relative to CSF, hypointense relative to gray and white matter on T1W1, and marked hyperintense relative to CSF, and brain on T2W1. On the basis of signal intensity differences, MRI can distinguish subdural empyemas from most sterile effusions and chronic subdural hematomas with similar CT appearances. MRI was found to be clearly more sensitive to subdural empyemas than CT, though such lesions missed on CT were considered to be relevant. MR was superior to CT in demonstrating the nature, presence, and extent of these lesions. In both cases, the capsule of the lesions demonstrated enhancement, and connection between each lesion was obvious on contrast-enhanced MRI. It seems that contrast-enhanced MR image may detect encapsulation of an abscess which can not be detected from contrast-enhanced CT. We emphasized that the most significant factor in the successful surgical management of multiple subdural empyema, particularly including interhemispheric collections is the accurate location of pus. This can be reliably achieved with MR imaging. PMID- 7845523 TI - [CT-guided stereotactic operation for cerebellar abscess by the transtentorial hiatus approach: a case report]. AB - We reported a case of cerebellar vermian abscess, well managed by CT-guided stereotactic aspiration and drainage via the transtentorial hiatus route. A 69 year-old man was admitted to our hospital because of acute deterioration of bronchiectasis. About one month later, he complained of headache and gait unsteadiness. CT scan revealed a multilocular abscess in the cerebellar vermis. Although conservative therapy with antibiotics was applied, the symptoms deteriorated and the lesion continued to grow. Aspiration and drainage were therefore performed for the main lesion by CT-guided stereotactic surgery via the transtentorial hiatus route. This was completed without complications. The postoperative course was good and the lesion had disappeared when enhanced CT was carried out about 2 months after the operation. We consider this stereotactic transtentorial hiatus operation to be an effective treatment for patients such as the present one with a superior vermian lesion and who is at risk due to a poor respiratory condition. PMID- 7845524 TI - [Gene therapy for brain tumors: induction of apoptosis and immunogenic modulation in glioma cells (series 5)]. PMID- 7845525 TI - [A case of atypical hemifacial spasm without involvement of orbicularis oculi muscles: possibility of functional topography in facial nerve]. AB - We reported a case of atypical hemifacial spasm that did not involve orbicularis oculi muscles. A 60-year-old woman suffered from intermittent involuntary movement of the orbicularis oris and buccinator muscles. Operative findings revealed that the rostrodorsal portion of the facial nerve root was compressed by a loop of AICA. Transposing this AICA, it was found that it was compressing one portion on the rostrodorsal part of this nerve root. In most cases, facial spasm involves orbicularis oculi muscles and compression of the anatomically caudal portion of the facial nerve root. Differentiation of the compressed portions of the nerve, therefore, may indicate a functional topography of the facial nerve. PMID- 7845526 TI - [A case of meningioma associated with intracerebral hemorrhage and acute deterioration]. AB - We report a case of convexity meningioma associated with sudden onset of intracerebral hemorrhage followed by acute deterioration. A 76-year-old previously healthy male suddenly collapsed into coma and was admitted to our department. On admission, he was deeply comatose. Computerized tomography (CT) scan revealed intracerebral hemorrhage in the right frontal lobe, together with an isodense mass lesion of about 5 cm in diameter. The density on the fronto medial side of the mass increased after administration of contrast medium, probably due to extravasation. However, there was no enhancement of the mass lesion. Cerebral angiography revealed marked prolongation in circulation time and extravasation via the right middle internal frontal artery. The right middle meningeal artery was dilated and elongated, but no tumor stain was found. The patient died on the following day. Autopsy disclosed massive hemorrhage in the right frontal lobe together with a convexity meningioma. Histological examination showed that the tumor was a fibroblastic meningioma. We review previously reported cases of convexity meningioma associated with intracranial hemorrhage, and discuss mainly the mechanism of bleeding. PMID- 7845527 TI - Neuroendocrine-immune interactions in homeostasis and autoimmunity. AB - Recent experimental evidence confirms the interrelationships between the central nervous, neuroendocrine and immune systems. Indeed, extensive duality exists in the use of neurotransmitters, hormones and receptors each system displays. In the present annotation, the effect of cytokines, soluble mediators of immune function, on the CNS and neuroendocrine systems is addressed and conversely, we discuss the modification of the immune compartment by the sympathetic nervous and neuroendocrine systems, with particular reference to the role of noradrenaline and corticosterone. Dysfunction between the systems is considered in the context of autoimmune conditions, with emphasis on experimental allergic encephalomyelitis and the contribution of corticosterone-driven T-cell apoptosis to recovery from the disease. Finally, we speculate on the relevance of neuroimmune interactions in the pathogenesis of multiple sclerosis. PMID- 7845528 TI - Hierarchical cortical control of neuroimmunomodulatory pathways. AB - The central nervous system and the immune system are both stimulus response systems with sophisticated memories mediating defence and adaptation to external and internal threats. There is mounting evidence that these two systems share their information in a bidirectional flow of cytokines, steroids, and neuropeptides. This review examines the influence of higher cognitive centres on immunity and highlights the central role played by the hypothalamus in enabling these two systems to function as an integrated unit to maintain homeostasis. The search for novel compounds that are capable of enhancing immunity by regulating these brain-immune feedback loops offers one of the most exciting areas for future neurobiological research. PMID- 7845529 TI - Detection of numerical chromosome aberrations in brain tumours by fluorescence in situ hybridization on smear preparations of small tumour biopsies. AB - We present a technique for the preparation and interphase cytogenetic analysis of native tumour cell nuclei from smear preparations of small biopsies of human brain tumours. The presence of tumour-specific numerical chromosome aberrations can be determined by fluorescence in situ hybridization (FISH) analysis using chromosome-specific repetitive DNA probes. The FISH analysis of smear preparations provides cytogenetic information about brain tumour samples, within 2 days, avoiding time-consuming and artefact-prone tumour cell culture. PMID- 7845530 TI - Selective closure of the vascular bed of an experimental glioma model during in situ saline perfusion. AB - Flow through the vasculature of an experimental rat glioma has been investigated during in situ perfusion of the brain, via the ascending aorta, with a simple saline solution. Using such a system, it has been shown previously that the blood brain barrier will remain intact with an adequate cerebral perfusate flow rate for at least 10 min, providing that the metabolic inhibitor 2,4-dinitrophenol is present. Cerebral perfusate flow rate was measured in both tumour and non-tumour areas using [14C] iodoantipyrine. The perfusion pump rate was set between 4.8 and 84 ml/min in different animals and the mean flow rate for cerebral hemisphere remote from the tumour was 1.03 +/- 0.67 ml/min/g (mean +/- sd; n = 17) whereas that for intracerebral tumour was considerably lower at 0.060 +/- 0.11 ml/min/g (mean +/- sd; n = 17). Linear regression of tumour flow on cerebrum flow showed a highly significant correlation (r = 0.88). Light and electron microscope examination of the tumour vessels revealed no luminal obstruction or perivascular oedema to explain the low flow. We suggest that perfusion with a low viscosity medium, at flow rates that result in a low intraluminal pressure, probably causes glioma vessels to close preferentially because they require a higher intraluminal pressure to remain patent than do normal cerebral vessels. PMID- 7845531 TI - How to detect gold, silver and mercury in human brain and other tissues by autometallographic silver amplification. AB - Gold, silver, mercury and zinc bind chemically to sulphide or selenide ions and create crystal lattices that can be detected in histological sections by a silver amplification technique called autometallography (AMG). The technique specifically magnifies such nanometer-sized catalytic crystals. For each metal, a detailed protocol has been worked out. If several different AMG metals/metal molecules are present in the same tissue, it is possible to distinguish one from another. The AMG technique is based on the capability of small crystal lattices of the aforementioned metals and metal molecules to initiate AMG silver amplification. Electrons released from adhering hydroquinone molecules reduce silver ions that are integrally connected with the crystal lattices. In this manner, particles consisting of only a few atoms of, say, gold, or molecules of mercury selenide (Figure 1), can be silver amplified to a size at which they can be detected in the electron microscope, or even further to dimensions that can be observed in the light microscope. Thus the AMG technique opens up the possibility of visualizing gold, e.g. in the nervous system of rheumatic patients who have been treated with aurothiomalate. Mercury can similarly be visualized in tissues from individuals who have been exposed to mercury, either through leaching from amalgam dental fillings, through eating fish, or by occupational exposure, and silver in the central (CNS) and peripheral nervous systems (PNS) and other tissues from individuals exposed to silver in one form or another. In the future, the possibility of demonstrating vesicular zinc, a particular pool of endogenous zinc that is found in terminals of zinc-enriched neurons (ZEN neurons), might prove valuable for pathological interpretation of diseases such as Alzheimer's disease. The vesicular zinc, present in some of the synaptic vesicles of ZEN neuron terminals, is most impressively demonstrated by AMG in telencephalic structures. It is becoming increasingly indisputable that vesicular zinc is related to synaptic activity influencing or modulating facilitatory synapses. ZEN neurons are probably a sub-population of glutaminergic neurons. A technique for the post-mortem demonstration of vesicular zinc in terminals of ZEN neurons in human brains is therefore urgently required. PMID- 7845532 TI - Transferrin receptors in the parkinsonian midbrain. AB - Several hypotheses have been put forward to explain the pathogenesis of Parkinson's disease (PD) and recently it has been suggested that alterations in iron homeostasis may be implicated. Because of the central role of the transferrin receptor in providing access of iron to cells, we have studied the distribution and density of transferrin receptors using [3H]-transferrin ([3H] Tf) binding and tritium film autoradiography in the normal and PD midbrain. High levels of [3H]-Tf binding were found in the dorsal raphe, oculomotor nucleus and periaqueductal grey whilst lower levels of [3H]-Tf binding were found in the tegmentum, red nucleus and substantia nigra. Significant reductions in binding were found in the substantia nigra, red nucleus and oculomotor nucleus in PD, the reductions in [3H]-Tf binding being similar to the loss of nigral neurons in PD. The data suggest that the increased iron content of surviving nigral neurons may reflect a compensatory metabolic response rather than abnormal transferrin receptor expression. PMID- 7845533 TI - Transferrin receptors in the normal human hippocampus and in Alzheimer's disease. AB - Several lines of evidence suggest that aluminium may play a role in the pathogenesis of Alzheimer's disease (AD). The iron transport protein transferrin is the major transport protein for aluminium, and aluminium gains access to cells by means of a specific cell surface transferrin receptor. We have assessed the distribution of transferrin receptors in the normal and AD hippocampal formation using [3H]-transferrin ([3H]-Tf) binding and tritium film autoradiography, in order to assess the role of the transferrin receptor in AD. In normal brain, [3H] Tf binding was highest in the pyramidal cell layers with CA2 > dentate gyrus granule cell layer > or = CA1 > CA3 > or = CA4 > subiculum > parahippocampal gyrus. In AD, significant reductions in [3H]-Tf binding were found in CA1, CA2 and CA4 pyramidal cell layers. The reduced [3H]-Tf binding in AD may, however, be due to poor pre-mortem agonal states which correlated with reduced [3H]-Tf binding. The discrepancy between the distribution of transferrin receptors in the hippocampus and those areas which are prone to the formation of senile plaques and neurofibrillary tangles suggests that if transferrin-mediated uptake of aluminium in AD/SDAT is significant in the pathogenesis of this disorder, it is not the only determinant of Alzheimer-type neuropathology. PMID- 7845534 TI - Freeze-fracture analysis of muscle plasma membrane in Becker's muscular dystrophy. AB - The intramembranous particle (IMP), orthogonal array (OA) and orthogonal array subunit particle (OASP) densities in skeletal muscle plasma membranes from eight patients with Becker's muscular dystrophy (BMD) were analysed by the freeze fracture technique. The results showed almost normal IMP density with the significant decrease of OA and OASP densities in BMD. The group mean densities +/ SE of IMPs on the protoplasmic faces with and without OASPs, and on extracellular faces/microns 2 were 2137 +/- 207, 1839 +/- 68 and 895 +/- 108, respectively in controls; whereas those of BMD were 1989 +/- 259, 1837 +/- 203 and 900 +/- 239, respectively (P > 0.1 by two-tailed t-test). The group median density of OAs and their pits/microns 2 was 4.89 with mid-ranges (25-75% values of the counts) of 2.66-10.18 in controls; whereas that in BMD was 2.15 with mid ranges of 1.14-4.31 (P < 0.01 by Wilcoxon rank-sum test). The group mean density +/- SE of OASPs in controls was 15.99 +/- 1.83; whereas that in BMD was 13.47 +/- 1.07 (P < 0.01 by two-tailed t-test). However, the diminution of OA and OASP densities in BMD muscle plasma membranes was not as severe as in Duchenne's muscular dystrophy. There was a relationship between OA density and clinical severity in BMD patients; the decrease of OA density in a severe BMD patient was more marked than that in mildly affected BMD patients. Therefore, it seems that marked depletion of OA density may lead to the severe disability in muscular dystrophies. PMID- 7845535 TI - Parvalbumin immunohistochemistry in denervated skeletal muscle. AB - Parvalbumin is a calcium-binding protein which, in muscle, is mainly found in type 2B fibres, whereas type 1 fibres lack parvalbumin immunoreactivity. Previous studies have shown that this pattern is highly dependent upon motor neuron innervation and is modified in denervated, cross-reinnervated or chronic low frequency stimulated muscles. In the present study, we have examined the modifications of parvalbumin immunocytochemistry in the anterior tibialis muscle of the rat at different intervals following section of the sciatic nerve. During the first 2 weeks after denervation, no changes in parvalbumin immunoreactivity were seen, although a global reduction of fibre diameter was observed. Three weeks after denervation, small angulated, strongly parvalbumin-immunoreactive fibres appeared. From the second month onwards, the pattern of parvalbumin immunohistochemistry was characterized by areas composed of small, strongly immunoreactive fibres separated by less atrophic areas displaying a normal chequerboard distribution of parvalbumin immunoreactivity. The increase of parvalbumin-immunoreactivity in denervated and reinnervated muscle, as seen in our study, indicates that important changes in parvalbumin distribution occurs in muscle fibres after denervation. These changes are probably produced in an attempt to bind the free cytosolic calcium which accumulates in denervated fibres, and further reinforces the role of parvalbumin in calcium homeostasis during denervation and reinnervation. PMID- 7845536 TI - Cholecystokinin B receptor gene expression in hypothalamic neurosecretory neurons after experimental manipulations. AB - Magnocellular neurons of the supraoptic (SON) and paraventricular (PVN) nuclei projecting to the neurohypophysis produce, in addition to the classical hormones vasopressin and oxytocin, a large number of other peptides, one of which is cholecystokinin (CCK). Binding sites for CCK have been identified in the posterior pituitary. Recently the cDNAs for CCKA and CCKB receptors were isolated and characterized, and CCKA and CCKB receptor mRNAs were localized in the SON and PVN. We have used complementary oligonucleotides and in situ hybridization histochemistry to study CCKB receptor mRNA in hypothalamic neurons. Changes in the expression of CCKB receptor mRNA in the SON and PVN were analysed in salt loaded as well as in hypophysectomized animals. Levels of CCKB receptor mRNA in the PVN and SON increased markedly in salt-loaded animals as compared to controls. An increase in CCKB receptor mRNA levels was seen in the SON and PVN after 3 days of salt loading, with high levels continuing through 5 and 7 days. At 14 days, the levels of CCKB receptor mRNA in the PVN were significantly lower as compared to 7 days. Hypophysectomy 5 days prior to sacrifice, resulting in a nerve lesion in the neurohypophysial pathway and removal of the anterior pituitary hormones, induced a significant increase in CCKB receptor mRNA levels in neurons of the PVN. The increase in CCKB receptor mRNA labelling after salt loading was mainly observed in the ventrolateral part of the PVN and in the dorsolateral part of the SON, corresponding to oxytocin-containing neurons, whereas the increase after hypophysectomy was mainly seen in the central part of the PVN and in the ventral part of the SON, corresponding to vasopressin containing neurons. The results suggest that the synthesis of CCKB receptors in magnocellular neurons is increased upon osmotic challenge and hypophysectomy. PMID- 7845537 TI - GABAA and NMDA receptor activation controls somatostatin messenger RNA expression in primary cultures of hypothalamic neurons. AB - GABAA receptors mediate the inhibition of somatostatin gene expression and NMDA receptors mediate its stimulation. The aim of this study was to determine whether the two major neurotransmitters in the central nervous system (GABA and glutamate) could interact to control somatostatin mRNA content in primary cultures of hypothalamic neurons. Neurons were incubated for 15 min on days 3, 5, 7 or 11 of culture with Mg(2+)-free medium containing either NMDA (20 microM) or bicuculline (50 microM) to investigate the ontogenesis of somatostatin somatostatin secretion in response to NMDA and GABA. We found that NMDA significantly elicited somatostatin release from day 3, and bicuculline-induced release was observed from day 5. An ontogenetic study of somatostatin mRNA levels revealed that it steadily increased up to day 5 (6-fold) and a slight but nonsignificant decrease was observed on day 7 which stabilized until day 13. Experiments were thus carried out on day 11 of culture. Pharmacological manipulations of the two types of receptors (NMDA and GABAA) were performed to study the effect of the interaction on somatostatin mRNA accumulation. Time course studies revealed the optimal time of action of the neurotransmitters (20 h). Our results demonstrated that bicuculline-induced mRNA accumulation was not additive with that elicited by NMDA after 20 h of incubation. In contrast, (+)-5 methyl-10,11-dihydro-5H-dibenzo(a,d')cyclohepten-5,10-imine hydrogen (MK-801) at 10 microM completely abolished the stimulatory effect of bucuculline during the same time period. In addition, muscimol was unable to decrease somatostatin mRNA levels when NMDA receptors were blocked by MK-801.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845538 TI - Progesterone receptor and neurotensin are colocalized in neurons of the guinea pig ventrolateral hypothalamus. AB - A double-labeling immunofluorescence procedure was used to determine whether progesterone receptor (PR)-containing neurons in the mediobasal hypothalamus of female guinea pig also contain neurotensin (NT). Animals were ovariectomized, primed by estradiol to induce PR and injected intracerebroventricularly with colchicine to visualize NT-immunopositive neurons. Approximately 24% of the NT immunoreactive (IR) neurons in the ventrolateral nucleus (VL) displayed PR immunoreactivity, accounting for 4% of the total population of cells containing PR in this region. The arcuate nucleus (AR) was observed to have both populations, but coexistence was rare. These findings provide neuroanatomical evidence that a subset of NT neurons is directly regulated by progesterone in the VL, a site that plays a key role in the control of female sexual behavior. PMID- 7845539 TI - Pituitary adenyl cyclase-activating peptide: a hypophysiotropic factor that stimulates proopiomelanocortin gene transcription, and proopiomelanocortin derived peptide secretion in corticotropic cells. AB - The biological effects of pituitary adenylate cyclase-activating peptide (PACAP) 27 and 38 on peptide secretion and gene regulation were studied in the mouse corticotrope-derived cell line AtT20. Treatment of these cells with PACAP 27/38 led to a dose-dependent increase in cAMP content and ACTH accumulation in the medium with an apparent ED50 value close to 10(-9) M. The genomic effects of PACAP were first investigated by using a reporter gene containing a cAMP responsive element (CRE: TGACGTCA) PACAP 27/38 stimulate transcription from this construction and the effect is further increased when cells are cotreated with the phosphodiesterase inhibitor rolipram. Furthermore, we show by measuring nuclear heterologous proopiomelanocortin (POMC) RNA levels or by using a reporter gene containing the POMC promoter region, that PACAP stimulates POMC transcription. This transcriptional stimulation is mediated by the cAMP-dependent protein kinase (PKA) since genetic inactivation of PKA by a dominant inhibitory mutant of this enzyme completely abolished the effect of PACAP on POMC transcription. Finally, we show that the transcriptional stimulation of POMC by PACAP is repressed by the glucocorticoid receptor agonist dexamethasone. Taken together, these data suggest that PACAP is a hypophysiotropic hormone that exert similar if not identical functions as corticotropin-releasing hormone (CRH) on corticotrope cells. PMID- 7845540 TI - In vivo and in vitro effects of arginine-vasopressin receptor antagonists on the hypothalamic-pituitary-adrenal axis in the rat. AB - Arginine-vasopressin (AVP) is regarded as a potent stimulator of pituitary adrenocorticotropin (ACTH) secretion and participates therefore in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis function in concert with the physiological activator of the axis, hypothalamic corticotropin-releasing hormone (CRH). We examined the effects of AVP and/or three synthetic V1b receptor antagonists on the activity of the HPA axis in vivo and in vitro in the rat. AVP was injected intravenously to Sprague-Dawley rats (1 microgram/rat) through an indwelling jugular catheter. AVP stimulated ACTH release, with maximal effect 10 min after injection. Intravenous injection of three V1b antagonists, [1-(beta mercapto-beta,beta-cyclopentamethylenepropionic acid), 2-O-ethyltyrosine, 4 valine] arginine vasopressin (d(CH2)5[Tyr(Et2)]VAVP (WK 1-1), 9-desglycine[1 (beta-mercapto-beta,beta- cyclopentamethylenepropionic acid), 2-O-ethyltyrosine, 4-valine] arginine vasopressin desGly9d(CH2)5 [Tyr(Et2)]-VAVP (WK 3-6), and 9 desglycine [1-(beta-mercapto-beta,beta- cyclopentamethylenepropionic acid),2-D-(O ethyl)tyrosine, 4-valine ] arginine vasopressin des Gly9d(CH2)5[D-Tyr(Et2)]VAVP (AO 3-21), prevented AVP-stimulated ACTH secretion. Explanted rat hypothalami incubated in vitro with graded concentrations of AVP (10(-14)-10(-5) M) secreted immunoreactive CRH (iCRH) in a concentration-dependent fashion. Maximal stimulatory effect occurred at the concentration of 10(-6) M. Incubation of hypothalami with WK 1-1, WK3-6, or AO 3-21 (10(-6) M) prevented AVP-stimulated iCRH secretion. Results suggest that AVP plays a relevant, multiple role in the activation of the HPA axis in the rat.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845541 TI - Hypothalamic-pituitary-adrenocortical axis changes in the rat after long-term treatment with the reversible monoamine oxidase-A inhibitor moclobemide. AB - The effects of the reversible monoamine oxidaseA (MAOA) inhibitor moclobemide on the rat hypothalamic-pituitary-adrenocortical (HPA) axis were studied. The time course experiments showed that moclobemide, given via the drinking water (4.5 mg/kg/day), produces significant decreases (p < 0.05) in adrenal weight after 5 ( 23%) and 7 weeks (-16%) of treatment. It was found that long-term moclobemide treatment had neuroanatomically distinct effects on corticosteroid receptor expression. Hippocampal mineralocorticoid receptor (MR) levels were upregulated at 2 (+65%), 5 (+76%) and 7 (+19%) weeks of treatment. Glucocorticoid receptor (GR) levels in this limbic brain structure were slightly up-regulated by 10% at 5 weeks, and indistinguishable from controls after 2 and 7 weeks of treatment. After 5 weeks of treatment, MR levels were unchanged in the hypothalamus, and increased by 44, 24 and 28% in the neocortex, amygdala and anterior pituitary, respectively. GR concentrations were elevated by 24 and 14% in the hypothalamus and anterior pituitary, respectively, whereas neocortical and amygdaloid receptor levels were not altered. After 5 weeks of moclobemide treatment, marked decreases in [125I]Tyr0-ovine corticotropin-releasing hormone ([125I])-oCRH binding capacity and proopiomelanocortin (POMC) mRNA content were observed in the anterior pituitary. Regarding the functional implications of long-term anti depressant treatment, moclobemide treatment (5 weeks, 4.5 mg/kg/day) significantly attenuated stress (30-min novel environment)-induced plasma ACTH ( 35%) and corticosterone (-29%) levels; no changes were observed in basal plasma ACTH and corticosterone levels. In conclusion, this study shows that moclobemide has a concerted influence on multiple elements of the HPA axis manifesting functionally as a reduced neuroendocrine responsiveness to stress. In previous experiments, it was found that the structurally and pharmacologically distinct antidepressant amitriptyline after long-term administration also attenuated HPA axis activity. We postulate that an adjustement of HPA axis activity may be regarded as a common denominator for clinically efficacious antidepressant drugs. PMID- 7845542 TI - Circadian changes of serum prolactin levels and tuberoinfundibular dopaminergic neuron activities in ovariectomized rats treated with or without estrogen: the role of the suprachiasmatic nuclei. AB - Variations of serum prolactin (PRL) levels and activities of tuberoinfundibular dopaminergic (TIDA) neurons during the afternoon of ovariectomized (OVX) rats treated with or without estrogen were determined in this study. Long-term OVX rats treated with or without polyestradiol phosphate (0.1 mg/rat, s.c.) were decapitated every hour from 10.00 to 19.00 h (except 11.00 and 13.00 h). Serum PRL and median eminence (ME) dihydroxyphenylacetic acid (DOPAC) or dihydroxyphenylalanine (DOPA) levels were determined by radioimmunoassay and high performance liquid chromatography plus electrochemical detection, respectively. A prominent PRL surge started and peaked around 14.00-15.00 h, and remained significantly higher than levels of 10.00 and 12.00 h throughout the afternoon. Significant decreases of ME DOPAC and DOPA concentrations were also observed between 14.00 and 19.00 h. In OVX rats with no estrogen replacement, no PRL surge was observed and the changes of ME DOPAC concentrations during the afternoon were not significant except for that at 17.00 h. The ME DOPA accumulation, however, exhibited significantly lower levels from 14.00 to 19.00 h than that at 12.00 h, indicating that an endogenous rhythm for DA synthesis existed in OVX rats. In estrogen-treated OVX rats bearing bilateral lesions of the suprachiasmatic nuclei, both changes in serum PRL level and TIDA neuron activity were abolished. We conclude that an endogenous rhythm of the activities of TIDA neurons may exist in both OVX and OVX plus estrogen-treated rats. The rhythm is regulated by the suprachiasmatic nuclei and may be amplified by estrogen for the induction of PRL surge. PMID- 7845543 TI - Effects of melatonin and time of day on in vitro pituitary gonadotropin basal secretion and GnRH responsiveness in the male golden hamster. AB - Melatonin, a pineal hormone, is known to play an important role in mediating changes in the reproductive system which occur in response to seasonal changes in the length of the day. An in vitro pituitary perifusion system has been used to examine both direct and indirect effects of melatonin on pituitary gonadotropin basal secretion and responsiveness to GnRH stimulation. Anterior pituitaries from adult male golden hamsters were perifused with an APS 10 perifusion system for 6 h. Both basal secretion and secretion in response to hourly GnRH stimulation (1 min, 35 ng/ml pulses) were evaluated for LH and FSH. In order to expose pituitaries to shorter and longer durations of melatonin, tissue was perifused with melatonin-containing medium following dissection in the daytime (when endogenous melatonin levels are low) and following dissection in the nighttime (when endogenous melatonin levels are high). Exposure of pituitary tissue from golden hamsters to melatonin during perifusion caused a decrease in basal secretion of LH but did not affect GnRH stimulated LH or FSH release regardless of the time of dissection. There was, however, an effect of some diurnal factor to lower FSH responsiveness to GnRH stimulation from tissue dissected in the nighttime. It is suggested that melatonin may be responsible for this diurnal difference. Therefore, melatonin can act directly at the anterior pituitary to lower basal LH secretion, and melatonin or some other diurnal factor can act in vivo to lower pituitary FSH secretion in response to GnRH stimulation during the night. PMID- 7845544 TI - Rhythmic secretion of melatonin by the superfused pike pineal organ: thermo- and photoperiod interaction. AB - In the pineal organ of the pike (Esox lucius, teleost), the rhythmic production of melatonin by the photoreceptor cells is governed by a population of endogenous circadian oscillators, synchronized and entrained by the light/dark (L/D) cycle. Production of melatonin is inhibited by light and highly increased in the dark. In the present study, isolated and superfused pike pineals were exposed to a 24 hour temperature cycle of high (10 degrees C) or low (4 degrees C) amplitude, either under L/D, or under constant darkness. Under L/D, photoperiod is the dominant entraining stimulus for the melatonin secretion rhythm. It was high during the dark phase and low during the light phase, either under cold light/warm dark or under warm light/cold dark conditions. Under a warm light/cold dark cycle, the amplitude of the melatonin rhythm was reduced. In pineals cultured at 10 degrees C, a 20 degrees C temperature pulse potentiated or reduced the night-induced rise in melatonin production when applied, during the dark or during the preceding light phase, respectively. Under constant darkness, high- or low-amplitude temperature cycles could synchronize the rhythmic production of melatonin, which peaked with the high temperature. However, the shape of the oscillation could appear modified under warm subjective-L/cold subjective-D, depending on the experimental conditions. Finally, the rhythmic release of melatonin synchronized by a temperature cycle under constant darkness was no longer observed after removal of the external zeitgeber. The present study provides direct evidence that the pineal acts as a photothermotransducer. PMID- 7845545 TI - Sleep and wakefulness affect the responsiveness of the pituitary-adrenocortical axis to arginine vasopressin in humans. AB - The secretory activity of the pituitary-adrenocortical axis at night is characterized by a quiescent period during the first hours of sleep, preceding a period of enhanced activity in the early morning hours. It is still controversial whether the typical nocturnal secretory pattern of adrenocorticotropic hormone (ACTH) and cortisol is a mere reflection of a circadian rhythm or whether mechanisms associated with the state of sleep influence the nocturnal secretion of these hormones. Here, we administered arginine vasopressin (AVP) to normal men during the first part of nocturnal sleep and compared the release of ACTH and cortisol with the release after a second administration during the second part of the same night and also with the release after administration of AVP at identical points of nighttime while subjects were kept awake in another night. Compared with wakefulness, the cortisol release in response to AVP was significantly lower during sleep, with this effect restricted to the early part of sleep. The ACTH release was lower after the first AVP administration during the early part of sleep as compared with the AVP injection during the second part of the same night. Our data demonstrate a sleep-associated inhibition of stimulated ACTH and cortisol release, suggesting a period of decreased responsiveness of the pituitary-adrenocortical axis during early sleep. PMID- 7845546 TI - Melatonin-induced decrease of body temperature in women: a threshold event. AB - Whether the biological effect of melatonin in humans is directly related to the circulating levels of the hormone, has not heretofore been investigated. In this study, we investigated whether previously described hypothermic melatonin properties are dose related. The nocturnal decline of the body temperature (BT) observed in 16 early follicular phase women, following placebo administration at 18.00 h, was compared with that observed during the preceding or following night, after melatonin suppression with the beta 1-adrenergic antagonist atenolol (100 mg). In 6 subjects (37.5%) with lower nocturnal melatonin levels (p < 0.05) atenolol induced a complete melatonin suppression and an attenuation of the nocturnal BT decline (p < 0.02), whereas in the remaining 10 subjects (62.5%) atenolol induced an incomplete melatonin suppression with no modification of the nocturnal BT decline. During a 3rd night, 2 of the 6 subjects with complete and 6 of the 10 subjects with incomplete melatonin suppression blindly received atenolol plus melatonin (1 mg at 19.30 h and 0.75 mg at 21.00 and 23.00 h). Exogenous melatonin restored the full expression of the nocturnal BT decline in the 2 subjects with complete melatonin suppression, but did not modify the BT decline in the 6 subjects with atenolol-induced incomplete melatonin suppression. Our data show that markedly, but not completely attenuated nocturnal melatonin levels are sufficient to exert maximal thermoregulatory effects, indicating rather a threshold than a dose-response effect of melatonin action on human BT. PMID- 7845547 TI - Development of tolerance to 8-OH-DPAT induced blockade of acquisition of a passive avoidance response. AB - We examined the effects of manipulating 5-HT1A receptors on the performance of a passive avoidance task in rats. Firstly, we studied the effect of racemic 8-OH DPAT and compared it to the pure enantiomers (subcutaneous injection, s.c.). Secondly, we investigated the effect (s.c.) of the selective 5-HT1A receptor antagonist (S)-UH-301 [(S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin] both alone and on 8-OH-DPAT-induced disruption of acquisition. Thirdly, we examined whether tolerance occurs to the effects of 8-OH-DPAT on passive avoidance acquisition. Finally, we examined the effects (s.c.) of the selective NMDA receptor antagonist dizocilpine, (+)-MK-801[(5R,10S)-(+)-5-methyl-10,11-dihydro 5H-dibenzo(a,d)cyclohe pten-5, 10-imine], on this tolerance development. Different doses of racemic 8-OH-DPAT were injected 10 min before rats were exposed to the acquisition phase of a step through passive avoidance response. When tested for retention 24 h later, 8-OH-DPAT-pretreated rats failed to exhibit any avoidance. R(+) and S(-)-8-OH-DPAT were also active with the R(+)-isomer being more active than the S(-)-isomer. The 5-HT1A antagonist (S)-UH-301 [(S)-5 fluoro-8-hydroxy-2-(dipropylamino)tetralin] was without effect on avoidance performance but antagonized the effect of 8-OH-DPAT. In a further experiment, rats were pretreated with racemic 8-OH-DPAT (0.3 mg/kg). Twenty four hours later, they received a challenge dose of 8-OH-DPAT and exposed to the acquisition phase of the avoidance response. When tested 24 hr later for retention, 8-OH-DPAT challenged rats failed to show any indication of an avoidance response.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845548 TI - Effects of acute and chronic treatment with amoxapine and cericlamine on the sleep-wakefulness cycle in the rat. AB - Antidepressant drugs, such as the tricyclics and the serotonin reuptake inhibitors, are well known to decrease paradoxical sleep and occasionally increase slow wave sleep in human and in animals. In order to examine whether amoxapine (a mixed NA reuptake blocker and 5-HT2/5-HT3 antagonist) and cericlamine (a selective 5-HT reuptake inhibitor) exert the same effect in rats, and to investigate the possible relationships between sleep, the action of antidepressants and the serotoninergic system, the effects of these two different drugs were examined under acute and chronic conditions. Acutely, amoxapine (1, 5 and 10 mg/kg; i.p.) and cericlamine (1, 8, 16 and 32 mg/kg; i.p.) decreased paradoxical sleep and increased deep slow wave sleep especially when they were given at a low dose. When administered for 14 days, amoxapine induced a sustained decrease of paradoxical sleep during the whole treatment, while some tolerance was observed with regard to the inhibitory effect of cericlamine on this state of sleep. In addition, a rebound of paradoxical sleep occurred on the first day of cericlamine withdrawal. Thus, amoxapine and cericlamine exerted the same effects on the states of vigilance in the rat as do other antidepressants. The effects of cericlamine on sleep probably reflect its blocking action on 5-HT uptake, whereas the more complex effects of amoxapine might involve its 5-HT2/5-HT3 antagonist properties. PMID- 7845549 TI - Quantitative autoradiography of 5-HT4 receptors in brains of three species using two structurally distinct radioligands, [3H]GR113808 and [3H]BIMU-1. AB - Recent radioligand binding studies have demonstrated the presence of 5-HT4 receptors throughout the nigrostriatal and mesolimbic systems of mammalian brain. In many regions, the binding has not yet been correlated with functional responses. The present study was carried out to fully characterize the regional distribution of 5-HT4 receptors in brain sections from three species using two structurally distinct radioligands, [3H]GR113808, and [3H]BIMU-1. The highest density of 5-HT4 receptors labeled with [3H]GR113808 was found in the olfactory tubercle, substantia nigra, ventral pallium and striatum of rat and guinea pig, and similar regions of pig-tail macaque monkey. A similar distribution of 5-HT4 receptors was observed in guinea pig brain using [3H]BIMU-1. With either ligand, the binding was saturable and of high affinity (Kd = 0.08-0.53 nM for [3H]GR113808; 1.4-3.0 nM for [3H]BIMU-1). These results extend previous distribution studies, confirm the heterogenous distribution of 5-HT4 receptors throughout the nigrostriatal and mesolimbic systems of three species, and demonstrate a similar distribution using two structurally distinct 5-HT4 radioligands. PMID- 7845550 TI - Zn2+: an endogenous modulator of ligand- and voltage-gated ion channels. PMID- 7845551 TI - Rapid desensitization determines the pharmacology of glutamate neurotoxicity. AB - Glutamate (Glu), the major excitatory neurotransmitter in the nervous system, is toxic to neurons when it accumulates at high concentrations in the extracellular space. Even though Glu is a mixed agonist, capable of activating N-methyl-D aspartate (NMDA) receptors and non-NMDA receptors, in many preparations Glu neurotoxicity is prevented by selective blockade of NMDA receptors. In cultures of hippocampal neurons, treatment with 500 microM Glu for 30 min killed more than 90% of the neurons. The simultaneous addition of the selective NMDA agonist methyl-10,11-dihydro-5-H-dibenzocyclo-hepten-5,10-imine (MK-801) reduced the cell loss to less than 30%. However, when Glu was combined with either diazoxide or cyclothiazide, two thiazides which dramatically diminish rapid Glu desensitization, MK-801 was no longer very protective and neuronal loss exceeded 80%. However, the non-NMDA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), in combination with MK-801, was able to prevent most Glu neurotoxicity in the presence of these thiazides. These experiments show that there are circumstances under which Glu neurotoxicity is produced by overactivation of non NMDA receptors. Our observations offer a possible explanation for the recent finding that blockade of non-NMDA receptors is much more beneficial than NMDA receptor blockade in protecting the brain in some in vivo models of global ischemia. PMID- 7845552 TI - Electrophysiological effects of selective opioid agonists on spontaneous and evoked neuronal activity in the dentate gyrus of the hippocampus in vivo. AB - The mechanism by which endogenous opioid peptides regulate neuronal excitability in the dentate gyrus of the hippocampus remains unclear. We studied the neurophysiologic responses to various receptor-selective opioids, given both iontophoretically and systemically, in anesthetized rats. Single unit action potentials and field potential recordings were taken from electrophysiologically classified dentate granule cells (DGCs) or dentate interneurons (INTs). The mu receptor agonist ([D-Ala2, NMe-Phe4, Gly-ol]-Enkephalin (DAMGO)) increased the responsiveness of DGCs to perforant path stimulation, although it did not induce spontaneous activity in DGCs. We did not see this facilitation with systemic morphine sulfate (MS). However, both DAMGO and MS produced similar, primarily inhibitory, effects on INTs. The responsiveness of an individual INT tended to be related to the cell's location in the dentate gyrus, and to a lesser degree, to its baseline spontaneous discharge frequency. U-50488H, a selective kappa receptor agonist, had little effect on either DGCs or INTs. Our results suggest that mu selective opioids have a complex neuropharmacology in this region involving interaction among different types of INTs to produce an effect on the principal output cells. PMID- 7845553 TI - Effect of selective mu 1, mu 2 and delta 2 opioid receptor agonists on gastric functions in the rat. AB - Because the role of mu and delta opioid receptors in modulating gastric functions remains uncertain, we studied whether intracerebroventricular (i.c.v.) and subcutaneous (s.c.) injections of new opioid peptides with high selectivity for mu 1 (Lys7-dermorphin), mu 2 (Trp4-Asn7-dermorphin) and delta 2 (D-Ala2 deltorphin II) opioid receptors would modify gastric secretion (after 2 hr pylorus ligature) and transit (after a phenol red meal) in the rat. Neither i.c.v. nor s.c. injections of the delta 2 opioid agonist affected the gastric functions. In contrast, the mu opioid agonists decreased gastric acid secretion and emptying, i.c.v. injections inducing more potent inhibition than s.c. administration. The mu 1 selective opioid antagonist naloxonazine had no effect on the inhibition of the gastric secretory and motor response to these peptides but naloxone completely blocked their effects. Our findings suggest (1) that in rats, stimulation of central naloxonazine insensitive opioid receptors (mu 2 sites) inhibits gastric acid secretion and emptying; and (2) that delta opioid receptors take no part in mediating these functions. PMID- 7845554 TI - Influence of GBR 12909 and d-amphetamine on indices of catecholamine synthesis and release in rat adrenal glands. AB - Our previous results have shown that dopamine (DA) levels in rat adrenal glands could be increased by DA D2 receptor agonists and that this effect could be blocked by the DA D2 antagonists domperidone (supposed to be only peripherally active) and raclopride. The data now presented are aiming to characterize the effects of two indirect DA agonists, GBR 12909 and d-amphetamine, on adrenal DA levels (taken as an index of adrenal catecholamine synthesis rate), and on adrenaline (Ad) levels in the heart (assumed to reflect the Ad release from the adrenal medulla). After various periods of s.c. drug administration the rats were decapitated and tissue catecholamine levels were determined in adrenal glands, hearts and forebrains according to standard techniques by high performance liquid chromatography (HPLC) with electrochemical detection. GBR 12909 (15 and 3 mg/kg), a highly selective DA-uptake inhibitor, induced a pronounced dose dependent increase in adrenal DA and heart Ad, though not until 4 hr after administration; this effect persisted for at least 16 hr. However, a statistically significant decrease in forebrain DOPAC was observed already after 30 min. The GBR 12909 effects on adrenal DA and heart Ad were blocked by raclopride, but not by domperidone, suggesting a central site of action. d-Amphetamine, in both doses used (2.5 and 5 mg/kg) induced a statistically significant decrease in forebrain DOPAC between 30 min and 2 hr, and an increase in adrenal DA. Heart Ad was not significantly changed.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845555 TI - Fever produced by interleukin-11 (IL-11) injected into the anterior hypothalamic pre-optic area of the rat is antagonized by indomethacin. AB - A number of cytokines including the family of interleukins and the macrophage inflammatory proteins act in the brain to produce fever. The purpose of this study was to determine whether the recently discovered hematopoietic progenitor cell stimulator, interleukin-11 (IL-11), alters the body temperature (Tb) of the rat when the cytokine is delivered directly to the thermosensitive and pyrogen reactive region of the hypothalamus. A guide cannula for micro-injection into the anterior hypothalamic pre-optic area (AH/POA) was implanted stereotaxically in each of 19 male Sprague-Dawley rats. A Mini-mitter transmitter for continuous monitoring of Tb of the animal was implanted i.p. Following postoperative recovery, recombinant human IL-11 was micro-injected in a volume of 1.0 microliter into the AH/POA in a dose of 2.7, 13.5, 27 or 250 ng. rhuIL-11 evoked a dose dependent fever with a mean rise in Tb of 0.91 +/- 0.06 degrees C, 1.68 +/ 0.11 degrees C and 0.99 +/- 0.08 degrees C following 13.5 ng, 27 ng and 250 ng, respectively. No significant change in Tb of the rats was produced by 2.7 ng IL 11 or the CSF control vehicle. A significant decline in the intake of food occurred also after the micro-injection of the 27 ng of IL-11. Prior treatment of the rat with 5.0 mg/kg of a prostaglandin synthesis inhibitor, indomethacin, administered intraperitoneally attenuated significantly the febrile response induced by the 250 ng dose of IL-11. These results demonstrate that IL-11 possesses potent thermogenic properties when acting within the ventral forebrain.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845556 TI - Asymmetry in behavioral responses to cholecystokinin microinjected into rat nucleus accumbens and amygdala. AB - The behavioral responses of rats to uni- or bilateral microinjections of the octapeptide cholecystokinin (CCK-8) into the left and/or right or both nucleus accumbens (NA) or amygdalae were studied. There were two main findings of effects of microinjections of CCK-8 into NA. First, bilateral injections of CCK-8 into NA dose-dependently decreased the horizontal activity. The second more important finding was that CCK-8 at a specific dose (0.01 micrograms) injected into the right NA increased the number of horizontal movements 6-fold as compared to the injection into the left NA. Neither uni- nor bilateral injections of CCK-8 into NA at all doses used induced changes in the vertical movements. CCK-8 injected into left, right or both amigdalae increased locomotion at the lowest dose (0.01 microgram), while at the high doses (0.5 and 1.0 microgram) it significantly decreased it. The plus-maze test confirmed the anxiogenic effect of CCK-8 (0.01 microgram) injected into amigdalae. CCK-8 exerted a favorable effect on learning and memory (shuttle-box) when injected into the left but not into the right amygdala. Injection of CCK-8 (0.01 micrograms) into left amygdala provoked a 4 fold increase of the number of avoidances as compared to the microinjection into the right amygdala. PMID- 7845557 TI - Activating effects of androgens on cognitive performance: causal evidence in a group of female-to-male transsexuals. AB - It is still unclear whether sex differences in cognitive functioning are mainly due to perinatal organizing effects of sex hormones on the brain, or to activating effects in adulthood. In a group of 22 female-to-male transsexuals a battery of visuospatial and verbal ability tests was administered twice: shortly before and 3 months after the start of androgen treatment. The administering of androgens was clearly associated with an increase in spatial ability performance. In contrast, it had a deteriorating effect on verbal fluency tasks. This study offers preliminary evidence that androgens directly and quickly affect cognitive performance in females. PMID- 7845558 TI - Differences in the visual control of pantomimed and natural grasping movements. AB - In a series of experiments, we studied the differences between natural target directed grasping movements and 'pantomimed' movements directed towards remembered objects. Although subjects continued to scale their hand opening for object size when pantomiming, grip formation and other kinematic variables differed significantly from those seen in normal target-directed actions. This was true whether the subjects had just seen the target object 2 sec before (Experiments 1 and 2) or whether the target object was still present and they were simply required to pantomime the grasping movement beside it (Experiment 3). We argued that these pantomimed reaches were being driven by stored perceptual information about the object, and were not utilizing the normal visuomotor control systems that direct actions in real time. This interpretation received strong support from observations of a patient with visual form agnosia who was also tested. In an earlier report, we had shown that this patient showed anticipatory scaling of her grasp despite her inability to discriminate between objects perceptually on the basis of size. The present study showed, however, that the requirement to remember an object even briefly, or to pantomime an action beside it, was enough to completely disrupt her visuomotor scaling (Experiments 2 and 3). That this reflected a failure of perception rather than imagery or understanding was supported by the fact that she could convincingly pantomime actions to imagined, familiar objects, the sizes of which were known to her (Experiment 4). All these results suggest that the mechanisms underlying the formation of perceptual representations of objects are quite independent of those mediating on-line visuomotor control. PMID- 7845559 TI - Dissociations in memory for item identity and item frequency: evidence from hemispheric interactions. AB - Evidence for a dissociation between memory for the identity of an item and memory for its frequency of occurrence was provided by two tachistoscopic studies employing lateralized abstract designs as stimuli. In both experiments, subjects viewed a random series of presentation trials, in which certain designs appeared only once, others 5 times, and still others 9 times. Then in a series of probe trials, subjects decided, on each trial, if a design was familiar or novel, either by an old/new decision (Experiment 1) or a forced-choice decision (Experiment 2), after which they estimated the frequency of item occurrence. Presentation and probe trials were either displayed in the same visual field (within-hemisphere trials) or opposite visual fields (across-hemisphere trials). Both experiments revealed that the pattern of interhemispheric processing as well as lateralized processing differed for item identity as compared to item frequency, providing further evidence for a dissociation between these two memory processes. PMID- 7845560 TI - Automatic and voluntary orienting of attention in patients with visual neglect: horizontal and vertical dimensions. AB - The present study was aimed at testing internally and externally-controlled mechanisms of covert orienting in patients with visuo-spatial neglect. Internally controlled orienting was tested by presenting central informative cues. Externally-controlled orienting was tested by presenting peripheral non informative cues. We also tested for the presence of vertical neglect in patients with horizontal neglect, and tried to assess whether altitudinal neglect is an attentional deficit. Finally we examined whether altitudinal neglect manifests itself only in the visual field contralateral to the lesion or, as has been shown for horizontal neglect, whether it is also present in the ipsilesional visual field. The results showed that patients with neglect have a deficit of externally controlled covert orienting in the visual field opposite to that of the lesion. Further, the impairment appeared to be more pronounced in the lower than in the upper visual field and to be mainly evident in the visual field contralateral to the lesion. The deficit could, however, be partially compensated for by the use of internally-controlled covert orienting. These findings seems to support the dual-mechanisms hypothesis which maintains that automatic and voluntary orienting are subserved by separate mechanisms possibly located in different parts of the brain. PMID- 7845561 TI - Motor learning after recovery from hemiparesis. AB - Twenty patients who had almost completely recovered from hemiparesis following unilateral cerebrovascular accident and 16 control subjects had to perform motor learning tasks including a three-dimensional motor problem and two standard precision tests. The ability of hemiparetic patients to solve simple spatial motor problems and to gain by training was preserved with limitations concerning high precision control. However, hemiparetic patients had a higher demand for time and corrections, as well as a reduced consistency of performance. Thus recovery from hemiparesis was accompanied by reduced skillfulness and automaticity of motor control. PMID- 7845562 TI - Planum temporale asymmetry and language dominance. AB - Language is lateralized to the left hemisphere in most individuals, and leftward asymmetry of the planum temporale has been reported in postmortem and imaging studies. In this study we measured the planum temporale on magnetic resonance imaging (MR) scans of patients (11 right-handers, 1 non-right-hander) who had selective hemispheric anesthesia or Wada testing performed for language lateralization. All subjects who had language lateralized to the left hemisphere (11 right-handers) had a leftward asymmetry of the planum temporale. One subject who had language lateralized to the right hemisphere (non-right-hander) had a strong rightward asymmetry of the planum temporale. These data suggest that planum temporale asymmetries determined by MR are associated with language dominance and may predict language laterality. PMID- 7845563 TI - Right-hippocampal contralateral-hand effect in the recall of spatial location in the tactual modality. AB - The recall of spatial location in the tactual modality was investigated in 53 patients with unilateral temporal lobectomy, one patient with bilateral hippocampal damage and 23 normal control subjects. Using only active touch, blindfolded subjects had to locate the position of a map pin within a circular space and then recall its position after a 12- or 24-sec delay. Left temporal lobe patients (N = 23) were found to perform normally as were right temporal-lobe patients with removals that did not exceed the pes of the hippocampus (N = 22). In contrast, right temporal-lobe patients with large hippocampal excision (N = 8) were impaired on the 24-sec (but not at the 12-sec) delay condition. When performance of the two hands was compared, no difference was found for the left temporal, right-temporal-small-hippocampal-removal and normal control groups. In contrast, for the right temporal-large-hippocampal-removal group performance on the hand contralateral to the side of temporal lobectomy (left hand) was impaired, whereas right-hand performance in this group was normal. The patient with bilateral hippocampal damage was inferior to the most impaired patient with unilateral temporal lobectomy. These findings suggest that the right and left medial-temporal regions differ in their functional relationships to cerebral areas mediating tactual processing, intact right medial-temporal structures being involved in tactuo-spatial retention bimanually while left medial-temporal structures serve a more specific role confined to the contralateral (right) hand. PMID- 7845565 TI - Speed and flexibility on word fluency tasks after focal brain lesions. AB - It was predicted that frontal lobe damaged patients are slower on word fluency tasks, especially on the generation of words beginning with a particular letter, and less flexible ("stuck-inset") on category alternation than patients with posterior lesions, whereas the latter commit a higher number of repetitions ("recurrent perseverations") than the former. Twenty-nine anterior and 31 posterior brain damaged patients were requested to say as quickly as possible (1) 20 animal names, (2) 10 words beginning with the letter S, and (3) alternately animals and S-words, 10 from each category without repeating the words already used in these tasks. The results failed to confirm the predictions. PMID- 7845564 TI - Verbal recall and recognition as a function of depth of encoding in patients with unilateral temporal lobectomy. AB - The hypothesis that impairment in cognitive organization is a significant causal factor in the verbal memory impairment known to follow left anterior temporal (LT) lobectomy was tested by assessing verbal recall and recognition as a function of depth of encoding in 20 patients with LT lobectomy (19 in the recognition condition), 20 patients with right temporal lobectomy and 20 normal control subjects. Subjects first made decisions regarding either the physical, phonemic or semantic aspects of 48 words. After the encoding phase, a free recall test was given, followed by a recognition test. As expected, the verbal memory of the LT group was impaired in both the recall and recognition conditions. However, the LT group followed the pattern of the other two groups in recalling and recognizing more words which had been subjected to semantic analysis. These findings do not support the hypothesis that a disruption in the normal relationship between cognitive organization and memory contributes to the memory impairment following LT lobectomy. In contrast the verbal recall of the LT group failed to follow the pattern of the other two groups in that it did not benefit from phonemic encoding. Taken together, these findings support the notion that left anterior temporal-lobe cortical structures are more specialized for the evocation of the sound of a word than for those processes that underlie the recall of semantically encoded verbal material. PMID- 7845566 TI - Transcortical alexia with agraphia following a right temporo-occipital hematoma in a right-handed patient. AB - We describe the case of a 51-year-old right-handed man who was affected by a transcortical alexia with agraphia and aphasia. Transcortical alexia produces errors in both reading and writing while copying is preserved. The patient had a severe alexia and was unable to read letters, words or sentences. Language examination showed mild aphasia with reduced fluency, intermittent paraphasia but a good comprehension and a normal repetition. Spontaneously and from dictation, writing was impaired by an agraphic jargon, but copying was excellent even though the patient was unable to read his own written production. There was no visual agnosia nor hemianopia. CT scan and MRI of the brain showed that there was a single right temporo-occipital hemorrhage but no lesion in the left hemisphere. Following surgical evacuation of the hematoma, the patient improved. One month after onset, his language was quite intact and reading was possible. We hypothesize that this particular syndrome was the result of a double disconnection: alexia would result from a disconnection of the right angular gyrus and the occipital associative areas by a subangular lesion; agraphia would result from a disconnection of the right angular gyrus and the semantic store, probably located in the right hemisphere. PMID- 7845568 TI - Visuoperceptual-spatial ability and visual memory in vascular dementia and dementia of the Alzheimer type. AB - This study investigated the relationship between visuoperceptual ability and visual memory in dementia. Twenty individuals with probable dementia of the Alzheimer type, 24 individuals with probable vascular dementia, and 20 healthy, elderly adults underwent neuropsychological evaluation. Hierarchical multiple regression analyses suggested that perceptual organization skills contributed to a significant amount of the variance in novel, but not famous, face recognition. This finding was most robust in the clinical groups. Causality cannot be attributed from this regression model. Results suggest, however, that visual processing deficits are more strongly related to the memory process at the time of encoding rather than during recognition of remote information. PMID- 7845569 TI - The relationship between eye dominance and head tilt in humans. AB - Previous data suggest that vertical imbalances between the eyes produced by lateral head tilt are linked to ocular dominance, but no studies have heretofore objectively measured head tilt in addressing this relationship. Photographic measurements of the head tilt of 70 subjects were made, along with measures of sighting dominance and vertical misalignment during sighting. The analyses revealed that photographically measured head tilt is significantly associated with vertical imbalances during sighting and with sighting dominance. These data support the theory that motoric dominance in humans is partly related to mechanisms underlying postural asymmetry. PMID- 7845567 TI - Reading of letters and words in a patient with Balint's syndrome. AB - A patient with bilateral parietal damage, and Balint's syndrome, named visual letters. These were presented individually or within four-letter strings. Solitary letters were identified very accurately. In the case of strings, more letters were correctly reported for words than for nonwords, and more for pronounceable than for unpronounceable nonwords. When required to read words as a whole, performance was better than predicted by letter-reports. These results extend the object-based limitation apparent in Balint's syndrome to the case of reading. The component letters of a string benefit when they form a familiar global object, rather than requiring representation as multiple separate objects. The patient occasionally made homophonic errors when listing the letters in a visual word. This suggests an attempt to bypass visual simultanagnosia by treating the string as a single object, deriving a holistic phonological code for it, and then decomposing this into component letters via spelling rules. PMID- 7845570 TI - Comparison of the precision of two standardized co-ordinate systems for the quantitation of brain anatomy: preliminary results. AB - We assessed reproducible definition of two standardized co-ordinate systems for intersubject analysis of brain images. The baselines in the two co-ordinate systems were a modification of the canthomeatal (mCM) line and the anterior posterior commissural (AC-PC) line. Axial spin-echo MR images of four subjects at 1.5T were used. Operator error was computed from the replicate analyses of two operators. The mCM line was determined by the lens of the eye and the internal auditory canal, and the AC-PC line was determined by the intersection of AC and PC with the interhemispheric fissure. Reproducibility of the mCM markers (SD = 0.59 mm) did not differ significantly from that of the AC-PC line (SD = 0.68 mm). The measurement error of the angle of the baseline (delta alpha), however, was more than 7 times as large for the AC-PC line as for the mCM line. An additional error affecting the rostrocaudal rotation of the co-ordinate systems, attributable to the distance between the anatomic markers, was 2.1 and 3.6 degrees (3 mm and 5 mm slice thickness) for the mCM co-ordinate system and 8.2 and 11.0 degrees (3 mm and 5 mm slice thickness) for the AC-PC system. The AC-PC line based co-ordinate system is therefore, less reproducible than the mCM line based system. This could be improved if a combination of axial and sagittal images were used for the definition of the AC-PC line. PMID- 7845571 TI - Significance of haemorrhagic lacunes on MRI in patients with hypertensive cerebrovascular disease and intracerebral haemorrhage. AB - Our purpose was to determine the frequency and significance of haemorrhagic lacunes (HL) on MRI in patients with a history of, or at risk for intracerebral haemorrhage. We examined 72 patients with old spontaneous intracerebral haemorrhage (ICH) using T1- and T2-weighted spin-echo sequences. MRI studies of 137 consecutive patients with cerebrovascular disease but no known ICH were also reviewed. Both groups showed about the same degree of age-related white matter change and nonhaemorrhagic lacunar infarcts, whereas the ICH group had a higher frequency of HL (12/72 patients) than the non-ICH group (6/131 patients, p < 0.01). These results correlate well with reported pathological findings. We conclude that haemorrhagic lacunes found on MRI studies of patients with cerebrovascular disease may suggest a higher risk of intracerebral haemorrhage. PMID- 7845572 TI - Marchiafava-Bignami disease: use of contrast media in CT and MRI. AB - We report two cases of Marchiafava-Bignami disease studied by CT and MRI. Both patients displayed persistent confusion and a disconnection syndrome but had a favourable outcome. In both cases, CT with intravenous contrast medium revealed enhancement of the corpus callosum in the early stage. MRI showed gadolinium uptake in both the genu and splenium of the corpus callosum in one case, 8 days after the onset. Three weeks after admission, cystic lesions appeared in the corpus callosum on MRI T1-weighted sagittal images in both cases. Contrast medium uptake may be useful in the diagnosis of Marchiafava-Bignami disease. PMID- 7845573 TI - Optic nerve injury demonstrated by MRI with STIR sequences. AB - We studied nine patients with optic nerve injury associated with closed head trauma by magnetic resonance imaging (MRI) with short inversion time inversion recovery (STIR) sequences on 11 occasions from 4 days to 14 years after the injury: three studies were within 17 days and eight over 4 months to 14 years. MRI revealed abnormal high signal in 10 of the 11 injured nerves. MRI 4 days after the injury showed no abnormality. PMID- 7845574 TI - Protrusion of the optic nerve into the ethmoid and sphenoid sinus: prospective study of 150 CT studies. AB - Damage to the optic nerve is a serious complication of intranasal sinus surgery. Protrusion of the optic canal into the sphenoid sinus is a major risk factor. In this prospective study of 150 CT studies, we found this anatomical variation in 8% of cases. It was consistently associated with pneumatisation of the ipsilateral anterior or clinoid process. Protrusion of the optic nerve into the posterior ethmoid cells was never observed. CT is a useful part of the preoperative investigation of patients undergoing intranasal sinus surgery. Axial and coronal images obtained or by direct acquisition by reconstructions are necessary to show the position of the optic nerve. PMID- 7845575 TI - Meningioma of the floor of the anterior cranial fossa with bilateral intraorbital extension. PMID- 7845576 TI - Computed tomographic ventriculography: a clinicoradiological study of 31 cases. AB - We present 31 patients whose diagnoses were established by the aid of computed tomographic ventriculography. The indications for and diagnostic value of this method are reviewed. PMID- 7845577 TI - Dynamic gadolinium-enhanced MRI in the detection of spinal arteriovenous malformations. AB - Arteriovenous fistulae and malformations (AVFs and AVMs) of the spinal cord are rare, potentially treatable causes of progressive disability. Although a variety of MRI abnormalities has been described, the diagnosis rests on the findings on selective spinal angiography. Collecting T2*-weighted MR images during the passage of a gadolinium bolus gives information about perfusion and blood volume. We carried out dynamic MRI in seven patients with vascular abnormalities (5 dural AVFs, 1 intramedullary AVM, 1 cryptic angioma) and in two patients without an AVM. High resolution T1- and T2-weighted sagittal images of the whole spinal cord were first obtained using a multiarray receiver coil. Sagittal radiofrequency spoilt gradient echo images (GE34/25, flip angle 10 degrees) were then obtained during bolus injection of gadolinium-DTPA. Abnormalities were seen in all seven patients with AVFs or AVMs. In the patient with an intramedullary AVM and four of the five with dural AVFs transient signal reduction was seen within the perimedullary venous plexus during passage of the bolus. The findings correlated well with those from selective spinal angiography. We conclude that dynamic MRI offers a useful adjunct to angiography and may localise an arteriovenous shunt when conventional MRI fails to do so. In combination with high-resolution imaging of the entire spinal cord the technique may make myelography redundant; it is simple, well tolerated and can be carried out without significant time penalty. PMID- 7845578 TI - In vitro study of haemodynamics in a giant saccular aneurysm model: influence of flow dynamics in the parent vessel and effects of coil embolisation. AB - The purpose of this study was to investigate the influence of flow dynamics in the parent vessel and of intra-aneurysmal coil embolisation on flow pattern and pressure in an in vitro model of giant aneurysm. A pulsatile perfusion with a glycerol aqueous solution was installed in a silicone model of a lateral giant aneurysm. Flow visualization and pressure measurements were performed while modifying the flow rate, the pulsatility and the pulse rate in the parent vessel, and after partial coil embolisation. Vortices were formed during systole at the downstream lip of the aneurysm and circulated around the aneurysm. The centre and dome of the aneurysm were areas of fluid stagnation. Flow rate and pulsatility were the main factors which varied the pattern of flow within the aneurysm. Partial coil embolisation induced major flow disturbances in the aneurysm, in particular fluid stagnation at the dome. Pressure measurements were similar in the aneurysm and in the parent vessel. It was concluded that the pulsatility of flow is an important as the flow rate when considering the haemodynamics in a giant aneurysm. In the clinical context, this could explain the efficacy of vertebral artery occlusion in thrombosing giant vertebrobasilar aneurysms. Studies with intra-aneurysmal coil embolisation showed early fluid stagnation at the dome. This could result in embolic migration during endovascular treatment. Partial coil embolisation may prevent early rebleeding; however, it may induce additional mural stresses resulting from new haemodynamic forces and compliance mismatch. PMID- 7845581 TI - 23rd annual meeting of the Japanese Neuroradiological Society. Theme: present and future of neuroradiological diagnosis and therapy. Kobe, Japan, 9-11 February 1994. PMID- 7845579 TI - Experimental saccular aneurysms. I. Review of surgically-constructed models and their laboratory applications. AB - Experimental models of intracranial saccular aneurysms are a useful contribution to our basic understanding of these lesions. Currently, the commonest in use are those constructed surgically in laboratory animals. We review the numerous surgical techniques available since the 1950s, and the research applications and uses of experimental aneurysms. Further development and use of such models is greatly encouraged in future pathophysiological, hemodynamic, and therapeutic investigations of intracranial saccular aneurysms. PMID- 7845580 TI - Experimental saccular aneurysms. II. A new model in swine. AB - A new technique for surgical construction of experimental lateral saccular aneurysms on the common carotid artery of swine is described. It involves end-to side suturing of an isolated segment of vein to an artery. During a short period of parent artery clamping, an elliptical arteriotomy is fashioned through the open-ended vein graft, the open end of which is subsequently tied and clamps are removed to form an aneurysmal vein pouch. The principal advantage of this technique is the short period of vascular clamping necessary to isolate a segment of the parent artery. This prevents severe endothelial injury and prolonged postoperative vasospasm, both of which may promote intra-aneurysmal thrombosis. Narrow- or wide-necked aneurysms can be created. Steps in the surgical construction of this model are detailed, and specific advantages of using swine are highlighted. PMID- 7845582 TI - Neuron-glia interactions in the release of oxytocin and vasopressin from the rat neural lobe: the role of opioids, other neuropeptides and their receptors. AB - The release of the neurohormones oxytocin and vasopressin from the neural lobe into the circulation is regulated in a complex manner, which has only been partly elucidated. At the level of the neural lobe, regulation of release can occur by various endogenous compounds that act on specific receptors present on the nerve terminals themselves. In addition, release may be modulated by an alternative pathway in which the local glia cells, the pituicytes, are involved. It is especially the latter pathway that is discussed in detail in this commentary. PMID- 7845583 TI - EPSP-spike potentiation during primed burst-induced long-term potentiation in the CA1 region of rat hippocampal slices. AB - Long-term potentiation induced by high-frequency stimulation in the CA1 region of the hippocampus exhibits EPSP-spike potentiation. This consists of an increase in population spike amplitude exceeding that predicted by EPSP potentiation alone. This phenomenon is apparently due to an increase in pyramidal cell excitability. Patterns of afferent stimuli which activate pyramidal cells to reproduce the theta rhythm observed in the hippocampus under physiological conditions, have been shown to induce LTP-like enhancement of synaptic responses in vitro. The aim of this study was to investigate the presence of EPSP-spike potentiation and/or changes in pyramidal cell excitability during the long-term potentiation induced in the CA1 region of rat hippocampal slices by theta-like patterns of stimuli: the primed burst and the patterned stimulation. Using extracellular recording, a significant leftward shift in the EPSP-spike relationship was found 30 min after primed burst or patterned stimulation. The magnitude of EPSP-spike potentiation induced by patterned stimulation was similar to that produced by high-frequency stimulation. Both were significantly greater than that induced by a primed burst, indicating that only a subset of pyramidal cells were potentiated by this kind of afferent activation. Modifications in synaptic efficacy and cell excitability brought about by a primed burst were investigated in 25 intracellularly recorded pyramidal cells. Consistent with extracellular results, it was found that only 11 out of 25 neurons receiving a primed burst were potentiated. In these cells the increase in probability of firing action potentials elicited by synaptic activation with test shocks was accompanied by enhanced cell excitability, but not by an increase in EPSP slope. High-frequency stimulation delivered 40 min after a primed burst invariably increased the EPSP slope, the probability of firing upon synaptic stimulation, and the excitability of cells. The presence of EPSP-spike potentiation and of increased excitability of potentiated cells during the primed burst-induced long-term potentiation strengthen the suggestion that theta pattern-induced synaptic potentiation can be considered similar to high frequency stimulation and long-term potentiation and supports the notion that the EPSP-spike potentiation is a constitutive characteristic of long-term potentiation. PMID- 7845584 TI - Hippocampal theta activity following selective lesion of the septal cholinergic system. AB - The characteristic electroencephalographic patterns within the hippocampus are theta and sharp waves. Septal neurons are believed to play an essential role in the rhythm generation of the theta pattern. The present study examined the physiological consequences of complete and selective damage of septohippocampal cholinergic neurons on hippocampal theta activity in rats. A selective immunotoxin against nerve growth factor receptor bearing cholinergic neurons (192 immunoglobulin G-saporin), [Wiley R. G. et al. (1991) Brain Res. 562, 149-153] was infused into the medial septal area (0.11-0.42 microgram). Hippocampal electrical activity was monitored during trained wheel running, drinking and the paradoxical phase of sleep, as well as following cholinomimetic treatment. A moderate dose of toxin (0.21 microgram) eliminated the septohippocampal cholinergic projection, as evidenced by a near total absence of choline acetyltransferase-immunoreactive neurons in the medial septum and the vertical limb of the diagonal band, and by the absence of acetylcholinesterase-positive fibers in the dorsal hippocampus. In the same rats, parvalbumin immunoreactivity, a reliable marker for septohippocampal GABAergic neurons, [Freund T. F. (1989) Brain Res. 478, 375-381], remained unaltered. In addition, retrograde transport of the tracer fluorogold demonstrated that the parvalbumin cell population preserved its axonal projection to the hippocampus. Following toxin treatment, the power of hippocampal theta, but not its frequency, decreased in a dose dependent manner. Reduction of theta power occurred between three and seven days after the toxin treatment and remained unaltered thereafter up to eight weeks. A dose which eliminated all septohippocampal cholinergic neurons (0.21 microgram) left a small but significant theta peak in the power spectra during wheel running, paradoxical phase of sleep and intraseptal infusion of carbachol (5 micrograms). Peripheral administration of physostigmine (1 mg/kg) induced only slow (1.5-2.0 Hz) rhythmic waves. No changes were observed in the gamma (50-100 Hz) band. These findings indicate that the integrity of the septohippocampal GABAergic projection is sufficient to maintain some hippocampal theta activity. We hypothesize that cholinergic neurons serve to increase the population phase locking of septal cells and thereby regulate the magnitude of hippocampal theta. PMID- 7845585 TI - Enhanced acetylcholine release in hippocampus and cortex during the anticipation and consumption of a palatable meal. AB - In rats trained for 14 days to consume a palatable liquid chocolate meal (Sustacal), in vivo brain microdialysis was used to measure release of acetylcholine in the frontal cortex and hippocampus during anticipation and consumption of the meal. Rats were trained in an experimental chamber in which they were separated from the Sustacal by a screen for 20 min (trained, rewarded group). The screen was then removed and the rats were allowed 20 min of access to the meal. Two control groups were run concurrently: these groups consisted of rats (i) that were trained over 14 days but only had access to water in the experimental chamber (trained, non-rewarded), or (ii) that were introduced into the experimental chamber for the first time on the final test (i.e. dialysis) session, and presented with Sustacal (naive). Different results were obtained in the hippocampus and frontal cortex. In the hippocampus there were no group differences with respect to acetylcholine release. Thus, in all three groups acetylcholine release increased to about 220% of basal values when animals were placed in the experimental chamber. In the frontal cortex, acetylcholine release also increased significantly in all three groups. However, the extent of this increase was significantly greater in the trained, rewarded group, reaching approximately 300% of basal values during the anticipatory and consummatory components of the task. The significant increases in acetylcholine release which occurred in both the hippocampus and frontal cortex of each of the three groups are consistent with an involvement of cholinergic basal forebrain neurons in the regulation of arousal or attention. In addition, however, acetylcholine release in the frontal cortex can be further selectively enhanced by the animal's past training experience, perhaps being associated with the anticipation of reward. PMID- 7845586 TI - Depolarization-induced acid secretion in gliotic hippocampal slices. AB - Gliotic hippocampal slices were used to study glial acid secretion in a tissue largely devoid of neural elements. Rat hippocampal slices were prepared 10-28 days after sterotaxic injection of kainate. Cresyl Violet staining and immunohistochemistry for glial fibrillary acidic protein demonstrated a loss of neurons and a proliferation of reactive astrocytes in area CA3. Extracellular pH and K+ shifts were recorded in CA3 in response to K+ iontophoresis. Elevation of K+ evoked an extracellular acid shift that was two- to three-fold larger in gliotic versus unlesioned tissue. Ba2+ caused a slow extracellular acidification, and blocked both the depolarizing responses of the glial cells and the acid shifts evoked by K+. The K(+)-evoked acid shifts were abolished in Na(+)-free media, and diminished in HEPES-buffered solutions. Inhibition of extracellular carbonic anhydrase caused a reversible enhancement of the K(+)-evoked acid shifts, an effect that could be mimicked during H+ iontophoresis in agarose gels. Gliotic acid shifts were unaffected by amiloride or its analogs, stilbenes, zero Cl- media, zero or elevated glucose, lactate transport inhibitors, zero Ca2+ or Cd2+. Smaller acid shifts could be evoked in normal slices which were also enhanced by benzolamide, and blocked by Ba2+ and zero Na+ media. It is concluded that acid secretion by reactive astrocytes is Na+ and HCO3(-)-dependent and is triggered by depolarization. The similar pharmacological and ionic sensitivity of the acid shifts in non-gliotic tissue suggest that these properties are shared by normal astrocytes. These characteristics are consistent with the operation of an electrogenic Na(+)-HCO3- co-transporter. However, the enhancement of the acid shifts by inhibitors of extracellular carbonic anhydrase suggests that CO3(2-), rather than HCO3-, is the transported acid equivalent. PMID- 7845587 TI - Depolarization-induced alkalinization of astrocytes in gliotic hippocampal slices. AB - Depolarization-induced, intracellular alkaline shifts were studied in reactive astrocytes within slices of gliotic hippocampus. Slices were prepared 10-28 days after sterotaxic injection of kainic acid into the hippocampus of anesthetized rats. Astrocytes in gliotic CA3 were impaled with double-barreled pH sensitive microelectrodes and depolarized by iontophoresis of K+ from an adjacent micropipette. Elevation of extracellular K+ produced an intracellular alkalinization that grew with increasing membrane depolarization, ranging from approximately 0.10 to 0.30 pH units. Exposure to Ba2+ depolarized the cells and produced a similar alkalinization. In the presence of Ba2+, the K(+)-induced depolarization and the associated alkaline shift were abolished. The depolarization-induced alkaline shifts were partially inhibited (40 +/- 8.9%) in Na(+)-free media and were enhanced in bicarbonate versus HEPES-buffered saline. The alkalinizations were unaffected by incubation in chloride-free media, or by the stilbene 4,4'-dinitrostilbene-2,2'-disulfonic acid. It is concluded that the depolarization-induced alkaline shift of reactive astrocytes is mediated in part by a Na+ and HCO3(-)-dependent mechanism that is insensitive to stilbenes. These characteristics correspond well with the properties of depolarization-induced acid secretion in the gliotic tissue. In addition, a separate, Na(+)-independent mechanism contributes to the depolarization-induced alkalinization. In view of the absolute Na+ dependence of acid secretion in the gliotic slices, we propose that the latter mechanism does not extrude acid across the plasma membrane. PMID- 7845588 TI - Phencyclidine induction of the hsp 70 stress gene in injured pyramidal neurons is mediated via multiple receptors and voltage gated calcium channels. AB - Non-competitive N-methyl-D-aspartate receptor antagonists, including phencyclidine, ketamine, and MK801, produce vacuoles and induce the hsp 70 stress gene in layer III pyramidal neurons of the rat cingulate cortex. This study shows that phencyclidine (50 mg/kg) induces hsp 70 messenger RNA and HSP70 stress protein primarily in pyramidal neurons in posterior cingulate and retrosplenial cortex, neocortex, insular cortex, piriform cortex, hippocampus, and in the basal nuclei of the amygdala. Several neurotransmitter receptor antagonists inhibited induction of HSP70 produced by phencyclidine (50 mg/kg): haloperidol (ED50 = 0.8 mg/kg), clozapine (ED50 = 1 mg/kg), valium (ED50 = 1 mg/kg), SCH 23390 (ED50 = 7 mg/kg) and muscimol (ED50 = 3 mg/kg). Baclofen had no effect. Nifedipine blocked the induction of HSP70 produced by phencyclidine in some regions (cingulate, neocortex, insular cortex) but only partially blocked HSP70 induction in other regions (piriform cortex, amygdala). These results suggest that phencyclidine injuries pyramidal neurons via dopamine D1, D2, D4, sigma and other receptors. Several factors appear to contribute to this unusual multi-receptor mediated injury. (1) Phencyclidine blocks N-methyl-D-aspartate receptors on GABAergic interneurons resulting in decreased inhibition of pyramidal neurons. This may help to explain why multiple excitatory receptors mediate the injury and why GABAA agonists decrease the injury produced by phencyclidine. (2) Phencyclidine blockade of an amine transporter helps explain why dopamine receptor antagonists ameliorate injury. (3) Phencyclidine depolarizes neurons and produces high, potentially damaging intracellular calcium levels probably by blocking K+ channels that may be linked to sigma receptors. Since nifedipine prevents injury in cingulate, insula, and neocortex, it appears that calcium entry through L-type voltage gated calcium channels plays a role in the pyramidal neuronal injury produced by phencyclidine in these regions. There are similarities between the cingulate neurons injured by phencyclidine and circuits recently hypothesized to explain receptor changes in cingulate gyrus of schizophrenic patients. The present and previous studies also provide approaches for decreasing the clinical side effects of N-methyl-D-aspartate receptor antagonists to facilitate their possible use in the treatment of ischemia and other disorders. PMID- 7845589 TI - Activation of dopaminergic neurons modulates ventral pallidal responses evoked by amygdala stimulation. AB - The ventral pallidum is a basal forebrain region that is thought to integrate cognitive processes with motoric behaviors. These functions are influenced by ventral pallidal inputs, which include projections from the amygdala and the ventral tegmental area/substantia nigra zona compacta. By examining the consequences of this convergence at the neuronal level, the present study indicates that electrical activation of ventral tegmental regions releases dopamine in the ventral pallidum which subsequently modulates pallidal electrophysiological responses evoked by stimulating the amygdala. Stimulation evoked responses were characterized for extracellular single unit recordings of spontaneously active ventral pallidal neurons from chloral hydrate anesthetized rats. Stimulation of the amygdala evoked short latency (< or = 12 ms; possibly monosynaptic) and/or long latency (> 12 ms; polysynaptic) responses in all ventral pallidal neurons tested. Fifty-nine per cent of the tested neurons responded to ventral tegmental stimulation with short latency inhibition, and these neurons were often sensitive to microiontophoretically applied dopamine. Iontophoresis of dopamine antagonists SCH23390 (a D1 antagonist) or sulpiride (a D2 antagonist) attenuated the ventral tegmental-induced inhibitions. These observations indicate that the evoked responding was the result of endogenously released dopamine, and that D1 and D2 receptors were involved in this effect. Ninety-two per cent of the ventral pallidal neurons that demonstrated short latency responses to amygdala stimulation also exhibited short latency responses to activation of the ventral tegmentum. This suggests that these inputs often converge onto the same pallidal neurons. Amygdala-evoked responses were consistently attenuated by prior stimulation of the ventral tegmentum. Similarly, microiontophoretic ejection of dopamine attenuated amygdala-evoked effects. These results indicate that dopamine modulates amygdala-evoked pallidal responses. Such modulation may contribute to the integrative functions of the ventral pallidum. PMID- 7845590 TI - Fine structural alteration in target-deprived axonal terminals in the rat thalamus. AB - Lesioning of thalamic target neurons in the adult rat provokes a resorption of terminal axonal branches of afferent neurons from the dorsal column nuclei. There is, however, no massive neuronal loss in the dorsal column nuclei. In the adult, therefore, the thalamic post synaptic target cells influence primarily the extent of the terminal component of the afferent neurons. The subcellular changes underlying the regression of these adult terminals are unknown. To address this issue, we have looked at the electron microscopic level for the ultrastructural correlates of this retraction of the terminal compartment of target-deprived neurons in the adult rat thalamus. By analysing the fine structure of target deprived axons and their immunoreactivity for a specific synaptic protein, synaptophysin, we have observed that all the organelles and the protein formed in the cell body, including dense-core vesicles, continue to be transported to the terminal compartment and accumulate at this level. At the terminal level, engorgement of organelles induces the formation of varicosities. An enormous increase in local degradative activity occurs in parallel to this accumulation. In contrast, organelles involved in membrane turnover and degradation (including synaptic and coated vesicles, multivesicular bodies, lysosomes) in the nerve terminals are clearly modified. There is a progressive loss of synaptic vesicles, whereas clathrin-coated vesicles and multivesicular bodies are numerous. We propose that the resorption of terminal axonal branches after thalamic target deprivation in the adult is associated with a bias of the system of membrane recycling at the axonal terminals towards degradation. In the absence of apparent changes in the pathways originating from the cell body in these conditions, it is unlikely that presynaptic neurons in the adult thalamus are dependent upon post synaptic target neurons for the delivery of organelles and proteins to the terminals. PMID- 7845591 TI - Quantitative autoradiographic study of somatostatin receptors in the adult human cerebellum. AB - The evolution of the distribution and density of somatostatin receptors was studied in the human cerebellum during ageing. The brain tissues were collected 3 30 h after death from 20 individuals aged from 28 to 86 years. In vitro autoradiographic experiments were performed on blocks of vermis and of right and left cerebellar hemispheres, using [125I-Tyr0,DTrp8]S14 as a radioligand. In the vermis, the mean concentrations of somatostatin receptors in the molecular layer, the granular layer and the medulla were 140 +/- 9, 150 +/- 22 and 61 +/- 13 fmol/mg proteins, respectively. For each individual, the density of sites in the two lateral lobes was similar. The mean concentrations of somatostatin receptors in the molecular layer, the granular layer and the medulla were 152 +/- 17, 190 +/- 20 and 56 +/- 11 fmol/mg proteins, respectively. The mean level of somatostatin receptors and the type of distribution of the receptors were not correlated to the age of the patients. Different distribution patterns of somatostatin receptors were noted among the patients studied. In the majority of patients (11/20), the density of somatostatin receptors was higher in the granular layer than in the molecular layer. Conversely, in four patients, the density of somatostatin receptors was higher in the molecular layer. The other individuals exhibited similar concentrations of somatostatin receptors in the granular and molecular layers. The present study indicates that the adult human cerebellum contains a high concentration of somatostatin receptors (> 100 fmol/mg proteins) and that the receptor level does not decline during ageing.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845592 TI - Distribution of cholinergic, GABAergic and serotonergic neurons in the medial medullary reticular formation and their projections studied by cytotoxic lesions in the cat. AB - As part of a larger study concerning the role of neurons in the medial medullary reticular formation in sleep-wake states, the distribution and projections of cholinergic, GABAergic and serotonergic neurons were studied within the lower brainstem of the cat. Cells were plotted with the aid of an image analysis system through the medullary reticular formation and raphe in adjacent sections immunostained for choline acetyltransferase, glutamic acid decarboxylase and serotonin. Immunostained fibres and varicosities were examined and quantified by microdensitometry in regions of the medulla, pons and upper spinal cord in normal and quisqualate-injected animals to assess the loss of local and distant projections following cytotoxic destruction of neurons in the medial medullary reticular formation. Choline acetyltransferase-immunoreactive neurons are unevenly and sparsely distributed, though none the less in significant numbers (estimated at approximately 9080 in total), through the medial medullary reticular formation, and are present in all tegmental fields, including the gigantocellular (approximately 3700) and magnocellular (approximately 1760) rostrally and the ventral (approximately 3240) and paramedian (approximately 380) caudally, and are absent in the midline raphe. Glutamic acid decarboxylase immunoreactive neurons are more evenly and densely distributed in large numbers (estimated at approximately 18,720) through the medial medullary reticular formation, being present in the gigantocellular (approximately 5960), magnocellular (approximately 8260), ventral (approximately 2280) and paramedian (approximately 2220) tegmental fields, and are also numerous within the raphe magnus and pallidus-obscurus nuclei (approximately 3880). Serotonin immunoreactive cells are sparse in the medial medullary reticular formation (estimated to total approximately 1540), where they are mainly located in the magnocellular tegmental field (approximately 1340), and are concentrated in larger numbers within the raphe nuclei (approximately 8060). Cholinergic varicose fibres were moderately densely distributed through the medial medullary reticular formation, as well as through more distant lateral, rostral and caudal brainstem and upper spinal regions. After cytotoxic lesions focussed in the gigantocellular and magnocellular tegmental fields, a loss of approximately 55% of the cholinergic neurons in the medial medullary reticular formation was associated with a minor decrease (approximately 35% in optical density measures) of local cholinergic fibres. Small and variable reductions in varicose fibres (and their optical density measures) were detected in distant structures (including the pontine lateral, gigantocellular and subcoerular tegmental fields and the caudal spinal trigeminal nucleus), that were none the less correlated with the number of intact medial medullary cholinergic cells, suggesting that these cells may project to distant brainstem targets, in addition to providing a minor proportion of the local cholinergic innervation of the medial medullary reticular formation.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7845593 TI - Importance of cholinergic, GABAergic, serotonergic and other neurons in the medial medullary reticular formation for sleep-wake states studied by cytotoxic lesions in the cat. AB - Previous evidence has suggested that neurons in the medial medullary reticular formation play a critical role in the modulation of forebrain and spinal cord activity that occurs during the sleep-waking cycle and particularly in association with the state of paradoxical sleep. The importance of these neurons, including cholinergic, serotonergic and GABAergic cells [Holmes C. J. et al. (1994) Neuroscience 62, 1155-1178] for sleep-wake states was investigated after their destruction with the neurotoxin quisqualic acid injected into the medullary gigantocellular and magnocellular tegmental fields in cats. To assess the effects of the neuronal loss, polygraphic recording and behavioural observations were performed in baseline and for three weeks after the lesion, and the changes in these measures were correlated with the volume of destruction of medullary regions and the numbers of chemically identified cells within those regions. Following the cytotoxic lesions, which affected approximately 60% of the medullary gigantocellular and magnocellular tegmental fields, there was a significant reduction in the amount of paradoxical sleep (to a mean of 64% of baseline) during the first postlesion week, that recovered variably across cats in the second and third weeks. There was little to no change in the amount or organization of waking and slow wave sleep. The individually variable amounts of postlesion paradoxical sleep were correlated positively with the number of surviving cholinergic cells, negatively with the number of surviving serotonergic cells and positively with the ratio of surviving cholinergic or GABAergic cells to serotonergic cells. The most marked effect of the lesion was a substantial increase in the amplitude of the nuchal electromyogram during slow wave sleep (to 198%) and paradoxical sleep (to 378% of baseline in the first postlesion week). The increase in muscle tone was associated with movements of the head, neck or limbs during paradoxical sleep. Although, in some cats, the abnormal neck muscle tone decreased with time, limb movements continued to occur during paradoxical sleep for the duration of the experiment. The ratio of the total number of remaining cholinergic or GABAergic cells to serotonergic cells correlated negatively with the increased muscle tone and/or movements. It was concluded that the neurons of the medial medullary reticular formation contribute to, but are not necessary for, the generation of paradoxical sleep, and have particular importance for the regulation of muscle tone and inhibition of movement during this state.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7845594 TI - Phenotypic characteristics of expressed tyrosine hydroxylase protein in the adult rat nucleus tractus solitarius: plasticity revealed by RU24722 treatment. AB - The phenotypic characteristics of expressed tyrosine hydroxylase protein have been precisely analysed in the rat nucleus tractus solitarius, which contains the majority of A2 noradrenergic and C2 adrenergic neurons of the medulla oblongata. This study was based upon quantitative analysis of immunohistochemical and immunoradioautographic staining of tyrosine hydroxylase protein in serial coronal sections. In control rats, there were few tyrosine hydroxylase-expressing cell bodies which express less than 2% of the immunoradiolabeled tyrosine hydroxylase protein measured in the structure. These cell bodies were scattered throughout an extensive immunopositive neuropile, which precisely delimited the topological space of the nucleus tractus solitarius quantiatively reconstructed using a polar coordinate system. The quantification of tyrosine hydroxylase tissue concentration from immunoradioautograms allowed us to subdivide the structure into two distinct regions. The posterior region of the nucleus tractus solitarius, which mainly corresponds to the A2 cell group, contains a relatively high tissue concentration of tyrosine hydroxylase protein (18.56 +/- 0.154 units per mg of tissue). The anterior region, which mainly corresponds to the C2 cell group, exhibits a relatively low concentration (12.09 +/- 0.81) of this protein. Three days after an intraperitoneal injection of RU24722, there was a strong increase (90 +/- 17%) in tyrosine hydroxylase protein content only in the anterior region of the nucleus tractus solitarius. This increase was associated with a dramatic elevation (142 +/- 20%) in the number of tyrosine hydroxylase expressing cell bodies. The additional cell bodies were mainly located inside the initial perikarya-containing area.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845596 TI - Neurons of visual cortex respond to visceral stimulation during slow wave sleep. AB - It is hypothesized here that the same cortical areas which process signals from exteroreceptors (visual, acoustic, etc.) in wakefulness process signals from visceral organs during sleep. To check this hypothesis, the activity of 49 neurons (hypercomplex, complex and simple, as defined by conventional visual stimulation) was recorded from visual areas V1 and V2 in chronic cats at different stages of the sleep-waking cycle. Neuronal responses to electrical stimulation of the area of stomach and small intestine (single pulses of 100-500 microA. 0.5 ms duration) were investigated. It was found that intraperitoneal stimulation delivered during slow wave sleep evoked clear excitatory responses in most simple and complex cells. In hypercomplex cells, only inhibitory responses were observed. All these responses disappeared in wakefulness. These observations are compatible with the above hypothesis. PMID- 7845595 TI - Organization of vestibular nucleus projections to the caudal dorsal cap of kooy in rabbits. AB - This study used retrograde and anterograde tracing methods to characterize the origin and terminal distribution of vestibular nuclear projections to the caudal dorsal cap of the inferior olive in albino rabbits. Comparisons of the retrograde labeling patterns from Cholera toxin B fragment-horseradish peroxidase and Fluoro Gold injection sites centred in either the caudal dorsal cap or the rostral dorsal cap plus ventrolateral outgrowth revealed that they receive projections from different vestibular nuclear regions. Tracer injections in the rostral dorsal cap and ventrolateral outgrowth produced a sparse bilateral distribution of labeled neurons in the superior vestibular nucleus and an almost exclusively ipsilateral pattern of labeled neurons in caudal pars alpha of the lateral vestibular nucleus. Injections in the caudal dorsal cap, though, labeled neurons bilaterally in the rostral medial vestibular nucleus, predominantly ipsilaterally in pars beta of the lateral vestibular nucleus and almost exclusively ipsilaterally in caudal pars alpha of the lateral vestibular nucleus and the rostral aspect of the inferior vestibular nucleus. Vestibular nucleus injections of the anterograde tracer Phaseolus vulgaris leucoagglutinin indicated (1) that a predominantly ipsilateral projection to the caudal dorsal cap originates bilaterally from the pars beta of the lateral vestibular nucleus and the rostroventral aspect of the rostral medial vestibular nucleus, (2) that the medial half of the caudal medial vestibular nucleus is the source of a predominantly contralateral projection to dorsal cap, (3) that the caudal aspect of nucleus prepositus hypoglossi contributes a predominantly ipsilateral projection to the medial accessory olive and (4) that the rostral aspect of inferior vestibular nucleus and the dorsal and lateral aspects of the caudal medial vestibular nucleus project to nucleus beta of the medial accessory olive. In addition, axons containing anterogradely transported PHA-L were observed bilaterally in the oculomotor and abducens nuclei from injection sites involving pars beta of the lateral vestibular nucleus. It is hypothesized that bilateral vestibulo-caudal dorsal cap pathways coordinate activity in the left and right flocculus and nodulus during horizontal head movements to facilitate the performance of conjugate vestibulo-ocular and optokinetic reflexes. PMID- 7845597 TI - Reappraisal of the innervation of rat intestine by vasoactive intestinal polypeptide and neuropeptide Y-immunoreactive neurons. AB - The occurrence and distribution of neurons and nerve fibres showing vasoactive intestinal polypeptide-like and neuropeptide Y-like immunoreactivity were re examined in the enteric nervous system of the small and large intestine of the adult rat using dual-labelling indirect immunofluorescence histochemistry to detect the co-existence of these neuropeptides. In the myenteric plexus of both small and large intestine, a population of neuropeptide Y-immunoreactive neurons that did not contain vasoactive intestinal polypeptide was noted; it accounted for 29-53% of neuropeptide Y neurons. Such neurons were also found in the submucosa but there they constituted at most 2% of neuropeptide Y-immunoreactive neurons. In both myenteric and submucous plexuses, regional variations were observed in the number of immunoreactive neurons and in the proportion of dual labelled neurons. In the myenteric plexus, for example, the density of neurons with immunoreactivity to these two neuropeptides was constant throughout the small intestine, whereas it progressively increased distally within the colon. In addition, a distinct but small subset of immunoreactive myenteric neurons was found to have a novel soma morphology, unclassifiable according to the criteria used for porcine or guinea-pig enteric neurons. Such neurons had one or more conspicuous processes, which were much longer than the short, lamellar somal processes of typical Dogiel Type 1 neurons; moreover, these protruded from an essentially smooth soma and terminated at distances of up to two cell diameters from their point of origin. Thus, our results suggest that the organization of the enteric nervous system of the rat differs from that of other species and indicate that investigation of the co-localizations of neuropeptides and biologically active mediators in the intestinal tract would be incomplete without reference to regional differences in the incidence and distribution of such neurochemicals. PMID- 7845598 TI - A daily rhythm of activator protein-1 activity in the rat pineal is dependent upon trans-synaptic induction of JunB. AB - The daily cycle of phenotypic variation in the mammalian pineal provides a unique model for the investigation of the molecular mechanisms that regulate neurotransmitter synthesis. In the rat, a circadian adrenergic mechanism directs a change in serotonin metabolism that results in the nocturnal production of melatonin. Activity of the activator protein-1 transcriptional regulatory complex, as demonstrated by band-shift assays of rat pineal gland extracts, has now been shown to exhibit a rhythm, in vivo, which is temporally correlated with the rhythm of melatonin synthesis. Thus, nocturnal activator protein-1 activity (23.00 h) is markedly elevated, being 8-fold higher than the level of light-phase activity (P < 0.005). The nocturnal activator protein-1 protein complex is induced through a trans-synaptic, beta-adrenoceptor-linked mechanism and is characterized by the prolonged participation of JunB as demonstrated using antibodies for specific activator protein-1 proteins. Indeed, JunB appears to be a major component of nocturnal changes in activator protein-1 activity, JunD forming an additional, constitutive component which is not affected by the nocturnal adrenergic signal. The alpha 1-adrenoreceptor-linked c-Fos protein, which is coordinately induced with JunB, does not form a stable component of nocturnal activator protein-1 activity. In contrast, parallel experiments showed that c-Fos does form a major component of the hippocampal activator protein-1 complex that is induced in rats following kainic acid treatment. In the pineal, a similar, although not identical, pattern of activator protein-1 activation has also been demonstrated in cultured glands following treatment with norepinephrine. Immunoblotting has demonstrated parallel accumulation of JunB and c-Fos protein in pineal nuclear fractions following stimulation both in vivo and in vitro. The results provide evidence of posttranscriptional selection of neurotransmitter-stimulated activator protein-1 protein complexes, a mechanism which complements the differential induction of fos and jun genes in the pineal, and serves to generate a specific activator protein-1 transcription factor complex. This finding has general implications for the functional interpretation of fos and jun gene induction in neuronal systems. The stable JunB complex demonstrated here may be considered as one component of a timing mechanism which acts to perpetuate synaptic signals and thereby maintain an appropriate period of nocturnal pineal function. PMID- 7845599 TI - Intraspinal release of immunoreactive calcitonin gene-related peptide during development of inflammation in the joint in vivo--a study with antibody microprobes in cat and rat. AB - This study addressed the intraspinal release of immunoreactive calcitonin gene related peptide in vivo during mechanical stimulation of the normal joint and during the development of an acute experimental inflammation in the knee joint in the anaesthetized cat (spinalized) and rat (not spinalized). Release was assessed using microprobes coated with antibody to calcitonin gene-related peptide; inhibition of binding of [125I]calcitonin gene-related peptide to these probes following insertion into the spinal cord is equated with intraspinal release of the endogenous (unlabelled) peptide. Probes inserted prior to inflammation showed marked basal release of immunoreactive calcitonin gene-related peptide in the dorsal horn with a maximum in the superficial dorsal horn in the absence of intentional stimulation. The pattern of binding of [125I]calcitonin gene-related peptide was not or only minimally changed by innocuous mechanical stimuli (flexion of and innocuous pressure to the knee in the cat and innocuous pressure to the knee of the rat) but was significantly altered by electrical stimulation of the tibial nerve in the cat (sufficient to excite unmyelinated afferent fibres), indicating release of the peptide by the latter stimulus. During the first hours of the development of an experimental inflammation in the knee joint induced by intra-articular injections of kaolin and carrageenan, the pattern of binding of [125I]calcitonin gene-related peptide changed. In the cat, the level of immunoreactive calcitonin gene-related peptide showed a persistent increase in the gray matter and up to the surface of the cord and release was slightly increased by innocuous stimuli. In the rat, increased levels of immunoreactive calcitonin gene-related peptide were mainly seen in the superficial and deep dorsal horn during innocuous pressure (this stimulus did not evoke release of the peptide prior to inflammation) and noxious pressure applied to the injected knee, whereas increased basal levels were only observed at later stages. These data show that the development of an acute experimental inflammation in the joint is associated with an enhancement of the intraspinal release of immunoreactive calcitonin gene-related peptide. Since the changes in the release were noted at an early stage, within the first hours, they could contribute to the generation of inflammation-evoked changes of the responsiveness of spinal cord neurons and hence to the mechanisms inducing inflammatory pain. PMID- 7845600 TI - Neural xenotransplantation: reconstruction of neuronal circuitry across species barriers. AB - Selective replacement of degenerated neurons in the adult brain with allogeneic fetal neuroblasts is a promising therapeutic modality for human neurodegenerative diseases, but is confounded with practical and potential ethical problems. To evaluate the potential of xenogeneic donors as a cell source for neural transplantation, we have critically examined the available experimental evidence in animal models pertaining to the survival, integration and function of xenogeneic fetal neuroblasts in the host brain. A statistical meta-analysis across multiple studies revealed that immunologically-related transplantation parameters (immunosuppression and donor-host phylogenetic distance) were the main determinants of neural xenograft survival. The immunological basis for xenograft rejection is reviewed in the context of novel immunoprotection strategies designed to enhance xenograft survival. Furthermore, the evidence for behavioral recovery based on anatomical and functional integration of neural xenografts in the host brain is examined with an awareness of developmental considerations. It is concluded that neural xenotransplantation offers a unique opportunity for effective neuronal replacement with significant potential for clinical use. PMID- 7845601 TI - Macro-EMG and motor unit recruitment threshold: differences between the young and the aged. AB - The relationship between macro-EMG (electromyography) and motor unit recruitment threshold was studied in the first dorsal interosseous (FDI) muscle of normal young and aged subjects. During voluntary isometric contraction, motor unit action potentials (MUAP) were collected by a special quadrifilar electrode and decomposed to each MUAP train (MUAPT) using an EMG signal decomposition technique. Macro-EMG was obtained from the electrode shaft, then triggered and averaged for each MUAPT. A positive linear correlation was observed in both the young and aged subjects. However, the correlation coefficients were significantly lower in the aged individuals than in the young individuals. PMID- 7845602 TI - High activity of retinal N-acetyltransferase in the early development of the chick embryo: independence of lighting conditions. AB - In this paper, we studied the activities of N-acetyltransferase (NAT), hydroxyindole-O-methyltranferase (HIOMT) and melatonin content in the retina of chick embryo from the 7th day of embryonic age to hatching. Our results confirm that the dependence on lighting conditions of NAT activity and melatonin content appears to develop prior to hatching, as evidenced by differences observed when chick embryos were incubated under constant darkness or constant light. Moreover, we found high NAT activity during the first stages of the embryonic development up to 13th day of incubation. This activity, unlike late retinal NAT, is not coupled to melatonin production and is not dependent on lighting conditions. PMID- 7845603 TI - Stimulation of D4-like dopamine receptor suppresses serotonin N-acetyltransferase activity but does not phase-shift the circadian oscillator in chick retina. AB - We have recently reported that dopamine (DA) receptor-regulating serotonin N acetyltransferase (NAT) activity in chick retina represents a D4-like subtype. In this work, effects of stimulation of DA-D4 receptors upon the circadian rhythm of retinal NAT activity were investigated in chicks. Systemic administration of quinpirole (QNP), a DA-D4 receptor agonist, resulted in a potent suppression of the nighttime NAT activity of chick retina but did not significantly affect the phase of subsequent cycles of the rhythmic oscillation of the enzyme activity in constant darkness. 6-h pulses of white light caused an acute suppression of NAT activity in chick retina and, in contrast to QNP, resetted the phase of the free running rhythm. It is suggested that, although D4-like DA receptors in chick retina are involved in the regulation of NAT activity by the circadian clock, they do not appear to be implicated in the regulation of the clock by light. PMID- 7845604 TI - MK-801 inhibits the induction of immediate early genes in cerebral cortex, thalamus, and hippocampus, but not in substantia nigra following middle cerebral artery occlusion. AB - Middle cerebral artery (MCA) occlusion in rats induced c-fos and junB mRNA 4h later in all ipsilateral cortex outside the MCA distribution and in many subcortical structures: medial striatum; most of thalamus including medial and lateral geniculate nuclei: substantia nigra; and hippocampus. The N-methyl-D aspartate (NMDA) antagonist, MK-801 (4 mg/kg, i.p.) inhibited c-fos and junB mRNA induction in the cortex, striatum, thalamus, and hippocampus but not in the substantia nigra. These data show that c-fos and junB mRNA induction in cortex, striatum, thalamus, hippocampus involves the activation of NMDA receptors whereas different receptors must be implicated in the induction in substantia nigra. PMID- 7845605 TI - Felbamate, an anti-convulsive drug, has anti-parkinsonian potential in rats. AB - The potency of felbamate, an anti-convulsive drug, to influence dopamine D1 (SCH 23390) and D2 (haloperidol) receptor-mediated catalepsy (akinesia and bradykinesia) was studied in rats. In the catalepsy test, felbamate antagonized dopamine D2 receptor- but not D1 receptor-induced akinesia. Bradykinesia in the open field was never influenced. The results demonstrate that felbamate has similar anti-parkinsonian potential as glycine site antagonists blocking the N methyl-D-aspartate (NMDA) receptor complex. PMID- 7845607 TI - Phosphatidylethanol formation and degradation in brains of acutely and repeatedly ethanol-treated rats. AB - The formation of the abnormal phospholipid phosphatidylethanol (PEth) was studied in hippocampus, cerebellum and cerebrum of rat brain after intraperitoneal ethanol administration. Prior to analysis by high performance thin layer chromatography PEth was purified. After one injection, PEth levels reached a maximum after 2 h and remained detectable for 14-24 h in all three regions. Repeated injections led to additional accumulation. Maximum in vivo levels of 30 50 nmol/g wet wt. were reached. PMID- 7845606 TI - Day- and nighttime content of monoamines and their metabolites in the pineal gland of rat and hamster. AB - Day- and nighttime content of catecholamines, serotonin and their metabolites were measured in the pineal gland of Sprague-Dawley rats and Djungarian hamsters. In addition, monoamine turnover rates were determined in the hamster pineal gland following administration of alpha-methyl-p-tyrosine. Animals were decapitated in the middle of the light or dark period, respectively, and pineal tissue was analysed by high performance liquid chromatography with electrochemical detection. Pineals of both species exhibited day/night-differences in serotonin, 5-hydroxyindole-3-acetic acid and dopamine content. The hamster pineal gland further showed day/night differences in its content of epinephrine and 3-methoxy 4-hydroxyphenylethyleneglycol. The dopamine turnover rate was augmented at night, while norepinephrine turnover was constant. Immunohistochemical incubations of pineal paraffine sections showed fibers and terminals stained by antisera to tyrosine-hydroxylase (TH) and dopamine-beta-hydroxylase, and a few perikarya-like structures exhibiting TH immunoreactivity. The results support the view that dopamine, rather than only functioning as a norepinephrine precursor, is actively involved in the control of melatonin synthesis. PMID- 7845608 TI - Increased expression of bcl-2 immunoreactivity in the developing cerebral cortex of the rat. AB - Bcl-2 proto-oncogene encodes a protein which may cancel the cell death programme in normal development and experimentally induced conditions. Strong bcl-2 immunoreactivity occurs in the neocortex and hippocampus of the developing rat during the 1st postnatal week. Bcl-2 immunoreactivity rapidly decreases from this age onwards to steady very low levels in adulthood. Since increased expression of bcl-2 immunoreactivity during cortical neurogenesis is coincidental in time with a special vulnerability of cortical neurons to naturally occurring cell death, it is suggested that bcl-2 may have a role in regulating cell death and survival during cortical morphogenesis. PMID- 7845609 TI - Electrophysiological characteristics of locus coeruleus neurons in the Maudsley reactive (MR) and non-reactive (MNRA) rat strains. AB - Extracellular single-unit recording techniques were used to evaluate the physiological and pharmacological characteristics of noradrenergic locus coeruleus (LC) neurons in urethane-anesthetized Maudsley reactive (MR) and non reactive (MNRA) rat strains, a presumed genetic model for differences in 'anxiety'. LC neurons from MNRA rats were found to have a significantly higher basal discharge rate than LC neurons from either the MR or Sprague-Dawley (SD) rats. The discharge pattern of MNRA LC neurons also differed significantly from that of LC neurons from SD and MR rats, with LC neurons from MNRA rats exhibiting a burst-like pattern of discharge. Finally, MNRA LC neurons were significantly less sensitive to the inhibitory effects of i.v. clonidine on spontaneous activity. PMID- 7845610 TI - Noradrenaline reduces synaptic responses in normal and tottering mouse entorhinal cortex via alpha 2 receptors. AB - The effects of noradrenaline (NA) on synaptic responses in layer II of the entorhinal cortex (EC) were studied in normal and spontaneously epileptic mutant mice tottering using intracellular recording in a slice preparation. Neither the membrane properties of neurones nor the responses to NA differed between normal and tottering mice. NA (50 microM) hyperpolarized most (29/54) of the neurones via alpha 2 adrenergic receptors. Synaptic responses of EC neurones were complex. NA (10-100 microM) reduced all the components of the synaptic response in a concentration-dependent and reversible manner. The pharmacological properties of the inhibitory effect of NA were characterised and quantified on one component of the complex synaptic response, the fast excitatory postsynaptic potential. The effect of NA was mimicked by the alpha 2 agonist UK 14,304 and blocked by the alpha 2 antagonist yohimbine. It is concluded that NA can inhibit via an alpha 2 receptor-mediated action synaptic responses in the superficial layers of the EC. PMID- 7845611 TI - Cu/Zn superoxide dismutase-like immunoreactivity in Lewy body-like inclusions of sporadic amyotrophic lateral sclerosis. AB - Cu/Zn superoxide dismutase (SOD)-like immunoreactivity (LI) was found within Lewy body-like inclusions (LBIs) in the spinal cords of patients with sporadic amyotrophic lateral sclerosis (ALS) by using an antibody to human Cu/ZnSOD. LBIs were detected in the anterior horn cells in 10 of 20 patients with sporadic ALS. In each of these patients, 7 to 60% of LBIs showed Cu/ZnSOD-LI. No Cu/ZnSOD-LI was detected in intact neurons and glia in the 20 ALS patients, as well as in these cells in 10 normal control individuals. The skein-like inclusions and Bunina bodies, which were found in all of the 20 ALS cases, showed no Cu/ZnSOD LI. Thus, Cu/ZnSOD appears to play roles in the production and/or degradation process of LBIs. PMID- 7845612 TI - Rapid development of D1 and D2 dopamine receptor supersensitivity as indicated by striatal and pallidal Fos expression. AB - Rats were injected with a single dose of the monoamine-depleting agent reserpine (5 mg/kg s.c.) or its vehicle. Twenty-four hours later rats were injected with either the selective D1 agonist SKF 38393 (5 mg/kg i.p.), the selective D2 agonist quinpirole (0.1 mg/kg i.p.) or saline, and perfused 2 h later. Fos-like immunoreactivity was visualized using a polyclonal antibody to the Fos protein and standard ABC methods. Reserpine rendered striatal D1 and D2 receptors supersensitive as indicated by 10- to 12-fold increases in striatal and pallidal Fos immunoreactivity. The short latency of the development of both D1 and D2 supersensitivity limits the candidate causative mechanisms to those that occur within hours of the initiating stimulus. PMID- 7845613 TI - Perchloroethylene exposure can induce colour vision loss. AB - We evaluated colour vision in 35 dry-cleaners exposed to perchloroethylene (PCE) and in a paired number of controls matched for sex, age, alcohol consumption and cigarette smoking. A subclinical colour vision loss, mainly in the blue-yellow range, was present in dry-cleaners. This effect was related to PCE exposure levels, and appeared at environmental concentrations of the solvent well below the current exposure limits for exposed workers. The results suggest that PCE exposure, even at low environmental levels, can induce a dose-related impairment of colour vision. PMID- 7845615 TI - Regulation of diacylglycerol kinase in rat brain membranes by docosahexaenoic acid. AB - The effect of docosahexaenoic acid (DHA) on the diacylglycerol kinase (DG kinase) activity in rat brain membranes was investigated. DHA at 500 microM concentration, stimulated the enzyme activity by about 2 fold. This effect was concentration- and time-dependent and was observed after very short periods of incubation (one min). DHA stimulation of DG kinase was observed only with rat brain membranes, and not with rat brain cytosol or rat liver membranes. Treating the rat brain membranes with phospholipase A2 which released free fatty acids including DHA, significantly stimulated the DG kinase activity. It is concluded that DHA through its stimulatory effect on DG kinase may regulate the signalling events in growth-related situations in the brain such as synaptogenesis. PMID- 7845614 TI - Myomodulin application increases cAMP and activates cAMP-dependent protein kinase in the accessory radula closer muscle of Aplysia. AB - Myomodulin A (MMA) application or stimulation of neuron B16, which releases MMA, increases cAMP levels in the accessory radula closer (ARC) muscle of Aplysia. MMA application also increases cAMP-dependent protein kinase (cAPK) activity in one subcellular compartment of the muscle. These results suggest that at least part of MMA's effects in this system are mediated via the cAPK signal transduction pathway. Since the effects of the small cardioactive peptides (SCPs) on ARC muscle contraction are similar to those of MMA, our results suggest that the convergent physiological effects of MMA and SCPB in this system may be due, in part, to the two peptide neuromodulators utilizing the same signal transduction pathway. PMID- 7845616 TI - The GABAA receptor antagonist picrotoxin induces a 'pain-like' behavior when administered into the thalamic reticular nucleus of the behaving rat: a possible model for 'central' pain? AB - In this study, we reported that the microinjection of the GABAA antagonist picrotoxin into the rat thalamic reticular nucleus produced a 'pain-like' behavior. This behavior was primarily characterized by repetitive lifting off the hindpaw from the floor contralateral to the injection site, sometimes accompanied by extension of the leg and maximal fingers separation. Surprisingly, these manifestations were not occurring when picrotoxin was applied to the ventrobasal complex itself, alternatively producing 'wet-dog' shakes. These data show that the local administration of picrotoxin is a relevant approach for studying pain of 'central' origin and complex GABAergic modulatory mechanisms within the thalamic sensory complex. PMID- 7845617 TI - Are humans able to voluntarily elicit maximum muscle force? AB - Previous investigators have used electrical stimulation superimposed on voluntary efforts to show that humans are capable of maximum muscle activation. In the present study this notion was tested using the interpolated twitch technique enhanced by triggered averaging and doublet stimulation of the human biceps brachii. It was found that the decline in extra torque evoked by percutaneous stimulation with increasing levels of voluntary effort was nonlinear and that none of the twelve subjects was able to elicit a voluntary effort large enough to prevent extra torque of elbow flexion. The exponential nature of the declining extra torque indicated that an extrapolated maximum muscle force could be considerably larger than that to which subjects were able to elicit voluntarily. PMID- 7845618 TI - Electrophysiological evidence for projections of myelinated and non-myelinated primary vagal afferents to the rat insular cortex. AB - Two types of vagal evoked potentials were recorded in chloralose-anesthetized rats: a positive-negative one and a negative-positive one in granular and agranular insular cortical subareas, respectively, the former being more susceptible to barbiturate. Both potentials consisted of two subtypes which were distinct as to threshold and latency. Peripheral conduction velocities as well as thresholds of these two subtypes corresponded to myelinated and non-myelinated primary afferents, respectively. Thus, these two primary vagal afferents are probably both represented in two insular cortical subareas, through pharmacologically distinct pathways. PMID- 7845619 TI - C mechanical nociceptive neurons in the crotaline trigeminal ganglia. AB - Using 32 Crotaline snakes, Trimeresurus flavoviridis, intrasomal recordings were made from 44 neurons of the trigeminal ganglia in vivo. They were 10 C neurons from 9 snakes and 34 A-delta mechanical nociceptive neurons from 23 snakes. 5 of the 10 C neurons were identified as mechanical nociceptive neurons. The neurons were labeled with iontophoretically injected HRP. Each of the 5 C nociceptive neurons had one receptive field, on which 1 spike was elicited by pricking the skin or mucosa with a pin. They were sensitized after repeated stimulation. The fields were insensitive to thermal stimulation. No background discharge was observed. Average conduction velocity was 0.95 m/s (+/- 0.4 S.D., n = 5). Mean resting potential was -62.5 mV (+/- 6.0 S.D., n = 4), and mean action potential amplitude was 88.0 mV (+/- 10.9 S.D., n = 4). Two somata were successfully visualized with HRP (22 microns x 20 microns, 20 microns x 18 microns). Total lengths of labeled axons were 1260 and 1480 microns peripherally to the edge of the section, and 1810 and 770 microns centrally. Neither of the neurons had branching of the peripheral or central axons in the ganglion. PMID- 7845620 TI - Glutamate-induced deporalization in earthworm ventral nerve cord. AB - We investigated glutamate-induced neuron response in the ventral nerve cord of the earthworm (Eisenia foetida) using a voltage-sensitive dye-imaging technique. Isolated earthworm ganglia were stained by fluorescence voltage-sensitive dye, RH414, and voltage image was acquired by a conventional charge-coupled device (CCD) technique or a confocal laser scanning microscope. The fluorescence images before and during the glutamate stimulation was acquired and the relative fluorescence change was imaged as pseudo-color. Bath-applied glutamate (1 mM) depolarized many neurons on the ventral side, and in the three giant fibers on the dorsal side. PMID- 7845621 TI - Calcium wave propagation in the giant axon of the earthworm. AB - We examined a spatio-temporal pattern of intracellular free Ca2+ concentration in the giant axons of the earthworm, Eisenia foetida, with a fluorescent imaging technique using conforcal laser-scanning microscope and calcium indicator. 'Calcium Green 1'. Electrical tetanic stimulation applied to the nerve cord induced calcium waves along the giant axon. The calcium waves propagated both anteriorly and posteriorly with various speeds, and sometimes were split into several waves with different velocities. The results suggest that some types of calcium-releasing mechanisms may be associated with the calcium wave propagation. PMID- 7845622 TI - Uncoupling of the pineal melatonin synthesis of rats from the circadian regulation. AB - We show that the pineal melatonin synthesis of rats can be uncoupled from the circadian regulation by exposing the animals to abnormally long light periods. Male rats were kept 7 days under 22.5/1.5-h light/dark conditions and then exposed to darkness at different times of the day. After a 60-min dark exposure, the melatonin synthesis increased independently of the time of the day (Expt. 1). During 22 h in darkness, the mean melatonin content did not return to the low daytime level (Expt. 2). A dark-induced, time-independent increase of melatonin was also found after the rats had been 3-7 days under constant light (Expts. 3 and 4). PMID- 7845623 TI - Neuropathological phenotype and 'prion protein' genotype correlation in sporadic Creutzfeldt-Jakob disease. AB - A systematic study of 'prion protein' genotype in cases of sporadic Creutzfeldt Jakob disease showing amyloid plaques staining with anti-prion protein antibody has been performed. This revealed a relative excess of cases with valine at position 129 of the gene's open reading frame. The observation emphasises the importance of this site of common polymorphism in influencing the neuropathological phenotype in human spongiform encephalopathy. PMID- 7845624 TI - Penetration of interleukin-6 across the murine blood-brain barrier. AB - Interleukin-6 (IL-6) can alter brain function after peripheral administration, suggesting that it, like IL-1 alpha, IL-1 beta and TNF-alpha, might be able to cross the blood-brain barrier (BBB). We used multiple-time regression analysis to measure the unidirectional influx constant (Ki) into brain of radioactively labeled murine and human IL-6 given i.v. Ki values ranged from 3.05 to 4.54 (10( 4)) ml/g/min and were inhibited by unlabeled IL-6 but not IL-1 alpha or TNF alpha, showing that the transport system for IL-6 is distinct from those for IL-1 alpha and TNF-alpha. Approximately 0.2% of the dose injected i.v. entered each gram of brain. The capillary depletion method showed that most of the IL-6 taken up by brain entered the parenchyma. However, only approximately 16% of the radioactivity recovered eluted as intact I-IL-6 in brain and approximately 50% in CSF after chromatographic separation by HPLC/Sephadex. The efflux rate for IL-6 injected into the lateral ventricle of the brain suggests that it enters the blood with the reabsorption of CSF. These results suggest that blood-borne IL-6 can reach sites behind the BBB, but that susceptibility to enzymatic degradation may limit contact time within the CNS. PMID- 7845625 TI - Shortening of a severed squid giant axon is non-uniform and occurs in two phases. AB - The shortening of severed squid giant axons (GAs) in vitro was analyzed using video light microscopy. Axonal shortening occurred in two temporal phases along the length of the GA: a rapid initial phase during the first 3.5 min after severance followed by a slower phase lasting at least 30 min. The rate of shortening was greatest near the cut end and declined with distance from the cut end for at least 30 min after transection. Axonal shortening may help pack injury induced vesicles [3] which facilitate sealing of the cut end [7] and/or retard the entry of various substances. PMID- 7845626 TI - The adult human cerebellum is a target of the neuroendocrine system involved in the circadian timing. AB - In an investigation aimed at comprehensive mapping of the adult human brain with respect to receptor sites for the pineal hormone melatonin, we consistently observed specific binding in the cerebellum. Autoradiography and in vitro binding analysis with 125I-labeled melatonin were used to examine the location and the properties of these binding sites. In all cerebellar lobes, highest-density specific binding was localized to the external zone of the molecular layer. The binding was rapid, saturable, displaceable, specific and of high affinity. Physiological concentrations of NaCl decreased the affinity, while presence of calcium ions promoted it. The non-hydrolyzable GTP analog, GTP gamma S, inhibited binding in a dose-dependent manner and provoked a shift towards low affinity. The results strongly suggest that these binding sites may be functional melatonin receptors, and indicate that the adult human cerebellum is a target of melatonin, the pineal hormone involved in the control of the circadian timing. PMID- 7845627 TI - Phenotypic changes of AADC-only immunopositive premammillary neurons in the brain of laboratory shrew Suncus murinus by systemic administration of monoamine precursors. AB - After 5-hydroxy-L-tryptophan (5-HTP) and L-3,4-dihydroxyphenylalanine (L-DOPA) were injected i.p. in the laboratory shrew Suncus murinus, immunocytochemical and immunofluorescence studies were conducted on continuous or same sections of the brain, using specific anti-tyrosine hydroxylase (TH), anti-aromatic L-amino acid decarboxylase (AADC), anti-dopamine (DA) and anti-serotonin (5-HT) antisera which were produced in our laboratory. The results of double-staining by the immunofluorescence method as well as immunoelectron microscopy strongly indicate that the cells of the premammillary nucleus of the laboratory shrew brain (AADC only-positive neurons) are capable of synthesizing DA and 5-HT simultaneously upon simultaneous administration of L-dopa and 5-HTP. PMID- 7845628 TI - Excitatory somato-sympathetic reflexes are relayed in the caudal ventrolateral medulla in the cat. AB - The caudal ventrolateral medulla (CVLM) modulates sympathetic outflow from the rostral ventrolateral medulla (RVLM). We studied the possible role of the CVLM in the transmission of excitatory somato-sympathetic reflexes in baro- and chemoreceptor denervated chloralose-anesthetized cats. Neurotoxic doses of kainate, injected in the CVLM, caused marked increases in baseline sympathetic nerve activity (SNA) and arterial blood pressure (BP). Concomitantly, excitatory somato-sympathetic reflex responses evoked by electrical stimulation of the 4th intercostal nerve disappeared almost completely. Similar effects on SNA and BP but not on somato-sympathetic reflexes were observed when the GABA-antagonist bicuculline was injected in the RVLM. Bicuculline injected in the RVLM after kainate had no additional effects. These results suggest that in addition to a tonic GABA-ergic inhibition on the RVLM, the CVLM controls somato-sympathetic reflex transmission through interneurons located in this region. PMID- 7845629 TI - Sex differences in the behavioural response to persistent pain in rats. AB - The behavioural response to formalin-induced persistent pain was examined in male and female rats both unfamiliar and familiar with the test apparatus. Rats were subcutaneously injected with 50 microliters of formalin (10%) in the hindpaw and placed in the test cage (60 min). Licking and Flexing duration and Paw-Jerk frequency were recorded. Licking and Flexing lasted longer in females than males, while Paw-Jerk occurred in both sexes with comparable frequencies. Flexing and Paw-Jerk were lower in animals unfamiliar with the test apparatus. Therefore, behavioural responses to pain appeared to be affected by sex and familiarization with the experimental setting in different and independent ways. PMID- 7845630 TI - Sleep-associated variations in plasma renin activity and blood pressure in the rat. AB - Plasma renin activity (PRA) was determined in plasma samples obtained approximately at 6-min intervals during consecutive non-rapid eye movement sleep (NREMS) and rapid eye movement sleep (REMS) periods in rats chronically implanted with EEG electrodes, a brain thermistor, and an intracardiac catheter. PRA was low in REMS and high in NREMS: this difference was statistically significant. The PRAs in wakefulness and NREMS were not different. Sleep-associated variations in systemic blood pressure (BP) were also recorded in a group of rats implanted with a chronic aortic catheter. During REMS, large oscillations superimposed on a tonic rise in BP were observed, and the end of REMS was followed by an abrupt fall in BP. This is the first demonstration of sleep-associated variations in PRA in a species other than man. The changes in BP in the rat during REMS confirm previous reports and, unlike those in many other species, are similar to those previously described in humans. The rat therefore provides a model for study of the mechanisms of the sleep-related variations in PRA and BP. The changes in PRA may reflect a regulatory response to variations in BP or may result from central mechanisms, e.g. the sleep-associated changes in serotonergic activity. PMID- 7845631 TI - Modulatory effect of plasminogen on NMDA-induced increase in intracellular free calcium concentration in rat cultured hippocampal neurons. AB - The effect of plasminogen on the intracellular Ca2+ concentration ([Ca]i) was examined in cultured rat hippocampal neurons. Plasminogen (100 nM) did not increase [Ca]i in the presence of tetrodotoxin (TTX, 3 microM) but increased [Ca]i in the absence of TTX. In all the cells which responded to plasminogen (100 nM), NMDA (5 microM) also increased [Ca]i in the presence of TTX. Furthermore, plasminogen (100 nM) enhanced the NMDA-evoked [Ca]i increase, and the potentiation by plasminogen was blocked by an NMDA receptor blocker, 2-amino phosphonovalerate (APV). These data suggest that plasminogen enhances glutamate evoked [Ca]i increase through modulation of NMDA receptor in hippocampal neurons. PMID- 7845632 TI - Lidocaine protects hippocampal neurons against ischemic damage by preventing increase of extracellular excitatory amino acids: a microdialysis study in Mongolian gerbils. AB - Extracellular levels of amino acids in the hippocampal CA1 region of the gerbil were analyzed by a microdialysis-HPLC procedure. Transient forebrain ischemia produced significant increase in aspartate, glutamate, glycine and taurine (760%, 1070%, 190% and 1210%, respectively), and neuronal blockade by perfusion with a lidocaine (4 mM)-containing medium resulted in 67%, 79%, 58% and 59% reduction in the peak values of each amino acid, respectively. On the other hand, an intracerebroventricular administration of lidocaine, 0.8 mumol or more, produced a protective effect against delayed damage of hippocampal CA1 pyramidal cells, which was caused by bilateral carotid artery occlusion for 4 min. The results suggest that lidocaine may protect neurons against ischemic damage, by preventing the ischemia-induced rise of extracellular concentration of excitatory amino acid. PMID- 7845634 TI - Violence: a medical concern in New Jersey. AB - Violence claims attention as a leading public health issue. Violence, one of the leading causes of death and injury in young people, is a major determinant in driving up the costs of health care. This special issue addresses violence in New Jersey. PMID- 7845633 TI - Suppression of suprachiasmatic nucleus neurone activity with a vasopressin receptor antagonist: possible role for endogenous vasopressin in circadian activity cycles in vitro. AB - Neurones of the rat suprachiasmatic nucleus (SCN) were tested with [Arg8]vasopressin (AVP) and the AVP receptor antagonist, [d(CH2)5,d Tyr(OEt)2,Val4,Cit8]-vasopressin in vitro. 52% of AVP-responsive neurones showed an antagonist-induced decrease in activity, indicative of the presence of an endogenous excitatory tone. The magnitude of this effect declined significantly between subjective light and dark phases, consistent with the possibility that circadian fluctuations in endogenous AVP excitation contribute to the cycle of electrical activity within the SCN. However, similar fluctuations in basal activity between the light and dark phases was observed for both antagonist sensitive and -insensitive neurones, indicating that endogenous AVP was not the only factor determining the circadian cycle. PMID- 7845635 TI - Violence: changing the paradigm in New Jersey. AB - Physicians must assist in making violence a major statewide public health issue. The medical profession with its concern for patients has a natural interest in seeing that the victims of violence are treated effectively. Physicians must help uncover the root causes of violence. PMID- 7845636 TI - An ethical basis for concern about violence. AB - The medical profession must be committed to being proactive in the prevention of violence and its early recognition. In addition, physicians must work for a lasting cure for violence, because with their knowledge and compassion, doctors can help to solve this problem. PMID- 7845637 TI - Violence: a public health issue in New Jersey. AB - Violence should be viewed from biological, psychological, ethnological, and anthropological perspectives. Consideration of theories on biopsychosocial vulnerabilities and cultural and environmental factors have implications for diagnostic, therapeutic, and rehabilitative approaches. PMID- 7845638 TI - A domestic violence primer for clinicians. AB - Physician awareness of domestic violence is vital. Adult domestic violence should be distinguished from other types of violent behavior. This article defines domestic violence and offers physicians guidelines for identifying domestic violence victims in any clinical setting. PMID- 7845639 TI - A domestic violence primer for clinicians. AB - The authors offer clinical treatment strategies for domestic violence victims. Physician awareness, management, and referral can reduce morbidity and mortality. The major therapeutic goals are to increase the patient's safety, provide support, and offer options. PMID- 7845640 TI - Violence: homicide and suicide in New Jersey. AB - Homicide and suicide data are examined for trends, patterns, and relationships to the public perception of violence. While homicide rates in poor urban-blighted areas in New Jersey are abominably high, there is no epidemic. We cannot afford to ignore the underlying factors that lead to violence. PMID- 7845641 TI - What physicians can do about firearm violence and prevention. AB - The United States is experiencing an epidemic of firearm-related homicide and suicide, especially among teenagers. New epidemiological evidence on the risk of a gun in the home should lead further public policy efforts to address this major public health problem. PMID- 7845643 TI - Histopathological study of anterior segments of the eye with the intraocular lens in the posterior chamber. AB - We conducted a histopathological study of the anterior segments of the eye of a female who died 2 years after insertion of an intraocular lens (IOL), which had one end of the supporting loop inserted in the lens capsule bag and the other in the ciliary sulcus. No changes were noted in the iris and ciliary body located within the capsule. However, in the part in the ciliary sulcus, the iris root was bent towards the chamber angle and the trabecular meshwork was depressed. Moreover, the ciliary body exhibited hyaloid degeneration. A secondary cataract had formed in the periphery of the IOL. These findings suggest that the ideal site of IOL insertion might be within the capsule. PMID- 7845642 TI - Direct immunofluorescence and scraping conjunctival cytology in the study of 912 patients affected by microfollicular conjunctivitis. AB - 912 patients affected by microfollicular conjunctivitis were submitted to a scraping conjunctival cytology before taking specimens for direct immunofluorescence. 264 patients proved to be positive to the direct immunofluorescence test for Chlamydia trachomatis (CT). In all cases the infection turned out to be bilateral with different degrees of positivity between one eye and the other. In 43 patients out of the 264 positive ones, the cytological examination showed the presence of eosinophils in both eyes. The presence of eosinophils poses the problem of a certain allergizing power of Chlamydia and of the possibility that the CT infection might easily develop in subjects with a preexistent allergic conjunctivitis. PMID- 7845644 TI - Possible correlations of ocular blood flow parameters with intraocular pressure and visual-field alterations in glaucoma: a study by means of color Doppler imaging. AB - The authors evaluated, by means of color Doppler imaging, the blood flow of the ophthalmic artery, ciliary arteries and central retinal artery in normal and glaucomatous subjects. In normals they found that flow velocities of all considered vessels progressively decline while resistivity indices increase with advancing age. In glaucomatous subjects there was a statistically significant reduction of the mean systolic peak flow velocity of the ophthalmic artery in comparison with normals. Glaucomatous eyes with uncontrolled IOP and with visual field worsening showed a statistically significant decrease in the end-diastolic flow velocities and an increase in the resistivity index values in ciliary arteries. PMID- 7845645 TI - Influence of topical anesthesia on tonometric values of intraocular pressure. AB - The air pulse noncontact tonometer provides a safe and reliable method for measuring intraocular pressure (IOP), and makes it possible to avoid topical anesthesia. Based on previous reports that suggested possible anesthetic-induced IOP variations, this study was undertaken to investigate with this procedure the influence of local anesthetics on IOP and of some topically used drugs that could modify IOP values. In 212 normal or glaucomatous patients who underwent IOP measurement with a noncontact tonometer, IOP was determined before and in the first minutes following instillation of one of four tested drugs, oxybuprocaine and betoxycaine, two topical anesthetics currently used in applanation tonometry, and indomethacin suspension and metipranolol as controls. No significant effect was observed when comparing IOP values successively measured with the air pulse tonometer or 1 min after instillation of indomethacin suspension and metipranolol. In contrast a significant decrease in IOP was observed 1 and 5 min after instillation of one drop of the local anesthetics oxybuprocaine (mean IOP: 15.53 mm Hg before, 14.77 mm Hg at the 1st minute; p < 0.001) and betoxycaine (16.06 mm Hg before, 15.70 mm Hg at the 1st minute; p = 0.023). This effect was observed at least to the 15th minute, and in some patients, the decrease in IOP reached 8 mm Hg. Metipranolol only decreased IOP significantly at the 15th minute as compared to initial values, which differed from IOP variations following topical anesthesia. This phenomenon could not be related to mechanical effects of repetitive IOP measurements or massage by eyelids secondary to corneal irritation by anesthetic eye drops.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845646 TI - Canaliculitis: difficulties in diagnosis, differential diagnosis and comparison between conservative and surgical treatment. AB - The most important clinical features of canaliculitis include a red, swollen eyelid in the area of the affected canaliculus, a unilateral conjunctivitis, a mucopurulent discharge and in some cases dacryoliths visible in the lacrimal punctum. Conservative therapy was found to be little effective: only 10% of the patients could be cured, 40% showed a recurrence after conservative treatment. 20 patients (50%) were treated by canaliculotomy: 16 of these were cured by this surgical treatment, 4 patients complained of epiphora, although diagnostic syringing showed free lacrimal pathways. The surgical treatment of canaliculitis in combination with conservative therapy yields far better results than conservative therapy alone. PMID- 7845647 TI - Hypotonic maculopathy after trabeculectomy with postoperative use of 5 fluorouracil. AB - We evaluated two patients who developed hypotonic maculopathy following trabeculectomy and adjunctive 5-fluorouracil injections. Both patients had ocular hypotony and decreased visual acuity following these injections. The first case showed marked choroidal foldings, retinal striae, increased retinal vascular tortuosity, engorgement and optic disc oedema. The second case had radial perifoveal retinal striae, increased retinal vascular tortuosity and engorgement. The first patient regained pre-operative visual acuity while the second case had a visual acuity of 20/25 without any intervention. Fundus changes were less marked 12 months after initial evaluation in both cases. Hypotonic maculopathy is a reversible complication of trabeculectomies with adjunctive use of 5 fluorouracil. PMID- 7845648 TI - Bilateral Acanthamoeba keratitis in a gas-permeable contact lens wearer. AB - Acanthamoeba keratitis is an uncommon but potentially devastating complication of contact lens wear that has been reported with increasing frequency since its first description in 1974. We describe a case of bilateral Acanthamoeba keratitis, which occurred in a 24-year-old man, wearing gas-permeable contact lenses. This is to our knowledge the first case of Acanthamoeba keratitis reported in Italy, and the fourth bilateral case reported in the literature. Medical therapy (carried out after the first week by a different institution, due to the absence of essential antiamebic drugs on the Italian market) was effective in stopping the progression of the disease. PMID- 7845649 TI - Time course of cytotoxic T lymphocyte activity after inoculation of herpes simplex virus into the anterior chamber of mice. AB - The time course of the activity of cytotoxic T lymphocytes (CTL) was studied after injecting herpes simplex virus (HSV) into the anterior chamber of C3H/He mice and compared with that following corneal inoculation. CTL activity in cervical lymph nodes was suppressed during the 14 days after the inoculation, while that in the spleen increased 2 days earlier compared with the activity after corneal inoculation. The difference between the peaks of CTL activity after inoculation via each route was not significant. Thus, CTLs from the spleen appear to play a role in the immune response defending mice against intraocular infection by HSV. PMID- 7845650 TI - An unusual orbital lesion: hepatoma metastatic to the orbit. AB - The authors describe a case of histologically proven orbital metastasis from a hepatic carcinoma in an 85-year-old patient with rapid onset of proptosis and visual loss. The clinical diagnosis of orbital metastatic lesion was established by standardized echography and CT scan. To the best of our knowledge, this is only the third histologically proven case of hepatoma metastatic to the orbit. PMID- 7845651 TI - Fungal keratitis due to Scopulariopsis brevicaulis in an eye previously suffering from herpetic keratitis. AB - In the case reported, herpes virus I after having caused relapsing keratitis in an eye promoted the formation of a severe corneal ulcer caused by Scopulariopsis brevicaulis, a saprophytic mycete found in soil, which only once has been described as the cause of keratitis in man. Scopulariopsis was identified microscopically after culturing the conjunctival secretion on Sabouraud dextrose agar medium, while DNA probe tests confirmed the absence of herpes virus I. Topical and oral administration of miconazole and scraping of the corneal infiltrate dispersed the infection. Subsequently local steroids were given to reduce the neovascularization, and a therapeutic contact lens was applied because of intercurrent corneal thinning. Three months after beginning antifungal therapy, the visual acuity had increased from 1/120 to 1/10. The case described confirms that S. brevicaulis can cause opportunist infections in a cornea previously damaged by a different agent. PMID- 7845652 TI - Optic disc cupping in arteritic anterior ischemic optic neuropathy. AB - Patients with anterior ischemic optic neuropathy due to giant cell arteritis are thought to develop optic disc cupping, resembling that seen in glaucomatous eyes, while such cupping does not seem to occur in nonarteritic anterior ischemic optic neuropathy. However, this remains controversial. We describe a patient with arteritic anterior ischemic optic neuropathy (the clinical diagnosis was confirmed with a biopsy from the temporal artery) who developed disc cupping within 4 months after acute episode. This patient never had elevated intraocular pressure, and prior to the acute event the optic nerve heads had had a normal appearance with a physiologic cup. PMID- 7845653 TI - No pigment deposition in a patient with advanced retinitis punctata albescens. AB - A 51-year-old woman had had night blindness since childhood and a progressive visual field defect. She was the product of a consanguineous marriage. The patient also exhibited numerous whitish-yellow punctate spots with no pigment deposition in her fundi, nonrecordable electroretinographic responses after 30 min of dark adaptation, and constricted visual fields bilaterally. We believe that our patient may be a case of retinitis punctata albescens without pigment. PMID- 7845654 TI - Improvement of Kearns-Sayre syndrome with controlled carbohydrate intake and coenzyme Q10 therapy. PMID- 7845655 TI - [Can rates of nosocomial infections be considered as quality indicators?]. AB - In the initial part of the article the efficacy of nosocomial infection control is discussed. It is established that no more than one third of nosocomial infections are preventable, but in practice hospitals are unlikely to achieve this prevention rate. Subsequently statistics on the rates of nosocomial infections in various countries are presented and the reasons are discussed why there are only estimated data available in Hungary. Then the technique of active nosocomial surveillance, a method accepted widely abroad for the collection of data is described. The use of this technique is still infrequent in Hungary. To clarify the relationship between the quality of medical care and the rates of nosocomial infections it would be appropriate that the majority of hospitals introduce some form of nosocomial surveillance. This would improve the effectiveness of nosocomial infection control and help to determine such optimal nosocomial infection rates which could serve as reliable indicators of the quality of medical care in hospitals. PMID- 7845657 TI - [Transcatheter embolization of the hypogastric artery as a hemostatic method in obstetrics and gynecology]. AB - Transcatheter embolization of the hypogastric artery and its branches (AHTE) is an effective procedure to identify the injured vessel and to stop the bleeding under angiographic guidance. In this work the author presents a review regarding the indications and technical performance of this method in the management of postpartum bleeding refractory to classical treatment. The advantages and place of the embolization are discussed as an alternative method compared to surgical hemostasis. AHTE in obstetric hemorrhage is a safe procedure compared to surgical ligation of the injured artery, especially in the cases of massive haematomas of the paravaginal and/or retroperitoneal space when local haemostasis is ineffective or impossible. The importance of the cooperation between gynecologist and radiologist, performing the adjuvant treatment has been emphasized. PMID- 7845656 TI - [Clinical aspects of IgA deficiency]. AB - The authors have carried out a retrospective study of 33 selective IgA-deficient patients. They have found the high frequency of respiratory infections, gastrointestinal (celiac disease, giardiasis), and also autoimmune-, allergic- and malignant diseases. They have called the attention to the variety of the clinical picture, the possible consequences of the haemo- and immunotherapy, as well as to the importance of the early diagnosis and examination of family members. PMID- 7845658 TI - [Thymostimulin in clinical practice]. AB - In insufficient function of bone marrow thymostimulin has an important role in the proliferation of haemopoetic cells, take part in the regeneration of lymphocytes, as well as in the normalisation processes of T lymphocytes. Its advantageous effect has been demonstrated in different viral infections, thus in herpes simplex, hepatitis B and C, as well as in AIDS virus induced diseases. It has also an important role in correction of the immunodeficiency of organism in various malignant diseases. PMID- 7845659 TI - [Menkes disease]. AB - The Menkes or kinky hair disease is a rare, sex-linked systemic disorder of the copper metabolism. It is lethal in the first three years due to cerebral and cerebellar degeneration. Apropos of their case the authors summarise the knowledge on the diagnosis, pathogenesis and therapy. PMID- 7845660 TI - [50th anniversary of the death of Gedeon Richter]. PMID- 7845661 TI - [Hungarian masters of pathological anatomy. Remembering Gusztav Scheuthauer]. PMID- 7845662 TI - [Multidrug resistance of testicular cancers. (Detection of P-glycoprotein and MDR1 gene expression and their clinical connection)]. AB - The most frequently reported alteration of multidrug-resistant cells is overexpression of a 170 kD glycoprotein (P-glycoprotein or P-170) encoding by the MDR1 gene family. Expression of the multidrug-resistance gene product P glycoprotein was screened in 55 untreated human germ cell testicular tumors using monoclonal antibody (C219) and immunoenzyme staining. In samples out of 17 seminomatous germ cell testicular tumors (SGCT) 2 seminomas, and out of 38 non seminomatous tumors (NSGCT) 20 carcinomas (15 teratomas, 4 embryonal carcinomas, 1 with Yolk sac differentiation and 1 embryonal rhabdomyosarcoma) showed high expression of P-glycoprotein. NSGCT-s, which are more refractory than seminomas to anticancer chemotherapy, frequently expressed P-glycoprotein. These immunohistochemically detected elevated P-170 expressions were correlated by the overexpression of MDR1 mRNA gene sequences. A relationship between clinical resistance and P-glycoprotein expression seems thus to exist in 4 teratomas 3 embryonal carcinomas, and 1 seminomas. A significant correlation (p < 0.02) between P-170 expression and clinical drug resistance in stage II-III germ cell testicular tumors could be demonstrated. The results suggest that a multidrug resistant phenotype may also occur and P-glycoprotein might contribute to drug resistance in testicular tumors. PMID- 7845663 TI - [Non-malignant cells in pleural fluid]. AB - Insufficient attention has been paid to the cytological examination of cellular elements of the pleural fluid besides or in the absence of tumour cells. 108 cases studied due to pleural fluid were selected. They were characterized by the following: 1. each had histological diagnosis established by either pleuroscopy or by pleural needle biopsy and 2. neither of the samples contained tumour cells. Relationship of the dominant cell type and the ethiology of the pleural fluid was analysed. In case of punctates rich in lymphocytes further cytopathological differentiation is possible, e.g. in case of tuberculotic origin the absence of large mesothelial cells with Giemsa-basophilic cytoplasm is rather characteristic. The use of bioptic methods in the clarification of the origin of pleural fluid is still indispensible. PMID- 7845664 TI - [Factitious hypoglycemia--Munchausen syndrome in diabetes mellitus]. AB - The medical history of a 43-year-old non-insulin-dependent diabetic patient is presented. The exact diagnosis of the cause of repetitive and severe hypoglycaemic episodes proved to be difficult. Finally, high serum insulin and low C-peptide values were found in peripheral venous blood during hypoglycaemia resulting in an elevated (> 1.0) molar ratio of insulin to C-peptide. The laboratory findings were assessed as consequences of surreptitious insulin administration. Factitious hypoglycaemia could be considered as a clinical manifestation of Munchhausen syndrome. Confronting the patient with evidences of surreptitious insulin injections, hypoglycaemic episodes abruptly discontinued to occur. PMID- 7845665 TI - [Clinical immunological features and interferon therapy in chronic hepatitis C]. AB - Clinical and immunological findings of 74 patients with chronic hepatitis C have been reported and experiences with interferon-alpha treatment of 31 patients are summarized. In addition, the first results of anti-HCV screening of blood donors are also briefly described. Transfusion in the history was noted in 69% of patients and the time, elapsed from the transfusion to the diagnosis was a mean of 7.15 +/- 8.1 years. Concerning the severity of the liver disease, chronic persistent hepatitis was established in 40%, active hepatitis in 45% and cirrhosis in 15% of the patients, respectively. Cholestasis was recorded in 32% of the cases. A significant elevation of serum immunoglobulin levels was noted in 83%, an antibody to liver specific protein (anti-LSP) has occurred in 80%, cryoglobulinaemia in 44% and circulating immune complexes in 33% of the patients. Natural killer cell activity of peripheral blood mononuclear cells significantly decreased. HLA B8 and DR3 antigens were found with elevated frequency (36.6% and 42.1%). Recombinant interferon-alpha at a weekly dose of 3MU thrice, for six months, has normalized serum alanine aminotransferase in 45% of patients and a sustained remission was found in 26%. The treatment resulted in the clearance of HCV-RNS from the serum in 40% of patients and that well correlated with the complete remission. In the good responders, a decrease in CD4+ cell count and a moderate decrease in CD8+ cell count as well as a transient rise in B cell count were seen during the treatment. Mitogen-induced lymphoproliferative response and natural killer cell activity increased. Predictors of response were as follows: female sex, shorter time elapsed from transfusion, absence of HLA, A1, B8, DR3 and serum anti-HBc negativity. Anti-HCV has been found in 0.33--0.38% of blood donors screened, and it is suggested, that a liver disease accompanied with elevated serum alanine aminotransferase, may be present in about 25-30% of anti HCV positive symptom-free persons. PMID- 7845666 TI - Products of alternatively spliced transcripts of the Wilms' tumor suppressor gene, wt1, have altered DNA binding specificity and regulate transcription in different ways. AB - The Wilms' tumor susceptibility gene, wt1, encodes a transcription factor of the zinc finger protein family. Mutations in the WT1 gene product have been detected in both sporadic and familial Wilms' tumors, suggesting that alterations in WT1 may disrupt its normal function as a transcriptional regulator. The transcripts of wt1 are alternatively spliced; however, roles of the alternatively spliced forms have not been defined. The major transcript of wt1 encodes a WT1 protein [WT1(+KTS)+17AA] that contains three amino acids (+KTS) between the third and fourth zinc fingers and a serine-rich, 17 amino acid (+17AA) domain N-terminal to the zinc finger region. We now show that the WT1 (+KTS) forms functionally bind to a unique G+C-rich sequence within the PDGF A-chain promoter. We also show that WT1 (+KTS)+17AA functions as a strong transcriptional repressor and that +17AA alone fused to the zinc-finger domain of WT1 or to the heterologous DNA binding domain of GAL4 functions independently as a repressor. Deletion of four serine residues within +17AA abolishes the repressor activity of +17AA. These results indicate that wt1 products with +17AA contain an additional dominant repressor domain and that the presence or absence of +KTS determines alternative DNA binding specificity. PMID- 7845667 TI - Multiple domains mediate transformation by the Ewing's sarcoma EWS/FLI-1 fusion gene. AB - The (11;22) chromosomal translocation found in Ewing's sarcoma and related tumors fuses the amino terminus of the EWS protein to the DNA-binding domain of the FLI 1 transcription factor. In contrast to normal FLI-1, the EWS/FLI-1 fusion transforms NIH3T3 cells and this activity requires both EWS and FLI-1 sequences. Reporter gene assays showed that the portion of EWS fused to FLI-1 encodes a strong transcriptional activation domain. To determine whether this function is necessary for transformation by EWS/FLI-1, deletion analysis of EWS was performed. We found that the EWS domain could be functionally subdivided into two regions: (i) an amino terminal domain (domain A) which transforms efficiently when fused to FLI-1 but has little transactivation activity in a model system and (ii) a distal region (domain B) which transactivates efficiently but transforms less efficiently when fused to FLI-1. Replacement of the EWS domain with known heterologous transcriptional activation domains yielded chimeric FLI-1 fusions that in some instances could transform NIH3T3 cells. Finally we demonstrate that EWS/FLI-1 and related FLI-1 chimeras are able to cooperate with another transcription factor to activate a model reporter gene. These results further demonstrate that EWS/FLI-1 is an aberrant transcription factor and suggest that the EWS domain mediates important protein-protein interactions with other factors resulting in the transcriptional modulation of target genes. PMID- 7845668 TI - Suppression of tumorigenicity of breast cancer cells by transfer of human chromosome 17 does not require transferred BRCA1 and p53 genes. AB - A number of candidate tumor suppressor genes located on the human chromosome 17 are thought to have a role to play in the development of breast cancer. In addition to the p53 gene on 17p13.1 and the BRCA1 gene mapped to 17q12-21, other chromosomal regions for tumor suppressor genes have been suggested to exist on 17p13.3 and both the central and the distal parts of 17q, although definitive functional proof of their involvement in breast cancer tumorigenesis is still lacking. In this report we show that microcell transfer of a human chromosome 17 into wild-type p53 breast cancer cells CAL51 results in loss of tumorigenicity and anchorage-independent growth, changes in cell morphology and a reduction of cell growth rates of the neo-selected microcell hybrids. In the hybrid cells, which express the p53 wild-type protein, only the p- and the distal parts of the q arm of donor chromosome 17 are transferred. Thus, our results provide functional evidence for the presence of one or more tumor suppressor gene(s) on chromosome 17, which are distinct from the p53 and the BRCA1 genes. PMID- 7845669 TI - Cell-specific modulation of the papovavirus promoters by tumor-suppressor protein p53 in the absence of large T-antigen. AB - The oncoproteins from several DNA tumor viruses form a complex with p53 and inactivate its function. Wild-type p53 is a transcription factor and can regulate eukaryotic promoters both positively and negatively. To elucidate the basis of the opposing functions and to understand whether and how oncoprotein synthesis in papovaviruses is regulated by p53, we studied modulation of the early promoters of SV40, polyomavirus and BK virus in the absence of the interfering effect of viral large T antigens. We here show that murine p53 can regulate the viral promoters either positively or negatively depending on the cell type. A temperature-sensitive mutant p53, 135 Val, at 37 degrees C also showed a cell specific effect. These results suggest that promoter activation by p53 is not solely determined by p53 binding site, but host factors modulate p53's transactivation function. A TATA-less polyomavirus late promoter was also repressed in HeLa cells and the level of repression was much less in the presence of active early promoter. As p53 and 135 Val were overexpressed to similar extent in different transfected cell lines, variation in transactivation function is not due to the difference in the level of expressed protein. Our observations thus suggest that p53 interactions with cellular factors in addition to the TATA binding protein (TBP) are important for activator and repressor functions of p53. Well-defined viral promoters could thus provide us with an important tool for the identification and characterization of cellular factors that modulate p53-binding dependent gene regulation in animal cells. PMID- 7845670 TI - The domain of p53 required for binding HPV 16 E6 is separable from the degradation domain. AB - The E6 proteins of specific cancer-associated human papillomaviruses (HPVs) complex with and mediate degradation of the cellular anti-oncogene p53 in vitro. A critical property of p53 is its ability to stimulate transcription from promoters containing its recognition sequence. HPV E6, mutant p53 proteins, and several DNA tumor virus oncogenes inhibit the transcriptional activity of wild type p53. In this report, the structural requirements for the interaction between HPV 16 E6 and p53 were examined both in vivo and in vitro. p53-stimulated transcription was efficiently inhibited by wild-type HPV 16 E6 and E6 mutants competent for p53 binding and degradation. A series of p53 deletions and hybrid proteins with heterologous DNA binding, dimerization and transactivation domains were analysed for transcriptional interaction with HPV 16 E6 to determine the domains of p53 required for transcriptional inhibition. These chimeric proteins were also analysed for E6 binding and E6-mediated degradation in vitro. In both assays, complex formation with E6 was mediated through the amino-terminal 345 amino acids of p53 without a specific requirement for its C-terminus. Hybrid proteins containing residues 161-345 of p53 also bound E6, but this segment of p53 was not susceptible to E6 induced proteolysis. A second region of p53, within its N-terminal 160 aa, is required for E6 induced degradation of complexed p53. Taken together, these results suggest that the complex formation between E6 and p53 is not mediated through the C-terminus of p53 and that binding and degradation are separable. PMID- 7845671 TI - A biological role for Egr-1 in cell survival following ultra-violet irradiation. AB - The response to ultra-violet (u.v.) irradiation varies among cells, but commonly involves the rapid increase in expression of one or more transcription factors. The specific roles of this increased expression are largely unknown. We show here that in mouse NIH3T3 cells, Egr-1 expression is increased two-fold 10 min after u.v. irradiation, rises to a maximum (eightfold induction) after about 2 h and then declines. The expression of p53 protein is also strongly induced but is maximal between 2 to 4 h before declining. In contrast, the expression of c-Fos, and C-Jun proteins are only slightly affected by u.v. The Egr-1 response is independent of the growth state of the cells but depends on tyrosine kinase and protein kinase C activities. c-Ha-Ras is also involved in the induction of Egr-1 in u.v. irradiated cells. Evidence presented suggests that the mechanism for the response involves oxidative stress rather than DNA damage. We show that Egr-1 functions in the protection of cells against u.v. damage since NIH3T3 cells that constitutively express antisense Egr-1 and consequently cannot produce an Egr-1 response to u.v., grow at a rate 26% less than similarly irradiated parental cells and 36% less than nonirradiated parental cells. This is the second protective role described for Egr-1. PMID- 7845672 TI - Molecular cloning and chromosomal localization of the human homologue of a B lymphocyte specific protein tyrosine kinase (blk). AB - A cDNA encoding the human homologue of the murine protein tyrosine kinase, blk, has been cloned from a human B-lymphocyte cDNA library by cross-species hybridization using the murine blk cDNA as a probe. The sequence of the 2608 bp human blk cDNA clone contains an open reading frame encoding a predicted 505 amino acid protein with SH3, SH2 and catalytic domains that contain consensus sequences of the src protein tyrosine kinase family. Comparison of human and murine blk sequences indicated that they share 86% amino acid identity, the most conserved region being the catalytic domain (93% identity). Like the murine blk gene human blk is expressed only in B lymphocytes. The human blk gene was mapped to chromosome 8 at p22-23. PMID- 7845673 TI - The yeast homologue YTIS11, of the mammalian TIS11 gene family is a non essential, glucose repressible gene. AB - The murine TIS11 primary response gene is rapidly and transiently induced in response to many extracellular signals. A CX8CX5CX3H sequence is present twice in the TIS11 protein, in two additional murine proteins, TIS11B and TIS11D, that share regions of strong sequence conservation with TIS11, and in a Drosophila homologue (DTIS11). Although immunolocalization of TIS11 protein to the nucleus and zinc binding have lead to the speculation that the TIS11 family proteins are transcription factors, no function for these proteins has yet been clearly determined. We have now identified a TIS11 homologue, YTIS11, from Saccharomyces cerevisiae. The Ytis11p protein conserves both the two putative zinc finger CX8CX5CX3H sequences and the spacing between them, as well as additional amino acids in this region. The amino terminal 169 amino acid portion of Ytis11p protein, which contains a large number of acidic amino acids, can serve as a transactivator when fused to the Gal4 DNA-binding domain. Expression of the YTIS11 gene is not induced in response to DNA damaging agents, heat shock, sporulation conditions, or mating factor. However, YTIS11 expression is subjected to rapid glucose repression. Disruption of the YTIS11 gene in the M12B strain of Saccharomyces cerevisiae does not effect viability, growth in rich or synthetic medium, mating, or spore formation. However, YTIS11 gene disruption causes an alteration in metabolism that is reflected by a pH color change when cells are grown on YP plates supplemented with 2% glucose. Overexpression of murine TIS11 or TIS11B proteins dramatically attenuates the growth of both ytis11 and wild type yeast. PMID- 7845675 TI - A novel point mutation in the tyrosine kinase domain of the RET proto-oncogene in sporadic medullary thyroid carcinoma and in a family with FMTC. AB - Germline mutations within one of six codons of the RET proto-oncogene account for the majority of cases of multiple endocrine neoplasia (MEN) type 2A and type 2B and familial medullary thyroid carcinoma (FMTC). MEN 2A and FMTC mutations characterised thus far occur exclusively in the cysteine-rich domain of the extracellular region of RET. We now report a missense mutation in the intracellular tyrosine kinase domain of RET in the germline of a family with FMTC that does not have a cysteine codon mutation. In this family, the mutation, which alters GAG (Glu) to GAC (Asp) at codon 768, segregates with the FMTC phenotype. The same mutation was also detected in sporadic MTC but not in corresponding constitutional DNA, confirming that it is likely to be of pathological significance rather than a rare polymorphism. PMID- 7845674 TI - Increased transforming activity of JunB and JunD by introduction of an heterologous homodimerization domain. AB - The closely-related proteins c-Jun, JunB and JunD form a family of transcription factors which require dimerization for DNA-binding and transcriptional activity. Dimerization is mediated by a conserved amphipathic alpha-helix located adjacent to a highly charged DNA-binding domain. The Jun proteins can form both homo- and heterodimers within the Jun family and can also cross-dimerize with the Fos proteins. When expressed at high levels in primary chicken cells, each mouse Jun displays distinct transforming capacities: c-Jun transforms efficiently, JunB transforms poorly, and JunD does not transform at all. The composition of the transforming dimers, however, is unknown. To study the activity of Jun-Jun homodimers we constructed artificial derivatives, denoted Juneb1, in which the naturally occurring dimerization domain has been replaced by an heterologous homodimerization domain from the Epstein-Barr virus transcription factor EB1. These derivatives were introduced into chicken cells and assayed for their ability to affect growth. Unexpectedly, all three Juneb1 proteins conferred a transformed phenotype to primary cultures, promoting sustained growth in low serum medium and colony formation from single cells in agar. These data demonstrate that when forced to accumulate as homodimers, both JunB and JunD can transform cells. They also suggest that the poor transforming activity of JunB and the absence of transforming activity of JunD may be due to their inability to accumulate to high levels as homodimers. PMID- 7845676 TI - Post-transcriptional regulation of the p53 tumor suppressor gene during growth induction of human peripheral blood mononuclear cells. AB - Regulation of p53 gene expression at the post-transcriptional level was investigated during growth induction of human peripheral blood mononuclear cells (PBMCs). Freshly isolated PBMCs, which are in the Go phase of the cell cycle, were shown to express low levels of p53 mRNA that was rapidly degraded with a half life of 1 h. The rapid decay of p53 mRNA in quiescent PBMCs was dependent on global protein synthesis as treatment with cycloheximide resulted in stabilization of the p53 message. PBMCs were stimulated to enter the cell cycle by treatment with a combination of the mitogenic lectin phytohemagglutinin (PHA) and phorbol ester (TPA). Progressive stabilization of the p53 message occurred in PBMCs during growth induction. By 24 h of incubation in the presence of PHA and TPA, the half life of p53 mRNA was 6 h and p53 mRNA steady state levels were increased 4.5 to 5.0-fold. p53 protein was not detected in quiescent PBMCs, but was readily detected in PBMCs stimulated for 24 h with PHA and TPA. Stabilization of p53 mRNA was observed in PBMCs treated with either PHA or TPA, but to a lesser degree than when PHA and TPA were used as co-stimulants. These results indicate that differential degradation of p53 messenger RNA occurs in quiescent vs mitogen stimulated PBMCs and suggest that post-transcriptional regulation importantly contributes to increased p53 mRNA steady state levels as PBMCs enter the cell cycle. PMID- 7845677 TI - Mutational hot spots within the carboxy terminal region of the LMP1 oncogene of Epstein-Barr virus are frequent in lymphoproliferative disorders. AB - We have recently identified in Epstein-Barr virus (EBV) positive Hodgkin's disease (HD) a variant of the latent membrane protein 1 (LMP1) oncogene characterized by four point mutations and a 30 base pair deletion. These findings led us to test whether such mutants were also present in other lymphoproliferative disorders (LPD). We analysed 98 EBV DNA positive cases (67 LPD, 15 benign conditions, 16 lymphoblastoid cell lines) by PCR for deletions within the LMP1 gene. DNA sequencing of the region coding for the carboxy terminal protein domain was performed on 24 cases. In 13 cases the same combination of 4 point mutations at positions 168,320, 168,308, 168,295 and 168,225 was identified. Of these cases, 12 had an additional point mutation at position 168,357 and eight at position 168,355, and nine had a 30 base pair deletion including nucleotides 168,285 to 168,256. These deletion mutants were identified in HD, angioimmunoblastic lymphadenopathy, B-immunoblastic lymphoma, peripheral T-cell lymphoma, and two lymphoblastoid cell lines. Our findings reveal a high frequency of non-random point mutations at preferential sites within the 3' (carboxy terminal) region of the LMP1 oncogene. The association of these mutational hot spots with LPD suggests that they are involved in EBV related lymphomagenesis and that they define a clinically relevant EBV strain. PMID- 7845678 TI - Transcriptional regulation of the c-fms (CSF-1R) proto-oncogene in human breast carcinoma cells by glucocorticoids. AB - Expression of the macrophage colony stimulating factor CSF-1 and its receptor, the c-fms proto-oncogene, has been observed in macrophages, trophoblast and in a variety of neoplasms of epithelial origin including those of the breast. We have reported earlier (Oncogene, 1991, 6: 941-952) that c-fms transcript and protein expression were dramatically increased in several breast carcinoma cell lines by glucocorticoids which are essential humoral regulators of normal mammary epithelial cell differentiation. In this communication, we demonstrate that levels of c-fms transcript and protein increased significantly within the first few hours of glucocorticoid treatment, and that these increases were completely abolished by pretreatment of cells with mifepristone (RU486). We also demonstrate that such early increases in c-fms transcript levels could not be attributed to prolongation of transcript half-life. Both promoters of the c-fms gene were found to exhibit some basal activity in breast carcinoma cell lines and both were stimulated 2-3-fold by glucocorticoids. However the first promoter was shown to be responsible for more than 95% of the observed c-fms transcription. Sequence upstream of both promoters was found to contain potential 'glucocorticoid response elements' (GREs), and in each case, elimination of the GRE closest to the promoter abolished glucocorticoid stimulation. Our observations suggest that one mechanism by which glucocorticoids regulate the proliferation and differentiation of neoplastic mammary epithelial cells is through their regulation of transcription of the gene for the receptor of a ubiquitous cytokine, CSF-1. PMID- 7845679 TI - Induction of the mitogen-activated p70 S6 kinase by adenovirus E1A. AB - Adenovirus E1A proteins can transform primary cells in culture in conjunction with other oncogenes, such as E1B or activated ras. The modulation of various cell cycle regulators by E1A is thought to be involved in this transformation process. In this paper we show that E1A enhances the expression of the mitogen inducible p70 S6 kinase (p70s6k), a kinase which is essential for G1 progression. p70s6k mRNA and protein levels are enhanced 3-4-fold in various E1A-expressing cell lines. Similarly, the activity of p70s6k is enhanced in E1A-expressing cells in a manner partially independent of enhanced expression of p70s6k. The induction of p70s6k correlates with the presence of conserved region 1 (CR1) of E1A and with morphological transformation by E1A. These results suggest that induction of p70s6k by E1A might be involved in transformation by E1A. PMID- 7845681 TI - Structural and kinetic analysis of p53-DNA complexes and comparison of human and murine p53. AB - Sequence-specific DNA binding by p53 is dependent upon protein conformation. The 1620+ form correlates with wild type p53 suppressor function and is a prerequisite for binding to the DNA consensus p53-CON in vitro. It has been reported that murine p53 changes conformation on interaction with high affinity DNA target sequences and in the present study we have analysed p53-DNA complexes using conformation-specific monoclonal antibodies against p53. For murine p53 (mp53) we show (i) the 1620+ form is retained and stabilised in complex with DNA, and (ii) the complexes are dissociated by the PAb1620 monoclonal antibody. In contrast, PAb1620 did not detect nor dissociate human p53-DNA complexes nor did it interfere with complex formation. In competition experiments murine p53 replaced human p53 (hp53) in p53-DNA complexes and this correlated with the greater lability observed for hp53-DNA complexes at a given temperature. Mixed human-murine p53 oligomers were competent for DNA binding with an estimated affinity around 5 x 10(-10) M, similar to that observed for either human or murine p53 alone. The potential significance of these observations is discussed in relation p53 function in vivo. PMID- 7845680 TI - The Epstein-Barr virus latent membrane protein-1 (LMP1) mediates activation of NF kappa B and cell surface phenotype via two effector regions in its carboxy terminal cytoplasmic domain. AB - The Epstein-Barr virus (EBV) encoded latent membrane protein, LMP1, is oncogenic in rodent fibroblasts and is an essential effector protein in EBV-induced growth transformation of human B lymphocytes. Previous structure-function studies with LMP1 have relied largely on rodent fibroblast transformation as a functional readout, with apparently conflicting results. We have now analysed several LMP1 mutants in various human cell types, including B cells, T cells and epithelial cells, using two independent functional assays; (i) activation of NF-kappa B, and (ii) induction of two cell surface activation markers, CD54 and CD40. The results suggest that the cytosolic N-terminus is not essential for LMP1 function in any cell type studied. The third and fourth transmembrane helices and the intracytosolic loops are dispensable for activation of NF-kappa B, but they do influence the induction of CD54 and CD40. The major effector domain appears to be the cytosolic C-terminus in which were identified two 'C-terminal activating regions', CTAR-1 (residues 194-232) and CTAR-2 (residues 351-386). Whilst the exact results depended upon the host cell line, CTAR-2 was generally more important for activation of NF-kappa B, and both CTAR-1 and CTAR-2 were required for optimal induction of CD54 and CD40. Analysis of NF-kappa B activation by LMP1 in Rat-1 fibroblasts indicated that many mutations that were functional in human cells were poorly tolerated in the rodent cells; a result that is in broad agreement with published Rat-1 transformation data. PMID- 7845682 TI - Expression patterns of the novel receptor-like tyrosine kinase, DDR, in human breast tumours. AB - Using a reverse transcriptase-polymerase chain reaction based differential screening procedure, we have identified the discoidin domain receptor as a protein tyrosine kinase that is expressed in lymph nodes containing breast tumour metastases. By Northern blotting and in situ hybridisation we have demonstrated the expression of the discoidin domain receptor in human primary breast tumour samples, metastasis-containing lymph nodes and a number of normal tissues. Direct comparison of malignant breast and adjacent normal epithelial tissue revealed over expression in the tumour cells. PMID- 7845683 TI - A functional analysis of tumor suppressor activity for peripheral neuroepitheliomas by monochromosome transfer. AB - The microcell hybridization technique provides a powerful method for the identification and characterization of tumor suppressor genes. By introducing chromosomes from a normal human cell into a tumor cell, several studies have presented functional evidence for the presence of tumor suppressor activity. In order to map the location(s) of functional tumor suppressor gene(s) for peripheral neuroepithelioma (PNET) cells, we have used the microcell hybridization technique to transfer three individual human chromosomes into three different PNET cell lines, A673, SK-N-MC and TC32. We could not isolate microcell hybrids from one of the cell lines as the transferred chromosome tended to fragment upon transfer. Introduction of chromosome 13 into the remaining two cell lines caused a marked inhibition of in vitro and in vivo growth. Chromosome 11 appeared to harbor a functional tumor suppressor gene while transfer of chromosome 17 caused a suppression of growth in culture, presumably due to the presence of the p53 tumor suppressor gene. Thus, each cell line showed a different response to the introduction of normal genetic information suggesting diverse genetic abnormalities among these tumors of similar histological or origin. PMID- 7845684 TI - E6 and E7 expression from the HPV 18 LCR: development of genital hyperplasia and neoplasia in transgenic mice. AB - Human papillomavirus type 18 infection is highly associated with malignant tumors of the genital tract. To investigate the tissue specificity of the HPV long control region (LCR) and the transforming ability of the E6-E7 oncoproteins, an HPV-18 transgene containing the viral LCR and E6 and E7 genes was introduced into mice. Three founder males exhibited enlarged seminal vesicles and preputial glands by 50 weeks of age. A line of transgenic mice was established by in vitro fertilization, and subsequent generations of transgenic males and females were monitored for lesions. Approximately 80% of hemizygous transgenic males exhibited enlarged seminal vesicles and preputial glands as early as 12 weeks of age. Histological examination indicated that this enlargement was due to distension by fluid, along with polyploid hyperplasia of the lining secretory epithelium. E6 and E7 transcripts were limited to affected organs and kidney. Approximately 41% of transgenic females developed cervical neoplasms between 1-2 years of age. Histologically, tumors were mesenchymal rather than epithelial in origin. E6 and E7 transcripts were restricted to cervical tumor tissue and kidney. These findings suggest that the HPV-18 LCR has an element(s) which directs expression specifically to the urogenital tract in transgenic mice. PMID- 7845685 TI - Polymorphisms and probable lack of mutation in the WAF1-CIP1 gene in colorectal cancer. AB - WAF1/CIP1, a gene up-regulated by p53 encodes an inhibitor of cyclin-dependent kinases. Induction of WAF1/CIP1 in cells with intact p53 is believed to be instrumental in cell cycle arrest and apoptosis caused by DNA damage. In a model system, WAF1/CIP1 has been shown to have tumor suppressive activity. It is not known however whether WAF1/CIP1 is mutated in human primary tumors. Cells from colorectal cancer have been shown to acquire a series of genetic alterations, including frequent p53 mutations. Thus colorectal tumors, particularly those without identified p53 mutations, are good candidate to search for putative WAF1/CIP1 mutations. DNA extracted from 45 tumors, (including 28 tumors for which p53 mutations had previously been searched for and not found) were PCR amplified for exon 2 of WAF1/CIP1. A search for point mutations was performed in each amplified product using a denaturing gradient gel electrophoresis (DGGE) technique which enables the efficient screening of codons 9 to 139 (i.e. 80% of the WAF1/CIP1 coding sequence). Two different DNA variants were identified and shown to be present in constitutional DNAs of the corresponding patients. The first variant, a C to A transversion at codon 31, changes a serine for an arginine and was detected in eight tumors (18% of the cases). The second variant, detected in a single case (2%) is a silent A to T transversion at the third base of codon 91. DNA extracted from 70 unrelated members from the Centre d'Etude du Polymorphisme Humain (CEPH) was screened for these polymorphisms. The ser/arg polymorphism of codon 31 was detected in seven cases (10%) thus suggesting that it is not associated with a marked colorectal cancer predisposition. The polymorphism on codon 91 was not detected. Two additional variants (arginine to histidine at position 67 and threonine to methionine at position 80) were observed once each in the CEPH family members. Somatic mutation of the WAF1/CIP1 gene was not observed, indicating that, unless there are hot spots for mutations outside the screened region, this gene is not a frequent site of point mutation in colorectal cancer. PMID- 7845686 TI - Deregulation of genes encoding microfilament-associated proteins during Fos induced morphological transformation. AB - The mechanism of Fos-induced transformation is still poorly understood. In the present study, we have asked whether genes whose products play a role in determining cell morphology might become deregulated in the course of Fos-induced transformation. A clear up-regulation in Fos-transformed rat fibroblasts was seen with ezrin, as well as tropomyosin (TM) -3 and -5B, while TM-1 was down regulated. Significantly, the same genes were deregulated in a very similar, but hormone-inducible way in cells expressing a Fos-estrogen receptor fusion protein. In agreement with these results, Fos-expressing cells showed decreased levels of two TM isoforms of 36 and 38 kDa, and showed an impaired TM network. The significance of these observations is strengthened by the fact that the deregulation of TM expression has been shown to contribute to morphological transformation in other experimental systems. Deregulation of the TM and ezrin genes preceeds the induction of morphological transformation suggesting that this deregulation is not merely a consequence of transformation. On the other hand, deregulation follows the induction of direct Fos target genes. We therefore propose that a cascade of regulatory events is triggered by Fos oncoproteins which eventually leads to the deregulation of genes encoding cytoskeleton associated proteins. PMID- 7845687 TI - Distinct structural characteristics of discoidin I subfamily receptor tyrosine kinases and complementary expression in human cancer. AB - Mammary carcinoma kinase 10 (MCK-10) and colon carcinoma kinase 2 (CCK-2) constitute a subclass of receptor tyrosine kinases characterized by a discoidin I motif in the extracellular domain and a large cytoplasmic juxtamembrane (JM) region. While the ectodomain structure suggests a common role in cell aggregation, the JM domains of MCK-10 and CCK-2 are structurally most divergent and display features that suggest an involvement in signal generation and definition. MCK-10 occurs in at least three isoforms, which contain alternatively spliced consensus sequences for internalization and SH3 domain interaction. The presence of the 37 amino acid insert affects receptor autophosphorylation and changes ectodomain glycosylation. Proteolytic cleavage within the extracellular domain of MCK-10 generates a membrane-anchored kinase domain and releases a soluble ectodomain fragment including the discoidin I homology domain. CCK-2 and MCK-10 expression was found in connective and epithelial tissues, respectively, which in cancers of epithelial origin results in mutually exclusive expression in stroma and tumor cells, indicating a possible involvement of this class of RTKs in tumor invasion. PMID- 7845688 TI - MTS-1 (CDKN2) tumor suppressor gene deletions are a frequent event in esophagus squamous cancer and pancreatic adenocarcinoma cell lines. AB - MTS-1 is a candidate tumor suppressor gene on chromosome 9p21-22, a region frequently observed to have loss of heterozygosity in esophagus squamous cell carcinomas and pancreatic ductal adenocarcinomas. In order to determine whether MTS-1 sequences are deleted or mutated in cell lines derived from these cancers, we performed PCR amplification of MTS-1 exons 1 and 2. In this fashion, we found that 67% of esophagus squamous cancer cell lines have deletions of both exons 1 and 2, and 50% of pancreatic cancer cell lines have similar deletions. Furthermore, an additional 30% of pancreatic cancer cell lines harbored point mutations or microdeletions based on DNA sequencing. MTS-1 encodes p16, an inhibitor of cyclin-dependent kinase 4 (cdk4) which complexes with cyclin D1. Our data suggest that MTS-1 deletions and mutations may play an important role in the molecular pathogenesis of esophagus squamous cell and pancreatic cancers. PMID- 7845689 TI - Longitudinal study of visual functions in young insulin dependent diabetics. AB - The aim of this study was to compare the visual functions of a group of young insulin dependent diabetes mellitus patients (IDDMs), (n = 42) with an age and sex matched control group (n = 24). Examinations were carried out every 3 months for 2 years. There were no significant differences in visual acuity between IDDMs and control subjects. The IDDMs made significantly more errors with the desaturated D15 compared with the control group (P < 0.05). The contrast sensitivity for the IDDMs was lower at each spatial frequency compared with the control group, being significantly different from 3 c/deg and above (P < 0.05). A negative correlation was found between HbA1 and contrast sensitivity at 6 and 12 c/deg; as the HbA1 increased the contrast sensitivity decreased (P < 0.05). As the blood glucose level decreased, the colour vision deteriorated (P < 0.05). There was no significant difference between the visual performance of those IDDMs with retinopathy (n = 5) compared to those without. PMID- 7845690 TI - Non-contact tonometry: optometrists' current practice in England and Wales. AB - A survey of 133 optometrists who used a non-contact tonometer indicates that in only a half of patients tested were more than two readings per eye taken. Most optometrists made the number of readings conditional on the intraocular pressure (IOP) shown by the initial readings. About 1% of patients aged over 40 years were called back for a second IOP test. In a follow-up questionnaire with 90 respondents, only 24 (27%) stated that they had rechecked any patient by Goldmann applanation tonometry during the previous 6 months. Of these 90 optometrists, 20 (22%) had not had their tonometer serviced within the previous 24 months. It was concluded that, whilst non-contact tonometry makes a major contribution to glaucoma detection, improvements could be made in current practice which require little extra time. PMID- 7845691 TI - Screening for glaucoma: the time taken by primary examiners to conduct visual field tests in practice. AB - A panel of 101 primary examiners (optometrists or their ancillary staff) in England and Wales prospectively recorded the time taken to examine the central visual fields of each of 10 (or more) of their patients. The results indicate that the time depended not only on the test procedure but on how frequently the examiner conducted such a test. A basic test with semi-automated field screening equipment, applied routinely by 30 examiners on 547 patients, took an average 3.7 min per patient; (lower quartile 2.8 min). For such examiners, a standard extended test took 4.9 min. Similar times applied whether tests were conducted by an optometrist or an assistant. It was concluded that visual field screening in a normal population could reasonably be assumed to take an average 4 min per patient. PMID- 7845692 TI - Non-compliance in contact lens wear. AB - Non-compliance is emerging as a critical issue in the contact lens field. This problem has been studied at depth in general health care situations and is seen as the responsibility of both practitioner and patient (client) working in a health care partnership. The contact lens practitioner and patient present a specific case for the study of non-compliance in areas such as hygiene, solution use, appointment attendance and wearing times. From 40 to 91% of contact lens patients have been reported as non-complaint in the use of recommended care and maintenance regimens and many of these are confused or ignorant about their behaviour. In order to arrive at a general set of conclusions from the studies published to date, it is important to understand the methodology of each study, it purpose, the definition of non-compliance used and the way the results were analysed and described. This review summarizes the research into non-compliance in the contact lens field to data. A set of general conclusions is drawn and a model for compliance in the context of contact lens practice is proposed. PMID- 7845693 TI - Double-masked placebo-controlled trial of precision spectral filters in children who use coloured overlays. AB - We selected 68 children who reported benefit from individually chosen sheets of coloured plastic placed upon the page when reading, and who used these regularly without prompting. These children viewed text illuminated by coloured light in an apparatus that allowed the separate manipulation of hue (colour) and saturation (depth of colour), at constant luminance. Many of the children reported improvements in perception when the light had a chromaticity within a limited range, which was different for each individual. A pair of plastic spectacle lenses ('experimental' lenses) was dyed so as to provide the appropriate chromaticity under conventional white (F3) fluorescent light. An additional pair was prepared having very similar colour but with a chromaticity outside the range in which perception was reported to improve ('control' lenses). Each pair was provided for 1 month in random order. The children kept diaries (36 completed) recording symptoms of eye-strain and headache. The children and those responsible for their assessment were unable reliably to distinguish 'experimental' from 'control' lenses. Nevertheless, symptoms were less frequent on days when the 'experimental' lenses were worn (P < 0.003). PMID- 7845694 TI - Ophthalmic, health and social profile of guide dog owners in Northern Ireland. AB - Only 96 out of an estimated 28,000 registerable visually impaired persons, resident in Northern Ireland, currently make use of guide dogs for the blind. Results from this study indicate that guide dog owners represent a young, healthy and highly motivated subgroup of blind persons who have been profoundly visually impaired for prolonged periods of time. The implications of future ophthalmological developments, and of the educational and employment requirements of the visually impaired, are discussed. PMID- 7845695 TI - Changes in refractive trends and optical components of Hong Kong Chinese aged 19 39 years. AB - The distribution of refractive errors and its relationship to the optical components in 105 Hong Kong Chinese aged 19-39 years was studied. Myopia was most frequent (71%) in this population. The mean spherical equivalent was -3.00 DS. The trend of changes of the direction of refractive and corneal astigmatism from with-the-rule to against-the-rule with increasing age was shown. Significant correlations were found between age and anterior segment distance. Ultrasound examination showed that an increasing axial length was associated with higher myopia. Men had flatter corneal radii, but longer axial length. The prevalence of myopia in the Chinese population seems to be a new trend for the younger Hong Kong Chinese when compared with adults aged over 40 years. Thus the importance of genetics in determination of myopia is called into question by these findings. PMID- 7845696 TI - Changes in refractive trends and optical components of Hong Kong Chinese aged over 40 years. AB - The age trends of refractive errors, astigmatism and optical components were studied in 220 Chinese subjects aged over 40 years. Myopia did not dominate in this age group. With increasing age, the prevalence of hyperopia increases from 2% at age 40-45 years to 66% at age > 65 years. Against-the-rule astigmatism was more prevalent than the other types. Significant correlations were found between age and spherical equivalent power, age and vitreous depth and axial length. Sex differences were found among the optical components but not in the refractive error. Myopia appears to be more prevalent among the younger age groups than the older age groups of the Hong Kong Chinese population, and the importance of genetics in determination of refractive error is called into question by these findings. PMID- 7845697 TI - Hybrid diffractive-refractive achromatic spectacle lenses. AB - The possible utility of high-power hybrid achromatic spectacle lenses, each consisting of a contact combination of refractive and diffractive components, is considered. It is shown that such a combination can, in principle, minimize blur due to transverse chromatic aberration in high-power prescriptions such as those for aphakes and high myopes. The combination has essentially the same thickness and weight as a conventional singlet lens. Some practical problems relating to hybrid designs are discussed. PMID- 7845698 TI - Direction of gaze and comfort: discovering the relation for the ergonomic optimization of visual tasks. AB - Perceived exertion caused by the extraocular muscles was assessed as a function of the direction of gaze and recorded in 114 subjects using a psychometric method. The results confirm statements in the literature that maximum comfort is achieved when gaze is aimed downwards. We found no correlations between perceived exertion and age or viewing distance. The relationship is relevant to ergonomics, for example in lens fitting and workplace layout. PMID- 7845699 TI - Unilateral ocular vascular stress in man and retinal responsivity in the contralateral eye. AB - Autoregulation (AR), the capacity of retinal vessels to maintain a constant flow of blood during alterations in vascular perfusion pressure, has been studied by a variety of techniques. Psychophysical and electrophysiological procedures have been used as indirect measurements of the effectiveness of AR for maintaining normal visual function during altered ocular perfusion pressure (OPP) in a single eye. However, there have been no studies in normal subjects which have investigated the responsivity of the contralateral eye while the fellow eye undergoes transient vascular stress. In the present study, the components of the bilaterally recorded scotopic flash electroretinogram (ERG) were used as objective indices of visual neural function during transiently altered OPP. The principal finding was that a decrease in the OPP for the test eye was associated with a reversible attenuation of the retinal responsivity in that eye, and a supranormal oscillatory potential index in the contralateral eye. The existence of a central control mechanism, triggered at the eye level, may be responsible for this contralateral neural phenomenon. PMID- 7845700 TI - Effects of colour adaptation and stimulus size on the detection of chromatic deviations from achromatic as a function of eccentricity in man. AB - By using constant size and M-scaled stimuli (the stimulus size was magnified towards the visual field periphery in inverse proportion to the lowest local sampling density of the human retina) we measured the thresholds for perceiving the complementary colours of blue, green and red (i.e. yellow, purple or blue green) under chromatic adaptation at the eccentricities of 0-15 degrees in the nasal visual field. The CIE 1931 (x, y) chromaticity coordinates corresponding to complementary hue perception were subtracted from the chromaticity coordinates of achromatic threshold. The difference was found to be constant irrespective of stimulus size and eccentricity. This means that the perception of chromatic deviation from achromatic under chromatic adaptation is independent of stimulus size and eccentricity. PMID- 7845701 TI - Occupational testing of near vision. AB - The quality of near vision depends on distance visual acuity, accommodation capability and near vision correction, and cannot therefore be expressed in acuity values. Most near vision tests do not recognize this, and the lack in standardization should be mainly attributed to this fundamental shortcoming. A new test, the Priegel test, with a basically different conceptual basis is introduced. Its characteristics are discussed and a comparison with existing near vision tests is made. Consequences for legal testing are drawn. PMID- 7845702 TI - New range of stand magnifiers based on standardized image position. AB - Combined Optical Industries Ltd. of Slough, UK, have released a new range of illuminated stand magnifiers. These have been designed with a uniform emerging vergence and are specified in terms of equivalent power according to the new standards. This paper describes these magnifiers in terms of their measured optical and ergonomic properties. The expected enlargement ratios achieved with typical presbyopic additions are tabulated. PMID- 7845703 TI - Derivation of corneal flattening factor, p-value. AB - A mathematical equation was derived to calculate the corneal p-value based on the central and peripheral corneal radii and the corresponding semichord diameters. The calculation was simplified by a computer program written using GWBASIC. The accuracy of corneal p-value generated from this program was checked with Douthwaite's modified keratometer with good correlation. This program could be used to find out the corneal p-value and apical radius ro for any topographic keratometer which only provides central and peripheral radii without any information of the p-value and apical radius. PMID- 7845704 TI - Reinvention of visual fatigue: accumulation of scientific knowledge or neglect of scientific history? AB - The development of science is believed to be a continuous accumulation of knowledge, giving rise to the somewhat false idea that the most recent knowledge is the most valid and most appropriate. Neglect of the history of a scientific discipline might therefore lead to reinvention of theories that have already been proposed and experimentally investigated. In the case of visual fatigue the pioneering works of Lucien Howe, Walter Lancaster and others at the beginning of this century are very similar to contemporary work in terms of conceptual definitions, methodological approach, assessment and results. The temporal and dynamic aspects of accommodation and vergence considered important today were intensely studied and discussed by Howe and others. PMID- 7845705 TI - Comparing techniques for evaluating retinal/neural function behind cataract. PMID- 7845706 TI - Concomitant malaria (Plasmodium gallinaceum) and filaria (Brugia pahangi) infections in Aedes aegypti: effect on parasite development. AB - Mixed infections with malarial (Plasmodium gallinaceum) and filarial (Brugia pahangi) parasites were carried out in 8 trials with filaria susceptible (REFM) and filaria refractory (REP-RR) Aedes aegypti strains. A secondary infection with B. pahangi microfilariae (mff) by intrathoracic inoculation, reduced the development rate of a pre-existing P. gallinaceum infection. The level of reduction ranged from 9.5 to 49% in REFM and from 50 to 90% in REP-RR. An immune response against oocysts was seen as melanization in mosquitoes with a double infection in the strain refractory to B. pahangi (REP-RR) and a reduction in oocyst size in both mosquito strains. Melanization was not observed in mosquitoes infected only with P. gallinaceum. This may indicate that activation of the prophenoloxidase (PPO) cascade in response to mff in the haemolymph can also be addressed against oocysts in the midgut. No significant difference in the number of filarial parasites recovered was observed when comparing groups with a single or double infection. Retardation in development of filaria larvae was observed in mosquitoes with double infection (REFM strain), together with melanization and a higher rate of abnormal development. Nutritional deficiency caused by superinfection might also be responsible for the delay in filarial development and reduced oocyst size. PMID- 7845707 TI - Parasitic infection in malnourished school children: effects on behaviour and EEG. AB - This paper describes a study of 194 children (aged 9-13) from a mountain village in Ecuador who were infected with one or more species of intestinal helminth or protozoan parasite. In addition to parasite load, the assessment consisted of a battery of psychological and neuropsychological tests, an EEG examination, measures of iodine level, presence of goitre and level of nutrition. We found that, in general, parasite infection, as measured at the baseline level, was not associated with cognitive impairment. The intensity of infection with A. lumbricoides, however, was correlated with the level of verbal ability and with inhibition-control aspects of cognitive behaviour. Multivariate analysis with level of nutrition, EEG status and parasite burden showed a consistent main effect of the degree of nutrition on neuropsychological performance, particularly the language, problem solving and inhibition-control dimensions. PMID- 7845708 TI - Karyotype plasticity in neotropical Leishmania: an index for measuring genomic distance among L. (V.) peruviana and L. (V.) braziliensis populations. AB - A method for phenetic analysis of karyotype data has been developed for Leishmania populations. Measurement of size difference between chromosomes recognized by a given DNA probe in different isolates led to the formulation of a Chromosome Size Difference Index (CSDI). The method was applied to phenetic analysis of 4 sets of chromosomes--each set being recognized by a different probe -in 37 L. (Viannia) peruviana isolates sampled along a North-South transect through the Peruvian Andes and, in 11 L. (V.) braziliensis isolates from the Amazonian forest (Peru, Bolivia and Brazil). Karyotype variability was better accounted for by CSDI than by a method based on disjunctive encoding of karyotype data. CSDI evidenced the nature of relationships between L. braziliensis and L. peruviana and it provided a coherent picture of geographical and genomic differentiation among parasite populations. The latter did cluster according to their geographical origin. L. braziliensis was found karyotypically more homogeneous than L. peruviana. Within L. peruviana, Northern populations were closer to L. braziliensis than to Southern L. peruviana populations. The validity of karyotypic populations, or karyodemes, was sustained. PMID- 7845709 TI - Q fever (Coxiella burnetii) reservoir in wild brown rat (Rattus norvegicus) populations in the UK. AB - Seroprevalence of Coxiella burnetii, the causal agent of Q fever in humans, was examined in wild brown rat populations from 4 Oxfordshire farmsteads (n = 127), 9 Somerset homesteads (n = 98), and 1 captive enclosure (n = 88) in the UK. Seroprevalence ranged between 7 and 53%, the lowest being within the captive population and the highest on dairy farmsteads with sheep present. This is the first reported investigation of C. burnetii in wild rats outside India. We suggest that the high seroprevalence among rats (i) provides evidence that wild rats constitute an important reservoir for C. burnetii in the UK, and (ii) explains why cats, as frequent predators of rats, are so important in the epidemiology of this disease. PMID- 7845710 TI - Maltose utilization by extracellular hydrolysis followed by glucose transport in Trichomonas vaginalis. AB - The amitochondriate parasitic protist Trichomonas vaginalis can utilize either glucose or maltose as carbon and energy source. The mechanisms of maltose utilization were explored with uptake experiments using radio-isotope labelled maltose in combination with the silicone-oil centrifugation technique and enzymatic assays measuring maltose hydrolysis. The uptake of maltose label became saturated after 2-3 h. The uptake of maltose as a function of the external maltose concentration was linear at low concentrations with no further increase at higher levels, kinetics characteristic of reactions obeying Michaelis-Menten kinetics preceded by a diffusion-limited step. Increased viscosity of the medium resulted in decreased maltose uptake, indicating an extracellular location of the diffusion-limited step. Most of the cellular alpha-glucosidase activity of T. vaginalis was detected on the cell surface, suggesting that maltose is hydrolysed to glucose outside the cell. Glucose interfered more with maltose uptake, and maltose less with glucose uptake, than would be expected if 1 mol of maltose were the equivalent of 2 mol of glucose. This pattern of interaction indicated that the interference occurs before the common metabolic pathway and even before the transport step, supporting the idea of extracellular maltose hydrolysis. We conclude that maltose is hydrolysed to glucose in the boundary layer of the cell, a process akin to membrane digestion in vertebrate enterocytes and on the teguments of helminths. The glucose formed is then transported by the glucose carrier of the organism. PMID- 7845711 TI - Change of mate and mating competition between males of Schistosoma intercalatum and S. mansoni. AB - Previous studies on mating behaviour of Schistosoma intercalatum and S. mansoni, two human schistosomes which may overlap in parts of Africa, have shown that in mixed infections in mice there are no physiological barriers preventing heterospecific pairings. However, when choice is possible, matings occur preferentially between partners of the same species. In this paper, further experimental studies on mating behaviour of the two species were conducted. Sequential infections showed that heterospecific pairs of worms change partners to homospecific pairs when given the opportunity. The change of mate is a progressive process requiring up to, at least 8 weeks, and this phenomenon is due to the male worm seeking the appropriate female. S. mansoni males are better at pairing with females than S. intercalatum males, and they will change partner to pair with homologous females in preference to heterologous females whenever given the opportunity. Moreover, in the absence of S. mansoni female worms, unpaired S. mansoni male worms pull away female S. intercalatum from male S. intercalatum. It appears from this study that S. mansoni males are much more competitive than S. intercalatum males at pairing with females, and this is a disadvantage for S. intercalatum in situations of sympatry. PMID- 7845712 TI - Schistosoma mansoni: patterns of codon usage and bias. AB - Codon usage and bias has been examined in 20 genes of Schistosoma mansoni. Significant heterogeneity was detected in the patterns of codon usage and bias among genes by metric multidimensional scaling and three general indicators of bias (GC3S, Nc and B). In keeping with observations on sporozoan parasites, codon usage bias was observed to be dependent on the overall base composition of the genes analysed, which in turn was reflected in the types of codons that were over or under-represented in the sequences. PMID- 7845713 TI - Trypanosoma cruzi exoantigen is a member of a 160 kDa gene family. AB - During the chronic stage of Chagas disease a 160 kDa antigen appears in the blood of patients and remains detectable many years after the onset of the disease. This antigen is secreted by the trypomastigote form of the parasite while it is undetectable in the epimastigote form. We report here that the chronic 160 kDa exoantigen is encoded by a gene family (CEA 160 family). We describe the cloning and partial nucleotide sequence of a gene (CEA 160-1) belonging to the CEA160 family. Comparison of the gene sequence with other sequences present in the databases revealed homologies with several Trypanosoma cruzi surface antigens. Highest amino acid identity (59%) was with members of a family containing epitopes that mimic nervous tissues (Van Voorhis et al. 1993). Another related group (18-22% amino acid identity) comprises proteins of 85 or 160 kDa sharing an amino acid motif that is conserved among bacterial neuraminidases (Fouts et al. 1991; Pollevick et al. 1991; Kahn et al. 1991; Takle & Cross, 1991; Franco et al. 1993). The amino acid identities with the different antigens were not homogeneously distributed. Regions of higher identity (40-60%) were grouped in the central region of each protein. PMID- 7845714 TI - Inoculum size, incubation period and severity of malaria. Analysis of data from malaria therapy records. AB - The size of the infecting inoculum may influence the severity of malaria, but evidence is scarce. Malaria therapy records provide a unique source of information on induced malaria in people. The therapy was given to large numbers of neurosyphilis patients and the malaria was left untreated as long as possible. Data from patients treated at the Horton Hospital, Epsom 1923-60 with a single strain of vivax malaria were analysed to assess the influence of inoculum size on severity of disease. Malaria was induced by mosquito bite, blood inoculation or direct sporozoite inoculation. The different measures of inoculum size were inversely correlated with pre-patent period, as expected. Overall, information was available on a total of 563 non-immune patients who were not treated during the first 5 days of patent parasitaemia. No strong or consistent relationships were found between measures of inoculum size and any of the measures of severity used: neither parasitaemia levels, nor peak fevers, nor number of paroxysms of fever. In the largest data set, longer pre-patent periods were associated with tertian fever, spontaneous recovery and less use of modifying treatment. Difficulties in interpreting the results are discussed, particularly with respect to misclassification of both exposure and outcome variables. While an inoculum size-severity relationship cannot be ruled out, a strong relationship is very unlikely. PMID- 7845715 TI - Immune response profiles in vaccinated and non-vaccinated high- and low-responder mice during infection with the intestinal nematode Trichinella spiralis. AB - NIH and C57 BL/10 (B10) mice show genetically determined differences in their response to Trichinella spiralis infection. This study examines the influence of these on parameters of the immune response to infection after vaccination using muscle-larval excretory-secretory antigen in Freund's complete adjuvant. Serum antibody levels were greatly elevated when mice of both strains were vaccinated prior to infection; however, NIH produced significantly higher-level antibody responses than B10. Vaccination accelerated and increased the capacity of mesenteric lymph node T-cells to proliferate in vitro in response to specific antigen stimulation in both mouse strains but, in general, the stimulation indices of NIH cells were higher than those of the B10. The capacity of mesenteric lymph node cells (MLNC) and spleen cells (SC) to produce IL-5 and gamma IFN was measured after specific in vitro stimulation and early gamma IFN secretion was noted in the supernatants of NIH MLNC and SC, but not in B10 SC. Concentrations of IL-5 rose steadily over the first 10-14 days after infection in cell cultures from both strains. Prior vaccination of these animals appeared to enhance cytokine levels. It is postulated that the efficacy of vaccination in NIH mice is a consequence of their genetically determined capacity to produce early and high-level responses to the antigens of T. spiralis and to express these in intestinal effector mechanisms. PMID- 7845716 TI - Influence of environmental factors on the infectivity of Echinococcus multilocularis eggs. AB - The sensitivity of eggs of Echinococcus multilocularis to environmental and controlled laboratory conditions was tested. Egg material was exposed and the infectivity was subsequently monitored by in vitro activation and by oral infection of the natural host, Microtus arvalis. To study the impact of environmental conditions in an endemic area of south-western Germany, eggs were sealed into bags of nylon mesh and exposed to the natural climate during various seasons. The maximal survival time of eggs was 240 days in an experiment performed in autumn and winter and 78 days in summer. A study of the tenacity of eggs under laboratory conditions revealed a high sensitivity to elevated temperatures and to desiccation. At 45 degrees C and 85-95% relative humidity the infectivity was lost after 3 h as well as after 4 h exposure to 43 degrees C suspended in water. Exposure to 27% relative humidity at 25 degrees C as well as exposure to 15% relative humidity at 43 degrees C resulted in a total loss of infectivity within 48 and 2 h, respectively. Temperatures of 4 degrees C and of 18 degrees C were well tolerated (478 days and 240 days survival, respectively), whereas exposure to -83 degrees C and to -196 degrees C quickly killed off the eggs (within 48 h and 20 h, respectively). Eggs of E. multilocularis were not killed off by exposure to various commercially available disinfectants applied according to the manufacturers' instructions and by exposure for 24 h to low concentrations of ethanol. Irradiation with 40 krad. from a 137Caesium source prevented the development of metacestodes but allowed seroconversion of infected rodents. PMID- 7845717 TI - Localization of Diploptera punctata allatostatin-like immunoreactivity in helminths: an immunocytochemical study. AB - The nervous systems of helminths are predominantly peptidergic in nature, although it is likely that the full range of regulatory peptides used by these organisms has yet to be elucidated. Attempts to identify novel helminth neuropeptides are being made using immunocytochemistry with antisera raised against peptides isolated originally from insects. One of these antisera was raised against allatostatin III, a peptide isolated originally from the cockroach, Diploptera punctata, and a member of a family of related peptides found in insects. Allatostatin immunoreactivity was found throughout the nervous systems of Mesocestoides corti tetrathyridia, and adult Moniezia expansa, Diclidophora merlangi, Fasciola hepatica, Schistosoma mansoni, Ascaris suum and Panagrellus redivivus. Immunostaining was observed in the nerve cords and anterior ganglia of all the helminths. It was also apparent in the subtegumental nerves and around the reproductive apparatus of the flatworms, in neurones in the pharynx of D. merlangi, F. hepatica, A. suum and P. redivivus, and in fibres innervating the anterior sense organs in the nematodes. Immunostaining in all species was both reproducible and specific in that it could be abolished by pre absorption of the antiserum with allatostatins I-IV. These results suggest that molecules related to the D. punctata allatostatins are important components in the nervous systems of a number of helminth parasites, and a free-living nematode. Their distribution within the nervous system suggests they function as neurotransmitters/neuromodulators with roles in locomotion, feeding, reproduction and sensory perception. PMID- 7845718 TI - Age-prevalence and household clustering of Strongyloides stercoralis infection in Jamaica. AB - The epidemiology of Strongyloides stercoralis was studied in families of clinical (reference) cases and their neighbours at endemic foci in Jamaica. Thirteen foci were studied based on the place of residence of a reference case. For each household of a reference case, the 4 most proximal neighbourhood households (spatial controls) were included in the study. Out of 312 persons contacted 244 were followed up using questionnaires, stool examination and serology. Prevalence of infection based on stool examination was 3.5% and on ELISA 24.2%. Prevalence increased with age but was not related to gender. Reference cases were significantly older than the general study population. The prevalence of infection based on both serology and stool examination was significantly higher in reference than in neighbouring households (the reference cases, themselves, were not included in the analysis). Furthermore, prevalence of infection was highest among persons who shared a bedroom with a reference case and decreased significantly with increasing spatial separation. This is indicative of close contact transmission which has not been previously shown for a geohelminth, but which is common among microparasites. PMID- 7845719 TI - High failure rate of dapsone and pentamidine as Pneumocystis carinii pneumonia prophylaxis in human immunodeficiency virus-infected children. PMID- 7845720 TI - Hepatitis B vaccine series compliance in adolescents. PMID- 7845721 TI - Cerebrospinal fluid interleukin 8 in children with purulent bacterial and tuberculous meningitis. PMID- 7845722 TI - Exanthem subitum and human herpesvirus 7 infection. PMID- 7845723 TI - Medical management of orbital infection. PMID- 7845724 TI - Sinusitis-induced transient diabetes insipidus. PMID- 7845725 TI - Herpes simplex virus type 2 meningitis and associated genital lesions in a three year-old child. PMID- 7845726 TI - Enterococcus faecium meningitis in a child. PMID- 7845727 TI - Obstruction of the common bile duct in histoplasmosis. PMID- 7845728 TI - Parvovirus B19 infection in a hypogammaglobulinemic infant with neurologic disorders and anemia: successful immunoglobulin therapy. PMID- 7845729 TI - Transient HBeAg positivity in the absence of HBsAg in a newborn infant. PMID- 7845730 TI - A febrile infant who developed cardiac dysrhythmia and congestive heart failure. PMID- 7845731 TI - The mechanism of efficacy of intravenous immunoglobulin in Kawasaki disease. PMID- 7845733 TI - Increased urinary frequency as a presentation of Plasmodium falciparum malaria. PMID- 7845732 TI - Catheter-associated nocardiosis. PMID- 7845734 TI - Acceptability of immunizations given in other countries. PMID- 7845735 TI - Lessons from recent studies on the epidemiology of otitis media. PMID- 7845736 TI - Pathogenesis of acute otitis media. PMID- 7845737 TI - The diagnosis of otitis media: new techniques. PMID- 7845738 TI - Viral-bacterial interaction in acute otitis media. PMID- 7845739 TI - Antimicrobial agents: resistance patterns of common pathogens. PMID- 7845740 TI - Considerations in selecting an antibiotic for treatment of acute otitis media. PMID- 7845741 TI - Surgical management of otitis media: current indications and role related to increasing bacterial resistance. PMID- 7845742 TI - Immunology: promise of new vaccines. PMID- 7845743 TI - Long term sequelae of otitis media: fact or fantasy? PMID- 7845744 TI - Management of febrile neonates: what to do with low risk infants. PMID- 7845745 TI - Application of criteria identifying febrile outpatient neonates at low risk for bacterial infections. AB - A total of 254 previously healthy outpatient neonates 31 days of age or younger with a rectal temperature > or = 38 degrees C were enrolled in a prospective study during an 18-month period to evaluate the validity of applying low risk criteria for bacterial infections in this population. All of the neonates received standard physical examinations and laboratory evaluations including blood and urine cultures at the time of admission. Those who had no evidence of ear, eye, soft tissue, umbilical or skeletal infection had between 5000 and 15,000 white blood cells/mm3, had a C-reactive protein of less than 20 mg/liter or an erythrocyte sedimentation rate less than 30 mm/hour and a normal urinalysis were considered at low risk for bacterial infections. Bacterial infections were confirmed by cultures of the various body fluids. Bacterial infections were present in 17.7% (45 neonates) and bacteremia or meningitis in 5.1% (13 neonates). Eight (6.0%) of the 134 neonates who met the criteria had bacterial infections, while only 1 (0.7%) had bacteremia and meningitis, compared with 37 (30.8%) and 12 (10.0%), respectively, of the 120 who did not meet the criteria (both P < 0.05). The negative predictive value of meeting the low risk criteria were 94.0% for excluding all bacterial infections and 99.3% for bacteremia and meningitis respectively.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845746 TI - Serious bacterial infections in febrile infants and children selected for lumbar puncture. AB - Lumbar puncture (LP) is performed frequently in pediatric emergency departments to diagnose meningitis in infants and young children with fever. Children selected to have LP who do not have meningitis may, however, have other serious bacterial infections. We surveyed lumbar punctures performed in the Boston City Hospital Pediatric Emergency Department and monitored the incidence of meningitis and other serious bacterial infections. Meningitis was diagnosed in 8% of children who underwent LP. An additional 10.5% of children who underwent LP and had normal cerebrospinal fluid had positive cultures of blood (3.1%), urine (4.1%) or stool (3.3%). The decision to perform lumbar puncture identifies children at risk of having not only meningitis but other serious bacterial illnesses. Those children 2 years of age and younger with normal cerebrospinal fluid should be considered for cultures of blood, urine and possibly stool. PMID- 7845747 TI - Salivary IgA antibodies to Giardia lamblia in day care center children. AB - An enzyme-linked immunosorbent assay was developed for the detection of specific salivary IgA antibodies to Giardia lamblia. Among 73 infants and children in a day care center 9 asymptomatic subjects had stools positive for G. lamblia. Salivary antigiardia IgA concentrations, expressed as OD units, were higher in the 2- to 4-year-old group: 0.899 +/- 0.03 vs. 0.660 +/- 0.03 in the < 2-year old group (P < 0.001). In both groups values were higher in the infected children (1.099 +/- 0.04 vs. 0.629 +/- 0.09 in the < 2-year-old group and 1.053 +/- 0.07 vs. 0.859 +/- 0.03 in the 2- to 4-year-old group). In children infected throughout the study period, salivary antigiardia antibodies remained consistently high and in 2 children whose stools were initially negative a significant rise in OD value was observed after stools tested positive. Total salivary IgA did not differ between the two age groups and did not correlate with specific salivary antigiardia antibodies in individual subjects. The enzyme linked immunosorbent assay for detection of specific salivary antibodies to G. lamblia can be used in the study of the mucosal immune response to the parasite, and may serve as an screening tool in monitoring the exposure of various populations to G. lamblia. PMID- 7845748 TI - Effect of maternal immunization with oral poliovirus vaccine on neonatal immunity. AB - During the summer of 1988, an outbreak of poliomyelitis caused by poliovirus 1 occurred in Israel, during which a national mass immunization campaign with oral poliovirus was undertaken. This prospective study was undertaken to assess the effect of maternal oral poliovirus immunization during the third trimester of pregnancy on neonatal immunity against poliovirus. Cord blood specimens of 88 neonates, born 2 to 7 weeks after maternal immunization, were examined for antipoliovirus antibodies and compared with 100 samples obtained from neonates 7 months before the outbreak. Blood samples were also obtained from the 62 mothers of neonates who had been immunized 2 to 5 weeks before delivery. Sera were tested for neutralizing antibodies to the 3 poliovirus types using a microneutralization technique. The geometric mean titer to poliovirus type 1 was significantly higher in neonates whose mothers were immunized during pregnancy (87.1) than in the offspring of the nonvaccinated group (53.0), P < 0.05. Two to 3 weeks after immunization, geometric mean titers against all 3 poliovirus types were higher in maternal blood than in cord blood whereas 4 to 5 weeks after vaccination a significant difference was found for type 3 only. Although oral poliovirus immunization during pregnancy resulted in higher neonatal antibody titers to poliovirus type 1, the proportion of newborns with titers of < 1:8 to the 3 poliovirus types did not change significantly. PMID- 7845749 TI - Tuberculosis in human immunodeficiency virus-exposed or -infected United States children. AB - This study was designed to provide a preliminary assessment of the occurrence of tuberculosis exposure, infection and disease within a national sample of infants and children with human immunodeficiency virus (HIV) exposure or infection, and to determine the prevalence of Mycobacterium tuberculosis isolates resistant both to isoniazid and rifampin in these patients or their adult source contacts. A retrospective questionnaire survey was conducted of infants and children with HIV exposure or infection evaluated by pediatric HIV referral centers in the United States comprising the pediatric units or subunits of the Pediatric Acquired Immunodeficiency Syndrome Clinical Trials Group (PACTG). Seventy of 72 sites during a mean period of 5 (range, 1 to 12) years participated in this study and had provided care for 14,038 patients. There were 75 cumulative total cases of tuberculosis disease seen since each site was established. Therapy for asymptomatic infection was given to another 40 children and for tuberculosis exposure to 71 children. Annualized case rates were 478/100,000 for sites established in 1990 to 1992, 117/100,000 for 1988 to 1989, 63/100,000 for 1986 to 1987 and 58/100,000 for 1981 to 1985 (P = 0.05, Spearman's p test for trend). By comparison, the 1992 age-specific tuberculosis case rate for all U.S. children < 5 years was 5.5/100,000. Twenty percent of isolates from PACTG patients and 15% of isolates from adult source contacts were resistant to isoniazid and rifampin.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845750 TI - A prospective study of vancomycin pharmacokinetics and dosage requirements in pediatric cancer patients. AB - Pharmacokinetics of vancomycin and dosage requirements were evaluated prospectively in 28 pediatric cancer patients 9 months to 13 years of age. The predictive performance of a two-compartment Bayesian forecasting program was also evaluated. A mean (+/- SD) daily dosage of 75 +/- 22 mg/kg/day was necessary to attain a mean peak serum vancomycin concentration (SVC) of 23.1 +/- 5.8 mg/liter and a mean trough SVC of 6.2 +/- 2.3 mg/liter. Mean vancomycin clearance, volume of distribution and serum half-life were 0.153 +/- 0.033 liter/hour/kg, 0.63 +/- 0.08 liter/kg and 2.95 +/- 0.48 hours. Final peak SVCs, which reflected the last dosage regimens received, were predicted with minimal bias (mean prediction error, -1.2 mg/liter) and accurate precision (root mean-squared prediction error, 2.0 mg/liter) whereas trough SVCs were predicted with even smaller bias (mean prediction error, -0.1 mg/liter) and greater precision (root mean-squared prediction error, 0.8 mg/liter). This study showed that pediatric cancer patients with normal renal function required vancomycin dosage regimens substantially greater than the standard 40 mg/kg/day to attain the desired SVCs. PMID- 7845751 TI - The etiology of pneumonia in malnourished and well-nourished Gambian children. AB - During a 2-year period 159 malnourished children ages 3 months to 5 years with radiologic evidence of pneumonia were investigated to determine the cause of their pneumonia. In addition 119 malnourished children without pneumonia, 119 well-nourished children with pneumonia and 52 well-nourished children without pneumonia were studied as controls. Percutaneous lung aspiration was performed on 35 malnourished and 59 well-nourished children with pneumonia. Bacteria were isolated from the blood, lung or pleural fluid of 28 (18%) malnourished children with pneumonia, 42 (35%) well-nourished children with pneumonia and from the blood of 5 (4%) malnourished children without pneumonia. Streptococcus pneumoniae and Haemophilus influenzae, which were the two organisms isolated most frequently in both groups of children with pneumonia, were found in 17 (11%) malnourished and 39 (33%) well-nourished children with pneumonia. Mycobacterium tuberculosis was detected in 5 malnourished children with pneumonia. A potentially pathogenic virus was identified in 35% of malnourished children with pneumonia and 40% of well-nourished children with pneumonia, and from 25% of children without pneumonia. The viruses identified most frequently were adenovirus and respiratory syncytial virus.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845752 TI - Bacterial colonization of the nasopharynx predicts very early onset and persistence of otitis media in Australian aboriginal infants. AB - Otitis media (OM) develops in the first months of life and persists throughout childhood in many rural Aboriginal children. We have followed Aboriginal and non Aboriginal infants from birth to determine the relationship of the early onset of OM to nasopharyngeal colonization with respiratory pathogens. Aboriginal infants were colonized with multiple species of respiratory bacteria (Moraxella catarrhalis, Haemophilus influenzae, Streptococcus pneumoniae) at a rate of 5% per day and the timing of colonization predicted the onset of persistent OM in individual Aboriginal infants. Non-Aboriginal infants became colonized by M. catarrhalis alone at the slower rate of 1% per day and experienced transient episodes of OM in the absence of colonization. We attribute early bacterial colonization in most Aboriginal infants to high rates of cross-infection due to overcrowding, poor hygiene and high rates of bacterial carriage. Early age of infection and the multiplicity of bacterial types may contribute to prolonged carriage and to eustachian tube damage leading to persistent OM. Thus Aboriginal infants are "otitis-prone" and might qualify for prophylactic antibiotics. PMID- 7845753 TI - Therapy of multidrug-resistant typhoid fever with oral cefixime vs. intravenous ceftriaxone. AB - We randomly allocated 80 children with suspected multidrug-resistant tyhpoid fever to therapy with either cefixime or ceftriaxone. Of these, an alternative diagnosis was subsequently made in 10 children and another 10 were excluded because cultures were negative. In 9 cases the typhoidal organisms isolated were susceptible to first-line drugs. In all, 50 children were randomly allocated to receive therapy with either intravenous ceftriaxone (65 mg/kg/day once daily, Group A, n = 25) or oral cefixime (10 mg/kg/day divided every 12 hours, Group B, n = 25) for 14 days. The two groups were comparable in their clinical characteristics, duration and severity of illness at the time of admission. The time to defervescence was comparable in both groups (8.3 +/- 3.7 vs. 8.0 +/- 4.1 days, P = not significant). An equal number (3 in each group) failed to respond and underwent a change in therapy. Three children in Group A and one in Group B relapsed. No adverse effects were seen in either group during the course of therapy. Our data suggest that oral cefixime can be used as effectively as parenterally administered ceftriaxone for management of typhoid fever in children. PMID- 7845754 TI - Recent developments with human caliciviruses. AB - Caliciviruses (CVs) are human and animal pathogens. The best known human CVs are Norwalk virus (NV) and Snow Mountain agent. Recent molecular studies have confirmed that CVs are a unique taxonomic family. These molecular studies also have clarified relationships among previously poorly characterized human enteric viruses, led to new diagnostic tests and identified potential relationships between human and animal CVs. The purpose of this review was to describe these recent developments. PMID- 7845755 TI - Paradigms for creativity. PMID- 7845756 TI - A new twist on the rotating-trapezoid illusion: evidence for neural-adaptation effects. AB - In a series of experiments, the selective-adaptation paradigm was applied to the rotating-trapezoid illusion in an effort to demonstrate neural-adaptation effects in the figural reversal of this classic illusion. Prior to viewing the standard trapezoid, the observer adapted to a rectangle rotating unambiguously in the same direction as the trapezoid or in the opposite direction. In accordance with the neural hypothesis, illusion strength was greatest when the two figures rotated in the same direction and weakest when the two figures rotated in opposite directions. Results were confirmed with two separate dependent variables: the observer's 'first look' at the illusion after adaptation and the observer's reversal rate during a test period. These findings were discussed in terms of (a) the basic similarity of results for the rotating trapezoid and reversible figures such as the Necker cube and (b) the need for a multiprocess model of both classes of illusions which emphasizes bottom-up and top-down processes. PMID- 7845757 TI - Do young children reverse ambiguous figures? AB - Most adult observers tend not to reverse ambiguous figures if they are not informed about the ambiguity of the figure. The question was asked whether very young children who have rarely, if ever, seen any kinds of ambiguous figures will reverse if uninformed, and also how they will behave if they are informed. It was found that 3 and 4 year olds never reverse when presented with two different kinds of ambiguous figures when uninformed, and only some do even when informed; further, those that do reverse do so only once or twice over a 60 s inspection period. These results are interpreted as further confirmation of an earlier finding with adults--that reversal is not simply a matter of prolonged inspection of an ambiguous figure leading automatically to neural satiation. Instead, cognitive factors such as utilization of memory and intention are implicated. PMID- 7845758 TI - Cue conflict and stereoscopic surface slant about horizontal and vertical axes. AB - The way in which a planar surface is defined or configured may affect its apparent slant about a given axis, and the magnitude of slant-axis anisotropies. The authors have previously suggested that (i) these within-axis and between-axis configuration effects may be attributable, in part at least, to the perspective disparity conflict generated when geometrically frontoparallel configured surfaces are slanted stereoscopically; and (ii) that implicit contours, defined by line endings or conjunctions, may have effects analogous to those seen with explicit contours. These possibilities were directly examined in two experiments. In experiment 1, slant-axis anisotropy was progressively induced by adding horizontal lines to a vertical-line (zero anisotropy) grid under conditions of cue conflict; slants about the vertical (but not the horizontal) were attenuated demonstrating a clear and systematic nexus between surface configuration and slant-axis anisotropy. The presence of regular implicit horizontals similarly and selectively attenuated the slant perceived about the vertical. In experiment 2, cue conflict was seen to exacerbate slant-axis anisotropy, but clearly could not fully account for it. There was an axis asymmetry in the effect of degrading implicit contours: degradation had a marked impact on perceived slant about the horizontal but not the vertical axis. PMID- 7845759 TI - On the contribution of a binocular 'AND' channel at contrast threshold. AB - Three experiments are reported in which an attempt was made to isolate the contribution of an AND channel by measuring aftereffects following alternating monocular adaptation. The first two were designed to test Wolf and Held's proposal that the binocular AND channel does not respond at contrast threshold. In the first experiment the relative sizes of monocular and binocular contrast threshold elevation were compared with the pattern of aftereffects obtained in a study of the suprathreshold tilt aftereffect. Identical patterns of results were obtained under the two adaptation conditions. In the second experiment, the monocular and binocular contrast-reduction aftereffect reported by Blakemore et al was measured over a wide range of reference contrasts. As in the previous experiment, the monocular effect was greater than the binocular effect. This occurred at all reference contrasts. These data support the conclusion that the AND channel contributes to visual performance in the same manner, irrespective of stimulus contrast. In the final experiment an alternative explanation for existing evidence against the existence of an AND channel was assessed. PMID- 7845760 TI - The effect of knowledge of object distance on accommodation during instrument viewing. AB - We present data in which instrument accommodation was measured while knowledge of object distance was varied. The accommodative feedback loop was 'semiopen'--an intermediate state between the closed-loop and open-loop conditions of previous experiments. The semiopen-loop situation mimicked the degraded-image conditions which are frequently encountered during instrument viewing. The results show that for some subjects knowledge of object distance is a more powerful cue for instrument accommodation than is the optical distance of the object; however, for the majority of subjects this is not the case. We also found that subjects whose accommodation is influenced by knowledge of object distance tend to have a more proximal dark focus than those whose accommodation is independent of knowledge of object distance. We propose that the Mandelbaum effect, in which involuntary accommodation occurs when a transparency is superimposed between the observer and the object of regard, could account for the accommodative behavior of all subjects. However, the Mandelbaum effect would have to be interpreted more broadly than before. In the broader interpretation, the transparency could be cognitive (ie known distance) rather than physical. PMID- 7845761 TI - Detecting changes in one's own velocity from the optic flow. AB - Experiments were designed to establish whether we can use the optic flow to detect changes in our own velocity. Subjects were presented with simulations of forward motion across a flat surface. They were asked to respond as quickly as possible to a step increase in simulated ego-velocity. The smallest change for which subjects could respond within 500 ms was determined. At realistic simulated speeds of locomotion, the simulated ego-velocity had to increase by about 50%. The threshold for detecting changes in simulated ego-velocity was hardly better than the threshold for detecting other changes in the acceleration of the dots on the screen. It made little difference whether the surface across which the subject appeared to move was built up of dots, lines, or triangles; neither did it matter whether subjects saw the same image with both eyes, or whether the simulation was presented in stereoscopic depth. The results show that we are very poor at detecting changes in our own velocity on the basis of visual input alone. PMID- 7845762 TI - The Hermann grid illusion: a tool for studying human perspective field organization. AB - Psychophysical research on the Hermann grid illusion is reviewed and possible neurophysiological mechanisms are discussed. The illusion is most plausibly explained by lateral inhibition within the concentric receptive fields of retinal and/or geniculate ganglion cells, with contributions by the binocular orientation specific cortical cells. Results may be summarized as follows: (a) For a strong Hermann grid illusion to be seen bar width must be matched to the mean size of receptive-field centers at any given retinal eccentricity. (b) With the use of this rationale, the diameter of foveal perceptive-field centers (the psychophysical correlate of receptive-field centers) has been found to be in the order of 4-5 min arc and that of total fields (centers plus surrounds) 18 min arc. These small diameters explain why the illusion tends to be absent in foveal vision. (c) With increasing distance from the fovea, perceptive-field centers increase to 1.7 deg at 15 deg eccentricity and then to 3.4 deg at 60 deg eccentricity. This doubling in diameter agrees with the change in size of retinal receptive-field centers in the monkey. (d) The Hermann grid illusion is diminished with dark adaptation. This finding is consistent with the reduction of the center-surround antagonism in retinal receptive fields. (e) The illusion is also weakened when the grid is presented diagonally, which suggests a contribution by the orientation-sensitive cells in the lateral geniculate nucleus and visual cortex. (f) Strong induction effects, similar to the bright and dark spots in the Hermann grid illusion, may be elicited by grids made of various shades of grey; and by grids varying only in chroma or hue. Not accounted for are: the illusory spots occurring in an outline grid ie with hollow squares, and the absence of an illusion when extra bars are added to the grid. Alternative explanations are discussed for the spurious lines connecting the illusory spots along the diagonals and the fuzzy dark bands traversing the rhombi in modified Hermann grids. PMID- 7845763 TI - Factors limiting large-scale localisation. AB - The mechanisms mediating relative spatial localisation in the visual system are still unclear. There is a growing amount of evidence that this capability is not merely limited by the processing of the front-end visual system. Models of localisation should, therefore, include higher-level processing stages. A careful study of the sources of error in localisation tasks may further our understanding of the nature of these processes. A study is reported in which the possible role of higher-order processing in relative spatial localisation is explicitly addressed. For this purpose the error sources of threshold performance were investigated for two similar relative-spatial-localisation tasks: two-dot separation discrimination and two-dot orientation discrimination. Fovea-centered stimuli with large dot separations were used. The front-end processing for these stimuli is probably identical in both tasks. Hence, differential effects of the variation of the experimental parameters on threshold performance for both tasks may reveal the characteristics of the higher-level processing involved. The effects of dot separation, stimulus orientation, and experimental procedure (single-stimulus binary forced choice versus two-alternative forced choice) on threshold performance for both tasks are reported. The results show that thresholds for both tasks increase proportionally with dot separation. However, separation-discrimination thresholds are always significantly higher than orientation-discrimination thresholds. Thresholds for separation discrimination are independent of stimulus orientation. In contrast, orientation-discrimination thresholds show an oblique effect: thresholds are consistently lower for horizontal stimuli. Both tasks also show a different dependency of threshold behaviour on the experimental procedure. For a horizontal stimulus orientation, separation discrimination is better with an explicit (physical) reference standard, whereas orientation discrimination is better with an implicit referent. These differential effects cannot be explained by any of the known characteristics of the front-end visual system. They suggest that large-scale spatial-localisation performance is probably limited at a processing level at which spatial relations are explicitly represented. PMID- 7845764 TI - A note on "Gravity as a monocular cue for perception of absolute distance and/or absolute size". PMID- 7845765 TI - Under the carpet. PMID- 7845766 TI - Vection: the contributions of absolute and relative visual motion. AB - Inspection of a visual scene rotating about the vertical body axis induces a compelling sense of self rotation, or circular vection. Circular vection is suppressed by stationary objects seen beyond the moving display but not by stationary objects in the foreground. We hypothesised that stationary objects in the foreground facilitate vection because they introduce a relative-motion signal into what would otherwise be an absolute-motion signal. Vection latency and magnitude were measured with a full-field moving display and with stationary objects of various sizes and at various positions in the visual field. The results confirmed the hypothesis. Vection latency was longer when there were no stationary objects in view than when stationary objects were in view. The effect of stationary objects was particularly evident at low stimulus velocities. At low velocities a small stationary point significantly increased vection magnitude in spite of the fact that, at higher stimulus velocities and with other stationary objects in view, fixation on a stationary point, if anything, reduced vection. Changing the position of the stationary objects in the field of view did not affect vection latencies or magnitudes. PMID- 7845767 TI - The contribution of motion, the visual frame, and visual polarity to sensations of body tilt. AB - Three types of visual information contribute to the sense of self orientation with respect to gravity: visual polarity of objects with a distinct top and bottom, the principal vertical and horizontal lines of the visual environment, and visual motion. Three visual displays were designed to investigate the contribution of each visual feature to illusory self tilt: a large sphere lined with dots, a cubic room lined with dots, and a furnished room with floor and ceiling. In experiment 1 the dotted room and the furnished room were tilted to various angles about the roll axis of the erect subject who set a visual line and an unseen rod to the apparent vertical. In the dotted room, settings were made either with respect to the nearest surface to the horizontal or with respect to the nearest diagonal of the room. In the furnished room, settings were made with respect to the nearest horizontal wall but not with respect to diagonals. In experiment 2 each of the three displays was rotated at constant velocity and subjects' responses were classified into four categories: illusory self tilt at a constant angle, alternating self tilt with the body becoming erect each time a surface became horizontal, continuous head-over-heels self rotation, and a feeling that the body was supine. Almost all responses were of constant tilt in the sphere. Constant and alternating tilt were the most common responses in the dotted room. In the furnished room 60% of subjects experienced full head-over heels self rotation. PMID- 7845768 TI - Perception of motion in depth from luminous rotating spirals: directional asymmetries during and after rotation. AB - Motion aftereffect (MAE) following spiral rotation is often asymmetrical: centrifugal MAE exceeds centripetal MAE. Pronounced MAE asymmetry has been reported for conditions--especially with a minimal background pattern--promoting perception of motion in depth. Such conditions are predicted to elicit motion asymmetry during adaptation. In the present study observers viewed luminous spirals monocularly in the dark; they timed, and scaled for convincingness, motion in depth during and after rotation. Motion in depth during rotation was often almost continuous, but recession was more convincing than was approach. Approaching MAE lasted longer and was more convincing than was receding MAE: the duration difference was more pronounced than has been found in other MAE studies, corroborating the link between MAE asymmetry and motion in depth. A possible line of explanation resides in comparing spiral motion in depth with real motion in depth of objects: in particular, the rapid visual change and collision with the observer that characterises real approach of an object is lacking in spiral approach. Interspecies differences for 'looming' and MAE are discussed. PMID- 7845769 TI - Binocular rivalry and fusion under scotopic luminances. AB - A study is reported of human binocular rivalry and fusion over a range of luminances from scotopic to photopic. At scotopic light levels, rivalry alternations were very slow and complete. Suppression spread over much larger areas of the visual field than at photopic light levels. As luminances decreased from photopic to scotopic levels there was a rod-cone break for binocular rivalry. Mean suppression durations became abruptly greater as light levels dropped below those allowing the cones to be active. Horizontal disparities allowing fusion were 4 to 6 times greater at scotopic than at photopic light levels. Binocular vision at scotopic luminances was sluggish and of low resolution. It is as though connections to, and within, binocular vision are changed when light levels allow only rod input. PMID- 7845770 TI - Angular induction as a function of the length and position of segments and gaps. AB - The perceptual distortions which are manifested in the Poggendorff illusion can be studied with the use of a more restricted set of stimulus elements. Experiments were designed in which angular induction effects between two line elements, known respectively as the test segment and induction segment, were evaluated. In some stimulus configurations the induction 'segment' consisted of a tandem pair of segments. Previous studies had shown that the induction segment will bias operant judgments of collinearity for a test segment, this effect being a function of the relative angle between the two. Six experiments are reported, in which the length and position of segments in relation to the tip of the test segment were varied. It was found that substantial induction is produced by a very short segment, and that this can bias judgment even when its displacement spans more than 10 deg of visual angle. Several aspects of the data suggest that the strength of effect is a log-linear function of segment position. However, the results from displacement of single or tandem segments do not conform to predictions based on length/response summation, and thus do not support a linear systems approach. Neural substrates for these interactions are given brief attention. PMID- 7845771 TI - The use of pigmentation and shading information in recognising the sex and identities of faces. AB - An investigation of what can be learned about representational processes in face recognition from the independent and combined effects of inverting and negating facial images is reported. In experiment 1, independent effects of inversion and negation were observed in a task of identifying famous faces. In experiments 2 through 4 the question of whether effects of negation were still obtained when effects due to the reversal of pigmentation in negative images were eliminated was examined. By the use of images of the 3-D surfaces of faces measured by laser, and displays as smooth surfaces devoid of pigmentation, only effects of inversion were obtained reliably, suggesting that the effects observed in experiment 1 arose largely through the inversion of pigmentation values in normal images of faces. The results of experiment 5 suggested that the difference was not due to the different task demands of experiments 2-4 compared with those of experiment 1. When normally pigmented face images were used in a task making similar demands to that of experiment 4, independent effects of inversion and negation were again observed. When a task of sex classification was used in experiments 6 and 7, clear effects of negation as well as inversion were observed on latencies, though not accuracies, of responding. The results are interpreted in terms of the information content of pigmentation relative to shape from shading in different face-classification tasks. The results also reinforce other recent evidence demonstrating the importance of image intensity as well as spatial layout of face 'features'. PMID- 7845772 TI - Facial aesthetics: babies prefer attractiveness to symmetry. AB - The visual preferences of human infants for faces that varied in their attractiveness and in their symmetry about the midline were explored. The aim was to establish whether infants' visual preference for attractive faces may be mediated by the vertical symmetry of the face. Chimeric faces, made from photographs of attractive and unattractive female faces, were produced by computer graphics. Babies looked longer at normal and at chimeric attractive faces than at normal and at chimeric unattractive faces. There were no developmental differences between the younger and older infants: all preferred to look at the attractive faces. Infants as young as 4 months showed similarity with adults in the 'aesthetic perception' of attractiveness and this preference was not based on the vertical symmetry of the face. PMID- 7845773 TI - Tactual object exploration and recognition in blind and sighted children. AB - Development of the haptic system was evaluated by examining object exploration and recognition in sighted children between the ages of 3 and 8 years. To determine the importance of visual experience for these abilities, the performance of seven congenitally blind children was compared with that of sighted peers matched for age and gender. Performance was evaluated in terms of the speed and correctness of object identification, thoroughness of exploration of object parts, representation of the global form versus local parts of objects, and the possible role of critical parts in object identification. Four types of common objects were presented: normal-sized, miniaturized small, miniaturized large, and oversized objects. All subjects were required to manipulate and identify these objects haptically, without the aid of vision. Results revealed the emergence of a developmental pattern in all performance measures for sighted children. Older sighted children were not only able to recognize more objects and to do so more quickly, but also were more thorough in their exploration patterns. With increasing age, children appear to change their representation of objects from one based predominantly on global shape to one that incorporates a balance of global shape and specific local parts. In agreement with this, critical parts also played a role in object identification, particularly in older children. Blind and sighted children did not differ in any performance measures, which suggests that previous visual experiences do not determine tactile exploration strategies and are not essential for haptic object recognition. PMID- 7845774 TI - The relationship between time of arrival of nontargets and their spatial location: evidence for asymmetries in visual attentional processing. AB - A brief advance of the presentation of distant nontargets has previously been shown to secure them an analysis, suggesting that even stimuli beyond the putative 'spotlight' of attention are analysed. In the present experiment nontargets were presented near to fixation or peripherally (at 0.6 or 1.9 deg of visual angle) for a duration of 17, 33, or 67 ms before being masked. After a subsequent period (SOA) of 0, 20, 40, 60, or 80 ms the target was presented at fixation. The results from the shortest nontarget duration show a time lag in the development of the effect of far nontargets on response to the target. At durations of 33 and 67 ms the identity of far nontargets has been established before masking takes place, since their effect is observable at zero SOA. However, while this effect remains relatively constant over SOAs of 20 to 80 ms it increases with SOA in the near condition, suggesting that, although both near and far nontargets have been identified, it is only the near nontargets which are subject to further processing during the interval between nontarget and target presentations. The results favour a model of attention in which stimuli are passively selected and subject to additional processing on the basis of their spatial location rather than that the location or representation of distractor items are actively suppressed. PMID- 7845775 TI - On the microgenesis of illusory figures: a failure to replicate. AB - Reynolds found in 1981 that with increased viewing time of a pattern which may or may not produce illusory contours there were: first, reports of the pattern without an illusory figure; then, at longer exposures, an increase in the frequency with which illusory figures were reported; and then, with still longer exposures, a decrease in such reports if the pattern contained elements which tended to contradict the possibility of such a figure. Unfortunately, however, three attempts to replicate these potentially very important findings--with the aid of substantially improved methodology--consistently failed to do so. It is suggested that this failure, although it is disappointing to those who subscribe to a 'problem solving' explanation of illusory contours, may not constitute a strong refutation of such a theory. Regardless, the purpose in the report is to clarify and rectify the published record concerning this part of the evidential underpinnings of that theory. PMID- 7845776 TI - Cardiostim '94. Proceedings. Nice, June 15-18, 1994. PMID- 7845777 TI - Quality-of-life in DDDR pacing: atrioventricular synchrony or rate adaptation? AB - Although differences in exercise performance have been observed between different rate adaptive modes, the relative impact of atrioventricular (AV) synchrony and rate adaptation on quality of life (QOL) have not been determined. Thirty-three patients with either sinoatrial disease (18) or complete atrioventricular (AV) block (15) received DDDR pacemakers (16 minute ventilation sensing, 17 activity sensing). There were 11 males and 22 females, with a mean age of 66 +/- 1 (range 39-78) years. The study was a double-blind, triple cross-over study comparing DDDR, DDD, and VVIR modes. At the end of each 8-week study period in each mode, QOL was assessed by a questionnaire evaluating patients' functional class (Classes I-IV), physical malaise inventory (41 items), illness perception (43 items), and overall QOL rating based on a 48 items measure covering different aspects of the patients' daily life adjustment. Two patients required early crossover from VVIR mode during the study. Patients experienced significantly fewer physical malaise such as temperature intolerance, dyspnea, and palpitations in the DDDR mode, compared with either DDD or VVIR pacing. DDDR pacing reduced the perception of illness in 5 of 43 items compared to VVIR pacing, and improved stamina and appetite compared to DDD pacing. The overall QOL score was 102 +/- 2, 105 +/- 2, 113 +/- 2 in the DDDR, DDD, and VVIR modes, respectively, with a higher score indicating a poorer QOL (DDDR/DDD vs VVIR, P < 0.02). There was no change in functional classes between the three pacing modes.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845778 TI - Quality-of-life during DDD and dual sensor VVIR pacing. AB - Twenty-one patients (mean age 68 +/- 8 years) with dual-sensor (QT+activity) DDDR pacemaker were randomly assigned to a crossover, double-blind study in order to evaluate their quality-of-life scores. All pacemakers were implanted for sick sinus syndrome (8 patients) or complete heart block (13 patients). The pacemakers were randomly programmed to VVIR or DDD pacing modes for 2-week periods and then the pacing mode was switched for another 2-week period. At the end of each period, the quality-of-life was evaluated by a questionnaire with regard to cardiovascular symptoms, physical activity, psychosocial and emotional functioning, and self-perceived health. Nineteen questions were scored 0-5 points each. Significant improvement in the mean total quality-of-life score (20.5 +/- 14.9 vs 34.8 +/- 17.4) as well as in dyspnea on effort, dizzy spells, palpitation, sweating, fatigue, lethargy, emotional functioning, and self perceived health was observed during DDD compared to VVIR pacing. No question was scored in favor of VVIR pacing mode. Significant improvements during DDD pacing was demonstrated in all subgroups of patients (sick sinus syndrome, chronotropically competent and incompetent patients, and patients with high degree AV block). Eighteen patients preferred DDD pacing mode, while only one preferred VVIR pacing mode. Two remaining patients expressed no preference. The results suggest that DDD pacing offers better quality-of-life than dual sensor VVIR pacing in all subgroups of patients commonly indicated for pacemaker implantation. PMID- 7845779 TI - Long-term stability of P wave sensing in single lead VDDR pacing: clinical versus subclinical atrial undersensing. AB - Optimal function of a single lead P wave synchronous rate adaptive ventricular pacing system (VDDR) requires reliable P wave sensing over time and during daily activities. The stability of P wave sensing and the incidence of sensitivity reprogramming in a single pass lead with a diagonally arranged bipole was assessed in 30 patients with complete atrioventricular block over a follow-up period of 12 +/- 1 months (range 6 months to 3 years). Atrial sensing was assessed during clinic visits, by physical maneuvers (postural changes, breathing, Valsalva maneuver, walking and isometric exercise), maximum treadmill exercise and Holter recordings. P wave amplitude at implantation was 1.21 +/- 0.09 (0.5-3.6) mV, and the atrial sensing threshold remained stable over the entire period of follow-up. Using an atrial sensitivity based on twice the sensing threshold at 1 month, P wave undersensing was found in 2, 4, 3, and 7 patients during clinic visit, physical maneuvers, exercise, and Holter recordings, respectively. Atrial sensitivity reprogramming was performed in three patients based on the correction of undersensing during physical maneuvers. Although eight patients had atrial undersensing on Holter recordings, the number of undersensed P waves was small (total 101 beats or 0.013% +/- 0.001% of total ventricular beats) and no patient was symptomatic. One patient had intermittent atrial undersensing at the highest sensitivity, but the VDDR mode was still functional most of the time. No patient had myopotential interference at the programmed sensitivity. One patient developed chronic atrial fibrillation and was programmed to the VVIR mode. Thus, single lead VDDR pacing is a stable pacing mode in 97% of patients.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845780 TI - Long-term follow-up of patients with single lead VDD stimulation. AB - The purpose of this study was to assess the long-term results of a single lead VDD pacing system (Phymos MPS) in 85 patients (48 males, 37 females, mean age 74 +/- 9 years). The system, which incorporates two atrial floating electrodes (Phymos 830-S), was implanted for second- or third-degree Mobitz II AV block. The percentage of AV synchronized pacing, the presence of fusion beats due to short AV delay, and the occurrence of supraventricular arrhythmias was evaluated by Holter monitoring at 6-month intervals. Over a mean period of follow-up of 44 months (range 2-56), over 90% of AV synchronized pacing events were noted in 74 patients (87%). The presence of persistent fusion beats was detected in 12 patients (14%). In ten patients the pacemaker was reprogrammed to VVI mode for supraventricular arrhythmias (7 patients, 8.2%) or unsatisfactory atrial sensing (3 patients, 3.5%). One pacemaker was removed for pocket infection and two for battery depletion. These observations support the use of VDD single lead pacing to combine a physiological mode of stimulation with simple implantation techniques. PMID- 7845781 TI - Clinical evaluation of a new single pass lead VDD pacing system. AB - Twenty-five patients with second- to third-degree AV block and normal sinus function (16 males, mean age 60 +/- 18; range 15-78 years) underwent implantation of VVD pacemakers (THERA VDD, Medtronic, Inc.) with a single pass (SP) lead. RESULTS: During implantation the mean amplitude of the atrial (A) signal was 3.9 +/- 1.4 mV (range 2.0-7.8 mV). Stable, acceptable A-signals during implantation were usually observed in the mid- or lower part of the right atrium. The lead tip electrical parameters were not compromised in any patient in order to obtain an acceptable A-signal. To verify VDD device function, patients underwent pacing system analysis on the second day and again 1, 3, and 6 months after implantation. Acute and chronic electrical measurements in the ventricle were similar to those with regular steroid leads. During follow-up tests, stable atrial sensing (A > or = 0.7 mV) was found in all but one patient (in whom A was 0.25-0.5 mV and an intermittent loss of atrial sensing occurred). There was no difference between serial measurements of A-signal amplitudes on the second day or 1, 3, and 6 months after implantation: 1.9 +/- 1.3 mV, 1.5 +/- 0.6 mV, 1.3 +/- 0.8 mV, and 1.5 +/- 1.1 mV, respectively. The mean implantation time was 54.0 +/- 17 minutes and the mean fluoroscopy time was 3.2 +/- 1.3 minutes. CONCLUSIONS: SP lead VDD pacing is reliable and easy to manage with dependable atrial sensing and ventricular pacing.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845782 TI - Long-term reliability of single lead atrial synchronous pacing systems using closely spaced atrial dipoles: five-year experience. AB - To assess the long-term capability of single atrioventricular (AV) lead VDD pacing systems using close atrial dipoles to assure reliable atrial guided pacing, the safety and efficacy of 86 VDD units implanted in 73 patients at a single center since November 1988 was reviewed. All patients suffered from advanced AV block with normal sinoatrial function. Sixty five patients received a LEM/CCS Twinal 30/30S system, four patients received a Vitatron-Saphir system, and four patients received a Medtronic Thera VDR 8348 system. All patients underwent provocative tests in search of myopotential interference, and Holter recordings; in a group of patients who underwent pacemaker replacement a comparison was made between implant and replacement measurements. The mean follow up duration was 27.3 months. A high percentage of successfully VDD paced patients and a low incidence of pacemaker malfunction, regularly solved by pacemaker reprogramming, was reported. Atrial signal amplitudes comparable to those measured at implant were found at replacement in all patients. These data support the long-term reliability of single AV lead VDD pacing systems with closely spaced atrial dipoles, as well as stable atrial sensing by floating bipolar atrial electrodes and effective atrial synchronous ventricular pacing over time. PMID- 7845783 TI - A new dual chamber single lead system. AB - A DDD pacing system normally requires the introduction and positioning of two separate electrode leads. A VDD system may use a single lead with a ventricular electrode at the tip and at least one atrial ring electrode. The disadvantage of VDD systems is that the full range of DDD stimulation and detection alternatives is not available. The present animal study was made to evaluate a new single lead design with the distal electrode placed in the atrium and the proximal ring electrode in the right ventricle. This design permits the full range of DDD options including atrial stimulation. Acute stimulation thresholds and sensing amplitudes were stable and comparable to conventional DDD systems. Long-term studies are on-going. PMID- 7845784 TI - Comparative evaluation of bipolar atrial electrogram amplitude during everyday activities: atrial active fixation versus two types of single pass VDD/R leads. AB - Endocardial P wave amplitude (PWA) is an important determinant of the atrial sensing capabilities of an atrial-based pacing system. Although changes in PWA during physical activities are known to occur in DDD/R pacing, there is little information on the P wave stability in single pass lead VDD/R pacemakers using floating P wave sensing. We investigated the variation of PWA during daily life activities using telemetry recorded atrial electrograms in 21 patients with DDDR pacemakers (Relay or Elite) and 29 patients with single lead VDD/R pacemakers (Unity or Thera). Physical activities resulted in marked individual variability of PWA but, as a group, there was no significant difference between PWA during sitting, standing, lying down, and coughing in both DDDR and VDD/R pacing. In the Elite II pacemaker, walking at 2 miles per hour resulted in significant reduction of PWA (11.6% compared with sitting, P < 0.05). The most consistent reduction in PWA occurred in the relaxation phase of the Valsalva maneuver (VM), with all pacemakers showing a reduction in PWA (mean reduction in PWA compared with sitting in DDDR and VDD/R were 16.6% and 12.8%, respectively). Two patients with DDDR pacemakers (Relay) and three patients with VDD/R pacemakers (1 Unity and 2 Thera) had atrial sensing failure during VM or walking. In conclusion, large variation in PWA occurs during daily life activities. The extent of variation is dependent on the patients, types of atrial lead, and the maneuvers performed. A twice sensing threshold may be insufficient to ensure adequate atrial sensing during these activities.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845785 TI - Avoiding atrial undersensing by assessment of P wave amplitude histogram data. AB - Reliable sensing of the P wave is an essential requirement for the appropriate functioning of any device that uses atrial tracking to provide AV synchrony. However, a single measurement of the P wave amplitude, either at implantation or during follow-up, may not be a reliable reflection of the P wave amplitudes that occur during daily life. The P wave amplitude histogram is a new feature that automatically measures the P wave amplitude at regular intervals and provides the distribution of these measurements. This enables the assessment of the smallest P wave amplitudes that occur. Two populations were studied: 104 patients with a fixed atrial lead and a DDDR pacemaker and 100 patients with a single pass VDD lead and a VDD pacemaker. Both pacemakers incorporate the P wave amplitude histogram feature. Data in the P wave amplitude histogram were compared with a single measurement of the P wave amplitude at each follow-up. Programming of a 100% safety margin based on a single measurement of the P wave amplitude provided reliable atrial sensing in only 72% and 43% of the patients of both populations, respectively. Data continued in the P wave amplitude histogram may be a useful adjunct for the optimal programming of atrial sensitivity. PMID- 7845786 TI - P wave recognition and atrial stimulation with fractally iridium coated VDD single pass leads. AB - The bottleneck of VDD systems is the reliable detection of the small atrial signals by a floating atrial electrode. Fractally iridium coated electrodes offer excellent sensing and pacing performance. In this study, the performance of such a floating atrial lead in P wave sensing and synchronous ventricular stimulation was examined. Atrial pacing was also used as a test of atrial wall contact. PATIENTS AND METHODS: A fractally iridium coated VDD lead was implanted in 18 patients. In 15 patients it was interfaced with a VDD pacemaker and in 3 patients with a DDD system depending on the P wave amplitude measured acutely (> or = 2 mV). Simultaneous recordings of the surface ECG and pacemaker telemetry were used to analyze P wave amplitudes and AV synchrony in different body positions, and during normal and deep breathing. Additionally, exercise tests based on daily life activities and 24-hour ECG monitoring were performed to test the pacemaker function. RESULTS: During implantation P wave amplitudes were 1.86 mV +/- 1.08 mV (range 0.5-4.9 mV) and during follow-up (6.6 +/- 5.6 weeks) 0.18-3.8 mV. Holter recordings revealed reliable P wave sensing at a sensitivity setting of 0.5 mV (95.5%). P wave sensing was further improved by a higher atrial sensitivity. AV synchronous pacing > or = 99.9% was achieved in all patients. In 7 patients the atrial electrode could be positioned close to the atrial wall enabling atrial stimulation thresholds at an average of 4.3 volts. CONCLUSION: This fractally iridium coated VVD lead allowed consistent and reliable P wave sensing at an atrial sensitivity as low as 0.5 mV in selected patients. PMID- 7845787 TI - A new pacemaker for paroxysmal atrial fibrillation treated with radiofrequency ablation of the AV junction. AB - Atrial fibrillation is a relative contraindication to atrial synchronous pacing because of the risk of the tracking of rapid atrial rhythms by the pacemaker. In this study, we describe the clinical results of an AV synchronous rate responsive pacemaker with an original algorithm, which is able to sense pathological increments in atrial rate and automatically to switch into a non-AV synchronous mode of pacing. This pacemaker was implanted in 12 patients who had undergone radiofrequency ablation of the AV junction in order to cure severely symptomatic, drug refractory, paroxysmal atrial fibrillation. In an acute, intrapatient comparison between the standard AV synchronous mode and the automatic switching mode, ventricular tracking of atrial fibrillation occurred in 35% and 4% of total beats at rest and in 24% and 2% of total beats during exercise, respectively (P < 0.001). During 5 +/- 4 months of follow-up, no further tachyarrhythmia related symptoms occurred. In conclusion, the standard DDDR mode is unable to eliminate ventricular tracking of atrial fibrillation, thus undermining the efficacy of AV junction ablation therapy. The automatic switching mode eliminates this adverse effect of dual chamber pacing. PMID- 7845788 TI - A new automode switch algorithm for supraventricular tachycardias. AB - Patients with complete heart block on a spontaneous, or iatrogenic basis who also have recurrent supraventricular tachycardias, particularly atrial fibrillation and flutter, are often difficult to manage. Various techniques include: independently programmable maximum tracking and maximum sensor rates, limiting the maximum atrial tracking rate to the sensor response of the pacemaker, or automatically switching from DDDR to VVIR based upon the sensed atrial rate. This article will describe a mode switch algorithm that allows for an independently programmable atrial tachycardia detection rate (ATDR). This allows mode switching to occur only in response to the patient's pathological tachyarrhythmia, and not during normal upper rate response. The ATDR is based upon a filtered atrial rate, which will prevent an isolated premature beat from initiating the algorithm. In addition, the unit can be programmed to switch to either DDI, DDIR, VVI, or VVIR. Extensive event counters in the pulse generator allows the system to record and store the number of algorithm activations, the average atrial rate which triggered each mode switch, and the duration of the mode switch. These reports are accessible at each follow-up visit. PMID- 7845789 TI - Initial experience with mode switching in a dual sensor, dual chamber pacemaker in patients with paroxysmal atrial tachyarrhythmias. AB - Mode switching algorithms have been developed to avoid tracking of atrial fibrillation (AF) or flutter (AFL) during DDD(R) pacing. Upon recognition of AF or AFL, the mode is switched to a nontracking, sensor driven mode. The Vitatron Diamond model 800 pacemaker does this on a beat-to-beat basis. Atrial events occurring within a "physiological range" (+/- 15 beats/min) calculated from a running average of the atrial rate are tracked. When atrial events are not tracked the escape interval is either determined by the sensor(s) or by a fallback algorithm thereby preventing large increases in V-V interval during mode switching. Loss of atrioventricular (AV) synchrony by atrial premature beats and after an episode of AF or AFL is prevented by atrial synchronization pulses (ASP), which are delivered after a safe interval (timed out from the sensed premature atrial event) has expired and before delivery of the next ventricular stimulus. We implanted 26 such devices in 18 men and 8 women with symptomatic second- or third-degree AV block and paroxysmal AF or AFL. Their ages ranged from 18-84 years (mean 60), and the follow-up ranged from 2-13 months (mean 8). During pacemaker check-up, exercise testing or 24-hour Holter monitoring one or more episodes of mode switching was documented in 8 patients. In these 8 patients a smooth transition (ventricular rate) from sinus rhythm to AF or AFL was documented on one or more occasions, without inappropriate increase in ventricular rate in the DDDR mode. None of the patients complained of palpitations.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845790 TI - Initial experience with a new algorithm for automatic mode switching from DDDR to DDIR mode. AB - Implantation of dual chamber devices in patients with paroxysmal atrial tachyarrhythmias who require permanent pacemakers may lead to significant complications due to an inappropriately triggered ventricular response. VVI/VVIR units cause loss of AV synchrony in the presence of sinus activity. A new DDDR device (THERA DR, model 7940), with an automatic mode switching (AMS) algorithm, was evaluated. When the mean atrial rate is > 182 beats/min, atrial tachyarrhythmia is detected, and AMS is activated. Twenty-three patients (12 males, mean age 71 +/- 7 years) underwent implantation of a THERA DDDR device with the AMS algorithm. Seventeen patients had AV block and/or sick sinus syndrome (SSS) and atrial arrhythmias, and 6 patients (2 with hypertrophic obstructive cardiomyopathy) had SSS and paroxysmal atrial fibrillation (PAF). The follow-up period was from 1-9 months. During follow-up, Holter monitoring and treadmill tests were performed. RESULTS: Eighty-seven episodes of AMS were recorded. Telemetered AMS recordings demonstrated episodes in which the DDDR mode switched to the DDIR mode in the presence of PAF, and reverted to DDDR when sinus rhythm returned. Paroxysmal supraventricular arrhythmias with a heart rate < 182 beats/min did not activate the mode switch. CONCLUSIONS: This early, short-term clinical experience with a DDDR device capable of AMS from DDDR to DDIR demonstrated appropriate clinical function and response to PAF. These preliminary results suggest that DDDR pacemakers with AMS to DDIR may significantly extend the current indications for dual chamber pacing. PMID- 7845791 TI - The "automatic mode switch" function in successive generations of minute ventilation sensing dual chamber rate responsive pacemakers. AB - Automatic mode switch (AMS) from DDDR to VVIR pacing is a new algorithm, in response to paroxysmal atrial tachyarrhythmias. With the 5603 Programmer, the AMS in the Meta DDDR 1250 and 1250H (Telectronics Pacings Systems, Inc.) operates when VA is shorter than the adaptable PVARP. With the 9600 Programmer, an atrial protection interval can be defined after the PVARP. The latest generation, Meta DDDR 1254, initiates AMS when 5 or 11 heart cycles are > 150, 175, or 200 beats/min. From 1990 to 1993, 61 patients, mean age 61 years, received a Meta DDDR: in 24 a 1250, in 12 a 1250H and in the remaining 25 a 1254 model. Indication for pacing was heart block in 39, sick sinus syndrome in 15, the combination in 6, and hypertrophic obstructive cardiomyopathy in 1. Paroxysmal atrial tachyarrhythmias were present in 43. All patients had routine pacemaker surveillance, including 52 Holter recordings. In 32 patients, periods of atrial tachyarrhythmias were observed, with proper AMS to VVIR, except during short periods of 2:1 block for atrial flutter in 4. In two others, undersensing of the atrial arrhythmia disturbed correct AMS. With the 1250 and 1250H model, AMS was observed on several occasions during sinus rate accelerations in ten patients. This was never seen with the 1254 devices. Final programmation was VVIR in 2 (chronic atrial fibrillation), AAI in 1 (fracture of the ventricular lead), VDDR in 1 (atrial pacing during atrial fibrillation), DDD in 5, and DDDR in 53, 48 of whom had AMS programmed on.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845792 TI - Quantitative comparison of rate response and oxygen uptake kinetics between different sensor modes in multisensor rate adaptive pacing. AB - Although multisensor pacing may mitigate the inadequacy of rate adaptation in a single sensor system, the clinical role of multisensor driven rate adaptive pacing remains unclear. The cardiopulmonary performance of six patients (mean age 63.5 +/- 10 years) who had undergone the implant of combined QT and activity VVIR (Topaz) pacemakers was assessed during submaximal and maximal treadmill exercise with the rate response sensor randomly programmed to either single sensor mode, QT and activity (ACT), or dual sensor mode, with equal contribution of QT and ACT (QT = ACT). The rate of response, the proportionality, oxygen kinetics, and maximal exercise performance of the various sensor modes during exercise were measured and compared. The ACT sensor mode "overpaced" and the QT and QT = ACT sensor modes "underpaced" during the first three quartiles of exercise (P < 0.05). The ACT sensor mode also gave the fastest rate of response with the shortest delay (13 +/- 1.5 sec vs 145 +/- 58 sec and 41 +/- 17 sec, P < 0.05), time to 50% rate response (39 +/- 2.7 sec vs 275 +/- 48 sec and 203 +/- 40 sec, P < 0.05), and time to 90% of rate response (107 +/- 21 sec vs 375 +/- 34 sec and 347 +/- 34 sec, P < 0.05) and a smaller oxygen debt (0.87 +/- 0.16 L vs 1.10 +/- 0.2 L and 1.07 +/- 0.18 L, P < 0.05) compared to the QT and QT = ACT sensor modes, respectively. These differences were most significant at low exercise workloads. Thus, different sensor combinations result in different rate response profiles and oxygen delivery, especially during low level exercise.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845793 TI - A rate responsive pacemaker that physiologically reduces pacing rates at rest. AB - Current rate responsive pacemakers incorporate sensors such as minute ventilation (MV) for adapting to changing patient conditions during exercise and periods of exertion. However, for sleep and/or rest periods, the only pacemakers currently on the market that slow the pacing rate utilize an internal timer to determine a decrease in pacing rate. It would be advantageous if the pacing rate could be automatically lowered during periods of sleep or rest. This study utilized a rate responsive sensor, MV, to track the patient's sleeping and resting periods and to decrease the pacing rate at such times. A total of eight patients implanted with Sentri 1210 single chamber MV sensor pacemakers were studied. A sleep rate (SR) of 45 beats/min was selected. A sleep rate response function, which indicated the relationship between changes in MV and corresponding heart rate, was initially set at a value of 16 and continually and automatically updated in a 3-month study. Adaptation was based on the premise that 3 hours per day should be spent at the SR. The average decrease in pacing rates from onset to 3 month for the eight patients was 12.4% +/- 5.3%. Correspondingly, the histograms of the lowest datalog histogram (40-59 beats/min) increased from 0% to 15.4% +/- 0.9% of paced beats. Correlation between the patients' 24-hour diary and Holter recordings showed that the pacing rates during sleep were consistently lower than when the patients were awake and active. This was also the case with a patient whose nocturnal and daily routine was intentionally altered.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845794 TI - Adjusting heart rate during sleep using activity variance. AB - In order to mimic the natural decrease in heart rate that occurs during sleep, an algorithm was devised to decrease the base rate to a programmable sleep rate. The algorithm was developed using activity and sinus rate data obtained from 18 normal subjects ranging in age from 22-80 years. The data were recorded in the event record of a "taped-on" pacemaker. The surface ECG signal was used to inhibit a pacer programmed to VVI at 45 ppm. The ECG documented the sinus rate while the accelerometer-based activity signals were recorded in an event record. An algorithm was used to estimate the smoothed acceleration variance every 26 seconds. The activity variance was stored in a histogram. RESULTS: The lower 7/24ths of the histogram entries were primarily attributable to sleep. If the activity variance was entered into the lower 7/24ths of the histogram and the accelerometer reading was below rate responsive threshold, the base rate was switched to sleep rate. Using least mean squares to estimate optimal slope, base rate, and sleep rate, the root mean square error between activity derived heart rate and sinus rate was 12 beats/min. CONCLUSION: This study supports using an estimate of activity variance to automatically decrease pacing rate below programmed base rate. This decrease may be actuated during an afternoon nap or nighttime sleep. PMID- 7845795 TI - Oxygen pressure as biosensor for rate adaptive cardiac pacing. AB - A new carbon based oxygen sensor for rate adaptive cardiac pacing has been developed. It measures oxygen partial pressure In mixed venous blood. The system was implanted in six sheep with a mean follow-up time of 261 days after implant. The sensor reacted in a physiological manner when the animals were at rest as well as during exercise. Long-term sensor stability and sensitivity were satisfactory, and we found excellent correlation with spontaneous heart rate variations and with oxygen saturation measurements. The sensor shows great promise although our experience is still limited and further development on the concept is on-going. PMID- 7845796 TI - Clinical study of a new activity sensor for rate adaptive pacing controlled by electrical signals generated by the kinetic energy of a moving magnetic ball. AB - A new rate adaptive pacemaker (Sensorithm) controlled by an activity sensor providing electrical signals induced by a magnetic ball moving freely in an elliptical cavity surrounded by two copper coils, was implanted in ten patients; mean age of 75 years (range 64-89). Six patients had atrioventricular block and four had sinus node disease. In auto-set testing procedure during a 1-minute walk in the corridor, a slope resulting in a maximum rate of 95 beats/min was selected in every patient, and a medium reaction time was programmed. During graded treadmill exercise tests the heart rate increased 63 +/- 7 beats/min to 135 +/- 6 beats/min in rate adaptive pacing mode (VVIR), and 15 +/- 6 beats/min (P < 0.0001) in ventricular pacing mode (VVI). The symptom-limited exercise time was 9.1 +/- 1.1 minutes and 8.2 +/- 1.2 minutes (P = NS), and the exercise distance was 501 +/- 95 meters and 428 +/- 92 meters (P < 0.05) in VVIR and VVI pacing mode, respectively. The maximum oxygen uptake was 20.6 +/- 2.6 mL/kg per minute in VVIR pacing and 18.1 +/- 2.1 mL/kg per minute (P < 0.05) in VVI pacing. The delay time until the pacing rate increased 10% of the total rate increase at onset of treadmill exercise was 4.4 +/- 0.7 seconds.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845797 TI - Clinical evaluation of a dual sensor, rate responsive pacemaker. AB - Dual sensor pacemakers should respond more appropriately during differing exercise modes than a single sensor device. The Topaz model 515 (QT and activity count [ACT] sensing) pacemaker shows appropriate rate response during treadmill exercise testing. We postulated that adjustments to relative sensor contribution should allow fine tuning of the onset of rate response. Eleven patients with this pacemaker were studied. Three standard exercise tests were performed with adjustment of sensor blending and activity threshold between each one. We also assessed the response to isometric exercise and a false positive activity signal. RESULTS: Times to 100 ppm (3.7 +/- 1.3, 4.4 +/- 2.0, 5.3 +/- 1.5 mins), times to peak rate (6.1 +/- 1.6, 5.6 +/- 1.4, 6.5 +/- 1.3 mins) and accelerations to peak (9.0 +/- 2.4, 9.2 +/- 5.3, 7.7 +/- 2.8 ppm/min) were measured in all three different sensor settings (QT = ACT, QT < ACT, and QT = ACT with decreased activity threshold). No significant difference in onset of rate response was seen between the three settings. Tapping (false-positive activity) provided a rapid rise in paced rate to 79 ppm from a resting value of 65 ppm. This came down to 71 ppm demonstrating satisfactory sensor cross-checking. Isometric exercise induced a moderate response from 65 ppm at rest to 74 ppm after 3 minutes. CONCLUSIONS: Satisfactory rate response was demonstrated in most patients to treadmill testing and to isometric exercise. However, small adjustments to relative sensor contributions do not predictably alter the onset of rate response. PMID- 7845798 TI - Stepwise analysis of the calibration procedure of an accelerometer-based pacemaker. AB - The rate modulation of Relay 294-03 is individually adjusted during a 3-minute calibration test corresponding to the collection of moderate acceleration signals (MAL), which are related to a programmable moderate pacing rate (PR). Those rate/acceleration values form a calibration point in the flat part of the rate response curve (RRC). To help in a more clinically oriented analysis of this feature, the stimulator was first calibrated while strapped on a volunteer who remained seated (low MAL), walked (medium MAL), or jogged (high MAL). The device was then mechanically submitted to three calibrated to and fro movements corresponding to the sensitivity spectrum of the sensor. Each movement was repeated ten times to test the influence of the slope (1-10). RESULTS: (1) One way ANOVA significant effect of the MAL recorded during the calibration test on subsequent rate modulation (P = 0.0001); (2) The sensor amplifier gain was inversely related to the MAL: high MAL induced lower amplifier gain and lower PR for identical accelerations; (3) Lower amplifier gain allowed to discriminate highest acceleration magnitudes before reaching an overflow of the sensor; (4) The maximum achievable PR increased not only with the programmed slope, but also with decreasing MAL (P = 0.0055): a low MAL shifts to the left calibration point located on the part of the RRC and makes the last steep part of the RRC start earlier, thus leading to higher maximum achievable PR. In conclusion the calibration procedure is crucial not only in defining a moderate acceleration intensity but also in determining the sensor amplifier gain and the maximum achievable PR. PMID- 7845799 TI - New algorithms to increase the initial rate response in a minute volume rate adaptive pacemaker. AB - BACKGROUND: Minute volume is a truly physiological sensor for rate adaptive pacing that correlates with metabolic expenditure throughout the range of physical activity. Criticism has centered on the slow initial response compared to less physiological sensors. A new algorithm, consisting of rate augmentation factor and programmable speed of response, has been incorporated in the 1206 META III pacemaker generator and was designed to improve the rate response at lower levels of exertions. Rate augmentation factor increases the programmed rate response factor by 3, 6, or 10 when set to low, medium, or high, respectively; this augmentation lasting to 50% of the maximum programmed rate. Response time can be programmed to medium or fast. METHODS: Nine patients were studied during the first 3 minutes of an exercise test (Bruce protocol) in a single blind manner. The pacemaker generator was randomly programmed with rate augmentation factor at off, low, or high and speed of response to medium or fast, giving six possible combinations. Heart rates were recorded continuously for the duration of the test and until resting heart rate was achieved during recovery. The test was repeated until all six combinations had been tested. RESULTS: During exercise significant differences appeared in response time from 30 seconds onward. Fast response and rate augmentation factor contributed to an improved rate response with greatest speed of response seen with fast response time and high rate augmentation factor. During recovery decreases in recovery time were seen with fast response time but rate augmentation factor prolonged recovery. CONCLUSIONS: Rate augmentation factor improves initial rate response in the early stages of exercise. Fast response gives an improved time to initial rate increase and shortens the duration of inappropriate postexercise tachycardia. These features improve the pattern of response of the minute ventilation sensor. PMID- 7845800 TI - A new pacing algorithm for overdrive suppression of atrial fibrillation. Chorus Multicentre Study Group. AB - Constant rapid pacing may suppress arrhythmias, but it is usually poorly tolerated in the long term. We report a pilot study of a new pacing algorithm for overdrive suppression of atrial premature complexes (APCs) and atrial fibrillation (AF), which prevents postextrasystolic pauses and varies the pacing rate in response to the frequency of APCs. The algorithm was tested in a multiple crossover study for 24 hours in dual chamber pacemakers implanted in 70 patients. Comparison was made on ambulatory recordings between the number of atrial arrhythmias commencing with the algorithm active and inactive. In all cases, the algorithm functioned as designed. No patient was aware of its operation, and no malignant arrhythmias were induced. The 36 recordings that showed atrial arrhythmia were included for analysis. The effects of the algorithm were: APCs (estimated from pacemaker statistics) reduced in 18 patients, increased in 8 (P = 0.02); atrial salvos reduced in 12, increased in 4 (P = 0.041); and AF reduced in 11, increased in 8 (P = NS). In all patients with frequent AF (> 5 episodes in total), fewer episodes occurred when the algorithm was active. We conclude that the algorithm is safe and well tolerated, reduces atrial ectopic activity, and may reduce the frequency of sustained atrial fibrillation. PMID- 7845801 TI - Four chamber pacing in dilated cardiomyopathy. AB - A 54-year-old man received a four chamber pacing system for severe congestive heart failure (NYHA functional Class IV). His ECG showed a left bundle branch block (200-msec QRS duration) with 200-msec PR interval, normal QRS axis, and 90 msec interatrial interval. An acute hemodynamic study with insertion of four temporary leads was performed prior to the implant, which demonstrated a significant increase in cardiac output and decrease of pulmonary capillary wedge pressure. A permanent pacemaker was implanted based on the encouraging results of the acute study. The right chamber leads were introduced by cephalic and subclavian approaches. The left atrium was paced with a coronary sinus lead, Medtronic SP 2188-58 model. An epicardial Medtronic 5071 lead was placed on the LV free wall. The four leads were connected to a standard bipolar DDD pacemaker, Chorus 6234. The two atrial leads were connected via a Y-connector to the atrial channel of the pacemaker with a bipolar pacing configuration. The two ventricular leads were connected in a similar fashion to the ventricular channel of the device. The right chamber leads were connected to the distal poles. The left chamber leads were connected to the proximal poles of the pacemaker. Six weeks later, the patient's clinical status improved markedly with a weight loss of 17 kg and disappearance of peripheral edema. His functional class was reduced to NYHA II. Four chamber pacing is technically feasible. In patients with evidence of interventricular dyssynchrony, this original pacing mode probably provides a mechanical activation sequence closer to the natural one.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845802 TI - Septal short atrioventricular delay pacing: additional hemodynamic improvements in heart failure. AB - Controversy exists as to whether short AV delay pacing is beneficial in left ventricular dysfunction with the studies performed coming to disparate conclusions. The right ventricular apical pacing previously studied results in asynchronous contraction and relaxation sequences and may limit the potential benefits of short AV delay pacing. In this study the hemodynamic effects of septal (resulting in a more physiological activation sequence) and apical right ventricular activation were compared in 15 patients with heart failure. VDD pacing with AV delays of 50, 100, and 150 msec was evaluated. Apical VDD pacing did not increase the cardiac output significantly, 4.1 +/- 0.75 to 4.45 +/- 0.74 L/min, whereas septal VDD pacing increased the cardiac output to 4.86 +/- 0.79 L/min (P = 0.037). Apical pacing increased the cardiac output in 10 patients and septal pacing in 11 patients. We conclude that selected patients with ventricular dysfunction benefit from short AV delay pacing. Septal ventricular activation confers significant hemodynamic improvements over apical activation. PMID- 7845803 TI - AV delay optimization and management of DDD paced patients with dilated cardiomyopathy. AB - Ten DDD paced patients, suffering from dilated cardiomyopathy in the NYHA functional classes III or IV were studied by means of Doppler echocardiography at different programmed values of atrioventricular (AV) delay (200, 150, 120, 100, and 80 msec). The following variables were evaluated: LV diameter, ejection fraction, mitral and aortic flow velocity integrals, and stroke volume. During VDD pacing, a resting AV delay associated with the best diastolic filling and systolic function was identified and programmed individually. Shortening of the AV delay to about 100 msec was associated with a gradual and progressive improvement. Further decrease caused an impairment of systolic function. The patients were clinically and hemodynamically reevaluated after 2 months of follow up. A reduction of NYHA class and an improvement of LV function were consistently found. The reported data suggest that programming of an optimal AV delay may improve myocardial function in DDD paced patients with congestive heart failure. This result may be the consequence of an optimization of left ventricular filling and a better use of the Frank-Starling law. PMID- 7845804 TI - Critical PQ interval for the appearance of diastolic mitral regurgitation and optimal PQ interval in patients implanted with DDD pacemakers. AB - Diastolic mitral regurgitation (MR) may be induced by prolonging atrioventricular (AV) delay, and a significant negative correlation has been described between the critical PQ interval for the appearance of diastolic MR and pulmonary capillary wedge pressure (PCWP) in patients with DDD pacemakers. We report the relationship between the critical PQ interval for the appearance of diastolic MR and the optimal PQ interval in 11 patients (69.1 +/- 12.6 years). Cardiac output (CO) and PCWP were measured by Swan-Ganz catheter and transmitral blood flow was recorded by pulsed-Doppler echocardiography. AV delay was prolonged stepwise by 0.025 seconds starting from 0.065 seconds. The pacing rate was fixed at 70 beats/min. CO was highest when the PQ interval was 0.18 +/- 0.04 seconds. There was a significant positive correlation between the critical PQ interval for the appearance of diastolic MR and the PQ interval at which CO was the highest (r = 0.91, P < 0.01). The PQ interval at which CO was the highest was 0.02 +/- 0.02 seconds shorter than the critical PQ interval for the appearance of diastolic MR (P < 0.05). When the PQ interval was increased by 0.025 seconds from the critical PQ interval for the appearance of diastolic MR, CO decreased from 4.3 +/- 0.6 L/min to 4.1 +/- 0.6 L/min and PCWP increased from 7.5 +/- 6.4 mmHg to 8.5 +/- 7.3 mmHg (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845805 TI - Importance of a systematic long-term follow-up to guide the choice of pacemaker electrodes: the experience of a single center with 18,132 leads. PMID- 7845806 TI - Analysis of the effectiveness of in-office and transtelephonic follow-up in terms of pacemaker system complications. AB - A study was undertaken to determine the most effective method of pacemaker follow up in terms of the total number of complications detected and yield per follow-up in single and dual chamber pacing systems. The analysis involved 9,786 patient records from 635 patients. The records were reviewed with respect to method of follow-up, number of chambers paced, and complications detected. Complications included: oversensing, undersensing, noncapture, pocket and diaphragmatic stimulation, pacemaker mediated tachycardia, crosstalk, pulse generator malfunction, lead malfunction, infection/erosion, premature end of service, exit block, and other miscellaneous problems. Eight thousand two hundred eighty-eight of the 9,786 follow-ups were performed in the office while 1,498 were transtelephonic. Single chamber pacing systems were implanted in 329 patients and 306 were dual chamber systems. A total of 599 complications were detected. Analysis yielded a per patient complication rate of 5.1% (single chamber) and 8.4% (dual chamber) for in-office follow-up. This compared to a transtelephonic follow-up per patient complication rate of only 0.3% (single chamber) and 1.0% (dual chamber). In-office pacemaker follow-up is significantly more effective (P < 0.001) than transtelephonic follow-up in detecting both single and dual chamber pacemaker system complications. PMID- 7845807 TI - Direct and telemetered lead impedance. AB - OBJECTIVES: We undertook this study to determine whether telemetered lead impedance measurements (LIM) can be correlated with direct LIM and to determine the stability of LIM over time when measured directly and via telemetry. METHODS: Direct LIM and telemetered LIM were measured in 91 patients; 101 leads during initial implantation and 40 leads during pulse generator replacement. Differences in direct LIM measured during initial implant and pulse generator replacement (direct-direct) were compared in 41 patients (28 atrial leads and 37 ventricular leads). The stability of telemetered LIM obtained immediately postoperatively, at 1 month and 1 year, postimplantation was assessed in 50 patients (23 atrial and 49 ventricular leads). RESULTS: In atrial leads acute direct LIM was 633.9 +/- 18.4 omega versus 575.8 +/- 18.5 omega for telemetered LIM (r = 0.58), and chronic direct LIM was 670.9 +/- 49.3 omega versus 607.0 +/- 36.3 omega for telemetered LIM (r = 0.87). In ventricular leads acute direct LIM was 747.3 +/- 16.9 omega and 684.7 +/- 16.4 omega for telemetered LIM (r = 0.69), and chronic direct LIM was 674.8 +/- 29.9 omega and 625.2 +/- 28.5 omega for telemetered LIM (r = 0.68). The mean direct-direct LIM rose 124 omega (P < 0.001) in atrial leads and 10 omega (P = NS) in ventricular leads. Telemetered LIM for atrial leads was 581.0 +/- 27.6 omega immediately postimplantation compared to 625.7 +/- 34.8 omega at 1 month and 754.1 +/- 43.0 omega at 1 year. Telemetered LIM for ventricular leads was 661.3 +/- 17.5 omega at implant, 684.6 +/- 20.7 omega at 1 month and 724.7 +/- 22.7 omega at 1 year. CONCLUSIONS: There is a good but limited correlation between direct and telemetered LIM. Mean direct LIM obtained at initial implantation is similar to that measured at pulse generator replacement. The telemetered LIM is stable over the first month postimplantation but tends to rise during the first year of follow-up and substantial changes in impedance are not uncommon in individuals with normal function. There is a tendency for LIM to rise with lead maturation. If telemetered LIM is to be followed over time, a baseline telemetered value should be obtained immediately postoperatively. PMID- 7845808 TI - Comparison of threshold values between steroid and nonsteroid unipolar membrane leads. AB - The aim of this study was to evaluate whether steroid membrane leads can reduce pacing thresholds and thereby save energy as compared to nonsteroid membrane leads. The study was a random sample, double blind test consisting of 90 patients between 49-94 years of age admitted to seven hospitals in Europe for pacemaker implantation. The two leads compared in this study had contoured activated carbon tips covered with ion exchange membranes. The leads were identical except that 30 micrograms of dexamethasone was dissolved in the ion exchange membrane of one of the leads. Normal lead implant procedures were used. Follow-up procedures were conducted at 2 weeks and 1, 3, 6, and 12 months after lead implantation. The pulse generator was programmed to an amplitude of 2.5 or 5 V and a duration of 0.5 msec. The stimulation threshold was measured using the VARIO function. The threshold was measured a total of three times in order to determine the presence of microdislocations. At the 2- and 4-week follow-ups, the stimulation threshold was significantly lower for the steroid leads than for the membrane leads without steroid (0.54 +/- 0.19 vs 0.76 +/- 0.25 V, P = 0.0005; and 0.59 +/- 0.19 vs 0.74 +/- 0.26 V, P = 0.005), but after 3 months, the threshold values were almost the same for both leads. PMID- 7845809 TI - Early complications after dual chamber versus single chamber pacemaker implantation. AB - This study was performed to compare the frequency of early complications after single chamber versus dual chamber permanent pacemaker implantation. Early complication was defined as one occurring in the 6-week period following implantation. We prospectively analyzed consecutive pacemaker implantation from January 1987 to June 1993 at our regional center. All complications were also analyzed for the relationship to operator experience, the venous access route, and the presence of temporary pacing wire at the time of implantation of the permanent pacing system. A total of 2019 new pacemaker units were implanted during this period. 1733 patients (85.8%) received a VVI pacemaker and 286 (14.2%) a DDD unit. Wound infection occurred in 11 (0.6%) VVI patients and 6 (2.1%) DDD patients. Lead displacement occurred in 18 (1%) VVI patients and 15 (5.2%) DDD patients (11 [3.8%] atrial and 4 [1.4%] ventricular). There were 10 (0.6%) pneumothoraces, 9 (0.5%) hematomas requiring drainage, 1 (0.06%) chylocele, and 2 (0.1%) deaths in the VVI group. There were 2 (0.7%) pneumothoraces, 2 (0.7%) hematomas, and no deaths in the DDD group. There was no significant increase in complications for experienced infrequent implanters (< 12 systems per year). In both groups the subclavian approach was associated with a risk of pneumothorax when compared to the cephalic approach. The rate of wound infection was higher in patients who had a temporary pacing wire in place. The use of prophylactic antibiotics does not appear to affect the incidence of wound infection.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845810 TI - Five-years experience with intravascular lead extraction. U.S. Lead Extraction Database. AB - From December 1988 to April 1994, the extraction of 2,195 intravascular pacing leads from 1,299 patients was attempted at 193 centers. Indications were: infection (54%, including 10% septicemia), pacemaker reoperation with removal of nonfunctional or incompatible leads (40%), and other causes (6%). Extraction was attempted via the implant vein using locking stylets and dilator sheaths, via the femoral vein using snares, retrieval baskets, and sheaths, or via both approaches. Leads had been implanted for 0.2 months to 24 years (mean 56 months). At the conclusion of the intravascular procedure, 86.8% of the leads were completely removed, 7.5% were partially removed, and 5.7% were not removed. For physicians performing their first case, 12% of leads were not removed; for physicians who had performed more than 10 cases, only 2% of leads were not removed. Of the 189 leads where extraction attempts had previously failed, 75.1% were completely removed, 14.8% were partially removed, and 10.1% were not removed. Scar tissue increased in severity with implant duration, was a complicating factor, and was the main cause of failure to remove leads. Use of the femoral approach increased with implant duration (5% of leads implanted 12 months or less, 11% of leads 13 months to 3 years, 20% of leads 4-7 years, and 31% of leads 8-24 years), primarily because of increasingly abundant scarring and prior lead damage. Fatal and near fatal complications occurred in 2.5%, including 8 (0.6%) deaths (3 hemopericardium/tamponade, 1 hemothorax, 3 pulmonary embolus, 1 stroke).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845811 TI - The effects of electronic article surveillance systems on permanent cardiac pacemakers: an in vitro study. AB - Five Siemens Pacesetter cardiac pacemakers (PM) were subjected to in vitro testing with six different electronic article surveillance (EAS) devices. The PMs consisted of polarity programmable, dedicated bipolar, and dedicated unipolar types. EAS equipment included UHF, RF, Magnetic, and Magnetoacoustic (MA) devices from two manufacturers. Prior to testing, each PM was interrogated and normal operation confirmed. Each PM was attached to a heart simulator via an eight foot cable and then subjected to testing within the EAS field. The PMs were passed through the field in two axes, positioned stationary within the field, and, worst case (WC), placed directly against the transmitter. During testing the ECG was observed and PM behavior recorded. In one PM (Synchrony III), Event Records, and Event Histograms were utilized. At the conclusion of testing with each EAS device the PM was evaluated for normal operation. RESULTS: No PM was reprogrammed by the EAS devices. UHF produced no effect on the PMs. RF produced noise response in one unipolar PM while in the WC position. High frequency and multifrequency magnetic units produced positive results only in the WC position. Unipolar PMs were affected more often than bipolar. MA and older magnetic EAS units produced more positive responses than newer lower power devices. One incident of close coupled (400 msec) ventricular pacing was seen with the MA EAS unit. CONCLUSIONS: UHF, RF, high frequency, and dual frequency magnetic EAS produced few effects during in vitro testing. Except with the MA and low frequency magnetic devices, positive results occurred only in WC conditions.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845812 TI - Outcomes of an ambulatory cardiac pacing program: indications, risks, benefits, and outcomes. AB - The purpose of this review was to evaluate the economical benefits and outcomes of an ambulatory pacing system implantation program that began in 1991 for new and replacement pacing system implantations. Patient access, incidence of complications, hospital bed day utilization, economic impact, safety, and practicality of the Ambulatory Pacing System Implantation Program was retrospectively reviewed from August 1991 to March 1994. The Ambulatory Pacing System Implantation Program includes pre-operative outpatient assessment in the pacemaker clinic, admission to the Day Medical Unit followed by same day pacing system implantation, discharge home after a short period of observation, and, in selected cases, cardiac monitoring, followed by pacemaker clinic visit 24-hours postimplantation. RESULTS: Two hundred four cardiac pacing systems, 154 new and 50 replacements (pulse generator/leads), were implanted under the guidelines of the Ambulatory Pacing System Implantation Program between August 1991 and March 1994. Eighty-seven percent of the patients were implanted with passive fixation leads, the remaining with active fixation leads; all but four of which were leads implanted in the atria. Preprocedure wait time was decreased from 16 to 2 days for elective pacing system implantation. The incidence of lead dislodgment in the first, second, and third year of the Ambulatory Pacing System Implantation Program was 20%, 12%, 5%, respectively; compared to 11% for a similar number of cases in previous years done as inpatients. The incidence of new infection was 2.4% compared to < 1% in previous years. Six of the 204 (2%) cases required admission overnight. A total savings of 1,456 bed days ($1,275,450.00; Canadian) has been realized for an equivalent number of cases when compared with previous years. The operational cost was reduced by $3,976.00 per case. CONCLUSION: It has been shown that the Ambulatory Pacing System Implantation Program has improved client access, and is a safe and economical approach to implantation of cardiac pacing systems. PMID- 7845813 TI - Improved epimyocardial pacing: initial experience with a new bipolar, steroid eluting, high impedance lead design. AB - Epicardial pacing typically is associated with decreased pacing and sensing capabilities compared with the endocardial approach. Since endocardial pacing is neither appropriate nor possible in all instances, this study was conducted to evaluate a new concept in a chronic epimyocardial lead design in six 3-month-old growing dogs. The new bifurcated lead (Medtronic model 10401) is a low current drain, high impedance, steroid-eluting, bipolar design. The implant is facilitated by a suture attached with an atraumatic needle. Twelve ventricular leads were implanted (2 per animal) and followed for 6 months with weekly analysis of pacing and sensing capabilities. Results at explant were compared with implant values. There were no significant differences between implant and explant in sensed R waves, or in the slew rate of the R wave in unipolar or bipolar modes. Lead impedances at explant remained high in both modes: bipolar, 1550 +/- 223; unipolar, 1234 +/- 262 omega (P < 0.05). Chronic voltage (v) threshold at 0.5 msec showed no significant change from implant values during the study: unipolar, 0.4 +/- 0.2 vs 0.7 +/- 0.3; bipolar, 0.5 +/- 0.4 vs 1 +/- 0.5. Histologic evaluations of the electrode tissue interface demonstrated negligible fibrotic capsule formation. This study introduces a new, easily implanted, high impedance, low threshold, bipolar epimyocardial pacing lead design with excellent chronic pacing and sensing characteristics. PMID- 7845814 TI - High atrial pacing impedance: efficient or wasteful? A comparison of an active and a passive fixation lead. AB - We compared the stimulation characteristics of two atrial fixation leads: the CPI model 4269 (n = 45) and Cordis-Telectronics model 327-752 (n = 42). The CPI lead uses an active fixation method, whereas the Cordis-Telectronics lead is fixated passively. Impedance and threshold were measured at implant and during 12 months of follow-up. P wave sensing was good with both types of leads. Follow-up of these 87 leads showed that both the impedance and threshold increased with the active leads, but not with the passive fixation leads. In the active fixation group, regardless of the high atrial pacing impedance, 93% could still be programmed to 2.5 V-0.6 msec (with a 2:1 threshold safety margin). It is concluded that the high chronic pacing impedance of the active fixation leads will be beneficial on current drain if no major increase in pacing threshold occurs simultaneously. PMID- 7845815 TI - Treatment of patients with prior exit block using a novel steroid-eluting active fixation lead. Model 4068 Investigators. AB - An increased interest has developed in active fixation leads for several reasons. Exit block is an uncommon complication that is seen with both active and passive fixation leads. Exit block has not been a significant problem with passive fixation steroid-eluting leads and has been treated with these leads. A new steroid-eluting active fixation lead was examined for its performance in patients in whom exit block had previously occurred. The lead function was evaluated prospectively in 24 patients with a history of exit block (15 ventricular and 9 atrial). The results in patients with atrial exit block are encouraging with an average chronic stimulation threshold of 0.19 msecs at 2.5 volts. Results in the ventricle are less encouraging with 3 occurrences of recurrent exit block in 15 patients; however, the remaining patients had a good mean threshold of 0.21 +/- 0.11 msecs at 2.5 volts. There were a remarkable number of non-lead related complications suggesting that this is a substantially different group than routine implantations. PMID- 7845816 TI - A comparison of VVIR and DDDR pacing following cardiac transplantation. AB - We compared the clinical course of patients paced in VVIR versus DDDR mode to determine the most appropriate method of pacing following cardiac transplantation. Pacemaker implantation was required in 9 of 90 orthotopic cardiac transplants (10%). Indications included sinus bradycardia or sinus arrest (8 patients) and AV node dysfunction (1 patient). VVIR pacemakers were implanted in four patients and DDDR in five patients. DDDR patients: The mean P wave was 1.7 mV and the mean atrial stimulation threshold was 0.8 V (at 0.5 msec). During follow-up of 20 months, two atrial lead complications developed (29% of leads in 33% of patients). No lead complications were directly related to endomyocardial biopsy. VVIR patients: All four patients developed VA conduction with mean VA time 180 msec (160-240 msec). Two patients developed pacemaker syndrome. CONCLUSIONS: VA conduction and pacemaker syndrome may develop in cardiac transplant recipients paced in the VVIR mode. Dual chamber pacing is technically feasible and preferable following cardiac transplantation. PMID- 7845817 TI - Bipolar intramyocardial electrogram from an implanted telemetric pacemaker for the diagnosis of cardiac allograft rejection. AB - Noninvasive detection of acute cardiac allograft rejection remains a challenge. Analysis of the epicardial electrogram transmitted by unipolar telemetric pacemaker can be of help in the detection of rejection with myocytolysis but is hampered by extracardiac factors. Instead, the contribution of a bipolar pacemaker for this purpose was studied. The bipolar peak-to-peak amplitude of epicardial electrograms (BPPA) from 25 patients implanted with a bipolar pacemaker at the time of heart transplantation was measured at the time of endomyocardial biopsies. BPPA was expressed as a percent of the baseline value. A voltage drop of more than 10% was considered an indication of rejection. Of 118 biopsies, 80 were free of rejection and 38 showed mild to moderate rejection (Grade 1A = 12; Grade 1B = 17; Grade 2 or 3 = 9). The mean value of BPPA was less for grade 2 biopsies (86.4 +/- 17%) than for biopsies with no or mild rejection (101.3 +/- 14.3% for Grade 0, 101.4 +/- 13.8% for Grade 1A, and 98.6 +/- 18% in Grade 1; P < 0.05). Diagnostic concordance between BPPA measurement and biopsy results increased with the histological severity of rejection (Grade 1A = 1/12, Grade 1B = 5/17, Grade > 2 = 7/9). Acute rejection was diagnosed with a sensitivity of 34% for Grade 1A, 46% for Grade 1B, and 78% for rejection episodes with myocytolysis (Grade > or = 2). Specificity remained approximately 90% for all histologic grades.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845818 TI - Sinus node dysfunction after orthotopic heart transplantation: the Vienna experience 1987-1993. AB - In the present study, the annual incidence of postoperative sinus node dysfunction and the type of sinus node abnormality after cardiac transplantation were followed over a 6 1/2-year period in 185 patients. Each year the sinus node function was systematically characterized by rhythm and corrected sinus node recovery time in a significant number of patients. Over the entire study period, there were 131 patients with normal sinus node function (corrected sinus node recovery time 318 +/- 55 msec) while 54 patients had latent (n = 24, sinus rhythm, corrected sinus node recovery time 8,053 +/- 2,198 msec) or manifest (n = 30, absence of sinus rhythm or pacemaker dependence) sinus node dysfunction. Twenty-nine patients had pacemaker placement. The incidence of sinus node dysfunction declined in absolute terms and when indexed by the actual number of patients transplanted per year (index 1987: 38.5; 1998: 17.6; 1989: 23.2; 1990: 29.1; 1991: 10.4; 1992: 7.5; 1993: 2.2). Among those with sinus node dysfunction, the annual percentage of patients presenting with prolonged recovery time, escape rhythm, and those reverting back to sinus rhythm until discharge did not change significantly over the study period (P = 0.22). On multivariate analysis, only the date of transplantation was significantly associated with the occurrence of postoperative sinus node deficiency (P = 0.0007) while age of recipient (P = 0.85) or donor (P = 0.96), the type of cardioplegia used (P = 0.09) and ischemic time (P = 0.09) were insignificant.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845819 TI - Dissimilar action of two cyclic adenosine-monophosphate analogues on the sodium current in intact rat papillary muscle. AB - In intact papillary muscles from rat we have found with the loose-patch-clamp technique an increase of the fast cardiac sodium current (INa+) by isoproterenol (ISO). In this study we have tested two membrane permeable analogues of the intracellular second messenger cyclic adenosine-monophosphate (cAMP) to investigate the intracellular pathway: 8-Br-cAMP (50 microM) and the newer developed Sp-5,6-Dichloro-1-beta-D-ribofuranosylbenzimidazole- 3',5'-cyclic monophosphorothioate (5,6-DCl-cBiMPS, 20 microM). The availability of INa+ was determined with test pulses to +/- 0 mV every 3.5 seconds after 2.5-second conditioning between -130 mV and -50 mV and a holding potential at the resting potential of the cell under examination, and after wash-in of either compound. The peak currents were fit to a Boltzmann equation, and expressed by the maximal attainable current INa+,max, the mid-point potential V1/2, and a steepness parameter alpha. Values are given by mean +/- SEM. 8-Br-cAMP showed a significant shift of the availability curve in the hyperpolarized direction (V1/2 = -82 +/- 2 mV vs -86 +/- 2 mV, n = 5, P < 0.05) with only minor changes of INa+,max and alpha. In contrast, 5,6-DCl-cBiMPS had no significant effect on V1/2 but increased INa+,max by 8% +/- 2% versus control (n = 5, P < 0.05). In an intact muscle preparation we have found that 5,6-DCl-cBiMPS has a similar effect as that observed with the beta-adrenergic agonist ISO (100 nM), whereas 8-Br-cAMP exhibited a dissimilar action.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845820 TI - Modulation of the electrical restitution of canine Purkinje fibers by local anesthetic drugs: a study with flecainide and propafenone. AB - Some antiarrhythmic drugs that depress conduction also influence action potential duration (APD). This could modify the time course of changes in the APD of premature stimuli (electrical restitution) and affect dispersion of repolarization and homogeneity of refractoriness. The effects of two potent local anesthetic drugs, i.e., flecainide and propafenone, on electrical restitution were studied in canine Purkinje fibers, superfused with Tyrode's solution and impaled with glass microelectrodes. APD was measured at 90% repolarization (APD90): fibers were stimulated for 3 minutes at cycle lengths (CLs) between 350 msec and 1.5 seconds, and kept quiescent for 5 minutes in between. For each run we calculated the percent ratio of the second APD (APD test = APDt) to the first APD after quiescence (APDo) (APDt/APDo x 100). The ratio was correlated with the CL of the run (i.e., the coupling interval between APDo and APDt = CI) by the monoexponential function APDt/APDo x 100 = 100-exp(-tau/CI), whose time constant tau indicates the speed of electrical restitution. At 1 microM, flecainide decreased tau by 26% +/- 4% (to 310 +/- 41 msec from 245 +/- 30 msec, n = 6, P < 0.05), while propafenone did not change it. Thus, unlike propafenone, flecainide slows the process of electrical restitution in Purkinje fibers. This may derive from the drug's action on currents other than Na current (i.e., IK), relevant to the duration of action potential. In a reentrant circuit, despite similar effects on conduction, APD and refractoriness of the first beat would be differently modulated by flecainide and propafenone. PMID- 7845821 TI - Inter- and intraindividual variations in shortening of ventricular effective refractory period after an abrupt decrease in pacing cycle length. AB - After an abrupt decrease in pacing cycle length (PCL), the ventricular effective refractory period (VERP) shortens. The pacing protocol needed to determine accurate and reproducible values for the VERP during this process is elaborate and time consuming. In this study, steady-state values of VERP at 800 and 350 msec PCL and dynamic values of VERP due to an abrupt change in PCL from 800 to 350 msec were determined. This was done for 11 different dogs to test the interindividual variation and repetitively in the same dog to test the intraindividual variation. The results for steady-state and dynamic values of the VERP show a wide range for both groups. This means that accurate prediction of steady-state and dynamic values of VERP based on previous measurements is not possible. PMID- 7845822 TI - Is the ventricular effective refractory period different when determined by incremental versus decremental scanning?: the effect of pacing cycle length, d sotalol, and levcromakalim. AB - In the clinical setting, the ventricular effective refractory period (VERP) is determined by an 8-beat drive train (S1S1), followed by a premature stimulus (S2), which is decremented in subsequent drive trains until capture is lost. Variation in intertrain pauses and capturing extra stimuli disturb steady-state conditions and reduce reproducibility of values found for the VERP. To increase reproducibility, a protocol without intertrain pause and incremental scanning (IS) of S2 was developed. In anesthetized dogs with chronic AV block, determination of the VERP using IS and decremental scanning (DS) without intertrain pause was compared at 800 and 350 msec pacing cycle length (PCL). The measurements were repeated after the administration of d-sotalol to lengthen the VERP and levcromakalim to shorten the VERP. The results showed no difference between IS and DS at both PCLs with or without medication. Recurrent and abrupt rate changes were avoided during IS, making this the protocol of choice when induction of arrhythmias is to be avoided. PMID- 7845823 TI - Dispersion of ventricular refractoriness in experimental myocardial infarction: effect of sotalol. AB - Dispersion of refractoriness may contribute to the propensity for reentrant arrhythmias. This study was performed to assess the effect of sotalol on the dispersion of refractoriness in experimental myocardial infarction. In 9 mongrel dogs, 14 days after induction of myocardial infarction by an occlusion reperfusion technique, programmed ventricular stimulation and epicardial mapping were performed before and during (3 mg/kg + 0.5 mg/kg per hour) sotalol administration. To assess the spatial distribution of refractoriness, ventricular fibrillation (VF) intervals were analyzed. The rationale for this method is that, during VF, when multiple reentrant wavelets are present, cells are excited as soon as they recover from previous activation. The coefficient of variation (standard deviation x 100) served as an index of spatial distribution of refractoriness. RESULTS: VF was induced before sotalol in 7 dogs and in 5 of 7 during sotalol administration. The mean value of the index VF intervals decreased from 19.8 +/- 2.3 at baseline to 15.8 +/- 2.6 during sotalol (P = 0.011), indicating a more homogeneous distribution of refractoriness. Thus, the antiarrhythmic effects of sotalol may be mediated by its action on the dispersion of refractoriness. PMID- 7845824 TI - Reversibility of electrophysiological abnormalities in subacute ischemia. AB - Twenty-four hours after occlusion of the left anterior descending coronary artery in the dog, ventricular tachycardia is the predominant rhythm. At this time, records of transmembrane potentials from the subendocardial Purkinje fibers adjacent to the infarct show a low maximum diastolic potential, prominent phase 4 depolarization, and slow response action potentials. Exposure of the fibers to pinacidil, 25-100 microM, increases resting potential to the estimated value of EK, abolishes the phase 4 depolarization, and restores action potential amplitude and Vmax toward normal. Perfusion of the bed of the occluded coronary artery with Tyrode's solution prior to isolation of the subendocardial tissues results in similar normalization of transmembrane potentials. These findings indicate: (a) that the major cause of the abnormal transmembrane potentials of the subendocardial tissues is the loss of resting potential; and (b) that abnormalities of the transmembrane potentials are caused by some substance that can be washed out by perfusion and not by a direct effect of ischemia. PMID- 7845825 TI - Frequency dependent effects of class I antiarrhythmic agents studied in patients with implanted pacemakers. AB - Use and frequency dependency are common properties of Class I antiarrhythmic agents, which block cardiac sodium channels in vitro. The purpose of this study was to examine the rate dependent effects of Class I agents on ventricular conduction in humans in a crossover fashion. Twelve patients with implanted pacemakers who required antiarrhythmic therapy were studied. Four Class I agents were administered as follows: lidocaine, 1 mg/kg bolus followed by 4 mg/min infusion; disopyramide, 1 mg/kg bolus followed by 0.02 mg/kg per hour; aprindine, 1 mg/kg bolus followed by 4 mg/min infusion; and flecainide, 100 mg/day orally for 1 week. Trains of ventricular test stimuli between 70-180 ppm were applied during stable VVI pacing at 60 ppm. QRS duration was determined using signal averaged as well as standard ECGs. Lidocaine produced significant QRS prolongation at rates > 110 ppm (3.0% +/- 1.4% at 120 ppm, P < 0.05; 7.2% +/- 1.8% at 180 ppm, P < 0.01). Aprindine, disopyramide, and flecainide produced significant QRS prolongation at rates as low as 70 ppm and in a frequency dependent manner: 12.7% +/- 1.5%, 9.6% +/- 1.6%, and 13.3% +/- 2.8% at 70 ppm, respectively, (P < 0.01); 21.6% +/- 0.6%, 14.7% +/- 2.4%, and 29.9% +/- 4.2% at 180 ppm, respectively, (P < 0.01). Time constants of the single exponential development of QRS prolongation when the pacing rate was abruptly increased to 150 ppm were 0.09 +/- 0.02 sec for lidocaine, 5.1 +/- 1.2 sec for aprindine, 8.1 +/- 1.7 sec for disopyramide, and 11.9 +/- 1.4 sec for flecainide.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845826 TI - Diagnosis of atrial arrhythmias using the Holter function of a new DDD pacemaker. AB - The extension of random access memory now makes it possible to store electrocardiographic (ECG) information, referred to here as Holter function (HF), in the memories of new pacemakers, which can be used as diagnostic tools during long-term follow-up. This report describes our experience in 26 consecutive patients for whom the device was used to detect episodes of atrial arrhythmias (AA). An illustrative case is also presented to describe in detail the device's analytical method. RESULTS: Fourteen AA profiles were successfully recorded in 10 patients by the pacemaker HF and correlated with confirmatory simultaneous surface ECG tracings. Three additional profiles were recorded in three other patients without simultaneous ECG recordings. A diagnosis of AA is established when the following findings are combined: (1) in all cases a large number of short interatrial intervals (A INT); (2) in presence of AV block, interventricular intervals (V INT) stored between the lower programmed pacing rate and the upper rate limit or the fallback rate; (3) in absence of AV block, V INT stored between the basic rate and the AV node refractory period; (4) in case of fallback, (VVI function) no stored AV INT; and (5) in absence of fallback, great variability of AV INT (Wenckebach function). CONCLUSIONS: (1) Diagnoses of AA can be made with the pacemaker HF; (2) The homogeneity of the HF profiles makes them useful for long-term follow-up and will probably contribute and clarify the natural history of AA in DDD patients; (3) HF may also serve to monitor the safety and efficacy of antiarrhythmic drug therapy during long-term follow-up. PMID- 7845827 TI - Regular ventricular rhythms before conversion of recent onset atrial fibrillation to sinus rhythm. AB - The incidence of fast atrial tachycardias with regular ventricular rhythm was assessed in a population of 243 patients with recent onset (< 72 hours) atrial fibrillation (AF), without heart failure, randomly treated with single loading oral dose of propafenone (600 mg), flecainide (300 mg), digoxin (1 mg), or placebo for acute conversion to sinus rhythm (SR). Fast atrial arrhythmias developed in 14 (6%) patients: 6/92 treated with propafenone, 3/34 treated with flecainide, 1/25 treated with digoxin, and 4/92 who received placebo (P = NS). Heart rate > 175 beats/min with 1:1 AV conduction ensued in 4 cases: 2 treated with flecainide and 2 treated with placebo; in the other cases 2:1 AV conduction was observed. Widening of QRS during regular tachycardia was observed in 4 patients; 3 who received propafenone and 1 who received flecainide. Conversion to SR within 4 hours was achieved in 55/92 (60%) patients treated with propafenone, 20/34 (59%) patients treated with flecainide, 7/25 (28%) patients treated with digoxin, and 19/92 (20%) treated with placebo (P < 0.001 propafenone vs placebo and flecainide vs placebo; P < 0.05 propafenone vs digoxin and flecainide vs digoxin). Periods of regular tachycardia are expected in recent onset AF and may not necessarily represent a proarrhythmic effect of Class 1C drugs, rather than mark the transition from AF to SR. Class 1C agents are probably responsible for widening of the QRS complex seen during these tachycardias. Propafenone and flecainide appear equally effective in converting recent onset AF. PMID- 7845828 TI - Correlation of signal-averaged P wave with electrophysiological testing for atrial vulnerability in strokes of unexplained etiology. AB - Atrial fibrillation is considered the main cause of cardioembolic strokes. After detailed investigations, about 30% of ischemic strokes remain unexplained. A percentage of these ischemic attacks may result from asymptomatic episodes of paroxysmal atrial fibrillation (PAF). Previous studies have demonstrated that electrophysiological testing and signal-averaged P wave (SAPW) ECG are useful to detect patients with PAF. METHODS AND RESULTS: Twenty patients with unexplained ischemic strokes had electrophysiological studies (EPS) to determine atrial vulnerability and SAPW recordings. At EPS, patients were classified in group I (10 patients) if they had a latent atrial vulnerability index < 2 and/or more than 1 minute of sustained atrial arrhythmia. Otherwise they were classified in group II (10 patients). In group I, the filtered P wave duration was greater: 142 versus 120 msec (P = 0.03) and RMS 30 tended to be lower: 2.54 versus 4.13 microV (P = 0.11) than in group II. A filtered P wave duration > 125 msec associated with a RMS 30 < 3 microV had a positive predictive value of 78% and a negative predictive value of 88% for the detection of patients with abnormal atrial vulnerability at EPS. CONCLUSIONS: SAPW may be useful to identify patients at risk of PAF who may be candidates for EPS. PMID- 7845829 TI - Esophageal balloon electrode catheter for transthoracic recording of His-bundle potential with transesophageal atrial pacing. AB - To evaluate the influence of transesophageal atrial pacing of the transthoracic His potential identification, we combined signal-averaged ECG with transesophageal atrial pacing with low threshold for pacing averaging ECG recording. A tripolar 10 French esophageal balloon electrode catheter, with one cylindrical electrode on the tip of the catheter and two balloon electrodes on the cardiac side of the catheter, used in 53 patients, allowed a painless transesophageal atrial pacing and a high signal to noise distance in the signal averaged ECG. Transesophageal atrial pacing allowed in 37 of 53 patients an identification of His potential by increasing the distance between the end of the atrial potential and the onset of the His potential in the pacing averaging ECG. The esophageal balloon electrode catheter allowed a painless transesophageal atrial pacing with low threshold for atrial capture during a long pacing time and a high signal to noise distance in the pacing averaging ECG. The increasing of the heart rate with transesophageal atrial pacing allowed the transthoracic identification of the His potential in the pacing averaging ECG. PMID- 7845830 TI - Mechanisms of AV node reentrant tachycardia in young patients with and without dual AV node physiology. AB - Recent advances in electrophysiological mapping and radiofrequency catheter ablation have demonstrated the participation of perinodal atrial tissue or pathways in atrioventricular node reentrant tachycardia (AVNRT). Current concepts of the role of these pathways in the genesis of the various forms of AVNRT continue to evolve. In view of these recent advances, this study investigated the electrophysiology of AVNRT in young patients, and factors potentially associated with variant forms of this arrhythmia. Detailed programmed stimulation and catheter mapping were performed in 35 consecutive young patients with AVNRT. This group consisted of 15 male and 20 female patients, with a mean age of 12.1 +/- 4.2 years (range 3-18 years). Of the 35 patients, 23 demonstrated dual AV node physiology, either in response to a critically timed extrastimulus (n = 17) or to rapid pacing (n = 6). The common form (antegrade slow-retrograde fast) of AVNRT was demonstrated in 21 of these 23 patients. Antegrade fast-retrograde slow (n = 1) and antegrade slow-retrograde slow (n = 1) forms of AVNRT were identified in the 2 other patients. In contrast, only 5 of the 12 patients who did not demonstrate dual AV node physiology had the common form of AVNRT (P = 0.03). Five of these patients also had the slow-slow form of AVNRT, while 1 patient each had a fast-slow and fast-fast form of AVNRT.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845831 TI - Specificity of retrograde conduction in screening for atrioventricular nodal reentrant tachycardia. AB - Baseline AV conduction properties (antegrade and retrograde) are often used to assess the presence of dual AV nodal physiology or concealed AV accessory pathways. Although retrograde conduction (RET) is assumed to be a prerequisite for AV nodal reentrant tachycardia (AVNRT), its prevalence during baseline measurements has not been evaluated. We reviewed all cases of AVNRT referred for radiofrequency ablation to determine the prevalence of RET at baseline evaluation and after isoproterenol infusion. RESULTS: Seventy-three patients with AVNRT underwent full electrophysiological evaluation. Sixty-six patients had manifest RET and inducible AVNRT during baseline atrial and ventricular stimulation. Seven patients initially demonstrated complete RET block despite antegrade evidence of dual AV nodal physiology. In 3 of these 7 patients AVNRT was inducible at baseline despite the absence of RET. In the other four patients isoproterenol infusion was required for induction of AVNRT, however only 3 of these 4 patients developed RET. One of these remaining patients had persistent VA block after isoproterenol. CONCLUSIONS: The induction of AVNRT in the absence of RET suggests that this is not an obligatory feature of this arrhythmia. Therefore, baseline AV conduction properties are unreliable in assessing the presence of AVNRT and isoproterenol infusions should be used routinely to expose RET and reentrant tachycardia. PMID- 7845832 TI - Atrioventricular nodal physiology after slow pathway ablation. AB - The AV nodal physiology before and 1 week after "slow pathway potential" guided catheter ablation was examined in 32 patients with AV nodal reentrant tachycardia. A mean of 4.9 applications of radiofrequency energy eliminated AV nodal reentrant tachycardia in all patients. There were no significant differences in sinus cycle length (815 +/- 159 msec vs 813 +/- 162 msec; P = NS) and fast pathway conduction properties before and 1 week after ablation. Slow pathway conduction was completely eliminated in 10 (31%) (group I) of 32 patients after ablation. In the remaining 22 patients residual slow pathway conduction associated with one AV node echo was observed. In 15 patients (47%) (group II), the effective refractory period of the slow pathway showed a change of < 30 msec (265 +/- 51 vs 266 +/- 51 msec; P = NS), and in 7 patients (22%) (group III), a prolongation of more than 80 msec (247 +/- 56 vs 340 +/- 42 msec; P = 0.0001) before and 1 week after ablation. Minimal and maximal A2-H2 interval over the slow pathway in group II was not significantly changed (Min A2-H2: 241 +/- 37 vs 247 +/- 40 msec; P = NS, Max A2-H2: 346 +/- 79 vs 350 +/- 60 msec; P = NS), while a significant prolongation was measured in group III (Min A2-H2: 261 +/- 53 vs 373 +/- 107 msec; P < 0.01, Max A2-H2: 359 +/- 41 vs 427 +/- 63 msec; P < 0.05) before and after ablation.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845833 TI - Radiofrequency catheter ablation and modulation of atrioventricular conduction in patients with atrial fibrillation. AB - We attempted radiofrequency ablation of the AV junction with a sequential right- and left-sided approach in 78 patients affected by severely symptomatic, drug refractory atrial fibrillation. Stable third-degree AV block was obtained in 99% of cases and, after 3 months, persisted in 92% of cases. Single session, stepwise, radiofrequency modulation of the AV node was attempted in 13 patients with paroxysmal atrial fibrillation. During sinus rhythm, ablation of the slow and fast AV node pathways was performed in order to increase the nodal refractory period or to slow conduction. Clinically successful modulation of AV conduction was achieved in 15% of cases and persisted during a 3-month follow-up. In conclusion, AV junction ablation is a well-established means of treating atrial fibrillation, but implies the implant of a permanent pacemaker. AV node modulation avoids the pacemaker implant, but is efficacious only in a minority of patients. Thus, in patients affected by paroxysmal atrial fibrillation, AV modulation should be attempted first; if this is ineffective, AV ablation can be performed during the same session. PMID- 7845834 TI - Long-term survival after closed-chest His-bundle ablation with DC shock for supraventricular arrhythmias: a 10-year experience with 317 consecutive patients. AB - Survival after closed-chest ablation of His bundle with DC shock for supraventricular arrhythmias was analyzed for a 10-year period (May 1982-December 1992) with 317 consecutive patients (167 males, 150 females; mean age 66 years; range 33-93 years). Of these, 54 patients died (17.3%) and 5 were lost to follow up. The mean age at ablation was 70.3 +/- 8.3 years with a range of 49-93 years. Of those who died, the mean survival was 30.5 +/- 28.6 months with a range of 36 hours to 120 months; the diagnosis of heart disease was: hypertension (n = 14), cardiomyopathy (n = 8), ischemic (n = 7), valvular (n = 6), cor pulmonale (n = 3), valvular and ischemic (n = 2), hypertension and ischemic (n = 1), miscellaneous (n = 3), and none (n = 10). Of the patients who died after ablation, the arrhythmias at the time of the ablation were atrial fibrillation (AF; n = 33), sick sinus syndrome (n = 5), atrial flutter (AFL; n = 4), paroxysmal AV junctional tachycardia (PAVJT; n = 4), AF + AFL (n = 4), atrial tachycardia (n = 2), PAVJT + AFL (n = 1), and AF +AFL + atrial tachycardia (n = 1). Death was sudden in 13 patients (25%), due to heart failure in 10 (19.2%), myocardial infarction in 4 (7.7%), stroke in 4 (7.7%), aortic vascular accident in 3 (5.8%), miscellaneous in 18 (34.6%), and undetermined in 2.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845835 TI - Intraoperative mapping is not necessary for VT surgery. AB - Surgical ablation of ventricular tachycardia is generally guided by the results of pre- and intraoperative cardiac mapping. However, in certain situations intraoperative cardiac mapping may not be possible and, therefore, surgery has to be based on information obtained preoperatively. This raises the question whether intraoperative mapping is necessary for the success of this approach. We describe our experience with encircling endocardial cryoablation for ischemic VT and examine the contribution of intraoperative mapping for this procedure. Thirty three patients with inducible VT refractory to medical therapy and a well defined anatomic scar were considered for surgery. All patients underwent baseline electrophysiology study and intraoperative mapping was attempted during normothermic cardiopulmonary bypass. In 14 patients, VT was inducible intraoperatively (Group 1) and surgical ablation was guided by this information, whereas in 19 patients, VT could not be mapped for various reasons (Group 2). Reasons for failure to obtain intraoperative map included noninducibility (3), nonsustained VT (8), polymorphic VT (4), VF (3), and incessant VT with hemodynamic collapse and cardiac arrest (1). The two groups did not differ with respect to age, location of myocardial infarction, or preoperative left ventricular ejection fraction. The operative procedures were similar in the two groups with respect to aortic cross clamp time, cardiopulmonary bypass time, number of cryoablation lesions, concomitant revascularization, aneurysmectomy, and ICD implantation. Encircling endocardial cryoablation was performed in 32 patients and one patient underwent partial right ventricular free wall disconnection (RV infarct). Thirteen patients underwent concomitant coronary artery bypass grafting (5 in Group 1 and 8 in group 2). One patient had prophylactic ICD patches (Group 1).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845836 TI - Maze 3 for atrial fibrillation: two cuts too few? AB - The Maze procedure has been developed as a surgical approach to the management of patients with atrial fibrillation refractory to medical treatment. The recent modification of the technique (Maze 3) achieves good rate control with coordinated AV contractions. However, the procedure involves cuts that completely isolate a block of left atrial (LA) wall, including the four ostia of the pulmonary veins. The electrical and mechanical activity of this isolated LA block are dissociated from the rest of the atrium, and the area may, in fact, continue to fibrillate. This may provide a nidus for the development of mural thrombus. The weight and endocardial surface area of the LA block and of the entire LA were estimated in ten formalin fixed hearts from trauma victims with no evidence of cardiac disease. In these samples, the LA block represented 35% of the endocardial surface area of the entire LA and 29% of the weight. The LA block is of sufficient size to allow macroreentrant circuits to form and has the potential to fibrillate if isolated from the rest of the atrium. We modified the Maze 3 procedure to recruit the otherwise isolated LA block by using two additional cuts around each pair of pulmonary veins as they enter the LA. The first patient who underwent the modified procedure demonstrated sinus rhythm on Holter monitoring postoperatively and remained in sinus rhythm following burst atrial pacing at 300 and 420 beats/min each for 30 seconds. In addition, atrial contractions were found to contribute 19% of the cardiac output.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845837 TI - Surgery as an effective nonpharmacological mode of treatment of atrial fibrillation resistant to standard therapy. AB - There are two surgical methods for atrial fibrillation (AF) treatment: Maze and corridoring procedures. The first one prevents AF occurrence by performing multiple atriotomies. During the second procedure a corridor between a sino atrial and the AV node is created together with an electrical isolation of the atria. During 1992 and 1993 seven patients, aged 27-55, mean 43-years-old, with recurrent, resistant to standard therapy AF were referred for surgical treatment to our department. Additional diagnoses include: concealed WPW syndrome in 1 patient, atrial septal defect (ASD) in 3 patients, coronary artery disease in 1 patient. Maze procedure was performed solely in 1 patient, in another together with 2 accessory pathways ablation, in 3 patients with ASD closure and in 1 patient with 2 bypass grafts. In one patient corridoring procedure was performed. Normal sinus rhythm was restored in every patient from 7 to 26 days after the procedure. No surgical complications were noted during the postoperative period. Mechanical function of the atria was documented with echo Doppler 2-6 weeks after the operation. No evidence for AF recurrence was noted within 3-14 months (mean 5 months) of follow-up. The preliminary results of Maze and corridoring procedures are encouraging. PMID- 7845839 TI - Comparison of signal-averaging electrocardiographic systems using device specific criteria in 104 normal subjects. AB - The advent of several signal-averaged electrocardiogram (SAECG) systems for late potential (LP) assessment warrants comparisons to assess intersystem reproducibility and variability. Simultaneous SAECGs on two systems, Arrhythmia Research Technology (ART) and Marquette (MEI), were performed on 104 normal volunteers (53 males, age 44 +/- 14 years), and analyzed filtered QRS duration (TFQRS), root mean square voltage (RMS40), and low amplitude signal duration (LAS40), filtered at 40-250 Hz. The Gomes criteria (TfQRS > 114 msec, RMS40 < 20 microV and LAS40 > 38 msec) were used as criteria for LP. The data was also analyzed using the recently proposed system specific criteria for MEI (TFQRS > 120 msec, RMS40 < 20 microV and LAS40 > 38 msec). Where appropriate, statistical analysis was performed using simple linear and Spearman's rank correlation, analysis of variance, Finn's R and McNemar's test. RESULTS: The means +/- SD for ART and MEI were: TFQRS: 97.2 +/- 8.9 vs 108.2 +/- 7.2 msec (R = 0.76), RMS40: 31.8 +/- 17.8 vs 45.3 +/- 19.9 microV (R = 0.53), and LAS40: 32.2 +/- 8.4 vs 30 +/- 7.4 (R = 0.54). When the Gomes criteria were applied, the number of subjects identified by each system as abnormal were: TFQRS = 3 vs 22 (P < 0.001), RMS40 = 20 vs 8 (P = 0.004), LAS40 = 21 vs 9 (P = 0.004), TFQRS/RMS40 = 3 vs 6 (P = 0.38), TFQRS/LAS40 = 3 vs 7 (P = 0.22), RMS40/LAS40 40 = 17 vs 8 (P = 0.02), and all three criteria = 3 vs 6 (P = 0.38) for ART vs MEI, respectively. Percent agreement was 81.7% for TFQRS and 84.6% for RMS40 and LAS40 when single criteria were applied. Agreement improved when combined criteria were utilized (87.5% 95.2% for any two criteria and 95.2% for all three criteria). The intersystem agreement that was not due to chance was 0.63-0.69 for single criteria and 0.75 0.90 for combined criteria. Disagreement was highly significant for the three criteria when used singly and for RMS40 and LAS40 combined. Disagreement was not significant when TFQRS was used in combination with > or = one other criteria. When the MEI criteria were applied, there was a decrease in the number of subjects identified by the MEI system as abnormal, using the TFQRS criteria singly or in combination. Percent agreement for system specific TFQRS measurements was 94.2% for single criteria and 97.1% for combined criteria. The intersystem agreement that was not due to chance improved (88-0.94). Disagreement between system specific criteria for TFQRS was not significant (P > 0.05). CONCLUSION: Our data indicate that although there is a general correlation between ART and MEI measurements, variability is substantial, leading to significant differences when the criteria for LP are applied, especially for single parameter determinations. Thus, there is a need to establish system specific normal ranges and more accurate criteria for LP parameters. PMID- 7845838 TI - Nonpharmacological therapy of ventricular tachyarrhythmias: observations in 554 patients. AB - It has been shown that conventional antiarrhythmic drug treatment is debatable, and there is growing interest in nonpharmacological techniques. We studied the outcome of 554 patients with ventricular tachycardia (VT) or ventricular fibrillation (VF) who underwent nonpharmacological techniques from March 1980 to June 1994 at our institution. Catheter ablation was performed in 51 patients (G1), map guided surgery in 147 (G2), and cardioverter defibrillator implantation (ICD) in 356 (G3). During a mean follow-up of 37 +/- 12 (< 1-137) months, incidence of sudden death (G1 4%, G2 6%, G3 3%) and cardiac death (G1 7%, G2 16%, G3 8%) were relatively low, and there was no significant differences between G1 G3. VT/VF recurrences occurred more frequently in G1 (57%) than in G2 (18%) (P < 0.01). ICD discharges occurred in 69% of patients. We conclude that nonpharmacological techniques lead to low sudden death rates; however, there is a high rate of recurrence in G1. Risk stratification is necessary to select the ideal therapy for each individual patient. PMID- 7845840 TI - High resolution ECG and left ventricular volume after acute myocardial infarction. AB - The presence of ventricular late potentials (LPs) early after acute myocardial infarction (AMI) was recently reported to correlate with left ventricular dilatation subsequent to AMI. We assessed prospectively the relationship between LP (time domain) in the late phase of AMI and left ventricular end-diastolic volume (EDV) measured by equilibrium radionuclide angiocardiography 4 weeks and 12 months after AMI. In 80 consecutive patients 4 weeks and 12 months after thrombolytic therapy for AMI, LP and EDV were determined (EDV1, EDV2). There was no significant correlation between QRS duration (r = 0.18), RMS40 (r = 0.08), or LAS40 (r = 0.1) and EDV1 or EDV2 in patients with or without LP at baseline. In both groups (patients with [n = 15] and without LP [n = 65]), EDV1 and EDV2 were comparable (128 +/- 32 mL vs 126 +/- 35 mL; 114 +/- 40 mL vs 117 +/- 36 mL; P = NS). In addition, there was no significant difference between EDV1 and EDV2 in patients who developed new LP (n = 6) or lost LP (n = 9) 12 months after AMI. In contrast to LP in the very early phase after AMI, there seems to be no significant correlation between the high resolution ECG in the late phase after thrombolytic therapy for AMI and left ventricular EDV. PMID- 7845841 TI - The effects of intravenous mexiletine on spectra of the signal-averaged ECG. AB - This study examined the effects of intravenous mexiletine on the time-domain and spectrotemporal signal-averaged ECG (SAECG). SAECGs were recorded in 60 postmyocardial infarction (MI) patients with more than 100 premature ventricular beats per hour, before and after a constant infusion of mexiletine, 7 mg/kg, given over 1 hour. Spectrotemporal analysis was done on a fixed analyzed signal duration of QRS complex and ST segment of X, Y, and Z leads using a temporal window of rectangular type, measuring the signal content between 10-120 Hz. Intravenous mexiletine produced no significant change in the mean values of any of the time-domain variables. However, mexiletine either increased or decreased the power density spectrum (PDS) and PDS ratio (40-120 Hz/25-120 Hz) of the SAECG, and in rare cases only did it not alter the spectra of the SAECG. When PDS ratio in lead Z decreased after mexiletine, it was usually higher at baseline in comparison with that when the PDS ratio increased, or vice versa. When the treatment with mexiletine was effective, PDS increased in comparison with that when the drug was ineffective, or vice versa. Not all ranges (10-120 Hz) of spectra of the SAECG, but only certain frequency bands (25-40 Hz in lead Z, P = 0.0253; 40-55 Hz in lead Y, P = 0.0096; 55-70 Hz in X lead, P = 0.0018; and in lead Z, P = 0.0002; 70-85 Hz in lead X, P = 0.0025; and in lead Z, P = 0.0075, 85 100 Hz in lead X, P = 0.0033) were associated with mexiletine efficacy.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845842 TI - Relationship between short- and long-term measurements of heart rate variability in patients at risk of sudden cardiac death. AB - Because of technical difficulties in analyzing heart rate variability (HRV) from ambulatory Holter recordings over 24-hour periods, short-term recordings are more practical for the clinical application of HRV. However, the relationship between short- and long-term recordings is unclear. In this study, short-term (10 min) electrocardiograms were assessed in the supine position, during passive head-up tilt and on standing in 15 patients (aged 39 +/- 14 years) with ventricular tachycardia/fibrillation not associated with coronary artery disease. Spectral HRV was computed as total frequency (TF: 0.01-1.00 Hz), low frequency (LF: 0.04 0.15 Hz), and high frequency (HF: 0.15-0.40 Hz) components. The short-term HRV parameters were compared with those obtained from long-term (24 hour) recordings from the same patients. There was a significant decrease in the HF component of HRV and a significant increase in LF/HF ratio during passive tilt or active standing compared with supine recordings, but no significant changes were observed in the TF or LF components. All frequency components of HRV for the 24 hour periods showed significant correlation with the values from short-term recordings (tau ranged from 0.67-0.87). Stepwise multivariate regression analysis showed that both the TF and HF components of HRV over 24 hours were predominantly related to the corresponding frequency components of HRV in the supine position, while the LF component of HRV over 24 hours was predominantly related to that on standing. Our observations suggest that the short-term HRV is related to the long term value, but global HRV over 24 hours cannot completely be replaced by the short-term recordings.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845843 TI - Autonomic imbalance assessed by heart rate variability analysis in vasovagal syncope. AB - In this prospective study, the autonomic modulation of the sinus node of 12 patients (mean age 28 +/- 7 years) suffering from vasovagal syncope (VVS) was compared to that of 11 sex and age matched control patients (mean age 32 +/- 4 years) by analysis of heart rate variability. Spectral indices (low frequency power [Plf], high frequency power [Phf], total power [Pt], sympathovagal balance [LF/HF]) and temporal indices, the mean of all coupling intervals between normal beats (mRR), the standard deviation about the mean (sdRR), the percentage of adjacent R to R intervals differing by more than 50 msec (pNN50), and the root mean square of variations in successive R to R intervals (rMSSD) were compared at baseline and during head-up tilt between and within groups. Baseline results were similar in both groups. During tilt testing, comparison of results between groups revealed only significantly higher sdRR and rMSSD and lower LF/HF ratio in VVS patients. Within VVS patients, comparison of temporal and spectral analysis between baseline and tilt showed a significant increase of most indices (Plf, Phf, Pt, sdRR, and rMSSD) but a comparable LF/HF ratio; in contrast, control patients exhibited only a significant increase of LF/HF ratio. In conclusion, VVS patients who developed vasovagal syncope during head-up tilt demonstrated a nonreciprocal modulation of the sinus node by the autonomic nervous system indicative of a pronounced physiological sympathetic surge along with a paradoxical vagal input to the cardiovascular system. PMID- 7845844 TI - Intraindividual reproducibility of heart rate variability before and during postural tilt in patients with syncope of unknown origin. AB - Fast Fourier analysis (FFT) of heart rate may be used to characterize overall heart rate variability (HRV) as well as low (LF: 0.06-0.10 Hz) and high (HF: 0.15 0.40 Hz) frequency components, which are attributable to sympathetic and vagal influences. This study examined the reproducibility of the spectral characteristics of HRV before and during postural tilt in patients being evaluated for unexplained syncope. Twenty patients (14 men, age 55 +/- 12 years) with a history of syncopal episodes underwent 2 tilt table tests (T1 and T2) 1 to 6 weeks apart. For purposes of analyses the patients were divided into 2 groups according to the results of tilt testing. In 11 patients (Group A: 7 men, mean age 53.5 +/- 12 years) syncope was induced in 1 (5 patients) or both tilt tests. In the remaining 9 patients (Group B: 7 men, age 56.7 +/- 14 years) syncope did not develop during either test. Spectral indexes (SI) of HRV were computed by FFT for 2-minute segments derived from Holter recordings before and during 60 degrees head-up tilt. We compared the SI measured in the two tilt tests during the following 2-minute periods: P1, just before tilt at rest, in a supine position; P2, immediately after tilt; P3, just before the end of the tilt. RESULTS: P1 and P2: There were no significant differences in SI between T1 and T2 for low frequencies, high frequencies, or total power in either Group. In Group A, LF at time of maximum tilt exposure (P3) tended to be slower during T2 than in T1 (5.58 +/- 1.44 vs. 6.56 +/- 1.11, P < 0.05). However, this difference primarily reflects the findings in the five patients in whom syncope did not occur during T2. When these 5 patients were excluded the LF were essentially identical (6.43 +/- 0.97 vs 6.80 +/- 1.30; P = NS). CONCLUSIONS: Spectral indexes of HRV before and during the early part of tilt testing are reproducible. The SI during the later part of the test are related to the patient's response. However, this response is not predictable on the basis of sympathetic or parasympathetic tone before or during the early part of the test. PMID- 7845845 TI - The effect of exogenous adenosine in patients with neurally-mediated syncope and sick sinus syndrome. AB - The effects of a 20-mg i.v., bolus of adenosine 5' triphosphate (ATP) on the heart rhythm was studied in 79 patients affected by neurally-mediated syncope (26 cases) or sick sinus syndrome (22 cases) or both syndromes (31 cases) and in 31 healthy control subjects in order to examine the sensitivity of cardiac purinoceptors in such circumstances. During ATP infusion, the sinus cycle lengthened to > 2 seconds in no control, in 1 (4%) patient with neurally-mediated syncope, in 5 (23%) patients with sick sinus syndrome, and in 13 (42%) patients with both neurally-mediated and sick sinus syndromes (P = 0.01). Atrioventricular block occurred in 14 (45%) of controls, in 10 (38%) patients with neurally mediated syncope, in 4 (18%) patients with sick sinus syndrome, and in 13 (42%) patients with both neurally-mediated syncope and sick sinus syndrome (n.s.). Thus, exogenous ATP exerts different effects on patients with neurally-mediated syncope and patients with sick sinus syndrome. In fact, intrisic disease of the sinus node is necessary to modulate an abnormal adenosine-mediated sinus arrest, whereas patients affected by neurally-mediated syncope alone show a normal sensitivity to the drug administration. The effect of ATP on atrioventricular conduction is greater than that on sinus node and is of similar magnitude in patients and controls; thus the clinical meaning of ATP induced atrioventricular block remains uncertain. PMID- 7845846 TI - Arrhythmias in centenarians. AB - BACKGROUND: Many studies have shown an increase in the prevalence of arrhythmias with advancing age. However, little is known about arrhythmias in centenarians. METHOD AND RESULTS: Thirty-two Japanese centenarians aged 100-106 years (14 males, 18 females) were studied. All of them had 12-lead ECGs, and 22 also had 24 hour ambulatory monitoring. As controls, 89 healthy Japanese elderly from the same geographic area underwent 12-lead ECG. Their mean age was 75 +/- 6 years with a range of 63-93 years, and there were 28 males and 61 females. Twenty-three of them also had Holter ECGs. On the 12-lead ECG, the heart rate was slightly, but significantly, higher in the centenarians (76.8 +/- 12.7 beats/min) than that in the elderly subjects (74.9 +/- 5.9 beats/min, P < 0.005). PQ and QTc were significantly longer in the centenarians (174 +/- 29 and 439 +/- 33 msec, respectively) compared with the elderly subjects (158 +/- 23 and 417 +/- 31 msec, P < 0.005 and P < 0.001, respectively). Supraventricular premature beats (SVPBs) were observed in 31% of the centenarians and in 4% of the elderly subjects (P < 0.001). First- and second-degree AV block was recorded in 25% of the centenarians and 1% of the elderly subjects (P < 0.001). Right bundle branch block was found in 19% of the centenarians and 7% of the elderly subjects (P < 0.05). There were no differences in the frequency of ventricular premature beats (VPBs) or QRS voltage. On the Holter ECG, there were no significant differences in average heart rate, maximum heart rate, minimum heart rate, or the longest RR interval. A subgroup of centenarians had frequent SVPBs. However, none of them had > 1,000 VPBs/day as opposed to four elderly subjects (P < 0.01). Atrial fibrillation was not observed in any records of the centenarians despite the presence of frequent SVPBs. CONCLUSION: These data suggest that conduction disturbances of the AV nodal--His-Purkinje system and frequent SVPBs are common in centenarians, whereas very frequent VPBs and atrial fibrillation seem less common. PMID- 7845847 TI - Ambulatory assessment of the QT interval in patients with hypertrophic cardiomyopathy: risk stratification and effect of low dose amiodarone. AB - This study aims to assess the dynamics of the QT interval in patients with hypertrophic cardiomyopathy (HCM). Three consecutive QT intervals and the preceding RR intervals were measured on 24 hour ambulatory electrocardiograms at 30-minute intervals in ten high risk patients with HCM (sudden cardiac death [SCD] and/or documented ventricular fibrillation), aged 29 +/- 17 years, compared with ten age and sex matched low risk patients with HCM (no syncope, no adverse family history, and no ventricular tachycardia on Holter monitoring), and ten normal subjects. Another ten patients who were on amiodarone therapy (200-mg daily) were also studied. Patients with intraventricular conduction defects were excluded. There were 4,424 pairs of QT intervals and their preceding RR intervals were measured in this study. A nonsignificant prolongation in the QT interval and a significant prolongation in QTc values (Bazett's and Fridericia's formulas) were demonstrated in patients with HCM compared with normals. There were no significant differences in the QT and QTc between high and low risk patients. The slope of regression line for the QT against RR interval was significantly different between normals and HCM (0.1583 +/- 0.040 vs. 0.2017 +/- 0.043, P < 0.05), but not between high and low risk patients. Amiodarone significantly prolonged the QT and QTc without significantly altering the slope of the regression line (0.2017 +/- 0.043 vs 0.2099 +/- 0.037, NS). Our findings support the observations that there is a prolonged QT interval in patients with HCM and that there is no significant use dependent effect of amiodarone on ventricular repolarization.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845848 TI - Recognition and management of pregnant adolescents in the pediatric emergency department. AB - The early initiation of comprehensive prenatal care is essential to avoid the complications associated with the more than one million adolescent pregnancies in the United States each year. Pediatric emergency physicians can play an important role in the initial diagnosis and appropriate referral of pregnant teenagers. However, previous studies have shown that the diagnosis of pregnancy can be difficult. The goals of this study were to characterize the spectrum of presenting complaints and to evaluate the assessment and disposition of pregnant teenagers presenting to a pediatric emergency department (PED). We retrospectively reviewed the medical records of 94 adolescents who presented with 95 pregnancies to our PED over an 18-month period. The mean age was 15.7 years (range 12 to 19 years). Only 8% mentioned pregnancy in their chief complaint at triage, and a concern about pregnancy was revealed by only 36% during the history of present illness. Ten percent denied they were sexually active. The most frequent complaints were gastrointestinal (77%); other complaints were gynecologic, urinary, or nonspecific. A concurrent sexually transmitted disease (32%) or urinary tract infection (31%) was frequently clinically suspected. At disposition, 26% were transported to an general emergency department for urgent obstetric evaluation; others were referred to a primary caregiver (23%) or obstetrician (39%). Pregnant teenagers present to the PED with a wide variety of complaints that may suggest other diagnoses. A high index of suspicion is required to diagnose pregnancy in adolescent girls so that appropriate care and referral can be initiated. PMID- 7845849 TI - Characteristics, workload, and job satisfaction of attending physicians from pediatric emergency medicine fellowship programs. Pediatric Emergency Medicine Collaborative Research Committee. AB - The purpose of this study was to determine the characteristics of academic Pediatric Emergency Medicine (PEM) faculty, the workload of these physicians, and the perceived effect this workload has had or will have on job satisfaction. A self-administered, seven-page, closed-end survey was used. participants were PEM departments with PEM Fellowship Training Programs. Surveys were completed by 37 PEM departments (84%). The average number of faculty per department was 7.33. Ninety-three percent of the faculty were board certified in Pediatrics, Emergency Medicine, or both. Only 15% of the faculty had an academic rank of associate or full professor. Fifty-four percent of the faculty had less than five years' experience. Average patient census per department was 43,400 per year. Physicians without administrative titles averaged 30 clinician hours per week. Attending physicians covered 85 to 100% of the overnight shifts in 17 programs (52%). Clinical workload was believed to be excessive in 17 programs (46%), with total number of hours given as the most common reason for this excess. In nine of these 17 programs, excess clinical workload had resulted in physician "burnout." Physicians from only eight programs (22%) believed they could practice PEM after 50 years of age. Shift work and overnight shifts were given as the most common reason. Stressed physician groups were significantly associated with programs whose attending physicians covered > or = 85% of the night shifts (P < 0.04) and reported excessive clinical workload (P < 0.002). Job satisfaction perceived by PEM faculty appears to be dependent on addressing the clinical workload and the adverse effects of overnight and shift work. PMID- 7845850 TI - Pediatric carbamazepine overdoses. AB - Thirty pediatric cases of carbamazepine overdoses were reviewed retrospectively for the frequency of toxic effects. Patients were divided into three groups, depending on the type of overdose: acute, acute-on-chronic, and chronic. Effects included lethargy in 93%, ataxia in 50%, nystagmus in 13%, and minor arrhythmias in 10%. Major effects included seizures in 20%, coma in 27%, and need for intubation in 20%. Higher serum carbamazepine levels were associated with these major effects in the acute and acute-on-chronic groups but not in the chronic group. Serum levels greater than 35 mg/L (147 mumol/L), were significantly associated with major toxicities. PMID- 7845851 TI - Occult bacteremia: is there a standard of care? AB - The evaluation and management of patients with occult bacteremia is controversial. The purpose of this study was to define the prevailing practices in the emergency management of occult bacteremia. Short, anonymous surveys were mailed to all 517 members of the Section on Emergency Medicine at the American Academy of Pediatrics. Three hundred six (59%) of those surveyed returned completed questionnaires. Eleven different temperature cutoff points are used, and 105 (34%) consider occult bacteremia in patients with temperature above 39 degrees C. Seventeen different age intervals are used to define the patients at risk for occult bacteremia, and the age range three to 24 months is used by 173 (57%) of those surveyed. Complete blood cell count is the most commonly used screening test; it is routinely ordered by 225 respondents (74%). One hundred thirty-seven participants (45%) routinely obtain blood cultures in all patients at risk for occult bacteremia, whereas 111 (36%) use the clinical appearance (toxicity) of the patient to determine whether a blood culture should be drawn. One hundred sixty-one (53%) of those surveyed routinely administer antibiotics to toxic-appearing patients pending the results of the blood culture. Laboratory criteria are used by 135 (44%) in the decision whether to administer empiric antibiotics. Ceftriaxone is the most commonly used antibiotic; it is routinely administered by 230 respondents (75%). Twenty participants (7%) routinely admit all patients with Streptococcus pneumoniae, whereas 217 (71%) admit all patients with Haemophilus influenzae bacteremia and 234 (76%) admit all patients with Neisseria meningitidis bacteremia. We conclude that diversity exists in the evaluation and management of occult bacteremia. PMID- 7845852 TI - Delayed incubation of blood culture bottles: effect on recovery rate of Streptococcus pneumoniae and Haemophilus influenzae type B. AB - This study investigated the effects of incubation delay on the rate of recovery of common pediatric pathogens from blood culture bottles. Known concentrations of Streptococcus pneumoniae and Haemophilus influenzae type b (three isolates each) were inoculated into BACTEC NR-6A bottles with 1.0 mL of donor blood. Bottles were subjected to a time delay (zero to six hours) before incubation. The BACTEC NR-660 was used for incubation and measurement of positive conversion. Data were analyzed using chi 2 analysis, Fisher's exact test, logistic regression, and multiple logistic regression, with P < 0.05 considered significant. Immediate incubation yielded positive blood cultures in 88 of 100 and 65 of 70 bottles containing S. pneumoniae and H. influenzae type b, respectively, in the concentration range 1.0 to 9.99 colony-forming units per milliliter (CFU/ml). For each organism, this was the minimal range required to produce a positive culture (P < 0.0001). Bottles inoculated with 1 ml of blood containing organisms in the range of 1.0 to 9.99 CFU/ml were then subjected to incubation delay. The recovery rate of S. pneumoniae significantly (P = 0.0003) decreased from a two-hour delay (57 of 60; 95%) to a three-hour delay (42 of 60; 70%). No significant change in recovery rate was seen in bottles inoculated with H. influenzae type b subjected to similar delays. Delayed incubation (two to six hours) of bottles inoculated with 1.0 ml of blood containing organisms in a concentration range of 1.0 to 9.99 CFU/ml of blood significantly decreases the recovery rate of S. pneumoniae but has no effect on H. influenzae type b. PMID- 7845853 TI - Personal computer teleradiology interhospital image transmission to facilitate tertiary pediatric telephone consultation and patient transfer: soft-tissue lateral neck and elbow radiographs. AB - Although teleradiology systems are available commercially, they are expensive ($30,000), and different makes are incompatible with each other, making them unusable for interhospital image transfers. Standard components were added to a personal computer (PC) to build a functional teleradiology unit capable of interhospital image transmission at a low cost ($600 upgrade). This PC teleradiology system was studied to assess its accuracy in the interpretation of soft-tissue lateral neck x-rays with epiglottitis or retropharyngeal abscesses and elbow x-rays with joint effusions, fractures, or both. A radiologist and a pediatric emergency physician were asked to read the PC teleradiology images. Both physicians read 13 of 13 soft-tissue lateral neck x-rays and 15 of 15 elbow x-rays correctly. This study supports the premise that PC teleradiology can be used to facilitate telephone consultation and patient transfers between tertiary pediatric emergency centers by transmitting pertinent radiographic information over a phone line. Although verbal communication can often suffice in a telephone consultation or transfer, there are many instances when visualizing a radiographic image such as an x-ray or computed tomography scan can provide important information that cannot be optimally described verbally. Rural hospitals can form interhospital image transmission links with tertiary center resources. Tertiary centers may elect to organize interhospital image transmission and referral networks with their rural hospital sources. PMID- 7845854 TI - Transient erythroblastopenia of childhood presenting with shock and metabolic acidosis. AB - Transient erythroblastopenia of childhood is usually a benign, self-limiting underproduction of red blood cells that often goes undetected clinically. The patient presented here, however, required crystalloid boluses and red blood cell transfusion for treatment of shock and metabolic acidosis in the emergency department. The emergency physician must be alert to the patient presenting with severe anemia and procure extra pretransfusion blood samples for anemia studies when transfusion appears imminent. The need for red blood cell transfusion in such a patient must be expeditiously recognized and, when the need exists, transfusions should be started as quickly as possible. PMID- 7845855 TI - Bites in the night: determining the etiology of bite marks on an infant. PMID- 7845856 TI - Nasopharyngeal carcinoma: early warning signs and symptoms. AB - Nasopharyngeal carcinoma is a tumor that is uncommon in children and adolescents. Presenting symptoms may be subtle and may include epistaxis, neck pain, hearing impairment, otorrhea, rhinorrhea, and, most likely, painless cervical adenopathy. The tumor is curable, but late diagnosis makes this possibility much less likely. Diagnosis of this tumor requires a high index of suspicion on the part of clinicians treating the pediatric population. PMID- 7845857 TI - Hyponatremia and dehydration in an 11-month-old infant from cerebrospinal fluid loss from an inapparent traumatic dural laceration. PMID- 7845858 TI - Prolongation of the prothrombin time after organophosphate poisoning. AB - Prolongation of the prothrombin time owing to a transient reduction in factor VII activity is described in a 14-month-old child with organophosphate poisoning. Correction after vitamin K administration suggested an organophosphate-related effect on vitamin K-dependent factor VII activity. Historically, coagulation screening has not been routinely recommended after organophosphate intoxications. We suggest, however, that routine screening in such patients may be important. A brief review of organophosphate poisoning and the unique features of our case are presented. PMID- 7845859 TI - Pediatric ventricular tachycardia: a review with three illustrative cases. PMID- 7845860 TI - Lump on forehead. PMID- 7845861 TI - Retinal hemorrhage. PMID- 7845862 TI - Mobile and stationary infant radiant warmers. PMID- 7845863 TI - Effects of prostatectomy on testicular androgenesis and serum levels of gonadotropins in mature albino rats. AB - The effects of prostatectomy on testicular steroidogenic enzymes, and on serum levels of gonadotropins, prolactin, and testosterone were studied. Adult male rats were prostatectomized and sacrificed after 14 and 21 days. There was augmentation of both delta 5-3 beta-hydroxysteroid dehydrogenase (delta 5-3 beta HSD) and 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) activities in the testes along with increased levels of FSH, prolactin, and testosterone in the serum, while no changes were observed in serum levels of LH. Hence it may be concluded that the prostate gland has an inhibitory effect on testicular androgenesis and can exert some influence in the regulation of FSH and prolactin secretion. PMID- 7845864 TI - 6-Methylene progesterone is cytotoxic to human cancer cell lines independent of its 5-alpha-reductase activity. AB - This investigation examined the effects of 6-methylene progesterone (6MP), an irreversible inhibitor of 5-alpha-reductase, on prostatic cancer (PC) cell lines. Dose titration microculture tetrazolium assays were used to evaluate cytotoxicity in cultures treated for 72 hr with 6MP (0-20 micrograms/ml). An androgen sensitive cell line, LNCaP, was drug-sensitive with a mean 50% lethal dose value (LD50) of 2.632 +/- 0.103. Hormone-resistant PC cell lines 1-LN, DU 145, and PC3 also demonstrated sensitivity with LD50 values between 0.8579-1.110 micrograms/ml with a group average of 1.023 +/- 0.082 micrograms/ml. Increasing dosages of dihydrotestosterone in the growth media did not alter 6MP cytotoxicity in androgen-insensitive prostatic cancer cell lines. No correlation between androgen responsiveness and 6MP-induced cytotoxicity was observed. In nonprostatic malignancies, 6MP inhibited adenocarcinoma cell lines with a mean group LD50 value of 0.7772 micrograms/ml +/- 0.110. J82, a transitional cell carcinoma cell line of bladder origin, exhibited an average LD50 value of 1.041 +/- 0.260. In an epidermoid cervical cancer cell line, ME180, an LD50 value of 0.5356 micrograms/ml +/- 0.010 was noted. In a melanoma cell line, Du Mel 6, a mean LD50 of 0.7428 +/- 0.023 micrograms/ml was achieved with 6MP. We conclude that 6MP, a novel 5-alpha-reductase inhibitor, has potential as a cytotoxic agent in prostatic carcinoma and additional human malignancies. Further study is justified. PMID- 7845865 TI - Allelic loss of the retinoblastoma gene in primary human prostatic adenocarcinomas. AB - Inactivation of the retinoblastoma (Rb) gene has been implicated in the genesis and progression of a number of tumor types, including prostatic adenocarcinomas. We have analyzed a series of 46 surgically-resected human prostatic adenocarcinomas for allelic loss of the Rb gene with PCR amplification of a highly polymorphic region of the gene. 41 of 46 tumors (89%) were informative and 11 of these (27%) had lost one Rb allele. The relative frequency of this occurrence suggests that inactivation of the retinoblastoma gene may be an important event in prostate carcinogenesis. PMID- 7845866 TI - Effects of estrogens and progestogens on the membrane permeability and growth of human prostatic carcinoma cells (PC-3) in vitro. AB - The effects of estrogens and progestogens in the management of prostatic adenocarcinoma are generally believed to be related to their suppressive effect on the hypothalamic-pituitary-testicular axis, but other mechanisms have also been suggested. The present study was designed to investigate if an androgen insensitive human prostatic cancer cell line (PC-3) is sensitive to estrogens or progestogens and to elucidate possible mechanisms of action. Both estrogens and progestogens in high doses (10(-5) M) suppressed tumor cell growth. At these high doses medroxyprogesterone acetate (MPA) most effectively reduced the uptake of 86rubidium chloride, indicating the strongest effect on ion transport and membrane permeability. Effects on rubidium transport were also seen after estrogen treatment. It is suggested that estrogens and progestogens have direct cytotoxic effects on prostatic carcinoma cells in vitro, possibly by an effect on the cell membrane. PMID- 7845867 TI - Chemo-endocrine therapy in patients with stage D2 prostate cancer. AB - There have only been a few studies of chemo-endocrine therapy compared with endocrine therapy alone in newly diagnosed prostate cancer patients. We assessed the effects of these two therapies by comparing long-term survival rates. One hundred and twenty-nine patients were entered in this study between November 1977 and March 1992. Seventy-seven patients were treated with endocrine therapy alone. Other 52 patients received chemo-endocrine therapy, which included orchiectomy and/or diethylstilbestrol diphosphate (DES-DP) plus Cisplatin, with or without other cytotoxic agents. All patients had bone metastasis at the beginning of the study. There was a significant difference in survival between patients who received endocrine therapy and chemo-endocrine therapy (P = 0.0078). That is, survival rate was superior for the chemoendocrine therapy patients throughout the entire follow-up period. These data suggest that early chemo-endocrine therapy containing Cisplatin, with or without maintenance chemotherapy, is a potentially effective treatment for newly diagnosed metastatic prostate cancer and is worth further investigation via a randomized trial. PMID- 7845868 TI - Gastroenteritis. PMID- 7845869 TI - Mental retardation. PMID- 7845870 TI - Myelodysplasia in childhood and adolescence. PMID- 7845871 TI - Anticipatory guidance for the adolescent: has it come of age? PMID- 7845872 TI - Consultation with the specialist. Evaluation of heart murmurs. PMID- 7845873 TI - Index of suspicion. Case 2. Diagnosis: urinary lithiasis. PMID- 7845874 TI - Index of suspicion. Case 3. Diagnosis: rhabdomyolysis. PMID- 7845875 TI - Cumulative author and subject index, volumes 13 (1992), 14 (1993), and 15 (1994). PMID- 7845876 TI - [Site-specific formation and repair of mutagenic DNA damage of genetic material]. PMID- 7845877 TI - [Enzymology of DNA replication in Escherichia coli]. PMID- 7845878 TI - [Perspectives of practical application for studies of gene p53]. PMID- 7845879 TI - [Estrogen receptor: structure and function in normal and neoplastic tissue]. PMID- 7845880 TI - [Ecdysteroid receptor from Drosophila melanogaster--one of the transcription factors controlling metamorphosis]. PMID- 7845881 TI - [Role of P450scc gene transcription in regulation of steroid hormone synthesis in the adrenal cortex]. PMID- 7845882 TI - [Molecular forms of cytochrome P-450 in rat liver]. PMID- 7845883 TI - Prenatal diagnosis and carrier detection in mucopolysaccharidosis type II by mutation analysis. A 47,XXY male heterozygous for a missense point mutation. AB - Identification of iduronate-2-sulphatase (IDS) gene mutations in patients with mucopolysaccharidosis type II (MPS II, Hunter syndrome) allows fast and reliable carrier detection and prenatal diagnosis. We describe here three cases of prenatal diagnosis by direct detection of the gene mutation. In addition to two affected male fetuses from two different families, a 47,XXY fetus carrying both the normal and the mutant allele was diagnosed in a third family. The latter pregnancy was carried to term and the child is obviously not affected by MPS II. PMID- 7845884 TI - Evaluation of prenatal diagnosis of limb reduction defects by a registry of congenital anomalies. AB - Prenatal diagnosis performed by ultrasound scan is now a routine part of antenatal care in our region. How many fetal anomalies are actually detected by this procedure? We have used our registry of congenital malformations to answer this question regarding limb reduction defects (LRDs). The mean time of detection of LRDs was 26 weeks of pregnancy (range 16-32 weeks). The sensitivity of prenatal diagnosis of LRDs by ultrasonographic examination was much lower for isolated malformations (fetuses with only one anomaly) than for multiply malformed children with LRDs, 4.0 and 18.2 per cent, respectively. For all cases of LRDs, the percentage of prenatal detection was 11.5. Termination of pregnancy was performed in 6.7 per cent of the cases. PMID- 7845885 TI - Tetrasomy 12p (Pallister-Killian syndrome): ultrasound indicators and confirmation by interphase fish. AB - Tetrasomy 12p (Pallister-Killian syndrome) is a mosaic aneuploidy syndrome in which the isochromosome is present in amniocytes with a much greater percentage than fetal lymphocytes. Two new cases identified by prenatal diagnosis are reported. Indications for prenatal diagnosis were advanced maternal age and fetal anomalies. The most consistent reported prenatal ultrasound findings for tetrasomy 12p include polyhydramnios with short femurs and a diaphragmatic hernia. Recognition of congenital malformation patterns prenatally may allow appropriate selection of tissue for chromosome analysis. Molecular cytogenetic analysis using fluorescence in situ hybridization was used retrospectively to confirm the presence of the isochromosome 12p in various formalin-fixed fetal tissues. The levels of mosaicism detected in fetal and placental tissues were lower than those detected prenatally. PMID- 7845886 TI - Umbilical artery velocity waveforms before and after chorionic villus sampling. AB - Because a vascular aetiology has been suggested for the limb and oromandibular defects described after chorionic villus sampling (CVS), to determine whether transabdominal (TA) CVS causes noticeable changes in umbilical artery velocity waveforms in first-trimester pregnancies, the pulsatility index (PI) of the umbilical artery was evaluated before and after TA-CVS in 175 pregnancies sampled between 10.0 and 13.0 weeks' gestation. In 139 uncomplicated pregnancies, the mean PI values (with 95 per cent confidence interval) were before TA-CVS 2.751 (2.692-2.809), after 10 min 2.723 (2.697-2.809), and after 1 h 2.781 (2.722 2.840). There were no significant changes in PI relative to the CVS procedure either in pregnancies with an abnormal result or in those ending in spontaneous abortion. Our data do not support any statistically significant change in umbilical artery PI relative to TA-CVS in first-trimester pregnancies. This procedure, despite its invasive character, does not appear to affect the feto placental circulation. PMID- 7845887 TI - Transplacental amniocentesis: is it really a higher-risk procedure? AB - The aim of this study was to compare transplacental with non-transplacental amniocentesis in terms of related complications. Between January 1991 and December 1992, 4564 genetic amniocenteses were performed in 4527 patients (4491 singleton, 35 twin, and one triplet pregnancy) at 15-16 weeks of gestation. All the procedures were ultrasound-guided and performed by the same operator. In 1487 cases, an anterior placenta was traversed with the needle, whereas in 3077 cases, the needle was inserted directly into the amniotic cavity without traversing the placenta. After the exclusion of patients in whom amniotic cell culture failed or in whom an abnormal karyotype was obtained, and of patients lost to follow-up, a total of 4454 patients (98 per cent) were followed for 30 days after amniocentesis. Two spontaneous abortions occurred after a transplacental procedure, and five after a nontransplacental procedure (P = not significant). There were no episodes of amniotic fluid leakage in the first group, whereas 16 ruptures of the membranes that resolved spontaneously occurred in the second group (P < 0.01). Our data suggest that transplacental amniocentesis carries a similar abortive risk to and a lower risk of transient rupture of the membranes than non-transplacental amniocentesis and may therefore be preferred at the gestational period examined (15-16 weeks). However, the risk of feto-maternal haemorrhage, which is reported to be higher for a transplacental procedure, must be considered in the case of an anterior placenta. PMID- 7845888 TI - The value of sonographic diagnosis of fetal malformations: different results between indication-based and screening-based investigations. AB - The advantages of a routine screening or indication-based ultrasound investigation during pregnancy are still under debate. This is the first study where both methods are compared in two different time periods. More malformations were diagnosed before the 24th week of gestation by means of screening-based than indication-based investigation (18 per cent vs. 5 per cent, P < 0.005), and before 28 weeks in 26 per cent compared with 15 per cent respectively (P < 0.01). Twenty-six per cent of all malformations were detected by means of screening based investigations as opposed to 15 per cent by means of indication-based scans. Primary fetal malformations were also diagnosed much earlier (25 weeks vs. 30 weeks). Except for the fetal head, the detection rate of malformations was higher in nearly all other body regions of the fetus in the screening-based investigation. The most important advantage of a screening-based ultrasound investigation during pregnancy is to detect the malformations early enough in pregnancy for possible intrauterine treatment or to offer safe termination of pregnancy for the woman, at least for those anomalies that are lethal or significantly handicapping. PMID- 7845889 TI - Pitfalls in the prenatal diagnosis of peroxisomal beta-oxidation defects by chorionic villus sampling. AB - Variability in the level of expression of very long chain fatty acids (VLCFAs) is documented in cultured chorionic villus (CV) cells derived from two fetuses, one at risk for an unusual peroxisomal fatty acid beta-oxidation defect, and the other at risk for the X-linked form of adrenoleucodystrophy (ALD). Cells from early subcultures of chorionic cells from both cases gave normal values for VLCFA ratios. The results for the fetus at risk for the beta-oxidation defect were interpreted to indicate that the fetus was not affected; however, at birth, the infant was clinically and biochemically affected. In the case of the fetus at risk for X-linked ALD, although VLCFAs were normal in subculture 1, the levels of these fatty acids increased dramatically in subculture 3, suggesting an abnormal fetus. Termination of the pregnancy and subsequent biochemical and morphological follow-up confirmed that the fetus was indeed affected by ALD. PMID- 7845891 TI - Syndromes identified in fetuses with prenatally diagnosed cephaloceles. AB - An evaluation of all fetuses from our institution with prenatally diagnosed cephaloceles was conducted to determine the frequency and spectrum of genetic syndromes associated with this abnormality. Review of the sonographic images, postnatal autopsy or pathology reports, delivery room records, paediatric neurosurgical findings, radiographs, and cytogenetic data were collected. Fifteen postnatally confirmed cases of prenatally diagnosed cephaloceles and two misdiagnosed cases were identified. Thirteen were midline occipital lesions, one was frontoparietal, and one was frontoethmoidal. Excluding microcephaly, hydrocephaly, and distortion of intracranial anatomy, 9 of 15 (60 per cent) had other associated anomalies, including two fetuses with aneuploidy. The prenatal diagnosis of a cephalocele should initiate a thorough search for other abnormalities. In this series, there were three multifactorial, two chromosomal, two sporadic, and two autosomal recessive syndromes identified. An accurate diagnosis is critical in determining the prognosis and providing appropriate genetic counselling. PMID- 7845890 TI - Feto-amniotic shunting--report of the experience of four European centres. AB - Few reports concerning intrauterine shunting are available. We investigated the impact of this method. In order to evaluate intrauterine shunting and the complication rate for different indications, we sent a questionnaire to all German-speaking level 3 centres. In four level 3 centres, 52 intrauterine catheters were inserted in 34 fetuses. The indications were uni- or bilateral hydrothorax in nine cases, cystic adenomatoid malformation of the lung in four cases, infravesical stenosis in 13 cases, and fetal ascites in eight cases. In three cases (6 per cent), difficulties occurred when the drain was inserted. In 15 cases (29 per cent), the function of the drain was reduced by dislocation or occlusion. The mortality rate caused by shunting was as high as eight per cent (four cases). The application of an intrauterine shunt currently represents a rarely performed ultrasound-guided therapeutic intervention in the fetus. In all cases, the indication for shunting is to avoid compression of normal tissue by cystic structures. A high complication rate restricts the application of drainage to selected cases. PMID- 7845892 TI - Second-trimester echogenic small bowel: an increased risk for adverse perinatal outcome. AB - 2267 singleton fetuses who had one ultrasound examination between 15 and 21 weeks' gestation were prospectively evaluated for echogenic small bowel. Thirty two cases of echogenic small bowel were detected--a prevalence of 1.4 per cent. Echogenic fetal small bowel was divided into two grades: grade 1, where the small bowel was more echogenic than the liver; and grade 2, where the small bowel had the echogenicity of bone. In contrast to 19/23 fetuses with grade 1 small bowel echogenicity, only 2/9 fetuses with grade 2 echogenic bowel had a normal pregnancy outcome (Fisher's exact test; P < or = 0.01). Complications associated with second-trimester echogenic small bowel included in utero cytomegalovirus infection, second-trimester growth restriction, intrauterine fetal demise, and chromosomal abnormalities. Second-trimester fetal echogenic small bowel is associated with an increased risk of an adverse outcome. The prevalence of perinatal and neonatal complications is significantly greater when small bowel echogenicity approaches that of bone. PMID- 7845893 TI - Experience with 500 prenatal diagnoses of sickle cell diseases: the effect of gestational age on affected pregnancy outcome. AB - Prenatal diagnosis of sickle cell diseases is obtained rapidly and precisely by polymerase chain reaction (PCR) with Ddel restriction analysis and dot-blotting with allele-specific oligonucleotides (ASO). Prenatal diagnosis of HgbSS and HgbSC was performed in 500 pregnancies, 196 by Southern blot and 304 by PCR. PCR drastically shortened the interval from sampling to reporting, allowing acceptance even of samples with unknown paternal phenotype, and resulted in an overall four-fold increase in diagnoses. In 108 pregnancies, the diagnosis was an affected fetus; 25 were HgbSC: 3 (12 per cent) were terminated; 83 were HgbSS: four ended in miscarriage; 40/79 (51 per cent) were terminated. The gestational age at the time of report to the mother appeared to be a major outcome determinant when the fetal diagnosis was HgbSS. The change-point in the maternal decision was found at 20 weeks of gestation. Before the 20th week, most mothers (64 per cent) chose termination; thereafter, the majority (72 per cent) chose continuation. The odds ratio of termination in earlier relative to later reporting was 4.7. In order to offer a choice to the mothers at risk of delivering a fetus affected by sickle cell disease, the diagnosis should be reported before the 20th week of gestation. PMID- 7845894 TI - Reasons for women's non-uptake of amniocentesis. AB - More than 10 years after a chromosomal anomaly screening programme was set up in France for pregnant women of advanced age, amniocentesis is still a controversial issue. The reasons why eligible women did not utilize the test and whether or not the existence of social welfare coverage determined women's access to prenatal diagnosis were studied. A group of 291 women aged > or = 35 years who recently gave birth to normal liveborns was interviewed by telephone. Among those aged 38 years and over, who automatically qualified for social security coverage, 75 per cent had undergone amniocentesis as opposed to 23 per cent in the 35 to 37-year old non-covered age group who did not qualify for social security coverage. In both groups, access to amniocentesis was found to depend on the physicians', women's and male partners' attitudes towards prenatal diagnosis and abortion. Among the younger group, the uptake depended mainly on socio-economic factors. Institutional policies should ensure greater equality of access while allowing for individual preferences. PMID- 7845895 TI - Prenatal sonographic diagnosis of a third ventricle choroid plexus papilloma. AB - We report a case of fetal hydrocephalus secondary to a third ventricle choroid plexus papilloma detected by ultrasound at 33 weeks' gestation. The prenatal sonographic and colour flow Doppler findings of this rare fetal intracranial tumour are discussed. PMID- 7845896 TI - Minute chromatin structures in cells of amniotic fluid-an interpretative dilemma. AB - Single copies of tiny chromosome fragments, appearing either as single or as double minutes, were observed in a high frequency in amniotic fluid cultures of five mothers who underwent prenatal testing because of advanced age. In four cases, the minutes had arisen de novo. The minutes were later confirmed in fetal skin following termination of pregnancy in one case; in another, in cord blood following the birth of a normal boy; and in the third, in peripheral blood of a normal 3-year-old girl. In the fourth case, the minutes were not confirmed in cord blood following the birth of a normal boy. A follow-up chromosome study of the baby boy in the fifth case was not possible but the minutes were maternally transmitted. PMID- 7845898 TI - Prenatal diagnosis of trisomy 12 mosaicism: physical and developmental follow-up. AB - Follow-up evaluations were performed on a child at the ages of 2 years 8 months and also at 5 years who had been found on prenatal amniocentesis to be mosaic for trisomy 12. Eight of 36 colonies (22 per cent) were trisomy 12 at amniocentesis, with the remaining colonies showing a normal female karyotype. Cord blood, amnion, chorion, placental, and skin fibroblast chromosome studies failed to show any further evidence of a trisomy 12 cell line. At her evaluations, the child had normal physical and neurological findings. Psychomotor development was appropriate for age on screening. PMID- 7845897 TI - Fetal renal vein thrombosis, hydrops fetalis, and maternal lupus anticoagulant. A case report. AB - Hydrops fetalis with fetal renal vein thrombosis in a mother with antiphospholipid antibody syndrome detected post-partum suggests an underlying pathogenetic association that may provide new strategies for treatment of a lethal disorder. PMID- 7845899 TI - In utero development of a mediastinal teratoma: a second-trimester event. AB - Mediastinal teratomas have rarely been discovered during the prenatal period. When seen during the neonatal period, these tumours have caused respiratory distress or hydrops fetalis. We present the sonographic and pathological findings of a rapidly developing anterior mediastinal teratoma causing hydrops fetalis and in utero demise at 27 weeks' gestation. PMID- 7845900 TI - Prenatal diagnosis of congenital gastric outlet obstruction. AB - A case of gastric outlet obstruction diagnosed prenatally at 22 weeks' gestation is described. The differential diagnosis and the clinical management of this rare condition are discussed, and an updated literature review is presented. PMID- 7845901 TI - Prenatal evaluation and in utero platelet transfusion for thrombocytopenia absent radii syndrome. AB - A fetus with absent radii in both forearms was discovered on routine ultrasound examination performed at 18 weeks of pregnancy. No other significant abnormalities were found, and no signs of haemorrhage were detected. Serial ultrasound examinations revealed no evidence of fetal internal bleeding. At 37 weeks of pregnancy, a CBC obtained by cordocentesis under ultrasound guidance confirmed the diagnosis of thrombocytopenia absent radii (TAR) syndrome. Apheresis platelets were transfused into the umbilical vein to correct the thrombocytopenia and was followed by an uncomplicated delivery. No bleeding was encountered during the remainder of the baby's neonatal course. We conclude that TAR syndrome can be readily identified prenatally on sonogram, and if severe thrombocytopenia is confirmed by cordocentesis, platelets should be transfused to diminish the risk of serious internal bleeding during and immediately after delivery. PMID- 7845903 TI - Disease prevention research at NIH: an agenda for all. October 6-8, 1993, Bethesda, Maryland. Conference proceedings. PMID- 7845902 TI - Amniotic fluid leakage and miscarriages after TA-CVS. PMID- 7845904 TI - Disease Prevention Research at NIH: An Agenda for All. Introduction. PMID- 7845905 TI - Disease prevention research at NIH: An Agenda for All. Workshop A: Diet and nutrition research as it relates to aging and chronic diseases. PMID- 7845906 TI - Disease Prevention Research at NIH: An Agenda for All. Workshop B: Health behaviors--predictors, mediators, and endpoints. PMID- 7845907 TI - Disease Prevention Research at NIH: An Agenda for All. Workshop C: The ambient environment--monitoring effects and initiating change. PMID- 7845908 TI - Disease Prevention Research at NIH: An Agenda for All. Workshop D: NIH interface with public translation and policy. PMID- 7845909 TI - Disease Prevention Research at NIH: An Agenda for All. Workshop E: Physical activity and health. PMID- 7845910 TI - Disease Prevention Research at NIH: An Agenda for All. Workshop F: Obesity. PMID- 7845911 TI - Disease Prevention Research at NIH: An Agenda for All. Workshop G: Involvement of the private sector in prevention research. PMID- 7845912 TI - Disease Prevention Research at NIH: An Agenda for All. Workshop H: Involvement of other PHS agencies and professional societies in prevention research. PMID- 7845913 TI - Disease Prevention Research at NIH: An Agenda for All. Workshop I: High-risk populations--screening and prevention research strategies. PMID- 7845915 TI - Disease Prevention Research at NIH: An Agenda for All. Summary of workshop recommendations. PMID- 7845914 TI - Disease Prevention Research at NIH: An Agenda for All. Workshop J: Prevention strategies, economic realities, and identification of prevention research needs. PMID- 7845916 TI - Disease Prevention Research at NIH: An Agenda for All. Opening remarks: the role of prevention research directed toward improving health. PMID- 7845917 TI - Future paradigms for prevention research. PMID- 7845918 TI - Contributions of observational evidence to prevention research. PMID- 7845919 TI - Nested case-control studies. AB - The nested case-control study design (or the case-control in a cohort study) is described here and compared with other designs, including the classic case control and cohort studies and the case-cohort study. In the nested case-control study, cases of a disease that occur in a defined cohort are identified and, for each, a specified number of matched controls is selected from among those in the cohort who have not developed the disease by the time of disease occurrence in the case. For many research questions, the nested case-control design potentially offers impressive reductions in costs and efforts of data collection and analysis compared with the full cohort approach, with relatively minor loss in statistical efficiency. The nested case-control design is particularly advantageous for studies of biologic precursors of disease. To advance its prevention research agenda, NIH might be encouraged to maintain a registry of new and existing cohorts, with an inventory of data collected for each; to foster the development of specimen banks; and to serve as a clearinghouse for information about optimal storage conditions for various types of specimens. PMID- 7845920 TI - The role of the human genome project in disease prevention. AB - The Human Genome Project has made it easier to genetically map and clone mutant genes which predispose to a great many human diseases. In addition to diseases inherited in a simple Mendelian fashion, there are many degenerative and infectious diseases, and sensitivities to environmental insults, in which the genetic make-up of an individual contributes to the course of the disease. Once a gene or genes associated with disease has been cloned, it is possible to design DNA-based diagnostics to detect altered forms of the gene which predispose to disease. The ability to predict the development of disease makes possible early intervention to limit the severity of a disease or to use gene therapy to cure inherited disorders. PMID- 7845922 TI - Challenges to the funding of prevention research. AB - With the dramatic increases in cost and complexity of medical treatment over the past few decades, the public has emphasized the need to increase efforts aimed at the primary prevention of major causes of illness and death. Screening, early detection, and preventive measures have become attractive alternatives to heroic treatment efforts that exhaust huge resources on the late stages of disease. A large number of research projects have demonstrated substantial public health benefits from preventive measures. While much more prevention research is needed, it is important to bear in mind that the answers to promising research questions are limited by a shortage of funding. The costly nature of prevention research in particular is a roadblock to funding. Due to the current organization of the National Institutes of Health, research in prevention often receives low priority. It is also increasingly apparent that coordination of the national research agenda for disease prevention needs to be better structured. This paper highlights a number of issues that need to be addressed in order to strengthen the prevention research program. PMID- 7845921 TI - The contribution of large, simple trials to prevention research. PMID- 7845924 TI - Cost-efficient designs of cluster unit trials. AB - BACKGROUND: Large field trials that randomize naturally occurring clusters such as communities, worksites, or schools are becoming widely accepted for evaluating complex interventions. The within-cluster measurement of individuals typically uses a cohort, followed throughout the trial or cross-sectional samples selected independently at each time point. The relative costs of these approaches is of concern in designing such trials. METHODS: This paper takes the unified model for analyzing large cluster unit trials developed by Feldman and McKinlay (Stat Med 1993) and combines the resulting expression for the variance of the treatment effect with a simple cost function into an algorithm that produces the optimal trial design in terms of the number of clusters and the number of observations per cluster. Using the unified model developed in the prior paper, this algorithm also allows direct comparison of the cost of designs with equivalent precision. In particular, designs that use cohorts in each cluster unit and observe cohort members over time are contrasted with designs that draw independent cross sectional samples from each cluster at each time point. RESULTS: Using the algorithm and a realistic design problem, it is demonstrated that cohort designs are more cost efficient for short trials and high (> or = 0.75) autocorrelations. CONCLUSIONS: The power of the algorithm in designing cost-efficient cluster unit trials is well demonstrated. Estimates of variance and cost components from prior trials need to be readily accessible for use in the algorithm, for planning subsequent trials. PMID- 7845923 TI - Community trials. AB - Community-wide or population approaches are essential in most health promotion and prevention strategies. However, much less is known about these methods compared with traditional clinical approaches. Why is the community approach essential? Most common health problems amenable to prevention have strong environmental, cultural, lifestyle, and behavioral components. People, communities, whole countries make choices about whether or not to consume alcohol, and drive, smoke cigarettes, exercise, or have their children immunized. All of these involve individual choices but also involve societal or cultural barriers and enticements, access, and availability, monetary and opportunity costs, laws, and other community-wide factors. While some prevention issues respond to traditional clinical or health care approaches, most do not. They require a coordinated community approach to support the preventive efforts of the health care sector and develop an environment and an educated population which makes prevention possible. If we are to approach true primary prevention or elimination of major health impairing conditions, the population approach is a necessary element. PMID- 7845925 TI - Prevention research and its interface with policy: defining the terms and challenges. AB - The United States has led the way in the development of new insights into the detection, treatment, and prevention of disease. Not only has the Nation's research community ushered in the virtual elimination of nutrient deficiency diseases, dramatic reductions in childhood vaccine-preventable diseases, and impressive gains against heart disease and stroke, it has also been at the forefront of basic research in genetics and molecular biology and the development of important diagnostic and therapeutic interventions. With health care reform comes an opportunity to build upon and strengthen the positive features of the Nation's health system, including health research--in particular, research that fosters the prevention of health problems and a better informed application of medical services. PMID- 7845926 TI - Maternal and child health: overview. PMID- 7845927 TI - The gene therapy of cancer. PMID- 7845929 TI - Vaccines. PMID- 7845928 TI - The prevention of low birthweight and its sequelae. AB - BACKGROUND: Low birthweight and its components preterm birth and fetal growth retardation account for the vast majority of perinatal mortality and more than 50% of the long term neurologic morbidity. METHODS: Historical trends and the effectiveness of various interventions designed to improve pregnancy outcomes associated with low birthweight were evaluated in an attempt to define which future research efforts might be useful. RESULTS: Practices aimed at achieving a reduction in the low birthweight rate (the use of tocolytics, enhanced prenatal care, nutritional interventions) have not generally been successful or have not been widely utilized (smoking cessation programs). Practices aimed at improving low birthweight survival and reducing morbidity (group B streptococcus prophylaxis, maternal corticosteroids, surfactant use, newborn ventilation) have been responsible for most of the improvements in outcome. CONCLUSION: Continued effort into discovering effective practices for reducing low birthweight, for understanding the most appropriate methods of implementing practices known to be effective in reducing low birthweight, and refinement of practices known to reduce mortality and long term handicap in low birthweight babies should be major foci of prevention research. PMID- 7845930 TI - Preventing childhood lead poisoning. AB - Of all the neurotoxins, lead is the longest known and best understood. Because we know so much about what it does, where it is, and what is required to remove it from the presence of children, lead poisoning should also be one of the easiest diseases to eradicate. Despite this, progress in the primary prevention of childhood lead poisoning has been halting and erratic. In this paper, I outline the rapidly advancing state of knowledge on the epidemiology and toxicology of lead, examine some of the reasons for the gap between what is known and what has been accomplished, and outline the steps toward authentic primary prevention. Eradication of childhood lead poisoning is a realizable goal. Its importance is unquestioned; former Secretary of the Department of Health and Human Services Louis Sullivan declared in 1991 that it is the most serious environmental disease of North American children. PMID- 7845931 TI - Brain injury in the premature infant--current concepts. AB - The magnitude of the problem of brain injury in the premature infant, and particularly the prevention of that injury, is enormous. Approximately 50,000 infants are born yearly in the United States with a birthweight < or = 1,500 g. Approximately 85% of these infants survive, and of the survivors, approximately 5 15% exhibit major spastic motor deficits, grouped under the rubric "cerebral palsy," and an additional 25-50% exhibit less prominent development disabilities, particularly school failure. Moreover, epidemiological studies show that in recent years the prevalence of cerebral palsy in infants of low birth weight, i.e., birth weight < or = 1,500 g, has increased, probably as a secondary result of the ever increasing survival rates for these fragile small infants. PMID- 7845932 TI - Directions for future research in drug abuse prevention. AB - This paper describes future directions for research in drug abuse prevention from six perspectives that are relevant to NIH: integrated demand and supply reduction, strategic prevention that addresses whole populations and high risk groups, comprehensive or extended prevention that includes multiple channels and periods for intervention delivery, technology transfer, prevention research methods development, and finally, the overarching perspective of interfacing basic and social science research approaches. Specific research questions are summarized that represent each perspective, with implications for NIH policy. PMID- 7845933 TI - Adolescents and young adults: overview. PMID- 7845934 TI - Prevention of HIV and STD infections. AB - The objective of this paper is to identify the key research questions that need to be addressed in order to improve our prevention efforts in the areas of HIV and other STDs. First, the dimension of the problem posed by HIV and other STDs will be summarized. Second, evidence of an epidemiologic synergy between HIV and other STDs will be reviewed. Finally, important research questions and innovative strategies for prevention of HIV and STD infections will be outlined. PMID- 7845935 TI - Violence prevention. PMID- 7845936 TI - Prevention of noise-induced hearing loss. AB - Sounds of sufficient loudness and duration will damage the human ear resulting in temporary or permanent hearing loss, often accompanied by tinnitus. Irreversible inner ear damage from repeated sound overstimulation can occur at any age, including early infancy, resulting in permanent noise-induced hearing loss. A typical noise-induced hearing loss impairs the understanding of speech sounds, which could degrade performance in the classroom and on the job. Utilizing current knowledge about ear protection, noise-induced-hearing loss is entirely preventable except in cases of accidental exposure. Unfortunately, widespread and consistent use of appropriate ear protection devices by individuals at risk has been an elusive public health goal. PMID- 7845937 TI - Prevention of secondary disabilities after brain injury and spinal cord injury: implications for future research. AB - Over the past decade there has been increased emphasis upon prevention of disability. Although it is obvious that preventing a disability is the most desirable approach, disabilities will nonetheless occur. When they do, we must treat them and prevent additional disabilities from following the original ones. Indeed, this separation of disabilities has led to a clearer understanding of their prevention, namely primary, secondary, and tertiary prevention. PMID- 7845938 TI - Research in tobacco use prevention: where should we go next? PMID- 7845939 TI - Prevention of alcohol use and abuse. AB - The primary goal of educational alcohol prevention programs is to lower the overall prevalence of alcohol use and abuse among populations at risk for negative alcohol-related outcomes. Youth are primarily targeted for prevention since there is ample evidence that alcohol-related injuries constitute a major risk for this group in particular. Prevention includes a goal to delay the onset of regular consumption and decrease high-risk consumption among youth who do drink. No matter what definition of alcohol use or abuse is adopted, the goal of prevention is to lower the proportion of youth who engage in that type of use. Among those who already use or abuse alcohol by any definition, the goal of prevention is to reduce the average intensity of use and prevent the progression of consumption to more severe levels. Reducing high-risk consumption may include preventing drinking while driving as well as promoting "responsible" drinking. Prevention programs may include a focus on reducing or eliminating consumption among occasional users. Prevention is also targeted at adults, primarily focusing on reduction of alcohol-impaired driving, reduction of alcohol-related violence, and reduction of alcohol consumption during pregnancy. PMID- 7845940 TI - Asthma etiology and management: primary to tertiary prevention. PMID- 7845941 TI - Research priorities for managing the transmission of vector-borne disease. PMID- 7845942 TI - Prevention of non-insulin-dependent diabetes mellitus. AB - Non-insulin-dependent diabetes mellitus (NIDDM) is a chronic disease which may take several years to develop, presumably starting in most cases with genetic susceptibility. Development of NIDDM is influenced by obesity and physical inactivity. As these risk factors can be altered by behavioral modification, and some of the physiologic abnormalities predicting diabetes, such as insulin resistance and impaired glucose tolerance, can be improved by behavioral modification and with drugs, NIDDM is potentially preventable. This potential needs to be demonstrated by randomized clinical trials. PMID- 7845944 TI - The prevention of needless pain: research opportunities. AB - The prevention of needless pain must begin with the obvious: research aimed at eliminating the injuries and illnesses that cause pain. Others have been assigned such topics at this meeting, and I will not further address primary prevention of pain by the elimination of its inciting tissue damage. There are pain prevention issues that are in great need of innovative research, but a necessary first step must be epidemiologic studies of the incidence, natural history, and distribution of significant painful conditions within our population. PMID- 7845943 TI - Prevention of periodontal diseases in adults: strategies for the future. AB - Gingivitis and periodontitis are the most prevalent periodontal diseases in adults. Gingivitis is characterized by inflammation of the gingiva without loss of connective tissue attachment to the teeth while periodontitis results in loss of attachment and alveolar bone and may lead to tooth loss. Gingivitis is highly prevalent in adults in the United States, and up to 70% of adults have at least mild periodontitis. In only a small proportion of adults (< 15%) does periodontitis progress to severe disease. The etiology of periodontal disease is infection with pathogenic dental plaque bacteria in a susceptible host. Strategies for preventing periodontal diseases therefore may intervene at the level of the initiation of the inflammatory process, or by preventing the progression of bone and attachment loss in periodontitis. Improved mechanical and chemical plaque control as well as improved restorative materials to facilitate plaque removal continue to enhance the patient's ability to control the plaque bacteria. Strategies to target prevention to the patients who need it most include risk factor assessment, new diagnostic methods, and further elucidation of the natural history of periodontal disease. Further study of the etiology and pathophysiology of periodontitis will aid in the prevention of further destruction through targeted use of local and systemic antibiotics and well as drugs to aid in the host response. Ultimately research may yield multivalent vaccines to be used in high-risk patients. PMID- 7845945 TI - Benefits from elimination of Helicobacter pylori infection include major reduction in the incidence of peptic ulcer disease, gastric cancer, and primary gastric lymphoma. AB - BACKGROUND: It has recently been recognized that gastritis, gastric ulcer, duodenal ulcer, gastric carcinoma, and primary gastric B-cell lymphoma are all associated with gastroduodenal infection with the bacterium Helicobacter pylori. Ten percent of Americans develop a peptic ulcer: one in six of those is infected. Four to five million Americans have peptic ulcer disease and ulcer disease is responsible for $43 to $44 billion in annual health care costs. METHODS: We review the accumulated data showing that successful treatment of H. pylori infection results in healing of gastritis and cure of peptic ulcer disease. Current data suggest that by elimination of H. pylori infection it may be possible to prevent most gastric carcinomas and primary gastric lymphomas. CONCLUSIONS: H. pylori infection is currently considered primarily as a cause of peptic ulcer. H. pylori infection is a major public health problem and elimination or prevention of the H. pylori infection will result in a tremendous reduction in medical costs, morbidity, and mortality. PMID- 7845946 TI - Amelioration of diabetes-like retinal changes in galactose-fed dogs. AB - Diabetic retinopathy, the leading cause of blindness among young adults in the developed world, is characterized by vascular changes of the retinal capillary bed. Beagles fed a diet containing 30% galactose develop retinal vascular lesions that are similar to those observed in diabetics. These progress from initial retinal changes which include aldose-reductase-linked formation of pericyte ghosts and the subsequent development of acellular capillaries, microaneurysms, and intraretinal hemorrhages to the appearance of occluded vessels, areas of nonperfusion, and intraretinal microvascular abnormalities (IRMA) and in the final stages, the formation of fibrovascular membranes on both the retinal surface and the posterior hyaloid membrane. In prevention studies utilizing 0.5, 5.0, 10, and 16 mg/kg/day of the aldose reductase inhibitor M79175 (2-methyl-6 fluoro-spirochroman-4-5'-imidazolidine-2',4'-dione), pericyte ghost formation, and the subsequent appearance of microaneurysms, intraretinal hemorrhages, acellular capillaries associated with background retinopathy were arrested in a dose-dependent manner. Similar dose-dependent changes in the appearance of cataracts were also observed. The dog represents the first animal model to demonstrate all of the clinical and histological retinal vessel changes observed in human diabetics. PMID- 7845948 TI - Prevention of cardiovascular disease--opportunities for progress. AB - Steady progress has been made in the prevention of cardiovascular disease. There has been a favorable trend in major risk factor reduction and an average 3% annual decline in cardiovascular disease death rates over the past decade. Yet, CVD death rates still exceed that for many countries and not all segments of the U.S. population have benefited equally. Cardiovascular disease remains the leading cause of death and disability in this country. The role of epidemiologic research and prevention strategies in addressing this issue has been underestimated. Unresolved research questions require further epidemiologic research in order to improve application of known preventive measures and explore other approaches toward the prevention of cardiovascular disease. It is well established that attention to life-style changes and pharmacologic approaches can prevent cardiovascular disease in those at high risk and reduce the likelihood of subsequent cardiac events among patients with known cardiovascular disease. Furthermore, small changes in the distribution of risk factors through community intervention can have tremendous impact on cardiovascular disease morbidity and mortality. Preventive research requires an appropriate framework and plan to satisfy or exceed the needs in keeping with the national goals for Healthy People 2000. The National Heart, Lung, and Blood Institute has addressed this issue by creating a Task Force to develop research priorities for epidemiology and prevention. PMID- 7845947 TI - Prevention of osteoporosis. PMID- 7845949 TI - Disease prevention for older adults: overview. PMID- 7845950 TI - Age-related cataracts: scope of problem and prospects for prevention. AB - Cataracts develop in the lens of the eye which is responsible for focusing incoming light onto the retina. Early in life the lens is transparent, and incoming light encounters no difficulty in its passage through the eye. With aging, the lens becomes less clear, incoming light is scattered to an increasing degree, and if loss of lens clarity is severe enough, vision is affected. When clouding of the lens impairs vision, a clinically significant cataract is present. Currently there is no medical treatment for age-related cataract. The only treatment is surgical removal of the affected lens when vision is sufficiently impaired. A major goal of past and on-going epidemiologic studies is the identification of risk factors for cataract, so that strategies for the prevention of cataract can be developed. PMID- 7845951 TI - Results of 20 years of research on the treatment of diabetic retinopathy. AB - Diabetic retinopathy is the leading cause of blindness in young adults, ages 20 55. Without treatment 50% of those with proliferative diabetic retinopathy will be blind within 5 years. Over the last 2 decades the National Eye Institute has supported four different multicenter randomized clinical trials for diabetic retinopathy. Implementation of the results from these clinical trials can markedly reduce the risk of blindness. PMID- 7845952 TI - Prevention of depression, recurrences, and complications in late life. AB - As emphasized in the recent NIH Consensus Statement on the Diagnosis and Treatment of Depression in Late Life, depression in the elderly is a persistent or recurrent disorder that can result from psychosocial stress or physiological effects of disease and can lead to excess disability, cognitive impairment, increased symptoms from medical illness, physiological effects, increased utilization of health care services, and increased rates of suicide and nonsuicide mortality. Primary prevention can target high-risk groups including those with specific medical illnesses, disabling chronic diseases, widows/widowers, and spousal caregivers. Secondary prevention of recurrences of major depression is possible through maintenance treatment with antidepressant medications. Secondary prevention of behavioral complications such as suicide and alcoholism and of excess disability, morbidity, and utilization of general health services in patients with psychiatric-medical comorbidity can be facilitated by systematic approaches to case identification and treatment for depression in medical patients. PMID- 7845953 TI - Influenza and pneumococcal vaccination of the elderly: newer vaccines and prospects for clinical benefits at the margin. AB - The continued importance of pneumonia and influenza as a cause of hospitalization and death in the United States provides ample evidence of the need for more effective means of prevention. Recent reports have greatly enhanced our understanding of the impact of these infections as major contributions to the morbidity and mortality of respiratory disease. Other reports have provided new evidence of the clinical effectiveness of current influenza and pneumococcal vaccines and the cost effectiveness of vaccination. Together with studies on long term outcomes of pneumonia patients, it is now clear that vaccination rather than pneumonia is truly "the old man's friend." These recent developments raise the question of what clinical benefits might be expected from new and improved influenza and pneumococcal vaccines. In all likelihood their marginal benefits will be small, and greater benefits might be achieved by overcoming problems in vaccine delivery and improving the implementation of public policies for vaccination. PMID- 7845954 TI - Prevention of falls and fall injuries in elderly persons: a research agenda. AB - In summary, falls and fall injuries represent common and potentially preventable causes of functional disability, morbidity, and increased health care utilization among elderly persons. While much has been learned about falls and fall injuries over the past decade, much further information is needed in order to identify the optimal prevention strategies. Some of the important questions that remain to be answered are listed in Table 1. While certainly not exhaustive, the topics listed in Table 1 and discussed in this paper provide a beginning template for a research agenda for fall and injury prevention among elderly persons. PMID- 7845955 TI - Prevention of oral complications in cancer patients. AB - This paper identifies future research strategies relative to prevention of oral complications of cancer and its treatment, with specific emphasis on radiation and/or myelosuppressive therapy. Data relative to both oral/pharyngeal cancers and cancers the treatment of which profoundly affects the oral cavity are highlighted. The basis for the presentation is: (a) the report that emanated from the 1989 National Institutes of Health Consensus Development Conference on "Oral Complications of Cancer Therapies: Diagnosis, Prevention, and Treatment," the proceedings of which were published in 1990; and (b) the Statistics Review Monograph "Cancers of the Oral Cavity and Pharynx, 1973-1987," published in 1991. In this context, discussion on preventive research strategies relative to surgical therapy of the cancer patient is minimal. Emphasis is placed on prevention of oral complications in the older adult cancer patient. PMID- 7845956 TI - [Bronchopulmonary precancerous conditions and tumors--risk groups from the occupational medicine viewpoint]. AB - Risk groups with regard to bronchopulmonary precancerous and tumor diseases of occupational origin can be deduced from current occupational disease statistics. Most prominent are those working with asbestos. Each year about 250 asbestos associated bronchial carcinomas and 400 mesotheliomas are recognized and compensated; the tendency is increasing. Because of the long latency time, the frequency peak will probably be reached in about 15 years in spite of the prohibition of asbestos usage. The second place is probably taken by malignomas among the underground uranium mine workers in Thuringia and Saxony (SDAG Wismut). Next come bronchial carcinomas with silicosis (carcinoma in scar tissue) after exposure to chromium(VI) and arsenic compounds as well as various other chemicals and metals. Dose-activity relationships are significant for all occupational carcinogenic agents, as there are also often syncancerogenic influences (especially smoking). From the data on previous loading, high risk groups, for example, among the insulation workers exposed to asbestos or uranium miners in the so-called "wild years", can be defined. A suitable screening method for the detection of bronchopulmonary tumors in the early stages has not yet been established. Medical checkups for the respective risk groups concentrate on the early X-ray detection of circular foci. As shown by recent studies, cytological sputum diagnosis, (fluorescence) bronchoscopy, and BAL cytology must be employed much more frequently in the high risk groups so that the prognostically more favorable stages of preneoplasm and carcinoma in situ can be detected and possibly treated curatively. These procedures are currently reaching a considerably higher sensitivity with the help of modern molecular biology techniques (e.g. detection of tumor-associated genetic changes and gene products). This contributes to an improvement in surveillance examinations with increasing detection of the curable early forms of tumors. However, only the further development of primary prevention, i.e. the greatest possible minimization or, if possible, total elimination of contact with carcinogenic agents and the consequent control of occupational protection will lead to a drastic reduction in the occupational risk of cancer. PMID- 7845957 TI - [Measuring pharyngeal pressure in patients with nCPAP ventilation]. AB - In 36 patients inspiratory and expiratory pressures in the pharynx were measured during nCPAP with pressures ranging from 5 to 20 mbar. The results were compared to the nasal resistance as measured by rhinomanometry and to minimal cross sectional area of the nose as measured by acoustic rhinometry. PMID- 7845958 TI - [Pneumocystis carinii pneumonia with recurrent pneumothorax and pleuritis]. AB - A report on three HIV-positive patients with recurrent pneumothorax in pneumocystis carinii pneumonia on whom partial parietal pleurectomy and in two cases also a wedge-shaped pulmonary resection were performed. Histology revealed granulomatous necrotising pneumonia involving the visceral pleura, and a partly honeycomb-shaped metaplasia of the pulmonary tissue. A fibrinous and partly granulomatous necrotising pneumocystis carinii pleuritis of both pleural membranes was seen, being the morphological correlate of an in all cases prolonged exudation to the pleural cavity. Conservative treatment remained unsuccessful due to the marked lung and pleura involvement in the inflammatory process, necessitating surgical revision. PMID- 7845959 TI - [Population morbidity in Sofia as a reflection of the territorial characteristics of air pollution in the city]. AB - A study of ambient air pollution differences over the residential areas in Sofia and the effect of the morbidity of the population has been carried out. Correlation analysis between the average concentrations of particulates, SO2, NO2, H2S, phenol and lead, and the incidence of several groups of diseases among adults and children has been performed. It has been found out that air pollution is more intensive in the centre of the city as a consequence of the heavy motor vehicle traffic and the old way of town planning. The results point out also that diseases of the lung, eye and skin are more frequent among the residents of city areas situated next to industrial zones, while diseases of the cardiovascular, hemopoietic and endocrine systems are more typical in the city centre as compared to a control residential areas. Although ambient air pollution has been found to the moderate, the correlation analysis suggests an influence of air pollution on the incidence of chronic diseases and immune imbalance. It is supposed that each pollutant possesses an individual risk potential. PMID- 7845960 TI - [The inhalational toxicity of the antibiotic preparation Bactericin for plant protection]. AB - The acute and subacute inhalation toxicity of a new Bulgarian antibiotic preparation "Bactericin" for plant protection is examined. It is meant for the treatment of seeds from tomatoes before sowing. The inhalational toxicity is evaluated by a complex of toxicometric, integral, behavioural, clinic-laboratory, biochemical and histological methods. The maximum concentration reached by dispersing is 40 mg.m-3. In the condition of acute (unrepeated exposure) and subacute (60 exposure) the concentration of 40 mg.m-3 causes no lethality, symptoms of intoxication and toxic effects in the organism of white rats therefore it could be accepted as not operative. The preparation conceals no danger of acute and chronic inhalational poisonings when working with the latter. On the basis of the performed investigations and bearing in mind, that the preparation is in the group of the antibiotics, a proposal is made for the purpose of orientation MAG in the air of the working zone -0.5 mg.m-3. PMID- 7845961 TI - [The acute toxicity of a bacterial insecticidal preparation containing a beta exotoxin]. AB - The acute toxicity of a new Bulgarian bioinsecticide preparation is determined, produced on the basis of Bacillus thuringiensis containing 0.1% beta-exotoxin by oral, dermal, inhalational and intraperitoneal introduction in experimental animals. The evaluation of the toxicity is performed by a complex of toxicometric, integral, haematologic and pathologicoanatomic methods according to the WHO and USA criteria for studying the safety of the microbic agents for plant protection. It is already established that the preparation introduced orally in dose 10,000 mg.kg-1 (1.6.10(11) cell kg.-1 10 micrograms.kg-1 beta exotoxin), applied dermally in dose 6000 mg.kg-1 (9.6.10(10), 6 micrograms.kg-1 beta exotoxin) and in concentration 300 mg.m-3 (4.8.10(10) cell m-3, 300 micrograms.m 3 beta exotoxin) provokes no lethality, intoxication and changes in the integral, haematologic and pathologicoanatomic studies of test animals. LD50 at intraperitoneal introduction in white rats is 387.20 mg (6.2.10(10), kg-1, 387.2 micrograms kg-1 beta exotoxin) for male and 364.0 mg kg-1 (0.58.10(9) kg-1 364.0 micrograms kg-1 beta exotoxin) for female animals. The investigations point out that according to rate of acute toxicity the bacterial preparation containing 0.1% beta exotoxin is referred to the low toxic substances and reveals no danger for acute oral, dermal and inhalational poisonings when the regulations for production and use are observed. PMID- 7845963 TI - [An infrared spectrophotometric method for determining acetone in the air of a work area in the presence of other solvents]. AB - The acetone is used on a large scale in practice as solvent of nitro-cellulose and acetyl-cellulose paints and lacquer, rubber and resins. A spectrophotometric method in the infrared area for direct determination of gas phase of acetone is developed by means of 20 m.gas cuvette. The determination is performed in the specific for the acetone peaks at 1216 cm-1 and 1737 cm-1. With the method could be determined the acetone concentrations of 10 mg/m3 to 2000 mg/m3. For this purpose are worked out different standard scales of the acetone at various length of the gas cuvette. The method is specific in the presence of the most frequently used organic solvents--toluol, ethanol, butanol, mineral turpentine and cyclohexan. Ketones only stand in the way of determination. PMID- 7845962 TI - [A rapid test for determining the content of residual monomer in polyvinyl chloride dust and granulate]. AB - Rapid and cheap test is developed on the basis of colorimetric tubes "Hygitest", produced in Bulgaria, which could substitute, in a number of cases, the more expensive chromatographic procedure. The method of gas extraction of the examined material is used in the test, and as measuring instrument are used colorimetric tubes "Hygitest" type "Vinylchloride-1-A", which are supplied with reinforced filter for humidity and with special scale. A specially constructed flask is used for thermal desorption. The test has reproducibility and sensitivity significant for performing screening and routine control on the raw materials for production of packings from polyvinylchloride for nutrition purposes. The method "Vinyl test" is standardized for control on the free monomer content in the packings for nutrition purposes with branch normal of the Ministry of Health and the State firm "Polychim" OH 02 77051-84 (Change No 1 of 8.07.1991). PMID- 7845964 TI - [An infrared spectrophotometric method for determining nitrous oxide and halothane in the air of operating rooms]. AB - Nitrous oxide and halothane are one of the most widely used anesthetics in the surgical practice. A spectrophotometric method in the infrared area is worked out for direct determination in gas phase simultaneously on nitrous oxide at 2236 cm 1 and on halothane at 813 cm-1 by means of 20 m gas cuvette. The sensitivity of the method for nitrous oxide is 20 mg/m3 and for halothane 5 mg/m3. The reproducibility of the method expressed as coefficient of variation is +/- 1-6%. The method is specific in the presence of other anesthesiological means. The air samples are taken in bags of Tedlar and depending on the sampling velocity the method can be used for recording the moment and average shift concentrations of nitrous oxide and halothane. PMID- 7845965 TI - [Diffusion indicator tubes for hydrogen chloride]. AB - In order to define the mean shift exposure of workers in the environment of hydrogen chloride, we could use, besides long-term colorimetric tubes also colorimetric tubes on the principle of diffusion, named also passive monitors. Experiments are performed on different reactionary principles and recipes of indicator compositions for hydrogen chloride: with pH-indicators as bromphenol blau, dimethyl yellow and benzopurpurine 4B, and also reactions for discoloration of silver chromate or lead sulfate. The successful variants are metrologically evaluated by means of gas generating device for calibration gas mixtures. Special attention is given to the accuracy of the results at different air humidity. Recipes with minimum effect of the air humidity on the results are developed and is proved, that concentrations of hydrogen chloride could be significantly measured, also at higher humidity of the examined air of those given in the literature. PMID- 7845966 TI - [The incidence of arterial hypertension and ischemic heart disease in workers manufacturing nitrogen and phosphorus fertilizers]. AB - Examinations are performed on 120 workers from the plant for nitrogen and 253 workers from the plant for phosphorous fertilizers. For comparison is used a control group of 103 persons having no professional contact with chemical noxa. The measuring of the arterial pressure and assessment of the arterial hypertension rate is performed after the standardised method of the World Health Organization (1984). The probability of ischemic disease of the heart is determined on the basis of the electrocardiographic changes (Minnesota code) and the data of the questionnaire of G. A. Rose (WHO, 1984). The results point out, that the arterial hypertension incidence and that of the ischemic disease of the heart in the exposed workers in both plants is insignificantly higher than that of the controls. There is no effect of the specialized length of service on the dissemination of the registered cardio-vascular diseases. The data of the carried out investigation show no presence of heightened risk of arterial hypertension and ischemic heart disease in workers from the nitrogen and phosphorous fertilizers production. PMID- 7845968 TI - [The assessment of the occupational risk for skin diseases in workers at the Storgoziia Plant, Pleven]. AB - A dermatological examination is performed on 95 workers (43 men and 52 women). In order to differentiate the type of contact dermatitis in connection with the expert examination of the skin changes in 20 workers was carried out epicutaneous test by specialized series PVH dust (pure), PVH--dust, containing dyes, by titanium oxide, with lead stearat and with paraloid, which is on acrylic base- all in concentrations 2% in carrier oil. It is established that in 26.3% of the examined are registered general skin diseases. In 7.4% are proved occupational skin diseases and in 3.2% allergic, in 4.2%--irritative. PMID- 7845967 TI - [Skin reactivity and the biological assessment of chromium exposure]. AB - Subject to the examination are 140 workers from the plant for hydraulic products "Iv. Tenev", town of Yambol. The dermatological examination embraces 57 workers from shop 21, 49 from shop 24 and control group of 24 persons. The examination establishes skin changes in 24.6% of the workers from shop 21 and in 38.7% in those from shop 24. In the same workers were proved occupational dermatoses respectively in 5.3% for these of the first shop and in 14.3% for those of the second shop. The results of the test of 10 workers from shop 24 gave positivation of the test with 0.5% chromic anhydride at 10.5%. The studies for toxicokinetics of chromium in the examined workers proved its high values in urine, erythrocytes and nails. Raised chromium levels are established in the urine of those working with chromium in comparison with the control group (p 0.0001). There is a good correlation dependence between the chromium in urine and in erythrocytes (r = 0.71; n = 45%; p < 0.0001). Persons, eliminating significant quantities of chromium in the urine have higher values of chromium in erythrocytes, which shows that the chromium entering the organism of workers in contact with chromium is 6 valent. The connection with the chromium in urine and in nails is more lightly expressed and is statistically insignificant (r = 0.35; n = 29; p < 0.05), which is due to the fact that the chromium in urine reflects the near exposure in time, while chromium in nails--the level of exposure before 6-8 months.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845969 TI - [Changes in electrolyte excretion in the saliva of 8th-grade students of a music school in Sofia]. AB - The present work is part of a complex study of the health problems concerning the training of schoolchildren from the musical school--Sofia in specialty violin and piano. In order to examine the changes in the activity of the sympathetic-adrenal system for tracing the concentrations of sodium, potassium and index sodium/potassium in saliva of schoolchildren from the musical school during the general education program and also during individual training. The changes established during the experiment show the dynamics in the functional state of the sympathetic-adrenal system. We have to mention, that during the individual training an increased activity of the adrenal is observed, in connection with the emotional adjustment and emotional expenditure of schoolchildren. PMID- 7845970 TI - [The effect of air pollution on the allergic reactivity of the population]. AB - An epidemiological study was carried out in several regions in Bulgaria polluted by industry and motor vehicle transport. The investigation included monitoring of ambient air pollution, a questionnaire study of 13040 persons, and allergological/immunological testing of representative groups of population. The testing was performed on persons selected by the questionnaire study, who were not exposed professionally to toxicants. The ambient air was contaminated by particulates and gaseous contaminants in the majority of the studies areas. The questionnaire study revealed an increased incidence of complaints indicative of allergic reactions, such as recurring skin eruptions, allergic rhinitis, conjunctivitis, asthmatic bronchitis. The positive skin tests were twice as common among the residents of polluted areas as compared to control. A decreased activity of the complement and increased levels of immunoglobulins (IgG, IgA, IgM) were found in the exposed population. The changes found in the study suggest a health risk for the population created by air pollution. PMID- 7845971 TI - [The health and demographic criteria in the assessment of and the approach to resolving the ecological problem in Bulgaria]. AB - The health and demographic aspects of the ecological problem are treated in scientific and theoretical plan. Data, illustrating the unfavourable changes in the health and demographic situation of the country, are given. They are interpreted as a result of the ecological stress and the existing crisis situation. The indices "local demographic potential" (LDP), "local health potential" (LHP) and "territorial health index" (THI) have the meaning of integral criteria for the urbanized environmental quality. They are elaborated on the basis of complete characteristics on the demographic process (birth-rate, mortality, infant mortality and natural growth) and all basic groups of diseases and nosological units, traced from 1980 up to now. Since 1986 an extremely dangerous tendency of rapid and socially significant deterioration of the health of the population has been observed. This country is in the process of depopulation from 1990. The data from the investigation confirm the priority significance of the activities concerning the protection and steadfast development of the environment with the principle objective--prevention and consolidation of the health of the population. PMID- 7845972 TI - [The direct health effects of air pollution in Vratsa in 1991]. AB - The effect of air pollution in the town of Vratsa on the daily morbidity of the population has been studied during the first half of 1991. Studies are performed on the correlation between the daily dynamics in the pollution according to specific for the town indices ammonia, hydrogen sulfide, sulphur dioxide, nitric oxides, dust, meteorological parameters temperature of the air, relative humidity, air velocity, barometric pressure and some respiratory and allergic diseases among the population. It is already established that the level of the air pollution in the town of Vratsa, among which dominate ammonia and hydrogen sulfide, have a direct effect on the acute respiratory morbidity, more expressed among the children. This influence is traced both in episodes of increased pollution, and in the course of several days afterwards and is conductive by the combination of unfavourable meteorological conditions, hindering the dispersion of the atmospheric pollutants. PMID- 7845973 TI - [The hygienic characteristics of the hospital environment in a cardiovascular pathology ward during the heating season]. AB - A study is carried out on the microclimate, physiological reaction of patients, chemical and bacteriological composition of the air in rooms of different location in the ward for cardiovascular pathology during the heating period of the year, according to some basic and integral indices. The characteristics of the interhospital environment in the rooms of the investigated ward is determined mainly by the irrational regime of heating, location, size of the glazed transparent area. In the hospital rooms are formed unsatisfactory hygienic norm parameters of the microclimate and the chemical composition of the air. The specific thermal environment affects the physiological reactions of the patients and leads to creation of conditions of discomfort and loading of the thermoregulation in direction of overheating. PMID- 7845974 TI - [An experimental study of the atherogenic effect of the vanadium and nickel contained in drinking water when combined]. AB - During an annual toxicological experiment on white male rats, receiving orally vanadium (V) and nickel (Ni) in doses, equivalent to the accepted in Bulgaria, maximum allowable norms for ist category surface waters (respectively 0.005 mg/kg and 0.0025 mg/kg), 2 and 6 times and 20 and 60 times higher, is studied the atherogenic effect of the latter after the indices: total cholesterol, beta lipoproteins, phospholipids, lecithin, total lipids, total protein and hexoses of glycoproteins in the serum; oxyproline, hexauranium acids and hexoses, hexosamines, connected with the proteins in the aorta. It is established that V and Ni in chronic combined effect in doses, equivalent to those accepted in Bulgaria, in maximum allowable concentrations for Ist category waters and surpassing them 2 and 6 time respectively, lead to no changes in the biochemical composition of the connective tissue of the aorta and to disorders in the lipidic and protein metabolism, while in higher doses is registered an increase of the glucoproteins and decrease in the glucosaminglycans in the aorta and decrease of the total lipids in the serum. The results point out, that V and Ni in the conditions of the experiment don't accelerate the processes of the natural ageing of the vessels and have no atherogenic effect. Juxtaposing the data for V and Ni concentrations in drinking waters in Bulgaria with our results give grounds to reckon, that their raised content in drinking waters in some regions do not represent a risk factor for the development of atherosclerosis. PMID- 7845975 TI - [Hygienic research on new soap preparations for intensive laundry use]. AB - The purpose of the study is to establish hygienic properties of the new preparations for intensive washing and their effect on the skin of man. Examinations are performed on 5 new washing preparations from firm "Verila": "Linda" (from the producer and from the trade network from the country--Ruse, Blagoevgrad, Stara Zagora, Pleven, Cherven Bryag, Plovdiv and Dobrich), recipe No 1, 2, 3 and 4. Sanitary and chemical examinations are carried out: organoleptic indices, nonionogenic surface active substances, total content of surface active substances, content of carbamide, sodium carbonate, ammonium nitrate, formaldehyde and free alkali. Investigations are made on 125 volunteers for skin irritative and allergenic effect, with epicutaneous test before and after 30-day washing--respectively with 0.5% and 2% and with 5% and 20% of the washing preparations. The results point out the absence of ammonium nitrate and formaldehyde and compliance with the content of the composition of the declared expenditure norms (except of "Linda" from the trade network of the country). There are no reactions of skin irritation and allergy in neither of the subjects with all washing preparations. Recommendations are given to the producer for observing the technological discipline and requirements to the packings. PMID- 7845976 TI - [The discomfort threshold studied in operators at the control consoles in automated production with a view to its use in job selection]. AB - The results from the investigation of the threshold of discomfort in 385 operators from firm "Kremikovtsi" are discussed. The most expressed changes are found in operators with increased tonal auditory threshold up to 45 and above 50 dB, in high confidential probability. The observed changes in the threshold of discomfort are classified into 3 groups: 1). Raised tonal auditory threshold (up to 30 dB) without decrease in the threshold of discomfort; 2). Decreased threshold of discomfort (with about 15-20 dB) in raised tonal auditory threshold (up to 45 dB); 3). Decreased threshold of discomfort on the background of raised (above 50 dB) tonal auditory threshold. On 4 figures are represented audiograms, illustrating the state of tonal auditory threshold, the field of hearing and the threshold of discomfort. The field of hearing of the operators from the III and IV groups is narrowed, and in the latter also deformed. The explanation of this pathophysiological phenomenon is related to the increased effect of the sound irritation and the presence of recruitment phenomenon with possible engagement of the central end of the auditory analyser. It is underlined, that the threshold of discomfort is sensitive index for the state of the individual norms of each operator for the speech-sound-noise discomfort.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845977 TI - [An estimation of the prevalence of risk factors for the cardiovascular system among female telephone operators]. AB - The dissemination of the standard risk factors for the cardiovascular system- smoking, family history of hypertension and abnormal weight in telephone operators is evaluated by including one, two or three of these factors (p = 260). A high relative part is taken by persons in the presence of the evaluated factors -75.8%, as the most highly spread is the factor "smoking" (58.8%) and smoking and family predisposition (15.4"). In persons with high blood pressure the dissemination of one or two of the examined risk factors is nearly the same, with heightened presence of "smoking and abnormal weight". In spite of the lack correlation between the studied risk factors and the arterial blood pressure, their dissemination on a large scale as well as the specific character of the telephone operators work certify a heightened risk of diseases of the cardiovascular system and the necessity of special attention to these endangered people. PMID- 7845978 TI - [Oscillographic studies of the temporal arteries in certain jobs in Bulgarian television]. AB - Oscillographic examinations on the temporal arteries of creative and technical specialists from the Bulgarian television are performed, who ensure direct transmission of the TV programs. The results point out to considerable increase in the level of the maximal temporal blood pressure and spastic oscillatory indices more strongly expressed in the creative specialists, which could be related to the nervous and psychic as well as emotional strain and high professional responsibility during the direct transmission of the TV programs. The data of the examinations confirm the significance of the functional oscillographic studies of the temporal arteries for revealing the early unfavourable changes in the cardiovascular system, in view of timely prevention of hypertension diseases. PMID- 7845979 TI - [Changes in the blood system under chronic toxic exposure]. AB - On the basis of accumulated experience from the numerous investigations of the elements of the peripheral blood in workers of different areas in industry and agriculture a classification is made of the injuries of the blood system under chronic toxic effects. Results from the peripheral blood state of 200 workers with chronic exposure to benzol and other aromatic hydrocarbons are given, as well as for 155 agricultural workers in contact with pesticides for many years and 308 children of the region with polluted by heavy metals (mainly lead) environment. Attention is drawn, that both the acute intoxications and chronic toxic effects have provoking role for the manifestation of concealed congenital, not rarely genetically stimulated insufficiency of Gl-6-PHD, which is manifested clinically as haemolytic anemia and secretly proceeding hemoglobinopathies, which clinically develop as thalassemia at entering of toxic doses of drugs, heavy metals, pesticides in the organism. PMID- 7845980 TI - [An assessment of the air pollution in the area of the Maritsa-Iztok Economic Union]. AB - The heating-electric plant "Maritsa Iztok" is situated in the area of Stara Zagora, on arable agricultural land, in close vicinity to settlements. It includes three heating plants, working with low caloric coals, of high ashen and sulphuric content and briquet fabric. Two stations for observation and evaluation of the atmospheric air in the district of plant "Maritsa Iztok", the meteorological conditions and geographic situation are chosen according to the Bulgarian State Standards 17, 2, 5, 01-81: station 1-"Gulubovo" and station 2 "Mednikarovo" for indices--dust, sulphur dioxide, hydrogen sulphide, ammonia, nitrogen peroxide. In order to determine the content of the already mentioned pollutants in the atmospheric air are used Bulgarian State Standards and the results are compared with the corresponding maximum allowable concentrations, according to Regulation No 2 of the Ministry of Health. PMID- 7845981 TI - [The action of the artichoke (Cynara scolymus) on the male gonads in an experiment]. AB - The gonadotropic effect of the Bulgarian preparation artichoke, developed on the basis of Cynara scolymus is studied. The preparation is used under the form of 50% aque emulsion, stabilized by emulgent Twin-80, in doses 35.70 and 150 mg/kg 1, 5 times weekly for 75 days. The evaluation is made on sexually mature white male rats Wistar, distributed into groups of 10. The results are compared with a control group. A complex of functional, quantitative morphological, classic histological tests are used, in compliance with the Bulgarian State Standards 15378-81. An electron microscopic study is performed. The 75-day introduction of artichoke [Cynara scolymus] in doses 35.70 and 150 mg/kg-1 leads to no significant changes in the structure of the semen of white rats, established on cellular and subcellular level. The single deviations in the function of the spermatozoid and the morphology of the spermatogenic epithelium give no grounds for conclusion concerning an injury or stimulating effect of the preparation in the conditions of the experiment. PMID- 7845982 TI - [An experimental evaluation of the cutaneous action of the preparation Bulmektin]. AB - The acute and subacute dermal toxicity, skin irritating and sensitizing effect of the preparation "Bulmektin" was examined for a period of 21 days. It contains 0.5% active substance Ivermectin. The experiments were carried out in conformity with the Bulgarian State Standards and the OECD methodical recommendations. The unrepeated dermal application of the preparation in dose 6000 mg/kg-1 for white rats provoked no lethality and signs of intoxication. No cumulative effect was established at the 21-day dermal toxicity. The threshold dose is 2000 mg/kg-1. On the basis of the investigations could be accepted, that the preparation carries no danger for acute and chronic dermal intoxications at observing the regulations for its production and use. No local irritation of the skin is established in rats and guinea pigs from the preparation. There is no development of contact allergy at the application of induced and allowed dose of 25% aqua suspension of the preparation on white guinea pigs. PMID- 7845983 TI - [Toxic substances from the use of coolant lubricants]. AB - The results from gas-mass analysis of the mixture of products from evaporation and volatile products from thermo-oxidizing destruction, eliminated at using lubricating-condensing devices point out, that the evaluation of the toxico chemical factor concerning only the lubricated aerosol contact is extremely insufficient. The presence of hydrocarbons of different homologs, oxygen and nitrogen derivatives of hydrocarbons has to be taken into consideration. For correct characterization of the conditions of work and risk for the workers of these productions, creating conditions for destructive processes with lubricating oils, is necessary a standardization of the leading components of the vapour-gas phase in the air of the working environment. PMID- 7845984 TI - [Harmful substances released during the thermal oxidative destruction of coolant lubricants]. AB - The use of lubricated oils in industry is related to processes of dispersing, evaporation and thermo-oxidizing destruction. As a result, in the air is eliminated a complex vaporous-gas aerosol mixture, consisting of lubricated aerosols, vapours and volatile products of evaporation and products of thermo oxidizing destruction. In the vapour-gas phase are identified hydrocarbons [saturated, unsaturated, aromatic and cyclic] oxygen- containing hydrocarbon derivatives-aldehydes, ketones, esters, alcohols] in some cases CO. HCL. The composition of the mixture depends on the type of the lubricated oils and on the specific technological operation. The detailed study of the components of the mixture is a prerequisite for determining the leading toxic substances and for correct evaluation of the exposure and professional risk in industries, allowing a course of destructive processes with the lubricated oils. PMID- 7845985 TI - [Methods for determining boron compounds in the air of a work area]. AB - The studies performed with the chinalizarin method the for determination of the concentration of boric compounds in the air of the working area, proved to be impracticable in the presence of geranium and beryllium compounds. A spectrometric method for analysis of boric compounds was developed, based on their interaction with fluoric and ferric ions in the presence of sulfo-salicylic acid, and a complex compound was received of light orange colour to red, depending on the boric concentration. The maximum of absorption was at wave length of 577 mm. The sensitivity of the method was 0.001 mg boric in the analyzed sample -2 cm3. There is a linear dependence between the boric concentration and the optic density of the developed samples of interval 0.001 0.15 mg borium. The accuracy of the method expressed by coefficient of variation in % is in interval 12.4-6.3% for borium concentrations of 0.001-0.1 mg. The field where the method could be applied is defined in the presence of titanium, copper and lead compounds. PMID- 7845986 TI - [Comparative studies of personal and steady-state sampling for determining dust exposure in different job groups]. AB - The variability of the dust concentration in time and space, as well as the change of worker's place during the working process, define the necessity of introducing personal sampling in the hygiene control practice. However, the laboratory equipment with personal devices is still not sufficient. The aim of this work is to assess the dust exposure of the basic professional groups from the ore- and coal production in Bulgaria by personal sampling in comparative studies of the static ambient sampling used up to now. 63 full-shift investigations of the dust factor were performed on professional groups of miners of the polymetal and coal pits by static ambient devices-[Hygitest production] and personal [from firms "Casella", "Strolein" and "Gilian"] devices, after standardized methods. The results are data processed-by means of logarithmic normal distribution of the relation of the respirable dust concentrations, determined personally and by static ambient sampling. The limits of variation of this correlation are from 0.5 to 4.1 at average geometric value -0.95 and standard geometric deviation-1.8 i.e. both types of sampling are intersubstitutional for the examined groups and sites, as in the underground ores the professional risk of respirable dust is underestimated up to 4 times at static ambient sampling. PMID- 7845987 TI - [The impact of the hostel life style on the health status of students]. AB - The work aims at studying the specificity of the social living conditions, organization, regimen, psychosocial and other factors of life and their effect on the health status of students from the hostels of the students' town in Sofia. An inquiry is used, including 69 questions, connected with the organization and the conditions of living and education in the hostels. A statistical method for examining the chronic somatic morbidity is applied. By the inquiry method are investigated 1034 young people (boys and girls), living in the hostels of the Student's town. The statistical method assists in studying the chronic morbidity of 10.051 students, living in the hostels and of 9.562 students living in other places. The results show that in the hostel form of living there are infringements of the conditions and organization of the living standard, daily regimen, nutrition etc. The registered negative deviations correlate with the presence of higher chronic somatic morbidity, higher prevalence in spreading of socially important diseases-cardio-vascular, gastro-intestinal, renal. A hygiene preventive program for improving the living standard, extending the dispensarization, carrying of prophylactic and treatment undertakings, etc. was recommended. PMID- 7845988 TI - [The affective-behavioral orientations of teenagers with an unequal social status]. AB - The study aims at establishing the affective-behavioral orientation in adolescents from the Homes for Children and Adolescents by examining their anxiety and readiness for aggression. In the investigation are included 227 children from 15 to 18 years old. The study is realized by using the questionnaire of Buss Durky for assessing the aggression, questionnaire for anxiety after Ch. Spilburgur and inquiry card for studying the problem of communication, directness of the personality etc. It is presumed that the unequivalant social conditions of life of adolescents from the Homes for Children and Adolescents have negative influence on the affective-behavioral orientation of the latter. We expect the raised aggressiveness to be with dominating hostile affective-cognitive orientation and in compliance with the high levels of uneasyness. The studying of predictors for emotional and behavioral derangements give us a possibility to reveal some subjective and social prerequisites, affecting the behavioral orientation and effective adaptation of juveniles from the Homes for Children and Adolescents. PMID- 7845989 TI - [The permissible concentrations of benzene in the atmospheric air of populated locations]. AB - When assessing the health risk of benzene and its allowable levels of exposure of special importance is its cancerogenic effect. Bearing in mind, that the cancerogenic substances have no threshold dose, as well as the genetic benzene activity, no safety level of benzene is recommended in the atmospheric air of settlements. The undertakings, in relation to the atmospheric air pollution with benzene, have to be conformed to the admissible risk. PMID- 7845990 TI - [The Healthy Cities Project of the World Health Organization and the approach to its realization]. AB - Our health prophylactic badly needs approaches and means for the realization of healthy policy, responding to the changing situations of health risk and shared responsibilities concerning the environment and man's health. The project "Healthy Cities" is a means of applying the already accepted in this country principles of the program "Health for all by the year 2000" on local standard. The city is accepted as a complex organism, which lives, develops and constantly changes. Healthy is this city which improves its environment and manages its resources in such a way as to ensure: high level of the health status; efficient health services; physical environment of high quality, including the living environment; steady ecosystems; society, supporting the health policy; offering good living conditions to every inhabitant; intensive social co-operation; steadfast economics; intensive cultural life and maintaining the connections with the cultural-historic and natural heritage; model and approach to the town planning, corresponding to the above mentioned nine parameters. The requirements of the project, related to the WHO priority strategies are given. A key mechanism in the realization of the health policy has to be the evaluation of the health and demographic state and its periodic reporting to the town authorities by means of suitable health criteria and indicators for the qualities of the environment. The analyses of the health state and the situation of the rural environment have to serve the Governmental decisions for the towns development. Conditions for participating in the project, the international initiatives and national priorities are presented.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7845991 TI - [An experimental study of the atherogenic effect of vanadium in body uptake with drinking water]. AB - During one year toxicological experiment on white male rats, receiving orally vanadium in doses 0.005 mg/kg, equivalent to the accepted in Bulgaria norm for ist category surface waters and 0.01 mg/kg, equivalent to the actually met in the drinking waters of some regions in this country heightened concentrations, its atherogenic effect is studied by indices: total cholesterol, beta-lipoproteins, phospholipid, lecithin, total lipids, total proteins, and hexoses of glycoprotein in blood serum; hydroxyproline, hexosamines, hexauronic acids and hexoses, connected with the proteins, in the aorta. A methodic approach is used for studying the atherogenic effect of vanadium on the processes of natural aging of the cardiovascular system. It is established that at chronic oral effect of the studied doses of vanadium no changes occur in the biochemical component of the connective tissue of the aorta and there are no infringements of the blood metabolism. In relation to the lipidic-only a decrease in the total cholesterol in the serum is established. The results show, that during the experiment vanadium causes no acceleration in the processes of natural aging of the blood vessels and has no atherogenic effect. Comparing the data for vanadium concentration in the drinking of Bulgaria to our results give grounds to reckon, that its heightened content in drinking waters of some regions presents no risk factor for the development of atherosclerosis. PMID- 7845992 TI - [An ergonomic and work physiology assessment of the risk factors for the musculoskeletal system in jobs performed by women]. AB - The purpose of the present work is to study the relation between the characteristics of the work activity and especially the parameters of the working posture and work place as well as the complaints of the musculoskeletal system (MSS) among professions where women are mainly engaged. The object of the study were 3 professional group: 1st group--telephone operators on video display (VD), IInd group--hairdressers and IIIrd group--television (TV) tuners. For the investigation was used inquiry-questionnaire for MSS complaints, which includes localization and type of the complaints, subjective evaluation of the working posture, organization and arranging the working place. A 3-step scale was used for each of the observed indices. The results point out, that the frequency of MSS complaints is very high in the examined professions. The complaints of the telephone operators on VD concern mainly the neck [66% of the examined], the shoulders and back [respectively 58% and 50%]; of the hairdressers--the shoulders and back [85% and 80%] and the legs [75%]; of the TV tuners--the fingers of the hand [60%], neck and shoulders [43% and 40%]. The MSS complaints are in positive correlation to the age and length of service of the workers [from 0.75 to 0.91]. The expert ergonomic evaluation shows that for the three examined professions, the working posture is the determining factor for MSS complaints. For hairdressers and TV tuners are the same degrees, followed by the telephone operators on VD. In the organization of the working place there are numerous ergonomic discrepancies: for the telephone operators the most considerable deviations of the ergonomic requirements are in the dimensions of the working places: for the hairdressers and TV tuners--in the dimensions of the working zones and the arrangement of the working place. A statistically positive correlation dependence was received between MSS complaints and the working posture for the three professional groups (r from 0.85 to 0.89) and between the complaints and the ergonomic discrepancies of the working place (r between 0.75 and 0.85). PMID- 7845993 TI - [An evaluation of the strain in the work of teachers]. AB - Psychophysiological studies on teachers' work include generally the evaluation of occupational stressors influencing the work load and strain and the assessment of transient and long-term changes in teachers' functional state and health due to these stressors. Results from investigations of some changes in the functional state of the organism of female teachers working in secondary and technical schools of different profiles were presented in this study. The following parameters were applied: subjective feeling of fatigue, heart rate [HR], excretion rates of 11-oxycorticosteroids (11-OCS), adrenaline (A) and noradrenaline (NA) during work. According to the mean HR values during work a moderate cardio-vascular strain was obtained (HR between 80-90 beats) min. Transient HR values over 100 beats/min were registered during periods connected with specific stressful working conditions. The levels of 11-OCS and the catecholamines excretion rates also indicated a moderate job strain. More pronounced changes in 11-OCS, NA and A were found when teaching in the upper classes of the secondary and technical schools. Significant correlations were established between the changes of HR, 11-OCS, NA and A and some individual characteristics of the examined persons, such as: age, length of service, HR at rest and level of neuroticism. Our data reveal the usefulness of the indices and procedures applied for the evaluation of teachers' strain at work. PMID- 7845994 TI - [The mapping of the masking effect of noise in relation to the adaptive potentials of the auditory analyzer for speech communication]. AB - The work considers the problem of ergonomic evaluation on the abilities of the auditory analyzer for speech information processing, depending on the zones of masking effect of noise and the rate of speech communication. Significant increase the loss of speech communication with increase in the intensity of the masking effect of noise (from 21.33% at L eq. 40 dB to 96% at L eq. 90 and above 90 dB/A). The speech communication is determined on scale in 4 zones, depending on the qualitative-quantitative criteria of the speech communication processing [I, II, III and IV zones]. Of point of view of ensuring the necessary conditions for perception of the speech communication is confirmed the correctness of the norm for masking noise L eq. 65 dB/A/, which guarantees a good speech communication. Equivalent levels of the masking noise about or equal to L eq. dB/A/ guarantee a satisfactory speech communication in the command desks. When the intensities of the masking noise are above the norms they are of specific importance, as they fall into the unaccepted (bad) zone, of the auditory perception of speech communication. PMID- 7845995 TI - [The hygienic protective area of the Kaliakra Medium-Wave Radio Station]. AB - A polemics on the ecological expedience of the transmitting station "Kaliakra", which is in the process of building, was held. The two opposing sides in the diaput are OOD "Bulgarian Posts and Power-line Communication" and the community of village Balgarevo, district of Varna. The ecological aspect of the project is very well known in the Ministry of the Environment and the Ministry of Public Health, as well as in the National Center of Hygiene, Medical Ecology and Nutrition. The latter has given an expert attitude for the hazardous zones around the site. As a result of this polemics is the delay of the building, i.e. blocking investments and missed opportunities, because of not realized exploitation. Stating the above we would like to expand the competent forum of the engaged in the problem. For this purpose we are ready to discuss with the participants in the Conference the methods and results of the calculations, as well as the normative basis, which were used in determining the hazardous zone. The control calculations point out, that the level of the electromagnetic exposure of the population in the district will be lower than the allowable values, which are given both in the Bulgarian State Standards and the foreign standard documents for hygiene control of nonionizing radiation. PMID- 7845996 TI - [An evaluation of the biological action of carbon disulfide in clinico-laboratory studies of exposed workers]. AB - A representative group of 122 workers from shop "Predilen" with 7 to 15 years length of service in specialty is taken. The professional groups are formed on the basis of measured average-shift concentrations of carbon bisulphide in the air of the working place, which vary from 4 to 50 mg.m-3. In order to establish deviations in some of the basic links of the biochemical mechanism of the toxic compounds effect the following indices are traced: copper metabolism [copper concentration and activity of ceruloplasmin in the serum]; lipidic metabolism [content of cholesterol, cholesterol of high and low density, triglycerides, beta lipoproteins and nonesterified lipidic acids in the serum]; intercellular substance of the connective tissue [glycoproteins, glycosaminoglycans and hexauronic acids in serum and urine]; immune status [immunoglobulins A, G and M in serum]; peripheral blood [leucocytes, DKK, morphology and lipid content in granulocytes]. Decrease of the lipids in granulocytes is registered, as well as reduction of the ceruloplasmin activity, increase of immunoglobulin M and glycosaminoglycans in urine. The already established deviations follow the "dose effect" and "dose-response" dependence. PMID- 7845997 TI - [Granulocyte alkaline phosphatase--a biomarker of chronic benzene exposure]. AB - In tracing the cellular population status in the peripheral blood of workers, exposed to benzene, was included and cytochemical determination of the alkaline phosphatase activity in leucocytes. This enzyme is accepted as marker of the neutrophilic granulocytes, as maturation of the cells and their antibacterial activity are parallel to the cytochemical activity of the enzyme. 78 workers from the coke-chemical production from state firm "Kremikovtsi" and 41 workers from the production "Benzene" and "Isopropylbenzene"--Oil Chemical Plant, Burgas are included. The benzene concentrations in the air of the working places in all productions are in the range of 5 to 50 mg/m3. For cytochemical determination of the alkaline phosphatase activity is used the method of L. Kaplow and phosphatase index was calculated. It was established that in 98.4% of all examined the alkaline phosphatase activity is inhibited to different rate, as from 46.5% [61 workers] it is zero. In considerably lower percentage of workers were established and other deviations: leucocytosis or leucopenia, neutropenia, increased percent of band neutrophils and toxic granules. The results of the investigation of the granulocyte population show that from all indices, the activity of granulocyte alkaline phosphatase demonstrates most convincing the early myelotoxic effect of benzene. PMID- 7845998 TI - [A comparative evaluation of the toxic and cumulative properties of the Takal drug group]. AB - The acute oral and dermal toxicity was studied as well as subacute oral toxicity [30 successive days] and skin irritating effect on experimental animals of new drug form "Takal 9", "Takal 14" and "Takal 16" with proved bactericidal and virucidal activity. A complex of toxicometric, unspecific, haematological, biochemical and histological studies were performed. The compositions "Takal 9", "Takal 14" and "Takal 16" are slightly toxic at oral and dermal application. LD50 for "Takal 9" and "Takal 16" is above 15,000 mg/kg-1 while for preparation "Takal 14" is not reached. At unrepeated dermal application LD50 for the examined group of preparations surpasses 5000 mg/kg-1. The products have no skin-irritative effect. No cumulative effect is established in the conditions of a 30-day oral treatment. On the background of no changes in the serum indices an activation of the aerobic and anaerobic oxidation in the liver is registered in animals treated with ethyl alcohol, "Takal 9" and "Takal 16". These deviations are due, most probably, to the participation of ethyl alcohol as solvent, in "Takal 9" and "Takal 16". On the basis of the experiments, as most suitable for use, is established the preparation "Takal 14". PMID- 7845999 TI - Pseudoaneurysm of the femoral artery following cardiac intervention: identification and management. AB - Pseudoaneurysm of the femoral artery following cardiac intervention is a complication requiring intuitive assessment and prompt intervention. The risk of femoral arterial injury from a cardiac catheterization is estimated at 0.6% to 17%, and should always be suspected when hematoma exists. Several factors contribute to the development and severity of vascular pseudoaneurysms following a transarterial intervention. Atherosclerotic occlusive disease at the site of arterial catheterization is a leading cause of pseudoaneurysms. Passage of large sheaths, particularly 8FR or greater contribute to more prevalent vascular complications. The associated use of multiple anticoagulation drugs before and after the cardiac procedure may result in difficulty in maintaining hemostasis allowing for the development of pseudoaneurysm. Once femoral pseudoaneurysm is detected clinical management includes ultrasonic guided compression or surgical repair. Optimal patient care requires careful assessment of the hematoma following invasive cardiac procedures and timely treatment. PMID- 7846000 TI - Women and coronary heart disease. AB - Research in the diagnosis and treatment of coronary heart disease has largely excluded women despite an increasing incidence, morbidity and mortality in women. This article outlines gender differences in cardiac anatomy and physiology; identifies risk factors in women; reviews primary prevention trials; discusses diagnostic techniques and therapeutic interventions in women. Understanding the strengths and weaknesses of the current knowledge of coronary heart disease in women is essential to planning effective, individualized nursing care. PMID- 7846001 TI - The educational needs of myocardial infarction patients. AB - Over the last 20 years, the educational needs of myocardial infarction (MI) patients have been addressed from the points of view of health care providers and patients. However, most teaching is based on the health care providers' perceptions of patients' educational needs. Little emphasis has been placed on patients' perception of educational needs. This article identifies the MI patients' perceived learning needs in the coronary care unit, in the post coronary care unit, and at home, and evaluates the extent of the effectiveness of various types of cardiac rehabilitation programs. Recommendations for educating first-time MI patients during each phase of cardiac recovery and for conducting future research studies are discussed. PMID- 7846002 TI - The role of magnesium in cardiovascular disease. PMID- 7846003 TI - Electrocardiographic changes in critically ill adults during intrahospital transport. AB - Critically ill patients are frequently transported out of the intensive care unit (ICU) for diagnostic tests and procedures. Advanced diagnostic testing and increased patient acuity have influenced the level of nursing care required during intrahospital transport. Previous studies have documented deleterious patient outcomes during intrahospital transport, but none have evaluated twelve lead electrocardiograms (ECGs). Using a prospective design, this study sought to describe ECG changes during intrahospital transport. A secondary purpose was to describe the nursing implications of transporting the patients in this sample. A convenience sample of 29 critical care patients (14 cardiac, 8 neurological, 5 medical, 2 transplant) was selected from three ICUs at a university hospital. In addition to the standard, single bipolar lead monitor, patients were monitored with a portable, interpretative electrocardiograph with continuous 12 lead ST segment analysis. Results of this study indicate that cardiac events during intrahospital transport may go undetected because of current monitoring practices and the mechanics of transport. PMID- 7846004 TI - Physiological differences in vascular reactivity in the African-American population. PMID- 7846005 TI - Use of nicotine patches in patients with coronary artery disease: are they safe? PMID- 7846006 TI - Body donation: the gift of knowledge. PMID- 7846007 TI - T wave alternans. PMID- 7846008 TI - Managed care: how your hospital is preparing to compete. PMID- 7846009 TI - Pancreatic cancer. PMID- 7846010 TI - Serological pancreatic tumor markers and the MUC1 apomucin. AB - Over 80% of adenocarcinomas of the pancreas originate from duct cells, which are the major source of mucins in the pancreas. Pathological conditions produce changes in the composition and structure of the oligosaccharides of colonic and pancreatic mucins, and it has been suggested that mucins may have a role in the detection of pancreatic cancer. Mucins are now the targets of a number of immunodiagnostic assays for cancer, and their possible use in therapy is being studied. This review describes the structure, biosynthesis, and release of mucins, as well as some of their therapeutic applications. The MUC1 type of mucin is emphasized because it is the main type present in both normal and malignant pancreas and because it is associated with several of the serological pancreatic cancer carbohydrate markers, including CA19-9. PMID- 7846011 TI - Blood-group sialyl-Tn antigen is more specific than Tn as a tumor marker in the pancreas. AB - The aim of this study was to evaluate the expression of blood group Tn and sialyl Tn antigens in the pancreas to determine whether they could help to interpret histochemically needle biopsies obtained from the pancreas. Lectin and immunohistochemistry was carried out using the biotin-labeled Vicia villosa agglutinin isolectin B4 and the mouse monoclonal antibody MLS102 to detect the Tn and sialyl-Tn blood-group antigens in the pancreas. All the pancreatic ductal adenocarcinomas (11/11) were positively stained by V. villosa agglutinin and MLS102 monoclonal antibody. None of the normals or chronic pancreatitics bound MLS102 monoclonal antibody. The acini of all the normals and chronic pancreatitics were V. villosa agglutinin positive, which was absent in the normal ductal cells and present only sparingly in the chronic pancreatitis ductal tissues (10/16). Thus, both the Tn and the sialyl-Tn blood-group antigens are present in pancreatic ductal tissues that have undergone malignant transformation. MLS102 is superior to V. villosa agglutinin in distinguishing malignant from normal and nonmalignant pancreatic tissues in needle biopsies. PMID- 7846012 TI - CA19-9 as a screening and diagnostic tool in symptomatic patients: the Japanese experience. AB - Although the prognosis for pancreatic cancer is generally poor, the Japanese Pancreatic Cancer Register reported in 1992 that the survival rate for resected pancreatic cancer was much higher than that for more conservative treatment. T1 and T2 pancreatic tumors are much more frequently resectable than are T3 and T4 tumors, and the 5-year survival rate for unresected T2, T3, and T4 cases is 0%. These findings emphasize the importance of early diagnosis of resectable pancreatic cancer. CA19-9 has shown satisfactory sensitivity in detecting advanced pancreatic cancer; we sought to determine the effectiveness of CA19-9 as part of a screening program for early cancer. Using elastase 1, CA19-9, and ultrasonography, we developed and tested a program of mass screening on persons presenting with and without abdominal complaints. PMID- 7846013 TI - Comparison of preoperative serum CA19-9 levels with results of diagnostic imaging modalities in patients undergoing laparotomy for suspected pancreatic or gallbladder disease. AB - A prospective, blinded study of CA19-9 in 2,467 patients having abdominal surgery yielded 356 patients with pancreatic, gallbladder, and biliary disease who submitted coded preoperative serum specimens. In this group, there were 84 patients with pancreatic cancer and 24 patients with gallbladder-biliary cancer; the remainder had benign lesions. The recorded imaging data and marker results were merged with the patients' demographic, clinical, and surgical data and tissue diagnoses for analysis. Receiver operator character calculation suggested that a reference value of 100 U/ml for CA19-9 was appropriate rather than the 37 40 U/ml value most frequently employed and yielded a specificity of 97% in the 467 operated patients with a sensitivity of 8.3% for all nonpancreatic-biliary cancers and 62% overall for these lesions. In the more diagnostically challenging nonicteric patients, CA19-9 sensitivity was 55%, specificity was > 99%, positive predictive value (PPV) was 97%, and negative predictive value (NPV) was 88%. When CA19-9 results were combined with those from endoscopic retrograde cholangiopancreatography, ultrasound (US), or computed tomography (CT), the PPV, and especially the NPV were increased. The addition of carcinoembryonic antigen results did not affect overall results. The addition of CA19-9 results to ambiguous or indeterminant imaging interpretation clearly improved the combined specificity, sensitivity, and PPV, but the change was less impressive, albeit positive, for NPV. The combination of CA19-9 and CT (or US) is a reasonable, cost effective, noninvasive approach to establishing the diagnosis of pancreatic, cholangitic, or biliary cancer in nonicteric patients. Although no single procedure or combination of procedures was found to detect early, small lesions, CA19-9 is clearly a clinically useful adjunct to imaging in nonjaundiced patients suspected of having these malignancies. PMID- 7846014 TI - CA19-9: the Italian experience. AB - This article reviews studies of the diagnostic value of CA19-9 determination in pancreatic cancer in Italy. Almost all of these studies show that CA19-9 determination has a good sensitivity in the diagnosis of advanced pancreatic cancer and that its diagnostic accuracy is superior to that of the other serum tumor markers currently available. Although data from patients with early pancreatic cancer are limited, they indicate that the diagnostic value of CA19-9 in these patients is low. PMID- 7846015 TI - Comparison of CA19-9 with other tumor markers in the diagnosis of cancer of the pancreas. AB - The carbohydrate antigen 19-9 (CA19-9) and radioimmunoassay have been shown to offer new hope for improving the diagnosis of pancreatic cancer, and various tumor markers (including SPan-1, DUPAN-2, and CA50) have been established. While clinical studies of these markers have found satisfactory sensitivities, only a few studies have compared these tumor markers on the same blood samples. We therefore evaluated the clinical efficacy of SPan-1, CA19-9, DUPAN-2, CA50, carcino-embryonic antigen, and Elastase 1 in detecting pancreatic cancer in identical blood samples. PMID- 7846016 TI - Diagnosis of pancreatic cancer and prediction of unresectability using the tumor associated antigen CA19-9. AB - Marked elevations of the tumor-associated antigen CA19-9 are relatively specific for pancreatic carcinoma and are associated with more advanced malignancies. We retrospectively reviewed 53 patients with CA19-9 values > 90 U/ml in whom the test had been done because of clinical suspicion of pancreatic malignancy. Pancreatic cancer was found in 45 patients (85%). If a cutoff value of CA19-9 > 200 U/ml is used, 36 of 37 (97%) patients had pancreatic cancer. Thirty patients with pancreatic cancer and no radiographic criteria of unresectability underwent attempted resection; five of these patients were judged to be potentially resectable and four of them underwent attempted resection. In only one patient with a CA19-9 value > 300 U/ml was resection possible; this patient had advanced carcinoma. Our results suggest that, in patients in whom the clinician suspects pancreatic carcinoma, CA19-9 > 90 U/ml is highly suggestive of pancreatic malignancy, while CA19-9 > 200 U/ml is virtually diagnostic of pancreatic malignancy. In similar patients with CA19-9 > 300 U/ml, resection is rarely possible and tumors are advanced. PMID- 7846017 TI - Prognostic values of preoperative and postoperative CEA and CA19.9 levels in pancreatic cancer. AB - Preoperative serum levels of carcinoembryonic antigen (CEA) and/or carbohydrate antigen 19.9 (CA19.9) were measured in 90 patients with advanced pancreatic cancer. CEA antigen was above the cutoff levels of 5.0 ng/ml in 51% of patients and CA19.9 was above the cutoff limit of 37 U/ml in 87% of patients. High preoperative CEA and CA19.9 levels were related to a poor prognosis of the patients. In multivariate analysis, the hazard rate was significantly higher in the high-CEA group (> 2.5 ng/ml) compared to the low-CEA group (< 2.4 ng/ml). An increase in CEA and/or CA19.9 within 1 month after the operation was also significantly related to the hazard rate. This study reconfirms the prognostic importance of preoperative and postoperative CEA and CA19.9. PMID- 7846018 TI - Evaluation of cytology and tumor markers of pure pancreatic juice for the diagnosis of pancreatic cancer at early stages. AB - To evaluate the value of cytology of pure pancreatic juice (PPJ) and tumor marker determination in PPJ and serum for the diagnosis of early pancreatic cancer (EPC), PPJ was obtained endoscopically from 16 patients with EPC (< 20 mm, confined to pancreas), 16 patients with chronic pancreatitis (CP), and 20 controls. Cutoff levels of CEA, CA19-9, and POA in PPJ were set from ROC curves at 40 ng/ml, 7,500 U/ml, and 1.5 U/ml, respectively. For the differentiation of EPC from CP, the sensitivity of CEA, CA19-9, and POA was 71.4, 42.9, and 50%, respectively; specificity was 93.3, 46.7, and 80%, respectively; and diagnostic accuracy was 82.8, 44.8, and 65.5%, respectively. Determination of serum tumor markers was useless. Sensitivity of cytology was 75%, specificity was 93.8%, and diagnostic accuracy was 84.4%. Combined cytology and CEA determination in PPJ increased the diagnostic accuracy to 93.1%. The combination was useful in supporting and supplementing endoscopic retrograde cholangiopancreatography (ERCP) findings for the correct diagnosis in 11 and 4 patients, respectively, with EPC; in one patient EPC was correctly diagnosed on ERCP findings alone. One of 16 patients with CP showed false-positive results. We conclude that cytology and CEA determination in PPJ with ERCP is a useful combination for the diagnosis of pancreatic cancer even in early stages. PMID- 7846019 TI - Immunohistochemical study of heparan sulfate proteoglycan in adenocarcinomas of the pancreas. AB - The prognosis for carcinoma of the pancreas is extremely poor. One of the characteristics of this tumor is its invasion of the surrounding tissues. Reduction of glycoprotein is considered to be conducive to invasion of the basement membrane by carcinoma cells. Heparan sulfate proteoglycan (HSPG), a kind of glycoprotein, is an important component of basement membrane. In this study, the relation between HSPG and carcinoma of the pancreas was examined by using the immunohistochemical method, and the survival rate of pancreatic adenocarcinoma was evaluated. We found that some carcinomas contained little or no HSPG. The poorer the differentiation of an adenocarcinoma of the pancreas, the lower was its content of HSPG. The level of HSPG was significantly different in carcinomatous and in noncarcinomatous cells. There was a close correlation among the content of HSPG, the degree of differentiation of carcinomas of the pancreas, and the survival time. HSPG seems to be useful in prognosis of adenocarcinoma of the pancreas. PMID- 7846020 TI - Prognostic significance of DNA ploidy in pancreatic carcinoma. AB - The nuclear DNA content was assessed by image cytometry on cytologic specimens obtained with fine-needle aspiration biopsy in 96 patients with pancreatic duct carcinoma. Twenty-two of these patients had pancreaticoduodenal resection. According to DNA analysis there were 27 (28%) diploid, 17 (18%) tetraploid, and 52 (54%) aneuploid tumors. The corresponding patient median survival times were 8, 5, and 4 months, respectively. Resectable tumors were more often DNA diploid (10 of 22) than nonresectable tumors (17 of 74) (p < 0.05). A Cox multivariate regression analysis demonstrated that surgical resection (p < 0.001) and diploid DNA pattern (p < 0.05) were factors associated with longer patient survival time. Although the difference in survival time was small, the data indicate that DNA diploid tumors represent a less aggressive subset of pancreatic carcinoma. PMID- 7846021 TI - The extramural exocrine pancreas program of the U.S. National Institutes of Health. AB - The National Institutes of Health (NIH) is the major agency in the federal government that supports both biomedical research and training in the digestive diseases as it relates to health maintenance, human development throughout life, disease prevention, and disease treatment. The present article summarizes the exocrine pancreas program in the context of digestive diseases expenditures of the NIH. This article is a follow-up review of the Pancreas Program as originally described by Roussos (Pancreas 1986;1:74-79). The period covered in this review is fiscal year (FY) 1987 to present. Data presented for FY 1987 to 1992 were provided by the NIH Data Book (U.S. Public Health Service, 1993). Fiscal data for FY 1993-FY 1994 are compiled from institutional databases. FY 1995 figures are presented from the President's budget request submitted to the Congress of the United States. PMID- 7846022 TI - Helix packing in proteins: prediction and energetic analysis of dimeric, trimeric, and tetrameric GCN4 coiled coil structures. AB - A simulated annealing method for atomic resolution structure prediction of alpha helical coiled coil proteins is described which draws upon knowledge of the oligomerization state, the helix directionality, and the properties of heptad repeat sequences. Unknown structural parameters, such as the coiled coil twist angle and the side chain conformations, are heavily sampled while allowing for flexibility in the helix backbone geometry. Structures of the wild-type GCN4 dimer [O'Shea et al., Science 254:539-544, 1991] and a mutant tetramer [Harbury et al., Science 292:1401-1407, 1993] have been generated and compared with the X ray crystal structures. The wild-type dimer model has a root mean square coordinate deviation from the crystal structure of 0.73 A for nonhydrogen atoms in the dimerization interface. Structures of a mutant dimer and a mutant trimer have been predicted. Packing energetics were analyzed for core leucine and isoleucine side chains in dimeric and tetrameric coiled coils. Strong packing preferences were found in the dimers but not in the tetramers. Thus, packing in the dimer may be responsible for the switch from a two-stranded to a four stranded coiled coil caused by the GCN4 leucine zipper mutations. PMID- 7846023 TI - Solvent-induced organization: a physical model of folding myoglobin. AB - The essential features of the in vitro refolding of myoglobin are expressed in a solvable physical model. Alpha helices are taken as the fundamental collective coordinates of the system, while the refolding is assumed to be mainly driven by solvent-induced hydrophobic forces. A quantitative model of these forces is developed and compared with experimental and theoretical results. The model is then tested by being employed in a simulation scheme designed to mimic solvent effects. Realistic dynamic trajectories of myoglobin are shown as it folds from an extended conformation to a close approximation of the native state. Various suggestive features of the process are discussed. The tenets of the model are further tested by folding the single-chain plant protein leghemoglobin. PMID- 7846024 TI - A special-purpose computer for molecular dynamics: GRAPE-2A. AB - Molecular dynamics simulations have been extensively used in research of proteins. Since these simulations are quite computer intensive, their acceleration is of main interest of the research. In molecular dynamics simulations, almost all computing time is consumed in calculating the forces between particles, e.g., Coulomb and van der Waals forces. We have designed and built GRAPE-2A (GRAvity PipE 2A), a special-purpose computer for use in simulations of classical many-body systems. GRAPE-2A calculates forces exerted on a particle from the other particles. GRAPE-2A can calculate force of an arbitrary functional form of a central force. The host computer, which is connected to GRAPE-2A through the VME bus, performs other calculations such as time integration. The peak speed of GRAPE-2A is 180 Mflops. We can also stimulate systems with periodic boundary conditions by the Ewald method, using GRAPE-2A and another special-purpose computer, WINE (Wave space INtegrator for the Ewald method). PMID- 7846025 TI - Cold adaption of enzymes: structural comparison between salmon and bovine trypsins. AB - The crystal structure of an anionic form of salmon trypsin has been determined at 1.82 A resolution. We report the first structure of a trypsin from a phoikilothermic organism in a detailed comparison to mammalian trypsins in order to look for structural rationalizations for the cold-adaption features of salmon trypsin. This form of salmon trypsin (ST II) comprises 222 residues, and is homologous to bovine trypsin (BT) in about 65% of the primary structure. The tertiary structures are similar, with an overall displacement in main chain atomic positions between salmon trypsin and various crystal structures of bovine trypsin of about 0.8 A. Intramolecular hydrogen bonds and hydrophobic interactions are compared and discussed in order to estimate possible differences in molecular flexibility which might explain the higher catalytic efficiency and lower thermostability of salmon trypsin compared to bovine trypsin. No overall differences in intramolecular interactions are detected between the two structures, but there are differences in certain regions of the structures which may explain some of the observed differences in physical properties. The distribution of charged residues is different in the two trypsins, and the impact this might have on substrate affinity has been discussed. PMID- 7846026 TI - Learning about protein folding via potential functions. AB - Over the last few years we have developed an empirical potential function that solves the protein structure recognition problem: given the sequence for an n residue globular protein and a collection of plausible protein conformations, including the native conformation for that sequence, identify the correct, native conformation. Having determined this potential on the basis of only some 6500 native/nonnative pairs of structures for 58 proteins, we find it recognizes the native conformation for essentially all compact, soluble, globular proteins having known native conformations in comparisons with 10(4) to 10(6) reasonable alternative conformations apiece. In this sense, the potential encodes nearly all the essential features of globular protein conformational preference. In addition it "knows" about many additional factors in protein folding, such as the stabilization of multimeric proteins, quaternary structure, the role of disulfide bridges and ligands, proproteins vs. processed proteins, and minimal strand lengths in globular proteins. Comparisons are made with other sorts of protein folding problems, and applications in protein conformational determination and prediction are discussed. PMID- 7846027 TI - Conformational analysis of hemopexin by Fourier-transform infrared and circular dichroism spectroscopy. AB - Hemopexin is a serum glycoprotein that binds heme with the highest known affinity of any characterized heme-binding protein and plays an important role in receptor mediated cellular heme uptake. Complete understanding of the function of hemopexin will require the elucidation of its molecular structure. Previous analysis of the secondary structure of hemopexin by far-UV circular dichroism (CD) failed due to the unusual positive ellipticity of this protein at 233 nm. In this paper, we present an examination of the structure of hemopexin by both Fourier-transform infrared (FTIR) and circular dichroism spectroscopy. Our studies show that hemopexin contains about 55% beta-structure, 15% alpha-helix, and 20% turns. The two isolated structural domains of hemopexin each have secondary structures similar to hemopexin. Although there are significant tertiary conformational changes indicated by the CD spectra, the overall secondary structure of hemopexin is not affected by binding heme. However, moderate changes in secondary structure do occur when the heme-binding domain of hemopexin associates with heme. In spite of the exceptionally tight binding at neutral pH, heme is released from the bis-histidyl heme-hemopexin complex at pH 5.0. Under this acidic condition, hemopexin maintains the same overall secondary structure as the native protein and is able to resume the heme-binding function and the native structure of the heme-protein (as indicated by the CD spectra) when returned to neutral pH. We propose that the state of hemopexin identified in vitro at pH 5.0 resembles that of this protein in the acidic environment of the endosomes in vivo when hemopexin releases heme during receptor-mediated endocytosis. PMID- 7846028 TI - Crystallization and characterization of the recombinant human Clara cell 10-kDa protein. AB - Crystals of recombinant human Clara cell 10-kDa protein were grown both from ammonium sulfate and polyethylene glycol (PEG) solutions. Crystals grown from ammonium sulfate solution have been characterized by X-ray diffraction studies as monoclinic with the space group C2 and lattice constants a = 69.2 A, b = 83.0 A, c = 58.3 A, and beta = 99.7 degrees. The monoclinic crystals diffract to beyond 2.5 A. Some of the crystals grown from PEG were of a similar habit to those grown from ammonium sulfate, but others were triclinic with the space group P1 and cell constants a = 40.3 A, b = 46.3 A, c = 51.3 A, alpha = 117.7 degrees, beta = 102.3 degrees, and gamma = 71.4 degrees. These crystals diffract to beyond 3.2 A. PMID- 7846029 TI - Preliminary crystallographic analysis of an enzyme involved in erythromycin biosynthesis: cytochrome P450eryF. AB - Cytochrome P450eryF was overexpressed in Escherichia coli and purified in high yield. Crystals of the protein in the presence of the substrate, 6 deoxyerythronolide B, have been obtained by the hanging drop vapor diffusion method, using polyethylene glycol 4000 as a precipitant. The crystals belong to the orthorhombic space group P2(1)2(1)2(1) with unit cell dimensions of a = 54.16 A, b = 79.67 A, and c = 99.48 A and one molecule per asymmetric unit. A complete native data set has been collected to a resolution of 2.1 A, and anomalous dispersion difference Patterson maps have revealed the location of the single heme iron atom. PMID- 7846030 TI - Differentiation and cancer: the conditional autonomy of phenotype. PMID- 7846031 TI - T cells induce terminal differentiation of transformed B cells to mature plasma cell tumors. AB - Major interest in the analysis of mature plasma cell neoplasias of mice and humans has focused on identification of precursor cells that give rise to mature malignant plasma cells. Although several laboratories have recently suggested that such cells are present in the granulomas of pristane-treated mice and the bone marrow of some multiple myeloma patients, the in vivo cellular interactions required for their differentiation into mature plasma cell tumors remains unclear. Given the extensive interactions of peripheral T cells and normal B cells, we assessed the potential role of T cells in plasma-cell tumor development, by using a myc, raf-containing retrovirus, J3V1, to induce plasmacytomas in normal BALB/c mice, T-cell-deficient nude mice, and T-cell reconstituted nude mice. The B-lineage tumors arising in normal BALB/c mice were uniformly mature plasmacytomas, most of which secreted immunoglobulin. In contrast, nude mice yielded predominantly non-immunoglobulin-secreting B-cell lymphomas with a phenotype characteristic of peripheral B cells. T-cell reconstitution of nude mice prior to tumor induction resulted in a shift from B cell lymphomas to plasmacytomas. These results imply that transformation can occur prior to terminal differentiation of B cells and that such transformed cells can be driven to terminal differentiation by peripheral T cells. These findings further suggest that, in human multiple myeloma, the ability of T cells to influence the differentiation state of transformed B cells may provide a mechanism by which malignant plasma cells found in the bone marrow could arise from clonotypically related less-mature B cells found in both the bone marrow and periphery. PMID- 7846032 TI - Photoaffinity labeling of retinoic acid-binding proteins. AB - Retinoid-binding proteins are essential mediators of vitamin A function in vertebrate organisms. They solubilize and stabilize retinoids, and they direct the intercellular and intracellular trafficking, transport, and metabolic function of vitamin A compounds in vision and in growth and development. Although many soluble retinoid-binding proteins and receptors have been purified and extensively characterized, relatively few membrane-associated enzymes and other proteins that interact with retinoids have been isolated and studied, due primarily to their inherent instabilities during purification. In an effort to identify and purify previously uncharacterized retinoid-binding proteins, it is shown that radioactively labeled all-trans-retinoic acid can be used as a photoaffinity labeling reagent to specifically tag two known retinoic acid binding proteins, cellular retinoic acid-binding protein and albumin, in complex mixtures of cytosolic proteins. Additionally, a number of other soluble and membrane-associated proteins that bind all-trans-[11,12-3H]retinoic acid with high specificity are labeled utilizing the same photoaffinity techniques. Most of these labeled proteins have molecular weights that do not correspond to any known retinoid-binding proteins. Thus, photoaffinity labeling with all-trans-retinoic acid and related photoactivatable retinoids is a method that should prove extremely useful in the identification and purification of novel soluble and membrane-associated retinoid-binding proteins from ocular and nonocular tissues. PMID- 7846033 TI - Murine mammary-derived cells secrete the N-terminal 41% of human apolipoprotein B on high density lipoprotein-sized lipoproteins containing a triacylglycerol-rich core. AB - The cDNA encoding the N-terminal 41% of human apolipoprotein B (apoB), apoB-41, was transfected into nonhepatic, nonintestinal, mammary-derived mouse cells (C127) to generate stably transfected cells expressing human apoB-41 (C127B-41). As determined by centrifugation, apoB-41 is secreted exclusively on lipoproteins (LPs) having a peak density of 1.13 g/ml. Electron microscopy of apoB-41 containing LPs purified by immunoaffinity chromatography showed round particles about 12 nm in diameter. No discoidal particles were observed. Characterization of apoB-41-associated lipids after labeling C127B-41 cells with [3H]oleate and immunoprecipitating the secreted LPs with antibodies to apoB showed that 3H labeled triacylglycerols were a major lipid class and accounted for about 54% of the total labeled lipids. Cholesterol esters and phospholipids accounted for about 6% and 22%, respectively. Incubation of cells with 0.4 mM oleate resulted in an increased incorporation of the added oleate into lipids associated with secreted apoB-41, along with a 2- to 3-fold increased secretion of apoB-41. The newly formed LPs appear to be transported through the Golgi complex, as brefeldin A (1 microgram/ml) and monensin (1 microM) greatly reduced (> 90%) the secretion of labeled apoB-41 and the amount of triacylglycerol and phospholipid associated with it. Microsomal triacylglycerol transfer protein (MTP) was not detected in these cells. Taken together, the data presented demonstrate that apoB-41 can direct the assembly and secretion of LPs that contain a triacylglycerol-rich core in nonhepatic cells that apparently lack MTP. These cells, therefore, represent an important model for studying LP assembly and may offer some advantages over cultured hepatic or intestinal cells that express their endogenous apoB gene. PMID- 7846034 TI - Antibiotic-based selection for bacterial genes that are specifically induced during infection of a host. AB - We have recently described a genetic system, termed in vivo expression technology (IVET), that uses an animal as a selective medium to identify genes that pathogenic bacteria specifically express when infecting host tissues. Here, the potential utility of the IVET approach has been expanded with the development of a transcriptional-fusion vector, pIVET8, which uses antibiotics resistance as the basis for selection in host tissues. pIVET8 contains promoterless chloramphenicol acetyltransferase (cat) and lacZY genes. A pool of Salmonella typhimurium clones carrying random cat-lac transcriptional fusions, produced with pIVET8, was used to infect BALB/c mice that were subsequently treated with intraperitoneal injections of chloramphenicol. Strains that survived the selection by expressing the cat gene in the animal were then screened for those that had low-level lacZY expression on laboratory medium. These strains carry operon fusions to genes that are specifically induced in vivo (ivi genes). One of the ivi genes identified (fadB) encodes an enzyme involved in fatty acid oxidation, suggesting that this enzyme might contribute to the metabolism of bactericidal or proinflammatory host fatty acids. The pIVET8-based selection system was also used to identify S. typhimurium genes that are induced in cultured macrophages. The nature of ivi gene products will provide a more complete understanding of the metabolic, physiological, and genetic factors that contribute to the virulence of microbial pathogens. PMID- 7846035 TI - Cloning and expression analysis of the murine lymphotoxin beta gene. AB - Tumor necrosis factor alpha (TNF-alpha) and soluble lymphotoxin (LT) (also called LT-alpha or TNF-beta) are cytokines with similar biological activities that are encoded by related and closely linked genes. TNF-alpha, a mediator of the inflammatory response, exists in soluble and transmembrane forms. LT-alpha can be secreted or retained at the cell surface by binding to a 33-kDa transmembrane subunit, LT-beta. The recently cloned human LT-beta gene encodes another TNF family member and is linked to the TNF/LT locus within the major histocompatibility complex locus. The cell surface LT is a heterotrimer consisting of LT-alpha and LT-beta, whose physiological function is not yet clearly defined. We now report the sequence analysis of the genomic region and cDNA of murine LT-beta gene, which is closely associated with the TNF-alpha and LT-alpha genes within the murine major histocompatibility complex locus. Unlike the TNF-alpha, LT-alpha, and human LT-beta genes, which contain four exons, the murine LT-beta contains three exons and encodes a 244-amino acid polypeptide with a 66-amino acid insert that is absent from the human homologue. In situ hybridization demonstrates constitutive expression of LT-beta in lymphoid and hematopoietic tissues. LT-beta transcription is maximal in the thymic medulla and in splenic white pulp. LT-beta mRNA is also detected in the skin and in specific regions of the brain. The LT-beta promoter region contains putative Ets-binding sites, suggesting that the expression of LT-beta may be regulated in part by Ets transcription factors whose pattern of lymphoid expression overlaps that of LT beta. PMID- 7846036 TI - A tissue-specific promoter that can drive a foreign gene to express in the suprabasal urothelial cells of transgenic mice. AB - Uroplakins are a group of integral membrane proteins that are synthesized as the major differentiation products of urothelium. The luminal portions of these proteins form 12-nm protein particles arranged in a two-dimensional crystalline array. The expression of uroplakin genes is bladder specific and differentiation dependent; little is known, however, about their molecular regulation. Here we describe the cloning of mouse uroplakin II gene and demonstrate, in transgenic mouse experiments, that a 3.6-kb 5'-flanking sequence of this gene can drive a bacterial lacZ (reporter) gene to express in the suprabasal cell layers of the urothelium. The transgene was not expressed in any tested (nonurothelial) epithelial and other tissues (except hypothalamus). These results suggest that most of the cis elements that confer the bladder-specific and differentiation dependent expression of mouse uroplakin II gene must reside in the 3.6-kb sequence. The availability of a promoter capable of delivering a foreign molecule to the differentiated cell layers of bladder epithelium opens avenues for studying normal and pathological urothelial differentiation in transgenic mice. PMID- 7846037 TI - Transgenic mice expressing an altered murine superoxide dismutase gene provide an animal model of amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder primarily involving motoneurons. A subset of individuals with familial autosomal dominant forms of the disease have mutations of the copper/zinc superoxide dismutase (Cu/Zn SOD, SOD-1) gene, which encodes a ubiquitously expressed enzyme that plays a key role in oxygen free radical scavenging. This observation suggests that altered or reduced SOD-1 activity may play a role in the neurodegenerative process. To explore this possibility further, we have introduced a mutation into the mouse SOD-1 gene that corresponds to one of the changes found in the human gene in familial amyotrophic lateral sclerosis. Integration and expression of this mouse gene in transgenic mice was identified by the presence of a unique restriction enzyme site in the transgene coding sequence generated by introduction of the mutation. We report here that high expression of this altered gene in the central nervous systems of transgenic mice is associated with an age-related rapidly progressive decline of motor function accompanied by degenerative changes of motoneurons within the spinal cord, brain stem, and neocortex. These findings indicate a causative relationship between altered SOD activity and motoneuron degeneration. Moreover, biochemical studies indicate normal levels of total SOD activity in transgenic mouse tissues, results that indicate that the neurodegenerative disorder does not result from a diminution of activity and, as such, represents a dominant "gain of function" mutation. PMID- 7846038 TI - The salivary gland-specific apyrase of the mosquito Aedes aegypti is a member of the 5'-nucleotidase family. AB - The saliva of hematophagous insects contains a variety of pharmacologically active substances that counteract the normal hemostatic response to injury in vertebrate hosts. The yellow-fever mosquito, Aedes aegypti, secretes an apyrase that inhibits ADP-dependent platelet aggregation. Apyrase was purified as an active enzyme from adult female salivary glands and subjected to tryptic digestion, and the resulting peptides were sequenced. The amino acid sequences obtained match the conceptual translation product of a cDNA clone isolated from an adult female salivary gland library. Sequence comparisons indicate similarities with a ubiquitous family of 5'-nucleotidases. The mosquito protein differs from other members of the family by lacking a carboxyl-terminal hydrophobic domain. The apparent conversion of a gene encoding an enzyme involved in a common metabolic event at the cellular level to a gene involved in the antihemostatic response of mosquitoes illustrates one way this particular insect has adapted to the challenges of bloodfeeding. PMID- 7846039 TI - Functional chicken gizzard heavy meromyosin expression in and purification from baculovirus-infected insect cells. AB - The heavy chain and the essential and the regulatory light chains of chicken gizzard heavy meromyosin (HMM) were coexpressed in Spodoptera frugiperda (fall armyworm) cells infected with a mixture of two recombinant Autographa californica baculoviruses. Soluble HMM consisting of the heavy chain and the two types of light chains was obtained. The recombinant HMM was purified from the virus infected cells and characterized. The regulatory light chain of the isolated recombinant HMM was phosphorylated by myosin light chain kinase in the presence of calmodulin in a Ca(2+)-dependent manner. The ATPase of the recombinant HMM was activated by rabbit skeletal muscle actin when myosin light chain kinase, calmodulin, and Ca2+ were present in the reaction medium. Chicken gizzard tropomyosin enhanced the actin-activated ATPase activity. The recombinant HMM decorated actin filaments, displaying the characteristic arrowhead pattern along the filaments. This report on a functional recombinant double-headed smooth muscle myosin fragment opens the way to detailed studies on the molecule. PMID- 7846040 TI - Discriminating compact nonnative structures from the native structure of globular proteins. AB - Prediction of the native tertiary structure of a globular protein from the primary sequence will require a potential energy model that can discriminate all nonnative structures from the native structure(s). A successful model must distinguish not only alternate structures that are very nonnative but also alternate structures that are compact and near-native. We describe here a method, based on molecular dynamics simulation, that allows generation of hundreds of compact alternate structures that are arbitrarily close to the native structure. In this way, a significant amount of conformational space in the neighborhood of the native structure can be sampled and these alternate structures can be used as a stringent test of protein folding models. We have used two sets of these alternate structures generated for six crystallographically characterized small globular proteins (1200 alternate structures in all) to test eight empirical energy models for their ability to discriminate alternate from native structures. Seven of the models fail to correctly identify at least some of the alternate structures as nonnative. An atomic solvation model is presented that succeeds in discriminating all 1200 alternate structures from native. PMID- 7846041 TI - X-ray structure of a DNA decamer containing 7,8-dihydro-8-oxoguanine. AB - We have determined the x-ray structure of a DNA fragment containing 7,8-dihydro-8 oxoguanine (G(O)). The structure of the duplex form of d(CCAGOCGCTGG) has been determined to 1.6-A resolution. The results demonstrate that GO forms Watson Crick base pairs with the opposite C and that G(O) is in the anti conformation. Structural perturbations induced by C.G(O)anti base pairs are subtle. The structure allows us to identify probable elements by which the DNA repair protein MutM recognizes its substrates. Hydrogen bond donors/acceptors within the major groove are the most likely element. In that groove, the pattern of hydrogen-bond donors/acceptors of C.G(O)anti is unique. Additional structural analysis indicates that conversion of G to G(O) would not significantly influence the glycosidic torsion preference of the nucleoside. There is no steric interaction of the 8-oxygen of G(O) with the phospho-deoxyribose backbone. PMID- 7846042 TI - A light-dependent complementation system for analysis of NADPH:protochlorophyllide oxidoreductase: identification and mutagenesis of two conserved residues that are essential for enzyme activity. AB - Protochlorophyllide reductase (NADPH:protochlorophyllide oxidoreductase; EC 1.6.99.1) catalyzes the light-dependent reduction of protochlorophyllide to chlorophyllide, a key regulatory step in the chlorophyll biosynthetic pathway. We have developed an expression system in which the protochlorophyllide reductase from pea (Pisum sativum L.) is used to complement protochlorophyllide reduction mutants in the photosynthetic bacterium Rhodobacter capsulatus, allowing analysis of wild-type and mutant forms of the enzyme. By protein sequence comparisons, we have identified the plant protochlorophyllide reductases as belonging to the family of short-chain alcohol dehydrogenases. Based on our protein sequence alignments, we have identified and mutated two conserved residues (Tyr-275 and Lys-279) within the proposed active site of the enzyme and shown that they are critical for activity. A model of the enzyme reaction mechanism for light dependent protochlorophyllide reduction is proposed. PMID- 7846043 TI - Abnormal calcium homeostasis and mitochondrial polarization in a human encephalomyopathy. AB - Patients with several inherited human encephalomyopathies exhibit systemic and neurological symptoms in association with specific mitochondrial mutations. The mechanisms by which these mitochondrial mutations result in cellular injury have not been elucidated. One potential cause of neuronal vulnerability is an inability to effectively buffer intracellular calcium. We report that fibroblasts from patients with one specific inherited encephalomyopathy, MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) syndrome, have elevated levels of ionized calcium and cannot normally sequester calcium influxes. Quantitative fluorescence imaging demonstrated that this abnormality was associated with a relative decrease in mitochondrial membrane potential compared to control fibroblasts. This documentation of pathological calcium homeostasis in a genetic neurological disease extends the calcium hypothesis of toxic cell injury to human mitochondrial encephalomyopathies. PMID- 7846044 TI - Nuclear localization signal binding proteins in higher plant nuclei. AB - The import of proteins into the nucleus is a vital process that is mediated by proteins which specifically recognize nuclear localization signals (NLSs). These factors have not been identified in plants. Previously, we demonstrated that higher plants possess a low-affinity binding site at the nuclear pore that specifically binds to several classes of functional NLSs. By the use of crosslinking reagents and a radiolabeled peptide to the bipartite NLS from the endogenous plant transcription factor Opaque2, two NLS binding proteins (NBPs) of 50-60 kDa and at least two NBPs of 30-40 kDa were identified. Competition studies indicated that labeling was specific for the functional NLS but not a mutant NLS impaired in vivo or a peptide unrelated to NLSs. Also, the apparent dissociation constant (100-300 microM) for labeling was similar to that of the binding site. Proteins of similar mass were labeled with two different crosslinking reagents, and concentration and time studies indicated that these NBPs were distinct proteins and not aggregates. Treatment with salt, detergent, or urea before or during NLS binding demonstrated that the properties of the binding site and the NBPs were identical. This tight correlation strongly indicates that some or all of the NBPs constitute the nuclear pore binding site. Overall, our results indicate that some components of NLS recognition are located at the nuclear pores in higher plants. PMID- 7846045 TI - Extradenticle protein is a selective cofactor for the Drosophila homeotics: role of the homeodomain and YPWM amino acid motif in the interaction. AB - The Drosophila homeotic selector (HOM) genes encode a family of DNA binding transcription factors that specify developmental fates of different body segments by differentially regulating the activity of downstream target genes. A central question is how the HOM proteins achieve their developmental specificity despite the very similar DNA binding specificities of isolated HOM proteins in vitro. Specificity could be achieved by differential interactions with protein cofactors. The extradenticle gene might encode such a cofactor since it interacts genetically in parallel with Ultrabithorax, abdominal-A, and perhaps other HOM genes. By using a yeast two-hybrid system, we demonstrate selective interaction of the extradenticle homeodomain protein with certain Ultrabithorax and abdominal A proteins but not with an Antennapedia protein or a more distant homeodomain protein. Strong interaction with Ultrabithorax proteins requires only the Ultrabithorax homeodomain and a 15-residue N-terminal extension that includes Tyr Pro-Trp-Met (YPWM), a tetrapeptide motif found near the homeodomain in most HOM proteins and their mammalian Hox counterparts. The size and sequence of the region between the YPWM element and the homeodomain differ among Ultrabithorax isoforms, and this variable region appears to affect the interaction detected in the assay. PMID- 7846046 TI - The developmentally regulated transcription factor AP-2 is involved in c-erbB-2 overexpression in human mammary carcinoma. AB - Overexpression of the c-erbB-2/HER2 protooncogene in breast carcinoma is controlled not only by the degree of amplification of the gene but also at the level of gene transcription. Thus, whether or not the gene is amplified, the activity of the c-erbB-2 promoter is enhanced in overexpressing cells through the binding of an additional transcription factor, OB2-1, whose activity is increased in these lines. Here we describe further characterization of OB2-1 and show that it is identical to the developmentally regulated transcription factor AP-2. Functional assays confirm that AP-2 is able to regulate c-erbB-2 expression in mammary-derived cell lines. Furthermore, although AP-2 is barely detectable in cells with the low c-erbB-2 expression phenotype, protein levels are clearly elevated in a panel of c-erbB-2-overexpressing lines. These findings demonstrate an important role for this transcription factor in human cancer. PMID- 7846047 TI - Rational design of nonnatural peptides as high-affinity ligands for the HLA B*2705 human leukocyte antigen. AB - From the three-dimensional structure of the class I major histocompatibility complex (MHC) HLA-B*2705 protein, several nonnatural peptides were designed either to optimize the interactions of one peptide amino acid (position 3) with its HLA binding pocket (pocket D) or to simplify the T-cell receptor-binding part by substitution with organic spacers. The stability of each MHC-ligand complex was simulated by 150-ps molecular dynamics in a water environment and compared with that of the natural complexes. All peptides were synthesized and tested for binding to the class I MHC protein in an in vitro assembly assay. As predicted from the computed atomic fluctuations and buried surface areas of MHC-bound ligands, bulky hydrophobic side chains at position 3 enhance the binding of a nonameric peptide to the HLA-B27 protein. Furthermore, it was possible to simplify half of the peptide sequence (residues 4-8) by replacement with organic fragments without altering the affinity of the designed ligands for the class I MHC protein. This study constitutes an initial step toward the rational design of nonpeptide class I MHC ligands for use in the selective immunotherapy of autoimmune diseases associated with particular HLA alleles. PMID- 7846048 TI - Apolipoprotein E is a kinetic but not a thermodynamic inhibitor of amyloid formation: implications for the pathogenesis and treatment of Alzheimer disease. AB - The apolipoprotein E4 (APOE4) allele is associated with an early age of onset of the nonfamilial form of Alzheimer disease (AD) and with increased beta protein amyloid deposition in the brain. These two observations may both arise from an effect of the apoE family of proteins on the rate of in vivo amyloidogenesis. We report here that apoE3, the common apoE isoform, is an in vitro amyloid nucleation inhibitor at physiological concentrations. A significant delay in the onset of amyloid fibril formation by the beta-amyloid protein of AD (beta 1-40) was observed at a low apoE3 concentration (40 nM), corresponding to an apoE3/beta protein molar ratio of 1:1000. The inhibitory activity of a proteolytic fragment of apoE3, containing the N-terminal 191 amino acids, is comparable to the native protein, whereas the C-terminal fragment has no activity. ApoE4 is equipotent or slightly less potent than apoE3, which may be due to its inability to form a disulfide dimer, since the apoE3 dimer is a significantly more potent nucleation inhibitor than apoE4. Neither apoE3 nor apoE4 inhibits the seeded growth of amyloid or affects the solubility or structure of the amyloid fibrils, indicating that apoE is not a thermodynamic amyloid inhibitor. We propose that the linkage between the APOE4 allele and AD reflects the reduced ability of APOE4 homozygotes to suppress in vivo amyloid formation. PMID- 7846049 TI - Emergence of multipotent hemopoietic cells in the yolk sac and paraaortic splanchnopleura in mouse embryos, beginning at 8.5 days postcoitus. AB - We show by an in vitro approach that multipotent hemopoietic cells can be detected in the body of the mouse embryo between the stages of 10-25 somites (8.5 9.5 days of gestation)--i.e., prior to liver colonization (28-32 pairs of somites). Interestingly, hemopoietic cells appear in parallel in this location, the paraaortic splanchnopleura, and in the yolk sac, where they represent a new generation by reference to the primitive hemopoietic stem cells. Lymphoid cell clones, which could differentiate into mature B cells, were obtained from yolk sac and paraaortic splanchnopleura cell preparations but not from other tissues of the embryonic body. These B-cell precursors were first detected around the stage of 10 somites; thereafter, their initial minute numbers increased in parallel in the yolk sac and the paraaortic splanchnopleura, suggesting that their emergence in the two sites was simultaneous. By single cell manipulation, we show that these precursors can generate B and T lymphocytes and myeloid cells; these precursors can thus be defined as multipotent hemopoietic cells. PMID- 7846050 TI - Regulation of bacterial sugar-H+ symport by phosphoenolpyruvate-dependent enzyme I/HPr-mediated phosphorylation. AB - The lactose-H+ symport protein (LacS) of Streptococcus thermophilus has a C terminal hydrophilic domain that is homologous to IIA protein(s) domains of the phosphoenolpyruvate:sugar phosphotransferase system (PTS). C-terminal truncation mutants were constructed and expressed in Escherichia coli and their properties were analyzed. Remarkably, the entire IIA domain (160 amino acids) could be deleted without significant effect on lactose-H+ symport and galactoside equilibrium exchange. Analysis of the LacS mutants in S. thermophilus cells suggested that transport is affected by PTS-mediated phosphorylation of the IIA domain. For further studies, membrane vesicles of S. thermophilus were fused with cytochrome c oxidase-containing liposomes, and, when appropriate, phosphoenolpyruvate (PEP) plus purified enzyme I and heat-stable protein HPr were incorporated into the hybrid membranes. Generation of a protonmotive force (delta p) in the hybrid membranes resulted in accumulation of lactose, whereas uptake of the PTS sugar sucrose was not observed. With PEP and the energy-coupling proteins enzyme I and HPr of the PTS on the inside, high rates of sucrose uptake were observed, whereas delta p-driven lactose uptake by wild-type LacS was inhibited. This inhibition was not observed with LacS(delta 160) and LacS(H552R), indicating that PEP-dependent enzyme I/HPr-mediated phosphorylation of the IIA domain (possibly the conserved His-552 residue) modulates lactose-H+ symport activity. PMID- 7846051 TI - In vivo evidence for the involvement of anionic phospholipids in initiation of DNA replication in Escherichia coli. AB - In vitro, anionic phospholipids can reactivate inactivated DnaA protein, which is essential for initiation of DNA replication at the oriC site of Escherichia coli [Sekimizu, K. & Kornberg, A. (1988) J. Biol. Chem. 263, 7131-7135]. Mutations in the pgsA gene (encoding phosphatidylglycerophosphate synthase) limit the synthesis of the major anionic phospholipids and lead to arrest of cell growth. We report herein that a mutation in the rnhA gene (encoding RNase H) that bypasses the need for the DnaA protein through induction of constitutive stable DNA replication [Kogoma, T. & von Meyenburg, K. (1983) EMBO J. 2, 463-468] also suppressed the growth arrest phenotype of a pgsA mutant. The maintenance of plasmids dependent on an oriC site for replication, and therefore DnaA protein, was also compromised under conditions of limiting anionic phospholipid synthesis. These results provide support for the involvement of anionic phospholipids in normal initiation of DNA replication at oriC in vivo by the DnaA protein. PMID- 7846052 TI - Chromosomal deletions around the albino locus in the mouse cause loss of hormone inducible expression of the unlinked structural gene encoding cytosolic aspartate aminotransferase. AB - A group of genes in the mouse encoding liver-specific gluconeogenic enzymes and mapping on different chromosomes lose their normal competence for hormone inducible expression in animals homozygous for chromosomal deletions around the albino locus on chromosome 7. The basal expression of these same genes remains normal. In previous investigations, glucocorticoid hormones as well as their receptors were found to be normal in the deletion homozygotes. The results reported here identify an additional unlinked structural gene whose regulation appears to be affected by the deletions--i.e., that encoding cytosolic aspartate aminotransferase, a housekeeping gene that participates in gluconeogenesis in the liver. In normal mice, its mRNA level increases sharply at birth, specifically in the liver, and can be increased even further by dexamethasone and cAMP treatment. These increases fail to occur in mice homozygous for the specific deletions in chromosome 7. Interestingly, prenatally at 18-19 days of gestation, the gene is expressed at the same basal level in liver and brain of both normal and mutant mice. These observations strengthen the evidence implicating the deleted gene(s) as an essential factor(s) in the normal mechanisms of hormone-inducible expression of particular unlinked structural genes. PMID- 7846053 TI - Programmed DNA rearrangement of a cyanobacterial hupL gene in heterocysts. AB - Programmed DNA rearrangements that occur during cellular differentiation are uncommon and have been described in only two prokaryotic organisms. Here, we identify the developmentally regulated rearrangement of a hydrogenase gene in heterocysts of the cyanobacterium Anabaena sp. strain PCC 7120. Heterocysts are terminally differentiated cells specialized for nitrogen fixation. Late during heterocyst differentiation, a 10.5-kb DNA element is excised from within the hupL gene by site-specific recombination between 16-bp direct repeats that flank the element. The predicted HupL polypeptide is homologous to the large subunit of [NiFe] uptake hydrogenases. hupL is expressed similarly to the nitrogen-fixation genes; hupL message was detected only during the late stages of heterocyst development. An open reading frame, named xisC, identified near one end of the hupL DNA element is presumed to encode the element's site-specific recombinase. The predicted XisC polypeptide is homologous with the Anabaena sp. strain PCC 7120 site-specific recombinase XisA. Neither XisC nor XisA shows sequence similarity to other proteins, suggesting that they represent a different class of site-specific recombinase. PMID- 7846054 TI - In situ detection, by spin trapping, of hydroxyl radical markers produced from ionizing radiation in the tumor of a living mouse. AB - Hydroxyl radicals are thought to be responsible for the toxicity associated with ionizing radiation in tissues. Measurements of hydroxyl radicals generated by ionizing radiation in cellular systems have failed thus far to elucidate higher level homeostatic responses to this and other reactive oxygen species. Careful assessment of prior indirect hydroxyl radical assays in living tissues indicates that they are prone to a variety of artifacts, making all but the most qualitative relationships difficult to establish. This paper describes the detection of hydroxyl radicals produced during radiation in the leg tumor of a living mouse, where the free radicals evolve; detection uses low-frequency electron paramagnetic resonance in combination with in vivo spin trapping. To our knowledge, this is the first report of such a direct measurement of free radical production in the tissues of a living animals. PMID- 7846055 TI - CD18 (beta 2 leukocyte integrin) promoter requires PU.1 transcription factor for myeloid activity. AB - Normal cellular differentiation is linked to tightly regulated gene transcription. However, the DNA elements and trans-acting factors that regulate transcription in myeloid cells are poorly defined. CD18, the beta chain of the leukocyte integrins, is transcriptionally regulated during myeloid differentiation. The CD18 promoter is active after transfection into myeloid cells. We demonstrate that a region of the CD18 promoter that contains two binding sites for the PU.1 transcription factor is required for activity in myeloid cells. These sites are bound by in vitro translated PU.1 and by PU.1 from myeloid nuclear extracts. Mutagenesis of these sites abrogates binding by PU.1 and substantially decreases promoter activity in myeloid cells. Thus, the leukocyte-specific transcription factor PU.1 is required for myeloid activity of CD18. PMID- 7846056 TI - Endonuclease-induced, targeted homologous extrachromosomal recombination in Xenopus oocytes. AB - Homologous recombination in gene targeting in most organisms occurs by an inefficient mechanism. Inducing a double-strand break in the chromosomal target may increase this efficiency by allowing recombination to proceed by the highly efficient single-strand annealing mechanism. A gene targeting experiment was modeled in Xenopus oocytes by using a circular plasmid to mimic the chromosomal target site and a homologous linear molecule (pick-up fragment or PUF) as an analogue of the vector DNA. When those two molecules were simply injected together, no recombination was observed. In contrast, when the circular plasmid was cleaved in vivo by injection of the site-specific endonuclease, I-Sce I, relatively efficient intermolecular recombination occurred, involving up to 17% of the cleaved molecules. Recombination was dependent on the stability of the PUF; product yield was increased by using longer fragments and by injecting larger amounts of linear DNA, both of which increased the lifetime of the PUF in the oocytes. These results demonstrate that in vivo double-strand breaks can induce homologous recombination of reluctant substrates and may be useful in augmenting the efficiency of gene targeting. PMID- 7846057 TI - CTLA4 mediates antigen-specific apoptosis of human T cells. AB - The regulation of T cell-mediated immune responses requires a balance between amplification and generation of effector function and subsequent selective termination by clonal deletion. Although apoptosis of previously activated T cells can be induced by signaling of the tumor necrosis factor receptor family, these molecules do not appear to regulate T-cell clonal deletion in an antigen specific fashion. We demonstrate that cross-linking of the inducible T-cell surface molecule CTLA4 can mediate apoptosis of previously activated human T lymphocytes. This function appears to be antigen-restricted, since a concomitant signal T-cell receptor signal is required. Regulation of this pathway may provide a novel therapeutic strategy to delete antigen-specific activated T cells. PMID- 7846058 TI - Solution structure of pleckstrin homology domain of dynamin by heteronuclear NMR spectroscopy. AB - The pleckstrin homology (PH) domain is a recognition motif thought to be involved in signal-transduction pathways controlled by a variety of cytoplasmic proteins. Assignments of nearly all 1H, 13C, and 15N resonances of the PH domain from dynamin have been obtained from homonuclear and heteronuclear NMR experiments. The secondary structure has been elucidated from the pattern of nuclear Overhauser enhancements, from 13C chemical shift deviations, and from observation of slowly exchanging amide hydrogens. The secondary structure contains one alpha helix and eight beta-strands, seven of which are arranged in two contiguous, antiparallel beta-sheets. The structure is monomeric, in contrast to the well defined intimate dimerization of the crystal structure of this molecule. Residues possibly involved in ligand binding are in apparently flexible loops. Steady state 15N(1H) nuclear Overhauser effect measurements indicate unequivocally the boundaries of this PH domain, and the structured portion of the domain appears to be more extended to the C terminus than previously suggested for other PH domains. PMID- 7846060 TI - Three populations of cells with dendritic morphology exist in peripheral blood, only one of which is infectable with human immunodeficiency virus type 1. AB - Conflicting data have been reported with regard to the infectability, dysfunction, and depletion of dendritic cells (DCs) in human immunodeficiency virus (HIV) disease. These discrepancies could potentially be explained by the existence of multiple subsets of cells with dendritic morphology in peripheral blood. The isolation of DCs in humans is accomplished through negative selection until a morphologically pure population is obtained. Recently, DC precursors purified from peripheral blood by negative selection have been observed to develop into functionally and morphologically mature DCs. In this report we identify three populations of cells in peripheral blood that have or can develop a dendritic morphology. The first population, when allowed to mature in culture, develops a dendritic morphology and gains the expression of HB15, a marker of DCs in blood, thymus, skin, and lymphoid organs. The second population expresses HB15 and has the phenotypic and morphologic characteristics of mature DCs. The third population is morphologically very similar to mature DCs but does not share the same T-cell-stimulatory activity and is the only population that is infectable with HIV. Understanding the heterogeneity of cells of dendritic lineage and/or morphology in the peripheral blood will aid in understanding their role as antigen-presenting cells in general and as potential participants in the immunopathogenesis of HIV disease. PMID- 7846059 TI - Immunization of low density lipoprotein (LDL) receptor-deficient rabbits with homologous malondialdehyde-modified LDL reduces atherogenesis. AB - Atherosclerotic lesions contain oxidized LDL (OxLDL), immunoglobulins, and immune competent cells. Low levels of circulating autoantibodies against malondialdehyde (MDA)-modified lysine, an epitope of OxLDL, occur in several species, and immune complexes between such autoantibodies and OxLDL are present in lesions. To study the potential role of autoantibodies against OxLDL in the atherogenic process, we prospectively hyperimmunized LDL receptor-deficient rabbits with homologous MDA LDL and determined the effects of this intervention on the development of atherosclerosis. Immunization with MDA-LDL generated high titers of antibodies with similar specificity as naturally occurring autoantibodies. Immunized animals showed a significant reduction in the extent of atherosclerotic lesions in the aortic tree after 6.5 months, compared with "saline"-immunized controls (48% vs. 68%, P < 0.005). Immunization with keyhole limpet hemocyanin produced no change in lesion formation. Although the mechanisms by which immunization led to a protective effect are unknown, these results suggest an important role for the immune system in modulating the atherogenic process and may indicate a novel approach for inhibiting the progression of atherosclerosis. PMID- 7846061 TI - The molecular mechanism underlying formation of deletions in Fanconi anemia cells may involve a site-specific recombination. AB - Spontaneous and induced chromosomal breakage is an important cellular feature of Fanconi anemia (FA), an inherited DNA repair disorder characterized by progressive bone marrow failure, developmental abnormalities, and predisposition to leukemia. We have previously reported that in comparison to normal cells, there is a substantial increase in frequency of intragenic deletions at an endogenous locus (HPRT) in FA lymphoblasts. Taken together with the increased chromosomal instability, these observations indicated that the wild-type FA gene(s) plays an important role in the maintenance of the genomic integrity. To obtain information on the mechanism(s) underlying the genomic rearrangements in FA, the breakpoint sites of deletions in 11 FA-derived HPRT- mutants were analyzed. The results indicate that a significant proportion of deletions involving a loss of a given exon are identical and that two deletions of different size have the same 3' breakpoint. Interestingly, it appears that in most of the mutants there is a common deletion signal sequence, which suggests that the mutations in the FA gene(s) may lead to an aberrant site-specific cleavage activity that might be responsible for the deletion proneness and the chromosomal instability characteristic of the FA pathology. From the similarity or even identity of the signal sequence at some of the breakpoints with the consensus heptamer which directs cleavage and joining in the assembly of immunoglobulin and T-cell receptor genes, we speculate that steps in common with the V(D)J recombinational process may be illegitimately involved in FA cells. PMID- 7846062 TI - Cloning and characterization of a functionally distinct corticotropin-releasing factor receptor subtype from rat brain. AB - The present study reports the isolation of a cDNA clone that encodes a second member of the corticotropin-releasing factor (CRF) receptor family, designated as the CRF2 receptor. The cDNA was identified using oligonucleotides of degenerate sequence in a PCR paradigm. A PCR fragment obtained from rat brain was utilized to isolate a full-length cDNA from a rat hypothalamus cDNA library that encoded a 411-amino acid protein with approximately 70% identity to the known CRF1 receptor over the entire coding region. When expressed in mouse Ltk- cells, this receptor stimulates cAMP production in response to CRF and known CRF-like agonists. CRF and the nonmammalian CRF-related peptides sauvagine and urotensin I stimulate adenylate cyclase activity in a dose-dependent manner with a rank order of potency different from that of the CRF1 receptor: sauvagine > urotensin > or = rat/human CRF > ovine CRF. Tissue distribution analysis of the mRNAs by reverse transcriptase-PCR shows CRF2 receptor mRNA is present in rat brain and detectable in lung and heart. In situ hybridization studies indicate specific expression within the brain in the ventromedial nuclei of the hypothalamus, the lateral septum, the amygdala, and entorhinal cortex, but there is unremarkable expression in the pituitary. An additional splice variant of the CRF2 receptor with a different N-terminal domain has been identified by PCR, encoding a putative protein of 431 amino acids. Thus, the data demonstrate the presence of another functional CRF receptor, with significant differences in the pharmacological profile and tissue distribution from the CRF1 receptor, which would predict important functional differences between the two receptors. PMID- 7846063 TI - The molecular basis of pediatric long chain 3-hydroxyacyl-CoA dehydrogenase deficiency associated with maternal acute fatty liver of pregnancy. AB - Mitochondrial long chain fatty acid beta-oxidation provides the major source of energy in the heart. Deficiencies of human beta-oxidation enzymes produce sudden, unexplained death in childhood, acute hepatic encephalopathy, skeletal myopathy, or cardiomyopathy. Long chain 3-hydroxyacyl-CoA dehydrogenase [LCHAD; long-chain (S)-3-hydroxyacyl-CoA:NAD+ oxidoreductase, EC 1.1.1.211] catalyzes the third step in beta-oxidation, and this activity is present on the C-terminal portion of the alpha subunit of mitochondrial trifunctional protein. We used single-stranded conformation variance analysis of the exons of the human LCHAD (alpha subunit) gene to determine the molecular basis of LCHAD deficiency in three families with children presenting with sudden unexplained death or hypoglycemia and abnormal liver enzymes (Reye-like syndrome). In all families, the mothers had acute fatty liver and associated sever complications during pregnancies with the affected infants. The analysis in two affected children revealed a G to C mutation at position 1528 (G1528C) of the alpha subunit of the trifunctional protein on both alleles. This is in the LCHAD domain and substitutes glutamine for glutamic acid at position 474 of mature alpha subunit. The third child had this G1528C mutation on one allele and a different mutation (C1132T) creating a premature termination codon (residue 342) on the second allele. Our results demonstrate that mutations in the LCHAD domain of the trifunctional protein alpha subunit in affected offspring are associated with maternal acute fatty liver of pregnancy. This is the initial delineation of the molecular basis of isolated LCHAD deficiency. PMID- 7846064 TI - Estimates for the pool size of releasable quanta at a single central synapse and for the time required to refill the pool. AB - Local superfusion of limited dendritic areas with hypertonic or hyperkalemic solutions stimulates the release of quanta from a small population of synapses made on rodent hippocampal neurons maintained in primary culture, and each quantal event can be detected in the postsynaptic neuron. With maintained stimulation, the initial release rate is about 20 quanta per sec per synapse, and this rate declines exponentially to a final low level. These observations can be interpreted as depletion of available quanta and, with this interpretation, a bouton would contain one to two dozen quanta in its readily releasable pool. Tests with a second application of the solution that produces release reveal that the pool of readily releasable quanta is replenished with a time constant of about 10 sec (36 degrees C). The pool of quanta defined in this way may correspond to the population of vesicles docked at the bouton's active zone. PMID- 7846065 TI - Absence of the blood-clotting regulator thrombomodulin causes embryonic lethality in mice before development of a functional cardiovascular system. AB - We have targeted the murine thrombomodulin (TM) gene in embryonic stem cells and generated embryos as well as mice with TM deficiency. The heterozygous TM deficient (TM+/-) mice as compared to wild-type (TM+/+) littermates exhibit 50% reductions in the levels of TM mRNA and TM protein. However, TM+/- mice appear normal and are free of thrombotic complications. The homozygous TM-deficient (TM /-) embryos die before embryonic day 9.5. An overall retardation in growth and development of TM-/- embryos is first evident on embryonic day 8.5 (8-12 somite pairs). However, no specific pathologic abnormalities are observed. These initial changes take place at a time when TM is normally expressed in the parietal yolk sac. The removal of embryonic day 7.5 TM-/- embryos from maternal decidua and their subsequent culture in vitro allow development to proceed to stages not observed in vivo (13-20 somite pairs) with the appearance of normal blood vessels in the visceral yolk sac and embryo. The results of our studies suggest that the failure of TM-/- embryos to survive at mid-gestation is a consequence of dysfunctional maternal-embryonic interactions caused by the absence of TM in the parietal yolk sac and demonstrate that the receptor is necessary for normal embryonic development in utero. PMID- 7846066 TI - A targeted mutation in the mouse E-cadherin gene results in defective preimplantation development. AB - The Ca(2+)-dependent cell adhesion molecule E-cadherin functions in the establishment and maintenance of epithelial cell morphology during embryogenesis and adulthood. Downregulation or complete shut-down of E-cadherin expression and mutation of the gene are observed during the progression of tumors of epithelial origin (carcinomas) and correlate with the metastatic potential. We have introduced a targeted mutation into the E-cadherin gene by homologous recombination in mouse embryonic stem cells. The mutation removes E-cadherin sequences essential for Ca2+ binding and for adhesive function. These embryonic stem cells were used to generate mice carrying the mutation. Heterozygous mutant animals appear normal and are fertile. However, the homozygous mutation is not compatible with life: E-cadherin -/- embryos show severe abnormalities before implantation. Particularly, the adhesive cells of the morula dissociate shortly after compaction has occurred, and their morphological polarization is then destroyed. Interestingly, the blastomers are still able to form desmosomes and tight junctions at sites of distorted cell-cell contact. Thus, maternal E cadherin suffices for initial compaction of the morula but not for further preimplantation development to occur. PMID- 7846067 TI - Separation of human breast cancer cells from blood by differential dielectric affinity. AB - Electrorotation measurements were used to demonstrate that the dielectric properties of the metastatic human breast cancer cell line MDA231 were significantly different from those of erythrocytes and T lymphocytes. These dielectric differences were exploited to separate the cancer cells from normal blood cells by appropriately balancing the hydrodynamic and dielectrophoretic forces acting on the cells within a dielectric affinity column containing a microelectrode array. The operational criteria for successful particle separation in such a column are analyzed and our findings indicate that the dielectric affinity technique may prove useful in a wide variety of cell separation and characterization applications. PMID- 7846068 TI - Expression of an insulin-responsive glucose transporter (GLUT4) minigene in transgenic mice: effect of exercise and role in glucose homeostasis. AB - The effects of a GLUT4 mini-transgene (containing 7 kb of 5' flanking and 1 kb of 3' flanking sequence and all exons and introns of the GLUT4 gene as well as a small foreign DNA tag) and of exercise training on expression of GLUT4 and glycemic control in mice were investigated. Transgenic mice harboring the minigene expressed < or = 2-fold the normal level of GLUT4 mRNA and protein in skeletal (gastrocnemius) muscle and adipose tissue. This modest tissue-specific increase in GLUT4 expression led to an unexpectedly rapid blood glucose clearance rate following oral glucose administration. In nontransgenic animals exercise caused a 1.5-fold increase in expression of GLUT4 mRNA and protein as well as a significant improvement of glycemic control. In transgenic animals harboring the minigene exercise increased expression of GLUT4 mRNA and protein derived from the minigene and endogenous gene and led to a further improvement of glycemic control. These findings indicate that the cis-regulatory element(s) controlling exercise-induced expression of the GLUT4 gene is located within the nucleotide sequence encompassed by the GLUT4 minigene. The fact that glycemic control is markedly improved by a relatively low level of expression of GLUT4 caused by the transfected minigene and is further enhanced by exercise in transgenic animals demonstrates that GLUT4 plays a pivotal role in glucose homeostasis in vivo. Of the effectors--i.e., cAMP, insulin, and arachidonic acid--known to down-regulate expression of GLUT4 by 3T3-L1 adipocytes in culture, only the decline in circulating arachidonate level in vivo correlated with up-regulation of GLUT4 caused by exercise. PMID- 7846069 TI - Differential activation of mitogen-activated protein kinase in response to basic fibroblast growth factor in skeletal muscle cells. AB - In the MM14 mouse myoblast cell line, fibroblast growth factor (FGF) stimulates proliferation and represses differentiation. However, the intracellular signaling pathways used by FGF to affect these cellular processes are unknown. The predominant FGF receptor present on MM14 cells, FGFR1, is a receptor tyrosine kinase capable of activating the mitogen-activated protein kinase (MAPK) cascade in fibroblast and neuronal cell lines. To determine whether the FGF signal is mediated via the MAPK cascade in myoblasts, MM14 cells were stimulated with basic FGF (bFGF) and activities of the various kinases were measured. After withdrawal from serum and bFGF for 3 hr, bFGF stimulated MAPK kinase (MAPKK) activity, but MAPK and S6 peptide kinase activities were not detected. In contrast, when serum and bFGF were withdrawn for 10 hr, the activities of MAPKK, MAPK, and S6 peptide kinase were all stimulated by bFGF treatment. The inability of bFGF to stimulate MAPK after 3 hr of withdrawal may be due, in part, to the presence of a MAPK phosphatase activity that was detected in MM14 cell extracts. This dephosphorylating activity diminishes during commitment to terminal differentiation and is inhibited by sodium orthovanadate. Thus, the ability of bFGF to stimulate MAPK in MM14 cells is correlated with the loss of a MAPK phosphatase activity. These results show that although bFGF activates MAPKK in proliferating myoblasts, the mitogenic signal does not progress to the downstream kinases, providing a physiological example of an uncoupling of the MAPK cascade. PMID- 7846070 TI - Intra- and intermolecular spreading of autoimmunity involving the nuclear self antigens La (SS-B) and Ro (SS-A). AB - We have tested the extent of immune self-tolerance to the ubiquitously expressed nuclear/cytoplasmic autoantigens La (SS-B) and Ro (SS-A) in healthy, nonautoimmune mice. Immunization of mice with recombinant mouse La resulted in a specific, isotype-switched autoantibody response, which was initially directed toward the La C subfragment (aa 111-242) but rapidly spread to involve the La A (aa 1-107) and La F (aa 243-345) regions of the La antigen. Intramolecular spreading of the anti-La antibody response was further demonstrated by the appearance of autoantibodies to multiple, nonoverlapping antigenic regions of La, after immunization of mice with the 107-aa La A subfragment. Moreover, immunization of mice with recombinant mouse or human La also elicited specific anti-60-kDa Ro IgG antibodies in all strains tested. Mice immunized with 60-kDa Ro produced a high titer anti-Ro antibody response, which was also associated with intermolecular spreading, resulting in the specific appearance of anti-La autoantibodies. These findings show that the development of autoantibodies to multiple components of the La/Ro ribonucleoprotein complex may follow initiation of immunity to a single component. In addition, the data reveal the incomplete nature of immune tolerance to La and Ro despite their endogenous expression in all nucleated cells. These observations are likely to account for the coexistence of anti-La/Ro antibodies in autoimmune disease and suggest a general explanation for the appearance of mixed autoantibody patterns in systemic autoimmune disorders. PMID- 7846071 TI - Dark-light: model for nightblindness from the human rhodopsin Gly-90-->Asp mutation. AB - A human rhodopsin mutation, Gly-90-->Asp (Gly90Asp), cosegregated with an unusual trait of congenital nightblindness in 22 at-risk members of a large autosomal dominant kindred. Although rhodopsin mutations typically are associated with retinal degeneration, Gly90Asp-affected subjects up to age 33 did not show clinical retinal changes. Absolute threshold for visual perception was elevated nearly 3 logarithmic units in 7 individuals tested (ages 11-64), indicating greatly compromised rod threshold signaling. However, in vivo rhodopsin density was normal. Although the 38-year-old proband could not perceive dim lights, his rod increment threshold function was normal on brighter backgrounds. The impaired rod vision for dim but not bright backgrounds is consistent with a mechanism of increased basal "dark-light" from thermal isomerization equivalent to an increase of > 10(4) over that of wild-type rhodopsin. The Gly90Asp mutation on the second transmembrane helix places an extra negative charge in the opsin pocket; this could contribute to partial deprotonation of the retinal Schiff base and thereby increase photoreceptor noise. In vitro evidence had suggested that transducin is activated by the Gly90Asp mutation in the absence of both the retinal chromophore and light, termed "constitutive activity." The apparent preservation of functioning rods despite extensive and lifelong night-blindness in this kindred is inconsistent with one current hypothesis that chronic rod activation from constitutively active mutant rhodopsin necessarily contributes significantly to photoreceptor demise in human retinal dystrophies. PMID- 7846072 TI - Coordinate regulation of tetrahydrobiopterin turnover and phenylalanine hydroxylase activity in rat liver cells. AB - This work had two purposes: (i) to determine in vivo whether liver phenylalanine hydroxylase (PAH) is regulated by its substrates phenylalanine and tetrahydrobiopterin (BH4) as studies with purified enzyme suggest and (ii) to investigate in vivo the relationship between PAH activity and BH4 turnover. We found there are two BH4 pools in hepatocytes, one that is metabolically available (free BH4) and one that is not (bound BH4). Bound BH4 appears bound to PAH; the PAH-BH4 complex has much less catalytic activity and is less readily phenylalanine activated than uncomplexed enzyme. Interconversion of activated and unactivated PAH and bound and free BH4 is driven by phenylalanine; and free BH4 concentration is determined by the state of activation and activity of PAH. In hepatocytes, BH4 and PAH (subunit) concentrations are equal, all intracellular BH4 appears to be available to PAH, and free BH4 turns over rapidly (t1/2 approximately 1 hr). There is no evidence for feedback inhibition of BH4 synthesis; the BH4 synthetic rate appears high when free BH4 concentration is high and low when free BH4 is low. The data provide support in vivo that phenylalanine and BH4 are positive and negative regulators of the activity and activation state of PAH in the proposed manner; they also imply that regulation of BH4 turnover and PAH activity are linked processes, which are both controlled by phenylalanine concentration. PMID- 7846073 TI - Complementation of the ionizing radiation sensitivity, DNA end binding, and V(D)J recombination defects of double-strand break repair mutants by the p86 Ku autoantigen. AB - Two ionizing radiation-sensitive (IRs) and DNA double-strand break (DSB) mutants, sxi-3 and sxi-2, were shown to be severely deficient in a DNA end binding activity, similar to a previously described activity of the Ku autoantigen, correlating with the xrs (XRCC5) mutations. Cell fusions with xrs-6, another IRs, DSB repair-deficient cell line, defined these sxi mutants in the XRCC5 group. sxi 3 cells have low expression levels of the p86Ku mRNA. Introduction of the Ku p86 gene, but not the p70 Ku gene, complemented the IRs, DNA end binding, and variable (diversity) joining [V(D)J] recombination signal and coding junction deficiencies of sxi-3. Thus, the p86 Ku gene product is essential for DSB repair and V(D)J recombination. PMID- 7846074 TI - A serine protease inhibitor, protease nexin I, rescues motoneurons from naturally occurring and axotomy-induced cell death. AB - Protease nexin I (PNI) is a member of the family of serine protease inhibitors (serpins) that have been shown to promote neurite outgrowth in vitro from different neuronal cell types. These include neuroblastoma cells, hippocampal neurons, and sympathetic neurons. Free PNI protein is markedly decreased in various anatomical brain regions, including hippocampus, of patients with Alzheimer disease. Here, we report that PNI rescued spinal motoneurons during the period of naturally occurring (programmed) cell death in the chicken in a dose dependent fashion. Furthermore, PNI prevented axotomy-induced spinal motoneuron death in the neonatal mouse. The survival effect of PNI on motoneurons during the period of programmed cell death was not associated with increased intramuscular nerve branching. PNI also significantly increased the nuclear size of motoneurons during the period of programmed cell death and prevented axotomy-induced atrophy of surviving motoneurons. These results are consistent with the possible role of PNI as a neurotrophic agent. They also support the idea that serine proteases or, more precisely, the balance of proteases and serpins may be involved in regulating the fate of neuronal cells during development. PMID- 7846075 TI - Mate finding via a trail sex pheromone by a parasitoid wasp. AB - In field observations and laboratory experiments, we found that virgin females of the solitary parasitoid Aphelinus asychis did not emit a volatile sex pheromone to attract males, contrary to what has been reported in many other parasitoid species. Instead, we found that virgin females deposited a sex pheromone on the substrate to which males responded by intensively searching on and near the marked area. Males did not respond to leaves exposed to mated females or to other males. In patches of 64 wheat leaves, males were dispersed from a central release point, and more males were subsequently observed on leaves exposed to virgin females than on unexposed leaves. The pheromone faded to inactivity in less than 24 h. To examine whether the trail pheromone would be sufficient for mate finding by males in the field, we modeled random movement of males among plant stems where the trail pheromone was the only cue males used to find females. The probability that females encountered at least one male in their lifetime increased with male density and time after female emergence. Given the range of densities of A. asychis in barley and wheat fields near Montpellier, France, the model generated an encounter probability sufficient to explain the survival of established populations. The model also suggested that difficulty in finding mates at low density might be a problem for invading populations. PMID- 7846076 TI - Vascular endothelial growth factor/vascular permeability factor expression in a mouse model of retinal neovascularization. AB - Neovascular diseases of the retina are a major cause of blindness worldwide. Hypoxia is thought to be a common precursor to neovascularization in many retinal diseases, but the factors involved in the hypoxic neovascular response have not been fully identified. To investigate the role of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) in retinal neovascularization, the expression of VEGF/VPF mRNA and protein were studied in a mouse model of proliferative retinopathy. RNA (Northern) blot analysis revealed that retinal VEGF/VPF mRNA expression increased 3-fold between 6 and 12 hr of relative retinal hypoxia and remained elevated during the development of neovascularization. In situ hybridization localized VEGF/VPF mRNA to cells bodies in the inner nuclear layer of the retina. Immunohistochemical confocal microscopy demonstrated that VEGF/VPF protein levels increase with a time course similar to that of the mRNA. The cells in the inner nuclear layer of the retina that produce VEGF/VPF were identified morphologically as Muller cells. These data suggest that VEGF/VPF expression in the retina plays a central role in the development of retinal ischemia-induced ocular neovascularization. PMID- 7846077 TI - Specific 5'-GGGA-3'-->5'-GGA-3' mutation of the Apc gene in rat colon tumors induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine. AB - The APC gene plays a major role in human colon carcinogenesis. We determined the genomic structure of the rat Apc gene, and we analyzed mutations in colon tumors induced in F344 rats by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), potent carcinogens contained in ordinary daily human food. Of eight PhIP-induced tumors, one tumor had two Apc mutations, two tumors had a mutation with loss of the normal allele, and one had a mutation. Two of the above five mutations were at nucleotide 1903, one at 2605, and two at 4237, all being a deletion of a guanine base at the 5'-GGGA-3' site and resulting in truncation of the APC protein. Of 13 IQ-induced tumors, 2 had an Apc mutation with loss of the normal allele. The two mutations were a missense mutation (T-->C) at nucleotide 1567 and a nonsense mutation (C-->T) at 2761. Alteration of the Apc gene was shown to play a more important role in PhIP induced than in IQ-induced rat colon carcinogenesis. PhIP-induced tumors are characterized by their specific and unique mutation, which may be useful for mutational fingerprinting of human cancers. PMID- 7846078 TI - Intracellular promiscuity in Schistosoma mansoni: nuclear transcribed DNA sequences are part of a mitochondrial minisatellite region. AB - It has been shown that the mtDNA of the parasitic trematode Schistosoma mansoni is hypervariable in size. We report here that this length variation is due to a large polymorphic minisatellite composed of two types of repeated sequences of 558 bp and 62 bp. Each minisatellite repeat is made up of a large 558-bp component and a variable tandem array of the small 62-bp unit. Of more fundamental interest was the finding that both the 558-bp and 62-bp components have significant homology with a gene, SM750, previously identified in the nuclear genome of S. mansoni. The small 62-bp unit is identical to the nuclear polymorphic repeat element, which is apparently spread throughout the nuclear genome and is abundant among transcripts, in addition to being present in five tandem copies in SM750. The presence, in the S. mansoni mtDNA, of fragments of genes that are present in and transcribed from the nuclear genome raises the question of the origin of these sequences. The arrangement and the variability that the mtDNA minisatellite embodies were explored as an identity test for S. mansoni based on the use of PCR for tallying the relative abundance of the several repeat numbers of the tandem arrays of the 62-bp unit within the minisatellite structure. PMID- 7846079 TI - The Saccharomyces Ty5 retrotransposon family is associated with origins of DNA replication at the telomeres and the silent mating locus HMR. AB - We have characterized the genomic organization of the Ty5 retrotransposons among diverse strains of Saccharomyces cerevisiae and the related species Saccharomyces paradoxus. The S. cerevisiae strain S288C (or its derivatives) carries eight Ty5 insertions. Six of these are located near the telomeres, and five are found within 500 bp of autonomously replicating sequences present in the type X subtelomeric repeat. The remaining two S. cerevisiae elements are adjacent to the silent mating locus HMR and are located within 500 bp of the origin of replication present in the transcriptional silencer HMR-E. Although the S. cerevisiae Ty5 elements no longer appear capable of transposition, some strains of S. paradoxus have numerous Ty5 insertions, suggesting that transposition is occurring in this species. Most of these elements are adjacent to type X telomeric repeats, and regions flanking four of five characterized S. paradoxus insertions carry autonomously replicating sequences. The genomic organization of the Ty5 elements is in marked contrast to the other S. cerevisiae retrotransposon families (Ty1-4), which are typically located within 500 bp of tRNA genes. For Ty3, this association reflects an interaction between Ty3 and the RNA polymerase III transcription complex, which appears to direct integration [Chalker, D. L. & Sandmeyer, S. B. (1992) Genes Dev. 6, 117-128]. By analogy to Ty3, we predict that Ty5 target choice is specified by interactions with factors present at both the telomeres and HMR that are involved in DNA replication, transcription silencing, or the maintenance of the unique chromatin structure at these sites. PMID- 7846081 TI - Praxic and nonverbal cognitive deficits in a large family with a genetically transmitted speech and language disorder. AB - A pronounced speech and language disorder affecting half of the 30 members of the four-generational KE family has been attributed by some researchers to a specific defect in the generation of morphosyntactic rules. The reported selectivity of the impairment has led to the view that the affected members suffer from a grammar-specific disorder. Our investigations of the same KE family indicate that the inherited disorder has a broad phenotype which transcends impaired generation of syntactical rules and includes a striking articulatory impairment as well as defects in intellectual, linguistic, and orofacial praxic functions generally. Although the evidence from this family thus provides no support for the existence of "grammar genes," their linguistic difficulties do constitute a prominent part of their phenotype. Investigations of the neural and genetic correlates of their disorder could therefore uncover important clues to some of the bases of the primary human faculties of speech and language. PMID- 7846080 TI - Functional neuroanatomy of antisaccade eye movements investigated with positron emission tomography. AB - Increasing interest in the role of the frontal lobe in relation to psychiatric and neurologic disorders has popularized tests of frontal function. One of these is the antisaccade task, in which both frontal lobe patients and schizophrenics are impaired despite normal performance on (pro)saccadic tasks. We used position emission tomography to examine the cerebral blood flow changes associated with the performance of antisaccades in normal individuals. We found that the areas of the brain that were more active during antisaccades than saccades were highly consistent with the oculomotor circuit, including frontal eye fields (FEFs), supplementary motor area, thalamus, and putamen. Superior parietal lobe and primary visual cortex were also significantly more active. In contrast, prefrontal areas 46 and 9 were not more active during antisaccades than during saccades. Performance of some frontal patients on the antisaccade task has been likened to a bradykinesia, or the inability to initiate a willed movement. It is the necessity to will the movement and inhibit competing responses that intuitively linked this task to the dorsolateral prefrontal cortex in frontal patients. Our data suggest that it is the FEFs in prefrontal cortex that differentiate between conditions in which the required oculomotor response changes while the stimulus remains the same, rather than areas 46 and 9, which, in human studies, have been linked to the performance of complex cognitive tasks. Such a conclusion is consistent with single-unit studies of nonhuman primates that have found that the FEFs, the executive portion of the oculomotor circuit, can trigger, inhibit, and set the target of saccades. PMID- 7846082 TI - Controlling oligomerization of pharmaceutical proteins. AB - The degree of oligomerization (or in some cases aggregation) often determines the physiological half-life and uptake rate of a protein preparation. High-resolution crystal structures of insulin and other pharmacologically interesting proteins have aided in the design of mutants with altered quaternary structure and physiological uptake rates. Analysis of the contacts between natural oligomers and protein complexes can indicate sequences that may enhance protein oligomerization. These sequences can be altered to produce monomeric protein. PMID- 7846083 TI - Formulation and in vitro study of antibacterial vaginal suppositories. AB - Vaginal suppositories frequently used in gynaecological therapy were studied. Several antibacterial pharmacons are used for the topical treatment of vaginitis of various origins. In view of the fact that the liberation of the given active substance and the subsequent therapeutic effect may be improved or inhibited by the vehicle, our aim was to find the optimal suppository base for vaginal suppositories containing sulfadimidine, chloramphenicol and gentamicin sulfate by means of in vitro experiments. On the basis of breaking hardness, disintegration time and spreading properties the French Suppocire NA product, and compositions of macrogols with lower molecular weight proved to be the best lipophilic and hydrophilic bases, respectively. Among the lipophilic bases the in vitro drug liberation of Suppocire NA was significantly better (P < 0.05) than the other lipophilic bases. This vehicle is recommended for the topical treatment of vaginitis, as these suppositories have the further advantage that they can easily be produced on a magistral, galenical or industrial scale as well. PMID- 7846084 TI - Inhibitory activity of 3-methylenhydroxy-5-methoxy-2,4-dihydroxy tetrahydrofurane isolated from Selaginella lepidophyla on smooth muscle of Wistar rat. AB - A new compound, 3-methylenhydroxy-5-methoxy-2,4-dihydroxy tetrahydrofurane, has been isolated from a methanol extract of Selaginella lepidophyla. The structure is based on 1H-NMR, 13C-NMR and MS analysis. The compound was tested on uterus (oestrus), ileum and duodenum of Wistar rats. It proved to have a slight inhibitory effect on the contraction response of the uterus, but it did not have any effect on the two other muscles. PMID- 7846085 TI - Cytotoxicity tests of antibacterial agents on human fibroblasts cultures. AB - The authors tried to determine and compare the cytotoxicity of several primary substances used in cosmetic or pharmaceutic industry as antimicrobial agents, on single-layer cultures of human fibroblasts. The cytotoxic effect of Germall 115*, Kathon CG* and Pentonium* was pointed out using the colorimetric method with MTT (3-[4-5-dimethyl thiazol 2-yl]-2,5 diphenyl tetrazolium bromide). For each one of these substances, we tested different concentrations with variable contact times. These trials allowed us to classify these products by increasing toxicity as follows: Kathon CG* and Pentonium*. In our experimental conditions, Germall 115* was not cytotoxic. PMID- 7846087 TI - Monthly Prostaglandin Bibliography prepared by Sheffield University Biomedical Information Service. PMID- 7846086 TI - Synthesis and analgesic properties of 5-acyl-arylhydrazone 1-H pyrazolo [3,4-b] pyridine derivatives. AB - A series of 5-acyl-arylhydrazone 1-H pyrazolo [3,4-b] pyridine derivatives (1), planned by applying classical ring isosterism, were synthesized in order to evaluate the structure-activity relationship (SAR), especially the participation of the structural acyl-arylhydrazone subunit in the analgesia. The synthetic route used produced the derivatives 1 in approximately 40% overall yield, using 9 as key intermediate. The results obtained from this study showed that in general the compounds of this series present a powerful analgesic activity in the test of abdominal contortions induced by acetic acid i.p. in albino mice, indicating the participation of the acyl-arylhydrazone moiety, as well the relevance of the substituent of the aryl ring, in the activity. PMID- 7846088 TI - Aquatic invertebrates open up new perspectives in eicosanoid research: biosynthesis and bioactivity. PMID- 7846090 TI - Effects of n-3 polyunsaturated fatty acids on the reacylation of arachidonic acid in peritoneal macrophages. AB - Mouse peritoneal macrophages were prelabelled with [3H]AA and activated ex vivo with phorbol myristate acetate (PMA) in the presence or absence of added n-3 polyunsaturated fatty acids (n-3 PUFA). The n-3 PUFA did not affect the release of [3H]AA from stimulated macrophages. Added AA, enhanced, in a dose-dependent manner, the amount of free [3H]AA in the medium after activating the cells with PMA. Both n-3 PUFA and AA were actively acylated into the lipids of PMA activated macrophages, but the n-3 PUFA did not compete with reacylation of AA. In unstimulated cells, in the absence of PMA, n-3 PUFA effectively competed with AA for acylation into membrane phospholipids. These studies suggest that distinct pools of AA exist in macrophages. PMID- 7846091 TI - The effect of zearalenone and 17 beta-estradiol on prostacyclin and thromboxane production in cell cultures from human umbilical cord veins. AB - The effect of zearalenone, a nonsteroidal mycotoxin with estrogenic activity, and of 17 beta-estradiol on prostacyclin and thromboxane production in human endothelial cells was investigated. Zearalenone stimulated prostacyclin production in low concentrations (10(-7) and 10(-8)M) and inhibited it at a higher concentration (10(-5)M). Estradiol alone in the concentration range 10(-5) 10(-8)M had no clear-cut effect on the prostacyclin production. The combination of both substances effected changes in prostacyclin production similar to that from zearalenone alone; with the exception of estradiol at a concentration of 10( 6)M which enhanced the effect of zearalenone. No distinct changes in the thromboxane production from the two substances could be found, either alone or in combination. PMID- 7846089 TI - Prostanoid production in hypoxic rat isolated atria: influence of acute diabetes. AB - The effects of hypoxia on prostanoid production were studied in atria from normal, acute diabetic and insulin-treated diabetic rats. Diabetes was induced by intravenous administration of 65 mg/kg of streptozotocin, the rats were killed 5 days later. Hypoxia was performed by incubation of the atria during 60 min in nitrogen-equilibrated glucose free Krebs' solution followed by 15 min of reoxygenation. The prostanoids 6-keto prostaglandin F1 alpha (6-keto PGF1 alpha) and thromboxane B2 (TXB2), stable metabolites of prostacyclin and TXA2, respectively, as well as PGF2, were measured by reversed phase HPLC-UV. In control atria, the production of 6-keto PGF1 alpha was equivalent to that of PGE2, whereas TXB2 was released in a much smaller amount. In diabetic atria, 6 keto PGF1 alpha production was reduced by 65%, whereas TXB2 release was increased by 158% compared to the controls. When the normal atria were exposed to 60 min of hypoxia, the release of 6-keto PGF1 alpha increased by 142% compared to basal values and remained elevated after 15 min of reoxygenation whereas in diabetic and insulin-treated diabetic tissues the 6-keto PGF1 alpha production was not modified by the hypoxia-reoxygenation period. The release of TXB2 was increased after 60 min hypoxia in normal as well as in diabetic and insulin-treated diabetic tissues and remained elevated during the reoxygenation. The PGE2 output increased only after the onset of the reoxygenation in the three groups studied.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7846092 TI - Inhibitory effects of prostacyclin analogue, TFC-132, on aortic neointimal thickening in vivo and smooth muscle cell proliferation in vitro. AB - Effects of a new prostacyclin analogue, TFC-132, on neointimal thickening following intimal mechanical injury and on the proliferation of cultured aortic smooth muscle cells (SMCs) were studied. The intimal injury was induced by indwelling of polyethylene tubing for 24 h in the rabbit aorta. Rabbits were killed 10 days after drawing out the tubing. TFC-132 (0.6 mg/kg or 1.2 mg/kg) was given orally at 8-h intervals through the experiment. The serum concentrations of the analogue rose significantly 1 and 2 h after administration. The mean intimal thickening in the TFC-132 treated groups was significantly thinner than in the control one. Human aortic SMCs were cultured and 3H-thymidine incorporation into DNA (DNA synthesis) was measured at the varying concentrations of TFC-132. The analogue inhibited DNA synthesis of cultured SMCs at 10(-6) and 10(-5) M. These data indicate that a new prostacyclin analogue, TFC-132, has an inhibitory effect on the neointimal thickening after intimal injury and on the aortic SMC proliferation. PMID- 7846093 TI - Renal effects of intermittent versus continuous infusion of ibuprofen in the primate. AB - The clinical use of nonsteroidal anti-inflammatory drugs is gaining wide acceptance and acute oliguric renal failure in association with the administration of ibuprofen has been reported. This study was designed to evaluate the renal effects of intermittent versus continuous intravenous infusion of ibuprofen (Motrin) over a 24-h period in the anesthetized non-pregnant baboon. A total of 50 mg/kg of ibuprofen was either infused continuously or given as a bolus in four divided doses (intermittent). Control animals received only normal saline. Mean aortic pressure showed a tendency to decrease with time in all groups studied with a significant decrease occurring in the infusion group. There were no significant changes in the renal artery flow, renal resistance, central venous pressure and heart rate within the groups. Serum urea nitrogen decreased and was significantly different from the baseline value at 24 h in the infusion group. Serum creatinine, however, showed no such changes. Although, urinary output and creatinine clearance showed a tendency to decrease in the treated groups, it was not significantly different. Plasma renin activity decreased from 9.95 to 2.3 ng/ml/hr in the control group but showed no significant changes in others. Serum levels of angiotensin converting enzyme were well maintained. The circulating levels of ibuprofen reached a steady state after 2 h in the infusion group. The results of this study demonstrate that continuous infusion of ibuprofen does not possess an advantage over its intermittent administration. Despite the modifications we have observed in renal flow and function, this drug appears to be safe in the dose levels we have used in these experiments. PMID- 7846094 TI - Highly purified guinea pig type II pneumocytes have the leukotriene A4 hydrolase but do not express 5-lipoxygenase activity. AB - Guinea pig lung cells have been obtained by enzymatic digestion of lung tissue and type II pneumocytes have been purified by centrifugal elutriation and adherence on Petri dishes coated with guinea pig IgG. The cells have been characterized by histochemical staining of alkaline phosphatase and by electron microscopy. Arachidonic acid metabolism was studied by incubating purified type II pneumocytes with exogenous arachidonic acid in the presence or absence of calcium ionophore A23187 or with leukotriene A4. The reverse phase high performance liquid chromatography profiles of cells stimulated with calcium ionophore and/or arachidonic acid did not show peaks co-eluting with authentic leukotrienes, which suggested that these cells do not express 5-lipoxygenase activity. On the other hand, type II pneumocytes converted exogenous leukotriene A4 into leukotriene B4; a small amount of peptido-leukotrienes, accounting for less than 5% of total leukotrienes produced, was also detected. It is suggested that transcellular metabolism of leukotriene A4 between type II pneumocytes and other lung cells containing the 5-lipoxygenase may contribute to the previously reported LTB4 production by guinea pig lungs. The type II pneumocyte purification technique described represents a useful alternative to cell culture for studying arachidonic acid metabolism and other cell functions. PMID- 7846095 TI - Spontaneous chemiluminescence of ETYA (5,8,11,14-eicosatetraynoic acid) is inhibited by catalase or peroxidase. AB - 5,8,11,14-eicosatetraynoic acid (ETYA), an isomorphic competitive analogue of arachidonic acid, spontaneously generates a chemiluminescence signal detected with a liquid scintillation spectrometer operated at ambient temperature in the out-of-coincidence mode. The intensity of the signal was 10- or more-fold above background, required oxygen for its generation, was inhibited by antioxidants, and approximately doubled in D2O. Arachidonic acid, which contains 4-alkene rather than alkyne bonds did no more than double the chemiluminescent signal above background. When examined at 37 degrees C in a Berthold AutoLumat 958 luminometer, DBA (lucigenin) was required to detect a signal above background. Catalase or peroxidase, and to a lesser extent mannitol or histidine but not superoxide dismutase, strongly diminished the signal intensity. These observations provide a baseline for interpreting the functional and electron microscopic changes produced by ETYA in PC3 prostate and A172 glioblastoma cell lines, consistent with a contribution from oxidative stress associated with free radicals, and the absence of these morphological changes in U937 monoblastoid cells. PMID- 7846096 TI - The effect of iron fortification on the fatty acid composition of plasma and erythrocyte membranes in primary school children with and without iron deficiency. AB - An intervention study was designed to evaluate the fatty acid (FA) status of children aged 6-11 years before and after iron fortification. Iron deficient (ID) and matched controls without ID (n = 30) were selected. All children received soup (160 mL) fortified with 20 mg iron and 100 mg vitamin C for 15 weeks on school days. Measurements before and after intervention included dietary intake, haematological and iron status and FA composition of plasma and erythrocyte membranes (EMBs). The prevalence of low plasma ferritin concentration and transferrin saturation decreased in the ID children by 40% and 56%, respectively, with intervention. Plasma FAs reflected dietary FA intake. In comparison with controls, the ID group presented with increased percentage total saturated FAs (SFAs; p = 0.0002) in their EMB phosphatidylcholine (PC) and reduced percentage total polyunsaturated FAs (PUFAs; p = 0.0037) before intervention. Lower total n 3 FAs (p = 0.0070) including eicosapentaenoic acid (EPA; p = 0.0034), docosapentaenoic acid (DPA; p = 0.0048) and docosahexaenoic acid (DHA; p = 0.0058) were observed in the ID group. The EMB phosphatidylethanolamine (PEA) of the ID children presented with lower percentages of alpha-linolenic acid (ALA; p = 0.0001), EPA (p = 0.0051) and DHA (p = 0.0084) compared to controls before intervention. Iron intervention was associated with an increase (p < 0,05) in the percentage of n-3 FAs in the EMB-PC and -PEA of the ID group to percentages comparable to that in the control group. It appears that iron status can influence FA metabolism of specific n-3 FAs in the EMBs of young children. PMID- 7846097 TI - Inhibitory effect of prostaglandin E1 on human neutrophil function. AB - Neutrophils accumulated in the lung are thought to play a pivotal role in the pathogenesis of host auto-injury such as adult respiratory distress syndrome (ARDS). We investigated the effect of prostaglandin E1 (PGE1) on several aspects of human neutrophil function. PGE1 significantly decreased reactive oxygen species (ROS), (O2-, H2O2, OH.) generation by neutrophils as well as neutrophil phagocytosis and chemotaxis. In contrast, the drug did not affect the levels of ROS generated by a cell-free ROS generating system. In addition, intracellular calcium concentrations ([Ca2+]i) in neutrophils stimulated by f-Met-Leu-Phe were decreased in the presence of PGE1. These data suggest that the reduction in ROS production and neutrophil phagocytosis and chemotaxis by PGE1 may contribute to the effectiveness of the drug in host auto-injury including ARDS. The suppression of the increase in [Ca2+]i may at least be responsible for inhibition of these neutrophil functions by PGE1. PMID- 7846099 TI - Monthly Prostaglandins Bibliography prepared by the University of Sheffield Biomedical Information Service. PMID- 7846100 TI - Eicosanoids and hepatic preservation for organ transplantation. PMID- 7846098 TI - Prostacyclin, thromboxane A2, and atherosclerosis in young hypercholesterolemic swine. AB - Plasma 6-keto-prostaglandin F1 alpha and thromboxane B2 levels were determined to evaluate their role as predictive indicators for the development and progression of coronary atherosclerosis in young hypercholesterolemic swine. 32 young swine were randomly assigned to the control or atherogenic diet group for 10, 30, 90, or 180 days. Lipid profiles were obtained at the onset and repeated throughout the study. Radioimmunoassays of plasma 6-keto-prostaglandin F1 alpha and thromboxane B2 were recorded at 10 day intervals in the 10 and 30 day subjects and at 30 day intervals in the 90 and 180 day subjects. Sections from the proximal left anterior descending coronary artery were classified based on their histological evidence of atherosclerosis by light microscopy. Hypercholesterolemia was positively correlated with development of coronary atherosclerosis (r = 0.704). However, plasma 6-keto-prostaglandin F1 alpha, thromboxane B2, and the thromboxane B2:6-keto-prostaglandin F1 alpha ratio were not found to be predictive indicators (p > 0.05) for the development or early progression of coronary atherosclerosis. PMID- 7846102 TI - Relationships between the fatty acid status and insulinemic indexes in obese children. AB - The relationship between the fatty acid (FA) status and indices of insulin secretion in young obese subjects at risk of developing insulin resistance and its complications was investigated. In 12 subjects (8-14 years) at first diagnosis of obesity the FA composition of total plasma and circulating and erythrocyte phospholipids was related to basal and peak insulinemia and the insulinemic area resulting from a standard oral glucose tolerance test. Negative correlations were shown between both delta-6-desaturation products and 20:5 n-3 levels and insulinemic values. On the contrary, circulating total saturated and monounsaturated FA and erythrocyte phospholipid products of delta-5- and delta-4 desaturation positively correlate with insulinemic indices. The observed relationships could be markers of developing insulin resistance and suggest the possibility of a dietary intervention. PMID- 7846101 TI - Clinical and experimental study on the long-term effect of dietary gamma linolenic acid on plasma lipids, platelet aggregation, thromboxane formation, and prostacyclin production. AB - Effects of a dietary intake of the polyunsaturated omega-6 essential fatty acids (EFAs) linoleic and gamma-linolenic acids (GLA) on blood lipids, platelet function, and vascular prostacyclin production were studied 12 hyperlipidemic patients (doses of 3 g/day) and 12 male Wistar rats (doses of 3 mg/kg/day) for 4 months. In humans, GLA supplementation decreased plasma triglyceride (TG) levels by 48% (p < 0.001) and increased HDL-cholesterol concentration by 22% (p < 0.01). Total cholesterol and LDL-cholesterol levels were significantly decreased by omega-6 EFAs. Platelet aggregation induced by low concentrations of adenosine diphosphate (ADP) and epinephrine, and serum thromboxane B2 decreased by 45% both in humans and animals after GLA supplementation. Bleeding time increased 40% (p , 0.01). In rats, vascular prostacyclin production measured by radioimmunoassay of 6-keto-PGF1 alpha was enhanced by GLA intake. These effects of omega-6 EFAs may contribute to cardiovascular protection and prevention of the atherosclerotic disease. PMID- 7846103 TI - PAF formation by H2O2-stimulated perfused canine carotid arteries. AB - Perfusion of noncytotoxic concentrations of hydrogen peroxide (H2O2) through canine carotid arteries potentiates neutrophil adhesion to vessel endothelium. Platelet-activating factor (PAF) receptor antagonists block neutrophil adhesion to vessels pretreated with low millimolar concentrations of H2O2. We have used a specific gas chromatographic-mass spectrometric (GC-MS) assay for PAF and applied this to studies of canine carotid arteries perfused with H2O2. Vessels perfused with 1 and 10 mM H2O2 for 20 min produced PAF in a dose-dependent manner, 331 +/- 67 pg/g tissue with 1 mM H2O2 and 1160 +/- 194 pg/g with 10 mM. Vessels that had been denuded of endothelium with a balloon catheter prior to H2O2 perfusion produced similar quantities of PAF in response to H2O2 (220 +/- 72 pg/g and 960 +/- 210 pg/g with 1 and 10 mM, respectively). Cultured canine jugular venous endothelial cells produced PAF in response to 10 mM H2O2 (809 +/- 117 pg/10(7) cells) but carotid arterial smooth muscle cells did not. These results suggest that vascular cells other than endothelial cells may produce PAF following H2O2 perfusion of canine carotid arteries. PMID- 7846104 TI - Mesothelial cell modulation of pleural repair: thrombin stimulated mesothelial cells release prostaglandin E2. AB - Repair of an injured pleura without fibrosis not only requires a re-establishment of the normal pleural mesothelial monolayer but also a downregulation of the inflammatory response, including inhibition of fibroblast proliferation and collagen synthesis. However, the role of the mesothelial cell in regulating these processes in the pleural space remains undefined. We therefore hypothesized that mesothelial cells, stimulated by thrombin, release prostaglandin E2 PGE2, which is capable of inhibiting fibroblast proliferation. In vitro rat visceral mesothelial cells were exposed to thrombin and PGE2 levels in the supernatant were measured using a competitive radioimmunoassay. Our results demonstrated that mesothelial cells produce PGE2 in a dose- and time-dependent manner. In addition, both anti-thrombin 3 and indomethacin completely blocked the PGE2 released. Finally, conditioned media from thrombin-stimulated mesothelial cells inhibited fibroblast [3H]thymidine incorporation. These results demonstrate that the mesothelial cell is capable of contributing to the repair process of pleural injury by the release of a local factor such as PGE2. PMID- 7846105 TI - Oxidation kinetics of caffeic acid by prostaglandin H synthase: potential role in regulation of prostaglandin biosynthesis. AB - The naturally occurring catechol derivative caffeic acid is a moderate stimulator of prostaglandin H synthase cyclooxygenase activity and a good reducing substrate for prostaglandin H synthase-compounds I and II. The discrepancy between the two properties is explained by a specific peroxidative mechanism that includes the formation of an inhibitory complex of caffeic acid with native enzyme followed by a three-step irreversible ping-pong peroxidation. The concentration of caffeic acid necessary to produce 50% stimulation of 0.2 mM arachidonic acid oxidation is 0.8 +/- 0.1 mM. The rate constant for the reaction of prostaglandin H synthase with hydrogen peroxide, determined from steady-state results, is (5.68 +/- 0.1) x 10(5) M-1 s-1. The rate constant for the reaction of prostaglandin H synthase compound II with caffeic acid is (1.25 +/- 0.1) x 10(6) M-1 s-1. The dissociation constant of caffeic acid from the inhibitory complex is 35 +/- 10 microM. In diluted enzyme solutions, caffeic acid binding is diminished and the enzyme exhibits higher peroxidase activity. Our results suggest that caffeic acid is not a O-demethylation product of ferulic acid degradation catalyzed by prostaglandin H synthase, nor a chelating agent for the heme iron. The oxidation of caffeic acid could be important in the regulation of both prostaglandin H synthase and lipoxygenase activities and hence prostaglandin and leukotriene biosynthesis. PMID- 7846106 TI - PGE2 inhibits acetylcholine release from cholinergic nerves in canine but not equine airways. AB - The effects of exogenous prostaglandin E2 (PGE2) and endogenous prostanoids on cholinergic neurotransmission were determined by measurement of acetylcholine (ACh) release from canine and equine airway tissues. Trachealis strips and bronchial segments were suspended in 2 ml tissue baths. ACh release was induced by electrical field stimulation (EFS), and its content in tissue bath liquid was measured by high pressure liquid chromatography (HPLC) with electrochemical detection. In canine airways, exogenous PGE2 (10(-9) to 10(-7) M) inhibited ACh release concentration-dependently, whereas inhibition of endogenous prostanoid production by indomethacin (3 x 10(-6) M) augmented ACh release. By contrast, in equine airways, exogenous PGE2 had no effect on ACh release in bronchi but at 10( 7) M augmented ACh release in the trachea. Cyclooxygenase inhibition by either indomethacin or meclofenamate (10(-6) M) did not influence ACh release. We conclude that exogenous PGE2 and endogenous prostanoids inhibit ACh release from cholinergic nerves in canine but not equine airways. PMID- 7846107 TI - In pigs, inhaled nitric oxide (NO) counterbalances PAF-induced pulmonary hypertension. AB - In 6 anesthetized mechanically ventilated pigs we have studied the effects of inhalation of 80 ppm of nitric oxide (NO) before and after platelet-activating factor (PAF) administration (50 ng/kg iv). Our results show that NO inhalation causes a decrease in pulmonary arterial pressure and in heart rate without affecting other circulatory parameters. PAF administration causes a pulmonary hypertension and a prompt and brief decrease in systemic pressure. Inhalation of NO reduces the pulmonary hypertension, without completely reversing PAF-dependent vasoconstriction. PAF administration to pigs pretreated with indomethacin produces a lesser increase in pulmonary vascular pressure. In this case, NO inhalation can restore to baseline values. Pretreatment of 3 of the 6 pigs with NG-nitro-L-arginine-methyl-ester did not prevent the prompt and brief PAF-induced systemic hypotension. In conclusion, our results show that NO reduces basal pulmonary vascular tone, acts as a pulmonary vasodilator on PAF-preconstricted vessels and is not involved in the brief systemic hypotension consequent to PAF administration. PMID- 7846108 TI - Salicylamide reverses the aspirin-antagonistic effect of salicylic acid on rat platelet cyclooxygenase. AB - The antagonistic effect of salicylic acid (SA), the major metabolite of aspirin, on aspirin (ASA)-induced inhibition of cyclooxygenase has been recognized in vivo and in vitro. Salicylamide is available with aspirin in some analgesic preparations. Salicylamide shares important characteristics with salicylic acid including the lack of effect on cyclooxygenase and platelet aggregation as well as a close structural resemblance. This prompted us to study the interaction of salicylamide with aspirin and/or SA on rat platelet and cyclooxygenase. Our results showed that salicylamide has, unlike SA, no blocking effect on the anticyclooxygenase effect of aspirin in vitro. Moreover, salicylamide could dose dependently prevent the aspirin-blocking effect of SA on platelet cyclooxygenase. These results suggest that salicylamide and SA compete for a receptor on cyclooxygenase different to that of aspirin. A functional model of cyclooxygenase enzyme is proposed. PMID- 7846109 TI - Effect of chronic REM sleep deprivation on pituitary, hypothalamus and hippocampus PGE2 and PGD2 biosynthesis in the mouse. AB - Given the often reported relationships between sleep-wake regulation and the cerebral prostaglandins (PGs), the effect of chronic rapid eye movement (REM) sleep deprivation on brain PGE2 and PGD2 biosynthesis in mouse was evaluated, since they are known to have opposite actions as respectively wake- and sleep inducing substances. Mice were subjected to 5 and 10 days of REM sleep deprivation by the flower pot technique. After sacrifice, PGE2 and PGD2 were determined in the pituitary, hypothalamus and hippocampus. Except in the pituitary where no changes were shown, the PGE2/PGD2 ratio was significantly enhanced after 5 and 10 days of REM sleep loss, when compared to control. These results showed an alteration of cerebral PGE2 and PGD2 biosynthesis, resulting in a shift from PGD2 toward PGE2. These results were not consistent with a role of PGD2 as a sleep-promoting substance as, if that was the case, it would be increased during the REM sleep deprivation. But they do not rule out its involvement as a facilitating substance. PMID- 7846110 TI - Role of prostaglandin E2 and prostacyclin in nonshivering thermogenesis during simulated birth in utero. AB - Prostaglandin E2 (PGE2) inhibits and prostacyclin (PGI2), stimulates lipolysis in vitro. Their role in initiating nonshivering thermogenesis at birth was investigated in 16 fetal sheep at 129-143 days gestation. In 10 fetuses indomethacin, a prostaglandin synthesis inhibitor, was infused; in 6 fetuses saline was administered as a control. 16 h later birth was simulated in utero. The plasma levels of PGE2 and PGI2 were unaffected by cooling. In the control fetuses, ventilation with oxygen caused PGE2 to fall, PGI2 to rise, and initiated moderate thermogenesis, signaled by a twofold increase in plasma free fatty acids (FFA). After umbilical cord occlusion, PGE2 decreased further (PGI2 was unchanged) and thermogenesis accelerated. In indomethacin-treated fetuses, in which the prostanoids had decreased and remained at approximately 20% normal, cooling initiated moderate nonshivering thermogenesis, and ventilation and cord occlusion caused no further changes. Changes in plasma adenosine were similar in control and indomethacin-treated groups. We conclude that declining PGE2 and rising PGI2 contribute to the initiation of thermogenesis at birth, but that other agents possibly of placental origin may play a contributory role. PMID- 7846111 TI - The role of prostanoids in the complications of extracorporeal shock wave lithotripsy (ESWL) in children. AB - ESWL is a safe and effective first-line treatment for urinary tract stone disease (UTSD) in children. The major complications arising from this procedure were upper urinary tract obstruction and ureteral colic. It was shown that prostaglandin synthetase inhibitors were effective in the treatment of urethral colic. The aim of this study was to measure urinary and plasma prostaglandin E2 (PGE2)- and leukotriene C4 (LTC4)-like activity in the patients who underwent ESWL before and after the treatment and investigate the role of cyclooxygenase (CO) and lipoxygenase (LO) products in early and late complications of ESWL. Urinary PGE2-like activity were increased 1 h after ESWL. (1.19 +/- 0.12 vs 1.59 +/- 0.15 g/ml, p < 0.02). The plasma values were decreased significantly after the treatment (16.7 +/- 1.7 vs 11.6 +/- 1.2 g/ml, p < 0.005). Urinary and plasma LTC4-like activities were found to be significantly decreased in the post-ESWL samples (0.58 +/- 0.006 vs 0.39 +/- 0.04, p < 0.002; 8.6 +/- 0.9 vs 4.2 +/- 0.6, p < 0.001, respectively). In conclusion, ESWL may stimulate the release of PG from the urinary tract resulting in increased peristaltism and the passage of stone fragments into the bladder. As this group of drugs has also nephrotoxic effects, they can be given prophylactically only to selected patients. PMID- 7846112 TI - Receptor blockade with monoclonal antibodies as anti-cancer therapy. AB - Human tumors express high levels of growth factors and their receptors, and many types of malignant cells appear to exhibit autocrine- or paracrine-stimulated growth. Therefore, antireceptor directed therapies have the potential of being useful anti-cancer agents. A series of murine monoclonal antibodies (MAbs) directed against human growth factor receptors and their corresponding growth factors have been produced. MAbs against the receptors for epidermal growth factor, Her2/Neu, transferrin, insulin-like growth factor, interleukin, (IL)-2 and IL-1 are currently being evaluated. MAbs directed against epidermal growth factor, transforming growth factor-alpha, bombesin, IL-2, and IL-6 also are under study. These MAbs have shown promising preclinical activity, and some of them are being tested in clinical trials. So far, anti-tumor responses have been observed with anti-IL-2 receptor, anti-bombesin and anti-IL-6 MAbs. Further research is focusing in the production of "chimeric" and "humanized" MAbs, in order to obviate the problem of host immune reactions. PMID- 7846114 TI - Human cysticercosis: parasitology, pathology, clinical manifestations and available treatment. AB - Human cysticercosis is a global health problem and neurocysticercosis a serious clinical syndrome. The diagnosis of neurocysticercosis can now be made with a high degree of accuracy by scrutiny of clinical signs and symptoms in combination with X-ray, computed tomography or magnetic resonance imaging, serological tests and laboratory examinations. Differential clinical diagnosis with tumor, and vascular and inflammatory conditions, may however, prove difficult in nonendemic areas. The management of cysticercosis has been radically changed by the advent of effective chemotherapy. Both the heterocyclic pyrazinoisoquinoline compound, praziquantel and the benzimidazole carbamate, albendazole, have now been extensively tested and successfully used for treatments of neurocysticercosis, usually in combination with corticosteroids. The definition of appropriate criteria and guidelines for the use of chemotherapy, may however, require further research. Surgical interventions continue to play an important role in certain clinical presentations. Recent advances in immunological research hold realistic promise for the development of a vaccine against Taenia solium. PMID- 7846113 TI - Vascular targeting--a new approach to the therapy of solid tumors. AB - An attractive approach to the therapy of solid tumors is to attack the endothelial cells of the tumor vascular bed rather than the tumor cells themselves, which circumvents the problem of poor penetration of tumor masses by monoclonal antibodies and other macromolecules. In this review, we will discuss the drawbacks of targeting solid tumors and the advantages of the 'vascular targeting' approach, describe the validation of the concept in a mouse model and summarize the properties of tumor endothelial cell markers, which are candidates for vascular targeting in humans. PMID- 7846115 TI - Inhibitors of the insulin receptor tyrosine kinase. AB - Insulin is a polypeptide hormone consisting of 51 amino acids. Insulin promotes a variety of anabolic enzymatic pathways and inhibits many catabolic enzymatic pathways involved in energy storage, as well as in synthesis of structural tissue proteins. In addition, insulin serves as a growth factor, modulating mitogenesis, growth and differentiation. Insulin mediates all of its effects by initially binding and activating its specific cell-surface receptor. Conformational changes induced by insulin binding lead to activation of intrinsic receptor tyrosine kinase. Thus, the study of tyrosine kinase inhibitors, whether synthetically produced or purified from microorganisms or humans, has led to elucidation of molecular details of physiological insulin signaling. PMID- 7846116 TI - Calcium antagonists and vasodilatation. AB - Calcium antagonists comprise a diverse group of chemically unrelated agents that interact with voltage-operated calcium channels (L-type) and thereby inhibit smooth muscle contractility. They are used to treat several major cardiovascular disorders, including hypertension and angina pectoris; they are also studied in congestive heart failure and in atherosclerosis. The current view is that their therapeutic action is related to vasodilatation. This view is an oversimplification, as will be shown in this review. It will also be illustrated that all calcium antagonists are not identical pharmacological agents. PMID- 7846117 TI - The role of the canalicular multispecific organic anion transporter in the disposal of endo- and xenobiotics. AB - Bile is an important excretory route for the elimination of amphiphilic organic anions, and hepatocytes are the primary secretory units of bile formation. The hepatocytic basolateral and canalicular membranes are equipped with various carrier proteins. Transport across the canalicular membrane represents a major concentrative step. Various ATP-dependent transporters have been identified, such as a multispecific organic anion transporter (canalicular multispecific organic ion transporter, cMOAT), a bile acid transporter and several P-glycoproteins. TR- rats, which lack cMOAT activity, have been valuable in defining the substrate specificity of cMOAT. A wide range of glucuronide-, glutathione- and sulfate conjugates are transported by this system. PMID- 7846118 TI - Sex steroids and lipoprotein metabolism. AB - Lipoprotein metabolism is involved in atherogenesis. Female sex-hormones have substantial effects on both lipoprotein metabolism and the vessel wall. Cholesterol, one of the major lipids in lipoproteins, is both the substrate for, and the target of, the steroidal sex hormones. PMID- 7846119 TI - Death from inside out: an overview. AB - Although a type of cell death strategically suited to participating in developmental processes has been well known for nearly thirty years, it is only in the recent past that the extraordinary ubiquity of such death has been appreciated. Apoptosis, a term first employed to describe such death defined in structural terms, is associated with a stereotyped set of effector processes, and is driven by genes most of which are familiar as oncogenes or oncosuppressor genes. Dysregulation of apoptosis leads to diseases of enormous social importance such as cancer and AIDS. PMID- 7846120 TI - The ins and outs of programmed cell death during C. elegans development. AB - During the development of the C. elegans hermaphrodite, 131 of the 1090 cells generated undergo programmed cell death. Genetic studies have identified mutations in 14 genes that specifically affect this process. These genes define a genetic pathway for programmed cell death in C. elegans. Two genes, ced-3 and ced 4, are required for cells to undergo programmed cell death, while a third gene, ced-9, protects cells that should live from undergoing programmed cell death. The proteins encoded by ced-3 and ced-9 show significant similarity to proteins that affect programmed cell death in vertebrates, suggesting that the molecular cell death pathway in which ced-3, ced-4, and ced-9 act has been conserved between nematodes and vertebrates. PMID- 7846121 TI - Programmed cell death in Drosophila. AB - During Drosophila development, large numbers of cells undergo natural cell death. Even though the onset of these deaths is controlled by many different signals, most of the dying cells undergo common morphological and biochemical changes that are characteristic of apoptosis in vertebrates. We have surveyed a large fraction of the Drosophila genome for genes that are required for programmed cell death by examining the pattern of apoptosis in embryos homozygous for previously identified chromosomal deletions. A single region on the third chromosome (in position 75C1,2) was found to be essential for all cell deaths that normally occur during Drosophila embryogenesis. We have cloned the corresponding genomic DNA and isolated a gene, reaper, which is capable of restoring apoptosis when reintroduced into cell death defective deletions. The reaper gene is specifically expressed in cells that are doomed to die, and its expression precedes the first morphological signs of apoptosis by 1-2 h. This gene is also rapidly induced upon X-ray irradiation, and reaper deletions offer significant protection against radiation-induced apoptosis. Our results suggest that reaper represents a key regulatory switch for the activation of apoptosis in response to a variety of distinct signals. PMID- 7846122 TI - Block of neuronal apoptosis by a sustained increase of steady-state free Ca2+ concentration. AB - Programmed death is a ubiquitous feature of the development of the vertebrate nervous system. This death is prevented in vivo by trophic factors and by afferent input. Death of neurons can also be prevented in culture models of programmed death by trophic factors and by chronic depolarization with elevated concentrations of K+ in the culture medium. The latter effect is mediated by Ca2+ influx through voltage-gated channels and may prevent death by mimicking survival promoting effects of naturally occurring electrical activity. Little is currently known about the mechanism by which either trophic factors or increased cytoplasmic Ca2+ promote survival. PMID- 7846123 TI - Apoptosis in the haemopoietic system. AB - Our previous studies have shown that haemopoietic stem cells undergo apoptotic death as a consequence of growth factor withdrawal. In this paper we review the new data that has accumulated since this observation and compare it with older data from the 'pre-apoptotic' age. Models of erythropoiesis and granulopoiesis that incorporate apoptosis as a normal physiological process controlling homeostasis are examined. The converse to cell death is cell survival, and we describe experiments which suggest that haemopoietic growth factors can not only act as mitogenic or differentiation stimuli but also act as survival signals. We, and others, have proposed that these growth factor-induced survival signals act through the membrane bound polypeptide receptors and share common features of signal transduction with proliferative responses. Enforced expression of bcl-2 in haemopoietic stem cells is able to overcome apoptosis following the withdrawal of growth factor, and the cells commit into different lineage differentiation programmes. Such cells spontaneously differentiate without cell division, suggesting a stochastic model of haemopoiesis in which the major role of haemopoietic growth factors is to suppress apoptosis and act as mitogens. We review the evidence that the underlying causes of some haematological diseases may be associated with change in the balance between cell survival and death. PMID- 7846124 TI - Programmed cell death and the control of cell survival. AB - We draw the following tentative conclusions from our studies on programmed cell death (PCD): (i) the amount of normal cell death in mammalian development is still underestimated; (ii) most mammalian cells constitutively express the proteins required to undergo PCD; (iii) the death programme operates by default when a mammalian cell is deprived of signals from other cells; (iv) many normal cell deaths may occur because cells fail to obtain the extracellular signals they need to suppress the death programme; and (v) neither the nucleus nor mitochondrial respiration is required for PCD (or Bcl-2 protection from PCD), raising the possibility that the death programme, like mitosis, is orchestrated by a cytosolic regulator that acts on multiple organelles in parallel. PMID- 7846125 TI - Integrated control of cell proliferation and cell death by the c-myc oncogene. AB - Regulation of multicellular architecture involves a dynamic equilibrium between cell proliferation, differentiation with consequent growth arrest, and cell death. Apoptosis is one particular form of active cell death that is extremely rapid and characterized by auto-destruction of chromatin, cellular blebbing and condensation, and vesicularization of internal components. The c-myc proto oncogene encodes an essential component of the cell's proliferative machinery and its deregulated expression is implicated in most neoplasms. Intriguingly, c-myc can also act as a potent inducer of apoptosis. Myc-induced apoptosis occurs only in cells deprived of growth factors or forcibly arrested with cytostatic drugs. Myc-induced apoptosis is dependent upon the level at which it is expressed and deletion mapping shows that regions of c-Myc required for apoptosis overlap with regions necessary for co-transformation, autoregulation, inhibition of differentiation, transcriptional activation and sequence-specific DNA binding. Moreover, induction of apoptosis by c-Myc requires association with c-Myc's heterologous partner, Max. All of this strongly implies that c-Myc drives apoptosis through a transcriptional mechanism: presumably by modulation of target genes. Two simple models can be invoked to explain the induction of apoptosis by c-Myc. One holds that death arises from a conflict in growth signals which is generated by the inappropriate or unscheduled expression of c-Myc under conditions that would normally promote growth arrest. In this 'Conflict' model, induction of apoptosis is not a normal function of c-Myc but a pathological manifestation of its deregulation. It thus has significance only for models of carcinogenic progression in which myc genes are invariably disrupted.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7846126 TI - The role of the p53 protein in the apoptotic response. AB - When mammalian cells or tissues are exposed to DNA damaging agents a programmed cell death pathway is induced as well as a cell cycle arrest. In mice in which the p53 gene has been inactivated by homologous recombination this response is profoundly diminished. These mice develop normally so that developmentally induced apoptotic events do not require p53. The p53 gene product is a 393 amino acid nuclear protein that binds specifically to DNA and can act as a positive transcription factor. High levels of p53 can induce the transcription of gene products involved in the cell cycle arrest and apoptotic pathway. The p53 proteins activity is very tightly controlled both by allosteric regulation of its DNA binding function and by regulation of the protein's stability. These results are discussed in the context of the mutations in p53 found in human tumours and their implications for the treatment of the disease by the use of radiation and chemotherapeutic agents that target DNA. PMID- 7846127 TI - Insights from transgenic mice regarding the role of bcl-2 in normal and neoplastic lymphoid cells. AB - The bcl-2 gene was first discovered by molecular analysis of the 14;18 chromosome translocation which is the hallmark of most cases of human follicular lymphoma. To date, it is unique among proto-oncogenes because, rather than promoting cell proliferation, it fosters cell survival. This review summarizes the impact of constitutive bcl-2 expression on the development and function of lymphocytes as well as their malignant transformation. Expression of a bcl-2 transgene in the B lymphoid compartment profoundly perturbed homeostasis and, depending on the genetic background, predisposed to a severe autoimmune disease resembling human systemic lupus erythematosus. T lymphoid cells from bcl-2 transgenic mice were remarkably resistant to diverse cytotoxic agents. Nevertheless, T lymphoid homeostasis was unaffected and tolerance to self was maintained. Expression of high levels of Bcl-2 facilitated the development of B lymphoid tumours but at relatively low frequency and with long latency. Co-expression of myc and bcl-2, on the other hand, promoted the rapid onset of novel tumours which appeared to derive from a lympho-myeloid stem or progenitor cell. Introduction of the bcl-2 transgene into scid mice facilitated the survival and differentiation of pro-B but not pro-T cells, suggesting that a function necessary to supplement or complement the action of Bcl-2 is expressed later in the T than the B lineage. Crosses of the bcl-2 transgenic mice with p53-/- mice have addressed whether loss of p53 function and gain of bcl-2 function are synergistic for lymphoid cell survival. PMID- 7846128 TI - Life, death and genomic change in perturbed cell cycles. AB - HeLaS3 cells undergo apoptosis after 18-24 h of cell cycle stasis irrespective of the agent employed (colcemid, aphidicolin, cis-platin). At high drug concentrations apoptosis occurs in cells arrested in the cell cycle in which the drug is applied and at a cell cycle position dependent on the mechanism of drug action. At low concentrations (or short exposure times) cells undergo apoptosis after progressing through an aberrant mitosis and only after 18 h of cell cycle stasis in a 'pseudo G1/S' cell cycle position. Aberrent mitoses result in multipolar mitoses, chromosomal breakage and interchromosomal concatenation events. We propose that the ability of cells to delay progression into aberrent mitosis, as well as their propensity to undergo apoptosis, are important determinants of clinical cytotoxicity. We also suggest that apoptosis plays an important role in preventing the generation of aneuploidy and recombination and rearrangement events commonly associated with cancer. PMID- 7846129 TI - Apoptosis and cancer chemotherapy. AB - The major disseminated cancers remain stubbornly resistant to systemic therapy. Drug-resistant tumours include both slow and fast growing types, with the carcinomas constituting the major problem. Strategies for drug discovery have, in the past, been focused on attempts to design antiproliferative agents, largely targeted to interfere with DNA integrity and replication. The malignant phenotype might be characterized by the emergence of cell populations with a greater survival potential: a lower proclivity to undergo apoptosis. This idea provides a possible explanation of the genesis and progression of cancer and of the inherent resistance of tumour cells to engage apoptosis. Work is described which identifies the molecular basis for differences in the survival potential of stem cells in the crypts of the colon and small intestine. The advantageous survival of colonic stem cells, provided by expression of bcl-2 and a muted p53 response to DNA damage, allows damaged cells to survive. Continued expression of bcl-2 renders tumour cells resistant to drug-induced DNA damage by a mechanism different from classical mechanisms of drug resistance. The attenuation of cell survival is described as a key component in strategies for the drug treatment of disseminated cancers. PMID- 7846130 TI - Granulocyte apoptosis and the control of inflammation. AB - We have described a novel pathway available for the clearance of extravasated granulocytes from inflamed tissues whereby aging granulocytes undergo apoptosis, a process which leads to their phagocytosis by inflammatory macrophages. By contrast with necrosis, which may also be seen at inflamed sites, apoptosis represents a granulocyte fate which by a number of mechanisms would tend to limit inflammatory tissue injury and promote resolution rather than progression of inflammation: (i) apoptosis is responsible for macrophage recognition of senescent neutrophils with intact cell membranes which exclude vital dyes and retain their potentially histotoxic granule contents; (ii) the apoptotic neutrophil loses its ability to secrete granule enzymes on deliberate external stimulation; (iii) the macrophage possesses a huge phagocytic capacity for apoptotic neutrophils which it rapidly ingests and degrades without disgorging neutrophil contents; and (iv) the macrophage utilizes a novel phagocytic recognition mechanism which fails to trigger the release of pro-inflammatory macrophage mediators during the phagocytosis of apoptotic neutrophils. Preliminary characterization of the recognition mechanism implicates the integrin alpha v beta 3 (vitronectin receptor) and CD36 (thrombospondin receptor) on the macrophage surface. Macrophage phagocytosis of apoptotic neutrophils is greatly influenced by the microenvironmental pH and by the presence of cationic molecules. Moreover, it can be specifically modulated by external cytokines and intracellular second messenger systems. By controlling the functional longevity of neutrophil and eosinophil granulocytes and their subsequent removal by macrophages, granulocyte apoptosis, with its potential for modulation by external mediators, is likely to play a key dynamic role in the control of the 'tissue load' of granulocytes at inflamed sites.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7846131 TI - Reliability of measurements of body center-of-mass momentum during sit-to-stand in healthy adults. AB - BACKGROUND AND PURPOSE: The purpose of this study was to determine the reliability of measurements of momentum of the body's center of mass (CM) during a sit-to-stand (STS) transfer in healthy adults. SUBJECTS: Nineteen healthy adults aged 25 to 38 years (mean = 31.7, SD = 4.2) participated. METHODS: Horizontal and vertical components of CM momentum were computed for STS transfers made at three movement speeds (fast, natural, and slow) with the aid of a motion analysis system. Two force platforms detected the time when the subject lost contact with the chair and the propulsive and braking impulses in the horizontal and vertical directions. Separate intraclass correlation coefficients (ICCs) were calculated for three temporal variables (time to peak horizontal and vertical momentum and time to when the subject lost contact with the chair) and two magnitude variables (peak horizontal and vertical momentum). RESULTS: The ICCs for magnitude variables were > or = .81 for all speeds of movement. The ICCs for temporal variables ranged from .28 for fast movements to .75 for slow movements. CONCLUSION AND DISCUSSION: Measurement of peak vertical and horizontal momentum magnitudes is highly reproducible during STS transfers. Measurement of temporal variables exhibits a range of reliability estimates. Implications include consideration of the speed at which STS transfer is performed and its effect on reliability estimates and the potential differences between reliability estimates for magnitude measurements versus temporal measurements. PMID- 7846132 TI - Neuromuscular coordination of squat lifting, I: Effect of load magnitude. AB - BACKGROUND AND PURPOSE: In this study, we examined changes in kinematic and electromyographic (EMG) measurements of the coordination (ie, the relative timing of joint movements and muscle activity) of a squat-lifting task in response to lifting increasing loads. SUBJECTS: Fifteen male industrial workers served as a sample of convenience. METHODS: Subjects lifted a weighted crate containing 15% to 75% of their maximum lifting capacity using a symmetrical squat-lift technique. Movement kinematics were obtained with videography. The relative phase between joint motions was derived. The EMG activity of the vastus lateralis muscle (VL) and the erector spinae muscle (ES) was recorded, and the relative timing of their onsets and peaks was estimated. RESULTS: The relative phase of movement between joints such as the knee and lumbar spine changed in a quasi linear fashion with increasing load during lifting but not during lowering. The relative time of onset of ES EMG activity and its peak activity changed in a manner consistent with the interjoint relative phase results. The timing of VL events were not affected by increasing the load. CONCLUSION AND DISCUSSION: Relatively continuous changes in interlimb coordination occur when increasing the load lifted from an initial squatting posture. Changes in EMG relative timing partially corroborate the kinematic evidence for changes in coordination with load scaling. The results indicate the need for further study to determine whether the observed changes in coordination are beneficial or detrimental to the musculoskeletal system. Clinicians should evaluate performance of this task under a range of task conditions. PMID- 7846133 TI - Neuromuscular coordination of squat lifting, II: Individual differences. AB - BACKGROUND AND PURPOSE: This article reports individual differences in the coordination (ie, the relative timing of joint movements and muscle activity) of squat lifting identified by extended analysis of data reported in the authors' companion article in this issue. SUBJECTS: Two post hoc groups of 6 subjects each were identified from the original sample of 15 subjects based on qualitative differences in knee-lumbar spine relative motion plots during load acceleration. METHODS: Subjects lifted a crate containing 15% to 75% of their maximum lifting capacity using a symmetrical squat-lift technique. Movement kinematic data were obtained with videography, and the electromyographic (EMG) activity of the vastus lateralis and erector spinae muscles was recorded with surface EMG. Measurements of coordination derived both kinematically and via EMG and the kinematic data were examined for group differences. RESULTS: Subjects in group 2 limited lumbar spine motion during load acceleration for all loads lifted, whereas those in group 1 limited lumbar spine motion more when lifting the heaviest loads. These differences were obvious both qualitatively, via knee-lumbar spine relative motion plots, and quantitatively, via measures of the relative timing of joint motions early in the lift. The effect of load on the coordination of these joints was the same for both post hoc groups after initial load acceleration. Significant differences in other kinematic measurements were also found between these groups. CONCLUSION AND DISCUSSION: Despite specific instructions about how to lift the load, individual subjects coordinated their joints differently during the initial, accelerative phase of squat lifting. Individual differences in coordination in response to load increases could be categorized into two patterns, although the data of 2 subjects were difficult to categorize and thus not included in these analyses. Whether the two dominant patterns have consequences for stress to the joints during lifting remains to be determined. PMID- 7846134 TI - Effect of continuous-wave ultrasound on blood flow in skeletal muscle. AB - BACKGROUND AND PURPOSE: The purpose of this study was to determine the effect of ultrasound on forearm, skin, and muscle blood flow. SUBJECTS: Twenty volunteers without known vascular problems (10 male, 10 female) participated. METHODS: All subjects received a treatment of continuous-wave ultrasound to the anterior forearm at a dosage of 1.5 W/cm2 for a duration of 5 minutes. The contralateral forearm served as the control and received identical treatment, except the ultrasound output remained at zero. Forearm blood flow was measured using venous occlusion plethysmography, and skin blood flow was measured using cutaneous laser Doppler flowmetry before and after ultrasound administration, with the difference being muscle blood flow. RESULTS: No differences between the control arm and the ultrasound-treated arm were found for muscle, skin, and forearm blood flow. CONCLUSION AND DISCUSSION: These results suggest that administration of continuous-wave ultrasound at the prescribed dosage had no effect on skeletal muscle blood flow for up to 30 minutes posttreatment. Thus, muscle hyperemia is probably not the primary mechanism responsible for the clinical benefits seen following the use of ultrasound as a therapeutic modality. PMID- 7846135 TI - A clinical tool for measuring functional axial rotation. AB - BACKGROUND AND PURPOSE: Motion of the neck and back accompany many daily functional activities. Available range of motion is usually measured regionally and within single planes of motion. This report describes a device and measurement technique that can be used to quantify axial motion in a functionally relevant context. Functional axial rotation (FAR) refers to the available motion that persons use to turn toward the posterior, without regard to the plane of motion; FAR-p refers to the physical motion available, and FAR-v refers to the ability to identify objects. SUBJECTS: Nine men and eight women, aged 20 to 74 years, participated. METHODS: Functional axial rotation was determined for each subject. The seated subjects were measured on 2 different days to determine test retest reliability. Fifteen subjects were measured by two different examiners on the same day to determine interrater reliability. Intraclass correlation coefficients (ICCs) were computed to determine reliability. RESULTS: The FAR-p ranged from 78 to 190 degrees; FAR-v ranged from 135 to 250 degrees. Test-retest reliability of FAR-p and FAR-v was excellent (ICC[1, 1] values of .95 and .90, respectively, to the right and equivalent to the left). Interrater reliability likewise was excellent, with ICC(2, 1) values of .97 to the right and equivalent to the left. CONCLUSIONS AND DISCUSSION: Functional axial rotation provides one means of quantifying a patient's axial motion as it would be used in functional context. The FAR device is easy to construct and portable. Measurement of FAR provides the clinician with reliable information regarding the patient's functional use of available spinal motion, combined with visual ability. PMID- 7846136 TI - Statistical analysis of single-subject designs. PMID- 7846137 TI - Reliability of measurements obtained with four tests for patellofemoral alignment. AB - BACKGROUND AND PURPOSE: A series of patellofemoral (PF) alignment tests have been described that are used to determine when and how PF taping techniques should be applied. The reliability of measurements obtained with these tests has not been reported. The purpose of this study was to determine the intertester reliability of measurements obtained with four PF alignment tests: medial/lateral displacement, medial/lateral tilt, medial/lateral rotation, and anterior tilt. SUBJECTS: Twelve physical therapists from four clinics served as testers. A total of 66 patients were evaluated. METHODS: Paired testers performed all four PF alignment tests on the same patient. The intertester reliability of judgments for each of the PF alignment tests was determined by a kappa correlation coefficient. RESULTS: Kappa correlation coefficients ranged from .10 to .36 for the four PF alignment tests. CONCLUSION AND DISCUSSION: These findings suggest that the reliability of measurements obtained with the PF alignment tests described in this report ranged from poor to fair. Potential factors affecting the reliability of these measurements are discussed. Alternative methods for deciding when and how to apply PF taping techniques are also discussed. PMID- 7846138 TI - The efficacy of traction for back and neck pain: a systematic, blinded review of randomized clinical trial methods. AB - BACKGROUND AND PURPOSE: The purpose of this study was to conduct a systematic analysis of the literature to assess the efficacy of traction for patients with neck or back pain. SUBJECTS: For this purpose, randomized clinical trials comparing traction with other treatments were selected. METHODS: A computer-aided search of the literature was conducted for relevant articles, followed by blinded assessment of the methods of the studies. The main outcome measures were (1) scoring for quality of the designated conduct of studies (based on a methodological checklist with four main categories: study population, interventions, measurement of effect, and data presentation) and the main conclusions of author(s) with regard to traction and (2) calculation of confidence intervals and power of the studies. RESULTS: Only three studies scored more than 50 points (maximum score = 100 points), suggesting that most of the selected studies were of poor quality. None of these three studies showed favorable results for traction. Only four studies, of which one scored more than 50 points, had an acceptable power (1- beta > 80%). CONCLUSION AND DISCUSSION: The available reports of studies on the efficacy of traction for back and neck pain do not allow clear conclusions due to the methodological flaws in their design and conduct. Most studies lacked power (1-beta) due to small sample sizes. To date, no conclusions can be drawn about whether a specific traction modality for back or neck pain is effective, or more efficacious than other treatments. There are no clear indications, however, that traction is an ineffective therapy for back and neck pain. Further trials are needed in which much more attention should be paid to proper design and conduct, as well as to clear descriptions of crucial methodological features and results. PMID- 7846139 TI - Activists target animal dealers. PMID- 7846140 TI - Black physiologists--where are they? PMID- 7846141 TI - John A. Clements wins Lasker Award. PMID- 7846142 TI - Mathematics of microbial plasmid instability and subsequent differential growth of plasmid-free and plasmid-containing cells, relevant to the analysis of experimental colony number data. AB - Differential growth of plasmid-containing and plasmid-free microbial cells occurs in many and probably most plasmid systems. Misinterpretation of differential growth as replicational, recombinational, or segregational stability or instability can unfortunately result in grossly erroneous conclusions about replication, recombination, or segregation in plasmid model systems for studies of such phenomena. The differential growth rate should ideally be measured every time that the rate of loss due to instability per se is measured. Unfortunately, the possibility of differential growth has been ignored in most plasmid model systems, since the mathematics of instability and differential growth has not usually been dealt with in ways that are intuitively understandable to experimental microbiologists. Nevertheless, rapid diagnosis of differential growth, and accurate estimation of differential growth rate and rate of loss due to instability per se, can be done by analysis of colony number data using only the relatively simple mathematics described in this review. This review is intended for experimental microbiologists rather than for theoretical population geneticists or for pure mathematicians. However, the same mathematics described in this review is also applicable to certain simple model systems for plasmid ecology or evolution in natural or clinical environments. PMID- 7846143 TI - Analysis of a complex plasmid insertion in a phototaxis-deficient transformant of Dictyostelium discoideum selected on a Micrococcus luteus lawn. AB - A novel method for clonal selection of G418-resistant Dictyostelium discoideum transformants on lawns of Micrococcus luteus was developed. The procedure was used to isolate transformants deficient in phototaxis after nontargeted insertion of shuttle vector DNA. Southern blot analysis as well as restriction, T-tracking, and sequencing analysis of plasmids rescued from the genomic DNA of one of the putative phototaxis gene disruptants showed that it contained a complex multicopy insertion of the vector. While insertions of such plasmid vectors might typically be in tandem multicopy format, they can be much more complex, containing, as in this case, inverse as well as tandemly duplicated copies and various deletions. PMID- 7846144 TI - Transformation of Bifidobacterium longum with pRM2, a constructed Escherichia coli-B. longum shuttle vector. AB - An Escherichia coli-Bifidobacterium longum shuttle vector, designated pRM2, was constructed by cloning a B. longum plasmid and an enterococcal spectinomycin resistance gene into a commercial E. coli vector. The plasmid was successfully introduced into B. longum cells by electroporation and into E. coli cells by both electroporation and chemical transformation. PMID- 7846145 TI - Localization and topology of VirB proteins of Agrobacterium tumefaciens. AB - Agrobacterium tumefaciens causes tumors on plants by transferring part of its Ti (tumor inducing) plasmid, the T-DNA or transferred DNA, to plant cells. The virB operon, the largest operon of the virulence (Vir) region located on the Ti plasmid, is necessary for tumor induction on all plant species. Previously, the complete nucleotide sequences of the virB operons of several Ti plasmids of A. tumefaciens were determined. The 11 predicted proteins mostly have signal sequences and/or hydrophobic domains. Hence, these proteins are thought to be located in or transported over the agrobacterial inner membrane. The VirB proteins are suggested to form a pore structure in the membrane through which the T-DNA-protein complex is transported. To obtain direct evidence for transport of these proteins over the inner membrane, we made fusions between genes of the virB operon and the gene for the enzyme alkaline phosphatase. Here we show the localization of several VirB proteins in the bacterial membrane and predict the topology of the membrane-localized VirB proteins. The finding of a fusion between the VirB7 protein and the enzyme alkaline phosphatase provides the first evidence for the expression of the small virB7 gene. The VirB2 protein shows similarity with the TraA propilin of the Escherichia coli F plasmid. Here we show that the predicted topology of the VirB2 protein in the inner membrane is identical to that of the TraA protein. Therefore, we hypothesize that the VirB2 protein is part of an agrobacterial pilus-like structure. PMID- 7846146 TI - A plasmid responsible for malonate assimilation in Pseudomonas fluorescens. AB - A novel, broad-host-range 60-kb R-plasmid, which encodes for malonate assimilation, was isolated from Pseudomonas fluorescens and was designated pPSF1. Pseudomonas, which can utilize malonate as a sole carbon source, was unable to grow on malonate medium upon curing with mitomycin C, indicating loss of plasmid pPSF1. Furthermore, Escherichia coli transformed with pPSF1 was able to grow on malonate medium as a sole carbon source. Malonate decarboxylase, a key enzyme in malonate assimilation, was detected in transformed E. coli grown on malonate. pPSF1 also encodes resistance to several antibiotics such as ampicillin, kanamycin, and streptomycin and is transmissible between E. coli and Pseudomonas by conjugation. PMID- 7846147 TI - DNA sequence of direct repeats of the sulI gene of plasmid pSa. AB - The restriction enzyme and genetic map of the antibiotic-resistance region of plasmid pSa is related to Tn21 integrons by the insertion of 5.4 kb containing a chloramphenicol resistance gene (catII) and a 1.1-kb direct repeat. We report here the nucleotide sequences of both copies of the repeat with adjoining sequences. They were identical for 1065 bp and contained the entire coding sequence of the sulfanilamide resistance gene, sulI. Since only the first copy of the repeat confers sulfonamide resistance, this leads to the conclusion that no promoter was available for the second copy. The sequence of the pSa sulI gene was identical to several published sulI sequences from other plasmids. The first junction point of the catII-containing insert was identical to the sequence for pDG0100; the second junction occurred farther into the 3'-conserved segment of integrons than does that of pDG0100. A recent report of these junction sequences for pSa and pDG0100 differs from our sequences by one nucleotide. Two additional differences were an insert of 41 bases and a single base insertion between sulI and ORF341 in our sequence. Our sequenced regions have been assigned GenBank Accession Nos. UO4277 and UO4278 for the first and second sulI genes of pSa, respectively. PMID- 7846148 TI - An analysis of the complete nucleotide sequence of the Haemophilus ducreyi broad host-range plasmid pLS88. AB - We present an analysis of the complete nucleotide sequence of pLS88, a naturally occurring, 4.8-kb broad-host-range plasmid isolated from Haemophilus ducreyi and encoding resistance to sulfonamides, streptomycin, and kanamycin. Sequence analysis of the genes encoding sulfonamide and streptomycin resistance revealed homology to the RSF1010 sulII and strA genes. The sulII-strA intergenic region of pLS88 has a 38-bp deletion identical to that of the RSF1010-like plasmid pHD8.1, isolated from Actinobacillus pleuropneumoniae. The kanamycin resistance gene shows strong homology to Tn903, but lacks the inverted repeats of the transposon. No other genes have been identified. The region downstream of the kanamycin resistance gene shows homology to the RSF1010 oriV region; however, this region is not essential to plasmid replication. The ori of pLS88 is contained within a 1060-bp region and does not appear to contain structures typical of plasmid origins. This region is flanked by DNA showing strong homology to regions both upstream and downstream of the Haemophilus influenzae ROB-1 beta-lactamase gene. Because of the small size of the origin, pLS88 appears to resemble the structure of narrow-host-range plasmids, but replicates, via an as yet unidentified mechanism, as a broad-host-range plasmid. PMID- 7846149 TI - Construction of a versatile promoter analysis vector and its use for analysis of the Serratia marcescens aspartase promoter region. AB - A new versatile promoter analysis vector, pLGlacZ7, which contains a multiple cloning site and the lacZ structural gene in a low-copy-number plasmid pLG339, has been constructed. This plasmid, which can be stably maintained in Escherichia coli and Serratia marcescens, is useful for analysis of gene expression using lacZ gene fusions. The multiple cloning site of pLGlacZ7 is convenient for the insertion or deletion of promoter DNA fragments, the latter by using exonuclease III. The promoter of the S. marcescens aspA gene encoding aspartase was analyzed using plasmid pLGlacZ7. The S. marcescens aspA gene is composed of 1434 nucleotides and codes for a protein with a Mr of 52,543 whose predicted amino acid sequence was very similar to that of the E. coli aspA gene product. Two functional regions that may participate in the transcription of the S. marcescens aspA gene were found in the promoter region by using lacZ gene fusions in pLGlacZ7. PMID- 7846150 TI - Isolation of thermosensitive mutants of Yersinia enterocolitica by transposon insertion. AB - During bacterial infection, pathogens are exposed to a variety of stimuli, e.g., sudden temperature increase on entering mammalian host or oxidative stress associated with exposure to phagocytes. Yersinia enterocolitica, which is a facultative intracellular bacteria, responds to macrophage phagocytosis by the production of a set of stress proteins; which are also induced by heat shock (Yamamoto et al., 1994, Microbiol. Immunol. 38, 295-300). To examine the role of bacterial stress proteins in the adaptation to environmental changes encountered during infectious processes, we have isolated stress-sensitive mutants from Y. enterocolitica in which mini-Tn10 transposon insertions allow bacterial growth at 28 degrees C but prevent growth at an elevated temperature, 39 degrees C. Eight independent insertions were obtained and preliminarily characterized by Southern blot hybridization and morphological analysis. PMID- 7846151 TI - Genes galore: a summary of methods for accessing results from large-scale partial sequencing of anonymous Arabidopsis cDNA clones. AB - High-throughput automated partial sequencing of anonymous cDNA clones provides a method to survey the repertoire of expressed genes from an organism. Comparison of the coding capacity of these expressed sequence tags (ESTs) with the sequences in the public data bases results in assignment of putative function to a significant proportion of the ESTs. Thus, the more than 13,400 plant ESTs that are currently available provide a new resource that will facilitate progress in many areas of plant biology. These opportunities are illustrated by a description of the results obtained from analysis of 1500 Arabidopsis ESTs from a cDNA library prepared from equal portions of poly(A+) mRNA from etiolated seedlings, roots, leaves, and flowering inflorescences. More than 900 different sequences were represented, 32% of which showed significant nucleotide or deduced amino acid sequences similarity to previously characterized genes or proteins from a wide range of organisms. At least 165 of the clones had significant deduced amino acid sequence homology to proteins or gene products that have not been previously characterized from higher plants. A summary of methods for accessing the information and materials generated by the Arabidopsis cDNA sequencing project is provided. PMID- 7846153 TI - The plasma membrane of Arabidopsis thaliana contains a mercury-insensitive aquaporin that is a homolog of the tonoplast water channel protein TIP. AB - Plant cells contain proteins that are members of the major intrinsic protein (MIP) family, an ancient family of membrane channel proteins characterized by six membrane-spanning domains and two asparagine-proline-alanine (NPA) amino acid motifs in the two halves of the protein. We recently demonstrated that gamma-TIP, one of the MIP homologs found in the vacuolar membrane of plant cells, is an aquaporin or water channel protein (C. Maurel, J. Reizer, J.I. Schroeder, M.J. Chrispeels [1993] EMBO J 12: 2241-2247). RD28, another MIP homolog in Arabidopsis thaliana, was first identified as being encoded by a turgor-responsive transcript. To find out if RD28 is a water channel protein, rd28 cRNA was injected into Xenopus laevis oocytes. Expression of RD28 caused a 10- to 15-fold increase in the osmotic water permeability of the oocytes, indicating that the protein creates water channels in the plasma membrane of the oocytes and is an aquaporin just like its homology gamma-TIP. Although RD28 has several cysteine residues, its activity is not inhibited by mercury, and in this respect it differs from gamma-TIP and all but one of the mammalian water channels that have been described. Introduction of a cysteine residue next to the second conserved NPA motif creates a mercury-sensitive water channel, suggesting that this conserved loop is critical to the activity of the protein. Antibodies directed at the C terminus of RD28 were used in combination with a two-phase partitioning method to demonstrate that RD28 is located in the plasma membrane. The protein is present in leaves and roots of well-watered plants, suggesting that its presence in plants does not require a specific desiccation regime. These results demonstrate that plant cells contain constitutively expressed aquaporins in their plasma membranes (RD28), as well as in their tonoplasts (gamma-TIP). PMID- 7846152 TI - Molecular genetics of the maize (Zea mays L.) aspartate kinase-homoserine dehydrogenase gene family. AB - Aspartate kinase (AK) and homoserine dehydrogenase (HSDH) are enzymes in the aspartate-derived amino acid biosynthetic pathway. Recent biochemical evidence indicates that an AK-HSDH bifunctional enzyme exists in maize (Zea mays L.). In this report, we characterize three genes that encode subunits of AK-HSDH. Two cDNAs, pAKHSDH1 and pAKHSDH2, containing the full-coding sequence, and one partial cDNA, pAKHSDH3, encode amino acid sequences similar to the reported monofunctional AK and HSDH enzymes from prokaryotes and yeast (Saccharomyces cerevisiae) and to AK-HSDH bifunctional enzymes of prokaryotes, yeast, carrot (Daucus carota), and Arabidopsis thaliana. Immunological and biochemical analyses verify that the cDNAs encode AK-HSDH and indicate that both the AK and HSDH activities are feedback inhibited by threonine. RNA blots identify a 3.2-kb transcript in all maize tissues examined. pAKHSDH1 and pAKHSDH2 map to chromosomes 4L and 2S, respectively. This study shows that maize contains AK-HSDH bifunctional enzyme(s) encoded by a small gene family of at least three genes. Maize AK-HSDH has conserved sequences found in communication modules of prokaryotic two-component regulatory systems, which has led us to propose that maize AK-HSDH may be involved in a similar regulatory mechanism. PMID- 7846154 TI - Metabolic regulation of the gene encoding glutamine-dependent asparagine synthetase in Arabidopsis thaliana. AB - Here, we characterize a cDNA encoding a glutamine-dependent asparagine synthetase (ASN1) from Arabidopsis thaliana and assess the effects of metabolic regulation on ASN1 mRNA levels. Sequence analysis shows that the predicted ASN1 peptide contains a purF-type glutamine-binding domain. Southern blot experiments and cDNA clone analysis suggest that ASN1 is the only gene encoding glutamine-dependent asparagine synthetase in A. thaliana. The ASN1 gene is expressed predominantly in shoot tissues, where light has a negative effect on its mRNA accumulation. This negative effect of light on ASN1 mRNA levels was shown to be mediated, at least in part, via the photoreceptor phytochrome. We also investigated whether light induced changes in nitrogen to carbon ratios might exert a metabolic regulation of the ASN1 mRNA accumulation. These experiments demonstrated that the accumulation of ASN1 mRNA in dark-grown plants is strongly repressed by the presence of exogenous sucrose. Moreover, this sucrose repression of ASN1 expression can be partially rescued by supplementation with exogenous amino acids such as asparagine, glutamine, and glutamate. These findings suggest that the expression of the ASN1 gene is under the metabolic control of the nitrogen to carbon ratio in cells. This is consistent with the fact that asparagine, synthesized by the ASN1 gene product, is a favored compound for nitrogen storage and nitrogen transport in dark-grown plants. We have put forth a working model suggesting that when nitrogen to carbon ratios are high, the gene product of ASN1 functions to re-direct the flow of nitrogen into asparagine, which acts as a shunt for storage and/or long-distance transport of nitrogen. PMID- 7846155 TI - The maize (Zea mays L.) Cat1 catalase promoter displays differential binding of nuclear proteins isolated from germinated and developing embryos and from embryos grown in the presence and absence of abscisic acid. AB - We previously demonstrated that amounts of Cat1 RNA in developing immature maize (Zea mays L.) embryos change in parallel with endogenous abscisic acid (ABA) content. In excised immature embryos, addition of ABA leads to a large increase in Cat1 RNA accumulation. The Cat1 transcript, however, also accumulates to high amounts in scutella of germinating embryos, where ABA content is low and decreasing. Here we show that application of ABA to germinated embryos no longer results in the up-regulation of the Cat1 transcript accumulation that is seen during embryogenesis. This suggests that factors other than ABA control Cat1 expression at this developmental stage. Using band-shift and southwestern analyses, we show that the change in sensitivity to ABA is paralleled by changes in nuclear proteins binding to a 28-bp region of the Cat1 promoter in vitro. One protein (CAT1BP-20) shows increased accumulation in the absence of ABA, suggesting that a repressor-mediated mechanism accounts for at least a portion of the ABA regulation of Cat1. PMID- 7846156 TI - A 42-kilodalton annexin-like protein is associated with plant vacuoles. AB - A 42-kD, calcium-dependent, membrane-binding protein (VCaB42) was associated with partially purified vacuole membrane. Membrane-dissociation assays indicated that VCaB42 binding to vacuole membranes was selective for calcium over other cations and that 50% of VCaB42 remained membrane bound at 61 +/- 11 nM free calcium. A 13 amino acid sequence obtained from VCaB42 showed 85% similarity with the endonexin fold, a sequence found in the annexin family of proteins that is thought to be essential for calcium and lipid binding. The greatest similarity in amino acid sequence was observed with annexin VIII (VAC-beta). The calcium-binding properties and sequence similarities suggest that VCaB42 is a member of the annexin family of calcium-dependent, membrane-binding proteins. Functional assays for VCaB42 on vacuole membrane transport processes indicated that it did not significantly affect the initial rate of calcium uptake into vacuole membrane vesicles. Because VCaB42 is vacuole localized (likely on the cytosolic surface of the vacuole) and is 50% dissociated within the physiological range of cytosolic free calcium, we hypothesize that this protein is a sensor that monitors cytosolic calcium levels and transmits that information to the vacuole. PMID- 7846157 TI - Deletion of the structural gene for the NADH-dehydrogenase subunit 4 of Synechocystis 6803 alters respiratory properties. AB - Chloroplasts and cyanobacteria contain genes encoding polypeptides homologous to some subunits of the mitochondrial respiratory NADH-ubiquinol oxidoreductase complex (NADH dehydrogenase). Nothing is known of the role of the NADH dehydrogenase complex in photosynthesis, respiration, or other functions in chloroplasts, and little is known about the specific roles of the perhaps 42 subunits of this complex in the mitochondrion. Inactivation of a gene for subunit 4 (ndhD-2, ndh4) of this complex in the cyanobacterium Synechocystis 6803 has no effect on photosynthesis, judging from the rate of photoautotrophic growth of mutant cells, but the mutant's respiratory rate is about 6 times greater than that of wild-type cells. Respiratory electron transport activity in cyanobacteria is associated both with photosynthetic thylakoid membranes and with the outer cytoplasmic membrane of the cell. Cytoplasmic membranes of mutant cells have much greater NADH-dependent cytochrome reductase activity than preparations from wild type cells; this activity remains at wild-type levels in isolated thylakoid membranes. It is suggested that the 56.6-kD product of ndhD-2 is not essential for the activity of a cytoplasmic membrane-bound NADH dehydrogenase but that it regulates the rate of electron flow through the complex, establishing a link between this ndh gene and respiration. The activity of the molecularly distinct thylakoid-bound NADH dehydrogenase is apparently unaffected by the loss of ndhD 2. PMID- 7846158 TI - Identification of a gene that complements an Arabidopsis mutant deficient in chloroplast omega 6 desaturase activity. AB - Membrane lipids of the fad6 (formerly fadC) mutant of Arabidopsis, which is deficient in chloroplast omega 6 desaturase activity, have increased levels of monounsaturated fatty acids and are deficient in trienoic fatty acids. A putative fad6 cDNA clone was isolated by probing a cDNA library with a degenerate oligonucleotide based on a conserved region within known omega 3 desaturase genes. Expression of the cDNA in transgenic plants of a fad6 mutant restored normal levels of all fatty acids. When used as a hybridization probe, the cDNA identified a restriction fragment-length polymorphism that co-segregated with the fad6 mutation. Thus, on the basis of a genetic complementation test and genetic map position, the fad6 gene is encoded by the cDNA. The cDNA encoded a 418-amino acid polypeptide of 47,727 D that displayed a high degree of sequence similarity to a delta 12 desaturase from the cyanobacterium Synechocystis. The fad6 gene exhibited less sequence homology to any known higher plant desaturase, including an endoplasmic reticulum-localized omega 6 desaturase corresponding to the Arabidopsis fad2 gene. PMID- 7846160 TI - Specificity of hydrolysis of phytic acid by alkaline phytase from lily pollen. AB - Phytases are the primary enzymes responsible for the hydrolysis of phytic acid, myo-inositol-1,2,3,4,5,6-hexakisphosphate (I-1,2,3,4,5,6-P6). A number of phytases with varying specificities, properties, and localizations hydrolyze phytic acid present in cells. The specificity of hydrolysis of phytic acid by alkaline phytase from lily (Lilium longiflorum L.) pollen is described. Structures of the intermediate inositol phosphates and the final product were established by a variety of nuclear magnetic resonance techniques (1H-, 31P-, and 31P-1H-detected multiple quantum coherence spectroscopy, and total correlation spectroscopy). On the basis of the structures identified we have proposed a scheme of hydrolysis of phytic acid. Initial hydrolysis of the phosphate ester occurs at the D-5 position of phytic acid to yield the symmetrical I-1,2,3,4,6 P5. The two subsequent dephosphorylations occur adjacent to the D-5 hydroxyl group to yield I-1,2,3-P3 as the final product. Alkaline phytase differs from other phytases in the specificity of hydrolysis of phosphate esters on the inositol ring, its high substrate specificity for phytic acid, and biochemical properties such as susceptibility to activation by calcium and inhibition by fluoride. The physiological significance of alkaline phytase and the biological role of I-1,2,3-P3 remain to be identified. PMID- 7846159 TI - Characterization and expression of an antifungal zeamatin-like protein (Zlp) gene from Zea mays. AB - A cDNA clone encoding a basic thaumatin-like protein of Zea mays was recovered from a mid-development seed cDNA library. The gene, Zlp, encoded a protein that was nearly identical with maize zeamatin and alpha-amylase/trypsin inhibitor. Expression of Zlp mRNA was highest in the endosperm tissue of seed 4 weeks after pollination. Expression of zeamatin-like (ZLP) protein correlated with mRNA; also, a low basal level of ZLP expression in leaf was not appreciably induced by abiotic stresses. ZLP was expressed with its own signal peptide in insect cells and in transgenic Arabidopsis and tomato plants. ZLP was secreted in all three systems, with correct processing of the signal peptide. ZLP expressed in transgenic tomato was found to be partially subjected to a proteolytic cleavage after residue 180, by an unknown mechanism, to give a "nicked" isoform of ZLP. Purified ZLP from all three sources, as well as purified "nicked" ZLP from tomato, demonstrated fungal inhibition against Candida albicans and Trichoderma reesei, with marginal inhibition observed against Alternaria solani and Neurospora crassa. PMID- 7846161 TI - The 30-kilodalton protein present in purified fusicoccin receptor preparations is a 14-3-3-like protein. AB - We have recently reported on the purification of the fusicoccin (FC) receptor from corn (Zea mays L.) and its identification by photoaffinity labeling (P. Aducci, A. Ballio, V. Fogliano, M.R. Fullone, M. Marra, N. Proietti [1993] Eur J Biochem 214: 339-345). Pure preparations of FC receptors, obtained under nondenaturing conditions, showed in sodium dodecyl sulfate-polyacrylamide gel electrophoresis two doublets of proteins with apparent molecular masses of 30 and 90 kD. In the present paper we describe the isolation and identification of the primary structure of the 30-kD doublet proteins. Sequencing studies of peptides resulting from the digestion of the 30-kD protein showed a full identity with a 14-3-3-like protein from corn, named GF14. The 14-3-3 family is a class of proteins that is widely distributed in eukaryotes and is known to play various regulatory roles. The 30-kD protein has been immunologically identified by specific antibodies prepared against a synthetic peptide based on the determined amino acid sequence. A similar protein is recognized in partially purified FC receptor preparations from bean and spinach leaves. PMID- 7846162 TI - Differential induction of mRNAs for the glycolytic and ethanolic fermentative pathways by hypoxia and anoxia in maize seedlings. AB - Fructose-1,6-biphosphate aldolase (ALD) and enolase (ENO) from the glycolytic pathway and pyruvate decarboxylase (PDC) and alcohol dehydrogenase 2 (ADH2) from the ethanolic fermentative pathway, are enzymes previously identified as among those synthesized selectively in O2-deficient roots of maize (Zea mays L.). The present study measured levels of transcripts representing these two pathways in 5 mm root tips, root axes (the remainder of the primary seminal root), and shoots of maize seedlings to determine how closely both pathways were co-induced and how they were modulated by changes in O2 concentration. In hypoxic seedlings with the roots in solution sparged with 5% (v/v) O2 (balance N2) and the shoots in the same gaseous atmosphere, mRNAs for Pdc1 and Adh2 in root tips both increased about 15-fold during the first 12 h, followed by a decline toward initial levels by 18 to 24h. Message levels for Ald1 and Eno1 showed only small changes during hypoxia. When expression was examined under anoxia, the extent to which all four mRNAs increased in different tissues depended on whether the seedlings had been previously acclimated to hypoxia or were anoxically shocked. The results show that although all the genes examined increased expression during hypoxia and/or anoxia, they differed in the rapidity and magnitude of the response and in the time to reach maximal message levels: there was no common pattern of change of message levels for the glycolytic or for the fermantative enzymes. PMID- 7846164 TI - Cloning of a temperature-regulated gene encoding a chloroplast omega-3 desaturase from Arabidopsis thaliana. AB - Previous genetic evidence suggested that the fad8 and fad7 genes of Arabidopsis thaliana encode chloroplast membrane-associated omega-3 desaturases. A putative fad8 cDNA was isolated by heterologous hybridization using a gene encoding an endoplasmic reticulum-localized omega-3 desaturase (fad3) as a probe. The cDNA encodes a protein of 435 amino acid residues with a molecular mass of 50,134 D. Constitutive expression of the cDNA in transgenic plants of a fad7 mutant resulted in genetic complementation of the mutation, indicating that the fad7 and fad8 gene products are functionally equivalent. Expression of the fad8 cDNA in transgenic plants often resulted in the co-suppression of both the endogenous fad7 and fad8 genes in spite of the fact that these two genes share only about 75% nucleotide identity. In contrast to all other known plant desaturases, including fad7, the steady-state level of fad8 mRNA is strongly increased in plants grown at low temperature. This suggests that the role of fad8 is to provide increased omega-3 desaturase activity in plants that are exposed to low growth temperature. The fad8-1 mutation created a premature stop codon 149 amino acids from the amino-terminal end of the fad8 open reading frame, suggesting that this mutation results in a complete loss of fad8 activity. PMID- 7846163 TI - Two genes encoding GF14 (14-3-3) proteins in Zea mays. Structure, expression, and potential regulation by the G-box binding complex. AB - Two maize (Zea mays) genes, designated GRF1 and GRF2, have been isolated and characterized. The proteins encoded by these genes, called GF14 proteins, participate in protein/DNA complexes and show more than 60% identity with a highly conserved, widely distributed protein family, collectively referred to as 14-3-3 proteins. Members of the 14-3-3 protein family have been reported to activate Tyr and Trp hydroxylases, modulate protein kinase C activity, and activate ADP-ribosyltransferase. The mRNAs of the GRF genes are encoded by six exons interrupted by five introns. The transcriptional units of the GRF genes were found to be very similar, with complete conservation of the intron positions. In addition, the length and nucleotide sequences of the two genes' introns were highly conserved. The 5' flanking sequences of the two GRF genes were compared and regions of homology and divergence identified. This comparison revealed the presence of a conserved G-box element in the 5' flanking region of both genes. Electrophoretic mobility shift assays of maize protein extract with the GRF G-box indicates that GBF binds to this G-box site in the 5' up stream region of GRF. Antibody supershifts indicate that GF14 protein is associated with the G-box-binding complex that interacts with the GRF upstream region. PMID- 7846165 TI - Structural features of the maize sus1 gene and protein. AB - Genomic clones, cDNA clones, and protein of the maize (Zea mays L.) Suc synthase1 (sus1) gene were isolated and sequenced. Termini (5' and 3') of the transcribed unit were identified. The SUS1 protein was purified from tissue culture cells as a phosphorylated protein. The overall structure of sus1 is virtually identical with that of the paralogous gene, shrunken1 (sh1); however, the last intron of sh1 is missing in sus1. This intron bears much sequence similarity with the adjacent exon, suggesting that the intron arose from an internal duplication. Although the placement of the other 14 introns is identical in both genes, the introns exhibit markedly greater differences in size and sequence relative to that shown by the exons. An explanation for the differential rate of divergence of exons and introns is selection pressure for gene function. Additionally, comparisons of coding regions of plant sucrose synthases show that sh1-like and sus1-like genes can be found in all monocots so far analyzed. These latter observations point to an important role played by both genes in this group of plants. PMID- 7846166 TI - Genomic nucleotide sequence of a proteinase inhibitor II gene. PMID- 7846167 TI - The aspartate aminotransferase-P2 gene from Lupinus angustifolius. PMID- 7846168 TI - Ribulose-1,5-bisphosphate carboxylase/oxygenase small subunit gene from the fern Pteris vittata. PMID- 7846169 TI - A cDNA encoding an HD-zip protein from sunflower. PMID- 7846170 TI - The gene c-ino1 from Citrus paradisi is highly homologous to tur1 and ino1 from yeast and Spirodela encoding for myo-inositol phosphate synthase. PMID- 7846171 TI - Genomic sequence of a calnexin homolog from Arabidopsis thaliana. AB - Calnexin is a membrane-bound protein of the ER in animal cells (Wada et al., 1991). It shows considerable similarity to the major calcium-sequestering protein of the ER lumen, calreticulin, with two calcium-binding regions--a high-affinity, low-capacity region in the ER lumen and a low-affinity, high-capacity region in the cytoplasm. The protein is postulated to act as a calcium-regulated chaperone during protein maturation (Ou et al., 1993). We have isolated a genomic sequence showing significant homology to the animal gene over the predicted coding sequence (Table I). A partial cDNA from Zea mays was isolated from an expression library made from 6-d coleoptiles (Clontech, Palo Alto, CA). The library was screened using a monoclonal antibody raised against a small number of microsomal proteins resulting from a partial purification of plasma membrane Ca2+ ATPase (Briars et al., 1988). The partial cDNA showed sequence homology to the calcium binding region common to calreticulin and calnexin. The fragment was used to screen a genomic library constructed from Arabidopsis thaliana (cv Larasbonerecta), and a 15-kb fragment was isolated and subcloned and the relevant subfragments were sequenced. The coding region contains five introns, two in the N-terminal region and three in the C-terminal region. The predicted amino acid sequence shows a high level of homology with the animal calnexin, although the terminal highly acidic calcium-binding region is shorter. A cDNA for a putative homolog of calnexin was isolated from A. thaliana (cv Columbia) by Huang et al.(1993); our coding sequence shows 85% identity and 92% similarity determined by FASTA (Wisconsin Genetics Computer Group package); however, the differences are greater than would be expected between cultivars of the same species. A Southern blot probed with DNA from the central calcium-binding region shows multiple bands. This, combined with the sequence heterogeneity, suggests that calnexin belongs to a family of related genes. PMID- 7846172 TI - Characterization of cDNAs corresponding to two Lhca4 alleles from Scots pine (Pinus sylvestris). PMID- 7846173 TI - Characterization of a Lhcb5 cDNA from Scots pine (Pinus sylvestris). PMID- 7846174 TI - Nucleotide sequence of a rice genomic pyruvate decarboxylase gene that lacks introns: a pseudo-gene? PMID- 7846175 TI - Genomic nucleotide sequence of tomato Asr2, a second member of the stress/ripening-induced Asr1 gene family. PMID- 7846176 TI - Characterization of a DNA Topoisomerase II cDNA from Arabidopsis thaliana. PMID- 7846177 TI - Nucleotide sequence of a tomato psbS gene. PMID- 7846179 TI - ERD15, a cDNA for a dehydration-induced gene from Arabidopsis thaliana. PMID- 7846178 TI - Nucleotide sequence and developmental expression of duplicated genes encoding protein disulfide isomerase in barley (Hordeum vulgare L.). PMID- 7846180 TI - Nucleotide sequence of a maize cDNA for a class II, acidic beta-1,3-glucanase. PMID- 7846181 TI - New members of the barley Kas gene family encoding beta-ketoacyl-acyl carrier protein synthases. PMID- 7846182 TI - Nucleotide sequence of a cDNA from Carthamus tinctorius encoding a glycerol-3 phosphate acyl transferase. PMID- 7846183 TI - A cDNA clone encoding a ferredoxin-NADP+ reductase from Chlamydomonas reinhardtii. PMID- 7846184 TI - Envy and malignant envy. AB - Envy begins early in psychic development and is initially characterized by destructive primal hatred. With maturation, envy becomes modified in intensity. Its primal murderous quality is attenuated, and, as object relationships develop, it becomes partly transformed into jealousy. Malignant envy is a retention of, or regression to, the original primal murderous affective mix. Clinically, one sees in malignant envy the phenomenon of the subject feeling with delusional intensity that what the envied one has is not only urgently wanted but has been stolen from the self--an intensity that is reacted to defensively by projection and delusion formation. This operates as a formidable resistance in analytic work. PMID- 7846185 TI - A psychoanalyst looks at a hypnotist: a study of folie a deux. AB - This paper traces my personal development from anesthetist to hypnotist, psychotherapist, and, finally, psychoanalyst. The change was precipitated by the successful treatment of a patient with congenital organic skin disease by hypnotism. Alongside my change of profession, I attempt to illustrate my change of ideas and the change of my relationship to patients which accompanies these other changes. I feel that my personal experience throws some light on the nature of suggestion and hypnotism and how they differ from each other and from psychoanalysis. I believe that observations support the idea that hypnotism is a folie a deux caused by mutual projective identification between two people and that in a less dramatic form this condition commonly occurs in normal development as well as in pathological psychological states. Several cases illustrate these ideas. PMID- 7846186 TI - A perspective on doing a consultation and making the recommendation of analysis to a prospective analysand. AB - This paper explores the premise that the analyst's optimistic attitude toward the efficacy of analysis significantly enhances the possibility of success in helping prospective analysands accept the recommendation of analysis. This enthusiastic attitude reflects the author's opinion that analysis is the optimal treatment, the best form of psychotherapy for most adults. From this perspective, all patients seen in consultation are regarded as analyzable; this attitude is maintained until a prospective analysand proves he/she is unanalyzable in a trial of analysis. Analytic data from six consultations conducted from this perspective are presented and discussed. PMID- 7846187 TI - Intuition and consciousness. AB - Intuition represents an unconscious cognitive activity, the results of which become conscious at some point. Some recent nonpsychoanalytic explorations of cognition and consciousness are examined to illuminate our understanding of these processes and their relation to the psychoanalytic process. Our thesis is that intuition may be most usefully viewed as a form of unconscious pattern-matching cognition, which becomes conscious under certain conditions and which is only loosely related to primary process. A clinical example is given of the analyst's intuition to illustrate the initial ostensibly theory-free nature of the raw intuition and the subsequent theory-bound explorations of the intuitive conclusion. Implications for teaching and learning psychoanalysis are noted. PMID- 7846188 TI - Dissolving the myth of the unified self: the fate of the subject in Freudian analysis. AB - Employing Lacan's conception of desire, this paper explores the distinction between self and subjectivity as it emerges in the psychoanalytic situation. Challenging the notion of the self as a singular, coherent, and bounded entity, I demonstrate, through a review of Dora's case, that the "Freudian subject" is a cast of characters, a loose net of contextual, contradictory, and shifting identifications enveloping not a discrete core, but its very absence. PMID- 7846189 TI - Asclepius: magic in transference to physicians. AB - Transference to physicians contains a fantasy of the physician as omnipotent healer who can control life and death. While there may be many variations of the fantasy that reflect differences in individual psychological makeup and experience, the fantasy of a multipotentialed, bisexual figure who can magically control the forces of nature is probably an element in all transference wishes that occur in a therapeutic setting. Material from the myth of Asclepius, from a patient of Freud's, and from two of the author's patients will be examined to elucidate this transference fantasy. PMID- 7846190 TI - A quantitative theory of acute tolerance to alcohol. AB - A theory of acute tolerance to alcohol is proposed that includes two assumptions: 1) acute tolerance is a linear process with time, and 2) the slope of the line is a measure of the magnitude of the acute tolerance effect. Evidence that supports the validity of the theory is presented both from studies in which blood alcohol level (BAL) was manipulated experimentally and from studies based on the one-dose method that is common in human research. The slope of the acute tolerance line defined by this theory is a measure of the percent decrement in maximum alcohol effect per unit time. Thus, quantitative comparisons can be made of acute tolerance effects obtained under different environmental conditions or experimental treatments, including comparisons of different drugs. Limitations of the proposed theory and the relation of this theory to other theories of tolerance to alcohol are discussed. PMID- 7846191 TI - Diazepam withdrawal: effects of diazepam and gepirone on acoustic startle-induced 22 kHz ultrasonic vocalizations. AB - It has proven difficult to demonstrate and study the "anxiogenic" quality of drug withdrawal states in animals. Ultrasonic vocalizations (USV) in response to acoustic startle stimuli have shown promise as a measure of affect and may represent "distress" responses during diazepam withdrawal. Three experiments evaluated the association between USV and "distress" by comparing the effects of diazepam as a prototypic benzodiazepine agonist and the putative anxiolytic gepirone with affinity for 5-hydroxytryptamine (5-HT1A) receptors in naive and diazepam-withdrawn subjects. Adult male Long-Evans rats were exposed to acoustic startle sessions consisting of nine 105 dB and nine 115 dB stimuli. USV at 20-30 kHz were readily emitted during startle and often commenced after the third or fourth stimulus presentation. Acutely, intraperitoneal (IP) administration of diazepam (0.1-3 mg/kg) and gepirone (0.1-1 mg/kg) decreased USV dose-dependently without affecting the startle reflex; gepirone also decreased tail flick latency. Startle-induced USV were also sensitive to the "anxiogenic" effects of withdrawal from diazepam exposure (0, 2.5, 5, 10 mg/kg b.i.d. IP x 5 days). Twenty-four hours after the last diazepam injection, rats were hyperreactive to startle stimuli and doubled their rate of USV over vehicle-treated controls. Gepirone (0.1-1 mg/kg IP), but not diazepam (3-20 mg/kg IP) antagonized the increased rate of USV in rats withdrawn from 10 mg/kg b.i.d. diazepam. Diazepam (2.5-10 mg/kg IP) antagonized the increased rate of USV in rats withdrawn from 2.5 mg/kg b.i.d. diazepam.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7846192 TI - Effects of oxazepam on eye movements and performance in vigilance tasks with static and dynamic stimuli. AB - The aim of the present study was to determine whether in a task with stimuli inducing frequent saccadic eye movements, ingestion of oxazepam impairs performance more than in a task in which the stimuli remained fixed at the same location, due to effects of oxazepam on the ocular system. Eighteen males performed a vigilance task with static and dynamic stimuli under the influence of oxazepam (20 and 40 mg) in a placebo-controlled, double blind, crossover design. Oxazepam (40 mg) had a larger effect on vigilance performance in the first part of the dynamic task, relative to its static counterpart. Oxazepam also had an effect on oculomotor behavior, but this effect was unrelated to impaired performance. There were dose-dependent effects of oxazepam on absolute, overall level of performance but not on the decrement with time. The non-dose-dependent aggravation of the decrement in correct detections, caused by the drug, could only partly be accounted for by pharmacokinetics and increased eyelid closures, and was also caused by pharmacodynamic effects of the drug, such as those on attention. Different effects were noted for the two signal detection measures of response behavior, B" and RI. PMID- 7846193 TI - Post-stroke depression: combined treatment with imipramine or desipramine and mianserin. A controlled clinical study. AB - In a 6-week study the efficacy of combined treatment of imipramine plus mianserin was compared to combined treatment of desipramine plus mianserin in patients with post-stroke depression. Patients were required to have a minimum baseline total score of 15 on the 17-item Hamilton Depression Scale (HAMD). The Melancholia Scale (MES) was also used to measure severity of depressive states to show that somatic symptoms had little influence on the evaluation of depression. Out of 120 stroke patients screened, 20 patients fulfilled the inclusion criteria. The doses of the drugs were flexible, using side-effects as a guide during treatment. Both intention to treat analysis and efficacy data (excluding patients who had dropped out during the first 2 weeks of treatment) showed that imipramine (mean dose 75 mg daily) plus mianserin (mean dose 25 mg daily) was superior to desipramine (mean dose 66 mg daily) plus mianserin (27 mg daily). The MES was found to be more sensitive than the HAMD for measuring change in depressive states during treatment. The assessment of side-effects using the UKU scale showed good tolerance in general. The only difference between the two treatment groups was seen in micturition disturbances, where the imipramine treated patients had most complaints after 14 days of treatment, but the symptoms disappeared despite continuous treatment. PMID- 7846194 TI - Atypical antipsychotics, clozapine and sulpiride do not antagonise amphetamine induced stereotyped locomotion. AB - An automated tracking system which converted an animal's path between quadrants of a circular open field into a series of trips was used to analyse stereotyped locomotion in amphetamine treated rats. Amphetamine (3.5 mg/kg) increased the horizontal distance moved and the number and proportion of thigmotaxic trips around the perimeter of the apparatus (length 4 trips). To investigate the hypothesis that classic antipsychotics, but not atypical antipsychotics, would antagonise the repetitive boundary patrolling associated with amphetamine-induced hyperactivity, animals were pretreated with haloperidol (0.01, 0.025, 0.05, 0.075 mg/kg), clozapine (5, 10, 20 mg/kg) or (+/-)sulpiride (10, 20, 50 mg/kg) 30 min before 3.5 mg/kg amphetamine. The results showed that the classic antipsychotic haloperidol antagonised both hyperactivity and the increased proportion of length 4 trips. In marked contrast, the atypical antipsychotics clozapine and sulpiride antagonised hyperactivity but did not reduce the proportion of length 4 trips. The inability of atypical antipsychotics to reduce the repetitive boundary patrolling associated with amphetamine-induced hyperactivity is consistent with the action of these drugs on other forms of amphetamine-induced stereotyped behaviour, and indicates that locomotor routes under amphetamine are stereotyped. The measurement of trip lengths provides a sensitive tool for examining drug action on the spatial distribution of open field locomotion. PMID- 7846195 TI - Controlled comparison of milnacipran and fluoxetine in major depression. AB - The efficacy and the tolerance of milnacipran (100 mg/day), a second generation antidepressant which equipotently inhibits both noradrenaline and serotonin reuptake, was compared to fluoxetine (20 mg/day), a selective serotonin reuptake inhibitor, in two parallel groups of, respectively, 97 and 93 major depressive outpatients. The duration of the study was 6 weeks, with assessments every 2 weeks by means of the Montgomery and Asberg depression scale (MADRS), the Hamilton depression scale, the clinical global impressions (CGI), and a checklist of symptoms and side-effects. Results showed significant superiority of fluoxetine over milnacipran on most rating instruments: MADRS (P = 0.01) including five individual items, Hamilton depression scale (P = 0.002) including ten individual items, CGI of severity (P = 0.01) and therapeutical index (P = 0.002). On visual analogue scales assessing the clinical profile of the compounds, fluoxetine was rated as exhibiting more psychostimulating activity than milnacipran (P = 0.0008). The tolerance of the two antidepressants was very similar, with the exception of symptoms of dizziness which were more frequently reported with milnacipran (P = 0.01). These differences in efficacy favoring fluoxetine could result from the selection of a dose of milnacipran below the optimal therapeutic dose for this type of psychiatric patients or to the administration of the compounds in single daily intakes, whereas milnacipran possesses a plasma elimination half-life of only 7 h. PMID- 7846196 TI - EEG profile of intravenous zolpidem in healthy volunteers. AB - Zolpidem is an imidazopyridine which binds specifically to the omega 1 receptor. Zolpidem demonstrated potent hypnotic activity at a dose of 10 mg. Pharmacodynamics and pharmacokinetics of zolpidem were studied after daytime administration in a randomised, double-blind, placebo-controlled, cross-over trial. Single doses of zolpidem (10 mg IV as a 3-min infusion and 20 mg orally) and placebo were firstly tested in 12 healthy young male volunteers. Two other doses (5 mg IV and orally) were then evaluated in 6 out of these 12 subjects. EEG (4 leads = Fp2-T4, Fp1-T3, T4-02 and T3-01), and Stanford Sleepiness Scale (SSS) were measured up to 5 h postdosing. Blood samples were also collected up to 24 h. The time course of the hypnotic activity of zolpidem, assessed by the score obtained on SSS, showed a similar profile whatever the route or the dose administered: slightly earlier onset after IV but sedative scores were reached at 30 min and the effect peaked between 1 and 1.5 h and lasted 4 h in both conditions. The EEG profile of zolpidem was characterised by a decrease of alpha activity and an increase in delta and in beta activity. The effect on beta activity was marked within the first hour and then disappeared. The time course of delta and alpha activities indicated a rapid onset (10 min after IV, 30 min after oral route) and a duration of 3-4 h. The amplitude of these relative EEG changes and their duration were independent of the route of administration and the dose administered. AUC and Cmax increased proportionally to the administered dose and elimination half life (2h), clearance and volume of distribution did not change according to the dose or the route of administration.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7846197 TI - Effect of smoking cessation and relapse on cardiovascular levels and reactivity. AB - This study was designed to investigate the effect of smoking cessation on heart rate, blood pressure, and finger temperature absolute levels and reactivity to a range of laboratory challenges. The 148 quitters (mean age = 43.3 years, mean amount smoked = 24.9 cigarettes per day, mean years smoked = 25.2) completed three assessments: an average of 4 +/- 2.8 days before cessation (Exam 1), an average of 2 +/- 1.0 days after cessation (Exam 2), and an average of 20 +/- 5.5 days after cessation (Exam 3). A nonsmoking group (n = 39) was similarly assessed three times to control for effects related to repeated testing. Comparison of group changes from Exam 1 to Exam 2 indicated that smoking cessation produced a significant decrease in heart rate during rest and during all stressors (mean = 8.9 bpm). Those quitters who remained abstinent or smoked occasionally showed minimal changes in heart rate from Exam 2 to Exam 3, but those quitters who returned to their previous smoking level showed a significant increase in heart rate from Exam 2 to Exam 3. None of the indices of cardiovascular reactivity changed across exams, and neither did absolute levels of blood pressure or finger temperature at rest or during stressors. The possible mechanisms producing a selective heart rate decline after smoking cessation in the absence of pressor or vasodilation effects are discussed. PMID- 7846198 TI - Effects of ipsapirone in healthy subjects: a dose-response study. AB - A dose-response study of ipsapirone (IPS), a 5HT1a partial agonist, was conducted in healthy male subjects. IPS was administered in doses of 5, 10 and 20 mg PO in a placebo-controlled, double-blind design to 15 subjects on 4 test days separated by at least 3 days. Oral temperature, ACTH, cortisol, prolactin, blood pressure, pulse rate and behavioral variables were assessed every 30 min for 3 h after administration of tablets (at 10:00 A.M.). IPS at 20 mg significantly decreased temperature and increased cortisol levels. Although IPS increased ACTH levels at 20 mg, this effect was variable and not significant. IPS did not affect prolactin levels nor did it have any behavioral effects. Although 20 mg IPS decreased blood pressure and pulse rate in one subject, overall it had no significant effect on these parameters. IPS at 20 mg PO appears a useful probe to test 5HT1a function when temperature and cortisol are used as response variables. These results replicate earlier studies on the effect of IPS in healthy human subjects. PMID- 7846199 TI - Effects of ethanol on the acoustic startle reflex in humans. AB - The effect of ethanol on human sensorimotor reactivity was assessed by examining the acoustic startle response. Twelve healthy normal subjects participated in a startle reflex experiment in which placebo or ethanol were given on separate days. Three types of startle probes were used. They consisted of pulse-alone bursts of white noise at 108 dB(A) and 99 dB(A) to explore startle reactivity, and of a 108 dB(A) pulse preceded by a 85 dB(A) prepulse stimulus (prepulse+pulse) to assess prepulse inhibition. Startle amplitude was larger to the 108 dB(A), compared to the 99 dB(A) pulse-alone probes. The prepulse stimulus significantly reduced the amplitude of the startle reflex elicited by the subsequent 108 dB(A) stimulus. The amplitude of the startle response was dramatically reduced by acute ethanol. The effects of ethanol on prepulse inhibition could not be assessed because the startle response was too small in the ethanol condition. PMID- 7846200 TI - Effect of selective 5-HT1A agonists and 5-HT2 antagonists on inherited catalepsy in rats. AB - The effects of the selective 5-HT1A agonists 8-OH-DPAT and flesinoxan and the selective 5-HT2 antagonists ritanserin and ketanserin on immobility time in rats bred for predisposition to catalepsy have been studied. Treatment with 8-OH-DPAT as well as flesinoxan caused a marked dose-dependent decrease in immobility time. Ritanserin and ketanserin did not affect immobility time at any dose tested. It was suggested that 5HT1A rather than 5-HT2 serotonin receptors are involved in the catalepsy and that an hereditary predisposition to catalepsy may be the result of an inherited alteration in 5-HT1A receptors. PMID- 7846201 TI - Blockade of neurotensin-induced motor activity by inhibition of protein kinase. AB - The administration of neurotensin into the ventral tegmental area stimulates dopamine neurons and locomotor activity. Furthermore, when neurotensin is microinjected daily into the ventral tegmental area the motor stimulant response increases. The role of protein kinases in the motor stimulant effect of neurotensin was evaluated by coadministration of the protein kinase inhibitors H8 and H7 into the ventral tegmental area with neurotensin. It was found that the acute motor stimulant effect of neurotensin was abolished in a dose-dependent fashion by H8 coadministration. Neurotensin-induced activity was also blocked by H7. However, acute motor stimulation following microinjection of the mu opioid, Tyr-d-Ala-Gly-MePhe-Gly(ol) or the potassium channel antagonist apamin into the ventral tegmental area was not affected by coadministration with H8. The behavioral sensitization produced by daily neurotensin microinjection into the ventral tegmental area was also prevented by the coadministration of H8. These data indicate that the motor stimulation produced by acute and repeated neurotensin microinjection into the ventral tegmental area is dependent upon activation of protein kinase(s). Furthermore, Tyr-d-Ala-Gly-MePhe-Gly(ol) and apamine elicit locomotion independently of protein kinase(s). PMID- 7846202 TI - Research diagnostic criteria for drug-induced akathisia: conceptualization, rationale and proposal. AB - This paper argues for consistency in the conceptualization and definition of drug induced akathisia (DIA), something found lacking in published research reports. It suggests the adoption of a common set of provisional categories with operationally defined diagnostic criteria. The categories proposed are acute, tardive, withdrawal and chronic DIA, with overlap of chronic DIA with the other three. The prerequisites for diagnosis are drug exposure, the presence of characteristic clinical features and the exclusion of non-drug causes. The frequency of the clinical features, and their nature, determine the level of certainty. A decision regarding severity is made independently of diagnostic certainty. Some ways of testing the usefulness and validity of these definitions are discussed. PMID- 7846203 TI - Flumazenil has an anxiolytic effect in simulated stress. AB - This study was designed to test whether or not flumazenil (1 mg IV) would change levels of anxiety induced by simulation of public speaking (PSS). Forty normal volunteers were randomly allocated in a parallel groups design to treatment with flumazenil or placebo (double-blind) and one of two stress conditions (PSS/control task). PSS increased anxiety and flumazenil antagonized this effect. The anxiolytic activity of flumazenil was particularly strong on anticipatory anxiety measures. The results were discussed in terms of the involvement of endogenous benzodiazepine-type ligands in the regulation of the human response to stress. PMID- 7846204 TI - A long-term cross-over pharmacokinetic study comparing perphenazine decanoate and haloperidol decanoate in schizophrenic patients. AB - The purpose of the study was to investigate clinical and pharmacokinetic parameters concerning perphenazine decanoate (PD) and haloperidol decanoate (HD) with an interval of 3 weeks during a study period of 51 weeks. This was done by using the available drug preparations in chronic schizophrenic patients in a randomised, double-blind, cross-over, multicentre study. In addition, an elimination phase of 6 weeks was added, when no IM injections of the depot drugs were given. Twenty-nine patients in a stable neuroleptic maintenance phase entered the study. The patients were rated during the trial according to the CPRS SCHZ and CGI scales, the UKU side effect scale and serum concentrations of the drugs and prolactin were monitored. There was no significant difference between the drugs in antipsychotic efficacy or side effects. Thus, the doses were equipotent with regard to the CPRS-SCHZ scores. However, the patients' global improvement rating was higher for PD (52%) than for HD (39%) (P > 0.05). The elimination of both drugs was very slow. No interaction effects between PD and HD were observed. The serum levels of HD were in most patients lower than those recommended for acute-subacute treatment. The mean doses were 117 mg (0.29 mmol), range 20-313 mg PD and 120 mg (0.32 mmol), range 20-350 mg HD. The serum concentrations in nmol/L of perphenazine and haloperidol (week 24) were 0.8-15.9 and 2.3-46.7, respectively. PMID- 7846205 TI - An open clinical and biochemical study of ritanserin in acute patients with schizophrenia. AB - The effect of the selective serotonin-2 antagonist ritanserin was investigated in an open study of patients with schizophrenia. The patients were in an acute psychotic state considered to require neuroleptic medication. No neuroleptic drug was allowed during the study or during the last month preceeding the study. Oxazepam or nitrazepam were allowed for sedation or sleep inducement. Safety, tolerability, potential antipsychotic effect, and drug effects on monoamine metabolites in serum and CSF and prolactin in serum were evaluated. Central D2 dopamine receptor occupancy was determined by positron emission tomography. Ten male patients (mean age 32.4) fulfilling DSM-III-R criteria for schizophrenia were included in the study. Nine of these patients completed 4 weeks' treatment with ritanserin 10 mg b.i.d. The clinical effect was evaluated by means of CPRS and SANS and significant improvement was seen after 4 weeks' treatment both in positive and negative symptoms. Ritanserin was well tolerated and no extrapyramidal symptoms or akathisia were seen. Concentrations of monoamine metabolites and prolactin did not change during treatment. Ritanserin did not occupy D2-dopamine receptors. Thus, no indications of any D2-dopamine antagonistic activity were obtained. All patients had expected ritanserin levels in plasma during the whole study. This first study of a selective serotonin-2 antagonist in the treatment of acute schizophrenic patients demonstrated significant clinical effects. However, the open design of the study does not allow us to conclude with any certainty that the patients' improvement was due to a specific blockade of serotonin-2 receptors or unspecific factors, although a direct D2-dopamine blockade could be ruled out. PMID- 7846206 TI - Buspirone, gepirone, ipsapirone, and zalospirone have distinct effects on the differential-reinforcement-of-low-rate 72-s schedule when compared with 5-HTP and diazepam. AB - The effects of four serotonin (5-HT)-1A compounds (buspirone, gepirone, ipsapirone and zalospirone) were compared with 5-hydroxytryptophan (5-HTP) [a 5 HT precursor with antidepressant (AD) efficacy], and diazepam (a benzodiazepine anxiolytic), on a differential-reinforcement-of-low-rate 72-s (DRL 72-s) schedule. Past research has shown that AD and anxiolytic compounds each have distinct effects on the DRL 72-s interresponse time (IRT) distribution profile. In the present paper, the profile of the IRT distribution was quantitatively characterized by three metrics: burst ratio, peak location and peak area. 5-HTP shifted the IRT distribution peak toward longer IRT durations, increased reinforcement rate and decreased response rate. The profile of the IRT distribution was not disrupted by 5-HTP. Diazepam disrupted the IRT distribution and increased bursting. In general, the arylpiperazine, 5-HT1A compounds increased reinforcement rate, decreased response rate and disrupted the profile of the IRT distribution. The effects of the four arylpiperazine 5-HT1A compounds on the IRT distribution profile were different from the AD profile of 5-HTP and the benzodiazepine anxiolytic profile of diazepam. Disruption of the IRT distribution by buspirone, gepirone, ipsapirone and zalospirone may result from decreased 5-HT transmission mediated by the presynaptic, somatodendritic 5-HT1A receptor. PMID- 7846208 TI - Non-contingent electric footshock facilitates the acquisition of intravenous cocaine self-administration in rats. AB - The experiments described below were designed to investigate whether contingent versus non-contingent electric footshock would affect the acquisition of intravenous cocaine self-administration in rats. During the first component of a multiple schedule, triads of rats were trained to respond under a discrete-trial, fixed-ratio 10 schedule of food reinforcement. Random footshock presentation (0.6 mA) for the first and second rats from each triad was yoked to food lever responding by the rats in the first group only, while the third group of rats was never shocked. When stable baselines of food-reinforced responding were obtained, all three rats from each triad were allowed to self-administer increasing doses of cocaine (0.031-0.5 mg/kg per infusion) during the second component. Rats from the second group, receiving non-contingent footshock presentation, self administered cocaine (0.125 mg/kg per infusion) at higher rates and at one-half the dose which maintained responding in rats from the other two treatment groups. Plasma corticosterone, measured before the acquisition of cocaine self administration, was highly correlated with drug intake at this concentration for all three groups of rats. These data demonstrate that non-contingent experimental stress facilities the acquisition of intravenous cocaine self-administration in rats. PMID- 7846207 TI - Spermine interacts with cocaine binding sites on dopamine transporters. AB - These studies were designed to assess the potential interaction of the polyamine spermine with cocaine binding to dopamine and serotonin transporters. The results of the experiments presented here indicate that spermine inhibits binding of the cocaine congener [3H] CFT to striatal synaptosomal membranes. Further, although [3H] CFT is known to interact with both dopamine and serotonin transporters, our results indicate that the observed inhibition of [3H] CFT binding is likely to reflect a specific inhibition of binding to dopamine transporters. Spermine significantly inhibited the binding of both [3H] CFT and [3H] mazindol to dopamine transporters, while it had no apparent effects on the binding of the potent serotonin uptake inhibitor [3H] paroxetine. Finally, saturation experiments show that the inhibition of ligand binding to the cocaine binding site on dopamine transporters appears not to be due to a modification of ligand affinity for the transporter, but to a decrease in the apparent density of ligand binding sites. The results of these experiments indicate that endogenously produced polyamines can alter cocaine binding to the dopamine transporter. The results are discussed in terms of possible impact on novel approaches for pharmacologically manipulating cocaine reinforcement and craving in clinical treatments for cocaine addiction, as well as for emergency treatment of cocaine overdose. PMID- 7846209 TI - Opioid physical dependence development: effects of single versus repeated morphine pretreatments and of subjects' opioid exposure history. AB - In acute dependence, signs and symptoms of opioid withdrawal are precipitated when an opioid antagonist (naloxone) is administered following acute (e.g. single dose) pretreatment with a mu agonist. This study examined the influence of amount of previous opioid exposure, both immediate and remote, on intensity of precipitated withdrawal effects in an acute dependence model. Two groups of subjects, opioid abusers (n = 20) and nonabusers (n = 20), received either one 15 mg/70 kg IM morphine pretreatment or two such pretreatments spaced 24 h apart. Naloxone challenge (30 mg/70 kg) followed 4.33 h after the second pretreatment. There were clear effects of morphine pretreatment condition (single versus repeated 15 mg) on the intensity of precipitated withdrawal responses elicited by naloxone. More intense effects were seen after the repeated pretreatment, suggesting that physical dependence escalates with repeated opioid exposures spaced at appropriate intervals. Subjects with an opioid abuse history reported greater liking of agonist drug effects than did nonabusers, whereas nonabusers reported more sedating effects. However, an opioid abuse history did not influence the intensity of precipitated withdrawal symptoms and signs. The latter finding suggests that a previous opioid exposure history does not dramatically modulate initial stages of physical dependence development during subsequent opioid exposure episodes. PMID- 7846210 TI - Effects of lorazepam on cardiac vagal tone during rest and mental stress: assessment by means of spectral analysis. AB - Dose-dependent effects of intravenously administered lorazepam on haemodynamic fluctuations were studied by means of spectral analysis, in order to elucidate sympathetic and parasympathetic components in cardiovascular control during situations of rest and mental stress after benzodiazepine administration. In a double-blind randomized cross-over study, nine male volunteers participated in two sessions: a placebo and lorazepam session. During these sessions, the subjects repeatedly performed a 10-min version of the Stroop Color Word Test (CWT), with 10 min of rest between the CWTs. Lorazepam was administered before each rest period in increasing doses of 0.0, 0.06, 0.13, 0.25 and 0.5 mg (total cumulative dose: 0.94 mg). During the placebo session the subjects received five placebo injections. For five of the nine subjects the lorazepam session was their first session. Heat rate (HR), blood pressure (BP) and respiration were recorded continuously. Power spectra were calculated per 2.5-min periods for HR, systolic (SBP) and diastolic BP (DBP). Spectral density was assessed for three frequency bands: low (LFB: 0.02-0.06 Hz), mid (MFB: 0.07-0.14 Hz) and high (HFB: 0.15-0.40 Hz). During the consecutive periods of rest, lorazepam induced a dose-dependent decrease in HR, and a dose-dependent increase in LFB, MFB and HFB power of HR, but lorazepam had no effect on BP. The effects were significant after 0.44 mg lorazepam for HR and HFB power, and after 0.94 mg lorazepam for the HR fluctuations in the LFB and MFB. Lorazepam did not influence the cardiovascular responses to the CWT.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7846212 TI - EEG alterations in patients treated with clozapine in relation to plasma levels. AB - It is well known that psychotropic drugs can induce EEG alterations. Dose dependence seems established; however, there are no data concerning the impact of plasma levels. The authors investigated the influence of clozapine plasma levels on the frequency of EEG alterations. Data from 29 inpatients (18 male, 11 female, 31.7 +/- 10.2 years) receiving clozapine in a dose range between 25 and 600 mg were collected prospectively. There was no psychotropic or anticholinergic comedication. All patients had normal EEGs before taking clozapine. Fifteen patients showed pathological changes (group 2) and 14 no changes (group 1). Discriminant analysis showed that EEG changes are dependent on plasma levels (P = 0.0009, plasma levels in group 1 mean 81.6 ng/ml, +/- SD 64.6, in group 2 235.7 ng/ml, +/- 169.8). A total of 72.4% of the patients were correctly classified as having either pathological EEG changes or none by this analysis. Variables such as dose, age, sex, weight and duration of treatment were not statistically relevant. It can therefore be suggested that clozapine plasma levels are a valid indicator for the appearance of electrophysiological reactions. PMID- 7846211 TI - Evidence that 5-HT2c receptor antagonists are anxiolytic in the rat Geller Seifter model of anxiety. AB - Four non-selective 5-HT2C/5-HT2A receptor antagonists, mianserin (2-8 mg/kg), 1 naphthyl piperazine (1-NP) (0.5-1 mg/kg), ICI 169,369 (20 mg/kg) and LY 53857 (5 mg/kg), increased punished responding for a food reward in the rat Geller-Seifter test 30 min after subcutaneous (SC) administration. This property was shared by the benzodiazepine anxiolytic chlordiazepoxide (5 mg/kg SC). However, the selective 5-HT2A receptor antagonists ketanserin (0.2-1 mg/kg SC) and altanserin (0.5, 1 mg/kg SC) had little effect. The 5-HT1A, 5-HT1B and beta-adrenergic receptor antagonists pindolol and cyanopindolol (6 mg/kg SC) did not affect punished responding either, nor did the 5-HT1D receptor partial agonist and alpha 2 adrenergic receptor antagonist yohimbine (2.5 mg/kg SC) or the histamine H1 receptor antagonist mepyramine (1 mg/kg SC). Unpunished responding was also modestly increased after some doses of the 5-HT2C/5-HT2A receptor antagonists. However, this effect was inconsistent and was also seen after chlordiazepoxide. Furthermore, it was not associated with the increase in punished responding observed in rats orally treated with mianserin (10, 20 mg/kg), 1-NP (10, 20 mg/kg) or ICI 169,369 (50 mg/kg). The action of the 5-HT2C/5-HT2A receptor antagonists tested is therefore consistent with anxiolysis. The results also strongly suggest that this effect is mediated by blockade of the 5-HT2C receptor, although the possibility of 5-HT2B receptor mediation is discussed. PMID- 7846213 TI - Influence of caffeine on selective attention in well-rested and fatigued subjects. AB - Effects of caffeine were studied in a visual focused selective search task in well-rested and fatigued subjects. A dose of 200 + 50 mg caffeine or placebo, dissolved in decaffeinated coffee, was administered in a double-blind and deceptive fashion. The task was to detect a target letter on one diagonal of a visual display designated as relevant and ignore stimuli presented on the irrelevant diagonal. Behavioral measures were supplemented by event-related potential (ERP) measures. Subjects reacted faster in the caffeine condition. Caffeine enhanced the N1 and the N2b components. Selection of relevant information apparently was more adequate in this condition. Search negativity was not affected by caffeine. Caffeine effects on the P3 elicited by target letters were more pronounced in the fatigued than in the well-rested subjects, indicating that the effects of caffeine are dependent on the state of the subject. The results suggest that caffeine has specific rather than general effects on information processing. PMID- 7846214 TI - Brain event-related potential correlates of overfocused attention in obsessive compulsive disorder. AB - A hypothesis of overfocused attention in obsessive-compulsive disorder was investigated by measuring auditory event-related potentials (ERPs) during a selective attention task. Unmedicated patients (n = 18) with this disorder showed significantly larger attention-related processing negativity (PN), with earlier onset and longer duration, than did normal controls (n = 15). In the N200 region (160-250 ms), PN was larger in patients with fewer nonspecific neurological soft signs. This task, however, did not yield any group differences in mismatch negativity (N2a) or classical N200 (N2b). P300 amplitudes for attended targets were smaller for patient than normal groups, but the reverse was true for P300 and positive slow wave amplitudes for unattended nontargets. Collectively, these ERP abnormalities suggest a misallocation of cognitive resources. Because of the importance of the frontal lobe in the control of selective attention, PN enhancement in patients with obsessive-compulsive disorder may reflect hyperactivation of this region. This conceptualization is consistent with recent functional neuroimaging findings. PMID- 7846215 TI - ERPs for infrequent omissions and inclusions of stimulus elements. AB - A negative event-related potential (ERP) wave called mismatch negativity (MMN) is elicited by an infrequent deviant stimulus in a sequence of frequent standard stimuli. Omission of a stimulus in a sequence of stimuli, however, has been considered to elicit a negativity different from MMN. The present study addressed this issue by examining ERPs for infrequent omissions and inclusions of compound stimuli or their elements. Three kinds of stimuli were presented: a 1000-Hz sine wave tone (Sine), white noise with the 1000-Hz frequency sharply filtered out (Noise), and a composite of the pure tone and the filtered white noise (SiNoise). All stimuli had 50 ms duration and were presented with a regular interstimulus interval of 650 ms. Intensities were 75 dB SPL for the tone and noise stimuli and slightly higher for the composite stimulus. The three kinds of stimuli were presented on separate runs, either as the frequent stimulus or one of two infrequent stimuli, each with 10% probability. Infrequent omission of the large stimulus element (Sine deviant to SiNoise) tended to elicit later MMN than inclusion of the same element (SiNoise deviant to Sine). Omission of the small stimulus element (Noise deviant to SiNoise) elicited a smaller and later MMN than did inclusion of the same element (SiNoise deviant to Noise). These data suggest that MMNs are also elicited by partial stimulus omissions, although they seem to be more sensitive to other kinds of stimulus deviances. PMID- 7846216 TI - Cardiac stimulus intensity and heartbeat detection: effects of tilt-induced changes in stroke volume. AB - The effects of variations in stroke volume on the intensity of cardiac stimuli was examined in a series of three experiments that employed classical psychophysical methods to assess heartbeat detection. Stroke volume was manipulated by passive body tilt and recorded using impedance cardiography while subjects performed heartbeat detection tasks. The postural manipulation generated little or no change in contractility or momentum but did produce substantial changes in stroke volume. However, this potential source of variation in cardiac stimulus magnitude did not influence either the precision of heartbeat detection or the temporal location of heartbeat sensations. It is concluded that the intensity dimension of the heartbeat stimulus is not determined by stroke volume. PMID- 7846217 TI - Modulation of the acoustic startle response by film-induced fear and sexual arousal. AB - The response matching model of Lang, Bradley, and Cuthbert (1992) predicts startle reflex facilitation during negative relative to positive emotional states. Using slide and imagery paradigms, larger eyeblink responses to startle probes for unpleasant than for pleasant conditions have consistently been reported. The present study extended the previously observed relationship between valence and startle to more complex stimuli, namely 1-min film fragments. Thirty three subjects viewed a sequence of 27 film fragments with neutral, negative (fearful), and positive (sexual) contents, presented in one of three mixed orders. Blink magnitude to brief bursts of white noise was larger during fearful fragments than during sexual fragments. Blink magnitudes habituated across successive film fragments, but the positive-negative difference remained stable within film fragments and during the entire length of the videotape (approximately 40 min). PMID- 7846218 TI - Autonomic cardiac control. I. Estimation and validation from pharmacological blockades. AB - Pharmacological blockades have been used to estimate the relative contributions of the autonomic branches to cardiac chronotropic control. Systematic biases in these estimates, however, can arise from both methodological and physiological factors. Selective blockades can be interpreted by two inferential models, and a single blockade condition can yield estimates of autonomic control for both autonomic branches. The residual autonomic control of the heart after blockade of a single division provides an index of the functional contribution of the unblocked branch. In contrast, the change in chronotropic state of the heart after blockade of the same division reflects the subtractive loss of that branch and thus provides an index of the normal contribution of the blocked branch. We demonstrate that the systematic biases that can arise in blockade studies introduce distortions of the subtractive and residual estimates that are of equal magnitude but opposite sign. Consequently, the discrepancy between the subtractive- and residual-model estimates provides a measure of bias in blockade studies and permits the derivation of validity indices that can facilitate interpretations of blockade data. PMID- 7846219 TI - Autonomic cardiac control. II. Noninvasive indices and basal response as revealed by autonomic blockades. AB - Heart period, systolic time intervals, low and high frequency heart period variability, blood pressure, and respiration were measured in female subjects under three drug conditions (saline, atropine sulfate, metoprolol) while sitting and standing on three consecutive days. Following preinfusion baseline recordings, saline, metoprolol (14 mg), or atropine sulfate (2 mg) was infused for 15 min (by using a double-blind procedure). Recordings were taken during a postinfusion baseline and in response to an orthostatic stressor (standing versus sitting postures). At the end of the metoprolol session, atropine sulfate was infused and responses were monitored during the postinfusion (i.e., double blockade) baseline and during orthostatic stressor. Analyses of the blockade data revealed that the preejection period (PEP) reflected sympathetic but not vagal influences on the heart, and high frequency (HF, 0.12-0.40 Hz) heart rate variability (respiratory sinus arrhythmia) reflected vagal but not sympathetic influences on the heart. No other measure provided a specific index of the tonic sympathetic or vagal activation of the heart. Postinfusion PEP under saline predicted individual differences in postinfusion cardiac sympathetic activation, whereas postinfusion heart period (but not HF variability) under saline predicted individual differences in postinfusion cardiac vagal activation. PMID- 7846220 TI - Autonomic cardiac control. III. Psychological stress and cardiac response in autonomic space as revealed by pharmacological blockades. AB - Behavioral contexts can evoke a variety of autonomic modes of response, characterized by reciprocal, coactive, or independent changes in the autonomic divisions. In the present study, we investigated the reactive autonomic control of the heart in response to psychological stressors, using quantitative methods for analyzing single and double autonomic blockades, and through the use of noninvasive indices based on heart period variability and systolic time intervals. Analysis of the effects of pharmacological blockades revealed an overall pattern of increased sympathetic and decreased parasympathetic control of the heart during speech stress, mental arithmetic, and a reaction-time task. Unlike the classical reciprocal sympathetic-parasympathetic response to orthostatic challenge, however, the responses of the autonomic branches to stress were uncorrelated. This reflected notable individual differences in the mode of autonomic response to stress, which had considerable stability across stress tasks. The putative noninvasive indices of sympathetic (preejection period) and parasympathetic (respiratory sinus arrhythmia) control changed in accord with the results of pharmacological blockades. Together, these results emphasize the substantial individual differences in the mode of autonomic response to stress, the advantages of a quantitative approach to analyzing blockade data, and the importance of validity estimates of blockade data. PMID- 7846221 TI - A technique for improved blood sampling during sleep studies. AB - Research protocols often require that blood samples be drawn during sleep. This study compares the efficacy of obtaining nocturnal blood samples using a standard heparinized intravenous setup versus the same intravenous setup used in conjunction with a small chemical heating pad. The chemical heating pad significantly improved the number of blood samples obtained and the maintenance of intravenous patency. The use of a chemical heating pad is an economical way to resolve the frustration of lost blood samples while maintaining a reasonable environment to monitor sleep. PMID- 7846222 TI - Two separate frontal components in the N1 wave of the human auditory evoked response. AB - Scalp current density analysis of the auditory evoked response to 1-kHz tone bursts delivered at various interstimulus intervals (ISIs) (from 1 s to 2 min in separate runs) shows that two different frontal components can be observed and functionally dissociated in the N1 time range: one is elicited for all ISIs, peaks at about 95 ms poststimulus, and has a full recovery time below 8 s; the second is elicited only by infrequent stimuli (ISIs > 4 s), peaks around 140 ms, and significantly increases in amplitude with increasing ISIs. The first component can be considered a new obligatory component in N1 elicited simultaneously with the responses in auditory cortex; the later component could correspond to the orienting Component III of Naatanen and Picton (1987). PMID- 7846223 TI - Delusional misidentification syndromes. AB - The editors first describe the principal symptoms of the Capgras delusion, the Fregoli delusion, the delusion of intermetamorphosis and the delusion of subjective doubles before developing the argument that it would be appropriate for international psychiatric diagnostic systems to include these disorders. Furthermore the similarity between them, the reduplicative paramnesias and deja and jamais vu are pointed out. By stressing a symptom-based approach it is possible to examine psychiatric, neurological and medical cases as arising from the same underlying disturbance in cognition function. The relationship between delusions of misidentification and other delusions is also touched upon. PMID- 7846224 TI - Proceedings of the conference on delusional misidentification syndromes. Paris, 1993. PMID- 7846225 TI - Joseph Capgras (1873-1950). PMID- 7846226 TI - Delusional misidentification: a plea for an agreed terminology and classification. AB - Since the publication of the seminal paper by Capgras and Reboul-Lachaux more than a dozen varieties of delusional misidentification have been reported in the psychiatric and neurological literature. Although subjected to increasingly sophisticated scrutiny, continuing confusion and disagreement over terminology, delineation of phenomenology and nosology hamper the systematic study of these phenomena. PMID- 7846227 TI - The classification of delusional misidentification syndromes. AB - The delusional misidentification syndromes are characterized by a belief in duplicates and replacements. They can be classified as forms of reduplication expressed in the modalities of person, place, time and event, objects, parts of the body and the self. Common features are selectivity, coexistence of forms, intact recognition and faulty identification, depersonalization, and symbolic representation of the patient's feelings, experiences and problems. A neural substrate of altered connectivity of multimodal cortical association areas and paralimbic and limbic structures resulting in a cognitive-perceptual-affective dissonance is suggested. PMID- 7846228 TI - Delusional misidentifications: facts and fancies. AB - The term 'delusional misidentification syndromes' (DMS) encompasses disparate clinical phenomena. This lack of agreement has resulted in a proliferation of definitions and classifications and impeded progress in aetiological research. It is suggested here that one reason for such confusion lies in current overemphasis on the content of such phenomena and a consequent neglect of their form. Research directed at clarifying the protean forms in which misidentifications manifest themselves should help to delineate more stable clinical phenomena and identify causal mechanisms. PMID- 7846229 TI - A continuum of misidentification symptoms. AB - A case study of a schizophrenic patient with differing forms of experiences of inappropriate familiarity is described. Reduplicative paramnesia is redefined as a delusion of familiarity related to a reduplication of time, place or person. The author proposes the concept of a continuum of positive and negative misidentification symptoms. The positive pole of the continuum ranges from the minor form of deja vu experience to reduplicative paramnesia. The negative pole ranges from depersonalisation to nihilistic delusions. Differentiation is based on the severity of the disturbance of reality testing. The argumentation is based on the fact that both deja vu experiences and depersonalisation occurring in pathological as well as non-pathological conditions are phenomenologically uniform. PMID- 7846230 TI - Prevalence of delusional misidentification syndromes. AB - The prevalence of delusional misidentification syndromes (DMS) in a consecutive sample of 195 inpatient admissions with functional psychosis was found to be 4.1%. It is argued that DMS symptoms are more common than previously supposed. PMID- 7846231 TI - Observations on the epidemiology of the delusional misidentification syndromes in the Boston metropolitan area: April 1983-June 1984. AB - Delusional misidentification syndromes (DMS) are beginning to be well described clinically but little is known about their epidemiology. To try and obtain an estimate of their prevalence, a survey was performed of all admissions to a locked psychiatric inpatient unit from April 1983 to June 1984. 26 patients satisfied clinical criteria for DMS during this time and overall 835 patients were admitted to the unit. Thus, a crude prevalence of 3.1% was found. The median age of the patients was 29 years. The overwhelming majority had a principal psychiatric diagnosis of paranoid schizophrenia and only 2 of an affective disorder. By a small margin, most patients were male. The implications and limitations of these findings are discussed. PMID- 7846232 TI - Psychodynamic approaches to the Capgras delusion: a critical historical review. AB - Over the last eight decades a plethora of psychodynamic explanations have been invoked to account for the Capgras delusion. While often ill-founded and convoluted, these formulations have, until recently, dominated many theoretical approaches to the phenomenon. Generally post hoc and teleological in nature, they postulate motives that are not introspectable and defence mechanisms that cannot be observed, measured or refuted. While psychosocial factors can and often do play a part in the development, content and course of the Capgras delusion in individual patients it remains to be proven that such factors are necessary and sufficient to account for delusional misidentification in general and the Capgras delusion in particular. PMID- 7846233 TI - Delusional misidentification: an exemplary symptom illustrating an interaction between organic brain disease and psychological processes. AB - Delusional misidentification provides us with an excellent example of how it is necessary to take both organic brain disease and psychological processes into account when describing the development of mental symptoms. A model of delusional misidentification is proposed which was developed in an attempt to explain this interaction. The model is based on the events that occur during preconscious processing of perceptions. It predicts an inverse relationship between the presence of organic brain disease and the presence of paranoid delusions. This was tested using a retrospective analysis of case reports. A graded and inverse relationship between the degree of organic disturbance and the presence of paranoid delusions preceding the delusional misidentification was found. A satisfactory model of delusional misidentification syndromes must be able to acknowledge the way these two forces are able to interact. PMID- 7846234 TI - Localization and lateralization in the delusion of substitution. Capgras symptom and its variants. AB - Five hundred and seventy cases in 252 reports of the delusion of substitution yielded 200 cases with an organic contributor to the occurrence of the delusion. In 79 cases lateralization or localization could be determined, with lesions primarily in the left temporal or right frontal areas. Factors related to 'feature recognition', 'familiarity' and 'reduplication' could be found and are discussed in relation to the neurobehavioral features of the symptom. PMID- 7846235 TI - The role of the right hemisphere in the Capgras delusion. AB - Following a general review of the literature linking right hemisphere dysfunction to psychoses in general and Capgras delusion (CD) in particular, two studies are described that confirm the link. Study 1 revealed that, compared with matched psychiatric controls, 3 CD patients were particularly poor at matching pairs of faces shown briefly in the left visual field-which implies dysfunctioning right hemisphere performance. However there was no difference in performance when the faces appeared bilaterally, which fails to support the hypothesis that poor interhemispheric communication may give rise to CD. The second study involved tests of face memory and word memory. CD and other delusional misidentification groups scored markedly low on the face test, again implying right hemisphere deficit. Finally, a model of what may be the right hemisphere mechanisms giving rise to CD was explored. This assumes two routes to face recognition, ventral and dorsal. It is argued that exclusive damage to the former may cause prosopagnosia and problems in the latter may give rise to the symptoms of CD. PMID- 7846236 TI - Capgras syndrome: agnosia of identification and delusion of reduplication. AB - In the Capgras syndrome (CS) there is a natural dissociation between recognition and identification and it deserves to be designated as an agnosia of identification. Joseph Capgras who first introduced this concept of agnosia, also suggested that the syndrome might be studied within the framework of 'meconnaissance systematique' (translated here as systematic unawareness), thus anticipating a type of interpretation in which the basis of CS (and other delusional misidentification syndromes) would be a lack of corporeal and/or egocentric space awareness. From two examples, it is suggested that the basic phenomenon of unawareness may be due to sensory deprivation. A particular process of awareness concerning personal objects is hypothesized which would explain the specific delusion of reduplication that occurs when these objects are misidentified. PMID- 7846237 TI - Delusional misidentification in Alzheimer's disease: a summary of clinical and biological aspects. AB - Delusional misidentification symptoms (DMS) are common in Alzheimer's disease (AD) and they are frequent sources of serious distress for patients and particularly caregivers. We observed DMS in around 30% of the patients with moderate to severe AD in two independent prospective studies; the Capgras type, phantom boarder, mirror and TV DMS were found most frequently. Patients with DMS showed increased EEG delta-power over the right hemisphere, their CT scans showed more severe right frontal lobe atrophy, and the number of their pyramidal cells in area CA1 was lower than in the patients without DMS. This may indicate that the development of DMS in AD can be promoted by certain patterns of brain degeneration which affect systems relevant to the recognition and updating of memories, while verbal skills may initially be left largely intact. PMID- 7846238 TI - Delusional misidentification: a clinical, neuropsychological and brain imaging case study. AB - The case of a young woman with a disorder involving Capgras syndrome, Fregoli syndrome, intermetamorphosis, and the subjective-doubles syndrome is reported. Neuropsychological assessment showed a low efficiency in the complex visuospatial organization tasks and in non-verbal memory. MRI found a left lenticular hypodensity, and two PET scans performed in the symptomatic and recovered states showed significant changes and asymmetries in cerebral glucose metabolism in the frontal, parietal, and subcortical regions. These findings are discussed with respect to recent models of delusional misidentification syndromes. PMID- 7846239 TI - SPECT data in a case of secondary Capgras delusion. AB - Capgras' delusion (CD) may be secondary to a neurologic lesion, particularly in the right frontal or occipital regions. A 40-year-old woman with multiple sclerosis underwent SPECT during and after an episode of CD. Analysis during delusion showed an uptake defect in the right parietal cortex with an 11% index of asymmetry (normal: < or = 4%). Post-delusion SPECT showed decreased bifrontal and biparietal cortical uptake indices but a normal index of asymmetry. Functional brain imaging may provide clues to the psychopathology of CD. PMID- 7846240 TI - Delusional misidentification syndromes and dangerousness. AB - Dangerousness in the delusional misidentification syndromes is studied by reviewing a sample of 82 cases defined by either verbal threats or physical violence caused by misidentification delusion. Eighty cases were obtained from a review of the anglophone psychiatric literature in which the patients exhibited some degree of dangerousness, to which we added 2 previously unreported cases. PMID- 7846242 TI - The Capgras and Cotard delusions. AB - We explore the relation between the Capgras delusion (the belief that your relatives have been replaced by impostors) and the Cotard delusion (the delusional belief that you have died). At first sight, these delusions would seem to have little to do with each other, except that they both involve bizarre claims about existence (for self or others). On closer examination, however, there are other parallels. Here, we summarise similarities in associated impairments of face perception, and argue that both delusions reflect an interaction of impairments at two levels. One set of contributory factors involves perceptual impairment, or anomalous perceptual experience. The other factors lead to an incorrect interpretation of this, for which we offer an explanation in terms of attribution theory. Although the Capgras and Cotard delusions are phenomenally distinct, they may therefore represent attempts to make sense of fundamentally similar experiences. PMID- 7846241 TI - The delusion of inanimate doubles. AB - A review of new cases of delusional misidentification reported between 1986 and 1992 suggests that the delusion of inanimate doubles is a variant of the Capgras phenomenon in approximately 10% of cases. It is argued that this variant makes current psychological theories of misidentification untenable. PMID- 7846244 TI - Differences in diagnosis and long-term course and outcome between monosymptomatic and other delusional disorders. AB - A presentation is given of a long-term personal follow-up investigation of patients with paranoid psychoses consecutively admitted at the University Psychiatric Department in Oslo. The patients were followed-up for the first time after a period of 5-18 years, and again after 22-39 years. On the basis of the findings, it is suggested that the diagnostic category will best indicate the course and outcome for cases with delusional misidentification syndromes. PMID- 7846243 TI - Self-substitution as a variant of the Capgras syndrome. AB - The variants of the Capgras syndrome can be organized into a structure, the delusion of substitution, which itself is embedded in other structures. PMID- 7846245 TI - Delusional disorders are a naturally occurring 'experimental psychosis'. AB - A delusion can only be 'explained' if it can be correlated with a demonstrable brain event, and this is only beginning to be possible. The misidentification syndromes are leading the way in demonstrating a close relationship between quite specific brain abnormalities and highly characteristic delusional symptoms. Although delusional disorder (DSM-IV 297.10) and its treatment are well described, virtually no investigations have been carried out on the neuropathological substrate. This article suggests that delusional disorder is a naturally occurring 'model psychosis' which would reward experimental study. PMID- 7846246 TI - Neuropsychological implications of brain changes in schizophrenia: an overview. AB - Schizophrenia is associated with structural changes in the brain but it is not clear whether the changes are localized. Studies in Manchester and elsewhere have reported abnormalities in biochemical markers of glutamate- and GABA-containing neurones in post-mortem brains from schizophrenic patients. The abnormalities occur in the ventral frontal cortex and anterior temporal lobe. It is suggested that these regions of the brain specifically encode information about social communication-language, gesture and facial expression. Many of the symptoms of schizophrenia become neuropsychologically understandable when seen as disturbances of social communication. In this and the following papers, experimental tests of this hypothesis are described. PMID- 7846247 TI - Affect judgement and facial recognition memory in schizophrenia. AB - Two experiments are described in which the performance of schizophrenic subjects was investigated, using tests of affect judgement and recognition memory for faces (Warrington), words, and semi-abstract patterns. Schizophrenic subjects were impaired in their ability to describe the emotional states portrayed by actors and presented on video and were more likely to comment on the physical description of the actor or to fail to comment on the emotion at all. Performance on the Warrington Recognition Memory Test for faces suggests a marked impairment in schizophrenia, although impaired performance on recognition memory tests for words and patterns indicates that this abnormality may not be specific for faces. PMID- 7846248 TI - Receptive and expressive social communication in schizophrenia. AB - Twenty-three schizophrenic subjects and 19 controls completed selected neuropsychological tests of frontal and temporal lobe function and a subgroup of subjects completed a series of tests to assess receptive and expressive aspects of social communication. This was to examine the relationship between deficits of receptive social communication and deficits of temporal lobe function, and deficits of expressive social communication and deficits of frontal lobe function. Schizophrenic subjects were significantly impaired compared to normal control subjects on measures of social communication. Normal performance on a word recognition task contrasted with impaired performance on a face recognition task. No clear pattern of relationships between neuropsychological tests of regional brain function and receptive or expressive social communication emerged. A stepwise logistic regression analysis generated three factors which discriminated between the two groups of subjects; two of these factors were measures involving the information conveyed in a human face. PMID- 7846249 TI - Comorbidity rates do not support distinction between panic disorder and generalized anxiety disorder. AB - Groups of patients with principal diagnosis of panic disorder (n = 54) and generalized anxiety disorder (n = 49) were compared on the basis of their comorbidity with other mental disorders. The rates and patterns of comorbidity were similar, except for comorbid simple phobia and past drug abuse. This finding was interpreted as failing to support a notion that there is essential distinction between panic disorder and generalized anxiety disorder. PMID- 7846250 TI - Multi-modal hallucinations. AB - A patient may experience hallucinations in more than one modality simultaneously or at different times and they may or may not appear to emanate from a single source. Current nomenclature is imprecise, often has particular diagnostic implications and fails to distinguish between these different phenomena. This has resulted in considerable confusion with a tendency to dismiss the importance of these symptoms. The various terms in current usage and the presence of these symptoms in a variety of different conditions are examined. To aid further research and improve clinical practice the authors advocate the use of the term multi-modal hallucinations and suggest operational criteria. PMID- 7846251 TI - Homicide in Capgras' syndrome. AB - A case of Capgras' syndrome associated with homicidal behavior is reported. The psychodynamic implications are discussed. Capgras' syndrome could lie at the base of aggressive and homicidal acts directed towards family members during psychotic breakdown. Capgras' syndrome should always be evaluated in order to prevent violent acts, understand the psychologic characteristics of the patient and undertake the corresponding treatment. PMID- 7846252 TI - Delusions of psychological change of the self. AB - Delusions of psychological change of the self are becoming increasingly appreciated as a type of misidentification delusions. Most available knowledge on delusions of psychological change of the self derives from single case studies. In this article, we present a study encompassing 30 cases of this delusion. Diagnostic and phenomenologic aspects of this delusion are discussed as well as its relation to other types of misidentification delusions. PMID- 7846253 TI - Seasonal affective disorder: are the DSM-III-R criteria valid? AB - Retrospective analysis of the stringency of diagnosis and therapeutic response was carried out in 80 patients with major recurrent winter depression (SAD) who had participated in controlled light therapy trials in Switzerland from 1984 to 1990. Two groups were formed with respect to anamnestic information: patients whose previous episodes of seasonal depression had been reconstructed graphically, and those who could only globally recollect prior depressive phases. These data were taken to test conformity to DSM-III-R criteria for seasonal pattern, as well as its prognostic usefulness for response to light therapy. The more liberal 'Rosenthal criteria' for SAD of at least two consecutive, seasonally recurring major depressive episodes were sufficient to predict improvement with light: none of the other DSM-III-R criteria differentiated further, and few patients could remember previous depressive episodes in precise detail. Our data support suggestions to revise the restrictive SAD diagnostic criteria for DSM-IV. PMID- 7846254 TI - The season of birth of schizophrenics and schizoaffectives. AB - We examined the birth distribution of 2,450 schizophrenic and 682 schizoaffective patients first admitted between 1971 and 1992 to the University Hospital for Psychiatry in Vienna. Our data showed an excess of schizophrenic births in the first quarter of the year and a deficit in the third quarter compared with expectation from census data. The quarterly distribution of schizophrenic births seemed to be different from the one of of schizoaffective patients. In schizoaffectives an excess of births in the first quarter of the year was present, but no other deviation from expectation. PMID- 7846255 TI - Children and adolescents with obsessive-compulsive disorder: an analysis of sociodemographic background. A case-control study. AB - The present study is an analysis of the sociodemographic background of children and adolescents with OCD and child psychiatric control patients. The case records of 61 children and adolescents with OCD and of 117 control patients aged 8-17 years, admitted to a Danish child psychiatric hospital during a 17-year period, were analyzed with regard to sociodemographic data. The OCD patients differed in many ways from their controls, regarding problems at school and family background. Significantly more parents of OCD patients belonged to the highest social classes, and significantly fewer OCD patients came from broken homes. Parents of OCD patients had fewer admissions to psychiatric hospitals and fewer abuse problems than in the control groups. PMID- 7846256 TI - Comparison of a diagnostic checklist with a structured interview for the assessment of DSM-III-R and ICD-10 personality disorders. AB - The International Diagnostic Checklists for the assessment of the DSM-III-R and ICD-10 personality disorders (IDCL-P) were compared with a structured interview, the International Personality Disorder Examination (IPDE), using a balanced test retest design with forty psychiatric inpatients. The results, using pairwise kappa for the calculation of agreement, were as follows: any personality disorder versus no personality disorder 0.52 for DSM-III-R diagnoses and 0.75 for ICD-10 diagnoses. The range for the single personality disorders diagnosed at least five times was from -0.07 to 0.71 for DSM-III-R diagnoses and from 0.38 to 0.68 for ICD-10 diagnoses. Only for DSM-III-R diagnoses do figures exist from three other studies comparing two structured interviews with each other. The results of all four studies suggest that 60% of the variance in personality disorder diagnoses represents variance not attributable to the patients, which is scientifically unacceptable. PMID- 7846257 TI - Affective prodromes of medical illness. PMID- 7846258 TI - Hepatic disease and psychiatric illness: relationships and treatment. AB - A relationship between hepatic diseases and psychiatric symptoms has long been speculated. While liver detoxication makes the exogenous substances harmless for the body, there are occasions where the liver may convert a harmless substance into a more toxic substance. With such an important role, the liver protects all the organs of the body. When liver is malfunctioning, toxic metabolites injurious to the brain may be produced. As the brain receives a high blood supply, a large amount of metabolites reach this organ. Hence, the metabolic function of the liver keeps a delicate reciprocal relationship between the two organs. In addition, a number of psychiatric medications affect liver functions. Another perplexing clinical problem is the difficulty in treating psychiatric symptoms in patients with liver disease. For example, benzodiazepines which do not affect the liver function in physically healthy psychiatric patients, may induce hepatic coma in patients with liver disease. Benzodiazepine antagonists produce dramatic and temporary improvement in patients with hepatic coma. Clinically, many psychoactive drugs produce hepatic complications. The very same drugs which produce hepatic side effects are required for the treatment of psychiatric symptoms in patients with hepatic disorders. To appropriately handle these situations, a thorough knowledge of the side effects of these drugs is necessary. PMID- 7846259 TI - Personality disorder comorbidity with major depression and response to fluoxetine treatment. AB - The relationship between depression and comorbid personality disorders is still poorly understood. The aims of this study were to examine differences in depression severity between depressed outpatients with and without comorbid personality disorders, to determine the effect of a fixed dose of fluoxetine on personality disorders, and to assess the predictive value of personality disorder diagnoses at baseline with regard to response to fluoxetine. Eighty-three outpatients with major depressive disorder (MDD) were assessed with a self-rating scale, the Personality Diagnostic Questionnaire-Revised (PDQ-R), before and after 8 weeks of treatment with fluoxetine 20 mg/day. The presence of a cluster B diagnosis before treatment predicted positive outcome as measured by the change in score on the modified 17-item Hamilton Rating Scale for Depression (HAM-D 17*). Following treatment, we found significant reductions in the frequency of most individual personality disorder diagnoses and total PDQ-R score. While patients no longer meeting criteria for cluster B personality disorders after treatment had similar reductions in depressive symptoms compared to those maintaining the diagnoses, subjects no longer meeting criteria for cluster A and cluster C diagnoses after treatment exhibited significantly greater decreases in depression severity than those who maintained the diagnoses. Overall, these results suggest that fluoxetine may be beneficial in the treatment of certain personality disorder traits in patients with MDD. PMID- 7846260 TI - The validity of Eysenck's neuroticism dimension within the Minnesota Multiphasic Personality Inventory in patients with duodenal ulcer. The Hvidovre Ulcer Project Group. AB - A psychometric analysis on patients with duodenal ulcer using latent structure coefficients (Loevinger and Mokken) showed that the MMPI subscales of depression, psychasthenia, hypochondriasis, hysteria, schizophrenia and social introversion all could be considered as indicators of Eysenck's dimension of neuroticism. Both a MMPI neuroticism scale of 15 items (MMPI/N-15) and of 21 items (MMPI/N-21) were psychometrically valid, i.e. the total score was a sufficient statistic. Patients with duodenal ulcer who improved during treatment also had a significant decrease in their neuroticism scores, whereas patients who did not improve had unchanged neuroticism scores. In other words, neuroticism is secondary to the clinical symptoms of duodenal ulcer (a psychological adjustment to illness) and not an etiological factor. PMID- 7846261 TI - Personality, endocrine and immune changes after eight months in healthy individuals under normal daily stress. AB - The impact of stress and its neuroendocrine correlates on immune function are well established and individual variations could be attributed to modulation by personality characteristics. To assess the influence of everyday life stress and personality on neuroendocrine and immune function, we administered, to 18 healthy adults, the Minnesota Multiphasic Personality Inventory (MMPI) to assess their personality, the State-Trait Anxiety Inventory to measure anxiety, the Reaction Scheme Test to assess their coping reaction style, the Life Events Survey to assess the impact of stressful life events, and the Subjective Stress Questionnaire to assess perceived stress. The endocrine evaluation comprised prolactin, cortisol, and growth hormone plasma levels, while the immunological evaluation assessed T4, T8, and T11 lymphocyte percentages, as well as natural killer cell count and activity. All evaluations were made at baseline and after 8 months. We found a reduction of the T11 lymphocyte percentage to be accompanied by a reduction in the scores of the MMPI scale of Subtle Defensiveness and by an increase in the scores of the Social Introversion Scale. A positive correlation was found between prolactin and T4 lymphocyte percentage. These preliminary data show that some personality and endocrine measures correlate with immune function. PMID- 7846262 TI - Psychosocial self-prognosis in relation to mortality and morbidity in hemophiliacs with HIV infection. AB - HIV-infected hemophiliacs participated in a psychosocial prognosis study. The Coping Wheel was filled out 1-2 years after the subjects had been told that they were HIV-infected and between 1 and 7 years after they had become infected. The number of significant signs of disease as well as mortality were recorded during the years following the psychosocial measurements. These measures were related to three measures of anticipated future activities derived from the Coping Wheel, namely 'number of activities for oneself', 'number of activities with others' and a combined measure 'number of activities for oneself in relation to number of activities with others'. The results indicated that the subject's own psychosocial prognosis added to the prediction of mortality. The most important psychosocial factor was the combined measure: those with few anticipated activities for oneself in relation to activities with others had a greater likelihood of dying soon during follow-up. The latter prediction was true even after adjustment for age and condition of the immune system (CD4 count) at the start of follow-up. The conclusion is that the Coping Wheel, applied as in the present examination, may be of help in prognosis and in identifying psychosocial needs in patients with HIV infection. PMID- 7846263 TI - Quality of life in patients with limited small-cell carcinoma of the lung receiving chemotherapy with or without radiation therapy, for cancer and leukemia group B. AB - Quality of life was assessed in 57 patients with limited small-cell carcinoma of the lung utilizing psychological scales that measured mood, functional status, and cognitive impairment. These patients received chemotherapy with or without radiotherapy to the primary tumor. All patients received prophylactic cranial radiation. Patients who received the combination of chemotherapy and radiotherapy to both the primary tumor and CNS had an increase in overall survival. However, because of the increased toxicity experienced by these patients, a decrease in quality of life was documented by measures of psychological distress when compared to patients receiving chemotherapy alone. The findings support the importance of utilizing quality of life measures in addition to measures of physical toxicity so that patients can make an informed choice regarding treatment options. PMID- 7846264 TI - Excessive food aversion, compulsive exercise and decreased height gain due to fear of obesity in a prepubertal girl. AB - A case of a 7-year-old girl with a remarkable food aversion and excessive weight reduction caused by fear of obesity, which has been demonstrated in pubertal girls with symptoms partly similar to anorexia nervosa, is reported. Although the patient's weight was reduced to the upper limits of the normal range with diet and exercise, she reduced her food intake more strictly and did not at all eat food consisting of carbohydrates. Exercise was performed longer than before. Her weight continued to decrease and height velocity lowered from 6.0 to 4.1 cm/year (mean +/- SD of the age-matched normal girls: 5.5 +/- 0.74 cm/year). Her eating behavior was normalized without specific psychotherapy for anorexia nervosa. It is suggested that food aversion with weight loss and decrease in height gain due to fear of obesity may occur in prepubertal children as well as in adolescent girls. PMID- 7846265 TI - Cognitive-behavioral treatment of choking phobia: 3 case studies. AB - The present study describes 3 case examples of patients with choking phobia who were given a brief, cognitive-behavioral treatment that combined the interventions of psychoeducation, cognitive restructuring, interoceptive and in vivo exposure. This program was designed to address fears of anxiety and choking sensations as well as fears of swallowing. The patients were treated for 11-13 sessions. All 3 patients responded to the program as measured by their progression on their food hierarchy and by weight gain. Issues in the treatment of these patients are discussed. PMID- 7846266 TI - Neurobiology of rhinitis. PMID- 7846267 TI - [Imagination and desire: reflections on the determination of male sexuality]. AB - Imagination and desire are looked upon as major determinants of male sexuality. In its various facets imagination represents one of the fundamental dimensions of human cognition. During the early phases of development the close interaction of imagination and erotic desire leads to the formations of psychical representatives of experiences of satisfaction that influence sexual and nonsexual behavior by establishing an internalized structure of blueprints for satisfaction. These blueprints can also be viewed as an important step in the development of autonomy. Sex differences can be found primarily in the function and employment of erotic fantasies. Compared to women men tend to use their erotic imagery to a much higher degree as a compensation for a lack of sexual satisfaction. Proceeding from the conceptual distinction of erotic and everyday realities, reflections on the zeitgeist of male sexuality and the relationship between the sexes are put forward focussing on the ambiguity of erotic imagination and the border crossing between the two realities. Based on these reflections therapeutic aspects of imagination and desire are touched upon and the problems of integrating erotic reality and everyday reality in long-term male female relationships are discussed. PMID- 7846268 TI - [The co-evolutional focus in individual, couple and family therapy]. AB - A concrete formulation of focus is proposed that in structure and use is suitable for individual as well as couples and family therapy. The concept of coevolution (Willi 1985, 1991) forms a basis for the supposition that important personal developments are realised in human relationships. The development of one person is challenged, taxed, or hindered by the development of other persons. The formulation of a coevolutional focus consists of four steps: 1) The context of the relationship in which the current conflict emerges; 2) The identification of delayed stages of development; 3) The personal and interactional conditions which block this development; 4) Concrete changes which make the progress in the intended development recognizable. The focus in couples and family therapy integrates the impending development of the participants in their collusive interactions. PMID- 7846269 TI - [Relations between intrapsychic and familial structures in schizophrenic patients]. AB - The authors present the results of a research project that points out the connections of the clinical signs of schizophrenia with the intrapsychic space referring to the repertory-grid test and with the circumplex model of family dimensions (Olson-Faces II). The acute psychotic episode was connected with characteristic arrangements of the representational elements in groups and with disintegration of the family rules system. Also the postpsychotic phase displayed a characteristic constellation of the representational elements in the repertory grid test. The results of the research project underline the important role of the affects during both the acute and the postpsychotic phase of schizophrenia as organizing and integrating factors of the affective-cognitive reference system described by Ciompi. PMID- 7846270 TI - [Psychotherapy of a schizophrenic patient in a large psychiatric hospital- therapeutic option or naive idealism]. AB - The psychotherapy of a schizophrenic points, as it is depicted, at some characteristics of the interactions with these patients. In this context also the weight and the restrictions of the institutional framing conditions are indicated. Despite all still open questions, difficulties and limitations the author pleads for the furthering of psychotherapeutic efforts with psychotic patients, as in a considerable number of cases they mitigate their suffering, lead to a better understanding of the psychological aspects of the illness, which are important to the patient, and finally afford insight to the therapist into a sphere at the limit of human experience and, by this means, add to his fundamentally competence. PMID- 7846271 TI - [Change in causal attributions and coping caused by inpatient client-centered psychotherapy]. AB - During 3-month client-centered hospital treatment 108 patients with neurotic depression, anxiety disorders and other neuroses (DSM-III-R) recovered from depressivity (Giessen-Test, MES), negative attributional styles and regressive coping (KCF). Gains were maintained over follow-up one and two years after therapy. Not only cognitive, but also rogerian psychotherapy leads to significant increment in cognitive coping efforts, even when grade of depressivity is regarded. Attributional style and coping strategies depended on grade of depressivity and status of patient (admission or follow-up); cognitions did not discriminate dysthymic (depressive) patients from other neurotic disorders. PMID- 7846272 TI - [Nuclear magnetic resonance tomography as a functional diagnostic method. New approaches to non-invasive quantification of cerebral blood volume and blood flow]. AB - This paper presents a brief introduction to the current status of cerebral blood volume and blood flow imaging with magnetic resonance imaging (MRI) techniques. A new method for the quantitative assessment of regional cerebral blood volume (rCBV) and regional cerebral blood flow (rCBF) on the basis of the indicator dilution theory is described and preliminary quantitative results from healthy volunteers are presented. The mean values for the rCBV are 8.27 +/- 1.85 ml/100 g for grey matter and 3.78 +/- 1.34 ml/100 g for white matter. The mean values for the rCBF are 44.8 +/- 11.29 ml/min/100 g for the grey matter and 20.88 +/- 8.42 ml/min/100 g for the white matter. These results are in good agreement with PET results from the literature. PMID- 7846273 TI - [Noninvasive diagnosis of cerebral ischemia with nuclear magnetic resonance tomography and near infrared spectroscopy]. AB - We describe the non-invasive assessment of cerebrovascular reserve capacity by means of near-infrared spectroscopy (NIRS) and magnetic resonance imaging. Both methods are compared with transcranial Doppler sonography. There is a good correlation of the three methods in the changes in cerebral oxygen saturation and in blood velocity following acetazolamide stimulation of cerebral blood flow, except found in one patient with unilateral carotid artery occlusion. In this patient we found a decreased cerebrovascular reserve capacity, revealed by a magnetic resonance technique designed to quantify CBV and CBF. We postulate a raised oxygen extraction as the cause of his changes in oxygen saturation. PMID- 7846274 TI - [Information improving secondary evaluation procedures in neuroradiology]. AB - The development of special computer and software systems has exerted great influence on computer-assisted image processing in neuroradiology. In this article we try to give an overview of the present and future applications. The applications can be subdivided into segmentation, image analysis, three dimensional imaging and image fusion. Segmentation plays an important role, because it is frequently the basis for the other methods. Image analysis, like planimetry, volumetry or the calculation of angles, is already used in clinical applications. In this way the course of diseases can be checked objectively. Three-dimensional imaging is especially useful in the planning of surgical and stereotactic approaches. The results and value of three-dimensional imaging depend on the segmentation technique. Therefore, they are evaluated differently. Image fusion allows the simultaneous presentation of image data of different modalities. In particular, the image fusion of morphological findings and functional parameters is applied in clinical neuroradiology. Our experience with these methods suggests that computer-assisted image processing will be of considerable help in neuroradiology. PMID- 7846275 TI - [Neuroradiologic diagnosis of intracranial epidermoid tumors]. AB - Intracranial epidermoids are primarily extracerebral congenital cysts. Intra- and extradural types are differentiated: intradural lesions originate in the intracranial CSF spaces, and extradural lesions in the bony skull. Epidermoids increase in size passively as the result of an increase in the cyst volume and not because of active growth. Clinically epidermoids behave like benign, slow growing cerebral tumours. Differential diagnosis includes other cysts and cystic tumours. Neuroradiologically epidermoids present as polycystic lesions showing extensive growth in the extracerebral CSF spaces and secondary invagination of the brain. On CT and MR, despite the high cholesterol content, epidermoids show the characteristics of liquor and not those of fat. It can be shown that the typical CT and MR appearance of an epidermoid is due to the different proportions of CSF in the cyst content, which results from diffusion or dehiscence of the cyst capsule. The present study was based on analysis of 6 cases selected from a total of 29 patients with CNS epidermoids. PMID- 7846276 TI - [Intracranial manifestations of Langerhans-cell histiocytosis. Nuclear magnetic resonance findings]. AB - We report on 3 patients with intracranial manifestations of Langerhans cell histiocytosis (LH). The results are correlated with histological, clinical and radiological reports on some 70 patients described in the literature as suffering from intracranial LH. Two different morphological pictures can be differentiated. First, typical infiltrates can be seen by microscopy; these can be located in every part of the brain, but are seen mainly in the region of the hypothalamus. These infiltrations are shown as space-occupying lesions with Gd-DTPA enhancement. The other manifestation is a demyelinized lesion with a sparse infiltration of Langerhans cells. These lesions, which are located mainly in the region of the nucleus dentatus of the cerebellum and the brain stem, show increased signal intensity in the T2 sequence and no Gd-DTPA enhancement on MRI. PMID- 7846277 TI - [Magnetic resonance tomography in epidural and subdural spinal hematoma]. AB - Epidural and subdural spinal hematomas were previously diagnosed by myelography and computed tomography (CT). Recent reports indicate that noninvasive detection is possible with magnetic resonance imaging. We report on nine patients who were investigated by magnetic resonance imaging (MRI) prior to surgery for epidural and subdural spinal hematoma. The MR examinations were performed on 1.5-T and 1-T units. We used surface coils and employed T1-, PD- and T2-weighted spin echo sequences and a T2*-weighted gradient echo sequence. CT was available in four patients and myelography in two patients. Surgical correlation was available in all patients. The hematomas were located in the cervical spine (n = 2), thoracic spine (n = 6) and lumbar spine (n = 2). They were epidural in five patients and subdural in four. Blinded reading correctly identified all five epidural hematomas and three of the subdural hematomas; one subdural hematoma was misjudged as epidural. Peracute hematomas (< 24 h) in three patients appeared isointense or slightly hyperintense on T1-weighted images and had mixed signal intensity on T2- and T2*-weighted images. Acute hematomas (1-3 days) in four patients were also isointense on T1-weighted images but were more hypointense on T2- and T2*-weighted images. Chronic hematomas in two patients (7 days and 14 days) were hyperintense on all sequences. Differentiation between epi- and subdural hematomas required transverse T2*-weighted gradient echo sequences. Our results underline that MRI at 1 and 1.5 T is capable of identifying epidural and subdural spinal hematoma in the acute and peracute stage.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7846278 TI - [Familial association of hypothalamic hamartoma and polysyndactyly]. AB - Hypothalamic hamartomas are congenital malformations. The association between hypothalamic hamartomas and other dysplasias, including polydactyly, is known to be a neonatal lethal syndrome. We report on two patients (mother and son) with asymptomatic large hypothalamic hamartomas and polysyndactyly. The relationship of the patients suggests an autosomal dominant transmission. PMID- 7846279 TI - [Treatment of lumbar facet joint syndrome by CT-guided infiltration of the intervertebral joints]. AB - INTRODUCTION: Lumbar facet joint syndrome is a common condition, involving about 79% of patients suffering from low back pain. Denervation by scalpel or electrofrequency is a well-known method of treating it. An alternative method for longer lasting pain relief is CT-guided intraarticular infiltration of facet joints with local anaesthetics and cortisone. METHODS: In 62 patients with facet syndrome a total of 205 joints were infiltrated, CT monitoring being used in all cases. Each facet joint was infiltrated with 0.3 ml bupivacaine and 0.8 ml methylprednisolone. The patients were divided into three groups. Group 1 consisted of 24 persons who had undergone lumbar disc surgery, group 2 of 23 patients with spondylarthrosis of the facet joints, and group 3 of 15 patients who had undergone lumbar disc surgery but had additional spondylarthrosis. Very good results were defined as pain relief for longer than 4 weeks, good results as pain relief for up to 4 weeks and poor results as brief pain relief or none at all. In 27 patients facet infiltration was performed for the purpose of diagnosis. RESULTS: Results were significantly in group 2 than in group 1 (Fisher's exact test P < 0.012). In group 3 results were better than in group 1, but worse than in group 2. These differences were not statistical by significant (Table 3). Seven patients in the diagnostic group had no pain relief, and facet syndrome was excluded. CONCLUSIONS: CT-guided facet joint infiltration is a good method for treatment and diagnosis of lumbar facet joint syndrome. It can be repeated and has no severe side effects. The best results were seen in patients with spondylarthrosis of the facet joints. After lumbar disc surgery the pain relief was shorter, though it also yielded good results. For patients with unspecific low back pain, facet joint injections are a very good diagnostic method, allowing definite exclusion of lumbar facet syndrome. PMID- 7846280 TI - [Intracerebral abscess 48 years after grenade splinter injury]. AB - The case report of a 54-year-old patient with a right frontal intracerebral abscess 48 years after a missile injury is presented. Treatment included surgical evacuation and antibiotic therapy. The patient was discharged without neurological deficit. PMID- 7846281 TI - [The cause of very severe headache?]. PMID- 7846282 TI - ATP sensitive potassium channels: potential drug targets in neuropsychopharmacology. AB - 1. K channels are a diverse and ubiquitous class of proteins that regulate a number of biological functions. 2. Ligands for the study of a variety of K channels are available. These include "openers" and antagonists for the ATP sensitive K channel and peptide toxins such as apamin and charybdotoxin that block other subtypes. 3. Antagonists of the ATP sensitive K channel are useful in the treatment of type II diabetes while "openers" of this channel are being tested in asthma and cardiovascular disease. 4. Intracerebroventricular administration of K channel "openers" block experimentally induced seizures in rodents through a hyperpolarization of neurons. K channel openers may also be useful in the treatment of neurodegenerative diseases, pain and cerebral ischemia. 5. A key to the development of psychopharmacological agents to modify brain K channel function is CNS selectivity. The promise of the ATP sensitive K channel openers suggests a bright future for this mechanism. PMID- 7846283 TI - The therapeutic potential of bromocriptine in neuropsychological rehabilitation of patients with acquired brain damage. AB - 1. Activation of neuropsychological rehabilitation by pharmacological agents is a promising therapeutic strategy. 2. Reports of single cases and case series claim improvement of akinetic mutism, non-fluent aphasia, apathy, attentional and other neuropsychiatric disturbances after treatment with bromocriptine, a D2 dopamine receptor agonist. 3. A critical review of published reports and own experiences discusses the results in the light of pharmacological and neurobiological considerations. 4. Dopaminergic stimulation after certain kinds of brain damage might influence neuronal recovery and/or substitute dopaminergical linked functions after destruction of the corresponding neurons. 5. Although controlled clinical studies are very difficult to design and such evidence is still lacking, preliminary recommendations are given with regard to differential indications, drug regime and evaluation criteria. PMID- 7846284 TI - Brain choline in depression: in vivo detection of potential pharmacodynamic effects of antidepressant therapy using hydrogen localized spectroscopy. AB - 1. Seven subjects with depression and matched controls were studied using proton spectroscopy to test the hypothesis that choline will be elevated in depression. 2. The proton spectroscopy was repeated after recovery from depression. 3. The study confirmed a state dependent increase in choline in the brain. 4. This change may be used as an in vivo marker of change in depression. PMID- 7846285 TI - The tolerability of dothiepin: a review of clinical studies between 1963 and 1990 in over 13,000 depressed patients. AB - 1. A total of 13,834 depressed patients were exposed to dothiepin most frequently at a dose of 150 mg/day and over 6 weeks, in 116 clinical studies between 1963 and 1990. 2. Overall, 2,066 (15%) patients were withdrawn prematurely from dothiepin for a variety of reasons, the most commonly specified reason being due to drug-related events in 500 (4%) patients. 3. In the remaining 11,768 patients, there were 9,312 reports of unwanted events most typically associated with the pharmacological effects of a tricyclic antidepressant although no serious sequelae were reported. 4. This review indicates that the incidence of serious adverse events associated with dothiepin at therapeutic doses is very low. PMID- 7846286 TI - Benzodiazepines and anxiety sensitivity in panic disorder. AB - 1. Benzodiazepines were discontinued in 16 patients who had recovered from panic disorder with agoraphobia after exposure treatment. 2. Drug discontinuation yielded a significant decrease in anxiety sensitivity and state anxiety in these long-term users. 3. Several likely explanations for the findings are discussed. 4. In the short term, treatment of panic disorder with benzodiazepines may lower anxiety symptoms. However, in the long run, it may decrease the individual tolerance to anxiety and discomfort. PMID- 7846287 TI - The assessment of sequential response organization in schizophrenic and control subjects. AB - 1. A novel analysis is introduced for the sequential organization of behavioral elements derived from the ergodic theory of nonlinear dynamical systems and statistical mechanics of physical systems. 2. This analysis yields the fluctuation spectrum of local dynamical entropies, S (h), which quantifies the contributions of subsequences with different degrees of association between elements to the overall observed behavior. In addition, q-dependent order parameter functions assess the relationship between the degree of association between consecutive behavioral elements and qualitative aspects of the subsequences. 3. A binary choice task paradigm is used to extract thought contingent responses in order to determine the organization of sequences of behavioral actions. 4. A group a schizophrenic patients and controls was tested with a binary choice task paradigm to determine the sequential organization of their responses. 5. The results indicate that the overall response sequences of both schizophrenics and controls are non-random. In addition, clear differences in qualitative aspects between response subsequences with different degrees of association are revealed. Finally, significant fluctuations within individual subjects were found between highly predictable and highly unpredictable response subsequences. 6. These results are discussed with respect to dysregulations in behavioral organization that could not be assessed previously and may provide new insights into the behavioral effects of the underlying dysregulated neural circuitry. PMID- 7846288 TI - Neurochemical effects of prolonged treatment with remoxipride as assessed by intracerebral microdialysis in freely moving rats. AB - 1. At three microdialysis sessions, dialysates were collected from the striatum of the same rats. 2. Microdialysis session 1. A single s.c. injection of remoxipride (40 mumol/kg), resulted in increased dialysate concentrations of dopamine, DOPAC and HVA. 3. Microdialysis session 2. Continuous administration of remoxipride (8.6 mumol/rat/day) for 14 days, using mini-osmotic pumps, produced maintained elevated levels of dopamine, DOPAC and HVA. 4. Microdialysis session 3. A challenge dose of remoxipride (40 mumol/kg s.c.), given to the rats after a 48-hour wash-out period following the continuous remoxipride treatment, increased the dialysate concentrations of dopamine, DOPAC and HVA to similar extent as at dialysis session 1. 5. It is concluded that after long-term treatment of remoxipride, an adaptation of the basal state of the DA system appears to take place, implying a lowering of basal DA release and DA metabolism. However, the capacity to respond with increased DA release and DA metabolism to renewed remoxipride treatment is retained, indicating little, if any, tolerance. PMID- 7846289 TI - Glutamatergic neurons projecting to the nucleus accumbens can affect motor functions in opposite directions depending on the dopaminergic tone. AB - 1. Intracerebral cannulas were implanted stereotactically into the nucleus accumbens, dorsal striatum or nucleus entopeduncularis of male NMRI mice. 2. Monoamine-depleted mice were injected intracerebrally with the competitive NMDA receptor antagonist AP-5, the non-competitive NMDA antagonist MK-801 or the AMPA kainate receptor antagonist CNQX. A marked locomotor stimulation was produced when AP-5 was injected into the nucleus accumbens, but not when injected into the dorsal striatum. Likewise, CNQX stimulated locomotor activity when injected into the nucleus accumbens. Neither AP-5 nor CNQX produced behavioral stimulation following injection into the nucleus entopeduncularis. 3. The tone in the monoaminergic systems influences the potency of competitive and non-competitive NMDA antagonists differently with regard to stimulation of locomotor activity. In the case of the competitive NMDA antagonist AP-5 the potency was higher in monoamine-depleted than in monoaminergically intact mice. In contrast, the potency of the non-competitive NMDA antagonist MK-801 was higher in monoaminergically intact than in monoamine-depleted animals. 4. A unilateral injection of AP-5 into the nucleus accumbens caused the animals to rotate: The rotation was predominantly ipsilateral in monoaminergically intact animals, whereas monoamine-depleted mice rotated exclusively contralaterally. When AP-5 was given to monoamine-depleted mice treated with the D-2 agonist quinpirole the animals rotated ipsilaterally, whereas monoamine-depleted mice treated with the D 1 agonist SKF 38393 still rotated contralaterally after AP-5 treatment. These data show that glutamatergic neurons projecting to the nucleus accumbens can affect behavior in different directions depending on the degree of dopamine D-2 receptor stimulation. PMID- 7846290 TI - [The search for historical truth: psychotherapeutic work with Bosnian refugees]. AB - The trauma haunting refugees from ex-Yugoslavia is inextricably bound up with complex processes of historical change. In order to be able to understand and treat their severe psychic problems, psychotherapists have to go in search of the historical truth, which is frequently masked by myths and obsolete notions. Only when a psychotherapist who has received the relevant interdisciplinary schooling acknowledges the existence of completely new historical experiences can s/he provide effective support for Bosnian Muslims fleeing "ethnic cleansing" and attempting to achieve self-healing, learning and growth after such an extreme form of collective and individual destruction. In this way the psychotherapist becomes an initiated listener and a unique witness of a form of historical truth that for the traumatized patients themselves is at first entirely or largely beyond recall and comprehension. PMID- 7846291 TI - [Psychotherapy with mothers and infants in problem families]. AB - This article reports on a project in which mothers living in conditions describable as suproletarian are given psychotherapeutic treatment alongside practical care. The special feature of this system of comprehensive care for mothers from so-called "hard-to-reach-families" is that it begins during pregnancy, is instituted via the agency of midwives and that the therapeutic sessions are designed on a long-term basis and take place in the mothers' own homes. In two detailed case reports the authors describe their methods and define the objectives pursued by this project - the stabilization of the mothers in their family life situation and the prevention, from birth, of disturbances and disabilities otherwise to be anticipated in the children themselves. PMID- 7846292 TI - [Do infants have fantasies?]. AB - The author develops a three-stage theory of mental processes. In his view the first psychic imprints take the form of sensory-motor schemata (Piaget), perception-affect-action patterns (Lichtenberg) and generalized representations of interaction (Stern). At the age of one-and-a-half, mental activity begins to exist in the form of the ability to freely evoke images. In this way the child is able to transcend reality and to think in terms of things which are absent or have never really existed. At this stage active imagination sets in, combining the real and the possible. The closing stage of this development is the linguistic encoding of the mental. The author suggests reserving the term "fantasy" for the second and third stages and discusses the implications of this proposal for the concept of unconscious fantasy. PMID- 7846293 TI - Role of endogenous nitric oxide in the control of gastric acid secretion, blood flow and gastrin release in conscious dogs. AB - Nitric oxide (NO) was shown to mediate gastric hyperemia following secretory stimulation but its role in the control of gastric secretion has not been clarified. Secretory studies were carried out on conscious dogs with chronic gastric fistula, Heidenhain pouch and esophageal fistula, while changes in gastric blood flow were measured in the mucosa of Heidenhain pouuch by laser Doppler flowmetry. Plasma gastrin was determined by radioimmunoassay. Infusion of NG-nitro-L-arginine (L-NNA) (bolus i.v. injection of 2.5 mg/kg followed by infusion of 0.5 mg/kg/h), a potent inhibitor of nitric oxide synthase, failed to affect basal gastric secretion or plasma gastrin level but suppressed an increase of this secretion induced by sham-feeding, ordinary meat feeding or i.v. infusion of bombesin (0.5 microgram/kg/h), pentagastrin (4 micrograms/kg/h) or histamine (40 micrograms/kg/h). In tests with feeding and bombesin infusion, L-NNA caused a significant and dose-dependent reduction in plasma gastrin levels. The inhibition by L-NNA of gastric acid secretory response to pentagastrin, histamine or feeding was accompanied by a decline in blood flow. Addition of L-arginine (bolus i.v. dose of 50 mg/kg followed by infusion of 5 mg/kg/h) significantly attenuated the L-NNA induced inhibition of gastric secretion and the reduction in plasma gastrin response as well as in the fall of gastric blood flow. We conclude that endogenous nitric oxide affects the gastric secretion and that this effect is mediated, at least in part, by the changes in the gastrin release and gastric blood flow. PMID- 7846294 TI - Loxiglumide inhibits cholecystokinin stimulated somatostatin secretion and simultaneously enhances gastric acid secretion in humans. AB - In vitro studies have demonstrated that cholecystokinin releases somatostatin from the gastric mucosa. To date, there is no information about the in vivo significance of this finding in man. Therefore, we have studied the effect of infusion of cholecystokinin resulting in plasma concentrations within the range found after meal-stimulation, on somatostatin release and on gastric acid secretion. In addition we have studied these functions during infusion of the type A cholecystokinin receptor antagonist loxiglumide. In eight healthy subjects, basal gastric acid secretion was distinctly stimulated by cholecystokinin. The effect of cholecystokinin on gastric acid secretion was markedly enhanced by loxiglumide. Cholecystokinin also significantly stimulated somatostatin output into the gastric lumen, but not into the systemic circulation. Somatostatin output into the gastric lumen during infusion of cholecystokinin was abolished by loxiglumide. The data indicate that on the one hand circulating cholecystokinin, like gastrin, stimulates gastric acid secretion probably by binding to less specific type B receptors on parietal cells that are not blocked by loxiglumide, but on the other hand that cholecystokinin, in contrast to gastrin, also inhibits gastric acid secretion probably by binding to specific type A receptors present on somatostatin producing D-cells in the gastric mucosa, that are blocked by loxiglumide. PMID- 7846295 TI - Effect of D-Ala-D-beta Nal-Ala-Trp-D-Phe-Lys-NH2 (KP-102) on GH secretion in urethan-anesthetized rats. AB - The effect of a newly developed growth hormone (GH)-releasing hexapeptide (KP 102) on GH secretion was studied in urethan-anesthetized adult male rats. Although KP-102 alone exerted a small influence on GH secretion, it produced a large plasma GH response in the presence of exogenous GH-releasing factor (GRF). During the continuous infusion of GRF, the somatotropes became refractory to a large bolus dose of GRF, but KP-102 induced a marked increase of plasma GH. The GH response to KP-102 alone or KP-102 with GRF was significantly augmented when antiserum to somatostatin (ASS) was previously administered. Although KP-102 and GRF acted synergistically on GH secretion in control animals, they acted additively in ASS-administered rats. The KP-102 effect on plasma GH was significantly attenuated in control animals and ASS-administered rats by prior i.v. injection of antiserum to GRF. Taken together, KP-102 stimulates GH secretion dependent on GRF and appears to act synergistically with GRF by antagonizing the SS effect. PMID- 7846296 TI - Immunoregulatory properties of hexapeptide isolated from porcine bone marrow cell culture. AB - Myelopeptide 1 (MP-1) is hexapeptide originally isolated from porcine bone marrow cell culture. It was synthesized and its immunoregulatory properties were studied. MP-1 caused a 1.5-2-fold dose-dependent increase of antibody production in the culture of mouse immune lymph node cells. It abolished Con A induction of T suppressors in the suspension of mouse spleen cells and counteracted the inhibitory effect of T suppressors on antibody production. The inoculation of MP 1 (1 x 10(-9) g/mouse) to mice two weeks after their gamma-irradiation (2 Gy) resulted in an increase of antibody production up to 80.2 +/- 15.5% as compared to that in the irradiated control 37.6 +/- 12.0%. Immunofluorescent analysis revealed the specific binding of MP-1 with receptors on the target cells in the suspension of mouse spleen cells. It is supposed that MP-1 participates in the immunoregulatory processes in the living organism. PMID- 7846297 TI - Up-regulation of insulin binding in fish skeletal muscle by high insulin levels. AB - The effects of insulin titres on regulation of receptor binding were studied in several fish species. Insulin receptors were semi-purified by affinity chromatography (WGA-agarose) from skeletal muscle of carp, brown trout and rainbow trout that had been subjected to increases in insulinemia produced either by arginine injection, food administration, or adaptation to an experimental diet (extruded diet with high-digestibility carbohydrates). Arginine injection provoked acute hyperinsulinemia in both carp and trout. Specific binding of insulin to the skeletal muscle was significantly increased 3 h after injection (from 5.8 +/- 0.3 to 9.6 +/- 0.9%/10 micrograms protein in carp and from 0.8 +/- 0.2 to 1.5 +/- 0.4%/10 micrograms in trout). The same effect was observed in carp liver preparations (from 6.0 +/- 0.75 to 9.9 +/- 1.25%/10 micrograms). No alterations in tyrosine kinase activity of the receptors were detected in either carp or trout preparations: basal activities of the receptors were maintained (3100 +/- 200 fmol P/fmol receptors/30 min and 3700 +/- 400 fmol P/fmol receptors/30 min, in carp and trout, respectively), as were the percentage of stimulation over basal levels obtained by incubation with insulin (227 +/- 25% and 160 +/- 10% respectively). Food ingestion raised plasma insulin levels more steadily. Specific binding also increased in skeletal muscle preparations, especially in carp (from 5.7 +/- 0.3 to 11 +/- 1.7%/10 micrograms at 4 h and 10 +/- 0.7%/10 micrograms at 8 h). Tyrosine kinase activity was maintained without significant changes. Rainbow trout adapted for 2 months to an extruded diet presented higher insulin titres and higher glycogen reserves in liver and muscle. Insulin binding to skeletal muscle preparations was also significantly increased (from 0.36 +/- 0.02 to 0.77 +/- 0.1%/10 micrograms), as was tyrosine kinase activity (from 132 +/- 4% to 156 +/- 6%, without alterations in the basal activity). Results showed that fish can respond to both acute and maintained increases in insulinemia by increasing the number of insulin receptors. Tyrosine kinase activity, in contrast, is only modified after long-term adaptation. PMID- 7846298 TI - 7B2 expression in intrapulmonary neuroepithelial bodies: immunocytochemical detection and colocalization with serotonin and calcitonin gene-related peptide. AB - In this study, the occurrence of 7B2, a highly conserved pituitary protein present in many neuroendocrine tissues and tumors, was investigated for the first time in the neuroendocrine cells (NEC) and neuroepithelial bodies (NEB) of hamster, rat and cat lung, as well as its colocalization with serotonin (5-HT) and calcitonin gene-related peptide (CGRP). Bouin fixed and wax embedded lung tissue was serially cut and immunoreactive sites for 7B2, 5-HT and CGRP were demonstrated on adjacent sections with polyclonal rabbit antibodies, using the streptavidin-biotin peroxidase method. 7B2 immunostained NEB were numerous in the intrapulmonary airways and the alveolar parenchyma, always representing a subpopulation of CGRP labelled NEB, but outnumbering those containing 5-HT. NEC, on the other hand, were only immunoreactive for CGRP and 5-HT. Our results suggest that mammalian NEB are storehouses of heterogenous bioactive substances, which may be important components in the development of bronchopulmonary tumors. Moreover, the ubiquitous presence of 7B2 in NEB supports the idea of a pre- and/or post-exocytotic role in the cellular secretory processes while the lack of 7B2 immunoreactivity in NEC might indicate a distinct function for each of both neuroendocrine cell types. PMID- 7846299 TI - Allatostatic neuropeptides from the cockroach Blattella germanica (L.) (Dictyoptera, Blattellidae). Identification, immunolocalization and activity. AB - Four allatostatic neuropeptides were isolated from extracts of the brain of the cockroach Blattella germanica. The primary structures of these peptides were assigned as Leu-Tyr-Asp-Phe-Gly-Leu-NH2 (BLAST-1), Asp-Arg-Leu-Tyr-Ser-Phe-Gly Leu-NH2 (BLAST-2), Ala-Gly-Ser-Asp-Gly-Arg-Leu-Tyr-Ser-Phe-Gly-Leu-NH2 (BLAST-3) and Ala-Pro-Ser-Ser-Ala-Gln-Arg-Leu-Tyr-Gly-Phe-Gly-Leu-NH2 (BLAST-4). Each of the peptides showed C-terminal amino acid sequence similarity to cockroach allatostatins and blowfly callatostatins. The four peptides inhibited in vitro juvenile hormone production by corpora allata from virgin females of B. germanica. Immunoreactivity against allatostatins was seen in the lateral neurosecretory neurons and in the axonal pathway leading to the corpora allata. PMID- 7846300 TI - Autoradiographic study of motilin binding sites in the rabbit gastrointestinal tract. AB - Although motilin receptors have been demonstrated by ligand binding studies, there have been no morphological studies of motilin binding site distribution. Light microscopic macro- and micro-autoradiography using highly purified iodinated Tyr23 canine motilin (10(-10) M) was carried out on the gastric antrum, duodenum, cecum and distal colon of the rabbit. Motilin binding sites were found on the smooth muscle layers of the gastric antrum, duodenum and colon, but no positive binding reaction was detected in that of the cecum. Specific binding sites were particularly abundant in the circular muscle layers, with low concentrations in the longitudinal muscle layers of the gastric antrum, duodenum and colon. No motilin binding sites were found in the mucosa of the gastrointestinal tract and pancreas. The intensity of the positive reaction was inhibited when the tissue was incubated with 10(-8) M unlabeled motilin and was completely abolished by 10(-7) M unlabeled motilin. These results are consistent with the difference in contractile response to motilin between the muscle layers of the gastrointestinal tract. PMID- 7846301 TI - Unit risk estimates for airborne arsenic exposure: an updated view based on recent data from two copper smelter cohorts. AB - The current unit risk for airborne arsenic, 4.29 x 10(-3), was established by the EPA in 1984. Using updated results from a cohort mortality study on Tacoma smelter workers and recent findings from a cohort study of 3619 Swedish smelter workers, new unit risk estimates were developed for the respective cohorts. Methods were analogous to those used by the EPA in 1984, and all estimates were derived under an absolute risk model. A new unit risk 1.28 x 10(-3), was estimated for the Tacoma smelter cohort which was a factor of 5 less than the EPA's earlier estimate, and a direct result of radically revised exposure estimates. A unit risk of 0.89 x 10(-3) was estimated from the Swedish study. Pooling these new unit risk estimates with the EPA's earlier estimates from the Montana smelter cohort yielded a composite unit risk of 1.43 x 10(-3). Based on this estimate, the present unit risk may overestimate the effects of airborne arsenic by a factor of 3. A need to update the unit risk for airborne arsenic and the collateral IRIS database is evident from the results. PMID- 7846302 TI - Bioavailability of cadmium in food and water: a case study on the derivation of relative bioavailability factors for inorganics and their relevance to the reference dose. AB - Published studies in which rats were exposed to CdCl2 in standard chow or drinking water were analyzed to compare the relative bioavailability of cadmium from the two media. Relative bioavailability was assessed from estimates of the rate of accumulation of cadmium in kidney cortex or liver. Data were grouped into tiers based on study design and reporting of data: Tier 1, identical experimental protocols and dosage can be estimated; Tier 2, very similar or identical protocols and dosage can be estimated; Tier 3, protocols may differ and dosage can be estimated; and Tier 4, protocols may differ and dosages cannot be estimated (but concentration of cadmium in food or water is reported). Tiers were nested, such that Tier 4 contained all relevant studies; Tier 3 included data sets from Tiers 1 and 2; and Tier 2 included the data set from Tier 1. Data within Tiers 1, 2, and 3 were subjected to a linear regression analysis with dosage as the independent variable and tissue accumulation rate as the dependent variable to determine whether bioavailability of cadmium was significantly different based on medium of administration. The results of this analysis show the following: (1) In rats receiving food and drinking water ad libitum, the bioavailability of cadmium in drinking water is not significantly different (P > 0.05) from the bioavailability of cadmium in food when dosages are less than 4 mg/kg body wt/day. (2) Cadmium decreases food and water consumption; therefore, assessments of relative bioavailability should be made based on actual dosage rather than exposure levels. (3) Diet composition and status of the gastrointestinal tract are probably a more important determinant of the bioavailability of cadmium than is the exposure medium. (4) Studies of the effect of total diet composition on bioavailability of cadmium may be more relevant than are studies of the effect of the exposure medium. It is concluded from this analysis that the bioavailability of cadmium in food is not different from that in water when diet is provided ad libitum. Therefore, we recommend that distinct RfDs for cadmium in food and drinking water should not be based on the assumption that the bioavailability of cadmium in drinking water is greater than that of cadmium in food. PMID- 7846303 TI - Asbestos in New York City public school buildings--public policy: is there a scientific basis? AB - The most recent of New York City's asbestos emergencies occurred in the late summer of 1993. It prevented schools from opening that fall, precipitated much media excitement, and caused a flurry of widespread abatement activities. This resulted in large measure from the U.S. Environmental Protection Agency's subjective school building inspection policy concerning identification of asbestos hazards in buildings and the subsequent Asbestos Hazard Emergency Response Act mandate for inspection. Data on concentrations of asbestos in the air, important for the calculation of risk to building occupants, were not required and therefore not obtained, as part of the abatement strategy or priority setting. Based on fiber-in-air measurements obtained elsewhere, the calculated risk to NYC school children, using the most pessimistic models, was less than six excess cancer deaths per million lifetimes equivalent to smoking less than a dozen cigarettes in a lifetime. The NYC administration responded to pressure from parent groups concerned with perceived asbestos risks to their children by closing the schools. The hysteria occurred because much of EPA's policy lacked a scientific basis for risk evaluation and assessment. PMID- 7846305 TI - Bladder cancer mortality in the United States, 1951-1989: increased environmental carcinogenesis in men. AB - Bladder cancer has been frequently associated with occupational chemical carcinogens. Increased occupational exposures may, in part, account for the increased risk of bladder cancer consistently observed in men. Age-specific bladder cancer mortality rates in the United States from 1951 to 1988 were analyzed using the Strehler-Mildvan modification of the Gompertz relationship between aging and mortality. This method of analysis, which distinguishes aggregate environmental and genetic influences upon mortality, also suggests that environmental influences upon bladder cancer mortality are significantly greater in U.S. men. PMID- 7846304 TI - The relevance of hepatic peroxisome proliferation in rats to assessment of human carcinogenic risk for pharmaceuticals. AB - There exists a strong association between the ability of drugs and other chemicals to induce hepatic peroxisomes in rodents and to increase the frequency of liver tumors in these same species. Despite several years of intensive investigation, a plausible mechanism causally relating peroxisome induction to tumor formation has not been found. Two major theories of how such compounds produce tumors--prolonged oxidative stress and cellular growth dysregulation- have limited experimental support. The oxidative stress demonstrated in rodents as a consequence of peroxisomal activity may be irrelevant to man since primates appear to be much less susceptible to peroxisome proliferation than are rats or mice. Cellular growth dysregulation and other effects of test materials that often accompany--but are not directly attributable to--peroxisome proliferation in rodents can be assessed in other, more relevant species if a causal relationship between their presence and tumor development is ultimately shown in rodents. Currently, there is no reason to specifically avoid the clinical assessment and commercial development of new therapeutic drugs that induce peroxisomes in rodents if other measurements indicate the absence of DNA damage or growth dysregulation at reasonable exposures in relevant species. PMID- 7846306 TI - Can cohort studies detect any human cancer excess that may result from exposure to dioxin? Maybe. AB - We use the available information about concentrations of dioxin in highly exposed humans along with estimates of the half-life of dioxin and durations of exposure to calculate lifetime average daily doses (LADDs) of dioxin in those populations. We compare those LADDs to the LADDs of dioxin used in rodent carcinogen tests, and we also compare the tissue levels of dioxin in exposed humans and the test rodents. Using the maximum likelihood estimate of the Environmental Protection Agency's (EPA) calculated potency factor for the carcinogenicity of dioxin, we calculate the number of cancers that dioxin might be expected to cause in the exposed human populations. If dioxin causes an increase in total cancers or of a common cancer such as lung cancer, the calculated expected increases in cancer are below the limit of detectability in epidemiologic studies. If, on the other hand, dioxin causes a tumor with incidence comparable to that of soft tissue sarcomas, the calculated expected increases should be detectable in dioxin exposed chemical workers and in the Seveso population. Our calculations lead to the conclusion that the failure of epidemiology to produce convincing evidence of any chronic human health effects from dioxin probably results from the relatively low exposures experienced by humans. From our analyses, there is no reason to allude to differential sensitivities between test animals and humans to explain the lack of convincing evidence for dioxin causing human cancers. PMID- 7846307 TI - Estimating upper confidence limits for extra risk in quantal multistage models. AB - Multistage models are frequently applied in carcinogenic risk assessment. In their simplest form, these models relate the probability of tumor presence to some measure of dose. These models are then used to project the excess risk of tumor occurrence at doses frequently well below the lowest experimental dose. Upper confidence limits on the excess risk associated with exposures at these doses are then determined. A likelihood-based method is commonly used to determine these limits. We compare this method to two computationally intensive "bootstrap" methods for determining the 95% upper confidence limit on extra risk. The coverage probabilities and bias of likelihood-based and bootstrap estimates are examined in a simulation study of carcinogenicity experiments. The coverage probabilities of the nonparametric bootstrap method fell below 95% more frequently and by wider margins than the better-performing parametric bootstrap and likelihood-based methods. The relative bias of all estimators are seen to be affected by the amount of curvature in the true underlying dose-response function. In general, the likelihood-based method has the best coverage probability properties while the parametric bootstrap is less biased and less variable than the likelihood-based method. Ultimately, neither method is entirely satisfactory for highly curved dose-response patterns. PMID- 7846308 TI - Estimated risk of occupational fatalities associated with hazardous waste site remediation. AB - This study presents a method to assess short term traumatic fatality risks for workers involved in hazardous waste site remediation to provide a quantitative, rather than qualitative, basis for evaluating occupational exposures in remediation feasibility studies. Occupational employment and fatality data for the years 1979-1981 and 1983 were compiled from Bureau of Labor Statistics data for 11 states. These data were analyzed for 17 occupations associated with three common remediation alternatives: excavation and landfill, capping, and capping plus slurry wall. The two occupations with the highest death rates, truck driver and laborer, contributed most to total exposure hours in each alternative. Weighted average death rates were produced for each alternative and multiplied by respective total person-years of exposure. The resultant expected number of fatalities was converted, using the Poisson distribution, to the risk of experiencing at least one fatality, as follows: 0.149 for excavation and landfill, 0.012 for capping, and 0.014 for capping plus slurry wall. These risks were discussed in light of the need to obtain more reliable and comprehensive data than are currently available on the occupational safety and health risks associated with hazardous waste site remediation and the need for a more scientific, quantitative approach to remediation decisions involving risks to workers. PMID- 7846309 TI - Urinary excretion of chromium following ingestion of chromite-ore processing residues in humans: implications for biomonitoring. AB - Biomonitoring programs for urinary chromium (Cr) typically attempt to evaluate occupational exposure via the inhalation route. This study investigated whether Cr can be detected in the urine of people following the ingestion of soils that contain relatively high concentrations of chromium in chromite ore processing residue (COPR). To evaluate the reasonableness of using urinary monitoring to assess environmental exposure, six volunteers ingested 400 mg of soil/day (low dose group), two others ingested 2.0 g of soil/day (high-dose group) for 3 consecutive days, and one person ingested a placebo on each of 3 days. The soil and COPR mixture contained concentrations of total chromium (Cr) and hexavalent chromium [Cr(VI)] of 103 +/- 20 and 9.3 +/- 3.8 mg/kg, respectively. Therefore, the low-dose group ingested 41 micrograms Cr/day [including 3.7 micrograms Cr(VI)] and the high-dose group ingested 206 micrograms Cr/day [including 18.6 micrograms Cr(VI)] on each of 3 consecutive days. All urine samples were collected and analyzed individually for total Cr on the day prior to dosing, during the 3 days of dosing, and up to the first void 48 h after the last dose. No significant increases in urinary Cr excretion were found when background excretion data were compared with data following each of the 3 days of dosing or in daily mean urine concentrations of the high- vs the low-dose groups. It appears that Cr present in a soil and COPR mixture at Cr doses up to 200 micrograms/day is not sufficiently bioavailable for biomonitoring of urine to be informative.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7846310 TI - Use of mechanistic models to estimate low-dose cancer risks. AB - The utility of mechanistic models of cancer for predicting cancer risks at low doses is examined. Based upon a general approximation to the dose-response that is valid at low doses, it is shown that at low doses the dose-response predicted by a mechanistic model is a linear combination of the dose-responses for each of the physiological parameters in the model that are affected by exposure. This demonstrates that, unless the mechanistic model provides a theoretical basis for determining the dose-responses for these parameters, the extrapolation of risks to low doses using a mechanistic model is basically "curve fitting," just as is the case when extrapolating using statistical models. This suggests that experiments to generate data for use in mechanistic models should emphasize measuring the dose-response for dose-related parameters as accurately as possible and at the lowest feasible doses. PMID- 7846311 TI - Multistage models of carcinogenesis: an approximation for the size and number distribution of late-stage clones. AB - Multistage models have become the basic paradigm for modeling carcinogenesis. One model, the two-stage model of carcinogenesis, is now routinely used in the analysis of cancer risks from exposure to environmental chemicals. In its most general form, this model has two states, an initiated state and a neoplastic state, which allow for growth of cells via a simple linear birth-death process. In all analyses done with this model, researchers have assumed that tumor incidence is equivalent to the formation of a single neoplastic cell and the growth kinetics in the neoplastic state have been ignored. Some researchers have discussed the impact of this assumption on their analyses, but no formal methods were available for a more rigorous application of the birth-death process. In this paper, an approximation is introduced which allows for the application of growth kinetics in the neoplastic state. The adequacy of the approximation against simulated data is evaluated and methods are developed for implementing the approximation using data on the number and size of neoplastic clones. PMID- 7846312 TI - Derivation of a target level of lead in soil at residential sites corresponding to a de minimis contribution to blood lead concentration. AB - Inability to define either a clear toxicologic threshold or a stochastic all-or nothing (cancer-type) response model for the noncarcinogenic effects of lead (Pb) in young children has posed difficulties for derivation of risk-based target levels of Pb in residential soil. Approaches based on empirical relationships between Pb levels in blood (PbB) and Pb in soil suffer from inability to specify the numerous variables which mediate between these two quantities. Approaches based on achieving a toxicologically de minimis target PbB level (e.g., 10 micrograms/dl) are subject to large uncertainty in estimating the distribution of existing PbB levels in a specific exposed population and in estimating the relative contribution from nonsoil sources of Pb. The multisource contribution to the distribution of PbB makes this approach unsuited for determination of a target Pb level in a single medium. An alternative approach is presented based on achieving a de minimis contribution to PbB (delta PbB) from soil. Contributions to Pb exposure from outdoor soil and indoor soil-derived dust (ISDD) are modeled and appropriate values are suggested for input parameters. This analysis predicts that chronic exposure of young children to 200 micrograms Pb/g (ppm) in residential soil will result in a delta PbB of 2 micrograms Pb/dl blood. This concentration of Pb in soil may provide an appropriate target level for residential soil when other significant sources of Pb exposure are present. In other cases, this approach can be used to predict a soil concentration of Pb corresponding to an appropriate non-de minimis delta PbB. PMID- 7846313 TI - Design of developmental toxicity studies for assessing joint effects of dose and duration. AB - In the assessment of developmental and reproductive effects, the timing and duration of exposures to chemical compounds or other environmental contaminants are of particular interest, as the gestational cycle is known to have periods of increased sensitivity. The goal of this research is to identify optimal experimental designs for conducting developmental toxicity studies when the effects of both exposure level and duration of exposure are of interest. The elements of the study design considered in this evaluation are the allocation of animals to dose-duration exposure groups and the determination of the most efficient intermediate exposure levels. The optimality of various designs is assessed via the accuracy of the estimated excess risk as well as testing criteria. Simulation studies are conducted to compare these criteria and determine optimal design strategies under various underlying dose-response patterns. Asymptotic results are also derived to lend support to the simulation studies. PMID- 7846314 TI - Reproducibility of the dose-response curve of steroid-induced cleft palate in mice. AB - Pregnant CD-1 mice were exposed to cortisone acetate at doses ranging from 20 to 100 mg/kg/day on days 10-13 by oral and intramuscular routes. Multiple replicate assays were conducted under identical conditions to assess the reproducibility of the dose-response curve for cleft palate. The data were fitted to the probit, logistic, multistage or Armitage-Doll, and Weibull dose-response model separately for each route of exposure. The curves were then tested for parallel slopes (probit and logistic models) or coincidence of model parameters (multistage and Weibull models). The 19 replicate experiments had a wide range of slope estimates, wider for the oral than for the intramuscular experiments. For all models and both routes of exposure the null hypothesis of equality of slopes was rejected at a significant level of p < 0.001. For the intramuscular group of replicates, rejection of slope equality could in part be explained by not maintaining a standard dosing regime. The rejection of equivalence of dose response curves from replicate studies showed that it is difficult to reproduce dose-response data of a single study within the limits defined by the dose response model. This has important consequences for quantitative risk assessment, public health measures, or development of mechanistic theories which are typically based on a single animal bioassay. PMID- 7846315 TI - The exact formula for tumor incidence in the two-stage model. AB - An exact formula for the tumor incidence rate in the usual two-stage model of carcinogenesis is presented. This formula is simple and easily implemented on calculators and computers. PMID- 7846316 TI - On the exact hazard and survival functions of the MVK stochastic carcinogenesis model. AB - The MVK two-stage carcinogenesis model is one of the most widely accepted mechanistic models in carcinogenesis modeling. However, due to a perceived difficulty in obtaining analytic solutions for the hazard and survival functions, approximations and numerical methods have been used to calculate these two fundamental quantities. This paper focuses on a special case of the homogeneous MVK model where the number of normal cells is constant. The probability generating function (pgf) for the number of tumor cells is derived, and the exact analytic solutions to the hazard and survival functions are obtained from the pgf. PMID- 7846317 TI - A psychological study of the inverse relationship between perceived risk and perceived benefit. AB - Judgments of risk and judgments of benefit have been found to be inversely related. Activities or technologies that are judged high in risk tend to be judged low in benefit, and vice versa. In the present study, we examine this inverse relationship in detail, using two measures of relationship between risk and benefit. We find that the inverse relationship is robust and indicative of a confounding of risk and benefit in people's minds. This confounding is linked to a person's overall evaluation of an activity or technology. Theoretical and practical implications of this risk-benefit confounding are discussed. PMID- 7846318 TI - Dose-response analysis using spreadsheets. AB - The task of fitting dose-response models to experimental data can be performed using a spreadsheet with a built-in optimization engine. This paper shows how the task of point and interval estimation can be performed using Microsoft EXCEL. A case study is presented on the carcinogenic dose-response behavior of chloroform. PMID- 7846319 TI - Gender, race, and perception of environmental health risks. AB - This paper reports the results of a national survey in which perceptions of environmental health risks were measured for 1275 white and 214 nonwhite persons. The results showed that white women perceived risks to be much higher than did white men, a result that is consistent with previous studies. However, this gender difference was not true of nonwhite women and men, whose perceptions of risk were quite similar. Most striking was the finding that white males tended to differ from everyone else in their attitudes and perceptions--on average, they perceived risks as much smaller and much more acceptable than did other people. These results suggest that socio-political factors such as power, status, alienation, and trust are strong determiners of people's perception and acceptance of risks. PMID- 7846320 TI - Biological models of carcinogenesis and quantitative cancer risk assessment. AB - Biologically-based models of carcinogenesis were originally developed to explain certain quantitative phenomena associated with carcinogenesis, and to provide a framework within which questions regarding the process could be addressed. Some limitations in the use of these models for quantitative cancer risk assessment are discussed. PMID- 7846321 TI - Limitations of biological models of carcinogenesis for low-dose extrapolation. PMID- 7846322 TI - The Valdez Air Health Study. RCAC Valdez Air Study Review Committee. PMID- 7846323 TI - Response: risk assessment for aflatoxin. PMID- 7846324 TI - Comments on "Comparing toxicologic and epidemiologic studies: methylene chloride- a case study". PMID- 7846325 TI - "Improving" risk communication and risk management: legislated solutions or legislated disasters? PMID- 7846326 TI - Risk assessment research: only the beginning. PMID- 7846327 TI - An alternative approach to dietary exposure assessment. AB - The method of dietary exposure assessment currently used by the Environmental Protection Agency (EPA), the Dietary Residue Evaluation System (DRES), combines a consumption distribution derived from the United States Department of Agriculture (USDA) 1977-1978 Nationwide Food Consumption Survey (NFCS) with a single estimate of residue level. The National Academy of Sciences recommended that EPA incorporate both the distribution of residues and the distribution of consumption into their exposure assessment methodology and proposed using a Monte Carlo approach. This paper presents an alternative method, the Joint Distributional Analysis (JDA), that combines the consumption and residue distributions, without relying on random sampling or fitting theoretical distributions like the Monte Carlo method. This method permits simultaneous analysis of the entire diet, including assessing exposure from residues in different foods. PMID- 7846328 TI - The effect of product safety regulation on safety precautions. AB - This paper explores the means by which lighter safety regulations alter the precautionary behavior of 200 subjects in a field test of cigarette lighters with a child-resistant feature. The new lighter design leads respondents to believe the lighters are safer, but there is no clear-cut evidence that the effect on perceived risk levels is excessive. Using the estimated relationship between cigarette lighter risk perceptions and a variety of measures of precautions, this paper provides explicit estimates of the effect of regulations on precautionary behavior and on lighter safety. On balance, the child-resistant feature will reduce fire-related injuries by much more than any diminished precaution taking. PMID- 7846329 TI - How children spend their time: a sample survey for use in exposure and risk assessments. AB - Children are becoming an increasingly important focus for exposure and risk assessments because they are more sensitive than adults to environmental contaminants. A necessary step in measuring the extent of children's exposure and in calculating risk assessments is to document how and where children spend their time. This 1990-1991 survey of 1000 households was designed for this purpose, targeting children between 5 and 12 years of age, in six states in varied geographic regions. The behavior of children was sampled on both weekdays and weekends over all four seasons of the year using a retrospective time diary to allocate time to activities during the previous 24 h. Information was obtained on the kinds and locations of activities, the nature of the microenvironments of the locations, and the time spent in the different environments. Measures of variability in addition to mean hours per day are reported. Results of this study closely match those of earlier research on California children's activities done by the California Air Resources Board. One important finding of the survey was that 5- to 12-year-old children in all geographic regions spend most of their time indoors at home, indicating that risk assessments should focus on indoor, onsite hazards. PMID- 7846330 TI - The risks of "Putting the numbers in context": a cautionary tale. AB - Despite the warnings of risk communication specialists, members of the technical community often urge that technological risks should be "put in context" by comparisons against risks that are more familiar. Little quantitative evidence is available on the actual behavioral consequences of such risk comparison efforts. In the present study, subjects were presented with two types of information about a hazardous waste incinerator--a simplified statistical summary and a comparison of incinerator risks against the risks of smoking. Statistical information led to a modest increase in the reported willingness to vote in favor of the incinerator in a community referendum, but the comparison against cigarettes led to a slight decrease in support; the difference between the two messages is statistically significant (p < .001). In combination with other results, this study's findings suggest that an implicit assumption of risk comparisons is in error: Opposition to controversial technologies may have little to do with citizens' levels of information about technology, having more to do with citizens' levels of trust in governmental and industrial actors. PMID- 7846332 TI - The diagnosis of occupational asthma. PMID- 7846331 TI - The importance of biological realism in dioxin risk assessment models. AB - Mechanistic mathematical models of hepatocarcinogenesis in the female rat were constructed to investigate possible relationships among the Ah, estrogen, and EGF receptors in TCDD hepatocarcinogenicity. Each model generates dose-response curves for the expression of biomarker liver proteins CYP1A1, CYP1A2, and residual plasma membrane EGF receptor consequent to exposure to TCDD. The shapes of the response curves were strongly dependent on the assumed mechanisms of constitutive expression of these proteins. Assuming a constant level of the hepatic Ah receptor, a sigmoidal dose-response of hepatic CYP1A1 to total liver TCDD was computed. However, inclusion of induction of the Ah receptor by TCDD in a physiologically realistic dosimetric model produced a linear low-dose response of CYP1A1. This behavior was computed to arise from the net effect of sublinear response of CYP1A1 mRNA to the concentration of the Ah-TCDD complex and supralinear response of the protein concentration to the mRNA level, illustrating the importance of biological realism in dose-response modeling. The dosimetric model also computed effects of TCDD on the hepatic estradiol concentration and consequent effects on the binding capacity of the EGF receptor and suggests plausible mechanisms for tumor promotion by TCDD. Setting circulating estradiol levels in the model to values typical of the male rat indicated possible sources of the differences in the responses of the EGF receptor and in development of tumors in the two sexes. PMID- 7846333 TI - Risk factors for indoor allergen exposure. PMID- 7846334 TI - Breathlessness in microvascular angina. AB - In patients with microvascular angina (MA), there is some evidence from studies of plethysmography, that there are widespread microvascular abnormalities. In addition to exertional chest pain, all these patients complain of breathlessness, with no evidence of airways obstruction or resting left ventricular dysfunction. Progressive exercise testing was performed in 12 age and sex matched controls and 12 patients (three males), in whom the diagnosis of MA was established on the basis of exertional chest pain, abnormal thallium scans, and an attenuated myocardial flow response to a vasodilator challenge, with angiographically entirely normal epicardial vessels. Symptom limited exercise was performed with on line ventilation and expired gas analysis, measuring minute ventilation, oxygen consumption and carbon dioxide production and arterial blood gas values using a transcutaneous system. Anaerobic threshold was calculated by curve fitting a plot of oxygen consumption against carbon dioxide production. Compared to controls (49.7 +/- 7.3 SD% predicted maximum VO2) in patients with MA, the anaerobic threshold was reduced (41.6 +/- 5.82; P < 0.02) although still within accepted normal limits. Maximal (symptom limited) oxygen consumption, as a percentage of predicted, was reduced 60.73 +/- 16.51 compared to 87.21 +/- 5.2 (P < 0.003). The ventilatory response (VE/VCO2 l l-1 CO2 output) was significantly increased in the MA patients compared to controls (35.9 +/- 8.01 and 27.5 +/- 3.08, respectively; P < 0.02).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7846335 TI - Tumour necrosis factor-alpha and nitric oxide, determined as nitrite, in malignant pleural effusion. AB - Pleurodesis treatment is often used to stop chronic pleural effusion in malignant pleurisy. During the treatment a strong intrapleural inflammation is induced leading to the cessation of exudation. In this study the concentrations of tumour necrosis factor (TNF-alpha) and nitric oxide (NO), determined as its immediate metabolite nitrite, were measured in pleural fluid, in order to investigate if they were involved in pleural inflammation and pleural fluid exudation. Determinations were made in pleural fluid from patients with malignant pleural effusion, before and during therapeutic quinacrine-induced pleural inflammation. TNF-alpha concentrations were measured by ELISA-technique and NO/nitrite by chemiluminescence. TNF-alpha increased significantly after quinacrine instillation. NO/nitrite was initially present at the same concentrations as found in normal serum, and increased significantly during treatment. Concentrations of TNF-alpha correlate with the amount of pleural fluid production after quinacrine instillation, in that a higher level of TNF-alpha is associated with more pleural fluid production. No correlation was found between TNF-alpha and NO/nitrite, whereas a weak but significant correlation was found between NO/nitrite and concentrations of another cytokine, interleukin-1 beta (IL-1 beta). The results suggest that TNF-alpha might contribute to pleural fluid exudation and that TNF-alpha and NO are of importance in induced pleural inflammation. IL-1 beta might be one of several stimuli for NO formation in this setting. PMID- 7846336 TI - Transbronchial lung biopsy through the fibre optic bronchoscope. Results and complications in 452 examinations. AB - During 1986-1989, diagnostic fibre optic bronchoscopy (FOB) was performed in local anaesthesia in 1144 consecutive patients. Of these, 405 (35%) patients, median age 59 years, had transbronchial lung biopsy (TBB) performed under fluoroscopic guidance; 47 patients had a rebronchoscopy, i.e. in total 452 FOB were evaluated. The indication for TBB was localized pulmonary lesions in 279 (69%) patients, and diffuse pulmonary lesions in 126 (31%) patients. Localized lesions: TBB yielded a clinically relevant diagnosis in 55.2% of the patients. Of the 110 patients with malignancy, the overall diagnostic strength was 45.5%. Of the 159 patients with non-malignant lesions, 65.4% were diagnosed by TBB. The diagnostic yield increased with the number of biopsy specimens (< or = 4 biopsies, 52%; > 4 biopsies, 70%. P < 0.05). In 155 patients with well defined, circumscribed lesions, the diagnostic yield of TBB increased with the size of the lesion (< 31 mm, 47%; 31-60 mm, 54%; > 60 mm, 60%, P = 0.09), and decreased with the distance of the lesion from the main carina < 61 mm, 70%; 61-100 mm, 52%; > 100 mm, 40% P < 0.02). Diffuse lesions: TBB yielded a clinically relevant diagnosis in 66.7% of the patients. Of the 15 patients with malignancy, 73.3% were diagnosed by TBB. Of the 93 patients with non-malignant lesions, 78.5% were diagnosed by TBB. The diagnostic yield showed a trend to increase with the number of biopsy specimens (< or = 4 biopsies, 65%; > 4 biopsies, 71%, P = 0.11).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7846337 TI - Early administration of hydrocortisone in the emergency room treatment of acute asthma: a controlled clinical trial. AB - STUDY OBJECTIVE: To determine whether early administration of a single dose of intravenous hydrocortisone (500 mg) modified the need for hospitalization and duration of treatment, and improve pulmonary function assessed by subjective and objective criteria of acute asthma patients. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: The emergency room (ER) of a large, urban hospital with primary and referral care responsibilities. PATIENTS: Ninety-eight patients from 18 to 50 years of age with acute bronchial asthma, with a PEFR and FEV1 in the first second below 50% of predicted value (FEV1 mean % of predicted = 27.8 +/- 10.0) and without history of chronic cough or other medical disease. INTERVENTIONS: The corticosteroid group received 500 mg of intravenous hydrocortisone whereas the control group received intravenous normal saline immediately after arrival to the ER. Additional treatment included salbutamol delivered with metered-dose inhaler into a spacer device (Volumatic), in four puffs actuated in rapid succession (100 micrograms per actuation), at 10-min intervals. The final mean dose was 5.7 mg for the steroid group and 5.6 mg for the control one (P = 0.86). Hospitalization was mandatory if total treatment time was greater than 6 h. MEASUREMENTS AND RESULTS: Age, sex, PEFR, FEV1, FVC, symptom index, and corticosteroids use were similar in both groups. FEV1 expressed as mean % of predicted was 54.6 +/- 17.3% in the control group and 54.6 +/- 17.4% in the steroid group (P = 0.75). Duration of ER treatment was 2.22 +/- 1.75 h in the corticosteroid group and 2.24 +/- 1.70 h in the control group (P = 0.81). The hospital admission rate was 10.2% for the corticosteroid group and 8.16% for the control group. There were no differences between the groups when patients admitted or discharged were examined separately. CONCLUSIONS: Early administration of corticosteroids does not modify outcome of ER treatment of asthma, and does not improve pulmonary function in the first 6 h of treatment. In accord with this, administration of corticosteroids to these patients could be delayed by several hours without modifying clinical outcome. When an aggressive beta-agonist bronchodilator regimen is used, it obviates the need for steroids in this early stage of treatment. PMID- 7846338 TI - Tuberculosis among the homeless people of Nagoya, Japan. AB - A survey was conducted in order to clarify the tuberculosis (TB) situation in the homeless during the period from 1982 to 1991 in an urban district of Nagoya, using the registration cards of pulmonary TB patients and the data of chest roentgenograms of the Nagoya City Nakamura Health Centre. The incidence and prevalence of pulmonary TB per 100,000 among the homeless were estimated at 950 2150 and 1900-3250, respectively, which were around 30 and 20 times higher than those for the non-homeless. An increase in the incidence rate among homeless pulmonary TB patients was found in 1989, after a gradual decrease to the year 1988. The detected prevalence rate by chest examinations of the homeless was also around 30 times higher than that for the non-homeless. The percentage of patients with cavities indicated by chest roentgenograms when they were first registered was 76.9% among the homeless, but only 42.9% among the non-homeless. PMID- 7846339 TI - Domiciliary air filtration units, symptoms and lung function in atopic asthmatics. AB - Air infiltration units (AFUs) incorporating a high efficiency particulate air filter are theoretically able to remove almost all potential airborne allergens. This may have implications for subjects with allergic lower respiratory disease. AFUs were placed in the living room of 12 atopic asthmatics, and the internal filters were inserted and removed in a double-blind fashion. No difference in subjective symptom scoring, spirometry or bronchial reactivity was demonstrated. Peak expiratory flow rate (PEFR) variability was significantly improved from baseline readings, and there was a trend towards higher mean PEFRs when the filters were present in the AFU. Trends towards lower levels of airborne micro organisms were also demonstrated when the filters were present, however no effect upon total airborne dust and airborne Der pI could be demonstrated. PMID- 7846340 TI - Domiciliary oxygen cylinders: indications, prescription and usage. AB - Oxygen therapy for use in the home can be prescribed in two forms: oxygen concentrators are used to provide long term domiciliary oxygen therapy (LTOT), and oxygen cylinders are used to provide oxygen intermittently for relief of symptoms. In this study prescription and usage of oxygen cylinders in the home were assessed. All patients using oxygen cylinders at home in the London Borough of Tower Hamlets in October 1992 were studied. A questionnaire was sent to each patient; further information was obtained from a questionnaire to the general practitioner and from hospital notes where available. Patients with a diagnosis of chronic obstructive pulmonary disease (COPD) were visited at home to measure oxygen saturation levels (SaO2). The main outcome measures were the proportion of oxygen cylinder users who had undergone a full respiratory assessment and the number who might benefit from LTOT. There were 56 patients using oxygen intermittently, 77% with COPD of which 28% had an SaO2 < or = 92%. In these 56 patients 27% had not been assessed by a hospital physician for their chest disease, 58% used their oxygen at least once a day and on average these patients used three cylinders each per month. Most patients using oxygen cylinders at home have a diagnosis of COPD and use oxygen regularly for short term relief of breathlessness; many have not been assessed by a respiratory physician. Measurement of SaO2 suggested that a significant minority might benefit from LTOT and would certainly warrant further evaluation. PMID- 7846341 TI - Pleural empyema caused by Clostridium perfringens. PMID- 7846342 TI - Bronchial atresia and mucocele: a report of two cases. PMID- 7846343 TI - Pulmonary haemorrhage associated with thrombolysis. PMID- 7846344 TI - Lung function testing. PMID- 7846345 TI - Compensating occupational asthma. PMID- 7846346 TI - Fentanyl versus midazolam as premedication for fibre optic bronchoscopy. PMID- 7846348 TI - Respiratory tract antioxidants in health and disease. Abstracts of the 13th summer meeting of the British Association for Lung Research. London, 19-20 September 1994. PMID- 7846347 TI - Guidelines for the measurement of respiratory function. PMID- 7846349 TI - [Linus Pauling and medicine]. PMID- 7846350 TI - [The importance of the autologous bone marrow transplant in the treatment of solid tumors]. PMID- 7846351 TI - [A randomized study of navelbine compared to navelbine and cisplatin compared to vindesine and cisplatin in the treatment of inoperable non-small-cell lung carcinoma. The results of a European multicenter study including 612 patients]. AB - The results are reported of three chemotherapy schedules in a multicentric, international, randomized trial of the therapy of unresectable non small cell lung carcinoma which included 612 patients. The antitumoral efficiency of the cisplatin + vindesine combination (200 patients) was compared with that of navelbine (206 patients), a recently available vinca alkaloid, and with a third therapeutical leg with cisplatin + navelbine (206 patients). After a very thorough response evaluation the combination cisplatin + navelbine obtained a response rate higher than the other combination (30% vs. 19%; p = 0.02) and also than navelbine (30% vs. 14%; p < 0.001). The median response durations were 9.3, 9.9, and 7.8 months for the combination with navelbine, vindesine and the new vinca alkaloid alone, respectively. After a median follow-up period of 26 months the combination cisplatin + navelbine achieved a higher survival rate than the combination cisplatin + vindesine (40 vs. 32 weeks) and navelbine (40 vs 31 weeks; p = 0.045). The most important toxicity with the combination cisplatin + navelbine was neutropenia, which although relevant in number was not of long duration. In summary, navelbine is an active agent in the therapy of non small cell lung carcinoma. In this trial the therapeutic superiority of its combination with cisplatin over the combination cisplatin + vindesine was observed; likewise, it was also more efficient than monotherapy with navelbine. PMID- 7846353 TI - [The effects of frying and grilling on the fat content of common foods (salmon, hake and beefsteak)]. AB - The effects of pan frying and deep frying in olive oil on the fat content in very lean meat (fat = 4.0%), salmon (fat = 26.0%) and hake (fat = 1.8%) have been studied. Both techniques produced fat loss in the meat: pan fried 0.5% (p = 0.07), deep fried 1.3% (p = 0.00036); and salmon: pan fried 11.7% (p = 0.0000026), deep fried 7.9% (p = 0.00012). Hake increased fat content with pan fried 2.4% (p = 0.002) and with deep fried 5% (p = 0.00001). Deep frying or pan frying of meat induce fat loss without dietetic relevance. Fat loss in salmon is nutritionally important specially when pan fried. Fat gain in hake is too small to be considered biologically relevant. This results can not be applied to frying with others fats than olive oil or to frying others food with the same oil. PMID- 7846352 TI - [High-dose chemotherapy and autologous bone marrow transplantation in high-grade metastatic sarcomas]. AB - Metastatic sarcomas have a poor prognosis with current therapeutic regimens. High dose chemotherapy (HDC) has proved to be efficient in a selected group of solid tumors. Nine patients with high grade metastatic sarcomas were treated with HDC followed by autologous bone marrow transplantation. Four patients received HDC as a consolidation of the complete response (CR) obtained with chemotherapy (CT) and two of them were free from disease at 27 and 41 months, respectively. Other four patients had a disease total or partially refractory to conventional CT, and in one case the sensitivity to the chemotherapeutical agents was unknown. In these five cases a partial response was observed in two of the three who had measurable response parameters, but all of them died because of disease progression in a short period of time. These results suggest that there are active HDC schedules on metastatic sarcomas, but its possible benefit would be limited to the consolidation of a CR obtained with previous CT. HDC is a therapeutical alternative under investigation in patients with metastatic sarcomas with an indication that could be extended to cover localized sarcomas with poor prognosis. PMID- 7846355 TI - [Inclusion-body myositis: a familial report of 3 cases]. AB - Inclusion body myositis (IBM) is a myopathy classified until now within the group of idiopathic inflammatory myopathies (IIM). Nevertheless, its clinical and histological features are specific and different from the other IIM. It is refractory to corticosteroid therapy. Recently, a few cases of IBM with familial transmission have been described, which is the first report in our country; previous reported cases in literature are reviewed. The similarities of some forms of IBM with muscle dystrophies, rather than with inflammatory myopathies are discussed. PMID- 7846354 TI - [Differences in the cellular response of the immune system in patients with Paget's disease of bone after elcatonin and etidronate administration]. AB - A cellular immunological defect is present in patients with Paget's disease of the bone. Low counts of CD4, high counts of CD8, and a low CD4/CD8 ratio were observed in 58 patients compared with controls. These findings were not correlated with the metabolic activity of the disease. After therapy with Elcatonine an improvement in the cellular immunological defect was observed in 15 patients. Etidronate improved the biochemical bone patterns but no changes were observed in the number of lymphocytic subpopulations. These changes can be related to the improvement in the bone metabolic disorder or be the result of an effect on the altered immunity in this disease. PMID- 7846357 TI - [The nutritional problems of the smoker. The role of diet in the appearance and progress of cataracts]. PMID- 7846356 TI - [Candida endocarditis in non-addict patients: a disease with high mortality. A clinico-pathological study of 3 cases]. AB - Candida endocarditis is a rare infection which occurs under particular epidemiological circumstances, such a drug addiction, immunosuppression, prolonged intravenous therapy and valvular replacement surgery. Diagnosis requires a high suspicious index and is based on the demonstration of the organism in cardiac vegetations, peripheral embolisms or in positive blood cultures; also when valvular insufficiency murmurs, embolic phenomena and echocardiogram-proved vegetations are present. In spite of antifungal therapy and valvular replacement, the mortality rate in Candida endocarditis is still higher than 80%. Three new cases of the entity are here reported stressing the diagnostic and therapeutical difficulties. PMID- 7846358 TI - [Epigastric pain and a filling defect in the second portion of the duodenum]. PMID- 7846359 TI - [Fever, jaundice and pain in the right hypochondrium]. PMID- 7846360 TI - [The treatment of Candida-induced endocarditis. The arguments for a medical surgical focus]. PMID- 7846361 TI - [An acute familial picture of headache and digestive disorders with a fatal outcome. Clinica Puerta de Hierro, Madrid (24 October 1994)]. PMID- 7846362 TI - [Hypoglycemia after the resection of a pheochromocytoma]. PMID- 7846363 TI - [Malignant lumbago-sciatica]. PMID- 7846364 TI - [Immune thrombocytic purpura as the form of presentation of a non-Hodgkin's lymphoma]. PMID- 7846365 TI - [Captopril-induced pemphigus]. PMID- 7846366 TI - [An upper digestive hemorrhage due to a primary aortoenteric fistula]. PMID- 7846367 TI - The role of laryngeal mask airway in cardiopulmonary resuscitation. AB - The laryngeal mask airway (LMA) has been newly introduced to anaesthesia practice as an alternative to the endotracheal tube (ETT) or face mask for airway management. It is capable of providing a rapid and easily achieved patent airway that permits positive pressure ventilation within confined limits. In this study, we aim to evaluate the role of the LMA in cardiopulmonary resuscitation (CPR) in 20 patients as an alternative to tracheal intubation. Study parameters included measurement of oxygen saturation by a pulse oximeter and end-tidal carbon dioxide level (ETCO2) using the Fenem CO2 analyser. Five of these 20 cases were resuscitated using endotracheal tubes as a control group. Seven cases were resuscitated using LMA only and eight cases were resuscitated using LMA initially followed by ETT for long term ventilation. In the LMA groups I and III, 12 patients had LMA inserted at the first attempt and three at a second attempt. We concluded that LMA is a good alternative to ETT, although it may not protect against aspiration. We recommend it to be included in CPR chart cards and all medical doctors, nurses and paramedical staff should learn how to use it. PMID- 7846368 TI - The laryngeal mask airway in resuscitation. AB - Previous work has shown that insertion of the laryngeal mask airway is a skill that is easily taught to inexperienced operators. In this study we have assessed the ability of non-anaesthetists to maintain an airway in a paralysed, anaesthetised patient in the controlled setting of an anaesthetic room. The methods used to maintain the airway included a tightly fitting facemask, using a one-handed and two-handed technique, and a laryngeal mask airway. The inspired volume delivered to the patients was standardised using a Penlon Nuffield ventilator attached to the breathing system. Our results showed no difference in success in maintaining the airway between the three techniques or in the mean expired volumes achieved during successful ventilation. PMID- 7846369 TI - Training for the use of the laryngeal mask in emergency and resuscitation situations. AB - It has been suggested that the laryngeal mask has a role to play in the management of the airway during resuscitation both from cardiac arrest and possibly major trauma. Should it be introduced for this purpose, there will be a need to provide training for a very large number of paramedical staff. Currently training in advanced airway management techniques involves live patient practice in theatres; clearly this system is already reaching a limit as paramedics in training often have some difficulty in reaching the prescribed number of procedures. This paper describes experience with a possible alternative utilising only classroom teaching. PMID- 7846370 TI - Active compression-decompression CPR: a progress report. AB - Within the last several years a new method of CPR, termed active compression decompression (ACD) CPR was developed. Based upon the theory that active rather than passive chest wall decompression would augment venous return and ventilation by causing an increase in negative intrathoracic pressure during the decompression phase of CPR, a hand-held device was designed and is now being used clinically. Studies in dogs and pigs in ventricular fibrillation have demonstrated a significant improvement in systolic blood pressure, coronary perfusion pressure and total brain and myocardial blood flow with ACD CPR compared with standard CPR. Animal and human studies suggest that the mechanism of ACD CPR is complex, with coronary perfusion occurring during both the compression and decompression phases. Clinical studies comparing ACD to standard CPR in patients in cardiac arrest demonstrate that immediate resuscitation rates are nearly doubled when ACD CPR is started within 10 min after cardiac arrest. The potential long term benefits of ACD CPR remain under investigation. PMID- 7846371 TI - Combined acute respiratory and renal failure: management by continuous hemodiafiltration. AB - OBJECTIVES: To study the impact of continuous hemodiafiltration (CHD) on the morbidity and mortality of acute combined respiratory and renal failure in critically ill patients. DESIGN: Prospective clinical study. SETTING: Intensive Care Unit of a tertiary institution. PATIENTS: One-hundred fifteen critically ill patients with combined acute respiratory and renal failure. INTERVENTIONS: Treatment of all patients with either continuous arteriovenous hemodiafiltration (CAVHD) or continuous venovenous hemodiafiltration (CVVHD). MEASUREMENTS: Assessment of illness severity, measurement of plasma urea, serum creatinine, electrolytes and arterial blood gases prior to and during treatment. Duration of oliguria, ICU stay, hospital stay, and final outcome. RESULTS: One hundred fifteen critically ill patients with combined respiratory and renal failure (mean APACHE II score, 28.1; mean number of failing organs, 4.1) were studied. Thirty five were treated with CAVHD and 80 with CVVHD for a mean treatment duration of 13.1 days per patient (range 2-47). Blood urea concentration fell from a mean of 29.4 mmol/l to a mean of 19.1 mmol/l (P < 0.001) and the serum creatinine concentration fell from a mean of 520 mumol/l to a mean of 374 mumol/l after 24 h of therapy (P < 0.001). The A-a gradient fell from a mean of 301 mmHg to a mean of 242 mmHg (P < 0.05). Despite the high degree of illness severity and the need for vasoactive drug infusion in 105 patients (91.3%), survival to hospital discharge was achieved in 33 patients (28.7%). For patients who required > 72 h of combined mechanical ventilation, survival was 22% (22 of 100 patients). Complications of continuous hemodiafiltration were few and all related to arterial vascular access. CONCLUSIONS: In critically ill patients with combined acute respiratory and renal failure, continuous hemodiafiltration controlled azotemia without hypotension and with early improvement in gas exchange. PATIENTS treated with this approach achieved promising survival rates. Our findings support the view that CHD is safe and effective and that it offers important advantages over intermittent hemodialysis. It may be the dialytic therapy of choice in critically ill patients with combined acute respiratory and renal failure. PMID- 7846372 TI - Cardiopulmonary resuscitation after thoracic surgery: echocardiographic observations. AB - We report echocardiographic observations during external chest compression in a patient with marked abnormalities in thoracic anatomy following emergency surgery of aortic arch aneurysm. Transesophageal echocardiography demonstrated direct right ventricular, aortic and left atrial compression, only minimal left ventricular compression and an open mitral valve during closed chest heart massage. Colour flow doppler demonstrated forward blood flow across the mitral valve and along the left ventricular outflow tract during the compression phase. Echocardiographic findings indicate that factors apart from simple cardiac pump mechanism contributed to blood flow during cardiopulmonary resuscitation (CPR) in this postoperative patient after a major thoracic surgical intervention. PMID- 7846374 TI - Ventilation caused by external chest compression is unable to sustain effective gas exchange during CPR: a comparison with mechanical ventilation. AB - OBJECTIVE: To compare the tidal volume, minute ventilation, and gas exchange caused by mechanical chest compression with and without mechanical ventilatory support during cardiopulmonary resuscitation (CPR) in a laboratory model of cardiac arrest. DESIGN: A laboratory swine model of CPR was used. Eight animals with and eight animals without mechanical ventilation received chest compression (100/min) for 10 min. Coronary perfusion pressure, tidal volume, and minute ventilation were recorded continuously. INTERVENTIONS: Ventricular fibrillation for 6 min without CPR, then mechanical chest compression for 10 min. RESULTS: During the first minute of chest compression, mean (+/- S.D.) minute ventilation was 11.2 +/- 5.9 l/min in the mechanically ventilated group and 4.5 +/- 2.8 l/min in the group without mechanical ventilation (P = 0.01). Minute ventilation gradually declined to 5.8 +/- 1.4 l/min and 1.7 +/- 1.6 l/min, respectively, during the last minute of chest compression (P < 0.0001). After 10 min of chest compression, mean arterial pH was significantly more acidemic in the group without mechanical ventilation (7.16 +/- 0.13 compared with 7.30 +/- 0.07 units) and PCO2 was higher (62 +/- 19 compared with 35 +/- 9 mmHg). Mixed venous PCO2 was also higher (76 +/- 15 compared with 61 +/- 8 mmHg). CONCLUSION: Standard chest compression alone produced measurable tidal volume and minute ventilation. However, after 10 min of chest compression following 6 min of untreated ventricular fibrillation, it failed to sustain pulmonary gas exchange as indicated by significantly greater arterial and mixed venous hypercarbic acidosis when compared with a group receiving mechanical ventilation. PMID- 7846373 TI - Changes in arterial and mixed venous blood gases during untreated ventricular fibrillation and cardiopulmonary resuscitation. AB - This investigation was designed to evaluate the changes in arterial and mixed venous acid-base conditions during untreated ventricular fibrillation and after institution of cardiopulmonary resuscitation (CPR). Fifty-two swine (weight: 25 40 kg) were studied after induction of ventricular fibrillation. In a subgroup of 10 animals, 10-min CPR trials were performed. Arterial and mixed venous blood gases were monitored at baseline, after 5 min of untreated ventricular fibrillation (nonintervention interval) and after 10 min of mechanical CPR. Standard CPR was performed at compression rates of 100/min with a 60% duty cycle. Arterial pH, Pco2, and HCO3 were unchanged when baseline values were compared with those obtained after 5 min of untreated ventricular fibrillation, while arterial Po2 decreased from 81 to 69 torr. Mixed venous pH decreased from 7.41 to 7.35, Pco2 increased from 43 to 48 torr, Po2 decreased from 40 to 38 torr and HCO3 decreased from 28 to 26 mEq/l (P < 0.05). Although these changes were statistically significant, many remain in the normal range. Both arterial and mixed venous pH and HCO3 fell further after 9 min of CPR and Pco2 increased (P < 0.05). Alterations in mixed venous pH and Pco2 were more apparent than corresponding changes in arterial blood gas composition. We conclude that untreated cardiac arrest may be accompanied by normal arterial and mixed venous blood gas levels. Tissue acidosis is only revealed after tissue perfusion is restored and is most accurately reflected in the mixed venous blood gas composition. This apparent paradox provides insight into the relationship between tissue perfusion and arterial and mixed venous acid-based composition. PMID- 7846375 TI - Management of peri-arrest arrhythmias. A statement for the Advanced Cardiac Life Support Committee of the European Resuscitation Council, 1994. PMID- 7846376 TI - European Resuscitation Council. PMID- 7846377 TI - Mediators, mechanisms and mortality in major trauma. PMID- 7846378 TI - The laryngeal mask in resuscitation. PMID- 7846379 TI - The role of the laryngeal mask airway in pre-hospital care. AB - Since its introduction into clinical practice in 1988, the laryngeal mask airway (LMA) has fundamentally changed the airway management of patients undergoing routine anaesthesia. Currently in the UK, the LMA is used in > 50% of surgical procedures where an endotracheal tube (ETT) would formerly have been used. It seems timely to review the role of this device in resuscitation and its potential role in the pre-hospital arena. PMID- 7846381 TI - Stereotactic microsurgical resection of cerebral lesions. AB - We describe our experience with stereotactic microsurgical resection of 27 lesions using the Leksell frame in 23 patients; 7 had cerebral metastases, 6 had gliomas, 6 had vascular malformations, 3 had meningiomas and 1 had radiation necrosis. Gross total removal of the lesion was accomplished in every case. All lesions were between 1.0 and 3.5 cm in greatest diameter and located either deep within the cerebral (n = 7) or superficially in areas of functional cortex (n = 20). There was no operative mortality and only minimal morbidity. Average length of operating time including frame application, imaging and resection was 4.4 h and most patients were discharged on the second postoperative day. The indications, advantages and limitations of stereotactic craniotomy are discussed and technical modifications that extend the usefulness and safety of this technique are described. PMID- 7846380 TI - Changes in hypothalamic met-enkephalin levels of rats induced by painful stimulation and morphine treatment. AB - The possible influence of painful stimulation and morphine analgesia on hypothalamic met-enkephalin levels, and the possible correlation between this biochemical parameter and animal behaviour was studied. The results indicate that both painful stimulation and morphine treatment induce an increase in hypothalamic metenkephalin. On the other hand, naloxone did not cause any variation. In animals submitted to painful stimulus, morphine treatment induced a decrease in hypothalamic met-enkephalin levels. Finally, when both morphine and naloxone were administrated before nociceptive stimulation, much higher levels were measured. There was no correlation between the level of hypothalamic met enkephalin and the pain rating. PMID- 7846382 TI - Accuracy in frame-based and frameless stereotaxy. AB - Stereotactic surgery is currently undergoing great changes with a large number of frameless methodologies being developed alongside traditional frame-based systems. As a result, there is considerable uncertainty over the future clinical roles of the numerous stereotactic options now offered. We have reviewed the current scientific issues regarding accuracy in both frame-based and frameless stereotaxy. Frame-based systems have the advantage of proven clinical utility and instrument carriage with a high degree of mechanical stability and accuracy. Frameless methods are more complex, but also more flexible, and may have wide applications in general neurosurgery if clinical efficacy is confirmed. PMID- 7846383 TI - Three-dimensional angiography for CT-guided stereotactic procedures: a new system. AB - A new CT-guided stereotactic system using tridimensional angiography is described. The trajectory is directly determined from a moving probe ('floating line') which appears on a tridimensional stereoscopic angiography, permitting the choice of an avascular trajectory with a high degree of accuracy. The authors have done 84 probe implantations with an excellent diagnostic and therapeutic rate and no morbidity-mortality. PMID- 7846384 TI - [Apropos of the article: "From sedimentation rate to inflammation profile"]. PMID- 7846385 TI - [Parenchymatous abscess in Streptococcus anginosus (Streptococcus milleri) septicemia. Value of their systematic search, apropos of 4 cases]. AB - Streptococcus anginosus, the term suggested to cover a set of streptococci previously known under various names (milleri, MG, anginosus, intermedius, constellatus), is characterized by a propensity to create parenchymatous abscesses, essentially cerebral or hepatic, particularly within the terms of septicemia. These abscesses are sometimes difficult to detect due to a difficult or non-existent symptomatology. The authors report on four cases illustrating the necessity to search for them systematically by cerebral CT scan and abdominal echography or CT scan in all cases of septicemia caused by Streptococcus anginosus. PMID- 7846386 TI - ["Primum non nocere". Prospective study of 115 cases of iatrogenic diseases collected over one year in 106 patients]. AB - One hundred and fifteen cases of iatrogenic disorders were observed in 106 patients during a one-year prospective study. Each case was included after informed agreement of two investigators. Each case was classified into 4 groups, according to duration time between iatrogenic disorder and hospitalization, and into 3 sections according to responsibility of causative agent. A control group of 200 patients matched for age and sex was studied. Patients represented 8% of the hospitalisations. Mean age (69.2 years) was higher than other patients hospitalized during the same period (61.6 years). Principal causative agents were diuretics (30), physchotrops (13) and technic examinations (12). Main pathologies were electrolytes disorders (28), orthostatic hypotension (19), confusion and/or alteration of mental functions (13), and cutaneous or allergic disorders (12). Mean induced hospitalization duration time was of 8 days. Mean estimate cost was 18,808 francs per patient. Associated factors were elderly, and an elevated number of drugs. A negligency could participate to iatrogenic disorders in 50% of cases. Half part of iatrogenic disorders could be avoided by using simple precautions: respect of contra-indications, restriction on self-therapy and of number of associated drugs. PMID- 7846387 TI - [From sedimentation rate to inflammation profile]. AB - The main biological sign of inflammation is an increase in erythrocyte sedimentation rate (ESR). However it can be falsely normal (polyglobulia, cryoglobulinemia, hemoglobinopathy) or spuriously high in the absence of inflammation (anemia, hypergammaglobulinemia). In cases of doubt, the acute phase reactants (APR) should be measured: C reactive protein (CRP), fibrinogen, haptoglobin, alpha 1 acid glycoprotein. They have different kinetics of variation and various degrees of increase (some--the so called "negative" proteins- actually decrease). Several pitfalls can be avoided if it is remembered that the APR themselves can be modified by causes other than inflammation: low fibrinogen in intravascular coagulation, very low haptoglobin in hemolysis, raised orosomucoide in renal insufficiency and elevated transferrin in iron deficiency. Furthermore liver insufficiency or leakage through the kidney or gut lesions can lower them. In some patients, the observed levels of APR are thus the result of opposite trends. In complex cases, these pathological mechanisms are more apparent on profiles which express the concomitant blood levels of several APR in a normalized or comparative manner. In medical practice, ESR serves first and foremost to detect an inflammatory syndrome. CRP is prominent among the APR because its changes show a great sensitivity, are independant of those of ESR and have a time course fitting closely that of the inflammatory processes. Profiles yield detailed information but rarely provide major evidence in the quest of a diagnosis or the choice of a treatment. Because of their cost they are to be used only in difficult cases. PMID- 7846388 TI - [Late post-irradiation cervical spinal cord disease. A case]. AB - A case of delayed progressive radiation myelitis (DPRM) which begin 11 months after naso pharyngeal carcinoma radiation, in a young man, is reported. The initial manifestation is often a Brown-Sequard's syndrome progressing to complete and permanent myelopathy, with notable absence of localized or radicular pain. The parenchymal change of the spinal cord in radiation myelopathy can be easily visualized with magnetic resonance imaging (MRI) however there may be cases in which MRI appearance alone does not distinguish specially between tumor and radiation necrosis with absolute confidence: therefore, DPRM is by necessity a diagnosis of exclusion, based on clinical, paraclinical results and course of disease. Corticosteroid therapy is accompanied by a significant remission of symptoms. The evolution is characterized by a worse prognosis, prevention is absolutely necessary based on perfect radiation technic, knowledge on tolerance of spinal cord to irradiation (time-dose-volume factors) and other risks factors (chemotherapy, age and vascular disease). PMID- 7846389 TI - [Cardiac complications in adult onset Still disease: from pericarditis to tamponade as manifestations]. AB - Pericarditis is a common manifestation of adult still's diseases (ASD), observed in 20% to 3% cases. Pericardial tamponade is more seldom, less than ten cases have been reported in the literature. We reported two observations of patients with ASD and pericardial tamponade above a series of 18 patients with ASD, in one case revealed the disease. The first patient was a 32-year-old women and had fever, arthritis, high white blood cell count and developed pericardial tamponade. The evolution was favourable with bolus of methylprednisolone. In the second case, cardiac tamponade occurred several years after the onset of the disease. Surgical drainage was first required (800 ml) because of inefficacity of oral prednisone. A dramatic improvement was observed after bolus of methylprednisolone. In conclusion pericardial tamponade is a seldom but sometimes the first manifestation of ASD and may required in first intention bolus of methylprednisolone. PMID- 7846390 TI - [Hepatic granulomatosis associated with mononucleosis syndrome secondary to cytomegalovirus infection: apropos of 2 cases in healthy adults]. AB - In this study, the authors report two observations of granulomatous hepatitis. The secondary appearance of a mononucleosis syndrome, three weeks after the onset of fever, in healthy adults, evoked the diagnosis of a cytomegalovirus infection. The authors insist on the histologic and virologic differences of the CMV infection between the healthy adults and the immunodepressed patients. They also note the difficulties of the diagnosis of the CMV infection in healthy adults. PMID- 7846391 TI - [Sarcoidosis of the upper respiratory tract. Review of the literature apropos of 2 cases]. AB - We describe two cases with sarcoidosis affecting upper respiratory tract. This uncommon localization, may occur in patients with previously diagnosed sarcoidosis, but it may be the first or the only manifestation of the disease. A severe upper airway obstruction can occur, necessitating urgent tracheostomy. Systemic corticosteroid therapy is the treatment of choice in most cases. PMID- 7846392 TI - [Antiemetic treatment and chemotherapy: general review]. AB - Chemotherapy-induced nausea and emesis are frequent and patients fearful. Emesis caused by cytotoxic agents can be related to their effects on central chemoreceptor or on the gut chemoreceptor by serotonin. 5HT3 receptor antagonists produce a major improvement in the control of cisplatin induced-emesis (70 to 80% of patients). The 5HT3-antagonist efficacy is significantly better than metoclopramide alone, or antimemetic combinations in highly emetogenic chemotherapy regimens but less good in moderately emetogenic chemotherapy. Studies with 5HT3 receptor antagonist plus corticosteroids show advantage over 5HT3 antagonist alone. Comparison studies between the different setrons didn't show any significant difference. Anticipary emesis are treated with anxiolytic drugs. The prevention of delayed emesis, not yet well controlled by 5HT3 antagonist, is a great therapeutic deal. Finally, some therapeutic problems are not resolved: minimal dose, use of oral route, efficacy in fractionated chemotherapy, treatment after loss of efficacy of 5HT3 antagonist. PMID- 7846393 TI - [Why teach anthropology of the body?]. AB - Man is not only a body. It is relevant to reiterate that task of medicine is to relieve man's suffering and not to repair a mechanism. If medicine is a science concerning human body, it is not a human science. Anthropology of the body studies perceptions, representations and values concerning the body in human societies. Its point of view is cultural, not biologic. To understand the cultural representations of the body allows us to understand and better cure man. Yet, medical and anthropological knowledge are bound together. PMID- 7846394 TI - [Guillain-Barre syndrome in Horton disease]. PMID- 7846395 TI - [Clinical and therapeutic characteristics of pneumococcal infections. A propos of a case]. PMID- 7846396 TI - [Polymyalgia rheumatica in primary biliary cirrhosis: value of the search for antimitochondrial antibodies in rhizomelic pseudo-polyarthritis and Horton disease]. PMID- 7846397 TI - [Mesangiocapillary glomerulonephritis of fatal outcome in Still's disease]. PMID- 7846398 TI - Proceedings of the Conference Quantitative Methods for Studying AIDS. Blaubeuren, Germany, 14-18 June 1993. PMID- 7846399 TI - Studies of AIDS and HIV surveillance. Screening tests: can we get more by doing less? AB - Estimating the prevalence of the human immunodeficiency virus (HIV) in a group is challenging; this is especially so when the prevalence is small. One reason is that the presence of measurement errors resulting from the limited precision of tests makes estimation, using traditional methods, impossible in some screening situations. Measurement error is real, ignoring it leads to severe bias, and inference about the prevalence becomes unsatisfactory. Indeed, in a low prevalence situation the expected number of false positives is very high, often even higher than the number of true positives. The second reason is that in the low prevalence areas the large sample is needed in order to obtain non-zero estimate. This is usually a very costly, and often unrealistic, solution. This paper considers the advantages and disadvantages of pooled testing as an alternative solution to this problem. We show that by pooling sera samples we not only achieve a cost saving but also, which is counterintuitive, an increase in the estimation accuracy. We also discuss the statistical issues associated with the resulting estimator. PMID- 7846400 TI - Seasonal and other short-term influences on United States AIDS incidence. AB - This paper models monthly AIDS diagnosis counts in terms of smooth secular trend, calendar month effects, and the number of workdays per month. A parameterization of month effects allows separation of true seasonal effects from a linear trend over the calendar year and an arbitrary June effect. There is strong evidence for seasonal patterns, other calendar month effects, and workday effects. Examination of subgroups defined by reporting delay, initial diagnosis, risk group, and region shows evidence for seasonal patterns in some diagnosis groups, for effects due to imputed diagnosis dates, and for effects due to patients' choices of when to seek diagnosis. PMID- 7846401 TI - Prediction and validation in the public health modelling of HIV/AIDS. AB - Mathematical models are an integral part of long-range scientific research and are broadly equivalent to the hypotheses to be tested. Validation consists: (1) in checking whether theoretical expectations are sufficiently close to observed values; and (2) in showing that theoretical constructions that pass the first test can also make verifiable predictions of future events. When modelling is used in operational situations to assist practical decision-making, as in the public health surveillance, prediction and control of infectious diseases, especially HIV/AIDS, it is easy to use the first criterion, but not so simple to implement the second. The paper discusses various methods of improving the validation of a specific classical compartmental model of HIV/AIDS geared to good serial public health data on AIDS incidence. These methods include model fitting to existing data, cross-checking findings with independent research results, general circumstantial support, and the possibility in special situations of the quasi-prediction of present or recent data using models fitted only to sufficiently distant past data. PMID- 7846402 TI - Dependent HIV incidences in back-projection of AIDS incidence data. AB - Techniques for reconstructing plausible HIV incidence curves from AIDS incidence data are called methods of back-projection, or back-calculation. Approaches to back-projection tend to make the simplifying assumption that the quarterly HIV incidences are independent, which is not even approximately true. Here we investigate whether smoothed non-parametric back-projection based on this simplifying assumption gives sensible back-projections and appropriate measures of precision for these reconstructed HIV incidence curves. Simple models for HIV transmission are shown to have much greater variation than the corresponding non homogeneous Poisson process arising from the independence assumption. Nevertheless, bearing in mind that the objective is to reconstruct the HIV epidemic curve for the current epidemic, it is argued that such back-projection does give sensible HIV curves. This conclusion is supported by a simulation study, which also finds that confidence intervals for the HIV incidences are wider for transmission data than those determined from independent Poisson data. PMID- 7846403 TI - Using time of first positive HIV test and other auxiliary data in back-projection of AIDS incidence. AB - Estimation of HIV incidence by the method of back-projection typically uses data on the time of diagnosis of AIDS cases, together with known information about the incubation distribution of AIDS. This paper discusses back-projection using auxiliary data on AIDS cases, particularly the time of first positive HIV test. We discuss the possibility that certain types of auxiliary data, including time of first positive test, can be useful in back-projection because they provide extra information about the incubation period of AIDS cases. Under a back projection model, theoretical efficiency calculations are given comparing back projection with and without the time of first positive HIV test of AIDS cases. These calculations suggest that such data have the potential to significantly improve HIV incidence estimates, particularly in the recent past. Smoothed non parametric estimates of both HIV incidence and time-dependent testing rates are described. These can be obtained using the EM algorithm, in conjunction with a smoothing step or a penalized likelihood. The benefit of these methods in practice needs to be assessed as such data become available. PMID- 7846404 TI - Backcalculation models of age-specific HIV incidence rates. AB - This paper extends the use of backcalculation to estimate past incidence of HIV infection in different age groups from age-specific counts of AIDS incidence. The approach is flexible and allows the distribution of age at HIV infection to change over time. In this new approach, the incubation distributions used to backcalculate HIV infection rates depend on the age at HIV infection, because younger age is associated with slower progression. The effect of age on progression is estimated from a joint analysis of natural history data from several cohort studies of gay and bisexual men. As in previous applications, the incubation distributions also change over time to accommodate treatment effects and the 1987 revision of the surveillance definition. The method is applied to AIDS incidence data for the United States population. Estimated infection incidence for the entire population declined from peak levels seen in the mid 1980s. However, persons under age 25 years have accounted for an increasing proportion of new HIV infections as the epidemic has progressed. Quantitative estimates were sensitive to the assumed incubation distribution, but the trend toward younger age at HIV infection was apparent using several models of the incubation distribution. Although the models are computationally intensive, they provide useful information about seroincidence trends in different age groups. PMID- 7846405 TI - Back-projection of German AIDS data using information on dates of tests. AB - The paper presents an application of back-projection methods to the reported AIDS data which are collected by the AIDS Center in the Federal Office of Health, Berlin. The analysis is based on all data reported up to 31 December 1992. The data are broken down by major risk groups. Correction for reporting delays takes into account temporal changes in their distribution. The paper applies the EMS algorithm for the estimation of HIV incidence. The incubation period is modelled according to a convolution of several exponential distributions which describe time dependent phenomena like change of case definition and therapy effects. For each case it is reported whether an antibody test has been performed before diagnosis, and if yes, at what time this test was performed. The modelling of the incubation distribution takes into account the transition from a state 'not yet tested' into a state 'tested'. Only tested individuals in three pre-AIDS states are eligible for treatment. The model allows us to estimate not only the current total HIV prevalence but also a breakdown into those that are not yet tested, those that are tested but not yet treated and those that are under treatment. The results depend on the assumptions about the effect of treatment and on the degree of smoothing applied in the EMS algorithm. PMID- 7846406 TI - Incorporating HIV test data into forecasts of the AIDS epidemic in Scotland. AB - For AIDS cases in Scotland the date of HIV antibody positive diagnosis (HIV test date) is recorded on the AIDS case reports. Data are also available on the total numbers of individuals with HIV positive test reports in Scottish laboratories in each year since testing became available. These data are incorporated into a model of the HIV epidemic described in terms of testing rates by calendar year. The HIV infection curve is modelled as a step function, and the testing rates are allowed to differ between steps. Results are presented for intravenous drug users (IDUs) and for homosexual/bisexual men. The estimated rates of testing for the IDUs (estimates from 19 per cent to 44 per cent per year) are considerably higher than those for homosexual/bisexual men (estimates of 10 per cent to 17 per cent per year). Data on the year of testing for AIDS diagnoses gave relatively little improvement in estimates of the HIV infection curve. However, when this information is combined with data on the total number of HIV positive diagnoses per year, there is a dramatic improvement in the estimate of the HIV infection curve. This is particularly marked for infections in the most recent period and for the estimates of cumulative infections up to the present. However, these improvements are gained at the cost of assumptions of similar testing rates applying to all sections of the HIV infected populations, which will be difficult to check in practice. This suggests that these methods should not be used in isolation but in combination with other evidence about the spread of HIV infection in a population. PMID- 7846407 TI - The effect of covariates on the induction time of AIDS using improved imputation of exact seroconversion times. AB - This paper explores the effects of covariates such as age, gender, chronological time of seroconversion, and mode of virus transmission on the interval between HIV seroconversion and the development of AIDS. For many cohorts which are available to provide information about such effects, both the time of seroconversion and the time of onset of AIDS may be right- or interval-censored. To analyse these doubly-censored data, we propose a method in which we first estimate the marginal distribution of the chronological time of seroconversion and use this distribution to impute the seroconversion time for each subject. Subsequently, we estimate the distribution of induction times conditional on the seroconversion distribution. We apply this technique to a cohort of HIV seropositive subjects recruited from various outpatient facilities throughout Italy and show that age at seroconversion has the greatest effect on induction time. PMID- 7846408 TI - Distribution of the latency period for perinatally acquired AIDS. AB - In the United States, over 86 per cent of paediatric cases of acquired immunodeficiency syndrome (AIDS) were infected through maternal or perinatal transmission and current estimates suggest that approximately 6000 children are born to infected women each year. In industrialized countries, less than 25 per cent of infants maternally exposed to the human immunodeficiency virus (HIV) are infected. The exact time of infection is unknown. However an endpoint, birth, exists from which the latency period or the time to diagnosis with clinical AIDS can be measured. In New York City, 7 years of reliable surveillance data were available for children with perinatally acquired AIDS. Using these data, the only estimable aspect of the latency is a conditional distribution, which conditions on diagnosis occurring before age 7. Because newborns carry maternal antibodies, a positive antibody test at birth is only an indication of maternal infection. Screening all newborns for HIV antibodies, while maintaining the anonymity of the mother and child, provides data on the number of children maternally exposed. The above conditioning can be removed by combining the surveillance and newborn screening data to obtain the unconditional latency distribution. We estimate a median diagnosis age of 4.1 years, somewhat longer than previously believed. PMID- 7846409 TI - Non-parametric analysis of transfusion-related HIV and AIDS incidence data. AB - The method for making non-parametric inferences about the probability distribution of the incubation period for AIDS from transfusion-related AIDS data is extended to include data on individuals who have tested positive for HIV but do not have AIDS at the time of analysis. The method is illustrated with data on individuals infected by transfusion in Australia. The shape of the incubation distribution, as represented by the truncated distribution function, can be estimated, but the additional data contribute very little to the estimation of this shape. With a general non-parametric form for the incubation distribution the additional data do not overcome the identifiability problem that exists for non-parametric estimation of this distribution from AIDS data alone. If quarterly rates for HIV testing are specified, the additional data make it possible to estimate the cumulative distribution function for the incubation period. This is also possible when a simple parametric form, with one or two unknown parameters, is used for the testing rates. However, the additional data do not allow effective estimation of the HIV testing rates. The estimated shape of the incubation distribution indicates a higher proportion of short incubation periods than an earlier estimate based on U.S. data. Estimates for the incubation distribution itself do not vary much over a plausible range of HIV testing rates. PMID- 7846410 TI - Marker values at the time of an AIDS diagnosis. AB - In this paper statistical methods are proposed to estimate the distribution of a CD4 T-cell number at the time of a clinical AIDS endpoint from serial measurements of CD4 T-cell values in a cohort study. The statistical formulation of the problem is that of survival analysis with interval censored data, but in which the endpoints are obtained with measurement error. A measurement error likelihood is developed, assuming normality of the CD4 distribution at AIDS. A maximum likelihood estimation procedure and a Gibbs sampling approach are implemented. PMID- 7846411 TI - A model for AIDS pathogenesis. AB - The idea is put forward and analysed numerically, that within an infected person HIV evolves to increase its reproductivity within the population of CD4+ cells. A mathematical model predicts initial viremia and CD4+ cell drop after HIV infection and thereafter a slow progressive decline in the number of CD4+ cells, although for an extended period HIV is kept at a relatively low level by an active immune response. The time span T until the number of CD4+ cells falls below 20 per cent of its normal value depends on several model parameters. Assuming Gaussian distributions for these parameters, the model predicts a distribution function for T which resembles the observed distribution function for the incubation period to AIDS. PMID- 7846412 TI - Non-parametric estimation and doubly-censored data: general ideas and applications to AIDS. AB - In many epidemiologic studies of human immunodeficiency virus (HIV) disease, interest focuses on the distribution of the length of the interval of time between two events. In many such cases, statistical estimation of properties of this distribution is complicated by the fact that observation of the times of both events is subject to intervalcensoring so that the length of time between the events is never observed exactly. Following DeGruttola and Lagakos, we call such data doubly-censored. Jewell, Malani and Vittinghoff showed that, with certain assumptions and for a particular doubly-censored data structure, non parametric maximum likelihood estimation of the interval length distribution is equivalent to non-parametric estimation of a mixing distribution. Here, we extend these ideas to various other kinds of doubly-censored data. We consider application of the methods to various studies generated by investigations into the natural history of HIV disease with particular attention given to estimation of the distribution of time between infection of an individual (an index case) and transmission of HIV to their sexual partner. PMID- 7846413 TI - Modelling the female-to-male per-act HIV transmission probability in an emerging epidemic in Asia. AB - The per-sexual-act probability of transmission of the human immunodeficiency virus type 1 (HIV) from an infected person to a susceptible sex partner can be determined from a simple model if the number of contacts each study participant has with infected partners is known. The unusual epidemiologic situation in the emerging HIV epidemic in Thailand allowed this quantity to be estimated from a cross-sectional study of young men conscripted into the Thai military in 1991. Although the simple model does not fit the data, an errors-in-variables approach provides a model with adequate fit. Other sources of lack of fit, including heterogeneity of the transmission probability, are discussed. With adjustment for measurement error, the per-act probability is estimated to be 0.056, an order of magnitude higher than similar estimates in North America. Because data indicate that recently infected persons may be more infectious, and because extensive HIV transmission in Thailand began in 1988, this difference may be due, in part, to a higher proportion of recently infected individuals in the emerging Thai epidemic from 1988 to 1991. PMID- 7846414 TI - Considerations in choice of a clinical endpoint for AIDS clinical trials. Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA). AB - In most clinical trials of antiretroviral therapy for patients infected with HIV, the major outcome variable has been the combined clinical endpoint of any new or recurrent AIDS defining event. We review features of combined endpoints and use data from the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) to evaluate this outcome measure in terms of relevance, diagnostic certainty and sensitivity. We conclude that this endpoint is not relevant because: (i) the 19 different events constituting the combined endpoint are equally weighted in analyses even though they vary considerably in terms of risk of death; and (ii) events after the first are ignored, thus the event profile of patients is not taken into account in making treatment comparisons. We also conclude that power may be low with use of this endpoint if treatments under study do not have an immediate impact on disease progression, if some events which occur soon after randomization represent a disease process that has already begun to incubate, or if treatment differences for the various events constituting the combined endpoint are differentially effected by treatment. Since the ease and certainty of diagnosis of each of the 19 events also vary, we recommend that survival be the primary endpoint of antiretroviral trials, and that all opportunistic events experienced by patients, not just the first, be collected and summarized. Trial reports should include comparisons of incidence of each event by treatment group so that readers can rank events as they please. A single summary measure which considers severity and the entire event profile, as described here, would also be useful for assessing the impact of treatments on quality of life. Further research on approaches for weighting and combining multiple outcome measures is needed. PMID- 7846415 TI - The effectiveness of interventions on incubation of AIDS as measured by secular increases within a population. AB - Methods are developed to estimate and test for the impact of intervention use on a population's survival function (time to AIDS). Each participant's history is divided into J + 1 components: omega 0 occurring before the intervention is available and omega 1 to omega J occurring later, as the intervention becomes successively more available. Distribution free truncated Kaplan-Meier models based on time since exposure fit separately to the risk sets/outcomes in omega 0 to omega J directly show the changing patterns of survival. Multivariate proportional hazards models can be used to adjust for covariates. Application of these methods indicates that availability of proven anti-AIDS interventions may have delayed time to AIDS by 8 months in an educated HIV-1 infected homosexual cohort with good access to medical care. PMID- 7846416 TI - Assessing drug compliance using longitudinal marker data, with application to AIDS. AB - The assessment of non-compliance to a study medication is an important issue in the evaluation of clinical trials of self-administered drugs. Traditional methods for evaluating the compliance of subjects include self-reported questionnaires and pharmacologic assays of drug levels in randomly-drawn blood samples, but each of these has important limitations. This paper adapts and extends changepoint methods to assess compliance from longitudinal data on laboratory markers that are affected by the drug. The maximum likelihood estimators for two models are developed and examined. The effect of the drug on the marker process, as well as the spacing of the observations of the marker process relative to the time of non compliance determine which model parameters are estimable. For the situations examined, the method of maximum likelihood is found to perform well in most cases. However, when non-compliance begins shortly before the last observation of the marker process, these (as well as any other) estimators cannot reliably distinguish non-compliance from compliance. The methods are illustrated with an example from a recent clinical trial of persons infected with HIV. PMID- 7846417 TI - Some statistical issues in HIV vaccine trials. AB - Efficacy trials of prophylactic HIV vaccines will be among the most difficult clinical trials ever attempted. Not only will there be challenges with the recruitment and retention of high-risk uninfected individuals, there will be many statistical challenges to the design, conduct, analysis, and interpretation of these trials. General features of an efficacy trial are described, including choice for the primary endpoint and testing for and estimating vaccine efficacy. Secondary objectives of trials are also discussed. These include determining the correlates of protective immunity, assessing the impact of HIV genetic variation on vaccine efficacy, and using biological markers such as viral load and CD4+ lymphocyte cell count to gain insight on a vaccine's ability to prevent or delay disease. The use of biological markers as surrogates for disease outcome is discussed. Last, trial designs for studying several candidate vaccines or other HIV prevention strategies in a single trial are examined. PMID- 7846418 TI - A method for evaluating needle exchange programmes. AB - This paper details a statistical method for evaluating needle exchange programmes. The approach relies only on needle exchange operations data and the results of HIV tests conducted on needles. We develop statistical models describing the needle infection process and how needle exchange interrupts this process. The method is illustrated using 20 months of data collected in conjunction with the evaluation of New Haven, Connecticut's needle exchange programme, and the results suggest that needle-borne HIV transmission among participating clients has been reduced by at least 33 per cent. PMID- 7846419 TI - Mid-P confidence intervals for the Poisson expectation. AB - Conventionally a confidence interval (CI) for the standardized mortality ratio is set using the conservative CI for a Poisson expectation, mu. Employing the mid-P argument we present alternative CIs that are shorter than the conventional ones. The mid-P intervals do not guarantee the nominal confidence level, but the true coverage probability is only lower than the nominal level for a few short ranges of mu. The implications for mid-P confidence intervals of various proposed definitions of two-sided tests for discrete data are discussed. PMID- 7846420 TI - On prediction of future observation in growth curve model. AB - Rao proposed and compared several approaches for predicting future observations in a growth curve model. The assessment of associated prediction efficiency for different prediction methods were evaluated by Cross-Validation Assessment Error (CVAE). He used three data sets, each with a limited number of subjects (13-27) and also with a limited number of repeated measurements (4-7) per subject, to illustrate the prediction methods. In the present paper, we applied four of the prediction methods discussed by Rao, on a data set with a relatively large number of subjects (174) and also with a larger number of measurements (21) per subject, using the polynomial function and log-linear function. We propose to use the restricted cubic spline function as an alternative growth curve model and compare its performance with the polynomial function and log-linear function. It turns out that, at least for larger data sets such as that used in this paper, the prediction methods perform somewhat better when the growth is described by restricted cubic spline function than when the growth is described by polynomial function and log-linear function. PMID- 7846421 TI - Testing for omitted variables and non-linearity in regression models for longitudinal data. AB - When fitting regression models to investigate the relationship between an outcome variable and independent variables of primary interest, there is often concern whether omitted variables or assuming a different functional relationship could have changed the conclusion or interpretation of the results. In longitudinal studies of aging, the concern with omitted variables is well known in the context of cohort and period effects, which refer to unmeasured variables systematically related to the individual's year of birth and secular trends in outcome, respectively. We present and compare three approaches to detecting omitted confounders and non-linearity in the random effects model for longitudinal data (Laird and Ware, 1982) with random slope and intercept across individuals. The first approach compares simple unweighted within and between regression coefficients, the second is the Hausman specification test for regression models, and the third approach involves testing directly the significance of functions of individual specific covariate means means i, in the random effects regression model. This last approach is motivated by the models that arise when cohort or period effects are ignored. We compare the three approaches, and illustrate their application. PMID- 7846422 TI - Cox regression analysis of multivariate failure time data: the marginal approach. AB - Multivariate failure time data are commonly encountered in scientific investigations because each study subject may experience multiple events or because there exists clustering of subjects such that failure times within the same cluster are correlated. In this paper, I present a general methodology for analysing such data, which is analogous to that of Liang and Zeger for longitudinal data analysis. This approach formulates the marginal distributions of multivariate failure times with the familiar Cox proportional hazards models while leaving the nature of dependence among related failure times completely unspecified. The baseline hazard functions for the marginal models may be identical or different. Simple estimating equations for the regression parameters are developed which yield consistent and asymptotically normal estimators, and robust variance-covariance estimators are constructed to account for the intra class correlation. Simulation results demonstrate that the large-sample approximations are adequate for practical use and that ignoring the intra-class correlation could yield rather misleading variance estimators. The proposed methodology has been fully implemented in a simple computer program which also incorporates several alternative approaches. Detailed illustrations with data from four clinical or epidemiologic studies are provided. PMID- 7846423 TI - On the development of the Medical Research Council trial of alpha-interferon in metastatic renal carcinoma. Urological Working Party Renal Carcinoma Subgroup. AB - This paper describes the steps taken by the British Medical Research Council (MRC) in developing the MRC RE01 trial, a randomized clinical trial for patients with metastatic renal cancer; we discuss the reasons for adopting a triangular sequential design and the impact that this has upon the monitoring of the trial. It had been suggested to the MRC that a trial of biological agents for metastatic renal carcinoma should be initiated. The Cancer Therapy Committee (CTC) of the MRC, through its associated site specific working parties, is responsible for designing and co-ordinating randomized trials of alternative treatments in cancer in solid tumours. Since no MRC working party for renal carcinoma existed at that time, development began by the formation of an ad hoc group set up under the auspices of the CTC. They assessed, by means of a postal questionnaire, U.K. interest in the trials of, and modalities utilized for, treatment of renal cancer. The responses focused attention on the important questions to ask and indicated the level of potential collaboration. These responses and related clinical and statistical issues suggested a protocol to compare medroxy progesterone acetate (MPA) against alpha-interferon (alpha-IFN). In view of the special problems of comparing an expensive and potentially toxic therapy with an inexpensive and non-toxic standard, a sequential design was used rather than a fixed sample size design. Statistical issues raised and solutions provided are described. The method of establishing the trial data monitoring committee and a brief review of mortality from renal carcinoma in England and Wales are also included. The trial opened to patient recruitment on 1 January 1992. The formal statements regarding statistical issues that appear in the formal trial protocol (RE01) are set out in the Appendix. PMID- 7846424 TI - A step-down procedure for multiple tests of treatment versus control in each of several groups. AB - Cheung and Holland extended Dunnett's treatment versus control multiple comparison procedure to the case of several groups. Dunnett and Tamhane provided a step-down procedure more powerful than that of Dunnett for situations where the researcher's interest is in testing and not in simultaneous confidence interval estimation. In this paper we show how one can use the approach of Dunnett and Tamhane to devise a testing procedure for the multi-group problem with power greater than that of Cheung and Holland. We illustrate the new procedure with reanalyses of published data from a clinical experiment. PMID- 7846425 TI - The paired availability design: a proposal for evaluating epidural analgesia during labor. AB - The paired availability design (PAD) can reduce selection bias when it is not possible to randomize subjects. PAD consists of independent pairs of experimental and control groups. Within each pair, the intervention is the availability of treatment not its receipt. In the experimental group, the new treatment is made available to all subjects although some may not receive it. In the control group, the experimental treatment is generally not available to subjects although some may receive it in special circumstances. We present a statistic to test a null hypothesis that the receipt of intervention will increase response by a specified non-zero amount delta. We propose this design for use in a study of the effect of epidural analgesia on the rate of Caesarean section. PMID- 7846426 TI - How to establish equivalence between treatments: a one-sided clinical trial in pediatric oncology. PMID- 7846427 TI - Methods for assessing difference between groups in change when initial measurement is subject to intra-individual variation. PMID- 7846428 TI - [Falls in the elderly]. PMID- 7846429 TI - [Patient compliance--possibilities for improvement]. AB - In this last of three parts on patient compliance possibilities to improve compliance are reviewed. Compliance-promoting measures include among others uncomplicated prescriptions (such as one daily dose, drug-combinations and written instructions), frequent, well organized controls and the self-involvement of the patient in his treatment. Employment of well educated assistants attending long term patients shows positive results. Furthermore installment of a good patient-physician relation is one of the most important prerequisites for a good compliance. PMID- 7846430 TI - [Percutaneous mitral valve balloon valvulotomy: technique, indications and results]. AB - Since its introduction into clinical practice ten years ago, percutaneous mitral balloon valvotomy has developed into a well accepted procedure for patients with tight mitral stenosis. The different techniques with their pros and cons are discussed. The indications for mitral balloon valvotomy are based on a solid clinical and echocardiographic examination. The procedure itself requires technical skill and experience. After the procedure there is often a dramatic decrease of symptoms by an almost doubled mitral valve area to values of 1.8 to 2.0 cm2. The rate of complications is acceptable and compares well with surgical valvotomy. The most feared complications are pericardial tamponade (1%) and the development of severe mitral regurgitation in 10%. Percutaneous mitral balloon valvotomy is therefore a first choice therapy for well selected patients with tight, pliable mitral stenosis. PMID- 7846431 TI - [Progesterone, progestagens in premenstrual syndrome, the perimenopause and the menopause]. AB - Progesterone has been the first isolated gestagen. After a short review on the physiology of secretion of progesterone some pharmacologic actions are considered by the authors. Among gestagens, derivatives of pregnane are of special interest, particularly because of fewer, notably androgenic, side effects. After reviewing commercial French and Swiss products the authors focus on three applications: the premenstrual syndrome where progesterone is of interest for local and systemic administration the perimenopause in which several pathologies treatable by gestagens occur Finally the menopause in which progesterone is important in view of its physiologic role. Among the reasons to use progesterone combined with estrogens during menopause, prevention of endometrial cancer is the most important but other advantages are also noted. The authors discuss risk factors for breast cancer during treatment with gestagens in menopause. Finally the authors review compliance and underline the importance of new treatment schedules for the menopause: Continuous treatment, on-demand treatment or menstruation every 3 months. PMID- 7846433 TI - [Acute abdomen caused by enalapril]. AB - This case report describes an unrecognized adverse effect of an ACE inhibitor (enalapril): attack of acute abdominal pain. This symptom was observed 3 times over a period of 5 years in a 43 year old woman, occurring 24 h after she was taking the ACE inhibitor, and disappearing 3 to 5 days after the withdrawal of enalapril. PMID- 7846432 TI - [Upper influx distension in a patient with HIV; unusual localization of an HIV associated lymphoma]. AB - A 33 year old patient was admitted to the hospital because of deteriorated general condition, upper abdominal pain and progressive dyspnea. He had a positive HIV-serology associated with i.v. drug abuse. The CDC classification on admission was B1. There was no history of opportunistic infections, the patient had refused all prophylactic treatment. The physical examination showed an elevated central venous pressure, decreased breath-sound and percussible dullness, the liver was enlarged and a tumor was palpable on chest. The x-ray of the thorax confirmed a pleural effusion. Cytology of the effusion revealed blasts of malignant non-Hodgkin's lymphoma of B-cell type. A CT-scan of the thorax and abdomen showed a tumor mass in the right ventricle and superior vena cava, a pleural effusion and multiple lesions in the liver. The patient refused a palliative chemotherapy with vincristine and prednisone and died few days after admission. PMID- 7846434 TI - [A case from practice (316). Hiccups in grade I reflux esophagitis and hiatal hernia. Suspected coronary heart disease in NYHA II angina pectoris]. PMID- 7846436 TI - [Interactive attention between practitioner and specialist]. PMID- 7846435 TI - [What is your diagnosis? Tinea nigra]. PMID- 7846437 TI - [The role of thyroid ultrasonography in the diagnostic approach to thyroid diseases]. AB - Echography is of increasing importance and is considered of value in the diagnostic approach to thyroid diseases. It is particularly useful for assessment of precise measurements of the thyroid gland and to the clinical physician when he has to judge the benign or malignant nature of nodular lesions, as a complement to fine-needle aspiration-biopsy. PMID- 7846438 TI - [What to do when faced with hyperprolactinemia?]. AB - Hyperprolactinemia causes a certain number of clinical syndromes whose sequels vary much depending on the age group. It is a common affection as frequent in women as in males and it necessitates prolonged treatment. It may have several causes, the most frequent ones are: adverse drug reactions, prolactinomas, disturbed distribution of dopamine and hyperthyroidism. Evaluation includes repeated measurements of prolactin, T4, and TSH, a radiologic work-up including a CT-scan or magnetic resonance imaging. In the case of a prolactinoma the choice of treatment depends on size and evolution of the adenoma. Bromocriptine permits to correct hyperprolactinemia in the majority of cases. After adequate treatment of pituitary adenoma these are no contraindications for pregnancy, once fertility has returned. PMID- 7846439 TI - [sensitivity of bacteria to chemotherapeutic agents (Zurich, 1993)]. AB - This paper describes the incidence of Gram-negative and Gram-positive bacteria susceptible to antibacterial agents. The data are based on all susceptibility tests performed at the Department of Medical Microbiology of the University of Zurich. The evaluation of the results from 1987 to 1993 shows that susceptibilities against the antimicrobial agents tested have not changed markedly in this period with few exceptions. The tables may be of help to the physician in his decision for a 'calculated chemotherapy' of bacterial infections. PMID- 7846440 TI - [Reflection on the comprehension and treatment of psychotic decompensation]. PMID- 7846441 TI - [Psychogeriatrics in Lausanne: retrospective]. PMID- 7846442 TI - [Frontal syndrome--entry point for behavioral psychogeriatrics]. PMID- 7846443 TI - [Senile dementia, vascular dementia]. PMID- 7846444 TI - [Involvement of the visual system in Alzheimer's disease]. PMID- 7846445 TI - [The institution and the multidisciplinary team: survey of a model]. PMID- 7846446 TI - [Should one face the Artridae?... Or, various observations apropos of elderly persons and their family interactions in the occurrence of mental disease]. PMID- 7846447 TI - [The coming together of 2 planets]. PMID- 7846448 TI - [Depressive affect in the elderly person from the viewpoint of psychodynamics]. PMID- 7846449 TI - [Psychogeriatric day hospital in Lausanne. Potential repercussions of the opening of medico-social centers and temporary admission units on part-time hospitalization]. PMID- 7846450 TI - [Consultation-liaison in psychogeriatrics at the Vaud University Hospital Center]. PMID- 7846451 TI - [Placement of a patient with Alzheimer's disease: a difficult decision for the family]. PMID- 7846452 TI - [Crisis in the psychogeriatric practice system]. PMID- 7846453 TI - [SEQUOIA: a contribution to information management for tomorrow's psychogeriatrics]. PMID- 7846454 TI - Regulation of sleep rate and circadian consolidation of sleep and wakefulness in an infant. AB - Observations of sleep and wakefulness were continuously made over an infant's first 6 months by Kleitman and Engelmann. Those data have been reanalyzed using a newly developed tool, fractional-time analysis, and two measures derived from it: 1) sleep rate, the rate at which the infant accumulated sleep; and 2) consolidation, the degree to which episodes of sleep and wakefulness were sustained and clustered. Changes in sleep rate and consolidation were independent and were attributed to separate underlying neural mechanisms. Consolidation increased over the 6-month course of development. This was explained by the development of circadian rhythmicity, which appeared during the 1st month as a free-running, endogenously generated rhythm in sleep-episode durations. Starting in the 2nd month, sleep rate was regulated, and it remained remarkably stable for weeks at a time. Sleep rate decreased over the 6-month period, perhaps because metabolic rate decreased as the infant grew. Short-term (weeks-long) changes in consolidation and sleep rate were explained by "beating" of the non-24-hour, endogenous sleep rhythm with direct effects of the 24-hour environment on sleep and wakefulness. Environmental stimuli eventually entrained the circadian pacemaker, bringing the consolidating periods of wakefulness and sleep into register with day and night. The infant was thereby efficiently exposed to periodic sensory and social stimuli, promoting normal neural development. A model of sleep-wake regulation based on independent mechanisms for circadian timing and sleep-wake regulation is proposed. PMID- 7846455 TI - Changes in sleep and sleep electroencephalogram during pregnancy. AB - The impairment of sleep quality is a common complaint during pregnancy. To investigate the changes in sleep in the course of pregnancy, the sleep electroencephalogram (EEG) was recorded and analyzed in nine healthy women on 2 consecutive nights during each trimester of pregnancy. Waking after sleep onset increased from the second (TR2) to the third (TR3) trimester, whereas rapid eye movement (REM) sleep decreased from the first trimester (TR1) to TR2. Spectral analysis of the EEG in nonrapid eye movement (NREM) sleep revealed a progressive reduction of power density in the course of pregnancy. In comparison to TR1, the values in TR2 were significantly lower in the 10.25-11.0-Hz and 14.25-17.0-Hz bands. In TR3, the significant reduction extended over the ranges of 1.25-12.0 Hz and 13.25-16.0 Hz. The largest decrease (30%) occurred in the 14.25-15.0-Hz band. In REM sleep, the spindle frequency range was not affected, and a minor reduction of power density in some frequency bins below 12 Hz was present only in TR3. The study documents major alterations of the sleep EEG that are not evident from the sleep scores and that may be associated with the characteristic hormonal changes occurring during pregnancy. PMID- 7846456 TI - Patterns of sleep and wakefulness in treated narcoleptic subjects. AB - In most reported studies of treatment for narcolepsy, the efficacy of treatment has been assessed in the sleep laboratory, but not in the natural work and home settings. We therefore assessed the sleep/wake patterns of 25 subjects with narcolepsy, whose symptoms were considered under satisfactory control by the subjects and their physicians, using polygraphic recorders, and compared these with the patterns of 25 control subjects matched for age and gender. Data from one matched pair of subjects were excluded for technical reasons. There was no difference between the two groups of subjects in the total amount of sleep obtained during the 24-hour monitoring period. Narcoleptic subjects had shorter nocturnal sleep latencies and more disrupted nocturnal sleep than control subjects. Despite taking their usual medications, narcoleptic subjects averaged 44 minutes of daytime sleep compared to 4.8 minutes for controls. There was wide variation in the amount of daytime sleep among narcoleptics: 10 subjects did not sleep during the day, whereas the other 14 averaged 2.7 naps per day for an average of 76.2 minutes of daytime sleep. These findings indicate that daytime sleep episodes were common in narcoleptic patients who considered their treatment satisfactory. Wide variations in the amount of daytime sleep may reflect differences in disease severity, responsiveness to medications or willingness to tolerate daytime sleep episodes. PMID- 7846457 TI - Neurochemical studies of human narcolepsy: alpha-adrenergic receptor autoradiography of human narcoleptic brain and brainstem. AB - Studies of human and canine narcolepsy-cataplexy syndrome suggest that noradrenergic function may be abnormal. We used quantitative autoradiography to assess noradrenergic alpha-1 and alpha-2 receptors in several regions of seven human narcoleptic and 18 control brains using [3H]prazosin to evaluate alpha-1 receptors, and [3H]UK14304 and [3H]rauwolscine to evaluate alpha-2 receptors. Specific blocking agents were used in combination with the tritiated ligands to assess alpha-1 and alpha-2 receptor subtypes. Although we found few statistically significant differences between narcoleptic and control brains, there were a number of trends. [3H]Prazosin binding to sites in the amygdala, globus pallidus and putamen was reduced by 22-68%, whereas binding was increased by 40% to the inferior olive and by 84% to portions of the dorsal pons. Binding was similar to control values in other regions. In all seven brainstem regions that were evaluated, the ratio of alpha-1b receptor binding to alpha-1a receptor binding was increased. Binding of [3H]UK14304 was increased by 35-74% in the caudate nucleus, putamen and portions of the amygdala and pons. [3H]rauwolscine binding data suggested that increase of alpha-2 receptor binding in the dorsal pons were not due to effects at the imidazole receptor. findings suggest that noradrenergic function may be altered in specific regions of the brain and brainstem in human narcolepsy, although the absence of statistical significance indicates that these trends should be considered preliminary. The trend toward a relative increase of alpha-1b receptor binding in narcoleptic brainstem is consistent with data from studies of canine narcolepsy and suggests that altered activity at this receptor may contribute to the pathogenesis of human narcolepsy. Studies of additional brains will be required to confirm these findings. PMID- 7846458 TI - Sleep paralysis in Chinese: ghost oppression phenomenon in Hong Kong. AB - Despite reports of wide variation in the prevalence of sleep paralysis among different ethnic groups, there has never been any study in Chinese. In Hong Kong, a condition known as ghost oppression is descriptively identical to sleep paralysis. To examine this phenomenon, the response of 603 undergraduate students to a questionnaire were analyzed. Thirty-seven percent had experienced at least one attack of ghost oppression. There was no sex difference in the prevalence, and the peak age of onset was at the range of 17-19 for both sexes. A strong familial association was found and 20% of subjects reported a positive family history. Over one sixth of the subjects identified sleep disruption and stress as precipitating events. PMID- 7846459 TI - Insulin levels, blood pressure and sleep apnea. AB - This report concerns the relative contributions of body weight and sleep apnea to the following cardiovascular risk factors: blood pressure, fasting insulin and fasting glucose. We cross-sectionally examined the relationship of various levels of apneic activity [apnea-hypopnea index (AHI)] and a measure of obesity [body mass index (BMI)] to mean morning blood pressure and fasting serum insulin and fasting blood glucose concentrations sampled the morning after polysomnography. Subjects were 261 males (age 47 +/- 13 years, mean +/- SD), who were referred to a sleep laboratory for symptoms of sleep-disordered breathing. The dependent variables, mean morning blood pressure, insulin and fasting blood glucose (FBG) levels, were significantly related to both AHI (eta'2 = 0.10) and BMI (eta'2 = 0.18). AHI and BMI combined to account for approximately 30% of the variability in the best linear combination of these three factors. Further analysis indicated that mean morning blood pressure and fasting insulin levels each correlated positively with BMI and AHI, whereas FBG correlated only with BMI. We conclude that, although these data do not prove a causal relationship, there is evidence for an independent association between sleep apnea and not only blood pressure, but also fasting insulin levels. PMID- 7846460 TI - Traffic accidents in commercial long-haul truck drivers: the influence of sleep disordered breathing and obesity. AB - This study assesses a possible independent effect of sleep-related breathing disorders on traffic accidents in long-haul commercial truck drivers. The study design included integrated analysis of recordings of sleep-related breathing disorders, self-reported automotive and company-recorded automotive accidents. A cross-sectional population of 90 commercial long-haul truck drivers 20-64 years of age was studied. Main outcome measures included presence or absence, as well as severity, of sleep-disordered breathing and frequency of automotive accidents. Truck drivers identified with sleep-disordered breathing had a two-fold higher accident rate per mile than drivers without sleep-disordered breathing. Accident frequency was not dependent on the severity of the sleep-related breathing disorder. Obese drivers with a body mass > or = 30 kg/m2 also presented a two fold higher accident rate than nonobese drivers. We conclude that a complaint of excessive daytime sleepiness is related to a significantly higher automotive accident rate in long-haul commercial truck drivers. Sleep-disordered breathing with hypoxemia and obesity are risk factors for automotive accidents. PMID- 7846461 TI - Surgical treatment of obstructive sleep apnea by maxillomandibular advancement. AB - In recent years obstructive sleep apnea syndrome has gained increasing interest. Treatment of choice is nasal continuous positive airway pressure ventilation during sleep for upper airway patency, which does not cure sleep apnea and has to be applied throughout a patient's lifetime. In respect to various underlying pathomechanisms, in certain cases with craniofacial disorders, causal therapy by craniofacial osteotomies seems possible. A series of 21 consecutive patients with maxillary and mandibular deficiency were treated primarily with a 10-mm maxillomandibular advancement by retromolar sagittal split osteotomy and Le Fort I osteotomy, respectively. Obstructive sleep apnea syndrome was considerably improved in all patients. In 20 of 21 patients, the postoperative respiratory disturbance index (RDI) was reduced clearly to under 10, oxygen saturation rose and sleep quality improved. This was achieved by a maxillomandibular advancement of 10 mm without secondary refinements. In one patient the RDI could only be reduced to 20, probably due to insufficient maxillary advancement; oxygen desaturations still existed despite secondary corrections. These results indicate that successful surgical treatment is possible in a high percentage of selected patients with certain craniofacial characteristics. In addition to cardiorespiratory polysomnography there should be routine cephalometric evaluation of all patients. Maxillomandibular advancement should be offered as an alternative therapy to all patients with maxillary and/or mandibular deficiency or dolichofacial type in combination with narrow posterior airway space. PMID- 7846462 TI - Clinical diagnoses in 216 insomnia patients using the International Classification of Sleep Disorders (ICSD), DSM-IV and ICD-10 categories: a report from the APA/NIMH DSM-IV Field Trial. AB - Three diagnostic classifications for sleep disorders have been developed recently: the International Classification of Sleep Disorders (ICSD), the Diagnostic and Statistical Manual, 4th edition (DSM-IV), and the International Classification of Diseases, 10th edition (ICD-10). No data have yet been published regarding the frequency of specific diagnoses within these systems or how the diagnostic systems relate to each other. To address these issues, we examined clinical sleep disorder diagnoses (without polysomnography) in 257 patients (216 insomnia patients and 41 medical/psychiatric patients) evaluated at five sleep centers. A sleep specialist interviewed each patient and assigned clinical diagnoses using ICSD, DSM-IV and ICD-10 classifications. "Sleep disorder associated with mood disorder" was the most frequent ICSD primary diagnosis (32.3% of cases), followed by "Psychophysiological insomnia" (12.5% of cases). The most frequent DSM-IV primary diagnoses were "Insomnia related to another mental disorder" (44% of cases) and "Primary insomnia" (20.2% of cases), and the most frequent ICD-10 diagnoses were "Insomnia due to emotional causes" (61.9% of cases) and "Insomnia of organic origin" (8.9% of cases). When primary and secondary diagnoses were considered, insomnia related to psychiatric disorders was diagnosed in over 75% of patients. The more narrowly defined ICSD diagnoses nested logically within the broader DSM-IV and ICD-10 categories. We found substantial site-related differences in diagnostic patterns. These results confirm the importance of psychiatric and behavioral factors in clinicians' assessments of insomnia patients across all three diagnostic systems. ICSD and DSM-IV sleep disorder diagnoses have similar patterns of use by experienced clinicians. PMID- 7846463 TI - Melatonin possesses time-dependent hypnotic effects. AB - The present study investigated the hypnotic effects of 5 mg melatonin in comparison with placebo when administered at 1200, 1700, 1900 and 2100 hours. Eighteen young adults were studied with the 7/13 ultrashort sleep-wake paradigm after an overnight sleep deprivation. Melatonin was administered according to a double-blind Latin square design. After each administration, melatonin significantly increased sleep propensity, the spectral power in the theta, delta and spindles bands, and subjective sleepiness. It significantly decreased the power in the alpha and beta bands and oral temperature. The latency to maximum effect varied linearly from 3 hours 40 minutes at 1200 hours to 1 hour at 2100 hours. These findings indicate that melatonin possesses a time-dependent hypnotic effect and suggest that endogenous melatonin may participate in sleep-wake regulation. PMID- 7846464 TI - A case of extremely long sleep and waking episodes. AB - This report analyzes the sleep/wake patterns of a 32-year-old severely mentally retarded person with extreme periods of sleep and waking. The sleep and waking patterns were obtained from behavioral observations for 1 year. The validity of these observations was assessed by parallel actigraph recordings and behavioral observations for 1 month. The mean sleep episode was 30.5 hours in length and the mean waking episode was 30.9 hours in length. The longest sleep episode was 131 hours and the longest wake episode was 154 hours. There was little evidence of systematic homeostatic or circadian patterning. PMID- 7846465 TI - Bibliography of recent literature in sleep research. PMID- 7846466 TI - [Postmenopausal hydrometra. Influence of tamoxifen]. AB - Vaginal ultrasonography of the uterus using a high frequency endocavitary probe was performed in 300 postmenopausal women: 150 receiving no replacement nor suppressive hormone therapy and 150 receiving adjuvant anti-estrogen treatment in the form of tamoxifen because of breast cancer. Evidence was found of hydrometra in 84 cases (28%): 10 in the group taking no hormone therapy (6.6%) as compared with 74 in the group exposed to tamoxifen (49.3%). The difference was statistically significant (p < 0.01). In addition, mean thickness of the endometrium was estimated at 6 mm (range: 2-40) in the first group versus 12 mm (range: 3-60) in the second (p < 0.001). It emerged from this comparative ultrasound study that the incidence of postmenopausal hydrometra was influenced by taking tamoxifen. Fluid secretion appearances seen one out of two in treated patients reflect the paradoxical proestrogenic type action of tamoxifen on the uterine mucosa. PMID- 7846467 TI - [Cervical conization in dysplasia and carcinoma in situ. Role of concomitant uterine curettage]. AB - OBJECTIVE: Reevaluation of the usefulness of routine uterine curettage with every cervical cone biopsy. MATERIAL: Retrospective analysis of 250 cervical cone biopsies over an 18 year period. RESULTS: 240 analysable cases were included. 90 patients had undergone cone biopsy only and 150 cone biopsy accompanied by uterine curettage. Curettage material was histologically normal 115 times (76.6%), negative or invalid 26 times (17.3%) and pathological 10 times (6.6%). Pathology consisted of 7 cases of hyperplasia and 3 of endometritis. CONCLUSION: Routine uterine curettage whenever cone biopsy is performed is of no value other than in certain special circumstances concerning clinical status and ultrasound findings. PMID- 7846469 TI - [Prenatal diagnosis of osteogenesis imperfecta]. AB - The authors report a prenatal diagnosis of osteogenesis imperfecta or Porak and Durante disease, in which the child survived. The diagnosis was made by ultrasonography which revealed major abnormalities of osteogenesis more particularly affecting the lower limbs, which were short and deformed. Other essential features of this syndrome are osteoporosis, hyperrelaxation of ligaments and blue sclerae. This rare and genetic condition is due to type I collagen abnormalities. It is often governed by dominant transmission but manifestation of the gene is variable within a given family. Molecular biology and genetic studies offer new possibilities of prenatal diagnosis, but ultrasonography remains the investigation of choice, possibly helped by X-ray of the uterine contents. PMID- 7846468 TI - [Delivery in the presence of cicatricial uterus. Apropos of 150 cases]. AB - Analysis of 150 cases of women with uterine scarring seen in our unit showed that vaginal delivery was possible in 49.7% of them provided that a number of rules, which the authors particularly stress, are applied. An attempt has been made to define factors likely to weaken the uterus and predispose to uterine rupture. Our maternal mortality rate of 0.6%, often due to infection and bleeding, agrees with that of the literature. The 0.4% uterine rupture rate was related to lack of health education of pregnant women. Fetal status at birth was usually good after vaginal delivery. The authors feel that knowledge of the circumstances of the first cesarean section and the subsequent course is essential, while hysterosalpingography has a major role to play in the choice of the most appropriate type of delivery. PMID- 7846470 TI - [Weight variations during woman's lifetime]. PMID- 7846471 TI - Prevalence of mental disorders, personality traits and mental complaints in the Lundby Study. A point prevalence study of the 1957 Lundby cohort of 2,612 inhabitants of a geographically defined area who were re-examined in 1972 regardless of domicile. AB - The Lundby Study is a prospective, psychiatric-epidemiological study of a normal population that has been repeatedly examined over a period of 25 years. Experienced psychiatrists made home visits and collected the basic information through personal examinations adding supplementary data from other relevant sources. The present book contains point prevalence data of mental disorders such as neuroses, psychoses, organic brain syndromes, psychosomatic disorders, psychopathy, mental retardation, alcoholism, mental complaints, and also of various personality traits in a normal population at two points of time, 15 years apart. Together with earlier published incidence studies the present monograph is intended to give as complete a picture as possible of the mental morbidity in a total population. Our most conspicuous finding was the increase over time of the prevalence of neurotic illnesses. Depressive illnesses represented the largest increase. In the male sex the rate of Neurosis trebled from Time 1 to Time 2, although the female preponderance still remained. Psychopathy and Alcoholism, on the other hand, were very markedly male disorders. A description of how the investigations were performed is included and also a list of publications originating from the Lundby Study. This book will be of interest to physicians and psychiatrists interested in epidemiology and also to governmental planners and social scientists. PMID- 7846472 TI - Are there still social inequalities in height and body mass index of Stockholm children? AB - Height and body mass index (BMI) of all non-immigrant schoolchildren in Stockholm in the age interval 10.0-10.9 years born in 1981 were related to the mother's educational level and the number of siblings. The two social variables were dichotomized and two extreme groups of socially more and less privileged children were formed. Socially less privileged boys were 1.1 cm shorter than their more privileged peers, whereas there was no difference as regards girls. Socially less privileged children were expected to show higher BMI, but the finding was contrary. More privileged boys were heavier. The findings were compared to a previous study of Stockholm children born in 1933-1963. Major social inequalities in height were levelled out for Stockholm children in the 1950s, a social gap reappeared in the 1960s and small disparities still exist for boys today. PMID- 7846473 TI - Suicides in the Baltic countries, 1968-90. AB - Trends of male and female suicides in the Baltic countries--Estonia, Latvia and Lithuania--in the years 1968-90 were studied. As throughout the former USSR, suicide rates declined sharply from 1986, the year marking the onset of turbulent social change. During the "period of stagnation" from 1968 to 1984, the mean value of male suicide rates per 100,000 males were 55.7 in Estonia, 52.5 in Latvia and 51.7 in Lithuania. The figures for female suicide rates were 14.3, 14.3 and 10.4, respectively. Suicide rates remained consistently high in Estonia and Latvia, while in Lithuania the male suicide rate rose gradually from 33.0 to 61.3 and the female rate from 8.0 to 13.1 during the stagnation period. In conjunction with perestroika in the former USSR (including a restrictive alcohol policy and the first tentative steps towards democracy), annual male suicide rates per 100,000 in the years 1986-90 fell considerably below those in the stagnation period. Mean values of male suicide rates decreased by 26.6% in Estonia, 26.6% in Latvia and 14.4% in Lithuania in the period 1986-90 compared with the mean values for the period 1968-84. Female suicide rates were relatively stable and the male-female ratio was accordingly lower in 1986-90 (Estonia and Latvia 3.1, Lithuania 4.2) than in 1968-84 (Estonia 3.9, Latvia 3.7 and Lithuania 5.0). PMID- 7846474 TI - Parasuicide in the Nordic countries. AB - This article gives an account of some findings of the WHO/EURO multicentre study on parasuicide from the five Nordic centres: Helsinki (Finland), Stockholm (Sweden), and the countries of Funen (Denmark), So-Trondelag (Norway) and Vasterbotten (Sweden). For parasuicide patients treated in hospital in these five Nordic centres, the parasuicide rates per 100,000 inhabitants per annum were 222 for women, 213 for men and 224 for both sexes combined. In all the Nordic centres except Helsinki, women had higher parasuicide rates than men. The female/male parasuicide ratio was 1.16 for all Nordic centres. The highest parasuicide rates in the whole material were found in Helsinki, Stockholm and Funen, and the lowest in Sor-Trondelag and Vasterbotten. The highest parasuicide rates lay in the 30-39 age interval, i.e. the peak of parasuicide rates was in older age groups than previously reported. Single people, especially divorcees and those who have never been married, constitute a high-risk group in both sexes. The risk of parasuicide for single men is three times that for married men in all the Nordic centres except Sor-Trondelag, where the risk is five times higher. The parasuicide risk for single women is twice as high as for married women except for women in Funen, where the risk for single and married women is almost equal. Exceptionally high parasuicide rates are also reported for Finnish citizens in Sweden, compared with Finns from the Helsinki centre. Parasuicide rates appear to be correlated with population density, since the densely populated areas of Helsinki, Stockholm and Funen evince higher parasuicide rates than the sparsely populated areas of Sor Trondelag and Vasterbotten. PMID- 7846475 TI - Mental health among immigrant and refugee children of divorced parents. AB - The mental status of 27 children in divorced immigrant families and 17 children in divorced refugee families was examined, and compared to that of 113 children in divorced Swedish families. Differences in divorce-pattern between these families and Swedish divorced families were analysed. Viewed together, the immigrant and refugee children displayed a significantly higher symptom load compared to Swedish children from both divorced and intact homes. When examined separately, the refugee children but not the immigrant children were more troubled than Swedish children from divorced families. The shorter time the children had spent in Sweden, the higher was their symptom load. In comparison to Swedish divorced couples, the immigrant and refugee couples had been married for a shorter time, had been unhappy for a longer time prior to divorce, and joint custody was less common. Most of the marriages had been unhappy before the arrival in Sweden, but a dissolution had not been seen as feasible earlier. As among the Swedish couples, it was the woman who had initiated the divorce in most cases, and it was also the mother who became the residential parent in most cases. PMID- 7846476 TI - Immigration and socio-economy as predictors of early retirement pensions. AB - The purpose of this study, performed in a Swedish municipality, was to obtain a view of early retirement pensioners, focusing on immigration and socio-economy as predictors of early retirement pensions. A questionnaire was sent to 453 early retirement pensioners with disorders of the musculoskeletal system. A corresponding questionnaire was sent to a randomly selected, age- and sex-matched control group of the same size. The response rate was 83%. The study concludes that immigration and low socio-economy are predictors of early retirement pension (ERP). The rate of immigrants was 19% among the ERPs compared to 5% among the controls. The early retired immigrants were comparatively young, and some of them were overqualified for their previous jobs. Of the ERPs 74% were blue-collar workers compared to 39% of the controls. Neither work satisfaction nor unemployment was found to predict ERP. PMID- 7846477 TI - Fertility, infertility and child survival of Somali women. AB - The relationship of reproductive patterns, some socio-economic factors and child survival was studied in 766 rural Somali women. A structured questionnaire was the method of data collection. Teenage marriage was the norm for the women, and divorce was very common. The mean number of live births was 5.2, and the mean number of surviving children was 3.7. 2/3 of the women aged 45+ had a parity of 6 or more, about one third had had at least one miscarriage and one fifth had experienced one stillbirth. Primary infertility was observed in 7% of the women aged 45+, while 20% were considered subfertile. Verbal autopsy showed that mortality was highest among infants and accounted for 63% of the child deaths. Major causes of death were neonatal tetanus, diarrhoea and respiratory diseases. Child survival and reproductive outcome ratios were found to be negatively related to the increasing age of the mother and parity. Divorce and widowhood were also found to be associated with low child survival. PMID- 7846478 TI - Health and health care use of Turkish and Dutch inhabitants of The Netherlands. PMID- 7846479 TI - A profile of HIV-risk behaviours among travellers--a population based study of Danes visiting Greenland. AB - The population of Greenland has behavioural characteristics that indicate a high risk of HIV spread once HIV is introduced into the population. Much depends, however, on the degree of exposure from visitors, particularly in an initial phase. We used a national questionnaire survey of 4,680 randomly selected Danes between 18-59 years to study HIV risk behaviours among Danes with (+travellers) and without (-travellers) travel experience to Greenland. Median number of lifetime sexual partners was more than twice as high among male +travellers (median = 12 partners) compared to -travellers (median = 5; p < 0.0001) and also slightly higher among women (p = 0.03). Furthermore, a significantly higher percentage of male +travellers than -travellers reported prostitute contact (OR = 2.3 (95% CI: 1.4-3.9)), with a peak of 32.0% among men aged 40-49 years. A history of a sexually transmitted disease was three times (95% CI: 2.0-4.5) as common among +travellers as in -travellers. +Travellers were also significantly more likely to have visited other places outside Europe and Greenland, including HIV endemic areas (OR = 2.9 (2.0-4.1)). Overall, sexual contact with someone considered at high risk of HIV infection (a homo/bisexual man, intravenous drug user, prostitute, or previous or present resident of Sub-Saharan Africa) was reported by 33.5% of male +travellers compared to 15.6% of -travellers and among women by 9.7% and 5.0%, respectively. In conclusion, travellers tend to have more sexual partners and more sexual interaction with high HIV-risk group members than non-travellers.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7846480 TI - Cigarette smoking and drinking of alcohol are not associated with rapid progression to acquired immunodeficiency syndrome among homosexual men in Norway. AB - In order to study the influence of cigarette smoking and drinking of alcohol on the progression to acquired immunodeficiency syndrome (AIDS), eighty HIV infected homosexual men were included in a prospective study from the date of diagnosed HIV seropositivity. Two men were lost to follow-up. The mean follow-up time was 62 months. By the end of the follow-up period 26 out of 78 subjects (33%) were diagnosed with AIDS. When controlling for age, year of HIV diagnosis, number of male lifetime partners and frequency of receptive anal intercourse, the adjusted relative risk of being diagnosed with AIDS for the group smoking 1-20 cigarettes daily was 0.4 (0.2-1.2, 95% confidence interval) and 1.1 (0.4-2.7, 95% confidence interval) for the group smoking more than 20 cigarettes daily, as opposed to the non-smoking group. The adjusted relative risk of progression to AIDS for daily alcohol drinkers as opposed to less frequent drinkers was 0.8 (0.3-2.2, 95% confidence interval). The adjusted relative risks of receptive anal intercourse often or usually and more than 500 lifetime male partners were 2.2 and 2.0, respectively. These estimates, however, were not significantly above 1.0. The lack of positive association between cigarette smoking, drinking of alcohol and progression to AIDS found in this study as well as in other studies, may have implication for the understanding of the pathogenesis of the HIV disease and for counselling HIV infected subjects. PMID- 7846481 TI - A birth weight adjusted comparison of perinatal mortality in the Faroe Islands and Denmark. AB - The objectives were to compare perinatal mortality (PNM) in the Faroes and Denmark while accounting for the high birth weights in the Faroes, and to discuss methodological aspects related to this task. We applied conventional methods employing absolute birth weight standards, and the Wilcox-Russell way of comparing relative birth weights. During 1977-85 perinatal mortality (PNM) in the Faroes was 14.7 (98 cases) per 1,000 births, and 1.57 times higher than that in Denmark. Conventional method: birth weight-standardised risk ratio for PNM in the Faroes v Denmark was 1.95; the risk ratio declined with increasing birth weight. Wilcox-Russell model: the risk tended to be more uniformly increased across the birth weight distribution when babies with same relative birth weights were compared; the residual component of the birth weight distribution (i.e. the excess of observed births in the lower tail beyond what could be predicted by a Gaussian distribution) was 2.1% in the Faroes and 3.6% in Denmark, which does not fit with the model assumption that the size of the residual component is a strong determinant of a population's PNM. PMID- 7846482 TI - Epidemiological analysis of serious occupational accidents in southern Finland. AB - The aims of this article were, on the one hand, to indicate the risk groups exposed to serious occupational accidents and, on the other hand, to examine what makes serious occupational accidents 'serious'. We compared the data on 99 serious occupational accidents gathered by ourselves to the information from official statistics. The results showed that the risk of a serious accident was highest for a man working in the manufacturing industry, at a construction site, or in transporting, and who was in his first year of service. Typical serious occupational accidents were falls from heights, accidents with machines, and getting run over by moving vehicles. The most general injuries were fractures, loss of extremities, and injuries to internal organs. Serious occupational accidents differ from minor accidents as regards type of accident and injured part of the body. PMID- 7846483 TI - Case report on a sick building: analysis and interpretation in the context of its disease history. AB - The sick building syndrome is a widespread, modern health problem with a probably very multifactorial causation. Studies of the syndrome have shown associations between its occurrence and a wide variety of factors related to the buildings, work environments and the individual occupants. The associations are often inconsistent and contradictory. The presented case report indicates that this might depend on the subjective nature of most of the symptoms of the syndrome, which makes it difficult to study and interpret. The case consists of a municipal office building where the personnel experienced two very protracted episodes of sick building syndrome. The study of it suggests that psychogenic mechanisms sometimes might be a stronger partial causative factor in the etiology of the sick building syndrome than is generally considered, and that quantitative information should be supplemented by qualitative in the study of sick buildings. PMID- 7846484 TI - The effects of tobacco sales promotion on initiation of smoking. PMID- 7846485 TI - Prevention of lung cancer through the use of knowledge on asbestos and other work related causes--Norwegian experiences. AB - This review attempts to estimate the contribution of different known work-related causes of lung cancer in the Norwegian male population in order to predict the potential of prevention of work-related cases. The presented estimates are based on data from epidemiologic studies made in Norway, but may be of significance for other countries with a similar work-force structure. Over the past decade asbestos-related lung cancer appears to have contributed about two-thirds of the lung cancers that have been related to work exposure in Norway, for example, possibly 125-175 of the 1100 cases that occurred among Norwegian men in 1987. The potential for prevention is, however, greater due to synergism. To a less extent compounds of nickel and chromium have also contributed, along with exposure to polycyclic aromatic hydrocarbons, radon daughters, seafaring work, and other, less significant specific and nonspecific determinants of lung cancer. PMID- 7846486 TI - Occupational asthma--time for prevention. AB - Incidence figures show that occupational asthma is increasing. It often takes a deteriorating course. Follow-up studies of workers suffering from the disease have uniformly reported persistence of symptoms over long periods, even among formerly exposed workers. New initiators of occupational asthma are continuously being reported. Still "old" agents, such as diisocyanates and flours, remain major causes. There seems to be some disconnection in the dialogue between the medical and the technical parties involved. For prevention, it is essential to ensure that important information not only reaches those who are responsible for designing and maintaining processes, but that it is presented in an intelligible form. Occupational asthma has become an important occupational disease that merits high priority. Recent achievements should facilitate preventive actions. However, prevention is a multidisciplinary enterprise needing the commitment of industrial hygienists and engineers, chemists, and allergologists, in addition to that of occupational health personnel. PMID- 7846487 TI - Organic dusts--from knowledge to prevention. AB - Vegetable, animal, and microbial aerosols (organic dusts) induce a variety of pulmonary disease and subjective symptoms. This review presents the pathology and clinical symptoms related to organic dust exposure. Most of the symptoms are related to inflammation, which is not unexpected in view of the many inflammatory agents present in organic dusts. Prevention is primarily a matter of dust control, information, and medical surveillance. In the future, specific agents like bacterial endotoxins should be controlled. PMID- 7846488 TI - Psychosocial criteria for good work organization. AB - A good work environment and good work organization are defined according to occupational health studies and interventions. Criteria for good work organization include such job characteristics as optimal quantitative and qualitative work loads, opportunities for control at work, clarified work roles balanced by other roles, and supportive social interaction. These characteristics can be promoted independently or in conjunction with strategies used to attain good work organization, such as mastery of work, management of change processes, support of employees by occupational health services, and emphasis on career stage and future perspectives. Typical for these job characteristics and interventive strategies as criteria for good work organization are their dependence on national and organizational culture and values. Their definition as health and well-being promoting is based on empirical research in which they have been associated with indicators of well-being, such as job satisfaction, active life and lack of subjective stress symptoms. PMID- 7846489 TI - Assessment of exposure in occupational epidemiology. AB - Recent progress in assessing exposure in occupational epidemiology studies is reviewed. Traditional methods based on surrogate and qualitative measures of exposure are no longer sufficient for searching for new risks, quantifying risks, and learning about their mechanisms. More sophisticated methods and exposure indices are needed that are aimed at estimating the exposure-response relation. Prospective studies, case-referent studies within cohorts, and community-based case-referent studies applying interviews of the subjects or confirming exposures from work-places are designs favoring exposure assessment. Exposure modeling is expected to improve the quality of estimates in industry-based studies. Job exposure matrices have proved useful, especially in analyses of large studies, provided that they are applied so that misclassification does not significantly bias the results. Misclassification of exposure should be regularly assessed and controlled in epidemiologic studies. Good documentation of the information used and studies on methodological validity and reliability are needed to develop exposure assessment. PMID- 7846490 TI - Assessment of physical exposure in relation to work-related musculoskeletal disorders--what information can be obtained from systematic observations? AB - Establishing an association between physical work load and work-related musculoskeletal disorders requires a quantitative assessment of exposure to the main risk factors. Commonly used methods are questionnaires, diaries, interviews, systematic observations, and direct measurements. While questionnaires provide subjective information and have low reliability, measurements are technically sophisticated, expensive, and unable to identify some important risk factors. Systematic observations offer a compromise. The observation methods devised during the past 15 years are described, together with their reliability and validity. Most of them use duration or frequency of certain postures or events as the main measure of exposure. Their ability to quantify the main risk factors posture, manual handling, and repetitive work differs. All available methods have drawbacks and have been used to a limited extent in epidemiologic studies. There have been improvements however, and it is concluded that observation methods will have a place in epidemiologic studies on musculoskeletal disorders. PMID- 7846491 TI - Biological monitoring today and tomorrow. AB - Biological monitoring is important in the assessment of both occupational exposure to chemical agents and the health risks involved. For some chemicals data from biological monitoring can be reliably translated into health risks, while for the majority it only indicates uptake. Several workplace chemicals can be analyzed from biological specimens, but no interpretation of health risk or exposure is possible. For such chemicals, comparing the results to data from similar industries may help to determine whether smaller levels of exposure are possible. The biggest problem with most biological monitoring is that no good interpretation is immediately available. This statement is equally true for classical specific analytical chemical analyses, nonspecific assays of exposure, and almost all effect monitoring. Health-based interpretation of biological monitoring will never become possible unless biological monitoring is performed (even in the absence of immediate interpretation) and the results are stored for future analysis in a retrievable and usable form. PMID- 7846492 TI - Has the Scandinavian solvent syndrome controversy been solved? AB - This article discusses the "Scandinavian solvent syndrome" and reviews epidemiologic studies on occupational solvent exposure and two related outcomes. High cumulative exposure to organic solvents in the 1960-1970s was related to early retirement from neuropsychiatric disorders, but solvent exposure alone was an unlikely cause of more severe dementia conditions. Heavy alcohol consumption seemed to modify the effect on solvent-related brain disorders strongly, but no reports exist of alcohol consumption as a confounding factor. Many cross sectional and experimental studies support functional impairment from high solvent exposure. The mists and myths around the "Scandinavian solvent syndrome" can now be cleared up: it was not a uniform syndrome, it might be reversible in many cases, it is not confined to the Scandinavian countries, the risk of more severe dementia is substantial for combined high solvent exposure and excessive alcohol consumption, and many solvent-exposed workers receive early retirement due to solvent-related neuropsychiatric disorders. PMID- 7846493 TI - Neurotoxic effects of selected metals. AB - A chemical is considered to be neurotoxic if it is capable of inducing a consistent pattern of neural dysfunction or lesion in the nervous system. Several metals are known as neurotoxic. Among them, four have been selected as being especially important from the occupational point of view, lead, manganese, aluminium, and mercury. All four have proved to be neurotoxic even though the toxic mechanisms may be unclear or unknown. This paper reviews the recently published documentation on the neurotoxic properties of these metals, from the general as well the occupational point of view. PMID- 7846494 TI - Is human fecundity declining--and does occupational exposures play a role in such a decline if it exists? AB - Demographers have analyzed fertility over time and between many populations for many decades. Much less is known about fecundity. Recent publications seem to indicate a decline in semen quality over time, but still no good data corroborate or refute this hypothesis. The very sparse data do not indicate any substantial changes in fecundity over the last 10-30 years in the United States, but none of the studies have a comparability which permit any firm conclusion. Several chemical and physical exposures interfere with human fecundity. Some are found at the worksite, sometimes in an intensity which does harm. The marked effect of dibromochloropropane on semen quality and fecundity was a clear warning to occupational health workers. Several other occupational exposures have shown an effect on gonads in men or women, and it is time to give more research priority to the topic. The rapidly rising cost of infertility treatment could be the stimulus to trigger the development of this research field. PMID- 7846495 TI - Electric and magnetic fields and health outcomes--an overview. AB - In recent years interest has increased in the biological effects and possible health outcomes of weak electric and magnetic fields. Studies have been presented on magnetic fields and cancer, reproduction, and neurobehavioral reactions. Epidemiologic studies on childhood leukemia and residential exposure from power lines seem to indicate a slight increase in risk, and excess leukemia and brain tumor risks have been reported in "electrical" occupations. In spite of a large number of experimental laboratory studies, however, no plausible and understandable mechanism has been presented by which a carcinogenic effect could be explained. International guidelines state that the scientific knowledge on magnetic fields and cancer does not warrant limiting exposure levels for the general public and work force down to the low levels of everyday exposure. Study results on reproduction, including adverse pregnancy outcomes, and neurobehavioral disorders are generally considered insufficiently clear and consistent to constitute a scientific basis for restricting exposure. PMID- 7846496 TI - Some recent developments in occupational epidemiology. AB - Occupational epidemiology has grown rapidly since the late 1970s. Case-referent studies have become popular, but more recent development relates to analyses of cohort data. Length of follow-up and employment status can now be adjusted for in such analyses. Attention should also be given to "time windows" of relevant exposure, not only in cancer studies. In cross-sectional studies of common diseases, the prevalence rate ratio should be used rather than the currently popular but unintelligible odds ratio as obtained by logistic regression. Exposure assessment should involve measures that would best reveal an existing risk and dose-response relationships. New achievements in molecular biology are currently influencing the development in occupational epidemiology. Not only DNA (or protein) adducts as markers of exposure or early effect, but also the possibilities to use data on metabolic polymorphism to identify genetically susceptible individuals attract interest. Activated oncogenes and inactivated tumor suppressor gene are useful for subspecifying various cancer types so as to obtain more sensitive studies. PMID- 7846497 TI - Where is the research frontier for hand-arm vibration? AB - A central question for current hand-arm vibration research is how to combine diagnostics with exposure evaluation so that reliable risk assessments can be made for different tools and work processes. The scientific foundation of the model, in annex of A of ISO 5349, for white finger (WF) risk prediction has been shown to be insufficient. Prospective epidemiologic studies are needed to establish exposure-response relationships addressing the specific etiologic factors. Another important research field concerns WF pathogenesis, which is likely to be a vessel wall lesion causing vasodilatory deficiency. Epidemiologic research, in combination with human and animal experimentation, on endothelium dependent mechanisms is desirable, among other things, because a therapy may be within reach. A model is presented for the manifestation of cold-triggered WF in persons with exposure to vibration and other environmental stressors as a result of lowered symptom threshold and a raised level of sympathetic activity. PMID- 7846499 TI - [Noninvasive heart function diagnosis using magnetic resonance tomography (MRI) and positron emission tomography (PET)]. AB - MR as well as PET are likely to permit substantial progress in cardiac diagnosis in the coming years. Due to the introduction of ultrafast MRI with acquisition times of 50 to 200 milliseconds per image, functional imaging capabilities arise which have hitherto been inconceivable. Wall motion studies and cardiac flow measurements within a maximum of 4 to 8 heartbeats can be acquired under breath hold conditions. Perfusion measurements of the entire heart can be obtained after a single contrast medium dose with a temporal resolution of 1-2 seconds, and in addition to imaging of the large coronaries, flow measurements within these vessels also should become feasible. Since the corresponding technologies still require substantial developments in hard- and software, it is too early to express a view on the relative merits of ultrafast MR relative to competing methods. The important conclusion at this time is that ultrafast MR will fundamentally expand the potential of cardiac MRI. MR spectroscopy at present yields interesting research data, but is far away from a clinical application. Cardiac PET has clearly advanced to the gold standard in the diagnosis of hibernating myocardium and is considerably more sensitive than the corresponding thallium examinations. PET has become much more efficient in the last two years and the capital investment as well as the running costs have fallen substantially. Thus PET can be considered a clinical examination method. Indications for PET are mainly in patients with terminal ischemic heart disease where it has to be decided whether any and what kind of invasive therapy should be administered to the patient.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7846498 TI - [Quality assurance in diagnostic radiology]. AB - Quality assessment is increasingly important in medicine in general as well as in diagnostic imaging. Quality in medicine includes state-of-the-art procedures, patient satisfaction, economic aspects, safety, and access to adequate care for the entire population. In order to measure quality more specifically in diagnostic imaging, several levels of efficacy have been defined. These include technical efficacy, diagnostic accuracy, diagnostic-thinking efficacy, therapeutic efficacy, outcome efficacy, and societal efficacy. Major factors in improving quality in diagnostic imaging include the expanded access to and use of databases, progress in continuing education, and increased research activities. PMID- 7846500 TI - [Actinic myelitis: diagnosis and treatment]. AB - Spinal cord damage is one of the main dose limiting processes in radiation therapy. Radiation myelopathy was first observed in 1941, but it was only in the early 1980s that more clear information on tolerance was available. Animal experimentation in particular has thrown light on pathogenesis and factors playing a role in this pathology. Total dose, dose per fraction, age at irradiation, and interval between fractions are some of the main factors influencing this tolerance. From the literature the risk of progressive chronic radiation myelitis in man is estimated at less than 5%, with doses of 45-50 Gy in 1.8 to 2 Gy per fraction. The risk increases markedly with total dose and dose per fraction increase, and decreasing age. Cases of radiation myelitis are usually due to gross overdosage due to technical errors. More recently hyperfractionated accelerated schedules have occasioned major concern, with several unexpected myelopathies. Total cord dose using the alpha/beta model had appeared safe. Insufficient inter-fraction time (3-4 hours) is therefore likely to be the cause of the cases observed. Long half time for repair (underestimated in the LQ model) of sublethal damage resulting from slow tissue turnover is the most likely underlying mechanism. Morphological alterations are predominantly in white matter: lesions may be partial, focal or reaching total demyelinisation, with necrosis and malacia. Vascular damage may or may not be present. A dual pathogenesis is postulated. Oligodendrocytes and endothelial cells are the most likely target cells.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7846501 TI - [Intervention in nuclear medicine kidney diagnosis]. AB - In the present review, the possibilities of ergometric and pharmacological "intervention" with a view to improving the validity of scintirenography are reported. Exercise renography at present does not have a defined role in clinical routine. This procedure, however, gives additional information in hypertensive patients with respect to renal ischemia. Captopril scintirenography can be recommended as a screening test for renovascular hypertension. Furosemide "intervention" differentiates between obstructive uropathy and dilatation of renal collecting system without obstruction. This is true especially in newborns with congenital abnormalities of the upper urinary tract, in order to stratify these young patients for surgical or conservative treatment. PMID- 7846502 TI - [Duodenal ancylostomiasis. 1880]. PMID- 7846503 TI - [Comparative studies of the use of linear array, curved array and sector technique in sonography of the infant hip]. AB - In an experimental study, the sonographic speed in the hyaline cartilage of the hip of the newborn is measured. With 1549 m/s it lies in the intermediate range of the equipment's pre-set calculation basis. By comparing large groups the study shows that the accuracy of the measurements of the angle alpha is independent of the technology used in the production of the hip sonogram. On the other hand, the image scale has a clear influence. The image scale of 1:1 is inadequate for a reliable repeated cross-sectional presentation and for measurements. The study shows that there are no statistically demonstrable differences when measuring hip sonograms regardless of whether they have been produced using linear array or sector scanning. This is shown both by repeated presentation of the respective cross-section by one and the same researcher and by measurement of identical sonograms by different researchers. PMID- 7846504 TI - [Possible errors in ultrasound hip imaging in patients with osteogenesis imperfecta]. AB - In ultrasonographic diagnosis of the hip severe bony deformities due to osteogenesis imperfecta are potential pitfalls. In this condition, even x-ray of the pelvis is unreliable, whereas MRT is a helpful diagnostic method. PMID- 7846505 TI - [Ultrasound diagnosis of isolated aplasia of the septum pellucidum]. AB - Absence of the septum pellucidum may occur as an isolated malformation. Some of the common paediatric ultrasound and radiology textbooks mention this anomaly. However, only 12 case reports have been published so far. Absent septum pellucidum is also seen in combination with other cerebral malformations like septo-optic pituitary dysplasia (SOPD, de Morsier), agenesis of corpus callosum, holoprosencephaly etc. More often it is seen as a secondary injury due to an increasing internal hydrocephalus. Occurrence of this aplasia and its significance are often underestimated. At a paediatric centre in Germany the anomaly is expected to occur in 1: 1,000 to 1:3,000 cerebral ultrasound examinations. After a review of the literature four cases are presented. All of them were observed by ultrasound during the neonatal period. Using ultrasonography diagnosis of the isolated absence of septum pellucidum can be easily performed by the experienced physician, and will usually be of eminent relevance for the patient. PMID- 7846506 TI - [A head and transducer holding technique for TCD monitoring of the vertebrobasilar circulation]. AB - For monitoring the Doppler spectrum of the vertebral and basilar arteries the authors have used a microball vacuum cushion for fixing the head of the patient in lateral, moderately anteflected position, and a three lockable joint type instrument holder allowing adjustment of the probe suboccipitally. This setting was used for transforaminal vertebrobasilar emboli monitoring in 5 patients having prosthetic heart valves. As an alternative technique a microball filled vacuum collar was tried out for immobilisation of the patient's head, and a snake neck type surgical instrument holder for guiding the probe. PMID- 7846507 TI - [Principles of quantitative color Doppler ultrasound of pelvic and leg arteries. Normal sample]. AB - Statistical analysis of a group of 25 healthy individuals, examined via angiodynography, shows a large range of scatter for all measured parameters in pelvic and lower extremity arteries. Blood flow and velocity values, systolic acceleration and vessel diameter decrease whereas the pulsatility index rises from the centre towards the periphery. Problem areas for morphological and quantitative evaluation are the abdominal aorta, pelvic vessels, superficial femoral artery in the distal adductor canal and the fibular artery. Nearly all vessels showed tri- or multiphasic spectral patterns. Biphasic waveform, however, may be normal in lower extremity arteries. The data yielded by colour-coded Doppler sonography were comparable to results obtained with other procedures. PMID- 7846508 TI - [Catheter-induced thromboses--duplex ultrasound studies of incidence and extent]. AB - The aim of the study was to detect the frequency and the extension of thrombosis caused by central venous catheters by means of Doppler-duplex ultrasound. 36 patients were examined. The visualization rate of catheters in jugular (91%) and femoral (62%) veins was excellent. In contrast, catheters in the subclavian vein could be detected only in 33 per cent of all cases. As a result the overall patency rate of catheters was only 37 per cent after a period between 8 hours and 60 days (12.2 +/- 11.3 days) following the introduction. There was no significant relation between the type of catheter, the management with central venous catheters and the rate of thrombosis. PMID- 7846509 TI - [Color-coded duplex sonography in postoperative evaluation of aortic aneurysms]. AB - One hundred patients with infrarenal abdominal aortic aneurysms were treated by surgery. Fifteen deaths occurred postoperatively. Eleven patients died during the follow-up of a medium period of 13 months. Three patients with a ruptured aneurysm died intraoperatively before the graft was implanted. Three patients were lost to follow-up. Sixty-four patients were examined with colour-coded Duplex sonography after surgical repair. Colour-coded Duplex sonography was able to image the aortic prostheses with the adjacent major vessels. Fifty-eight patients showed a normal prosthesis, 3 dilatation proximal of the prosthesis, 1 dilatation distal of the prosthesis, 1 mild stenosis, 1 haematoma. Colour-coded Duplex sonography imaged the intraluminal space of the prosthesis more easily than ultrasound. Colour-coded Duplex sonography was able to differentiate between intraluminal and extraluminal lesions. PMID- 7846510 TI - [Follow-up of vena cava filters with color Doppler ultrasound]. AB - In 49 patients, colour-coded Duplex sonography was performed after implantation of a Greenfield caval filter. A plain film radiograph of the abdomen was taken additionally. The examination could be assessed free of artifacts in the longitudinal and transverse section in a total of 41 patients (84%). The procedure facilitates not only a diagnosis of thrombotic changes in the vena cava but can also display the topographical position of the filter and the venous flow. Caval thrombosis was verified in 5 patients. In 7 cases there was a decentral position of the filter apex with tilting. The penetration of filter struts through the vein wall eluded sonographic diagnosis as did morphological changes to the filter (e.g. filter fracture). In combination with the plain film radiograph, colour-coded Duplex sonography can replace cavography or computed tomography in the investigation of position and venous flow. PMID- 7846511 TI - [Doppler ultrasound evaluation of blood flow direction in distal occlusion of arteries of the lower leg]. AB - It is necessary to observe the direction of the blood flow for measurement of the ankle pressure by the Dopplermethod. Obliteration of the ankle pressure by the Dopplermethod. Obliteration of the anterior tibial artery can be compensated by collaterals from the posterior tibial artery. Through this the blood flow is reversed in the dorsalis pedis artery. If this possibility is disregarded, the pressure of the anterior tibial artery will yield false data. The situation of the blood flow can be clarified by a compression test of the posterior tibial artery. This also applies to obliterations of the other arteries of the ankle. PMID- 7846512 TI - Aquatic genotoxicity testing with rat hepatocytes in primary culture. II. Induction of micronuclei and chromosomal aberrations. AB - River water samples with varying degrees of contamination by municipal and industrial effluents were analyzed for their potential to induce sister chromatid exchanges, micronuclei and chromosomal aberrations in the primary rat hepatocyte assay. The direct comparison of these three parameters showed that SCE's are the most sensitive genotoxic endpoint induced by contaminated water samples, followed by micronuclei and chromosomal aberrations. The dose response curves are comparable, although shifted to higher concentrations for the latter two endpoints. No linear dose response was observed, indicating either concentration dependent increases in toxicity, saturation of drug metabolizing enzymes, induced expression of detoxifying enzymes or the induction of repair functions. The analysis of the data also showed that contaminated surface water samples contain unstable or highly volatile compounds leading to a storage time-dependent decrease in the micronucleus frequency accompanied by an increasing mitotic index. Therefore, genotoxic potential should be determined as rapidly as possible after sampling. Additionally, since the samples vary according to their potential to induce specific genotoxic endpoints, all three parameters should be determined simultaneously to obtain a more reliable estimation of the genotoxic potential of the samples. PMID- 7846513 TI - Copper, iron, manganese and zinc contents in human colostrum and transitory milk of French women. AB - Copper, iron, manganese and zinc were measured in breast milk samples collected from 82 healthy lactating mothers. Samples were collected from day of delivery to 7 days postpartum. Zn was analysed by flame atomic absorption spectrometry and the other elements by electrothermal atomic absorption spectrometry. Copper concentrations remained constant. Iron declined from 14.2 +/- 7.3 mumol/l at day 1 to 5.6 +/- 3.1 mumol/l at day 5 postpartum. Zinc and manganese declined from a maximum at 2 days postpartum (Zn: 183 +/- 70 mumol/l; Mn: 218 +/- 102 nmol/l) to 77 +/- 22 mumol/l (Zn) and 62 +/- 29 nmol/l (Mn) at 6 days postpartum. Copper concentrations are related to parity (r = 0.317, P < 0.001) and mother body mass index (r = 0.324, P < 0.001). PMID- 7846514 TI - Copying articles. PMID- 7846515 TI - Copying articles. PMID- 7846516 TI - Human diversity in Colombia. PMID- 7846517 TI - Nicaragua's research agenda. PMID- 7846518 TI - External ethics for scientists. PMID- 7846519 TI - Clinton holds the line on R&D. PMID- 7846520 TI - A strategy for sequencing the genome 5 years early. PMID- 7846521 TI - German reunification. Blending biology, technology, and economic development. PMID- 7846522 TI - Bisexual fruit flies point to brain courtship centers. PMID- 7846524 TI - Points of light in Latin America. PMID- 7846523 TI - Protein studies try to puzzle out Alzheimer's tangles. PMID- 7846525 TI - Brazil. A deadly parasite spurs up-to-the-minute biology. PMID- 7846526 TI - Mexico. A stubborn amoeba takes center stage. PMID- 7846527 TI - Casein kinase II in theileriosis. PMID- 7846528 TI - Programmed cell death in bacterial populations. PMID- 7846529 TI - High sex ratios in China's future. AB - In China in recent years, male live births have exceeded those of females by amounts far greater than those that occur naturally in human populations, a trend with significant demographic consequences. The resulting imbalance in the first marriage market is estimated to be about 1 million males per year after 2010. These "excess" males were not easily accommodated in models with substantial changes in first-marriage patterns. The current sex ratio at birth has little effect on a couple's probability of having at least one son, so future increases in the sex ratio may well occur, especially given increasing access to sex selective abortion. PMID- 7846530 TI - Effects of competition, colonization, and extinction on rodent species diversity. AB - Analyses of long-term experimental data from the Chihuahuan desert revealed that species diversity of other rodents was higher on plots from which kangaroo rats (Dipodomys spp.) had been removed. The difference was due to consistently higher colonization and lower extinction probabilities of small granivorous rodents in the absence of competitively dominant kangaroo rats. The results of this ecosystem experiment demonstrate the importance of both competitive exclusion and metapopulation dynamics for biological diversity in a natural community. PMID- 7846531 TI - Synergistic roles for receptor occupancy and aggregation in integrin transmembrane function. AB - Integrin receptors mediate cell adhesion, signal transduction, and cytoskeletal organization. How a single transmembrane receptor can fulfill multiple functions was clarified by comparing roles of receptor occupancy and aggregation. Integrin occupancy by monovalent ligand induced receptor redistribution, but minimal tyrosine phosphorylation signaling or cytoskeletal protein redistribution. Aggregation of integrins by noninhibitory monoclonal antibodies on beads induced intracellular accumulations of pp125FAK and tensin, as well as phosphorylation, but no accumulation of other cytoskeletal proteins such as talin. Combining antibody-mediated clustering with monovalent ligand occupancy induced accumulation of seven cytoskeletal proteins, including alpha-actinin, talin, and F-actin, thereby mimicking multivalent interactions with fibronectin or polyvalent peptides. Integrins therefore mediate a complex repertoire of functions through the distinct effects of receptor aggregation, receptor occupancy, or both together. PMID- 7846532 TI - Casein kinase II alpha transgene-induced murine lymphoma: relation to theileriosis in cattle. AB - Infection of cattle with the protozoan parasite Theileria parva results in a fatal lymphoproliferative syndrome that is associated with the overexpression of casein kinase II. The role of this enzyme in the pathogenesis of lymphoproliferative disorders was investigated by expressing the catalytic subunit in lymphocytes of transgenic mice. Adult transgenic mice displayed a stochastic propensity to develop lymphoma; co-expression of a c-myc transgene in addition to casein kinase II resulted in neonatal leukemia. Thus, the casein kinase II gene can serve as an oncogene, and its dysregulated expression is capable of transforming lymphocytes in a two-step pathway with c-myc. PMID- 7846533 TI - Selfish behavior of restriction-modification systems. AB - Plasmids carrying gene pairs encoding type II DNA restriction endonucleases and their cognate modification enzymes were shown to have increased stability in Escherichia coli. The descendants of cells that had lost these genes appeared unable to modify a sufficient number of recognition sites in their chromosomes to protect them from lethal attack by the remaining restriction enzyme molecules. The capacity of these genes to act as a selfish symbiont is likely to have contributed to the evolution of restriction-modification gene pairs. PMID- 7846535 TI - Small cell lung cancer: can treatment results be improved further? PMID- 7846534 TI - Genetic feminization of brain structures and changed sexual orientation in male Drosophila. AB - The neural basis of sexual orientation in Drosophila was studied by the production of males with regionally feminized brains. Such flies express the female form of the sex determination gene transformer in a limited number of neurons under the control of GAL4 enhancer trap inserts. This method facilitated the creation of lines with a stable pattern of feminization. In tests of sexual preferences, flies that were feminized in a portion of the antennal lobes or in a subset of the corpora pedunculata (mushroom bodies) courted both males and females. These two brain structures, both of which are involved in olfactory processing, may function in the recognition of sex-specific pheromones, in the control of sex-specific behaviors, or both. PMID- 7846536 TI - Ifosfamide, doxorubicin, vincristine, and etoposide in small cell lung cancer. AB - From 1982 to 1989, the cyclophosphamide/doxorubicin/vincristine/etoposide combination was the standard treatment for small cell lung cancer in our center. Radiotherapy was started after three cycles, since little further response to chemotherapy could be expected. In 1989, ifosfamide replaced cyclophosphamide, and preliminary results from a pilot study showed impressive early responses. By December 1993, 36 patients had been evaluated, 20 of whom had limited disease and 16 of whom had extensive disease. The response rate was 81% after one cycle and 86% after the second cycle. Median survival time in patients with limited disease was 12 months; in those with extensive disease, it was 7.5 months. Five patients with limited disease are alive and fully active, with an observation time ranging from 29 to 58 months. Based on these findings, our standard treatment protocol has been revised to institute radiotherapy after two cycles of chemotherapy. PMID- 7846537 TI - Induction chemotherapy with ifosfamide, etoposide, and anthracycline for small cell lung cancer: experience of the European Lung Cancer Working Party. AB - Prospective trials comparing drug analogues in the treatment of small cell lung cancer are rare. The European Lung Cancer Working Party has conducted a randomized trial with a primary end point of determining the effect on survival of maintenance chemotherapy and a secondary end point of comparing doxorubicin (45 mg/m2) with a bioequivalent epirubicin dose (60 mg/m2) in one set of patients, and a standard with a high epirubicin dose (60 v 90 mg/m2) in a second set of patients. Anthracycline was given on day 1 of induction chemotherapy in combination with ifosfamide (1.5 g/m2 intravenously days 1 through 3) and etoposide (80 mg/m2 intravenously days 1 through 3). Six courses were given at 3 week intervals. In all, 235 eligible previously untreated patients with pathologically proven small cell lung cancer were randomized: 106 to the comparison of doxorubicin and epirubicin and 129 to the comparison of standard dose versus high-dose epirubicin. There was no difference between the regimens in terms of objective response rate or survival, and the regimen containing the lower (60 mg/m2) epirubicin dose was better tolerated, with fewer toxic deaths and less need for dose and schedule adjustments. PMID- 7846538 TI - The place of ifosfamide in chemotherapy of small cell lung cancer: the Eastern Cooperative Oncology Group experience and a selected literature update. AB - In a randomized Eastern Cooperative Oncology Group study, single-agent ifosfamide used to treat extensive-disease small cell lung cancer patients produced a 49% response rate compared with 56% for patients receiving standard combination chemotherapy (cyclophosphamide/doxorubicin/vincristine). When the drug was combined with carboplatin and etoposide to treat extensive-disease small cell lung cancer patients, overall response rate was 83%, median survival time was 9 months, and 2-year survival rate was 14%. The major toxicity was myelosuppression. These results confirm those of other investigators who have shown the effectiveness of the ifosfamide/carboplatin/etoposide regimen in treating patients with small cell lung cancer. PMID- 7846539 TI - Hoosier Oncology Group studies in extensive and recurrent small cell lung cancer. AB - Significant advances have been made in the treatment of small cell lung cancer (SCLC) during the past two decades. Major and indisputable improvement has been achieved in patients with limited disease. However, progress in extensive SCLC has been more elusive. Despite thousands of patients entered into numerous phase II and phase III studies, it is still debatable whether any particular regimen is superior to older combination chemotherapy regimens first studied 20 years ago. From May 1989 through January 1993, 171 patients with extensive SCLC were entered into a Hoosier Oncology Group phase III study comparing etoposide/cisplatin (VP) with etoposide/ifosfamide/cisplatin (VIP). There were 166 patients fully evaluable for response and survival. As expected, hematologic toxicity was more severe in the patients in the VIP arm, but both arms had a 6% to 7% treatment related mortality rate. The response rate were similar (70% v 66%, with 18% and 21% complete remissions). However, there was improved survival in the VIP arm (P = .03). This was most pronounced at the tail of the survival curves, with 2- and 3-year survival rates of 12% and 5% for VIP compared with 5% and 0% for VP. A different form of VIP chemotherapy for patients with refractory SCLC with no prior ifosfamide also was evaluated. From February 1990 to August 1993, 46 patients with previously treated SCLC were treated with daily oral etoposide/ifosfamide/cisplatin. Thirty-one of 41 evaluable patients had prior cisplatin plus intravenous etoposide. Myelosuppression was significant, with six treatment-related deaths. Twenty-two of 41 patients (54%) had an objective response, including six (15%) complete remissions. The median length of survival was 29 weeks (range, 1 to 76 weeks). Despite the toxicity, these results are competitive with many first-line chemotherapy programs. This is a reasonable, aggressive regimen for selected patients with refractory SCLC. PMID- 7846540 TI - A summary of the Milan experience with multimodality therapies in patients with small cell lung cancer: attempts to improve long-term outcome. AB - From February 1985 to June 1993, 173 consecutive, previously untreated patients with small cell lung cancer received individualized treatment tailored to disease extent. Almost all patients (14 of 16) with stage I and II disease and 30 patients with operable stage III disease were submitted to surgery preceded or followed by chemotherapy. Chest irradiation and prophylactic brain radiotherapy (in complete responders) were administered at the end of treatment in 42 of 44 cases. Patients with inoperable limited disease received chemotherapy followed by radiotherapy in 67 of 71 cases, while chemotherapy alone or followed by radiotherapy in sites of either initially bulky or residual disease was administered to 58 patients with extensive disease. The overall response rate was 77% (complete response, 45%; partial response, 32%). Complete responses were documented more frequently in limited disease than in extensive disease (57% v 22%; P < .001). The 2- and 5-year freedom from progression rates (24% and 16%, respectively), as well as overall survival rates (31% and 16%, respectively) were significantly affected by disease extent. No patient with extensive disease was progression free and alive at 2 years, while more than half of stage I and II patients were disease free and alive at 5 years. This retrospective analysis performed on a large number of consecutive, nonrandomized patients suggests that, at least in patients with limited disease, it is possible to achieve favorable long-term results using treatment tailored to disease extent. Nonetheless, the disappointing results commonly achieved in the treatment of small cell lung cancer strongly support the need for either prospective, randomized studies to confirm recently reported improved results or new pilot studies with investigation of entirely innovative approaches. PMID- 7846541 TI - [Glutamate receptor and GABA receptor expressed in amphibian oocytes after injection of chicken retina mRNA]. AB - The glutamate receptor and GABA receptor of chicken retina were studied with the expression system of amphibian oocyte. Some important results were obtained: L glutamate, kainate, AMPA and quisqualate could all induce rapid and smooth depolarizing currents in oocytes. NMDA, L-AP4, trans-ACPD and L-aspartate had no effects. The antagonism of kainate response by AMPA and quisqualate was found, and it seemed that AMPA, quisqualate and KA could act on the same receptor. Comparing the responses to L-Glu and NMDA, it was found that the mRNA abundance of metabotropic glutamate receptor and NMDA receptor in chicken retina was much lower than that of chicken brain. The GABA receptor in chicken retina was very different from that of bovine retina. And although about 10% of the GABA response was insensitive to bicuculline, but most GABA receptors in chicken retina were proved as GABAA receptors. PMID- 7846542 TI - [Reversal of the inhibitory effect of electroacupuncture on the nociceptive response of neurons in parafascicular nucleus by naloxone and atropine in acute arthritic rats]. AB - Rats with adjuvant arthritis were used as an animal model of pathological pain in this experiment and the nociceptive response of neurons in parafascicular nucleus (Pf) were recorded and intracerebroventricular (icv) injection of naloxone and atropine was adopted in order to investigate the effect of electroacupuncture (EA) and to analyze the neurotransmitters involved. The main results were as follows: (1) The nociceptive response of the majority of Pf neurons (29/34) in arthritic rats was significantly inhibited by EA at acupoints of "Zusanli" and "Sanyinjiao"; (2) The inhibitory effect of EA was reversed in 12/13 units by icv injection of naloxone (4 micrograms/10 microliters); (3) The inhibitory effect of EA was also reversed in 11/12 units by icv injection of atropine (5 micrograms/10 microliters) (4) The spontaneous unit discharge of Pf neurons in arthritic rats was increased after icv injection of naloxone or atropine. Experimental results suggest that EA could have an inhibitory effect on the nociceptive response of Pf neurons in arthritic rats, which might be mediated by opioid system and cholinergic system in the brain, and that opioid system and cholinergic system might have a tonic inhibitory effect on the spontaneous unit discharge of Pf neurons in arthritic rats. PMID- 7846543 TI - [Autoradiographic approach to the developmental study on the binding sites of AVP4-8 in rat hippocampus]. AB - The localization of the 35S-labelled AVP4-8 binding sites in the rat hippocampus was studied by using autoradiographic approach via observing the selective damages of hippocampal neurons by neurotoxins, and the developmental regulation of the hippocampal AVP4-8 receptor by pretreatment with exogenous AVP4-8 was observed. In adult rat hippocampus, the binding sites of AVP4-8 were assembled on the whole hippocampal pyramidal cell layer and granular cell layer of the dentate gyrus. Treatment of colchicine caused parallel disappearances of granular cells and the AVP4-8 binding sites in the gyrus, while treatment of kaininc acid destroyed the CA3-CA4 pyramidal cell layer and abolished the binding sites in this area. The developmental emergences of AVP4-8 binding sites were normally on postnatal day 6 in pyramidal cell layer and postnatal day 7 in the dentate gyrus. However, postnatal daily treatments of exogenous AVP4-8 enhanced the formations of both pyramidal and dentate binding sites, as they appeared rather densely on postnatal day 5. The characterized distribution of AVP4-8 binding sites in the rat hippocampus and the relationship between their developmental enhancements and facilitation of learning behaviors in mature rat by neonatal treatment of exogenous AVP4-8 were discussed. PMID- 7846544 TI - [Effects of vocalization and respiration and fiber connections on hyperstriatum ventrale pars caudale in Fringilla montifringilla]. AB - In urethane-anesthetized Fringilla montifringilla, effects of electrically stimulating the hyperstriatum ventrale pars caudale (HVc) on vocalization and respiration were observed. Central connections of HVc were investigated by means of injecting CB-HRP into HVc. The results were as follows: (1) Electrical stimulation of HVc caused vocal response. (2) Long train electrical pulses stimulation of HVc elicited significant respiratory facilitating effects, that is, increase of respiratory rate and depth. (3) Short train stimulation administered in HVc during inspiratory phase terminated switching-off of inspiration, and during expiratory phases produced the prolongation of expiratory phase so to coordinate vocalization and then increasing the respiratory rate and depth. (4) CB-HRP traces revealed that HVc projected to robust nucleus of the archistriatum, and atea X of lobus parolfactorius. HVc received projections from medial nucleus magnocellularis of the anterior neostriatum, nucleus interfacialis of midneostriatum, telencephalic auditory nucleus-field L, nucleus uvaeformis of the thalamus, and locus ceruleus of the pons. These results showed that, besides vocal control, HVc may be involved in neural regulations of respiratory facilitation, the effect on respiration seeming specific. It is suggested that HVc may play an important role in coordinating singing and respiration. PMID- 7846545 TI - [A study of automatic activity and morphology of guinea-pig aortic vestibule]. AB - The automatic activity of aortic vestibule was studied in 82 guinea-pig heart preparations with intracellular microelectrode. Spontaneous activity could be recorded in 16 preparations (19.5%), while in 61 preparations (74.4%) automatic activity could be induced by electrical stimulation. Of these preparations, they were all found a very small region below the right and the poster valves, the response showed a slow and low rising phase and a marked spontaneous depolarization in phase 4. The response could be blocked by Mn2+ and nifedipine. Outside of the specialized valve region, all recorded vestibule action potentials pertain to the fast type. Light and electron microscopic examination showed that the structure of the specialized local aortic vestibule region was similar to that of ordinary myocardium possessing slow automatic activity instead of the ordinary ventricular musculature. PMID- 7846546 TI - [The roles of protein kinase C and Na(+)-H+ exchange in the angiotensin II induced hypertrophic response]. AB - In order to study the roles of protein kinase C (PKC) and Na(+)-H+ exchange in [Sar1] ANG II-induced hypertrophic response, 3H-Leucine incorporation into serum free cultured neonatal rat cardiomyocytes were interfered with staurosporine, phorbol 12-myristate 13-acetate (PMA) or amiloride. With [Sar1] ANG II, a dose dependent augmentation of protein synthesis was observed. Activator of PKC (PMA) could also accelerate the rate of protein synthesis to a significant extent, while pretreatment of cardiac myocytes with PKC inhibitor (staurosporine) or Na(+)-H+ exchanger inhibitor (amiloride) would block [Sar1] ANG II-induced increase 3H-Leucine incorporation. These results demonstrated that activation of PKC and Na(+)-H+ exchange might mediate the hypertrophic response initiated by [Sar1] ANG II. However, inhibition of cellular Na(+)-H+ exchange did not affect the increase in protein synthesis due to activation of PKC, a finding indicating that the two resorts to regulate cell growth are mediated by independent pathways. PMID- 7846547 TI - [Effect of alpha 1-adrenoceptor subtypes on beta-adrenoceptor mediated positive inotropic response in rat left atria]. AB - The distribution of the alpha 1-adrenoceptor (alpha 1-AR) subtypes and the effects of activation of alpha 1-AR subtypes on the beta-adrenoceptor (beta-AR) mediated positive inotropic response were investigated. The radioligand binding assays indicated that the Bmax and Kd values were 11.7 +/- 18 fmol/mg.protein and 86.0 +/- 9.6 pmol/L respectively. Pretreatment of the preparations with 20 mumol/L chloroethylclonidine (CEC) which inactivated alpha 1B subtype, decreased the Bmax to 45.7 +/- 5.2 fmol/mg.protein (P < 0.01). The inhibition curves of 5 methyl-urapidil were best fitted to two site model and indicated that alpha 1A subtype took 28.5% of total 125IBE specific binding sites. In the functional experiments, norepinephrine (NE) induced a positive inotropic response in a concentration dependent manner by activation of both beta- and alpha 1-AR. The concentration-response curves (CRC) for NE were shifted rightward after the pretreatment of the preparations with 20 mumol/L CEC, but leftward in the presence of 1 nmol/L WB4101. In the presence of 10 mumol/L phentolamine which inactivated both alpha 1-AR subtypes, the CRC for NE were shifted leftward. When alpha 1-AR was activated by phenylephrine the CRC for isoproterenol (selective beta-AR agonist) were shifted rightward. The results suggested that the alpha 1B subtype enhanced while the alpha 1A subtype inhibited the beta-AR mediated positive inotropic response. When both alpha 1A and alpha 1B subtypes were activated simultaneously the alpha 1A subtype showed a dominate role. PMID- 7846548 TI - [Effects of atrial natriuretic peptide on aortic baroreceptor activity in rats]. AB - Effects of atriopeptin III (AP III) on the aortic baroreceptor activity in rats were studied in the isolated aorta arch-aortic nerve preparation in situ. By perfusing the isolated aortic arch with AP III (2.0 micrograms/ml) in rats, at constant intra-aortic pressure (IAP) of 13.3 kPa, the integral of aortic nerve activity (IANA) was increased by 64 +/- 27% (P < 0.001), the stepwise increases and decreases of IAP were correspondingly accompanied by increase and decrease in IANA, while the saturation pressure (SP) and the operating range (OR) of aortic baroreceptor activity were decreased from 22.5 +/- 0.5 to 21.3 +/- 0.5 kPa (P < 0.05) and 12.1 +/- 0.4 to 10.6 +/- 0.4 (P < 0.05), respectively, and the threshold pressure (TP) did not show any changes. The function curve of aortic baroreceptor was shifted to left and upward, and the peak integral value (PIV) and the peak slope (PS) of the curve were increased from 508 +/- 66 to 730 +/- 52% (P < 0.05), 55.6 +/- 7.5 to 93.2 +/- 6.8%.kPa-1 (P < 0.05), respectively. After washing out of AP III, the IANA returned to the control level. By perfusing the aortic arch with sodium nitroprusside (NP, 1.0 microgram/ml), at constant intra-aortic pressure (IAP) of 13.3 kPa, although the IANA was decreased as compared with the control, there was no statistical significance (P > 0.05).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7846549 TI - [Specific binding sites of [3H] cortisol and [3H] dexamethasone in rat liver cell membrane]. AB - By using [3H] cortisol and [3H] dexamethasone (DEX), a class of specific binding sites of glucocorticoids (GC) in rat liver cell membrane was observed. These binding sites had saturability, high affinity and low capacity. The kinetic parameters of [3H] cortisol and [3H] DEX were: Kd = 12.84 +/- 6.58 nmol/L (n = 4) and 40.27 +/- 23.44 nmol/L (n = 3) respectively; Bmax = 2.57 +/- 1.84 pmol/mg protein and 0.64 +/- 0.18 pmol/mg protein respectively (mean +/- SE). The Kd obtained from the kinetic studies was corresponding to the results of Scatchard analysis. Scatchard plots from the equilibrium experiments showed the straight line. The Hill coefficients were 0.9880 and 0.9990 respectively. The competitive displacement experiments indicated that cortisol possessed the higher specificity for the [3H] cortisol binding sites than other tested steroids (prednisolone, progesterone, RU486, DEX). The competitive ability of cortisol was at least 40 folds higher than mentioned steroids. By means of autoradiography technique, the existence of [3H] cortisol labelled particles on the liver cell membrane was found. PMID- 7846550 TI - [Studies on glycine receptor, acetylcholine receptor and ion channels expressed in amphibian oocytes after injection of chicken retina mRNA]. AB - Glycine receptor, acetylcholine receptor and voltage dependent ion channels expressed in amphibian oocytes after injection of chicken retinal mRNA were studied by using voltage clamp technique. The current response to glycine was proved as small, and the acetylcholine receptor was identified as N type. Aspartate, serotonin and dopamine induced no responses. In addition, voltage dependent ion channels were detected, and were identified as delayed rectifier potassium channel and sodium channel. PMID- 7846551 TI - [Enhancement effect of tetramethylpyrazine on slow inward current in guinea pig papillary muscles]. AB - Tetramethylpyrazine (TMP) could potentiate the force of contraction and increase the action potential duration (APD) of isolated guinea pig papillary muscles in a dose-dependent manner. Similar effects were also observable in BaCl2 or histamine induced contraction and the accompanied slow action potential (SAP). In fact, contraction and SAP could also be induced by TMP itself at 3.0 mmol/L concentration and antagonized by verapamil (1 mumol/L) within 10 min. In the presence of propranolol or in experiments carried out in catecholamine-depleted (reserpine 2.5 mg/kg, i.p. 15 h prior to the experiment) muscles, TMP was unable to induce SAP and contraction. These results suggested that the effects of TMP on enhancing Isi were mediated by the release of catecholamine in myocardium. PMID- 7846552 TI - [On the central inhibition action of tetrahydroberberine without relevance to GABA receptors]. AB - Using an earthworm (Eisenia foetida) dorsal muscle preparation, it was shown that tetrahydroberberine (THB, 10(-7)-10(-4) mol/L) did not affect both GABA and ACh receptors. DA receptor antagonist haloperidol (HAL) also exerted no effect. Owing to the blocking action of isonicotinyl hydrazine (INH) and thiosemicarbazide (TSC) on biosynthesis of GABA, and of picrotoxin (PT) and bicuculline (Bic) on the GABA-BZ receptor complex mediated transmission, all these agents could induce convulsion in mice. This action could be antagonized by amino- oxyacetic acid (AOAA) and benzodiazepine (BZ), but not by DA receptor antagonists THB and HAL. All the above observations indicate that the GABA inhibition is not involved in the central action of THB. PMID- 7846553 TI - [Role of cardiac renin-angiotensin system in swimming induced physiological myocardial hypertrophy]. AB - To determine the contribution of cardiac renin-angiotensin system (RAS) to the physiological myocardial hypertrophy induced by swimming training and the relationship between locally produced and circulating RAS, both ventricular and plasma angiotensin (Ang) I and II contents, ventricular angiotensin converting enzyme (ACE) and plasma renin activity (PRA) were detected by means of radioimmunoassay and biochemical method. It was shown that after 5 weeks of swimming, the ventricular wet weight to body weight ratio (V/Bwt) and Ang II in both left and right ventricles and ACE activity increased markedly as compared with the controls (P < 0.05). Furthermore, significantly positive correlation was found between the ventricular Ang II and V/Bwt (r = 0.7721, P < 0.001), while the plasma Ang I and II and PRA remained at the control level. No correlation was found between plasma Ang II and V/Bwt. These above findings suggest that cardiac RAS may play an important role in physiological myocardial hypertrophy and to a large extent is in dependent on circulating RAS. PMID- 7846554 TI - [Effect of tyrosine on progesterone production by perifused rat large and small corpus luteal cells]. AB - The effect of tyrosine on progesterone production by rat large and small luteal cells was studied by perifusion method. The large and small luteal cells were separated by sucrose density gradient centrifugation. After pre-perifusion for 1 h the effluent from the perifused large or small cells was separately collected at 10 min intervals by a fraction collector. Progesterone content of each sample was measured by RIA. Results showed that the basal progesterone production by large luteal cells was 2-fold more than that of the small ones. However, the suppressive effect of tyrosine on hCG- induced progesterone production was more pronounced in small luteal cells. These differences may be due to the fact that small luteal cells uptake more 3H- tyrosine. PMID- 7846555 TI - Place, space and health. PMID- 7846556 TI - Firm behavior in the U.S. market for factor VIII: a need for policy? AB - In this paper, we historically examine the market for Factor VIII concentrate, a collection of blood products used in the treatment of hemophilia A. With the introduction of HIV-1 into the U.S. blood supply, a majority of American hemophiliacs became infected with the virus. In response to contamination, the pharmaceutical manufacturers producing Factor VIII concentrate developed highly purified products which were introduced in the late 1980s at four to five times the price of the older, intermediate purity products. These new products are highly valuable in protecting the 30% of hemophiliacs who are HIV-1 seronegative; however, for those individuals previously infected by the virus, the extra benefit of the more costly products was questionable at the time they were first introduced. We postulate that there has been some level of industry coordination among the producers of Factor VIII concentrates to supply only the more expensive, highly purified products even though there appeared to be significant demand for the intermediate purity products by HIV-1 infected hemophiliacs. We develop and present a model that is useful for testing an inter-product collusion hypothesis. Further, we hypothetically discuss the model's implications and develop some public health policy options that might improve the competitive performance of the market. PMID- 7846557 TI - Social status and the health of families: a model. AB - The aim of this study is to examine the association of family health and social status, taking the family as the unit of analysis. One particular dimension of social status, lifestyle incongruity, is examined as a predictor of family health, relative to other stressors and sociodemographic variables. Lifestyle incongruity refers to the degree to which style of life (measured by the accumulation of consumer goods and the adoption of specific leisure activities) exceeds economic status (as assessed by occupational class and educational credentials). Using the 1980 General Household Survey of the United Kingdom, it was found that lifestyle incongruity discriminated between households with and without chronically ill members, and was associated with a global rating of family health, controlling for a variety of factors. The logic of studying the health of families, and the implications of these results for future research are discussed. PMID- 7846558 TI - Sense of coherence, coping and caregiver role overload. AB - The focus of the present study is to examine the relationship between Antonovsky's Sense of Coherence (SOC), the nature of patient pathology, situational coping responses, and role overload in Belgian primary caregivers to dementing and nondementing chronically ill family members (n = 126). The hypotheses that caregivers with a strong SOC are likely to cope in situationally appropriate ways were confirmed. Sense of Coherence appears to have a protective effect, in the sense of being related to management of the meaning of the situation, the selection of realistic coping strategies, and the avoidance of potentially maladaptive or unhealthy behaviors. Multi-variate analyses revealed that SOC alone predicted 29% of the variance in role overload for caregivers to dementing patients, while strategies to manage the situation and symptoms of distress were the only significant, yet maladaptive, coping responses for caregivers to nondementing patients. It is arguable that these findings indicate a threshold effect of the nature of patient disability on the protective effects of the sense of coherence. The multi-dimensional impact of caring for a patient with a dementing disorder exerts a unique and particular strain, one that requires caregivers to be able to cope by redefining the meaning of their relationship with their dependent. The theoretical rationale for the hypothesized threshold effect is explored. PMID- 7846559 TI - QALYs, HYEs and individual preferences--a graphical illustration. AB - The choice of outcome measure in cost-utility analysis has been a matter of concern. In particular the theoretical properties of quality-adjusted life-years (QALYs) and healthy-years equivalents (HYEs) have been debated. In this paper the underlying preference assumptions of QALYs and HYEs are illustrated graphically. For QALYs the assumptions of mutual utility independence, constant proportional trade-off, and risk neutrality are explained and illustrated. Mutual utility independence is shown to guarantee that the quality weight with the standard gamble method is independent of the number of years in the health state and constant proportional trade-off is shown to guarantee that the quality weight with the time-trade-off method is independent of the number of years in the health state. Together these two assumptions leads to a utility function over life-years that exhibits constant proportional risk posture, which is the basis for the risk-adjusted QALY model. The more commonly used risk-neutral QALY model is shown to be a valid cardinal utility function if risk neutrality over life years holds for all health states. For HYEs to be a valid cardinal utility function the somewhat less restrictive assumption of risk neutrality over life years in full health has to be made. It is also shown graphically that the proposed two-stage procedure to measure HYEs in theory gives the same result as directly using the time-trade-off method. Finally, it is shown that by estimating the certainty-equivalent number of HYEs it is possible in theory to obtain a measure that will always rank risky health profiles according to individual preferences. It is concluded that further empirical work should be undertaken to test the ranking properties of the different measures. PMID- 7846560 TI - Household headship and child nutrition: a case study in western Kenya. AB - The effect of female household headship on child nutrition has been hypothesized by some to be negative, based on the assumption that mothers alone will be poorer and will have greater demands on their time and resources. On the other hand, there is some evidence in Kenya that the nutritional status of children of female heads may be better than that of children of male heads, suggesting that when women have more control over resources, more goes to the children. In Kenya, de facto female headship is common due to male labor migration. This study examines the relationship between child nutrition and de facto female vs male household headship in western Kenya through the examination of family income and decision making patterns. Women in male-headed households had greater financial responsibility for household maintenance. Female heads assumed more farming responsibilities and had higher remittances from husbands. Husbands of female heads purchased food and other goods in the city for use by the household. Male headed households produced more food crops and used a larger proportion of them for home consumption. In this study, children of female heads consumed a greater variety of foods. Despite a greater prevalence of stunting, there was a lower prevalence of low weight for age among children of female heads. However, in statistical analyses, headship did not relate significantly to nutritional intake or status. In attempting to understand the possible factors influencing the relationship between headship and nutritional status, we found trade-offs in the ways families were coping, which appeared to balance some of the negative and positive effects of each situation. PMID- 7846561 TI - Self-medication among Hong Kong Chinese. AB - A randomized telephone survey on the practice of self-medication in the preceding 2 weeks was carried out from October 1989 to April 1990 among Chinese living in Hong Kong. 1068 people were interviewed. Self-medication was a common and universal practice by Hong Kong Chinese with a prevalence of 32.5% in 2 weeks. Those who reported illness were significantly more likely than those who did not use self-medication (65 vs 18.2%) and to have used more than one item of medications (39 vs 20%). Chinese tonics were the most frequently used self medications although they were the least known. Chinese medicines were used as often as Western medicines in the self-treatment of illnesses. People used self medication mainly because they felt that they knew what to do. About 80% of the Western and Chinese medicines were perceived to be effective but only 49% of the tonics were reported so. Side effects were reported from all types of medications with an overall prevalence of 6.4%. There was a lack of knowledge of the possible side effects in over 96% of the self-medications which is an area for patient education. The popularity but the relative lack of knowledge of Chinese tonics call for more scientific research and better regulation on their sales. PMID- 7846563 TI - Changes in active life expectancy in Taiwan: compression or expansion? AB - The 1986-1989 supplements on Elderly Living Conditions to the Monthly Surveys of Human Resources in the Taiwan area are used to estimate active life expectancy and to examine evidence for a compression of disability. Unlike recent results generated in Western countries in favour of the expansion of morbidity hypothesis, our findings tend to support the hypothesis that declining mortality leads to a compression of disability. In Taiwan fatal diseases (e.g. heart disease, stroke, and cancer) play a more important role in disability than to nonfatal diseases (e.g. arthritis, dementia, sensory impairments, and osteoporosis, etc.). Fatal diseases are still the leading causes of disability; modern technology has not prolonged life significantly to Taiwanese who contract such diseases. Hence the improvement in recent life expectancy is very slow and the duration between age at onset of fatal diseases and death tends to be short. As a result of such short duration, the area between the disability and the mortality curve in the life table narrows. PMID- 7846562 TI - Sexual behaviour in Kenya: implications for sexually transmitted disease transmission and control. AB - Sexual behaviour in Kenya in relation to STD transmission was investigated with a view to forming a basis for the more rational design of STD/HIV control interventions. Questionnaires were administered to a sample of 762 men and women attending eight health facilities in two urban centres. Equal numbers of STD patients (cases) and non-STD related clinic attenders (clinic controls) were selected, matched by gender and clinic. Another sample of 427 men and women was obtained from a random sampling of households in a slum area in Nairobi (community controls). Male STD patients who were unmarried, or married but living apart from their wives, reported a higher mean number of sex partners in the previous three months than did male clinic or community controls. Unmarried female STD patients reported a higher mean number of sex partners in the previous three months than did unmarried female clinic or community controls. Both male and female STD patients were more likely to report having been involved in commercial sex transactions in the previous three months than clinic or community controls. Considerable heterogeneity in sexual behaviour was apparent. In multivariate analysis, the most important predictor of STD acquisition for both men and women was the number of reported sex partners in the previous three months. In addition, for men only, marital status (unmarried, or married but living apart from their wives) and purchasing sex were significant predictors of being an STD patient. These data confirm the importance of commercial sex in STD transmission, and suggest that men play a bridging role between female sex workers and the general population of women.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7846564 TI - Psychotropic drugs: long-term use, dependency and the gender factor. AB - The study examines the factors contributing to the initiation, continuation and termination of use among female and male long-term users of minor and major tranquilizers. The findings show the importance of the lay-referral system as a channel of introduction to psychotropic drug use, especially for men. The issue of dependency is explored both in terms of the users' own interpretation of its nature and their reports on the professional responses to their long-term use. The findings indicate that gender and drug use are intricately linked in both the non-professional and professional treatment of anxiety and insomnia. PMID- 7846565 TI - Stress disorders of families of the disappeared: a controlled study in Honduras. AB - The effect of forced disappearance on the physical and psychological health of family members was assessed by interviews carried out in Honduras. Families of the disappeared were compared with two control groups: (1) families who lost a member due to accident or illness; and (2) families where no one had died within the past 10 years. Constellations of stress-related symptoms commonly seen in post-traumatic stress disorder and other anxiety disorders were approx. 2 times more prevalent in families of the disappeared as compared to the other two groups, indicating that families of the disappeared suffer over and above that due to normal grieving. It is suggested that the atmosphere of fear and isolation experienced by families of the disappeared is a causative factor in the prolongation of stress-related disorders years after the traumatic event. PMID- 7846566 TI - Interposition in the U.S. tobacco market. PMID- 7846567 TI - The third decade. Cervical Spine Research Society New York, New York, December 1993. PMID- 7846568 TI - Rheumatoid involvement of the cervical spine. An overview. AB - OBJECTIVE: This symposium is an update of current knowledge regarding rheumatoid involvement of the cervical spine. SUMMARY OF BACKGROUND DATA: The pathophysiology of rheumatoid involvement in the neck is the same as it is in the peripheral joints. Information regarding the natural history of this condition is incomplete, and more data are needed regarding the natural history in the untreated patient as well as the outcomes of operative management. CONCLUSIONS: Long-term studies of the natural history in the untreated patient as well as the results of operative management will be needed before definitive statements can be made regarding treatment recommendations. However, the latest information available is being presented to guide treatment at this time. PMID- 7846569 TI - Rheumatoid arthritis. Neuroanatomy, compression, and grading of deficits. AB - STUDY DESIGN: The authors summarize published data regarding cervical spine involvement in rheumatoid arthritis, define the neurologic manifestations, and provide recommendations for management of these complex and difficult problems. OBJECTIVES: The authors attempted to accurately define the neurologic lesions resulting from rheumatoid involvement of the cervical spine despite the complexity of the neuroanatomy of the cervicomedullary region and the diversity of pathology. SUMMARY OF BACKGROUND DATA: Despite the long-standing recognition of cervical spine involvement in rheumatoid arthritis, appreciation of the different neurologic manifestations of this disease has been lacking or misunderstood. METHODS: The authors reviewed the relevant neuroanatomy, neurovascular anatomy, and neuropathologic lesions that interact to create these complex and often confusing clinical situations. RESULTS: Rheumatoid arthritis produces encroachment on the brainstem and cervical spinal cord. The minimum space available at the craniocervical junction for the neural structures is 13 to 14 mm, which is fairly constant. Below C2, the available space is only 12 mm. When the amount of space reduced below this amount, there is, by definition, neural compression. The site of compression and/or repeated microcontusions will determine subsequent neurologic deficits. At the craniovertebral junction, neural compression and traumatic injury typically occur anteriorly at the pyramidal decussation producing cruciate paralysis with considerable weakness in both arms and minimal leg involvement. Cranial settling can result in lower medulla and cranial nerve dysfunction. Subaxial stenosis typically results in a more typical myelopathy. CONCLUSIONS: Accurate diagnostic studies are mandated to determine the location of compression and to fully appreciate the resultant neurologic deficits. To improve more complete comprehension of the neurologic manifestations of rheumatoid arthritis, the relevant neuroanatomy, neurovascular anatomy, and neuropathologic lesions must be understood. PMID- 7846570 TI - Postmortem osseous and neuropathologic analysis of the rheumatoid cervical spine. AB - METHODS: Eleven patients with paralysis, secondary to rheumatoid arthritis of the cervical spine were analyzed postmortem. Neurologic classification (Ranawat) included one Class 2, four Class IIIA, and six Class IIIB. Rheumatologic changes included atlantoaxial subluxation, basilar invagination, and subaxial subluxation. During autopsy the entire cervical spine was removed, including the occiput and foramen magnum. The spinal cord and medulla oblongata were removed en toto and examined histologically by a neuropathologist. RESULTS: Nine of the eleven cases revealed abnormal histology of the spinal cord, and in two patients, the spinal cords were normal. Three histologic types of spinal cord compression were identified. In Type 1 (four cases) severe chronic mechanical compression revealed marked mechanical distortion, flattening, and destruction of the cord with secondary Wallerian degeneration of the ascending and descending tracts without anoxicischemic neuron changes. In Type 2 (three cases), there was vascular compression showing ischemic damage to the cord with necrosis of the lateral columns in the ischemic watershed regions supplied by anterior and posterior spinal arteries. In Type 3 (two cases), there was mild mechanical compression showing focal gliosis at the site of compression without ascending or descending tract injury. Two of the eleven cases had thrombosis of the vertebral arteries. Of the eleven cases analyzed, two had normal spinal cords. CONCLUSION: This autopsy analysis of rheumatoid cervical spine suggests that paralysis can be due to both mechanical neural compression and/or vascular impairment. PMID- 7846571 TI - Rheumatoid arthritis of the cervical spine. Surgical decision making based on predictors of paralysis and recovery. AB - OBJECTIVE: This article reviews the current knowledge of predictors of paralysis and the potential for neurologic recovery in patients with rheumatoid arthritis involving the cervical spine. The primary goal is to prevent the onset of an irreversible neurologic deficit. SUMMARY OF BACKGROUND DATA: Use of the posterior atlantodental interval of less than 14 mm as measured from lateral cervical radiographs is a reliable screening tool for identifying high risk patients who require further evaluation with magnetic resonance or computed tomography/myelography. The primary technical objective of surgery in patients with impending neurologic deficit is stabilization of the diseased spine segments and relief of spinal cord compression via reduction of subluxation or direct decompression. Complications are not uncommon, but tend to occur less frequently in patients who have surgical intervention before the onset of severe myelopathy. Pain relief is good when a solid arthrodesis is achieved, and neurologic recovery is most favorable when severe cord compression is not present preoperatively. CONCLUSION: An improved understanding of the natural history, physical findings, and radiographic parameters will allow the construction of a management strategy for timely intervention in rheumatoid patients with progressive cervical disease. PMID- 7846572 TI - Spinal cord injury. Role of steroid therapy. AB - STUDY DESIGN: The authors review the evidence supporting the role of glucocorticosteroids in spinal cord injury, critique published studies, and provide recommendations for steroid use in this complex and difficult problem. OBJECTIVES: The authors detail the evolution of the use of glucocorticosteroids for acute spinal cord injury and objectively assess the results of NASCIS I and II. SUMMARY OF BACKGROUND DATA: Glucocorticosteroids were first used in patients with acute spinal cord injury in the 1960s. An initial randomized clinical trial (NASCIS I) did not demonstrate a difference in outcome between the low- and high dose steroid therapy. A subsequent study (NASCIS II) demonstrated that a treatment could enhance neurologic recovery. METHODS: The authors critically review the preclinical studies of glucocorticosteroids, NASCIS I and NASCIS II: The majority of the critique focuses on NASCIS II and independent analysis of the data generated by that trial. RESULTS: NASCIS II suggests clinical benefit from high-dose intravenous methylprednisolone therapy. The true benefit of steroid therapy is unclear because of the difference in outcome of the two placebo groups who entered the protocol before and after 8 hours. The initial promising results may be negated by the better recovery of the delayed treatment and/or untreated group of patients in the greater than 8-hour placebo group. However, until the raw patient data from NASCIS II is made available for independent review, the actual benefit of intensive steroid therapy will remain elusive. CONCLUSIONS: Even with the controversies and unresolved issues, we advocate initiation of intensive glucocorticosteroid therapy as soon as possible after acute spinal cord injury, and not beyond the first 8 hours. There is too much data available to arrive at any other conclusion. PMID- 7846573 TI - Cervical spine trauma. AB - STUDY DESIGN: The authors reviewed the results of a large number of studies of patients with acute cervical spine dislocations and subluxations. OBJECTIVES: The authors make recommendations regarding the evaluation and treatment of acute cervical spine dislocations based on a thorough review of the available literature. SUMMARY OF BACKGROUND DATA: Realization that a significant percentage of patients with acute cervical dislocations also have disc herniations has led to some controversy regarding the timing of MRI evaluation and attempted closed reduction. This article review studies of spine dislocations at one institution. METHODS: The review of the literature included 131 consecutive patients with acute cervical spine dislocations treated by the senior author followed both retrospectively and prospectively. These results were compared with those of many other authors. RESULTS: Emergent attempted closed reduction remains the treatment of choice for alert cooperative patients with acute cervical spine dislocations. Open or closed reduction under general anesthesia with an uncooperative or unconscious patient should be preceded by an MRI scan. In this situation, the presence of a herniated disc mandates decompression before reduction. PMID- 7846574 TI - Early outcome in cervical spinal cord injured patients older than 50 years of age. AB - STUDY DESIGN: This study retrospectively reviewed consecutive spinal cord injured patients older than 50 years of age. OBJECTIVE: This study established reasonable expectations for the early clinical outcome of cervical spinal cord injured patients greater than 50 years of age. SUMMARY OF BACKGROUND DATA: Previous studies of cervical spinal cord injuries have concentrated on long-term morbidity and mortality. Little data has been reported on the early clinical outcome during rehabilitation. METHODS: Forty-two consecutive patients older than 50 years of age at the time of cervical cord injury were reviewed. Data was collected from the time of injury to discharge from rehabilitation (< 4 months) and included morbidity, mortality, and disposition of the patient. RESULTS: There were 15 complete and 27 incomplete cervical cord lesions. Forty-five percent were caused by falls, 42% by motor vehicle accidents. Serious associated morbidity was 81% in complete cord injuries and 34% in incomplete lesions. Overall mortality was 23%. Complete cord injury mortality rate was 60% in this age group. All patients over 65 years of age with complete cord injuries died. CONCLUSIONS: Incomplete cervical cord lesions have the best prognosis for return to home and a functional lifestyle. Complete cervical cord injuries in patients older than 50 years of age have a 60% mortality rate. Complete cervical cord injuries in patients over 65 years have a poor prognosis for survival. PMID- 7846575 TI - Cervical spine injuries in patients 65 and older. AB - STUDY DESIGN: This study was a retrospective data-base review of patients with cervical injuries admitted to a regional spinal cord injury center over a 9-year period. OBJECTIVES: Patients < 40 and > or = 65 were analyzed separately to determine differences in etiology, neurologic findings, mortality, and neurologic recovery. SUMMARY OF BACKGROUND DATA: Previous studies of cervical injuries in older patients have found a high percentage of falling as an etiology, a high incidence of injuries to C2, and a high mortality rate with spinal cord injury (SCI). METHODS: Three databases containing information on all SCI patients, SCI patients with 1-2 year follow-up, and neurogically intact spinal injury patients were reviewed retrospectively. RESULTS: A higher percentage of older patients had cervical injuries, and this group did not show the typical male predominance seen in young patients (4:1 vs. 1:1). Neurologic deficits were more common in the younger age group. In the older patients, falls were a much more common etiology, and upper cervical injuries, especially odontoid fractures, predominated. Cervical spondylosis and stenosis were more common in the older patients, and the mortality with associated SCI was 60 times higher than in younger patients. Younger patients more commonly had complete neurologic injuries, but had more early functional motor return in incomplete lesions. The older patients did show late functional return in incomplete deficits. CONCLUSIONS: Cervical spine injury commonly occurs with relatively minor trauma in patients > or = 65, with a mortality rate of approximately 26% with associated SCI. Return of functional motor recovery is delayed in older patients with incomplete deficits, but can be expected. C2 injuries, especially odontoid fractures, must be ruled out in older patients with neck pain after even a minor injury. PMID- 7846576 TI - Transverse atlantal ligament disruption associated with odontoid fractures. AB - OBJECTIVES: The authors evaluated transverse atlantal ligament integrity in patients with fractures of the odontoid process of the axis. SUMMARY OF BACKGROUND DATA: Injuries of the transverse atlantal ligament can result in atlantoaxial instability after fractures of the atlas or axis, even if osseous healing occurs. METHODS: The clinical histories and follow-up examinations and radiographic data of 30 patients with odontoid fractures were reviewed, using a combination of magnetic resonance (MR) imaging, thin-cut computed tomography (CT), and plain radiographs to evaluate osseous and ligamentous injuries. RESULTS AND CONCLUSIONS: Osteoperiosteal ligamentous avulsion injuries were identified on MR imaging in three patients and were associated with acute and delayed instability and nonunion. The combination of MR imaging, CT, and plain radiographs is useful in evaluating unstable odontoid fractures to facilitate rational treatment planning. Odontoid fractures with transverse ligament injuries should be considered for early surgical stabilization because this combination of injuries is unlikely to heal nonoperatively. Anterior odontoid screw fixation should be avoided when the ligament is injured. PMID- 7846577 TI - Respiratory complications after cervical spinal cord injury. AB - STUDY DESIGN: Sixty-five consecutive cases of acute cervical spinal cord injuries were reviewed retrospectively for respiratory complications. OBJECTIVES: The objectives were to identify factors that may contribute to respiratory dysfunction and to evaluate therapeutic measures designed to reduce respiratory complications. SUMMARY OF BACKGROUND DATA: Respiratory complications continue to be a major cause of morbidity and mortality after cervical spinal cord injury with a reported incidence from 36 to 83%. METHODS: Multiple factors were evaluated which could potentially influence the incidence or severity of respiratory complications. These included age, pre-existing cardiac or pulmonary disease, accompanying major injuries, and the severity of the spinal cord injury. The effects of various therapeutic measures were also assessed including the benefit of rotating beds, early fracture stabilization and patient mobilization. RESULTS: Respiratory complications occurred in 62% of these patients and were transient in nature, variable in severity and duration, strongly associated with the severity of spinal cord injury, and only marginally affected by therapeutic interventions. CONCLUSIONS: The characteristics of respiratory dysfunction following cervical spinal cord injury correspond to those of spinal shock. PMID- 7846578 TI - Astrocyte response and transforming growth factor-beta localization in acute spinal cord injury. AB - STUDY DESIGN: An experimental histologic and immunohistological investigation of acute spinal cord injury was performed in a rat model. OBJECTIVE: This study determined (1) the immediate cellular and molecular responses within the spinal cord that result from a clinically relevant compression injury, (2) the acute astrocytic response to injury using the astrocyte specific GFAP antibody, and (3) the temporal pattern of cellular and extracellular localization of transforming growth factor-beta 1 (TGF-beta 1) within the spinal cord injury zone immediately after injury. SUMMARY OF BACKGROUND DATA: Ultimate neurologic outcome from spinal cord injury results from both the primary mechanical trauma and a subsequent cascade of cellular and molecular events that are termed the secondary injury. Efforts aimed at improving neurologic outcome may depend on the manipulation of cellular and molecular mechanisms that are responsible for propagating this secondary injury cascade. Astrocytes and TGF-beta are two potentially key components of this secondary injury. METHODS: Twenty-one Sprague-Dawley adult rats underwent open thoracic spinal cord injuries using the Allen weight-drop technique. Spinal cord specimens were harvested at 0, 1, 2, 4, 8, 24, and 72 hours after injury for histologic and immunohistochemical evaluation. Harvesting of injured and surrounding uninjured cord was performed before sectioning in sagittal and transverse planes. These paraffin-embedded sections were stained with polyclonal antibodies against glial fibrillary acidic protein (GFAP, an astrocytic cytoskeleton marker) and TGF-beta 1. RESULTS: A complex astrocytic response to the spinal cord injury was found within 24 hours of injury. Both the geographic and temporal patterns of astrocyte localization suggest a role in the regulation of spinal cord injury propagation. High concentrations of extracellular TGF-beta were seen immediately after injury within the hematoma at the zone of impact. Subsequently, intracellular TGF-beta was seen in astrocytic nuclei and cytoplasm, intramedullary and extramedullary capillary endothelial cells, and in motor neurons. CONCLUSIONS: The neurologic outcome in patients with SCI results in part from a secondary injury whose cellular and molecular mechanisms are poorly understood. This study suggests that both astrocytes and TGF-beta are involved in the regulation of spinal cord secondary injury. An improved understanding of their specific roles may result in novel treatments to improve the outcome from SCI. PMID- 7846579 TI - Morphologic analysis of the cervical spinal cord, dural tube, and spinal canal by magnetic resonance imaging in normal adults and patients with cervical spondylotic myelopathy. AB - STUDY DESIGN: Transverse areas of the spinal canal, the dural tube and the spinal cord of the cervical spine of normal adults and patients with cervical spondylotic myelopathy (CSM) were analyzed by magnetic resonance imaging (MRI). OBJECTIVES: Correlations of the results of MRI to clarify the pathogenesis of CSM. SUMMARY OF BACKGROUND DATA: Relationships between the area of the spinal cord and that of the dural tube or the spinal canal have been reported, but there is no report to compare the relationships among the three in patients with CSM and normal adults. METHODS: T1-weighted MR images of the cervical spine of 96 normal adults and 74 patients with CSM were evaluated by measuring the transverse areas of the three structures mentioned above in the axial plane. RESULTS: In normal adults, the maximal transverse area of the spinal cord was 85.8 mm2 at C4/5 and the minimal transverse areas of the dural tube and the spinal canal were 186.0 mm2 at C5/6 and 236.1 mm2 at C4, respectively. At the unaffected level of C3, the ratio of the canal to the spinal cord was significantly higher in CSM patients than in age-matched normal adults. The transverse area of the spinal cord and the ratio at the maximal compression level showed significant correlations with the severity of neurological symptoms. CONCLUSION: These results suggest that the narrow area and high ratio of the spinal canal to the spinal cord are responsible for a static factor in CSM. PMID- 7846580 TI - Spinal motion after cervical fusion. In vivo assessment with roentgen stereophotogrammetry. AB - STUDY DESIGN: A roentgen stereophotogrammetric (RS) technique using metallic markers was used to determine in vivo three-dimensional (3-D) motion data in the post-operative cervical spine. Two patients were examined with RS following fusion for up to 12 months at scheduled intervals. OBJECTIVES: The study was designed to develop a technique and provide an in vivo assessment of the fusion process following surgery. Besides the researchers and surgeons, this type of information is of particular interest to the FDA and implant manufacturers. SUMMARY OF BACKGROUND DATA: The high accuracy of the roentgen stereophotogrammetric (RS) technique using metallic markers to predict displacements across body joints, including spinal joints, has been well established in the literature. Its applications in the lumbar region to assess the fusion process as a function of time following surgery have also been reported. Similar in vivo applications (and results) dealing with the cervical region are lacking. METHODS: A roentgen stereophotogrammetric (RS) technique using metallic markers was developed. Appropriate in vitro studies were undertaken to assess its accuracy for in vivo applications in the cervical spine region. Following this, three Vitallium beads were surgically implanted in anatomically appropriate positions in of each the exposed vertebrae of two patients at the time of surgery. The patients were followed with RS serially for 12 months after surgery at scheduled intervals. At each RS session, roentgen stereo pairs of the cervical spine in neutral, maximum voluntary flexion, and maximum voluntary extension were obtained using a biplanar radiographic system. The metallic beads on the radiographs were digitized using an in-house software package to determine vertebral motions across the fused segments. RESULTS: In patient 1 (atlantoaxial fusion), the flexion-extension range of rotational motion decreased with time while the corresponding AP translation at the fusion level increased from 6 mm at 3 months post-op to 13 mm at 6 and 12 months postoperatively. The abnormal AP translation at 6 months and beyond was evident on extension/extension lateral radiographs, but the AP translation at 3 months was not visually evident. In patient 2 (anterior discectomy and interbody fusion), motions of small magnitude were observed at the fused level in all three axes. These motions actually increased over the one year observation period, but were never large enough to be visually detectable on lateral extension/extension radiographs. Patient 2 had a good clinical result despite these small motions. CONCLUSIONS: Roentgen stereophotogrammetry may detect motion in the in vivo cervical spine with a sensitivity heretofore unavailable. In patient 1, we were able to detect motion before it was visually manifest. In patient 2, small motions were detected at the level of a successful anterior cervical fusion, the significance of which remain uncertain. PMID- 7846581 TI - Anterior cervical discectomy with and without fusion. Results, complications, and long-term follow-up. AB - STUDY DESIGN: This study retrospectively reviewed the outcomes of 126 patients treated for cervical radiculopathy with either simple anterior cervical discectomy (ACD) or anterior cervical discectomy and fusion (ACF). OBJECTIVES: Complications, short-term, and long-term outcomes were compared to determine which was the superior procedure in the treatment of cervical radiculopathy. SUMMARY OF BACKGROUND DATA: Both procedures were performed for identical reasons on similar patient groups in an identical manner. The ACF group had a tricortical autograft implanted after the discectomy. METHODS: Complications and short-term follow-up were determined by review of hospital and office charts and radiographs. Long-term follow-up was by phone interview. RESULTS: Anterior cervical discectomy had a significantly reduced mean operative time, blood loss, and hospital stay. There were 16 complications for ACF, 15 of which were graft related and 4 complications for ACD. There was, however, no difference in mean time to return to work between the two groups. Long-term follow-up demonstrated an average low level of neck and arm pain in both groups. Continued donor site pain was not a long-term problem. Slightly more ACF than ACD patients were satisfied with the long-term results of their surgery. CONCLUSIONS: Neither procedure is ideal for the treatment of cervical radiculopathy. Anterior cervical discectomy results in decreased hospital cost and surgical morbidity. Anterior cervical discectomy and fusion results in more rapid resolution of patient pain. The ideal procedure would appear to be ACF performed with a theoretical biomaterial that would be minimally expensive and consistently promote successful arthrodesis. PMID- 7846582 TI - Prediction of bone graft strength using dual-energy radiographic absorptiometry. AB - STUDY DESIGN: A biomechanical study of anterior iliac crest bone was done to investigate a relationship between the compressive strength of tricortical iliac crest grafts and bone mineral density (BMD) of the iliac crest measured by dual energy x-ray absorptiometry (DEXA). OBJECTIVES: This study investigated the potential usefulness of DEXA for measuring BMD of the iliac crest and documented bone graft strength predictability by BMD measurements. SUMMARY OF BACKGROUND DATA: The corticocancellous iliac bone is frequently used as an interbody graft for anterior spine fusion. The decreased compressive strength of bone graft may lead to collapse, pseudarthrosis and recurrence of symptoms, particularly in the osteoporotic patient. The DEXA accurately determines BMD of the spine and the hip, but no previous studies are available on the pelvis. METHODS: The BMDs were measured on the intact pelvis of the elderly and the corresponding tricortical grafts, using DEXA. The strut and Smith-Robinson type grafts were placed under axial loading using Material Testing System. Load to failure and compressive strength were obtained and statistically correlated to BMDs. RESULTS: There was a high correlation between the BMDs of the intact pelvis and each graft (R = 0.8, P < 0.001). The ultimate load to failure and compressive stress were linearly correlated to the BMD of the intact pelvis (R = 0.82, P < 0.001, R = 0.78, P < 0.001, respectively) as well as to the BMD of the graft (R = 0.77, P < 0.001, R = 0.75, P < 0.001, respectively). CONCLUSIONS: These results suggest that the biomechanical strength of the iliac bone graft is very dependent on its BMD, and DEXA has a potential clinical value in predicting iliac bone graft strength for cervical spine fusion. PMID- 7846583 TI - Occipitocervical fusion with posterior plate and screw instrumentation. A long term follow-up study. AB - STUDY DESIGN: Thirty-two patients at one institution underwent occipitocervical fusions with posterior plate and screw instrumentation. The average follow-up was greater than 4 years (50 months). METHODS: AO plates and screws were used and in more than 50% of the cases, the Magerl transarticular C1-C2 screw technique enhanced the occipitocervical instrumentation. In nine patients, cement was used and thus are excluded in evaluation of fusion results. All 23 patients attained solid fusions. No pseudarthrosis occurred. The average time to fusion was 13 weeks. Halos or traction immobilization was not used postoperatively. The average time of the simple orthosis wear was 11 weeks. Patients were out of bed on an average of the second postoperative day with a range of 1-4 days postoperatively. Reduction of the atlantoaxial joint was required in 10 of the 23 patients. At follow-up, nine remain reduced. RESULTS: In one patient, the atlantodens interval approximated the preoperative distance and radiographs demonstrated one transarticular C1-C2 screw was not placed satisfactorily. The average operative time was 172 minutes, and the average blood loss was 956 cc. The neurologic status of the patients improved or remained the same. No patient deteriorated neurologically. A total of 78 occipital screws were placed. No complications resulted from any of these screws. One intraoperative complication occurred secondary to massive bleeding after a transarticular screw hole was drilled. Bone wax was placed over the drill hole and the bleeding ceased. No postoperative problems occurred in this patient. Most specifically, no central nervous system sequela was evident. CONCLUSIONS: The conclusions from this study are that posterior occipitocervical fusion can be performed very safely with plate and screw instrumentation. An extremely high fusion rate can be expected with minimal complications and minimal postoperative immobilization. This technique, however, is technically demanding. PMID- 7846584 TI - Biochemical effects of the nucleus pulposus component. PMID- 7846585 TI - Spine update. Spine manipulation. PMID- 7846586 TI - Spinal cord monitoring in patients undergoing surgery for neuromuscular scoliosis. PMID- 7846587 TI - Manual therapy with steroid injections--a new approach to treatment of low back pain. PMID- 7846588 TI - Decompression for lateral lumbar spinal stenosis. Results and impact on sick leave and working conditions. AB - STUDY DESIGN: One hundred patients underwent lumbar nerve root decompression without fusion. All patients were registered preoperatively in a computer-coded protocol and followed at regular intervals: 4, 12, and 24 months after surgery. A number of subjective and objective variables were investigated including data on preoperative and postoperative working conditions and sick listing. Patients' opinions on pain relief were assessed using a 4-grade scale. OBJECTIVES: Surgical results and impact on sick leave and working conditions in patients who underwent surgery for lateral spinal stenosis were evaluated in a prospective, consecutive study. SUMMARY OF BACKGROUND DATA: Preoperatively, 81 of the patients were employed, 21 in sedentary work, 36 in moderately heavy work, and 24 in heavy work. The majority of the patients (78%) were off work (sick listed) with a mean duration of 13 months. Mean preoperative duration of sciatic pain was 2.5 years. METHODS: Working conditions were classified into one of three categories: sedentary, moderately heavy, and heavy work. Distribution of working conditions preoperatively and postoperatively was assessed in conjunction with duration of sick leave. Change of work category postoperatively was evaluated and related to preoperative working conditions. RESULTS: The effect of decompression for sciatica due to lateral spinal stenosis was gratifying in most cases with excellent results in 65% and fair in 23% of the patients concerning leg pain. The majority of patients employed preoperatively (73%) returned to work after a postoperative sick leave of 5.5 months. Patients who received disability pension postoperatively had significantly inferior surgical result concerning back pain and were also sick listed significantly longer preoperatively. CONCLUSION: Thus, lateral spinal stenosis was improved in the majority of patients (88%) who underwent surgery, and the majority of patients who were employed before surgery returned to work after. PMID- 7846589 TI - Lumbar disc excisions in patients under the age of 21 years. AB - STUDY DESIGN: This study retrospectively analyzed 15 patients in the rarely seen young (under 21 years) age group who had undergone discectomy without fusion for prolapsed (herniated) lumbar disc. OBJECTIVES: The results were analyzed for degree of success in several outcome parameters to relate the efficacy of this patient group/procedure pair to that of other studies. SUMMARY OF BACKGROUND DATA: Sixteen operations were performed on this patient group, including six by a conventional procedure and ten by a microsurgical technique. Although most previous studies tend to support the use of discectomy, some physicians have reportedly been reluctant to implement these procedures in young patients. METHODS: Patients were followed in a short-term (median 3.3 months) assessment using records of post-operative office visits. Long-term (median, 10.5 years) follow-up was done by a mailed, self-report questionnaire that quantified pain in leg and back and scored for degree of success in ability to return to normal activities and satisfaction with the results of surgery. RESULTS: The short-term results were excellent for all but one patient. Long-term follow-up yielded the following successful outcomes: relief of back pain, 77%; and relief of leg pain, return to normal activities, and satisfaction with surgery, each 85%. CONCLUSION: Despite some tendency to delay discectomy in children and young adults, physicians are urged to be aware of this rare condition and the excellent long term outcomes and limited complications resulting from timely implementation of discectomy after a failed course of conservative therapy. Moreover, fusion should be avoided except in cases of vertebral instability. PMID- 7846590 TI - Direct current stimulation of allograft in anterior and posterior lumbar interbody fusions. AB - STUDY DESIGN: Interbody spinal fusion rates were compared in patients with and without direct current stimulation. OBJECTIVE: To determine whether direct current improves interbody fusion rates. BACKGROUND: High pseudarthrosis rates have been reported for anterior lumbar interbody fusions and failure of posterior lumbar interbody fusions pose difficult problems for the surgeon. Use of direct current to enhance interbody fusions is based on prior reports of electrically stimulated posterolateral lumbar fusions. METHODS: A modified Crock surgical technique with allograft was performed and stimulator cathodes, when used, were wrapped around the graft. Fusion was assessed using multiplanar computed tomographic reconstructions, radiographs, and tomograms. RESULTS: Overall fusion rates were significantly higher in stimulated patients (93% vs. 75%). Particularly striking were high risk groups such as smokers (92% vs. 71%), and those with no internal fixation (91% vs. 65%) and L4-L5 fusions (91% vs. 59%). CONCLUSION: Lumbar interbody fusion rates are improved by direct current treatment. PMID- 7846591 TI - Neurophysiologic detection of a unilateral motor deficit occurring during the noncritical phase of scoliosis surgery. AB - STUDY DESIGN: A four-path neurophysiologic monitoring system was designed for spinal cord monitoring during spinal surgery. It was used mainly during scoliosis surgery. OBJECTIVE: To evaluate the efficacy of this technique. METHODS: Sensory and motor pathways were continuously monitored bilaterally from skin incision to awakening, with independent evaluation of the right and left pathways for each modality. RESULTS: This monitoring technique detected a transient unilateral motor deficit that occurred during the dissection phase of spinal surgery for scoliosis before any instrumentation or mobilization of the spine. PMID- 7846592 TI - A biomechanical comparison of Gardner-Wells tongs and halo device used for cervical spine traction. AB - SUMMARY OF BACKGROUND DATA: Unstable cervical spine fractures and dislocations are often reduced by the application of axial traction using a halo or Gardner Wells tongs. Failure of tong or halo attachment can cause substantial morbidity and usually occurs at the pin-bone interface. Institutions commonly clean and reuse tongs. The effect of tong wear on pullout strength and the strength of the halo used as a traction device have not been documented. METHODS: A skull model biomechanically similar to human calvarium was used to compare the axial pullout strengths of four sets of new tongs, three sets of rarely used tongs, and one set of heavily used tongs, as well as a standard four-pin halo. RESULTS: The pullout strength of tongs tightened to the manufacturer's recommended level appeared to decrease with increased use. Measurement of the pin force generated by each set of tongs and of the spring constant of each spring, as well as inspection of the tongs after testing, suggested that the decrease in pull-out strength may be partly attributable to spring and/or pin wear. The pullout strength of the halo or of the new or slightly used tongs but not the heavily used tongs exceeded the maximum weight used clinically in cervical spine traction. CONCLUSION: The data suggest that consideration be given to replacement or recalibration of heavily used tongs. PMID- 7846593 TI - Biomechanics of the lumbar spine in sagittal/lateral moments. AB - STUDY DESIGN: The nonlinear stress analysis of the entire ligamentous lumbar spine (L1-S1) in single flexion, extension, right lateral, and left lateral moments of up to 15 Nm was performed. In sagittal moments, both disc fiber angles of 27 degrees and 30 degrees were considered. Moreover, in extension moment, the effects of larger gap limit (the distance at which the contact initiates) at all facet joints and of removal of left or left/right L4-L5 facet joints also were studied. OBJECTIVES: The overall and intersegmental biomechanics of the lumbar spine under sagittal moments with particular emphasis on the role facets were studied. METHODS: The analysis was performed using a nonlinear three-dimensional finite element model. RESULTS: Intersegmental results were nonlinear and varied from one level to the next. Overall, the lumbar flexibility and disc pressures were larger in flexion. Conversely, larger facet forces were computed in extension whereas flexion caused negligible contact forces. Unilateral and bilateral removal of L4-L5 facets in extension reduced the stiffness and increased the disc pressure at the same level while the remaining levels were nearly unaffected. In contrast, larger gap limit for articulation increased stiffness, reduced disc pressure, and increased loads on facets at all segmental levels. Disc fiber layers are most loaded in flexion and least loaded in extension. Large tensile strains occur in disc fibers under flexion and lateral moments. This suggests the vulnerability of disc fibers to failure under movements involving large flexion and lateral rotations. PMID- 7846594 TI - Effects of bone mineral density on pedicle screw fixation. AB - STUDY DESIGN: In an attempt to evaluate the effects of bone mineral density on the quality of fixation of pedicle screws in the lumbar spine, the axial pullout force was determined and compared in normal and osteoporotic human lumbar spines. OBJECTIVES: Four techniques of screw hole preparation were evaluated. Two pedicle screw/offset laminar hook constructs also were evaluated to determine whether the adjunct fixation of the laminar hooks would improve quality of fixation to a level sufficient to allow their use in the osteoporotic lumbar spine. METHODS: Pedicle screws were inserted by one of the listed techniques into fresh frozen cadaveric human spines. The fixation strength then was evaluated by pullout on a uniaxial testing frame. RESULTS: Bone mineral density was a strong influence on axial pullout force. In normal bone, the method of screw hole preparation did not significantly affect the quality of fixation. However, in the osteoporotic spine, either an untapped screw hole or the tapping of a screw hole with a 5.5 mm tap improved the pullout force a statistically significant amount (P < 0.003). Also, a pedicle screw with offset hooks at two adjacent levels improved the fixation significantly, increasing the pullout force to twice the expected value. CONCLUSION: Pedicle screw pullout strength was highly correlated with bone mineral density. A 5.5 mm tap or preparation with a ganglion knife improved pullout strength. Use of pedicle screws in conjunction with laminar hooks at two levels improved pullout strength. PMID- 7846595 TI - The effect of neck and leg flexion and their sequence on the lumbar spinal cord. Implications in low back pain and sciatica. AB - STUDY DESIGN: Fresh cadavers of five baboons were used to assess lumbar spinal cord movement. Window dissection at the L3 level was performed to observe the relative displacement of the cord to bony landmark, when the neck and hip were moved. OBJECTIVES: To examine the effect of the neck and hip flexion alone and in combination on the movements of the lumbar spinal cord relative to the third lumbar vertebral body. To investigate also the effect of the sequence of flexions. SUMMARY OF BACKGROUND DATA: Several clinical studies claim that cervical flexion together with straight leg raise tensions the lumbar nerve root. Although previous studies describe the effect of each of these movements, there have been no measurements of the combined effect or the effect of the sequence of movements. METHODS: Five fresh baboon cadavers were dissected to expose the L3 nerve root. The movement of the lumbar cord at that level was measured relative to a pin on the L3 vertebra. The neck and leg of the cadavers were moved by two operators. RESULTS: Cervical flexion always moved the lumbar cord in a cephalad direction. The degree of displacement was more pronounced if the cervical flexion followed hip flexion rather than hip extension. Hip flexion also moved the lumbar cord in a cephalad direction. However, the difference in cord displacement attributable to different sequences in hip movements were not found to be statistically significant. Cervical flexion elicited a greater cord displacement than traction. CONCLUSION: These findings would advocate that a test that comprises both neck and hip movements would be more sensitive in assessing nerve root movements than one that only uses neck or hip movements. Such a test should also consider the use of various sequences of neck and hip movements. PMID- 7846596 TI - Experimental study of intervertebral disc allografting in the dog. AB - STUDY DESIGN: An investigation of the use of intervertebral disc allografting as a potential alternative to intervertebral fusion was performed. In 13 adult mongrel dogs, intervertebral disc units cryopreserved after slow freezing were grafted. OBJECTIVES: To evaluate the morphologic and biosynthetic damage caused by cryopreserving the canine intervertebral disc before allografting. SUMMARY OF BACKGROUND DATA: Cryopreservation did not alter the normal histologic appearance. The metabolic activity, measured by 35S-sulfate incorporation, was observed to be 44% of the fresh control. METHODS: Transplanted intervertebral discs were examined histologically and radiographically at 12, 24, and 48 weeks after surgery. RESULTS: The allografted disc had preserved anular and nuclear architecture with moderate loss of chondrocytes 12 weeks after grafting. However, the intervertebral disc showed evidence of progressive disc degeneration 1 year after transplantation. CONCLUSIONS: More investigation of storage methods is needed to enhance the viability of the intervertebral disc for successful intervertebral disc allografting. PMID- 7846597 TI - Axon regeneration after decompression of the conus medullaris. AB - STUDY DESIGN: The effect of acute spinal stenosis (simulating fracture) and decompression of stenosis on axon regeneration was evaluated in an animal model. OBJECTIVES: Clinical function and quantitative histomorphometry were used to gain insight into the clinicopathologic effects of acute spinal stenosis and decompression. SUMMARY OF BACKGROUND DATA: Decompression of extrinsic compression after thoracolumbar fractures has been suggested to maximize recovery of neurologic function. Clinical studies seem to support this, but the histologic results of decompression are poorly understood. METHODS: Experimental spinal stenosis was created in 5 female beagle dogs, followed by decompression in three of the beagles at 6 weeks. Clinical function and histologic appearance were analyzed using a monoclonal antibody to neurofilaments. RESULTS: Stenosis consistently produced significant neurologic deficit and axon degeneration within motor roots distal to the stenosis. Decompression resulted in improved neurologic function and a tendency for the axons to return to normal number and volume based on quantitative histomorphometry. CONCLUSION: This study provides an animal model and functional and histologic data that support the use of decompression of acute spinal stenosis of 50% or more canal compromise at the level of the conus medullaris and a neurologic deficit. This may be seen clinically in thoracolumbar fractures. PMID- 7846598 TI - Computed tomographically guided biopsy of the spine. AB - STUDY DESIGN: Efficacy of the percutaneous biopsy of the spine under computed tomographic guidance was investigated. Seventy-five patients, ranging in age from 7 to 72 years, underwent this procedure. OBJECTIVES: To determine the usefulness of computed tomographically guided biopsies in the treatment of patients with spinal disorders. SUMMARY OF BACKGROUND DATA: The results of 68 biopsies (90.6%) were judged to be accurate insofar as the samples of tissue obtained could be diagnosed as specific types of neoplasm, infective lesions, reactive lesions of nonspecific type, or normal bone. METHODS: Biopsies that yielded a specific abnormality were categorized as true positives. The "normal" biopsies were followed for 6-18 months and were then deemed true negatives. Nondiagnostic ones were considered false negatives. RESULTS: The results are acceptable with an accuracy rate of 90.6%. It is a safe and simple procedure with a short learning curve. CONCLUSIONS: Computed tomographically guided biopsy of the spine is recommended as a procedure of choice, especially in cervical and thoracic lesions. Computed tomography is superior to fluoroscopy when dealing with small, deep-seated lesions especially in the cervical and thoracic regions and with lesions picked up on bone scan only, radiographs being negative. Needle biopsy under computed tomographic guidance is safe and precise. PMID- 7846599 TI - Thermal deficit in lumbar radiculopathy. Correlations with pain and neurologic signs and its value for assessing symptomatic severity. AB - STUDY DESIGN: The relationship between areas of thermal deficit and areas exhibiting other symptoms and neurologic signs, and the significance of the magnitude of thermal deficit in lumbar radiculopathy were analyzed. OBJECTIVES: To determine the clinical significance and value of thermal deficit as a sign of lumbar radiculopathy. SUMMARY OF BACKGROUND DATA: Thermal deficit has been discussed as a factor in the diagnosis of involved nerve roots. However, it has not been previously correlated with any particular symptoms or signs. METHODS: Sixty-eight healthy subjects and one hundred nine patients with lumbar radiculopathy due to intervertebral disc herniation underwent thermography. Sensitivity, specificity, and the agreement rate of thermal deficit to symptoms and neurologic signs were calculated in ten body regions. Total temperature difference of the affected limb was compared with the Japanese Orthopaedic Association scoring system. RESULTS: The agreement rates of thermal deficit with pain, muscle tenderness, motor weakness, and sensory disturbance were 60.9, 69.3, 71.8, and 71.8%, respectively. Sensitivity and specificity of thermal deficit to symptoms and signs were approximately 30% and 80%, respectively. The correlation coefficient of temperature decrease of the affected limb and the Japanese Orthopaedic Association score was 0.57, indicating a moderate correlation. CONCLUSIONS: Thermal deficit should be considered an independent sign of lumbar radiculopathy. The relatively high specificity suggests that a normal temperature may indicate an asymptomatic region. Symptomatic severity of lumbar radiculopathy may be assessed by measuring the magnitude of thermal deficit in the affected limb. PMID- 7846600 TI - Magnetic resonance imaging for the diagnosis of tuberculous spondylitis. AB - OBJECTIVES: The purposes of this study were to evaluate the nature of the paraspinal soft tissue mass and the location of the lesion involved using magnetic resonance imaging and to correlate these observations with surgical findings. SUMMARY OF BACKGROUND DATA: In the past, tuberculous spondylitis was diagnosed by plain radiography and since the 1970s, computed tomography has been a useful method for assessing tuberculous spondylitis. In contrast to most imaging methods, MRI has the advantages of improved contrast resolution for bone and soft tissues and versatility of direct imaging in multiple planes. METHODS: Medical records and magnetic resonance imaging studies of 22 patients with bacteriologically and/or histologically proved tuberculous spondylitis were reviewed. In each patient, the numbers of vertebrae involved were evaluated as well as which columns of vertebrae were affected and the signal intensities of lesions. In addition, an attempt was made to determine if granulation tissue differed from the abscess based on magnetic resonance imaging appearance and to compare the outcome with surgical findings. RESULTS: The average number of vertebrae involved per patient was 2.8 and T8 and T9 were the vertebrae most frequently affected. The destruction of vertebrae and discs was easily identified in both sagittal and axial planes. The peripheral margins were exclusively enhanced in all cases. Of particular interest, the posterior aspect of the vertebral body was predominantly involved. Mostly the involvement of both anterior and middle columns was noted. With the aid of intravenous administration of magnetic resonance contrast agents, magnetic resonance imaging was highly accurate in distinguishing the granulation tissue from the cold abscess. CONCLUSIONS: Magnetic resonance imaging demonstrated excellent images of bone destruction and soft tissue mass, and provided information in multiple planes, thereby delineating the extent of involvement in tuberculous spondylitis. Magnetic resonance imaging is most helpful in planning a surgical approach to tuberculous spondylitis. PMID- 7846601 TI - Dorsal hemivertebrae in children's lumbar spines. AB - STUDY DESIGN: Only small numbers patients with dorsal hemivertebrae have been reported. The natural course of this disease remains unpredictable, especially regarding the development of neurologic impairment. Two children with congenital dorsal hemivertebra with progressive kyphosis of the lumbar spine are presented. Onset and method of treatment are discussed. OBJECTIVES: Two boys with kyphosis due to dorsal hemivertebrae of the lumbar spine were followed with clinical examination, anteroposterior roentgenograms, and magnetic resonance imaging. One patient was in follow-up for more than 4 years postoperatively. The other patient, who has not undergone surgery, has been in follow-up for more than 2 years, undergoing reassessment every 4 to 6 months. SUMMARY OF BACKGROUND DATA: Spastic paralysis developed in one patient with dorsal hemivertebra and spina bifida. The other patient with dorsal hemivertebra and sacral agenesis had no neurologic deficit. METHODS: A dorsal approach with resection of the dorsal hemivertebra and short dorsal fusion with internal fixation was done in one patient. The other patient underwent clinical and radiologic follow-up. Method and onset of surgical treatment were compared with other studies. RESULTS: Progressive spasticity was seen in our first patient. This could be reversed by resection of the hemivertebra and monosegmental fusion. Alignment of the spine and normalization of the width of spinal canal were achieved. The second patient has not had a neurologic problem. Surgical treatment will be performed when indicated. CONCLUSIONS: A posterior approach is recommended for a dorsal hemivertebra. Decompression of the spinal canal can be achieved by resection of the dorsal hemivertebra and short dorsal fusion with internal fixation. Surgery should be done early to avoid late neurologic impairment. PMID- 7846603 TI - Cord compression due to extramedullary hemopoiesis in a patient with thalassemia. AB - STUDY DESIGN: This is a case report of a patient with thalassemia who had acute spinal cord compression at the T3 to T8 level and presented for treatment. METHODS: Magnetic resonance imaging and surgical decompression and transfusion therapy was chosen as the preferred treatment modality. RESULTS: Neurologic recovery was satisfactory from the immediate postoperative period, and full recovery was observed 2 months after surgery. CONCLUSION: Clinical awareness is important for early diagnosis. Documentation with an imaging technique, such as magnetic resonance imaging, is mandatory. Optimal treatment is tailor-made and depends on the clinical situation and the expertise available. PMID- 7846602 TI - Two-level thoracic disc herniation. AB - STUDY DESIGN: A double, contiguous disc herniation in the thoracic spine (T7-T8, T8-T9) in a 44-year-old man is reported. The patient complained of intermittent episodes of weakness and numbness in the lower extremities, paraesthesias radiating to the anterior and medial surfaces of the thigh and the leg (mostly on the left side), and mild sexual and urinary dysfunction. OBJECTIVE: The treatment must achieve complete spinal cord decompression, prevent further herniation, and prevent iatrogenic vascular damage to the cord. A transthoracic approach seems to offer the largest surgical view. SUMMARY OF BACKGROUND DATA: Twenty-six other cases of two-level thoracic disc herniation were found in the literature, only five of which were treated with a transthoracic approach. METHODS: Treatment consisted of complete disc excision (T7-T8 and T8-T9) with a right anterior transthoracic approach. Complete and safe removal of the discs required hemicorporectomy of T8 and subsequent grafting and plating. Spinal cord angiography, showing the Adamkiewicz artery originating from the left T10, was performed before surgery. Computed tomography-guided methylene blue injection in the retropleural interspace of T7-T8 was done for intraoperative level localization. RESULTS: At 1 year follow-up, complete relief of neurologic symptoms was observed, as was solid interbody fusion. CONCLUSION: In this case, a transthoracic approach was safe and effective for disc excision and cord decompression via hemicorporectomy. PMID- 7846604 TI - Extradural synovial thoracic cyst. AB - SUMMARY OF BACKGROUND DATA. Case studies documenting the incidence of thoracic intraspinal, extradural synovial cysts are limited. The occurrence of synovial cysts is associated with varied symptoms that differ among cervical, thoracic, and lumbar regions. The clinical appearance may be similar to other spinal diseases. METHODS. This report describes symptoms exhibited by and care provided for a patient with extradural synovial thoracic cyst. PMID- 7846605 TI - Spine update. Animal use in spinal research. AB - Progress in biomedical research often has depended on the use of animals as a testing ground for both experimental and clinical hypotheses. Animal models have been widely used in all specialties of medicine and have been crucial for acquiring basic science and clinical knowledge pertaining to spinal surgery. In addition to overcoming the many ethical and societal restrictions normally encountered in human studies, the use of animal models permits certain methodologic approaches inapplicable in humans. The purpose of this article is to: 1) review the general concepts of models, 2) discuss recommendations and regulations regarding the use of animals in biomedical research, and 3) present guidelines for the selection of the most suitable model for a particular study. Animal data are only as applicable as the model from which it is derived. Thus, future animal models must be carefully chosen using rational guidelines and should overcome the deficiencies and limitations of previous models. PMID- 7846606 TI - Hubert von Luschka. Pioneer of clinical anatomy. PMID- 7846607 TI - Trunk strength testing in patient evaluation and treatment. AB - A wide variety of trunk strength testing devices has been developed, the goal being to quantify back strength, patient effort, and spinal function or dysfunction. Although the idea of applying quantitative values to spine function is appealing, controversy exists regarding the reliability and validity of these testing systems. In this issue, two experienced investigators give their opinions as to the values and pitfalls of lumbar trunk strength testing, and provide insight into the most appropriate applications of these often costly systems. PMID- 7846608 TI - The goal of spinal imaging. PMID- 7846609 TI - [CT diagnosis of invagination in the adult]. PMID- 7846610 TI - [Diagnosis of aortic arch abnormalities with CT angiography]. PMID- 7846611 TI - [Vascular interventions on forearm and hand arteries]. PMID- 7846612 TI - [Cerebral and spinal superficial siderosis. Case report]. PMID- 7846613 TI - [Lumbar spinal nerve root compression syndrome in synovial cyst of the intervertebral joint]. PMID- 7846614 TI - [Maximal findings of arterial occlusive disease with occlusion of the brachiocephalic trunk, the left subclavian artery and the abdominal aorta in conjunction with stenosis of the left common carotid artery--case report]. PMID- 7846615 TI - Changing practices in ventilator management: a review of the literature and suggested clinical correlations. PMID- 7846616 TI - Parathyroid adenoma weight and the risk of death after treatment for primary hyperparathyroidism. AB - BACKGROUND: Patients operated on for primary hyperparathyroidism run an increased risk of death, as was found in a previous long-term follow-up of 896 patients. METHODS: In the present study the adenoma weight was determined in 713 patients with single parathyroid gland disease operated on between 1956 and 1982 and followed up in 1986. The adenoma weight was investigated for its usefulness as a prognostic factor. RESULTS: The analysis showed that the adenoma weight was significantly related to the risk of death (p < 0.001). Also a relationship was noted between glandular weight and preoperative serum calcium level (p < 0.001), although the serum calcium level had no predictive value in relation to the risk of death beyond that of the adenoma weight. The risk increase was also estimated as a function of adenoma weight. A moderate adenoma weight increase in a patient with primary hyperparathyroidism was found to imply an increased risk of death, corresponding to the increased risk of smokers as compared with nonsmokers. CONCLUSIONS: The results of this study support surgical treatment at an early stage of primary hyperparathyroidism. PMID- 7846617 TI - Use of the circular stapler in 1000 consecutive colorectal anastomoses: experience of one surgical team. AB - BACKGROUND: This study was performed to assess the exact performance of the conventional way of stapling colorectal anastomoses. Information collected from 1000 consecutive anastomoses performed by one surgical team could be considered as reliable reference with which results obtained by new approaches could be compared. METHODS: One thousand consecutive anastomoses were performed from 1979 to 1992. Characteristics of the procedure, intraoperative events, mortality rate, complications, and clinical outcome were detailed. RESULTS: There were 528 men and 472 women (age range, 20 to 90 years; average age, 63 years). Anastomoses were constructed by means of a circular stapler loaded with the largest cartridge in 82.3% of the cases. Imperfections were identified during operation in 124 cases. A diverting colostomy was performed in 127 cases. Postoperative mortality rate averaged 2.2%. Clinical anastomotic leaks developed in 35 patients: in 11.4% after low stapling (less than 5 cm from the dentate line) and in 2.2% after high stapling. The presence of a diverting colostomy influenced the leakage rate in patients with very low anastomoses. Total failure rate (death, definitive colostomy) as a result of anastomotic leak was 1.6%. Among the 933 survivors who had follow-up examination, the incidence of bad functional results decreased from 10% at the first attendance to 4.3% at the last one. Transanal dilatation and restapling were required for symptomatic narrowing in three and one patients, respectively. CONCLUSIONS: The conventional way of stapling colorectal anastomoses in reliable, but it requires strict observance of the rules for anastomosing intestine and a careful check of the stapled sutures. Results obtained by new approaches could be compared with these data. PMID- 7846618 TI - Primary sclerosing cholangitis: liver transplantation or biliary surgery. AB - BACKGROUND: Little information is available on the indications for, and the efficacy and timing of, liver transplantation in patients with primary sclerosing cholangitis (PSC). This issue is particularly relevant because prolonged survival has been reported in patients who do not undergo transplantation. METHODS: Long term results of therapeutic interventions including liver transplantation was assessed in a representative series of 51 patients. Patient survival was compared with that expected from prognostic models. RESULTS: Actuarial symptom-free survival rate in patients treated by nontransplantation biliary surgery (n = 23) was 35% at 10 years. Actuarial survival rate from onset of PSC (56% at 10 years) was identical to that expected from the prognostic model. Actuarial patient (n = 28) survival rate 5 years after transplantation was greater than that expected from prognostic models (89% versus 31%; p < 0.001). Previous abdominal surgery was associated with an increased in-hospital mortality rate (p < 0.05). Cumulative actuarial incidence of cancer 5 and 10 years after the onset of PSC was 13% and 31%, respectively. CONCLUSIONS: Liver transplantation improves the prognosis of patients with PSC. Failure to identify patients who will benefit from nontransplantation therapeutic interventions or in whom a cancer will develop, and the risk associated with previous abdominal surgery, suggest that liver transplantation should be indicated early after onset of symptoms. PMID- 7846619 TI - Outcomes of open cholecystectomy in the elderly: a longitudinal analysis of 21,000 cases in the prelaparoscopic era. AB - OBJECTIVE: We sought to obtain unbiased estimates of open cholecystectomy outcomes in a population-based cohort of elderly patients during the immediate prelaparoscopic era. METHODS: Medicare claims data were used to identify 21,131 patients aged 65 years or more who underwent open cholecystectomy in Pennsylvania between 1986 and 1989 and to develop longitudinal histories of hospitalizations and physician services utilization for these patients. Study patients were divided into three groups: simple cholecystectomy, cholecystectomy with intraoperative cholangiography (IOC) alone, and cholecystectomy with common bile duct exploration (CBDE). Outcomes examined included 30- and 90-day postoperative mortality rates and postoperative complications. RESULTS: Postoperative mortality rates in all patients was 2.1% at 30 days and 3.6% at 90 days. Patients in the CBDE group had a significantly higher mortality rate than those in the simple cholecystectomy or IOC groups; adjusted for differences in case mix, the mortality rate in the CBDE group was 47% higher at 30 days and 29% higher at 90 days. Rates of retained or recurrent common duct stones, bile duct stricture, and recurrent biliary tract surgery by 42 to 60 months after cholecystectomy were 2.8%, 0.4%, and 1.0%, respectively. CBDE was a strong risk factor for these complications. In contrast, the IOC group had a significantly lower risk of having clinically manifest retained or recurrent common duct stones develop by 42 months after operation. CONCLUSIONS: This study provides an unbiased assessment of open cholecystectomy outcomes necessary for future comparisons of open and laparoscopic cholecystectomy in elderly patients. Estimates of the excess mortality rates associated with CBDE provide a benchmark for assessing the outcomes of alternative strategies for managing common duct stones during laparoscopic cholecystectomy. Findings regarding the rates of retained or recurrent common bile duct stones in patients undergoing simple cholecystectomy and IOC challenge widespread beliefs about the limited clinical importance of unsuspected common duct stones, at least in the elderly population, and are relevant to the debate about routine IOC. PMID- 7846620 TI - Effect of lymph node dissection on the prognosis in patients with node-negative early gastric cancer. AB - BACKGROUND: Our objective was to evaluate the long-term benefit of R2/3 lymph node dissection compared with that of R1, even in node-negative cases. METHODS: We analyzed clinicopathologic data on 373 surgically treated patients with early gastric cancer and without microscopic nodal involvement. RESULTS: Five- and 10 year survival rates for patients treated with R2/3 gastrectomy were 97.3% and 95.4%, respectively. These values were significantly higher than the 90.1% and 81.1% noted for R1 gastrectomy (p < 0.01). Although no difference was found in morbidity and mortality, the incidence of death from a recurrence of the gastric cancer was significantly higher in patients treated with R1 gastrectomy than those with R2/3. Multivariate analysis with the Cox's proportional hazard model revealed patients' age and R2/3 gastrectomy to be independent prognostic factors in patients with node-negative early gastric cancer. CONCLUSIONS: These data show that prophylactic lymph node dissection can potentially prolong the survival time of patients with node-negative early gastric cancer by preventing a recurrence of the gastric cancer. PMID- 7846621 TI - Congenital hepatoportal arteriovenous fistula. AB - BACKGROUND: Two children with congenital hepatoportal arteriovenous fistulas have been investigated and treated surgically. These cases have been reviewed with five cases previously reported. METHODS: Two children, 5 months and 14 months of age, presenting with failure to thrive, hepatosplenomegaly, ascites, and recurrent gastrointestinal bleeding with evidence of portal hypertension, were found to have congenital hepatoportal arteriovenous fistulas. RESULTS: Doppler ultrasonographic examination was important in identifying abnormal portal venous flow. Angiogram identified the fistulas, confirming the diagnosis. Both patients had significant portal hypertension (pressure more than 30 mm Hg). Surgical resection in one child was unsuccessful, but surgical ligation of the hepatic artery controlled the symptoms in both patients. CONCLUSIONS: Rapid collateralization of the hepatic arterial blood supply made embolization a short term therapeutic measure, and surgical ligation of the hepatic artery is the treatment of choice for congenital hepatoportal arteriovenous fistulas. PMID- 7846622 TI - A second course of extracorporeal membrane oxygenation in the neonate--is there a benefit? AB - BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is an effective therapy for infants with severe respiratory failure and pulmonary hypertension. In most patients once the disease reverses, it does not recur. However, in some patients pulmonary hypertension recurs and these infants meet criteria for a second course of ECMO. We evaluated the survival rate and feasibility of a second course of ECMO in neonates. METHODS: A questionnaire was sent to all active ECMO programs that requested data about patients who received two courses of ECMO. A retrospective review of the results from responding centers was performed to evaluate indications and outcome. RESULTS: The overall survival rate for the 58 neonates was 40%. Thirty-four patients with congenital diaphragmatic hernia had a survival rate of 47%, and 12 infants with primary persistent pulmonary hypertension had an 8% survival rate (p < 0.05). Most patients were treated with venoarterial ECMO for both courses. CONCLUSIONS: There is a reasonable survival rate for selected neonates who are treated with a second course of ECMO. Infants with primary persistent pulmonary hypertension should be carefully examined before institution of a second course of ECMO. PMID- 7846623 TI - Comparison of endothelial function between in situ and reversed vein graft: differences in endothelium-dependent responses. AB - BACKGROUND: The endothelium releases endothelium-derived relaxing factors that are potent vasodilators and inhibitors of platelet aggregation. Experiments were performed to determine whether the endothelium-dependent responses differed between in situ and reversed vein grafts. The influence of valve disruption or of dissection of the adventitia was also examined. METHODS: Segments of canine jugular veins were grafted into the carotid arteries during procedures such as reversed grafting, in situ grafting with valve disruption, in situ grafting without valve disruption, and in situ grafting with dissection of adventitia. After 4 weeks the endothelium-dependent responses of the grafts were examined by isometric tension recording. RESULTS: In the reversed and in situ vein graft with valve disruption, acetylcholine caused endothelium-independent contractions, whereas in the in situ vein graft without valve disruption acetylcholine-induced endothelium-dependent relaxations were preserved. Adenosine diphosphate (ADP) caused comparable endothelium-dependent relaxations in the in situ vein graft irrespective of valve disruption. In the reversed vein graft ADP-induced relaxations were significantly impaired. In the in situ vein graft with dissection of the adventitia, relaxations in response to acetylcholine and ADP were significantly reduced. CONCLUSIONS: These results suggest that endothelial function, in terms of endothelium-derived relaxing factors in the in situ vein graft, can be preserved and that adventitial dissection in the in situ vein graft should be minimized to preserve endothelial function. PMID- 7846624 TI - Transplantation of allogeneic hepatocytes without immunosuppression: long-term survival. AB - BACKGROUND: Hepatocyte transplantation could be an alternative to whole liver transplantation. Allogeneic hepatocytes are rejected if transplanted without immunosuppression. The aim of this study was to transplant allogeneic hepatocytes in the peritoneum and to protect them from rejection by encapsulation in a new semipermeable membrane. METHODS: Rat hepatocytes were encapsulated in hydrogel based hollow fibers, obtained from AN69 copolymer, before being transplanted into the peritoneum of rats. Outcome of allogeneic hepatocytes encapsulated in hollow fibers was compared with that of syngeneic hepatocytes encapsulated in hollow fibers, with that of free allogeneic hepatocytes, and with allogeneic hepatocytes encapsulated in hollow fibers left open. Cell viability was assessed by erythrosin exclusion, structure by electron microscopy, and function by albumin release. RESULTS: Up to 90 days, viability of allogeneic hepatocytes in hollow fibers was greater than 80%. The structure remained normal at electron microscopy. Albumin release was 16.5 +/- 0.3 micrograms/24 hr/10(6) hepatocytes (day 15), 14.2 +/- 2.0 micrograms/24 hr/10(6) hepatocytes (day 30), 8.8 +/- 0.1 micrograms/24 hr/10(6) hepatocytes (day 60), and 11.4 +/- 0.3 micrograms/24 hr/10(6) hepatocytes (day 90). Free hepatocytes and hepatocytes in hollow fibers left open did not survive at day 15. CONCLUSIONS: Viability and function of encapsulated allogeneic hepatocytes were maintained up to 90 days after transplantation, without immunosuppression. PMID- 7846625 TI - Leukocytes contribute to hepatic ischemia/reperfusion injury via intercellular adhesion molecule-1-mediated venular adherence. AB - BACKGROUND: Leukocytes are suggested to modulate ischemia/reperfusion injury via membrane receptor-controlled interaction with the microvascular endothelium. METHODS: With the use of intravital fluorescence microscopy we investigated the role of the intercellular adhesion molecule-1 (ICAM-1) in a rat model of hepatic reperfusion injury with a neutralizing monoclonal antibody (anti-ICAM-1). RESULTS: Sixty minutes of left lobar ischemia and reperfusion (isotype-matched immunoglobulin G1 control antibody) caused leukostasis in sinusoids (240 +/- 15 cells per liver lobule), leukocyte adherence in postsinusoidal venules (679 +/- 76 cells per mm2 endothelial surface of postsinusoidal venules), nutritive perfusion failure (15% +/- 2% nonperfused sinusoids), excretory dysfunction (bile flow, 1.2 +/- 0.3 microliters.min-1.gm-1), and loss of hepatocellular integrity (serum aspartate aminotransferase, 1353 +/- 317 units.L-1; serum alanine aminotransferase, 1055 +/- 265 units.L-1). Anti-ICAM-1 did not affect sinusoidal leukostasis; however, it effectively inhibited postischemic leukocyte adherence to the venular endothelial lining (217 +/- 38 cells/mm2, p < 0.01). Concomitantly, hepatic reperfusion injury, including sinusoidal perfusion (6% +/- 1% nonperfused sinusoids, p < 0.01), excretory function (bile flow, 1.8 +/- 0.1 microliters.min-1.gm-1, p < 0.05), and hepatocellular integrity (aspartate aminotransferase, 480 +/- 108 units.L-1; alanine aminotransferase, 447 +/- 80 units.L-1, p < 0.05), was significantly ameliorated by anti-ICAM-1. CONCLUSIONS: These findings prove in vivo the pivotal role of ICAM-1 in leukocyte-dependent manifestation of postischemic liver damage. PMID- 7846626 TI - Induction of acute pancreatitis in germ-free rats: evidence of a primary role for tumor necrosis factor-alpha. AB - BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) has been implicated as a mediator of the systemic manifestations associated with acute pancreatitis. The purpose of this study was to show that TNF-alpha expression in pancreatitis is a primary response and is not the result of endotoxemia. METHODS: Severe acute pancreatitis was induced in germ-free rats, which have no source of endogenous endotoxin, by ductal infusion of artificial bile. Control animals underwent sham operation and ductal infusion of saline solution. TNF-alpha levels were measured by the WEHI bioassay. Endotoxin was measured by the Limulus assay. RESULTS: TNF alpha levels remained low in the sham group (mean, 24.6 +/- 8.0 pg/ml) but were significantly elevated in normal rats with pancreatitis (181 +/- 26.8 pg/ml; p < 0.001 versus sham group) and in germ-free rats with pancreatitis (213 +/- 90 pg/ml; p < 0.002 versus sham group). No endotoxin was detected in any of the experimental rats. CONCLUSIONS: Our results indicate that TNF-alpha levels are elevated in acute pancreatitis despite the absence of endotoxin, indicating a primary role of TNF-alpha in this disease. PMID- 7846627 TI - Protein kinase C regulates prairie dog gallbladder ion transport. AB - BACKGROUND: Gallstone formation is characterized by increased biliary calcium (Ca2+) level and altered gallbladder absorption. Recent studies suggest that luminal Ca2+ regulates gallbladder ion transport via intracellular calcium ([Ca2+]ic). Ca2+-calmodulin and protein kinase C (PKC) are two major systems through which [Ca2+]ic carries out second-messenger functions in many cell types. We have previously shown that Ca2+-calmodulin regulates basal gallbladder ion transport in prairie dog. The present study tests the hypothesis that PKC is also essential in regulation of gallbladder ion transport in this model. METHODS: The role of PKC in regulation of gallbladder ion transport was determined by studying the effects of phorbol esters, synthetic analogues of diacylglycerol, which directly activates PKC. Gallbladders were mounted in Ussing chambers, and standard electrophysiologic parameters were recorded after exposing tissues to either 10(-5) mol/L of 4-alpha-phorbol 12,13-didecanoate (PDD), 4-beta-phorbol 12 myristate 13-acetate, 4-beta-phorbol 12,13-dibutyrate (PDB), or 10(-4) mol/L serotonin. Unidirectional Na+, Cl-, and H2O fluxes were measured before and after treatment with only inactive PDD and most active PDB. RESULTS: Mucosal and serosal exposure of tissues to either 4-beta-phorbol 12-myristate 13-acetate or PDB resulted in a decrease in short-circuit current and transepithelial potential difference without any change in tissue resistance. Serotonin induced similar changes in gallbladder electrical properties. PDB caused an inhibition of mucosal to serosal fluxes of Na+, Cl-, and H2O, with a decrease in net Na+ absorption, an increase in net Cl- secretion, and a conversion of net H2O absorption to net H2O secretion. Serosal-to-mucosal fluxes of Na+, Cl-, and H2O did not change. Inactive PDD had no effect on either electrophysiologic parameters or ion and water fluxes. Pretreatment of tissues with PKC antagonist 1-(5 isoquinolinylsulfonyl)-2-methylpiperazine blocked the phorbol ester-induced inhibition of ion transport. CONCLUSION: PKC regulates gallbladder ion transport in the prairie dog by inhibiting Na+ absorption and stimulating Cl- secretion. PMID- 7846628 TI - Cytokines regulate endotoxin stimulation of endothelial cell arginine transport. AB - BACKGROUND: Endotoxin (lipopolysaccharide) stimulates transmembrane L-arginine transport in pulmonary artery endothelial cells (PAECs). The proinflammatory cytokines tumor necrosis factor (TNF) and interleukin-1 (IL-1) mediate many of the pathophysiologic effects of endotoxemia and sepsis. Endothelial cells secrete TNF and IL-1 in response to endotoxin. We hypothesize that lipopolysaccharide stimulation of plasma membrane L-arginine transport is mediated via an autocrine cytokine loop involving TNF and IL-1. METHODS: Confluent porcine PAECs were incubated with various concentrations of lipopolysaccharide, TNF, or IL-1, and arginine uptake was determined by assaying the uptake of 3H-L-arginine in the presence or absence of Na+ at different time points. PAECs were then incubated with lipopolysaccharide or saline solution after pretreatment with either anti TNF antibody or IL-1-receptor antagonist, and transport was measured 12 hours later. RESULTS: Lipopolysaccharide, IL-1, and TNF all increased both Na+ dependent and Na+-independent carrier-mediated L-arginine transport in a fashion that was both time and dose dependent. Maximal increases in stimulated arginine uptake occurred 8 hours after exposure to the cytokines and 12 hours after exposure to lipopolysaccharide. Pretreatment of endothelial cells with anti-TNF antibody blocked lipopolysaccharide stimulation of both Na+-independent and Na+ dependent transport by 100% and 90%, respectively. In addition, IL-1-receptor antagonist inhibited lipopolysaccharide stimulation of both Na+-independent and Na+-dependent transport by 65% and 85%, respectively. CONCLUSIONS: The marked increase in carrier-mediated L-arginine transport activity produced by lipopolysaccharide, IL-1, and TNF may represent an adaptive response by the pulmonary endothelium to support arginine-dependent biosynthetic pathways during sepsis. Furthermore, lipopolysaccharide stimulation of arginine transport is mediated in part through an autocrine mechanism involving IL-1 and TNF. PMID- 7846629 TI - Alpha-tocopherol attenuates lung edema and lipid peroxidation caused by acute zymosan-induced peritonitis. AB - BACKGROUND: Inflammation-induced disease as seen with trauma and infection can lead to increased lung oxidant activity resulting in cell membrane lipid peroxidation. Acute zymosan-induced peritonitis in rats produces lung inflammation, edema, and lipid peroxidation. We determined whether administered alpha-tocopherol (vitamin E), the key antioxidant protection against cell membrane lipid peroxidation, would improve this process. METHODS: Male Wistar rats were given 0.75 mg/kg of intraperitoneal zymosan, volume resuscitated, monitored, and killed at 4 or 24 hours. Lung histologic changes and levels of conjugated dienes, a marker of lipid peroxidation, were used to monitor injury. The levels of vitamin E, vitamin C, and catalase were used to monitor antioxidant defenses. The effect of administering alpha-tocopherol (50 mg/kg) by gavage immediately after zymosan on the degree of the lung injury was then determined. RESULTS: Twenty-four hours after zymosan was administered, the vitamin E levels in plasma were significantly decreased, but lung tissue vitamin E levels were maintained, whereas tissue catalase and vitamin E levels decreased. Lung tissue conjugated diene levels, alveolar edema, and neutrophil count were significantly increased. alpha-Tocopherol treatment increased the postzymosan plasma vitamin E levels by 50%. Lung tissue vitamin E levels did not increase; however, the degree of lung injury and lipid peroxidation was significantly attenuated. Tissue catalase levels were also maintained. CONCLUSIONS: We conclude that alpha tocopherol given at the onset of a progressing inflammatory injury can protect the lung from oxidant damage and attenuate the degree of lung injury. PMID- 7846630 TI - Ten-year survival after hepatectomy for advanced gallbladder carcinoma: report of two cases. PMID- 7846631 TI - Local epinephrine injection as treatment for delayed hemorrhage after hemorrhoidectomy. PMID- 7846632 TI - Reconstruction of the middle hepatic vein tributary during right anterior segmentectomy. PMID- 7846633 TI - True confessions. What office managers wish doctors knew. PMID- 7846634 TI - Address for success. As Shakespeare said, "Mend your speech a little, lest you may mar your fortunes.". PMID- 7846635 TI - Postmortem on reform. PMID- 7846636 TI - Battle scars. For plastic surgeons, psychological effects linger from silicone breast implant controversy. AB - When the first mammoplasty using silicon-gel-filled implants was performed in 1962, no oracle could have predicted what the ensuing 30 years would hold for the procedure. Breast augmentation grew to become the most oft-performed plastic surgery, with conservative estimates placing the number of procedures at nearly 1 million. PMID- 7846637 TI - Walking in their shoes. Awareness program shows civic leaders the challenges confronting teen mothers. AB - Donna Bacchi, MD, stood before a group of Austin business and community leaders hoping they would be disturbed by what they were about to see and hear. How would they react when an 18-year-old, 7-month-pregnant girl told them about living in the backseat of her aunt's car? Or the tale of a 16-year-old mother who had been living on the streets before finding shelter in a drug house? PMID- 7846638 TI - Health expenditures in Texas during 1989 and 1990. AB - To monitor the growth of the health-care sector in Texas, we made annual estimates of aggregate health spending in 1989 and 1990 and compared them with estimates from prior years and with national trends. Expenditures are grouped by total spending, spending by the state government, and distribution of payment. To achieve data that could be compared with national figures, we followed the methods used by the federal government to estimate national health spending. Results indicate a return to the rapid rates of growth experienced in the early 1980s. Possible explanations for some major trends in spending and in sources of payment are provided. Basic features of recent efforts to contain costs are addressed and related to the trends. PMID- 7846639 TI - Unilateral facet dislocation of the cervical spine. PMID- 7846640 TI - Physicians may get paid for hospice care. PMID- 7846641 TI - Cooperation needed to encourage more primary care physicians. PMID- 7846642 TI - Reform will rise again, but invisibly. PMID- 7846643 TI - Gene-culture coevolution and sex ratios: the effects of infanticide, sex selective abortion, sex selection, and sex-biased parental investment on the evolution of sex ratios. AB - The evolutionary consequences of culturally transmitted practices that cause differential mortality between the sexes, thereby distorting the sex ratio (e.g., female infanticide and sex-selective abortion), are explored using dynamic models of gene-culture coevolution. We investigate how a preference for the sex of offspring may affect the selection of genes distorting the primary sex ratio. Sex dependent differences in mortality have been predicted to select for a male- or female-biased primary sex ratio, to have no effect, or to favor either under different circumstances. We find that when a mating pair's behavior modifies mortality rates in favor of one sex, but does not change the number of offspring produced in the mating, the primary sex ratio will evolve a bias against the favored sex. However, when the total number of offspring of a mating pair is significantly reduced as a consequence of their prejudice, the primary sex ratio will evolve to favor the preferred sex. These results hold irrespective of whether the sex ratio is distorted by the mother's, the father's or the individual's own autosomal genes. The use of dynamic models of gene-culture coevolution allows us to explore the evolution of alleles which distort the sex ratio, as well as the final equilibrium states of the system. Gene-culture interactions can provide equilibria different from those in purely genetic systems, slow the approach to these equilibria by orders of magnitude, and move the primary (PSR) and the adult sex ratio (ASR) away from any stable equilibrium for hundreds of generations. PMID- 7846644 TI - A theoretical study of the socioecology of ungulates. II. A dynamic programming study of the stochastic formulation. AB - We develop a stochastic version of a previously discussed model of optimal herd size selection in ungulates. We assume that a large herd size confers to the animals a high level of protection against predators, but reduces the amount of food which can be eaten by each individual; on the contrary animals belonging to small herds would have access to large amounts of food but would bear a high risk of being killed by predators. Employing a dynamic programming approach we analyze the optimal trade-off between starvation and predation risks under the hypothesis that the animals would try to maximize their expected reproductive fitness during the incoming breeding period. We compare the optimal strategy in environments described by different kinds of stochastic food distributions (including the deterministic limit) for different values of predation pressure and of overall food availability. We obtain general information about the effect of the level of randomness of food distribution on the mean individual fitness and on the number of reproducers (the animals which survive to the beginning of the reproductive season). Moreover we discuss how a certain number of behavioral and ecological processes--which have been often described in natural populations of ungulates and which are usually explained in terms of phenological variations of the ecological landscape--may be interpreted as caused by intrinsic variations of the animals' strategy. PMID- 7846645 TI - [Marketing of inhalation steroids]. PMID- 7846646 TI - [A questionable guideline on solid food to breast-fed children]. PMID- 7846647 TI - [Is blood pressure treatment as effective in the population as in controlled trials?]. PMID- 7846648 TI - [Tracing of splenectomized patients in general practice]. PMID- 7846649 TI - [Medicine and outlook on life--dependence and autonomy]. PMID- 7846650 TI - [Suicide in Norway]. PMID- 7846651 TI - [The good crisis]. PMID- 7846652 TI - [Diagnosis-related groups--problematic birth and uncertain prognosis]. PMID- 7846653 TI - [Variations of suicide rate in the population. Historical perspective with special reference to the 1970s and 1980s]. AB - The registration of suicide in Norway started in 1826. In the 19th century the statistics were based on information from clergymen. Today they are based on death certificates and additional information. By setting 8.0 per 100,000 population as the division between high versus low suicide rates, the period 1826 1990 can be divided into three parts; high rates 1826-65 and 1966-90 with an intervening a period of 100 years with low rates. There has been an increase in the number of suicides in the period 1970-89. From 1989 to 1992 deaths from suicide have decreased from 708 to 616. Among young men the increase has halted. PMID- 7846654 TI - [Psychosocial preventive work among war refugees. A task for primary health care?]. AB - During the two first years of the war in Bosnia (1992-93) refugees came both to Norway and to other European countries. Bosnian "war refugees" are released prisoners from Serbian concentration camps, and their close families. Most of the former prisoners and their families had experienced extreme traumas, qualifying them for help from expert psychotherapists. No such help was available. The aim of the present project was to find out whether useful psychosocial preventive work can be done within the primary health services. Our intervention, which was carried out during a six month period in 1993-94, included two semi-structured interviews with each refugee family in the centre, and follow-up contacts with persons who indicated major psychological problems. All the refugees reported that they experienced deep sorrow, and the majority had difficulty in sleeping and concentrating. A pessimistic view of their future was common. Most of the refugees were positive towards participating in the interviews. Several of them have reported that the interviews were of direct help. In the majority of cases we have experienced that the ordinary health contacts later have been meaningful. PMID- 7846655 TI - [Psychosocial aspects in presymptomatic testing for genetic diseases. Experiences after 2 years of counseling in Huntington disease]. AB - The authors describe their experience from the psychiatric assessment and psychosocial counselling of 28 persons who sought presymptomatic testing for Huntington's chorea. Half of the persons had lived with a disease-affected parent during childhood and early adolescence. Nine of these persons had suffered from a psychiatric disorder at least once. Of the whole sample, 32% had a psychiatric disorder at the time of the assessment. Most persons experienced major emotional distress in relation to the testing but severe psychiatric responses were not observed. Suicidal ideation in relation to the testing was most often reported by persons who had had extremely negative experiences during childhood with their own affected parent. In some persons who were found to be free of risk, the main problem was guilt owing to survival. The psychosocial and psychiatric aspects of the possibilities of gene technology in the future must be addressed more seriously. PMID- 7846656 TI - [Medical and legal aspects of rape. Referrals to a team for care of rape victims at the regional hospital in Trondheim during the period 1989-1992]. AB - Since 1989 a special team of nurses and gynaecologist have taken care of rape victims at the Department of Obstetrics and Gynaecology, University Hospital of Trondheim. Information on cases during the period 1989-92 was recorded retrospectively in a preformulated system. During this period, 141 persons were examined. In 23% of the cases the victim did not want to press charges. Most of the victims were young, 38% were below 20 years of age. A considerable proportion (40%) reported alcohol intake. 78% of the sexual assaults involved penile-vaginal contact. Severe physical violence, more severe assaults than physical restraint, were reported by 24%. Signs of non-genital injuries were documented in 35% of all the victims. 13% showed genital injury. Presence of sperm was documented in 16% of all the examinations. In 67 of the cases there was an identified assailant and a victim who had pressed charges. The conviction rate was 48%. Characteristics of the assault and findings at the examination were related to judicial outcome. Reporting of severe violence (OR (odds ratio) = 5.3), documented genital injuries (OR = 6.5) and the presence of sperms (OR = 5.6) were associated with conviction. These associations were statistically significant. Reported alcohol intake by the victim was negatively associated with conviction (OR = 0.3). Adjusted for lapse of time between the event and the examination and the victim's age, the only factor that still showed a statistically significant association with conviction was the report of severe violence. PMID- 7846657 TI - [Crib death in the eastern regions of Norway 1984-1992. A survey of risk factors]. AB - Cot death is the most important cause of death during the first year of life after the newborn period in Norway. A case control study was performed by sending questionnaires to 188 cot death parents and 475 control parents with infants matched for age, sex and time of birth. 76% of the cot death parents and 79% of the control parents completed the questionnaires. The male/female ratio of the babies in both groups was 64/36. The age distribution showed a peak between two and four months. 65% succumbed during the winter months. During the winter 32% died outdoors. This was true for only 16% of those who died during summer. A higher proportion of the cot death cases than the controls were premature (more than eight weeks). 78% of the cot death victims usually slept prone, whereas this was true for only 50% of the controls (p < 0.01). 91% of the cot death victims were found dead in a prone position. When comparing live babies during the first three months of life, significantly more cot death mothers than control mothers had stopped breastfeeding. A larger proportion of the cot death victims than the controls had had apparent life threatening events (p < 0.01). Foam mattresses were equally frequent in both groups. PMID- 7846658 TI - [Reduced physical tolerance in patients with heart failure. Mechanisms and therapeutic effects]. AB - Physical performance is markedly reduced in patients with congestive heart failure, but the reason has not been precisely defined. It has been generally assumed that reduced exercise performance is related to ventricular systolic performance, or as more recently suggested, to impaired left ventricular diastolic function. However, there is no clear relationship between the indices of left ventricular performance and exercise capacity, and there is a dissociation between improvement in haemodynamic parameters and exercise performance. Recent studies suggest that peripheral changes may be major determinants of exercise performance. This may involve reduced blood flow to the exercising limbs because of impaired vasodilatory capacity or intrinsic changes in the skeletal muscle itself. In this review, these factors are considered, and the impact of different therapeutic strategies is discussed. PMID- 7846659 TI - [A fatal case of hereditary angioedema]. AB - A 27 year old woman suffered from recurrent attacks of laryngeal oedema due to C1 inhibitor deficiency, and was treated with danazol and tranexamic acid. The trachea was intubated with great difficulty, twice on one occasion. Two and a half years later she was admitted to the Intensive Care Unit with dyspnoea and dysphagia. Tranexamic acid, corticosteroids, adrenaline (also inhalated), were administered intravenously, but dyspnoea progressed. During preparation for tracheostomy the patient suffered from sudden airway collapse. Attempts to ventilate by mask, puncture of the cricothyroid membrane and intubation were unsuccessful. A small tube was eventually inserted into the trachea after four minutes. The patient was then severely cyanotic with a pulse of thirty, and had dilated pupils. The next morning convulsions ensued and a CT scan showed cerebral oedema. In spite of treatment with pentothal, mannitol and hyperventilation she died. The authors advocate the use of intravenous infusion of C1-inhibitor concentrate, since traditional treatment is inadequate. Persons with hereditary angio-oedema should have a personal supply of C1-inhibitor at hand. PMID- 7846660 TI - [Beta 3-receptors: incidence and properties, possible clinical significance]. AB - Beta 3-adrenoceptors is a term used for atypical beta-adrenoceptors which do not fit into either the beta 1- or beta 2-receptor as classified by pharmacological methods. The receptor has been cloned and is thus also genetically defined. Beta 3-adrenoceptors appear to be widely distributed. Until now their importance has been based on studies using agonists with high potency, but yet not selective for beta 3-adrenoceptors. The distribution and functional importance in humans are unclear, and will probably not be clarified before selective antagonists and labelled ligand are developed. Agonists for the beta 3-adrenoceptors may be of clinical value in the treatment of obesity, non-insulin dependent diabetes mellitus, gastrointestinal disorders like irritable colon, inflammatory lung diseases and depression. PMID- 7846661 TI - [Herniography. A 3-year material from a central hospital]. AB - Herniography is the roentgenographic demonstration of hernias in the pelvic region by positive contrast peritoneography. The main indication for herniography is obscure groin pain and the suspicion of a hernia not visible at clinical examination. In a review of the last 75 patients from 1991-93, 30 hernias and 18 other findings were demonstrated. 13 patients have been operated till now, and their results are presented. Only 5.6% of Norwegian hospitals perform ten or more herniographies a year. We find herniography to be a reliable and safe diagnostic method that should receive more attention. PMID- 7846662 TI - [Excision of tumors in the face]. AB - Excision of tumours in the face is a surgical challenge. Most general practitioners and surgeons are reluctant to undertake such procedures. In our opinion there are no reason why small tumours and lesions in the face, which can be excised by a fusiform excision, should not be handled by most doctors. The aim of this article is to remind doctors of well known general principles, so as to obtain a cosmetically good result after surgery. PMID- 7846663 TI - [When a trauma becomes a taboo--is it pathogenetic? Communication in the family about psychological traumas]. AB - Case histories and clinical studies have pointed to the harmful effect on their children when traumatized parents do not communicate their traumatic experiences. The present paper argues that it is not the lack of communication in itself that is harmful. Lack of communication should rather be regarded as a coping mechanism which could indicate intrapersonal and interpersonal problems within the family. PMID- 7846664 TI - [The EDP systems for internal hospital cost accounting]. AB - Computer systems for hospital cost accounting are in widespread use in foreign hospitals. In Norway, few hospitals have adopted such systems. Two products are currently being developed in Norway: KosPa (a system for calculating DRG costs) and Nirvana (a system intended for presentation of costs, rather than for overhead allocations and cost calculations). Both of these systems will have rather limited uses. If an organization needs a more comprehensive system with a wider selection of features, there are no Norwegian alternatives. It should be possible to implement a foreign system without too much trouble. PMID- 7846665 TI - [Relating costs to activities in hospitals. Use of internal cost accounting]. AB - During the last few years hospital cost accounting has become widespread in many countries, in parallel with increasing cost pressure, greater competition and new financing schemes. Cost accounting has been used in the manufacturing industry for many years. Costs can be related to activities and production, e.g. by the costing of procedures, episodes of care and other internally defined cost objectives. Norwegian hospitals have lagged behind in the adoption of cost accounting. They ought to act quickly if they want to be prepared for possible changes in health care financing. The benefits can be considerable to a hospital operating in a rapidly changing health care environment. PMID- 7846666 TI - [Alcohol--no universal drug against heart disease]. AB - Alcohol is part of the normal culture for a majority of the population in western countries. Few investigators or clinicians disagree with the contention that there is a positive relationship between cardiovascular disease and mortality in the upper part of the alcohol consumption curve. No such general agreement exists when infrequent users and non-users are studied. Epidemiological evidence of the relationship between cardiovascular mortality and levels of alcohol consumption is scrutinized, with emphasis on how alcohol anamnestic data are collected, the characterization of non-users, and the authors' definition of moderate consumers. The results indicate that there is hardly any evidence to advocate moderate consumption of alcohol as a health-promoting activity. On the other hand there seems to be a positive relationship between moderation in many aspects of lifestyle and some health gain. PMID- 7846667 TI - [American Medical Association--a fighter in a crisis?]. PMID- 7846668 TI - [Medicine in front of a new view on man. In the light of alternative medicine, humanism and christianity]. PMID- 7846669 TI - [An ethical dilemma--compulsory treatment of non-psychotic patients]. PMID- 7846670 TI - [How good is our knowledge of adrenergic receptor mechanisms?]. PMID- 7846671 TI - [Do we need a new definition of crib death?]. PMID- 7846672 TI - [Midlife crisis]. PMID- 7846673 TI - [Field trial with a subunit rhinopneumovaccine]. PMID- 7846674 TI - [Discospondylitis and immune-mediated polyarthritis in a Bernese mountain-dog]. AB - In this case report we describe the clinical picture and treatment of a Bernese mountain dog with discospondylitis and a presumably reactive immune-mediated polyarthritis. The clinical signs consisted of apathy, fever, anorexia, and a stiff gait. The diagnosis was based on the typical radiographic signs of discospondylitis and the cytology of the synovial fluid. The dog was treated with a broad-spectrum antibiotic for 6 weeks and thereafter with a synthetic glucocorticoid for the polyarthritis. Five months after cessation of therapy, the dog was free from the initial signs. PMID- 7846675 TI - [Copper deficiency in newborn lambs]. AB - On 2 sheep-farms copper deficiency in newborn lambs was diagnosed. The lambs were able to lift up their head but they were unable to get up or to stay. At post mortem an internal hydrocephalus was present and the copper values in liver and kidney were low. PMID- 7846676 TI - [The Dutch Research Association of Animal Sciences and Animal Health gets a start. Approach to veterinary and zoological problems through joint research]. PMID- 7846677 TI - [Leukorrhea in cows]. PMID- 7846678 TI - [Corticosteroids in viral infections]. PMID- 7846679 TI - [Stomach torsion, stomach dilatation and the veterinary disciplinary tribunal]. PMID- 7846680 TI - Hindquarter vascular resistance as compensator for hypotension in conscious rats. AB - The purpose of this study was to test whether hindquarter (terminal aortic) vascular resistance uniquely increases in order to compensate for interventions which result in a lowering of arterial pressure. Changes in hindquarter resistance were compared to changes in superior mesenteric resistance after the administration of the nitrovasodilator drug, molsidomine. Hindquarter blood flow or superior mesenteric flow was measured in conscious rats using an electromagnetic flow probe implanted around the terminal aorta or the superior mesenteric artery, respectively. Twenty minutes after an intravenous bolus injection of molsidomine (1 mg/kg), ganglionic blockade with hexamethonium bromide (25 mg/kg, i.v.) significantly decreased hindquarter resistance, but not superior mesenteric resistance. In the absence of molsidomine, ganglionic blockade has no effect on resistance in either vascular bed. These findings suggest that excitation of sympathetic vasoconstrictor fibers supplying the hindquarters but not those supplying the superior mesenteric area occurred in response to the hypotensive effect of molsidomine. This is consistent with the hypothesis that augmenting-hindquarter resistance is the first line of defense against hypotensive interventions. PMID- 7846681 TI - Effects of unilateral phrenic nerve denervation on diaphragm contractility in rat. AB - We examined the early effects of phrenic nerve denervation on the diaphragm muscle 1, 3, 7 and 14 days after unilateral denervation in rats. In the denervated hemidiaphragms, force frequency curves at 3, 7 and 14 days decreased significantly by 51%, 50% and 38% respectively of the peak tension of the force frequency curves of the diaphragms of rats with sham operation. Twitch tensions increased significantly at 14 days, and contraction times and half relaxation times slowed significantly at 3, 7 and 14 days. The tensions of denervated diaphragms at 5 min during the fatigue runs was significantly increased at 14 days. As determined by histological staining, the mean cross sectional area of fast-twitch fibers (type II) decreased significantly from 2,742 (sham) to 1,599 microns (14 days), but that of the slow-twitch fibers (type I) did not change significantly during the same period. These findings suggest that, during the first two weeks of denervation, fast twitch fibers (type II) atrophy more rapidly than slow twitch fatigue resistant fibers (type I), as confirmed by the contractile properties and histological findings. PMID- 7846682 TI - The variation of action potential and impedance in human skeletal muscle during voluntary contraction. AB - We used an insulated acupuncture needle to deliver a 20 kHz alternative current to detect the changes on the electromyogram (EMG) and deep muscle impedance. We found that impedance increased (with a duration of 224.1 +/- 75.3 msec) and then decreased (with a duration of 293.4 +/- 97.3 msec) after motor unit action potential (MUAP) firing during isometric voluntary contraction (VC) of the tibialis anterior muscle (TAM). We divided the positive peak into pattern I (with a latency range of > or = 30 msec and < or = 75 msec) and pattern II (with a latency range of > 75 msec and < or = 140 msec). These patterns of change corresponded to the contraction times of tension caused by the electrical stimulation and VC. These impedance changes may be caused by a change in the extracellular and intracellular fractions, and may reflect the variance of tension intensity in the muscle tissue. PMID- 7846683 TI - Catecholamine-induced cAMP response in streptozotocin-induced diabetic rat liver. AB - The effect of prolonged diabetic state on catecholamine-induced adenosine 3',5' monophosphate (cAMP) response in the rat liver was examined using isolated liver perfusion. Epinephrine- or isoproterenol-induced cAMP production was enhanced (10 fold of the control) in the liver from extremely emaciated (intraperitoneal adipose tissue was absent completely) diabetic rats 4 weeks after streptozotocin injection kept without insulin, but not from adipose tissue-present diabetic rats. Glucagon-induced cAMP production was decreased in the diabetic rat liver 4 weeks after streptozotocin regardless of the presence or absence of adipose tissue. Secretin-induced cAMP production was also decreased in the adipose tissue absent diabetic rat liver. Plasma levels of glucose or insulin were not different between adipose tissue-present and -absent diabetic rats. Liver dysfunction (elevated AST and ALT levels) was observed 1 week after streptozotocin-injection, and worsened at 4 weeks. Forskolin-induced production of cAMP, and oxymetazoline (an alpha 2-adrenergic agonist)-induced suppression of it were not different among the control, newly diabetic (1 week after streptozotocin-injection), and the adipose tissue-absent diabetic rat liver. IN CONCLUSION: 1) enhanced beta adrenergic, and decreased glucagon- or secretin-induced cAMP production seems to be caused by different mechanisms; 2) the prolonged severe diabetic state losing adipose tissue may cause a considerable change in metabolism and the characteristics of hepatocyte, and lead to enhanced beta-adrenergic cAMP production. PMID- 7846684 TI - Histomorphometric analysis of age-related changes in epithelial thickness and Langerhans cell density of the human tongue. AB - Human tongues were taken from 529 cadavers (age, 0-105 years; 298 males and 231 females). Age-related changes in epithelial thickness and Langerhans cell (LC) density were histomorphometrically analyzed. The epithelial section area (ESA) per 10-mm epithelial surface length (ESL) was measured in the dorsum linguae. After measurement with a computed image processing system at a magnification of x20, the mean epithelial thickness was calculated. LCs were identified by an immunohistochemical stain with anti-S-100 protein polyclonal antibody and Fontana Masson's stain. The number of LCs was counted in the measured ESA at a magnification of x400. LC density per mm ESL and per mm2 ESA was calculated. The lingual epithelium in the older age groups was significantly thinner than that in the younger age groups. The LC density per mm ESL and per mm2 ESA in the older age groups was significantly lower than that in the younger age groups. These results suggest that both physical and immunological defenses of the lingual mucosa might be compromised in old age. PMID- 7846685 TI - Histological verification of bone bonding and ingrowth into porous hydroxyapatite spinous process spacer for cervical laminoplasty. AB - Three spinous processes of the cervical spine and implanted porous hydroxyapatite spacers were removed from a patient with a recurring intramedullary tumor at revisional laminectomy one year after spinous process splitting laminoplasty. Histological examination of undecalcified sections revealed direct bone bonding to the spacer at three of the six bone-hydroxyapatite interfaces. Bone ingrowth was observed up to 400 microns into the implant pores. Fibrous tissue was observed to intervene between the other three bone-hydroxyapatite interfaces. The suspected bone bonding with the spacer on CT scans before the revision was confirmed by the histological findings. PMID- 7846686 TI - A high-salt diet alters circadian blood pressure rhythm in Dahl rats. AB - To determine whether salt loading and salt sensitivity are related to the circadian variation in blood pressure (BP), we studied the circadian rhythm of BP in Dahl rats. Thirteen Dahl salt-sensitive (Dahl-S) and 14 salt-resistant (Dahl R) rats were fed a high- or low-salt diet after weaning. Mean arterial pressure (MAP) and heart rate (HR) were measured every 4 sec throughout 24 hr in freely moving rats, and the data obtained were analyzed quantitatively by the cosinor method. MAP mesor was significantly elevated in Dahl-S rats on a high-salt diet (SH), as compared with those on a low-salt diet (SL), but there was no difference in the MAP mesor between Dahl-R rats on a high-salt diet (RH) and those on a low salt diet (RL). MAP amplitude was significantly greater and HR amplitude was smaller in SH rats than in SL rats; the amplitudes of MAP and HR in RH rats were similar to those in RL rats. MAP acrophase was significantly delayed in SH and RH rats as compared with SL and RL rats, respectively; the time delay in the MAP acrophase was not accompanied by a synchronized delay in HR acrophase. The time delay in MAP acrophase was greater in SH rats than in RH rats. These results indicate that salt loading influences the amplitude and acrophase of BP, and that the effect of salt loading on circadian BP rhythm is modulated by salt sensitivity. PMID- 7846687 TI - Frequent overexpression of vascular endothelial growth factor gene in human renal cell carcinoma. AB - Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen and an inducer of angiogenesis. Expression of the VEGF gene was investigated in 20 patients with renal cell carcinoma by Northern blot hybridization analysis. Of the 20 tumors, 12 (60%) overexpressed the gene 3.0 times more than in normal renal tissues. No significant correlation was found between overexpression of the VEGF gene and the histopathological data such as grade, cellular and structural subtypes, stage and size of tumor. These results suggest that VEGF is produced by the tumor cells and is responsible for development of this hypervascular tumor. PMID- 7846688 TI - Properties of Duvernoy's secretions from opisthoglyphous and aglyphous colubrid snakes. AB - Relatively little attention has been given to the biological properties of Duvernoy's secretions produced by opisthoglyphous and some aglyphous colubrid snakes. A review is presented of literature pertaining to these secretions. Most detailed analyses of Duvernoy's secretions and their biological properties have been performed since the late 1970s. The dispholidines, Dispholidus typus and Thelotornis sp., and the natricines, Rhabdophis tigrinus and R. subminiata, have received the most attention due to the high toxicity of their secretions and their medical importance. These species produce secretions with variably strong prothrombin-activating activity, defibrinating activity, and hemorrhagic potential. Boigines, and natricines other than Rhabdophis, produce secretions of low to moderate toxicity and are variably hemorrhagic and proteolytic. Xenodontines and homalopsines similarly show hemorrhagic potential with low to moderate toxicity. Neurotoxic activity has been reported only from secretions of the boigines, Boiga blandingi and B. irregularis and the xenodontine, Heterodon platyrhinos. These species produce secretions containing postsynaptically acting components. Analyses of some of these secretions have shown that enzymes common to many ophidian venoms such as phospholipases A and L-amino acid oxidase are uncommon in the colubrid secretions studied. This may be due to few studies assaying for multiple enzyme activities and/or the unavailability of many secretion samples for study. Methods of secretion extraction, storage, and assay are discussed. Projected future research and the adaptive implications of Duvernoy's secretions are considered. PMID- 7846689 TI - Purification of a basic phospholipase A2 from Indian saw-scaled viper (Echis carinatus) venom: characterization of antigenic, catalytic and pharmacological properties. AB - A major basic phospholipase A2 was purified from the Indian saw-scaled viper (Echis carinatus) venom by the combination of column chromatography and electrophoresis. The purified phospholipase A2 (EC-IV-PLA2) has a mol. wt of 14,000 by SDS-PAGE. It is a basic protein with a pI value between 7.2 and 7.6, and has a fluorescence emission maxima at 340 nm. It induces neurotoxicity and oedema in mice with an i.p. LD50 of 5 mg/kg body weight. It is devoid of direct haemolytic, myotoxic, cytotoxic and anticoagulant activities. Rabbit polyclonal antibodies prepared against EC-IV-PLA2 inhibited the in vitro enzymatic activity dose dependently, but did not neutralize the toxic effects of EC-IV-PLA2 in experimental animals. PMID- 7846690 TI - Pharmacological studies of stonefish (Synanceja trachynis) venom. AB - The present study was designed to examine some of the pharmacological properties of venom from the stonefish (Synanceja trachynis), with particular reference to the presence in the venom of pain-producing/enhancing substances. Stonefish venom (1-6 micrograms/ml) produced concentration-dependent contractile responses in guinea-pig isolated ileum. No tachyphylaxis, or reduction in responses with time, was observed to venom (3 micrograms/ml) in ileum. The response to venom (3 micrograms/ml) was not significantly affected by the histamine antagonist mepyramine (0.5 microM), or a preceding anaphylactic response. Mecamylamine, 5HT desensitization or EXP3174 failed to have any significant effect on responses to venom (3 micrograms/ml). Responses to venom (3 micrograms/ml) were significantly inhibited by the cyclooxygenase inhibitor indomethacin (5 microM), the leukotriene D4 receptor antagonist FLP55712 (1 microM), the thromboxane A2 receptor antagonist GR32191B (1 microM), the muscarinic receptor antagonist atropine (10 nM) and the neurokinin-1 receptor antagonist CP96345 (0.1 microM). Venom (6 micrograms/ml) produced contractile responses in the rat isolated vas deferens which were abolished by the alpha 1-adrenoceptor antagonist prazosin (0.3 microM) and significantly potentiated by the neuronal uptake inhibitor DMI (1 microM). However, noradrenergic transmitter depletion with reserpine (5 mg/kg, i.p.) did not significantly inhibit responses to venom (6 micrograms/ml). Histamine fluorometric and phospholipase A2 assays failed to detect significant quantities of either substance in the venom. These results suggest that stonefish venom may cause the release of acetylcholine, substance P, and cyclooxygenase products, or contain components which act at these receptors. The venom also appears to contain a component which is a substrate for neuronal uptake and has a direct action at alpha 1-adrenoceptors. PMID- 7846691 TI - Mygalomorph spider bites: a report on 91 cases in the state of Sao Paulo, Brazil. AB - From 1966 to 1991 91 cases of bites due to mygalomorph spiders were recorded at the Hospital Vital Brazil, Instituto Butantan, Sao Paulo, Brazil, representing less than 1% of all spider bites. The diagnosis was confirmed by positive identification of the spider involved. Envenoming is generally mild, the main symptom is local pain, and there is minor oedema and erythema. The data confirm the assumption that these nonaggressive spiders pose no health problem. PMID- 7846692 TI - Haemodynamic and haematologic effects of Acanthaster planci venom in dogs. AB - This study was designed to examine haemodynamic and haematologic effects of the crown-of-thorns starfish venom (Acanthaster planci venom: APV) in dogs. Severe systemic hypotension, thrombocytopenia and leukopenia were induced by APV (1.0 mg protein/kg i.v.), followed by gradual return to the baseline level within 60 min. Hypotension was presumably caused by two factors: an early decrease in systemic vascular resistance and the large reduction in cardiac output due to reduced ventricular filling. Indomethacin, a cyclooxygenase inhibitor, remarkably suppressed systemic hypotension induced by APV. The peak reduction in systemic pressure was associated with concomitant rise of plasma 6-keto-PGF1 alpha, a major stable metabolite of prostacyclin. Thus, the hypotensive effect of APV may be caused primarily by prostacyclin and/or some vasodilating prostaglandins. In contrast, thrombocytopenia and leukopenia were not affected by cyclooxygenase inhibitor, 5-lipoxygenase inhibitor or platelet activating factor (PAF) receptor antagonist. When APV was administered repeatedly, tachyphylaxis was developed in haemodynamic effects, but not in haematologic effects. These findings suggest that APV-induced hypotensive effects may occur mainly through endogenous production of vasodilating prostaglandins including prostacyclin, although APV induced thrombocytopenia and leukopenia may be caused by other mechanism(s) unrelated to arachidonate metabolites and/or PAF. PMID- 7846693 TI - Isolation and characterization of Textarin, a prothrombin activator from eastern brown snake (Pseudonaja textilis) venom. AB - The venom of P. textilis contains two different enzymes which convert human prothrombin into thrombin. Prothrombin activation by Textarin, a serine proteinase containing a calcium-binding molecule site, with a molecular mass of 50,000 to 53,000 Da and I.P. 5.5, separated from crude venom by either barium citrate adsorption or hydroxyl apatite chromatography, is strongly stimulated by phospholipid and calcium ions. A second activator, found in the supernatant of barium citrate adsorbed venom solution, activates prothrombin in the absence of any co-factor. Human plasma coagulation induced by Textarin, phospholipid and calcium ions is affected by lupus anticoagulants. Textarin may thus be used for the detection of lupus anticoagulants in patient plasma samples. PMID- 7846694 TI - Isolation and partial characterization of an anti-bothropic complex from the serum of South American Didelphidae. AB - An anti-bothropic fraction (ABF) with anti-Bothrops jararaca venom activity tested in mice was isolated from the serum of some South American Didelphidae (Didelphis marsupialis, Philander opossum and Lutreolina crassicaudata) by DEAE Sephacel chromatography. ABF from D. marsupialis was shown to be 12 times more active in protection assays on a weight basis than the serum proteins. A similar fraction obtained from Metachirus nudicaudatum serum was shown to be inactive. An anti-bothropic complex (ABC) was isolated from D. marsupialis ABF. HPLC gel permeation chromatography of ABC from D. marsupialis indicated the presence of a main peak with mol. wt of 84,000. SDS-PAGE of this ABC showed the presence of two subunits of 48,000 and 43,000. The active ABF isolated from P. opossum and L. crassicaudata also showed the presence of these subunits by SDS-PAGE. Isolation of the 48,000 mol. wt D. marsupialis subunit by HPLC-hydrophobic interaction chromatography demonstrated that the 43,000 subunit was essential for the protective action of the complex. Both subunits from D. marsupialis, P. opossum and L. crassicaudata were Western-blotted and N-terminal sequenced. No N-terminal amino acid was found for the 43,000 subunit, whereas for the 48,000 subunit a high degree of homology was found: D. marsupialis: H2N-L K A M D P T P P L W I K T E X P . ; L. crassicaudata: H2N-L K A M D P T P P L W I Q T E . . . ; P. opossum: H2N-L K A M D T T P E . . . No significant homology with known proteins was detected. PMID- 7846695 TI - A clean-up method for analysis of trace amounts of microcystins in lake water. AB - A clean-up method using high performance liquid chromatography (HPLC) and liquid chromatography/mass spectrometry (LC/MS) was developed to pursue trace amounts of microcystins in lake water. The method consisted of the combined usage of octadecyl silanized (ODS) silica gel and silica gel cartridges. In the first clean-up process, the retention behavior of microcystin RR on ODS silica gel cartridge was carefully observed together with microcystin LR, and 10% water methanol was chosen as the best solvent system to elute microcystins from the ODS silica gel cartridge. Because many impurities still remained in the desired fraction from the raw water even after the clean-up with ODS silica gel, an additional clean-up process was developed using various cartridges. As a result of extensive experiments, the second clean-up process using silica gel cartridge was established, and the impurities were effectively eliminated. The present method including a tandem cartridge system allowed a precise analysis of microcystins in water samples from three different lakes at a 0.02 ppb level. PMID- 7846696 TI - Isolation of serotonin from the accessory salivary glands of the marine snail Nucella lapillus. AB - We report here the presence of a bioactive compound in the secretion of the accessory salivary glands (ASGs) of Nucella lapillus. We have purified the compound using HPLC and identified it as serotonin by mass spectrometry, UV spectroscopy, HPLC and capillary electrophoresis. Serotonin was not found in the secretions of the acinous salivary glands or the hypobranchial gland. The amount of serotonin in the secretion of the ASGs does not show seasonal or regional variation. PMID- 7846697 TI - An investigation on the antigenic cross-reactivity of Calloselasma rhodostoma (Malayan pit viper) venom hemorrhagin, thrombin-like enzyme and L-amino acid oxidase using enzyme-linked immunosorbent assay. AB - Indirect ELISA shows that the antibodies to Calloselasma rhodostoma venom hemorrhagin (CR-HMG), thrombin-like enzyme (CR-TLE) and L-amino acid oxidase (CR LAAO) exhibited strong to moderate cross-reactions with most crotalid and viperid venoms, but only anti-CR-LAAO cross-reacted with the elapid venoms. However, the indirect ELISA failed to detect some antigenic similarities demonstrable by cross neutralization study. The double-sandwich ELISA for the three anti-C. rhodostoma venom components exhibited a much lower level of cross-reactions than the indirect ELISA. PMID- 7846698 TI - Studies on venom and venom apparatus of Fea's viper, Azemiops feae. AB - Enzyme activities tested in the venom gland extract of Azemiops feae snake are similar to those of viperine venoms, except that Azemiops venom has no blood clotting, haemorrhagic or myolytic activities. The venom gland exhibits the characteristic feature of a viperine gland, but the fangs possess a ridge at the tip laterally to the venom orifice and a blade-like structure on the back seen only in some opisthoglyphous and Atractaspidae snakes. PMID- 7846700 TI - The first reported case of human ciguatera possibly due to a farm-cultured salmon. AB - This study is an individual case report of an imported cultured salmon which may have caused ciguatera. The individual's documented clinical symptoms, along with our immunological tests and bioassays (hemolytic, mouse toxicity and guinea-pig atrial assays) of the salmon extracts, strongly suggest that the salmon may have contained a ciguatoxin-like toxin (or toxins). The unique ability of the toxin(s) to block the sodium channel of the guinea-pig atrium, however, distinguishes it from ciguatoxin-1 isolated from moray eel liver. PMID- 7846699 TI - Muscle extract of hedgehog, Erinaceus europaeus, inhibits hemorrhagic activity of snake venoms. AB - The antihemorrhagic activity of muscle extract of hedgehog, Erinaceus europaeus, was tested on various snake venoms with hemorrhagic activity. The extract inhibited strongly hemorrhagic activity of venoms from Bitis arietans, Bothrops jararaca and Vipera latastei gaditana, and remarkably that of venoms from Agkistrodon halys blomhoffi, Bitis gabonica rhinoceros, Bitis nasicornis, Bothrops atrox asper, Crotalus horridus horridus and Vipera berus. The antihemorrhagic activity against eight other snake venoms was below the detection level. PMID- 7846702 TI - Bibliography of toxinology. PMID- 7846701 TI - Comparison of the hepatotoxicity of toxin T-514 of Karwinskia humboldtiana and its diastereoisomer in primary liver cell cultures. AB - Toxin T-514 of Karwinskia humboldtiana has been demonstrated to be hepatotoxic in vivo and in vitro. Recently a diastereoisomer of T-514 has been isolated. In the present study we have evaluated and compared the in vitro hepatoxicity of the diastereoisomer of T-514 using primary cultures of rat hepatocytes. Cytotoxicity was evaluated by release of cytoplasmic enzyme lactate dehydrogenase (LDH), and mitochondrial metabolic function (MTT reduction). The diastereoisomer was shown to be almost as hepatoxic in vitro as toxin T-514. PMID- 7846703 TI - [Experimental and clinical bases for the use of antioxidants as agents for treating and preventing periodontitis]. AB - The contribution of free-radical lipid and biopolymer oxidation to the pathogenesis of periodontitis is analyzed as reflected in published Russian and foreign literature. Enhanced autooxidation in periodontal tissue is shown to represent one of the mechanisms of the disease genesis, this prompting the use of antioxidants in the treatment an prophylaxis of periodontitis. Antioxidant effects on the course of the disease have been demonstrated experimentally and clinically. Criteria of antioxidants use as a means of treatment and prevention of periodontitis are offered. PMID- 7846704 TI - [The etiology of dental caries]. PMID- 7846705 TI - [The quantitative determination of dentinal fluid during the treatment of deep caries]. AB - A method for dentin fluid measurements has been developed permitting an indirect judgement on remineralizing effect of drugs. The study was carried out in 36 teeth of 23 patients. Hydroxyapatite, tricalcium phosphate, and, as a reference agent, calmecin were used in the treatment of deep caries. A reliable remineralizing effect of hydroxyapatite and tricalcium phosphate was revealed. PMID- 7846706 TI - [The dynamics of functional hyperemia in the periodontium]. AB - Time course of functional hyperemia in the periodontium was studied by quantitative rheography in 99 subjects, 55 of these presenting with periodontal diseases and 43 with clinically normal periodontium. Chewing of 5 cm3 of raw carrots for 30 sec on the working side was used as a functional exercise. In normal or reduced tone of regional vessels an oscillatory process of functional hyperemia with a latent period was developing, presumably at the expense of rise of osmotic pressure of tissue fluid. In initial vasoconstriction functional hyperemia develops without latent period and oscillatory process. A similar picture is observed in periodontal diseases, but the bloodstream volume is far less. PMID- 7846707 TI - [The clinical picture, diagnosis and treatment of the stomatological manifestations of Sjogren's disease]. AB - Eighty-three patients with Sjogren's disease, 23 with chronic parotitis and periodontitis, 325 controls were examined by general clinical, dental, X-ray, microbiological, immunological, and morphological methods. A clinico-pathogenetic analysis of dental manifestations of Sjogren's disease was carried out: atrophy and inflammatory process in the buccal mucosa, multiple caries. A pathogenetically based program of therapeutic and prophylactic measures making use of encad, bensilol, bensilol+trimecain is suggested for patients with Sjogren's disease. PMID- 7846708 TI - [Plasmosorption in the combined treatment of patients with phlegmons of the maxillofacial area in diabetes mellitus]. AB - Diabetes mellitus and surgical infection coursing intermittently aggravate each other, and therefore search for methods of treatment permitting a simultaneous impact on the pyoinflammatory process and on diabetes mellitus is a priority. Plasmasorption method used at present at Chair for maxillofacial surgery and dentistry of the Russian State Medical University meets these requirements to a great measure. Clinical and laboratory studies showed that plasmasorption used in multiple-modality treatment helps effectively control a purulent process, reduces intoxication of the body, corrects the development of insulin resistance in patients with maxillofacial phlegmons coursing in the presence of diabetes mellitus. In patients with grave and medium-severe diabetes the same insulin doses injected after plasmasorption reduce blood sugar levels by 1.5-1.7 times on an average, and in slight forms of the condition even normalize them. Secondary healing of postoperative wounds is accelerated in diabetics with maxillofacial phlegmons, and hospital stay of such patients is reduced by 9.5-10 days, on an average. PMID- 7846709 TI - [The surgical procedure in facial nerve injuries]. AB - Nine patients with cancer of the parotid glands were operated on. Parotidectomies involved resection of the facial nerve. In 3 patients neuroplasty was simultaneously carried out: the nerve was epineurally sutured end-to-end. Facial nerve function recovered in these patients. PMID- 7846710 TI - [The use of demineralized bone brephomatrix in the plastic repair of different postoperative defects in the jaws]. AB - The aim of this research was assessment of the results of bone brephoplasty of the jaws. Bone tissue defects after cystectomy, granulectomy, and tooth removal were filled with fragmented transplant, demineralized osseous brephomatrix. Low frequency ultrasound was used for antibacterial treatment of the recipient osseous bed. A total of 103 patients were operated on, brephoplasty was carried out in 60. Demineralized osseous brephomatrix is characterized by excellent plastic and osteoinductive properties, due to which bone regeneration processes are completed 1.5-2 times sooner in comparison with the control. PMID- 7846711 TI - [The immunotropic and allergenic activity of hydroxyapatite with an ultrahigh degree of dispersion]. AB - Hydroxyapatite is a well-known biologic material intended for intraosseous implantation which is widely used in practical dentistry. The agent causes no inflammatory reaction at the site of administration and is not characterized by acute or chronic toxicity. The possibility of development of specific contraindications against hydroxyapatite has not yet been studied; such contraindications might be connected with its possible immunotropism and allergenic activity which are to this or that measure present in all materials used for implantation into the bone. Since hydroxyapatite is known as surfactant, we used in our studies its modification characterized by the highest specific surface known at present, and therefore the most biochemically active. "Cold", that is, not exposed to high-temperature treatment ceramics was used in order to prevent reduction of hydroxyapatite reaction capacity. Complex of animal experiments showed that hydroxyapatite cannot possess immunotropic or allergenic characteristics. PMID- 7846712 TI - [A new method of treating lip cancer and a device for its implementation]. AB - Immediate and late results of treatment of labial cancer in 132 patients are analyzed. The patients were exposed to radio-, thermoradio-, and thermochemoradiotherapy using a special electrode device which permits exerting a multifactorial physiopharmacological impact on the tumor. Complete resorption of the tumor occurs when total focal radiotherapeutic dose is reduced by 50%. Such a noticeable reduction of radiotherapeutic dose rules out quite a number of local and general complications. PMID- 7846713 TI - [The expert esthetic evaluation of the face]. AB - The authors suggest a scale for assessment of face esthetics, based on the notion of "esthetic perception" and anthropometric data. The scale consists of 6 grades, from disproportional (1 score) to proportional harmonic (6 scores). The method of expert evaluation of face esthetics facilitates planning of comprehensive treatment of patients with maxillodentofacial abnormalities and deformations and helps more objectively assess the results of treatment and the efficacy of this or that treatment modality. PMID- 7846714 TI - [The auto-oxidative system of the acinar cells in acute postoperative parotitis]. AB - The major constituents of acinar cell auto-oxidative system in acute postoperative parotitis were determined in experiments on 32 dogs. Two types of cellular reactions were identified: free-radical processes with increased levels of lipid peroxidation products and insufficiency of enzymatic and nonenzymatic glutathion antioxidants and reaction of defense metabolism inhibition. A conclusion is made about the necessity of altering the current methods for prevention and therapy of postoperative parotitis. PMID- 7846716 TI - [The dental pulp reaction to microbial action in different methods of treating the carious cavity]. AB - Under study were the effects of bacterial stimulation of prepared dentin on dental pulp. Traditional method of drug treatment of prepared cavity with alcohol and either was compared with methods reducing dentin permeability making use of calcium hydroxide, potassium nitrate, and calcium oxalate. Inflammatory reaction of the pulp was more pronounced after traditional treatment. Reduction of dentin permeability with agents blocking dentin tubes reduced the severity of inflammatory reaction. PMID- 7846715 TI - [Functional disorders of the masticatory muscles and temporomandibular joint in pathological tooth abrasion]. AB - Altogether 568 patients, 308 women and 260 men aged 30 to 64 with abnormal teeth abrasion were examined by clinical, anthropometric, X-ray (spot and panoramic radiography of the teeth and jaws, tomography of the temporomandibular joint), electromyography, and rheoparodontography. Pathological teeth abrasion was associated with various morphological and functional disturbances in the maxillodental system. Two types of abrasion were distinguished: with and without masticatory function disorders. The latter condition was detected in 252 (44.36%) patients. Painful dysfunction of the temporomandibular joint was observed in 66 (11.6%) patients. Three factors contribute to the pathogenesis of these functional disorders in abnormal teeth abrasion: reduction of occlusion height (interalveolar distance) and shortening of the lower third of the face, blocking of mandibular movements, lateral and distal shift of the mandible. PMID- 7846717 TI - [The effect of partial tooth loss in periodontal diseases on the muscle activity of the maxillofacial area]. AB - Electromyographic examinations of subjects with partial loss of teeth caused by periodontal disease and resulting in maxillodental deformation revealed dysfunction of the masticatory, temporal, and suprasublingal muscles which augments in relation to loss of antagonistic pairs of teeth and to dentition defect class: the lesser is the number of occlusion contacts with mobile teeth, the more manifest are functional disorders. PMID- 7846718 TI - [Hemodynamics in the pulp of abutment teeth after their preparation for metal ceramic denture restoration]. AB - The paper presents the results of functional examination of pulpal and periodontal vessels in 57 patients who underwent preparation of supporting teeth for making cermet dentures. Pulpal hemodynamics was studied by using rheodentography before and 1, 3, 7, 14, 21, and 28 days after tooth preparation. After preparation, the tooth pulp exhibited inflammatory sings which gradually alleviated and 14-28 days later there was stabilization of rheographic parameters of regional hemodynamics. In patients with intact periodontium, circulatory recovery occurred on days 14-21, while in those with periodontitis it took place on days 21-28. PMID- 7846719 TI - [The efficacy of the local fluoridation of the teeth]. AB - Application of 2% sodium fluoride solution in children aged 10 to 11 result in a noticeable reduction of caries development: by 50% during the first year, by 43.18% during the second, by 46.05% during the third, and by 42.85% during the fourth year of such treatment. Caries-preventive effect persists for only 12 months after two-year applications, caries reduction being 35.21% in the first year and only 5.7% in the second year after the treatment discontinuation. PMID- 7846720 TI - [Morphological changes in the primordia of the deciduous teeth during an exacerbated course of the antenatal period]. AB - Histologic examination of 380 rudimentary deciduous teeth of 91 stillborn babies or corpses of newborns dead within 16 days after birth and comparison of the results with clinical data brought the authors to a conclusion that the diagnosis of enamel hypoplasia is erroneous because all dental tissues are involved during this condition. Pathohistologic changes in the enamel, dentin, and tissues adjacent to dental rudiment are described in detail, all these tissues developing under unfavorable conditions of antenatal odontogenesis. PMID- 7846721 TI - [A finely dispersed copper alloy for amalgams--a prospective filling material in pediatric dentistry. II. Clinical research]. AB - The authors assess clinical efficacy and possibility of using finely dispersed copper alloy for CMTA amalgam in dentistry. They compare their results with the data of clinical trials of tableted cooper amalgam TMAC-01 which is commercially manufactured at present. CMTA cooper amalgam was found preferable to TMAC-01 amalgam at all stages of carious process compensation in children due to its better strength, increased color stability, and corrosion resistance. This material is recommended for pedodontics for filling carious cavities of the first, second, and fifth class in deciduous molars. PMID- 7846722 TI - [The working conditions of medical personnel handling the SMTA brand copper amalgam]. AB - To assess the working conditions of medical staff the authors compared mercury vapor concentrations released during manipulations with various copper amalgams, TMAC-01 tableted copper amalgam manufactured by Nikitiv Mercury Plant, its foreign copper analog manufactured be "Becht" (Germany), and a new CMTA capsulated copper amalgam. Use of CMTA copper amalgam was found not hazardous for medical staff provided sanitary and hygienic regulations were adhered to. Moreover, mercury vapor concentrations released during work allow its use in rooms without ventilation cabinets, whereas tableted copper amalgams TMAC-01 and Becht may be used only in dentistry rooms equipped with such cabinets. PMID- 7846723 TI - [The use of netromycin in suppurative maxillofacial surgery in children]. PMID- 7846724 TI - [An experimental study of the action of an intraosseous implant of hydroxylapatite ceramic granules on the processes of reparative bone formation (experimental morphological research)]. AB - Presents a morphologic picture of the time course of repair osteogenesis after replacement of femoral bone defect in rats by hydroxyapatite ceramic granules. Excellent morphofunctional quality of newly formed bone regenerate in optimal terms is demonstrated. PMID- 7846725 TI - [The electrical stimulus of the neuromuscular apparatus of the maxillofacial area in children with congenital cleft palate]. AB - Maxillofacial neuromuscular status in health and in cleft palate was studied in children aged 3.5 to 7 using the data of extended neuromuscular diagnosis and blink reflex. Changes in masticatory and mimic muscles are of a function redistribution nature involving disarrangement of tone-regulating mechanism. Electric excitability of the soft palate muscles correlates with the disease severity and its disorders are qualitative. Correction of the muscular system in the pre- and postoperative period is necessary. PMID- 7846726 TI - [Traditional echography and dopplerography in the diagnosis of vascular neoplasms of the maxillofacial area in children]. AB - Twelve patients with hemangiomas of maxillofacial soft tissues aged 9 months to 15 years were examined by B-mode echography and color doppler imaging of the bloodstream. Combination of these two methods helps confirm the presence of a vascular neoformation, assess its dissemination, volume, and syntopy, specify the morphological variant of its structure, evaluate bloodstream velocity in various parts of the neoplasm. The notion of bloodstream intensity is introduced for the first time, reflecting the number of actively functioning vessels per unit of tumor volume. Causes of artefact appearance have been detected and approaches to their elimination out outlined. Echographic signs permitting selection of the optimal treatment strategy for each patient have been defined. PMID- 7846727 TI - [Secondary jaw deformities accompanying tumors and tumor-like formations in children and adolescents]. AB - Clinical follow-up of children aged 2 to 14 with tumors and tumor-like formations permitted diagnose secondary deformations of maxillary bones in 44. Symptomatology of these deformations had signs which distinguished intraosteally growing tumors from extraosseous ones localized in soft tissues adjacent to jaw bones. Good results were attained with the use of protective labial and buccal plates which not only shielded bone formations from tumor pressure before surgery but created a support for compressive dressing during sclerosing therapy of vascular tumors in children. Reconstructive and orthodontic measures, implantation of prostheses are necessary in the active period of growth and formation of maxillofacial and dental system after organ-destroying surgery for tumors and tumors-like formations in order to not only repair the anatomical shape but more so to optimize the conditions for normal functioning of the growing and forming maxillofacial and dental system of a child. PMID- 7846728 TI - [A denture for treating a deep bite]. PMID- 7846729 TI - [A method for the prevention and treatment of alveolitis]. AB - The majority of the know methods for therapy of alveolitis are aimed at liquidation of an inflammation in the well and include drug and physiotherapy combined with the required surgical treatment of a well. The aim of our research was development and validation of a method for treatment and prevention of alveolitis providing the optimal conditions for well healing, reducing the period of treatment, and preventing progressive atrophy of the alveolar process. The method consists in the well curettage, its filling with a transplant, and subsequent suturing of the mucosa. The immediate and late results of treatment were good. PMID- 7846730 TI - [The esthetic restoration of the anterior teeth damaged by fluorosis using plastic facings. A 5-year observation]. AB - Presents the results of five-year follow-up of a female patient with fluorosis who was fitted with plate plastic linings stuck with evicrol to the enamel of 321 perpendicular 123 teeth. After 4-year use of dentures plate linings were replaced by new ones made of the same sinma plastic because of partial plastic abrasion and loss of the lining. Control check-up showed satisfactory results. PMID- 7846731 TI - [Salivary gland hypertrophy. The mechanisms of its development and the methods for its modelling]. PMID- 7846732 TI - How steroid-specific antibodies came about: a personal history. PMID- 7846733 TI - Post-transcriptional regulation of c-fms proto-oncogene expression by dexamethasone and of CSF-1 in human breast carcinomas in vitro. AB - The c-fms proto-oncogene encodes the receptor for a hematopoietic growth factor, CSF-1. Recently, the importance of c-fms and its ligand CSF-1 in malignancies of non-hematopoietic origin, such as breast, ovarian, endometrial, pulmonary, and trophoblastic cancers has been recognized. We have previously shown that glucocorticoids induce a large increase in c-fms mRNA and protein levels in breast carcinoma cell lines. In this report, we investigate the mechanism underlying such c-fms overexpression by dexamethasone. We show that dexamethasone treatment of two breast carcinoma cell lines (BT20-c-fms expressor, and SKBR3-co expressor of both c-fms and CSF-1) does not increase the rate of c-fms gene transcription, suggesting a post-transcriptional mechanism of regulation of c-fms expression by dexamethasone. The effect of protein synthesis inhibition was studied to help determine whether there was a role for intermediary regulatory proteins in the regulation of c-fms expression. We find that several protein synthesis inhibitors interfere with dexamethasone induction of c-fms transcripts, suggesting the existence of regulatory proteins. These regulatory proteins do not appear to be constitutively expressed, as we show no effect of protein synthesis inhibition on c-fms transcript expression in resting BT20 cells. These findings suggest that the putative regulatory proteins are induced by dexamethasone. Furthermore, the addition of a protein synthesis inhibitor, pactamycin, to dexamethasone-treated BT20 cells results in a decrease in c-fms mRNA stability.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7846734 TI - Alterations in estradiol metabolism in MCF-7 cells induced by treatment with indole-3-carbinol and related compounds. AB - In mammals, estradiol (E2) metabolism primarily involves mutually exclusive hydroxylation at either C-2 or C-16 alpha. We have previously reported a consistent increase in the C-16 alpha hydroxylation activity in human breast cancer and in mouse strains with high levels of mammary tumors. Here we show that the dietary compound indole-3-carbinol (I3C) increases C-2 hydroxylation five fold in MCF-7 cells in culture but has minimal effect on the reaction at C-16 alpha. Because I3C-induced changes in E2 metabolism result in a metabolite ratio inverse to that observed in women with breast cancer we have separately examined whether this shift conferred an anti-tumorigenic advantage to estrogen target cells. The preferential changes induced by I3C on estradiol metabolism in MCF-7 cells parallel its anti-tumorigenicity in mice. These results suggest that changes in the metabolism of estradiol via the C-2 pathway might play a significant role in decreasing risk for breast cancer in women. Indole-2-carbinol is readily available as a chemical and as a dietary component of cruciferous vegetables. Feasible dietary changes show promise of having clinical utility in the prevention of breast cancer and other hormone-dependent cancers. PMID- 7846735 TI - Effect of estradiol and progesterone on cholesterol 7 alpha-hydroxylase activity in rats subjected to different feeding conditions. AB - The regulation of cholesterol 7 alpha-hydroxylase activity by estradiol and progesterone was investigated in liver microsomes isolated from rats fed standard diet, either ad libitum or fasted for 24 h, and diet containing the bile acid sequesterant cholestyramine. Differential effects were observed when the direct action of estradiol and progesterone on microsome preparations was examined. Cholesterol 7 alpha-hydroxylase activity was inhibited by progesterone in a dose dependent way to almost complete abolition; similar patterns of declines were found in the three feeding groups under study. In contrast, the addition of 5 microM estradiol induced small and selective 7 alpha-hydroxylase increases in fasting and cholestryamine-fed animals, then activity declined to control values and consistent decreases were found from 20 microM. The administration of estradiol (50 micrograms) or progesterone (100 micrograms) for 21 days resulted in depressed cholesterol 7 alpha-hydroxylase activity in rats with high bile acid synthesis basal rate due to cholestyramine feeding. In rats receiving a standard diet, either ad libitum or after 24 h fasting, the hormonal effects did not reach significance. Declines in the content of free cholesterol were provoked by progesterone, not by estradiol, in liver microsomes prepared from all feeding groups. No changes in cholesterol 7 alpha-hydroxylase activity and microsomal free cholesterol were observed after administration of the sex hormones for 3 days. Rapid and transient inhibitions in 7 alpha-hydroxylase activity were found after the single injection of progesterone to fed animals. Estradiol, on the contrary, was unable to alter rapidly the hepatic 7 alpha-hydroxylase capacity.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7846736 TI - N-butyl, N-methyl, 11-[3',17' beta-(dihydroxy)-1',3',5'(10')-estratrien-16' alpha yl]-9(R/S)-bromo undecanamide: synthesis and 17 beta-HSD inhibiting, estrogenic and antiestrogenic activities. AB - The synthesis of a 16 alpha-(bromoalkylamide) derivative of estradiol (N-butyl, N methyl, 11-[3',17' beta-(dihydroxy)-1',3',5' (10')-estratrien-16' alpha-yl] 9(R/S)-bromo undecanamide) was performed by two different approaches starting from estrone. Each approach has the same key intermediate, containing an aldehyde group, but differs by the bromination step and the timing of formation of the amide group. This compound was found to cause, at 100 microM, a complete inhibition of 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) responsible for the interconversion of estrone and estradiol. The corresponding IC50 value was 10.6 microM. In the estrogen-sensitive ZR-75-1 human breast cancer cell line, this estradiol derivative has no estrogenic activity at 30 nM and only a minimal estrogenic activity (10% above the basal level) at 1 microM. At this latter concentration, this compound causes a 28% inhibition of 0.1 nM E2-induced cell proliferation (antiestrogenic activity). Thus, the introduction of a side-chain with a secondary bromide and a butyl methyl amide group at the 16 alpha-position of estradiol has two interesting effects; namely an inhibition of cytosolic 17 beta-HSD and a blockade of the estrogenic effect of estradiol. PMID- 7846737 TI - Effect of A-ring isomers of estradiol-17 beta on gene products in MCF-7 cells. AB - Two-dimensional polyacrylamide gel-electrophoresis analysis of in vitro translation products from extracted cellular mRNAs was utilized to examine the effect of A-ring isomers of estradiol (E2) on the synthesis of proteins involved in the response of MCF-7 cells to estrogens. An 8 h pulse with 10(-8) M E2 showed 11 polypeptides of interest, 9 displayed a transient increase in mRNA accumulation and 2 showed a temporary decreased level in the presence of this hormone. A distinct set of 2 mRNAs displayed increased amounts only after a 24 h E2 pulse. Position of the A-ring hydroxyl group on the estratrien-17 beta-ol moiety had a discriminatory effect on the mRNAs for the 11 polypeptides responsive to E2. The accumulation of three mRNAs (A, C, and E) were increased by the 3 A-ring isomers (1-, 2-, and 4-hydroxyestratrien-17 beta-ol) to a degree comparable to that brought about by E2. One mRNA (H) was decreased by all estrogens. The pattern of responses depicted in the remaining 7 polypeptides was different depending on the position of the A-ring hydroxyl group of the estrogen. Subtle changes in the structure of E2 appear to attenuate the ability of this natural ligand to regulate certain estrogen responsive genes and not others. This phenomenon may be related to the interaction of TAF-2 in ligand bound receptor with the various regulators in the promoter region of specific estrogen responsive genes. PMID- 7846738 TI - A sensitive radioimmunoassay for fludrocortisone in human plasma. AB - Fludrocortisone has been a mainstay of therapy for orthostatic hypotension for many years. Clinical experience suggests that there exists a substantial interindividual variation in responsiveness to the drug. To assess this, we have developed an assay that permits measurement of the low concentrations of fludrocortisone found in human plasma. Fludrocortisone was detected by radioimmunoassay. A polyclonal rabbit antibody, raised against dexamethasone which cross-reacts strongly with fludrocortisone, was reacted with either standard or unknown samples in the presence of [125I]fludrocortisone-3-TyrNH2 (synthesized by coupling tyrosine amide to fludrocortisone-3-oxime and iodinating with chloramine T oxidation). The ED10, ED50, and ED80 were 0.34, 5.0, and 30 ng/mL of plasma, respectively. The cross reactivity with other 9-fluorinated steroids was found as follows: dexamethasone, 340%; betamethasone, 230%; and triamicinolone, 8%. To preclude an erroneous result, subjects who were pregnant or receiving any steroid medication were excluded from the study. The percent cross-reactivity with the main naturally occurring steroids was as follows: 11 desoxycortisol 3.2%, cortisol 1.1%, DOC 0.3%, pregnenolone 0.1%, corticosterone 0.06%, progesterone 0.05%, and aldosterone < 0.05%. The only compound with potential for interference, because of its high level in the circulation in the early morning, was cortisol.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7846739 TI - Gas chromatography/mass spectrometric analysis of 24R,25-dihydroxyvitamin D3 using 24R,25-dihydroxy[6,19,19-2H]vitamin D3 as internal standard. AB - Gas chromatography/mass spectrometric (GC/MS) analysis of 24R,25-dihydroxyvitamin D3 (24,25-(OH)2D3, 1a) in rat serum is examined using 6,19,19-trideuterated derivative (24,25-(OH)2[6,19,19-2H]D3, 1c) as an internal standard. Pyro- and isopyro-24,25-(OH)2D3 (2a and 3a) are synthesized and the structures are determined unambiguously by their spectral data including nuclear overhauser enhancement study of the NMR spectra. The two peaks which appear on the total ion chromatogram of 24,25-cyclic n-butyl boronate-3-trimethylsilyl derivative of 24,25-(OH)2D3 are identified to be those of the pyro and isopyro isomers (2a and 3a) by direct comparison with the synthetic standards. Analysis of the GC/MS spectrum of 24,25-(OH)2[6,19,19-2H]D3 (1c) indicated that the CH3(19) is preferentially eliminated in the fragmentation giving rise to a base peak (M TMSOH-Me)+. Thus the molecular ion peak, which is about 20% of the base peak, rather than the base peak is used for GC/MS assay of 24,25-(OH)2D3 in serum. PMID- 7846740 TI - Saliva versus blood sampling for therapeutic drug monitoring in children: patient and parental preferences and an economic analysis. AB - The objective of this study was to conduct an assessment of patient and parental preferences and an economic analysis of hospital costs in sampling blood and saliva for therapeutic drug monitoring (TDM). Costs and preferences were evaluated in the course of a study, which compared anticonvulsant concentrations in blood routinely drawn for therapeutic monitoring and in saliva in infants and children attending a pediatric neurology clinic. Parents of 84.8% of children, and half of the children, indicated a preference for saliva sampling over venous blood drawing. Children who had been on medications that required therapeutic monitoring for < 2 years were more likely to prefer saliva sampling as compared to those who were under treatment for > or = 2 years. Computation, based upon a basic assumption that a registered nurse obtained blood and a medical technician or a registered nurse assistant sampled saliva, indicated that for every 1,000 cases of changing from blood to saliva sampling, total cost savings would amount to $1,930 for cooperative children and $1,660 for infants and uncooperative children. This saving is equivalent to approximately 100 h of a registered nurse's initial salary. The important contributions to the differential cost were derived from the requirements for more highly trained individuals to take the blood sample and from the doubling time required for the procedure.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7846741 TI - Pharmacokinetics and pharmacodynamics of famotidine in children with gastroduodenal ulcers. AB - We treated 14 boys, six with gastric ulcers and eight with duodenal ulcers, to determine famotidine pharmacokinetics and its inhibition of gastric acid secretion (pharmacodynamics). Famotidine (1 mg/kg/day) was administered either intravenously or orally at a dose of 0.5 mg/kg twice a day (maximum: 40 mg/day). Blood samples were collected from all subjects and the intragastric pH monitored in eight. Pharmacokinetic parameters were calculated assuming a one-compartment model. Volume of distribution, elimination half-life, and area under the serum concentration-time curve were 1.52 +/- 0.37 l/kg, 2.29 +/- 0.38 h, and 1.14 +/- 0.32 ng.h/ml, respectively. The mean oral bioavailability of famotidine was 50.6%. Both intravenously and orally administered famotidine neutralized gastric acidity during sleep but failed to continuously maintain the intragastric pH > 5.0. All subjects' ulcers healed within 8 weeks. There were no side effects noted during famotidine treatment. Twice daily administration of 0.5 mg/kg famotidine for 8 weeks appears to be a tolerated and effective treatment of children with gastroduodenal ulcers. PMID- 7846742 TI - Comparison of the effects of cyclosporin G (OG37-325), cyclosporin A, and their metabolites on the release of endothelin and prostacyclin from primary renal and aortic endothelial cell lines. AB - Cyclosporin G (OG37-325) (CsG), an analogue of cyclosporin-A (CsA), has been reported in preliminary clinical trials to induce fewer renal side-effects than CsA. CsA and its metabolites have been shown to alter release of vasoactive substance both in vitro and in vivo, and this may be a contributing factor to the decreased renal blood flow and glomerular thrombosis associated with CsA-induced renal side-effects. However, the effects of CsG and its metabolites on release of such substances has not been investigated. In this study, the toxic effects of several CsG metabolites were investigated in primary cultures of rabbit endothelial and mesangial cells. The majority of the metabolites had little effect on cell growth and DNA synthesis. GM9 was the most cytotoxic metabolite, having a potency ratio of 0.18-0.36 for inhibition of cell growth. The effects of individual metabolites were examined on basal release of prostacyclin (PGI2) and endothelin (ET-1). The majority of metabolites had no effect on release of these analytes; however, GM1, at 5,000 micrograms/L resulted in a significant (p < 0.05) increase in ET-1, while GM9 at both 500 and 5,000 micrograms/L resulted in a significant (p < 0.01) decrease in PGI2 from mesangial cells. To more accurately compare the effects of CsA, CsG, and metabolites, parent drug and metabolites were added to cultures at concentrations comparable to those trough values observed at steady state in transplant recipients.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7846743 TI - Plasma antiepileptic drug monitoring in a neurological practice: a 25-year experience. AB - Rates for being free of all epileptic seizures for at least 1 year and for ceasing therapy after 3-5 years of full seizure control were similar in 548 treated epileptic patients referred from 1962 to 1970, during which period plasma antiepileptic drug concentration monitoring became available (32.7 and 17.0%, respectively), in 960 patients referred from 1971 to 1979, when such monitoring was used increasingly (29.6 and 14.9%, respectively), and in 348 patients referred from 1980 to 1989, when this monitoring was widely available (30.5 and 10.1%, respectively). However, monitoring was associated with higher rates of full seizure control in patients seen within 6 months of their first seizure, even when patients with only a solitary seizure were excluded. Possibly, monitoring then helped achieve early complete suppression of not yet established seizure processes, but had less effect on already entrenched seizure mechanisms. Plotting cumulative percentages of patients with fully controlled seizures versus plasma antiepileptic drug concentrations yielded data that were broadly in keeping with conventional 'therapeutic' ranges for phenytoin, carbamazepine, phenobarbital, and ethosuximide monotherapy. With a given plasma phenobarbital (but not phenytoin or carbamazepine) concentration, rates of full seizure control were appreciably higher for generalized onset than for partial onset seizures. Use of a second antiepileptic drug was associated with improved full seizure control in both generalized onset and partial onset seizures, which had not been controlled by monotherapy; adding a third drug yielded little further benefit. PMID- 7846744 TI - Influence of sex, age, weight, and carbamazepine dose on serum concentrations, concentration ratios, and level/dose ratios of carbamazepine and its metabolites. AB - We have conducted a comprehensive study in a group of epileptic children (25 boys and 30 girls) receiving carbamazepine (CBZ) monotherapy. The influence of sex, age, weight, and CBZ daily dose on serum CBZ, carbamazepine-10,11-epoxide (CBZ E), and trans-10,11-dihydroxy-10,11-dihydro-carbamazepine (CBZ-H) concentrations, concentration ratios, and level/dose ratios were investigated. Compared with girls, boys required significantly larger CBZ dose and showed higher CBZ apparent clearances and lower level/dose ratios of CBZ and its metabolites. There were no significant differences between boys and girls in serum concentrations, concentration ratios, and free fractions of CBZ and its metabolites, although there were trends that boys had slightly higher concentration ratios. The relationship analysis suggested that there was a dose-dependent autoinduction of CBZ metabolism, and CBZ metabolism was decreased as patients mature, as measured by weight and age. Age showed a significant positive relationship with the free fractions of CBZ and its metabolites, indicating decreased protein binding of CBZ and its metabolites with the increase of age. Serum CBZ concentration is not a reliable index of CBZ dose, as there is only a weak correlation between them. Serum CBZ-H concentration showed strong positive correlations with CBZ dose and might be a valuable index in assessing patient compliance. The influence of sex, body weight, age, and CBZ dose on CBZ and its metabolites should be taken into consideration in further clinical studies. PMID- 7846745 TI - Cisplatin pharmacokinetics in elderly patients. AB - The treatment of elderly patients with cancer may be difficult because of the narrow therapeutic index of antineoplastic drugs, the decline in the performance of organs and functions, and frequent comorbidity. In these patients, therapeutic drug monitoring may be useful in optimizing chemotherapy. Six patients older than 70 years with a variety of solid tumors received a total of 21 cycles of cisplatin (DDP)-based chemotherapy program (DDP dose, 50-65 mg/m2). Total and ultrafilterable platinum (Pt) were determined in plasma and urine during the first cycle of the therapy by means of atomic absorption spectroscopy. Pharmacokinetic parameters were analyzed with use of a two-compartment open model. The treatment was generally well tolerated. The most important side effects were a significant increase in serum creatinine level (from 0.98 to 1.23 mg/dl) and a decrease in creatinine clearance (from 44.4 to 38.9 ml/min) in comparison with pretreatment values. The mean decrease in hemoglobin levels was slight. The values of the main pharmacokinetic parameters of total Pt agreed well with the data obtained with other adult patients. Total and ultrafilterable Pt had a short distribution phase (t1/2 alpha = 0.35 and 0.54 h, respectively) followed by a prolonged elimination phase (t1/2 beta = 63.08 and 58.91 h, respectively). A reduced ability to clear ultrafilterable Pt (ClT = 123.52 ml h-1 kg-1) was evident and, as a result, the area under the curve increased (15.47 mg h L-1). The limited number of patients and the concomitant use of other agents prevent any firm conclusions.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7846746 TI - Rapid determination of the antimycotic drug flucytosine in human serum by micellar electrokinetic capillary chromatography with direct sample injection. AB - The rapid determination of flucytosine (5-FC) in human serum by micellar electrokinetic capillary chromatography (MECC) with direct sample injection is discussed. Minute (nanoliter) quantities of patient sera are applied to the beginning of a fused silica capillary filled with a phosphate/borate buffer (pH 9.2) containing 75 mM sodium dodecyl sulfate. Upon application of an electric field along the capillary, endogenous and drug substances are transported toward the cathode and separated into distinct zones that are detected by on-column ultraviolet absorption. Depending on the capillary and instrument used, 5-FC is shown to elute within 2-3.5 min of current application and free of endogenous interferences. 5-FC becomes also well separated from another often coadministered antimycotic drug, amphotericin B. Thus, quantitation of 5-FC is accomplished without any sample pretreatment. MECC data of 60 patient sera produced on two different automated instruments and 5-FC serum levels obtained by an agar-based bioassay are shown to agree well. For MECC, intraday and interday reproducibility data (80 micrograms/ml level) are shown to be < or = 4.5 and < 7%, respectively. Due to short run times and short capillary equilibration time intervals between runs, a sample throughput of 15/h is feasible. Thus, this technology is suitable for rapid determination of 5-FC serum levels, the time requirement for running a complete calibration, two control sera, and several patient samples being approximately 1 h only. PMID- 7846747 TI - The stability of anticonvulsant drugs in whole blood. AB - The stability of four commonly used anticonvulsant drugs, viz., valproic acid, carbamazepine, phenytoin, and phenobarbital in whole blood was investigated after storage at conditions simulating storage and transport from outlying rural clinics. Storage conditions included 24 h at 23-25 degrees C, 24 h at 37 degrees C, 48 h at 37 degrees C, and 48 h at 23-25 degrees C. Valproic acid, carbamazepine, and phenobarbital were stable for 48 h at both storage temperatures. Phenytoin was stable at 23-25 degrees C for 48 h. However, small but statistically significant decreases in phenytoin concentrations were observed in samples that were stored for 24 h or longer at 37 degrees C. These changes may not be clinically significant. PMID- 7846748 TI - Microsampling homogeneous immunoassay with Cedia digoxin reagents on the Technicon CHEM 1 chemistry analyzer. AB - We report the determination of digoxin concentration in serum with Microgenics Cedia digoxin reagents on the Technicon CHEM 1. The Technicon CHEM 1 clinical chemistry analyzer has a throughput of 720 tests per hour and uses only 7 microliters each of two reagents. A 100 test kit can perform 2,640 tests. The within-run coefficient of variation (CV) range is 2.3-0.9% and the total CV is 6.3-2.9% at concentrations tested ranging from 1.10 to 2.94 ng/ml. The results of the Technicon CHEM 1 (y) assay correlated well with those by the Technicon RA 1000 system (x) with 31 clinical serum samples (y = -0.03 + 1.11x, r = 0.96). We concluded that the Cedia digoxin assay on the Technicon CHEM 1 provides a very cost-effective, precise, rapid, and accurate means to determine digoxin concentration in serum. PMID- 7846749 TI - Determination of piroximone in human plasma by high-performance liquid chromatography. AB - A rapid and selective high-performance liquid chromatographic (HPLC) method using solid-phase extraction (SPE) for measuring piroximone in plasma samples has been developed. Human plasma and internal standard were pipetted onto a Bond Elut C18 extraction cartridge conditioned with methanol and water. Impurities and proteins were washed out with water. Piroximone and internal standard were eluted with methanol. After evaporation, the residue was dissolved in the mobile phase and the aliquot injected into the HPLC system. Piroximone and its related compounds were separated on a reversed phase C18 HPLC column maintained at 50 degrees C using a mobile phase consisting of phosphate buffer and methanol. Piroximone-N oxide, piroximone, and internal standard were detected spectrophotometrically at 340 nm. The extraction recovery for piroximone was 94%. The within- and between run coefficients of variation were < 3% in the concentration range of 320-5,000 ng/ml and < 17.5% at lower concentrations, e.g., 20 ng/ml. The limit of detection was 10 ng/ml. PMID- 7846750 TI - Solid-phase extraction and high-performance liquid chromatography for therapeutic monitoring of haloperidol levels. AB - This laboratory has developed a simple and efficient solid-phase extraction method that is combined with a high-performance liquid chromatographic method for rapid and precise therapeutic monitoring of haloperidol (Haldol) blood levels. The solid-phase extraction utilizes a mixed bed column. Sensitivity of the chromatographic method is 0.5 ng/ml (1.3 nM) of drug in serum, and separations can be performed in a 15-min chromatographic run. Advantages of this approach include enhanced speed, sensitivity, and efficiency. A high level of sensitivity may be achieved because of the absence of interferences from other drugs, metabolites, or serum components. PMID- 7846751 TI - A simplified high-performance liquid chromatographic method for direct determination of warfarin enantiomers and their protein binding in stroke patients. AB - A simplified method for direct determination of warfarin enantiomers by high pressure liquid chromatography with fluorescence detection has been developed. This method involves solid phase extraction of warfarin in plasma, precolumn derivatization to form diastereoisomeric esters, and post-column reaction to discriminate each enantiomer separately. Ultrafiltration was employed in the separation of unbound warfarin enantiomers. Twelve plasma samples from six stroke patients taking warfarin regularly were analyzed. The average concentration of total warfarin was 0.47 +/- 0.17 mg/L for the S-isomer and 0.69 +/- 0.18 mg/L for the R-isomer. The average protein binding was 99.67 +/- 0.33% for S-warfarin and 99.44 +/- 0.33% for R-warfarin. This methodology provides a quick and reliable technique for determining enantiomeric protein binding of warfarin in clinical settings. PMID- 7846752 TI - Vancomycin pharmacokinetics in a patient population: effect of age, gender, and body weight. AB - The effects of age, gender, and body weight on the pharmacokinetics of vancomycin were examined using data collected as part of routine therapeutic drug monitoring in patients. One thousand eighty-five sets of steady-state peak and trough serum concentrations obtained from 704 different patients were used to calculate elimination rate constant (k), volume of distribution (V), and clearance (Cl) using a one-compartment model. The median half-life of vancomycin was 6.5 h. Clearance was significantly correlated with creatinine clearance as estimated using the Cockcroft-Gault equation [Cl = 0.771 (Clcr) + 18.9; r = 0.63]. V averaged 0.69 L/kg ideal body weight (IBW) with increased values in females, patients over age 60, and obese patients. V ranged from 0.58 L/kg IBW in normal weight males under age 40 to 1.17 L/kg IBW in obese females over age 60. V was not different in underweight patients and those of normal weight (43.8 vs. 44.4 L). Regression analysis indicated that V was more predictable in women than in men and that vancomycin distributed into excess body weight (EBW) to a greater extent in women. However, the correlation coefficients from multiple regression analysis of V with IBW, EBW, and age did not exceed 0.60, and the high root mean square error values of 11-15 L suggest considerable variability in V is not accounted for by these factors alone. Despite these limitations, dosing of vancomycin may be improved by adjusting initial estimates of V for patient age, gender, and obesity. PMID- 7846753 TI - Cyclosporine disposition and metabolite profiles in renal transplant patients receiving a microemulsion formulation. AB - Several lines of evidence suggest that cyclosporine may undergo prehepatic metabolism, the possible contribution of which to the overall biotransformation of the drug is, however, unclear. A recently developed oral formulation of cyclosporine, Sandimmune Neoral, which incorporates the drug in a microemulsion preconcentrate, exhibits a faster rate of absorption and a shorter residence time in the gastrointestinal tract compared to the currently marketed formulation, Sandimmune. If prehepatic metabolism plays an important role, this could, theoretically, have an impact on the metabolite profile from the microemulsion formulation. Therefore, the pharmacokinetics of cyclosporine and its major metabolites were assessed in 13 clinically stable renal transplant patients receiving the commercial and the new formulations at steady state. Whole blood samples were collected over a dosing interval and analyzed by high-performance liquid chromatography (HPLC). Model-fitting of the concentration-time profiles of the parent compound indicated that while the systemic disposition was similar between formulations, absorption-related pharmacokinetic differences were evident. This was manifested in patients at steady state as shorter lag time and faster rate of absorption of the parent compound from the microemulsion formulation. The metabolite-to-parent area under the curve (AUC) ratios for the major metabolites AM1, AM4N, and AM9 were comparable between formulations. Specifically for metabolites AM1 and AM9, which predominated in whole blood and could, therefore, be fully characterized, the area ratios were bioequivalent when comparing the two formulations. Hence, absorption-related differences between the two oral formulations does not affect the systemic metabolite profile during steady-state administration in patients. PMID- 7846754 TI - Comparison of high-performance liquid chromatography and monoclonal fluorescence polarization immunoassay for the determination of whole-blood cyclosporin A in liver and heart transplant patients. AB - Conflicting conclusions have been drawn from comparisons of high-performance liquid chromatography (HPLC) and the Abbott Diagnostics monoclonal fluorescence polarization immunoassay (mFPIA) for cyclosporin. The aim of this study was to compare whole blood cyclosporin A (CsA) concentrations measured by both mFPIA and HPLC in liver and heart transplant patients. One hundred and twenty-four liver and 62 heart transplant patient samples were assayed by both methods. Assay imprecision for both methods during the studies was < 7% over the range 150-800 micrograms/L. At an HPLC-determined concentration of 100 micrograms/L, mFPIA overestimated CsA by 60% (liver) and 77% (heart). At 300 micrograms/L, the overestimation was 40% (liver) and 45% (heart). On this basis, the mFPIA is not interchangeable with HPLC. PMID- 7846755 TI - Acute digoxin overdose in a newborn with renal failure: use of digoxin immune Fab and peritoneal dialysis. AB - Digitalis intoxication is a common problem, mainly because of the narrow margin of safety of digoxin. These patients may have concomitant renal failure. In patients who have renal failure and who have been treated with digoxin-Fab, the elimination of the digoxin-Fab complex is significantly delayed, and there is a risk of dissociation of the complex with rebound of free digoxin and recurrence of toxicity. The high molecular weight of digoxin and digoxin-Fab complex prevents its elimination by hemodialysis or continuous arteriovenous hemofiltration. A 3-day-old newborn with digoxin overdose and acute renal failure was treated with digoxin immune Fab and peritoneal dialysis. Low levels of total digoxin were measured in the dialyzate, indicating poor elimination of the digoxin-Fab complex through peritoneal dialysis. PMID- 7846756 TI - Once-daily dosing of gentamicin: experience with therapeutic drug monitoring and Bayesian pharmacokinetics. PMID- 7846757 TI - Complexities of metabolic regulation. PMID- 7846758 TI - Just plain vanilla? PMID- 7846759 TI - NMR studies of human brain function. AB - Recent advances in magnetic resonance imaging and spectroscopy make it possible to measure localized changes in human brain activity and metabolism in single subjects during sensory stimulation and cognition. Differences between stimulated and unstimulated subjects can be visualized to a resolution of mm3 in less than 1s, a significant improvement over the more established method, positron emission tomography. Magnetic resonance spectroscopy of the human brain, measuring fluxes in several cm3, has followed changes in metabolic rates during visual stimulation. PMID- 7846760 TI - How much is a stabilizing bond worth? AB - It is commonly supposed that the contribution of a bond to protein or nucleic acid stability is equal to the in situ stability of the bond itself. This is not true for the noncovalent bonds that stabilize molecular folding. In general, a bonding interaction contributes a free energy increment to protein or nucleic acid stability that is larger, an enthalpy increment that is smaller, and entropy and heat capacity increments that are more positive than the corresponding bond parameter. PMID- 7846761 TI - A TPR domain in the SNAP secretory proteins. PMID- 7846762 TI - The WW domain: a signalling site in dystrophin? PMID- 7846763 TI - Proteasome sequences in eubacteria. PMID- 7846764 TI - Superfluous 'primary sequence'. PMID- 7846765 TI - The pancreatic beta-cell glucose sensor. AB - Pancreatic beta cells secrete insulin in response to an increase in the level of blood glucose above 5 mM, which is characteristic of the fasting state. Glucose metabolism is essential for glucose sensing, and both the high-Km glucose transporter GLUT2 and the high-Km glucose phosphorylating enzyme glucokinase have been implicated in coupling insulin secretion to extracellular glucose levels. Experiments in isolated islets, immortalized beta-cell lines and transgenic animals, together with findings in humans with maturity-onset diabetes of the young, indicate that the primary beta-cell glucose sensor is glucokinase. Although the level of GLUT2 is frequently reduced in animal models of type II diabetes, GLUT2 does not limit glucose metabolism in beta cells and does not appear to regulate glucose induction of insulin secretion. PMID- 7846766 TI - Beta-catenin: a common target for the regulation of cell adhesion by Wnt-1 and Src signaling pathways. AB - Beta-catenin is a cytosolic protein originally identified through its association with the cadherin class of cell-adhesion proteins. However, recent studies have demonstrated that there are cadherin-independent pools of beta-catenin and that beta-catenin binds at least one other protein, the product of the tumor suppressor gene APC. Furthermore, beta-catenin is the target of two signal transduction pathways mediated by the proto-oncogenes src and wnt-1. This raises the possibility that beta-catenin plays a pivotal role in balancing cellular responses to both adhesive and proliferative signals. PMID- 7846767 TI - Cystosolic chaperonin subunits have a conserved ATPase domain but diverged polypeptide-binding domains. AB - CCT (also called the TCP-1 complex or TriC) is a chaperonin found in the eukaryotic cytosol, and has unique structural and functional features. Unlike homo-oligomeric chaperonins, CCT comprises at least eight different subunits, and appears to have a limited range of physiological substrates. We have analysed CCT sequences in light of the recent determination of the crystal structure and mutational identification of the functional domains of the bacterial chaperonin GroEL. A high level of identity among all chaperonin subunits is observed in those regions that correspond to the ATP-binding site of GroEL. By contrast, no significant identity is shared in the region corresponding to the polypeptide binding region of GroEL, either between CCT subunits or between CCT subunits and GroEL. This suggests that the polypeptide-binding sites of CCT subunits have diverged both from each other and from GroEL, which may explain the apparently different range of substrates recognized by CCT. PMID- 7846768 TI - TGF-beta-receptor-mediated signaling. AB - Transforming growth factor beta (TGF-beta) and its many relatives are thought to play key roles in the control of cell proliferation and differentiation. In particular, the ability of TGF-beta to induce growth arrest in epithelial cells has drawn considerable attention. The recent cloning of TGF-beta receptors, which are considered to be prototypes of a new class of cell-surface receptors, has provided a first insight into how TGF-beta signaling induces a variety of intracellular changes. Furthermore, recent advances in the characterization of the cell-cycle machinery have stimulated studies aimed at understanding how TGF beta signaling leads to growth arrest in the late G1 phase of the cell cycle. PMID- 7846769 TI - Scop: structural classification of proteins. PMID- 7846770 TI - Methods and reagents. Glowing blue gels and nuked nucleases. AB - Methods and reagents is a unique monthly column that highlights current discussions in the newsgroup bionet.molbio.methds-reagnts, available on the Internet. This month's column discusses some unidentified blue fluorescence observed emanating from agarose gels, and the use of microwave ovens for DNA restriction digests. For details on how to partake in the newsgroup, see the accompanying box. PMID- 7846771 TI - [Serological diagnosis in rheumatologic practice]. PMID- 7846772 TI - [Use of rheumatoid factor IgM analysis. A questionnaire study among the users]. AB - The aim of this study was to describe who orders the rheumatoid factor analysis (RF-IgM) and the clinical indication compared to the result of the analysis. All analyses over a one month period were registered. The doctor who had ordered the analysis was contacted in order to answer a questionnaire asking about the clinical symptoms, results of other analyses and whether this analysis were the first or more. Four hundred and sixty-seven analyses were registered (population: about 300,000), 21% with a positive ELISA result (cut-off: 6 IU/ml). Thirty-one percent of the patients had clinical symptoms associated with rheumatoid arthritis. Sixty-seven percent of the analyses were ordered by the general practitioner. If we changed the cut-off to 15 or 20 IU/ml only 14 or 12 analyses were registered as having a positive result. We conclude that the analysis is often used for case-finding, perhaps the frequency could be reduced if the analysis were used more specifically and that the doctor who receives the answer has to be aware of the influence of the cut-off used by the local laboratory. PMID- 7846774 TI - [Is Vibrio cholerae serotype 0139 a potential cause of a new pandemic?]. AB - Vibrio cholerae O139, a new V. cholerae serotype that does not react with the 138 so far known antisera, was first isolated in 1992 in Madras, India. Although a V. cholerae non-O1, it behaved quite differently from this particular group of organisms by its clinical appearance in causing epidemic cholera-like disease. The organism possessed the same register of virulence factors as V. cholerae O1. Biochemical and genetic analyses have shown that V. cholerae O139 was closely related to the El Tor biotype and it has been suggested that it might be a mutant of this biotype. Despite the fact that V. cholerae O139 isolates were very homologous in many respects, ribotyping of Thai isolates showed a certain degree of genetic diversity. From its rapid spread in populations, pattern of infection and ability to survive in aquatic environments, it may be suggested that we are dealing with a more infectious, more virulent and in an ecological sense more robust organism, whose pandemic potential appears significant. Commercial cholera vaccines offer no or only limited protection. Treatment comprises an adequate rehydration and use of effective antibiotics--at present tetracycline, ampicillin, erythromycin and ciprofloxacin. Tourism and perhaps the import of foods from Third World countries may excert a potential risk for the Danish population. PMID- 7846773 TI - [When can tuberculosis be eradicated in Denmark?]. AB - Eradication is here defined as a tuberculosis (tbc.) incidence below one case of contagious tbc. per million per year and a Mycobacterium tuberculosis (Mt) infection prevalence of 1% or lower and declining. The situation is evaluated separately for Danes and foreigners. Late cases of tbc due to Mt infection more than five years earlier will decline with declining Mt infection prevalence over 50 years. Early tbc. due to Mt infection within five years can with good case finding, effective treatment, and contact examination be kept at a level of 33% of late cases. Relapses are now 15% of all cases and will also decline relatively. HIV/tbc. will only be a limited problem for a few years due to a low Mt infection prevalence. Continued limited immigration will only have minor influence on tbc. among Danes. Tbc. in immigrants already living in Denmark will decline over 10-20 years to around 20/100,000 but can not be eradicated in first generation immigrants. MT resistance will not be of importance for eradication. It is estimated that only major social disasters will be able to prevent eradication of tbc. among Danes by 2040. PMID- 7846775 TI - [Progressive multifocal leukoencephalopathy]. AB - Progressive multifocal leucoencephalopathy (PML) is a rarely occurring demyelinating disease of the central nervous system caused by a neurotropic papovavirus named JC virus (JCV). The most frequently affected areas are the cerebral hemispheres, especially the parieto-occipital region, followed by the cerebellum and brain stem. The disease occurs predominantly in individuals with an immunocompromised state and impaired cellular mediated immunity (CMI) due to other underlying illness. More extensive use of irradiation and immunosuppressive therapy in relation to increased transplantational activities as well as treatment of autoimmune diseases and malignancies, in addition to the appearance of the acquired immunodeficiency syndrome (AIDS) as a consequence of infection with the human immunodeficiency virus (HIV), has caused a considerable increase in the occurrence of PML. The course of the disease is still most often rapidly progressive and fatal, but several cases with prolonged survival and even remission have been reported, and various antiviral treatments have been tried. The only drug that until now has shown favourable results is cytosine arabinoside. In HIV-infected PML-patients immunomodulation with AZT/zidovudine may alleviate the course and improve the prognosis in some patients. Suspicion of PML should lead to an extensive immunological investigation before considering of brain biopsy, which is still the only specific test. On the basis of the increased frequency of PML in relation to HIV-infection, it is likely that our knowledge of the pathogenetic aspects will increase, which, hopefully, may lead to an effective therapeutic strategy. A review of this disease, based upon studies of the literature, is presented. PMID- 7846776 TI - [Immediate and late complications of hysterosalpingography. A comparison between Madsen's obturator and intrauterine balloon catheter]. AB - Forty females who underwent hysterosalpingography (HSG) were randomized to a procedure using either an external cervical obturator or an intrauterine balloon catheter. All patients were interviewed about adverse events during and after the examination (six days). The balloon catheter turned out to be easier to place correctly and caused the fewest adverse events as regards bleeding and pain. It is concluded that a balloon catheter for HSG is preferable both from the doctor's and the patient's viewpoint. PMID- 7846777 TI - [Objective assessment of the habitual dietary fat content in patients with obesity]. AB - A diet rich in fat may be an important precipitating factor of obesity, but studies on this relation have been hampered by the lack of an objective method to assess habitual dietary fat content. We measured 24-h fat oxidation in a respiration chamber in 38 overwight or obese and 35 nonobese women, and used it as an estimate of habitual dietary fat energy (%). After adjustment for confounders, obese women had higher oxidative fat energy than nonobese women [40.2% (37.8-42.6) vs. 36.0% (33.6-38.5), p < 0.02]. Adjusted oxidative fat energy (%) increased with increasing size of fat mass, and this relation suggest that a 10-kg change in fat mass may be caused by a change in dietary fat energy of > or = 1.6%. This objective assessment supports the contention that obese subjects consume a diet with a higher fat content than nonobese individuals, and the high-fat diet may have causal importance for the development and maintenance of obesity. PMID- 7846778 TI - [Dependence of the arterial blood pressure on cardiac filling in severe orthostatic hypotension]. AB - The present study aimed at an investigation of the relation between arterial blood pressure and cardiac filling in patients with severe postural hypotension. Seven patients aged 49 to 84 years were studied during head-up tilt at three different tilt angles (median values: 0, 25, and 45 degrees) using intraarterial blood pressure recordings and estimates of left ventricular volumes by radioisotope ventriculography. Mean arterial blood pressure was reduced from 105 mmHg (79-129) in the horizontal position to 97 mmHg (61-112) and 83 mmHg (36-93; p < 0.0001), respectively, in parallel with a reduction in left ventricular end diastolic volume index from 59 ml m-2 (30-65) to 36 ml m-2 (23-44) and 22 ml m-2 (16-38; p < 0.001). Left ventricular contractility was high, and the postural reductions in cardiac output were unopposed by vasoconstriction. The study has demonstrated that blood pressure is strongly dependent upon cardiac filling in severe postural hypotension, and has underlined the importance of intravascular volume expansion as a measure against postural hypotension. PMID- 7846779 TI - [Lymphangioleiomyomatosis]. AB - Lymphangioleiomyomatosis (LAM) is a rare disease, which only affects women of childbearing age. A case of LAM in a 36-year-old woman is presented. Patho anatomical findings are smooth muscle hyperplasia leading to obstruction of lymphatics (possibly resulting in chylothorax), blood vessels (possibly resulting in haemoptysis) and bronchi (possibly resulting in emphysema and pneumothorax). High resolution computed tomography (HRCT) of the chest can show the typical multiple small cysts and bullous emphysema distributed diffusely throughout both lungs together with interstitial fibrosis. Treatment of the disease aims at an inhibition of the presumed growth-promoting effect of oestrogen on the smooth muscle cells. However, progression is often seen in spite of treatment. PMID- 7846780 TI - [Unjustified confusion of signals on healthy food habits]. PMID- 7846782 TI - [Does the Danish Cardiologic Society dare to explore acupuncture?]. PMID- 7846783 TI - [Growth hormone substitution in adults?]. PMID- 7846781 TI - [Chemotherapy of metastasising breast cancer]. PMID- 7846784 TI - [Inguinal herniotomy--which kind of anesthesia? Economical considerations]. AB - Economical aspects of three different types of anaesthesia for inguinal hernia repair are discussed on the basis of relevant papers and economical estimates. Infiltration anaesthesia is found to be less expensive than both spinal and general anaesthesia. The reduction in cost is mainly based on a reduced demand for observation facilities during and after the operation as well as for preoperative evaluation. Early postoperative analgesia is improved after inguinal field block. Urinary retention is seen with a reduced frequency after inguinal field block. The risk of wound complication seems unrelated to the type of anaesthesia. The risk of serious complications related to anaesthesia (i.e. aspiration pneumonitis and significant circulatory events) is probably lower after infiltration anaesthesia. It is recommended that infiltration anaesthesia be employed for hernia repair. PMID- 7846785 TI - [Pain and convalescence after ambulatory inguinal herniotomy during local anesthesia]. AB - Postoperative pain and convalescence following ambulatory inguinal herniotomy in local infiltration anesthesia was evaluated in this descriptive study. Sixty consecutive patients (median age 63 yr) were included. Per- and postoperative pain treatment were pre- and postoperative oral tenoxicam and methadone plus infiltration of the surgical field with up to 60 ml of 0.25% bupivacaine. Intraoperative pain intensity was slight and was treated with supplemental bupivacaine. Patients were totally relieved of pain at rest and during mobilisation in the first hours after surgery, but more than half of the patients had moderate pain from the first to the third postoperative day and still had light pain seven days after surgery. Normal daily activity was re-established five days postoperatively (median). Fifty-two patients were satisfied with the anesthesia and eight patients not satisfied due to fear of intraoperative pain. This study shows that inguinal herniotomy can be performed routinely as an outpatient procedure under local infiltration anesthesia. However, late postoperative pain was significant and should be improved with multi-modal analgesia. PMID- 7846786 TI - [Growth hormone deficiency in adults--clinical picture and treatment]. AB - The clinical symptoms and signs of the growth hormone deficiency syndrome in adults as well as the results of growth hormone replacement therapy are summarized. It is concluded that growth hormone deficiency in adult life is associated with a variety of clinical symptoms and signs--all of which can be partially or totally alleviated by growth hormone replacement therapy. PMID- 7846787 TI - [Psychiatric treatment--methods and ethics]. AB - The success rate of psychiatric treatment is satisfactory for selected disease categories, but is hardly so when all psychiatric ailments are considered together. This is amongst other things reflected in psychiatric patients' high frequency of readmission, their increased mortality, their large and frequently long-term use of medications and in their social conditions. A low success rate is a problem not only for the individual patient who does not receive sufficient help, but also for psychiatry as a whole. Psychiatry's reputation depends largely on treatment success, and this reputation is vital for the confidence of patients when seeking treatment and of society when allocating resources. Treatment success may be improved by a methodical development of treatment technology, in psychiatric terms first and foremost a coordination of medical therapy, psychotherapy and social treatment. A technological advance is however not sufficient in itself. Treatment success also depends on a suitable demarcation of those problems that psychiatry takes it upon itself to solve. The professional debate has been particularly lacking in this area, and often out of touch with the debate in the rest of society. If people with thought or emotional disturbances or abnormal behaviour are to be satisfactorily helped, it is necessary that society's different groups giving professional treatment enter a dynamic development that constantly adjusts the balance between the groups to be helped and the helpers of different educational background that are available. PMID- 7846788 TI - [Magnesium treatment of patients with acute myocardial infarction. A meta analysis]. AB - The object of the study was to investigate the effect of intravenous magnesium in acute myocardial infarction. It was carried out as an overview of available randomized trials in which patients were allocated to receive either magnesium or placebo, the trials having taken place in the coronary care units of several hospitals. The subjects were 2438 patients with acute myocardial infarction in nine blind randomized trials combined in a meta-analysis and 54,822 patients in one unblinded randomized multi-centre trial. The main outcome measure was the relative chance of survival and relative chance of avoiding ventricular tachyarrhythmia. In the meta-analysis, the relative chance of survival was significantly increased in the magnesium group (RR = 1.049, 95% CI = 1.020-1.078, p < 0.0007). Hypothetically 25 papers with a mean of 271 patients and an RR of 1.0 should be included to make the result insignificant. The relative chance of avoiding ventricular tachyarrhythmia was not significantly increased in the magnesium group (RR = 1.041, 95% CI = 0.996-1.089, p = 0.07). The risk of accepting the null hypothesis (RR = 1.0) if the alternative hypothesis (RR = 1.041) is correct is 0,58 (the type 2 error). There was no effect on survival in the multi-centre study (RR = 0.996). It is concluded that intravenous treatment with magnesium increases survival in patients with acute myocardial infarction by 4.9% in nine blind trials, but has no effect in a large open multi-centre study. PMID- 7846790 TI - [Prevalence of risk factors in cerebral ischemia]. AB - The prevalence of risk factors for ischaemic stroke is described in 270 patients with transient ischaemic attacks or ischaemic stroke. Smoking was the most common risk factor (46%) followed by hypertension (30%) and increased levels of serum cholesterol (26%). Diabetes mellitus, atrial fibrillation and earlier myocardial infarction were less common risk factors. Ninety-one patients (34%) had two or more risk factors. In conclusion, vascular risk factors are frequently present in patients with transient ischaemic attacks or ischaemic stroke. It is still not yet clarified if risk factor modification is of any value in prevention of stroke recurrence. PMID- 7846789 TI - [Serum myoglobin as a non-invasive marker of coronary reperfusion after intravenous thrombolytic therapy in patients with acute myocardial infarction]. AB - Non-invasive methods for evaluation of intravenous thrombolytic treatment in patients with acute myocardial infarction (AMI) are needed, since approximately 30% of the patients never obtain coronary reperfusion. These patients could be candidates for additional thrombolytic treatment or acute PTCA. This study included 63 AMI patients. Intravenous and/or intracoronary thrombolysis was given to 52 patients, and 11 patients received conservative treatment (placebo). Serum myoglobin was measured every 15 min. Acute coronary angiography showed a patent coronary artery in 49 patients ("Reperfusion" group), and 14 patients had no coronary reperfusion ("No-Reperfusion" group). Mean time to peak serum myoglobin was 149 (57-194) minutes in the "Reperfusion" group and 476 (330-660) minutes in the "No-Reperfusion" group, p < 0.0001. An observed peak serum myoglobin < 5 hrs. after initiation of intravenous thrombolysis would indicate coronary reperfusion with sensitivity = 0.94; specificity = 0.79; predictive values of positive and negative test: 0.94 and 0.79, respectively. It is concluded that an peak serum myoglobin < five hrs. after start of thrombolysis predicts reperfusion status with a high level of accuracy. PMID- 7846791 TI - [Transplantation of lung lobe from a mother to a child previously transplanted with her bone marrow]. AB - The lower lobe of the left lung was transplanted from a mother to her child, who previously had received a bone marrow transplant from the mother because of an immune defect. After the bone marrow transplant the child had developed progressive pulmonary fibrosis (obliterative bronchiolitis). The surgical procedure and the early postoperative period has been uncomplicated. Immunosuppression with corticosteroids was only given for a short period, after which no immunosuppressive treatment has been given. The operation and results for both donor and recipient are described. The early results are promising, but rehabilitation is progressing slowly. PMID- 7846792 TI - [Non-immunological hydrops fetalis]. AB - Hydrops foetalis is an uncommon condition, occurring in 1/1400-1/4000 of all pregnancies. The possible etiologies to the disease are numerous and up to now the prognosis has been very dull, with a mortality-rate of 40-90%. A successfully treated case story is presented. It is concluded, that it is essential from the very beginning to treat the child aggressively to restore normal respiratory and circulatory function. When this is performed the child will have a good chance of surviving and developing normally. PMID- 7846793 TI - [Congenital kyphoscoliosis complicated by paraplegia]. AB - Congenital scoliosis accounts for 10% of all scolioses which require treatment. Correct treatment demands an exact and early detection of the deformity. Early intervention may only require a minor operation. Two cases are presented with paraplegia as the first presenting symptom of congenital kyphoscoliosis. In both cases anterior decompression and spondylodesis was followed by early neurological recovery. After a second operation with posterior spondylodesis and instrumentation ad modum Cotrel-Dubousset the patients were mobilised. Patients with congenital spinal deformity ought to be investigated and treated in a highly specialized department of spinal surgery. PMID- 7846794 TI - [Prevention of allergies in infants]. PMID- 7846795 TI - [The Scandinavian Simvastatin Survival Study]. PMID- 7846796 TI - [Fibromyalgia: "the golden mountain" does not exist]. PMID- 7846797 TI - [Is alcohol healthy?]. PMID- 7846798 TI - [Obsessive-compulsive disorders--psychiatric or neurologic diseases?]. PMID- 7846799 TI - [Fleroxacin]. PMID- 7846800 TI - [Role of computerized tomography in the diagnosis of osteomas of the sphenoid sinus with intracranial extension]. AB - The paper reports two rare cases of sphenoidal osteoma which occur statistically in 1.9% of sphenoidal osteomas. Two women underwent computed tomography because of complaints of progressive headaches. The patients had recurrent unilateral exudative otitis media. CT localized the tumor spread into the cerebral cranium and promoted further treatment design. The authors state that indications to CT diagnosis in patients with headaches should be increased. It is also suggested to make CT-diagnosis more frequently in cases of recurrent unilateral exudative otitis. PMID- 7846801 TI - [Characteristics of lesions of paranasal sinuses in patients with optic chiasm arachnoiditis]. AB - The paper provides data on a comprehensive rhinological and x-ray examination of 201 patients suffering from optochiasmal arachnoiditis (OCA). Paranasal affection (as a rule polysinusitis) was disclosed in 75.6% of the examinees. The lesion occurred primarily in the sphenoidal sinuses and frequently combined with ethmoidal labyrinth and maxillary sinus involvement. Rhinological and x-ray symptoms in OCA are rarely prominent giving grounds to physicians for defining it as the syndrome of minor clinical signs. The latter hold importance for diagnosis which enables early cleansing of the paranasal sinuses in combined treatment of OCA. PMID- 7846802 TI - [Sorption methods in the treatment of nose and paranasal sinus diseases]. AB - The responses to sorption treatment have been analysed for 373 patients suffering from staphylococcal, allergic, purulent, polypous-purulent rhinosinusitis. For enterosorption a coal spherical phi EH sorbent was used. Application sorption was performed with fabric sorbent AYT-M2, nonfabric sorbent AHM-pi, dust phi EH sorbent. Gelevin was tried for tampon-free postoperative management after dissection of the paranasal sinuses. Sorbents application advances the efficacy of nasal and paranasal disease treatment. PMID- 7846803 TI - [Timed retrograde catheterization of the nasolacrimal duct as a method of treatment in congenital dacryocystitis and acquired stenosis of the nasolacrimal duct in children]. AB - The authors propose a procedure of timed catheterization of the nasolacrimal duct for use in children with the duct stenosis and congenital dacryocystitis. The catheter is inserted for 7-10 days. Out of 27 children treated (20 cases of congenital dacryocystitis and 7 cases of the stenosis), a persistent effect was achieved in 24. The authors advocate the method as effective and promising in the above conditions. PMID- 7846804 TI - [Structure of causes of mortality of patients with otorhinolaryngologic diseases]. AB - 42 lethal outcomes have been registered for 9 years in the ENT department of the Andizhan regional hospital and in the department of the head and neck tumors of the regional cancer hospital. Among the causes of the patients' death, ENT cancer ranked the first (73.6%) followed by intracranial otogenic complications. The least frequent causes were esophageal and respiratory foreign bodies, acute stenotic laryngotracheitis. The averaged annual lethality was stable (0.25%). A further decrease of lethality depends on fitting out updated medical units and instruments, on perfection of the personal's skill, on earlier hospitalization of priority cases with ENT diseases. PMID- 7846805 TI - [Plastic surgery of the frontonasal anastomosis using a hydroxyapatite prosthesis]. AB - The authors offer a method of plastic reconstruction of the frontonasal anastomosis after radical surgery on the frontal sinus. The prosthesis made of hydrooxyappatite ceramics is established in the anastomosis created during radical surgery without additional fixation. Due to special biological properties of the material, the prosthesis firmly consolidates with bone walls of the anastomosis warranting reliable drainage and aeration of the frontal sinus. PMID- 7846806 TI - [Non-puncture treatment of sinusitis in nasal septal defects]. AB - The [symbol: see text] sinus-catheter was used to treat purulent sinusitis with septal perforation or defective septum of the sinuses. The procedure described implies simultaneous introduction of two sinus-catheters the functioning channels of which unite into one output by means of T-joint. The method has been successfully tried in the treatment of exudative and aggravated chronic purulent hemisinusitis (6 cases). The authors hold that communication between nasal sinuses is not a contraindication for sinus-catheter application. This fact widely extends potentialities of its use. PMID- 7846807 TI - [A case of successful treatment of resistant tumors with fast neutrons]. AB - The authors report two cases of resistant to standard treatment tumors cured by fast neutrons. The recurrence-free period after the treatment with 6.0 MeV neutrons lasted 5 and 2 years for follicular thyroid cancer and breast cancer metastases, respectively. To avoid acute radiation reaction of the laryngeal mucosa copper laser radiation was used. PMID- 7846809 TI - [Ear reoperation and surgical tactics after earlier radical operation]. AB - In the Izhevsk hospital ENT department, medical aid in 1985-1992 was rendered to 572 patients with chronic otitis media purulenta, 139 patients underwent radical and nonradical surgery. 12 of them needed reoperation. One patient had intracranial complication, 2 patients developed subperiosteal retroauricular abscess. According to the author, recurrent inflammation in the operated on ear was due to: cholesteatoma recurrence, osteomyelitis foci, predisposition to keloid formation in the postoperative cavity, carious anvil, filling material in the cavity (3, 5, 2, 1 and 1 cases, respectively). The author emphasizes an important role of the initial operation accuracy in prevention of postoperative recurrences. PMID- 7846808 TI - [Results of collalysine treatment of children with adhesive otitis media]. AB - Upon a clinical and audiological examination of 92 children with adhesive otitis media the patients were assigned to standard treatment or to treatment with a new proteolytic enzyme collalysin. The indications to these therapies were based on the degree of cicatrization, hearing loss and the disease duration. Conventional treatment yielded effect only in the disease duration less than 3 years, an insignificant hearing loss and nonsevere tympanic scars. Otoscopic, acoustic and tympanometric improvement after collalysin electrophoresis was observed in marked scars of the tympanic membrane, in a hearing loss by more than 30 dB, in shorter duration of the disease. 80% of the patients on collalysin functionally benefited from the treatment. PMID- 7846810 TI - [Method of fixation of transplanted free graft in the formation of a large tympanic cavity]. PMID- 7846811 TI - [Case of acute unilateral neurosensory hearing loss caused by massage of the trapezius muscle]. PMID- 7846812 TI - [Cholesteatoma of the tympanic cavity and fistula in the lower wall of the external acoustic meatus in a 4-year-old boy]. PMID- 7846813 TI - [A case of barotrauma with prolonged liquorrhea]. PMID- 7846814 TI - [Life threatening nosebleed requiring ligation of major cervical blood vessels]. PMID- 7846815 TI - [A rare case of giant fibroma of the palatine tonsil removed after tracheotomy]. PMID- 7846816 TI - [Cholesteatoma of the frontal sinus]. PMID- 7846817 TI - [Abscess of the root of the tongue complicated by complete esophageal obstruction]. PMID- 7846818 TI - [Case report of a patient with tuberculosis of palatine tonsils]. PMID- 7846819 TI - [History of the treatment of ORL diseases]. PMID- 7846820 TI - [Vestibulocochlear syndrome in lesions of the midbrain]. AB - Midbrain affection can be evidenced by pronounced central cochleovestibular syndrome which presents with converging spontaneous nystagmus, elements of monocular nystagmus, early impairment of optokinetic nystagmus in all the directions, bilateral neurosensory hypoacusis, a dramatic decrease of speech intelligibility in several sound sources, disturbed binaural hearing in normal or symmetrically reduced hearing, the absence of sound lateralization in Weber test under acute hearing asymmetry or unilateral deafness. Midbrain tumors are characterized by early hypertensive otoneurological syndrome indicated by caloric nystagmus of longer duration and greater tonicity. One case of midbrain lesion is detailed. PMID- 7846821 TI - [Method of objective assessment of hearing function according to the findings of recording short-latency auditory evoked potentials (an experimental study)]. AB - This experimental study was performed to compare amplitude and time characteristics of SLAEP spike 4 in healthy animals with those in animals having induced conductive and neurosensory hypoacusis. SLAEP analysis by the logarithmic function of spike 4 amplitude of its latent period provided distinctions in the curve shapes typical for conductive versus neurosensory hypoacusis. These differences may help in the practice of differential diagnosis. PMID- 7846822 TI - A comparison of canine distemper vaccine and measles vaccine for the prevention of canine distemper in young puppies. AB - Two groups of six-week-old beagle puppies were vaccinated with either high titre canine distemper virus or human measles virus, a third group remaining unvaccinated. All the puppies were subsequently challenged by the nasopharyngeal route at 10 weeks old with the virulent Snyder-Hill strain of canine distemper. Severe clinical signs were observed in 90 per cent of the unvaccinated dogs but both groups of vaccinated dogs survived the challenge. High temperatures were recorded in 20 per cent of the measles vaccinates and abdominal petechial rashes were observed in 60 per cent of them. The only clinical signs observed in the puppies vaccinated with distemper virus were transient rashes in 20 per cent of the group. The high titre canine distemper vaccine stimulated a humoral response quickly in 78 per cent of the puppies in the presence of maternally derived antibody and protected them against challenge with the virulent Snyder-Hill strain of distemper virus. The remaining dogs responded sluggishly but were still protected against challenge. The results of field surveys showed that 95 per cent of young puppies with different levels of maternally derived antibodies responded to the distemper component in a vaccine also containing canine parvovirus. No incompatibility was observed between the two components. PMID- 7846823 TI - Laparoscopy through the vaginal fornix of cows for the repeated aspiration of follicular oocytes. AB - A simple method is described for the repeated laparoscopic examination of the internal reproductive organs of cows and heifers through the vaginal fornix. It can be performed in a simple crush in less than 15 minutes, does not require surgery and can be used under field conditions. The method has been used for aspirating oocytes from follicles which were at least 2 mm in diameter in animals under sedation and epidural anaesthesia. In a preliminary study 11 cows and eight heifers were allocated into two groups: 12 animals were treated weekly with 500 iu pregnant mare's serum gonadotrophin and seven animals were not stimulated with gonadotrophin. The mean numbers of oocytes collected from the treated cows (6.3) and heifers (3.3) did not differ significantly from the numbers collected from the stimulated cows (5.5) and heifers (4.0). After the procedure had been established a mean oocyte collection rate of up to 75 per cent of follicles aspirated was obtained in 12 unstimulated heifers. When follicles were aspirated twice instead of once a week, the mean number of follicles observed (16.2 vs 7.0) and the mean number of oocytes collected per week (12.2 vs 5.2) were significantly higher (P < 0.05). PMID- 7846824 TI - Enrofloxacin treatment of gram-negative infections. PMID- 7846825 TI - Avulsion of the origin of the medial head of the gastrocnemius muscle in a dog. PMID- 7846826 TI - Perosomus elumbus in a goat in Trinidad, West Indies. PMID- 7846827 TI - Efficacy of ivermectin against goat warbles (Przhevalskiana silenus Brauer) in Pakistan. PMID- 7846828 TI - Comparison of the dot-blot enzyme linked immunoassay with immunofluorescence for detecting antibodies to Ehrlichia canis. PMID- 7846829 TI - Manpower and education. PMID- 7846831 TI - Transport of live animals for slaughter. PMID- 7846830 TI - Rabies policy. PMID- 7846832 TI - Veterinary nursing examinations. PMID- 7846833 TI - Pig welfare and carcase quality: a comparison of the influence of slaughter handling systems at two abattoirs. AB - Pigs from four farms (two producing 'easy' and two 'difficult to handle' pigs) were slaughtered at two abattoirs, each with two slaughter handling systems, so that 25 pigs of each behavioural type were slaughtered by all four handling systems on each day; there were 16 replicates (3200 pigs) in total. The pigs at abattoir X were electrically stunned, either in a floor pen holding five pigs or in a race-restrainer. At abattoir Y the pigs were stunned either in a floor pen holding five pigs or in a dip-lift carbon dioxide stunner. The following measurements were made: hot carcase weight and backfat thickness at P2, degree of rigor mortis 35 minutes post mortem, skin blemish, pH and muscle reflectance in the m longissimus dorsi at 60 minutes and 18 hours post mortem, and pH and muscle reflectance in the m adductor at 18 hours post mortem. At abattoir X, the pigs slaughtered in the race-restrainer had heavier carcases (74.0 kg vs 73.0 kg, P < 0.05), developed rigor mortis more rapidly (8.1 mm vs 7.3 mm, P < 0.01), had more skin blemish (2.8 vs 2.7, P < 0.01), paler m longissimus dorsi muscles after one hour (15.7 vs 13.9, P < 0.01) and 18 hours (27.8 vs 26.6, P < 0.05), and paler m adductor muscles (24.5 vs 22.7, P < 0.001) after 18 hours. At abattoir Y, the pigs handled through the floor pen system had more skin blemish (2.7 vs 2.6, P < 0.05) and a tendency to develop rigor mortis more quickly (6.11 vs 5.32, P = 0.089).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7846834 TI - Artificially dehydrated lucerne for horses. AB - Artificially dehydrated lucerne produced in the United Kingdom has been shown to be a better source of nutrients for horses than grass hay. Horses eat more lucerne when it is pelleted, and the processing has little effect on its nutritive value. Lucerne does not appear to contain any antinutritional factors of significance to horses. Lucerne contains readily available calcium and protein and can thus be used as a cereal-balancer or to upgrade poor quality roughages. Because lucerne is a good source of digestible nutrients it has therapeutic applications, including the correction of electrolyte imbalances and hoof horn problems, and it can be used for intragastric nutrition and for feeding old horses. PMID- 7846835 TI - Detection, cloning and characterisation of papillomaviral DNA present in sarcoid tumours of Equus asinus. AB - Molecular investigations on 18 naturally occurring sarcoid tumors removed from donkeys identified papillomaviral DNA homologous to bovine papillomavirus (BPV)-2 DNA under stringent conditions, in all the samples. Restriction endonuclease analysis of 15 of the tumours demonstrated papillomaviral DNA similar to BPV-1 and BPV-2. The type of DNA was not specific to either the site or the type of lesion. The analysis of the nucleotide base sequence of a cloned papillomaviral element from a sarcoid showed that the isolate was 96 and 98 per cent homologous to BPV-1 in the L1 and E5 open reading frames, respectively. It was concluded that the disease in the donkey is similar to that in the horse and that the E5 open reading frame may be involved in oncogenesis in the sarcoid. PMID- 7846836 TI - 'Flying scapulas', a post turnout myopathy in cattle. PMID- 7846837 TI - Protection of goats against capripox using a subunit vaccine. PMID- 7846838 TI - Congenital anomaly of the cervical vertebral column of a dog. PMID- 7846839 TI - A new spectrofluorometric procedure for sexing birds. PMID- 7846840 TI - Future of veterinary research. PMID- 7846841 TI - Equine motor neuron disease and grass sickness. PMID- 7846842 TI - Organophosphorus sheep dips. PMID- 7846843 TI - Spongiform encephalopathies in zoos. PMID- 7846844 TI - Understanding and control of parasitic diseases of animals. Proceedings of the 14th International Conference of the World Association for the Advancement of Veterinary Parasitology. Cambridge, U.K., 8-13 August 1993. PMID- 7846845 TI - Parasite control in transhumant situations. AB - Transhumance is defined as 'seasonal moving of livestock to regions of different climate'. It is an integral part of livestock production in many parts of the world and takes several forms including moving of livestock from lowland to mountainous pastures or from dry to humid areas. The impact of transhumance on parasite populations of livestock and on parasite control is described, mainly using examples from Europe. The epidemiology of trichostrongylidosis of cattle, mainly caused by Ostertagia ostertagi and Cooperia oncophora, is characterised by prolonged survival of overwintered infective larvae until the end of June. Cattle moved to such contaminated pastures in a transhumant grazing system are exposed to these larvae and may be protected, during the second half of the grazing season until autumn, by a late application (June/July) of an intraruminal drug release device. Community pastures used in a transhumant system with mixed grazing of young cattle originating from various farms may enhance transmission of dictyocaulosis. Therefore, specific prophylactic measures are required. Hill sheep nematode populations may differ from those in lowland sheep in that Haemonchus contortus generally plays a minor role in hill sheep in which Ostertagia circumcincta and Nematodirus spp. predominate. Infections with Fasciola hepatica and Dicrocoelium dendriticum can be acquired on mountainous pastures by cattle, sheep and other livestock grazing in a transhumant system as intermediate hosts of these parasites may find suitable habitats in these regions. There is evidence that in the prealpine and alpine area both parasites are mainly transmitted in two-season cycles. Further examples for the impact of transhumance on parasite-host inter-relationships include cysticercosis in cattle, echinococcosis, psoroptic manage in sheep, tick-borne fever of cattle, and hypodermosis in cattle. These are described and discussed. PMID- 7846846 TI - W.A.A.V.P. and Pfizer Award for excellence in research in veterinary parasitology. Veterinary helminthology 1954-1993: a personal view of four decades of research. PMID- 7846847 TI - Modelling of parasite populations: gastrointestinal nematode models. AB - This paper surveys models of nematode parasites of veterinary importance. A distinction is drawn between generic models which are usually simple formulations applicable to whole classes of parasite and specific models which are often more complex and designed to address questions concerning a particular species. Most of the models considered employ a deterministic framework. Four main groups are considered: generic models of trichostrongylid infection of domestic ruminants, specific models of trichostrongylid infection of domestic ruminants, specific models of experimental laboratory infections of rodents, and a specific model of nematode infections in wildlife. PMID- 7846848 TI - Modelling of parasitic populations: cestodes. AB - The philosophy of mathematical modelling as it applies to the epidemiology of cestode populations is reviewed. A model provides, via the "threshold theorem", a criterion for deciding in advance if a control programme can succeed in eradicating the parasite. In order to use this criterion it is necessary to have an estimate of the basic reproduction ratio, R0, which can only be obtained if reliable epidemiological data are available before the control programme is started. A model has been used to describe the population dynamics of Echinococcus granulosus, Taenia hydatigena and Taenia ovis in sheep and dogs in New Zealand. For these parasites, data from a 40-year longitudinal study, as well as short-term field and laboratory studies, were available. A model has also been used to evaluate a proposed control programme directed against Echinococcus multilocularis in foxes and voles in France. Here the type and extent of control intervention is predetermined by the existing rabies control programme. These two examples, which demonstrate the different techniques required to model cestodes in domestic and wild-animal populations, are reviewed, and the use of a model as the basis for a benefit/cost analysis of control options is discussed. These techniques could, in principal, be used to design control programmes for Taenia saginata or Taenia solium in humans. PMID- 7846849 TI - Genetic resistance to parasitic disease: particularly of resistance in ruminants to gastrointestinal nematodes. AB - There is substantial variation among individuals in susceptibility to a wide variety of parasitic diseases and part of this variation in susceptibility is due to genetic factors. The challenge now is to determine the best methods of using the variation to improve our understanding of parasitic infection and to reduce the ravages of parasitic disease. Scientific and commercial applications will depend upon the type of genetic variation. Variation among breeds can be easily exploited by a policy of breed substitution. Variation within a breed can be exploited by selective breeding to improve resistance to infection or to disease, but more work is needed to develop selection indices which are acceptable to livestock breeders. Identifying genes which contribute to the variation in resistance provides a better understanding of the mechanisms of resistance but more work is needed to determine if such genes, alone or in combination, account for a sufficient proportion of the variation in resistance to allow marker assisted selection. A comparison of responses in susceptible and resistant stock provides a powerful tool to distinguish among protective, irrelevant and pathological responses. These themes have been illustrated by three studies of gastrointestinal nematode infections in ruminants. PMID- 7846850 TI - Vaccination against animal parasites. AB - A decade of molecular parasitology is beginning to bear fruit, with the appearance of several new, highly effective, practical vaccines against parasitic diseases. Recombinant antigen vaccines have been developed against cestode, nematode, trematode, protozoan and arthropod parasites. Greatest progress has been made with veterinary vaccines, where the ability to test numerous vaccine formulations in challenge trials has allowed more rapid identification of host protective antigens than is possible with many medically important parasites. Several quite different approaches to vaccine development have been successful. The traditional approach using live, attenuated parasites continues to provide effective vaccines against several protozoan and nematode parasites. Recombinant DNA technology, monoclonal antibody technology, protein chemistry and immunochemistry have played critical roles in the outstanding success which has been achieved over the last 5 years in the development of defined-antigen vaccines. Two approaches have been successful in research towards defined antigen vaccines against parasites: (1) the 'natural antigen' approach where immune responses are stimulated to parasite molecules which are normally antigenic, and possibly host-protective, in infected hosts; (2) the 'naive antigen' approach where parasite molecules which are not antigenic, or of very low antigenicity, in infected hosts are used to raise immune responses capable of killing the parasite. This review examines the successful approaches taken towards the development of effective anti-parasite vaccines and the vaccines which have been produced to date. PMID- 7846851 TI - Vaccines against blood-sucking arthropods. AB - This paper provides selected personal insights on the development of vaccines against blood-sucking arthropods, with particular emphasis on vaccines against ticks. The emergence of novel or concealed antigens of haematophagous ectoparasites as candidate vaccine antigens is reviewed and the effect of feeding by the parasite on the expression of protective antigens is considered. The distribution of protective antigens through life cycle stages, the stage of the life cycle targeted by protective responses, and the nature of these responses, are commented on briefly. Concealed antigens of the gut, including the peritrophic membrane, and other internal organs, are evaluated for the role they play in induction of immunity artificially. Some of the work carried out to purify and characterise protective antigens of tick guts is described. A commentary is developed on vaccines that combine both "concealed" and "exposed" antigens. Some of the problems associated with the infestation and challenge of vaccinated hosts in the field are identified and the delivery of parasite antigens as vaccines that are both protective and "user-friendly" is emphasised as a major problem to be solved. PMID- 7846852 TI - Chemotherapy and delivery systems: haemoparasites. AB - Chemotherapy of haemoparasitic diseases in domestic animals is dependent on a limited number of compounds, many of which are chemically closely related. In this review, a summary is given of each of the drugs currently available for treatment and prophylaxis of trypanosomosis and the tick-borne diseases theileriosis, babesiosis, anaplasmosis and cowdriosis. In contrast to the situation with the drugs used for tick-borne diseases, drug resistance appears to be becoming an increasing problem associated with the compounds used for trypanosomosis. The literature that has been reviewed, therefore, is that which relates to the methods used to identify and quantify drug resistance in trypanosome populations, reports of resistance to trypanocides, and cross resistance between trypanosome populations, reports of resistance to trypanocides, and cross-resistance between trypanocides. The possible reason(s) for the apparent lack of development of resistance to the compounds used for treatment of tick-borne diseases is also discussed. Local toxicity at the site of injection is a problem that is particularly associated with many of the trypanocides when used on a long-term basis in individual animals. Various alternative preparations of the currently used trypanocides therefore have been evaluated in an attempt to reduce this toxicity, and are summarised. Finally, future developments in haemoparasitic chemotherapy are considered and, for trypanosomosis, highlight the importance of integrating chemotherapeutic and chemoprophylactic programmes with control of the vector when drug resistance becomes a significant constraint. PMID- 7846853 TI - W.A.A.V.P. and Pfizer Award for excellence in teaching veterinary parasitology. PMID- 7846855 TI - Anthelmintic resistance. AB - Anthelmintic resistance is widespread in nematode parasites of sheep, goats and horses. Resistance is also developing in nematode parasites of cattle and has been detected in pig parasites. Benzimidazole, levamisole/morantel and ivermectin resistances occur in nematodes of sheep and goats and closantel resistance has been found in Haemonchus contortus. Anthelmintic resistance is likely to develop wherever anthelmintics are frequently used and be detected if it is investigated. Worm count or egg count reduction after treatment are useful for the detection of all types of anthelmintic resistances. More economical, faster and more sensitive in vitro assays for the detection of anthelmintic resistance have been developed. Some, such as the egg hatch assay are specific for a particular class of anthelmintic, whilst others such as larval development assays can be used with most anthelmintics. Improvements in our understanding of the biochemistry and molecular genetics of anthelmintic actions should lead to the development of more sensitive assays for the detection of anthelmintic resistance in individual nematodes. Levamisole/morantel resistance appears to be associated with alterations in cholinergic receptors in resistant nematodes. Ivermectin appears to act by binding to a glutamate receptor of a membrane chloride channel. This receptor has been expressed in vitro so that further studies of the interaction of ivermectin with this receptor and its possible alteration in ivermectin resistance will be feasible. Benzimidazole resistance in nematodes and fungi appears to be associated with an alteration in beta-tubulin genes which reduces or abolishes the high affinity binding of benzimidazoles for tubulin in these organisms. This knowledge can be exploited for DNA probes for benzimidazole resistance/susceptibility in individual organisms. PMID- 7846854 TI - Chemotherapy and delivery systems--helminths. AB - The milbemycins are the only novel broad spectrum anthelmintic chemicals to reach the market place in the last 10 years. Many new systems for delivery and strategies for rational use have, however, been introduced. Boluses which are retained by virtue of specific gravity and by variable geometry are now available. They contain benzimidazoles, morantel, ivermectin and levamisole. Their release mechanisms involve preferential corrosion of a retaining metal core, constant diffusion from a laminated ethylene acetate sandwich, and a hydrostatic pump driven by osmotic pressure. Some are biodegradable. Experimental delivery systems have been developed incorporating ear implants and liposomes. The anthelmintic efficacy of some drugs has been potentiated by the synergistic action of metabolic inhibitors and these combinations hold promise for the future. Much new information is now available on those factors which affect anthelmintic efficacy such as concurrent administration with food and the presence of the target parasites themselves. This knowledge provides a sound basis for the rational use of anthelmintic drugs. PMID- 7846856 TI - Teaching veterinary parasitology. AB - The history of parasitology and the teaching of veterinary parasitology in South Africa are reviewed briefly. Courses in veterinary parasitology are presented at the faculties of veterinary science at the University of Pretoria and the Medical University of South Africa as well as at the Pretoria Technicon. At the University of Pretoria, the three disciplines of veterinary parasitology, entomology, helminthology and protozoology, are covered in 330 core lectures; from 13 to 40% of the contact time is devoted to practical classes. Teaching veterinary parasitology is both labour intensive and costly, viz. R1700 (US$570) per student per annum. Such costs are justified by the R148.8 million (US$49.6 million) spent every year in South Africa on anthelmintics, ectoparasiticides and vaccines to control parasites. Veterinary parasitology is a dynamic subject and the curriculum must be revised regularly to incorporate new information. Because the parasite faunas are so diverse no single textbook can satisfy the requirements of the various institutions worldwide which teach the subject, with the result that extensive use is made of notes. In Australia and in Europe, ticks and tick-borne diseases are less important than they are in Africa; consequently insufficient space is devoted to them in textbooks to satisfy the requirements of the subject in African countries. Parasite control under extensive and intensive conditions is dealt with adequately at the University of Pretoria, but increasing emphasis will be given to small-scale farming systems, particularly if alternative food animals are to be kept. PMID- 7846857 TI - Parasites, animal production and sustainable development. AB - Ecologically sustainable development is aimed at reducing environmental degradation while enabling economic development with equity between the developed and developing worlds and between generations. Parasite control in livestock can both contribute to, and take advantage of, sustainable agriculture. This will tend towards less intensive, lower input, diversified crop and animal production with less risk of parasite-induced losses and greater opportunities for integrated control including the exploitation of grazing management. Chemotherapy will continue to play a part but the most serious problem is resistance in the target species. Except for a few isolated issues, currently used parasiticides are relatively minor contaminants of the food supply or the environment. Nevertheless, the compounds of the future will need to be narrow-spectrum, non persistent and rapidly degraded, with convenience in the hands of the user reduced in importance. Environmentally friendly alternatives to chemotherapy, including genetic resistance of hosts, vaccines, and biological control, show considerable promise and must be pursued. Sustainable systems pose optimisation problems and more attention must be given to systems research, models and products to aid decisions. If governments are serious about sustainable development, greater support will be needed for longer-term patient, multi disciplinary research. PMID- 7846858 TI - Workshop summary: wildlife situations. PMID- 7846859 TI - Workshop summary: donkey parasitology. PMID- 7846860 TI - Workshop summary: parasitic zoonoses--new issues. PMID- 7846861 TI - Workshop summary: hydatid--new approaches. PMID- 7846862 TI - Workshop summary: pathophysiology of gastrointestinal parasites. PMID- 7846863 TI - Parasitology in the United Kingdom and elsewhere over 30 years of the World Association for the Advancement of Veterinary Parasitology. PMID- 7846864 TI - Workshop summary: sustainable production systems. PMID- 7846865 TI - Workshop summary: strategies and economics of parasite control in Africa. PMID- 7846866 TI - Workshop summary: cyclical and non-cyclical trypanosomes. PMID- 7846867 TI - Workshop summary: antiparasitic testing guidelines. World Association for the Advancement of Veterinary Parasitology. PMID- 7846868 TI - Workshop summary: anthelmintic resistance. PMID- 7846869 TI - Workshop summary: vaccine development. PMID- 7846870 TI - Workshop summary: vaccination against coccidiosis. PMID- 7846871 TI - Workshop summary: genetics in parasitology. PMID- 7846872 TI - Parasitic control in intensive vs. non-intensive systems--ruminants. AB - The acquisition and intensity of infection with gastrointestinal nematodes and with Oestrus ovis are compared over 2 years in sheep grazed intensively (26-36 sheep ha-1) or non-intensively (12 sheep ha-1) in the winter rainfall Overberg region of South Africa. Sheep grazing intensively on grass/legume pastures, spray irrigated in summer, acquired massive mixed infections of Trichostrongylus, Haemonchus and Teladorsagia. Infections were fatal for sucking lambs. Lambs from ewes grazed non-intensively on dry land lucerne in winter became infected with Nematodirus and then with Teladorsagia and Trichostrongylus spp.; resistance to Nematodirus was apparent after 12 weeks; spontaneous cure of Teladorsagia began in hoggets grazing on safe wheat stubble pasture; but Trichostrongylus survived in the sheep. Helminth-induced host mortality was not observed on the non intensive farm. The efficacy of various methods of control was examined in the intensively managed sheep. Removal from pasture, mixed grazing (cattle before sheep) and an albendazole slow release bolus all significantly (P < 0.05) reduced levels of infection in animals so treated, compared with control sheep which were treated periodically with anthelmintics as standard farm management practice. Removal of sheep from the pasture for 30 days in the summer seemed to have beneficial effects. Treatment of sheep weekly with albendazole increased levels of infection in the sheep over controls. The status of vaccination is described and the potential of intergenic competition in grazing management and perhaps vaccination is discussed. Resistance of nematodes to anthelmintics was relatively wide-spread. In both intensive and non-intensive systems. Oestrus ovis larvae were present in flock sheep for 10-12 months per year. Imagines failed to develop from 27 April-9 August and it was concluded that larvae had to overwinter in sheep to survive. Recommendations for integrated control are made for both intensive and non-intensive systems. PMID- 7846873 TI - Epidemiology and control of helminth infections in pigs under intensive and non intensive production systems. AB - Swine production systems are characterised by a high diversity with regard to management type and the level of intensity of management. The number of helminth species and their infection levels are strongly influenced by the different systems. The present paper focuses on the situation in northern Europe, with examples from Denmark, and describes a decrease in both the number of helminth species and in their infection levels as a result of a shift from non-intensive to highly intensive production systems. Differences in the basic biological requirements of the pre-infective larvae, and in the transmission characteristics and immunogenicity of the various helminth species, explain why some species are more vulnerable to manage mental changes than others. Finally, control measures for the different production systems are discussed. Even though it is well documented that proper hygiene and management may prevent transmission of helminths, use of anthelmintics is still the single most important action taken by pig farmers to control worm infections. It is emphasised that anthelmintics should not be used uncritically, but should be integrated with management practices and the production system to achieve optimum effect and to avoid development of anthelmintic resistance. PMID- 7846874 TI - Epidemiology and control of parasites in nomadic situations. AB - Nomadism is a highly specialised mode of life that enables humans to exploit resources that are widely distributed over space and time. The isolation and remoteness of many nomad populations have limited studies on the macroepidemiology of parasitic infection in nomad populations. From the available information, the influence of a number of factors on the prevalence and transmission of parasitic infections in nomads is discussed. Environmental conditions, especially relative humidity and temperature, profoundly influence parasitic diseases. Human behaviour varies with cultural factors and influences exposure to disease. Periodic movements of nomads may either remove them and their animals from contaminated environments or may bring then into contact, often seasonally, with infections. There may be a strong ecological interdependence between diet and infection and disease in nomadic groups. Finally, the influence of drought can be profound in that seasonal or prolonged drought promotes concentration of populations in small areas or their sedenterisation, often with an increase in parasite transmission. Relevant information that needs to be acquired to develop appropriate practical and cost effective health and veterinary care and control programmes for nomadic populations and their livestock is outlined. PMID- 7846875 TI - [Deresinated naphthalan in the treatment of psoriatic arthritis]. AB - The paper presents pathogenetic validation for introduction of naphthalane oil as a therapeutic modality in psoriatic arthritis. The criteria of the inflammation activity are specified. As a result of deresinified naphthalane treatment, 43 psoriatic patients exhibited positive trends in clinical and laboratory manifestations of the inflammation, reduced intensity of the disease, declined articular and skin syndromes. The response persisted for 6 months. PMID- 7846876 TI - [Nitroglycerin electrophoresis in the treatment of patients with ischemic heart disease]. AB - 105 patients with coronary heart disease and functionally varying angina pectoris received in sanatoria or inpatiently segmental nitroglycerin electrophoresis. The microcirculatory bed was studied with bulbar biomicroscopy in comparison with clinical effects. There appeared a relationship between improvements in microcirculation and clinical symptoms. The course of 10-15 procedures at maximum strength of current 0.03 mA/cm2 proved effective in 78% and 95% of inpatients and sanatorium patients, respectively. PMID- 7846877 TI - [Holter ECG monitoring in the early detection of coronary insufficiency in patients at a health resort]. AB - Holter ECG monitoring registered episodes of asymptomatic myocardial ischemia in 17.1% of patients at risk of coronary heart disease receiving treatment at the sanatorium. Such patients were recommended to adhere to sparing exercise regimen. Therapeutic measures were also taken to correct coronary heart disease risk factors. PMID- 7846878 TI - [The use of water-soluble beta-carotene (vetoron) in the combined treatment of patients with duodenal peptic ulcer and chronic proctosigmoiditis at Krainka general health resort]. AB - Oral administration of water-soluble beta-carotin (vetoron) in combined treatment of duodenal ulcer induces more significant reduction of inflammatory and atrophic lesions, faster healing in the test subjects compared to the controls. Vetoron microclysters with oil stimulate regression of the atrophy, recover small surface vessels, reduce inflammation in colon mucosa of patients affected with chronic proctosigmoiditis. PMID- 7846879 TI - [The effect of combined health resort treatment on the energy metabolism of patients with duodenal peptic ulcer]. PMID- 7846880 TI - [Physical factors in the therapy of secondary chronic pyelonephritis]. AB - The authors have developed combined therapy of secondary chronic pyelonephritis with immune and urodynamic dysfunctions. The treatment includes physical factors: decimeter microwaves, gangleron-electrophoresis with sinusoidal modulated currents, sodium chloride baths, oral mineral water Moskovskaia. The adjuvant use of the above physical factors proved advantageous. PMID- 7846881 TI - [The comparative efficacy of the treatment at Sochi of women with inflammatory diseases of the lesser pelvis who live in different climatic and geographical regions of Russia]. AB - 225 females of reproductive age were treated in Sochi for inflammatory diseases of the small pelvis. The patients underwent climate, balneological, laser treatments and received thymogen. Therapeutic results estimated clinically, by adaptive responses, protein metabolism, proteolysis and ceruloplasmin activity, concentrations of proteolysis inhibitors and middle-mass molecules were analyzed with respect to the patients' residence and the season of their stay in the sanatorium. The best results in warm seasons were achieved in women from south regions. In northerners and some residents of middle Russia there were adaptive failures. For them, cool seasons were more advantageous. The authors recommend cool Sochi weather for treatment of small pelvis diseases in women living in the north, south and middle Russia. PMID- 7846883 TI - [The differential use of electrosleep for restoring the work capacity of athletes]. AB - A comparative study has been made of the effects which might be produced on body functions of athletes by electric sleep. The induction of the sleep was conducted using square electric pulses with 10 and 100 Hz frequencies. The latter frequency (8-10 sleep procedures) stimulated the examinees somatically and psychologically, whereas electrotherapeutic sleep procedures at 10 Hz displayed sedative effects and thus were indicated for overstrained sportsmen and in some diseases. PMID- 7846882 TI - [Experimental research on the physicochemical action of impulse currents when applied transcerebrally]. AB - Thymocyte function and lipid peroxidation in cell membranes of the cerebral cortex and the myocardium of 72 rats were examined to study the stress-limiting mechanism of 10 and 1000 Hz impulse current effect. The additional measurements were as follows: rat and thymus weight, their proportional relations, thymocyte nuclear population, 11--OCS, thyroid hormones (T3, T4), plasma testosterone and insulin, myocardial and cerebral cortical protein. The animals were immobilized for 6 days in individual tight cages where they had food and water. Antioxidant and antistress effects of impulse currents were revealed at definite regimens of their application: 10 Hz stress limiting action was more potent when applied to stressed animals, but 1000 Hz current proved to be an effective prophylactic procedure. PMID- 7846884 TI - [The efficacy of speleotherapy in atopic dermatitis in children]. AB - After proper clinical and immunological examinations 112 children with atopic dermatitis underwent immunocorrective speleotherapy in a chamber with artificial microclimate created with the use of natrium chloride spraying. During the treatment positive trends were observed in the patients' dermatological status and immune homeostasis. A complete 6-24-month response was reported in 58%, partial in 20%, no response in 6.9% of patients. The method is recommended for treatment of atopic dermatitis. PMID- 7846885 TI - [The general principles in selecting for sanatorium-health resort treatment the population exposed to radiation as a consequence of the accident at the Chernobyl Atomic Electric Power Station]. PMID- 7846886 TI - [The scientific organizational principles of the rehabilitative treatment of children exposed as a consequence of the accident at the Chernobyl Atomic Electric Power Station]. PMID- 7846887 TI - [The current requirements for assessing the qualitative composition of mineral waters and peloids]. PMID- 7846888 TI - [The preparation of radon water from air containing radon by means of dissolving it under pressure]. PMID- 7846889 TI - [A therapeutic alpha-applicator with radon daughters]. PMID- 7846890 TI - [The photodynamic therapy of laryngeal tumors]. PMID- 7846891 TI - [The use of manual therapy in the initial forms of cerebrovascular diseases]. AB - An original combination of manual procedures has been tried in management of initial cerebrovascular symptoms which appeared against neurological signs of osteochondrosis involving thoracic and cervical spine. Positive results of the treatment were recorded in 100 patients manually, neurologically, electrophysiologically and biochemically. Practical recommendations for the performers are provided. PMID- 7846892 TI - [The combined use of electromagnetic decimeter waves and deresinated naphthalan in patients with vertebrogenic humeroscapular periarthrosis (its experimental and clinical validation)]. AB - Physicochemical and experimental studies on pond snail neuron were made to validate combined or simultaneous usage of decimeter microwaves and deresinified naphthalane. Clinical and neurophysiological trials in 133 patients with vertebrogenic scapulohumeral periarthritis revealed that the above treatment is clinically beneficial and corrects functional activity of segmental-peripheral neuromotor system. PMID- 7846893 TI - [The metabolic syndrome. Pathophysiologic causes, diagnosis, therapy]. AB - The individual components of the metabolic syndrome such as central obesity, dyslipidemia with increased triglycerides and decreased HDL-cholesterol, hyperuricemia, hypertension and progressive glucose intolerance are markers for an increased risk of atheroma and type 2 (non-insulin-dependent) diabetes. All components, with the exception of hyperuricemia, are associated with skeletal muscle insulin resistance, leading to compensatory chronic hyperinsulinemia. Insulin resistance/hyperinsulinemia, in turn, is associated with a series of hypertensiogenic and atherogenic side effects, aggravating the individual components of the metabolic syndrome. From a more pathophysiologically orientated point of view, early identification of individuals obviously at risk for atheroma and type 2 diabetes, as well as early intervention aimed at the improvement of reduced insulin action may play a central role in an integrated life-style approach of primary prevention of atherosclerosis and type 2 diabetes. PMID- 7846894 TI - [Insulin resistance and cardiovascular complications]. AB - Several epidemiologic and clinical studies over the past years have shown that insulin resistance and hyperinsulinemia are related to dyslipidemia, hypertension, android obesity and non-insulin-dependent diabetes mellitus (NIDDM). The insulin-resistance syndrome is thus closely associated with a cluster of potent cardiovascular risk factors, thereby explaining the 3-4 times higher incidence of cardiovascular disease in NIDDM. Recent observations point to the fact that insulin resistance is genetically determined and can be diagnosed a long time before the clinical manifestation of diabetes mellitus in the prediabetic stage (stage of hyperinsulinemia, hypertension and hyperlipidemia). Hence, it is not surprising that many NIDDM subjects suffer from cardiovascular complications already at the time diabetes is diagnosed. The pathogenetic mechanism of insulin resistance/hyperinsulinemia as cardiovascular risk factor is considered to be a direct atherogenic action of insulin on vessel wall cells and an indirect effect on upper body obesity, blood pressure, lipids and hemostasis. PMID- 7846895 TI - [Lipid metabolism and insulin resistance--clinical aspects and pathobiochemistry]. AB - About 3 decades ago insulin resistance has been described as the pathogenetic factor leading from abnormal fat metabolism to diabetes mellitus. Within the metabolic syndrome insulin resistance is related to the upper body (android) type of obesity, hypertriglyceridaemia, hypertension, and diabetes mellitus ("deadly quartet"). It precedes the development of arterial hypertension and the metabolic disorders. The pathomechanisms leading from obesity and hypertriglyceridaemia to insulin resistance may be described by the glucose fatty acid cycle of Randle et al. According to their metabolic scheme increased supply of fatty acids results in reduced glucose oxidation. Concomittantly hepatic glucose production is increased. On the other hand insulin resistance combined with hyperinsulinaemia may lead to an elevation of VLDL-triglycerides and to a decrease of HDL cholesterol in blood, thus creating a vicious cycle, in which elevated VLDL triglycerides reinforce insulin resistance via the glucose fatty acid cycle. Interventions to improve insulin sensitivity and thereby lower plasma insulin should reduce obesity and hypertriglyceridaemia by dietary treatment. They usually improve promptly diabetic metabolism. New developments in pharmacological inhibition of fatty acid oxidation are discussed. PMID- 7846896 TI - The influence of diet and physical activity on insulin sensitivity. AB - This article reviews the effects of diet and exercise on insulin sensitivity in patients with type II diabetes (non-insulin-dependent diabetes mellitus, NIDDM). Dietary caloric restriction operative through weight loss decrease the insulin resistance characteristic of the disease by increased glucose transport. The precise localization of this effect is unknown, as is the defect in the insulin signalling pathway in type II diabetes. Inherent problems are the inability to clearly separate obesity and type II diabetes and methodological difficulties in the distinction of dietary effects from exercise-induced effects. The mechanism of exercise-induced insulin sensitivity has gained considerable understanding through the detection of the glucose transporter molecule GLUT-4 in muscle. It is now clear that the presence of insulin is not mandatory and mere electrical stimulation of the muscle produces similar effects through distinct signalling pathways. Exercise-induced increased blood flow and decreased vascular resistance may also play an important role. In contrast to these newer experimental data, clinical studies and feasibility studies aimed to implement exercise as a valuable therapeutic measure in type II diabetes have failed to delineate promising long-lasting effects and can therefore not be generally recommended. Encouraging epidemiological data have recently been found with respect to the prevention of type II diabetes by increased physical activity in patients at risk. PMID- 7846897 TI - [Hypertension, microalbuminuria and insulin resistance in diabetes mellitus]. AB - Patients with diabetes mellitus are more frequently hypertensive than age-matched non-diabetic subjects. They are confronted with a markedly increased risk of coronary vascular disease, of progressive nephropathy and renal end-stage diseases. The most common type of hypertension in type I and type II diabetics is essential hypertension, probably as a consequence of insulin resistance and hyperinsulinemia. Hyperglycemia and hypertension are both significantly involved in the progression of diabetic nephropathy. Hence, the modern therapeutic concept consists of optimal blood glucose control and strict blood pressure control. Progression of the nephropathy may be halted in most of the cases by adhering to set limits in mean arterial blood pressure, glycated hemoglobin and urinary albumin excretion rate. Furthermore, a significant decrease in cardiovascular mortality may be achieved. In case the blood pressure targets cannot be met by non-drug therapies and life-style modifications, antihypertensive drug therapy has to be initiated. The selection of antihypertensives should be based on the concomitant diabetes mellitus with its additional cardiovascular risk factors hyperlipidemia and hyperinsulinemia. In general, preference should be given to so called metabolic neutral substances such as ACE inhibitors or calcium antagonists or to alpha-blockers which may have positive metabolic effects. Meanwhile, data from several prospective studies claim that ACE inhibitors and calcium antagonists exert nephroprotective effects beyond their beneficial blood pressure lowering effects, thereby preventing the progression of diabetic nephropathy. However, these drugs should not be uncritically used and we should be aware of their potential adverse effects. The differential therapy of hypertension in diabetes mellitus requires mature consideration before initiation of therapy, an individualized concept of therapy, and careful monitoring during treatment. PMID- 7846898 TI - [The value of metformin in therapy of type 2 diabetes: effect on insulin resistance, diabetic control and cardiovascular risk factors]. AB - In this review article recently published controlled clinical studies of metformin treatment in type-2 diabetic patients are summarized. Several studies demonstrate that body weight decreases and insulin resistance improves--as evaluated by peripheral glucose utilisation--under metformin treatment. HbA1c is lowered by approximately 20% (absolute decrease of HbA1c: 1.0%-1.5%). Since plasma lipid values and plasminogen-activator-inhibitor (PAI-1) concentrations are also lowered under metformin therapy, it currently represents the treatment of choice for the obese group of type-2 diabetic patients. PMID- 7846899 TI - From Kocher to Allgower: the International Society of Surgery/La Societe Internationale de Chirurgie. PMID- 7846900 TI - Manuscripts presented at the 35th World Congress of the International Society of Surgery. Hong Kong, August 1993. PMID- 7846901 TI - Dynamic accumulation of neutrophils in lungs and visceral organs during early abdominal sepsis in the pig. AB - Activation and accumulation of polymorphonuclear leukocytes (PMNs, neutrophils) in the lungs is considered an important mechanism in the pathogenesis of pulmonary dysfunction in association with sepsis. It probably constitutes only part of a general cellular response; and a corresponding reaction has been implicated in other organs during sepsis (e.g., the liver). In this experiment a model was developed that allows study of the dynamic PMN reaction in the lungs and visceral organs during early abdominal sepsis. The animals were divided into two groups. In the septic group (n = 8) a bacterial challenge was attempted through the intraperitoneal administration of Escherichia coli (1 x 10(11)/kg). Five animals served as controls. All animals in the septic group developed bacteremia, leukopenia, and a hypodynamic circulatory response. PMNs were selectively labeled with 111In-oxine. The activity over the organs was followed dynamically with a gamma camera. The animals subjected to peritonitis exhibited a significant increase in 111In-oxine activity (i.e., neutrophil trapping) in the lungs, compared to the controls at 40 minutes and onward during the observation period. A similar picture was seen over the liver and abdomen, with significance after 70 minutes. The findings in this study indicate that accumulation of PMNs is an early phenomenon not only in the lungs but also in the liver during the development of sepsis. The present model offers possibilities for further studies of the cellular reactions during sepsis. PMID- 7846902 TI - Stimulation of wound healing by the immunomodulator LS-2616 (Linomide). AB - LS-2616 (Linomide), a quinoline-3-carboxamide, is an immunomodulator that has been suggested to act on macrophage-like cells. Based on a hypothesis that LS 2616 would stimulate macrophages in the wound and affect the healing process, the effects of LS-2616 on developing granulation tissue were evaluated using a wound model in rats. Subcutaneously implanted cylindrical cellulose sponges were used as an inductive matrix for the ingrowth of granulation tissue. LS-2616 was continuously present at a concentration of 1.2 mg/ml in the drinking water either for 7 days before implantation or starting at the implantation of sponges. Seven days after implantation LS-2616 treatment increased the mean amounts of nitrogen and collagen hydroxyproline over the control level [+20% (p < 0.05) and +59% (p < 0.05), respectively]. The effect was less pronounced in the rats receiving LS 2616 in advance [+7% (NS) and +38% (p < 0.05), respectively]. The mean amounts of nucleic acids and proteoglycans tended to decrease in the rats receiving LS-2616 in advance compared to the control rats [-12% to 13% (NS) and -25% (p < 0.05), respectively]. It was concluded that continuous oral administration of LS-2616 enhanced wound repair in the rat. This immunoenhancement of wound healing results in increased accumulation of collagen. PMID- 7846903 TI - Bronchoplastic procedures for lung cancer: clinical study in 136 patients. AB - Between 1969 and 1991 a total of 136 patients (119 men, 17 women) underwent bronchoplastic procedures for lung cancer. A bronchoplastic procedure with angioplasty was performed in 37 patients. Ages ranged from 30 to 79 years (mean 62 years). The histologic type of cancer was squamous cell carcinoma in 97 patients (70.0%). The 30-day mortality was 5.1% (7 patients), and morbidity was 30.1% (41 patients). The most common complications were bronchopleural fistula in nine (6.6%), stricture or stenosis in eight (5.9%) and atelectasis in eight patients. Local recurrence occurred in nine (6.6%) patients. The overall 5-year survival for patients undergoing bronchoplastic procedures was 37.1%: 60.1% for patients with stage I disease (n = 41), 31.7% for stage II (n = 17), and 29.7% for stage IIIA (n = 66). We conclude that bronchoplastic procedures are effective therapy for selected patients with lung cancer. PMID- 7846904 TI - Association of immunohistochemical p53 tumor suppressor gene protein overexpression with prognosis in highly proliferative human mammary adenocarcinomas. AB - An increasing body of evidence suggests that in addition to conventional histopathologic tumor characteristics, DNA content measurements, cell kinetic data, and investigations of tumor suppressor gene expressions might be of valuable information in breast cancer patients. Against this background we investigated immunohistochemically overexpression of the interphase associated protein proliferating cell nuclear antigen (PCNA) and the mutant p53 protein in routinely paraffin-embedded surgical specimens from 180 breast cancer patients with known nuclear DNA profiles. The mean clinical follow-up was 16 years (range 13-20 years). The percentage of PCNA immunoreactive tumor cell nuclei ranged between < 5% and 60% (mean 13.59 +/- 10.85%). There was a direct association between high levels of PCNA expression (> 20%) and p53 protein overexpression (p = 0.001), high histologic tumor grade (p = 0.009), and DNA aneuploidy (p = 0.019). Mutant p53 protein overexpression was found in 44 of 180 (24%) cases and was significantly related to high histologic tumor grade (p = 0.004), DNA aneuploidy (p = 0.001), and high levels of PCNA expression (p = 0.001). Patients with highly proliferative carcinomas (> 20% PCNA expression) had a shortened distant metastases-free survival when their neoplasms overexpressed p53. In contrast, the distant metastases-free survival of patients with highly proliferative, p53-negative tumors was significantly longer (p = 0.03). Immunohistochemical p53 protein overexpression thus appears to be indicative of an increased malignant potential in breast cancer patients. Highly proliferative tumors composed of p53 immunoreactive neoplastic cells clinically seem to behave more aggressively than the highly proliferative p53-negative tumors. PMID- 7846905 TI - En bloc resection for extensive hepatocellular carcinoma: is it advisable? AB - When the adjacent organ is partially invaded by a hepatocellular carcinoma (HCC), whether to go on an aggressive resection is a difficult but challenging problem. To investigate the worth of en bloc resections, a retrospective controlled study was conducted. During a 9-year period, nine patients (seven men, two women: group I) who had HCC with invasions to extrahepatic adjacent organs had undergone en bloc resections. The adjacent organs included diaphragm (eight cases), adrenal gland (two cases), abdominal wall (one case), and spleen (one case). The patients selected for en bloc resections were those with a solitary tumor without evidence of vascular invasion or intravascular tumor thrombi, daughter nodule(s), or distant metastasis. The evidence was based on preoperative evaluation by ultrasonography, computed tomography, arteriography, and intraoperative ultrasonography. Eighteen matched patients with HCC but no involvement of neighboring organs were selected as controls (14 men, 4 women: group II). Though patients of group I had wider invasion of HCC and more extensive resection, their surgical morbidity, mortality, hospital mortality, disease-free interval, and survival time were similar to those of group II, who had more limited HCC and resections. Eighteen months after operation, the HCC recurrence rate was 44% and 41% in groups I and II, respectively, and the percent survivals were 71% and 63%, respectively. We suggest that in cases of large HCC with local invasion to neighboring organs, aggressive en bloc resection is recommended after appropriate patient selection. PMID- 7846906 TI - Basic study on hepatic resection under partial perfusion cooling. AB - To improve liver quality after reperfusion following partial hepatectomy under total or partial cooling of the liver (HPC), a new perfusion solution containing 100 mM L-histidine (KM solution) was developed. The livers of Lewis rats were removed and perfused for 2 hours at 20 degrees C with lactated Ringer's (LR) solution (group A) or the KM solution (group B). They were reperfused with rat blood at 37 degrees C at a perfusion pressure of 5 cmH2O while monitoring the portal and peripheral tissue blood flows. At the end of reperfusion, bile production, lactate dehydrogenase (LDH) secretion, and tissue adenosine triphosphate (ATP) was measured. Recovery of portal and peripheral tissue blood flows of the group B livers after reperfusion were significantly better than those of group A. Viability of the group B livers, assessed by bile production, tissue ATP value, and LDH release, was preserved better than that of group A livers. In situ total liver perfusion with LR (group C) and KM (group D) solutions for 1 hour at 20 degrees C followed by partial hepatectomy of the left lateral lobe was performed. The 1-week survivals of the group C and D rats were 25% and 100%, respectively (p < 0.05). It was concluded that KM solution is suitable for HPC. PMID- 7846907 TI - Simple method of hyperthermo-chemo-hypoxic isolated liver perfusion for hepatic metastases. AB - As a regional therapy for hepatic malignancy, we developed a simple method of isolated liver perfusion (hyperthermo-chemo-hypoxic). In the present study, the influence of this method on the hepatic tissue and other organs was experimentally evaluated and applied it to seven patients. Experimentally, all dogs survived without hepatic insufficiency and systemic toxicity. Clinically, one patient died on postoperative day 14 of hepatic failure. The reason was that liver temperature reached 43 degrees C, which seemed to be the maximum limit for thermal toxic effect to the human liver. The other six patients well tolerated the perfusion with mild increases of serum aminotransferase and total bilirubin levels and decreases of hepaprastin levels. Serum aminotransferase and total bilirubin and hepaprastin levels returned to normal levels by postoperative day 14. There were no significant differences between the isolated liver perfusion group (n = 7) and hepatectomy-only group (n = 27). Six patients were disease-free during the observation period after the perfusion. This system is a simple, useful method for treating patients with metastatic cancer limited to the liver. PMID- 7846908 TI - Pyogenic liver abscess: studies of therapy and analysis of risk factors. AB - Experience with 46 patients diagnosed with liver abscesses over a 13-year period was reviewed to ascertain the impact of percutaneous versus surgical drainage. In most of the cases the abscesses were diagnosed by sonography or computed tomography. The most common pathogenetic mechanism was ascending biliary tract infection. Of the 46 total patients, 27 were primarily treated surgically, whereas 19 underwent percutaneous drainage. In the surgical group five (18.5%) patients required reoperation. Percutaneous drainage failed in four patients (21.1%). Multivariate stepwise logistic regression analysis revealed that a high APACHE II score, low hemoglobin level, and high serum bilirubin level were significant predictors of a complicated clinical course. Death was related more closely to the overall condition of the patient, as expressed by a high APACHE II score, and the underlying disease (malignancy) than to the mode of therapy. PMID- 7846909 TI - Diagnostic evaluation and surgical management of hydatid disease of the liver. AB - Human echinococcosis is still endemic in some areas of the world, including Mediterranean countries. Because there is no effective medical therapy, surgery remains the principal mode of treatment. A consecutive of 132 patients operated on for liver hydatid disease between January 1977 and February 1993 were analyzed. There were 60 men (45.4%) and 72 women (54.6%) aged 31 to 88 years (mean 56 years). The right lobe of the liver was affected in 68 cases (51.5%), the left lobe in 31 cases (23.5%), and both lobes in 14 cases (10.6%); there were multiple liver cysts in 7 cases (5.3%), concomitant cysts in other parenchymal organs in 4 cases (3.0%), and disseminated intraabdominal hydatid disease in 8 cases (6.1%). Clinical symptomatology consisted of abdominal pain, fever, jaundice, urticaria, and an abdominal mass. Preoperative diagnosis was established using imaging studies: plain abdominal films, ultrasonography, computed tomography, and serologic tests. Three patients (2.3%) underwent simple closure without drainage, 7 patients (5.3%) cyst excision, 4 patients (3.0%) marsupialization, 1 patient (0.8%) left lateral segmentectomy, 15 patients (11.3%) external drainage, 69 patients (52.3%) omentoplasty, and 33 patients (25.0%) combinations of procedures. Postoperative morbidity was low and consisted of hepatic abscess development, wound infection, bowel obstruction, and biliary leaks. Six patients (4.5%) had recurrent disease. One patient died during the postoperative period because of septic complications. Among the surgical techniques we used, excision of the cyst (when feasible) and omentoplasty produced the lowest complication rates and the best clinical results. PMID- 7846910 TI - Impact of transjugular intrahepatic portosystemic shunt on orthotopic liver transplantation. AB - Transjugular intrahepatic portosystemic shunt (TIPS) is being increasingly utilized prior to liver transplantation for portal hypertensive bleeding refractory to sclerotherapy or as initial management of variceal bleeding. The impact of TIPS on subsequent orthotopic liver transplantation (OLT) is uncertain. The purpose of this study was to analyze the effect of TIPS on OLT in terms of operative transfusion requirements, operative time, length of hospital stay, and graft and patient survival. The results in 17 patients undergoing TIPS for control of initial or recurrent variceal bleeding prior to OLT between June 1991 and December 1992 were compared to two other groups undergoing transplantation: 32 control patients with a history of variceal bleeding not treated by TIPS and 11 patients with a previous surgical portosystemic shunt. Compared with control and surgical shunt patients, patients who underwent TIPS had less transfusion requirement for packed red blood cells and fresh frozen plasma during OLT. The operative time and hospital stay of the TIPS patients were slightly, but not significantly, less. In contrast to patients having TIPS, the patients with a history of a previous surgical shunt had an increased requirement for packed red blood cells, longer operative time, and longer stay in the intensive care unit and hospital. Two patients had recurrent variceal bleeding after TIPS; one patient was found to have an occluded stent, and the other patient (with a patent stent) responded to sclerotherapy. Of the 14 patients with ascites, 8 patients improved and 6 patients had complete resolution after TIPS. There were no major complications related to TIPS, although 3 patients had new or recurrent hepatic encephalopathy that was easily manageable.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7846911 TI - Significant prognostic factors by multivariate analysis of 3926 gastric cancer patients. AB - Univariate and multivariate analyses of 3926 selected gastric cancer patients collected between 1981 and 1991 were made to confirm several clinicopathologic prognostic factors and to evaluate the effectiveness of postoperative immunochemotherapy with OK-432, 5-FU, and mitomycin C in stage III gastric cancer. Five-year survival rates for each category of prognostic variables were obtained; and in the univariate analysis, most of the factors (including age, depth of invasion, lymph node metastasis, location of primary tumor, histologic differentiation, and gross type except for sex) showed some significance. Multivariate analysis was conducted and verified significant prognostic factors. Depth of invasion and lymph node metastasis were found to be the most powerful factors (p < 0.001); gross type, location, and histologic differentiation were additional significant factors (p < 0.05). For postoperative treatment, immunochemosurgery was most effective in stage III patients (p < 0.05). In conclusion, we may predict a prognosis for gastric cancer more precisely on the basis of these independent prognostic factors, and immunochemosurgery may be a valuable means to treat advanced gastric cancer. PMID- 7846912 TI - Simultaneous surgery for coronary artery disease and gastric cancer. AB - Of 26 patients who underwent both coronary artery bypass grafting and abdominal surgery at our institution between 1977 and 1992, nine had severe coronary artery disease associated with UICC stage I gastric cancer. They were treated by coronary artery bypass grafting followed by a curative operation for gastric cancer; the initial four patients underwent two-staged surgery (group A), and the most recent five patients underwent simultaneous surgery (group B). The cardiac surgery was performed first in all patients, and in group A the interval between the two procedures was 2 to 7 weeks. There were no significant differences between the two groups in terms of preoperative characteristics: sex, age, preoperative complications, NYHA class, prior myocardial infarction, ejection fraction, cardiac index, number of vessels diseased, or number of grafts. There were no significant differences between the two groups in terms of blood loss during the gastric operation (A: 649 +/- 194 ml; B: 842 +/- 326 ml) or the operating time (A: 371 +/- 106 minutes; B: 343 +/- 46 minutes). Two group A patients had postoperative complications (one had arrhythmia, and one died of sepsis caused by sutural insufficiency). On the other hand, four group B patients had complications (three cases of transient hyperbilirubinemia and one case of postoperative bleeding; none died). The postoperative hospital stay after gastrectomy was not prolonged in group B compared with group A (A: 41.7 +/- 22.7 days; B: 46.0 +/- 25.0 days). In conclusion, simultaneous procedure of coronary artery bypass grafting and gastric surgery can be performed safely, although careful management is indispensable. PMID- 7846913 TI - Total gastrectomy for cancer: is reconstruction or a gastric replacement reservoir essential? AB - Malnutrition is a frequently observed complication of total gastrectomy. Does the mode of reconstructing the alimentary tract bear part of the responsibility? We assessed our experience from January 1975 to 1992 to analyze this issue. A series of 64 total gastrectomy patients [40 men, 24 women; aged 59 +/- 11 (SD) years] were considered. Preoperative and periodic follow-up evaluations were prospectively documented: upper gastrointestinal series, endoscopic examination, complete blood count, serum and liver biochemistry profiles, serum proteins, tranferrin, serum iron and calcium, iron-binding capacity, oral glucose tolerance test, ultrasonography or computed tomography, actual and ideal body weight and performance (AJCC/UICC) assessments. Symptoms were classified by means of Cuschieri's scoring system. Esophageal mucosal changes (edema, hyperemia, erosions, ulcerations) were documented on endoscopy. There were 36 of 58 operative survivors who had no evidence of tumor recurrence and were available for long-term evaluation (12-132 months). An RY loop had been constructed in 25 patients, 5 with a Hunt pouch; 9 had an isoperistaltic jejunal interposition (IJI), 4 with a Kock pouch; and 2 had a Braun loop. A 60 to 70 cm long jejunal limb was always utilized. Statistical analyses were obtained by means of the Student t-test and the equality of medians test. Progressive malnutrition was observed in patients with the Braun (omega) loops, both patients displaying persistent esophagitis and dietary restrictions. Both recovered ideal body weight after remedial surgery that transformed the omega loop into an RY loop. Both RY and IJI loops effectively prevented alkaline esophagitis.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7846914 TI - Curative surgery for gastric cancer: study of 166 consecutive patients. AB - From January 1980 to December 1991 we operated on 295 patients with a gastric carcinoma. In 166 cases (56.3%) surgery was performed with curative intent. In 93 patients (56%) a subtotal gastrectomy was performed, and in 73 cases (44%) a total gastrectomy. In all the cases a D-2 type lymphadenectomy was used. The global morbidity rate was 23%, and in-hospital mortality was 3.6%. The morbidity and mortality rates of these two operations were statistically different. Global 5-year survival estimate for the whole series is 61.3%. Univariate and multivariate analysis according to T and N (TNM classification), the number of positive nodes resected, and the relation of positive per resected nodes, revealed statistically different outcomes. This kind of quantitative classification allowed identification of high risk groups irrespective of site of nodal involvement. Tumors classified as intestinal or diffuse type by the Lauren classification had similar survival curves and 5-year survival estimates (p = 0.834). By univariate and multivariate analysis this classification did not reveal a prognostic value in this group of patients. In our opinion, tumor penetration and lymph node involvement are at present the most reliable prognostic factors available. PMID- 7846915 TI - Early stage gastric lymphoma: is operation essential? AB - To assess the efficacy of primary chemotherapy for treatment of early stage patients with gastric lymphoma, multiple agent chemotherapy was given to patients prior to surgery. Five patients with stages IE and IIE of primary gastric lymphoma (54-65 years of age; three men, two women) were treated with multiple agent chemotherapy prior to gastric resection. In all patients the diagnosis was established by endoscopic biopsy. Two patients had stage IE disease, and three had stage IIE. Histopathologically, there was one diffuse large cell lesion and four diffuse medium cell lesions. All patients received two cycles of VEPA every 4 weeks. On the 16th to 44th day after completion of chemotherapy, total gastrectomy, systematic dissection of regional lymph nodes with resection of the caudal pancreas, and splenectomy were performed. Swelling of the regional lymph nodes was noted in four cases. In all five cases, histologic findings revealed no residual cells of malignant lymphoma in the resected specimen. None of the patients had no evidence of recurrence at 12 to 40 months after surgery. Primary chemotherapy alone thus resulted in the disappearance of malignant cells in stage IE/IIE gastric lymphoma. Our results suggest that surgery may not be an essential procedure for treatment of early stage gastric lymphoma. PMID- 7846916 TI - Selective use of ERCP in patients undergoing laparoscopic cholecystectomy. AB - With the advent of laparoscopic cholecystectomy (LCH) various strategies have been proposed for the management of common bile duct (CBD) stones. In a consecutive series of 1140 patients subjected to LCH, preoperative endoscopic retrograde cholangiopancreatography (ERCP) was attempted in 128 patients (11.2%) and successfully accomplished in 121 (94.5%). Based on the prediction of CBD stones by laboratory tests, ultrasonography, and intravenous cholangiography, prelaparoscopic ERCP was performed in 106 patients (9.3%). CBD stones were identified in 56 patients and benign papillary stenosis in 5 patients (57.5%). Of these 61 patients, 58 (95%) were treated by endoscopic sphincterotomy (ES) and stone extraction followed by LCH after a mean interval of 1.6 days. Three patients with failure of endoscopic ductal stone extraction required open CBD exploration. In 39 of the 106 patients (36.8%) ERCP was negative for ductal stones but revealed unexpected ampullary and pancreatic cancer in two cases. Six patients (of the 106) with preoperative ERCP cannulation failure (5.7%) were managed either by LCH and intraoperative cholangiography or by open CBD exploration. In 22 of the 1140 total patients (1.9%) ERCP was performed at various intervals after LCH. Retained CBD stones were found in eight patients, and ES and ductal clearance was achieved in all eight. There was no mortality among the entire surgical group who underwent perioperative ERCP/ES. Including two cases of ES-related pancreatitis, the overall morbidity was 5.5% (7 of 128). Perioperative ERCP/ES in conjunction with LCH is an attractive approach for patients with cholecystocholedocholithiasis, at least until laparoscopic ductal clearance becomes a standard procedure. PMID- 7846917 TI - Necrotizing pancreatitis: operating for life. AB - Infected necrotizing pancreatitis is the most fulminant variety of this disease. Colonic involvement and retroperitoneal fasciitis are particularly lethal. The reported mortality is up to 50%. The purpose of this study is to review our combined experience at the Princess Alexandra Hospital and the Royal Brisbane Hospital, Brisbane, to determine whether patient survival was related to a particular etiology, treatment, or complication. All patients treated since 1986 with infected pancreatitis who required surgical necrosectomy and then ventilation in the intensive care unit (ICU) were studied. There were 48 patients so managed. The median age of survivors was 52 years, and for those who died it was 64 years (p = 0.001). The etiology was gallstones in 22 and alcoholism in 12. Of the alcoholics, 11 survived and 1 died. Of the patients with gallstones, 13 survived and 9 died. There was an overall mortality of 31%. Survivors were in hospital for a median of 73 days, whereas deaths occurred after a median of 35 days (p = 0.04). Seven patients underwent hemofiltration; five survived, and two died. N-Acetylcysteine has been used in four patients, of whom three survived and one died. The abdomen was left open in 38 patients and kept closed in 10. Although Ranson's criteria at admission to the ICU did not predict survival, it was found that the median APACHE II score in survivors was significantly lower than in those who died (p = 0.025).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7846918 TI - Local versus general anesthesia for Shouldice repair of the inguinal hernia. AB - Since February 1992 local anesthesia (LA) has been used routinely for repair of inguinal hernias at our surgical department. All patients undergoing Shouldice repair of primary uncomplicated inguinal hernia between January 1990 and March 1993 were analyzed retrospectively concerning the need for analgesics, length of stay in hospital, and rate of complications. In addition 50 patients after LA and 50 patients after general anesthesia underwent prospective pain analysis using a visual analogous score and spirometric tests (FEV1 and peak flow). After LA we found less need of analgesics, shorter hospital stays, and fewer complications. The pain level was lower, and ventilatory function was less affected. Repair of the inguinal hernia using LA is a safe method to lower the risk of the operation and to improve the patient's comfort without increasing complications. PMID- 7846919 TI - Results of mandatory exploration for penetrating neck trauma. AB - Management of penetrating wounds to the neck remains controversial despite decades of discussion in the literature. We assessed 393 consecutive stab wounds penetrating the platysma operated at our trauma service between January 14, 1991 and September 30, 1992 to evaluate our policy of mandatory neck exploration (NE). Injury to the common (n = 19 cases), external (n = 7), internal carotid (n = 5), innominate (n = 2), subclavian (n = 20), vertebral (n = 12), facial (n = 2), and intercostal (n = 2) arteries; the external (n = 36), internal (n = 65), subclavian (n = 20), and innominate (n = 4) veins; the pharynx/esophagus (n = 21); and the trachea (n = 28) was considered a positive NE (n = 167). 226 NEs were negative. Except for hemiparesis and bruit, the presence of clinical signs (shock, active hemorrhage, hematoma, surgical emphysema, dysphagia, blowing wound) did not predict a positive NE. Clinical signs were absent in 30% of positive NEs and in 58% of negative NEs. Complications of positive NE included wound infection (n = 7 cases), chyle drainage (n = 6), cerebellar stroke (n = 1), pneumonitis (n = 8), reoperation for recurrent hemorrhage (n = 1), subclavian artery graft occlusion (n = 1), bronchopleural fistula (n = 1), and cerebrospinal fluid leak (n = 1). Negative NEs were complicated by a wound infection in four cases and pneumonitis in one case. The mean hospital stay was 4.3 days for those with a positive NE and 1.5 days for those with a negative NE.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7846920 TI - Expression of basic fibroblast growth factor in hyperplastic parathyroid glands from patients with multiple endocrine neoplasia type I. AB - Primary hyperparathyroidism was investigated using the presence of basic fibroblast growth factor (bFGF) from the immunohistochemical viewpoint with an anti-bFGF antibody in hyperplastic parathyroid glands of patients with multiple endocrine neoplasia type I (MEN-I) and of patients with non-MEN. The results corresponded well with the data from the DNA analysis. Twenty-five hyperplastic parathyroid glands from 11 patients with MEN-I and 38 glands from 20 patients with non-MEN primary hyperparathyroidism were stained immunohistochemically according to the avidin-biotin-peroxidase complex procedure. When 50% or more of the cells appeared uniformly stained, it was judged positively stained. In addition, 18 hyperplastic parathyroid glands from patients with MEN-I patients and 24 hyperplastic parathyroid glands from non-MEN patients were also analyzed for DNA using flow cytometry. The ratio of positively stained hyperplastic parathyroid glands was 72% in MEN-I patients and 18% in non-MEN patients. The difference between the two groups was significant (p < 0.01). The nodules consisted of oxyphilic cells in 7 of 25 hyperplastic parathyroid glands from MEN I patients and in 10 of 38 hyperplastic parathyroid glands from non-MEN patients, and all the cells were positive for bFGF. There was no significant correlation between bFGF staining and the DNA ploidy pattern. bFGF possibly plays a role in the development of parathyroid gland hyperplasia, especially in MEN-I patients. The increase of oxyphilic cells may be correlated with the expression of bFGF. PMID- 7846921 TI - Selective decontamination of the colon before elective colorectal surgery. West of Scotland Surgical Infection Study Group. AB - The controversy over the route of administration of antibiotic prophylaxis in patients undergoing elective colorectal operations persists for oral, parenteral, and a combination of the two routes. The oral antibiotics commonly administered for colorectal prophylaxis, neomycin and eythromycin base, are not absorbed in the gastrointestinal tract (GIT). However, the 4-fluoroquinolones are absorbed in the upper GIT and are excreted in part by the colonic mucosa. Their action is then to remove, or severely depress, the gram-negative aerobic bacilli leaving the anaerobic flora unaffected. This action is the principle of selective decontamination. We have assessed the efficacy of oral ciprofloxacin in a prospective randomized clinical trial in which all patients received piperacillin 4 g i.v. as single-dose parenteral prophylaxis. A group of 327 evaluable patients were randomized to receive ciprofloxacin 500 mg b.i.d. with the preoperative cathartic (group OA, n = 159) or no oral antibiotic (group NOA, n = 168). Postoperative wound infection occurred in 18 (11.3%) patients in group OA and 39 (23.2%) patients in group NOA (chi 2 = 7.2, p = 0.007). Operation-related infection of any type occurred in 23 (14.5%) patients in group OA compared with 55 (32.7%) in group NOA (chi 2 = 14.0, p = 0.0002). The median postoperative hospital stay was 11 days (interquartile range 4.5 days) for group OA and 12 days (interquartile range 8 days) for group NOA (Mann Whitney U test, p = 0.005). Ignoring the treatment group, the median postoperative hospital stay was 17 days (interquartile range 10 days) for infected patients and 11 days (interquartile range 4 days) for those not infected.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7846923 TI - Intraluminal shunt for the thoracic aorta: spinal cord and visceral blood flow in acute studies. AB - Aortic cross-clamping during surgery of the thoracic aorta may result in paraplegia or kidney failure. Difficulties associated with external shunts and bypasses have limited their use. Therefore we compared intraluminal shunting to the nonshunting method of repair in neonatal pigs. Blood flow to the spinal cord and viscera was measured with radiolabeled microspheres before, during, and after thoracic aortic cross-clamping or shunting. Two no-shunt groups were studied: One group was clamped distal to the left subclavian artery for 30 minutes and the other for 1 hour. In the intraluminal shunt group, a shunt was placed in the aorta just below the ligamentum arteriosum for 1 hour; it was then removed and the aorta repaired. In the no-shunt groups, there was virtually no blood flow to the lower cord and viscera during the cross-clamp period. Hyperemia of the lower thoracic and lumbar cord occurred in the no-shunt 30-minute group 15 minutes after clamp removal. In the no-shunt 60-minute group, flow initially returned to the lumbar cord but then declined; and after 1 hour of reperfusion it was significantly lower than baseline. Renal blood flow was even more severely affected in the no-shunt 60-minute group, with minimal recovery during the reperfusion period. In the intraluminal shunt group baseline spinal cord and visceral blood flow were maintained during thoracic aortic cross-clamping, without the problems associated with extracorporeal circulation. PMID- 7846922 TI - Adjunctive antimicrobial therapy for complicated appendicitis: bacterial overkill by combination therapy. AB - Although single antimicrobials with broad-spectrum aerobic and anaerobic coverage are effective in patients with appendicitis, many general surgeons continue to use multiple agents. A prospective, double-blind, randomized trial was designed to detect any clinical correlate of in vitro susceptibility advantage of multiple antimicrobials as adjunctive therapy for 114 patients undergoing operation for complicated appendicitis. There was clinical resolution of intraabdominal infections with no occurrence of postoperative infectious complications in 90% (36 of 40) of the cefotetan group and 86% (31 of 36) of the clindamycin/amikacin group (p = 0.11). The number of patients who had changes in antibiotic therapy due to postoperative complications was higher in the clindamycin/amikacin group: five (12.5%), compared to one (2.8%) in the cefotetan group (p = 0.07). Although Bacteroides fragilis group organisms resistant to cefotetan were identified, none was responsible for the postoperative infections. Adverse drug events in 28% of the cefotetan group and 26% of the clindamycin/amikacin group consisted primarily of transient elevations of liver function tests. Monotherapy with a second generation, broad-spectrum cephalosporin, such as cefotetan, given twice a day is an economical and effective adjunctive regimen in patients with complicated appendicitis for which operation is the definitive treatment. Aminoglycosides and other, more potent antimicrobials should be reserved for resistant organisms or nosocomial infections. PMID- 7846924 TI - Prevention of gastric ulcer or acute gastric mucosal lesions accompanying bleeding after abdominal aortic aneurysm surgery. AB - We have previously reported that the decrease in gastric mucosal blood flow (GMBF) and consumption coagulopathy (CC) mainly contribute to the development of postoperative bleeding in the upper gastrointestinal (GI) tract in patients with abdominal aortic aneurysm (AAA). In the present study, we investigated whether our treatment for patients with low GMBF or CC effectively prevented postoperative gastric bleeding induced by gastric ulcer or acute gastric mucosal lesion. Preoperative endoscopic examinations in 66 patients with AAA and 60 patients with arteriosclerosis obliterance (ASO) revealed that 50.0% of AAA and 16.6% of ASO patients had accompanying gastric ulcer or multiple erosions. In 38 AAA and 36 ASO patients, GMBF was measured using a laser Doppler flowmeter through an endoscope. The GMBF was severely impaired in AAA patients and moderately impaired in ASO patients. The platelet counts and fibrinogen levels were significantly decreased in these 38 AAA patients compared with controls. Furthermore, fibrinogen degeneration product (FDP) levels in 36.8% of AAA patients were more than 20 micrograms/dl. Based on these findings, patients with low GMBF were treated postoperatively with H2-blocker, and patients with CC were treated preoperatively with heparin. After these treatments, only 1 of 38 AAA patients developed postoperative upper GI tract bleeding and could be treated conservatively after 1988, whereas in prior years postoperative upper GI tract bleeding developed in 7 of 112 patients, three of whom required emergency surgery. PMID- 7846926 TI - [Methods, topography and mechanisms of radiofrequency ablation of AV-nodal reentry tachycardia]. AB - Three different methods of radiofrequency catheter ablation of AV nodal reentrant tachycardia were investigated in 128 patients. Results, relapses, and complications using anterior approach (n = 15), moved catheter (n = 20), and posterior-inferior approach (n = 93) were compared. Eight mechanisms of ablation of AV nodal reentrant tachycardia were distinguished: 1) Ablation of fast pathway (n = 8), 2) of slow pathway (n = 22), 3) modification of fast (n = 12), 4) slow (n = 54), or 5) both pathways (n = 13), 6) Ablation of fast and modulation of slow pathways (n = 4), 7) ablation of slow and modulation of fast pathways (n = 12), and 8) ablation of both pathways (n = 3). The criteria of diagnosis of these mechanisms and a mapping grid of Koch's triangle were proposed. The fast pathway is located in the anterior septum in a region with identical amplitudes of atrial and ventricular deflections and the slow pathway could be found posteriorly in a more ventricular location. The anatomical location of the slow pathway differed more widely than the location of the fast pathway. The best method with lowest risk could be recommended as the ablation of the slow pathway. This method implicated the lowest incidence of complications. We observed relapses in 12 patients during control studies 30 min, 3-5 days, and 3-6 months after first ablation procedure. These arrhythmias could be ablated in a second attempt in eight and in a third procedure in four patients. With increasing experience the radiofrequency catheter ablation of AV nodal reentrant tachycardia will be the method of first choice in patients with recurrent tachycardia. PMID- 7846925 TI - Vascular involvement in Behcet's disease: 8-year audit. AB - Behcet's disease is a multisystemic disorder characterized by recurrent ulcers of the mouth and genitalia and relapsing iritis. Four types of vascular lesion are recognized in Behcet's disease: arterial occlusions, aneurysms, venous occlusions, and variceal development. The incidence of vascular involvement reported in the literature ranges from 7% to 29%. The aim of this study was to determine the rate of vascular involvement in Behcet's disease at our hospital between 1983 and 1992. Of 1200 patients with Behcet's disease, 173 (14.4%) had venous manifestations and 19 (1.6%) had arterial manifestations (in some patients more than one organ was involved). In the group of patients with venous manifestations, there were 154 (12.8%) with venous thrombosis, 17 (1.4%) with vena cava superior syndrome, 5 (0.4%) with inferior vena cava syndrome, 5 (0.4%) with varices, 2 with upper extremity venous thrombosis, 1 with internal jugular vein thrombosis, 1 with cavernous sinus thrombosis, and 1 with hepatic vein thrombosis. In the arterial manifestation group there were 7 femoral, 3 abdominal, 3 popliteal, 2 iliac, 2 pulmonary, 1 axillary, and 1 carotid artery aneurysm as well as 3 arterial occlusions. We concluded that vascular surgeons dealing with young adults should bear Behcet's disease, an uncommon clinical entity, in mind. PMID- 7846927 TI - [Amiodarone therapy after sotalol-induced torsade de pointes: prolonged QT interval and QT dispersion in differentiation of pro-arrhythmic effects]. AB - In a 70-year-old patient with sotalol-induced torsade de pointes, QT-dispersion in the 12-lead surface ECG was determined in an attempt to evaluate the role of this method in determining risk factors for the development of proarrhythmic effects. After recovery from torsade, the patient was successfully treated with amiodarone over a 3-month follow-up period. Whereas the degree of QT prolongation was comparable during amiodarone therapy to that observed with sotalol, QT dispersion was markedly less (47 ms) than during previous treatment with sotalol (77 ms). During drug-free control, QT dispersion was 43 ms. This case-report indicates that determination of QT dispersion can provide information with respect to identification of patients prone to class III antiarrhythmic drug induced proarrhythmic effects. PMID- 7846928 TI - [Accelerated idioventricular rhythm]. AB - The term accelerated idioventricular rhythm describes an ectopic ventricular rhythm with 3 or more consecutive ventricular premature beats with a rate faster than the normal ventricular intrinsic escape rate of 30 to 40 beats per minute, but slower than ventricular tachycardia. Accelerated idioventricular rhythm differs from ventricular tachycardia by additional features such as the onset with a long coupling interval, the end by a gradual decrease of the ventricular rate or increase of the sinus rate and, last but not least, by a good prognosis. Clinically, accelerated idioventricular rhythm can occur in any form of structural heart disease and occasionally in adults or children without structural heart disease. Accelerated idioventricular rhythm most often can be seen in patients with coronary artery disease. Its occurrence after thrombolysis during acute myocardial infarction is a marker of successful reperfusion. Since accelerated idioventricular rhythm is usually hemodynamically well tolerated and not associated with malignant ventricular tachycardias; as a rule, no specific treatment other than care of the underlying heart disease is necessary. The present overview discusses electrocardiographic criteria, possible mechanisms, and the clinical significance of accelerated idioventricular rhythms. PMID- 7846929 TI - [Intermittent focal cerebral ischemia in hypotension due to pacemaker syndrome]. AB - A pacemaker syndrome manifested as transient sensoric aphasia in a 68-year-old woman with a VVI-pace-maker implanted after SA-block. The attack occurred during long-term blood pressure recording and Holter monitoring. Borderline hypotension was documented during ventricular pacing which induced a retrograde excitation of the atrium. Clinical investigations excluded any intracranial abnormality, any source of embolism or stenosis of extra- and intracranial cerebral arteries. Cerebral blood flow measurements revealed a significant increase during pacing at elevated heart rate. Therefore, a device for AV-sequential pacing was implanted and basic pacing rate was elevated. The present case report indicates that focal and not only global cerebral ischemia can be produced by an impairment of systemic hemodynamics due to hypotension and a pacemaker syndrome. Improvement of cerebral blood flow during pacing is an unexpected finding contrasting with the concept of autoregulation. In addition, pacemaker implantation should be discussed in patients with transient cerebral perfusion deficits if an improvement of cerebral blood flow is documented along with rising heart rate. PMID- 7846930 TI - [Improvement in oxygen consumption by frequency-adjusted pacemaker stimulation: effect of intrinsic heart rate]. AB - More than half of all pacemaker systems currently implanted function rate adaptively. Our objective was to determine which patients benefit from rate adaptive pacing in terms of improvement in maximum performance and aerobic capacity. Thirty patients with implanted accelerometer-driven, rate-adaptive pacemakers were examined ergospirometrically and patient symptom-limited while walking on a treadmill. The patients were divided into three groups depending on the intrinsic heart rate achieved during maximum workload: Group I achieved < or = 90 bpm, Group II achieved 90 to < or = 110 bpm, Group III achieved > 110 bpm. Group I demonstrated a significant increase (p < or = 0.01) in maximum oxygen uptake from 16.4 +/- 5.6 ml/kg/min with fixed-rate pacing to 23.2 +/- 11.1 ml/kg/min (+41.5%) with rate-adaptive pacing. At the anaerobic threshold, oxygen uptake significantly increased (p < or = 0.01) from 11.8 +/- 2.7 ml/kg/min to 15.7 +/- 5 ml/kg/min (+33.1%). Group II showed an increase in maximum oxygen uptake from 23.3 +/- 5.4 ml/kg/min to 25.3 +/- 4.9 ml/kg/min (+8.5%, p < or = 0.05) as well as an increase in oxygen uptake at the anaerobic threshold from 15.9 +/- 2.6 ml/kg/min to 18.1 +/- 2.9 ml/kg/min (+13.8%, p < or = 0.05) with rate-adaptive pacing. Group III demonstrated no significant difference between the two pacing methods (from 25.6 +/- 9.4 ml/kg/min to 25.9 +/- 9.3 ml/kg/min and from 15.8 +/- 5.5 ml/kg/min to 16.3 +/- 6 ml/kg/min). No difference in maximum oxygen uptake and in oxygen uptake at the anaerobic threshold was evident between the three groups when paced rate-adaptively (n.s.).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7846931 TI - [Pectoral cardioverter-defibrillator implantation combined with transvenous bipolar defibrillation electrodes]. AB - Ultimately, implantable cardioverter-defibrillators (ICD) will one day be implantable like present pacemakers. However, due to the size of the pulse generator and the low defibrillation efficacy of monophasic shocks, only a few selected patients have been implanted transvenously-pectorally. Therefore, we have prospectively investigated whether a transvenous-pectoral approach is in general feasible with a new downsized ICD capable of delivering biphasic shocks. Out of 33 patients, 76% received a bipolar transvenous defibrillation lead system. In the first 13 consecutive patients, a randomized crossover study showed that this high efficacy was above all achieved by a superior defibrillation efficacy of the biphasic waveform in comparison to the monophasic waveform (69% vs. 23%; p = 0.03). Not a single patient could be defibrillated exclusively with the monophasic waveform. In a further 15 consecutive patients, a crossover study showed that a position of the transvenous anode within the Vena anonyma instead of the Vena cava superior is, in general, not superior (87% vs. 80%; p = 0.67). Only one patient could be exclusively defibrillated with the V. anonyma position. Intraoperatively, no complications occurred and all but one patient received a pectoral implantation of the pulse generator. Postoperatively, in five patients local complications related to the ICD system were seen; two needed a surgical revision. In two patients movements of the left shoulder joint were temporarily restricted. Thus, in the majority of patients a new downsized ICD capable of biphasic shocks can be implanted transvenously-pectorally like a pacemaker. PMID- 7846932 TI - [Acceptance and quality of life after implantation of an automatic cardioverter/defibrillator]. AB - The cardioverter defibrillator therapy has proven to be effective in preventing sudden cardiac death. However, there are only few reports that this kind of therapy will change the life of patients. Therefore, the purpose of the present study was to further evaluate this item. The quality of life of 195 patients with implanted cardioverter defibrillator (ICD) was investigated with the help of a questionnaire and a personal interview. An increased or unchanged quality of life was reported by 89% of patients. The acceptance of the therapy was high (92% of the patients). Anxiety was reported by 25% of patients, the estimation of the received shocks was depending on the amount of shocks. No influence was seen by the operative technique of implantation (epicardial versus transvenous lead system) with regard to the opinion of the patients toward the operation stress. The ICD gives a feeling of safety to 90% of the patients and this kind of therapy is marked by a high degree of acceptance. PMID- 7846933 TI - Atrial baffle procedures for complete transposition of the great arteries: natural course of sinus node dysfunction and risk factors for dysrhythmias and sudden death. AB - 359 patients after the Mustard (275) or Senning (84) operations for transposition of the great arteries were followed-up for a mean of 103.7 (range 0.4 to 204) months. 259 patients had postoperative 24-h Holter recordings. In 129 Mustard children serial (mean 4.4) postoperative Holter recordings were available for evaluation. Criteria based on Holter and scalar electrocardiograms at normal sinus node functions were used for rhythm analysis. Postoperative dysrhythmias appeared in 70% of the patients: sinus node dysfunction in 62.8%, second or third degree atrioventricular block in 3.2%, sustained atrial tachycardia or atrial flutter in 4.5%, and significant ventricular arrhythmia (Lown 2-5) in 21.4%. The prevalence of sinus node dysfunction increased slightly from 50.8% during the first 2 postoperative years to 64.4% in patients more than 10 years postoperatively. Fifteen patients (4.2%) died suddenly during follow-up. By multivariate analysis severe tricuspid regurgitation and/or right ventricular dysfunction and uncontrolled supraventricular tachydysrhythmias were identified as the two significant risk factors for sudden death. PMID- 7846934 TI - [Balloon dilatation of postoperative and congenital aortic isthmus stenoses]. AB - From July 1987 to December 1992, 52 patients underwent balloon-angioplasty of aortic coarctation at three units of pediatric cardiology in Austria (Graz = 35 patients, Innsbruck = 15 patients, and Vienna = 2 patients). 35 patients had postoperative and 17 had native coarctation. Mean age at intervention was 7 10/12 years with 2 patients under 1 year and 5 patients over 18 years old. The mean relation balloon diameter-coarctation diameter was 2.6 +/- 0.9. The blood pressure gradient between upper and lower extremities decreased from a mean of 44 +/- 16 mm Hg to 15 +/- 13 mm Hg (p < 0.0001). The diameter of the stenosed segment was increased from 5 +/- 3 mm to 8.5 +/- 3.5 mm (p < 0.0001). Native coarctation showed a significantly better result in respect to decrease of the gradient (36 +/- 12 mm Hg) than did postoperative coarctations (25 +/- 19 mm Hg) (p < 0.03). 13 patients did not respond adequately to angioplasty. 10 patients out of this group had tubular narrowings and belonged to the group of postoperative coarctations, whereas localized stenoses in native coarctations gave the best results. Localized wall irregularities were found in 4 patients with native coarctation. Balloon angioplasty of postoperative and native coarctations in childhood and adolescence is a secure and effective means of treatment and should be considered as therapy of first choice. The best results can be found in the group of the circumscript type of stenoses in native coarctation, whereas long and tubular stenoses in the group of postoperative coarctations give less satisfying results. PMID- 7846936 TI - [Atrial fibrillation: current aspects. Munster, October 1993. Proceedings]. PMID- 7846935 TI - [Capillary hemangioma of the heart: a case report]. AB - In a 52-year-old man, within the left ventricle, a globular mass 1.5 cm in diameter was detected incidentally by echocardiography. Selective coronary angiography showed a mobile patch of hypervascularity suggesting the vascular nature of the cardiac mass. The patient was operated and a pedunculated tumor originating from the anterolateral papillary muscle was removed. Histological examination revealed a benign capillary hemangioma. Six months after surgery the patient was reevaluated by echocardiography. There was no evidence of tumor recurrence. PMID- 7846937 TI - [Atrial fibrillation and atrial flutter: pathophysiology and pathogenesis]. AB - Chronic atrial fibrillation is a very common arrhythmia affecting 2 to 4% of the population older than 60 years of age. Atrial fibrillation may cause disabling symptoms and serious adverse effects, such as impairment of cardiac function or thromboembolic events. It is also associated with an increased risk of death. In the past, the most common underlying heart disease related to chronic atrial fibrillation was rheumatic heart disease. Today, this disease occurs relatively rarely. Nevertheless, the incidence of atrial fibrillation is likely to increase in the future due to the aging of the population, since its prevalence increases with age. In most patients with chronic atrial fibrillation, the arrhythmia can be attributed to organic heart disease or metabolic disorders. In western countries ischemic and hypertensive heart disease (including sick sinus syndrome) and alcohol (holiday heart syndrome) are numerically more important than the classical causes of atrial fibrillation--rheumatic heart disease and thyrotoxicosis--which are declining in incidence. Overall, atrial fibrillation is associated with an increased mortality. In about 15% of patients with chronic atrial fibrillation, no underlying cardiac or metabolic abnormality can be found, also the arrhythmia can itself give right to atrial dilatation. Atrial fibrillation consists most probably of several coexisting reentrant wave fronts of activation within the atria. Atrial activation and atrial fibrillation is as follows: multiple wavelets sweep round the atria in irregular, shifting patterns; completed reentrant circuits are the exception. Atrial flutter in its common form is characterized by evidence of atrial activity at a rate of 250-350 bpm, and usually almost exactly 300 bpm.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7846938 TI - [Amiodarone and verapamil/quinidine in treatment of patients with chronic atrial fibrillation]. AB - Rapid, reliable and safe reestablishment of sinus rhythm is the major aim of pharmacologic treatment in patients with chronic atrial fibrillation. The mainstay of therapy in this arrhythmia has been quinidine. More recently, amiodarone was shown in noncomparitive studies to be superior to class IA agents under certain conditions. In 40 patients with atrial fibrillation persisting for 4 weeks up to 2 years, the efficacy and safety of either quinidine and verapamil (days 1 to 3, quinidine 1,500 mg/day; days 4 to 6, quinidine 1,500 mg+verapamil 240 mg/day) or amiodarone therapy (days 1 to 3, amiodarone 1,200 mg/day intravenously; days 4 to 14, amiodarone 800 mg/day orally) were randomly examined. Responders continued on their effective medication for 3 months. Thereafter, all patients were treated with a fixed regimen of quinidine (480 mg/day) plus verapamil (240 mg/day) for up to 2 years. During atrial fibrillation, quinidine reduced mean ventricular cycle length by 40 ms (-5%), quinidine and verapamil increased mean cycle length by 57 ms (8%) and amiodarone by 192 ms (28%, p < 0.01). In addition, quinidine and verapamil had a characteristic "rate-smoothing" effect on atrioventricular conduction during atrial fibrillation. The rhythm was converted to sinus rhythm after quinidine in 5 (25%) of 20 patients and after the combination of quinidine and verapamil in 11 (55%) of 20 patients. Amiodarone restored sinus rhythm in 12 (60%) of 20 patients. Overall, a shorter duration of atrial fibrillation (p < 0.05) and a smaller left atrial size (p < 0.01) were predictive of successful conversion of the arrhythmia.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7846939 TI - [Sotalol and quinidine/verapamil (Cordichin) in chronic atrial fibrillation- conversion and 12-month follow-up--a randomized comparison]. AB - Atrial fibrillation is one of the most common arrhythmias, leading at least in a subset of patients to severe symptoms (palpitations, weakness, syncope), and to hemodynamic impairment especially in the clinical setting of left ventricular dysfunction. Thus, in many cases restauration of sinus rhythm is indicated because of the negative effects of reduced cardiac output. Quinidine has been the first line drug for many years and has been proven to be highly effective especially when combined with Verapamil. But there is growing concern about using quinidine and other class I-anti-arrhythmic agents because of some hints in clinical trials for increased longterm mortality on these drugs. This study was undertaken to test the efficacy of Sotalol, a beta-blocker with additional strong class-III antiarrhythmic action, compared to a fixed combination of Quinidine and Verapamil for conversion of chronic atrial fibrillation and maintenance of sinus rhythm after medical or electrical cardioversion. To avoid early proarrhythmic effects, potassium values in the range of "high"-normal values (> 4.3 mval/L) were tried to be obtained. 82 patients were randomly assigned to receive either Sotalol or Quinidine/Verapamil. There was no difference between the groups as far as the underlying heart disease, duration of atrial fibrillation (mean 219 days) and other clinical features including echocardiographic parameters were concerned. The dose of the drug was weight-related individually adjusted, and the drug was continued thereafter. If sinus rhythm could not be established at that time, electric cardioversion was performed and the drug was continued in lower dosage thereafter.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7846940 TI - [Atrial fibrillation and flutter: experimental and clinical electrophysiology]. AB - Several early publications already provided indirect evidence that atrial fibrillation is due to multiple, simultaneously activated reentrant wavelets. However, direct proof of this "multiple wavelet hypothesis" could only be obtained by means of activation mapping, which was conducted more recently in experimental as well as clinical atrial fibrillation. The surgical techniques for the treatment of atrial fibrillation are based on the knowledge on the pathophysiology of the arrhythmia. Similarly, early studies already suggested single, large reentrant circuits as the mechanism underlying atrial flutter. It could be demonstrated that a surgical lesion between the superior and inferior vena cava provided the basis for stable reentry around this large anatomical obstacle. But not only anatomical, but also functional obstacles, may be found in the center of a reentrant circuit. In typical atrial flutter, a long arc of functional conduction block extends from the inferior to the superior vena cava. In atypical atrial flutter, the central obstacle may be found anywhere in the right or, less frequently, in the left atrium. These experimental findings are supported by the clinical observation that a lesion in the area between the inferior vena cava and the nearby AV ring reproducibly terminates typical atrial flutter. PMID- 7846941 TI - [High frequency catheter ablation of left-sided manifest accessory conduction pathways during sinus rhythm and in continuous atrial fibrillation]. AB - Atrial fibrillation is frequently initiated during radiofrequency catheter ablation of accessory pathways. It has been generally believed that initiation of atrial fibrillation may complicate the localization of accessory pathway. Therefore, most centers currently perform cardioversion in order to continue the ablation session. The purpose of the present study was to assess the feasibility and the electrophysiologic criteria for successful radiofrequency catheter ablation of left sided accessory pathways during atrial fibrillation in patients with WPW-syndrome. Radiofrequency ablation was performed in 87 patients with left sided manifest accessory pathways during atrial fibrillation (n = 16) or during sinus rhythm (n = 71). The criteria for localization of accessory pathways were recording of stable accessory pathway potentials, local ventricular activation preceding the onset of the intrinsic flection of the unipolar electrogram and a QS pattern of the unipolar electrogram. Overall, the accessory pathways were successfully interrupted in 85/87 patients (98%). During the first ablation procedure, abolishing of accessory pathways was achieved in 15 of 16 patients (94%) during atrial fibrillation compared to 64 of 71 patients (90%) during sinus rhythm (n.s.). The total procedure time and fluoro time was significantly shorter during atrial fibrillation than during sinus rhythm (161 +/- 91 min vs. 216 +/- 128 min, p < 0.05, and 31 +/- 24 vs. 41 +/- 26 min. p < 0.05, respectively). Thus, it is feasible and very effective to perform radiofrequency ablation of left-sided manifest accessory pathways during atrial fibrillation. Precise localization of accessory pathway during atrial fibrillation seems even easier than during sinus rhythm as indicated by shorter procedure and fluoro times in the atrial fibrillation group. PMID- 7846942 TI - [Atrial fibrillation and the autonomic nervous system]. AB - The autonomic nervous system plays an important role in the genesis of various cardiac rhythm disorders. Experimental studies have indicated that in atrial fibrillation particularly vagal activity may have a decisive influence on the electrophysiologic properties of atrial myocardium. In patients with paroxysmal atrial fibrillation, a carefully taken history and electrocardiographic findings obtained during Holter monitoring can help to distinguish vagally mediated from adrenergically mediated atrial fibrillation. The former is considered to represent a form of lone atrial fibrillation affecting particularly males aged 40 to 50 years. The arrhythmic episodes manifest themselves most often during the night lasting from minutes to hours. There is a lack of tendency towards the development of permanent atrial fibrillation. Digitalis glycosides or beta receptor antagonists are not helpful in the therapy of this form of atrial fibrillation whereas class I antiarrhythmic drugs have been shown to be more effective. Adrenergically mediated atrial fibrillation is in general less frequently observed than the vagally-induced form. In patients with episodes of atrial fibrillation provoked by emotional or physical stress, the diagnosis of adrenergically mediated atrial fibrillation should be suspected. The episodes of atrial fibrillation occur mostly during daytime. beta-receptor antagonists play a major role in the treatment of this form of atrial fibrillation. PMID- 7846943 TI - [Clinical aspects and prognosis of atrial fibrillation]. AB - Atrial fibrillation is alleged to be one of the most frequently occurring arrhythmia. Many patients with atrial fibrillation are asymptomatic. Others, however, complain of palpitations and paroxysmal atrial tachycardias. And especially in patients with preexisting heart failure, atrial fibrillation can lead to a clear worsening of cardiac output. Not only rheumatic but nonrheumatic atrial fibrillation as well are associated with an increased risk of thromboembolic complications. Arterial hypertension, a history of thromboembolism as well as signs of heart failure are clinical parameters which additionally increase the risk of embolism. On the other hand, this increased risk does not hold true for younger patients with idiopathic atrial fibrillation and is also low in patients with only one additional risk factor. Thus, it would indeed be false to anticoagulate every patient with atrial fibrillation. In each case, a careful individual risk stratification including an extensive history and detailed clinical examination should be performed before deciding on antithrombotic therapy. PMID- 7846944 TI - [Atrial fibrillation--the value of transesophageal echocardiography]. AB - Transesophageal echocardiography is superior to transthoracic echocardiography in detection of superior to transthoracic echocardiography in detection of left atrial thrombi and spontaneous echocardiographic contrast, particularly in patients with atrial fibrillation and spontaneous echocardiographic contrast, thrombus formation is likely. In addition to the morphology, Doppler echocardiography can be used to access left atrial appendage function. In patients with lone atrial fibrillation, reduced velocity was found in 60%, and no flow was detected in the left atrial appendage in 40%. These patients had a higher risk for spontaneous echocardiographic contrast and thrombus formation. As left atrial thrombi are found in 12% of patients, transesophageal echocardiography can be used to avoid cardioversion in these patients, which may lead to cerebral or peripheral emboli. Despite ruling out left atrial thrombi, embolism occurred after cardioversion when anticoagulation was insufficient or not performed. Current investigations are undertaken in order to demonstrate the clinical benefit of transesophageal echocardiography in patients with left atrial fibrillation. PMID- 7846946 TI - [Cardioversion in atrial fibrillation]. AB - Atrial fibrillation is often not only associated with palpitations, but also with hemodynamic detoriation and high incidence of thromboembolic complications. However, since the establishment or maintenance of a sinus rhythm with antiarrhythmic drugs may also lead to an increased mortality, sinus rhythm should only be achieved by external electrical cardioversion and should be limited to those patients who have been shown to, or may be expected to markedly improved by this intervention. Internal electrical cardioversion should be restricted to those patients who fail external cardioversion. Implantable devices to automatically cardiovert atrial fibrillation are still under clinical investigation and will require further evaluation. PMID- 7846945 TI - [Prevention of embolisms in atrial fibrillation: anticoagulation and antiplatelet therapy]. AB - Over the past five years, the results of six prospective randomized trials have set new standards in the primary and secondary prevention of thromboembolism in "nonvalvular" ("nonrheumatic") atrial fibrillation. On the one hand, they have confirmed the increased risk of stroke in these patients amounting to about 5% per year and an annual recurrence rate after a recent transient ischaemic attack or minor stroke of 12%. On the other hand, the results of these trials have unanimously demonstrated a > or = 60% risk reduction with oral anticoagulation at an acceptable risk of major bleeding complications. A reduced intensity of anticoagulant therapy with a target INR of 2.0-3.0 is effective in most of these patients. Both clinical and echocardiographic features allow the identification of subgroups at low or high risk of thromboembolic complications and provide the basis for the individual benefit-to-risk assessment of anticoagulant therapy. Aspirin is currently recommended as a second choice therapy for patients who are poor candidates for oral anticoagulants or who are considered to be at low risk for thromboembolism. PMID- 7846947 TI - [Problems with anti-arrhythmia therapy in atrial fibrillation]. AB - The prevalence of atrial fibrillation increases with age, with rates of 2-5% among people over the age of 60 years. Patients may be highly symptomatic or may suffer from hemodynamic compromise or thromboembolic complications. However, antiarrhythmic drug treatment implies problems like the choice of the suitable drug, the individual benefit/risk profile, and alternative treatment strategies. Experimental and clinical data support the concept that atrial fibrillation in the clinical setting in most cases is due to multiple reentrant wavelets. A critical number of three to six simultaneously circulating reentrant wavelets seems to be necessary for the maintenance of atrial fibrillation. Consequently, antiarrhythmic drugs may terminate or prevent atrial fibrillation by prolonging the refractory period or slowing conduction velocity, thereby leading to conduction block. In clinical practice, antiarrhythmic therapy may act by slowing of the ventricular rate due to depression of atrioventricular nodal conduction or by termination and/or prevention of atrial fibrillation. Digitalis is commonly used for the control of the ventricular rate. Betablocking drugs and verapamil are effective in this respect during exercise performance. For antiarrhythmic conversion and prophylaxis of recurrences of atrial fibrillation, class Ia (e.g., quinidine), Ic (e.g., flecainide and propafenone), and class III (e.g., amiodarone and sotalol) drugs of the Vaughan Williams classification are useful. Presently, no general concept exists whether medical or electrical cardioversion should be used as a first line approach for termination of atrial fibrillation. In the individual patient with atrial fibrillation, the potential benefit of restoring sinus rhythm must be weighed against the morbidity and mortality of the arrhythmia and the morbidity and mortality of the antiarrhythmic agents used.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7846948 TI - [The use of digitalis glycosides in atrial fibrillation]. AB - The role of cardiac glycosides for conversion of atrial fibrillation to simus rhythm is controversially discussed. In a prospective study, 45 patients with paroxysmal atrial fibrillation were randomly assigned to one of three treatment groups (of 15 patients each). Group I received oral digoxin, three times 0.125 mg up to twice 0.25 mg daily; group II oral digoxin twice 0.125 mg and quinidine hydrogen sulphate 750-1000 mg daily; group III oral digoxin three times 0.125 mg and flecaimide 200-300 mg daily. During a mean observation period of 11 months, digoxin alone was significantly less effective (p < 0.05) in reducing or suppressing paroxyms of atrial fibrillation than digoxin plus quinidine or flecainide. The use of digoxin remains a mainstay of treatment for rate control in atrial fibrillation. To convert atrial fibrillation to sinus rhythm, however, the addition of a type I or III antiarrhythmic agent is necessary. PMID- 7846949 TI - [The pro-arrhythmic effects of anti-arrhythmia agents]. AB - Proarrhythmia is defined as the provocation of new cardiac arrhythmias or the aggravation of preexisting arrhythmias by antiarrhythmic drugs. The possible types of manifestation of proarrhythmia are manifold. With respect to prognosis, drug-induced ventricular tachyarrhythmias seem to be of particular importance. Monomorphic ventricular tachycardia and ventricular tachycardias of the torsade de pointes type have to be distinguished. The former seem to be mainly based on reentrant mechanisms, while the later is supposed to result from triggered activity. Drug-induced monomorphic tachycardia is most often observed during therapy with drugs which slow conduction (class I agents, proarrhythmic potency: IC > IA > IB). Patients with depressed left ventricular function and previously documented life-threatening tachyarrhythmias are the most susceptible candidates. Torsade de pointes can be preferentially observed during therapy with antiarrhythmic drugs which prolong myocardial repolarization (i.e. class IA and class III agents). Electrolyte abnormalities and/or bradycardia are factors which often predispose to the development of this particular type of proarrhythmia. The physician who prescribes antiarrhythmic drugs must be aware of the different types and clinical manifestations of proarrhythmia. This is necessary to assess the degree of proarrhythmic risk and to determine the benefit/risk ratio before the start of drug therapy. PMID- 7846950 TI - [Drug prevention of recurrence in paroxysmal and chronic atrial fibrillation]. AB - In many patients with paroxysmal or chronic atrial fibrillation, long-term antiarrhythmic drug therapy is performed to prevent recurrences of atrial fibrillation or to reduce the incidence of paroxysmal attacks of atrial fibrillation. The results of several studies on the efficacy of antiarrhythmic drugs in patients with paroxysmal atrial fibrillation have revealed that the incidence of recurrent attacks of atrial fibrillation can be reduced and the duration of arrhythmia free intervals can be prolonged by antiarrhythmic drug therapy. However, complete prevention of atrial fibrillation can be achieved only in a minority of patients. At present, there is no evidence that antiarrhythmic drug treatment of patients with paroxysmal atrial fibrillation might worsen the prognosis by an increase in cardiac mortality induced by antiarrhythmic drugs. In patients with chronic atrial fibrillation, the recurrence rate of the arrhythmia can be significantly reduced by antiarrhythmic drug therapy within the first year of treatment. However, there is evidence that antiarrhythmic drugs might worsen the prognosis when compared to patients with atrial fibrillation not treated with antiarrhythmic drugs. Accordingly, the indication for antiarrhythmic drug therapy to prevent recurrences in patients with chronic atrial fibrillation has to be made restrictively and should be largely based on the symptomatic status of the patients. Antiarrhythmic drug therapy seems to be indicated only in patients who are significantly symptomatic or compromised by the arrhythmia. In patients without or with only mild symptoms, medical therapy with the aim to slow the ventricular response with digitalis, calcium antagonists or betablocking agents seems to be more adequate. Currently, with respect to efficacy and safety, there is no antiarrhythmic drug that has been proved to be superior to others and that can thus be recommended as the drug of first choice for patients with paroxysmal or chronic atrial fibrillation to prevent recurrences. The choice of the optimal antiarrhythmic drug should be made by taking individual factors (e.g., etiology of the arrhythmia, patient compliance, liver and renal function of the patient, additional medical therapy) into account. Major problems during long-term antiarrhythmic drug therapy may arise in patients with pre-existing sinus node dysfunction or conduction disturbances of the atrioventricular node. In addition, the conversion of atrial fibrillation with relatively slow ventricular rates to the atrial flutter with fast ventricular rates that is occasionally observed during treatment with class I-antiarrhythmic drugs may complicate long-term therapy.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7846951 TI - [Subtypes of muscarinic receptors--aspects of their physiologic significance for controlling heart rate in the human]. AB - The cDNAs for five different muscarinic cholinoceptors have been cloned. The biochemical and physiological relevance of the m1, m2 and m3 receptors is understood in many aspects. The pharmacological defined M1, M2 and M3 related to antagonists binding studies closely correspond with those cloned. We compared effects of atropine and of the subtype selective M-cholinoceptor antagonists pirenzepine and AF-DX 116 in humans. Dose- or time-response curves have been established for heart rate. Plasma samples were drawn in parallel with the effect measurements and analysed for drug concentrations. Subtype-selective radioceptor assays of the samples served to estimate the respective receptor occupancy in vivo. After low dosis of pirenzepine (M1-selective blockade) a negative chronotropic effect on heart rate could be observed. After high doses of pirenzepine or atropine (M-unselective blockade) the wellknown tachycardia appeared in parallel with occupancy of both the M2 and M3 subtypes. AF-DX 116 induced a tachycardia without a decrease of salivary flow in agreement with its selectivity profile (M2 > M1 > M3). Gastric emptying was only slightly inhibited by AF-DX 116 but nearly completely by a very high dose of pirenzepine blocking M1 , M2- and M3-cholinoceptors. The negative chronotropic effect on heart rate of a low dose of pirenzepine (M1 selective) was multi-folded by pretreatment with isoprenaline but disappeared during bicycle exercise. The implications of the functional M cholinoceptor heterogeneity in humans revealed by antagonists are discussed according to its possible importance for the control of autonomous nerve system. PMID- 7846952 TI - [Non-pharmacologic therapy of atrial fibrillation]. AB - Since patients with recurrent atrial fibrillation are prone to recurrences, even under treatment with antiarrhythmic agents, alternative treatment modalities are being sought. Today, the non-pharmacological treatment modalities such as modification or ablation of the AV node or the operative procedures ("maze" or "corridor" operation) do not cure these patients. The non-pharmacological therapies are indicated if severe symptoms are due to high ventricular rate with hemodynamic compromise. In such cases, His bundle ablation followed by rate adaptive pacing can achieve control of symptoms in the majority of patients. In the future, more refined techniques for ablation or the introduction of automatic atrial cardioverters will extend therapeutic options. PMID- 7846953 TI - [Hepatocellular carcinoma]. PMID- 7846954 TI - [Liver cancer: diagnostic possibilities and value of pathology]. AB - The high differentiation of treatment options for patients with liver carcinoma resulted in more extensive questions to the pathologist. Resection rate for HCC is about 30%, thus the multitude of diagnoses has to be made on biopsies. An histological (rarely cytological) diagnosis has to be the section specimens with regard to typing, grading, R classification and results of studies on molecular pathology of this tumor. Essential statements on resection specimens include pTNM classification, R classification, typing, and grading. Based on these data, more parameters expected to be of prognostic value can be evaluated. PMID- 7846955 TI - [Hepatocellular carcinoma: molecular biology aspects]. AB - Chronic liver diseases, in particular chronic HBV and HCV infections, frequently progress to liver cirrhosis and HCC. The molecular events underlying hepatocarcinogenesis are not yet well defined. It appears likely, however, that HCCs result from a stepwise carcinogenesis: due to chronic liver disease there is liver cell necrosis, inflammation and regeneration with a high mitotic rate of liver cells. In this setting, chromosomal DNA rearrangements occur which may result in the activation of cellular oncogenes or inactivation of tumor suppressor genes. Viral genes or gene products as well as cofactors, such as alcohol or aflatoxins, may make a specific contribution to these molecular events. Apart from the molecular aspects of hepatocarcinogenesis, for clinical practice the implementation of measures to prevent or treat chronic liver diseases should reduce the incidence of HCCs, one the most frequent malignancies in some areas of the world. PMID- 7846956 TI - [The status of liver transplantation in therapy of hepatocellular carcinoma]. AB - The state of the art in liver transplantation for hepatocellular carcinoma is presented through a review of our own data and the pertinent literature. Preoperative evaluation should stage the tumor precisely to allow therapeutic consequences to be drawn. The major obstacle is correct preoperative lymph node staging which is currently possible in less than 50% of the patients. If candidates are selected for transplantation, early vascular exclusion should be performed during the operation to prevent tumor cell dissemination. The results of recent reports on liver transplantation for hepatocellular carcinoma following strict selection criteria are encouraging. Patients with cirrhosis and hepatocellular carcinoma (diameter < 10 cm) fared significantly better after liver transplantation than after resection. Patients with uninodular or binodular disease and tumors smaller than 3 cm even showed a recurrence-free 3 year survival of 83% [3]. We conclude that for some patients liver transplantation offers the only chance for cure. Only prospective, controlled trials will define the patients that profit most from liver transplantation. The rising need for donor organs will currently restrict this modality to a highly selected group of patients. Once effective adjuvant therapies become available more patients might, however, become eligible. PMID- 7846957 TI - [Noradrenaline-assisted selective chemoembolization of hepatocellular carcinoma]. AB - Despite the postulated tumour affinity of Lipiodol is liver dysfunction after chemoembolization of hepatic malignancies common. Vasoconstricting action of noradrenaline to protect non malignant tissue was studied. 70 patients with unresectable HCCs (UICC IV: 61%) were treated via percutaneous catheter. After noradrenaline (0.1-0.8 mg) induced and documented vessel constriction a suspension of Lipiodol (5-8 ml) and Mitomycin C (10-20 mg) was injected. In addition minced dehydrated dura suspended in Lipiodol occluded the major tumour feeding vessels. 120 (73%) of a total of 164 chemoembolizations were performed after intrahepatic noradrenaline (0.1-0.8 mg) bolus injection. Arterial perfusion of non malignant liver parenchyma was significantly reduced in 95%. 24 hours later selective tumor retention of lipiodol was noticed in 67%. Side effects were fever (79%), thoracoabdominal pain (67%), nausea and emesis (43%) and tachycardia (15%). There were two treatment related deaths: one each from liver failure and cardiac arrest. By WHO response criteria there were 17 (23%) partial remissions (PR), 34 (49%) stable diseases (SD) and 20 (28%) patients had progression (PD). The median survival time from initiation of treatment was 312 days. Bilobal and multiple tumors reduced survival time (90 days). These findings suggest that noradrenaline guided chemoembolization is feasible in Europe and even in patients with pylethrombosis well tolerated. PMID- 7846958 TI - [Hepatocellular carcinoma: systemic chemotherapy, perspectives of gene or immunotherapy]. AB - The systemic chemotherapy of hepatocellular carcinoma with single agent or combination chemotherapy has not resulted in reproducible response rates above 20%. Correspondingly, an effect on the survival of the treated patient population has not been shown so far. The most effective single agent is doxorubicin, which should, however, not be used outside of clinical studies in the systemic treatment of hepatocellular carcinoma. The results of hormonal treatment of hepatocellular carcinoma are also disappointing: the response rates of agents like tamoxifen, ketoconazol, nilutamid, LHRH-agonists or megestrol are usually below 10% and the survival of patients can not be improved. New approaches that are currently tested in vitro and in mouse models are pharmacological or immunological interactions with tumor cells that make use of molecular biology techniques and are summarised under the term "gene therapy". Some of these projects are in clinical phase I studies and first results can be expected in the next three to five years. PMID- 7846959 TI - [The Chang mesocaval side-to-side shunt, an alternative shunt form after previous operations and portal vein thrombosis]. AB - Over the time period from July 01, 1983 to June 01, 1993, 15 patients with portal hypertension and relapsing bleedings from esophageal varicosis were treated with Chang's mesocaval side-to-side shunt at the Department of General Surgery, University Hospital of Gottingen. All patients were pre-operated in the upper abdomen or exhibited thrombosis of the portal vein. While five cases revealed a prehepatic block, ten patients had an intrahepatic block, based on cirrhosis of the liver (Child classification A or B). The time required for operations was 180 +/- 32 minutes; the pressure in the portal circulation decreased by 56%. In three cases, patients suffered relapsing bleedings despite of regular shunt conditions. Complications which were due to the procedure were seen in two patients (one revealed intraabdominal posthemorrhage, followed by therapy-resistant coagulopathy; the other patient exhibited stenosis of the anastomosis). One patient developed encephalopathy. Given a rigid indication, we regard the procedure described herein an alternative to the mesocaval interposition shunt, and we consider the low rate of thrombosis (so far < 10%) without continued postoperative anticoagulant therapy as well as the avoidance of an interposition as important advantages of this technique. PMID- 7846960 TI - [Effectiveness of regular after-care in R0-resected rectal carcinoma]. AB - Regular follow-up programs after radical resections of rectal carcinoma have been introduced in numerous hospitals. The main goal of a regular follow-up program is the early diagnosis of tumor recurrence in the asymptomatic stage to allow further radical resection. We evaluated the efficiency (quote of further resections of asymptomatic tumor recurrences) of regular follow-up after resection of 288 rectal carcinomas. 88 patients developed recurrent disease (47 primary locoregional recurrence, 27 distant metastasis, 14 locoregional and distant recurrence). Only 31 patients were asymptomatic at the time of recurrence (metastasis 55.6%, locoregional recurrence 31.9%, local and distant recurrence 7.1%; p < 0.05). In 31 patients (13 asymptomatic, 18 symptomatic) further R0 resection was possible. Locoregional recurrences were resected more often following anterior resection than after abdominal perineal resection. With 13 radical resections of asymptomatic recurrence the efficiency of regular follow-up was only 4.5%. Therefore efficiency alone does not justify regular follow-up examinations. Follow-up still makes sense for psychosocial support, diagnosis of metachronous colonic carcinoma, treatment of postoperative complications and critical evaluation of the results of surgery. Furthermore the follow up data can be used to plan adjuvant therapy studies. PMID- 7846961 TI - [Involvement of platelet activating factors in pathologic leukocyte-endothelium interactions in the liver after hemorrhagic shock]. AB - INTRODUCTION: Microcirculatory disturbances and increased adhesion of leukocytes to the hepatic endothelium immediately following hemorrhagic shock have been observed. It is currently discussed, that mediators released by activated macrophages may have regulative functions for these alterations. The aim of the study performed was to investigate the effects of platelet activating factor (PAF) by application of PAF-receptor antagonists in respect to disorders of liver microcirculation and leukocyte adhesion following hemorrhagic shock. METHODS: Sprague-Dawley rats, anesthetized with pentobarbital, were exposed to hemorrhagic shock by depression of the mean arterial blood pressure (MABP) to 40 mmHg for 60 min by controlled blood removal. Three hours following adequate volume replacement together with blood retransfusion (60%) and at normalized MABP as well as supranormal cardiac output levels, the livers of the animals were investigated by intravital microscopy in respect to leukocyte adhesion and microcirculation. Evaluation of the microcirculation of 5 liver lobules/animal was performed on SVHS recorded images using a computer-assisted image analysis system. Three shock groups (n = 6 rats) and one sham-operated control group (n = 8) were compared. Shock/NaCl group received 0.1 ml NaCl 0.9% 15 min prior to shock induction and 1 min prior to shock therapy i. v., respectively. Shock/BN group received a total of 10 mg/kg of the PAF-antagonist BN 52021 (Dr. Braquet, Paris) and Shock/WEB group 2 mg/kg of the PAF antagonist WEB 2086 (Boehringer, Ingelheim), respectively in 2 injections with identical volume. RESULTS: The course of hemodynamic parameters MABP and cardiac output were comparable in all 3 shock groups. Metabolic parameters such as acid-base state and hematocrit values did not reveal differences. Evaluation of liver microcirculation indicated in all shock groups a reduction of sinusoidal diameters and a slight increase of velocity of leukocytes. The significantly increased temporary adhesion of leukocytes with an adhesion time shorter than 20s in the shock/NaCl group (adhesion index 154.1 +/- 63.2s/100 leukocytes; mean +/- SD) was reduced significantly by the PAF antagonists BN 52021 (82.2 +/- 24.2) and WEB 2086 (86.0 +/- 30.0). Permanent adhesion with an adhesion time longer than 20s was increased significantly particularly in zone I of the liver acinus (portal region) in all shock groups without specific effects of the PAF antagonists. CONCLUSIONS: Liver microcirculation following adequately treated hemorrhagic shock was disturbed, as indicated by narrowed sinusoids and increased adhesion of leukocytes. PAF seems to have no effect on sinusoidal narrowing in this period, however, it seems involved in temporary adhesion of leukocytes. The relevance of these early changes following hemorrhagic shock in respect to the development of organ dysfunction should be further addressed. PMID- 7846962 TI - [Friedrich Trendelenburg 1844-1924: a tribute on his 150th birthday]. AB - Life and scientific work of Friedrich Trendelenburg are gratefully appreciated on the occasion of his 150th birthday. The education by his parents, the great impressions gained during a visit in Scotland as a young man and the molding influence of his academic teacher v. Langenbeck are presented. There was only a short time when he was the head of the surgical department of the Friedrichhain Hospital in Berlin, because his real aim was an academic career. In the presented paper his famous merits in science and practical work as well as his enormous aura as the director of the surgical departments of the universities of Rostock, Bonn and Leipzig are described. Trendelenburg was an always strictly scientifically acting surgeon. His technical inventions and new operative procedures were of high value with a worldwide acknowledgement. Objectivity, modesty and human grandeur were the eminent characteristics of this hero of surgery who never looked for personal appreciation but always got it. PMID- 7846963 TI - [Pouch sites in gastrointestinal surgery]. PMID- 7846964 TI - [Reconstruction of reservoir organs of the gastrointestinal tract]. PMID- 7846965 TI - [Jejunum pouch after total gastrectomy--clinical and scintigraphic studies of function and quality of life]. AB - The formation of a pouch is a surgical procedure to restore the lost of reservoir function after resection of the stomach. After total gastrectomy the intestinal passage can be reconstructed by a jejunal pouch performing a Siewert/Peiper esophagojejunoplication. Regarding the postoperative quality of life we supposed that there is an advantage for this reconstruction method compared to simple esophagojejunostomy. The following study investigated whether the pouch reconstruction by jejunoplication can develop a reservoir function and therefore a better clinical course compared to jejunostomy. Without evidence of a local recurrence after total gastrectomy 18 patients with and 18 without pouch reconstruction were evaluated by alimentary scintigraphy for at least 6 months after operation. Only patients were included with a tumor stage not exceeding T2 (UICC). The results of the transit times with a solid radioactively labelled test meal were correlated with the complaints and nutritional status of the patients, evaluated with a standardized questionary for creating an individual score note. The transit in a jejunal pouch follows a linear decreasing function and is significantly slower compared to the exponential passage of the jejunostomy. Both patterns remain still significantly accelerated compared to the physiological ranges of gastric emptying. Patients with a pouch judge their postoperative individual state better than patients with simple jejunostomy indicated with an on average symptom related score note better than 3. As long as the tumor stage is associated with a beneficial prognosis and the tumor localisation allows the reconstruction by an esophagojejunoplication the formation of a pouch after total gastrectomy is recommended because of an improved transit pattern and clinical course. PMID- 7846966 TI - [Technique and significance of the Kock pouch]. AB - The development of the continent ileostoma (Kock pouch) is delineated and its results are reviewed. Leading centers achieved continence in more than 90%. High rates of complications and relaparotomies in the early phase could be significantly reduced by technical modifications. Development of ileoanal pouch procedures have, however, confined the continent ileostomy to special indications. PMID- 7846967 TI - [Experiences with the Kock continent ileostomy]. AB - First experiences with Kock-pouches (KP) in 34 patients operated on between 1987 and 1992 with stapler-stabilization of the nipple-valve are reported. 18 patients (52.9%) suffered from ulcerative colitis (CU), 7 patients (20.6%) from familiar adenomatous polyposis (FAP) and 9 patients (26.5%) from Crohn's colitis (CC). Each patient was inappropriate for ileo-anal pouch-procedure (IAP) and desired fecal control. Special indications for KP were identic with medical contraindications for IAP in 52.9%, refusal of IAP in 17.6% and loss of sphincter in 29.4%. In 25 patients with CU and FAP the rate of specific early complications was 24%. In 5 of 6 cases operative correction was successful. The rate of success was 96%, which could be maintained over time with a rate of 8.3% of late complications, that had to be corrected. In 9 patients with CC the rate of success was 77.8% due to two pouch resections in the early postoperative course. It decreased to 66.6% in the further course due to another resection later on. In CC, 3 out of 7 patients had repeated reoperations due to inflammatory complications of the disease not impairing pouch-function. A severe pouchitis was only observed in 2/18 patients with CU (11.1%). Thus, high rates of success in KP surgery can be achieved for CU and FAP-patients. But it has to be kept in mind, that KP is not in concurrence with IAP, it is also an alternative to Brooke ileostomy. Patients with CC are less appropriate, because the necessity for repeated reoperations due to recurrent disease reduces significantly the overall benefit of the patients, even if continence is preserved. PMID- 7846968 TI - [Pelvic pouches]. AB - Since Nissen performed his first ileo-anal anastomosis for a benign large bowl disease in 1933, restorative proctocolectomy has undergone substantial developments, thus especially in the last two decades. Different pouch designs (J , S-, W- and H-pouch) obtain normal defecation in patients treated with proctocolectomy. Many groups prefer the J-Pouch for it's technical simplicity and good results. PMID- 7846969 TI - [Technique and results of the ileoanal pouch after proctocolectomy]. AB - Nowadays restorative proctocolectomy and ileal pouch-anal anastomosis represent the standard procedure in the treatment for ulcerative colitis and familial polyposis. Although various pouchdesigns are described, the J-pouch is the one most frequently used. This study reviewed 311 operations of restorative proctocolectomy and ileal pouch-anal anastomosis between January 82 and December 93. The indication was ulcerative colitis in 234 and familial polyposis in 77 cases. In 67% of the cases the standard two-stage procedure involving secondary ileostomy closure was chosen. Due to the complex nature of the operation, postoperative morbidity--which is higher for ulcerative colitis--must not be undermined. Complete exstirpation of the pouch was required in 4.2% of the patients with ulcerative colitis and in one case with familial polyposis. In 12.4% and 1.3% a severe pouchitis was found in ulcerative colitis and familial polyposis respectively. In general postoperative functional results were satisfactory. Continence was established in over 90% of the patients while the mean stool frequency was 6 per day. PMID- 7846970 TI - [Colo-anal pouch after total rectum resection]. AB - The coloanal anastomosis is in low rectal cancer for oncological reason the appropriate procedure, if the sphincter is not involved, but is followed often by impaired continence. For better continence a colonic-J-pouch anal anastomosis was performed in 11 consecutive operated patients after rectal resection predominantly for rectal cancer. The clinical and physiological results in 10 out of 11 patients having a colonic-J-pouch anastomosis (CPA) and in 11 out of 21 patients having a straight coloanal anastomosis (SAA) were compared. 1 CPA patient and 2 SAA patients were incontinent. 7 SAA and no CPA patient had minor incontinence. 9 CPA and 2 SAA patients were fully continent. The stoolfrequency per 24 hours was 3 in the CPA while it was 6 in SAA on average (p < 0.005) 5 months after closure of the protective colostomy. There was no significant difference in anal resting pressure and squeeze pressure and in the frequency of the sphincterinhibitory reflex in the two groups. The compliance was different in both groups (4.4 in CPA vs 1.9 in SAA patients) but not significantly. The patients with a colonic J-pouch had a better continence than the patients with a straight coloanal anastomosis. The better continence is associated with an higher compliance, which results in a more favorable reservoir function. PMID- 7846971 TI - [The colo-anal pouch: indications, function and results]. AB - Low anterior resection of rectal cancer with preservation of the anal sphincter has comparable recurrence and survival rates when compared to abdominoperineal excision. Stool frequency and leakage rates are high after coloanal anastomosis. The colonic J-pouch improves function. Endosonographic tumor stages ES T1 and ES T2 for cancer in the distal third rectum and ES T3 tumors in die middle third rectum are indications for rectal resection with preservation of the sphincter and reconstruction with the colonic pouch. In 33 patients the technique was safe, with no deaths and no reoperation. Three diverting colostomies are not yet closed. 25 patients are perfect continent, two are incontinent for gas, three have minor and one patient major incontinence. Only one patient has more than three bowel movements in 24 hrs. For selected cancers of the distal half of the rectum total resection with preservation of the anal sphincter is a safe operation. Good function is provided by the colon J-pouch. PMID- 7846972 TI - [Techniques of follow-up examination of the ileoanal and colo-anal pouch]. AB - For the assessment of ileoanal and coloanal pouches different diagnostic tests should be applied. Apart from case history and rectal digital examination the most important methods comprise a radiologic evaluation of the pouch and its afferent loop as well as anorectal manometry for the assessment of pouch motility and sphincter function. Increasingly transanal endosonography is being used for the precise examination of size, volume, and shape of ileoanal and coloanal pouches. The afferent loop is also easily accessible to endosonography, e.g. for evaluation of bowel wall morphology and function. Furthermore, in cases of coloanal pouches following an oncologic lower anterior resection, endosonography is used in follow-up examinations for the detection of local tumor recurrence. PMID- 7846973 TI - [Malignant lymphoma of the small intestine as a cause of small intestine perforation]. AB - The malignant non-Hodgkin-lymphoma is the main cause of spontaneous extraduodenal small intestine perforation. This rare incidence occurs as a consequence of an enteropathic associated affection manifested extranodally, mostly in the higher part of the jejunum. The diagnosis is made after a spontaneous perforation. The risk of a recurrent perforation is high. In a female patient we made the diagnosis not before resecting the small intestine. PMID- 7846974 TI - [Experimental studies of the value of the pouch after gastrectomy]. AB - AIM OF THE STUDY: Clinical relevant follow up parameters were used to examine the influence of an additional pouch for reconstruction after gastrectomy in Roux-en Y technique and jejunal interposition in rats. METHOD: 3 months old rats were gastrectomized and reconstructed as follows: Roux-en-Y (RY n = 50), jejunal interposition (JI n = 55) and each of these combined with a jejunal J-pouch (RYP n = 33; JIP n = 26). Up to 9 months postoperatively body weight, hemoglobin, iron, total protein and amylase as well as the pouch volume and esophageal mucosa were followed up. RESULTS: All gastrectomized animals show deficiencies compared to non operated controls (n = 6). The severity depends on the type of reconstruction. The RY group overall has the lowest values; hemoglobin (9 month) 4.2 g/dl, body weight (6 mon) 77% total protein (9 mon) 47 g/l. JI causes less defect: Hb (9 mon) 8.3 g/dl, BW (6 mon) 109%, TP (9 mon) 61 g/l. Animals with additional pouch have better values than those with the similar type of reconstruction but without pouch; RYP: Hb (9 mon) 12.7 g/dl, BW (6 mon) 95%, TP (9 mon) 55 g/l; JIP: Hb (9 mon) 15.1 g/dl, BW (6 mon) 107%, TP (9 mon) 64 g/l. Hemoglobin and total protein do not significantly differ between the combination of interposition and pouch and the control group (p > or = 0.05). The volume of the pouch increases 1:3 during 6 months. Animals with pouch do not show severe reflux esophagitis as do those without pouch. CONCLUSION: With global follow-up parameters the postgastrectomy deficiency can be evaluated in this experimental model. Interposition combined with the pouch is superior to the other methods as demonstrated by less deficiencies. Furthermore the pouch serves as a functional food reservoir and as reflux barrier. PMID- 7846975 TI - [Postoperative behavior of gastrectomized rats in an open field after Roux-Y reconstruction with and without pouch]. AB - In a series of experimental studies on rat behavior following reconstructive surgery after gastrectomy the effects of Roux-Y-Pouch-technique (RY-P) as compared to Roux-Y (RY) alone were observed. 12 rats with RY-P and 13 rats with RY were tested on days 100-105 post surgery using the Open-Field-test paradigm. Feeding behavior and weight were additionally controlled. Data analysis of repeated measurement design (ANOVA) revealed significant group x time-interaction between type of reconstruction and exploratory behaviors (p < .01). Moreover, RY P rats consumed more food (p < .001), had higher weight gain (p < .01), and tended to more normal defecation. Overall, results favour the more physiological type of reconstruction. PMID- 7846976 TI - ["The elderly man of Westring". On the death of Prof. Dr. med. Dr.h.c. Hermann Goecke]. PMID- 7846977 TI - [The importance of genetic factors for development of breast cancer]. AB - It is well documented that breast cancer aggregates in certain families suggesting a genetic etiology for this cancer. Numerous epidemiologic studies have shown that women with a first degree relative (mother, sister) with breast cancer have double the risk of developing this cancer when compared to women in the general population. More recent studies have shown that the magnitude of the risk of developing breast cancer is dependent on the age at diagnosis and the number of relatives affected. Aggregation of breast cancer in families in itself does not clarify the true nature of the underlying factors which could be genetic or due to familial resemblance in other risk factors. Complex segregation analyses of breast cancer families suggest that breast cancer susceptibility is inherited in some families as an autosomal dominant trait. Recently, a breast cancer susceptibility gene, BRCA1, has been mapped to chromosome 17q12-q21 through linkage analyses. BRCA1 appears to play a role in families with a large number of breast cancer cases who have developed breast cancer before the age 45, and/or who have breast and ovarian cancer cases. The risk of cancer for female carriers of the BRCA1 mutation has been estimated to be 87% for breast cancer and 44% for ovarian cancer by the age of 70. BRCA1 seems to play a role in only a proportion of affected families and it is likely that other genes are also involved. In the majority of breast cancer families with two or three cases, BRCA1 appears to play a small role. PMID- 7846978 TI - [Changes in surgical treatment of cystic teratoma--620 cases]. AB - Among 3492 patients with ovarian tumors subjected to operation between 1/1957 and 3/1994 at the Department of Obstetrics and Gynaecology at the University of Rostock 620 (17.8%) cases of teratomas were found. Histology findings, age, tumor size, bilaterality and malignity of these 620 cases were analyzed. The histologic differentiation yielded 604 (17.3%) mature teratomas (dermoid cysts), 15 monodermale and 1 immature teratoma. Division of total period in the time before and after 1990-since then we have got the possibility of laparoscopic operation reveals that presumably by increasing use of ultrasound a decrease in mean age at time of diagnosis from 40.2 +/- 20 to 30.7 +/- 12 as well as in tumor size (9 +/- 4 resp. 4 +/- 2 cm) has been achieved. A secondary malignant transformation of epithelial component has been found in 0.5% (3/604) and bilaterality in 11% of the cases. With regard to general rules of laparoscopic operations the intact dermoid cyst enucleation is recommended in premenopausal and extirpation in postmenopausal women. For opening, reduction of volume, and removal of the dermoid cyst from the abdominal cavity, an endo-bag or endo-catch respectively should be used. PMID- 7846979 TI - [Recurrent vulvar carcinoma at the Halle/S. University Gynecologic Clinic 1971 1990--diagnosis and results of therapy]. AB - We analysed the recurrences of vulvar carcinoma diagnosed at the Gynecological University Hospital of Halle/S. between 1971 and 1990. 37 cases were evaluated. 75.7% of all patients had a local recurrence of the vulvar region; no distant site of recurrent tumour outside the pelvis was described. Only 48.6% of the recurrences occurred within a period of two years after primary therapy. The five year survival after diagnosis of recurrent disease was 56%. The influence of potential prognostic factors on survival was evaluated by a multivariate analysis according to the Cox model. Only the localisation of recurrence represented a statistically significant prognostic factor. Patients with a local recurrent carcinoma had a significant survival advantage as compared to those cases with inguinal or pelvic node tumour (p = 0.0021). PMID- 7846980 TI - [Treatment of endometriosis with the GnRH agonist leuprorelin acetate depot (Enatone-Gyn monthly depot): a multicenter study]. AB - In an open, non-randomized prospective phase-III-study the clinical and endocrine efficacy as well as the safety of leuprorelin acetate depot (Enantone-Gyn Monats Depot) were investigated. The therapeutic results of 198 patients, gathered from 5 university institutions and two city hospitals, are reported. Endometriosis was classified by the revised American Fertility Society score (r-AFS) before and at the end of treatment. Serum levels of LH, FSH, prolactin, estradiol, progesterone, androstenedione, testosterone and leuprorelin acetate were determined by radioimmunoassay. The mean total r-AFS score changed as follows: before surgical intervention during first-look laparoscopy 21 +/- 24 at the end of first-look laparoscopy 15 +/- 19 at the end of the GnRH-treatment 8 +/- 14 During leuprorelin acetate treatment the r-AFS stages changed as follows: [table; see text] Using the scoring system 85.2% of the patients improved. Relief of dysmenorrhoea could be achieved in 95.4%, relief of dyspareunia in 64% and of pelvic pain in 69.4% of patients. Baseline hormone levels dropped sharply during treatment. [table; see text] Androstenedione, testosterone, blood pressure, body weight, haematological parameters, liver enzymes, creatinine, electrolytes and HDL-/LDL-cholesterin remained more or less unchanged. Side effects being hot flushes, sweating, sleeplessness, headache, nausea, depression and vaginal dryness were due to estradiol deprivation. In 135 patients resumption of menstruation occurred in 95.6% within the first three months post-treatment. 23 patients of whom 21 were judged as infertile, became pregnant immediately after treatment was finished. The study results confirm the efficacy of leuprorelin acetate depot in the treatment of even advanced stages of endometriosis. PMID- 7846981 TI - [Increasing age in surgical interventions]. AB - The percentage of octogenerians and older patients receiving surgical therapy has increased from 1.1% to 4.6% in the last 10 years in the department of gynecology and obstetrics of the AKH Celle. The indications for surgery can be subdivided into two categories in these very old patients: total or subtotal prolapse often accompanied by a large degree of individual suffering and carcinoma or at least suspected carcinoma. The postoperative complication rate amounted to 6.8% which is only insignificantly more than the general complication rate. An improvement of quality of life is the primary factor for the surgical indication. PMID- 7846982 TI - [Treatment of osteoporosis by the gynecologist]. AB - At least one of four women is suffering from osteoporosis with fractures of vertebrae, forearm or hip. Maintenance of bone-mass is a crucial argument for long-term estrogen replacement for prophylaxis of osteoporosis. 2 mg estradiol or 0.625 mg conjugated estrogens, or 50-100 micrograms estradiol percutaneously are equally sufficient for prevention of osteoporosis. The additional use of a progestagen in women with intact uterus may support the antiresorptive effects of estrogens. Improvement of patients' compliance of estrogen substitution- administered today in only 25% of postmenopausal women in Germany--by sufficient information upon estrogen replacement therapy provided by the medical community is an awarding task for physicians and scientists engaged in the field of menopause and prevention of osteoporosis. PMID- 7846983 TI - [Hysteroscopic therapy of recurrent hemorrhage in long-term anticoagulant therapy]. AB - Women suffering from menorrhagia during anticoagulation therapy are risk patients for surgery. The successful hysteroscopic treatment of 2 of these patients is described. PMID- 7846984 TI - [Vaginal ultrasound cervix imaging in pregnancy--predictive value of suspicious findings on the subsequent course of pregnancy]. AB - To evaluate the use of serial measurement of cervical length and width of internal os by means of vaginal ultrasound 144 pregnant women were examined prospectively. We hypothesized, that cervical length and width of the internal os would be significantly different in normal patients and those with preterm labor or cervical incompetence. Predictive validity of suspicious findings indicating the occurrence of preterm labour and cervical incompetence in further course of pregnancy should be assessed. Anamnestic, sonographic and outcome data were analysed. To assess sensitivity, specifity, positive and negative predictive values, different values of cervical length and width of internal os between 20 and 27 weeks were analysed. Significant differences of cervical length and width of internal os in normal and pathologic pregnancies could be documented early in pregnancy course. By further investigation early suspicious findings indicating the developing pathology were found only for the subgroup with cervical incompetence. Sensitivity of vaginal ultrasound examination between 20 and 27 weeks indicating the whole pathologic collective was only 30%, whereas up to 55.5% of pregnancies complicated by cervical incompetence were detected. Specifity (up to 95%) and negative predictive value (90%) were high. The results show that cervical examination by vaginal ultrasound allows early detection of developing cervical incompetence. The high specifity and the high negative predictive value may be useful to exclude cervical incompetence in clinically unclear cases thus helping to avoid unnecessary therapeutical interventions. PMID- 7846986 TI - [Meeting of the "Pulse Oximetry in Obstetrics" Study Group in Frankfurt, 9 June 1994]. PMID- 7846985 TI - [Metabolic acidosis in the 32nd week of pregnancy--uncontrolled diabetes in pregnancy, dehydration or sequela of tocolysis?]. AB - We describe a case of keto- and lactic acidosis in a 22 year old, healthy woman hospitalized for preterm labor at week 32 of gestation. One former pregnancy was normal. Blood glucose level at admission was 115 mg/dl after 8 mg of betamethasone. Continuous salbutamol infusion was used for management of preterm labour. 18 hours later, the patient complained about nausea and dyspnoea followed by tachypnoea and hyperventilation. Blood gas analysis showed severe metabolic acidosis (ph 7.25, BE-17.5, pO2 114 mm Hg, pCO2 15.5 mm Hg). At this moment blood glucose level was 178 mg/dl. Ketone bodies in urine were positive, serum lactate level was also elevated at 8.6 mmol/l. Cesarean section was performed because of prolonged fetal bradycardia. 6 months post partum type-I-diabetes could be excluded. We conclude that this case of acidosis was due to both, beta-2 adrenergic treatment and beginning gestational diabetes. PMID- 7846987 TI - Laparoscopic adrenalectomy in pheochromocytoma and Cushing's syndrome. Reflections about two case reports. AB - Laparoscopic adrenalectomy is possible as well on the left as on the right side using a percutaneous transabdominal approach. The exposure of the glands seems better than it could be achieved with an open method. In combination with intraoperative infusion of nicardipine, a calcium-channel blocker, the laparoscopic removal of a pheochromocytoma was performed safely and under stable conditions. In case of Cushing's syndrome, the laparoscopic approach reduces the problems related to poor healing. In all cases of laparoscopic adrenalectomy, this approach could offer the clear advantages of smaller incisions, reduced postoperative pain and incisional discomfort as well as complications related to large and invasive procedure and finally allows quicker recovery. Moreover, conversion to open surgery remains always possible, if needed. PMID- 7846988 TI - Surgical management of hepatocellular carcinoma in genetic haemochromatosis. AB - From 1975 to 1989, 51 patients presenting with hepatocellular carcinoma complicating genetic haemochromatosis were managed in our institution. Twenty-one patients underwent a laparotomy. Laparotomy was limited to surgical exploration or palliation in 8 patients in whom the tumour was deemed unresectable. Thirteen patients underwent either a partial hepatectomy (11 patients) or a total hepatectomy and liver transplantation (2 patients). Actuarial survival at 1 and 3 years following partial hepatectomy was 56% and 40% respectively. There was one hospital death in the resection group and in the transplant group. Only 3 patients have remained free of tumour recurrence after a mean follow-up of 18 months. Common clinical and histological features for patients with this condition included masculine gender, age 50 years or above, 10 or more years of history of diagnosed genetic haemochromatosis, high alcohol intake, and grade III or IV hepatic fibrosis. PMID- 7846989 TI - Duodenal diverticula--diagnosis and management of complicated forms: report of two clinical cases and review of the literature. AB - Duodenal diverticula are frequent, they are present in 22% of the cases at autopsy. However, radiological assessment demonstrates duodenal diverticula in 1 to 5% of the patients only. Perforation, the main complication, is very rare. Preoperative diagnosis is exceptional. In a 69-year patient admitted for diffuse abdominal pain, a computerized abdominal tomography, completed by opacification of the gastroduodenal transit allowed diagnosis. In the second case, diagnosis was made peroperatively. Based on these two observations, the authors review the elements of diagnosis and management in complicated duodenal diverticula. PMID- 7846990 TI - Early diagnosis of adult intestinal intussusception at four different locations. AB - Four cases of adult intestinal intussusception at four different locations (two ileocolic type, two colocolic type involving the transverse and the rectosigmoid colon) are reported. The most beneficial diagnostic procedures were emergency contrast studies of the colon or computed tomogram of the abdomen. Three cases were associated with primary malignancy. Surgical resection without reduction is favoured because an underlying primary malignancy should be suspected in adult patients. The literature about the causes and the more recent considerations involved in the management of adult intussusception is reviewed. PMID- 7846991 TI - Primary squamous-cell carcinoma of the colon: a case report. AB - We report a new case of S.C.C. of the large bowel with multiple liver metastases. A resection of the primary tumour and liver biopsies were performed with administration of a postoperative chemotherapy (5-Fluorouracil). After a stabilization of 3 months, the metastases were rapidly progressive and the patient died a year after the diagnosis. About 70 cases of S.C.C. of the colon and rectum have been described in the literature. It is most common in the fifth decade and occurs equally in male and female. The most frequent locations are the rectum and the sigmoid. Clinical and physical features and common diagnostic methods do not differentiate the S.C.C. from adenocarcinoma. Treatment is the same but the prognosis of S.C.C. appears to be worse than that of adenocarcinoma. PMID- 7846992 TI - The effect of peritoneal lavage on peritoneal cellular defense mechanisms. AB - To assess the effect of peritoneal lavage on peritoneal cellular defense mechanisms, peritoneal fluid total cell counts, cell types, phagocytic activity and polymorphonuclear leukocytes (PMNL) chemotaxis before and 4 hours after saline lavage was studied on 70 rats. Lavage with 10 ml saline decreased the peritoneal total cell counts of rats from 10.6 x 10(6) to 6.6 x 10(6) (p < 0.005). Among the peritoneal cells, the fraction of PMNL increased whereas the macrophages, lymphocytes and mast cells decreased (p < 0.005). The phagocytic activity of peritoneal phagocytic cells did not change significantly by peritoneal lavage. However, after lavage, PMNL instead of macrophages were the prominent phagocytic cells. Chemotactic index of peritoneal PMNL also did not change with saline lavage. It is concluded that although the phagocytic and chemotactic activity of peritoneal fluid cells are not affected by peritoneal lavage, cellular defense of the peritoneum may be compromised by altering the total cell counts and their composition. PMID- 7846993 TI - Sensory recovery after microsurgical repair of digital nerves. AB - The authors study 65 cases of repair of digital nerve lesions performed in 60 patients. They evaluate the quality of sensory recovery by clinical (Dellon and Weber Tests) and electrophysiological tests (velocity, amplitude and duration of the Compound Sensory Action Potential). The results show a complete recovery in 26%, a recovery of discrimination sensitivity in 73.8% and a recovery of protective sensation in 96.9% of the cases. Age and severity of the associated trauma are the most important factors influencing the quality of the sensory recovery. PMID- 7846994 TI - Fine needle aspiration of the pancreas. In quest of accuracy. AB - Percutaneous fine needle aspiration (FNA) is the diagnostic method of choice for patients with a pancreatic mass. A positive cytologic diagnosis allows administration of neoadjuvant therapy in patients with resectable disease and avoids laparotomy in patients with locally advanced or metastatic disease. Ninety patients underwent computed tomographically guided FNA of the pancreas, and the results were compared to the final histologic diagnosis. The initial sensitivity for diagnosis of pancreatic adenocarcinoma was 70%. To improve our diagnostic accuracy, 19 independent cytologic criteria were evaluated for each case. Multivariate logistic-regression analysis identified three major criteria (nuclear crowding and overlapping, nuclear contour irregularity, irregular chromatin distribution) and four minor criteria (nuclear enlargement, single epithelial cells, necrosis, mitoses) as the most important predictors of malignancy. In the presence of two or more major or one major and three minor criteria, the sensitivity and specificity for the diagnosis of pancreatic adenocarcinoma were 100%. Objective application of these criteria improved our diagnostic sensitivity to 90%. PMID- 7846995 TI - Fine needle aspiration cytology of primary epithelioid sarcoma of the vulva. A case report. AB - The cytopathologic features of the fine needle aspiration cytology of the local recurrence of a vulvar epithelioid sarcoma were documented. The cytologic findings included round polygonal cells with abundant eosinophilic cytoplasm and an eccentrically located nucleus. Despite their epithelioid aspect, the cells in the smears had a sarcomatous arrangement, consisting of isolated cells and loosely cohesive groups. The cytologic findings correlated well with the histologic features of the tumor, which consisted of nodules of eosinophilic epithelioid cells. We discuss the clinical characteristics and prognostic factors in this unusual, vulvar location of this soft tissue sarcoma. PMID- 7846997 TI - Accuracy and morphologic aspects of pancreatic and biliary duct brushings. AB - One hundred eight brushing cytology specimens with adequate follow-up were obtained from strictures of the biliary and pancreatic ducts. The material was classified as benign, reactive, low grade dysplasia, high grade dysplasia or adenocarcinoma. A diagnosis of carcinoma was made in 18 patients, high grade dysplasia in 12, low grade dysplasia in 6 and benign, nonneoplastic in the remaining cases. The diagnostic sensitivity for carcinoma was 44%, with a specificity of 98%. Ten of 12 patients with high grade dysplasia demonstrated other evidence of carcinoma. No complications were encountered. Brushing cytodiagnosis of extrahepatic biliary and pancreatic duct strictures appears to be a safe procedure, with high specificity but only modest sensitivity. PMID- 7846996 TI - Fine needle aspiration diagnosis of orbital plasmacytoma with amyloidosis. A case report. AB - Fine needle aspiration (FNA) cytology of the orbit was used to diagnose an unusual case of multiple myeloma with secondary amyloid deposition in a 27-year old man who presented with bilateral keratoconjunctivitis and left-sided ptosis. The FNA smears revealed immature plasma cells, extracellular eosinophilic material (amyloid) and numerous multinucleate giant cells. Subsequent histologic studies of excised tissue confirmed the cytologic diagnosis of plasmacytoma with secondary amyloidosis. Amyloid was further confirmed by electron microscopy. The patient was subsequently diagnosed as having multiple myeloma. The cytologic features of amyloidosis and plasmacytoma are presented. The differential diagnosis and the diagnostic utility of FNA cytology in the evaluation of these orbital lesions are also discussed. This apparently was the first case of orbital amyloidosis diagnosed by FNA cytology. PMID- 7846998 TI - Cytologic appearance of Rhodococcus equi in bronchoalveolar lavage specimens. A case report. AB - Immunocompromised patients are at risk of developing infections caused by Rhodococcus equi, a gram-positive bacillus that can cause pneumonia in patients with acquired immunodeficiency syndrome. To the author's knowledge this is the first report describing the cytologic features of the infection in a patient who had a confirmatory tissue biopsy and positive culture. Infection with R equi may go unrecognized by pathologists unaware of its presentation and appearance in cytologic material. PMID- 7846999 TI - Cytology of pulmonary Fusobacterium nucleatum infection. A case report. AB - A patient with pulmonary Fusobacterium nucleatum infection presenting as a solitary nodule is reported. The infectious nature of the lung nodule was disclosed by ultrasound-guided percutaneous transthoracic fine needle aspiration cytology (FNAC) with Liu's stain. The cytologic characteristics of F nucleatum infection are described. The usefulness of real-time ultrasound in fine needle aspiration diagnosis of a peripheral lung lesion is demonstrated, and the role of Liu's stain in FNAC is emphasized. PMID- 7847000 TI - Fine needle aspiration cytology of mycobacterial spindle cell pseudotumor. A case report. AB - We report a case of mycobacterial spindle cell pseudotumor (MSP) in a lymph node from an acquired immunodeficiency syndrome patient diagnosed by fine needle aspiration (FNA). The FNA cytology was characterized by spindle cell proliferation without the typical foamy histiocytes usually seen in mycobacterial infections and mimicked a mesenchymal neoplasm, particularly Kaposi's sarcoma. This case illustrates the importance of including MSP in the differential diagnosis of lymph node FNAs from immunocompromised patients, particularly those that show spindle cell proliferation suspicious for Kaposi's sarcoma or another mesenchymal neoplasm. PMID- 7847001 TI - Small giant cell carcinoma of the lung diagnosed preoperatively by transthoracic aspiration cytology. A case report. AB - Giant cell carcinoma (GCC) of the lung is considered an aggressive form of lung cancer. Most patients with GCC have large tumors with widespread metastases on hospital admission. We describe a small GCC in the lower lobe of the right lung. Preoperative aspiration cytology showed numerous bizarre, giant epithelial cells, highly suggestive of GCC. The resected tumor measured 1.2 x 1.0 x 0.7 cm in diameter, with an ill-defined margin. Histologically the tumor was composed of pleomorphic mononucleate or multinucleate giant cells without adenocarcinoma or squamous cell differentiation. The tumor cells were loosely organized and noncohesive or free in the alveolar space. The histology was interpreted as GCC of the lung. The clinicopathologic features of giant cell carcinoma are discussed. PMID- 7847002 TI - Fine needle aspiration cytology in operative scar nodules in breast carcinoma. PMID- 7847003 TI - Adult female Wuchereria bancrofti nematode in a fine needle aspirate of the lymph node. PMID- 7847004 TI - Imprint cytology of the gallbladder mucosa. Its use in diagnosing macroscopically inapparent carcinoma. AB - The diagnosis of early gallbladder carcinoma is almost impossible before surgery; in many cases the tumors are grossly inapparent. The usefulness of imprint cytology in detecting early carcinoma of the gallbladder mucosa was assessed. Eight macroscopically inapparent carcinomas were diagnosed, and nine grossly evident carcinomas were confirmed by imprint cytology in 120 cholecystectomies. The sensitivity of cytologic diagnosis of macroscopically inapparent carcinoma was 80%, specificity and predictive value were 100%, and efficiency was 97.7%. If overt carcinomas are included, both the sensitivity and efficiency increase, to 89.6% and 98%, respectively. For the diagnosis of dysplasia the sensitivity and predictive value was 84%, specificity 97.6% and efficiency 95.8%. Because of the simplicity and rapidity of imprint cytology of gallbladder mucosa, coupled with its high sensitivity and reliability, it is recommended for the detection of inapparent carcinoma during cholecystectomy in patients at high risk of cancer. PMID- 7847005 TI - Intraoperative cytology of pancreatic masses. A 10-year experience. AB - The results of intraoperative fine needle aspiration biopsy (FNAB) of 92 pancreatic masses (1982-1992) are reported. The high sensitivity (1.00) and specificity (1.00) values are believed to be due to the presence of a cytopathologist in the operating room. The cytopathologist assesses the adequacy of the sampled material and, using rapid staining, can make a cytologic intraoperative diagnosis. This procedure led to the diagnosis of inflammatory lesions and of common and rare pancreatic neoplasms in a few minutes. Emphasis is laid on the characteristics of pancreatic FNAB vs. the more invasive procedures (e.g., wedge biopsies). PMID- 7847006 TI - Adjunctive endoscopic brush cytology in the detection of upper gastrointestinal malignancy. AB - The role of exfoliative cytology as an adjunct to endoscopic biopsy in the detection of upper gastrointestinal malignancy is controversial insofar as some claim that its use is of little clinical benefit. The role of cytology in the differentiation of benign from malignant mucosal lesions in 2,183 consecutive patients who underwent esophagogastroduodenoscopy was examined. Malignancy was confirmed in 394 patients. Both endoscopic biopsy and cytology were positive in 275 of 394 (69.8%) patients. Endoscopic biopsy provided the diagnosis in the presence of negative cytology in 73 of 394 (18.5%) cases, while cytology was positive after a negative biopsy in 36 of 394 (9.2%) patients. Ten of 394 (2.5%) patients were not diagnosed preoperatively using either modality. Endoscopic biopsy yielded a sensitivity of 88.3%, specificity of 99.9%, positive predictive value of 99.7% and negative predictive value of 97.6%. Cytology alone, in contrast, yielded a sensitivity of 79%, specificity of 98.5%, positive predictive value of 92.3% and negative predictive value of 95.6%. With the additional use of cytology, the diagnostic yield was increased from 88.3% to 97.5%. We conclude that upper gastrointestinal exfoliative cytology is a useful adjunct in the investigation of patients with suspicious mucosal lesions. PMID- 7847007 TI - Diagnosis of progressive multifocal leukoencephalopathy by stereotactic brain biopsy utilizing immunohistochemistry and the polymerase chain reaction. AB - This report describes the diagnosis of progressive multifocal leukoencephalopathy (PML) in nine patients using cytopathologic and histopathologic examination of computed tomographically guided stereotactic brain biopsies in combination with immunostaining for SV-40-related antigen and the polymerase chain reaction (PCR) for the JC virus. In four patients the diagnosis of PML was based on the microscopic appearance of the biopsies and immunostaining for SV-40-related antigen. In one of these patients the diagnosis was also supported by PCR for the JC virus. In two patients whose biopsies were only suggestive of PML, a definitive diagnosis was possible utilizing immunohistochemistry and PCR. In another case the histopathologic features were atypical of PML, and the diagnosis was established with immunostaining and PCR. The diagnosis of PML was established by PCR alone in two patients whose biopsies showed only suggestive or nonspecific findings. We conclude that the accuracy of stereotactic biopsy in the diagnosis of PML is enhanced by using a combination of light microscopy, immunohistochemistry and PCR. PMID- 7847009 TI - Inaccuracy of cytologic diagnosis in high grade squamous intraepithelial lesions (CIN 3). AB - Through a retrospective review of records, this study attempted to determine whether a correlation between cytology and histology would change with time in one laboratory. The study encompassed a geographic area of Scotland with a female population of 175,500 served by one colposcopy clinic, at Ninewells Hospital and Medical School, Dundee. The subjects were referred to the Nine-wells colposcopy clinic between January 1, 1985, and December 31, 1990. The results showed many women with high grade squamous intraepithelial lesions (SILs) (CIN 3) and cytology revealing abnormalities milder than severe dyskaryosis, for an average of 71.9% over the six years of the study. The referral of women for colposcopic assessment if they have persistent smears showing mild dyskaryosis suggestive of low grade SILs seems to be worthwhile. PMID- 7847008 TI - Cervical cytology associated with levonorgestrel contraception. AB - Cytologic monitoring of cervical smears was carried out in 686 women receiving two modes of levonorgestrel contraception, one in the form of a subdermal implant and the other as an intrauterine device. The period of contraception with both delivery systems ranged from six months to five years. No case of malignant neoplasia was seen in any of the 44 subjects even after five years of continued levonorgestrel contraception. Preinsertion cytology revealed eight dysplastic smears (seven mild and one moderate); the lesions reverted to normal six months later and remained normal after one to four years of hormone use. A total of 19 dysplastic smears (18 mild and 1 moderate) were detected in the postinsertion smears collected after one to five years of contraception, giving an incidence of 2.8%, which was nonsignificant when compared with the control figure of 1.3%. Regression of the lesion to normal was observed in all 19 dysplasias on follow-up and in none did the dysplasia progress to a higher grade or frank malignancy. The incidence of dysplasia was more than twice as high with the intrauterine device as with the implant (4.9% vs. 2.1%). Hence, the implant appeared to be safe during five years of contraceptive use in terms of cervical pathology. However, longer follow-up of a large number of women is needed to reach a definitive conclusion. PMID- 7847010 TI - Cytologic features of peripheral squamous cell carcinoma of the lung. AB - Cytologic features of 32 peripheral squamous cell carcinomas of the lung were reviewed. Fine needle aspiration biopsy and curettage showed most of the tumor cells to be arranged in irregular cell fragments consisting of relatively small cells with scanty cytoplasm. They possessed round to oval nuclei with coarsely granular chromatin, and some had large, prominent nucleoli. Keratinization was usually observed in small numbers of scattered cells, and a nuclear streaming arrangement was noted in some areas. When both keratinization and streaming arrangements were absent, correct subtyping was impossible (12 cases). These cytologic features were different from those of 31 hilar squamous cell carcinomas studied as controls; there many carcinoma cells showed keratinization, and small carcinoma cells were infrequent. However, in all cases, sputum cytology was correctly interpreted because squamous differentiation was easily recognized. PMID- 7847011 TI - Cytologic characterization of bronchial epithelial changes in small cell carcinoma of the lung. AB - Cytologic specimens obtained by fiberoptic bronchoscopy were examined in 111 cases; the diagnosis of small cell carcinoma of the lung was established with this procedure. The findings of cytologic examination were compared to those of histologic examination of the biopsy specimens obtained simultaneously. Our aim was to evaluate other cell components in the specimen besides small cell carcinoma. The majority of the cases showed morphologic changes in the bronchial epithelium, which ranged from benign squamous metaplasia (59%) to atypical squamous metaplasia (8%) and squamous cell carcinoma (8%). In 6% of cases a large cell carcinoma component was found in addition to the small cell carcinoma. The findings show a good correlation with those of histologic examination of the biopsy specimens, indicating that cytologic examination is an excellent procedure for detecting concomitant changes in the bronchial epithelium in the setting of small cell carcinoma of the lung. PMID- 7847012 TI - Phenotypic analysis of cerebrospinal fluid cells over the course of Lyme meningoradiculitis. AB - Cytologic cerebrospinal fluid abnormalities that most distinctly point to the diagnosis of Lyme meningoradiculitis are pronounced mononuclear pleocytosis composed mainly of T lymphocytes, large amounts of plasma cells and IgM-positive B cells. In this study, repeat examinations revealed decreasing cell numbers and almost normal cell counts 100-130 days after the onset. B cells persisted over the whole observation period in five of six patients and were not related to any clinical symptoms or signs indicative of persistent meningitis or central nervous system involvement. The CD4/CD8 ratio of the helper/inducer and suppressor/cytotoxic lymphocyte subsets declined in all the patients after antibiotic treatment. It might be useful as a marker of the disease activity. PMID- 7847013 TI - Fine needle aspiration biopsy in the diagnosis of lymphadenopathy in 1,103 patients. Role, limitations and analysis of diagnostic pitfalls. AB - Fine needle aspiration biopsy (FNAB) is widely used for the assessment of various lesions. The results of FNABs of lymph nodes on 1,103 patients, performed over a 14-year period, from 1978 to 1992, are presented. The patients ranged in age from 1 to 90 years. Cervical nodes were the site sampled most frequently (47%). Of all the aspirates, 593 were diagnosed cytologically as malignant, 61 as suspicious for malignancy and 329 as benign. The material was classified as unsatisfactory in 120 cases. Aspirates from supraclavicular nodes were most likely to be malignant (85%), followed by those from deep nodes (67%). The most challenging lesions to assess using FNAB were lymphomas, accounting for 15 of the 23 false negatives. Most of these were related to difficulty in the interpretation of well differentiated neoplasms in the early years of this study, prior to the use of immunocytochemistry. Sampling errors accounted for eight false-negative diagnoses; they included all the cases of metastatic carcinomas that had been missed. There were only three false-positive diagnoses; two of these involved the misinterpretation of lipid-rich lesions as metastatic clear cell carcinomas. The results of this study support the accuracy of FNAB and its value in investigating lymphadenopathies. FNAB of nodes provides a high level of diagnostic accuracy, as shown by the 3.4% false-negative and 0.9% false-positive rates. Lymphoid marker studies of cytologic material greatly enhance our ability to diagnose and properly classify lymphomas and reduce the false-negative rate. PMID- 7847014 TI - Conventional scraping versus fine needle aspiration cytology in the diagnosis of cutaneous leishmaniasis. AB - Cutaneous leishmaniasis is an endemic parasitic disease, the diagnosis of which is important for its successful management. Whereas conventional scraping is a technique widely employed for detecting the parasite, fine needle aspiration cytology (FNAC) is used rarely. The value of these two techniques for confirming the clinical diagnosis was compared prospectively in 46 cases. The study indicated that both methods are comparable if performed by trained individuals. However, FNAC is easier to perform and repeat and takes less time to demonstrate the organism. Therefore, FNAC is recommended as the method of choice in confirming the clinical suspicion of cutaneous leishmaniasis in endemic areas. PMID- 7847015 TI - A polycarbonate thin film technique for cytologic preparation of fluid specimens. AB - The use of polycarbonate membrane filters for the routine cytologic analysis of fluid specimens is well established. These filters are also currently used as integral components in some commercially available fully automated machines for the formation of monolayer cell spreads of cytologic specimens. We describe a simple manual polycarbonate filter technique for the production of similar preparations, utilizing commonly available laboratory materials, for all types of cytologic fluid specimens. The method is rapid, eliminates the cumbersome processing of whole filters, provides excellent morphologic detail and obviates the need for automated or cytocentrifugation instruments. The method is thus well suited to laboratories in which the number of fluid specimens is not large enough to justify the financial resources needed for these relatively expensive machines. PMID- 7847016 TI - A modified cell block technique for fine needle aspiration cytology. AB - A modification of the cell block technique, useful in processing material obtained by fine needle aspiration (FNA), is described. Four hundred six aspirates, obtained from 333 consecutive patients, were studied after immediate fixation in 4% buffered paraformaldehyde. Conventional histochemical and immunohistochemical staining methods were used. Histologic verification of the cytologic diagnoses made by FNA was possible in 67 cases. The overall accuracy was 97%, with a sensitivity of 95% and specificity of 100%. A major disadvantage of the cell block technique is time. Therefore, even if this technique increases the accuracy of cytologic diagnosis, its routine use is impractical because the delay in diagnosis when compared with smears may be considerable. The cell block technique is a valuable method, particularly when immunohistochemical staining for a battery of markers is required. PMID- 7847017 TI - The epidemiology of multiple pregnancies. AB - Over the last decades the frequency of multiple births has been on the decline in most developed countries. This trend, however, has been restricted to dizygotic twins, while monozygotic rates have remained stable or risen slowly. In more recent years, however, the fall in multiple dizygotic birth rates has ceased and a slight increase is observed. This trend and the increased frequency of triplets or higher-order births, registered from the early 1980s onwards, are essentially related to treatments for infertility. No single risk factor, such as maternal age, parity, oral contraceptive use, or declining fertility rates can explain the overall declining trends. In this paper we review the descriptive epidemiology and the main risk factors for multiple pregnancies. PMID- 7847018 TI - Mortality and morbidity among twins: recent observations from the United States. AB - The increasing number of twin (and higher order) births is a matter of national concern for two reasons: First, the differential rates of preterm (< 37 weeks) delivery and low birthweight (< 2,500g) among twins compared to singletons; and second, the inordinate contribution of these infants to overall infant mortality, morbidity and long-term handicap. Data from all births in the U.S. during 1987 and 1988 was used to calculate distribution frequencies for gestational age at delivery, and birthweight, as well as mortality and handicap rates and the corresponding relative risks of these latter events for twins compared to singletons. A suggestion for improvement in the mortality and handicap rates and reduced costs among survivors is presented. This proposal is based upon data from the singleton and twin literature and the use of the prenatal invervention of adequate maternal nutrition during the pregnancy. PMID- 7847019 TI - Twin study today. PMID- 7847020 TI - International Congress on the Occasion of the 40th Anniversary of the Foundation of the Gregor Mendel Institute: Twin Study Today. Rome, Italy, 24-25 February 1994. Proceedings and abstracts. PMID- 7847021 TI - Obstetrical implications in multiple pregnancies. AB - In the present study 90 multiple pregnancies were examined. These were subdivided on the basis of the number of embryos involved (74 twins, 10 triplets, 6 quintuplets) and on whether they were followed at our clinic for the entire pregnancy or not. In each group we analysed certain variables, calculating the respective mean values and standard deviations. We used the ANOVA test to discriminate the eventual differences in the means of the variables analysed, operating a p < 0.05 significance value. In addition, significant differences were analysed by the test of Contrasts (Scheffe F-test). The concept that emerged from the data investigated is that careful management of these pregnancies, carried out in high-level structures, can reduce the incidence of complications on both the maternal and fetal side and thus prevent "minimal brain damage" in the newborn. PMID- 7847022 TI - Maternal and child care: the Canadian model. PMID- 7847023 TI - Paediatric care of twins. AB - For many parents, the joy of having twins and triplets is reduced by the unexpected emotional as well as physical and financial stresses which they experience with children who may suffer from prematurity and low birthweight, and who have a higher risk of language delay and disability. Paediatric care should start from the time of ultrasound diagnosis. The Multiple Births Foundation holds regular meetings for expectant parents. Twins Clinics are held in three centres in the UK as well as three special clinics (Growth, Supertwins and Bereavement), where families may discuss problems relating to the twinship as well as sharing their experiences with parent volunteers. PMID- 7847024 TI - Structural congenital defects in multiple births. PMID- 7847025 TI - Twin studies in auto-immune disease. AB - Immune-mediated diseases affect up to 5% of the population and are a major cause of morbidity and mortality. These diseases can be organ specific, such as insulin dependent diabetes (IDDM) and non-organ specific, such as Rheumatoid Arthritis (RA). Identical and non-identical twins have been used to establish whether these diseases are determined by genetic or environmental factors. The results of these studies have been collated in a new section of the Mendel Institute in Rome. Diseases included in these studies included IDDM, RA, Systemic Lupus Erythematosus (SLE), Multiple Sclerosis (MS) and Myasthenia. Striking differences in concordance rates between identical and non-identical twins in all these studies suggest that genetic factors are important in causing these diseases. All the diseases are known to be associated with HLA genes on chromosome 6 which may account for some or all of the genetic susceptibility. However, in the majority of pairs the affected twin has an unaffected co-twin. These observations suggest that non-genetically determined factors, probably environmental factors and not somatic mutations, are critical. The study of unaffected co-twins, who are at high disease-risk, has allowed the identification of changes which precede and predict the clinical disease. The immune-mediated destruction in many of these diseases is probably caused by T-lymphocytes. Twin studies have shown the importance of genetic factors in determining T-cell responses. Identical twins should, therefore, provide the perfect test bed to assess the role of T-cells in immune-mediated diseases. PMID- 7847026 TI - Knowledge data base system for twins study. AB - The medical research on twins, carried out at the Gregor Mendel Institute for Medical Genetics and Twin Study in Rome over the past four decades, has resulted in a vast collection of clinical paper records. A challenge was presented by the need for a more secure method of storage to preserve this enormously valuable historical and scientific patrimony and to render its contents more easily accessible for research purposes. We met the challenge by planning and developing the computerization of this material. New concepts, currently being explored in biomedical informatics, were applied to build a Knowledge Data Base System, using a fourth-generation language (SQL). This architecturally innovative computer system enables its users to manipulate data supplied, rather than just simply storing it. Based on heuristic relational criteria between variables and parameters, the system is employed to solve problems of sibling design analysis typically arising from twins' records, but is also equipped to meet future data base requirements. Another feature of the system is its users' ability to pull off data in the form of regular automated reports, which are distributed through a Local Area Network (LAN). Through a Bulletin Board System (BBS) and modem, any scientist (outside as well as within the Institute) is thus able to access data and exchange scientific information. PMID- 7847027 TI - The National Academy of Sciences--National Research Council Veteran Twin Registry. PMID- 7847028 TI - The Mercurio Project and Twins. How to use a registry. PMID- 7847029 TI - [Characteristics of functional assays for evaluation of immune red cell destruction and their clinical application]. PMID- 7847030 TI - [Apoptosis (programmed cell death) in the immune system and hemopoiesis]. AB - Apoptosis, or programmed cell death, is a series of controlled sequential events resulting in the demise of cells without evoking an inflammatory response. Although first described 20 years ago, this phenomenon evokes now renewed interest in this phenomenon, particularly in the light of our greater understanding of cellular signalling pathways and their genetic control. This is especially pertinent to haemopoiesis and overall maintenance of a functional immune system. PMID- 7847031 TI - [Anagrelide--new antiplatelet drug]. AB - Anagrelide is a quinazoline compound developed as a potent inhibitor of platelet aggregation. During studies in human it has produced rapid and selective thrombocytopenia and has therefore been evaluated for use in conditions associated with thrombocythaemia. Anagrelide significantly inhibits human megakaryocyte colony development in vitro by preventing full megakaryocyte maturation, and inhibits platelet aggregation as a result of potent inhibition of cyclic adenosine monophosphate (cAMP) phosphodiesterase activity. In 60 to 93% of patients with essential or myeloproliferative thrombocythaemia anagrelide produces sustain reductions in platelet counts and also reduces the incidence of disease-related symptoms. Most adverse effects are related to its vasodilatory or positive inotropic properties. This new agent appears promising in the treatment of thrombocytosis in patients with chronic myeloproliferative diseases, especially in younger persons in whom the risk of leukaemogenic transformation with some alternative drugs is of particular concern. PMID- 7847032 TI - [Leukostasis in blood diseases: pathogenesis, manifestations, management]. AB - The leukostasis syndrome is a severe complication of leukemias with hyperleukocytosis. The pathogenesis, manifestations, and management of this syndrome are presented. The early diagnosis and aggressive therapy of leukostasis are likely to increase the complete remission rate in acute leukemias with hyperleukocytosis. PMID- 7847033 TI - [Acute basophilic leukemia]. AB - Acute basophilic leukemia is a relatively uncommon variant of acute nonlymphocytic leukemia accounting for 4-5 percent of cases of acute nonlymphocytic leukemia and less than 2 percent of all hematopoietic malignancies. It is usually characterized by a very rapid clinical course, symptoms of hyperhistaminemia, peptic ulceration, gastrointestinal cerebrovascular bleeding and resistance to therapy. This leukemia is somewhat heterogeneous in term of morphology, immunology and chromosome alterations. No specific marker chromosome has been described but trisomy 8 and monosomy 7 are the most frequent chromosomal abnormalities. The cytochemical reactions in basophilic leukemia are positive results with toluidine blue and Astra blue stains. Peroxidase stain is reported to show positive reactions. Ultrastructural analysis usually reveals immature basophil granules and provides evidence of basophilic differentiation of the blasts. PMID- 7847034 TI - Flowcytometric pattern of leucocyte recovery after therapy induced aplasia. AB - 33 aplastic episodes in 24 patients undergoing bone marrow ablative therapy for the treatment of haematological malignancies were monitored with automated flowcytometric counts with particular emphasis to BLAST, MONO (monocytes) and LUC (large unstained cells) determined by Technicon H1, and MFR and HFR reticulocytes determined by Sysmex R1000. We found regular pattern of appearance of flowcytometric parameters, which were predictive for leucocyte recovery. A transient increase of BLAST to > 10% and MONO+LUC to > 0.08 x 10(9)/l were predictive for leukocyte recovery after aplastic episodes following ABMT, BMT and high dose AraC therapy, but not after conventional chemotherapy. The prognostic value of MFR+HFR reticulocytes increase over 5% was limited to ABMT and BMT. This report demonstrates the capabilities of automated flowcytometric analysis in early prediction of haematological recovery. PMID- 7847035 TI - [Significance of histologic bone marrow evaluation in diagnosis of chronic granulocytic leukemia. I. Reticulin fibrosis]. AB - The aim of the study was the evaluation of bone marrow reticulin fibrosis in non treated patients suffering from chronic granulocytic leukaemia (cgl). We have examined 40 patients (19 female and 21 male, average age 41.2 years) with chronic phase, Ph'-positive cgl. Reticulin fibrosis grade I and II (according to Dekmezian and co.) was detected in 47.5% of patients and grade III and IV in 42.5%. Statistically significant correlation was found between reticulin fibrosis intensity and spleen size, platelets count and Sokal index. We believe that reticulin fibrosis assessment is of prognostic value. PMID- 7847036 TI - [Outcome of hemorrhage treatment in children with hemophilia A related to factor VIII inhibitor]. AB - The results of bleedings treatment in 11 children with haemophilia A and factor VIII (f. VIII) inhibitor was presented. Concentrates of human and porcine f. VIII and activated prothrombin complex concentrate were used in the treatment. The method of treatment depended on the level of human and porcine f. VIII inhibitors. In patients with level of human f. VIII inhibitor lower than 10 jB/ml the concentrates of human f. VIII in doses 2-3 times higher than usually used in haemophiliacs without inhibitor were successful. When inhibitor level was higher than 10 jB/ml, but low cross-reactivity of porcine f. VIII was stated, concentrates of porcine f. VIII were used with good result. In children with high level of antibody against human and porcine f. VIII, the best results were achieved using activated prothrombin complex concentrates. PMID- 7847037 TI - [Survival of patients and DNA-ploidy of cells in non-Hodgkin's lymphoma of low grade malignancy]. AB - DNA-ploidy in lymphoma cells obtained from lymph nodes of 107 patients with non Hodgkin's lymphomas of low grade malignancy was studied prior to the treatment introduction. The survival of patients was within the range of 24-126 months (median 63 months). There were 70 hyperdiploidic and 37 diploidic patients. The statistical tendency to prolonged survival was seen among patients with lymphocytic lymphoma (CLL) as compared to other histological types of the disease. There were no statistical differences in the probability of survival (p P) between diploidic and hyperdiploidic patients either in the whole studied group or in particular histologic types of lymphoma. PMID- 7847038 TI - [Emperipolesis of megakaryocytes in bone marrow of rats]. PMID- 7847039 TI - The potential for contamination of continuous spinal catheters. AB - The distal tip of 100 spinal catheters were cultured. They were obtained from 100 patients receiving continuous spinal anesthesia, 32 of whom underwent orthopedic surgery and 68 urologic surgery. The catheters remained in place 24 to 72 hours. Six of the catheters were found contaminated; five of the six were obtained from orthopedic patients and one of an urologic patient. There was a statistically significant difference between the duration of implantation and contamination, in the time span of 24 to 72 hours. There was no statistical significance between the duration of implantation and contamination neither in orthopedic nor in urologic patients. None of these catheters caused any clinical infection. PMID- 7847040 TI - Effect of processed Aconiti tuber on catecholamine and indoleamine contents in brain in rats. AB - Processed Aconiti tuber (Aconitum carmichaeli) has been known as a potent analgesic herbal medicine in Japan and China. TJ-3021 [Tsumura Kampo Medicine Shuchi-Bushi Powder for Ethical Dispensing] is a herbal medicine produced from Aconiti tuber by autoclaving to decrease its toxicity. In the present investigation the antinociceptive mechanism of TJ-3021 in rats was studied. It was observed that under repeated cold stress (RCS), the administration of distilled water (p.o.) significantly increased the contents of norepinephrine (NE) in the cerebral cortex compared with rats without RCS. However, the administration of TJ-3021 decreased the NE contents in the cerebral cortex in rats with RCS. On the other hand, the administration of water in rats with RCS significantly decreased the contents of serotonin (5-HT) in the medulla. The administration of TJ-3021, on the other hand, increased 5-HT contents in the medulla in rats with RCS. It might be possible that the antinociceptic mechanism of the action of TJ-3021 could be attributed to the improvement of dysfunction of descending nociceptive 5-HT system. PMID- 7847041 TI - Anesthetic management of two patients undergoing laparotomy & hepatectomy for carcinoid syndrome. AB - In this report we present two patients with carcinoid syndrome who underwent excision of a carcinoid tumor of the bowel and hepatectomy for secondaries in the liver. The preoperative preparation, the intraoperative problems and management as well as the outcome are described. PMID- 7847042 TI - Gaucher's disease and pregnancy. AB - For a long time, pregnancy has been discouraged for patients with Gaucher's disease. Because of the scarcity of complications found in the literature, the obstetrical attitude is favorable towards an authorization of pregnancy for patients with Gaucher's disease. We describe the evolution of pregnancy of a woman suffering from Gaucher's disease type I and the anesthesiological support provided. PMID- 7847043 TI - Clinical variability of possible malignant hyperthermia as revealed by two cases. AB - Two cases of possible clinical malignant hyperthermia are described. The variability of the clinical symptoms and signs is discussed and the necessity of performing the diagnostic in vitro muscle contracture test is emphasized. PMID- 7847044 TI - Pancreatitis pain treatment: an overview. AB - Pain associated with chronic pancreatitis in particular is one of the most difficult and challenging syndromes that are presented to pain centers. Narcotic addiction is a common feature in this population. In this contribution an overview will be provided of the most pain treatment modalities based upon recent developments in the field of physiopathology, surgery, medical imaging and locoregional anesthetic techniques. Based upon personal experience it becomes progressively more clear that the most efficient alternative is not offered via neurolysis of the coeliac plexus. A shortlasting cure of 7-10 days with local anesthetics, injected via a coeliac plexus- or interpleural catheter may offer comparable but better reproducible durations of analgesia. Addition of corticosteroids during celiac plexus anesthesia may have additional benefits. Despite the progress in the field of internal medicine and surgery, a permanent solution is still far away for these patients. PMID- 7847045 TI - [Development and establishment of electron microscopic cytochemistry]. PMID- 7847046 TI - Three-dimensional fine structure of the lingual papillae and their connective tissue cores in the human tongue. AB - The three-dimensional structure of the four types of lingual papillae and their connective tissue cores (CTCs) in the human tongue was studied by scanning electron microscopy after removal of the epithelial cell layer, and was compared to those of other mammalian species. Filiform papillae are densely distributed on the dorsal surface of the anterior two-thirds of the tongue. Each filiform papilla has numerous slender protrusions on the top. After removal of the epithelium, the CTC of the filiform papilla has a columnar primary core with 10 30 rod-shaped small secondary cores surrounding an upper central depression. A few long spine-like protrusions are frequently found in the center of this upper depression. The number, thickness and length of each secondary protrusion of the filiform CTC show some variations at the region distributed on the tongue. Fungiform papillae with spherical heads are scattered among these filiform papillae and are numerous at the anterior margin of the tongue. The CTC of the fungiform papilla shows a coralliform structure with numerous small rod-shaped protrusions on the lateral surface, and its branched top has flat areas with a few small round depressions harboring taste buds. It must be emphasized that human fungiform papilla has some taste buds not only in the young, but also in the adult age. Several to 12 vallate papillae are distributed in front of the terminal groove and had the CTC of pinecone-like structure with numerous small thorns (secondary connective tissue cores). Foliate papillae consist of 10-15 parallel folds at the posterior margin of the tongue. The CTC of the foliate papillae appears as ridges and grooves. Small protrusions are scattered on the surface of the ridges. The underside view of the exfoliated epithelium of the vallate as well as the foliate papillae revealed numerous taste buds arranged in single file in the lateral epithelium. The dorsal surface of the root of the tongue has evenly distributed short rod-shaped protrusions of the connective tissue. PMID- 7847048 TI - Morphological traits of crania in modern Kyongsangnam-do Koreans. AB - The crania of modern Kyongsangnam-do or Southeastern Koreans were examined metrically and nonmetrically. In comparison with those of several modern samples from the northeastern Asia, the modern Kyongsangnam-do crania are characterized by their brachycranic and high cranial vaults as well as their high facial skeletons with the flat frontal and zygomaxillary regions. The modern Kyongsangnam-do shows a close affinity to the modern Central Koreans in the analyses of metric and nonmetric cranial traits. In the same Kyongsangnam-do, the cranial vaults are higher and shorter, and the nasal bones are not flatter in the modern than in the Yean-ri (4th to 7th century A.D.) samples. However, both the modern and the Yean-ri have morphological cranial traits similar to Asian continental Mongoloid in terms of the large upper facial height, the flatness in the frontal and zygomaxillary regions, and the close relationship of Smith's MMD based on 22 nonmetric cranial traits. Thus, it is suggested that these cranial traits, which are common with those of the Asian continental Mongoloid, have been kept from the Yean-ri to the modern Koreans in Kyongsangnam-do. PMID- 7847047 TI - Morphometric studies on the facial skeleton of humans and pongids based on CT scans. AB - The changes of the skull, which we can observe during the anthropogenesis, are reflected especially in the different skull proportions. We carried out metric measurements at the median level on 10 adult skulls each of humans, chimpanzees and gorillas as well as 11 skulls of orangutans. All skulls were scanned with a CT at the median level. We measured the lines and angles of the scans and the means and the standard deviations were calculated. We carried out a correlation analysis to observe the relation of their characteristics. We showed that there is a relation between the length of the skull base and the facial length in all species. From the results of the correlation analysis, we can also conclude that a relation exists between the degree of prognathism and the different length measurements of the facial skeleton. We also found a bending of the facial skeleton in relation to the cranial base towards the ventral side, also known as klinorhynchy, in all observed species. The highest degree of klinorhynchy was found in humans and the lowest in orangutans. We will discuss the different definition of the term klinorhynchy and its importance in the evolution of the hominoids. PMID- 7847049 TI - [High endothelial venule and lymphocyte homing of the musk shrew palatine tonsil]. AB - Homing of lymphocytes into secondary lymphoid organs is essential for an adequate immune response in vivo. Adherence of the lymphocytes to the high endothelial venule (HEV) is the crucial step of the homing. In contrast to lymph nodes and Peyer's patch, study of lymphocyte homing to the palatine tonsil has been hampered by the lack of useful laboratory animals that possess the tonsil. Herein, we examined the preferential adhesion of lymphocytes to the tonsillar HEV using the musk shrew; a new laboratory animal which has a pair of immunocompetent palatine tonsils. The palatine tonsils of the musk shrew had the morphologically detectable HEV in the parafollicular region. Immunofluorescent staining showed that more B cells were located in the lumen of the tonsillar HEV rather than T cells. The in vitro lymphocyte-HEV binding assay indicated some preferential adhesion of the lymphocytes to the tonsillar HEV. First, adhesion of B cells to the tonsillar HEV was more preferential than that of T cells, which was consistent with the result in the assay of Peyer's patch. Second, adhesion of the lymphocytes from axillar and inguinal lymph nodes was similar to that of the lymphocytes from the mesenteric lymph nodes, that differed from the result in the assay of Peyer's patch. These findings suggest that, in the musk shrew, the regulation of lymphocyte homing through the HEV has differences between tonsil and Peyer's patch, at least in part. This may be related to the role of the lymphoid organs in each local immune response. PMID- 7847050 TI - Three-dimensional structure of two different lymphatic spaces in rat testis, and the route of flow fluxes of their lymphatic fluids. AB - In addition to the collecting vessels, two initial lymphatic spaces were observed with light and electron microscopes. In the deep parenchyma, the peritubular lymphatic spaces surrounding the tubules were observed as polygonal piles after a corrosion casting to the testis. They were joined to the adjacent piles through fenestrae to form a loose spongiform structure. In the superficial parenchyma, the peritubular lymphatic spaces communicated to the subtunical lymphatic space on one side. The subtunical lymphatic spaces anastomosed to each other through small bypasses to form a rich network. Near the mediastinum, the peritubular lymphatic spaces bifurcated and narrowed on another side. Microradiography demonstrated two fluxes of the intratesticular lymphatic fluids; fast and slow flows. The fast flow was observed as a shaded line running into the subtunical lymphatic spaces immediately after injection of the contrast media. It remained 1 or 2 minutes and then disappeared. In contrast, the slow flux was observed as a spongiform shade shifting from the anteroposterial quadrant to the posterosuperior portion of the testis. Seven to 15 minutes were needed for the contrast media to reach near the mediastinum. Both lymphatic spaces are functionally discussed with relation to the two different fluxes of the lymphatic fluids. PMID- 7847051 TI - Components of the mylohyoid nerve degenerate during evolutionary progress in primates. AB - The vibrissal, cutaneous and muscular branch of the mylohyoid nerve was studied on both sides in 67 individuals in 16 species of 14 genera (Rattus, Canis, Felis, Suncus, Talpa, Tupaia, Lemur, Nicticebus, Galago, Pithecia, Ateles, Papio, Macaca, Pan) with particular reference to the phylogenic change of these branches. In this series of studies in rats, dogs, cats, tree shrews, and 5 sides out of 30 crab-eating monkeys, a fine branch of the mylohyoid nerve proceeds to the vibrissal hair follicle. The vibrissal branch passes through the platysma and enters the vibrissal hair follicle at the middle of the body. It is conceivable that the intermandibular vibrissae had been reduced from the intermandibular skin during the phylogenic progress of prosimians. The vibrissal branch of the mylohyoid nerve may retire from the intermandibular region according to the disappearance of the intermandibular vibrissae. The cutaneous branches of the mylohyoid nerve were detectable in almost all of the specimens. The cutaneous branch seems to be retained despite the reduction of the intermandibular vibrissae in primates. It must be considered to retire from the intermandibular skin during the evolutional progress of the hominids. In spite of the alteration of the muscular arrangement, the mylohyoid nerve is preserved as the innervation to the anterior belly of the digastric muscle and to the mylohyoid muscle in all specimens examined. PMID- 7847052 TI - [Use of ultrasonic generator for preparing skeletal specimens in combination with papain]. PMID- 7847053 TI - Interobserver variation in the evaluation of neurological signs: observer dependent factors. AB - Interobserver variation among four observers in evaluation of eight selected neurological signs was investigated. MATERIAL & METHODS--Two hundred and two consecutive unselected inpatients were examined by two senior neurologists and two trainees, all without knowledge of the neurological case history. The signs examined were: anisocoria, jerky eye movements, facial palsy, elbow extension force, finger-nose test, Barre sign, knee jerk, and extensor plantar reflex. Observed agreement rates and kappa coefficients were calculated in order to compare the interobserver variability among neurologists and trainees, and to evaluate differences in the interobserver variability between signs. RESULTS- Observed agreement rates varied from 0.80 to 0.95 for neurologists and from 0.65 to 0.98 for trainees. For neurologists kappa coefficients ranged from 0.40 to 0.67 and for trainees from 0.22 to 0.81. The neurologists had higher kappa values than the trainees in 5 signs, but this difference was only statistically significant for jerky eye movements. For the individual signs the observed agreement rates were between 0.50 and 0.93 for all four examiners combined, and overall kappa values varied from 0.32 to 0.71 with highest agreement for facial palsy and lowest for knee jerk. CONCLUSION--The magnitude of the interobserver and intersign variation indicates that the interpretation of the neurological signs tested, without knowledge of the case history, should be done with some caution. PMID- 7847054 TI - Rising mortality from motor neurone disease in Sweden 1961-1990: the relative role of increased population life expectancy and environmental factors. AB - Recent studies of mortality from motor neurone disease (MND) in Sweden have demonstrated rising levels of mortality from the disease, especially amongst older age groups. Case-control investigations have suggested that certain environmental factors are significantly related to variations in mortality from the disease, and are associated with a probable individual susceptibility to MND. This study applies an innovative epidemiological technique to longitudinal and cohort analysis of Swedish mortality from MND during the period 1961 to 1990. Survival modelling shows that a subpopulation susceptible to MND exists in Sweden, as has been demonstrated in other countries. The increased life expectancy of the Swedish population since 1961 has resulted in more of that susceptible population living to the ages at which MND is expressed, explaining the majority of the increase in mortality from the disease. However, environmental factors may play a role in accelerating the course of MND and may affect the timing of death within the susceptible sub-population. PMID- 7847055 TI - Parkinson's disease and immunological abnormalities: increase of HLA-DR expression on monocytes in cerebrospinal fluid and of CD45RO+ T cells in peripheral blood. AB - The etiology of Parkinson's disease is mainly unknown. Immune abnormalities have been described, but the cause of such abnormalities has not been resolved. We examined by two-colour flow cytometry HLA-DR antigen expression on monocytes from cerebrospinal fluid (CSF) and blood and, moreover, lymphocyte subpopulations (CD4+ CD45RO+, CD4+ CD45RA+, CD8+ CD11b+high) in peripheral blood from patients with Parkinson's disease compared with age-matched patients with other neurological diseases (OND) and tension headache. We found higher HLA-DR expression on CSF monocytes compared with blood monocytes. This difference was restricted to Parkinson's disease patients. T helper cell analysis revealed a decreased percentage of CD45RA+ "naive" and an increased percentage of CD45RO+ "memory" T cell subset from CD4+ T cells in peripheral blood of patients with Parkinson's disease compared with patients with tension headache. The proportions of CD8+ CD11b+high "suppressor" T cells remained unchanged, among the three patient groups compared. A selective loss of CD4+ CD45RA+ cells, previously observed in diseases like multiple sclerosis and Down's syndrome as compared with healthy controls suggests a common immunological abnormality in neurological disorders. PMID- 7847056 TI - Thalamic stroke: correlation of clinical symptoms, somatosensory evoked potentials, and CT findings. AB - We studied 18 patients with a single ischemic thalamic lesion, who had somatosensory disturbances and/or central pain in the opposite hemibody, by correlating their clinical symptoms, somatosensory evoked potentials (SEPs), and computed tomography (CT) findings. Patients were divided into three groups: (1) those with somatosensory deficits, central pain, and abnormal SEPs, which comprised two thirds of the patients (classic thalamic pain syndrome), (2) those with somatosensory deficits, no central pain, and abnormal SEPs (analgetic thalamic syndrome), and (3) those with almost normal sense perception, central pain, and normal SEPs (pure algetic thalamic syndrome). CT evidence of a paramedian or anterolateral thalamic lesion might be an indicator for the development of central pain, because these types of infarctions occurred only in patients with the classic thalamic syndrome or the pure algetic thalamic syndrome. The differentiation of the thalamic syndrome into three subtypes is of prognostic value, because patients with a loss of cortical SEPs and a posterolateral ischemic thalamic lesion on the CT scan probably will not exhibit central pain. PMID- 7847057 TI - Effect of subclavian syndrome on the basilar artery. AB - Fifty-five patients with a permanent or intermittent subclavian steal syndrome demonstrated by continuous wave Doppler were included in a prospective study: 25 patients without vertebro-basilar symptoms, 8 symptomatic patients with defined vertebro-basilar symptoms and 22 with hemodynamic vertebro-basilar occurrences. The basilar artery velocity was recorded by Transcranial Doppler Sonography in baseline conditions, and after a hyperaemia test to the upper limb. A spontaneous, incomplete basilar steal was diagnosed in seven patients, and a complete basilar steal in one patient, (14.5% of the cases). After hyperaemia test, 18 other incomplete basilar steal were observed. The occurrence of a basilar steal was higher in the vertebro-basilar group (57% of the cases) especially in 7 of the 8 cases with defined vertebro-basilar symptoms; it was lower in the patients without vertebro-basilar occurrences (36% of the cases). This basilar steal was also seen in five of the six symptomatic patients with opposite vertebral artery stenosis above a 50% diameter. Transcranial Doppler Sonography could help to define a subgroup of subclavian steal syndrome with a high risk of strokes. PMID- 7847058 TI - Diagnosis of thoracic outlet syndrome. Relative value of electrophysiological studies. AB - The diagnostic utility of various electrophysiological techniques was evaluated in patients with thoracic outlet compression syndrome (TOCS). Our results suggest that in true neurogenic TOCS, there is no standard electrophysiological picture, but that this evolves with the severity of the syndrome. The first changes observed are electromyographic, followed by changes in F-wave and SEPs, followed finally by changes in nerve conduction parameters. EMG study was certainly more informative, showing neurogenic damage not only in limbs with neurological signs but also in about 1/4 of limbs with only subjective symptoms. The study of F-wave and SEPs does not seem to be particularly helpful, however, in view of the peculiar changes found in these patients, SEPs may be a useful complement to EMG. Nerve conduction studies were of little utility since changes in these parameters are only found in patients with long-standing anomalies and severe atrophy. PMID- 7847059 TI - Dopamine D2-receptors in human narcolepsy: a SPECT study with 123I-IBZM. AB - Increased dopamine D2 receptor binding in basal ganglia has been reported in human narcolepsy. These studies have been based on post-mortem material of 8 patients, most of them also medicated for narcolepsy. We studied six narcoleptics without stimulant or anticataplectic medication. The patients had an unambiguous history of cataplexy, and they were also studied polygraphically. Single photon emission computed tomography (SPECT) imaging was performed. The D2 receptor density was determined by using 123I-iodobenzamide (IBZM). The control subjects were 8 unmedicated Parkinson patients with one-sided (hemiparkinsonian) clinical symptoms. The D2 receptor density in them is known to be normal or somewhat increased compared to healthy normals. The striatum/frontal D2 activity ratio was 1.331 +/- 0.084 (with phantom study correction 2.101 +/- 0.300) in the narcoleptic patients, and in the parkinsonian controls 1.321 +/- 0.052 (2.067 +/- 0.185) for the asymptomatic side and 1.335 +/- 0.025 (2.117 +/- 0.090) for the symptomatic side (i.e. contralateral to the side with the clinical extrapyramidal signs). There was no statistical difference between the groups or between the symptomatic and asymptomatic side in the Parkinson patients. Thus, our results differ from the earlier post-mortem studies. PMID- 7847060 TI - Quantitative SPECT cisternography in normal pressure hydrocephalus. AB - Twenty-one patients with normal pressure hydrocephalus (NPH), 8 patients with various brain diseases with an element of hydrocephalus, and 7 patients with miscellaneous dementia disorders were investigated with quantitative radionuclide cisternography (RC) using single photon emission computerized tomography (SPECT). The total intracranial counts as well as the counts in the lateral and third ventricles were measured. All 15 NPH patients accessible for postoperative examination were improved after shunt surgery. In all groups the ventricular and total intracranial counts level increased during the measurement period but remained constant in distribution in each group. The NPH patients had a higher relative count value in the lateral and third ventricles compared to the patients with miscellaneous dementia disorders. The relative values in the third and lateral ventricles were predictive for the outcome of shunt surgery. Quantitative SPECT RC appears to be a useful diagnostic procedure in NPH investigations. PMID- 7847061 TI - Modified Robinson-Smith procedure for the treatment of cervical radiculopathy. AB - In the present study, a modified Robinson-Smith procedure was used surgery for cervical radiculopathy in 52 patients. Thirty-one one-level and 21 two-level operations were performed. All patients were followed up between 1 and 3 years (mean 23 months) after surgery with a clinical evaluation by an independent investigator including a radiological examination. In 26 patients the postoperative result was classified as excellent, in 23 the result was good, in 2 satisfactory, while one patient was unchanged compared to the preoperative examination. No patient developed worsening of symptoms after surgery. Of 18 patients with duration of symptoms of more than 4 years, 16 demonstrated markedly improvement. No permanent postoperative complications were seen. A modified Robinson-Smith procedure appears to be safe and reliable and can be recommended in surgery for cervical radiculopathy. PMID- 7847062 TI - Risk factors for recurrences of febrile convulsions. AB - Risk factors for predicting recurrences of febrile seizures were studied in an unselected series of 169 children after their first febrile seizure. Follow-up data covering 2.1-6.8 (mean 3.8) years from the first febrile seizure were available from 167 of them (98.8%) including 72 girls. Altogether 35/167 (21.0%, 95% confidence intervals (CI) 14.6% to 29.1%) had further febrile seizures, and multivariate logistic regression analysis showed the number of febrile episodes (p = 0.011) and the occurrence of such seizures among first degree relatives (p = 0.015, relative risk 3.75, CI 1.22 to 11.5) to be significant risk factors for recurrences. Our findings indicate that more emphasis should be placed on preventing febrile episodes rather than concentrating only on preventing seizures with antiepileptic therapy. PMID- 7847063 TI - Brain involvement in myotonic dystrophy: MRI features and their relationship to clinical and cognitive conditions. AB - A prospective, case-control study was carried out on 25 patients with myotonic dystrophy (MyD) and 25 healthy subjects using brain magnetic resonance imaging (MRI). The frequency and severity of white matter hyperintense lesions (WMHL) and brain atrophy in MyD patients were compared with their clinical features and cognitive impairment using an extensive neuropsychological battery. Eighty-four per cent of MyD patients showed WMHL, compared with 16% of controls (p < 0.0001). These lesions involved all cerebral lobes, without hemispheric prevalence. Twenty eight per cent of MyD patients also showed particular WMHL at their temporal poles. Myotonic patients had significantly more cortical atrophy than controls. No relationship between atrophy and WMHL was found on the MRI scans. The extent of brain abnormalities (WMHL or atrophy) was not correlated to age, disease duration, physical disability or severity of neuropsychological impairment. Central nervous system abnormalities revealed by MRI appear to be an almost constant feature of MyD, but they are not found to be related to clinical or cognitive parameters. Their nature is still unclear: some of them, located at the temporal poles, seem to be characteristic of the disease, while others small, diffuse WMHLs, similar to the age related alterations revealed by MRI occurring during young and adult age in MyD patients. PMID- 7847064 TI - Fits of weeping as an unusual manifestation of reflex epilepsy induced by speaking: case report. AB - We report the case of a 62-year-old man with no past CNS history who for some weeks had had fits of weeping that lasted from 30" to 3', precede by any aura; sensorium was clear; there were no symptoms of any kind after the paroxysm; in the course of them his facial expression was that of weeping with sobbing and tears, but no corresponding affective-emotional content, as reported by the patient, who was able to converse during these episodes. The fits were easily triggered by speaking. EEG during an episode showed a slight flattening of the trace, high voltage sharp waves at 4-6 c/s appeared, especially over the left hemisphere. CT brainscan and cerebral angiogram revealed a large space-occupying lesion of cystic-necrotic appearance with considerable mass effect and characteristics of glioblastoma. Treatment with barbiturates ended the paroxysmal weeping. We consider that these episodes were simple partial epileptic seizure according to the WHO classification of 1981. PMID- 7847065 TI - Prognosis of centro-temporal spikes on the EEG in children without seizures. PMID- 7847066 TI - Plasma and CSF amino acid levels in ALS. PMID- 7847067 TI - Amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam: quantitative neuropathology, immunohistochemical analysis of neuronal vulnerability, and comparison with related neurodegenerative disorders. AB - Amyotrophic lateral sclerosis/parkinsonism-dementia complex (lytico-bodig) is a chronic neurodegenerative disorder with high prevalence among the native Chamorro population of Guam. Neuropathological, biochemical, and immunohistochemical analyses were performed on a relatively large series of Guamanian cases and compared to Alzheimer's disease cases. Thioflavin S and antibodies to amyloid beta A4 and tau proteins were used for analysis of pathological changes, and antibodies to the calcium-binding proteins parvalbumin and calretinin, and to a nonphosphorylated epitope on neurofilament protein to study select neuronal populations. A differential distribution of neurofibrillary tangles was observed in the neocortex of Guamanian cases compared to Alzheimer's disease cases, with much higher lesion counts in supragranular than in infragranular layers. Also, Guamanian cases with predominant parkinsonism had generally higher neurofibrillary tangle densities than cases with predominant amyotrophic lateral sclerosis. In addition, there was a certain degree of heterogeneity, qualitatively and quantitatively, in the biochemical distribution of tau proteins among Guamanian and Alzheimer's disease cases as revealed by Western blot analysis. Previous studies have suggested that the clinical symptomatology observed in patients suffering from Alzheimer's disease is related to the dramatic loss of specific corticocortically projecting neurons in the neocortex. Interestingly, a subset of neurofilament-rich pyramidal neurons known to be dramatically affected in Alzheimer's disease appears to be resistant in lytico bodig. Finally, as in Alzheimer's disease, calcium-binding protein-containing interneurons are not affected. These data suggest that the set of projection neurons affected in Guamanian cases may not correspond to those involved in Alzheimer's disease, and that both disorders are characterized by specific patterns of neuronal vulnerability. PMID- 7847068 TI - Amyotrophic lateral sclerosis of Guam: the nature of the neuropathological findings. AB - To elucidate the fundamental differences and similarities of the neuropathological features and etiopathogenesis of the amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia complex (PDC) of Guam, we conducted a topographic, quantitative and histological investigation of tau-containing neurons, neurofibrillary tangles (NFTs), Bunina bodies and ubiquitinated inclusion bodies in 27 non-ALS non-PDC Guamanian subjects, as well as 10 Guam ALS patients, 28 PDC patients, and 5 patients with combined ALS and PDC (ALS-PDC). The topographic distribution of NFTs was basically the same in each disease and also in the non-ALS non-PDC group. There were relatively few, if any, NFTs in non ALS non-PDC subjects and ALS patients, but there were many, especially in the frontal and temporal cortex, in Guam PDC and ALS-PDC patients. The histological and ultrastructural features of Bunina bodies in Guam ALS and ALS-PDC patients were similar to those reported in classic ALS. The ratio of occurrence of the inclusion in Guam ALS and ALS-PDC patients was similar to that reported so far in classic ALS. Ubiquitinated skein-like inclusion bodies were observed in the spinal anterior horn cells in Guam ALS and ALS-PDC patients. These findings indicate that classic ALS does exist on Guam, that NFTs in Guam ALS patients are merely a background feature widely dispersed in the population, that the mechanism of neuronal degeneration of Guam ALS is basically different from that of PDC, and that Guam ALS occurs initially are classic ALS. PMID- 7847069 TI - Presence of apolipoprotein E on extracellular neurofibrillary tangles and on meningeal blood vessels precedes the Alzheimer beta-amyloid deposition. AB - The localization of apolipoprotein E (ApoE) has been examined immunohistochemically in the autopsied brains of middle-aged and old-aged control subjects, with and without amyloid beta protein (A beta) deposits, and of Alzheimer's disease patients. Senile plaques were consistently labeled with ApoE antiserum even in the very early stage of senile plaque formation seen in the fifth decade. In the cerebellar molecular layer, small dots of ApoE immunoreactivity, which were prominent in the Alzheimer's disease subjects, were observed in addition to immunoreactivity in diffuse plaques. ApoE antisera labeled all of the extracellular neurofibrillary tangles (NFT), whereas only a small minority of extracellular NFT were positive for A beta. A punctate pattern of ApoE immunoreactivity was seen at the media of the meningeal vessels lacking amyloid, when senile plaques were present in the nearby cortex. In the early stage of amyloid angiopathy, the distribution of ApoE immunoreactivity was much more extensive than that of A beta positivity. These findings suggest that ApoE accumulates in the early stage of senile plaque formation and, furthermore, that ApoE accumulation precedes A beta deposition in extracellular NFT and amyloid angiopathy. PMID- 7847070 TI - Interphase cytogenetics of glioblastoma and gliosarcoma. AB - Interphase cytogenetics, i.e., in situ hybridization using probes to chromosome specific DNA, enables histological identification of cells bearing numerical chromosome aberrations and cytogenetic analysis of composite tumors. We studied routinely processed tissues from seven glioblastomas and three gliosarcomas using biotinylated probes to pericentromeric alpha-satellite sequences on chromosomes 10, 17 and X. By applying various pretreatment protocols, an evaluable compromise between morphology and signal intensity was obtained in most cases. Compared to vascular cells with normal chromosomal counts, a significant subpopulation of glioblastoma cells showed monosomy 10 (four of five cases), monosomy 17 (one of seven cases) and loss of one X chromosome (one of seven cases). All monosomy 10 cases comprised additional areas where two copies of chromosome 10 were retained. Among the gliosarcomas, both the glioma and the sarcoma portion showed monosomy 10 in one case and monosomy 17 in another case. In contrast, in the third case of gliosarcoma, monosomy 10 was found only in the glioma portion, whereas a gain of chromosome X was observed in the sarcoma portion. We conclude that: (1) numerical chromosome aberrations can be detected in routinely processed brain tumor biopsy specimens using interphase cytogenetics, making retrospective studies feasible; (2) glioblastomas show intratumoral cytogenetic heterogeneity with formation of monoclonal cell clusters; and (3) sarcoma and glioma elements in gliosarcomas may exhibit the same or different numerical chromosome aberrations, suggesting various histogenetic pathways of the sarcoma-like portion. PMID- 7847071 TI - A comparison of perineurial and vascular basal laminal changes in diabetic neuropathy. AB - Measurements were made of the thickness of the basal lamina of perineurial cells in the sural nerve in a series of patients with diabetic neuropathy and compared with a group of patients with type I hereditary motor and sensory neuropathy (HMSN) and with organ donor control cases. The thickness was significantly greater in the diabetic patients as compared both with the HMSN cases and the organ donor controls. This was most obvious for the intermediate layers of the perineurium. Perineurial basal laminal thickness was only slightly greater in the HMSN cases than in the organ donor controls and the difference was not statistically significant. The thickening of the perineurial cell basal laminae was compared with the thickening of the basal laminal zone around the endoneurial microvessels. No significant correlation was found either for the diabetic neuropathy or HMSN cases or for the organ donor controls. As had been observed previously, the basal laminal zone around the endoneurial capillaries was of increased thickness both in the diabetic neuropathy and the HMSN cases and, although it was greater for the diabetic neuropathy patients, the difference was not statistically significant. Taken together, these findings indicate that the thickening of the basal lamina of the perineurial cells is a more characteristic feature of diabetic neuropathy than is thickening of the basal laminal zone around the endoneurial capillaries. The results suggest that the causative mechanisms are likely to differ, a conclusion supported by the morphological appearances: the basal laminal thickening around the perineurial cells is uniform, whereas that around the capillaries consists of basal laminal reduplication.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7847072 TI - Markers of axonal injury in post mortem human brain. AB - beta-Amyloid precursor protein (beta APP) can be detected immunocytochemically at sites of axonal injury in the brain, and has recently been found to be a useful marker for injured axons in patients who survived for only 3 h after head trauma. It is transported by fast axonal transport and is thought to accumulate in detectable levels where the cytoskeleton breaks down. If this theory is correct, other substances should accumulate here in the same way, so we have used antibodies to other neuronal proteins to compare their efficacy as markers of axonal injury. SNAP-25, chromogranin A and cathepsin D also marked injured axons at all survival times studied (2.5 h-2 weeks), although they were not as sensitive or specific as beta APP. Immunolabelling for the 68-kDa neurofilament subunit (NF68) was present in most uninjured axons, and allowed axonal swellings to be seen in some cases. Synaptophysin, GAP-43, ubiquitin or tau did not label any normal or injured axons in this study. We, therefore, suggest that beta APP should be the immunocytochemical marker of choice for the detection of injured axons. This study also showed that microwave antigen retrieval significantly enhances the immunoreactivity of SNAP-25, chromogranin A, synaptophysin, GAP-43, ubiquitin and tau, in addition to that of beta APP, in formalin-fixed, paraffin embedded tissue, and reveals NF68 antigenicity where it was not previously detectable. PMID- 7847073 TI - Alzheimer's disease with asymmetric atrophy of the cerebral hemispheres: morphometric analysis of four cases. AB - To examine the clinicopathological correlations in rare Alzheimer's disease patients with asymmetric cerebral atrophy and to compare their pattern of cortical involvement by senile lesions with that observed in other cases with atypical Alzheimer's disease, we performed an extensive neuropathological analysis of the cerebral cortex in four such cases. Three patients presented with severe language impairment but relatively good preservation of praxis and gnosis even after several years of clinical evolution. Cerebral autopsies of these cases revealed a predominant left hemisphere atrophy. Conversely, in one case with marked right hemisphere atrophy, all of the cognitive functions were involved early in the course of dementia. Neurofibrillary tangles and senile plaques were preferentially localized in the prefrontal, temporal and posterior parietal cortex in both hemispheres, whereas the hippocampal formation displayed lower lesion densities than neocortical areas. Significantly higher neurofibrillary tangle and senile plaque densities were found in the more atrophic side in most of the areas studied. The ratio of neurofibrillary tangle and senile plaque densities between the two hemispheres was not correlated with the number of these lesions in the cerebral cortex. These results indicate that the degenerative process in demented cases with interhemispheric asymmetric cerebral atrophy is characterized by a widespread involvement of the neocortex by senile lesions and lacks clear regional topography of neurofibrillary tangle and senile plaque distribution. Moreover, the relative sparing of the hippocampus, comparable to that found in cases with focal progressive dementia, suggests that the dementing process may involve different cortical structures in cases with asymmetric cerebral atrophy than in typical Alzheimer's disease cases. PMID- 7847074 TI - Pleomorphic pineocytoma with extensive neuronal differentiation: report of two cases. AB - Two pineal parenchymal tumors are presented, arising in a 54-year-old man and a 72-year-old woman; respectively. They showed isomorphic, cellular areas of small cells, often with characteristic pineocytomatous rosettes, and of medium-sized cells, as well as less cellular regions with highly pleomorphic, often ganglioid large cells. Immunohistochemistry disclosed extensive neuronal differentiation. There was intense positivity for neurofilament protein and microtubule-associated protein 2 in the pleomorphic areas and more variable expression in the isomorphic regions. Diffuse synaptophysin positivity was seen, accentuated along the borders of pleomorphic cells and in the rosettes, as well as diffuse interstitial and/or cytoplasmic expression of neuron-specific enolase, PGP 9.5 and tau. beta-Tubulin III was detected in most cells and slight positivity was found in the rosettes. Expression of glial fibrillary acidic protein, however, was restricted to resident astrocytes and an interstitial network of processes. These neuronally differentiated pleomorphic pineocytomas underline the broad histomorphological spectrum of pineal parenchymal tumors. PMID- 7847075 TI - Dorsal root ganglia cocultured with macrophages: an in vitro model to study experimental demyelination. AB - The present investigation introduces an in vitro model to study macrophage properties during demyelination. Rat dorsal root ganglia (DRG) were cultured for obtaining myelinated peripheral nerve fibers. These cultures were exposed to non resident macrophages. In untreated control cultures, there was no indication of myelin removal by the added macrophages. DRG were exposed to enzymatically generated oxygen radicals using the xanthin/xanthin oxidase or the glucose/glucose oxidase system. Assessment of Schwann cell viability and ultrastructural morphology revealed different patterns of cell cytotoxicity and morphological changes in different experiments. High concentrations caused complete tissue necrosis of the DRG, while low concentrations did not affect either cell viability or ultrastructural morphology. Under intermediate experimental conditions, oxygen radicals caused non-lethal Schwann cell damage leading to Schwann cell retraction and myelin sheath rejection. Myelin lamellae were disrupted and decompacted. These changes were followed by a selective macrophage attack on myelin sheaths, resulting in demyelination. Axons, Schwann cells and sensory ganglion cells survived this attack. The specificity of the oxygen radical effects was tested in experiments using the oxygen radical scavengers catalase and superoxide dismutase. Catalase prevented the described effects on cell morphology and subsequently blocked demyelination by non-resident macrophages. PMID- 7847076 TI - An immunohistochemical study of p53 and proliferating cell nuclear antigen expression in progressive multifocal leukoencephalopathy. AB - Nuclear p53 immunoreactivity is demonstrated in infected oligodendroglia, as well as in a proportion of reactive and bizarre astrocytes, in seven progressive multifocal leukoencephalopathy (PML) biopsies. This likely represents binding to, and prolongation of the half-life of, wild-type p53 protein by JC virus T antigen. Other possible mechanisms are considered. The same cells show proliferating cell nuclear antigen (PCNA) positivity, as do a proportion of morphologically normal oligodendroglia and astrocytes, reflecting proliferating populations of these glial sub-types. It is possible that functional inactivation of p53 in nonlytically infected astrocytes may allow neoplastic astrocyte clones to emerge. However, p53 and PCNA immunoreactivity per se cannot be regarded as indicative of neoplasia in PML, and caution must be exercised in the interpretation of such nuclear staining profiles. PMID- 7847077 TI - Debrisoquine hydroxylase gene polymorphism in meningioma. AB - Cytochrome P450 CYP2D6 polymorphism is an autosomal recessive trait associated with impaired debrisoquine metabolism in 5-10% of caucasian populations. This polymorphism has been associated with susceptibility to Parkinson's disease, bladder cancer, various forms of leukemia and possibly melanoma. In many other cancer forms, the data remained contradictory due to the technical limitations for identifying affected individuals (poor metabolizers). A recently developed polymerase chain reaction-based assay allows convenient screening of approximately 80% of known mutations. We have tested brain tumors correlated with chromosome 22 deviations for genetic polymorphism in the cytochrome P450 CYP2D6 locus localized on chromosome 22q13. Thirty-one meningioma samples were analyzed and the observed frequency of heterozygotes and homozygotes for the G to A mutation did not deviate significantly from the distribution in a normal population. These data are comparable to previous observations in for example breast and colon cancer and indicate that the CYP2D6 locus on chromosome 22q13 is not involved in the pathogenesis of meningiomas. PMID- 7847078 TI - Mitochondrial changes in acute myopathy after treatment of respiratory failure with mechanical ventilation (acute relaxant-steroid myopathy). AB - A case of acute myopathy was observed in the course of treatment of respiratory failure with mechanical ventilation combined with prolonged neuromuscular blockade and administration of corticosteroids. A muscle biopsy revealed degeneration of muscle fibres. Electron microscopy showed loss of thick filaments as well as nemaline rods, vacuoles and cytoplasmic bodies. The mitochondria were increased in number, many harbouring paracrystalline inclusions, which were hitherto unknown in this condition. PMID- 7847079 TI - Severe panencephalic Pick's disease with Alzheimer's disease-like neuropil threads and synaptophysin immunoreactivity. AB - We report a case of a 69-year-old woman with an 11-year history of progressive dementia, who was found at autopsy to have classic Pick's disease pathology, as well as extensive paired helical filament -- immunoreactive neurities, with few Alzheimer's disease (AD)-like neurofibrillary tangles and no senile plaques. Both Pick bodies and neuritic degeneration were extensive in the neocortex and hippocampal complex. In addition, synaptophysin immunostaining of the hippocampal complex showed a bilaminar pattern of immunoreactivity in the outer molecular layer as previously described in AD. PMID- 7847080 TI - Cerebellar astrocytoma with extensive lipidization mimicking adipose tissue. AB - We report the case of an elderly woman with a history of headache, vomiting and dizziness while walking. On CT scans a mass was identified in the right cerebellar hemisphere exhibiting radiological characteristics of lipomatous tissue. Surgery revealed a compact lesion consisting of whitish-yellow tissue with a fatty aspect and texture. Smears of tissue samples and paraffin sections showed features suggestive of tissue mainly composed of fully differentiated lipocytes. Lipid-specific stainings on fresh frozen material confirmed univacuolar intracytoplasmic fat accumulation. However, immunohistochemistry for glial fibrillary acidic protein and electron microscopy clearly demonstrated the glial lineage of these lipid-laden cells. Therefore, the tumor was diagnosed as a highly lipidized astrocytoma. In our view, this case represents a variant of lipidized gliomas that has not been described previously and that differs phenotypically from the entities documented earlier. PMID- 7847081 TI - Neuronal lineage in ethyl-nitrosourea-induced brain tumors. PMID- 7847082 TI - Tubulovesicular structures in Gerstmann-Straussler-Scheinker disease. PMID- 7847084 TI - Uptake of [99mTc]technetium methylene diphosphonate in the growth plates of the rabbit tibia during the final part of epiphyseal growth activity. AB - Uptake of 99mTc-MDP was measured in the proximal and distal growth plate of the rabbit tibia during the final phase of growth. Scintigraphic data were compared with roentgenographically measured tibial length and signs of bony fusion of the growth plates. Uptake by the proximal tibial growth plate was higher than in the distal tibial plate. Uptake decreased on cessation of growth and during subsequent bony fusion. In particular in the proximal tibial region, uptake was still high after cessation of longitudinal growth, which illustrates that during the final period of growth uptake of 99mTc-MDP by a roentgenographically still open growth plate does not necessarily indicate that such a growth plate still contributes to longitudinal growth. Decrease in uptake during the final phase of growth should be considered, when bone scanning is part of a research protocol. PMID- 7847083 TI - [Experimental study of the deformations of the acetabulum in unipodal stance]. AB - This work is based on an experimental simulation of unipodal stance using skeletons obtained from fresh nonembalmed cadavers, including pelvis, the two last lumbar vertebrae, and both femurs. Periacetabular deformations in unipodal stance were recorded in 10 pelves, which were bilaterally tested (20 acetabuli). Measurements concerned circumferential deformations (tangential to the periphery of the acetabulum), and normal deformations (perpendicular to the periphery of the acetabulum). Deformations of the medial wall and relative displacements between both acetabular walls were simultaneously recorded. A tridimensional interpretation of acetabular deformations is proposed based on the following classification: acetabuli in which the acetabular notch widens and acetabuli in which the acetabular notch closes itself with lateral displacement of the acetabular walls on the circumference of the femoral head. Acetabular deformations appeared dependent on the shape of the femoral head, but were not influenced by the action of the muscular model. PMID- 7847085 TI - The required resultant abductor force and the available resultant abductor force after operative changes in hip geometry. AB - The required abductor force (Freq) and the available abductor force (Fav) are calculated for different positions of the hip rotation center (RC) and different greater trochanter (GT) shifts in the frontal plane of the body in the one-legged stance. It is biomechanically favorable that Fav exceeds Freq and that the magnitude of the resultant hip joint force (R) after the operation is decreased. The difference between Fav and Freq, which represents the relative abductor strength, increases after medialization of RC and after lateralization of GT. On the contrary, after medialization of GT and after lateralization of RC, the difference decreases, which has unfavorable biomechanical effects. Distalization of GT is favorable because it increases the relative abductor strength. PMID- 7847086 TI - Long-term results of elbow arthroscopy in 67 patients. AB - Based on the results of a retrospective study of 67 patients with diagnostic and surgical arthroscopy of the elbow from 1977 until 1991, we present our technique, results, complications, and indications for elbow arthroscopy. The average age of the patients was 26 years (range: 11-59). At the time of follow-up the patients were examined clinically as well as radiologically. The results were scored according to Figgie's score, which is based on the criteria of pain, function, power and range of motion. The overall score significantly increased from 61.6 preoperatively to 85.3 postoperatively. The age of the patient did not influence the results. However, patients who were laborers had a poorer outcome than the others. Patients with preoperative pain for 2 months to two 2 years had better results than patients with a preoperative course of more than 2 years. PMID- 7847087 TI - Arthroscopic treatment of anterior impingement of the ankle. AB - We report the results of the arthroscopic treatment of anterior ankle impingement in 13 consecutive subjects. Our patients were treated conservatively for an average period of 30 months, ranging from 2 to 120 months. They did not respond to corticosteroid infiltrations, NSAIDS or physical therapy. Debridement consisting of the removal of the bony spurs with a burr and shaving of hypertrophic synovial tissue was carried out. All 13 patients were reviewed 3 to 41 months after the operation, with a mean follow-up of 19 months. Of the ankles, 92% showed good (38%) or excellent (54%) results. Only one ankle rated fair. Out of the 13 patients, 10 went back to their preoperative sports after a mean of 4 months. We had no complications. In patients where conservative management fails, arthroscopic debridement of the anterior ankle compartment is an effective treatment. PMID- 7847088 TI - Arthroscopic ankle arthrodesis. Preliminary report. AB - A review of the first 10 arthroscopic ankle fusions at our institution was performed. Union was obtained in 7 of the 10 ankles with an average time to fusion of 4 months. There were 3 nonunions. Arthroscopic ankle fusion is less invasive than open techniques and less painful for the patient. However, there is a learning curve, and the arthroscopic technique is time-consuming. Arthroscopic ankle fusion has restricted indications, as patients with significant angulation, rotatory malalignment and extensive avascular necrosis of the talus can only be treated with open techniques. PMID- 7847089 TI - [Supple intervertebral stabilization according to Graf. Evaluation of its use and technical approach]. AB - The authors report their clinical experience with Graf's supple intervertebral stabilization system. The results are discussed with respect to the biomechanical and clinical definitions of vertebral instability and the natural evolution of degenerative disease of the lumbar spine. The result are favorable for the cases with clinical instability, but are not as good for the degenerative cases or after discectomy. In spite of the short-term clinical benefits for the cases with pathological articular hypermobility, the authors are cautious regarding the use of this technique. They emphasize the unknown long-term clinical and biomechanical evolution and the difficulties encountered for secondary arthrodesis caused by the volume of the pedicular screws. PMID- 7847090 TI - Excision or Silastic replacement for comminuted radial head fractures. A long term follow-up. AB - This report comprises a follow-up of 39 patients after simple excision and 16 patients after Silastic replacement of the radial head for displaced comminuted fractures. Prostheses were used when similar fractures were associated with an unstable elbow. The excision group was followed up for 6.1 years on average, and the replacement group for 5.7 years. The objective result after simple excision was good in 55% of cases, fair in 26% and poor in 19%. The results in the replacement group were only 13% good, 38% fair, 37% poor and in 12% the prostheses had to be removed. PMID- 7847091 TI - [Study of the correlation between magnetic resonance imaging and surgery in the diagnosis of chronic Achilles tendinopathies]. AB - Eighteen cases of chronic lesions of the heel cord were evaluated by MRI and operated. The sensitivity of MRI is high in detecting intratendinous lesions (positive predictive value of 0.94); this sensitivity is linked with an unsurpassed anatomical precision. The specificity in the diagnosis of intratendinous lesions is limited as regards partial rupture versus chronic inflammation. This technique can be improved by systematically making fine cuts in the transverse plane, absolutely perpendicular to the heel cord. PMID- 7847092 TI - The open palm technique in the treatment of Dupuytren's disease. AB - Twenty-eight patients (33 hands) were reviewed an average 2.5 years after an open palm technique combined with partial fasciectomy for the correction of Dupuytren's disease. They were assessed by diathesis evaluation and Tubiana's score. Results show a recurrence rate of 33.5% (3% severe), an extension rate of 51.5% and an overall complication rate of 21% without reflex sympathetic dystrophy. Fifteen percent and 12% had an important deficit in flexion and extension respectively. These findings are comparable to those found in the literature. PMID- 7847093 TI - [Benign osteonecrosis of vertebral body versus neoplastic lesions. Limitations of CT and magnetic resonance imaging]. AB - A case of vertebral necrosis of L4 is reported in a young woman without previous steroid therapy. Only the intraoperative histological examination was able to confirm the diagnosis as a benign vertebral collapse, because the CT scan and MR imaging were suggestive of a malignant involvement. The authors report the various criteria proposed to distinguish benign and malignant vertebral collapse with magnetic resonance imaging. These equivocal criteria should be viewed within the context of tissue replacement within the necrotic area during the evolution. Transpedicular biopsy is emphasized. Only the histological examination is specific and allows right planning of the surgical procedure. PMID- 7847094 TI - Isolated avulsion fracture of the lesser tubercle of the humerus in children. AB - Isolated avulsion fracture of the lesser tuberosity of the humerus has been reported in few instances. We present a case in a 15-year-old boy who was injured 2 years earlier. Clinical, radiological and interoperative findings are presented and discussed. PMID- 7847095 TI - Displaced radiocarpal dislocation with multiple associated fractures. AB - An unusual case of radiocarpal dislocation in a 33-year-old man is reported. He was treated with closed reduction and plaster immobilization with a good functional result. PMID- 7847096 TI - Achilles tendon ossification. AB - The authors describe the case of a patient who had an ossified Achilles tendon without fracture. Such ossification is uncommon, occurring most often after trauma or surgery. PMID- 7847097 TI - Regression of an intraosseous ganglion of the scaphoid following fracture. PMID- 7847098 TI - [Xth National Congress. The effects of sulphureo-sodiobromo-iodic water on catarrhal upper respiratory inflammations. 2-3 October 1993]. PMID- 7847099 TI - Role of androgens in the regulation of the human menstrual cycle. AB - Although previous investigations have examined the importance of androgens in the regulation of the human menstrual cycle, no consensus has been reached, due to conflicting results. We have therefore used the non-steroidal anti-androgen flutamide as a pharmacological probe to evaluate the role of androgens in the control of gonadotropin secretion in normally cycling women. Eight women were studied during control and treatment cycles, during which either placebo (as control) or flutamide (750 mg orally) was given daily. Blood was sampled every other day during the follicular and luteal phases and daily around the expected midcycles for determination of luteinizing hormone (LH), follicle stimulating hormone (FSH), estradiol, progesterone and androgens (testosterone, androstenedione, dehydroepiandrosterone sulfate) by radioimmunoassay and immunoradiometric assay. To establish unstimulated and gonadotropin releasing hormone (GnRH)-stimulated gonadotropin profiles, blood samples were frequently collected (every 10 min for 8 h, GnRH 25 micrograms i.v. after 7 h on day 10 in both the control and treatment cycles. Compared to control conditions, the durations of both the follicular and luteal phases did not change considerably during flutamide treatments. Serum androgen levels (testosterone, androstenedione, dehydroepiandrosterone sulfate) were significantly (p < 0.01) reduced during androgen antagonism. Daily gonadotropin and estradiol levels did not differ between control and flutamide cycles, while progesterone secretion tended to be attenuated (p = 0.2) during the luteal phases of the flutamide cycles. The LH and FSH secretory profiles and the GnRH-stimulated gonadotropin responses remained virtually unchanged during androgen antagonism.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7847100 TI - Immunohistochemical localization of interferon-gamma in normal human ovary. AB - There is increasing evidence that cytokines are important intraovarian non steroidal regulators. The aim of the present study was to evaluate the presence in the human ovary of interferon (IFN)-gamma, a cytokine produced by T lymphocytes after mitogenic or antigenic stimulation. Very low levels of IFN gamma (0.025-0.057 IU/ml) were found in follicular fluid of large spontaneously maturing follicles, in the ovarian vein (< 0.01-0.079 IU/ml) or peripheral blood (< 0.01-0.06 IU/ml). The avidin-biotin immunocytochemical technique, with appropriate monoclonal antibodies, was used to localize IFN-gamma-positive cells, human leukocyte antigen (HLA)-DR molecules, activated T cells, T helper/inducer cells and T cytotoxic/suppressor cells. IFN-gamma-positive cells were only detected in preovulatory follicles, associated with the follicular basal lamina, thecal vessels and interstitial tissue. In the same large follicles very few T helper/inducer cells were detected, but a high proportion of T lymphocytes expressed the CD8 phenotype in the theca, interstitial tissue and follicular cavity. No IFN-gamma-positive cells were observed in preantral and small antral follicles. The results indicate that the human ovary contains immunoreactive IFN gamma, suggesting that the cytokine plays a paracrine role in human ovarian function. PMID- 7847101 TI - Low luteal phase serum progesterone levels in regularly cycling women are predictive of subtle ovulation disorders. AB - Serial hormonal and ultrasound measurements were performed in a group of 50 infertile women with regular menstrual cycles of normal length, and evidence of luteinization by measurement of biphasic basal body temperature (BBT). The progesterone levels however, remained below a critical threshold of 32 nmol/l (1 nmol/l = 0.315 ng/ml) in two cycles. In 50 cycles, 25 showed definite abnormalities. In 16 other cycles, ovulation was observed, but relatively low luteal progesterone followed. Although pregnancy in these 16 cycles could be less likely, the real significance of this finding is questionable. The etiology of these 'subtle cycle anomalies' is not clear and may be multifactorial. For this reason, no therapy other than use of ovulation-inducing agents by trial and error is as yet available. Preliminary results indicate that cycle disturbances may persist under ovulation induction, even though progesterone levels are normalized. PMID- 7847102 TI - Positive response to compound CV 205-502 in hyperprolactinemic patients resistant to or intolerant of bromocriptine. AB - The clinical effects of CV 205-502, a potent and non-ergot-derived dopamine agonist, were investigated in 24 selected patients with hyperprolactinemia previously treated with standard oral bromocriptine, the slow-release oral form of bromocriptine (BRC-SRO) and/or the long-acting injectable form of bromocriptine (BRC-LAR); 14 were chosen because of their resistance to treatment and ten because they were intolerant of the different forms of bromocriptine. A macroprolactinoma was present in seven patients and a microprolactinoma in ten, whereas seven had no radiological images of a pituitary tumor and were classified as having non-tumoral hyperprolactinemia. All the 24 patients were treated with CV 205-502 at a daily dose of 0.075-0.6 mg for 3-12 months. All the patients had gonadal dysfunction and galactorrhea. Basal serum prolactin values ranged from 70 to 1677 ng/ml. CV 205-502 was effective in 11 of the 14 patients resistant bromocriptine, BRC-SRO and BRC-LAR; serum prolactin levels became normal within 6 months and a tumor shrinkage was obtained in five of the seven macroprolactinomas. In general, the drug was effective and well tolerated. Only three patients (two resistant and one intolerant) manifested nausea, vomiting and postural hypotension. In conclusion, this study shows that CV 205-502 is effective in bromocriptine-resistant hyperprolactinemic patients. Furthermore, CV 205-502 has insignificant and tolerable side-effects in patients intolerant of bromocriptine. CV 205-502 can, therefore, be considered a useful and effective drug, and an interesting therapeutic alternative to the ergot-derived dopamine agonist drugs in use today. PMID- 7847103 TI - Induction of aromatase in human granulosa cells by both follicle stimulating hormone and insulin-like growth factor-I involves tyrosine phosphorylation. AB - Evaluation of the intracellular signalling mechanisms of follicle stimulating hormone (FSH) and insulin-like growth factor-I (IGF-I) was performed in luteinized and non-luteinized human granulosa cells. A severalfold increase in estradiol production from androstenedione was induced by both hormones in these cells, while only FSH led to a concomitant increase in cAMP. IGF-I bound specifically to its receptor in these cells. Specific tyrosine kinase inhibitors (tyrphostins) blocked the effects of both FSH and IGF-I on aromatase activity without altering FSH-induced cAMP accumulation. These findings demonstrate an involvement of a tyrosine kinase pathway in the intracellular signalling mechanism of the IGF-I effect on aromatase activity. Furthermore, since FSH induction of aromatase activity can be blocked by a tyrosine kinase inhibitor without affecting the level of cAMP production, it can be suggested that tyrosine kinase(s) act downstream of cAMP production and protein kinase A activation. PMID- 7847104 TI - Estrogen therapy in women over 60 years of age. PMID- 7847105 TI - The role of insulin in ovarian size in patients with the polycystic ovary syndrome. AB - The objective of this study was to evaluate whether the degree of suppression of ovarian volume effected by a gonadotropin releasing hormone (GnRH) agonist in patients with polycystic ovary syndrome (PCOS) correlated with basal insulin secretion and insulin secretion provoked by a glucose challenge. Eighteen PCOS patients received the GnRH agonist D-tryptophan-6-LHRH (Decapeptyl, 3.75 mg monthly i.m.) for 6 months and had blood glucose and insulin measured during a 75 g oral glucose tolerance test (OGTT) prior to and at the end of therapy. According to ovarian volume suppression after GnRH agonist therapy, two groups were defined: in group A (n = 10; mean body mass index (BMI) +/- SEM, 25.6 +/- 1.6 kg/m2) ovarian volume regressed from 17.9 +/- 1.6 to 6.7 +/- 0.3 ml (full responders) and in group B (n = 8; mean BMI +/- SEM, 28.1 +/- 2.3 kg/m2) from 21.5 +/- 1.1 to 15.1 +/- 1.0 ml (partial responders). Results showed that GnRH agonist therapy did not affect significantly BMI or fasting levels and area under the curve (AUC) for glucose and insulin in the respective groups. Fasting insulin levels correlated positively with ovarian volume prior to (r = 0.56, p < 0.05) and after 6 months of GnRH agonist therapy (r = 0.80, p < 0.005). The suppressibility of ovarian volume with GnRH agonist therapy correlated negatively with the difference between maximal and basal levels (r = -0.68), the area under the curve (r = -0.62) and maximal levels (r = -0.72) for insulin during the OGTT.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7847106 TI - New perspectives in the treatment of postmenopausal osteoporosis: ipriflavone. AB - The efficacy and safety of ipriflavone, a new anti-osteoporotic agent, has been evaluated in an open study in 100 agent, has been evaluated in an open study in 100 osteoporotic women. Ipriflavone was administered as oral capsules dosed at 200 mg, 3 times a day for 12 months. Ninety women completed the study, and the results indicate that the bone mineral density was increased by 2% and 5.8% after 6 and 12 months, respectively. Pain and rachis mobility seemed to be positively influenced by ipriflavone. Only three women complained of side-effects (gastralgia and nausea) and asked to stop the therapy. PMID- 7847107 TI - Effect of two different progestins (cyproterone acetate and norgestrel), administered in a cyclical estradiol valerate regimen, on markers of bone turnover. AB - It has been suggested that some progestogens could have a stimulating effect on bone formation. This study was therefore undertaken in order to compare the influence of cyproterone acetate and norgestrel on bone metabolism when administered in a discontinuous, sequentially combined regimen with estradiol valerate. Twenty healthy early postmenopausal women were randomly assigned to treatment with either Cyclo-Progynova, containing 0.5 mg of norgestrel, or Climen, containing 1 mg of cyproterone acetate (CPA), over two 28-day cycles. Markers of bone resorption-fasting urinary hydroxyproline/creatinine and calcium/creatinine ratios - and of bone formation-serum alkaline phosphatase and osteocalcin-were determined initially, before the start of treatment and thereafter twice weekly (a total of 17 assessments for each women) during the 8 week treatment period. Serum osteocalcin concentrations were slightly but not significantly higher throughout the study period in women receiving Climen, compared to those taking Cyclo-Progynova. Cyclical fluctuation of serum osteocalcin levels were more pronounced in women with a high baseline level of osteocalcin. During the period of progestogen administration, osteocalcin concentrations were either similar to or even lower than those in the phase of administration of estradiol valerate alone. Serum calcium and alkaline phosphatase concentrations were relatively stable during the study period with both treatment regimens. Urinary excretion of calcium and hydroxyproline varied during the cycle but the variation was unrelated to either type or time of progestogen administration. Mean urinary hydroxyproline excretion during the 8 week study period was similar for both preparations, although the mean decrease in the urinary hydroxyproline/creatinine ratio was insignificantly higher for the CPA-containing preparation.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7847108 TI - Impact of different GnRH analogs in benign gynecological disorders related to their chemical structure, delivery systems and dose. AB - This review addresses the question of whether the different gonadotropin releasing hormone (GnRH) agonists in clinical use might have different impacts, related to their chemical structure, delivery system and dose. Impact was investigated in benign gynecological disorders, i.e. endometriosis and leiomyoma. Arguments are presented indicating that a difference in impact of different analogs can be expected. All currently used intranasal, daily subcutaneous and depot preparations finally give rise to low levels of serum estradiol. The number of days before the first ovulatory menstruation after discontinuation of GnRH agonist treatment is remarkably constant. Four weeks after the last impact of the agonist, there is resumption of follicle growth. This phenomenon is independent of chemical structure, delivery system and dose. One should realize, however, that it generally takes about 30 days before the impact of a depot preparation disappears. Consequently, the impact of a depot preparation lasts 4 weeks longer than that of an otherwise applied agonist. Thus resumption of pituitary activity after discontinuation of a depot formulation takes 4 weeks longer than after discontinuation of non-depot formulations. All agonists have an impressive effect on endometriosis, independent of their chemical structure and delivery system. However, there are no studies comparing different agonists with the same delivery system in comparable endometriosis groups. Similarly, all agonists considerably reduce myoma volume, independently of their chemical structure and delivery system.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7847109 TI - Cervical inflammation and preterm delivery in pregnant women with a history of preterm delivery. AB - BACKGROUND: A previous preterm delivery is a risk factor for preterm delivery in a subsequent pregnancy. We tested the hypothesis that evidence of inflammation on a Papanicolaou smear obtained during pregnancy is a risk factor for preterm delivery for women with a history of preterm delivery. METHODS: We studied women who had two singleton deliveries at a university hospital during an 8-year period. Women eligible for our study were those whose first delivery was preterm (< 37 weeks of gestation) and for whom a Papanicolaou smear was obtained during the second pregnancy. These smears were examined for evidence of inflammation by a cytopathologist. Information about the second pregnancy was obtained by chart review. RESULTS: The cytopathologist reviewed Papanicolaou smears from 92 study pregnancies and found evidence of cervical inflammation on 34 smears (37 percent). Preterm delivery ended 24 (26.1 percent) of the second pregnancies. The incidence of preterm delivery in women with inflammation on Papanicolaou smear was 41.2 percent compared with an incidence of 17.2 percent in women without inflammation (relative risk of 2.40 with a 95 percent confidence interval of 1.19 to 4.83). This association remained significant after controlling for potential confounding variables. A stratified analysis found that the association of cervical inflammation with preterm delivery was limited to women who had systemic exposure to an antibiotic during pregnancy. CONCLUSION: Among pregnant women with a history of preterm delivery, evidence of inflammation on Papanicolaou smear was associated with an increased risk of preterm delivery. If replicated in other studies, this finding might have implications for the management of pregnancies in women with a history of preterm delivery. PMID- 7847110 TI - Improving the immunization coverage of children less than 7 years old in a family practice residency. AB - BACKGROUND: This prospective cohort study was designed to evaluate the effectiveness of mail and telephone contact with parents as a means to improve the immunization coverage of children less than 7 years old in a family practice residency clinic. METHODS: Immunization records for 519 children enrolled in an outpatient clinic were reviewed and updated. Children whose immunizations were current (55) were excluded, which left 464 children whose immunizations were more than 1 month behind for their age groups. A random sample of one-half of these children (231) were mailed a postcard listing the immunizations that they required to be up to date. The mailing was followed up with telephone contact, when necessary, to prompt compliance. The other one-half of the children were not contacted and served as the control group. Immunizations provided to the two groups were compared 6 months after the initial mailing. RESULTS: Before the initiation of the study, only 10.6 percent of the infants and children in the practice had their immunizations completed or were up to date. There were 124 immunizations given to 49 children in the intervention group compared with 84 immunizations to 33 children in the control (P < 0.047). Thirty-four children were brought up to date in the control group compared with 17 in the intervention cohort (P < 0.011). CONCLUSIONS: Direct mail reminders and telephone contact with parents of children who were behind in their immunizations were effective methods to encourage compliance. The increased number of immunizations received by the children in the intervention group was overshadowed by the poor coverage of the entire practice, a highly mobile and predominantly indigent group. Additional interventions are urgently needed to improve immunization levels in infants and children. PMID- 7847111 TI - Clarithromycin-carbamazepine interaction in a clinical setting. AB - BACKGROUND: Clarithromycin was used to treat lower respiratory tract infection in several developmentally disabled men who were also taking carbamazepine for seizure disorder. METHODS: We studied retrospectively the use of clarithromycin in 5 patients taking carbamazepine. Because a drug interaction was suspected, the carbamazepine dosage was decreased during treatment, and serum levels were measured 3 to 5 days after change in therapy. In this study, we compared these findings with the base-line pretreatment and posttreatment dosage and serum levels of carbamazepine. RESULTS: Despite decreasing the dosage of carbamazepine by 30 to 40 percent, the serum levels of this drug increased in all of our patients while taking clarithromycin, including 3 patients who developed toxic serum levels of carbamazepine. CONCLUSION: There is a serious drug interaction between carbamazepine and clarithromycin. If possible, we believe that using clarithromycin should be avoided in patients taking carbamazepine. If clinical judgment suggests clarithromycin should be used, however, we suggest decreasing the dosage of carbamazepine by 30 to 50 percent, monitoring the serum drug levels closely, and warning the patient about the signs and symptoms of carbamazepine toxicity. PMID- 7847112 TI - The public hospital district for ambulatory care: an option to stabilize rural health services in crisis. PMID- 7847113 TI - First Annual Nicholas J. Pisacano Lecture. Words can hurt you: some reflections on the metaphors of managed care. PMID- 7847114 TI - Public health and health care reform: implications for family practice. PMID- 7847115 TI - Bilateral testicular cancer. AB - Although the case we described is not common, the incidence of testicular cancer, as well as bilateral testicular cancer, is rising. The primary care physician can help reduce morbidity in these patients by encouraging monthly self-examinations of the testicles and by paying attention to high-risk subgroups, such as those with a family history of testicular cancer, a personal history of cryptorchidism, infertility, or a contralateral testicular volume less than 12 mL. The primary care physician should, in at least these cases, discuss the option of a testicular biopsy to rule out CIS in the contralateral testicle. Treatment and follow-up options can then be explored to reduce further sequelae from this disease. PMID- 7847117 TI - Thrombolysis in pulmonary embolism: an adolescent with protein S deficiency. AB - Because of the low incidence of pulmonary embolism in children, the therapeutic approach is extrapolated from guidelines for adults. An adolescent boy with a massive pulmonary embolism associated with protein S deficiency was cared for successfully with intravenous thrombolytic therapy using 1.3 mg/kg of rt-PA with a 2-hour infusion time. In the absence of contraindications, most physicians consider using thrombolytic drugs in hemodynamically unstable patients who have a pulmonary embolism. A recent study described a subset of hemodynamically stable patients with right-ventricular dysfunction who also might benefit from thrombolytic therapy. PMID- 7847116 TI - Meperidine-induced seizure in a sickle cell patient using a patient-controlled analgesia pump. PMID- 7847118 TI - Family-general practice models in Canada. PMID- 7847119 TI - Obstetrics and the family physician: a medical historian's perspective. PMID- 7847120 TI - Health care reform. PMID- 7847121 TI - Consultation and referral. PMID- 7847122 TI - Full-term abdominal pregnancy. PMID- 7847123 TI - Morphological assessment in pinealectomy and foetal pineal gland transplantation in rats: Part I. AB - The effects of pineal gland, an endocrine organ known to affect the physiology of various organs and systems including the hypothalamo-hypophyseal axis, on the morphological characteristics of target organs were investigated in rats after pinealectomy and foetal pineal gland transplantation to a subpial cortical area close to the pinealectomized region. It was demonstrated that weight gain was significantly slower in pinealectomized male rats (p < 0.01); pituitary gland weight was lower in the pinealectomized group (p < 0.01) and transplantation had no effect on the weight of this organ; weight of adrenal gland and testis were lower after pinealectomy (p < 0.01) but restored back to control levels after transplantation; the mitotic activity in seminiferous tubules increased with pinealectomy and returned back to control indexes after transplantation. Research on hypothalamic catecholaminergic content revealed a diminished histofluorescence in pinealectomized rats which showed a potentiated restoration after transplantation. The innervation of the pineal gland was studied by anterograde and retrograde injections of Wheat Germ Agglutinin Horse Radish Peroxidase from superior cervical ganglion and pineal gland, respectively. It was demonstrated that cell bodies were traced both at the transplanted tissue and hypothalamus. In view of these data, the multifunctional and a probable high level homeostatic harmony regulator essence of pineal gland is discussed. PMID- 7847124 TI - A multidisciplinary approach to tumours involving the orbit: orbital re construction, a 3-dimensional concept. AB - Radical tumour removal in the region of the anterior skull base with involvement of the orbit requires not only good exposure but also acceptable reconstruction with good cosmesis, no visible scars and no injury to the eye. The possible approaches, which should be flexible and adapted to the location and extent of the pathology and the appropriate methods of reconstruction, are illustrated by four patients. The relevant literature is reviewed. Emphasis on the need for a 3 dimensional concept in the reconstruction and the importance of a multi disciplinary team is stressed. PMID- 7847125 TI - Posterior fossa haemangioblastomas. AB - 36 consecutive years' experience in treating 104 cases of posterior fossa haemangioblastomas is described and discussed. The mortality was 24%, with a tendency to decrease, reaching 20% in the last 15 years. About half the patients returned to neurological normality and full working capacity. Dividing the lesions into solid and cystic tumours, cystic tumours were more frequent, their survival was longer, recurrence less and postoperative state somewhat better. PMID- 7847127 TI - Long-term evaluation of asymptomatic patients operated on for intracranial epidermoid cysts. Comparison of the diagnostic value of magnetic resonance imaging and computer-assisted cisternography for detection of cholesterin fragments. AB - Magnetic resonance imaging (MRI) and/or computer-assisted cisternography (CAc) assessment of latent late recurrences in long-term asymptomatic patients surgically treated for intracranial epidermoid cyst is here presented. MRI was exclusively utilized in one patient; CAc was exclusively employed in three patients with metalic operative clips; both CAc and MRI were employed in another four patients. CAc appears to be more reliable than MRI in detecting cholesterin fragments in asymptomatic patients operated on for intracranial epidermoid cyst. PMID- 7847126 TI - Craniocerebral epidermoid and dermoid tumours: a review of 32 cases. AB - We reviewed 22 epidermoid and 10 dermoid tumours of the skull and brain from patients operated on consecutively at Henry Ford Hospital between 1975 and 1991. There were 19 intradural (16 epidermoid, 3 dermoid) and 13 extradural (6 epidermoid, 7 dermoid) lesions. The average age at presentation was 35 years for patients with epidermoids and 15 years for those with dermoids. Common clinical presentations for patients with intradural lesions included headache, visual deficits, and seizures, whereas patients with extradural lesions harbored asymptomatic scalp masses. All patients with intradural lesions were investigated with computed tomography (CT) and cerebral angiography, and 8 patients underwent magnetic resonance imaging (MRI). Total resection was possible in 12 (92%) of 13 extradural tumours, all with excellent outcomes. Eight (42%) of the intradural tumours were completely resected. Overall, with the intradural tumours we had good to excellent results in 17 patients (90%), poor results in 1 (5%), and 1 death (5%). Re-operation was needed in 5 intradural recurrences (26%) with deterioration in only one patient's neurologic status postoperatively. From a review of ours and others' data, we conclude that 1) these tumours have an insidious onset despite significant size and mass effect as demonstrated by imaging studies; 2) CT, angiography, and particularly MRI help to define the extent of subarachnoid tumour spread and involvement of neurovascular structures, thus permitting better surgical planning; 3) a significant number of intradural tumours are difficult to excise because of their adherence to neurovascular structures, and thus are related to higher morbidity and mortality; and 4) because of extremely slow growth, complete tumour resection should not be the goal at the risk of injury to neurovascular structures. PMID- 7847128 TI - Aneurysmal bleeding. A plea for early surgery in good-risk patients. AB - From 1985 onwards we have aimed at operating on good-risk patients, i.e., those graded I-III on the WFNS SAH Scale, within 3 days after the aneurysmal bleed. We report on a series of 100 consecutive operations for saccular aneurysm, covering a period of 5 1/2 years. Early operations (in the above sense) were done in 57 good-risk but otherwise unselected patients. After a one year follow-up, 47 of them (82%) were found to have made a good recovery (Glasgow Outcome Score I). The outcome of (mostly early) surgery in 15 selected poor-risk patients (WFNS SAH Scale IV and V) was much less favourable. Late surgery (4 or more days after SAH) was performed in 28 good-risk patients, most of whom had been admitted several days or weeks after the bleeding. Almost all of these patients had a good outcome. It is argued that the known management results of delayed surgery, which during the deliberately chosen interval exposes the patient to the risk of rebleeding and vasospasm, have by now been surpassed by those of early surgery. However excellent the surgical results of delayed operations may be, early operation should become the treatment of choice in good-risk patients. PMID- 7847129 TI - Potential of O6-methylguanine or O6-benzylguanine in the enhancement of chloroethylnitrosourea cytotoxicity on brain tumours. AB - The purine analogues O6-methylguanine and O6-benzylguanine are well-known as a chemical modulator of the DNA repair enzyme O6-methylguanine-DNA methyltransferase. Inactivation of the enzyme by O6-methylguanine or O6 benzylguanine is expected to enhance sensitivity of tumours to chloroethylnitrosoureas. We studied the effect of O6-methylguanine or O6 benzylguanine pretreatment on cytotoxicity of 1-(4-amino-2-methyl-5 pyrimidinyl)methyl-3- (2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) in brain tumour cells and transplanted brain tumours. Two-hour exposure of O6 methylguanine at higher concentrations (500 microM, 1,000 microM) increased ACNU cytotoxicity by only 2 times in ACNU-resistant C6-1 brain tumour cells. O6 Benzylguanine at concentrations between 10 and 100 microM markedly enhanced the cytotoxic effect. The ACNU sensitivity of the tumour cels pretreated with O6 benzylguanine was 5-40 times that of the cells without O6-benzylguanine. Neither O6-methylguanine nor O6-benzylguanine appreciably enhanced ACNU cytotoxicity of 9 L cells, which were originally sensitive to ACNU. Intracarotid ACNU with O6 methylguanine or O6-benzylguanine decreased proliferating activity of transplanted C6-1 brain tumours significantly during 48 hours. O6-Benzylguanine pretreatment resulted in a greater degree of suppression for a long time. The C6 1 tumours treated only with intracarotid ACNU showed a transient inhibition and a rapid regrowth during 24 hours after the treatment. These results indicate that O6-methylguanine or O6-benzylguanine increases ACNU cytotoxicity and may be feasible for effective combination therapy with chloroethylnitrosourea in the chemotherapy of malignant brain tumours. PMID- 7847130 TI - Magnetic resonance angiography (MRA) of ruptured cerebral aneurysm. AB - The purpose of this study was to evaluate the high resolution magnetic resonance angiography (MRA) as pre-operative angiography for the detection of ruptured cerebral aneurysms. MRA was performed on 1.5 tesla system using the 3-dimensional time of flight (3D-TOF) method. The field of view was 16 cm or 20 cm and matrix size was 192 x 256 or 256 x 512. Twenty patients with ruptured cerebral aneurysms and 35 cases of non-ruptured aneurysms (incidental aneurysm) examined by both conventional angiography and MRA were included in this study. All the ruptured aneurysms were operated on based on the information obtained from conventional angiography and MRA. Aneurysms smaller than 3 mm in size were difficult to visualize on MRA. However, most ruptured aneurysms were clearly visualized because they were generally larger than 3 mm. The image quality of MRA was satisfactory for planning surgery. Screening for non-ruptured cerebral aneurysms using MRA is controversial. However, in ruptured aneurysms larger than 3 mm in size, MRA clearly revealed the aneurysm, and MRA findings were informative enough to plan surgery. It is concluded that this noninvasive examination can be selected as a first-choice examination especially in cases of ruptured aneurysm. PMID- 7847131 TI - Prevention of delayed ischaemic deficits after aneurysmal subarachnoid haemorrhage by intrathecal bolus injection of tissue plasminogen activator (rTPA). A prospective study. AB - Among a series of 224 patients with aneurysmal subarachnoid haemorrhage (SAH) admitted over a period of three years, 52 patients were prospectively treated with intrathecal tissue plasminogen activator (rTPA). All of these patients were admitted and operated on within 72 h after SAH. SAH was confirmed by CT scan and the volume of blood accumulated in the basal cisterns was graded according to Fisher's scale. All patients had a SAH according to Fisher's grade III, as a prerequisite for inclusion into the study. In 21 patients additional intraventricular bleeding was detectable on CT scan. The diagnosis of a single intracerebral aneurysm as the bleeding source was established by pan-angiography, which also excluded additional cerebro-vascular malformations. The control group consisted of 68 patients, which were also treated within 72 h after SAH. Age and sex distribution as well as the clinical patterns were comparable to the rTPA group. In all patients the aneurysm was clipped using standard microsurgical techniques. After the aneurysm had been excluded from the parent vessel, 10 mg of rTPA, dissolved in 10 ml of its solution fluid, were slowly instilled into the basal cisterns in the treatment group. In patients with additional severe intraventricular bleeding, 5-10 mg of rTPA were injected into the ventricles via an intraventricular catheter at the end of the operation. Apart from the intrathecal application of the thrombolytic substance, the surgical protocol was identical in the patients of the control group. During the postoperative period, the patients in both groups were examined neurologically and by transcranial Doppler on a daily basis.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7847133 TI - Ruptured supratentorial arteriovenous malformations associated with venous aneurysms. AB - Six patients with ruptured supratentorial arteriovenous malformation (AVM) and an associated venous aneurysm (ectasia, dilatation, varix, pouch) are described. At presentation, patients ranged in age from 16 to 61 years and were equally distributed according to sex. Maximal AVM diameter was between 2.5 and 5.0 cm at presentation while the maximal size of the venous aneurysm ranged between 0.75 and 3.0 cm. One patient had multiple venous pouches while 5 patients had a single venous aneurysm. Three patients had a single bleed; 1 patient had 2 bleeds; and 2 patients had 3 bleeds. Hemorrhage around the venous aneurysm was seen in 4 of 5 patients who underwent magnetic resonance imaging of the brain. One patient, who suffered 3 bleeds over a several year period, had both an increase in the size of the venous aneurysm as well as enlargement of the AVM. The following features did not appear to influence hemorrhage: AVM size or location; venous aneurysm size or location; age; sex; pattern; location or number of draining veins; or external circulation feeders. These observations suggest that a venous aneurysm may increase the risk of hemorrhage from a supratentorial AVM and may be an ominous feature. PMID- 7847132 TI - Platelet-activating factor and antiphospholipid antibodies in subarachnoid haemorrhage. AB - The purpose of this study was to measure plasma platelet-activating factor (PAF) concentration, PAF-acetylhydrolase activities, anti-phospholipid antibody (aPLs) titers, and platelet function in patients with subarachnoid haemorrhage (SAH) and to assess the association of these variables with the development of cerebral vasospasm. Thirty-two patients with SAH due to ruptured cerebral aneurysm were studied. Plasma PAF concentration, PAF-acetylhydrolase activity, platelet count and aggregability, and plasma factor 4 (PF4) concentrations were measured regularly until approximately 2 weeks after SAH. aPLs, including lupus anticoagulant and anti-cardiolipin IgG and IgM were measured within 3 days after SAH. Plasma PAF concentration in patients with SAH showed the highest value on the occasion during 5 to 9 days after SAH. The concentrations were higher in patients with infarction due to vasospasm than in patients without cerebral infarction on any occasions after SAH. Plasma PAF-acetylhydrolase activities did not change in patients, regardless of the presence of cerebral infarction after SAH. Increased platelet consumption and aggregability and higher concentrations of PF 4 were detected in patients with cerebral infarction and not in patients without cerebral infarction. The patients with cerebral infarction due to cerebral vasospasm had aPLs more frequently than the control volunteers. Our findings indicate that increased plasma PAF and aPLs may contribute to the pathogenesis of cerebral vasospasm after SAH. PMID- 7847134 TI - Preservation of the temporal branch of the facial nerve in pterional transzygomatic craniotomy. AB - The temporal branch of the facial nerve may be saved in a pterional transzygomatic craniotomy if the dissection is carried beneath the superficial temporal fascia. The anatomical and technical aspects of this exposure are described in this report. PMID- 7847135 TI - Vascularized bone flap for anterior skull base reconstruction. AB - A case is reported where a vascularized outer-table of the frontal bone was successfully used to reconstruct a large defect in the anterior skull base following excision of a massive olfactory groove meningioma extending into the ethmoid sinuses. The flap provided a firm barrier between the cranial cavity and paranasal air sinuses, as the dural and bony integrity of the base was compromised after the radical resection of the tumour. It appears that such a flap can be effectively used for skull base reconstruction. PMID- 7847136 TI - Toxic shock syndrome in transsphenoidal neurosurgery. AB - An overlooked toxic shock syndrome (TSS) may lead to a fatal outcome. In neurosurgery a transsphenoidal approach with post-operative nasal tamponade may promote toxic shock syndrome without signs of local wound infection. By discussing the case history of a patient after hypophysectomy by the transsphenoidal route, we propose that after the appearance of the first signs of toxic shock syndrome, quick removal of the nasal tamponade is a life saving procedure. PMID- 7847137 TI - Open thrombectomy combined with thrombolysis in massive intracranial sinus thrombosis. AB - A case of complete thrombosis of the superior sagittal sinus in a pregnant women with multiple haemorrhages and hydrocephalus is described. Due to acute onset and progressive neurological deterioration, the decision was taken to remove the clot surgically. A sinotomy was performed removing the thrombotic material followed by local infusion of tissue plasminogen activator (t-PA). The combination of surgical removal and thrombolysis was life-saving for this young patient. PMID- 7847138 TI - Anomaly of venous system in congenital occipital dermal sinus. AB - We report two cases of congenital occipital dermal sinus in which elongation of the vein of Galen, elevation of the straight sinus, division of the superior sagittal sinus, elevation of the confluence of sinuses, elevation of transverse sinus and narrowing of the torcular angle were observed in the venous phase of cerebral angiography. Enhanced computed tomography (CT) revealed enlargement of the supracerebellar cistern, elevation of the straight sinus and of the confluence of sinuses, but no evidence of intracranial lesions. In order to study the relationship between anomalies in the dural venous sinuses and congenital occipital dermal sinus, we examined both cases from an embryological viewpoint. PMID- 7847139 TI - Effects of increased intracranial pressure in brain surface microcirculation in rats. AB - The effects of increased intracranial pressure (ICP) on pial vessel diameters were investigated in rats using a cranial window and fluorescence microscopy. The brain surface was superfused with mock cerebro-spinal fluid (CSF) at a constant rate (5 ml/h), and the ICP was raised up to 20 mmHg by elevating a CSF-reservoir connected to the CSF-outlet of the window. Arterioles dilated as the ICP increased (+ 12% dilation at 20 mmHg ICP). Following a rapid reduction of the raised ICP to normal, arteriolar diameters did not return to control values (+ 7% dilatation), while venules dilated (+ 3%), indicating reactive hyperaemia. At this time, CO2 inhalation induced a low response in the arterioles (+ 0.4%/mmHg PaCO2 increase) and an over-response in the venules (+ 0.3%/mmHg). The CO2 response decreased in smaller arterioles (< or = 30-40 microns phi). In addition, a few animals showed extravasation of Na(+)-fluorescein administered intravenously. Our results indicate that reactive hyperaemia can take place following a rapid return from an increased ICP to an normal level, even in cases of mild intracranial hypertension; a disruption of the blood-brain barrier may follow. PMID- 7847140 TI - Development of the neurocranium after transsutural fixing by new, resorbable poly L-lactide miniplates. A comparison to fixing with the common titanium miniplates. AB - The right coronal sutures of twelve (12) newborn rabbits were fixed with commercially available, self-reinforced poly-L-lactide miniplates, with eight (8) rabbits sham treated with titanium miniplate fixation as reference experiments, in order to demonstrate the possible effects on skull growth. After six (6) months follow-up, both types of plate were detected to have caused a similar asymmetry in the neurocranium. Therefore, in our opinion, fixing across growing sutures, even with the new biodegradable devices, should be avoided. PMID- 7847141 TI - Parameters in electrode positioning in thoracic percutaneous facet denervation: an anatomical study. AB - The purpose of the present study was to verify if needle placement in thoracic percutaneous facet denervation (PFD), based on bony landmarks, and under fluoroscopic guidance, would lead to constant anatomical positioning; and hence to an adequate placement at the assumed target, i.e., the medial branch of the dorsal ramus of the spinal nerve; and furthermore to determine if interpretation of the needle position by CT is more reliable than by fluoroscopy. The procedures were carried out bilaterally at all 12 levels on two cadavers, simulating the clinical setting as much as possible. In 44 cases the position of the needles was determined on hard copies of fluoroscopic images, 1.5 mm interval CT-images, surface-photographs, and on counterstained 25 microns sections obtained by a multirange heavy duty cryomicrotome. The sections established that standardized use of bony landmarks under fluoroscopic control can result in reproducible anatomical needle positioning in thoracic PFD. Nervous tissue was hit in 27 (61%) cases, but the supposed target structure, i.e., the medial branch "stem" was never hit. In none of the procedures was an accidental pleural puncture observed. The correlation between fluoroscopic images and sections was poor. The correlation between CT and sections was better, except for the mediolateral direction. The results of the present study suggest that "pure" anatomical positioning based on bony landmarks analogous to those used in the lumbar region is not reliable enough for thoracic PFD, and that corrections after electrostimulation substantially contribute to obtaining an adequate position of the needle. PMID- 7847142 TI - The lumbar and lumbosacral facet-syndrome. Diagnostic measures, surgical treatment and results in 119 patients. AB - The authors present their diagnostic and therapeutic protocol as well as the surgical outcome in a series of 119 patients with the lumbar facet syndrome. By use of different surgical techniques such as translaminar screw fixation (n = 56), Louis plate fixation (n = 36), Cotrel-Dubousset instrumentation (n = 11) and soft system stabilization according to Graf (n = 14) excellent, good, satisfactory, moderate and poor results were obtained in 78 (67%), 20 (17%), 14 (12%), 4 (3%), and 1 (1%) instances, respectively. PMID- 7847143 TI - Percutaneous nucleotomy in the treatment of lumbar disc herniation results after a mean follow-up of 2 years. AB - We have evaluated the clinical outcome of 45 consecutive patients who underwent percutaneous nucleotomy for a single-level disc herniation. Included were 28 (62%) woman and 17 (38%) men, with a mean age of 46 years. The mean postoperative follow-up time was 2 years. Intra-operatively, disc herniation was graded as a protrusion in 23 (51%) patients and as a prolapse in 22 (49%) patients. During the follow-up, sciatic pain completely recovered or markedly diminished in 38 (84%) patients and 35 (78%) patients returned to work. The occupational outcome of the patients operated on for a protrusion was inferior to that of the patients operated on for a prolapse: only 22% of the patients who underwent surgery for a protrusion reported to manage their work well, while as many as 41% of those with a prolapse managed well (p = 0.04). Pre-operatively, clinical examination revealed segmental instability of the lumbar spine in 11 (24%) patients. There was a significant association between instability and unsatisfactory long-term outcome: of the patients with pre-operative instability, 45% were postoperatively retired or on sick leave because of the back, as compared to 15% of the 34 patients without instability (p = 0.03). Furthermore, patients with instability suffered from sciatica and low back pain significantly (p = 0.02) more often than those without instability. Surgical complications were infrequent. There were no nerve root lesions and no vascular injuries. Postoperative discitis developed in 2 (4%) patients. Of all patients, only 1 (2%) has been re-operated on for a recurrent disc. PMID- 7847144 TI - Duration of symptoms as a predictor of outcome after lumbar disc surgery. AB - Retrospectively 93 consecutive patients operated on for lumbar disc herniation were studied in order to evaluate the prognostic value of symptoms (lumbar pain and sciatica) and sick-leave. Surgical results were evaluated 1-3 years postoperatively by a questionaire. The duration of the present attack of sciatica and sick-leave prior to surgery was significantly longer in the group with unsatisfactory outcome compared to the group with satisfactory outcome. Patients with duration of the present attack of sciatica of less than 6 months had a significantly better result concerning outcome compared to patients with duration of 6-12 months and more than 12 months. Patients who returned to the same type of work had a preoperatively statistically significant shorter duration of present sick-leave, compared to the patients who had changed the type of work and the patients who did not return to work. The patients with duration of their present sick-leave of less than 6 months had a significantly higher percentage of returning to the same type of work compared to patients with duration of their present sick-leave of 6-12 months and more than 12 months. We conclude that the duration of sciatica and sick-leave before the operation has value as predictive factors concerning the over-all result after surgery for lumbar disc herniation. PMID- 7847145 TI - Facial motor responses evoked by direct electrical stimulation of the trigeminal root. Localizing value for radiofrequency thermorhizotomy. AB - In Sweet's description of RF-thermocoagulation for trigeminal neuralgia, the trigeminal nerve was stimulated at 50 c/s to evoke paraesthesias, in order to check the electrode location before the thermolesion is made. In 1979, we changed the frequency to 5 c/s, so as to produce in addition twitches in the masticatory muscles (in stead of the less detectable tetanization produced by 50 c/s stimulation). Since then, we started to observe, also, twitches in the muscles innervated by the facial nerve. These twitches were not always in the Orbicularis oculi (which corresponds to the classical blink reflex), but also in the lower facial muscles. Such clinically observable evoked motor responses (EMR)-which had not been reported before--were noticed in 44% of the 459 procedures performed from 1979 to 1988. When EMR were present, the threshold to evoke paraesthesias before thermolesion, and the duration of the thermolesion for obtaining a marked hypoaesthesia covering the entire painful territory, were significantly lower, respectively p < 0.01 and p < 0.001, than when EMR were absent. This indicates that the electrode was closer to the nerve when EMR were present. As a probable consequence, recurrence of pain was significantly lower in the EMR (+) group: 1.4%, than in the EMR (-) group: 5.8% (p < 0.05). The twitches corresponded to the territory of the evoked paraesthesias in 95%, and to the hypoaesthetic area created by the thermolesion in 96%. So, getting EMR in the territory of the pain can be a helpful indicator for an accurate location of the electrode in the trigeminal root, according to its somatotopic organization. These EMR are hypothesized to be due to a trigemino-facial reflex. A preliminary intra operative EMG study clearly shows that for EMR in the upper part of the face we are dealing with blink-like reflexes, whilst for EMR in the lower face, mechanisms still remain unclear and need further study to be understood. PMID- 7847146 TI - Clinical and neurophysiological correlations in patients with refractory partial epilepsy and intracranial structural lesions. AB - Twenty patients (13 males, 7 females), who presented with refractory partial epilepsy and a CT and/or MR detected intracranial intra-axial structural lesion were admitted to the University of Gent Epilepsy Monitoring Unit. Mean duration of the epilepsy was 17 years (2-47 years). All patients were enrolled in a comprehensive presurgical protocol including neurological examination, video scalp-EEG monitoring with prolonged interictal and ictal recording, neuropsychological assessment and positron emission tomography (PET). Intracranial EEG monitoring was performed in 5 patients in whom discrepancies between different tests were found during the non-invasive evaluation. Clinical neurological examination was normal in 16 patients; 4 patients had a mild contralateral hemiparesis. Lesions were mainly located in the temporal lobe (55%). Most patients presented with complex partial seizures (90%). Clinical seizure characteristics correlated well with the lesion location in 55% of patients. Interictal EEG showed focal epileptic activity and focal slowing in respectively 85% and 30% of patients. Interictal EEG lateralization was congruent with the side of the lesion in 17 patients (85%). Interictal EEG localization was congruent with the lobe of the lesion in 13 patients (65%). Ictal EEG lateralized correctly in 14 patients (70%) and localized correctly in 10 patients (50%). Neuropsychological assessment lateralized and localized congruently in respectively 8/17 (47%) and 7/17 (41%) of patients. Interictal PET showed focal interictal hypometabolism, congruent with the lesion, in 13/16 (81%) of patients. Intracranial EEG was congruent with the lesion location in 3 patients but non congruent in 2 patients. All patients underwent surgical procedures: average follow-up was 14 months (6-24 months). Complete surgical removal of the lesion with free margins resulted in a more than 90% reduction of seizures without postoperative neurological deficit in 12/13 patients. PMID- 7847147 TI - Behavioural assessment of pinealectomy and foetal pineal gland transplantation in rats: Part II. AB - Pineal gland is an endocrine organ which exerts regulatory effects on the activity of various organs and systems. The present study was undertaken to highlight in experimental animals the possible integrative function of this endocrine organ on a behavioural pattern. Pinealectomy and foetal pineal gland transplantation to a subpial cortical area close to the pinealectomized region was performed. Behaviour was defined through motor activity induced by low (2 mg/kg) and high (10 mg/kg) doses of amphetamine in rats. It was shown that pinealectomy produced significant different patterns of behaviour induced by low and high doses of amphetamine. In sham operated animals low dose amphetamine induced a significant locomotor stimulation but without stereotyped activity. High dose amphetamine induced stereotyped activity. After pinealectomy even low dose amphetamine produced the behavioural pattern of stereotyped activity resembling a high dose amphetamine-induced behaviour. This differential effect of amphetamine, seen in pinealectomized rats, was completely restored after transplantation. On the other hand, melatonin treatment did not generate a significant alteration of behavioural profile either in the control or pinealectomized group of rats. Results are discussed with regard to the general regulatory function of the pineal gland. PMID- 7847148 TI - Subdural and depth electrodes in the presurgical evaluation of epilepsy. AB - From 1987 to 1992, invasive EEG studies using subdural strips, grids or depth electrodes were performed in a total of 160 patients with medically intractable epilepsy, in whom scalp EEG was insufficient to localize the epileptogenic focus. Dependent on the individual requirements, these different electrode types were used alone or in combination. Multiple strip electrodes with 4 to 16 contacts were implanted in 157 cases through burrholes, grids with up to 64 contacts in 15 cases via boneflaps, and intrahippocampal depth electrodes in 36 cases using stereotactic procedures. In every case, localization of the electrodes with respect to brain structures was controlled by CT scan and MRI. Visual and computerized analysis of extra-operative recordings allowed the localization of a resectable epileptogenic focus in 143 patients (89%), who subsequently were referred for surgery, whereas surgery had to be denied to 17 patients (11%). We did not encounter any permanent morbidity or mortality in our series. In our experience, EEG-monitoring with chronically implanted electrodes is a feasible technique which contributes essentially to the exact localization of the epileptogenic focus, since it allows nearly artefact-free recording of the ictal and interictal activity. Moreover, grid electrodes can be used for extra operative functional topographic mapping of eloquent brain areas. PMID- 7847150 TI - Middle fossa transpetrosal-transtentorial approaches for petroclival meningiomas. Selective pyramid resection and radicality. AB - Forty-two patients with petroclival meningioma were operated upon by the middle fossa transpetrosal-transtentorial approaches since 1977. Half of those showed tumour extension into the middle fossa and one-third in the cavernous sinus. Seventeen (40%) had a large tumour of 40 mm in diameter or larger, and 8 of those had a broad attachment from the clivus to petrous pyramid of the temporal bone. The site of pyramid resection was selected from three types, depending on the tumour location and the patients' pre-operative hearing. There was no surgical mortality. Significant risk of lower cranial nerves palsy was minimal and useful hearing was preserved in 18 out of 21 patients. The follow-up, an average of 4 and a half years, showed tumours were completely eradicated in 32 patients (76%) and there was regrowth in 3 (7%). Thirty-four patients (81%) were independent, 3 disabled and only one died of rapid tumour regrowth. The most influential factor on surgical results was the extent to which the tumour had invaded the brain stem. The presence or absence of arterial encasement and of peritumoural oedema on MRI were important in the selection for radical surgery. PMID- 7847149 TI - Premature craniosynostosis. A retrospective analysis of a series of 52 cases. AB - A retrospective analysis of a consecutive series of 52 cases with premature craniosynostosis is presented. Excellent functional, cosmetic, and social results could be achieved by resection of prematurely fused sutures and the creation of artificial growth sutures. Pronounced skull deformities have been corrected using the "basket handle", the "visor plasty", and the "T- bone" techniques or a combination of several of these skull form correction techniques. The surgical correction of the skull base by the "frontal advancement" technique in combination with orbitotomy was only necessary in 2 of our cases and could have been considered in 2 additional cases viewed retrospectively. Our results support the hypothesis that the primary cause of skull deformity is the premature closure of vault sutures and not a primary deformity of the skull base. PMID- 7847151 TI - Giant cranial base tumours. AB - Thirty-three patients with giant (diameter > or = 4.5 cm) cranial base tumours who underwent surgery at the Hadassah Hospital over the last ten years are described. Twenty-three of the patients had meningiomas, 4 neurinomas, one giant cell tumour, one haemangiopericytoma, and 4 had malignant meningiomas. Four tumours were at the cerebellopontine angle, 9 within the anterior cranial fossa, 8 petroclival, 8 on middle fossa floor, and 4 along the sphenoid ridge. The average pre-operative symptom duration was 31 months, range 3-180 months. Nineteen patients had a radical tumour resection, 10 subtotal, and 4 a partial resection on an average 1.7 operations per patient. The mean follow-up period from the first operation was 39 months (range 2-120). There was no mortality peri operatively or during the follow-up period. The mean pre-operative Karnofsky score was 68 and at the last follow-up 76. There was no correlation between histology and degree of resection, complications, or status at last follow-up. The best resections (92% radical) and outcome (mean Karnofsky 92) with the least number of operations (mean 1.4) were in the anterior fossa and along the sphenoid wing. The patients requiring the most operations (mean 2.1), having the smallest percentage of radical resections (25%) and the least favourable outcomes (mean Karnofsky 52) were those with petroclival tumours. Patients with giant cranial base tumours have a good overall long-term prognosis, but especially those with petroclival tumours challenge us to improve our techniques. PMID- 7847152 TI - The long-term growth rate of residual acoustic neurinomas. AB - The growth rate of 19 residual acoustic neurinomas was examined in a long-term follow-up study (median, 10 years; range, 5 to 17 years) following intracapsular removal. Of these, 10 (53%) had regrowth, three (16%) showed regression, and six (32%) were unchanged. The 10 acoustic neurinomas showing regrowth were divided into two categories, either solid or cystic, according to computed tomographic findings. Five acoustic neurinomas with cyst formation showed rapid regrowth, with the tumour doubling time ranging from 0.15 to 5.0 years (median, 4.5 years), and required re-operation. Five solid tumours showed slow regrowth, with the tumour doubling time ranging from 9 to 34 years (median, 15 years). Although cyst formation is a major factor in rapid regrowth, residual acoustic neurinomas without cyst formation have a slower growth potential. In this study, 74% of the residual acoustic neurinomas have never required re-operation. It is advisable to choose intracapsular removal if there is major risk of neurological deficits. PMID- 7847154 TI - Angiographic characteristics of dural arteriovenous malformations that present with intracranial hemorrhage. AB - Dural arteriovenous malformations (dAVMs) are uncommon lesions that constitute about 12% of all the arteriovenous malformations. Depending on the location and the hemodynamics of the lesion, bruit, focal neurological deficit, and visual symptoms represent the more common presentation modalities. Although uncommon, intracranial hemorrhage can occur. In the present study, we report six patients with dural arteriovenous malformation that presented with intracranial hemorrhage. In five cases the hemorrhage was intraparenchymal (localized to the parietooccipital area in three), while it was confined to the subarachnoid space in the remaining one. The dAVM involved the transverse sinus in three cases, was based along the tentorial incisura in two, and was at the level of the torcular Herophili in one. Leptomeningeal drainage was present in all the cases. Aneurysmal dilatation of the draining vein(s) was identified in three. Sinus stenosis/occlusion was identified in two of the four patients with a dAVM draining into a major dural sinus. Four patients underwent pre-operative embolization, and all patients had surgical resection of their lesions. Anatomical cure, as defined by absence of any residual dAVM on postoperative angiogram, was achieved in all six patients. We conclude that several findings such as leptomeningeal drainage, location outside a major venous sinus, variceal dilatation, sinus stenosis/occlusion increase the risk of bleeding and are frequently observed in those dAVMs that present with intracranial hemorrhage. Recognition of these angiographic features is critical in planning a therapeutic approach tailored to the characteristics of the individual case. When these angiographic findings are present, prompt and definitive treatment is mandatory.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7847153 TI - Pilocytic astrocytomas of the posterior fossa. A follow-up study in 33 patients. AB - The extent of resection in pilocytic astrocytoma of the posterior fossa often remains undefined and the indications for further treatment in incompletely resected tumours are a matter of debate. It has been also realized that the problem of hydrocephalus in patients with pilocytic astrocytoma of the posterior fossa has not yet been solved and the diagnostic impact of postoperative CT findings remains questionable. We retrospectively reviewed the data from 33 patients harbouring a pilocytic astrocytoma of the posterior fossa to evaluate the impact of surgical technique in terms of radicality and of postoperative imaging results upon prognosis and adjunctive treatment. In addition, the issue of hydrocephalus was considered and related to different treatment modalities. Thirty patients underwent surgical treatment whereas 3 had open biopsy of the tumour. Macroscopically gross total resection of the tumour was performed in 20 patients, whereas resection was partial in 10. Follow-up was obtained in 29 patients for a period which ranged between 2 and 184 months (85 months +/- 56 months). Outcome was good in 24 patients who had only slight neurological deficit and poor in 3 patients, who were severely disabled. Two patients died during the follow-up period. Recurrent tumour growth occurred in 2 cases with incompletely resected tumours. From the series presented, it was concluded that long-term follow-up with CT seems mandatory in cases with contrast-enhancing residual tumour. Recurrent tumour growth should be assumed in postsurgical patients with an enlarging area of enhancement shown in follow-up CT studies. Permanent ventriculoperitoneal shunting is required in certain patients with pre- or postoperative hydrocephalus.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7847155 TI - Dural arteriovenous malformations in the anterior cranial fossa. AB - Two cases of dural arteriovenous malformation (DAVM) fed by the anterior ethmoidal artery in the anterior cranial fossa are reported, one of them examined by magnet resonance imaging (MRI). Only one other case with MRI findings so far has been published. Fourty-eight previously reported cases are reviewed. One of our patients presented with subdural haematoma (SDH) without subarachnoid or intracerebral haemorrhage. The other patient had a nasal bleed without any neurological manifestations. In comparison with previously reported cases, the clinical manifestation of our cases is infrequent (1 patient with nasal bleed, and 2 patients with pure SDH that is 2 and 4%, respectively, in the literature). Feeder was the anterior ethmoidal artery either unilateral or bilateral. Drainage of DAVMs was through a markedly dilated vascular sac into the superior sagittal sinus (SSS). The high incidence of haemorrhage from DAVM in the anterior fossa is related to this vascular sac. Magnetic resonance imaging (MRI) showed a flow void area in the left frontal region on T 1-weighted images in one case. These cases were treated by surgical excision of the malformation with good results. Aetiology, clinical presentation, and treatment of these rare DAVMs in the anterior cranial fossa is discussed. PMID- 7847156 TI - Effect of intraventricular haemorrhage and rebleeding following subarachnoid haemorrhage on CSF eicosanoids. AB - CSF eicosanoid levels are raised following subarachnoid haemorrhage but not sufficiently to be vasoactive per se within the cerebral circulation. Rebleeding and intraventricular haemorrhage are two factors associated with a worse outcome after aneurysmal SAH. We have examined the effects of these two factors on the CSF levels of TXB2 (TXA2 metabolite), PG6-keto F1 alpha (prostacyclin metabolite), PGF2 alpha and PGE2 in 44 patients following subarachnoid haemorrhage. In 15 patients who had received no non-steroidal anti-inflammatory agent or dexamethasone, intraventricular haemorrhage increased the median levels of all four eicosanoids in ventricular CSF by 2.1-5.1-fold. In 4 patients who rebled, the CSF median levels of all four eicosanoids were raised up to 250-fold over the normal range. These concentrations are just sufficient to have cerebrovascular and neuromodulatory effects. PMID- 7847157 TI - Remote subarachnoid haemorrhage in the posterior fossa following supratentorial surgery. Clinical observation of 6 cases. AB - Haemorrhage in regions remote from the site of following intracranial operations is rare, but they do occur. We performed supratentorial craniotomy on 639 patients between the time of introduction of computed tomography (CT) for clinical use in 1983 and June 1992; subarachnoid haemorrhage (SAH) in the posterior fossa occurred postoperatively in six of these cases. These included four patients with tumours in the sellar region, one with an arteriovenous malformation (AVM) and one who underwent superficial temporal artery (STA)-middle cerebral artery (MCA) anastomosis. The ages of the six patients ranged from 17-72 years. Haemorrhage occurred on the day of operation in one case and was detected on CT examination on the day following surgery in the remaining five cases. Of three patients with disturbance of consciousness, two underwent suboccipital craniectomy for reduction of intracranial pressure, while one received barbiturate therapy and later underwent cerebrospinal fluid (CSF) shunt surgery. No special treatment was necessary for the remaining three patients with less serious lesions. Five of the six patients ultimately recovered their pre operative neurological status apart from the primary diseases. Factors inducing such haemorrhages seem likely to include displacement of the cerebellum by reduced CSF pressure during and after operations, and stretching and tearing of the veins and venules in the sulci of the tentorial surface of the cerebellum. Consideration should therefore be given to the maintenance of an appropriate CSF pressure during operation; this is particularly important in elderly patients and those with an atrophied cerebral cortex. PMID- 7847158 TI - Effects of superficial temporal to middle cerebral artery bypass for ischaemic retinopathy due to internal carotid artery occlusion/stenosis. AB - The effects of superficial temporal artery to middle cerebral artery (STA-MCA) anastomosis for retinopathy is discussed and analysed in 19 cases of occlusive internal carotid artery disease (4 with stenosis and 15 with occlusion) according to Doppler sonography (DS) of the retinal artery, optic fundi and visual impairment symptoms. Preoperatively, all cases showed abnormal DS findings (stenosis patterns in 2 cases and the reversed flow patterns in 17 cases). All cases showed ischaemic changes of the optic fundi. Visual symptoms were amaurosis fugax in 2 cases, decline of visual acuity in 13 cases and both in 4 cases. At one month after the bypass, two stenosis pattern cases showed almost normal DS findings. In the 17 reversed flow pattern cases, 13 cases had a marked improvement of the reversed flow. The ischaemic changes of the optic fundi were ameliorated in 12 cases. In the follow-up stage, greater improvement in the DS findings and the optic fundi could be seen in all cases. In all cases worsening of the visual acuity was prevented, and in some cases the decreased visual acuity improved. The above improvements correlated well with the improvement of DS findings. It is believed that this procedure should be performed to prevent and improve ischaemic retinopathy caused by ischaemic ICA lesion. PMID- 7847159 TI - Change in regional cerebral blood flow following glycerol administration predicts. Clinical result from shunting in normal pressure hydrocephalus. AB - Cerebral haemodynamics were measured in 22 adult patients with secondary normal pressure hydrocephalus (NPH) before and after glycerol administration to determine which patients might benefit from a shunt procedure. Of these 22 patients, 14 were found to be shunt-responsive (group 1) and 8 were shunt unresponsive (group 2). Measurement of regional cerebral blood flow (rCBF) was performed by xenon-enhanced computerized tomography (XeCT). Clinical factors such as the Evans' index and the presence or absence of brain atrophy, periventricular lucency (PVL), ventricular reflux, stagnation of cerebrospinal fluid on cisternography, and increased intracranial pressure were not statistically significant predictors of shunt responsiveness. Preoperative rCBF values did not differ between groups 1 and 2. The rCBF value in every cerebral region of group 1 patients increased significantly after shunting except for the basal ganglia. On preoperative rCBF measurement, all rCBF values in group 1 significantly increased after glycerol administration except for the periventricular lucency (PVL). Patients in group 2, however, lacked such an increase in rCBF. We therefore propose that, in patients with secondary NPH, shunt surgery will be likely to be effective in those with a demonstrated rise in rCBF after glycerol administration. PMID- 7847160 TI - Brain oedema induced by ventricular puncture. A study by magnetic resonance on a series of forty-one normal-pressure hydrocephalic patients. AB - After ventricular catheterization magnetic resonance (MR) imaging very often demonstrates a focal area of high signal along the drain track which corresponds to parenchymal oedema. This high signal seemed to be more pronounced when the frontal area was catheterized than when the junctional parieto-temporo-occipital parenchyma (or trigonal area) was catheterized. In order to confirm this impression, we prospectively studied 41 consecutive patients with normal-pressure hydrocephalus in whom both of these brain regions were catheterized for intracranial pressure monitoring. Each patient was evaluated by serial MR. The extent of the MR hypersignal induced by both catheterizations was computed from digitized MR masks. The extent of the MR high signal area was significantly greater when the frontal area was catheterized compared to the trigonal area suggesting that the frontal area could be more prone to injury. PMID- 7847161 TI - Can lacerations of the thoraco-lumbar dura be predicted on the basis of radiological patterns of the spinal fractures? AB - Encroachment upon the spinal canal, separation of the pedicles, associated fractures of the laminae are assumed to be related to dural lacerations consequent to burst fractures of the thoracolumbar spine. Owing to the possible occurrence of early or delayed complications of meningeal discontinuations, the predictive value of these signs has been analyzed in a consecutive series of 50 patients, who were submitted to surgery. Dural tears were found to occur at a rate of 60%, without any statistically significant relation with any of the examined signs. The results were not consistent with the thesis that lacerations of the dura can be predicted on the basis of radiological signs. PMID- 7847162 TI - Effect of tirilazad mesylate given after permanent middle cerebral artery occlusion in rat. AB - The effect of the antioxidant drug tirilazad mesylate (U-74006F) on histopathological and neurological outcome 3 days after permanent middle cerebral artery (MCA) occlusion was evaluated in rats. Several previous studies have demonstrated the efficacy of tirilazad in reducing infarct size when administered before and during MCA occlusion, whereas post-treatment may be less effective in permanent focal ischaemia. We sought to determine if a protective effect of tirilazad could be demonstrated when administered after the insult only. U-74006F (3 mg/kg, i.v.) or sterile vehicle, was randomly given to rats 10 minutes and 3 hours after permanent MCA occlusion produced by transcranial proximal electrocauterization. Infarct volume and hemisphere volumes were estimated blindly from histological sections of defined levels of the brain after 72 h of ischaemia. Neurological score was determined blindly 1, 2, and 3 days after insult. There was no significant difference in infarct volume, volume of non infarcted tissue, or neurological score between the tirilazad and placebo-treated rats. In conclusion, our results support the conception that post-treatment with tirilazad mesylate is not efficacious in reducing infarct size in permanent focal ischaemia, while pre-treatment, as reported by other groups, appears to be effective in both permanent and temporary focal ischaemia models. In temporary focal ischaemia, the limited data available suggest that also post-treatment with tirilazad may prove to be neuroprotective. PMID- 7847163 TI - The development of a decision support system for the pathological diagnosis of human cerebral tumours based on a neural network classifier. AB - This study describes the use of a topological mapping system in the classification of cerebral tumours and the development of a decision support system based upon that classifier. Fourteen pathological parameters from two hundred primary cerebral tumours are presented as vectors to a topological map. The map, consisting of a grid of neurones, learns the features of each tumour by means of a shortest Euclidean distance algorithm, after which self adaptation of the neurons occurs. An LVQ algorithm performs the final classification. Study of the map reveals that it can correctly classify tumors following their malignancy potential and their cytogenesis. The decision support system uses the network at its core and helps not only in reaching a diagnosis but also in finding the optimal way to reach that diagnosis. The usefulness of such a mapping system lies in the field of education, clinical research and medically acceptable cost reduction. PMID- 7847164 TI - Cortical blood flow and cognition after extracranial-intracranial bypass in a patient with severe carotid occlusive lesions. A three-year follow-up study. AB - The long-term effect of extra-intracranial arterial bypass on cerebral circulation was examined. Cortical blood flow and cognitive ability were evaluated pre- and up to 3 years post-bypass in a 58-years-old man with severe carotid occlusive lesions, who presented with 3 transient cerebral ischaemic attacks which resulted in mental deterioration over 3 years. Regional cerebral blood flow (rCBF) was evaluated pre- and up to 33 months post-bypass by 123Iodine N-isopropyl-p-iodoamphetamine (IMP) single-photon emission CT (SPECT). Mental abilities were evaluated before and up to 33 months after surgery by the Hasegawa's dementia rating scale (HDRS). Pre-operatively, cerebral angiography showed left carotid siphon occlusion and hypoplastic stenosis of left anterior cerebral artery with collaterals from the anterior communicating artery. CT and MRI showed left temporo-parietal borderzone infarction and an enhanced T 1 lesion by gadolinium-DTPA at left periventriculum. rCBF showed extensive hypoperfusion in left anterior-parieto-temporal-cortex. HDRS scores deteriorated apparently on days 3, 5, which recovered gradually on days 8, 10, 75 after onset of mental deterioration. A bypass was performed 4 months after onset. rCBF showed gradual recovery in the left anterior-parietal cortex up to 33 months after bypass. Semiquantitative rCBF showed gradual decreases of regional asymmetry after the bypass. HDRS scores returned to their maximum up to 37 months after onset. Three year follow-up shows improved cortical rCBF and cognition after the bypass. PMID- 7847165 TI - Intraventricular haemorrhage and hydrocephalus caused by intraventricular parasitic granuloma suggesting cerebral sparganosis. AB - A 67-year-old female farmer presented with acute loss of consciousness. Computed tomograms showed a calcified mass in the cavum septi pellucidi with intraventricular haemorrhage and obstructive hydrocephalus. The patient became fully conscious after urgent external ventriculostomy and subsequently underwent craniotomy for the excision of the mass. Pathological examination of the mass demonstrated a granuloma surrounding a degenerating larva compatible with Spirometra mansonoides whose mimicking an intraventricular tumour has not been reported before. PMID- 7847167 TI - In memoriam Charles C. Spiker (1925-1993). Cofounding editor Advances in Child Development and Behavior. PMID- 7847166 TI - European Society for Stereotactic and Functional Neurosurgery. Abstracts selected for presentation at the 11th Congress. Antalya, Turkey, September 24-27, 1994. PMID- 7847168 TI - Strategy utilization deficiencies in children: when, where, and why. AB - By the early 1980s, a clear picture of the role of strategies in memory development was emerging. Strategies generally help recall and thus are a main contributor to memory development. Young children have a production deficiency that is overcome during the grade school years. By the early 1990s, the process appeared to be a good deal more complex. Although spontaneously produced strategies often help recall, they do not inevitably do so, especially among novice strategy producers--even when their strategy production appears proficient. In the 1980s and 1990s, a main theme of research on children's strategies of memory has been that children begin to use strategies earlier than previously thought. Researchers have identified rudimentary strategies of even 2- and 3-yr-olds. Our research suggests that we also need to take a careful look at the other end of the spectrum. A strategy may continue to develop well beyond the point at which an apparently full-blown strategy is produced. Producing a relevant strategy does not mark the end of strategy development. Rather, it marks the beginning of the development of a proficient, low-effort strategy that enhances recall. Even after a child spontaneously produces the strategy fully and consistently, the strategy gradually becomes less effortful to access and to execute and is integrated with other mnemonic strategies and activities. As a result, the strategy is increasingly likely to facilitate recall. Researchers need to conduct a fine-grained analysis of the actual implementation of a strategy--how the strategy of interest dovetails with a set of strategic, metamemorial, information-processing, and motor-control processes. The utilization deficiency phenomenon may challenge current conceptions of how and why skills develop. Why do children spontaneously use and continue to use a skill that helps them little or not at all? The usual assumption has been that children acquire and perfect skills because they have some benefit for them. This benefit is still true in the long run, but not the short run. The utilization deficiency, Bjorklund and Green's (1992) account of young children's overoptimism, and Siegler's (e.g., McGilly & Siegler, 1989) observation that children sometimes reject, at least temporarily, a strategy that helps them, describe behaviors that do not fit easily into current models of children as rational problem solvers. We need a different conceptualization of the course of strategy development and perhaps skill development more generally. PMID- 7847169 TI - The development of children's ability to use spatial representations. PMID- 7847170 TI - Fostering metacognitive development. PMID- 7847171 TI - The Home Inventory: review and reflections. PMID- 7847172 TI - Social reasoning and the varieties of social experiences in cultural contexts. PMID- 7847173 TI - Mechanisms in the explanation of developmental change. AB - Despite extensive use of the term mechanism in developmental psychology, and in theories of cognitive development in particular, scant attention has been given to specification of what the concept entails. The principal aim of this paper, by focusing on its implicit assumptions, has been to detail at least one view of how mechanism should be conceptualized. As with any general concept, the illustrations of its use in selected developmental theories point to differences in the ways aspects of the concept are treated. They suggest, too, why consensus in arriving at a unified concept of mechanism has been and will continue to be difficult. Nevertheless, the following conclusions can be drawn from the foregoing conceptual analysis and the analysis of selected applications. In the explanation of the operation of a mechanism, one must assume a temporal (asymmetrical) relation of either a single set or a series of initial conditions to an event, condition, or structure denoted as an effect. The relation of the antecedent to the consequent event(s) is describable by some theory of causal explanation. Implicit in any description of mechanism, then, is a theory of causal explanation. However, a strict account of causal relations, in which necessary and sufficient conditions of causal explanation are met, is not possible in any of the sciences. In addition, adequate reference to mechanisms requires the specification of structures, whether material or immaterial, and their constituent parts, with the parts related to each other in a systematic way. Such systems of structural components are operated upon by some process or set of processes that produces particular effects. Hence, mechanism and process are not interchangeable terms, nor does mechanism underlie process. Instead, in a mechanism, structure and process are complements of each other. Among the specific models of development mechanisms examined, all provide varying notions of process, but only some are directly concerned with the specification of structure. To the extent that they omit structures they are limited in their accounts of the mechanisms they are purported to describe and explain. Neuroscience accounts of developmental change most directly confront structure function relations. In being closely allied to biological theories, they forthrightly acknowledge structural and functional forms of causal explanation. Dynamic system theories, in contrast, in emphasizing the dynamics of change, appear to place their primary, if not sole emphasis on the functional aspects of development. Nevertheless, implicit in their accounts are references to structure, often couched in the language of organization.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7847174 TI - A unifying framework for the development of children's activity memory. PMID- 7847175 TI - Development differences in associative memory: strategy use, mental effort, and knowledge access interactions. AB - The deployment of memory strategies is resource demanding and more so for younger children than for older children and adults. The associative memory studies reviewed show that accessibility to relevant event knowledge is directly related to the resource demands of using an elaboration strategy. The greater efficiency of strategy use by older children and adults permits the use of available mental resources to support additional task-relevant processing of to-be-learned items. This additional processing might include alternate or more durable encodings of pair relationships, creation of retrieval opportunities (strategies), and effective strategy monitoring. The additional processing enabled by the freeing of information-processing resources is hypothesized to be responsible for the developmental increase in the efficacy of elaboration and other associative strategies. Knowledge access also affects the nature of the relational strategy selected and the recall benefits observed. Although increases in "elaboration" were hypothesized to account for developmental differences in associative memory, the evidence clearly shows that other associative strategies are also involved. Although these other associative strategies involve elaboration in a nontechnical sense, the observed dissociations between them and the elaboration strategy argue for maintaining the distinction. Moreover, further analysis is needed to understand the interactions between strategy selection and knowledge access. In this regard, the initial strategy deployed by a learner is dependent on his or her knowledge about the relative effectiveness of various relational associations and interactions with knowledge access. For example, a younger subject might forgo "elaboration" if the items are "captured" by an "other associative" relationship activated during strategy deployment (particularly if the initial search for an elaboration is very effortful). In contrast, an older subject might persevere at retrieving a relevant event because of his or her knowledge about the benefits of encoding "direct" interactions for pair members. The learner's subsequent strategy selection, either for additional processing or encoding of new pairs, is undoubtedly more complex because of increases in the learner's knowledge about the relationships between strategy use, knowledge access, and resource demands. In conclusion, research examined in this chapter verified relationships between strategy use, mental effort, and knowledge access. Moreover, interactions between strategy use and knowledge access were exposed. These relationships are presumed to underlie developmental differences in the efficacy of memory strategies. PMID- 7847177 TI - Meeting report: environmental pollution and allergy. PMID- 7847176 TI - Genetics and osteoporosis: role of the vitamin D receptor gene. PMID- 7847178 TI - The role of semicarbazide-sensitive amine oxidase with a high affinity for benzylamine (Bz. SSAO) in the catabolism of histamine in the mesenteric arterial bed of the rat. AB - In the mesenteric arterial bed of the rat the semicarbazide-sensitive amine oxidase with a high affinity for benzylamine (Bz. SSAO) (E.C. 1.4.3.6) is also able to oxidize histamine. In the perfused mesenteric arterial bed of the rat the complete inhibition of the Bz. SSAO obtained with a specific inhibitor, B24, almost completely reduces the efflux of imidazole acetic acid and increases the relaxing effect of histamine. Bz. SSAO appears to be the only enzyme present in these blood vessels able to catabolize histamine. PMID- 7847179 TI - The role of the mast cell in acute inflammatory responses of copper-deficient rats. AB - Macromolecular leakage associated with mast cell degranulation was studied in the cremaster muscle microcirculation of copper-deficient rats. Male Sprague-Dawley rats were fed a purified diet either adequate for copper (6 micrograms copper/gram diet) or deficient (no added copper) 4 weeks prior to experimentation. The rats were anesthetized and the cremasters (with nerve and blood supply intact) were spread in a tissue bath filled with Kreb's solution. In vivo television microscopy was used to observe the microcirculation. Intravascular fluorescein isothiocyanate conjugated to bovine serum albumin was injected and interstitial fluorescent emission intensity was used as an index of macromolecular leakage. Topical administration of the mast cell degranulator compound 48/80 (1.0 and 10.0 micrograms/ml) induced a significantly greater macromolecular leakage in the copper-deficient animals. The compound 48/80 leakage was blocked in both groups of rats by pretreatment with diphenhydramine which is a histamine H1 receptor blocker. Topical administration of the inflammatory mediators histamine, serotonin, and bradykinin all induced macromolecular leakage which was not significantly different between groups. These results suggest that copper deficiency increases macromolecular leakage associated with mast cell degranulation by a primary effect on the mast cell rather than on the endothelium. PMID- 7847180 TI - Imipramine reduces the local inflammatory response to carrageenin. AB - Imipramine was administered chronically to LEW/N, outbred and F344/N rats which were then exposed to the aseptic irritant carrageenin in order to determine whether the decreased hypothalamic expression of CRH m-RNA previously shown to be associated with imipramine affects peripheral immune processes. Both LEW/N and outbred but not F344/N rats had vigorous inflammatory responses to carrageenin, and imipramine was associated with significant decreases in the local cellular inflammatory response to carrageenin. Imipramine was also associated with changes in the expression of peripheral blood cell MHC class II expression in LEW/N and outbred rats. These results suggest that at doses comparable to those used clinically imipramine has significant effects on response to an inflammatory stimulus. PMID- 7847181 TI - Protective effects of papaverine salicylate in mouse ear dermatitis and PAF induced rat paw oedema. AB - Papaverine salicylate (MR-800) has been tested as a topical antiinflammatory agent in several models of skin inflammation in rodents, such as mouse ear dermatitis induced by croton oil, cantharidin or zymosan, and rat paw oedema induced by PAF. MR-800 exerted a dose-dependent inhibitory activity in all assays, when equimolar doses of sodium salicylate or papaverine were less effective, suggesting the existence of a favourable synergism between salicylate and papaverine. PMID- 7847182 TI - Differential effects of phosphoramidon and captopril on NK1 receptor-mediated plasma extravasation in the rat trachea. AB - We sought to confirm the identity of the tachykinin receptor subtype that mediates plasma extravasation in the rat trachea, and assess the respective contributions of neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE) in regulating this tachykinin-induced response. To achieve these aims, we determined the relative potencies of several natural tachykinins and receptor selective synthetic agonists, both before and after inhibiting NEP with phosphoramidon and ACE with captopril. We also determined the effects of these peptidase inhibitors, and the NK-1 receptor antagonist L-703,606, on the plasma extravasation produced by capsaicin, which releases tachykinins endogenously from sensory nerve endings. We found that the rank order of potency for producing plasma extravasation in the rat trachea was NK-1 receptor agonist ([Sar9, Met(O2)11] SP) > substance P > neurokinin A > neurokinin B. The NK-2 ([Nle10]NKA (4-10)) and NK-3 ([MePhe7]NKB) receptor agonists were without effect. We observed no change in the relative potencies of these peptides after giving rats phosphoramidon or captopril, which suggests that the different peptide potencies are not simply the consequence of different rates of enzymatic degradation. Nevertheless, the responses to substance P and neurokinin A were clearly potentiated in rats given phosphoramidon, indicating that NEP effectively degrades tachykinins in vivo. No significant potentiation was evident for any peptide in rats given captopril. Similarly, the plasma extravasation produced by capsaicin was potentiated in rats given phosphoramidon, but not in those given captopril. Pretreating rats with L-703,606 abolished the response to capsaicin.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7847183 TI - Inhibitory activity of a series of coumarins on leukocyte eicosanoid generation. AB - Sixteen plant-derived or synthetic coumarins with different patterns of substitution were tested for their capacity to modify A23187-induced synthesis of leukotriene B4 and thromboxane B2 via the 5-lipoxygenase and cyclooxygenase pathways of arachidonate metabolism in rat peritoneal exudate leukocytes. Five of the 16 coumarins inhibited LTB4 production: all contain orthodihydroxy substitutions (approximate IC50 values 8-100 microM). The mechanism is likely to depend upon a combination of the coumarins' iron-chelating and iron ion-reducing abilities, properties which also confer beneficial activities of these compounds as scavengers of reactive oxygen species (Paya et al., Biochem. Pharmacol. 44, 205-214 (1992)). Inhibition of the cyclooxygenase pathway was only demonstrated by one compound, 5,7-dihydroxy-4-methylcoumarin, which did not inhibit 5 lipoxygenase, indicating that the cyclooxygenase inhibitory mechanism is different. Similar effects of the active coumarins were obtained using arachidonic acid as substrate for rat leukocyte eicosanoid generation, confirming that they act at the 5-lipoxygenase/cyclooxygenase level. The same profile of activity was also shown when the coumarins were tested against 5-lipoxygenase in human polymorphonuclear neutrophils. Taken together, these antioxidant and anti eicosanoid properties of coumarins could be exploited for the design of potentially valuable non-toxic anti-inflammatory agents for treating diseases in which eicosanoid generation and the production of reactive oxygen species are involved. PMID- 7847184 TI - Antirheumatic drug profiles evaluated in the adjuvant arthritis of rats by multiparameter analysis. AB - Freund's adjuvant arthritis (FAA) in susceptible rats (male, Lewis strain) is a well-established experimental model of rheumatoid arthritis to evaluate inherent drug properties, i.e. anti-inflammatory and/or immunosuppressive/immunomodulatory properties which are only ascertained by combining multiple parameter analysis. We employed a synoptic multiparametric evaluation system for the multifaceted FAA, a so-called "spider scheme", to facilitate a more rapid and easier comparison of qualitative and quantitative drug properties by visual display than that achieved by mere tabulation of the data. The spider scheme comprised six well-established parameters to evaluate the FAA disease (primary and secondary hind paw swelling, arthritic index which included macroscopic alterations of non injected paws, nose, ears and tail, body weight changes and relative organ weights of thymus and spleen). By calculation of an index as a percent change in comparison to control and untreated diseased animals, the degree of improvement or impairment of the FAA by a tested compound could easily be entered into the spider scheme. The FAA parameter spider scheme clearly differentiated the most beneficial immunomodulatory properties of cyclosporin A from those of the immunosuppressive agents dexamethasone and cyclophosphamide as well as from the mere anti-inflammatory cyclooxygenase inhibitors. Among this latter class of non steroidal anti-inflammatory compounds, a similar profile was demonstrated for indometacin and diclofenac, as well as for tenidap, which is claimed to have cytokine-modulating properties, as reflected by the reduction of acute-phase proteins in patients with rheumatoid arthritis. Yet, in this FAA model, with tenidap, no additional qualitative drug properties could be discerned.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7847185 TI - Inhibitory effect of allopurinol on adjuvant arthritis in rats. AB - The effect of Allopurinol (ALLO), on adjuvant arthritis was studied in rats and compared with the effect of indomethacin (IND). Drugs were given by intraperitoneal injection for each day beginning from the day of adjuvant injection (day 0) and continued until the 16th day. Paw swelling was measured on days 4, 17 and 29, and secondary lesions were assessed on days 17 and 29. Polymorphonuclear leukocyte (PMNs) count was also evaluated on day 17. ALLO, at relatively high doses (25-50 mg/kg), reduced paw swelling of the adjuvant injected extremity on day 4; lower doses (6.25-12.5 mg/kg), however, elicited the same inhibitory effect on day 17. IND (0.25 mg/kg) also prevented paw swelling on days 4 and 17. Both ALLO and IND reduced the secondary lesions on days 17 and 29 and prevented the increase in polymorphonuclear leukocytes during the development of adjuvant arthritis. Possible mechanisms of the antiinflammatory effect of ALLO in adjuvant arthritis are discussed. PMID- 7847186 TI - Wasting in adjuvant-induced arthritis and its relationship to plasma zinc, copper and liver metallothionein. AB - The appearance of joint inflammation (JI) 14 days after the injection of adjuvant (AJ) in the tail of rats is associated with a cachectic syndrome which is characterised by marked weight loss (WL). The degree of weight loss was examined in relation to the extent of change in other markers of inflammation including increased plasma copper (pCu), decreased plasma zinc (pZn) and increased hepatic metallothionein (hMT). At 14 days post-AJ injection, arthritic rats showed the following changes, relative to the controls: body weight, 12% decrease, pZn, 50% decrease; pCu, 90% increase and hMT, 11-fold increase (all p < 0.001). Significant relationships were observed between JI, WL, pZn and hMT. The following coefficients of determination (r2) were observed; JI and WL, -0.530, JI and pZn, -0.485; JI and hMT, 0.286; WL and hMT, -0.510 (all p < 0.007). There was a strong relationship between the decreased pZn and increased hMT; r2 = 0.456 (p < 0.001). While increased pCu was clearly associated with AJ-arthritis in these rats, there was no quantitative relationship between the extent of change in pCu and the other parameters measured (r2 all < 0.01). The highest correlation observed was between pZn and WL (r2 = 0.637, p < 0.001). While the initial depression of pZn may be the result of increased hepatic hMT levels, longer term reductions in pZn levels are linked to systemic inflammation, the degree of arthritis and associated weight loss. PMID- 7847187 TI - Hypotensive action of aggregated IgG in rats. Study of the unresponsiveness to a second dose following restoration of the blood pressure. AB - Human IgG preparations containing aggregates have been reported to induce hypotension in rats. Animals surviving a hypotensive dose of such a preparation were found unresponsive to a second dose given the next day. Unresponsiveness was induced by an isolated fraction of aggregated IgG, but not by purified monomers. Preparations containing aggregated and monomeric IgG appeared more efficient in inducing unresponsiveness than aggregates alone. The phagocyte function in vivo was assessed in unresponsive animals. No significant difference was found in the carbon clearance and in the human erythrocyte clearance test suggesting that a general impairment of the phagocyte function is not necessary for unresponsiveness. Previous studies indicated the involvement of PAF in hypotension by aggregated IgG. Hypotension was elicited by the injection of PAF in rats made "refractory" to aggregated IgG like in controls. PMID- 7847188 TI - Inhibition of IL-1 induced articular inflammation of rats by 4 aminothiazolidines, LY 221068 and LY 269415. AB - LY 221068 and LY 269415 are representative compounds from a chemical series of 4 aminothiazolidines, with potent antioxidant properties in vitro. We have evaluated these two compounds in a rat model of articular inflammation caused by the administration of recombinant human IL-1 beta into the knee joints. IL-1 injection into the knee joints has been shown to cause a complex series of changes resulting in synovitis, mesenchymal proliferation, and subchondral bone and cartilage erosion. The inflammatory response of the knee joint was measured by determining the changes in the joint swelling and also by histological evaluation of the knee joints. Rats pretreated (p.o.) with 10-25 mg/kg of either of these compounds (4 h prior to IL-1 injection) displayed greatly reduced soft tissue swelling with an IC50 of 7.5 mg/kg. Evaluation of histological lesions revealed, however, that LY 269415 (IC50 of 10 mg/kg) was more potent than LY 221068 (IC50 of 25 mg/kg) in reducing the severity of histological changes. The results demonstrate that antioxidants of this chemical series either directly or indirectly display anti-inflammatory properties and could be beneficial as therapeutic agents in inflammatory arthritis. PMID- 7847189 TI - Fasting or dexamethasone treatment reduce protease content in rat lung mast cells and modulation of histamine synthesis by H3 receptors. AB - The sensitivity of mast cells to H3-receptor modulation was studied in rat lung under various hormonal conditions. The heterogeneity of mast cell sub-populations in rat lung was assessed by the tissue content of rat mast cell protease I (RMCP I) and rat mast cell protease II (RMCP II). After 24 h fasting, concentrations of RMCP I were unchanged whereas the concentration of RMCP II was significantly reduced by 49%. The [3H]histamine (HA) synthesis was concomitantly decreased by 35%. In addition, the modulation of [3H]HA synthesis by the H3 receptor agonist, (R)alpha-methylHA and by the antagonist, thioperamide, observed in control rats, was lost in fasted rats. Single and repeated administrations of dexamethasone did not influence RMCPI concentrations, but decreased the concentrations of RMCP II with a parallel decrease in [3H]HA synthesis. The inhibitory effect of (R)alpha methylHA on [3H]HA synthesis was also reduced. These results suggest that a subpopulation of RMCP II-containing mast cells, very sensitive to environmental factors, could be the mast cells synthesizing HA in an H3-receptor-dependent manner. PMID- 7847190 TI - Superoxide dismutase inhibits interleukin-1-induced degradation of human cartilage. AB - Interleukin-1 (IL-1) is a key mediator in the pathogenesis of cartilage destruction in arthritis-related disorders. Human recombinant superoxide dismutase (SOD) blocked IL-1-mediated cartilage destruction but had no effect on IL-1-mediated changes in glycosaminoglycan and prostaglandin E2 synthesis. These data suggest that superoxide anions may be one factor of IL-1-mediated cartilage destruction. PMID- 7847191 TI - Endotoxin and arachidonic acid metabolites in portal, hepatic and arterial blood of cattle with acute ruminal acidosis. AB - Ruminal acidosis was induced experimentally with 70 g barley/kg body weight in 2 rumen fistulated cows with chronic indwelling catheters in the portal vein, in a hepatic vein and the carotid artery. The cows were followed for 24 and 20h after the overfeeding and evaluated clinically and by clinical chemistry. The 2 cows exerted different responses to the treatment. Both cows showed signs of severe ruminal acidosis. Both cows had endotoxin in portal and hepatic vein blood, but only 1 of the cows convincingly developed a systemic endotoxaemia. A pre-hepatic release of the stable prostacyclin and thromboxane metabolites, 6 ketoprostaglandin F1 alpha and thromboxane B2 was demonstrated in this cow. The results of the present study show that endotoxin and arachidonic acid metabolites of pre-hepatic origin may be factors involved in the pathogenesis of ruminal acidosis, and that investigation of the factors affecting translocation of ruminal endotoxin and subsequent clearing in the liver, will be of importance. PMID- 7847192 TI - Effects of the long-acting somatostatin analogue octreotide on abomasal function and plasma level of insulin and glucagon in sheep. AB - The effects of the long-acting somatostatin analogue octreotide were studied in sheep. Octreotide was given subcutaneously at a dose of 0.75 microgram/kg bodyweight and, as a control, 0.9% saline solution was injected in a change-over design. Octreotide inhibited abomasal acid secretion and retarded the turnover time of digesta through the abomasum. The plasma levels of insulin and glucagon decreased due to the octreotide injection, while the plasma glucose level was not affected. The effects of octreotide lasted for 3-4h. There were no significant effects of the saline injection. The effects of octreotide showed similarities with results from previous studies on monogastric species. PMID- 7847193 TI - Prefeeding plasma acetoacetate and glucose in healthy, lactating heifers. Variations related to milk yield, metabolic balances and stage of lactation. AB - When measured before morning feeding plasma acetoacetate (ACAC) increased and glucose (GL) decreased significantly with increasing milk yield (fat corrected, FCM) within 2 groups of half-sister related heifers which did not suffer from clinical ketosis. The groups received respectively A: 7 kg and B: 4 kg/d of concentrates in addition to grass silage ad libitum (each group 88 animals). Correlation coefficients of the same magnitude between the 3 variables mentioned were obtained in the 1st and 3rd month of lactation in spite of a narrowing of the ACAC range from 0.024-0.66 to 0.019-0.16 mmol/l. Reproducibility of differences between animals in milk yield and in the plasma components was evidenced by significant correlations between measurements in the 1st and 3rd month. The B-animals produced 2.4 kg/d less FCM than the better fed A group (A, 1st month of lactation 19.8 +/- 3.1 kg/d) while the mean values for ACAC and GL remained practically unaffected by the difference in feeding. B cows gave consistently 5-6% lower GL means (p < 0.01) than A animals with identical yields. Animals which showed marked ACAC increment during the first 5-6 weeks of lactation produced 3-4 kg more FCM/d than equally fed animals with constantly low ACAC levels. The estimated energy deficit of this ketonaemic, high-producing category corresponded to the production of 4.5-6 kg FCM/d from body reserves. Low ACAC values (< 0.05 mmol/l) were reproduced with a standard deviation of +/- 4% with the automated nitroprusside method described. PMID- 7847194 TI - Insemination results with slow-cooled stallion semen stored for approximately 40 hours. AB - Semen from 3 stallions was extended using 2 methods (Kenney extender and a modified Kenney extender), slowly cooled, and stored for 41 +/- 6 (s.d.) h before insemination. An insemination dose (40 ml) contained 1.5-2 billion spermatozoa. In the experiment, 26 mares were inseminated in 30 cycles. The pregnancy rate per cycle obtained with sperm stored in the Kenney extender was 87% (n = 15). When the semen was extended with the modified extender, centrifuged and stored, the pregnancy rate was 60% (n = 15). Inseminations were done every other day until ovulation was detected. If a mare ovulated more than 24 h after the last insemination, she was inseminated also after ovulation. The single-cycle pregnancy rate was 58% when the mares were inseminated only before ovulation (n = 19) but the rate was 100% when the inseminations were done both before and after ovulation (n = 9) or only after ovulation (n = 2). The difference in pregnancy rates was significant (p < 0.05), indicating that postovulatory inseminations probably serve to ensure the pregnancies. The extending and handling methods used in this study resulted in a combined pregnancy rate of 73%, and appear thus to be useful for storing stallion semen for approximately 2 days. PMID- 7847195 TI - Hypophosphatemia induced by dietary aluminium hydroxide supplementation in growing pigs: effects on erythrocytes, myocardium, skeletal muscle and liver. AB - Three groups of pigs were studied during and after 10 weeks of treatment with either Al(OH)3 (Al[OH]3-group, n = 8) to induce hypophosphatemia. AlPO4 (AlPO4 group, n = 8, aluminium control without hypophosphatemia) or no addition to the feed (control group, n = 8). Blood samples were taken at the start of the experiment and after 3, 6 and 10 weeks and were analyzed for phosphate, calcium and 2,3-diphosphoglycerate (2,3-DPG). Samples from myocardium, skeletal muscle and liver were obtained in connection with exsanguination and analyzed for glycogen, adenosine-tri-phosphate (ATP), creatine phosphate (CP), glucose-6 phosphate (G-6-P) and lactate. The Al(OH)3-group became hypophosphatemic and hypercalcemic with low levels of 2,3-DPG in erythrocytes within 3 weeks and showed a retarded growth rate. After 10 weeks the Al(OH)3-group had low levels of ATP in myocardium as compared with the control-group and low levels of G-6-P as compared with the AlPO4-group. No disturbances on electro-cardiograms registered at rest could be documented. G-6-P concentration was low in the biceps muscle in the Al(OH)3-group as compared with the AlPO4-group and in the liver low G-6-P concentration was seen in addition to high lactate concentration. The fibre type composition in M. Longissimus did not differ between groups, but the Al(OH)3 group had, due to retardation in growth, smaller mean fibre-areas than pigs in the AlPO4-group.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7847196 TI - Long-term study of Toxoplasma gondii infection in a Swedish sheep flock. AB - The infection rate of Toxoplasma gondii was studied during 6 years in a sheep flock in central Sweden. The flock consisted of 165-249 breeding ewes of which 20 35% were lambs less than 1 year old. Most ewes were slaughtered when 5 years old. The sheep were kept indoors from end of September to early May. Lambing took place in March and April. Individual serum samples were collected twice a year, once just before turning the sheep out to pasture in the spring and again after housing in the autumn. Sera were analysed by ELISA for antibodies to T. gondii. The seroprevalence varied between 10% and 45% during the 6 years of observation. Seroconversion was detected predominantly at the autumn sampling, indicating that in most cases infection was acquired at pasture. Subclinical effects of T. gondii infection on lamb weight, litter size, total litter weight and ewe weight were also studied. Lambs born to chronically infected ewes were lighter at birth than those of uninfected ewes, but this disparity was no longer evident at weaning. PMID- 7847197 TI - Influence of medetomidine on acid-base balance and urine excretion in goats. AB - Seven goats were given medetomidine 5 micrograms/kg as an iv bolus injection. Venous blood samples were taken repeatedly and urine was collected continuously via a catheter up to 7h after the injection. Medetomidine caused deep clinical sedation. Base excess, pH and PCO2 in venous blood rose after medetomidine administration. There were no significant changes in plasma concentrations of sodium, calcium, magnesium, creatinine or osmolality, whereas potassium and bicarbonate concentrations increased, and phosphate and chloride decreased. Medetomidine increased plasma glucose concentration, and in 4 of 7 goats glucose could also be detected in urine. Medetomidine did not influence urine flow rate, free water clearance, bicarbonate and phosphate excretion or pH, but renal chloride, sodium, potassium, calcium, magnesium and creatinine excretion were reduced. The results suggest that the metabolic alkalosis recorded after medetomidine administration is not caused by increased renal acid excretion. PMID- 7847198 TI - Intraruminal fluid administration to goats: effects of handling and fluid temperature. AB - Physiological stress response to intraruminal fluid administration was studied in 5 female goats. The fluid was given through a stomach tube. The water was cold (10 degrees C) or warm (38 degrees C) and in an amount of 7.5-10% of body weight. Plasma concentrations of adrenaline, noradrenaline and cortisol increased significantly after both treatments. Adrenaline and noradrenaline responses were greater and more longlasting after cold water administration, but there was no difference in cortisol response between cold and warm water. Haematocrit and plasma protein concentrations increased also and the effects of cold water lasted longer. Blood pressure showed a sharp rise of short duration and was independent of water temperature. The immediate tachycardiac response was similar with both treatments, but cold water caused an additional peak 15 min later. The cooling did not increase plasma histamine level. The results suggest that stomach intubation and administration of water into the rumen leads to strong activation of hormonal and cardiovascular stress parameters even in goats well adapted to handling. Low temperature of the fluid further heightens the effect. Warming of fluids to near body temperature before their administration is thus recommended. PMID- 7847199 TI - Effect of cooking on residues of the quinolones oxolinic acid and flumequine in fish. AB - The effect of cooking on residues of the quinolones oxolinic acid and flumequine in fish was investigated. Salmon containing residues of oxolinic acid and flumequine was boiled or baked in the oven. Samples of raw and cooked muscle, skin, and bone, as well as of the water in which the fish was boiled and juice from the baked fish, were analysed. Oxolinic acid and flumequine did not degrade at the temperatures reached when cooking the fish. However, fish muscle free from drug residues may be contaminated during boiling and baking due to leakage of the drug from reservoirs in the fish. PMID- 7847200 TI - Equine herpesviruses 1 and 4: amplification and differentiation by polymerase chain reaction. PMID- 7847201 TI - Aneurysms related to cerebral arteriovenous malformations: superselective angiographic assessment in 58 patients. AB - PURPOSE: To report the comprehensive superselective angiographic characteristics of aneurysms associated with cerebral arteriovenous malformations. METHOD: One hundred consecutive patients referred for cerebral arteriovenous malformation embolization underwent preembolization superselective angiography. Superselective angiograms were obtained after microcatheterization of arteriovenous malformation pedicles, and assessed for number and location of aneurysms related to the malformation. A chi 2 test was conducted to correlate these parameters with the onset of intracranial hemorrhage. RESULTS: Aneurysms were demonstrated in 58 of 100 patients. Single aneurysms were found in 24 patients and multiple aneurysms in 34. Presence and number of aneurysms were found to correlate significantly with a clinical presentation of hemorrhage. CONCLUSION: Superselective angiography was found to be of paramount importance in elucidating the precise and detailed angioarchitecture of brain arteriovenous malformations. PMID- 7847202 TI - MR angiography of intracranial aneurysms: proceed, but with caution. PMID- 7847204 TI - A pitfall in detection of intracranial unruptured aneurysms on three-dimensional phase-contrast MR angiography. AB - We report three cases of intracranial unruptured aneurysm evaluated with MR angiography using both three-dimensional time-of-flight and three-dimensional phase-contrast techniques. It has been said that the phase-contrast technique has advantages over the time-of-flight technique in the detection of intracranial aneurysms. However, in our three cases, three-dimensional time-of-flight MR angiography clearly showed the intracranial unruptured aneurysms, but three dimensional phase-contrast MR angiography failed to show them. PMID- 7847203 TI - Intracranial aneurysms and MR angiography: questions and answers. PMID- 7847205 TI - A method for using MR to evaluate the effects of cardiovascular disease on the brain: the cardiovascular health study. AB - PURPOSE: To do a pilot study for the Cardiovascular Health Study (a population based, longitudinal study of coronary heart disease and stroke in adults 65 years of age and older designed to identify risk factors related to cerebrovascular disease, particularly stroke): (a) to determine the feasibility of adding brain MR to the full-scale study; (b) to evaluate the reliability of standardized MR image interpretation in a multicenter study; and (c) to compare the prevalence of stroke determined by MR with that by clinical history. METHODS: Protocol-defined MR studies were performed in 100 subjects with clinical histories of stroke and 203 subjects without reported histories of stroke. MR scans were independently evaluated by two trained neuroradiologists for the presence of small (< or = 3 mm) and large (> 3 mm) "infarctlike" lesions. The sizes of the cerebral sulci and lateral ventricles and the extent of white matter disease were graded on a scale of 0 to 9. RESULTS: Eighty percent of the Cardiovascular Health Study participants who were invited to undergo MR studies agreed to do so; 95% of those agreeing to the procedure successfully completed the exams. Intrareader and interreader reliability of infarctlike lesion identification was high for large lesions (kappa, 0.71 and 0.78, respectively) but not for small lesions (kappa, 0.71 and 0.32, respectively). Relaxed intrareader and interreader kappa scores for sulcal and ventricular sizes and extent of white matter disease were greater than 0.8 MR evidence of infarctlike lesions was present in 77% of the participants with histories of stroke but was also present in 23% of the participants without clinical histories of stroke. Seventy-nine percent of the infarctlike lesions were larger than 3 mm. CONCLUSIONS: This preliminary study indicates that a large, prospective, epidemiologic study of elderly subjects using MR scans of the brain for identification of cerebrovascular disease is feasible and that the interpretative results are reproducible, and suggests that MR evidence of stroke is more prevalent than reported clinical history of stroke. PMID- 7847206 TI - Carotid stenosis by digital subtraction angiography: reproducibility of the European Carotid Surgery Trial and the North American Symptomatic Carotid Endarterectomy Trial measurement methods and visual interpretation. AB - PURPOSE: To evaluate different carotid stenosis estimation methods with digital subtraction angiography. METHODS: We assessed the intraobserver reproducibilty and interobserver variability of visual interpretation and the measurement methods used by the European Carotid Surgery Trial and the North American Symptomatic Carotid Endarterectomy Trial. Angiographic stenosis measurements according to both criteria were performed twice by a radiologist, a neurologist, and a vascular surgeon. Eighty bifurcations of consecutive symptomatic patients underwent 480 pairs of measurements. In addition, four radiologists estimated the stenoses visually. RESULTS: Intraobserver consistency was slightly better by the European (kappa, 0.86 to 0.94) than by the North American (kappa, 0.68 to 0.91) trial criteria or by visual interpretation (kappa, 0.79 to 0.81). No significant interobserver variability was found, except in the subgroup of mild stenoses by the North American Trial criteria. By kappa statistic, the interobserver agreement was excellent by the European trial method (kappa, 0.72 to 0.86), good by the North American trial method (kappa, 0.59 to 0.77), and good to excellent by visual evaluation (kappa, 0.68 to 0.88). The visual estimation agreed more closely with the European (kappa, 0.73 to 0.92) than with the North American trial (kappa, 0.55 to 0.74) criteria measurements. CONCLUSIONS: All three methods have good reproducibility in digital subtraction angiography. Interobserver differences become more important in the estimation of mild stenosis. PMID- 7847207 TI - Evaluation of subclavian steal with two-dimensional phase-contrast and two dimensional time-of-flight MR angiography. AB - We describe two MR angiographic methods of diagnosing subclavian steal in each of three patients. By using phase-directional information from a single two dimensional phase-contrast sequence, we were able to show that the direction of flow in the affected vertebral artery was reversed. The same vertebral artery showed no signal on a 2-D time-of-flight sequence with a concatenated presaturation pulse applied above each section. PMID- 7847208 TI - MR cisternography: initial experience in 41 cases. AB - PURPOSE: To present our initial experience with MR cisternography, an application of fast spin-echo MR with fat suppression, and compare it with routine MR cranial studies in the evaluation of the subarachnoid cisterns and their contents. METHODS: MR cisternography is a heavily T2-weighted fast spin-echo technique with high spatial resolution; it uses fat suppression and video reversal of the images. A small number of individual sections (two to four) are compressed into a composite image by a maximum-intensity projection algorithm, providing better depiction of anatomy in three dimensions. MR cisternography enhances the signal intensity of the cerebrospinal fluid (CSF) with suppression and subtraction of the background. A total of 41 patients were examined during a period of 6 months. MR cisternography was performed as an additional one (n = 31) or two (n = 10) sequences after conventional MR study. RESULTS: Twenty-one cases of disease were examined by MR cisternography, including 8 neoplasms, 4 CSF fistulas, and 3 large intracranial aneurysms. MR cisternography provided information unavailable by conventional MR studies in 17 cases. These included visualization of fistulous tracks in patients with CSF rhinorrhea, origin of a large suprasellar aneurysm, an additional loculus of a posterior fossa aneurysm and its relation to surrounding structures, and proper location of three tumors (intraaxial versus extraaxial). Clear depiction of the pituitary gland separate from the cavernous sinus was noted in 60% of the cases, and a new observation of a CSF sleeve around the third nerve in the posterior cavernous sinus was made in 85% of the cases. CONCLUSION: MR cisternography is superior to conventional MR studies in depicting anatomic structures within the subarachnoid spaces. This technique is recommended in the evaluation of cranial CSF fistulas and suprasellar and posterior fossa masses and in diagnosis of intraaxial versus extraaxial location of intracranial tumors. PMID- 7847209 TI - Time-of-flight intracranial MR venography: evaluation of the sequential oblique section technique. AB - PURPOSE: To implement a time-of-flight MR angiographic technique using the oblique acquisition of thin gradient-echo sections to evaluate the intracranial venous system, and to assess the feasibility of application of this technique in a routine clinical setting. METHODS: The MR angiographic technique consisted of a two-dimensional gradient-echo technique with sequential overlapped sections obtained with an oblique orientation, angled from the sagittal toward the coronal plane. Parameters were evaluated during 41 measurements in 21 healthy volunteers with the section orientation varying from direct sagittal to direct coronal, followed by 64 examinations in 53 patients with an angle of obliquity of 15 degrees to 20 degrees from the sagittal toward the coronal plane. Confirmation of MR venographic findings was through correlation with clinical data and imaging studies. RESULTS: The volunteer data demonstrated optimal visibility of the smaller midline structures with an angle of obliquity of 15 degrees or greater. Patient examinations with this angle demonstrated sinus obstruction or thrombosis (n = 11), sinus compression (n = 2), and apparent sinus stenosis (n = 1). CONCLUSIONS: Oblique-acquisition time-of-flight MR venography seems to provide a rapid, robust technique for intracranial venous examination and can be applied as a useful adjunct to parenchymal MR in the evaluation of suspected venoocclusive disease. This oblique technique demonstrated improved vessel contrast over direct sagittal acquisition, required significantly fewer sections and thus a shorter acquisition time than direct coronal acquisition, and was applied without difficulty in the vast majority of patients in the clinical setting. PMID- 7847210 TI - In vitro evaluation of papaverine hydrochloride incompatibilities: a simulation of intraarterial infusion for cerebral vasospasm. AB - PURPOSE: To elucidate, in light of reports of complications associated with intraarterial infusion of papaverine hydrochloride, the known propensity of papaverine hydrochloride to form precipitate in combination with other solutions or pharmaceuticals. METHODS: Initially simulating a situation experienced during an intraarterial papaverine infusion for cerebral vasospasm, we mixed various concentrations of papaverine with serum, nonheparinized and heparinized saline, and nonionic contrast material. RESULTS: Papaverine in concentrations of 0.3% (300 mg/100 mL of normal saline) or greater formed a precipitate when mixed with human serum (blood). The precipitate crystals were 50 to 100 microns in size and could be returned to solution simply by the addition of more serum. CONCLUSION: Crystal emboli are a possible transient cause of complications experienced during treatment of vasospasm with its attendant altered flow dynamics. PMID- 7847211 TI - Transient neurologic events associated with intraarterial papaverine infusion for subarachnoid hemorrhage-induced vasospasm. AB - This report describes three patients who experienced transient neurologic events associated with intraarterial papaverine infusion in the vertebrobasilar system. Two of these involved respiratory depression and underscore the need for careful monitoring and, when required, cardiopulmonary support. PMID- 7847212 TI - Efficacy of endovascular treatment of meningiomas: evaluation with matched samples. AB - PURPOSE: To evaluate the clinical efficacy, cost-effectiveness, and safety of presurgical devascularization of meningiomas. METHODS: Matched samples of embolized and nonembolized groups of meningiomas were compared. The study variables for clinical efficacy were estimated blood loss, number of transfusions, surgical resection time, and length of hospitalization. The cost effectiveness was evaluated by adjusting all hospital costs to 1991 dollar amounts, and adding additional embolization costs and fees to the hospital cost totals for the embolized group. A qualitative comparison of complications was made. RESULTS: All dependent variables evaluating the clinical efficacy of the procedure (estimate blood loss, 533 cc versus 836 cc; number of transfusions, 0.39 units versus 1.56 units; surgical resection time, 305.8 minutes versus 337.5 minutes; and length of hospitalization, 10.6 days versus 15.0 days) displayed trends of higher means in the nonembolized group; however, only the estimated blood loss and number of transfusions variables were significant. The cost effectiveness of the procedure was not statistically significant. The mean cost was $29,605 for the embolized group and $38,449 for the nonembolized group. There were three major and nine minor complications in the nonembolized group and zero major and six minor complications in the embolized group. There were four additional minor complications caused by the embolization procedure. CONCLUSION: Endovascular devascularization of meningiomas is beneficial for large meningiomas because it diminishes the necessity of intraoperative transfusions and decreases blood loss. The additional day of hospitalization, emolization costs, and costs of complications do not conversely increase treatment costs. There were no major complications or adverse long-term effects caused by the embolization procedure. PMID- 7847213 TI - Dynamics of cerebral metabolism in patients with chronic subdural hematoma evaluated with phosphorous 31 MR spectroscopy before and after surgery. AB - PURPOSE: To determine whether the depression of cerebral bioenergetic metabolism caused by chronic subdural hematomas can account for neurologic dysfunction and whether the degree of metabolic depression may be useful for clinical assessment and therapy. METHODS: Sixteen patients who had chronic subdural hematomas with hemiparesis and/or mental disturbances underwent phosphorous 31 MR spectroscopy before and 10 to 14 days after surgery. Phosphorous 31 MR spectroscopy was also performed on 5 patients who had chronic subdural hematomas with only slight headaches who were treated by conservative therapy and on 10 healthy volunteers. RESULTS: The peroperative phosphocreatine-to-inorganic phosphate ratio (2.10 +/- 0.36) improved to normal values (2.69 +/- 0.44) after evacuation of hematomas. This improvement was accompanied by complete disappearance of hemiparesis and/or mental disturbance. Brain tissue pH also improved from 7.07 +/- 0.11 to 7.205 +/- 0.13 after surgery. On the other hand, patients who had chronic subdural hematomas with only slight headaches had the same phosphocreatine-to-inorganic phosphate ratio and brain intracellular pH as healthy volunteers. CONCLUSION: The phosphocreatine-to-inorganic phosphate ratio may be useful for determining when to operate on patients with chronic subdural hematomas and to assess the efficacy of treatment. PMID- 7847214 TI - Crossing the rubicon; or, 'who's in charge?'. PMID- 7847215 TI - CT and MR appearance of recurrent malignant head and neck neoplasms after resection and flap reconstruction. AB - PURPOSE: To describe the appearance of recurrent malignant neoplasms in patients who have undergone resection of primary head and neck tumors with flap reconstruction. METHODS: Thirty-two examinations, 26 CT and 6 MR scans, were retrospectively reviewed in 25 patients with documented recurrent malignant neoplasms. Confirmation of disease was by biopsy or disease progression. The flaps included 15 myocutaneous, 6 free composite, 2 jejunal free grafts, and 2 combined jejunal and myocutaneous flaps. RESULTS: The most common location of recurrence was in the primary tumor bed involving the undersurface or suture line of the reconstruction flaps, 14 of 32 scans; both nodal and flap recurrence was seen in 12 of 32 scans. CONCLUSIONS: When examining patients who may have recurrent disease after flap reconstruction, the radiologist should be aware of the type of flap used and the expected appearance. Tumor recurrence in this patient population is manifest either as a focal recurrent mass at or near the suture line of the reconstruction flap, or nodal disease, usually in the contralateral neck. PMID- 7847216 TI - T stages of tumors of the tongue and floor of the mouth: correlation between MR with gadopentetate dimeglumine and pathologic data. AB - PURPOSE: To define MR accuracy in the evaluation of the T stages of tumors of the tongue and floor of the mouth. METHODS: Fifty-two patients affected by squamous cell carcinoma were studied with a superconductive system at 1.5 T. The study was performed with spin-echo T1- and T2-weighted images before contrast and short spin-echo T1-weighted and gradient-echo sequences after gadopentetate dimeglumine administration. The results obtained with MR were compared with pathologic data. RESULTS: Good correlation of T stages (TNM system) was obtained in 45 of 52 cases. MR did not show four superficial lesions. In one case, infiltration of the cortical bone of the mandible was not demonstrated (MR, T2; pathologic, T4), and in another the lesion was classified as T2 instead of T3, as it was pathologically. One lesion was classified as T4 on MR because of infiltration of the alveolar ridge but was classified as T2 at surgery. In 46 patients who underwent surgery, the accuracy of MR was excellent for predicting the relationship of tumor to midline and oral floor musculature. The results obtained with gadopentetate dimeglumine were better than those obtained in noncontrast studies in 32 (62%) of 53 cases. CONCLUSION: MR showed high accuracy in the study of tumors of the tongue and floor of the mouth. PMID- 7847217 TI - Hemangioma of the mandibular condyle and ramus. PMID- 7847218 TI - Fat-suppressed MR of the orbit and cavernous sinus: comparison of fast spin-echo and conventional spin-echo. AB - PURPOSE: To compare T2-weighted fat-suppressed fast spin-echo imaging with fat suppressed conventional spin-echo imaging in the detection of normal intraorbital and pericavernous anatomy and orbital disease, and to determine the efficacy of fat saturation with T2-weighted fast spin-echo imaging of the cavernous sinus. METHODS: Contrast-to-noise ratios of normal intraorbital anatomy were calculated and compared in 10 consecutive patients using fat-suppressed fast spin-echo and conventional spin-echo T2-weighted images. Contrast-to-noise ratios of common intraorbital lesions were calculated and compared using fat-suppressed fast spin echo and fat-suppressed conventional spin-echo. Qualitative evaluation was performed and compared for normal intraorbital anatomy using both fat-suppressed fast spin-echo and fat-suppressed conventional spin-echo in 16 patients. Qualitative evaluation for the detection of normal anatomic structures of the pericavernous region was performed and compared using fast spin-echo with and without fat suppression and fat-suppressed conventional spin-echo T2-weighted images in 16 patients. Fat saturation was performed using standard commercially available chemical saturation technique. RESULTS: Reduced imaging time allowed more acquisitions for fat-suppressed fast spin-echo images, which significantly improved visibility of intraorbital and pericavernous anatomy over fat-suppressed conventional spin-echo. Anatomic visibility was also improved because of reduced motion, phase encoding, and susceptibility artifacts. There was no significant difference between contrast-to-noise ratios for fat-suppressed fast spin-echo and fat-suppressed conventional spin-echo imaging of the lateral and medial rectus muscles. Contrast-to-noise ratios of fat suppressed fast spin-echo of orbital disease was significantly greater than contrast-to-noise ratios of fat-suppressed conventional spin-echo. Detection of several normal anatomic structures of the pericavernous region was significantly improved with non-fat-suppressed fast spin echo over fat-suppressed fast spin-echo because of significantly reduced magnetic susceptibility artifact. CONCLUSIONS: Fat-suppressed fast spin-echo is superior to fat-suppressed conventional spin-echo for T2-weighted orbital imaging. Non-fat suppressed fast spin-echo is the preferred pulse sequence for T2-weighted imaging of the cavernous sinus because of the minimal susceptibility artifact. PMID- 7847219 TI - Cerebellar MR changes in patients with olivary hypertrophic degeneration. AB - PURPOSE: To describe MR changes in the cerebellar cortex and the dentate nucleus in patients with inferior olivary nucleus hypertrophy. METHODS: MR scans of 11 patients with palatal myoclonus were reviewed. Among them, we selected 5 cases that showed lesions in the central tegmental tract and the ipsilateral inferior olivary nucleus. We evaluated MR changes of the cerebellar cortices and dentate nuclei contralateral to the affected inferior olivary nuclei. Evaluation was performed by side-to-side comparison in each case. Six cases were excluded, because comparison of the cerebellar hemispheres or dentate nuclei with those of the opposite sides was not possible. RESULTS: The dentate nuclei opposite affected inferior olivary nuclei showed mild to moderate shrinkage of the normal low-signal areas and increases in signal intensity on T2-weighted images in 4 of 5 patients. The cerebellar cortices on the same sides as the involved dentate nuclei showed atrophic changes in 4 of 5 patients. CONCLUSION: Our MR findings suggest that there is a degenerative process involving the dentate nucleus and the cerebellar cortex associated with the hypertrophic degeneration of the inferior olivary nucleus. PMID- 7847220 TI - Cerebrotendinous xanthomatosis (van Bogaert-Scherer-Epstein disease): CT and MR findings. AB - PURPOSE: To describe the CT and MR findings in the brain and spinal cord of patients with cerebrotendinous xanthomatosis and to seek possible correlations between clinical, biochemical (cholestanol levels), and neuroimaging findings. METHODS: Ten patients with well-defined clinical and biochemical diagnoses of cerebrotendinous xanthomatosis were examined. Brain CT was performed in eight cases. In all patients MR was obtained using spin-echo and gradient-echo sequences. In eight patients spine MR was also performed. RESULTS: Neuroradiologic findings included diffuse cerebral and cerebellar atrophy. In half the cases, atrophy of the brain stem and corpus callosum was also found. In the majority of patients cerebellar bilateral focal lesions and mild white matter signal alterations were present. Spinal cord MR did not show signal abnormalities or atrophy. CONCLUSIONS: We found cranial alterations in patients with severe neurologic impairment, but there was no correlation with cholestanol plasma levels. No spinal cord abnormalities were present. PMID- 7847221 TI - MR of intracranial tumors: combined use of gadolinium and magnetization transfer. AB - PURPOSE: To study the potential combined application of gadolinium and magnetization transfer in the MR imaging of intracranial tumors. METHODS: Twenty two patients were imaged at low field strength (0.1 T). Corresponding gradient echo partial saturation images without and with magnetization transfer pulse were produced. Images with intermediate repetition times were obtained in 18 cases; five different sequences were produced in 4 cases. Gadopentetate dimeglumine was used at a dose of 0.1 mmol/kg. RESULTS: Magnetization transfer effect increased the contrast between enhancing lesion and normal brain and the contrast between edema and normal brain; the contrast between enhancing lesion and edema was not significantly changed. On intermediate-repetition-time magnetization transfer images the contrast between enhancing tumor and normal brain and the contrast between edema and normal brain were superior to short-repetition-time magnetization transfer images, but the differentiation between enhancing tumor and edema was poorer. CONCLUSION: Magnetization transfer can be used to improve contrast in Gd-enhanced MR imaging. Combining magnetization transfer with an intermediate-repetition-time image provides the possibility for displaying both enhancing and nonenhancing lesions on a single MR image. PMID- 7847222 TI - Visibility of epidermoid tumors on steady-state free precession images. AB - PURPOSE: To determine whether steady-state free precession sequences improve the MR visibility of epidermoid tumors in comparison with spin-echo images. METHODS: Patients were four women and three men with epidermoid tumors in the subarachnoid spaces. MR was performed with a 1.5-T superconductive unit. For steady-state free precession imaging, three-dimensional Fourier transform fast imaging with steady state free precession (FISP) images were used (20-40/7 [repetition time/echo time], flip angle of 25 degrees). The visualization and contrast-to-noise ratio were compared in FISP images and spin-echo images. In one case, the images of FISP and fast low-angle shot were obtained with variable repetition times and flip angles to evaluate the best pulse sequences for the visualization of epidermoid tumors. RESULTS: The contrast-to-noise ratios between tumors and cerebrospinal fluid ranged from 7.9 to 17.5 (average was 12.9) on FISP images. The average of contrast-to-noise ratios on T1, T2, and proton density-weighted spin-echo images were 1.6, 2.0, and 4.2, respectively. Three-dimensional Fourier transform FISP images best showed central nervous system and demonstrated epidermoid tumors excellently. CONCLUSIONS: Epidermoid tumors in the subarachnoid spaces were better demonstrated on steady-state free precession (three dimensional Fourier transform FISP) than on conventional spin-echo images. PMID- 7847223 TI - Radiologic-pathologic correlation. Gliomatosis cerebri. PMID- 7847224 TI - Cerebellar MR in Fukuyama congenital muscular dystrophy: polymicrogyria with cystic lesions. AB - PURPOSE: To determine the MR appearance of cerebellar abnormalities in Fukuyama congenital muscular dystrophy. METHODS: We reviewed brain MR images of 25 patients with Fukuyama congenital muscular dystrophy and examined the autopsy specimens of a 23-month-old girl with the disease to determine the pathologic nature of the MR findings. RESULTS: MR studies revealed two characteristic cerebellar abnormalities: (a) disorganized cerebellar folia (16 cases) that were recognized as unusual distortions of the cortex; and (b) clusters of intraparenchymal cysts (23 cases). The two lesions were located close to each other, and milder lesions tended to affect only the superior semilunar lobule. The autopsy specimen revealed small cerebellar cysts, which consisted of dilated subarachnoid spaces buried beneath the malformed cortex. CONCLUSION: The disorganized folia represent cerebellar polymicrogyria, and the presence of cerebellar cysts is related to the polymicrogyria. These two MR changes are often present in Fukuyama congenital muscular dystrophy and are distinct enough to suggest the radiologic diagnosis. PMID- 7847225 TI - Adrenoleukodystrophy: a scoring method for brain MR observations. AB - PURPOSE: To develop a scoring method for brain observations in patients with X linked adrenoleukodystrophy. METHODS: One hundred seventy-five brain MR scans in 83 male subjects less than 20 years of age with proved biochemical defects were reviewed. A severity score (0 to 34), based on a point system derived from location and extent of disease and the presence of focal and/or global atrophy, was calculated for each exam. RESULTS: Fifty-five of the 83 patients showed MR findings consistent with adrenoleukodystrophy. Two major patterns were observed. A posterior pattern (mean score, 9; range, 0.5 to 25) was present in 80% of patients, and an anterior pattern (mean score, 10; range, 2 to 18) was present in 15% of patients. Serial MR imaging, positive for adrenoleukodystrophy in 34 patients (mean follow-up, 23 months; range, 2 months to 6 years 11 months), showed progressive disease in 52%, progressive disease with subsequent stabilization in 18%, stable disease in 24%, and minimal improvement in 6%. CONCLUSION: The adrenoleukodystrophy MR severity scoring method is a measure that can be used with standard MR images. When used in conjunction with clinical parameters, this scoring method may help define better the natural history of adrenoleukodystrophy and monitor response to developing therapies. PMID- 7847226 TI - Childhood cerebral form of adrenoleukodystrophy: short-term effect of bone marrow transplantation on brain MR observations. AB - PURPOSE: To report the serial brain MR observations in patients with childhood onset cerebral adrenoleukodystrophy 1 to 2 years after bone marrow transplantation. METHODS: Eight boys with childhood-onset cerebral adrenoleukodystrophy have undergone successful transplantation at our institution. Seven patients (mean age, 8 years 10 months; range, 5 years 3 months to 11 years 9 months) had serial MR studies before and after transplantation. An MR severity score (0 to 34) based on disease location and the presence or absence of focal atrophy was calculated for each patient scan. RESULTS: Posttransplantation serial MR showed improvement in two patients, stabilization in three patients, and worsening of MR signal changes in two patients. The patient with the most striking progression had systemic graft-versus-host disease. Although the adrenoleukodystrophy MR severity score did not change in three patients after transplantation, two of these patients did show improved margination of disease. CONCLUSION: Bone marrow transplantation can affect brain MR observations in childhood-onset cerebral adrenoleukodystrophy. Although brain MR findings do not typically resolve, they do seem to stabilize, which is an improvement over the natural MR history of the disease. PMID- 7847228 TI - Valproic acid-induced hyperammonemic encephalopathy: MR appearance. PMID- 7847227 TI - Persistent enhancement after treatment for cerebral toxoplasmosis in patients with AIDS: predictive value for subsequent recurrence. AB - PURPOSE: To determine the predictive imaging (CT and/or MR) features of brain toxoplasmosis recurrences in acquired immunodeficiency syndrome. METHODS: The imaging studies of patients with brain toxoplasmosis were retrospectively reviewed. Forty-three patients with significant decrease or disappearance of brain lesions under specific treatment on follow-up imaging examinations were included. MR examinations were performed using T2- and T1-weighted sequences, before and after intravenous administration of gadolinium-DOTA. RESULTS: A recurrence occurred in 11 (26%) of 43 cases. Ten (91%) of these 11 patients with recurrence showed focal persistent enhancement after the initial treatment of toxoplasmosis abscess. One of the 11 patients with recurrence showed no persistent enhancement; 3 patients showed persistent enhancement but had no recurrence. CONCLUSIONS: Recurrences of brain toxoplasmosis in our series correlated with persistent contrast enhancement. We hypothesize that demonstration of persistent areas of contrast enhancement after treatment for initial toxoplasmosis may be a valuable sign for identifying patients at risk for recurrence. PMID- 7847229 TI - MR of isolated leptomeningeal glioma. AB - We report the MR study of a case of high-grade glioma that mimics leptomeningeal carcinomatosis. Superficial gliomas should thus be included in the differential diagnosis of isolated meningeal enhancement. PMID- 7847230 TI - Unusual coil-release method. PMID- 7847231 TI - Brain iron and T2 signal. PMID- 7847232 TI - MR of pineal cysts. PMID- 7847233 TI - Lesions in oculocerebrorenal syndrome. PMID- 7847234 TI - Annotated bibliography. PMID- 7847235 TI - The seductive patient. PMID- 7847236 TI - The implications of sexual misconduct in a physician's practice. PMID- 7847237 TI - Stress. The profession, the family and you. PMID- 7847238 TI - Professional sexual misconduct: the current realty, current concepts, ignorance is not excuse. PMID- 7847239 TI - Psychotherapists who transgress sexual boundaries with patients. AB - The causes of therapist-patient sex are complex and multidetermined. Efforts to understand why psychotherapists transgress sexual boundaries are hampered by the lure of reductionism and oversimplification. Most of those who examine this issue would prefer to categorize all such therapists as "bad" and "corrupt" as away of distancing themselves and disavowing any similarities between these therapists and themselves. The pathology of therapists who commit sexual boundary violations generally falls into four broad categories: (1) psychotic disorders, (2) predatory psychopathy and paraphilias, (3) lovesickness, and (4) masochistic surrender. Although a variety of individual psychodynamic factors are involved within each group, this classification is highly useful for informed treatment planning. PMID- 7847240 TI - Gene therapy and pharmacy practice: Part 1. PMID- 7847241 TI - Pharmacy computer systems and patient safety--Part 1. PMID- 7847242 TI - Why aren't more pharmacists counseling? AB - Clearly, the answers to the question "Why aren't more pharmacists counseling patients?" are complex. Factors affecting counseling vary by practice site, geographical region, and pharmacists' attitudes. Advocates of patient counseling may label many factors mentioned by workshop participants as "just excuses not to change" or may question their validity. However, our experiences have shown that these are real problems with logical explanations and relatively simple solutions. By focusing this column on the steps for overcoming these common barriers to counseling, we hope to help pharmacists expand their role in patient care. PMID- 7847243 TI - Is methotrexate interaction critical? PMID- 7847244 TI - Rheumatoid arthritis and osteoarthritis: current and future therapies. PMID- 7847245 TI - Pharmacists' information sources. PMID- 7847246 TI - Pharmacists' information sources. PMID- 7847247 TI - Pharmacist in Richmond launches pharmaceutical care program. PMID- 7847248 TI - Compliance devices preferred by elderly patients. AB - Many elderly patients take several medications for chronic conditions, a situation which causes problems in compliance with drug regimens. This study surveyed patients' preferences among four devices designed to make compliance easier: rub-off reminder labels, medication organizer trays, a container cap with a modified alarm clock, and a digital elapsed timer. Thirty-one enrolled patients used each device for one month then reported their ratings of four device attributes--clarity of directions for use, ease of use, convenience, and effectiveness in preventing dosing errors. The patients showed a strong preference for the medication organizer tray and generally preferred less-complex devices to those that were more difficult to learn to use. PMID- 7847249 TI - Can we lead pharmacy into the 'right jungle'? PMID- 7847250 TI - Understanding bone marrow transplantation--Part 1. PMID- 7847251 TI - A phase 1-2 trial of superselective carboplatin, low-dose infusional 5 fluorouracil and concurrent radiation for high-grade gliomas. AB - Recent trials have suggested that low-dose infusional 5-FU is more efficacious when given during radiotherapy than is bolus 5-FU. Additionally, intra-arterial cisplatin for brain tumors has been shown to be associated with both high response rates as well as significant toxicity. A dose escalation study was therefore performed using superselective carboplatin, a cisplatin analogue with a favorable CNS toxicity profile in combination with 6 weeks of infusional 5-FU at 225 mg/m2 and concurrent radiotherapy. Eight patients were treated at the starting dose of 200 mg/m2 carboplatin and 11 patients were treated at 300 mg/m2. No toxicity was observed that was attributable to infusional 5-FU. However, two ischemic events related to the superselective delivery of carboplatin were observed, and one patient was noted to have asymptomatic retinal toxicity from the carboplatin. Of 19 patients, 5 had objective responses with 25% or greater reduction in tumor volumes. Continuous infusional 5-FU can be given in combination with partial brain radiotherapy without significant toxicity. Superselective carboplatin delivery is associated with a low incidence of stroke, but no significant retinal toxicity. PMID- 7847252 TI - Cancer incidence and mortality in patients with heart disease. Effect of oral anticoagulant therapy. AB - Cancer incidence and mortality were reviewed in patients (683) who, during the period 1969-1988, had been attending the Cardiological Center of Pisa University for more than 1 year for valvular (494), ischemic (183), or myocardial (6) disease. Oral anticoagulant therapy (tromexan, acenocoumarol or warfarin) was administered to 312 of these 693 patients and regulated to prolong prothrombin time to a value between 20% and 40% of normal controls. The duration of treatment ranged from 1 to 14 years, with a mean of 4 years. As clinical and radiological controls were performed on all the patients at regular intervals (2-12 months), cancer incidence and mortality were recorded. Cancer incidence and mortality in the 312 patients treated with anticoagulants were compared with that of the 381 patients who did not receive this therapy. Furthermore, cancer mortality in the patients on anticoagulants was compared to that expected on the basis of national tumor registry rates. The age of the patients varied from 20 or under to 80 or over in both groups. The total observation period was 1415 patient-years (555 for males and 860 for females) in the former and 1617 patient-years (735 males and 882 females) in the latter. The proportion of the patient-years of the men over 45 (with the highest risk of cancer mortality) was higher in the group treated with anticoagulants (83%) than in the controls (72%) (p < .001). The proportion of the patient-years of the women over 45 was also higher in the former (84% vs 62%; p < .001). Six cancers were observed in the patients treated with oral anticoagulants (3 men, 3 women), while 12 cancers occurred in the control group (9 men, 3 women). There were 3 deaths in the former (1 man, 2 women) and 6 in the latter (5 men, 1 woman). On the basis of the national tumor registry rates, deaths expected in men and women on oral anticoagulants were 3 and 2. These data are compatible with the hypothesis that oral anticoagulants might reduce cancer incidence and mortality in humans. PMID- 7847253 TI - A phase II trial of 5-fluorouracil and high-dose leucovorin in recurrent epithelial ovarian carcinoma. A Gynecologic Oncology Group Study. AB - In this series 49 patients with epithelial ovarian carcinoma previously treated with platinum-based chemotherapy received leucovorin 200 mg/m2 i.v. bolus followed by 5-fluorouracil at 370 mg/m2 i.v. bolus daily for 5 days every 4 weeks for the first two courses and subsequent courses were given every 5 weeks. Of this group, 47 patients were evaluable for toxicity and 44 for response. Of the patients evaluable for response, 15 were considered platinum-sensitive and 29 were platinum-refractory. The overall response rate was 6/44 (13.6%). There were two complete responders (4.5%) and four partial responders (9.1%). In the platinum-sensitive patients, there was one complete response, yielding a response rate of 6.6%, whereas in the platinum-refractory patients, there were four partial responses and one complete response for a response rate of 17.2%. Five responses were in the pelvis and there was one response at an extrapelvic site in the abdominal mesentery. The median number of courses delivered was three (range: 1-10). The major adverse effect was myelosuppression with 16/47 (34.0%) experiencing granulocytopenia < 1,000/mm3. The median white blood count nadir for the patients experiencing any leukopenia was 2,700 (range: 400-3,900/mm3). There was one episode of grade 3 thrombocytopenia. Grade 3 intestinal toxicity was seen in seven patients (14.9%). There were no treatment-related deaths. In this previously treated population, 5-fluorouracil with high-dose leucovorin exhibited activity of interest in the platinum-refractory population and warrants further investigation. PMID- 7847254 TI - A phase II trial of intraperitoneal high-dose carboplatin and etoposide with granulocyte macrophage-colony stimulating factor support in patients with ovarian carcinoma. AB - Based upon results obtained in a Phase I study, we conducted a Phase II trial of high-dose CBDCA and etoposide administered via the intraperitoneal (IP) route in patients with ovarian cancer. CBDCA at a dose of 600 mg/m2 and etoposide at a dose of 400 mg/m2 were administered rapidly into the peritoneal cavity. The total dose of each agent was calculated and given daily over 3 days in amounts equal to one-third of the total dose. On day 1 of therapy, one-third of the dose was mixed in 2 liters of D5W and administered intraperitoneally as rapidly as possible. On days 2 and 3, one-third of the dose was mixed in 1 liter of D5W and administered similarly. GM-CSF was begun on day 4 as a subcutaneous injection at a dose of 500 micrograms/m2/day. A total 53 courses of treatment was administered to 18 patients; 9 of 13 patients (69%) with evaluable disease demonstrated evidence consistent with a partial response; however, the majority were response determined by a decrease in tumor marker (CA-125). One patient who had pathologic evidence of disease at second look laparotomy, but no measurable disease, was treated and shown at subsequent reexploration to have no further evidence of disease. This patient remains free of disease at 17+ months. The toxicity encountered in this trial was formidable, resulting in the removal of 78% of the patients from the study prior to completing 6 cycles of therapy. PMID- 7847255 TI - A phase I study of recombinant interferon-alpha administered as a seven-day continuous venous infusion at circadian-rhythm modulated rate in patients with cancer. AB - A Phase I trial of interferon-alpha (IFN-alpha) administered at circadian-rhythm modulated rate was carried out to evaluate maximum tolerated dose (MTD) and toxicity in patients with advanced malignancies. Recombinant IFN-alpha-2b was administered as a 7-day continuous venous infusion with maximum delivery between 6 p.m. and 3 a.m. Entry dose levels were 0.2, 2 and 4 MU/m2/day. The dose was escalated by an amount equal to the starting dose until a maximum of 6 entry dose levels was achieved, with a 1-week rest between each cycle. The maximal daily dose of IFN-alpha administered was 24 MU/m2/day. A programmable-in-time ambulatory pump was used, so that all patients could receive their treatment at home. Eighteen patients were entered in the study and 16 were evaluable for toxicity. Toxicity was mild to moderate except for two patients who developed WHO grade III toxicity. No significant decline in performance status was associated with treatment. Two objective responses were observed in patients with previously treated metastatic renal cell carcinoma. As compared to standard s.c./i.m. administration or continuous nonchronomodulated i.v. infusion of IFN-alpha, this circadian schedule has allowed to deliver high doses of drug with acceptable toxicity. PMID- 7847256 TI - Carcinoma of the anal canal. AB - From 1975 to 1990 65 patients with carcinoma of the anal canal received radiation therapy alone or in conjunction with other modalities. Follow-up ranged from 12 to 171 months (mean: 59 months; median: 44 months). Actuarial disease-free survival (including salvage surgery) for T1-3 N0 lesions was 88% +/- 7% at 10 years. This was independent of T stage (91% for T1, 88% for T2, and 100% for T3). Disease-free survival was significantly worse for T1-3 N+ lesions (52% +/- 23% disease-free at 10 years, P = .025) and T4 lesions (0/8 disease free by 21 months, P < .001). Of the 57 patients with T1-3 lesions, 46 received low to moderate doses of radiation (< or = 5,000 cGy) in conjunction with infusional 5FU based chemotherapy. These were reviewed for treatment related factors. Among patients treated with low to moderate dose chemoradiotherapy the local control (including salvage surgery) was excellent: 100% for T1 lesions and 88% +/- 6% for T2, 3 lesions. There was a suggestion that increasing the dose of radiation to the tumor may reduce the need for surgery for T2, 3 lesions. For T2, 3 lesions the local control excluding surgery was 63% +/- 12% with 3,000 cGy plus chemotherapy, as opposed to 77% +/- 11% with 4,000-5,000 Gy (mean 4,600 cGy) plus chemotherapy. The most important factor for posttreatment toxicity was the addition of pelvic surgery to chemotherapy and radiotherapy. Eighteen patients who received chemoradiotherapy either had a history of prior pelvic surgery (five cases) or underwent APR following chemotherapy (13 cases). There were a total of nine grade 3 or 4 complications (including all five cases of small bowel obstruction) in this group. There was a significantly lower (P = .04) incidence of complications in the remaining patients: 2/47 (4%). It should be noted that no patient required a colostomy for management of treatment sequelae, the interventions taken were all successful in managing complications, and no complication was fatal. Nonetheless these results suggest that, for some T3 and T2 lesions, measures which reduce the need for salvage surgery might improve overall quality of life by reducing complications, although it may prove difficult to demonstrate an improvement in the excellent disease-free survival. In addition, measures should be taken to reduce the volume of irradiated bowel if a patient has a history of prior pelvic surgery. PMID- 7847257 TI - Lactation after conservative breast surgery combined with radiation therapy. AB - Radiosensitivity of the mammary gland and the effect of therapeutic radiation on lactation has not been defined. To investigate lactation following conservative surgical management and megavoltage radiation treatments for early breast carcinoma, data were collected from a national survey of 2,582 members of the American Society of Therapeutic Radiology and Oncology. This study reports 53 women who became pregnant after lumpectomy, axillary dissection, and radiation treatments with an average dose of 180-200 cGy. The mean daily total dose to the breast was 49.4 Gy and to the boost area 15 cGy either with electrons or implant. Of these patients, 34% were able to exhibit some form of lactation from the irradiated breast; 24.5% were able to successfully breast-feed from the involved breast. Results of the study document that bilateral lactation can successfully occur after conservative surgery and radiation therapy in approximately 1 in 4 women. PMID- 7847258 TI - Infusional chemotherapy (EPOCH) in patients with refractory or relapsed lymphoma. AB - Seventeen patients with refractory (7 cases) or relapsed (10 cases) lymphoma were treated with a continuous infusion of etoposide, vincristine, and doxorubicin, in addition to cyclophosphamide (bolus) and prednisone (regimen EPOCH). Six patients (4 with Hodgkin's disease) achieved a complete response (CR) (35%; 95% CI: 14 62%). However, 5 of 6 patients had achieved a CR with their initial therapy. Myelosuppression was the most serious effect (29% of patients with grade IV leukopenia after the first course). There were two treatment-related deaths. Doses were lower than originally reported (median: 68%). Infusional therapy with EPOCH is an active regimen in these heavily pretreated patients, particularly in relapsed Hodgkin's disease. It seems a useful protocol to prove chemosensitivity before bone marrow transplantation. However, the true role of infusional treatment has to be determined in clinical trials. PMID- 7847259 TI - Concomitant administration of interleukin-2 plus tumor necrosis factor in advanced non-small cell lung cancer. AB - Based upon in vitro and clinical data suggesting antitumor activity of interleukin-2 (IL-2) plus tumor necrosis factor (TNF) in non-small cell lung cancer (NSCLC), we conducted two parallel pilot studies of the combination in patients with advanced disease. Eight patients at the University of Wisconsin received 6 x 10(6) international U/m2/day of IL-2 by continuous infusion on days 1-4, 8-11, and 15-18 with 50 micrograms/m2/day of TNF administered intramuscularly on the same days. Seven patients at the University of Pittsburgh received IL-2 as a continuous infusion for 5 days at a dose of 6 x 10(6) U/m2/day, every 14 days. TNF was administered intramuscularly on days 1 through 5, starting at a dose of 50 micrograms/m2. Patients with no evidence of grade 3 or 4 toxicity on the first cycle had their dose of TNF escalated from 50 to 100 and then to 150 micrograms/m2. No responses were observed. The therapy was not well tolerated, with 11 of 15 patients developing grade 3 or 4 toxicity at some point during their therapy. The most common grade 3 or 4 toxicities were pulmonary (6 episodes) or cardiac (4 episodes) events. Constitutional symptoms were common, but not dose-limiting. Despite the lack of observed responses, the median survival was 11 months, with one patient with metastatic disease alive over 30 months later. We conclude that IL-2 plus TNF was not effective in inducing responses in patients with advanced NSCLC, but the prolonged survival suggests a role for IL-2 in NSCLC, which needs to be further defined by means other than classic response criteria. PMID- 7847260 TI - A phase II trial of zeniplatin in metastatic melanoma. AB - A third-generation platinum analogue, zeniplatin, was administered at a dose of 145 mg/m2 intravenously over 60-90 minutes every 21 days as the initial chemotherapy to 21 patients with metastatic melanoma. Prehydration and mannitol diuresis was introduced after the first 7 patients. There were 17 males and 4 females. The median age was 52 (range: 29-81). ECOG performance status was 0 in 10 patients, 1 in 8 patients and 2 in 3 patients. Major disease sites were lymph nodes, skin, lung, liver, and bone. Patients received a median of 2 cycles (range: 1-7). Two patients achieved partial responses. One with nodal disease progressed after 166 days and the other with buccal mucosal disease after 142 days. A third patient showed partial regression of nodal disease but developed cerebral metastases. Gastrointestinal toxicity included WHO grade 3 vomiting in 8 patients and nausea in 2. Antiemetics were used, but ondansetron was not available. WHO grade 3 hematologic toxicities included neutropenia in 8 patients and anemia and thrombocytopenia in 1 patient. Thrombocytosis was seen in 35% of courses. Dosage reduction was required in 15% of courses and escalation in 5% of courses. Three patients developed phlebitis related to the infusion. One patient developed a reversible rise in serum creatinine, but, unlike other studies, no severe nephrotoxicity was reported. Zeniplatin demonstrated only modest activity in melanoma with significant gastrointestinal and hematologic toxicity. PMID- 7847261 TI - Lung cancer in patients with human immunodeficiency virus infection. AB - This retrospective study determined the clinical course of lung cancer in patients with human immunodeficiency virus (HIV) infection. A total of 23 patients with HIV infection archived as lung cancer were studied: 16 were identified from about 1,000 lung cancer patients entered in the tumor registry and medical records of Jackson Memorial Hospital, 7 were identified from about 1,000 HIV-positive patients entered in the Special Immunology registry of Veterans Administration Medical Center, 4 patients did not have pathologic confirmation of lung cancer, and 19 patients, all men, met the criteria for analysis (histopathologic diagnosis of lung cancer and HIV+ by serology). The median age was 47 (range: 36-66). Risk factors for HIV were homosexuality (6 patients), blood transfusion (3), promiscuity (5), intravenous drug abuse (4), and none (3). Six patients had a history of coexistent pulmonary tuberculosis and 5 had Pneumocystis carinii pneumonia. Median survival from diagnosis of lung cancer was 3 months. Advanced stages of both HIV infection and lung cancer may account for the poor survival. All patients were men and noted to be younger than other patients with lung cancer. PMID- 7847262 TI - A phase II study of recombinant interferon-gamma following combination chemotherapy for patients with extensive small cell lung cancer. CALGB. AB - A total of 71 patients with extensive small cell lung cancer were enrolled in CALGB study 8733. Chemotherapy was administered with cisplatin 33 mg/m2, i.v. infusion days 1-3, doxorubicin 45 mg/m2 i.v. day 1, cyclophosphamide 800 mg/m2 i.v. day 1, and etoposide 80 mg/m2 i.v. infusion days 1-3 (PACE). Following four courses of PACE, patients achieving a CR or PR were started on recombinant interferon-gamma (rINF-gamma) 0.2 mg s.c. daily until grade IV toxicities or progression occurred. Of the 71 patients enrolled, 67 are evaluated (47 males and 20 females), median age 59 years, and median PS1. The response rate to PACE was 48/67, 72%. Grade 3-4 toxicities included granulocytopenia, thrombocytopenia, and five treatment-related deaths (7%). Forty-one patients were started on rINF gamma. Of these 41 patients, 11 were in CR, 30 in PR. The objective response rate to rINF-gamma was 2/30 or 6.7%. Recombinant rINF-gamma is inactive in small cell lung cancer, even when the tumor burden has been substantially reduced by prior chemotherapy. PMID- 7847263 TI - Spontaneous recurrent tumor lysis syndrome in breast cancer. AB - A case of spontaneous recurrent acute tumor lysis syndrome is presented in a woman with inflammatory breast cancer. The occurrence of tumor lysis syndrome in solid tumors is unusual, and spontaneous cases are rare. This and other unusual aspects of this case are discussed. PMID- 7847264 TI - Combination chemotherapy with carboplatin and methotrexate in the treatment of advanced urothelial carcinoma. A phase II study. AB - The activity and toxicity of a carboplatin (300 mg/m2, day 1) and methotrexate (50 mg/m2, days 8 and 15) combination chemotherapy in the treatment of advanced urothelial cancer (UC) was evaluated in the present study. A total of 49 patients entered the study: 44 patients were evaluable for response, and 48 for toxicity. A complete response (CR) was found in 4/44 patients (9.1%) and a partial remission (PR) in 12/44 patients (27.2%) for an overall response rate of 16/44 (36.3%). Stable disease was found in 21/44 patients (47.7%), and progressive disease in 7/44 patients (15.9%). Survival was significantly longer in responding patients than nonresponders (median: 62 weeks vs 50 weeks, P < .05). Hematologic and renal toxicities were mild, thrombocytopenia and leukopenia being the most relevant side effects. The first consecutive 7 patients received methotrexate also on day 22; 5 of them underwent grade III-IV hematologic toxicity, so methotrexate on day 22 was omitted in the subsequent patients. No toxic deaths were reported. CBDCA and MTX combination chemotherapy is well tolerated and moderately active in the treatment of advanced urothelial cancer and may represent a valid alternative to cisplatin-containing regimens in patients with poor performance status and/or impaired renal function. PMID- 7847265 TI - Effects of thymostimulin with combination chemotherapy in patients with aggressive non-Hodgkin's lymphoma. A report from the Italian Lymphoma Study Group (GISL). AB - The purpose of this study was to test the efficacy and safety of thymostimulin (TS) administered in addition to conventional chemotherapy in patients with intermediate- and high-grade non-Hodgkin's lymphoma (IG, HG-NHL). A total of 150 patients with newly diagnosed IG- or HG-NHL were entered in a multicenter trial to compare the effectiveness of two different third-generation regimens (MACOP-B versus ProMACE-CytaBOM) and were randomized to receive chemotherapy (CT) alone or CT + TS. In both regimens doxorubicin was replaced by a 20% higher dose of epidoxorubicin. TS was administered i.m. at a dose of 1 mg/kg daily on days 22-28 of each drug course to patients treated with ProMACE-CytaBOM, and on days 22-29, 50-57, and 77-85 to patients treated with MACOP-B. There were 134 fully evaluable patients: 68 treated with CT alone and 66 treated with CT + TS. Patients treated with CT + TS had a higher complete remission (CR) rate compared to patients given CT alone (59.1% vs 42.4%; P = .05). CR were significantly higher for patients treated with CT + TS in the groups with IG-NHL (P = .01), in those aged less than 60 years (P = .05), with good performance status (P = .05), and normal hemoglobin levels (P = .05). Four-year survival rates are 64.5% for patients treated with CT + TS and 43.0% for those treated with CT alone (P = .30). No difference between the two treatment arms have been observed as regards drug-related toxicity and the number and severity of infectious episodes. The use of TS during the 7 days before chemotherapy has been associated with a significantly superior CR rate. The advantage of CT + TS was mostly obtained in patients with IG-NHL, and those with good performance status or normal hemoglobin levels. In these patients TS may have potentiated the host reactions against the tumor, leading to an increase in NK activity and the production of cytokines. This postulated increase in the effectiveness of chemotherapy after TS might also explain the absence of the expected myeloprotective action. PMID- 7847266 TI - Mixed-lineage acute myeloid leukemia associated with a suprasellar dysgerminoma. AB - An association between primary mediastinal germ cell tumors and hematologic malignancies has been recognized since 1985. We present a patient with a suprasellar germ cell tumor and an associated leukemia. A 20-year-old black female presented in December 1987 with a 6-month history of headaches and weight loss, confusion, polyuria, and polydipsia. Evaluation revealed hypernatremia, normal neurologic examination except poor recall, and an enhancing inhomogeneous suprasellar mass on cranial computed tomography. Biopsy of the mass diagnosed a dysgerminoma, which was treated with craniospinal radiation. In February 1988, the patient developed pancytopenia, which resolved with discontinuation of cimetidine and phenytoin. She did well until June 1988 when she presented with skin lesions over the trunk and extremities. Skin biopsy revealed a leukemic infiltration. She was admitted with a WBC 1,500/microliter (without blasts), Hb 11.6 g/dl, PLT 210,000 microliter. Bone marrow biopsy revealed hypercellularity with 50% blasts, demonstrating mixed-lineage acute myeloblastic leukemia (myelomonocytic-M4; megakaryoblastic-M7). The patient was induced with a standard Ara-C/daunorubicin regimen. Two weeks postinduction, she became septic and expired. An autopsy demonstrated leukemic involvement of the spleen, liver, bone marrow, and skin, without residual dysgerminoma. This represents the first reported case of suprasellar dysgerminoma associated with a mixed-lineage leukemia not related to chemotherapy. PMID- 7847267 TI - Clear cell chondrosarcoma of rib following repetitive low-impact trauma. AB - A case of clear cell chondrosarcoma of the rib in a 30-year-old man is described. The tumor developed at the site of repetitive low-impact trauma (on the arm of a wheelchair) over a period of 24 years. An association between chondrosarcoma and external trauma has not been previously reported. Chondrosarcoma has been described in previously irradiated bone and in Paget's disease. In both these examples there is an increase in new bone formation associated with necrosis of bone and increased resorption of bone, respectively. A possible mechanism in our case is increased new bone formation elicited by repeated microfractures of trabeculae of rib bone. PMID- 7847268 TI - Intrusion anchorage potential of teeth versus rigid endosseous implants: a clinical and radiographic evaluation. AB - The purpose of this study was to compare the intrusion anchorage potential of teeth to osseointegrated titanium implants. Titanium implants were surgically placed unilaterally in a healed mandibular fourth premolar extraction site in eight adult mongrel dogs. The implants were surgically uncovered 3 months later and second stage abutments with soldered edgewise brackets secured. Edgewise brackets were also placed on the ipsilateral third premolars and on the contralateral third and fourth premolars. Segmental edgewise arch wires were placed between the implant and the third premolar and between the contralateral third and fourth premolars. Intrusion arch wire bends (v-bends) just mesial to the implant and the fourth premolar brackets were adjusted to apply a 50 to 60 gm intrusive force to the third premolars, bilaterally. Seven weeks later this force was increased to approximately 100 gm. Force levels were monitored biweekly for a total period of 16 weeks. Superimposition of initial and final periapical radiographs with bone markers demonstrated that for each dog the implant remained immobile and the third premolar on the implant anchor side was intruded in a curved path. On the contralateral side of the arch the dental anchor (fourth premolar) underwent an adverse reactive tip-back movement, and the third premolar was not intruded. We conclude that rigid endosseous implants are superior to dental anchorage for orthodontic intrusion of teeth and offer a potential means to intrude anterior teeth in adult patients with missing posterior teeth. PMID- 7847270 TI - The morphologic basis for the extraction decision in Class II, division 1 malocclusions: a comparative study. AB - The purpose of this study was to compare the pretreatment dentofacial characteristics of persons with Class II, Division 1 malocclusions treated with either an extraction or a nonextraction approach. Such comparisons might help identify which parameters influence the extraction decision. Lateral cephalograms were available on 91 Class II, Division 1 cases, 44 were eventually treated with first premolar extractions and 47 were treated nonextraction. Twenty-four landmarks were located and digitized on each cephalogram. From these landmarks, 33 angular and linear dimensions were obtained. The Class II cases were also compared with normal subjects matched for age and sex. Comparisons between the Class II, Division 1 groups and normals indicated that, in general, the Class II, Division 1 malocclusion is associated with a larger overjet, deeper overbite, larger ANB angle, more retrusive mandible, and a convex soft tissue profile. Comparisons between subjects treated with and without extractions indicated that at pretreatment, the extraction groups had significantly larger tooth size-arch length discrepancies in both the maxillary and mandibular arches. In addition, the upper and lower lips in male subjects, and the lower lip in female subjects were significantly more protrusive in the subjects who were eventually treated with four first premolar extractions. These results indicate that in this group of patients, lip protrusion is one of the important parameters on which the extraction decision was based. PMID- 7847269 TI - Lateral cephalometric analysis of skeletal patterns in patients with and without internal derangement of the temporomandibular joint. AB - Twenty-three female volunteers with normal temporomandibular joints (TMJ) were compared with 24 female patients with documented TMJ internal derangements. Magnetic resonance imaging and lateral cephalometric radiographs were used to investigate the relationship between TMJ disk displacement and skeletal facial form. Results indicated that the patients with internal derangements have significantly smaller mandibles and maxillae. However, these sagittal measurements of jaw length were not associated with disproportionate changes in other cephalometric variables. In general, no district relationship was found between the morphologic features of the face and the internal derangements of the temporomandibular joint. PMID- 7847271 TI - Periodontal evaluation of teeth in bone grafted regions in patients with unilateral cleft lip and cleft palate. AB - In 28 patients with unilateral cleft lip and cleft palate who were provided treatment that included bone grafting at an age of 8 to 13 years, periodontal conditions of teeth in the cleft region were monitored from a time point before bone grafting until the canine was fully erupted through the grafted region. Widths of keratinized and attached gingiva tended to increase between preoperative and postoperative examinations. Gingival recession was observed preoperatively for the tooth mesial to the cleft in 14 of the 28 patients. Postoperatively, only three of these patients showed recession. Improvements of the marginal bone level were observed both for teeth mesial and distal to the cleft. Canines having erupted through the grafted defect showed periodontal conditions similar to those of the contralateral canine. The findings demonstrate that treatment, which included osseous grafting before the eruption of the canine, resulted in satisfactory periodontal conditions for teeth in the cleft region. PMID- 7847272 TI - Tinnitus, vertigo, and temporomandibular disorders. AB - Although tinnitus and vertigo have been reported as associated with temporomandibular disorders (TMD) for many years, no control studies have been reported. This study was designed to include two large control populations, as well as a large TMD sample. The null hypothesis was tested. The results revealed that tinnitus and vertigo were significantly more prevalent in the TMD group than in either control group. Reasons for the association of TMD and these otologic symptoms have been proposed and they are discussed. Presently the cause is unknown. PMID- 7847273 TI - Direct bonding to porcelain. AB - Orthodontic brackets were bonded to 180 faces of 45 porcelain cubes that were divided into three groups according to their surface preparation. In group I, the glaze had been removed with a sandpaper disk, whereas in group II, it was maintained. A solution of acidulated phosphate fluoride (APF) gel was applied to the samples in groups I and II for 5 minutes after pumicing. In group III, the glaze had been removed with a coarse diamond bur. Each group was further divided into four subgroups, depending on whether a priming agent had been used, and the type of composite used to bond the brackets. Shear force was used to debond the brackets, and the results showed that the APF solution was unable to provide enough retention on porcelain surface to bond brackets. Mechanical retention, obtained with a coarse diamond bur, was necessary to increase bond strength, which can be further improved by chemical bonding, with a silane priming agent. Therefore bonding to porcelain is clinically possible and is an acceptable procedure in orthodontic treatment. PMID- 7847274 TI - Multidisciplinary HIV Conference to offer latest information in management of HIV positive dental patients. PMID- 7847275 TI - The Probability Index. AB - The clinical study of the treatment of a sample of Class II malocclusions was made. This information from both successful and unsuccessful Class II malocclusion correction was recorded. The objective of the study was to determine whether there are predictive characteristics of Class II cases that could give, with reasonable accuracy, an indication of those Class II malocclusions that would more readily respond to treatment and those that would have less chance of conventional treatment being successful. This information could give the orthodontist differential diagnostic guidance before starting treatment to determine whether alternative treatment strategy should be considered. The study used five very important cranial and dental cephalometric measurements that individually had significance, but no predictive value. However, these measurements, when combined, and given a weighted value that reflected a relative importance of each criteria, were found to collectively give a predictive capability in determining whether the case was favorable for Class II correction. The five angles selected were (1) the Frankfort mandibular plane angle (FMA); (2) the point A nasion point B, (ANB) angle; (3) the occlusal plane, Frankfort plane angle; (4) the Frankfort-mandibular incisor (FMIA) angle; (5) the sella-nasion point B, (SNB) angle. The Probability Index is the sum of the weighted values of the five cranial, and dental angles and seems to have significant predictive value in the differential diagnosis and treatment planning of the Class II malocclusion. PMID- 7847276 TI - The validation of the Peer Assessment Rating index for malocclusion severity and treatment difficulty. AB - The Peer Assessment Rating (PAR) index is a British occlusal index that measures the severity of dental malocclusion and has been used in several investigations that have evaluated the effectiveness of orthodontic treatment provision in Europe. As part of its development, the PAR index was validated for malocclusion severity, by using the opinions of a panel of 74 dentists and orthodontists. The present investigation was carried out to validate the PAR index, by using the opinion of an American panel of orthodontists. Eleven orthodontists examined a sample of 200 sets of study casts and rated them for malocclusion severity and perceived treatment difficulty. Multiple regression techniques were used to evaluate the predictive power of the components of malocclusion on the panel's scores. Weightings were calculated from the partial regression coefficients and, when these weightings were applied to the PAR index, the association between the panel's opinion and the PAR index scores was increased. PMID- 7847277 TI - The accuracy of video imaging in orthognathic surgery. AB - Video imaging is an important emerging technology in planning orthognathic surgery and educating patients about the esthetic effects of treatment. The presurgical cephalograms of 56 patients, 41 with mandibular advancement alone and 15 with mandibular advancement plus genioplasty, were digitized, and the computer generated soft tissue "line drawing" predictions were compared with the actual posttreatment cephalograms. Video images of the patients' presurgical lateral view were obtained, and two experienced clinicians compared the computer generated video image predictions with the actual posttreatment profile. Video images judged very good or excellent were considered acceptable for treatment planning; 60% to 83% met this criterion, depending on the profile area viewed. The percentage of acceptable images in the lower lip, labiomental fold, and chin area decreased with the addition of a genioplasty. The predicted and actual posttreatment soft tissue line drawings were quite similar for all areas except for the lower lip region, where statistically significant differences were noted, with the predicted lower lip more retrusive and thinner than the actual contours. For the lower lip and chin, a 2 mm or more discrepancy was observed in 20% of the patients. In all cases, the actual image was judged more esthetic than the predicted image, allaying fears of unrealistically optimistic computer generated predictions. PMID- 7847278 TI - An introduction to the Internet. PMID- 7847279 TI - Continuing education program in orthodontics for international graduates. PMID- 7847280 TI - Three-dimensional analysis for skeletal problems. PMID- 7847281 TI - How common is acute upper gastrointestinal bleeding? PMID- 7847282 TI - Esophageal alkaline reflux: does the bell toll? PMID- 7847283 TI - Terminology of chronic hepatitis. International Working Party. PMID- 7847284 TI - The intestinal response to critical illness. AB - Critical illness is characterized by the presence of several factors that can cause marked alterations in the structure and function of multiple organ systems (1-2). These factors include injury, ischemia, sepsis, and starvation (Fig. 1). It is common for more than one of these problems to be present in the individual patient. Our current understanding of the effect of these various factors on intestinal structure and function has increased markedly during the past decade (3). Furthermore, the patterns of intestinal dysfunction that occur in response to these conditions have also been better characterized. Although malabsorption and motility disorders have long been recognized as clinical problems, more recently loss of intestinal barrier function and immune dysfunction have gained attention. This improved understanding of the response of the intestine to critical illness may lead to prevention of intestinal failure or permit more specific therapy when it occurs. The goals of this manuscript are to describe the response of the small intestine to critical illness and to identify potential therapeutic strategies for preventing and treating intestinal failure in this setting. PMID- 7847285 TI - Is hepatitis A more severe in patients with chronic hepatitis B and other chronic liver diseases? AB - There are several published case series of acute hepatitis A, with coverage ranging from epidemics to case reports, that provide information regarding the clinical course and outcome of hepatitis A in patients with underlying chronic hepatitis B virus (HBV) infection (1-12). Only a few reports have addressed the outcome of hepatitis A in patients with other chronic liver diseases (2, 13). Some, but not all, of these reports suggest that hepatitis A superimposed on chronic hepatitis B or other chronic liver diseases is associated with higher peak laboratory abnormalities, more severe disease, including fulminant hepatic failure, and a higher case fatality rate. In addition, analysis of HBsAg titer and serum markers of HBV replication, including HBeAg, HBV DNA, and DNA polymerase, reveals suppression of HBV replication. With the availability of hepatitis A virus (HAV) vaccine in many countries and its imminent approval for use in the United States, the issue of whether or not patients with chronic liver diseases, including chronic HBV infection, should be a target group for vaccination to prevent hepatitis A warrants consideration. The purpose of this review is to analyze the published literature addressing the clinical course and outcome of acute hepatitis A in patients with chronic HBV infection and other chronic liver diseases to determine if hepatitis A is more severe in these patients. PMID- 7847286 TI - Epidemiology of hospitalization for acute upper gastrointestinal hemorrhage: a population-based study. AB - OBJECTIVES: To obtain epidemiological data on hospitalization for acute upper gastrointestinal hemorrhage (AUGIH) in a demographically defined population. METHODS: Adults hospitalized in 1991 with AUGIH [from a San Diego health maintenance organization (270,699 adult members)] were identified from discharge codes in the International Classification of Diseases, 9th Revision, Clinical Modifications, and their records were reviewed. RESULTS: There were 276 hospitalizations among 258 patients, an annual incidence rate of 102.0 hospitalizations per 100,000. Patient analysis, including the first admission of 15 patients with multiple hospitalizations, revealed rates of 128.3 in males and 65.8 in females. The rate increased with age in males (p = 0.008) and females (p = 0.001) more than 30-fold between the 3rd and 9th decades of life. AUGIH started before admission in 242 (93.8%) patients and after admission for other disorders in 16 (6.2%) patients. Endoscopy was performed in 241 (93.4%) patients. Diagnoses were: peptic ulcer, 159 (61.6%); mucosal erosive disease, 37 (14.3%); varices, 16 (6.2%); miscellaneous, 25 (9.7%); and unknown, 21 (8.1%). Peptic ulcer patients were similar to other patients (mean +/- SE) in age [60.6 +/- 1.2 vs. 60.7 +/- 1.5 yr] and gender [104 (65.4%) vs. 60 (60.6%) males], but were more often nonsteroidal anti-inflammatory drug (NSAID)-users [87 (54.7%) vs. 34 (34.3%) (p = 0.002)]. Older age, female gender, and NSAID use independently predicted gastric ulcer (p < or = 0.03). The severity of bleeding was similar in patients with peptic ulcers and in those with mucosal erosive disease and was not related to NSAID use in peptic ulcer patients. Patients whose AUGIH started after admission were older than those whose AUGIH began before admission [70.4 +/- 2.9 vs. 60.0 +/- 1.0 yr (p = 0.002)], and they had a higher mortality rate [4 (25%) vs. 9 (3.7%) (p = 0.005)]. CONCLUSIONS: 1) The annual incidence of hospitalization for AUGIH was 102.0 per 100,000, increased markedly with age, and was twice as high in males as in females. 2) Peptic ulcer was the most common cause. 3) Gastric ulcer was associated with older age, female gender, and NSAID use. 4) Mortality rates were high when AUGIH started after hospitalization for another disorder. PMID- 7847287 TI - Characteristics of distal partial gastrectomy patients with esophageal symptoms of duodenogastric reflux. AB - OBJECTIVES: Partial gastrectomy patients with anatomic alterations to the pylorus and acid secretion are excellent models for studying the controversial role of duodenogastric reflux in producing esophageal symptoms and esophagitis. METHODS: We studied 13 partial gastrectomy patients who had recent upper gastrointestinal endoscopies and chronic duodenogastric reflux symptoms. Simultaneously, acid and duodenogastric reflux were assessed by ambulatory 24-h esophageal pH and bilirubin monitoring. Abnormal values for both acid and bilirubin reflux were defined by previous studies of healthy volunteers from our laboratory. Symptoms were recorded and correlated with acid and duodenogastric reflux episodes. RESULTS: Mean percent time bilirubin reflux for the entire group was 26.8 +/- 7.2% (range 0.4-91.2%), whereas mean percent total acid reflux was 4.6 +/- 2.4% (range 0.0-26.1%). Ten (77%) patients had abnormal duodenogastric reflux, but three patients (23%) also had associated abnormal acid reflux. Only these three patients had esophagitis, two ulcerative and one Barrett's esophagus. A total of 75 symptoms (36 heartburn, 33 epigastric pains, three regurgitation, two nausea/vomiting, one abdominal distension) were reported; 65% were acid related. Of patients with heartburn and regurgitation, 97% were associated with acid reflux episodes. CONCLUSIONS: Although excessive amounts of duodenogastric reflux are common in partial gastrectomy patients, esophagitis and Barrett's esophagus are seen only in patients with concomitant acid reflux, and most esophageal symptoms are acid related. Therefore, acid rather than duodenogastric reflux is the main culprit in this syndrome and should be aggressively treated. PMID- 7847288 TI - Crohn's disease and colorectal carcinoma: rectal cancer complicating longstanding active perianal disease. AB - OBJECTIVES: Reports of Crohn's disease (CD)-associated colorectal carcinoma are being cited in the medical literature with increasing frequency. Our aim was to identify subgroups of patients with risk factors that may account for this. METHODS: We reviewed the medical records of 16 patients with the simultaneous diagnosis of CD and colorectal carcinoma and, in addition, reviewed previously reported cases of CD-associated colorectal carcinoma. RESULTS: Eight male and eight female patients presented with 18 carcinomas: four right colon, four transverse, two descending colon, and eight rectal lesions. Median age at presentation was 48 yr. The mean duration of CD before presentation of carcinoma was 19.7 yr. Two lesions were discovered in strictured bowel segments. Two patients had multiple cancers. One had simultaneous cecal and left colon adenocarcinomas. The other underwent resection of a right colon lesion and 5 yr later presented with transverse colon carcinoma. Eight patients had rectal cancer; all were diagnosed preoperatively. Six of these patients had a history of severe perianal CD. Six had undergone multiple incision and drainage procedures for perirectal abscesses and fistulas. Two developed malignancies in defunctionalized rectal stumps. One of these patients presented with simultaneous squamous rectal carcinoma and papillary bile duct cholangiocarcinoma. CONCLUSIONS: Gastrointestinal malignancy in association with CD has been reported. Symptoms of chronic inflammatory disease may obscure clinical manifestations of occult malignancy and thereby delay diagnosis. Crohn's patients with long-standing anorectal or perianal disease and stricture may well warrant surveillance endoscopy and biopsy of involved areas with the hope of earlier detection and treatment of these rectal cancers. PMID- 7847289 TI - Paradoxical response to heparin in 10 patients with ulcerative colitis. AB - OBJECTIVES: A patient with ulcerative colitis refractory to standard therapy was treated with heparin for a deep vein thrombosis. Paradoxically, rectal bleeding did not increase; instead, his colitis rapidly went into remission. The same effect occurred when this patient was later treated for a pulmonary embolism. On the basis of these observations and reports of a hypercoagulable state in ulcerative colitis, heparin was tested as a therapeutic agent in nine additional patients. METHODS: Nine of the 10 patients had ulcerative colitis poorly controlled on sulfasalazine and prednisolone. Two had associated thromboembolic disease, and one was on no medication. Patients were started on heparin in hospital, taught to self-inject subcutaneously, and discharged to continue on 10,000 U of unfractionated heparin twice daily. Current doses of sulfasalazine were maintained; prednisolone was tapered and stopped. Patients were carefully monitored for adverse side-effects. Sections of colonic mucosa from nine patients were examined for intravascular thrombosis of the mucosal blood vessels. RESULTS: Nine patients became asymptomatic (normal stool frequency, no rectal bleeding) on combined heparin and sulfasalazine therapy; one patient had a partial improvement in symptoms. Highly significant statistical differences between pre- and posttreatment mean scores were found for all disease parameters. Intravascular fibrin thrombi were identified in sections from six of nine patients. No serious complications were associated with this use of heparin. CONCLUSIONS: The heparin linked remission of ulcerative colitis, observed by chance in our first patient, was followed by similar responses in eight of nine further patients. This suggests that, used as described, heparin may have a role in treating refractory ulcerative colitis. PMID- 7847290 TI - [13C]urea breath test to confirm eradication of Helicobacter pylori. AB - OBJECTIVE: To determine the utility of the [13C]urea breath test in confirming the eradication of Helicobacter pylori. METHODS: We reviewed our H. pylori database for patients who underwent [13C]urea breath test at baseline and 6 wk after triple therapy with tetracycline, metronidazole, and bismuth subsalicylate. Baseline infection was defined by the identification of the organism on antral biopsies or a reactive CLO test. Eradication was defined as a negative Warthin Starry stain and a non-reactive CLO test at 24 h. All patients had a positive baseline [13C]urea breath test defined as [13C] enrichment > 6% at 60 min. RESULTS: One hundred eighteen H. pylori-infected patients (mean age 58.3 +/- 13.9 yr) met the review criteria (61 duodenal ulcers, 24 gastric ulcers, 33 non-ulcer dyspepsia). In 101/118 patients (86%), H. pylori was successfully eradicated (mean baseline breath test value 25.8 +/- 1.6). Of 101 patients, 95 had a negative 6-wk follow-up breath test (mean 2.2 +/- 0.2, p < 0.001). Of the 6/101 patients in whom treatment was successful, and who remained breath test positive at 6 wk, 4/6 were breath test negative when retested at 3 months. The remaining two patients were lost to follow-up. In 17/118 (14%) patients, H. pylori failed to be eradicated (mean baseline breath test 22.4 +/- 3.6). Fifteen of 17 patients had a positive breath test at 6 wk (mean 19.9 +/- 3.7). Two of 17 with a negative breath test at 6 wk tested positive when the breath test was repeated at 3 months. The sensitivity and specificity of [13C]urea breath test at 6 wk posttreatment are 97% and 71%, respectively. The positive and negative predictive values are 94% and 88%, respectively. CONCLUSIONS: [13C]urea breath test is a sensitive indicator of H. pylori eradication 6 wk after treatment. Antral biopsies are unnecessary to confirm eradication of H. pylori after completion of treatment. PMID- 7847291 TI - Conventional cleaning and disinfection techniques eliminate the risk of endoscopic transmission of Helicobacter pylori. AB - OBJECTIVE: To determine whether endoscopes serve as a reservoir for Helicobacter pylori and whether two commonly used cleaning and disinfection methods eliminate the risk of H. pylori transmission. METHODS: A prospective study was carried out in 107 patients who were undergoing upper gastrointestinal endoscopy for routine clinical indications. H. pylori DNA was assayed by polymerase chain reaction (PCR) of endoscope washes before and after procedure, in gastric aspirates and in endoscope washes after cleaning and disinfection of endoscopes. Gastric biopsies were assayed by rapid urease test (CLOtest, Tri-Med Specialties Inc., Lenexa, KS) of two antral biopsies. RESULTS: Forty-one of 107 (38%) patients were H. pylori positive by PCR. Endoscopes were contaminated after 25 of 41 (61%) H. pylori positive procedures. However, 107 of 107 pre-endoscopy and postcleaning aspirates were negative, indicating that decontamination was 100% effective. The urease test was positive in 25 of 41 H. pylori-positive patients, a sensitivity of 61%. PCR was positive in 41 of 41 H. pylori-positive patients, a sensitivity of 100%. In 5 of 16 PCR-positive/urease-negative patients, the identification of H. pylori was clinically relevant. CONCLUSION: Endoscopes are frequently contaminated with H. pylori after endoscopy in H. pylori-infected patients, but conventional cleaning and disinfection techniques are highly effective in eliminating H. pylori. When appropriate negative control samples are obtained from the endoscope, PCR of endoscopic gastric aspirates appears to be a sensitive test that can detect clinically relevant H. pylori infection that is missed when only a rapid urease test is used. PMID- 7847292 TI - Endoscopic sphincterotomy and biliary drainage in patients with cholangitis due to common bile duct stones. AB - OBJECTIVES: In a prospective study, we analyzed 95 consecutive patients undergoing endoscopic papillotomy (EP) for cholangitis due to common bile duct (CBD) stones; our purpose was to evaluate the risk factors influencing the complication rate due to cholangitis, with special attention to the clinical history. METHODS: Patients with previous gastric surgery or EP were excluded. Complications subsequent to sphincterotomy were recorded over a 3-month period. RESULTS: In patients with persistent cholangitis before EP, the risk for complications due to cholangitis increased with increasing delay between the onset of cholangitis and biliary drainage. In patients with a good response to antibiotics before EP, the delay in biliary drainage did not influence the risk of complications. After complete CBD stone removal, the morbidity (42% vs. 4%, p = 0.001) and the mortality (8% vs. 0%, NS) due to cholangitis were much higher in 12 patients with progressive cholangitis for > 3 days before biliary drainage, compared with 73 cases who had experienced a good response to antibiotics before EP and/or early drainage (< 3 days) after the onset of cholangitis. Two patients with advanced cholangitis and septic shock at the time of EP died < 12 h after completed sphincterotomy with CBD stone removal. Three patients with retained CBD stones and failed biliary drainage after EP experienced disastrous morbidity (100% vs. 9%, p < 0.01) and mortality (67% vs. 1%, p < 0.01) due to cholangitis, compared with 85 patients without retained CBD stone(s). CONCLUSIONS: We recommend emergency biliary drainage in all patients presenting with calculous cholangitis who are severely ill with continuous fever for several days. Emergency nasobiliary drainage without EP or after a limited EP may be a safer treatment in patients with (impending) septic shock. We believe that a more conservative approach is justified in patients presenting with symptoms of mild cholangitis, restricting emergency biliary drainage for those who do not respond rapidly (< 24 h) to antibiotics. Further emergency surgical or percutaneous biliary drainage should be performed immediately on patients in whom CBD stones are retained, after EP and drainage fails, especially if a stone is left impacted distally. PMID- 7847293 TI - Preoperative staging of extrahepatic bile duct cancer with intraductal ultrasonography. AB - OBJECTIVE: To evaluate the tumor extension of extrahepatic bile duct cancer by means of intraductal ultrasonography (IDUS). METHODS: IDUS preoperatively assessed the tumor extensions in 25 patients with extrahepatic bile duct cancer. The diagnostic accuracy of IDUS was investigated by comparison with other diagnostic imaging modalities in all cases and with histopathological findings of resected specimens in 18 cases. RESULTS: IDUS proved useful in assessing the extension of cancer invasion to the pancreas parenchyma, portal vein, and right hepatic artery. The limitation of the degree of accuracy, based on the group staging criteria, was 68%. IDUS could not assess tumor invasion to the perimuscular loose connective tissue. Therefore, it could not distinguish stage II from stage I. IDUS could not sufficiently assess epicholedochal lymph node metastases (differential diagnosis between stages II and III) and could not demonstrate distant metastases (differential diagnosis between stages IVA and IVB) because of the inevitable attenuation of the echo itself. IDUS could assess cases of stage IVA correctly in 8/8 (100%) cases. The combination of PTC/ERC and IDUS could assess the horizontal extension correctly in 13/18 (72%) cases. The combination of PTC/ERC, percutaneous transhepatic cholangioscopy (PTCS), and IDUS assessed the horizontal extension in 14/15 (93%) cases. CONCLUSION: 1) IDUS, with a high-frequency probe, was very useful for assessing tumor infiltration in the hepatoduodenal ligament. 2) IDUS could not assess tumor extension outside of the hepatoduodenal ligament, but conventional ultrasonography and angiography could compensate for it. 3) The combination of PTC/ERC, PTCS, and IDUS could assess horizontal extension correctly. PMID- 7847294 TI - Antimitochondrial antibody-negative primary biliary cirrhosis. AB - OBJECTIVES: We reviewed our experience with patients who had biochemical and histological features of primary biliary cirrhosis in the absence of antimitochondrial antibodies (AMA) to better understand this variant of the syndrome. METHODS: During the period between 1976 to 1992, 597 patients with clinical and histological features of primary biliary cirrhosis were seen at the Mayo Clinic. Thirty-five (5.8%) of these patients were negative for antimitochondrial antibody and had normal cholangiographic studies. The records of these patients were reviewed for this study. RESULTS: No difference was found between the two groups with respect to age, gender, or biochemical features. IgM and gamma-globulin levels were higher in the antimitochondrial antibody-positive than the antimitochondrial antibody-negative patients. What is more important, 96% of the AMA-negative patients who could be tested were positive for antinuclear antibody or anti-smooth-muscle antibodies. These tests were positive in only 56% of the antimitochondrial antibody-positive group (p < 0.05). The response of five of these patients to ursodeoxycholic acid appeared comparable to the response seen in antimitochondrial antibody-positive patients. CONCLUSIONS: Patients with histological features of primary biliary cirrhosis, whether antimitochondrial antibody positive or negative, are quite comparable with respect to clinical and biochemical features. Other autoantibodies, such as antinuclear or anti-smooth-muscle antibodies, are more common in the antimitochondrial antibody-negative group. These two conditions might be part of a spectrum that has been termed "autoimmune cholangitis" and that is characterized by chronic cholestasis, histological features of chronic nonsuppurative destructive cholangitis, and the presence of any of a variety of serum autoantibodies. PMID- 7847295 TI - Cognitive assessment in primary biliary cirrhosis: a case-control study. AB - OBJECTIVES: Primary biliary cirrhosis (PBC) patients frequently complain of fatigue and loss of memory. The aim of this study was to evaluate the mental performance and the neuropsychological assessment in patients with PBC. METHODS: A case-control study was performed that included 36 PBC patients (34 female, two male, mean age 55 yrs, 11 with stage II, 16 with stage III, and nine with stage IV disease) and 36 sex and age-matched controls with rheumatoid arthritis. A preliminary routine neurological examination failed to show any abnormality in each patient, including signs of encephalopathy. A battery of neuropsychological tests was administered to each subject, including: the Global Deterioration Scale; the Mini Mental State Examination; Buschke test; Gatterer's test; the Wechsler Memory Scale; the Blessed-Roth memory test; and the Clifton Assessment Schedule. RESULTS: The overall score for each test was not statistically different in PBC patients compared with rheumatoid arthritis patients, except for the Global Deterioration Scale and the Clifton Assessment Schedule; the performance was significantly poorer for these measures in PBC patients compared with rheumatoid arthritis patients. In both groups no correlation was found between the score of each test and age and/or duration of the disease. However, in the PBC group the score of BR was negatively correlated with the histological stage (p < 0.0025). CONCLUSION: The global mental status is not altered in PBC, but early changes in orientation and in personal memory are present in cirrhotic stage. PMID- 7847296 TI - Circadian acidity pattern in gastric ulcers at different sites. AB - OBJECTIVE: Continuous intragastric pH monitoring was used in a large group of gastric ulcer patients to assess whether the 24-h acidity pattern varies in relation to the ulcer location within the stomach and to assess whether there is a circadian rhythm of pH fluctuations in this disease. METHODS: One hundred and thirty-three consecutive patients (79 male and 54 female, mean age 53 yr) with endoscopically and histologically proven benign gastric ulcer and 131 healthy subjects (70 male and 61 female, mean age 48 yr) were studied with a pH minielectrode positioned in the gastric corpus. Ulcer patients were divided into four subgroups in relation to the crater site: 1) above the angulus (n = 23); 2) angularis (n = 42); 3) antral (n = 26); and 4) prepyloric (n = 42). RESULTS: Subgroups 1 and 2 are characterized by significantly lower acidity (p < 0.0001) than healthy subjects for every time segment examined (24-h, day and night). Antral ulcers are less acidic than normal for both the total 24-h period (p < 0.01) and the night period (p < 0.0001), whereas prepyloric ulcers are less acidic for the night only (p < 0.01). In all subgroups of gastric ulcer, the acidity is higher during the evening than the night. CONCLUSIONS: The circadian acidity of gastric ulcer patients is significantly lower than normal, and this is particularly true during the nocturnal period. There is a gradient of gastric acidity that increases progressively as the lesion approximates to the pylorus. The well known circadian rhythm of gastric acidity with relatively higher acid levels during the evening than the night was maintained in all of the gastric ulcer subgroups we created. PMID- 7847297 TI - High dose interferon alpha-2b therapy for chronic hepatitis C: an open label study of the response and predictors of response. AB - OBJECTIVES: The current recommended dose of interferon (IFN) for chronic hepatitis C is 3 million units (m.u.) 3 times a wk for 6 months, although the optimal dose is uncertain. In an open label cohort format, we evaluated the response rate at 6 months, the relapse rate at 12 months, the predictors of response, and adverse effects in 34 patients (mean age 42.4 +/- 2.4 yr) with chronic hepatitis C who were treated with 5 m.u. IFN 3 times a wk for 6 months. RESULTS: Twenty-nine patients (85%) responded either totally (TR) or partially (PR), and five (15%) showed no response (NR). Of 18 TR, eight (45%) showed a sustained response (SR), and nine (50%) patients relapsed at 12 months of follow up with an overall SR rate of 24%. Despite the high frequency of side effects (17 70%), all patients completed the treatment. Of interest, two of three PR treated for an additional 3-6 months with 7.5 m.u. of IFN became TR at 12 months. Univariate and multivariate analysis demonstrated that the known duration of hepatitis and/or abnormal ALT elevation was longer in responders (43.5 +/- 9.1 months) compared with NR (8.2 +/- 1.4 months) (p = 0.018). Age, alcohol abuse, mode of acquisition, transaminase levels, and liver histology did not differ significantly between responders and NR. HCV-RNA in serum by RT-PCR assay was performed in six TR and four PR pretreatment, immediately posttreatment, and 3-6 months later. Five TR showed disappearance of viral RNA posttreatment with reappearance at low concentrations in two patients who relapsed. In four PR, viral RNA was detectable at low concentrations posttreatment. CONCLUSIONS: 1) Higher dose IFN therapy yields higher response rates at 6 months than the dose currently recommended with acceptable toxicity, but does not improve the sustained response rate; 2) the only predictor of a favorable response in this study was a longer known duration of hepatitis/abnormal ALT elevations; 3) serum HCV-RNA levels often disappear with a total response and may be used to monitor the response to treatment and relapse. PMID- 7847298 TI - Recombinant interferon-alpha and ursodeoxycholic acid versus interferon-alpha alone in the treatment of chronic hepatitis C: a randomized clinical trial with long-term follow-up. AB - OBJECTIVES: The purpose of this study was to compare, within a randomized controlled trial, the efficacy of recombinant interferon-alpha in combination with ursodeoxycholic acid versus interferon-alpha alone in the treatment of chronic HCV hepatitis. METHODS: Forty anti-HCV positive chronic hepatitis patients with ALT levels persistently greater than 3 times the upper normal level were randomized to receive either interferon-alpha (6 million units three times/wk for 6 months) plus ursodeoxycholic acid (10 mg/kg/day for 9 months) (n = 20) or interferon-alpha (6 million units three times/wk for 6 months) alone (n = 20). Disease activity was monitored monthly by ALT measurement until 18 months after interferon-alpha cessation. Serum HCV-RNA was measured at baseline and after 6, 9, and 24 months. Liver biopsies (basal and at the 9th month) were evaluated blindly and scored by Knodell's criteria. RESULTS: The probability of full or partial response during interferon-alpha treatment was similar in the two groups. The probability of biochemical relapse (i.e, any persistent return of ALT above normal) after 18-month of posttreatment follow-up was 75% in both the combination and the monotherapy group. Relapse, however, occurred significantly later in the combination than in the monotherapy group (6.6 +/- 5.4 [SD] months and 1.8 +/- 1.6 months after IFN-alpha cessation, respectively, p < 0.02). Severe biochemical relapse (i.e., a persistent ALT elevation greater than 3 times normal) occurred more frequently and earlier (p = 0.05) in patients treated with interferon-alpha (58.3%) than in those receiving the combination therapy (27.3%). The cumulative duration of normalized ALT periods during and after treatment was significantly greater (p = 0.005, chi 2) in patients treated with IFN-alpha + UDCA than with monotherapy (189/354 months vs 136/323 months. Lobular necrosis improved in both groups (p = 0.056 and p = 0.001, respectively), whereas portal inflammation improved (p = 0.009) only in the combination therapy group. Among the 30 patients who were viremic at entry, plasma HCV-RNA was no longer detectable after 6 months in four from the combination group and in five from the monotherapy group, yet all patients but one returned HCV-RNA positive 3 months after interferon-alpha cessation and were still viremic after 18 months. Cox's multiple regression identified the histological degree of posttreatment portal inflammation as the sole positive indicator of relapse. CONCLUSIONS: The combination of interferon-alpha and ursodeoxycholic acid prolongs the efficacy of interferon-alpha alone in chronic hepatitic C by delaying the probability of biochemical relapse and/or by reducing its severity, without affecting HCV viremia. PMID- 7847299 TI - Circadian variations in gastric acid and pepsin secretion and intragastric bile acid in patients with reflux esophagitis and in healthy controls. AB - OBJECTIVES: Duodenogastric reflux is a physiological phenomenon in both fasting and postprandial state. Because this suggests that bile acids may reflux into the esophagus together with the acid in patients with reflux esophagitis, we investigated the circadian variations of acid and pepsin secretion and intragastric bile acid concentrations in 25 patients with reflux esophagitis and in 15 healthy controls. METHODS: Between-meal, nocturnal gastric and meal stimulated acid and pepsin secretion and bile acid concentrations were measured by continuous gastric aspiration and intragastric titration. RESULTS: Bile acids were found in 85 and 59% of gastric samples (p < 0.05). Intragastric bile acid concentrations were 6-8-fold higher in esophagitis patients than controls during the day. Approximately 10% of gastric samples from reflux esophagitis patients had a pH greater than 7, and all contained more than 500 mumol/L bile acids. Bile acids and pepsin were simultaneously revealed in 98% of the gastric samples from patients with reflux esophagitis with pH less than 4. Mean daily acid output (meal excluded) averaged 3.5 +/- 0.1 in healthy subjects and 2.7 +/- 0.2 mmol/30 minutes in esophagitis patients (p < 0.05); meal-induced acid secretions were similar. Total (24-h) acid secretion averaged 192.3 +/- 12.4 and 162.4 +/- 10.5 mmol/24 h (p < 0.05). There were no differences in the daily pepsin output. CONCLUSIONS: Our data indicate that almost all "acid" gastroesophageal refluxes should be considered as "mixed" refluxes. Because bile acids are found in the stomach irrespective of whether the environment was acid or alkaline, pH-metry provides no useful information on the pattern of duodenogastric reflux into the esophagus. Variability in the composition of the gastro-esophageal refluxate may explain why the severity of esophageal lesions differs in patients with similar pattern of acid refluxes. PMID- 7847300 TI - Randomized comparison of gastric pH control with intermittent and continuous intravenous infusion of famotidine in ICU patients. AB - OBJECTIVE: To compare gastric pH control using intravenous famotidine as a primed, continuous infusion versus intermittent infusion. METHODS: In a prospective, double-blind study, 40 ICU patients at risk for stress ulceration were randomly assigned to receive either famotidine 20 mg intravenous bolus followed by 1.67 mg/h infusion or famotidine 20 mg intravenously every 12 h. Intraluminal gastric pH was recorded at baseline and every 4 h using a glass electrode. Clinical outcome indicators were also monitored. Subjects were studied for a minimum of 24 h and a maximum of 6 days. Continuous variables were analyzed by ANOVA and nominal variables by Fisher's exact test (alpha = 0.05). RESULTS: Nineteen patients were randomized to the continuous infusion group, and 21 were randomized to the intermittent group. Using gastric pH greater than 4.0 as an endpoint, the continuous group exhibited better pH control, both in terms of percentage of total measurements (83% versus 63%, p < 0.001) and time spent above pH 4.0 (91% versus 76%, p < 0.01). Similar results were found at pH greater than 5.0 (78% versus 56% for all measurements for the continuous and bolus groups, respectively (p < 0.001), and 88% versus 72% for the time spent above pH 5.0 (p < 0.01). Clinical outcomes, including evidence for gastrointestinal bleeding and hospital mortality, did not differ significantly between groups. CONCLUSION: Famotidine infusion at 1.67 mg/h, when preceded by a bolus dose of 20 mg, provides a greater and more sustained increase in gastric pH than intermittent administration of famotidine 20 mg every 12 h. PMID- 7847301 TI - Hypertensive lower esophageal sphincter pressures and gastroesophageal reflux: an apparent paradox that is not unusual. AB - The association of a hypertensive lower esophageal sphincter pressure (LESP) with significant gastroesophageal reflux (GER) has always seemed paradoxical because of the original association of a hypotensive sphincter with reflux. OBJECTIVES AND METHODS: In this study, the manometric and ambulatory pH studies of a group of consecutive patients evaluated over a 3-yr period were reviewed to identify and characterize patients with a hypertensive LESP and abnormal GER as defined by increased acid exposure in the distal esophagus as measured on ambulatory pH monitoring. RESULTS: Eighteen such patients were identified, which represented 5.2% of all patients with abnormal GER and 23.4% of all patients with a hypertensive LESP. Heartburn (nine patients) and chest pain (nine patients) represented the dominant symptoms. LESP ranged from 47 to 73 mm Hg. Incomplete LES relaxation in response to swallow was found in nine out of 18 patients. Intact peristalsis was found in all patients, and seven patients had a nutcracker esophagus. Patients showed a wide range of abnormal distal esophageal acid exposure times with only slightly abnormal recumbent or upright reflux times to greater than 25% pH less than 4 total (although most patients had mild reflux with 17 out of 18 patients having total distal esophageal acid exposure less than 10%). There was no correlation between LESP and total % pH less than 4 (r = 0.11). Of 16 patients, 12 responded to antireflux treatment, including the three patients who required fundoplication. The four patients who did not respond to treatment had poor correlation of reflux episodes to symptoms on pH monitoring, had markedly elevated LESPs, and did not present with heartburn. CONCLUSIONS: The association of a hypertensive LESP and abnormal GER is not uncommon. When abnormal GER does occur in these patients, it tends to be mild but can be clinically important and respond to antireflux treatments. We recommend that patients with a hypertensive LESP and/or nutcracker esophagus who present with heartburn or chest pain should undergo ambulatory pH monitoring to evaluate the possibility of GER disease. PMID- 7847302 TI - The effect of cisapride on segmental colonic transit time in patients with spinal cord injury. AB - OBJECTIVES: The pathophysiological consequences of spinal cord injury (SCI) on function of the colon are complex and poorly understood. Regardless of the mechanism, many patients with SCI have deficient bowel control, which is frustrating and difficult to treat. We designed a study to assess whether a new prokinetic medication, cisapride, might be useful in this setting. METHODS: Total and segmental colonic transit time were measured using the radiopaque marker technique in nine subjects with spinal cord injury and seven control subjects after the double-blind administration of cisapride (10 mg q.i.d.) or placebo. RESULTS: In five quadriplegic subjects with prolonged colonic transit time, administration of cisapride was found to reduce left-sided colonic transit time from 24.2 to 13.8 h. In three of these five subjects, cisapride administration resulted in subjective improvement. No effect of cisapride on right-sided, rectosigmoid, or total colonic transit time was observed. CONCLUSION: The data suggest that cisapride might be a useful adjunctive measure in treating a subset of SCI patients with colonic inertia, but a larger study is needed before this can be routinely recommended. PMID- 7847303 TI - Brunner's gland hamartomas: clinical presentation and pathological features of 27 cases. AB - OBJECTIVES: The aim of this study was to characterize the clinical presentation, pathological features, and outcome of a series of patients with Brunner's gland hamartomas. METHODS: We reviewed the clinical and pathological features of 27 patients who presented with Brunner's gland hamartomas, and we obtained follow-up information. RESULTS: Patients (12 men and 15 women) presented predominantly in the fifth and sixth decades of life either with gastrointestinal hemorrhage (n = 10) or obstructive symptoms (n = 10); there were also patients whose tumors were discovered as an incidental finding (n = 7). The tumors were generally pedunculated, were located in the first portion of the duodenum, and were in the range of diameter from 1 to 6 cm. Histologically, the hamartomas were characterized by the presence of nondysplastic, lobulated Brunner's glands with intervening bands of fibrous tissue and variable adipose and lymphoid tissue. Focal sclerosis was found in 93% of the hamartomas, possibly mimicking an adenocarcinoma. Whether managed surgically (24 patients) or endoscopically (three patients), the outcome was uniformly favorable. After a median period of 7-yr follow-up, no tumors recurred, and no additional morbidity was identified. CONCLUSIONS: Brunner's gland hamartomas are rare duodenal tumors occurring in middle age that present either with gastrointestinal hemorrhage, obstructive symptoms, or as an incidental finding. Surgical or endoscopic excision is uncomplicated, and the long-term outcome is favorable. PMID- 7847304 TI - Nephrotic syndrome and acute renal failure associated with hepatitis A virus infection. AB - Acute renal failure has been documented in association with hepatitis A virus (HAV) infection. This report describes a temporal relationship between HAV infection and immune complex mesangial proliferative glomerulonephritis associated with nephrotic syndrome. Animal experimental data have already shown that this is indeed a histological lesion associated with HAV infection. This case report is the first English documentation associating HAV infection with immune complex mesangial proliferative glomerulonephritis. PMID- 7847305 TI - Small bowel obstruction in pregnancy. AB - OBJECTIVES: Small bowel obstruction (SBO) is an unusual complication of pregnancy. Our objective was to review our experience at two urban hospitals. METHODS: To this end, we conducted a retrospective chart review of all pregnant patients with a discharge diagnosis of intestinal obstruction at Grace Hospital, Detroit, MI (January 1, 1972 to January 1, 1992) and Hutzel Hospital, Detroit, MI (January 1, 1977 to January 1, 1992). RESULTS: During the study period, nine cases of SBO were identified and 150,386 deliveries occurred (one case per 16,709 deliveries). Patients' ages ranged from 16 to 37 yr. There were six primiparas. Cases of SBO by trimester: four in second, four in third, and one in puerperium. Previous abdominal surgery was documented in eight patients. Duration of symptoms before admission ranged from 3 h to 3 days. Primary symptoms were abdominal pain (89%), vomiting (89%), and obstipation (80%). At admission, only one patient was febrile, and four had hypoactive bowel sounds. Abdominal x-rays were compatible with SBO in seven patients. Ultrasound identified SBO in one of four cases. Patients were hospitalized 6 h to 23 days before surgery. The admission diagnosis was incorrect in four cases. One patient was treated conservatively and, at 36 wk, vaginally delivered a healthy infant. The eight surgical patients had lysis of adhesions, with one requiring resection of gangrenous small bowel. There were three fetal deaths (at 22, 24, and 30 wk of gestation). No maternal deaths occurred. CONCLUSION: SBO is a rare, but often catastrophic, complication during pregnancy and the puerperium. Clinical suspicion is critical and should be increased in a patient with an abdominal scar. If suspected, prompt abdominal x rays, ultrasound, and surgical consultation are warranted. PMID- 7847306 TI - Membranous obstruction of the hepatic portion of the inferior vena cava: is this an underdiagnosed entity in developing countries? AB - Chronic liver disease due to obstructive lesion of the hepatic inferior vena cava (IVC) is common in Nepal. This study presents 10 patients with cavographically documented membranous obstruction of the hepatic IVC with minimal symptoms and a benign course. One patient with an incomplete membrane had balloon dilation of the lesion. The duration of the disease among these patients varied from 5 months to 23 yr; eight patients have been followed for periods varying from 1 to 15 yr, with an average of 6 yr. In developing countries, the possibility of hepatic IVC obstruction should be considered in the differential diagnosis of hepatomegaly or hepatosplenomegaly, even in the absence of ascites and external cava-caval collateral. Routine liver and hematology tests in these patients usually are normal, and liver biopsy findings may not always be specific. Ultrasound, however, has proved to be the best diagnostic procedure for the condition. The lesion can be demonstrated easily by cavography. The disease runs a chronic course, and, in the absence of resistant ascites or repeated variceal bleeding, surgical procedures such as cavoatrial bypass, which are a significant cause of death in developing countries, may be contra-indicated. PMID- 7847307 TI - Acute gastritis associated with infection of large spiral-shaped bacteria. AB - We report a case of gastric colonization of large spiral-shaped bacteria in a patient with acute gastritis. Endoscopy showed an acute erosive and hemorrhagic gastroduodenitis. Histopathological examination of antral biopsies revealed intense neutrophil infiltrates with microabscesses. Numerous large spiral-shaped bacteria were seen in the Gram-stained smear of the gastric biopsy. The patient was treated with colloidal bismuth subcitrate and cimetidine. Biopsy taken after treatment showed resolution of infection and histological gastritis. The results provide further evidence that large spiral-shaped bacteria are another infective cause of acute neutrophilic gastritis in humans. PMID- 7847308 TI - Therapy for spontaneous umbilical hernia rupture. PMID- 7847309 TI - Transient protein S deficiency associated with cerebral venous thrombosis in active ulcerative colitis. AB - Cerebral venous thrombosis is an uncommon complication of ulcerative colitis. We report the case of a 29-yr-old female with a recent diagnosis of ulcerative colitis who suffered stroke secondary to thrombosis of the veins of Galen and straight sinus. A search for a hypercoagulable state revealed a nonfamilial transient protein S deficiency. Possible involvement of C4b-binding protein in this hypercoagulable state is discussed. PMID- 7847310 TI - Hemoperitoneum due to spontaneous rupture of the umbilical vein. AB - Portal hypertension often leads to collateralization of blood flow via variceal vessels that shunt blood from the portal to the systemic circulation. Rupture of an intra-abdominal varix is an unusual complication of portal hypertension that can lead to life-threatening hemoperitoneum. We describe a patient with portal hypertension secondary to liver cirrhosis who presented with acute intra abdominal hemorrhage. At laparotomy, she was found to have a rupture of the umbilical vein. The vessel was ligated, and the patient recovered uneventfully. The causes of hemoperitoneum in cirrhosis are discussed, and the previously reported cases of intra-abdominal variceal bleeding are reviewed. PMID- 7847311 TI - Fatal peliosis of the liver and spleen in a patient with agnogenic myeloid metaplasia treated with danazol. PMID- 7847312 TI - Intussusception of the cecum with calcified fecaliths. AB - We treated a patient with a complete invagination of the cecum that contained two large laminated calcified fecaliths. Colonofiberscopy showed a dimpling submucosal tumor that was palpated as a bony hard tumor at laparotomy. This finding suggested that the fecaliths caused intussusception of the cecum and that such an intussusception should be suspected when a bony hard, dimpling submucosal tumor is found in the cecum. To our knowledge, this is the first reported case of a cecal invagination accompanied by calcified fecaliths without an appendical intussusception. PMID- 7847313 TI - CMV gastric ulcer as the presenting manifestation of AIDS. PMID- 7847314 TI - Retinopathy as a systemic complication of acute pancreatitis. AB - We describe three cases of sudden severe retinopathy in patients with acute pancreatitis. The relative times of the organ manifestations and comparisons with other published cases strongly suggest that pancreatitis was the cause of the retinal changes. This systemic complication is unknown to most physicians, but approximately 35 cases have been published. The pathogenesis is not well known. We briefly discuss the significance of this complication and several possible pathogenetic mechanisms. PMID- 7847316 TI - Expandable metallic stents for benign pancreaticbiliary disease: clinical benefit or endoscopist's anxiety? PMID- 7847315 TI - A juvenile polyp presenting as massive lower gastrointestinal hemorrhage in an adult. PMID- 7847317 TI - Is loperamide contraindicated in the treatment of bacillary dysentery? PMID- 7847318 TI - Does localized flare reaction to intravenous meperidine reduce sedation and pain control during conscious sedation for endoscopy? PMID- 7847319 TI - Elevation of hepatocyte growth factor levels in portal and hepatic veins immediately after hepatic resection in cirrhotic patients. PMID- 7847320 TI - Mucopeptic cell expansion in gastric foveolar epitheleum in Helicobacter pylori positive, body-fundic chronic superficial gastritis. PMID- 7847321 TI - Pancreas divisum provides a unique opportunity for study. PMID- 7847322 TI - Characterization of autoantibodies against the platelet glycoprotein antigens IIb/IIIa in childhood idiopathic thrombocytopenia purpura. AB - The majority of children with idiopathic thrombocytopenia (ITP) have an acute self-limiting course and no diagnostic test has been identified which will predict the course of thrombocytopenia and detect those with the chronic autoimmune form. The detection of autoantibodies directed against the platelet glycoprotein complex IIB/IIIa, may identify patients with chronic ITP. Serum anti GP IIb/IIIa antibodies were assessed by the indirect MAIPA assay in 54 children with immune thrompocytopenia at initial presentation along with an additional 7 children previously diagnosed with chronic ITP, to determine if there was a difference in antibody positivity between acute and chronic ITP patients, and whether the identification of antibodies could be used as a predictive test at diagnosis. There was no significant difference in the percentage of antibodies detected in children classified with acute ITP (27/40-68%) compared to children with chronic ITP (13/21-62%, P > 0.05). Patients with acute ITP had significantly lower mean platelet counts at diagnosis compared to the chronic ITP group (16,225/mm3 vs 32,250/mm3, P < 0.05), though there was no significant difference in the bleeding manifestations between the acute and chronic ITP groups. Serum anti-GP IIb/IIIa antibodies are detected in a high percentage of children with ITP and autoantibodies appear to be involved in the pathogenesis of both acute and chronic ITP. The detection of anti-GP IIb/IIIa antibodies at diagnosis, however, does not appear to be a useful prognostic test in childhood ITP. PMID- 7847323 TI - Leukodepleted-ABO-identical blood components in the treatment of hematologic malignancies: a cost analysis. AB - To assess the effect of ABO-identical, filtration leukodepleted transfusions on resource consumption and costs of care we performed a cohort study in consecutive adult patients admitted for induction therapy of acute myeloid or lymphoid leukemia during 1985-92 (n = 120) and consecutive adult patients admitted for autologous bone marrow transplantation for Hodgkin's or non-Hodgkin's lymphoma during 1989-1991 in our university hospital. Patients with acute leukemia received either ABO unmatched, unfiltered transfusions (1985-89), ABO identical, unfiltered transfusions (1987-90), or ABO identical, filtered transfusions (1990 92). Patients with lymphoma received either ABO unmatched, unfiltered transfusions (1989-90) or ABO identical, filtered transfusions (1990-91). Mean platelet transfusion requirements per patient decreased with ABO identical platelets and filtered transfusions: from 143 to 71 units in the transplant setting; from 146 to 83 in acute leukemia (P < 0.05). Mean hospital ancillary service charges in 1992 dollars decreased with ABO identical platelets and filtered transfusions approximately $14,000 per patient for acute leukemia and $26,000 for for lymphoma. Per patient actual costs for filters ($643 in transplantation for lymphoma and $875 in leukemia) were offset by savings in actual blood component purchase costs alone ($4,127 in lymphoma and $3,283 in leukemia). In our setting, introduction of ABO identical platelets and filtration leukodepletion were implemented with substantial decreases in costs. PMID- 7847324 TI - Adult T-cell leukemia/lymphoma with two distinct clones in the peripheral blood and lymph node. AB - A case of adult T-cell leukemia/lymphoma (ATL) with two different clones in the peripheral blood and lymph nodes is reported here. When cellular DNA from the lymph node was digested with EcoRI, one band larger than 9 Kb was detected. Digestion of the cellular DNA with PstI resulted in one clear band in addition to three internal fragments. In contrast, when cellular DNA from malignant peripheral blood lymphocytes (PBL) was digested with the same endonucleases, distinct bands at positions different from those observed in the lymph node were detected, indicating two separate malignant clones in the patient. Monoclonality of the tumor cells was shown by T-cell receptor-beta (TCR-beta) gene rearrangement in both PBL and lymph node. Furthermore, there was a difference in the surface phenotype between tumor cells taken from peripheral blood (CD4+, CD8 ) and lymph node (CD4+, CD8+). These findings suggest the presence of two different ATL clones in PBL and lymph node in a single patient simultaneously, which is distinguishable by the integration pattern of human T-cell leukemia virus type I (HTLV-I) proviral DNA. PMID- 7847325 TI - Combined factor IX and protein C deficiency in a child: thrombogenic effects of two factor IX concentrates. AB - We have recently described an unusual situation which involved a combination of a factor IX and a protein C deficiency in a young child who presented, according to the bleeding tendency, as a hemophilia B patient. In this particular hemophiliac, baseline prothrombin fragment F1 + 2 levels were unexpectedly elevated and increased after an injection of a very high purity factor IX concentrate. This observation raised a question regarding the substitution schedule in the case of repeated injections of factor IX, since the thrombotic tendency has been a major concern with some factor IX concentrates. We monitored factor IX, prothrombin fragment F1 + 2, and D-dimer plasma levels before and during the 6 hr following the injection of an immunopurified factor IX concentrate. The results showed an increase in the F1 + 2 levels after the factor IX injection, but an increase lower than previously observed with an ion-exchange chromatography-purified concentrate. Furthermore, the F1 + 2 level returned to baseline value 6 hr after administration. This factor IX concentrate seems to be best for use in the patient where repeated injections are involved (as employed during surgery). Moreover, the data point out the advantage of a monoclonal antibody-purified factor IX concentrate over less purified concentrates in a specific situation, with regard to the thrombogenic risk. PMID- 7847326 TI - Pernicious anemia presenting with acute generalized thrombocytopenic purpura. PMID- 7847327 TI - Spurious fibrinogen levels secondary to pyroglobulinemia in Waldenstrom's macroglobulinemia. AB - We report two cases of pyroglobulinemia detected in the course of routine determination of fibrinogen levels measured by the heat-precipitation method and that led to the diagnosis of Waldenstrom's macroglobulinemia. The incidence of pyroglobulinemia is briefly discussed, and the potential significance of this laboratory artifact is emphasized. PMID- 7847328 TI - Spectrum of beta-thalassemia mutations in Calabria: implications for prenatal diagnosis. AB - Using a combination of oligonucleotide probes and restriction endonuclease enzymes, we characterize beta-thalassemic mutations in 91 homozygous patients and 86 unrelated carriers. Overall, 268 beta-thalassemic genes were obtained. Eleven beta-globin mutations were identified, confirming the wide molecular heterogeneity of beta-thalassemia in Calabria. Information from the present study represents the mainstay for the development of a program of early prenatal diagnosis by direct detection of mutations in Calabria. PMID- 7847329 TI - Molecular genetics of "X-linked" sideroblastic anemia. PMID- 7847330 TI - Mitoxantrone and etoposide in breast milk. PMID- 7847331 TI - Profound thrombocytopenia complicating dietary erucic acid therapy for adrenoleukodystrophy. PMID- 7847332 TI - Agranulocytosis induced by macrolide antibiotics. PMID- 7847333 TI - Simultaneous procainamide-induced immune thrombocytopenia and lupus anticoagulant. PMID- 7847334 TI - Hodgkin's disease in CLL. PMID- 7847335 TI - Recombinant human erythropoietin for the treatment of anemia in myelofibrosis with myeloid metaplasia. PMID- 7847336 TI - Myocardial infarction in a patient with acute lymphoblastic leukemia during L asparaginase therapy. PMID- 7847337 TI - Superior mesenteric vein thrombosis associated with anticardiolipin antibody without autoimmune disease. PMID- 7847338 TI - Idiopathic thrombocytopenic purpura. PMID- 7847339 TI - Sudden dyspnea and hypoxemia in patients with acute leukemia prior to granulocyte recovery. PMID- 7847340 TI - Density distribution of erythrocytes is not subject to the ABO blood group antigen component of its membrane. PMID- 7847341 TI - A case of recessive type 2N von Willebrand's disease due to Arg 53 Trp substitution. PMID- 7847342 TI - Crescentic glomerulonephritis during treatment with interferon-alpha 2b. PMID- 7847343 TI - CD7+, CD5+, CD4-, CD8-, and CD3- T-cell malignancy of the spleen after remission of invasive thymoma. PMID- 7847344 TI - Prognostic factors in low tumour mass asymptomatic multiple myeloma: a report on 91 patients. The Groupe d'Etudes et de Recherche sur le Myelome (GERM). AB - Between January 1985 and July 1989 we diagnosed asymptomatic stage I multiple myeloma according to Durie and Salmon [Durie and Salmon: Cancer 36:842, 1975] in 91 patients. All patients were followed without chemotherapy. Disease progression occurred in 41 patients and the median time to progression for all patients was 48 months. In the Cox multivariate regression analysis, hemoglobin levels < 12 g/dl (P < .01), bone marrow plasmacytosis > 25% (P < .01), and M-component size > or = 30 g/l for Ig G or > or = 25 g/l for Ig A (P < .01) were the only significant prognostic factors for progression. The 38 patients without any harmful factor remained free of progression for a median of more than 50 months. The 18 patients with two or three of these characteristics (high-risk group) had the shortest median time to progression of 6 months. Despite different times to progression, the response rate and survival after chemotherapy were similar for all groups of patients. Patients in the high-risk group for progression have to be frequently monitored for disease progression and might benefit from early treatment. PMID- 7847345 TI - Genetic interactions in thalassemia intermedia: analysis of beta-mutations, alpha genotype, gamma-promoters, and beta-LCR hypersensitive sites 2 and 4 in Italian patients. AB - In order to verify the genetic factors influencing the clinical expression of beta-thalassemia we have studied 292 Italian patients, 165 with thalassemia intermedia and 127 with thalassemia major. The beta-globin gene mutations were defined in all cases. The number of alpha-globin genes and the integrity of specific control regions of the beta-globin cluster--gamma promoters and beta Locus Control Region (beta-LCR)--were studied in selected cases. Homozygosity for mild mutations (group I) accounts for 24% of the intermedia patients and it is not represented among major patients. Forty-four percent of intermedia patients had combinations of mild/severe (group II) mutations and 32% had homozygosity or double heterozygosity for severe mutations (group III). Seventy-six percent of patients with thalassemia major were classified in group III and 24% in group II. Deletion type-alpha3.7 thalassemia, assessed in a part of the cases, was found in 5% of thalassemia major and 19.5% of intermedia patients in groups II and III. Structural analysis of gamma promoters and beta-LCR HS2 and HS4 regions, carried out in order to look for alterations associated with Hb F increase, did not reveal new mutations. Only rare polymorphic changes were observed at the HS2 and HS4 level. The -158G gamma C T change was found with an increased incidence in intermedia patients in groups II and III. A subset of 10 beta-thalassemia heterozygotes with mild intermedia phenotype resulted from coinheritance of a triplicated alpha-locus. We have been unable to find a molecular basis for the benign clinical course in approximately 20% of patients with thalassemia intermedia. Other genetic or acquired factors must be hypothesized which ameliorate the clinical condition. PMID- 7847346 TI - Molecular cytogenetic analysis of monosomy 7 in pediatric patients with myelodysplastic syndrome. AB - Monosomy 7 is a non-random cytogenetic abnormality that is frequently associated with myelodysplastic syndromes (MDS). Twenty-four bone marrow samples from five pediatric patients with MDS were analysed using both traditional and interphase cytogenetic analysis. The majority of the metaphases were monosomic for chromosome 7 while interphase cytogenetic analysis consistently detected a disomic cell population in nondividing cell populations. This suggests that the monosomy 7 cells have a distinct proliferative advantage compared to the disomic cell population. The results demonstrate that interphase cytogenetic analysis provides important cytogenetic information about non-dividing cell subpopulations, enhancing our understanding of the cell dynamics of normal and monosomy 7 cells in MDS. PMID- 7847347 TI - The link between hypertension and nephrosclerosis. AB - Nephrosclerosis is literally defined as hardening of the kidneys (Greek derivation: nephros, kidney; sklerosis, hardening). It is the result of scarring or replacement of the normal renal parenchyma by dense collagenous tissue. In practice, nephrosclerosis refers to diseases with predominant pathologic changes occurring in the preglomerular microvasculature and secondarily involving the glomeruli and interstitium. The relationship between mild to moderate hypertension and either nephrosclerosis or end-stage renal disease (ESRD) remains circumstantial, although these syndromes have long been associated in the medical literature. Nephrologists credit hypertension as the etiology of nephrosclerosis in 25% of patients initiating Medicare-supported renal replacement therapy, even though other processes may cause similar renal pathologic findings. Strikingly, serum creatinine values infrequently increase in patients with long-standing mild to moderate hypertension. Patients classified as having hypertensive ESRD typically present with advanced disease, making the processes that initiated the renal disease difficult to detect. Nephrologists are twice as likely to label an African-American patient as having hypertensive nephrosclerosis, compared with a white patient, when presented with identical clinical histories. This review proposes that many patients classified as having hypertensive nephrosclerosis actually have intrinsic renal parenchymal diseases, renal artery stenosis, unrecognized episodes of accelerated hypertension, or a primary renal microvascular disease. The familial clustering of ESRD attributed to hypertension in African-Americans and the identification of genes associated with renal injury in animals support the concept that inherited factors may predispose to renal failure. African-American families often have members with ESRD from disparate etiologies, including hypertensive ESRD. This suggests that common mechanisms, be they inherited or environmental, underlie the development of progressive renal failure in diverse forms of nephropathy. Identification of the mechanisms producing susceptibility to progressive renal disease would support the concept that mild to moderate elevations in blood pressure per se are uncommon causes of nephrosclerosis. PMID- 7847349 TI - Acute renal failure associated with immunoglobulin therapy. AB - Four cases of acute renal failure induced by intravenous immunoglobulin are presented, and the literature on the subject is reviewed. The clinical course varies from asymptomatic serum creatinine elevation to anuric renal failure occurring within days of the institution of therapy, followed by the rapid recovery of renal function after termination of therapy. The renal histology demonstrates severe tubular vacuolization with cellular swelling and preservation of the brush border. Glomerular endothelial, mesangial, and epithelial cells also may demonstrate swelling and vacuolization. There is no evidence for inflammatory or immune complex-mediated etiologies. The immunoglobulins or carbohydrate additives in the preparations appear to have a unique and reversible effect on the glomerular and tubular cell function. PMID- 7847348 TI - Nonacidotic kidney proximal tubulopathy with absorptive hypercalciuria. AB - We studied three patients with proximal tubulopathy characterized by defective reabsorption of phosphate, glucose, amino acids, urate, and low molecular weight proteins. This tubulopathy differs from Fanconi syndrome in that the patients had normal plasma bicarbonate and absorptive hypercalciuria associated with increased 1,25-dihydroxyvitamin D levels. The youngest patient was rachitic and may be classified with previously described patients, whereas the other two patients presented with nonrachitic osteopenic bone disease and their tubulopathy started during adult life. Kidney defects appeared sequentially in one of the nonrachitic patients. The two brothers of the youngest patient had similar kidney and bone disturbances. One of the other two patients had a brother with similar kidney reabsorption defects; an additional brother was probably affected and a sister presented with glycosuria, but no other reabsorption defects. The findings in these two families suggest a genetic transmission of proximal tubulopathy. The third case was sporadic. Renal histology of the three patients showed a great number of giant cells in the tubular lumen. We conclude that, at least in our adult patients, tubulopathy may represent a new entity among the proximal tubular dysfunction cases described to date. The features of this proximal defect suggest that it may be caused by a selective alteration of luminal cell membrane transport of phosphate, glucose, amino acids, urate, and proteins in the presence of a normal sodium gradient across the tubular cell membrane. PMID- 7847350 TI - Familial hyperuricemic nephropathy. AB - This report describes a Polynesian family that had the rare combination of hyperuricemia, precocious gout, hypertension, and renal failure at an early age, with an autosomal dominant inheritance. One family member had renal biopsy evidence of interstitial urate crystal deposition, a surprisingly uncommon observation in such families, and most had decreased fractional excretion of urate, reflecting either decreased secretion or enhanced postsecretory renal reabsorption of uric acid. One patient has had a successful renal transplant. On the basis of these observations, family members of any such index case should be screened for this disorder. Treatment of affected members might include a uricosuric agent and/or allopurinol early in the course of the disorder. PMID- 7847351 TI - Karyomegalic interstitial nephritis: further support for a distinct entity and evidence for a genetic defect. AB - Karyomegalic interstitial nephritis was first described in 1979 by Mihatsch, who was reporting three such cases. We report here four additional cases as well as two family investigations. Our findings support the association of karyomegaly and interstitial nephritis as a distinct entity. Typical clinical features are asymptomatic progressive renal failure in the third decade of life and recurrent infections, mostly of the upper respiratory tract. Histologic alterations consist of markedly enlarged and hyperchromic nuclei in many tubular epithelial cells throughout the nephron accompanied by interstitial fibrosis in the surrounding atrophic tubules. Karyomegaly is not limited to the kidneys. In one case, autopsy revealed karyomegaly in epithelial and mesenchymal cells of many other organs. However, no association of karyomegaly with further histologic damage is evident except in the kidneys. Because of the familial clustering, karyomegalic interstitial nephritis seems to be an inherited disease. Examination of the nuclear proliferation-associated structures proliferating cell nuclear antigen/cyclin, Ki 67, and p53 suggests an inhibition of mitosis in karyomegalic cells. The finding of the same HLA haplotype, A9/B35, in four of six HLA-typed cases suggests the possibility of a genetic defect on chromosome 6, which is inherited and linked to the HLA locus. PMID- 7847352 TI - Distribution of the granulocyte serine proteinases proteinase 3 and elastase in human glomerulonephritis. AB - The serine proteinases proteinase 3 (PR3) and elastase are target antigens of antineutrophil cytoplasmic autoantibodies (ANCAs), which are found in various systemic vasculitides with rapidly progressive glomerulonephritis (RPGN). The expression of both proteinases was studied immunohistologically (avidin-biotin complex method) with murine monoclonal antibodies against PR3 (WGM2) and elastase (NP 57) in 122 human renal biopsy specimens to investigate their role in mediating renal damage. Expression of PR3 predominated in ANCA-associated RPGN and was independent of the serologic ANCA pattern (c-/p-ANCA). The PR3 staining pattern was patchy and not always related to distint granulocytes due to antigen spreading by disintegrating cells. It was found in crescentic glomeruli and the interstitum of ANCA-positive RPGN. In contrast, glomerular and interstitial elastase staining pattern was much more granulocyte related and was even found in noncrescentic glomeruli in c-ANCA- and p-ANCA-positive pauci-immune RPGN. Endothelial cell and glomerular basement membrane-bound PR3 or elastase expression were not observed. A faint glomerular PR3/elastase expression was seen in Goodpasture's syndrome and within the interstitium in crescentic mesangioproliferative glomerulonephritis (granulocyte related). Both serine proteinases were found in the glomeruli in ANCA-negative acute postinfectious glomerulonephritis. In conclusion, this study provides evidence, for the first time, for the implication of the granulocyte serine proteinases PR3 and elastase in mediating pauci-immune ANCA-positive RPGN and different forms of proliferative glomerulonephritis. The expression of ANCA antigens in ANCA-negative glomerulonephritis suggests that this finding is a marker of neutrophil activation.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7847353 TI - Dialysis staff influence patients in formulating their advance directives. AB - Patients on chronic dialysis were surveyed to determine the degree to which completion of advance directives (ADs) was influenced by personal factors that patients bring to their dialysis situation (eg, demographic characteristics or personal preferences) and by environmental factors that are not under their control (eg, interaction with dialysis staff or hospital system). Of the 113 questionnaires distributed to the population of 40 hemodialysis and 73 peritoneal dialysis patients, 90 (80%) were completed. Although only 17% of the respondents had actually completed written ADs previously, respondents seemed to have a good general understanding of ADs, as evidenced by the 80% overall accuracy on a 19 question portion of the survey that tested knowledge regarding ADs. While a few personal factors, such as gender, dialysis, modality, perceived quality of life, and attitude toward death, were associated with completion of ADs, most other demographic variables, including age, marital status, religion, work status, number of years of education, disability status, locus of control, renal diagnosis, and number of years on dialysis, were not correlated. More prominently correlated with completion of ADs were environmental factors, such as having dialysis staff discuss ADs with patients, patients being asked to complete ADs at the time of hospitalization, and perception of staff as being comfortable discussing ADs with patients. The overall results of the survey suggest that discussing ADs as an ongoing activity may have been positively influenced by the Federal Patient Self-Determination Act of 1991.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7847355 TI - Death during the first 90 days of dialysis: a case control study. AB - Comparison of survival data among centers may be used to assess performance, but may be influenced by the number of patients who die during the first 90 days of renal replacement therapy (RRT). Data published by registries in Europe do not detail these deaths, and US data generally exclude them from analysis for financial reasons. To study factors influencing such deaths we compared 42 patients who died within 90 days of first commencing RRT in one Scottish renal unit (group A) between 1971 and 1992 with 42 age- and sex-matched controls who started RRT over the same period and survived longer (group B). Patients who died within 90 days of RRT ranged in age from 25.3 to 83.7 years and had a mean age of 65.2 (SEM, 1.6; 95% confidence interval, 61.9 to 68.4). The proportion of patients who died during the first 90 days of RRT increased from 2% of all patients treated before 1981 to 12% in subsequent years. Thirty-three patients in group A received emergency dialysis via temporary venous access compared with only nine in group B (P < 0.055). There were more patients in group A with a diagnosis of arteriosclerotic renal artery stenosis (14 v 1) and with a history of smoking (15 v 2) than in group B (P < 0.0005). Median renal or nonrenal follow up before RRT was 1.1 month in group A and 10.6 months in group B (P < 0.0001). Fewer patients in group A had no coexisting disease (1 v 17; P < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7847354 TI - Correlation of venography, venous pressure, and hemoaccess function. AB - We analyzed the anatomic features of both grafts and fistulas and correlated these features with access function. We also attempted to determine venous pressures predicting access dysfunction (critical venous pressures) at various blood flow rates (BFRs). Therefore, accesses of 46 chronic hemodialysis patients were studied by venography in a prospective fashion. We defined the incidences of various lesions and the effects of venous collaterals on graft function, and determined critical venous pressures at various BFRs. Eighty-three percent of the accesses had outflow obstruction. Five types of anatomic lesions were identified. The incidences were venous stenosis of the draining vein immediately proximal to the venous anastomosis, 36.4%; central vein, 23.6%; venous anastomosis, 25.5%; arterial anastomosis, 10.9%; and intragraft hyperplasia, 3.6%. Twelve patients had multiple lesions. When the homogenous polytetrafluoroethylene arm graft population was studied for the effect of venous collaterals, we found that venous collaterals conferred protection but did not prevent graft failure. Venous pressure measurements were good predictors of access failure at the lower BFRs. Venous pressures increased with increasing BFRs. A critical venous pressure of 145 mm Hg was found for a BFR of 250 mL/min. At a BFR of 300 mL/min, the critical venous pressure was 170 mm Hg. A critical venous pressure could not be found for a BFR of 400 mL/min. PMID- 7847356 TI - A comparison of coronary angioplasty and coronary artery bypass grafting outcomes in chronic dialysis patients. AB - The objective of this study was to compare the outcomes of angina, myocardial infarction (MI), cardiac death, and all-cause death following percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass grafting (CABG). The study design was based on retrospective, nonrandomized analysis and was set in referral teaching hospitals and community hospitals. Eighty-four chronic dialysis patients with symptomatic coronary artery disease without prior revascularization were included in the study. Twenty-four patients underwent PTCA of one or more vessels, and 60 patients underwent CABG. Recurrence of angina, MI, cardiac death, and all-cause death following revascularization as well as the number of inpatient days preprocedure and postprocedure were recorded. The two patient groups were comparable in terms of age, sex, history of MI, left ventricular mass and function, and angina severity. Diabetes mellitus was more prevalent in the PTCA group. The CABG group had more severe coronary artery disease. The 2-year survival rate of the CABG patients (66%; 95% confidence interval = 53.79) did not differ from that of the PTCA patients (51%; 95% confidence interval = 27.65). Thirteen PTCA patients were restudied 106 +/- 108 days after recurrence of angina; nine (69%) of these patients were found to have angiographic restenosis. The postprocedure risk of angina and the combined endpoints of angina, MI, and cardiovascular death were significantly greater following PTCA than CABG. Percutaneous transluminal coronary angioplasty was the only consistent predictor of outcomes; the adjusted relative risks (compared with CABG) of postprocedure angina and combined endpoints were 16.4 and 10.2, respectively, and were several-fold higher than the unadjusted risks. We conclude that in chronic dialysis patients with symptomatic coronary disease, patients undergoing PTCA have a higher risk of subsequent angina and combined angina, MI, and cardiovascular death than those undergoing CABG. The optimal approach to coronary revascularization in this patient population remains to be determined. PMID- 7847357 TI - Limitations of pulse oral calcitriol therapy in continuous ambulatory peritoneal dialysis patients. AB - Calcitriol is increasingly used for therapy of secondary hyperparathyroidism in patients with end-stage renal disease. Its therapeutic efficacy, however, often has been limited by the associated increase in intestinal calcium and phosphorus absorption. Previous studies reported that these side effects could be avoided by intermittent administration of calcitriol in high doses, subsequently referred to as pulse therapy. The present study was designed to investigate pulse oral calcitriol therapy in a patient subgroup especially susceptible to the development of hypercalcemia and hyperphosphatemia under standard continuous calcitriol treatment. We examined 15 peritoneal dialysis patients with moderate degrees of hyperparathyroidism (intact parathyroid hormone [iPTH] levels, 150 to 903 pg/mL) ingesting between 1.5 and 6 g of calcium salts as the sole phosphate binders. Treatment consisted of 0.5 microgram calcitriol twice weekly. Eight of these patients had been previously converted to low calcium dialysate to tolerate the necessary doses of phosphate-binding calcium salts. During the study period, comprising 8 pretreatment weeks and 8 weeks of therapy, dialysates and doses of calcium salts were not changed, so that only calcitriol influenced the determined parameters. As expected, iPTH levels decreased rapidly in all patients (P < 0.0001). However, within 4 weeks of treatment a marked increase in calcium phosphorus products was observed (P < 0.0001). Overt hypercalcemia developed in five patients. We concluded that pulse oral calcitriol has to be carefully monitored in peritoneal dialysis patients receiving high doses of calcium salts because of the increased risk for hypercalcemia and hyperphosphatemia. PMID- 7847358 TI - Pneumoperitoneum in peritoneal dialysis patients. AB - There has been recent controversy regarding the clinical significance of pneumoperitoneum in patients undergoing peritoneal dialysis. The incidence of pneumoperitoneum has been estimated to be 21.2% to 33.7% in prior studies of peritoneal dialysis patients. Of the peritoneal dialysis patients with pneumoperitoneum, only a small percentage (5.9% to 14.3%) had documented visceral perforations. The controversy arises in that anywhere from 20% to 100% of peritoneal dialysis patients with pneumoperitoneum and peritonitis had visceral perforation, and 32.4% to 57.1% of chronic ambulatory peritoneal dialysis patients had asymptomatic pneumoperitoneum of unknown etiology. These disparate incidences made clinical interpretation of pneumoperitoneum difficult. In addition, prior study result disagreed as to the usefulness of the extent of pneumoperitoneum in predicting visceral perforation. We retrospectively reviewed 694 chest x-ray film and acute abdominal series reports from 1982 to 1993 in 75 peritoneal dialysis patients, with 9.3 +/- 1.3 (mean +/- SEM) x-ray films per patient. The reports were confirmed by reviewing 363 x-ray films (52%). Eight patients (10.7%) had 10 episodes of pneumoperitoneum. Six of these eight patients had asymptomatic pneumoperitoneum from a known etiology: four had undergone abdominal surgery for catheter placement the prior week and two had catheter manipulation immediately preceding the x-ray. One patient had three episodes of pneumoperitoneum: one after catheter placement and two not associated with a known etiology for pneumoperitoneum while on the cycler. One patient had a surgically confirmed colonic perforation with a large pneumoperitoneum and peritonitis.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7847359 TI - Methylprednisolone retards the progression of inherited polycystic kidney disease in rodents. AB - Polycystic kidney disease in adult laboratory animals and humans is associated with enlarged kidneys and a progressive decline of renal function, resulting in death from uremia. Interstitial inflammation and fibrosis typically are observed in association with the development of renal insufficiency. To determine whether amelioration of interstitial inflammation and fibrosis may diminish cyst expansion/kidney enlargement and stabilize renal function, we administered methylprednisolone, an anti-inflammatory drug with antifibrogenic effects, to mice and rats with hereditary polycystic kidney disease. The experiment was repeated once for each species. Mice were studied both in America and in Japan. Weanling male and female mice (DBA/FG pcy/pcy [cystic] and +/+ [normal], n = 87 and 20, respectively) and rats (Han:SPRD Cy/+ and +/+, n = 70 and 33, respectively) were administered methylprednisolone (1 to 2 mg/kg/d) in the drinking water for 100 days (mice) or 42 days (rats). Control animals drank distilled water. In normal DBA +/+ mice, methylprednisolone had no effect on serum urea nitrogen (SUN) levels, kidney weight, or kidney/body weight. Untreated male and female mice developed cystic kidneys and azotemia to an equal extent. Methylprednisolone administered in America to mice with renal cystic disease decreased kidney weight, kidney/body weight, SUN levels, volume density of cysts, and severity of interstitial fibrosis. In Japan, methylprednisolone decreased kidney weight and SUN levels of animals with cystic disease, but the effect on kidney/body weight did not reach statistical significance. In contrast to mice, male rats developed more severe renal cystic changes and were more azotemic than female rats. Methylprednisolone administered to male rats with cystic disease decreased SUN levels, kidney weight, kidney/body weight, volume density of cysts, and severity of interstitial fibrosis. Methylprednisolone had no effect on kidney/body weight or SUN levels in female rats with renal cystic disease. In normal Han:SPRD (+/+) rats of both sexes, kidney and body weight were decreased by methylprednisolone, but kidney/body weight and SUN levels were unchanged. On the basis of this study, we conclude that methylprednisolone decreased the extent of renal enlargement, reduced renal interstitial fibrosis, and preserved kidney function in mice and rats with relatively severe forms of inherited polycystic kidney disease. PMID- 7847360 TI - Effects of flaxseed and flax oil diets in a rat-5/6 renal ablation model. AB - The objective of this study was to assess the effects of flaxseed and flax oil diets in the rat renal ablation model. Flaxseed is a rich source of alpha linolenic acid, an 18:3n3 omega-3 fatty acid, which has anti-atherogenic and anti inflammatory properties. Flaxseed, but not flax oil, is also rich in lignans, which are platelet-activating factor-receptor antagonists. Rats were subjected to 5/6 nephrectomy, fed a regular laboratory diet (RLD) for 1 week, then divided into three groups to receive either the RLD (n = 8), a 15% flaxseed diet (n = 8), or a 15% flax oil diet (n = 7). Blood pressure, proteinuria, glomerular filtration rate, and urinary prostaglandins (thromboxane B2 and 6-keto prostaglandin F1 alpha) were measured presurgery and at 1 week (before dietary allotment) and 20 weeks postnephrectomy when blood for plasma lipids and kidneys for histology and tissue-phospholipid analyses were obtained. Blood pressure increased progressively in the RLD group but not in the flax diet groups. Plasma triglycerides and cholesterol increased in all groups, but this increase was significantly attenuated by both flax diets. Proteinuria increased 1 week postsurgery and continued to increase in the RLD group but not in the flax diet groups. Glomerular filtration rate decreased progressively, but this decline in renal function was attenuated significantly by the flax diets. Both of the flax diets prevented glomerulosclerosis and mesangial expansion. Renal alpha-linolenic acid was increased by both the flax diets (flax oil > flaxseed), but eicosapentaenoic acid increased in the flax oil group only. The flaxseed group had greater renal-arachidonic acid levels than the flax oil and RLD groups. The total omega-3 fatty acids increased twofold to threefold in the flax oil group compared with the two other groups. The total saturated fatty acids were lower and the polyunsaturated fatty acids were increased in both flax diet groups. A progressive increase in urinary thromboxane B2 occurred in the RLD group but not in the flaxseed group; the level decreased in the flax oil group. The ratio of prostaglandin F1 alpha/thromboxane B2 was preserved in the flax oil group only. In conclusion, the dietary flax seed and flax oil attenuated the decline in renal function and reduced glomerular injury with favorable effects on blood pressure, plasma lipids, and urinary prostaglandins. While we have not proven any specific synergistic effects of the constituents of the flaxseed diet, the benefits of flax-derived alpha-linolenic acid with or without lignans in the rat-5/6 renal ablation model seem clear from this experiment. PMID- 7847362 TI - Hemolytic uremic syndrome complicating postinfectious glomerulonephritis in the adult. AB - Hemolytic uremic syndrome/thrombotic thrombocytopenic purpura is known to occur as a secondary complication of primary renal diseases, specifically of lupus nephritis, membranous glomerulonephritis, and focal segmental glomerulosclerosis. In a patient without a family history of hemolytic uremic syndrome/thrombotic thrombocytopenic purpura we observed biopsy-confirmed postinfectious glomerulonephritis with humps, with simultaneous subendothelial hyaline deposits and fibrinoid thrombi in arterioles. The patient had a history of febrile pharyngitis with diarrhea 10 days prior to renal biopsy. He presented with transient elevation of serum creatinine, a nephritic sediment, and hypertension not exceeding 160/100 mm Hg. The patient also had purpura, transient thrombocytopenia, and signs of intravascular hemolysis. Results of verocytotoxin serology were negative. With the exception of isolated microhematuria, all findings reverted to normal within 8 weeks without any specific treatment. This case illustrates that hemolytic uremic syndrome/thrombotic thrombocytopenic purpura may complicate primary postinfectious glomerulonephritis in adults. PMID- 7847361 TI - Glomerulonephritis with anti-glomerular basement membrane antibody during pregnancy: potential role of the placenta in amelioration of disease. AB - A case of rapidly progressive glomerulonephritis with glomerular deposition of anti-glomerular basement membrane (anti-GBM) antibody during pregnancy is described. Development of precipitous renal failure postpartum raised the possibility that the placenta may have served as an adsorptive surface for the autoantibody, thereby ameliorating its manifestations antepartum. Sera from the patient obtained during pregnancy contained low titers of anti-GBM immunoglobulin G. No antibody was identified in the serum from the healthy infant. Additional studies of this patient's sera, as well as sera from other patients with documented anti-GBM antibody-mediated glomerulonephritis, demonstrated that binding of anti-GBM antibody to placental membranes can occur, although it appears weaker than binding to basement membranes in renal glomeruli. We postulate that the patient's accelerated decline in renal function postpartum may have been due to removal of the ameliorating influence of the placenta. PMID- 7847363 TI - Evolution of immunoglobulin A nephropathy into Henoch-Schonlein purpura in an adult patient. AB - We report the first case of the evolution of immunoglobulin A (IgA) nephropathy into Henoch-Schonlein purpura in an adult patient. A 28-year-old man presented with an episode of gross hematuria and acute renal failure. The serum IgA level was increased and renal biopsy findings were diagnostic of IgA nephropathy. In addition, many renal tubuli were filled by red blood cell casts and presented a marked tubular necrosis. Coincidental with the disappearance of gross hematuria, renal function progressively improved. The patient continued to have microhematuria, normal renal function, and isolated bouts of macroscopic hematuria. Ten years later, the patient developed arthralgias, a purpuric rash in the legs, gross hematuria, and an elevated serum creatinine level. A skin biopsy showed leukocytoclastic vasculitis with IgA deposits. The renal biopsy showed histologic lesions very similar to those observed in the first biopsy 10 years before: mesangial proliferation with mesangial deposition of IgA and tubular necrosis with obstruction of renal tubuli by red blood cell casts. The serum creatinine level returned to normal. Recurrent episodes of purpura associated with macroscopic hematuria persisted during the follow-up, but without worsening of renal function. An interesting feature of our patient was the development of reversible renal failure associated with macroscopic hematuria on two different occasions. Although this complication has been described in IgA nephropathy, it has been rarely reported in Henoch-Schonlein purpura. It is possible that IgA nephropathy and Henoch-Schonlein purpura are different clinical manifestations of the same disease and probably share a common pathogenesis. Our case is a demonstrative example of this hypothesis. PMID- 7847365 TI - Hypervitaminosis A in two hemodialysis patients. AB - We present two cases of hemodialysis patients developing vitamin A toxicity related to excessive consumption of nutritional supplements containing large quantities of vitamin A. In one patient, severe hypercalcemia was the lone presenting sign; in the other, hypercalcemia was associated with unusual neurologic manifestations. We will discuss the reason why hemodialysis patients are at special risk for the development of hypervitaminosis A and review the mechanism leading to the associated hypercalcemia. PMID- 7847364 TI - Acid dialysate correction of metabolic alkalosis in renal failure. AB - Severe metabolic acidosis may occur during hemodialysis when the incorrect acid dialysis concentrate from a two-part bicarbonate dialysis system is used in an acetate dialysis machine. We deliberately applied this technique to correct severe metabolic alkalosis in a patient with chronic renal failure. Rapid correction of the metabolic alkalosis was achieved and the procedure was well tolerated. PMID- 7847366 TI - The low birth weight hypothesis as a plausible explanation for the black/white differences in hypertension, non-insulin-dependent diabetes, and end-stage renal disease. AB - It is well known that black Americans have a higher risk for low birth weight (LBW) than white Americans. In addition, blacks are at a higher risk for hypertension (HT), non-insulin dependent diabetes mellitus (NIDDM), and end-stage renal disease (ESRD), particularly ESRD attributed to HT (ESRD-HT) and NIDDM (ESRD-NIDDM). It has been shown that LBW is associated with postpartum anatomic and functional alterations in the kidney and pancreas as well as with progressive renal damage in animals and increased risk for HT and NIDDM during adulthood in humans. Based on these empirical findings, it is here proposed that a greater risk of HT, NIDDM, and ESRD, particularly ESRD-HT and ESRD-NIDDM, in black Americans during adulthood may be partly related to their higher risk of LBW. However, LBW is proposed here as a component factor rather than a sufficient cause or a necessary factor for the development of these diseases. The ultimate contribution of LBW to the black/white disparities regarding HT, NIDDM, and ESRD may depend not only on the black/white differences in LBW but also on the race specific prevalences of other component factors, both environmental/behavioral and genetic, that may or may not require the presence of LBW to cause each of these diseases. PMID- 7847367 TI - Hepatitis B virus infection in chronic uremia: long-term follow-up of a two-step integrated protocol of vaccination. PMID- 7847368 TI - Response to treatment in hereditary metabolic disease: 1993 survey and 10-year comparison. AB - Knowledge about cause, pathogenesis, and manifestations of hereditary metabolic diseases puts them among the best known of all human diseases. On the other hand, outcomes of treatment are cause for uncertainty and concern. In 1985, Hayes et al. analyzed efficacy of treatment up to 1983 in 65 of these diseases selected randomly from the McKusick catalogs. Disease scores were calculated for seven parameters: longevity; reproductive capability; somatic and cognitive development; and handicaps affecting schooling, work, and cosmetic appearance. Scores of the untreated and treated phenotypes were then compared. We have now measured progress over the past decade by calculating scores on the same 65 diseases from data in several hundred new reports published since 1983. All seven parameters in the 1993 survey reflect improved efficacy of treatment in the 10 year interval. However, the percent of diseases for which all manifestations of the disease were removed by treatment has not changed (12% in 1983; 12% in 1993). The group in which manifestations were untouched by treatment has become smaller (48% in 1983; 31% in 1993), and the group partially ameliorated by treatment had increased reciprocally (40% in 1983; 57% in 1993). Progress in the treatment of hereditary metabolic disease is thus better than it was, but it is still only a partial success. The advances are attributable to greater success with organ and tissue transplantation, better pharmacotherapy, and better support systems. Restoration of normal homeostasis, the key to successful treatment, remains an elusive challenge and is a logical, major focus for research in human genetics. PMID- 7847369 TI - Achondroplasia is defined by recurrent G380R mutations of FGFR3. AB - Genomic DNA from 154 unrelated individuals with achondroplasia was evaluated for mutations in the fibroblast growth factor receptor 3 (FGFR3) transmembrane domain. All but one, an atypical case, were found to have a glycine-to-arginine substitution at codon 380. Of these, 150 had a G-to-A transition at nt 1138, and 3 had a G-to-C transversion at this same position. On the basis of estimates of the prevalence of achondroplasia, the mutation rate at the FGFR3 1138 guanosine nucleotide is two to three orders of magnitude higher than that previously reported for tranversions and transitions in CpG dinucleotides. To date, this represents the most mutable single nucleotide reported in the human genome. The homogeneity of mutations in achondroplasia is unprecedented for an autosomal dominant disorder and may explain the relative lack of heterogeneity in the achondroplasia phenotype. PMID- 7847370 TI - Hypokalemic periodic paralysis and the dihydropyridine receptor (CACNL1A3): genotype/phenotype correlations for two predominant mutations and evidence for the absence of a founder effect in 16 caucasian families. AB - Hypokalemic periodic paralysis (hypoPP) is an autosomal dominant disorder belonging to a group of muscle diseases involving the abnormal function of ion channels. This group of muscle diseases also comprises hyperkalemic periodic paralysis and paramyotonia congenita, both sodium-channel diseases, and myotonia congenita, a chloride-channel disorder. HypoPP is characterized by acute attacks of muscle weakness concomitant with a fall in blood potassium levels. We recently localized the hypoPP locus (hypoPP1) to chromosome 1q31-32, in an interval where the alpha 1 subunit of the dihydropyridine receptor calcium channel (CACNL1A3) also maps. Subsequently, deleterious mutations in the voltage-sensor segment S4 were found, establishing the dihydropyridine receptor CACNL1A3 as the causative gene for hypoPP. In this paper, we report the study of 16 hypoPP families of Caucasian origin. We found only two mutations--Arg528His and Arg1239His--that cosegregated with hypoPP, each in half of the families. Analysis of the clinical characteristics of both groups of families demonstrated that incomplete penetrance is a distinctive feature of the Arg528His mutation. Using dinucleotide repeats contained within or close to the dihydropyridine receptor gene, in conjunction with evidence of a de novo Arg1239His mutation, we show that a founder effect is unlikely to account for the two predominant mutations. PMID- 7847371 TI - X-linked liver phosphorylase kinase deficiency is associated with mutations in the human liver phosphorylase kinase alpha subunit. AB - Two Dutch patients with liver phosphorylase kinase (PhK) deficiency were studied for abnormalities in the PhK liver alpha (alpha L) subunit mRNA by reversed transcribed-PCR (RT-PCR) and RNase protection assays. One patient, belonging to a large Dutch family that expresses X-linked liver PhK deficiency, had a C3614T mutation in the PhK alpha L coding sequence. The C3614T mutation leads to replacement of proline 1205 with leucine, which changes the composition of an amino acid region, containing amino acids 1195-1214 of the PhK alpha L subunit, that is highly conserved in different species. The patient showed normal levels of PhK alpha L mRNA. The second patient, from an unrelated family, was found to have a TCT (bp 419-421) deletion in the PhK alpha L coding sequence, resulting in a phenylalanine 141 deletion. The same deletion was found in the PhK alpha L coding sequence from lymphocytes of the patient's mother, together with a normal PhK alpha L coding sequence. The phenylalanine that is absent in the PhK alpha L coding sequence of the second patient is a highly conserved amino acid between species. Both the C3614T mutation and the TCT (bp 419-421) deletion were not found in a panel of 80 control X chromosomes. On the basis of these results, it is postulated that the mutations found are responsible for liver PhK deficiency in the two patients investigated. PMID- 7847373 TI - A gene for late-onset fundus flavimaculatus with macular dystrophy maps to chromosome 1p13. AB - Fundus flavimaculatus with macular dystrophy is an autosomal recessive disease responsible for a progressive loss of visual acuity in adulthood, with pigmentary changes of the macula, perimacular flecks, and atrophy of the retinal pigmentary epithelium. Since this condition shares several clinical features with Stargardt disease, which has been mapped to chromosome 1p21-p13, we tested the disease for linkage to chromosome 1p. We report here the mapping of the disease locus to chromosome 1p13-p21, in the genetic interval defined by loci D1S435 and D1S415, in four multiplex families (maximum lod score 4.79 at recombination fraction 0 for probe AFM217zb2 at locus D1S435). Thus, despite differences in the age at onset, clinical course, and severity, fundus flavimaculatus with macular dystrophy and Stargardt disease are probably allelic disorders. This result supports the view that allelic mutations produce a continuum of macular dystrophies, with onset in early childhood to late adulthood. PMID- 7847372 TI - An RNA-splicing mutation (G+5IVS20) in the type II collagen gene (COL2A1) in a family with spondyloepiphyseal dysplasia congenita. AB - Defects in type II collagen have been demonstrated in a phenotypic continuum of chondrodysplasias that includes achondrogenesis II, hypochondrogenesis, spondyloepiphyseal dysplasia congenita (SEDC), Kniest dysplasia, and Stickler syndrome. We have determined that cartilage from a terminated fetus with an inherited form of SEDC contained both normal alpha 1(II) collagen chains and chains that lacked amino acids 256-273 of the triple-helical domain. PCR amplification of this region of COL2A1, from genomic DNA, yielded products of normal size, while amplification of cDNA yielded a normal sized species and a shorter fragment missing exon 20. Sequence analysis of genomic DNA from the fetus revealed a G-->T transversion at position +5 of intron 20; the affected father was also heterozygous for the mutation. Allele-specific PCR and heteroduplex analysis of a VNTR in COL2A1 independently confirmed the unaffected status of a fetus in a subsequent pregnancy. Thermodynamic calculations suggest that the mutation prevents normal splicing of exon 20 by interfering with binding of U1 small-nuclear RNA to pre-mRNA, thus leading to skipping of exon 20 in transcripts from the mutant allele. Electron micrographs of diseased cartilage showed intracellular inclusion bodies, which were stained by an antibody to alpha 1(II) procollagen. Our findings support the hypothesis that alpha-chain length alterations that preserve the Gly-X-Y repeat motif of the triple helix result in partial intracellular retention of alpha 1(II) procollagen and produce mild to moderate chondrodysplasia phenotypes. PMID- 7847374 TI - Brachydactyly and mental retardation: an Albright hereditary osteodystrophy-like syndrome localized to 2q37. AB - We report five patients with a combination of brachymetaphalangia and mental retardation, similar to that observed in Albright hereditary osteodystrophy (AHO). Four patients had cytogenetically visible de novo deletions of chromosome 2q37. The fifth patient was cytogenetically normal and had normal bioactivity of the alpha subunit of Gs (Gs alpha), the protein that is defective in AHO. In this patient, we have used a combination of highly polymorphic molecular markers and FISH to demonstrate a microdeletion at 2q37. The common region of deletion overlap involves the most telomeric 2q marker, D2S125, and extends proximally for a maximum distance of 17.6 cM. We suggest this represents a consistent phenotype associated with some deletions at 2q37 and that genes important for skeletal and neurodevelopment lie within this region. Screening for deletions at this locus should be considered in individuals with brachymetaphalangia and mental retardation. Furthermore, 2q37 represents a candidate region for type E brachydactyly. PMID- 7847375 TI - A gene for familial total anomalous pulmonary venous return maps to chromosome 4p13-q12. AB - Total anomalous pulmonary venous return (TAPVR) is a cyanotic congenital heart defect that, without surgical correction, has a high mortality rate in the first year of life. It usually occurs without a family history and has a low recurrence risk. However, we recently reported a large Utah-Idaho family in which TAPVR segregates as an autosomal dominant trait with decreased penetrance. Linkage mapping with highly polymorphic microsatellite markers localizes the disease locus in this pedigree to the centromeric region of chromosome 4 (maximum lod = 6.51 at theta = .00). Apparent genetic anticipation in the pedigree prompted a search for expanded trinucleotide repeats by using repeat expansion detection. We have found no evidence for a trinucleotide repeat expansion that segregates with TAPVR. A vascular endothelial growth-factor receptor that is thought to have a role in vasculogenesis maps near the pericentric region of chromosome 4 and is a candidate gene for both familial and sporadic cases of TAPVR. PMID- 7847376 TI - Homozygosity mapping, to chromosome 11p, of the gene for familial persistent hyperinsulinemic hypoglycemia of infancy. AB - Familial persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is a rare, autosomal recessive disease of unregulated insulin secretion, defined by elevations in serum insulin despite severe hypoglycemia. We used the homozygosity gene-mapping strategy to localize this disorder to the region of chromosome 11p between markers D11S1334 and D11S899 (maximum LOD score 5.02 [theta = 0] at marker D11S926) in five consanguineous families of Saudi Arabian origin. These results extend those of a recent report that also placed PHHI on chromosome 11p, between markers D11S926 and D11S928. Comparison of the boundaries of these two overlapping regions allows the PHHI locus to be assigned to the 4-cM region between the markers D11S926 and D11S899. Identification of this gene may allow a better understanding of other disorders of glucose homeostasis, by providing insight into the regulation of insulin release. PMID- 7847377 TI - Autosomal dominant distal myopathy: linkage to chromosome 14. AB - We have studied a family segregating a form of autosomal dominant distal myopathy (MIM 160500) and containing nine living affected individuals. The myopathy in this family is closest in clinical phenotype to that first described by Gowers in 1902. A search for linkage was conducted using microsatellite, VNTR, and RFLP markers. In total, 92 markers on all 22 autosomes were run. Positive linkage was obtained with 14 of 15 markers tested on chromosome 14, with little indication of linkage elsewhere in the genome. Maximum two-point LOD scores of 2.60 at recombination fraction .00 were obtained for the markers MYH7 and D14S64--the family structure precludes a two-point LOD score > or = 3. Recombinations with D14S72 and D14S49 indicate that this distal myopathy locus, MPD1, should lie between these markers. A multipoint analysis assuming 100% penetrance and using the markers D14S72, D14S50, MYH7, D14S64, D14S54, and D14S49 gave a LOD score of exactly 3 at MYH7. Analysis at a penetrance of 80% gave a LOD score of 2.8 at this marker. This probable localization of a gene for distal myopathy, MPD1, on chromosome 14 should allow other investigators studying distal myopathy families to test this region for linkage in other types of the disease, to confirm linkage or to demonstrate the likely genetic heterogeneity. PMID- 7847378 TI - Haplotype analysis in Australian hemochromatosis patients: evidence for a predominant ancestral haplotype exclusively associated with hemochromatosis. AB - Hemochromatosis (HC), an inherited disorder of iron metabolism, shows a very strong founder effect in Australia, with the majority of patients being of Celtic (Scots/Irish) origin. Australian HC patients thus provide an ideal group in which to examine HC-gene-region haplotypes, to analyze the extent of linkage disequilibrium and genetic heterogeneity in HC. We have analyzed chromosomes from 26 multiply affected HC pedigrees, and we were able to assign HC status unambiguously to 107 chromosomes--64 as affected and 43 as unaffected. The haplotypes examined comprise the following highly polymorphic markers: the serological marker HLA-A and the microsatellites D6S248, D6S265, HLA-F, and D6S105. All show highly significant allelic association with HC and no evidence of separation from the disease locus by recombination. Analysis identified a predominant ancestral haplotype comprising alleles 5-1-3-2-8 (marker order: D6S248-D6S265-HLA-A-HLA-F-D6S105), present in 21 (33%) of 64 affected chromosomes, and exclusively associated with HC (haplotype relative risk 903). No other common haplotype was significantly associated with HC. Haplotype analysis in Australian HC patients thus provides strong evidence for (a) the introduction of HC into this population on an ancestral haplotype, (b) a common mutation associated with HC in Australian patients, and (c) a candidate HC-gene region extending between and including D6S248 and D6S105. PMID- 7847379 TI - Failure of imprinting at Igf-2: two models of mutation-selection balance. AB - The failure of maternal imprinting at the insulin-like growth factor II (Igf-2) locus predisposes individuals to several clinical conditions, including Wilms tumor. Having two functional Igf-2 genes, therefore, is selectively disadvantageous, and the condition is probably maintained in human populations by recurrent mutation. We propose two models that predict the expected frequency of functionally diploid individuals in a large population, in terms of a mutation rate, mu, and the selection coefficient against functionally diploid individuals, s. In the first model a mutant Igf-2 allele that cannot be imprinted arises from the standard, imprintable allele at a rate mu. Our second model hypothesizes a second modifier locus at which a recessive allele arises at rate mu. Mothers who are homozygous for this recessive modifier allele fail to imprint their eggs. Both models predict the expected frequency of affecteds to be 2 mu/s(1 + mu), approximately twice that predicted by the standard one-locus model of a recessive allele in mutation-selection balance. This frequency suggests that < or = 25% of the cases of Wilms tumor are due to the failure to imprint the maternal Igf-2 gene. PMID- 7847380 TI - Studies on phenotypic complementation of ataxia-telangiectasia cells by chromosome transfer. AB - Cells derived from patients with the cancer-prone inherited disorder ataxia telangiectasia (A-T) show an abnormal response to ionizing radiation-induced DNA damage, such as an increased cell killing and a diminished inhibition of DNA synthesis. The enhanced killing of A-T (group D) cells by X-rays can be corrected by multiple cDNAs, mapping to different chromosomes (6, 11, 17, and 18). In order to examine whether genes located on these chromosomes complement AT-D cells, normal neo-tagged chromosomes 6, 11, 17, and 18 were introduced into AT-D cells by microcell-mediated chromosome transfer. However, correction of the enhanced killing of AT-D cells by X-rays could only be achieved by chromosome 11 and by none of the other chromosomes tested. The enhanced killing of A-T (complementation group C) cells was also corrected by chromosome 11. Usually, but not in all microcell hybrid clones, chromosome 11 also corrected the radioresistant DNA synthesis (RDS) phenotype of AT-D and AT-C cells. These results (i) confirm findings by others suggesting assignment of the ATD and ATC genes to chromosome 11, (ii) demonstrate that several genes can modify the cellular radiation response when they are taken out of their normal genomic context and/or control, and (iii) indicate that the RDS phenotype and the enhanced cell killing in A-T are independent pleiotropic features resulting from the primary mutations in A-T. Also, our findings underscore that, in establishing cDNAs as candidate genes for A-T, microcell-mediated chromosome transfer studies are needed to exclude nonspecific correcting effects of these candidate cDNA genes. PMID- 7847381 TI - Molecular studies of chromosomal mosaicism: relative frequency of chromosome gain or loss and possible role of cell selection. AB - Studies of uniparental disomy and origin of nonmosaic trisomies indicate that both gain and loss of a chromosome can occur after fertilization. It is therefore of interest to determine both the relative frequency with which gain or loss can contribute to chromosomal mosaicism and whether these frequencies are influenced by selective factors. Thirty-two mosaic cases were examined with molecular markers, to try to determine which was the primary and which was the secondary cell line: 16 cases of disomy/trisomy mosaicism (5 trisomy 8, 2 trisomy 13, 1 trisomy 18, 4 trisomy 21, and 4 involving the X chromosome), 14 cases of 45,X/46,XX, and 2 cases of 45,X/47,XXX. Of the 14 cases of mosaic 45,X/46,XX, chromosome loss from a normal disomic fertilization predominated, supporting the hypothesis that 45,X might be compatible with survival only when the 45,X cell line arises relatively late in development. Most cases of disomy/trisomy mosaicism involving chromosomes 13, 18, 21, and X were also frequently associated with somatic loss of one (or more) chromosome, in these cases from a trisomic fertilization. By contrast, four of the five trisomy 8 cases were consistent with a somatic gain of a chromosome 8 during development from a normal zygote. It is possible that survival of trisomy 8 is also much more likely when the aneuploid cell line arises relatively late in development. PMID- 7847382 TI - An analysis of human sperm chromosome breakpoints. AB - Sperm chromosome analysis of 19 sperm donors with either normal or balanced karyotypes was carried out in order to explore the nature of sperm chromosome structural aberrations. A total of 2,389 cells (range 36-298/donor) were karyotyped after in vitro penetration of hamster eggs. The median percentage of sperm structural aberrations was 9.3% (SD +/- 4.7; range 0%-17.8%), with a total of 247 breakpoints, of which 220 could be characterized fully. Two sets of donors were studied in two different centers: center 1 (United States) and center 2 (Spain). The frequencies of nonrejoined and rejoined chromosome-type aberrations were very similar between center 1 and center 2: 83.6% and 10.0%, and 75.0% and 10.3%, respectively. Chromatid-type aberrations were more frequent in center 2 (14.7%) than in center 1 (6.4%) (P = .037). Chromosome 4 had less than the expected number of breakpoints (P < .001). A positive significant correlation was found between sperm breakpoints reported in this study and sites of balanced chromosome de novo rearrangements detected at prenatal diagnosis and reported in the literature (P = .0001). PMID- 7847383 TI - Population genetics of dinucleotide (dC-dA)n.(dG-dT)n polymorphisms in world populations. AB - We have characterized eight dinucleotide (dC-dA)n.(dG-dT)n repeat loci located on human chromosome 13q in eight human populations and in a sample of chimpanzees. Even though there is substantial variation in allele frequencies at each locus, at a given locus the most frequent alleles are shared by all human populations. The level of heterozygosity is reduced in isolated or small populations, such as the Pehuenche Indians of Chile, the Dogrib of Canada, and the New Guinea highlanders. On the other hand, larger average heterozygosities are observed in large and cosmopolitan populations, such as the Sokoto population from Nigeria and German Caucasians. Conformity with Hardy-Weinberg equilibrium is generally observed at these loci, unless (a) a population is isolated or small or (b) the repeat motif of the locus is not perfect (e.g., D13S197). Multilocus genotype probabilities at these microsatellite loci do not show departure from the independence rule, unless the loci are closely linked. The allele size distributions at these (CA)n loci do not follow a strict single-step stepwise mutation model. However, this features does not compromise the ability to detect population affinities, when these loci are used simultaneously. The microsatellite loci examined here are present and, with the exception of the locus D13S197, are polymorphic in the chimpanzees, showing an overlapping distribution of allele sizes with those observed in human populations. PMID- 7847384 TI - Methods for genetic linkage analysis using trisomies. AB - Certain genetic disorders are rare in the general population, but more common in individuals with specific trisomies. Examples of this include leukemia and duodenal atresia in trisomy 21. This paper presents a linkage analysis method for using trisomic individuals to map genes for such traits. It is based on a very general gene-specific dosage model that posits that the trait is caused by specific effects of different alleles at one or a few loci and that duplicate copies of "susceptibility" alleles inherited from the nondisjoining parent give increased likelihood of having the trait. Our mapping method is similar to identity-by-descent-based mapping methods using affected relative pairs and also to methods for mapping recessive traits using inbred individuals by looking for markers with greater than expected homozygosity by descent. In the trisomy case, one would take trisomic individuals and look for markers with greater than expected homozygosity in the chromosomes inherited from the nondisjoining parent. We present statistical methods for performing such a linkage analysis, including a test for linkage to a marker, a method for estimating the distance from the marker to the trait gene, a confidence interval for that distance, and methods for computing power and sample sizes. We also resolve some practical issues involved in implementing the methods, including how to use partially informative markers and how to test candidate genes. PMID- 7847385 TI - A strategy for constructing high-resolution genetic maps of the human genome: a genetic map of chromosome 17p, ordered with meiotic breakpoint-mapping panels. AB - Genetic linkage analyses with genotypic data obtained from four CEPH reference families initially assigned 24 new PCR-based markers to chromosome 17 and located the markers at specific intervals of an existing genetic map of chromosome 17p. Each marker was additionally genotyped with an ordered set of obligate, phase known recombinant chromosomes. The breakpoint-mapping panels for each family consisted of two parents, one sib with a nonrecombinant chromosome, and one or more sibs with obligate recombinant chromosomes. The relative order of markers was determined by sorting segregation patterns of new markers and ordered anchor markers and by minimizing double-recombination events. Consistency of segregation patterns with multiple flanking loci constituted support for order. A genetic map of chromosome 17p was completed with 39 markers in 23 clusters, with an average space of 3 cM between clusters. The collection of informative genotypes was highly efficient, requiring fivefold fewer genotypes than would be collected with all the CEPH families. Given the availability of large numbers of highly informative PCR-based markers, meiotic breakpoint mapping should facilitate construction of a human genomic map with 1-cM resolution. PMID- 7847386 TI - Breakpoint analysis: precise localization of genetic markers by means of nonstatistical computation using relatively few genotypes. AB - Placing new markers on a previously existing genetic map by using conventional methods of multilocus linkage analysis requires that a large number of reference families be genotyped. This paper presents a methodology for placing new markers on existing genetic maps by genotyping only a few individuals in a selected subset of the reference panel. We show that by identifying meiotic breakpoint events within existing genetic maps and genotyping individuals who exhibit these events, along with one nonrecombinant sibling and their parents, we can determine precise location for new markers even within subcentimorgan chromosomal regions. This method also improves detection of errors in genotyping and assists in the observation of chromosome behavior in specific regions. PMID- 7847387 TI - Two statistical tests for meiotic breakpoint analysis. AB - Meiotic breakpoint analysis (BPA), a statistical method for ordering genetic markers, is increasing in importance as a method for building genetic maps of human chromosomes. Although BPA does not provide estimates of genetic distances between markers, it efficiently locates new markers on already defined dense maps, when likelihood analysis becomes cumbersome or the sample size is small. However, until now no assessments of statistical significance have been available for evaluating the possibility that the results of a BPA were produced by chance. In this paper, we propose two statistical tests to determine whether the size of a sample and its genetic information content are sufficient to distinguish between "no linkage" and "linkage" of a marker mapped by BPA to a certain region. Both tests are exact and should be conducted after a BPA has assigned the marker to an interval on the map. Applications of the new tests are demonstrated by three examples: (1) a synthetic data set, (2) a data set of five markers on human chromosome 8p, and (3) a data set of four markers on human chromosome 17q. PMID- 7847388 TI - Rapid multipoint linkage analysis of recessive traits in nuclear families, including homozygosity mapping. AB - Homozygosity mapping is a powerful strategy for mapping rare recessive traits in children of consanguineous marriages. Practical applications of this strategy are currently limited by the inability of conventional linkage analysis software to compute, in reasonable time, multipoint LOD scores for pedigrees with inbreeding loops. We have developed a new algorithm for rapid multipoint likelihood calculations in small pedigrees, including those with inbreeding loops. The running time of the algorithm grows, at most, linearly with the number of loci considered simultaneously. The running time is not sensitive to the presence of inbreeding loops, missing genotype information, and highly polymorphic loci. We have incorporated this algorithm into a software package, MAPMAKER/HOMOZ, that allows very rapid multipoint mapping of disease genes in nuclear families, including homozygosity mapping. Multipoint analysis with dozens of markers can be carried out in minutes on a personal workstation. PMID- 7847390 TI - ASHG Report. Report from the ASHG Information and Education Committee: medical school core curriculum in genetics. ASHG Information and Education Committee. PMID- 7847391 TI - An open letter to The American Society of Human Genetics: the neglected genetic issue--the why and how of curbing population growth. PMID- 7847389 TI - Association of LMP2 and LMP7 genes within the major histocompatibility complex with insulin-dependent diabetes mellitus: population and family studies. AB - LMP2 and LMP7, two subunits of the proteasomes encoded in the major histocompatibility complex, are speculated to play a role in the generation of endogenous peptides for presentation by class I molecules to cytotoxic T cells. Their possible role in the pathogenesis of insulin-dependent diabetes mellitus (IDDM) has not been documented. In this study of Caucasian subjects, we have analyzed the polymorphisms of four genes within the HLA class II region (LMP2, LMP7, and HLA-DRB1 and -DQB1) in 198 unrelated IDDM patients and 192 normal controls ascertained from the southeastern United States. A genomic polymorphism of LMP7 was found strongly associated with IDDM, and the Arg/His-60 polymorphism in LMP2 was found associated with IDDM only in subjects containing an HLA DR4 DQB1*0302 haplotype. To determine whether the apparent associations between LMP genes and IDDM resulted from the strong linkage disequilibria observed between LMP and HLA-DR/DQ genes, we compared LMP gene frequencies in extended LMP-HLA haplotypes derived from control and diabetic families. Our results suggest that LMP genes have independent effects on IDDM susceptibility. PMID- 7847392 TI - A novel microsatellite DNA marker at locus D7S1870 detects hemizygosity in 75% of patients with Williams syndrome. PMID- 7847393 TI - Cystic fibrosis carrier screening in Hispanics. PMID- 7847394 TI - Federal guidelines offer choices for treatment of otitis media with effusion. PMID- 7847395 TI - Felbamate linked to aplastic anemia; warning issued on drug's use. PMID- 7847397 TI - 111 cases of hepatitis C linked to Gammagard. Patient screening recommended. PMID- 7847396 TI - Famciclovir released for shingles treatment. PMID- 7847398 TI - New York State researchers find safer i.v. devices effective but costly, in need of refinement. PMID- 7847399 TI - Submitting reports of adverse drug reactions to AJHP. PMID- 7847400 TI - Handling nonformulary requests for returning or transfer patients. PMID- 7847401 TI - Raising a new crop--of students. PMID- 7847402 TI - Making a difference. PMID- 7847403 TI - ASHP national survey of pharmaceutical services in federal hospitals--1993. AB - The results of a national mail survey of pharmaceutical services in federal hospitals conducted by ASHP from May to July 1993 are reported. Mailing lists were compiled of all Air Force, Army, Navy, Public Health Service, and Department of Veterans Affairs (VA) hospitals, as well as some federal prison hospitals. Questionnaires were mailed to each chief of pharmacy. The adjusted gross population size was 326. The net response rate was 76%. Complete unit dose drug distribution was offered by 85% of respondents, and 83% offered complete, comprehensive i.v. admixture programs. About half of the pharmacies provided decentralized services. Over 99% provided services to ambulatory care patients. A computerized pharmacy system was present in 99% of the departments. More than 95% of hospitals participated in adverse drug reaction, medication error management, and drug-use-evaluation programs. A total of 93% provided drug therapy monitoring, and 89% provided patient education. About 70% provided written documentation of pharmacist interventions in the medical records, and 57% participated in drug research. A total of 42% provided pharmacist-managed drug clinics, 41% participated in drug management of medical emergencies, 30% provided written medication histories, and 30% provided drug therapy management planning. Pharmacokinetic consultations were provided by 64% of departments. About 90% had a well-controlled formulary system and prescribing restrictions. Therapeutic interchange was practiced by 64%. Diversified pharmaceutical services included telephone or mail-in refill services (80%), mail-out pharmaceutical services (58%), and services to long-term-care facilities (49%). A total of 70% of the hospitals were affiliated with a pharmacy school. The first ASHP national survey of pharmaceutical services in federal hospitals showed that comprehensive distributive and clinical services were offered by most of the facilities. PMID- 7847404 TI - Drug therapy during labor and delivery. AB - Situations related to labor and delivery that may require drug therapy are discussed, and treatment options are reviewed. The goal of labor induction and augmentation at term is to facilitate vaginal delivery of a healthy infant. The primary uterine stimulant used for this purpose is oxytocin. Low-, intermediate-, and high-dose protocols have been reported; augmentation requires approximately half as much oxytocin as induction does. Mifepristone has also been used for labor induction. Prostaglandins are the primary agents used for cervical ripening, but oxytocin, relaxin, and mifepristone have also been used. Mechanical dilators are available for cervical dilation, which may be necessary when prostaglandins are contraindicated. Oxytocin is the drug of choice for preventing postpartum hemorrhage; if it is not effective, methylergonovine or carboprost may be used to control the hemorrhage. Labor induction during the midtrimester may be necessary because of obstetrical or medical complications or fetal death. These situations call for aggressive dosing of uterine stimulants (e.g., high-dose oxytocin, intravaginal dinoprostone suppositories, carboprost, mifepristone). Drug therapy may be required for labor induction or augmentation, cervical ripening or dilation, and prevention or control of postpartum hemorrhage. Oxytocin is the most commonly used agent for labor induction or augmentation and for prevention of postpartum hemorrhage; prostaglandins are frequently used for cervical ripening. Aggressive dosing of uterine stimulants is required when labor must be induced during the midtrimester. PMID- 7847405 TI - Conformity with guidelines for antimicrobial prophylaxis against bacterial endocarditis. AB - The extent to which prescribed antimicrobial prophylaxis against bacterial endocarditis conformed with American Heart Association (AHA) guidelines was determined and the frequency of nonconformity with specific elements of the guidelines was evaluated. Patients with conditions defined by AHA as placing them at risk for developing endocarditis were identified through medical records for a four-year period at an 850-bed hospital. Data about the procedures they underwent and prophylaxis prescribed were compared with the AHA guidelines. Conformity with the guidelines was evaluated according to whether prophylaxis was recommended, optional, or unnecessary; nonconformity with specific elements of the guidelines (indication, choice of antimicrobial, dose, dosage interval, timing, and duration) was also evaluated. The following variables were evaluated for possible association with nonconformity to the guidelines: patient's age and sex, penicillin allergy, use of a consultant, and whether the procedure was the first performed in the patient after identification of the cardiac condition. Of the 131 cases analyzed, 29 (22%) involved prophylaxis that conformed with the AHA guidelines. Conformity with the guidelines was significantly lower when prophylaxis was recommended or optional than when it was unnecessary. Nonconformity was most common with the following elements: indication, choice of antimicrobial, and dose. Recommended prophylaxis was given more often in children than in adults and more often before first procedures than before subsequent procedures. More of the regimens prescribed for children exceeded the recommended duration than those prescribed for adults. Unnecessary prophylaxis was given more often when a consultant was involved than when no consultant was involved. In hospitalized patients, conformity with AHA guidelines for antimicrobial prophylaxis against endocarditis was low. PMID- 7847406 TI - Stability of isradipine in an extemporaneously compounded oral liquid. AB - The stability of isradipine in an extemporaneously compounded oral liquid was studied. A suspension was prepared from the powder of commercially available 5-mg isradipine capsules and sufficient Simple Syrup, NF, to make a final volume of 50 mL. A control suspension was prepared from analytical-grade isradipine powder and Simple Syrup, NF. The final concentration of isradipine in both suspensions was 1 mg/mL. Three identical volumes of each suspension were stored in 2-oz amber glass prescription bottles, which were stored at 4 degrees C. Immediately after preparation and at 7, 16, 22, 28, and 35 days, samples were visually inspected and assayed in duplicate by high-performance liquid chromatography; the pH of the samples was also determined. At least 95% of the initial isradipine concentration remained throughout the study period in all samples of both suspensions. Color, odor, and pH did not change appreciably. Isradipine 1 mg/mL in an oral liquid compounded from Simple Syrup, NF, and powder from capsules was stable for at least 35 days in amber glass bottles at 4 degrees C. PMID- 7847407 TI - Pursuing publication of an unethical investigation. PMID- 7847408 TI - Treatment of AIDS-associated Kaposi's sarcoma with oral tretinoin. PMID- 7847409 TI - Adverse reactions related to i.v. infusion of high-dose cyclophosphamide in bone marrow transplant patients. PMID- 7847410 TI - Reducing cost in a teaching hospital by requiring justification for the use of vecuronium bromide. PMID- 7847411 TI - Glucose oxidase test for in vitro detection of enteral feeding products. PMID- 7847412 TI - GI bleeding associated with nabumetone. PMID- 7847413 TI - Compatibility of 10% sodium benzoate plus 10% sodium phenylacetate with various flavored vehicles. PMID- 7847414 TI - Making the switch from i.v. to p.o. PMID- 7847415 TI - NIH funds network of centers for pediatric drug research. Pharmacists' involvement is key. PMID- 7847416 TI - Common problems plague emergency-department care of heart attack patients. Report sets 30-minute treatment goal. PMID- 7847417 TI - Drug-related disorders costing Medicare dearly. PMID- 7847418 TI - Waking ourselves up to the worth of the night shift. PMID- 7847419 TI - Buffering lidocaine with sodium bicarbonate. PMID- 7847420 TI - Biorhythms and chronotherapy in cardiovascular disease. AB - Recent findings about the effects of biorhythms on cardiovascular disorders are reviewed, and their implications for drug therapy are discussed. The chronobiological approach to physiology evaluates time-dependent changes in biological functions and considers those changes to be multifactorial. Characterization of disease states with this approach allows more accurate determination of the times when patients are at highest risk and therefore in greatest need of preventive measures; it also provides a mechanism for designing optimal drug regimens. There is evidence of circadian variations in the occurrence of myocardial ischemia, acute myocardial infarction, ventricular tachycardia, and sudden cardiac death. Many cardiovascular disorders occur with greatest frequency between 0600 and 1200 in the general population. Blood pressure, too, follows a distinct circadian pattern. Factors affecting circadian variations in cardiovascular disorders include physiological determinants, such as heart rate, catecholamine release, and platelet aggregation--which themselves vary cyclically--and exogenous factors, such as mental stress, anxiety, and physical activity. In chronotherapy, circadian variations in disease states and in the pharmacodynamic properties of drugs are exploited to improve prevention and treatment. Conditions in which research suggests a chronotherapeutic approach may be advantageous include thromboembolism, hypertension, stable exertional angina, variant angina, sustained ventricular tachycardia, and acute myocardial infarction. Information on circadian patterns in the occurrence of many cardiovascular disorders is enabling clinicians to tailor treatment in ways that may lead to improved patient outcomes. PMID- 7847421 TI - Exponential smoothing method for forecasting drug expenditures. AB - A model for forecasting a hospital pharmacy drug budget is described, and its results in 10 hospital pharmacy departments are evaluated. A model for forecasting inpatient drug expenditures was developed based on the method of exponential smoothing. Exponential smoothing predicts a value based on the forecast for the prior period, with adjustment for the error of that forecast. Recent data are weighted more heavily than older data; as data become older, weights decline exponentially. The model incorporates changes in workload in addition to drug expenditure data. The variable used for workload can vary from one hospital to another, depending on the statistics that are available. The model was designed to be more accurate than current methods, easy and quick to use, and usable with a minimal knowledge of statistics and forecasting theory. The model was tested on fiscal 1988-1992 drug budget data from 10 British Columbia hospital pharmacy departments. Four departments had insufficient data; of the remaining six, the forecasting model performed better than the hospitals' current methods in four departments. The mean absolute deviation between budgeted (by current methods) and actual drug expenditures was 8.70% (range, 6.19-15.16%). The forecasting model yielded a mean absolute deviation of 5.93% (range, 3.13 7.66%). Better forecasts resulted when pharmacy medication-order volume was used as a workload variable, as compared with hospital inpatient days. An exponential smoothing model improved the accuracy of drug-budget forecasts in four of six pharmacy departments. PMID- 7847422 TI - Capillaritis (purpura simplex) associated with use of aminoglutethimide in Cushing's syndrome. PMID- 7847423 TI - Pharmacoeconomic analysis in formulary decisions: an international perspective. AB - The greatest health care challenge of the next decade is making the best use of limited available resources to attain the highest quality for the lowest cost. This will require the use of economic information in all health care decisions, but particularly those concerning drug formularies. Pharmacoeconomic data have become increasingly available and will be playing a major role in formulary decisions in many countries around the world. In preparation, P&T committees must consider how such information will be dealt with in the formulary decision-making process at the institutional and organizational levels. PMID- 7847424 TI - The burning issue of smoking. PMID- 7847425 TI - Posted list of emergency drugs and antidotes. PMID- 7847426 TI - Calcium phosphate compatibility in 3-in-1 parenteral nutrient admixtures. PMID- 7847427 TI - Medically safe rate of weight loss for the treatment of obesity: a guideline based on risk of gallstone formation. AB - OBJECTIVE: Currently recommended rates of weight loss for obese persons are not based on demonstrated health risks. The authors attempt to determine a medically safe rate of weight loss based on currently available data on the risk of gallstone formation during active weight loss. METHODS: All prospective studies published in the English language on the formation of gallstones in obese persons during active weight loss were reviewed and evaluated. A statistical analysis was performed using studies of at least 4 weeks' duration that included information on diet composition, rates of weight loss, length of follow-up, and incidence of gallstone formation. A statistical model was fit to the data from the studies that met the criteria. RESULTS: Nine subject groups derived from five published reports met the criteria for inclusion in the analysis. When the results of these groups were evaluated statistically, a curvilinear relationship between incidence of gallstone formation and rate of weight loss was demonstrated. The relationship was best described by an exponential regression curve, with an adjusted r2 of 0.98 and a dramatically increasing risk of gallstone formation at rates of weight loss above 1.5 kg per week. CONCLUSION: Risk of gallstone formation in obese persons during active weight loss seems to increase in an exponential fashion. The data suggest that rates of weight loss should not exceed an average of 1.5 kg per week. PMID- 7847428 TI - The relationship between systemic hypertension and obstructive sleep apnea: facts and theory. AB - This article provides an in-depth overview of the relationship between primary hypertension and adult obstructive sleep apnea syndrome. The background data and research are taken from the English-language literature through 1993. Primary hypertension is a common cause of major medical illnesses, including stroke, heart disease, and renal failure, in middle-aged males. Its prevalence in the United States is around 20%, with the rate of newly diagnosed hypertensive patients being about 3% per year. Sleep apnea syndrome is common in the same population. It is estimated that up to 2% of women and 4% of men in the working population meet criteria for sleep apnea syndrome. The prevalence may be much higher in older, non-working men. Many of the factors predisposing to hypertension in middle age, such as obesity and the male sex, are also associated with sleep apnea. Recent publications describe a 30% prevalence of occult sleep apnea among middle-aged males with so called "primary hypertension." Is this association fortuitous, related to a high prevalence of both diseases in the same population, or is it caused by a factor common to both diseases, such as obesity? Should the diagnosis of apnea be actively sought with sleep studies in hypertensive populations? If a diagnosis of "asymptomatic" sleep apnea is made in a hypertensive person, should the apnea be treated? Current research data provide only partial answers to these and other questions regarding the association of apnea and hypertension. Logic dictates that clinically symptomatic patients in hypertensive clinics should receive appropriate evaluation for apnea, but broad populations of hypertensive individuals should not be referred for sleep studies. PMID- 7847429 TI - Persistent lipolytic effect of exogenous growth hormone during caloric restriction. AB - PURPOSE: In previous studies in which obese volunteers were calorically restricted to 24, 18, or 12 kcal/kg of ideal body weight (IBW) per day, we observed that the growth-hormone-induced acceleration of body fat loss was variable and that the severity of caloric restriction modulated the magnitude of fat loss and the anabolic response to growth hormone. The present study was undertaken to characterize the effects of caloric restriction to 15 kcal/kg IBW per day on the metabolic response to growth hormone and to determine whether acceleration of body fat loss by growth hormone could be reproduced under conditions predicted to be optimal. PATIENTS AND METHODS: Eleven obese subjects were studied during two 38-day periods of caloric restriction. During one of these periods they received injections of growth hormone, 0.05 mg/kg IBW, for 28 days. Measurements of nitrogen balance, body fat content, insulin like growth factor I (IGF-I), free fatty acids, and glycerol concentrations were performed. RESULTS: Growth hormone injections caused an approximate 2.5-fold increase in IGF I concentrations so that the mean IGF-I concentration was significantly greater during the injections than during diet alone (growth hormone 69.3 +/- 29.3 nmol/L; diet alone 26.6 +/- 7.6 nmol/L; P < 0.001). Growth hormone also caused nitrogen sparing, and the mean daily nitrogen balance was significantly greater during the injections (growth hormone 36.9 +/- 121.1 mmol/day; diet alone -122.3 +/- 125.9 mmol/day; P < 0.001). This nitrogen-sparing response to growth hormone attenuated over the 4 weeks of the injections. Growth hormone had a persistent lipolytic effect manifested by increases in glycerol concentrations, and body fat loss was greater during injections than during diet alone (fraction of weight lost as fat during injections 0.77 +/- 0.07; diet alone 0.63 +/- 0.06; P < 0.001). CONCLUSION: We conclude that growth hormone exerts anabolic effects that attenuate over time during caloric restriction but maintains its lipolytic effect despite hyperinsulinism and results in accelerated fat loss. PMID- 7847431 TI - Warehouse workers' headache: emergency evaluation and management of 30 patients with carbon monoxide poisoning. AB - BACKGROUND: Carbon monoxide (CO) is the leading cause of fatal toxic inhalation in the United States, but the medical literature contains few reports of mass exposures. Warehouse workers' headache (WWH) is an infrequently reported form of CO poisoning due to industrial exposure. METHODS: We describe 30 persons who developed WWH after inhaling exhaust from a propane-fueled forklift, their emergency medical management at a small community hospital, and their long-term courses. RESULTS: Workers with more direct exposures to vented exhaust had significantly higher expired CO levels (21.1 +/- 0.7% versus 8.4 +/- 4.8%, P < 0.0001) and higher acute symptom scores (9.0 +/- 2.2 versus 4.7 +/- 3.3, P = 0.01) than persons with less direct exposures. Work location, expired CO levels, and acute symptom scores did not correlate with symptom scores 2 years after exposure. Workers experiencing acute difficulty concentrating or confusion had higher expired CO levels than persons with neither of these symptoms (16.3 +/- 6.7% versus 8.4 +/- 5.2%, P = 0.005) and developed higher chronic symptom scores (3.9 +/- 3.0 versus 1.1 +/- 1.5, P = 0.04), suggesting that this subgroup may require closer follow-up for long-term complications. CONCLUSION: With earlier recognition of ongoing CO toxicity, this disaster would likely have been averted. Since CO exposures are more common than is often recognized, general internists must be familiar with the manifestations of CO toxicity, its timely evaluation, management, and prevention. PMID- 7847430 TI - Cognitive function in patients with insulin-dependent diabetes mellitus during hyperglycemia and hypoglycemia. AB - BACKGROUND: To determine the impact of glycemic control, gender, and other relevant parameters on cognitive function during exposure to different blood glucose levels in patients with insulin-dependent diabetes mellitus (IDDM), we examined neuropsychologic function during experimentally induced periods of hyperglycemia and hypoglycemia. METHODS: We studied 20 men and 22 women, aged 18 to 44 years, with IDDM duration of 3 to 14 years and HbA1 values ranging from 5.8% to 18.0% (nondiabetic range 5.4% to 7.4%). We used a controlled experimental setting involving tests of sensory perceptual processing, simple motor abilities, attention, learning and memory, language, and spatial and constructional abilities at plasma glucose levels of 2.2, 5.6, 8.9, 14.4, and 21.1 mmol/L. Patients were blind to the glucose level. Tests used at each glucose level included reaction time (simple and choice), digit vigilance, trail making part B, word recall, digit sequence learning, and verbal fluency. RESULTS: All aspects of neuropsychologic function were diminished at 2.2 mmol/L when compared with basal levels of performance at 8.9 mmol/L, whereas no alterations were observed at 14.4 or 21.1 mmol/L. Tests involving associative learning, attention, and mental flexibility were the most affected during hypoglycemia. Glycemic control was not correlated with neuropsychologic function at any glucose level. Women demonstrated less of an impairment in neuropsychologic function than men at 2.2 mmol/L. CONCLUSIONS: Cognitive function in IDDM patients was generally well preserved even at substantially elevated blood glucose levels. Deficits in all relevant areas of cognitive function occurred during hypoglycemia (2.2 mmol/L), irrespective of prior glycemic control, and women with IDDM were less cognitively impaired than men with IDDM during hypoglycemia. PMID- 7847432 TI - A randomized trial of hydroxychloroquine in early rheumatoid arthritis: the HERA Study. AB - PURPOSE: Studies of the efficacy of hydroxychloroquine in rheumatoid arthritis have had methodological flaws and have failed to produce definitive results. The benefits and toxicity of hydroxychloroquine sulfate in 120 patients with rheumatoid arthritis of less than 2 years duration are assessed. PATIENTS AND METHODS: A 36-week randomized double-blind, placebo-controlled trial was conducted at two university centers and four community rheumatology private practices. Patients had to have had their disease for less than 2 years and to have never received a second-line drug. Patients were randomly assigned to receive hydroxychloroquine or an equivalent number of placebo tablets in a dose of up to 7 mg/kg per day (maximum 400 mg/day). The initial dose was half the maximum dose and, if after 2 weeks of treatment there had been no side effects, the full dose was prescribed. There were four a priori primary outcomes: (1) a joint index composed of the tender joint count, the swollen joint count, the grip strength, and the duration of morning stiffness; (2) a pain index composed of the pain dimension of the Arthritis Impact Measurement Scales (AIMS) and the visual analog pain scale of the Health Assessment Questionnaire (HAQ); (3) a physical function index composed of the HAQ, the physical disability dimension of the AIMS, and the McMaster-Toronto Arthritis Patient Performance Disability Questionnaire; (4) the psychological function subscale of the AIMS. Secondary outcomes included adverse events, patient and physician global assessments, hematocrit, erythrocyte sedimentation rate (ESR) and corticosteroid usage. An intent-to-treat analysis assessed improvement at 36 weeks by Student's t-test and average improvement over the course of the study by analysis of variance for repeated measures. RESULTS: Of 148 eligible patients, 120 were randomized. The characteristics of those randomized to hydroxychloroquine compared to placebo were similar at the study onset. At 36 weeks and over the course of the study there was statistically significant improvement in the joint index (P = 0.004, P = 0.034, respectively), the pain index (P = 0.007, P = 0.001, respectively), and the physical function index (P = 0.020, P = 0.011, respectively) in the group receiving hydroxychloroquine compared to the placebo group. There was no improvement in psychological function for hydroxychloroquine compared to placebo (P = 0.837 at 36 weeks, P = 0.89 over the course of the study). Among the secondary outcomes there was significant improvement only in the patient's (P = 0.01) and the outcome assessor's (P = 0.03) assessment of change and a trend towards a fewer number of intra-articular corticosteroid injections (P = 0.05) in the hydroxychloroquine-treated group. There were no important differences in the side effects between hydroxychloroquine or placebo. CONCLUSION: Over 36 weeks, hydroxychloroquine had a significant benefit on synovitis, pain, and physical disability of recent-onset rheumatoid arthritis, but did not benefit psychological function. PMID- 7847433 TI - Cytomegalovirus esophagitis in AIDS: a prospective evaluation of clinical response to ganciclovir therapy, relapse rate, and long-term outcome. AB - PURPOSE: Although cytomegalovirus (CMV) esophagitis is an important complication of acquired immunodeficiency syndrome, there has been little study specifically addressing the response to currently available antiviral therapy, relapse rate without maintenance therapy, and long-term outcome. PATIENTS AND METHODS: Over a 45-month period, 44 patients with CMV esophagitis established endoscopically and histopathologically were prospectively identified from among all human immunodeficiency virus (HIV)-infected patients undergoing endoscopy. Induction therapy consisted of intravenous ganciclovir at 10 mg/kg per day for approximately 14 days. Foscarnet was given at 60 mg/kg every 8 hours for nonresponders to ganciclovir. RESULTS: Of these patients, 35 completed induction ganciclovir therapy, resulting in a complete response in 17 (49%) and a partial response in 10 (29%), yielding a 77% overall response rate. Seven of 8 nonresponders were subsequently treated with foscarnet, with a clinical response seen in 5 patients. In the 18 eventual complete responders to ganciclovir or foscarnet followed up without maintenance therapy, 7 (39%) relapsed at a median of 4 months (range 2 to 18 months). In all cases, relapse was manifested by recurrent odynophagia. Reinduction ganciclovir therapy yielded a complete response in 1 patient and a partial response in 2, and induction foscarnet treatment resulted in a complete response in the other treated patients. During long-term follow-up, 1 complete responder developed CMV colitis with concurrent retinitis, and 4 other patients developed retinitis. The median survival after diagnosis was 8.2 months, although survival for greater than 1 year was seen in 4 patients. No patient died as a direct result of esophageal disease, although ulcer-related bleeding may have contributed to death in 2 patients with end-stage liver diseases and hepatic encephalopathy. CONCLUSIONS: CMV esophagitis has a favorable response to induction ganciclovir therapy, and a long-term remission may occur after induction therapy alone. Despite the favorable response to ganciclovir therapy, the long-term survival is poor, reflecting the severe immunodeficiency of these patients. PMID- 7847434 TI - The tolerance for zidovudine plus thrice weekly or daily trimethoprim sulfamethoxazole with and without leucovorin for primary prophylaxis in advanced HIV disease. California Collaborative Treatment Group. AB - PURPOSE: Trimethoprim-sulfamethoxazole (TMP/SMX) is the preferred agent for prophylaxis of Pneumocystis carinii pneumonia (PCP) in patients with HIV infection, but frequent adverse events limit its usefulness. Intermittent dosing and supplementation with leucovorin have been tried in attempts to improve tolerance. We evaluated these strategies in persons with advanced HIV disease. METHOD: One hundred seven patients were enrolled. All had HIV infection, < 200 CD4+ lymphocytes per mm3, and no history of PCP. Fifty-two were randomized to TMP/SMX twice daily (BID); of these, 26 were randomized to leucovorin with each dose. Fifty-five patients were randomized to TMP/SMX (BID) 3 times per week; of these, 27 were randomized to leucovorin with each dose. All patients took zidovudine concurrently. RESULTS: The 24-week risk of discontinuation due to protocol-defined limiting toxicity was 24% with thrice-weekly TMP/SMX versus 42% with daily TMP/SMX (risk ratio 0.4; 95% CI 0.2 to 1.0). The risks of discontinuation for any reason were 41% and 59% (risk ratio 0.4; 95% CI 0.2 to 0.8). Clinical toxicity, such as headache and gastrointestinal distress, accounted for the observed difference in tolerance between dosing regimens. The 24-week risk of discontinuation due to protocol-defined toxicity was 33% in both the leucovorin and non-leucovorin groups (risk ratio 1.1; 95% CI 0.5 to 2.5). The risks of discontinuation for any reason were 53% and 47% (risk ratio 0.8; 95% CI 0.3 to 1.7). CONCLUSION: Intermittent therapy with TMP/SMX BID thrice weekly is better tolerated than daily BID therapy. Leucovorin use does not improve tolerance for chronic TMP/SMX dosing in AIDS, even among patients taking tablets daily. PMID- 7847435 TI - Increase of myocardial inhibitory G-proteins in catecholamine-refractory septic shock or in septic multiorgan failure. AB - PURPOSE: The aim of the study was to investigate the mechanisms of myocardial catecholamine refractoriness in septic shock. METHODS: The inhibitory guanine nucleotide-binding proteins (Gi alpha) were studied with pertussis toxin labeling and radioimmunologically in myocardium from patients who died while in catecholamine-refractory septic shock and from patients who died of noncardiac disease. RESULTS: An increase by 62% (immunological Gi alpha) and 221% (pertussis toxin substrate) of myocardial Gi alpha was observed in patients with catecholamine-refractory shock compared with controls. The increases of Gi alpha were greater than those found in chronic heart failure reported earlier. CONCLUSIONS: An increase in the expression of Gi alpha could also be important in conditions other than chronic heart failure, eg, septic shock. An increase of Gi alpha could play a pathophysiologically relevant role in catecholamine refractoriness in septic shock and could provide a target for pharmacologic treatment in this condition. PMID- 7847436 TI - Chronic fatigue: risk factors for symptom persistence in a 2 1/2-year follow-up study. AB - BACKGROUND: The prolonged disability of patients suffering from chronic fatigue may be due to sustaining factors that are independent of the cause and subject to intervention. This study reexamined a cohort of patients with chronic fatigue to define medical and psychiatric predictors of persistent symptoms. METHODS: Seventy-eight patients with chronic fatigue present for 6 months or more (not required to meet the Centers for Disease Control case definition for chronic fatigue syndrome [CFS]) completed a self-report, follow-up questionnaire to measure the overall improvement or worsening of their condition at a mean of 2.5 years after their initial examination. At the time of initial evaluation, patients underwent a structured psychiatric examination, physical examination, laboratory studies, and self-report measures of psychological distress and functional disability. The psychiatric examination queried the patient about 28 somatic symptoms that are separate from those associated with CFS. Discriminant analysis was used to determine which variables present at the initial examination were significant predictors of persistent symptoms and disability at 2.5 years. RESULTS: The factors most important at the time of initial presentation in predicting persistent illness were: (1) more than eight medically unexplained physical symptoms separate from those associated with CFS case definition; (2) lifetime history of dysthymia; (3) duration of chronic fatigue symptoms greater than 1.5 years; (4) less than 16 years of formal education; and (5) age older than 38 years. None of the results of the initial physical examination, or immunologic, general laboratory, or viral antibody measurements were significant in predicting persistence of symptoms. Recovery rates for those who met the criteria for CFS by either of two case definitions were lower than the rate of noncases, but the differences were not statistically significant. The five aforementioned variables formed a significant discriminative function, correctly classifying 78% of those who recovered and 74% of those with persistent symptoms. CONCLUSIONS: At initial examination, patients with chronic fatigue, more than eight medically unexplained physical symptoms (excluding symptoms in the case criteria for CFS), a lifetime history of dysthymic disorder, longer than 1.5 years of chronic fatigue, less than 16 years of formal education, and who were older than 38 years were the most likely to have persistence of symptoms of chronic fatigue at the 2.5-year follow-up. PMID- 7847437 TI - Adverse effects of inhaled corticosteroids. AB - Inhaled corticosteroids are considered by many to be the anti-inflammatory therapy of choice in adult asthma, given their remarkable efficacy and apparent safety. They are presently being prescribed to more patients, at larger doses, and for longer periods of time than ever before. Oropharyngeal candidiasis and dysphonia are the most commonly recognized adverse effects of therapy, but these topical phenomena cause no significant morbidity and are easily managed. By contrast, there is now increasing concern about the potential systemic effects of inhaled corticosteroids. These putative effects may include adrenal suppression, bone loss, skin thinning, increased cataract formation, decreased linear growth in children, metabolic changes, and behavioral abnormalities. Changes in adrenal function have been noted in patients using medications such as beclomethasone dipropionate and budesonide in doses exceeding 1,500 micrograms/day. The clinical relevance of these changes has yet to be clarified. Several short-term and cross sectional studies have also revealed changes in biochemical markers of bone turnover and retrospective studies have found reduced bone density in asthmatics treated regularly with inhaled steroids. Long-term prospective studies assessing bone density changes remain to be done. Although much controversy exists, there is no unequivocal evidence that conventional doses of inhaled steroids significantly retard bone growth in children. Reports on skin changes, increased cataract formation, and behavioral changes are difficult to interpret because of several confounding factors. Although inhaled steroids should, at the present time, continue to be a recommended therapeutic option to all patients with symptomatic asthma, they should always be used in the lowest dosage compatible with disease control. PMID- 7847438 TI - A higher standard. PMID- 7847439 TI - Clinical staging system for acute pancreatitis. PMID- 7847440 TI - Clinical staging system for acute pancreatitis. PMID- 7847441 TI - Hemodialysis and the heart. PMID- 7847442 TI - Hypertension revisited after 55 years: how it has changed! PMID- 7847443 TI - Emanuel Libman and infective endocarditis: comments on the etiology of subacute infective endocarditis. PMID- 7847444 TI - 86 years of Buerger's disease--what have we learned? PMID- 7847446 TI - Adolescent medicine in pediatric practice: a survey of practice and training. AB - This study was designed to assess the relation between training in adolescent medicine, during and after residency, and self-reported practice of adolescent medicine. This is a cross-sectional study. A questionnaire was mailed to all members of the South Carolina Chapter of the American Academy of Pediatrics. After 2 mailings, 198 (83%) questionnaires were returned. Adolescent medicine training in residency was associated with more adolescent patients enrolled in a practice (P < 0.01) and more adolescent patient visits (P < 0.01) but not with an increase in perceived competence in the practice of adolescent medicine. Adolescent medicine continuing medical education was associated with seeing more adolescent patients and with increased competence in many areas, including contraceptives, suicide, and school problems (P < 0.05). training in adolescent medicine during and after residency is associated with treating more adolescent patients. Continuing medical education also is associated with increased perceived competence in areas related to adolescents. PMID- 7847445 TI - The Semmes-Weinstein monofilament as a potential predictor of foot ulceration in patients with noninsulin-dependent diabetes. AB - The objective was to evaluate the Semmes-Weinstein monofilament as a potential predictor of foot ulceration. A case-control study was carried out in a teaching hospital clinic specializing in diabetes and hyperlipidemic disorders. Two groups of patients with noninsulin-dependent diabetes mellitus were studied: 168 with no history of foot lesions (No-Ulcer group, aged 58.1 +/- 9.7 years, duration 11.5 +/- 7.8 years) and 14 who had at least one foot ulceration during the last year (foot ulcer group, aged 60.8 +/- 7.8 years', duration 17.1 +/- 10.5 years). The authors defined and measured a "monofilament index" using a size 5.07 Semmes Weinstein monofilament on three locations on each foot and then measured peroneal nerve current perception thresholds using the Neurometer at three frequencies: 5 Hz, 250 Hz, and 2,000 Hz. The monofilament index score was lower in patients in the foot ulcer group than in patients in the No-Ulcer group (1.71 +/- 2.36 vs 5.21 +/- 1.81, P < 0.001). A cutoff point at an index of 5 out of 6 yielded a sensitivity rate of 85.71% and a false-positive rate of 16.07%. The peroneal nerve current perception threshold was higher (P < 0.005) in patients in the foot ulcer group than in patients in the No-Ulcer group for all frequencies (605.8 +/- 414.6 vs 181.5 +/- 272.3 for 5 Hz; 743.2 +/- 361.7 vs 251.6 +/- 283.7 for 250 Hz; 859.4 +/- 220.2 vs 423.3 +/- 252.6 for 2,000 Hz). (ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7847447 TI - Discrimination between metachromatic leukodystrophy and pseudo-deficiency of arylsulfatase A by restriction digest of amplified gene fragments. AB - Mutations causing metachromatic leukodystrophy and pseudo-deficiency were detected in the arylsulfatase A gene by methods based on different wild-type and mutant restriction sites. After polymerase chain reaction amplification of fragments of the arylsulfatase A gene and digestion by the appropriate endonuclease, the mixtures were separated by polyacrylamide gel electrophoresis and visualized by ethidium bromide staining. The common splice mutation in intron 2 (459 + 1G-->A) causing, in homozygosity, late-infantile metachromatic leukodystrophy and the common missense mutation in exon 8 (P426L) causing, in homozygosity, adult or juvenile metachromatic leukodystrophy were found to abolish Bst NI and Aci I sites, respectively. The polyadenylation pseudo deficiency mutation (1619A-->G) was found to create a Mae III restriction site. The N-glycosylation pseudo-deficiency mutation (N350S) does not produce or destroy any known restriction site, and in this case, introduction of a single nucleotide mismatch in one of the primers enabled the authors to create a Bfa I site in the mutant allele. PMID- 7847448 TI - Molecular biology, virulence, and pathogenicity of mycobacteria. AB - The diseases resulting from infections with Mycobacterium species are important sources of morbidity and mortality throughout the world today, with particularly devastating effects in tropical and developing countries. Almost 2 billion people have been infected with Mycobacterium tuberculosis, the causative agent of tuberculosis, and approximately 3 million people die each year from this disease. Tuberculosis also has re-emerged as an important public health problem in the United States, and this resurgence has been accompanied by an increased incidence of tuberculosis resistant to the standardly used anti-tuberculosis drugs. Researchers' ability to investigate the molecular basis of the pathogenicity and drug resistance of the mycobacteria has been hampered by a lack of appropriate experimental tools. However, during the past 5 years, tremendous progress has been made in the development of the molecular biology of mycobacteria, and molecular tools are now available for detailed analysis of their genetics and for elucidation of the molecular mechanisms of their pathogenicity. The development of these tools is briefly reviewed, and the uses of the tools to investigate drug resistance in Mycobacterium tuberculosis, to identify mycobacterial virulence factors, and to explore intracellular survival strategies are described. PMID- 7847449 TI - Evaluation and treatment of erectile dysfunction. PMID- 7847450 TI - History of nephrology. Reports from the 1st International Conference on the History of Nephrology. Naples, Italy, October 28-30, 1993. PMID- 7847451 TI - Empiricism versus science in the teaching of nephrology. AB - Recent changes in medical courses in Italy reflect a recognition that both theoretical education and clinical practice are essential components of a doctor's training. These two parallel branches of medical education find their origins in the beliefs of Galen, mentor of medicine as a pure science, and of Alexander of Aphrodisias, promoter of the predominant role of empiricism. Neither a dogmatic nor an empiric approach to the study of medicine, however, is sufficient on its own. PMID- 7847452 TI - Monastic incorporation of classical botanic medicines into the Renaissance pharmacopeia. AB - Ancient Greek physicians believed that health resulted from a balance of natural forces. Many, including Dioscorides, made compilations of plants and medicines derived from them, giving prominence to diuretics, cathartics and emetics. During the Roman Empire, although Greek physicians were highly valued, the Roman matron performed many medical functions and magic and astrology were increasingly used. In Judaic and later Christian societies disease was equated with divine disfavor. After the fall of Rome, the classical Greek medical texts were mainly preserved in Latin translation by the Benedictine monasteries, which were based around a patient infirmary, a herb garden and a library. Local plants were often substituted for the classical ones, however, and the compilations became confused and inaccurate. Greek medicine survived better in the remains of the Eastern Roman Empire, and benefitted from the influence of Arab medicine. Intellectual revival, when it came to Europe, did so on the fringes of the Moslem world, and Montpellier and Salerno were among the first of the new medical centers. Rather than relying on ancient experts, the new experimental method reported the tested effects of substances from identified plants. This advance was fostered by the foundation of universities and greatly aided by the later invention of the printing press, which also allowed wider dissemination of the classical texts. PMID- 7847454 TI - Arabic medicine and nephrology. AB - During the Dark Ages following the fall of the Roman Empire, the Arabic world was instrumental in fostering the development of the sciences, including medicine. The quest for original manuscripts and their translation into Arabic reached its climax in the House of Wisdom in Baghdad, and the dissemination of the compiled texts was facilitated by the introduction of paper from the East. Foremost among the Arabic physicians were Rhazes, Avicenna, Haly Abbas and Albucasis, who lived during the period 950-1050 AD. Their writings not only followed Hippocrates and Galen, but also greatly extended the analytical approach of these earlier writers. The urine was studied and the function and diseases of the kidneys described. Despite the fact that experimentation on the human body was prohibited by religion, some anatomic dissection and observation seems to have been undertaken, and the pulmonary circulation was described by Ibn Nafis. Anatomic illustrations began to appear in Arabic texts, though they did not have the detail and artistic merit of those of Vesalius. PMID- 7847453 TI - Hippocratic medicine and nephrology. AB - The history of nephrology is a part of culture in general and should be treated not as a hobby or an isolated specialty of medical science, but as closely connected with medical education and everyday clinical practice. In the age of the apotheosis of renal biotechnology, medicine more than ever needs to combine Hippocratic messages with renal technologic achievements, in order both to restore quality of life in patients with renal disease and to bring harmony and balance to individuals impaired in body and soul. Indeed, Hippocratic medicine lies at the root of the development of clinical nephrology. Hippocratic writings have not lost their nephrologic interest, despite the enormous recent advances in renal technology. Today's practising nephrologist can still learn not only from Hippocratic clinical observations, but also from the prognostic thoughts, the ethical principles, the philosophic concepts and the humane messages of the 'father of clinical nephrology'. PMID- 7847455 TI - The biblical view of the kidney. AB - The biblical view of the kidney differs radically from the modern perception. For example, there is no reference in the Bible to the fact that the kidneys make urine. The kidneys were viewed as the seat of conscience and of ethical feelings and yearnings, and the source of mortality and ethical activity. The kidneys were believed to be associated with the innermost parts of the personality. There are references to God examining the ethical nature of man through the kidneys or punishing man by injuring the kidneys. The fat around the kidneys was considered to be of special value for sacrifice and may have symbolized luxury or opulence. Much of the biblical understanding of the anatomy of the kidneys and the anatomic relationships between the kidneys, perirenal fat and the liver appears to be derived from observations made in domestic animals. PMID- 7847457 TI - Nephrology from the middle ages to humanism: the Italian influence in Spain (12th 16th centuries). AB - The influence of medieval Italian medicine first reached Catalonia via Montpellier. Physicians from Salerno are known to have worked in Aragon, and many Italian medical and surgical texts circulated in Catalonia. By the end of the 15th century it was Valencia that maintained close ties with Italy, and in the 1st third of the 16th century, at the height of Renaissance humanism, the Castilian universities became the greatest Spanish patrons of medicine. Post Vesalian anatomists were active and many Castilian doctors were educated in Italy. In both medieval and Renaissance Spain the most commonly described renal pathology was lithiasis. The works of Joanes Jacobi (14th century) and Julian Guttierez (15th century) are outstanding, and foreshadow the monograph on lithiasis by Sanchez de Oropesa (16th century) and the work of Francisco Diaz, probably the greatest Spanish contributor to modern nephrology. He devoted 3 books of his collected professional experience to lithiasis, renal ulcers and sores, kidney inflammation and other processes including haematuria. His view of renal anatomy was totally modern, and he strongly advocated autopsy as a means of determining the cause of death. This underlines the new anatomopathological approach to investigation that was adopted in Renaissance Spain. PMID- 7847456 TI - Critical and historical approach to Theophilus' De Urinis. Urine as blood's percolation made by the kidney and uroscopy in the middle ages. AB - In classical Greek medicine, neither Hippocrates nor Galen considered the condition of the urine to be an important sign of systemic diseases, and they did not relate its characteristics to definite illnesses, except in obvious cases of urinary tract disease. In their teaching, urine was used together with other physical signs as a prognostic indicator. With Theophilus, however, uroscopy gained an important role, and the appearance of the urine became pathognomic of specific diseases. De Urinis owed its popularity to this new approach and to its didactic character, as it was written as a practical handbook. After the 12th century, De Urinis occupied an assured position among the few ancient medical treatises that in Latin translation formed a worldwide teaching canon for medieval and Renaissance medical schools. PMID- 7847458 TI - History of medicine and nephrology in Asia. AB - The beginning of Chinese medicine has been attributed to 3 mythical emperors who gathered herbs for medicines. During the 2nd century BC, Han dynasty physicians developed cranial trephining and sedation with wine and herbs for anesthesia. Chiang Chung-Ching (142-212 AD) used the appearance of rashes in diagnosis, treated infections with anthelmintics and asthma with ephedra, described the symptoms of diabetes mellitus and expanded medical ethics. The specialties of obstetrics, pediatrics, ophthalmology and dentistry were described in the records of the Han and Tang dynasties, and methods of setting fractures and treating trauma were comparable with those of Roman military doctors. Shen Tua (1031-1095 AD) compiled a pharmacopeia and studied acupuncture and the pulses. Forensic medicine was developed during the 10th century by Sung Tse, who also advocated hand washing with sulfur and vinegar to avoid infection during autopsies. The Daoist physicians used androgens and estrogens to treat hypogonadism with therapeutic preparations of placentas. They also had an advanced knowledge of alchemy, claiming to achieve 'immortality' by their preservation techniques. Qualifying examinations for physicians were conducted by the Chinese state as early as the 1st century AD, and later incorporated philosophy and art to conform with the Confucian ideal. Throughout these eras, Chinese medicine profited from contact with western Asia. In ancient Chinese medicine, the excretory function of the kidney was attributed to the bladder. 'Kidney weakness', which refers to somatized depression, was treated by acupuncture along the 'kidney channel'. Pulse examination was also used to give a measure of the imbalance of renal Yin and Yang.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7847459 TI - The Aristotelian kidney. AB - Aristotle incorrectly observed the absence of the kidney in fish and birds and deduced that it was not essential for the existence of a living organism. This underlies his observations on structure and function of the kidney. From examination of rhesus monkeys he generalized that the right kidney is higher than the left. Aristotle did not consider that the renal pelvis is divided by a filter membrane into 2 chambers, and wrote that no blood reaches the renal pelvis. The theory of the 'filter kidney' cannot thus be attributed to Aristotle. The function of the kidney was described as being to separate the surplus liquid from the blood inside the renal meat (not in the renal pelvis) and to transform this liquid into what Aristotle called residuum, i.e. the urine. Aristotle also considered that the kidneys acted to anchor the blood vessels to the body. He only briefly considered renal pathology. PMID- 7847460 TI - Maimonides: physician and nephrologist. AB - Maimonides (Moses ben Maimon) was born in 1135 in Cordoba, the son of a Jewish rabbi. After a seminomadic upbringing in Spain and North Africa during the rule of the Almohades, Maimonides settled in Fostate (Old Cairo), where he became renowned as a physician, eventually being appointed as court physician to Saladin and his son. Maimonides wrote both religious and medical treatises, the latter including the Medical Aphorisms of Moses in which he deals with almost all aspects of health and disease. His aphorisms on urine and the kidney were influenced by Galen, to whose contributions he added new dimensions. His aphorisms dealt with a variety of renal diseases recognized today. PMID- 7847461 TI - The Consilium ad Calcolum of Alberto de'Zancari. AB - Zancari was born in 1278 and practised medicine in Ravenna and Bologna. He is mentioned in the Decameron of Boccaccio and in court records of Bologna in connection with 4 of his students who were accused of exhuming a body for medical research. Zancari's writings are found in several manuscript versions and include commentaries on Galen and Consilium ad Calcolum, which deals with renal calculosis. His therapeutic rules are summarized in 74 lines and cover both acute and quiescent calculi and prevention. The treatments prescribed do not differ from those in general use at the time, nor are any new concepts introduced. PMID- 7847462 TI - The Medical School at Ravenna. AB - The existence of the Ravenna School of Medicine can be deduced from a codex in the Ambrosian Library of Milan, which contains Latin translations of 3 Hippocratic works and commentaries on 4 works by Galen. Although it was written in the 9th century, the codex appears to be a copy of an earlier work, probably 7th century. The Ambrosian commentaries follow other commentators on Aristotle, rather than the original Aristotelian works, and contain a number of misinterpretations. Nevertheless, the commentaries make it clear that the earliest literature in Salerno had its roots in the studies of classical medicine at the Ravenna School of Medicine, where the teaching was essentially Galenic in structure. PMID- 7847463 TI - Alexander Schumlansky's De structura renum. AB - The overall structural organization of the kidney, its vasculature and its excretory units, the nephrons, was the subject of intense study and disagreement for hundreds of years. In 1783, Schumlansky received a doctoral degree with the dissertation De structura renum, in which he presented a detailed and comprehensive description of the major blood vessels of the kidney, the blood vessels of the medulla and pyramids of Ferrein and the malpighian glandula. He concluded the dissertation with a description of 3 experiments on a pig kidney, deducing a connection between the glomerulus and the uriniferous tubule, though his illustration of it was far from convincing. It was only 59 years later that Bowman proved Schumlansky to be correct. PMID- 7847464 TI - Domenico Cotugno and his interest in proteinuria. AB - Cotugno (1736-1822) was the first to describe the presence of albumin in the urine of a patient with nephrotic syndrome, though he did not place much emphasis on this discovery, which is buried in his many other observations in anatomy, physiology, medical pathology and therapy. Cotugno was a well-known scholar of his time, though he came from a humble background and was largely self-taught. He gained a medical degree from the Salerno School of Medicine at the age of 20 years. He was a prolific researcher and writer, conscientious practitioner of medicine, and a collector of books and antiquities. Much of his library was lost after his death or burned by his wife for unknown reasons. PMID- 7847465 TI - Bizzozero and the discovery of platelets. AB - Bizzozero was born in 1846 and graduated in medicine at the age of 20 years. After working in Pavia for some years he was appointed Professor of General Pathology in Turin. Here he collaborated with many famous scientists in Italy and abroad. His interest in hematopoietic cells culminated in a description of platelets and their essential involvement in the blood clotting mechanism in vivo. Before Bizzozero's work, the description of platelets had been unclear, and both red and white cells were thought to be required for formation of blood clots. Although Bizzozero's discovery was disputed vigorously for several years, he was finally vindicated in 1892, unfortunately 1 year after his death. Apart from his extensive work, he bequeathed to science the benefit of his logical descriptions and rigorous experimental approach. PMID- 7847466 TI - The nature of life in the history of medical and philosophic thinking. AB - The vitalistic doctrine of Aristotle and Galen, in which the soul is an indissoluble part of the body, was undisputed throughout most of the Middle Ages. The first radical change came with Telesio, who developed philosophic naturalism in which the soul has a reality of its own, though it is connected to the body. The definitive change came with Descartes, who believed that all biologic phenomena can be explained by the laws of mechanics, and only man is distinguished by the possession of a soul. For the next 300 years, this mechanistic view would be challenged by a new vitalism, in which the 'vital force' has an existence in its own right. PMID- 7847467 TI - Carl Ludwig, Jacob Henle, Hermann Helmholtz, Emil DuBois-Reymond and the scientific development of nephrology in Germany. AB - Medical science in the 2nd half of the 19th century proceeded in a stepwise fashion, when the development of new techniques permitted the evaluation of living processes by direct microscopic or endoscopic inspection, as well as by quantitative measurements of the underlying physical and chemical forces. Ludwig, Henle, Helmholtz and DuBois-Reymond all contributed in different ways to the evolution of medicine and physiology into natural sciences, freed from romantic, philosophic speculation. Nephrology benefitted from this development and from the contributions of the non-nephrologists to natural science. PMID- 7847469 TI - The age-old spirit of nephrology from the oldest university in the world. AB - The University of Bologna began teaching in 1088, and the Faculty of Medicine was granted the same rights as lawyers in 1288, largely due to the reputation and teaching skills of Taddeo Alderotti. Among the other famous names associated through the ages with the Bologna School of Medicine are Malpighi, Valsalva and Murri. From the earliest times in Bologna, nephrologists attempted to show an interaction of the kidney with the outer environment (astronomy and astrology) and with other organs (anatomy) and an integration of the sophisticated structures within the kidney itself (microscopy). At the turn of the 19th century, the biochemical frontier was reached, and a new teaching methodology emphasizing careful consideration of all possible differential diagnoses was developed. PMID- 7847468 TI - Jacob Henle: the kidney and beyond. AB - The progress in science made by Henle depended on the improvements in light microscopy achieved in the 19th century. The advent of achromatic lenses in particular made it possible for Henle and his contemporary and friend Schwann to uncover the typical structures of cells, thus bringing order at the microscopic level to the world of living tissues. Henle's 'comprehensive' approach--4 basic types of tissue: epithelial, connective, muscular and nervous, contrasted with the accepted doctrine of Bichat of 21 different types of tissues that enter into different combinations in forming the organs of the body--together with rapid progress in chemistry and physics permitted the subsequent intimate probing of cellular physiology. Henle's work was not confined to the description of anatomic structures. After he had observed microorganisms in the excretions of diseased animals, he embraced the unpopular theory of 'contagion' as the source of infection, though he himself was not able to prove that microorganisms were the direct cause of diseases. His discovery of the renal tubule that now bears his name came comparatively late in his career, and although he described its structure in detail he offered no suggestions as to its function. PMID- 7847470 TI - John Bostock MD FRS (1773-1846): physician and chemist in the shadow of a genius. AB - John Bostock has a reasonable claim to being one of the first chemical pathologists. Most of his work was done before that of William Prout, with whom both he and Bright were in contact. Bostock's work was done about the same time as that of his friends and colleagues Marcet and Wollaston. Although other, notably Cruickshank, Wells and Blackall had previously studied the chemistry of normal and pathological urine, the breadth and detail of Bostock's observations were unprecedented, and he and Wells were the first to relate findings in the urine in disease to findings in the serum. Bostock, however, was the first to realize the relationship between the diminution of urea in urine as it rose (or in his terms, appeared) in the blood, while the albumin in the blood fell as that in the urine increased. PMID- 7847471 TI - John Blackall (1771-1860): failure to see the obvious in dropsical patients with coagulable urine? AB - Despite his success in publishing a book which was widely read and which drew attention to the fact that some cases of dropsy are associated with coagulable urine, John Blackall failed to make the link between this phenomenon and disease of the kidneys. Thus, to Richard Bright must go the credit for providing the critical understanding of the phenomenon. The single most probable reason for Bright's success and Blackall's failure was that Bright carried out post mortem examinations of almost all of his patients. In addition, Bright was ruthlessly systematic in documenting his autopsy findings, and not least was the fact that he possessed the rare talent of being objective in looking at his data, without being influenced by the preconceptions of the times. PMID- 7847472 TI - Joseph Jacob Plenck (1735-1807). AB - Joseph Jacob Plenck (1735-1807) is considered to be the forerunner of modern European dermatology, who also compiled a list of about 800 plants with medicinal uses. Of these about 115 have diuretic properties and are currently included in various pharmacopeias. They were traditionally used to cure ascites of various causes, in urolithiasis, nephritis, cystitis, bladder ulcers, strangury, urinary retention and incontinence. Few of these plants have been fully investigated by modern medicinal chemists, and many are worthy of further study. PMID- 7847473 TI - Beginnings of renal pharmacology and early conceptualization of diseases of the kidney. Introduction. PMID- 7847474 TI - Wizards and scientists: the pharmacologic experience in the Middle Ages. AB - During the Dark ages, Greco-Roman science survived in the eastern Roman Empire and the most important advances in pharmacology and pharmacy were made in Byzantium. As the Arab empires spread in the 7th and 8th centuries, they incorporated earlier learning, and the most important contribution of Arabic medical writers was probably the introduction of formularies to aid in the preparation of medicines. In turn, the later spread of Arabic knowledge to the West introduced little-known plants and fostered an interest in collecting and cultivating them, and also introduced the palatable dose forms preferred by the Arabic doctors. In the West, however, the Christian Church taught a doctrine of unquestioning faith, and despite the centers of learning, e.g. at Salerno, most ordinary people depended on the healing power of faith, religious relics and traditional folk medicine. Hydrology was also well developed in the Middle Ages. The formularia that survive describe many indigenous plants, but with few illustrations. Their gathering and preparation is generally guided by magic ceremonies and ritual, and plants often took their properties from their habitat, e.g. the wayside plantain was thought good for tired or wounded feet. Concepts of therapeutic plants were also influenced by alchemy and were linked to related metals and planets. PMID- 7847476 TI - Useful plants in renal therapy according to Pliny the Elder. AB - The Naturalis Historia of Pliny the Elder consists of 37 books, of which 16 are devoted to botany. About 900 plants are named, but many names are synonyms and identification is often impossible. Where identification is possible it is achieved by comparison of the actual names with the vernacular names in related languages or by indirect evidence from their medical use. In this way 130 plants used in renal therapy during Roman times can be identified. Many were eaten as part of the diet, and the distinction between medicinal and edible plants was not clearcut. Pliny was also the first author to comment that wild species are more active than cultivated ones. Most of the plants reported by Pliny are also mentioned by Dioscorides, and more than 30 of them were also listed by Plenck. Several are still quoted in modern pharmacopeias. PMID- 7847475 TI - Women, medicine and life in the Middle Ages (500-1500 AD). AB - The status of women in the Middle Ages was ambiguous, because although they had great responsibility and expertise in practical affairs they were viewed as chattel and inferior to men. They were skilled in cookery, often of highly spiced dishes using a variety of ingredients and flavorings, and they were taught the use of medicinal herbs. They were often skilled in simple first aid, though they were not allowed to practise outside the home. An important exception of this was Hildegarde von Bingen, whose Physica brought her great renown. In it she became the first woman to discuss plants in relation to their medicinal properties. For most people in the Middle Ages, treatment revolved around herbs and diet, together with faith and holy relics and the use of (forbidden) pagan incantation and ritual. Astrology was often a necessary adjunct to treatment. In Salerno, however, medicine had been practised from classical times, and medical training could last for 7 years or more. One of the greatest medieval medical texts is the Tacuinum Sanitatis, which describes in detail the 6 essentials for the preservation of man's health. Several vegetables and herbs are mentioned in connection with the kidneys, the picking and preparation of which are imbued with magic. PMID- 7847477 TI - Some plants described by Pliny for the treatment of renal diseases. AB - Pliny the Elder described medicinal plants in books XX-XXVII of Naturalis Historia, reporting the therapeutic properties and preparations of the plants for use in different parts of the body. An exhibition of 20 plants chosen from those indicated for renal diseases is described. PMID- 7847478 TI - Some plants described by Dioscorides for the treatment of renal diseases. AB - The original De Materia Medica of Dioscorides has been lost, but several copies remain. Unlike the original, these contain an alphabetical listing of plants and color plates. The source for the plants described in this paper is a 16th century translation into vernacular Italian and the Codex Neapolitanus. In all, 12 plants listed by Dioscorides for treatment of renal diseases can be positively identified. PMID- 7847479 TI - Diuretic plants in the paintings of Pompeii. AB - The plants that appear in the paintings and mosaics of Pompeii are chiefly edible and medicinal, though flowers with purely esthetic appeal are also shown. An important example is one of the floor mosaics from the House of the Faun, in which it is possible to identify lemon, cherry, strawberry, pomegranate, grape and olive, leaves of grape, fig, apple and olive, and flowers of corn cockle. The diuretic properties of some of these plants are mentioned in the Naturalis Historia of Pliny the Elder. A silver cup from the House of Menandro, one of the most refined examples of plant decoration in antiquity, shows olive branches and fruits. The presence of plants in such artefacts confirms that people of classical times were conscious that plants were important producers of food, oils, fibers, woods and medicines. PMID- 7847480 TI - A history of salt. AB - The medical history of salt begins in ancient times and is closely related to different aspects of human history. Salt may be extracted from sea water, mineral deposits, surface encrustations, saline lakes and brine springs. In many inland areas, wood was used as a fuel source for evaporation of brine and this practice led to major deafforestation in central Europe. Salt played a central role in the economies of many regions, and is often reflected in place names. Salt was also used as a basis for population censuses and taxation, and salt monopolies were practised in many states. Salt was sometimes implicated in the outbreak of conflict, e.g. the French Revolution and the Indian War of Independence. Salt has also been invested with many cultural and religious meanings, from the ancient Egyptians to the Middle Ages. Man's innate appetite for salt may be related to his evolution from predominantly vegetarian anthropoids, and it is noteworthy that those people who live mainly on protein and milk or who drink salty water do not generally salt their food, whereas those who live mainly on vegetables, rice and cereals use much more salt. Medicinal use tended to emphasize the positive aspects of salt, e.g. prevention of putrefaction, reduction of tissue swelling, treatment of diarrhea. Evidence was also available to ancient peoples of its relationship to fertility, particularly in domestic animals. The history of salt thus represents a unique example for studying the impact of a widely used dietary substance on different important aspects of man's life, including medical philosophy. PMID- 7847481 TI - Familial hypertension in Morgagni's De Sedibus et Causis Morborum per Anatomen Indagatis. AB - Morgagni was a contemporary of Malpighi, but unlike the latter he concentrated on macroscopic clinical and anatomic observations. His De Sedibus et Causis Morborum per Anatomen Indagatis consists of 5 books, written as letters to other scientists and members of foreign academies. He dealt with diseases of the head, the chest and the abdomen and with surgically treatable diseases. The final book contains corrections to the previous 4 in the light of new studies and extended clinical experience. One case history presented, of a patient of Valsalva's who died with edema and a bladder stone, can probably be considered as the first description of familial hypertension. From his clinical and autopsy investigations, Morgagni concluded that the patient died of hereditary bladder stone disease and apoplexy. PMID- 7847482 TI - Hypertension as cause and consequence of renal disease in the 19th century. AB - The pioneering work of Richard Bright, who introduced the concept of the renal origin of cardiovascular disease, initiated the continuous unfolding of knowledge on renal disease and its close interrelationship with arterial hypertension in the 19th century. Hypertension as a clinically and pathologically defined entity, however, was not established. The partial elucidation of the problem that the diseased kidney was sometimes the cause and sometimes the consequence of elevated blood pressure is not only fascinating but also remarkable, given the crude techniques available to physicians at that time. Subsequent workers came to regard 'Bright's disease' as consisting of several conditions differing in clinical manifestation and pathology. In particular, Johnson and Gull and Sutton drew attention to the small blood vessels in renal disease. Only the invention of a clinically applicable method of measuring blood pressure indirectly allowed Mahomed and Allbutt to show that hypertension may occur in the absence of renal disease. They paved the way for a clear separation of hypertensive renal disease from other forms of 'Bright's disease', culminating in the classification introduced by Fahr and Volhard. PMID- 7847483 TI - Clinical nephrology in 19th century Germany. AB - Bright's work led to the recognition that coagulable protein in the urine indicated macroscopic kidney disease. After light microscopy was introduced, Simon, Nasse, Henle and Frerichs identified the major constituents of urinary sediment. By 1896, Senator had deduced that hyalin cylinders arise in the kidney tubules, and only the discovery of the Tamm-Horsfall protein in the next century separated him from the modern concept. Chemical analysis of urine also advanced greatly. Recognition of the pressure-volume relationship by Traube was probably the most brilliant achievement related to renal disease, and became the basis of the later pressure-natriuresis relationship. Traube also linked left ventricular hypertrophy with renal disease, recognizing that it maintained circulatory homeostasis at a higher level of pressure. The concept of nephritis changed considerably with technical progress, and Gluge was the first to see inflamed Malpighian bodies or glomeruli. The primary site of damage was disputed by many, including Henle, Pfeufer, Virchow, Reinhardt and Frerichs, but all these workers had to reconstruct the sequence of events leading to the autopsy findings. The term glomerulonephritis was first coined by Klebs, and the classification of nephritis adopted by Senator in 1896 led directly to the classic monograph of Volhard and Fahr (1914) on Bright's disease. PMID- 7847484 TI - Luciano Armanni. AB - Luciano Armanni (1839-1903) worked as an assistant to Schron in Naples after graduating in medicine. He was later appointed as Professor of Histopathology, and in 1887 became a full professor. During his life he was Dissector of the Anatomic Institute of the Ospedale degli Incurabili and later director of this hospital. He founded many institutions, including the Cotugno Hospital, but died poor and suffering from diabetes mellitus and tuberculosis, contracted during a post-mortem examination. Armanni is given credit for discovering the contagious nature and specificity of the lesions due to caseous material in tuberculosis, and also the renal lesion in diabetes mellitus that now bears his name (Armanni Ebstein lesion). PMID- 7847485 TI - The history of urinary microscopy to the end of the 19th century. AB - In the 17th and 18th centuries, several authors performed urinary microscopy occasionally and were often unable to give their observations a practical diagnostic application. Such men included De Peiresc, Boerhaave, Ledermuller and Galeazzi. In the 1st half of the 19th century, however, urinary microscopy began to be used systematically. Rayer and Vigla identified for the first time elements other than crystals in urine and contributed to the methodology of handling samples for microscopy. Becquerel described dysmorphic erythrocytes, and Simon and Henle observed casts in urine and in histological preparations. In contrast, Bird mentioned casts only in passing, though he described many other elements and published the first complete book on urinary microscopy. The 2nd half of the 19th century was characterized by further advances, and in the book of Beale tubular cells were distinguished from other epithelial cells. Different types of casts were also linked with different renal diseases. By 1875 the classification of casts was complete. The work of the 19th century microscopists culminated in Rieder's book on clinical microscopy, which described each element of urinary sediment through 36 beautiful chromolithographic plates. PMID- 7847486 TI - Osmoregulation at the Zoological Station of Naples at the end of the 19th century. AB - The Zoological Station of Naples was founded in 1872 by Anton Dohrn as a research institute for zoology and comparative anatomy. Although the original fields of interest were the morphology of vertebrates and comparative embryology, a department of physiology was added to the station in 1888. Osmoregulation in marine organisms has been extensively studied, notably by Bottazzi, who investigated chemical composition, electrical conductivity, surface tension, osmotic pressure and extracellular viscosity in circulating fluids in man and lower animals. Bottazzi classified aquatic animals into 2 groups, a distinction that is accepted today. More recent workers at the station include Bern, who made important contributions to the study of the essential role played by prolactin in regulation of hydromineral metabolism in euryhaline teleost fish in a freshwater environment. PMID- 7847487 TI - Kidney and urologic disorders in the age of enlightenment. AB - The Enlightenment, a unique period in the history of Europe, was founded in the scientific and intellectual revolution of the 17th century. Renal anatomy and physiology advanced through the work of men like Eustachio, Malpighi, von Rosenstein and Cotugno, who described both normal and pathologic structures. Despite the earlier discovery of renal tubules and glomeruli, their anatomic and physiologic relationship remained unclear during the 18th century. The definitive explanation would not come until the work of Bowman and Bright in the 19th century. Similarly, the role of renal nerves would not emerge until the 19th century, when Claude Bernard elucidated their role in controlling urine flow in the dog. A key figure was Morgagni (1682-1771), who provided highly precise descriptions of a number of urinary tract anomalies and forms of obstructive nephropathy and developed many insights into renal pathophysiology by pure deductive reasoning. He gave a remarkably accurate description of the basis of reflux nephropathy and recognized that urinary calculi could have many etiologies. Lithotomy was performed as a last resort, and Cheselden reduced the mortality to 17% with a perineal approach; Baseilhac designed a new instrument to facilitate the suprapubic approach. Despite the high quality of men such as Morgagni, physicians had a reputation for quackery and rapacity, and most of their efforts met with little success. PMID- 7847488 TI - Johann Lukas Schonlein and his contribution to nephrology and medicine. AB - Schonlein published few papers, and most of what is known of his achievements in nephrology comes from notes and publications of his students. It seems, however, that he described the combination of rheumatic fever, affection of internal muscular organs, a typical exanthem and oliguria, coining the name purpura rubra to describe this syndrome. Although patients with symptoms of Schonlein's syndrome had been described earlier, Schonlein was the first to describe purpura rheumatica as an entity. Schonlein's greatest contribution was the discovery of the anthropophilic pathogenic fungus Trichophyton schonleinii as the cause of the contagious skin condition favus (honeycomb ringworm). This opened a new field- mycology--and allowed therapy to be aimed specifically at the cause of the disease. PMID- 7847489 TI - The urologic tradition of Preci. AB - The Preci School was not as well known as those of Salerno and Montpellier, and its members were often confused with quack doctors from nearby Cerretani who begged for alms for medical and religious foundations as a profession. The Preci School surgeons performed lithotomy, phlebotomy and castration, designing and making their own instruments, which were well ahead of their time and used by other surgeons only centuries later. Lithotrity was commonly employed using such tools, before it was known elsewhere. They practised cauterization and disinfection by fire. The Preci School was also familiar with differential diagnosis and uroscopy, which were essential before treating stone disease. The school came to an end after 1751, when a Papal edict declared that only surgeons with a degree could remove stones. PMID- 7847490 TI - Cultural links between Salerno and Montecassino. AB - A meeting on the History of Nephrology is an opportunity to discuss the links between science and faith which were split until the 6th century. However, this was changed by Cassiodorus and monasticism. From the times of Abbot Bertario (died 883 AD) in Montecassino, medicine was regarded as an art and a science. Codex 97 from Cassino offers a program of professional deontology, based on sensitivity, discretion, respect and responsiveness to the need of patients. PMID- 7847491 TI - The Salerno School of Medicine. AB - The cultural revival in Salerno was linked to Benedictine monasticism, with its main center at Montecassino. Historical evidence of the activity of the Salerno School of Medicine dates back to the 10th century, though the most productive period of the Salerno masters was in the 11th-13th centuries. The school's knowledge was broadened in the 12th century by the work of Constantinus Africanus, who translated many classical texts from Arabic into Latin. Circa Instans, a fundamental text on medicinal botany, was also produced by Mattaeus Platearius. Towards the middle of the 12th century, the school gradually became a theoretical center, rather than a primarily practical one, and many commentaries on earlier texts were produced. Uroscopy was pre-eminent in the teachings of Salerno, which was also one of the first medical centers to recognize the contribution of surgery to treatment. The precepts of the school were widely disseminated by the Regimen Sanitatis Salernitanum, which contained remedies for every occasion and advice on keeping healthy. PMID- 7847492 TI - Uroscopy in the Salerno School of Medicine. AB - Uroscopy was one of the basic diagnostic tests of the Salerno School of Medicine. The De Urinis of Magister Maurus was the work to which all urologic knowledge of the 12th and 13th centuries referred. His urologic doctrine was organized according to the theory of the 4 strata, and represented the extreme opposite from that of Cofone, according to whom the vital stream of urine expressed the depurative needs of the organs themselves. Salerno was also interesting in that it devoted as much attention to urology in women as in men, recognizing their fundamental role in the survival of the species. Unfortunately, much of the original work has become obscured by the many additions to the works of the masters and the spurious texts of lesser physicians. PMID- 7847493 TI - Codices on the art of medicine in the Montecassino Archives. PMID- 7847494 TI - Codex Casinensis 69: anonymi varia excerpta medica (saec. IX). PMID- 7847495 TI - Saliva test gets FDA approval. PMID- 7847496 TI - Using standardized forms. PMID- 7847497 TI - A place for placebos? PMID- 7847498 TI - Lesson about med errors. PMID- 7847499 TI - Freeing your patients from restraints. AB - New regulations and guidelines are pushing toward the goal of no restraints at all. Here's how to apply that ideal to the realities of acute care. PMID- 7847500 TI - Clinical snapshot: seizures. PMID- 7847501 TI - Kristine Gebbie. Interview by Marietta Lee. PMID- 7847502 TI - How to manage diuretic therapy. AB - All diuretics are not created equal. How they act, where they act, and how they interact with other drugs can make a big difference. Here are the ins and outs of diuretic therapy--and the crucial assessments you need to make. PMID- 7847503 TI - The nursing life: all in a day's leisure. PMID- 7847504 TI - Wound care. Selecting the right dressing. PMID- 7847505 TI - If we're lucky, the patient will complain. PMID- 7847506 TI - Emergency: recognizing torsade de pointes. PMID- 7847507 TI - Cultural diversity on the unit. PMID- 7847508 TI - Numbing. PMID- 7847509 TI - While Rome burns. PMID- 7847510 TI - Business cards at the bedside. AB - A three-inch business card may seem like a minor tool in a nurse's pocket. But it can be a powerful means of developing respect for the profession inside and outside the hospital. PMID- 7847511 TI - Exchanging gifts. PMID- 7847512 TI - The gynecologist and the prevention of cardiovascular disease. AB - This article reviews current concepts regarding the prevention of cardiovascular disease for women, with particular attention to modifiable risk factors. The background describes the magnitude of the problem, assesses the quality of the data with respect to risk factor reduction, and emphasizes several important concepts. Changes at menopause, states of endocrine aberration, and benefits and risks of hormone substitution need to be understood in conjunction with all other potentially modifiable and nonmodifiable cardiovascular risk factors. Primary care physicians have a window of opportunity to prevent this number one women's health problem. Integrating behavior modification is the key to prevention as part of the regular gynecologic visit. PMID- 7847513 TI - Is tubal ligation a risk factor for low bone density and increased risk of fracture? AB - OBJECTIVE: Osteoporosis is a major women's health problem, because it is responsible for about 1.3 million fractures in the United States each year. Estrogen deficiency is a major risk factor in the pathogenesis of osteoporosis. Recent evidence has indicated that tubal ligation may cause menstrual dysfunction and estrogen deficiency. This study examined the association between tubal ligation and bone mass in a group of elderly postmenopausal women. STUDY DESIGN: Subjects were 2215 white women > or = 65 years old participating in the Baltimore center of the Study of Osteoporotic Fractures. Bone mineral density of the proximal and distal radius and the calcaneus was measured by single photon absorptiometry. Multiple regression analysis was performed to determine whether tubal ligation had an independent effect on bone density. The effect of tubal ligation on the risk of hip and osteoporotic fractures was estimated by Cox proportional hazards model. RESULTS: Women who reported a tubal ligation had lower, although not statistically significant, bone density of the radius and calcaneus. The relative risk of hip (1.05, 95% confidence limit 0.84 to 1.32) and osteoporotic fractures (1.01, 0.80 to 1.29) was not significantly increased in women with tubal ligation. CONCLUSION: We conclude that elderly women who had a tubal ligation have small changes in bone density that are not of sufficient magnitude to increase their risk of osteoporotic fractures. PMID- 7847514 TI - Septate uterus: new idea on the histologic features of the septum in this abnormal uterus. AB - OBJECTIVE: Our purpose was to examine some of the classic concepts about the histologic features of the uterine septum. STUDY DESIGN: Four biopsy specimens were taken from 16 patients with septate uteri during Tompkins metroplasty: biopsy A from the septum near the serosal layer, biopsy B from the midpoint of the septum, biopsy C from the tip of the septum, and biopsy D from the left posterior aspect of the uterus away from the septum. Thirteen characteristics were examined in these specimens by means of mean ridit analysis and Bonferroni criteria for multiple comparisons in relation to connective tissues (four characteristics), muscles (four characteristics), and vessels (five characteristics). RESULTS: In the septum the mean ridit score was less for the amount of connective tissues (p < 0.001) and higher for the amount of muscle tissue (p < 0.025), amount of muscle interlacing (p < 0.05), and vessels with a muscle wall (p < 0.005). However, the Bonferroni criterion for multiple comparisons was only significant for the amount of connective tissue (p < 0.001). CONCLUSION: Our findings of less connective tissue in the septum, which was confirmed by the Bonferroni criterion for multiple comparisons and the mean ridit results for the three other significant findings, were contrary to the classic view about the histologic features of the septum. PMID- 7847515 TI - The role of color Doppler imaging in the diagnosis of polycystic ovary syndrome. AB - OBJECTIVE: Our purpose was to evaluate whether intraovarian and uterine blood flow variations are associated with clinical, ultrasonographic, and endocrine polycystic ovary syndrome findings. STUDY DESIGN: Thirty-two hirsute, oligomenorrheic patients and 18 volunteer women underwent in the early follicular phase ultrasonographic evaluation of ovarian volume, echodensity, and follicle number; transvaginal color Doppler measurement of the uterine and intraovarian vessel variations; and radioimmunologic dosage of luteinizing hormone, follicle stimulating hormone, estradiol, progesterone, testosterone, androstenedione, and other hormonal compartments. RESULTS: In the patients with polycystic ovary syndrome (increased luteinizing hormone/follicle-stimulating hormone ratio, elevated androstenedione levels, high number of subcapsular follicles by ultrasonography-augmented ovarian volume and echodensity) (n = 22) we observed, at Doppler analysis, significantly elevated uterine artery pulsatility index values associated with a typical low resistance index of stromal ovary vascularization. The pulsatility index was positively correlated with the luteinizing hormone/follicle-stimulating hormone ratio, and the resistance index was negatively correlated. The elevated uterine artery resistance was correlated with androstenedione levels. CONCLUSION: Doppler analysis can be a valuable additional tool for the diagnosis of polycystic ovary syndrome. PMID- 7847516 TI - Transdermal estrogen with a levonorgestrel-releasing intrauterine device for climacteric complaints: clinical and endometrial responses. AB - OBJECTIVE: Our purpose was to study the effects of intrauterine release of a daily dose of 20 micrograms levonorgestrel by an intrauterine device on climacteric symptoms, bleeding pattern, and endometrial histologic features in postmenopausal women receiving transdermal estrogen replacement therapy. STUDY DESIGN: Forty parous postmenopausal women were randomly allocated into two groups for 1 year: 20 women receiving a continuous transdermal daily dose of 50 micrograms of estradiol had a levonorgestrel-releasing intrauterine contraceptive device inserted, and the control group of 20 women received a continuous oral dose of 2 mg of estradiol valerate and 1 mg of norethisterone acetate daily. The climacteric symptoms, bleeding patterns, endometrial thickness, and endometrial changes in biopsy samples were analyzed. Serum levels of estradiol in both groups and levonorgestrel levels in the intrauterine device group were also determined. RESULTS: Both treatment regimens effectively relieved climacteric symptoms. Spotting was more common in the intrauterine contraceptive device group than in the oral therapy group for the first 3 months. After that, the proportion of women without any bleeding was similar in both groups. Two patients in each group dropped out because of bleeding. CONCLUSION: These preliminary findings suggest that the levonorgestrel-releasing intrauterine contraceptive device is a useful alternative mode of progestin administration for certain selected women receiving estrogen replacement therapy. PMID- 7847517 TI - Neurovascular injury during removal of levonorgestrel implants. AB - Injury to major neurovascular structures of the upper arm is a complication to be kept in mind, especially during difficult levonorgestrel implant removal. The risk of such an injury may be higher if the implants are inserted deeply over the brachial groove, where four major structures, namely, the basilic vein, the ulnar and median nerves, and the brachial artery, are located. PMID- 7847518 TI - The appendix as the cause of chronic lower abdominal pain. AB - The records of 63 patients who had appendectomy for chronic lower abdominal pain were reviewed. Histologically 92% of the removed appendices revealed abnormality, and 95% of these patients were completely cured. It is concluded that appendicopathy does exist and could be the cause of chronic lower abdominal pain. PMID- 7847519 TI - Transvaginal endoscopic oophorectomy. AB - Four women underwent transvaginal endoscopic oophorectomy during vaginal hysterectomy. The adnexa were visualized with a laparoscope inserted into the upper vagina. Bilateral salpingo-oophorectomy or oophorectomy was carried out with standard laparoscopic instruments introduced through the vagina without a pneumoperitoneum; Endoloop sutures and bipolar electrocoagulation were used for hemostasis. PMID- 7847520 TI - Pregnancies complicated by HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets): subsequent pregnancy outcome and long-term prognosis. AB - OBJECTIVE: Our purpose was to describe subsequent pregnancy outcome and long-term maternal prognosis in women with HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets) during the index pregnancy. STUDY DESIGN: This is a descriptive and analytic study of women with HELLP syndrome admitted to E.H. Crump Women's Hospital between August 1977 and July 1992. HELLP syndrome was defined by previously published laboratory criteria. Only patients who were delivered > 2 years ago were included (median 4 years, range 2 to 14 years). Data on these patients were obtained from our obstetric clinics, local physicians, local health departments, and hospital records. RESULTS: Adequate follow-up data were available on 341 patients. One hundred fifty-two women subsequently became pregnant. One hundred thirty-nine normotensive women had 192 subsequent pregnancies. Complications included preeclampsia (19%), preterm delivery (21%), intrauterine growth restriction (12%), abruptio placentae (2%), perinatal death (4%), and HELLP syndrome (3%). Seven of the 113 women with at least 5 years' follow-up (6.2%) had chronic hypertension, and 98 received oral contraceptive pills without complications. Thirteen women with preexisting chronic hypertension had 20 subsequent pregnancies. These women had a higher rate of preeclampsia (75%), preterm delivery (80%), intrauterine growth restriction (45%), abruptio placentae (20%), and perinatal death (40%) but a low rate of recurrent HELLP syndrome (5%). CONCLUSIONS: Women with HELLP syndrome have an increased risk of obstetric complications in future pregnancies but a low risk for recurrent HELLP syndrome. Oral contraceptive pills should not be contraindicated in normotensive women. PMID- 7847521 TI - Pyelonephritis in pregnancy: once-a-day ceftriaxone versus multiple doses of cefazolin. A randomized, double-blind trial. AB - OBJECTIVE: The purpose of this study was to compare the efficacy of a single daily dose of intravenous ceftriaxone with that of multiple-dose cefazolin in the treatment of acute pyelonephritis in pregnancy. STUDY DESIGN: This was a double blind, randomized, clinical trial. Patients admitted to the hospital with the diagnosis of acute pyelonephritis in pregnancy were enrolled and randomized according to a computer-generated randomization schedule. The study group received a single daily 1 gm dose of ceftriaxone intravenously along with two additional doses of normal saline solution. The comparison group received three daily 2 gm doses of cefazolin intravenously. All infusions were given on an 8 hour schedule. Treatments were continued until the patient became afebrile. Each patient was discharged from the hospital on a regimen of appropriate oral antibiotics as directed by urine culture and sensitivities. At follow-up visits test-of-cure cultures were obtained. RESULTS: During the 2-year study period, 178 patients were randomized: 88 received cefazolin and 90 ceftriaxone. Patient demographics and presenting signs and symptoms were similar in both groups. No differences were noted between the groups regarding days of febrile morbidity, length of hospital stay, or treatment failures. CONCLUSIONS: Daily single-dose intravenous ceftriaxone is as effective as multiple-dose cefazolin in the treatment of patients with acute pyelonephritis during pregnancy. PMID- 7847522 TI - Fetal fibronectin as a marker to predict the onset of term labor and delivery. AB - OBJECTIVE: We examined whether the presence of fetal fibronectin in cervicovaginal secretions may be a marker to predict the onset of term labor and delivery. STUDY DESIGN: A prospective study was performed in 100 primiparous and multiparous women having reached their expected date of confinement. Fetal fibronectin was assayed by taking samples of both the cervical and vaginal mucus with two different fetal fibronectin tests. The study population was divided into women delivering within 48 hours and women giving birth > 48 hours after sampling. RESULTS: Seven patients had to be excluded from evaluation. Of the remaining 93 women, 37 were delivered within 48 hours; fetal fibronectin was detected in 30. Fifty-six women were delivered later than 48 hours; 51 of them had negative results for fetal fibronectin (positive accuracy 86%, negative accuracy 88%, p < 0.0001). CONCLUSION: Fetal fibronectin in the cervicovaginal secretions of women who have reached their expected date of confinement is a useful predictor of the onset of term labor and delivery. PMID- 7847523 TI - The irritable uterus: a risk factor for preterm birth? AB - OBJECTIVE: Our aim was to determine the incidence and preterm delivery rate along with the indication for delivery in patients with uterine irritability. STUDY POPULATION: In this retrospective, descriptive study, 17,186 patients with well defined high-risk factors were compared with 2637 women with uterine irritability. RESULTS: The incidence of preterm labor in patients with uterine irritability was 18.7%, significantly less than in those with other high-risk factors (odds ratio 0.35, 0.31 < odds ratio < 0.38). However, women with uterine irritability who experience preterm labor, compared with other high-risk factors, are much more likely to deliver before 34 weeks' gestation (odds ratio 2.50, 2.07 < odds ratio < 3.03) and more than twice as likely to deliver as a result of advanced preterm labor or membrane rupture (odds ratio 2.20, 1.75 < odds ratio < 2.78). CONCLUSIONS: The incidence of preterm labor in women with uterine irritability is not as frequent as in patients with other high-risk factors. However, preterm labor does occur in patients with uterine irritability at a rate higher than that in the general obstetric population (18.7% vs 11.0%). Because it appears that women with uterine irritability have more resistance to conventional tocolytic therapy, this condition should prompt the physician to use more aggressive perinatal assessment. PMID- 7847524 TI - Progesterone: a critical role in the pathogenesis of uterine myomas. AB - Uterine leiomyomas are monoclonal tumors. However, the factors involved in their initiation and growth remain poorly understood. The neoplastic transformation of myometrium to leiomyoma likely involves somatic mutations of normal myometrium and the complex interactions of sex steroids and local growth factors. Traditionally, estrogen has been considered the major promoter of myoma growth. The purpose of this review is to highlight the biochemical, histologic, and clinical evidence that supports an equally important role for progesterone in the growth of uterine myomas. Biochemical studies suggest that progesterone, progestins, and the progesterone receptor modulate myoma mitotic activity. Several clinical trials demonstrate that progestins inhibit and/or reverse the ability of hypoestrogenism induced by a gonadotropin-releasing hormone agonist to shrink uterine myomas, suggesting a critical role for progesterone in growth of myomas. A new hypothesis to explain the pathogenesis of myomas is presented. PMID- 7847525 TI - Longitudinal measurement of amniotic fluid index in postterm pregnancies and its association with fetal outcome. AB - OBJECTIVE: Our purpose was to study the association between dynamic changes in serial amniotic fluid index measurements and adverse fetal outcome in postterm pregnancies. STUDY DESIGN: Serial amniotic fluid index values were obtained semiweekly in 139 reliably dated, uncomplicated, singleton pregnancies at > 41 weeks' gestation. Adverse fetal outcome was defined by the presence of moderate or thick meconium, fetal heart rate decelerations, cesarean delivery for fetal distress, neonatal intensive care unit admission, and perinatal mortality. RESULTS: Prominent changes in the amniotic fluid index (i.e., > 50% increase or decrease) had no association with adverse fetal outcome irrespective of rate of change, provided the final value remained > 5.0 cm. A significant association with fetal heart rate decelerations and the presence of meconium was detected only in patients whose final amniotic fluid index was < or = 5.0 cm (p = 0.007 and p = 0.003, respectively). CONCLUSION: Irrespective of the rate of change in amniotic fluid index, postterm pregnancies are significantly associated with potential complications such as fetal heart rate decelerations and meconium staining when the final amniotic fluid index is < or = 5.0 cm. PMID- 7847526 TI - Changes in protein C and protein S levels in normal pregnancy. AB - OBJECTIVE: The objective of the study was to determine the normal changes in the plasma concentrations of protein C and protein S that occur during each trimester of pregnancy. STUDY DESIGN: The study was a prospective cross-sectional study of 91 normal pregnant women who had plasma concentrations of protein C and protein S measured during the first, second, and third trimesters. RESULTS: There was no statistically significant change in antigenic or functional protein C levels during normal pregnancy. Total protein S levels also remained unchanged. Free protein S levels fell significantly from first to second trimesters (0.45 U/ml mean to 0.26 U/ml mean, p < 0.001), but no further fall occurred during the third trimester. CONCLUSIONS: The second-trimester fall in free protein S levels is a physiologic pregnancy adaptation. Women with a thromboembolic event appearing for the first time during pregnancy should have investigations for protein S deficiency delayed until the postpartum period, to avoid misdiagnosis and treatment. PMID- 7847527 TI - Fetal Doppler and behavioral responses during hypoglycemia induced with the insulin clamp technique in pregnant diabetic women. AB - OBJECTIVE: This study was undertaken to assess human fetal behavior and fetal blood flow after insulin-induced symptomatic maternal hypoglycemia of sufficient magnitude to elicit counterregulatory hormones and a symptomatic response. STUDY DESIGN: Plasma glucose was lowered from approximately 95 mg/dl to 45 mg/dl in decrements of 10 mg/dl every 40 minutes with the insulin clamp technique. In 10 insulin-dependent diabetic women in the third trimester, the fetus was studied by monitoring fetal heart rate and recording fetal body and breathing movements and by performing Doppler waveform analysis with real-time ultrasonography. Maternal levels of glucagon, cortisol, epinephrine, and growth hormone were measured at each plasma glucose level. RESULTS: The mean number of fetal limb and body movements at the start of the study was 25 +/- 16 per 15 minutes, which increased to a mean of 38 +/- 28 at a glucose level of 60 mg/dl and then declined to a mean of 23 +/- 10 at a glucose level of approximately 45 mg/dl. These changes, however, did not achieve statistical significance. In addition, no significant reductions in fetal breathing movements or heart rate were observed, although maternal epinephrine and growth hormone levels were significantly (p < 0.001) increased. No consistent changes in Doppler velocity waveforms were observed. CONCLUSION: These data suggest that fetal well-being remains unaltered in spite of moderate maternal hypoglycemia in diabetic women. PMID- 7847528 TI - Epidemiologic predictors of cesarean section in nulliparous patients at low risk. RADIUS Study Group. Routine Antenatal Diagnostic Imaging with Ultrasound Study. AB - OBJECTIVES: We sought to determine whether certain maternal and fetal characteristics influenced the risk of maternal- and fetal-indicated cesarean sections in pregnant women at low risk for adverse perinatal outcomes. STUDY DESIGN: From a cohort of 6393 low-risk nulliparous patients maternal and fetal indicated cesarean section rates with 95% confidence intervals were calculated and stratified by demographic, anthropometric, and clinical tests and measurements. The strongest risk factors were modeled by means of multiple logistic regression. RESULTS: Few risk factors distinguished maternal from fetal characteristics preceding cesarean delivery. Maternal age was associated with increased cesarean section risk in the tallest group of women only, and cesarean section rates decreased with increasing height, increased with higher prepregnancy weights, and was highest in women carrying male fetuses. Higher first prenatal visit diastolic blood pressure, increasing numbers of nonstress tests, > or = 2+ prenatal urine protein, late sonograms, geographic region, and practice type were statistically significant risk factors as well. Interestingly, results of prenatal visit tests and measurements contributed less to the prevalence of cesarean section than did age, fetal sex, and anthropometric parameters. However, the generalizability of these results is limited to low-risk (predominantly white) populations. CONCLUSIONS: Of the risk factors we were able to assess, a large proportion of the incidence of cesarean section in this population of nulliparous patients at low risk was attributable to age, sex of fetus, and anthropometric patient profiles. PMID- 7847529 TI - Renal elimination of ceftazidime during pregnancy. AB - OBJECTIVE: Our purpose was to study the pharmacokinetics of ceftazidime at different stages of pregnancy and in the nonpregnant state to determine whether glomerular filtration rate is altered and whether tubular secretions occurs. STUDY DESIGN: Twelve pregnant women with asymptomatic bacteruria were given a bolus dose of 400 mg of ceftazidime followed by a constant infusion for 4 hours. Inulin was infused simultaneously to determine glomerular filtration rate. Blood samples were drawn every 30 minutes. Urine was collected immediately after the bolus dose and then every hour. The same study procedure was then repeated twice: 2 weeks before the expected delivery and after termination of breast-feeding. RESULTS: At term clearance values were raised by 50% to 100% compared with the values found in the postpartum period. At all observation points a close correlation between inulin and ceftazidime clearance values were found. CONCLUSION: The results strongly indicate that ceftazidime is excreted exclusively by glomerular filtration with no tubular reabsorption. During pregnancy the excretion pattern is unaltered, but renal elimination is increased. PMID- 7847530 TI - Use of Norplant contraceptive implants in the immediate postpartum period: safety and tolerance. AB - OBJECTIVE: Our purpose was to determine the safety and tolerance of levonorgestrel contraceptive implants (Norplant, Wyeth-Ayerst, Philadelphia) when inserted immediately post partum, to document the effects on weight and blood pressure, and to determine the side effects. STUDY DESIGN: After vaginal delivery, 250 women were randomized to receive Norplant within 48 hours of delivery (study group) or at the 4- to 6-week postpartum visit (control group). Baseline measurements were recorded and compared with those obtained at the 4- to 6-week follow-up visit. A diary was maintained by patients who recorded bleeding and side effects. Statistical analysis was performed with t test and chi 2 analysis. RESULTS: There were no episodes of acute postpartum hemorrhage or clinically significant bleeding. Compared with the control group, the immediate group reported significantly more bleeding days (p < 0.01). There was no significant difference between the two groups in the hemoglobin values obtained at 4 to 6 weeks post partum. The immediate insertion group reported significantly more headaches (p < 0.01) and acne (p = 0.01). CONCLUSION: Norplant is well tolerated and should be available for interested patients immediately post partum. PMID- 7847531 TI - A case-control study of cocaine use in pregnancy. AB - OBJECTIVE: This study analyzed the relationships between cocaine use, various other parameters, and perinatal outcomes. STUDY DESIGN: A case-control study of cocaine use was conducted among pregnant women delivered at a large urban hospital in New Orleans, Louisiana. Two control patients for each case, matched for age, race, parity, and month of delivery, were selected. RESULTS: Between April and September 1990, there were 2332 admissions to the obstetric service; urine toxicology screens were obtained on 2225 patients. Cocaine metabolites were identified in 166 patients; 138 of these women had data that could be evaluated. These data were compared with those of 276 control patients, and the findings were analyzed. Complications that occurred significantly more often in study patients included vaginal bleeding, abruptio placentae, premature rupture of the membranes, meconium staining of the amniotic fluid, and low birth weight. Study patients were found to use prenatal care less often (45.0% vs 86.4%) and to smoke cigarettes more often (67.4% vs 35.1%). Regression analysis identified lack of prenatal care and smoking as important variables in birth weight. When these two variables were excluded, identifiable differences in bith weight between cocaine and control mothers were no longer present. CONCLUSION: The reduction in birth weight experienced by patients who used cocaine may be explained by lack of prenatal care and by smoking. Other identified differences observed between study and control patients were not significantly altered by smoking or prenatal care. PMID- 7847532 TI - Role of the sodium-calcium exchange mechanism and the effect of magnesium on sodium-free and high-potassium contractures in pregnant human myometrium. AB - OBJECTIVE: Periodic uterine relaxation in labor relieves the fetus from hypoxia related to sustained contractions. A reduction in intracellular calcium is essential for relaxation. Therefore we aimed to clarify the extrusion mechanisms of intracellular calcium ions in pregnant human myometrium. STUDY DESIGN: Isometric contraction of small muscle bundles obtained from human myometrium at term was recorded. High-potassium and sodium-free solutions could induce stable contractures that revealed initial phasic contractions followed by tonic contractions. The effects of external calcium, external magnesium, nifedipine, and calcium adenosine triphosphatase inhibitors on both contractures were then examined. RESULTS: Because maximum tonic contraction was induced by 48 mmol/L potassium, this concentration was used. Both contractures depended on external calcium concentrations. Nifedipine, 10(-7) mol/L inhibited both initial phasic contractions and the tonic phase of the high-potassium contracture; however, it could not suppress the tonic phase of the sodium-free contracture. Calcium adenosine triphosphatase inhibitors, cyclopiazonic acid and lauryl sulfate, potentiated the tensions of tonic phases in both contractures; the effect of lauryl sulfate was stronger than that of cyclopiazonic acid. When external magnesium was gradually increased (from 0 to 9.6 mmol/L), both phasic contractions and the tonic phase of the high-potassium contracture transiently increased, followed by a reduction of tension, whereas the tonic phase of the sodium-free contracture was markedly inhibited by magnesium in a dose-dependent manner. CONCLUSION: The presence of the sodium-calcium exchange mechanism and the specific inhibitory effect of magnesium were indicated in human myometrium during pregnancy. These mechanisms might prevent the long tonic contractions, to protect the fetus from hypoxia during pregnancy and parturition. PMID- 7847533 TI - The impact of cocaine and marijuana use on low birth weight and preterm birth: a multicenter study. AB - OBJECTIVE: Our aim was to evaluate prospectively the effects of cocaine and marijuana use on pregnancy outcomes. STUDY DESIGN: A prospective multicenter cohort study was conducted at seven university-based prenatal clinics in the United States from 1984 to 1989. The cohort described herein consisted of a multiethnic population of 7470 pregnant women. Information on the use of drugs was obtained from personal interviews at entry to the study and assays of serum obtained during pregnancy. Pregnancy outcome data (low birth weight [< 2500 gm], preterm birth [< 37 weeks' gestation], and abruptio placentae) were obtained with a standardized study protocol. RESULTS: A total of 2.3% of the women used cocaine and 11.0% used marijuana during pregnancy. Cocaine use was not associated with having a low-birth-weight infant (adjusted odds ratio 0.7, 95% confidence interval 0.4 to 1.3) or a preterm birth (1.3, 0.9 to 2.0). There was no association between short-term exposure to cocaine and preterm delivery (1.1, 0.3 to 4.0). However, cocaine use was strongly associated with abruptio placentae (adjusted odds ratio 4.2, 1.9 to 9.5). Marijuana use was not associated with low birth weight (1.1, 0.9 to 1.5), preterm delivery (1.1, 0.8 to 1.3) or abruptio placentae (1.3, 0.6 to 2.8). By comparison, 35% of the women smoked cigarettes during pregnancy, and cigarette smoking was positively associated with low birth weight (1.5, 1.2 to 1.8). CONCLUSIONS: In this population of women receiving prenatal care, cocaine use was uncommon and was not related to most adverse birth outcomes. Marijuana use was relatively common and was not related to adverse pregnancy outcomes. Tobacco is still the most commonly abused drug during pregnancy, 15% of all cases of low birth weight in this study could have been prevented if women did not smoke cigarettes during pregnancy. PMID- 7847534 TI - Sera of preeclamptic women are not cytotoxic to endothelial cells in culture. AB - OBJECTIVE: The null hypothesis of this study was that sera of women with preeclampsia are not cytotoxic to endothelial cells in culture. STUDY DESIGN: Endothelial cells were incubated in the presence of sera (30% vol/vol) of either preeclamptic patients (n = 11) or normal pregnant women (n = 11). Release of chromium 51 from prelabeled cells was measured after exposure to the different sera. Viability of the cells was evaluated by trypan blue exclusion and plating efficiencies. Deoxyribonucleic acid and protein synthesis were studied by measuring incorporation of tritiated thymidine and leucine into deoxyribonucleic acid and proteins, respectively. Cell growth was determined by monitoring the number of cells per culture dish during a 5-day incubation period. RESULTS: Release of chromium 51 from endothelial cells incubated in the presence of sera from preeclamptic women was similar to controls (26.3% +/- 4.7% vs 26.7% +/- 2.5%). There was no difference in the number of trypan blue-positive cells in cultures incubated in the presence of sera from preeclamptic women and controls. Seeding the cells in either sera from preeclamptic or control women gave the same percentage of attached cells. Similarly, preincubation of endothelial cells with either one of the two sera resulted in the same number of attached cells when they were reseeded (45% +/- 6% vs 40% +/- 15%, respectively). Incubation of endothelial cells with sera from preeclamptic or control women affected neither deoxyribonucleic acid nor protein synthesis of the endothelial cells. Furthermore, cell proliferation was similar in cultures incubated with sera from preeclamptic women and controls. CONCLUSION: No evidence was found that sera of women with preeclampsia are cytotoxic to endothelial cells in culture. PMID- 7847535 TI - Biochemical corroboration of endothelial involvement in severe preeclampsia. AB - This prospective, nested, case-control study investigated whether elevated plasma cellular fibronectin concentrations previously reported in preeclamptic women likely reflect endothelial dysfunction. In addition to higher maternal plasma concentrations of cellular fibronectin, we found higher levels of von Willebrand factor, tissue plasminogen activator, and plasminogen activator inhibitor-1 in maternal plasma, providing biochemical corroboration of endothelial dysfunction in severe preeclampsia. PMID- 7847536 TI - Climatic factors and preeclampsia-related hypertensive disorders of pregnancy. AB - Seasonal variations of temperature and humidity are said to influence the incidence of hypertensive disorders of pregnancy. Pregnant women with hypertensive disorders of pregnancy were assessed on the basis of temperature and relative humidity at diagnosis. Temperature variations with constant high humidity do not influence the incidence of preeclampsia-eclampsia-related hypertensive disorders of pregnancy. PMID- 7847537 TI - Percutaneous fetal cystoscopy and endoscopic fulguration of posterior urethral valves. AB - Percutaneous fetal cystoscopy was performed in a male fetus with ultrasonographic evidence of lower urinary tract obstruction at 19 weeks of gestation. The diagnosis of posterior urethral valves was confirmed. Percutaneous endoscopic fulguration of the valves was successfully performed at 22 weeks of gestation, and urethral patency was established. This case illustrates the feasibility of performing diagnostic and therapeutic endoscopic procedures within the human fetus for the management of a congenital anomaly. While we believe that fetal cystoscopy may improve our diagnostic, prognostic, and therapeutic capabilities in the management of fetuses with lower obstructive uropathy, studies are needed to establish the actual value, risks, and limitations of this new approach in fetal medicine. PMID- 7847538 TI - Third-trimester hyperechogenic bowel in Down syndrome. AB - The association between second-trimester hyperechogenic bowel and Down syndrome has been well established in the literature. In this report we present a case of Down syndrome in which this finding was only detected during the third-trimester scan, after normal bowel echogenicity was documented in the second trimester. This report suggests that hyperechogenic bowel could be a late manifestation of Down syndrome. PMID- 7847539 TI - Use of the Foley Cordostat grasping device for selective ligation of the umbilical cord of an acardiac twin: a case report. PMID- 7847540 TI - Salmonella abscess of the ovary. AB - A 13-year-old patient with an ovarian abscess caused by Salmonella paratyphi C1-7 had positive stool cultures for the same organism. She recovered after surgical removal of the abscess and intravenous antibiotics. PMID- 7847541 TI - Heterotopic quadruplet gestation with laparoscopic resection of ruptured interstitial pregnancy and subsequent successful outcome of triplets. AB - A heterotopic quadruplet gestation after in vitro fertilization and embryo transfer was complicated at 8 weeks by rupture of an interstitial pregnancy. Laparoscopic resection was performed and subsequently triplets were delivered at 34 weeks. To our knowledge, this is the first report of such a case. PMID- 7847542 TI - Case report of interferon alfa therapy for multiple myeloma during pregnancy. AB - Interferon alfa is broadly accepted as treatment for multiple myeloma, but its potential teratogenicity and mutagenicity during pregnancy in the human are still in dispute. We report a case of successful delivery after interferon alfa therapy for multiple myeloma during the first trimester of pregnancy. We reviewed the cases of interferon alfa treatment given during pregnancy for a malignancy and discovered that all of them have had successful deliveries and normal healthy babies. Additional studies should be encouraged to confirm the safety of interferon alfa therapy during pregnancy. PMID- 7847544 TI - Methyldopa hepatotoxicity in pregnancy: a case report. AB - A case of hepatotoxicity in a multiparous Native woman, who was begun on a regimen of methyldopa for control of chronic hypertension, is described. The patient was first seen for clinical evidence of hepatotoxicity approximately 3 weeks after initiation of treatment. At presentation the aspartate aminotransferase level was 1800 IU/L and alanine amniotransferase was 2415 IU/L. There was also a significant prolongation of clotting time, which required therapy. Resolution of symptoms occurred after cessation of the medication. Although methyldopa is considered to have a wide margin of safety in the treatment of chronic hypertension in pregnancy, potentially serious adverse effects can occur. It is important to monitor serum aminotransferase levels after initiation of methyldopa therapy. PMID- 7847543 TI - The Zavanelli maneuver for relief of abdominal dystocia associated with gastroschisis. AB - A patient with acute hydramnios and advanced preterm labor at 34 weeks was seen after gastroschisis had been diagnosed by second-trimester fetal ultrasonography. The fetus also had meconium peritonitis and acute ascites. The distended abdomen did not decompress spontaneously during the second stage of labor. Severe abdominal dystocia was resolved with the Zavanelli maneuver (cephalic replacement) and cesarean delivery. This is the first reported use of the Zavanelli maneuver for abdominal dystocia. PMID- 7847545 TI - Ultrasonographic diagnosis of uterine rent at 33 weeks' gestation with history of curettage. AB - A 30-year-old pregnant woman with a history of an uncomplicated curettage for incomplete abortion was seen at 33 weeks' gestation with decreased fetal movement and intermittent abdominal pain for 1 week. Ultrasonographic evaluation demonstrated a singleton vertex pregnancy, oligohydramnios, and a fundal uterine rent continuous with a large, fluid-filled cystic mass. Laparotomy revealed a right cornual uterine rent with hourglass amniotic sac and fluid. A healthy infant was delivered by cesarean section. PMID- 7847546 TI - Primary prevention of gynecologic cancers. AB - A shift from treatment to prevention of the three major gynecologic cancers is overdue. The traditional approach to cervical, endometrial, and ovarian cancers has been secondary or tertiary prevention--early detection and treatment or mitigation of damage, respectively. We reviewed the literature on these cancers to identify strategies for primary prevention. Cervical cancer behaves as a sexually transmitted disease. As with other such diseases, barrier and spermicidal contraceptives lower the risk of cervical cancer; the risk reduction approximates 50%. Combination oral contraceptives help prevent both endometrial and epithelial ovarian cancers. The risk of endometrial cancer among former oral contraceptive users is reduced by about 50% and that of ovarian cancer by about 30% to 60%. Weight control confers strong protection against endometrial cancer. Breast-feeding and tubal sterilization also appear to protect against ovarian cancer. Although women have a range of practical, effective measures available to reduce their risk of these cancers, few are aware of them. Without this information, women cannot make fully informed decisions about their health. PMID- 7847547 TI - [The etiology, concept and prevention of childbed fever. 1861]. PMID- 7847548 TI - Amniotic fluid volume assessment. PMID- 7847549 TI - Does the amniotic fluid index reflect actual amniotic fluid volume? PMID- 7847550 TI - Comment on the effectiveness of induction of labor for postterm pregnancy. PMID- 7847551 TI - Varicella in pregnancy: problems in management. PMID- 7847552 TI - Routine ultrasonography in pregnancy. PMID- 7847553 TI - Invasive fetal monitoring and human immunodeficiency virus transmission. PMID- 7847554 TI - Hemodynamic changes in fetuses with absent end-diastolic velocity in umbilical artery. PMID- 7847555 TI - Is maternal obesity a risk factor for open neural tube defects? PMID- 7847556 TI - Fetal and maternal plasma endothelin levels during the second half of pregnancy. AB - OBJECTIVE: Our objective was to evaluate maternal and fetal endothelin concentrations in uncomplicated pregnancies across the second half of pregnancy. STUDY DESIGN: Paired (n = 64) maternal venous and fetal umbilical venous or arterial samples were obtained during cordocentesis. In addition, eight neonatal umbilical vein samples were obtained immediately after delivery. Samples were assessed for hematocrit and pH, and concentrations of endothelin were measured by sensitive enzyme immunoassay. RESULTS: No significant correlation was found between either fetal or maternal endothelin levels and gestational age (r = 0.01, p = 0.91 and r = 0.07, p = 0.5, respectively). Fetal plasma endothelin concentrations were significantly lower than neonatal umbilical vein endothelin levels [median 2.5 pg/ml (range 0.9 to 5.73) vs 15.77 pg/ml (8.12 to 19.58), respectively; p < 0.0001] but significantly higher than maternal levels [1.3 pg/ml (0.8 to 3.25); p < 0.0001]. In addition, endothelin values were higher in the umbilical artery than in the umbilical vein, but this difference failed to achieve statistical significance [2.89 pg/ml (1.61 to 5.73) vs 2.29 pg/ml (0.9 to 5.70), respectively; p = 0.06]. No correlation was noted between fetal and maternal endothelin levels (r = 0.12, p = 0.36). CONCLUSION: Fetal endothelin levels were significantly higher than maternal levels, but neither correlated with gestational age across the second half of pregnancy. PMID- 7847557 TI - Crown-rump length in chromosomally abnormal fetuses at 10 to 13 weeks' gestation. AB - OBJECTIVE: Our purpose was to investigate whether fetuses with aneuploidies demonstrate evidence of growth retardation during the first trimester. STUDY DESIGN: This was a retrospective, cross-sectional study of singleton pregnancies undergoing fetal karyotyping at 10 to 13 weeks' gestation. Measurements of crown rump length in 135 chromosomally abnormal fetuses were compared with those in 700 chromosomally normal fetuses. RESULTS: The median crown-rump length of fetuses with trisomy 18 (n = 32) was significantly reduced. In contrast, in fetuses with trisomy 21 (n = 72), trisomy 13 (n = 11), 47,XXX (n = 6), 47,XXY (n = 6), 45,X (n = 5), and triploidy (n = 3) the crown-rump length was not lower than normal. CONCLUSION: At 10 to 13 weeks' gestation fetuses with trisomy 18 are growth retarded, whereas in trisomy 21, trisomy 13, and sex chromosome aneuploidy growth is normal. PMID- 7847558 TI - The T/QRS ratio of the electrocardiogram does not reliably reflect well-being in fetal lambs. AB - OBJECTIVE: Our purpose was to determine the diagnostic power of the T/QRS ratio of the electrocardiogram to predict fetal well-being. STUDY DESIGN: In 47 fetal lambs (3 to 5 days after surgery, gestational age 123.5 +/- 3.0 days) asphyxia was induced by restriction of uterine perfusion. Fetuses were either pretreated with an adenosine transport inhibitor (n = 16) or a calcium channel blocker (n = 12) or served as controls (n = 19). Arterial oxygen content > or = 1.5 mmol/L or pH > or = 7.15 were chosen as limits for fetal well-being. RESULTS: Arterial oxygen content was reduced from 3.3 (+/- 1.0) to 1.3 (+/- 0.5) mmol/L, and pH decreased to 7.03 (+/- 0.10). Mortality was 53%. Both drugs did not affect well being, survival, or the T/QRS ratio. Maximum T/QRS ratios were reached at the peak of asphyxia. Sensitivity and specificity of the T/QRS ratio were 24.0% and 42.6% to predict hypoxemia and 25.1% and 45.3% to predict acidemia. Pearson correlation coefficients for T/QRS ratio versus oxygen content and pH were 0.169 and 0.192, respectively. CONCLUSIONS: (1) In fetal lambs the T/QRS ratio failed to predict hypoxemia or acidemia. (2) Fetal survival was not correlated with the height of the T/QRS ratio during or after asphyxia. PMID- 7847559 TI - Confined placental mosaicism and intrauterine growth retardation: a case-control analysis of placentas at delivery. AB - OBJECTIVE: Our purpose was to determine the frequency of confined placental mosaicism in newborns with unexplained intrauterine growth retardation compared with infants with appropriate in utero growth. STUDY DESIGN: Amnion, chorion, and villi from 12 growth-retarded infants and 24 appropriately grown, matched controls were karyotyped. Fluorescence in situ hybridization with chromosome specific probes was then used to confirm the karyotypic abnormality at additional uncultured placental sites. RESULTS: Karyotype analysis revealed placental mosaicism involving either aneuploidy or polyploidy in three of 12 (25%) cases versus two of 24 (8.3%) controls. Fluorescence in situ hybridization confirmed the karyotypic abnormalities in the placentas from growth-retarded infants only. CONCLUSION: Confined placental mosaicism was identified three times more frequently from placentas of growth-retarded infants compared with those of newborns with appropriate growth. Molecular studies of the placentas suggested a wider distribution of cells with abnormal karyotypes in cases compared with controls and support a biologic influence of placental mosaicism on fetal growth. PMID- 7847560 TI - The fetal central venous pressure waveform in normal pregnancy and in umbilical placental insufficiency. AB - OBJECTIVE: Our purpose was to study the fetal central venous pressure waveform recorded noninvasively from the inferior vena cava in normal and complicated pregnancies by means of newly developed equipment to follow the vessel lumen diameter. STUDY DESIGN: A paired ultrasonic phase-locked loop echo tracking system with a high sampling frequency (3000 Hz) was used to follow the movement (point displacement) of diametrically opposite points of the vessel wall. The lumen was measured as the interval between these points. We studied 70 normal fetuses (20 to 40 weeks) and 54 complicated pregnancies with increased umbilical placental resistance. RESULTS: The four component waves of the central venous pressure waveform (A, X, V, Y) were identified and measured in the fetal recording. The crests of the A and V waves were of approximately equal height. An increase in the descent of the Y trough was observed with advancing gestation. By means of data from the normal group, the complicated group was divided into three subgroups. In 10 fetuses the waveform was normal. In 31 there was a high pulsatile pattern with deep descent from the A crest to X trough so that the pulsatility of the waveform appeared increased. In 13 this was shallow and the pulsatility appeared reduced. Clinical outcome (nonreactive fetal heart rate, percentile birth weight, days in neonatal intensive care unit) was significantly worse in both these latter two subgroups in comparison with normal and in the low compared with the high-pulsatile group. CONCLUSIONS: Human fetal central venous pressure waveforms can be simply recorded and represented by the transluminal diameter waveform. In fetal compromise the high pulsatility waveform may result from a reduced ventricular ejection and increased end-diastolic pressure in response to the increase in ventricular afterload caused by the placental vessel obliteration. In the most profoundly compromised fetuses the low pulsatility waveform may indicate depressed myocardial function and output. PMID- 7847561 TI - Neutrophil and monocyte beta 2-integrin expression in maternal and fetal blood. AB - OBJECTIVE: The aim of this study was to investigate fetal and maternal leukocyte beta 2-integrin expression throughout pregnancy. STUDY DESIGN: In a cross sectional study of 173 fetuses at 18 to 40 weeks' gestation, 114 women with normal singleton pregnancies at 6 to 40 weeks, and 25 adult volunteers, flow cytometry was used to determine neutrophil and monocyte expression of beta 2 integrins. RESULTS: The surface density of beta 2-integrins on fetal neutrophils and monocytes increased significantly with gestation, except for the expression of fetal monocyte CD11b, which did not change. There were no significant changes in maternal beta 2-integrin expression with gestation. During the third trimester fetal expression of CD18, CD11b, and CD11c on neutrophils and CD11b on monocytes was lower, and maternal expression of CD11a on neutrophils and CD18, CD11a and CD11c on monocytes was higher than were the control adult values. CONCLUSIONS: These data demonstrate that pregnancy is associated with changes in the expression of maternal beta 2-integrins and illustrate the pattern of immunophenotypic maturation of fetal beta 2-integrins on neutrophils and monocytes. PMID- 7847562 TI - Control of peripartal collagenolysis in the human chorion-decidua. AB - OBJECTIVE: This study was designed to observe the in vivo status of chorion decidua gene expression for some major metalloproteinases, an inhibitor (tissue inhibitor of metalloproteinase-1), and an activator (tissue plasminogen activator) and the hormone relaxin at accessible time points in the peripartal period. STUDY DESIGN: Chorion-decidua from patients at cesarean section with and without labor and after spontaneous labor and delivery was used for preparation of poly (A)+ ribonucleic acid and quantitative Northern analyses with a series of oligo and complementary deoxyribonucleic acid probes. RESULTS: In the period designated as the period before parturition, relaxin and matrix metalloproteinase 1 (interstitial collagenase) gene expression were relatively high, reflecting the controlled loss of amniotic collagen necessary for fetal membrane expansion without rupture as the uterine volume increases. When active labor has begun, but before delivery, matrix metalloproteinase-3 (stromelysin) and matrix metalloproteinase-9 (type V collagenase) gene levels significantly increased. After normal spontaneous labor and delivery, tissue plasminogen activator and tissue inhibitor of metalloproteinase-1 messenger ribonucleic acids significantly increased, together with a marginally increased expression of the genes for matrix metalloproteinase-1, matrix metalloproteinase-2 (type IV collagenase), and relaxin. CONCLUSION: The expression of the genes for some major collagenolytic enzymes, an inhibitor, activator, and relaxin in the chorion-decidua, is different at the different stages of parturition. PMID- 7847564 TI - Isolated fetal choroid plexus cysts and trisomy 18: a review and meta-analysis. AB - OBJECTIVE: Risk of trisomy 18 in a fetus with ultrasonographic diagnosis of choroid plexus cysts and no other anomalies is controversial. Using our data and current literature, we performed a meta-analysis and estimated the positive predictive value of isolated choroid plexus cysts for trisomy 18. STUDY DESIGN: Between Jan. 1, 1989, and Dec. 31, 1992, all women undergoing ultrasonographic examination at our institution were prospectively evaluated for fetal choroid plexus cysts and cytogenetic outcome. In addition, all reports dealing with fetal choroid plexus cysts obtained from MEDLINE (1983 through 1992) were assessed. Only prospective studies with > 10 cases of choroid plexus cysts were further evaluated to determine the total number of fetuses with choroid plexus cysts and otherwise normal sonograms. Frequency of aneuploidy was determined by analysis of our data and the included studies. To estimate the positive predictive value of choroid plexus cysts from trisomy 18, a theoretic 2 x 2 table was constructed with values available from the literature. RESULTS: Eighty fetuses with choroid plexus cysts were identified in our unit. Of 74 fetuses with isolated choroid plexus cysts, there were no cases of trisomy 18. Meta-analysis identified 2 cases of trisomy 18 among 748 fetuses with isolated cysts (1/374). To derive a positive predictive value of isolated choroid plexus cysts for trisomy 18, we reviewed the literature and found a total of 50 fetuses with trisomy 18 who underwent ultrasonographic examination in the midtrimester. There were 3 cases of isolated choroid plexus cysts, and 12 of 50 (24%) had otherwise normal ultrasonographic results. Using a midtrimester incidence of 1 in 2461 for trisomy 18 (Hsu LYF. In: Milunsky A, ed. Genetic disorders of the fetus. 3rd ed. Baltimore: Johns Hopkins University Press, 1992: 155-210; Hook et al. Am J Hum Genet 1989; 45:855-61) and a prenatal prevalence of 0.95% for choroid plexus cysts (based on a review of the literature), we obtained a positive predictive value of 1 in 390. CONCLUSION: On the basis of the risk for trisomy 18 obtained from our meta-analysis (1/374) and its close approximation to the estimated positive predictive value (1/390), our data do not support the routine offering of invasive prenatal cytogenetic testing in cases of isolated choroid plexus cysts. PMID- 7847563 TI - The action of two natriuretic peptides (atrial natriuretic peptide and brain natriuretic peptide) in the human placental vasculature. AB - OBJECTIVE: Our purpose was to compare the actions of atrial natriuretic peptide and brain natriuretic peptide in the human placental vasculature. STUDY DESIGN: Isolated placental cotyledons were dually perfused with fetal perfusion pressure used as an index of vascular response. The effect of angiotensin II (10(-10) to 10(-6) mol/L bolus injection) was established in the absence or presence of atrial natriuretic peptide (10(-8) mol/L) or brain natriuretic peptide (10(-8) mol/L final concentration). The role of nitric oxide as a mediator of natriuretic peptide action was investigated by perfusion of n-nitro-L-arginine (10(-3) mol/L), an inhibitor of nitric oxide synthase. Attenuation of the action of atrial natriuretic peptide by placental peptidases was studied by perfusion with the peptidase inhibitor benzamidine (2 x 10(-2) mol/L). Statistical significance was determined by analysis of variance and paired t test. RESULTS: Significant attenuation of vasoconstrictor responses to angiotensin II occurred within both atrial natriuretic peptide and brain natriuretic peptide; however, brain natriuretic peptide was more effective. n-Nitro-L-arginine did not affect the attenuation of angiotensin II-induced vasoconstriction by atrial or brain natriuretic peptides. In the presence of benzamidine atrial natriuretic peptide exerted a significantly greater vasodilator effect. CONCLUSION: Brain natriuretic peptide is a more potent vasodilator of the placental vasculature than is atrial natriuretic peptide. The low efficacy of atrial natriuretic peptide may be related to placental peptidases. Nitric oxide does not mediate the action of atrial natriuretic peptide or brain natriuretic peptide. PMID- 7847565 TI - Onset of menopause in women exposed to diethylstilbestrol in utero. AB - OBJECTIVES: As part of a larger health survey, we sought to determine whether prenatal exposure to diethylstilbestrol is associated with onset of early menopause or menopausal symptoms. STUDY DESIGN: Diagnosis of premature ovarian failure and symptoms of menopause were determined in a telephone interview with 542 women whose mothers participated in a randomized clinical trial of the use of diethylstilbestrol in pregnancy in the early 1950s. These women were aged 37 to 39 at the time of the interview. Medical records were obtained to confirm diagnosis of premature ovarian failure. RESULTS: The prevalence of menopausal symptoms (specifically hot flashes and night sweats) did not differ for exposed and unexposed women. One exposed woman and no unexposed women had a medically confirmed diagnosis of premature ovarian failure. CONCLUSIONS: Prenatal diethylstilbestrol exposure was not related to diagnosis or symptoms of menopause in this study. Further follow-up will be necessary to determine if a difference in age at menopause emerges as these women become older. PMID- 7847566 TI - Recipient's age does not adversely affect pregnancy outcome after oocyte donation. AB - OBJECTIVE: Our purpose was to examine the effect of the recipient's age on pregnancy and miscarriage rates after oocyte donation. STUDY DESIGN: A retrospective analysis of 307 consecutively performed donor oocyte cycles was undertaken. Recipients were divided into two groups: younger group < or = 42 years old (165 cycles) versus older group > 42 years old (145 cycles). Pregnancy outcomes between groups were compared. Confounding variables such as donor and cycle characteristics, recipient characteristics, and male parameters were also examined. RESULTS: Both groups had the same incidence (6%) of failed fertilization cycles. At least one embryo was transferred in the remaining 286 cycles. Ongoing or delivered pregnancy rates per embryo transfer were similar for younger and older groups (30.2% vs 30.6%). Differences in miscarriage rates were not statistically significant (9.8% vs 16.3%). There were no differences in the cycle parameters related to donor age, number of oocytes aspirated, number of oocytes fertilized, and number of embryos transferred. Donor sperm was more frequently utilized in the older group (19 vs 4 cycles, p = 0.0002). In the remaining cycles male partners of older recipients were significantly older (37.9 +/- 0.5 years vs 43.9 +/- 0.6 years, p < 0.0001), but there were no differences in semen parameters or fertilization rates. Older recipients were more likely to be parous but also to have experienced a previous miscarriage. CONCLUSION: Recipient age does not adversely affect cycle outcome with donor oocytes. This implies that aging of the uterus is not of clinical significance to patients electing this method of infertility treatment. PMID- 7847567 TI - Antisocial disorders in hyperactive subjects from childhood to adulthood: predictive factors and characterization of subgroups. AB - A comprehensive chart review of 66 hyperactive patients, who were followed prospectively for 15 years at five-year intervals, identified four subgroups in the developmental course of antisocial behavior in adulthood: those who never presented with antisocial problems, those with continuing antisocial problems from childhood to adulthood, those who showed initial antisocial behavior that did not continue, and those who exhibited antisocial behavior initially and in adolescence, but not in adulthood. PMID- 7847568 TI - A comparison of boys and girls with attention problems: kindergarten through second grade. AB - In a nonclinical sample of boys and girls, gender-based norms were used to identify children at risk for academic and behavior problems and to differentiate those with from those without attention problems. At-risk children with attention problems were rated higher on behavior problems, demonstrating significant increases in such problems from kindergarten to second grade, and scored significantly lower on simultaneous processing tasks. Both at-risk groups performed below a not-at-risk control group on reading achievement. PMID- 7847569 TI - Risk and protective factors for disruptive behavior disorders in children. AB - Biological, psychological, and social risk and protective factors in the development of disruptive behavior disorders were assessed in 50 disordered and 50 control preadolescents. Significant risk factors included learning difficulties, hyperactivity, perinatal complications, and violence in the home. Significant protective factors included ability to express feelings and a good relationship with grandparents. PMID- 7847570 TI - Children at risk: fostering resilience and hope. AB - A number of children, many with ADHD and learning disabilities, are at high risk for developing long-lasting problems affecting many areas of their lives, including their social relationships, academic and later professional success, tolerance of frustration and failure, and self-esteem. Factors that contribute to resiliency in these high-risk children are examined, and implications for interventions to enhance their lives are discussed. PMID- 7847571 TI - Psychosocial coping resources in elementary school-age children of divorce. AB - The psychosocial coping resources of elementary school-age children living in the sole custody of a divorced single parent were compared with those of their peers living with nondivorced parents. Children of divorced parents were found to have lower levels of self-efficacy, self-esteem, and social support, and less effectual coping styles. Contact with the noncustodial parent was found to have a positive influence on their attitudes toward divorce. PMID- 7847572 TI - From paternalism to partnership: family and professional collaboration in children's mental health. AB - A survey of 455 caregivers of children with severe emotional disorders identified four empirically distinct dimensions of collaboration between mental health professionals and the children's family members. Characteristics of families, professionals, and the service delivery process associated with the dimensions are examined, as is the relationship between collaboration and family satisfaction. PMID- 7847573 TI - Clinical, sociodemographic, and systems risk factors for attrition in a children's mental health clinic. AB - Clinical, sociodemographic, and systems risk factors for attrition at a child guidance clinic were identified. All patients who completed the intake process were followed through various clinic phases. Lower socioeconomic status and low family cohesion predicted dropout. Dropouts and continuers were equally psychiatrically impaired. The Family Environment Scale was the only standardized measure that distinguished between dropouts and continuers. PMID- 7847574 TI - Psychological correlates of help-seeking attitudes among children and adolescents. AB - A self-report measure of attitudes about seeking help from adults for psychosocial problems was administered to approximately 200 children and adolescents. More negative help-seeking attitudes were associated with male gender, adolescence, depressive symptomotology, and lower self-efficacy. Implications for effective delivery of mental health services to at-risk youth are discussed. PMID- 7847575 TI - Preventive intervention groups for parentally bereaved children. AB - A model of time-limited intervention groups for parentally bereaved children is described, and common emergent themes are discussed. These suggest that youngsters continue to struggle with death-related stress well beyond the time of the loss. The need to maintain an emotional attachment to internal representations of the deceased parent appears to be an important component of the bereavement process. PMID- 7847576 TI - Impact of parental terminal cancer on adolescents. AB - Psychological and emotional concerns of adolescents during a parent's terminal cancer are described. Compared to younger children, the adolescents' greater cognitive and emphatic capacities allowed them to be more aware of losses and of the parent's physical and emotional pain. Parental illness also precipitated conflict around issues of developmentally appropriate separation. The capacity to use intellectual defenses, search for meaning and deeper understanding, and seek help were potent coping abilities. Contrary to the prevailing view, most of the adolescents coped with stress without resorting to severe acting out. PMID- 7847577 TI - Psychotherapist reactions to the suicide of a patient. AB - A patient's suicide may evoke the therapist's personal grief and influence professional competence or suicide prevention skills. The incidence of suicide by patients in therapy is examined and empirical studies of therapist response- which commonly includes grief, guilt, self-blame, anger, fear, and self-doubt- are reviewed. Bereavement theories and support programs are described. PMID- 7847578 TI - Adaptive and maladaptive aspects of dependency: an integrative review. AB - Although dependence in adults has typically been viewed as a flow or deficit in functioning, a review of the literature reveals that high levels of dependency are associated with both positive and negative qualities on the part of the dependent person. Studies confirming this association are discussed, along with the theoretical and practical implications of their findings. PMID- 7847579 TI - The early psychological tasks of marriage: Part I. AB - To build a gratifying and enduring marriage, couples must address and resolve seven psychological tasks during the early years of the marriage and again at the milestones of the adult life course. The formulations of the tasks are described in this preliminary report of a longitudinal study of 50 happy marriages. PMID- 7847580 TI - Social-psychological dilemmas and coping of atomic veterans. AB - Memories and perceptions of exposure to radiation were explored in open-ended interviews with 16 atomic veterans. Findings suggest that resolution of these events involves emotional and cognitive processing of a new perspective that is in contradiction with prior beliefs. PMID- 7847581 TI - Physician assistant training for Native Alaskan community health aides: the MEDEX Northwest experience. AB - BACKGROUND-From 1980 through 1990, 16 Native Alaskan Community Health Aides and 21 non-Native Alaskans began physician assistant training at MEDEX Northwest at the University of Washington. This study was done to assess the outcome of training Native Alaskan health workers as physician assistants, specifically whether Native Alaskan graduates are working in settings that serve Alaska Natives. METHODS-The backgrounds, educational experiences and deployment locations of Native and non-Native Alaskans accepted for training were compared using MEDEX Northwest student records. The 1991 graduate survey was used to compare differences in practice setting, specialty and salary between Native and non-Native graduates working in Alaska in 1991. RESULTS-All of the non-Natives and 81% of the Natives completed the program. Of those completing the program, 100% of the Natives returned to Alaska where 91% found work as primary care physician assistants in clinics serving predominantly Native communities. By comparison 78% of the non-Native graduates returned to Alaska to work as physician assistants, 60% of them in primary care and 15% of them in predominantly Native communities. There were no significant differences in salary or benefits between Native and non-Native graduates. CONCLUSIONS-Physician assistant training for entry level health workers is a viable strategy for increasing the number of under-represented minorities in the health professions. The Native graduates of MEDEX Northwest are returning to communities where they serve Native people both as health care providers and as professional role models. PMID- 7847582 TI - Nursing staff educational preparation and patient inflicted injuries in a 160 bed psychiatric hospital. AB - This is a retrospective study of the incidence and severity of patient inflicted injuries upon nursing staff in a 160 bed psychiatric hospital over a period of two years. The investigation explored possible relationships between the basic educational preparation of the injured staff members, the severity of their injuries, and whether they used the behavior management techniques learned in the Mandt System classes. (The Mandt System has been used at Alaska Psychiatric Institute since 1979 to train nursing staff in how to safely deal with assaultive people.) PMID- 7847583 TI - Epinephrine for anaphylaxis. PMID- 7847584 TI - Rx for health care costs: resolving addictions in the general medical setting. AB - The literature on addictions treatment cost offsets suggests that resolving addictive disorders in the general medical setting will drive down the demand for health care, promote more efficient use of care by both patients and their families, and preserve scarce resources that can be deployed more wisely elsewhere. The demand to reduce waste and trim health care expenditures challenges the historic gulf between general medical practice and the management of addictive behaviors. An example of an addiction treatment technology developed in medical settings for use by medical personnel, brief intervention, is reviewed, with reference to its cost-saving potential under health care reform. PMID- 7847585 TI - Alcohol and magnesium. Introduction to the symposium. PMID- 7847586 TI - Role of magnesium and calcium in alcohol-induced hypertension and strokes as probed by in vivo television microscopy, digital image microscopy, optical spectroscopy, 31P-NMR, spectroscopy and a unique magnesium ion-selective electrode. AB - It is not known why alcohol ingestion poses a risk for development of hypertension, stroke and sudden death. Of all drugs, which result in body depletion of magnesium (Mg), alcohol is now known to be the most notorious cause of Mg-wasting. Recent data obtained through the use of biophysical (and noninvasive) technology suggest that alcohol may induce hypertension, stroke, and sudden death via its effects on intracellular free Mg2+ ([Mg2+]i), which in turn alter cellular and subcellular bioenergetics and promote calcium ion (Ca2+) overload. Evidence is reviewed that demonstrates that the dietary intake of Mg modulates the hypertensive actions of alcohol. Experiments with intact rats indicates that chronic ethanol ingestion results in both structural and hemodynamic alterations in the microcirculation, which, in themselves, could account for increased vascular resistance. Chronic ethanol increases the reactivity of intact microvessels to vasoconstrictors and results in decreased reactivity to vasodilators. Chronic ethanol ingestion clearly results in vascular smooth muscle cells that exhibit a progressive increase in exchangeable and cellular Ca2+ concomitant with a progressive reduction in Mg content. Use of 31P NMR spectroscopy coupled with optical-backscatter reflectance spectroscopy revealed that acute ethanol administration to rats results in dose-dependent deficits in phosphocreatine (PCr), the [PCr]/[ATP] ratio, intracellular pH (pHi), oxyhemoglobin, and the mitochondrial level of oxidized cytochrome oxidase aa3 concomitant with a rise in brain-blood volume and inorganic phosphate. Temporal studies performed in vivo, on the intact brain, indicate that [Mg2+]i is depleted before any of the bioenergetic changes. Pretreatment of animals with Mg2+ prevents ethanol from inducing stroke and prevents all of the adverse bioenergetic changes from taking place. Use of quantitative digital imaging microscopy, and mag-fura-2, on single-cultured canine cerebral vascular smooth muscle, human endothelial, and rat astrocyte cells reveals that alcohol induces rapid concentration-dependent depletion of [Mg2+]i. These cellular deficits in [Mg2+]i seem to precipitate cellular and subcellular disturbances in cytoplasmic and mitochondrial bioenergetic pathways leading to Ca2+ overload and ischemia. A role for ethanol-induced alterations in [Mg2+]i should also be considered in the well-known behavioral actions of alcohol. PMID- 7847587 TI - Magnesium deficiency in alcoholism: possible contribution to osteoporosis and cardiovascular disease in alcoholics. AB - Magnesium (Mg) deficiency occurs frequently in chronic alcoholism and may contribute to the increased incidence of osteoporosis and cardiovascular disease seen in this population. Mg deficiency is primarily due to renal Mg-wasting and is exacerbated by dietary Mg deprivation, gastrointestinal losses with diarrhea or vomiting, as well as concomitant use of drugs such as diuretics and aminoglycosides. Osteoporosis is prevalent in the alcoholic population. Mg deficiency may contribute to increased bone loss by its effects on mineral homeostasis. In Mg depletion, there is often hypocalcemia due to impaired parathyroid hormone (PTH) secretion, as well as renal and skeletal resistance to PTH action. Serum concentrations of 1,25-vitamin D are also low. These changes are seen with even mild degrees of Mg deficiency and may contribute to the metabolic bone disease seen in chronic alcoholics. Hypomagnesemia in alcoholics may also contribute to increased cardiovascular disease by altering platelet function. Mg deficiency has been demonstrated to enhance platelet reactivity. In these studies, Mg was shown to inhibit platelet aggregation against various aggregation agents. Patients with Mg deficiency were shown to have increased platelet aggregation that was normalized with Mg therapy. The antiplatelet effect of Mg may be related to the finding that Mg inhibits the synthesis of thromboxane A2 and 12-hydroxyeicosatetraenoic acid, eicosanoids thought to be involved in platelet aggregation. Mg also inhibits the thrombin-induced Ca2+ influx in platelets, as well as stimulates synthesis of prostaglandin I2, the potent antiaggregatory eicosanoid. Therefore, Mg deficiency may increase platelet aggregation and cause increased hypertension and atherosclerotic cardiovascular disease in alcoholics. PMID- 7847588 TI - Family history of alcoholism and childhood adversity: joint effects on alcohol consumption and dependence. AB - Empirical studies provide substantial evidence that having a family history of alcoholism increases the risk of developing alcohol dependence; however, some of this effect may be caused by nonspecific childhood socioeconomic adversity common in families with an alcohol-dependent parent. In this study, we examine joint effects of family history and childhood adversity within a sample of 509 men and 217 women over age 40. The measures analyzed were included in routine screening assessments for participants in various studies at the University of Michigan Alcohol Research Center. About 60% of the men and 45% of the women were alcohol dependent. About 30% reported an alcoholic parent. Degree of family history affected drinking behavior for both men and women. There were also environmental effects on the same measures for both men and women. Childhood socioeconomic adversity was reported more frequently by participants with an alcoholic parent, but adversity effects were also shown for those with a negative family history. The risk of alcohol dependence was additively increased by a positive family history and childhood socioeconomic adversity. The environmental effects identified in this study are promising evidence for nonspecific factors that moderate family history risk for development of alcohol problems. PMID- 7847589 TI - Comparison of alcohol dependence in subjects from clinical, community, and family studies. AB - This study contrasts the prevalence of alcohol-related symptoms, ages of onset of alcoholism milestones, and lifetime prevalence of other psychiatric disorders in three samples of alcohol-dependent individuals: alcoholics sampled from a variety of clinical settings (not necessarily alcoholism treatment facilities), relatives of alcoholic probands who participated in a Family Study of alcoholism, and alcoholics identified in the St. Louis Epidemiologic Catchment Area survey. Alcohol dependence (with or without abuse) was assessed using DSM-III diagnostic criteria for all samples. Clinical alcoholics had significantly more lifetime alcohol symptoms than Family Study and Community alcoholics and a significant excess of many alcohol symptoms. Onset information indicated that the three groups were similar in terms of appearance of milestones of alcohol dependence. For females aged 45 or younger, lifetime prevalence of major depression was high in both Clinical and Family Study alcoholics compared with Community alcoholics; male alcoholics from the Community Study had an excess of drug dependence. Findings suggest that, although alcoholics identified in clinical settings may have more severe alcohol dependence, certain types of psychiatric comorbidity are present to a greater degree in other samples of untreated alcoholics. PMID- 7847590 TI - Clinical predictors of alcohol withdrawal delirium. AB - Up to now, clinical predictors for the course of the alcohol withdrawal syndrome, especially for the occurrence of a delirium, are lacking. Thus, this study was undertaken to examine whether clinical routine investigations at admission before the withdrawal syndrome can reveal factors indicating a higher risk for the development of a delirium. Our results showed that decreased serum electrolyte concentrations (i.e., chloride and potassium), elevated ALT, and gamma glutamyltransferase serum levels, as well as ataxia and polyneuropathy at the neurological examination, indicate a higher risk for the development of an alcohol withdrawal delirium. PMID- 7847591 TI - Carbohydrate-deficient transferrin and other markers of high alcohol consumption: a study of 502 patients admitted consecutively to a medical department. AB - An isoform of transferrin, carbohydrate-deficient transferrin (CDT) is increased in a high percentage of abusing alcoholics and has been found superior in its specificity compared with other biological markers. We used serum CDT as a screening parameter in 502 patients consecutively admitted to our medical department during a 4-week period. The intake of ethanol during the last 4 weeks was registrated by personal interviews and the mean daily consumption calculated. Serum CDT was measured at admission (CDTect) and compared with gamma glutamyltranspeptidase (GGT), AST, ALT, and mean corpuscular volume (MCV). Serum CDT detected 18 of 26 (69%) patients who consumed > 50 g ethanol daily. The clinical sensitivity of CDT of detection ethanol consumption > 50 g daily was 69%, compared with 73%, 50%, 35%, and 52% for increased values of GGT, AST, ALT, and MCV, respectively. Altogether, 38 of 476 patients (8%) with a daily ethanol consumption < 50 g also had increased serum CDT levels. The specificity of CDT was 92%, compared with 75%, 82%, 86%, and 85% for GGT, AST, ALT, and MCV, respectively. In the 60 patients who consumed > 10 g ethanol daily, we found a significantly positive correlation between CDT and ethanol consumption (r = 0.52, p < 0.001). A positive correlation was also found between serum transferrin and CDT (r = 0.51, p < 0.001). In conclusion, the specificity of CDT is much higher compared with GGT in detecting alcohol abuse. Some acute and chronic illnesses may increase the serum level of CDT. False-positive CDT levels may be caused by changes in serum transferrin concentration. PMID- 7847592 TI - Platelet monoamine oxidase activity in alcoholics, alcoholics with drug dependence, and cocaine addicts. AB - The main objective of this investigation was to study the influence of drug dependence on platelet monoamine oxidase (MAO) activity in the presence and absence of alcoholism. One hundred and thirteen admissions to alcohol and drug treatment facilities participated in the study. Twenty-six met the criteria for alcoholism (group I), seventy-eight subjects were alcohol-/cocaine- and cannabis dependent (group II), and the remaining nine were patients with DSM-III-R diagnosis of cocaine addiction (group III). MAO activity was assayed radiochemically with [14C]tyramine as a substrate (221 microM). The results of this study showed that platelet MAO activity [nmol of product formed x (mg protein)-1 x hr-1] (mean +/- SE) was significantly (p < 0.01) lower in all of these subjects (group I, 5.50 +/- 0.80; group II, 3.90 +/- 0.50; group III, 4.3 +/- 1.60) as compared with controls (14.85 +/- 1.13). Measurements of platelet MAO activity may provide us with a reliable biochemical marker for alcoholism and perhaps addiction to other substances of abuse (i.e., cocaine). PMID- 7847593 TI - Examination of the tridimensional personality hypothesis of alcoholism using empirically multivariate typology. AB - Cloninger (1987) has hypothesized a tridimensional personality theory for two types of alcoholism, type 1 and type 2, that exhibit opposing clinical characteristics and personality traits. The Tridimensional Personality Questionnaire (TPQ) is designed to test this hypothesis on three independent dimensions--novelty seeking (NS), harm avoidance (HA), and reward dependence (RD) -to evaluate the personality trait. We examined the tridimensional personality hypothesis by comparing TPQ scores between two empirically derived multivariate types of alcoholism. The present study included 191 male subjects with alcoholism. A cluster analysis was conducted using clinical characteristics, and two empirical types, type A and type B, were identified. Type A is similar to Cloninger's type 1 and type B is similar to type 2. The TPQ scores given to these two empirical types were compared. Scores on the NS and RD scales were in good agreement with the hypothesis, whereas the HA score was discordant with the hypothesis. HA is highly correlated with the depression scale score that is elevated in type B. We discussed the possibility that type B, which may be called a familial early-onset alcoholism, is related to character spectrum disorder. PMID- 7847594 TI - Effects of fetal alcohol exposure on infant reaction time. AB - Fetal alcohol exposure is associated with slower reaction times (RTs) in children, suggesting an alcohol-related deficit in "speed of central processing." This study examined effects of prenatal alcohol exposure on a new paradigm which, for the first time, directly assesses RT in infancy. RT was assessed in 103 Black, inner-city, 6.5-month-olds born to women recruited prenatally based on alcohol consumption during pregnancy. Maternal drinking was related to longer RTs and to fewer fast responses, after controlling for potential confounders. The incidence of fast performance was reduced in infants whose mothers averaged at least 0.5 oz absolute alcohol/day, indicating an impact at lower levels than those associated with fetal alcohol syndrome. The RT deficits were dose-dependent and not attributable to maternal depression, intellectual stimulation, prenatal drug exposure, or postpartum maternal drinking. This study provides the first evidence of an alcohol-related RT deficit in infancy. PMID- 7847595 TI - Effect of citalopram on alcohol intake in heavy drinkers. AB - The effect of the selective serotonin reuptake inhibitor citalopram (40 mg daily dose) on alcohol intake was investigated in a double-blind, placebo-controlled cross-over study. Thirty men with heavy alcohol consumption (mean daily alcohol intake 111 +/- 51 g pure alcohol) completed the study. After a 2-week baseline period, subjects were randomly allocated to treatment with either citalopram or placebo for 5 weeks. In the total sample of heavy drinkers, no difference was found between citalopram and placebo treatment in alcohol consumption or days of abstinence. However, the response to citalopram was negatively correlated (rs = 0.67, p < 0.01) with baseline levels of mean daily alcohol intake. Therefore, we divided the total sample into two subgroups with baseline mean daily alcohol intake above and below median (107 g pure alcohol), respectively. In the group with the higher baseline values (138 +/- 25 g pure alcohol), citalopram was not different from placebo in reducing the daily alcohol intake, but in subjects with the lower baseline values (85 +/- 15 g pure alcohol), citalopram was significantly (p < 0.01) superior to placebo. Consequently, citalopram at the present dose appears capable of reducing alcohol intake only in a subgroup of heavy drinkers with a mean daily consumption of between 60 and 100 g pure alcohol. PMID- 7847596 TI - Monoamine oxidase and homovanillic acid in boys with predispositions to substance abuse. AB - Both dopaminergic dysregulation and abnormalities in monoamine oxidase (MAO) have been postulated as etiological factors in substance abuse. This study assessed whether MAO activity differed in sons of substance-abusing fathers compared with sons of nonsubstance-abusing fathers. It also assessed the levels of homovanillic acid (HVA), the metabolite of dopamine, and MAO in a group of substance-using/ abusing boys compared with peers without this history in the same setting. Sixty five boys admitted to a residential center were evaluated on blood tests for HVA and MAO, and on a series of diagnostic instruments and questionnaires designed to elicit information about parental substance abuse and about the subject's own substance use/abuse. The results indicated tentatively that younger (< 12.0 years) sons of substance-abusing fathers had higher levels of MAO than younger sons of nonsubstance-abusing fathers. Levels of MAO in older (> or = 12.0 years) sons of substance-abusing and nonsubstance-abusing fathers did not differ. Boys with histories of significant use/abuse of substances themselves had significantly higher MAO levels and significantly lower HVA levels than peers of the same age without substance use/abuse histories. PMID- 7847597 TI - Differences in recent life events between alcoholic and depressive nonalcoholic suicides. AB - The purpose of this study was to investigate the main differences in recent life events preceding suicide between alcoholic and depressive nonalcoholic suicide victims, how much these differences were sex- and age-dependent, and how social support varied between these groups. Using the psychological autopsy method, retrospective best-estimate diagnoses by DSM-III-R criteria were assigned to a randomized 16.4% sample (n = 229) of suicide victims drawn from a 1-year total nationwide suicide population (n = 1,397) in Finland. Life events during the last 3 months (32 items) and social support (6 items) of 75 suicide victims with alcohol abuse/dependence diagnoses were compared with those of 69 nonalcoholic depressive victims. Among male suicides, the alcoholics had experienced more separations and family discord, financial trouble, and unemployment, whereas the depressives had experienced more somatic illness. Among females, adverse interpersonal events had been common in both alcoholic and depressive victims. Among the alcoholics, unlike the depressives, the number of adverse interpersonal life events had not diminished with increasing age. Living alone had been twice as common among the alcoholic suicides and, in these cases, recent separation, unemployment, and financial trouble were remarkably common, suggesting a concurrent stressor effect. Our results confirm and extend the earlier findings of excess interpersonal stressors among alcoholic suicides compared with depressive suicides. The findings suggest that multiple adverse life events and living alone need to be taken into account in clinical practice when assessing psychosocial stress and suicidal danger in alcoholism. PMID- 7847598 TI - Comparison of different methods for detecting carbohydrate-deficient transferrin. AB - Different methods for detecting carbohydrate-deficient transferrin (CDT) were compared. In addition, their efficiency for detecting alcohol abuse among men not having clinical evidence of liver disease was studied in controls (n = 26), weekend (n = 16) and daily (n = 12) heavy drinkers, and alcoholics (n = 28). Comparisons were made between anion-exchange separation of iron-saturated transferrin (Tf) by microcolumns (CDTect) and by the Fast Protein Liquid Chromatography (FPLC% and FPLC-MG), followed by double-antibody radioimmunoassay of collected fractions. Tf fractions with pl > or = 5.7 were also measured by two different isoelectric focusing (IEF) methods, followed by immunofixation (SA-IEF CDT and IEF-CDT-TOT), the latter method being used also for detection of asialotransferrin (IEF-CDT-AS). The cut-off was 20 units/liter for CDTect, 4.4% of total Tf for SA-IEF-CDT, and the mean +2 sd of the control group for FPLC-MG (as mg/liter of Tf), FPLC-%, IEF-CDT-TOT, and IEF-CDT-AS (all as percentage of Tf). The overall accuracies (combining sensitivity and specificity) for detecting heavy drinkers of CDTect, FPLO (mg/liter), FPLC (%), SA-IEF-CDT, IEF-CDT-TOT, and IEF-CDT-AS were 63%, 59%, 61%, 74%, 57%, and 63%, respectively; for detecting alcoholics, 87%, 83%, 81%, 89%, 37%, and 76%, respectively. In conclusion, the methods were in rather good agreement with each other. Diagnostic characteristics among heavy drinkers and correlations between methods differed slightly, probably depending on the ability of different methods to separate and detect asialo-, monosialo-, and disialotransferrin.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7847599 TI - Screening for pregnancy risk-drinking. AB - The efficacy of alcohol screening questionnaires, the TWEAK, T-ACE, NET, MAST, and CAGE, in detecting periconceptional risk-drinking, > or = 1 oz absolute alcohol/day, was investigated in 4743 African-American women attending an inner city prenatal clinic who had reported ever drinking. Sensitivity, specificity, positive predictive value, efficiency, follow-up rates, and receiver operating characteristics of the questionnaires were examined to compare the overall effectiveness of the questionnaires and their performance at cut-points defining positive scores ranging from 1 to 3. Relatively little difference between TWEAK, T-ACE, and MAST was seen in the receiver operating characteristic accuracy indices; NET and CAGE lagged behind. Sensitivity/specificity scores for the two questionnaires most sensitive at cut-point 1 were TWEAK (87/72) and T-ACE (83/75). At cut-point 2, sensitivity was optimized with respect to specificity; TWEAK (79/83) was significantly more sensitive than T-ACE (70/85; p = 0.002). At cut-point 3, the two most sensitive tests were MAST (61/92) and TWEAK (59/94). In general, measures of merit were not greatly affected by the time between conception and the administration of the screens. Screening was most sensitive for women interviewed during the first 15 weeks of pregnancy; risk-drinkers tended to delay entry into prenatal care, increasing positive predictive values associated with screening later in pregnancy. This study confirms the utility, when screening for risk-drinking during pregnancy, of brief questionnaires that assess alcohol intake indirectly by asking women about their tolerance to alcohol's effects, psychological consequences of drinking, and significant others' concern about their drinking. It validates T-ACE and provides preliminary data indicating that TWEAK may outperform T-ACE. PMID- 7847600 TI - A double-blind, placebo-controlled pilot study to evaluate the efficacy and safety of oral nalmefene HCl for alcohol dependence. AB - A dozen studies have been published showing that opiate antagonists suppress alcohol drinking in animals, and two independent placebo-controlled, double-blind clinical trials of naltrexone found this agent was associated with decreased alcohol craving and consumption in alcohol-dependent patients. Nalmefene is a newer opiate antagonist that has a number of potential advantages over naltrexone in the treatment of alcoholism, including no dose-dependent association with liver toxicity and more effective binding to central opiate receptors. Consequently, a double-blind pilot study was conducted to gather preliminary data on the safety and efficacy of nalmefene for reducing alcohol consumption in alcohol-dependent subjects. Twenty-one alcohol-dependent subjects meeting admission criteria were randomly assigned to 12 weeks of double-blind treatment with 40 mg nalmefene, 10 mg nalmefene, or placebo, resulting in 7 patients/treatment group. Nalmefene was well tolerated, with no serious adverse drug reactions. The 40 mg group had a significantly lower rate of relapse (p < or = 0.05), and a greater increase in the number of abstinent days/week (p < or = 0.09), than the other treatment groups. A significant decrease in the number of drinks/drinking day was noted for both nalmefene groups (p < or = 0.04), but not for placebo. These results were supported by parallel decreases in ALT. These pilot data provide preliminary support for the hypotheses that nalmefene can be safely given to alcoholics, and that nalmefene may have a role in reducing alcohol consumption and preventing relapse, particularly at the 40 mg level. A full-scale study is underway to confirm these preliminary findings. PMID- 7847601 TI - Women, alcohol, and red cells. AB - Alcohol abuse is known to increase erythrocyte mean cell volume mainly as a consequence of direct toxic effect on the developing red cell. The influence of alcohol on other red cell parameters is unclear. The objective of this cross sectional survey was to examine the consequences of different alcohol amounts on red cell parameters among women. We compared red cell parameters between female alcoholics, heavy drinkers, and controls. Controls (n = 138) and heavy drinkers (n = 65) consisted of consecutive 40- and 45-year-old women participating in the health screening, and alcoholics (n = 73) of consecutive women coming to a detoxification clinic. Alcoholics had significantly smaller erythrocyte counts (p < 0.01), and higher erythrocyte mean cell volume values (p < 0.001), reticulocyte counts (p < 0.01), and red cell distribution width values (p < 0.001) than controls. No difference between these groups was found, however, in hemoglobin distribution width value. The only red cell difference between controls and heavy drinkers was erythrocyte mean cell volume, which was significantly higher among heavy drinkers (p < 0.001). In alcoholics, red cell distribution width values were even more often increased (in 44%) than erythrocyte mean cell volume values (in 34%). This increase in red cell distribution width was not solely explained by iron deficiency or liver disease. Chronic alcohol abuse not only affects erythrocyte mean cell volume values, but also leads to anisocytosis seen in blood count as an increased red cell distribution width value. PMID- 7847602 TI - Drinking history is related to persistent blood pressure dysregulation in postwithdrawal alcoholics. AB - We have previously demonstrated that alcoholics with transitory (< 72 hr) elevations in blood pressure (BP) during withdrawal continue to show residual cardiovascular dysregulation up to 4 weeks of abstinence. The present study replicates and extends these findings. Alcoholic inpatients were divided into three subgroups (ns = 14) based on BP during the first 72 hr of withdrawal: transitory hypertensives (tHTs; BP > 160/95 mm Hg), transitory borderline hypertensives (tBHs; 140/90 < or = BP < 160/95), and normotensives (NTs; all BPs < 140/90). All patients had normal resting pressures after 72 hr of withdrawal. At 3-4 weeks postadmission, the alcoholics and 14 nonalcoholic controls (CONTs) were tested at rest and during a 5-min handgrip task. The tHTs showed an exaggerated systolic and diastolic BP response to handgrip compared with NTs and CONTs, with tBHs intermediate (ps < 0.05). Drinking history showed the tHTs had the highest reported level of alcohol consumption and severity of withdrawal symptoms (ps < 0.05). Regression analyses indicated that consumption of hard liquor was the variable most predictive of admission BPs; further, parental history of hypertension potentiated this relationship for systolic BP. Age and consumption of nicotine and caffeine were not significant predictors of admission BP. The results suggest a persistent cardiovascular dysregulation in alcoholics showing transient hypertensive withdrawal BPs. These alcoholics may be at increased risk for future alcohol-related cardiovascular disorder. PMID- 7847603 TI - Predictors of mortality in alcoholic women: a 20-year follow-up study. AB - Very little is known about the factors that predict mortality in female alcoholics. This study investigates these predictors in 103 female alcoholics who were psychiatrically hospitalized between 1967 and 1968 and followed for over 20 years. The findings showed that age, benders, and/or delirium tremens, comorbidity, and 3-year posttreatment drinking status were associated with time to death. That older alcoholics and those with pathological drinking within 3 years after treatment had a significantly shorter time to death was not surprising. However, the association of benders with mortality indicated that women may be very sensitive to short periods of high concentrations of alcohol. Comorbidity also had an intriguing effect in that women with a history of depression were more likely to survive. The predictors of mortality in these female alcoholics differed from those of the male alcoholics in this sample. These differences will be discussed in future publications. PMID- 7847604 TI - Changes in transaminases over the course of a 12-week, double-blind nalmefene trial in a 38-year-old female subject. AB - A 38-year-old female was drinking 30 drinks/week before entering a 12-week, double-blind study of nalmefene for the treatment of alcohol dependence. Liver function tests (LFTs) were within normal limits at baseline and week 4, but on week 8, the ALT showed a 7-fold increase, and the AST showed a 4-fold increase from baseline. A decision was made to continue study medication based on the patient's positive response to this therapy (i.e., achieving complete abstinence) and no known dose-dependent association with liver toxicity in over 1300 patients treated with nalmefene for other indications. LFTs were repeated serially to assess the trend of the LFT values. The patient achieved total abstinence over the course of the study period and at the 3-month posttreatment follow-up was continuing to maintain these gains from the study program, and her LFTs had returned to normal. A gradual return to normal in ALT and AST, while treatment with nalmefene continued, does not support the role of nalmefene as an hepatotoxin. Relapse to drinking was excluded because of normal values for the gamma-glutamyltransferase, and verification of sobriety by self-report, significant other, and breathalyzer. A virology panel ruled out the presence of viral hepatitis. Dietary intake before the elevation in LFTs contained elements that have established association with hepatocellular changes. The routine prescription of serial LFTs in alcoholism pharmacotherapy trials may be expected to reveal clinically nonsignificant elevations that could potentially be related to exogenous factors, such as dietary composition and should not be reflexively attributed to medication under investigation and/or drinking. PMID- 7847605 TI - Low-level hyperbaric antagonism of ethanol's anticonvulsant property in C57BL/6J mice. AB - This study investigated the ability of hyperbaric exposure to antagonize ethanol's anticonvulsant effect on isoniazid (INH)-induced seizures. Drug-naive, male C57BL/6 mice were injected intraperitoneally with saline, 1.5, 2.0, or 2.5 g/kg ethanol followed immediately by an intramuscular injection of 300 mg/kg of INH. The mice were then exposed to either 1 atmosphere absolute (1 ATA) air, 1 ATA helium-oxygen gas mixture (heliox), or 12 ATA heliox at temperatures that offset the hypothermic effects of helium. Ethanol increased the latency to onset of myoclonus in a dose-dependent manner. Exposure to 12 ATA heliox antagonized ethanol's anticonvulsant effect at 2.0 and 2.5 g/kg, but not at 1.5 g/kg. Ethanol also increased the latency to onset of clonus in a dose-dependent manner beginning at 2.0 g/kg. Exposure to 12 ATA heliox antagonized this anticonvulsant effect. When exposed to 12 ATA heliox, the blood ethanol concentrations at time to onset of myoclonus were significantly higher in mice treated with 2.5 g/kg of ethanol as compared with blood ethanol concentrations of mice exposed to 1 ATA air. These findings extend the acute behavioral effects of ethanol known to be antagonized by hyperbaric exposure and support the hypothesis that low-level hyperbaric exposure blocks or reverses the initial action(s) of ethanol leading to its acute behavioral effects. PMID- 7847606 TI - The subchronic effects of the TRH analog TA-0910 and bromocriptine on alcohol preference in alcohol-preferring rats: development of tolerance and cross tolerance. AB - In a previous study, we showed that a single injection of the thyrotropin releasing hormone analog TA-0910 dose-dependently reduced alcohol intake in alcohol-preferring (P) rats and increased their water intake over a 24-hr period. In the present study, the effects of seven consecutive, once-daily injections of TA-0910 (0.75 mg/kg, ip) on alcohol preference were determined. P rats developed tolerance to the attenuating effects of TA-0910 on alcohol intake within 3-5 days. Following the development of tolerance to TA-0910, rats were injected with the dopamine agonist bromocriptine (0.5 mg/kg, sc). In the presence of tolerance to TA-0910, the attenuating effect of bromocriptine on alcohol intake was reduced. When rats were made tolerant to the attenuating effects of bromocriptine, they exhibited tolerance to the attenuating effects of TA-0910. These findings indicate that tolerance to the effects of TA-0910 on alcohol intake occurs and suggest dopamine involvement in the mechanism of action of TA 0910 in reducing alcohol intake in P rats. PMID- 7847607 TI - Studies of the oxidation of ethanol to acetaldehyde by oxyhemoglobin using fluorigenic high-performance liquid chromatography. AB - We noted a rise in acetaldehyde levels in clinical samples of venous whole blood containing ethanol that did not occur in samples from teetotalers. Experiments were performed to define the mechanism involved in acetaldehyde production. The addition of 0.10% ethanol to whole blood produced an immediate increase in acetaldehyde due to acetaldehyde in the stock solution followed by a subsequent increase that became statistically significant by 48 hr. Separation of blood into components documented that the increase in acetaldehyde was associated with the red cell but not plasma fraction. Incubation of isolated hemoglobin with ethanol produced a rise in acetaldehyde levels. Incubation of oxygenated whole blood with ethanol produced a linear increase in acetaldehyde, whereas nitrogen-exposed blood produced no increase. The rise of acetaldehyde in the presence of ethanol was dependent on the concentration of oxygenated hemoglobin A0. Addition of inhibitors of catalase, alcohol dehydrogenase, and glycolytic enzymes (aminotriazole, azide, pyrazole, sodium fluoride, sodium citrate, and iodoacetate) did not inhibit the rise of acetaldehyde, but addition of the hemoglobin ligand cyanide abolished the rise in acetaldehyde. Kinetic analysis with oxygenated whole blood plus inhibitors revealed a Km of 2.5 mM and Vmax of 1.42 microM/min. We conclude that oxyhemoglobin contributes to the metabolism of ethanol to acetaldehyde. These findings may explain in part the high levels of acetaldehyde found in red cells compared with plasma. The results also have implications for the optimum storage of blood samples for acetaldehyde analysis. PMID- 7847608 TI - Effect of acute and chronic alcohol administration to rats on the expression of interleukin-6 cell-surface receptors of hepatic parenchymal and nonparenchymal cells. AB - Rats were treated with alcohol either acutely (continuous, 7-hr intravenous infusion; blood alcohol levels approximately 35 mM) or chronically (liquid diet, 12-14 weeks). Three hr before killing, the animals received Gram-negative bacterial lipopolysaccharide (LPS) or saline. Hepatocytes, Kupffer cells, and liver sinusoidal endothelial cells were isolated by liver collagenase perfusion and centrifugal elutriation, and used for measurements of recombinant human [125I]interleukin-6 binding. Dissociation constant (Kd) and the amount of cell surface receptors (Bmax) were measured on whole cells, at 4 degrees C. Two binding sites were detected on all three cell types: high-affinity (Kd1, from 20 to 125 pM) and low-affinity (Kd2, from 0.2 to 2 nM), with low Bmax (Bmax, from 0.4 to 12 fmol/10(6) cells) and high Bmax (Bmax2, from 10 to 210 fmol/10(6) cells). Hepatocytes displayed an 8-fold higher binding capacity for high-affinity sites (Bmax1) than the other two cell types. Acute ethanol treatment induced the following significant changes in the binding parameters: a decrease in Kd1 for hepatocytes and Kupffer cells, an increase in Bmax2 for hepatocytes, and a decrease in Bmax1 for Kupffer cells. Although the control (nonalcoholic) liquid diet per se completely suppressed the high-affinity binding sites, alcohol containing diet induced only one change: a significant increase in Kd2 for hepatocytes. No changes in the binding parameters were seen after LPS administration to the chronically treated group. In the acute group, LPS mimicked alcohol action on hepatocyte binding parameters. Alcohol blunted LPS effects.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7847609 TI - Effects of ethanol feeding on the interaction of rat hepatocytes with laminin peptides. AB - Laminin, a complex glycoprotein of the extracellular matrix, contains a number of biologically active sites. These sites are involved in cell growth, attachment, differentiation, and gene expression. Our previous studies have shown that chronic ethanol consumption by rats impairs hepatocyte attachment to various components of the extracellular matrix including laminin. In this study, three synthetic peptides (PA22-2, YIGSR, and RGD) that correspond to three distinct functional sites on the laminin molecule were used to investigate the effect of ethanol consumption on their cognate receptors. Initially, varying concentrations of each peptide were incubated with isolated hepatocytes from ethanol-fed and pair-fed control rats. These hepatocytes were then assayed for the ability to attach to laminin. The results indicated that all three peptides effectively inhibited laminin-mediated cell adhesion: the degree of inhibition appeared similar between pair-fed controls and ethanol-fed animals. Of the three peptides, PA22-2 showed the most dramatic inhibition of attachment. Therefore, we investigated the ability of hepatocytes to attach directly to PA22-2 itself. Attachment of hepatocytes from ethanol-fed animals to PA22-2 was impaired by 30% after 4 days and 90% by 14 days. Conversely, no significant difference in attachment to the entire laminin molecule was observed in ethanol-fed animals at these early time points. These results indicated that the ethanol-induced impairment of hepatocyte attachment to laminin may be caused by the decreased interaction of hepatocytes with specific functional sites on the laminin molecule and that specific receptors on the hepatocyte may be affected differently.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7847610 TI - Purification and characterization of Helicobacter pylori alcohol dehydrogenase. AB - Alcohol dehydrogenase of Helicobacter pylori (HPADH) was purified from the soluble fraction of cultured bacteria (strain NCTC 11637) by anion exchange and affinity chromatography. On sodium dodecyl sulfate-polyacrylamide gel electrophoresis, the 160-fold purified enzyme displayed one protein band with a mobility that corresponded to an M(r) of 38,000. Although HPADH was capable of utilizing both NADP and NAD as cofactors in alcohol oxidation, it showed a strong preference for NADP over NAD. Kinetic studies revealed a Km value of 26 mM and a kcat value of 530 min-1 for ethanol/active site at 37 degrees C in 0.1 M potassium phosphate buffer (pH 7.4). The enzyme was considerably more active toward primary aliphatic alcohols than secondary alcohols. The Km and kcat values decreased as the chain length of the alcohol increased. Benzyl alcohol was a 100 times better substrate than ethanol in terms of kcat/Km values. At neutral pH, HPADH was more effective in aldehyde reduction than in alcohol oxidation. Because of its high specific activity for ethanol (14 units mg-1) under physiological conditions, HPADH can also effectively produce acetaldehyde at higher ethanol levels. This reversed function of HPADH and the production of toxic and reactive acetaldehyde could account for at least some of the gastrointestinal morbidity associated with H. pylori infection. PMID- 7847611 TI - Delayed pro-opiomelanocortin activation after ethanol intake in man. AB - To elucidate the effect of ethanol on the secretion of ACTH and beta-endorphin (BE) as the representatives of the pro-opiomelanocortin (POMC) system, as well as cortisol as the hypophyseally regulated peripheral hormone, we measured concentrations of serum ethanol and plasma ACTH, BE, and cortisol at 1- to 4-hr intervals for 12 hr after administration of 0.5 and 1.0 g ethanol/kg of body weight and placebo drinks between 1900-1945 hr to nine healthy volunteers according to a double-blind, cross-over design. Plasma ACTH, BE, and cortisol showed an expected diurnal rhythm with the highest levels at 0700 hr. Intake of ethanol had no statistically significant effects on plasma ACTH up to 0700 hr in the morning. The higher dose caused increased levels of BE at 0100 hr and both doses at 0200 hr. Plasma cortisol at 0400 hr was higher in subjects receiving 1.0 g ethanol/kg than in those receiving placebo (p < 0.05). Our present observation that plasma ACTH was unchanged after ethanol intake, but plasma BE was increased at 0100-0200 hr may be due to the fact that our BE antiserum cross-reacts with beta-lipotropin, which has a considerably longer half-life than ACTH or BE, and also to the long sampling interval. Thus, the POMC system may have been stimulated after ethanol intake. The nocturnal rise of plasma cortisol levels at 0400 hr, 2-3 hr after the peak in plasma BE, may be caused by the increased secretion of POMC. Because the ethanol dose of 1.0 g/kg body weight stimulated the POMC system but the 0.5 g/kg body weight did not, we conclude that higher ethanol doses induce increases in stress hormone secretion. PMID- 7847612 TI - Magnitude, origin, and implications of the discrepancy between blood ethanol concentrations of tail vein and arterial blood of the rat. AB - The rat is widely used as an animal model for experiments involving ethanol, and alcohol concentrations in blood obtained from the tail routinely are used to monitor ethanol exposure and metabolism. The present study demonstrates that during periods of rising and declining ethanol levels, the alcohol concentrations in tail vein blood lags far behind that of arterial, jugular, or femoral vein blood. As a result, tail vein ethanol concentrations markedly underestimate the concentration in arterial blood and rapidly perfused tissue during periods of increasing body ethanol, whereas the reverse is true as body ethanol declines. This discrepancy, which appeared to result from the low blood perfusion:tissue water ratio in the tail, disappeared when the tail was heated to 37 degrees C. Compared with arterial blood, alcohol measurements performed on tail vein blood yielded a much higher apparent Km for ethanol clearance and a somewhat lower estimate of ethanol reaching the peripheral circulation. We conclude that, for a variety of studies, analyses of arterialized blood from the heated tail should yield a more accurate and reproducible measure of ethanol exposure and/or metabolism than does the conventional collection from the unheated tail. PMID- 7847613 TI - Prenatal alcohol exposure alters the hypothalamic-pituitary-adrenal axis response of immature offspring to interleukin-1: is nitric oxide involved? AB - We have previously shown that following prenatal alcohol exposure, immature offspring showed blunted ACTH released in response to the peripheral administration of interleukin-1 beta (IL-1 beta). The present studies were conducted to investigate the role of changes in corticosteroid feedback (measured by altered adrenal responses to ACTH), corticotropin-releasing factor (CRF) content of the median eminence (ME), and the influence of endogenous nitric oxide (NO). The injection of several doses of ACTH failed to indicate measurable differences between the corticosterone responses of offspring born to dams fed ad libitum [control (C)], pair-fed (PF), or fed alcohol [ethanol (EtOH) = E]. CRF content in the ME, taken as an index of the amount of releasable peptide, showed a small, but statistically significant, decrease following prenatal alcohol exposure. A comparable change, however, was also noted in PF rats. As expected, the subcutaneous injection of IL-1 beta (0.5 microgram/kg) induced smaller increases in plasma ACTH levels of E than C pups. The response of PF animals was intermediate between that of E and C rats. Finally, we observed that inhibition of NO formation by the administration of the arginine derivative L omega nitro-L arginine-methylester significantly augmented ACTH secretion in all three experimental groups, and reversed the decreased corticotrophs' response to IL-1 beta caused by prenatal alcohol. Taken together, our results suggest that the ability of prenatal alcohol exposure to alter ACTH released by immature pups in response to blood-borne IL-1 beta is probably not mediated through changes in adrenal responsiveness.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7847614 TI - Ganglioside GM1 reduces fetal alcohol effects in rat pups exposed to ethanol in utero. AB - We have investigated the effect of in utero ethanol exposure and ganglioside GM1 pretreatment on the endogenous ganglioside profile of the rat fetal brain. Prenatal ethanol exposure on gestation day (GD) 7 and GD8 and/or GD13 and GD14 leads to a very significant increase in the ganglioside GM1 content in at least 50% of the pup brains when assayed on GD20. This treatment protocol also results in significant decrease in the content of polysialogangliosides GD1a, GT1b, and GQ1b. GM1 treatment of pregnant dams before ethanol administration prevented this alteration in pup brain ganglioside profile. Ganglioside GM1 pretreatment appears to block the cellular membrane changes associated with fetal alcohol effects and thereby minimizes alterations in brain maturation and associated behavioral dysfunction. PMID- 7847615 TI - Vapor phase exposure to acetaldehyde generated from ethanol inhibits bovine bronchial epithelial cell ciliary motility. AB - Acetaldehyde is a toxic product of the oxidation of ethanol and is known to induce slowing of ciliary motility in airway epithelium. Alcohol ingestion results in high exhaled breath concentrations of ethanol where lung microsomes and upper airway bacterial flora are capable of metabolizing it to acetaldehyde. Because acetaldehyde is very volatile, we hypothesized that the production and release of acetaldehyde vapor into the airway may result in ciliary slowing or ciliastasis. To test this hypothesis, ciliated bovine bronchial airway epithelial cells were maintained on collagen-coated dishes for 48 hr before coincubation with a separate dish containing control or test mixtures. In this arrangement, the ciliated cells were exposed only to the volatile components of the separate dish. The separate dish contained ethanol, acetaldehyde, or an acetaldehyde generating system (AGS) that consisted of ethanol + glucose + glucose oxidase + catalase. This mixture was placed next to the ciliated cells within in a transparent sealed chamber. Ciliary motility was recorded at room temperature by video microscopy, and ciliary beat frequency was determined using computerized frequency spectrum analysis. Exposure to the AGS resulted in time- and concentration-dependent ciliary slowing with complete ciliastasis, with as low as 20 mM ethanol in the AGS. Direct vapor phase exposure to acetaldehyde alone served as a positive control and also resulted in time-dependent ciliary slowing with complete ciliastasis reached by 4 hr. The AGS-induced ciliastasis was reached 2 hr later than with acetaldehyde alone. When cells were pretreated with cyanamide, which is known to block acetaldehyde dehydrogenase, the time to ciliastasis was decreased by 10-30 min compared with untreated cells.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7847617 TI - Influence of ethanol intake on mammary gland morphology and cell proliferation in normal and carcinogen-treated rats. AB - Alcohol consumption has been reported to increase breast cancer risk in a majority of epidemiological studies and to enhance, at specific dietary concentrations, both the initiation and promotion stages of chemically induced rat mammary tumorigenesis. However, there is limited information regarding possible mechanisms for this effect. The present studies were conducted to examine a possible mechanism for the promoting effect of ethanol on chemically induced mammary tumorigenesis. The influence of chronic ethanol intake by female rats on the progress of differentiation and on the rate of target structure cell proliferation of the mammary gland was evaluated. Results of these studies indicate that ethanol intake at 20% and 30% of calories by female rats between the ages of 55 and 94 days (a period associated with the promotion stage of experimental mammary tumorigenesis) results in a delay in the differentiation of the mammary gland. This delay in gland maturation observed for rats consuming ethanol was evidenced by an increase in the quantity of less mature terminal-end bud (TEB) structures and a decrease in the quantity of more mature alveolar bud structures. The DNA labeling index of the target structure TEB increased significantly for rats consuming ethanol. These changes in mammary gland maturation and in TEB DNA labeling index were observed for both normal and carcinogen-treated rats consuming ethanol. Also, serum progesterone, but not estradiol, was significantly decreased for animals consuming ethanol at 30% of calories compared with isocaloric controls. The correlation of these changes in the mammary gland with the reported enhancement by ethanol of the promotion stage of experimental rat mammary tumorigenesis is discussed. PMID- 7847616 TI - Genetic polymorphism and activities of human colon alcohol and aldehyde dehydrogenases: no gender and age differences. AB - Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) isoenzyme patterns from 69 (men, 47; women, 22) surgical colon mucosal specimens were identified by agarose isoelectric focusing. gamma-ADH was found to be the predominant form in the mucosa, whereas only beta-ADH was detectable in the muscle layer. ALDH1, ALDH2, and ALDH3 were detectable in the mucosa, with cytosolic ALDH1 being the major form. At pH 7.5, the ADH activities in the colon mucosae with the homozygous phenotype (exhibiting gamma 1 gamma 1) and the heterozygous phenotype (exhibiting gamma 1 gamma 1, gamma 1, gamma 2, gamma 2, gamma 2) were determined to be 183 +/- 13 and 156 +/- 30 nmol/min/g tissue, respectively. The ALDH activities in the ALDH2-active and ALDH2-inactive phenotypes were determined to be 40.2 +/- 2.3 and 34.6 +/- 2.0 nmol/min/g tissue, respectively. The lack of significant difference in the ALDH activities between these two phenotypic groups can be attributed to the very low expression of the mitochondrial ALDH2 in the colon mucosa. No significant differences in the ADH or the ALDH activities were found between the men and women studied and between the three age groups (20-40, 49-70, and 72-83 years). The ascending, transverse, descending, and sigmoid colons exhibited similar ADH and ALDH activities. The isoenzyme patterns of ADH and ALDH remained unaltered in colon carcinomas, except that a significant reduction of the enzyme activities was found in the cancer tissue as compared with the adjacent normal portions. it is concluded that human colon mucosa exhibits significant amounts of ethanol- and acetaldehyde-oxidizing activities. PMID- 7847618 TI - Acute ethanol exposure suppresses the repair of O6-methylguanine DNA lesions in castrated adult male rats. AB - Alcohol has clearly been associated with an increase of cancers in numerous tissue, including the respiratory tract, colon, rectum, liver, but especially the esophagus, larynx, pharynx, and mouth. Alcohol alone has not been shown to be a mutagen until it is converted to acetaldehyde and, therefore, alcohol presumably acts as a cocarcinogen. Previous data has shown that alcohol concentrations of 2% or greater inhibits DNA repair, and in light of the widespread consumption of alcoholic beverages with alcohol contents ranging from 4 to 5% (beer and wine coolers) to 50% (whiskey), interest in determining the mechanism(s) responsible for alcohol-induced carcinogenesis has heightened. Although previous studies, in intact rats, have investigated the effects of chronic alcohol exposure on some aspects of DNA repair, we have begun to address the effects of acute or "binge" alcohol exposure on mammalian DNA repair. Toward this end, we report the inhibition of O6-methylguanine-DNA methyltransferase (MGMT) by a single intraperitoneal injection of 30% ethanol in adult male castrated rats. This inhibition lasted for at least 24 hr. We also observed a dose-response effect of ethanol on MGMT activity, again only in the castrated rats. The finding of ethanol's effect on MGMT activity in castrated and not intact rats implies a hormonal component of MGMT DNA repair response, which has only been alluded to in past research. PMID- 7847619 TI - Differences between alcohol-preferring (AA) and alcohol-avoiding (ANA) rats in the prodynorphin and proenkephalin systems. AB - The motivation to drink alcohol and the eventual risk of becoming addicted are in part genetically determined. Because opioid peptides are considered central to motivated behaviors, we have analyzed opioid peptides in relevant areas of the brain of two outbred lines of rats: the alcohol-preferring [Alko Alcohol (AA)] line who voluntarily drink alcohol and the alcohol-avoiding [Alko Non-Alcohol (ANA)] line with negligible intake. (Met)enkephalinArg6Phe7 (MEAP) was measured as a marker of proenkephalin, and dynorphin A, dynorphin B, and (Leu)enkephalinArg6 as markers of the prodynorphin system. The major line differences and effects of alcohol intake were observed in mesolimbic brain areas. The mesolimbic dopamine pathway, which projects from the ventral tegmental area (VTA) to the nucleus accumbens, is central in the reward system. Basal levels of MEAP and dynorphin peptides were low in the nucleus accumbens of AA rats, whereas (Leu)enkephalinArg6 levels were lower in the VTA of these rats. Alcohol drinking caused MEAP levels in the accumbens to rise, but had no effect on prodynorphin peptides. Opioids also influence the nigrostriatal dopamine pathway. However, this study showed no significant differences for any peptide between rat lines, or effect of alcohol intake, in either substantia nigra or striatum, except for a decrease of nigral and striatal (Leu)enkephalinArg6 levels in alcohol-drinking AA rats. Large line differences were observed in the pituitary gland. AA rats had high basal levels of MEAP, which became even higher after voluntary alcohol consumption for 4 weeks, and low levels of dynorphin peptides, not affected by alcohol drinking.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7847620 TI - Markedly enhanced cytochrome P450 2E1 induction and lipid peroxidation is associated with severe liver injury in fish oil-ethanol-fed rats. AB - We evaluated the role of changes in cytochrome P-450 2E1 (CYP 2E1) and lipid peroxidation in relation to development of severe liver injury in fish oil ethanol-fed rats. The experimental animals (male Wistar rats) were divided into 5 rats/group and were fed the following diets for 1 month: corn oil and ethanol (CO+E) or corn oil and dextrose (CO+D), and fish oil and ethanol (FO+E) or fish oil and dextrose (FO+D). For each animal, microsomal analysis of CYP 2E1 protein, aniline hydroxylase activity, fatty acid composition, and conjugated dienes was conducted. Also, evaluation of severity of pathology was done for each rat. The mean +/- SD of the pathology score was significantly higher (p < 0.01) in the FO+E (6.0 +/- 1.3) group than in the CO+E group (3.0 +/- 0.5). No pathological changes were evident in the dextrose-fed controls. The CYP 2E1 protein levels (mean +/- SD) were significantly higher (p < 0.01) in the FO+E group (13.1 +/- 2.0) compared with the CO+E (4.7 +/- 1.2) and FO+D (1.8 +/- 0.5) groups. Higher levels of eicosapentaenoic and docosahexaenoic acids and lower levels of arachidonic acid were detected in liver microsomes from rats fed fish oil compared with corn oil. A significant correlation was obtained between CYP 2E1 protein and conjugated diene levels (r = 0.78, p < 0.01). Our results showing markedly increased CYP 2E1 induction and lipid peroxidation in the FO+E group provides one possible explanation for the greater severity of liver injury in this group. PMID- 7847621 TI - Polyunsaturated lecithin and alcoholic liver disease: a magic bullet? PMID- 7847622 TI - Oxygen sensors based on luminescence quenching: interactions of metal complexes with the polymer supports. AB - Oxygen quenching of [Ru(Ph2phen)3]Cl2 (Ph2phen = 4,7-diphenyl-1,10 phenanthroline) has been studied in a diverse series of polymers, most with a common poly-(dimethylsiloxane) (PDMS) component. Systematic variations in the polymer properties have been made in order to delineate the structural features important for satisfactory use of supports for oxygen sensors. Most measurements were made using homo- or copolymers containing a PDMS region, although some measurements were made on small ring siloxane polymers. In particular, quenching behavior was examined as a function of polymer structure as well as the type of and amount of polar copolymer cross-linkers. Cross-linkers were added to enhance the solubility of oxygen probes in an otherwise nonpolar polymer. In addition, hydrophobic silica was added to alter quenching properties. Domain models are used to explain the variations in oxygen quenching properties as a function of additives and cross-linkers. These considerations have led to the most sensitive ruthenium-based sensor reported to date. The relative affinity of the different domains for the complex and the efficacy of the domains for oxygen quenching control the overall behavior of the sensing response. Guidelines for design of suitable polymer supports for oxygen sensors are proposed. PMID- 7847623 TI - Electrospray tandem mass spectrometry for analysis of native muramic acid in whole bacterial cell hydrolysates. AB - Muramic acid is an amino sugar found in eubacterial cell walls and not elsewhere in nature. This study explored the use of electrospray tandem mass spectrometry (ESI MS/MS) in analysis of underivatized muramic acid in bacterial hydrolysates. Fungal hydrolysates were used as negative controls. The only processing used was hydrolysis in sulfuric acid followed by extraction with an organic base (N,N dioctylmethylamine) to remove the acid prior to ESI MS/MS analysis. Compared with pure muramic acid, bacterial hydrolysates produced more complex ESI mass spectra, such that the protonated molecular ion at m/z 252 was barely detectable. In contrast, product ion spectra of m/z 252 were identical among pure muramic acid, Gram positive bacteria, and Gram negative bacteria. However, no characteristic product ion spectrum was manifested from m/z 252 in fungal samples. This allowed ready, visual differentiation of bacteria and fungi. Multiple reaction monitoring (MRM) following muramic acid fragmentations (m/z 252-->144 and m/z 252-->126) increased sensitivity and allowed quantitative differentiation when compared with the MRM of the internal standard N-methyl-D-glucamine (m/z 196-->44). ESI MS/MS required minimal sample preparation and allowed rapid sample throughput for analysis of muramic acid in whole bacterial cell hydrolysates. PMID- 7847624 TI - Stable isotope methods for the study of beta-carotene-d8 metabolism in humans utilizing tandem mass spectrometry and high-performance liquid chromatography. AB - This report presents analytical methods for the isolation and quantification of all-trans-beta-carotene-d8 in human plasma following a 73 mumol oral dose. Retinol-d4 derived from beta-carotene-d8 was also determined in the same plasma. Plasma samples drawn over a 24 day period were analyzed. beta-Carotene and retinol were isolated and purified for analysis using a solid phase extraction protocol with aminopropyl-bonded silica sorbent. Ratios of beta-carotene-d8/beta carotene were determined using reversed-phase HPLC with spectrophotometric detection, which fully resolved the isotopomers, and by tandem mass spectrometry (MS/MS) with electron ionization. Results obtained from MS/MS and HPLC analysis showed close agreement and demonstrated improved selectivity relative to analysis using a single mass analyzer. Retinol-d4 was converted to its tert butyldimethylsilyl ether and analyzed by gas chromatography/mass spectrometry using selected ion monitoring. The ability to resolve the beta-carotene isotopomers by HPLC makes it feasible for investigators without mass spectrometers to investigate the dynamics of absorption and metabolism of beta carotene-d8 in humans. PMID- 7847625 TI - Calcium stoichiometry determination for calcium binding proteins by electrospray ionization mass spectrometry. AB - Electrospray ionization mass spectrometry was used for the determination of calcium-binding stoichiometry for calcium-binding proteins. Bovine calmodulin, bovine alpha-lactalbumin, and rabbit parvalbumin were found to bind specifically to 4, 1, and 2 Ca(2+) ions, respectively, in agreement with previously reported results obtained by using other physical methods. This mass spectrometry method could also be applied to proteins that bind more than one type of metal ion. The Zn(2+)- and Ca(2+)-binding stoichiometries for human stromelysin catalytic domain were determined to be 3 and 2, respectively. PMID- 7847626 TI - Glycerol-enhanced separation of DNA fragments in entangled solution capillary electrophoresis. AB - (Hydroxyalkyl)methylcellulose additives to borate buffers have been used to create physically entangled solutions for fractionation of biological molecules by high-performance capillary electrophoresis, i.e., ESCE. We have observed that addition of glycerol to an entangled solution containing (hydroxypropyl)methylcellulose (HPMC) in Tris-borate buffer markedly improved the separation of double-strand DNA molecules ranging from less than 100 bp to about 1 kb by ESCE. This range of DNA fragment sizes is well suited to many PCR-based studies. We attribute the improved ESCE performance to the borate present in the buffer system. Borate can form dimeric 1:2 borate:didiol complexes with both glycerol and HPMC, acting as a central linkage to allow an entangled solution with different pore size to form chemically. PMID- 7847627 TI - Theory of field-programmed field-flow fractionation with corrections for steric effects. AB - This paper deals with the principal perturbation to ideal normal-mode elution of particles in field-flow fractionation (FFF). This perturbation is due to the finite size of particles undergoing migration in the FFF channel. The effects of a first-order correction for particle size are examined. Equations are derived for retention time, fractionating power, and steric inversion diameter for operation at constant field strength, as well as under conditions of both exponential and power programmed field decay. Useful limiting equations for fractionating power are derived and their validity is confirmed for typical experimental conditions. The derived equations are necessary for the future development of a systematic optimization strategy for the selection of operating conditions for particle size analysis by FFF. Calculations confirm our previous conclusion that the fractionating power for exponential field programming varies strongly with particle size; this variation is only slightly reduced by steric perturbations. The uniform fractionating power of power programming is slightly disturbed by steric effects although fractionating power remains much more uniform than for exponential programming. It is shown that a higher uniformity in fractionating power can be gained by manipulating the parameters of power programming but that no improvement is possible with exponential programming. Phenomena giving rise to higher order perturbations and to secondary relaxation are discussed and the conditions identified under which these effects are minimized. PMID- 7847628 TI - Effects of linear polyacrylamide concentrations and applied voltages on the separation of oligonucleotides and DNA sequencing fragments by capillary electrophoresis. AB - Oligonucleotides and DNA sequencing fragments have been separated by capillary electrophoresis employing linear polyacrylamide (LPA) as a sieving matrix. A commercially available apparatus equipped with a laser-induced fluorescence (LIF) detection system has been utilized, but the capillary cartridge has been modified to position the capillaries without coiling. The performance of the separation, the relationship between resolution and analysis time, has been examined using poly(dT)16-500 by changing LPA concentration, capillary length, and electric field strength. It was found that, for large DNA fragments, the migration time interval between bands decreases linearly as DNA fragment size increases. This implies that there exists a maximum base number to be resolved, irrespective of the band width (we named the maximum base number Nmax). The higher value of Nmax is obtained when the applied field strength is lower, but this accompanies longer analysis time with a concomitant increase in band width. Simple experimental equations have been proposed to calculate resolution and migration times of DNA fragments separated in our system at given electrophoretic conditions. Using 9% T LPA and an electric field strength of 100 V/cm, single-base resolution of M13mp10 DNA fragments up to 520 nucleotides has been obtained. PMID- 7847629 TI - Determination of urinary albumin using high-performance immunoaffinity chromatography and flow injection analysis. AB - The detection of low levels of albumin in urine can be an important aid in the early diagnosis of kidney disease. In this study, an automated system for urine analysis was developed that could simultaneously measure both albumin and creatinine, an indicator of urine output and volume. Albumin was determined by use of a column that contained immobilized anti-albumin antibodies. An on-line flow injection analysis system was used to measure creatinine as this solute eluted nonretained from the antibody column. The total analysis time of the system was 5 min per injection. Limits of detection for albumin and creatinine in a 20 microL sample (at S/N = 2) were 3 and 5 mg/L, respectively. The response for these compounds covered the range of clinical interest. Within-run precision for both analytes was +/- 1-2% at normal urine concentrations. The results of this method showed good agreement with those obtained by reference techniques. This approach can be adapted for the detection of other urine components by changing the type of antibody column used in the system. PMID- 7847630 TI - Time-resolved immunofluorometric determination of specific mRNA sequences amplified by the polymerase chain reaction. AB - We report a highly sensitive time-resolved immunofluorometric method for quantification of polymerase chain reaction (PCR)-amplified mRNA sequences. The PCR primers are labeled at their 5' ends, one with biotin and the other with a hapten. The modified primers are incorporated, during PCR, in the amplified product. The PCR product is captured, through its biotin moiety, to a streptavidin-coated solid phase and subsequently is detected with an alkaline phosphatase-labeled antibody. The phosphate ester of fluorosalicylic acid is used as a substrate. The fluorosalicylate produced forms a highly fluorescent ternary complex with Tb(3+)-EDTA, which is measured by time-resolved fluorometry. We chose the determination of PCR-amplified chronic myelogenous leukemia-specific mRNA as a model system. mRNA molecules corresponding to 0.1 leukemic cell in the presence of 0.5 million normal cells may be detected (signal-to-background ratio of 1.5). The method provides a sensitive and rapid nonisotopic alternative to Southern blot and hybridization with radioactive probes. PMID- 7847631 TI - Two-dimensional high-performance liquid chromatography using monodisperse polymer beads containing segregated chemistries prepared by pore size specific functionalization. Single-column combinations of size exclusion or ion exchange with reversed-phase chromatography. AB - Separation media for the complete separation of complex samples that require a combination of size exclusion or ion-exchange with reversed-phase chromatographic modes in a single column have been prepared from size monodisperse 10 microns poly(glycidyl methacrylate-co-ethylene dimethacrylate) beads using a pore size specific functionalization process. To achieve the first combination of chromatographic modes, the large pores of the beads were selectively hydrolyzed to diols using aqueous poly(styrenesulfonic acid), while highly hydrophobic octadecyl groups were introduced into the small pores by reaction of the remaining epoxide groups with octadecylamine. These beads provide excellent protein recoveries and may be used for the direct injection separation of samples containing both hydrophilic proteins and hydrophobic drugs. Beads containing diethylamino groups in the large pores and octadecyl functionalities in the small pores were also prepared by size-selective modification. A plot of log k' against ionic strength of the mobile phase for these beads shows the absence of hydrophobic interactions and documents the clean ion-exchange mechanism of protein separation. Examination of the small pores in both types of separation media confirmed that their hydrophobicity was sufficient to allow the separations of small molecules in reversed-phase mode. Column packed with these dual chemistry beads exhibited high efficiencies and were used successfully for the separations of proteins and alkylbenzenes or drugs. PMID- 7847632 TI - Measurement in vitro of human plasma glycerol with a hydrogen peroxide detecting microdialysis enzyme electrode. AB - Human plasma glycerol was determined with a microdialysis electrode, containing the enzymes glycerol kinase and glycerol phosphate oxidase held stationary within the electrode. A microdialysis electrode is essentially a conventional microdialysis probe, with a platinum working electrode inserted into the tip of the dialysis fiber and reference and counter electrodes contained in the upper compartment. The linear range of response to glycerol was directly dependent on the concentration of ATP. At 4 mM ATP, the linear range was 0.5-500 microM. A fast response time of 20 s was obtained. Two types of interferences were observed when plasma glycerol was measured: direct oxidation of interferents at the electrode and attenuation of response to glycerol by reaction with hydrogen peroxide and/or poisoning of the platinum electrode. Ascorbate, urate, and acetaminophen were removed from plasma samples by a pretreatment step involving peroxidase and catalase. Any remaining interferent current was reduced by electropolymerizing o-phenylenediamine onto the platinum electrode. Adsorption of plasma proteins on the dialysis fiber was minimal and was not reduced by the preadsorption of human serum albumin. Very good correlation was obtained between the electrode and the standard spectrophotometric technique for the variation in glycerol concentration with time. PMID- 7847633 TI - Labeling of double-stranded DNA by ROX-dideoxycytosine triphosphate using terminal deoxynucleotidyl transferase and separation by capillary electrophoresis. AB - Terminal transferase is used to add a single fluorescently labeled dideoxynucleotide to double-stranded DNA prepared by restriction endonuclease action on a bacteriophage. The product is separated by capillary electrophoresis with both hydroxypropylmethylcellulose and non-cross-linked polyacrylamide. The reaction products generate single peaks for each fragment with hydroxypropylmethylcellulose. However, the higher resolution separation produced by non-cross-linked polyacrylamide shows that the product contains two components for each restriction digest fragment. This labeling technique should be useful in restriction fragment length polymorphism studies. PMID- 7847634 TI - Collision-induced dissociation for mass spectrometric analysis of biopolymers: high-resolution Fourier transform ion cyclotron resonance MS4. AB - Efficient collision-induced dissociation multistage tandem high-resolution mass spectrometry of peptide ions is demonstrated for the first time. Specifically, four-stage Fourier transform ion cyclotron resonance collision-induced dissociation tandem-in-time MS4 is demonstrated for bradykinin quasimolecular ions, MH+, produced by matrix-assisted laser desorption/ionization. We combine off-resonant excitation and ion axialization to improve the efficiency of parent ion dissociation and product ion collection and detection at every MS stage. We observe successive loss of water/ammonia from the C-terminus to leave an (MH NH3/H2O)+ ion in the second stage, followed by successive losses of the next two amino acids, arginine and phenylalanine. High mass resolving power is achieved throughout all four MS stages, in an experiment that consumes approximately 10 pmol of peptide and takes only approximately 5 min. We project that it should be possible to automate this experiment for high-speed sequencing of biopolymers. PMID- 7847635 TI - Error-tolerant identification of peptides in sequence databases by peptide sequence tags. AB - We demonstrate a new approach to the identification of mass spectrometrically fragmented peptides. A fragmentation spectrum usually contains a short, easily identifiable series of sequence ions, which yields a partial sequence. This partial sequence divides the peptide into three parts-regions 1, 2, and 3 characterized by the added mass m1 of region 1, the partial sequence of region 2, and the added mass m3 of region 3. We call the construct, m1 partial sequence m3, a "peptide sequence tag" and show that it is a highly specific identifier of the peptide. An algorithm developed here that uses the sequence tag to find the peptide in a sequence database is up to 1 million-fold more discriminating than the partial sequence information alone. Peptides can be identified even in the presence of an unknown posttranslational modification or an amino acid substitution between an entry in the sequence database and the measured peptide. These concepts are demonstrated with model and practical examples of electrospray mass spectrometry/mass spectrometry of tryptic peptides. Just two to three amino acid residues derived by fragmentation are enough to identify these peptides. In peptide mapping applications, even less information is necessary. PMID- 7847636 TI - Correlates of attitudes concerning human immunodeficiency virus and acquired immunodeficiency syndrome among hospital workers. AB - BACKGROUND: Correlates of attitudes related to HIV and AIDS for both clinical and nonclinical support hospital workers have not been well described. METHODS: A cross-sectional study was conducted among employees of an acute care, inner-city hospital to assess attitudes related to HIV and AIDS. RESULTS: A 51% response rate was obtained, with completed questionnaires obtained from 321 clinical workers and 245 nonclinical workers. The proportions tolerant of patients with HIV infection were 83% and 78%, respectively. Factors associated with a tolerant attitude in clinical workers included personally knowing someone with AIDS, high scores on general AIDS knowledge, high knowledge scores on modes of transmission, low levels of fear, and accurate perceptions of occupational risk. In nonclinical workers, factors associated with tolerance included having been tested for HIV, personally knowing someone with AIDS, accurate perceptions of occupational risk, low levels of fear, high scores on general AIDS knowledge, and high knowledge scores on modes of transmission. CONCLUSIONS: Although the study was cross sectional, the data suggest potentially modifiable factors associated with AIDS related attitudes. These factors may be amenable to intervention among both clinical and nonclinical support hospital employees. PMID- 7847637 TI - Analysis of needlestick injuries to health care workers providing home care. AB - BACKGROUND: This research analyzed needlestick injuries sustained by employees working in the home health environment to determine to what extent existing infection control policies and procedures in home health care are effective in reducing the risk of transmission of blood-borne infections. METHODS: In June and July 1992, a random sample of 600 directors of home health care agencies in the United States were sent questionnaires concerning written blood-borne infection control policies and procedures of home health care agencies. Agency characteristics were also identified. RESULTS: A 46% response rate (n = 278) was obtained. Of the 226 agencies that reported needlestick injury rates, 102 agencies reported no needlestick injuries to home health care agency employees in the "last year" and 124 agencies reported from one to 134 needlestick injuries, for a cumulative total of 475. Statistical analyses revealed that agencies with "safer" sharps containers, "safer" hypodermics, or "safer" access to intravenous administration lines did not have statistically significantly rates of lower needlestick injury than agencies without these "safer" products. CONCLUSIONS: This study should be considered exploratory; causal relationships cannot be established. Although written blood-borne infection control policies and procedures do not appear to provide protection to home health care workers from the risk of needlestick injury, limitations in the data exist. Consequently, results should be viewed with caution and additional research is needed. PMID- 7847638 TI - Lack of compliance with influenza immunization for caretakers of neonatal intensive care unit patients. AB - BACKGROUND: Both the Centers for Disease Control and Prevention and the American Academy of Pediatrics have recommended influenza immunizations for neonatal intensive care unit staff. Compliance rates for influenza immunization among neonatal intensive care unit staff have not yet been reported. METHODS: To determine both the rates and the associated factors for compliance between 1990 and 1993 among neonatal intensive care unit nursing staff, interviews were conducted at three Hartford area hospitals by means of a structured questionnaire. RESULTS: Compliance rates at the three hospitals were 15% in 1990 to 1991, 20% in 1991 to 1992, and 17% in 1992 to 1993 (89% sampling of all nurses with direct patient care). Sixty-three percent were not immunized between 1991 and 1993, 26% were vaccinated once, 9% were vaccinated twice, and 2% were vaccinated three times within the 3-year period. Convictions regarding vaccine safety and effectiveness, concern about getting influenza, and awareness of national recommendations for annual influenza immunization were shown to be associated with vaccination compliance. Concern over exposing neonates, peer influence, pain from injection, and previous adverse reaction were not statistically significant factors differentiating compliers from noncompliers. CONCLUSIONS: There is a poor acceptance of the influenza vaccine among our neonatal intensive care unit nursing staff. Educational and research efforts directed toward influenza risks among neonates and vaccine safety and effectiveness, along with incentives to comply, may improve compliance rates. PMID- 7847639 TI - Creutzfeld-Jakob disease: recommendations for infection control. AB - Creutzfeld-Jakob disease, an infectious, progressive, degenerative neurologic disorder, has a presumably long incubation period but a rapid, fatal course. Brain tissue at autopsy resembles that seen in spongioform encephalopathies of other species. Creutzfeld-Jakob disease is transmitted by a proteinaceous infectious agent, or "prion." Epidemiologic patterns remain uncertain; various studies have reported conflicting risk factors in different populations, and genetic susceptibility may be involved. Although natural transmission routes are still unclear, both iatrogenic and nosocomial transmissions have been identified. Transmission has occurred through contaminated electrodes, contaminated biologic products from cadaveric brains, and infected donor tissues, including dura mater and corneas. Because the prion is difficult to eradicate, stringent sterilization precautions must be taken with all surgical instruments. Some tissues and body fluids (e.g., brain, ocular, central nervous system) from the patient with Creutzfeld-Jakob disease are highly infectious and must be contained or incinerated. Some body fluids, however, are not considered infectious. Persons with known or suspected Creutzfeld-Jakob disease, or with exposure to potential sources of iatrogenic infection, should not be considered as donors for any tissues or biologic products. Occupational transmission to health care and pathology workers is also possible. Therefore, specific preventive measures are necessary. Many questions remain regarding transmission and risk factors for Creutzfeld-Jakob syndrome, and the precautions presented here must be considered only preliminary. PMID- 7847640 TI - Acinetobacter calcoaceticus anitratus outbreak in the intensive care unit traced to a peak flow meter. AB - BACKGROUND: A cluster of seven cases of Acinetobacter caleoaceticus anitratus in a community teaching hospital intensive care unit was discovered (the seventh case was located in a step-down unit next to an infected patient recently transferred from the intensive care unit.) METHODS: An outbreak investigation, including detailed epidemiologic, clinical, and laboratory investigation, was performed. RESULTS: A single strain of A. calcoaceticus anitratus was responsible for infection in all seven patients. All patients had tracheostomies, were in respiratory failure, and were ventilator dependent. Patients ranged in age from 27 to 81 years. No common causative variable or explanatory findings were present except that the same peak flow meter (manual weaning criteria machine) was used to facilitate weaning all seven patients from mechanical ventilation. Culture of the mouthpiece isolated a A. calcoaceticus anitratus strain with the identical susceptibility pattern and biochemical profile as that from the infected patients. CONCLUSION: A. calcoaceticus anitratus was transmitted by a peak flow meter nosocomially to seven patients receiving mechanical ventilation. Disposable mouthpieces were introduced to prevent cross-contamination. A 2% glutaraldehyde solution was used to disinfect the machine between uses. No further outbreaks of A. calcoaceticus anitratus pneumonia were identified during 3 years of follow-up. PMID- 7847641 TI - Infection control instruction and screening for students. AB - Cook County Hospital is a large, municipal teaching hospital with multiple academic affiliations. We sought to provide uniform infection control orientation and screening for students because many had no previous training in body substance isolation systems or infection control and trainees may be more likely to be exposed to hospital-acquired infections because of their inexperience. Each student or visiting resident must complete an educational program once each year. The program consists of a pretest, a video, and group discussion, with examples of needle-disposal boxes and protective gear, information about ways to avoid needlesticks and mucosal splashes, what to do if a contact occurs, and information on isolation and tuberculosis. The session ends with a posttest, which is then retained on file. All trainees are also required to provide a "certificate of compliance" with the hospital's infectious disease serology screening program, which includes measles, rubella, and hepatitis B surface antigen testing, as well as tuberculin skin testing. Trainees must provide an updated form annually. The program is costly, both in dollars and in personnel time, for visiting students and the hospital. Tuberculin skin test screening detected a cluster of purified protein derivative skin test conversions in medical students. PMID- 7847642 TI - Fluorouracil plus levamisole as effective adjuvant therapy after resection of stage III colon carcinoma: a final report. AB - OBJECTIVE: To determine the effectiveness of two adjuvant therapy regimens in improving surgical cure rates in stage III (Dukes stage C) colon cancer. DESIGN: Randomized, concurrently controlled clinical trial. SETTING: Major cancer centers, universities, and community clinics affiliated with the North Cancer Treatment Group, the Southwest Oncology Group, and the Eastern Cooperative Oncology Group. PATIENTS: Those who had had curative-intent resections of stage III colon cancer in the previous 1 to 5 weeks. INTERVENTION: Patients were assigned to observation only, to levamisole alone (50 mg orally three times/d for 3 days, repeated every 2 weeks for 1 year), or to this regimen of levamisole plus fluorouracil (450 mg/m2 body surface area intravenously daily for 5 days and then, beginning at 28 days, weekly for 48 weeks). MEASUREMENTS: Rates of cancer recurrence and death. Early- and late-treatment side effects. RESULTS: With all 929 eligible patients able to be followed for 5 years or more (median follow-up, 6.5 years), fluorouracil plus levamisole reduced the recurrence rate by 40% (P < 0.0001) and the death rate by 33% (P = 0.0007). Levamisole reduced the recurrence rate by only 2% and the death rate by only 6%. With few exceptions, toxicity was mild and patient compliance was excellent. No evidence of late side effects was seen. CONCLUSION: Fluorouracil plus levamisole is tolerable adjuvant therapy to surgery; it has been confirmed to substantially increase cure rates for patients with high-risk (stage III) colon cancer. It should be considered standard treatment for all such patients not entered into clinical trials. PMID- 7847643 TI - Physical activity, obesity, and risk for colon cancer and adenoma in men. AB - OBJECTIVE: To determine whether physical inactivity and obesity increase risk for colon cancer and adenomas, which are precursors of cancer, and whether the abdominal distribution of obesity is an independent risk factor for these events. DESIGN: Prospective cohort study. SETTING: United States. PATIENTS: 47,723 male health professionals, 40 to 75 years of age, who responded to a questionnaire mailed in 1986. MEASUREMENTS: Questionnaires in 1986 about physical activity level and body mass index, and questionnaires in 1987 (31,055 respondents) about waist and hip circumferences. Between 1986 and 1992, 203 new patients were diagnosed with colon cancer and 586 were diagnosed with adenomas. RESULTS: Physical activity was inversely associated with risk for colon cancer (high compared with low quintiles of average energy expenditure from leisure-time activities: relative risk, 0.53 [95% CI, 0.32 to 0.88], P for trend = 0.03) after adjustment for age; history of colorectal polyp; previous endoscopy; parental history of colorectal cancer; smoking; body mass; use of aspirin; and intake of red meat, dietary fiber, folate, and alcohol. Body mass index was directly associated with risk for colon cancer independently of physical activity level. Waist circumference and waist-to-hip ratio were strong risk factors for colon cancer (waist-to-hip ratio > or = 0.99 compared with waist-to-hip ratio < 0.90: multivariate relative risk, 3.41 [CI, 1.52 to 7.66], P for trend = 0.01; waist circumference > or = 43 inches compared with waist circumference < 35 inches: relative risk, 2.56 [CI, 1.33 to 4.96], P for trend < 0.001). These associations persisted even after adjustment for body mass and physical activity. Similar associations were seen between obesity and physical inactivity and adenomas of 1 cm or more, but no association was observed for smaller adenomas. Height was also associated with a higher risk for colon cancer (height > or = 73 inches compared with height < or = 68 inches: multivariate relative risk, 1.76 [CI, 1.13 to 2.74], P for trend = 0.02). CONCLUSIONS: The results support an inverse association between physical activity and risk for colon cancer, whereas height and obesity, particularly abdominal adiposity, are associated with an elevated risk. PMID- 7847644 TI - Incremental value of the leukocyte differential and the rapid creatine kinase-MB isoenzyme for the early diagnosis of myocardial infarction. AB - OBJECTIVE: To test whether automated measurements of cortisol-induced changes in the leukocyte differential can provide an early marker of myocardial infarction, especially when combined with the rapid creatine kinase-MB isoenzyme. DESIGN: A prospective, blinded study of these measurements at the time of initial assessment in the emergency department. SETTING: Large multispecialty clinic hospital. PATIENTS: 511 consecutive patients presenting to the emergency department with chest pain. One hundred twenty-seven patients with infection, trauma, or metastatic cancer or receiving myelosuppressive or glucocorticoid therapy were excluded. MEASUREMENTS: Automated leukocyte differentials, rapid creatine kinase-MB levels, cortisol levels, and routine clinical measurements. RESULTS: Of 69 patients with myocardial infarction, only 39% had diagnostic electrocardiographic ST-segment elevation. ST-segment elevation had a specificity of 99% and a positive predictive value of 93%. A relative lymphocytopenia (lymphocyte decrease < 20.3%) or elevated rapid creatine kinase-MB level (> 4.7 ng/mL) was more sensitive than ST-segment elevation (sensitivities of 58% and 56%, respectively) but less specific (specificities of 91% and 93%, respectively). The presence of both a relative lymphocytopenia and an elevated rapid creatine kinase-MB level had a sensitivity of 44%, a specificity of 99.7%, and a positive predictive value of 97% (95% Cl, 80% to 99%). Both a relative lymphocytopenia and an elevated rapid creatine kinase-MB level were independent (P < 0.001) predictors of infarction in patients without ST-segment elevation. If myocardial infarction was suspected by the presence of both abnormal markers or ST-segment elevation, the sensitivity for early diagnosis increased from 39% (ST elevation alone) to 65% (Cl, 52% to 76%); the specificity was 99%; and the positive predictive value was 94% (Cl, 82% to 98%). CONCLUSIONS: The presence of both a relative lymphocytopenia and an elevated rapid creatine kinase-MB level was an accurate early marker of myocardial infarction that appeared to improve the sensitivity of early diagnosis compared with that of ST-segment elevation alone. PMID- 7847645 TI - Predicting future functional status for seriously ill hospitalized adults. The SUPPORT prognostic model. AB - OBJECTIVE: To develop a model estimating the probability of an adult patient having severe functional limitations 2 months after being hospitalized with one of nine serious illnesses. DESIGN: Prospective cohort study. SETTING: Five teaching hospitals in the United States. PARTICIPANTS: 1746 patients (model development) who survived 2 months and completed an interview, selected from 4301 patients in the Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments (SUPPORT); independent validation sample of 2478 patients. MEASUREMENTS AND MAIN OUTCOMES: Patient function 2 months after admission categorized as absence or presence of severe functional limitations (defined as Sickness Impact Profile scores > or = 30 or as activities of daily living scores > or = 4 [levels that require near-constant personal assistance]). A logistic regression model was constructed to predict severe functional limitation. RESULTS: One third (n = 590) of patients who were interviewed at 2 months had severe functional limitations. Changes in functional status were common: Of those with no baseline dependencies (not dependent on personal assistance), 21% were severely limited at 2 months; of those with 4 or more baseline limitations, 30% had improved. The patient's ability to do activities of daily living was the most important predictor of functional status. Physiologic abnormalities, diagnosis, days in hospital, age, quality of life, and previous exercise capacity also contributed substantially. Model performance, assessed using receiver-operating characteristic curves, was 0.79 for the development sample and 0.75 for the validation sample. The model was well calibrated for the entire risk range. CONCLUSIONS: Functional outcome varied substantially after hospitalization for a serious illness. A small amount of readily available clinical information can estimate the probability of severe functional limitations. PMID- 7847646 TI - Proarrhythmia in patients with the Wolff-Parkinson-White syndrome after standard doses of intravenous adenosine. PMID- 7847647 TI - The effects of organizational structure on primary care outcomes under managed care. AB - The advent of managed care in the United States brings with it more and larger organizations involved in providing primary care. Studies of organizations in general suggest that large managed care organizations will have difficulty providing high-quality primary care largely because of their complexity and the fragmentation of their work force. Existing data confirm that these organizations have shortcomings in both patient and physician satisfaction. There are few data to indicate whether such organizations can mitigate these problems by saving costs through economies of scale. To offset their inherent weaknesses, large primary care organizations need to ensure patients' accessibility to their physicians, the continuity of the physician-patient relationship, a care environment conducive to a high-quality physician-patient interaction, and the clinical autonomy of physicians. Much additional research needs to be done to further understand these issues. PMID- 7847648 TI - Noninvasive carotid artery testing. A meta-analytic review. AB - PURPOSE: To compare the operating characteristics of six noninvasive tests for carotid artery stenosis. DATA SOURCES: A structured search was done using MEDLINE, reference lists from selected articles, and bibliographies from neurology textbooks that focused on the diagnosis of carotid artery stenosis in humans. The search yielded 568 articles. STUDY SELECTION: Articles were selected if the noninvasive test results they presented used carotid angiography as the reference standard for comparison, if carotid artery occlusion was considered as a separate category, and if contingency tables could be constructed. DATA EXTRACTION: At least two physicians reviewed all selected articles. Items abstracted included patient demographics, study design, sites of patient enrollment, whether the interpretation of test outcomes was blinded, and specific results. Sensitivity, specificity, receiver operating characteristic (ROC) curves, and summary measures of effectiveness for each test were calculated. RESULTS: Carotid duplex ultrasonography, carotid Doppler ultrasonography, and magnetic resonance angiography have sensitivities between 0.82 and 0.86, specificities at 0.98, and test-effectiveness measures at or exceeding 3.0 when predicting 100% occlusion. For carotid stenosis of 70% or more, these three tests and supraorbital Doppler ultrasonography all have sensitivities of 0.83 to 0.86, specificities of 0.89 to 0.94, test-effectiveness measures approaching 3.0, and composite ROC areas of 0.91 to 0.92. Limiting analysis to studies that enrolled consecutive patients and those in which interpretation of the noninvasive tests was independent of the angiograms did not substantially change our results. CONCLUSIONS: Carotid duplex ultrasonography, carotid Doppler ultrasonography, and magnetic resonance angiography are all similarly successful at predicting 100% carotid artery occlusion and 70% stenosis. Other factors, such as cost, availability, and local experience may influence the decision to use these tests to screen for carotid artery atherosclerosis that may respond to surgery. PMID- 7847649 TI - Nonabandonment: a central obligation for physicians. AB - Nonabandonment is one of a physician's central ethical obligations; it reflects a longitudinal commitment both to care about patients and to jointly seek solutions to problems with patients throughout their illnesses. The depth of this commitment may vary depending on the physician's and the patient's values and personalities, their shared experiences, and the patient's clinical circumstances. Traditional principled ethical analyses must balance the personal histories, values, motivations, and intentions of the participants with more general considerations. Such analyses often focus on a particular act, isolated in time, and yet the consequences of one decision immediately lead to a new set of choices. Nonabandonment places the physician's open-ended, long-term, caring commitment to joint problem solving at the core of medical ethics and clinical medicine. There is a world of difference between facing an uncertain future alone and facing it with a committed, caring, knowledgeable partner who will not shy away from difficult decisions when the path is unclear. PMID- 7847650 TI - The future of Annals. PMID- 7847651 TI - Nonabandonment: an old obligation revisited. PMID- 7847652 TI - Telecommunications and rural health communities. PMID- 7847653 TI - Rural primary care. American College of Physicians. AB - This overview of rural health care today shows the role that internal medicine can and should play in delivering primary care to rural populations. The American College of Physicians recommends changes to improve access to and delivery of primary care in rural areas. There are six specific recommendations. 1. Implementing universal health care coverage through a system that makes primary care equally affordable to rural populations. 2. Increasing the supply of primary care providers in rural areas by lessening specialty and geographic differentials in physician income. 3. Increasing the supply of primary care providers in rural areas by changing medical education to emphasize training enough rural physicians. 4. Decreasing professional isolation in rural areas through accessible continuing medical education and through telecommunications technology. 5. Identifying tertiary care needs at the community level and using state and federal funds to assist rural hospitals where access to care would be threatened by hospital closure. 6. Using innovative delivery systems that emphasize coordination and cooperation among providers, institutions, and communities. PMID- 7847654 TI - Pharmacoepidemiology of niacin. PMID- 7847655 TI - Hyperthyroidism. PMID- 7847656 TI - Hyperthyroidism. PMID- 7847657 TI - Hyperthyroidism. PMID- 7847658 TI - Helicobacter pylori and peptic ulcer. PMID- 7847659 TI - Crohn disease and the myelodysplastic syndrome. PMID- 7847660 TI - Castleman disease and renal amyloidosis. PMID- 7847661 TI - Transient ischemic attack after air contrast echocardiography in patients with septal aneurysm. PMID- 7847662 TI - Anaphylactoid reactions to ciprofloxacin. PMID- 7847663 TI - Nonsteroidal anti-inflammatory drugs and high blood pressure. PMID- 7847664 TI - Calcium hypothesis of Alzheimer's disease and brain aging. PMID- 7847665 TI - Alzheimer's disease: membrane-associated metabolic changes. PMID- 7847666 TI - Cellular and system neuroanatomical changes in Alzheimer's disease. PMID- 7847667 TI - Probing membrane bilayer interactions of 1,4-dihydropyridine calcium channel blockers. Implications for aging and Alzheimer's disease. AB - The results of this study demonstrate that the equilibrium nonspecific binding of DHP Ca2+ channel blockers to the membrane bilayer is highly dependent on cholesterol content. The molecular explanation for this observation appears to be related to the fact that cholesterol and DHPs occupy a similar molecular location in the membrane hydrocarbon core (Fig. 4). The membrane location of amlodipine may also be critical for subsequent receptor recognition and binding to voltage sensitive Ca2+ channels in peripheral and CNS tissue. Finally, changes in the cholesterol content of neural plasma membranes isolated from diseased cortical regions of subjects with AD were reported and may be indicative of a general defect in lipid metabolism. Further studies are underway to characterize in greater detail possible changes in cholesterol content with aging and AD. The implication of these changes for structure/function relationships in the membrane is also being explored. PMID- 7847668 TI - Calcium-mediated processes in neuronal degeneration. PMID- 7847669 TI - Calcium and excitotoxic neuronal injury. PMID- 7847670 TI - Neurodegenerative disease: autoimmunity involving calcium channels. PMID- 7847671 TI - Elevated intracellular calcium blocks programmed neuronal death. PMID- 7847672 TI - AIDS-related dementia and calcium homeostasis. AB - Approximately a third of adults and half of children with acquired immunodeficiency syndrome (AIDS) eventually suffer from neurological manifestations, including dysfunction of cognition, movement, and sensation. Among the various pathologies reported in the brain of patients with AIDS is neuronal injury and loss. A paradox arises, however, because neurons themselves are for all intents and purposes not infected by human immunodeficiency virus type 1 (HIV-1). This paper reviews evidence suggesting that at least part of the neuronal injury observed in the brain of AIDS patients is related to excessive influx of Ca2+. There is growing support for the existence of HIV- or immune related toxins that lead indirectly to the injury or death of neurons via a potentially complex web of interactions between macrophages (or microglia), astrocytes, and neurons. Human immunodeficiency virus-infected monocytoid cells (macrophages, microglia, or monocytes), especially after interacting with astrocytes, secrete substances that potentially contribute to neurotoxicity. Not all of these substances are yet known, but they may include eicosanoids, that is, arachidonic acid and its metabolites, as well as platelet-activating factor. Macrophages activated by HIV-1 envelope protein gp120 also appear to release arachidonic acid and its metabolites. These factors can lead to increased glutamate release or decreased glutamate reuptake. In addition, gamma interferon (IFN-gamma) stimulation of macrophages induce release of the glutamate-like agonist quinolinate. Human immunodeficiency virus-infected or gp120-stimulated macrophages also produce cytokines, including tumor necrosis factor-alpha and interleukin-1 beta, which contribute to astrogliosis. A final common pathway for neuronal susceptibility appears to be operative, similar to that observed in stroke, trauma, epilepsy, neuropathic pain, and several neurodegenerative diseases, possibly including Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This mechanism involves the activation of voltage dependent Ca2+ channels and N-methyl-D-aspartate (NMDA) receptor-operated channels, and therefore offers hope for future pharmacological intervention. This review focuses on clinically tolerated calcium channel antagonists and NMDA antagonists with the potential for trials in humans with AIDS dementia in the near future. PMID- 7847673 TI - Use of cultured fibroblasts in elucidating the pathophysiology and diagnosis of Alzheimer's disease. PMID- 7847674 TI - Molecular mechanisms of memory and the pathophysiology of Alzheimer's disease. AB - Research on molecular and biophysical mechanisms of associative learning and memory storage identified a number of key elements that are phylogenetically conserved. In both vertebrates and invertebrates, K+ channels, PKC, Cp20, and intracellular Ca2+ regulation play a fundamental role in memory mechanisms. Because memory loss is the hallmark and perhaps the earliest sign of Alzheimer's disease, we hypothesized that these normal memory mechanisms might be altered in AD. With the use of a variety of experimental methodologies, our results revealed that one of the critical elements in memory storage, K+ channels, are dysfunctional in AD fibroblasts. Moreover, beta-amyloid induced the same K+ dysfunction in normal cells. Intracellular Ca2+ release, also associated with molecular memory mechanisms, was found altered in fibroblasts from patients with AD. The results therefore strongly suggest that biophysical and molecular mechanisms of associative learning could be altered in AD and that they may contribute to the memory loss observed early in the disease. PMID- 7847675 TI - The ability of amyloid beta-protein [A beta P (1-40)] to form Ca2+ channels provides a mechanism for neuronal death in Alzheimer's disease. PMID- 7847676 TI - Molecular pharmacology of voltage-gated calcium channels. PMID- 7847677 TI - Differential phosphorylation, localization, and function of distinct alpha 1 subunits of neuronal calcium channels. Two size forms for class B, C, and D alpha 1 subunits with different COOH-termini. PMID- 7847678 TI - Biophysical and pharmacological characterization of a class A calcium channel. PMID- 7847679 TI - Derangements in calcium-dependent membrane currents in senescent human fibroblasts are associated with overexpression of a novel gene sequence. PMID- 7847680 TI - Calcium imaging in hippocampal neurons using confocal microscopy. PMID- 7847681 TI - Modulation of voltage-dependent calcium channels in cultured neurons. PMID- 7847682 TI - Neuropharmacology of nimodipine: from single channels to behavior. AB - To supplement the existing pharmacological evidence describing the effects of nimodipine, a 1,4-dihydropyridine with calcium channel blocking properties, our group has used a multidisciplinary approach. This work attempts to characterize the mechanism of action of nimodipine in neurons as well as investigate the effects of nimodipine in models of neurodegeneration and dementia. Patch voltage clamp studies demonstrated high-affinity nimodipine block of voltage-dependent L type calcium channel activity in central neurons from primary cultures of neonatal rat hippocampus. Nimodipine potently blocks depolarization-induced increases in free calcium throughout the soma of these hippocampal neurons. In addition, somatic free calcium elevations induced by acute beta A4(25-35) exposure are also potently blocked by nimodipine. In behavioral studies, nimodipine produced enhanced retention in aging rabbits on eyeblink conditioning and also was shown to protect against medial septal lesion-induced retention deficits in a spatial learning task. These findings, from channel to behavioral effects, support the therapeutic usefulness of nimodipine in the treatment of aging and dementia and are consistent with the view that calcium regulation is important in disorders of neuronal degeneration. PMID- 7847683 TI - Increased hippocampal Ca2+ channel activity in brain aging and dementia. Hormonal and pharmacologic modulation. PMID- 7847684 TI - Possible role of apoptosis in Alzheimer's disease. PMID- 7847685 TI - Age-dependent changes in calcium currents and calcium homeostasis in mammalian neurons. PMID- 7847686 TI - The calcium rationale in aging and Alzheimer's disease. Evidence from an animal model of normal aging. PMID- 7847687 TI - Ion transport systems and Ca2+ regulation in aging neurons. PMID- 7847688 TI - Calcium and neuronal dysfunction in peripheral nervous system. PMID- 7847689 TI - Cerebrovascular, neuronal, and behavioral effects of long-term Ca2+ channel blockade in aging normotensive and hypertensive rat strains. AB - The pathogenesis of essential hypertension is not fully understood, but most of the cardiovascular, metabolic, neurogenic, and humoral abnormalities are explained by dysfunctions in the control of intracellular Ca2+ concentrations in the cells of the vascular wall. Most theories of disturbed calcium regulation focus on the calcium concentration within vascular smooth muscle cells. The implications of hypertension for the increased calcium content of aging arteries seem to be clear, but were only studied in the peripheral circulation; hypertension prominently augments the aging-related accumulation of calcium in the vessel wall. Although the contribution of calcium overload in hypertensive cerebrovascular damage is well documented, it is not clear yet if hypertension per se is the main cause of hypertension-associated calcium-dependent cerebral damage. Thus far, the hypotensive effects of most calcium antagonists were extensively described, and their efficacy in stroke prevention was proven. Earlier studies indicated that chronic administration of nimodipine revealed a protective effect in the occurrence of strokes in SHR-SP rats, yielding a decreased mortality rate. Because nimodipine did not lower the extremely high blood pressure of these animals, the mechanisms behind such nimodipine-induced stroke prevention may be attributed to a direct cerebrovascular and/or neuronal action of nimodipine. Hypertension is generally considered a vascular pathologic condition, and most research has been directed towards the influences of hypertension on large peripheral arteries such as the aorta and coronary artery. The influence of the CNS on the regulation of cardiovascular system and blood pressure regulation was described in detail, and the role of the CNS in hypertension also was the subject of study. The increased risk of stroke in hypertensive subjects generated numerous studies on the precise nature of compromised cerebrovascular functioning under hypertensive conditions. Few data are available on Ca2+ alterations in cerebral neurons during hypertension. Honda et al. demonstrated that voltage-dependent Ca2+ uptake was higher in cortical synaptosomes from SHR than form normotensive animals and suggested that an important alteration in Ca2+ channel characteristics may occur in SHR brain synaptosomes. Although the density of L-type calcium channels was shown to be higher in the hippocampus of SHR rats, others reported that the number of L-type calcium channels was significantly lower in the brain of SHR rats than WKY normotensive controls. The latter data suggest that hypertension may be associated with similar alterations in neuronal calcium homeostasis as demonstrated for aging in normotensive subjects.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7847690 TI - Comparison of structural synaptic modifications induced by long-term potentiation in the hippocampal dentate gyrus of young adult and aged rats. PMID- 7847691 TI - Calcium antagonists in aging brain. PMID- 7847692 TI - Calcium and neuronal injury in Alzheimer's disease. Contributions of beta-amyloid precursor protein mismetabolism, free radicals, and metabolic compromise. AB - Alzheimer's disease (AD) is defined by degeneration of specific populations of neurons and the presence of insoluble aggregates of cytoskeletal proteins and amyloid beta-peptide (A beta) within affected brain regions. Alzheimer's disease does not appear to result from a single alteration, but in some cases of inherited AD a specific genetic defect can precipitate the disease. In this article, metabolic compromise, altered metabolism of the beta-amyloid precursor protein (beta APP), and an excitotoxic form of neuronal injury are considered central to the pathogenesis AD. The hypothesis is forwarded that destabilization of neuronal Ca2+ homeostasis underlies neuronal degeneration and that multiple age-associated and/or genetic alterations contribute to the loss of Ca2+ homeostasis. Recent studies showed that the secreted forms of beta APP (APPss) stabilize intracellular free calcium levels ([Ca2+]i) and protect neurons against excitotoxic insults. In contrast, A beta which arises from alternative processing of beta APP forms free radical peptides and aggregates that destabilize [Ca2+]i and make neurons vulnerable to metabolic insults. Increased expression (eg, Down's syndrome) or altered processing (eg, beta APP mutations) of beta APP may increase the A beta/APPs ratio. The death of neurons in AD most likely has an excitotoxic component because: the vulnerable neurons possess high levels of glutamate receptors; experimentally induced excitotoxicity shows several features similar to those of neurofibrillary tangles; and A beta can destabilize [Ca2+]i homeostasis and render neurons vulnerable to neurofibrillary degeneration. Selective vulnerability may result from cell type-specific differences in expression of proteins involved in regulating [Ca+]i. In addition, many intercellular signals are involved in determining whether a neuron is able to maintain [Ca2+]i within a range of concentrations conducive to cell survival and adaptive plasticity. In this regard, it was recently shown that several growth factors can stabilize [Ca]i and protect neurons against excitotoxic injury and A beta toxicity. Age-related changes in the brain (eg, ischemic conditions, reduced glucose uptake, and increased glucocorticoid levels) may compromise the mechanisms that normally regulate [Ca2+]i adaptively. PMID- 7847693 TI - Calcium-activated neutral proteinase (calpain) system in aging and Alzheimer's disease. AB - Calpains (CANPs) are a family of calcium-dependent cysteine proteases under complex cellular regulation. By making selective limited proteolytic cleavages, they activate or alter the regulation of certain enzymes, including key protein kinases and phosphatases, and induce specific cytoskeletal rearrangements, accounting for their suspected involvement in intracellular signaling, vesicular trafficking, and structural stabilization. Calpain activity has been implicated in various aging phenomena, including cataract formation and erythrocyte senescence. Abnormal activation of the large stores of latent calpain in neurons induces cell injury and is believed to underlie neurodegeneration in excitotoxicity, Wallerian degeneration, and certain other neuropathologic states involving abnormal calcium influx. In Alzheimer's disease, we found the ratio of activated calpain I to its latent precursor isoform in neocortex to be threefold higher than that in normal individuals and those with Huntington's or Parkinson's disease. Immunoreactivity toward calpastatin, the endogenous inhibitor of calpain, was also markedly reduced in layers II-V of the neocortex in Alzheimer's disease. The excessive calpain system activation suggested by these findings represents a potential molecular basis for synaptic loss and neuronal cell death in the brain in Alzheimer's disease given the known destructive actions of calpain I and its preferential neuronal and synaptic localization. In surviving cells, persistent calpain activation may also contribute to neurofibrillary pathology and abnormal amyloid precursor protein trafficking/processing through its known actions on protein kinases and the membrane skeleton. The degree of abnormal calpain activation in the brain in Alzheimer's disease strongly correlated with the extent of decline in levels of secreted amyloid precursor protein in brain. Cytoskeletal proteins that are normally good calpain substrates become relatively calpain resistant when they are hyperphosphorylated, which may contribute to their accumulation in neurofibrillary tangles. As a major effector of calcium signals, calpain activity may mirror disturbances in calcium homeostasis and mediate important pathologic consequences of such disturbances. PMID- 7847694 TI - Phosphorylation of neuronal cytoskeletal proteins in Alzheimer's disease and Lewy body dementias. PMID- 7847695 TI - [Celioscopic surgery in duodenal ulcer. The gastroenterologist's point of view]. PMID- 7847696 TI - [Treatment of closed trauma of the liver]. PMID- 7847697 TI - [Hyperparathyroidism and intrathyroid parathyroid gland. 43 cases]. AB - The rate of occurrence of intrathyroidal parathyroid glands in patients treated surgically for hyperparathyroidism (HPT) varies across studies. Among 1200 consecutive patients who underwent surgery for HPT at the Lille Hospital, France, between December 1965 and July 1992, 43 (3.6%) had 47 histologically-proven intrathyroidal parathyroid glands, including 44 lower and three upper parathyroid glands. Fifteen patients had a thyroid gland abnormality. Of the 14 patients who had a preoperative ultrasound study, eight exhibited an abnormal image. Thirty four of the 47 intrathyroidal parathyroid glands were visible at the surface of the thyroid gland, five were felt on palpation, and eight were discovered upon examination of a lobectomy specimen. A normal or abnormal parathyroid gland can be completely concealed within the thyroid gland, even in the absence of concomitant thyroid gland disease. In most cases, the ectopia affects one or both lower parathyroid glands, although in some instances the two glands on the same side are intrathyroidal. There is no fail-proof means for detecting intrathyroidal parathyroid glands preoperatively. An apparently missing fourth parathyroid gland or a fifth gland should be looked for in the thyroid gland when the cause of HPT is not found during a first cervicotomy procedure. Pre- or intra operative ultrasonography may be the most informative imaging method for detecting intrathyroidal parathyroid glands and should be performed routinely when a repeat procedure for persistent HPT is being considered. PMID- 7847698 TI - [Treatments of inguinal hernias by celioscopy. Preliminary results apropos of 162 cases]. AB - Mesch insertion is a reliable means for repairing inguinal hernias. Results in 162 patients treated laparoscopically via an intraperitoneal approach are reviewed herein. Analgesics were not required after the first postoperative day in 71% of patients. Fourteen patients were treated on a day-care basis. There were two recurrences due to inadequate fixation of the mesch to Cooper's ligament. The two patients who developed an infection did not require removal of the patch and had a strong, completely healed wall at the follow-up evaluation after four and ten months, respectively. The number of patients and duration of follow-up are still inadequate. However, these preliminary data warrant continued use and evaluation of this technique. PMID- 7847700 TI - [Risk of locoregional recurrence after resection of cancer of the rectum]. AB - Using the Registre des Tumeurs Digestives of the Cote-d'Or, a survey was conducted to study the risk of local recurrence of patients after curative surgery for rectum cancer diagnosed between 1976 and 1984 in the above mentioned department. Data was available in May 1987 for 448 patients, or 95% of the recorded cases. The cumulative local recurrence rate was 5.9% at 1 year, 19.1% at 3 years and 24.4% at 5 years. It was independent of sex, age, site of the cancer, time of diagnosis and length of distal margin (for cancers treated by anterior resection). On the other hand, the risk of local recurrence varied with macroscopic appearance (distinguishing fungating cancers from other macroscopic types), size (less than 6 cm on more than 6 cm), extension into the bowel wall (cancer limited or not to the wall) and degree of node invasion (no node involvement, 1 or 2 invaded nodes, more than 2 invaded nodes). The results of Cox model indicate that these 4 variables independently influence the risk of local recurrence. These data, which are interesting because of having been collected from a general population, are useful in planning therapeutic trials and in specifying postoperative surveillance methods. They suggest that, independently of extension into the bowel wall and node involvement, the macroscopic appearance and size of the cancer influence the risk of local recurrence. PMID- 7847699 TI - [Proctectomy and colo-anal anastomosis after high-dose irradiation of cancers of the lower third of the rectum. Functional and oncological results]. AB - This prospective study was designed to evaluate morbidity and functional and oncological outcomes in patients with carcinoma of the distal third of the rectum treated by high-dose radiation therapy followed by conservative surgery. Twenty two patients with adenocarcinoma of the distal third of the rectum treated after June 1990 were included in the study. Mean distances separating the tumor from the upper edge of the levator ani muscle and from the anal verge were 17 mm and 47 mm, respectively. None of the tumors were fixed; preoperative stage, established by endoscopic ultrasound, was T2 in 12 patients and T3 in 10. Patients received induction radiation therapy in two series delivered three weeks apart (40 Gy on the pelvis, then 20 Gy on the tumor only) followed by surgical resection (proctectomy with colo-anal anastomosis in 17 cases and amputation in five). After radiation, two tumors were negative for malignant cells, 12 were Astler-Coller B1, two were B2, and six were C2. Mean safety margin after colo anal anastomosis was 16.8 mm; all the resection margins were negative. Mortality and morbidity were not increased by the high-dose radiation protocol. Conservation of the sphincter was possible in 80% of patients. All the patients were continent. Functional outcome was rated good in 77% of cases, fair in 9% and poor in 4%. During the mean follow-up of 24 months, there were three disease related deaths, including one due to a strictly regional recurrence; metastatic dissemination to the lungs occurred in two patients and the remaining 17 patients (80%) were disease-free. These data suggest that high-dose radiation therapy followed by conservative surgery ensures satisfactory functional outcomes in patients with carcinomas of the distal rectum. Evaluation of oncological outcomes will require a longer follow-up. PMID- 7847701 TI - Biochemical laboratory data in patients before and after restorative proctocolectomy. A study on 83 patients with a follow-up of 36 months. AB - From 1980 to 1987 ileoanal pouches were made in 83 patients. Specimen for a set of laboratory analyses were taken preoperatively, during the ileostomy and loop ileostomy periods and repeatedly during 36 months of follow-up. Cobalamine absorption and 14C-triolein breath tests were performed preoperatively in electively operated patients and postoperatively in all patients at 12 and 36 months. Low S-Ca was most pronounced preoperatively in patients who were to undergo acute colectomy (53%). Decreased S-Mg was detected in 16-36% at all stations. None had signs or symptoms of hypomagnesemia. Low S-albumin was rarely seen except for preoperatively in acute patients. Increased IgM was found in 40% of the patients during the loop ileostomy phase compared to 6-10% preoperatively. Substantially increased orosomucoid and/or haptoglobin were seen in patients during the functional periods but these increased values could not be correlated to episodes with acute pouchitis. High values of S-ALAT and ALP were much more frequent during the loop ileostomy periods than it was preoperatively and during pouch function. Low S-haemoglobin and/or iron were noticed during the functional period in 3-8% and 10-16%, respectively. Severe anaemia, due to iron deficiency developed in one patient after 2.5 years of pouch function. Preoperatively, slight decreases of S-B12 were found in 13% and impaired cobalamine absorption was revealed in 38% of the electively operated patients. The corresponding figures were 3% and 31% after 12 months and 5% and 36% after 36 months of follow up, respectively. B12 substitution was given to in all 8 patients during the follow-ups. Lipid absorption was disturbed in 38% preoperatively and in 35% and 41% at 12 and 36 months, postoperatively. PMID- 7847702 TI - [Diagnostic and therapeutic strategy of Zollinger-Ellison syndrome. Groupe de Recherches et d'Etudes du Syndrome de Zollinger-Ellison (GRESZE)]. AB - The current strategy recommended for Zollinger-Ellison syndrome (ZES) has significantly improved the outcome of this condition. Diagnosis is based on determinations of basal and post-secretin gastric acid output and serum gastrin levels. A crucial step is differentiation of patients with sporadic ZES from those with multiple endocrine neoplasia type 1 syndrome. Only the former should undergo excision of the tumor when feasible. All available imaging techniques should be used pre- and intra-operatively to detect tumorous lesions. Exploratory laparatomy is warranted in patients who have sporadic ZES without evidence of liver metastases. PMID- 7847703 TI - [Insufflators for endoscopy]. AB - Operative laparoscopy needs a space to be made inside the abdominal cavity. This can only be achieved by suspension or by positive pressure. The endoscopic insufflator makes it possible to create this positive pressure, and does indeed enable the operating space to remain open. But it would be too limiting to consider these devices from the visibility point of view only, for they can also be exploited for their action on hemostasis and dissection. With this in mind we feel that the endoscopic surgeon ought to be perfectly familiar with his apparatus and not simply limit himself to adjusting the pressure and flowrate at the beginning of the operation. This hyper pressure in the abdomen is not without consequences for the patients' homeostasis and can indeed require an operation to be halted or converted to laparotomy. So knowledge of the biomedical aspects of his equipment will also enable the surgeon to increase the safety of his operations. PMID- 7847704 TI - [The Milligan-Morgan method of hemorrhoidectomy, used by the Saint-Marks Hospital]. PMID- 7847705 TI - [Ferguson's method of closed hemorrhoidectomy]. AB - The technique of closed hemorrhoidectomy (Ferguson hemorrhoidectomy) is described in details. The surgical indications, advantages, pre-operative preparation, choice of anesthesia and technical details are addressed in sequence. The original references by Dr. Ferguson are included. PMID- 7847706 TI - [Death to Whitehead, hurray for Toupet! or total circular hemorrhoidectomy revisited. Its technique, their indications and their results]. AB - For surgical excision of hemorrhoids, the Whitehead procedure is considered a poor technique responsible for anal stenosis, anal incontinence, prolapse, and mucous ectropion. However, with the modifications suggested by Andre Toupet, these complications do not occur. The Whitehead procedure as modified by A. Toupet requires considerable experience in anorectal surgery. Indications include total hemorrhoid prolapse, in particular with thrombosis, and mucous prolapse. PMID- 7847707 TI - [Post-traumatic hemobilia. How to treat? Apropos of a case]. AB - Severe hemobilia after blunt hepatic trauma is one of the limits for a conservative medical treatment. Urgent percutaneous highly selective embolization of the bleeding vessel is the treatment of choice today. Failures of radiological treatment require surgery. Primary direct ligation of the bleeding vessel carries a risk of recurrence and prevents subsequent embolization. Under these conditions, when the surgeon prefers a conservative approach, preoperative embolization using permanent material can be performed as reported in our case study. PMID- 7847709 TI - [Laparoscopy-guided percutaneous endoscopic gastrostomy: a possibility after failure of classic percutaneous endoscopic gastrostomy]. PMID- 7847708 TI - [Gastroduodenal intussusception on gastric tumor]. AB - Gastroduodenal intussusception is a rarely documented condition. A distinction has to be made between complete gastroduodenal intussusception (CGDI) and either prolapse of a pedunculated tumor through the pylorus or mucosal prolapse through the pylorus. CGDI usually occurs secondary to a pedunculated benign gastric tumor. More rarely the tumor is malignant. We report a case of CGDI associated with gastric adenocarcinoma. We emphasize diagnostic difficulties that can be generated by CGDI. PMID- 7847710 TI - [History of augmentation mammaplasty]. PMID- 7847711 TI - [Introduction to silicone chemistry]. PMID- 7847712 TI - [Clinical applications of silicone chemistry]. PMID- 7847713 TI - [Chemistry of hydrogels]. PMID- 7847714 TI - [Manufacture of breast prostheses]. PMID- 7847715 TI - [Standards for manufacturing implantable breast prostheses]. PMID- 7847716 TI - [Smooth-walled pre-filled silicone breast prostheses]. PMID- 7847717 TI - [Inflatable breast prostheses]. PMID- 7847718 TI - [Double-lumen breast prostheses]. PMID- 7847719 TI - [Textured breast prostheses]. PMID- 7847721 TI - [Indications and surgical approaches of augmentation mammaplasty]. PMID- 7847720 TI - [Breast prostheses pre-filled with hydrogel]. PMID- 7847722 TI - [Unsuitable breast implants]. PMID- 7847723 TI - [Early complications of breast prostheses other than contraction]. PMID- 7847724 TI - [Rupture of prostheses pre-filled with silicone gel]. PMID- 7847725 TI - [Adverse reactions capsular retraction excepted]. PMID- 7847726 TI - [Histology of periprosthetic environment]. PMID- 7847727 TI - [The hard breast phenomenon]. PMID- 7847728 TI - [Silicone breast prostheses and autoimmune diseases]. PMID- 7847729 TI - [Breast prostheses and breast cancer]. PMID- 7847730 TI - [Carcinologic risk of silicone gel breast prostheses in women treated for breast cancer]. PMID- 7847731 TI - [Female identity]. PMID- 7847732 TI - [Assessment of patient satisfaction after implant insertion]. PMID- 7847733 TI - [Civil liability of the plastic surgeon: from esthetics to prostheses]. PMID- 7847734 TI - [Report of experts: on possible adverse effects of breast implants with silicone gel]. PMID- 7847735 TI - [Future of breast implants]. PMID- 7847736 TI - [Breast prostheses. Freedom of decision]. PMID- 7847737 TI - ["Advantages" and disadvantages of breast implants]. PMID- 7847738 TI - Occupational health services. PMID- 7847739 TI - A study of occupational skin disease in the metal industry (1986-1990). AB - A retrospective study of the epidemiology of occupational skin disease among metal workers showed that irritant contact dermatitis (75%) prevailed over allergic contact dermatitis. Most workers belonged to the age group 20 to 29 years. There was a slight preponderance of Malays and Indians compared to the working population of Singapore. Most presented for treatment within 10 days of their dermatitis. Ninety-five percent presented with dermatitis on the hands and arms. There was no significant difference in the prevalence of atopy between workers with irritant and allergic contact dermatitis. In most cases of allergic contact dermatitis from cutting fluid, the causative allergen in the cutting fluid cannot be identified. PMID- 7847740 TI - Study of the effects of occupation and industry on sperm quality. AB - Most of the environmental exposures known to affect testicular function and/or male fertility are to pharmacologic agents, alkylating agents and antitestosterone agents. There are however, few firmly-based associations with occupational exposure. The aim of this study was therefore to determine if there is any association between different semen parameters (viz. sperm count and motility) in relation to occupations and industrial groupings. A total of 614 subjects who attended an andrology clinic were studied. The investigation included a detailed occupational history, clinical examination and seminal analysis for volume, sperm count, and sperm motility. Each subject's last occupation and the industry he represented was classified according to the standard classification code of the Singapore Standard Occupational Classification (SSOC) and the Singapore Standard Industrial Classification (SSIC), respectively. The results showed that subjects who worked as "plant and machine operators" had a significantly higher risk of oligozoospermia, with an adjusted (for age, smoking, medical history, and testicular size) odds ratio (OR) of 1.93 (1.12-3.30), as compared with other occupational groups. Exposure to excessive heat was a possible factor for the poorer sperm count. "Senior officials and managers" were less likely to have poor sperm count, adjusted OR = 0.52 (0.32-0.84), compared to individuals from other occupations. As for abnormal sperm motility, workers from the "transport and communication" industry had significantly higher adjusted OR of 1.80 (1.08-3.00) when compared to the other occupational groups. This could not be attributed to excessive noise, heat or solvent exposure at the workplace. PMID- 7847741 TI - Chronic neurobehavioural effects in paint formulators exposed to solvents and noise. AB - Twenty-one male paint formulators with an average age of 41.3 years (range 27 53), educational level of 7.4 years (range 5-10) and exposure level of 0.09 times Threshold Limit Value (TLV) index of solvent mixture (range 0.003-0.24 times TLV index) for 20.2 years (range 7-39) were studied with a battery of neurobehavioural performance tests including digit span, digit symbol, Benton visual retention, finger tapping, grooved peg board, and aiming test. A group of 21 male workers matched for age (mean 40.8 years, range 25-53) and education (mean 6.9 years, range 5-12), and with no history of exposure to neurotoxic agents were selected as controls. In all the neurobehavioural tests, the exposed workers' performances were observed to be poorer than the controls'. Statistically significant differences were observed in digit span, grooved peg board, and the Z score after adjusting for age, level of education and ethnicity. The least square means for digit span were 11.7 (standard error [SE] 0.77) and 9.2 (SE 0.79); for grooved peg board were 60.5 (SE 2.1) and 69.7 (SE 2.1); and for neurobehavioural Z score were 0.02 (SE 0.11) and 0.50 (SE 0.11) in the controls and exposed workers respectively. The exposed group also performed significantly poorer in aiming test error score and digit span when compared to the controls after adjusted for age, education and ethnicity. The least square means for aiming test error score were 6.5 (SE 2.7) and 12.8 (SE 2.8) for the controls and exposed workers respectively.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7847742 TI - Urinary excretion of tubular brush-border antigens among lead exposed workers. AB - The brush-border of the human renal proximal tubule is extremely sensitive to toxic, ischaemic and inflammatory insults. A monoclonal antibody to a brush border antigen (BB-50) had been shown to identify increased urinary excretion of BB-50 (UBB-50) among workers exposed to heavy metals and hydrocarbons as well as patients on cisplatin and patients with early diabetic nephropathy. This study describes the use of this antibody to quantify UBB-50 among lead exposed workers. The study population consisted of 154 workers from a factory manufacturing lead stabilisers. Of these 91 workers had less than 6 months of exposure and formed the control group. The remaining 63 workers with a median exposure of 3 years formed the exposed group. Several blood lead (PbB) indices were used as exposure indices. These include the most recent PbB (PbBrec), a time-integrated blood lead index (PbBint), an absolute change in recent PbB (PbB delta), a relative change in PbB (PbB delta%), as well as the number of times the PbB measurements were above 40, 50 and 60 micrograms/100 ml (PbB40, PbB50, PbB60 respectively). Urinary levels of beta-2-microglobulin (U beta 2m), alpha-1-microglobulin (U alpha 1m), retinol binding protein (URBP), albumin (UAlb), activity of total N-acetyl-D-beta glucosaminidase (NAG-T) and heat stable NAG isoenzyme (NAG-B) were measured along with the serum beta 2m (S beta 2m). Through stepwise analysis, UBB-50 was best correlated with PbBint, PbB40 and PbB delta% (r2, 0.271). Of these, PbBint and PbB40 had about twice the contribution to the variation in UBB-50.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7847743 TI - Sickness absence in a Singapore refinery, 1981-1992. AB - Sickness absence among the unionised staff of the largest petroleum refinery in Singapore was followed up from 1981 to 1992. The changes seen throughout these 12 years were related to national, organisational and personal factors. Initially because of increasing competitiveness in the industry, and later because of a national recession, manpower in the refinery was progressively reduced from 1981 to 1986. This however was not the main cause of the reduction in sickness absence rates from 8.4 working days in 1981 to 5.8 days in 1983. Organisational changes to medical leave entitlements and improved means of supervision of absence were responsible for the early fall in absence rates. Personal factors, such as the increasing age of the population, did not affect the amount of short-term absences, while shift work was associated with higher absences. From 1986 absence rates rose again, eventually to almost 1981 levels by 1992, a reflection of the tendency for sickness absence to increase with time, unless active measures are undertaken for its control. PMID- 7847744 TI - Medical selection of military pilots: a Republic of Singapore Air Force perspective. AB - A comprehensive selection examination in the Republic of Singapore Air Force (RSAF) aims to minimise medical wastage of military pilots who have to function safely in the unnatural environment. Of the 8642 applicants examined, 657 (7.6%) were rejected for non-medical reasons before completion of medical examination. Of the remaining 7778, 58.7% passed the selection examination while 41.3% failed. Ophthalmological (34.3%), anthropometry (23.7%), and ENT (13.7%) conditions were the three major causes for failure (71.7%). Myopia and astigmatism accounted for 57.6% while squints accounted for 22.1% of the ophthalmological conditions. Amongst ENT conditions, 70.8% were for marked vasomotor rhinitis, sinusitis and nasal septum deviation with marked narrowing of one or both nasal passages, while 22.4% were for permanent abnormal hearing threshold shifts above the minimum standards. PMID- 7847745 TI - Effects of sleep deprivation on performance of Naval seamen: I. Total sleep deprivation on performance. AB - Sleep deprivation leads to impairment in performance, loss of efficiency and deterioration in mood states such as tension, depression, aggression, fatigue, confusion and vigour. These can be detrimental to combat readiness and could contribute to "battle stress". In the present study, a homogeneous group of 20 seamen under total sleep deprivation was rated 6 hourly with the Stanford Sleepiness Scale (SSS), Profile of Mood States (POMS) and a battery of performance tests including the trail making, grooved peg board, digit span, digit symbol, sea-shore rhythm, flicker fusion, dynamometer and naval tasks. With the exception of the trail making test and naval tasks, the test performance was observed to correlate significantly (P < 0.05) with the SSS. A higher sleepiness score was associated with a poorer performance in test scores. On the time trends of sleep deprivation on the performance tests measured, a dip in performance was observed in all the tests at 42 hours of sleep deprivation and continuous deterioration of performance was observed after 72 hours of sleep deprivation. The cognitive, vigilance, mood and sleepiness tests were substantially affected by sleep deprivation. Greater effect was observed in tests that involved cognition, speed and precision and smaller effect was observed in routine tasks that involved gross manual movement. The decrease in performance observed at 42 hours of sleep deprivation was 5.9 standard deviation from initial values for SSS; 3.9 for sea-shore rhythm, 3.0 for grooved peg board; 2.6 for dynamometer; 2.4 for mood; 1.8 for digit span; 1.6 for trail making and digit symbol; 1.0 for naval tasks and addition; and 0.9 for flicker fusion.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7847746 TI - Effects of sleep deprivation on naval seamen: II. Short recovery sleep on performance. AB - Twenty male naval volunteers, aged 18 to 20 years, with 12 to 14 years of education, underwent a total sleep deprivation experiment on board a Republic of Singapore Navy landing ship in the South China Sea for a period of 42-102 hours. The sleep group comprised eight volunteers who dropped out at the 44th-46th h of the experiment and were randomly assigned to a 2 or 4 h sleep regime. The rest served as sleep-deprived controls. Neurobehavioural performance tests, profile of mood state and the Stanford Sleepiness Scale were applied 6 hourly starting from 6.00 am on the first experimental day. No thresholds were observed in the performance of tests related to manual tasks and subjective feeling, including naval tasks, mood and sleepiness scale during the sleep deprivation experiment. However, thresholds were observed in the performance of tests requiring cognitive and perceptive skills, including the grooved peg board, trail making, sea-shore rhythm, addition, digit span, digit symbol, flicker fusion and dynamometer tests. Performances in these tests were observed to deteriorate only after approximately 30 h of sleep deprivation. The Z score for the non-threshold tests (Z-N) deteriorated from -0.01 at the start of the experiment to 1.25 at the 42nd h of the experiment just before the imposed sleep and improved to 0.81 at the 48th h of the experiment just after the imposed sleep; and the Z score for the threshold tests (Z-T) varied from -0.07 at the start to 0.49 just before sleep (at the 42nd h) and to continuously deteriorate to 0.83 just after sleep (at the 48th h).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7847747 TI - Occupational burns in the Burns Centre at the Singapore General Hospital. AB - This study reviewed all work-related burn injuries within the period 1 April 1992 to 31 March 1993 for the purpose of establishing data on occupational burns in Singapore to identify the specific at-risk population and formulate prevention strategies. All 163 patients who were admitted to the Burns Centre, Singapore General Hospital, as a result of burns suffered in the workplace were reviewed using the World Health Organisation Burns Data Protocol. Burns data recorded included demography, industrial sector involved, aetiology, extent of injury and eventual outcome in terms of mortality and morbidity. Occupational burns accounted for 45% of all admissions to the Burns Centre. Male workers in the 20 to 40-year age group predominated with 90% of admissions. The most common aetiology was flame burns and explosions (52.8%) followed by scalds (24.5%) and electrical (10.4%), chemical (6.1%) and contact (6.1%) burns. The average body surface area (BSA) involved was 8% (range 0.25% to 90%). Twenty-seven patients suffered full-thickness burns and the average area of involvement was 2% (range 0.25% to 90%). The most common anatomical regions involved were the upper limbs (46.3%) followed by lower limbs (31.9%). Eighteen patients (11.0%) sustained major burns requiring fluid resuscitation and 39 patients (23.9%) sustained respiratory burns. Seven patients died, giving a mortality rate of 4.3%. The average BSA for these patients was 46.4% and all had respiratory burns. In all, occupational burns accounted for 2011 patient-days of hospitalization, 630,637 lost days at work and inpatient treatment costs amounting to S $1.32 million.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7847748 TI - Occupational exposures to carcinogens in developing countries. AB - There have been very few studies of exposure to occupational carcinogens in developing countries, and even fewer studies of the health consequences of such exposures. However, all industrial chemicals, occupations and industrial processes classified by the International Agency for Research on Cancer (IARC) as Group 1 or Group 2A (carcinogenic or possibly carcinogenic to humans) have been described in developing countries, and there is growing concern that the health impact of many chemicals used in the developing world has been underestimated. In all regions a very large workforce is employed in the construction industry, in which substantial exposure to asbestos may occur, and there has been a rapid increase in production in countries such as Brazil and India. There is, for instance, a similar pattern for tyre production with a large increase in production in developing countries in the 1980s. Thus, the number of workers in industries entailing a carcinogenic risk is increasing in developing countries, partly as a result of the transfer of hazardous industry from industrialized countries. There is much that could be achieved in the prevention of occupational cancer in developing countries, and there have been a number of successful initiatives. However, the greatest progress in the prevention of occupational cancer in developing countries is most likely to come from political and economic changes. PMID- 7847749 TI - Common industrial processes and occupational irritants and allergens--an update. AB - This paper reviews the recent development of the industrial processes in the construction, electronics and metal industries which are the predominant industries in developing countries. Common occupational irritants and allergens are presented. The information is essential for occupational dermatologists and physicians managing patients with occupational skin diseases. In the construction industry, the prefabrication construction methods are now widely used. The commonest irritant is cement and the allergens are chromate, rubber chemicals and epoxy resins. In the electronics industry, the commonest irritants include soldering flux, solvent and fibreglass, and allergens include resins and metals, rubber chemicals and amines and colophony. Cutting fluid is the commonest occupational irritant in the metal industry. Biocides and metals in The electro discharge machining process now widely used in the metal industry for precision engineering uses the electrodischarge machining fluids (EDM fluids) which are a strong skin irritant. Preventive measures including health education are most effective against occupational dermatitis. PMID- 7847750 TI - Shift work and health--a critical review of the literature on working hours. AB - Working outside normal hours either by extended days or shift work is a fact of industrial society. Its economic advantages must be weighed against detrimental effects on the individual worker in the form of circadian rhythm disturbance, poorer quality and quantity of sleep and increased fatigue. The link between shift work and increased cardiovascular morbidity and mortality has strengthened in recent years. The case for an association with gastrointestinal disease remains quite good. Evidence of poorer work performance and increased accidents, particularly on the night shift, is persuasive, although individual factors may be as important as workplace factors. Correct shift work scheduling is important and for rotating shifts, rapid forward rotation is the least disruptive option. The compressed working week of 10 to 12-hour shifts is gaining popularity but evidence is too scant at present to suggest there are many long-term health and safety risks provided the rest day block is preserved. Optimal hours for the working week cannot be formulated on present scientific evidence, though working more than 48-56 hours a week probably carries serious health and safety implications. The inherent conflict between the interest of the worker and the enterprise over unsocial hours can be mitigated by improvements in working conditions especially at night and by advice to the worker on coping strategies. Further research is needed on the effects of the compressed working week, as well as the influence of culture, task and gender on any health effects. Studies to define individual characteristics which may cause shift work intolerance would be of great practical use. PMID- 7847751 TI - Health of female shiftworkers in Singapore. AB - More than 200,000 persons in Singapore work shifts. Over half of these shiftworkers are females. With the continued emphasis on capital-intensive industries and growing demand for "round-the-clock" services, shiftwork is increasingly an economic necessity for more and more industries and a way of life for many Singaporeans. It is generally accepted that about 20% of those who start shiftwork may find it difficult to continue in such work, usually for social rather than medical reasons. For those who continue on shiftwork, concerns have been raised regarding possible health effects, such as increased incidence of digestive disorders and ulcers, chronic fatigue and cardiovascular disorders. In the case of female shiftworkers, there is also the concern that the added responsibilities of looking after the home and young children may further aggravate sleep problems associated with shiftwork, thus adversely affecting their health. So far, our own studies of female electronics workers on 8-hour as well as 12-hour shift schedules indicate no serious long-term health effects. The study subjects had been employed in such work for at least over a year, some as long as 17 years and 6 years, respectively. Except for complaints of sleep problems and tiredness among some rotating shiftworkers, no significant differences in symptom prevalence, blood pressure or sickness absence were found between the shift and day workers. While the findings are reassuring, further studies may be needed to determine if preventive measures can be taken to minimise the common complaints of sleep problems and tiredness, particularly among rotating shiftworkers. PMID- 7847752 TI - Application of neurophysiological methods in occupational medicine in relation to psychological performance. AB - Many years ago, we introduced advanced neurophysiological and psychobehavioural methods to our laboratory and have since applied our techniques on workers exposed to various occupational factors. In this article, we summarized our recent findings on the neurophysiological subclinical effects of lead, mixed solvents, toluene, styrene, local vibration and visual display terminal (VDT) work in relation to psychobehavioural effects. The methods used were as follows: 1) cerebral evoked potentials, i.e. short-latency somatosensory and visual evoked potentials (SSEP and VEP) and brainstem auditory evoked potential (BAEP), 2) event-related potential (P300), 3) psychological performance test, 4) computerized static posturography, 5) electrocardiographic R-R interval variability (CVRR), 6) distribution of nerve conduction velocities (DCV), and 7) conventional nerve conduction velocity (NCV). The following results were obtained: 1) Delay in SSEP latency in lead workers, in VEP latency in lead and VDT workers, in BAEP latency in vibrating tool workers and in P300 latency in lead workers, as well as significant correlations of P300 latency with blood lead concentrations in lead workers and of BAEP latency with length of work in brush saw operators; 2) Increase in postural sway and its significant correlation with urinary hippuric acid in toluene workers; 3) Decrease in CVRR in lead, mixed solvent, toluene, styrene and vibrating tool workers, and a significant correlation of the CVRR with length of exposure in mixed solvent workers; 4) Slowing of faster nerve fibre conduction in DCV and of NCV in lead, mixed solvent, styrene and vibrating tool workers, and their correlations with blood lead and length of work in lead and chain saw operators, respectively; 5) Decrease in the score on picture completion test in lead and styrene workers and its correlation with blood lead in lead workers. These findings suggest that recent advances in neurophysiological methods have enabled the detection of subclinical effects of various occupational and environmental factors. PMID- 7847753 TI - Occupational heat stress. AB - Heat stress is an occupational health problem affecting Man in diverse, hostile environments ranging from deep mining to outer space. Healthy, young military recruits and industrial workers exposed to hot, humid environments are typically at risk. The International Classification of Diseases classifies heat disorders into 10 separate entities, of which the most clinically significant are heat cramps, heat exhaustion and heat stroke. The latter is a medical emergency of the first order. Clinical management hinges upon early treatment based on a high index of suspicion. Effective preventive measures and adequate education of those at risk form the basis for its control. PMID- 7847754 TI - Serial peak expiratory flow rate monitoring--a useful tool in epidemiological studies on occupational asthma. AB - Occupational asthma is the leading occupational respiratory disease. Epidemiological studies of occupational asthma have made use of the serial peak expiratory flow rate (PEFR) monitoring as a tool to identify cases, describe prevalence and to compare the mean diurnal variation (DV) in PEFR with an unexposed control group. Various indices of PEF variability can be used. The serial PEFR is a useful additional tool to the respiratory questionnaire and spirometry as it measures airway variability. It is also a practical alternative to histamine or methacholine inhalation testing. It has the advantage of providing multiple sequential readings of PEF and simple indices are available to express the airway variability of almost every subject studied. The validity of the serial PEFR recording should be further evaluated considering both the technical and human aspects. The monitoring protocol should be standardised and some criteria for validity should be pre-set. Factors that may affect DV in PEFR such as age, sex, smoking, race and the mean or maximum PEFR should be taken into account when comparing with controls. PMID- 7847755 TI - Case of occupational asthma due to glue containing cyanoacrylate. AB - Cyanoacrylates are a rare cause of occupational asthma, there being only six cases reported previously. High humidity has been implicated to be protective in the pathogenesis of the asthma. This is a case report of occupational asthma due to cyanoacrylate glue after working three years in a factory manufacturing doors. Diagnosis was made by history, serial peak flow measurements on and off work and specific inhalation challenge which elicited a delayed bronchoconstrictive response. An unusual feature of this case was the positive reaction to cyanoacrylate despite the high ambient humidity in Singapore. PMID- 7847756 TI - A case of occupational asthma due to barley grain dust. AB - We report a case of occupational asthma due to barley grain dust, species Hordeum Vulgare L, in a 32-year-old storeman of a trading company's department that dealt with packaging of flour, barley and peanuts. He developed immediate symptoms of sneezing, cough and dyspnoea on exposure to barley only. These symptoms showed work relationship. He became asymptomatic after his transfer to another department dealing with sales only. Bronchial provocation testing to the barley confirmed the diagnosis. PMID- 7847757 TI - Occupational health through primary health care clinics in Singapore. AB - The training of primary health care workers in occupational health is important for the provision of occupational health care to the workforce. In Singapore, over 400 Designated Factory Doctors, mostly general practitioners, have been trained. Occupational health is also incorporated in the training of family medicine trainees. Referral centres for cases of suspected work-related diseases are also available. Two specialist occupational health clinics function within Government polyclinics serving the large working population in Singapore. One such clinic operates every Wednesday morning at the Jurong Polyclinic. In the last four years, 485 patients with work-related complaints were seen. There were 268 cases (55%) of occupational skin disease, 74 patients (15%) with respiratory complaints, 38 patients (8%) with acute toxic exposures and 36 patients (7%) with musculoskeletal complaints. Three hundred and forty-nine of the referrals (72%) came from the Jurong Polyclinic doctors, with small numbers from other polyclinics and neighbouring private practitioners. The experience gained in conducting this clinic demonstrated that significant numbers of diseases seen at the polyclinic are work-related in varying degrees. Hence, there is a need for the further development of occupational health care delivery within the primary health care system. This can be achieved by improving occupational health training for all primary health care workers, providing an occupational health resource person at primary health care centres, and raising the awareness of such referral facilities in occupational medicine. PMID- 7847759 TI - Health care costs in industry. AB - The costs of providing health care in industries must remain affordable and rational. While recognising that employers have a moral commitment to workers' health and welfare, it must also be realised that resources committed to this end are finite. Furthermore, if these resources are spent on the minority, then all the more, the interests of the majority must be defended, as ultimately, medical expenses must form part of the wage costs. Both demand and supply factors of health care must be tempered. The factors influencing demand include the abuse and inappropriate use of health services, unhealthy lifestyle factors, the ageing of the population and the threat of litigation, while the factors affecting supply include new technology, easy accessibility and the creation of demand by doctors. Cost containment strategies should include the collection and interpretation of data on health care costs, the rationing of services, and cost sharing. Cost sharing is one of the most persuasive means through which a sense of cost sensitivity on the part of the consumer can be achieved. This can, and should, be incorporated in whatever form of purchase plan that employers wish to implement. PMID- 7847758 TI - Impact of statutory medical examinations on control of noise-induced hearing loss. AB - Noise at work is ubiquitous and presents a major occupational health problem in many countries. Prolonged exposure to loud noise can cause deafness of varying degrees. This is insidious in the early stages, but can be detected by audiometric examination. In the prevention of noise-induced hearing loss, control of noise at its source would be ideal. But for practical purposes, a multipronged approach is often necessary. Every noisy workplace should set up an in-plant Hearing Conservation Programme (HCP) which includes periodic audiometric examination of workers. In Singapore, since 1985, workers in many noisy workplaces are required to undergo statutory pre-employment and annual audiometric examinations arranged by their employers. The examinations are carried out by Designated Factory Doctors who have undergone a course of training in occupational health and are registered with the Labour Ministry. The doctors' role includes advising workers and employers on the prevention of noise-induced deafness (NID). Doctors notify cases of NID to the Ministry of Labour which conducts investigations where indicated. Since NID is insidious, workers with the condition would not be detected in the early stages without an audiometric examination. With the introduction of the statutory examinations, more noise exposed workers were examined and cases of early hearing impairment picked up. The statutory medical examinations have helped to highlight the problem of the noise hazard. Individual companies are able to monitor the noise problem in their workplaces, using the audiometric results to supplement the noise assessments. Susceptible workers can be identified and followed up more closely, and health education intensified.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7847760 TI - Silica and lung cancer: a continuing controversy. AB - The question whether silica is carcinogenic is not new, but there has been a resurgence of research over the last two decades with the use of more powerful epidemiological methodologies. There is sufficient evidence for the carcinogenicity of crystalline silica in animals. A large number of cohort and case-control studies consistently suggest a modest excess of lung cancer in workers with occupational silica exposure (relative risk less than 2). However, in many studies, the association is confounded by exposures to cigarette smoke, and environmental cocarcinogens like radon daughters, polyaromatic hydrocarbons and asbestos. The excess risk of lung cancer is more pronounced in workers with silicosis (relative risk of 2 to 4). Silica may act as a direct carcinogen or indirectly by the adsorption of cocarcinogens such as polyaromatic hydrocarbons from cigarette smoke or industrial pyrolysis products, and/or by impairing pulmonary clearance, thereby increasing the effective dose and duration of exposure to these carcinogens. Pulmonary fibrosis itself may be a precursor to the development of lung cancer. PMID- 7847761 TI - Options for provision of occupational health services in developing countries. AB - Different models of occupational health care are available for developing countries to consider in developing their provisions for occupational health services. Even in developed countries there are differences between legal requirements for personnel and services, and voluntary provision of services. The range of activities covered by occupational health services can be extensive. Developing countries often focus on the provision of clinical care and treatment facilities at the workplace with less emphasis on preventive services. This may be related to the perceived value of the clinical skills of the doctor and nurse available at the workplace, plus the lack of other occupational health personnel, and the limited access to occupational hygiene and laboratory facilities. For future occupational health provisions, developing countries have to consider the balance between preventive services versus other clinical and non-clinical services. There will be benefits in reviewing the experience of developed countries in terms of the essential skills and training of occupational health personnel, and the contribution this would make to the health of the workforce in developing countries. PMID- 7847762 TI - Drug-induced impaired performance. AB - The use of medication is becoming increasingly common in the workforce in an effort to minimise the time away from work. Little is written about the behavioural impact of drugs and rarely is it considered in risk assessments. Employees may equally suffer from the effects of illicit drugs, alcohol or even the residual effects of anaesthesia after day-case or minimally invasive surgery. This paper sets out to accomplish three objectives: first, to review methods of evaluating behavioural effects of drugs, their strengths and weaknesses; second, to review established performance effects of principal classes of behaviourally toxic drugs on driving as a model; and third, to propose some guidelines to assist occupational physicians and other clinicians in assessing the risks incurred from drug-induced impaired performance. PMID- 7847763 TI - Health issues in the global semiconductor industry. AB - The microelectronics industry began in the United States less than 50 years ago. It quickly spread to Japan and to a number of European countries and, in recent years, to much of the remaining world. The experience of US manufacturers is that some serious occupational and environmental problems occur, in particular, with the production of semiconductor devices. But before the occupational and environmental problems were adequately addressed, the industry had migrated to many countries around the world, especially to East Asia and Southeast Asia. This paper summarizes the limited number of studies of the health of semiconductor workers conducted thus far in the United States. It is also a call for further research and for caution in the development of the microelectronics industry in areas of the world that lack sufficient regulation and enforcement of laws to protect workers from occupational hazards and the community from environmental hazards that have occurred wherever microelectronics companies have been established. PMID- 7847764 TI - Twenty-five years of national service--changes in height, weight and body mass index. AB - The height and weight of 18-year-old Singapore National Service enlistees were extracted from computer records spanning 25 years (1967-1991). These were analysed for mean height, weight and body mass index (BMI) which overall show increases of 4.12 cm, 10.13 kg and 2.60 kg/m2 respectively. All ethnic groups (Chinese, Malay, Indian and Others) show a similar rising trend. While mean height appears to have stabilised in recent years, mean weight continues to rise. This is reflected in an increasing mean BMI. The proportion of 18-year-old male recruits with a BMI in the overweight range (> or = 25 kg/m2) increased from 1.37% in 1967 to 12.07% in 1991. PMID- 7847766 TI - Evaluation of non-surgical treatment of benign oesophageal stricture. AB - Benign oesophageal stricture is a disabling problem associated with oesophageal surgery, injection sclerotherapy and patients with reflux problems. Fortunately, mechanical dilatation has emerged as an effective treatment of choice. In recent years, balloon dilatation appears to have gained popularity because of its efficacy and safety. This study of 43 patients compares manual dilatation with balloon dilatation. Twenty-one patients underwent manual dilatation with either Eder-Puestow or Gum Elastic dilators. There were 4 failures which were then treated successfully with balloon dilatation. Two other patients developed perforation and needed emergency surgery. Nine patients required 3 or more graduated dilatations within one month. Another group of 22 patients were treated successfully by balloon dilatation without any complications. Ten patients developed recurrent dysphagia and needed another repeat dilatation after an interval averaging 4.5 months. The results show quite conclusively that balloon dilatation is superior to manual dilatation. PMID- 7847765 TI - Detection of protein C or protein S deficiency in patients on warfarin therapy--a study of nine patients. AB - This review studied 9 cases of young or middle-aged patients with protein C or protein S deficiency presenting with thrombotic events in the venous or arterial system. The clinical features were consistent with those described in the literature. Affected family members with similarly low levels were also detected in family studies, some of whom did not have any thrombotic history. Serial measurement of protein C, factor II and factor X at various International Normalization Ratio (INR) levels showed a correlation between suppression of these vitamin K dependent factors and degree of anticoagulation. Furthermore, there was a distinguishable difference in these indices (protein C level, protein C: factor II, protein C: factor X ratio) in warfarinized protein C deficient patients when compared with warfarinized patients who were not protein C deficient. This provides a means in diagnosing protein C deficiency even in warfarinized patients. Such a pattern was not found for protein S deficient patients, which may be due to the assay method used. PMID- 7847767 TI - Malignant change in cutaneous neurofibromas--case reports. AB - Neurofibromatosis is the most common single gene disorder to affect the nervous system, with an estimated incidence of 1 in 3000 live births. Neurofibromatosis (NF) may be classified into von Recklinghausen NF (NFI) and bilateral acoustic NF (NFII) based on the distribution of lesions. The most common lesion associated with the von Recklinghausen type is the neurofibroma. Various complications are associated with neurofibromatosis, the most feared of which is malignant change in the neurofibroma. This article describes the study of 7 cases of proven malignant change in neurofibromas with regards to presentation, clinical progress and treatment followed by a review of the present literature. PMID- 7847768 TI - Bilateral temporomandibular joint ankylosis with micrognathia: a case report. AB - A case ov bilateral intra-articular ankylosis with micrognathia is reported, with the most likely etiology considered to be continuous trauma over the chin during the first month of life. PMID- 7847769 TI - Exposure of the pregnant patient to ionizing radiation. AB - Because of the increased recognition of the lifetime risks from the exposure to low levels of ionizing radiation, it is recommended that alterations be made to the currently accepted guidelines for prescribing radiographs for pregnant patients. Particularly so, because it has been shown that optimal radiographic practices in dental schools and dental offices are not universally followed. PMID- 7847770 TI - The role of the time of application of the promoter in two-stage chemically induced carcinogenesis in the oral mucosa: experimental study in the rat. AB - The purpose of this study is to determine the role of the time of application of the promoter (in this case, mechanical irritation) in two-stage chemically induced oral carcinogenesis. One hundred fifty-five male rats were divided into seven groups. Group 1, 2 and 3 each received two intraperitoneal injections of the carcinogen N-nitroso-N-methylurea (NMU): 50 mg/Kg BW. Mechanical irritation was applied on the left buccal mucosa, 7 days before the first injection of NMU (group 1), 16 days (group 2), and 80 days (group 3) after the carcinogenic administration. Animals of groups 4, 5, 6 and 7 served as controls. Only group 1 and 2 animals developed tumors in the irritated buccal mucosa. From the results of this study we conclude that the delay of the application of the promoter does not lead to tumor formation. This could be explained by the repair of the carcinogenic lesion at the cellular level. PMID- 7847771 TI - Salivary gland tumors studied by means of the AgNOR technique. AB - Silver-binding nucleolar organizer regions (AgNORs) were counted in sections from formalin-fixed, paraffin-embedded tissue blocks of 14 benign and 17 malignant tumors of minor salivary glands. The difference in the mean number of AgNORs count per nucleus between benign and malignant tumors was found to be statistically significant (p < 0.001). A positive correlation between the AgNORs count and the degree of malignancy of the malignant salivary gland tumors was generally observed. The AgNORs technique can be used as a diagnostic aid in differentiating between benign and malignant salivary gland tumors, and possibly the salivary duct carcinoma from the acinic cell carcinoma and poorly differentiated mucoepidermoid carcinoma. PMID- 7847772 TI - Distributing dentists throughout the nation. AB - Reports on the changes in national dental manpower levels do not describe the variations that exist at the state level. An historical and prospective review indicates an increasingly more uniform distribution of professionally active dentists (but not specialists). Despite increasing numbers of practitioners, unserved populations continue to exist in many states. PMID- 7847773 TI - Great expectations: the impact of research on dental practice and education. Part I. PMID- 7847775 TI - Change, yes: but the dental profession will survive and prosper! PMID- 7847774 TI - Eosinophils in oral and cutaneous lesions of erythema multiforme. AB - The purpose of this retrospective clinicopathologic study was to investigate the presence of eosinophils in oral and skin lesions of erythema multiforme. Seventeen cases were selected which fulfilled clinical and histopathologic criteria for the disease. Twelve out of 13 sections taken from skin biopsies and 4 out of 5 sections taken from oral lesions contained eosinophils in varying densities. The occurrence of eosinophils in the lesions of erythema multiforme is parallelized and discussed with the existence of certain clinical and histopathologic aspects. Therefore, we suggest that eosinophils occur in cutaneous and oral lesions of erythema multiforme and are occasionally numerous. PMID- 7847776 TI - The pathologist's role in multidisciplinary management of bladder cancer. AB - The pathologist plays an important role in management of bladder cancer, as a member of the multidisciplinary team of urologists, radiation therapists, and medical oncologists. The therapeutic goal is saving the bladder function as long as possible. The pathologic determinants utilized for selection of therapeutic modalities are described in 172 consecutively treated patients with transitional cell carcinoma and 20 patients with other forms of bladder tumors during a five year period. Based on histologic type, pathologic stage, and status of the urothelium, 100 patients were treated by resection and intravesical instillation of cytostatic drugs or bacille Calmette-Guervin (BCG). Seventy patients underwent radical cystectomy and bladder substitution by continent urinary diversion. Serial transurethral resection (TUR) biopsies and cytologic evaluations were found adequate in evaluating pathologic determinants for progression and for survival except in cases of Grade 2 papillary transitional carcinomas where additional experimental studies need to be further developed, such as nuclear ploidy and molecular genetic studies, to identify patients at high risk for progression. Of the 70 patients with radical cystectomy and 5 with partial cystectomy, 49 are living, a median of 36.8 months since surgery. There was one intraoperative death and one post-operative death within 30 days post operatively. PMID- 7847777 TI - Testing for thyroid function recovery in children and adolescents with Hashimoto thyroiditis. AB - Thyroid function in children and adolescents with primary hypothyroidism owing to Hashimoto thyroiditis was studied to evaluate criteria for the discontinuation of thyroxine therapy. A cohort of 29 children and adolescents was prospectively studied for one year. A thyrotropin-releasing hormone stimulation test with measurements of basal and stimulated thyrotropin and thyroxine was performed at the beginning of the study and 6 and 12 months later. In 59 percent of patients, persistent biochemical evidence of hypothyroidism was observed. Interindividual variations and variations among measurements in individual patients were much greater than those reported for healthy individuals. In one patient, all measured values were consistently normal, and the therapy was successfully discontinued. No single measurement or test could predict the natural course of disease. In summary, children and adolescents with hypothyroidism owing to Hashimoto thyroiditis can not have discontinued replacement thyroxine therapy on the basis of any single evaluation of thyroid function, as proposed for adults. If the decision to discontinue the therapy in this age group is made on the basis of previous follow-up, a substantial possibility of relapse remains and continuous follow up is necessary. PMID- 7847778 TI - Primary multicystic undifferentiated embryonal sarcoma of the liver in an adult presenting with peripheral eosinophilia. AB - Primary undifferentiated embryonal sarcoma of liver is an extremely rare pathologic entity in the adult population. An unusual case is reported of a 44 year-old female who presented with multiple hepatic cysts and peripheral eosinophilia, initially thought to be hydatid disease of the liver. Angiogram revealed neovascularization. Surgical biopsy showed an anaplastic mesenchymal neoplasm. Pathologic findings are presented and the relevant literature reviewed. Hepatic undifferentiated embryonal sarcoma should be included in the differential diagnosis of eosinophilia accompanying hepatic cysts. PMID- 7847779 TI - Iron transport and subcellular distribution in Hep G2 hepatocarcinoma cells. AB - Thalassemic patients with iron overload are presently treated with deferoxamine or the experimental chelator deferiprone. To understand how these agents remove iron from the liver, cultured human hepatoma cells loaded with iron were previously used as a model for hepatic iron overload. The present study was undertaken to characterize further the pathways of iron transport and distribution in these cells. The activation energy for Fe2+ transport is 19 kJ/mol greater than for Fe3+, and the rate of Fe2+ transport--but not that of Fe3(+)--decreases with temperature above 25 degrees C, suggesting distinct uptake processes for different redox states of iron. Iron loading, which promotes a greater rate of Fe3+ transport, also caused a proportionally greater deposition of iron in the microsomal and cytosolic compartments and specifically lowered the activities of succinate-cytochrome c reductase and 5'-nucleotidase, representative markers of the mitochondria and plasma membrane, respectively. Both deferiprone and deferoxamine decreased total cellular iron and iron in each fraction except cytosol, indicating mobilization of iron for clearance from the cell via the cytosol. This model may be useful in characterizing the determinants of effective chelation in patients. PMID- 7847780 TI - Intestinal microsporidiosis. Report of five cases. AB - Five cases of intestinal microsporidiosis are reported, including one case of a heterosexual female acquired immunodeficiency syndrome (AIDS) patient, three homosexual males, and one bisexual male AIDS patients with detailed description of their clinical course. These five cases underscore the severity of immunodeficiency in patients with microsporidiosis. All patients had multiple opportunistic infections and a CD4 cell count below 100/microliters long before diarrhea developed. This is the first kinetic study of helper T-lymphocytes in cases of microsporidiosis. Diagnosis was made by duodenal biopsies stained with Brown and Brenn or Gram-Weigert technique (confirmed by electron microscopy) and by stool smears stained with a modified trichrome technique. However, the best preparation was plastic sections stained with toluidine blue, which demonstrated both the spores and plasmodia clearly. In our evaluation, Giemsa stain was also acceptable for identification of microsporidian spores in both intestinal biopsies and stool smears, but there was a failure to identify the organism on hematoxylin and eosin, acid-fast, periodic acid-Schiff, and Gomeri's methenamine silver stained preparations. Therapeutic attempts using albendazole, metronidazole, octreotide, and zidovudine (AZT) failed to eradicate microsporidia in these patients. PMID- 7847781 TI - Low density lipoprotein cholesterol and whole blood viscosity. AB - Whole blood viscosity (WBV) was measured in a normal population and was analyzed in relation to packed cell volume, (hematocrit, PCV), fibrinogen, white blood cell count (WBC), platelet count, and plasma lipids, including total cholesterol, triglycerides, high density lipoprotein cholesterol (HDLc) and low density lipoprotein cholesterol (LDLc). Conventional assays were used for all blood and lipid measurements. Whole blood viscosity was measured under disaggregating conditions with a disposable, porous bed viscometer. As expected, the strongest correlation was seen between WBV and PCV (r = 0.78, p < 0.001). Significant positive correlations also were demonstrated between WBV and cholesterol (r = 0.22, p < 0.001), triglycerides (r = 0.14, p < 0.001) and LDLc (r = 0.21, p < 0.001). A significant negative correlation was found between HDLc and WBV (r = 0.20, p < 0.001). Correlation analysis by sex showed only the correlation of LDLc was significant for both men and women. A stepwise multiple regression analysis of WBV indicated that LDLc, fibrinogen (Fbg) and platelet (Plt) counts correlated independently of PCV to WBV. The equation derived from multiple regression and partial correlation analysis was: WBV (mPa.sec) = -9.317 + 0.0047 (LDLc) + 0.381 (PCV) + 0.00152 (Plt) + 0.0021 (Fbg). The calculated mean specific contribution of PCV was 90.8 percent, LDLc 3.5 percent, and fibrinogen 3.3 percent to observed mean WBV. This study shows that LDLc is the principal lipoprotein independently influencing whole blood viscosity and its effect is similar in magnitude to fibrinogen. Further studies to elucidate the mechanism and clinical significance of the effects of LDLc on WBV are indicated. PMID- 7847782 TI - Immunity status to poliovirus in Veneto region (north-east Italy). A seroepidemiological survey. AB - The immunity state to poliovirus types 1, 2, and 3 of a population aged 2 to 75 years was determined by examining 274 sera collected in the Venice mainland (North-East Italy). Altogether, the neutralizing antibody prevalences (at a titre > or = 1:2) for poliovirus 1, 2, and 3 were 99.0 percent (geometrical mean titres [GMT]: 72.1), 99.6 percent (GMT: 95.9) and 98.2 percent (GMT: 17.3), respectively, and all the age groups also showed very good levels of humoral immunity. High antibody titres (> or = 1:256) to one or more types of poliovirus were demonstrated in older age groups also, possibly indicating exposure to natural polioviruses or contact with vaccine strains. Although probably all the older subjects had practically acquired their antibodies as a result of natural infection and those under 30 through vaccination, these results indicate that the humoral immunity against poliomyelitis in our population is satisfactory, and the maintenance of such good protection level depends on an effective immunization program. PMID- 7847783 TI - Macrophage conditioned media affects steroid hormone production by placental cultures. AB - Placental steroid hormone production appears to be critical in maintaining pregnancy and possibly initiating parturition. Cytokines, produced by activated macrophages and decidua, are present during delivery, but their role in this process is not yet clear. To our knowledge, only one recent study, which used JEG 3 choriocarcinoma cells as an in vitro model, has evaluated the possibility that cytokines might affect placental steroidogenesis. Our current study reports observations on the effect of macrophage conditioned media (MCM, known to contain several cytokines) on the synthesis of progesterone and estradiol by term, normal, human placenta. Macrophage conditioned media significantly decreased progesterone (36 percent) and increased estradiol (76 percent) production by short-term placental organ cultures. These results suggest that macrophage secretory products might significantly alter placental steroidogenesis which could make them important factors in the physiology of parturition. PMID- 7847784 TI - Combined strategy of conventional cytogenetics, fluorescent in situ hybridization and chromosome morphometry for analysis of parotid gland tumor. AB - The limiting factors in conventional cytogenetic analysis of cell culture, especially of solid tumors, include insufficient metaphases, overgrowth of abnormal mitotic cells by normal cells, and suboptimal quality of harvesting and banding. Despite the availability of numerous protocols to induce G-banding, as well as Q-, R-, and C-banding, occasions still arise in which the analysis is severely limited by these factors and incomplete conclusions are often drawn as to the precise nature of the chromosomal abnormality, if indeed any can be detected. By adopting a rational approach of (1) close monitoring of cultures and rapid harvesting as soon as it is feasible, and (2) analysis of available metaphases by a combination of the GTG technique, fluorescent in situ hybridization (FISH), and chromosome morphometry using a graphic arts tool, a significant improvement in success rate may be more readily achieved. Here pathological and cytogenetic data are presented of a case of parotid gland carcinoma ex mixed tumor with the karyotype of 46, XX, del(5)(q12), dir ins(8;5)(q12;q12qter), add(12)(p13)/46, XX. This case is utilized to illustrate the importance of application of our combined strategy. PMID- 7847785 TI - [Mechanisms of pain in chronic pancreatitis and its therapeutic management]. PMID- 7847786 TI - [Rotor's syndrome. Apropos of a case]. AB - Rotor's syndrome is a rare hereditary non hemolytic hyperbilirubinemia. The authors report a new case of a 22-year-old man, with chronic asymptomatic fluctuating jaundice. Liver function tests such as alkaline phosphatase, gammaglutamyl transferase and aminotransferase were normal, the same applying to globulin levels. The diagnosis was confirmed by a typical bromsulphalein clearance test, oral cholecystography, and increased total urinary coproporphyrin as well as coproporphyrin isomer I. PMID- 7847787 TI - [An unusual cause of dysphagia: esophageal tuberculosis]. AB - Esophageal tuberculosis is a rare etiology of dysphagia. Such a location is also rare in comparison with other digestive tract sites of the disease (3.2%). Esophageal involvement may be secondary or primary. Diagnosis is particularly difficult in the latter situation. At any event, the diagnosis can only be histological by examination of endoscopic biopsy material. Treatment is essentially medical and leads to recovery in most patients. PMID- 7847788 TI - [Transplantation of allogeneic hepatocytes without immunosuppression: long-term survival]. AB - Hepatocyte transplantation could be an alternative to whole liver transplantation. Allogeneic hepatocytes are rejected if transplanted without immunosuppression. The aim of this study was to transplant allogeneic hepatocytes in the peritoneum and to protect them from rejection by encapsulation in a new semi-permeable membrane. METHODS: rats hepatocytes were encapsulated in hydrogel based hollow fibers, obtained from AN69 polymer, before being transplanted into the peritoneum of rats. Outcome of allogeneic hepatocytes encapsuled in hollow fibers was compared to that of free allogeneic hepatocytes. Cell viability was assessed by erythrosine exclusion, morphology by electronic microscopy and function by albumin release. RESULTS: Up to 90 days, viability of allogeneic hepatocytes in hollow fibers was above 80%. The morphology remained normal at electronic microscopy. Albumin release was 16.5 +/- 0.3 (day 15), 14.2 +/- 2.0 (day 30), 8.8 +/- 0.1 (day 60) and 11.4 +/- 0.3 mg/24h/10(6) hepatocytes (day 90). Free hepatocytes did not survive at day 15. CONCLUSION: Viability and function of encapsulated allogeneic hepatocytes were maintained up to 90 days after transplantation, without immunosuppression. PMID- 7847790 TI - [Non-Hodgkin's lymphoma of the digestive system. General epidemiology and epidemiological data concerning 100 Lebanese cases seen between 1965 and 1991]. AB - It is classical to separate gastro-intestinal non Hodgkin lymphomas into two epidemiological profiles: an "occidental" type frequently encountered in West countries (Europe and USA) and an "occidental" type which is dominant in the Middle East regions and is distinguished from the occidental type by the following features: the younger age of patients, the rarity of gastric involvement compared to the small intestinal involvement, the prevalence of Immuno Proliferative Small Intestinal Disease within the small intestinal non Hodgkin lymphomas. An epidemiological study was done on 100 cases of digestive non Hodgkin lymphomas seen in Lebanon between 1965 and 1991 in hospitals affiliated with Saint-Joseph University. The statistical analysis of our study leads to several conclusions: the ISPID is disappearing in Lebanon during the last twenty-five years; the site of gastrointestinal involvement is changing with time, the small intestinal involvement becoming more rare and the gastric involvement more frequent. So during this twenty-five years period, there was an occidentalization of the epidemiological profile. This varying pattern with time in the epidemiology of gastrointestinal non Hodgkin lymphomas could be due to changing in the environmental factors like the intestinal bacterial and parasitological infestation. PMID- 7847789 TI - [Absorption, distribution and excretion of vitamin B12]. AB - During our first communication [1], the complexity of vitamin B12 digestive transport was considered. This second presentation demonstrates the route of the vitamin in the body. As cobalamin or vitamin B12 has existed for four billion years, they figure without any doubt amongst those molecules which have the most complex structure. The rarity of an architecture organised around a cobalt atom confirms their high level of originality. Their exceptional character is reflected in their cycle such as for mammals and for man where the intervention of binders, such as intrinsic factor, transcobalamin and haptocorrin is necessary for transporting them. As far as cellular metabolism is concerned, it is especially loaded sometimes with folates in the transfer of the methyl group. The molecules are spiked with hydrophobic sites. Their membrane transfer is facilitated by several types of receptors. The intestinal absorption, which appears to require the presence of two receptors and two transporters, remains for the moment a unique assimilation model. The very probable existence of an enterohepatic cycle as well as a renal reabsorption saves this molecule, itself synthesised by microorganisms only. PMID- 7847791 TI - Mapping the human genome. AB - The haploid human genome contains approximately 70,000 different genes in its 3200 megabases of chromosomal DNA. High resolution maps of all chromosomes are urgently required both for functional analysis of the genome as a whole and for the identification and characterization of its constituent gene sequences. To this end, a variety of markers including genes, anonymous DNA segments and sequence-tagged sites are being recruited as single copy landmarks which can be readily incorporated into both genetic and physical maps. Current progress toward the generation of physical, genetic and cytogenetic maps of human chromosomes and their integration is reviewed. PMID- 7847792 TI - [New tumor suppressor genes intervening in the regulation of the cycle]. AB - Eukaryotic cell cycle progression is governed by multiple cyclin and cyclin dependent kinases interactions that are in turn regulated by multiple factors. Recently, inhibitors of cyclin/cyclin-dependent kinases activities have been characterized and their genes have been cloned. Alterations of some these genes may play a major in tumor initiation or progression. PMID- 7847793 TI - [The BCL2 gene, prototype of a gene family that controls programmed cell death (apoptosis)]. AB - The BCL2 gene is the most representative member of a family of genes that control cell homeostatic processes in the course of the developmental and adult life. Some members of the BCL2 family (bcl-2 alpha, bcl-xL) inhibit apoptosis, whereas some other (Bax, Bclxs) induce it. The biological activity of these proteins is dictated by: 1) their capacity to be integrated in specific membranes of the cytoplasm; 2) their ability to homo- or hetero-dimerize, due to the presence of two highly conserved domains which are a signature of this gene family. The bcl-2 protein exhibits two main biochemical properties: it acts in an antioxidant metabolic pathway aimed at eliminating oxygene free radicals that induce lesions in DNA, lipids and proteins; it modulates intracellular Ca++ fluxes. BCL2 (and presumably its congeners) interplay with other genes involved in the tight control of cell proliferation and programmed cell death (c-myc, p53). A more comprehensive view of BCL2 functions should benefit to cancer chemotherapy by improving rational approach of the antitumor drug mechanisms. PMID- 7847794 TI - Molecular characterization of two extra marker chromosomes detected at prenatal diagnosis. AB - Two non-familial extra supernumerary abnormal chromosomes (ESAC) were detected in fetuses monitored by midtrimes ter amniocentesis. Characterization of these ESACs was carried out using conventional cytogenetic analysis, fluorescence in situ hybridization, and DNAse I hypersensitivity. Based on these studies it was concluded that the two ESACs were derived respectively from chromosomes 14/22 and isodicentric chromosome 15. Based on cytogenetic results it was argued that unconsistent phenotypic effect was associated with the two aneuploidies. This optimistic view was confirmed at birth of unaffected babies and unremarkable follow up at 6 and 12 months. PMID- 7847795 TI - Tetrasomy 9p: prenatal diagnosis and fetopathological findings in a second trimester male fetus. AB - In this report the authors describe the fetopathological findings in a second trimester male fetus with pure 9p tetrasomy. The prenatal diagnosis was based on the echographic finding of severe internal anomalies of the central nervous, cardiovascular and urogenital systems. PMID- 7847796 TI - Possible genes for left heart formation on 11q23.3. AB - A case of balanced translocation t (10; 11) (q 24; q 23) is presented. This female newborn showed no other malformation than hypoplastic left heart syndrome. According to several cases of 11q- and hypoplastic left heart in the literature and to this observation the authors postulate genes for left heart formation on chromosome 11q23.3. PMID- 7847797 TI - Interstitial deletion 12p13.1-13.3 in a mildly retarded infant with unilateral ectrodactyly. AB - The authors report a case of a deletion at 12p13.1-13.3. Only one similar observation was published [16]. The infant is mildly retarded and shows unilateral ectrodactyly. PMID- 7847798 TI - Lens dislocation and optic nerve hypoplasia in ring chromosome 21 mosaicism. AB - Data on the physical and cognitive development of patients with chromosomal aberrations are scarce. In this report the authors present data on the longterm evolution in a boy with 45, XY,-21/46, XY, r(21) mosaicism, from birth up to the age of 14 years. Ophthalmological examination revealed lens dislocation and optic nerve hypoplasia. PMID- 7847799 TI - Maternal derivation of inv dup (22) and clinical variation in cat-eye syndrome. AB - Cytogenetic analysis in a male child with dismorphies and renal anomalies showed an extra bisatellited chromosome. In situ hybridization and an analysis of cytogenetic polymorphisms revealed that the abnormal chromosome derived from a single maternal chromosome 22. PMID- 7847800 TI - Tetrasomy 18p in two cases confirmation by in situ hybridization. AB - Two cases with an extra small metacentric chromosome are described. Classic cytogenetic analysis was insufficient for identification of the marker origin. High resolution banding and fluorescence in situ hybridization (FISH) using a chromosome specific painting probe indicated that both marker chromosomes originated from chromosome 18. The correlation between phenotype, cytogenetics and FISH results allowed us to conclude that the patients are tetrasomic for 18p. A comparison of the clinical features of our two patients with other twelve previously reported patients where tetrasomy 18p was confirmed, is also presented. PMID- 7847802 TI - Numerical aberrations of chromosome 17 detected by FISH with DNA-specific probe in oral tumors. AB - Numerical aberrations of chromosomes were investigated in oral tumors by using fluorescence in situ hybridization (F1SH) with 4 chromosome centromere-specific DNA probes. The hybridization signals of the centromere sequence were easily detected and counted within interphase nuclei as well as metaphase chromosomes. The number of hybridized signals for chromosome 17 significantly increased in oral malignant tumors compared to benign tumors, which had two spots as well as normal lymphocytes. Cell lines derived from oral squamous cell carcinoma also showed numerical aberrations of chromosomes 1, 4 and 11, in addition to chromosome 17. These findings suggested that numerical aberrations of chromosomes occur during the development of malignant tumors of the oral cavity. PMID- 7847801 TI - High expression of the EGFR in fibroadenomas compared to breast carcinomas. AB - The epidermal growth factor receptor and its ligands have been implicated as being involved in normal mammary development and breast cancer genesis. Northern blotting was used to assay the mRNA levels of the epidermal growth factor receptor and three of its ligands: the epidermal growth factor, the transforming growth factor alpha and the Amphiregulin in 16 primary carcinomas, 2 metastases and 5 fibroadenomas. In addition, the mRNA levels of the other members of the epidermal growth factor receptor family, erbB2 and erbB3 were also analysed. We found limited expression in the breast carcinomas while all the fibroadenomas showed expression at high levels. Therefore we suggest that the epidermal growth factor receptor plays an important role in the development of fibroadenomas. The erbB2 and erbB3 were more strongly expressed than the epidermal growth factor receptor in the primary carcinomas. This suggests that they could be of importance in breast carcinogenesis. PMID- 7847803 TI - Human myelopoiesis in culture of liquid medium lacking colony stimulating factors: therapeutic implications for cancer patients with leukopenia. AB - Patients with cancer often develop leukopenia caused by chemotherapy. Since their treatment with human colony stimulating factors (CSFs) has limitations, it is imperative to determine if CSFs are essential in regulating human myelopoiesis. For this purpose, human primary precursor myeloid cells were cultured in media lacking exogenous human CSFs and stem cell factor (SCF), and supplemented with human sera, or with fetal bovine or other types of animal sera. Cells cultured in human sera survive well, proliferate actively, and differentiate toward granulocytes. Most cells cultured in fetal bovine serum die, few differentiate toward monocytes-macrophages. Cells cultured in other types of animal sera die rapidly. Antibodies neutralizing human serum's CSFs and SCF do not abolish its myeloregulatory activity. It is concluded that cell growth factors other than CSFs and SCF present in human serum regulate human myelopoiesis in vitro. These findings bear important therapeutic implication for patients with cancer having leukopenia. PMID- 7847804 TI - Urinary gonadotropin peptide (UGP) as a marker of gynecologic malignancies. AB - Urinary gonadotropin peptide (UGP) was measured in 866 urines from normal women and women with benign and malignant gynecologic disease using the Triton UGP enzyme immunoassay. The greatest level of overexpression of the marker was observed in patients with ovarian cancer. Using a cutoff of 4 fmol/mg creatinine, UGP was overexpressed in samples from 2% of normal premenopausal women, 15% of normal postmenopausal women, 5% of women with benign gynecologic disease, and 59% of women with ovarian cancer. UGP expression was independent of the histologic type of ovarian cancer. The expression of UGP and CA 125 were not correlated and use of the two markers in tandem increased the sensitivity of detection of disease by greater than 20% over that which was observed using each marker individually. UGP levels were correlated with clinical status, and doubled in value in 67% of patients with progressive disease, and were halved in 93% of patients who were in remission at the time of the study. PMID- 7847805 TI - Potentiation of antitumor activities of carboplatin and camptothecin by interleukin-1 alpha against human ovarian carcinoma in vivo. AB - Interleukin-1 alpha significantly potentiated the cytotoxicity of carboplatin (8 fold) and camptothecin (4-fold) during simultaneous drug exposure in human ovarian NIH: OVCAR-3 cancer cells in vitro. Treatment of human ovarian tumor cells grown as xenografts in nude mice with IL-1 alpha followed by either carboplatin or CTP-11 at minimally toxic doses significantly (2-3-fold and 7-fold for carboplatin and CTP-11, respectively) enhanced antitumor activity of either agent alone, indicating that IL-1-alpha-drug combinations may be potentially more effective for the treatment of ovarian tumors, including those difficult to cure in the clinic. PMID- 7847806 TI - Rearrangement of chromosome band 11q13 in HeLa cells. AB - Previous somatic cell genetic and molecular genetic studies have localized the Hela cell tumor suppressor gene to the long arm of chromosome 11. To determine if loss of heterozygosity has occurred for the inactivation of the tumor suppressor gene, we investigated the molecular status of chromosome 11 in the HeLa cells. The restriction fragment length polymorphic (RFLP) analysis of four different HeLa sublines showed retention of heterozygosity for the long and short arm specific probes in three of the sublines. Fluorescence in situ hybridization (FISH) studies using whole chromosome painting probes identified 11 material in a marker chromosome in addition to the two normal appearing 11's in these three cell lines. The fourth cell line contained only two 11's. This cell line had lost the 11 material from the marker chromosome. Both molecular and karyotypic analyses indicated q13 as the common site of rearrangement in the derivation of these marker chromosomes. We therefore conclude that 11q13 rearrangement could contribute to the abnormal growth behaviour of HeLa cells in vivo and/or in vitro. PMID- 7847807 TI - Evidence for paracrine regulation of experimental metastasis in 13762NF rat mammary adenocarcinoma cell clones. AB - The ability of tumor cell lines to form experimental pulmonary metastases is determined in part by characteristics which are stable over many cell generations; in part by characteristics that are acquired by adaptation or phenotypic instability; but also in part by characteristics which may change over less than one cell generation. This study was designed to examine the hypothesis that tumor cells secrete and respond to paracrine factors which can reversibly modulate metastasis. The number of experimental lung metastases increased for 13762NF rat mammary adenocarcinoma cell clones MTF7 and MTLn3 as they approach 100% confluence. This observation corresponded to increased attachment to bovine brain capillary and bovine corneal endothelial monolayers and to ability of tumor cells to invade reconstituted basement membrane barriers in the Membrane Invasion Culture System (MICS), but did not correspond to cell cycle distribution, susceptibility to NK or PMN cell killing or average cell size/Coulter volume. While changing confluence did not qualitatively alter metastatic potential, modification of metastasis in a quantitative manner suggested that some properties pertinent to metastasis are transient and manipulatable. Tumor cell conditioned medium (CM) collected from donor cells grown to defined levels of confluence when placed onto recipient cells reversibly raised or lowered metastatic potential depending upon the medium source and confluence of the recipient cells. CM from 20% confluent donor cultures reduced recipient cell metastatic potential. In contrast CM from 100% confluent cultures increased metastatic potential of subconfluent cells. Replacement with fresh unconditioned medium or leaving the medium unchanged did not alter experimental metastasis. These data suggest that metastasis involves steps which may be influenced by paracrine factors elaborated by tumor cells. PMID- 7847808 TI - Intertumoral heterogeneity of receptor-tyrosine kinases expression in human melanoma cell lines with different metastatic capabilities. AB - Human melanocytes respond to several growth factors whose receptors have tyrosine kinase activity. Abnormalities in the expression of tyrosine kinase receptors may play an important role in the initiation and progression of melanoma. We therefore determined the steady-state mRNA expression of five tyrosine kinase receptors, epidermal growth factor receptor (EGF-R), c-met, nerve growth factor receptor (NGF-R), colony-stimulating factor receptor (CSF-R) and c-kit, in eleven human melanoma cell lines with different metastatic potentials in nude mice. All cell lines except for one nonmetastatic line established from a primary melanoma lost expression of c-kit. Expression of the other four tyrosine kinase receptors varied among the lines. The expression level of individual tyrosine kinase receptor did not correlate with the metastatic potential of the cells. These results suggest that metastatic human melanoma cell lines are heterogeneous for expression of tyrosine kinase receptors, with each cell type manifesting a distinct repertoire of receptor tyrosine kinases. The different profile of tyrosine kinase activities in different metastatic melanomas complicates its use for prognosis. PMID- 7847809 TI - Differential effects of recombinant interferon-alpha and 5-fluorouracil against colon cancer cells or against peripheral blood mononuclear cells. AB - Comparative studies on the suppressive effects of recombinant interferon-alpha (IFN-alpha), 5-fluorouracil (5-FU), or IFN-alpha + 5-FU have been performed in vitro on colon carcinoma cells (HT-29 cell line) and PHA-stimulated mononuclear cells (MNC) of peripheral blood obtained from healthy donors. IFN-alpha was used at 500 U/ml against HT-29 cells and at 1000 U/ml against MNC on day 1 of culture; 5-FU was used at 250 microM against HT-29 and at 1400 microM against MNC on day 2 of culture. The results show that: (a) IFN-alpha inhibited MNC and HT-29 cells by 13.4% and 32.9%, respectively; (b) 5-FU inhibited MNC and HT-29 cells by 54.7% and 87.0%, respectively; (c) IFN-alpha + 5-FU resulted in a stronger inhibition of HT-29 cells (i.e., 96.1%). In contrast, that combination was significantly less suppressive than 5-FU alone when MNC were used as targets (i.e., 35.9% inhibition). Natural cell-mediated cytotoxic activity relative to 10(6) MNC was not markedly altered by all agents alone or in combination. Moreover, treatment with IFN-alpha, 5-FU or IFN-alpha + 5-FU resulted in a marked increase in the number of HT-29 cells positive for the CEA surface antigen. These data seem to provide further rational support of the clinical use of IFN-alpha + 5-FU in colorectal cancer, based on the differential toxicity of this drug combination on tumor versus normal immunocompetent cells. PMID- 7847810 TI - A correlative approach for the identification of antimutagens that demonstrate chemopreventive activity. AB - Seventy natural and synthetic compounds were tested for potential to inhibit mutation induced by 7,12-dimethylbenz(a)anthracene (DMBA) in Salmonella typhimurium strain TM677. Results were compared with their ability to inhibit DMBA-induced preneoplastic lesions in a mouse mammary gland organ culture system. The response mediated by fifty-five of the test compounds was either positive or negative in both test systems, indicating that the combined use of these assays should aid in the discovery of antimutagenic agents that have cancer chemopreventive potential. PMID- 7847811 TI - Cytotoxic effects of alkylphosphocholines or alkylphosphocholine-liposomes and macrophages on tumor cells. AB - The influence of the alkylphosphocholines (APC) on macrophage activation to tumor cytotoxicity was investigated in vitro with both mouse peritoneal and rat liver macrophages. For this purpose the compounds were used either in micellar or in liposomal form. The cytotoxic effect of micellar or liposomal APC was increased with prolongation of the aliphatic chain and was reduced for the liposomal form. Peritoneal macrophages incubated with APC-liposomes gave a comparable cytotoxic effect on MethA cells to that of the free, highly toxic APC alone. These liposomes can activate rat liver macrophages (Kupffer cells) in vitro to a moderate tumor cytotoxicity on C26 colon carcinoma cells, while the micellar APC were toxic to macrophages. A significant release of NO-radicals from peritoneal macrophages was obtained with Liposomes but not with micellar lipid. The release of tumor necrosis factor (TNF) was stimulated by incubation with micellar or liposomal HPC. Whereas the micellar HPC was comparable to lipopolysaccharide (LPS) in TNF release stimulation, the HPC-liposomes caused a much higher release. PMID- 7847812 TI - Human melanoma metastasis related to specific adhesion with lung cells rather than direct growth stimulation. AB - We previously established a model to study human tumor spontaneous metastasis in immunosuppressed newborn rats. Different observations suggested that the development of pulmonary metastases of human melanoma cells in this animal might reflect, at least partially, an organ specificity phenomenon. We thus examined the "soil" property of the rat lung in terms of growth stimulating activity and specific interactions between tumor cells and pulmonary cells. We could not demonstrate any melanoma cell growth-promoting activity in lung conditioned medium. On the other hand, tumor cell adhesion was drastically enhanced when measured on pulmonary fibroblast monolayers or derived extracellular matrix. Adsorption of lysates of 7GP122 highly metastatic melanoma variant on viable total lung cells enabled us to detect at least 10 proteins or protein subunits which could specifically interact with pulmonary cell membranes, while only one of these proteins was detectable when the same experiment was performed with control liver cells. Conversely, we could show that there exist several corresponding structures on pulmonary cells which could adsorb on tumor cells. Thus, specific cell surface adhesion molecules, leading to specific adhesion between melanoma cells and pulmonary cells, may lead to preferential metastatic development in rat lung. PMID- 7847813 TI - The CREB/ATF family of transcription factors: modulation by reversible phosphorylation. AB - Changes in genetic programming of a cell are brought about by modulating the activity of transcription factors which control the initiation of gene transcription by RNA polymerase II. Phosphorylation of transcription factors as a regulatory mechanism is both rapid and readily reversible. Moreover, because a transcription factor can be targeted by several protein kinases and phosphatases, this covalent modification can effectively integrate information carried by multiple signal transduction pathways, thereby providing a palette for great versatility and flexibility in the regulation of gene expression. The CREB/ATF family of transcription factors serves as a paradigm illustrating the phosphorylation-mediated transfer of regulatory information from the cell surface to the nucleus. PMID- 7847814 TI - Quantumchemical structure of carcinogenic benz[c]acridines. AB - Resonance energies, circuit resonance energies and bond currents of benz[c]acridines were calculated by Aihara's IRE theory. Consequently, it was shown that these compounds had very stable aromatic characters with positive resonance energies and that the resonance energies per pi-electron values for the compounds with lack of the double bond corresponding to the K-region from parent skeleton were more stable than those of their parent compounds. Carcinogenic activity of the compounds was related to the charge at QK, QN and QL and high electron density on HOMO orbital. PMID- 7847815 TI - Fine structural observation of a nucleolar-nuclear matrix-lamina-intermediate filament system in transformed cells. AB - The nuclear matrix is a nonchromatin structure of the nucleus normally concealed by a much larger mass of chromatin. Several methods have been developed to remove chromatin from nucleus while preserving the underlying matrix architecture to some degree. The present study showed that after extraction of PtK2 cells and cervical carcinoma cells (CC3) with Triton X-100, ammonium sulfate and DNase, the nucleolar-nuclear matrix-intermediate filament (Nu-Nm-L-IF) network remained. The nucleolus was oval in shape and appeared as a fibrillar mass with an accentric dense fibrillar centre. This nucleolar skeleton was in direct connection with the nuclear matrix which in turn is connected with cytoplasmic intermediate filaments by lamins. It is concluded from these observations that the Nu-NM-L-IF system forms a continuous system which plays an important role in the maintenance of the nucleolar, nuclear and cytoplasmic integrity and cellular function. PMID- 7847816 TI - Evidence for the involvement of sulfhydryl groups in the expression of antitumor activity of streptococcal acid glycoprotein (SAGP) purified from crude extract of Streptococcus pyogenes. AB - An acidic glycoprotein (SAGP), purified from crude extract (CE) of Streptococcus pyogenes, inhibits the growth of murine fibrosarcoma (Meth A) cells in vitro and prolongs the life span of mice inoculated with the same cells. This study revealed that the growth inhibitory activity of SAGP on Meth A cells in vitro was lowered in the presence of sulfhydryl-oxidizing agents such as cystamine and 5, 5'-dithiobis (2-nitrobenzoic acid) in a dose dependent manner. The activity of SAGP was also diminished by pretreatment of SAGP with cystamine. Inactivation of SAGP by cystamine was reversed by dithiothreitol. Furthermore, the effect of CE on prolonging the life span of Meth A-bearing mice was reduced by the administration of cystamine. These findings suggest that SH-groups are involved in the expression of anti-tumor activity of SAGP or CE in vitro and in vivo. PMID- 7847817 TI - Proton NMR spectroscopy of plasma lipoproteins: a marker of the immune function in cancer disease? AB - 1H-NMR spectroscopy of cancer plasma statistically detects significant narrowing of the methyl and methylene line widths. This change is due to relative increase in light density lipoproteins (VLDL and LDL) compared to heavy density lipoproteins (HDL). This observation had raised great hopes for a simple and universal screening test of cancer patients. Furthermore, the same signal can be observed in the plasma of pregnant women and heart transplanted patients undergoing an immunosuppressive treatment. This signal disappears after child's birth and during graft rejection processes. These observations suggest that the test initially proposed by Fossel in 1986 reveals a specific immunological status developed by the organism in "symbiosis" with "foreign" cells, rather than a cancerous disease. PMID- 7847818 TI - Mutant p53 proteins behave in a dominant, negative fashion in vivo. AB - The p53 encodes a cellular phosphoprotein that has been association with both neoplastic transformation and the control of cellular growth. Recent studies have reported that p53 also acts as a transcriptional regulator. We have studied transactivational properties of human wild-type and mutant p53 proteins representing 4 major mutational hotspots (codons 141, 175, 248, 273) as well as a double mutant Tyr141/His273 and a p53 with the transcriptional activating region removed (pcDC2). Transactivation by p53 was shown with a p53 concensus binding sequence controlled CAT reporter gene, and activity was assayed after co transfection of the reporter with either wild-type or mutant p53 expression constructs. Wild-type p53 as well as one mutant p53 [(mutation of arginine to histidine at codon 273 (His 273)], had strong transactivating activity, but all other mutant p53s were inactive in transcriptional activation, including the double mutant Tyr141/His273 suggesting that the Tyr141 mutation was dominant over the His273 mutation in the same protein. Moreover, when mutant p53 (Tyr141, His175, Trp248, or Tyr141/His273) was cotransfected with either wild-type p53 or mutant His273 p53, these mutants inhibited the transactivation of coexpressed wild-type p53. The p53 vector (pcDC2), which contains p53 oligomerization sequences, but not the transactivational domain, markedly inhibited wild-type p53 transactivational activity. Each of the mutant p53s similarly inhibited the transactivation of His273 p53. Therefore, with the exception of His273, each of the other mutant p53 were unable to transactivate and each behaved in a dominant negative fashion. PMID- 7847819 TI - Effects of cytostatic agents on the expression of epidermal growth factor receptor in ovarian cancer cells. AB - The effects of cytostatic agents on proliferation and epidermal growth factor receptor (EGF-R) expression were examined in the ovarian carcinoma cell line OVCAR-3. These cells were found to express about 84,000 high-affinity EGF binding sites per cell. Treatment of OVCAR-3 cells with cisplatin, etoposide or epirubicin for two hours resulted in a marked augmentation of EGF-R expression and growth inhibition, on the other hand, incubation with substances blocking RNA or protein synthesis, actinomycin-D and cycloheximide, resulted in a reduction of both EGF-R expression and growth rate. An up-regulation of EGF-R has thus been shown only for DNA-affecting agents, but not for those inhibiting transcription or translation. This response may be explained as a frustrated escape mechanism of the cancer cell to cytotoxic agents. PMID- 7847820 TI - Antioxidative activity of benzylideneascorbate and its effect on adriamycin induced cardiotoxicity. AB - The in vitro antioxidative activity of benzylideneascorbate (SBA) and the in vivo effect on adriamycin (ADR)-induced cardiotoxicity in a mouse model were investigated. The radical-scavenging activity of SBA was assayed in terms of reduction of chemiluminescence induced by O2-, generated in xanthine/xanthine oxidase and macrophage/phorbol myristate acetate reaction systems. SBA showed a strong antioxidative activity (IC50 = 3 to 4 microM) in both assay systems, though its activity was weaker than that of ascorbic acid (Asc). In the assay of the antioxidative activity against auto-oxidation of linolenic acid, SBA was stable and retained its potency for a long period of time in comparison with Asc, 6-palmitoylascorbic acid (6-P-Asc) and cysteamine (CysNH2). Electron spin resonance examination indicated that SBA strongly scavenged both superoxide anion and hydroxy radical. The in vivo protective effect of SBA against ADR-induced cardiotoxicity, in which active oxygen radicals play a role, was examined. The serum creatine phosphokinase activity, a parameter of cardiotoxicity, was remarkably increased from the 3rd day until the 4th day after ADR treatment. This elevation was significantly suppressed by SBA treatment, whereas Asc, 6-P-Asc and CysNH2 were ineffective. SBA could have clinical potential for the treatment of diabetes and other disorders in which active oxygen species play a pathogenic role. PMID- 7847821 TI - Direct antiproliferative effect of triptorelin on human breast cancer cells. AB - We investigated the effect of Triptorelin (Decapeptyl, DEC) alone or combined with Tamoxifen (TAM) or Medroxyprogesterone acetate (MPA) in human breast cancer cells. DEC did not affect the growth of estrogen-insensitive MDA-MB-231 cells, while it inhibited the estrogen-stimulated proliferation of MCF-7 and CG-5 cells. No amplification of growth inhibition induced by TAM or MPA was determined by DEC. Progesterone receptor levels of CG-5 cells were significantly enhanced by DEC in the presence of 17 beta-estradiol (E2) with respect to those in control and E2-treated cells. PMID- 7847822 TI - Characterization of KW smooth muscle-like human myometrial cells. AB - We characterized the human KW cell line to investigate whether it can serve as a model to study uterine muscle physiology in vitro. KW cells stained (a) positive for vimentin, smooth-muscle-specific alpha actin, tissue-type plasminogen activator (tPA), urokinase-type PA (uPA), uPA receptor, PA inhibitor 1, latent transforming growth factor beta 1 (latent TGF-beta 1) and 17 beta-hydroxysteroid dehydrogenase type I, and (b) negative for desmin, endoglin and cytokeratin 19. Insulin-like growth factor I, epidermal growth factor and platelet-derived growth factor stimulated the DNA synthesis in KW cells in a dose-dependent manner. Therefore, KW cells express a phenotype compatible with human uterine muscle cells. Hence, they can serve as a model to study uterine muscle physiology in vitro. PMID- 7847823 TI - Establishment and characterization of five human small cell lung cancer cell lines from early tumor xenografts. AB - Five small-cell lung carcinoma (SCLC) cell lines were established from xenografted tumor lines. These tumor lines were established after transplantation into nude mice of primary tumors or metastatic foci obtained surgically, from untreated (IRSC-2M, IRSC6M, IRSC-10M and IRSC-61M) or treated patients (IRSC 74M). They were then set-up in culture as parallel cell lines. Histologically, these tumor lines were classified as being of the classic (IRSC-2M, IRSC-10M and IRSC-61M) or intermediate type (IRSC-6M and IRSC74M). Four of these 5 SCLC cell lines grew as floating cell aggregates, while one (IRSC6M) grew as an adherent cell monolayer. Growth rates were slow (doubling times ranged between 120 and 194 h) but could be accelerated (67 to 144 h) by cultivating cells in medium mixed (v/v) with self-conditioned medium. Electron microscopical examination revealed that all SCLC cell lines contained dense core granules, characteristic of their neuroendocrine origin. These cell lines formed colonies in agarose with colony forming efficiencies ranging from 0.02-0.36%. The classic-type cell lines retained their tumorigenic capacity when re-injected intracranially into naive nude mice, whereas the intermediatetype cells did not. Cytogenetic analysis confirmed the human origin of SCLC xenografts and cultured cell lines. Various numerical and structural chromosome abnormalities were found, with deletion in the short arm of chromosome 3 being the most common (4 of the 5 cell lines). Deletions in or loss of the chromosome 10 were also observed. Oncogene expression was studied in 3 representative cell lines (IRSC-10M, IRSC-2M and IRSC-74M). L myc was overexpressed only in IRSC-74M, while the GRP gene was overexpressed in the classic (IRSC-2M and IRSC-10M) but not in the intermediate-type cells (IRSC 74M). The Ki-ras oncogene was overexpressed in the 3 cell lines, while c-myc, N myc, Ha-ras, N-ras, erb B2 and sis were not detected in any of them. The 3 cell lines weakly expressed the MDR1 gene, while the GST-pi gene was not expressed. These cell lines constitute a multifaceted well-characterized in vitro model for studying the biology of these phenotypically diverse cancer cells. PMID- 7847824 TI - Ascorbic acid induces lipid peroxidation on neuroectodermal SK-N-LO cells with high endogenous ferritin content and loaded with MAb-ferritin immunoconjugates. AB - Neuroblasma-and other malignant cells often contain elevated amounts of iron-rich ferritin and H2O2 and may therefore be a potential target for pro-oxidative effects of ascorbic acid (AA), generating cytotoxic products e.g. by lipid peroxidation (LPO). The influence of H2O2 and iron, either in its free form or bound to ferritin, on AA induced LPO was first investigated using erythrocyte ghosts as a model system. Results of these experiments showed that AA induced LPO not only in the presence of free available iron but also in the presence of ferritin. Similarly, AA induced significant LPO in neuroectodermal SK-N-LO cells with elevated intracellular ferritin levels. These LPO promoting effects of ferritin in the presence of AA on SK-N-LO cells could also be observed using ferritin-immunoconjugates: for this purpose, ferritin was bound to human monoclonal antibodies (MAb-ferritin) recognizing ganglioside GD2 which is present in large quantities on cell surfaces of SK-N-LO and many neuroblastoma cells. We conclude that the pro-oxidative effects of AA could be exploited in the treatment of ferritin rich neuroblastoma in combination with chemotherapy or with MAb ferritin immunoconjugates. PMID- 7847826 TI - Inhibition of growth and induction of differentiation of promyelocytic leukemia (HL-60) by carotenoids from Crocus sativus L. AB - The effects of carotenoids of Crocus sativus L. (saffron) on cell proliferation and differentiation of HL-60 cells have been studied and compared with those of all-trans retinoic acid. Our results demonstrated that the doses inducing 50% inhibition of cell growth were 0.12 microM for all-trans retinoic acid (ATRA) and for carotenoids of saffron 0.8 microM for dimethylcrocetin (DMCRT), 2 microM for crocetin CRT and 2 microM for crocins (CRCs). At 5 microM, all these compounds induced differentiation of HL-60 cells, at 85% for ATRA, 70% for DMCRT, 50% for CRT and 48% for CRCs. In these experiments, leukemic cells were cultured for 5 days in the absence or in the presence of up to 5 microM ATRA or seminatural and natural carotenoids. Since retinoids have a potential application as chemopreventive agents in humans, their toxicity as an important limiting factor for their use in treatment should be extensively explored. The seminatural (DMCRT and CRT) and natural carotenoids (CRCs) of Crocus sativus L. are not provitamin A precursors and could therefore be less toxic than retinoids, even at high doses. PMID- 7847825 TI - Barrett's oesophagus: mucin composition, neuroendocrine cells, p53 protein, cellular proliferation and differentiation. AB - There is strong association of Barrett's oesophagus (BO) with adenocarcinoma. The sequence of events preceding malignancy appears to be reflux oesophagitis - ulceration - BO - dysplasia. One hundred and five biopsies of heterotopic columnar epithelium were stained for H&E, PAS/Alcian Blue and HID/Alcian Blue for the routine histology and neutral/acidic sialo- and sulphomucin staining. Other sections were silver impregnated by the Grimelius technique. Immunohistochemical techniques were applied for the assessment of the accumulation of p53 protein, "S" phase of the replication cell cycle using proliferating cell nuclear antigen (PCNA), marked for cell differentiation and proliferation using EGF and TGFa. 105 cases of heterotopic columnar epithelium consisted of 74 cases of BO, 25 junctional and 7 corpus mucosa. Dysplastic BO (n = 9) showed similar amount of sulphomucin and endocrine cell number when compared to non-dysplastic. PCNA study revealed a close similarity between dysplastic, indefinite for dysplasia and non dysplastic, mucosal positive counts. Growth factors activity was significantly higher in dysplastic and indefinite than in non-dysplastic, but no such difference was found between dysplastic and indefinite for dysplasia BO. There was a significant concurrent p53 expression in dysplastic and indefinite for dysplasia BO. In conclusion, the practical utility of mucin stainings, endocrine cell count, assessment of cell proliferation and differentiation by PCNA, EGF and TGFa seems to be limited in differentiation of the dysplastic and indefinite for dysplasia BO. Altered expression of p53, particularly in combination with EGF and TGFa, may be useful in studying these lesions. PMID- 7847827 TI - Expression of p53 tumor suppressor gene, oncoprotein c-erbB-2, cellular proliferation and differentiation in malignant and benign pancreatic lesions. AB - The expression of oncoprotein, tumor suppressor gene, cellular proliferation and differentiation markers were studied in 64 malignant and benign pancreatic tumors, adjacent and distant to the tumor duct epithelium. Activity of these markers was compared to 16 cases of chronic pancreatitis. Tumor suppressor gene p53 and transforming growth factor alpha were overexpressed in the majority of malignant tumors. The expression of c-erbB-2 oncoprotein and cellular proliferation marker Ki67 was less common in malignant lesions, but was absent in the benign cases. The positive staining of all markers in ductal epithelium outside of the tumor, particularly in pancreatic duct carcinoma, suggest the ductal histogenesis of this malignancy. The presence of c-erbB-2 and Ki67 in malignant lesions only suggest their possible use in the differentiation of pancreatic malignancies and chronic pancreatitis. PMID- 7847828 TI - The role of regulated phosphorylation in the biological activity of transcription factors SRF and Elk-1/SAP-1. AB - The promoters of many genes whose expression is rapidly and transiently increased upon growth factor or mitogen stimulation of susceptible cells harbor a common regulatory element, the serum response element (SRE). The transcription factors that interact with the SRE of these immediate-early genes are being intensively studied so as to elucidate the signal transduction cascades that link cell surface receptors to the SRE, and to determine the mechanisms by which signal dependent phosphorylation events modulate their function. PMID- 7847829 TI - Improved engraftment of human tumours in SCID mice pretreated with radiation and anti-asialo GM1. AB - The effects of sublethal radiation (3 Gy) and anti-asialo GM1 (anti-ASGM1) on engraftment of human tumour cell lines and fresh tumour were evaluated in the severe combined immunodeficient (SCID) mouse. Four tumour cell lines (colonic adenocarcinoma LS174T, malignant melanoma MEWO, lung adenocarcinoma H125, chronic myelogenous leukemia K562) and a fresh colon cancer metastasis were injected subcutaneously, intraperitoneally or intravenously into SCID mice. Tumour volume and metastatic spread of implanted tumours were evaluated 3-8 weeks following inoculation. Pretreatment with radiation and anti-ASGM1 resulted in more rapid and extensive uptake of subcutaneous and intraperitoneal tumours. Tail vein injection into pretreated animals also resulted in a greater number of lung metastases of H125, MEWO and K562 cell lines. This study demonstrates that sublethal radiation and the elimination of murine NK cell activity with anti ASGM1 improves tumour take rates. These findings should prove useful for investigations of human cancer immunotherapy using SCID mice engrafted with human lymphocytes and human tumours. PMID- 7847830 TI - Cytogenetical observations and hormone receptor expression in five extra-uterine leiomyomas. AB - The chromosomes were studied by an in vitro technique in four parametrial and one gastric leiomyomas. The findings in parametrial myomas (the present four cases and one published earlier) differed from the observations in uterine cases by the absence of normal stemlines and the absence of 1p,6p and 7q changes. As has been shown earlier for intraocular melanomas, the location within an organ or organ system could be the explanation for the chromosomal differences. The scanty data for leiomyomas in the digestive tract (the present case and two in the literature) suggest evolutionary patterns different from those in myomas in the genital tract. The reasons for this are unknown but differences in hormonal sensitivity, as reflected by estrogen and progesterone receptor expression, might at least be a contributory factory. PMID- 7847831 TI - Evaluation of cisplatin response in three radiation resistant and three radiation sensitive cell lines. AB - The cisplatin response was studied in three radiation sensitive mutant cell lines each paired with normally responding or radiation resistant cell lines of parental or similar origin. The radiation sensitive cell lines V3 (CHO), AT5BI (human fibroblast) and HT144 (melanoma) also showed reduced or lack of ability to repair sublethal radiation damage. Also, V3 did not repair radiation induced DNA double strand breaks and AT5BI was excision repair deficient. None of these cell lines show any cross sensitivity to cisplatin treatment. Instead the response was more like the paired normally radiation responding cell lines, except for AT5BI which showed cisplatin resistance. Thus the mechanisms causing radiation sensitivity in the three cell lines are not involved in cisplatin sensitivity. PMID- 7847832 TI - In vitro antiproliferative effects of albumin-doxorubicin conjugates against Ewing's sarcoma and peripheral neuroectodermal tumor cells. AB - The 3-5 year survival rates of patients with disseminated Ewing's sarcoma (ES) or the closely related peripheral primitive neuroectodermal tumors (PNET) remain low, even under aggressive treatment involving highly toxic multidrug chemotherapeutic regimens. ES and PNET are sensitive to doxorubicin, but may escape treatment by expression of the multidrug-resistant phenotype and/or other mechanisms. In this study, we have identified albumin as growth supporting factor for ES and PNET cells in IGF-I-supplemented serum-free tissue culture medium. To investigate the specificity and toxicity of albumin-based drug conjugates, doxorubicin was coupled to bovine serum albumin (BSA) by either a two step glutaraldehyde or carbodiimide-C4-spacer technique, yielding monomeric DOX albumin conjugates with conjugation numbers ranging from 3-20 moles DOX/mole BSA. Cellular uptake of fluorescein-isothiocyanate-(FITC)-labeled albumin and DOX albumin conjugates could be demonstrated by flow cytometric measurements of cell associated fluorescence and confocal microscopy. The cytostatic activity of these conjugates against ES/PNET cell lines, a neuroblastoma (LAN-1) and prostate cancer carcinoma cell line (PC-3) and normal lymphoblasts was tested in short term proliferation assays (48 h). The results show a high selectivity of the DOX albumin conjugates for ES/PNET cell lines, with highest growth inhibition by conjugates with low DOX conjugation numbers (n = 3) in serum-supplemented medium (17-32 fold loss of activity compared to free DOX), followed by 20-DOX-C4-albumin in serum-free medium and low activity of the other conjugates. In conclusion, DOX albumin conjugates inhibit the growth of ES/PNET cell lines selectively, showing low activity against the unrelated carcinoma line PC-3 and sparing normal lymphoblasts. The inverse correlation of activity and conjugation number demonstrates a low cytotoxic activity of DOX in acid-stable binding to monomeric albumin, pointing to a selective cytostatic activity of the modified albumin against ES and PNET cells, even in the presence of a 100 fold excess of unmodified serum albumin. PMID- 7847833 TI - The selective 5-lipoxygenase inhibitor A63162 reduces PC3 proliferation and initiates morphologic changes consistent with secretion. AB - We examined the effect of A63162 (Abbott), a selective inhibitor of 5 lipoxygenase on human prostate (PC3) cell proliferation. Within 5 min DNA synthesis was reversibly inhibited by 40 microM A63162, without altered cellular attachment or uptake of trypan blue. After 72 Hr, cells continued to be attached and exclude dye, were reduced in number and their histology was altered. Many treated cells were larger, more pleomorphic, with nuclear and cytoplasmic ultrastructural changes consistent with preparation for secretion. Some cells contained moderately swollen, distorted mitochondria. ETYA, a less selective inhibitor of 5-lipoxygenase that also inhibits cell replication, acutely reduced O2 uptake by 40%, but A63162 did not. The retention of the supravital mitochondrial dye, rhodamine 123 was increased by ETYA at 4 hr, but not after 24 hr; retention was not altered by A63162. Although the mechanism by which A63162 reversibly inhibits PC3 proliferation and initiates preparation for secretion is not identified, additional studies should further define its role in these events. PMID- 7847834 TI - In vitro activity of titanocenedichloride versus cisplatin and doxorubicin in primary and recurrent epithelial ovarian cancer. AB - BACKGROUND: Titanocenedichloride (MKT 4) is a new antineoplastic metal complex with proven activity in several experimental tumors. MATERIAL AND METHODS: In the present study, the cytotoxic activity of titanocenedichloride in fourteen primary and twelve recurrent ovarian carcinomas (OvCA) was evaluated by an in vitro adenosine triphosphate (ATP) bioluminescence assay. RESULTS: In primary tumors, MKT 4 was found to be at least as effective as cisplatin (DDP) and doxorubicin (DOX). In samples derived from pretreated patients, titanocenedichloride was even more active. In both groups of tumors, a lack of cross resistance between the two metal compounds as well as between MKT 4 and DOX was apparent. The new agent was found to be active in eight of seventeen DDP-resistant (primaries: n = 4; recurrences n = 4) and also eight of seventeen DOX-resistant tumors (primaries: n = 4; recurrences n = 4). CONCLUSIONS: These results indicate a remarkable in vitro activity of titanocenedichloride in native OvCA specimens, even in those exhibiting resistance against cisplatin or doxorubicin. The putative role of this novel drug for the future therapy of OvCA should be evaluated by additional in vitro and in vivo studies. PMID- 7847835 TI - Inhibition of early 3-methyl-4-dimethylaminoazobenzene-induced hepatocarcinogenesis by gomisin A in rats. AB - The effects of gomisin A, a lignan component of Schizandra fruits, on hepatocarcinogenesis caused by 3'-methyl-4- dimethylaminoazobenzene (3'-MeDAB) in male Donryu rats were investigated. Gomisin A significantly inhibited the appearance of foci stained for glutathione S-transferase placental form (GST-P) in the liver of rats given feed with 0.06% 3'-MeDAB. Gomisin A (30 mg/kg/daily, po) decreased the concentration of 3'-MeDAB-related azo dyes in the liver, and increased their excretion in the bile. The ratio of diploid to tetraploid nuclei increased during ingestion of 3'-MeDAB, but gomisin A delayed the increase. After the withdrawal of 3'-MeDAB, carcinogen-related azo dyes were not detected in the liver or bile, but the proportion of diploid nuclei remained high, although it decreased with a 0.03% gomisin A diet. The results suggested that the effects of gomisin A are related to improved liver function and reversal of abnormal ploidization. PMID- 7847836 TI - Feasibility of thymidine labelling index on fine needle aspirates from breast cancer: comparison with surgical samples. AB - Fine-needle aspiration (FNA) provides a suitable diagnostic tool in the management of patients with breast cancer lesions. The current study reports on tumor proliferative activity, by 3H-Thymidine Labelling Index (TLI), assessed on 59 FNA (TLI1) and 28 surgical specimens (TLI2) from the same breast cancer patients. Median TLI values from FNA and surgical material were 1.0% and 0.7%, respectively. In the 28 patients, evaluable for the comparison between TLI1 and TLI2, the association was found to be highly significant (p = 0.000). Moreover, no change in tumor proliferative activity was observed in the majority (79%) of cases when evaluated preoperatively and at surgery. This study confirms the feasibility of TLI analysis on FNA from breast cancer and provides results superimposable on those obtained in a tissue sample from the same patient. PMID- 7847837 TI - Protective effects of potato extracts and 16,16-dimethyl prostaglandin E2 on the induction of hepatic foci by cotreatment of gamma radiation and diethylnitrosamine. AB - We investigated the effect of potato extracts and 16,16-dimethyl prostaglandin E2 (DiPGE2) on the induction of glutathione S-transferase P-positive (GST-P+) altered hepatic foci in newborn Sprague-Dawley rats given single treatment with 60Co gamma irradiation and diethylnitrosamine (DEN) alone or in sequential combination. Intraperitoneal injection of 0.15 mumol/g body weight of DEN 1 hour after gamma radiation significantly increased the frequencies of GST-P+ hepatic foci compared to DEN or gamma radiation alone and DEN injection 1 hour before irradiation (p < 0.001). Potato extract was given at a dose of 2 mg/ml in drinking water for 3 weeks and DiPGE2 given at a dose of 10 micrograms/mouse 30 minutes before irradiation. Potato extracts and DiPGE2 decreased significantly the number (p < 0.001), area (p < 0.001) and Dmax (p < 0.05) of GST-P+ hepatic foci compared to the corresponding control. These results suggest that potato extracts and DiPGE2 have radio-protective potential and further studies for underlying mechanisms will be necessary. PMID- 7847838 TI - The establishment of a macrophage-like cell line (Ymnu) from NMRI mice treated with N-methyl-N-nitrosourea. I. Characterization of the cell line. AB - Here we describe the establishment of a cell line from peritoneal exudate cells for NMRI-mice treated with methylnitroso urea, which we designate Ymnu. Tests for macrophage specific characteristics have shown that 54% of Ymnu cells possess Fc gamma receptors, 30% are nonspecific esterase positive and 65% possess the macrophage specific antigen Mac-1, indicating their macrophage origin. Although of macrophage origin, the majority of these cells are round, 13 microns in diameter. The cells grow partially in suspension and have doubling times varying from 3 to 1.75 days depending on serum concentration. Cultures of Ymnu cells achieve after 14 days densities 4 times higher than those achieved by NIH-3T3 cells. Ymnu cells have lost the anchorage dependence of growth and grew very well on semi-solid media. In addition, they possess an oncogenic potential and build tumors when injected subcutaneously in nude mice. PMID- 7847839 TI - Non-isotopic in situ hybridization of human papilloma virus on histologic sections: an amended protocol. AB - The authors report on their experience with an HPV non-radioactive in situ hybridization kit and describe the favorable results gained with the amended protocol, which are as follows: 1. The application of a decreased amount of both the probe and the chromogen substrate did not alter the quality of reactions. Therefore we were able to make 60 reactions instead of the originally suggested 21. 2. The proteolytic enzyme digestion time could be prolonged by changing proteinase-K for pepsin which intensifies the signal of hybridization. 3. By changing the order of hybrid detection and posthybridization washing, we succeeded in removing the excess amount of probe-ABC-AP-BAAV-ABC-AP conglomerates without losing the target sequence. 4. Using alkaline phosphatase or ABC-AP-BAAV ABC-AP complex instead of peroxidase it was possible to demonstrate a very low number of gene copies, even if they were not detectable following the original instructions. PMID- 7847840 TI - Characterization of four drug-resistant P388 sublines: resistance/sensitivity in vivo, resistance-and proliferation-markers, immunogenicity. AB - It was the aim of this study to compare drug-resistant sublines of the murine P388 in relation to resistance markers, the resistant phenotype and immunogenicity. Resistance to drugs either belonging to the MDR type (Doxorubicin, Vincristine, Mitoxantrone) or to the non-MDR type (Methotrexate) was generated in vivo in order to mimic the clinical situation. All resistant sublines expressed the mdr1 gene and the p-glycoprotein determined on m-RNA level or immunohistochemically, while no expression was registered in the parent P388. The rhodamine 123 fluorescence as marker for the energy dependent drug efflux pump was decreased only in the MDR-sublines, while the parent P388 and the Methotrexate-resistant line retained 100% or 90% of the dye, respectively. This indicates that the rhodamine efflux is a more function-related marker for MDR than the mdr1 gene and the pgp. The in vivo characterization of the sublines as regards their sensitivity to cytostatics revealed a clear-cut cross-resistance to MDR drugs in the MDR-lines, while the Methotrexate resistant subline was only cross-resistant to Cytarabine. In each resistant subline collateral sensitivity to certain but different cytostatics was observed. Experiments to overcome resistance by concomitant treatment with the modulators Nifedipine, Verapamil, Cyclosporin A and Chloroquin led to only limited success. The sublines P388/Mitox, P388/Vinc and P388/MTX developed immunogenicity which was never registered in the original P388. Vaccination with lethally irradiated drug resistant cells resulted in a substantial rejection of viable tumor cells of the same line. With the P388/Mitox and P388/Vinc also an over-cross immunization was possible. This generation of immunogenicity as a concomitant characteristic of resistance should be considered as therapeutic potential also in the treatment of clinical cancer. PMID- 7847841 TI - The effect of tamoxifen and fenretinimide on human colorectal cancer cell lines in vitro. AB - BACKGROUND: The natural history of colorectal neoplasia may be influenced by steroid hormones and nutritional compounds. We evaluated the effect of the anti estrogenic tamoxifen (Tx), and the synthetic retinoid fenretinimide (4-HPR) on the growth of human colorectal cancer cells. METHODS: DLD-1, CACO-2, SW-620, and COLO-205 colon cancer cells, and SW-1463 and SW-837 rectal cancer cells were cultured under serum-free conditions. Quadruplicates wells (4 x 10(4) cells/well) were created for each treated, and untreated groups in each cell line. Cells were treated with 1 microM Tx, 5 microM Tx, 1 microM 4-HPR, 1 microM Tx with 1 microM 4-HPR, and 5 microM Tx with microM 4-HPR. Cell growth was measured colorimetrically with the hexosaminidase assay (405 nm), and was compared among the different groups. Cells were analyzed for estrogen receptors using an enzyme immunoassay. RESULTS: Tamoxifen, 4-HPR, or both, inhibited the growth in DLD-1 (P = .001), COLO-205 (P = .02), SW-620 (P = .001), and CACO-2 (P = .02) cell lines. Tamoxifen with 4-HPR inhibited cell growth more (P = .03) than did either Tx or 4 HPR in DLD-1, COLO-205, and SW620 cancer cells. Tamoxifen, 4-HPR, or both, had no effect on the growth of SW-837 (P = .14) cancer cells. Tamoxifen with 4-HPR promoted (P = .02) growth in SW-1463 cells, but not when added separately. Estrogen receptors were not found in any of the cells. CONCLUSIONS: Under serum free conditions, Tx, 4-HPR, or both, inhibit the growth of human colon cancer cells but not of rectal cancer cells. Combined treatment with Tx and 4-HPR is more effective than treatment with either of the agents alone in inhibiting of cell growth. The mechanism of inhibition is not clear yet, and further studies are warranted. PMID- 7847842 TI - Differential competitive inhibition: the theory of a concept. AB - The concept of differential competitive inhibition of cell surface isoenzymes is discussed. If the isoenzymes have different structures and functions it is likely that they will handle active site directed molecules at different rates. This could be tested by employing two competitive inhibitors in sequence and exploited if the second inhibitor is fluorescent. Two practical examples of this technique will be presented in the following manuscripts. PMID- 7847843 TI - Differential competitive inhibition of a cell surface protease on normal epithelial cells and carcinoma cells of the colon. AB - The cell surfaces of normal colonic epithelial cells and colonic carcinoma cells both possess a protease referred to as guanidinobenzoatase (GB). Previous studies have shown that these cells possess two distinct isoenzymic forms of GB which could be distinguished by their selective recognition of cytoplasmic protein inhibitors of GB. In the present study we have used competitive inhibitors of GB to demonstrate the differential inhibition of the GB on normal colonic epithelial cells whilst the GB on colonic carcinoma cell surfaces remains active. The enzymic status of GB on these cells has been determined by challenging the treated cells in frozen sections with a second fluorescent inhibitor, followed by fluorescence microscopic analysis. PMID- 7847845 TI - Fluorescent location of malignant cells in smears obtained from sputum. AB - A fluorescent probe (rhodamine a-N-agmatine) has been used to locate cells possessing a surface protease in sputum smears. Malignant epithelial cells possess this protease and can be quickly located by this technique. These results have been confirmed by using a second fluorescent probe (9-animo acridine) for this same cell surface protease. PMID- 7847844 TI - The fluorescent location of abnormal cervical cells employing the principle of differential competitive inhibition. AB - The screening of cervical smears is concerned with the detection of abnormal epithelial cells which may be indicative of cervical intraepithelial neoplasia (CIN). Several types of cells in cervical smears possess a cell surface protease where isoenzymic forms of this enzyme can be differentially inhibited. Using this phenomenon a simple fluorescent technique has been developed in conjunction with differential competitive inhibition which enables abnormal cervical epithelial cells to bind the fluorescent probe whilst other cells do not bind the probe. The abnormal cells can then be located by fluorescence microscopy and their co ordinates recorded for subsequent characterisation of these cells by nuclear analysis employing haematoxylin to stain the nuclei. PMID- 7847846 TI - Growth factors in mouse mammary cell interactions in vitro. AB - Paracrine interactions may be important in homeostasis of mammary gland. We have previously reported that normal mammary epithelial cells and stromal cells stimulate the growth of mammary tumor cells in 3-dimensional cultures in collagen gels. We now describe the ability of EGF, TGF beta, bFGF, aFGF, and PDGF to directly affect growth of tumor cells in 3-dimensional cultures in collagen gels. In addition, we assessed the ability of neutralizing antibodies against each growth factor to disrupt interactions between normal mammary cells and mammary tumor cells. Only bFGF and PDGF directly stimulated growth of the mouse mammary tumor cells. However, neither anti-bFGF nor anti-PDGF abrogated the stimulation of tumor cells by normal mammary epithelial cells or normal mammary stromal cell. PMID- 7847847 TI - The canine p53 gene is subject to somatic mutations in thypoid carcinoma. AB - In many different types of tumors in man and mouse, p53 is the tumor suppressor gene most frequently affected by a combination of somatic mutation and loss of the wildtype allele. In order to develop a molecular tool to study the genetic evolution of tumors in the dog, we have cloned an evolutionary conserved part of the canine homologue of p53. The isolated genomic segment, 534 bp in length, contains the 3' half of exon 5, the complete exon 6 and the 5' half of exon 7, as well as the intronic intervening sequences. The gene organization of this segment shows strong homology to that published earlier for a number of other species, including man, mouse, and Xenopus laevis. This conservation is apparent at the DNA sequence level, as well as at the deduced aminoacid sequence level. mRNA expression can be detected at low levels in normal tissues with increased mitotic activity, and in the Madin-Darby canine kidney cell line. A-->G T transversion was found in 1 out of 23 investigated primary thyroid carcinomas at a position corresponding to codon 174 in the human p53, and was predicted to give rise to an aminoacid substitution in the protein. These results suggest that p53 plays a role in the development of malignancy in the dog, in a way comparable to that in man. PMID- 7847848 TI - Effect of doxorubicin on glutathione and glutathione-dependent enzymes in cultured rat heart cells. AB - The effect of doxorubicin (DOX) on heart cell glutathione (GSH)-based enzyme systems was investigated in a rat heart myocyte model. Cellular levels of GSH decreased commensurate with viability following exposure to DOX or to the unrelated alkaloidal cardiotoxin emetine. GSH depletion by L-buthionine sulfoximine (L-BSO) did not alter myocyte viability nor doxorubicin (DOX) dose response. The nitrosourea carmustine (BCNU), which impairs GSH reductase activity, also did not alter DOX cardiotoxicity. Doxorubicin significantly increased glutathione-S-transferase (GST) activity in a time-dependent fashion. In contrast, selenium-dependent glutathione peroxidase activity was reduced by 50%. These findings demonstrate that lowered GSH or GSH reductase levels do not enhance DOX cardiotoxicity in vitro and suggest that DOX may be a substrate for GST. PMID- 7847849 TI - Cytotoxicity and mode of action of substituted indan-1, 3-diones in murine and human tissue cultured cells. AB - N-Substituted indan-1.3-diones have proven to be potent cytotoxic agents effective against the growth of single cell leukemia tumors and cell lines derived from solid tumors. A number of the derivatives were active against growth of solid tumors e.g. colon, lung bronchogenic and osteosarcoma for which few effective agents are available to inhibit their growth. These agents inhibited DNA and RNA synthesis of L1210 cells. The de novo purine synthetic pathway was inhibited at PRPP amido transferase and IMP dehydrogenase. The pyrimidine synthetic pathway was inhibited at aspartate transcarbamylase. Other sites which demonstrate minor inhibition were DNA polymerase alpha, r- and t-RNA polymerase, ribonucleoside reductase, dihydrofolate reductase, nucleoside kinases and thymidylate synthetase. In addition d(NTP) pool levels were reduced by the drugs. L1210 DNA strand scission was evident after exposure to drugs for 24 hr. at 100 microM. PMID- 7847850 TI - Cure of hepatoma in rat with the nitrosourea carmustine (BCNU). AB - Two experiments were performed with a chemically induced hepatoma in the rat. In the first, tumors were inoculated subcutaneously into both flanks. After 10 days, when all rats had tumors, treatment was given intravenously on two successive days with 10 mg carmustine/kg body weight/day. All control rats displayed growing tumors and had to be killed 12 days after treatment. Treated rats initially lost weight with a slight increase in tumor size. After 3 weeks all tumors disappeared and the rats grew normally. After 4 months the rats were killed and had no tumors. In a second experiment, tumors were inoculated under the liver capsule. Treatment was given via the hepatic artery. Control rats had large tumors after 2 weeks and had to be killed. All treated rats were without tumors at sacrifice. One of them developed a liver cyst and was killed after 3 months, the others after 4 months. PMID- 7847851 TI - 3-Aminothymidine inhibits growth of cultured human T-cell acute lymphoblastoid leukemia cells. AB - N3-Aminated derivatives of thymidine, deoxyuridine and deoxycytidine were synthesized and their cell growth inhibition activity was tested using two cultured human cell lines, CCRF-HSB-2 and KB. Among the compounds tested, 3 aminothymidine showed growth inhibition activity against CCRF-HSB-2 cells and inhibited DNA synthesis in these cells. PMID- 7847852 TI - Increased resistance to apoptosis associated with HL-60 myeloid differentiation status. AB - Morphologically HL-60 leukaemia cells largely resemble promyelocytes and can be induced to terminally differentiate in vitro. Upon reaching terminal maturation these cells rapidly undergo apoptosis. Using three chemotherapeutic agents with known apoptosis inducing capability, the susceptibility of RA - and PMA - differentiated cultures was monitored by morphological means and flow cytometry. We observed that as cells with morphological characteristics of mature granulocytes/monocytes became more prominent in the populations, there was an increased resistance to apoptosis. The inhibition of the typical internucleosomal DNA fragmentation was confirmed by agarose gel electrophoresis. However, activation of a CA+/Mg+ independent endonuclease in isolated nuclei was not affected. Flow immunocytometry revealed reduced levels of c-myc and bcl-2 oncoproteins in RA and PMA treated cells. These observations suggest that HL-60 derived granulocytes/monocytes become increasingly resistant to the induction of apoptosis and that this resistance is independent of c-myc and bcl-2 expression. Together these results demonstrate that the phenotypic changes associated with RA and PMA induced differentiation, inhibit a critical step in the progression of apoptosis. PMID- 7847853 TI - Stem cell kinetics and intestinal cancer. AB - The conventional view that intestinal stem cells divide every few days so that each stem cell undergoes several thousand divisions in a lifetime is challenged. It is proposed that fully differentiated cells, even in old age, are no more than sixty divisions from the zygote. This concept leads to a model in which the intestinal crypts are maintained by a linear hierarchy of stem cells. The model is consistent with experimental data on the clonal origin of intestinal crypts and the observed crypt mutant frequency following exposure to chemical carcinogens. It also provides an explanation for an important paradox in cancer which is that cancer incidence rises rapidly with age but less rapidly with carcinogen dose even though both are thought to act through the same mechanism. PMID- 7847854 TI - Outcome research in neurology: incorporating health-related quality of life. PMID- 7847855 TI - What is the pathogenesis of human T-cell lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis? PMID- 7847856 TI - Basic mechanisms of generalized absence seizures. AB - Generalized absence seizures are neurophysiologically, pharmacologically, and developmentally unique and comprise the primary seizure type in a number of different absence epilepsy syndromes. Over the last 10 years, the availability of a number of animal models of generalized absence seizures and of sophisticated in vitro electrophysiological techniques that allow investigation of cortical and thalamic networks has begun to shed light on the pathogenesis of this disorder. The basic underlying mechanism appears to involve thalamocortical circuitry and the generation of abnormal oscillatory rhythms from that particular neuronal network. Biochemical mechanisms operative within thalamocortical circuitry during this neuronal oscillation seem to entail phase-locked gamma-aminobutyric acid (GABA)B-mediated inhibition alternating with glutamate-mediated excitation. The basic cellular mechanism operative within this tension between excitation and inhibition appears to involve the T-type calcium current. Local circuitry within the thalamus may influence these oscillatory rhythms by GABAA-mediated inhibition. Pharmacological factors at play external to thalamocortical circuitry include cholinergic, dopaminergic, and noradrenergic mechanisms. Pathways that utilize these various neurotransmitters project onto the thalamus and/or cortex from sites distant to those structures and may modulate the process either up or down. Perturbation of one or more of these neuronal networks may lead to abnormal neuronal oscillatory rhythms within thalamocortical circuitry, with a resultant generation of bilaterally synchronous spike wave discharges that characterize generalized absence seizures. Our increasing understanding of the basic mechanisms that underlie generalized absence seizures promises to allow, for the first time, a rational design of drug treatment for a seizure disorder based on the pathogenesis of that disorder. PMID- 7847857 TI - Outcome assessment for epilepsy surgery: the impact of measuring health-related quality of life. AB - Epilepsy surgery is an increasingly common treatment for intractable epilepsy; yet there is no clear consensus among experts on how to report epilepsy surgery outcome. Most published outcome reporting systems focus on seizure frequency and type but differ in how they define clinically distinct outcome categories. We used a reliable and valid measure of self-reported health-related quality of life (HRQOL), the Epilepsy Surgery Inventory (ESI)-55, as an external standard by which to evaluate seven previously published, seizure-based outcome classification systems. The ESI-55 was administered to 133 adults who had previously undergone surgery for intractable epilepsy, and results were linked to data on their seizure occurrence before and after surgery (over the year prior to their HRQOL reports). These 133 patients were classified according to each seizure-based outcome system, and variation in HRQOL across outcome groups was evaluated using analysis of variance. Results reveal noteworthy variation in the extent to which different systems reflect patients' HRQOL at follow-up. We modified existing systems to derive a seizure-based surgery outcome system that most closely reflects HRQOL when applied over the latest 1-year postoperative interval. PMID- 7847858 TI - Detection of human T-lymphotropic virus type I (HTLV-I) tax RNA in the central nervous system of HTLV-I-associated myelopathy/tropical spastic paraparesis patients by in situ hybridization. AB - Autopsy specimens from 3 patients with human T-lymphotropic virus (HTLV-I) associated myelopathy/tropical spastic paraparesis (HAM/TSP) were examined for the presence of HTLV-I in the central nervous system (CNS). In situ hybridization using an HTLV-I tax RNA probe detected cells containing HTLV-I RNA in spinal cord and cerebellar sections. HTLV-I infected cells were located within the white matter and, in particular, within the anterior and lateral funiculi of the spinal cord. Consistent with previously described HAM/TSP pathology, there were perivascular infiltrates in these CNS specimens. Significantly, HTLV-I RNA was not localized to these infiltrates but was detected deeper within the neural tissue. Furthermore, phenotypic analysis demonstrated that at least some of the infected cells were astrocytes. While previous polymerase chain reaction studies have demonstrated the presence of proviral HTLV-I in CNS specimens, here we provide evidence for the in situ expression of HTLV-I RNA in the CNS of HAM/TSP patients. PMID- 7847859 TI - Analysis of the SCA1 CAG repeat in a large number of families with dominant ataxia: clinical and molecular correlations. AB - Autosomal dominantly inherited ataxias are a clinically and genetically heterogeneous group of neurodegenerative disorders. The gene involved in one subtype, spinocerebellar ataxia 1 (SCA1), was first localized to chromosome 6p. An unstable CAG repeat has been identified as the responsible mutation. In this study, 88 families with various types of inherited ataxias and 16 individuals with sporadic cerebellar ataxia were investigated to determine the frequency of this mutation, the behavior of the SCA1 CAG repeat during transmission, and the clinical features specific to this form of disease. Only 12 of the families carried the SCA1 mutation; 10 of the 12 were of French origin. When transmitted paternally, the repeat was more unstable and larger in size. Age at onset was inversely correlated with the number of CAG repeats. Anticipation in age at onset of about 11 years was observed in offspring. Analysis of the clinical features did not distinguish SCA1 from other forms of dominantly inherited ataxias. In the absence of distinguishing clinical characteristics, the diagnosis of SCA1 in single affected patients or family members can only be made by direct detection of the mutation, opening the way for presymptomatic testing. PMID- 7847860 TI - Changes in excitability of motor cortical circuitry in patients with Parkinson's disease. AB - Using the technique of transcranial magnetic stimulation over the motor areas of cortex and recording electromyographic (EMG) responses from the first dorsal interosseous muscle, we measured the excitability of corticocortical inhibitory circuits at rest using a double pulse paradigm, in 11 patients with Parkinson's disease (PD) studied both on (ON) and off (OFF) (after overnight withdrawal) their normal medication and in 10 age-matched control subjects. There was a significant decrease in the amount of corticocortical inhibition at short (1-5 msec) interstimulus intervals in patients relative to their controls, which improved after L-dopa intake. For comparison with previous reports using transcranial magnetic stimulation we also measured the duration of the EMG silent period when stimuli were given to voluntarily active muscle, and the threshold for evoking an EMG response in both the active and relaxed states. There was no change in the threshold for evoking EMG responses whether muscles were active or relaxed. However, the silent period was significantly prolonged when ON compared with OFF, although in neither state was the duration significantly different from that seen in normals. We suggest that there may be abnormalities of motor cortical inhibitory mechanisms in patients with Parkinson's disease that are not readily detected using threshold or silent period measurements alone. PMID- 7847861 TI - Multiple sclerosis: limited diversity of the V delta 2-J delta 3 T-cell receptor in chronic active lesions. AB - T lymphocytes bearing the gamma delta T-cell receptor have been found in the central nervous system of patients with multiple sclerosis in association with demyelinated lesions. Although the biological function of these cells remains to be established, it has been proposed that they are involved in the response to highly conserved antigens, such as heat shock proteins (hsp), expressed during tissue damage and thus may contribute to the development of an autoimmune response. Using polymerase chain reaction, we probed for the presence of T-cell receptor gamma delta cells in fresh-frozen early autopsy brain tissue from patients with multiple sclerosis and patients with non-multiple sclerosis conditions. The results demonstrated the presence of two major V-J combinations of the T-cell receptor delta chain--V delta 2-J delta 3, V delta 2-J delta 1--and we used a direct sequencing technique to determine whether this gamma delta T cell population was clonal or diverse. In chronic-active plaques from 9 patients with multiple sclerosis, we found a striking predominant gene rearrangement within the V delta 2-J delta 3 T-cell receptor population that was not present in central nervous system tissue from patients with other neurological diseases. In contrast, within the V delta 2-J delta 1 T-cell receptor population, a predominant rearrangement pattern was detected in only 1 of the multiple sclerosis patients. The sequence of the predominant V delta 2-J delta 3 gene rearrangement was confirmed by cloning and sequencing the gene products from 1 multiple sclerosis patient.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7847862 TI - Differentiation of multiple system atrophy from idiopathic Parkinson's disease using proton magnetic resonance spectroscopy. AB - Proton magnetic resonance spectroscopy, localized to the lentiform nucleus, was carried out in 7 patients with the pure or predominantly striatonigral variant (SND) of multiple system atrophy (MSA), 5 patients with the olivopontocerebellar variant of MSA, 9 patients with a clinical diagnosis of idiopathic Parkinson's disease (IPD), and 9 healthy age-matched controls. The MSA group with predominantly striatonigral involvement showed a significant reduction in the N acetylaspartate (NAA)/creatine ratio (median, 1.19; range, 0.96-2.0; p < 0.02) compared with the NAA/creatine ratio from the control group (median, 1.76; range, 1.61-2.0). In contrast, the IPD group had a normal NAA/creatine ratio (median, 1.82; range, 1.19-2.31; p > 0.05). The NAA/creatine ratio was markedly reduced in 6 of the SND patients and in only 1 IPD patient. The choline/creatine ratio was also significantly lower in the SND group (median, 1.02; range, 0.91-1.23; p < 0.04) compared with the control group (median, 1.22; range, 1.05-1.65). The IPD group showed a normal lentiform choline/creatine ratio (median, 1.13; range, 0.89 1.65; p = 0.25) compared with controls. The olivopontocerebellar group also showed a significant reduction in the NAA/creatine ratio from the lentiform nucleus (median, 1.47; range, 1.22-1.68; p < 0.01) compared with the controls as well as a nonsignificant reduction in the choline/creatine ratio (median, 0.93; range, 0.85-1.27; p < 0.4).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7847863 TI - Huntington's disease gene: regional and cellular expression in brain of normal and affected individuals. AB - Huntington's disease (HD) is an autosomal dominant disorder characterized by involuntary movements, dementia, and progressive, global, but regionally accentuated, brain atrophy. The disease affects the striatum most severely. An expansion of a trinucleotide repeat on chromosome 4p16.3 within the coding region of a gene termed IT15 has been identified as the mutation causing HD. The normal function of IT15 and the mechanisms by which the presence of the mutation causes HD are unknown. Although IT15 expression has been detected in the brain, as well as in other organ tissues, by Northern blot and in situ hybridization, it is not known whether a preferential regional or cellular expression of IT15 exists within the central nervous system of normal, affected, and presymptomatic individuals. Using quantitative in situ hybridization methods, we examined extensively the regional and cellular expression of IT15. In controls, IT15 expression was observed in all brain regions examined with the highest levels seen in cerebellum, hippocampus, cerebral cortex, substantia nigra pars compacta, and pontine nuclei. Expression in the striatum was intermediate and expression in the globus pallidus was low. IT15 was expressed predominantly in neurons; a low but significant level of expression was seen in glial cells. Analysis of grain counts per square micrometer in neurons showed that the regional differences in the level of mRNA expression were related to density and size of neurons in a given region and not primarily to differences in levels of mRNA expression in individual cells after correction for cell size. Neurons susceptible to degeneration in HD did not selectively express high levels of IT15 mRNA. In HD brains (grades 2-4), the distribution and levels of IT15 mRNA were comparable with controls in all areas except in neostriatum where the intensity of labeling was significantly reduced. Presymptomatic HD brains had a striatal expression similar to controls and surviving striatal neurons in more advanced HD had an expression of IT15 within normal limits. It is apparent from these results that the presence of expanded trinucleotide repeats in HD does not result in the absence of IT15 mRNA expression or in altered patterns or levels of expression. The lack of correlation between the levels of IT15 mRNA expression and susceptibility to degeneration in HD strongly suggests that the mutant gene acts in concert with other factors to cause the distinctive pattern of neurodegeneration in HD. PMID- 7847864 TI - Acute human stroke studied by whole brain echo planar diffusion-weighted magnetic resonance imaging. AB - Our purpose was to use whole brain echo planar magnetic resonance imaging (MRI) to identify and characterize diffusion abnormalities in acute cerebral ischemia. We studied 40 patients as early as 3 hours after onset of signs and symptoms of cerebral ischemia. Diffusion-weighted imaging (DWI) of the entire brain could be completed in 3 seconds or, using seven different diffusion sensitivities (maximum b = 1,271 sec/mm2), in 48 seconds. Measurements and synthetic maps were made of apparent diffusion coefficients (ADC), a physiological parameter that characterizes the self-diffusion of water in tissue. Early ischemic lesions were identified with DWI as hyperintense regions of decreased ADC in all patients who subsequently developed infarction, before changes were evident on conventional MRI in cases studied earlier than 6 hours after onset of ischemic symptoms. Lesions as small as 4 mm in diameter were identified. The extent of lesions within white matter was best defined by controlling for the anisotropic effect of axonal orientation. The mean ADC (+/- SD) for control regions in the 36 patients was 9.15 (+/- 2.91) x 10(-4) mm2/sec. Mean ADC of ischemic regions was 56% of control values at 6 hours or less and stayed significantly reduced for 3 to 4 days after onset of ischemia. The relative ADC increased progressively over time to be pseudonormalized at 5 to 10 days and elevated in the chronic state, making the distinction of acute lesions adjacent to chronic infarcts readily apparent. DWI with echo planar imaging measures a unique physiological parameter that is sensitive to ischemic changes before conventional MRI. Its potential role in the quantitative study of human stroke pathophysiology and therapeutics is the subject of further investigation. PMID- 7847865 TI - Apolipoprotein E genotypes in Parkinson's disease with and without dementia. AB - The apolipoprotein E gene (Apo E) type 4 allele is a genetic risk factor influencing the development and age of onset of Alzheimer's disease. Because Parkinson's disease shares many characteristics of Alzheimer's disease, we studied the frequencies of Apo E genotypes in a cohort of 52 Parkinson's disease patients with dementia and 61 patients without dementia. Dementia was determined per National Institute of Neurological and Communicative Disorders and Stroke criteria and Mattis Dementia Rating Scale (DRS) < 126. Normal cognition was defined as DRS > 132. Apo E genotype and allele frequencies did not differ between demented and nondemented parkinsonian patients. Neither group's genotype and allele frequencies differed from that of a nondemented population of 78 controls. We conclude that the Apo E epsilon 4 allele influences neither the development of Parkinson's disease nor the dementia associated with Parkinson's disease. PMID- 7847866 TI - Topical lidocaine gel relieves postherpetic neuralgia. AB - Postherpetic neuralgia (PHN) following herpes zoster is a common and disabling neuropathic pain syndrome. In a double-blind, three-session study, 5% lidocaine gel or vehicle was applied simultaneously to both the area of pain and to the contralateral mirror-image unaffected skin. In the local session, lidocaine gel was applied to the painful skin area. In the remote session, lidocaine gel was applied to mirror-image skin. In the placebo session, vehicle was applied bilaterally. For cranial PHN, gel was applied without occlusion for 8 hours. For limb or torso PHN, gel was applied under occlusion for 24 hours. The 16 subjects with cranial PHN reported pain relief significantly favoring local drug application at 30 minutes, 2, 4, and 8 hours. The 23 subjects with torso or limb PHN reported significantly lower pain intensity with local drug application at 8 hours and both pain relief and reduced pain intensity at 24 hours. Remote lidocaine application to mirror-image skin was no different from placebo. No systemic adverse effects were reported and blood levels did not exceed 0.6 microgram/ml. Topical application of 5% lidocaine gel relieves PHN pain by a direct drug action on painful skin. PMID- 7847867 TI - Apolipoprotein E and Alzheimer's disease: ethnic variation in genotypic risks. AB - The presence of the apolipoprotein epsilon 4 (apo epsilon 4) allele significantly increases the risk of Alzheimer's disease. Whether this is due to biological effects of the apo epsilon 4 protein or reflects linkage disequilibrium with an as yet unidentified Alzheimer's disease susceptibility gene is of critical importance. In a community study in northern Manhattan we found a fivefold increase in the risk of Alzheimer's disease among African-Americans, Hispanics, and whites homozygous for apo epsilon 4. Overall, the risk between Alzheimer's disease and apo epsilon 4 heterozygosity was also increased by twofold, but the association was somewhat weaker for African-Americans than for Hispanics and whites. In contrast, the apo epsilon 2/epsilon 3 genotype was associated with an eightfold increased risk of Alzheimer's disease in African-Americans but it was associated with reduced risk in whites. Variability in the strength and type of association between Alzheimer's disease and the apo E polymorphisms in the three ethnic groups could not be fully explained by age differences. The allelic frequency of apo epsilon *4 was significantly higher in patients than control subjects in all ethnic groups at age 70 or younger, reflecting the higher proportion of apo epsilon 4 homozygotes, but this difference diminished with increasing age. The allelic frequency of apo epsilon *2 for African-Americans and Hispanics, but not whites, was significantly higher in patients than control subjects, but only after age 70.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7847868 TI - Plasticity of nerve afferents to nigrostriatal neurons in Parkinson's disease. AB - Clinical symptoms in Parkinson's disease do not appear until almost total depletion of dopamine has occurred in the striatum, suggesting the existence of compensatory mechanisms to offset the loss of nigrostriatal dopaminergic neurons. This compensation has been attributed mainly to an increased turnover of dopamine in the remaining dopaminergic neurons. Besides this biochemical phenomenon intrinsic to dopaminergic neurons, we tested whether morphological changes in the nerve afferents to the dopaminergic neurons could participate in these compensatory mechanisms. The afferents to the dendrites of dopaminergic neurons were analyzed ultrastructurally in the substantia nigra of parkinsonian patients and matched controls, using simultaneous histochemical detection of acetylcholine like cation and tyrosine hydroxylase. The size of acetylcholine-like cation containing terminals in contact with dopaminergic dendrites increased significantly by 38% in the substantia nigra of parkinsonian patients; whereas their number per section of dopaminergic dendrite showed an increase of 60%, although not reaching statistical significance. The number of the terminals devoid of acetylcholine-like cation per section of dopaminergic dendrite decreased significantly by 52% in the substantia nigra of parkinsonian patients. These results suggest (1) a plasticity of excitatory cholinergic neurons targeting nigral dopaminergic neurons and (2) an involution of noncholinergic nerve terminals, mostly originating from inhibitory nigral, pallidal, and striatal GABAergic neurons. The findings provide evidence of a capacity for neuronal plasticity in the elderly human brain, even in the presence of neurodegenerative disorders. PMID- 7847869 TI - Molecular and clinical findings in a family with dentatorubral-pallidoluysian atrophy. AB - Herein we describe the molecular and clinical findings in a North American Caucasian family with dentatorubral-pallidoluysian atrophy (DRPLA). These patients all presented with an autosomal dominant neurodegenerative disorder characterized by a variable combination of clinical symptoms including seizures, ataxia, dementia, choreiform movements, mental retardation, and psychiatric disease. Neuroradiologic findings in the index case revealed deep subcortical white matter changes on magnetic resonance imaging. Prior to referral, the family carried a diagnosis of Huntington's disease (HD). Subsequent direct molecular testing for HD failed to identify the HD expansion mutation in affected individuals. Molecular testing for DRPLA, however, demonstrated the presence of the recently characterized DRPLA expansion mutation in all affected individuals. The size of the expansion correlated with the age of onset of clinical symptoms. As DRPLA has rarely been reported in North American and European populations, the molecular confirmation of DRPLA in this family provides support for the hypothesis that DRPLA may not be as geographically restricted as once thought. PMID- 7847870 TI - Concentrations of amyloid beta protein in cerebrospinal fluid of patients with Alzheimer's disease. AB - Deposition of fibrillar amyloid beta protein (A beta) is increased in brains of patients with Alzheimer's disease. Concentrations of A beta were measured in cerebrospinal fluid with an enzyme-linked immunosorbent assay in 10 neurological patients free from neurodegenerative disease, 28 patients with Parkinson's disease, and 18 patients with probable Alzheimer's disease. Levels of A beta in cerebrospinal fluid were not significantly different among these groups. This observation suggests that concentrations of soluble A beta in cerebrospinal fluid as measured in this study do not reflect the amount of fibrillar, aggregated A beta in the brain of patients with Alzheimer's disease. PMID- 7847871 TI - Proton magnetic resonance spectroscopic imaging in patients with frontal lobe epilepsy. AB - Proton magnetic resonance spectroscopic imaging (1H MRSI) has demonstrated decreased N-acetyl compounds (NA) in the epileptogenic hippocampus in patients with temporal lobe epilepsy. We studied 8 patients with frontal lobe epilepsy and found mean NA/creatine (Cr) in the epileptogenic frontal lobe decreased by 27% compared with that of the contralateral homologous region (1.81 +/- 0.36 vs 2.49 +/- 0.60, p < 0.008). In every patient, NA/Cr was decreased in the epileptogenic region by at least 5%. These findings suggest that 1H MRSI may be useful in the presurgical evaluation of patients with frontal lobe epilepsy. PMID- 7847872 TI - No protective effect of apolipoprotein E epsilon 2 allele in Dutch hereditary cerebral amyloid angiopathy. PMID- 7847873 TI - Antiviral and immunomodulating inhibitors of experimentally-induced Punta Toro virus infections. AB - A major component of a US Army Medical Research and Development Command-supported program to discover and develop new drugs for the treatment of Rift Valley fever, sandfly fever, and Crimean-Congo hemorrhagic fever has been to study candidate test materials against hepatotropic infections of C57BL/6 mice induced by the related but less biohazardous Punta Toro virus (PTV). The effects of 75 compounds, some of which were considered immunomodulators in their primary mechanism of activity, were studied in the PTV infection model. Of these, ribavirin, ribamidine, ribavirin 2',3',5'-triacetate, tiazofurin, tiazofurin-5' monophosphate, tiazofurin-2',3',5'-triacetate, selenazofurin, pyrazofurin, 3 deazaguanine, and 3-deazaguanosine were considered significantly inhibitory, acting against the infection by a direct antiviral (non-immunomodulatory) fashion. These compounds had therapeutic indices (TI) ranging from > or = 5 to 65, using increased survivors as the evaluation parameter. Immunomodulators considered significantly inhibitory to this infection were poly (ICLC), ampligen, human recombinant interferon-alpha-A/D, MVE-1, MVE-2, AM-3, AM-5, mannozym, bropirimine, CL246,738, phenyleneamine, and 7-thia-8-oxoguanosine. Utilizing increased survivor numbers as measure of activity, these inhibitors had TI ranging from > or = 16 to 1000. Other antiviral effects exerted by the active compounds included reduction of hepatic icterus, lowered serum glutamic oxaloacetic and pyruvic acid transaminases, and inhibition of recoverable serum and liver virus titers. The active immunomodulators were significantly effective when therapy was initiated as late as 48 h after virus inoculation, at a time when clinical signs of the PTV disease were being manifested in the animal. PMID- 7847874 TI - Anti-influenza virus activity of the neuraminidase inhibitor 4-guanidino Neu5Ac2en in cell culture and in human respiratory epithelium. AB - The anti-influenza activity of the neuraminidase inhibitor 4-guanidino-Neu5Ac2en (4-G-NAc) was determined in Madin-Darby canine kidney (MDCK) cells by yield reduction and ELISA and in explants of human respiratory epithelium by yield reduction. In MDCK cells, 50% inhibitory concentrations (EC50) averaged 0.5 microgram/ml for influenza A/Virginia/88(H3N2) and 0.04 microgram/ml for A/Texas/36/91(H1N1) by ELISA, and < 0.01 microgram/ml for influenza A/Virginia by yield reduction. In human adenoid explants, concentrations causing at least 1.0 log10 TCID50/ml decrease in yield (EC90) at 48 h were < 0.01 microgram/ml for A(H1N1) and A(H3N2) viruses and 0.25 microgram/ml for B/Hong Kong/5/72. 100 micrograms/ml 4-G-NAc did not inhibit outgrowth of human adenoid epithelium at 6 days, whereas ribavirin 10 micrograms/ml reduced outgrowth by > 50%. 4-G-NAc is a potent and selective inhibitor of clinical isolates of influenza A and B viruses in human respiratory epithelium. PMID- 7847875 TI - Inhibition of retrovirus-induced syncytium formation by photoproducts of a brominated 1,8-naphthalimide compound. AB - A major disadvantage of conventional phototherapy is the requirement for the in situ delivery of stimulating photoenergy subsequent to the binding of photochemicals to target malignant cells, or virus-infected cells, or viruses. This drawback has resulted in considerable limitation in the use of photochemicals in photomedicine. To circumvent this problem, we have investigated the antiviral efficacy of a brominated 1,8-naphthalimide photocompound, termed LY66Br [3-bromo-4-(hexylamino)-N-hexyl-1,8-naphthalimide], which upon exposure to visible light at 420 nm generates independently of oxygen one or more stable antiviral molecular photoproducts (e.g., is 'preactivated'). Human cell lines infected with the human immunodeficiency virus type 1 (HIV-1), or with the human T-lymphotropic virus type-1 (HTLV-I) exposed to photochemical products of LY66Br (P-LY66Br) completely lost their ability to form syncytia in vitro. Photoproducts of P-LY66Br retain full antiviral activity for at least 3 and 6 weeks when stored at room temperature and at -80 degrees C, respectively. Concentrations of P LY66Br, effective in inhibiting syncytium formation mediated by HIV-1 and HTLV-I, were nontoxic to normal red cell components of whole blood (red blood cell 2,3 diphosphoglyceric acid, adenosine triphosphate, osmotic fragility or blood type antigens). Additionally, no evidence of acute toxicity was demonstrated in mice following an intravenous bolus inoculation to achieve plasma concentration of 600 microM of P-LY66Br. These findings represent the first demonstration of inhibition of retrovirus-induced syncytium formation by a photochemical product, and justify further investigation of the preactivation process of photochemicals in the treatment of systemic viral infections such as the acquired immunodeficiency syndrome (AIDS), in cancer therapy, and in sterilization of banked blood products. PMID- 7847876 TI - Generalized cytomegalovirus (CMV) infection and CMV-induced pneumonitis in the rat: combined effect of 9-(1,3-dihydroxy-2-propoxymethyl)guanine and specific antibody treatment. AB - The combined effect of 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG, ganciclovir) and hyper immune serum (HIS) was studied in two different rat models. In the first model, a lethal generalized rat cytomegalovirus (RCMV) infection was established in immunosuppressed Brown Norway (BN) rats. Treatment with DHPG or hyper immune serum (HIS) effectively reduced both mortality rate and virus titers in the liver and lungs. By combined treatment the effective dose of both DHPG and HIS was reduced to 25%. The fractionary effective dose was 0.5, indicating a moderate synergistic effect on survival. Combined treatment also established a significant reduction of virus titers in lungs and liver (P < 0.01), but not in spleen. In the second model, interstitial pneumonia (IP) was established in RCMV-infected immunosuppressed BN rats after allogeneic bone marrow transplantation. IP was characterized by infiltration of mononuclear cells and diffuse thickening of the alveolar septal wall. DHPG reduced virus titers in the lungs but had no effect on IP. In contrast, HIS significantly reduced both virus titers and histopathologic changes in the lungs. Combined DHPG and HIS treatment minimized virus titers in internal organs and CMV-induced IP. Likewise, combined DHPG and control immune serum treatment significantly reduced immunopathologic changes in the lungs. PMID- 7847877 TI - Synthesis and antiviral activity of new carbonylphosphonate 2',3'-dideoxy-3' thiacytidine conjugates. AB - The synthesis of new potential PFA-BCH-189 conjugate analogues is described and their molecular structure clearly identified through NMR and mass spectra techniques. The anti-HIV-1 activity was determined according to the inhibition of syncytium formation in MT-4 cells, while the anti-HBV activity was determined in infected duck hepatocytes. Both antiviral activities of the PFA-BCH-189 conjugates were much lower than those of the parent BCH-189 (2',3'-dideoxy-3' thiacytidine) (1). Whereas a prodrug effect, following cleavage and release of the free BCH-189 and PFA, cannot be ruled out, poor cellular permeation of the drug seems to be the most likely reason for the reduced activities against HIV and DHBV. The presence of the PFA moiety appears to be detrimental for both the anti-HIV and anti-DHBV activity of PFA-BCH-189 cases. PMID- 7847878 TI - The prevention of cell adhesion and the cell-to-cell spread of HIV-1 in vitro by the alpha-glucosidase 1 inhibitor, 6-O-butanoyl castanospermine (MDL 28574). AB - The intercellular adhesion molecule (ICAM-1, CD54) and its counter receptor, the integrin leukocyte function associated antigen 1 (LFA-1, CD11a/CD18), have important roles in the immune response. These include guiding leukocytes to sites of inflammation (Issekutz and Issekutz, 1992), enhancement of antigen presentation (Moy and Brian, 1992) and potentiation of cytotoxic cell function (Umehara et al., 1992; Sanchez-Madrid et al., 1982). In addition to these activities LFA-1 and ICAM-1 are implicated in the cell-to-cell transmission of human immunodeficiency virus (HIV-1) since antibodies to CD18, CD54 or synthetic peptide analogs of ICAM-1 antagonise the formation of virus-induced syncytia (Fecondo et al., 1993; Gruber et al., 1991; Hildreth and Orentas, 1989; Valentin et al., 1990). The alpha-glucosidase 1 inhibitor 6-O-butanoyl castanospermine (MDL 28574) has antiviral activity for HIV which is manifested by a decrease in syncytia as well as the production of virus with altered gp120 and a reduced infectivity (Taylor et al., 1991). Previously, it has been shown that the alpha glucose 1 inhibitor (MDL 28574) treatment of human leukocytes in vitro or mouse lymphocytes in vivo affects the detection of LFA-1 but not domain 1 of CD4 nor several other CD markers (Bridges et al., submitted for publication). Here, we demonstrate that pre-treatment of HIV-permissive CD4+ cells with MDL 28574 substantially reduces their capacity to bind with cells chronically infected with HIV-1 which results in reduced virus production.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7847879 TI - 9-(2-Phosphonylmethoxyethyl) adenine increases the survival of influenza virus infected mice by an enhancement of the immune system. AB - PMEA (9-(2-phosphonylmethoxyethyl)adenine) is a potent inhibitor of DNA viruses and retroviruses able to enhance natural immune functions such as natural killer cell activity and interferon production. The results reported in this paper show that the treatment with PMEA significatively decreased the mortality of mice challenged with influenza A/PR8 virus (an RNA virus, non sensitive to the antiviral effect of PMEA) compared to untreated, infected controls (median survival 8.64 days and 7.61 days, respectively), and reduced lung weight and consolidation (two surrogate markers of virus infection). Furthermore, virus titer obtained from lung homogenates was substantially decreased in PMEA-treated mice compared to controls. Finally, enhancement of natural killer cell activity was achieved in PMEA-treated A/PR8-infected mice compared to A/PR8-infected controls. Overall, results suggest that PMEA decreases the influenza virus related mortality and morbidity through the enhancement of some immune functions, and that this effect might be additive or even synergystic with the direct inhibitory effect of DNA viruses or retroviruses induced by PMEA itself. This supports the importance of evaluating this drug in patients with diseases related to herpesviruses or to human immunodeficiency virus. PMID- 7847880 TI - Transcriptional induction of genes by IFN-beta in mouse cells is regulated by a transcription factor similar to human ISGF-3. AB - Previous studies of IFN-stimulated transcription factors in murine cells have identified a variety of trans-acting factors that bind to the IFN-stimulated response element (ISRE) whose role in gene expression remain unclear. The present investigation was undertaken to delineate the signal transduction pathway as well as to identify the transcription factors regulated by murine IFN-beta in L929 cells. Tyrosine kinase inhibitor, Genistein, abrogated gene induction and activation of transcription factors by IFN-beta. As early as 5 min after IFN-beta treatment, a transcription factor was activated in the cytoplasm which subsequently migrated into the nucleus. Anti-phosphotyrosine antibodies detected a specific transcription factor induced by mIFN-beta. Antibodies raised against human ISGF-3 subunit proteins p48, p84, p91 and p113 recognized this factor in the cytoplasm as well as in the nucleus of IFN-beta-treated L929 cells. An antibody raised against an oligopeptide of human p113 (residues 435-450) recognized the ISGF-3 complexes both in human and murine cells. However, a different antibody against the C-terminus of human p113 (residues 671-806) did not recognize the ISGF-3 like complex in mouse cells, indicating differences in the primary sequence of these proteins. PMID- 7847881 TI - 2nd European Conference on Fungal Genetics. Lunteren, The Netherlands, April 1994. PMID- 7847882 TI - Nitrogen regulation in fungi. AB - Nitrogen regulation has been extensively studied in fungi revealing a complex array of interacting regulatory genes. The general characterisation of the systems in Aspergillus nidulans and Neurospora crassa shall be briefly described, but much of this paper will concentrate specifically on the recent molecular characterisation of areA, the principle regulatory gene from A. nidulans which mediates nitrogen metabolite repression. Three areas shall be explored in detail, firstly the DNA binding domain, which has been characterised extensively by both molecular and genetic analysis. Secondly we shall report recent analysis which has revealed the presence of related DNA binding activities in A. nidulans. Finally we shall discuss the mechanism by which the nitrogen state of the cell is monitored by the areA product, in particular localisation of the domain within the areA product which mediates the regulatory response within the protein. PMID- 7847883 TI - Regulatory circuits of the amdS gene of Aspergillus nidulans. AB - The amdS gene codes for an acetamidase enzyme that hydrolyses acetamide to acetate and ammonium thus providing A. nidulans with a source of carbon and nitrogen. The exceptionally favourable genetics of this system combined with molecular analysis have enabled many regulatory circuits affecting amdS to be identified genetically. Characterization of the regulatory genes and the definition of the cis-acting sites involved have been done using both in vivo and in vitro mutagenesis. Recent results on the analysis of the system are presented. PMID- 7847884 TI - In vitro transcription and binding analysis of promoter regulation by a host specific signal in a phytopathogenic fungus. AB - The PDA1 promoter of the phytopathogenNectria haematococca MPVI (anamorph Fusarium solani) offers a model for regulation of a fungal virulence gene in response to plant host-specific signals. Expression of the PDA1 gene, encoding pisatin demethylase, is induced in culture by pisatin, the isoflavanoid phytoalexin of pea. This pisatin induction is suppressed by nutritional factors. We have been studying the mechanism of pisatin induction through in vitro identification of regulatory factors and regulatory elements of the PDA1 promoter. We have developed an in vitro transcription system for N. haematococca which accurately initiates at the PDA1 promoter and reflects the pisatin induction of PDA1 mRNA observed in vivo. This in vitro activity allowed a functional test of a limited set of 5' upstream deletions in the PDA1 promoter. In vitro binding studies have identified a DNA binding factor which is appears in mycelial extract after treatment of the mycelium with pisatin. This pisatin responsive factor binds to a minimum size region of 35 bp approximately 500 bp upstream of the transcription initiation site. Tests using the in vitro transcription assay and in vivo competition both indicate a role for this binding region in the high expression of PDA1 under pisatin-induced conditions. Southwestern blotting has identified one component of this binding activity to be a approximately 35 kDa protein. The availability of these functional and structural tests of function, in conjunction with complementary in vivo tests, allow the detailed dissection of the signal pathway leading from exposure of the cell to pisatin towards the activation of PDA1 transcription. PMID- 7847885 TI - Control of mating and development in Ustilago maydis. AB - In Ustilago maydis the a and b mating type loci control pathogenicity as well as sexual development. We review the function of these loci in controlling the cell fusion step, the switch from yeast-like to filamentous growth and subsequent pathogenic development. Our special emphasis will be the role of pheromones and pheromone signaling in these processes. PMID- 7847886 TI - Population genetics of filamentous fungi. AB - Population genetics aims to understand causes and consequences of the genetic structure of populations, i.e. distributions of genetic variants in space and time. Among the most important determinants of the genetic population structure is the genetic system itself, which is the collection of processes and mechanisms responsible for the transmission of genetic information. Filamentous fungi offer excellent opportunities for studying the effects of the genetic system on genetic population structure. Apart from their advantage as laboratory organisms, they exhibit a wide variety of genetic systems. In particular, their inherent capacity for anastomosis provides unique possibilities for investigating rates and consequences of horizontal gene transfer. Furthermore, the temporary confinement of the products of meiosis in a common structure (the ascus) enables the study of competitive and antagonistic interactions between the meiotic products. An intriguing example of the latter is the phenomenon of 'spore killing', resulting in distorted meiotic segregation. This paper concentrates on population level research of the occurrence of vegetative incompatibility in Aspergillus and Neurospora species and to what extent this will inhibit horizontal transmission of genetic information, and on spore killing in Podospora anserina. PMID- 7847887 TI - Suppression of gene expression by homologous transgenes. AB - When a wild-type strain of Neurospora crassa is transformed with different portions of the carotenogenic albino 1 or albino 3 genes, up to 30-35% of the transformants show an albino phenotype. The albino transformants presented a variety of phenotypes ranging from white or yellow to dark yellow colour. The ectopically integrated sequences provoke a severe impairment of the expression of the endogenous al-1 or al-3 genes. This phenomenon, that has been termed quelling, is found to be spontaneously and progressively reversible. In fact, all of the albino transformants have an unstable phenotype and revert progressively to wild type or intermediate phenotypes over a prolonged culturing time. The phenotypic reversion is characterised by a progressive release of the transcriptional inhibition and seems to correlate with the reduction of the number of the ectopic integrated sequences. However, there is no strict correlation between the copy number of the ectopic sequences and the intensity of quelling, as indicated by the existence of albino transformants containing only 1 2 ectopic sequences. The nature of the molecular events determining the onset of quelling is unclear, in any event, these are likely to involve some kind of interaction between the resident genes and ectopically integrated exogenous sequences. Recent evidences on a possible mechanism are presented. PMID- 7847888 TI - Protein targeting and secretion in filamentous fungi. A progress report. AB - Although the application of filamentous fungi, such as Aspergillus niger for the production of extracellular proteins is well established for several decades, hardly any information is available about the molecular mechanisms of the process of protein secretion in these organisms. Two lines of research initiated towards a systematic analysis of the mechanism of protein targeting and secretion are presented in this paper. 1--To study routing and targeting of proteins in filamentous fungi the availability of a versatile reporter/carrier protein will be of considerable importance. Experiments towards the identification of such a protein are presented. 2--In analogy to the situation in Saccharomyces cerevisiae, the availability of defined (conditional) mutations in the secretion pathway will provide very important information about the organisation of the pathway. Therefore, based on results obtained in S. cerevisiae, the cloning of several fungal 'secretion' genes was started. The results of the cloning and characterisation of one of these genes is presented. PMID- 7847889 TI - Genetics and gibberellin production in Gibberella fujikuroi. AB - Gibberella fujikuroi (Fusarium moniliforme) is a complex group of plant pathogens. Some strains produce gibberellic acid and other gibberellins that promote growth and regulate various stages in plant development. The paper describes the research effort directed to development of genetic tools for this species. Furthermore the main features of the gibberellin biosynthetic pathway as established in Gibberella are described. PMID- 7847891 TI - Strategies for improving heterologous protein production from filamentous fungi. AB - Despite the naturally high capacity for protein secretion by many species of filamentous fungi, secreted yields of many heterologous proteins have been comparatively low. The strategies for yield improvement have included the use of strong homologous promoters, increased gene copy number, gene fusions with a gene encoding a naturally well-secreted protein, protease-deficient host strains and screening for high yields following random mutagenesis. Such approaches have been effective with some target heterologous proteins but not others. Approaches used in heterologous protein production from filamentous fungi are discussed and a perspective on emerging strategies is presented. PMID- 7847890 TI - Expression of genes and processing of enzymes for the biosynthesis of penicillins and cephalosporins. AB - The genes pcbAB, pcbC and penDE encoding the enzymes (alpha-aminoadipyl-cysteinyl valine synthetase, isopenicillin N synthase and isopenicillin N acyltransferase, respectively) involved in the biosynthesis of penicillin have been cloned from Penicillin chrysogenum and Aspergillus nidulans. They are clustered in chromosome I (10.4 Mb) of P. chrysogenum, in chromosome II of Penicillium notatum (9.6 Mb) and in chromosome VI (3.0 Mb) of A. nidulans. Each gene is expressed as a single transcript from separate promoters. Enzyme regulation studies and gene expression analysis have provided useful information to understand the control of genes involved in penicillin biosynthesis. The enzyme isopenicillin N acyltransferase encoded by the penDE gene is synthesized as a 40 kDa protein that is (self)processed into two subunits of 29 and 11 kDa. Both subunits appear to be required for acyl-CoA 6-APA acyltransferase activity. The isopenicillin N acyltransferase was shown to be located in microbodies, whereas the isopenicillin N synthase has been reported to be present in vesicles of the Golgi body and in the cell wall. A mutant in the carboxyl-terminal region of the isopenicillin N acyltransferase lacking the three final amino acids of the enzymes was not properly located in the microbodies and failed to synthesize penicillin in vivo. In C. acremonium the genes involved in cephalosporin biosynthesis are separated in at least two clusters. Cluster I (pcbAB-pcbC) encodes the first two enzymes (alpha-aminoadipyl-cysteinyl) valine synthetase and isopenicillin N synthase) of the cephalosporin pathway which are very similar to those involved in penicillin biosynthesis. Cluster II (cefEF-cefG), encodes the last three enzymatic activities (deacetoxycephalosporin C synthetase/hydroxylase and deacetylcephalosporin C acetyltransferase) of the cephalosporin pathway. It is unknown, at this time, if the cefD gene encoding isopenicillin epimerase is linked to any of these two clusters. Methionine stimulates cephalosporin biosynthesis in cultures of three different strains of A. chrysogenum. Methionine increases the levels of enzymes (isopenicillin N synthase and deacetylcephalosporin C acetyltransferase) expressed from genes (pcbC and cefG respectively) which are separated in the two different clusters of cephalosporin biosynthesis genes. This result suggests that both clusters of genes have regulatory elements which are activated by methionine. Methionine-supplemented cells showed higher levels of transcripts of the pcbAB, pcbC, cefEF genes and to a lesser extent of cefG than cells grown in absence of methionine. The levels of the cefG transcript were very low as compared to those of pcbAB, pcbC and cefEF.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7847892 TI - Molecular genetics of Aspergillus pathogenicity. AB - Aspergillus fumigatus is the most frequent cause of Invasive Pulmonary Aspergillosis (IPA), a life-threatening disease of immunosuppressed patients. In addition to a number of general physiological attributes of this fungus, it has been suggested that extracellular elastase and toxins might facilitate its growth in lung tissue. We have investigated the roles of two extracellular proteins, an alkaline protease with elastase activity (AFAlp), and the ribotoxin restrictocin in murine models of IPA. Gene disruption was used to create stable null mutant strains of the fungus lacking one or other protein, and their virulence and histopathological features were compared with an isogenic parental strain in steroid-treated and neutropenic mice. We have been unable to demonstrate any significant differences between the three strains, which shows that, considered independently, these proteins are not important virulence determinants. We are also interested in identifying fungal-specific gene products involved in general metabolism and which are required for growth in the lung, because these could represent new targets for antifungal drugs. For this work a model of murine IPA involving Aspergillus nidulans was established, to take advantage of the many well characterised mutations affecting metabolic pathways. Pathogenicity tests with strains carrying one of two auxotrophic mutations, lysA2 and pabaA1, have shown while lysine biosynthesis is not essential for the fungus to cause pulmonary disease, biosynthesis of p-aminobenzoic acid is essential. We are now in the process of cloning the A. fumigatus pabaA homologue to determine its function and whether this gene is required for growth of the clinically important species in the lung. PMID- 7847893 TI - Molecular communication between host plant and the fungal tomato pathogen Cladosporium fulvum. AB - Host genotype specificity in interactions between biotrophic fungal pathogens and plants in most cases complies with the gene-for-gene model. Success or failure of infection is determined by absence or presence of complementary genes, avirulence and resistance genes, in the pathogen and the host plant, respectively. Resistance, expressed by the induction of a hypersensitive response followed by other defence responses in the host, is envisaged to be based on recognition of the pathogen, mediated through direct interaction between products of avirulence genes of the pathogen (the so-called race-specific elicitors) and receptors in the host plant, the putative products of resistance genes. The interaction between the biotrophic fungus Cladosporium fulvum and its only host tomato is a model system to study fungus-plant gene-for-gene relationships. Here we report on isolation, characterization and biological function of putative pathogenicity factors ECP1 and ECP2 and the race-specific elicitors AVR4 and AVR9 of C. fulvum and cloning and regulation of their encoding genes. Disruption of ecp1 and ecp2 genes has no clear effect on pathogenicity of C. fulvum. Disruption of the avr9 gene, which codes for the race-specific 28 amino acid AVR9 elicitor, in wild type avirulent races, leads to virulence on tomato genotypes carrying the complementary resistance gene Cf9. The avirulence gene avr4 encodes a 105 amino acid race-specific elicitor. A single basepair change in the avirulence gene avr4 leads to virulence on tomato genotypes carrying the Cf4 resistance gene. PMID- 7847894 TI - Location of pathogenicity genes on dispensable chromosomes in Nectria haematococca MPVI. AB - Nectria haematococca MPVI can be found in many different biological habitats but has been most studied as a pathogen of pea (Pisum sativum). Genetic analyses of isolates obtained from a variety of biological sources has indicated that a number of genes control pathogenicity on pea but that one important PEa Pathogenicity (PEP) gene is PDA, which confers the ability to detoxify the pea phytoalexin pisatin. In these studies, all naturally occurring isolates that lacked PDA (i.e. Pda- isolates) and all Pda- progeny were essentially non pathogenic on pea. However, we have demonstrated recently that Pda- mutants created by transformation-mediated gene disruptions, while having a modest reduction in virulence, and more virulent than any naturally occurring Pda- isolates. In addition we know that PDA genes are on dispensable (DS) chromosomes in this fungus. We believed that the gene disruption mutants have allowed the detection of other PEP genes that are present on the DS chromosomes along with PDA and that naturally occurring Pda- isolates usually lack this DS chromosome. This would explain why naturally occurring Pda- isolates are always low in virulence. We propose that the DS chromosomes in fungi are analogous to bacterial plasmids which allow those microorganisms to colonise different habitats, i.e. the DS chromosomes of Nectria haematococca contain genes that allow individual isolates of this broad host range pathogen to occupy different biological niches. PMID- 7847895 TI - Soluble and immobilized catalase. Effect of pressure and inhibition on kinetics and deactivation. AB - This article examines the effect of pressure on the steady-state kinetics and long-term deactivation of the enzyme catalase supported on porous alumina. The reaction studied is the decomposition of hydrogen peroxide. The results of studies carried out in a continuous stirred-tank reactor under isothermal conditions are presented and compared with results obtained for soluble catalase. For soluble catalase, it is found that in the range of pressures studied, the oxygen flow rate increases with increase in pressure up to a certain value and then decreases. Hydrogen peroxide concentration appears to have a strong influence on pressure effects. With immobilized catalase, the pressure effects are not as prominent. Fluorescent microscopy studies of the immobilized enzyme suggest that this is probably because of pore diffusional limitations. PMID- 7847896 TI - Glucose sensors based on enzyme immobilization onto biocompatible membranes obtained by radiation-induced polymerization. AB - Amperometric glucose biosensors based on glucose oxidase immobilized onto poly(2 hydroxyethylmethacrylate) membranes obtained by gamma radiation-induced polymerization were constructed. In a three-electrode configuration, smooth or platinized platinum electrodes with different shapes were used, in order to detect the amount of hydrogen peroxide produced in the glucose oxidation. A saturated calomel electrode and a platinum foil were used as a reference and counterelectrode, respectively. The biocompatible obtained sensors were characterized as regards the temperature effect, the response, and lifetime. The determination of glucose in standard solutions was carried out, and linear calibration curves were obtained. Depending on the electrode configuration, the sensor had a response time of 1-4 min, and the measuring range extended from 5 x 10(-5) to 4 x 10(-3) M. PMID- 7847897 TI - Immobilization, characterization, and laboratory-scale application of bovine liver arginase. AB - Arginase isolated from beef liver was covalently attached to a polyacrylamide bead support bearing carboxylic groups activated by a water-soluble carbodiimide. The most favorable carbodiimide was N-cyclohexyl-N'-(methyl-2-p-nitrophenyl-2 oxoethyl) aminopropyl carbodiimide methyl bromide, but for practical purposes, N cyclohexyl-N'-morpholinoethyl carbodiimide methyl tosylate was used. The optimal conditions for the coupling procedure were determined. The catalytic activity of the immobilized arginase was 290-340 U/g solid or 2.9-3.4 U/mL wet gel. The pH optimum for the catalytic activity was pH 9.5, the apparent temperature maximum was at 60 degrees C and Kmapp was calculated to be 0.37M L-arginine. Immobilization markedly improved the conformational stability of arginase. At 60 degrees C, the pH for maximal stability was found to be 8.0. The immobilized arginase was used for the production of L-ornithine and D-arginine. PMID- 7847898 TI - Kinetic studies of the urease-catalyzed hydrolysis of urea in a buffer-free system. AB - The kinetics of urea hydrolysis catalyzed by urease, mainly in the absence of buffers by use of the self-buffer effect of the products, was investigated. The effect of pH, temperature, and concentration of enzyme, substrate, product, salt ions, and buffers on the kinetic behavior of urease was examined. A kinetic model of a modified Michaelis-Menten form, incorporating substrate and product inhibition, pH dependence, and temperature effect, was developed to describe the reaction rate. Experimental data indicated that urease in a buffer-free solution was less susceptible to the inhibition of substrate product. The Michaelis constant keeps almost constant with the variation of pH and temperature, and increases with the addition of buffers and salts. The data also suggested that the noncompetitive pattern of the product inhibition, which is not significantly affected by temperature, increases gently with increasing pH. A Monod form rate expression was proposed to analyze the pH effect on the maximum rate. The proposed kinetic model was also examined by the long-time experiments in which pH, substrate, and product concentration varied obviously during the reaction course. PMID- 7847900 TI - How well will we manage care? PMID- 7847899 TI - Extraction and chemical investigation of Kulthi (Macrotylona uniflorus, Lam.) seed protein. AB - Studies have been carried out on the protein solubility profile of Kulthi (Macrotylona uniflorus, Lam.) seed in aqueous solution over various pHs and at different concentrations of NaCl, Na2SO3, CaCl2, and MgCl2 at pH 8.0. Amino acid analysis of isolated protein identified 17 amino acids, 9 of which are essential. Gel-permeation chromatography on Sephadex G-200 revealed the presence of seven components in the protein fraction. Their molecular weights were determined by two comparable standard methods. Extractable Kulthi seed proteins in salt solutions were separated electrophoretically into eight fractions whose molecular weights were found to be 186,200, 131,800, 108,400, 91,200, 53,700, 44,700, 38,000, and 27,500. PMID- 7847901 TI - Special report: DSM-IV: overview and examination of major changes. AB - The American Psychiatric Association published the fourth edition of the Diagnostic and Statistical Manual (DSM-IV) in May 1994. Referred to by some in the popular media as the mental health profession's diagnostic bible, the decisions reflected in this fourth edition are likely to shape diagnostic practice and education and may impact on treatment approaches as well. This article describes the goals and process involved in preparing this document, examines the major changes from DSM-III-R to DSM-IV and comments on the relevance of DSM-IV to psychiatric/mental health nursing. PMID- 7847902 TI - Ethnic identity, role integration, quality of life, and depression in Korean American women. AB - Little is known about how living between two cultures affects the mental health of immigrant women. This study examined the relationships between ethnic identity, role integration, quality of life, and depression in 76 Korean-American women. Quality of life was positively associated with role integration (r = .68, p < .01). Role integration and quality of life were negatively and significantly associated with depression (r = -.59 and r = -.72, p < .01, respectively). An exploratory path analysis was performed to examine the relationships between demographics and conceptual variables. Only quality of life and length of residence in the United States were strongly associated with depression. Findings have implications for psychiatric nursing practice. PMID- 7847903 TI - The relationship between social support, help-seeking behavior, and psychological distress in psychiatric clients. AB - A descriptive exploratory design was used to examine the relationship between the level of social support, the level of psychological distress, and the extent of help-seeking behavior in a nonprobability sample of 53 hospitalized adult psychiatric patients. The subjects completed the Norbeck Social Support Questionnaire, the Brief Symptom Inventory, and a researcher-designed Help Seeking Behavior Questionnaire. The Pearson Product Moment Correlation coefficients and t test were used to analyze the data. No significant correlation was found between the level of psychological distress and either the level of social support or the extent of help seeking. Social support and help seeking were highly correlated. These results have an implication for nursing practice pertaining to the focus of patient treatment both during hospitalization and in postdischarge planning. PMID- 7847905 TI - The challenge of change: rethinking alcohol abuse. AB - Nurses usually conceptualize alcohol abuse and dependence as a progressive disease that can be managed but never cured. Yet there are millions of Americans for whom this approach is not helpful. Impressive results have been reported by the alcohol research community with interventions that are guided by the assumption that many alcohol problems are learned habits that can be changed. This article reviews the clinical research in the area of brief interventions and moderation training with alcohol abusers. Nursing's vital role in advocating for and delivering such interventions is identified. Resistance to implementing alternative approaches for the treatment of alcohol problems is explored. PMID- 7847904 TI - A model for assessment of inpatient suicide potential. AB - Psychiatric inpatient suicides have unique characteristics compared with suicides that occur on an outpatient basis. A number of factors play a role in determining whether patients will kill themselves in the hospital. Central to suicide is ambivalence. Several factors influence ambivalence; they include: interactions with professionals, environmental safeguards, biological therapies, and external support as well as the inpatient's perception of these factors. A proposed model is presented as a grounding for further exploration of this process. PMID- 7847906 TI - A self psychological approach to treating the mentally ill, chemical abusing and addicted (MICAA) patient. AB - There is a growing population of mentally ill, chemical abusing and addicted (MICAA) patients being admitted to inpatient psychiatric units. This article proposes a self psychological approach for this population and discusses how this model addresses the underlying intrapersonal and interpersonal reasons for chemical abuse. A synopsis of self psychology is presented and applied to both addiction and MICAA patients. A self psychological treatment approach is reviewed, including specific nursing interventions. PMID- 7847907 TI - Proceedings of the Swiss Society for Obstetrics and Gynecology annual meeting. Lausanne, 29 June-2 July 1994. PMID- 7847908 TI - [Cholestasis and pregnancy: hepatopathies specific to pregnancy]. PMID- 7847909 TI - [Liver pathology within the scope of HELLP syndrome]. AB - Liver pathology is one of the main features of HELLP syndrome and develops on the basis of a generalised activation of intravascular coagulation. Fibrin deposits and haemorrhagic necrosis predominantly develop in the periportal areas and may eventually lead to subcapsular haematomas or even rupture of the liver. While the compensated form of activation of intravascular coagulation, which is diagnosed by a decrease in antithrombin III and an increase in thrombin-antithrombin III complex (TAT) and the appearance of fibrin, monomers and D-dimers, is found in almost all cases of HELLP syndrome, the decompensated form of intravascular coagulation with prolonged bleeding time (PT, PTT) and drop in fibrinogen is found only in the most severe forms. The development of a decompensation of coagulation correlates with the appearance of severe complications such as liver haematoma, abruptio placentae, renal failure and pulmonary oedema. The best prophylaxis against the development of life-threatening complications is early diagnosis and termination of pregnancy after stabilisation of the maternal condition, consisting of magnesium sulphate infusion, antihypertensive treatment with dihydralazine or calcium antagonists, steroids etc. Severe complications of HELLP syndrome have occasionally been observed in the postpartum period. As prophylaxis against postpartal worsening of HELLP syndrome, curettage of the uterus and continuation of the treatment with calcium antagonists and dexamethasone have been recommended. PMID- 7847910 TI - [Subcapsular hematoma of the liver]. PMID- 7847912 TI - [Effects of liver diseases in pregnancy on the newborn infant]. PMID- 7847913 TI - [The gynecologist-obstetrician and death]. PMID- 7847914 TI - [Grief in maternity: experience with multidisciplinary considerations]. PMID- 7847911 TI - [Liver transplantation and pregnancy: 1994 perspectives]. AB - The authors report a case of pregnancy in a 24-year-old, gravida-3, para-1 patient who had previously undergone liver transplantation for alveolar echinococcosis. Pregnancy and delivery were uneventful with no obstetrical or liver complications. Pregnancy seems to have little effect on liver transplants and rejection is seldom observed. Primary maternal complications are hypertension, preeclampsia, anemia and hyperbilirubinemia. Primary fetal complications include premature delivery and growth retardation. The mode of delivery depends on the obstetrical situation. Cyclosporin may be used during pregnancy. The risk of breastfeeding has not been clearly established. Pregnancy after liver transplantation is possible after 9 to 12 months but requires strict multidisciplinary surveillance. Barrier methods remain the preferred method of contraception for liver transplant patients. PMID- 7847915 TI - [The idealized child and reality]. PMID- 7847916 TI - [Premature neonatal death]. PMID- 7847917 TI - [Grief work of the menopausal woman]. PMID- 7847918 TI - [The gynecologist/obstetrician and death. Attempt at a synthesis]. PMID- 7847919 TI - New aspects of the aetiology of male fertility disorders. AB - Classification of male fertility disorders should take into account the cause and severity of a disturbance as well as its effect on the fertilizing capacity of spermatozoa. A reasonable approach is the analysis of sperm morphology according to the Dusseldorf classification, which is based on defects of spermatid differentiation. The kind and frequency of malformed spermatozoa allow conclusions about basic testicular and epididymal disorders, which will facilitate the detection of epididymal sperm motility disturbances and, therefore, initiation of causal treatment. The effect of inflammatory processes on fertility depends on the site of inflammation. In addition, the necessity for varicocele treatment can be determined more exactly under consideration of sperm morphology and hormonal tests. So far, irregular chromatin condensation as a cause of disturbed male fertility has not been attributed to genetic reasons, whereas microdeletions of the Y chromosome are increasingly being discussed. Both the role of oxygen radicals and the significance of environmental factors need to be investigated in the future. PMID- 7847920 TI - [Role of the urologist in infertility problems]. PMID- 7847922 TI - [Sexuality and hormones]. PMID- 7847921 TI - [How do contraceptive methods affect sexuality of the woman?]. PMID- 7847924 TI - [Formulating indications for treatment of benign tumors of the uterus]. PMID- 7847923 TI - [Sexuality, discussion and family planning]. PMID- 7847925 TI - [Uterine myoma: modalities and indications for coelioscopic treatment]. AB - Only complicated fibromas refractory to medical treatment should be treated surgically. Two types of operations can be proposed for interstitial and subserosal fibromas: myomectomy and hysterectomy. The indication, based on a through preoperative assessment, depends on the patient's age and the size, number and sites of the fibromas and associated lesions. Preliminary series confirm the feasibility of these two operations performed by laparoscopy, as a result of the progress in this modality over recent years. In the future, larger series will determine the respective place of each of these surgical procedures in relation to others surgical possibilities. PMID- 7847926 TI - [Disposable instruments--cost-benefit considerations]. PMID- 7847927 TI - [Myometrium and endometrium. Histopathologic aspects of benign lesions]. PMID- 7847928 TI - [Surgical hysteroscopy. Comparison of Nd-Yag laser with electrosurgery]. PMID- 7847929 TI - [Total and subtotal hysterectomy--psychosexual aspects]. AB - Surgery on genital organs is taken with anxiousness and leads generally to a temporary impairment of sexual function. Sexual life after hysterectomy is possible. Intercourse, sexual desire and orgasmic capacity are as a rule not negatively changed and in a great part even improved. Through discussion (during pre-operative consultancy and at the time of discharge and follow-up examinations) that also deals with the sexual function, lasting or chronic sexual disturbances can be largely avoided. The incidence of psychosomatic disturbances which also influence sexual behavior is then under 10%: they are projected onto the operation and have intra-psychic or psycho-social roots that are independent of it. A certain method of hysterectomy cannot have any decisive significance with regard to the capacity to experience sexual pleasure. An all-too local/genital approach deflects us from our understanding of the orgasm, as the latter is a central experience in which extra-genital and, above all, psychological factors also play an important part. PMID- 7847930 TI - [Applications of fluorescence in situ hybridization in prenatal diagnosis]. PMID- 7847931 TI - [Intracytoplasmic sperm injections in treatment of severe male subfertility]. PMID- 7847932 TI - Present status and potential role of high-dose adjuvant chemotherapy in breast cancer with poor prognosis. PMID- 7847933 TI - [Endoscopic surgery: from the possible to the sensible]. PMID- 7847934 TI - [Study Group of the Swiss Society of Fertility-Sterility and Family Planning]. PMID- 7847935 TI - Congenital aortic valve disease: evolving management. PMID- 7847936 TI - National surveys: are they helpful? PMID- 7847937 TI - Thalidomide as replacement for steroids in immunosuppression after lung transplantation. AB - Steroids have been implicated in postoperative complications after lung transplantation: infections, delayed wound healing, and poor bronchial anastomotic healing. Thalidomide (alpha-phthalimidoglutarimide), a sedative drug with known immunomodulatory properties, was used to replace corticosteroids after canine lung transplantation. Fifteen mongrel dogs underwent single-lung transplantation: group I (n = 5) received cyclosporin A (20 mg/kg twice a day), azathioprine (2.5 mg/kg once a day), and thalidomide (50 mg/kg twice a day). Group II (n = 5) received standard immunosuppression of cyclosporin A (20 mg/kg twice a day), azathioprine (2.5 mg/kg once a day), and prednisone (2 mg/kg once a day), and group III (n = 5) received cyclosporin A (10 mg/kg twice a day), azathioprine (2.5 mg/kg once a day), and thalidomide (50 mg/kg twice a day). Open lung biopsy and bronchoscopy were performed weekly until sacrifice on day 28. Serum thalidomide and cyclosporin A levels were followed up weekly. Group I showed essentially no rejection until week 2 and minimal rejection (grade 1) until day 28. Group II had moderate rejection (grade 2) of the graft at all time points. Group III animals had moderate to severe rejection (grades 3 to 4) after 21 days (p < 0.05 for group I versus groups II and III). The number of clinically evident episodes of pneumonia was also significantly lower in group I than in groups II and III (p < 0.05). We conclude that thalidomide appears to replace corticosteroids effectively in early postoperative immunosuppression after lung transplantation and is associated with a decreased incidence of pneumonia.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7847938 TI - Have PTCA failures requiring emergent bypass operation changed? AB - From 1980 through 1990, 9,145 patients had balloon angioplasty with failure of the procedure requiring emergent surgical revascularization within 24 hours occurring in 253 patients (2.8%). Patients were divided into two cohorts based on the date of the percutaneous transluminal coronary angioplasty (PTCA): 1980 to 1985 (n = 109) and 1986 to 1990 (n = 144). The incidence of PTCA failure was 3.8% during 1980 to 1985 (109/2,903) and decreased to 2.3% (144/6,242) for 1986 to 1990. Comparison of pre-PTCA patient characteristics between the two periods showed that only a history of a previous PTCA and class III or class IV symptoms were more common in the recent years (p < or = 0.05). In-hospital mortality after emergency operation was 4.6% (5/109) during 1980 to 1985 and 7.6% (11/144) from 1985 to 1990 (p = not significant). This trend toward increased mortality appeared to be related to an increased number of patients who underwent operation in a state of severe hemodynamic compromise in the more recent period. The in hospital mortality rate for patients in shock or undergoing cardiopulmonary resuscitation was 28.3% (13/46) compared with 1.4% (3/207) for patients with less severe hemodynamic derangement (p < 0.001). Use of the intraaortic balloon pump preoperatively increased from 12.8% to 32.6% (p < 0.01). Late survival was 92% at 2 and 87% at 5 postoperative years. Although the incidence of PTCA failure necessitating emergent surgical intervention has decreased over time, there has been a trend toward an increased in-hospital mortality rate for those patients that does not appear to be related to more severe pre-PTCA characteristics.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7847939 TI - Direct effects of thrombin on myocyte contractile function. AB - Cardiopulmonary bypass activates the clotting cascade, resulting in elevated circulating levels of thrombin. In light of the fact that the function of a wide variety of cell types is modulated by thrombin, we hypothesized that thrombin may have a direct effect on myocyte function. Isolated left ventricular myocyte contractile function was measured from 6 adult dogs using videomicroscopy at baseline and after increasing concentrations of thrombin (1 to 10 U/mL). Indices of myocyte contractile function were reduced in a dose-dependent manner in the presence of increasing concentrations of thrombin. For example, myocyte percent shortening fell by 18% with 1 U/mL thrombin and by 43% with 2 U/mL thrombin. The addition of hirudin, a highly selective thrombin inhibitor, completely blocked the effects of thrombin on myocyte contractile function. beta-Adrenergic agonists are commonly used in the early post-cardiopulmonary bypass period. Accordingly, a final set of experiments examined the effects of thrombin on myocyte beta adrenergic responsiveness using isoproterenol (25 nmol/L). In myocytes preincubated with 1 U/mL thrombin, myocyte beta-adrenergic responsiveness was significantly reduced. For example, in the presence of 1 U/mL thrombin, myocyte velocity of shortening fell by 25% from isoproterenol alone values. The results from the present study provide evidence that thrombin has a direct negative effect on steady-state contractile function and beta-adrenergic responsiveness in adult mammalian ventricular myocytes. These findings suggest that thrombin may be an additional contributory factor toward the transient left ventricular dysfunction that has been observed after cardiopulmonary bypass. PMID- 7847940 TI - Acute hemodynamic effects of atrio-biventricular pacing in humans. AB - Standard postoperative dual-chamber pacing uses ventricular leads placed on the right ventricle that produce dysynchronous ventricular activation and contraction. The hypothesis that simultaneous stimulation of both ventricles by atrio-biventricular pacing improves hemodynamic performance compared with that observed with standard atrio-monoventricular pacing was tested in 18 patients 12 to 36 hours after elective coronary artery revascularization. Temporary epicardial pacing electrodes were placed on the right atrium and into anterior paraseptal sites on the right and left ventricle. Simultaneous biventricular activation was documented by fusion morphology of surface electrocardiograms and by isochronal epicardial activation mapping during biventricular pacing. Hemodynamic data were acquired after 10 minutes of pacing at a fixed overdrive rate during atrial pacing and during dual-chamber pacing using unipolar right ventricular, unipolar left ventricular, and bipolar biventricular (left ventricular cathode) leads. Atrio-biventricular pacing increased cardiac index and decreased systemic vascular resistance compared with atrial pacing and with atrio-right ventricular and atrio-left ventricular dual-chamber pacing (p < 0.05). These data support the use of atrio-biventricular pacing employing paraseptal electrodes to optimize hemodynamic performance. PMID- 7847941 TI - Efficacy of a skeletal muscle-powered dynamic patch: Part 1. Left ventricular assistance. AB - In this study, we examined the capability of a skeletal muscle-powered, dynamic patch to provide left ventricular assistance. An actuator was developed that used linear traction power furnished by the latissimus dorsi muscle and liquid as the medium for power transfer. The proximal portion of the muscle was dissected and was reattached to the actuator. The left ventricular apex was excised, and the dynamic patch lined with autologous pericardium was implanted during cardiopulmonary bypass. Hemodynamic studies were performed in 8 dogs after weaning from cardiopulmonary bypass. Muscle stimulation was found to significantly increase the systolic aortic pressure (91.6 versus 112.1 mm Hg; p < 0.01), the mean aortic pressure (65.2 versus 73.0 mm Hg; p < 0.01), and aortic blood flow (0.77 versus 0.92 L/min; p < 0.01). The left atrial pressure decreased from 17.9 to 16.6 mm Hg (p < 0.01). This "hybrid" left ventricular assist device possesses notable clinical advantages because of its remarkable efficacy in assisting circulation. Further experimental studies using preconditioned skeletal muscle are necessary to assess the long-term effects of this technique. PMID- 7847942 TI - Efficacy of a skeletal muscle-powered dynamic patch: Part 2. Right ventricular assistance. AB - The purpose of this study was to assess the feasibility of using a skeletal muscle-powered dynamic patch to assist the failing right ventricle. Seven adult mongrel dogs were used in the study. The proximal portion of the left latissimus dorsi muscle was harvested and reattached to the actuator to serve as a skeletal muscle energy convertor. The right ventricular free wall was fully excised and the dynamic patch was implanted under cardiopulmonary bypass. After weaning from cardiopulmonary bypass, the latissimus dorsi muscle was stimulated using a burst frequency of 33 Hz, a burst duration of 200 ms, and 1:2 synchronous mode stimulation with the native R wave. Latissimus dorsi muscle stimulation increased systolic aortic pressure (78 versus 91 mm Hg; p < 0.01), mean aortic pressure (56 versus 62 mm Hg; p < 0.05), aortic blood flow (0.73 versus 0.97 mL; p < 0.01), and systolic right ventricular pressure (41 versus 56 mm Hg; p < 0.01). The mean right atrial pressure decreased from 14 to 9.6 mm Hg (p < 0.01). Our results demonstrate that the use of a right ventricular dynamic patch powered by a skeletal muscle linear-type actuator can not only function as a right ventricular free wall substitute but also lead to the augmentation of right ventricular and global cardiac function. PMID- 7847943 TI - Unstented semilunar homograft replacement of tricuspid valve in Ebstein's malformation. AB - Tricuspid valve pathology in Ebstein's malformation requires replacement when it is not possible to repair or reconstruct this valve. In smaller children, in whom the right-sided atrioventricular valve is severely dysplastic and right ventricular volume is prohibitive, prosthetic replacement is not always possible. We report here on 3 patients who underwent stentless semilunar homograft replacement (top-hat procedure) of tricuspid valve for Ebstein's anomaly with good short-term outcome. This provides an attractive alternative in the management of a certain difficult subset of patients, avoids long term anticoagulation and probably is more durable. PMID- 7847944 TI - Postoperative symptomatic internal thoracic artery stenosis and successful treatment with PTCA. AB - From 1988 to 1992, 4,182 coronary bypass grafting procedures were performed at the University of Ottawa Heart Institute. The left internal thoracic artery (ITA) was used in 2,913 patients, the right ITA in 79, and bilateral ITAs in 61 for a total of 3,053 patients with ITAs. This study assessed patients requiring angioplasty for symptomatic ITA stenosis after operation. A total of 29 patients (0.95%) with a mean age of 55.3 +/- 1.9 years underwent angioplasty for ITA stenosis from 4 days to 34 months after operation (mean, 6.5 +/- 1.6 months). Internal thoracic artery stenosis was identified in 18 patients (62.1%) within 3 months after operation. Angina was present in 26 patients (89.7%), a positive stress test in 8 (27.6%), and myocardial infarction in 1 (3.4%). At angiography, a total of 34 stenotic sites were identified in ITA grafts. Angioplasty was successful (< 50% residual stenosis) in 31 sites (91.2%). Follow-up was available for 28 of 29 patients (96.6%) at 24.6 +/- 2.3 months. Four patients (14.3%) returned with restenosis within 3 months, 2 of whom had successful repeat angioplasty, and 1 required reoperation. Canadian Cardiovascular Society anginal class after angioplasty was less than class II in 84.6% of patients. In conclusion, symptomatic postoperative ITA stenosis is uncommon, occurs most frequently at the site of distal anastomosis, and generally presents within 3 months of operation. It may be safely and effectively treated with angioplasty with a low recurrence rate. PMID- 7847946 TI - Successful canine bilateral single-lung transplantation after 21-hour lung preservation. AB - A canine bilateral single-lung transplantation model was used to evaluate 21-hour lung preservation with low-potassium dextran glucose solution. Donor lungs were flushed with low-potassium dextran glucose solution (50 mL/kg), inflated with 100% oxygen (35 mL/kg), and preserved at 8 degrees C. Bilateral single-lung transplantation was performed without using cardiopulmonary bypass. The ischemic times to the right and left lungs were designed to be 3 and 6 hours, respectively, in group 1 (n = 5) and 18 and 21 hours in group 2 (n = 6). After bilateral single-lung transplantation, animals were maintained on a ventilator for 12 hours and lung function, including arterial blood gas and pulmonary hemodynamics, was measured. All 5 dogs in group 1 and 5 of 6 dogs in group 2 completed bilateral single-lung transplantation successfully and survived for 12 hours with excellent lung function. Arterial oxygen tension and mean pulmonary artery pressure were stable during the 12-hour assessment period in both groups and did not differ significantly from donor values. Twelve hours after reperfusion, mean arterial oxygen tension (inspired oxygen fraction = 1.0) was 590 +/- 18 mm Hg in group 1 and 604 +/- 8 mm Hg in group 2. After the 12-hour assessment period, the animals were extubated and immunosuppressed. Two dogs in group 2 survived for 7 and 8 days, respectively, with a mean arterial oxygen tension of 74 mm Hg on room air at 5 days.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7847945 TI - Platelet activating factor inhibition reduces lung injury after cardiopulmonary bypass. AB - Because cardiopulmonary bypass (CPB) produces a diffuse inflammatory reaction that may injure multiple organs and complicate cardiac surgical procedures, we examined the use of a competitive inhibitor of platelet activating factor (SDZ HUL-412) in a porcine model of CPB as a means to ameliorate pulmonary injury after CPB. Thirteen pigs (35 to 40 kg) underwent CPB at 28 degrees C for 2 hours, followed by 2 hours of observation. Group I (n = 6) received SDZ HUL-412 (a quinolinium compound) intravenously (3 mg/kg loading dose and 2 mg.kg-1.h-1 continuous infusion) starting before sternotomy. Group II (n = 7) received a saline vehicle. Peak airway pressure, pulmonary arterial pressure, left atrial pressure, and arterial blood gases were measured and flow cytometry evaluated surface expression of adhesion molecule subunit CD18 on circulating neutrophils. Pulmonary function was significantly improved in group I. Fifteen minutes after CPB, dynamic lung compliance in group I was 91% +/- 12% of baseline versus 49% +/ 5.2% in group II (p = 0.06 by analysis of variance). After CPB, the arterial oxygen pressure was also significantly better in group I than in group II (425 +/ 61 versus 234 +/- 76 mm Hg) (p < 0.05). The rise in pulmonary vascular resistance after CPB was less in group I (p < 0.05) (323 +/- 55 to 553 +/- 106 dynes.s.cm-5) than in group II (531 +/- 177 to 884 +/- 419 dynes.s.cm-5) at the end of the observation period. CD18 up-regulation increased similarly in the two groups during CPB.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7847947 TI - Aortic to right ventricular shunt for pulmonary atresia and intact ventricular septum. AB - Acute or chronic myocardial ischemia may develop in patients with pulmonary atresia with intact ventricular septum and right ventricular-dependent coronary circulation. In such cases an aorta to right ventricle shunt may be used to reverse this ischemia. This report summarizes our experience with the placement of an aortic to right ventricular shunt in 5 patients. The shunts were made of Gore-Tex and ranged from 4 mm to 8 mm. Associated procedures were bidirectional Glenn (n = 2) and Fontan (n = 2). All 5 patients survived the procedure with documented early graft patency and no evidence of ischemia. PMID- 7847948 TI - The role of thoracoscopy in the diagnosis of interstitial lung disease. AB - A study was undertaken to evaluate the safety and efficacy of thoracoscopic lung biopsy for interstitial lung disease. The relation between operative findings, pathologic findings, and preoperative computed tomographic scan findings was examined. Twenty-six patients, 10 male and 16 female, underwent thoracoscopic lung resection to diagnose interstitial lung disease. Sixteen patients were outpatients for an elective procedure; 10 were inpatients including 2 who were ventilator dependent. The mean length of operation was 54 minutes and the mean length of chest tube duration, 1.3 days. There were no deaths. Staphylococcal pneumonia developed in 1 patient postoperatively. One patient with systemic pulmonary hypertension was ventilator dependent for 48 hours. A double-lumen endotracheal tube was used in all but 2 patients. Twelve-millimeter trocar ports were used to allow easy interchange of staplers and endoscopic instruments. Biopsy of at least two lobes was performed in each patient with resection of a piece of grossly abnormal lung. A single chest tube was left routinely. The pathologic diagnosis was usual interstitial pneumonitis in 7 patients. Four patients had interstitial fibrosis and 4, granulomas. Three patients had diffuse alveolar damage and 3, Wegener's granulomatosis. Two patients had bronchiolitis obliterans with organizing pneumonia. One patient each had lymphangioleiomyomatosis, eosinophilic granuloma, and cytomegalovirus. Sixteen patients underwent preoperative computed tomographic scanning. The scans were assessed by 2 radiologists who were blinded to the surgical results. Computed tomography accurately predicted the site of disease in most instances. Four patients had at least one lobe with no evidence of disease on computed tomography but with interstitial lung disease found thoracoscopy.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7847949 TI - Anatomic spectrum of abnormal ventriculoarterial connections: surgical implications. AB - To clarify the salient anatomic features of surgical significance, we investigated 33 specimens representing the spectrum of abnormal ventriculoarterial connections. In those with tetralogy of Fallot or double outlet right ventricle with subaortic ventricular septal defect, the muscular outlet septum separating the subarterial outflow tracts was always inserted into (or in front of) the anterior limb of the septomarginal trabeculation (septal band). In those having double-outlet right ventricle with doubly committed ventricular septal defect, the outlet septum was lacking. When the ventricular septal defect was in subpulmonary position, with either double-outlet or discordant ventriculoarterial connections, the outlet septum was attached to the posterior limb of the septomarginal trabeculation. The outlet septum was deviated into the subpulmonary outlet in hearts with discordant ventriculoarterial connections and pulmonary stenosis. It is the interrelations between the septomarginal trabeculation, the outlet septum, and the ventriculoinfundibular fold that hold the key to the understanding of surgical anatomy and determine the optimal choice of procedure for definitive biventricular repair. PMID- 7847950 TI - Myocardial protection for acquired heart disease surgery: results of a national survey. AB - To study current myocardial protection practices, all 4,393 United States board certified thoracic surgeons were surveyed in 1992. Of the 1,413 respondents (32% total response), 936 are in active practice dealing with acquired heart disease. Based on their frequency of cases, respondents perform approximately 32% of all acquired heart disease operations in the United States yearly and individually average 157 patients/year. For myocardial protection, 98% of respondents routinely use cardioplegic arrest. The primary method of cardioplegia delivery is antegrade 36%, retrograde 4%, and a combination of antegrade and retrograde 60%. The types of cardioplegic solutions used are blood 72%, crystalloid 22%, and oxygenated crystalloid 6%. Continuous warm blood cardioplegia is used by 10% of respondents, whereas most (75%) have adopted a skeptical "wait and see" attitude or have abandoned it (6%). Overall, most surgeons (78%) report that they are very satisfied with their present methods of myocardial protection, whereas only 2% are dissatisfied. Still, the three areas believed most important for future research are reperfusion injury (74%), acutely infarcting myocardium (61%), and metabolic enhancers in cardioplegia (58%). PMID- 7847951 TI - Combining percutaneous bypass with coronary retroperfusion limits myocardial necrosis. AB - After an acute coronary occlusion that results in hemodynamic instability, the institution of percutaneous bypass (PB) can effectively support the failing myocardium. However, PB cannot augment coronary blood flow, and substantial regional myocardial necrosis can still occur. This experimental study was undertaken to determine whether combining PB with coronary venous retroperfusion using pressure-controlled intermittent coronary sinus occlusion (PICSO) would limit myocardial necrosis after an acute coronary occlusion. In 30 pigs, the second and third diagonal vessels were occluded with snares for 90 minutes followed by 30 minutes of cardioplegic arrest and 180 minutes of reperfusion with the snares released. During the period of coronary occlusion, 10 pigs were placed on PB, 10 pigs received PB+PICSO, and 10 pigs received no support (unmodified). Hearts treated with the combination of PB+PICSO had the highest wall motion scores (unmodified, 1.4 +/- 0.3; PB, 1.4 +/- 0.3; PB+PICSO, 2.8 +/- 0.3 [p < 0.05 versus unmodified and PB]) and the lowest area of necrosis in the area at risk (unmodified, 73% +/- 3%; PB, 43% +/- 2%; PB+PICSO, 14% +/- 2% [p < 0.05, PB and PB+PICSO versus unmodified; p < 0.05, PB+PICSO versus PB]). We conclude that combining PB with coronary venous retroperfusion significantly limits myocardial necrosis. PMID- 7847952 TI - Prolonged open sternotomy after pediatric open heart operation: experience with 113 patients. AB - Between April 1990 and November 1993, 1,252 open heart operations were performed in infants and children with congenital heart defects. Prolonged open sternotomy was used in 113 patients (9%) in 10 surgical categories. Thirty-six of these children (32%) were infants and 43 (38%) were newborns. Twenty-four patients (21%) had undergone operation previously; 3 newborns had been treated with extracorporeal membrane oxygenation before the operation. The patients were grouped according to indications for prolonged open sternotomy as follows: group I, 31 patients with squeezed (large) heart syndrome (1 death); group II, 14 patients with hemodynamic instability after sternal approximation (2 deaths/14.2%); group III, 35 patients with low output state after bypass (17 deaths/48.5%); group IV, 21 patients with extracorporeal circulatory assist devices (15 deaths/71.4%); group V, 3 patients with severe arrhythmias (no deaths); and group VI, 9 patients with atypical tamponade that necessitated reopening the sternum in the intensive care unit (6 deaths/66.6%). Overall mortality was 36.2% (41 patients). Four group IV patients were weaned successfully from extracorporeal membrane oxygenation and heart transplantation was performed successfully on two others. All but one of the deaths occurred before delayed sternal closure. After hemodynamic stabilization was achieved, the sternum was closed in all 72 surviving patients with absorbable sutures (in 86% within the first 6 days after operation). In 50 patients (69% of survivors) pericardial substitution with a polytetrafluoroethylene membrane was performed. One newborn with mediastinal infection after extracorporeal membrane oxygenation was treated successfully with retrosternal drain and suction lavage.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7847953 TI - Color-flow duplex ultrasound assessment of internal thoracic artery graft after coronary bypass. AB - In an effort to develop a noninvasive method to evaluate flow characteristics of the internal thoracic artery (ITA) graft after coronary artery bypass grafting, we performed color-flow duplex ultrasound studies of the right and left ITAs of 42 patients before and 5 weeks after bypass grafting. The ITA was visualized with a duplex scanner (5.0-MHz probe) through the first or second intercostal space. We recorded the diameter, peak systolic velocity, and end-diastolic velocity for each patient. Preoperative measurements of the native ITAs were obtained easily in all patients. Postoperatively, the unused right ITA was seen in all patients. Postoperative visualization of the left ITA graft was adequate to make reliable measurements in 40 patients (95%). Postoperative end-diastolic velocities of the unused right ITA and the left ITA graft were markedly higher than the preoperative end-diastolic velocities of the native ITAs (p < 0.001). Whereas there was a marked increase in the peak systolic velocity of the postoperative unused right ITA (p < 0.05), the postoperative peak systolic velocity of the left ITA graft was significantly lower than the preoperative value (p < 0.001). We conclude that postoperative visualization of the left ITA graft is possible with the use of color-flow duplex ultrasound. Ultrasonic surveillance of postoperative ITAs may reveal ITA graft velocity abnormalities before overt graft failure is manifested in the patient who has undergone coronary artery bypass grafting. PMID- 7847954 TI - Retrograde cerebral perfusion: clinical experience in emergency and elective aortic operations. AB - We recently have used retrograde cerebral perfusion via the superior vena cava in association with hypothermic circulatory arrest as an adjunct to cerebral protection during aortic arch operations. Between April 1993 and March 1994, 23 patients (14 male; 9 female; median age, 64 years; age range, 25 to 76 years; 14 emergency, 9 elective) underwent operation on the ascending aorta, aortic arch, or both for acute dissection (11) or aneurysm (12). Aortic root replacement was performed in 13 patients (7 with arch replacement), ascending aortic replacement in 7 (4 with arch replacement), isolated aortic arch replacement in 2, and repair of sinus of Valsalva aneurysm in 1. Coronary artery bypass grafting was performed in 4 patients. Hypothermic circulatory arrest (15 degrees C) and retrograde cerebral perfusion were implemented in all cases (median circulatory arrest time, 21 minutes; range, 13 to 51 minutes; median retrograde cerebral perfusion time, 20 minutes; range, 12 to 50 minutes). Three hospital deaths occurred (atheromatous embolic stroke, sepsis, rupture of infrarenal aortic aneurysm). The remaining patients had no neurologic damage (median intensive therapy unit stay, 1 day; range, 1 to 5 days). Retrograde cerebral perfusion is easy to establish and safe, and may improve brain protection during hypothermic circulatory arrest. PMID- 7847955 TI - Intermittent antegrade warm blood cardioplegia. AB - Intermittent antegrade warm blood cardioplegia has been used routinely at our institution over the last 3 years. We report here a comparison between the first 250 consecutive patients undergoing elective coronary artery bypass grafting in which intermittent antegrade warm blood cardioplegia was used (group A) and the last 250 consecutive patients who received intermittent antegrade cold blood cardioplegia, during bypass grafting (group B). There were no differences in sex, age, number of grafts, and functional status between the two groups; left ventricular ejection fraction was lower in group A. The overall mortality rate in group A was 0.8% versus 3.6% in group B (p < 0.05). There was no in-hospital mortality among high-risk patients (ejection fraction < or = 0.35) in group A (0/53) versus two deaths in group B (2/28) (p < 0.05). No patient in group A needed circulatory assistance; 4 patients in group B received intraaortic balloon pumping. Only 1 patient in group A required inotropic support versus 20 patients in group B (p < 0.0005), and 5 patients in group A received lidocaine hydrochloride for ventricular arrhythmias versus 18 in group B (p < 0.01). The rates of myocardial infarction and stroke were not different between the two groups. The peak concentration of the myocardial-specific isoenzyme of creatine kinase were higher in group B in absolute value (51 +/- 30 IU/L) than in Group A (38 +/- 38 IU/L) (p < 0.0005) and in percent of total creatine kinase (8.2% +/- 4.1% versus 6.2% +/- 2.9%, respectively). PMID- 7847956 TI - Systolic and diastolic function after patch reconstruction of left ventricular aneurysms. AB - Left ventricular function after patch reconstruction for postinfarction left ventricular aneurysms is largely unknown. In this study, 16 patients with an anteroseptal-lateral left ventricular aneurysm were treated by reconstruction of the left ventricle using a Dacron patch. Coronary artery bypass grafting was performed concomitantly in 9 patients. The size of the patch used was 57% +/- 19% of the resected myocardial scar area, including the sewing cuff area to be sutured. In these patients, the ejection fraction increased significantly from 0.28 +/- 0.12 to 0.39 +/- 0.12 (p = 0.007) at rest and from 0.32 +/- 0.14 to 0.41 +/- 0.10 (p = 0.008) during exercise. The left ventricular end-diastolic pressure and left ventricular end-diastolic volume index were reduced significantly from 14 +/- 7.0 to 8 +/- 3.2 mm Hg (p = 0.032), and from 178 +/- 116 to 92 +/- 21 mL/m2 (p = 0.016). The peak filling rate was improved significantly from 1.2 +/- 0.47 to 1.8 +/- 0.6/s (p = 0.048) postoperatively. The ratio of the peak flow velocity during the atrial kick phase to the peak flow velocity in the rapid filling phase, at the level of the mitral valve, improved (p = 0.016) after operation and remained improved up to 16 to 24 months after operation. Patch reconstruction of the left ventricle resulted in the recovery of systolic and diastolic function soon after operation, which has persisted into the late postoperative period. PMID- 7847957 TI - Pneumonectomy for chronic infection: fraught with danger? AB - Pneumonectomy for chronic lung infections has been avoided because of potential intraoperative and postoperative complications. A retrospective review of 13 cases requiring pneumonectomy for aspergillus (8), Mycobacterium tuberculosis (2), actinomycosis, Pseudomonas aeruginosa, and bronchiectasis revealed increased operating time, blood loss, and transfusion requirements. Operative records documented problems with dense adhesions, lack of an extrapleural plane, and distortion of hilar structures. Although mortality was acceptable (8%), early and late morbidity (total, 38%), especially bronchopleural fistula (23%), was significant. It is concluded that when justified, pneumonectomy for complete resection of chronic infection can be performed with acceptable risk. However, specific problems should be anticipated. This review has led to modifications in operative technique. PMID- 7847959 TI - Effect on blood flow of rotation and position of the internal mammary artery pedicle. AB - The internal mammary artery is the preferred conduit for coronary artery bypass grafts. The effect on flow through the artery of both rotation and position of the artery pedicle was tested in an in-vitro setting on 20 arteries using a perfusate closely approximately the normothermic viscosity of blood. It was found that the effect of rotation on blood flow was highly significant (p < 0.0004) and that this occurs after a degree of rotation that is dependent on the pedicle length. The critical degree of rotation required to significantly affect blood flow is 30 degrees for each centimeter of pedicle length. The degree of rotation required to stop flow altogether is 45 degrees per unit length. Flow through the arteries was found to be inversely proportional to the length of the artery but was not affected by changes in the position of the artery provided there was not a rotational component. Tension of the pedicle did not influence flow in either a linear or rotated position. These results were verified in a clinical setting. This study supports that a 180-degree rotation of the internal mammary artery pedicle in any clinical setting will not alter blood flow. For rotations of 360 degrees or greater, however, the effect on flow becomes significant when this is 12 cm or less. Although flow is independent of linear pedicle deformity, as flow is inversely proportional to length, excess pedicle length is best avoided. PMID- 7847958 TI - Expression of Lewis-related antigen and prognosis in stage I non-small cell lung cancer. AB - Immunohistochemical expression of Lewisy, sialyl Lewisx, and sialyl Lewisa were examined in relation to blood vessel invasion and prognosis in 133 patients with stage I non-small cell lung cancer who had a curative resection from 1980 to 1991. Expression of sialyl Lewisx in adenocarcinomas was higher than in squamous cell and large cell carcinomas, and Lewisy immunoreactivity was the highest among the three antigens. The frequency of blood vessel invasion was significantly higher in tumors with expression of Lewisy or sialyl Lewis antigen (sialyl Lewisx or sialyl Lewisa), however, Lewisy expression was even more significant. The postoperative survival was significantly shorter when tumors expressed both the Lewisy and sialyl Lewis antigen. However, the survival of patients with either Lewisy or sialyl Lewis antigen expression was similar to that of patients whose tumors did not express either the Lewisy or sialyl Lewis antigens. These results suggest that Lewisy and sialyl Lewis antigen may be of prognostic value for metastatic potential but have different functional roles in tumor cells. PMID- 7847960 TI - The forgotten interleaflet triangles: a review of the surgical anatomy of the aortic valve. AB - Surgical descriptions of the aortic root are not always in keeping with anatomy as observed in the autopsied heart. Although all surgeons appreciate that the concept of the aortic annulus does not imply the presence of a straight ring as a hinge point, the nature of the supporting fibrous structures relative to the semilunar attachment of the leaflets has yet to be clarified. We have analyzed 50 normal aortic roots, two fetal aortic roots sectioned histologically in horizontal and sagittal planes, respectively, and two autopsied adult hearts in which prosthetic aortic valves had been inserted during life. Our results demonstrate the important interrelationships between aortic sinuses, valvar leaflets, and supporting left ventricular structures that produce the three fibrous interleaflet triangles. It is the structure and location of these triangles that is the key to the understanding of the surgical anatomy. Our results also show that the presently used definition of commissure does not reflect adequately the extent of the zones of apposition between adjacent valvar leaflets, essential for normal function when the valve is closed. PMID- 7847961 TI - Hypoxic preconditioning enhances functional recovery after prolonged cardioplegic arrest. AB - The purpose of this study was to assess the ability of hypoxic preconditioning to improve myocardial salvage after prolonged hypothermic cardioplegic arrest. Isolated working rat hearts were arrested at 4 degrees C with St. Thomas' Hospital cardioplegic solution and immersion stored for 4 or 6 hours. Two groups were studied, control and hypoxically preconditioned (HP) hearts. After 4 hours' preservation, aortic flow, coronary flow, and the first derivative of aortic pressure were 8.7 +/- 1.6 mL/min, 17.8 +/- 1.6 mL/min, and 2,064 +/- 123 mm Hg/s, respectively, in control hearts (n = 11) and 25.7 +/- 2.5 mL/min, 27.1 +/- 2.5 mL/min, and 2,655 +/- 93 mm Hg/s, respectively, in HP hearts (n = 11) (p < 0.05). After 6 hours' preservation, aortic flow, coronary flow, and the first derivative of aortic pressure were 3.5 +/- 1.2 mL/min, 18.8 +/- 0.4 mL/min, and 1,622 +/- 226 mm Hg/s, respectively, in control hearts (n = 6) and 21.5 +/- 3.2 mL/min, 25.5 +/- 2.3 mL/min, and 2,439 +/- 239 mm Hg/s, respectively, in HP hearts (n = 6) (p < 0.05). After 6 hours' preservation, adenine nucleotides and creatine phosphate levels were not significantly different between the two groups, but lactate dehydrogenase release was significantly increased (p < 0.05) in control versus HP hearts (4.66 +/- 0.58 IU/L versus 1.98 +/- 0.28 IU/L). We conclude that hypoxic preconditioning reduces cellular necrosis and preserves myocardial function after prolonged hypothermic cardioplegic arrest. PMID- 7847962 TI - Extent of aortopulmonary collateral blood flow as a risk factor for Fontan operations. AB - Between November 1987 and January 1990, 33 patients (tricuspid atresia, 9 patients; mitral atresia, 3; single ventricle, 15; others, 6) underwent Fontan operations. The rate of blood flow returning to the heart during aortic cross clamping was measured as an indication of the extent of development of aortopulmonary collateral arteries. Percent cardiac return (calculated by dividing the blood flow rate returning to the heart by the cardiopulmonary bypass blood flow rate and expressing the value as a percentage), were 1% to 9%, 7 patients; 10% to 19%, 11; 20% to 29%, 9; 30% to 39%, 4; 40% to 49%, 1; and 50% to 59%, 1 patient. Percent cardiac return showed a significant correlation with postoperative mean systemic venous pressure (r = 0.6, p < 0.01). In those patients in whom percent cardiac return was more than 33%, the mean systemic venous pressure after operation was high (more than 17 mm Hg), and none of these patients survived. To predict percent cardiac return preoperatively, the conventional indices of systemic ventricular volume, pulmonary artery area index, arterial blood oxygen saturation, pulmonary blood flow index, and pulmonary vascular resistance were analyzed. None of these showed significant correlation with percent cardiac return. However, all the patients who had a high percent cardiac return (more than 30%) also had both high arterial blood oxygen saturation (more than 75% in room air) and small pulmonary artery area index (less than 55%). In addition, the age at operation showed good correlation (r = 0.6, p < 0.01) to percent cardiac return.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7847963 TI - Direct mechanical assistance of the right ventricle with the Hemopump in a porcine model. AB - In 6 pigs, a 14F Hemopump was placed through the pulmonary artery into the right ventricle. The pulmonary artery was banded proximal to the outflow port of the Hemopump, and tightening the band increased right ventricular peak systolic pressure by 50%. There were significant falls in right ventricular stroke volume (from 43 +/- 7.3 mL [+/- the standard deviation] to 27 +/- 8.0 mL; p < 0.001) and cardiac output (from 4.94 +/- 0.76 L/min to 3.70 +/- 0.95 L/min; p < 0.01) and increases in right ventricular peak systolic pressure (from 28 +/- 9.7 mm Hg to 42 +/- 17.1 mm Hg; p < 0.01) and end-diastolic pressure (from 2 +/- 0.8 mm Hg to 12 +/- 6.4 mm Hg; p < 0.02). Mean aortic pressure fell (from 65 +/- 29.9 mm Hg to 61 +/- 9.6 mm Hg; p < 0.01), but systemic vascular resistance was unchanged, thus indicating a fall in left ventricular output reflected by a decrease in mixed venous oxygen saturation (from 60% +/- 8.9% to 47% +/- 7.6%; p < 0.01). After 15 minutes with the Hemopump at maximum speed, these variables returned to control levels (stroke volume, 38 +/- 4.5 mL; cardiac output, 4.50 +/- 0.63 L/min; right ventricular peak systolic pressure, 29 +/- 8.3 mm Hg; right ventricular end diastolic pressure, 4 +/- 2.0 mm Hg; mean aortic pressure, 72 +/- 10.4 mm Hg; mixed venous oxygen saturation, 56% +/- 4.6% [all, p = not significant versus controls]).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7847964 TI - Distal circulatory support for thoracic aortic operations: effects on intracranial pressure. AB - Spinal cord ischemia can result from aortic clamping during thoracic aortic operations. The perfusion gradient for spinal cord perfusion is positively influenced by distal aortic pressure and negatively influenced by intracranial pressure (ICP). Hemodynamic and ICP changes were examined in a swine model of descending thoracic aortic surgery where distal aortic perfusion was achieved under one of three conditions: (1) clamping without support, (2) a passive aortofemoral shunt, or (3) a left atrium-femoral artery bypass system. With aortic clamping alone, ICP increased from 9.8 +/- 2.2 mm Hg to 15.2 +/- 2.8 mm Hg (p < 0.05). With passive shunting, ICP was decreased to 13.8 +/- 3.0 mm Hg, which was still significantly elevated above baseline. However, with active bypass, ICP remained at control level (9.8 +/- 2.2 mm Hg). Mean distal aortic pressure, which was 82 +/- 10 mm Hg in the control state, decreased to 20 +/- 0.5 mm Hg with clamping alone and to 39 +/- 9 mm Hg with passive shunting, whereas with active support, a distal pressure of 64 +/- 8 mm Hg was achieved. In contrast to passive shunting, active distal bypass results in maintenance of ICP at baseline levels and results in distal aortic pressure significantly greater than that achieved with either aortic clamping alone or passive shunting. Thus, active distal circulatory support produces the greatest salutary effect on the two determinants of the spinal cord perfusion pressure gradient: ICP and distal aortic pressure. This support modality may be the best adjunctive technique to maintain the spinal cord perfusion gradient and hence minimize the risk of ischemic injury. PMID- 7847965 TI - The role of mediastinoscopy in superior vena caval obstruction. AB - The role of mediastinoscopy in superior vena caval obstruction is not defined. To examine the safety and efficacy of mediastinoscopy, we reviewed 34 patients with superior vena caval obstruction who required mediastinoscopy to establish a histologic diagnosis after less invasive techniques had failed. They were referred to one surgical team between 1982 and 1993. Of the 34 patients, 26 had lung cancer, 6 had lymphoma, 1 had malignant thymoma, and 1 had fibrosing mediastinitis. Definitive tissue diagnosis was obtained in all patients. There was one complication of mediastinoscopy where arterial bleeding from the innominate artery occurred and limited sternotomy was required to control the bleeding. We conclude that mediastinoscopy is a safe and effective technique for establishing histologic diagnosis in superior vena caval obstruction when less invasive techniques have been unsuccessful. The use of blind radiotherapy means that patients with lymphoma and small cell carcinoma will not receive optimum therapy with chemotherapy and patients with benign lesions will receive inappropriate therapy. PMID- 7847966 TI - Antegrade/retrograde cardioplegia in arterial bypass grafting: metabolic randomized clinical trial. AB - The metabolic effects of combined antegrade/retrograde and antegrade cardioplegia on myocardial protection were evaluated and compared in 30 patients who underwent myocardial revascularization. All patients had three-vessel coronary artery disease, and the revascularization was done with exclusive use of arterial grafts (internal mammary artery, gastroepiploic artery). Myocardial protection consisted of oxygenated crystalloid cardioplegia, topical slushed ice, and moderate systemic hypothermia (34 degrees C). The patients were randomly separated into two groups: group A (n = 15), who received antegrade cardioplegia, and group A/R (n = 15), who received combined antegrade/retrograde cardioplegia. There was no significant difference between the two groups concerning preoperative and intraoperative data. After the first dose of cardioplegia, right ventricular temperature was significantly lower in group A/R (15 +/- 2 degrees versus 19 +/- 5 degrees C; p < 0.05), and there was no significant difference between the two groups in left ventricular temperature. Coronary sinus blood samples were obtained before bypass and 5, 10, and 15 minutes after reperfusion; there was no difference between the two groups concerning lactates, superoxide dismutase, and glutathione peroxidase. After reperfusion, malondialdehyde levels increased significantly in group A and there was no change in group A/R, with a significant difference between the two groups (at 10 minutes after reperfusion, 0.80 +/- 0.20 versus 0.53 +/- 0.16 mumol/L; p < 0.05). Right and left ventricular myocardial biopsies were performed before bypass and 15 minutes after reperfusion; there was no significant difference between the two groups concerning adenosine triphosphate and creatine phosphate myocardial concentrations.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7847967 TI - Risk of thromboembolism with the aortic Carpentier-Edwards bioprosthesis. AB - Porcine bioprostheses provide an excellent alternative to mechanical prostheses for heart valve replacement in patients unable to comply with systemic anticoagulation and in the elderly. Long-term results of this prosthesis, however, demonstrated identical survival and parallel event-free status, albeit at a lower rate than the mechanical valves. Some discrepancy exists as to the need for and duration of systemic anticoagulation in the bioprosthesis, and some evidence exists to contraindicate anticoagulation due to a higher late mortality rate in patients with an aortic bioprosthesis. The records of 561 patients having the Carpentier-Edwards bioprosthesis in the aortic position as an isolated valve procedure were reviewed. The overall rate of bioprosthetic failure events was low (0.23%/patient year) and the survival (5 year, 74.8 +/- 2.4%; 10 year, 52.9 +/- 4.9%) and event-free statistics (5 year, 67.9 +/- 2.6%; 10 year, 42.4 +/- 5.1%) were excellent. No gender difference was present. A vulnerable period for neurologic events was identified by hazard function whereby the incidence of stroke was high; these were increased in the patient variables of compromised ejection fraction (0.54; p < or = 0.003), older age (< or = 73 years; p < or = 0.02), and preoperative atrial fibrillation or paced rhythm (p < or = 0.01). This pattern was similar for both transient ischemic events and strokes and rapidly decreased over the first few months of the first year and the first few years of the 12-year follow-up. These patients were not routinely anticoagulated.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7847968 TI - Combined microneurosurgical and thoracoscopic removal of neurogenic dumbbell tumors. AB - The resection of posterior mediastinal dumbbell tumors has until now required laminectomy and some form of open access to the thoracic cavity. Over a 1-year period, a novel surgical approach combining posterior microneurosurgical and anterior video-assisted thoracoscopy techniques was used in 4 patients. In 3 patients, the tumor was removed successfully with minimal postoperative discomfort and rapid recovery. In the fourth patient, limited thoracotomy became necessary to control bleeding. This new approach, which combines modern-day neurosurgical and general thoracic surgical techniques, appears safe and could become the preferred method for removing most benign posterior mediastinal dumbbell tumors. PMID- 7847969 TI - A bicuspid pulmonary valve is not a contraindication for the arterial switch operation. AB - There are no obvious criteria concerning the optimal repair for complete transposition with bicuspid pulmonary valve if neither the organic changes in the valve nor the pressure gradient between the left ventricle and the pulmonary trunk are severe. Instead of intraatrial switching or intraventricular rerouting in such circumstances, we have proceeded to the arterial switch procedure in 6 patients with an adequate diameter of the pulmonary valve (greater than 100% of the calculated normal aortic orifice). Postoperative catheterization (at approximately 8 months after the procedures) showed no pressure gradient between the left ventricle and the neoaorta except for a finding of 34 mm Hg difference in 1 patient who had undergone simultaneous subpulmonary myotomy. Echocardiography (7 years later in the longest follow-up) has shown no more than slight regurgitation across the bicuspid neoaortic valve, with no progressive increase of blood velocity across the valve. From these results in the middle term, we conclude that the arterial switch procedure remains an option of choice for patients with initially bicuspid pulmonary valve, providing there is no severe subpulmonary stenosis. PMID- 7847970 TI - Tricuspid valve dysfunction in the transplanted heart. AB - Mild degrees of tricuspid regurgitation are common in the orthotopically transplanted heart, probably secondary to the geometry of the right atrial anastomosis. At the University of Utah, 5 (0.95%) of 526 patients with transplantations performed from March 1985 to December 1993 have presented with severe tricuspid regurgitation requiring operative intervention. Echocardiographic findings confirmed at the time of operation consisted of ruptured chordae to the tricuspid valve. Standard tricuspid valve repair and replacement techniques were used with good results. We postulate the chordal disruption found in these patients is secondary to injuries incurred at the time of endomyocardial biopsy. PMID- 7847971 TI - Thyroid hormones homeostasis in pediatric patients during and after cardiopulmonary bypass. AB - The concentrations of thyroid hormones were measured in 14 pediatric patients before, during, and after cardiopulmonary bypass. The ages of the patients ranged between 18 months and 14 years. Patients were kept normothermic, or moderate or deep hypothermia was induced depending on the specific pathologic condition involved. A marked reduction in the levels of total triiodothyronine, total thyroxine, free triiodothyronine, and thyroid-stimulating hormone, and in the ratio of free triiodothyronine to free thyroxine was detected during the time frame of the study. The minimum levels of each hormone were reached between 12 and 48 hours after cardiopulmonary bypass, indicating that changes in thyroid function and in the conversion of thyroxine to triiodothyronine are triggered by cardiopulmonary bypass and represent specific phenomena, and that these changes are progressively exacerbated during the post-operative period. The thyroid stimulating hormone level was markedly reduced versus its baseline values (24% +/ 0.13%), despite low levels of both total (40% +/- 18%) and free (39% +/- 20%) triiodothyronine: it returned to its preoperative level by the third postoperative day, but both the total (75% +/- 10%) and free (74% +/- 3%) triiodothyronine levels remained below their baseline values for 7 days postoperatively. Neither hemodilution nor hypothermia was responsible for the alteration observed. We conclude that pediatric patients undergoing cardiopulmonary bypass manifest changes in hormone metabolism similar to those seen in adult patients. These changes increase progressively during the postoperative period, and are still present 7 days postoperatively. The exact mechanism responsible for causing these changes is not thoroughly understood. Whether triiodothyronine replacement therapy is beneficial or deleterious remains controversial. PMID- 7847972 TI - A cardiothoracic surgery information system for the next century: implications for managed care. AB - The United States health care system is under tremendous pressure to cut costs while maintaining quality. One mechanism to reduce costs is managed care--a system with both risks and benefits for patients, providers, and payors, and one that requires large volumes of data to ensure optimal medical and financial decision-making. In this review, we describe the types of information needed by managed care systems, including medical outcome data (satisfaction, survival, quality of life, and complications) and financial data (costs and long-term resource utilization). From a provider's point of view, the customers for these data range from individual patients to large self-insured corporations, and we describe the data required for each potential customer. Finally, as a concrete example of how data can be collected and analyzed to improve a provider's competitiveness, we describe the Cedars-Sinai Medical Center cardiothoracic surgery database from a managed care perspective. The concepts presented are generalizable to other subspecialties, and will become more important in the increasingly competitive milieu of American health care. PMID- 7847973 TI - Effect of topical vasodilators on internal mammary arteries. AB - The internal mammary artery (IMA) is the conduit of choice for grafting the left anterior descending artery. However, arterial spasm and reduced early flow has been a cause of postoperative morbidity. The purpose of this study is to evaluate the effect of vasodilators on IMA flow. Fifty patients who had the IMA harvested in preparation for bypass grafting were studied. The IMA was mobilized from the subclavian vein to below the bifurcation of the IMA. The artery was prepared for grafting at least 3 cm proximal to the bifurcation. The IMA was allowed to bleed freely, and flow was determined (flow 1). The patients were divided into five groups: group I (n = 10) had 10 mL of saline solution applied topically to the IMA; group II had topical papaverine (5 mg/10 mL normal saline solution) applied to the IMA; group III had nitroglycerin (5 mg/10 mL normal saline solution) applied to the IMA, group IV had sodium nitroprusside (2.5 mg/10 mL) applied to the pedicle, and group V had 5 mL of papaverine mixed in 5 mL of saline solution injected into the periarterial tissues of the IMA pedicle. Before cardiopulmonary bypass, the flows were remeasured (flow 2). With each measurement, hemodynamic parameters were recorded. The time between measurements was recorded. There was no difference in blood pressure or pulse at the time of measurement.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7847974 TI - Tailoring aortoplasty for repair of fusiform ascending aortic aneurysms. AB - To evaluate the effectiveness of tailoring aortoplasty used to treat fusiform aneurysms of the ascending aorta, we reviewed the results of operation in 17 patients. Nine patients had tailoring aortoplasty alone, and 8 patients had aortoplasty with Dacron wrap of the ascending aorta. Fourteen of 17 patients were discharged from the hospital, and 12 patients were alive at follow-up between 2 and 120 months. Of two late deaths, neither was due to aneurysmal disease. Actuarial survival at 1 and 10 years was 81% and 63%, respectively. In selected cases, tailoring aortoplasty can achieve long-term results comparable with those of resection and graft replacement of fusiform ascending aortic aneurysms. PMID- 7847976 TI - Heparin-induced thrombocytopenia and heart operation: management with tedelparin. AB - Anticoagulation for cardiopulmonary bypass in the infrequent clinical setting of thrombocytopenia associated with the use of unfractionated heparin is a very serious problem. We describe a case in which a low-molecular-weight heparin (tedelparin) was selected for this purpose based on a platelet aggregation test, permitting adequate anticoagulation during cardiopulmonary bypass for valve replacement. This case report might help establish an adequate anticoagulation protocol when faced with a patient suffering from this condition. PMID- 7847975 TI - Magnesium sulfate prophylaxis after cardiac operations. AB - One hundred patients undergoing elective cardiac operations were randomized into placebo (n = 54) and magnesium (n = 46) groups. The magnesium group received six doses of 2.4 g (19.2 mEq) magnesium sulfate intravenously in the first 24 hours after the cardiac operation. The magnesium group had higher serum magnesium concentrations postoperatively (1.09 +/- 0.20 versus 0.75 +/- 0.13 mmol/L; p < 0.0001), postoperative day 1 (1.49 +/- 0.34 versus 0.70 +/- 0.12 mmol/L; p < 0.0001) and postoperative day 2 (0.96 +/- 0.19 versus 0.76 +/- 0.07 mmol/L; p < 0.0001). Patients in the magnesium group had a lower incidence of ventricular tachyarrythmias (VTs) (17.3% versus 51.9%; p = 0.0006), less need for treatment (6.5% versus 20.3%; p < 0.0001), fewer VT episodes/patient (0.3 +/- 0.8 versus 1.39 +/- 1.9; p < 0.0001), and a reduction in the severity of VTs as measured by the modified Lown grade (p = 0.0002). No differences were demonstrated with respect to supraventricular tachyarrythmias. The magnesium group had reduced absolute creatine kinase-MB levels (5.3 +/- 4.2 versus 28.4 +/- 28 IU/L; p = 0.001) as well as creatine kinase-MB fraction (0.01 +/- 0.02 versus 0.05 +/- 0.04; p = 0.001) on postoperative day 1. Serum magnesium concentrations were lower during VTs than during periods of sinus rhythm (0.75 +/- 0.75 versus 1.02 +/- 0.35 mmol/L; p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7847977 TI - Thrombolysis for obstructed CarboMedics mitral valve prosthesis. AB - Prosthetic valve thrombosis, a rare but fatal complication, can be successfully treated with tissue-type plasminogen activator and monitored by transthoracic and transesophageal echocardiography. PMID- 7847978 TI - Unilateral pulmonary agenesis, esophageal atresia, and distal tracheoesophageal fistula. AB - A small-for-gestational-age, premature infant with the combination of unilateral pulmonary agenesis, esophageal atresia, and distal tracheoesophageal fistula was treated successfully by early gastrostomy and delayed fistula division with esophagoesophagostomy. Only 2 other successfully treated cases have been reported previously. Both were full-term infants treated with early division of the tracheoesophageal fistula and esophagoesophagostomy. Gestational age, size, and associated medical problems need to be considered when planning operative therapy for these babies. PMID- 7847979 TI - Left atrial thrombus after lung transplantation. AB - We report on a 16-year-old boy who developed a thrombus at the left atrial suture line after undergoing a bilateral sequential single lung transplantation. The diagnosis was made by transesophageal echocardiogram. PMID- 7847980 TI - Aortic translocation for D-TGA associated with LVOTO and VSD. AB - Aortic translocation is a useful surgical option in certain difficult subsets of transposition of great arteries with ventricular septal defect and left ventricular outflow tract obstruction. We report here the use of this technique with pulmonary homograft reconstruction of right ventricular pulmonary artery continuity in a child with transposition of the great arteries, left ventricular outflow tract obstruction, and restrictive ventricular septal defect. PMID- 7847981 TI - Single-stage repair of thoracic ectopia cordis. AB - Thoracic ectopia cordis is a rare congenital defect most often seen in association with sternal and congenital heart defects. Surgical correction of these defects is complex and generally requires a staged closure including (1) coverage of the "naked heart," (2) placement of the heart into the thoracic cavity, and (3) sternal or thoracic reconstruction. Survival past the perioperative period is rare, with only 2 reported cases in the English-language literature. As with our case, neither had any discernable intracardiac defect. We present a case report of a patient with thoracic ectopia cordis repaired in a single stage using polytetrafluoroethylene membrane and skin for coverage and closure of the heart and thoracic defect. PMID- 7847982 TI - Overseas transport of a patient with an extracorporeal left ventricular assist device. AB - An 18-year-old boy with end-stage cardiomyopathy who was undergoing support with an extracorporeal pneumatic left ventricular assist device was transported from Japan to the United States. During the 17-hour flight, the patient's condition was stable, and the pneumatic assist device worked well under low atmospheric pressure in the cabin. Subsequently, he had a successful heart transplantation after 119 days of left ventricular assist device support. PMID- 7847983 TI - False hydatic aneurysm of the thoracic aorta. AB - In this article we report the successful treatment of a lower descending thoracic aorta hydatidosis that mimicked a posterior saccular aneurysm; surgical excision was performed and the aorta was repaired with a prosthetic Dacron patch. At a 26 month follow-up, the patient is alive and conducting a normal life. Discussion about the management of this rare case also is given. PMID- 7847984 TI - Innominate artery and tracheal compression due to aberrant position of the thymus. AB - A 3-month-old infant with failure to thrive was found on bronchoscopy to have tracheal obstruction thought to be secondary to innominate artery compression. Subsequent diagnostic evaluation with magnetic resonance imaging revealed superior and posterior extension of the thymus with resultant compression of the innominate artery and trachea within the narrow confines of the thoracic inlet. Resection of the aberrantly positioned and enlarged thymus and aortopexy resulted in relief of tracheal compression. PMID- 7847985 TI - Rupture of congenital peripheral pulmonary aneurysm. AB - A 58-year-old man presenting with solitary aneurysm of a peripheral pulmonary artery was treated by left lower lobectomy. Histologically, the aneurysmal wall showed medial hypertrophy with the loss of smooth muscle fibers, without evidence of a mycotic process or inflammatory exudate. The aneurysm appeared to be congenital in origin. PMID- 7847986 TI - Transcervical repair of distal membranous tracheal laceration. AB - A laceration of the distal membranous trachea usually has been repaired through a right thoracotomy, and occasionally through a lateral cervical approach. In the case reported here, a simple method of treating this complication was used that involved a mediastinoscopy incision. Suturing of the tear is carried out easily through a vertical incision made in the anterior wall of the trachea, which is then closed with no further consequences. The patient made a quick recovery, and the cosmetic result was excellent. PMID- 7847987 TI - Simple arterial graft holder for coronary artery bypass grafting. AB - We describe a simple device for facilitating arterial graft anastomosis during coronary artery bypass grafting. This device can be constructed in seconds from an intravenous catheter. It helps the operator to make the first several stitches on the arterial graft heel, and also helps the assistant to hold the arterial graft easily. PMID- 7847988 TI - Continuous and stable recording of the His bundle electrogram during open heart operations. AB - We describe a method for continuously recording the stabilized His bundle electrogram from the aortic root during open heart surgical procedures. This simple technique was useful in all surgical procedures for the oblation of supraventricular tachyarrhythmias in the region around the atrioventricular conduction system. PMID- 7847989 TI - As originally published in 1988: Noninvasive three-dimensional reconstruction of the heart and great vessels by ECG-gated magnetic resonance imaging: a new diagnostic modality. Updated in 1995. PMID- 7847990 TI - Revascularization of the transplanted heart. PMID- 7847991 TI - Defibrillator twiddler's syndrome. PMID- 7847992 TI - Post-CABG conduction disturbances. PMID- 7847993 TI - Normothermic cardiopulmonary bypass. PMID- 7847994 TI - How should one resuscitate patients who have undergone cavopulmonary connections? PMID- 7847995 TI - How prolonged is "prolonged air leak"? PMID- 7847996 TI - Arachidonic acid metabolism after heparin reversal with protamine. PMID- 7847997 TI - Awareness of an occupational hazard: intervertebral disc herniation. PMID- 7847998 TI - The Society of Thoracic Surgeons' National Congenital Heart Surgery Database. PMID- 7847999 TI - [Effectiveness of new quinolones in experimental aerogenic plague infection of albino mice]. AB - It was shown that unlike nalidixic acid the 3rd generation quinolones i.e. the nitrogen-containing quinolones (LIB-71 and LIB-80) and the fluorine-containing quinolones (pefloxacin and ciprofloxacin) were highly efficient in the prophylaxis and treatment of experimental plague in albino mice infected via the plague microbe inhalation. By the ED50 the efficacy of pefloxacin was 25-30 times higher than that of nalidixic acid and 60-90 times higher than that of ciprofloxacin. The fluorine-containing quinolones proved to be more active than the nitrogen-containing ones. PMID- 7848000 TI - [Comparative evaluation of the effectiveness of fluoroquinolones in experimental anthrax infection]. AB - Comparative antibacterial activity and protective efficacy of ciprofloxacin, pefloxacin and lomefloxacin were estimated in a model of anthrax. The MICs of the three drugs determined by the method of serial dilutions for three vaccinal strains of Bacillus anthracis were 0.5 to 1.0 microgram/ml. The protective efficacy of the chemotherapeutics in experimental anthrax induced by the spores of the vaccinal strain 71/12, Tsenkovsky was evaluated in mathematically designed four-factor experiments. It depended on the infective dose and the chemotherapy term and amounted in the protective use of the drugs in the daily doses, equivalent to those for humans, to 80-100-percent protection of the animals infected with 10 LD50 of the biological agent, to 50-80-percent protection with the use of 100 LD50, to 40-70-percent protection with the use of 1000 LD50 and to 50-90-percent protection in the therapeutic use of the fluoroquinolones. This was indicative of the fact that the fluoroquinolones were chemotherapeutically highly active in the treatment of experimental anthrax. The marked therapeutic efficacy of the fluoroquinolones and the high percentage of the animal protection after their urgent prophylactic use in a single dose are their obvious merits. The total values of the protective efficacy of the three fluoroquinolones with respect to anthrax were practically the same. PMID- 7848001 TI - [Problems of ecology. Technology of submerged biological treatment of sewage]. AB - A technological process is described for the submerged biological treatment of household and industrial sewage and in particular pharmaceutical industry and pooled sewage. The submerged biological treatment of the sewage to the maximum permissible concentrations adopted for the water in fish farming is achieved by the use of submerged and immobilized microorganisms in a multistage process under anaerobic and aerobic conditions and the use of chemically active and inert materials as carriers of the microorganisms inducing certain biological processes. The data on the ecological estimation of the treated sewage by the stages of the technological process are presented. PMID- 7848002 TI - [Use of hydrogen peroxide in the process of treating sewage from antibiotic production]. AB - The data on the hydrogen peroxide oxidation of surface active substances (SAS) and other pollutants contained in the waste fermentation broth filtrates of antibiotic production are presented. The efficiency of the sewage treatment increased in the presence of FeSO4, a homogeneous catalyst. The influence of the pH value on the efficiency of the treatment was studied with the use of model solutions of the SASs and addition of H2O2. The process of the sewage local treatment with hydrogen peroxide is applicable when the subsequent electrical cleaning is used. PMID- 7848003 TI - [Use of ofloxacin in the treatment of infections of the lower respiratory tract]. AB - The taxonomy of the causative agents of lower respiratory tract infections (LRTI) isolated from patients in the Moscow Region was studied and the clinico microbiological efficacy and tolerance of ofloxacin used in their treatment were estimated. The microbiological tests of the sputum specimens from 168 patients with LRTIs most frequently detected gram positive cocci with the predominance of Streptococcus spp. (65.2 per cent) and in particular the Str. viridans group (57.7 per cent). Neisseria spp. and B. catarrhalis (18.1 per cent) were more frequent among the gram negative isolates. Gram negative bacilli were isolated in 14.3 per cent of the cases with the predominance of Pseudomonas spp. and Enterobacter spp. In 80.8 per cent of the cases the microorganisms were isolated in the form of 2-3-component associations. By the in vitro antimicrobial activity against 167 clinical isolates ofloxacin was superior to penicillins, cephalosporins, aminoglycosides, tetracyclines and cotrimoxasol. Good and satisfactory clinical effects in the treatment of 29 patients with LRTIs were observed in 17 cases (70.8 per cent). Adverse reactions were stated in 3 patients (11.5 per cent). Superinfection due to ofloxacin resistant enterococci, S. pyogenes, Neisseria spp. and yeast-like fungi developed in some patients treated with ofloxacin. PMID- 7848004 TI - [Functioning of integrative vectors, based on phage phi C 31, in the strain Streptomyces bambergiensis 712]. AB - Actinomycete integrative vectors were constructed. The vectors contain the Escherichia coli plasmid ColE1 replicon, the thiostrepton resistance gene used for selection in Streptomyces and a fragment of the phi C31 actinophage genome with integrative functions. The pS133 and PS135 vector DNAs transformed Streptomyces bambergiensis 712, a strain producing the phosphoglycolipid antibiotic moenomycin. Two types of the transformants were detected. The first type was not affected in the ability to produce moenomycin and the vector pS135 DNA was shown to integrate into the S. bambergiensis 712 genome by the site specific pattern with the psi C31 phage DNA fragment. The second type of the transformants lost the ability to produce moenomycin. The Southern analysis and cloning of the inserted DNA indicated that in this case the vector pS135 and pS133 DNAs also integrated specifically into the genome but the integration took place not within the phage DNA fragment. Its realization was suggested to proceed via homologous recombination. PMID- 7848005 TI - [Azithromycin in the treatment of syphilis]. AB - The results of the use of azithromycin (sumamed) in the treatment of 100 patients with fresh syphilis were analyzed. The antibiotic was used in accordance with two treatment schemes: 500 mg daily for 10 days and 500 mg every two days. The total course dose was 5 g in both the cases. The results of the treatment with azithromycin were compared with those of the treatment with erythromycin (30 g) and penicillin (300,000 U every 3 hours for 16-28 days depending on the disease stage). The results were estimated by the rate of the elimination of Treponema pallidum and syphilids as well as by the time course of the seroreactions. The analysis provided a conclusion that the therapeutic efficacy of sumamed in the treatment of patients with fresh manifest syphilis was high: by comparison with penicillin and erythromycin it more rapidly eliminated the clinical signs of syphilis and in the majority of the cases induced negativation of the cutaneous serological reactions within the first 4 months of the treatment. PMID- 7848007 TI - [State of intestinal microbiocenosis and its correction in pregnancy women living under conditions of increased radiation pollution]. AB - The contents of the large intestine were investigated bacteriologically in 44 pregnant women at the pregnancy term of 27-28 weeks living in the areas contaminated with radionuclides at a concentration of 15-40 C/km2. It was found that in 9.6 per cent of the women the intestinal microbiocenosis was within the normal and in 19.1 per cent there was detected marked dysbacteriosis. In the other women compensated or subcompensated intestinal dysbacteriosis was recorded. The state of the large intestine microbiocenosis in the pregnant women did not depend on urogynecological or infectious diseases in the case histories. The prophylactic treatment with eubiotics (bifidumbacterin per rectum and lactobacterin intravaginally) aimed at the correction of the impaired microbiocenosis had a favourable effect which did not depend on urogynecological or infectious diseases in the case histories. After the completion of the prophylaxis course with the eubiotics some indices improved but the percentage of the pregnant women isolating colibacilli with the properties of virulence increased. PMID- 7848006 TI - [State of vaginal microbiocenosis and its correction in pregnant women living under conditions of constant exposure to low doses of radiation]. AB - Microflora of the vaginal mucosa was investigated bacteriologically in 44 pregnant women at the pregnancy term of 27-28 weeks. It was shown that in half of the women the vaginal microbiocenosis was within the normal and did not depend on urogynecological diseases in the case histories. In the women with impaired microbiocenosis the level of the impairment depended on gynecological diseases in the case histories. In the pregnant women without urogynecological diseases only slightly pronounced changes in the vaginal microbiocenosis were detected. The prophylactic use of eubiotics (bifidumbacterin and lactobacterin) was not efficient. In the women with urogynecological diseases in the case histories the levels of the microbiocenosis impairment were different. The prophylactic use of the eubiotics was efficient when the changes in the vaginal microbiocenosis were slightly pronounced or marked. When the changes were extreme the prophylactic use of the eubiotics failed. PMID- 7848008 TI - [Ceftizoxime--antibacterial activity, pharmacokinetic properties, clinical application]. PMID- 7848009 TI - [Askostatin--a fungicide from Streptomyces viridovulgaris]. AB - Askostatin is a fungicide isolated from the culture of Streptomyces viridovulgaris. It was separated by the countercurrent distribution procedure into components A and B. By the mass and NMR spectra and the biological findings the components were identified with cycloheximide and isocycloheximide respectively. PMID- 7848010 TI - Effect of cumulative doses of NG-nitro-L-arginine methyl ester on coronary blood flow of anesthetized and conscious dogs. AB - To examine the effect of cumulative doses of NG-nitro-L-arginine methyl ester (LNAME), an inhibitor of nitric oxide synthesis, on coronary blood flow, basal left circumflex artery blood flow and acetylcholine-induced flow increment were observed in anesthetized and conscious dogs. Four doses of LNAME (10(-5) M, 10( 4) M, 10(-3) M and 10(-2) M in the left circumflex artery blood were cumulatively infused into the left circumflex artery. All dogs were pretreated with 8 phenyltheophylline and acetylsalicylic acid to inhibit endogenous adenosine and vasodilator prostaglandin, respectively. In anesthetized dogs (n = 10), systolic blood pressure was increased with 10(-2) M of LNAME and heart rate was decreased with > or = 10(-3) M of LNAME. All doses of LNAME significantly decreased the left circumflex artery blood flow in a dose-dependent manner, without affecting the rate-pressure product. The acetylcholine-induced flow increment was significantly attenuated with all doses of LNAME. However, no further attenuation was induced by > or = 10(-3) M of LNAME and the maximal dose did not completely abolish the effect of acetylcholine. In conscious dogs (n = 7), LNAME showed similar effects to those seen in anesthetized dogs: the left circumflex artery blood flow decreased with > or = 10(-4) M of LNAME, without affecting the rate pressure product; the acetylcholine-induced flow increment was attenuated with > or = 10(-4) M of LNAME, but not completely abolished. Thus, there is a basal nitric oxide release from the endothelium in the coronary resistance vessels of anesthetized and conscious dogs. However, (an)other mechanism(s) than the L arginine-nitric oxide pathway seem(s) to be involved in the acetylcholine-induced vasodilatation. PMID- 7848011 TI - Protective effects of a novel calcium antagonist with platelet-activating factor antagonistic action, F-0401, against ischemic brain damage. AB - The protective effects of a novel dihydropyridine calcium antagonist with platelet-activating factor-antagonistic action, F-0401, on ischemic brain damage were investigated using experimental ischemia models in rats and gerbils. F-0401 (1 and 10 mg/kg, i.p.) prevented increases in water content, determined by the wet-dry method, in ischemic areas 24 hr after 1 hr of middle cerebral artery occlusion in the rat. Pretreatment with F-0401 (1 and 10 mg/kg, i.p.) prevented extravasation of Evans blue dye in the brain following 2 hr of bilateral carotid artery occlusion and 2 hr of reperfusion in the rat. Pretreatment with F-0401 (1 and 10 mg/kg, i.p.) protected against neuronal damage to hippocampal CA1 pyramidal cells following 3 and 5 min of forebrain ischemia in the gerbil. Immunostaining against microtubule-associated protein-2 also demonstrated preservation of CA1 neurons in F-0401-treated animals. Thus, this study shows that F-0401 prevents the occurrence of brain edema, disruption of blood-brain barrier and neuronal damage caused by cerebral ischemia. The results demonstrate that F-0401 may be a powerful candidate as a therapeutic agent in the treatment of acute stroke in man. PMID- 7848012 TI - Cardioprotective effects of hydrolyzed bopindolol against contractile dysfunction produced by coronary stenosis and reperfusion in dogs. AB - The effects of the active metabolite (18-502) of bopindolol, which is a new nonselective beta-adrenoceptor antagonist, were studied on the ischemic changes in myocardial segment shortening, cardiac lactate metabolism and S-T segment of subendocardial electrocardiogram during coronary stenosis and on their recoveries after reperfusion in anesthetized dogs, and were compared with those of propranolol at a dose exhibiting a comparable degree of beta 1-blocking activity. In the presence of coronary stenosis, intravenous administration of 18-502 (5 micrograms/kg) and propranolol (0.2 mg/kg), but not saline, produced significant improvements of regional myocardial dysfunction, lactate production and S-T segment elevations in the ischemic myocardium, which were associated with significant decreases in heart rate and cardiac contractility. After release of the stenosis, administration of 18-502, but not propranolol, resulted in a significantly accelerated recovery of the ischemic segment function as compared with the control group. In rat heart homogenates, 18-502 inhibited the lipid peroxidation approximately 4 times more potently than propranolol. These data show that 18-502 exerts favorable effects during myocardial ischemia produced by coronary stenosis and that it has a cardioprotective action against the contractile dysfunction following reperfusion. PMID- 7848013 TI - Antihypertensive effects of a new transdermal delivery system for clonidine (M 5041T) in spontaneously hypertensive rats. AB - The antihypertensive effects of a new transdermal delivery system for clonidine (clonidine tape; M-5041T) were investigated in spontaneously hypertensive rats and normotensive Wistar-Kyoto rats. In spontaneously hypertensive rats, M-5041T, at doses of 0.5-4.5 mg/kg (1.25-11.25 cm2/kg), produced a dose-dependent decrease of both systolic blood pressure and heart rate for 24 hr during transdermal application. These significant hypotensive effects lasted for 24 hr following the patching of M-5041T on the back of the animals at a dose of 4.5 mg/kg. In normotensive Wistar-Kyoto rats, the hypotensive and bradycardic effects of M 5041T were weak compared with those in spontaneously hypertensive rats. In both rat strains, M-5041T (4.5 mg/kg) caused behavioral changes such as sedation, piloerection and exophthalmos, accompanied by hypotensive effects. Both M-5041T (1.5 mg/kg) and clonidine (50 micrograms/kg, subcutaneously and 100 micrograms/kg, orally) induced similar hypotensive effects, accompanied by sedation. The hypotensive effects following transdermal M-5041T or systemic clonidine administrations were correlated with the time courses of the plasma clonidine concentration. In contrast to clonidine administered subcutaneously or orally, M-5041T produced a gradual increase in the plasma clonidine concentration, which persisted at a consistent level for at least 12 hr thereafter. Significant hypotensive effects lasted for 12 and 24 hr following M 5041T patching at 1.5 and 4.5 mg/kg, respectively. The present findings suggest that M-5041T can serve as an efficient and useful antihypertensive transdermal delivery system to achieve persistent blood pressure control. PMID- 7848014 TI - Effects of MPC-1304, a novel calcium antagonist, on stroke-prone spontaneously hypertensive rats. AB - The effects of MPC-1304, a newly developed 1,4-dihydropyridine derivative, on blood pressure and hypertensive complications in stroke-prone spontaneously hypertensive rats fed a high-salt diet (0.8% NaCl), were investigated. The antihypertensive effectiveness of nicardipine was used for the purpose of comparison. MPC-1304 and nicardipine were added to the diet, in doses of 0.01% (0.01% MPC-1304 diet), 0.03% (0.03% MPC-1304 diet) and 0.1% (0.1% nicardipine diet), respectively, throughout the experimental period (8 to 30 weeks of age). This chronic ingestion of MPC-1304 and nicardipine inhibited the development of hypertension and reduced the concentration of blood urea nitrogen, creatinine, triglyceride and total cholesterol in serum. Treatment with MPC-1304 inhibited the incidence of cerebral stroke, cardiac fibrosis, proliferative and fibrinoid arteriolitis and malignant nephrosclerosis. There was no significant difference in the antihypertensive effectiveness between 0.01% MPC-1304 and 0.1% nicardipine diets. Thus, MPC-1304 had antihypertensive effects in stroke-prone spontaneously hypertensive rats. PMID- 7848016 TI - Relaxation of human uterine artery in response to pinacidil: predominant role for ATP-dependent potassium channels. AB - The effect of pinacidil on human isolated uterine artery rings was investigated. Pinacidil (10 nM-300 microM) induced a concentration-dependent relaxation of the precontracted arterial segments (pD2: 6.26; maximal response: 98.5%). Apamin (1 microM) and tetraethylammonium (6 mM) had no effects on the pinacidil-evoked relaxation, while 4-aminopyridine (0.1-6 mM) and glibenclamide (1-10 microM) competitively antagonized the response to pinacidil. The dissociation constants for 4-aminopyridine and glibenclamide were 240 microM and 0.40 microM, respectively. It is concluded that, in human uterine arteries, pinacidil induces relaxation. On the basis of differential antagonist affinities, we suggest that pinacidil produces a relaxation of this blood vessel through activation of glibenclamide-sensitive, ATP-dependent potassium channels. PMID- 7848015 TI - Potassium channel-opening and vasorelaxant profiles of a novel compound YM099 in rat isolated portal vein and rabbit isolated aorta. AB - The potassium channel-opening and vasorelaxant profiles of YM099, a newly synthesized benzoxadiazol derivative K channel opener, were evaluated in vitro. In the rat isolated portal vein, YM099 and a benzopyran derivative K channel opener levcromakalim concentration-dependently inhibited the frequency of spontaneous rhythmic contractions, with IC50 values of 104 and 38 nM, respectively. In the rabbit isolated aorta, YM099 (10(-7)-3 x 10(-5) M) and levcromakalim (10(-7)-3 x 10(-5) M) also concentration-dependently relaxed the contractions induced by 20 mM KCl, but they were ineffective against the contractions induced by 50 mM KCl. These effects of YM099 and levcromakalim were competitively antagonized by a K channel blocker glibenclamide (10(-7)-3 x 10(-6) M). In the rabbit isolated aorta, YM099 (3 x 10(-8)-3 x 10(-6) M), but not the calcium antagonist nifedipine (10(-8)-3 x 10(-6) M), relaxed the contractions induced by norepinephrine (10(-6) M) or prostaglandin F2 alpha (3 x 10(-6) M). These vasorelaxant effects of YM099 were also antagonized by glibenclamide. In conclusion, YM099 is a potent vascular smooth muscle-relaxant agent and possesses a vasorelaxant effect different from that of nifedipine. These effects of YM099 may be mediated, like those of levcromakalim, by the opening of glibenclamide sensitive K channels. PMID- 7848017 TI - Effects of TMB-8, a putative calcium antagonist, on neuromuscular transmission and muscle contractility in the mouse phrenic nerve-hemidiaphragm preparation. AB - The effects of TMB-8 [8-(N.N.-diethylamino)octyl-3,4,5-trimethoxybenzoate], a putative calcium antagonist, on directly and indirectly evoked isometric twitches, tetanic contractions and potassium- and caffeine-induced contractures, were investigated in the mouse isolated phrenic nerve-hemidiaphragm preparation. In the lowest concentration tested (10(-6) M), TMB-8 produced an augmentation of both directly and indirectly induced twitches. In higher concentrations (10(-5)-3 x 10(-5) M), this augmentation was followed by twitch reduction. In the highest concentrations (10(-4) M-3 x 10(-4) M), only twitch reduction in a concentration dependent manner was observed. TMB-8 also depressed both directly and indirectly induced tetanic contractions. However, the drug was more effective in depressing neurotransmission than in reducing muscle contractility. Elevated Ca2+ (4-8 mM) or 3,4-diaminopyridine (10(-4) M) produced a good reversal of neuromuscular blockade but this effect was transient. Pretreatment with 4 mM Ca2+ had no significant effect on the time required to produce a 50% or a 90% inhibition of directly or indirectly induced twitches. However, 8 mM Ca2+ significantly prolonged the inhibitory effects of TMB-8 on indirectly, but not directly induced twitches. On the other hand, neostigmine (3 microM) appeared to hasten the blockade of transmission. Submaximal potassium-induced contractures were markedly depressed while caffeine-induced contractures were only slightly depressed by TMB 8 in the concentration range tested (10(-5)-3 x 10(-4) M). The results are consistent with the hypothesis that TMB-8 inhibits skeletal muscle contractility by a reduction in transmembrane Ca2+ movement, a depression of postsynaptic acetylcholine receptor sensitivity, and a decreased mobilization of sequestered calcium from the sarcoplasmic reticulum. PMID- 7848018 TI - The role of nitrates in coronary heart disease. AB - The organic nitrates are a safe and effective choice for the management of ischemic syndromes related to coronary heart disease. Although the anti-ischemic effects of these compounds have been recognized for more than a century, the mechanisms by which they exert their beneficial effects are still being delineated. In addition to their well-established venodilative activity, nitrates are now known to cause vasorelaxation of coronary arteries, coronary stenoses, and coronary collateral vessels and to prevent episodic coronary constriction. An antiplatelet effect has also been hypothesized. The three nitrate compounds currently available in the United States--nitroglycerin, isosorbide dinitrate, and isosorbide mononitrate--are provided in a variety of dosage forms, including sublingual, transmucosal, oral, and transdermal preparations. The rapid- but short-acting nitrate preparations are useful in arresting and preventing acute attacks of angina pectoris, whereas longer-acting oral and transdermal formulations are indicated for the relief of chronic symptomatic and asymptomatic ischemia. The intermittent nitrate dosing regimens introduced in recent years have reduced the likelihood of tolerance, which greatly limited the usefulness of long-acting nitrates in the past. Intravenous infusion of nitroglycerin is particularly appropriate for the management of unstable angina and the early complications of acute myocardial infarction. Preliminary evidence suggests that intravenous nitroglycerin may also be beneficial in preventing postinfarction ventricular remodeling, although it cannot yet be recommended for this purpose. PMID- 7848019 TI - Starting prophylaxis for venous thromboembolism postoperatively. AB - A large proportion of hospitalized patients who are at high risk for venous thromboembolism (VTE) do not receive prophylaxis. Reluctance to use VTE prophylaxis in surgical patients may be due to fear of perioperative bleeding when anticoagulants are given preoperatively. We preformed a literature review to determine (1) whether prophylaxis for VTE is effective when it is started postoperatively and (2) the relative efficacy of preoperatively and postoperatively initiated prophylaxis. Studies were included in the review (1) if they were randomized trials with "blind" assessment of appropriate VTE outcomes, and (2) if prophylaxis was started postoperatively. Randomized, controlled trials establish that pharmacologic and nonpharmacologic methods of prophylaxis that are effective when started preoperatively are also effective when they are started postoperatively, with relative risks for VTE of 0.16 to 0.49. Low rates of VTE in noncontrolled randomized trials that included postoperatively initiated prophylactic regimens support this finding. The relative efficacy of preoperatively and postoperatively initiated VTE prophylaxis could not be determined definitively, as direct comparisons of the same regimens have not been performed. Indirect comparisons suggest that any loss of efficacy resulting from deferring VTE prophylaxis until after surgery is unlikely to be marked. Randomized trials are required to resolve this question. This comparison may be of greatest clinical importance when twice-daily, low-molecular-weight heparin is used to prevent VTE after major orthopedic surgery. PMID- 7848020 TI - A paradigm for consensus. The University Hospital Consortium guidelines for the use of albumin, nonprotein colloid, and crystalloid solutions. AB - OBJECTIVE: To develop contemporary, comprehensive guidelines for the appropriate and efficient use of albumin, nonprotein colloid, and crystalloid solutions. DESIGN: A systematic, literature-based, consensus exercise employing a modified Delphi method. PARTICIPANTS: Thirty-one medical and allied health professionals from 26 University Hospital Consortium (Oak Brook, Ill) member institutions were initially chosen to participate. Participants were selected on the basis of their recognized research in the use of albumin, nonprotein colloid, and crystalloid solutions, and/or experience in the review of appropriateness of such use. A total of 24 participants completed the exercise. MAIN OUTCOME MEASURES: Group responses were statistically analyzed in an iterative consensus development process. Five separate questionnaire rounds were designed to establish criteria for the appropriate use of albumin, nonprotein colloid, and crystalloid solutions. RESULTS: Consensus guidelines were developed outlining the appropriate use of these products for 12 clinical indications, including hemorrhagic shock, nonhemorrhagic (maldistributive) shock, hepatic resection, thermal injury, cerebral ischemia, nutritional intervention, cardiac surgery, hyperbilirubinemia of the newborn, cirrhosis and paracentesis, nephrotic syndrome, organ transplantation, and plasmapheresis. CONCLUSIONS: The Delphi method, a systematic, literature-based consensus process, was shown to be useful in the development of complex clinical practice guidelines for the use of albumin, nonprotein colloid, and crystalloid solutions. It is anticipated that the guidelines will assist health care providers to develop local institutional policies and procedures for the appropriate and efficient use of albumin and albumin alternatives. Institutions reviewing and updating existing local guidelines may use the University Hospital Consortium guidelines as a model for comparison. PMID- 7848021 TI - Flavonoid intake and long-term risk of coronary heart disease and cancer in the seven countries study. AB - OBJECTIVE: To determine whether flavonoid intake explains differences in mortality rates from chronic diseases between populations. DESIGN: Cross-cultural correlation study. SETTING/PARTICIPANTS: Sixteen cohorts of the Seven Countries Study in whom flavonoid intake at baseline around 1960 was estimated by flavonoid analysis of equivalent food composites that represented the average diet in the cohorts. MAIN OUTCOME MEASURES: Mortality from coronary heart disease, cancer (various sites), and all causes in the 16 cohorts after 25 years of follow-up. RESULTS: Average intake of antioxidant flavonoids was inversely associated with mortality from coronary heart disease and explained about 25% of the variance in coronary heart disease rates in the 16 cohorts. In multivariate analysis, intake of saturated fat (73%; P = 0.0001), flavonoid intake (8%, P = .01), and percentage of smokers per cohort (9%; P = .03) explained together, independent of intake of alcohol and antioxidant vitamins, 90% of the variance in coronary heart disease rates. Flavonoid intake was not independently associated with mortality from other causes. CONCLUSIONS: Average flavonoid intake may partly contribute to differences in coronary heart disease mortality across populations, but it does not seem to be an important determinant of cancer mortality. PMID- 7848022 TI - Efficacy of low-dose cholesterol-lowering drug therapy in men with moderate hypercholesterolemia. AB - OBJECTIVE: To test the potency of low-dose cholesterol-lowering drug therapy in patients with moderate hypercholesterolemia and to evaluate the effectiveness for cholesterol lowering of a safe regimen to be used in primary prevention of coronary heart disease. DESIGN: The efficacy of three drug regimens (cholestyramine resin, 8 g/d; cholestyramine resin, 8 g/d, plus lovastatin, 5 mg/d; and lovastatin, 20 mg/d) was tested in 26 men aged 31 to 70 years with moderate hypercholesterolemia after a Step-One cholesterol-lowering diet. Each drug period was 3 months in duration, interspersed by a 1-month period of the Step-One diet only. Blood for lipid and lipoprotein measurements was obtained on 5 different days during the last 2 weeks of each drug and diet-only period. RESULTS: Cholestyramine resin therapy at 8 g/d achieved a significant reduction in low-density lipoprotein cholesterol levels from 4.47 mmol/L (173 mg/dL) to 3.90 mmol/L (151 mg/dL) (P < .005). The addition of 5 mg of lovastatin to cholestyramine therapy achieved even lower levels, averaging 3.39 mmol/L (131 mg/dL) (P < .005). Lovastatin therapy at 20 mg/d produced lowering of low-density lipoprotein cholesterol levels similar to that of the low-dose combination. CONCLUSIONS: Low-dose combination drug therapy for the management of hypercholesterolemia appears to be an effective means of lowering cholesterol levels that remain persistently elevated after dietary therapy, at the same time, it should carry a low risk of toxic effects. PMID- 7848023 TI - Clinical and epidemiologic features of infection with Mycobacterium genavense. Swiss HIV Cohort Study. AB - OBJECTIVES: To characterize clinical and epidemiologic features of infections with Mycobacterium genavense. DESIGN: Case series and case-control studies. Patients with M genavense were compared with two control groups: CD4 controls were matched on the basis of CD4 counts, and Mycobacterium avium-intracellulare complex controls had disseminated infection with M avium-intracellulare complex. RESULTS: Fifty-four patients with disseminated infections caused by M genavense were found, from Europe (37), North America (15), and Australia (two). All were infected with human immunodeficiency virus. The median CD4 count was 0.016 x 10(9)/L (16/mm3) (range, 0.001 to 0.082 x 10(9)/L). Eighty-seven percent had fever and weight loss, 44% had diarrhea, 43% had splenomegaly, 39% had hepatomegaly, and 72% had anemia. In Swiss university hospitals, M genavense was responsible for 12.8% of nontuberculous disseminated mycobacterial infections in patients with human immunodeficiency virus from 1990 to 1992. The median survival was 190 days after the first isolation of M genavense. Among the patients who had been treated with at least two antimycobacterial drugs for 1 month or more, median survival was 263 days (95% confidence interval, 144 to 382 days), compared with 81 days (95% confidence interval, 73 to 89 days) for those not treated (P = .0009). Survival in patients with M genavense was similar to the survival of M avium-intracellulare complex controls. However, patients with similar CD4 counts (CD4 controls) survived longer (median, 342 days; 95% confidence interval, 269 to 415 days; P < .0003). CONCLUSIONS: Infection with M genavense may be responsible for more than 10% of disseminated nontuberculous mycobacterial infections in patients with human immunodeficiency virus infection. Its clinical presentation and response to treatment are similar to those of infection with M avium intracellulare complex. PMID- 7848024 TI - Blood pressure effects of the angiotensin II receptor blocker, losartan. AB - BACKGROUND: Losartan potassium, the first nonpeptide selective blocker of angiotensin II at the AT1 receptor, has been shown to exhibit clinical antihypertensive effects. The aim of the present study was to characterize the efficacy and duration of action of losartan by ambulatory blood pressure monitoring. METHODS: The study was performed in nonblack hypertensive patients whose baseline untreated clinical diastolic blood pressures were 95 mm Hg or higher and whose average 24-hour ambulatory diastolic blood pressures were 85 mm Hg or higher. Patients were randomized, double-blind, into four treatment groups: placebo (n = 32) or losartan, 50 mg once daily (n = 29), 100 mg once daily (n = 30), or 50 mg twice daily (n = 31). Clinical and 24-hour ambulatory blood pressures were measured at baseline (off treatment for at least 4 weeks) and after 4 weeks of treatment. RESULTS: By clinical sphygmomanometer measurements at the end of the 24-hour or 12-hour dosing intervals (trough), all three losartan dosages were significantly more effective than placebo at decreasing systolic and diastolic blood pressures. By average 24-hour ambulatory systolic/diastolic blood pressure measurements, the decreases produced were 0.0/0.2 mm Hg for placebo and 9.2/6.9, 9.9/6.4, and 13.2/8.5 mm Hg, respectively, for losartan, 50 mg once daily, 100 mg once daily, and 50 mg twice daily. All drug effects were different from placebo (P < .01). The effects of losartan, 50 mg twice daily, were not significantly different from those of losartan, 100 mg once daily, but, as expected, the effects were greater than those of losartan, 50 mg once daily (P < .05). Addition of hydrochlorothiazide, 12.5 mg/d, during an additional 2-week treatment period in patients whose clinical diastolic blood pressure remained at 85 mm Hg or higher while receiving monotherapy produced additional and clinically meaningful blood pressure decrements that were similar in all four treatment groups. There was no clinically important difference in the incidence of adverse events among the losartan-treated and placebo groups [corrected]. CONCLUSION: Ambulatory blood pressure monitoring, which virtually eliminated antihypertensive placebo responses, demonstrated clear 24-hour efficacy for losartan, 50 mg once daily, as well as for higher doses of 100 mg once daily and 50 mg twice daily. This AT1 receptor blocker had antihypertensive effects that appeared additive when combined with low-dose diuretic therapy. Losartan was generally well tolerated. PMID- 7848025 TI - Miles run per week and high-density lipoprotein cholesterol levels in healthy, middle-aged men. A dose-response relationship. AB - OBJECTIVE: To examine the association between miles run per week and high-density lipoprotein cholesterol levels in healthy middle-aged men. BACKGROUND: Regular exercise increases levels of high-density lipoprotein cholesterol. However, the exercise requirements for such increases are not well defined. METHODS: Healthy, nonsmoking men (n = 2906; age, 43 +/- 4 years) completed a questionnaire on health habits and physical activities and a symptom-limited exercise test. They were then stratified on the basis of the number of miles run per week. Six groups, with mileages of 0, 5, 9, 12, 17, and 31 per week, were established. RESULTS: A gradual increase in high-density lipoprotein cholesterol level was observed with increased miles (0.008-mmol/L [0.308-mg/dL] increase in high density lipoprotein cholesterol level per mile). Most of the changes were associated with distances of 7 to 14 miles per week. Levels of low-density lipoprotein cholesterol, triglycerides, and the ratio of total cholesterol to high-density lipoprotein cholesterol also improved with weekly mileage. The high density lipoprotein cholesterol level correlated significantly with all exercise components, anthropometric measures, and alcohol consumption. Group comparisons disclosed significant differences (P < .05) in exercise time to exhaustion, miles run per week, body fat, body weight, and body mass index. Age and alcohol consumption were similar across groups. CONCLUSIONS: These results indicate a dose-response relationship between miles run per week, high-density lipoprotein cholesterol level, and other lipoprotein-lipid levels. Most changes were noted in those who ran 7 to 14 miles per week at mild to moderate intensities. A mile-age threshold for changes in high-density lipoprotein cholesterol level was not observed. However, when compared with those of the nonexercising group, high density lipoprotein cholesterol levels attained statistical significance at 7 or more miles per week. PMID- 7848026 TI - Patient-perceived barriers to preventive health care among indigent, rural Appalachian patients. AB - OBJECTIVE: To examine perceptions of a cohort of rural Appalachian patients regarding barriers to the use of preventive health measures. METHODS: Consecutive new patients (N = 188) at a clinic for the indigent were confidentially surveyed about their use of six preventive health measures: blood pressure screening, cholesterol level, diphtheria-tetanus immunization, mammography, cervical Papanicolaou smear, and physical examination. When any of these measures was lacking, patients were asked why, and whether they would have the measure performed if the relevant barriers were removed. RESULTS: Applicable screening measures lacking were as follows: blood pressure screening, 16%; cholesterol level, 60%; diphtheria-tetanus immunization, 67%; mammography, 69%; Papanicolaou smear, 22%; and physical examination, 32%. Of the patients, 85% were lacking at least one measure. Patients most often identified the following reasons for having omitted these measures: lack of knowledge about prevention (51%) and cost (36%). Older and less educated patients more often identified cost (P < .01 and P = .06, respectively), and men were more likely to list lack of knowledge (P = .04). If the identified barriers could be removed, 72% of those lacking a screen indicated they would obtain the screening measures. DISCUSSION: This indigent population expressed a desire for preventive care. Our patients identified cost and lack of knowledge as the major reasons for omitting these health screening measures. Data obtained from health care providers, rather than patients, may fail to disclose the barriers these patients face. Adequate education about disease prevention may be as crucial as sufficient funding in improving compliance with preventive guidelines. PMID- 7848027 TI - Management of suspected lower-extremity deep venous thrombosis. PMID- 7848028 TI - Value of flexible sigmoidoscopy. PMID- 7848029 TI - Optometric care and undetected eye disease: a case of Berkson's bias? PMID- 7848030 TI - [Pregnancy in patients with heart valve prosthesis. A French retrospective cooperative study (155 cases)]. AB - A French cooperative study of 155 pregnancies in 103 women with valvular prosthesis (95 mechanical, 60 bioprostheses including 27 bivalvular prostheses) is reported. Therefore, a total of 182 prostheses (108 mechanical and 74 bioprostheses) were exposed to the risk of pregnancy. The maternal outcome in the group of 108 mechanical prostheses was complicated by 16 thromboembolic events (TE) including 10 prosthetic valve thromboses which required emergency valve replacement in 4 cases, 6 systemic TE in 13 mitral, 2 aortic and 1 pulmonary mechanical prostheses. The TE were four times more frequent in patients on heparin than in those on oral anticoagulants. There were 4 deaths, 3 among the 10 prosthetic valve thromboses (one reoperation, two sudden deaths). Seven of the 74 bioprostheses were reoperated for degeneration on average 5.9 years after the initial operation but there were no deaths or TE. The outcome of pregnancy was 99 children (63%), 49 of which were born to mothers with mechanical prostheses (53%) and 50 to mothers with bioprostheses (80%) (p < 0.001). Seven of the children were born prematurely, all mothers being on anticoagulant therapy. The birth weight was over 400 grams heavier (3 kg versus 2.6 kg) in the bioprosthesis group (p < 0.05). The 20 spontaneous abortions (13%) were more common in patients on anticoagulants (17%) than in those without (2%) (p < 0.02). Congenital defects due to oral anticoagulants were rare (one certain case). There was one case of phocomelia, an abnormality which has never been described in this context. The 36 remaining pregnancies were still deaths (N = 5), abortion due to maternal death (N = 4), maternal complications (N = 8), therapeutic (N = 9) or voluntary abortions (N = 10) (28 mechanical and 8 bioprostheses).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7848031 TI - [Pre- and postoperative ventricular arrhythmia in mitral valve insufficiency]. AB - In order to assess the prevalence and prognosis of ventricular arrhythmias in patients with surgical mitral regurgitation, a prospective cooperative study was undertaken in 14 French cardiological centres. Seventy-nine patients (45 men, 34 women, average age 62.8 +/- 12.8 years), who underwent mitral valvuloplasty (44 cases) or valve replacement (35 cases), were included. Three 24 hour Holter recordings were performed before, 15 days and 6 months after surgery. Etiology of mitral disease was dystrophic in 49 patients, degenerative in 11, rheumatic in 10, post-endocarditis in 3 and undetermined in 6. Only 5 patients had a left ventricular ejection fraction < or = 45 %. Complex ventricular arrhythmias (Lown > or = 4) were recorded before surgery in 22 patients (28 %), more often in dystrophic disease (17/49 versus 5/30, p = 0.04). No significant correlation was observed between the ventricular arrhythmias and the other preoperative findings, except for a tendency to an inverse correlation between the left ventricular ejection fraction and the Lown grade. Two patients died in the immediate postoperative period (Lown 1); 1 died of a non-cardiac cause at the 2nd month (Lown 4A). The prevalence of complex arrhythmias was unchanged after surgery (34 % on early Holter and 22% on late Holter recordings) with no difference between valvuloplasty and valve replacement. In conclusion, these results indicate that ventricular arrhythmias do not influence the early and 6 month postoperative prognosis in mitral regurgitation with good left ventricular function. PMID- 7848032 TI - [Inferior wall myocardial infarction and atrioventricular block; angiography and prognosis]. AB - This study was based on 42 cases of 2nd or 3rd degree atrioventricular block out of 292 cases of inferior wall myocardial infarction. The criteria of selection were monitoring in the intensive care unit during the acute phase, selective coronary angiography in the first 48 hours to 5 days, and regular clinical follow up during the first year after infarction. The conduction defect was either immediately recorded on the first ECG, delayed (between the 12th and 24th hour) or late (after the 3rd day). These 42 inferior wall infarcts with atrioventricular block (incomplete in 14 and complete in 28 cases) differed from inferior infarction without block by: - the severity of the clinical signs during the acute phase (35% with cardiac failure, 19% with cardiogenic shock); - the severity of the coronary lesions (71.4% with triple vessel disease in infarction with atrioventricular block compared with 32% in those without block, p < 0.02); the prevalence of the association of > 70% stenosis of the right coronary and left anterior descending arteries; - the alteration of left ventricular function (53% patients with atrioventricular block had ejection fraction of under 30%); - the severity of these infarcts was not related to the atrioventricular block which regressed in 95% of cases but to the severity of the coronary disease, the left ventricular dysfunction and the advanced age of the patients (72.3 +/- 8 years). PMID- 7848033 TI - [Aneurysm of the interatrial septum. Apropos of a retrospective study of 41 cases]. AB - The authors undertook a retrospective study of 41 patients in whom an atrial septal aneurysm (ASA) had been diagnosed at transoesophageal echocardiography performed for ischaemic cerebrovascular events in 26 cases. No significant differences in this size, thickness or mobility of the ASA or the associated cardiac abnormalities were demonstrated in this context. However, patients presenting with cerebrovascular accidents were older, had several cardiovascular risk factors and more cardiac arrhythmias. These arrhythmias were usually related to other cardiac pathology such as ventricular hypertrophy or chronic cor pulmonale. Moreover, the probability of the cerebrovascular accident being related to the ASA was only acknowledged in 11 cases. These results mean a certain degree of discretion in diagnostic investigation and therapeutic management of these cases. PMID- 7848034 TI - [Contribution of transesophageal echocardiography to the diagnosis of pulmonary embolism]. AB - Between September 1992 and August 1993 transoesophageal echocardiography was undertaken in 30 patients with clinical and scintigraphic signs of pulmonary embolism. The diagnosis was confirmed by pulmonary angiography (1 patient had failure of venous puncture; 1 patient refused the investigation). The aim of this study was to assess the tolerance and to determine the diagnostic value of transoesophageal echocardiography in patients with suspected pulmonary embolism (PE). Two groups of patients were identified: Group 1: presence of thrombus in the pulmonary artery on transoesophageal echocardiography and group 2: absence of visible thrombus. The produce was well tolerated in all patients. In 21 cases (group 1) 21 thrombi were observed in the right pulmonary artery and 4 thrombi in the left pulmonary artery. The appearances were those of a mobile venous thrombosis in 20 cases (91%) and of clearcut amputation of the proximal segment of the right pulmonary artery in 1 case. No thrombus was detected in 9 patients (group 2). In group 1, the first clinical signs occurred 12 +/- 12 days and the latest signs 2 +/- 3 days before the investigation. One patient had a history of chronic bronchitis. Two patients had a history of PE but with no sign of chronic post-embolic cor pulmonale. Twenty patients underwent pulmonary angiography. Miller's index was 71 +/- 9% and obstruction of proximal pulmonary arteries was observed in 20 patients. In group 2, the PE was confirmed at angiography in 8 cases. The first clinical signs dated from 27 +/- 54 days and the latest signs were observed 6 +/- 4 days before investigation.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7848035 TI - [Pericardium and heart transplantation]. AB - The authors emphasise the role of the pericardium in the post-operative complications of cardiac transplantation: its role is as important as it is underestimated in its frequency, severity and the pathogenic discussions that it induces. This study, based on a retrospective analysis of 191 anatomo-clinical cases (156 autopsies and 35 retransplantations) of patients undergoing cardiac transplantation before the 1/03/1993 including macroscopic and histopathologic analysis of the pericardial lesions, histochemical analysis of the lymphocytic populations, and analysis of associated coronary and myocardial lesions. The results were classified as early or late (after the 75th postoperative day) complications. Early complications included 27 suppurating mediastino pericarditis (13 aspergillosis and 14 bacterial), 16 autonomous non-infective pericardial complications (6 haemopericardiums, 6 organised compressive haematomas, 4 early constrictive pericarditis) and 9 lymphocytic epicarditis associated with acute myocardial rejection. Late complications included one common constrictive symphysis and 14 reactivated epicarditis associated with transplantation coronary disease (chronic rejection) with associated lymphoplasmocytic nodules and a myocardial vasculitis. These observations suggest two important conclusions: 1) the need for active diagnostic measures to detect pericardial complications in cases of cardiac transplant dysfunction in the early postoperative period with no signs of acute rejection on myocardial biopsy: the presence of epicardial lesions on biopsy should be taken into account and not just assumed to be a postoperative epiphenomenon; 2) the presence of epicarditis due to reactivated epicarditis may cause inextensible hardening of the epicardium which adds to the effects of restrictive cardiomyopathy of chronic rejection. PMID- 7848037 TI - [Immediate and long-term results of coronary angioplasty in patients with low ejection fraction]. AB - Left ventricular function is the main predictive factor for survival in coronary patients and the results of coronary bypass surgery in left ventricular dysfunction have been widely reported. The authors undertook a retrospective study of the success rate, the risks and clinical outcome after coronary angioplasty of 182 patients with a left ventricular ejection fraction < or = 35% (30 +/- 4%). The average age was 61 +/- 10 years and 78% were men. One hundred and fifty three patients had a history of myocardial infarction. The primary success rate of angioplasty was 95% (271/284 lesions) including the multiple procedures in 24% of cases. There was a 7.1% frequency of major complications (7 deaths, 3 non-Q wave infarctions, 4 emergency coronary bypass procedures). An average follow-up period of 32 months was obtained in 98.4% of patients. Seven patients developed a myocardial infarction and 14 patients were rehospitalized for cardiac failure (N = 6) or severe ventricular arrhythmias (N = 8). A control coronary angiography was performed in 100 cases either as a routine investigation or for recurrence of symptoms. Restenosis was demonstrated in 33 cases, an aggravation of lesions on another vessel in 12 cases and restenosis associated with aggravation of other lesions in 5 cases, leading to redilatation in 26 cases, atherectomy in 2 cases and coronary bypass surgery in 16 cases. Forty-one patients died (25%). Ten patients died before the 6th month and 31 died secondarily. The only parameter which was significantly correlated with survival was the value of the ejection fraction.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7848036 TI - [Isotopic study of myocardial perfusion and innervation in 28 patients with primary hypertrophic cardiomyopathy: relation to ventricular arrhythmia]. AB - Ventricular arrhythmias are frequent, sometimes complex and severe, in primary hypertrophic cardiomyopathy. They carry a poor prognosis. Some workers have reported that these arrhythmias are more common in patients with abnormal myocardial perfusion. Other groups have underlined the important role of the sympathetic nervous system in the development of ventricular hypertrophy and the genesis of ventricular arrhythmias. Therefore, a population of 28 patients with primary hypertrophic cardiomyopathy (PHCM) were studied by thallium 201 myocardial scintigraphy and sympathetic innervation was assessed using a structural analogue of noradrenaline, meta-iodobenzyl-guanidine (MIBG). Then, perfusion and innervation were correlated with ventricular arrhythmias observed on 24 hours holter monitoring electrocardiogram. Perfusion abnormalities were observed in 60% of patients: stable in mild left ventricular hypertrophy, labile in severe left ventricular hypertrophy. They were not related to the presence of muscular bridges and systolic compression of septal arteries demonstrated by coronary angiography. These perfusion abnormalities were closely correlated to ventricular extrasystoles observed on Holter monitoring. In this series, and compared to controls, the fixation of MIBG as determined by the Heart/Mediastinum (H/M) ratio was significantly decreased (2.27 +/- 0.31 versus 2.57 +/- 0.33 in controls). Uniform myocardial uptake of MIBG with no defect or significant global hypofixation was observed in 32% of PHCM. Regional and occasionally global hypofixation was observed in 68% of patients. In moderate hypertrophy, reduced uptake was not uniform, the lateral wall and apex being the most abnormal. Uptake of MIBG was significantly correlated to septal wall thickness and to left ventricular mass index. These defects were related to abnormal neuronal uptake of MIBG.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7848038 TI - [Coronary transluminal angioplasty using 6-french diagnostic catheters. A preliminary study]. AB - This preliminary study was undertaken to assess the potential indication and limitations of the use of 6 French guiding catheters for percutaneous transluminal coronary angioplasty (PTCA). Between September 1992 and October 1993, 100 consecutive patients with an average age of 64 +/- 11 years underwent 6 F angioplasty for: stable angina (38.7%), unstable angina (32.4%), non Q-wave or infarction recanalized by thrombolytic therapy (18%), and acute myocardial infarction (10.8%). Eighty per cent of the pTCAs were performed immediately after diagnostic coronary angiography. Single vessel disease accounted for 93.7% of cases. Of the 118 lesions treated, 46.6% were types A or B1, 44.9% were type B2 and 8.4% were type C. The success rate of 6 F PTCA was 96.4% using an average of 1.08 guides and 1.25 balloon catheters per patient. Stenosis decreased from 83 +/ 10% to 26 +/- 16%. There were 4 technical failures: in 1 case it was not possible to pass a chronic occlusion, in 1 case coronary dissection was complicated by infarction, and in 2 cases a 7 F guiding catheter was required for successful PTCA. No patients required emergency coronary bypass surgery and there were no fatalities during the procedure. Four patients required perfusing balloon catheters and 8 were stented with a Palmaz-Schatz endoprosthesis with the 6 F catheter. These results are comparable to those obtained with larger diameter guiding catheters. In view of the good coronary ostial tolerance, the lower rate of local complications at the site of arterial puncture and the possibility of earlier mobilisation of patients after the procedure, the indications for 6 F PTCA should increase. PMID- 7848039 TI - [Feasibility and accuracy of pulmonary blood flow measurement by Doppler echocardiography. Apropos of 100 consecutive cases]. AB - One of the main advantages of Doppler echocardiography is the possibility of non invasive measurement of blood flow at each valvular orifice. This method enables quantification of valvular regurgitation, the measurement of Qp/Qs in cardiac disease with atrial or ventricular shunts, and the interpretation of gradients and functional surface areas in valvular stenosis or prosthesis with respect to the underlying haemodynamics. In each of these application, the measurement of pulmonary blood flow is valuable as the reference blood flow, and even indispensible in cases of shunts. The authors' objective was to study the feasibility and accuracy of pulmonary flow measurement in 100 consecutive patients (40 women and 60 men, average age 56.7 +/- 17.5 years) with cardiac disease (82%) or healthy hearts (18%). A grading from A to D was accorded depending on the technical difficulty of the examination, each grade having three degrees: 1) difficulty of recording and poor quality Doppler spectrum, 2) difficulty of measuring orifice diameter by 2D echocardiography, 3) necessity of analysis of color coded anterograde flow to measure the pulmonary valvular orifice. Grade A was distributed to easily recordable measurements with no difficulty; grade B for measurements with one difficulty; grade C for measurements with 2 difficulties and grade D for investigations judged to be impossible or unreliable (3/3 criteria). The feasibility of measurement of the cardiac output at the pulmonary orifice was 88% (A:55%, B:25%, C:8%). The correlation between the pulmonary flow and reference measurements at the aortic and/or mitral valve and/or mitral annulus was 0.96. The average difference between the pulmonary and reference flow was 51 +/- 273 cc/min.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7848040 TI - [Enzyme histochemical study of tha atrioventricular junction area. Correlation with slow and fast atrial pathways]. AB - It was traditionally admitted that junctional tachycardia was based on an intranodal reentry pathway. However, lesions created at a distance from the atrioventricular node by surgery or other physical means (fulguration or radiofrequency energy ablation) demonstrated that the reentry circuit could use the slow and fast atrial pathways. This study performed in 6 human hearts less than 1 hour after death was undertaken to perform enzyme histochemical analysis of the atrial pre-nodal region. The specimens were rapidly frozen in liquid nitrogen and sliced with a cryostat. After localisation of the different regions by routine staining methods, histochemical reactions were performed using the semi-permeable membrane method for weakly bound enzyme. Ten enzymes were studied covering the principal metabolic pathways. Though routine histological stain did not show any particular structures, the enzyme histochemical reactions showed a band of myocardium following the septal insertion of the tricuspid valve, joining the orifice of the coronary sinus to the posterior part of the compact atrioventricular node. This zone of myocardium had an enzymatic make-up similar to that of the sinus node. An analogous structure was also observed above the insertion of the anterior mitral leaflet. These two regions could constitute the trajectory of the slow conduction pathways. PMID- 7848041 TI - [Abnormal origin of the left coronary artery from the pulmonary artery trunk; a fortuitous discovery in a 52 year-old man]. AB - Anomalous origin of the left coronary artery from the pulmonary artery is a rare congenital abnormality but with a very poor prognosis at birth. Myocardial ischaemia, infarction and sudden death are common. Cases diagnosed in adulthood are exceptionally rare. The authors describe the case of an asymptomatic 52 year old man with this congenital abnormality diagnosed after routine electrocardiography had shown sequellae of anterior myocardial infarction. This case would seem to be one of the rarest cases diagnosed fortuitously at this age. In view of the good clinical tolerance of the disease and the absence of residual ischaemia on effort, the patient was treated medically. PMID- 7848042 TI - [Partial pulmonary embolectomy without extracorporeal circulation. Apropos of a case]. AB - The authors report a case of massive pulmonary embolism compromising the haemodynamic status of a 52 year old man with a formal contraindication to thrombolytic therapy. Unilateral pulmonary embolectomy was performed without cardiac pulmonary bypass, preceded by partial interruption of the inferior vena cava. Postoperative controls confirmed the success of the surgical procedure. Although the indications of surgical embolectomy are limited, especially without cardiopulmonary bypass, it may be considered for the treatment of certain cases of massive pulmonary embolism. PMID- 7848043 TI - [Spontaneous dissection of the common trunk and principal branches of the left coronary arterial system. Apropos of a case]. AB - The authors report the case of a 45 year old woman presenting with inaugural anterior myocardial infarction due to spontaneous dissection of the left main and principal branches of the left coronary arterial system. Two attempts of thrombolysis at a one hour interval were made within 6 hours of the onset of symptoms with signs of reperfusion but the ECG and echocardiography showed anterolateral myocardial infarction. A recurrence of chest pain on the fifth day led to emergency coronary angiography. The extent and severity of the observed lesions led to emergency surgical revascularisation with no post-operative complications. Skin biopsy showed signs of dystrophy of the elastic tissues. Angiographic control ten months after surgery showed complete regression of the lesions, especially those of the left main coronary with, however, occlusion of the second segment of the left anterior descending artery and sequellae of anterior myocardial infarction. Treatment of this type of disease is difficult as the outcome is unpredictable and has to be decided case by case. PMID- 7848044 TI - [Valvuloplasty of a tricuspid bioprosthesis by the Inoue's technique]. AB - The authors report the case of a patient who had undergone tricuspid valve replacement with a bioprosthesis in 1985 after infectious endocarditis complicated by paradoxical embolism. The appearance of signs of right heart failure eight years later led to the diagnosis of stenotic degeneration of the bioprosthesis. Inoue balloon valvuloplasty was performed with no complications leading to significant improvement in the patient's condition. PMID- 7848045 TI - [Jean-Paul Cachera. 1930-1993]. PMID- 7848046 TI - Critical review of psychosocial interventions in cancer care. AB - The need for a large variety of psychosocial interventions is enhanced as increasing numbers of patients with cancer have longer survival. This article reviews the four interventions used most commonly: (1) education, (2) behavioral training, (3) individual psychotherapy, and (4) group interventions. It examines the outcomes of each type of intervention. This comprehensive review of the intervention literature reveals the availability of a wide range of options for patients with cancer and their potential psychological and physical health benefits. PMID- 7848047 TI - Switching from 'unipolar' to bipolar II. An 11-year prospective study of clinical and temperamental predictors in 559 patients. AB - BACKGROUND: Given the therapeutic and prognostic importance of the unipolar bipolar dichotomy, predicting which patients will become bipolar subsequent to index diagnosis of major depressive disorder (MDD) is of paramount clinical significance. We sought to characterize the profile of patients with MDD who would convert to the more subtle bipolar subtype (known as BPII) on the basis of clinical and personality variables obtained during MDD episodes. METHODS: A total of 559 patients, comprehensively evaluated with the Schedule of Affective Disorders and Schizophrenia and "unipolar" MDD at entry, were administered 17 self-report personality measures. Hypomanic and manic episodes were systematically recorded over a prospective observation period of up to 11 years. We compared 48 converters to BPII (8.6%) with 22 converters to bipolar I (BPI) (3.9%) and the remaining larger group of unipolar patients. RESULTS: Except for greater acuteness, severity, and psychotic symptomatology, BPI converters were essentially similar to MDD nonconverters. By contrast, BPII converters were robustly distinguished from those with MDD who remained unipolar on the basis of self-report measures along the newly derived factors of Mood Lability, Energy Activity, and Daydreaming. This profile was associated with early age at onset of MDD and pleomorphic psychopathology beyond the usual affective realm, high rates of substance abuse, as well as educational, marital, and occupational disruption and minor antisocial acts prior to discrete hypomanic episodes. Overall, BPII switchers had a more protracted and tempestuous course with shorter well intervals. "Habitual self" descriptions of temperamental instability during MDD episodes provided useful clinical information for predicting which depressed patients will switch to BPII, attaining a sensitivity of 91% for all three factors combined (23 items); Mood Lability alone (nine items) was the most specific predictor (86%), though of lower sensitivity (42%). CONCLUSIONS: The BPII subtype is best understood by such lability intruding into, and possibly its accentuation during, depressive episodes, thereby creating an intimate interweaving of trait and state. Clinicians must note that the foregoing temperamental profile appears more fundamental in defining the affective dysregulation of the BPII subtype than hypomanic episodes emphasized in DSM-IV. PMID- 7848048 TI - Structure and course of positive and negative symptoms in schizophrenia. AB - BACKGROUND: This article focuses on the underlying structure and temporal course of the symptoms of schizophrenia. METHODS: Ratings of symptoms in 90 schizophrenic patients were made each month for 10 years following the first hospitalization. The analytic methods consisted of cross-tabulation, dichotomous factor analysis, and bivariate dichotomous time series. RESULTS: The factor analyses revealed positive and negative factors with a slight tendency to merge over time. The prevalence of positive and negative symptoms declined in the year following first hospitalization and was stable thereafter. Positive and negative symptoms in 1 month were highly predictive of the same type of symptoms in the next month. Neither type of symptom was strongly associated with the other type in the following month when both types were included in the model. The predictability of the process increased with time. CONCLUSIONS: With a few minor caveats, the results suggest that the positive and negative symptom clusters are independent, both cross-sectionally and longitudinally. PMID- 7848049 TI - Guanine nucleotide-binding proteins in bipolar affective disorder. Effects of long-term lithium treatment. AB - BACKGROUND: This study examines recent suggestions from a number of investigators that signal-transducing guanine nucleotide-binding (G) proteins may be involved in the pathophysiology of bipolar affective disorder and may represent molecular targets for lithium's mood-stabilizing actions. METHODS: We used selective antibodies to quantitate the levels of the G protein alpha subunits that regulate adenylate cyclase activity (G alpha s and G alpha i2) and phosphoinositide turnover (G alpha q/11). We also quantitated levels of pertussis toxin-catalyzed phosphate 32-labeled adenosine diphosphate ([32P]ADP) ribosylation in platelet and leukocyte membranes from a group of 14 untreated (predominantly manic) patients with bipolar affective disorder, 20 lithium-treated euthymic patients with bipolar affective disorder, and 11 healthy controls. RESULTS: In both tissues, the immunolabeling of the 45-kd form of G alpha s was higher in the bipolar affective disorder group considered as a whole (treated or untreated) compared with controls, effects that reached statistical significance in the leukocyte membranes. There were no significant differences in the immunolabeling of G alpha i1/2, G alpha q/11, or pertussis toxin-catalyzed [32P]ADP ribosylation in either tissue in the untreated bipolar affective disorder group compared with controls. In both tissues, lithium-treated subjects demonstrated lower levels of G alpha q/11 and higher levels of pertussis toxin-catalyzed [32P]ADP ribosylation, which reached significance in the platelet membranes. CONCLUSIONS: Our results are complementary to the previously reported findings of elevated G alpha s levels in postmortem brain tissue form patients with bipolar affective disorder and in mononuclear leukocytes obtained from depressed patients with bipolar (but not unipolar) affective disorder. The significantly higher levels of pertussis toxin-catalyzed [32P]ADP ribosylation in the subjects receiving long term lithium-treatment replicates our findings in rat cortex and in healthy volunteers and adds to the growing body of evidence implicating G alpha i as a target of lithium's actions. PMID- 7848050 TI - In quest of identifying vulnerability markers for psychiatric disorders by all night polysomnography. AB - BACKGROUND: The persistence of a depressionlike sleep pattern in fully remitted depressed patients suggests that the pattern is a trait characteristic of sleep measurements. However, in the past, subjects have undergone investigation only after the onset of the disorder, and, therefore, the altered sleep pattern may merely represent a biological scar. METHODS: We polysomnographically investigated 54 healthy subjects who had no lifetime or current diagnosis of a psychiatric disorder but had at least one first-degree relative with major depression or a bipolar disorder and at least one further close relative with major depression, a bipolar disorder, or a schizophrenic disorder. Twenty unrelated control probands without a personal and family history of psychiatric disorders and 18 unrelated inpatients with major depression served as reference groups. Prior to investigation, all healthy subjects had been free of any prescription and nonprescription drug for at least 3 months. The depressed patients were free of drugs for at least 1 week. All subjects slept for 2 nights in the sleep research unit. The sleep of the second night was recorded and visually scored. RESULTS: Analysis of the individual sleep cycles in these subjects revealed both a reduced amount of slow wave sleep and increased rapid eye movement density in the first sleep cycle. Discriminant analysis showed that 10 subjects (18%) had sleep patterns similar to those of depressed patients. CONCLUSIONS: According to our observations, one fifth of the healthy subjects with a high genetic load for psychiatric disorders showed a conspicuous (depression-like) sleep pattern. The follow-up will determine whether this sleep pattern indeed represents a trait marker indicating vulnerability. PMID- 7848051 TI - Tryptophan depletion in stable lithium-treated patients with bipolar disorder in remission. PMID- 7848052 TI - Biochemical effects of antidepressant augmentation. PMID- 7848053 TI - Developmental brain abnormalities in schizophrenia: contributions of genetic and perinatal factors. PMID- 7848054 TI - Reciprocal lateralization of frontal lobe functions. PMID- 7848055 TI - Depression in patients with cancer. Diagnosis, biology, and treatment. AB - This article reviews the challenge of diagnosing depression in patients with cancer. Major depression and depressive symptoms, although commonly encountered in medical populations, are frequently underdiagnosed and undertreated. This is especially true for patients with cancer in whom the diagnosis of major depression is clouded by neurovegetative symptoms that may be secondary to either cancer or depression. Well-established biological markers for major depression are proposed as diagnostic adjuncts in patients with cancer. Studies using biological markers in depressed patients with and without cancer are reviewed, and the implications of diminished immune function in depressed patients with cancer are discussed. The limited database on treatment of depression in patients with cancer also is reviewed. Treatment of depression in these patients improves their dysphoria and other signs and symptoms of depression, improves quality of life, and may improve immune function and survival time. Guidelines for future research are proposed. PMID- 7848056 TI - Malignant fibrous histiocytoma phenotype in pleomorphic sarcoma differentiation in recurrent disease. PMID- 7848057 TI - Ordering accuracy. A College of American Pathologists Q-Probes study of 577 institutions. AB - Five hundred seventy-seven institutions examined how accurately physicians' test orders on inpatients were transmitted to the laboratory. Written orders could be found on laboratory requisitions or the medical record for 97.5% of 224,431 completed tests (median institution = 99.3%). Participants indicated that entry of extra tests into a hospital computer was the most common reason for completing unordered tests. In a multivariate analysis, factors associated with completing unordered tests were the lack of a policy requiring nursing staff to recheck computer orders against the medical record, average census of 301-450 patients, College of American Pathologists accreditation, and the use of preprinted "checkoff" order forms. Overall, 97.1% of 225,457 test orders were completed by the laboratories (median institution = 98.1%). Factors associated with not completing ordered tests were the lack of a policy requiring staff to check computer orders, teaching hospital status, and urban hospital location. Several interventions commonly thought to improve communication of orders were not found to affect performance. These results indicate that many institutions have a problem accurately transmitting test orders to their clinical laboratories. PMID- 7848059 TI - Rapid Mycobacterium species assignment and unambiguous identification of mutations associated with antimicrobial resistance in Mycobacterium tuberculosis by automated DNA sequencing. AB - OBJECTIVE: To develop and demonstrate the utility of automated DNA sequencing strategies for rapid and unambiguous identification of Mycobacterium species and mutations associated with antimicrobial resistance in Mycobacterium tuberculosis. DESIGN AND SPECIMENS: A 360-base pair segment of the gene (hsp65) encoding a 65 kd heat shock protein was characterized from 91 isolates assigned to 24 Mycobacterium species by traditional biochemical techniques. Areas of seven genes recently shown to contain mutations associated with antimicrobial resistance in M tuberculosis strains were also sequenced in a sample of 128 resistant organisms. Early positive BACTEC 460 cultures and acid-fast, bacterium-positive sputum specimens from patients with tuberculosis were also studied. RESULTS: Automated DNA sequencing identified species-specific polymorphism in the target segment of hsp65, successfully identified organisms to the species level in smear-positive sputum samples, and unambiguously characterized seven genes associated with antimicrobial resistance in M tuberculosis. CONCLUSIONS: Rapid identification of M tuberculosis and other Mycobacterium species is possible by automated DNA sequencing of a portion of hsp65. The technique is also feasible for analysis of some smear-positive sputum specimens. Unambiguous characterization of target segments of genes harboring mutations associated with antimicrobial resistance in M tuberculosis is possible from primary patient specimens. Taken together, the data demonstrate the feasibility of mycobacterial species identification and potential to identify mutations associated with antimicrobial resistance in less than 48 hours. PMID- 7848058 TI - Practice guidelines for autopsy pathology. Autopsy reporting. Autopsy Committee of the College of American Pathologists. AB - The Autopsy Committee of the College of American Pathologists has prepared this guideline in conjunction with representatives of other organizations to assist pathologists in the reporting of autopsies. The guideline is to be regarded as being primarily an educational tool. Application of these recommendations on autopsy reporting is to be made on the basis of the judgment of the pathologist engaged in a specific case. PMID- 7848060 TI - Screening for human immunodeficiency virus antibody in urine. AB - OBJECTIVE: To determine the diagnostic accuracy of an investigational test for human immunodeficiency virus (HIV) envelope antibodies in urine. DESIGN: Matched blood and urine specimens were tested for HIV by two independent laboratories, both of which were blinded to all results at the other site. Duplicate positive enzyme-linked immunoassay (EIA) results were confirmed by immunofluorescent antibody or western blot. SETTING: Six alcohol treatment centers in the San Francisco metropolitan area. PATIENTS: Five hundred ninety-two recovering alcoholics. MAIN OUTCOME MEASURES: Diagnosis of HIV infection by blood and urine EIA and western blot. RESULTS: The experimental urine EIA, when confirmed by urine western blot, led to a correct diagnosis in all samples. One sample was negative by urine EIA screening, positive by blood EIA, and exhibited an indeterminate blood western blot pattern (p24 band only). CONCLUSIONS: We encountered no false positive or false negative results using an investigational HIV antibody test for urine samples. There are several important advantages to HIV testing of urine versus serum or blood; however, there are also cogent reasons for limiting the use of alternative specimens for HIV testing. PMID- 7848061 TI - A rapid method for the diagnosis of von Willebrand's disease subtypes by the clinical laboratory. AB - Von Willebrand's disease represents the most prevalent form of the inheritable bleeding disorders. Appropriate clinical management of these patients requires subtyping of the disease by examination of von Willebrand factor multimers following agarose gel electrophoresis of plasma. Previously described methods for the preparation of agarose gels in this application require extensive manipulation of the gel mold during pouring of the separating, stacking, and cathode portions of the agarose gel. We describe an improved gel mold design that expedites preparation of agarose gels by eliminating the need to disassemble the mold during preparation. In addition, using relatively inexpensive computer hardware and scanning densitometry, we have demonstrated the ability to both quantitate the von Willebrand factor antigen present and prepare a visual record of the multimer pattern for medical records. PMID- 7848062 TI - Comparison of the Syva Microtrak enzyme immunoassay and Abbott Chlamydiazyme in the detection of chlamydial infections in women. AB - An enzyme immunoassay for detection of Chlamydia trachomatis antigen, Syva Microtrak, was compared with Abbott Chlamydiazyme to evaluate the performance of the Microtrak assay in the diagnosis of chlamydial genital tract infection in women. Duplicate endocervical swabs from 550 women were tested by both methods, and discrepancies were resolved by direct immunofluorescence on pelleted material from the collection tubes. Forty-six specimens were positive by the Syva Microtrak assay (resolved sensitivity, 95%), and 34 specimens were positive by the Chlamydiazyme assay (resolved sensitivity, 79%). The results from this small study suggest that the Syva Microtrak enzyme immunoassay is more sensitive than Chlamydiazyme for the detection of chlamydial antigen in endocervical specimens. This test should be useful for the diagnosis of chlamydial genital tract infection in females. PMID- 7848063 TI - Gene analysis in 18 cases of cutaneous lymphoid infiltrates of uncertain significance. AB - BACKGROUND AND DESIGN: Patients with cutaneous lymphoid infiltrates that appear reactive histologically and immunophenotypically may develop clinically overt cutaneous lymphoma, suggesting the possibility of misdiagnosis by classical methods. We investigated DNA rearrangement in such cases of lymphoid infiltrates of uncertain significance to determine whether this more sensitive method could detect an occult monoclonal lymphoid proliferation. METHODS AND PATIENTS: Skin biopsy specimens were taken from 18 cutaneous lymphoid infiltrates diagnosed as reactive on the basis of clinical, histopathological, and immunohistochemical criteria. Specimens included 12 cases with mixed lymphoid infiltrates rich in polytypic B cells and inconstant follicle formation and 6 cases with exclusive T lymphoid infiltrates. Southern blot analysis for immunoglobulin and T-cell receptor beta-chain gene rearrangements was performed in all cases. RESULTS: No specimen showed T-cell-receptor beta-chain gene rearrangement. Clonal immunoglobulin gene rearrangement was demonstrated in one case with polytypic B cells, but no clinical malignancy has appeared 19 years after disease onset duration and 7 years after detection of the B-cell clone. CONCLUSIONS: In the present series, the results suggest that histological and immunohistological criteria are appropriate to establish the diagnosis of most cases of cutaneous lymphoid infiltrates. The detection of a B-cell clone is remarkable by absence of clinical malignancy, suggesting that such a discovery does not necessarily mean an aggressive evolution. Nevertheless, there is presently no way to predict the prognosis of a clonal lymphoid proliferation, indicating that a long-term follow up is necessary. PMID- 7848064 TI - Primary gastric Hodgkin's disease. Morphologic, immunohistochemical, and immunogenetic analyses. AB - Two cases of primary gastric Hodgkin's disease were examined morphologically and immunohistochemically. Immunogenetic studies were also made in one of the cases. Case 1 was diagnosed as nodular sclerosis and case 2 as mixed cellularity Hodgkin's disease. Large atypical mononuclear or multinucleated giant cells were immunohistochemically positive for BerH2, whereas they were negative for LCA, L26, DAKO CD3, MT1, UCHL-1, S100 protein, and MAC387. In case 1, large atypical cells examined immunohistochemically on frozen tissue specimens were positive for Ki-1 and negative for T- and B-cell markers. Southern blot hybridization studies performed on material from case 1 revealed germline configuration of immunoglobulin JH and T-cell-receptor beta-chain genes. To our knowledge, this is the first report in which primary gastric Hodgkin's disease has been studied immunogenetically. Although rare in incidence, the existence of Hodgkin's disease in the stomach must be noted. PMID- 7848065 TI - Causes of death in patients with sarcoidosis. A morphologic study of 38 autopsies with clinicopathologic correlations. AB - To evaluate the contribution of sarcoidosis to death, we reviewed 38 autopsy cases. The diagnosis of sarcoidosis was established or suspected antemortem in 17 (45%) of 38 cases. Sarcoid was fatal in 67% and incidental in 33%. Of 28 fatal cases, 14 (50%) resulted from cardiac involvement and 12 (43%) from pulmonary disease. Antemortem diagnosis was made in 4 (29%) of 14 fatal cardiac cases versus 9 (75%) of 12 fatal pulmonary cases. This study reveals that antemortem diagnosis of sarcoidosis is challenging and that heart and lung involvement are the most significant contributors to fatal outcome. Cardiac sarcoidosis is frequently first diagnosed postmortem and is a more common cause of death than previously reported. Unlike previous studies, we found that fatal cardiac sarcoidosis is commonly associated with significant extracardiac disease, implying that antemortem diagnosis may be suspected without endomyocardial biopsy in most patients. PMID- 7848066 TI - Fetal weights and measurements as determined by postmortem examination and their correlation with ultrasound examination. AB - Two hundred fifty fetuses from healthy singleton pregnancies terminated other than on health grounds at 21 to 26 weeks gestation were examined by ultrasound in utero and by autopsy. No significant maturational difference between male and female fetuses was noted, although larger biparietal distances (0.2 cm) and smaller femur lengths (0.2 cm) were seen in female fetuses at 23 weeks gestation, and heavier body weights were also noted (80 g). No maturational difference was noted between white and nonwhite populations. Maternal age was not a significant variable. Organ weights and fetal anthropometric measurements are provided. Biparietal diameter as determined by ultrasound examination of the fetus in utero is an excellent predictor of gestational age and correlated well with actual caliper measurements on the fetus (coefficient of variation [CV] < 5%). Femur length determined by ultrasound examination of the fetus in utero is significantly low compared with actual length (CV = 23%) and is not a reliable indicator of fetal development. A large CV (17%) was also seen for calculated fetal weight. PMID- 7848067 TI - Basaloid squamous cell carcinoma of the head and neck with a spindle cell component. An unusual histologic variant. AB - We describe two cases of basaloid squamous cell carcinoma of the head and neck with a spindle cell component. One tumor arose from the tonsil and the other in the larynx. Of the 30 cases of basaloid squamous cell carcinoma seen at this medical center, only 2 (6.6%) have demonstrated this histologic feature. To our knowledge, scant information exists with regards to a prominent spindle cell component occurring in basaloid squamous cell carcinoma, and none has been officially documented. PMID- 7848068 TI - Squamous differentiation in small-cell carcinoma of the parotid gland. AB - Small-cell anaplastic carcinomas comprise 1% to 2% of major salivary gland malignant tumors and demonstrate an aggressive clinical course. The initial classification of salivary small-cell anaplastic carcinoma was based on the ultrastructural identification of membrane-bound dense core granules, confirming neuroendocrine differentiation. These neuroendocrine-type small-cell carcinomas were felt to arise from neuroendocrine stem cells that migrated to the salivary gland from the neural crest. Absent neuroendocrine differentiation by ultrastructural evaluation was felt to signify origin from ductal cells. Immunohistochemical study has revised this concept because many small-cell carcinomas express at least one neuroendocrine marker, even in the absence of ultrastructural evidence of neuroendocrine differentiation. In addition, glandular differentiation both by ultrastructural and light microscopic study has been found in cases showing neuroendocrine differentiation. Ultrastructural evidence for squamous differentiation, such as desmosomes and tonofilaments, has also been recognized. These new findings have led to a revision of the old histogenetic hypothesis. All of these small-cell carcinomas are presumed to arise from a hypothetical ductal stem cell that can undergo neuroendocrine, squamous, or glandular differentiation. We report a small-cell anaplastic carcinoma of the left parotid gland in a 61-year-old man with squamous differentiation identified by light microscopy and confirmed by immunohistochemical expression of predominantly high rather than low molecular weight cytokeratins. This tumor is distinctive because it shows an abrupt transition from small-cell anaplastic carcinoma with neuroendocrine differentiation to well-differentiated squamous differentiation, which was identified readily by light microscopy. Our findings support this new hypothesis of a single multipotential stem cell by demonstrating bidirectional neuroendocrine and squamous differentiation. PMID- 7848069 TI - Rehabits: a common language of functional assessment. AB - Probabilistic measurement models offered by Rasch and others can be used to link different functional assessment instruments into a single measurement system. This study assessed 54 subjects (diagnoses: 8 brain injuries, 7 neuromuscular, 22 musculoskeletal, 7 spinal cord, 10 stroke) admitted to a free-standing rehabilitation hospital at admission and discharge using both the Functional Independence Measure (FIM) and the Patient Evaluation and Conference System (PECS). Thirteen FIM and 22 PECS motor skills items were scaled together into a 35-item instrument, providing scale values for all items in the same unit of measurement. Separate FIM and PECS measures produced for each subject correlate .94 and .91 (p < .0001), respectively, with the cocalibration measures, and 0.91 (p < .0001) with each other. Either instrument's ratings are easily and quickly converted into the other's using the common unit of measurement, the rehabit (rehabilitation measuring unit). This article argues that the stability of the PECS and FIM item difficulty estimates over thousands of subjects, dozens of hospitals, hundreds of raters, and years of assessment is convincing evidence in support of the widespread use of their cocalibrated, common scale values as a functionometric ruler. PMID- 7848070 TI - Why rehabilitation research does not work (as well as we think it should) AB - Establishing treatment effectiveness is a high priority for rehabilitation research. The use of traditional quantitative null hypotheses to achieve this priority is reviewed. Three problems are identified in the analysis and interpretation of investigations based on statistical testing of hypotheses: (1) confusion of clinical and statistical significance, (2) low statistical power in detecting clinically important results, and (3) a failure to understand the importance of replication in developing a knowledge base for rehabilitation practice. Technical aspects associated with each problem are reviewed and examples presented illustrating the impact of low statistical power and the results of misinterpreting statistical significance tests. Several specific recommendations are made to improve the clinical usefulness of quantitative research conducted in rehabilitation. PMID- 7848071 TI - Outcomes of post-spinal cord injury marriages. AB - The purpose of this study was to compare the divorce rate among persons who got married after spinal cord injury with that of the non-spinal cord-injured population of comparable age and gender and to identify factors associated with increased likelihood of divorce. The study included 622 persons enrolled in the National Spinal Cord Injury Statistical Center data set since 1973. These persons were followed between 1 and 15 years after their marriage (mean = 3.5 years). The status of each marriage was determined at the time of their most recent routine annual follow-up examination. Overall, 126 divorces occurred, whereas 74 were expected, based on 2,190 person-years of follow-up and age-sex-specific annual divorce rates for the United States population. Men and remarried persons had divorce rates 2.07 times and 1.80 times higher, respectively, than women and persons married for the first time. The divorce rate was 1.85 times higher among persons without college educations and was lower for persons with lumbosacral injuries than for persons with higher injury levels. In general, the impact of spinal cord injury appears to be almost as great on postinjury marriages as it is on preexisting marriages. However, this study yields descriptive rather than causal information. Other factors must be identified before a clinically useful model to predict persons at high risk for divorce can be developed. PMID- 7848072 TI - Effect of body training position on outcomes of an aerobic training study on individuals with quadriplegia. AB - The use of the supine training position to enhance aerobic training was evaluated in a 10-week upper-body exercise study. Fourteen subjects with quadriplegia (QD) were matched on initial peak power output (PO) values and then randomly assigned to either a supine (SUP, n = 7) or sitting (SIT, n = 7) training group. Peak VO2 and PO were measured pretraining and posttraining in both the supine and sitting positions. There were significant (p < .01) increases in peak VO2 (720 to 780 mL.min-1) and PO (29.3 to 33.3W) with training. Although the SIT group exhibited a small training effect size (0.1), while the SUP group exhibited a moderate effect size (0.6), the interaction between time and training group failed to reach significance (p = .07) because of a large injury level-related variation in VO2. The training effect achieved by the SUP group generalized to the sitting position, as their peak VO2 increased 80mL.min-1 in the sitting position. Endurance improved (p < .0001) in all subjects, with time to exhaustion increasing from 52min to 135min over the 10 weeks of training. The sum of 4 skinfolds decreased (p < .05) from 67.5 to 61.0mm. The lack of change in stroke volume at rest and at 50% of peak PO suggests that an inotropic adaptation of the heart, commonly observed in subjects without SCI, did not occur in this population. However, a 4.7bpm increase (p < .01) in resting heart rate (HR) and a near significant increase (p = .07) in peak HR from pretraining to posttraining suggests a training-induced chronotropic adaptation of the heart. Although improvements in aerobic capacity can be achieved by training in either supine or sitting positions, the training effect size was larger in the supine position. Improvements in SV were not observed in either training position; this may be because of low absolute workloads were used. Central cardiovascular adaptation may occur in subjects with QD but changes are reflected as chronotropic and not inotropic adaptations. PMID- 7848073 TI - Biomechanical assessment of quiet standing and changes associated with aging. AB - The kinematics of standing balance were analyzed in 24 normal subjects, aged 21 to 78 years, to examine differences attributable to age, visual input, and sex. Movements of individual body segments, displacement of the center of gravity (COG), and position of the center of pressure (COP) were measured, and total path length and variability about the mean position were derived from the resulting values. Aging was associated with an increase in variability of the COG, head, and hip, but not in path length. The changes, which may be clinically interpreted as excess postural sway, do not show stability deficits as a consequence of aging. On the contrary, older subjects seem to adopt a postural control strategy that achieves comparable stability during quiet standing. Eye closure increased the anterior-posterior COP path length without corresponding changes in the COG, indicating an increase in small accelerations without associated instability. There was more medial-lateral movement in women than in men. Quantitative electromyographic measures showed that, in general, quiet standing requires very little muscular activity. We conclude that the task of quiet standing produces no evidence of postural instability concurrent with aging. The altered postural control strategy may be less effective when balance is suddenly or severely compromised. PMID- 7848074 TI - Influence of aging on leg muscle reflex responses to stance perturbation. AB - The effect of age on latency and amplitude of leg muscle responses to stance perturbations was studied in 75 control subjects. They stood upright on a platform and were displaced by toe-up (upward tilt) and toe-down (downward tilt) platform rotations. Perturbations were induced during free and supported stance (holding on to a stable structure). Surface electromyograms (EMG) of the soleus (Sol) and tibialis anterior (TA) were recorded and latency and area of responses were measured. Body sway variables during stance with open or closed eyes were also recorded. Upward tilt evoked a short-latency response (SLR) in Sol and a long-latency response (LLR) in TA. Downward tilt evoked a medium-latency response (MLR) in TA and a LLR in Sol. This pattern of EMG responses was similar in both young and elderly subjects, although there were some differences in latency and amplitude. There was a significant relationship between latency of all responses and age. Slope of the regression lines of TA LLR, TA MLR, and Sol LLR was steeper than that of Sol SLR. Area of Sol SLR was unrelated to age, but a positive trend was identified in the other responses, significant for TA LLR. Under supported stance condition, amplitude of TA MLR, TA LLR, and Sol LLR was decreased to a similar extent in both young and elderly subjects. There was a weak relationship between age and most body sway variables. A significant relationship was found between most sway variables and latency of Sol SLR and LLR, chiefly with eyes closed. Neither TA MLR nor LLR were significantly correlated with sway variables, but a trend was present for TA MLR with eyes closed.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7848075 TI - A video-based version of the pendulum test: technique and normal response. AB - The pendulum test, where the leg is dropped and the knee allowed to swing passively in the manner of a pendulum, has been recognized as a reliable and potentially valuable measure of hypertonia. In this study the traditional form of the test, where a goniometer is attached to the leg, has been replaced by a procedure involving computerized video motion analysis. Using 77 control subjects, a battery of 10 amplitude and time-based measures were obtained for purposes of investigating reliable and valid indicators of the damped, unsustained, oscillatory motion that characterizes this test. The results from the control subjects were congruous with those obtained by other workers using the goniometric version of the test. The measures of the response considered in this study showed evidence of increasing resistance to pendular passive joint motion with advancing age. Retest reliability of pendulum test responses in 14 subjects examined on average 26.8 days apart, produced Intraclass Correlation (2,1) values for the entire pendulum test response of an average of 0.84. It is concluded that the video-based pendulum test is a simple reliable source of measures with considerable potential for the clinical and physiological investigation of neurological and nonneurological features of normal and abnormal passive joint motion, and as a standard against which the effects of therapeutic intervention, such as medication, may be evaluated. PMID- 7848076 TI - Exercise effect of modified contralateral stabilization bar during one-legged isokinetic exercise. AB - We compared the electrical activities recorded from the muscles of the unexercised leg with changing the position of the contralateral stabilization bar to determine whether the degree of muscle contraction was influenced by the position of the bar during one-legged isokinetic exercise using an isokinetic dynamometer. The root mean square (RMS) values recorded from the medial hamstring sites of the unexercised legs showed a significantly higher value when the bar was located behind and on both in front of and behind the unexercised leg during one-legged extension exercise. Results from the isokinetic knee flexion exercise test indicated that a significantly greater RMS value was recorded from the vastus lateralis sites when the bar was located in front of and on both sides of the unexercised leg. During one-legged isokinetic extension-flexion exercise, the mean values of RMS voltage were greater when the bar was positioned in front of and on both sides of the unexercised leg in the vastus lateralis site. At the medial hamstring site, a greater value was noticed when the bar was located behind or on both sides. PMID- 7848077 TI - Accuracy of three-dimensional linear and angular estimates obtained with the Ariel Performance Analysis System. AB - Computer-assisted video motion analysis is a method of evaluating human kinematics that offers promise both for research and for clinical application. This study determined the upper limits of accuracy and consistency of linear and angular measures obtained using the Ariel Performance Analysis System. Reference standards included a meter stick and a universal 360 degrees goniometer. Average mean error observed for reconstruction of absolute point estimates was found to be less than 3.5 mm. Mean error estimate for three-dimensional (3D) reconstruction of a linear standard was found to be 1.4 mm (SD 0.30). Average mean angular error observed for 3D reconstruction of goniometer settings 10 degrees to 170 degrees was found to be 0.26 degrees (mean SD 0.21). System users are cautioned that some increased error associated with software derivation of joint angles exists as angles approach 180 degrees, use of wide-angle lens accessories introduces a systematic field-dependent bias; and planar rotation introduces some (< 2 degrees) random error. PMID- 7848078 TI - Rheumatoid arthritis: new approaches for its evaluation and management. AB - Rheumatoid arthritis is a chronic, progressive disease with a long-term outcome characterized by significant morbidity, loss of functional capacity, and increased mortality. The cornerstone of therapy includes the appropriate melding of pharmacological, rehabilitative, and surgical treatments. New developments in the care of patients with rheumatoid arthritis have focused on aggressive pharmacological therapy early in the course of the illness, ongoing assessment of disease activity and patient function, and a better understanding of the role of rehabilitative techniques such as therapeutic exercise and behavioral approaches to education. This article synthesizes information from studies on recent advances in the management of rheumatoid arthritis outlining diagnosis and assessment, disability issues, outcome studies, current status of traditional and experimental pharmacological therapies, and new strategies of nonpharmacological treatments aimed at the clinician challenged by this fascinating disorder. PMID- 7848079 TI - Subcutaneous bupivacaine for treatment of spasticity: a case report. AB - In a previous report, we described heretofore undiscovered possibilities that neuropathic pain and spasticity may share some common pathophysiological mechanisms. Currently, systemically delivered local anesthetics are being used for the evaluation and treatment of neuropathic pain. We present a case describing the treatment of spasticity of spinal origin with continuous subcutaneous infusion of 0.75% bupivacaine in a patient who did not respond to traditional treatments and has become tolerant to intrathecal baclofen. PMID- 7848080 TI - Recommendations for use of uniform nomenclature pertinent to patients with severe alterations in consciousness. American Congress of Rehabilitation Medicine. AB - There continues to be considerable confusion and controversy on the use of diagnostic and clinical terms assigned to patients with severe alterations in consciousness. This confusion results largely from the lack of a uniform classification system that is based on behaviorally defined criteria. This position paper provides recommendations for defining coma, vegetative state (including persistent and permanent vegetative state), akinetic mutism, the minimally responsive state, and locked-in syndrome based on neurobehavioral and neuropathologic features. Current controversies surrounding use of these terms also are discussed. PMID- 7848082 TI - Incidence, complications, and management of Meckel's diverticulum. AB - OBJECTIVES: To elucidate the incidence of Meckel's diverticulum; to determine the correlation between the histologic type of the diverticulum's mucosa and its clinical presentation; and to review our experience with Meckel's diverticulum. DESIGN: Case-control study. SETTING: University hospital in Ioannina, Greece. PATIENTS: A total of 2074 patients undergoing an appendectomy were examined intraoperatively for Meckel's diverticulum (subgroup A1). In addition, Meckel's diverticulum was found incidentally in 15 patients who were undergoing intra abdominal surgery (subgroup A2). An operation for a complicated Meckel diverticulum was performed in an additional 15 patients (group B). RESULTS: Thirty-three (1.59%) Meckel diverticulae were found incidentally among 2074 patients in subgroup A1. A positive correlation between Meckel's diverticulum and male sex was found (P < .004), but no difference was found in sex distribution between patients in group B and subgroup A1 (P < .6744). The histologic type of the mucosa (gastric) had significant positive correlation with the clinical presentation of the diverticulum (complicated) (P < .001). CONCLUSION: Resection of the unexpected Meckel diverticulum can be performed safely with a low complication rate, regardless of the patient's age. PMID- 7848081 TI - Observations on the developmental patterns and the consequences of pancreatic exocrine adenocarcinoma. Findings of 154 autopsies. AB - OBJECTIVE: To improve our future care of the patient with exocrine pancreatic cancer by seeking, within the limitations of our present approaches, additional information on the growth and spread of the cancer and its influences on the patient. DESIGN: Consecutive autopsies of all patients with exocrine pancreatic cancer were reviewed retrospectively by two surgeons and three pathologists. SETTINGS: Three teaching hospitals of the Medical College of Ohio, Toledo. MATERIALS: One hundred fifty-four consecutive autopsies of patients with exocrine pancreatic cancer during the period between 1952 and 1992. RESULTS: Intrapancreatic metastases or multicentric cancers were found in 12 patients. In 32 patients, pancreatic cancer skipped the lymph nodes, primarily draining the respective areas of the pancreas to metastasize to the secondary chain of nodes. In 13 patients, pulmonary metastases occurred without hepatic metastasis. Intrapancreatic contiguous extension was identified in 34 patients. Carcinoma of the body and/or tail of the pancreas was characterized by transperitoneal as well as hematogenous dissemination to a greater extent than was carcinoma of the head of the pancreas. Seven of 11 small tumors (< 2 cm in diameter) were associated with remote metastases. Relatively severe chronic obstructive pancreatitis was found to have resulted from pancreatic carcinoma in 18 cases, whereas in seven patients, pancreatic carcinoma probably developed in preexisting chronic pancreatitis. Thromboembolic disease was found in 30 patients, more frequently in the patients with the mucin-producing tumors of the pancreatic body and tail. In 21 patients, the amount of ascites was not proportional to the severity of peritoneal dissemination, vessel invasion, or recognizable hepatic dysfunction. Thromboembolic disease, severe infection, stress ulcer, and acute hemorrhagic erosive gastroenteritis were frequent systemic complications contributing to death. Malnutrition in the form of cachexia was undoubtedly a major, even dominant, feature in many patients that could not be quantitated from this data. CONCLUSIONS: Metastasizing cells frequently bypass the initial filters in lymph nodes, liver, or lung to become established in secondary or tertiary sites. Intrapancreatic metastases or multicentric tumors also may develop more frequently than generally has been recognized. Small cancers (< 2 cm in diameter) are often associated at autopsy with remote metastases. These facts would appear to limit the usefulness of the current staging of resected cancers of the pancreas. Cancers of the body or tail are characterized by transperitoneal and hematogenous spread to a greater extent than are those of the head. Anatomical studies often do not explain the cause or the extent of ascites associated with pancreatic adenocarcinoma. As previously indicated, chronic pancreatitis appears to be further confirmed as a precursor of pancreatic cancer. PMID- 7848083 TI - Comparison of blood flow and myoelectric measurements in two chronic models of mesenteric ligation. AB - OBJECTIVE: To determine whether the predictive accuracy of intestinal motility and blood flow measurements is altered by the magnitude of ischemic damage. DESIGN: Inception cohort study (dogs). Motility was measured using a probe that quantifies both the electromyographic (EMG) measurements and the magnitude of evoked contractile response (ECR). Intestinal blood flow was assessed using Doppler ultrasonography in the marginal artery and perfusion fluorometry, which quantifies fluorescein in the bowel wall in dye fluorescence units. SETTING: Vivarium animal research facilities at a medical school. INTERVENTIONS: The blood supply of a 40-cm length of ileum was ligated in 102 dogs: 52 in which the marginal artery was ligated at two points 8 cm apart (severe model), and 50 in which the marginal artery was ligated only once (moderate model). Twenty-four hours after ligation, the motility and blood flow parameters were measured in normal bowel and at 2-cm intervals within the 40-cm ischemic segment. Resection and anastomosis of ischemic bowel was then performed using either EMG, ECR, or fluorometry to determine the site of resection. OUTCOME MEASURE: Anastomotic leak from progressive ischemia. RESULTS: There were 26 fatal anastomotic leaks, all due to necrosis at the anastomosis. Perfusion fluorometry and ECR measurements did not correlate with survival in either model. An audible Doppler pulse in the marginal artery correlated with survival in the moderate (P < or = .02) but not the severe model (P = .59). The EMG measurements were significantly greater in survivors vs nonsurvivors in both models. CONCLUSIONS: The EMG measurements may be useful in bowel viability assessment. Correlation of Doppler ultrasonographic findings with survival in the moderate model suggests that blood flow measurements may be more reliable in predicting viability in less ischemic bowel. PMID- 7848084 TI - Orthotopic liver transplantation for benign hepatic neoplasms. AB - OBJECTIVE: To evaluate the frequency and outcome of liver transplantation for symptomatic, unresectable, benign hepatic neoplasms. DESIGN: Retrospective study. SETTING: Presbyterian University Hospital, a tertiary care referral center for liver transplantation affiliated with the University of Pittsburgh (Pa). PATIENTS: All 3239 liver transplant recipients at the University of Pittsburgh from January 1981 until January 1993. RESULTS: Twelve (0.37%) of 3239 patients required liver transplantation for benign, highly symptomatic hepatic neoplasms that were unresectable. Origins included adenoma (n = 6), mesenchymal hamartoma (n = 2), massive hepatic lymphangiomatosis (n = 1), hilar fibrous angiodysplasia (n = 1), focal nodular hyperplasia (n = 1), and hemangioma (n = 1). There were three perioperative deaths and two late deaths at 56 and 84 months. The remaining patients are alive, with follow-up ranging from 36 to 145 months. Median survival for the nine patients who survived the perioperative period is 88 months. The early deaths were attributable to hemorrhagic complications (n = 2) and necrotizing pancreatitis (n = 1). The two late deaths were due to disseminated aspergillosis and hepatitis-associated cirrhosis. CONCLUSION: Patients with severe symptoms from benign hepatic neoplasms that are not resectable can be treated by total hepatectomy and orthotopic liver transplantation, with the expectation of good long-term results. PMID- 7848085 TI - A new approach for liver surgery. Transdiaphragmatic hepatectomy for cirrhotic patients with hepatocellular carcinoma. AB - OBJECTIVE: To clarify the efficacy of transdiaphragmatic hepatectomy. DESIGN: Transdiaphragmatic hepatectomy and transabdominal hepatectomy were retrospectively compared. SETTING: This technique is used in cirrhotic patients with hepatocellular carcinoma located near the diaphragm. PATIENTS: Thirty-six cirrhotic patients with hepatocellular carcinoma who underwent transdiaphragmatic (group 1 [n = 8]) or transabdominal (group 2 [n = 28]) hepatectomies between April 1985 and March 1993 were investigated. All patients underwent a partial hepatectomy for hepatocellular carcinoma less than 3 cm in diameter located in segment VII or VIII or near the confluence of the hepatic veins. MAIN OUTCOME MEASURE: Intraoperative and postoperative clinical parameters, including operative time, blood loss, and length of hospital stay. RESULTS: The mean +/- SD operative time was significantly shorter in group 1 (184 +/- 25 minutes) than in group 2 (270 +/- 79 minutes). The intraoperative blood loss was significantly smaller in group 1 (857 +/- 622 mL) than in group 2 (1318 +/- 926 mL). The rate of postoperative complications was lower in group 1 (13% [n = 1]) than in group 2 (43% [n = 12]). The postoperative hospital stay was significantly shorter in group 1 (16 +/- 5 days) than in group 2 (23 +/- 16 days). CONCLUSIONS: Transdiaphragmatic hepatectomy is a useful technique for cirrhotic patients with hepatocellular carcinoma located near the diaphragm. PMID- 7848086 TI - Evaluation of a new hemostatic agent in experimental splenic laceration. AB - OBJECTIVES: To compare the effectiveness of several hemostatic agents and to evaluate a new hemostatic agent (ReClot) in controlling splenic hemorrhage. DESIGN: Rabbits were anesthetized and catheters placed. A celiotomy was performed and a splenic injury produced; hemostatic agent and compression were applied. EXPERIMENTAL GROUPS: In group 1 (n = 8), the splenic laceration was compressed with a dry sponge and 75 g of pressure until hemorrhage ceased. In groups 2, 3, and 4 (n = 10 each), splenic injury was treated with Avitene, Collastat, and ReClot, respectively. Hemostatic agent was applied to the splenic laceration and a dry sponge and pressure were applied as described for group 1. In group 5 (n = 9), a splenic laceration was produced, ReClot applied, and aggressive fluid resuscitation was initiated; the volume of crystalloid was adjusted to maintain mean arterial pressure. RESULTS: Application of a hemostatic agent reduced total blood loss compared with that measured in the control group, but there was no difference in blood loss among experimental groups treated with a hemostatic agent. The time required to achieve control of blood loss was less in the ReClot treated group compared with the Avitene- and Collastat-treated groups. CONCLUSIONS: The hemostatic agent ReClot had a significant advantage over other hemostatic agents for the time required to achieve control of splenic bleeding. Aggressive fluid resuscitation did not limit the ability of ReClot to produce hemostasis. PMID- 7848087 TI - Interleukin-2 receptor expression and function following thermal injury. AB - BACKGROUND/OBJECTIVE: Serious traumatic or thermal injury is associated with depression of cellular immunity, including the failure of T-lymphocyte proliferation in response to stimulation that depends both on production of interleukin-2 (IL-2) and on expression of functional IL-2 receptors (IL-2R). While decreased IL-2 production following thermal injury is undisputed, the status of IL-2R expression and function in this setting is controversial; therefore, we sought to investigate this issue. DESIGN: A total of 220 male A/J mice (n = 22 per group) were subjected to a 20% scald burn injury or sham burn, killed 4, 7, 10, 14, or 21 days later, and splenocytes harvested. In vitro parameters of both IL-2R expression and function were measured. RESULTS: On day 7, splenic lymphocyte proliferation and IL-2 production in response to mitogenic stimulation were both suppressed following burn injury to 50% and 60% of controls, respectively. Northern blot analysis revealed normal IL-2R p55 messenger RNA expression in response to mitogenic stimulation on days 7, 10, and 14 in thermally injured animals. Phenotypic IL-2R p55 expression in concanavalin A-stimulated CD3+ cells was unchanged following burn injury. Binding of fluorescein-labeled IL-2 to cell membranes was increased in burned animals at days 10 and 14. The addition of IL-2 to cultures of spleen cells from burned mice consistently restored the mitogenic response to that of the controls. CONCLUSIONS: Thermal injury in this model does not result in either quantitative or functional suppression of IL-2R. Suppression of T-cell activation and proliferation, seen following thermal injury, appears primarily related to abnormal IL-2 production. PMID- 7848088 TI - Do prehospital trauma center triage criteria identify major trauma victims? AB - OBJECTIVE: To evaluate anatomic, physiologic, and mechanism-of-injury prehospital triage criteria as well as the subjective criterion of provider "gut feeling." DESIGN: Prospective analysis. SETTING: A state without a trauma system or official trauma center designation. PATIENTS: Patients treated by emergency medical services personnel statewide over a 1-year period who were injured and met at least one prehospital triage criterion for treatment at a trauma center. MAIN OUTCOME MEASURES: Outcome was analyzed for injury severity using the Injury Severity Score and mortality rates. A major trauma victim (MTV) was defined as a patient having an Injury Severity Score of 16 or greater. The yield of MTV and mortality associated with each criterion was determined. RESULTS: Of 5028 patients entered into the study, 3006 exhibited a singular entry criterion. Triage criteria tended to stratify into high-, intermediate-, and low-yield groups for MTV identification. Physiologic criteria were high yield and anatomic criteria were intermediate yield. Provider gut feeling alone was a low-yield criterion but served to enhance the yield of mechanism of injury criteria when the two criteria were applied in the same patient. CONCLUSIONS: A limited set of high-yield prehospital criteria are acceptable indicators of MTV. Isolated low- and intermediate-yield criteria may not be useful for initiating trauma center triage or full activation of hospital trauma teams. PMID- 7848089 TI - Accuracy of disincorporation for identification of vascular graft infection. AB - OBJECTIVE: The presence or absence of prosthetic graft incorporation with surrounding tissue was assessed relative to bacterial culture results, using enhanced microbiologic culture techniques. DESIGN: Criterion standard. SETTING: University and Veterans Affairs hospital. PATIENTS: Prosthetic samples were removed from 113 aortofemoral, extra-anatomic, infrainguinal, and hemoaccess sites at the time of vascular reoperative surgery. Harvested grafts were sonicated. Density of organisms was determined by quantitative culture. MAIN OUTCOME MEASURES: The culture result was predicted from the status of prosthetic incorporation or disincorporation as determined at surgery. For purposes of this study, any bacterial growth represented graft infection. RESULTS: Cultures positive for bacteria were obtained from 31 sites; cultures with no growth, from 82. Thirty-one of the 113 sites were disincorporated, of which 23 yielded cultures positive for bacteria, and eight, no growth. The remaining 82 sites were well incorporated, of which 74 yielded cultures negative for bacteria, and eight, bacterial growth. Sixteen (14%) incorrect predictions were noted. The concurrence of disincorporation and a culture positive for bacteria relative to all culture positive grafts (sensitivity) was 74%. The concurrence of incorporation and cultures negative for bacteria relative to all culture-negative grafts (specificity) was 90% in prostheses implanted for longer than 2 weeks; in prostheses implanted for longer than 12 weeks, specificity was 97%. CONCLUSIONS: The surgical finding of incorporation or disincorporation accurately predicted the culture result in 89% of the sites. Disincorporation correlated with presence of bacteria in 71%; incorporation reliably excluded the presence of bacteria in 97%. PMID- 7848090 TI - The effect of regional trauma care systems on costs. AB - OBJECTIVE: To assess cost savings from regional trauma care systems. DESIGN: Multivariate regression analysis is used to isolate the effects of regional trauma care systems on medical costs while controlling for personal and injury characteristics and other factors likely to influence medical costs. Percentage reductions in costs are translated into dollar cost savings with corrections for excluded costs and losses from premature death. SETTING: Injuries to workers filing workers' compensation lost workday claims. PARTICIPANTS: Randomly sampled workers' compensation claims from 17 states filed between 1979 and 1988 (N = 217,000). MAIN OUTCOME MEASURE: Medical payments per episode of four injury groups: lower-extremity fractures and dislocations, upper-extremity fractures and dislocations, other upper-extremity injuries, and back strains and sprains. We distinguish hospitalized from nonhospitalized claims. RESULTS: Statistical analyses reveal that states with trauma care systems have 15.5% lower costs per hospitalized injury episode. Savings average $1025 per case in 1988 dollars. Costs per episode for disabling nonhospitalized injury are 10% lower in states with trauma care systems, with savings averaging $75 per case. The largest savings are for back injuries. CONCLUSIONS: Extending trauma care systems nationwide could lower annual medical care payments by $3.2 billion. Including productivity losses due to premature death, the savings could total $10.3 billion, 5.9% of national injury costs. PMID- 7848091 TI - Current management and long-term prognosis of hepatolithiasis. AB - OBJECTIVE: To assess the surgical and endoscopic treatment results and long-term prognosis of hepatolithiasis. DESIGN: Retrospective case series. SETTING: University hospital. PATIENTS: Eighty-five consecutive patients with hepatolithiasis treated between 1980 and 1993. MAIN OUTCOME MEASURES: Location of calculi, associated diseases, treatment procedures, and long-term prognosis were analyzed. RESULTS: Thirty-eight percent of the 85 patients had stones only in intrahepatic ducts, while others had intrahepatic and extrahepatic calculi. Seventy-two percent of the patients had repeated biliary surgery, and 14% were associated with liver cirrhosis. After surgery combined with cholangioscopy and electrohydraulic lithotripsy, the complete stone clearance rate was 71%. The treatment-related mortality rate was 3.8%; the stone recurrence rate after complete stone removal was 11%. However, it was notable that 17 patients (20%) died of related diseases during a mean follow-up of 6 years. The reasons for death were liver failure, bleeding from esophageal varices, hepatocellular carcinoma, and cholangiocarcinoma. CONCLUSION: Improvement of stone clearance rate is evident by a systematic approach. Complete relief from calculi, bile stasis, and cholangitis at an early stage of the disease is mandatory to prevent progressive liver damage, because repeated recurrence of intrahepatic calculi and cholangitis ultimately lead to irreversible liver damage and hepatobiliary carcinomas with a high mortality. PMID- 7848092 TI - Hospital mortality of major hepatectomy for hepatocellular carcinoma associated with cirrhosis. AB - OBJECTIVE: To define the safety of major hepatectomy for hepatocellular carcinoma (HCC) associated with cirrhosis and the selection criteria for surgery in terms of hospital mortality. DESIGN: Major hepatectomy for HCC in the presence of cirrhosis is considered to be contraindicated by many surgeons because the reported mortality rate is high (26% to 50%). Previous workers recommended that only selected patients with Child's A status or indocyanine green (ICG) retention at 15 minutes of less than 10% undergo major hepatectomy. A survey was made, therefore, of our patients with HCC and cirrhosis undergoing major hepatectomy between 1989 and 1994. SETTING: A tertiary referral center. PATIENTS: The preoperative, intraoperative, and postoperative data of 54 patients with cirrhosis who had major hepatectomy were compared with those of 25 patients with underlying chronic active hepatitis and 22 patients with normal livers undergoing major hepatectomy for HCC. The data had been prospectively collected. INTERVENTION: Major hepatectomy, defined as resection of two or more liver segments by Goldsmith and Woodburn nomenclature, was performed on all the patients. MAIN OUTCOME MEASURE: Hospital mortality, which was defined as death within the same hospital admission for the hepatectomy. RESULTS: Preoperative liver function in patients with cirrhosis was worse than in those with normal livers. The intraoperative blood loss was also higher (P = .01), but for patients with cirrhosis, chronic active hepatitis, and normal livers, the hospital mortality rates (13%, 16%, and 14%, respectively) were similar. The hospital mortality rate for patients with cirrhosis in the last 2 years of the study was only 5%. Patients with cirrhosis could tolerate up to 10 L of blood loss and survive the major hepatectomy. By discriminant analysis, an ICG retention of 14% at 15 minutes was the cutoff level that could maximally separate the patients with cirrhosis with and without mortality. CONCLUSION: Major hepatectomy for HCC in the presence of cirrhosis is associated with a mortality rate that is not different from the rate for patients with normal livers. An ICG retention of 14% at 15 minutes would serve as a better selection criterion than the 10% previously used. PMID- 7848093 TI - TPN-induced sympathetic activation is related to diet, bacterial translocation, and an intravenous line. AB - OBJECTIVE: To investigate the effects of an intravenous line and the administration of a total parenteral nutrition (TPN) formula by the parenteral and oral routes on bacterial translocation and urinary catecholamine excretion in rodents. METHODS: Rats were fed chow with or without an intravenous line and a fat-free TPN solution either orally or intravenously for 5 consecutive days. Urine was collected on the first, third, and fifth days of feeding and quantitatively analyzed for norepinephrine and epinephrine excretion. Mesenteric lymph nodes were cultured for bacteria at the end of the study (day 5). RESULTS: Oral and intravenous TPN diets significantly increased norepinephrine excretion over time (P < .0001) compared with excretion in rats fed chow. Oral TPN diets increased epinephrine secretion after 5 days of feeding. The route of feeding TPN solution had no effect on norepinephrine or epinephrine excretion. Chow-fed rats with intravenous lines tended to have increased norepinephrine excretion over 5 days of feeding compared with chow-fed rats without intravenous lines (55% vs 13%, P = .08). Rats with bacterial translocation had greater norepinephrine excretion (mean +/- SEM, 136 +/- 23 pmol/mumol of creatinine) than rats without bacterial translocation (64 +/- 14 pmol/mumol of creatinine) (P < .05). CONCLUSIONS: Intravenous and oral fat-free, hypertonic glucose diets increase sympathetic nervous activity. This diet-induced sympathetic activity may be related to the presence of an intravenous line, bacterial translocation, the thermic effects of hypertonic glucose, and/or the absence of orally ingested food substances in rodent chow. In this model of rodent feeding, increased sympathetic activity may account for alterations in intestinal and immunologic defenses. PMID- 7848094 TI - The impact of a dedicated trauma program on outcome in severely injured patients. AB - BACKGROUND: In recent years, many trauma centers have been closing or scaling down their operations because of financial losses and lack of commitment by the relevant authorities. OBJECTIVE: To investigate the effect of commitment to trauma and the establishment of a dedicated trauma program on injury outcome. DESIGN: In 1992, a well-funded dedicated trauma program was implemented at the Los Angeles County--University of Southern California Medical Center, Los Angeles. We analyzed the outcome in severely injured patients (Injury Severity Score [ISS] > 15) before and after implementation of the program (1991 and 1993). SETTING: Large, urban, level 1 trauma center. PATIENTS: Patients with trauma and an ISS higher than 15. RESULTS: There were 737 patients with an ISS higher than 15 in 1991 and 812 patients with an ISS higher than 15 in 1993. The overall mortality rate was 30% in 1991 and 24.5% in 1993 (P = .018), which is a reduction by 18.3%. In patients with blunt trauma and an ISS higher than 15, mortality was reduced by 33% (mortality rate of 31.1% in 1991 vs 20.8% in 1993) (P < .002). Mortality in patients with penetrating trauma and an ISS higher than 30 was reduced by 42.7% (mortality rate of 59.3% in 1991 vs 34% in 1993) (P = .019). There was also a trend toward lower permanent disabilities among survivors with an ISS higher than 15 (14.7% in 1991 vs 11.3% in 1993). CONCLUSION: Commitment of financial and human resources for the establishment of a dedicated trauma program is a sound investment in terms of improved survival and fewer permanent disabilities in critically injured patients. PMID- 7848095 TI - Angiosarcoma of the breast. Initial misdiagnosis is still common. AB - Primary angiosarcoma of the breast is a rare and often misdiagnosed disease. The most common clinical presentation is a painless mass in the affected breast, but the often varied presentation and the high incidence of histologic misdiagnosis make early detection rare. The tumor size and the histologic type correlate with the prognosis. The treatment for angiosarcoma of the breast is early and complete surgical excision of the mass with adequate margins. Axillary dissection is not indicated because the predilection for nodal metastasis is rare. The definitive role of adjuvant therapy remains undetermined. Chemotherapy and radiotherapy may play an important role in survival; however, the data are inconclusive. A high index of suspicion for angiosarcoma is a crucial tool in its proper diagnosis and treatment. It should always be noted that a vascular lesion that is associated with any breast mass is an angiosarcoma until proven otherwise. PMID- 7848096 TI - Thromboembolism from occult subclavian arterial stenosis during chemotherapy for breast carcinoma. AB - Cancer chemotherapy has been associated with hypercoagulability, causing thromboembolic complications. Three unusual and strikingly similar cases of upper extremity arterial thromboembolism were encountered in women undergoing chemotherapy following surgical treatment for breast carcinoma. In all cases, previously asymptomatic stenosis of the subclavian artery due to extrinsic cause was suspected as the source of distal thromboembolism. These cases illustrate the interplay between transient hypercoagulability and underlying arterial disease in the pathogenesis of arterial thromboembolism. PMID- 7848097 TI - Transjugular intrahepatic portosystemic shunt for Budd-Chiari syndrome after failure of surgical shunting. AB - A case of acute Budd-Chiari syndrome in a 26-year-old woman is reported. After a mesocaval shunt, the patient remained asymptomatic for 21 months, but ascites and hepatomegaly reappeared due to inferior vena cava stenosis subsequently treated by balloon dilation. Recurrence of stenosis indicated the need for a cavoatrial shunt with an expanded polytetrafluoroethylene prosthesis, which was followed by a complete recovery during the next 29 months. Radiological follow-up with magnetic resonance imaging demonstrated progressive hepatomegaly, thrombosis of the cavoatrial shunt, and stenosis of the mesocaval shunt. A transjugular intrahepatic portosystemic shunt was carried out, despite the absence of any patent residual hepatic vein at the usual level, by perforating the inferior vena cava and liver up to the right portal vein. An expandable 12-mm stent was successful in decreasing liver congestion. Dilation of the transjugular intrahepatic portosystemic shunt was done 15 months later, and the patient remains asymptomatic after a follow-up of 18 months. PMID- 7848099 TI - [Various forms of breast cancer]. AB - 844 observations of mammary carcinoma special forms were analyzed. In 48% of cases there was a combined structure, primary multiple carcinoma was in 23.6%, bilateral in 2.8% cases. Morphological and immunohistochemical investigation with use of monoclonal antibodies to the membrane antigen of lipid globules were performed. The clinical features of different forms are described. PMID- 7848098 TI - [Mitotic regimen of histologic variants infiltrating duct carcinoma of the breast]. AB - Mitotic regimen was studied in 197 cases of infiltrating duct mammary carcinoma found at mammography screening and subdivided according to the prognostic F. Linell classification (1980) into two groups (1-tubular, duct-tubular and II comedo-type carcinoma). Indices of the mitotic regimen and particularly mitotic index showed statistical differences in these groups. Comedo-type carcinoma with a poorest prognosis is characterized by a high mitotic index (near 20% and higher) and pronounced mitosis pathology correlated with a degree of cell polymorphism. Mitotic index of a tubular and duct-tubular carcinoma is much lower (as a rule lower than 10%) this reflecting their more favourable prognosis. PMID- 7848100 TI - [Cell oncogene expression in normal, metaplastic, dysplastic epithelium and squamous cell carcinoma of the uterine cervix]. AB - Immunohistochemical analysis of the protein expression c-myc, ets 1, ets 2, TPR met, c-fos, c-jun, c-ras-pan, p53, yes, src in 79 samples of normal, metaplastic squamous epithelium, intraepithelial and invasive squamous cell carcinoma of uterine cervix was performed using polyclonal rabbit antibodies to the synthetic peptides homologous active areas of corresponding oncoproteins. Higher content of myc, fos, ets2, p53, ras is noted in metaplasia, dysplasia and in tumours as compared to the normal tissues. Protein myc is revealed in the cytoplasm at a grave dysplasia and in the nucleus in the intraepithelial carcinoma: this may serve as a criterion at a differential diagnosis of these conditions. Expression of the oncoproteins fos, ets2, p53, src in the metaplastic squamous cell carcinoma was higher than in the true squamous cell (ectocervical) carcinoma. When compared to the advanced carcinomas, increase of ets2, p53, and at some degree that of myc, the increase is noted in the latter. Invasive carcinoma with a high level of oncoproteins showed a tendency to the synchronization of myc and ras expression. Poor prognosis was associated with a low level (before treatment) of the expression of the majority of the oncoproteins studied. PMID- 7848101 TI - [Problems of pathology in Russia]. PMID- 7848102 TI - [Comparative clinico-morphologic characteristics and prognosis of forms of ulcerated stomach cancer]. AB - 300 cases of ulcerated and non-ulcerated stomach carcinoma and chronic stomach ulcer are analyzed. New criteria for a differential diagnosis and prognosis of ulcerated carcinomas are found. PMID- 7848103 TI - [Proliferative activity of basal cell and metatypical cell carcinoma of the skin]. AB - Using avidin-biotin, immunoperoxidase techniques and antibodies to proliferating cell nuclear antigen (PC10), 32 cases of primary basal cell carcinoma (BCC), 10 cases of recurrent BCC and 8 cases of metatypical carcinoma (MTC) of the skin were studied. The majority of cases of primary BCC had low level of cell proliferative activity, whereas high cell proliferative index was found only in 7 cases. Recurrent BCC as well as MTC exhibited high level of cell proliferative index that 3-4 times exceeded the same index of primary BCC. BCC had either uniform or regional distribution of proliferative cells. Tumors with regional distribution of proliferative cells are characterized by a low level of proliferation. The revealed difference in cell proliferation between primary BCC, recurrent BCC and MTC may be valuable criterion for detecting the degree of tumor malignancy. PMID- 7848104 TI - [New data on the epidemiology and morphology of Viliuisk encephalomyelitis]. AB - Viliuisk encephalomyelitis (VEM) appears to be endemic disease, affecting native population in Yakutia (Yakut, Even, Evenk). The infectious nature of VEM is very likely, but not yet established with certainty. The mortality rate caused by VEM from 1950 to 1990 was 17.4 per 10000 of native population. The maximum morbidity can be seen in Viliui and Central zones of Yakutia. Women were affected one and a half times more than men. VEM is characterized by multiple micronecrotic foci with marked inflammatory reactions and gliosis in the brain tissue. The vascular component in VEM is manifested by vasculitis, plasmarhagies, obliteration of the capillary lumen with development of capillarofibrosis, progressive reduction of the microcirculatory bed, the deformation of walls in major vessels with atrophy of their muscular layer, in some cases--by hyaline thrombi. The data presented give no grounds to consider the vascular component as secondary, relating only to the brain atrophy. PMID- 7848105 TI - [Diabetic glomerulonephritis--the first stage of diabetic glomerulopathy]. AB - 20 puncture renal biopsies and 16 pancreatic biopsies from patients with insulin dependent diabetes mellitus were studied ultrastructurally. The stages in the development of kidney changes depending on the functional state of Langerhans islands B-cells were established. The 1st stage includes signs of segmentary mesangioproliferative glomerulonephritis- segmentary increase of the mesangium due to the hypercellularity, variability of the basal membrane thickness in the glomeruli capillaries, leucocytes in the lumen, subendothelial deposits. This stage may be due to the persistence of the etiologic factors(virus), formation of circulating immune complexes, antibodies excess and relative preservation of B cells and their function. Thinning of the capillary basal membrane, decrease of the mesangial matrix surface, cell destruction are characteristic for the 2nd stage- stage of the mesangiolysis. The duration of disease up to 15 years has no influence on the formation of glomerulosclerosis. PMID- 7848106 TI - [Diabetic glomerulosclerosis--a prolonged stage of diabetic glomerulopathy]. AB - Formation of diabetic glomerulosclerosis was followed by the electron microscopy of 21 puncture renal biopsy and 12 incisive pancreatic biopsies from patients with insulin-dependent diabetes mellitus. The influence of the B-cell destruction and the decrease or absence of their activity (the presence of serum C-peptide) on the degree of renal damage and clinical symptoms of the diabetic nephropathy (proteinuria, hypertension) is noted. Dynamics of the diabetic glomerulosclerosis formation is as follows: 1st group--thickening of capillary basal membrane in the glomeruli, mesangial ectopy, formation of nodules at the periphery of loops; 2nd group--increase of the mesangial matrix, doubling of the glomerular capillary basal membrane, hyalin droplets in the capsule membrane. 4 stages in the development of diabetic glomerulopathy are distinguished: diabetic segmentary mesangioproliferative glomerulonephritis, mesangiolysis, two stages of glomerulosclerosis progression. Duration of the disease more than 15 years predetermines the development of diabetic glomerulosclerosis. PMID- 7848107 TI - [Possible mechanism of hypothalamic regulation of endocrine pancreatic function in mice of the diabetic strain C57bl/KsJ]. AB - In mice hetero- and homozygotic in relation to the diabetic gene db, it was shown that the regulation of the pancreatic endocrine function by hypothalamus is mediated at least by two mechanisms: neurohumoral one connected with hormone secretion by paraventricular and supraoptical nuclei and by a neuroconductivity mechanism connected with the ventromedial nucleus and lateral hypothalamic area. PMID- 7848108 TI - [Structural-functional features of the large and small bronchi and differences in their inflammatory reactions]. AB - Structural-functional features of bronchi reflect the differences in the inflammation in their walls. This should be taken into consideration by pathologists studying biopsies and by clinicians evaluating lungs roentgenologically and by ultrasound. PMID- 7848109 TI - [Morphofunctional features of the immunocompetent system of harmoniously developed large newborns]. AB - Immune system of 70 large newborns was compared to 50 newborns of an average weight. Large newborns showed domination of lymphopoiesis over epithelioreticulopoiesis in the thymus against the background of the cortical thymocytes apoptosis delay and decrease of the thymus hormonal activity; enhancement of myelopoiesis, T and B-zone hyperplasia in the peripheral organs, decrease of the immunoglobulins production, alteration of T and B-lymphocyte maturation. Inadequate response to the antigenic stimulus is characteristic for large newborns this resulting in a higher susceptibility of these children to bacterial and viral infections and tendency to the allergic conditions during first 9 years of their life. PMID- 7848110 TI - [Diverticula and calculi in acute appendicitis]. AB - 200 appendices surgically removed because of the acute appendicitis were studied. Pseudo-diverticula are found in 42 cases (21%) and only in 3 of them signs of acute inflammation were absent. Diverticulum perforation was observed in 5 cases. In 35 appendices (17%) obturating faecal stones were found. All appendices with stones contained acute destructive alterations. Faecal stones were associated with diverticula in 11 cases and were cause of their development and inflammation. PMID- 7848112 TI - [Malignant fibrous histiocytoma of the heart with metastases to the brain and thyroid gland]. PMID- 7848113 TI - [Is there a need for a pathology specialty with a pediatric profile?]. PMID- 7848111 TI - [Analysis of hospital mortality related to alcoholic intoxication and alcoholism for 1991-1993 (according to autopsy results)]. AB - The conclusion is made about the permanent growth of the percentage of lethal cases connected with alcoholism, particularly in 1993. Among persons dying from alcoholism the percentage of young people and women is increased. Several unusual cases are described. PMID- 7848114 TI - [Fifty years of the Pathology Chair at Yaroslavl Medical Institute (1944-1994)]. PMID- 7848115 TI - [Thrombosis and embolism as paraneoplastic syndrome]. AB - Arterial and venous thrombotic occlusions, migrating thrombophlebitis, pulmonary artery branches embolism, abacterial thrombotic endocarditis, paradoxal hemorrhages, thrombotic microangiography arising in patients with various malignant tumours are understood under hemostasiologic paraneoplastic syndrome. The following factors are at the basis of paraneoplasia pathogenesis: 1) procoagulants synthesis by tumour cells, namely tissue factor and activators of blood coagulation factor X; 2) procoagulant activity of tumour-associated macrophages and their activity in the extra- and intravascular conversion of fibrinogen into fibrin; 3) damage of vascular endothelium by tumour cells and cytokines, for example necrotizing factor of tumours; 4) multifactorial enhancement of thrombocyte aggregational properties. According to the current concepts, such neoplastic phenomena as metastasizing, uncontrolled growth, escaping from immunological control, secondary tumour changes are viewed through the disturbances of hemostasiologic balance. PMID- 7848116 TI - [Position of ocular amyloidosis among various forms of amyloidosis]. AB - New data, concerning incidence, morphology, clinical manifestations of eye amyloidosis are obtained following its study using modern verification methods. Eye amyloidosis is represented either by its local forms or is associated with a generalized amyloidosis. Local eye amyloidosis predominated and may be isolated and combined. Isolated amyloidosis is represented by two variants: with an involvement of the anterior part of the eye in the form of pseudoexfoliative amyloidosis (PEA) and involvement of the posterior part of the eye with the development of senile macular degeneration (SMD). Local amyloidosis may be associated with senile cerebral amyloidosis, insular amyloidosis of pancreas and both. Predominant involvement of the eye vessels and extraocular structures is an important feature of the ocular amyloidosis as a manifestation of generalized forms. Vitreous body is involved mainly in FAP. New clinico-morpho-pathogenetic classification is suggested. PMID- 7848117 TI - Survival in amyotrophic lateral sclerosis. PMID- 7848118 TI - End-stage Alzheimer's disease: Glasgow Coma Scale and the neurologic examination. PMID- 7848119 TI - Migraine and subsequent risk of stroke in the Physicians' Health Study. AB - OBJECTIVE: To evaluate, in a prospective design, whether migraine is an independent risk factor for subsequent stroke. DESIGN: Evaluated as part of the Physicians' Health Study, a randomized, double-blind, placebo-controlled trial of aspirin and beta-carotene in the primary prevention of cardiovascular disease and cancer begun in 1982. The aspirin component of the study was terminated in 1988, with average follow-up of 60.2 months. SETTING: Conducted by mail among male physicians throughout the United States. PARTICIPANTS: A total of 22,071 US male physicians aged 40 to 84 years in 1982 with no prior history of cancer or cardiovascular diseases who were enrolled in the Physicians' Health Study. INTERVENTIONS: Participants were randomized to receive 325 mg of aspirin or aspirin placebo every other day and to receive 50 mg of beta-carotene or placebo on alternate days. MAIN OUTCOME MEASURES: The primary outcomes of the Physicians' Health Study were cardiovascular disease and cancer. Because stroke was a main outcome, this provided the opportunity to evaluate the association between migraine headaches and stroke. RESULTS: Physicians reporting migraine (n = 1479) had significantly increased risks of subsequent total stroke and ischemic stroke compared with those not reporting migraine. After adjustment for age, aspirin and beta-carotene treatment assignment, and a number of cardiovascular risk factors, the relative risks were 1.84 (95% confidence interval, 1.06 to 3.20) for total stroke and 2.00 (95% confidence interval, 1.10 to 3.64) for ischemic stroke. There were too few hemorrhagic strokes in the study to evaluate this end point. No associations were seen between ordinary nonmigraine headache and subsequent stroke or between migraine and subsequent myocardial infarction or cardiovascular death. CONCLUSION: These data raise the possibility that vascular events associated with migraine may also have causative importance in stroke but require confirmation in other studies specifically designed to evaluate this question. PMID- 7848120 TI - Cerebral blood flow during migraine attacks without aura and effect of sumatriptan. AB - OBJECTIVE: To study regional cerebral blood flow (rCBF) during migraine attacks without aura and after treatment with sumatriptan. DESIGN AND INTERVENTION: We performed three technetium Tc99m hexemethyl-propyleneamineoxime single photon emission computed tomography scanning procedures in patients with migraine who participated in a double-blind, placebo-controlled, randomized clinical trial (1) outside an attack, (2) during an attack, and (3) after treatment of the attack with 6 mg of subcutaneous sumatriptan. SETTING: University hospital. PATIENTS: We studied 20 patients with migraine without aura, 15 of whom were evaluated under all three conditions and five of whom were evaluated under only two conditions. OUTCOME MEASURES: The single photon emission computed tomographic images were evaluated semiquantitatively with regard to (1) the degree of asymmetry of the rCBF between the headache side and the nonheadache side and (2) the ratio of the rCBF in regions of interest to the rCBF in two reference areas (cerebellum or frontal cortex). RESULTS: We found no significant rCBF asymmetries outside or during the attack or after treatment with sumatriptan, and there were no significant changes of the rCBF ratios during the attack (compared with outside the attack) or after treatment of the attack (compared with during the attack). CONCLUSION: Migraine attacks without aura and treatment of the attacks with 6 mg of subcutaneous sumatriptan are not associated with detectable focal changes of the rCBF. PMID- 7848121 TI - Idiopathic intracranial hypertension. Lack of histologic evidence for cerebral edema. AB - OBJECTIVE: To study brain histologic features in two cases of idiopathic intracranial hypertension (pseudotumor cerebri) at autopsy. DESIGN: Formaldehyde solution-fixed sections of cerebral white matter in two cases and structures of the sensory visual system in one case were analyzed. SETTING: University medical center. PATIENTS: Two patients with idiopathic intracranial hypertension who died unexpectedly. MAIN OUTCOME MEASURE: Histologic study of cerebral white matter in the two patients. RESULTS: We did not find histologic evidence of any type of cerebral edema in our patients. Review of a portion of the material from a previous report is also consistent with this conclusion. CONCLUSION: If patients with idiopathic intracranial hypertension have histologically apparent cerebral edema, it is not a consistent finding. PMID- 7848122 TI - Clinical correlates of Alzheimer's disease with and without silent radiographic abnormalities. AB - OBJECTIVE: To determine whether patients with Alzheimer's disease (AD) who do not have historical or clinical evidence of stroke but who do have computed tomographic or magnetic resonance imaging evidence of noncortical lesions smaller than 2 cm or periventricular "caps" differ from other patients with AD. METHODS: The computed tomographic or magnetic resonance imaging scans of 158 patients meeting criteria of the National Institute of Neurological Disorders and Stroke Alzheimer's Disease and Related Disorders Association for probable AD were reviewed by one neuroradiologist. Two measures of disease severity--the Modified Mini-Mental State examination and the Blessed Dementia Rating Scale (Part I)- were subjected to two-way analysis of variance with scan type (computed tomography or magnetic resonance imaging) and lesion number as between-group factors and age and disease duration as covariates. RESULTS: No relationship was seen between lesion number or periventricular caps and disease severity. CONCLUSION: In this cross-sectional analysis using these clinical measures, patients with AD who have well-defined radiographic abnormalities cannot be differentiated from patients with AD who do not have them. PMID- 7848123 TI - Electrocardiographic changes in patients with brain tumors. AB - OBJECTIVE: Electrocardiographic (ECG) abnormalities in patients with cerebral tumors involving the limbic system without known organic heart disease. DESIGN: Retrospective survey. SETTING: A university hospital in Berlin, Germany. PATIENTS: From among 169 consecutive patients with brain tumors, 57 patients were excluded on the basis of preexisting cardiac or other diseases and 27 patients were excluded because neuroimaging revealed multiple lesions or suggestive evidence of raised intracranial pressure. MAIN OUTCOME MEASURES: We compared ECG changes in 85 otherwise healthy patients with limbic and extralimbic brain tumors without evidence of increased intracranial pressure. Tumors were localized by magnetic resonance imaging and, in 15 cases, by computed tomography. Categorization of patients into limbic and extralimbic system groups was specified before routine preoperative ECGs were examined and classified by an independent cardiologist. RESULTS: Electrocardiographic changes were found in 40% of all patients. Abnormal ECG results were associated nearly three times more often with tumors located in the limbic system compared with extralimbic locations (72% vs 27%). Prolonged QTc intervals were significantly more frequent in the limbic system group than in the extralimbic group (mean rates, 113.3% vs 103.6%). CONCLUSIONS: Lesions of limbic structures do exert cardioarrhythmogenic effects and may provide an explanation for ECG abnormalities in patients with cerebral tumors. PMID- 7848124 TI - Neuropsychological effects of cranial irradiation in young children with acute lymphoblastic leukemia 9 months after diagnosis. The Children's Cancer Group. AB - STUDY OBJECTIVE: To determine the effects of cranial irradiation on neuropsychological test performance evident 9 months after diagnosis. DESIGN: A companion study to a randomized clinical trial (CCG-105). SETTING: Institutions participating in Childrens Cancer Group cooperative treatment trials. PATIENTS: Seventy-four children aged 3.0 to 6.5 years with average-risk acute lymphoblastic leukemia. Children with central nervous system leukemia at the time of diagnosis, preexisting mental retardation, or Down's syndrome or for whom English was not the primary language were not eligible for study. INTERVENTIONS: Children were randomized to receive treatment with one of four systemic chemotherapy regimens and either intrathecal methotrexate sodium during induction and consolidation plus 18 Gy of cranial irradiation or intrathecal methotrexate during induction, consolidation, and maintenance as central nervous system prophylaxis. MEASUREMENT AND RESULTS: The groups were comparable with regard to chronologic age, sex, and family socioeconomic status. Children who received cranial irradiation plus intrathecal methotrexate scored significantly lower on the McCarthy Motor Scale (P < .05) and the Token Test (P < .05) than children who received intrathecal methotrexate alone. The groups did not differ significantly on the McCarthy General Cognitive Index, Developmental Test of Visual Motor Integration, or Peabody Picture Vocabulary Test-Revised. CONCLUSIONS: Findings suggest that the combined effects of cranial irradiation and intrathecal methotrexate therapy on neuropsychological performance may be evident in young children as early as 9 months after diagnosis. Follow-up assessment of these children will reveal whether these effects remain constant, intensify, or resolve. PMID- 7848125 TI - Concurrent cisplatin therapy and iodine 125 brachytherapy for recurrent malignant brain tumors. AB - OBJECTIVE: Toxicity and safety study of concurrent cisplatin therapy and iodine 125 (125I) brachytherapy. BACKGROUND: Iodine 125 brachytherapy has an established role in surgically accessible recurrent tumors of brain. Cisplatin has antitumoral activity against glial neoplasms and has demonstrated sensitization of tumor to radiotherapy. DESIGN/METHODS: In 16 patients (age range, 13 to 68 years, median, 47 years), stereotactically placed catheters were afterloaded with 125I sources. A median 50-Gy minimum treatment volume dose was delivered during a 100-hour period along with cisplatin (20 mg/m2 per day for 5 days). Histologic diagnoses included glioblastoma multiforme (n = 11), anaplastic astrocytoma (n = 3), ependymoma (n = 1), and anaplastic oligodendroglioma (n = 1). Tumor volumes ranged from 7.0 to 73 cm3 (median, 25 cm3). RESULTS: Early complications included headache (n = 7), transient exacerbations of preexisting neurologic deficits (n = 5), seizures (n = 3), and nausea/vomiting (n = 3). Late complications included steroid dependency (n = 10), progressive dementia in the absence of recurrent tumor (n = 1), and radiation-induced necrosis (n = 9) requiring reoperation (n = 9). Fifteen of 16 patients were assessable, with a median follow-up time of 9.5 months. Brachytherapy was discontinued in one patient owing to an acute subdural hematoma. A partial response was seen in five patients, disease remained stable in seven patients, and disease progressed in three patients. CONCLUSIONS: We conclude that 125I brachytherapy with concurrent cisplatin therapy is associated with an acceptable level of toxic effects and warrants further investigation. PMID- 7848126 TI - Cognitive impairment in early-onset multiple sclerosis. Pattern, predictors, and impact on everyday life in a 4-year follow-up. AB - OBJECTIVES: To assess the evolution of cognitive dysfunction in early-onset multiple sclerosis, to identify clinical predictors of mental decline, and to determine its impact on a patient's everyday life. DESIGN: The cognitive performance of 50 patients with multiple sclerosis on a neuropsychological battery was compared with that of 70 control subjects initially and again after a 4-year interval. Clinical predictors of cognitive impairment and its effect on daily life were analyzed by stepwise linear regression. SETTING: The research clinic of a university department of neurology. PARTICIPANTS: A consecutive sample of 50 inpatients and outpatients with multiple sclerosis (mean disease duration, 1.58 years) and 70 demographically matched healthy control subjects selected from the patients' relatives and friends. MAIN OUTCOME MEASURES: Mean psychometric test scores of both groups at the initial and follow-up testing. Regression coefficients measuring the relationship between clinical parameters and cognitive capacity and between mental decline and performance of common tasks measured by the Environmental and the Incapacity Status scales. RESULTS: Multiple sclerosis-related deficits in verbal memory and abstract reasoning on initial testing remained more or less stable on the retest, at which time linguistic disturbances on the Set and Token tests also emerged. A patient's initial disability level predicted decreased performance on only four of 13 cognitive variables, and disease duration did so on only two. Extent of intellectual decline on initial testing, initial disability level, and progressive course were independent determinants of handicap in a patient's work and social activities. CONCLUSIONS: Cognitive and neurological deficits appear not to develop in parallel. Yet cognitive dysfunction proves to be a predictor of handicap in everyday life, even in patients in the incipient phase of multiple sclerosis. PMID- 7848127 TI - Tailored anterior temporal lobectomy. Relation between extent of resection of mesial structures and postsurgical seizure outcome. AB - OBJECTIVE: The purpose of this study was to assess the relationship between the extent of resection of mesial temporal structures and postsurgical seizure outcome in a group of patients who had undergone a tailored anterior temporal lobectomy. METHODS: Twenty-four patients with unilateral interictal and ictal foci restricted to anterior/mesial temporal regions underwent resection of mesial and temporal lateral structures, the extent of which was tailored by intraoperative electrocorticographic findings and functional mapping of eloquent cortex. The extent of resection was determined with postoperative magnetic resonance imaging scans, using a semiquantitative method, based on a 20 compartment model of the temporal lobe. The magnetic resonance imaging scans were rated by three investigators blinded to seizure outcome. Follow-up period ranged between 18 months and 5 years. RESULTS: Amygdala and hippocampus were spared in six patients; nine patients had a partial to total resection of amygdala, eight patients had a resection of amygdala and the anterior third of the hippocampus, and one patient underwent resection of amygdala and anterior two thirds of hippocampus. Twenty-one of the 24 patients were seizure free (Engel's class I) and three had rare seizures (Engel's class II). Among these three patients, one had a resection of amygdala; one had resection of amygdala and anterior third of hippocampus; while in the third patient, mesial structures were spared. CONCLUSION: These data suggest that in patients with an anterotemporal seizure focus, the sparing or limited resection of amygdala and/or hippocampus is not necessarily associated with a poor seizure outcome, as had been previously suggested, provided that the decision not to resect is based on the absence of epileptiform activity during intraoperative electrocorticography or during recordings with depth electrodes. PMID- 7848129 TI - Long-term prognosis of poststroke aphasia studied with positron emission tomography. AB - OBJECTIVE: To evaluate positron emission tomography with the use of fludeoxyglucose F 18 as a predictor of the long-term outcome of poststroke aphasia. BACKGROUND: Positron emission tomography shows functional deficits after stroke even in morphologically intact brain regions. The regional metabolic impairment can be related to the clinical deficit. Little is known about whether regional hypometabolism early after stroke predicts the long-term prognosis of stroke sequelae. PATIENTS AND METHODS: Twenty-two patients with language disturbance caused by a single lesion in the territory of the left middle cerebral artery were studied with fludeoxyglucose positron emission tomography and with a neuropsychological test battery that included a test of receptive language (Token Test) and a test of word fluency (/f/, /a/, /s/ test). The neuropsychological test was readministered about 2 years after the initial test. RESULTS: Regional cerebral metabolic rates of glucose measured early after stroke showed a highly significant correlation with the results of the 2-year follow-up test. The receptive language disorder best correlated with cerebral metabolic rates of glucose in the left superior temporal cortex, and word fluency correlated with cerebral metabolic rates of glucose in the left prefrontal cortex. CONCLUSION: Cerebral metabolic rates of glucose in speech-relevant brain regions measured early after stroke are a predictor of the eventual outcome of aphasia. PMID- 7848130 TI - White matter hyperintensities in Parkinson's disease. Clinical correlations. AB - OBJECTIVES: To verify recent preliminary data indicating that white matter hyperintensities on magnetic resonance imaging are more abundant in patients with Parkinson's disease (PD) than in healthy subjects and to examine possible correlation between these abnormalities and clinical features of PD. DESIGN: Magnetic resonance imaging data on patients with PD and normal subjects were compared as to frequency, extent, and topographic location of white matter hyperintensities; moreover, in the PD group, we studied the possible correlation of white matter hyperintensities with clinical features such as severity, disease duration, and therapy. SETTING: The outpatient clinic of the Institute of Clinical Neurology and the Neuroradiology Unit of the University of Pisa (Italy). PATIENTS: We studied 102 nondemented patients with idiopathic PD and 68 sex- and age-matched healthy controls, all screened for absence of cerebrovascular risk factors. OUTCOME MEASURES: White matter hyperintensities were classified as periventricular hyperintensities and deep hyperintensities. Frequency, extent, and topographic location of both periventricular and deep hyperintensities were evaluated. The clinical parameters examined were disease duration, treatment type, and disease severity (using Hoehn and Yahr staging and the Unified Parkinson's Disease Rating Scale), as well as disease progression index (ratio between Hoehn and Yahr stage and disease duration). RESULTS: The frequency and the extent of periventricular hyperintensities were significantly higher in patients with PD than in healthy subjects. Moreover, within the PD group, the patients who had periventricular hyperintensities had significantly shorter disease duration and greater disease severity, ie, a higher disease progression index, than those who did not. CONCLUSION: These data suggest that periventricular hyperintensities may represent a marker for a clinical subtype of PD characterized by a more rapid neurodegenerative process. PMID- 7848128 TI - Clinical/metabolic correlations in multiple system atrophy. A fludeoxyglucose F 18 positron emission tomographic study. AB - OBJECTIVE: To evaluate the regional cerebral metabolic involvement; the relationships among regional brain metabolism, clinical features, and quantitative measures of disease severity; and the patterns of brain involvement that can be related to the different types of onset: striatonigral degeneration vs olivopontocerebellar atrophy. DESIGN: Fludeoxyglucose F 18 positron emission tomography (PET) studies performed in patients with multiple system atrophy (MSA) were evaluated for their clinical features at the onset of the disease and at the time of the PET study. CASES: Seventeen patients diagnosed as having probable MSA and 10 age-matched controls. RESULTS: The hypometabolism in the putamen-pallidum complex and in the cerebellum was the best discriminant for disease classification. The efficacy of levodopa treatment was positively correlated with the metabolic activity of the putamen-pallidum complex. The patients with olivopontocerebellar atrophy type (N = 8) had a prevalent hypometabolism in the cerebellum, while the patients with striatonigral degeneration type (N = 9) had a prevalent impairment in the pallidum-putamen complex. We demonstrated a negative correlation between (1) severity of parkinsonism and metabolic values of putamen and caudate; (2) severity of cerebellar signs and metabolism in the cerebellum; and (3) autonomic dysfunction and metabolic activity in the thalamus, frontal, and temporal regions, bilaterally. CONCLUSIONS: These findings support the selective metabolic reduction in the putamen and cerebellum as a marker of MSA. The clinical/metabolic correlations, demonstrating the expected dependence of extrapyramidal and cerebellar signs by dysfunction of basal ganglia and cerebellum, also support a possible involvement of central nervous system structures in autonomic control. PMID- 7848132 TI - Psychiatric classification of nonconversion nonepileptic seizures. AB - OBJECTIVE: To determine the frequency and type of non-conversion nonepileptic seizures (NES). BACKGROUND: Although conversion disorder is the most common psychiatric disorder among patients with NES, many patients with nonepileptic paroxysmal behavioral events have other psychiatric disorders, with natural histories and treatments different from those of conversion disorder. DESIGN: Retrospective review of a series of consecutive admissions for video electroencephalography monitoring. All patients identified with NES were interviewed by a psychiatrist. Patients with conversion and other psychiatric disorders were divided into separate groups. SETTING: A comprehensive epilepsy center. RESULTS: Twenty-one patients evaluated for possible epileptic seizures had a psychiatric disorder other than conversion that accounted for their events. Among these patients, Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition (DSM-III-R) anxiety disorders (n = 9) were the most common diagnosed category, followed by all forms of psychotic disorders (n = 7) and impulse control problems in the setting of attention deficit disorder residual type (n = 2). In contrast to 71 patients with conversion NES seen over the same period of time, the non-conversion group showed no female predominance and the nonconversion patients were significantly less likely than the conversion patients to have been physically or sexually abused in childhood or adolescence. CONCLUSIONS: These results support the validity of the nosologic distinction of nonconversion from conversion NES and suggest that DSM-III-R anxiety disorders are an important diagnostic confound in clinical epilepsy. PMID- 7848131 TI - Plasma cobalamin levels affect information processing speed in a longitudinal study of HIV-1 disease. AB - OBJECTIVE: To determine whether information processing speed is influenced by change in plasma cobalamin status in human immunodeficiency virus type 1 disease. DESIGN: A longitudinal study, using autoregression, to evaluate the relationship between plasma cobalamin status and change in information processing speed assessed by Posner Letter Matching, Sternberg Short-Term Memory Search, Figure Visual Scanning and Discrimination of Pictures, and continuous paired associates learning tasks. SETTING: University of Miami (Fla) School of Medicine from fall 1987 through summer 1991. PARTICIPANTS: Eighty-four human immunodeficiency virus type 1-infected homosexual men aged 20 to 55 years. None of the subjects displayed acquired immunodeficiency syndrome-defining symptoms at baseline; over the course of the study, 9.5% progressed to acquired immunodeficiency syndrome. MAIN OUTCOME MEASURES: Biochemical measurement of plasma cobalamin; performance on information processing speed tasks. RESULTS: Significant improvement in the Posner Letter Matching NI-PI (Name Identity minus Physical Identity) differential was associated with becoming cobalamin adequate or remaining adequate. Becoming cobalamin deficient, in contrast, was associated with a significant decline in the speed of accessing overlearned name codes. CONCLUSION: Normalization of plasma cobalamin inadequacy in human immunodeficiency virus type 1 disease may provide significant improvement in the speed of retrieving overlearned information from long-term memory. PMID- 7848133 TI - Subarachnoid hemorrhage and family history. A population-based case-control study. AB - OBJECTIVE: To evaluate family history as a risk factor for subarachnoid hemorrhage. DESIGN AND SETTING: A population-based case-control study in King County, Washington. SUBJECTS: Cases consisted of 149 patients with spontaneous subarachnoid hemorrhage. Two control subjects who were matched to cases by gender and age within 5 years were identified for each case using random digit telephone dialing. MAIN MEASURE: Detailed information on family history was obtained through an in-person interview. RESULTS: Some 11.4% of cases had a first-degree relative with a history of subarachnoid hemorrhage, compared with 6.4% of controls, yielding an odds ratio of 1.8 (95% CI, 0.92 to 3.7). The odds ratio for a positive family history among other relatives was 2.4 (95% CI, 1.1 to 5.2), likely reflecting family information bias. Findings were similar after adjustment was made for potential confounding variables, including cigarette smoking, a history of hypertension, and number of siblings and children. CONCLUSION: Although familial factors may be important in some families, overall they account for few cases of subarachnoid hemorrhage. PMID- 7848134 TI - Neurology should not become a consulting specialty. PMID- 7848135 TI - Neurology as a consulting specialty. PMID- 7848136 TI - Neurology. Increasing quantity or quality? PMID- 7848137 TI - The neuropathology of Williams syndrome. Report of a 35-year-old man with presenile beta/A4 amyloid plaques and neurofibrillary tangles. AB - OBJECTIVE: To study neuropathologically Williams syndrome in a 35-year-old patient. METHODS: Sections from multiple regions of the brain were examined with luxol fast blue and hematoxylineosin staining, and selected sections were stained with the silver impregnation technique (Bielschowsky technique) and Congo red. In addition, immunohistochemistry with monoclonal antibodies against glial fibrillary acidic protein, beta/A4 amyloid, paired helical filaments, and phosphorylated tau protein was performed on cortical, hippocampal, amygdaloid, and basal ganglian sections. RESULTS: No specific macroscopic or microscopic abnormalities were recognized that are specific for Williams syndrome. The histopathologic examination did, however, demonstrate the presence of Alzheimer type changes, including beta/A4 amyloid-containing senile plaques and scattered neurofibrillary tangles in neocortex and medial temporal lobe structures (entorhinal cortex, CA1 area of the hippocampus, and amygdala). Plaques were most numerous in the amygdala (7/mm2) and in the entorhinal cortex (4/mm2). Neurofibrillary tangles were less numerous (< 1/mm2), except in the hippocampus, where approximately 2/mm2 were found. CONCLUSIONS: To our knowledge, ours represents the first neuropathologic description of a patient with Williams syndrome. Although Williams syndrome is usually sporadic, familial cases have been reported along with candidate chromosomal loci. If our findings are confirmed in additional patients with Williams syndrome, they may provide clues to other factors that are important in the pathogenesis of senile plaques (with beta/A4 amyloid deposition) and neurofibrillary tangles. PMID- 7848138 TI - What's happened to the tradition of Hippocrates? PMID- 7848139 TI - Generic substitution of pharmaceuticals. PMID- 7848140 TI - Treatment of chronic non malignant pain in general practice. AB - The chronic pain patient can represent a daunting challenge to even the most experienced general practitioner. This article aims to describe the complex nature of such patients and to suggest some guidelines for their management. PMID- 7848142 TI - Neural blockade in chronic pain. AB - Neuroblockade techniques can serve many functions in the management of the chronic pain patient. These various functions are discussed and a brief insight given for their use in specific pain syndromes. A run-down of the type of blocks useful in the management of cancer pain is also given. PMID- 7848141 TI - A behavioural approach to the management of chronic pain. A self management perspective. AB - Both patient and doctor can influence the outcome significantly by their behaviour. Tables 3 and 4 summarise the behaviours that will support the healing process, recovery of a more normal lifestyle, and long-term pain relief. Finally, the power of beliefs cannot be overestimated. The patients who do best are those who develop positive attitudes. The treating doctor can become skilled at identifying the limiting beliefs and assist the person in pain to change their perceptions and actions. Table 5 provides some examples. The most difficult patient can become the most rewarding. PMID- 7848143 TI - Post whiplash syndrome. AB - Whiplash is a poorly understood problem that attracts accusations of malingering and compensation neurosis. Recent research has revealed a variety of occult lesions that can be responsible for the chronic pain and suffering after whiplash; however, appropriate diagnostic techniques are still either lacking or not widely used. While there are reasonable options for acute management there is no proven therapy for the chronic situation. PMID- 7848144 TI - Failed back surgery syndrome. AB - Patient selection for repeated spinal surgery is not uniform and must be further refined. A multidisciplinary approach with careful evaluation of physical, psychological and environmental factors is ideal. Improved imaging should delineate disorders more clearly, and advances in surgical technique may improve outcome. It is likely, however, that a number of patients will continue to require long-term pain management. PMID- 7848145 TI - Management of chronic orofacial pain. AB - The diagnosis and management of chronic orofacial pain can be difficult due to the multifactorial nature of the problem involving organic, psychological and social and cultural variables. The establishment of multidisciplinary pain clinics can assist the medical practitioner in both diagnosis and treatment. A review of 185 patients complaining of chronic orofacial pain is presented to show the main conditions diagnosed at a pain clinic. PMID- 7848146 TI - Management of angina. AB - The management of angina is determined by a number of factors including the pattern and frequency of angina, associated medical problems, the patient's age, and the results of further investigations both non invasive and invasive. Most cases occur on the basis of obstructive coronary artery disease. Aspirin has been shown to reduce the risk of myocardial infarction and may reduce mortality rates in these patients. Other therapies are aimed at symptomatic control, these including nitrates, beta-blockers, and calcium antagonists. In patients with suitable anatomy and persisting symptoms despite medical therapy, revascularisation is effective. In certain instances such as significant left main coronary artery disease, and three-vessel coronary artery disease with impaired left ventricular function, coronary artery bypass surgery has both symptomatic and prognostic benefit. Of utmost importance for these patients is to further asses their general lifestyle and risk factors for the development of coronary artery disease and make appropriate modifications. PMID- 7848147 TI - Quality control and quality assurance in the office laboratory. PMID- 7848148 TI - Continuities. PMID- 7848149 TI - Case of recurrent boils. PMID- 7848150 TI - Prescription drugs: the problems with substitutions. PMID- 7848151 TI - HIV drug mislabelled. PMID- 7848152 TI - Risk regions for Japanese encephalitis. PMID- 7848153 TI - Suspected child abuse. PMID- 7848154 TI - Practice tip. Multiple ragged lacerations. PMID- 7848155 TI - Peak flow monitoring--which asthmatics, when and how? PMID- 7848156 TI - Peak expiratory flow meters (PEFMs)--who uses them and how and does education affect the pattern of utilisation? AB - BACKGROUND: Asthma control may be assisted by educating patients to use peak expiratory flow meters (PEFMs). AIMS: To find out the sociodemographic and clinical characteristics of asthmatics attending an Emergency Room (ER) who owned PEFMs. METHODS: We undertook a study of 352 asthmatics aged seven to 55 years who attended an ER. The following were analysed: their pattern of peak flow monitoring (PFM), the factors associated with 'appropriate' or daily PFM on entry to the study and then prospectively; whether asthma education influenced utilisation and whether there was a reduction in ER use or admissions in those who acquired a PEFM. RESULTS: Those owning a PEFM at entry to the study (54%) had more asthma morbidity (p = 0.0001), had had asthma for longer (p = 0.0001), had seen their medical practitioners more often in the previous nine months (p = 0.0001), were on more asthma medications (p = 0.0001) and were more likely to have been to an Asthma Clinic (p = 0.0001). Those not owning a PEFM were more likely to be of lower social class (p = 0.016) and of Pacific Island origin (p = 0.0001) suggesting that distribution is not ideal and is influenced by disease severity, amount of health care use and sociodemographics. Patients with a self management plan (35% of PEFM owners) and those receiving 'good care' or management, were more likely to use PFM 'appropriately' and to mention PFM in a scenario evaluating their response to worsening asthma control and argues for PEFMs to be distributed only in conjunction with a self-management plan, and therefore in close association with the patients' medical practitioners. Most patients (75%) appeared to prefer making management decisions based on symptoms rather than on their peak expiratory flow (PEF) and few (16%) performed daily PFM at entry to the study and fewer (6%) nine months later. There was an improvement in the pattern of PFM after education, but the acquisition of a PEFM made no difference to the frequency of ER use or admission. CONCLUSION: More realistic goals need to be defined in relationship to PFM which may improve patients' acceptance of the strategy, and therefore, hopefully their compliance. Such strategies need to be consistently reinforced over time for them to have an impact on asthma morbidity. PMID- 7848157 TI - Doppler echocardiography and the early diagnosis of carditis in acute rheumatic fever. AB - BACKGROUND: The incidence of acute rheumatic fever in New Zealand remains relatively high. Reliable early diagnosis of carditis is difficult and important in management. AIM: To determine if Doppler echocardiography contributed to the early diagnosis of carditis in acute rheumatic fever. METHODS: Forty-seven patients admitted to hospital with suspected acute rheumatic fever and 19 control patients, with a febrile illness due to a documented non-cardiac bacterial infection, were assessed two days and two weeks following admission. Presence or absence of clinical carditis was determined by a cardiologist unaware of the suspected diagnosis, from clinical examination, chest radiograph, electrocardiogram (ECG) and two dimensional echocardiogram. Doppler echocardiography was then performed and interpreted by a second cardiologist unaware of the diagnosis. After completion of the study the Jones criteria were applied, to categorise the patients with suspected acute rheumatic fever into four groups for the final diagnosis: no acute rheumatic fever, possible acute rheumatic fever, definite acute rheumatic fever without carditis, and definite acute rheumatic fever with carditis. RESULTS: In 19 patients with a final diagnosis of acute rheumatic fever and carditis at the baseline assessment carditis was detected by clinical assessment in 15 patients, compared with 19 patients with evidence of significant valve regurgitation by Doppler echocardiography. Following the two week assessment, all 19 patients had both clinical and Doppler evidence of carditis. Five patients with a final clinical diagnosis of possible acute rheumatic fever or definite acute rheumatic fever without carditis, had a Doppler abnormality detected. There was no clinical or Doppler abnormality in the febrile controls. CONCLUSIONS: Doppler echocardiography is more sensitive than clinical assessment in the detection of carditis in acute rheumatic fever, and can contribute to earlier diagnosis. PMID- 7848158 TI - Volumetric and visual assessment of the mesial temporal structures in Alzheimer's disease. AB - BACKGROUND: Alzheimer's disease is the commonest cause of dementia. Clinical diagnosis of Alzheimer's disease may be difficult. Magnetic resonance imaging has a role to play in diagnosis. AIM: To assess whether volumetric and/or visual assessment of the mesial temporal structures is useful in separating patients with Alzheimer's disease from age matched controls. METHODS: Twenty-four patients with Alzheimer's disease diagnosed by NINCDS/ADRDA criteria and 15 age matched controls were studied with magnetic resonance imaging (MRI) and volumetric techniques. Segmented volumes of the mesial temporal structures were assessed visually and volumetrically. RESULTS: Volumetric analysis demonstrated significant (p < .001) differences between the two groups, but showed overlap in individual cases. Discriminant function analysis predicted correct group membership (patient or control) in 85% of cases. Visual assessment alone demonstrated a sensitivity of 92% and a specificity of 93% in distinguishing the Alzheimer patients from controls. CONCLUSION: Volumetric and visual assessment of the mesial temporal structures is useful in separating Alzheimer patients from controls. Overlap is present in individual cases. Visual assessment was as useful in separating the two groups as the volumetric analysis. PMID- 7848159 TI - Simultaneous transplantation of the heart and kidney. AB - BACKGROUND: Multiple organ transplants have become frequent. Combined heart-and kidney grafting has been reported recently and we have pursued this in selected cases. AIMS: To devise a protocol for simultaneous heart-and-kidney transplantation, review our clinical experience with the procedure and the causes of cardiac and renal disease in this group. METHODS: Seven patients with advanced cardiac failure (LV ejection fraction < 0.29 units; five with IDCM), and chronic renal failure (serum creatinine > 375 mumol/L) due to a variety of causes, were accepted for combined heart-and-kidney transplantation. Four males, of mean age 33 years, underwent the procedure. Each received his organs from a single cadaveric donor with ABO blood group compatibility and a negative 'current' lymphocytotoxic cross-match, but without regard to HLA-antigen matching. Cardiac ischaemic time averaged 3 hours 40 minutes, the renal first warm time was 0 minutes in all cases, and renal cold and second warm ischaemic times averaged 5 hours 17 minutes and 52 minutes respectively. The heart was grafted first and the kidney second in a procedure which averaged seven hours. Immunosuppression was achieved by induction with antithymocyte globulin, thence steroids, azathioprine and cyclosporin A. RESULTS: No patient required post-operative dialysis. One patient had early urological complications requiring operative correction, but no serious opportunistic infections were observed. Early cardiac rejection on biopsy (ISHT grade 3a) was seen in three patients at four-ten weeks and responded promptly to increased steroids, but severe steroid-resistant rejection of both heart and kidney contemporaneously occurred in one of these three at 19 months and required a course of muromonab-CD3. All four patients developed hypertension. Mean creatinine clearance was 1.23 +/- 0.22 mL/second (74 +/- 13 mL/minute) at last follow-up. All four recipients were alive, well and rehabilitated 5, 20, 28 and 35 months after grafting. Two patients died while waiting for the double procedure and another patient eventually died after being taken off the dual waiting list and receiving a renal transplant only. CONCLUSIONS: In experienced hands, combined heart-and-kidney transplantation is feasible and offers a compelling therapeutic solution in the treatment of advanced cardiac and renal failure. IDCM is a frequent cause of the heart failure in this group. PMID- 7848160 TI - Low serum cholesterol is not associated with depression in the elderly: data from an Australian community study. AB - BACKGROUND: Low serum cholesterol may contribute to depressive symptoms in the elderly. AIMS: To test the relationship between depressive symptoms and low serum cholesterol in an elderly cohort. METHODS: This was an examination of cross sectional data in a community study of 1237 men and 1568 women aged 60+ years in Dubbo, NSW. Quintiles of serum cholesterol were defined for men and women. The Center for Epidemiological Studies Depression Scale was used as a continuous, dependent variable in multiple regression analyses. RESULTS: Low serum cholesterol was not associated with depressive symptoms in older men or women. Health status, measured by poorer self-ratings, recent hospitalisation, higher disability levels and higher consumption of prescribed and self-prescribed drugs, predicted depressive symptoms. As well, the significance in the statistical model of financial difficulties, low self esteem, low feelings of self efficacy, the adequacy of practical help and emotional support, and recent widowhood, confirmed the importance of social origins of depressive symptoms. PMID- 7848161 TI - The boundaryless hospital. PMID- 7848162 TI - Rheumatic complications of influenza vaccination. PMID- 7848163 TI - Precipitated insulin: a potentially life-threatening problem. PMID- 7848164 TI - Meningococcal purpura fulminans treated with antithrombin III concentrate: what is the optimal replacement therapy? PMID- 7848165 TI - Thrombolysis and previous aortic surgery. PMID- 7848166 TI - Omeprazole induced acute interstitial nephritis. PMID- 7848167 TI - Early onset of coronary heart disease is associated with apo AI-CIII SstI polymorphism. PMID- 7848168 TI - Mononeuritis multiplex complicating Henoch-Schonlein purpura. PMID- 7848169 TI - Haemophilus paraphrophilus--an unusual cause of endocarditis. PMID- 7848170 TI - Codeine induced rhabdomyolysis. PMID- 7848171 TI - Paroxysmal cerebellar ataxia: use of phenytoin as a provocation test. PMID- 7848172 TI - Thromboembolic complications after pharmacologic cardioversion of atrial fibrillation. PMID- 7848173 TI - The use of clozapine in Parkinson's disease. PMID- 7848174 TI - Radiofrequency catheter ablation of atrioventricular junction. PMID- 7848175 TI - Screening for genetic haemochromatosis in a rheumatology clinic. PMID- 7848176 TI - Acute confusion, Chinese herbal medicines and tuberculous meningitis. PMID- 7848177 TI - Diet and periodontal disease in dogs and cats. AB - A review of relevant literature was undertaken because of concerns about a possible relationship between pet foods, development of periodontal disease, and secondary adverse effects on general health. It was concluded that, while changes in feeding methods in recent decades have arguably improved pet health by reducing or preventing diseases associated with nutritional deficiencies and excesses, periodontal disease remains a serious, diet-related problem. There is reasonable evidence that soft diets are associated with increased frequency and severity of periodontal disease, and that harder foods requiring vigorous prehension and mastication are preferable for dogs and cats. While it is plausible that periodontal disease could cause diseases in other organs and tissues, the evidence for this is limited at present. Further research is needed to better define the relationship between diet types and oral health. In the meantime, veterinarians and pet owners should pay attention to the physical qualities (textures, abrasiveness, 'chewiness') of foods they provide for dogs and cats, as well as to their nutrient content, and should consider additional methods to control plaque and prevent periodontal disease where necessary. PMID- 7848178 TI - Osteochondral fragmentation of the plantar/palmar proximal aspect of the proximal phalanx in racing horses. AB - The clinical presentation and outcome of treatment is presented for 26 cases of osteochondral fragmentation of the plantar/palmar proximal aspect of the proximal phalanx. Twenty-three were racing Standardbreds and three were racing Thoroughbreds. The most common reason for presentation was an inability to run straight at high speed. Only eight horses presented for lameness, although on examination 19 were lame. A positive flexion test was recorded in 90% of affected fetlock joints and effusion in 48%. Arthroscopic fragment removal was performed on 23 occasions in 21 horses and arthrotomy in one horse. Of the 16 horses that had returned to racing, 12 had improved their performance, while three showed no improvement, and one was retired for other reasons. In three horses refragmentation occurred after surgery, two of which had improved after initial arthroscopic removal. Degenerative changes within the fetlock joint were detected at surgery in eight horses. Of the four horses treated conservatively, one returned to its previous level of performance temporarily after intra-articular medication, one showed no improvement and two were still resting. Plantar/palmar osteochondral fragmentation of the proximal aspect of the first phalanx is a common cause of low-grade lameness in racing horses, and arthroscopic removal results in improvement in race performance in a high percentage of cases. PMID- 7848179 TI - Diagnosis and management of food allergy and intolerance in dogs and cats. AB - This paper reviews food allergy and intolerance in dogs and cats. Adverse reactions to ingested food components can affect many systems and can produce signs involving the skin, gastrointestinal tract, respiratory tract and central nervous system, and these clinical signs are reviewed. Most basic food ingredients have the potential to induce an allergic response, although most reactions are caused by proteins. In particular, dogs and cats can become sensitive to cow's milk, beef, fish or cereal. Food allergy and intolerance is rare in dogs and cats, although the incidence in practice is difficult to establish. Clinical signs are quite variable, depending on the individual response, although the major clinical sign is pruritus. Diagnosis can be difficult, as there is no single test available to help the clinician to confirm or refute the presence of food sensitivity. Diagnosis is based on dietary investigation in the form of elimination diets and test meals. Elimination diets for dogs include lamb, chicken, rabbit, horse meat and fish as sources of protein, with rice or potatoes. Successful elimination diets for cats include lamb, chicken, rabbit or venison, with rice. Improvement in clinical signs while on the elimination diet is suggestive of food allergy. The diagnosis should be confirmed by feeding the original diet, with the development of clinical signs within 7 to 14 days of feeding. PMID- 7848180 TI - Feline lower urinary tract disease: dietary considerations. PMID- 7848182 TI - Nutritional support of hospitalised dogs and cats. AB - Nutritional support of hospitalised dogs and cats improves recovery from illness, reduces mortality, and improves responses to trauma and stress. The primary goal of nutritional support is to prevent use of tissue protein. This is accomplished by the provision of sufficient calories and dietary protein in optimal proportions. For nutritional support, calorie intake is adjusted according to the patient's metabolic rate so that the animal may be fed above or below its usual intake. Nutritional support should always be started gradually, no matter what the final calorie goal may be. For many sick dogs fed enterally, diets proved about 30% of calories from fat and at least 27% of calories from protein. Carbohydrates in nutritional support diets should not include maize, wheat or, especially, soy. Sick cats fed enterally should receive at least 30% of calories from both fat and protein. PMID- 7848183 TI - Clinical nutrition of exotic pets. AB - Successful nutritional management requires knowledge of the natural history of exotic pets, nutrient contents of foods, and roles of water, calories, and nutrients in optimal health. Unestablished dietary requirements, lack of balanced commercial diets and mismanagement by owners cause nutritional problems that affect health and recovery from illness and trauma. When presented with a sick exotic pet, veterinarians should check for provision of appropriate wholesome water and food in optimal amounts. Malnutrition and dehydration are common in exotic pets and often result from mismanagement. Starvation is common in carnivores eating whole vertebrate prey, whereas specific nutrient deficiencies are more common in herbivores and insectivores. The more common nutritional deficiencies are calcium and vitamin D3, vitamin A, thiamin, and vitamin E. When treating sick exotic pets, nutrition and fluid support may be critical to recovery. PMID- 7848181 TI - Dietary management of renal senescence and failure in dogs. AB - The need for dietary management of renal senescence and the beginning of chronic renal failure should be evaluated in all middle-aged dogs. One survey found that 35% were overweight and 10% underweight; another that 25% were mildly azotaemic, with 5% showing slight clinical signs of chronic renal failure. Dogs in prime condition or overweight are candidates for a diet low in energy (for example 3.0 3.3 kcal/g dry matter, DM), but thin dogs need a higher caloric density (such as 4.0-4.5 kcal/g DM). Healthy older dogs need higher dietary protein than the minimum for maintenance (about 20% on a metabolisable energy basis, ME) of young mature dogs. Thin older dogs showing signs of renal insufficiency may benefit from moderate protein and near-minimal phosphorus in the diet. In dogs with chronic renal failure, clinical, haematological and biochemical responses to the combination of low protein (13-16% ME) and low phosphorus (0.4% DM) were positive in one clinical trial but not in three others. Only beneficial responses, such as less proteinuria, less renal impairment and lower mortality, have been reported for diets containing low phosphorus and moderate protein (20-31% ME). Individual dietary goals for energy, protein and phosphorus should be chosen for each middle aged or older dog; these goals may be met by a single product or mixtures of products. PMID- 7848184 TI - The potential for dietary polyunsaturated fatty acids in domestic animals. AB - The metabolism and clinical potential for dietary polyunsaturated fatty acids (PUFAs) modifications using oil supplements containing n-3 and n-6 fatty acids are reviewed. Their use in such disorders as renal disease, inflammatory and immune-related disorders, and dermatological conditions in dogs and cats is discussed. The influence of n-3 fatty acid-rich rations on the endotoxin response in horses is described. Progress has been made toward understanding the clinical potential for PUFAs in these species. However, they have not yet been shown to be efficacious in any of the conditions investigated. PMID- 7848185 TI - Use of goose red blood cells for detection of infection with psittacine beak and feather disease virus by haemagglutination and haemagglutination inhibition. PMID- 7848186 TI - Serogroups of Australian isolates of Serpulina hyodysenteriae. PMID- 7848187 TI - Prevalence of virulent footrot in sheep flocks in southern New South Wales. PMID- 7848188 TI - Cilia-associated respiratory bacillus infection in laboratory rats with chronic respiratory disease. PMID- 7848189 TI - Circoviridae: new viruses of pigs, parrots and chickens. PMID- 7848190 TI - RPS 'Opus Meum'. 1968-1993. Jubilee symposium for Professor Rodney P. Shearman. Sydney, 29 September-3 October 1993. Proceedings. PMID- 7848191 TI - Tribute to Rodney P. Shearman scientific obstetrics, past and future. PMID- 7848192 TI - Placental function. PMID- 7848193 TI - Fetal lung maturation. PMID- 7848194 TI - Autoimmune disease and pregnancy. AB - Autoimmune diseases are relatively common in women, and tend to occur in the childbearing years. These disorders fall broadly into two groups: (i) Multisystem diseases such as systemic lupus erythematosus (SLE) and related connective tissue disorders (CTD). This group includes the 'pre-clinical' antiphospholipid or lupus obstetric syndrome which may first manifest itself as a pregnancy disorder causing recurrent abortion, fetal death, fetal growth retardation and early onset severe pre-eclampsia. (ii) Tissue- or organ-specific disorders such as autoimmune thrombocytopaenic purpura (ATP), autoimmune thyroid disease (Graves' disease, Hashimoto's autoimmune thyroiditis, and post-postum thyroiditis), autoimmune haemolytic anaemia, and the very rare myasthenia gravis. The study of autoimmune diseases against the background of pregnancy as an experimental system of nature has provided important insights into the nature of the disease processes and the relevance or otherwise of circulating autoantibodies to pathological effects. Thus, for example, if neonatal manifestations of adult disease are causally related to the transfer of autoantibodies across the placenta, they will disappear over a time course consistent with the catabolism of IgG, providing no permanent damage is produced. Conversely, if autoantibodies are demonstrable in the neonate, in the absence of clinical effects, they may only be an epiphenomenon of the maternal disease. In addition, on occasions, disease manifestations may be seen in the baby when the mother shows none. This may occur when the mother is in remission, but still has circulating antibodies, or when she has an occult form of the disease.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7848195 TI - Diabetes and fetal abnormalities. PMID- 7848196 TI - What the breast does for the baby, and what the baby does for the breast. AB - Breastfeeding is nature's effective method of child-spacing, provided that feeding is exclusive and prolonged. Yet, its popularity has been limited in modern societies for a range of cultural, social and medical reasons. It is a matter of surprise and regret that no medical specialty has claimed overall 'ownership' of the physiology, function, pathology and management of this conspicuous organ, the female breast. The breast has major benefits for the baby in protecting against debilitating diarrhoea, necrotising enterocolitis and certain allergies, as well as providing highly specific nutritional requirements for the human neonate. It is less widely appreciated that, in addition to its major child-spacing benefits for the mother, breastfeeding also provides major protection against the development of breast cancer, up to 50% reduction in incidence in one study. Few other measures can approach this. PMID- 7848197 TI - The ovary--control from above and within. PMID- 7848198 TI - Folliculogenesis--the natural way. AB - Natural cycle IVF (NIVF) arose from a wish to understand intrafollicular events in couples with unexplained infertility. Single follicle aspiration required unusual technical skill and a precise understanding of the endocrinology in the ostensibly normal cycle. The application of NIVF to all candidates for assisted conception resulted in a low delivery rate. However once data had accumulated it became apparent that age, follicular phase FSH concentrations and other endocrine abnormalities were associated with high failure rates. The concept of using NIVF as a preliminary screening cycle arose. By early elimination of some candidates and selective inclusion of others a highly cost effective regime can be developed. Taking delivery rates into account the cost per maternity is only half that of stimulated IVF. Using clear cut algorithms for the investigation of different categories of infertility the place of NIVF can be defined. Current UK discussions relate to exclusions from access to IVF. Biological exclusions such as age could further enhance the cost effectiveness of NIVF. When NIVF can contribute to at least 50% of cycles in an assisted conception programme it has the potential to have a major economic impact. PMID- 7848199 TI - Folliculogenesis--the stimulated way. AB - The initial techniques of stimulating follicular development in the anovulatory woman involved the use of human pituitary gonadotrophin (hPG) and thus replaced the function of the pituitary gland. Despite extreme care with administration of hPG and extensive monitoring to assess the ovarian response, ovarian hyperstimulation and multiple pregnancy were common. Less expensive and easier methods of treatment soon followed with oral clomiphene citrate (early 1960s), oral bromocriptine (early 1970s) and pulsatile gonadotrophin-releasing hormone (late 1970s) being used. Currently all of these methods, alone or in combination, are employed and successful ovulation induction (except in women with elevated FSH levels) can now virtually be guaranteed. Controlled ovarian hyperstimulation, just the outcome one was attempting to avoid in the treatment of anovulatory women, has become the treatment of choice for women having in vitro fertilization (IVF) or gamete intrafallopian transfer (GIFT). The extra oocytes produced by this treatment results in more embryos being available for transfer and/or freezing and improves the overall pregnancy rate. The concurrent use of gonadotrophin-releasing hormone agonists (GnRH-a) has resulted in more mature oocytes being developed, less cancelled cycles for a spontaneous midcycle LH surge, and allowed even more embryos to be produced thereby increasing the pregnancy rate further to the current expected 20% per cycle commenced. As techniques are further modified, adverse effects of elevated LH levels on pregnancy and take home baby rates should be able to be overcome, and oocyte freezing and long-term storage should become a possibility.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7848200 TI - Ovulation and the polycystic ovary syndrome. AB - In the 1930s, Stein and Leventhal added amenorrhoea to anovulatory dysfunctional uterine bleeding among the known clinical manifestations of the polycystic ovary syndrome (PCOS). Whatever the menstrual pattern, infrequent or absent ovulation with symmetrical enlargement of the ovaries is now a familiar abnormality in women of reproductive age. Diagnosis of PCOS has developed from just the clinically obvious to an appreciation, through ultrasound imaging of the ovaries and endocrine testing, of its subtler forms. Today's clinicians will identify PCOS on the ultrasound image of many small follicles apparent in the periphery of both ovaries, on raised serum unbound testosterone assays, on exaggeration of serum LH levels with the start of pulsatile GnRH therapy, and on follicular overresponsiveness to injections of FSH. Once among the most treatable causes of infertility, ovulation-induction for PCOS remained unsophisticated while microsurgery and assisted conception dissolved frontiers for other causes of infertility. Whereas we now have the benefit of high technology embryo cryostorage to cope with embarrassingly high yields of PCOS oocytes, we still need to explain why, the bigger the ovaries, the more likely (we have long known it to be) that PCOS can be cured simply by reducing ovarian mass. Some cases of PCOS are hereditary and most seem constitutionally determined. PCOS is so common that the questions must be asked, Are we appreciating an extreme of normal? Could the milder forms of PCOS have--or could PCOS have had--evolutionary usefulness? PMID- 7848201 TI - Amenorrhoea and the experiments of nature. PMID- 7848202 TI - Intraovarian regulation by the ovarian renin-angiotensin system. PMID- 7848203 TI - The menopause: when it is all over or is it? AB - The menopause is defined rigorously as the cessation of menstruation as a result of ovarian follicular depletion. Although in common clinical usage, the term is used to encompass the menopausal transition, a period which may average 4 years in duration, and during which alterations in menstrual regularity and/or flow may be accompanied by somatic or psychological symptoms. Measurement of serum follicle-stimulating hormone (FSH) with or without oestradiol (E2) is frequently advocated as providing a useful indicator of menopausal status. Several studies have shown an increase in serum FSH, with or without decrease in E2, in women over the age of 40 years who continue to cycle regularly. Abrupt fluctuations in serum FSH and E2 may be observed, with typically post menopausal levels subsequently returning to the normal reproductive range. In a cross sectional study, of regularly cycling women randomly selected from the Melbourne community, and over the age of 45 years, 7% had FSH levels typical of the post menopause, and 39% had levels above those found during the follicular phase in women aged less than 35 years. It is concluded that serum FSH is of little diagnostic value in the assessment of menopausal status, which can currently be made only on clinical grounds. An elevated serum FSH level cannot tell us reliably 'when it is all over'. PMID- 7848204 TI - The global view of reproductive health. AB - Reproductive health is a condition in which the reproductive process is accomplished in a state of complete physical, mental and social well-being and is not merely the absence of disease or disorders of the reproductive process. The Daily Reproductive Health News in our global village does not paint a bright picture. The past few decades have witnessed a revolution in reproductive behaviour, with a major expansion in contraceptive use in developing countries. Between 1960-65 and 1985-90, the number of contraceptive users in all developing countries has increased from an estimate of 31 million to 381 million. The major expansion in contraceptive use in developing countries has consequences for the quality of life, for the present and for the future, for the society at large and for the individuals and their families. Major challenges, however, still lie ahead. There is a major unmet need for family planning. The rhetoric about population and family planning is not matched by allocation of resources. PMID- 7848205 TI - You win some and you lose some--contraception and infection. PMID- 7848206 TI - The safety of modern contraceptives. PMID- 7848207 TI - Practical problems which women encounter with available contraception in Australia. AB - Australian women face major difficulties with contraception because of the limited range of choices, the need for meticulous attention to compliance with most available methods and because of cost limitations for a significant minority of the population. The most commonly used methods are oral contraceptive pills and barrier methods, and each has substantial compliance problems which can be minimized with care and counselling. There is an urgent need for a wider range of options in Australia and for good information and publicity about them. Present progress in this direction gives some hope for the near future. PMID- 7848208 TI - Breast cancer risk with oral contraceptives and oestrogen replacement therapy. AB - A detailed review of the international epidemiological literature is very reassuring in confirming that exogenous oestrogen in oral contraceptives and postmenopausal hormone replacement therapy does not induce breast cancer in women. However, there may sometimes be a promotional effect which accelerates the time of breast cancer diagnosis in certain subgroups of women. This promotional effect may occur in young oral contraceptive users, and in long term users of high dose oestradiol postmenopausal replacement formulations. Use of oral contraceptives while young may protect against the development of breast cancer after age 45. Physiological doses of conjugated equine oestrogens do not appear to increase breast cancer risk even with long-term postmenopausal use. Current data do not support an effect of progestogens in increasing or decreasing risk of breast cancer. PMID- 7848210 TI - Contraceptives of the future in the light of HIV infection. AB - The AIDS and sexually transmissible disease pandemics have helped to focus the world's attention on the need for good protection against transmission of infections during sexual intercourse. Most of the highly effective modern contraceptives provide only limited protection against STD transmission, although recent progress with the development of loose-fitting plastic male condoms and new spermicides gives some hope. Urgent attention must continue to be given to contraceptives with STD protective qualities which are under the woman's control. Refinements of the female condom and vaginal sponges with new spermicides and microbicides may be a step in this direction. PMID- 7848209 TI - Vaccination for contraception. AB - Vaccination for birth control has several advantages over currently available methods of family planning and should prove an attractive addition to the contraceptive armamentarium both in developing countries and in a developed country such as Australia. Concerns have been voiced by consumer health advocates that vaccines, like other long acting contraceptive methods, may be abused by health authorities in developing countries and by their use in vulnerable groups such as aborigines in our own country. These concerns need to be recognised and addressed. More difficult to accommodate are the anxieties expressed by feminist groups about the 'loss of control' and 'lack of body awareness' inherent in a method, such as a vaccine, that is relatively easily administered and has no overt side effects. There is no evidence that these concerns are shared by women in general. The antifertility vaccine that will most likely be applied first in family planning programmes is one directed against the pregnancy hormone hCG. A WHO vaccine directed against the C-terminal peptide of beta-hCG provokes a specific and safe immune response and will enter Phase 2 trials in Sweden this year. Subsequent developments with this vaccine will include the replacement of the current emulsion vehicle by a delivery system based on biodegradeable microspheres which will give a more sustained antigen release and duration of effectiveness. PMID- 7848211 TI - The biochemistry of prostaglandins: a primer. AB - The membranes of cells serve to endow structural integrity, compartmentalize regions of the cell and allow the generation of a stable intracellular milieu. The lipid component of the membrane forms a matrix for structurally and functionally important proteins. It is also increasingly obvious that these lipids form substrates for the synthesis of a range of molecules which have a central role in cellular communication and regulation. The prostaglandins were the first class of such molecules described and to some extent may serve as an archetype for an understanding of the various classes of lipid mediators. The release of arachidonic acid from lipids (phospholipids in particular) is achieved by lipases (phospholipase A2). Arachidonic acid itself may act directly on cells to modify function. For instance, it may modulate ion channel function. However, it is more often a substrate for cyclooxygenase which produces prostaglandin H2, being the precursor for further prostaglandin and thromboxane synthesis, or for lipoxygenase, to produce the precursor for leukotrienes (a related class of mediators). The prostaglandins may act intracellularly, are readily released from cells to act in an autocrine or paracrine fashion, and may enter the blood vessels or lymphatics to exert endocrine effects. Target cells may contain receptors with relative specificity for various members of the prostaglandin family, thus eliciting some specificity of action by the mediators. PMID- 7848212 TI - Mechanisms of the onset of labour: the New Zealand perspective. PMID- 7848213 TI - Prostaglandin E2, fetal maturation and ovine parturition. AB - The major source of PGE2 in ovine pregnancy is the placenta, with secretion occurring bidirectionally into fetal and maternal circulations. The placental output of PGE2 appears to increase when demand on placental function is increased, suggesting that the normally observed increase in its concentration towards term is driven by the growing demands of the fetus. The fetal pituitary is also involved in the control of PGE2 synthesis. PGE2 has potent stimulatory actions on the fetal pituitary to increase both the absolute concentration and the bioactive fraction of ACTH-containing peptides in the fetal circulation. It also directly stimulates glucocorticoid secretion from the fetal adrenal gland. We propose that PGE2 provides a tonic stimulation of the fetal HPA axis in late gestation, contributing to phenomena such as the apparent insensitivity of the pituitary to cortisol feedback and the increasing sensitivity of the fetal adrenal. Because of its apparent responsiveness to placental workload, it may transduce stimuli from the placenta and transmit them to the fetal HPA axis, giving a possible biochemical basis to the empirically observed correlation between fetal metabolic demand and gestation length. PMID- 7848214 TI - Prostaglandins and biological control of cervical function. AB - The uterine cervix is a vital structure for the success of pregnancy. It must remain firmly closed to contain the developing conceptus within the uterus until the fetus has grown to a stage of maturity appropriate for extra-uterine survival. During the birth process itself, the cervix must undergo the rapid opening known as dilatation to allow the fetus to travel through the birth canal with a minimum of stress and trauma. The process of cervical dilatation must be preceded by the phenomenon of effacement whereby the substance of the cervix shortens and thins out. Both effacement and dilatation would be impossible unless the dense fibrous connective tissue of the cervix had undergone a radical modification. Cervical ripening requires a change of the collagen within the cervical stroma from a highly organised network of tightly bound collagen fibrils to a much looser arrangement whereby the tissue becomes more compliant. This is associated with profound changes in the composition of the ground substance of the cervical stroma with an alteration in the concentration and type of glycosaminoglycans (GAGs) which constitute the proteoglycan complexes. It was formerly assumed that these changes were under the control of those cellular elements within the cervical stroma (fibroblasts and smooth muscle cells) but it seems quite possible that the ripening process is associated with an infiltration of inflammatory cells especially neutrophils. Currently much interest is centering on the possible role of cytokines such as interleukin-8 and there may also be a role in cervical ripening for leukotrienes.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7848215 TI - Maintenance of high risk pregnancies: role of prostaglandins and other mediators. AB - The initiation of a complex cascade of events resulting in the delivery of a healthy newborn appears to involve the integrated actions of the fetus, mother and the placenta. Many putative factors have already been extensively reviewed. Instead of concentrating on the action of estrogen and progesterone, the role of regulators of myometrial activity such as prostaglandins as well as the fetal pituitary-adrenal system, oxytocin, corticosteroids, leukotrienes, platelet activating factor, endotoxin and cytokines to name a few, will be discussed. Nevertheless, there is an increasing weight of evidence suggesting that many of the above agonists converge upon a final pathway of prostaglandin production which subsequently increases myometrial responsiveness. Prostaglandins are involved at levels of myometrial regulation such as myometrial gap junction formation, intracellular calcium flux modulation, synchronisation of myometrial contraction via interaction with oxytocin thus having stimulatory effects on uterine contractility, as well as cervical maturation (via PGE2). Importantly, there has been clinical benefit of a more thorough understanding of the physiology of myometrial regulation at the time of partuition. The approach to the treatment of preterm delivery has improved, eventhough the exact mechanism(s) and cause(s) of this phenomenon remain an enigma. Current tocolytic therapy is not generally prophylactic but commences after labour, contractions and cervical dilatation are underway. Key regulatory pathways have been pin-pointed that present opportunity for tocolysis including:-c-AMP inhibition of contraction by beta-mimetic agents, inhibition of calmodulin-calcium function, inhibition of calcium influx by calcium channel blockers, inhibition of prostaglandin production, modulation of myometrial function by peptide hormones or antagonists (e.g. relaxin, VIP and oxytocin antagonists).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7848216 TI - Prostaglandins and progesterone receptor antagonists in human fertility regulation. AB - Anti-progesterone medicines have now been extensively studied for human fertility regulation. The combination of the anti-progesterone Mifepristone with prostaglandin analogues such as Gemeprost and Misoprostol have been used in several European centres for medical abortion. Used before nine weeks gestation, these medicines have similar efficacy to surgical abortion. In addition, administration of progesterone antagonists within five days of unprotected intercourse appear effective in pregnancy prevention. Anti-progesterone medicines are not currently available in Australia. The introduction of progesterone receptor antagonists and modern prostaglandins would save approximately $10,000,000 per year to the Australian Health Budget. Furthermore, the introduction of progesterone receptor antagonists for emergency contraception would have even greater financial and emotional savings for Australian women. In Australia, when known carcinogens can be purchased over the counter, it is surely time for Australians to consider effective emergency contraception bought over the counter. PMID- 7848217 TI - The Shearman report--Milestone or Millstone? PMID- 7848218 TI - Strategic planning of obstetric services: the United Kingdom way. AB - From 1944 when the first British Report on a National Maternity Service was published until 1989 there have been seven publications on the Maternity Services. Against this background the Shearman Report is described in comparison with its British counterparts. There has however been much debate in the UK since 1989 with a redesign of the National Health Service. A sub committee of the House of Commons (Winterton) advocated major changes in maternity services and the Government responded with a detailed critique announcing the appointment of an Expert Maternity Group (Cumberlege) which has just published its recommendations for widespread consultation. The three Royal Colleges have published a joint report and in the next year Government policy will be published. Scotland however has developed an independent view and has progressed further an analysis and rational planning. The fate of the Shearman report will be awaited with interest. PMID- 7848219 TI - Strategic planning of obstetric services: the Australian way. AB - This paper presents a number of documents developed at State and Territory Government level including the 'Shearman Report' concerning the strategic planning of obstetrical services. The papers are presented in chronological order. The aims, objectives and implementation arising from the reports are discussed including the mechanism by which the various studies were undertaken. The author acknowledges the existence of the many other reports relating to strategic planning for obstetrical services which were not able to be discussed due to the constraints of the presentation. PMID- 7848220 TI - Training the obstetrician of the 21st century. PMID- 7848221 TI - The Shearman report: a health planner's perspective: or what will it cost? PMID- 7848222 TI - 'Opus meum'. Finale. PMID- 7848223 TI - Syphilis in pregnancy: experience from a rural aboriginal community. AB - Syphilis in pregnancy is seldom encountered in urban Australia. This retrospective study reports on the high prevalence of syphilis and its associated complications in a group of pregnant Aboriginal women attending the Dareton Community Health Centre for antenatal care between September, 1989 and September, 1991. During this time, the centre provided antenatal care for 71 Aboriginal pregnancies and maternal syphilis was found in 20 (28%). The mean age of the women was 21.3 years (range of 14-33 years). The perinatal mortality rate was 48 per 1,000 births. All stillbirths were associated with maternal syphilis. The relative risk of stillbirth in the presence of syphilis was 4 (95% CI 2.56-6.25, p = 0.022). Prematurity was associated with maternal syphilis. The odds ratio for premature delivery was 21.5 (95% CI 2.26-2.05, p = 0.003). There was no statistical difference between the mean birth-weight and mean placental weight of term infants born to women with syphilis and women without syphilis (p = 0.35 and p = 0.31 respectively). When the placental:birth-weight ratios were considered, an apparent larger placenta was seen in association with syphilis but this was secondary to the lower birth-weights in association with prematurity. Late and poor attendance for antenatal care was a feature of all women attending this centre and not a feature associated with syphilis. The treatment and follow-up of syphilis were hindered by poor compliance. PMID- 7848224 TI - Caesarean section rate reduced. AB - The Caesarean section rate in consecutive years was decreased from 20.5% to 11.1% of total public deliveries (p < 0.0001). On retrospective analysis the emergency Caesarean section rate decreased from 10.9% to 6.0% (p < 0.0001) and elective Caesarean section rate from 9.6% to 5.1% (p < 0.0001) in consecutive years. Interventions which have accounted for the decrease were 3-fold. Firstly, vaginal birth after Caesarean delivery was encouraged, secondly, the active management of labour and thirdly, extensive, regular peer review were introduced as unit policy. The decrease in the Caesarean section rate was not achieved at the expense of the fetus as judged by perinatal mortality rates and 5-minute Apgar scores of less than 7. PMID- 7848225 TI - Prediction of caesarean section from ultrasound and clinical assessment of fetal size. AB - One hundred and five women with singleton pregnancies and cephalic presentation were assessed. Fundal height and a clinical estimate of fetal weight were recorded. The fetal biparietal diameter, abdominal circumference and femur length were measured with ultrasound. Ultrasound estimated fetal weight was calculated using 3 different formulas (Shepard, Campbell and CUHK). The liquor volume was assessed using the amniotic fluid index. Ultrasound was able to predict Caesarean section with more reliability than clinical assessment of fetal size or weight. The biparietal diameter, fundal height and amniotic fluid index were poor predictors of mode of delivery. The measurements which best predicted the mode of delivery were the fetal femur length and abdominal circumference. Femur length, but not abdominal circumference, was a statistically better predictor of Caesarean section than clinical estimation of fetal weight. There was no improvement in prediction using ultrasound estimated fetal weight. PMID- 7848226 TI - Risk factors for wound infection following caesarean section. AB - A prospective study was performed between April 1, 1991 and April 30, 1992 to determine factors involved in the development of post-Caesarean section wound infection. During this period there were 4,857 deliveries, 428 by Caesarean section (8.8%). Complete data were available on 328 (76.6%) patients. Wound infection occurred in 25.3% of women and was confirmed by positive bacteriology in 77.1%; 36% of wound infections were diagnosed following the patients' discharge from hospital. A negative correlation was found between maternal age and development of wound infection up to age 40 (p = 0.03). Maternal weight was a highly significant indicator of subsequent wound infection development (p = 0.0001), the relationship between increasing maternal weight and infection appearing linear. Antibiotic prophylaxis was found to be the most significant protective factor (p = 0.0007) in the reduction of postoperative wound infection. This relationship was independent of maternal weight. PMID- 7848227 TI - Value of cardiotocography in women with antepartum haemorrhage--is it too late for caesarean section when the cardiotocograph shows ominous features? AB - Caesarean section is thought to be indicated by an ominous antepartum cardiotocograph (CTG). However, the fear remains that infants delivered for this indication in the presence of antepartum haemorrhage, especially when premature, are destined to have severe hypoxic neurological damage. We therefore reviewed our experience of cardiotocography in women with antepartum haemorrhage (APH) from 1989 to 1992. There were 472 women with APH who had a CTG performed. Of them, 68 had abruptio placentae and 317 had an APH of undetermined cause. For the group with abruptio placentae, the perinatal mortality rate (PMR) was 230.7 per 1,000 when the CTG was abnormal, but only 18.2 per 1,000 if the CTG was normal (odds ratio 16.2, 95% confidence interval [CI] 1.53-171.9, p = 0.02). For APH of undetermined cause, the corresponding rates were 90.9 per 1,000 and 9.8 per 1,000 (odds ratio 10.1, 95% CI 0.96-105.8, p = 0.13). There were no perinatal losses in women with APH due to placenta praevia (87 cases). There were 6 cases of critical fetal reserve identified on a CTG in women with abruptio or APH of undetermined cause. All were delivered by Caesarean section, with 4 surviving infants, 3 with normal neurological outcome and 1 lost to follow-up. There were 3 cases of APH resulting in an infant with cerebral palsy, all of whom had had a normal antepartum CTG. Our data suggest that cardiotocography allows pregnancy to be safely prolonged in pregnancies complicated by abruptio placentae or APH of undetermined cause, and that Caesarean section is an appropriate form of delivery when the CTG becomes abnormal in these cases. PMID- 7848228 TI - Biochemical and clinical evaluation of the efficiency of intracervical extraamniotic prostaglandin F2 alpha and intravenous oxytocin infusion to induce labour at term. AB - A prospective randomized study of 296 patients was undertaken to evaluate the efficiency of 15 mg prostaglandin F2 alpha (PGF2 alpha) suspended in tylose gel and applied intracervically for labour induction. The control group was treated with standard oxytocin intravenous infusion. Results indicated that local PGF2 alpha was superior to oxytocin therapy in shortening the duration of labour (6.3 +/- 2.3 versus 8.1 +/- 2.6 hours, p < 0.05). Only 19% of the patients treated with PGF2 alpha required oxytocin augmentation during labour. Our data suggest that PGF2 alpha treatment is associated with few maternal side-effects, few failed inductions, a low operative delivery rate and favourable neonatal outcome. To investigate the influence of PGF2 alpha for labour promotion we have measured interstitial collagenase and elastase activity in the lower uterine segment after both methods of labour induction. The total collagenase activity was 22 times higher in tissue samples obtained from patients in active spontaneous and oxytocin-induced labour, compared with women not in labour (at term) (p < 0.001). The total interstitial elastase activity was 2-fold higher in women in active labour than in patients at term (p < 0.03). A significantly higher collagenase and elastase activity was observed in uterine specimens obtained from patients treated with PGF2 alpha compared to oxytocin, and this indicates that cervical collagen may be digested more quickly in the presence of exogenous prostaglandin F2 alpha. PMID- 7848229 TI - Chorionic villus sampling incidence--still rising despite a bad press. PMID- 7848230 TI - A perinatal audit of stillbirths in a teaching hospital in Hong Kong. AB - In a 5-year period, the stillbirth rate in a teaching hospital in Hong Kong was 4.4 per 1,000 total births, which accounted for 61% of the perinatal deaths. The stillbirth rate was 5.8 times higher in twin pregnancies, and 17 times higher in triplet pregnancies. One quarter of the patients were nonbooked, and 14.5% had no antenatal care. The stillbirth rates were 3.8 and 8.0 per 1,000 among the booked and nonbooked cases respectively. The major causes of stillbirths were congenital abnormalities, haemoglobin Bart disease, abruptio placentae and gestational diabetes. No specific cause could be found in 46% of cases. There were 31 intrapartum deaths, of which 5 were potentially salvageable. PMID- 7848231 TI - The obstetrician and the extremely immature fetus (24-26 weeks): outcome to 5 years of age. AB - The aims of this study were to determine the outcome to 5 years of age for fetuses 24-26 weeks of gestational age from the obstetric viewpoint, and to determine if their outcome has improved over time. Consecutive fetuses with gestational ages from 24-26 weeks born at the Royal Women's Hospital, Melbourne, during 2 separate eras, Era 1 (1977-1982; n = 198) and Era 2 (1985-1987; n = 128) were studied and their outcome to 5 years of age determined. Fetuses referred with lethal malformations or clearly dead before the onset of labour were excluded. The stillbirth rates were similar in both eras (Era 1 23.7%, Era 2 21.9%), but the proportion of survivors to 5 years of age was much higher in Era 2 (Era 1 19.7%, Era 2 30.5%, X2 = 5.0, p < 0.03; odds ratio 1.80; 95% confidence interval [CI] 1.07 to 3.04). Overall, both the proportion and the absolute number of severely disabled children fell over time; 4 children survived with severe sensorineural disability in the 5 1/4 years of Era 1, but only one child in the 3 years of Era 2. From the obstetric viewpoint, only 1.5% of total births survived with a severe sensorineural disability, no higher than the rate expected for children born at term. Fetuses born at 24-26 weeks of gestational age need not contribute disproportionately to the number of severely disabled children in the community; furthermore, their outcome is improving over time. From the obstetrician's viewpoint, survival chances rather than sensorineural outcome should dominate decision-making at these extremely preterm gestations. PMID- 7848232 TI - The incidence of gestational diabetes mellitus in the Illawarra area of New South Wales. AB - The incidence of gestational diabetes in the Illawarra area is 7.2% (95% CI: 6.0 8.4). This was determined by data collected by 2 prenatal clinics and 3 private practitioners during 1993. The incidence rate varied between 5.1% at one hospital to 11.3% with a private practitioner. This variation was mainly due to differences in age and ethnic background. The highest incidence rate of 11.9% was found in women of Asian background. PMID- 7848233 TI - Fetal pulse oximetry: a new method of monitoring the fetus. AB - Experimental pulse oximetry devices, similar to the existing systems used in adult and neonatal monitoring, can be used on the fetus to provide safe, and rapid information about oxygenation. They have been calibrated using fetal lambs and validated in human cross-sectional studies. Experiments have shown that fetal oxygen saturation decreases during normal labour, and drops after a uterine contraction especially with oxytocin-induced tachysystole. When the mother is given oxygen the fetal oxygen saturation increases. Readings are effected by caput and movement, and trends seem to be more meaningful than absolute values. Pulse oximetry can predict fetal outcome and a normal oxygen saturation result is specific for a good outcome perhaps even if the CTG is abnormal. However the technique is still experimental and there is insufficient data to support its use as a replacement for fetal blood sampling or a discriminator for an abnormal fetal heart trace. PMID- 7848234 TI - Spontaneous abortion: a medical approach to management. AB - The conventional management of spontaneous abortion is surgical evacuation of the uterus to prevent complications which may arise from retained products of conception (POC). This procedure is not without complications and also demands operating theatre resources. The purpose of this study was to determine the efficacy of a medical approach to the management of spontaneous abortion using the prostaglandin analogue, gemeprost. From an initial 212 women presenting with spontaneous abortion, 4 groups were defined according to what they required in the way of initial management. A group of 20 women were excluded from conservative medical management at presentation because they were bleeding heavily and judged to be unsuitable. Sixty women initially required no further management other than determining that they had a complete abortion using transvaginal sonography (TVS). The 132 women were treated with the prostaglandin analogue, gemeprost. Sixty were judged to need no further management afterwards and were initially discharged. The remaining 72 women underwent evacuation of retained products of conception (ERPC) after the gemeprost treatment as medical evacuation of the uterus appeared to had been incomplete. In each of these 4 groups so defined, there was 1 case where an ERPC was required after the patients have been discharged because of complications attributable to retained POC. We therefore found that no ERPC was necessary in the management of 118 out of 212 (55.6%) women who presented with spontaneous abortion. This has important implications in patient management and economical use of hospital resources. PMID- 7848235 TI - The Swedish Insemination Act and its impact. AB - In the debate surrounding secrecy in donor insemination (DI), the semen donor is often cited as a person needing the protection of anonymity. Sweden's unique legislation, the 1985 Insemination Law which, among other things, gives mature DI offspring the right of access to donor identity, has attracted much comment. Prior to the legislation's enactment, there were fears that the law would result in a rapid and irreversible decline in DI as a treatment in Sweden. It was also predicted that it would be almost impossible to recruit donors under the legislation. This paper describes the provisions of the legislation and examines what its impact has been in terms of the reactions of the medical profession, DI treatment provision, and the availability and recruitment of donors. PMID- 7848236 TI - Laparoscopic evaluation of apparently normal infertile women. AB - Laparoscopy was used to evaluate 130 women whose basic infertility survey revealed no abnormalities. Overall 75 (57.7%) patients were found to have evidence of pelvic disease while the remainder were completely normal. Pelvic endometriosis was the most common pathology accounting for 27.7%, pelvic adhesions 20.8% and mild pelvic inflammatory disease 6.2%. Appropriate treatment of the pelvic conditions resulted in 31 (42.5%) pregnancies compared with 7 (12.3%) pregnancies in the no treatment group. The outcome of this study suggests that additional pregnancies do occur as a direct result of laparoscopic examination and subsequent therapy. We believe that laparoscopy should be performed on all women to search for a tubal or pelvic cause of infertility when all other examinations have been normal. PMID- 7848237 TI - The impact of maternal age on clinical pregnancy and spontaneous abortion in women undergoing in vitro fertilization and gamete intra-fallopian transfer. AB - The age at which women should be advised against proceeding with initial or further infertility treatment is one of the many unresolved questions in this area of women's health and was the subject of investigation in this study. One of the major difficulties in determining the impact of maternal age on outcomes is the practice of researchers (publishing in journals) and infertility practitioners (reporting to national registers) of coding age as a categorical rather than a continuous variable. In this study, groups of younger (< 30 years) and older (> 35 years) women undergoing assisted reproduction treatments were compared with regards to clinical pregnancy and spontaneous abortion rates following in vitro fertilization (IVF) or gamete intra-Fallopian transfer (GIFT). Response to different ovarian stimulation protocols was also assessed for the 2 groups. The significance of the relationship between maternal age, clinical pregnancy rates, spontaneous abortion rates and the type of treatment and stimulation protocol employed, was tested using a series of binomial distributions. The results indicated that maternal age adversely affects both clinical pregnancy rates and rates of spontaneous abortion, when summed across treatments and stimulation protocols. However, while the age/outcome relationship held for IVF, the GIFT by age relationship was not significant. Stimulation protocols using clomiphene citrate (CC) or gonadotrophin agonists (GnRHa) may impact negatively on older women.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7848238 TI - Stage 1 endometrial cancer: treatment modalities and factors influencing recurrence. AB - One hundred and nineteen patients treated for FIGO Stage 1 endometrial adenocarcinoma were reviewed retrospectively to determine if adjuvant radiotherapy reduced disease recurrence. The patients had all been treated in the Hunter Region of New South Wales over a 10-year period from 1978 to 1988. Median follow up was 82 months with a range of 24 to 163 months. Treatment consisted of surgery alone (75.6%), surgery and brachytherapy (17.6%), surgery and megavoltage therapy (4.2%), and surgery with both brachytherapy and megavoltage therapy (2.5%). The overall recurrence rate was 10.1%. Recurrence at the vaginal vault alone occurred in 3.4%. The median time to recurrence was 25.0 months. A statistically significant correlation was found between overall recurrence risk and poorly differentiated lesions (p < 0.0001). Just failing to reach statistical significance were age over 70 years (p < 0.06) and patient weight less than 70 kg (p = 0.06). Depth of myometrial invasion (p = 0.17), use of adjuvant radiotherapy (p = 0.17) and uterine cavity size (p = 0.48) were not significantly correlated with risk of recurrence. The 5-year survival rate was 93.8%. PMID- 7848239 TI - Low cost, patient acceptable, local analgesia approach to gynaecological outpatient surgery. A review of 817 consecutive procedures. AB - The objective of this study was to evaluate safety, cost effectiveness and patient acceptability, of performing a wide variety of gynaecological procedures, including endometrial resections, in a clinic using only local analgesia. Eight hundred and seventeen consecutive gynaecological procedures were performed under local analgesia only, with no sedation, including endometrial resections, cone biopsies, terminations of pregnancy, hysteroscopies, and local vaginal and plastic vulval procedures, as well as many combined procedures (figure 1) in a day-surgery ward annexe in the Department of Gynaecology, St John's District General Hospital, Chelmsford Essex. The main outcome measures were patient acceptability, safety and encountered side-effects of procedures performed under local analgesia as well as evaluation of cost-effectiveness and reduction in theatre waiting list times. A high degree of safety and patient acceptability was achieved, with other considerable benefits being short waiting times and much quicker recovery. The only complications were from the endometrial resection group, with only 8 (3.6%) of these requiring intravenous sedation intraoperatively, and 6 (2.7%) requiring overnight admission. No transfers to theatre during any procedure occurred. Savings per procedure, in cost and in patient's time, were very considerable. CONCLUSION: The local analgesia approach for a wide variety of gynaecological procedures in a combined outpatient theatre is safe and is highly acceptable to patients. There are also considerable benefits in cost and patient convenience, with a reduction in operating list waiting time, which in the current economic climate are worth considering. PMID- 7848240 TI - Transcervical resection of the endometrium using intracervical block only. A review of 278 procedures. AB - The objective of this study was to assess the efficacy and safety aspects of performing transcervical endometrial resection (T.C.R.E.) on a selected group of 278 patients with menstrual disorders under local analgesia (intracervical block) only. Patient acceptance of the procedure was high, with only 3 cases not completed due to insufficient analgesia (1.07%), although a further 9 (3.2%) were completed with the help of intravenous sedation. Patient satisfaction at 4 months was 90%. There were 4 perforations (1.4%), but no laparotomy was required. Five cases (1.7%) of haemorrhage required a Foley catheter, with 1 needing a transfusion. There was no case of clinically evident glycine overload. Twelve patients required an overnight stay. Patient acceptance of T.C.R.E. under local analgesia, and the incidence of major complications, compared favourably with other published series, including a series of 330 cases performed concurrently by the same operators under general anaesthesia. PMID- 7848241 TI - Transabdominal ultrasound as an aid to advanced hysteroscopic surgery. AB - At the Nepean Hospital transabdominal ultrasound has been used to assist the hysteroscopic surgeon when performing complicated transcervical operations. The 2 main areas of use appear to be either to direct the surgeon within the uterus to the site of pathology or to prevent inadvertent perforation of the uterine wall. The cases vary from haematometra following endometrial ablation to Asherman syndrome and subseptate uteri. PMID- 7848242 TI - Laparoscopic hysterectomy: do we need to remove the cervix? PMID- 7848243 TI - Management of vaginal agenesis with a functioning uterus. Is hysterectomy advisable? AB - Cryptomenorrhoea associated with vaginal agenesis is uncommon. However, when laparoscopy or ultrasound reveal the uterus to be present early laparotomy is mandatory unless there is clear evidence of haematocolpos, in order to define the cervix and undertake reconstructive surgery. Once a uterovaginal tract has been established prolonged use of a mould is necessary to maintain patency of the neovagina. If the cervix is absent or atretic then immediate hysterectomy is required. PMID- 7848245 TI - Early discharge following major gynaecological surgery. AB - This prospective study was to assess the safety and acceptability to patients of early discharge after major gynaecological surgery. Selective patients who fulfilled certain criteria were offered early discharge after their operations. Forty patients were discharged within 72 hours. Fourteen of them had undergone abdominal hysterectomy, 5 with a mid-line incision; 13 had vaginal hysterectomy; 9 laparoscopy and laparotomy for ectopic pregnancy; 3 laparotomy for ovarian surgery and 1 a Manchester repair. The patients were discharged home on average 2.4 days after their operations. All were satisfied with their pain relief at home. There were 4 postdischarge complications. Two had superficial drip-site phlebitis, 1 a possible urinary tract infection and 1 a wound abscess. There was only 1 readmission 2 weeks post discharge for constipation. Thirty-one out of 40 (77.5%) of the patients had expressed that the home environment was more conducive to speedy recovery and 92.5% of the patients would choose early discharge again if given the option. PMID- 7848244 TI - Sexual function after pelvic surgery in women. AB - To assess the prevalence of sexual dysfunction after pelvic floor surgery for nonmalignant conditions, a retrospective survey was performed. Replies from a postal survey were received from 66 of the 200 women canvassed. Dyspareunia developed in 10 patients who had never had it before the operation, however of those who had it preoperatively the pain stopped completely in 12 of 23. Reduced libido was noted in 16 of 54 (29%), reduced lubrication in 21 (38%), and reduced genital sensation in 10 (18%). Lack of information about the potential effects of surgery on sexual function was identified as a major deficit and of considerable concern to 35 of the 66 women. Sexual function after surgery should be evaluated more intensively, and the subject discussed openly before any contemplated operation. PMID- 7848246 TI - Ureaplasma urealyticum chorioamnionitis. AB - Controversy reigns over the role of Ureaplasma urealyticum in determining pregnancy outcome. U. urealyticum infection of the chorioamnion is strongly associated with chorioamnionitis (1-3), premature birth (2-4), and perinatal morbidity (4-6). We present 4 cases of U. urealyticum chorioamnionitis and associated morbidity and mortality. PMID- 7848247 TI - The incidence of histological chorioamnionitis in IVF/GIFT preterm births. AB - A retrospective case control study was designed to investigate the role of subclinical infection as a risk factor for the high rate of preterm deliveries in IVF/GIFT pregnancies. The cases and the controls were identified from the records of consecutive livebirths of < 35 weeks' gestational age (GA), at King George V Hospital from 1987-1993. Fifty one singleton and 58 twin IVF/GIFT preterm births were matched for GA, year of birth, plurality, maternal age, parity, preclampsia and antepartum haemorrhage. As a marker of subclinical infection, the incidence of histological chorioamnionitis (HCA) in the 2 groups (as defined by the standardized, semiquantitative method of Benirschke) was compared. The matched variables did not differ significantly between the IVF/GIFT group and the control group. No significant difference in the incidence of HCA was detected between IVF/GIFT and control groups for singletons or twins. Overall 24% of IVF/GIFT and 30% of controls showed evidence of HCA, odds ratio (95% confidence intervals), 0.72 (0.40-1.31). This study showed no evidence that the incidence of HCA, is significantly increased in IVF/GIFT preterm births compared with other matched, preterm births. Therefore, we conclude that subclinical infection/inflammation cannot explain the 4-fold increase in preterm births in the IVF/GIFT population. PMID- 7848248 TI - The effect of scavenging on nitrous oxide pollution in the delivery suite. AB - United States standards recommend limits to occupational exposure to nitrous oxide. This can be achieved by the scavenging of waste anaesthetic gases, a routine practice in the operating suite, but less common in the delivery suite. In this study, nitrous oxide levels in the delivery room were measured, and scavenged and unscavenged levels were compared. Unacceptable levels of nitrous oxide were found in unscavenged delivery rooms, and in the majority of cases, scavenging reduced nitrous oxide pollution to within recommended limits. PMID- 7848249 TI - Acute puerperal coital headache and hypertension. AB - An unusual case of acute headache and hypertension occurring at the height of sexual excitement during the puerperium is presented. The patho-mechanism of this phenomenom is discussed and the literature reviewed. PMID- 7848250 TI - Prenatal ultrasound diagnosis of Beckwith-Wiedemann syndrome. PMID- 7848251 TI - Intrapartum haemorrhage due to idiopathic rupture of the fetal placental artery. PMID- 7848252 TI - Cervical pregnancy following in vitro fertilization: evacuation after uterine artery embolization with subsequent successful intrauterine pregnancy. AB - A case is described in which a cervical pregnancy followed in vitro fertilization. Treatment was delayed at the request of the patient until the second trimester, and was successfully managed by preoperative bilateral angiographic uterine artery occlusion, surgical evacuation, and postoperative balloon tamponade. Subsequent embryo transfer of previously cryopreserved embryos resulted in a normal intrauterine pregnancy and delivery without complications. This case highlights the need for awareness of cervical pregnancy following in vitro fertilization and the success of management which preserves fertility. PMID- 7848253 TI - An unusual cause of vaginal bleeding and abdominal pain--prolapsed ureterocele. PMID- 7848254 TI - Endocervicosis of the urinary bladder. AB - A further case of endocervicosis of the urinary bladder is described. It is important that gynaecologists and pathologists be aware of this entity and its possible relationship to previous Caesarean section to avoid confusion with a neoplastic process. PMID- 7848255 TI - 'More information please'. PMID- 7848256 TI - Oestrogen and testosterone implants. PMID- 7848257 TI - Antepartum screening and non-selective intrapartum chemoprophylaxis for group B streptococcus. PMID- 7848258 TI - Electronic fetal heart rate monitoring with epidural analgesia. PMID- 7848259 TI - Re: Prostaglandin E2 (prostin E2) PMID- 7848260 TI - Postmenopausal hirsutism: the forgotten face. PMID- 7848261 TI - A non-modular endo-beta-1,4-mannanase from Pseudomonas fluorescens subspecies cellulosa. AB - Pseudomonas fluorescens subsp. cellulosa when cultured in the presence of carob galactomannan degraded the polysaccharide. To isolate gene(s) from P. fluorescens subsp. cellulosa encoding endo-beta-1,4-mannanase (mannanase) activity, a genomic library of Pseudomonas DNA, constructed in lambda ZAPII, was screened for mannanase-expressing clones using the dye-labelled substrate, azo-carob galactomannan. The nucleotide sequence of the pseudomonad insert from a mannanase positive clone revealed a single open reading frame of 1257 bp encoding a protein of M(r) 46,938. The deduced N-terminal sequence of the putative polypeptide conformed to a typical prokaryotic signal peptide. Truncated derivatives of the mannanase, lacking 54 and 16 residues from the N- and C-terminus respectively of the mature form of the enzyme, did not exhibit catalytic activity. Inspection of the primary structure of the mannanase did not reveal any obvious linker sequences or protein motifs characteristic of the non-catalytic domains located in other Pseudomonas plant cell wall hydrolases. These data indicate that the mannanase is non-modulator, comprising a single catalytic domain. Comparison of the mannanase sequence with those in the SWISSPROT database revealed greatest sequence homology with the mannanase from Bacillus sp. Thus the Pseudomonas enzyme belongs to glycosyl hydrolase Family 26, a family containing mannanases and endoglucanases. Analysis of the substrate specificity of the mannanase showed that the enzyme hydrolysed mannan and galactomannan, but displayed little activity towards other polysaccharides located in the plant cell wall. The enzyme had a pH optimum of approx. 7.0, was resistant to proteolysis and had an M(r) of 46,000 when expressed by Escherichia coli. PMID- 7848262 TI - Confocal fluorescence microscopy for studying thapsigargin-induced bivalent cation entry into B cells. AB - We studied thapsigargin-induced bivalent-cation entry into antigen-specific B cells (TP67.21) with a confocal fluorescence microscope. Confocal fluorescence images of fluo-3-loaded B cells showed that thapsigargin-stimulated Ca2+ signals were transferred not only to the cytoplasm but also to the nucleus. In the absence of external Ca2+ ions, the free Ca2+ concentrations both in the cytosol and in the nucleus declined to basal levels by 5 min after addition of thapsigargin. However, subsequent addition of Ca2+ in the external medium made the fluo-3 (fura-2) fluorescence intensity rise, reflecting the fact that Ca2+ accumulated again in the nucleus as well as in the cytoplasm. Then, we added Ba2+ and Mn2+ instead of Ca2+, because Ba2+ and Mn2+ are known to enter via Ca2+ channels. The addition of Ba2+ and Mn2+ in the external medium quenched the fluo 3 fluorescence both in the nucleus and in the cytoplasm of B cells. This suggested the possibility that the increase in intranuclear Ca2+ after thapsigargin stimulation may come from the cytoplasm, not from the nuclear stores. PMID- 7848263 TI - Methional derived from 4-methylthio-2-oxobutanoate is a cellular mediator of apoptosis in BAF3 lymphoid cells. AB - 4-Methylthio-2-oxobutanoic acid is the direct precursor of methional, which is a potent inducer of apoptosis in a BAF3 murine lymphoid cell line which is interleukin-3 (IL3)-dependent. Cultures treated for 8 h with methional in the presence of IL3 show extensive DNA double-strand breaks on flow cytometric analysis, increases in DNA fragmentation as measured by the amount of non sedimentable DNA present in the 30,000 g supernatant of cell lysates and the typical laddering pattern of multiples of 180 bp seen upon agarose gel electrophoresis. No such features of apoptosis were found in cells treated with 4 methylthio 2-oxobutanoic acid or propanal, suggesting that the simultaneous presence of the methylthio group on the propanal moiety is essential for apoptosis to take place. Methional is further metabolized in cells by two reactions: oxidation via aldehyde dehydrogenase to (methylthio)propionic acid or beta-hydroxylation to malondialdehyde. The formation of malondialdehyde from methional in vitro by chemical hydroxylation under the conditions of the Fenton reaction provides a mechanism for the beta-hydroxylation which takes place in vivo. During apoptosis induced by IL3 deprivation, the ratio of 2,4-DNPH MDA to 2,4-DNPH methional is 0.94 in cells in IL3- medium compared with 0.54 in cells in IL3+ medium. These results support a role of cellular methional and malondialdehyde in apoptosis. PMID- 7848264 TI - The expression of interstitial collagenase in human endometrium is controlled by progesterone and by oestradiol and is related to menstruation. AB - Human endometrial tissue, sampled at different periods of the reproductive cycle, expressed interstitial collagenase mRNA, protein and activity only just before and during the menstrual period. This clear-cut correlation and the inhibition of collagenase expression by progesterone and oestradiol in tissue culture point to a pivotal role of this proteinase in the mechanism of menstrual tissue breakdown and bleeding. PMID- 7848266 TI - Escherichia coli chorismate synthase: a deuterium kinetic-isotope effect under single-turnover and steady-state conditions shows that a flavin intermediate forms before the C-(6proR)-H bond is cleaved. AB - We report the observation of a deuterium kinetic isotope effect for the conversion of 5-enolpyruvylshikimate-3-phosphate into chorismate (6proR2HV = 1.13 +/- 0.03) using recombinant chorismate synthase from Escherichia coli. Similar isotope effects were observed for the decay of a spectroscopically characterized flavin intermediate (6proR2Hk = 1.17 +/- 0.04) during single-turnover experiments. The main rate-limiting steps and C-(6proR)-H bond breaking are therefore distinct and both must occur after the formation of the flavin intermediate and either before or concomitant with its decay. PMID- 7848267 TI - Different molecular forms of rat kidney gp330, the dominant autoantigen of active Heymann nephritis. AB - The primary structure, consisting of 1650 amino acid residues, of the C-terminal end of the dominant autoantigen of active Heymann Nephritis, gp330, from rat kidney was obtained by cloning and sequencing of cDNA clones. Comparison of this sequence with the previously published sequences of fragments of the C-terminal end of gp330 [Raychowdhury, Niles, McCluskey and Smith (1989) Science 244, 1163 1165] revealed certain differences in their primary structures. These differences included several single amino acid substitutions, replacement of a stretch of 15 amino acid residues by a different stretch of six amino acid residues, and different lengths of cytoplasmic domain (188 versus 213 amino acid residues). These findings of two different primary structures of gp330 provide direct evidence for the existence of two molecular forms of gp330. PMID- 7848268 TI - Construction and characterization of a chimeric beta-glucosidase. AB - The amino acid sequences of beta-glucosidases from Cellvibrio gilvus and Agrobacterium tumefaciens show significant similarity in most of the parts. However, the pH/temperature optima and stabilities of the two enzymes are quite different. C. gilvus beta-glucosidase exhibits an optimum pH of 6.2-6.4 and temperature of 35 degrees C, whereas the corresponding values for A. tumefaciens are 7.2-7.4 and 60 degrees C respectively. To analyse these properties further, a chimeric beta-glucosidase was constructed by replacing a segment from the C terminal region of C. gilvus beta-glucosidase gene with that of A. tumefaciens. The partially purified chimeric enzyme was characterized with respect to pH/temperature activity and stability and substrate affinity. Our results suggest that C-terminal segment(s) might be important in beta-glucosidase specificity, and shuffling of even a small segment of gene in this region might significantly alter or improve the enzymic properties such as thermal stability. PMID- 7848265 TI - Platelet-activating factor: the biosynthetic and catabolic enzymes. PMID- 7848269 TI - Vesicle-associated membrane protein-2 (synaptobrevin-2) forms a complex with synaptophysin. AB - Vesicle-associated membrane protein (VAMP) (or synaptobrevin), a type II membrane protein of small synaptic vesicles, is essential for neuroexocytosis because its proteolysis by tetanus and botulinum neurotoxins types B, D, F and G blocks neurotransmitter release. The addition of cross-linking reagents to isolated small synaptic vesicles induces the formation of 30 and 50 kDa complexes containing the isoform 2 of VAMP (VAMP-2). Whereas the 30 kDa band is a VAMP-2 homodimer, the 50 kDa species results from the cross-linking of VAMP-2 with synaptophysin. This heterodimer also forms in detergent-solubilized vesicles and involves the N-terminal part of VAMP-2. The implications of the existence of a synaptophysin-VAMP-2 complex in the processes of vesicle docking and fusion with the presynaptic membrane are discussed. PMID- 7848270 TI - Identification of a substrate site for transglutaminases on the human protein synthesis initiation factor 5A. AB - Protein synthesis initiation factor 5A (eIF-5A) from human erythrocytes was found to be a substrate for both plasma transglutaminase (Factor XIIIa) and guinea pig liver transglutaminase (GPLTG). When purified eIF-5A was incubated with GPLTG or Factor XIIIa in the presence of succinylated beta-casein, a covalent complex was identified. By isolating and analysing the product of the transglutaminases (TGases) reaction, the site of modification on eIF-5A has been identified as the unique amino acid hypusine. The complex beta-casein.eIF-5A was enzymatically digested with proteinases and the predicted covalent cross-link of gamma-glutamyl omega-hypusine was isolated from the digests by ion-exchange chromatography and purified by reversed-phase h.p.l.c. Acid hydrolysis of the purified dipeptide yielded equimolar amounts of hypusine and glutamic acid. Furthermore, fast atom bombardment m.s. analysis confirmed the isomer assignment to be gamma-glutamyl omega-hypusine. These data indicate that hypusine-50 of the eIF-5A chain functions as acyl acceptor substrate for TGases, and reveal that eIF-5A may be cross-linked to intracellular proteins by TGases. Because the precise function of eIF-5A is still unknown, our results appear particularly stimulating in the light of the recent finding of a new biological role for this protein as a cellular factor binding specifically to the human immunodeficiency virus-1 Rev activation domain [Ruhl, Himmelspach, Bahr, Hammerschmid, Jaksche, Wolff, Auschauer, Farrington, Probst, Bevec and Hauber (1993) J. Cell Biol. 123, 1309-1320]. PMID- 7848271 TI - Identification by photoaffinity labelling of a pyridine nucleotide-dependent tri iodothyronine-binding protein in the cytosol of cultured astroglial cells. AB - High-affinity 3,3',5-tri-iodo-L-thyronine (T3) binding (Kd approximately 0.3 nM) to the cytosol of cultured rat astroglial cells was strongly activated in the presence of pyridine nucleotides. A 35 kDa pyridine nucleotide-dependent T3 binding polypeptide (35K-TBP) was photoaffinity labelled using underivatized [125I]T3 in the presence of pyridine nucleotides and the free-radical scavenger dithiothreitol. Maximum activations of T3 binding and 35K-TBP photolabelling were obtained at approx. 1 x 10(-7) M NADP+ or NADPH, or 1 x 10(-4) M NADH. NAD+ and other nucleotides were without effect. NADPH is the form which activates T3 binding and 35K-TBP photolabelling, since cytosol contains NADP(+)-reducing activity, and the activation of both processes in the presence of NADPH and NADP+ was prevented by an exogenous NADPH oxidation system. NADPH behaved as an allosteric activator of T3 binding. The NADPH oxidation system promoted the release of bound T3 in the absence of any change in the total concentration of the hormone. The 35K-TBP photolabelling and [125I]T3 binding were similarly inhibited by non-radioactive T3 (half-maximum effect at 0.5-1.0 nM T3). The concentrations of iodothyronine analogues that inhibited both processes were correlated (3,3',5-tri-iodo-D-thyronine > or = T3 > L-thyroxine > tri iodothyroacetic acid > 3,3'5'-tri-iodo-L-thyronine). Molecular sieving and density-gradient centrifugation of cytosol identified a 65 kDa T3-binding entity, which included the 35K-TBP. These results indicate that 35K-TBP is the cytosolic entity involved in the pyridine nucleotide-dependent T3 binding, and suggest that the sequestration and release of intracellular thyroid hormones are regulated by the redox state of astroglial cell compartment(s). PMID- 7848272 TI - Binding of histone H1e-c variants to CpG-rich DNA correlates with the inhibitory effect on enzymic DNA methylation. AB - Within the H1 histone family, only some fractions enriched in the H1e-c variants are effective in causing a marked inhibition, in vitro, of enzymic DNA methylation and, in gel retardation and Southwestern blot experiments, in binding double-stranded (ds) CpG-rich oligonucleotides. Both the 6-CpG ds-oligonucleotide and the DNA purified from chromatin fractions enriched in 'CpG islands' are good competitors for the binding of H1e-c to 6-meCpG ds-oligonucleotide. Because of their ability to bind any DNA sequence and to suppress the enzymic methylation in any sequence containing CpG dinucleotides, these particular H1 variants could play some role in maintaining linker DNA at low methylation levels and even in preserving the unmethylated state of the CpG-rich islands which characterize the promoter regions of housekeeping genes. PMID- 7848273 TI - Heterologous expression in Escherichia coli of native and mutant forms of the major intrinsic protein of rat eye lens (MIP26). AB - The complete cDNA of rat eye lens major intrinsic protein (MIP26) was sequenced using the dideoxy chain termination method. The sequence displayed 89% nucleotide identity and 95% identity at the amino acid level with bovine MIP26 [Gorin, Yancey, Cline, Revel and Horwitz (1984) Cell, 39, 49-54]. Both native and mutant cDNAs coding for rat MIP26 were amplified by PCR and subcloned into the pPOW expression vector for expression of Escherichia coli. A membrane signal peptide (PelB) was used for secretion of MIP26 into the cytoplasmic membrane. A hydrophilic octapeptide tail (FLAG) was fused to either the N- or C-terminus of MIP26 to aid monoclonal antibody-mediated identification and purification. Heterologously expressed MIP26 was identified by using a monoclonal antibody corresponding to the FLAG peptide located at the termini of MIP26. Immunofluorescently labelled monoclonal antibody was used to determine the localization of MIP26 in the cytoplasmic membrane. The majority of the protein was integrated into cell plasma membrane. MIP26 was extracted with n-octyl beta-D glucopyranoside and then purified on an affinity gel column. Rat MIP26 cDNA contains an -Asn-Gly- sequence at the C-terminus, which has been shown in other proteins to be particularly susceptible to spontaneous deamidation [Takemoto and Emmons (1991) Curr. Eye Res. 10, 863-869]. We therefore modified the MIP26 molecule using a site-directed mutagenesis method to generate a mutant MIP26 at the appropriate asparagine residue (Asn244-->Asp) near the C-terminus. The mutation was confirmed by DNA sequencing. The mutant MIP26 protein was also expressed in E. coli and incorporated predominantly into the cytoplasmic membrane. PMID- 7848274 TI - Isoform I (mdr3) is the major form of P-glycoprotein expressed in mouse brain capillaries. Evidence for cross-reactivity of antibody C219 with an unrelated protein. AB - P-glycoprotein (P-gp) is expressed in various non-cancerous tissues such as the endothelial cells of the blood-brain barrier. We used several monoclonal antibodies (mAbs) and isoform-specific polyclonal antibodies to establish which P gp isoforms are expressed in isolated mouse brain capillaries. P-gp class I isoform was detected in capillaries with a Western immunoblotting procedure using a specific antiserum. No immunoreactivity was observed with either class II- or class III-specific antisera. Immunoreactivity was observed with mAb C219. However, this antibody detected two distinct immunoreactive proteins (155 and 190 kDa) in the isolated brain capillaries. These two proteins comigrated as a broad band when the samples were submitted to heat prior to gel electrophoresis. The glycoprotein nature of these two antigens was evaluated by their sensitivity to N glycanase treatment. Following this treatment, the size of the proteins was reduced from 190 and 155 kDa to 180 and 120 kDa, respectively. Triton X-114 phase partitioning studies showed that the 190 kDa immunoreactive protein was poorly solubilized by Triton X-114, while the 155 kDa protein was partitioned in the detergent-rich phase. In labelling experiments, only the 155 kDa protein was photolabelled with [125I]iodoarylazidoprazosin. These results show that a 190 kDa protein detected by antibody C219 is an antigen unrelated to the three P-gp isoforms presently known. Cross-reactivity of C219 with an unrelated protein emphasizes the fact that more than one antibody should be used in the assessment of P-gp expression in cell lines and tissues. PMID- 7848275 TI - A gelsolin-related protein from lobster muscle: cloning, sequence analysis and expression. AB - The tail muscle of the lobster Homarus americanus contains an actin-binding protein with an apparent molecular mass of 105 kDa determined by SDS/PAGE and gelsolin-like properties. We isolated this protein and peptide sequences were obtained after limited proteolysis with chymotrypsin. A tail-muscle-specific cDNA library was constructed in a lambda expression vector and a full-length clone was obtained by screening with a polyclonal anti-(crustacean gelsolin) antibody. The cDNA insert of approx. 3.2 kb length was sequenced. The cDNA contained an open reading frame of 2.265 kb, and the deduced amino acid sequence of 754 residues (83,469 Da) identified the protein as a cytoplasmic member of the gelsolin/villin protein family. Comparison of the lobster gelsolin amino acid sequence with other members of this protein family revealed the characteristic 6-fold repeated segmental structure as well as the three conserved sequence motifs typical of each segment [Way and Weeds (1988) J. Mol. Biol. 203, 1127-1133]. Strong homologies were found with Drosophila gelsolin, human gelsolin, villin core, Dictyostelium severin and Physarum fragmin. In addition, the gelsolin-like protein from lobster muscle revealed motifs that were clearly similar to the actin-bundling region of human villin headpiece although it did not itself contain a distinct headpiece domain. The recombinant lobster gelsolin-like protein, expressed in Escherichia coli as a fusion protein, was purified from inclusion bodies and renatured as a functional protein. There were no significant differences in the biological activity tested between the recombinant and the native protein isolated from lobster muscle. PMID- 7848276 TI - Platelet-derived growth factor and angiotensin II stimulate the mitogen-activated protein kinase cascade in renal mesangial cells: comparison of hypertrophic and hyperplastic agonists. AB - Exposure of mesangial cells to platelet-derived growth factor (PDGF) BB caused a significant stimulation of cell proliferation and protein synthesis, as measured by [3H]thymidine incorporation and [3H]leucine incorporation respectively. In contrast, cells treated with angiotensin II had no significant increase in [3H]thymidine incorporation, but demonstrated a marked increase in [3H]leucine incorporation. Furthermore, angiotensin II significantly increased total protein content per cell. These data show that, whereas PDGF-BB is a mitogen and stimulates mesangial-cell hyperplasia, angiotensin II causes hypertrophy of the cells without hyperplasia. Treatment of mesangial cells with PDGF and angiotensin II rapidly and dose-dependently stimulated mitogen-activated protein (MAP) kinase activity, as shown by an assay for activity in vitro using myelin basic protein as a substrate, and by immunoprecipitation of 32P-labelled cells with specific antibodies against the 42 kDa and 44 kDa mitogen-activated protein kinases p42mapk and p44mapk, respectively. Whereas stimulation with PDGF-BB caused a potent and sustained (for more than 30 min) phosphorylation and activation of p42mapk and p44mapk, as well as of the upstream activators MAP kinase kinase and c-Raf, the effect of angiotensin II was less potent, reaching a peak at 5-10 min and thereafter declining rapidly. In summary, these results suggest that PDGF-BB and angiotensin II differ in their potency and duration of activation of the MAP kinase cascade, which may explain why PDGF-BB is a potent mitogen for mesangial cells, whereas angiotensin II only triggers mesangial-cell hypertrophy. PMID- 7848277 TI - Circular-dichroism and fluorescence studies on melittin: effects of C-terminal modifications on tetramer formation and binding to phospholipid vesicles. AB - Studies were performed on a series of melittin analogues with selective alterations to the positively charged amino acid sequence at the C-terminus. Fluorescence studies were undertaken using the sole tryptophan residue in the analogues as an intrinsic fluorescence probe for indications of tetramer formation in free solution, and binding and insertion of the melittins into phospholipid bilayers. Studies were performed under conditions of low-salt buffer with increasing concentrations of phosphate added to promote self-association of the melittin monomers, and also in the presence of phospholipid vesicles. C.d. studies were also performed under conditions of increasing phosphate concentrations and in the presence of lipid vesicles to monitor the alpha-helical content of the melittins. It was found that selective replacement of the C terminal basic amino acids by glutamine has different effects on self association, alpha-helix formation and lipid binding of melittin. PMID- 7848278 TI - The effect of histone H1 and DNA methylation on transcription. AB - We have previously shown that DNA methylation acts as a focus for the formation of inactive chromatin in vivo. We have investigated the mechanism further by in vitro transcription of a template containing two tRNA genes and an extensive (G+C)-rich sequence characteristic of a CpG island. The extent of transcription from the unmethylated or fully methylated template was assayed in the presence of varied levels of histone H1. The transcriptional activity of both templates was inhibited by increasing amounts of histone H1, although inhibition with the methylated template occurs at a lower H1:DNA ratio. The H1c variant shows the greatest preferential inhibition of the methylated template. We demonstrated that histone H1 complexed to DNA is one of the factors that inhibits transcription by preventing the formation of initiation complexes, particularly on methylated template, rather than the formation of disordered H1.DNA aggregates. PMID- 7848279 TI - Cooperative interaction of oestrogen receptor 'zinc finger' domain polypeptides on DNA binding. AB - The consensus oestrogen response element (ERE) contains two inverted copies of an AGGTCA consensus hexameric half-site, spaced by three base pairs. It differs from many other hormone response elements, such as consensus thyroid (TREp) and retinoic acid (DR-5 RARE) response elements, only in the relative spacing and orientation of these sequences. In the present study we report values for cooperativity (omega) of an oestrogen receptor DNA-binding domain polypeptide upon binding to these sequences. The polypeptide binds with negative cooperativity, or without cooperativity to retinoic acid and thyroid response elements respectively, but with high cooperativity to the ERE. We have also examined cooperativity upon binding of the polypeptide to an ERE variant. Since naturally occurring EREs commonly contain one hexamer which is considerably more degenerate than the other, we designed a hybrid response element in which one hexamer is a consensus ERE, while specific mutations were introduced into the other. We chose to mutate the second half-site to a glucocorticoid response element (GRE) half-site sequence (AGAACA), since normally no binding of the DNA binding domain polypeptide to a GRE hexamer alone can be detected. In the hybrid response element, however, the GRE half-site is recognized with relatively high affinity, although binding to this sequence is dependent on the previous binding of a polypeptide to the ERE hexamer. Thus, cooperative interactions are capable of mediating the recognition of ERE sequence degeneracy. The ability of protein protein interactions to mediate recognition of DNA sequence degeneracy may also have implications for transcription factors in general. PMID- 7848280 TI - Tissue differences in the response of the pyruvate dehydrogenase complex to a glucose load during the development of obesity in gold-thioglucose-obese mice. AB - The activity of pyruvate dehydrogenase (PDHC), a key enzyme complex in the oxidative disposal of glucose, was measured after an oral glucose load in the heart, liver, quadriceps muscle, white adipose tissue (WAT) and brown adipose tissue (BAT) of gold-thioglucose (GTG)-obese mice at different stages during the development of obesity and in age-matched controls. Significant responses to the glucose load were seen 30 min post-gavage in heart, WAT and BAT of control mice but no change was observed in quadriceps muscle. The increase in activity of the active form of PDHC (PDHCa) in response to glucose in heart was reduced 2 weeks after the induction of GTG-obesity with no response in 5 or 10 week obese mice. A 2-3-fold increase in the PDHCa response in both WAT and BAT of 2 week obese mice was absent in 5 and 10 week obese animals. Basal PDHCa activity in quadriceps muscle was increased in 2 week obese mice but subsequently returned to control levels as obesity progressed. The glucose load produced no change in the activity of PDHCa in quadriceps muscle of obese mice. These results demonstrate that changes in the capacity for oxidative glucose disposal in different tissues, as indicated by changes in PDHCa activity, may contribute to glucose-intolerance and insulin-resistance in GTG-obese mice and that the response of the PDHC to insulin during the development of obesity varies in different tissues. PMID- 7848281 TI - Respiratory-deficient human fibroblasts exhibiting defective mitochondrial DNA replication. AB - We have characterized cultured skin fibroblasts from two siblings affected with a fatal mitochondrial disease caused by a nuclear genetic defect. Mitochondrial respiratory-chain function was severely decreased in these cells. Southern-blot analysis showed that the fibroblasts had reduced levels of mitochondrial DNA (mtDNA). The mtDNA was unstable and was eliminated from the cultured cells over many generations, generating the rho0 genotype. As the mtDNA level decreased, the cells became more dependent upon pyruvate and uridine for growth. Nuclear-encoded subunits of respiratory-chain complexes were synthesized and imported into the mitochondria of the mtDNA-depleted cells, albeit at reduced levels compared with the controls. Mitochondrial protein synthesis directed by the residual mtDNA indicated that the mtDNA was expressed and that the defect specifically involves the replication or maintenance of mtDNA. This is a unique example of a respiratory-deficient human cell line exhibiting defective mtDNA replication. PMID- 7848282 TI - Topological organization of the Rieske iron-sulphur protein and subunit IV in the cytochrome bc1 complex of Rhodobacter sphaeroides. AB - The ubiquinol-cytochrome c2 oxidoreductases (cytochrome bc1 complex) of Rhodobacter sphaeroides contains highly conserved cytochrome b, cytochrome c1 and Rieske FeS subunits, as well as a unique 14 kDa polypeptide, designated as subunit IV, thought to function as a ubiquinol-binding protein [Yu and Yu (1991) Biochemistry 30, 4934-4939]. As the topology of subunit IV is unknown and that of the FeS subunit remains a matter of debate, both the inner (cytoplasmic) and outer (periplasmic) surfaces of the intracytoplasmic membrane (ICM) were digested with proteinase K, and cleavage products were identified by immunoblotting. In uniformly oriented chromatophore vesicles (inner ICM surface exposed), fragments of approx. 4 and 1 kDa were removed from subunit IV and the FeS protein respectively. Neither subunit IV nor the FeS protein was cleaved from the outer ICM surface as exposed in osmotically protected spheroplasts or as presented to proteinase K after microencapsulation of the protease in unilamellar liposomes and fusion of these structures to chromatophore vesicles. Studies with the isolated bc1 complex, however, suggested that the C-terminal domain of the Rieske FeS, thought to reside on the periplasmic side of the ICM, was resistant to proteinase K. Overall, these results suggest a single N-terminal transmembrane helix for the FeS protein, with exposure of the N-terminus to the cytoplasm and an orientation in which a major, N-terminal portion of subunit IV is located in the cytoplasm with the predicted C-terminal transmembrane domain anchoring this polypeptide to the membrane. PMID- 7848283 TI - Expression of human platelet-activating factor receptor gene in EoL-1 cells following butyrate-induced differentiation. AB - Platelet-activating factor (PAF) is a potent lipid mediator of allergic inflammation through its interaction with eosinophils. Expression of the PAF receptor is modulated by many agents, including those responsible for cell differentiation. We report here that differentiation of a human eosinophilic leukaemia cell line, EoL-1, by sodium n-butyrate is associated with induction of PAF receptor gene expression, as indicated by: PAF receptor mRNA accumulation; increases in the binding of [3H]WEB 2086, a PAF antagonist; analysis of cell surface expression of PAF receptor protein using a monoclonal anti-(PAF receptor) antibody; and augmentation of PAF-induced increase in the intracellular concentration of calcium. Using cDNA cloning, the receptor expressed in EoL-1 cells was identified as 'Transcript 1', one of two transcripts which was previously reported from human genomic analysis (Mutoh, Bito, Minami, Nakamura, Honda, Izumi, Nakata, Kurachi, Terano and Shimizu (1993) FEBS Lett. 322, 129 134). The PAF-induced calcium response and phosphoinositide turnover were decreased by pertussis toxin (PTX) treatment, suggesting that these signals are coupled largely with PTX-sensitive G-protein(s) in EoL-1 cells. These systems may provide a useful experimental model with which to investigate the relationship between eosinophilic differentiation and PAF receptor induction, and the role of eosinophils in allergic responses. PMID- 7848284 TI - Activation of hepatic glutaminase by spermine. AB - Glutaminase activity in intact mitochondria from rat liver is activated by spermine, as indicated both by increased glutamate production from glutamine and by increased respiration with glutamine as sole substrate. Glutaminase activity assayed in membranes from frozen-thawed mitochondria, is activated by spermine about 6-fold at physiological concentrations of its other effectors (NH4+ at 0.7 mM, Pi 5 mM) and at pH 7.4. Spermine decreased the apparent Km for glutamine from 38 to 15 mM at 5 mM Pi, and increased the sensitivity of the enzyme for phosphate activation so that the concentration required for 50% stimulation decreased from 15 to 4 mM. Half-maximal spermine effects occurred at 0.15 mM, which is in the physiological range. Spermine was effective in the presence of physiological concentrations of Mg2+. We suggest that spermine may be a physiological activator of hepatic glutaminase. PMID- 7848285 TI - Identification of a 23 kDa protein from maize photoaffinity-labelled with 5-azido [7-3H]indol-3-ylacetic acid. AB - A 23 kDa protein (p23) was identified in microsomal extracts from maize coleoptiles by photoaffinity labelling with 5-azido-[7-3H]indol-3-ylacetic acid ([3H]N3IAA). Labelling of p23 was blocked by unlabelled IAA, N3IAA, indol-3 ylbutyric acid and indol-3-yl-lactate. In addition, labelling was efficiently decreased by tryptophan, as well as by the scavenger p-aminobenzoic acid. Labelling was, however, not affected by synthetic auxins such as 1-naphthylacetic acid or 2,4-dichlorophenoxyacetic acid. Competition data suggest that the label was probably bound via the indole ring, and hence labelling was not specific for auxins. The 23 kDa protein was solubilized from crude microsomes by extraction with Triton X-100 and purified to homogeneity by ion-exchange, size-exclusion and reversed-phase chromatography. After electroblotting, the amino acid sequences of the p23 N-terminus as well as the several tryptic peptides were obtained. Database comparisons revealed sequence identity with a maize manganese superoxide dismutase. We conclude that photoaffinity labelling of p23 was pseudo-affinity, and therefore the binding site for IAA is not specific. PMID- 7848286 TI - Arachidonic acid is functioning as a second messenger in activating the Ca2+ entry process on H1-histaminoceptor stimulation in DDT1 MF-2 cells. AB - This study was carried out to identify the cellular component activating the histamine-stimulated Ca2+ entry in vas-deferens-derived DDT1 MF-2 cells. H1 histaminoceptor stimulation resulted in a rise in intracellular Ca2+ concentration, caused by Ca2+ release from inositol phosphate-sensitive Ca2+ stores and Ca2+ entry from the extracellular space, accompanied by a transient Ca(2+)-activated outward K+ current. The histamine-evoked K+ current was still observed after preventing inositol phosphate-induced Ca2+ mobilization by intracellularly applied heparin. This current was activated by Ca2+ entry from the extracellular space, because it was abolished in the presence of the Ca(2+) channel blocker La3+ or under Ca(2+)-free conditions. H1-histaminoceptor activated Ca2+ entry was also observed in the presence of intracellularly applied Ins(1,4,5)P3 and Ins(1,3,4,5)P4, depleting their respective Ca2+ stores and pre activating the inositol phosphate-regulated Ca2+ entry. Thus the ability of histamine to activate Ca2+ entry independently of Ca2+ mobilization and the formation of inositol phosphates suggests that another component is involved to initiate the Ca(2+)-entry process. It was observed that H1-histaminoceptor stimulation resulted in a pronounced release of arachidonic acid (AA) in DDT1 MF 2 cells. Exogenously applied AA induced a concentration-dependent increase in internal Ca2+ due to activation of Ca2+ entry from the extracellular space. Slow inactivation of the AA-sensitive Ca2+ channels is suggested by the slow decline in Ca2+ entry. In accord, the histamine-induced Ca2+ entry was not observed with AA-pre-activated Ca2+ channels. Inhibition of the lipoxygenase and cyclo oxygenase pathway did not affect the AA-induced Ca2+ and the concomitant K+ current were decreased in the presence of AA and caused by Ca2+ mobilization from internal stores. Blocking this internal Ca2+ release by heparin, in the presence of AA, resulted in abolition of the histamine-induced Ca(2+)-regulated K+ current. These observations show that AA, released on H1-histaminoceptor stimulation in DDT1 MF-2 cells, is functioning as a second messenger to activate plasma-membrane Ca2+ channels promoting Ca2+ entry from the extracellular space. PMID- 7848287 TI - The effect of increasing nucleotide-sugar concentrations on the incorporation of sugars into glycoconjugates in rat hepatocytes. AB - Treatment of rat hepatocytes with 0.5 mM concentrations of uridine and cytidine results in increased cellular concentrations of UTP, UDP-sugars and CTP, whereas that of CMP-N-acetylneuraminate remained unchanged [Pels Rijcken, Overdijk, Van den Eijnden and Ferwerda (1993) Biochem. J. 293, 207-213]. The incorporation of radioactivity from 3H-labelled sugars into the cell-associated and secreted glycoconjugate fraction was influenced by these altered cellular concentrations of the nucleotides. For [3H]glucosamine, pretreatment with uridine resulted in a reduction of the glycosylation in both fractions. Increases in the secreted fractions were observed for fucose with both uridine and cytidine and for N acetylglucosamine with uridine only. With [3H]N-acetylglucosamine, similar specific radioactivities for UDP-N-acetylhexosamine and CMP-N-acetylneuraminate were found, regardless of the pretreatment conditions. With [3H]N acetylmannosamine, the specific radioactivity of CMP-N-acetylneuraminate showed an almost 2-fold increase on pretreatment. The latter increase did not result in an increased incorporation of radioactivity into the glycoconjugates. It was estimated that, in untreated cells, the ratio of radioactivity incorporated from [3H]glucosamine into glycoconjugate-bound N-acetylhexosamine and N acetylneuraminate amounted to 2:3. In pretreated cells this ratio changed to approx. 2:1. Overall, the data show that pretreatment resulted in an increased incorporation of N-acetylhexosamine into cell-associated and secreted glycoconjugates, accompanied by a reduction in sialylation. It was concluded that an increased availability of UDP-N-acetylhexosamine caused the increased incorporation of N-acetylhexosamine. The elevated cytosolic level of UDP-N acetylhexosamine (and of compounds like CMP) is suggested to impair the transport of CMP-acetylneuraminate to the Golgi, resulting in reduced sialylation. This study demonstrates that protein glycosylation can be regulated at the level of the availability of the various nucleotide-sugars in the Golgi lumen. PMID- 7848288 TI - Measurement of the spin concentration of metalloprotein samples from saturation magnetization data with particular reference to cytochrome c oxidase. AB - A protocol for obtaining high-quality saturation-magnetization data from metalloprotein samples, employing a superconducting quantum interference device (SQUID) magnetometer, has previously been reported [E. P. Day, T. A. Kent, P. A. Lindahl, E. Munck, W. H. Orme-Johnson, H. Roder and A. Roy (1987) Biophys. J. 52, 837-853 and E. P. Day (1993) Methods Enzymol. 227, 437-463]. Following studies of several dozen different metalloprotein derivatives, the methodology has been further refined, particularly in the area of sample preparation. The details of the sample-handling procedures now in use are described, and moreover, the critical issue of verifying that contamination by paramagnetic impurities remains insignificant is considered. Importantly, it is shown that an independent determination of the quantity of paramagnetic sample present in the magnetometer is undesirable. Much more reliable parameters concerning the ground-state magnetic properties of the system under study are obtained if enough saturation magnetization data are collected to enable the spin concentration to be determined during the subsequent fitting procedure. As proof of the validity of this method, the results of magnetization studies on ferricytochrome c, ferrocytochrome c and the benzohydroxamic acid adduct of horseradish peroxidase are presented. The ability of saturation-magnetization measurements to routinely determine spin concentration to within +/- 4% of accepted values is firmly established. In addition, a saturation-magnetization study has been performed on resting and fully reduced derivatives of cytochrome c oxidase. These results provide an illustration of the usefulness of the technique in probing some systems which have proved difficult to study by other methods. The increased difficulties inherent in obtaining meaningful data from these cytochrome c oxidase and other integer spin systems are delineated. PMID- 7848289 TI - Biphasic and differential modulation of Ca2+ entry by ATP and UTP in promyelocytic leukaemia HL60 cells. AB - ATP and UTP cause mobilization of Ca2+ from the intracellular stores with similar potency in several cell types including both undifferentiated and differentiated HL60 cells. We show here that, in HL60 cells with Ca2+ stores that had been fully and irreversibly emptied using the endomembrane Ca(2+)-ATPase inhibitor thapsigargin, both nucleotides produced a biphasic effect on Ca2+ entry, first rapid inhibition and then delayed (about 15 s) activation. ATP was more effective at producing the initial inhibition of Ca2+ entry, whereas UTP was more effective at activating the delayed Ca2+ entry. Previous incubation with UTP desensitized the Ca2+ mobilization and the delayed activation of Ca2+ entry induced by ATP but not the inhibition of Ca2+ entry. The ATP analogue 2-methylthioATP (2-MeSATP) barely mobilized stored Ca2+ but inhibited Ca2+ entry. These results could be explained by the presence of two receptors: (i) a P2u receptor sensitive to ATP and UTP, responsible for activation of phospholipase C and Ca2+ mobilization, early inhibition of Ca2+ entry and delayed activation of Ca2+ entry and (ii) a P2y-like receptor sensitive to ATP and 2-MeSATP which produces only inhibition of Ca2+ entry. The inhibition of Ca2+ entry by nucleotides increased greatly during differentiation. Given that Ca2+ mobilization by nucleotides is not modified by differentiation, this suggests that a component of the mechanism of inhibition of Ca2+ entry is gradually expressed during differentiation of HL60 cells. PMID- 7848290 TI - Comparative study of the structural and functional properties of a bovine plasma C-type lectin, collectin-43, with other collectins. AB - Collectin-43 (CL-43) is a recently described bovine plasma protein containing both collagenous regions and C-type-lectin domains [Holmskov, Teisner, Willis, Reid and Jensenius (1993) J. Biol. Chem. 268, 10120-10125; Lim, Willis, Reid, Lu, Laursen, Jensenius and Holmskov (1994) J. Biol. Chem. 269, 11820-11824]. CL-43 was purified by affinity chromatography on mannan-Sepharose. On SDS/PAGE under reducing conditions the purified lectin showed a double band at about 43 kDa, with the upper band representing the intact molecule and the lower band a truncated form that lacked the N-terminal nine amino acid residues. Under non reducing conditions, only one band was seen at 120 kDa. Analytical gel chromatography and sucrose-density-gradient centrifugation of the purified molecule, showed a Stokes radius of 9.1 +/- 0.3 nm (91 +/- 3 A) and a sedimentation coefficient (s20,w) of 3.6 +/- 0.1 S. These values correspond to a molecular mass of 119-138 kDa under non-denaturing condition in solution. The frictional coefficient (f/f0) was 2.7, indicating extreme elongation due to the collagenous segment. Only monomer subunits, with 37.4 +/- 1.7-nm-long rods, were seen by electron microscopy. These findings indicate that CL-43, in contrast with the other circulating collectins, is found only as a single subunit composed of three polypeptide chains. Two-dimensional gel electrophoresis showed that CL-43 has two isoforms, with pI values of 4.9 and 5.3, corresponding to the native form and the truncated form of the molecule respectively. CL-43, like conglutinin, lung surfactant protein A and mannan-binding protein (MBP), was shown to bind to the collectin receptor. Bovine MBP caused the activation of the complement system as revealed by the deposition of complement component C4 upon incubation of diluted serum in wells containing MBP bound to solid-phase mannan. CL-43, lung surfactant protein D (SP-D) and conglutinin showed no complement-activating properties under the same conditions. Conglutinin binds fluid- and solid-phase iC3b, while CL-43 and MBP do not show such reactivity. PMID- 7848291 TI - Measurement of the absolute number of functioning low-density lipoprotein receptors in vivo using a monoclonal antibody. AB - MAC188 S/S is a monoclonal antibody which can be used in vivo to measure the absolute number of functioning low-density lipoprotein (LDL) receptors in a rabbit. The antibody binds to the extra-cellular domain of the LDL receptor and binding is not blocked by the presence of LDL. When the antibody-receptor complex is internalized, receptor recycling is inhibited for several hours. Thus when saturating doses of MAC188 S/S are administered intravenously, the amount of antibody removed from the blood (minus non-specific removal) is determined solely by the total number of LDL receptors in an animal. In this study MAC188 S/S was used to measure the number of LDL receptors in control rabbits and in animals treated with 17 alpha-ethinyl oestradiol. After treatment (which caused a 47% decrease in plasma cholesterol), receptor-mediated removal of MAC188 S/S from the blood was saturated in both groups following injection of 3.0 mg of antibody per kg body weight. Based on the amount of antibody removed via the LDL receptor at this dose, the total number of accessible LDL receptors was calculated as (2.0 +/ 0.3) x 10(15) receptors per kg body weight in control rabbits and (4.0 +/- 0.4) x 10(15) receptors per kg body weight in oestrogen-treated animals. The number of receptors in various organs was also determined. The monoclonal antibody approach therefore, allows accurate determination of LDL receptor numbers in animals with markedly different concentrations of circulating LDL, conditions in which the use of endogenous ligand would be subject to significant errors. PMID- 7848292 TI - Increased response to cholesterol feeding in apolipoprotein C1-deficient mice. AB - The function of apolipoprotein (apo) C1 in vivo is not well understood. From in vitro studies it has been reported that an excess of apoC1 relative to apoE inhibits receptor-mediated uptake of remnant lipoproteins [Sehayek and Eisenberg (1991) J. Biol. Chem. 266, 22453-22459]. In order to gain a better understanding of the role of apoC1 in lipoprotein metabolism in vivo, we have generated apoC1 deficient mice by gene targeting in embryonic stem cells. Homozygous mutant mice are viable and do not show overt abnormalities. Serum triacylglycerol levels are increased by 60% on both a standard mouse diet and a mild hypercholesterolaemic diet compared with controls. Total serum cholesterol levels are similar to controls on the two diets. However, the level of high-density lipoprotein cholesterol in the apoC1-deficient mice fed on the mild hypercholesterolaemic diet is slightly decreased, which is accompanied by a 3-fold increase in very-low density plus low-density lipoprotein (VLDL+LDL) cholesterol. On a severe atherogenic diet, the homozygous apoC1-deficient mice become hypercholesterolaemic, with a serum cholesterol level of 10.7 +/- 3.3 mM compared with 6.7 +/- 1.8 mM and 5.1 +/- 1.6 mM in heterozygous and control mice respectively. The increase in cholesterol is mainly confined to the VLDL+LDL sized fractions. Binding experiments revealed that lipoproteins lacking apoC1 with d < 1.006 g/ml are poor competitors for 125I-labelled LDL binding to the LDL receptor on HepG2 cells. This suggests that total apoC1 deficiency leads to impaired receptor-mediated clearance of remnant lipoproteins rather than enhanced uptake, as was expected from data reported in the literature. PMID- 7848293 TI - Cell-type specificity of inhibition of glycolysis by 5-amino-4 imidazolecarboxamide riboside. Lack of effect in rabbit cardiomyocytes and human erythrocytes, and inhibition in FTO-2B rat hepatoma cells. AB - The nucleoside AICAriboside (5-amino-4-imidazolecarboxamide riboside) has been shown to inhibit glycolysis in isolated rat hepatocytes [Vincent, Bontemps and Van den Berghe (1992) Biochem. J. 281, 267-272]. The effect is mediated by AICA ribotide (ZMP), the product of the phosphorylation of AICA-riboside by adenosine kinase. To assess the cell-type specificity of the effect, studies were conducted in rabbit cardiomyocytes, human erythrocytes and rat hepatoma FTO-2B cells. AICA riboside had no effect on glycolysis in cardiomyocytes, and a slight stimulatory effect in erythrocytes, but inhibited glycolysis by 65% at 250 microM concentration in FTO-2B cells, although only when tissue-culture medium was replaced by Krebs-Ringer bicarbonate buffer. At 500 microM AICAriboside, ZMP remained undetectable in cardiomyocytes, but reached 0.65 mM in erythrocytes and 5 mM in FTO-2B cells. In the latter, AICAriboside provoked up to 2-fold elevations of glucose 6-phosphate and fructose 6-phosphate, accompanied by a decrease in fructose 1,6-bisphosphate. This indicated inhibition of 6 phosphofructo-1-kinase (PFK-1). Accordingly, in FTO-2B cell-free extracts, the activity of PFK-1, measured under physiological conditions, was inhibited by approx. 70% by 5 mM ZMP. ZMP had a less pronounced effect on the activity of PFK 1 in normal rat liver; it did not influence the activity of PFK-1 in rat muscle, rabbit heart and human erythrocytes. It is concluded that the inhibitory effect of AICAriboside on glycolysis is dependent on both (1) the capacity of the cells to accumulate ZMP and (2) the presence of target enzymes which are sensitive to ZMP. PMID- 7848294 TI - Regulatory effects of ATP and luciferin on firefly luciferase activity. AB - ATP and luciferin are not only substrates of firefly luciferase, but can, in addition, modulate its activity. High concentrations of luciferin induce a conformational change of the enzyme that temporarily reduces the catalytic rate. Re-activation takes approx. 20 min and is independent of variation in the concentration of enzyme or ATP, but lengthens with increasing luciferin concentration. High concentrations of albumin reduce this luciferin effect. The kinetic properties of firefly luciferase determined from initial rates and at steady state after 1 min of catalysis have been analysed according to Michaelis Menten kinetics. There is only one active site for each of the substrates. At steady state the Km and Vmax. values for both substrates are reduced in an uncompetitive manner. Hyperbolic Lineweaver-Burk plots indicate an activation by ATP probably by binding to an allosteric site. A model is presented which incorporates luciferin induced de- and re-activation effects. Experimental conditions to avoid the regulatory effects of substrates during ATP monitoring are proposed. PMID- 7848295 TI - Changes in the structure of bovine phospholipase A2 upon micelle binding. AB - Phospholipase A2 (PLA2) is a calcium-dependent enzyme which hydrolyses the 2-acyl ester bond of phospholipids. The extracellular PLA2s are activated by as much as 10000-fold on binding to micelles or vesicles of substrate, possibly due to a conformational change induced in the enzyme. We have studied the complex of bovine pancreatic PLA2 with micelles of SDS by ultracentrifugation, equilibrium dialysis, microcalorimetry, fluorescence and n.m.r. spectroscopy. Ultracentrifugation and equilibrium dialysis measurements showed that on average 1.28 (+/- 0.17) PLA2 molecules and 26.4 (+/- 3.1) SDS molecules are involved in the complex and that there is a rapid equilibrium between micellar species containing one or more enzyme monomers. The estimated heat of formation of the complex, measured calorimetrically as the heat released when PLA2 was injected into excess 10 mM SDS, was 162.3 +/- 1.5) kJ/mol [38.8 (+/- 0.35) kcal/mol] of PLA2 added. The fluorescence of the single tryptophan at position 3 in the N terminal helix of the protein increases when PLA2 binds to SDS micelles, indicating that this part of the protein is in a more hydrophobic environment in the complex. The structural changes in PLA2 on addition of [2H25]SDS were monitored using n.m.r. spectroscopy. The overall structure of the protein is unchanged, but changes in nuclear Overhauser effects (NOEs) were observed for residues in the N-terminal helix, at the active site region and in a lysine-rich region near the C-terminus. The NOE changes at the N-terminus indicate that this portion of the protein molecule adopts a more ordered, helical conformation when bound to a micelle. We suggest that these conformational changes could be the mechanism by which the enzyme becomes activated in the presence of aggregated substrate. PMID- 7848296 TI - Insulin-independent and extremely rapid switch in the partitioning of hepatic fatty acids from oxidation to esterification in starved-refed diabetic rats. Possible roles for changes in cell pH and volume. AB - The requirement for a normal insulin response in mediating the starved-to-refed transition, with respect to the partitioning of hepatic fatty acids between beta oxidation and esterification to glycerol, was studied. Diabetic rats were starved for 24 h and refed ad libitum for various periods of time. There was no increase in plasma insulin in response to the meal. However, the fatty acid oxidation:esterification ratio was very rapidly decreased from the starved to the fed value, most of the transition being achieved within the first hour of refeeding. There was a 2 h lag in the response of hepatic malonyl-CoA concentration, such that this rapid switch from oxidation to esterification could not be explained on the basis of changes in the absolute concentration of this inhibitor of carnitine palmitoyltransferase I (CPT I). Hepatic pyruvate and lactate concentrations both increased by several-fold upon refeeding and peaked after 1 h and 3 h, respectively. The hepatic lactate:pyruvate ratio increased 3.2 fold during the first 3 h of refeeding, suggesting that the cytosolic NAD(+)-NADH couple became much more highly reduced during the lag-period between the onset of inhibition of flux of fatty acids towards oxidation and the rise in malonyl-CoA concentration. This may be indicative of a lowering of intracellular pH, which would amplify greatly the sensitivity of CPT I to the inhibitor. In view of the very rapid and high food intake by these diabetic rats, the possibility is also considered that portal concentrations of amino acids and other metabolites could give rise to an increase in liver cell-volume that would inhibit CPT I acutely by an as yet unknown mechanism [M. Guzman, G. Velasco, J. Castro and V. A. Zammit (1994) FEBS Lett. 344, 239-241]. PMID- 7848297 TI - Conformational changes and in vitro core-formation modifications induced by site directed mutagenesis of the specific N-terminus of pea seed ferritin. AB - Plant ferritin has a three-dimensional structure predicted to be very similar to that of animal ferritin. It has, however, an additional specific sequence of 24 amino acids at its N-terminus named extension peptide (EP). In order to determine precisely the interactions between EP and other domains of the pea seed ferritin subunit, three point mutations were performed. The mutated residues were chosen by three-dimensional computer modelling of the pea seed ferritin subunit structure [Lobreaux, Yewdall, Briat and Harrison (1992) Biochem. J. 228, 931 939]. The mutant recombinant proteins were expressed in Escherichia coli and purified to homogeneity; all the mutants were found to be assembled as 24-mers. When Ala-13 was replaced by His, as in mammalian ferritins, ferroxidase activity was significantly reduced. Moreover, in vitro iron-core formation in Pro-X-->Ala, Lys-R-->Glu and Ala-13-->His mutants was increased after denaturation by urea followed by renaturation; this was also observed with the EP deletion mutant (r delta TP/EP). The recombinant ferritins were also analysed using tryptophan fluorescence spectra. The r delta TP/EP, Pro-X-->Ala and Lys-R-->Glu mutants were found to be more susceptible to denaturation by urea than the native r delta TP pea seed ferritin. PMID- 7848298 TI - In vitro association between the Jun protein family and the general transcription factors, TBP and TFIIB. AB - Transcriptional activator proteins interact with the general transcription factors TATA-binding protein (TBP), TFIIB and/or other TBP-associated factors (TAFs). Using affinity chromatography we demonstrate that members of the Jun family of transcriptional activators interact with both TBP and TFIIB in vitro. TBP binds to both the N-terminal activation domain and C-terminal bZIP regions of c-Jun, whereas TFIIB binds to only the c-Jun bZIP domain. This interaction requires the dimerization of the Jun protein. The ability of the N-terminal activation domains of c-Jun, JunB, JunD and v-Jun to interact with TBP in vitro correlates with their transcriptional activity in vivo. Domain mapping experiments indicate that c-Jun interacts with the conserved C-terminus of TBP. Studies using a set of TFIIB inframe deletion mutants demonstrate that C-terminal amino acids 178-201 and 238-316 play an important role in modulating the interaction between TFIIB and c-Jun. Although phosphorylation of the c-Jun N terminal activation domain stimulates c-Jun transcriptional activity in vivo, it has no effect on the ability of c-Jun to interact with either TBP or TFIIB in vitro. These data suggest that the Jun family of activator proteins may activate transcription by interacting with the general transcription factors TBP and TFIIB. PMID- 7848299 TI - Hepatic molecular conversion and detoxification of ferritin iron in adult lampreys (Geotria australis), following natural and induced iron loading. AB - Weekly intramuscular injections of 3 mg of iron as horse spleen ferritin into adult Geotria australis over 10 weeks, resulted in a progressive increase in that form of iron in the serum. However, as with control animals, the ferritin in the liver of injected lampreys consisted of one subunit type, whose M(r) (20,300) differed from those of the two subunit types of horse spleen ferritin. Thus, lampreys had converted horse spleen ferritin iron into endogenous ferritin iron, presumably in their liver. Marked rises in hepatic non-haem iron during the first 2 weeks and between weeks 8 and 10 of iron injections were accompanied by pronounced increases in superoxide dismutase (SOD) activity. This rise, which parallels the rise in SOD activity that occurs as iron increases during the very protracted upstream migration of G. australis, is consistent with the view that SOD protects against iron-mediated damage by removing the superoxide radical, which facilitates the formation of the highly toxic hydroxyl radical. A levelling off of the iron concentration between weeks 2 and 8 was accompanied by a decline in SOD activity, even though nonhaem iron levels were well above those of control animals. Enhanced SOD activity may therefore only be required when there is an elevated flux of iron in the liver through low-molecular-mass intermediates. A small amount of ferritin iron was converted into the more inert haemosiderin iron. PMID- 7848300 TI - A single-chain insulin-like growth factor I/insulin hybrid binds with high affinity to the insulin receptor. AB - 1. To investigate the structure/function relationship of the interaction between ligand and receptor in the insulin-like growth factor I (IGF-I) and insulin receptor systems we have prepared and characterized a single-chain insulin/IGF-I hybrid. The single-chain hybrid consists of the insulin molecule combined with the C domain of IGF-I. The single-chain hybrid was found to bind with high affinity to both truncated soluble insulin receptors and membrane-bound holoreceptors. The affinity for interacting with the soluble truncated insulin receptors was 55-94% relative to insulin, and affinity for membrane-bound insulin receptors was 113% of that of insulin. Furthermore we found that the affinity of the single-chain hybrid molecule for IGF-I receptors was 19-28% relative to IGF I. 2. The affinity of the single-chain hybrid for chimeric insulin/IGF-I receptors exceeded that of either natural ligand. This indicates that coordinately changing domains of the receptors and the ligands can induce higher affinity of ligand for receptor, supporting the idea that these receptors have a common ligand-binding site [Kjeldsen, Andersen, Wiberg, Rasmussen, Schaffer, Balschmidt, Moller and Moller (1991) Proc. Natl. Acad. Sci. U.S.A. 88, 4404 4408]. 3. In contrast with what was generally assumed about the ligand structure required for binding to the insulin receptor we demonstrate the first single chain insulin analogue that can bind with high affinity to the insulin receptor. PMID- 7848301 TI - Translocation of nucleophosmin from nucleoli to nucleoplasm requires ATP. AB - The movement of nucleophosmin from nucleoli to nucleoplasm in HeLa cells induced by cytotoxic drugs and detected by immunofluorescence is inhibited by concomitant treatment with antimycin A in glucose-free medium. Incubation of HeLa cells with antimycin A (300 nM; 30 min) and glucose-free medium resulted in an approximately 90% decrease in cellular ATP pools. To study the biochemical events involved in nucleophosmin translocation, we used an in vitro system consisting of Triton permeabilized HeLA cells. Incubation of permeabilized cells with ATP (0.5 mM; 1 h) resulted in the translocation of nucleophosmin from nucleoli to nucleoplasm and cytoplasm. Similarly to drug-induced nucleophosmin translocation in whole cultured cells, there is no reduction (measured by e.l.i.s.a.) or degradation of nucleophosmin or change in the ratio of the high-molecular-mass form to the monomeric form (ascertained by Western blotting) during ATP treatment of permeabilized cells. Together, these results indicate a requirement for ATP for redistribution of nucleophosmin from nucleoli to nucleoplasm. Because this permeabilized cell model is simple and efficient and works effectively with exogenous factors, it should provide a powerful tool for investigating the biochemical features of nucleophosmin translocation from nucleoli to nucleoplasm. PMID- 7848302 TI - Sulphation of L-tyrosine in mammalian cells: a comparative study. AB - Chang liver cells, Caco-2 human intestinal epithelial cells and Madin-Darby canine kidney (MDCK) cells, labelled with [35S]sulphate in the presence of different concentrations of cycloheximide, produced 87.7-95.3%, 35.8-41.1% and 23.2-25.9%, respectively, of the amounts of free tyrosine O-[35S]-sulphate (Tyr[35S]) formed by corresponding cells labelled in the absence of cycloheximide. Homogenates prepared from the three kinds of cells showed the presence of enzymic activities catalysing the sulphation of L-tyrosine, with specific activities in the order: Caco-2 cells > MDCK cells > Chang liver cells. In all three cases, most of the tyrosine sulphotransferase' activity was found in the cytosolic fraction, indicating the enzyme to be a cysolic protein. A tyrosine dependence experiment revealed that, for all three kinds of cells labelled with [35S]sulphate, the production of free Tyr[35S] was proportional to the concentration of L-tyrosine present in the culture medium. These results imply an involvement of sulphation in removing excess intracellular L-tyrosine. PMID- 7848304 TI - Inhibition of the production and effects of interleukin-1 and tumor necrosis factor alpha in rheumatoid arthritis. AB - This review has summarized information published over the last 5 years on the presence and pathophysiologic role of IL-1 and TNF alpha in RA. The evidence to date shows that 5 of 6 criteria for identifying mediators of tissue damage in human autoimmune diseases are satisfied (Table 1). The last criterion, prevention of clinical progression in patients with RA, is currently being evaluated. Many new therapeutic approaches are currently being developed, including the use of soluble receptors to IL-1 or TNF, monoclonal antibodies to TNF alpha, a specific IL-1 receptor antagonist, and gene therapy with the latter molecule. It should be emphasized that both IL-1 and TNF alpha play important roles in normal host defense; the possible complications of blocking their production or effects need to be carefully evaluated in long-term studies. A recent review has emphasized that although IL-1 and TNF alpha have many overlapping biologic properties, each may exhibit distinct effects in joint disease (99). Anti-TNF treatment may be primarily antiinflammatory but blocking IL-1 may be more effective in preventing cartilage destruction (100). The possibility exists that simultaneous inhibition of TNF alpha and IL-1 may be more therapeutically efficacious than blockade of either agent alone, as was recently demonstrated with IL-1ra and soluble TNF receptors in bacterial cell wall-induced arthritis in rats (101). The next level of clinical studies in rheumatoid arthritis should include the use of two biologic response modifiers together, or one agent combined with a more traditional form of therapy. PMID- 7848303 TI - Glyoxalase III from Escherichia coli: a single novel enzyme for the conversion of methylglyoxal into D-lactate without reduced glutathione. AB - A single novel enzyme, glyoxalase III, which catalyses the conversion of methylglyoxal into D-lactate without involvement of GSH, has been detected in and purified from Escherichia coli. Of several carbonyl compounds tested, only the alpha-ketoaldehydes methylglyoxal and phenylglyoxal were found to be substrates for this enzyme. Glyoxalase III is active over a wide range of pH with no sharp pH optimum. In its native form it has an M(r) of 82000 +/- 2000, and it is composed of two subunits of equal M(r). Glutathione analogues, which are inhibitors of glyoxalase I, do not inhibit glyoxalase III. Glyoxalase III is found to be sensitive to thiol-blocking reagents. The p-hydroxymercuribenzoate inactivated enzyme could be almost completely re-activated by dithiothreitol and other thiol-group-containing compounds, indicating the possible involvement of thiol group(s) at or near the active site of the enzyme. PMID- 7848305 TI - Does childhood sexual abuse cause fibromyalgia? PMID- 7848306 TI - Role of interleukin-1, tumor necrosis factor alpha, and interleukin-6 in cartilage proteoglycan metabolism and destruction. Effect of in situ blocking in murine antigen- and zymosan-induced arthritis. AB - OBJECTIVE: To determine the involvement of interleukin-1 (IL-1), tumor necrosis factor (TNF), and IL-6 in the cartilage pathology of murine antigen-induced arthritis (AIA) and zymosan-induced arthritis (ZIA). METHODS: Arthritis was induced by intraarticular injection of zymosan in naive mice or by subcutaneous injection of methylated bovine serum albumin in sensitized animals. Mini-osmotic pumps releasing human recombinant IL-1 receptor antagonist (IL-1ra) protein were implanted intraperitoneally 2 days before arthritis induction, and neutralizing antibodies directed against murine IL-1 alpha, IL-1 beta, TNF alpha, or IL-6 were administered 1 day before. Proteoglycan (PG) synthesis and degradation were assessed in patellar cartilage. RESULTS: Murine IL-1 alpha and IL-1 beta injected intraarticularly at doses of 0.1-100 ng suppressed chondrocyte PG synthesis. The highest dose of TNF tested (100 ng) decreased PG synthesis marginally. In contrast, the maximum dose of IL-6 (1 microgram) stimulated PG synthesis 2 days after injection. Treatment of AIA with neutralizing monoclonal antibodies against either TNF alpha or IL-6 did not reduce either the PG degradation or the suppression of its synthesis. However, treatment with anti-IL-1 (alpha + beta) polyclonal antibodies totally prevented PG suppression, although the initial breakdown of PG was unaffected. This effect was confirmed when IL-1ra was administered in high doses. Moreover, treatment of ZIA with anti-IL-1 (alpha + beta), but not with anti-TNF, resulted in normal PG synthesis, confirming the key role played by IL-1 in the inhibition of PG synthesis. Treatment of AIA with anti IL-1 did not affect inflammation during the acute phase, but a significant reduction of ongoing inflammation was noted at day 7, and there was a marked reduction in the loss of cartilage PG. CONCLUSION: The suppression of PG synthesis in both ZIA and AIA in mice is due to the combined local action of IL-1 (alpha + beta), and neither IL-6 nor TNF is involved. Moreover, the normalization of PG synthesis brought about by blocking of IL-1 ameliorates the cartilage damage associated with AIA. PMID- 7848307 TI - Changes in cartilage composition and physical properties due to stromelysin degradation. AB - OBJECTIVE: To determine the effects of stromelysin treatment on biochemical, histologic, and swelling characteristics of intact cartilage explants and to correlate these effects with changes in the functional physical properties of the tissue. METHODS: Bovine articular cartilage explants were cultured for up to 3 days in the presence or absence of recombinant human stromelysin (SLN). Damage to matrix proteoglycans and collagens was assessed and characterized by N-terminal sequencing and Western blot analysis, respectively. Explants were mechanically tested to assess the ability of the tissue to withstand cyclic and static compressive loads. RESULTS: Treatment with SLN resulted in a time- and dose dependent loss of proteoglycans from cartilage explants, with significant loss seen after 3 days of exposure to 20 nM SLN: Histology indicated that initial loss of proteoglycans occurred in regions near the tissue surface and proceeded inward with increasing time of SLN exposure. SLN treatment resulted in degradation of matrix collagen types IX and II, and a concomitant increase in tissue swelling. This matrix degradation resulted in severe alterations in functional physical properties of the tissue, including compressive stiffness. The initial, focal loss of proteoglycans that resulted from SLN treatment was most accurately detected with high-frequency streaming potential measurements. CONCLUSION: Exposure of intact cartilage to SLN caused specific, molecular-level degradation of matrix molecules, which resulted in changes in the swelling behavior and marked deterioration of functional physical properties of the tissue. PMID- 7848308 TI - Correlation of soluble adhesion molecules in the peripheral blood of scleroderma patients with their in situ expression and with disease activity. AB - OBJECTIVE: To correlate serum levels of the soluble adhesion molecules intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), E-selectin, and P-selectin with (a) clinical disease activity and progression and (b) the in situ expression and distribution of these adhesion molecules in lesional skin, in patients with systemic sclerosis (SSc). METHODS: Serum samples from 12 SSc patients and 36 healthy controls were examined by enzyme-linked immunosorbent assay. Immunohistologic staining was carried out on cryostat sections of lesional skin. RESULTS: Patients whose SSc was in the early inflammatory stage or who had prominent disease progression showed elevated serum levels of soluble adhesion molecules. Serum levels correlated positively with the expression of these molecules on endothelial cells and fibroblasts in lesional skin. CONCLUSION: Serum levels of soluble ICAM-1, VCAM-1, P-selectin, and, to a lesser degree, E-selectin correlate well with their in situ activity and with clinical disease activity. These parameters therefore provide a useful tool for the characterization of disease stage, progression, and prognosis in SSc. PMID- 7848309 TI - Antigen-based heteropolymers. A potential therapy for binding and clearing autoantibodies via erythrocyte CR1. AB - OBJECTIVE: To determine if complexes containing monoclonal antibodies to CR1 cross-linked with antigen (antigen-based heteropolymers [AHP]) can bind the corresponding autoantibody to primate erythrocyte CR1 and promote autoantibody clearance from the circulation. METHODS: AHP were constructed by cross-linking double-stranded DNA (dsDNA) to monoclonal antibodies to CR1. The ability of AHP to facilitate binding of human anti-dsDNA antibodies to primate erythrocytes was studied in vitro using a variety of radioimmunoassays (including Farr assays), enzyme immunoassays, and fluorescence-activated cell sorting. In addition, we used a monkey model to study in vivo the AHP-mediated clearance of passively infused human anti-dsDNA antibodies. RESULTS: Large amounts of lupus IgG anti dsDNA antibodies can be specifically bound to human erythrocytes via the complexes, and studies in 2 rhesus monkeys indicate that the erythrocyte-bound antibodies are rapidly cleared from the circulation. CONCLUSION: This methodology may allow for development of a new therapy to facilitate autoantibody clearance in autoimmune disease. PMID- 7848310 TI - Acceleration of experimental lapine osteoarthritis by calcium pyrophosphate microcrystalline synovitis. AB - OBJECTIVE: To investigate the effects of chronic calcium pyrophosphate dihydrate (CPPD) synovitis on the development of osteoarthritic (OA) lesions in an animal model. METHODS: OA was induced in the right knees of 30 male New Zealand white rabbits by partial lateral meniscectomy and section of the fibular collateral and sesamoid ligaments (PLM/LS), followed by 8 weekly intraarticular (IA) injections of 1 mg (low-dose) or 10 mg (high-dose) of CPPD crystals in 3 sets of experiments (10 rabbits each). The contralateral left knees served as controls: experiment 1 PLM/LS alone, experiment 2 8 weekly IA injections of CPPD crystals alone, and experiment 3 sham surgery plus 8 weekly IA injections of CPPD crystals. RESULTS: At 8 weeks, repeated IA injections of low-dose and high-dose CPPD crystals into meniscectomized right knees resulted in more severe OA than in meniscectomized but noninjected left knees (experiment 1) (P = 0.003 and P = 0.001, respectively). One-fourth of the meniscectomized knees (11 of 40), both CPPD injected and noninjected, showed embedded synovial cartilage shards. CONCLUSION: The data demonstrate a worsening effect of chronic CPPD crystal-induced synovitis on experimental OA produced in the rabbit knees by PLM/LS, and support a possible role for CPPD microcrystalline inflammation in the progression of OA lesions in clinical CPPD crystal deposition disease. PMID- 7848311 TI - Serum cytokines in juvenile rheumatoid arthritis. Correlation with conventional inflammation parameters and clinical subtypes. AB - OBJECTIVE: To examine the usefulness of determining extended serum cytokine profiles in patients with juvenile rheumatoid arthritis (JRA), for the purpose of improving differential diagnosis and monitoring disease activity. METHODS: In a 2 year prospective study, serum levels of interleukin-1 beta (IL-1 beta), soluble IL-2 receptor (sIL-2R), IL-6, IL-8, tumor necrosis factor alpha (TNF alpha), and the p55 soluble TNF receptor (sTNFR) were repeatedly determined by enzyme-linked immunosorbent assay in 40 patients with JRA, 13 patients with postinfectious arthropathies, and 30 healthy controls. The data were compared with conventional parameters of inflammation, such as C-reactive protein (CRP), iron and hemoglobin levels, erythrocyte sedimentation rate (ESR), white blood cell (WBC) counts, and platelet counts. WBC subsets were analyzed by flow cytofluorometry. RESULTS: At the first visit and at the peak of inflammatory activity according to CRP levels and/or ESR, serum levels of sIL-2R, IL-6, and sTNFR in JRA patients correlated significantly with conventional inflammation indicators, whereas IL-1 beta, IL-8, and TNF alpha did not. No changes in leukocyte subset distribution were noted. Among the different clinical subtypes of JRA, sIL-2R, IL-6, and sTNFR values at the time of the initial visit showed a pattern similar to CRP, whereby patients with systemic disease exhibited by far the highest values. TNF alpha and IL-1 beta were variably elevated in certain JRA subtypes. Patients with postinfectious arthropathies showed elevated levels of CRP, sIL-2R, TNF alpha, and sTNFR, which did not differ significantly from levels in the various JRA subtypes with the exception of systemic disease. Detailed analysis of types I and II pauciarticular JRA revealed that levels of CRP, IL-1 beta, and TNF alpha were elevated in patients with type I disease. While these parameters were invariably normal in patients with type II disease, sTNFR and sIL-2R were still found to be significantly elevated. Followup studies suggested that persistently high sTNFR values are a better indicator of JRA activity than are measurements of other cytokines or CRP. CONCLUSION: JRA is associated with significant and consistent changes in serum levels of inflammatory cytokines and soluble receptors. For the clinical monitoring of JRA, determination of levels of sTNFR, and to some extent sIL-2R, may be particularly useful, since these determinations yield information about subtype and/or activity of disease that is not available from conventional parameters of inflammation. PMID- 7848312 TI - A genetic association between juvenile rheumatoid arthritis and a novel interleukin-1 alpha polymorphism. AB - OBJECTIVE: The genetic factors that predispose to the development of juvenile rheumatoid arthritis (JRA) and its complications are not completely understood. The cytokine interleukin-1 (IL-1) has been implicated in the pathogenesis of JRA and other inflammatory diseases. This study was performed to test whether polymorphisms of the IL-1 alpha gene might be associated with JRA. METHODS: We sequenced the 5' regulatory region (containing the promoter) of the human IL-1 alpha gene in 18 normal subjects. This revealed a C (IL-1A1) to T (IL-1A2) transition polymorphism at position -889. We studied the frequencies of both alleles in patients with JRA (n = 269) and controls (n = 99). RESULTS: An increased gene carriage of IL-1A2 was found in patients with early-onset, pauciarticular JRA (EOPA-JRA; n = 103) compared with controls (0.66 versus 0.49; P = 0.01, odds ratio [OR] = 2.1). Within this subset of JRA, the association with IL-1A2 was particularly strong in the patients in whom chronic iridocyclitis developed (n = 28) compared with those without chronic iridocyclitis (0.89 versus 0.57; P = 0.002, OR = 6.2). Within the group of EOPA-JRA patients, IL-1A2 was also associated with elevation of the erythrocyte sedimentation rate (P < 0.0025). CONCLUSION: This is the first report of a cytokine gene association with JRA, and we conclude that IL-1 alpha itself, or a gene for which the IL-1 alpha polymorphism is a marker, may contribute to the pathogenesis of EOPA-JRA and the ocular complications found in this group. PMID- 7848314 TI - Sexual and physical abuse in women with fibromyalgia syndrome. AB - OBJECTIVE: To determine the prevalence of sexual and physical abuse in female patients with fibromyalgia syndrome (FMS), as compared with rheumatic disease control patients. METHODS: Eighty-three female FMS patients and 161 consecutive female rheumatology (non-FMS) control patients answered a standardized confidential questionnaire recording previous sexual and physical abuse, drug and alcohol abuse, and eating disorders. Demographic information was collected on age, education, economic status, and cultural group. RESULTS: Overall abuse was greater in FMS patients than in control patients (53% versus 42%; P not significant). Significant differences were observed for lifetime sexual abuse (17% versus 6%), physical abuse (18% versus 4%), combined physical and sexual abuse (17% versus 5%), and drug abuse (16% versus 3%). There was a trend toward a higher incidence of childhood sexual abuse (37% versus 22%) and of eating disorders (10% versus 3%) in the FMS patient group. CONCLUSION: A high frequency of sexual abuse was identified both in control patients and in FMS patients. A statistical association was demonstrated between FMS and the frequency and severity of sexual abuse, and the frequency of physical abuse and drug abuse. These results raise the possibility that abuse may have an effect upon the expression and perpetuation of FMS in adult life. PMID- 7848313 TI - The prevalence of sexual abuse in women with fibromyalgia. AB - OBJECTIVE: To determine the prevalence of sexual abuse in women diagnosed as having fibromyalgia (FM) compared with controls. METHODS: A self-administered questionnaire designed to obtain information regarding demographics, health care utilization, and history of sexual and physical abuse was completed by 40 women with FM and by 42 women who had no evidence of connective tissue disease or other major medical condition. RESULTS: Women with FM reported more physical symptoms and were significantly different on multiple indices of health compared with controls. Twenty-six FM subjects (65%) reported sexual abuse, in comparison with 22 controls (52%). The prevalence and type of abuse were not significantly different between groups. Sexually abused FM subjects reported significantly more symptoms than did non-sexually abused FM women, but did not differ in the number of symptoms for which they sought medical treatment. CONCLUSION: Sexual abuse does not appear to be a specific factor in the etiology of FM, but is correlated with the number and severity of associated symptoms. PMID- 7848315 TI - Renal biopsy findings and clinicopathologic correlations in rheumatoid arthritis. AB - OBJECTIVE: To evaluate renal biopsy findings and clinicopathologic correlations in patients with rheumatoid arthritis (RA). METHODS: Retrospective study of renal biopsy specimens from 110 RA patients in whom the clinical renal disease was probably due to RA itself and/or to antirheumatic therapy. RESULTS: The most common histopathologic finding was mesangial glomerulonephritis (GN) (n = 40), followed by amyloidosis (n = 33), membranous GN (n = 19), focal proliferative GN (n = 4), minimal-change nephropathy (n = 3), and acute interstitial nephritis (n = 1). Amyloidosis was the most common finding in patients with the nephrotic syndrome. In patients with isolated proteinuria, amyloidosis, membranous GN, and mesangial GN were almost equally common. Although mesangial GN was found in almost two-thirds of the RA patients with hematuria (with or without proteinuria), there still remained a 1 in 5 chance that the biopsy would reveal membranous GN or amyloidosis. Membranous GN was closely related to gold or D penicillamine therapies, whereas mesangial GN probably related to RA itself. CONCLUSION: The renal morphologic lesion in RA patients with isolated proteinuria and those with hematuria cannot be accurately predicted on the basis of clinical symptoms and signs. Biopsy is thus useful in differential diagnosis, assessment of prognosis, and decision-making with regard to treatment. PMID- 7848316 TI - Reduced red blood cell deformability in patients with rheumatoid vasculitis. Improvement after in vitro treatment with dipyridamole. AB - OBJECTIVE: To assess red blood cell deformability (RCD) in patients with rheumatoid arthritis (RA) without extraarticular manifestations and in RA with vasculitic complications (RV), and to assess whether in vitro dipyridamole improves RCD. METHODS: An improved filtration technique was used to measure RCD in 15 patients with RA, 18 patients with RV, and 20 age- and sex-matched normal control subjects. Washed erythrocytes suspended in buffer, at 5% hematocrit, were filtered through 4.7 mu Nuclepore Hemafil PC membranes. The initial steady-state relative filtration pressure (iRFP) was used as an index to assess RCD. A lower iRFP value reflects increased deformability, a higher value reflects a decrease. For each sample, 2 cell suspensions were prepared, one blank (control) and one containing 5 microM dipyridamole. RESULTS: The mean iRFP values of cells obtained from patients with RV were significantly higher than those of cells obtained from normal controls. There were no appreciable differences in iRFP between RA patients and normal controls. When the erythrocytes were pretreated in vitro with 5 microM dipyridamole before filtration, their deformability improved markedly (iRFP values were reduced) in all study subjects, compared with untreated cells. CONCLUSION: RCD is reduced in patients with RV, and treatment with dipyridamole may be beneficial if reduced RCD contributes to impaired microvascular perfusion. PMID- 7848317 TI - HLA type as a predictor of mixed connective tissue disease differentiation. Ten year clinical and immunogenetic followup of 46 patients. AB - OBJECTIVE: To determine any clinical or genetic markers of differentiation and outcome in a previously described cohort of 46 patients with mixed connective tissue disease (MCTD). METHODS: Patients were clinically evaluated, chart notes reviewed, and HLA subtyping and immunology profiles performed where possible. Eleven had died and 7 were lost to followup. RESULTS: MCTD had differentiated into systemic lupus erythematosus in 12 patients and into systemic sclerosis in 13. The latter was associated with HLA-DR5 (P = 0.038), and nondifferentiation was associated with HLA-DR2 or DR4 (P = 0.007). Three HLA-DR4 positive patients had MCTD that evolved into rheumatoid arthritis. Erosive and/or deforming arthritis was associated with HLA-DR1 or DR4 (P = 0.015). HLA-DR3 was associated with interstitial lung fibrosis (P = 0.044) and keratoconjunctivitis sicca (0.001 < P < 0.01). Severe Raynaud's phenomenon predicted higher mortality (0.01 < P < 0.05). CONCLUSION: We suggest that MCTD is, for most patients, an intermediate stage in a genetically determined progression to a recognized connective tissue disease. Those whose disease remains undifferentiated might be considered a distinct subset. PMID- 7848318 TI - The independence and stability of socioeconomic predictors of morbidity in systemic lupus erythematosus. AB - OBJECTIVE: We studied the relationship between systemic lupus erythematosus (SLE) morbidity and socioeconomic status (SES) at 5 centers. METHODS: Ninety-nine patients who met American College of Rheumatology criteria for SLE were randomly sampled at each center, balancing by race and insurance status. Subjects were interviewed for current and past SES factors, such as insurance, occupation, employment, education, and income. SLE disease activity was measured by the SLE Activity Measure (SLAM). RESULT: Higher education, private insurance/Medicare, and higher income were associated with less disease activity at diagnosis. Controlling for SES, race, and center, the best predictors of less active disease at diagnosis were private insurance/Medicare (P = 0.002) and higher education (P = 0.007). From the time of diagnosis to the study visit (mean 3.5 years), insurance, income, and employment status changed for a significant number of subjects (37%, 16%, and 21%, respectively). CONCLUSION: Private insurance or Medicare and higher education are associated with less active disease at diagnosis of SLE. Health insurance, income, and employment status are unstable measures of socioeconomic status and may explain the variability in conclusions of previous studies on the role of SES in SLE. PMID- 7848319 TI - Long-term survival in systemic lupus erythematosus. Patient characteristics associated with poorer outcomes. AB - OBJECTIVE: To investigate the associations of age, sex, race, and socioeconomic status with long-term survival in patients with systemic lupus erythematosus (SLE). METHODS: We examined survival in an inception cohort of 408 patients with SLE. The cohort included 177 black females, 162 white females, 49 white males, and 20 black males. The median duration of followup was 11 years (range 0.1-22 years). RESULTS: One hundred forty-four patients died during the study. The 5-, 10-, and 15-year survival estimates for the entire cohort were 82%, 71%, and 63%, respectively. In univariate analyses, mortality rates increased with age and were higher among males, blacks, those without private medical insurance, and those living in census tracts with lower household incomes. In multivariate analyses, age, sex, and both socioeconomic indicators were associated with total mortality (mortality from any cause), while race was not. Lower socioeconomic status and increased age were also associated with higher rates of death from SLE. CONCLUSION: Socioeconomic status, but not race, is associated with mortality in SLE. SLE-related mortality also tends to increase with age, which suggests that SLE may not be less severe when it occurs later in life. PMID- 7848320 TI - Pseudoseptic inflammatory knee effusion caused by phagocytosis of sickled erythrocytes after fracture into the knee joint. AB - A 57-year-old black man with sickle cell disease was admitted to the hospital because of a painful crisis. After a fall with a fracture into the right knee joint, he developed an acutely painful, swollen knee. Synovial fluid from the right knee showed leukocyte counts of up to 154,000/mm3 and was negative for urate and calcium pyrophosphate dihydrate crystals. Gram stains and cultures were negative. Some sickled red cells were seen by light microscopy; electron microscopy revealed crystal-like arrays of sickled hemoglobin tactoids in erythrocytes which were enfolded and phagocytized by the cells of the synovial fluid. We suggest that this phagocytosis of sickled red cells is the likely cause for the otherwise unexplained inflammation. PMID- 7848321 TI - Radiologic vignette. Complete rotator cuff tear. PMID- 7848322 TI - Interstitial pneumonia due to cytomegalovirus following low-dose methotrexate treatment for rheumatoid arthritis. PMID- 7848323 TI - Evaluation of bone turnover and bone mass during tapering estrogen therapy: a preliminary report. PMID- 7848324 TI - Serum concentrations of two cartilage matrix proteins reflecting different aspects of cartilage turnover in relapsing polychondritis. PMID- 7848325 TI - Creating a care-effective cost-effective strategy for methotrexate liver toxicity monitoring in rheumatoid arthritis: comment on the article by Kremer et al. PMID- 7848326 TI - HLA-Dw4 association with rheumatoid arthritis: comment on the article by Nelson et al. PMID- 7848327 TI - Reproductive and developmental toxicity of the dopamine agonist pergolide mesylate in mice. AB - Pergolide (Permax, LY127809, CAS 66104-23-2) a dopamine agonist for the treatment of Parkinson's disease, was evaluated for reproductive and developmental toxicity. Pergolide was administered in the diet at levels of 0, 5, 15, or 50 ppm to male and female ICR mice. In the F0 generation, the males were treated for 9 weeks prior to mating and throughout mating. The females were treated for 2 weeks prior to mating and throughout mating, gestation, and location (postnatal segment only). Females assigned to the teratology segment were killed on gestation day 18 for evaluation of fetal viability, weights, and morphology. Females assigned to the postnatal component were allowed to deliver and maintain their offspring throughout a 21-day lactation period. One male and one female were selected from each litter to continue as the F1 generation. Possible exposure of the F1 generation to pergolide ended at weaning. Growth of the F1 animals was monitored and reproductive performance evaluated. Treatment-related effects in the F0 generation were consistent with the pharmacologic effects of a dopamine agonist. These effects included pregnancy blockage at the 50-ppm dietary level and dose related body weight depression in lactating dams and suckling progeny at the 15- and 50-ppm dietary levels. An increase in progeny mortality at the 50-ppm dietary level was attributed to lactation failure of the treated dams. The F1 mice of the 15- and 50-ppm groups remained smaller than the control mice until termination at approximately 20 weeks of age, although weight gains following weaning were not depressed and no impairment of mating performance or fertility was observed.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7848328 TI - Metabolic actions of a single atenolol and metoprolol dose. AB - Atenolol (CAS 29122-68-7) and metoprolol (CAS 37350-58-6) are beta 1-selective adrenoceptor antagonists without intrinsic sympathomimetic activity. beta Receptor blockers influence carbohydrate- and lipid metabolism. Liver is a central organ of these processes. The metabolic fate of a single oral atenolol and metoprolol dose and their actions on carbohydrate- and lipid parameters have been investigated. Healthy male rats received a dose reducing heart beat/min by 25% (atenolol: 6 mg/kg; metoprolol: 10 mg/kg). About 9% of atenolol is metabolized by cytochrome P-450 (P-450). P-450-dependent functions (aminopyrine-N demethylase, hexobarbital biotransformation time) were not inhibited. Serum bilirubin was normal. Triglyceride (TG), total cholesterol and HDL-cholesterol levels of the plasma were not affected. Transient blood glucose increase was measured returning to initial value at 120 min. Metoprolol is metabolized by hepatic monooxygenases. P-450-dependent functions were inhibited correlating to the lowered P-450-content of the microsomes. High TG level and decreased HDL cholesterol content were measured. Blood glucose was significantly high. The liposoluble metroprolol affected the hepatic functions more than the hydrophilic atenolol. The monitoring of blood glucose during beta-receptor antagonist treatment may be suggested. PMID- 7848329 TI - Pharmacokinetics of the organic nitrates trans-N-(4-nitroxycyclohexyl)-urea in dogs and trans-N-(4-nitroxycyclohexyl)-acetamide in dogs and in man. AB - The pharmacokinetic behavior of the organic nitrates BM 12.1247 (trans-N-(4 nitroxycyclohexyl)-urea) and BM 12.1307 (trans-N-(4-nitroxycyclohexyl)-acetamide, CAS 137291-91-3) were examined in beagle dogs after oral and intravenous administration. To this end, a reliable and specific assay using capillary gaschromatography with electron capture detection (GC-ECD) was developed. BM 12.1247 showed its maximum plasma level after 2.2 h by oral application; the bioavailability was nearly 100%. The elimination half-life of 8.8 h p.o. Corresponded to the half-life after i.v. administration, concerning BM 12.1307, the elimination half-lives were still longer, they reached 11-13 h and bioavailability reached 68-70%; these results were confirmed by crossover tests. In a first application of healthy volunteers it was possible to show that the organic nitrate BM 12.1307 is eliminated much more slowly in man than in dog, the half-life of the compound in man being longer than the half-life in dog by a factor of 2.3. PMID- 7848330 TI - Pharmacokinetics and pharmacodynamics of the alpha 1-adrenergic antagonist bunazosin retard in hypertensives. AB - The pharmacokinetics and pharmacodynamics of an alpha 1-blocker a sustained release formulation of bunazosin (Detantol R, E1015, 4-amino-2-(4 butyrylhexahydro-1H-1,4-diazepin-1-yl)-6,7- dimethoxyquinazoline hydrochloride, CAS 52712-76-2), were investigated in hypertensive patients with normal renal function (NRF) and those with impaired renal function (IRF). The subjects were hospitalized and placed on a constant sodium diet (NaCl 7 g/day) throughout the study. A 6 mg dose of bunazosin was administered orally once a day for 8 days. Measurement of blood pressure (BP) and sampling of blood and urine specimens were made on the first and last days of treatment. A significant decrease in both systolic and diastolic BP was observed after consecutive dosing of bunazosin compared to baseline values over 24 h in the NRF and for 8 h in the IRF. There were no significant differences in plasma profiles of bunazosin in both groups after single and consecutive dosing. The pharmakokinetic parameters of bunazosin in the NRF and IRF groups did not differ after the single and the consecutive dosing, except for plasma peak levels (Cmax) which were significantly higher in the IRF than those in the NRF. There were, however, neither prolongation of apparent elimination half-life (t1/2), nor increase in Cmax, nor area under the plasma concentration-time curve (AUC0-24) after consecutive dosing in both groups. Cumulative urinary excretion rates of bunazosin were less than 1.1% of dose in both groups, and those did not differ significantly between the NRF and IRF groups in both single and consecutive studies.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7848331 TI - Antiaggregant and antivasospastic properties of the new thromboxane A2 receptor antagonist sodium 4-[[1-[[[(4-chlorophenyl)sulfonyl]amino]methyl]cyclopentyl] methyl]benzeneacetate. AB - LCB 2853 (sodium 4-[[1-[[[(4-chlorophenyl)sulfonyl]amino]methyl]cyclopentyl] methyl]benzeneacetate, CAS 141335-11-7) was demonstrated to be a potent thromboxane A2/prostaglandin H2 (TXA2/PGH2) receptor antagonist in in vitro, ex vivo and in vivo experiments. The specific mechanism of action was studied in [3H]SQ 29548 receptor binding studies (pKi = 7.93) and was shown to be of competitive nature in U 46619-induced platelet aggregation (pA2 = 6.82). TXA2 dependent platelet rich plasma (PRP) aggregation (U 46619, arachidonic acid (AA), collagen, ADP or serotonin second phase) was inhibited in vitro in humans (IC50:0.037-0.65 mumol/l) and different animal species, as well as ex vivo i.v. rat and p.o. guinea-pig AA-induced aggregation (ED50 = 48 and 57 micrograms/kg). The U 46619-induced contractions of aorta, caudal artery and trachea were inhibited in a dose-dependent way (IC50 = 0.07, 0.02 and 0.5 mumol/l respectively). In vivo, both against platelet aggregation and vasoconstriction, LCB 2853 showed an ED50 lower than 1 mg/kg i.v. in rat AA-induced thrombocytopenia or U 46619-induced hypertension (ED50 = 0.25 and 0.16 mg/kg) as well as in AA-induced sudden death in the mouse (ED50 = 0.44 mg/kg). The U 46619 induced bronchoconstriction was blocked after i.v. administration of LCB 2853 (ED50 = 18.4 micrograms/kg). The duration of action observed in different models was 6 h by oral route and between 3 and 5 h by intravenous route. These properties in TXA2-dependent models led to further investigations of the antithrombotic activity of this novel TXA2 antagonist. PMID- 7848332 TI - Pharmacodynamics and antithrombotic effects after intravenous administration of the new thromboxane A2 receptor antagonist sodium 4-[[1-[[[(4 chlorophenyl)sulfonyl]amino]methyl]cyclopentyl] methyl]benzeneacetate. AB - The antiplatelet and antithrombotic activities of LCB 2853 (sodium 4-[[1-[[[(4 chlorophenyl)sulfonyl]amino]methyl]cyclopentyl] methyl]benzeneacetate, CAS 141335 11-7) a novel thromboxane A2 (TXA2) receptor antagonist were examined after intravenous administration. The correlation between LCB 2853 plasma concentration and ex vivo inhibition of arachidonic acid-induced aggregation was observed in rats, for 4 h, as long as LCB 2853 was detected in plasma by HPLC analysis. Pharmacokinetic parameters were determined. The antithrombotic activity was tested in arterial and venous thrombosis models. In dog coronary stenosis, LCB 2853 shown a very high efficacy (ED50 = 7.2 micrograms/kg), whereas acetylsalicylic acid (ASA) was only active at 3.2 mg/kg and ticlopidine was ineffective at 12.8 mg/kg. In rat venous thrombosis induced by combination of venous injury and blood stasis, perfused LCB 2853 decreased the weight of thrombi in a dose related manner (ED50 = 220 micrograms/kg/min). In a comparative study, at 250 micrograms/kg/min, ticlopidine was less potent and ASA failed to show any protection. The potent immediate efficacy of LCB 2853 and the advantageous comparisons with ASA (which was ineffective in some models) or ticlopidine (which needs metabolization lag time) observed in many models suggest that this compound may have beneficial effects in patients with TXA2-associated disturbances. PMID- 7848333 TI - Effect of the platelet activating factor antagonist (+)-cis-3,5-dimethyl-2-(3 pyridyl)thiazolidin-4-one hydrochloride on endotoxin-induced hypotension and hematological parameters in rats. AB - The intravenous administration of endotoxin to anesthetized rats resulted in different hypotensive reactions depending on its dosage. More than 10 mg/kg of endotoxin induced biphasic hypotension; the first phase consisted in a small and transient depression (approximately 15 mmHg) of mean arterial pressure occurred within 1 min after the administration, and the second phase was a large and sustained depression (maximally 40 mmHg) observed from 1 h after the injection. At less than 3 mg/kg of endotoxin, the first phase of hypotension did not occur whereas the second phase of hypotension was observed. Pre-treatment or post treatment with a specific platelet activating factor (PAF) antagonist, SM-12502 ((+)-cis-3,5-dimethyl-2-(3-pyridyl)thiazolidin-4-one HCl, CAS 119383-00-5) inhibited the second phase of endotoxin (1 mg/kg)-induced hypotension. In addition, post-treatment with another PAF antagonist, (3-(4-(2-chlorophenyl)-9 methyl-6H-thieno (3,2-f) (1, 2,4)-thiazolo-phenone) also inhibited the second phase of hypotension. Blood PAF-like substance level, measured by the PAF radioimmunoassay, slightly increased at 1 min after administration of endotoxin (30 mg/kg). At 90 min after the injection, endotoxin (1 mg/kg) induced a significant increase of PAF-like substance level.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7848334 TI - Effect of nisoldipine on red cell deformability and platelet aggregation in stroke patients. AB - Reduced red cell deformability and increased platelet aggregability are assumed to contribute to various ischemic diseases, and it has been postulated that these abnormalities may be improved by drug treatment. In this study, the effect of nisoldipine (Bay K 5552, CAS 63675-72-9) on red cell deformability and platelet aggregation in patients with chronic ischemic cerebrovascular disease and hypertension was examined. Administration of nisoldipine for 4 weeks caused a significant improvement of red cell deformability and platelet aggregability without causing any adverse effects. PMID- 7848335 TI - Impairment of macrophage eicosanoid and nitric oxide production by an alkaloid from Sinomenium acutum. AB - The effects of sinomenine (7,8-didehydro-4-hydroxy-3,7-dimethoxy-17-methyl- 9 alpha,13 alpha,14 alpha-morphinan-6-one), a pure alkaloid extracted from the Chinese medical plant Sinomenium acutum, on different macrophage capacities were investigated in vitro using resident mouse peritoneal macrophages and the macrophage-like cell line RAW 264.7. Sinomenine markedly decreased prostaglandin E2 and leukotriene C4 synthesis of macrophages stimulated by zymosan or calcium ionophore and also significantly inhibited the nitric oxide production of RAW 264.7 cells activated by interferon-gamma/lipopolysaccharide. It can be considered that these effects are part of the analgesic, anti-inflammatory, and antirheumatic mechanisms of sinomenine. PMID- 7848336 TI - General toxicology of the new antitussive moguisteine. AB - Moguisteine (R,S(+/-)-2-(2-methoxyphenoxy)-methyl-3-ethoxycarbonylacetyl- 1,3 thiazolidine, CAS 119637-67-1), a new oral non-narcotic peripherally acting antitussive drug, was submitted to toxicological evaluation. The oral (gavage) and intraperitoneal routes in mice and rats and the oral route in rabbits produce very low acute toxicity. Administered by oral route, moguisteine proved to be well tolerated for 26 consecutive weeks and did not induce any general or local effect at up to the respective doses of 240 and 60 mg/kg/day for rats and dogs. In oral (dietary) carcinogenicity studies, moguisteine did not exhibit any carcinogenic effect in mice and rats treated for 87 and 104 weeks, respectively, at up to the dose of 600 mg/kg/day. These results are supported by the absence, both in vitro and in vivo, of mutagenic potential. Considering the overall results of the toxicological studies, it can be affirmed that moguisteine enjoys reliable tolerability, as also shown by a wide safety margin calculated on the basis of the animal and human exposures. PMID- 7848337 TI - [Pharmacokinetics of two theophylline sustained-release preparations in healthy humans]. AB - In an open, randomized change-over study the steady state profile of two theophylline (CAS 58-55-9) sustained-release preparations (Theophyllard resp. reference preparation) in 24 healthy volunteers was evaluated with respect to AUC, Cmax, Cmin, and tmax. Cmax of the test preparation is higher than that of the reference. During the daytime the adjusted Cmax-values are about 25% higher than the Cmax-values of the reference, during the night they are 10% higher. Tmax of the test preparation is 6 h; tmax of the reference is 5 h. PMID- 7848338 TI - Increase of streptozocin toxicity by magnesium deficiency in the diabetic rat model. AB - To study interactions between magnesium (Mg) and diabetes mellitus, female SD rats weighing ca. 230 g were rendered Mg-deficient by offering a diet providing only 20% of the rat's requirement. After 14 days the animals were injected 75 mg streptozocin (STZ) per kg body weight intraperitoneally. Placebo-treated controls received the same diet, however their drinking-water was enriched with 20 mmol/l Mg as the magnesium-L-aspartate hydrochloride. Mg deficiency remarkably increased STZ-induced lethality from 3.8% to 61.1% on day 35. Pronounced hyperglycemia and necrosis of pancreatic beta cells also suggest an increased effect of STZ on the pancreas during Mg deficiency. The underlying mechanisms are discussed. Food consumption was decreased in Mg-deficient animals and steeply increased 7 days following STZ treatment. Similarly consumption of drinking-water also increased. Since diabetic rats lost body weight, relative and absolute Mg intake via food or drinking-water increased. In this way further Mg depletion of diabetic rats was prevented. PMID- 7848339 TI - Urinary bladder-selective action of the new antimuscarinic compound vamicamide. AB - 1. The inhibitory action of vamicamide (FK176, (+/-)-(2R*,4R*)-4-dimethylamino-2 phenyl-2-(2-pyridyl)valeramide, CAS 132373-81-0) on the responses of various tissues to the cholinergic agonists, carbachol and McN-A-343 (4-[m chlorophenylcarbamoyloxy]-2-butynyl-trimethylammonium chloride, CAS 55-45-8), was investigated in isolated tissue preparations. Vamicamide showed competitive antagonistic actions against all the preparations tested and its pA2 value for the urinary bladder was 6.82, which was higher than that for the atria (5.94) and almost the same as that for the vas deferens (6.90) and for the stomach (6.81). The pA2 values of oxybutynin hydrochloride (oxybutynin) and atropine sulfate monohydrate (atropine) were nearly the same in all the tissues tested. 2. Oral administration of vamicamide 0.1-1.0 mg/kg inhibited dose-dependently spontaneous bladder contractions caused by raising the intravesical volume in conscious rats. Inhibitory actions were also obtained with 0.32-3.2 mg/kg of oxybutynin or 0.0032 0.032 mg/kg of atropine, but the duration of action of oxybutynin was shorter than that of vamicamide or atropine. Vamicamide further inhibited bladder contractions in rats following intravesical administration of 0.05-0.5 mg/ml solution. 3. Vamicamide had no effect or only slightly inhibited spontaneous motility of the stomach and distal colon in conscious rats, as well as heart rate and salivary secretion in conscious dogs, after oral dosing with 3.2 mg/kg of the compound. Similar results were obtained with oxybutynin, excepting the occurrence of tachycardia.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7848340 TI - Effect of long-term therapy with nipradilol on esophageal varices in patients with compensated cirrhosis. Results of a multicenter open study. AB - The effect of long-term administration of nipradilol (NIP, Hypadil Kowa, CAS 81486-22-8), a beta-blocker with a vasodilatory action, on esophageal varices was studied in 66 patients with compensated liver cirrhosis. Administration of NIP (6 12 mg/d) for 3-12 months produced progressive improvement of endoscopic findings over time (30% for C, 25% for F, and 40% for the R-C sign after 12 months). At the last examination (mean: 9 +/- 4 months), the improvement rates were 16.7%, 16.7% and 22.7%, respectively. No significant relationship was found between endoscopic improvement and the Child-Pugh score or the dose of NIP. Gastrointestinal bleeding occurred in five patients: one had bleeding esophageal varices, three had bleeding gastric varices, and one had a bleeding gastric ulcer. The systolic blood pressure was decreased significantly (4.6-12.3%) at 2 weeks as well as 1 and 2 months, and the heart rate showed a significant decrease throughout the study (10-18.4%). With the exception of the patients who had gastrointestinal bleeding, no symptoms of decompensation appeared, and there was no deterioration of laboratory parameters including ammonia. Adverse effects occurred in about 10% of the patients, most of which were related to bradycardia and/or hypotension, and they improved when the drug was withdrawn or the dose reduced. These results suggest that long-term administration of NIP is useful in the treatment of esophageal varices. PMID- 7848341 TI - [Immunoactive action of mistletoe lectin-1 in relation to dose]. AB - Galactoside-specific mistletoe lectin-1 (ML-1) was isolated by affinity chromatography from proprietary mistletoe extract and checked in BALB/c-mice for its immunoactive potency. To investigate the optimal immunomodulating dosage, ML 1 (0.5, 1.0, 2.5, 5.0 ng/kg body weight, b.w.) was subcutaneously administered for three subsequent days followed by another injection 48 h later. These studies proved that injections of 1 ng ML-1/kg b.w. induced optimal immunomodulation, since thymocyte proliferation, maturation and emigration were significantly enhanced in this murine model as compared to non-treated control mice. Further on, counts of peripheral blood lymphocytes and monocytes as well as expression of relevant activation markers on these cells revealed significant increases after ML-1 (1 ng/kg b.w.) administration. However, increase of cell counts and activity of peritoneal macrophages were less pronounced but still statistically significant for this ML-1 concentration. Determination of immune responses after low dose ML-1 treatment (0.5 ng/kg b.w.) presented relevant (partly statistically significant) increases, too. However, high dose ML-1 treatment (2.5, 5.0 ng/kg b.w.) did not enhance (but suppress) relevant immune functions. For future clinical/therapeutical treatment strategies, ML-1 dosages ranging from 0.5-1.0 ng/kg b.w. may be supposed to be optimal. PMID- 7848342 TI - Synthesis and orally macrofilaricidal evaluation of niclosamide lymphotropic prodrugs. AB - The development of new macrofilaricidal drugs is described following a strategy for the promotion of the lymphatic transport of anthelminthic drugs by-passing the liver. The selected compound was niclosamide (CAS 50-65-7) which is very effective in vitro against infective larvae but has no significant antifilarial activity when orally administered at 200 mumol/kg. To estimate the interest of such an approach, the synthesis of 5 prodrugs was achieved in a first stage. The intrinsic antifilarial activity and the delayed effect of these compounds were evaluated in vitro. Then, in vivo tests were performed with Molinema dessetae infective larvae to select the best ligands. The prodrug V 1,3-dihexadecanamido-2 [4-chloro(2- chloro-4-nitroanilinocarbonyl)phenyloxy-carbonylpropanoyl oxy]propane (having a diamide function) was responsible for an in vitro delayed effect and an orally in vivo activity (200 mumol/kg when administered in a single dose). The biological improvement of this easily micellizable prodrug which is stable to intestinal enzymes in respect to Niclosamide confirms such a strategy. PMID- 7848343 TI - In vitro clastogenicity of optical isomers of nadifloxacin. AB - The potential of optical isomers of the fluoroquinolone antibacterial agent nadifloxacin (NDFX, CAS 124858-35-1) to induce chromosomal aberrations in vitro was investigated in cultured Chinese hamster lung (CHL) cells for 24 h of continuous treatment. S- and R-enantiomers of NDFX showed significant differences in the results of the chromosomal aberration test, but no marked differences in the results of cytotoxicity test, i.e., S-NDFX induced chromosomal aberrations, but R-NDFX did not. These results were equivalent to those obtained with ofloxacin (OFLX, CAS 83380-47-6), which has a chemical structure similar to that of NDFX. Moreover, although neither NDFX nor OFLX induced aberrations, their mixtures, prepared from equal amounts of S- and R-enantiomers, did. This finding suggests that the racemic compound and the mixture of S- and R-enantiomers exist under different conditions within the solution. PMID- 7848344 TI - Dermal absorption of fluprednidene-21-acetate and miconazole from a new topical preparation in pigs. AB - The dermal absorption of fluprednidene-21-acetate (CAS 1255-35-2) and miconazole nitrate (CAS 22832-87-7) of a new combination cream (Decoderm tri) was studied in pigs after application of 0.5 g cream/kg body weight under occlusive dressing for 5 h. 3H-labelled fluprednidene-21-acetate and 14C-labelled miconazole nitrate were introduced into the base cream as single components or in combination. The three resulting creams were tested in groups of 3 pigs each. To obtain a basis for the assessment of the data after dermal application the two labelled drugs were also examined after intravenous injection. Based on the comparison of the AUC of the radioactive labels an absorption of 4.4% for fluprednidene-21-acetate was calculated when administered alone and 2.4% when administered in the combination cream. For miconazole a smaller absorbed fraction of the dermal dose of 0.5 and 0.8%, resp., was found. Since the differences between single and combined administration were not significant, it follows that there is no relevant reciprocal influence of the two compounds on their dermal absorption. PMID- 7848345 TI - Preclinical testing of iopromide. 2nd communication: toxicological evaluation. AB - Toxicological characteristics of the non-ionic monomeric X-ray contrast agent iopromide (Ultravist, CAS 73334-07-3) were evaluated in rats, rabbits, guinea pigs and dogs. The scope of investigations included acute toxicity studies, systemic tolerance investigations with repeated applications, reproduction toxicity studies, examinations on the genotoxic and contact-sensitizing potential and local tolerance studies. Iopromide could be shown to be well tolerated in all the tests and species. PMID- 7848346 TI - [A new method for assessment of mental performance during simultaneous, quantitative, topographical electroencephalometry and psychometry in pharmacology. Proof of the effect of a combination of biogenic amines, vitamins, minerals and trace elements]. AB - Assessment of the Mental Performance during Simultaneous Quantitative Topographical Electroencephalometry and Psychometry in Pharmacology/Proof of influence of a biogenic amine-vitamin combination. The aim of this study was to verify the effect of a combination medicine (Vita-Gerin-Geistlich) on the human EEG pattern during psychometric (cognitive) tests given to 43 patients with poor concentration and thinking problems. A randomised, parallel, placebo-controlled double-blind study was performed. Applying 17-channel quantitative electroencephalometry and psychometric tests simultaneously this study revealed a test-dependent increase in absolute spectral EEG power in the delta and theta frequency bands, mainly observed in the frontotemporal cortex. After 8 weeks the increase in EEG power differed significantly with respect to taking placebo and verum (1 capsule/day). Verum caused a stronger rise in spectral delta and theta power, the psychometric test performance also improved. Both effects could be verified statistically. The novel EEG-controlled psychometric test set (enabling artefact-free EEG recording during psychometric tests) which was developed and used in this study represents a valid tool for future pharmacological research. PMID- 7848347 TI - Pharmacology of the new selective A2a adenosine receptor agonist 2-hexynyl-5'-N ethylcarboxamidoadenosine. AB - The pharmacological profile of 2-hexynyl-5'-N-ethylcarboxamidoadenosine (2HE NECA, CAS 141018-30-6), a new selective A2a adenosine receptor agonist, was characterized. In binding studies on both rat and bovine brain, 2HE-NECA was more potent on A2a receptors (Ki = 2.2 and 1.5 nmol/l, respectively) than the reference A2a agonist, 2-[4-(2-carboxyethyl)-phenethylamino]-5'-N ethylcarboxamidoaden osi ne (CPEC) or the non-selective adenosine agonist 5'-N ethylcarboxamidoadenosine (NECA). The drug displayed a good A2a vs A1 receptor selectivity in brain tissues of both animal species (60- and 160-fold, respectively). In functional studies, 2HE-NECA showed marked vasodilating properties in rat aorta, bovine and porcine coronary arteries. The vasodilatory response in the porcine coronary preparation was greater for 2HE-NECA (EC50 = 23.3 nmol/l) than for CPEC (EC50 = 58.7 nmol/l) or NECA (EC50 = 76.6 nmol/l). In the rat Langendorff model, in which global ischemia was induced, 2HE-NECA (100 nmol/l) significantly prevented the risk of diastolic pressure and coronary perfusion pressure occurring during postischemic reperfusion. The in vitro antiaggregatory activity of 2HE-NECA (IC50 = 0.07 mumol/l), as tested in rabbit platelets, was higher than that found with NECA (IC50 = 0.2 mumol/l) or CPEC (IC50 = 2.16 mumol/l). In spontaneously beating rat atria, which are responsive to A1-receptor stimulation, 2HE-NECA did not show any negative chronotropic activity up to micromolar concentrations. In conscious spontaneously hypertensive rats, 2HE-NECA administered intraperitoneally caused a dose-dependent reduction in systolic blood pressure (ED30 = 0.005 mg/kg) with minimal reflex tachycardia.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7848348 TI - Pharmacology of the highly selective A1 adenosine receptor agonist 2-chloro-N6 cyclopentyladenosine. AB - The pharmacological profile of 2-chloro-N6-cyclopentyladenosine (CCPA, CAS 37739 05-2), a highly selective A1 adenosine receptor agonist, was characterized. Its effects were compared with those of the non-selective adenosine receptor agonist 5'-N-ethylcarboxamidoadenosine (NECA). In binding studies on both rat and bovine brain, CCPA was highly potent on A1 receptors (Ki = 1.3 and 0.5 nmol/l, respectively) and displayed good A1 vs A2a receptor selectivity (500- and 920 fold, respectively). In functional studies, CCPA showed marked negative chronotropic activity in spontaneously beating rat atria (EC50 = 8.2 nmol/l). This effect was antagonized dose-dependently by the A1 selective antagonist 8 cyclopentyl-1,3-dipropylxanthine (DPCPX). In the rat Langendorff model, in which global ischemia was induced, CCPA (3 nmol/l) prevented significantly the rise of diastolic pressure and coronary perfusion pressure during postischemic reperfusion. In vascular preparations, a functional activity responsive to A2a adenosine receptor stimulation, CCPA did not show any vasodilating properties up to micromolar concentrations, whereas NECA had a good relaxing activity in bovine coronary arteries (EC50 = 167 nmol/l). In rabbit platelets, a model sensitive only to A2a-receptor stimulation, CCPA did not elicit any relevant antiaggregatory properties, whereas NECA was found to be effective (IC50 = 200 nmol/l). Likewise, in an in vivo model of platelet aggregation in the rabbit using a non-invasive radioisotopic technique, CCPA (100 micrograms/kg, 30 min i.v. infusion) did not influence platelet function, whereas NECA (10 micrograms/kg, 30 min i.v. infusion) decreased peak value for platelet accumulation by 35%.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7848349 TI - Bioequivalence evaluation of two glyceryl trinitrate patches after 12-h usage in healthy volunteers. AB - The study objective was to determine the bioavailability and main pharmacokinetic parameters of glyceryl trinitrate (GTN, CAS 55-63-0) following cutaneous application of two different glyceryl trinitrate patches using a randomized cross over design. The two patches investigated were Deponit 5 (a newly developed test patch) and an already marketed reference patch. Thirty-seven healthy male volunteers were included in this study; 36 of them completed the investigation. Blood samples were withdrawn up to 15 h after start of patch application and plasma concentrations of glyceryl trinitrate were quantified by a GC/MS method. For the areas under the curve from time 0 to the last quantifiable sample, AUC(O Tlast), mean values of 1545 (test patch, n = 35) and 1686 h.pg/ml (reference patch, n = 35) were found. The corresponding peak glyceryl trinitrate plasma levels were 253 and 263 pg/ml, respectively; they were reached after 6.58 h (test patch) and 7.72 h (reference patch). The statistical comparison (ANOVA, confidence intervals) of the pharmacokinetic parameters found in the study resulted in bioequivalence of both patches. Typical side-effects known and described under glyceryl trinitrate therapy were also observed in this study. PMID- 7848350 TI - Bioequivalence evaluation of the metabolites 1,2 and 1,3-glyceryl dinitrate of two different glyceryl trinitrate patches after 12-h usage in healthy volunteers. AB - In the course of this study both the bioavailability and main pharmacokinetic parameters of the glyceryl trinitrate (GTN, CAS 55-63-0) metabolites 1,2 and 1,3 glyceryl dinitrate (1,2-GDN and 1,3-GDN) were to be determined following transdermal application of a glyceryl trinitrate test patch (Deponit 5) and an already marketed reference patch. For this purpose, both patches were examined in healthy volunteers according to a randomized two-way cross-over design, blood samples were withdrawn up to 15 h after start of patch application and the plasma concentrations of both metabolites were quantified using a GC/MS method. The investigation showed the following results: Metabolite 1,2-glyceryl dinitrate: For the area under the curve from time 0 to the last quantifiable sample (AUC(0 Tlast) arithmetic mean values of 23.77 h.ng/ml (test patch) and 27.83 h.ng/ml (reference patch) were found. The corresponding peak plasma levels were 2.45 ng/ml and 2.93 ng/ml, respectively; they were reached after 6.4 h (test patch) and 8.31 h (reference patch). Metabolite 1,3-glyceryl dinitrate: The arithmetic mean values for AUC(0-Tlast) were 3.32 h.ng/ml (test patch) and 3.81 h.ng/ml (reference patch). The maximum plasma levels were 0.35 ng/ml and 0.41 ng/ml for the test and reference preparation, reached after 6.4 h and after 7.86 h, respectively. The statistical comparison (ANOVA, confidence intervals) showed bioequivalence between both patches concerning the metabolites investigated. The typical side effects known after nitrate therapy also occurred in the course of this study. PMID- 7848351 TI - [Long-term antihypertensive therapy with isradipine. Improvement of coronary flow reserve in patients with arterial hypertension and microvascular angina]. AB - Antihypertensive Long-term Therapy with Isradipine/Improvement of coronary flow reserve in patients with arterial and microvascular angina In patients with arterial hypertension coronary flow reserve is often impaired due to left ventricular (LV) hypertrophy and alterations of the coronary microcirculation. Experimental and clinical studies have shown that calcium channel blockers can induce regression of myocardial hypertrophy. Objective of the present study was to see whether chronic antihypertensive treatment with calcium channel blockers can improve the diminished coronary reserve in patients with arterial hypertension and microvascular angina pectoris. Fifteen hypertensive patients with microvascular angina (61 +/- 7 years, normal coronary angiogram, mild LV hypertrophy) were treated with isradipine (CAS 75695-93-1) (5.3 +/- 0.9 mg/d) for 12 +/- 2 months. Before and after therapy (after a washout period of 1 week) coronary flow was quantitatively measured by the gas chromatographic Argon method. Coronary reserve was calculated as the quotient of coronary resistance under baseline conditions and after dipyridamole (0.5 mg/kg i.v.). Under isradipine therapy systolic blood pressure was lowered from 165 +/- 20 to 140 +/- 13 mmHg (p < 0.01) and diastolic blood pressure from 98 +/- 8 to 88 +/- 6 mmHg (p < 0.01). The LV muscle mass index decreased by 10% from 154 +/- 33 to 139 +/- 28 g/m2 (p < 0.05). Baseline coronary blood flow (81 +/- 13 versus 83 +/- 16 ml/min x 100 g, n.s.) was identical before and after therapy. There were also no differences in coronary perfusion pressure, heart rate, myocardial oxygen consumption and arterio-coronary venous oxygen difference before and after therapy.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7848352 TI - Gastrointestinal tolerance of [2,2-dimethyl-6-(4-chlorophenyl-7-phenyl- 2,3 dihydro-1H-pyrrolizine-5-yl]-acetic acid in the rat. AB - The gastrointestinal tolerance of [2,2-dimethyl-6-(4-chlorophenyl)-7- phenyl-2,3 dihydro-1H-pyrrolizine-5-yl]-acetic acid (ML 3000, CAS 156897-06-2) has been tested in comparison with indometacin, after both single and multiple administrations for 5 and 11 days in an in vivo rat assay. A single oral administration of ML 3000 at doses of 10, 30 and 100 mg/kg produced no gastrointestinal damage. Repeated oral administration of ML 3000 at daily doses of 10, 30 and 100 mg/kg produced slight gastrointestinal damage, but the effect was minimal and was not found to be statistically significant. Indometacin produced highly statistically significant gastric and duodenal damage following one single administration of 10 mg/kg. Repeated oral administration, at 3 mg/kg each day, produced moderate and statistically significant gastric and slight duodenal damage on Day 5 of dosing. However, by Day 11 pronounced duodenal damage was observed which was shown to be statistically highly significant. These results indicate that ML 3000 is clearly better tolerated by the gastrointestinal tract than indometacin after single and multiple administration up to 11 days in rats. PMID- 7848353 TI - [Relative bioavailability of paracetamol in suppositories preparations in comparison to tablets]. AB - Relative Bioavailability of Paracetamol as Suppositories Compared to Tablets. The relative bioavailability of paracetamol (CAS 103-90-2) in ben-u-ron 500 mg and ben-u-ron 1000 mg suppositories (test formulations) was compared with that of Benuron tablets 500 mg (reference product) in an open, intraindividual, 3-period changeover-study in 18 healthy subjects. Plasma concentrations of paracetamol were determined using a specific and sensitive HPLC method with UV detection. For the assessment of bioavailability AUC, Cmax, tmax and HVD were used as pharmacokinetic characteristics. Bioequivalence of the rectal formulations was tested by calculating 90% confidence intervals using the Two-one-sided-t-tests procedure and log-transformed data of AUC and Cmax. For AUC the confidence intervals were required to be in the 80 and 125% range, for Cmax between 70 and 143% (inclusion rule). Data from 17 subjects could be evaluated. Bioavailability of paracetamol was 89 and 90% for the 500 and 1000 mg suppositories, respectively compared with that of the 500 mg reference tablets. Mean maximum paracetamol plasma concentrations (Cmax) were 3.55 and 6.02 or 7.16 mg/l after administration of the 500 and 1000 mg suppositories or the 500 mg tablets, respectively. These maximum concentrations were achieved 2.0, 2.7 and 0.6 h (tmax) after administration of the respective preparations. The corresponding HVD values were 4.3, 5.2 and 2.0 h, respectively. After dose adjustment of the results for the 1000 mg suppositories relative bioavailabilities of paracetamol from both rectal formulations exceeded 80% of that from the tablets.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7848354 TI - Accumulation of granulocytes in the lung and skin of guinea pigs. Inhibition by the anti-H1 antiallergic agent epinastine. AB - The aim of this study was to investigate whether the antiallergic/H1-antagonistic drug epinastine (WAL 801, Alesion, CAS 108929-04-0) inhibited inflammatory granulocyte infiltration in respiratory or dermal tissue. A late-phase bronchial eosinophilia was induced in sensitized and challenged guinea pigs, and a skin chamber technique was developed for assessing leukotriene-B4 (LTB4) induced transdermal chemotaxis in vivo in this species. Oral epinastine as well as the reference compounds beta-methasone and the LTB4-receptor antagonist 7-[3-(4 acetyl-3-methoxy-2-propylphenoxy) propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2 carboxylic acid (ADCA) demonstrated a dose-dependent inhibition of granulocyte accumulation. The rank order of oral activity was epinastine > betamethasone > ADCA for bronchial eosinophilia and betamethasone > epinastine = ADCA for transdermal chemotaxis. These animal studies suggest a non-antihistamine activity of epinastine which may contribute to its clinical efficacy as an antiallergic drug. PMID- 7848355 TI - Reproductive toxicology of the new antitussive moguisteine. AB - Moguisteine (R,S(+/-)-2-(2-methoxyphenoxy)-methyl-3-ethoxycarbonylacetyl- 1,3 thiazolidine, CAS 119637-67-1), a new oral non narcotic peripherally acting antitussive drug, was examined for effects in the rat on general reproductive performance (at 0, 50, 212, 900 mg/kg/d,) for embryotoxicity (at 0, 25, 75, 225, 900 mg/kg/d) and for peri-postnatal toxicity (at 0, 62.5, 250, 1000 mg/kg/d). Embryotoxicity (at 0, 75, 225, 900 mg/kg/d) was also examined in the New Zealand White rabbit. In all the studies, moguisteine was administered orally as a suspension by gavage. At the tested doses, moguisteine did not interfere with general reproductive performance, either in the F0 or in the F1 generation. The drug did not show any toxic effect on the dams and their fetuses, nor did it have any teratogenic effect in either of the tested species. Finally, moguisteine had no adverse effects, either on parturition or on peri-and postnatal survival and/or development of the offspring. PMID- 7848356 TI - Single and subacute local and systemic toxicity studies of benzalazine. AB - Benzalazine (2-hydroxy-5-[(4carboxyphenyl) azo]benzoic acid, CAS 64896-26-0), a new agent for the treatment of ulcerative colitis and Crohn's disease of the large intestine, was investigated regarding its toxicological properties following single and subacute local and systemic applications. After single oral application of the maximum dose of 10 g benzalazine/kg b.w. to rats no pathological findings concerning clinical signs, body weight, food consumption and macroscopical post mortem findings could be observed (LD50 > 10000 mg/kg b.w.). The 24-h LD50 values for benzalazine after single intraperitoneal application were determined as 755 mg/kg b.w. in female rats and 1200 mg/kg b.w. in male rats. The oral administration of benzalazine at 2000 mg/kg b.w./d or more for 4 weeks to rats gave rise to slight sedation, a reduction in body weight increase, increased organ weights (heart, kidneys, suprarenal glands, spleen) and dose-related histopathological findings (liver, kidneys, heart, thyroid gland, duodenum, spleen, suprarenal glands, testes). The daily dose of 500 mg benzalazine/kg b.w. for 4 weeks was without any effects under these experimental conditions. In acute local tolerance studies in rabbits, benzalazine is to be considered as a mild irritant agent for skin (employing an occlusive patch for 24 h) and eye. After a 10-day intra-rectal application of benzalazine to rabbits no substance-related changes at the application sites in the colon were observed. PMID- 7848357 TI - Twenty-six-week oral toxicity study of benzalazine in rats. AB - A 26-week toxicity study by oral gavage administration was performed in Sprague Dawley rats with benzalazine (2-hydroxy-5-[(4-carboxyphenyl) azo] benzoic acid, CAS 64896-26-0), a new agent for the treatment of ulcerative colitis and Crohn's disease of the large intestine, as a part of a safety evaluation program. Dosages of 0 (control), 300, 900 and 2700 mg/kg b.w./d were selected for this study. Except slight changes in the urinary status (decreased pH value and increased specific gravity) from 900 mg/kg b.w./d p.o. onwards, which were probably substance related, no further intolerance reactions were observed. The urine had a dark-yellow colour which was probably an indication of metabolites of benzalazine or benzalazine itself which were excreted via the urine. Behaviour, external appearance, body weight gain, food and water consumption, haematology, clinical biochemistry, organ weight analysis, macroscopic and microscopic examinations revealed no substance-related influence. Therefore, on the basis of the results obtained, it is concluded that the non-toxic dose level in this study is considered to be 300 mg benzalazine/kg b.w./d p.o. following daily administration for 26 weeks. PMID- 7848358 TI - Twenty-six-week oral toxicity study of benzalazine in dogs. AB - The 26-week oral toxicity of benzalazine (2-hydroxy-5-[(4-carboxyphenyl) azo]benzoic acid, CAS 64896-26-0), a new agent for the treatment of ulcerative colitis and Crohn's disease of the large intestine, was investigated in beagle dogs of both sexes. No change was observed in the 160 mg/kg group. A reduction of the aspartate aminotransferase activity was observed from 800 mg/kg b.w./d onwards. In high-dosed dogs (1600 mg/kg b.w./d) liver weights were increased and substance-related neutral fat disposition in liver cells was observed. The non toxic dose was 160 mg/kg b.w./d under these experimental conditions. PMID- 7848359 TI - Mutagenicity studies of benzalazine. AB - Benzalazine (2-hydroxy-5-[(4-carboxyphenyl) azo] benzoic acid, CAS 64896-26-0), a new agent for the treatment of ulcerative colitis and Crohn's disease of the large intestine, was studied for genotoxic effects by using the following short term in vitro and in vivo test: 1. reverse mutation test (Ames method) on Salmonella typhimurium, 2. HGPRT (hypoxanthine-guanine phosphoribosyl transferase) point mutation test on V79 hamster cells, 3. in vivo cytogenetic test on Chinese hamster cells, and 4. in vivo sister chromatid exchange test on Chinese hamster cells. Benzalazine did not show any positive response in the reverse mutation test, HGPRT-point mutation test, in vivo cytogenetic and sister chromatid exchange test. PMID- 7848360 TI - Reproductive toxicity studies of benzalazine in rats and rabbits. AB - Embryotoxicity studies of benzalazine (2-hydroxy-5-[(4-carboxyphenyl) azo]benzoic acid, CAS 64896-26-0), a new agent for the treatment of ulcerative colitis and Crohn's disease of the large intestine, were performed in rats and rabbits. Benzalazine elicited no evidence of teratogenicity when administered orally during the fetal organogenesis period to pregnant rats at doses up to 2000 mg/kg b.w./d, or to pregnant rabbits at doses up to 1000 mg/kg b.w./d. Rat fetuses in the 400 and 2000 mg/kg groups exhibited decreased body weights; the placentae weights were decreased in these dose groups, too. Rabbit fetuses in the high-dose group (1000 mg/kg b.w./d p.o.) also showed decreased body weights. Decreased body weight gain and reduced food intake were seen in rat dams in the high-dose group (2000 mg/kg b.w./d p.o.). In rabbit dams a decrease in body weight gain in the high-dose group (1000 mg/kg b.w./d p.o.) and a dose-dependent reduction in food intake from 200 mg/kg b.w./d p.o. onwards were noted. No further disturbances were observed in the behaviour of the rat and rabbit dams. External appearance, faeces, consumption of drinking water and macroscopical inspection during autopsy did not indicate any influence of the test compound. No retardations or malformations were seen even at the highest tested dose levels (rat: 2000 mg/kg b.w./d p.o.; rabbit: 1000 mg/kg b.w./d p.o.). PMID- 7848361 TI - Oncogenicity studies of benzalazine in mice and rats. AB - Oncogenicity studies of benzalazine (2-hydroxy-5-[(4-carboxyphenyl) azo]benzoic acid, CAS 64896-26-0), a new agent for the treatment of ulcerative colitis and Crohn's disease of the large intestine, were carried out in male and female mice and rats. The compound was administered in the diet for 119 weeks (rats) and 120 weeks (mice) at dose levels of 100, 300 and 900/1800 mg/kg b.w./d for mice and of 300, 900 and 2700/1800 mg/kg b.w./d for rats. The administration of benzalazine produced no effects on survival, appearance or behaviour. Body weights of the high-dosed male mice and rats (both sexes) were occasionally significantly decreased when compared to the controls. A slight but in most cases statistically significant reduction of the relative food consumption of the female mice of all treated groups was observed between test weeks 6 and 12. In the high-dosed rats a statistically significant increase of the relative food consumption was found between test weeks 17 and 109. At necropsy, there was no evidence of treatment related changes, nor were these seen on histopathological examination. All microscopic changes seen in mice and rats were of the usual type commonly occurring in untreated aged NMRI mice and Sprague-Dawley rats. However, an increased incidence of thyroid cystic hyperplasia was found in the rats of the high dose-level group. In addition, an increased incidence of thyroid adenomas was found in the male rats of the high-dosed group only as compared to the control groups. This increased tumour incidence is regarded as a marginal finding and may be of a spontaneous nature within the normal range of the background data. However, a substance-related influence cannot completely be excluded. In conclusion, the administration of benzalazine for more than 24 months to NMRI mice and Sprague-Dawley rats produced only slight effects on body weight in the high-dosed male mice and in rats (both sexes) with a no-effect level of 300 mg/kg b.w./d in the diet for mice or 900 mg/kg b.w./d in the diet for rats. There was no evidence of an oncogenic effect of benzalazine. PMID- 7848362 TI - Pharmacokinetic studies of benzalazine. AB - The pharmacokinetic properties of benzalazine ((2-hydroxy-5-[(4 carboxyphenyl)azo]benzoic acid, CAS 64896-26-0), a new agent for the treatment of ulcerative colitis and Crohn's disease of the large intestine, were investigated. From jejunal loops of rats in situ no noteworthy absorption of benzalazine was observed. All attempts to demonstrate metabolic conversion of benzalazine in mucosal homogenate of the small intestine of rats were without any success. In faecal suspensions, the half-life of the metabolic conversion of benzalazine was determined as 15 min and the formation of the metabolite 5-aminosalicylic acid (5 ASA) was demonstrated qualitatively. 72 h after single oral administration of 300 mg benzalazine/kg b.w. to rats, an average of 71.83% of the administered dose was recovered in urine and faeces. Only a small amount of unmetabolized benzalazine was excreted with urine and faeces (0.75% and 1.47% of the administered dose, respectively). The benzalazine metabolite 5-ASA and the 5-ASA metabolite acetyl-5 aminosalicylic acid (Ac-5-ASA) were excreted mainly with the faeces (29.22% and 20.66% of the administered dose, respectively) and only in small amounts with the urine (2.54% and 11.06% of the administered dose, respectively). PMID- 7848363 TI - Antitumor activity of a piperidine phospholipid. AB - A piperidine phospholipid ((+/-)-2-[hydroxy] [1-octadecyloxycarbonylpiperidin-3 yl]methoxy-phosphinyl] oxy]-N,N,N, trimethylethaniminium hydroxide inner salt, SDZ 62-826) has been prepared that exhibited weak direct cytotoxicity and strong macrophage-induced cytotoxicity in vitro against a variety of murine and one human tumor cell lines. This compound was found to be as effective as ET-18-OCH3 and SRI 62-834, phospholipids with both strong direct and macrophage-induced cytotoxicity, in increasing survivors and reducing tumor volume when given either orally or intravenously in the mouse MethA fibrosarcoma model. These findings suggest that the macrophage-induced cytotoxicity exhibited by ET-18-OCH3 and other phospholipids may play an important role in this tumor model. PMID- 7848364 TI - Pain assessment after intramuscular injection. AB - Several parameters (pH, osmotic pressure) influencing the local tolerance of injectable drugs have been well-documented; however, little attention has been paid to pain following an injection--a common problem in clinical practice. A pain questionnaire was used to record pain up to 24 h after a deep ventrogluteal injection. Two groups of healthy volunteers were recruited: the first group (n = 6) received 3 different cotrimoxazole preparations and placebo and the second group (n = 10) received 4 different multivitamin preparations and placebo (double blind, cross-over). Parameters monitored during and after injection included pain localization (line drawing), pain intensity (visual-analog scale: VAS) and verbal description of pain (pain rating index: PRI). In both groups, the equality of pain (VAS, PRI) induced by the preparations was rejected in all cases (Friedman's test, p < or = 1%). The pairwise comparisons of the groups showed significant differences (p < or = 5%) between various preparations. The correlation (Spearman's rank correlation) between pain parameters VAS and PRI was high. The present investigations have shown that the pain questionnaire is a valuable tool to investigate the subjective pain symptoms during and after the injection of different preparations. PMID- 7848365 TI - Prevention of coronary heart disease in clinical practice: recommendations of the Task Force of the European Society of Cardiology, European Atherosclerosis Society and European Society of Hypertension. PMID- 7848366 TI - Transformed rat arterial smooth muscle cells induce platelet aggregation. AB - Atherogenesis is characterized by a proliferation of arterial smooth muscle cells that may be of transformed nature. Platelets are implicated in the progression of atherosclerotic lesions through thrombotic complications. The present study was designed to investigate whether transformed arterial smooth muscle cells (SMC) could specifically aggregate platelets. We used rat transformed arterial SMC lines, V6- and V8-lines, that we had previously established. Experiments were performed with an in vitro homologous rat system. Suspensions of SMC were added without any other aggregating agent to rat heparinized platelet-rich plasma (PRP) in a coagulo-aggregometer. The effect of transformed V6-line and V8-line SMC was compared to that of their normal parental counterparts, V6- and V8-parent cells. Suspensions of transformed SMC induced, in a dose-dependent manner, an immediate and reversible ADP-like platelet aggregation. The amplitude of platelet aggregation was much higher with addition of transformed cells than of the corresponding control SMC (7.39 +/- 0.75 cm vs. 0.85 +/- 0.62 cm with 2 x 10(6) SMC, V6-line vs. V6-parent cells, respectively). ADP-like aggregation did not significantly differ between the two transformed V6- and V8-lines. ADP-like platelet aggregation was also obtained with supernatants of transformed SMC suspensions, the amplitude being higher with supernatants than with cell suspensions (21.0 +/- 3.64 cm vs. 6.8 +/- 1.22 cm with 1.0 x 10(6) V8-line cells, supernatant vs. cell suspension, respectively). The transformed SMC-induced aggregation of platelets was inhibited by apyrase (125 microM) and iodoacetate (25 mM) and thus was ascribable to ADP released by the SMC. In addition, all suspensions of SMC, normal or transformed, but not their supernatants, induced plasma clotting after variable coagulation times. Coagulation was inhibited by hirudin (25 to 100 U/ml) and phospholipase A2 (10 U/ml) indicating thrombin generation through activity of the SMC membrane tissue factor. The present results show that transformed arterial smooth muscle cells may directly aggregate platelets via a release of ADP and this could be of pathophysiological relevance for thrombosis associated with atherosclerosis. PMID- 7848367 TI - Progression and regression of atherosclerotic findings in the descending thoracic aorta detected by enhanced computed tomography. AB - Reports evaluating the progression and regression of atherosclerosis by non invasive procedure are still limited. We investigated the progression and regression of atherosclerotic intimal thickening of the descending thoracic aorta non-invasively measured by enhanced computed tomography in 83 patients (average age 51.0 years) at the beginning and end of a 2.5 year period. The patients were not taking anti-hypertensive, lipid-lowering or hypoglycemic drugs and therefore we consider them as a natural history cohort. At entry, the extent of aortic intimal thickening was 35.2% of the circumference of the cross-section of the wall, which increased to 39.7% after 2.5 years. Spontaneous progression was associated directly with age, elevated levels of total cholesterol, LDL cholesterol, LDL/HDL cholesterol ratio, diastolic blood pressure, and inversely to HDL-cholesterol. There was little correlation with triglycerides, systolic blood pressure, fasting glucose or body mass index. In 65 of the patients, aortic atherosclerosis progressed, while in 9 patients it remained unchanged, and in a further 9 it regressed. The levels of lipid variables, apart from HDL cholesterol, and diastolic blood pressure in the patients with spontaneous progression were significantly higher than in the unchanged and spontaneous regression. Thus, this study verified the natural history of aortic atherosclerosis non-invasively measured by enhanced CT. PMID- 7848368 TI - Oxidation of low density lipoprotein in patients on regular haemodialysis. AB - Patients undergoing chronic haemodialysis are known to have a high incidence of premature atherosclerosis for reasons which have not been fully elucidated. The susceptibility of low density lipoprotein (LDL) to oxidation by copper ions in vitro is widely used as a measure of its atherogenicity in vivo. We measured the susceptibility of LDL to oxidation using copper ions in haemodialysis patients and found, surprisingly, a markedly increased resistance to oxidation. The experiment was therefore repeated using an alternative free radical generator, AAPH [2,2'-azobis-(2-amidinopropane hydrochloride)], to promote LDL oxidation; using AAPH, the susceptibility to oxidation was similar in the dialysis group compared to controls. Abnormal LDL composition in the dialysis patients was also demonstrated. We suggest that, in such situations, susceptibility of LDL to oxidation in vitro may be highly dependent on the biochemical method employed and therefore may not accurately reflect atherogenic risk. PMID- 7848369 TI - Apolipoprotein epsilon 4 homozygosity--a determinant of restenosis after coronary angioplasty. AB - Conventional coronary risk factors have not consistently been found to be related to restenosis after coronary angioplasty. Apolipoprotein E (apo E) gene polymorphism and/or plasma apo(a) levels were determined in 195 subjects undergoing prospective follow up and angiographic study 6 months after elective balloon angioplasty of a previously untreated coronary obstruction. Restenosis (stenosis > or = 50% plus loss of > or = 50% of initial gain) had occurred in 59 of 150 subjects for whom E genotypes were available. The apo epsilon 4 allele frequency in those with restenosis was higher than those without (0.20 vs. 0.10, P < 0.01), attributable to an excess of epsilon 4 homozygotes in the restenosis group (5 of 59 vs. 1 of 91, P < 0.04). Restenosis was not related to plasma apo(a) and the apo epsilon 4 allele was not associated with elevated levels of apo(a) as has been reported elsewhere. No relationship was found between E genotype and serum lipid and lipoprotein levels; paradoxically, LDL cholesterol was significantly lower and HDL cholesterol higher in those with restenosis. In conclusion, homozygosity for apolipoprotein epsilon 4 appears to be an important determinant of restenosis after coronary angioplasty. PMID- 7848370 TI - Characterization of atherosclerosis in a patient with familial high-density lipoprotein deficiency. AB - We describe the cardiovascular state of a 60-year-old homozygous patient with familial HDL deficiency (Tangier disease). The patient was examined by coronary angiography and intravascular ultrasound because of chest pain at rest and on exertion. We found a normal left ventricular function, moderately diffuse coronary sclerosis without stenosis and no critical stenosis of peripheral arteries. Intravascular ultrasound revealed the three layer appearance of arterial intima, media and adventitia with normal thickness. No calcified plaques or intimal hyperplasia could be detected apart from a single, discrete atherosclerotic lesion in one iliac artery segment. Concentric non-occlusive atherosclerotic lesions which are readily detectable with intravascular ultrasound were not found. The lack of severe atherosclerosis was remarkable insofar as massive foam cell formation and the virtually complete absence of circulating HDL is characteristic of Tangier disease and has been previously demonstrated in this patient. Our findings suggest that HDL deficiency and foam cell formation in Tangier disease are not necessarily associated with accelerated development of atherosclerosis. PMID- 7848371 TI - Fluid wall shear stress measurements in a model of the human abdominal aorta: oscillatory behavior and relationship to atherosclerosis. AB - Clinically significant atherosclerosis in the human aorta is most common in the infrarenal segment. This study was initiated to test the hypothesis that flowfield properties are closely related to the localization of plaques in this segment of the arterial system. Wall shear stress was calculated from magnetic resonance velocity measurements of pulsatile flow in an anatomically accurate model of the human abdominal aorta. The wall shear stress values were compared with intimal thickening from 15 post-mortem aortas measured by quantitative morphometry of histological cross sections obtained at standard locations. Wall shear stress oscillated in direction throughout most of the infrarenal aorta, most prominently in the distal region. The time-averaged mean wall shear stress ( 1.7 to 1.4 dyn/cm2) was lowest near the posterior wall in this region. These hemodynamic parameters coincided with the locations of maximal intimal thickening. Statistical correlation between oscillatory shear and intimal thickness yielded r = 0.79, P < 0.00001. Low mean shear stresses correlated nearly as well (r = -0.75, P < 0.00005). Comparison of our data with surface maps of Sudan Red staining and early lesions as reported by others revealed similar conclusions. In contrast, pulse and maximum shear stresses did not correlate with plaque localization as has been shown for other sites of selective involvement by atherosclerosis (r < 0.345). Simulated exercise conditions markedly changed the magnitude and pattern of wall shear stress in the distal abdominal aorta. These results demonstrate that in the infrarenal aorta, regions of low mean and oscillating wall shear stresses are predisposed to the development of plaque while regions of relatively high wall shear stress tend to be spared. PMID- 7848372 TI - Dietary vitamin E increases the resistance to lipoprotein oxidation and attenuates endothelial dysfunction in the cholesterol-fed rabbit. AB - This study was conducted to determine if vitamin E could reverse or attenuate endothelial dysfunction following an atherogenic diet. Rabbits were initially fed 1% cholesterol for 4 weeks to induce endothelial dysfunction. During the next 4 weeks the rabbits were fed either 1% cholesterol +0.2% vitamin E or 1% cholesterol alone, and were then killed. Endothelium-dependent responses to acetylcholine, calcium ionophore A23187 and sodium nitroprusside (SNP) were studied in the preconstricted perfused rabbit ear. Dietary vitamin E partially reversed the impaired endothelium-dependent responses to acetylcholine associated with cholesterol feeding. The maximum decrease in perfusion pressure in response to acetylcholine was 77.8% +/- 3.6% in control animals, 35.3% +/- 2.6% in cholesterol-fed animals, and 49.1% +/- 4.7% in cholesterol+vitamin E treated animals. The response to A23187 or sodium nitroprusside did not differ between the groups. The susceptibility of rabbit beta-VLDL to oxidation was markedly decreased in the vitamin E treated animals as assessed by the formation of conjugated dienes. The formation of lipid peroxidation products were also significantly inhibited by vitamin E. These data suggest that dietary vitamin E is beneficial in reducing the oxidative injury that may lead to the impairment of nitric oxide (NO)-mediated responses in early hypercholesterolaemia. PMID- 7848373 TI - Cholesterol enrichment inhibits Na+/K+ pump in endothelial cells. AB - We have previously shown that cholesterol enrichment reduces 3H-ouabain binding in cultured vascular endothelial cells. The present study aimed to determine the effect of cholesterol enrichment on ouabain-sensitive 86Rb (as a substitute for K+) influx, i.e. K+ transport via the pump, and to examine whether cellular K+ content was affected in human umbilical vein endothelial cells. 86Rb influx was inhibited by both ouabain and bumetanide in a dose-dependent manner. Consistent with an earlier report [1], inhibition achieved was greater for ouabain (approximately 70% at mM range) than for bumetanide (approximately 55% at 0.1 mM), indicating that K+ influx via Na+/K+ pump was greater than that via Na(+) K(+)-Cl- cotransport in these cells. After incubation of 18 h or more with cholesterol-enriched liposomes (2:1 cholesterol to phospholipid ratio), a significant reduction (> 20%) of the ouabain-sensitive K+ influx and an increase in cellular cholesterol content were observed. The inhibitory effect was observed only at liposome concentrations above 2 mg/ml. Following 18 h incubation with 2 mg/ml cholesterol-enriched liposomes, cellular K+ content was significantly decreased. The phospholipid liposome treatment did not alter K+ content, suggesting that the inhibitory effect on Na+/K+ pump and the cellular K+ content reduction was not due to liposome fusion alone or to the phospholipid present. These findings indicate that cholesterol enrichment inhibits Na+/K+ pump and thus reduces cellular K+ content in endothelial cells, and may play a role in the widely observed abnormal endothelium-dependent vascular response induced by hypercholesterolemia. PMID- 7848374 TI - Intimal hyperplasia of experimental autologous vein graft in hyperlipidemic rabbits with poor distal runoff. AB - Poor distal runoff and hyperlipidemia are factors affecting the fate of an implanted graft. In the present study, combined effects of poor distal runoff and hyperlipidemia on intimal hyperplasia (IH) of the vein graft were examined in a newly developed poor distal runoff model in rabbits. A poor distal runoff model was prepared in the right hindlimb of 30 rabbits. These animals were divided into two groups, depending on the diet provided; normolipidemic diet group (Group NL, n = 14) and hyperlipidemic 1% cholesterol diet group (Group HL, n = 16). Four weeks after preparing the poor runoff model, the femoral vein was implanted into the ipsilateral femoral artery. At 2, 4 and 6 weeks, the grafts were harvested. IH of the graft was measured and macrophages in the IH were examined immunohistochemically. Intimal cell proliferation was also determined by bromodeoxyuridine (BrdU) incorporation. IH of the vein graft was significantly accelerated in cases of poor distal runoff and hyperlipidemia. There were no macrophages in the IH in the NL group. In the HL group, macrophages infiltrated the outer layer of IH, sometimes just above the internal elastic lamina, and increased with time. In the poor distal runoff limbs at 6 weeks, macrophages also appeared in the subendothelial layer but were absent in that layer in the controls. Intimal cell proliferation expressed as the BrdU labeling index (LI) was maximum at 2 weeks. In the HL group, BrdU LI of IH in the poor distal runoff limb was higher than in the control at 2 and 4 weeks. Throughout the experiments, BrdU LIs in the HL group were significantly higher than in the NL. Hyperlipidemia accelerates intimal cell proliferation to a greater extent, then does IH. In cases of a poor distal runoff, the enhancement of cell proliferation by hyperlipidemia is augmented. These responses, in the presence of a hyperlipidemia, may be closely related to the migration of macrophages. PMID- 7848375 TI - Atypical features of tinea in newborns. PMID- 7848376 TI - NF1: a prevalent cause of tumorigenesis in human cancers? PMID- 7848377 TI - Anger attacks in unipolar depression, Part 1: Clinical correlates and response to fluoxetine treatment. AB - OBJECTIVE: Anger attacks are sudden, intense spells of anger associated with a surge of autonomic arousal including such symptoms as tachycardia, sweating, flushing, and a feeling of being out of control. The purpose of this study was to determine whether depressed patients with and without anger attacks exhibit distinct psychological characteristics and whether these attacks respond to treatment with fluoxetine. METHOD: The Anger Attacks Questionnaire, the Hamilton Rating Scale for Depression, the Symptom Questionnaire, and the Cook-Medley Hostility Scale were among the scales administered at the Depression Research Program of the Clinical Psychopharmacology Unit at the Massachusetts General Hospital to 127 medication-free outpatients with major depression and to 85 of these patients after 8 weeks of open treatment with a fixed dose (20 mg/day) of fluoxetine. RESULTS: At baseline, 44% of the depressed outpatients reported having anger attacks; these patients had significantly higher scores on measures of anxiety, somatization, and state and trait hostility than did the subjects who did not exhibit such attacks. After treatment, there were significant reductions in these measures, and the anger attacks disappeared in the majority (71%) of the patients who had previously reported them. There was a trend toward greater overall clinical improvement for patients with anger attacks than for patients without them. CONCLUSIONS: This study identified a subgroup of highly irritable and hostile depressed patients who report the presence of anger attacks and have a psychological profile distinct from that of depressed patients without anger attacks. Furthermore, fluoxetine treatment appears to be beneficial in reducing anger and hostility in these patients. PMID- 7848378 TI - The 1945 Gluckman Report and the establishment of South Africa's health centers. PMID- 7848379 TI - Elective cardiac arrest with a hyperpolarizing adenosine triphosphate-sensitive potassium channel opener. A novel form of myocardial protection? AB - BACKGROUND: Hyperkalemic depolarized cardiac arrest has been the cornerstone of myocardial protection during cardiac surgery for more than 30 years. Many of the advances in myocardial protection seek to minimize the cellular damage and to reduce the ongoing metabolic processes occurring as a direct consequence of the depolarized state. Ideally, cardiac arrest at hyperpolarized cellular membrane potentials--the natural resting state of the heart--will meet all the requirements of modern cardioplegia, namely, electromechanical asystole and cardiac relaxation, while preserving the vital integrity of the heart itself. METHODS AND RESULTS: To determine whether activation of adenosine triphosphate sensitive potassium channels by pharmacologic agents could produce hyperpolarized cardiac arrest, we tested the ability of aprikalim, a known adenosine triphosphate-sensitive potassium channel opener, to arrest the intact beating heart. In a normothermic (37 degrees C) isolated rabbit heart preparation, aprikalim was found to rapidly shorten the action potential duration and produce cardiac asystole that was maintained during 20 minutes of "no-flow" global ischemia without a rise in end-diastolic pressure. Cardiac rhythm and function were fully restored by reperfusion alone (developed pressure was 100.6% +/- 7.9% of prearrest value after 30 minutes of reperfusion). In contrast, 20 minutes of unprotected normothermic global ischemia resulted in a 2.7 +/- 0.55 mmHg rise in end-diastolic pressure and only 58.2% +/- 3.8% recovery of developed pressure after 30 minutes of reperfusion. By way of comparison, 20 minutes of standard hyperkalemic depolarized normothermic rest was accompanied by a 1.2 +/- 0.6 mmHg rise in end-diastolic pressure and only 80.8% +/- 2.6% recovery of developed pressure after 30 minutes of reperfusion. To directly compare hyperkalemic depolarized cardiac arrest to hyperpolarized cardiac arrest induced by potassium channel openers and to better define the characteristics of such hyperpolarized arrest, we studied a fixed (4 mmHg rise in end-diastolic pressure--contracture) ischemic injury model. The time to development of the contracture was prolonged by hyperkalemic arrest (35.8 +/- 1.7 minutes) and significantly more so by hyperpolarized arrest (47.0 +/- 3.3 minutes) when compared with that of unprotected hearts (24.0 +/- 1.2 minutes). Moreover, aprikalim resulted in significantly better postischemic recovery of function (developed pressure was 69.0% +/- 6.7% of prearrest value after 30 minutes of reperfusion) than after no cardioplegia (45.4% +/- 7.5%) or standard hyperkalemic cardioplegia (44.3% +/- 5.7%). CONCLUSIONS: Pharmacologic activation of adenosine triphosphate-sensitive potassium channels can result in predictable and sustainable hyperpolarized cardiac arrest that is reversible by reperfusion. This method of myocardial protection was found to fully preserve cardiac electromechanical function after a 20-minute period of global normothermic ischemia. Furthermore, hyperpolarized arrest induced by potassium channel openers significantly prolonged the period to the development of contracture and afforded a significantly better postischemic recovery of function than obtained in either hearts protected with hyperkalemic depolarized arrest or those not protected by any form of cardioplegia. PMID- 7848380 TI - Management of uveal melanoma. A continuing dilemma. PMID- 7848381 TI - Prognosis and treatment of disseminated uveal melanoma. AB - BACKGROUND: The clinical course of uveal melanoma differs greatly from that of cutaneous melanoma. METHODS: Twenty-four patients with metastatic uveal melanoma (13 men and 11 women; median age at diagnosis, 56 years [range, 17-67 years]) were evaluated retrospectively. RESULTS: Main sites of metastases were liver (87%), lung (46%), bone (29%), and skin (17%). Median relapse-free survival time was 36 months (range, 5-240 months). Median survival time after clinical detection of metastases was 9 months (range, 1-54 months). Relapse-free survival time was significantly greater in patients 50 years of age or younger. After manifestation of metastases, the clinical course was more favorable in patients in whom the liver was either not involved at all or not among the first sites of dissemination. These patients had a median survival time of 19 months, compared with 7 months for patients in whom the liver was involved initially. First-line systemic treatment of metastatic disease yielded three cases of stable disease lasting 6-14 months, but no complete or partial response. Three patients received intraarterial liver perfusion as first- or second-line treatment, resulting in one partial response, which lasted 6 months. CONCLUSION: Treatment and prognosis results of patients with metastatic uveal melanoma were poor, especially when the disseminated to the liver; survival time of approximately 9 months can be expected. PMID- 7848382 TI - Surgery in the management of chylothorax after coronary artery bypass with left internal mammary artery. PMID- 7848383 TI - Excerpts from the 1993 USRDS Annual Data Report. PMID- 7848384 TI - The role of psychologists in the treatment, management, and prevention of chronic mental illness. AB - In addition to suffering from the severe psychiatric symptoms of chronic mental illness (CMI), people with this type of disorder suffer from a variety of secondary disabilities and face societal obstacles that interfere with their ability to maximize their personal, social, and vocational potentials. Following the deinstitutionalization of long-term psychiatric patients in recent decades, many different understandings of the etiology, treatment, and management of CMI have evolved, including those derived from the biological, vulnerability, cognitive, case management, rehabilitation, and psychoeducational models. Because psychologists are trained in a wide range of psychological theories and a broad repertoire of applications, they have unique contributions to make within each model, particularly, as discussed here, to prevent, treat, and manage CMI through research, assessment, and intervention. PMID- 7848385 TI - Destructive operations in modern obstetrics in a developing country at tertiary level. PMID- 7848386 TI - Chiropractic scope of practice. PMID- 7848387 TI - Amplification of human APO(a) kringle 4-37 from blood lymphocyte DNA. AB - We have been able to amplify the lysine binding pocket region of human apo(a) kringle type 5 starting from the DNA isolated from peripheral blood lymphocytes. This development now permits the identification of Lp(a) mutants that by lacking their ability to bind to lysine/fibrin would have a lesser thrombogenic potential. PMID- 7848388 TI - Comparison of two fentanyl doses to improve epidural anaesthesia with 0.5% bupivacaine for caesarean section. AB - Ninety women undergoing elective caesarean section under epidural anaesthesia were double blindly randomised into three groups to receive either 2 ml of saline or 50 or 100 micrograms of fentanyl in 2 ml volume added to 0.5% bupivacaine. Both doses of fentanyl intensified the epidural anaesthesia and reduced patient discomfort during the operation. In both fentanyl groups the epidural blockade more often reached the 5th thoracic segment (P = 0.0258), the patients had significantly less pain (P = 0.0256), needed less intravenous diazepam medication during the operation (P = 0.0005) and the operating conditions were were better when compared to the saline group (P = 0.0416). There was no difference between the groups in the condition of the neonates as assessed by the Apgar score and cord blood pH. The postoperative time until treatment for pain was requested by the patients was more than 1 h longer in the fentanyl groups, but there was no difference in the total amount of postoperative analgesics needed during the first 24 h when compared to the saline group. Mild pruritus not requiring treatment was more common in fentanyl groups than in the saline group (P = 0.0187). The results suggest that 50 micrograms of fentanyl added to 0.5% bupivacaine increases patient comfort and improves the quality of epidural anaesthesia for caesarean section, and that adding 100 micrograms does not give further advantage. PMID- 7848389 TI - Influenza immunization in children with chronic arthritis: a prospective study. AB - OBJECTIVE: Influenza immunization is recommended for children with chronic conditions and children receiving chronic acetylsalicylic acid therapy. Our study assessed the safety and immunogenicity of this vaccination in children with chronic arthritis. METHODS: The frequency of possible adverse reactions following influenza vaccination, and virus specific HI antibody levels prior to and 4 weeks after vaccination with an inactivated split virus vaccine prepared for the 1991/92 season, were assessed in a prospective open study of children with chronic arthritis. Thirty-four patients were assessed clinically at vaccination and one month later. Local symptoms at the injection site and systemic symptoms were assessed by diary in 26 patients and 13 immunized healthy control children. RESULTS: Tenderness and/or redness at the injection site, and fever occurred equally in patients and controls. Malaise/nausea occurred in 12 patients and 3 controls (p = 0.3), but patients had more symptomatic days than controls (p = 0.01). No child with inactive arthritis developed a swollen joint following immunization. There were no significant differences between the 2 visits for a.m. stiffness, pain (VAS), global assessment, joint count or erythrocyte sedimentation rate (ESR). More patients improved than deteriorated by each measure. Three patients deteriorated by global assessment, 7 patients had an increased joint count. At least 95% of patients developed presumably protective levels of antibodies (HI titers > or = 40) to each virus. Preimmunization titers, seroresponse rates (4 x rise or rise from < 20 to > or = 40) and final titers were the same between patients (whether or not they were taking prednisone or a second line antirheumatic drug) and controls. CONCLUSION: There was no convincing evidence that influenza vaccination is associated with significant adverse reactions or arthritis flares in children with chronic arthritis. Children with chronic arthritis appeared to respond adequately to influenza vaccination. PMID- 7848390 TI - Abnormal responses to electrocutaneous stimulation in fibromyalgia. AB - OBJECTIVE: As disturbed nociception may be relevant to the pathogenesis of fibromyalgia, nonnoxious electrocutaneous stimulation was used as a tool to investigate nociceptive status. METHODS: Perception threshold and pain tolerance were studied in the upper limbs of 10 patients with fibromyalgia and 10 healthy volunteers. RESULTS: Perception threshold did not differ between the groups but the marked reduction in pain tolerance found in patients with fibromyalgia was accompanied by spread and persistence of dysesthesiae. CONCLUSION: The upper limbs of patients with fibromyalgia resembled regions of secondary hyperalgesia, which may imply that perturbation of central nociceptive mechanisms is involved in the pathogenesis of this syndrome. PMID- 7848391 TI - Direction of catheter insertion and incidence of paresthesias and failure rate in continuous epidural anesthesia: a comparison of cephalad and caudad catheter insertion. AB - BACKGROUND AND OBJECTIVES: Paresthesias and unblocked segments during continuous epidural anesthesia--sometimes leading to higher doses of local anesthetics--can increase the risk of this technique. A cephalad insertion of the epidural catheter might decrease the incidence of these problems, but this has not been evaluated before in a controlled study. METHODS: In a prospective, double-blind, randomized study, we compared the incidence of paresthesias during catheter insertion and the failure rate of continuous epidural anesthesia in two groups of obstetric patients. In group 1 (n = 52), the Tuohy needle bevel was directed cephalad during catheter insertion. In group 2 (n = 53), it was directed caudad. The catheter was introduced 4-5 cm into the epidural space, and bupivacaine 25 mg plus fentanyl 50 micrograms were administered through it. RESULTS: Twenty percent of the patients in group 1 had paresthesias versus 40% in group 2 (p = 0.0249; 95% confidence interval of the difference 1-40%); intensity of paresthesias was greater in group 2. Pain relief was complete in 75% and 80% of the patients in groups 1 and 2, respectively (NS); three patients in group 1 and one in group 2 had unblocked segments (NS). CONCLUSIONS: Our results support the contention that the catheter should be directed cephalad during insertion for continuous epidural anesthesia. PMID- 7848392 TI - Universal screening for infant hearing impairment: not simple, not risk-free, not necessarily beneficial, and not presently justified. PMID- 7848393 TI - Survival superiority of females with melanoma. A multivariate analysis of 6383 patients exploring the significance of gender in prognostic outcome. AB - OBJECTIVE: To evaluate the effects of gender on prognostic outcome of patients with melanoma. DESIGN: Retrospective cohort study, including 20 years of follow up. SETTING: Duke University Melanoma Clinic, Durham, NC, a referral center for patients with melanoma. PATIENTS: Patients with melanoma (N = 6383), consisting of 45% females and 55% males, obtained from a referred sample. Eligibility requirements were nonocular melanomas and white race. MAIN OUTCOME MEASURES: Time to metastases and survival. RESULTS: Females with melanoma demonstrated a superior prognostic outcome over males, with a 34% survival advantage and a 28% disease-free advantage. When each of the variables of age, site, Clark's level, histologic type, and tumor thickness was explored for possible influences on prognostic outcome, female survival advantage persisted, although modified by independent variables. The greatest influence came from the variables of site, Clark's level, and Breslow's thickness. Age, specifically in premenopausal vs postmenopausal age groups, was not significant in altering females' prognostic advantage. A multivariate analysis combining the effects of all the variables resulted in females still maintaining a 22% survival advantage and a 17% disease free advantage. CONCLUSIONS: Females with melanoma have a significant prognostic advantage over their male counterparts that cannot be fully explained by influences from the variables of age, site, Clark's level, histology, and Breslow's thickness. This superior prognostic outcome does not appear to be associated with menstrual status. Evidence does suggest that the protective factor for females occurs at the level of metastases. PMID- 7848394 TI - Rotation: a valid premanipulative dizziness test? Does it predict safe manipulation? AB - OBJECTIVE: The purpose of this study was to investigate the validity of cervical spine rotation as a test of patency of the vertebral arteries (VAs) and the internal carotid arteries (ICAs). DESIGN: A descriptive study was undertaken. SETTING: Testing was carried out in a private clinical vascular unit attached to a large Sydney public hospital. PARTICIPANTS: Twenty healthy volunteers, both male and female, who were free of risk factors commonly associated with vascular disease, participated in the study. INTERVENTIONS AND MAIN OUTCOME MEASURES: An AutoSector 5 Duplex Doppler ultrasound instrument was used to record mean and peak frequency of blood flow (a measure of blood velocity) in the right and left VAs and ICAs in the cervical spine positions of neutral, 45 degrees contralateral rotation and full range contralateral rotation. To determine general hemodynamic stability, blood pressure and heart rate were recorded pre- and posttest, as well as in all tested positions. RESULTS: There was a significant trend for blood velocity to increase in 45 degrees contralateral rotation and to decrease in full rotation (p < .01). This trend was not consistent across vessels. Blood velocity decreased with rotation from neutral head position in the right VA, and continued to increase throughout rotation in the right ICA. CONCLUSION: It appears that sustained rotation influences blood velocity in the extracranial vessels. This may have relevance in patients with abnormal blood flow who are candidates for cervical manipulation. PMID- 7848395 TI - Omeprazole versus H2-receptor antagonists in treating patients with peptic stricture and esophagitis. AB - BACKGROUND/AIMS: Although dysphagia in patients with peptic stricture is attributed to a decreased luminal diameter, coexistent esophagitis may be an equally important cause. The goals of this study were to determine whether medical healing of esophagitis in patients with stricture improves dysphagia and decreases dilatation need and to compare the efficacy and cost-effectiveness of omeprazole versus H2-receptor antagonists (H2RA). METHODS: Thirty-four dysphagic patients with peptic stricture and erosive esophagitis were dilated and randomized to omeprazole 20 mg every day versus H2RA (ranitidine 150 mg twice daily or famotidine 20 mg twice daily). Patients received further dilatations only if dysphagia frequency was greater than or equal to once per week. At 3 and 6 months, patients were assessed for esophagitis healing, dysphagia relief, and bougienage requirements. Cost-effectiveness of omeprazole and H2RA was determined. RESULTS: Patients with healed esophagitis at 3 and 6 months were more likely to dysphagia-free and to require fewer dilatations than patients with persistent esophagitis. At 6 months, omeprazole produced a significantly (P < 0.01) higher rate of esophagitis healing, dysphagia relief, and fewer dilatations compared with H2RA. Omeprazole was also 40%-50% more cost-effective. CONCLUSIONS: Esophagitis healing improves dysphagia and decreases dilatation need in patients with peptic stricture. Omeprazole heals esophagitis and relieves dysphagia more efficaciously than H2RA while decreasing costs to patients. PMID- 7848396 TI - Malignant rhabdoid tumour of colon. PMID- 7848397 TI - Tetanus in a 74-year-old woman. PMID- 7848398 TI - A comparison of three types of tracheal tube for use in laryngeal mask assisted blind orotracheal intubation. AB - Laryngeal mask assisted blind orotracheal intubation is a technique that is best mastered under controlled circumstances. The influence of the type of tracheal tube, and positioning of the head, on the success rate of this procedure was evaluated in 90 gynaecological patients presenting for elective procedures under general anaesthesia. After induction, a laryngeal mask was introduced and its position was confirmed. Up to three attempts at blind orotracheal intubation using one of three tracheal tubes (Argyle, Portex or Kendall Curity) passed through the laryngeal mask were permitted in each patient. The success rates after a single attempt at blind oral intubation were 3.3%, 70.0% and 30.0% respectively (p < 0.001 and p < 0.05 when Portex was compared to Argyle and Kendall Curity types). After a maximum of three attempts, success rates were 30.0% (Argyle), 93.3% (Portex) and 76.7% (Kendall Curity). The first attempt at tracheal intubation was performed in the 'sniffing the morning air position' and this was successful in 52% of successful intubations; the second attempt using extension at the atlanto-occipital joint was successful in a further 35% of successful intubations; the third attempt used varying degrees of neck flexion and extension at the atlanto-occipital joint and this permitted successful placement of the tracheal tube in the remaining 13% of patients in whom tracheal intubation was possible. PMID- 7848399 TI - Thyroid hormone use and bone mineral density in elderly women. Effects of estrogen. AB - OBJECTIVE: To determine the effect of long-term use of thyroid hormone on bone mineral density (BMD) in elderly women and the potential mitigating effects of estrogen replacement therapy. DESIGN: Cross-sectional, community-based study. SETTING: Rancho Bernardo, Calif. PARTICIPANTS: A total of 991 white women aged 50 to 98 years who participated in a study of osteoporosis. MAIN OUTCOME MEASURES: Bone mineral density at the ultradistal radius and midshaft radius using single photon absorptiometry and at the hip and lumbar spine using dual-energy x-ray absorptiometry. RESULTS: A total of 196 women taking thyroid hormone for a mean duration of 20.4 years were compared with 795 women who were not using thyroid hormone. Women taking daily thyroxine-equivalent doses of 200 micrograms or more had significantly lower BMD levels at the midshaft radius and hip compared with those taking less than 200 micrograms. Daily doses of 1.6 micrograms/kg and greater were associated with lower bone mass at all four sites compared with nonuse, whereas doses less than 1.6 micrograms/kg were not associated with lower BMD levels. These associations were independent of age, body mass index, smoking status, and use of thiazides, corticosteroids, and estrogen. Women taking both estrogen and a thyroid hormone dose of 1.6 micrograms/kg or greater had significantly higher BMD levels at all four sites than women taking the same thyroid hormone dose alone. Women taking both thyroid hormone and estrogen had BMD levels comparable with those observed in women taking only estrogen. CONCLUSIONS: Long-term thyroid hormone use at thyroxine-equivalent doses of 1.6 micrograms/kg or greater was associated with significant osteopenia at the ultradistal radius, midshaft radius, hip, and lumbar spine. Estrogen use appears to negate thyroid hormone-associated loss of bone density in postmenopausal women. PMID- 7848400 TI - A randomized, controlled assessment of the canalith repositioning maneuver. AB - The efficacy of the canalith repositioning maneuver in the treatment of benign positional vertigo was assessed in this controlled, randomized trial of 38 subjects. Treated subjects underwent the maneuver and control subjects did not. All were reevaluated 1 month after treatment. The number of persons experiencing subjective improvement was not statistically significantly different between the treatment and control groups. All patients, in both experimental and control groups, in this study experienced substantial improvement. Although the maneuver is safe it does not have treatment benefit for benign positional vertigo. PMID- 7848402 TI - Chaotic family dynamics. AB - This article illustrates the basic features of chaotic systems and demonstrates some of the differences between chaotic and nonchaotic systems. To facilitate the explanation of advanced mathematical ideas, this presentation is couched in terms of the interactions within two families: the Limit family and the Scroll family. A nonchaotic model of the Limit family leads to repetitive sequences of affection and hostility between husband and wife. The Scroll family model demonstrates the dynamics of a truly chaotic system; it leads to alternating episodes of mutual endearment and mutual aversion between mother and daughter. Problems of measurement that would accompany the use of these models are mentioned. PMID- 7848401 TI - Effects of varying carbohydrate content of diet in patients with non-insulin dependent diabetes mellitus. AB - OBJECTIVE: To study effects of variation in carbohydrate content of diet on glycemia and plasma lipoproteins in patients with non-insulin-dependent diabetes mellitus (NIDDM). DESIGN: A four-center randomized crossover trial. SETTING: Outpatient and inpatient evaluation in metabolic units. PATIENTS: Forty-two NIDDM patients receiving glipizide therapy. INTERVENTIONS: A high-carbohydrate diet containing 55% of the total energy as carbohydrates and 30% as fats was compared with a high-monounsaturated-fat diet containing 40% carbohydrates and 45% fats. The amounts of saturated fats, polyunsaturated fats, cholesterol, sucrose, and protein were similar. The study diets, prepared in metabolic kitchens, were provided as the sole nutrients to subjects for 6 weeks each. To assess longer term effects, a subgroup of 21 patients continued the diet they received second for an additional 8 weeks. MAIN OUTCOME MEASURES: Fasting plasma glucose, insulin, lipoproteins, and glycosylated hemoglobin concentrations. Twenty-four hour profiles of glucose, insulin, and triglyceride levels. RESULTS: The site of study as well as the diet order did not affect the results. Compared with the high-monounsaturated-fat diet, the high-carbohydrate diet increased fasting plasma triglyceride levels and very low-density lipoprotein cholesterol levels by 24% (P < .0001) and 23% (P = .0001), respectively, and increased daylong plasma triglyceride, glucose, and insulin values by 10% (P = .03), 12% (P < .0001), and 9% (P = .02), respectively. Plasma total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol levels remained unchanged. The effects of both diets on plasma glucose, insulin, and triglyceride levels persisted for 14 weeks. CONCLUSIONS: In NIDDM patients, high-carbohydrate diets compared with high-monounsaturated-fat diets caused persistent deterioration of glycemic control and accentuation of hyperinsulinemia, as well as increased plasma triglyceride and very-low-density lipoprotein cholesterol levels, which may not be desirable. PMID- 7848403 TI - Purification and characterization of sialyl-Le(a)-carrying mucins of human bile; evidence for the presence of MUC1 and MUC3 apoproteins. AB - Purification of sialyl-Le(a)-carrying mucins from primary human bile by trichloroacetic acid precipitation, delipidation, and gel filtration in guanidinium chloride gave three separable fractions, one of which was further purified by affinity chromatography. These fractions, named SBG1 (for soluble bile glycoprotein), SBG2, and SBG3 had molecular masses of > 1100, 800-950, and 100-250 kDa, respectively, as estimated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Their mucin characteristics were indicated by a high carbohydrate content, ranging from 74 to 95%. The carbohydrate compositions indicated the presence of very long fucosylated polylactosamine chains. Amino acid analyses showed high abundance of serine and threonine in all three fractions (19-36%), confirming their mucin-like nature. Immunochemical analyses of deglycosylated samples detected the MUC1 mucin apoprotein in SBG2 and the MUC3 protein in SBG1. To our knowledge, this is the first report of a MUC3 mucin being purified. This mucin showed no significant reduction in size upon trypsin treatment or disulfide bond reduction and alkylation. Gel filtration of three samples of secondary bile showed that the size distribution of sialyl-Le(a) carrying glycoproteins was similar to that found in primary bile, and immunochemical analysis showed that the MUC1 protein was present in all three samples. In one sample an additional fraction was isolated, which was insoluble in 6 M guanidinium chloride, but was solubilized upon reduction and alkylation. mRNAs from gallbladder epithelia were analyzed in Northern blot hybridizations showing that the MUC1 and MUC3 but not the MUC2 mucin apoprotein genes were expressed. PMID- 7848404 TI - Intensive diagnostic follow-up after treatment of primary breast cancer. A randomized trial. National Research Council Project on Breast Cancer follow-up. AB - OBJECTIVE: To evaluate the effectiveness of early detection of intrathoracic and bone metastases in reducing mortality in breast cancer patients. DESIGN: Randomized clinical trial allocating breast cancer patients to two alternative follow-up protocols (intensive vs clinical) for at least 5 years. SETTING: Twelve breast clinics (referral centers) in different areas in Italy. PATIENTS: A total of 1243 consecutive patients (either premenopausal or postmenopausal) surgically treated for unilateral invasive breast carcinoma with no evidence of metastases. The two study groups were well balanced in terms of clinical and prognostic characteristics. INTERVENTION: Patients in both treatment groups had physical examination and mammography, while patients of the intensive follow-up group had, in addition, chest roentgenography and bone scan every 6 months. MAIN OUTCOME MEASURES: Vital status at 5 years was the main outcome; information was available for all except five patients (0.4%). Relapse-free survival was also analyzed. RESULTS: Overall, 393 recurrences (104 local and 289 distant) were observed during the study. Increased detection of isolated intrathoracic and bone metastases was evident in the intensive follow-up group compared with the clinical follow-up group (112 vs 71 cases), while no difference was observed for other sites and for local and/or regional recurrences. The 5-year relapse-free survival rate was significantly higher for the clinical follow-up group, with patients in the intensive follow-up group showing earlier detection of recurrences. No difference in 5-year overall mortality (18.6% vs 19.5%) was observed between the two follow-up groups. CONCLUSIONS: Periodic chest roentgenography and bone scan allow earlier detection of distant metastases, but anticipated diagnosis appears to be the only effect of intensive follow-up, and no impact on prognosis is evident after 5 years. Periodic intensive follow-up with chest roentgenography and bone scan should not be recommended as a routine policy. PMID- 7848405 TI - The promise of one great anesthesia society. The 1939-1940 proposed merger of the American Society of Anesthetists and the International Anesthesia Research Society. PMID- 7848406 TI - Skeletal muscle relaxation in patients undergoing electroconvulsive therapy. PMID- 7848407 TI - Genomic imprinting--defusing the ovarian time bomb. AB - Why do mammals imprint their parental genomes? Imprinting is seen in many phyla, but that in mammals is by far the most dramatic. Is there something peculiar to mammals that calls for such a striking phenomenon? We propose that imprinting is a device that protects female mammals from the potential ravages of ovarian trophoblast disease. Without imprinting, the ovarian teratomas that frequently arise from parthenogenetically activated oocytes in situ might be capable of forming malignant trophoblast. An allele that favored imprinting would spread rapidly because of the great increase in fitness associated with suppressing a lethal cancer of females. PMID- 7848408 TI - The dead do tell tales. PMID- 7848409 TI - Lower back pain and sciatica: how best to manage them. AB - In this age of easy access to non-invasive computed tomography and magnetic resonance imaging, the clinician is faced with the dilemma of whether or not to remove the patient's intervertebral disc herniation in order to relieve the pain caused by lumbosacral nerve root compromise. This review outlines the rationale for instituting a series of epidural injection techniques, before resorting to surgery. PMID- 7848410 TI - Medical management of endocarditis. AB - The treatment of infective endocarditis with antibiotics is one of the great medical success stories of this century, reducing mortality from 100% to as low as 10%. It is important for all medical and dental practitioners to be aware of endocarditis as the disease may be inadvertently caused by the treatment of other conditions. PMID- 7848411 TI - The use of clenbuterol in large animal obstetrics: manual correction of bovine dystocias. AB - This study was undertaken to test the effect of clenbuterol, a smooth muscle relaxant, as an aid for the manual correction of bovine dystocias in a rural Quebec practice. The drug was given initially by intravenous coccygeal or jugular injection at a dose of 0.6 micrograms-0.8 micrograms/kg of body weight to parturient cows affected with fetal malpresentations (n = 37), malpostures (n = 112), or uterine torsions (n = 70). These cases comprised 32% (219/688) of the manually corrected dystocias encountered in cattle during the trial. Ease provided for obstetrical maneuvers of different types of dystocias was the evaluation criteria used in this report. The drug's myometrial relaxant effect made corrections easier for the veterinarian, and shorter and less traumatic for the dam. The success rates achieved for vaginal corrections and delivery of uterine torsions were 84% (76/91) and 77% (70/91), respectively. Other recorded benefits included the need for less frequent use of epidural anesthesia and a significantly lower incidence of retained fetal membranes (chi 2 = 11.18, p < 0.001). No adverse reactions were observed at any time. Clenbuterol proved to be a useful drug for manual correction of dystocias in cattle. PMID- 7848412 TI - Indigenous falciparum malaria in Israel: a case report. PMID- 7848413 TI - Keyhole surgery. PMID- 7848414 TI - Postischemic accumulation of the lipid peroxidation product 4-hydroxynonenal in rat small intestine. AB - 4-Hydroxynonenal (HNE) as an indicator of lipid peroxidation was determined in rat jejunal mucosa. HNE was extracted as the dinitrophenylhydrazone derivative from the tissue, partially separated from other carbonyl compounds by thin-layer chromatography and measured by HPLC. During reperfusion of the small intestine following an ischemic period of 60 minutes a marked increase of the tissue concentration of HNE was observed. The mucosal HNE level passed a maximum value of 3.0 +/- 0.5 microM 10 min after the onset of reperfusion in comparison with 0.7 +/- 0.2 microM as initial value. The increased tissue level of the highly cytotoxic 4-hydroxyalkenal is suggested to be involved in the reperfusion induced morphological and biochemical changes of the small intestine. PMID- 7848415 TI - QALYs for resource allocation: a rejoinder to a reply. PMID- 7848416 TI - Preventing Rh immunisation. PMID- 7848417 TI - Assessment and management of foot disease in patients with diabetes. AB - Limb- or life-threatening complications in patients with diabetes can be prevented with an integrated, multidisciplinary approach. Most patients seen in clinical practice are in the early stages of the disease process. Glycemic control retards the progression of neuropathy, which is the most important risk factor for ulceration. Early detection of the loss of protective sensation and implementation of strategies to prevent ulceration will reduce the rates of limb threatening complications. Clinicians should routinely examine the feet of diabetic patients. Education in foot care, proper footwear, and close follow-up are required to prevent or promptly detect neuropathic injury. If ulceration occurs, removal of pressure from the site of the ulcer and careful management of the wound will allow healing in most cases. The failure to heal despite these measures should prompt a search for associated arterial insufficiency. If infection is present, appropriate antimicrobial therapy combined with immediate surgical intervention, including revascularization when necessary, will increase the chances of saving the limb. With this comprehensive approach, it is possible to achieve the goal of a 40 percent decrease in amputation rates among diabetic patients by the year 2000. PMID- 7848418 TI - Radiofrequency catheter modification of atrioventricular conduction to control the ventricular rate during atrial fibrillation. AB - BACKGROUND: In some patients with atrial fibrillation, the ventricular rate may be difficult to control with medications. We evaluated a radiofrequency catheter technique to modify atrioventricular conduction in atrial fibrillation in order to control the ventricular rate without creating pathologic atrioventricular block. METHODS: We studied 19 consecutive patients with atrial fibrillation and uncontrolled ventricular rates refractory to drug therapy. They had had atrial fibrillation for a mean (+/- SD) of 5.5 +/- 4.9 years, had had 4.9 +/- 0.9 unsuccessful drug trials, and were 62 +/- 15 years old. Before the procedure, the maximal ventricular rate during exercise was 180 +/- 39 beats per minute. A total of 11 +/- 5 radiofrequency-energy applications were delivered to the posterior septal or midseptal right atrium, near the ostium of the coronary sinus. RESULTS: Successful control of the ventricular rate without pathologic atrioventricular block was achieved in 14 of the 19 patients (74 percent). Persistent third-degree atrioventricular block requiring a permanent pacemaker occurred inadvertently in four patients (21 percent). Atrioventricular conduction was intentionally ablated in one patient. The 14 patients who had successful modification of conduction had persistent reductions in maximal ventricular rate during exercise (rate at three months, 126 +/- 24 beats per minute; P < 0.01). These patients had resolution of symptoms related to rapid rates during 8 +/- 2 months of follow-up. One patient had a recurrence of a rapid ventricular rate but was again asymptomatic after a second modification procedure. One patient with dilated cardiomyopathy died suddenly, five months after a successful procedure. CONCLUSIONS: A catheter technique to modify atrioventricular conduction without creating pathologic atrioventricular block is feasible in the majority of patients with symptomatic atrial fibrillation and a rapid ventricular rate refractory to drug therapy. PMID- 7848419 TI - Muslim customs surrounding death, bereavement, postmortem examinations, and organ transplants. AB - Muslims are always buried, never cremated. It is a religious requirement that the body be ritually washed and draped before burial, which should be as soon as possible after death. Those carrying out this duty should be immunised against hepatitis B and be aware of the hazards of AIDS. Muslim women never attend burials and it is rare for funeral directors to be involved. Muslim jurists from the Arab world can justify organ transplantation, but those from the Indian subcontinent are against it. They are united in the belief of the sacredness of the human body and thus deplore postmortem examinations. PMID- 7848420 TI - The electrocardiogram is a more sensitive indicator than echocardiography of hypertrophic cardiomyopathy in families with a mutation in the MYH7 gene. AB - BACKGROUND: Mutations in the cardiac beta myosin heavy chain gene causing hypertrophic cardiomyopathy have been identified, and to assist both diagnosis and prediction of outcome attempts have been made to correlate phenotype and genotype. Two new mutations in codon 403 of the gene in three unrelated families are described and attention drawn to variable or even absent phenotypic expression in different family members. METHODS AND RESULTS: The polymerase chain reaction and heteroduplex analysis on Mutation Detection Enhancement gels were used to search for mutations in the globular head of the beta myosin heavy chain gene in families with hypertrophic cardiomyopathy. Two mutations were found in exon 13 (codon 403) of the gene. In two unrelated Polish families the mutation resulted in the conversion of arginine to tryptophan (CGG: >TGG). A second mutation, found in a British family, converted the same arginine to leucine (CGG: >CTG). These mutations were detected in family members who had electrocardiographic and echocardiographic features typical of hypertrophic cardiomyopathy; however, they were also detected in 7 other adult relatives with an abnormal electrocardiogram but a normal echocardiogram. Two unrelated adult relatives had completely normal clinical findings but carried the gene mutation. CONCLUSIONS: Identification of a specific mutation gives no guide to the clinical phenotype. There is considerable variability in the phenotypic expression of hypertrophic cardiomyopathy. Mutations were detected in adults previously regarded as normal or in whom the diagnosis was questionable. The fact that the clinical significance of the mutation in these people is still unknown emphasises the dilemma facing screening programmes. Isolated, unexplained electrocardiographic abnormalities in first degree relatives in a family with a definitive diagnosis of hypertrophic cardiomyopathy should be regarded as evidence of a carrier state. PMID- 7848421 TI - Dipstick urinalysis screening, asymptomatic microhematuria, and subsequent urological cancers in a population-based sample. AB - Screening urine for microhematuria as an indicator of serious disease is controversial because of the low positive predictive value of such screening and the costs and risks of the associated evaluation. To further evaluate test properties, we retrospectively examined the outcomes of 20,571 men aged > or = 35 years and women aged > or = 55 years who voluntarily had a Personal Health Appraisal in 1980 as members of a large prepaid health plan. Hematuria was detected by dipstick in 876 cases (4.3%); 278 were excluded because of evidence of previous urological disease which could cause hematuria. Review of the medical records of 598 patients with asymptomatic microhematuria as shown by a positive dipstick result indicated that 99% had a follow-up evaluation within 3 months of positive test results for hematuria and had various levels of urological evaluation thereafter. However, urological cancers (2 prostate, 1 bladder) developed in only 3 patients within the next 3 years. On the basis of San Francisco-Oakland Surveillance, Epidemiology, and End Results program data, rates of urological cancer were evaluated among patients whose test results were negative for hematuria, and these cancer rates were found to be almost the same as the rate among patients with asymptomatic microhematuria. Sensitivity of a single dipstick urinalysis result using microhematuria to indicate urological cancer within 3 years was 2.9%; specificity was 96.7%; and positive predictive value was 0.5%. Multivariate analysis which adjusted for age, gender, and race showed that the relative risk of 2.1 (95% confidence interval, 0.7-6.6) for urological cancer was not significantly elevated among patients with asymptomatic microhematuria compared with patients who had negative test results. These findings based on a single test are consistent with the current lack of recommendations for screening for microhematuria among asymptomatic adults. PMID- 7848422 TI - Reactive oxygen metabolites and reperfusion injury: aberrant triggering of reticuloendothelial function. PMID- 7848423 TI - Hypersecretion of luteinising hormone: a significant cause of infertility and miscarriage. PMID- 7848424 TI - Routine prenatal determination of chorionicity in multiple gestation: a plea to the obstetrician. PMID- 7848425 TI - Changing childbirth, I and II. PMID- 7848426 TI - The laryngeal mask airway. PMID- 7848427 TI - Drugs are not enough: the dynamics of antituberculosis treatment in India. PMID- 7848428 TI - Histopathology and medical laboratory scientific officers. MLSOs are efficient and save money. PMID- 7848429 TI - Kleihauer testing. Subjectivity leads to inaccuracy. PMID- 7848430 TI - Kleihauer testing. Many cases of sensitisation may be avoidable. PMID- 7848431 TI - Cardioprotective effect of hormone replacement therapy. Benefits women with established cardiovascular disease. PMID- 7848432 TI - Overseas Doctors Training Scheme. PMID- 7848433 TI - Prehospital thrombolysis. Poses storage and cost problems. PMID- 7848434 TI - Persistent post-traumatic stress disorder. May not need treatment in war veterans. PMID- 7848435 TI - Audit improves neonatal (Guthrie) screening programme. PMID- 7848436 TI - German junior doctors in Britain. Training in Germany is unstructured. PMID- 7848437 TI - Active management of labour. Non-randomised studies cannot be ignored. PMID- 7848438 TI - Active management of labour. WHO partogram helps. PMID- 7848439 TI - Acanthamoeba keratitis. PMID- 7848440 TI - Importance of awareness of religious customs. PMID- 7848442 TI - New diagnoses for old diseases. PMID- 7848443 TI - Reliability of guide to pregnancy risk grading. PMID- 7848441 TI - A new missense mutation, Arg719Gln, in the beta-cardiac heavy chain myosin gene of patients with familial hypertrophic cardiomyopathy. PMID- 7848444 TI - Terminology vs physiology and mechanics. PMID- 7848445 TI - Is there a place for aminophylline in cardiopulmonary resuscitation? PMID- 7848446 TI - Cholecystokinin and satiety. PMID- 7848447 TI - Rhabdomyolysis: a neglected priority in the early management of severe limb trauma. PMID- 7848448 TI - Substantiation of immunosuppression. PMID- 7848449 TI - Correction for report on severe prepartum ketosis in a cow. PMID- 7848450 TI - The meaning of menstruation in the elimination of abnormal embryos. PMID- 7848451 TI - Pain, blood loss, and death from leaking abdominal aortic aneurysms. PMID- 7848452 TI - Chiropractic magazines. PMID- 7848453 TI - Absence of GVH diseases in AIDS. PMID- 7848454 TI - Juvenile hallux abducto valgus. PMID- 7848455 TI - Early profound jaundice following blunt hepatic trauma: resolution after lobectomy. PMID- 7848456 TI - Re: Ileocecal valve reconstruction during continent urinary diversion. PMID- 7848457 TI - Regarding "Surgical transluminal femoropopliteal angioplasty: multivariate analysis outcome". PMID- 7848458 TI - Leucocyte-depleted or buffy-coat-depleted blood in surgery for colorectal cancer. PMID- 7848459 TI - Acting in medical practice. PMID- 7848460 TI - Keyhole surgery in tropical countries. PMID- 7848461 TI - Risk of recurrent abortion after appearance of a chorionic sac or heart rate on vaginal ultrasound. PMID- 7848462 TI - Breast cancer. PMID- 7848463 TI - Six preventable Hib cases. PMID- 7848464 TI - Benefits of adjuvant fibrin glue in skin grafting. PMID- 7848466 TI - Canalith repositioning maneuver. PMID- 7848467 TI - Universal screening for infant hearing impairment. PMID- 7848465 TI - Movement disorders stereotactic surgery for Parkinson's disease. PMID- 7848468 TI - Universal screening for infant hearing impairment. PMID- 7848469 TI - Universal screening for infant hearing impairment. European Concerted Action on Otoacoustic Emissions. PMID- 7848470 TI - Approaches offered for curbing violence in the health-care workplace. PMID- 7848471 TI - Alteration in serum pituitary hormone levels in postmenopausal women with stroke. PMID- 7848472 TI - Veterinarians and zoological medicine. PMID- 7848473 TI - Homosexuality: is it a choice? PMID- 7848474 TI - Alpha interferon for hypereosinophilic syndrome. PMID- 7848475 TI - Treatment for chronic fatigue syndrome. PMID- 7848476 TI - Validity of the Scale to Assess Unawareness of Mental Disorder. PMID- 7848477 TI - Laryngeal oedema, a marker of an "at risk" airway? PMID- 7848478 TI - Prevalence of behaviour disorders in low birthweight infants. PMID- 7848479 TI - Autoimmune phenomena in DiGeorge syndrome. PMID- 7848480 TI - Serum erythropoietin assays. PMID- 7848481 TI - Influenza immunization in children with chronic arthritis. PMID- 7848482 TI - Effect of previous nontransplant cardiac operations on the outcome of heart transplantation. PMID- 7848483 TI - Low-molecular-weight heparin versus aspirin and dipyridamole after femoropopliteal bypass grafting. PMID- 7848484 TI - The care of injection-drug users with HIV infection. PMID- 7848485 TI - Insect stings. PMID- 7848486 TI - Refusing the ovarian time bomb. PMID- 7848487 TI - Respirators and tuberculosis. PMID- 7848488 TI - Tacrine for Alzheimer's disease. PMID- 7848489 TI - Changing office routines to enhance preventive care. The preventive GAPS approach. AB - While family physicians aspire to provide their patients with the best possible preventive care, the services actually provided sometimes fall short of this ideal. Enhancing the provision of preventive care may require changes in office operations. Through working with more than 200 community practices in the Cancer Prevention in Community Practice Project, we have developed the Preventive GAPS Approach, which can help physicians and their practice staff to enhance their preventive care. The approach is based on teamwork among clinicians, staff, and patients; routines that encourage opportunistic provision of indicated preventive care; and flexibility, which allows physicians and their staffs to tailor their improvement strategy and the pace of change to their own unique situation. The approach includes the following four-step method (or GAPS): goal setting regarding preventive care; assessment of existing routines that support preventive care and of the current level of attainment of preventive goals; planning to modify existing routines that support preventive care; and starting and maintaining the improved preventive care office system. PMID- 7848490 TI - The attenuation of radiation by porcelain and its effect on polymerization of resin cements. AB - The influence of porcelain thickness and opacity on the polymerization of two dual activated (microfine and hybrid) and one light irradiated (hybrid) resin cements was assessed by hardness measurements. The surface microhardness values of the upper and lower surface of 1 mm thick resin cement specimens were determined. Specimens were polymerized using 40s irradiation beneath different thicknesses and opacities of porcelain discs. The results showed that increasing the thicknesses and opacity of the porcelain produced a statistically significant decrease in microhardness of the resin-based cements. The effect of attenuation is less for the microfine cement than for the hybrids. In the case of hybrid cements, the light activated material performed better than the dual activated cement. PMID- 7848491 TI - Characterization of T-cell receptor V beta repertoire in ovarian tumour-reacting CD3+ CD8+ CD4- CTL lines. AB - T cells from tumour infiltrating lymphocytes (TIL) cultured in media containing IL-2 were shown to mediate in vitro and in vivo antitumor responses. To characterize the T-cell antigen receptor (TCR) V beta expression in autologous cytotoxic effectors we isolated CD3+ CD8+ CD4- cells from cultures of TIL and tumour-associated lymphocytes (TAL) and analysed the TCR V beta repertoire of CD3+ CD8+ CD4- lines of known HLA-A, -B and -C phenotype, using polymerase chain reaction (PCR). These lines showed preferential lysis of autologous tumours and lysed, to a much lesser extent, NK and LAK cell-sensitive targets. Tumour lysis was inhibited by antibodies to CD3 and MHC class I antigens indicating that they are cytotoxic T lymphocytes (CTL). These CD8+ CTL lines expressed a broad distribution of TCR V beta repertoire which was dominated by particular groups of V beta families in each CTL line. However, no predominant expression of one or the same V beta segment in all CTL lines was observed although statistical correlations between V beta family usage and magnitude of the antitumour cytolytic response were found. These results suggest that certain TCR V beta families may be selected by antigen in ovarian tumour-reactive T cells and this selection may be affected by Ag expression, and/or host factors. To our knowledge, this is the first documentation of TCR V beta repertoire of human ovarian tumour-reactive CD3+ CD8+ CD4- CTL from different individuals of known HLA types. PMID- 7848493 TI - Increased susceptibility of EDL muscles from mdx mice to damage induced by contraction with stretch. PMID- 7848492 TI - Propofol anaesthesia in electroconvulsive therapy. Reduced seizure duration may not be relevant. AB - BACKGROUND: The induction agent propofol is known to reduce electroconvulsive therapy (ECT) seizure duration. It is assumed that outcome from depression is adversely affected by this agent. This study compares propofol and methohexitone as induction agents for ECT. METHOD: In a prospective, randomised, double-blind study 20 subjects with major depressive disorder (DSM-III-R criteria) received propofol or methohexitone anaesthesia. The Hamilton Depression Rating Scale and Beck Depression Inventory were used to assess depression before therapy, at every third treatment, and at the end of therapy. Seizure duration was measured using the cuff technique. RESULTS: Mean seizure durations (P < 0.01) and mean total seizure duration (P < 0.01) were shorter in the propofol group. There was no difference in outcome. CONCLUSIONS: Use of propofol may not adversely affect outcome from depression and it is not necessarily contraindicated as an induction agent for ECT. Our results should be interpreted cautiously, and larger studies are needed. PMID- 7848494 TI - Prophylaxis for chicken pox. PMID- 7848495 TI - Reducing the risk of falls among the elderly. PMID- 7848496 TI - Replicative senescence and cell death. PMID- 7848497 TI - [Purification systems using plants. Principles--method variations--use possibilities]. AB - Constructed wetlands are natural (waste) water treatment systems that combine biological, chemical and physical processes. In recent years various plants with distinct design features such as size, flow characteristics and type of vegetation have been built and operated worldwide. Meanwhile a lot of data regarding the efficiency and reliability are available that enable engineers, operators and water boards to select a suitable system for many applications. PMID- 7848498 TI - [Tetrahymena pyriformis--a cell test system for environmental medicine. The effect of harmful substances on the cell morphology of Tetrahymena pyriformis]. AB - In the region of Middle Germany phenols and their derivatives are important toxicological compounds for the environment and man. These compounds from wastes water of brown coal mining are source of danger, which can't estimate now. The influence of phenolic compounds on cells and organisms will be investigated with a species of ciliates-Tetrahymena pyriformis as testing system. T. pyriformis is a single-celled eucaryotic organism, which is comparable in sensitiveness and responsiveness to human tissue cells. That's why this cell system is very suitable to investigate on the influence of environmental pollutants. In our investigations phenol and 2,3-Dichlorophenol were used. Both compounds have a very toxic effect on cells. The toxicity of 2,3-Dichlorophenol is 50 times higher than the toxicity of pure phenol. Investigations of vitality by turbidimetry and morphology by image analysis have show that these compounds had an complex of the organisms. PMID- 7848499 TI - Study of the prevalence of Listeria spp. in surface water. AB - The quantity of Listeria species was determined in 49 samples of various types of water (river, brackish water, urban wastewater). Twenty nine strains of Listeria were isolated. These were mainly identified as Listeria monocytogenes (72,4%), but Listeria innocua, Listeria grayi, Listeria ivanohovii and Listeria welshimeri were also present. With the exception of water taken from the estuary, 74.4% of samples contained Listeria in mean concentrations of between 2 MPN/100 ml and 1320 MPN/100 ml in fresh surface water and untreated sewage respectively. PMID- 7848500 TI - [Composting facilities. 1. Microbiological quality of compost with special regard to disposable diapers]. AB - At three different composting facilities, co-composting of used panty diapers with an addition of 10% (weight) to the usual plant input was investigated for various hygienic and microbiological parameters. In nearly any case, a sufficient degree of germ reduction above 99.9% could be observed by determination of reduction rates of B. subtilis spores. The concentrations of "total microorganisms" ranged from 3.9 x 10(5) to 3.3 x 10(11) colony forming units per gram compost (CFU/g) in composts without and from 3.3 x 10(5) to 4.7 x 10(9) CFU/g in composts with panty diapers in the input. The concentrations of "gram negative bacteria" ranged from 3.3 x 10(4) to 1.3 x 10(9) CFU/g (without panty diapers) resp. from 3.3 x 10(5) to 3.5 x 10(8) CFU/g (with panty diapers), the concentrations of "fecal streptococci" from 1.7 x 10(3) to 7.7 x 10(7) CFU/g (without panty diapers) resp. from 1.4 x 10(4) to 1.4 x 10(8) CFU/g (with panty diapers). Facultatively pathogenic microorganisms showed a broad variety, but no common trend in composts with and without panty diapers in the input. Statistical validity of the determination of contents of microorganisms in compost samples was guaranteed by the collection and analysis of 20 parallel samples with an average sample mass of 10 to 15 kg. From the analyzed quantitative and qualitative hygienic-microbiological parameters, it can be concluded that no negative hygienic-microbiological effects, caused by the addition of 10% (weight) of used panty diapers in the input, have to be expected. Under the aspects of epidemiologic hygiene, composting of used panty diapers together with usual input materials seems to cause no increased risks under the tested conditions. Under the aspect of consumer protection, there is no increase in the risk of infection when using compost produced with addition of panty diapers, compared to compost produced without panty diaper addition to the input. PMID- 7848501 TI - Filtration of airborne allergens in various households. AB - The filtration system investigated in this study uses the thermic convection caused by radiators for the adsorption of airborne particles. The effect of this filtration system on the reduction of clinical symptoms of allergic bronchial asthma was tested as well as its capability in retaining airborne allergens, in particular those of the house dust mite Dermatophagoides pteronyssinus (D. pter.), which are responsible for this special kind of asthma. Dust samples were taken before and after the heating season in households of 36 persons with D. pter. caused asthma. Their mite content was investigated using mite flotation and direct microscopy, their guanine content using the Acarex-test. An allergen extract obtained from the filters was tested on its allergen content by RAST inhibition. It could be observed that compared to the preceding heating season 55% of the volunteers felt an improvement of their asthmatic symptoms. It was possible to extract allergens of D. pteronyssinus, house dust and mould from the filters. All these results show the capability of the filters to adsorb house dust mite (HDM) allergens. PMID- 7848502 TI - [The temperature stability of bovine parvovirus]. AB - The stability of the bovine Parvovirus, strain Haden against moist heat in the temperature range 75 to 90 degrees C was tested. It was found that the resistance depended largely on the medium (distilled water, water of standardized hardness (WSH), plasm) in which the viruses were suspended during heating. In WSH the resistance was highest. When heated in plasm, the viruses were inactivated in two phases. From the temperature dependence of the D-values, z-values of 5,6 for distilled water and 8,2 for WSH were found. It is recommended to use the Parvovirus for the evaluation of chemo-thermic and thermic disinfection procedures in view of virucidal effectiveness. The usual pasteurizing procedures fail to inactivate the Parvovirus. To eliminate Parvoviruses from blood products, other methods are, therefore, necessary. PMID- 7848503 TI - The risk assessment of faecal contamination by MAR indexing of Escherichia coli. AB - Multiple Antibiotic Resistance (MAR) index of faecal indicator bacterium Escherichia coli, isolated from water and sediment in the Bhavani river was employed to assess the quality of the river, and the risk of contamination. The MAR index of all the stations exceeded the high risk level (0.250) of contamination. The study of MAR index for individual isolates also showed high resistance against the tested antibiotics and it was found that these antibiotic resistant E. coli were distributed throughout the length of river sampled. It is concluded that the river is contaminated with faecal enteric bacteria, originating from high risk sources such as night soil, commercial poultry farms etc. It is implied that the quality of river water is not safe for drinking purpose and that adequate measures may be taken before use. PMID- 7848504 TI - Wound photography: an alternate use. PMID- 7848505 TI - Making positive choices: body image and the new ostomy patient. PMID- 7848506 TI - Physical therapy and wound care: what's the connection? PMID- 7848507 TI - Bladder elimination options. PMID- 7848508 TI - The role of hardiness in adjustment to an ostomy. AB - The purpose of this descriptive study was to explore the effects of the personality characteristic hardiness on adjustment to an ostomy in the elderly ostomy patient. The Health Related Hardiness Scale (HRHS) was used to measure hardiness and the Ostomy Adjustment Scale (OAS) was used to determine adaptation to the ostomy. Results included a modest but significant inverse relationship ( 0.3978) (p < 0.05) between the control aspect of hardiness and adjustment to an ostomy. The relationship between hardiness and selected demographic variables was not significant. PMID- 7848509 TI - Ileoanal teaching tools: developing a tool to meet a specific need. AB - As ET nurses working with ileoanal surgery patients for the first time in 1979, we discovered that there were no tools or materials available for teaching our patients how to care for themselves during the various stages of the procedure. Over the years, therefore, we have created a compilation of data based on answers to questionnaires completed by recent patients. This data base contains information on topics such as skin care and diet, and enables us to create teaching tools tailored to our own patient population. Although there are now other materials available for teaching self-care to ileoanal surgery patients, the ongoing collection of data from a particular group of patients can also help to create valuable teaching tools and enhance overall understanding of this complex procedure. PMID- 7848510 TI - Major and minor Kb-restricted epitopes encoded by the endogenous ecotropic murine leukemia virus AKR623 that are recognized by anti-AKR/Gross MuLV CTL. AB - C57BL/6 mice can generate a type-specific and class IH-2Kb-restricted CTL response against histocompatible AKR/Gross murine leukemia virus (MuLV) cell surface antigen positive (GCSA+) tumor cells. These anti-AKR/Gross MuLV CTL are also known to lyse SC.Kb/623 target cells expressing the molecular MuLV clone AKR623 (derived from the endogenous ecotropic MuLV provirus emv-11). To help identify AKR623 viral epitopes recognized by these CTL, four chimeric proviruses were constructed from two parental plasmids, pAKR623 and pAK7. It has been shown that SC.Kb/7 fibroblast targets expressing the emv-14-derived molecular clone AK7 are only poorly lysed by anti-AKR/Gross MuLV CTL. Data from experiments employing SC.Kb cells infected with the chimeras as targets against anti-AKR/Gross MuLV CTL supported the location of a previously identified immunodominant epitope located within the viral p15E transmembrane envelope protein, peptide TM134-141 (KSP WFTTL). Furthermore, the use of Kb-motif-defined AKR623 encoded peptides together with data obtained using the chimeric viruses allowed the identification of three additional anti-AKR/Gross MuLV CTL epitopes. Peptides representing these epitopes, MA125-132 (RSALY-PAL), RT142-149 (SHRWYTVL), and RT456-463 (RMTHYQAM), are characterized herein with respect to their ability to confer lysis upon EMV- target cells and to stimulate tumor primed splenocytes in vitro. The identification and characterization of these additional epitopes allow for a better understanding of both the CTL response against GCSA+ tumor cells and the dysfunctional CTL response against EMV-14 and AK7. PMID- 7848511 TI - Lack of correlation between phenotype activation markers of CD8 lymphocytes and cytotoxic T lymphocyte (CTL) function in HIV-1 infection: evidence for rescue with rIL-2. AB - CTL activity against HIV-1 antigens expressed on HLA-A-matched EBV-transformed B target cells was detected in 33% (6/18) of freshly isolated PBMC (FPBMC) from patients in the early stages of HIV-1 infection (CDCII). No CTL activity was detected in FPMBC in patients with AIDS (CDCIV). However, the presence of CTL activity did not correlate with the expression of CTL activation markers. A dual color flow cytometric examination revealed that the CD8+ lymphocytes bearing the memory (CD29) and activation (S6F1) surface molecules increased in number as the HIV-1 infection progressed. This functional and phenotypic discrepancy in memory CD8+ lymphocytes suggests that the memory CD8+ lymphocytes have lost cytotoxic function and become "paralyzed" as the HIV disease progresses. Incubation of PBMC of HIV(+) patients with rIL-2 reactivated predominantly HIV-specific CTL. However, rIL-2 stimulation also activated a "polyclonal or polyreactive" cytotoxic function. The reactivation of CTL function is rIL-2 dosage dependent and the amount of rIL-2 required for reactivation is associated with the severity of the disease. HIV antigen specific CTL in HIV(+) patients can be selectively expanded by HIV antigen stimulation in the presence of rIL-2. These results suggest that the in vivo IL-2 deficiency occurring in HIV-1 infection may be responsible in part for the "paralysis" of HIV specific CTL activity. Such activity can be rescued nonspecifically by exogenous rIL-2 stimulation and expanded specifically by HIV-1 antigen stimulation. PMID- 7848512 TI - Serum levels of alpha and gamma interferons in hemorrhagic fever with renal syndrome. AB - Hemorrhagic fever with renal syndrome is an acute viral disease caused by Hantavirus. On the basis of clinical observation, the illness is divided into five sequential stages: febrile, hypotensive, oliguric, diuretic, and convalescent. Because interferons can be induced by viruses, and because their stimulating effects on immune cells can alter the course of viral infections, we examined the presence of alpha interferon (IFN-alpha) and gamma interferon (IFN gamma) in 276 serum samples collected from 110 patients during the Korean Conflict. We tested these sera for IFN-alpha by bioassay with bovine kidney MDBK cells, and for IFN-gamma by a sandwich ELISA with antibodies specific for human IFN-gamma. We found variable, but persistently elevated levels of IFN-gamma throughout the various phases of the disease, which suggested persistent immune activation through convalescence. Moderate levels of IFN-alpha were found in all stages of infection. PMID- 7848513 TI - New perspectives on rheumatoid arthritis. AB - Rheumatoid arthritis (RA) remains one of the most common, puzzling and poorly treated diseases of humans. However, a surge of interest in the biology of chronic inflammation and in the design of more-potent and specific inhibitors of pro-inflammatory pathways heralds an optimistic era for the treatment of RA. A recent symposium provided a multidisciplinary perspective on the current status of such studies. PMID- 7848514 TI - When is an autoimmune disease not an autoimmune disease? AB - What are the environmental triggers and genetic susceptibilities underlying the development of autoimmune diseases? These and other questions were addressed at a recent meeting in Finland. PMID- 7848515 TI - Applications of monoclonal antibodies in clinical oncology. AB - Application of monoclonal antibodies (mAbs) to clinical settings has proved to be slower than originally hoped. However, a recent conference provided evidence that the field is coming of age, and that antibodies, and their recombinant derivatives, will continue to find a role in the clinic. PMID- 7848516 TI - The type II 'decoy' receptor: a novel regulatory pathway for interleukin 1. AB - The interleukin 1 (IL-1) system plays a central role in inflammation and immunity. Of the two receptors that bind IL-1, the type I receptor is known to mediate signaling activity, whereas the function of the type II receptor remains unknown. Here, Francesco Colotta and colleagues review the properties of these receptors and summarize evidence indicating that the type II receptor acts as a regulated decoy target for IL-1. PMID- 7848517 TI - Inflammatory cytokines in the brain: does the CNS shape immune responses? AB - Immune responses in the central nervous system (CNS) have traditionally been regarded as representing the intrusion of an unruly, ill-behaved mob of leukocytes into the well-ordered and organized domain of thought and reason. However, results accumulated over the past few years suggest that, far from being an immunologically privileged organ, T lymphocytes may be regular and frequent visitors to the CNS, for purposes of immune surveillance. Here, Trevor Owens and colleagues propose that the brain itself can regulate or shape immune responses therein. Furthermore, given that the immune cells may be subverted to autoimmunity, they suggest that the study of inflammatory autoimmune disease in the brain may shed light on the ability of the local environment to regulate immune responses. PMID- 7848518 TI - Accessory cell signals regulate Th-cell responses: from basic immunology to a model of helminthic disease. AB - Schistosome helminths inflict serious tissue damage by eliciting T helper (Th) cell-mediated granulomatous inflammation around parasite eggs. The egg granulomas are large in acute disease and smaller in chronic disease. To explain this downregulation in chronic disease, Miguel Stadecker and Pedro Flores Villanueva describe a mechanism whereby CD4+ Th1-type lymphocytes, which are associated with the initial vigorous granuloma formation, are rendered anergic to subsequent antigenic stimulation. This results in the reduction of granuloma size and in the dominance of Th2-type lymphocyte responses. PMID- 7848519 TI - The Th1-Th2 hypothesis of HIV infection: new insights. AB - In their earlier, much quoted, viewpoint article, Mario Clerici and Gene Shearer examined the role of T helper 1 (Th1)- and Th2-type responses in immune dysregulation associated with human immunodeficiency virus (HIV) infection. In this article, they consider the complications of a Th1-Th2 model raised by the nomenclature, discuss the issue of cytokine production by non-T cells, and compare data obtained from T-cell clones with heterogeneous populations of leukocytes from patients. They define Th-cell responses and cytokine profiles as 'type 1' and 'type 2', and reemphasize the importance of strong cellular immune responses, along with the cytokines that augment and maintain such responses, in protective immunity against HIV infection and AIDS progression. Finally, they present a model of activation-induced, cytokine-modulated, programmed cell death as a major factor in the pathogenesis of HIV infection and AIDS. PMID- 7848520 TI - Bcl-2 and Bcl-x: regulatory switches for lymphoid death and survival. AB - The survival and death of lymphoid cells is under the control of a genetic program. Cell death is activated at different stages of development and serves to remove unnecessary and autoreactive lymphocytes, as well as to limit the immune response. The survival of cells is regulated by a set of genes that act as repressors of the cell death mechanism. Of these, bcl-2 and bcl-x exhibit a striking pattern of regulation during lymphoid maturation and can inhibit several forms of apoptotic cell death. Here, Gabriel Nunez and colleagues review recent developments in the field, particularly focusing on the role of the Bcl-2 and Bcl x proteins in regulating lymphoid death and survival. PMID- 7848522 TI - Adaptive thinking in immuno-nomenclature and immuno-evolution. PMID- 7848521 TI - Immunology of AS in AAU patients. PMID- 7848523 TI - Progressive changes in milk protein gene expression and prolactin binding during lactation in the tammar wallaby (Macropus eugenii). AB - Changes in milk protein gene expression and specific prolactin binding were quantified in mammary tissue from the tammar wallaby (Macropus eugenii) at different stages of lactation. The transition from early (phase 2) lactation to late (phase 3) lactation was characterized by the induction of the gene for late lactation protein, a novel whey protein. During the same period, the levels of beta-lactoglobulin and beta-casein gene expression increased, whereas there was no change in the levels of expression of alpha-lactalbumin and alpha-casein genes. Prolactin binding in the mammary gland doubled during the latter half of phase 2 of lactation but declined significantly during the transition to phase 3 of lactation. These changes in prolactin binding resulted from changes in the number of receptors and not from a change in the affinity of the receptor for prolactin. Treatment of membranes with concanavalin A increased the number of prolactin-binding sites by 40% in membranes from phase 2 mammary tissue but decreased binding by 40% in membranes from phase 3 tissue, indicating that significant changes had occurred in the membranes of cells during this period. The tammar wallaby can secrete phase 2 and phase 3 milk from adjacent mammary glands (asynchronous concurrent lactation) and the developmental changes in milk protein gene expression and prolactin binding observed during lactation were reflected in these individual glands. Taken collectively, these findings suggest that mammary development and milk secretion in the tammar wallaby are regulated by both endocrine and local (intramammary) mechanisms. PMID- 7848524 TI - Growth hormone induces tyrosine phosphorylation but does not alter insulin-like growth factor-I gene expression in human IM9 lymphocytes. AB - GH induces hepatic IGF-I synthesis by increasing transcription of its gene. IGF-I is synthesized, however, in many other tissues where the effect of GH on its gene expression is less well characterized. IGF-I and GH are produced by human lymphocytes and may function as autocrine regulators of lymphoproliferation. We have therefore used the human IM9 lymphocyte cell line to (A) define the IGF-I gene transcripts expressed and (B) investigate the effect of GH on early (protein tyrosine phosphorylation) and late (changes in IGF-I mRNA levels) events in intracellular signal transduction. Multiple IGF-I mRNA species, ranging in size from 0.9 to 5.8 kb, were detected by Northern hybridization of poly(A)+ mRNA from IM9 cells. The human IGF-I gene contains at least six exons and alternative splicing produces a number of transcripts. Solution hybridization with exon specific riboprobes and amplification by PCR using exon-specific primers revealed that multiple transcripts were expressed in IM9 cells, and that exon 2 was the dominant leader exon. Treatment of IM9 cells with 200 ng recombinant human (rh)GH/ml led to the specific tyrosine phosphorylation of three intracellular proteins (93, 120 and 134 kDa), which are involved in the initial signalling of the GH transduction pathway. However a solution hybridization assay using the IGF IA specific riboprobe on IM9 cell RNA from similar experiments revealed that GH treatment did not change IGF-I gene expression. This study has demonstrated (A) that the IGF-I gene is expressed in human IM9 lymphocytes, (B) that in contrast to other human tissue, exon 2 is the major leader exon, and (C) that rhGH induces tyrosine phosphorylation of 93, 120 and 134 kDa proteins but does not alter IGF-I gene expression. The IM9 cell may form an important model to investigate a GH transduction pathway not coupled to the IGF-I gene. PMID- 7848525 TI - Effect of in vivo oestradiol treatment on cell-free transcription in trout liver nuclear extracts. AB - In order to perform later studies on the transcriptional regulation of hormone dependent genes in fish liver, we firstly examined the potential of trout liver nuclear extracts in a cell-free transcription system. As reporter genes, we used DNA sequences without G (G-free cassettes) under the control of three promoters derived from the 5' flanking sequence of the Xenopus vitellogenin B1 gene; two of them were responsive to the oestrogen receptor (ER) through oestrogen responsive elements (ERE). Maximal transcriptional activity was obtained within a range of 40-130 micrograms protein per extract depending on the extract preparation. Transcription was maximal in reactions carried out at 25 degrees C. Similar transcriptional activities for the three promoters were observed when transcription was performed in extracts from untreated male trout. In contrast, we observed a 4.5- to 6-fold increase in the transcription with ERE-containing promoters in comparison with that with the minimal promoter bearing only a TATA box when extracts from oestradiol-treated male trout were used. This effect was correlated with the increase in the nuclear ER concentration induced by in vivo hormonal treatment. This enhanced transcription was specifically inhibited by the addition of a 25- to 100-fold excess of ERE oligonucleotide competitor. These data demonstrated, therefore, that transcription was ERE-dependent in this system and suggest strongly that it was mediated by the trout ER. Addition of oestradiol or the anti-oestrogens hydroxytamoxifen or ICI 164384 had no effect on the transcriptional activity of the two ERE-containing promoters, indicating that transcription was hormone-independent in trout liver nuclear extracts. PMID- 7848526 TI - Evidence that a calmodulin-like calcium-binding domain of the FSH beta-subunit is involved in FSH-induced calcium uptake by Sertoli cells. AB - We have previously shown that a synthetic peptide amide corresponding to residues 1-15 of the human FSH beta-subunit (hFSH-beta-(1-15)) possesses structural characteristics and calcium-binding properties similar to the calcium-binding loops of calmodulin (CaM). The calcium-binding property of hFSH-beta-(1-15) correlated well with its ability to stimulate uptake of calcium (as 45Ca2+) by cultured rat Sertoli cells and proteoliposomes enriched with bovine calf testis FSH receptors. A sequence found in the calcium-binding loops of CaM and a number of other calcium-binding proteins can be represented by the motif +-+-+-+-+--+, where + represents a calcium-binding residue and - represents a non-binding residue. A sequence containing a similar motif appears in hFSH-beta-(1-15) between residues 4 and 15: +-++-+---+-+. Using a synthetic peptide strategy, we undertook to determine whether the first three residues of hFSH-beta-(1-15) were required to induce uptake of calcium by cultured rat Sertoli cells and FSH receptor-enriched proteoliposomes, and to assess whether rearrangement of the putative calcium-binding ligands (+) of hFSH-beta-(1-15) to correspond to their linear sequence in CaM would enhance the ability of hFSH-beta-(1-15) to induce calcium uptake in these two model systems.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7848527 TI - Restricted expression of a zinc finger protein in male germ cells. AB - Zfp-37 is a zinc finger protein gene expressed in male germ cells. The cDNA detected two transcripts on Northern blots of testis RNA, with expression first detected at around day 19. To establish the pattern of expression of the protein we have raised antibodies to ZFP-37 and used them on thin sections of testis and on Western blots. On Western blots the antibody detected two proteins exclusively in testis extracts, confirming the previous mRNA expression data. A time-course study revealed that the larger of the two proteins appears at about day 22 but the smaller one is not detected until day 34. Analysis of the expression of these two proteins in purified germ cell preparations revealed that the smaller protein is only detectable in the elongating spermatids or residual bodies. Data from thin sections showed that most, but not all, of the protein recognized by the antibody is in the nucleus, a result further confirmed by Western blotting. These results are discussed in the light of the possible role of this protein in regulating spermatogenesis. PMID- 7848528 TI - 'Liver-type' 11 beta-hydroxysteroid dehydrogenase cDNA encodes reductase but not dehydrogenase activity in intact mammalian COS-7 cells. AB - 11 beta-Hydroxysteroid dehydrogenase (11 beta-HSD) catalyses the metabolism of corticosterone to inert 11-dehydrocorticosterone, thus preventing glucocorticoid access to otherwise non-selective renal mineralocorticoid receptors (MRs), producing aldosterone selectivity in vivo. At least two isoforms of 11 beta-HSD exist. One isoform (11 beta-HSD1) has been purified from rat liver and an encoding cDNA cloned from a rat liver library. Transfection of rat 11 beta-HSD1 cDNA into amphibian cells with a mineralocorticoid phenotype encodes 11 beta reductase activity (activation of inert 11-dehydrocorticosterone) suggesting that 11 beta-HSD1 does not have the necessary properties to protect renal MRs from exposure to glucocorticoids. This function is likely to reside in a second 11 beta-HSD isoform. 11 beta-HSD1 is co-localized with glucocorticoid receptors (GRs) and may modulate glucocorticoid access to this receptor type. To examine the predominant direction of 11 beta-HSD1 activity in intact mammalian cells, and the possible role of 11 beta-HSD in regulating glucocorticoid access to GRs, we transfected rat 11 beta-HSD1 cDNA into a mammalian kidney-derived cell system (COS-7) which has little endogenous 11 beta-HSD activity or mRNA expression. Homogenates of COS-7 cells transfected with increasing amounts of 11 beta-HSD cDNA exhibited a dose-related increase in 11 beta-dehydrogenase activity. In contrast, intact cells did not convert corticosterone to 11-dehydrocorticosterone over 24 h, but showed a clear dose-related 11 beta-reductase activity, apparent within 4 h of addition of 11-dehydrocorticosterone to the medium.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7848529 TI - Developmental changes in the distribution of pro-opiomelanocortin and prolactin mRNA in the pituitary of the ovine fetus and lamb. AB - Ontogenic changes in pituitary pro-opiomelanocortin (POMC) mRNA and prolactin (PRL) mRNA were examined during gestation and early neonatal life using in situ hybridization histochemistry. Pituitaries were harvested from fetuses at days 60 80, 100-120, 135-140 and 142-143 of gestation and at term, and from lambs at days 1-7 and 30-60 of age and adults. POMC mRNA, present by day 60, rose during mid- and late gestation. Concurrently there was a change in corticotroph distribution, resulting in a relatively greater quantity of POMC mRNA at the base of the pars distalis. At term, there was a significant (P < 0.05) further elevation of POMC mRNA. POMC mRNA levels remained high in the newborn lamb but decreased in the adult. Cells in the pars intermedia expressed large amounts of POMC mRNA early in fetal life and this pattern persisted throughout gestation and into the neonatal period. Changes in the expression of the POMC gene correlated closely with the presence of immunoreactive (ir)ACTH in the pituitary; in fetuses the proportion of irACTH-positive cells rose to 10% of pars distalis cells by day 100 and did not change significantly thereafter. The lactotrophs contained PRL mRNA by day 60, and the quantity increased towards parturition (P < 0.05). PRL mRNA subsequently decreased in the neonate, but rose as the lamb matured. These results indicate that in the fetal pituitary: (1) the POMC gene is highly expressed during gestation in both the pars distalis and the pars intermedia, (2) changes in the amounts of POMC mRNA and PRL mRNA in the pars distalis correlate with the distribution of irACTH and irPRL respectively, and (3) POMC mRNA is distributed primarily in the inferior aspect of the pars distalis, and in this region its quantity is highest immediately prior to parturition. PMID- 7848530 TI - Dual activity of human pituitary thyrotrophin isoforms on thyroid cell growth. AB - Alkaline (pI 8.6-7.5) and neutral (pI 7.0-6.0) isoforms of human TSH have been isolated from a highly purified intrapituitary preparation by isoelectric focusing and compared for their respective actions on thyroid cell proliferation. Both TSH isoforms displayed the same ability to bind to porcine thyroid membranes as the original hormone preparation, indicating a similar recognition at the receptor sites. Alkaline forms showed a higher potency in inducing either cyclic AMP (cAMP) production or [3H]thymidine incorporation in FRTL-5 cells (half maximal effective doses (ED50 values) = 0.25 and 0.29 nM respectively) compared with their neutral counterparts (ED50 values = 0.66 and 0.70 nM respectively). Increasing the concentration of alkaline forms in the presence of a half-maximal concentration of neutral TSH resulted in a profound inhibition of cell growth without a significant change in cAMP. Conversely, increasing the amount of neutral forms in the presence of a half-maximal dose of alkaline TSH resulted in an additive response for cAMP production but not in cell proliferation. To assess whether glycosylation might be responsible for the variation in hormone action, both alkaline and neutral TSH isoforms were tested for recognition of their carbohydrate chains by concanavalin A (Con A) and ricin. No major difference was found in binding to Con A, indicating that the contribution of carbohydrates to changes in hormone pI was not related to core branching. Very few galactose residues were accessible in either hormone fraction since little binding to ricin was observed. Isoelectric focusing of TSH forms before and after neuraminidase treatment revealed that neutral forms had a higher sialic acid content than alkaline TSH. In conclusion, the current findings show that TSH isoforms differentially affect cAMP production and cell growth. TSH fractions with a high sialic acid content and a low mitogenic activity behave as antagonists to the more active forms for cell proliferation. It is suggested that physiological control of TSH action at the thyroid gland may reside in the respective amounts of various TSH forms which, once bound to their receptor, can induce variable activation of post-receptor events while controlling cell proliferation. PMID- 7848531 TI - Importance of the extracellular domain of the human thyrotrophin receptor for activation of cyclic AMP production. AB - The mechanism by which the TSH receptor is activated is unknown. Current knowledge leads us to consider that G protein-coupled receptors are activated by positioning of their ligand in the pocket formed by the hydrophobic transmembrane segments. Furthermore, activation of an N-terminally truncated LH receptor lacking most of the extracellular domain has been described, suggesting the existence of a mechanism involving a direct interaction between LH and the transmembrane segments. The high conservation of the transmembrane segments among G protein-coupled receptors is a strong indication for a common mechanism of receptor activation. To test this hypothesis for the TSH receptor we have constructed four N-terminally truncated TSH receptor mutants with 5 or 69 amino acids of the extracellular domain joined to signal peptide regions consisting of the first 23 or 33 amino acids. The four fragments were amplified by PCR and subcloned into pBSK+. Sequences were confirmed after subcloning in M13. After joining the four fragments in pBSK+, the four TSH receptor constructs were subcloned in pSVL and transiently or stably expressed in COS and Chinese hamster ovary (CHO) cells respectively. In contrast to results obtained for the LH receptor, stimulation of the transfectants with 10 microM human chorionic gonadotrophin or 350 mU TSH/ml did not increase cyclic AMP (cAMP) concentrations in cultures of transiently transfected COS cells or stably transfected CHO cells. However, mRNA for the TSH receptor could be detected by RNase protection assay in all stable transfectants used for stimulation of cAMP.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7848532 TI - Pancreatic islet response to dicarboxylic acid esters in rats with type 2 diabetes: enzymatic, metabolic and secretory aspects. AB - This study aimed to compare the metabolic and secretory responses of pancreatic islets from animals with non-insulin-dependent diabetes to D-glucose with the effects of the methyl esters of succinic acid (SME) and glutamic acid (GME). The insulin secretory response to D-glucose was impaired in islets from rats with diabetes which was either inherited (Goto-Kakizaki (GK) rats) or acquired (streptozotocin-treated (STZ) rats). This coincided with a preferential alteration of oxidative relative to total glycolysis in intact islets and a selective defect of FAD-linked mitochondrial glycerophosphate dehydrogenase (m GDH) in islet homogenates. This enzymatic defect was also found in purified B cells from STZ rats. It contrasted both with unaltered activities of glutamate dehydrogenase and succinate dehydrogenase in the islets of diabetic animals and with a normal or even increased activity of m-GDH in the livers of GK and STZ rats. The oxidation of [1,4-14C]SME and [U-14C]GME appeared decreased in islets of GK or STZ animals when compared with control rats, but no significant difference between control and diabetic rats was observed when the oxidative data were expressed relative to the rate of [U-14C]GME hydrolysis. Nevertheless, the absolute values for insulin release evoked by a non-metabolized analogue of L leucine (BCH), by SME and by the association of BCH with either SME or GME were invariably lower in islets of GK and STZ rats than in those of control animals.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7848533 TI - Cardiac pre-admission teaching program. AB - The Royal Columbian Hospital's (R.C.H.) Cardiac Pre-admission Clinic (PAC) in New Westminster, B.C., is an effective new program for patients planning elective coronary angiograms, coronary angioplasties, and cardiac surgeries. Patients are seen in the out-patient clinic approximately one week before their procedure for nursing assessments, diagnostic pre-operative testing, and screening of test results. These pre-admission activities provide the opportunity for the early detection of abnormalities. During the clinic appointment patient teaching is also done. As a consequence, these assessment and teaching activities contribute to the overall PAC goal of improving bed utilization. Since cardiac teaching is a strong clinic focus, teaching plans were developed regarding: coronary angiogram, percutaneous transluminal coronary angioplasty, and coronary artery bypass graft (CABG) Surgery. These detailed teaching plans serve as a reference tool for the clinic nurse and as a guide for new clinic staff. The following article discusses the teaching program's background, design, structure, and evaluation. The benefits of pre-admission teaching are presented and the specific CABG surgery teaching session is described. PMID- 7848534 TI - The methodological "breadth" of Canadian cardiovascular nursing research. PMID- 7848535 TI - The effect of testing anxiety on blood pressure. AB - The effect of stress on blood pressure is under debate. Of concern, with the trend toward fitness, is whether anxiety about one's body image may also raise blood pressure. The purpose of this study was to evaluate the effect of testing anxiety on the blood pressure of persons taking a lifestyle and fitness evaluation test. First year nursing students had their blood pressures measured by fitness program technicians as part of a fitness test. Students then had their blood pressures measured by the same technicians in a non-testing situation. Students also completed a social physique anxiety scale to separate those with high and low physique anxiety. Analysis of variance revealed that there was a significant difference in diastolic blood pressure between the evaluative (during the fitness test) and the non-evaluative situations (p = 0.0001). There was no significant difference in blood pressure in those students with high versus low social physique anxiety but those with high anxiety had higher diastolic blood pressures during the non-evaluative situation than did those with low anxiety. These findings indicate that, while the evaluative situation appears to be a more important factor in the evaluation of diastolic blood pressure than anxiety regarding one's physique or body image, there is an interaction effect that should be further examined. PMID- 7848536 TI - Quality of life of people six months post percutaneous transluminal coronary angioplasty. AB - The purpose of this study was to describe the quality of life of people six months post percutaneous transluminal coronary angioplasty (PTCA). Health related quality of life with components: functional capacity, perception of health status, life satisfaction, symptoms and expectations of treatment with satisfaction of actual outcome were used as the conceptual bases. Data were collected using a combination of standardized and investigator developed instruments. Descriptive and correlational analysis were completed on the sample who met the inclusion criteria. The subjects experienced improvement in their quality of life six months post PTCA as indicated by less severity of angina, higher perception of health status, and low impact to illness score. The subjects prior expectations of PTCA were related to satisfaction with treatment outcome. Those subjects with several chronic illnesses had a lower life satisfaction and a higher physical impact to illness score. However, as age increased so did the perception of health. Persons needing PTCA should be encouraged by the positive results of PTCA identified by this study. PMID- 7848537 TI - [Presentation of the monographic issue: micronutrient deficiencies in the Americas]. PMID- 7848538 TI - [Elimination of iodine deficiency: a challenge for the end of the century]. AB - The purpose of this article is to review some essential elements that should be considered in the development of national and regional strategies for the prevention and control of iodine deficiency disorders. Another objective is to analyze the current status of this deficiency, the criteria and parameters for evaluating the progress of control programs, and the political, legal, and institutional issues that must be borne in mind in order to reach the virtual elimination of iodine deficiency disorders in the present decade. PMID- 7848539 TI - [Hypovitaminosis A: epidemiology of a public health problem and strategies of its prevention and control]. AB - Vitamin A deficiency occurs when body stores are low enough to result in adverse health consequences, even though there is no clinical sign observable, a situation that exists in parts of Latin America and The Caribbean. Deficient populations can be identified by using a combination of biological and ecological indicators. Such populations generally live under conditions of economic, social and ecologic deprivation where young children and women in their reproductive years are most vulnerable, particularly during periods of seasonal food shortage and of peak infection incidence. Sustainable preventive strategies are those that support changes in diet and conditions at the household level that increase the intake of vitamin A-containing foods in quality and quantity by the vulnerable groups and decrease the frequency they suffer infections. The use of vitamin A supplements in areas lacking clinical deficiency, such as in Latin America and The Caribbean, should be carefully considered (perhaps by targeting to high-risk groups) so as not to deter efforts to reach permanent solutions. PMID- 7848540 TI - [Vitamin A deficiency and actions for its prevention and control in Latin America and the Caribbean, 1994]. AB - Since the 1970s, the prevalence of protein-energy malnutrition has declined in the countries of Latin America and the Caribbean. However, micronutrient deficiencies, especially of iodine, iron, and vitamin A, have not diminished to the same extent. Based on clinical criteria, vitamin A deficiency continues to be a public health problem in Brazil, the Dominican Republic, Ecuador, El Salvador, Guatemala, Haiti, Honduras, and Nicaragua. This deficiency is also common in poor communities in Bolivia, in some parts of Mexico and Peru, and among indigenous groups in Panama. Trends in general health and nutrition indicators in Colombia, Cuba, Guyana, Paraguay, and Venezuela suggest the need to update information on vitamin A deficiency in those countries. At the close of the 1980s, increasing interest was manifested in reducing vitamin A deficiency in the Region of the Americas; this interest has led to epidemiologic studies, national and regional meetings, and the implementation of plans and interventions at the local, national, and regional levels. In the medium and long term, a permanent solution to the problem of vitamin A deficiency can be attained through sustained economic and social development, accompanied by specific actions to diversify diets in order to increase consumption of foods rich in vitamin A, fortification of popular foods, and nutritional education. In the short term, temporary measures- such as periodic administration of vitamin A supplements to high-risk groups--can be applied. PMID- 7848541 TI - [Advances in the process of fortification of sugar with vitamin A in Central America]. AB - Fortifying sugar with vitamin A was adopted by various Central American countries as their main strategy for reducing vitamin A deficiency in the seventies, but after being in effect a few years, such fortification became lax. Nationwide studies from the late eighties and early nineties showed that vitamin A deficiency was still a widely prevalent public health problem in Guatemala, El Salvador, Honduras, and Nicaragua. The situation led to the reappearance and strengthening of national programs for the fortification of sugar. Experience gathered over the past three years confirms the fact that such fortification is technically feasible and that it is safer, more effective, and more practical than other types of interventions. Essential to the success of this program is the establishment of a reliable and permanent quality control system for guaranteeing that, through sugar, households receive vitamin A in sufficient amounts to complete an adequate dietary supply. At present a quality control system is being implemented at three levels: production, government supervision, and community monitoring. INCAP has developed analytical methodologies that are fit to support control measures in each of these three levels. It is surmised that a program aimed at fortifying sugar with vitamin A, if optimally executed, would render a preventive supplementation program unnecessary. However, constant monitoring and supplementation of natural sources of vitamin A are always recommended in children under 3 and lactating mothers. PMID- 7848542 TI - Antiendotoxin monoclonal antibodies. What future now? PMID- 7848543 TI - Comparative tolerability profiles of oral antidiabetic agents. AB - The sulphonylureas and the biguanides are widely used as adjuncts to dietary measures in the treatment of non-insulin-dependent (type 2) diabetes mellitus (NIDDM). Adverse effect profiles differ markedly between the sulphonylureas and biguanides, reflecting differences in chemical structure and mode of action. Sulphonylureas are generally well tolerated, although pharmacokinetic differences between these agents have important clinical implications. The main adverse effect associated with sulphonylureas is hypoglycaemia. This effect is a predictable consequence of the principal pharmacological effect of these drugs, i.e. sensitisation of the islet beta-cell to glucose, resulting in enhanced endogenous insulin secretion. Sulphonylurea-induced suppression of hepatic glucose production may cause profound and protracted hypoglycaemia, especially in elderly patients, in individuals with intercurrent illnesses and reduced caloric intake, or when taken in combination with other compounds with hypoglycaemic potential, e.g. alcohol (ethanol). Sulphonylureas with a longer duration of action, notably chlorpropamide and glibenclamide (glyburide), are more liable to induce serious hypoglycaemia, particularly when drug elimination is reduced by renal impairment. Other drugs such as salicylates may potentiate the actions of sulphonylureas, thereby increasing the risk of hypoglycaemia. Biguanide therapy is associated with alterations in lactate homeostasis which under certain clinical circumstances may result in fatal lactic acidosis. Phenformin is associated with a markedly greater risk of lactic acidosis than metformin. Phenformin has been withdrawn in many countries for this reason. All biguanides must be avoided in patients with renal impairment, hepatic dysfunction and cardiac failure--conditions where drug accumulation or disordered lactate metabolism may predispose to lactic acidosis. Phenformin should not be given to individuals who exhibit a severe, genetically conferred hepatic defect of hydroxylation which impedes metabolism of this drug. Less seriously, the biguanides are associated with a relatively high incidence of gastrointestinal adverse effects which limit compliance. Acarbose, a competitive inhibitor of intestinal alpha-glucosidases, has recently been introduced. In contrast to the sulphonylureas and biguanides, acarbose has not been associated with life threatening adverse effects. This reflects the low systemic absorption of the drug and, predictably, its principal unwanted effects are gastrointestinal disturbances resulting from iatrogenic carbohydrate malabsorption. PMID- 7848544 TI - Clinically significant drug interactions with antituberculosis agents. AB - Standard short-course regimens for tuberculosis are used worldwide with very few problems. Unfortunately, the emergence of multiple drug-resistant tuberculosis in many parts of the world is leading to a diversification of drug regimens and to the use of drugs that are more toxic per se and more likely to interact with others. In addition, the treatment of HIV/AIDS patients with tuberculosis or disease due to Mycobacterium avium-intracellulare complex (MAC) infection with new drugs and multidrug regimens has added to the problem of drug interactions, especially as such patients may often be receiving concomitant treatment for a range of bacterial, fungal and viral infections. In general, there are very few clinically significant interactions between the first-line antituberculosis drugs themselves, although problems of bioavailability, notably of rifampicin (rifampin), have been encountered in the manufacture of combination tablets. Of the first-line drugs used to treat tuberculosis, i.e. rifampicin, isoniazid and pyrazinamide, rifampicin is particularly likely to cause clinically significant drug interactions as it is a potent inducer of the cytochrome P450 enzyme group, which is involved in the metabolism of many drugs, in particular oral contraceptives, corticosteroids, oral anticoagulants and cyclosproin. The use of quinolones to treat multiple drug-resistant tuberculosis and AIDS-related MAC disease raises further problems of drug interactions as, in contrast to rifampicin, these drugs inhibit some cytochrome isoenzymes, leading to reduced metabolism of certain drugs. PMID- 7848545 TI - Risks and benefits of drugs used in the management and prevention of gout. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) are now commonly used for the treatment of acute gout, but caution is required in view of their adverse effects, especially in the elderly. Colchicine is still an effective acute agent, but care must be taken to monitor toxicity. Intra-articular glucocorticosteroid therapy is useful and very safe; oral steroids and corticotrophin (adrenocorticotrophic hormone) may have a small role in acute therapy and seem safe when used over short time spans. Low dose colchicine may have a cost and toxicity advantage over NSAIDs in the prophylaxis of gout when commencing therapy aimed at reducing elevated plasma urate concentrations. Allopurinol is more frequently used than uricosuric agents such as probenecid, and toxicity may be largely avoided by tailoring dosage schedules according to renal function. PMID- 7848547 TI - Toxicological problems resulting from exposure to traditional remedies and food supplements. AB - The National Poisons Unit, London, carried out a pilot survey to investigate the frequency and severity of adverse effects/toxicity from exposure to traditional medicines and food supplements reported to the Unit. Enquiries related to suspected poisoning events were reviewed retrospectively from January 1983 to March 1989, and prospectively in 1991. Further information about cases identified by the prospective review was obtained, when appropriate, by follow-up questionnaire, clinical consultation by a consultant toxicologist, toxicological analyses of samples from patients and from products, and botanical identification of dried plant material. In total, 5536 enquiries were identified. Symptoms were reported in 657 (12%) of these. There was a large number of reports of accidental ingestion of vitamin preparations by children under 5 years. Appropriate assessment was possible in only relatively few cases, due to insufficient documentation, and poor labelling of certain products. A probable link between exposure and adverse effects was identified in 42 cases, and was highly probable in two. Heavy metal poisoning resulting from use of contaminated traditional remedies was confirmed in 5 cases. There was evidence that some patients took excessive doses of food supplements, without realising that this might result in toxic effects. The results of this pilot study suggest that there is a need for further surveillance to provide an appropriate risk assessment of food supplements and herbal remedies, improved quality control and labelling of these products, and increased awareness of their potential hazard. PMID- 7848548 TI - The effects of tetrandrine (TT) and polyvinylpyridine-N-oxide (PVNO) on gene expression of type I and type III collagens during experimental silicosis. AB - In the screening tests of drugs for silicosis in our laboratory, we found that TT, a type of alkaloid isolated from Stephania tetrandra, could inhibit the development of experimental silicosis of rats and the synthesis of collagen in rat lung. Chest X-rays of silicotic patients treated with TT for 1-3 years showed obvious changes. The silicotic nodules became smaller and shadows became clearer. PVNO was proved to have anti-silicotic effect on animal and clinically. This presentation reports the effect of them on collagen mRNA. Dot blot results showed that alpha 1 (I) and alpha 1 (III) mRNA levels increased significantly at 60 and 120 days after the rats were exposed to silica dust. The mRNA levels went down at 1 and 3 months after treated by TT and PVNO. In situ hybridization observation revealed that the silver grains of Type I and Type III collagen were scattered within the fibroblasts in cellular nodules and in thickened interstitium of silicosis tissue. The amounts of mRNA silver grains decreased in the lung tissue treated by TT and PVNO. It was suggested that TT and PVNO may inhibit the gene expression of collagen during silicosis. PMID- 7848549 TI - Fluoride-induced early teeth wearing in Argentinian cattle. AB - The relationship between observed early teeth wearing in cattle and the existence of large areas where excess fluoride in underground water prevails in Argentina, but has never been studied. Average values of bone fluoride exceeding 5000 ppm and well water containing up to 10.5 ppm of this element were found in a farm (ETWF) where early teeth wearing is observed, while in a control farm (NETWF), those values were 1480 ppm and 3.0 ppm respectively. Urine samples from animals from the ETWF contained almost 4 times more fluoride than those from the latter. Forage in both farms contained about the same levels of fluoride (15 to 25 ppm). None of the farms was exposed to industrial, volcanic, or geothermal activity. Lactating and adult animals were transferred from one farm to the other. After 30 months, adult animals from the NETWF showed no damage in teeth, while adults from the ETWF continued a rapid teeth wearing. Young animals from the NETWF developed severely damaged permanent teeth, while young animals from the ETWF developed normal teeth. We concluded that the problem exists in the ETWF and being a standard farm, the condition could be extrapolated to other areas. PMID- 7848546 TI - The beta 2-agonist controversy. Observations, explanations and relationship to asthma epidemiology. AB - Links between frequent use of inhaled beta 2-agonists and morbidity and mortality from asthma appear probable. Two mortality epidemics followed the marketing of potent inhaled adrenergic agents. Case-control studies in New Zealand linked mortality with prescription of fenoterol, especially in severe asthma. A Saskatchewan case-control study confirmed an association of mortality with fenoterol, and also with frequent use of salbutamol (albuterol). Cardiac effects of beta 2-agonists do not cause mortality, but frequent use of these agents may increase the chronic severity of asthma, hence increasing the number of asthmatic patients at risk of death in an acute attack. Frequent use of beta 2-agonists may reduce lung function, increasing airway responsiveness, and impair control of asthma, despite use of inhaled corticosteroids. Mechanisms for this effect may include tachyphylaxis to nonbronchodilator effects, increased responsiveness to allergen, interaction with corticosteroid receptors, altered mucociliary function, differential effects of enantiomers, and masking of symptoms by beta 2 agonist use. The withdrawal of fenoterol from New Zealand in 1990 was associated with a substantial decline in morbidity and mortality. Overall, the evidence suggests that frequent use of inhaled beta 2-agonists has a deleterious effect on the control of asthma. Epidemics of mortality are explained by an increase in chronic severity of asthma following introduction of more potent beta 2-agonists. While beta 2-agonists remain essential for relief of breakthrough symptoms, long term use, particularly with high doses of potent agents, appears to be detrimental. PMID- 7848550 TI - Determination of pyrethroids in human urine by gas chromatography. AB - A gas chromatographic method for the determination of deltamethrin and fenvalerate in human urine is described. Both deltamethrin and fenvalerate have been analysed by gas chromatography with a electron capture detector. The least detectable concentration of both pyrethroids in urine is 0.2 g per litre. The precision and accuracy of the method were within acceptable limits. The method has been used to determine the pyrethroids in urine samples obtained from packers, spraymen and acute pyrethroids poisoning patients. PMID- 7848551 TI - Metallothionein genes in the nematode Caenorhabditis elegans and metal inducibility in mammalian culture cells. AB - Genomic DNAs of metallothionein I and II in Caenorhabditis elegans (CeMT-I and CeMT-II) were isolated by YAC library/polytene filter hybridization followed by subcloning of corresponding cosmid clones. Both genes are mapped at chromosome V. Although the similarities of 5'-flanking regions and coding regions have shown only 55-58%, the introns are split at the same position in both genes, indicating that these two genes are originally from the same gene. While several metal responsive elements are conserved among eukaryotes, only one metal responsive element was found in the promoter region in CeMT-II and not in CeMT-I. Indeed, neither of 5'-flanking regions of CeMT-I nor CeMT-II connected to chloramphenicol acetyltransferase reporter gene is responsive to heavy metals in mammalian culture cells by transient transfection analysis. These results would suggest that the metal regulatory factors in C. elegans might be different from those conserved in invertebrates and vertebrates, although the MTs in C. elegans revealed the similarities to mammalian MTs in several points. PMID- 7848552 TI - Induction of metallothionein in rat liver by cadmium chloride: probable mechanism of action. AB - The mechanism of action of cadmium in the inductive pathway of metallothionein (MT) synthesis was studied in the rat. Cadmium significantly elevated the MT level by 872% which was antagonised by coadministration of either verapamil (343.5%) or ionophore (570%). The Ca-dependent biomolecules such as cyclic AMP or calmodulin remained depressed in all treatment regimens except calmodulin in the ionophore treated rat. Total Ca2+ showed no increase in its profile except in the ionophore treatments either alone or with CdCl2. The Na+ profile is, however, significantly elevated in all cases except the ionophore treated rat. The present study clearly indicates that (a) Ca2+ has no first messenger role in the schematic events leading to MT synthesis and (b) Na+ may be regarded as a possible candidate in the molecular events of Cd-induced MT synthesis. PMID- 7848553 TI - Studies on the induction of cross-resistance by low dose radiation or by low concentrations of chemicals. AB - The cross-resistance induced by low-level radiation and low concentration of chemical mutagens was studied using human lymphocytes in vitro and mouse bone marrow cells and germ cells in vivo. The chemical mutagens used in these experiments included the MMC, H2O2 and CP. The results reported here, in addition to those that have appeared in the literature, show the following features documented for the first time: (1) MMC as an adaptive treatment could also induce the adaptive response to radiation-induced cytogenetic damage; (2) resistance against MMC-induced damage could be induced by low dose radiation in vivo; (3) it is in mouse germ cells that low dose radiation or chemical mutagens could induce the cross-adaptation; (4) the cells pretreated by low dose X-rays could show the high resistance to H2O2-induced cytogenetic damage; (5) CP as D1 treatment could not induce the adaptive response to radiation and low dose radiation also could not induce the adaptive response to CP. PMID- 7848554 TI - Influence of in vitro methods, receptor fluids on percutaneous absorption and validation of a novel in vitro method. AB - In vitro experiment using excised skin has been valuable for studying the mechanism of percutaneous absorption. Based on previously established static diffusion cell system in this laboratory, a novel model-perfused glass diffusion cell system is designed. The results of initial comparative study on percutaneous absorption between glass perfused diffusion cell and static diffusion cell, in vitro and in vivo permeation as well as factors affecting permeation with seven radiolabelled chemicals are presented. The results demonstrate that the perfused diffusion cell system, which used a perfusion fluid below the surface of skin to take up the materials which penetrated the skin, is more similar to physiologic condition, convenient and automatic than that of the static cell. It well predicts the in vivo percutaneous absorption if appropriate receptor fluid is chosen. The results also show that the selection of receptor fluid is critical for in vitro permeation of chemicals with different solubility. PMID- 7848555 TI - Some recent mosquito-related studies and developments in Sri Lanka. PMID- 7848556 TI - Effect of low dose radiation on intracellular calcium and protein kinase C in lymphocytes. AB - It is first reported in the present paper that whole-body irradiation (WBI) with low dose X-rays could increase intracellular calcium ions ([Ca2+]i) and stimulate protein kinase C (PKC) activity of mouse lymphocytes. Following WBI of male Kunming mice with 75 mGy X-rays at a dose rate of 12.5 mGy/min the mobilization of [Ca2+]i with Con A in CD4+ and CD8+ Cells in the thymus and spleen was potentiated and the amplitude of [Ca2+]i mobilization in thymocytes in response to anti-CD3 monoclonal antibody increased with time from 4 to 24 h following low dose radiation. The PKC activity in the homogenate of spleen was markedly stimulated 12 h after WBI with 75 mGy, reaching its peak value at 24-48 h and coming down to lower than normal on day 7. However, the PKC activity in the separated T lymphocytes reached its peak value at 12 h and that in the B lymphocytes reached its peak value on day 4, both coming down to below control on day 7. The implications of this facilitation of signal transduction in T lymphocytes in the mechanism of immunoenhancement after low dose radiation were discussed. PMID- 7848557 TI - The three-dimensional NMR solution structure of alpha-cobratoxin at pH 7.5 and conformational differences with the NMR solution structure at pH 3.2. AB - The 3D solution structure of alpha-cobratoxin, a neurotoxin purified from the Naja naja siamensis snake venom, has been determined by Nuclear Magnetic Resonance spectroscopy, in conjunction with distance geometry and restrained molecular dynamics, at pH 7.5. A total of 490 distance restraints were obtained from NOE intensities and 25 phi dihedral angle restraints deduced from J-coupling data. The generated structures are well defined with root mean square deviations from a geometrical mean structure of 0.107 +/- 0.036 nm for the backbone atoms and 0.128 +/- 0.073 nm for the side-chain atoms (considering residues 1 to 66 minus 26 to 35). A comparison between the generated structures at pH 7.5 and the mean NMR solution structure at pH 3.2 revealed that the 3D structure of alpha cobratoxin is more compact at neutral pH. This major difference is mainly due to the pH-dependent conformational variations of three residues His18, Thr44 and Thr59. PMID- 7848558 TI - Molecular dynamics simulation of equine infectious anemia virus Tat protein in water and in 40% trifluoroethanol. AB - Two molecular dynamics (MD) simulations were performed in order to increase the understanding of the dependence of protein conformation on solvent environment. The protein used for these simulations is the transcriptional activator of the equine infectious anemia virus (EIAV-Tat). The structure of this protein has been determined by nuclear magnetic resonance (NMR) in aqueous solution (Willbold et al., Science 264, 1584 (1994)) and in 40% (v/v) trifluoroethanol (TFE) (Sticht et al., Eur. J. Biochem., submitted) showing considerable differences in the stability of the secondary structure elements. In order to investigate the influence of the solvent MD simulations (300 K: 200 ps) were carried out in water and in a solvent containing 40% (v/v) TFE. In both simulations the structure as determined in 40% TFE by NMR showing three-helices and a tight type II turn, was used as the initial structure. The MD simulations clearly indicate a decreased stability of the secondary structure elements in aqueous environment as made obvious by larger atomic motions and stronger fluctuations in the length of the hydrogen bonds. Complete unfolding of the helices was not observed on a 200 ps timescale. The root mean square deviation (RMSD) values of the backbone atoms after 200 ps simulation compared to the starting structure underline the strong influence of the solvent on the protein stability. This RMSD value is 1.95 A for the simulation in water and 1.29 A for the simulation in TFE/water. This result supports the notion that TFE acts as a secondary structure inducing and stabilizing solvent. The differences apparent from the MD simulations are in good agreement with the data derived from NMR measurements, showing the relevance of MD as a method for estimating conformational and dynamical properties of proteins. PMID- 7848559 TI - Application of 3-dimensional homology modeling of cytochrome P450 2B1 for interpretation of site-directed mutagenesis results. AB - Three-dimensional structures of cytochrome P450 2B1 were modeled based on the crystallographic structure of P450cam. The effect of the alignment, loop choice, and minimization with or without water was assessed. Although final models were similar in overall structure, the identity of active site residues depended upon the alignment. An example is Phe-206, which may or may not form part of the active site. The choice of the loop conformation had a lesser effect, while including water in the final minimization step was essential for preserving the shape and size of the active site. The best model (model 2) was in good agreement with the data from site-directed mutagenesis studies, and correctly predicted the effect of substitutions at 9 out of 10 amino acid positions. Thus, residues important for P450 2B1 activity, such as Ile-114, Phe-206, Ile-290, Thr-302, Val 363, and Gly-478, constitute part of the active site and are able to interact with the substrate androstenedione through hydrophobic interactions. On the other hand, Ser-303, Ser-360 and Lys-473 are far from the active site and/or cannot interact with the substrate, in agreement with experimental data. The model indicates other residues likely to be important for enzyme function, such as Tyr 111, Leu-209, Ile-477, and Ile-480, which can be tested experimentally. The substrate may assume numerous binding orientations consistent with observed patterns of hydroxylation at C15 and C16. The replacement in the model of certain amino acid residues to mimic residue substitutions from site-directed mutagenesis studies and docking of the substrate into the modified active site allowed a plausible explanation for alterations in regio- and stereospecificities of some mutants of P450 2B1, such as Gly-478-->Ala or Val-363-->Ala. PMID- 7848560 TI - Characterization of the structural conformation adopted by (TTAGGG)n telomeric DNA repeats of different length in closed circular DNA. AB - Telomeric DNA sequences are known to adopt unusual DNA structures upon protonation when contained into negatively supercoiled DNA. In this paper, the structural properties of (T2AG3)n telomeric sequences of different length is analyzed in detail. Transition to the protonated form is observed at very low pH for (T2AG3)n > or = 8 sequences. Formation of the protonated form is facilitated by negative supercoiling. The patterns of chemical modification obtained with different chemical reagents indicate that protonation induces denaturation of the (T2AG3)n telomeric sequences. Upon denaturation, the "C-rich" strand becomes structured forming, most likely, hairpin-like conformations stabilized by the formation of C+.C pairs and, probably, of A+.A pairs. The "G-rich" strand of the (T2AG3)8 sequence shows also signs of becoming structured giving rise to various structural conformers which might include triple- and tetra-stranded conformations. However, in the case of shorter sequences, the "G-rich" strand remains basically single-stranded. PMID- 7848561 TI - Theoretical design, chemical synthesis and footprinting analysis of a novel peptide derivative of the intercalator 7-H pyridocarbazole targeted towards the major groove of DNA. AB - In order to target the major groove of DNA, we have designed novel peptide derivatives of 7-H pyridocarbazole, which is the chromophoric ring of ditercalinium, a potent antitumor bisintercalator. We will present here the results obtained with a compound that has a D-Asn tethered to the pyridinium nitrogen of the ring by a protonated beta-alanyl-ethyl chain. We have investigated two alternative means of intercalation of the chromophore: first, into the (pyrpur) sequences, d(CpG)2 and d(CpA).d(TpG); second, into the (pur pyr) sequences, d(GpC)2 and d(GpT).d(ApC). For the first intercalative mode, the best bound triplet sequences are d(ACG).d(CGT) and d(ACA)d(TGT), namely with an adenine immediately upstream from the intercalation site. In these complexes, the chromophore has its concave side in the major groove, its long axis nearly colinear with the mean long axis of the two base pairs of the intercalation site, and a bidentate H-bonded configuration occurs which involves the C = O and NH groups of the D-Asn side chain and HN6 and N7 (resp.) of the adenine base upstream. One alkylammonium proton is H-bonded to N7 of the guanine of the intercalation site, on the strand opposite to the one bearing the adenine. In the second intercalative mode, the chromophore's concave site now faces one DNA strand, and both alkylammonium protons are involved in H-bonds with N7 and O6 of the 3' guanine on the same strand. The peptide's complexes with sequences having A, G, or C upstream of this guanine were computed to be energetically competitive with those with the best (pyr-pur) triplets. This provides a rare example of energetically favourable drug intercalation in-between (pur-pyr) sequences as compared to the standard (pyr-pur) ones. The synthesis of this compound was performed, and a series of footprinting experiments undertaken on a total of approximately 300 nucleotides. These experiments were consistent with the inferences from the theoretical computations. PMID- 7848563 TI - Structure of three-way DNA junctions. 2. Effects of extra bases and mismatches. AB - The structure of three-way DNA junctions, containing two linear double helices (arms) and a hairpin as a third arm, was studied by means of a cyclization technique. In addition to branched molecules containing perfect base-pairing in helical parts, three-way junctions with mismatches and extra non-complementary nucleotides (bulges) at junction points were studied. Molecules thus designed were ligated at identical conditions and their geometry was compared through the analysis of the efficiency of circle formation. The analysis showed that irregularities in base pairing listed above dramatically change the static and dynamic structural characteristics of the three-way junctions. All mismatches facilitate the kink between linear arms, but quantitatively, the effect depends on the position of the mismatch. The effect is maximal for GG-mismatch placed at the hairpin junction point. The results for bulges are of different kind, and they lead us to conclude that the three-way DNA junction with unpaired nucleotides adopts a T-like geometry with an angle around 90 degrees between arms containing the bulge and two other arms coaxially stacked. Broad distribution of circles indicates that this T-form geometry of bulge-containing junction is more flexible than initial pyramidal structure predominantly due to high mobility of the third arm. PMID- 7848562 TI - Binding of echinomycin to d(GCGC)2 and d(CCGG)2: distinct stacking interactions dictate the sequence-dependent formation of Hoogsteen base pairs. AB - Molecular dynamics simulations have been used to explore the behavior of the complexes of echinomycin with the DNA tetramers d(GCGC)2 and d(CCGG)2 in which the terminal bases have been paired according to either a Hoogsteen or a Watson Crick hydrogen bonding scheme. The energy of the four resulting complexes has been monitored along the dynamics trajectories and the interaction energy between echinomycin and DNA has been decomposed into contributions arising from the planar aromatic systems and the depsipeptide part of the antibiotic. Our calculations predict a large increase in overall stabilization upon protonation of the terminal cytosines and subsequent Hoogsteen pair formation in the complex of echinomycin with d(GCGC)2 but not with d(CCGG)2, in agreement with the experimental evidence [Gao and Patel, Quart. Rev. Biophys. 22, 93-138 (1989)]. The conformational preferences appear to arise mainly from differential stacking interactions in which the electrostatic component is shown to play a dominant role. Differences in hydrogen bonding patterns are also found among the complexes and these are compared in relation to available crystal structures. The binding of echinomycin to DNA appears as a complex process involving many interrelated variables. PMID- 7848564 TI - Conformations of t-RNA: base pairing and stacking. AB - The Phe t-RNA structure can be fit with one point per nucleotide to lattice models, and a fit for the 76 points to a face-centered cubic lattice is achieved with an RMS of 1.76 A. There are 32 chain folds possible upon these points. Because it is impossible to calculate directly all combinations of potential base pairs for these cases, an alternative is to determine low energy secondary structures and subsequently the tertiary pairs. For each lattice fold, the low energy secondary structures are generated from a list of proximal bases. From the lists of remaining possible tertiary pairs, all combinations are generated, and these include 2,365,440 allowed conformers. Among the possible types of non native conformational variations observed is slip pairing, accompanied by a bulge, at the end of a stem. Small changes in secondary structure can result in different tertiary pairs. Other calculations, not constrained to the t-RNA shape, are presented that involve the packing of rigid stems on a flexible internal loop. For a simple cubic lattice there are 36,484,128 lattice folds for the sixteen bases enclosing the internal loop. By attaching rigid stems and accounting for their excluded volume these are reduced to only 258,979 possible configurations. The most common stacking arrangements involve the usual two pairs of stacked stems indicated in the crystal structure. The present enumerations suggest that a completely thorough exploration of three dimensional RNA structures is feasible only with prior specification of restrictions on conformational freedom, such as those given by secondary structures. PMID- 7848565 TI - B-Z transition of synthetic oligonucleotides containing non-Z forming elements. AB - Ten oligonucleotides of the length 8-12 base pairs have been synthesized, which contain, in addition to the obligatory sequences CG/CG, sequences not favorable for the transition to the Z conformation (A.T pairs, GG/CC or AA/TT sequences). Conformational transitions of these oligonucleotides in high concentrations of NaClO4 in the absence and in the presence of Ni2+ were investigated using CD spectroscopy. The B-Z transition is affected by the length and sequence of the oligonucleotide. Increasing the NaClO4 concentration alone the transition of only one of the oligonucleotides studied. (CGCGCGTGCACGCGCG)2, can be induced. Other oligonucleotides remain in the B conformation or only partial transition to the Z conformation can be observed. Most other oligonucleotides can be converted into the Z conformation at intermediate concentrations of NaClO4 (2.0-3.2 M) by an addition of Ni2+ ions. In some cases, however, Ni2+ can destabilize the double stranded structure of the sample. We have studied the effect of the presence of A.T pairs in the G.C containing oligonucleotides and the effect of the presence of pu-pu/pyr-pyr sequences. The presence of the latter sequences in the Z form implicates the formation of a Z-Z'junction which makes the transition quite difficult. Despite the fact that some oligonucleotides contained several structural elements not favorable for the transition, we did not find any sequence which would completely block the ability of the oligonucleotide to adopt the Z conformation. PMID- 7848566 TI - Mode of DNA binding of bis-benzimidazoles and related structures studied by electric linear dichroism. AB - The binding mode of a series of bis-benzimidazole analogues of Hoechst 33258 to a variety of DNAs and polynucleotides has been investigated by electric linear dichroism. Two groups of compounds were examined: (i) benzoxazole and pyridoimidazole derivatives and (ii) pyridoimidazole analogs substituted with an N-alkoxyalkyl group either directed towards the minor groove or directed away from the minor groove. The ELD data indicate that the mode of binding of these drugs varies significantly with the sequence of the target DNA sequence. The DNA binding properties of these drugs are related to their topoisomerase inhibitory properties. PMID- 7848567 TI - DNA polymorphism under the influence of low pH and low temperature. AB - The polymorphic behaviour on the conformation of a alternating GC polymer and its methylated analogue has been studied under the influence of low pH, low temperature and low ionic strength from the measurements of UV-absorption and circular dichroic spectroscopy. Studies indicate that both the polymers isomerize to a stable left handed type conformations. The duplex nature of these conformations were inferred from thermal denaturation curves and the temperature dependence of the CD spectra. In natural DNA, the influence of low pH and low temperature also shows a defined conformational change, characterized by two positive CD bands. This conformational status is achieved in all DNAs irrespective of base composition or sequence of base pairs. Further evidence to this altered polymorphic state of natural DNAs is inferred from ethidium binding study. PMID- 7848568 TI - Calorimetric and spectroscopic studies on the poly[d(GA).d(CT)] structural polymorphism induced by zinc. AB - The interaction of zinc (II) with poly[d(GA).d(CT)] and salmon testes DNA has been investigated by Differential Scanning Calorimetry (DSC) and Circular Dichroism (CD). We have detected and energetically characterized the existence of two different structural forms in poly[d(GA).d(CT)] which behave differently during a DSC experiment. The overall melting of DNA shows two calorimetric transitions at different temperatures. Moreover, the presence of zinc, at an input ratio of ion to nucleotide (r) above two, renders a complex DSC profile which is characterized by a negative enthalpy transition. Besides, the low temperature transition observed in the presence of zinc is practically reversible after re-cooling/re-heating cycles. Nevertheless, the high-temperature transition characterized by a negative delta H degree cal does not appear in re-heating experiments, and remains stable below 100 degrees C. A calorimetric negative enthalpy transition is also found using salmon DNA in the presence of zinc ions. It seems that the combination of a temperature effect and zinc binding might induce the production of a stable metal-DNA complex, which can also be detected by changes in some bands in the CD profiles. The experimental results show that the presence of DNA structures and binding processes involving a negative calorimetric enthalpy contribution might be more widespread than previously reckoned. PMID- 7848569 TI - DNA-carbohydrate interaction. The effects of mono- and disaccharides on the solution structure of calf-thymus DNA. AB - We report the interaction of calf-thymus DNA with D-glucose, D-fructose, D galactose and sucrose in aqueous solution at physiological pH with sugar/DNA(P)(P = phosphate) molar ratios (r) of 1/10, 1/5, 1, 5 and 10. FTIR difference spectroscopy was used to characterize the nature of sugar-DNA interaction and correlations between spectral changes and structural variations for both sugar and DNA complexes have been established. PMID- 7848570 TI - Alignment of (dA).(dT) homopolymer tracts in gene flanking sequences suggests nucleosomal periodicity in D. discoideum DNA. AB - It has been shown that the frequency versus size distribution of A and T overlapping and non-overlapping homopolymer tracts of N > 5 in D. discoideum gene flanking and intron regions are significantly greater than in coding regions(1). In the present report, we demonstrate, that a spatial periodicity exists in long A and T tracts (N > 10) in long flanking sequences by scored alignments of those tracts (N > 10) with the nucleosomal repeat. A tract spacing was found at 185-190 bp that corresponds to a maximum alignment score. This is exactly the average spacing of D. discoideum nucleosomes determined experimentally. A majority of A and T tracts in flanking sequences are often spaced by short DNA stretches and the total length of adjacent A and T tracts plus the interrupting short DNA stretch corresponds closely to the average experimentally measured nucleosomal linker DNA size in D. discoideum-42 bp. These data suggest a model which has A and T runs of N > 10 bp in flanking DNA of D. discoideum organized in a regular phase with nonhomopolymer sequences along the DNA. This model has functional implications for A and T tracts, suggesting that they are found in nucleosomal linker DNA regions of chromatin during some necessary portion(s) of the life of the cell. PMID- 7848571 TI - Neuropeptides in the human dorsal vagal complex: an immunohistochemical study. AB - The distribution of twelve biologically active neuropeptides, i.e., thyrotropin releasing hormone, corticotropin-releasing factor, pro-opiomelanocortin-derived peptides (adrenocorticotropic hormone, beta-endorphin, alpha-melanocyte stimulating hormone), leucine-enkephalin, dynorphin A, dynorphin B, cholecystokinin, substance P, galanin and calcitonin gene-related peptide, was examined by immunohistochemistry in the human dorsal vagal complex including the nucleus of the solitary tract, the dorsal motor nucleus of the vagus and the area postrema. Immunoreactivity of all the twelve neuropeptides was found widely distributed in the various subdivisions of the nucleus of the solitary tract, showing a unique distribution for every peptide. Neuronal cell bodies immunostained with leucine-enkephalin, galanin and dynorphin B were found in this region. There were no immunopositive perikarya for any of the peptides in the other structures studied. Fibers containing galanin, corticotropin-releasing factor, substance P, dynorphin B, thyrotropin-releasing hormone and calcitonin gene-related peptide were observed at a relatively high density in the nucleus of the solitary tract. In the same structure, a moderately dense network of fibers immunostained with dynorphin A, cholecystokinin and leucine-enkephalin, but only solitary pro-opiomelanocortin-derived peptides-containing fiber fragments were observed. In the dorsal motor nucleus of the vagus the most prominent network of fibers was found to contain thyrotropin-releasing hormone, galanin and substance P. In contrast to these, no beta-endorphin immunoreactivity was detected. The area postrema contained only moderate to low densities of galanin-, substance P-, calcitonin gene-related peptide-, dynorphin B- and cholecystokinin-immunoreactive fibers. PMID- 7848572 TI - Ultrastructural study of delta-opioid receptors in the dorsal horn of the rat spinal cord using monoclonal anti-idiotypic antibodies. AB - The ultrastructural localization of delta-opioid receptors was studied using monoclonal anti-idiotypic antibody prepared with an anti-D-Ala2-D-Leu5 enkephalin. Immunocytochemical techniques were used on vibratome sections from rats perfused with paraformaldehyde. A high density of immunoreactivity was observed in the dorsal horn of the spinal cord, particularly the two superficial layers, the dorsolateral funiculus and the area surrounding the central canal. The labelling was absent when the antibody was preincubated with the immunogen. Competition between the anti-idiotypic antibody and different ligands, delta or mu, was controlled by preincubation of tissue sections with the ligand in the presence of peptidase inhibitors for 3-4 h before addition of the anti-idiotypic antibody. Enkephalin, dermenkephalin and naltrindole induced disappearance of the labelling at 10(-9) M while dermorphin or dermorphin Lys7 were ineffective at the same concentration. Lamina II of the dorsal horn was studied by electron microscopy. The immunolabelling was mainly localized on cell membranes at appositions between the two neurons. About one third were localized between an axon terminal and a dendrite, the same proportion of labellings were between two axon terminals. Labelling was occasionally observed at appositions between a glomerular terminal and a dendrite or a terminal or at axoglial appositions. Axosomatic localizations were rare. The presynaptic localization of the labelling is in favor of a presynaptic mechanism of action for delta-opioids in the spinal cord, providing that these receptors are functional. delta-Opioid peptides probably act non-synaptically since receptors were never localized on synaptic differentiations. PMID- 7848573 TI - Absolute number and size of pigmented locus coeruleus neurons in young and aged individuals. AB - Significant loss of noradrenergic neurons of the locus coeruleus in aging and Alzheimer's disease has been reported. The interpretation of these analyses, however, is problematic because of the model- and assumption-based nature of conventional sampling and estimation techniques. In the present study, unbiased stereological methods were used to estimate the total number and mean cell volume of pigmented neurons of the locus coeruleus in the brains of young and aged nondemented persons. No side-to-side differences are seen, and there is no change in pigmented cell number or size in the locus coeruleus of nondemented older persons as compared with that of young individuals. In light of previous studies that show severe locus coeruleus cell loss in Alzheimer's disease, these data support further critical investigations into the possible protective role of noradrenaline in normal cognitive functions and emphasize the importance of avoiding methodological bias in quantitative neuroanatomical studies. PMID- 7848574 TI - Perspectives on stomach cancer. PMID- 7848575 TI - Prevalence of EBV RNA in sinonasal and Waldeyer's ring lymphomas. AB - A high incidence of a T cell phenotype of sinonasal lymphomas in other Asian countries has been associated with a high incidence of Epstein Barr virus (EBV) infection. We analyzed 13 sinonasal and 18 Waldeyer's ring lymphomas for the prevalence of EBV encoded RNA (EBER) using a sensitive and specific in situ hybridization. In addition, we examined the relationship of histologic findings and immunophenotype as well as the location of the lymphomas to the presence of EBV. The EBER was detected in each of 12 sinonasal lymphomas with a T cell immunophenotype. One B cell sinonasal lymphoma was EBER negative. Four of 18 Waldeyer's ring lymphomas were positive for EBER, including two T cell lymphomas. Two of 16 B cell Waldeyer's ring lymphomas were EBER positive. Morphologically, 11 of 20 diffuse large cell lymphomas, 2 diffuse mixed small and large cell lymphomas, 2 of 4 immunoblastic lymphomas and 1 lymphoplasmacytic lymphoma were EBER positive. Four follicular large cell lymphomas were EBER negative. A characteristic angiocentric or angiodestructive pattern was found in most T cell lymphomas and EBER positive cases. These findings indicate that EBV infection is more strongly associated with the T cell immunophenotype, angiocentric pattern and sinonasal location of the lymphoma. PMID- 7848576 TI - Oncogenic osteomalacia: a clinicopathologic study of 17 bone lesions. AB - Oncogenic osteomalacia is an unusual and rare clinicopathologic syndrome characterized by mesenchymal tumors that apparently produce osteomalacia and biochemical abnormalities consisting of hypophosphatemia, normocalcemia, and increased levels of alkaline phosphatase. We collected from the Mayo Clinic files and from our consultation files the records for 17 cases of osteomalacia associated with bone lesions. There were five cases of fibrous dysplasia, three of hemangiopericytoma, and two of phosphaturic mesenchymal tumor. There was one case each of osteosarcoma, chondroblastoma, chondromyxoid fibroma, malignant fibrous histiocytoma, giant cell tumor, metaphyseal fibrous defect, and hemangioma. In this study we can figure out that the most common characteristic histologic features of our cases were hemangiopericytomatous vascular proliferation, fine lace-like stromal calcification, and stromal giant cells. In most of the cases, the clinical and biochemical symptoms and signs resolved soon after complete resection of the lesion. When the lesion recurred or metastasized, the symptoms and signs also recurred. PMID- 7848577 TI - p53 protein overexpression and allele loss of p53 gene in gastric adenocarcinoma. AB - Gene alterations of p53 tumor suppressor gene such as point mutations, deletions or insertions occur in various human cancers. p53 protein overexpression was studied immunohistochemically in 80 gastric adenocarcinomas using an anti-human p53 antibody (Pab 1801) and the avidin-biotin-peroxidase technique. We have also analyzed allele loss of the human p53 gene in 54 cases of gastric adenocarcinoma using polymerase chain reaction and restriction fragment length polymorphism. p53 immunostaining was also demonstrated in 48 of 80 carcinomas (60%). Normal mucosa was always negative. No relation could be found between p53 immunostaining and the degree of differentiation. 21 of the 54 patients(39%) were informative for the p53 exon 4. In ten of these informative cases(47.6%), tumor DNAs showed allele loss when compared with nonmetastatic lymph node DNAs. Seven of the ten(70%) showed p53 immunoreactivity. These findings suggest that mutations of the p53 gene may play a role in the development of gastric adenocarcinoma and that allele loss of p53 frequently occurs in p53 immunoreactive gastric adenocarcinoma. PMID- 7848578 TI - Estimation of the geometric means and the reference values of blood lead levels among Koreans. AB - Blood lead concentrations of Koreans who have not been exposed to lead occupationally, show a wide range of variation. Despite the fact that blood lead concentration reveals a long-normal distribution, geometric means and standard deviations have not been presented in almost all studies on blood lead levels in Koreans. A new meta-analytical method was applied to estimate the theoretical geometric means, the standard deviations of the logarithm, and the reference values of blood lead concentrations among Koreans based on arithmetic means and standard deviations reported, and to compare them to those of other countries. Estimated geometric means of Korean men, women, and men and women, were 18.03, 13.13, and 15.80 micrograms/dl, respectively. Values of 90, 95, and 99 percentile for Korean men were 31.81, 37.36, and 50.52 micrograms/dl, for women, 28.41, 35.34, and 53.24 micrograms/dl, and for men and women, 31.42 micrograms/dl, 38.17 micrograms/dl, and 54.95 micrograms/dl, respectively. These values are higher than those of neighboring countries, such as China and Japan. PMID- 7848579 TI - Development of altered hepatocyte foci by separate and combined treatments with radiation and diethylnitrosamine in neonatal rats. AB - To establish an in vivo radiation carcinogenesis model using glutathione S transferase placental form positive (GST-P+) hepatic foci, newborn rats were irradiated once by 0.5 Gy and 2 Gy of gamma ray or 0.15 Gy and 0.6 Gy of neutron with or without 0.05% phenobarbital (PB). When the rats were sacrificed at the 12th or 21st week, the incidence of GST-P+ foci induction by radiation alone was very low. The neutron was more sensitive than the gamma ray at week 12 and the reverse phenomenon was observed in the groups at week 21. PB combination showed an increased incidence of GST-P+ foci in gamma ray irradiated groups. The neutron irradiation combined with PB did not show any significant difference compared with the corresponding PB untreated groups. We also investigated the combined effect of diethylnitrosamine (DEN) and 0.75 Gy of gamma ray irradiation. Intraperitoneal injection of 0.15 mumol/g body weight of DEN at 1 hour after gamma ray irradiation showed significantly increased the number and area of GST P+ foci compared with those of DEN alone or DEN at 1 hour before gamma radiation (P < 0.001). From these data, after more defined experiments, an in vivo radiation carcinogenesis model will be established by radiation alone or a combination of radiation and carcinogens. PMID- 7848580 TI - Clinicopathologic comparison of eroded polypoid hyperplasia and solitary rectal ulcer syndrome. AB - We experienced two unusual cases of tumor-like polypoid lesions involving the rectosigmoid colon. They could not be readily classified into any well known polypoid tumors of the rectosigmoid colon, but appeared to have some similarities to the previously documented "eroded polypoid hyperplasia (EPH)". A collective review of our seven cases of solitary rectal ulcer syndrome (SRUS), which proved to be due to paradoxically over-reactive muscle tone of the puborectalis, was performed, and clinicopathologic comparisons between EPH and SRUS were carried out. They shared histopathologic characteristics such as vascular congestion, crypt hyperplasia, and eroded surface, but they were different from each other in clinical symptoms, location of lesions and gross features. Furthermore, in one EPH case there was an altered much profile which was similar to that seen in SRUS and complete rectal prolapse. Conceivably, the pathological features of both EPH and SRUS were thought to have a possible connection with mucosal prolapse syndrome (MPS). Considering that MPS is a group of diseases encompassing SRUS and the related disorders of the colorectum and the anus, it is speculated that EPH of the rectosigmoid colon might be the proximal analogue of SRUS, a mucosal prolapse of the more distal colon. PMID- 7848581 TI - Incidence estimation of female breast cancer among Koreans. AB - The authors conducted a nationwide survey to estimate the incidence rates of female breast cancer among Korean women in 1990-1991. We identified potential breast cancer cases based on the claims sent by medical care institutions throughout Korea to the Korea Medical Insurance Corporation (KMIC) from January 1988 to December 1989, whose diagnoses in the claims included one of the following diagnostic codes; ICD-9 174-175 (malignant neoplasms of the breast), 217 (benign neoplasms of the breast), 610-611 (benign mammary dysplasia and other disorders of the breast), 233 (carcinoma in situ of the breast and genito-urinary system), or 195-199 (malignant neoplasms with uncoded sites). In order to collect the final diagnosis of the potential cases, abstracting medical records was performed through visiting or mailing an abstracting format to the corresponding medical institutions. Thereafter oncologists reviewed the abstracting formats and confirmed the incident cases of female breast cancer among the potential breast cancer cases. Using these data from the KMIC, the incidence patterns of female breast cancer among Korean women were estimated as of July 1, 1988 to June 30, 1989. The incidence rate of female breast cancer adjusted for the Korean population was estimated to be 9.9 (95% confidence interval: 9.5-10.4). The cumulative rates for the ages 0-64 and 0-74 were 0.85% and 1.0%, respectively. The standardized rate for the world population was 10.9, which was lower than those of any other Asian country including China and Japan in 1983-1987.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7848582 TI - Congenital bilateral perisylvian syndrome: analysis of the first four reported Korean patients. AB - The advent of MRI technique has enabled the diagnosis of neuronal migration disorders(NMD) and made it possible to make "in vivo" diagnosis. Congenital bilateral perisylvian syndrome(CBPS) is a recently described disease identify characterized by pseudobulbar palsy, epilepsy, mental retardation, and migration disorders in the bilateral perisylvian area. We have identified four CBPS patients based on neuroimaging and dysarthria patterns among the candidates for epilepsy surgery. All the patients had orofacial diplegia and variable degrees of mental retardation. In the spectrographic analysis of dysarthria, the loss of specific characteristics of formants of vowels and increment of noise in the high frequency formants were observed. Epilepsy was present in all, but only one patient showed intractable seizure requiring surgical intervention. MRI was most helpful in identifying NMD and polymicrogyria in both centroparietal areas in this context. Great alertness is needed to identify this disorder to determine the etiology of epilepsy and dysarthria of uncertain origin. PMID- 7848583 TI - Plasma type IV collagen and fibronectin concentrations in diabetic patients with microangiopathy. AB - In diabetes mellitus, thickening of basement membrane in capillaries and small vessels is a well-known finding and important in the progression of diabetic microangiopathy. We evaluated whether the plasma levels of type IV collagen and fibronectin, which are important factors of basement membrane, are related with the presence of diabetic microangiopathy. Plasma type IV collagen and fibronectin levels were measured in 40 healthy controls (Mean +/- SD, age; 50.3 +/- 5.5 yr) and 94 diabetic patients (age; 52.4 +/- 13.5 yr) with and without microvascular complications. The mean plasma levels of type IV collagen (5.3 +/- 2.9 ng/ml) and fibronectin (474.4 +/- 119.4 ug/ml) in diabetic patients were significantly higher (p < 0.01) than in healthy controls (3.7 +/- 1.3 ng/ml and 319 +/- 50.9 ug/ml). The mean plasma level of type IV collagen in diabetic patients with complications (6.6 +/- 3.7 ng/ml) was significantly higher (p < 0.01) than in those without complications (4.3 +/- 1.7 ng/ml) and became higher in more complicated patients. Furthermore, the severity of retinopathy and several indicators of nephropathy such as serum BUN, creatinine and proteinuria were closely associated with plasma type IV collagen level and a significant correlation was found between plasma type IV collagen and creatinine clearance (r = -0.31, p < 0.001). There was no significant difference in plasma fibronectin concentrations, however, between the diabetic patients with complications and those without complications.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7848584 TI - A case of nephrotic syndrome associated with protein S deficiency and cerebral thrombosis. AB - Protein S is found in two forms in plasma; as free and functionally active protein S, and complexed to C4b-binding protein. Patients with nephrotic syndrome are at risk for arterial and venous thrombosis at various localizations, and acquired protein S deficiency due to the selective urinary loss of the free form may be a risk factor for the development of thromboembolic complications. We report a case of cerebral arterial thrombosis associated with decreased level of free protein S antigen (44%) in a 39-year-old female patient with nephrotic syndrome. PMID- 7848585 TI - Duodenal ectopic pancreas complicated by chronic pancreatitis and pseudocyst formation--a case report. AB - Ectopic pancreas is no longer a rare clinical condition, but its unusual clinical manifestations, locations or complications are of clinical interest. We experienced a case (a 48 year-old male patient) of duodenal ectopic pancreas complicated by chronic pancreatitis and pseudocyst formation of which preoperative imaging findings mimicked a large duodenal submucosal tumor with cystic degeneration such as a leiomyosarcoma. Simultaneous chronic pancreatitis was also demonstrated in the isotopic pancreas of the patient postoperatively. Herein we report a rare clinical condition occurring in an ectopic pancreas with a brief review of the literature. PMID- 7848586 TI - Oxidant and acid aerosol exposure in healthy subjects and subjects with asthma. Part I: Effects of oxidants, combined with sulfuric or nitric acid, on the pulmonary function of adolescents with asthma. AB - Both peak flow decrements in children at summer camps and increased hospital admissions for asthma have been associated with summer "acid haze," which is composed of ozone and various acidic species. The objective of this study was to investigate the pulmonary effects of acid summer haze in a controlled laboratory setting. Twenty-eight adolescent subjects with allergic asthma, exercise-induced bronchospasm, and a positive response to a standardized methacholine challenge enrolled in the study; 22 completed the study. Each subject inhaled one of four test atmospheres by mouthpiece on two consecutive days. The order of exposure to the four test atmospheres was assigned via a random protocol: air, oxidants (0.12 parts per million [ppm]* ozone plus 0.30 ppm nitrogen dioxide), oxidants plus sulfuric acid at 70 micrograms/m3 of air, or oxidants plus 0.05 ppm nitric acid. Exposure to each of the different atmospheres was separated by at least one week. The exposures were carried out during alternating 15-minute periods of rest and moderate exercise for a total exposure period of 90 minutes per day. Pulmonary function was measured before and after exposure on both test days and again on the third day as a follow-up measurement. A postexposure methacholine challenge was performed on Day 3. Low methacholine concentrations were chosen for the postexposure challenge to avoid provoking a response. The protocol was designed to detect subtle changes in airway reactivity. The statistical significance of the pulmonary function values was tested using paired t tests. First, we compared the difference between baseline and postexposure measurements after air exposure on Day 1 with the differences between baseline and postexposure measurements after Day 1 exposure to each of the other three atmospheres. Second, we compared the difference between baseline and postexposure measurements after the Day 2 air exposure with the differences between baseline and postexposure measurements after the Day 2 exposure to each of the pollutant atmospheres. Third, we compared the difference between baseline measurements on Day 1 of each exposure atmosphere with measurements after exposure to the same atmosphere on Day 2 to detect delayed effects. No changes in any of the pulmonary function parameters were statistically significant when compared with changes after clean air exposure. Six subjects left the study because of uncomfortable symptoms associated with the exposures. These all occurred after exposure to pollutant atmospheres and not after exposure to clean air.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7848587 TI - Oxidant and acid aerosol exposure in healthy subjects and subjects with asthma. Part II: Effects of sequential sulfuric acid and ozone exposures on the pulmonary function of healthy subjects and subjects with asthma. AB - These studies were undertaken to evaluate pulmonary responses of humans sequentially exposed to acidic aerosols and ozone at levels that could reasonably be encountered in actual environmental exposures. Subjects first were exposed to sulfuric acid (H2SO4) aerosol to sensitize the airways to ozone. The exposure protocols were designed to provide more quantitative information about the threshold levels of ozone that produce adverse biological effects and to provide exposure-response data on ozone. Two groups of 30 nonsmoking volunteers of both sexes, between the ages of 18 and 45 years, were recruited. The healthy study population comprised 16 men and 14 women with an average age of 28 years and no airway hyperreactivity. The second group comprised 10 men and 20 women comparable in age to the control group, but with allergic asthma and positive skin tests. The study examined an exposure-response relationship using three levels of ozone ranging from below the current standard to one and one-half times the ambient air quality standard (0.08, 0.12, and 0.18 ppm* [parts per million]) with preexposure 24 hours earlier to H2SO4 (100 micrograms/m3) or sodium chloride (NaCl) (control) aerosol in a 45-m3 environmental chamber. The study used an incomplete block design in which each subject was exposed to four of the six paired experimental atmospheres. Both the selection of paired exposures and the order in which they were presented were randomized. The exposure protocol required nine days: Day 1, training and baseline preexposure measurements; Day 2, the first of the three hour particle (H2SO4 or NaCl) exposures; Day 3 (24 hours after Day 2), ozone exposure at 0.08, 0.12, or 0.18 ppm for three hours; Day 4 (two to four weeks later), exposure to the same ozone concentration as on Day 4. After at least another two weeks, Days 6, 7, 8, and 9 repeated Days 2, 3, 4, and 5 using a second ozone concentration. All three-hour exposures included several predetermined periods of exercise and pulmonary function measurements. To examine for delayed effects, pulmonary function tests were measured two and four hours after exposure on the ozone days. Data were analyzed over the time course of exposure and by exposure level of ozone at each time point to reveal dose response relationships more closely. The main findings of the study are as follows. No significant symptomatic or physiologic effects of exposure to either aerosol or ozone on lung function were found for the healthy group.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7848588 TI - How effective are risk-reduction interventions targeting injecting drug users? PMID- 7848589 TI - Cloning and biological characterization of human single-chain Fv fragments that mediate neutralization of HIV-1. AB - OBJECTIVE: To develop recombinant single-chain Fv fragments against HIV-1 gp120. METHODS: A panel of human monoclonal antibody Fv fragments were generated against the HIV-1 gp120 by affinity selection from an antibody library expressed on the surface of filamentous phage. The library was prepared from peripheral blood lymphocytes of an asymptomatic HIV-1-infected mother with a high neutralization titer. This mother did not transmit HIV-1 to her offspring (non-transmitter). Heavy and light chains were initially amplified separately and combined by splicing by overlap extension to generate Fv fragments. RESULTS: Several clones expressing single-chain Fv fragments bind strongly to HIV-1 gp120 and several were found to neutralize cell-free HIV-1IIIB. Gross epitope mapping suggest that different clones bound to different functional regions on the envelope. The clones also exhibited sequence diversity. CONCLUSIONS: This strategy of cloning resulted in the development of functional human-derived antibody reagents with different anti-HIV-1 biological properties in vitro. These recombinant Fv fragments have potential utility as immune reagents, as well as in the design of potential immunotherapeutics. In addition, these antibody reagents may provide information on the relationship between humoral immunity and maternal-fetal (vertical) HIV-1 transmission. PMID- 7848590 TI - Viro-immunological studies in acute HIV-1 infection. AB - OBJECTIVE: To monitor a patient who presented with symptomatic HIV-1 infection for virological and immunological parameters in relation to the clinical course. METHODS: Virological studies included determination of frequency of productively HIV-1-infected peripheral blood mononuclear cells (PBMC) and viral RNA load in plasma and p24 antigenaemia. Immunological studies included the analysis of T cell subsets, the expression of activation markers, CD45RO and CD45RA antigens, the frequency of cells programmed for death, and T-cell function. RESULTS: During the first week post onset of primary HIV-1 infection symptoms high plasma titres of p24 and HIV-1 RNA were observed. The number of productively HIV-1-infected PBMC peaked, coinciding with CD4+ T lymphocytopaenia, during week 2 when clinical improvement started. CD8+ T lymphocytosis was observed 10 days post onset of clinical symptoms, the expanded cell population being of the CD8+CD38+, CD8+CD27+ and CD8+CD28- phenotype. CD8+ T lymphocytosis was paralleled by a high percentage of cells undergoing programmed cell death on in vitro culture. In vitro T-cell function was severely depressed during the first 10 days post onset of clinical symptoms. Within about 3 weeks, following resolution of clinical symptoms, phytohaemagglutinin-induced proliferation was restored to normal levels while responses to the CD3 monoclonal antibody only showed a partial restoration. During follow-up, concomitant with the rise of activated CD8+ T cells, p24 antigen levels and viral RNA load in serum as well as the number of HIV-producing PBMC steeply declined after 2 weeks. CONCLUSION: These findings demonstrate HIV-1 induced abnormalities during severe clinical symptoms of primary HIV-1 infection. The subsequent strong immune response, which is believed to be responsible for efficient control of viral replication, appears to precede clinical improvement. PMID- 7848591 TI - Antiviral efficacy, intracellular uptake and pharmacokinetics of free and liposome-encapsulated 2',3'-dideoxyinosine. AB - OBJECTIVE: To evaluate the effect of liposome encapsulation on the in vitro antiviral efficacy, intracellular uptake and in vivo pharmacokinetics of 2',3' dideoxyinosine (ddl). METHODS: The accumulation of free and liposome-encapsulated ddl was determined in murine monocyte-macrophage RAW 264.7 cells and human premonocytoid U937 cells. The antiviral efficacy was evaluated in U937 cells infected with HIVIIIB. Tissue distribution and pharmacokinetics of free and liposomal ddl were determined in female Sprague-Dawley rats following the administration of a single intravenous bolus dose (3 mg ddl/kg). RESULTS: The entrapment of ddl in liposomes results in a lower drug accumulation in both U937 and RAW 264.7 cells. A lower antiviral efficacy against HIVIIIB replication in U937 cells was observed on encapsulation of ddl in liposomes. Improved pharmacokinetics were observed on entrapment of ddl in liposomes. Higher drug levels were found in plasma for the liposomal formulation. The systemic clearance of the liposomal drug was 120 times lower than that of free drug. Liposome encapsulation of ddl greatly enhanced the drug accumulation in organs of the reticuloendothelial system. CONCLUSION: The encapsulation of ddl in liposomes modified the tissue distribution and plasma pharmacokinetics of the antiviral agent resulting in a marked improvement of drug biodisponibility. The antiviral efficacy of liposomal ddl was lower than that of free drug in HIVIIIB-infected U937 cells. PMID- 7848592 TI - Octreotide therapy of large-volume refractory AIDS-associated diarrhea: a randomized controlled trial. AB - OBJECTIVE: To compare the effect of octreotide (a long-acting somatostatin analog) to that of antidiarrheal therapy plus placebo on large-volume refractory AIDS-associated diarrhea. DESIGN: A randomized controlled trial. SETTING: Referral-based clinic and hospital in a tertiary care center. PATIENTS: Twenty male patients with AIDS and refractory diarrhea, with stool volume > 1000 ml/day who failed to improve after initial supportive management. All patients finished the study. INTERVENTIONS: Patients were randomly given either octreotide in doses of 100, 200 and 300 micrograms subcutaneously every 8 h, or high doses of loperamide and diphenoxylate orally plus placebo subcutaneously for 10 days. MAIN OUTCOME MEASURES: Bowel movements and stool volume were registered before and every day after treatment by the patients themselves and the nursing personnel. RESULTS: Patients from both groups were similar for age, time of AIDS diagnosis, duration of diarrhea and etiology. Baseline mean bowel movements per day (9.4 +/- 2.8 in the octreotide group versus 10 +/- 3.1 in controls) and baseline mean stool volume (2753 +/- 840 versus 2630 +/- 630 ml/day, respectively) were similar in both groups before therapy (P < 0.05). Mean bowel movements per day after 10 days of therapy was 2.1 +/- 1.6 in the octreotide group versus 7 +/- 3 in controls (P < 0.05). Mean stool volume after 10 days of therapy was 485 +/- 480 in the octreotide group versus 1080 +/- 420 ml/day in controls (P < 0.05). Complete response (stool volume < 250 ml/day) was observed in two patients from the octreotide group and none from controls; partial response (decrease > 50% in stool volume) in four and two; and no response (decrease < 50% or no change) in four and eight (P < 0.05), respectively. Side-effects occurred in eight out of 10 octreotide patients and three out of 10 controls (P < 0.05), but none were significant to result in discontinuation of medication. CONCLUSION: Octreotide proved to be superior to conventional therapy in this short-term treatment of large-volume refractory AIDS-associated diarrhea. PMID- 7848593 TI - Cytokine gene expression in HIV-infected intestinal mucosa. AB - OBJECTIVE: Cytokine dysregulation has been implicated in AIDS pathogenesis and the gastrointestinal tract, containing approximately 40% of the body's lymphoid tissue, is likely to act both as a reservoir of viral infection and a site for immune dysregulation. In this study evidence of cytokine dysregulation in intestinal mucosa has been sought using the reverse transcriptase polymerase chain reaction (RT-PCR) to amplify cytokine mRNA. METHODS: RT-PCR was performed on intestinal biopsies obtained from 50 HIV-infected patients and 31 controls. Tissue was obtained at diagnostic endoscopy and total RNA extracted using an RNAzol technique. Following RT, cDNA was amplified using primers specific for beta-actin, interleukin (IL)-1 beta, tumour necrosis factor (TNF)-alpha, interferon (IFN)-gamma, IL-2, IL-4, IL-10 and IL-13. RESULTS: There was a significant increase in the expression of the proinflammatory cytokines IL-1 beta and IFN-gamma in the HIV-infected compared with the control small intestinal samples (P < 0.01). IL-10 was significantly reduced in the respective groups' large intestine (P < 0.02). The expression of IL-2 was also reduced in both the small and large intestinal HIV samples although this was not significant. IL-13 mRNA was only detected in one control patient. CONCLUSIONS: Dysregulation of cytokine gene expression occurs in the intestinal mucosa of patients with HIV infection and is characterized by increased expression of proinflammatory cytokine mRNA. Further studies are needed to localize the cellular origin of such dysregulation and to quantify the degree of abnormality. PMID- 7848594 TI - Predictors of disease progression in HIV-infected homosexual men with CD4+ cells < 200 x 10(6)/l but free of AIDS-defining clinical disease. AB - OBJECTIVE: To study progression of HIV infection in individuals who are free of AIDS-defining clinical disease with CD4+ cell counts < 200 x 10(6)/l. DESIGN: Prospective and nested case-control study. SETTING: Amsterdam cohort study on HIV infection, The Netherlands. PARTICIPANTS: Prospective study: 148 asymptomatic HIV infected individuals with < 200 x 10(6)/l CD4+ cells. Nested case-control study: 58 men with AIDS-free follow-up more than 2 years after CD4 count < 200 x 10(6)/l, compared with 63 who progressed to AIDS within 2 years. MAIN OUTCOME MEASURES: Progression to AIDS according to the 1987 Centers for Disease Control and Prevention case definition and death. RESULTS: Median AIDS-free interval was 22 months, median interval to death 41 months. Presence of syncytium-inducing (SI) HIV variants, HIV p24 antigen, and a low T-cell response after stimulation with phytohaemagglutinin (PHA) were independent predictors of progression to AIDS. Probability of 1 year AIDS-free survival varied between 89 and 38% by the presence or absence of these additional markers. Effect of early treatment could only be detected in men with HIV p24 antigen and SI variants. Case-control analysis showed similar changes over time regarding prognostic markers in both groups although at a lower rate in the AIDS-free men. Eight men remained AIDS free more than 4 years, SI variants were absent in seven, and all eight were p24 seronegative. CONCLUSIONS: HIV-infected individuals can remain disease-free for more than 4 years with very low CD4+ cell counts, provided that they lack other progression markers: SI variants, p24 antigen and a low PHA-induced T-cell reactivity. A beneficiary effect of early treatment may be limited to men with SI variants and/or p24 antigen. PMID- 7848596 TI - HIV infection among homeless adults and runaway youth, United States, 1989-1992. Field Services Branch. AB - OBJECTIVES: Homeless persons have an increased risk of HIV infection because of a high prevalence of HIV-related risk behaviors. These include drug use, sexual contact with persons at risk for HIV infection, and the exchange of sex for drugs. The objectives of this investigation were to describe HIV seroprevalence rates in homeless adults and runaway youth. METHODS: In 1989, the Centers for Disease Control and Prevention began collaboration with state and local health departments to conduct HIV seroprevalence surveys in homeless populations. Unlinked HIV seroprevalence surveys were conducted in 16 sites; 11 provided medical services primarily to homeless adults, and five to runaway youth aged < 25 years. RESULTS: From January 1989 through December 1992, annual surveys were conducted in 16 sites in 14 cities. Site-specific seroprevalence rates ranged from 0-21.1% (median, 3.3%). Among homeless adults in three sites, rates were higher among men who had sex with other men and those who injected drugs than among persons with other risk exposures (28.9 versus 5.3%). In general, rates were higher for heterosexual men than for women and higher among African Americans than whites. In sites providing services to homeless youth, HIV seroprevalence rates ranged from 0-7.3% (median, 2.3%). CONCLUSIONS: These data indicate that HIV infection among homeless adults and runaway youth is an important public health problem. HIV prevention and treatment should be integrated into comprehensive health and medical programs serving homeless populations. PMID- 7848595 TI - Incident HIV-1 infection in a cohort of young women in Butare, Rwanda. AB - OBJECTIVE: To determine the incidence of HIV-1 infection and associated risk factors among young, seronegative, and sexually active women in a mixed rural and urban population in southern Rwanda. DESIGN: A prospective cohort study. METHODS: Between October 1991 and April 1993, we completed a 2-year follow-up survey among HIV-1-seronegative women aged < or = 30 years at the time of their initial HIV-1 screening during pregnancy. All women aged < or = 25 years and a randomly selected sample of 26-30-year olds were invited to participate from five prenatal clinics in the Butare region. The interview focused on potential risk factors for HIV-1 acquisition during the 2-year interval between blood collection. RESULTS: Out of 1524 women selected, 1150 (75%) participated in the follow-up survey. The 2-year incidence of HIV-1 infection was 2.7% [95% confidence interval (CI), 1.8 3.9]. Teenage women were at the highest risk (incidence, 10.5%; 95% CI, 5.2 19.4), with incidence leveling off with increasing age (P < 0.001). Women who began sexual activity recently were also at higher risk; the lowest risk category consisted of women aged 26-30 years with 5 or more years of sexual experience. The more urban the geographic residence of the woman, the more likely she was to have acquired HIV-1 infection (P < 0.001). In the urban and peri-urban zones, the poorest women were at significantly higher risk of incident HIV-1 infection than women reporting higher household income. In a multivariate analysis, young maternal age, marital status (being single, divorced or widowed), multiple sexual partners, and a history of sexually transmitted diseases remained strongly associated with incident HIV-1 infection. Geographic residence, hormonal contraception, and receipt of injections were no longer significantly associated with incident HIV-1 infection when these other factors were accounted for simultaneously. CONCLUSION: Among young Rwandan women, the early years of sexual activity are particularly dangerous for acquisition of HIV-1 infection. Interventions should focus on young teenagers before they become sexually active. PMID- 7848597 TI - HIV testing in Switzerland. AB - OBJECTIVES: To obtain information about the prevalence of, reasons for, and adequacy of HIV testing in the general population in Switzerland in 1992. DESIGN: Telephone survey (n = 2800). RESULTS: Some 47% of the sample underwent one HIV test performed through blood donation (24%), voluntary testing (17%) or both (6%). Of the sample, 46% considered themselves well or very well informed about the HIV test. Patients reported unsystematic pre-test screening by doctors for the main HIV risks. People having been in situations of potential exposure to risk were more likely to have had the test than others. Overall, 85% of those HIV tested had a relevant, generally risk-related reason for having it performed. CONCLUSIONS: HIV testing is widespread in Switzerland. Testing is mostly performed for relevant reasons. Pre-test counselling is poor and an opportunity for prevention is thus lost. PMID- 7848599 TI - Estimating the number of HIV transmissions through reused syringes and needles in the Mbeya Region, Tanzania. AB - OBJECTIVE: HIV infection attributable to medical injections is suspected to be low, although case-control studies have not provided definite results. This study aims to determine the number of HIV infections caused by the reuse of syringes and needles in the Mbeya Region, Tanzania. METHODS: The direct identification or detection of HIV in syringes and needles under field conditions was not appropriate, therefore a surrogate marker consisting of two components for possible HIV transmission was used: insufficient sterilization, and blood remaining from a previous patient. The assumption was that HIV infection can only occur if both markers are positive. Samples were collected in nine health-care facilities. All syringes and needles prepared for use in these facilities were collected without prior notification. The samples were rinsed and the resulting fluid was cultured for bacteria. Traces of blood were detected by urine stick test for haemoglobin volumes > 0.0015 microliters. RESULTS: Bacterial contamination was found in 32.8% of the total 1219 syringes and needles; 67% was caused by improper handling of the equipment after sterilization. Blood was detected in 12.5% of the samples. In the following three sampling strata, both contamination criteria were positive either on the syringe or the needle: wards/outpatient departments (OPD), 1.39%; laboratories, 7.45%; expanded programme on immunization (EPI), < 0.1%. We calculated that from 1.1 million patients injected in wards/OPD in any 1 year, fewer than 13 become infected, in laboratories fewer than 12 (160,000 blood-taking procedures), and less than one child in the EPI (850,000 vaccinations). CONCLUSION: With an established AIDS intervention programme supporting the health system, less than 0.4% of the total annual incidence of 4500-8500 is attributable to medical injections in the Mbeya Region. PMID- 7848598 TI - Gonorrhea as a risk factor for HIV acquisition. AB - OBJECTIVE: The role of gonorrhea in facilitating acquisition of HIV infection has only recently been studied. A previous nested case-control analysis in a cohort of female sex workers in Zaire found a strong association between HIV seroconversion and prior gonorrheal infection. The objective of this study was to replicate the Zaire study analysis in a cohort of 273 Cameroonian sex workers to determine whether gonorrhea increased the risk of HIV acquisition, and if the crude association between gonorrheal infection and HIV acquisition was weakened when the level of unprotected coitus was more carefully controlled. METHODS: We conducted a nested case-control study of initially HIV-1-negative women (n = 273) followed prospectively (with monthly sexually transmitted disease check-ups and 3 monthly HIV-1 serology). As in Zaire, cases (seroconverters, n = 17) were compared with controls (women who remained HIV-1-negative, n = 68) for incidence of gonorrhea and sexual exposure during the presumed period of HIV-1 acquisition. RESULTS: The association between gonorrheal infection and subsequent HIV acquisition was stronger in Zaire than in Cameroon [crude odds ratios (OR), 6.3 versus 2.2]. In both the Zaire and Cameroon data the crude OR were reduced (6.3 to 4.8, and 2.2 to 1.7, respectively) by controlling for risk factors including a dichotomous variable indicating irregular or no condom use. When this variable was replaced in the Cameroon data with a more precise continuous variable indicating the percentage of unprotected coital acts, the gonorrhea OR was further reduced to 1.4 (95% confidence interval, 0.4-4.9). CONCLUSION: These results suggest that in the Cameroon cohort, gonorrheal infection did not facilitate HIV acquisition, but that having gonorrhea was a marker for unprotected coitus that facilitated HIV acquisition. The data demonstrate how OR can be overestimated when imprecise dichotomous measures of unprotected coitus are used. Future studies should plan for better control of self-reported condom use. PMID- 7848600 TI - HIV-2-infected patients survive longer than HIV-1-infected patients. AB - OBJECTIVE: To compare survival of patients infected with HIV-1 and HIV-2. DESIGN: Longitudinal follow-up of 175 HIV-1- and 294 HIV-2-infected patients identified in, or referred to a hospital in The Gambia. METHODS: Survival analysis methods were used and the death rate ratios for HIV-2 relative to HIV-1 patients were estimated using proportional hazard regression models that allowed for age, sex and clinical or immunological features. RESULTS: The overall death rate ratio for HIV-2 relative to HIV-1 was 0.67 [95% confidence interval (CI), 0.49-0.91] when adjusted for age, sex and World Health Organization Bangui clinical classification. When allowing for age, sex and three strata of CD4+ count, the rate ratio was 0.64 (95% CI, 0.43-0.94), and for three strata of beta 2 microglobulin levels 0.60 (95% CI, 0.42-0.84). CONCLUSION: Mortality rate in HIV 2-infected patients is approximately two-thirds of that for HIV-1-infected patients. PMID- 7848601 TI - CD4+ T-lymphocytopenia in HIV-infected patients receiving interferon therapy for chronic hepatitis C. HIV-Hepatitis Spanish Study Group. PMID- 7848602 TI - HIV-1MN recombinant gp120 vaccine serum, which fails to neutralize primary isolates of HIV-1, does not antagonize neutralization by antibodies from infected individuals. PMID- 7848603 TI - Early detection of HIV-1 in men from Kenya using a synthetic peptide and a p24 antigen enzyme-linked immunosorbent assay. PMID- 7848604 TI - Prevalence of HIV-1 subtype O infection in Cameroon: preliminary results. PMID- 7848605 TI - Sensitivity of screening kits for anti-HIV-1 subtype O antibodies. PMID- 7848606 TI - Accuracy of exposure assessment in prospective studies of risk factors for HIV infection among intravenous drug users. PMID- 7848607 TI - Reconstruction of subregional diffusion of HIV infection among injecting drug users in Southeast Asia: implications for early intervention. PMID- 7848608 TI - Marked impact of the expanded AIDS case definition in Spain. PMID- 7848609 TI - Use of doxycycline in the management of a patient with toxoplasmic encephalitis. PMID- 7848610 TI - Statistics from the Centers for Disease Control and Prevention. PMID- 7848611 TI - Glycoluril. AB - The crystal structure of glycoluril [tetrahydroimidazo-[4,5-d]imidazole 2,5(1H,3H)-dione, C4H6N4O2] has been determined. The molecule has two equivalent planes containing urea moieties, and hence exhibits C2v symmetry. The dihedral angle is found to be 124.1 (4) degrees. PMID- 7848612 TI - Structure of ascidiacyclamide as the ethanol water solvate, a cytotoxic cyclic peptide from Ascidian. AB - The X-ray crystal structure determination of the C2H5OH.H2O solvate of ascidiacyclamide (C36H52N8O6S2), a cytotoxic cyclic peptide from marine tunicate Ascidian, revealed a C2-symmetric saddle-shaped rectangular conformation of the molecule. The water and ethanol molecules are located on the crystallographic diad axis and are held by hydrogen bonds and van der Waals contacts with the polar ring N atoms and nonpolar D-Val side-chain atoms, respectively. The molecular conformation and the interaction with solvent molecules are nearly the same as those of the compound with C2H5OH.2H2O [Ishida, In, Doi, Inoue, Hamada & Shioiri (1992). Biopolymers, 32, 131-143]. PMID- 7848613 TI - (-)-Norcocaine. AB - The title compound, [2R,3S-(2 beta,3 beta)]-methyl 3-(benzoyloxy)-8 azabicyclo[3.2.1]octane-2-carboxylate, C16H19NO4, is a metabolite of the tropane alkaloid cocaine. The molecule crystallized as the free base with the piperidine ring in a chair conformation. The tropane ring system and its methoxycarbonyl and benzoyl groups are rigid; only rotational flexibility is allowed in the conformation of the substituents. PMID- 7848614 TI - Salt sensitivity of blood pressure in patients with 17 alpha-hydroxylase deficiency. AB - To clarify the salt sensitivity of blood pressure in 17 alpha-hydroxylase deficiency (17 alpha-HD), a mineralocorticoid-induced hypertension, we examined the responses of blood pressure to salt loading (250 mEq/day for 6 days) after salt restriction (25 mEq/day for 3 days) in two 17 alpha-HD patients who had markedly high plasma deoxycorticosterone (DOC) (5.27 and 6.59 ng/mL; normal, 0.08 to 0.28) and corticosterone (B) (93 and 357 ng/mL; normal, 0.35 to 8.42). In case 1, moreover, the same study was repeated when plasma DOC and B restored to almost normal with the dexamethasone treatment (1 mg/day) (0.34 and 0.45 ng/mL). Salt loading elevated mean blood pressure markedly in both patients (14% and 20%), associated with cumulative sodium retention and body weight gain. Hemodynamic study showed marked increases in cardiac output (25% and 69%), but only slight decreases in systemic vascular resistance with salt loading. On the other hand, the treatment with dexamethasone could attenuate the salt-induced increase in blood pressure (2%), accompanied by lesser sodium retention, body weight gain, and elevation of cardiac output (7%) in case 1. The slope of the renal function curve for sodium excretion was decreased in these patients, and was restored toward normal by dexamethasone in case 1. We conclude that the patients with 17 alpha-HD showed salt-sensitive hypertension due to excessive DOC and B, through the impaired renal function for sodium excretion, disproportionate increase in cardiac output, and inadequate vasodilation. PMID- 7848615 TI - Female preponderance for lisinopril-induced cough in hypertension. AB - In a double-blind double-dummy multicenter study, patients with mild to moderate essential hypertension were randomized to receive either nifedipine (n = 416, 47.6% women) or lisinopril (n = 412, 50% women), and side effects were registered by specific questioning, by spontaneous reports, and by use of visual analog scales. Cough was spontaneously reported to occur in 8.5% with lisinopril compared to 3.1% with nifedipine. Women treated with lisinopril reported cough spontaneously three times more often than men, 12.6% v 4.4%, whereas no differences between the sexes were observed during the placebo period or during nifedipine treatment. Similar gender differences were observed during specific questioning. Furthermore, nonsmokers reported an increase in cough more often than did smokers. PMID- 7848616 TI - Sustained volume expansion and [Na,K]ATPase inhibition in chronic renal failure. AB - Hypotheses regarding the pathogenesis of volume-dependent hypertension have invoked an endogenous sodium pump inhibitor or digitalis-like factor (DLF) to link altered sodium homeostasis to the rise in blood pressure. Our goal was to develop a clinical protocol that achieved predictable, sustained volume expansion, with the premise that renal failure patients on peritoneal dialysis would increase intravascular volume, gain weight, and raise blood pressure (BP) in relation to measured increases in DLF. In a 5-day protocol, dialysis was kept constant but dietary NaCl and fluids were modified in 7 patients. DLF was measured as inhibition of [Na,K]ATPase. Likewise, the first 2 L of daily peritoneal dialysate (PD) was processed on HPLC and the eluate analyzed for DLF. The group achieved significant weight gain (WT) by day 3 (delta WT = 4.1 +/- 1.2 kg, P < .05). Likewise, mean arterial pressure (MAP) and plasma DLF activity increased significantly. All variables were highly correlated (DLF v WT: R = 0.88, P = .004; MAP v DLF: R = 0.82, P = .01; MAP v WT: R = 0.90, P = .003). Although a number of HPLC fractions contained agents that interacted with the assay, only one PD HPLC fraction (at 19.5 min) contained DLF activity that correlated with changes in MAP (R = 0.60, P = .002), and body weight (R = 0.67, P = .0003). We conclude that candidate DLF responds to sustained volume expansion and the relationship suggests that it could influence blood pressure. Moreover, the application of stringent criteria to the confusing array of factors in plasma that may affect assays for DLF appears to reduce the field dramatically, to a single candidate in this setting. PMID- 7848617 TI - Up-regulation of hepatic LDL receptor gene expression by monatepil, a novel calcium antagonist, in high cholesterol diet-fed Japanese monkeys. AB - The action of the novel antihypertensive calcium antagonist monatepil on the hepatic LDL receptor was investigated at the gene expression level to clarify the mechanism of its hypolipidemic effect. In cholesterol-fed control monkeys, the LDL receptor mRNA level decreased to approximately 30% of that in the normal diet fed monkeys. However, the administration of monatepil increased LDL receptor mRNA to normal levels (three- to fourfold stimulation). It is suggested that monatepil raises the number of LDL receptors in liver tissue and that this increase may accelerate the removal of plasma LDL. Treatment with prazosin, an alpha 1 adrenoceptor antagonist, also increased the LDL receptor mRNA level, but this restorative effect was much weaker than that of monatepil, suggesting that mechanisms additional to its alpha 1-adrenoceptor blocking activity are involved in the hypolipidemic effect of monatepil. PMID- 7848618 TI - Blood pressure monitor-induced petechiae and ecchymoses. AB - A case is presented of a diabetic, hypertensive, female patient who suffers from a bleeding complication from application of an ambulatory blood pressure monitor. A recent literature search is referred to and practitioners are cautioned against this adverse reaction. PMID- 7848619 TI - Antihypertensive effects of the neutral endopeptidase inhibitor SCH 42495 in essential hypertension. AB - The antihypertensive effects and safety of a novel neutral endopeptidase inhibitor, SCH 42495, were investigated in hypertensive patients. A multicenter, open clinical trial was conducted in 27 patients with essential hypertension, WHO Stage I or II. Mean age was 64 +/- 1 years. After 2 to 4 weeks of a placebo run in, 50 mg twice daily, was started, with the dose increased to 100 mg twice daily, and 200 mg twice daily, every 2 weeks, if necessary, to achieve a predetermined response. Blood pressure and pulse rate were monitored every 2 weeks. Blood chemistry, plasma atrial natriuretic peptide (ANP), and plasma cGMP levels were determined before and after the 8-week treatment period. Blood pressure was significantly reduced, from 171 +/- 1/100 +/- 1 mm Hg to 146 +/- 3/84 +/- 2 mmHg (P < .001) at the end of the 8-week treatment period. No change in pulse rate was noted. Efficacy rate was evaluated in 25 patients treated for 4 weeks or more. Efficacy rate was 44% with 50 mg twice daily, 60% with 100 mg twice daily, and 80% with 200 mg twice daily. Adverse reactions such as headaches and palpitation were observed in six patients (22.2%), with treatment discontinued in five. Significant correlation was observed between increment in plasma ANP levels and blood pressure reductions (r = -0.53, P < .05). Increase in plasma cGMP was positively correlated with increments in plasma hANP (r = 0.80, P < .001). SCH 42495 has potent antihypertensive effect associated with an enhancement of endogenous hANP and may be clinically useful as a new class of antihypertensive drug. PMID- 7848620 TI - Gender differences in insulin-stimulated glucose utilization among African Americans. AB - The purpose of this study was to determine whether there are gender differences in plasma insulin levels or insulin resistance in young adult African-Americans. Male (n = 53) and female (n = 45) subjects (age 23 to 28 years) included normotensives (N, blood pressure [BP] < 135/85 mm Hg) and borderline hypertensives (BH, BP > 135/85 mm Hg). Plasma insulin concentration was measured during an oral glucose tolerance test (OGTT) in all subjects. In 50 cases, insulin clamps were performed. Plasma estradiol and free testosterone were analyzed in a subsample (n = 15) of women. Data were analyzed for BP and gender groups by two-way ANOVA. Compared to men, women in each BP group had higher plasma insulin: glucose ratios (P < .01) and sums of insulin on OGTT (P < .02). The insulin clamp data also demonstrated significantly lower insulin-stimulated glucose utilization (M) in women compared to men in each BP group (N males 7.28 +/- 0.72 v N females 4.94 +/- 1.2 mg/kg-min; BH males 5.28 +/- .56 v BH females 2.59 +/- 0.50 mg/kg-min; P < .004 for gender differences). Analysis of the sex hormone data found a significant correlation in the ratio of free testosterone/estradiol (T/E) with plasma glucose, insulin, insulin/glucose, and systolic BP (P < .05), and no correlation of T/E with body mass index or triceps skinfold thickness. These data indicate that there are significant gender differences in plasma insulin levels and in insulin sensitivity in African Americans. The relationship of plasma insulin to sex hormones suggests that in females, hyperinsulinemia cosegregates with increased androgenicity. PMID- 7848621 TI - Altered phospholipid fatty acid content and metabolism in heart cell cultures from newborn spontaneously hypertensive rats. AB - Genetic hypertension has been proposed to be associated with impaired lipid metabolism. To investigate whether lipid metabolism is altered in young rats of the spontaneously hypertensive Okamoto strain (SHR), we have compared the phospholipid fatty acid content and metabolism in cultured heart myocytes and fibroblasts from SHR and normotensive Wistar-Kyoto (WKY) newborn rats. The phospholipid-bound fatty acid profile and metabolism were altered in SHR cardiomyocytes and unchanged in SHR fibroblasts. In SHR myocytes, the fatty acid composition of the phospholipid fraction was modified, with a lowered proportion of linoleic (P < .05) and eicosapentaenoic acid (P < .001), resulting in a decreased polyunsaturated to saturated fatty acid ratio (1.16 +/- 0.08 in SHR v 1.44 +/- 0.08 in WKY, P < .02). The metabolism of radioactive arachidonate (C20:4) and linoleate (C18:2) also differed between SHR and WKY myocytes. Their release was increased (P < .004 and .05 for C20:4 and C18:2, respectively). The labeled phospholipid species also differed between the two strains, suggesting an altered phospholipid turnover in SHR. This study demonstrates modifications of phospholipid fatty acid profile and metabolism in spontaneously contractile cardiac cells from newborn prehypertensive SHR, in the absence of neural, hormonal, and hemodynamic influences. PMID- 7848622 TI - Influence of extracellular volume expansion on circulating PTH1-84 in subjects with mild essential hypertension. AB - The effect of acute volume expansion by saline (1 L/40 min) on serum parathyroid hormone (PTH) concentration was studied in 28 subjects with mild essential hypertension. At the zenith volume expansion there was a significant increase in systolic pressure (7 +/- 2 mm Hg, P < .01) while diastolic pressure and heart rate showed minor (NS) variations. The rise in systolic pressure was accompanied by a significant (P = .02) decrease in plasma ionized calcium (from 1.12 +/- 0.03 to 1.08 +/- 0.03 mmol/L) and by a marked PTH increase (from 36 +/- 3 to 60 +/- 4 pg/mL, P < .01). The arterial pressure variations were independent of changes in serum PTH. In a second experiment (n = 11), aimed at preventing the changes in calcium concentration brought about by hemodilution, we infused the same volume of saline with the addition of 1.25 mmol of elemental calcium. In this study PTH showed a small, nonsignificant, decrease while systolic pressure changes were similar to those of the first study (ie, an isolated 9 +/- 4 mm Hg increase in systolic pressure). In a third experiment (n = 7), aimed at studying the effect of raised plasma PTH concentration in isocalcemic conditions, PTH1-38 was continuously infused (1 ng/kg/min) during the volume expansion phase performed with the same solution as used in the second experiment. The hemodynamic changes were again identical to those of the other studies (an isolated 9 +/- 3 mm Hg increase in systolic pressure).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7848623 TI - Urinary albumin and N-acetyl-beta-D-glucosaminidase excretions in mild hypertension. AB - Renal effects of mild hypertension and therapy have not been established. Since urinary albumin and N-acetyl-beta-D-glucosaminidase excretions reflect renal effects of hypertension, they were related to blood pressure, other cardiovascular risk factors, cardiac target organ effects, and response to therapy in mild hypertension (diastolic blood pressure 85-99 mm Hg). Participants were from two clinics of the Treatment of Mild Hypertension Study (TOMHS), a multicenter randomized, double-blind, controlled trial. Participants received nutritional-hygienic therapy and one of five active drugs or placebo. Urinary albumin and N-acetyl-beta-D-glucosaminidase excretions were assessed prospectively using office "spot" collections from one clinic (n = 213) and retrospectively using overnight collections from the other clinic (n = 210). Relationships were determined between protein excretions and blood pressure, age, gender, race, blood glucose, cholesterol concentrations, and indices of body mass and left ventricular mass and function at baseline. Treatment effects were assessed after 3 to 12 months. Spot and overnight albumin excretions related positively to baseline systolic blood pressure by univariate analyses. Spot albumin excretion related positively to systolic blood pressure, age, creatinine clearance, and left ventricular function while overnight albumin excretion related positively to left ventricular mass and female gender by multiple regression analyses. Spot, but not overnight, albumin excretion declined significantly with active drug therapy. N-acetyl-beta-D-glucosaminidase excretion did not relate to blood pressure or decline with therapy. The combined results suggest albumin excretion correlates with blood pressure, decreases with antihypertensive drug therapy, and is associated with greater left ventricular function and mass, as well as glomerular filtration rate, even at mild levels of hypertension. PMID- 7848624 TI - Cardiovascular effects of orally administered ABBOTT-81988, an angiotensin II antagonist, in conscious spontaneously hypertensive rats. AB - ABBOTT-81988 (A-81988), 2-(N-propyl-N[(2'-[1H-tetrazol-5-yl]biphenyl- 4yl)methyl] amino) pyridine-3-carboxylic acid, a nonpeptide angiotensin II (AII) antagonist was studied in the conscious spontaneously hypertensive rate (SHR) (male, 18 to 21 weeks) for cardiovascular effects of oral administration. Oral A-81988 at 0.3 to 3 mg/kg produced a dose-related 10 to 29% decrease in mean arterial pressure (MAP) in SHR (control, 161 to 177 mm Hg; n = 19) for 12 to 24 h without changing heart rate. Oral A-81988 at 3 mg/kg daily maintained MAP in SHR at normotensive levels (97 to 120 mm Hg) during a 5-day protocol with no rebound hypertension at termination of treatment. There was an increase in plasma renin activity in nanograms AI/milliliter/hour in SHR treated with A-81988 (32 +/- 3, n = 6 v 5 +/- 2, n = 6 for vehicle) during its antihypertensive action. The oral potency of A 81988 was enhanced about 10-fold in furosemide-treated SHR. The pressor response to AII was inhibited selectively in SHR even after an 8-day treatment with A 81988 (approximately 3 mg/kg/day orally). Total peripheral resistance was lowered and cardiac output unchanged in SHR administered A-81988 (3 mg/kg/day orally for 2 days). A-81988 (3 mg/kg orally) did not cause orthostatic hypotension in SHR.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7848625 TI - Antihypertensive effects of 2-octynyladenosine (YT-146), a selective adenosine A2 receptor agonist, in Dahl salt-sensitive rats. AB - The antihypertensive effects of a novel adenosine A2 receptor agonist, 2-octynyl adenosine (YT-146), were evaluated in Dahl salt-sensitive rats. After rats were fed a high-salt (8% NaCl) diet for 2 or 3 weeks, they received oral YT-146 (0.1 or 1.0 mg/kg) or vehicle as a single dose (acute study) or once daily for 10 days (chronic study). In the acute study, tail-cuff blood pressure (BP) and pulse rate (PR) were measured before and 3, 6, and 24 h after administration, and blood samples were collected 3 h after administration. In the chronic study, BP and PR were measured 3 and 24 h after administration and urine was collected for 24 h on day 9. Blood samples were also collected 3 h after administration on day 10. BP was significantly lowered by 1.0 mg/kg of YT-146 in either the acute study (from 184 +/- 3 to 152 +/- 5 mm Hg, P < .01) or the chronic study (from 226 +/- 4 to 201 +/- 2 mm Hg, P < .01), while an increase in PR was not observed (acute study: from 382 +/- 8 to 366 +/- 3 beats/min; chronic study: from 420 +/- 8 to 411 +/- 8 beats/min). YT-146 had no effect on plasma renin activity (PRA), plasma aldosterone, vasopressin (ADH), and atrial natriuretic peptide (ANP) in the acute study.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7848626 TI - Accuracy of single concentration estimations of platelet angiotensin II receptor number. Its usefulness in screening for pregnancy-induced hypertension. AB - Platelet angiotensin II (AngII) receptor number has been suggested as a screening test for pregnancy-induced hypertension. However, markedly different false positive rates have been reported, perhaps the result of differing methods used. We sought therefore to compare the two methods. Platelet AngII receptor number was determined by saturation analysis with computerized curve fitting and specific binding at a single radioligand concentration. The two methods were compared by correlation and by plotting their differences v their means, to determine their limits of agreement. There were significant correlations between the value obtained by saturation analysis and each of the three single ligand concentrations studied (1 nmol/L, P < .001; 500 pmol/L, P < .001; and 250 pmol/L, P < .01). However, for none of the three did the regression line approach the line of equality. Assessment of agreement by comparing differences and means for each subject showed increasing scatter with increasing receptor number and 95% confidence intervals too large to be clinically relevant. We conclude that the receptor number estimated from specific binding at one ligand concentration differs significantly from that obtained by saturation analysis. The limits of agreement of the two methods are wide and we urge caution in the use of single ligand concentration methods for estimating binding site densities. PMID- 7848627 TI - [Biopharmaceutics and pharmacokinetics. 10. Integration of the two concepts: A. Monocompartmental models]. PMID- 7848628 TI - The body of a trial master file for a pivotal phase I study. AB - This paper describes in detail the documentation which would form the body of a Trial Master File for Phase I pivotal investigations filed to render easily and totally auditable all the documentation. The body of a Trial Master File is formed by formal documents (study protocol, research report), by documents to be attached to the research report (clinical report, analytical validation report, statistical report, blank case report form, blank consent form, approval from Ethics Committee), by documents to be kept in file (investigator's brochure, clinical source documentation, clinical trial supplies, filled case report forms, monitoring reports, auditing reports, letters, contracts, faxes, phone notes) and by confidential documents that must be filed in the Clinical Unit only (signed consent forms which contain the subjects' identification). PMID- 7848629 TI - Determination of ketorolac in blood and plasma samples by high-performance liquid chromatography. AB - A new method for determination of ketorolac in blood or plasma samples by reversed-phase high-performance liquid chromatography has been developed. The method includes a double extraction with diethyl ether and detection by absorbance at 313 nm. Quantitation was performed by height ratios of ketorolac and the internal standard (sodium tolmetin). Detection limit of the method was 3 ng/ml using 1 ml of plasma and 10 ng/ml using 0.2 ml of blood. The method is linear in the range of concentrations typically obtained after therapeutic doses of the drug, has the advantages of using low volume of body fluid and the internal standard used is commercially available. Those characteristics allow us to conclude that this method is suitable for pharmacokinetic or drug monitoring studies. PMID- 7848630 TI - Forum: surveillance of surgical site infections. PMID- 7848631 TI - Forum: surveillance of surgical site infections. PMID- 7848632 TI - Notes from the ninth international conference on AIDS. PMID- 7848633 TI - Forum: surveillance of surgical site infections. PMID- 7848635 TI - Forum: a perspective on hepatitis. PMID- 7848634 TI - Are universal precautions (UPs) up for question? PMID- 7848636 TI - Forum: a perspective on hepatitis. PMID- 7848637 TI - Focus on Chile. PMID- 7848638 TI - Multiresistant Staphylococcus aureus (MRSA): the Chilean experience. PMID- 7848639 TI - Endoscopic sinus surgery. AB - Endoscopic nasal surgery has become the single major advance in the specialty of otolaryngology since the introduction of the operating microscope and middle ear surgery. The value of improved assessment of nasal and sinus pathology using the endoscope diagnostically cannot be overstated. Once pathology is better evaluated, therapy will at least be more appropriate. It is now possible to carry out such nasal surgery as polypectomy, antrostomy and turbinoplasty more accurately and more safely, as well as provide better postoperative care. The use of the endoscope has afforded a useful sub-cranial route for the repair of at least small cerebrospinal fluid leaks, while it is likely that such procedures as dacrocystorhinostomy will eventually be mostly performed using the nasal endoscope. Some orbital decompressions will also be suitable for medial orbitotomy via the endoscope. Additionally, assessment of the extent of extrusion of orbital contents after blow-out injury has been invaluable, as is evaluation of the posterior wall of the frontal sinus after frontal bone trauma. Functional endoscopic sinus surgery (FESS) has an undoubted place in the surgery of frontoethmoidal mucocoeles. While few oncologists would be sanguine about its use in the surgery of nasal tumors, it is still of great value in evaluation and biopsy. Although FESS confined to the osteomeatal complex in the presence of early sinus disease is almost certainly an advance, what is still not proven, is the place of endoscopic sphenoethmoidectomy in the treatment of chronic rhinosinusitis. PMID- 7848640 TI - Superoxide dismutase in in vitro cultures of middle ear fibroblasts from the rabbit. AB - The present study was undertaken to establish whether intra- and extracellular concentrations of the antioxidative enzyme superoxide dismutase (SOD) in cultures of rabbit middle ear and skin fibroblasts were affected by increasing normal oxygen tensions from 7% to 21% and cause structural damage. The DNA amount was measured fluorometrically and intra- and extracellular concentrations of SOD were determined spectrophotometrically by the inhibition of formazan absorbance. Results demonstrated that SOD was located primarily intracellularly in middle ear fibroblasts and that exposure to atmospheric air gave rise to a significant increase in the SOD concentration from the 6th day following altered oxygen tension (P < 0.0044). Extracellular SOD was sparse in cultures at 7% oxygen whereas atmospheric air induced a significant increase in formazan absorbance from 5% to 60% (P < 0.0163). Inhibition studies indicated that the latter was partly the result of compounds with reducing capabilities similar to superoxide anions. These findings suggest that exposure of middle ear fibroblasts to atmospheric air may involve generation of oxygen-derived free radicals in vitro as well as in vivo but the complexity and significance of these changes need further investigation. PMID- 7848641 TI - Histamine and leukotriene C4 effects on in vitro ciliary beat frequency of human upper respiratory cilia. AB - Decreased mucociliary transport can occur in patients with type I (IgE-mediated) allergic rhinitis or allergic asthma. This study investigated if the allergic mediators histamine and leukotriene C4 (LTC4) could interfere with ciliary beat frequency (CBF) of in vitro human upper respiratory cilia and eventually result in decreased mucociliary transport. Ciliated epithelium of human adenoid tissue was used in the experiments and CBF was determined using a computer-assisted photoelectric method. Histamine in concentrations of 10(-6) - 10(-3) M (n = 12) and LTC4 as 10(-9) - 10(-6) M solutions (n = 10) showed no statistically significant dose-dependent effect on CBF in vitro. PMID- 7848642 TI - Clinical experiences with surgical techniques and treatment results in patients undergoing subtotal laryngectomies. AB - After a period of critical evaluation, subtotal laryngectomies are now considered to be valuable additions to the surgical management of laryngeal neoplasms. It is now possible to obtain good functional and oncological results in treating clinical situations that until a few years ago appeared curable only by radical surgery. We now report our clinical experiences with Labayle and Majer-Piquet types of subtotal laryngectomies and discuss indications and contra-indications to such surgery. Our current preference is to use Labayle technique, since it permits better functional recovery and a shorter clinical course. PMID- 7848643 TI - Clinical experiences with surgical therapy of cervical metastases from head and neck cancer. AB - Indications for the various techniques of neck dissection can undergo substantial variations according to the metastatic picture found, biological aggressiveness of tumor, nodal volume and personal philosophies of the attending clinician. In the present paper we report our clinical experience with radical neck dissections, "functional" neck dissections and selective neck dissections-in total, 1658 neck dissections carried out between 1976 and 1991. We discuss the indications and contra-indications of the various surgical techniques of neck dissection and evaluate the long-term results. Our current preference is to use the Suarez-Bocca "functional" technique of neck dissection for prophylactic treatment of the neck and for therapeutic treatment of the neck when intracapsular metastases already exist. PMID- 7848644 TI - Multiple metachronous skin squamous cell carcinomas and epidermodysplasia verruciformis in the head region: a human papilloma virus-associated disease. AB - Data from a young adult man with epidermodysplasia verruciformis (EV) and multiple metachronous spinaliomas in the head and neck region are presented. Diagnosis of this rare, human papilloma virus (HPV)-associated disease was based on: (1) Typical skin lesions, including viral warts, verruca plana-type lesions and pityriasis versicilor; (2) typical histological features, including "foamy giant keratinocytes"; (3) evidence of HPV 5, 8 and 20 in pityriasis versicilor like lesions; (4) a cellular immunodeficiency due to a relative T-helper-cell deficit. No specific treatment of EV is known, so that therapy concentrates on early removal of spinaliomas and treatment of intercurrent infections. Since EV patients have numerous benign skin lesions and frequently develop metastatic and non-metastatic carcinomas, molecular changes of HPV during carcinogenesis can be studied. PMID- 7848645 TI - Absence of HIV-1 DNA in cartilage from HIV-positive patients. AB - Human immunodeficiency virus (HIV) infections are mainly transferred by blood, semen or organ transplantations. Since allogenic transplants have an established place in reconstructive surgery, the possibility of transferring HIV with such transplants has been a subject of much concern. Postmortem cartilage samples were obtained from eight HIV-infected patients and examined using the polymerase chain reaction in order to detect proviral HIV-1 DNA (gag, pol, env). Blood, brain and spleen samples were also obtained and used as positive controls. Results showed that no cartilage sample contained any HIV-DNA, whereas proviral sequences were clearly demonstrated in perichondrium from six patients. These findings indicate that HIV is not present in cartilage of HIV-infected patients, making HIV transmission through cartilage grafting improbable when transplants from HIV negative donors are used. PMID- 7848646 TI - Role of skull base surgery for local control of sarcoma of the nasal cavity and paranasal sinuses. AB - Sarcomas of the nose and paranasal sinuses are rare neoplasms and comprise less than 1% of the malignancies arising in the sinonasal tract. From 1977 to 1989, we had the opportunity to treat 15 patients presenting with these tumors at The Eye & Ear Institute of the University of Pittsburgh. The clinical charts of these patients were reviewed retrospectively for demographic data, characteristics of disease, treatment considerations and clinical outcome. Data were also analyzed with special attention to the role of skull base surgery for the local control of tumors. Seven patients underwent cranial base surgery as part of their original therapy. Two of these patients are alive with no evidence of disease, one patient died of other causes, and four are dead of disease. Two patients died with local disease. Although not statistically significant due to the small number of patients, these data suggest that cranial base surgery can improve the local control of sarcomas of the sinonasal tract that approach or invade the skull base. PMID- 7848647 TI - Morphological changes in the tectorial and basilar membranes of aged rats. AB - Using both light and transmission electron microscopy presbycusic degeneration of the cochlea was observed in particular in the tectorial and basilar membranes, in naturally aged rats. These animals showed a descending auditory pattern as determined by auditory brainstem response. Ultrastructurally, the number of collagen fibers in the tectorial membrane was reduced and straight type A fibers were increased relative to branched, coiled type B fibers. The basilar membrane in the basal turn was also thickened by an increased homogeneous ground substance. These findings indicate that the specificity of vibration of the tectorial and basal membranes is very different in aged and young rats. PMID- 7848648 TI - Effect of perchloroethylene inhalation on nasal mucosa in mice. AB - An experimental group of 16 male pure-bred mice was exposed to perchloroethylene gas at 300 ppm for 6h daily for 5 days. Histopathological study of the nasal mucosa was performed sequentially 1, 2, 4, and 7 days after exposure. Erosion of the olfactory epithelium and dilatation of Bowman's glands were observed from 1 to 7 days after exposure. Atrophy of the olfactory nerves was observed from 4 to 7 days after exposure. At 4 days after exposure, regenerating epithelial cells were observed, indicating that these cells represented the first step of the repair process after exposure. Nonetheless, epithelial degeneration in the nasal mucosa without erosion was observed for 4-7 days after exposure. Such epithelial lesions were more severe in the olfactory mucosa and appeared earlier than in other sites in the respiratory mucosa. The present study revealed that perchloroethylene gas exerted a more potent harmful action on the olfactory mucosa than on the general respiratory mucosa. PMID- 7848649 TI - The effect of lymphocytic infiltration on clinical survival in cancer of the tongue. AB - Many factors have been claimed to influence the clinical prognosis of cancer of the tongue, one of them being the inflammatory response at the advancing tumor border. In a retrospective study of 60 patients with squamous cell carcinoma of the oral tongue, lymphocytic peritumoral inflammation was not found to be an objective prognostic marker. PMID- 7848650 TI - Castleman's disease as a uncommon cause of a neck mass. AB - Castleman's disease is an uncommon cause of a neck mass; in only 6% of the cases reported in the literature was the disease located in the neck. We present the case of a 21-year-old woman who developed a swelling in the left side of her neck that was subsequently diagnosed as Castleman's disease. The different forms of the disease and its histopathology are discussed. PMID- 7848652 TI - Magnetic resonance imaging of the cardiovascular system. PMID- 7848651 TI - A simple instrument for endoscopic laryngeal and pharyngeal surgery. AB - A simple suture instrument for endoscopic microlaryngeal surgery is presented. It is made from a common sewing machine needle that is soldered in a 25 cm pipe-like holder and is slightly bent near the point. The needle tip is so threaded that the thread can pierce through both edges of a wound following placement with an endoscopic tube. The thread is held by a forceps, the instrument withdrawn and the suture knotted. In practice, wounds can be sutured very quickly, easily and comfortable. An example of its application is use of the instrument to shorten significantly and simplify the performance of endoscopic arytenoidectomy. PMID- 7848653 TI - [Contribution to the prenatal diagnosis of congenital cardiopathies]. AB - After concluding a local teaching program to obstetric echographists about prenatal diagnosis of congenital heart disease (CHD), we compared 2 periods of activity in fetal echocardiography, that before, lasting 3 and one half years (G.I) and the other 6 months after (G.II). During the second period 20 newborn consecutively admitted with CHD (G.III) were also studied. Teaching program protocol for the 10 district hospitals visited is described. The results show a rise from 25 to 58 foetus per month observed, comparing the two periods, being 4 and 7% respectively those referred with suspicion of CHD, and 54 and 33% the obstetric accuracy. Total incidence of CHD was 4,2%, 41 in G.I and 6 in G.II. Types of CHD, treatment and evolution are described, being the mortality 68 and 50% respectively. Of the 20 newborn from G.III, 90% had no prenatal diagnosis of CHD, being 30% high risk pregnancies. Mortality in this group was 20%, 50% in the newborn from high risk pregnancies; eight newborns were operated on without mortality, 5 to aortic coarctation and 2 with arterial switch for transposition. It is concluded the necessity of continuing teaching programs so that prenatal diagnosis of CHD may improve and the care of the newborn may so be anticipated and ameliorated. PMID- 7848654 TI - [Value of transesophageal echocardiography in the assessment of blunt chest trauma: correlation with electrocardiogram, heart enzymes, and transthoracic echocardiogram]. AB - OBJECTIVE: To asses the feasibility, usefulness and clinical rentability of the transesophageal echocardiography (TEE) in the evaluation of patients suffering a severe blunt chest trauma as well as to correlate the TEE findings with those provided by the conventional electrocardiogram (ECG), cardiac isoenzymes assay and transthoracic echocardiography (TTE). DESIGN: Prospective study using ECG, blood cardiac enzymes assay, TTE and TEE. SETTING: Intensive care unit of a general hospital. PATIENTS: We studied 34 patients admitted with blunt chest trauma and suspected cardiac contusion in spite of the existence of other traumatic injuries in some of them. There were 23 (67.6%) males and 11 females, with a mean age of 37.1 +/- 19.4 years (range: 16-69 years). MATERIAL AND METHODS: Patients with a previous history of cardiovascular or chronic pulmonary disease, cardiac arrest upon admission or positive cocaine or amphetamine levels in the urine were excluded from the study. Suspected cardiac contusion was established by clinical data, electrocardiographic findings, enzymes blood values (CPK-total and MB-fraction) and TTE findings. Additionally, a TEE was performed in each patient. Patients were stratified into two groups according to the TEE findings: Group A patients had signs compatible with cardiac contusion and in Group B patients there was a lack of evidence to substantiate this diagnosis. Those tests were evaluated in respect to their accuracy in the diagnosis of cardiac contusion when compared to transesophageal echocardiography and TEE findings were compared, whenever possible, to surgical or necropsic findings. RESULTS: We found TEE signs of cardiac injury in 22 (64.7%) patients and a wide spectrum of traumatic cardiac abnormalities were identified. TEE signs of ventricular injury were found in 15 pts of Group A (68.2%) being the right ventricle the most frequent affected. There were also two cases of mitral leaflet rupture, one case of tricuspid valve prolapse (with severe tricuspid regurgitation and associated with right ventricle wall motion abnormalities) and seven cases of pericardial effusion as well as one case of thoracic aortic dissection. In every patient submitted to cardiothoracic surgery or necropsy the TEE findings were confirmed. TEE provided significant information, sometimes crucial, to the patient evaluation and management, it was performed without any difficulty and it doesn't carried out any related complication. TTE was technically suboptimal in 53% and fail to demonstrate many cases of cardiac contusion and the thoracic aorta lesion, being the number of cardiovascular injuries demonstrated by TEE significantly higher (p = 0.029). No statistically significant difference was found between the number of patients with either an abnormal ECG or high values of CPK-MB in each group. Neither clinical findings, cardiac enzymes values, serial ECG's nor TTE predicted all the patients who had traumatic cardiac injury and those would subsequently developed complications related to cardiac contusion. CONCLUSIONS: A severe blunt chest trauma frequently results in cardiac injury. The ECG and the CPK-MB measurements appears both to be fairly sensitive and specific tests in the cardiac contusion diagnosis. TTE has shown to have important limitations in these patients, thus not allowing neither a complete echo evaluation nor a reliable one. TEE plays an important role in the evaluation and management of this type of patients providing rapid diagnostic information and being of high value in the rule out cardiac contusion as well as in the establishment of a specific diagnosis of cardiac and/or thoracic aorta injuries with a consequent better assessment and treatment strategy in these patients. PMID- 7848655 TI - [Pulse wave velocity as initial marker of atherosclerosis]. AB - OBJECTIVE: To evaluate the influence of hypercholesterolaemia on arterial distensibility. MATERIAL AND METHODS: 43 male New Zealand White rabbits, with similar ages and weights, were included in the present study. The animals were divided in two groups: Group A (n = 15) was fed a normal diet; Group B (n = 28) was fed normal diet plus 0.1% cholesterol. at the beginning and after 6 and 9 months, blood samples were obtained for determination of serum cholesterol (total, esterified, LDL) and Triglyceride levels. Pulse wave velocity (PWV) was also evaluated, by mecanography, after 6 and 9 months of the beginning of the experiment. After 6 months (Group A = 4 and Group B = 7) and 9 months (Group A = 6 and Group B = 7) of the experiment, some animals were killed for anatomopathological studies. RESULTS: Major differences were obtained between the two groups, specially in what concerns to LDL and cholesterol levels (p < 0.001). There was also a remarkable difference in PWV between the two groups (6.078 +/- 0.162/9.002 +/- 0.196 m/s at 6 months and 7.639 +/- 0.590/9.557 +/- 0.543 m/s at 9 months) from the rabbits fed normal or cholesterol diet, respectively. The anatomical lesions were only significant after 9 months. However there was a decrease in aorta internal diameters at thoracic and renal levels at 6 months (34% and 53%) and at 9 months (29% and 33%), without significant changes in their thickness. In the heart, the left ventricle (LV) had a significant thickness increase after 6 months (about 43%). CONCLUSIONS: These data indicate that even before anatomical lesions had occurred, important functional changes are present, in the arterial wall. Then, the evaluation of the PWV could be a promising non invasive diagnostic method of early atherosclerosis, with obvious implications concerning its prophylaxis and therapy. PMID- 7848656 TI - [Pacemaker implantation in a patient with persistent left superior vena cava and atresia of the right superior vena cava]. AB - Persistent left superior vena cava with absence or atresia of right superior vena cava is a congenital abnormality of systemic venous return to the heart which may complicate the insertion of a pacemaker electrode. We present a case report of a patient with conduction system disturbances in whom this abnormality was diagnosed during pacemaker implantation, with the possibility of using a transvenous electrode without active fixation system. PMID- 7848658 TI - Notes on protozoa in agricultural soil with emphasis on heterotrophic flagellates and naked amoebae and their ecology. AB - Heterotrophic flagellates and naked amoebae are usually very numerous in agricultural soils; with numbers in the magnitude of 10,000 to 100,000 (active+encysted) cells per gram of soil. In 'hotspots' influenced by living roots or by dead organic material, the number may occasionally be as high as several millions per gram of soil. An exact enumeration of these organisms is virtually impossible. As they most often adhere closely to the soil particles, direct counting will underestimate numbers since the organisms will be masked. The method usually applied for enumeration of these organisms, the 'most probable number (MPN) method', is based on the ability of the organisms to grow on particular culture media. This method will in many cases underestimate the total protozoan number (active+encysted). It is uncertain how many of the heterotrophic flagellates and naked amoebae are actively moving and how many are encysted at a particular time; the 'HCl-method' which has usually been used to discriminate between active and encysted has proven to be highly unreliable. Despite the methodological difficulties many investigations of these organisms indicate that they play an important role in agricultural soils as bacterial consumers, and to a minor extent as consumers of fungi. Because of their small size and their flexible body they are able to graze bacteria in small pores in the soil in which larger organisms are precluded from coming. Key factors restricting the number and activity of heterotrophic flagellates and naked amoebae in soils seem to be water potential and soil structure and texture. In micro-cosm experiments, small heterotrophic flagellates and naked amoebae regulate the size and composition of the bacterial community. Bacterial activity seems to be stimulated by these organisms in most cases as well as the mineralization of carbon and nitrogen and possibly other mineral nutrients. In the rhizosphere of living plants the activity of protozoa has proven to stimulate uptake of nitrogen in pot experiments, and it has been hypothesized that organic matter liberated by plants in the root zone will stimulate bacterial and protozoan activity, leading to mineralization of organic soil nitrogen which is subsequently taken up by the plants. PMID- 7848657 TI - [Molecular pathobiology in heart failure]. AB - Heart failure is a pathophysiological state resulting from disturbed cardiac function. It is based on complex molecular processes, many of which are not fully understood. During heart failure adaptive mechanisms, that reinstall altered cardiac function, are activated. The main mechanisms are: a) Alteration of the structure and composition of myocytes by myocardial hypertrophy, reexpression of fetal and neo-natal proteins and the expression of certain proto-oncogenes; b) Activation of the neuroendocrinal system, specifically the sympathetic nervous system, renin-angiotensin-aldosterone system and vasopressin release; c) Activation of autocrine and paracrine systems. However, when these systems are activated beyond a certain limit they contribute to heart failure aggravation. This can also be promoted by alteration of the calcium metabolism inherent in heart failure. The synthesis of the counterregulator atrial natriuretic factor is also increased. PMID- 7848659 TI - Resistance to arsenic compounds in microorganisms. AB - Arsenic ions, frequently present as environmental pollutants, are very toxic for most microorganisms. Some microbial strains possess genetic determinants that confer resistance. In bacteria, these determinants are often found on plasmids, which has facilitated their study at the molecular level. Bacterial plasmids conferring arsenic resistance encode specific efflux pumps able to extrude arsenic from the cell cytoplasm thus lowering the intracellular concentration of the toxic ions. In Gram-negative bacteria, the efflux pump consists of a two component ATPase complex. ArsA is the ATPase subunit and is associated with an integral membrane subunit, ArsB. Arsenate is enzymatically reduced to arsenite (the substrate of ArsB and the activator of ArsA) by the small cytoplasmic ArsC polypeptide. In Gram-positive bacteria, comparable arsB and arsC genes (and proteins) are found, but arsA is missing. In addition to the wide spread plasmid arsenic resistance determinant, a few bacteria confer resistance to arsenite with a separate determinant for enzymatic oxidation of more-toxic arsenite to less toxic arsenate. In contrast to the detailed information on the mechanisms of arsenic resistance in bacteria, little work has been reported on this subject in algae and fungi. PMID- 7848660 TI - Industrial production of heterologous proteins by fed-batch cultures of the yeast Saccharomyces cerevisiae. AB - This review concerns the issues involved in the industrial development of fed batch culture processes with Saccharomyces cerevisiae strains producing heterologous proteins. Most of process development considerations with fed-batch recombinant cultures are linked to the reliability and reproducibility of the process for manufacturing environments where quality assurance and quality control aspects are paramount. In this respect, the quality, safety and efficacy of complex biologically active molecules produced by recombinant techniques are strongly influenced by the genetic background of the host strain, genetic stability of the transformed strain and production process factors. An overview of the recent literature of these culture-related factors is coupled with our experience in yeast fed-batch process development for producing various therapeutic grade proteins. The discussion is based around three principal topics: genetics, microbial physiology and fed-batch process design. It includes the fundamental aspects of yeast strain physiology, the nature of the recombinant product, quality control aspects of the biological product, features of yeast expression vectors, expression and localization of recombinant products in transformed cells and fed-batch process considerations for the industrial production of Saccharomyces cerevisiae recombinant proteins. It is our purpose that this review will provide a comprehensive understanding of the fed-batch recombinant production processes and challenges commonly encountered during process development. PMID- 7848661 TI - [The distribution of gene frequencies of immunoglobulin allotype G2m(23) factor in Chinese populations]. AB - The distribution of G2m(23) gene frequencies in eight Chinese populations, which cover three ethnic groups, was studied by enzyme linked immunosorbent assay inhibition test. According to the results of multiple linear regression and multiple liner correlation there exists a cline of G2m(23) gene frequencies along with the height and latitude in China. In addition, an equation of multiple linear regression which can be used to expect the G2m(23) gene frequencies in some Chinese populations was established. Some possible reasons for this cline were also discussed. PMID- 7848662 TI - [A study of the distribution of PGM1 subtypes in fifteen nationalities in Yunnan Province China]. AB - A study of the distribution of PGM1 subtypes in the fifteen nationalities in Yunnan province in China, including Han, Yi, Bai, Kucong, Hani, Dai, Yao, Jino, Blang, Wa, Lahu, Hui, Lisu Naxi and Pumi, was carried out, using ultrathin-layer polyacrylamide gel isoelectric focusing (ULPAGIEF). Gene frequencies and probabilities of discrimination (DP) of PGM1 subtypes in these nationalities were calculated. Statistical tests show: That there is a clear nationalistic discrepancy in the fifteen nationalities; but there is not an areal discrepancy in the Han nationality, living in different areas, on the distribution of PGM1 subtypes. The result of the study also shows, that there are high probabilities of discrimination for PGM1 subtypes in all fifteen nationalities. PMID- 7848663 TI - [Localization of GH gene to bovine chromosome 5q22-26 by in situ hybridization]. AB - The bGH entire gene (3.0kb), as a probe which was cloned into recombinant plasmid pbGH was used for in situ hybridization. The E. coli RR1, as a receptor, was transformed by recombinant plasmid pbGH. Recombinant plasmid DNAs were amplified, extracted and purified, the bGH fragments were collected and labelled by nicktranslation. The metaphase and early-metaphase chromosome spreads were prepared from TdR-BrdU-synchronized peripheral blood lymphocytes in Beijing Black white dairy cattle. After in situ hybridization and autoradiography, chromosomal G-bands were stained with FPG method. The number of silver grains on every chromosome was calculated. The result showed that bGH gene is located at chromosome 5q22-26. This assignment of the GH gene in cattle differs from those of previous assignments. Finally, the relationships between probe, mapping method and mapping accuracy were discussed. PMID- 7848664 TI - [The genetic mechanism of intersexuality in milk goats of Saanen breed of Xinong]. AB - Intersexual goats of Saanen breed of Xinong at Northwestern Agricultural University were studied in anatomy, histology, cytogenetics and genetics. The different types of intersexuality were seen, ranging from psuedohermaphroditic female to male types, including testicular hypoplastic and sex reverse male. All of them were genetic female type (60, XX), the karyotype, normal, so the intersexual bodies caused by the gene, which located at autosomes, having masculinizing effect, and in homozygote made female turn to male incompletely. It was pointed that intersexuality and polledness were controlled by different genes, the half century standing problem on intersexual inheritance of goats has been solved. The normal: the intersexual = 3:1, but the intersexual came from genetic female, this is a very special segregative ratio. PMID- 7848665 TI - [Study on the genetics of Drosophila auraria species complex]. PMID- 7848666 TI - [Plasmid from Halobacterium halobium and its restriction map]. AB - In this paper, ten strains of H. halobium were screened for the occurrence of plasmid by four methods. Six of the strains harbored plasmids of high molecular weight. Of all the detecting methods, the TENS method was the best for H. halobium. J7 strain contains only one type of plasmid named as pHH205 which showed stationary CCC form. The highest copy number of the plasmid was observed in late stationary growth phase, which was approximately 49 copies per cell. The molecular weight is 16.7kb. The sites of five endonucleases had been determined for pHH205 and three of them, namely BamHI, HindIII and XbaI, were single sites neighboring to each other. PMID- 7848667 TI - Board certification among preventive medicine residency graduates: characteristics, advantages, and barriers. AB - In 1991, a mail survey was conducted of graduates (1979-1989) of general preventive medicine/public health (GPM/PH) residency programs to obtain information about the graduates' demographic characteristics, training, and present professional work. Specifically, we evaluated the survey data for percentage of graduates with board certification, advantages of board certification, and barriers to board certification in preventive medicine (PM). The survey response rate was 74% (797 of 1,070 graduates). Only 45% of the respondents were board certified in PM as of 1991. The percentage of respondents board certified in PM was highest among military PM residency graduates and lowest among those from the Centers for Disease Control (CDC) PM residency. Reasons for not taking the board examination included the perception of limited benefit of board certification in current employment or professional endeavors, previous board certification in a clinical specialty, lack of a master of public health (MPH) degree, high cost and time commitment for the examination, and uncertainty about examination admission requirements. PM residency graduates with board certification in PM were more likely to be involved in public health and preventive medicine programs, devoted more time to administration and management, and earned more income than those PM residency graduates without PM board certification. Increasing the percentage of residency graduates who pursue PM board certification will require increasing the advantages of certification for practice, encouraging all residents to identify themselves as practicing the specialty of PM, and addressing the unique concerns of physicians who train both in PM and in a purely or primarily clinical specialty. PMID- 7848669 TI - Physician delivery of smoking-cessation advice based on the stages-of-change model. AB - The purpose of this study is to assess whether a stage-based program of brief physician-delivered smoking-cessation advice changes smoking stages of readiness to quit smoking. First-year residents were trained to assess the stage of their continuity care patients who smoke, using Prochaska and DiClemente's methods, and to deliver brief messages and handouts based on the stages of precontemplation, contemplation, and action. Concurrent with the training, we administered a survey to 252 smokers, before their physician encounter. Eighty-nine smokers saw trained residents (intervention group), and 163 saw untrained residents (usual care group). A follow-up survey was administered six months later. Seventy-four percent of the subjects completed the follow-up survey. After we controlled for baseline stage, the percentage of precontemplators was lower in the intervention group (25%) than in the usual care group (36%) (P < .05, log-linear model). In the intervention group, 50% of the subjects had positive stage shifts versus 40% in the usual care group (P = .2). Subjects in the intervention group moved ahead a mean of 0.63 stage per subject, whereas subjects in the usual care group moved ahead 0.34 stage per subject (P < .05). The self-reported cessation rate was 15.5% and did not differ between the two groups. We conclude that our stage specific brief advice program enhances short-term movement through the stages-of change of smoking cessation. Measurement of this movement may be an important intermediary in evaluating small clinical trials of brief advice. Our findings indicate potential benefits of a staged approach for both clinicians and their patients. PMID- 7848668 TI - Use of preventive interventions by persons infected with type-1 human immunodeficiency virus (HIV-1). The Pulmonary Complications of HIV Study Group. AB - Measures aimed at preventing complications and slowing progression of type-1 human immunodeficiency virus (HIV-1) can potentially reduce morbidity. Although little is known about the use of such measures, such data are critical for program planning. This study was performed to quantify the frequency and patterns of use for such interventions. We enrolled 1,171 persons infected with HIV, but without an acquired immunodeficiency syndrome (AIDS) defining diagnosis, in a multicenter prospective study of the pulmonary complications of HIV infection. Participants were homosexual/bisexual men, injection drug users (IDUs), or female sexual contacts of HIV-infected men. Centers were university-based and geographically dispersed across the United States. Standardized questionnaires were administered on entry and at three-month or six-month intervals; we correlated use of general and HIV-related preventive measures before entry and during the first three years in study with clinical/epidemiologic characteristics. Overall use of preventive interventions was low; only one third of study entrants had used such measures. Use was greatest among those with advanced HIV infection, but only half used preventive measures on entry; IDUs were less likely than homosexuals to use these services. Although use of interventions such as anti-Pneumocystis and antiretroviral agents increased during study participation, general measures such as pneumococcal vaccine and tuberculosis prophylaxis were used by less than 30% of those eligible for use. Among IDUs, cumulative use of these measures remained below 20% during the first three years of this study. We conclude that HIV-infected persons underuse preventive interventions, particularly general measures.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7848670 TI - Effects of intervention on compliance to referral and lifestyle recommendations given at cholesterol screening programs. AB - To enhance compliance to physician referral as well as dietary and other lifestyle recommendations given at blood cholesterol (BC) screening programs, we randomized Pawtucket Heart Health Program SCORE (screening, counseling, referral event) participants with elevated BC levels into one of four groups: usual care group; a participant intervention group (mailed reminder letter and refrigerator magnet); a physician intervention group (mailed packet to participant's physician including letter, National Cholesterol Education Program [NCEP] guidelines, and preaddressed postcard to mail to patient); and a group that received both interventions. Beginning four months after the screening, we surveyed study subjects by phone. The participant intervention increased recall of physician referral and dietary recommendations; however, neither intervention successfully improved compliance to referral or dietary and lifestyle recommendations. Overall, 58%, 67% and 34% of subjects reported complying to physician referral, dietary recommendations, and lifestyle recommendations, respectively. Referral compliance was associated with a longer time interval between screening and survey (relative risk [RR] = 1.3, 95% confidence interval [CI[ = 1.0, 1.7), possession of medical insurance that covered physician visits (RR = 2.1, 95% CI = 0.98, 4.4), and history of hypertension (RR = 2.6, 95% CI = 1.1, 5.8). Dietary compliance was positively associated with baseline BC levels > or = 240 mg/dL (RR = 3.3, 95% CI = 1.4, 7.3) and negatively associated with increasing age; each one year increase in age corresponded to a 3% decrease in compliance (RR = 0.97, 95% CI = 0.9. 1.0).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7848671 TI - A supermarket cardiovascular screening program: analysis of participants' solicitation of follow-up care. AB - We conducted a cardiovascular screening program in 54 supermarkets in the province of Quebec, Canada to determine cardiovascular risk factors, including total cholesterol, blood pressure, tobacco use, height, weight, and physical activity levels. A 10-minute debriefing counseling session followed. Of the 3,432 screening participants 18-74 years of age, 2,420 participated in a nutrition study, consisting of answering a brief questionnaire before the screening. Three months after the screening, 1,293 individuals returned the posttest nutrition questionnaire sent to them by mail. We report follow-up care activity for low risk and high-risk individuals for respondents of the posttest nutrition questionnaire. Overall, 53% of respondents reported seeing a physician within three months after the screening to discuss their blood cholesterol or blood pressure results, and the percentage ranged from 25% for individuals with normal cholesterol (< or = 199 mg/dL) and normal blood pressure (< 140/90 mm Hg) to 83% for individuals with high cholesterol (> or = 240 mg/dL) and high blood pressure (> or = 140/90 mm Hg). Respondents who saw a physician following the screening were more likely to be (1) those on medication at the time of the screening for high blood cholesterol and high blood pressure, (2) older individuals, (3) those found to have high blood cholesterol and high blood pressure values during the screening, (4) women, and (5) individuals with a lower level of education. Seventy-nine percent identified as having high blood cholesterol during the screening reported that their blood cholesterol was remeasured. The majority of high-risk participants and their physicians took appropriate follow-up action.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7848672 TI - Correctness of racial coding of American Indians and Alaska Natives on the Washington State death certificate. AB - Underestimation of death rates for specific races can obscure health problems and impair the ability of public programs to prevent premature death and disability. For accurate race-specific death rates, the racial classification of both the population at risk and the decreased population must be accurately ascertained. However, studies suggest that the American Indian (AI) and Alaska Native (AN) races may be not be accurately recorded on the death certificate. We performed a computerized linkage between the Indian Health Service (IHS) patient registry and the 1985-1990 computerized Washington State death certificate data. The deceased was correctly identified as AI or AN on the death certificate for 1,088 (87.2%) of 1,248 matched deaths. The majority (93%) of deceased persons identified on the death certificate as not AI or AN were listed as white. The percentage of American Indian ancestry was strongly associated with correct racial classification on the death certificate (P < .001). Birth in Washington State, membership in a large Washington State tribe, and death from an alcohol condition independently added to the likelihood of correct AI or AN racial classification. Persons who died from cancer were significantly less likely to be correctly coded as AI or AN on the death certificate. PMID- 7848673 TI - Cardiovascular disease risk factors in native Americans: a literature review. AB - Cardiovascular disease (CVD) has become the leading cause of death for Native Americans and Alaska Natives. CVD risk factors (diabetes, hypertension, obesity, hypercholesterolemia, smoking, and sedentary lifestyle) have been studied in a number of Native American tribes, and such studies are increasing as the CVD mortality rate rises. This article reviews the literature between 1980 and 1991 concerning the prevalence of CVD risk factors in this population. In addition to summarizing the data, we describe limitations inherent in comparison and address the need for standardization of methodology in future studies. PMID- 7848674 TI - Nutrition counseling--should physicians guide their patients? AB - This article summarizes the findings of a study initiative under-taken by the U.S. Public Health Service to examine its own role in fostering a more effective education of U.S. physicians in nutrition. The study was completed in response to a congressional request that the federal government examine the need for a more productive government role in this important area. The literature, dating back to the turn of the century, is relatively uniform in its conclusions that U.S. physicians are woefully undertrained in nutrition. The training inadequacy might be dismissed, indeed, has been dismissed by many programs, yet the role of nutrition in promoting health becomes clearer with each passing year. We ask: Will either the government or the medical education community begin to equip our physicians with the knowledge needed to bring nutrition into play as an active therapeutic approach to complement other therapies? PMID- 7848675 TI - Preventive medicine in transition. PMID- 7848676 TI - Tenth anniversary perspectives on AIDS. Host-HTLV type I interaction at the molecular level. PMID- 7848677 TI - Interleukin 10 blocks HIV replication in macrophages by inhibiting the autocrine loop of tumor necrosis factor alpha and interleukin 6 induction of virus. AB - Human interleukin 10 is a pleiotropic cytokine capable of suppressing cytokine production from macrophages and T cells; in addition, it exerts complex regulatory effects on CD8+ T cells, natural killer cells, vascular endothelial cells, and B lymphocytes. Levels of IL-10 are elevated in HIV-infected individuals, suggesting that this cytokine may play a role in the suppression of T cell and monocyte/macrophage function typical of HIV disease. In this article, IL-10 blocked HIV-induced tumor necrosis factor alpha and interleukin 6 secretion and inhibited HIV replication in monocyte-derived macrophages (MDMs). The inhibition by IL-10 was correlated with a block in endogenous TNF-alpha and IL-6 secretion from HIV-infected MDMs. PMID- 7848678 TI - Stimulation of HIV type 1 gene expression and induction of NF-kappa B (p50/p65) binding activity in tumor necrosis factor alpha-treated human fetal glial cells. AB - In vitro, HIV-1 infection of human fetal glial cells initiates a noncytopathic, productive infection that results in a long-term persistence during which the viral genome remains latent. The cytokines tumor necrosis factor alpha (TNF alpha) and interleukin 1 beta (IL-1 beta) reactivate HIV-1 gene expression in these cells, leading to production of infectious virus. Here we show that treatment of human fetal glial cells with TNF-alpha and IL-1 beta increase expression of the reporter gene chloramphenicol acetyltransferase (CAT) when placed under the control of the HIV-1 5' LTR. We also show that treatment of human fetal glial cells with TNF-alpha leads to increased binding of the nuclear transcription factor NF-kappa B (p50/p65) to a consensus kappa B-binding site present in the HIV-1 5'LTR. Our results suggest that TNF-alpha stimulation of HIV 1 gene expression in primary cultures of human fetal glial cells is mediated by an increase in binding of NF-kappa B (p50/p65) to the HIV-1 LTR. This is the first report documenting NF-kappa B-binding activity in primary cultures of human fetal glial cells. PMID- 7848679 TI - Association of alterations in NF-kappa B moieties with HIV type 1 proviral latency in certain monocytic cells. AB - Human immunodeficiency virus type 1 (HIV-1) replication is controlled by a complex array of virally encoded and cellular proteins. A wide spectrum of levels of HIV-1 expression have been demonstrated in various cells, both in cell culture and in vivo. Molecular mechanisms leading to restricted HIV-1 replication may differ between certain cell types. It is now demonstrated that HIV-1 proviral latency in the monocytic cell line U1, in which only extremely low levels of HIV 1 expression are detected in the baseline unstimulated state, is associated with alterations in nuclear factor-kappa B (NF-kappa B) moieties demonstrated in these cells by electrophoretic mobility shift assays (EMSAs) and in situ UV cross linking studies. A predominance of p50 NF-kappa B moieties and possibly p50 homodimers or closely related species, rather than the p50-p56 heterodimer of NF kappa B that is the predominant NF-kappa B species in most T lymphocytic and monocytic cells, is demonstrated in the nuclei of U1 cells. This pattern of NF kappa B-related moieties differs from the latently infected T lymphocytic cell line ACH-2, and from the U937 monocytic line, the parental cell line of the U1 cellular clone. As such, these data suggest that different proximal mechanisms may lead to restricted HIV-1 replication in various cell types. PMID- 7848680 TI - HIV type 1 induction of interleukin 1 and 6 production by human thymic cells. AB - In vitro and in vivo studies have demonstrated that HIV can infect thymocytes at different maturational stages and lead to changes in the thymic microenvironment. To determine the effect of HIV on thymic stromal cells and the production of cytokines important in thymocyte development, three types of adherent thymic cultures were established and studied: thymic epithelial cells (TECs), macrophage enriched, and mixed cultures of macrophages and TECs (M phi/TEC). Cultures were exposed to HIV-1 strains HIV-1IIIB and HIV-1Ba-L, and studied from day 2 to day 26 for the presence of infection, cytopathology, and cytokine (IL-1 alpha, IL-1 beta, and IL-6) production. M phi/TEC and macrophage-enriched cultures were infected by both HIV strains without cytopathic changes. The TECs grew well in culture for at least 6 weeks and showed no evidence of infection, cytopathology, or changes in cytokine production with HIV. Only cultures containing macrophages (M phi/TEC or macrophage enriched) showed changes in cytokine production with HIV. Sustained production of IL-1 alpha was seen for up to 20 days, with small or no increases in IL-1 beta. M phi/TEC cultures produced high constitutive levels of IL-6 that were not changed by HIV. Unstimulated macrophage-enriched cultures produced small amounts of IL-6 that were increased by HIV 20-fold. This study suggests that HIV infection in vivo can lead to infection of thymic macrophages resulting in cytokine abnormalities and a constant source for HIV to infect maturing thymocytes. These cytokine effects could lead to abnormal maturation and contribute to the lack of regeneration of the mature CD4+ T cell pool. PMID- 7848681 TI - Fusogenic activity of amino-terminal region of HIV type 1 Nef protein. AB - We have studied two isoforms of Nef, Nef-27 and Nef-25, which were produced in E. coli. Nef-25 lacked the first 18 N-terminal residues of Nef-27 and both were nonmyristylated. Nef-27 fuses small unilamellar dipalmitoyl phosphatidylcholine vesicles (SUVs), as indicated by enhanced light scattering of SUVs and lipid mixing using concentration-dependent fluorescence dequenching. Nef-27 also causes the appearance of a shifted isotropic peak in the 31P NMR spectra of these vesicles, suggesting that protein interactions induce nonlamellar lipid structures. Recombinant Nef-25, which lacks only the 18 N-terminal residues of Nef-27, does not fuse vesicles and has little effect on the 31P NMR spectra. On the other hand, synthetic peptides consisting of 18 or 21 of the N-terminal residues of Nef-27 are strongly membrane perturbing, causing vesicle fusion and inducing isotropic peaks in the 31P NMR spectrum. Endogenous fluorescence spectra of the N-terminal peptide (21 residues) with SUVs show that the N-terminal sequence of Nef may achieve these perturbing effects by inserting its hydrophobic side into the lipid bilayer. Theoretical calculations using hydrophobic moment plot analysis indicate that short-length stretches (i.e., six amino acid residues) of the N-terminal sequence may insert into the lipid bilayer as multimeric alpha helices or beta sheets. The above-described membrane activities of Nef-27, which principally reside in its N-terminal domain, may play critical role(s) in certain functional properties of the full-length protein. For example, the fusogenic activity of the N-terminal sequence may be involved in the extracellular release of Nef-27, much of which appears to be associated with small membrane vesicles. The fusion activity may also be relevant to the ability of Nef-27 to downregulate CD4 and IL-2 receptors when this protein is electroporated into cultured lymphocytes, an activity not possessed by Nef-25. PMID- 7848682 TI - Viral DNA burden and decline in percentage of CD4-positive cells in the lymphoid compartment of SIV-infected macaques. AB - The decline in CD4+ cells and increased viral DNA and RNA burden in the blood of human immunodeficiency virus (HIV)-infected individuals have been used as closely related correlates of disease progression. However, little is known about levels of total or unintegrated viral DNA in lymphoid tissue of HIV-infected patients and how they relate to CD4+ cell decline or disease progression. Exploiting the similarities between HIV- and simian immunodeficiency virus (SIV)-induced disease, we examined lymphoid organs and peripheral blood from SIV-infected macaques for total (pol) and unintegrated 2-LTR circular viral DNA by polymerase chain reaction (PCR). Two SIV isolates (SIVmac/251 and SIVmne/E11S) that differ markedly in their biological and clinical properties were studied. The results indicate that total viral DNA burdens vary considerably between isolates. There was no strong association between total viral DNA levels and CD4% in lymphoid tissues when isolates were compared and death was not associated with any particular level of viral pol DNA. In contrast, accumulation of unintegrated viral DNA was closely associated with decline in CD4/CD8 ratios in lymphoid organs and AIDS. The appearance of both pol and unintegrated viral DNA in thymus of infected macaques also emerged as one of the single best correlates or possible predictors of advanced disease yet studied. Their roles in pathogenesis are discussed. PMID- 7848683 TI - An animal model for antilentiviral therapy: effect of zidovudine on viral load during acute infection after exposure of macaques to simian immunodeficiency virus. AB - We analyzed the kinetics of the virological and immunological events that occurred in four AZT-treated cynomolgus macaques during the acute infection that followed their exposure to the simian immunodeficiency virus (SIVmac251) grown on monkey PBMCs in a cell-free stock solution. These events included changes in the CD4+ and CD8+ T lymphocyte subsets, p27 antigenemia, infectious serum virus, and cell-associated virus loads. The kinetics of these changes proved strikingly similar to those reported in human HIV-1 infection. Four other SIV-exposed macaques were treated with placebo instead of AZT. We demonstrated that AZT does not prevent SIV infection, even when administered before SIV inoculation. However, the peaks of p27 antigenemia and of serum and cellular viremia were significantly smaller and occurred significantly later in the monkeys given AZT than in those given placebo. PMID- 7848684 TI - Isolation of simian immunodeficiency viruses from two sooty mangabeys in Cote d'Ivoire: virological and genetic characterization and relationship to other HIV type 2 and SIVsm/mac strains. AB - OBJECTIVE: To search for the presence of SIV in sooty mangabeys and other monkey species in Cote d'Ivoire, West Africa, and to compare viral isolates with HIV-2 strains from the same region. METHODS: Forty-three captive housed monkeys (28 African green monkeys, 6 sooty mangabeys, 6 baboons, and 6 patas monkeys) were tested for the presence of HIV and SIV antibodies. Virus was isolated from the peripheral blood lymphocytes of seropositive animals and from HIV-2 antibody positive patients originating from Cote d'Ivoire, Ghana, Senegal, and Belgium. Viruses were characterized by Western blot and radioimmunoprecipitation assay. Proviral DNA was amplified by PCR, cloned, and sequenced to construct a phylogenetic tree. RESULTS: One African green monkey and three sooty mangabeys had antibodies that cross-reacted with HIV-2. From two mangabeys lentiviruses were isolated and designated as SIVsmCI2 and SIVsmCI8. Serological, virological, and sequence data showed that these isolates are members of the HIV 2/SIVsm/SIVmac group of primate lentiviruses. Furthermore, in the phylogenetic tree, these two new viruses form a distinct subgroup that is equidistant to the HIV-2 strains and the previously described SIVsm/SIVmac viruses. CONCLUSION: This study provides additional evidence that sooty mangabey monkeys can be infected with a lentivirus in their natural habitat. Within the SIVsm and SIVmac viruses extensive genetic variation is observed. PMID- 7848685 TI - Fine analysis of humoral antibody response to envelope glycoprotein of SIV in infected and vaccinated macaques. AB - To characterize the serological response to SIV envelope, induced by vaccination with different envelope immunogens or by SIV infection, plasma samples from 11 cynomolgus macaques infected with simian immunodeficiency virus (SIV) and from 16 macaques vaccinated with three different recombinant envelope proteins were analyzed by (1) ELISA, using a variety of antigens including overlapping peptides encompassing the entire sequence of the envelope protein of SIV, and (2) competition assays, using neutralizing monoclonal antibodies to SIV gp120. Seven regions of SIV envelope were predicted to be antigenic. Peptides representing four of these, in the second and third variable regions (V2 and V3) and the fourth constant (C4) region of gp120 and the Gnann region of gp41, were recognized by the majority of sera from infected and vaccinated animals. Additional antigenic regions were identified in the first and fourth variable domains (V1 and V4) and the carboxy terminus (C5) of gp120 and in three additional regions of gp41. Most infected and vaccinated animals made antibodies that competed with the binding of the three conformational MAbs. Among the vaccinated groups, antibodies induced by vaccination with precursor glycoproteins (gp140 or gp160) recognized several additional gp120 epitopes when compared with antibodies induced by external glycoprotein gp130. Sera from infected animals showed a more restricted gp120 response (17 of 46 peptides recognized) compared to animals vaccinated with precursor glycoproteins (31 peptides recognized). The converse was true for antibodies to gp41. Sera from animals vaccinated with recombinant gp140, produced in insect cells, were the only group that failed to compete with the binding of conformational MAbs. Finally, the development of antibodies to specific epitopes of gp120 and gp41 revealed differences between long-term survivors and nonsurvivors, implying that responses to specific epitopes may be important in conferring resistance to disease progression. PMID- 7848686 TI - Mechanisms of HIV/SIV mucosal transmission. AB - The Division of AIDS (DAIDS), National Institute of Allergy and Infectious Diseases (NIAID), organized a Workshop on HIV/SIV Pathogenesis and Mucosal Transmission on March 14-17, 1994, attended by over 300 participants. The purpose of the workshop was to foster research in the areas of HIV pathogenesis, mucosal transmission, and host factors modulating HIV infection and disease. This article summarizes workshop presentations that focused on mechanisms of HIV or SIV mucosal transmission. The following are highlights from the workshop. The epidemiological data indicating a low probability of infection from a single sexual exposure are consistent with observations that infectious cell-free or cell-associated HIV could be isolated from only 10-57% of semen samples, and that high levels of SIV are required for infection by a mucosal route. Several lines of circumstantial evidence suggest that an important property of a transmitted HIV or SIV is the ability to infect macrophages. A potential mechanism for cell associated mucosal transmission is provided by the observations that CD4-negative epithelial cells in culture are efficiently infected by direct contact with HIV infected T cells, and that HIV-infected epithelial cells are observed in vivo. Cell-free HIV virions contain partial reverse transcripts of viral RNA into DNA, and conditions that promote DNA reverse transcripts, such as incubation in seminal fluid, increase viral infectivity. Finally, evidence is accumulating that transient or abortive infection with short-term recovery of infectious virus in blood can occur in the absence of seroconversion. PMID- 7848687 TI - Long terminal repeat sequence analysis of HTLV type I molecular variants identified in four north African patients. PMID- 7848688 TI - [Behavioral profile of the patient with Crohn's disease]. AB - The present study describe epidemiology, clinics and psychology of 92 patients with Crohn's Disease. The study has been designed in order to assess the psychological repercussion and the way of life secondary to Crohn's Disease; and assess the relationship between environmental factors and behavioral reactions with the symptomatology. The psychological assessment show higher levels of neurosis (66.9% vs 50%), anxiety (55% vs 50%), depression (49.2 vs 35) and stress (13 vs 10) in these patients than in a normal population. The patients describe stresses related to Crohn's Disease: the disease's severity and chronicity, ineffectiveness of the medical treatment and the limited way of life; 83.9% of patients describe concurrent psychosocial stress not directly attributable to Crohn' Disease: conflicts with parents, friends, work. We confirm the utility of psychological treatment in the management of these patients. PMID- 7848689 TI - [Effect of overexpression of P53 protein in colorectal carcinoma on short-term prognosis]. AB - BACKGROUND AND METHODS: p53 protein expression was studied immunohistochemically in 73 colorectal adenocarcinomas, using monoclonal antibody D07 in alcohol fixed, paraffin embedded tissue. RESULTS: Immunoreactivity was found in 49% of specimens, detected in the nuclei of the cancer cells. There was no significant correlation between the expression of p53 and the clinicopathological parameters age, sex, tumor size and site, lymphatic invasion, and lymph node metastasis. However, the p53 overexpression correlated with stage of disease, histologic grade, vascular invasion and with the presence of villous or tubular adenomas in the resected specimens. The p53 positive tumors showed a higher rate of recurrence than the p53 negative tumors; however, the difference was not statistically significant. The short-term survival rate (follow-up 7-48 months, median 30 months) was 90% for 20 patients with p53 negative tumors, and 65% for the patients with p53 positive tumors; a significant difference in the survival between the two groups of patients was found. CONCLUSIONS: These results suggest that in colorectal carcinoma, immunohistochemical detection of p53 protein can be used along with other established indicators to asses prognostic outcome, specially to identify patients with a poor short-term prognosis. PMID- 7848690 TI - [Immunologic changes in chronic post-transfusion positive hepatitis C and non-A non-B non-C hepatitis]. AB - OBJECTIVES: To study some aspects of the immunological abnormalities of C and non A non-B non-C posttransfusional chronic hepatitis through the spontaneous and mitogen-stimulated "in vitro" production of immunoglobulins by peripheral blood lymphocytes. EXPERIMENTAL DESIGN: Peripheral blood lymphocytes from non-A non-B posttransfusional chronic hepatitis patients and from healthy volunteers were cultured in presence and absence of Pokeweed mitogen and the secreted immunoglobulins (IgG, IgA and IgM) were measured by ELISA in the supernatants. The results in both groups were compared. PATIENTS: 23 posttransfusional chronic hepatitis patients, 11 males and 12 females with an average age of 46.73 +/- 11.2 yrs (range: 24-69 yrs), have been studied. The histological diagnosis was chronic active hepatitis (CAH) in 13 cases, CAH with bridge necrosis in 6 patients and CAH with associated cirrhosis in 4 cases. The control group was composed by 11 healthy volunteers, 5 male and 6 female, with an average age of 38.45 +/- 12.77 yrs (range: 26-65 yrs). No one of the control group was positive for anti-HCV antibodies while in the posttransfusional chronic hepatitis patients group, 19 were positive and 4 negative. RESULTS: No significant differences in the spontaneous production of immunoglobulins between both groups has been found, however, when peripheral blood lymphocytes were stimulated with Pokeweed mitogen, a statistically significant lower production of immunoglobulins was observed in chronic hepatitis patients when compared with the control group. In non-A non-B posttransfusional chronic hepatitis patients, no relation has been found between the immunoglobulins production and histological findings or anti-HCV antibody titles. CONCLUSIONS: In the chronic phase of C and non-A non-B non-C posttransfusional chronic hepatitis, stimulated immunoglobulin production is significantly decreased for each immunoglobulin compared with the control group. These results suggest a failure in T-B lymphocyte cooperation in these infections since 82.6% of our patients were positive for HCV serological markers. PMID- 7848691 TI - [Quality of life of cirrhotic patients before and after liver transplantation]. AB - In this study we assessed the quality of life of a group of cirrhotic patients who underwent liver transplant using a psychological test to evaluate family relations, work activity, emotional state and social relations. The quantification of hospital dependence and degree of fitness for work, before and after the transplant were also analyzed. 32 patients were included in the study with the diagnosis of hepatic cirrhosis and minimum post-transplant follow-up of 6 months. The average age of the study population was 44.8 +/- 10.5 years; there were 23 males and 9 females, with an average follow-up of 15 months. The psychological test used was the Quality of Life Scale (QLS), which consists of 21 items, each scoring from 1 to 6 points. The questionnaire was completed before the transplant by all the patients, and after the transplant by 32 patients at 6 months, 20 at 12 months and 12 at 24 months. Hospital dependence was evaluated by number of admissions and number of days per admission. Lastly, we compare the rate of unfitness for work before the transplant and at one and two years after the transplant. The QLS test showed a post-transplant improvement in the 4 aspects assessed, specially in the personal aspects (emotions and family) (p < 0.001). Hospital dependence following pre-transplant situation (p < 0.01). Finally, the post-transplant percentage of unfitness for work decreased with time, reaching significant differences 2 years after the liver transplant (p < 0.05). PMID- 7848693 TI - [Is the carbohydrate antigen Ca 19.9 useful in the diagnosis of pancreatic carcinoma?]. AB - OBJECTIVE: To determine the sensitivity and specificity of the tumor marker Ca 19.9 in subjects with suspected pancreatic cancer. MATERIAL AND METHODS: Levels of Ca 19.9 antigen were measured by enzymeimmunoassay during a 3 year period to 72 patients investigated for suspected pancreatic cancer. RESULTS: A threshold of 100 U/ml resulted in sensitivity of 94.7%, specificity of 39.6%, positive predictive value of 36% and negative predictive value of 95.4%. CONCLUSION: Levels of Ca 19.9 antigen > 100 U/ml are suggestive of malignancy in patients investigated for suspected pancreatic cancer. PMID- 7848692 TI - [Biliary drainage in the diagnosis of acute idiopathic pancreatitis]. AB - The identification of a casual agent in the so-called "idiopatic acute pancreatitis" is of great interest in relationship with the prognosis and the election of correct therapy. We have performed a duodenal drainage for the microscopic study of the bile, looking for cholesterol crystals and bilirrubinate's in a group of 19 patients with idiopatic acute pancreatitis. The results have been compared with a control group composed by 45 assymptomatic individuals. In the patients group drainage results were abnormal in 11 cases (57.9%) vs. 11.2% in the control group (difference statistically significant). In 4 of the 11 cases, a cholecystectomy was performed showing biliary pathology. Patients at follow-up were assymptomatic. Duodenal drainage is an easy method without risks that must be used always in idiopatic acute pancreatitis. It allows the diagnosis of microlithiasis and may help in the therapeutic indication of cholecystectomy. PMID- 7848694 TI - [Colloidal bismuth subcitrate: several pharmacokinetic considerations and of clinical application]. PMID- 7848696 TI - [Ultrasonography of acute diverticulitis of the colon]. AB - Ultrasonographic findings in two patients with acute diverticulitis of the left colon are described. Echographic identification of diverticula and thickened (> 4 mm) hypoechoic bowel wall were common findings. The final diagnosis was confirmed by contrast enema and colonoscopy. Patients had clinical signs and symptoms of acute diverticulitis. Diverticula were visualized as echogenic shadowing foci in thickened bowel wall (1 case) or as outpouches of the intestinal wall in the pericolonic soft tissues (1 case). One patient had edema of the pericolic fat. Additional studies are needed to confirm the usefulness of ultrasounds in the diagnosis of colonic diverticulitis. PMID- 7848695 TI - [Lynch syndrome. (Hereditary colonic carcinoma without polyposis)]. AB - Colonic carcinoma is a well-defined tumor with a low frequency among young people. We report the case of a 34 year old patient having two synchronous colorectal carcinomas of the right colon, who also had a family history of colonic and extracolonic neoplasms. We performed an extended right colectomy without chemotherapy. Fourteen months after surgery he had tumor recurrence and liver metastases. We reviewed then the clinical features, inclusion criteria, screening and the discussed treatment of the hereditary non-poliposis colorectal cancer or Lynch Syndrome, limited to the colon or associated to extracolonic carcinoma (Lynch I and II). A clear and detailed familial history is the only definite criteria for the diagnosis. We recommend early colonoscopy follow-up on first degree relatives considered as a high risk population. PMID- 7848697 TI - [Bouveret syndrome: 5 cases]. AB - Five cases of duodenal obstruction due to biliary stones (Bouveret's syndrome) are reported. Presenting symptoms were gastric outlet obstruction, upper gastrointestinal bleeding or jaundice. Diagnosis was achieved either by endoscopy, upper gastrointestinal X-Ray series or at the operating room. Surgical procedures to remove obstruction were needed in every case: cholecystectomy was simultaneously performed on two occasions. After reviewing the literature, previous biliary symptoms were found in 65% of the cases; diagnosis was achieved preoperatively in 85%, mainly by endoscopy procedures; simultaneous cholecystectomy was carried out in 56% of cases; postoperative mortality was 24%, rising when simultaneous cholecystectomy was performed. PMID- 7848698 TI - [Campylobacter fetus, an infrequent microbe, as a cause of spontaneous bacterial peritonitis in cirrhosis]. AB - Campylobacter fetus has been implicated in the etiology of sepsis and bacteriemias in immunosupressed subjects. In a few cases, it has also been reported to be responsible for spontaneous bacterial peritonitis in cirrhotic patients. We describe the clinical picture of a woman with terminal liver cirrhosis who had bacteriemia and spontaneous bacterial peritonitis caused by this agent. We argue about the history of cleansing enemas and their probable role in the development of the infection. We stress the excellent response to the antibiotic treatment. PMID- 7848699 TI - [Caroli's syndrome: a variable entity]. AB - We present the case of a 56 year old woman with Caroli's disease associated to congenital liver fibrosis, renal nephrocalcinosis and cutaneous vasculitis of the legs. Clinical signs of portal hypertension were treated by a shunt technique. After an asymptomatic period, the patient suffers now from crisis of angiocholitis. PMID- 7848700 TI - [Biliary tract cancer following bilioenteric anastomosis]. AB - Two cases of carcinoma of bile ducts after bilioenteric anastomosis are presented. The first one arose in the gallbladder eleven years after cholecystojejunostomy; the second, in the common bile duct three years after cholecystectomy and choledocoduodenostomy. The reflux into the bile duct and recurrent infections can be risk factors in tumor development. Although palliative resection was feasible in one case, the early tumor spread and the invasion of the enteric structure, resulted in a poor outcome in the second case. PMID- 7848701 TI - [Crohn's disease and primary hyperparathyroidism: a casual association?]. PMID- 7848702 TI - [Erythromycin: a useful alternative in the treatment of post-vagotomy gastroparesis]. PMID- 7848703 TI - [Crural mixed Littre hernia. Prognosis significance]. PMID- 7848704 TI - The concept of neurotransmitter release. PMID- 7848705 TI - A novel mammalian guanine nucleotide exchange factor (GEF) specific for rab proteins. PMID- 7848707 TI - Localization of calcium concentration microdomains at the active zone in the squid giant synapse. PMID- 7848706 TI - GTP-binding proteins: necessary components of the presynaptic terminal for synaptic transmission and its modulation. AB - Using synapses that form between somata of Helisoma neurons in cell culture, we have studied the presynaptic regulation of synaptic transmission. Guanosine 5' triphosphate (GTP)-binding proteins play critical roles in regulating synaptic transmission. Injection of guanine nucleotide analogues has demonstrated that one or more GTP-binding protein is necessary for transmitter release. Heterotrimeric G proteins continuously regulate the amount of transmitter released at the synapse by modulating potassium and calcium channels, and by controlling the secretory response to calcium. Perturbations of the synapse using guanosine 5' diphosphate (GDP) beta S, GTP gamma S, and rab effector domain peptides suggest that small GTP-binding proteins also play critical roles in the synapse. We discuss the possibility that rab3, or related proteins, are required for exocytosis, and by cooperating with other proteins maintain vesicles in a docked state in the synapse. PMID- 7848709 TI - Distinctive properties of a neuronal calcium channel and its contribution to excitatory synaptic transmission in the central nervous system. PMID- 7848708 TI - Molecular pathways for presynaptic calcium signaling. AB - The results presented in this article describe two distinct, Ca-regulated molecular pathways in presynaptic terminals and implicate these two pathways in differentially mediating neurotransmitter secretion and PTP. Our current view of the Ca-dependent triggering of secretion and PTP is shown in Fig. 9. According to this scheme, differential activation of these two pathways is achieved by a combination of diffusion-based dilution of Ca that enters the terminal through voltage-gated Ca channels and by coupling these pathways to Ca receptors with different affinities for Ca ions. A simple way to achieve these conditions is to position these two receptors at different distances from the Ca channels, as shown in Fig. 2. Given that Ca ions are involved in activating many different presynaptic processes (Fig. 1), we propose that closer scrutiny of the molecular physiology of nerve terminals will reveal a wide variety of Ca-activated pathways responsible for producing these diverse processes. PMID- 7848710 TI - Exocytosis and endocytosis in single peptidergic nerve terminals. PMID- 7848711 TI - Glutamate exocytosis from isolated nerve terminals. PMID- 7848712 TI - Central glutamatergic transmission. A view from the presynaptic axon. PMID- 7848713 TI - Differential release of classical transmitters and peptides. PMID- 7848714 TI - Quantal analysis of excitatory postsynaptic currents at the hippocampal mossy fiber-CA3 pyramidal cell synapse. AB - Unitary excitatory postsynaptic current (EPSC) amplitude histograms obtained from synapses between mossy fibers (MF) and CA3 pyramidal cells in hippocampus were analyzed with the aim of deriving the mean peak current of quantal events, its coefficient of variation CVq, the number of release sites NS, and the release probability PR. Unitary EPSC histograms with multiple peaks were fitted satisfactorily under the assumption that quantal events have a slightly skewed amplitude distribution and that the release mechanism is described by models with either binomial (standard), nonuniform, or nonstationary statistics. The average peak current of the quantal event derived from these fits reflected the opening of between 15 and 65 glutamate receptor (GluR) channels of the AMPAR subtype. The variability in the amplitude of quantal events is characterized by a CVq of 25% to 30%. The best fits to multiple peak EPSC histograms are obtained if it is assumed that the number of release sites contained within a single MF-bouton is between 8 and 21, a value comparable to the published number of morphologically measured presynpatic active zones and postsynaptic densities (PSDs) of individual MF-CA3 synapses. This suggests that at the MF-CA3 synapse each presynaptic zone and its associated PSD act as independent units, contributing one quantal event to unitary EPSCs. Simulations of unitary EPSC distributions, based on measurements of PSD size could, however, indicate that the interpretation of multipeak EPSC amplitude distributions at MF-CA3 synapses in terms of fluctuating release probabilities might be an over-simplification, and that postsynaptic factors may contribute significantly to fluctuations of unitary EPSC amplitudes. PMID- 7848715 TI - The nature of quantal transmission at central excitatory synapses. PMID- 7848716 TI - Quantal analysis of the synaptic excitation of CA1 hippocampal pyramidal cells. PMID- 7848717 TI - The one-vesicle hypothesis and multivesicular release. PMID- 7848718 TI - Synapsin I, an actin-binding protein regulating synaptic vesicle traffic in the nerve terminal. PMID- 7848719 TI - Probabilistic secretion of quanta at excitatory synapses on CA1 pyramidal neurons. PMID- 7848720 TI - Low synaptic convergence of CA3 collaterals on CA1 pyramidal cells suggests few release sites. PMID- 7848721 TI - Depression and augmentation of quantal release in adrenal chromaffin cells. PMID- 7848722 TI - Nonuniformity and plasticity of quantal release at crustacean motor nerve terminals. PMID- 7848724 TI - Quantal secretion from single visualized synaptic varicosities of sympathetic nerve terminals. PMID- 7848723 TI - Regulation of transmitter release by muscle length in frog motor nerve terminals. Dynamics of the effect and the role of integrin-ECM interactions. AB - Changes in muscle length cause large changes in the probability of transmitter release from frog motor nerve terminals. A 5% to 10% stretch from rest length can increase EPP amplitude or mEPP frequency by more than 100%. The phenomenon is fully reversible and extremely rapid. Within 7-10 milliseconds of the stretch, the enhancement is complete, and it is maintained essentially constant at the new level for as long as the stretch is sustained. Given these properties, the length modulation of release is unquestionably of functional importance, strongly amplifying the spinal stretch reflex. The stretch-induced enhancement of transmitter release persists at a reduced level in a 0 Ca++, 2 mM Mg++ Ringer. This finding indicates a lack of dependence on Ca++ influx from outside the terminal. Release of Ca++ from intracellular stores close to release sites cannot be ruled out as a contributing factor. Our results, however, suggest a mechanism involving physical connections between the extracellular matrix and the nerve terminal that can alter release probability directly. Morphological evidence for connections that might be responsible can be demonstrated in micrographs of deep etched freeze fractures through neuromuscular junctions. Hypothesizing that the ECM-nerve terminal connections responsible for the stretch effect involve proteins from the integrin family and knowing that many of the integrin-ECM binding interactions occur at sites on the ECM proteins containing the amino acid sequence RGD, we treated preparations with 0 Ca++, 2 mM Mg++ Ringer to reduce integrin binding and then returned the muscle to normal Ringer containing 0.1-0.2 mM of a six-amino-acid peptide containing the RGD sequence. This peptide strongly suppressed the stretch effect, while a control peptide (RGE) had no effect. A 50 microM Ca++/50 microM Mg++ Ringer had little effect on stretch enhancement but permitted a strong inhibition of enhancement when RGD was present. The identity of the ECM molecule(s), the integrin(s), and the mechanism of enhancement of release are unknown. However, our findings imply that much or all of the length dependent modulation of release probability is mediated by an RGD-sensitive integrin-ECM interaction that depends more on external Ca++ than on Mg++. PMID- 7848725 TI - Neurotransmitter release mechanisms in autonomic nerve terminals. PMID- 7848727 TI - Tetanus and botulinal neurotoxins. Tools to understand exocytosis in neurons. PMID- 7848726 TI - Spatiotemporal pattern of quantal release of ATP and noradrenaline from sympathetic nerves: consequences for neuromuscular transmission. AB - The recent explosive development in research concerning the fundamental mechanisms of synaptic transmission helps put the present paper in context. It is now evident that not all transmitter vesicles in a nerve terminal, not even all those docked at its active zones, are immediately available for release (36). We watch, fascinated, the unraveling of the amazingly complex cellular mechanisms and molecular machinery that determine whether or not a vesicle is "exocytosis competent" (77,78,39,79). Studies on quantal release in different systems show that neurons are fundamentally similar in one respect: that transmitter release from individual active zones is monoquantal (2). But they also show that active zones in different neurons differ drastically in the probability of monoquantal release and in the number of quanta immediately available for release (3). This implies that one should not extrapolate directly from transmitter release in one set of presynaptic terminals (e.g., in neuromuscular endplate or squid giant synapse) to that in other nerve terminals, especially if they have a very different morphology. As shown here, one should not even extrapolate from transmitter release in sympathetic nerves in one tissue (e.g., rat tail artery) to that in other tissues or species (e.g., mouse vas deferens). It is noteworthy that most studies of quantal release are based on electrophysiological analysis and therefore deal with release of fast, ionotropic transmitters from small synaptic vesicles at the active zones, especially in neurons in which these events may be examined with high resolution (49,48,46,33,32). Such data are useful as general models of the release of both fast and slow transmitters from small synaptic vesicles at active zones in other systems, provided that these transmitters are released in parallel, as are apparently ATP and NA in sympathetic nerves. They tell us little or nothing, however, about the release of transmitters (e.g., neuropeptides) from the large vesicles, nor about the spatiotemporal pattern of monoquantal release from small synaptic vesicles in the many neurons that have boutons-en-passent terminals. They show that the time course of effector responses to fast, rapidly inactivated transmitters such as ACh or ATP is necessarily release related. But they do not even address the possibility that the effector responses to slow transmitters such as NA, co released from the same terminals, may obey completely different rules and perhaps rather be clearance related (7).(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7848728 TI - The role of Ca2+ in transmitter release and long-term potentiation at hippocampal mossy fiber synapses. PMID- 7848729 TI - Communication of synaptic potentiation between synapses of the hippocampus. PMID- 7848730 TI - Activity-dependent modulation of developing neuromuscular synapses. AB - Spontaneous and impulse-evoked synaptic currents were observed immediately following nerve-muscle contact in Xenopus cell cultures. The functional significance of this early synaptic activity was examined. Stimulation of pre- and/or post-synaptic cells was found to exert immediate and persistent effects on the efficacy of synaptic transmission. Exogenous application of calcitonin gene related peptide (CGRP) and neurotrophins, factors that may be coreleased with ACh in activity-dependent manner at the developing neuromuscular junctions, also modulate either the postsynaptic ACh response or presynaptic ACh release. These results underscore the plasticity of developing neuromuscular synapses and suggest a complex interplay between electrical activity and chemical factors during the formation and maturation of neuronal connections. PMID- 7848731 TI - Molecular and structural changes underlying long-term memory storage in Aplysia. PMID- 7848732 TI - Synaptic vesicle proteins and exocytosis. PMID- 7848733 TI - Intracellular membrane fusion. AB - The NSF, SNAP, and SNAP receptors are key elements of the intracellular membrane fusion machinery. We use an affinity purification scheme, based on the function of SNAP receptor in assembling 20S fusion particles from NSF and SNAP proteins, to purify SNAP receptors from brain. Remarkably, each of the four SNAP receptors (or, SNAREs) thus delineated resides in synapses, with one receptor originating in the synaptic vesicle and another in the presynaptic plasma membrane that is targeted for fusion. This suggests a simple mechanism in which the general NSF/SNAP fusion machinery can assemble to bridge partner membranes in a complex containing elements of both vesicle and target membranes, and implies that similar fusion machines drive both constitutive fusion (ER-->Golgi-->surface and endocytosis) and regulated exocytosis. The vesicle (v-SNARE) and the target associated t-SNAREs from the synapse are each members of compartmentally-specific families of membrane proteins found in yeast, animal cells, and neurons, thus raising the possibility that v-SNAREs and t-SNAREs encode specificity in membrane fusion processes that utilize a common mechanism. PMID- 7848734 TI - Final steps in Ca(2+)-triggered exocytosis in neuroendocrine cells. PMID- 7848735 TI - Nominations for excellence: collegial advocacy for nurse practitioners. AB - This study examined physician nomination data submitted for Syntex Nurse Practitioner of the Year Awards for 1988, 1989, and 1990. The physicians identified nurse practitioner contributions to patient care, community service/outreach, and education and research. A content analysis of the text data yielded themes within four major domains that described outstanding nurse practitioners in mutual practice relationships with physicians. The domains were clinical expertise, holistic caring, patient-centered activism, and leadership. The findings in this study indicated that physicians value the contributions of nurse practitioners that enhance the quality and scope of health care for patients within a mutual practice. PMID- 7848736 TI - Survey and analysis of post-master's nurse practitioner educational programs. PMID- 7848737 TI - A systematic approach to warfarin dosing using a decision-making algorithm. PMID- 7848738 TI - Food allergy, the hidden culprit. AB - Food is frequently the trigger of commonly encountered primary care allergic problems. This paper includes a review of the prevalence, immunology and pathophysiology, manifestations, and factors that influence the development of food allergy. The focus is on the delayed or cyclic reaction. History and associated physical findings are identified. Diagnosis and recommendations for management of the disease process, including lifestyle impact, are discussed. PMID- 7848739 TI - 25+ and going strong: nurse practitioners and nursing practice. AB - The purpose of this study was to examine relationships between role attitudes and values of nurse practitioners and their level of confidence about practice knowledge and skills. The stratified random sample comprised 482 nurse practitioners representing the specialty areas of certified nurse practitioners. Findings indicate a relationship between level of confidence and role orientation. The sample also rated themselves as more confident about hands-on skills than about indirect role components such as utilization of research, change theory, and evaluation of practice outcomes. PMID- 7848740 TI - Health information needs of the pregnant adolescent. PMID- 7848741 TI - FDA news: preventing accidental iron poisoning. PMID- 7848742 TI - Hypertension: complications and problems. PMID- 7848743 TI - Chronic fatigue syndrome: a review and practical guide. AB - Diagnosis and management of chronic fatigue syndrome (CFS) is a difficult challenge for nurse practitioners. The syndrome is widespread, poorly-defined, and problematic. Despite extensive etiologic research, no cause has been identified. Each case should be carefully evaluated for possible organic, psychiatric, and other factors reported as potential causes. Clinical manifestations, possible causes, and options for management are reviewed. PMID- 7848744 TI - Demographic predictors of smoking at initiation of antenatal care. AB - The purpose of the retrospective epidemiologic study was to determine smoking prevalence and its correlates among pregnant women. Data for the study were collected from 477 randomly selected medical records of pregnant women attending a Kentucky obstetrical clinic. Logistic regression analysis, when controlling for age and education, showed that significant predictors of smoking prior to pregnancy were being married and being a woman of color. Significant demographic predictors of smoking at initiation of antenatal care were being married, being a woman of color, early age at onset of smoking, and number of cigarettes smoked per day. PMID- 7848745 TI - Principles of pharmacokinetics. PMID- 7848746 TI - Welsh water should reinstate fluoridation on Anglesey. AB - In 1992, Welsh Water withdrew the successful water fluoridation scheme on Anglesey. Despite evidence of the benefits of water fluoridation and the rise in number of children with tooth decay since the scheme's withdrawal, Welsh Water is still not prepared to re-establish the scheme. PMID- 7848747 TI - North West Water and water fluoridation. AB - Campaigners for fluoridation in the north-west eagerly awaited publication of the Oral Health Strategy for England in the hope that it would include the Government's plan of action to ensure the implementation of fluoridation where most needed and most cost effective. The Government's strategy was 'in areas which do not presently enjoy fluoridated supplies, health authorities and water suppliers should now re-examine how this public health need can best be met.' This account of how health authorities in the north-west have been examining for 25 years just how this public health need can best be met, and the surprising way in which they have been treated by their water supplier over the last 7 years, calls the effectiveness of such a strategy into question. PMID- 7848748 TI - Fifty years of water fluoridation. AB - On January 25, 1945, the city of Grand Rapids, Michigan, began adding sodium fluoride to its drinking water. This action culminated a 14-year period of research which continues to have far-reaching effects on both public health and the practice of dentistry. The fact that the oral health of children and young adults today has never been higher is a direct consequence of this research. These events, and the group of rather extraordinary people who were the principal actors in them, are so important a part of dentistry's development that they are worth a brief retelling. PMID- 7848749 TI - Recalled dental attendance. PMID- 7848750 TI - Recalled dental attendance. PMID- 7848751 TI - Recalled dental attendance. PMID- 7848752 TI - Levels of burnout in GDPs in the south-east of England. PMID- 7848754 TI - Amalgam. PMID- 7848753 TI - Recalled dental attendance. PMID- 7848755 TI - Local anaesthetics. PMID- 7848756 TI - The future provision of specialist oral surgery. PMID- 7848757 TI - Fluoridation in Anglesey 1993: a clinical study of dental caries in 5-year-old children who had experienced sub-optimal fluoridation. AB - Several studies since the commencement of fluoridation in 1955 have demonstrated over 50% reduction in mean dmft for 5-year-old Anglesey children in comparison with local control groups. From 1987 fluoridation became intermittent and in 1991 it was terminated. In the present study, carried out in 1993, the total number of children examined was 725 (88.4% of the entire population of 5-year-old school children), of whom 498 had continually resided in specific water distribution zones. The mean dmft for the entire number examined was 2.01 (SD = 3.27). For those who had experienced fluoridation during approximately 35% of their lives (n = 230) it was 1.81 (SD = 2.86) and for those who had experienced fluoridation for less than 10% of their lives (n = 268) it was 2.28 (SD = 3.48). In 1987/88, the last year of optimal fluoridation, the mean dmft of Anglesey 5-year-old children was 0.80 (SD = 1.43) and for those resident on the non-fluoridated Gwynedd mainland it was 2.26 (SD = 3.17). The study demonstrates the serious consequences for dental health when fluoridation is withdrawn and how difficult it will be to reach dental health targets in North Wales without fluoridation. PMID- 7848758 TI - The effect of 25 years of water fluoridation in Newcastle assessed in four surveys of 5-year-old children over an 18-year period. AB - In 1994, the dental health of 496 5-year-old children who had lived in continuously fluoridated (at 1.0 mg F/litre) Newcastle was compared with the dental health of 436 children of the same age in non-fluoridated (less than 0.1 mg F/litre) south east Northumberland. The study also reported changes in the dental health of 5-year-old children in four surveys in these areas during the period 1976 to 1994. The mean dmft of children in the fluoridated area was 1.33 compared with 2.41 in the non-fluoridated area--a difference of 1.08 per child (45%). The corresponding dmfs scores were 2.80 in the fluoridated area and 5.77 in the non-fluoridated area--a difference of 2.97 tooth surfaces per child (52%). Thirty-nine per cent of children in the fluoridated area had experienced dental caries, compared with 55% in the non-fluoridated area. Only 10% of children in the fluoridated area had experienced dental caries in more than four teeth, compared with 22% in the non-fluoridated area. The prevalences of lifetime experience of toothache, extractions and general anaesthesia for dental extractions were greater in the non-fluoridated area than in the fluoridated area. When the results of this survey were compared with the results of similar surveys in the same areas in 1976, 1981 and 1987, it appeared that there has been a further reduction in dental caries levels following the levelling off observed between 1976 and 1981. PMID- 7848759 TI - Munchausen's syndrome: oral presentations. AB - Munchausen's syndrome is a rare psychiatric disorder in which patients repeatedly confabulate so as to cause unnecessary investigations and operative treatments to be carried out on them. Two cases are reported and the literature reviewed. The first patient complained of repeated dental pain and subsequently underwent repeated endodontic treatment; the second had salivary gland pain and glossopharyngeal neuralgia. Munchausen's syndrome can only be diagnosed by the exclusion of organic and other disease. PMID- 7848760 TI - Patient-induced malocclusion. PMID- 7848761 TI - Celebrating 50 years of fluoridation: a public health success story. AB - Community water fluoridation has served Americans extremely well as the cornerstone of dental caries prevention activities for over 49 years. While January 25, 1995, marks the fiftieth anniversary of fluoridation's inauguration at Grand Rapids, Michigan, the dental and general health benefits associated with the ingestion of water-borne fluorides have been well known by researchers for an even longer period. Continued research has repeatedly confirmed the safety, effectiveness and efficiency of community water fluoridation in preventing dental caries for the world's population. PMID- 7848762 TI - Clinical decision making--an art or a science? Part I: An introduction. AB - In order to make the most appropriate decision in a given set of circumstances, an understanding is needed of how people formulate decisions on the basis of their surroundings. Using a case history, this article introduces the factors involved in clinical decision making and highlights the relevance of those factors in the decision making process. These will be discussed in depth in later sections of this series. PMID- 7848763 TI - Forging new partnerships. Case management in radiology. PMID- 7848764 TI - Redesigning care using total quality management and outcome/variance analysis. PMID- 7848765 TI - Team building: getting beyond the hype and into outcomes. PMID- 7848766 TI - School-based and school-linked health centers: core issues for nurse executives. PMID- 7848767 TI - [Perioperative transfusions and survival after interventions for potentially curable stomach cancer: the preliminary considerations from a retrospective sampling study]. PMID- 7848768 TI - [Variations in the antibiotic sensitivity of bacterial strains after contact with the metals used for the construction of prosthetic implants]. AB - The antibiotic sensitivity of 19 Gram-positive bacterial strains (11 Staphylococcus aureus and 8 Staphylococcus epidermidis) and 16 Gram-negative strains (8 Escherichia coli and 8 Proteus species) was evaluated after contact with stainless steel and with some metals compounding the alloys used for prosthetic devices. The hypothesis was that the resistance to antibiotic therapy of infections associated with prosthetic implants is also due to a modification in the sensitivity of microorganisms. The results, compared to those obtained from control tests, showed only slight variations in the antibiotic sensitivity of the strains put in contact with the metals. In Gram-positive strains, after contact with metals, the increase in sensitivity occurred more frequently than the reduction. In Gram-negative strains, the decrease in sensitivity was more frequent than the increase. Proteus strains showed sensitivity variations more frequently than Escherichia coli strains. Titanium and nickel induced the highest number of variations, both in Gram-positive and Gram-negative strains. PMID- 7848769 TI - [Immune evaluations in cancer patients after colorectal resection]. AB - The authors report a protocol of immunomodulation and monitoring of the intestinal function in coloresected patients using fermented milk (yoghurt). Intestinal immunity was evaluated with respect to CD4+ cells armed with secretory intestine-derived IgA, and to CD8+ cells armed with IgG aiming to an additional effect in the host protection against Gram-negative strains, such as Salmonella typhi, whose particularly high incidence in Apulia accounts for an increased immunitary activity. Ten patients (six females, four males), age ranging from 44 to 85 years, who underwent surgery between 1989 and 1992, each of whom had been prescribed a daily ration of 500 gr skimmed yoghurt for one month, were observed. The authors suggest that yoghurt may determine a higher release of gamma-IFN with activation of CD4+ and CD8+ cells. The Lactobacillus stimulation of the B lymphocytes of the Peyer plates seems to induce an increased production of secretory IgA that bind to the CD4+ surface, and of IgG (as an anamnestic response to challenge with yoghurt lactobacilli). Coloresected patients show an immunitary deficiency related to the Gram+ bacterial flora reduction and consequently a decrease in the physiological stimuli. Although these date concern a limited sample, the authors stress the importance of the restoration of bacterial flora in coloresected patients. PMID- 7848771 TI - [Surgery of the obstructive complication of carcinoma of the left colon. The clinical problems and the authors' personal experience with 56 surgical cases]. AB - A retrospective analysis was carried out on 56 pts., (37 M, 19 F), mean age 64 yrs., operated for moderate to severe obstruction due to left colon carcinoma. Clinical and pathological features, treatment and results were compared with those of 108 pts. with left colon cancer who underwent elective surgery. Mean duration of obstructive symptoms was 5.3 days and mean delay between admission and operation was 1.15 days. Site and nature of the obstruction were assessed pre operatively in 80.3% of the pts. Distribution of tumor localization was similar in the two groups. ASA risk was statistically higher in pts. with obstruction. Staging according to the Astler-Coller (mod. 1978) classification, showed a greater incidence of more advanced stages in the obstructing tumors. In the group with obstruction a three stage surgery was carried out in 18 pts. (32.1%), a two stage in 6 (10.7%), a primary resection in 6 (10.7%) and a decompressive colostomy in 26 (46.5%). Radicality and resectability rates were 50% and 53.6% vs 69.4% and 82.4% in elective surgery. Mean post-operative stay was 42 and 21 days respectively in the two groups. Overall post-operative death rate was 19.6% vs 9.2%, and 3.3% vs 7.8% after resective surgery. Post-operative complications accounted for 21.4% vs 21.3%. 5-year survival rate after curative surgery was 47.8% vs 76.8%. On the basis of their results and on Literature reports the Authors suggest a reevaluation of a staged surgical treatment for obstructing left colon cancer based on primary decompression following an E.L. when needed. Consequent resection and intestinal reconstruction should be performed after 2-3 weeks.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7848770 TI - [Adenocarcinoma of the small intestine. A case report and the clinico-therapeutic considerations]. AB - Adenocarcinoma of the small bowel is a rare tumor. The diagnosis is often tardy and surgical treatment is still palliative in most cases. A major interest toward this kind of tumor as well as an early diagnosis may give the opportunity to perform a radical operation allowing better results in terms of survival. PMID- 7848772 TI - [Current trends in the treatment of giant nonparasitic cysts of the liver]. AB - The authors report 10 cases of giant non-parasitic congenital cysts of the liver (7.7-25 cm in size). All the patients were symptomatic; preoperative ultrasonography was diagnostic in all cases allowing to discover the cyst. Six patients underwent partial resection of the cyst (in one of these a cystojejunostomy was performed), while atypical hepatic resection was performed in two cases, enucleation in one and left lobectomy in another case. No evidence of malignant degeneration was found in the histologic study of the specimens. No mortality nor morbidity were registered. All patients were followed up for 1-20 years and no recurrences were found. The authors point out that partial resection of the cyst is a safe operation with good immediate and long-term results. PMID- 7848773 TI - [The superior thoracic outlet syndrome: a clinical case report and review of the literature]. PMID- 7848774 TI - [Lipoma of the colon: a case report]. PMID- 7848775 TI - [Gastric angiodysplasia: a rare cause of bleeding from the upper digestive tract]. AB - Two cases of bleeding gastric angiodysplasia treated with a different approach, on the basis of the endoscopic features, are reported. Arteriovenous malformations may arise from any site of the digestive tract: gastric angiodysplasia represents one of the less frequent localizations, causing 2-5% of upper gastrointestinal bleeding. Several diagnostic tools are currently available and the choice of the most appropriate therapeutic strategy depends on many features: site and number of the lesions, patient's hemodynamic conditions, endoscopic skill. Surgery is preferred only when multiple and disseminated lesions within the gastric wall occur or when endoscopic approach fails. PMID- 7848777 TI - Use of ferrous sulphate and immunomagnetic separation to recover Salmonella enteritidis from raw eggs. AB - Contaminated eggs or foods containing eggs have been a source of food borne salmonellosis, with a significant proportion of these outbreaks being attributed to Salmonella enteritidis. Since the level of contamination in individual eggs or a pool of such eggs may be low, enrichment to increase cell numbers can take several days. Pre-enrichment of raw blended eggs which have been supplemented with ferrous sulphate at a concentration of 35 mg/l, for 6 h at 37 degrees C, significantly enhanced the growth of Salmonella. Using Dynabeads Anti-Salmonella (Dynal, Oslo), a new commercial product for selective enrichment of Salmonella from food samples, we have defined a protocol based on immunomagnetic separation, specially for raw eggs. The application of this protocol enables definitive detection of Salmonella enteritidis from eggs within 30 h. PMID- 7848776 TI - Microbial biofilms in the food processing industry--should they be a concern? AB - Biofilm formation will occur on solid surfaces in contact with a liquid. Organic and inorganic material in the liquid sediment onto the solid material. Subsequently, biologically active microorganisms will be attracted to this conditioned surface and adhere to it. The microbial cells will initiate growth, form an attachment matrix and develop into a complex community forming a microbial biofilm. Such microbial biofilms are common on solid surfaces in contact with many different kinds of liquids, fresh water, sea water, oil, milk and so on. These biofilms may be of benefit or be detrimental to the environment where they form. The goal of this review has been to summarize the literature on the development of microbial biofilms in these different environments with particular emphasis on what occurs in the environment of a food processing plant. Methods to control adherent microorganisms and subsequent biofilms in the food processing plant are discussed. It is apparent from the data that has been reviewed that the potential for the development of microbial biofilms in the environment of the food processing plant exists. However, the cleaning and sanitizing practices carried out in the food industry have been shown to control biofilm formation on food contact surfaces. Microbial attachment has been shown to occur on non-food contact surfaces and these attached microbes, if left undisturbed, will form biofilms. The potential for contamination of food with undesirable spoilage and pathogenic bacteria from attached microbes and biofilms exists in these food processing systems. Biofilm formation on non-food contact surfaces needs to be studied further and methods developed to prevent and control these biofilms. PMID- 7848778 TI - IMS: a new selective enrichment technique for detection of Salmonella in foods. AB - In a study designed to evaluate the performance of Dynabeads Anti-Salmonella, immunomagnetic separation (IMS) followed by plating (IMS-Plating) proved far superior to the conventional ISO Salmonella methodology and the Modified Semi solid Rappaport-Vassiliadis (MSRV) method. Salmonella species were isolated and detected from 135 out of the 180 diverse poultry samples by IMS analysis as against 98 by the conventional method and 33 by the MSRV technique. All results were confirmed biochemically and serologically. It appeared from the data generated that some of the salmonellae isolated using IMS were greatly inhibited in Rappaport-Vassiliadis enrichment broth at 42 degrees C and to a lesser extent in selenite cystine broth at 37 degrees C. A moderately selective plating medium like XLD proved to be better in isolating these possible sensitive wild-type strains of salmonellae than the more selective BGA. PMID- 7848779 TI - Identification of psychrotrophic Micrococcaceae spp. isolated from fresh beef stored under carbon dioxide or vacuum. AB - Seventy-four Gram-positive, catalase-positive coccal strains were isolated from fresh beef stored under carbon dioxide (< 500 ppm O2) or vacuum for up to 15 weeks at 0, 2 or 4 degrees C. Isolates were identified using biochemical tests listed in several published protocols and the API Staph-Ident System. No isolates were identified as Staphylococcus aureus. Twenty-nine isolates were identified as Staphylococcus saprophyticus (five distinct groups), 24 isolates were identified as Staphylococcus gallinarum and 21 isolates were identified as Micrococcus varians. The staphylococcal isolates were coagulase-negative, non-hemolytic and novobiocin resistant. They produced acid from several carbohydrates under aerobic conditions, hydrolysed gelatin but not collagen, showed lipolytic activity and grew in 15% NaCl. The Micrococcus varians isolates also were salt-tolerant, produced acid only from glucose, fructose and galactose (two strains), and were resistant to lysozyme (1600 micrograms/ml). Lactic acid was the major end product of aerobic glucose metabolism. All S. saprophyticus and M. varians isolates tested contained cell wall fatty acids with chain length > or = C20:0. PMID- 7848780 TI - Characterisation of lactic acid bacteria isolated from naturally fermented Greek dry salami. AB - A total of 348 lactic acid bacteria isolated from five batches of naturally fermented dry salami at various stages of ripening were characterised. The majority of the strains were assigned to two main phylogenetic groups of species: (i) the psychrotrophic, formerly called atypical, meat streptobacteria (169 strains) and (ii) a new genus Weissella (120), which was recently proposed (Collins et al., 1993) to include Leuconostoc paramesenteroides and some other closely related species. Meat streptobacteria were identified as Lactobacillus curvatus (88 strains) and L. sake (76), whereas 5 strains were indistinguishable and, thus designated L. sake/curvatus. Non-psychrotrophic streptobacteria were also isolated and identified as L. plantarum (34 strains), L. farciminis (10), L. coryniformis (1) and L. casei subsp. pseudoplantarum (1). The majority of the Weissella strains (86) were leuconostoc-like bacteria; four of them were identified as W. viridescens, 11 belonged to the newly described W. hellenica (Collins et al., 1993), another 11 resembled W. paramesenteroides, whereas 60 isolates were not classified to any species. The latter group comprised strains that produced D(L)-lactate. The remaining Weissella were gas-forming, arginine positive rods assigned to W. minor (31) and W. halotolerans (3). Other species identified were Enterococcus faecium (10), Leuconostoc mesenteroides (1), L. brevis (1) and Pediococcus sp. (1). The main criteria used to distinguish between above species as well as their distribution on the five salami batches in relation to their succession with time and suitability as starters were discussed. PMID- 7848781 TI - Reduction of Yersinia enterocolitica and Listeria spp. on pig carcasses by enclosure of the rectum during slaughter. AB - By sealing off the rectum with a plastic bag immediately after it had been freed, the spread of Y. enterocolitica O:3/biovar 4 to pig carcasses could be considerably reduced. The organism was recovered from only 0.8% of carcasses when the plastic bag technique was employed. Y. enterocolitica O:3/biovar 4 was recovered from 10% of pig carcasses when eviscerating procedures did not include the use of the plastic bag technique. There was thus an obvious risk of the bacteria further contaminating meat cuts and other meat products. The plastic bag technique was effective both in connection with manual excision of the rectum/low throughput (90 per h), and mechanical freeing of the rectum/high slaughter rate (240 per h). L. monocytogenes was not detected in any of the samples taken from 120 pig carcasses in Norway or from 120 pig carcasses in Sweden. The plastic bag technique was used on half of these pigs. L. innocua was tested for in 120 pigs slaughtered in Sweden. The bacterium was recovered from 33% of the carcasses eviscerated without using a plastic bag, and from 10% of the carcasses in which this technique was employed. The results suggested that there were other, non faecal, sources of contamination. Other measures in addition to the plastic bag technique are therefore required to limit the spread of Listeria spp. By incorporating the plastic bag technique into the slaughtering procedures, the meat industry would contribute to preventing the dissemination of Y. enterocolitica and other pathogens which spread via the faeces. PMID- 7848782 TI - Heat resistance of Saccharomyces cerevisiae strains isolated from spoiled peach puree. AB - The heat resistance of three Saccharomyces cerevisiae strains isolated from spoiled peach puree, in McIlvaine buffer (pH 4 and 7) and peach puree (pH 3.9) was studied. The D60-values in buffer at pH 7 were 0.75, 1.32 and 0.14 min for the strains 173, 180 and 325, respectively. The pH of the buffer did not influence the heat resistance of the three strains studied. The thermal sensitivity for all strains assayed was higher when peach puree was used with D60 values of 0.53, 0.20 and 0.10 min for the strains 173, 180 and 325, respectively. The menstrua used had limited influence on the z-values, varying between 3 (strain 173, pH 4) and 4 (strain 325, peach puree). PMID- 7848783 TI - Malate and glucose in milk incubated with psychrotrophic bacteria. AB - L-Malate consumption by the natural microflora of milk and a strain of Pseudomonas fluorescens was followed during storage of milk at 7 degrees C. Use of milk malate by somatic cells from mastitic milk was investigated and found to be insignificant. L-Malate seems to be a potential indicator for the growth of psychrotrophic bacteria in refrigerated milk at levels between 10(5) and 10(7) CFU/ml. PMID- 7848784 TI - Presence of Aeromonas hydrophila in slaughtered animals. AB - The fate of Aeromonas hydrophila after a bacteriaemia in four healthy pigs intravenously inoculated with 10(9) and 10(15) cells of the bacterium was investigated. In two pigs slaughtered 30 min after inoculation the bacteria were found in blood (8 x 10(2)/ml and 4.2 x 10(2)/ml), meat and fatty tissues (1 10/g), but not in liver, spleen and superficial inguinal lymph nodes. A. hydrophila was not found in blood, meat, fatty tissue, liver, spleen, kidneys and superficial inguinal lymph nodes of other two pigs slaughtered 5.5 h postinoculation, with exception of one superficial inguinal lymph node of one pig. PMID- 7848785 TI - Influence of the inoculum concentration on the recovery of Listeria from meat by L-Palcamy enrichment. AB - Concentration of the inoculum in L-Palcamy broth enrichment had a marked influence on the recovery of Listeria from meat samples. A 1/100 dilution of ground meat yielded twice as many positive samples as the usually recommended tenfold dilution, whereas no such effect was observed with cheese or vegetables. PMID- 7848786 TI - Short-comings of irgasan ticarcillin chlorate broth for the enrichment of Yersinia enterocolitica biotype 2, serotype 9 from meat. AB - Recovery of Yersinia enterocolitica serotype 0:9 from artificially contaminated minced pork with the enrichment medium irgasan ticarcillin chlorate broth (ITC) was poor. This was due to the lower growth rate of this serotype in comparison with serotype 0:3. Tests on the behaviour of serotype 0:3 and 0:9 towards some selective agents in ITC broth showed that the minimal inhibitory concentration of chlorate was much lower for serotype 0:9 than for serotype 0:3. Omitting chlorate in the ITC enrichment stimulated the growth of pure cultures. Reduction of MgCl2 and malachite green to 80% of the original concentration further increased the growth, so that after 48 h of incubation similar counts (10(7)-10(8) cfu/ml) as for serotype 0:3 were obtained. PMID- 7848787 TI - Hazards of self-medication. PMID- 7848788 TI - A multicentre study to compare the therapeutic efficacy of sustained-release diltiazem and enalapril in the treatment of patients with mild to moderate hypertension. AB - A 14-week study was conducted in order to compare the efficacy and tolerability of a twice-daily sustained-release diltiazem preparation (120 or 180 mg) and once daily enalapril (10 or 20 mg). Patients not achieving an adequate response after 6 weeks on monotherapy were given a combination therapy of twice-daily diltiazem 120 mg and once-daily enalapril 10 mg. Of the 147 patients admitted to the study, 70 received diltiazem and 77 received enalapril; 17 patients subsequently received combination therapy. Blood pressure reductions in patients completing 12 weeks of therapy were (sitting values): diltiazem 120 mg, 10.2/15.2 mmHg; diltiazem 180 mg, 19.1/14.7 mmHg; enalapril 10 mg, 25.7/17.5 mmHg; enalapril 20 mg, 19.6/14.0 mmHg; and combination therapy, 24.6/15.1 mmHg. No significant differences in the incidence level of individual symptoms were seen between the two groups: 34 (49%) in the diltiazem, 37 (48%) in the enalapril group; and, between weeks 6 and 12, 9 (53%) patients taking combination therapy. Two patients withdrew from the enalapril group and 8 from the diltiazem group. No unexpected side-effects were seen during the study and no deaths occurred in any treatment group. Twice-daily sustained-release diltiazem 120 or 180 mg was shown to be an effective antihypertensive agent and equal in efficacy and patient acceptability to once-daily enalapril 10 or 20 mg. Combination therapy effectively lowered blood pressure in patients in whom monotherapy was ineffective. PMID- 7848789 TI - Doxazosin in hypertension: results of a general practice study in 4809 patients. AB - The safety and efficacy of the selective alpha 1-adrenoceptor antagonist doxazosin were evaluated in a 10-week open, non-comparative multicentre trial in 4809 hypertensive patients (sitting diastolic blood pressure 95-114 mmHg) in general practice. Multiple coronary risk factor were present in the study population (mean age 58.4 years, 1486 patients > or = 65 years) on entry: mean blood pressure was 173/103 mmHg, 21% were cigarette smokers, and baseline blood cholesterol (mean 6.84 mmol/l) exceeded 6.5 mmol/l in 56% and 5.2 mmol/l in 88% of patients. In all, 4385 patients (91%) completed the study, including 89% of those > or = 65 years. Blood pressure was controlled (diastolic BP < or = 90 mmHg or a reduction > or = 10 mmHg) in 81% of patients with a mean reduction of 21/15 mmHg and a mean final daily dose of 2.9 mg doxazosin. Adverse events were reported in 827 patients (17%), were severe in 72 (1.5%), and led to withdrawal in 269 patients (5.7%). Dizziness and related symptoms (6%; severe 1.1%), headache (3.8%) and fatigue (2.6%) were most frequent; dizziness led to study withdrawal in 1.3% of patients. Fainting or syncope occurred in 13 patients (0.3%). Differences in adverse event frequency between younger (< 65) and older patients were small (dizziness: younger 5.1%, older 8.1%). Troublesome postural hypotension was uncommon as a clinical problem. Modest but statistically significant reductions occurred in blood total (4.09%) and LDL (5.13%) cholesterol. These results are in accord with those of controlled studies, and help confirm the suitability of doxazosin as part of a multiple risk factor approach to the management of hypertension. PMID- 7848790 TI - Eosinophil cationic protein and prophylactic treatment in pollinosis in natural allergen provocation. AB - In this study, prophylactic treatment with ketotifen and examination of subjective symptoms, blood eosinophil count and serum eosinophil cationic protein (ECP) values were carried out from the pre- to postpollinosis season to evaluate the effects of ECP and characterise the effects of prophylactic treatment on the appearance of these mediators in relation to clinical symptoms. We found that: serum ECP values during the season and post-season were significantly higher than those during the pre-season; there was a significant correlation between serum ECP value and blood eosinophil count during the season; and the levels for all three of the above parameters in the prophylactic treatment group were significantly lower than those in the no-treatment group during the season. PMID- 7848791 TI - Compliance with prescribed medicines in general medical and surgical wards. AB - A total of 6833 doses of medication were prescribed to 753 hospital inpatients in general wards over a 24-hour period (excluding medicines prescribed on an as required basis and medicines prescribed for the first time during the 24-hour period). Of these, 574 (8.4%) doses were omitted, representing at least one omitted dose in 242 (32.1%) patients. Many of the omitted doses were of symptomatic treatments and in 43% of instances omission was deemed, retrospectively, to have been beneficial. Some omissions, however, were of a potentially life-threatening nature. The most common reasons for omission were that the patient refused the drug or that the nurse thought the drug unnecessary, the patient was on 'nil by mouth' or was too ill or unable to take the medicine. Thus, omission of prescribed medicines in general wards is common, often of little consequence or even beneficial, but of a potentially serious nature. PMID- 7848792 TI - A survey of neurological disability at a district general hospital. AB - Neurological disease accounts for 20% of all admissions to medical wards, but the number of inpatients with neurological disability is unknown. The notes of all adult inpatient in a district general hospital were reviewed to identify all those with a neurological disorder. Over 40% of inpatients on medical wards and 4% on surgical wards had a neurological disorder. Stroke was the most common neurological diagnosis, accounting for 36% of neurological disorders and 22% of all patients on medical wards. Other neurological diagnoses included dementias 10%, degenerative disorders 10%, epilepsy 7%, demyelination 4%, and head injuries 3%. Neurological patients have long inpatient stays (mean 80 days), and often remain in hospital awaiting changes in accommodation. Seven patients under 65 years stayed more than 6 months awaiting long-term care. Neurological disorders contribute significantly to the inpatient workload. Identifying those requiring rehabilitation and concentrating them on one ward could improve the quality and efficiency of their care. PMID- 7848793 TI - How many stool specimens are enough? PMID- 7848794 TI - Evaluating the use of a semiautomated cuff-oscillometric sphygmomanometer in the hypertension clinic. AB - Measuring blood pressure in the clinic setting is confounded by 'white coat' hypertension, observer bias and digit preference. In this study a semiautomatic blood pressure measuring device (the UA-751) was tested for its use as a reliable assessment of blood pressure and improved patient management in the hypertension clinic. Blood pressures were recorded in 156 patients and compared with physicians' readings measured using a standard mercury sphygmomanometer. The mean blood pressure differences between the two methods showed that the device gave consistently higher readings for both systolic (1.4-3.6 mmHg) and diastolic (3.6 3.8 mmHg) pressure, whether it was used before or after physician consultation. No reduction in 'white coat' hypertension was thus apparent. There was considerable variability between recordings made by the two methods on the same individual. Digit preference was apparent with physician readings, with zero recorded in 57.8% of systolic readings compared with 12.2% using the machine. Different management decisions would have been taken in 20 (13.6%) patients had the UA-751 recordings been used. The device is thus of no value in patient management in the setting of the hypertension clinic. PMID- 7848795 TI - Structural changes in hypertension, the potential for their prevention, arrest and reversal: a focus on felodipine. AB - Hypertension is accompanied by a series of structural adaptations and pathological alterations in the heart and vessels. These include hypertrophy of the left ventricle and walls of resistance vessels, degeneration of elastic components in the walls of large arteries, atherosclerosis and glomerulosclerosis. In order to improve prognosis it is important that the antihypertensive drugs used can prevent or regress these processes, and this review focuses on the experience with the vascular selective calcium antagonist felodipine. Clinical studies show that antihypertensive treatment with felodipine promotes regression of left ventricular hypertrophy, increases compliance of large arteries, and has favourable effects on renal function. In addition, experimental data have shown that felodipine inhibits atherosclerotic plaque development. As structural cardiovascular changes appear early in hypertension, intervention with antihypertensive therapy is better initiated sooner than later. Vascular selective calcium antagonists, such as felodipine, appear effective in reducing blood pressure and in ameliorating hypertension-induced structural changes. PMID- 7848796 TI - Have we identified the factors affecting prognosis following coronary artery bypass surgery? AB - Although coronary artery bypass graft (CABG) surgery has been an established therapeutic alternative for more than 20 years in the palliation of symptoms of ischaemic heart disease, the associated risk factors for subsequent mortality and morbidity in these patients remain unclear. This is pertinent, as CABG surgery does not affect the underlying pathological process and different factors affect the early and late postoperative outcomes. As one objective of CABG surgery is to provide symptomatic relief of angina, it is desirable to identify (and perhaps modify) the factors affecting prognosis and outcome. An awareness of these factors will allow better patient selection and the development of better screening and therapeutic interventions. PMID- 7848797 TI - The use of bisphosphonates in osteoporosis. AB - Bisphosphonates comprise a relatively new class of drug developed to inhibit bone resorption. They are used in Paget's disease and tumour bone disease and recently also in osteoporosis. In the latter, they inhibit further bone loss in postmenopausal osteoporosis as well as other types of bone loss, such as that suffered during immobilisation or steroid therapy. PMID- 7848798 TI - Therapy options in Alzheimer's disease. AB - The aetiology of Alzheimer's disease and senile dementia of the Alzheimer type (AD/SDAT) are unknown, and primary prevention is thus infeasible. As overactivity in the hypothalamic-pituitary-adrenal axis (possibly indicating maladaptation to stress) and vitamin B12 deficiency are common, secondary prevention should focus on stress and dietary factors. Nerve growth factors and ganglioside GM1 have been used to inhibit progression of the disorder, but this treatment is still at an experimental stage, as are efforts to prevent the formation of amyloid. Breakthroughs in AD/SDAT treatment have been seen in trials with supplementation of neurotransmitter deficits. Tacrine, a drug that inhibits acetylcholinesterase, has proved to have a cognitive-enhancing effect, but this is limited in time and the drug has side-effects. Selective serotonin reuptake inhibitors have a proven effect on the emotional disturbances seen in AD/SDAT. PMID- 7848799 TI - Buprenorphine and hepatic pruritus. AB - Pruritus in cholestatic liver disease can be difficult to treat. It may be related to impaired excretion of large opioid peptides. Buprenorphine, a drug with partial opiate antagonist properties, was used in a double-blind trial of five patients with uncontrollable itching. One patient improved clinically, one patient had good relief from pruritus and three had intolerable side-effects. Buprenorphine may be of limited use in intractable pruritus. PMID- 7848800 TI - Simultaneous exposure to lead, arsenic and mercury from Indian ethnic remedies. AB - We report the case of an Asian woman who was exposed to toxic levels of lead, arsenic and mercury through the use of Indian ethnic remedies, and who suffered symptomatic lead poisoning. We know of no other case of exposure to such a combination of heavy metals from this source. We believe that control of the dispensing of these compounds is essential. PMID- 7848801 TI - Undisclosed self-medication--a clinical pitfall. AB - Over-the-counter medication may produce side-effects or precipitate hospital admission. Our patient's self-medication, initially not admitted, led to much mental and physical morbidity. PMID- 7848802 TI - Follicular carcinoma of thyroid presenting as back pain leading to a delay in diagnosis. AB - The case is described of a 53-year-old man presenting with right-sided low back and thigh pain. Non-urgent investigations showed a metastatic lesion in his right hemipelvis arising from a thyroid primary. PMID- 7848803 TI - Self-inflicted IM injection of air into the hand. PMID- 7848804 TI - An unusual presentation of gas gangrene complicated by penicillin allergy. AB - A case is reported of non-clostridial gas gangrene that presented in a similar way to deep venous thrombosis and then developed into septic shock. Management was complicated by penicillin allergy. PMID- 7848805 TI - It's not cricket! Myocardial infarction following non-penetrating blunt chest trauma. AB - While playing a game of cricket, a 42-year-old man was struck on the chest by the ball. The blunt trauma precipitated a myocardial infarct in the absence of other risk factors or evidence of pre-existing coronary artery disease. Probable pathophysiological mechanisms and potential problems of immediate treatment are discussed. PMID- 7848807 TI - Congenital dislocation of the knee as a consequence of persistent amniotic fluid leakage. PMID- 7848806 TI - Vestibulocochlear dysfunction following epidural anaesthesia in labour. AB - A case is reported of vestibulocochlear dysfunction following accidental dural tap during epidural anaesthesia in labour. The aetiology and the world literature are reviewed. PMID- 7848808 TI - Rectoperineal fistula: an unusual cause of anogenital discharge. AB - The serendipitous presentation of a rectoperineal fistula in a 34-year-old nulliparous woman is described. This surgically correctable cause of an anogenital discharge posed a risk (if unrecognised) of producing a rectovaginal fistula at the time of vaginal delivery. PMID- 7848809 TI - 31P NMR in vivo study of the acute effects of different doses of gamma-radiation on rat brain phosphate metabolism. AB - Changes in relative levels of brain phosphates and intracellular pH at selected time intervals after total gamma-irradiation of a rat at a single dose of 6.5 or 300 Gy were studied by 31P NMR in vivo. Irradiation yielded only minor changes in the spectra. Irradiation at a dose of 6.5 Gy caused a reversible decrease in Pi and an alkaline pH shift of 0.2 units after day 1, with no change in ATP. The signal, which consisted of alpha-ATP, alpha-ADP, NAD+/NADH and diphosphodiesters, declined after day 6, possibly due to a fall in NAD+/NADH concentration. Irradiation at a dose of 300 Gy led to an increase in ATP from 10 to 13% of total phosphates after day 1. Homeostasis of brain energy metabolism was characterized by the Z-index (normalized sample correlation coefficients averaged over the correlation matrix for NMR-measured phosphomonoesters, Pi, pH, phosphocreatine, gamma-ATP+beta-ADP, alpha-ATP+alpha-ADP+NAD+/NADH+diphosphodiesters and beta ATP). The Z value rose from -0.18 +/- 0.02 to -0.02 +/- 0.02 by day 6 or from 0.19 +/- 0.02 to -0.07 +/- 0.02 by day 1 after irradiation at a dose of 6.5 or 300 Gy, respectively. This may indicate a pathological state of brain energetics as a system and a decrease in its stability. PMID- 7848810 TI - 13C NMR kinetic studies of the rapid stimulation of glucose metabolism by estrogen in immature rat uterus. AB - Glucose metabolism in control and estrogen stimulated rat uteri was investigated using 13C NMR spectroscopy. By employing an NMR adapted perifusion system, and developing protocols and methods based on the application of [1-13C]glucose labeling, it was possible to measure, with a temporal resolution of 10 min, the kinetics of glucose consumption, lactate production and 13C incorporation into glutamate, alanine and glycogen. In control immature rat uteri, under aerobic conditions, the rates (+/- SEM) of [1-13C]glucose consumption and [3-13C]lactate production were 24 +/- 2 and 7.5 +/- 0.5 mmol/g wet weight/h. The rates of synthesis of [4-13C]glutamate, [3-13C]alanine and 13C labeling of glycogen at C1 of its glucose moieties were significantly lower and were in the range 0.3-0.6 mmol/g wet weight/h. Thus, ca 35% of the labeled glucose was accounted for by the glycolytic and other observed pathways. In vitro stimulation of the uteri by estrogen was found to increase significantly, within 1 h, glucose consumption by 80%, lactate production by 150% and glutamate and glycogen synthesis by 150%, in parallel to a rapid hormonal induction of mRNA for the brain type isozyme of creatine kinase. PMID- 7848811 TI - Saturation correction in human cardiac 31P MR spectroscopy at 1.5 T. AB - This study was conducted to verify the validity of using saturation factors obtained from unlocalized 31P spectra containing both chest wall and heart muscle signals for correcting human heart muscle phosphocreatine/beta-adenosine triphosphate (PCr/beta-ATP) ratios. Saturation factors and T1 relaxation times were determined from 31P magnetic resonance spectra of human chest wall and heart muscle simultaneously in healthy volunteers using one-dimensional spectroscopic imaging in combination with a two-dimensional ISIS sequence by using adiabatic 180 degrees inversion and adiabatic 90 degrees excitation pulses at 1.5 T. Blood corrected saturation factors for PCr/beta-ATP at a TR of 2.4 s were significantly different in heart muscle and chest wall muscle, 1.30 +/- 0.25 and 1.73 +/- 0.31, respectively (p < 0.05). T1 values for PCr and beta-ATP in heart muscle were 4.28 +/- 0.72 and 2.99 +/- 0.52 and in chest wall muscle 6.82 +/- 1.07 and 3.39 +/- 0.48, respectively. The T1(PCr)/T1(beta-ATP) ratios in chest wall and heart muscle were not identical. The mean PCr/beta-ATP ratios in heart and chest wall muscle of six healthy volunteers were 1.23 +/- 0.17 and 3.71 +/- 0.53, respectively. PMID- 7848812 TI - Comparison of calibration strategies for the in vivo determination of absolute metabolite concentrations in the human brain by 31P MRS. AB - Cerebral concentrations of phosphorus metabolites can be assessed non-invasively by 31P MRS provided the metabolite signals are calibrated with the signal of a standard of known concentration. The reliability of the concentration estimates depends mainly on the strategy of calibration. Three strategies were compared by assessing the concentrations both in a test dummy and in the brain of volunteers. The first strategy utilized tissue water as an internal heteronuclear concentration standard. The second and third strategies used as phosphorus solution as an external homonuclear standard; this solution was either put into a reference bottle placed on top of the head or into a simulation phantom measured instead of the head. Localization was always achieved with the ISIS pulse sequence. The two external homonuclear strategies achieved a higher accuracy (mean error approximately 5%) and reproducibility (mean SD approximately 8%) of the concentration estimates than the internal heteronuclear strategy (mean error approximately 11%; mean SD approximately 15%). PMID- 7848813 TI - Decrease in brain choline-containing compounds following a short period of global ischemia in gerbils as detected by 1H NMR spectroscopy in vivo. AB - Cerebral metabolism was studied in the postischaemic gerbil brain using surface coil 31P and 1H NMR spectroscopy. The ratio of choline-containing compounds (Cho) to total creatine (Cr) in the brain decreased from 0.46 +/- 0.02 to 0.32 +/- 0.02 by the fifth day following exposure to 5 min of global ischaemia and it remained at this low level for at least 19 days. The amounts of cerebral Cho as quantified by 1H NMR in vivo were 1.70 +/- 0.15 and 1.09 +/- 0.22 mmol/kg in control and postischaemic animals, respectively. The T2 of Cho was longer in the postischaemic cerebral cortex than in the control one. N-acetyl aspartate (NAA) as determined by 1H NMR in vivo did not differ in the two animal groups. High resolution 1H NMR of acid-extracted brain cortices showed a decrease in total Cho (glycerophosphocholine, phosphocholine and choline) by 31%, but no changes in NAA, total creatine, taurine and myo-inositol, in the brain cortex seven days postischaemia relative to control animals. The decrease in acid extractable Cho was mainly due to the drop in glycerophosphocholine concentration. 31P NMR indicated normal energy state and phosphomonoester/phosphocreatine (PCr) and phosphodiester/PCr ratios in the in vivo brain 7 days postischaemia. Silver impregnation did not reveal neuronal degeneration but immunohistochemical staining showed a number of glial fibrillary acidic protein expressing astrocytes as indicators of reactive gliosis in the postischaemic cerebral cortex. These data show, for the first time, that a 1H NMR decrease in Cho metabolites takes place as a consequence of brief ischaemic episode even in the absence of obvious neuronal degeneration. PMID- 7848814 TI - Investigation of broad resonances in 31P NMR spectra of the human brain in vivo. AB - Broad resonances that lie underneath the familiar small molecule profile of in vivo 31P NMR spectra can make accurate spectral integration of these mobile phosphates difficult. The two major broad components are the phosphate contained in the hydroxyapatite in cranial bone and the phosphodiester moiety in partially mobile membrane phospholipids. They can be removed with post-acquisition processing but this results in distortion of lineshapes and intensities and interferes with accurate quantitation. We have employed an off-resonance saturation procedure to eliminate the bone resonance and isolate the signal from the membrane phospholipids by subtraction. Selective saturation of the phospholipid resonance increases the clarity of the sharp peaks downfield from the phosphocreatine peak. Selective saturation 3-D chemical shift imaging techniques were used to create a localized phospholipid profile of the entire brain simultaneously. Monitoring localized phospholipid concentration may be important in studying demyelinating diseases. PMID- 7848815 TI - Internal temperature calibration for 1H NMR spectroscopy studies of blood plasma and other biofluids. AB - A method for temperature calibration of human blood plasma and cerebrospinal fluid (CSF) samples inside a high resolution NMR spectrometer is presented. This calibration is based on the temperature dependence of the chemical shift difference between the water signal and that from the H-1 proton of endogenous alpha-glucose or, in some circumstances, beta-glucose. This dependence can be fitted using a second-order polynomial equation and functions for both human blood plasma and human CSF are given. Similar graphs could easily be generated for other fluids. The blood plasma calibration appears to be accurate to +/- 0.9 K in test samples. The use of the blood plasma calibration graph has also been evaluated using the 1H NMR spectra of CSF and shown to overestimate the CSF internal temperature by ca 1.3 K. This approach should have a general applicability to blood plasma and CSF samples from normal and pathological situations or from other species, because there are unlikely to be large changes in ionic strength or pH even in disease states. Knowledge of the exact internal temperature of plasma samples is likely to be of particular importance in the investigation of lipid and lipoprotein interactions because of the significant temperature dependence of lipid and lipoprotein NMR linewidths in such samples. PMID- 7848816 TI - Infectious syphilis. AB - Optimistic predictions about the extinction of syphilis have proven to be premature. During the beginning of the decade, the reported numbers of infectious syphilis cases were the highest in 40 years. Despite numerous publications about syphilis, the disease continues to challenge clinicians with its protean cutaneous and systemic manifestations. Co-infection with the human immunodeficiency virus does not appear to significantly influence the stage at presentation, clinical course or serologic positivity in most patients, but coinfected patients may be at risk of developing neurosyphilis and late complications even after administration of adequate treatment. PMID- 7848817 TI - Ectoparasites as sexually transmitted diseases. AB - Although Sarcoptes scabii and Phthirus pubis infestations in humans are not always associated with the presence of other sexually transmitted diseases, usually they are. Therefore, patients presenting with scabies or P. pubis should be routinely tested for various sexually transmitted diseases. These very uncomfortable infestations are easily curable with proper therapy. Lindane 1% preparations effectively exterminate both vermin. We have not seen any resistant strains. Especially with P. pubis, all household contacts should be treated to avoid reinfestation. PMID- 7848818 TI - Management of genital herpes infection. AB - Genital herpes infections are a major source of morbidity. These infections are responsible for significant health problems, including direct physical discomfort associated with outbreaks, potential complications such as neonatal transmission, and the often devastating psychological effects of a chronic illness. In addition, herpes infections have been identified as a significant co-factor in the transmission of human immunodeficiency virus infection. Accurate and rapid diagnosis and treatment are important steps necessary to minimize these effects. PMID- 7848819 TI - Sexually transmitted diseases in neonates and infants. AB - With the current resurgence of sexually transmitted diseases (STDs), familiarity with the clinical manifestations of STDs in neonates and infants is essential to minimize the tragic consequences. The recognized routes of transmission of the diseases include transplacental, intrapartum, and postpartum exposure. This discussion will be confined to infections caused by syphilis, herpes simplex virus, human papillomavirus, gonorrhea, and chlamydia emphasizing clinical aspects in this population. PMID- 7848820 TI - Vulvar manifestations of sexually transmitted diseases. AB - On the vulva, the appearance of sexually transmitted diseases (STD) is modified for several reasons. Recognition of the special characteristics of vulvar epithelium facilitates diagnosis of both sexually transmitted diseases and vulvar dermatoses that may be mistaken for STDs. The first section will review examination techniques and anatomic considerations. The second section will describe distinctive manifestations of vulvar herpes, human papillomavirus (HPV), molluscum contagiosum, scabies, and syphilis. The final section will provide differential diagnoses for primary and secondary vulvar lesions including erythema, papules, plaques, pustules, bullae, erosions, and ulcers. PMID- 7848821 TI - The 1993 sexually transmitted disease treatment guidelines. AB - This article will review the 1993 STD Treatment Guidelines of particular importance to dermatologic clinical practice. Topics include STD/HIV prevention, management of sexual partners, STD in persons with HIV co-infection, genital ulcer disease (GUD) including syphilis, herpes simplex virus (HSV) infection, lymphogranuloma venereum (LGV) and chancroid, therapy of nongonococcal (NGU) and chlamydial urethritis and cervicitis, gonococcal (GC) infections, HPV infection, hepatitis B virus (HBV) infection, pediculosis pubis, and scabies. PMID- 7848822 TI - Cutaneous clues to HIV infection: diagnosis and treatment. AB - The skin is one of the most important organs involved in patients with HIV infection. Because it is the one most readily evaluated by inspection, it is essential that clinicians be expert in the recognition of skin disorders that herald the presence of HIV disease or a change in the immune status of one already known to be infected. In this article, the most important cutaneous disorders in patients with HIV infection are discussed with special emphasis on those that can be used to assess prognosis or detect the presence of an opportunistic infection. PMID- 7848823 TI - The politics of acquired immune deficiency syndrome/human immunodeficiency virus. AB - The political process is a decisive factor in determining how governmental funds are allocated for control of all diseases especially one as highly politicized as AIDS/HIV. This article discusses how this process works and how various community groups such as homosexual men, women, African-Americans, and the elderly are affected by the outcome. PMID- 7848825 TI - The location of the third cleavage plane of Xenopus embryos partitions morphogenetic information in animal quartets. AB - Analysis of the developmental potential of animal quartets (the set of four animal blastomeres isolated from the 8-cell stage Xenopus embryo) provided insight into the manner in which morphogenetic information is distributed along the animal-vegetal axis. Gravity treatments were employed to alter the partitioning plane. Animal quartets isolated from embryos exposed to simulated weightlessness had larger animal blastomeres, and they formed structures such as a groove and a protrusion more often than 1g-control animal quartets. Animal quartets with an unusual non-horizontal third cleavage plane were also found to have a higher frequency of protrusion formation than animal quartets with a typical horizontal cleavage plane. The increase in the frequency seen in simulated weightlessness animal quartets was not due to their increased size. Fusing two animal quartets isolated from hypergravity (3g) exposed embryos (small blastomeres and low incidence of protrusions) did not affect the frequency of protrusion formation. Molecular analyses revealed that a partial induction was associated with the protrusion formation. Transcripts of the dorsal lip specific homeobox gene, goosecoid, and alpha-cardiac actin were detectable by PCR amplification in the animal quartet with a protrusion, and alpha-cardiac actin mRNA was found by whole-mount in situ hybridization to be localized in the protrusion. Taken together, all these results are consistent with the notion that both animal and vegetal information is necessary for normal development and the partitioning of morphogenetic information into animal quartets results in gravity dependent differential morphogenesis and gene regulation. PMID- 7848824 TI - Comparative analysis of TGF beta s, BMPs, IGF1, msxs, fibronectin, osteonectin and bone sialoprotein gene expression during normal and in vitro-induced odontoblast differentiation. AB - Immobilized TGF beta 1 and BMP2 are able to promote the differentiation of odontoblast-like cells in isolated mouse dental papillae cultured in vitro. These cells polarize and accumulate predentin-like matrix at their apical pole. Immobilized IGF1 mainly promoted polarization with disturbed matrix accumulation. In situ hybridization demonstrated that TGF beta 1 combined with heparin mirrored the physiological processes of odontoblast differentiation. Normal odontoblast and in vitro induced odontoblast-like cells expressed transcripts encoding for TGF beta 1 and 3, BMP2 and 4, bone sialoprotein and osteonectin whereas either ubiquitous expression or no expression could be detected for TGF beta 2, IGF1 or fibronectin mRNAs. Odontoblast-like cells obtained in the presence of IGF-1 combined with heparin did not express TGF beta 1 transcripts and expressed weakly TGF beta 3 transcripts. Our results suggest that in vivo an epithelial-derived member of the TGF beta family trapped by basement membrane-associated components interacts with competent preodontoblasts and promotes the polarization by triggering the transcription of growth factor gene(s) like TGF beta itself and/or selector gene(s) like msx2. PMID- 7848826 TI - Developmental expression of neurofilament and glial filament proteins in rat cerebellum. AB - Neurofilament protein (NFP) consists of three subunits: NF200, NF150 and NF68. Several studies on expression of NFP in developing brain have shown that NF200 appears later than NF150 and NF68. However, there are some reports on simultaneous appearance of these subunits in development. The present study is an attempt to resolve this controversy. Rat cerebellum was chosen as most of its development takes place during the first three weeks of postnatal period. Cytoskeletal and NFP preparations from newborn (P0), postnatal day 8 (P8), P15, P21, P30 and adult (3 months) rat cerebella were subjected to electrophoresis on 7.5% SDS-PAGE. All the NFP subunits were present from P0 onwards and there was an increase in NFP content and glial fibrillary acidic protein (GFAP) with age as revealed by the densitometric scanning. Immunoblots of NFP preparations confirmed the presence of NF200 in the early postnatal cerebellum. In vivo phosphorylation studies indicated the presence of phosphorylated NF subunits from P8 onwards, which was confirmed by staining in immunoblots by SMI31. Immunohistochemical studies on Bouin's fixed tissues revealed that in P0 cerebella, the deeper neurones (soma and processes) expressed all the NFP subunits while from P8 onwards they were negative for NF200. Similarly, Purkinje cells (soma) expressed transiently NF200 subunits on P8 and ceased to express them from P15 onwards. The white matter was immunopositive for NF200 and NF150 on P0 and the intensity of staining increased progressively. Astrocytes expressing GFAP were seen in cerebellar white matter from P8 onwards and the staining in radial glia could be detected from P15 onwards.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7848827 TI - Transient expression of SPARC in the dorsal axis of early Xenopus embryos: correlation with calcium-dependent adhesion and electrical coupling. AB - Our comprehension of the molecular mechanisms underlying embryogenesis has been greatly enhanced by the identification and characterization of associated extracellular matrix macromolecules. Using Xenopus laevis as a model, we investigated the expression and distribution of SPARC (Secreted Protein, Acidic, Rich in Cysteine; also called osteonectin and BM-40) during early embryonic development. SPARC has been found to be enriched in tissues undergoing rapid morphological development, differentiation, and remodeling. In Xenopus, SPARC transcripts are first expressed by primordial cells which give rise to the first embryonic tissues, the notochord and somites. SPARC RNA levels remained high throughout the rapid morphological development and differentiation phase of these tissues, and then rapidly decreased. Of particular interest, SPARC protein began to accumulate within the intersomitic clefts at the onset of trunk myotome contraction. The intersomitic enrichment of SPARC remained high as long as the myotomes remained electrically coupled, principally by gap junctions. As myotomes became innervated, SPARC expression decreased dramatically within the somites. SPARC was also found to be enriched within other tissues, such as the neural tube and epidermis. In addition, the selective spatial-temporal enrichment of SPARC suggests it makes important calcium-dependent contributions to early morphological development. PMID- 7848828 TI - Dorsoventral polarization and formation of dorsal axial structures in Xenopus laevis: analyses using UV irradiation of the full-grown oocyte and after fertilization. AB - Xenopus laevis embryos which had been UV-irradiated as full-grown oocytes (UV-O) or after fertilization (UV-F) showed typical UV syndrome, namely dorsal axial deficiency. Morphological comparison revealed that UV-O embryos showed a clear dorsoventral polarity from early cleavage to gastrula stage, but UV-F embryos showed radially symmetrical development throughout embryogenesis. Although UV-O embryos developed morphologically normal-looking dorsal lips of the blastopore, they failed to develop dorsal axial structures at later stages. Implantation of dorsal lips demonstrated that the dorsal lip of UV-O embryos had less activity as Spemann's organizer than the dorsal lip of normal embryos. It is thus suggested that a morphological differentiation of the dorsal lip of the blastopore does not necessarily imply a functional differentiation of Spemann's organizer. Dorsal or ventral cytoplasm from normal embryos at the 8-16 cell stage was injected into a blastomere of UV-F and UV-O embryos at the same stage as the donor. The injection of the dorsal cytoplasm could rescue partially the UV syndrome of UV-F but not of UV-O embryos. PMID- 7848829 TI - Degradation of the dental basement membrane during mouse tooth development in vitro. AB - During tooth development, the basement membrane is degraded at the late bell stage, but the developmental significance of this event is not known. Organ culture offers a method where developmental processes can be manipulated in controlled conditions. We cultured bell-stage tooth germs either in a chemically defined or a serum-containing medium and analyzed the degradation of the basement membrane by different methods. Type IV collagen was present throughout the dental basement membranes at the epithelial-mesenchymal interface at the onset of culture. After 10 days of culture, irrespective of the medium used, type IV collagen and laminin had disappeared from the cuspal areas but were present at the cervical loop. As was the case in vivo, the expression of 72 kDa type IV collagenase gene was intense in the differentiating preodontoblasts and in the odontoblasts during secretion of the first predentin matrix near the cuspal tips. Ultrastructural observations showed that the basal lamina had been removed in all cultured tooth organs. Also, the breakdown of the basement membrane occurred irrespective of the presence of mineral in the dentin matrix. Our observations suggest in contrast to earlier observations, that there are no major differences in basic events leading to dentino- and amelogenesis, when tooth organs are cultured in the presence or absence of serum. PMID- 7848830 TI - Evidence for the role of the enamel knot as a control center in mammalian tooth cusp formation: non-dividing cells express growth stimulating Fgf-4 gene. AB - The main morphological features of the mammalian tooth crown are cusps, but the developmental mechanisms that cause the formation of cusps are unknown. Tooth cusp formation commences at cap-stage with the appearance of the enamel knot, which is a cluster of non-dividing epithelial cells. In this study, enamel knot was first seen in embryonic mice molar teeth at the onset of cap-stage. Later in tooth development, secondary enamel knot structures were observed at the cusp tips and their appearance corresponded to the formation of individual cusp morphology. Comparisons of the pattern of cell proliferation in embryonic mouse molars and the expression of fibroblast growth factor-4 (Fgf-4) gene revealed that expression of Fgf-4 mRNA is strictly localized to the non-dividing cells of the enamel knot. However, when FGF-4 protein was introduced onto isolated dental tissues in vitro, it stimulated the proliferation of both dental epithelial and mesenchymal cells. Based on these results, we suggest that the enamel knot may control tooth morphogenesis by concurrently stimulating cusp growth (via FGF-4 synthesis) and by directing folding of cusp slopes (by not proliferating itself). PMID- 7848831 TI - Serially homologous engrailed stripes are generated via different cell lineages in the germ band of amphipod crustaceans (Malacostraca, Peracarida). AB - A monoclonal antibody (mAb 4D9) was used to analyze engrailed expression in amphipod embryos. As in other arthropods, engrailed is expressed in iterated transverse stripes in the germ band. In the anterior region these stripes are generated without a recognizable division pattern, and their appearance and formation show some irregularities. In the posterior region of the germ band, engrailed expression is correlated with a stereotyped cell division pattern resulting in a highly ordered formation and array of stripes. The engrailed positive cells mark the anterior border of genealogical units, which therefore can be compared with parasegments in Drosophila. Expression starts in the mandibular segment and proceeds first anteriorly and subsequently in a posterior direction. Initial stripes are one cell wide. The widening of stripes is caused by both division of engrailed positive cells and recruitment of new cells that did not previously express engrailed. The widening process is related to segment formation as the intersegmental furrows are established behind the engrailed expressing cells, which are restricted to the posterior portion of the forming segments. A comparison of the modes of engrailed expression in different segments suggests that initial engrailed expression is independent of a certain cell lineage or division pattern. The comparison of the development of the early engrailed stripes in different insects and crustaceans reveals some similarities which show that early engrailed expression is not necessarily clonally inherited. PMID- 7848833 TI - Expression of transforming growth factor alpha (TGF alpha), epidermal growth factor receptor (EGF-R) and cell proliferation during human palatogenesis: an immunohistochemical study. AB - Transforming growth factor alpha (TGF alpha) is not only a potent mitogen for several cell types, it interferes with cell differentiation. To investigate the possible role of TGF alpha in the fusion of the palatal processes in humans, the distribution of TGF alpha and its receptor (epidermal growth factor receptor = EGF-R) were studied using immunohistochemistry. 23 human palates were obtained from embryos and fetuses at 6 to 12 weeks of gestation and embedded in paraffin. In each case, the degree of cell proliferation was assessed using an antibody reacting with the nuclear antigen Ki-67. The epithelial and mesenchymal cell phenotypes were studied with anti-cytokeratin and anti-vimentin antibodies. TGF alpha and its receptor were detected in all the human palates, regardless of the stage of fusion. They were more highly expressed in the epithelial cells than in the mesenchymal cells of the palatal shelves. At first, proliferative activity was intense in both the mesenchyme and the epithelia and was later principally limited to the nasal or oral epithelia and also to the degenerating epithelial seam. At 10 weeks, when the midline palatal seam broke up into epithelial islands, the epithelial cells remained immunolabeled for TGF alpha, EGF-R and showed an increased number of proliferating cells. Programmed cell death (PCD) of medial edge epithelia (MEE) has been well documented, however other mechanisms must be considered during palatogenesis. Complex interactions between different growth factors have a probable role in epithelial mesenchymal transformation (EMT) and migration as well as in extracellular matrix synthesis. PMID- 7848832 TI - Expression of proliferating cell nuclear antigen in the mouse germ line and surrounding somatic cells suggests both proliferation-dependent and -independent modes of function. AB - The distribution of proliferating cell nuclear antigen (PCNA) in specific somatic and germ cells of the adult mouse ovary and testis was assessed using immunocytochemical staining and immunoblot analysis and was correlated with cellular proliferation and differentiation. In the adult ovary, immunocytochemical staining for PCNA within follicular cells varied depending on the stage of follicular growth. Since PCNA staining has proven to be a useful indicator of cells involved in DNA synthesis and repair, the pattern of PCNA staining in the ovary was compared to previous studies which used tritiated thymidine labeling as a marker for DNA synthesis. In the testis, PCNA was detected in the mitotically proliferating spermatogonia, but not in spermatocytes which had just entered meiosis. PCNA staining was again observed in spermatogenic cells in later stages of meiotic prophase, in particular zygotene and pachytene spermatocytes. As these cells are undergoing meiotic recombination, the presence of PCNA in these meiotic prophase cells could reflect a second function of PCNA, that of DNA excision repair. PMID- 7848834 TI - Morphological and biochemical analysis of regeneration after cardiotoxin injury of Xenopus laevis fast muscles. AB - The anterior brachial muscle of Xenopus laevis forelimb was characterized as a fast-type muscle composed of type II fibers exclusively. Larval and adult muscles showed three distinct isomyosins composed by two different heavy chains, HCl and HCf, respectively, associated with the same fast light chains. Muscle regeneration was examined after degeneration of the myofibers by injection of cardiotoxin, a snake toxin. 24 h after the injury no myofibers and no myosin were detected. New myosins of larval and adult fast types started to be synthesized two weeks after the injury, during a stage of proliferation of mononucleated cells. 1 month after the injury, the regenerated muscles which showed structural differences with the normal muscle contained only fast isomyosins. The precocious larval to fast heavy chain transition observed in regenerating muscles of the adult X. laevis without any thyroid hormone influence shows that the myogenic program in adult muscle regeneration is regulated by factors that are different from those regulating normal development. PMID- 7848835 TI - The release from metaphase arrest in blue mussel oocytes. AB - In Mytilus edulis, shed oocytes are arrested at metaphase I of meiosis until fertilization. We previously suggested (Dube and Dufresne, J. Exp. Zool. 256:323 332, 1990) that such a metaphase arrest depends upon a continuous synthesis of short-lived proteins, the destruction of which is sufficient to induce meiosis resumption. We further investigated the mechanism of metaphase release in blue mussel oocytes as triggered either by fertilization or by inhibition of protein synthesis (emetine) or phosphorylation (6-dimethylaminopurine, 6-DMAP). Treatment of unfertilized oocytes (UF) with emetine induces completion of the first meiotic cycle including extrusion of the polar body, followed by chromosome decondensation and by the formation of large membrane-bound nuclei, as visualized by Hoechst staining and transmission electron microscopy (TEM). Inhibition of protein phosphorylation with 6-DMAP induces directly chromosome decondensation and the formation of multiple nuclei surrounded by nuclear membrane. These interphasic nuclei exhibit continuous 3H-thymidine incorporation. p13 precipitation of p34 and associated proteins reveals "putative" cyclins in UF, no longer detected after metaphase/anaphase transition due to fertilization or emetine treatment. In the presence of 6-DMAP, new migrating forms are observed. The phosphorylated p34cdc2 homolog becomes dephosphorylated after fertilization or emetine treatment, whereas 6-DMAP induces its phosphorylation on tyrosine. Histone H1 kinase activity is reduced after these treatments, compared to the UF sample. Our results suggest that the metaphase/anaphase transition triggered by fertilization in blue mussel oocytes is induced by the rapid destruction of a set of continuously synthesized proteins accompanied by decreased histone H1 kinase activity. These events can be mimicked by inhibiting protein synthesis. Inhibition of protein phosphorylation would drive the cell to interphase without commitment to meiosis I. PMID- 7848836 TI - Differential synthesis and cytolocalization of prosomes in chick embryos during development. AB - Prosomes, also called "multicatalytic proteinase" or proteasomes, were purified from chick embryos of different developmental stages by a simple, single-step procedure. These were characterized by their characteristic protein patterns determined by SDS polyacrylamide gel electrophoresis (SDS PAGE) and immunoblotting with four monoclonal antibodies, namely, anti-p27, -p28, -p29 and p31, prepared against duck prosomes. In vitro labeling of embryos with 35S methionine followed by SDS PAGE and fluorography of the purified prosomes revealed that their polypeptides are differentially synthesized at various stages during development. Among 12 polypeptides (p21 to p56), p21 is synthesized at the beginning of gastrulation (stage 2) followed by the synthesis of p24 at stage 3. Nine other polypeptides (p25 to p35) are synthesized at the head-fold stage (stage 6), while the synthesis of polypeptide p56 is only detected at stage 10 (10-somite stage). Indirect immunofluorescence studies, with the 4 monoclonal antibodies, demonstrated 3 distinct, developmental stage-specific patterns of cytodistribution of these four prosome polypeptides in the embryos. During early embryogenesis, these are uniformly nuclear in location, while at later stages (stage 4 onwards) they are also present in the cytoplasm. Interestingly, one of the antigens (p 28), although found uniformly in all types of tissues in the embryos up to the gastrulation stage, is undetectable in the neural tissues and nonuniformly distributed in other tissues of stage-10 embryos. These data suggest that there are subcomponents of prosomes which are synthesized as well as distributed in an independent manner during development, possibly reflecting subcomponent-specific multiple functions of these particles. PMID- 7848837 TI - Interleukin-1 and interleukin-6 differentially regulate the accumulation of newly synthesized extracellular matrix components and the cytokine release by developing chick embryo skin fibroblasts. AB - In the present study, we demonstrate that both interleukin-1 (IL-1) and interleukin-6 (IL-6) induced a significant decrease in glycosaminoglycan (GAG) synthesis and, more strikingly, secretion by 7 and 13 day-old chick embryo skin fibroblasts. We demonstrated that interleukin treatment also inhibited the synthesis of collagenase-digestible proteins (type I collagen). In addition, tissue culture supernatants (conditioned media, CM) were tested for reactivity for IL specific ELISAs and for their ability to stimulate proliferative responses in mouse thymocytes and hybridoma cells. Our findings demonstrate that chick embryo skin fibroblasts spontaneously produce IL-1 and, in even greater amounts, IL-6. Highest levels of interleukin secretion were found in the CM of 13 day-old fibroblasts and the IL-1 beta isoform was predominant over IL-1 alpha. Pretreatment of the fibroblasts with either IL-1 or IL-6 increased the secretion of both cytokines. Increased IL-1 levels were correlated with enhanced IL-1 bioactivity in the CM of IL-6 treated fibroblasts. By contrast, the raised concentrations of IL-1 in the CM of IL-1 treated cells and IL-6 in the CM of IL-1 or IL-6 treated fibroblasts failed to translate into augmented bioactivity. These observations, taken together, indicated that IL-1 and IL-6 are able to regulate the synthesis and secretion of ECM macromolecules of developing connective tissues and the cytokine release by chick embryo skin fibroblasts.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7848838 TI - Follistatin expression in ES and F9 cells and in preimplantation mouse embryos. AB - Activins are thought to play a role in mesoderm induction in amphibian development. Studies of the expression patterns of activin during mouse embryogenesis are consistent with the proposal that they are also involved in mesoderm formation in mammals. Activins are expressed both maternally and zygotically at preimplantation stages, and at postimplantation stages transcripts are present at high levels in the deciduum, suggesting that mesoderm is induced by maternally-derived activin. The functions of activin can be modulated by follistatin. At postimplantation stages follistatin is expressed in the deciduum in a pattern reciprocal to that of activin. In the embryo proper, follistatin transcripts are localized to the primitive streak region during gastrulation and later in the somites and in rhombomeres 2, 4 and 6 of the hindbrain. In this paper we show that follistatin, like activin, is expressed throughout pre implantation mouse development. Transcripts are present at low levels in undifferentiated F9 and ES cells, but they increase greatly on differentiation of both cell types. Expression of activin mRNA is decreased in differentiated F9 and ES cells, and the simultaneous increase in follistatin may create an efficient and rapid means of decreasing levels of functional activin. PMID- 7848839 TI - Conservation in the Hox code during morphological evolution. AB - The expression domains in paraxial mesoderm of the chicken embryo are described for Hoxb-3, a-4 and c-6 genes, and these are compared with published expression data for the corresponding genes in the mouse. In both species, it is found that the anterior limits of Hoxb-3 and a-4 expression lie in the upper cervical region, and the anterior limits of Hoxc-6 expression lie in the upper thoracic region. This finding is remarkable because the cervical region, or neck, of the chicken (with fourteen cervical vertebrae) is much longer than that of the mouse (seven cervical vertebrae). The results suggest that the Hox code, at least in the development of homologous axial structures, is conserved between species (Hoxb-3 and a-4, for example, being associated with an anterior cervical phenotype; Hoxc-6 being associated with an anterior thoracic phenotype). The results also suggest that an evolutionary change in body proportions is accomplished by a shift in the relative positions of Hox expression domains during embryonic development. PMID- 7848840 TI - Integrin regulatory switching in development: oscillation of beta 5 integrin mRNA expression during epithelial-mesenchymal interactions in tooth development. AB - Integrin receptors for extracellular matrix molecules are thought to play important roles in morphogenesis since they mediate aspects of embryonic cell adhesion and migration. Using in situ hybridization, the mRNA expression pattern of the beta 5 integrin receptor subunit was examined during murine tooth development, a classical system for studying morphogenesis. In developing tooth, high-level expression of beta 5 integrin mRNA alternates from epithelium to mesenchyme and back to epithelium. Each switch in localization occurs within one day. These results demonstrate that an integrin mRNA can be precisely and rapidly up- and down-regulated over unexpectedly short time spans, and that expression can oscillate between adjacent, interacting epithelial and mesenchymal tissues during morphogenesis. This rapid modulation of mRNA expression suggests a potential regulatory role for the beta 5 integrin receptor in morphogenesis. PMID- 7848841 TI - [Endocrinological ambulatory care]. PMID- 7848842 TI - [Development of gender identity and sexuality in children]. PMID- 7848843 TI - [Epilepsy and its history]. PMID- 7848844 TI - [Occupational science in pediatric nurses training]. PMID- 7848846 TI - [Gentle care]. PMID- 7848845 TI - [The work of the pediatric nurse in the baby room of the obstetrics department]. PMID- 7848847 TI - [Service instructions for the handling of cytostatic agents]. PMID- 7848848 TI - [Accompaniment and care of a dying child]. PMID- 7848849 TI - [The legal nursing insurance. The 5th pillar of Social Security]. PMID- 7848850 TI - [Diagnosis and intensive care of congenital cyanotic heart defects]. PMID- 7848851 TI - [Care of a child after cardiac surgery]. PMID- 7848852 TI - [Immediate care of a premature infant, followed by admission to an intensive care unit. I. First care after delivery]. PMID- 7848853 TI - [Immediate care of a premature infant, followed by admission to an intensive care unit. II. Care at the intensive care unit]. PMID- 7848854 TI - [Salmonella gastroenteritis (salmonellosis) in children--clinical aspects]. PMID- 7848855 TI - [Infant nutrition in diarrhea]. PMID- 7848856 TI - [Prevention and treatment of infectious enteritis--prevention and control of Salmonella in clinical everyday life from the hygiene specialist's viewpoint]. PMID- 7848857 TI - [The plague in India is no special event]. PMID- 7848858 TI - [Pediatric nursing at home--six months of home care for a patient with spinal muscular atrophy]. PMID- 7848860 TI - [The abused and neglected child--concept of a medical consulting center]. PMID- 7848859 TI - [Separation anxiety in parents and children in the hospital]. PMID- 7848861 TI - [Statutory pension insurance--an important branch of Social Security]. PMID- 7848862 TI - [Educational policies for nursing occupations in reverse? Saxonia is cementing inequalities of chances for nursing professions]. PMID- 7848863 TI - [Poisonous and less poisonous plants. 16]. PMID- 7848864 TI - Foot care for the diabetic patient: an overview. AB - Person with diabetes are at high risk for amputation. Patient education in techniques of good foot care can reduce their chance of amputation. Major principles of foot care education include examination of the feet, footwear, and hygiene of the skin and nails. This article reviews the literature regarding patient education for the diabetic patient about techniques of good foot care. PMID- 7848865 TI - Protein S deficiency: a case study. AB - Protein S deficiency, a life-threatening defect in the body's protective mechanism against activated coagulation, can result in recurrent or atypical patterns of thrombosis. A case study describing diagnosis and treatment of protein S deficiency and the nursing care of a patient requiring a vena cava filter is presented. It is important for nurses to be aware of the vital role they play in assessing, managing, and assisting both the patient and family as they adjust to this rare disorder. PMID- 7848866 TI - Caring for patients with complications after elective abdominal aortic aneurysm surgery: a case study. AB - The risks associated with elective repair of an abdominal aortic aneurysm have been reduced in recent years, but occasionally the extent of the aneurysm and the severity of the atherosclerotic process lead to life-threatening complications. The complications of myocardial infarction, acute renal failure, bleeding, and ischemia are examined in this article. To illustrate the complexities of nursing care when patients experience complications, the case of Mr. S is presented. Assessment and monitoring are considered as key components of nursing care, and ways to help patients and their families cope with unanticipated complications are outlined. PMID- 7848867 TI - Therapeutic walking program: an alternative to a formal vascular rehabilitation program. AB - A formalized 3-day-a-week structured exercise program proved unsuccessful in a regional, inner-city referral center. However, a large number of patients who needed exercise training were seen. In response to this demand, a "Therapeutic Walking Program" was designed. This article describes the nurse's role, the exercise program, patient screening, and indications for future research. PMID- 7848868 TI - Prevention beyond the bedside: who is responsible and who is your community? PMID- 7848869 TI - Transjugular intrahepatic portosystem shunt: a new approach to variceal bleeding. PMID- 7848870 TI - Expression of a novel Toll-like gene spans the parasegment boundary and contributes to hedgehog function in the adult eye of Drosophila. AB - Many proteins involved in signal transduction and cell adhesion are characterized by the presence of an extracellular domain with repeated copies of a leucine-rich motif (LRR). Here we report the isolation and characterization of a novel gene, tlr (for Toll-like receptor), which encodes a protein containing multiple LRRs in its presumed extracellular domain, a single transmembrane segment and homology to the cytoplasmic domain of the interleukin 1 receptor in its presumed intracellular domain. The pattern of tlr expression at the extended germ band stage is characterized by 15 transverse stripes in the gnathal and trunk segments, with four patches of expression corresponding to head segments and an additional patch of expression in the presumptive hindgut. The segmentally repeated tlr stripes in the trunk overlap both the wingless and engrailed stripes and thus span the parasegment boundary. The tlr stripes require pair rule gene function for their establishment and later become dependent upon segment-polarity gene function for their maintenance. Segmental modulation of tlr expression later in the tracheal system is dependent upon the function of the homeotic genes of the bithorax complex. The tlr gene also is prominently expressed in the imaginal discs. In the eye disc, this expression occurs in two stripes at the anterior and posterior margins of the morphogenetic furrow; this expression is consistent with a genetic interaction between a tlr mutation and an eye-specific allele of hedgehog. All of these data combine to suggest a role for tlr in interactions between cells at critical boundaries during development. PMID- 7848871 TI - Dissection of the Drosophila pourquoi-pas? promoter: complex ovarian expression is driven by distinct follicle cell- and germ line-specific enhancers. AB - The pourquoi-pas? (pqp) gene of Drosophila melanogaster encodes a zinc finger protein present in the oocyte nucleus, the nurse cells and, at a lower level, in the follicle cells. Null mutations of the pqp gene lead to female sterility. We have undertaken a functional dissection of the pqp promoter by following the expression of the lacZ reporter gene in the ovaries of transgenic flies. pqp sequences, necessary for expression of the lacZ gene in a pattern similar to that of the endogenous pqp gene, are located between positions -210 and +30, relative to the transcription start site. These sequences, subdivided in follicle cell- and germ line-specific regions, appear to function in a direction-independent and distance-sensitive manner. The -210/-40 region, sharing stretches of sequence similarity with 5' sequences of follicle cell-specific genes, promotes lacZ expression only in the follicle cells. The -80/+30 region is germ line-specific. The promoter limits, deduced from the deletion experiments presented here, are in accordance with the molecular analysis of pqp mutants. PMID- 7848872 TI - The murine Hoxc cluster contains five neighboring AbdB-related Hox genes that show unique spatially coordinated expression in posterior embryonic subregions. AB - A common feature of the murine Abdominal B (AbdB) -related Hox genes, located in the 5' regions of the four Hox clusters, appears to be a function in patterning the developing limb. As a prerequisite for studying the role of the AbdB-related Hoxc genes during limb development, we have isolated and mapped the three predicted AbdB-related Hoxc-11, -12, and -13 loci, thus defining the 5' end of the Hoxc cluster. Sequence comparisons based on the homeobox sequences of presumably all murine AbdB-related Hox genes strongly support the concept of a two step process in their evolution. As expected, Hoxc-11, -12 and -13 exhibit nested and extremely posteriorly restricted expression domains, whose anterior boundaries reflect their map positions, in accordance with the colinearity rule. A limited comparison of the primary expression domains of all five AbdB-related Hoxc genes in the developing hindlimb revealed nested and increasingly restricted domains of expression in the mesenchyme for only Hoxc-9, -10 and -11. However, separate localized expression was detected for Hoxc-9, -10, -11, -12 and possibly -13 in distal epidermal regions of the developing hind- and forelimb, whereas no expression of any of the five genes was observed in mesenchymal tissues of the developing forelimb. These data suggest a specific role for the AbdB-related Hoxc genes in patterning the hindlimb and pelvic girdle, which is separate from a second role relevant for both hind- and forelimb development. PMID- 7848873 TI - Modulation of wingless signaling by Notch in Drosophila. AB - Extensive genetic and molecular analyses indicate that Notch acts as a transmembrane receptor in an evolutionarily conserved cell interaction mechanism that appears to control a common step in the progression of an uncommitted cell towards the differentiated state. In Drosophila, Notch mutations were shown to affect the development of a broad spectrum of tissues, including the wing. We found that mutations in the segment polarity gene wingless are capable of acting as dominant enhancers of notchoid, a recessive Notch allele affecting the wing. The Wingless protein is homologous to the mammalian proto-oncoprotein Wnt-1 and is thought to act as the signal in a cell interaction mechanism that specifies differentiation of the embryonic epidermis as well as imaginal structures such as the wing. Although some components of the Wingless signal transduction pathway have been identified, the receptor for Wingless remains elusive. This genetic link between the Wingless and Notch pathways has been further examined by determining the relative expression patterns and subcellular localization of Notch and Wingless in mutant and wild-type backgrounds. We find that Notch is necessary for the implementation of the Wingless signal in specifying normal wing development. We discuss the possibility that Notch is directly involved in the reception of Wingless in the light of current models for the developmental action of Notch. PMID- 7848874 TI - A formal analysis of stressor and stress-proneness effects on simple information processing. AB - This study examined visual information processing under a stressor of recurring loud sound among groups divided according to psychometrically identified stress susceptibility. Formal models of task performance were employed to address several issues concerning stress effects on cognitive functioning. Examined were effects on parallel versus serial processing structure, task-wise processing capacity, strategies of allocating processing resources to task components, and curtailment of processing of relevant task elements. Contrary to prediction, stressor presence generated slightly more rather than less evidence of a parallel versus serial processing structure. There was some suggestion of central-task capacity depletion among more susceptible subjects, in line with certain theoretical positions. Evidence of curtailed exhaustive processing of relevant stimulus items was negative. Most notable was the disruption by stress among susceptible subjects of performance-enhancing strategies of deploying processing resources across the different task components (elements of the visual display and within-trial stages of processing). Such effects have received relatively little attention in this research domain; their investigation is shown to be made tractable, however, through the application of selected formal models of information processing. PMID- 7848875 TI - A hierarchical neural network assembly for classification of cervical cells in automated screening. AB - Experiments are described using artificial neural networks to classify cells imaged in cervical smears according to their degree of abnormality. This problem of classification was broken into 3 subtasks, each of which an independent back propagation neural network was trained to solve. Input patterns were fed to the first network for classification of the cells as essentially normal or abnormal and then, depending on the outcome of the classification, a second stage was invoked for classifying the cell as (i) normal or mildly dysplastic, or (ii) moderately or severely dysplastic. It is shown that the correct choice of normalization of input data, as well as the use of a hierarchy of neural networks, each optimised for a specific subtask of the whole classification process, yields a predictive value hitherto unattained by automated systems. PMID- 7848876 TI - Malignancy associated changes in squamous epithelium of the head and neck region. AB - Subtle cellular changes are known to exist in normal host tissue adjacent to tumours. These are called malignancy associated changes (MAC). To get more insight into the degree of expression and local spread of such changes we performed high resolution image cytometry on visually normal intermediate cell nuclei in smears from patients with laryngeal or pharyngeal squamous cancer. The smears were taken from the tumour surface, from a border region of the tumour and from a distant unsuspicious buccal site. In addition buccal smears from healthy control persons were examined. In a pilot study smears from 12 cancer patients and 11 control persons and in a succeeding validation study 63 controls, 18 non tumour patients and 25 cancer patients were investigated. In both studies the occurrence of MACs was demonstrated quantitatively. In cancer patients normal appearing intermediate cells from the three different sampling sites could be discriminated with 65% in the pilot study and with 53% correct classification in the validation study. In addition the influences of smoking behaviour and sex were investigated in the control group. Only in the latter case there was a significant difference between female and male with a 63% correct cell and 71% correct specimen classification. PMID- 7848877 TI - Polymorphism of spermatocytic seminoma. A morphometric study. AB - Spermatocytic seminoma (SS) is one of the testicular tumours. It is distinguished from other germ cell neoplasms by a special type of polymorphism. The aim of the present study was a morphometric analysis (Microplane II image system) of this phenomenon. In histological slides we measured the profile area of nuclei in about 500 adjacent cells. The basic material consisted of 12 cases (c.) of infiltrating SS, and the comparative material included intracanalicular SS (IcSS 1c.), other types of seminoma--typical (TS-2c.), anaplastic (AS-2c.) and spermatogenesis in an elderly man (Sg-1 c.). We carried out a statistical analysis of the populations of cellular nuclei: we determined nuclear population similarities and differences, as well as their relation to various types of standard distributions such as Erlang, gamma, lognormal, normal and Weibull. Part of the SS histograms including IcSS showed similarities. The mean value of the profile area range from 32.5 to 56.5 microns2. In other types of seminomas this value was much higher. The Kolmogorov-Smirnov two-sample test showed differences between the compared nuclear populations. Lack of the differences was found only between certain SS (including IcSS). The results of comparisons of the populations studied with standard distributions showed that the analysed nuclear populations can be successfully described by more than one theoretical distribution. However, among the spermatocytic seminomas analysed, in contrast to TS and AS, we found distributions not corresponding to any of the standard distributions. The results of our findings argue also against the occurrence of haploid nuclei in SS cells.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7848878 TI - Rapid identification of marker chromosomes by in situ hybridization under different stringency conditions. AB - Six metacentric non-satellite chromosome markers and 4 satellite markers of unknown origin were discovered by routine cytogenetic analysis. These markers were then investigated by isotopic and nonisotopic (FISH) in situ hybridization. In order to determine the origin of small marker chromosomes, a special protocol involving sequential application of defined alphoid and 'classical' satellite DNA probes with chromosome specificity was used. In situ hybridization under low stringency conditions has been performed with DNA probes specific for 4 groups of chromosomes. After preliminary analysis and determination of the possible origin of these marker chromosomes, DNA probes with high chromosome specificity were used under high stringency conditions. Marker chromosomes were found to be derivatives of chromosomes 7, 9 (3 cases), 13, 14 or 22, 21 (2 cases), X and Y. PMID- 7848879 TI - Where do we stand with respect to the use of peripheral blood progenitor cells? PMID- 7848880 TI - Second tumours after breast cancer: is it still too soon to tell? PMID- 7848881 TI - Gene transfer in tumor therapy. PMID- 7848883 TI - Treatment of early and intermediate stages of supradiaphragmatic Hodgkin's disease: the Swedish National Care Programme experience. Swedish Lymphoma Study Group. AB - PURPOSE: Since 1985 a Swedish National Care Programme has provided tailored principles for the staging, treatment and follow-up of patients with Hodgkin's disease (HD). This report presents treatment results for all patients below 60 years of age who were diagnosed with early and intermediate stages, between 1985 and 1989. PATIENTS AND TREATMENT: During that period, 210 patients with supradiaphragmatic HD in clinical (CS) and pathological (PS) stages IA+IIA, PS IB+IIB, and PS III1 A were diagnosed in five Health Care Regions in Sweden. In patients with CS IA, staging laparotomy was not recommended provided that the radiological assessment of the abdomen was adequate, whereas this procedure was recommended in stages CS IB, IIA and IIB in order to minimize treatment. In the absence of bulky mediastinal disease, patients with CS+PS IA and PS IIA were treated with mantle (occasionally mini-mantle) irradiation alone, while patients with bulky disease, as well as those with stages PS IB+IIB+III1 A, were treated with one cycle of MOPP/ABVD prior to mantle (PS III1 A sub-total nodal) irradiation. Full chemotherapy followed by radiotherapy to initial sites with bulky disease was recommended for patients with CS IIA who did not undergo laparotomy. RESULTS: After a median follow-up in excess of five years, treatment results are 'favourable' for all stages, provided the recommendations were followed. In patients with CS+PS IA treated according to the recommendations, recurrence rates were 14% (9/65) with all but one patient (64/65, 98%) remaining in continuous first or second remission. These figures were worse in patients treated inadequately (9/26 [35%] and 22/26 [85%], respectively). In PS IIA, adequately-treated patients had a recurrence rate of 13% (7/52) whereas 5/7 (71%) of those with bulky disease who received only mantle irradiation developed recurrences. Similar patterns also emerged in patients with CS IIA, PS IB+IIB and PS III1 A. CONCLUSIONS: The tailored principles, which usually entail less staging and/or treatment than is generally the case, produced favourable results when applied to an entirely unselected group of patients with early and intermediate stages of HD. PMID- 7848882 TI - Second malignancies following CMF-based adjuvant chemotherapy in resectable breast cancer. AB - BACKGROUND: Only a few studies have evaluated the long-term effects of adjuvant chemotherapy for breast cancer. Furthermore, neither the relation between the risk of second malignancies and type of adjuvant regimen utilized nor the interaction between chemotherapy and breast irradiation or age of the patients have been described in detail. METHODS: A total of 2,465 patients entered into prospective studies of CMF-based adjuvant chemotherapy carried out at the Milan Cancer Institute between June 1973 and July 1990 were evaluated. The median follow-up was 12.0 years and detailed information about therapy was available for all patients. RESULTS: At 15 years, the cumulative actuarial risk of second malignancies (excluding contralateral breast cancer and basal skin cancer) was 6.7% +/- 0.8% for the total series. The figures were 8.4% +/- 2.9% after local regional treatment alone, 6.4% +/- 0.9% following CMF, and 5.1% +/- 1.0% following CMF plus Adriamycin (doxorubicin; Farmitalia-Carlo Erba, Milan, Italy). Compared to the general female population, the relative risk following CMF-based adjuvant chemotherapy was 1.29. Three patients, all of whom had received CMF based chemotherapy, developed acute non-lymphocytic leukemia (cumulative risk 0.23% +/- 0.15%; relative risk 2.3). No differences were evident when breast irradiation was considered, but the cumulative risk of second tumors was slightly higher in women aged > or = 50 years at surgery (7.7% +/- 1.3%) than in younger patients (6.0% +/- 1.0%). CONCLUSIONS: At present, there is no evidence of a significantly increased risk of second malignancies following adjuvant CMF-based chemotherapy such as the one given in this case series. A low risk of acute leukemia was associated with the cumulative total dose of cyclophosphamide administered, and breast irradiation did not enhance this risk. IMPLICATIONS: Our findings suggest that there is no reason to omit alkylating agents from short term effective adjuvant chemotherapy. PMID- 7848884 TI - Dose-finding study of tropisetron in cisplatin-induced nausea and vomiting. AB - BACKGROUND: The purpose of these two studies was to define the optimal therapeutic dose of the 5-HT3 receptor antagonist tropisetron (Navoban, ICS 205 930) in cisplatin-induced nausea and vomiting. PATIENTS AND METHODS: In two multicentre, dose-finding studies of tropisetron in the prevention of cisplatin induced emesis, cancer patients naive to chemotherapy or who had not vomited previously were randomly assigned to tropisetron 5, 10, 20 or 40 mg (study I, 143 patients) or 2 or 5 mg (study II, 74 patients), administered as a single intravenous dose over 15 minutes just before the start of chemotherapy. RESULTS: In study I total control of acute symptoms (no nausea and no vomiting) was achieved in, respectively, 66%, 50%, 64% and 50% in the 5-, 10-, 20- and 40-mg groups of patients. A total absence of vomiting alone was seen in, respectively, 71%, 51%, 61% or 58% of patients. None of the differences were statistically significant. In study II there was total acute control in 57% of patients in the 2-mg group and 63% in the 5-mg group (p = NS). Total or major control of vomiting (< or = 2 emetic episodes) was the primary endpoint in study II and was seen in 68% of patients for the 2-mg and 86% for the 5-mg group (p = 0.055). In this study failures ( > 3 vomiting) were rescued with a second infusion of tropisetron (5-mg fixed dose). Three of 8 rescue infusions administered in the 2-mg group prevented further vomiting whereas none of 5 were successful in the 5-mg group during course 1 of chemotherapy. The most frequently reported adverse effects (over all three courses) were headache (6.0% of 217 patients) hypertension (3.7%) and diarrhoea (2.8%). None of the 25 deaths which occurred during the two studies were attributable to tropisetron. CONCLUSIONS: Thus, a single dose of tropisetron provides 24-hour protection against cisplatin-induced nausea and vomiting and is well tolerated. These studies do not allow a firm conclusion but suggest that 2 mg may be subtherapeutic and that 5 mg is as effective as higher doses. PMID- 7848885 TI - Paclitaxel (Taxol) in heavily pretreated ovarian cancer: antitumor activity and complications. AB - OBJECTIVE: To analyze the efficacy and toxicity of Taxol in patients with ovarian cancer who had failed at least two previous chemotherapy treatment regimens. PATIENTS AND METHODS: Sixty-eight patients with advanced pretreated ovarian cancer, with either measurable or evaluable disease who were shown to have disease progression were entered on a National Cancer Institute sponsored 'compassionate' treatment referral center protocol and received intravenous infusion of Taxol over 24 hours 135 mg/m2, (after steroid-containing premedication) repeated every 3 weeks and continued while showing no evidence of progression. RESULTS: Of the 68 patients enrolled, 10 patients (15%) had a partial response and one assessable by marker only had improvement of disease. In addition, 27 others (40%) were stable on continued Taxol for a median time of 6.4 months and CA-125 decreased in 20 patients out of 59 patients with elevated baseline CA-125s. Twenty-seven patients progressed while receiving 1-6 cycles of treatment. Three patients were not evaluable for response. Neutropenia and its complications occurred primarily during the first two cycles of Taxol treatment. Febrile episodes requiring antibiotic treatment occurred in 44% of patients which is a higher incidence than in prior series. CONCLUSIONS: Taxol as a single agent has modest activity in heavily pretreated ovarian cancer patients but appears to be useful and is subjectively well tolerated by many. The high incidence of infection in comparison with other series of patients with ovarian cancer treated with chemotherapy suggests this pretreated patient population has enhanced susceptibility to develop complications from neutropenia. Safer treatment in this advanced setting should include more aggressive use of cytokines and/or less myelosuppressive regimens (e.g. shorter Taxol infusions). PMID- 7848886 TI - P-glycoprotein expression in primary and metastatic transitional cell carcinoma of the bladder. AB - BACKGROUND: To determine the expression of P-glycoprotein in pre- and post chemotherapy tumor tissue samples from patients with transitional cell carcinomas treated with M-VAC (methotrexate, vinblastine, adriamycin and cisplatin). PATIENTS AND METHODS: Fresh frozen tissue sections of primary and metastatic urothelial tumors were stained with mouse monoclonal antibody HYB-241 which recognized an external epitope of P-glycoprotein, using an avidin-biotin immunohistochemical technique. Immunoreactivity was scored separately in tumor cells and endothelial cells. RESULTS: Untreated primary lesions showed immunostaining in 6 of 46 cases (13%), while 6 of 16 (38%) post-therapy primary tumors were immunoreactive. None of the untreated metastases (0 of 17) were positive, however, 6 of 11 (55%) post-therapy specimens showed varied percentages of positivity for p-glycoprotein (p = 0.002). The highest percentage, 50%-70% of tumor cells stained, was observed in metastatic lesions from patients who had received 6 or more chemotherapy cycles. No difference in the proportion of endothelial cells stained was observed in pre- and post-therapy specimens. However, 3 of 6 post-therapy samples obtained from 5 individual patients showed MDR1 up-regulation on endothelial cells. CONCLUSIONS: The data show that an increase in the proportion of cells expressing P-glycoprotein occurs after exposure to a combination chemotherapy program containing drugs known to select for P-glycoprotein expression in vitro. The observation of increased immunoreactive endothelial cells suggests transactivation of the MDR1 in these cells. While data are preliminary, P-glycoprotein expression in capillary endothelial cells may contribute to drug resistance. Taken together, these mechanisms may contribute to therapeutic failure in patients with bladder tumors treated with chemotherapy. PMID- 7848887 TI - Primary mediastinal large cell lymphoma is characterized by an inverted pattern of large tumoral mass and low beta 2 microglobulin levels in serum and frequently elevated levels of serum lactate dehydrogenase. AB - BACKGROUND: Primary mediastinal large cell lymphoma (PMLCL) is an emerging entity. New parameters can help define it. MATERIALS AND METHODS: Retrospective analysis of medical records from 35 patients treated at The University of Texas M.D. Anderson Cancer Center from 1985 to 1990. Immunohistochemical evaluation of tissue specimens. Determination of survival (S) and time to treatment failure (TTF). RESULTS: The median age was 34 years and 69% were females. Eight-three percent presented with symptoms of mediastinal involvement. While 100% of the patients presented with bulky mediastinal disease and 72% had elevated pretreatment serum lactate dehydrogenase, only 6% presented with an elevated pretreatment serum beta 2 microglobulin. The lymphoma cells lacked CD21 staining. For the 18 patients treated initially at M.D. Anderson Cancer Center, S and TTF curves rates after doxorubicin-based regimens (plus radiotherapy in 14 cases) were 72% and 61%, respectively, at 5 years follow-up (median, 42 months). Four out of six patients who received autologous bone marrow transplant as salvage therapy are currently alive without disease at follow-up times of 21, 25, 32, and 54 months. CONCLUSION: Primary mediastinal large cell lymphoma has characteristic clinicopathological features to which another can be added, that of an inverted pattern of bulky disease, high LDH and low beta 2 M in serum. The response to therapy is comparable to that of intermediate-grade lymphomas, although the numbers in the study are small. Our preliminary data suggest a possible role for autologous bone marrow transplantation (ABMT) as salvage therapy. PMID- 7848888 TI - Weekly high-dose 5-fluorouracil and folinic acid as salvage treatment in advanced gastric cancer. AB - BACKGROUND: A weekly schedule of a 24-h high-dose 5-FU infusion in combination with folinic acid was investigated as salvage therapy in patients with advanced gastric cancer. PATIENTS AND METHODS: Seventeen patients with progressive disease after chemotherapy were treated with a weekly schedule of 500 mg folinic acid/sqm by i.v. 2-h infusion followed by an i.v. 24-h infusion of 2.6 g 5-FU/sqm times six. Fourteen of the 17 patients (82%) had been pretreated in regimens which included 5-FU/folinic acid i.v. bolus. RESULTS: Toxicity was mild, with diarrhea, mucositis and nausea; WHO grade III/IV diarrhea was observed in only two patients. Three patients achieved partial remissions (18%; 95% confidence interval: 0%-38%) and 7 patients stable disease (41%; 95% confidence interval: 17%-64%). Their median survival time was five months (range 1.5-10 months) after the onset of salvage therapy. CONCLUSIONS: This schedule of weekly 24-h infusions of high-dose 5-FU and folinic acid is effective, even in patients pretreated with or resistant to regimens including 5-FU/folinic acid i.v. bolus. Based on these data, it appears that this schedule of high-dose 5-FU/folinic acid in first-line combination chemotherapy merits investigation. PMID- 7848889 TI - Phase II study of gemcitabine (2',2'-difluorodeoxycytidine) given as a twice weekly schedule to previously untreated patients with non-small cell lung cancer. PMID- 7848890 TI - Phase II trial of weekly IV vinorelbine in first-line advanced breast cancer chemotherapy. AB - PURPOSE: The study investigated the therapeutic effect of single-agent IV weekly vinorelbine (Navelbine, Pierre Fabre Oncologie, Boulogne, France) a semi synthetic vinca-alkaloid, in women who had received no prior treatment for advanced or metastatic breast cancer. PATIENTS AND METHODS: Fifty-four patients with assessable advanced or metastatic breast cancer who had received no prior chemotherapy were entered into the study. Fifty patients were evaluable for toxicity and response by WHO criteria; 4 patients were not evaluated because they did not meet the eligibility criteria of the study. Vinorelbine was given as a weekly 30 mg/m2 short IV infusion; and treatment was continued until disease progression or the occurrence of unacceptable toxicity. RESULTS: The overall response rate was 50% (complete response 2%, partial response 48%). The response rate according to target was: lymph nodes 64%; liver 28%; lung 66%; local recurrence 60%. The median duration of response was 9 months, the median time to treatment failure was 5 months and the median survival was 15 months. TOXICITY: Six-hundred thirty cycles were given to 54 patients (53 assessable for tolerance). At least one episode of WHO grade 3/4 granulocytopenia was seen in each of 71% of the patients. Significant nausea/vomiting (WHO grade 3) was seen in less than 1% of cycles and other side effects were uncommon. CONCLUSION: This study confirms that vinorelbine has major single-agent anti-tumour activity as front-line therapy in advanced breast cancer. Given its excellent tolerance profile and low morbidity, it should be considered for inclusion in first-line combination chemotherapy regimens. PMID- 7848891 TI - Hepatitis C virus acute exacerbation during chemotherapy and radiotherapy for oesophageal carcinoma. AB - AIMS: We report the first case of an hepatitis C virus positive patient presenting with a solid tumor and developing an exacerbation of his hepatitis C after chemotherapy. CASE REPORT: A 56-year-old white male, previously infected with hepatitis C virus and treated for epidermoid carcinoma of the oesophagus, developed hepatitis (alamine aminotransferase 2376 U/l and aspartate aminotransferase 2262 U/l) after chemotherapy with cisplatin and vinblastine. METHODS: Polymerase chain reaction detected hepatitis C virus RNA in the serum during the acute phase, which returned to negative 14 weeks later. DISCUSSION: Viral replication was probably increased during immunosuppression induced by chemotherapy. Enhanced cellular immune response in the recovery phase was the most likely cause of the hepatitis. CONCLUSIONS: More attention should be paid to liver function tests in patients with a previous history of hepatitis C virus infection. Polymerase chain reaction identification of hepatitis C virus RNA can be a very useful tool that permits rapid diagnosis and appropriate management of such cases. PMID- 7848892 TI - Anosmia associated with alpha-interferon treatment. PMID- 7848893 TI - Preoperative taxol induces objective responses in primary breast cancer not responding to FEC treatment. PMID- 7848894 TI - Is the senescent heart overloaded and already failing? AB - Heart failure mainly occurs during the last decades of life, and it is important to know if the senescent heart is not an already failing heart. During aging, both contraction and relaxation of papillary muscle are impaired. Such an impairment is compensated in vivo and the cardiac output remains normal. In spite of a loss in myocytes, the heart weight/body weight ratio is unchanged, but the myocytes are bigger. Arrhythmias are permanent and are accompanied by a loss of the normal heart rate variability. Changes in specific mRNAs include: a shift in myosin heavy chain (MHC) isogene expression leading to an increased beta MHC content; decreased densities of Ca2+ ATPase of the sarcoplasmic reticulum, beta 1 adrenergic receptor, and muscarinic receptors; and attenuation of the Na+/Ca2+ exchange activity. Most of these changes, but not all, resemble those observed during cardiac overload and are accompanied by an increased duration of both the action potential and the intracellular calcium transient. However, the senescent heart is still able to further modify its phenotype in response to mechanical overload. The senescent heart is a diseased heart, and the origin of the "disease" is multifactorial and includes the general process of senescence, hormonal changes, and the myocardial consequences of senescence of the vessels. PMID- 7848895 TI - Endothelin and myocardial ischemia. AB - Endothelin is a potent vasoconstrictor with a wide range of effects on the heart. Changes in myocardial and circulating levels of endothelin have been described in various experimental models of myocardial ischemia, and in humans with acute myocardial infarction and different forms of angina pectoris. The role played by endothelin in the different states of myocardial ischemia is unclear. However, myocardial damage has been shown to be reduced in several experimental models of myocardial infarction by administering agents that block the action of endothelin. The aim of this review article is to present the current literature concerning the interaction between endothelin and the various forms of myocardial ischemia, and to explore the significance of such interactions. PMID- 7848896 TI - Short and long-acting oral nitrates for stable angina pectoris. AB - Nitroglycerin (NTG) spray and sublingual tablets rapidly relieve an established attack of angina, and their infrequent use is not associated with the development of tolerance. Although, following a suitable nitrate-free interval, the first dose of oral, long-acting nitrates produces significant hemodynamic effects, increases angina free walking, and decreases exercise-induced ischemia, during continued long-term therapy tolerance limits their usefulness. Appropriate dosing regimens of controlled-release formulations of isosorbide dinitrate (ISDN) and controlled-release NTG during long-term therapy have not been established. Use of immediate-release formulation of 15-120 mg of ISDN in a qid regimen lead to a marked reduction in the size and duration of antianginal effects compared to the initial dose. Asymmetric tid therapy with 30 mg of ISDN (7 a.m., 1 p.m., and 6 p.m.) is also associated with the development of partial tolerance and appears to provide antianginal prophylaxis for only a period of 6 hours each day. Asymmetric bid therapy with ISDN at 7 a.m. and noon may give sustained effect but is supported by only a single, small study that did not examine effectiveness after the noon dose in long-term use. Isosorbide-5-mononitrate (IS-5-MN) has been the subject of more recent studies than other nitrates because of attempts to bring a number of products into the U.S. market. IS-5-MN in qid, tid, and standard bid (8 a.m. and 8 p.m.) dosing regimens produce tolerance. Asymmetric regimens of immediate-release IS-5-MN (10 and 20 mg) given bid (once in the morning and again 7 hours later) decrease the development of tolerance compared to symmetric regimens and produce an increased exercise duration after each dose of the day; the 20 mg bid dosing is more effective. Similarly, once-daily 120 and 240 mg controlled-release IS-5-MN does not produce tolerance and gives a sustained increase in daytime exercise duration. Both asymmetric bid immediate-release and once-daily controlled-release IS-5-MN preparations do not produce deterioration in exercise performance prior to the administration of the medication in the morning (i.e., no zero-hour effect). Further studies are needed to establish useful dosing regimens for ISDN, for controlled-release ISDN, and for controlled release nitroglycerin. None of the dosing regimens of any oral, long-acting nitrate (including IS-5-MN) provide 24 hour antianginal and antiischemic effects.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7848897 TI - Ointments and transdermal nitroglycerin patches for stable angina pectoris. AB - Nitroglycerin (NTG) ointment is used for the prophylaxis against angina pectoris, but there are no data to support its effectiveness during long-term therapy. Continuous, once-daily application of isosorbide dinitrate cream produces tolerance with complete loss of efficacy within 1 week. Nitroglycerin patches are very popular and continuous once-daily application is still claimed by some investigators to provide 24 hour antiischemic and antianginal efficacy. This claim is based on data from postmarketing studies in a very large number of patients and placebo-controlled studies in smaller groups of patients from Italy, Yugoslavia, Greece, and Germany. In contrast, studies from the United States, Canada, England, and some centers in Germany have failed to show superiority of patches over placebo during continuous therapy. This controversy was addressed by the NTG cooperative study group, in which a total of 562 patients who were responders to sublingual nitroglycerin were studied. Patients received either placebo or NTG patches delivering low (15-30 mg/24 hr), moderate (45-60 mg/24 hr), or large (75 and 105 mg/24 hr) amounts of NTG. Four hours after the initial application, NTG patches increased exercise duration compared to placebo, but this beneficial effect had disappeared by 24 hours. Furthermore, after 8 weeks of continuous therapy, none of the NTG patches were superior to placebo, whether patients were or were not taking concomitant beta-blockers. Therefore, current opinion is that continuous therapy with NTG patches produces pharmacologic tolerance and is ineffective.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7848898 TI - Nitrates in myocardial infarction. AB - Until two decades ago nitroglycerin was contraindicated in acute myocardial infarction (MI). Studies in the canine model demonstrated that low-dose intravenous (i.v.) infusion, carefully titrated to decrease mean blood pressure by 10% but not below 80 mmHg, during early stages of acute MI produced marked reduction of left ventricular (LV) preload, improvement in regional perfusion, and limitation of infarct size and remodeling. However, more i.v. nitroglycerin to decrease blood pressure further resulted in a paradoxical J-curve effect, with hypoperfusion and increased infarct size. Clinical studies have confirmed that low-dose i.v. nitroglycerin infusion for the first 48 hours after acute MI is safe, not only for improving performance in LV failure, but also for limiting ischemic injury, infarct size, remodeling, and infarct-related complications, including deaths in-hospital and up to 1 year. Recent studies suggest that more prolonged therapy with nitrates spanning the healing phase of acute anterior Q wave MI can further limit LV remodeling and preserve function. Preliminary results of the recently completed ISIS-4 megatrial suggest, however, that long term nitrate in patients with suspected MI in the 1990s does not improve survival significantly. PMID- 7848899 TI - Effect of the angiotensin-converting enzyme inhibitor, perindoprilat, and of angiotensin-II on the transient inward current of rabbit ventricular myocytes. AB - Angiotensin-converting enzyme (ACE) inhibitors protect the myocardium from experimental lethal ventricular arrhythmias induced by ischemia or reperfusion. Hypothetically, such arrhythmias may result from the calcium-dependent transient inward current Iti. It is already known that perindoprilat decreased the transient inward current in guinea-pig myocytes [1]. In the same preparation, however, angiotensin-II decreased the transient inward current, an effect opposite to that required to prove that the ACE inhibitor exerted its beneficial effects on Iti by lessening the action of angiotensin-II. We, therefore, selected another species, the rabbit, in which angiotensin-II was known to have a positive inotropic effect. Perindoprilat (1 microM but not 0.01 microM) decreased the transient inward current from -8.93 +/- 0.80 microA/cm2 to -5.33 +/- 0.74 microA/cm2 (p < 0.05). Perindoprilat (1 microM) also protected from the effects of angiotensin-II (0.01 and 0.1 microM), which on its own increased the amplitude of the transient inward current. Based on our results, we conclude that perindoprilat (1 microM) prevents the effect of angiotensin-II in promoting the transient inward current in the rabbit. Hence our data support the hypothesis that the ACE inhibitor, perindoprilat, might in relatively high concentrations have an antiarrhythmic effect, at least in part through inhibition of angiotensin II-evoked calcium-dependent Iti. PMID- 7848900 TI - Electrophysiologic effects of amlodipine vs. diltiazem in patients with coronary artery disease and beta-blocking therapy. AB - This study compares the electrophysiologic effects of amlodipine and diltiazem in patients with coronary artery disease concomitantly treated with background beta blocking therapy. Thirty patients were included in an open-label parallel study in two phases. During phase 1, patients were screened and placed on maintenance atenolol therapy at 50 or 100 mg/day, while phase 2 consisted of right-sided catheterization and randomization of patients to either amlodipine (10 mg i.v.) or diltiazem (10 mg i.v.). Following treatment with amlodipine, no significant alteration in markers of electrophysiological activity was observed. Treatment with diltiazem resulted in a significant lengthening of sinus cycle length (SCL, p < 0.04), AH interval (p < 0.02), and Wenckebach CL (WCL, p < 0.001), and a trend towards an increase in sinus node recovery time (SNRT, p = 0.057). No effects were observed with regard to HV interval and corrected SNRT. The results of this study indicate that 10 mg intravenous amlodipine has no significant electrophysiological action on sinus or AV node function in patients receiving beta-blocker therapy with atenolol, suggesting that amlodipine can be added to beta-blockers to treat patients with myocardial ischemia and/or hypertension without any significant increase in the risk of bradyarrhythmias. PMID- 7848901 TI - Hypolipidemic and antioxidant effects of Commiphora mukul as an adjunct to dietary therapy in patients with hypercholesterolemia. AB - The effects of the administration of 50 mg of guggulipid or placebo capsules twice daily for 24 weeks were compared as adjuncts to a fruit- and vegetable enriched prudent diet in the management of 61 patients with hypercholesterolemia (31 in the guggulipid group and 30 in the placebo group) in a randomized, double blind fashion. Guggulipid decreased the total cholesterol level by 11.7%, the low density lipoprotein cholesterol (LDL) by 12.5%, triglycerides by 12.0%, and the total cholesterol/high density lipoprotein (HDL) cholesterol ratio by 11.1% from the postdiet levels, whereas the levels were unchanged in the placebo group. The HDL cholesterol level showed no changes in the two groups. The lipid peroxides, indicating oxidative stress, declined 33.3% in the guggulipid group without any decrease in the placebo group. The compliance of patients was greater than 96%. The combined effect of diet and guggulipid at 36 weeks was as great as the reported lipid-lowering effect of modern drugs. After a washout period of another 12 weeks, changes in blood lipoproteins were reversed in the guggulipid group without such changes in the placebo group. Side effects of guggulipid were headache, mild nausea, eructation, and hiccup in a few patients. PMID- 7848903 TI - Structural and functional analysis of p53: the acidic activation domain has transforming capability. AB - The p53 gene encodes a transcriptional activator that is able to suppress transformation. The protein can be divided into three functional domains: the acidic activation domain at the amino terminus; the oligomerization and nonspecific DNA binding regions in the carboxyl terminus; and the conformation domain, responsible for specific DNA binding, in the middle. To further examine the structural/functional relationship of p53, we undertook a functional study of deletion mutants of the protein. We assayed these mutants for their abilities to activate transcription, transform rat embryo fibroblasts, and oligomerize. Analysis of the results indicates that: (a) besides specific DNA binding, an intact conformation domain is necessary for the transactivation and oligomerization functions of p53; and (b) p53 mutants that contain the amino and carboxyl termini do not oligomerize with wild-type p53, yet they transform cells. In fact, the amino terminus alone transforms rat embryo fibroblasts. Transformation by these mutants is probably effected by the amino terminus binding and sequestration of factors essential for wild-type p53 function. PMID- 7848902 TI - Guidelines for the treatment of hypertension: a critical review. PMID- 7848904 TI - Opioids induce while nicotine suppresses apoptosis in human lung cancer cells. AB - Previously, we have shown that opioids acting via specific receptors inhibit the growth of human lung cancer cells while nicotine, acting through nicotinic acetylcholine receptors, reverses this inhibition. Therefore, we studied the role of apoptosis in these processes. Treatment of human lung cancer cells with 0.1-1 microM morphine or methadone resulted in morphological changes and cleavage of DNA into nucleosome-sized fragments characteristic of apoptosis. Quantitation of DNA fragmentation showed that a dose-dependent increase occurred within 2 h of opioid treatment and was blocked by the antagonist naloxone. The apoptotic effect of opioids was suppressed by nicotine, while the nicotinic acetylcholine receptor antagonists, hexamethonium and decamethonium, reversed this suppression. In contrast, sphingosine, a protein kinase C inhibitor, caused significant DNA fragmentation which was not suppressed by nicotine. Unexpectedly, the combination of hexamethonium and opioids or hexamethonium and nicotine stimulated apoptosis. We found that nicotine, like phorbol 12-myristate 13-acetate, increased total protein kinase C (PKC) activity, while morphine and sphingosine decreased PKC activity, and nicotine reversed morphine inhibition of PKC activity. In contrast, methadone unexpectedly increased PKC activity. These results indicate that engagement of opioid receptors in human lung cancer cells induces apoptosis, while engagement of nicotine receptors suppresses apoptosis, which in some cases appear to be working through a PKC pathway. They also suggest complexities in the system where blockade of C6 or C10 nicotinic receptors can lead to facilitation of apoptosis. These findings suggest new strategies for treatment and prevention of cancer using opioids or nicotine receptors antagonists and are consistent with the idea that nicotine functions as a tumor promoter. PMID- 7848905 TI - Activation of p34cdc2 coincident with taxol-induced apoptosis. AB - Toxicity elicited by the antitumor compound taxol has been linked to irreversible tubulin polymerization, cell cycle block at mitosis, and cell death from apoptosis. We have used pulsed drug exposure of synchronized populations to identify two points, one in transition from G0 to G1 and the other at G2/M of cell cycle, that are most sensitive to taxol-induced cell killing. By analyzing these lesions separately, we have differentiated events related to mitotic block from those that may contribute to apoptosis. The taxol lesion forms rapidly and stably in transition or mitotic cells, because secondary washes to remove residual drug will decrease cytotoxicity except for cells in these populations. Both G2/M cells and G0/G1 transition cells synchronously initiated apoptotic DNA fragmentation within 20 h of pulsed taxol treatment, indicating that a sustained mitotic block is not requisite to initiate cell death. Apoptosis was inhibited by cyclohexamide and by 2-aminopurine and sodium orthovanadate; thus, cell cycle progression appeared requisite for cell death. Taxol treatment of G0/G1 or G2/M cells clearly leads to a block of mitosis followed by a perturbation of tyrosine phosphoprotein regulation; however, protein tyrosine phosphorylation correlated with mitotic block rather than time after drug exposure. Conversely, p34cdc2 kinase activation does not occur at mitotic block but rather 20 h after drug exposure and coincident with DNA fragmentation. Taken together, these results suggest that mitotic block may not be a sufficient signal for taxol-induced apoptosis and that the taxol lesion initiates apoptosis via a phosphoregulation pathway possibly involving the p34cdc2 kinase. PMID- 7848906 TI - Release from G0/G1 arrest induced by dimethyl sulfoxide in human lymphoid cells: regulation of synthesis and activation of the p33cdk2 and p34cdc2 kinases. AB - Raji cells, a human Burkitt's lymphoma-derived cell line, will accumulate in a G0 like state upon prolonged (5-6 days) incubation in medium containing 1.5% dimethyl sulfoxide (DMSO). After removal of DMSO, the cells reenter the cell cycle in a synchronous manner and proliferate. After 5.5 days incubation in DMSO, S phase entry occurs at about 21-24 h after release, which is about the length of the first G1 phase of normal human lymphocytes which are stimulated in vitro to enter the cell cycle. The G0-like state of arrested cells and the sequence of events occurring after release from DMSO mimic, in most ways studied, those of normal lymphocytes. Arrested Raji cells lack many cell cycle-regulated molecules, including cyclin A, proliferating cell nuclear antigen, and the p34cdc2 kinase. They contain only hypophosphorylated p110Rb and a low level of enzymatically inactive p33cdk2 kinase. After reentering the cell cycle, a series of events occurred, including phosphorylation of p110Rb and accumulation of the cyclin A and proliferating cell nuclear antigen proteins in mid-G1 and the accumulation of the p33cdk2 and p34cdc2 proteins beginning in late G1, just prior to S-phase entry. Cyclin E levels in Raji cells appeared to be less regulated than in normal cells, with high levels of this protein being present in resting cells and throughout the entire cell cycle. The time courses of activation of the p34cdc2 and p33cdk2 kinases were similar; both became detectable at about 21 h after release and increased greatly in early S.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7848907 TI - Adenovirus E1A expression controlled by the red pigment promoter in transgenic mice: a model for developmental abnormalities of the eye. AB - Four transgenic founder mice were produced that carry the adenovirus E1A gene under control of the human red pigment promoter. Two of the founder animals passed the transgene to progeny, and one line was bred to homozygosity. The line of mice homozygous for the transgene expressed E1A-specific RNA at a low level in their eyes; no expression could be detected in other tissues that were tested. Either the founder animals or their progeny exhibited developmental abnormalities of their eyes, including a small eye phenotype, retinal dysplasia, anterior cleavage syndrome, and retinal pigment epithelium dysplasia. Individuals from the same line of mice exhibited subsets of the abnormalities, e.g., many animals had one normal size eye and one small eye, even though both eyes contained E1A specific RNA. No tumors resulted from E1A expression in animals monitored for 22 months. PMID- 7848908 TI - 12(S)-hydroxyeicosatetraenoic acid regulates DNA synthesis and protooncogene expression induced by epidermal growth factor and insulin in rat lens epithelium. AB - Neonatal rat lens epithelium has a high 12(S)-hydroxyeicosatetraenoic acid [12(S) HETE] synthetic capacity, which decreases as epithelial cell proliferation decreases with age. To determine whether products of the 12-lipoxygenase pathway are involved in lens cell proliferation, we measured the effect of 12 lipoxygenase inhibitors on endogenous 12-HETE production, epidermal growth factor/insulin-stimulated DNA synthesis and protooncogene expression in cultured neonatal rat lens epithelial cells. Incubation of neonatal rat lenses in epidermal growth factor plus insulin, which stimulated endogenous 12-HETE production 8- to 10-fold, also produced a transient induction of c-fos and c-myc mRNAs after 2 to 3 h, followed by a round of DNA synthesis approximately 20 h later. The lipoxygenase inhibitor, cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate, strongly inhibited both the endogenous 12-HETE synthesis and growth factor stimulated DNA synthesis with a half-maximal inhibition between 10 and 20 microM. Cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate (10 microM) also inhibited the expression of c-fos and c-myc mRNA and, to a lesser extent, c-jun mRNA. The inhibitory effects of cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate on protooncogene expression and DNA synthesis were prevented by 0.3 microM 12(S) HETE but not by equivalent concentrations of either 5(S)-HETE or 15(S)-HETE. These findings suggest that endogenously synthesized 12(S)-HETE may mediate epidermal growth factor/insulin-stimulated DNA synthesis in neonatal rat lens epithelial cells by regulating protooncogene expression. PMID- 7848909 TI - Insulin and insulin-like growth factor signaling are defective in the MDA MB-468 human breast cancer cell line. AB - Polypeptide growth factors including the insulin-like growth factors (IGFs), insulin, and transforming growth factor-alpha are mitogens for many breast cancer cell lines and may act as regulators of cancer cell growth. In a human breast cancer cell line MCF-7, which expresses IGF-I receptor (IGF-IR), stimulation with insulin or IGFs resulted in autophosphorylation of the IGF-IR in an increased proportion of ras bound to GTP and in the association of phosphatidylinositol 3' kinase (PI3K) activity and of p85-PI3K with M(r) 185,000 phosphotyrosinylated proteins corresponding in size to insulin/IGF-IR substrates. These events were associated with enhanced proliferation. MDA MB-468 is a human breast cancer cell line which expresses insulin receptor and high levels of epidermal growth factor/transforming growth factor alpha receptor but low levels of IGF-IR. In this cell line, insulin stimulated autophosphorylation of IR at physiological concentrations and promoted the association of PI3K activity and of p85 with phosphotyrosine-containing proteins. Insulin did not, however, induce increased ras.GTP, and the cells exhibited minimal proliferation in response to insulin. Unlike insulin treatment, epidermal growth factor stimulation of MDA MB-468 cells is mitogenic and resulted in increased ras.GTP content, suggesting that the failure of insulin to induce these changes is not due to alterations in these signaling molecules. We conclude that there is a postreceptor defect in insulin signaling in MDA MB-468 which prevents the activation of ras and the induction of mitogenesis. Activation of PI3K by insulin is not sufficient to mediate mitogenesis.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7848910 TI - Expression of insulin-like growth factor (IGF)-II and IGF-I receptor during proliferation and differentiation of CaCo-2 human colon carcinoma cells. AB - We have studied the expression of insulin-like growth factor type II (IGF-II) and its autocrine role during the proliferation and differentiation of the CaCo-2 colon carcinoma cell line. IGF-II RNA levels were high in proliferating cells and decreased by more than 10-fold when cells ceased to proliferate and differentiated. Immunoreactive IGF-II protein was high in the conditioned media of proliferating cells and decreased 20-fold in the media of differentiated cells. Reduced IGF-II expression was associated with a decrease in IGF-I receptor number that was high in proliferating cells (approximately 80,000 binding sites/cell) and reduced by 4-fold in differentiated cells. Exogenously added IGF II was able to stimulate proliferation of serum-deprived cells in a dose dependent fashion. IGF-II acted through the IGF-I receptor, since both basal and IGF-II-stimulated cell proliferation was inhibited by the monoclonal antibody alpha-IR3, which blocks the binding sites of the IGF-I receptor. The inhibition of CaCo-2 basal cell growth by the alpha-IR3 antibody suggests that IGF-II may act as an autocrine growth factor for these cells. PMID- 7848911 TI - Similarities between somatic cells overexpressing the mos oncogene and oocytes during meiotic interphase. AB - The mos protooncogene encodes a serine/threonine kinase and is a key regulator of oocyte meiotic maturation. After acute infection of Swiss 3T3 cells with virus containing the v-mos oncogene, cells expressing high levels of v-Mos round up and detach from the monolayer (floating cells), while cells that remain attached express 10-fold lower levels of v-Mos and are transformed. The floating cells are growth arrested with their chromosomes partially condensed in the absence of histone H1 kinase activity, while mitogen-activated protein kinase activity is very high. Collectively, these properties are similar to properties observed in maturing oocytes between meiosis I and II. In v-mos-transformed cell populations, mitogen-activated protein kinase activity is also elevated, correlating with the degree of morphological transformation and the level of Mos expression. Moreover, phosphoprotein modifications specific for M are found in both the floating cells and in v-mos-transformed cells, regardless of their cell cycle stage. One explanation for both morphological transformation and the phenotypes of the floating cells is that Mos imposes a meiotic program on different stages of the somatic cell cycle. The extent of this meiotic phenotype is proportional to the level of v-Mos expression. These results suggest that both morphological transformation and the phenotypes of the floating cells induced by Mos in Swiss 3T3 cells are related to its normal activities during oocyte maturation. PMID- 7848912 TI - Activation of the Axl receptor tyrosine kinase induces mitogenesis and transformation in 32D cells. AB - axl is a transforming receptor tyrosine kinase isolated from DNA of patients with chronic myelogenous leukemia. Association of axl expression with myelogenous leukemias and its expression in primitive hematopoietic cells suggests a role for axl in myeloid biology. To study the cellular function of axl, we constructed a chimeric receptor tyrosine kinase composed of the extracellular and transmembrane domains of the EGF receptor and the cytoplasmic domain of axl; this chimera was named EAK for EGFR-Axl-Kinase. The EAK chimeric receptor was expressed in the mouse myeloid progenitor cell line 32D, which is dependent on interleukin 3 (IL 3) for proliferation and survival. Treatment of the 32D-EAK cells with EGF stimulated the tyrosine phosphorylation of the axl kinase domain and enabled proliferation through EGF rather than IL-3. Thus, axl can effectively couple with mitogenic signaling pathways intrinsic to 32D myeloid cells. Assay of proteins phosphorylated in response to different cytokine treatments showed that IL-3 and EGF exposure produced unique profiles in the 32D-EAK cells. Furthermore, Jak-2 is phosphorylated only in response to IL-3 treatment in these cells. This suggests that IL-3 receptor and axl transduce mitogenic signals through separate pathways. In addition, exposure of cells expressing the chimeric receptor to EGF for 19 days converted the cells to factor-independent growth, a phenomenon not seen with other receptor tyrosine kinases. Generation of this transformed phenotype is absolutely dependent on axl activation by foster ligand. The tyrosine phosphorylation level of the axl kinase domain in the factor-independent subclones is 40-fold greater than the factor-dependent cells. The association of a unique axl phosphorylation level with the factor-independent phenotype suggests that there is a threshold phosphorylation level of the axl kinase for transformation. The fact that activation of the axl receptor leads to transformation of 32D cells suggests that axl can play a role in leukemic conversion of myeloid cells, either through inappropriate expression or improper activation. PMID- 7848913 TI - Coordinate expression of the lineage-specific growth factor colony-stimulating factor (CSF)-1 and its receptor selectively promotes macrophage maturation during differentiation of multipotential progenitor cells. AB - The multipotent hematopoietic precursor line A4GMV#2, derived by infection of FDCP-mix cells with a retroviral vector expressing the granulocyte-macrophage colony-stimulating factor (CSF) gene, proliferates continuously in interleukin 3 and presents the unique advantage of synchronous granulocyte and macrophage differentiation upon interleukin 3 withdrawal. Using this system, we showed previously that the mRNAs for lineage-specific receptors (granulocyte-CSF receptors, CSF-1 receptors, and Erythropoietin receptors) and ligands (granulocyte-CSF and CSF-1) are up-regulated during myeloid maturation. Here we address the specific question of the regulation of the expression of CSF-1 and its receptor and of their relevance to macrophage differentiation. Both genes were transcribed with equal efficiency in undifferentiated and differentiating cells. CSF-1 mRNA was detected in undifferentiated cells and increased slightly in the early phases of differentiation. CSF-1 receptor mRNA, absent in undifferentiated cells, accumulated early in differentiation (24 h) and remained constant thereafter. The production of both proteins, detected later during the differentiation of A4GMV#2 cells and of bone marrow-derived myeloid precursors, was therefore controlled at the posttranscriptional level. CSF-1 was produced by cells of the macrophage lineage and accumulated in mature phagocytes. A neutralizing anti-CSF-1 serum selectively impaired macrophage differentiation of A4GMV#2 cells and, most significantly, of primary myeloid precursors. These data indicate that CSF-1 and its receptor interact productively during differentiation and that the resulting autocrine stimulation selectively promotes macrophage maturation. PMID- 7848914 TI - Functional characterization of two cholecystokinin-B/gastrin receptor isoforms: a preferential splice donor site in the human receptor gene. AB - The cholecystokinin-B and gastrin receptor is encoded by a single gene composed of five exons and spanning over 10 kilobases on human chromosome 11p 15.5-->15.4. Exon 4 has two possible alternative splicing donor sites that seem to be conserved in other species such as the canine, rat, Mastomys, and mouse. They could generate two receptor isoforms (short- and long-form), which differ in their putative third cytoplasmic domain of the serpentine G-protein-coupled receptors. In the present study, we examined whether an alternative splicing is operated in a tissue-specific manner and whether two receptor isoforms have functional differences. RNase-protection assay and S1 nuclease mapping demonstrated the preferential expression of the short-form in the human brain as well as the digestive organs, stomach and pancreas. The two putative isoforms of the cholecystokinin-B/gastrin receptor expressed in mouse fibroblasts showed the same characteristics in their ligand-bindings, the major signal transduction such as phosphoinositides production, cytoplasmic Ca2+ increase, tyrosine phosphorylation of focal adhesion kinase, activation of mitogen-activated protein kinase, and the induction of early-responsive genes such as c-fos, c-myc, and c jun. Moreover, the ligand-dependent trophic effect was seen in both receptor isoforms. Taken together with the absence of tissue-specific expression of two receptor isoforms, these results suggest a species-specific dominant splice donor site in exon 4 of the human receptor gene. PMID- 7848915 TI - Serum-responsive expression from the murine thymidine kinase promoter is specifically disrupted in a transformed cell line. AB - Thymidine kinase (TK) gene expression is controlled in normal cells at both the transcriptional and posttranscriptional levels. Together, these regulatory systems mediate the 20-50-fold induction of TK mRNA observed as cells traverse the G1-S boundary of the cell cycle. Previously, we have reported that a "Yi" protein complex was observed to bind the mouse TK promoter in a cell cycle dependent manner in nontransformed cells (Q-P. Dou, J. L. Fridovich-Keil, and A. B. Pardee, Proc. Natl. Acad. Sci. USA, 88: 1157-1161, 1991) and bound constitutively in transformed cells (D. W. Bradley, Q-P. Dou, J. L. Fridovich Keil, and A. B. Pardee, Proc. Natl. Acad. Sci. USA, 87: 9310-9314, 1990). Nonetheless, TK mRNA levels in these cells continue to exhibit a marked S specific induction (> 10 fold), raising the question: what is the status of TK promoter-mediated, as opposed to posttranscriptional, gene regulation in these transformed cells? To address this question, we have used cell synchrony experiments involving both transformed and nontransformed cells stably transfected with a TK promoter-beta-globin reporter gene construct. We have found that, in marked contrast to the tight regulation of reporter gene expression observed in nontransformed cells (J. L. Fridovich-Keil, J. M. Gudas, Q-P. Dou, I. Bouvard, and A. B. Pardee, Cell Growth & Differ., 2: 67-76, 1991), reporter gene expression in the transformed cells is constitutive and, therefore, closely parallels the presence of Yi DNA-binding activity. These data are fully consistent with other recently published observations concerning differential controls of TK transcriptional and posttranscriptional regulation (J. M. Gudas, J. L. Fridovich-Keil, and A. B. Pardee, Cell Growth & Regul., 4: 421-430, 1993) and support the hypothesis that, in transformed cells, endogenous TK is regulated predominantly at the posttranscriptional level. PMID- 7848916 TI - Enhanced expression by the brain matrix of P-glycoprotein in brain capillary endothelial cells. AB - P-glycoprotein (PGP), an active efflux pump of antitumor agents in multidrug resistant tumor cells, exists in brain capillary endothelium and could be functionally involved in the blood-brain barrier. To study the regulatory mechanism of PGP expression in brain capillary endothelium, various mouse tissue matrices were tested for their abilities to enhance the expression of PGP in mouse brain capillary endothelial cells (MBEC), which express relatively small amounts of PGP. Of the four tissue matrices we examined, PGP expression in MBEC cultured on the brain matrix increased 2.0-fold. The PGP-inducing activity was similarly detected in bovine brain matrix, and the activity was enriched in the fraction of pl 9.0 by isoelectric focusing. The fraction, named PIC-fraction (PGP inducing component), increased the PGP expression in MBEC 3.5-fold. By Northern blot analysis, a 3.3-fold enhancement of mdr gene expression was observed in MBEC cultured on the PIC-fraction. The PGP-inducing activity of the PIC-fraction was reduced by the treatment with trypsin but not with collagenase, suggesting that a proteinaceous factor distinct from type I collagen might be responsible for the PGP-inducing activity of PIC-fraction. Although the PIC-fraction increased the PGP expression in other mouse brain capillary endothelial cells, the PIC-fraction did not increase PGP expression in mouse aortic endothelial cells and KB carcinoma cell lines expressing various amounts of PGP. These observations suggest that PGP expression in brain capillary endothelium is specifically regulated by a tissue-specific factor in the brain matrix. PMID- 7848917 TI - Modulation of tumor immunogenicity of rat glioma cells by s-Myc expression: eradication of rat gliomas in vivo. AB - The Myc family proteins represented by c-Myc are thought to play a crucial role in cellular proliferation, differentiation, transformation, and apoptosis. In this study, we demonstrated the novel role for a Myc family protein in elicitation of immunogenic phenotypes in tumor cells. Injection of rat 9L or C6 glioma cells, together with the s-myc gene linked to the cytomegalovirus promoter, completely prevented formation of both brain tumors and s.c. tumors derived from the parental glioma cells. However, introduction of the s-myc gene had no inhibitory effect on development of B104-derived neuroblastoma. In addition, unlike the s-myc gene, injection of the c-myc or wild type p53 (wt-p53) gene together with glioma cells did not modulate the tumor immunogenicity and resulted in formation of gliomas in the animals. These findings suggest that s Myc expression may stimulate the presentation of a tumor antigen common to 9L and C6 cells to T lymphocytes and augment the activity of the host immune system, resulting in prevention of glioma formation in vivo. This success in tumor eradication indicates the possibility of application of the s-myc gene for gene therapy of human brain tumors. PMID- 7848918 TI - Kiz-1, a protein with LIM zinc finger and kinase domains, is expressed mainly in neurons. AB - The olfactory epithelium is the only neuronal tissue capable of generating new neurons during adult life and hence must express genes responsible for this phenomenon. Therefore, we have used mRNA from immortalized olfactory epithelial cells to search for novel protein tyrosine kinases by polymerase chain reaction, using as primers conserved sequences from the catalytic domain of known kinase genes. A full-length complementary DNA clone corresponding to one such polymerase chain reaction product was isolated and sequenced. This complementary DNA, designated Kiz-1, encodes a protein containing two prominent domains; the NH2 terminal region contains a cysteine/histidine-rich moiety previously identified as a zinc-finger domain in proteins of the LIM family, while the COOH-terminus contains a kinase domain. Kiz-1 is expressed mainly in the brain of adult mice but also in a range of cultured cell lines, regardless of their tissue of origin. Immunohistochemical studies on adult mouse brain demonstrated that Kiz-1 is expressed exclusively in neurons, not in astrocytes or oligodendrocytes. In the developing embryo, however, Kiz-1 is expressed in all tissues. In COS cells transfected with Kiz-1 complementary DNA and in the immortalized olfactory epithelial cells, Kiz-1 was found mainly in the cytoplasm, but in neurons of the adult brain, it resided also in the nucleus. Two Kiz-1 mRNA species are expressed in cell lines as well as in the murine and human brain. One transcript lacks a region of 60 nucleotides, which lies within the catalytic domain of the kinase and is encoded by a separate exon. Our results suggest that Kiz-1 may play distinct roles in dividing cells and in differentiated neurons. PMID- 7848919 TI - Isolation and characterization of an epithelial-specific receptor tyrosine kinase from an ovarian cancer cell line. AB - A protein receptor tyrosine kinase (RTK 6) has been isolated from a complementary DNA library of SKOV-3, an epithelial ovarian cancer cell line, using a polymerase chain reaction (PCR)-mediated approach. The primary structure of the predicted amino acid sequence of the protein shows a novel NH2-terminal region which has homology to a factor VIII-like domain. The juxtamembrane region is proline and glycine rich and is the longest for any known receptor kinase. The COOH-terminal catalytic domain has all of the canonical sequence motifs of a receptor tyrosine kinase with homology to the TRK-2H protein (49%). A single transcript of 4.5 kilobases is expressed at low levels in heart, placenta, lung, liver, muscle, kidney, and pancreas, with high levels of expression in the brain. Ribonuclease protection assay showed a varying level of expression of message in a panel of eight ovarian cancer cell lines compared to placenta. In situ hybridization analysis demonstrated localization of mRNA in the epithelial cells of the ovary, kidney, small bowel, lung, thymus, and brain. There was a lower level of message in normal, benign, and borderline tumors of the ovary compared to malignant tumors of the ovary. Polyclonal antisera raised against a COOH-terminal synthetic peptide recognize a M(r) 140,000 protein in ovarian cancer cells, which autophosphorylates in an in vitro kinase assay. PMID- 7848920 TI - Protein kinase C isozymes in progressively transformed rat embryo fibroblasts. AB - The role of individual protein kinase C (PKC) isoforms in progressive transformation of a rat embryo fibroblast cell line (REF52 cells) has been evaluated. Normal (REF A) cells were transfected with SV40 to produce the partially transformed REF B cell line. REF B cells are morphologically transformed but have only limited capacity for growth in soft agar. Message and protein levels for PKC-alpha and PKC-delta were similar in REF A and B cells, indicating that expression of SV40 large T did not directly influence the amounts of PKCs. However, PKC-alpha localization was influenced. PKC-alpha was associated with focal contacts of REF A but not REF B cells, indicating that changes in location rather than content are an early event in REF52 cell transformation. Clones of REF B cells were selected for growth in soft agar (REF C cells). Levels of PKC-delta, but not PKC-alpha or epsilon, were increased in several of these clones, suggesting that increased PKC-delta content may facilitate anchorage independent growth. In other studies, we have determined that PKCs interact with their binding proteins/substrates through their regulatory domains (RD; L. Liao et al., Biochemistry, 33: 1229-1233, 1994). These results predict that RDs could potentially inhibit PKC signaling by competing with endogenous wild-type PKCs for binding protein/substrate interactions. Overexpression of the RD of PKC-delta inhibited growth in soft agar of one representative REF C clone, whereas overexpression of the RD of PKC-alpha promoted growth in soft agar. These results suggest that RD expression may be a useful approach for dominant negative PKC inhibitors with potential isozyme specificity. PMID- 7848921 TI - Overexpression of protein kinase C-zeta stimulates leukemic cell differentiation. AB - A function for protein kinase C-zeta (PKC-zeta), a member of the phorbol ester nonresponsive atypical protein kinase C subfamily, in modulating differentiation was examined in the leukemic U937 cell. Transfected U937 cells stably overexpressing PKC-zeta displayed a longer doubling time, lower saturation density at confluency, and an increase in adherence to plastic as compared to control cells. PKC-zeta cells expressed a more differentiated phenotype as assessed by changes in morphology, surface antigen expression, and lysosomal enzyme activities and were distinct from parental U937 cells stimulated to differentiate by exposure to phorbol esters. In contrast to parental U937 cells, PKC-zeta cells constitutively expressed mRNA transcripts for c-jun and a low mobility AP-1 binding activity. Thus, PKC-zeta overexpression stimulates a type of phenotypic differentiation that differs significantly from maturation occurring upon activation of other PKC subfamilies induced by phorbol ester treatment. Increased expression of the c-jun protooncogene and an increase in AP 1 binding activity in PKC-zeta cells provides a potential mechanism for explaining the altered differentiation status of this cell. PMID- 7848922 TI - Okadaic acid-elicited transcriptional activation of collagenase gene expression in HT-1080 fibrosarcoma cells is mediated by JunB. AB - Okadaic acid (OA) is a novel, non-phorbol ester-type tumor promoter, which is a specific inhibitor of protein phosphatases 1 and 2A. Treatment of human fibrosarcoma HT-1080 cells with OA resulted in induction of collagenase and stromelysin-1 mRNA levels, while mRNA levels for tissue inhibitor of metalloproteinases-1 were enhanced to a lesser extent. Induction of collagenase and stromelysin-1 mRNA levels was dependent on protein synthesis. Exposure of HT 1080 cells to OA resulted in marked and persistent induction of junB, junD, and c fos mRNA levels up to 24 h, while c-jun mRNA levels were only slightly elevated. In transiently transfected HT-1080 cells, OA-elicited activation of a 3.8 kilobase collagenase promoter/reporter gene construct was entirely dependent on junB expression, as determined by cotransfection with a junB antisense expression construct. Overexpression of JunB in HT-1080 cells enhanced collagenase promoter activity by 10-fold, and OA augmented trans-activation of collagenase promoter by c-Jun and JunB. The results indicate that induction of collagenase gene expression by OA is mediated by enhanced JunB expression, as well as enhanced trans-activating capacity of AP-1 complexes containing c-Jun and JunB. These results also suggest that selective overexpression of junB may enhance invasive and metastatic potential of neoplastic cells. PMID- 7848923 TI - Regulation of CD9 expression during 12-O-tetradecanoyl-phorbol-13-acetate- induced differentiation of human myeloid leukemia (HL-60) cells. AB - CD9 antigen is a member of the tetra spans superfamily of proteins which are expressed on the surface of a variety of hematopoietic and epithelial cell types. CD9 appears to play a role in platelet activation and to enhance sensitivity of cells to diphtheria toxin through its association with the diphtheria toxin receptor. Although several studies indicate that treatment of specific hematopoietic cells with the tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA), induces CD9 expression, the mechanisms by which CD9 expression is regulated have not been elucidated. Here, we provide evidence that, in HL-60 cells, increases in the level of CD9 protein occur in parallel with TPA-induced differentiation. More than 80% of HL-60 cells exposed to 17 nM TPA become CD9 positive within 24 h. CD9 mRNA levels increase within 8-10 h after starting TPA treatment. Activation of CD9 transcription occurs during the same time period. Both transcriptional activation and accumulation of CD9 mRNA require protein synthesis. However, once CD9 mRNA has accumulated, inhibition of protein synthesis has no effect on its level or rate of turnover. These results suggest that CD9 expression in TPA-treated HL-60 cells is regulated at the transcriptional level and that activation of transcription occurs subsequent to the production of proteins induced as an immediate-early response to TPA. Since CD9 expression is not induced in HL-60TR cells, which respond to TPA but are resistant to its differentiating effects, the results also indicate that CD9 expression may serve as a marker for monocyte/macrophage differentiation of HL-60 cells. PMID- 7848924 TI - Arsenate perturbation of human keratinocyte differentiation. AB - Treatment of cultured malignant human keratinocytes with sodium arsenate greatly suppressed expression of involucrin, a specific marker of keratinocyte differentiation. This action was primarily attributable to inhibition of involucrin transcription according to message run-on and stability measurements. Involucrin was suppressed in nontumorigenic keratinocytes as well, although the efficacy of suppression was less dramatic in cells derived from clinically normal epidermis. Several transition metal oxyanions (vanadate, molybdate, and tungstate) also substantially suppressed involucrin expression, but okadaic acid was ineffective. Immunoblotting detected marked increases in tyrosine phosphorylation of several proteins as a consequence of arsenate treatment of the cultures, while mobility shift analysis revealed a dramatic loss of DNA binding by the transcription factor AP2. These findings support a proposed role for altered levels of protein tyrosine phosphorylation in keratinocyte differentiation. They also suggest that arsenate perturbs the differentiation program in target cells by altering this phosphorylation level and transcription factor activity. PMID- 7848925 TI - Differential binding of nuclear c-ets-1 protein to an intron I fragment of the c myb gene in growth versus differentiation. AB - For growth, ML-1 human myeloblastic leukemia cells require insulin-like growth factor 1 together with transferrin, whereas for differentiation they depend upon transforming growth factor beta in combination with transferrin. As shown in this study, growth stimulation is accompanied by c-myb expression, whereas initiation of differentiation results in the cessation of c-myb expression through premature termination of transcription in the first intron of the myb gene. Growth factor stimulated c-myb elongation was found to correlate with an elevated level of nuclear c-ets-1 protein and with increased binding of this protein to an 18-base pair sequence in intron 1 of the c-myb gene containing the putative regulatory element PEA 3. In contrast, differentiation factor-initiated ML-1 cell maturation was accompanied by a very low level of nuclear c-ets-1 protein, by the inability to detect binding of the protein to the 18-base pair sequence, and by the cessation of c-myb expression. These results show a correlation to exist between c-ets-1 binding to intron 1 of the c-myb gene and c-myb expression. The mechanism underlying this correlation is under further study. PMID- 7848926 TI - Retinoids suppress proliferation, induce cell spreading, and up-regulate connexin43 expression only in postconfluent 10T1/2 cells: implications for the role of gap junctional communication. AB - The antiproliferative actions of retinoids in the C3H/10T1/2 cell system are exhibited as a decrease in proliferation rate and a decreased cell saturation density at confluence. These actions correlate with up-regulated gap junctional communication (GJC) driven by the retinoid-induced increased expression of the gap junctional protein connexin43 (Cx43). Here we examine which actions of retinoids occur only in cells making extensive intercellular contacts, and thus may be mediated through GJC, and which are exhibited in the absence of extensive intercellular contacts and thus may be independent of GJC. In confluent cultures, the synthetic retinoid tetrahydrotetramethylnapthalenyl-propenylbenzoic acid (TTNPB) increased GJC, reduced the already low [3H]thymidine-labeling index of G1 growth-arrested confluent cells from 4.2 to < 0.1%, and increased the area occupied by each cell by 42%. In contrast, none of these parameters was altered in logarithmic growth phase cells with very limited intercellular contacts. In order to separate cell-cell contact from cell cycle-related phenomena, non contacting cells were arrested in early G1 by lovastatin. In this situation, Cx43 expression was low and inducible by retinoids, as in G1/G0 growth-arrested confluent cells; however, no cell spreading was induced by TTNPB. In contrast, in non-contacting cycling cells or in cells arrested by aphidicolin, Cx43 expression was higher than in confluent cells. In this situation, TTNPB did not induce Cx43 and did not induce spreading. These data demonstrate the cell cycle phase dependence of connexin43 expression and of retinoid action.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7848927 TI - 1994 Gaston Labat Award Lecturer. Phillip O. Bridenbaugh. PMID- 7848928 TI - 1994 Gaston Labat Award lecture. Anesthesiology and pain management: medical practice or perception. PMID- 7848929 TI - Epidural analgesia versus intravenous patient-controlled analgesia. Differences in the postoperative course of cancer patients. AB - BACKGROUND AND OBJECTIVES: This study evaluated 462 consecutive surgical cancer patients who underwent uncomplicated surgeries of the thorax or abdomen, or both, of more than 3 hours duration between 1989 and 1991. METHODS: Patients received either epidural analgesia (EA group) with 0.1% bupivacaine, 0.01% morphine sulfate after combined general-epidural anesthesia, or parenteral morphine therapy via intravenous patient-controlled analgesia (IV-PCA) after balanced general anesthesia after the operation. Patients in both the EA (n = 352) and IV PCA (n = 100) groups were compared for demographics, length of surgical intensive care unit (SICU), and hospital stays. Moreover, the same comparisons were performed when patients were allocated into surgical subgroups: thoracic (TH), upper abdominal (UA), lower abdominal (LA), radical hysterectomies (RH), and RH with colon resection (RHCR). RESULTS: No differences existed with respect to age or sex between the EA and IV-PCA groups. All patients reported adequate dynamic pain control as evaluated with visual analog pain scores (VAS < 4/10), during the treatment periods (5 +/- 3 versus 5 +/- 2 days, EA versus IV-PCA). Overall, 262 (58%) patients were admitted to the SICU after the operation, 205 (58%) from the EA group and 57 (57%) from the IV-PCA group. Patients in the EA group required less ventilatory support than did those in the IV-PCA group (0.5 +/- 0.8 versus 1.2 +/- 0.9 days, P < .05). Patients in the EA group also spent less time in both the SICU (1.3 +/- 0.8 versus 2.8 +/- 0.6 days, P < .05) and in the hospital (11 +/- 3 versus 17 +/- 5 days, P < .05) than did their counterparts in the IV-PCA group. Significant differences were also found when subgroup comparisons were made. CONCLUSIONS: The use of both analgesic techniques was associated with satisfactory postoperative pain control. However, patients receiving epidural anesthesia and analgesia experienced faster recovery as judged by shorter mechanical ventilation time, and decreased SICU and hospital stays, resulting in significantly lower hospitalization costs. The use of perioperative epidural techniques should be considered to expedite recovery of surgical patients, and has the added benefit of being cost effective by reducing hospital stays. PMID- 7848930 TI - Comparison of the efficacy of epidural morphine given by intermittent injection or continuous infusion for the management of postoperative pain. AB - BACKGROUND AND OBJECTIVES: To compare the effectiveness and side effects of epidural morphine sulfate (MSO4), delivered by continual infusion or intermittent bolus. METHODS: Thirty patients undergoing upper abdominal surgery were randomized into two equal groups to receive MSO4 through a thoracic epidural catheter by one of two methods. Group 1 patients received an initial bolus of morphine (0.07 mg/kg) at the end of surgery, followed by injections of 2-5 mg morphine into the epidural catheter on demand. Patients in group 2 received an initial bolus of morphine (0.03 mg/kg) during surgical peritoneal closure and were immediately started on an infusion of 0.01% morphine at 5 mL/hour (0.5 mg/hour). The infusion dose was titrated from 0.2 to 1.0 mg/hour, dependent on side effects. Outcome measurements included pulmonary function studies, arterial blood gases, morphine plasma levels, pain relief scores, global evaluations, and side effects. RESULTS: No difference existed between groups in forced vital capacity, forced expiratory volume in 1 second, or in arterial blood gas measurements. Side effects were similar in both groups. Respiratory depression was not seen in either group. Group 2 reported significantly better analgesia than group 1 on postoperative days 1 and 2 (P < .01). Peak plasma morphine levels for group 1 were significantly higher than the steady state plasma morphine levels for group 2 (P < .05). CONCLUSIONS: Continuous epidural infusion provides better analgesia without increased side effects for postoperative pain when compared with an intermittent (or demand) bolus technique. PMID- 7848931 TI - Duration of spinal anesthesia in infants less than one year of age. Comparison of three hyperbaric techniques. AB - BACKGROUND AND OBJECTIVES: Although numerous reports of the use of spinal anesthesia have appeared in recent literature, little information is available on the duration of anesthesia provided by standard doses of the commonly used drugs: lidocaine with epinephrine, tetracaine, or tetracaine with epinephrine. The authors evaluated the duration of spinal anesthesia using standard doses of local anesthetics and an objective endpoint of motor recovery in infants less than 1 year of age. METHODS: After reviewing historic literature to select doses, the duration of hyperbaric spinal anesthesia in 100 infants from 1-month to 12-months of age undergoing surgery below the diaphragm was evaluated. Spinal anesthesia was induced, cutaneous level of anesthesia determined by the infant's response to tetanic stimulation with a peripheral nerve stimulator, and time from injection to flexion of hip in response to stimulus was recorded. RESULTS: Lidocaine 3 mg/kg with epinephrine lasted 56 +/- 2.5 minutes, while tetracaine 0.4 mg/kg lasted 86 +/- 4 minutes and tetracaine 0.4 mg/kg with epinephrine lasted 128 +/- 3 minutes. CONCLUSIONS: The three subarachnoid techniques produced varying levels of duration of motor block. The authors recommend lidocaine 3 mg/kg with epinephrine for very brief procedures, tetracaine 0.4 mg/kg for procedures with a potential duration of 1 hour or less, and tetracaine 0.4 mg/kg with epinephrine for procedures estimated to last 90 minutes in infants less than 1 year of age. PMID- 7848932 TI - Do patient variables influence the subarachnoid spread of hyperbaric lidocaine in the postpartum patient? AB - BACKGROUND AND OBJECTIVES: Age, height, weight, body mass index (weight/height2), and vertebral column length may affect the subarachnoid spread of local anesthetics. Little information exists concerning the relationship between these variables and the spread of hyperbaric lidocaine. The authors studied the influence of patient demographics on the block produced by hyperbaric lidocaine in women undergoing postpartum tubal ligation. METHODS: Within 48 hours of vaginal delivery, the authors studied 44 ASA class 1-2 women agreeing to spinal anesthesia for postpartum tubal ligation. Before induction of anesthesia, the authors weighed each patient, measured her height and vertebral column length, and calculated body mass index. In a standardized manner, the authors induced spinal anesthesia with 5% lidocaine 75 mg. An observer, blinded to the measured variables, evaluated loss-of-temperature sensation and loss-of-sensation of sharpness to pinprick bilaterally every 5 minutes for 30 minutes and again at 45 and 60 minutes. RESULTS: There was no correlation between age, weight, body mass index, vertebral column length, or time from delivery to placement of the block, and the spread of sensory block after subarachnoid injection of hyperbaric lidocaine. Only height weakly correlated with the spread of block (r2 = 0.15). CONCLUSIONS: While height may have some small influence on the spread of sensory block, the variation in spread of block within patients of the same height is large. The data suggest that adjusting the dose of local anesthetic injected based on differences in patient height would provide no clinically significant benefit. PMID- 7848933 TI - Differential epidural block. Does the choice of local anesthetic matter? AB - BACKGROUND AND OBJECTIVES: It is well established that spinal anesthesia results in a differential block to the sensations of pinprick and cold temperature discrimination. However, the existence of differential block during epidural anesthesia has not always been accepted. Recently, it has been shown that lumbar epidural anesthesia with chloroprocaine and lidocaine produces a differential block to pinprick and cold sensation. The purpose of this study was to determine if the choice of local anesthetic used for epidural anesthesia has any influence on the relative levels of anesthesia, analgesia, and cold sensation. METHODS: The authors studied nine healthy subjects; each was studied three times and received one of three local anesthetics (0.75% bupivacaine, 2% lidocaine, and 3% chloroprocaine) via an epidural catheter placed into the second or third lumbar epidural space. The authors tested the following modalities compared to an unblocked dermatome: anesthesia, loss of sensation to pinprick; analgesia, loss of an equally sharp sensation to pinprick; and cold sensation, loss of cold sensation to alcohol. RESULTS: Twenty minutes after injection of the local anesthetic, zones of differential sensory block existed for all three agents tested. Anesthesia and analgesia were the most caudad and cephalad, respectively, while loss-to-cold sensation was found to be between these two levels. There was no significant difference in the dermatomal level achieved among the three local anesthetics tested. Sensory testing data observed 10 minutes later showed that no significant change had occurred. CONCLUSIONS: This study reaffirms the existence of differential sensory block during epidural anesthesia and establishes that the observed differential block appears to be independent of the local anesthetic used. PMID- 7848934 TI - Interscalene brachial plexus block for shoulder surgery. AB - BACKGROUND AND OBJECTIVES: To evaluate the efficacy of interscalene brachial plexus block as the primary anesthetic for shoulder surgery, the influence on blood loss, and the rate of complication. METHODS: Retrospective review of 676 reconstructive surgical procedures of the shoulder for anesthetic technique (regional or general), regional anesthetic technique (paresthesia versus nerve stimulator), local anesthetic agent selected, success rate, estimated blood loss by procedures, and complications. RESULTS: A total of 563 patients had interscalene anesthesia, exclusively, and 117 had general anesthesia. Mepivacaine, 1.4% with 1/200,000 epinephrine, was the most frequently used agent (480). Others included 0.5% bupivacaine (33) and 0.625% bupivacaine (50). Of 563 interscalene blocks attempted, 34 required general anesthesia to either initiate or complete the surgery (success rate, 94.1%) with 20 in the 0.5% bupivacaine group, 10 in the mepivacaine group, and 9 in the 0.65% bupivacaine group. For blood loss calculations, failed interscalene blocks were included with the general anesthesia group. Three surgical procedures were identified: total shoulder arthroplasty, acromioplasty with and without repair of the rotator cuff, and capsular advancement for recurrent shoulder dislocation. Comparing general and interscalene anesthesia, blood loss was less in the overall group and in the acromioplasty-rotator cuff group when interscalene block was compared to general anesthesia. There were four complications with two seizures and two subdural injections. CONCLUSIONS: Interscalene anesthesia is an effective anesthetic for elective shoulder surgery that may decrease intraoperative blood loss with a low complication rate. PMID- 7848935 TI - Atlanto-occipital joint pain. A report of three cases and description of an intraarticular joint block technique. AB - BACKGROUND AND OBJECTIVES: The atlanto-occipital (AO) joint is a true, innervated synovial joint with the potential to cause pain. METHODS: A detailed description of an AO joint injection technique is provided, as none was found on review of the literature. RESULTS: Using this technique, three illustrative cases provide preliminary evidence that intraarticular injection of the AO joint may have both diagnostic and therapeutic value for the treatment of upper cervical pain and headaches. CONCLUSIONS: Although AO joint injections may prove to be an effective adjunct to more traditional forms of conservative treatment, additional prospective studies are needed to better define the role of intraarticular AO joint injections in the diagnosis and treatment of head and neck pain. PMID- 7848937 TI - Subdural anesthesia as a complication of an interscalene brachial plexus block. Case report. AB - BACKGROUND AND OBJECTIVES: Interscalene brachial plexus block is performed in the groove between the anterior and middle scalene muscles at the level of C6, just over the transverse process. Injection occurs within 1-2 cm of the dural sleeve and could be misdirected into the epidural, subdural, or subarachnoid spaces. METHODS: Interscalene block was performed by elicitation of paresthesia with 40 mL 1.4% mepivacaine, 1/200,000 epinephrine. RESULTS: Initially, complete interscalene block was achieved that evolved into apnea, high motor, and sensory block; requiring induction of general anesthesia. CONCLUSIONS: The case represents a partial injection of local anesthetic intended for the interscalene brachial plexus into the subdural space. The diagnosis is based on the normal evolution of the block into full motor and sensory anesthesia of the ipsilateral brachial plexus that evolved into a patchy, sensory, and motor block involving many dermatomes outside the brachial plexus, with minimal sympathetic block, and evidence of a normal interscalene block on emergence from general anesthesia. Subdural injection must be considered when unusual motor and sensory block occurs after interscalene block, especially after a time interval too long for epidural or subarachnoid injection, or with minimal evidence of sympathetic block, after suspected high central block injection. PMID- 7848936 TI - Colonic resection with early discharge after combined subarachnoid-epidural analgesia, preoperative glucocorticoids, and early postoperative mobilization and feeding in a pulmonary high-risk patient. AB - BACKGROUND AND OBJECTIVES: A pulmonary high-risk patient undergoing right hemicolectomy for cancer was treated with a combination of intense afferent neural block with subarachnoid-epidural local anesthetics followed by continuous epidural analgesia, preoperative high-dose glucocorticoids, and early oral feeding and mobilization. METHODS: Intraoperative subarachnoid anesthesia was followed by epidural analgesia with bupivacaine and morphine for 72 hours and oral acetaminophen 1 g every 6 hours. RESULTS: The technique resulted in a pain free postoperative course (rest and mobilization) with unchanged pulmonary function. Nocturnal episodic oxygen desaturation, hyperthermia, and postoperative fatigue were prevented. Defecation occurred on the first postoperative day and oral caloric intake was normal after 24 hours with no postoperative weight loss. Self care was normalized on the third postoperative day and the patient discharged from the hospital 80 hours after surgery. CONCLUSIONS: The technique of combined neural and humoral mediator block should be evaluated in other high risk patients undergoing major surgical procedures, where minimal invasive techniques are not possible. PMID- 7848938 TI - Combined spinal-epidural anesthesia in parturient with Harrington rods. PMID- 7848939 TI - Broad unilateral analgesia. PMID- 7848940 TI - Incidence of postdural puncture headache in morbidly obese parturients. PMID- 7848941 TI - Inventors of the pencil-point spinal needle. PMID- 7848942 TI - Preventing epidural catheter disconnection. PMID- 7848943 TI - Backache after spinal anesthesia. PMID- 7848944 TI - Combined spinal-epidural-general anesthesia. PMID- 7848945 TI - 1993 John J. Bonica Lecture. Postoperative pain relief. A look from the other side. PMID- 7848946 TI - Epidural catheters for obstetrics. Terminal hole or lateral eyes? AB - BACKGROUND AND OBJECTIVES: Controversy exists over the choice of the ideal epidural catheter for obstetric use, particularly whether the catheter should have a single terminal hole or three lateral eyes. METHODS: A randomized single blind study of 200 obstetric patients undergoing epidural block for analgesia in labor or for cesarean delivery was undertaken, using either a catheter with a terminal hole or three lateral eyes. The extent and quality of the block was recorded, as well as the presence of any complications. RESULTS: The study was abandoned after 102 patients had been assessed, as the incidence of unsatisfactory blocks with terminal eye catheters was found to be unacceptably high (32%), when compared with the lateral eye catheters (12%) (P < .05). Four of the terminal eye catheters (8%) had to be resited compared with one of the lateral eye catheters (2%). One case of intravascular injection (2%) occurred through a terminal eye catheter, despite repeated negative attempts at aspiration. CONCLUSIONS: The use of terminal eye epidural catheters in our obstetric patients has led to an unacceptably high incidence of both unsatisfactory blocks and catheter replacement. Lateral eye catheters produced better results in our circumstances. PMID- 7848947 TI - Spinal anesthesia with meperidine as the sole agent for cesarean delivery. AB - BACKGROUND AND OBJECTIVES: Meperidine is an opioid with local anesthetic properties that produces spinal anesthesia after subarachnoid injection for surgical procedures. The aim of this study was to evaluate the clinical relevance of spinal meperidine for cesarean delivery. METHODS: Twenty-eight ASA I-III parturients scheduled for cesarean delivery were included in the study. Meperidine 1 mg/kg was administered subarachnoid. Patients were monitored for appropriate anesthesia and side effects. RESULTS: Cesarean delivery was successfully performed under spinal meperidine in 22 cases: two cases required general anesthesia before incision and the duration of sensory anesthesia was too short in four cases. Side effects included moderate hypotension (decrease in arterial blood pressure > 30 mm Hg in 36% of the cases), nausea (32%), and pruritus (10.7%). No respiratory depression was documented in mothers and newborns. CONCLUSIONS: Although short-acting, meperidine can be used as a substitute for local anesthetics for cesarean delivery, especially when local anesthetics are not available. PMID- 7848948 TI - Metoclopramide decreases emesis after spinal anesthesia supplemented with subarachnoid morphine. AB - BACKGROUND AND OBJECTIVES: The authors studied whether metoclopramide decreases the incidence of emesis after spinal anesthesia supplemented with subarachnoid morphine. METHODS: Patients underwent total hip arthroplasty under spinal anesthesia using tetracaine with norepinephrine and morphine 0.2 mg. Forty-eight patients were included in the study conducted with a paired design, using sequential analysis. Patients were allocated randomly and double-blinded to the treatment with metoclopramide or to the control group. In one group, metoclopramide 20 mg intramuscularly was given before and after surgery; patients in the control group were given equal volumes of saline. The presence of emesis for 5 hours postoperatively was recorded. RESULTS: In the postoperative period, emesis was noted in 58% of control patients but in only 17% of patients given metoclopramide (P < .05). CONCLUSIONS: The data suggest that metoclopramide is effective against postoperative emesis after spinal anesthesia supplemented with subarachnoid morphine. PMID- 7848949 TI - Effects of neurolytic concentrations of alcohol and phenol on Dacron and Gore-Tex vascular prosthetic grafts. AB - BACKGROUND AND OBJECTIVES: Neurolytic nerve block, using either alcohol (A) or phenol (P), is frequently used to treat intractable pain. However, these agents may disrupt the integrity of prosthetic vascular grafts. To investigate this possibility, the tensile strength of Dacron (Meadox Medicals, Oakland, NJ) and Gore-Tex (W.L. Gore Associates, Flagstaff, AZ) vascular grafts was determined after in vitro exposure to various clinically used concentrations of A or P. METHODS: Segments of Dacron and Gore-Tex graft were placed in the following solutions: saline (S), 6% and 9% P, and 25%, 50%, 75%, and 100% A, and stored at 23 degrees +/- 1 degree C for 72 hours. Axial maximum load (in kilonewtons, KN) and strain (in mm/mm) were determined with an Instron universal testing machine (Instron Corporation, Camden, MA). Samples from the S, 9% P, and the 100% A groups were evaluated using a scanning electron microscope. RESULTS: Dacron tensile strength decreased a maximum of 23% after exposure to 50%, 75%, and 100% A. Dacron strain capacity decreased after exposure to A (50%, 75%, 100%) and P (6%, 9%). Scanning electron microscope of both P and A showed significant degradation. No changes were found in the Gore-Tex group after exposure to P or A, however, scanning electron microscope of the 100% A sample showed moderate fiber degradation. CONCLUSIONS: The study shows that Dacron woven grafts are degraded by concentrations of A of at least 50%, and to a lesser extent, concentrations of at least 6%, while Gore-Tex had only minimal changes. While neurolytic block offers distinct advantages in patients with terminal cancer pain, the findings suggest that the use of more conservative modalities, such as oral medication regimens, be considered for the treatment of intractable pain in patients with vascular prosthetic grafts that are proximate to the proposed site of neurolysis. PMID- 7848950 TI - Radial or brachial artery injections for intraarterial regional anesthesia for hand surgery? AB - BACKGROUND AND OBJECTIVES: The aim of this study was to determine the optimal injection site for the intraarterial regional anesthesia for hand surgery. METHODS: Forty-two adult patients undergoing elective hand surgery were studied. 0.5% lidocaine plain 1.5 mg/kg was injected over 3 minutes into the radial artery (group 1), or the brachial artery (group 2) through a 22 or 20 gauge Teflon catheter. RESULTS: Two patients (one in each group) were excluded due to technical problems. Onset of analgesia in the hand was faster after radial artery injection (P < .05). Onset of analgesia in the forearm was similar in both groups. Catheterization time, operating conditions, motor block, offset of analgesia, injection, surgical and tourniquet pain scores, and patient's acceptance were similar. Ten patients in group 1 and nine patients in group 2 needed supplemental analgesia at the start of surgery. Median nerve paresthesias were unintentionally elicited during catheterization in three patients in group 2. Six patients (two in group 1 and four in group 2) had minor systemic adverse effects after tourniquet release. Seven patients in group 1 and five in group 2 developed minor bruises after catheterization. No permanent sequelae of injections were observed. CONCLUSIONS: Radial artery is preferred for intraarterial regional anesthesia. Compared with the brachial artery, injection in the radial artery produces faster analgesia in the hand and reduces the risk of damage to the median nerve. PMID- 7848951 TI - Evaluation of intravenous tenoxicam for postoperative cesarean delivery pain relief. Preliminary report. AB - BACKGROUND AND OBJECTIVES: To assess safety and efficacy of tenoxicam for postoperative pain relief after cesarean delivery. METHODS: Postoperative pain relief, supplemental analgesic requirements, and adverse side effects were evaluated in 80 patients undergoing cesarean delivery. Forty patients received a slow intravenous injection of tenoxicam at a fixed dose of 20 mg (2 mL), immediately before induction of spinal anesthesia with 15 mg (3 mL) of 0.5% hyperbaric bupivacaine. The other 40 patients received 2 mL of saline solution. Newborns were evaluated by means of Apgar score and umbilical cord blood gases. RESULTS: There was a significant prolongation of analgesia in the tenoxicam group (365 +/- 91.1 minutes versus 305 +/- 53.2 minutes in control group, P < .001). Supplementary analgesic requirements were significantly decreased by intravenous tenoxicam (1.55 +/- 0.70 versus 2.25 +/- 0.68). Adverse side effects did not differ between groups and few complaints of phlebitis were noted. Apgar scores and blood gas analyses were similar in neonates from both groups. CONCLUSIONS: Intravenous tenoxicam is safe and slightly increases the length of postoperative analgesia provided by the local anesthetic. It is effective in decreasing analgesic consumption in cesarean delivery patients. PMID- 7848952 TI - Unintentional epidural administration of thiamylal. Case report. AB - BACKGROUND AND OBJECTIVES: A 36-year-old woman was scheduled for surgery of bicornuate uterus under epidural anesthesia. METHODS: As a test dose, 3 mL 2.5% thiamylal was injected unintentionally through the epidural catheter instead of 1.5% lidocaine with 15 micrograms epinephrine. RESULTS: Immediately the patient complained of burning pain in the low back area. Administrations of 10 mL 2% lidocaine without epinephrine and 10 mL normal saline containing hydrocortisone 100 mg were performed through the epidural catheter. CONCLUSIONS: The patient recovered without permanent neurologic sequelae. PMID- 7848953 TI - Autonomic hyperreflexia in a pregnant paraplegic patient. Case report. AB - BACKGROUND AND OBJECTIVES: Pregnant patients with spinal cord injuries are predisposed to autonomic hyperreflexia, which if unrecognized or untreated can lead to death. Hypertension occurring in laboring patients at risk for autonomic hyperreflexia must be managed aggressively. METHODS: Epidural anesthesia can safely control autonomic hyperreflexia during labor and delivery, but because spinal cord impaired patients lack sensory and motor function below the level of injury, it is difficult to determine the dermatomal spread of epidural anesthesia by the usual methods. This difficulty is highlighted by the following case, reporting an epidural that failed during labor, with the subsequent development of autonomic hyperreflexia. RESULTS: Previously, autonomic hyperreflexia occurring in pregnant patients (undergoing surgical procedures) was treated with intravenous antihypertensive agents. During labor, however, titrating these agents to coincide with uterine contractions is difficult. In this case, epidural anesthesia was repeated and the autonomic hyperreflexia resolved. CONCLUSIONS: Autonomic hyperreflexia can develop in unanesthetized laboring paraplegic patients (failed epidural) but it can be successfully managed with adequate epidural anesthesia. PMID- 7848954 TI - Delayed respiratory arrest in combined spinal-epidural anesthesia. Case report. AB - BACKGROUND AND OBJECTIVES: A case of delayed respiratory arrest in the combined spinal-epidural anesthesia (CSEA) is described. This event was likely due to morphine injected through the epidural catheter, unintentionally entering into the subarachnoid space through the hole in the dura that was made previously by the spinal needle in the needle-through-needle technique. METHODS: The CSEA is a popular new regional anesthesia that combines the benefits of the spinal and epidural injections. The needle-through-needle technique, which is only one of the various techniques to accomplish CSEA, may increase the risk of unintentionally allowing the entry of the epidural catheter into the subarachnoid space because the spinal needle and epidural catheter have the same pathway. RESULTS: This is the second case report of this event with the needle-through needle technique. The FDA has recently approved this needle-through-needle technique. CONCLUSIONS: Careful attention to technique is necessary with utilization of CSEA. PMID- 7848955 TI - Use of glycopyrrolate to treat intraoperative penile erection. Case report and review of the literature. AB - BACKGROUND AND OBJECTIVES: Penile erections following the initiation of either axial regional or general anesthesia is rare; however, when it occurs in patients undergoing urologic procedures it may delay, or even cancel, the planned surgery. The purpose of this case report and review is to enhance anesthesiologists' understanding of this phenomenon so that they may better formulate a logical treatment scheme in such an event. METHODS: We present a case of intraoperative erection after the initiation of continuous spinal anesthesia that was treated with intravenous glycopyrrolate. From the literature, 72 references were reviewed. RESULTS: Glycopyrrolate successfully treated intraoperative penile erection. The physiology and pharmacology of erection are reviewed, and pharmacologic treatment options and surgical treatments are reviewed. CONCLUSIONS: In patients with coronary artery disease, or in situations where cardiovascular stability is desired, glycopyrrolate is an effective means of relieving intraoperative penile erections. Other pharmacologic interventions, based on the physiology of erections, are presented. Nitric oxide, a potent smooth muscle relaxant, has been shown to be involved in the initiation and maintenance of erections; future research involving specific inhibitors of this chemical is indicated for the possible treatment of intraoperative penile erections. PMID- 7848956 TI - The first spinal anesthesia. Who deserves the laurels? AB - BACKGROUND AND OBJECTIVES: One year after the discovery of the anesthetic properties of cocaine, the American neurologist Corning injected the drug between the spinous processes of the lower dorsal vertebrae, first in a young dog and then in a generally healthy man. He published the results in a paper entitled "Spinal Anaesthesia and Local Medication of the Cord." For many years, there has been controversy as to whether Corning's injection was a spinal or an extradural block. METHODS: To settle this controversy, a detailed review was undertaken, in the original language, of Corning's publication, as well as of two major initial articles describing authentic spinal anesthesia, namely that by the surgeon Bier of Germany and Tuffier of France. Mention of cerebrospinal fluid, dose of injected cocaine, onset of action, and height of sensory analgesia were compared. RESULTS: Corning's dose of local anesthetic was eight times higher than the doses of the same drug used by Bier and Tuffier; yet, the onset of analgesia in his patient was slower and the ultimate sensory level lower. Cerebrospinal fluid was not described in contrast to the other two publications. In addition, Corning proposed the action of cocaine to result from absorption into the venous circulation and subsequent transport to the cord. CONCLUSIONS: Corning's injection was extradural, and Bier deserves the laurels for introducing spinal anesthesia. PMID- 7848957 TI - Dose is the product of volume and concentration. PMID- 7848958 TI - Genitofemoral nerve block: a transpsoas technique. PMID- 7848959 TI - Prevention of epidural morphine pruritus by intramuscular promethazine in parturients. PMID- 7848960 TI - Treatment of reflex sympathetic dystrophy with EMLA cream. PMID- 7848962 TI - Which way do the epidural catheters go? PMID- 7848961 TI - Evaluation of brachial plexus anesthesia for upper extremity surgery--comments. PMID- 7848963 TI - Refolding of RNAse A at high concentrations: identification of non-native species. AB - In this paper, we present an analysis of the soluble species formed on refolding of RNase A at various concentrations, in order to characterize these species with respect to structure and activities. Studies were carried out using reverse-phase high-performance liquid chromatography, circular dichroism, chromatography and ultracentrifugation. At all concentrations of protein used, RNase A refolded to the native form, together with formation of non-native species. These non-native species are either misfolded monomers or aggregates; the percentage of such species increases with increasing concentration of enzyme. Such aggregation appears to be a non-random process governed by intermolecular disulfide crosslinking between monomers. These results reaffirm the principle that the information for folding of the protein is encoded in the amino acid sequence itself. PMID- 7848964 TI - Solubility and structure of N-carboxymethylchitosan. AB - N-Carboxymethylchitosan from crab and shrimp chitosans was obtained in water soluble form by proper selection of the reactant ratio, i.e. using equimolar quantities of glyoxylic acid and amino groups. HPLC determinations of glyoxylic and glycolic acids, in conjunction with NMR analysis, permitted identification of the structure of the product, which is partly N-mono-carboxymethylated (0.3), N,N dicarboxymethylated (0.3) and N-acetylated depending on the level of deacetylation of the starting chitosan (0.08-0.15). The preparation can be made successfully even in the presence of large concentrations of glycolic acid. The use of enzymes exerting hydrolysing activity on the high-molecular-weight fractions helps to avoid gel formation during storage and precipitate formation on addition of anti-microbial agents. PMID- 7848965 TI - Elucidation of pKa values for Ca2+ binding sites in calmodulin by spectrofluorometry. AB - Calmodulin (CaM) was purified from bovine brain and identified on the basis of its phosphodiesterase activity. Its purity was further tested by electrophoretic migration in polyacrylamide gels in the presence of sodium dodecyl sulfate. Apo CaM was prepared from holo-CaM using hydroxyapatite chromatography. The Ca2+ binding sites on CaM and the pKa of each of the functional groups bound to Ca2+ were identified from the dependence of Ca2+ interaction with the functional group as a function of pH. EGTA was found to diminish the peaks corresponding to the pKa values of the groups bound to Ca2+. The use of bromophenacyl bromide, a modifier for aspartate and glutamate residues in proteins, diminished the peaks at pH = 3.4 and 4.3. Diethyl pyrocarbonate, a modifier for histidine residues, reduced the peak at pH = 6.2, corresponding to the pKa of the imidazole group in histidine. Furthermore, the peak at pH = 11.6 was eliminated using the specific tyrosine modifier, N-acetylimidazole. Diethylpyrocarbonate also eliminated four small peaks at pH = 7.2, 7.8, 8.2 and 8.8. This effect could be attributed to the binding of threonine and serine residues. The crystallographic results for parvalbumin, which has a similar molecular structure, suggest identical Ca2+ binding sites. PMID- 7848966 TI - Conformations and stabilities of human Glu1- and Lys78-plasminogen and of the fragments mini- and microplasminogen, analysed by circular dichroism and differential scanning calorimetry. AB - The conformations and stabilities of two forms of human plasminogen, Glu1 plasminogen (Glu1-HPg, Glu1-Asn791) and Lys78-plasminogen (Lys78-HPg, Lys78 Asn791), and two enzymatically derived plasminogen fragments, miniplasminogen (mini-HPg, Val443-Asn791) and microplasminogen (micro-HPg, Lys531-Asn791) were analysed by circular dichroism and differential scanning calorimetry. The two plasminogen forms differ by the lack of 77 N-terminal amino acids in Lys78-HPg in comparison to Glu1-HPg. Mini-HPg is composed of kringle 5 and the protease domain of HPg whereas micro-HPg is built from the protease domain of HPg and a stretch of about 15 amino acids from kringle 5. Differential scanning calorimetric measurements of Glu1-HPg and Lys78-HPg reveal seven thermal transitions for both plasminogen forms. The results obtained for Lys78-HPg largely agree with recently published data (Novokhatny, V. V., Kudinov, S. A. and Privalov, P. L. J. Mol. Biol. 1984, 179, 215). Three thermal transitions corresponding to kringle 5 and to two subdomains of the C-terminal protease region were identified for mini-HPg. In micro-HPg, the two thermal transitions of the protease region were found but one of the protease subdomains was modified and its stability was much higher than in any of the other studied proteins. According to the microcalorimetric data obtained for mini-HPg and micro-HPg, transitions 5 and 6 of Glu1-HPg and Lys78-HPg were reassigned to kringle 5 and to a subdomain of the protease region, respectively, in contrast to literature data.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7848967 TI - Structure factor calculations for a side-by-side model of B-DNA. AB - In this paper, the side-by-side model of DNA proposed by Premilat and Albiser is investigated. The axial repeat of the model is equal to the c-axis repeat in the observed B-DNA unit cell in fibres. However, the model does not pack into the unit cell as efficiently as the B-DNA double helix does, nor is it as successful as the double helix in predicting the observed Bragg amplitudes. When the azimuthal orientations and the relative axial displacements of the two molecules in the unit cell are allowed to take general values, the best crystallographic R factor for the side-by-side model is 43.43% compared with 34.33% for the double helix. If constraints consistent with the accepted B-DNA space group, P2(1)2(1)2(1), are applied, the best R factors are 45.53% for the side-by-side model and 34.51% for the double helix. Therefore, the side-by-side model can be rejected as a possible conformation for B-DNA in crystalline fibres. PMID- 7848968 TI - Single crystals of V amylose complexed with n-butanol or n-pentanol: structural features and properties. AB - Rectangular single crystals of amylose complexed with n-butanol or n-pentanol were prepared by adding these precipitants to metastable aqueous solutions of amylose. The crystals were analysed by electron and X-ray diffraction. It was confirmed that the crystals have an orthorhombic P2(1)2(1)2(1) symmetry with cell parameters: a = 2.74 nm, b = 2.65 nm and c (chain axis) = 0.8 nm. Within the unit cell, the amylose chains were organized in antiparallel pairs of parallel 6(5) amylose helices with four molecules of precipitant located between the helices and occupying about 10% of the cell volume. Upon desolvation, the crystals were invariably converted to the hexagonal close-packed VH amylose. The crystals could also be swollen in a series of solvents or solvent mixtures without losing their single crystal characteristics. Such treatments retained the orthorhombic symmetry but resulted in an expansion of their a and b cell parameters while c remained constant at 0.8 nm. PMID- 7848969 TI - Modification of crystallinity and crystalline structure of Acetobacter xylinum cellulose in the presence of water-soluble beta-1,4-linked polysaccharides: 13C NMR evidence. AB - Cellulose produced by Acetobacter xylinum in medium containing 0.5% xyloglucan or glucomannan showed altered crystallinities and shifted I alpha/I beta ratios when analysed by solid-state 13C-NMR. By estimating the spectra of cellulose components in each composite, a decreased I alpha content was shown to be countered by increased I beta content in cellulose aggregated in the presence of xyloglucan, causing minimal loss of crystallinity. However, the I alpha decrease was linked primarily to increased disordered content in cellulose produced in medium containing glucomannan. These results are considered in the light of two models for the morphological disposition of the I alpha phase: (i) a series model, proposed on the basis of electron diffraction measurements for an algal cellulose, in which regions of I alpha and I beta alternate along the length of a microfibril, and (ii) a superlattice model, in which the I alpha and I beta domains co-exist throughout the cross-section of each microfibril and form as a result of hierarchical aggregation. The latter model offers clearer insight into the role of the polysaccharides in inhibiting the formation of I alpha crystalline regions. In this superlattice model, polysaccharides adsorbed on surfaces of the most elementary aggregates are displaced to varying degrees during subsequent aggregation, with the presence of these polysaccharides altering the extent of I alpha production at interfaces. PMID- 7848970 TI - Perimetry--back to the future? PMID- 7848971 TI - Traditional eye medicines--good or bad news? PMID- 7848972 TI - Molecular epidemiology and ophthalmology. PMID- 7848973 TI - Traditional eye medicine use among patients with corneal disease in rural Malawi. AB - Over a 15 month period all patients with corneal ulcers presenting at two district hospitals were interviewed regarding demographic and clinical characteristics and their use of traditional eye medicines (TEM). Of the 583 patients interviewed, 33.8% reported using TEM. There were no age or sex differences in TEM use. Patients who reported TEM use took, on average, 51 days between onset of symptoms and presentation while patients who denied TEM use took 13 days. Sixteen per cent of TEM users had a vision in the affected eye of < 3/60 on presentation compared with 5% of non-TEM users. The frequent use of TEM and the presence of numerous traditional healers in rural areas of Africa suggest that eye care programmes could benefit greatly by including traditional healers in primary eye care activities. PMID- 7848974 TI - Molecular epidemiology of trachoma in a Gambian village. AB - The application of a diagnostic and genotyping technique based on the polymerase chain reaction (PCR) to the study of trachoma epidemiology in the Gambian village of Jali is reported. PCR based on the major outer membrane protein (MOMP) gene of Chlamydia trachomatis appears to be more sensitive than either isolation or antigen detection by enzyme immunoassay; it had a specificity of 95% and sensitivity of 51% against clinical signs. PCR genotyping identified genotypes A and B of Chlamydia trachomatis circulating in Jali. Sequencing revealed a Pst1 restriction endonuclease site in the amplified MOMP gene of some B strains but not others; Pst1 digestion of the PCR product proved an easy method of distinguishing these strains. The distribution of serotypes and B strain variants shows a significant degree of household clustering (p < 0.001). PCR based genotyping combined with strain typing provides a new and powerful epidemiological tool for the study of transmission events in trachoma. PMID- 7848975 TI - Effect of trabeculectomy on pulsatile ocular blood flow. AB - Trabeculectomy, despite producing an effective reduction in intraocular pressure, may not prevent continued visual field loss. This may be because of the presence of other factors in the pathogenesis of glaucoma. Vascular factors have been suggested as being particularly important. To study the effect of trabeculectomy on ocular blood flow the technique of ocular pulse analysis has been used to derive a measure of pulsatile ocular blood flow in 17 patients (average age 65.6 (SD 1.8) years) undergoing trabeculectomy. A significant increase in pulsatile ocular blood flow of 29% was observed in the group as a whole in the standing position following operation but in some individuals blood flow changed only slightly despite a large reduction in intraocular pressure. The significance of these findings in relation to the prognosis of visual field preservation following trabeculectomy is discussed. PMID- 7848976 TI - First experience with a new echographic contrast agent. AB - The intravenous injection of an ultrasound contrast agent can enhance signals from blood flow. Broad toxicological and pharmaceutical studies in animals confirmed the safety and efficacy of an ultrasound contrast agent made of microparticles of galactose with stabilised microbubbles in watery suspension (SH U 508 A). In this paper 10 patients with different malignant orbital and ocular tumours have been evaluated with an echo colour Doppler machine before and after the injection of SH U 508 A. An enhancement of the Doppler signals in the lesions in different degrees has been detected. This echographic contrast agent seems to be very important not only in the evaluation of vascular lesions, but also in evaluating the effectiveness of radiotherapy in malignant tumours and could spread the echographic indications in several other ophthalmic fields. PMID- 7848977 TI - Retinal thickness change after focal laser treatment of diabetic macular oedema. AB - Laser photocoagulation has been used successfully for the treatment of clinically significant macular oedema to reduce the risk of loss of vision in diabetic patients. A quantitative method for measuring retinal thickness was applied to 20 patients with diabetic macular oedema before and 4 months after focal laser treatment to assess the reduction in retinal thickening and its relation to visual acuity. The degree of thickening at each location, defined by thickness index, was determined relative to the corresponding average value in normal subjects. Comparison of quantitative retinal thickness measurements before and after treatment demonstrated that treatment at thickness indices of approximately 1.6 (60% thickening) has nearly 50% probability for reversal of thickening to within the normal range (< or = 1.3), whereas at thickness indices greater than 2.8 (180% thickening) there is less than 2.5% probability that reversal will occur. The level of foveal thickening before treatment strongly correlated with the degree of thickening after treatment. Most of the eyes with an improvement in visual acuity had a foveal thickness within the normal range at 4 months' follow up. These findings suggest that quantitative retinal thickness measurement provides an objective assessment of the degree of macular oedema and can be useful for monitoring the efficacy of focal laser treatment in reducing the thickening and relating the latter to visual outcome. PMID- 7848978 TI - Strange physical treatments. PMID- 7848979 TI - Ocular findings associated with a 3 base pair deletion in the peripherin-RDS gene in autosomal dominant retinitis pigmentosa. AB - Affected members of a family with autosomal dominant retinitis pigmentosa were found to have a 3 base pair deletion at codon 118 or 119 of the retinal degeneration slow gene. This mutation causes the loss of a highly conserved cysteine residue in the predicted third transmembrane domain of peripherin-rds, a photo-receptor specific structural glycoprotein localised to both rod and cone outer segment disc membranes. Four of these individuals underwent detailed clinical, psychophysical, and electroretinographic testing in order to characterise their photoreceptor dysfunction. Nyctalopia was reported early in the second decade by all patients. Global rod and cone dysfunction was recorded by the third decade with severe reduction of both photopic and scotopic function by age 30 years. This retinal degeneration slow gene mutation may lead to the primary loss of both rod and cone photo-receptor function. PMID- 7848980 TI - Sex differences in the left and right hemifields of normal subjects with computerised static perimetry. AB - Results of routine perimetric testing of the left and right hemifields in normal subjects have been assumed to be symmetric although asymmetry due to hemispheric dominance has been established for other psychophysical tests. These asymmetries have sometimes been related to sex. With the advent of computerised static perimetry, subtle differences between the left and the right hemifields might be found that were not obvious before. This study investigated differences in retinal sensitivity between the hemifields and the role of sex and eye dominance. Forty three unequivocally right handed and right eye dominant normal adult volunteers, 24 females and 19 males, underwent Humphrey 24-2 testing, half beginning with the left eye, the other half with the right eye. The Peridata program was used to calculate decibel totals per hemifield. Four subjects were excluded because of poor cooperation or test artefacts. In females, the total of the left hemifield was significantly less than the right (p < 0.01) by a mean 18.2 (SD 24) dB equivalent to a difference of 0.34 dB per tested point. No significant difference in hemifields was found for males, between the sexes for both eyes combined, or between the two eyes for either sex. It was concluded that asymmetries in retinal sensitivity with respect to the vertical axis may be physiological and found in females, but not in males. PMID- 7848981 TI - 8 mm bimedial rectus recession in infantile esotropia of 80-90 prism dioptres. AB - Sixteen patients with large angle infantile esotropia with deviations of 80-90 prism dioptres were operated at the age of about 2 years. All patients underwent 8 mm bilateral medial rectus recessions. At the last follow up examination, 6 to 48 months postoperatively (average 16.3 months), successful horizontal alignment was achieved in 12 patients (75%). Four patients (25%) were undercorrected. Clinically significant limitation of adduction or convergence was not observed postoperatively in any of the patients. Consecutive exotropia was not encountered in this series but a longer follow up is probably needed in order to assess its delayed appearance. These results suggest that 8 mm recession of the medial recti is an effective procedure for the correction of large angle infantile esotropia of 80-90 prism dioptres and can be considered as an acceptable alternative to operations on three or four muscles. PMID- 7848982 TI - Carbohydrate deficient glycoprotein syndrome type I: ophthalmic aspects in four Sicilian patients. AB - Four patients with carbohydrate deficient glycoprotein (CDG) syndrome type I underwent ophthalmic examination. All of them had retinitis pigmentosa with extinguished scotopic electroretinogram. The importance of CDG syndromes as one of the metabolic causes of retinal dystrophy with 'bony spicule' pigment is stressed. PMID- 7848983 TI - Suppurative keratitis caused by Streptococcus pneumoniae after cataract surgery. AB - Six elderly patients are described (age range 76-86 years) in whom a characteristic peripheral suppurative keratitis developed 1-36 months after uncomplicated cataract surgery. A corneal section had been used in all patients and four or five interrupted nylon sutures were present at the time of onset. Streptococcus pneumoniae was cultured from a corneal scrape in all cases. Treatment with appropriate antibiotics resulted in slow resolution though supplementary topical steroids were necessary in five of the six patients, and corneal opacification persists in all cases. PMID- 7848984 TI - Detection of human immunodeficiency virus, hepatitis B virus, and hepatitis C virus in donor eyes using polymerase chain reaction. AB - Detection of human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) in donor eyes was performed. DNAs were extracted from the uvea, and they were amplified using the polymerase chain reaction (PCR). Amplified viral DNAs were detected with liquid hybridisation and chemiluminescent assay in which no radioactive materials were used. This method was shown to have a sensitivity limit of fewer than 10 copies of HIV, making it much more sensitive than the current techniques employed in eye banks. The method was applied to 120 donor eyes, including four from donors seropositive for HBV. The HBV gene was detected in one case in which the donor's blood had not been tested for HBV. HIV and HCV genes were not detected in any of the samples. The assay could be an effective screening test for the detection of these viruses in eye bank eyes. PMID- 7848985 TI - Improved preservation of human corneal basement membrane following freezing of donor tissue for epikeratophakia. AB - Current methods for the production of lenticules for epikeratophakia involve rapid freezing, cryolathing, and slow warming of the donor cornea. We have found that this procedure causes structural damage to the epithelial basement membrane in the donor cornea which may subsequently contribute to poor postoperative re epithelialisation of the implant, leading to graft failure. Endeavouring to overcome these problems, the effects of cryoprotection of donor cornea were investigated, using dimethyl sulphoxide, in conjunction with different cooling and warming rates as part of the protocol for cryolathing. The structural integrity of the epithelial basement membrane zone (BMZ) was then assessed by electron microscopy and by immunofluorescence microscopy using antibodies to types IV and VII collagen, components of the basal lamina and anchoring fibrils respectively, and an antibody to a component of the anchoring filaments. No differences in the pattern of immunostaining for these components were detected, indicating that the composition of the BMZ was unaltered by the different treatment regimens applied. However, electron microscopy showed that preservation of basement membrane ultrastructure was markedly improved when cornea was warmed rapidly rather than slowly, both in cryoprotected and non-cryoprotected tissue. Epithelial cell retention and preservation of stromal architecture appeared superior in cryoprotected samples, while keratocyte structure was heterogeneous throughout the experimental groups. Further work is in progress to assess the efficacy of these protocols in the preservation of keratocyte viability in association with improved basement membrane structure in donor tissue for epikeratophakia. PMID- 7848986 TI - Syntactic structure analysis in uveal melanomas. AB - Syntactic structure analysis was carried out successfully on 92 paraffin embedded uveal melanomas, taken from patients with a minimum follow up of 5 years. This simple, fast, and reproducible method of describing the tumour architecture has been significantly correlated with malignancy in tumours from several sites. Paraffin sections 5 microns thick, were cut and stained with haematoxylin and eosin. Tumours were classified according to a modification of the Callender classification. A minimum spanning tree (MST), using the centre points of tumour nuclei, was constructed in five randomly chosen fields with an interactive digitising video overlay system. Ten syntactic structure features were derived from each MST; subsequently, the mean and standard deviation of the five fields analysed were calculated for further statistical analysis. Reproducibility was acceptable with a mean correlation coefficient of 0.70. In univariate survival analysis, the percentage of points with three neighbours yielded prognostic significance (p < 0.05). Minimum spanning tree variables were compared (chi 2 test) with classic tumour prognosticators and there was a significant correlation between Callender cell type and the following MST parameters: mean number of points (p < 0.003); MST length (p < 0.003); mean line length (p < 0.01); number of nuclei with one neighbour (p < 0.004); number of nuclei with two neighbours (p < 0.02), and number of nuclei with three neighbours (p < 0.005). Syntactic structure analysis is an evolving technique, but may be able to mathematically (and reproducibly) describe melanoma architecture across the spectrum of the Callender classes. This would also allow architectural grading of tumours within the specific Callender groups, providing more precise prognostic information. Further modifications of this technique are necessary to optimise prognostic potential when applied to uveal melanomas. PMID- 7848987 TI - Selective cell death in glaucoma: does it really occur? PMID- 7848988 TI - Localised unilateral blepharochalasis. PMID- 7848989 TI - Superior oblique myokymia--a topical solution? PMID- 7848990 TI - Exploding bottles: eye injury due to yeast fermentation of an uncarbonated soft drink. PMID- 7848991 TI - Spontaneous regression of a choroidal metastasis from renal carcinoma. PMID- 7848992 TI - The management of the mandible in mouth cancer. AB - Surgical necessity or the ravages of disease frequently result in the loss of mandibular continuity with consequent disruption of function and form. The role of the maxillofacial surgeon is central to the restoration as far as possible of maximum cosmesis and oral function. The suggestion in the recent consultative document on future organisation of cancer services lends weight to this role where it states 'In future the surgical management of cancer should be carried out by surgeons who specialise in a particular anatomical area'. PMID- 7848993 TI - A comparison of different imaging modalities and direct inspection after periosteal stripping in predicting the invasion of the mandible by oral squamous cell carcinoma. AB - OBJECTIVE: To compare the predictability of orthopantomograms (OPG), bone scans, computerised tomography (CT), magnetic resonance imaging (MRI) and periosteal stripping with direct inspection in predicting both the presence and extent of tumor invasion of the mandible. DESIGN: Prospective study. SETTING: Queen Elizabeth Hospital, Birmingham; Wordsley Hospital, Stourbridge; North Staffordshire Royal Infirmary, Stroke-on-Trent. SUBJECTS: 35 consecutive patients requiring a mandibular resection as part of their treatment for oral squamous cell carcinoma. MAIN OUTCOME MEASURES: The prediction of the extent of bone invasion for each of the investigations and direct inspection after periosteal stripping. The actual extent of invasion of the mandible from a detailed histological assessment. RESULTS: The OPG underpredicted the width and depth of invasion by on average 13 mm and 2 mm. There were 5 false negative reports. Bone scans overpredicted the width and depth by 14 mm and 15 mm with 1 false negative. CT scans underpredicted the width of invasion by 5 mm and overpredicted depth by 3 mm, but 7 false negatives were returned. MRI scans overpredicted width and depth of invasion by 19 mm and 10 mm with 1 false negative. Direct inspection after periosteal stripping underpredicted the width and depth of invasion by 5 mm and 3 mm with 1 false negative. CONCLUSION: OPG's and bone scans are useful for the initial assessment of all tumours in the region of the mandible. MRI is a more useful investigation than CT in the assessment of mandibular invasion by oral squamous cell carcinomas. Exploratory periosteal stripping at the time of resection can accurately predict the presence of tumour invading the mandible. PMID- 7848994 TI - Impaired perception of moving objects after minor injuries to the eye and midface: the Pulfrich phenomenon. AB - Delayed conduction along one optic nerve can result in an incorrect appreciation of moving objects. The temporal mismatch between the two different pathways results in altered perception of the vector of a moving target and is known as 'the Pulfrich phenomenon'. This is a well-recognised handicap in patients with multiple sclerosis, but has not previously been reported as a consequence of injury. All 187 patients who presented during 1991 with reduced visual acuity as a result of midfacial injuries were examined with a pendulum. Six had the defect and five of these had symptoms. In each case the patients were disturbed by car travel, because they perceived oncoming traffic moving in a hyperbolic curve towards them. These patients have been examined in detail and given a tinted lens for the normal eye to eliminate the illusion by delaying the input from the normal side to equal that on the damaged side. We recommend that this phenomenon is sought in all patients with mid-facial injuries or with later evidence of mild traumatic optic neuropathy, particularly if they are disturbed by car travel. PMID- 7848995 TI - An investigation into the accuracy and validity of three points used in the assessment of autorotation in orthognathic surgery. AB - OBJECTIVE: To assess the accuracy and validity of three points used in the cephalometric assessment of autorotation in orthognathic surgery. DESIGN: A retrospective study of 15 cases of maxillary surgery. SETTING: A postgraduate dental hospital in London. SUBJECT: Fifteen well-documented cases of maxillary surgery with mandibular autorotation, treated by a single surgical, team were examined. Cephalometric surgical predictions were prepared, using the planned surgical movements, incorporating three different points advocated as centres of mandibular autorotation, for each case. These predictions were compared with the results achieved at surgery. MAIN OUTCOME MEASURES: The discrepancy between the predictions and the surgical result in each case was measured and subjected to statistical analysis. The method error was assessed and considered with the measured discrepancy. RESULTS: Individual variation was seen, both between the individual landmarks and the individual cases studied. The discrepancies measured were broadly similar for each of the centres of autorotation. Statistical analysis failed to show any significant differences between the points studied. CONCLUSION: All 3 points of autorotation examined will approximate mandibular autorotation following maxillary surgery and all can be considered equally valid. PMID- 7848996 TI - Mandibular reconstruction using a 'parasitic' flap. AB - A case of reconstruction of a large mandibular defect is presented, in which a 17 cm free vascularised fibular bone graft was first anastomosed to a radial fasciocutaneous flap in situ in the forearm, and then the combined flap was transferred and revascularised in the neck. PMID- 7848997 TI - Percutaneous dilatational tracheostomy. AB - This paper describes a method of tracheostomy using a percutaneous dilatational technique. The authors report their experience of 50 elective cases and discuss the technique as an alternative to formal surgical tracheostomy. They suggest that the lower complication rate associated with the percutaneous dilatational method makes feasible its extended use in elective head and neck surgery. PMID- 7848998 TI - Symptoms from impacted wisdom teeth. AB - A study of patients referred for wisdom teeth removal was carried out, to investigate symptoms prior to consultation and during the period on the waiting list for surgery. The reasons for treatment of asymptomatic wisdom teeth were investigated. Pain was the main indication for surgery in 73.7% of patients waiting for consultation. 168 patients waiting for consultation consumed a total of 271 courses of antibiotics, averaging 1.6 courses of antibiotics per patient. The antibiotic consumption increased to an average of 2.5 courses per patient in 94 patients waiting for operation. 67 out of 423 patients had an average of three lost working days due to symptoms from wisdom teeth. The long waiting list for consultation and treatment added further to the discomfort. The extent of symptoms from wisdom teeth may be underestimated. PMID- 7848999 TI - The sensory distribution of the buccal nerve. AB - The buccal nerve is frequently anaesthetised, and occasionally cut during surgical procedures, but its distribution is poorly documented. The aim of this study was to determine its distribution by mapping areas of sensory loss following administration of a local anaesthetic solution. Observations in 40 patients revealed marked variation in the area supplied solely by the buccal nerve and a substantial overlap with the area supplied by the inferior alveolar nerve. PMID- 7849000 TI - Complications associated with peripheral alcohol injections in the management of trigeminal neuralgia. AB - A retrospective study was carried out on 82 patients whose symptoms of trigeminal neuralgia were controlled by repeated peripheral alcohol nerve blocks in order to assess the associated complications. Peripheral alcohol nerve blocks were invariably associated with swelling and discomfort lasting several days. Significant complications occurred in 3 out of 413 nerve blocks administered over a 20-year period. PMID- 7849001 TI - Multiple oral mucoceles treated with gamma-linolenic acid: report of a case. AB - Multiple mucoceles are an extremely rare condition in the oral cavity. We report a case which responded entirely to systemic gamma-linolenic acid but which recurred several months following discontinuation of therapy. Spontaneous resolution of the condition seems unlikely and it would appear that gamma linolenic acid could have an effect on minor salivary gland composition and/or viscosity and may be worth prescribing on a trial basis prior to surgical treatment of this rare condition. PMID- 7849002 TI - Isolated bilateral fractures of zygomatic arches: report of a case. AB - Isolated unilateral fractures of the zygomatic arch are uncommon. Isolated bilateral fractures of the zygomatic arches are even more rare. Indeed a search of the literature failed to find any previous report of this fracture pattern. PMID- 7849003 TI - A method of zygomatic arch stabilization. AB - A new method for zygomatic arch stabilization with a silicone tube placed under the zygomatic arch is described. The method is safe, easy to perform and, in our experience, without complications. PMID- 7849004 TI - The use of thromboembolic prophylaxis in oral and maxillofacial surgery. PMID- 7849005 TI - Complete restoration of activity to inactive mutants of Escherichia coli thymidylate synthase: evidence that E. coli thymidylate synthase is a half-the sites activity enzyme. AB - Escherichia coli thymidylate synthase (TS) is a dimeric protein containing identical subunits. When R126E, an inactive mutant of this enzyme, was incubated at room temperature with other inactive mutants of E. coli, TS enzyme activity gradually reappeared. The rate of activity restoration was dependent on the mutant employed. In the case of C146W, an active site mutant, the half-time required for maximal activity restoration was about one hour, which was about 500 fold faster than that obtained with C146S. The final specific activity of the mutant mixtures, based on the concentration of R126E, was equivalent to that of the wild-type TS (WT-TS). However, when the activities of E. coli WT-TS and mutant TS mixtures were compared for their extents of renaturation following denaturation as described for Lactobacillus casei TS [Pookanjanatavip, M., Yuthavong, Y., Greene, P. J., & Santi, D. V. (1992) Biochemistry 31, 10303 10309], only about one-half of the activity of WT-TS was restored, implying that the denaturation-renaturation procedure was less efficient than allowing the native TS mutant dimers to exchange subunits. If, as proposed, subunit exchange is responsible for the observed restoration of activity to the E. coli mutant TS mixtures, it would suggest that only one active site cysteine, that provided by R126E in the dimer (R126E)-(C146W), is sufficient to yield the same kcat as WT TS, which contains one active site cysteine in each subunit. Other mutant dimers that contain both active site cysteines such as (R126E)-(Y94A) and (R126E) (I264Am) are also fully active, even though one of the subunits is functionally inactive.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7849006 TI - Structural basis for pleckstrin homology domain mutations in X-linked agammaglobulinemia. AB - Deficiencies in a tyrosine kinase, designated Btk, cause X-linked agammaglobulinemia (XLA) in man, a hereditary defect of B-cell differentiation. Mutations in the newly found PH domain located at the N-terminus of Btk have been shown to be the direct cause of XLA, and here two new mutations, T33P and V64F, are presented. Btk is thus far the only protein in which mutations of the PH domain have been found to cause a disease. The three-dimensional structure of the Btk PH domain was modeled on the basis of the dynamin PH structure. Despite a relatively low sequence similarity the Btk PH domain seems to have the same two beta-sheet structure observed in the known structures. The model was used to interpret the structural basis for disease in five independent point mutations and in an insertion in patients with XLA. The mutated residues F25, V64, and V113, and possibly residue(s) around Q103, could form a binding site, since these amino acids are located close to each other on the surface of the molecule. PMID- 7849007 TI - Roles of individual kringle domains in the functioning of positive and negative effectors of human plasminogen activation. AB - In order to identify the individual contributions of the kringle (K) domains of human plasminogen (Pg) to the epsilon-aminocaproic acid (EACA) induced stimulation of Pg activation by low-molecular-weight urokinase-type plasminogen activator (LMW-uPA) and inhibition of this same activation by Cl-, we constructed the most conservative recombinant- (r-) Pg mutants possible that would greatly reduce the strength of the EACA binding site in the omega-amino acid binding kringles, [K1Pg] ([D139-->N]r-Pg), [K4Pg] ([D413-->N]r-Pg), and [K5Pg] ([D515- N]r-Pg). In each case, this involved mutation of a critical Asp (to Asn) within these three kringle domains in intact Pg. The three r-mutants were expressed in r baculovirus-infected lepidopteran insect (Trichoplusia ni) cells. In the presence of Cl-, the positive activation effector, EACA, first stimulated and then inhibited the LMW-uPA-catalyzed initial activation of wild-type (wt) r-[Glu1]Pg and, to a lesser extent, the [K5Pg] mutant, [D518-->N/Glu1]r-Pg. The concentration of EACA that produced 50% stimulation of activation (C50) occurred at 3.3 mM for wtr-[Glu1]Pg and at 0.7 mM for [D518-->N/Glu1]r-Pg. Subsequent inhibition by EACA occurred with a C50 of approximately 15 mM and is likely due to inhibition of the amidolytic activity of plasmin generated during the activation. Similar initial activation rates of both [D139-->N]r-Pg and [D413N]r Pg did not display this initial EACA-mediated stimulatory phase but did undergo ultimate inhibition with a C50 for this process that was similar to wtr-[Glu1]Pg and [D518-->N/Glu1]r-Pg.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7849008 TI - Structural origins of substrate discrimination in trypsin and chymotrypsin. AB - Converting the specificity of trypsin to that of chymotrypsin has been shown to require the exchange of amino acids in multiple portions of the protein, including two surface loops which do not directly contact the substrate. Crystallographic analysis of two mutant trypsins possessing chymotrypsin-like specificity now reveals that these distal surface loops alter function by directly determining the structure of the primary binding site. Efficient acylation of cognate substrates correlates with a distinct backbone conformation of the conserved Gly216 residue. This amino acid is located on the surface of the specificity pocket and forms two main-chain hydrogen bonds with a nonspecific portion of substrate. By contrast, the improvement in substrate binding affinity effect by the substitution of the distal Tyr172 residue with Trp derives from structural rearrangements at the extreme base of the pocket. Together, the kinetic and crystallographic data strongly suggest that both Asp189 and Gly216 must be considered as primary determinants of substrate specificity in trypsin. PMID- 7849009 TI - Mechanism of manganese catalase peroxide disproportionation: determination of manganese oxidation states during turnover. AB - X-ray absorption near-edge structure (XANES) spectroscopy has been used to determine the oxidation state composition of the Mn site in Mn catalase under turnover conditions. The XANES data are consistent with parallel assignments based on electron paramagnetic resonance (EPR). However, a major advantage of the XANES assignments is that they permit the direct determination of the average oxidation states for derivatives that are EPR silent. In agreement with earlier work [Khangulov, S. V., Barynin, V. V., & Antonyuk-Barynina, S. V. (1990) Biochim. Biophys. Acta 1020, 25-33], these data show that the binuclear Mn site is reduced to Mn(II)/Mn(II) when peroxide is added in the presence of halide inhibitors. In addition, the present data provide the first direct evidence that the reduced enzyme is oxidized if peroxide is added in the absence of inhibitors. Under turnover conditions, the enzyme contains approximately a 2:1 ratio of Mn(II) and Mn(III). Similar results are obtained following incubation with dioxygen. These results are consistent with a Mn(II)/Mn(II)<==>Mn(III)/Mn(III) catalytic cycle and demonstrate that halide inhibition involves trapping the enzyme in the reduced state. PMID- 7849010 TI - Cu(II) coordination in arthropod and mollusk green half-methemocyanins analyzed by electron spin-echo envelope modulation spectroscopy. AB - Hemocyanin (Hc) is a dinuclear copper protein that binds oxygen reversibly. The structure of the Cu(II) site in a derivative of hemocyanin known as green half met (GHM) has been analyzed using the pulsed EPR technique of electron spin-echo envelope modulation (ESEEM) spectroscopy. The derivative, prepared by treating the native protein with nitrite at low pH, contains a mixed-valent binuclear copper center. It was shown through chemical assays and the ligand exchange reaction products identified by EPR spectroscopy to contain a nitrite ligand bound to Cu(II). The ESEEM spectra of green half-methemocyanins from mollusks and arthropods indicated that three imidazole ligands are coordinated to Cu(II). Therefore, a tetragonal N3O ligand structure (O is an oxygen of nitrite) is proposed. For GHM Hc from the mollusks Octopus vulgaris and Rapana thomasiana, the isotropic nitrogen nuclear hyperfine coupling constant, aiso, for the N delta (or remote) nitrogen of two imidazoles was approximately 1.4 MHz, while for the third, aiso congruent to 2.2 MHz. The difference between the two weaker nitrogens and the single, more strongly coupled nitrogen was smaller by 0.2 MHz in the GHM Hcs from the arthropods Carcinus maenas, Homarus americanus and Panulirus interruptus. The nitrogen nuclear quadrupole coupling constants and asymmetry parameters, e2Qq and eta, for the N delta nitrogens in nearly all cases were near 1.4 MHz and 0.8, respectively, although Rapana thomasiana GHM Hc exhibited a reduction in eta that may indicate weaker hydrogen bonding in the active site of this protein. The g and ACu (copper nuclear hyperfine coupling) values for the derivatives, and the finding of three similar nuclear hyperfine coupling constants for the N delta sites of imidazole ligands, when considered with the orientation-specific information obtained using angle-selection methods for simulation of ESEEM spectra, suggest a distorted tetragonal Cu(II) structure in which three imidazoles and a nitrite ligand are bound near the equatorial plane. The finding that the two molluscan GHM Hcs exhibit differences associated with the remote nitrogen of imidazoles bound to Cu(II) may be related to a structural variability in the active sites of these proteins not found in the arthropodan GHM Hcs examined. PMID- 7849011 TI - Structural characterization of mononuclear Cu(II) and its nitrite complex in the active site of Carcinus maenas hemocyanin. AB - The preparation of a mononuclear Cu(II) derivative of Carcinus maenas hemocyanin (Cu(II)-Hc) and a nitrite complex of the derivative (Cu(II)-Hc-NO2-) are described. Several techniques have been used in their characterization, including X-ray absorption, continuous wave (cw) EPR, and electron spin-echo envelope modulation (ESEEM) spectroscopies. EXAFS results for Cu(II)-Hc indicate the presence of three ligands at 1.99 +/- 0.01 A and a fourth one at 2.26 +/- 0.01 A from the copper. The same coordination number and very similar bond lengths were obtained for Cu(II)-Hc-NO2-. On the basis of simulations of three-pulse ESEEM spectra, three equivalent imidazole nitrogens coupled to Cu(II) were identified in Cu(II)-Hc. Upon the binding of nitrite, a decrease in the hyperfine interaction for two of the three imidazole nitrogens was observed by ESSEM. Further, the results of a two-pulse ESEEM experiment are consistent with the assignment of the protons of a water ligand to Cu(II), which is displaced when nitrite is added. An analysis of X-ray absorption K-edge spectra suggests a coordination geometry intermediate between square-planar and tetrahedral for the metal centers in Cu(II)-Hc and Cu(II)-Hc-NO2-, in agreement with the g and ACu values determined by cw-EPR. On the basis of these results, an equivalent structure is suggested for Cu(II)-Hc-NO2- and the Cu(II) site in green half methemocyanin, a partially oxidized binuclear derivative formed in the reaction of the native protein with nitrite. PMID- 7849012 TI - The reaction of cyanide with peroxidatic forms of cytochrome oxidase. AB - The interaction of peroxidatic derivatives of cytochrome c oxidase with cyanide has been investigated by optical spectroscopy and the stopped-flow method. Two reactions were found in the conversion of peroxy cytochrome oxidase to its cyanide complex. The first reaction is characterized by the loss of the 607 nm band, an increase in absorbance at 655 nm, and a decrease in absorbance at 432 nm resulting from a blue-shift of the Soret band; this reaction occurred with a bimolecular rate constant of about 90 M-1 s-1. The second reaction is observed as an absorbance increase at 585 and 432 nm; the latter was due to a red-shift of the Soret band. This second process proceeded with a rate constant of about 22 M 1 s-1. Both reaction rates are linearly dependent on the concentration of cyanide between 5 and 100 mM. The reappearance of the 655 nm band at the completion of the first reaction suggests that cytochrome a3 becomes transiently high-spin, a finding which implies that cyanide is not initially bound to this heme center. It appears that preparations of oxidized CcO contain small but variable amounts of the peroxy form. The variable content of this form is probably responsible for the different response of oxidized oxidase to low concentrations of cyanide [Berka, V., Vygodina, T., Musatov, A., Nicholls, P., & Konstantinov, A. A. (1993) FEBS Lett. 315, 237-241] and may explain the biphasic reduction of the binuclear center with dithionite [Cooper, C. E., Junemann, S., Ioannidis, N., & Wrigglesworth, J. M. (1993) Biochim. Biophys. Acta 1144, 149-160]. PMID- 7849013 TI - Histidine oxidation in the S2 to S3 transition probed by FTIR difference spectroscopy in the Ca(2+)-depleted photosystem II: comparison with histidine radicals generated by UV irradiation. AB - FTIR difference and EPR spectroscopies were used to identify the organic radical species formed during the S2 to S3 transition in Ca(2+)-depleted, EGTA-treated, and polypeptide-reconstituted photosystem II membranes (denoted S2' and S3', respectively). Ferricyanide was added to the samples to act as an exogenous electron acceptor. Using EPR spectroscopy, it was shown that, under the experimental conditions used, only the species oxidized in the S3' state was detected during the time required for the acquisition of the FTIR difference spectra. No contributions from the electron acceptor side were observed. The corresponding S3'/S2' FTIR difference spectra were recorded at 10 degrees C in H2O, D2O, and with 15N-labeled photosystem II membranes. Spectra were compared with radical-minus-neutral FTIR difference spectra of amino acid model compounds generated by UV irradiation at low temperature. Under our experimental conditions, we did not observe FTIR difference signals consistent with tyrosine oxidation in the S2' to S3' transition. The infrared signals characteristic of radical formation with 4-methylimidazole and histidine obtained by UV irradiation of 4-methylimidazolium at pH 6 and of a His-Tyr dipeptide at pH 7 are presented. The analogy found between these spectra and the S3'/S2' spectrum obtained in situ supports the oxidation of a histidinium in the S2' to S3' transition. PMID- 7849014 TI - Site-directed mutagenesis of conserved histidines in the helix VIII domain of PsaB impairs assembly of the photosystem I reaction center without altering spectroscopic characteristics of P700. AB - The chloroplast psaB gene encodes one of the polypeptides of the photosystem I reaction center heterodimer that coordinates the electron transfer components P700, A0, and A1. Histidine residues in the most highly conserved region of the PsaB protein are predicted to coordinate the P700 reaction center chlorophyll(s) and the initial electron acceptor, A0. Oligonucleotide-mediated site-directed mutagenesis and chloroplast transformation of Chlamydomonas reinhardtii have been used to determine the importance of these conserved histidines in photosystem I reaction center biogenesis and function. It is demonstrated that these histidine residues are essential for stable accumulation of the photosystem I reaction center. Protein pulse-labeling shows that changing the histidine residues impairs a post-translational step in reaction center assembly. Photosystem I complexes from the mutants have been characterized by Electron Nuclear Double Resonance and Electron Spin Echo Envelope Modulation spectroscopy to determine the impact of any mutations on P700+. In all cases we determine that spectroscopic characteristics of P700+ remain unchanged. The implications of these results to current models of the photosystem I reaction center and related bacterial reaction centers are discussed. PMID- 7849015 TI - Enzymatic and chemical cleavage of the core light-harvesting polypeptides of photosynthetic bacteria: determination of the minimal polypeptide size and structure required for subunit and light-harvesting complex formation. AB - To ascertain the minimal structural requirements for formation of the subunit and core light-harvesting complex (LH1), the alpha- and beta-polypeptides of the LH1 from three purple photosynthetic bacteria were enzymatically or chemically truncated or modified. These polypeptides were then used in reconstitution experiments with bacteriochlorophyll a (BChla), and the formation of subunit and LH1 complexes was evaluated using absorbance and circular dichroism spectroscopies. Truncation or modification outside of the conserved core sequence region of the polypeptides had no effect on subunit or LH1 formation. However, the extent of formation and stability of the subunit and LH1 decreased as the polypeptide was shortened inside the core region within the N-terminal domain. This behavior was suggested to be due to the loss of potential ion-pairing and/or hydrogen-bonding interactions between the polypeptides. While the spectroscopic properties of the subunit complexes generated using truncated polypeptides were analogous to those obtained using native polypeptides, in some cases the resulting LH1 complex absorption was blue-shifted relative to the control. Thus, truncation within the N-terminal domain may have long-range effects on the immediate BChla binding environment, since the putative BChla binding site resides near the C-terminal end of the polypeptides. It was also demonstrated that the His located within the membrane-spanning domain on the N-terminal end of the beta-polypeptide is not participating in ligation of the BChla in the reconstituted subunit and therefore probably not in LH1. PMID- 7849016 TI - Comparison of the motile and enzymatic properties of two microtubule minus-end directed motors, ncd and cytoplasmic dynein. AB - Cytoplasmic dynein and ncd, a kinesin-related protein from Drosophila, are motor proteins that move toward the minus ends of microtubules, while kinesin moves to the microtubule plus end. In previous work, we examined the nucleotide dependence of motility and enzymatic activity by kinesin [Shimizu, T., Furusawa, K., Ohashi, S., Toyoshima, Y. Y., Okuno, M., Malik, F., & Vale, R. D., (1991) J. Cell Biol. 112, 1189-1197]. In this study, we examined these activities of the cytoplasmic dynein from bovine brain and ncd in order to explore what enzymatic features might be shared by these two minus-end-directed motors. Both ncd and cytoplasmic dynein demonstrated an activation of ATPase activity upon the addition of microtubules (30-fold and 6-fold, respectively). A significant difference between ncd and cytoplasmic dynein was their relative sensitivity to vanadate and to aluminum fluoride. In contrast to cytoplasmic dynein, ncd polypeptide was not cleaved by UV-vanadate treatment, and its ATPase and motility were unaffected by vanadate (up to 0.1 mM). When the nucleotide requirement for movement as examined using a battery of 20 nucleotides and nucleotide analogues, cytoplasmic dynein was found to exhibit a specificity very similar to that of axonemal dyneins from Tetrahymena. Surprisingly, however, the nucleotide specificities of in vitro motility produced by ncd or its construct, GST/MC1 (a fusion protein of glutathione S-transferase and 210-700 of the predicted ncd amino acid sequence), were quite distinct from that of kinesin. Thus, the nucleotide specificity profiles of members of the kinesin motor superfamily do not appear to be identical. PMID- 7849017 TI - Localization of the calcium-sensitive actin monomer binding site in gelsolin to segment 4 and identification of calcium binding sites. AB - Gelsolin is composed of six repeating segments of sequence (G1-6) and contains three distinct actin binding sites, two that bind to G-actin and one that binds to filaments. The calcium-dependent actin monomer binding site present in the carboxyl-terminal half of the protein (G4-6) plays a critical role both in the cooperative binding of actin by gelsolin and in its nucleating activity. Here we have localized this actin binding site to segment 4 (G4) by expressing the segments G4, G4-5, G5, and G5-6 in Escherichia coli and analyzing their actin binding properties. In addition we have measured their calcium binding. G4-5 and G5-6 each bind a single calcium ion, but there is no binding by G4 or G5. The affinity of binding by G5-6 is 10 times higher than that of G4-5, and calcium binding by G4-6 shows two sites of different affinity. Thus each actin binding site of gelsolin is restricted to a single segment (G1, G2, and G4), but the nonbinding segments G5 and G6 play an important role in the calcium regulation of actin binding and other activities of gelsolin. PMID- 7849018 TI - Differential agonist-induced displacement of quinacrine and ethidium from their respective histrionicotoxin-sensitive binding sites on the Torpedo acetylcholine receptor. AB - Fluorescence spectroscopy was used to begin to localize the agonist inhibitory binding site on the nicotinic acetylcholine receptor (AcChR) from Torpedo californica. High concentrations of three cholinergic agonists, suberyldicholine (SubCh), acetylcholine (AcCh), and carbamylcholine (CCh), differentially inhibited the binding of two noncompetitive inhibitors (NCIs), quinacrine and ethidium, which bind at distinctly different loci on the desensitized AcChR at zero membrane potential. The agonist-induced inhibition of quinacrine binding occurred at significantly lower (17-fold) concentrations than the inhibition of ethidium binding. Schild plots of SubCh inhibition of ethidium and quinacrine binding showed the competitive nature of the agonist inhibition of the binding of these two NCIs. The quenching constants for short-range quenching of receptor bound quinacrine and ethidium fluorescence by spin-labeled acetylcholine were about the same as their inhibition constants for agonist-induced displacement of AcChR-bound quinacrine and ethidium. The results demonstrate that agonists can directly bind to both the quinacrine and the ethidium binding sites, albeit at different agonist concentrations. Because the agonist-induced displacement of receptor-bound quinacrine occurs at significantly lower concentrations than the displacement of ethidium, the quinacrine binding site is more likely than the ethidium binding site to form part of the agonist inhibitory binding site. PMID- 7849019 TI - Involvement of detergent-insoluble complexes in the intracellular transport of intestinal brush border enzymes. AB - A number of transmembrane digestive enzymes of the porcine small intestinal brush border membrane were found to be partially Triton X-100-insoluble at 0 degree C and colocalized in gradient centrifugation experiments with the GPI-anchored alkaline phosphatase in low-density, detergent-insoluble complexes commonly known as glycolipid "rafts". Thus, aminopeptidase N (EC 3.4.11.2), aminopeptidase A (EC 3.4.11.7), dipeptidyl peptidase IV (EC 3.4.14.5), and sucrase-isomaltase (EC 3.2.1.48-10) were 34-48% detergent-insoluble. Maltase-glucoamylase (EC 3.2.1.20) was markedly less detergent-insoluble (20%), and lactase-phlorizin hydrolase (EC 3.2.1.23-62) was essentially fully soluble in detergent. In radioactively labeled, mucosal explants, the newly synthesized brush border enzymes began to associate with detergent-insoluble complexes while still in their transient, high mannose-glycosylated form, and their insolubility increased to that of the steady state level soon after they achieved their mature, complex glycosylation, i.e., after passage through the Golgi complex. Detergent-insoluble complexes isolated by density gradient centrifugation were highly enriched in brush border enzymes, and the enrichment was apparent after only 1 h of labeling, where aminopeptidase N, sucrase-isomaltase, and alkaline phosphatase together comprised 25-30% of the total labeled, detergent-insoluble proteins, showing that sorting of newly made brush border membrane proteins into the glycolipid "rafts" does take place intracellularly. I therefore propose that, in the enterocyte, the brush border enzymes are targeted directly from the trans-Golgi network toward the apical cell surface. PMID- 7849020 TI - Mechanistic studies of lantibiotic-induced permeabilization of phospholipid vesicles. AB - Nisin is a cationic polycyclic bacteriocin secreted by some lactic acid bacteria. Nisin has previously been shown to permeabilize liposomes. The interaction of nisin was analyzed with liposomes prepared of the zwitterionic phosphatidylcholine (PC) and the anionic phosphatidylglycerol (PG). Nisin induces the release of 6-carboxyfluorescein and other small anionic fluorescent dyes from PC liposomes in a delta psi-stimulated manner, and not that of neutral and cationic fluorescent dyes. This activity is blocked in PG liposomes. Nisin, however, efficiently dissipates the delta psi in cytochrome c oxidase proteoliposomes reconstituted with PG, with a threshold delta psi requirement of about -100 mV. Nisin associates with the anionic surface of PG liposomes and disturbs the lipid dynamics near the phospholipid polar head group-water interface. Further studies with a novel cationic lantibiotic, epilancin K7, indicate that this molecule penetrates into the hydrophobic carbon region of the lipid bilayer upon the imposition of a delta psi. It is concluded that nisin acts as an anion-selective carrier in the absence of anionic phospholipids. In vivo, however, this activity is likely to be prevented by electrostatic interactions with anionic lipids of the target membrane. It is suggested that pore formation by cationic (type A) lantibiotics involves the local perturbation of the bilayer structure and a delta psi-dependent reorientation of these molecules from a surface-bound into a membrane-inserted configuration. PMID- 7849022 TI - Composition and sequence specific resonance assignments of the heterogeneous N linked glycan in the 13.6 kDa adhesion domain of human CD2 as determined by NMR on the intact glycoprotein. AB - CD2, a T cell specific surface adhesion receptor, is critically important for T lymphocytes to mediate their regulatory and effector functions. The amino terminal domain of human CD2 is responsible for cell adhesion, binding to CD58 on antigen-presenting cells or target cells. This adhesion domain in human CD2 contains a single high-mannose N-glycan. This carbohydrate or part of it appears to be required to maintain the native conformation of the polypeptide and its ability to bind CD58. To better understand the structural aspects that regulate human CD2 adhesion functions, we had previously determined the solution structure of the protein part of the N-glycosylated adhesion domain of human CD2 (hu sCD2(105); MW approximately 13.6 kDa) by NMR spectroscopy. Here, we have identified protein--carbohydrate and carbohydrate--carbohydrate interactions and, in combination with previous knowledge from electrospray ionization mass spectrometry, have determined the composition of the heterogeneous high-mannose glycan in hu-sCD2(105). These contacts clearly define the carbohydrate's orientation with respect to the protein. The NMR data further suggest that one arm of the glycan is folded toward the trisaccharide core consisting of GlcNAc1 GlcNAc2-Man3. A detailed comparison between chemical shift data of free model oligosaccharides with those of the glycomers present in our hu-sCD2(105) sample reveals that only the resonances of the two GlcNAc residues are significantly different from those of free high-mannose glycans. This work was based on a new strategy to achieve sequential assignments of the 1H and 13C resonances of the heterogeneous high-mannose carbohydrate [(Man)nGlcNAc2, n = 5-8] in hu-sCD2(105) on the intact glycoprotein using a combination of homonuclear 1H-1H and heteronuclear 1H-13C NMR experiments at natural abundance. PMID- 7849021 TI - Glyceride synthesis catalyzed by cutinase using the monomolecular film technique. AB - The monomolecular film technique previously used to study the kinetics of lipase hydrolysis was adapted to synthesizing oleoyl glycerides (monoolein, diolein, and triolein). The water subphase was replaced by glycerol, and a film of oleic acid was initially spread on the glycerol surface. In this system a recombinant cutinase from Fusarium solani was able to catalyze oleoyl glyceride synthesis. More than 50% of the oleic acid film was acylated after 7 min of reaction. The surface pressure applied to the monomolecular film acts as a physical selectivity factor since glyceride synthesis can be steered so as to produce either diolein or triolein. PMID- 7849023 TI - Determination of local protein structure by spin label difference 2D NMR: the region neighboring Asp61 of subunit c of the F1F0 ATP synthase. AB - Purified subunit c from the H(+)-transporting F1F0 ATP synthase of Escherichia coli folds as an antiparallel pair of extended helices in a solution of chloroform-methanol-water. A similar hairpin-like folding is predicted for the native protein in the multisubunit transmembrane Fo sector of the ATP synthase. A single Cys variant (A67C) of subunit c was created and modified with a maleimido PROXYL [[3-(maleimidomethyl)-2,2,5,5-tetramethyl-1-pyrrolidinyl]oxy] spin label. Pairs of 1H 2D correlation and NOE spectra were collected with the nitroxide oxidized (paramagnetic) and reduced (diamagnetic). The pairs of spectra were subtracted, yielding difference spectra containing only cross-peaks from 1H within 15 A of the spin label. These greatly simplified spectra were easily analyzed to provide complete assignments for residues 10-25 and 52-79 of the protein, 150 NOE distance restraints, and 27 hydrogen-bonding restraints. The chemical shifts and NOE patterns observed in the derivatized mutant were virtually identical to those which were resolved in the unmodified wild-type protein, strongly suggesting that the spin label was not perturbing the protein structure. The restaints enabled us to calculate a detailed structure for this region of subunit c. The structure consisted of two gently curved helices, crossing at a slight (30 degrees) angle. The C-terminal helix was disrupted from Val60 to Ala62 near the essential Pro64. Asp61, the residue thought to undergo protonation--deprotonation with each H+ transported across the membrane, was in ver der Waals contact with Ala24. The proximity of these residues had been predicted from mutant analyses, where H+ translocation was retained on moving the Asp from position 61 to 24. PMID- 7849024 TI - Structure-function in Escherichia coli iron superoxide dismutase: comparisons with the manganese enzyme from Thermus thermophilus. AB - The crystal structure of dimeric Fe(III) superoxide dismutase (SOD) from Escherichia coli (3006 protein atoms, 2 irons, and 281 solvents) has been refined to an R of 0.184 using all observed data between 40.0 and 1.85 A (34,879 reflections). Features of this structure are compared with the refined structure of MnSOD from Thermus thermophilus. The coordination geometry at the Fe site is distorted trigonal bipyramidal, with axial ligands His26 and solvent (proposed to be OH-), and in-plane ligands His73, Asp156, and His160. Reduction of crystals to the Fe(II) state does not result in significant changes in metal-ligand geometry (R = 0.188 for data between 40.0 and 1.80 A). The arrangement of iron ligands in Fe(II) and Fe(III)SOD closely matches the Mn coordination found in MnSOD from T. thermophilus [Ludwig, M.L., Metzger, A.L., Pattridge, K.A., & Stallings, W.C. (1991) J. Mol. Biol. 219, 335-358]. Structures of the Fe(III) azide (40.0-1.8 A, R = 0.186) and Mn(III) azide (20.0-1.8 A, R = 0.179) complexes, reported here, reveal azide bound as a sixth ligand with distorted octahedral geometry at the metal; the in-plane ligand-Fe-ligand and ligand-Mn-ligand angles change by 20-30 degrees to coordinate azide as a sixth ligand. However, the positions of the distal azide nitrogens are different in the FeSOD and MnSOD complexes. The geometries of the Fe(III), Fe(II), and Fe(III)-azide species suggest a reaction mechanism for superoxide dismutation in which the metal alternates between five- and six-coordination. A reaction scheme in which the ligated solvent acts as a proton acceptor in the first half-reaction [formation of Fe(II) and oxygen] is consistent with the pH dependence of the kinetic parameters and spectroscopic properties of Fe superoxide dismutase. PMID- 7849025 TI - X-ray absorption spectroscopy of the iron site in Escherichia coli Fe(III) superoxide dismutase. AB - The local structure of the iron site in ferric superoxide dismutase from Escherichia coli has been characterized by X-ray absorption spectroscopy. In the resting state of the enzyme at pH 7.0, the iron is five-coordinate with an average metal-ligand bond length of 1.98 A. Binding of azide causes a reduction in the intensity of the bound state 1s-->3d transition and an increase of 0.08 A in average bond length. Both are indicative of an increase in the iron coordination number. Raising the pH from 7.0 to 10.5 causes a similar 0.08 A increase in the average bond length, again suggesting an increase in the iron coordination number. At intermediate pH (9.4), the average bond length is 2.03 A, consistent with an approximately 50:50 mixture of the limiting high and low pH forms. Similarly, the absorption edge structure varies continuously from pH 7 to 10.5. These spectra can be fit to a titration curve with a pKa of approximately 9.8. These data suggest that the pH-dependent transition, previously identified by UV-vis, EPR, and activity measurements, may be the conversion of the iron from five- to six-coordinate, presumably through coordination by hydroxide. The 1s- >3d transition for ferric superoxide dismutase at high pH is broader but not significantly less intense than that at pH 7. This suggests that the high pH form may be significantly distorted from octahedral symmetry. At pH 7, the ferric and ferric + azide samples undergo slow X-ray induced photoreduction.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7849026 TI - Ligand-induced conformational changes of thymidylate synthase detected by limited proteolysis. AB - Limited tryptic proteolysis was used to investigate conformational changes of thymidylate synthase from Lactobacillus casei induced by ligand binding. Most of the identified sites of proteolysis were between R72 and R178, a region that includes a large loop containing residues 90-139 that is absent in thymidylate synthase from most other sources. Hydrolysis at both ends of this region was affected by the presence of dUMP. With dUMP, the preference of initial hydrolysis at the N-terminus of this region was switched from R78 to R72, and hydrolysis at R178 was retarded; the latter effect may be primarily a consequence of steric hinderance since R178 is involved in binding the phosphate moiety of dUMP. Orthophosphate had an effect similar to that of dUMP, not only in retarding hydrolysis at the phosphate binding site (R178) but also in retarding hydrolysis at R78 in favor of R72. Alkylation of the catalytically essential sulfhydryl group of thymidylate synthase by iodoacetamide also resulted in R72 being favored over R78 as a site of initial proteolysis. Its effect on hydrolysis at R178 was, as expected, less than that of dUMP or phosphate. These results indicate that dUMP binding induces conformational changes in thymidylate synthase. Phosphate binding and sulfhydryl alkylation also induce conformational changes similar to those resulting from dUMP binding. While the similarity of the proteolytic behavior of thymidylate synthase in the presence of dUMP or phosphate agrees with the report by Finer-Moore et al.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7849027 TI - Aminolevulinate synthase: functionally important residues at a glycine loop, a putative pyridoxal phosphate cofactor-binding site. AB - 5-Aminolevulinate synthase catalyzes the first step of the heme biosynthetic pathway in nonplant higher eukaryotes. The enzyme functions as a homodimer and requires pyridoxal 5'-phosphate as its cofactor. Lysine-313 in murine erythroid aminolevulinate synthase has been identified as the residue involved in the Schiff base linkage with pyridoxal 5'-phosphate [Ferreira, G. C., Neame, P. J., & Dailey, H. A. (1993) Protein Sci. 2, 1959-1965]. However, other residues involved in binding and orienting the cofactor remain unknown. We studied the informational content of each residue within an 11 amino acid glycine-rich region, which we propose to be part of the phosphate-binding motif, based on amino acid sequence comparison with other pyridoxal 5'-phosphate-dependent enzymes and nucleotide-binding proteins. Partial random mutagenesis of this region in murine erythroid aminolevulinate synthase gene was followed by an efficient biological selection, using a hemA- Escherichia coli strain to recover functional unnatural enzymes. Among the total of 5444 variants produced, 283 were found to be functional. DNA sequencing results of 226 functional mutants indicated that most residues in this region contained a low informational content, being able to tolerate several other amino acid substitutions. However, three residues, namely, Arg-149, Gly-142, and Gly-144, were found to contain high informational content; Arg-149 was conserved in all of the functional mutants sequenced, while Gly-142 and Gly-144 could only tolerate alanine replacement. Two codon-specific random libraries of Arg-149, and Gly-142 and -144, respectively, were constructed to test further the stringency of these three positions.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7849028 TI - Analysis of nuclear pore protein p62 glycosylation. AB - Glycoprotein components of the nuclear pore are essential for nuclear transport and are modified by both glycosylation and phosphorylation. The function and control of these post-translational modifications are poorly understood. Glycosylation of the major rat nuclear pore glycoprotein, p62, was examined in vitro using recombinant p62 as a substrate. Rat p62 was expressed in Escherichia coli and purified to near homogeneity. Kinetic analysis using a partially purified mammalian transferase suggests that the recombinant protein is an excellent substrate (Km = 0.30 microM) for the transfer of GlcNAc from UDP-GlcNAc (Km = 1.8 microM). Localization of the sites of O-linked GlcNAc glycosylation of rat p62 was performed by a combination of deletion analysis of in vitro translation products and by immunoprecipitation of [14C]GlcNAc-labeled proteolytic fragments. The amino terminus of rat p62 is poorly glycosylated with no O-linked GlcNAc sites between Lys22 and Lys97; the carboxyl terminus has one known glycosylation site at Ser471. The majority of the glycosylation sites in rat p62 are likely to occur on the six clustered Ser residues in the central Ser/Thr-rich region from Ser270 to Thr294. A synthetic peptide derived from this region is a good substrate for O-GlcNAc addition (Km = 30 microM) and a potent competitive inhibitor of p62 glycosylation (Ki = 15 microM). It is proposed that this Ser/Thr-rich domain functions as a linker region between the amino-terminal beta-pleated sheet and the carboxyl terminal alpha-helical domains. O Glycosylation and phosphorylation of this linker region could provide a dynamic means of altering the conformation of p62 during nuclear pore assembly and disassembly. PMID- 7849029 TI - Protein fragments as models for events in protein folding pathways: protein engineering analysis of the association of two complementary fragments of the barley chymotrypsin inhibitor 2 (CI-2). AB - Two fragments of chymotrypsin inhibitor-2, CI-2(20-59) and CI-2(60-83), derived from cyanogen bromide cleavage at Met-59, associate to give a native-like structure. We analyze the kinetics and equilibria of association of mutant fragments derived from cleaving mutant proteins at the same methionine residue. The changes in free energy of association have been measured both from isothermal studies of the binding of fragments and from thermal denaturation of the complexes. In general, there is a good correlation between the changes on mutation of the free energy of association of fragments and the changes in free energy of folding of the uncleaved parent protein. The notable exceptions are for residues in regions of the fragments that form nonnative hydrophobic clusters in the isolated fragments; mutation of the hydrophobic residues involved in these clusters decreases the equilibrium constant for formation of the noncovalent complex less than it does the equilibrium constant for folding of intact protein. The dissociated fragments must be destabilized by mutation of those hydrophobic residues, but to a lesser extent than is the complex itself. These clusters are thus less important energetically in the denatured state of the intact protein. The second-order rate constants for the major phase of association change with mutation, similar results being obtained from fluorescence measurements of the regain of tertiary structure and from circular dichroism measurements of the regain of secondary structure. The rate constants for association correlate well, in general, with the rate constants of refolding of the respective uncleaved proteins.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7849030 TI - Perturbation of a tertiary hydrogen bond in barstar by mutagenesis of the sole His residue to Gln leads to accumulation of at least one equilibrium folding intermediate. AB - A specific tertiary hydrogen bond that is present between the side-chain hydroxyl group of Tyr30 and the side-chain N delta 1 atom of His17 in the small, monomeric, single-domain protein, barstar, has been perturbed by site-directed mutagenesis of the sole histidine residue (His17) to a glutamine residue. The effect of the perturbation has been studied in the resultant mutant protein, H17Q, by equilibrium unfolding methods. Both guanidine hydrochloride (GdnHCl) induced denaturation and thermal denaturation studies have been performed, with unfolding monitored by UV absorption, intrinsic tryptophan fluorescence, near-UV and far-UV circular dichroism (CD), and size exclusion chromatography. While wild type (wt) barstar shows a two-state unfolding transition when denatured by either GdnHCl or heat, the mutant protein H17Q undergoes unfolding through a transition that involves at least one equilibrium intermediate I, which is populated at intermediate concentrations of denaturant or at intermediate temperatures. In the case of GdnHCl-induced denaturation, the midpoint of the fluorescence-monitored denaturation curve is 1.4 +/- 0.1 M, that of the near-UV CD-monitored denaturation curve is 1.6 +/- 0.1 M, and that of the far-UV CD-monitored denaturation curve is 1.8 +/- 0.1 M. The accumulation of I is also evident in gel filtration experiments which indicate that I forms slowly from the fully-folded form, F, and that once formed, I rapidly equilibrates with the unfolded form, U. The gel filtration data for H17Q suggest that in 1.5 M GdnHCl, there is no F present and that I is the predominant form. I does not appear to possess hydrated hydrophobic surfaces, which is reflected in its inability to bind 8-anilino-1 naphthalenesulfonic acid (ANS). At least one equilibrium-unfolding intermediate is also observed upon thermal denaturation. The midpoints of the thermal denaturation curves of H17Q are 63.0 +/- 0.5 degrees C when monitored by absorbance at 287 nm or by intrinsic fluorescence at 332 nm; 65.0 +/- 0.5 degrees C when monitored by mean residue ellipticity at 275 nm; and 68.3 +/- 0.5 degrees C when monitored by mean residue ellipticity at 220 nm. In contrast, all four optical probes yield the same midpoint, 71.5 +/- 0.5 degrees C, for the wt protein. The results indicate that perturbation of the tertiary hydrogen bond leads to the accumulation of at least one intermediate (I) in both thermal denaturation studies and GdnHCl-induced denaturation studies. The intermediate(s) I are characterized by a greater disruption of tertiary structure than of secondary structure. PMID- 7849031 TI - Comparison of the refolding of hen lysozyme from dimethyl sulfoxide and guanidinium chloride. AB - The folding of hen egg white lysozyme is complex, involving parallel pathways and distinct folding domains [Radford, S.E., Dobson, C.M., & Evans, P.A. (1992) Nature 358, 302-307]. In the present work the refolding of this protein from two denatured states that have different conformational properties, one generated by the presence of guanidinium chloride (GdmCl) and the other by dimethyl sulfoxide (DMSO), has been examined. Refolding was initiated by rapid dilution and followed by hydrogen-exchange pulse labeling, stopped-flow circular dichroism (CD) in the near-ultraviolet region, and stopped-flow fluorescence experiments. When the final refolding conditions were identical (545 mM GdmCl, 8% (v/v) DMSO, and 20 mM sodium acetate, pH 5.5, 20 degrees C), the folding behavior from the different denatured states monitored by near-UV CD and hydrogen-exchange pulse labeling was indistinguishable. These experiments indicate that the folding process of hen lysozyme is not significantly dependent on the nature of the two denatured states. The complexities in the pathway, therefore, appear to arise from properties of the collapsed state which is formed within the first few milliseconds of refolding. The kinetics of folding were found to be dependent on the concentration of DMSO in the final refolding buffer, although the fundamental properties of the pathway, including the existence of parallel events and distinct folding domains, are preserved under all the conditions studied. Inclusion of DMSO in the refolding buffer increases the rate of formation of native-like structure and of the native state itself. This could result from destablization of species formed early in folding, allowing them to rearrange more rapidly to permit productive folding to proceed. The results indicate that examination of a wide range of conditions will contribute substantially to a more complete understanding of protein folding pathways. PMID- 7849032 TI - Conserved cysteine residues in the shaker K+ channel are not linked by a disulfide bond. AB - Many voltage-activated K+ channels contain two conserved cysteine residues in putative transmembrane segments S2 and S6. It has been proposed that these cysteines form an intrasubunit disulfide bond [Guy, H.R., & Conti, F. (1990) Trends Neurosci. 13, 201-206]. This proposal was tested using site-directed mutagenesis followed by electrophysiological and biochemical analysis of the Shaker B K+ channel. Each Shaker B subunit contains seven cysteine residues, including the conserved residues C286 and C462 and a less conserved cysteine, C245. Each cysteine in the Shaker B protein can be mutated individually without eliminating functional activity, indicating that the protein does not contain a disulfide bond that is essential for protein folding or the assembly of active channels. To determine whether there is a nonessential disulfide bond, Shaker B protein was subjected to limited proteolysis. Fragments were analyzed by electrophoresis under reducing and nonreducing conditions followed by immunoblotting. The results indicate that the two conserved residues C286 and C462 do not form a disulfide bond with each other or with C245. In addition, the subunits are not linked by disulfide bonds. In HEK293T cells, Shaker B protein is first made as an incompletely glycosylated precursor that is converted to the fully glycosylated mature protein. Glycosylation occurs at two positions in the S1-S2 loop. PMID- 7849033 TI - Fluorescence study of the three tryptophan residues of the pore-forming domain of colicin A using multifrequency phase fluorometry. AB - We have identified the steady-state and time-resolved fluorescence of the three tryptophan residues (Trp-86, Trp-130, and Trp-140) of the pore-forming domain of colicin A using site-directed mutagenesis in order to construct two- and one tryptophan-containing mutant proteins. Fluorescence lifetimes were measured via multifrequency phase fluorometry. The fluorescence of the pore-forming domain of colicin A is dominated by Trp-140 which contributes almost 53% to the fluorescence intensity. Mutation of Trp-140 results in a decrease in fluorescence quantum yield and average lifetime. Colicin A wild-type and all mutant proteins display multiple lifetimes which belong to three different lifetime classes: 0.38 0.57 ns for tau 1, 1.6-1.87 ns for tau 2, and 3.6-4.41 ns for tau 3 at pH 5. At pH 7, the three classes are 0.64-0.89 ns for tau 1, 2.01-2.19 ns for tau 2, and 4.23-4.94 ns for tau 3. This pH effect influences all the lifetimes and must be attributed to a general conformational change. In wild-type colicin A, tau 3 originates mainly from Trp-140 while Trp-86 and Trp-130 both provide a major contribution to tau 2. The pH dependence of the fluorescence intensity gives rise to a pKa of 5.2. The different lifetime components of two of the three single tryptophan-containing mutants show different quenching properties toward acrylamide, indicating that each lifetime is coupled to a different microenvironment. The linear combination of the lifetimes of the single tryptophans into pairs simulates very well the behavior of the two-tryptophan containing mutants except for one, the mutant containing Trp-86 and Trp-130. The lifetimes of the wild-type protein can only be obtained by the linear combination of the lifetimes from the mutant containing the tryptophan pair Trp-86/Trp-130 and the mutant containing Trp-140. Mutual energy transfer between Trp-86 and Trp 130 is assumed to be the explanation of this deviation since the mutant proteins display no structural or dynamic aberrances. The calculated energy transfer efficiency amounts to 65% for energy transfer from Trp-86 to Trp-130 and 21% for the reverse transfer and is in agreement with our measurements. PMID- 7849034 TI - The internal equilibrium of the hammerhead ribozyme reaction. AB - The effects of temperature, pH, and magnesium ion concentration on the internal equilibrium of the hammerhead ribozyme reaction were determined in order to better understand why the ribozyme-bound substrate RNA is 99% cleaved at equilibrium. Cleavage of substrate is more efficient at higher temperatures because a large entropy gain upon cleavage outweighs an enthalpically unfavorable generation of a 2',3'-cyclic phosphate product. The delta H of the reaction is as expected from bond energies, and provides no indication of high-energy ribozyme/substrate interactions that are lost upon cleavage. The rate constants of both cleavage and ligation increase log-linearly with pH between 5.6 and 8.0, indicating that a deprotonation step is required for both cleavage and ligation. The magnesium ion dependence of the internal equilibrium suggests that either the number or the affinity of bound magnesium ions changes upon cleavage. Since the very slow rate of hydrolysis of the 2',3'-cyclic terminus of product P1 was unaffected by the presence of the ribozyme, we conclude that hydrolysis is not a significant side reaction of the hammerhead cleavage reaction. PMID- 7849035 TI - Monoclonal antibodies to yeast poly(A) polymerase (PAP) provide evidence for association of PAP with cleavage factor I. AB - Purified yeast poly(A) polymerase (PAP) was used to produce monoclonal antibodies which recognize the enzyme in immunoblots. Epitope mapping using truncated forms of PAP and cyanogen bromide cleavage products revealed two classes of antibodies. One class (N-term) recognizes an epitope in the first 100 amino acids, and a second class (C-term) is specific for a determinant located in the last 20 amino acids of PAP. These C-terminal 20 amino acids can be removed without affecting the nonspecific poly(A) addition activity of the purified enzyme. Neither antibody inhibits the nonspecific poly(A) polymerase activity or the sequence specific activity observed in processing extracts. The antibodies show species specificity and cannot recognize mammalian, Xenopus, or vaccinia PAP. The C-term antibodies can deplete PAP from yeast whole cell extracts, resulting in loss of poly(A) addition activity. This immunodepletion also causes a reduction in the cleavage activity which can be restored by addition of yeast cleavage factor I [CF I; Chen, J., & Moore, C. (1992) Mol. Cell Biol. 12, 3470-3481], a factor needed for both the cleavage and poly(A) addition reactions. This demonstrates that a complex of PAP and CF I exists in extracts in the absence of ATP or exogenous RNA substrate. The monoclonal antibodies against yeast PAP will be a useful tool for further study of factors required for yeast mRNA 3' end processing. PMID- 7849036 TI - Photoaffinity labeling and photoinactivation of the O2(-)-generating oxidase of neutrophils by an azido derivative of FAD. AB - A photoactivable derivative of FAD, 4-[N-(4-azido-2-nitrophenyl)amino]butyryl-FAD (NAP4-FAD), was synthesized in a tritiated form with tritium placed in the NAP4 moiety of the photoprobe. [3H]NAP4-FAD was used to photolabel the putative flavin binding site of the O2(-)-generating NADPH oxidase located in the plasma membrane of bovine neutrophils. Effective photolabeling required partial deflavination of membranes, which was achieved by mild treatment with ammonium sulfate added to 50% saturation and 0.05% Triton X-100 for 30 min at 2-4 degrees C. Under these conditions, 40-50% of the oxidase activity was lost, but it could be fully recovered by the addition of nanomolar amounts of FAD (KM = 10-20 nM). Added FAD could be substituted by [3H]NAP4-FAD in photolabeling experiments. In the dark, [3H]NNAP4-FAD bound reversibly with high affinity to deflavinated neutrophil plasma membranes (Kd = 50 nM), did not transport electrons, and efficiently inhibited the FAD-dependent restoration of oxidase activity (Ki = 60 nM). Upon photoirradiation of neutrophil plasma membranes in the presence of [3H]NAP4-FAD, the nitrene derivative formed bound covalently to a 80-120 kDa protein that was identified as the beta-subunit of cytochrome b558 by immunodetection and enzymatic deglycosylation. The amount of [3H]NAP4-FAD covalently incorporated into the beta-subunit of cytochrome b558 was 80-90% of the amount of photoprobe specifically bound to neutrophil plasma membranes. A linear relationship between the extent of specific photolabeling by [3H]NAP4-FAD and the percentage of NADPH oxidase inactivation was observed for percentages of inactivation of up to 70 80%, extrapolating to 0.5 mol of covalently bound [3H]NAP4-FAD per mol of heme b558. PMID- 7849037 TI - cDNA cloning and deduced amino acid sequence of prothrombin activator (ecarin) from Kenyan Echis carinatus venom. AB - The complete amino acid sequence of ecarin is deduced from the nucleotide sequence of a cDNA clone isolated by screening a venomous gland cDNA library of Kenyan Echis carinatus. The cDNA sequence with 2379 base pairs encodes an open reading frame of 616 amino acids with a remarkable sequence homology to the putative precursor protein of trigramin from Trimeresurus gramineus venom (61% identity) and a large hemorrhagin, jararhagin, from the pit viper Bothrops jararaca venom (62% identity). Thus, ecarin, as well as jararhagin and trigramin, is translated as a precursor protein, which may be processed posttranslationally. The ecarin proprotein has a "cysteine switch" motif (-Pro-Lys-Met-Cys-Gly-Val-) similar to that involved in the activation of matrix metalloproteinase zymogens. The processed mature protein consists of 426 amino acid residues (residues 191 616), showing the strongest sequence similarity with that of Russell's viper venom factor X activator (RVV-X) heavy chain (64% identity). Like RVV-X heavy chain, ecarin contains metalloproteinase, disintegrin, and cysteine-rich domains. The metalloproteinase domain has a typical zinc-chelating sequence (-His-Glu-Xaa Xaa-His-Xaa-Xaa-Gly-Xaa-Xaa-His-), as found in crayfish astacin. In the disintegrin domain of ecarin, the Arg-Gly-Asp sequence is replaced by Arg-Asp Asp, as found in the disintegrin domains of RVV-X heavy chain (Arg-Asp-Glu) and a guinea pig sperm fusion protein, PH-30 beta (Thr-Asp-Glu). These findings show that while there are structural and evolutionary relationships among these proteins, each has a unique functional activity. PMID- 7849038 TI - Gin invertase of bacteriophage Mu is a dimer in solution, with the domain for dimerization in the N-terminal part of the protein. AB - The Gin protein of bacteriophage Mu mediates recombination between two inverted repeat sequences. Gin binds as a dimer to each of these recombination sites. We show that Gin is a dimer in solution also, and that the dimerization is probably stabilized by hydrophobic interactions between the subunits. The subunits of the dimer could efficiently be cross-linked with the 4-A cross-linker diepoxybutane. Spontaneous oxidation of Cys(24) and/or Cys(27) also resulted in intersubunit cross-linking. One or both cysteine residues are located at the interface of the Gin dimer, which maps the dimerization domain in the N-terminal part of the protein. Binding of the disulfide-bonded dimers of Gin to a recombination site was strongly reduced, suggesting that the subunits need to reorient in order to form a stable protein-DNA complex. In the protein-DNA complex, however, oxidation of cysteine residues still seems to be possible, indicating that the N-terminal parts of two Gin subunits are also in close proximity when bound to DNA. PMID- 7849039 TI - Dissection of the extracellular human interferon gamma receptor alpha-chain into two immunoglobulin-like domains. Production in an Escherichia coli thioredoxin gene fusion expression system and recognition by neutralizing antibodies. AB - The extracellular interferon gamma receptor alpha-chain (IFN gamma R) is believed to comprise two discrete approximately 110 amino acid immunoglobulin-like domains, perhaps similar to those seen in the crystal structure of the extracellular human growth hormone receptor [De Vos, A. M., Ultsch, M., & Kossiakoff, A. (1992) Science 255, 306-312], a distant relative in the cytokine receptor superfamily. In accord with this idea, we show that these IFN gamma R immunoglobulin-like domains can be produced separately in a soluble form with a native-like fold. The N-terminal domain (residues 1-108), with a Cys105 to Ser105 mutation, was produced at a high level, in a soluble form, as a thioredoxin interferon gamma receptor fragment fusion protein in the cytoplasm of Escherichia coli. Upon extraction, the receptor Cys60-Cys68 disulfide bond formed spontaneously, to generate a native-like structure directly without the need for refolding. Cleavage of the fusion protein by enterokinase released the receptor fragment (approximately 12 kDa), which was recognized by several neutralizing antibodies with affinities, measured using surface plasmon resonance technology, that were essentially indistinguishable from those seen with the full length extracellular IFN gamma R produced in eukaryotic cells. Circular dichroism and 1D 1H nuclear magnetic resonance spectra indicated that the receptor fragment adopts a folded state, with mainly beta-sheet and reverse turn secondary structure. The second membrane-proximal Ig-like domain of the IFN gamma R (residues 90-229) was produced, albeit less efficiently, and characterized in a similar way. The production of these two independently folded proteins provides experimental support for the two domain organization of the IFN gamma R and opens new avenues for structural studies on these Ig-like molecules by NMR and crystallographic methods. PMID- 7849040 TI - 3-Methyladenine and 7-methylguanine exhibit no preferential removal from the transcribed strand of the dihydrofolate reductase gene in Chinese hamster ovary B11 cells. AB - The removal of cylclobutane pyrimidine dimers from cellular DNA occurs preferentially in actively transcribed genes of cells subjected to ultraviolet radiation. In contrast, reports concerning the transcription-dependent repair of N-methylpurines formed in cellular DNA following exposure to methylating agents are quite conflicting, with some studies suggesting that no biased clearance of these lesions occurs and others indicating that preferential removal of these adducts transpires in active genetic loci. Even in the cases where no preferential clearance was demonstrated, a slight but statistically insignificant biased removal of N-methylpurines from the transcribed strand of active genes was often evident. We proposed that these results might be due to the preferential clearance of only one of the two principal N-methylpurines formed, 3 methyladenine, or to the source of the methylating species to which the cells were exposed. Therefore, we investigated the clearance of 3-methyladenine and 7 methylguanine as individual lesions from the amplified dihydrofolate reductase gene of Chinese hamster ovary cells, and we examined the gene-specific removal of N-methylpurines formed by several different methylating agents as well. We observed no biased clearance of 3-methyladenine toward the transcribed strand of the locus being examined. This result indicates that any minor gene-specific preferential repair that has been observed previously for N-methylpurines in toto -which actually reflects the removal of the predominant methylated purine 7 methylguanine--is not due to biased clearance of the transcription-inhibiting 3 methyladenine lesion.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7849041 TI - Effects of the DNA-damaging enediyne C-1027 on intracellular SV40 and genomic DNA in green monkey kidney BSC-1 cells. AB - This study describes the selective ability of C-1027 to induce limited double strand damage in a viral DNA target. The effect of the cellular environment on C 1027 activity was examined by assaying the extent, as well as the specificity, of damage to simian virus 40 (SV40) DNA in lytically infected mammalian BSC-1 cells and in purified SV40 DNA preparations. C-1027 damage to intracellular SV40 DNA was quantitated by topological forms conversion analysis. A gradual decrease in intracellular supercoiled form I accompanied by an increase in form III was observed with C-1027 concentrations from 2 to 100 nM, with a 50% reduction in form I observed at 50 nM. Damage to purified SV40 DNA also was most pronounced between 10 and 100 nM C-1027. When concentrations were expressed as r values (drug/DNA molar ratio), the amount of C-1027 necessary to effect a 50% reduction in form I was lower for intracellular (r = 0.002) than for purified SV40 DNA (r = 0.0035). Double-strand damage was more likely to occur with C-1027 treatment of intracellular compared to purified SV40 DNA. However, with both purified and intracellular DNA, restriction enzyme digestion analysis revealed double-strand damage at a number of specific sites throughout the genome, particularly within the early region of the SV40 genome (e.g., within the coding sequence for large T antigen). No significant damage was observed in either the origin (ORI) or the termination (TER) regions of SV40 replication. The extent of C-1027 damage to uninfected BSC-1 cell DNA was also quantitated using pulsed-field gel electrophoresis. At 0.1 nM (r = 2.8 x 10(-5), where incorporation of [3H]thymidine was reduced by 80%, 600 rad equiv of damage was detected in uninfected BSC-1 cells. At C-1027 r values from 1 x 10(-4) to 40 x 10(-4), double strand breaks were from 80- to 40-fold more frequent in SV40 than in BSC-1 cell genomic DNA. By contrast, 50-fold more drug was necessary to inhibit intracellular SV40 DNA accumulation compared to [3H]thymidine incorporation into uninfected BSC-1 cells. Thus, SV40 DNA synthesis appeared to be less sensitive to C-1027-induced lesions than replication in uninfected BSC-1 cells. PMID- 7849042 TI - Insulin receptor autophosphorylation and signaling is altered by modulation of membrane physical properties. AB - Many membrane functions are modulated by the bulk biophysical properties of the membrane. Various compounds which alter membrane physical properties were investigated for their ability to modulate insulin receptor autophosphorylation and signaling. Compounds which raise the bilayer to hexagonal phase transition temperature in model membranes, including carbobenzoxydipeptides, apolipoprotein A-I, acyl carnitines, and lysophosphatidylcholine, inhibited insulin stimulation of insulin receptor tyrosine phosphorylation of isolated receptors as well as in cells overexpressing human insulin receptor. For compounds of similar structure, the inhibition of insulin receptor tyrosine phosphorylation correlates well with their bilayer-stabilizing potency. Most of the compounds which inhibit tyrosine phosphorylation of the insulin receptor also inhibited glucose uptake in the same cells. Compounds which lower the bilayer to hexagonal phase transition temperature in model membranes enhanced insulin stimulation of autophosphorylation in isolated receptors, with no effect on insulin receptor activity in NIH 3T3 HIR 3.5 cells. The effects of cationic amphiphiles were not readily predictable from their membrane modulating activity. All of the compounds tested exert their effects independent of changes in insulin binding to the receptor or changes in the basal tyrosine kinase activity of the receptor. This provides evidence that mechanism of modulation of insulin signaling by these additives lies in their ability to alter the bulk physical properties of the membrane. The results suggest that membrane monolayer curvature strain is a factor contributing to the efficiency of insulin signal transduction. PMID- 7849043 TI - Influenza hemagglutinin-mediated membrane fusion: influence of receptor binding on the lag phase preceding fusion. AB - Fusion of influenza virus with liposomes is triggered by low pH, resulting in a conformational change in the fusion protein (HA) and the insertion of fusion peptides from HA into the liposomal membrane. Fusion does not take place immediately after insertion but is preceded by a lag phase, the duration of which, as we have found previously, depends on the presence of ganglioside receptors in the liposomal membrane [Stegmann, T., White, J. M., & Helenius, A. (1990) EMBO J. 9, 4231-4241]. Here we have investigated why that is the case. Surprisingly, the 2-4-fold shorter lag phase observed with phosphatidylcholine (PC)/phosphatidylethanolamine (PE)/ganglioside liposomes was not due to slower or more readily reversible binding of the virus to PC/PE liposomes lacking receptors. Nevertheless, using liposomes with various glycolipids as targets, it was found that specific HA-receptor interactions were required for a shorter lag, and not just the negative charge of the gangliosides, or the presence of ceramide lipid tails in the liposomal membrane. Receptor binding also did not facilitate the conformational change in HA. Surprisingly, however, it was found that after an incubation of the virus at low pH in the absence of target membranes at 0 degrees C for several minutes, the binding and fusion activity of virus using PC/PE liposomes, but not PC/PE/ganglioside liposomes as targets, was decreased. The population of virus that did still bind to and fuse with the PC/PE liposomes after low pH preincubation did so after a significantly increased lag time.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7849044 TI - Enhanced binding of enterotoxigenic Escherichia coli K99 to amide derivatives of the receptor ganglioside NeuGc-GM3. AB - A natural receptor in pig small intestine [Teneberg, S., Willemsen, P., de Graaf, F. K., & Karlsson, K.-A. (1990) FEBS Lett. 263, 10-14] for the enterotoxigenic bacteria Escherichia coli K99 is the ganglioside NeuGc-GM3 (NeuGc alpha 3Gal beta 4Glc beta Cer) [e.g., H. Smit, W. Gaastra, J. P. Kamerling, J. F. G. Vliegenthart, & F. K. de Graaf (1984) Infect. Immun. 46, 578-584]. Chemical modifications of the carboxyl group of this ganglioside were performed, giving five different amides, the methyl ester, and the primary alcohol. The products were purified, and their structures were investigated by negative FAB mass spectrometry. Binding of E. coli K99 was tested by incubating 35S-labeled bacteria with derivatized compounds separated on thin-layer chromatograms. Modification of the carboxyl group to a primary amide strengthened the binding at least 5-fold, as estimated from autoradiography of dilutions on thin-layer plates. Some strengthening of the binding was also obtained with the methylamide as well as with the carboxyl group reduced to the alcohol. The ethylamide bound equally well as the underivatized NeuGc-GM3. Amide substituents as large as propyl amide and benzyl amide were still recognized by the bacteria, although they bound weaker. The methyl ester was not stable in the chromatogram-binding assay with silica gel and water present, and it reverted to the acid. PMID- 7849045 TI - Overproduction and characterization of the erythromycin C-12 hydroxylase, EryK. AB - Hydroxylation of C-12 is one of the final steps in the biosynthesis of erythromycin A (ErA). A point of uncertainty in the erythromycin pathway has been whether the C-12 hydroxylase operates on each of two possible substrates, erythromycin B (ErB) and erythromycin D (ErD). Stassi et al. have cloned the gene, designated eryK, which encodes the P-450 monooxygenase responsible for erythromycin C-12 hydroxylation in Saccharopolyspora erythraea [Stassi, D., Donadio, S., Staver, M. J., & Katz, L. (1993) J. Bacteriol. 175, 182-189]. We report the overproduction of EryK in Escherichia coli as insoluble inclusion bodies; the solubilization, refolding, and reconstitution of active holo-EryK; and kinetic confirmation of a 1200-1900-fold preference of the enzyme for ErD over the alternative C-12 hydroxylase substrate ErB. Our results indicate that ErB is a shunt metabolite in the erythromycin biosynthetic pathway. PMID- 7849046 TI - Local and global dynamics during the folding of Escherichia coli dihydrofolate reductase by time-resolved fluorescence spectroscopy. AB - Time-resolved fluorescence techniques were utilized to monitor the kinetic refolding reaction of Escherichia coli dihydrofolate reductase (DHFR). Measurements of emission and anisotropy decay lifetimes of both the five intrinsic tryptophan residues and the fluorescent probe 1-anilinonaphthalene-8 sulfonate (ANS) during the folding reaction were used to characterize the compactness and development of tertiary structure in transient intermediates formed during the folding of DHFR. Experiments monitoring bound ANS show that a rapidly-formed intermediate (< 20 ms) has a rotational time of approximately 10 ns and, therefore, a compactness similar to that for the native conformation. All of the tryptophan residues in this burst phase species rotate as freely as in the unfolded state. In the set of four intermediates which then appear over the next few hundred milliseconds, the apparent rotational time measured by ANS fluorescence increases to a maximum rotational time of approximately 20 ns. An increase in the average tryptophan lifetime for these intermediates suggests these side chains become excluded from solvent and associated dynamic quenching mechanisms. As the folding reaction proceeds to a set of four native conformers the bound ANS rotational time then decreases to approach that for the native protein, 10.5 ns, and the average tryptophan rotational time increases to the same value. During these rate-limiting, final steps in folding, the static quenching effects which reflect the formation of specific tertiary contacts involving tryptophans also appear. PMID- 7849047 TI - Compactness of thermally and chemically denatured ribonuclease A as revealed by volume and compressibility. AB - The conformational changes of ribonuclease A due to thermal and guanidine hydrochloride denaturation were monitored by means of precise density and sound velocity measurements. It was found that the apparent molar volume decreased but the adiabatic compressibility increased on thermal denaturation under acidic conditions (pHs 1.60, 1.90, and 2.08). On the other hand, guanidine hydrochloride denaturation (pH 2.00) brought about large decreases in the compressibility and apparent molar volume. These results indicate that the conformation of the denatured protein is greatly different between the two types of denaturation: the thermally denatured state corresponds to the structure with enhanced thermal fluctuation having a residual secondary structure and a high local concentration of nonpolar groups exposed, but the guanidine hydrochloride denaturation leads to exposure of a large amount of amino acid residues, resulting in an increase in hydration and a decrease in the internal cavity. The compressibility changes due to both types of denaturation were not correlated to a loss of the secondary structure, as judged by means of circular dichroism. These findings suggest that the compactness and thermal fluctuation of the protein cannot be described by a two-state denaturation model and that there are some molten-globule-like intermediates in the denaturation processes. PMID- 7849048 TI - Stereoselectivity of induction of the retinoblastoma gene product (pRb) dephosphorylation by D-erythro-sphingosine supports a role for pRb in growth suppression by sphingosine. AB - Sphingosine has been shown to inhibit cell growth in many cell lines although the mechanism of this effect remains obscure. More recently, D-erythro-sphingosine has been shown to act as an early inducer of dephosphorylation of the retinoblastoma gene product (pRb) in the lymphoblastic leukemia cell line MOLT-4 [Chao, R., Khan, W., & Hannun, Y.A. (1992) J. Biol. Chem., 267, 23459-23462]. In the current study, the role of the natural D-erythro-sphingosine in regulation of cell growth and pRb dephosphorylation was evaluated using chemically synthesized pure isomers of sphingosine. Of the four possible stereoisomers of sphingosine, D erythro-sphingosine was most active in inducing dephosphorylation of pRb protein with an EC50% of 0.6 microM whereas its enantiomer L-erythro-sphingosine was 8 fold less potent with an EC50% of 5 microM. The dose responses for inhibition of cell growth were nearly identical to the EC50% for pRb dephosphorylation with D erythro-sphingosine causing 50% inhibition at 0.6 microM whereas L-erythro sphingosine was 5-6-fold less potent. All of the stereoisomers were taken up by the cells, and the greater potency of D-erythro-sphingosine was not due to differences in cellular uptake. The metabolism of D-erythro-sphingosine was also studied to evaluate the possible role of sphingosine metabolites on regulation of retinoblastoma protein. Evidence is provided against a role for ceramide or sphingosine 1-phosphate as mediators of the effects of sphingosine on pRb dephosphorylation.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7849049 TI - The binding of distinct segments of actin to multiple sites in the C-terminus of caldesmon: comparative aspects of actin interaction with troponin-I and caldesmon. AB - Thin-filament-based regulation of the contractile response is considered to involve the interaction of actin with troponin-I in striated muscle and the interaction of actin with caldesmon in smooth muscle. The nature of the interaction with actin of these inhibitory proteins has been studied by proton magnetic resonance spectroscopy using segments of caldesmon and troponin-I which mimic their functional properties. Caldesmon is shown to interact with two distinct sites on the N-terminal residues 1-44 of actin subdomain 1 with corresponding contacts on caldesmon domain 3 and domain 4 at its C-terminus. We demonstrate that, whereas inhibition by the troponin-I fragment (residues 96-117) is effected by its interaction with the N-terminal region of actin, the separate inhibitory ability of different regions of the C-terminus of caldesmon (domains 4a and 4b) is mediated by interaction with noncontiguous segments on subdomain 1 of actin. Our studies of the spatial relationship of these actin contacts on caldesmon further suggest that one molecule of caldesmon may associate with two actin monomers. The demonstrated interactive nature of these caldesmon attachments to distinct regions of actin is relevant to the mechanism of calcium modulation of inhibition of actomyosin ATPase by caldesmon. PMID- 7849050 TI - In vitro activation of purified human heat shock factor by heat. AB - A major regulatory step in the heat-induced transcription of heat shock protein (hsp) genes in eukaryotes is the activation of heat shock factor (HSF). In metazoans and Schizosaccharomyces pombe, HSF is present in unstressed cells but is unable to bind to its target DNA sequence element, the heat shock element (HSE). Heat induction of the DNA binding activity of HSF is a critical component required for activation of heat shock genes. Inactive HSF in extracts of non-heat shocked human cells can be heated in vitro to activate HSF, suggesting the factors required to sense temperature and activate HSF are soluble factors [Larson, J. S., Schuetz, T. J., & Kingston, R. E. (1988) Nature 335, 372-375]. We utilized the ability to purify human HSF in the active form to characterize further the in vitro activation of HSF. Here we have developed a procedure to deactivate the DNA binding ability of HSF. When purified and deactivated HSF is heated, the DNA binding ability of HSF is activated. This activation occurs most efficiently at 43 degrees C (heat shock temperature), but, in contrast to activation in the crude system, some activation of HSF is observed at 37 degrees C (non-heat shock temperature). We show that purified and deactivated HSF is similar to natural inactive HSF in both size and shape. Thus, the monomer to trimer transition that activates HSF can occur in a temperature-dependent fashion in the absence of other proteins. It is possible that these biochemical properties of HSF contribute to the ability of HSF to respond to heat in vivo. PMID- 7849051 TI - Coordinated regulation of synapsin I interaction with F-actin by Ca2+/calmodulin and phosphorylation: inhibition of actin binding and bundling. AB - The synapsins are a family of synaptic vesicle phosphoproteins whose role seems to be to limit the availability of small synaptic vesicles for exocytosis by linking them to the cytoskeleton. One member of the family, synapsin I, has been shown to bind calmodulin in a Ca(2+)-dependent manner. In this study, we have examined whether or not calmodulin can regulate one of the activities of synapsin I, namely, its interaction with F-actin. Synapsin I is an actin bundling protein: this activity is controlled by phosphorylation. Here we show that calmodulin in the presence of Ca2+ is a competitive inhibitor of both actin binding and bundling by synapsin I. Under the conditions of our assay (0.45 microM synapsin I, 4 microM F-actin), half-maximal inhibition of actin binding and bundling by unphosphorylated synapsin I was found with 4.3 and 3.7 microM calmodulin, respectively. The actin binding activity of synapsin I phosphorylated by cAMP dependent protein kinase or by calmodulin-dependent protein kinase II showed similar sensitivity to calmodulin inhibition to unphosphorylated synapsin I. However, inhibition of bundling was potentiated. Half-maximal inhibition of bundling by synapsin I phosphorylated by cAMP-dependent kinase was achieved at approximately 0.5 microM calmodulin. Half-maximal inhibition of bundling by synapsin I phosphorylated by calmodulin-dependent protein kinase II was achieved at less than 0.2 microM calmodulin, although the maximum binding under the conditions of the assay was lower.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7849052 TI - Characterization of two membrane-bound forms of OmpA. AB - The insertion of the outer membrane protein A (OmpA) into lipid bilayers was studied by limited proteolysis, polarized Fourier transform infrared (FTIR) spectroscopy, and fluorescence spectroscopy. In the native state, OmpA is thought to form a barrel of eight antiparallel beta-strands. For the present study, it was isolated in an unfolded form, purified, and exposed to performed vesicles of 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC), dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), and three phospholipids that were brominated in different positions of their sn-2 chains (4,5-BrPC, 9,10-BrPC, and 11,12-BrPC). Limited proteolysis revealed two membrane-bound forms of OmpA, namely an "adsorbed" (35 kDa) and an "inserted" (30 kDa) form [Surrey, T., & Jahnig, F. (1992) Proc. Natl. Acad. Sci. U.S.A. 89, 7457-7461]. Which form was found after membrane binding and refolding depended on the lipids used and on the temperature. Polarized attenuated total reflection (ATR)-FTIR spectra were recorded with OmpA bound to germanium-supported bilayers in both forms. The position of the amide I' band indicated quite large fractions of beta-structure of OmpA in both membrane-bound forms (35-45% in the adsorbed form and 45-55% in the inserted form). Measurements of the linear dichroism of the amide I' bands in the inserted form are consistent with an antiparallel beta-barrel in which the strands are inclined at about 36 degrees from the membrane normal. The average angle of the beta-strands to the bilayer normal is likely larger in the 35 kDa form than in the inserted form.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7849053 TI - Interaction of polycyclic aromatic hydrocarbons and flavones with cytochromes P450 in the endoplasmic reticulum: effect on CO binding kinetics. AB - The flash photolysis technique was used to examine the kinetics of CO binding to cytochromes P450 in rat liver microsomes. The effect of polycyclic aromatic hydrocarbons (PAHs) and flavones was used to distinguish the kinetic behavior of the PAH-metabolizing P450 1A1 from that of the remaining multiple microsomal P450s. Applying this approach to microsomes from 3-methylcholanthrene-treated rats showed that although all tested PAHs accelerated CO binding to P450 1A1, the extent varied markedly for different PAHs. The tricyclic PAHs phenanthrene and anthracene enhanced CO binding by 37- and 49-fold, respectively, while several tetracyclic and pentacyclic PAHs increased the rate by 3-16-fold. The results indicate that PAHs exert a dual effect on the rate of CO binding to P450 1A1: a general enhancement via widening of the CO access channel and a reduction that is dependent on PAH size. Although 5,6-benzoflavone increased the rate of CO binding to P450 1A1 by 3.5-fold, it additionally decelerated binding to a constitutive P450 by 15-fold. This flavone thus exerts markedly different effects on two P450s within the same microsomal sample. In contrast, the sole effect of 7,8 benzoflavone was acceleration of CO binding to P450 1A1 by 18-fold. The divergent effects of these isomeric flavones, which only differ in positioning of an aromatic ring, illustrate the sensitivity of CO binding to substrate structure. The varying effects of these PAHs and flavones on CO binding kinetics show that they differentially modulate P450 conformation and access of ligands to the P450 heme and demonstrate that binding of carcinogens to a specific target P450 can be evaluated in its native microsomal milieu. PMID- 7849054 TI - Enzymic activities of covalent 1:1 complexes of cytochrome c and cytochrome c peroxidase. AB - We have obtained several cysteine mutants in or around the cytochrome c peroxidase binding domain of rat and yeast iso-1 cytochrome c by site-directed mutagenesis. These cysteine residues were specifically labeled with the bifunctional photoactive cross-linker 4-azidophenacyl bromide (APB). 1:1 covalent complexes of cytochrome c peroxidase and cytochrome c were generated by cross linking these specifically labeled cytochromes c to cytochrome c peroxidase, and the 1:1 complexes were purified. Steady-state kinetic studies of the purified 1:1 complexes with free yeast and horse cytochromes c showed the following: (1) Cytochrome c peroxidase has two distinct catalytic sites--a high-affinity and a low-affinity site. (2) Other than the difference in affinity, the binding of substrate at the low-affinity site is similar to that at the high-affinity site, with yeast cytochrome c interacting more strongly than the horse protein, the binding of both substrates being sensitive to ionic strength, and both sites able to transfer electrons. (3) HPLC chromatography of purified 1:1 complex showed multiple forms of 1:1 complexes, supporting the idea of multiple possible interactions between cytochrome c and the high-affinity site on cytochrome c peroxidase. (4) An allosteric or electrostatic effect exists between the two substrate binding sites, the binding of cytochrome c to the high-affinity site decreasing the binding affinity of the low-affinity site to cytochrome c. The higher the equilibrium binding affinity of the mutant cytochrome c to the peroxidase, the larger the apparent allosteric/electrostatic effect when that mutant protein is covalently bound to the high-affinity site of the enzyme. Furthermore, different locations of the covalently bound cytochrome c at the high affinity site on the enzyme surface result in different degrees of allosteric/electrostatic effect. The presence of two active sites on the enzyme allows a simple interpretation of some of the differences in the steady-state kinetic behavior of cytochrome c peroxidase with horse and yeast iso-1 cytochrome c. PMID- 7849055 TI - Influence of alpha-subunits on the high-pressure stability of apo and holo beta 2 subunits in the bienzyme complex tryptophan synthase from Escherichia coli. AB - At a hydrostatic pressure of up to 2 kbar, the isolated alpha-subunit of tryptophan synthase from Escherichia coli proved to be a stable enzyme by virtue of specific activity as well as UV absorption and fluorescence emission spectra. The protein can therefore be regarded as a suitable effector for the investigation of structure-function relationships in the dimeric beta 2-subunit under the influence of high hydrostatic pressure. Complete deactivation of the beta 2-component in the alpha 2 beta 2 bienzyme complex occurs above 1300 bar (midpoint of transition for alpha apo beta 2, 790 bar; for alpha 2 holo beta 2, 1057 bar). Sucrose (13%) shifts both midpoints of transition to values higher by about 300 bar. As shown by sucrose gradient centrifugation and limited trypsinolysis, deactivation of the beta 2-dimer is paralleled by dissociation into denatured beta-chains. At 10 degrees C, the corresponding dissociation constants K at 1 bar as well as the reaction volumes of dissociation delta V are calculated as 4.2 x 10(-9) M and -196 mL/mol for the apo-beta 2-component and as 9.8 x 10(-19) M and -632 mL/mol for the holo-beta 2-component in the bienzyme complex. Furthermore, large negative activation volumes are determined, reflecting the rate increase with increasing pressure: -89 mL/mol for the apo beta 2-dimer and -195 mL/mol for the holo-beta 2-dimer.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7849057 TI - The proximal ligand variant His93Tyr of horse heart myoglobin. AB - The spectroscopic and structural properties of the His93Tyr variant of horse heart myoglobin have been studied to assess the effects of replacing the proximal His residue of this protein with a tyrosyl residue as occurs in catalases from various sources. The variant in the ferric form exhibits electronic spectra that are independent of pH between pH 7 and 10, and it exhibits changes in absorption maxima and intensity that are consistent with a five-coordinate heme iron center at the active site. The EPR spectrum of the variant is that of a high-spin, rhombic system similar to that reported for bovine liver catalase. The 1D 1H-NMR spectrum of the variant confirms the five-coordinate nature of the heme iron center and exhibits a broad resonance at 112.5 ppm that is attributable to the meta protons of the phenolate ligand. This result indicates that the new Tyr ligand flips at a significant rate in this protein. The thermal stability of the Fe(III) derivative is unchanged from that of the wild-type protein (pH 8) while the midpoint reduction potential [-208 mV vs SHE (pH 8.0, 25 degrees C)] is about 250 mV lower. The three-dimensional structure of the variant determined by X-ray diffraction analysis confirms the five-coordinate nature of the heme iron center and establishes that the introduction of a proximal Tyr ligand is accommodated by a shift of the F helix (residues 88-99) in which this residue resides away from the heme pocket. Additional effects of this change are small shifts in the positions of Leu29, a heme propionate, and a heme vinyl group that are accompanied by altered hydrogen bonding interactions with the heme prosthetic group.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7849056 TI - Photoaffinity ADP analogs as covalently attached reporter groups of the active site of myosin subfragment 1. AB - The enzymatic properties of rabbit skeletal myosin subfragment 1 (S1) have been determined after photoaffinity labeling the active site with two ADP analogs. These analogs, 2-[(4-azido-2-nitrophenyl)-amino]ethyl diphosphate (NANDP) and the fluorescent analog 3'(2')-O-(4-benzoylbenzoyl)-1,N6-ethenoadenosine diphosphate (Bz2 epsilon ADP), label the heavy chain residues Trp 130 and Ser-324, respectively. These residues in the crystal structure of chicken skeletal S1 are on either side of the entrance to the active site pocket (Rayment et al., 1993b). Here S1 was photolabeled with NANDP or Bz2 epsilon ADP after trapping with vanadate (Vi). Both of the photolabeled S1 preparations had normal MgATPase activities after removal of vanadate by actin treatment. These results show that the covalently tethered nucleotide analogs could move out of the active site and be replaced by MgATP. Experiments that monitored the fluorescence emission intensity, polarization, and quenching by acrylamide of S1 photolabeled with Bz2 epsilon ADP show that the covalently linked analog was displaced out of the active site cleft by MgATP (or MgATP and actin) but not by ATP in the absence of Mg2+ ions. The effective concentration of the tethered ethenoadenosine diphosphate at the active site, determined by competition with MgATP, was calculated to be 10 mM. In the absence of Mg2+ ions, ATP was unable to compete with the bound analog. Binding constants of the S1 photolabeled with Bz2 epsilon ADP to actin were 1.5 x 10(5) and 5.8 x 10(5) M-1 at 200 and 20 mM ionic strength, respectively, showing that actin binding affinities are similar to those obtained for S1.ADP. The binding of actin in the absence of MgATP did not produce any change in the emission intensity, polarization, or quenching by acrylamide of the tethered ethenoadenosine diphosphate, indicating that the conformation of the pocket around the adenine ring was unchanged. However, the binding of actin did destabilize Vi, which had been previously trapped in the form of photolabeled S1-Vi complexes. These results indicate that actin binding primarily affects the gamma-phosphate binding site but not the adenine ring binding site. PMID- 7849058 TI - Identification of an essential tyrosyl residue in the binding site of Schizophyllum commune xylanase A. AB - Ultraviolet difference spectroscopy studies with the Schizophyllum commune xylanase in the presence of inhibitors and substrates indicated the participation of one or more tyrosyl residues in the binding of substrates to xylanase. Chemical modification experiments with group-specific reagents in the absence and presence of substrates confirmed the essential role of a tyrosyl residue in substrate binding while discounting the participation of tryptophan. A fourth derivative absorbance spectroscopic method was developed to facilitate the quantitation of modified tyrosyl and tryptophanyl residues. This analysis showed that two tyrosyl residues of the xylanase are modified by tetranitromethane in the absence of substrate with the concomitant loss of catalytic activity. Protection of the xylanase with xylooligosaccharides resulted in the nitration of only one residue, and such enzyme derivatives retained 94% catalytic activity. Differential modification of the xylanase with tetranitromethane generated an enzyme derivative with the characteristic absorbance at 428 nm of 3 nitrotyrosine. Amino acid analysis and N-terminal sequencing of peptides with strong absorbance at 428 nm isolated from the protease-digested modified enzyme by reverse-phase HPLC identified the essential residue as Tyr97. Alignment of the S. commune xylanase amino acid sequence with those of the 18 other known family G xylanases revealed that Tyr97 is a conserved aromatic residue, further suggesting its essential role in substrate binding. PMID- 7849059 TI - Determination of the metal ion separation and energies of the three lowest electronic states of dimanganese (II,II) complexes and enzymes: catalase and liver arginase. AB - The dimanganese (II,II) catalase from Thermus thermophilus, MnCat(II,II), arginase from rat liver, Arg(II,II), and several dimanganese(II,II) compounds, LMn2XY2, which are functional catalase mimics, all possess a pair of coupled Mn(II) ions in their catalytic sites. For each of these, we have measured by EPR spectroscopy the relative energies separating the three lowest electronic states (singlet, triplet, and quintet), described a general method for extracting the individual spectra for these states by multicomponent analysis, and determined the Mn-Mn separation. The triplet-singlet and quintet-singlet energy gaps were modeled well by fitting the temperature dependence of the EPR intensities to a Boltzmann expression for a pair of Mn(II) ions coupled by isotropic Heisenberg spin exchange (-2JS1S2). This dependence indicates diamagnetic ground states with delta E10 (cm-1) = magnitude of 2J = 4 and 11.2 cm-1 for Arg-(II,II)(+borate) and MnCat(II,II)(phosphate), respectively. This large difference in magnitude of 2J reflects either a difference in the bridging ligands or, possibly, a weaker ligand field (larger ionization potential) for the Mn(II) ions in arginase. In n butanol/CH2Cl2 the triplet-singlet energy gaps for [LMn2(CH3CO2)](C1O4)2 (1), [LMn2(CH3CO2)3] (2), and [LMn2Cl3] (3), where HL = N,N,N',N'-tetrakis(2 methylenebenzimidazole)-1,3-diaminopropan+ ++-2-ol, are 23-24 cm-1. Comparison of the Heisenberg exchange interaction constants for more than 30 dimanganese(II,II) complexes suggests a possible bridging structure of (mu-OH)(mu-carboxylate)1-2 for MnCat(II,II), while the 3-fold weaker coupling in Arg(II,II) suggests mu-aqua in place of mu-hydroxide. EPR spectra of both the triplet and quintet electronic states were extracted and found to exhibit zero-field splittings (ZFS) and resolved 55Mn hyperfine splittings indicating spin-coupled Mn2-(II,II) species. The major ZFS interaction could be attributed to the magnetic dipole-dipole interaction between the Mn(II) ions. A linear correlation is observed between the crystallographically determined Mn-Mn distance and the ZFS of the quintet state (D2) for five dimanganese pairs for which both data sets are available. Using this correlation, the Mn-Mn distance in Arg(II,II) is predicted to be 3.36-3.57 A for the native enzyme (multiple forms) and 3.59 A for MnCat(II,II)(phosphate). Addition of the inhibitor borate to Arg(II,II) simplifies the ZFS, indicative of conversion to a single species with mean Mn-Mn separation of 3.50 A. The second metal ion in dinuclear complexes possessing a shared bridging ligand has been shown to attenuate the strength of the mu-ligand field potential, as monitored by the strength of the single ion ZFS.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7849060 TI - 1H NMR studies of sarafotoxin SRTb, a nonselective endothelin receptor agonist, and IRL 1620, an ETB receptor-specific agonist. AB - 1H NMR studies on the nonselective endothelin receptor agonist sarafotoxin SRTb have identified a helix between residues Asp 8 and His 16, and a beta-turn involving residues Cys 3 to Met 6; however, the biologically important C-terminal five residues were found to be conformationally variable. The average RMSD, measured for the final 43 refined structures to the average structure over residues 1-16, was 0.78 +/- 0.18 A for the backbone atoms and 1.39 +/- 0.22 A for all atoms. The torsion angles Cys 3 psi/Lys 4 theta, Thr 7 psi/Asp 8 theta and Gln 17 theta were identified as sites of conformational variability. Differences were found between the structures in the bicyclic loop region for SRTb and those published for ET1, another nonselective receptor agonist, which may explain the observed differences in potency of these peptides. The conformation of an ETB receptor-specific agonist, IRL 1620, which lacks the N-terminal seven residues and the two intrachain disulfides, was found by NMR and circular dichroism spectroscopy to be predominantly random coil, despite the fact that its affinity for the ETB receptor almost equals that of ET1. However, close analysis of the NMR results indicated the presence of turn-like structures, or a nascent helix, in the part of the sequence corresponding to the helical region in the parent peptides. These results suggest that the helical conformation may be required for ligand binding to the ETB receptor as well as to the ETA receptor. PMID- 7849061 TI - Energetics of denaturation and m values of staphylococcal nuclease mutants. AB - In a continuation of an earlier study [Carra, J., Anderson, E., & Privalov, P. (1994) Biochemistry 33, 10842-10850], we used differential scanning calorimetry to measure the enthalpy and heat capacity changes of denaturation for 11 mutant forms of staphylococcal nuclease, including the triple mutant [V66L+G88V+G79S]. Several mutant proteins with m- characteristics of guanidinium chloride denaturation were found to denature via a three-state mechanism with increasing temperature. Enthalpy changes for the transitions from the native to intermediate and from the intermediate to denatured states were determined. In the case of the triple mutant, the enthalpy of the second endothermic transition is greater than that of the first. Observation of this second transition provides an explanation for the previously reported large changes in the delta H denaturation for the triple mutant versus wild-type nuclease. The sequence specificity of structure in the intermediate state is discussed with relevance to m values of guanidinium chloride denaturation. The enthalpic level of the intermediate state depends upon the amino acid sequence, suggesting that stabilizing mutations can increase the extent or cohesion of structure present in the intermediate. PMID- 7849062 TI - Triplex formation at the rat neu gene utilizing imidazole and 2'-deoxy-6 thioguanosine base substitutions. AB - Triplex-forming oligodeoxyribonucleotides (TFOs) can be designed so as to form antiparallel triple helices with duplex DNA by means of GGC and TAT or AAT base triplets, and these have been shown to be useful as sequence-specific DNA binding agents. Using TFOs targeted to the promoter region of the rat neu oncogene, it is shown here that substitution of an imidazole-nucleoside chimera at a single site in a neu specific TFO results in an increase in TFO binding affinity and specificity. This effect is discussed in terms of the stabilizing effect of local imidazole-TA triplet formation. It is also found that site-selective substitution of 2'-deoxy-6-thioguanosine for guanosine (S6-dG) in the TFO results in an increase in triplex formation in the presence of physiological levels of potassium ion. The utility and positioning of S6-dG base substitutions is discussed in the context of an intramolecular tetrad model. PMID- 7849063 TI - Metabolism and distribution of intramolecular excimer-forming dipyrenebutanoyl glycerophospholipids in human fibroblasts. Marked resistance to metabolic degradation. AB - Metabolism and intracellular distribution of fluorescent 1, 2-dipyrenebutanoyl derivatives of phosphatidylcholine, -ethanolamine, and -serine and phosphatidic acid (diPyr4PC, -PE, -PS, and -PA, respectively) in human skin fibroblasts (HF) has been studied. When HF cells were co-incubated with phospholipid vesicles containing diPyr4PC at 8 degrees C, considerable amounts of fluorescent lipid were incorporated into the cells. This incorporation occurred mainly by spontaneous diffusion, since 10-fold less of the vesicle marker, [3H]cholesteryl oleate associated with the cells. Also diPyr4PE, -PS, and -PA were incorporated efficiently into the cells, probably by the same mechanism. HPLC analysis of the cells labeled with diPyr4PA at 8 degrees C for 1 h showed that a considerable fraction of the lipid had been metabolized to the corresponding diglyceride and triglyceride. No metabolism of the other dipyrenyl lipids was observed at this temperature. When the cells were shifted to 37 degrees C, diPyr4PA was further metabolized to diPyr4PC, which represented 90% of total diPyr4 lipids after 8 h of incubation. DiPyr4PS was converted to diPyr4PE with an apparent half-time of 3 h, probably by decarboxylation in the mitochondria. In contrast to the PA and PS derivatives, no head-group modification of either diPyr4PC or diPyr4PE was observed even at this temperature. Stability of dipyrenyl lipids toward phospholipase A degradation was investigated by labeling the cells simultaneously with diPyr4PC and NBD6PC, a commonly used fluorescent glycerophospholipid derivative, followed by incubation at 37 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7849064 TI - Recombinant human replication protein A binds to polynucleotides with low cooperativity. AB - Replication protein A (RPA) is a multisubunit single-stranded DNA-binding protein that is involved in multiple aspects of cellular DNA metabolism. We have determined quantitative estimates of the binding parameters of human replication protein A (hRPA) from equilibrium binding isotherms. The intrinsic binding constant (K) and cooperativity parameter (omega) were determined from analysis of changes in the intrinsic fluorescence of hRPA that occurred upon binding single stranded DNA homopolynucleotides. The cooperativity of hRPA binding to both poly(dT) and poly(dA) was found to be low (omega = 10-20) at all NaCl concentrations examined (0.3-2 M). In contrast, the apparent binding affinity (K omega) of RPA decreased significantly with increasing salt concentration, such that log [NaCl]/log K omega was -2.8 for poly(dT) and -4.8 for poly(dA). We conclude that the salt dependent decrease in binding affinity resulted from changes in the intrinsic binding constant (K). These data suggest that the interaction of hRPA with single-stranded DNA involves significant electrostatic interactions, similar to other single-stranded DNA-binding proteins. The apparent binding affinity (K omega) of RPA was higher for poly(dT) than for poly(dA); extrapolation of our data indicated that the apparent binding affinity at 0.2 M NaCl was 1.6 x 10(10) M-1 for poly(dT) and 1.1 x 10(9) M-1 for poly(dA). PMID- 7849065 TI - Redox reaction of poly(ethylene oxide)-modified hemoglobin in poly(ethylene oxide) oligomers at 120 degrees C. AB - Human hemoglobin, modified with poly(ethylene oxide) with average molecular weight of 3500 (PEO-Hb) was dissolved in PEO200 (molecular weight of 200) containing 0.5 M KCl. A quasi-reversible redox reaction of the PEO-Hb was found in PEO oligomers by alternatingly changing the potential polarity (+/- 1.2 V vs Ag). The PEO-Hb showed redox reactions in PEO200 even at 120 degrees C. PEO modification was concluded to give the thermal stability in some extent. In phosphate buffer at 70 degrees C, the electrochemical redox reaction of native Hb was not observed spectroscopically, but that of PEO-Hb was detected. The most effective factor was, however, concluded to be the use of PEO oligomers as a solvent. The molecular motion of PEO oligomers should be milder than that of water at higher temperature. This lower molecular motion was suggested to keep the redox activity of PEO-Hb in the PEO oligomer at 120 degrees C. However, the PEO-Hb in PEO200 was stable in the oxidized form at 30 degrees C; it was reduced without giving potential at 120 degrees C. Cyclic voltammetry revealed that this autoreduction was attributed to the shift of redox potential with elevating temperature. PMID- 7849066 TI - Gene transfer with synthetic cationic amphiphiles: prospects for gene therapy. PMID- 7849067 TI - Conjugates of double-stranded oligonucleotides with poly(ethylene glycol) and keyhole limpet hemocyanin: a model for treating systemic lupus erythematosus. AB - Two types of oligonucleotides were synthesized with linker groups attached at the 5'-end. Both were repeating dimers of deoxyribocytidine and deoxyriboadenosine. A 20-mer was prepared with a thiol-containing linker, masked as a disulfide, and a 50-mer was prepared with a vicinal diol-containing linker. A tetraiodoacetylated poly(ethylene glycol) (PEG) derivative was synthesized and reacted with the thiol containing 20-mer to provide an oligonucleotide PEG conjugate of precisely four oligonucleotides on each PEG carrier. The vicinal diol on the 50-mer was oxidized to an aldehyde and conjugated to keyhole limpet hemocyanin (KLH) to provide an oligonucleotide-KLH conjugate by reductive alkylation. The conjugates were annealed with complementary (TG)n strands. While the double-stranded oligonucleotide-KLH conjugate is an immunogen, eliciting the synthesis of antibodies against oligonucleotides, the PEG conjugate has the biological property of specifically suppressing (tolerizing) B cells which make antibodies against the immunizing oligonucleotide. PMID- 7849068 TI - Fluorescent derivatives of diphenyl [1-(N-peptidylamino)alkyl]phosphonate esters: synthesis and use in the inhibition and cellular localization of serine proteases. AB - Three fluorescein- and one Texas Red-labeled derivatives of [1-(N dipeptidylamino)alkyl]phosphonate diphenyl esters were synthesized and evaluated as inhibitors of serine proteases. The two fluorophores, FITC and TXR, were attached to the peptide phosphonates via an epsilon-aminocaproyl unit that acts as a spacer group and facilitates the binding of the phosphonate inhibitor to the targeted enzymes. These derivatives are potent and specific inhibitors of chymotrypsin, porcine pancreatic elastase (PPE), and human leukocyte elastase (HLE). FTC-Aca-Phe-Leu-PheP(OPh)2 (3) inhibited chymotrypsin very potently (k(obsd)/[I] = 9500 M-1 s-1) and 600-fold better than it did PPE (k(obsd)/[I] = 16 M-1 s-1). FTC-Aca-Ala-Ala-MetP(OPh)2 (1) was a more effective inhibitor of chymotrypsin (k(obsd)/[I] = 190 M-1 s-1) than PPE and HLE (k(obsd)/[I] = 13 and 22 M-1 s-1, respectively). Only HLE and PPE were inhibited by FTC-Aca-Ala-Ala AlaP(OPh)2 (2) (k(obsd)/[I] = 41 and 22 M-1 s-1, respectively). The specificity of these inhibitors toward the targeted serine proteases depends on the sequence of the tripeptide portion and was not affected by the presence of the fluorescent label. Trypsin, for instance, was not inhibited by any of these compounds. In some cases, the inhibitory potency was increased by the fluorescent label. For example, chymotrypsin was inhibited by the fluorescent compounds, FTC-Aca-Ala-Ala MetP(OPh)2 (1) and FTC-Aca-Phe-Leu-PheP(OPh)2 (3), more potently than by the nonfluorescent compounds, Boc-Ala-Ala-MetP(OPh)2 (5) and Z-Phe-Leu-PheP(OPh)2 (7).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7849069 TI - Complete inactivation of target mRNA by biotinylated antisense oligodeoxynucleotide-avidin conjugates. AB - Biotinylation of phosphodiester oligodeoxynucleotides (PO-ODN) allows for conjugation to avidin-based transcellular delivery systems. In addition, biotinylation of PO-ODN at the 3'-terminus provides complete protection against serum 3'-exonuclease degradation. The present study was undertaken to determine if antisense 3'-biotinylated PO-ODN-avidin constructs are able to recognize and inactivate the target mRNA through RNase H-mediated degradation. A 21-mer antisense PO-ODN complementary to the tat gene encompassing nucleotides 5402-5422 of the HIV-1 genome was synthesized with biotin conjugated to the 3'-terminus (bio-tat). Gel mobility assays using [5'-32P]-labeled bio-tat ODN and avidin showed that the bio-tat ODN was fully monobiotinylated. Aliquots of [32P]-labeled sense or antisense tat RNA (337 and 351 nucleotides, respectively) were prepared from transcription plasmids and were preincubated with an excess of bio-tat ODN with or without avidin constructs and digested with RNase H. Products were resolved with sequencing gel and analyzed by autoradiography. Complete conversion to predicted RNA fragments resulting from RNase H digestion of the RNA-ODN duplex (53 and 263 nucleotides) was observed when [32P]-tat sense RNA was incubated with antisense bio-tat ODN or conjugated to avidin or an avidin-cationized human serum albumin (cHSA) complex. Conversely, no degradation of [32P]-tat-antisense RNA was observed after incubation with antisense bio-tat ODN and RNase H. In addition, the avidin-cHSA complex significantly increased (84-fold) the uptake of [32P] internally labeled bio-tat ODN and its stability against cellular nuclease degradation in peripheral blood lymphocytes.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7849070 TI - Site-specific conjugation of an enzyme and an antibody fragment. AB - A site-specific immunoconjugate was prepared between an F(ab')2-like fragment of the monoclonal anti-CEA murine IgG1 A5B7 and a mutant of the dimeric enzyme carboxypeptidase G2 possessing an N-terminal Thr in place of Ala. First an aldehyde was introduced at the N-terminus of the enzyme by mild periodate oxidation and a residue of carbohydrazide was specifically introduced at the C terminus of the truncated heavy chain of the F(ab')2-like fragment by reverse proteolysis. Then the two modified proteins were conjugated by the formation of a hydrazone bond between the hydrazide and the aldehyde groups. The conjugate obtained retained both enzymic activity and antigen-binding capacity. The antigen binding capacity was better than that of a similar conjugate made conventionally by random reaction with side chains. PMID- 7849071 TI - Glutaramyl-beta-alanyl spacer group for haptenic coupling to proteins. Preparation of immunogens for antibody production against polychlorinated biphenyls. AB - By use of a glutaramyl-beta-alanyl spacer group, a hapten for the polychlorinated biphenyl, 2,2',4,4',5,5'-hexachlorobiphenyl (1), viz., 2-amino-2',4,4',5,5' pentachlorobiphenyl (2), was successfully conjugated to carrier proteins to provide immunogens with high hapten/protein molar substitution ratios (MSR's). The procedure allows for the incorporation of beta-[3H]-alanine into the immunogen, thereby providing an accurate radiochemical method for the quantitative assessment of MSR. The use of the glutaramyl spacer group was prompted by the observation that the corresponding succinamyl group was subject to side reactions manifested by succinimide formation during the carboxyl activation step to an activated ester for subsequent coupling to proteins, thus severely compromising the coupling yields. The glutaramyl-beta-alanyl spacer group should be generally applicable for protein conjugation of any hapten with an amino functional group in the molecule. PMID- 7849072 TI - Characterization of ribosome-inactivating proteins isolated from Bryonia dioica and their utility as carcinoma-reactive immunoconjugates. AB - Two ribosome-inactivating proteins (RIPs) were isolated and characterized from the roots of Bryonia dioica. One of these was a novel 27-kDa protein termed bryodin 2 (BD2), while the second was a previously reported RIP, referred to here as bryodin 1 (BD1). The amino-terminal sequence obtained for BD2 was similar, but distinct from BD1, ricin A chain, trichosanthin, and momorcharin. BD2-specific monoclonal antibodies were generated and found not to react with BD1 or ricin A chain. Purified BD1 and BD2 RIP inhibited protein synthesis in a cell-free in vitro translation assay at EC50 values of 7 and 9 pM, respectively. Intravenous administration of BD1 was less toxic to mice than BD2, with LD50 values of > 40 for BD1 and 10-12 mg/kg for BD2. Primary human endothelial cells were 5-8-fold less sensitive to BD1 and BD2 than compared to ricin A chain. BD1 and BD2 were constructed as immunoconjugates with the chimeric form of BR96 (chiBR96), a carcinoma-reactive, internalizing antibody. ChiBR96-BD1 and chiBR96-BD2 were found to bind to and kill BR96 antigen-positive carcinoma cells while not killing antigen-negative carcinoma cells. Bryodins represent RIPs that may be useful in constructing immunotoxin conjugates with reduced toxicity and vascular sensitivity, as compared to ricin A chain immunotoxins. PMID- 7849073 TI - Targeting glucose oxidase at aspartate and glutamate residues with organic two electron redox mediators. AB - The bimolecular rate constants for the reactions of five organic two-electron redox mediators with reduced glucose oxidase (GOx) were determined by measuring voltammetric electrocatalytic currents at glassy carbon electrodes in the presence of excess glucose under anaerobic conditions. The mediators studied were thionine, brilliant cresyl blue, azure A, daunomycin, and dopamine, and the bimolecular rate constants for electron transfer between GOx and the oxidized mediator (M-1 s-1) are 1.6 x 10(4), 4.0 x 10(2), 9.8 x 10(2), 9.0 x 10(3), and 1.2 x 10(6), respectively. GOx was covalently derivatized using 1-ethyl-3-[3 (dimethylamino)propyl]carbodiimide and N-hydroxysulfosuccinimide to form amide bonds between the aliphatic primary amine groups on daunomycin and dopamine and carboxylate side chains of aspartate and glutamate residues. Derivatives with 2.5 +/- 0.1 daunomycin groups and 4 +/- 1 dopamine groups were obtained, with activities of 50% and 75%, respectively, relative to native GOx in a dye peroxidase assay. Although the daunomycin derivative did not show measurable intramolecular electron-transfer rates, the dopamine derivative rapidly transfers electrons from active-site FADH2 groups to the oxidized (quinone) form of dopamine. Because the heterogeneous oxidation of dopamine is relatively slow, the currents measured at +0.75 V vs Ag/AgCl were not at their limiting (plateau) values, and only a minimum value of the intramolecular rate constant (4.5 s-1) could be determined. This value is > 20 times larger than values obtained for GOx ferrocene derivatives in which surface lysine residues were covalently modified using identical coupling reagents and similar reaction conditions. This work shows that targeting GOx carboxylate groups with electron-transfer mediators may represent a promising approach to the design of reagentless glucose biosensors. PMID- 7849074 TI - Synthesis and characterization of conjugates formed between periodate-oxidized ribonucleotides and amine-containing fluorophores. AB - The synthesis and purification of new fluorescently labeled derivatives of GDP and ATP are described. The fluorescent groups are coupled initially through amine containing linker arms to periodate-oxidized nucleotides. Reduction of the initial product yields primarily a six-membered morpholine-like ring. Fluorescein labeled GDP, rhodamine-labeled GDP, and fluorescein-labeled ATP were characterized by absorbance spectroscopy and TLC. NMR and FAB-MS studies were carried out on a single nucleotide derivative formed by reacting periodate oxidized guanosine and benzylamine with subsequent reduction to establish the modification to the ribose moiety. The synthesis of the guanosine-benzylamine conjugate led to a mixture of products that were separated. The predominant product (70%) resulted in conversion of the ribose moiety to a six-membered morpholine-like ring having no hydroxyl group, and the minor product (30%) resulted in an open ring structure having one hydroxyl. When NaCNBH3 was used as the sole reductant, only the product with the morpholine-like ring was formed. These probes were prepared for use in solution studies of the interactions of eukaryotic initiation factor-2 with other components of mammalian protein synthesis initiation. PMID- 7849075 TI - Double-stranded cyclic oligonucleotides with non-nucleotide bridges. AB - A series of double-stranded, cyclic oligodeoxynucleotides with non-nucleotide bridges have been synthesized, and their physicochemical properties and susceptibility to enzymes have been investigated. These bridged duplexes are of potential interest for their binding properties to transcription factors and other DNA-binding proteins. Triethylene glycol has been employed as the bridge to alter the lipophilicity of the duplex and avoid the potential for enzymatic cleavage. The synthetic route involved the synthesis of a 3'-phosphorylated, nicked double-stranded precursor with the final internucleotide bond being formed chemically using a water soluble carbodiimide. These bridged duplexes have high thermal dissociation temperatures, and the Tm for a triethylene-bridged 20 base pair duplex was higher than that for the corresponding pentathymidylate-bridged duplex. EcoR I endonuclease cleaved a ligated, bridged duplex at a slower rate than the corresponding unmodified duplex, whereas the unligated, bridged duplex was cleaved more rapidly. Sufficient amounts of the bridged octamer and dodecamer were prepared for proton NMR spectroscopic studies, and 2D COSY and NOESY spectra were obtained. The results indicate that the ligated duplex has a B-form conformation. PMID- 7849076 TI - Fluorogenic N-nitrosoamides: active-site labeling reagents for chymotrypsin-like proteases. AB - Two fluorogenic N-nitrosoamides, N-nitroso-N-((7-methoxycoumarin-4-yl)methyl)-N' isobutyrylalaninamide (6a) and N-nitroso-N-((6-methoxyquinolin-2-yl)methyl)-N' isobutyrylalani namide (6b), were synthesized. Both N-nitrosoamides inhibited alpha-chymotrypsin irreversibly; they show promise as labeling reagents for the active sites of chymotrypsin-like proteases. PMID- 7849077 TI - Immunoassay reagents for thyroid testing. 1. Synthesis of thyroxine conjugates. AB - Immunoreagents were designed to improve the performance of a commercial fluorescent polarization immunoassay for thyroxine. The thyroxine immunogen was prepared by selective coupling of N-acetyl-L-thyroxine to BSA via an aminocaproic acid spacer arm. The fluorescent tracer was prepared by a multistep reaction sequence which relied on extensive use of orthogonal protecting groups. PMID- 7849078 TI - Use of psoralens for covalent immobilization of biomolecules in solid phase assays. AB - The ability of compounds to adsorb passively to hydrophobic polymer surfaces composed of, e.g., polystyrene generally is restricted to limited types of molecules such as proteins. Some proteins, many peptides, polysaccharides, oligonucleotides, and small molecules as well as pro- and eucaryotic cells cannot adsorb directly to such surfaces. Also, solid phase adsorbed antigens, antibodies, or gene probes may not be recognized by its corresponding ligand due to denaturation or steric hindrance of the molecular tertiary structure. Covalent binding, on the other hand, orientates all immobilized compounds in a defined way on the solid phase, thereby exposing the interacting sites on the enzymes, antibodies, gene probes, etc. Here we describe a method for modifying a polymer surface by contacting the polymer with derivatives of psoralen under irradiation with long-wavelength UV light. The psoralen derivatives were immobilized covalently on the polymer surface by this process. The psoralen molecules was conjugated to appropriate chemical linkers, incubated in aqueous solutions, and irradiated with UV light. This resulted in solid phase introduction of functional groups such as, e.g., amino groups on the polystyrene surface. The functional groups could subsequently be used for immobilization of biomolecules using conventional cross-linker technology. The method only involved premodification of the psoralens to be immobilized whereas no pretreatment of the polymer was required. Psoralen modified microtiter plates seems to have future application for the development of solid phase hybridization and immunoassays. PMID- 7849079 TI - Synthesis of oligoarginine-oligonucleotide conjugates and oligoarginine-bridged oligonucleotide pairs. AB - Conjugates consisting of oligoarginine peptides linked to oligodeoxynucleotides have been synthesized, including a new type of conjugate, in which a pair of oligonucleotides is bridged by a cationic peptide. Two different 9-mer oligonucleotides were conjugated to the terminal cysteine residues of the peptide series H-Cys-(Arg)n-Cys-NH2 (n = 3, 5, 7). Different thiol protecting groups were utilized on the amino- and carboxy-terminal cysteine residues of the peptide to allow selective attachment to the 3'- or 5'-terminus of each specific oligonucleotide. The conjugates containing oligoarginine peptides were purified by anion-exchange chromatography, and their structures were confirmed by polyacrylamide gel electrophoresis and amino acid analysis. PMID- 7849080 TI - Antitumor combilexin. A thiazole-containing analogue of netropsin linked to an acridine chromophore. AB - We report the synthesis, DNA-binding properties and antitumor activity of ThiaNetGA, a hybrid molecule in which are conjugated a thiazole-lexitropsin and an intercalating anilinoacridine chromophore. This combilexin molecule binds to DNA via a bimodal process involving minor groove binding of the lexitropsin moiety and intercalation of the acridine moiety. The uptake and distribution of the hybrid in L1210 leukemia cells were investigated by ESR spectroscopy using a spin-labeled derivative. The nitroxide-containing conjugate accumulates preferentially in the cell nuclei and rapidly saturates the nuclear receptor sites. Both in vitro and in vivo assays indicate that the drug is practically nontoxic but exhibits moderate antitumor activity against P388 leukemia cells in mice. PMID- 7849082 TI - Improved method for preparing N-hydroxysuccinimide ester-containing polymers for affinity chromatography. AB - N,N,N',N'-Tetramethyl(succinimido) uronium tetrafluoroborate is proposed as a reagent of choice for the activation of carboxyl groups and formation of N hydroxysuccinimide esters on polymers. Unlike conventional methods which generate unstable gels, the reaction is appropriate for hydroxy-containing resins like Sepharose, cellulose, and dextran. The yields of activation and subsequent coupling capacity for ligands and proteins are very high. The respective columns can be used for affinity chromatography and immobilization of proteins. PMID- 7849081 TI - Fc site-specific labeling of immunoglobulins with calf intestinal alkaline phosphatase. AB - A strategy is described for the site-specific conjugation of alkaline phosphatase to the Fc region of immunoglobulins. Mild oxidation of immunoglobulins by sodium periodate followed by reductive amination with excess cystamine and sodium cyanoborohydride covalently attaches cystamine specifically to the oligosaccharide chains of the antibody's Fc region. The disulfide bonds of the conjugated cystamine moieties are then reduced to free thiols with a low concentration of dithiothreitol. The thiol-modified antibodies (typically containing three to four thiols per Fc region) are then brought into contact with maleimide-functionalized alkaline phosphatase to form antibody-alkaline phosphatase conjugates. The Fc site-specific conjugation methodology was optimized and successfully applied to a number of different monoclonal and polyclonal antibodies. The conjugates prepared show assay performances superior to those prepared by more conventional means. Evidence obtained indicates that this superior conjugate performance results from total retention of the antibody's antigen binding activity following the Fc site-specific conjugation procedure. PMID- 7849083 TI - Regulation of normal and transformed tracheobronchial epithelial cell proliferation by autocrine growth factors. AB - Several peptide growth factors have been identified as autocrine regulators of normal tracheobronchial epithelial cells, including the transforming growth factors alpha and beta. Using in vitro tissue culture models of multistep neoplastic transformation as well as cell lines derived from human bronchogenic tumors, a significant number of growth factors have been found to function as autocrine factors for neoplastic tracheobronchial cells as well. In several instances, the regulation of the autocrine pathway is disrupted in neoplastic tracheobroncial cells compared with their normal counterparts. These results indicate that there are multiple aberrations in growth factor pathways occurring in tracheobronchial epithelial cells during progression to the neoplastic phenotype. PMID- 7849084 TI - Chromosome fragility and instability in human cancer. AB - The development of cancer is a multistep process triggered by physical, chemical, or biological carcinogenic factors, with the progression to an invasive phenotype requiring cumulative genetic alterations. Not all cellular genomic sequences are equally susceptible to carcinogenic factors or involved in pathologically relevant genetic alterations. Because of structural chromatin organization and DNA replication, certain genomic regions exhibit an increased fragility and tendency to recombination. At these regions, called fragile sites, there is a convergence of specific deletions, translocations, chemically induced lesions, and virus integrations. Isolation and cloning of sequences at fragile sites are important to a better understanding of the carcinogenesis process and to development of preventive measures. PMID- 7849085 TI - Retroviral determinants of leukemogenesis. AB - The slowly transforming, leukemogenic retroviruses of humans and other mammals induce malignant disease after prolonged latency but lack an oncogene to which their malignant potential can be attributed directly. The leukemogenic activity of these retroviruses can be attributed to at least three factors, including (1) transcriptional regulatory sequences in the long terminal repeat: (2) the insertional mutagenesis of cellular protooncogenes, thus activating their malignant potential; and (3) the actions of structural and regulatory proteins encoded by viral genes. The goal of this review is to summarize recent findings regarding the roles of these factors in retroviral leukemogenesis. The focus of the review is on the slowly transforming, leukemogenic retroviruses of mammals, including humans and experimental animals. PMID- 7849086 TI - The nature of Reed-Sternberg cells: phenotype, genotype, and other properties. AB - The most recent sophisticated investigations have provided new and revealing but also contradictory and controversial informaiton on the biological nature and the cellular origin of Hodgkin and Reed-Sternberg (H-RS) cells. Immunophenotypic analyses have shown consistent expression of CD15, CD30, CD74, and HLA-Dr antigens, but generally lack of T- or B cell-associated markers in H-RS cells. The H-RS cells are also devoid of many monocyte/macrophage-associated antigens. Molecular genetic studies have demonstrated heterogeneous findings with respect to rearrangements of T-cell receptor and immunoglobulin genes. Only a small percentage of the cases have rearrangements; this cannot always be attributed to the threshold of sensitivity of the method and/or the scarcity of the malignant cells in tissues examined. The H-RS cells do not express transcription factors such as BSAP, TCF-1, and GATA-3, known to be associated with lymphoid cells. It appears that evidence to support a lymphoid origin for H-RS cells is still lacking. On the contrary, the mechanism responsible for the unique clinical and histopathologic alterations associated with this disease has become clear. The H RS cells have been shown to secrete IL-1, IL-5, IL-6, IL-9, TNF-a, M-CSF, and TGF b, and, less frequently, IL-4 and G-CSF. These cytokines are likely to be responsible for the increased cellular reaction and fibrosis observed in tissues involved by HD and for the immunosuppression in patients with HD. Like most lymphomas, the etiology or pathogenesis of HD remains unknown. The Epstein-Barr virus (EBV) genomes are clonally integrated in the H-RS cells of about half the cases. The significance of these findings, whether EBV is a causative agent or an epiphenomenon, remains to be elucidated. PMID- 7849087 TI - Recent developments in the molecular genetic understanding of breast cancer. AB - The molecular genetic characterization of breast cancer has implicated or identified the involvement of at least 10 distinct gene alterations in the genesis or progression of this disease. The genes involved fall into three distinct classes, possibly reflecting their particular function in the tumorigenic process. First, there is a class of genes that is being amplified to various levels in clinically manifest breast cancer, most conspicuously c-neu, c myc, and cyclin D1. Second, an as-yet unknown number of genes are targets for loss of heterozygosity or allelic imbalance events on a number of different chromosomes. Presumably, this reflects the presence of tumor suppressor genes located on chromosomes 3p, 6q, 16q, 17, and possibly a few additional chromosomes. Finally, at least three genes are implicated to confer heritable predisposition to breast cancer. These include the p53 oncogene on 17p, an as yet unknown gene on 17q, and at least one locus outside these regions. While a number of presently unknown genes will soon be identified and cloned, it is becoming evident from genetic mapping studies that the complexity of gene involvement in breast cancer has not yet seen its very limits. A comprehensive multidisciplinary molecular profiling of a large series of tumors of various histological subtypes may aid in understanding how the different genes may cooperate to cause breast cancer. PMID- 7849088 TI - Rat tumor cytogenetics: a critical evaluation of the literature. AB - Cancer cytogenetics is a valuable tool for the analysis of cellular and molecular aberrations during malignant transformation and tumor progression. The rat has served as an important experimental model to investigate various steps in oncogenesis. An attempt was made to compile data on rat tumor cytogenetics from previously published data in order to provide a basis for further research, especially when combining classic and molecular cytogenetics, a yet underdeveloped area of research in rat tumorigenesis. The wealth of data presented here provides a contrast to its impact on biological specificity. Because of the different experimental procedures involved with tumor induction and the application of carcinogens at relatively high dosages, as well as occasional less than careful histological documentation, a delineation of unambiguous chromosome alterations, critical in the process of carcinogenesis, is rare in the rat. Future studies should be performed with spontaneously arising rat tumors and/or tumors after low, single-dose carcinogen exposure in order to reduce unspecific karyotype alterations not intrinsically related to tumor initiation and progression. Short-term culture or early passages in vitro should be methods of choice, especially for solid tumors, to avoid erroneous karyotype analyses because of contaminating normal cells. The combined karyological and molecular genetic approach to an analysis of tumor-specific changes, still hindered by an almost complete lack of cell type-, chromosome-, or gene-specific molecular probes for the rat, should become a focus of research in order to continue having the advantages this species offers for stage-specific analysis of tumorigenesis. PMID- 7849089 TI - The tumor-promoting effect of wounding: a possible role for TGF-beta-induced stromal alterations. AB - From clinical, chemical carcinogenesis and transgenic animal studies, it is evident that wounding has a tumor-promoting effect. We discuss the role of TGF beta (with special emphasis on TGF-beta 1) in this process and suggest that stromal alterations during wound healing, induced by TGF-beta, can be an important determinant of tumor growth. A tumor and a wound both require similar stromal microenvironments. Thus, a chemically initiated or an oncogene-expressing cell could be complemented to grow into a tumor if it finds itself in a hospitable wound-healing stroma. PMID- 7849090 TI - The c-erbB-2 protein in oncogenesis: molecular structure to molecular epidemiology. AB - The c-erbB-2 (HER-2, neu) oncogene has been implicated frequently in many human tumors. This oncogene codes for a 185-kDa protein that functions as a transmembrane growth factor receptor. Overexpression of the normal protein or point mutations in the transmembrane domain of the protein have been shown to have a transforming effect. Molecular structure studies of the transmembrane domain provide a plausible explanation for this transforming effect in both cases and relate this to the process of receptor dimerization in the membrane, degradation of the protein with release of the extracellular domain (ECD) into the extracellular environment, and aberrant signal transduction. The release of the ECD into the extracellular environment provides a potential biomarker for the study of signal transduction at the molecular level in vivo. The ECD can be quantitated immunologically in the serum of individuals with cancers associated with p185 overexpression and in individuals at risk for the development of such cancers and can be used to distinguish these individuals from normal, healthy controls. Identification of such individuals by their serum ECD levels combined with specific chemotherapeutic/chemoprophylactic interventions could allow for improvement treatment and prevention of c-erbB-2-related cancers. PMID- 7849091 TI - Yes, Abbey, you are right. PMID- 7849092 TI - Gene therapy and genetic diseases: revisiting the promise. PMID- 7849093 TI - Primary fibroblasts from human adults as target cells for ex vivo transfection and gene therapy. AB - Diploid fibroblast (dFb) cultures were established from a total of 106 skin and serosa biopsies of human adults. Using an optimized enzymatic dissociation procedure, 10(11) dFb/cm2 skin were obtained from patients younger than 60 years after an average time of 89 +/- 8 days, with a mean population doubling time of 3.87 +/- 1.4 days. Enzymatic dissociation of skin biopsies yielded cultures of significantly higher growth capacity of dFb than those prepared by mechanical dissociation followed by spontaneous outgrowth of cells. The plating efficiency that may be crucial for clonal selection of transfected cells was negligible when dFb were plated without feeder cells at low density, while it was enhanced to 9 24% by the addition of a feeder layer of irradiated human embryonal fibroblasts. DFb secreted various cytokines with spontaneous release of interleukin-6 (IL-6) in high quantities of up to 20 ng/10(6) cells/24 hr. In addition, one-third of the culture secreted substantial amounts of granulocyte-macrophage colony stimulating factor (GM-CSF), while low amounts of tumor necrosis factor-alpha (TNF-alpha) were detectable in some cases after irradiation of the cells. Comparison of various transfection methods by a transient luciferase expression assay demonstrated that receptor-mediated gene transfer was approximately 10-fold more efficient than cationic lipofection of dFb, while electroporation resulted in substantially less expression of the reporter gene. We conclude that primary dFb can be obtained reproducibly from human adults and represent a suitable target cell population for receptor-mediated gene transfer and cationic lipofection.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7849094 TI - Gene transfer in baboons using prosthetic vascular grafts seeded with retrovirally transduced smooth muscle cells: a model for local and systemic gene therapy. AB - Prosthetic vascular grafts containing retrovirally transduced autologous vascular smooth muscle cells were studied as a model for introduction of human genes into baboons. Retroviral vectors encoding beta-galactosidase (beta-Gal) (LNPoZ) or human purine nucleoside phosphorylase (LPNSN-2), a control gene, were used for ex vivo transduction of autologous baboon smooth muscle cells obtained from vein biopsies. Transduced cells were placed into a collagen solution and seeded into the interstices of polytetrafluoroethylene vascular grafts. Endothelial cells were then seeded onto the luminal surface of the grafts to reduce thrombus formation. One LNPoZ-seeded graft and one LPNSN-2-seeded control graft were implanted bilaterally into the aorto-iliac circulation of each of 4 animals. All grafts remained patent until they were removed after 3-5 weeks and examined histochemically for vector-expressing cells. All histological cross-sections from the beta-Gal vector seeded grafts contained cells staining blue with the X-Gal chromogen. For the four grafts, the mean fraction of LNPoZ expressing cells was 10%, with a range of 2-20%, while no sections from the control grafts contained stainable cells. Smooth muscle cells expressing the reporter gene were localized within the graft wall but not in the newly forming intima or outer capsule of fibrous tissue. Implantation of transduced cells within this type of vascular graft may provide a useful approach for long-term local and systemic gene therapy. PMID- 7849095 TI - Prolonged transgene expression in cotton rat lung with recombinant adenoviruses defective in E2a. AB - Recombinant adenoviruses have tremendous potential for gene therapy of cystic fibrosis (CF) lung disease. First-generation recombinant viruses, rendered replication defective by deleting E1, have been associated with high-level recombinant gene expression in airway epithelial cells when administered directly to the lung. Experience in mice and non-human primates indicates that transgene expression is transient (i.e., lasting less than 21 days) and associated with the development of inflammation. We suggest an hypothesis to explain these findings that is based on expression of viral proteins in genetically modified cells that leads to destructive cellular immune responses and repopulation of lung epithelia with non-transgene-containing cells. This hypothesis has been evaluated in the current study using the cotton rat model. Instillation of the first-generation lacZ virus, H5.010CBlacZ, into cotton rat airway led to high-level gene expression in conducting and respiratory airway that was transient and associated with a substantial mononuclear, CD8-dominated, infiltrates. Treatment of the animals with cyclosporine blunted the inflammatory response and prolonged recombinant gene expression in both conducting and respiratory airways. Expression of viral early and late genes was detected in a subpopulation of lacZ expressing epithelial cells of conducting airway and alveoli. Instillation of virus into cotton rat tracheal xenografts grown in athymic nu/nu mice led to efficient and stable transgene expression in the absence of pathology, underscoring the importance of T cell-mediated immunity. A recombinant adenovirus was constructed that is disabled in its capacity to replicate by the introduction of a temperature-sensitive mutation in the E2a gene as well deletion of E1 sequences. Instillation of this virus into cotton rat airway led to high-level transgene expression that was more stable than that achieved with the first generation virus and was associated with less early and late gene expression as well as a diminished infiltration of CD8+ T cells in conducting airway epithelium. Interestingly, the introduction of the E2a mutation had no effect on the persistence of transgene expression, the pattern of late viral gene expression, nor the CD8+ T cell response within alveolar cells. These data suggest that cell-specific variation in the cell biology of recombinant adenoviruses exists in the lung. The present studies in cotton rats confirm the role of cellular immunity in the biology of adenovirus-mediated gene therapy to the lung and suggest that modifications in the design of recombinant adenoviruses to minimize or ablate transgene expression will be useful in improving the potential of this technology for gene therapy of CF. PMID- 7849096 TI - Systemic delivery of secreted protein by grafts of epidermal keratinocytes: prospects for keratinocyte gene therapy. AB - Grafts of autologous keratinocytes genetically altered to secrete a new gene product are a potential vehicle for gene therapy. To consider the feasibility of such an approach, we have examined the ability of keratinocytes to secrete and deliver apolipoprotein E (apoE) to the circulation of mice bearing grafts of human keratinocytes. The grafted keratinocytes secreted two forms of apoE, an endogenous apoE encoded in the genome and a recombinant apoE encoded in a transfected gene construct. In vitro studies showed that endogenous apoE was secreted from basal keratinocytes whereas recombinant apoE was secreted from basal as well as suprabasal cells. On the basis of amounts of recombinant apoE present in the serum of grafted mice, we estimate that a graft occupying 2% of the surface area of an adult human would deliver 6.5-8.3 mg of recombinant apoE protein per day. PMID- 7849097 TI - Adenoviral vector-mediated gene transfer into sheep arteries using a double balloon catheter. AB - The potential for catheter-based in vivo delivery of genetic material to the arterial wall is incompletely explored. We evaluated the level of recombinant protein production as well as the anatomic distribution and duration of gene expression following adenoviral vector-mediated gene transfer into sheep arteries via a double balloon catheter. Catheters were positioned in the carotid or femoral arteries of 20 sheep via a combined percutaneous and surgical approach, and virions infused over a 30-min period. Three days later, recombinant gene expression was identified in approximately 30% (range 0-80%) of the luminal endothelial cells within the targeted area of the artery. Persistent recombinant protein expression was identified histochemically for up to 4 weeks, although the number of positive cells decreased steadily. High levels of both beta galactosidase (beta-Gal) activity and protein (mean 20 mU and 44 ng per vessel) were measured in vessel extracts 3 days after gene transfer, again decreasing significantly over a 4-week period. Transgene expression was limited almost entirely to the intima and adventitia; adventitial gene transfer occurred virtually exclusively along the vasa vasorum. In comparison to previous studies of catheter-based gene transfer, adenoviral vectors delivered by double balloon catheter resulted in a particularly high efficiency of endothelial cell gene transfer. The efficiency and amount of recombinant gene expression achieved in this study suggest that catheter-based gene delivery may eventually be applicable to the treatment of focal human arterial disease. PMID- 7849098 TI - Codon context and protein synthesis: enhancements of the genetic code. AB - The sequence around stop codons strongly affects termination efficiency and the probability of alternative events to termination such as frameshifting and stop codon readthrough. Where tRNA suppressors of nonsense codons are present, both the efficiency of suppression and of the termination process appear to be affected by stop codon context. Since context can affect suppressor tRNA function directly, an influence on sense codon translation or suppression might be expected, but has not yet been clearly demonstrated. Statistical analyses of coding sequences indicate non-random contexts for both stop and sense codons, and non-random occurrence of codon pairs. Highly expressed genes show clear preferences among stop codons and their contexts, whereas inefficient stop signals are exploited in a variety of recoding processes. PMID- 7849099 TI - Interest of photochemical methods for induction of lipid peroxidation. AB - Lipid peroxidation, which plays a part in a wide variety of biological processes, is an integral process in the oxidation of unsaturated fatty acids via a radical chain reaction. Among the various species which may induce this reaction in vivo, reactive forms of oxygen such as peroxide anion, the hydroxyl radical and singlet oxygen are of cardinal importance. These species may be generated enzymatically, chemically or by various radiochemical and photochemical reactions. We present here the advantages of photochemical induction of peroxidation, and we describe the principles of the reactions, the photosensitizers that can be employed to generate the various reactive species of oxygen, and the techniques, direct (ESR) or indirect (specific traps), used to detect the reactive species. Photosensitization can induce the formation of a whole gamut of products of lipid peroxidation: conjugated dienes, aldehydes, hydroperoxides, etc. The relative proportions of the various hydroperoxides of fatty acids or cholesterol depend on the nature of the reactive species involved. Utilization of photochemical reactions is an effective and clean way of inducing peroxidation, allowing fine control of both initiation and orientation. PMID- 7849100 TI - Identification of the 30 kDa polypeptide in post mortem skeletal muscle as a degradation product of troponin-T. AB - Although a 30 kDa polypeptide frequently is seen by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) analysis of post mortem (pm) skeletal muscle and in turn is used as an indicator of proteolysis, its origin has not been conclusively identified. We used antibodies to selected myofibrillar proteins, including some known to be degraded pm, to identify this polypeptide. The left side of eight beef carcasses was electrically stimulated (ES) within 1 h after slaughter, and the right side served as the non-stimulated (NS) control. The longissimus lumborum (LL) muscle was removed from the carcass at 24 h pm and was stored at 2 degrees C. Myofibrils were prepared from the LL muscle immediately after stimulation (0 day) and from the stored muscle sample at 1, 3, 7, 14 and 28 days pm for analysis of SDS-PAGE and Western blots. By SDS-PAGE, troponin-T (TN-T) decreased in amount more rapidly pm in ES samples than in NS samples. By SDS-PAGE, a 30 kDa band increased and became a prominent band by 7 days pm in both NS and ES samples. A monoclonal antibody (mAb) to TN-T labeled purified TN-T, as well as the TN-T in myofibrils, a prominent 30 kDa polypeptide and a family of lower molecular mass polypeptides in pm muscle. This mAb also labeled a 30 kDa band that had been electrophoretically purified from pm muscle.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7849101 TI - The N-terminal half of initiation factor IF3 is folded as a stable independent domain. AB - Initiation factor IF3 plays an essential role in the initiation of protein translation by binding to the 30S ribosomal subunit and selecting a proper tRNA(fMet)/initiation codon complex. The domain structure of IF3 from Escherichia coli has been investigated by limited proteolysis followed by mass spectrometry and protein sequencing of the resulting peptides. This analysis revealed a highly segmented structure with two independent domains connected by a charged linker peptide, highly susceptible to proteolytic cleavage. The N-terminal domain is very stable and comparison of its 2-D NMR spectrum with that of intact IF3 revealed that it retains its three-dimensional fold. PMID- 7849102 TI - Chain condensation in protein folding. AB - Three reactions (relaxation times: tau 1 = 140 +/- 8 ms, tau 2 = 840 +/- 30 ms and tau 3 = 30 + 3 s, at pH 7.0 at 25 degrees C) have been resolved by the stopped-flow kinetic method for the folding of the acid denatured staphylococcal nuclease (Chen et al (1991) J Mol Biol 220, 771; Biochemistry (1992) 31, 1483). Of the three reactions only the tau 2 reaction was dependent on the viscosity of the solution in a manner consistent with the diffusion/collision/coalescence model. Experiments with site-directed mutagenesis suggest that the forming of local structures by the electrostatic interactions between Glu75 and His121 and Lys9 may induce the chain condensation. PMID- 7849103 TI - Transfer and isomerization of the ribose moiety of AdoMet during the biosynthesis of queuosine tRNAs, a new unique reaction catalyzed by the QueA protein from Escherichia coli. AB - The enzyme QueA of E coli is involved in the biosynthesis of the hypermodified tRNA nucleoside queuosine. The enzyme catalyzes the synthesis of an epoxycyclopentane moiety and transfers this compound to specific tRNAs containing the queuosine precursor 7-(aminomethyl)-7-deazaguanine (preQ1). S adenosylmethionine (AdoMet) is the sole cofactor that is required for this reaction (Slany et al, 1993, Biochemistry 32, 7811-7817). To proof that the ribose moiety of AdoMet is the precursor of the epoxycyclopentane moiety, labeled AdoMet, was generated from different types of 3H ATP and methionine by the AdoMet synthetase enzyme (MetK) from E coli. The resulting 3H labeled AdoMet was directly used as the cofactor for the QueA reaction. Using [2,5', 8-3H]ATP, containing tritium at C5' of the ribose ring, resulted in an incorporation of radioactivity into preQ1 tRNA, whereas this was not the case when [2,8-3H]ATP was applied. A model for the reaction catalyzed by the S-adenosylmethionine:tRNA ribosyltransferase-isomerase QueA is proposed. PMID- 7849104 TI - Effects of plasminogen and interleukin-1 beta on bone resorption in vitro. AB - Inflammatory bone resorption, a characteristic feature of periodontal disease and rheumatoid arthritis, appears to be mediated by interleukin-1 beta (IL-1 beta). IL-1 beta has been shown to stimulate a wide range of proteolytic enzymes, including collagenases and plasminogen activators, in particular chondrocytes, synovial cells, and isolated osteoblasts. In this study, we have examined the hypothesis that IL-1 beta may stimulate bone loss by inducing the activity of plasminogen activators (PAs) in bone cultures. The latter would convert plasminogen to plasmin, which in turn can activate precursor procollagenase to collagenase. Active collagenase would then break down the bone collagen matrix. In the present study, release of 45Ca from fetal rat long bones in culture was studied in the presence of plasminogen and IL-1 beta. Plasminogen and IL-1 beta separately enhance resorption of fetal rat long bones in vitro. When plasminogen and IL-1 beta are added together at suboptimal levels, mainly additive effects are observed. The presence of heat-inactivated serum does not alter these results. These data tend to indicate that IL-1 beta is stimulating bone resorption through both PA-dependent and PA-independent pathways. PMID- 7849105 TI - High level expression of rat gamma-D-crystallin in Escherichia coli. AB - Gamma-crystallins have been implicated in various kinds of cataracts. In order to facilitate studies elucidating the molecular mechanism of cataractogenesis, large quantities of rat recombinant gamma-D-crystallin were produced in E coli. A full length cDNA clone coding for gamma-D-crystallin was isolated from a rat lens lambda gt11 cDNA library using a synthetic oligonucleotide as a probe. The coding region of this cDNA was inserted into a cloning vector pKK233-2 under the control of the trc promoter. The resulting construct, pKKCR91, was transfected into E coli to produce rat gamma-D-crystallin in an amount of 10-15% of the total bacterial proteins. The crystallin produced was purified to an apparent homogeneity as judged by SDS gel electrophoresis. The sequence of the N-terminal 11 amino acids of the purified crystallin was determined, showing that it is completely identical to that predicted from the cDNA sequence. Measurements of the far-UV CD spectra also revealed that recombinant rat gamma-D-crystallin thus produced retains a native conformational structure. PMID- 7849106 TI - Diadenosine 5',5"-P1,P4-tetraphosphate (Ap4A), ATP and catecholamine content in bovine adrenal medulla, chromaffin granules and chromaffin cells. AB - The level of diadenosine 5',5"-P1-P4-tetraphosphate (diadenosine tetraphosphate or Ap4A), catecholamines, ATP and other nucleotides has been investigated in perchloric acid extracts of bovine adrenal medulla, chromaffin granules and cultured chromaffin cells. As a control, the amount of Ap4A and ATP has also been measured in human blood platelets. The following values (nmol/mg protein) were found in adrenal medulla: Ap4A, 0.019 +/- 0.004; ATP, 109 +/- 11; ADP, 23.8 +/- 5.8; AMP, 11.3 +/- 1.5; p4A, 0.18 +/- 0.08; catecholamines, 460 +/- 57. The level of Ap4A, catecholamines and ATP (nmol/mg protein) found in chromaffin granules and in chromaffin cells were, respectively: (0.15 +/- 0.07; 2175 +/- 99; 531 +/- 66) and (0.22 +/- 0.14; 1143 +/- 277; 222 +/- 53). In all the cases investigated, the ratio catecholamines/ATP and catecholamines/Ap4A were around 5 and in the order of 10(3), respectively. The amount of Ap4A found here, in bovine adrenal medulla, chromaffin granules and chromaffin cells, is two orders of magnitude lower than previously reported. PMID- 7849107 TI - 2,4-D and alkaloid accumulation in periwinkle cell suspensions. AB - Omission of 2,4-D from culture medium during one subculture of Catharanthus roseus cells, strain C20, resulted in an increased alkaloid accumulation, without effect on growth. Alkaloid accumulation, rather than growth, seemed to be more sensitive to 2,4-D. 2,4-D inhibited alkaloid accumulation essentially during growth phase, but its inhibitory effect during this period was partially reversible. As this reversibility was underlined only during the stationary phase, this suggested that this action could be situated upstream in a terpenoid non-specific pathway. 2,4-D feeding showed that inhibition is weaker and weaker as the alkaloid accumulation period proceeds. Auxin action during this period could take place downstream in specific alkaloid pathways. The lower alkaloid accumulation obtained after loganic acid feeding compared to that obtained with secologanin and loganin could indicate that loganic acid methylation should be one of the 2,4-D target(s). PMID- 7849108 TI - Cyclic AMP regulation of annexins I, II, V synthesis and localization in cultured porcine thyroid cells. AB - Porcine thyroid cells cultured in the presence of TSH (0.1 mU/ml) or forskolin (10(-5) M) for 4 days display an increased annexin I, II, V biosynthesis when compared with unstimulated cells. Annexin I mostly accumulates in the cytosolic fraction and annexins II and V in the particulate fraction. TSH and forskolin affect in the same manner annexin biosynthesis and localization. In the TSH and forskolin treated cells PGE2 production is very low in comparison with the very high PLA2 activity observed in the dedifferentiated control cells. A strong inhibition of the PGE2 production is observed in control cells incubated with a purified annexin V preparation. These results suggest the existence, in porcine thyroid cells, of a cross-talk between the adenylyl cyclase system and the phospholipase A2 mediated pathways. Annexins' biosynthesis and localization are under the control of the adenylyl cyclase system and participate in this cross talk. PMID- 7849109 TI - Stress proteins in the polychaete annelid Nereis diversicolor induced by heat shock or cadmium exposure. AB - We have exposed the polychaete annelid Nereis diversicolor to heat shock or cadmium. Two-dimensional electrophoresis and fluorography techniques indicated the synthesis by the worms of at least 15 stress proteins including the universal one referred to as 'stress 70' and a lot of low molecular weight (LMW) proteins. 'Stress 70', synthesized by Nereis diversicolor in response to both stressors, appeared on fluorograms as an array of three charge isomers. We observed that most of the LMW stress proteins built up in response to heat shock were different from those observed after cadmium exposure. Furthermore, Nereis, which resists high levels of cadmium, did not appear to synthesize metallothioneins, small proteins known to prevent cellular damage by sequestering toxic metal ions. As no cadmium-binding proteins were visualized on fluorograms, the mechanism by which Nereis resists cadmium injury remains to be disclosed. PMID- 7849110 TI - Potential secondary structure at the translational start domain of eukaryotic and prokaryotic mRNAs. AB - In order to identify conserved potential secondary structures within translational start sites, mRNA sequences derived from different species were studied with programs able to depict such features. The potential secondary structure of 71 bases around the initiator AUG or AUGs in the coding sequences of 290 eukaryotic mRNAs was first examined and compared to 290 similarly analyzed regions derived from prokaryotic mRNA sequences (Nucleic Acids Res (1987) 15, 345 360). In both sets of sequences the initiator codon was often found to be in an open potential structure whereas a denser region characterized by nearly-periodic spacings defined the coding regions. Randomization of the sequences obliterated the observed patterns suggesting that the structure of the mRNA may determine these differences. Three sets of eukaryotic and prokaryotic mRNAs of approximately equal length were analyzed and found to preserve an open unpaired non-coding region 5' to the start codon. The start codon was found free of potential secondary structure in over 80% of all the sequences analyzed. These data, and study of mutants that restrict the accessibility of the start codon to the ribosomal initiation complex, suggest that both the prokaryotic and eukaryotic mRNA start sites must occur free of potential secondary structure for efficient initiation. A striking difference of the eukaryotic mRNA sequences analyzed was the high propensity of the coding region vicinal to the start codon to form secondary structures. Certain translation-defective mutants exhibit impaired formation of these secondary structures suggesting that the structure of the coding regions adjacent to the start codons of eukaryotic mRNAs may be an important, thus far unexamined, determinant of initiation. We propose that, for all genes studied, the transition in secondary structure between the coding and non-coding regions may be an important determinant of initiation. PMID- 7849111 TI - Proteins of the Thermus thermophilus ribosome. Purification of proteins from the large ribosomal subunit. AB - Special procedures have been developed to isolate and purify 26 of the 30 individual proteins of the large ribosomal subunit from Thermus thermophilus. Sixteen of them have been purified under non-denaturing conditions to be used for crystallization and further structural studies. These proteins have been characterized by their amino acid content, molecular mass, UV-spectrum and extinction coefficient. An additional 10 proteins have been purified by reverse phase chromatography. Thirteen proteins have been identified by homological E coli proteins. PMID- 7849112 TI - A direct spectrophotometric method for monitoring the kinetics of T-cell cytolysis. AB - A simple and sensitive assay is demonstrated for monitoring the kinetics of T cell cytolysis by direct spectrophotometric detection of genomic DNA and protein released from target cells. The kinetics of cell lysis has been quantitatively evaluated and shows good agreement with results obtained by use of extracellular fluorescent reporter molecules, or enzyme-coupled assays. PMID- 7849113 TI - Gynaecological disorders and human immunodeficiency virus infection. AB - It is increasingly apparent that the differences in the prevalence and severity of various gynaecological conditions are a function of immunosuppression and differences in behavioural factors, rather than a direct effect of HIV itself. Women infected with HIV will present with their gynaecological disorders initially to their carers in both primary care and genitourinary medicine clinic settings. It is therefore essential that all those involved in the management of these women are aware of the interactions between HIV infection, immunosuppression and various gynaecological conditions so that they may be appropriately managed. PMID- 7849114 TI - Quality of care in genitourinary medicine. PMID- 7849115 TI - Problems with non-gonococcal urethritis. PMID- 7849116 TI - Why do antenatal attenders decide to have the HIV antibody test? AB - The aim of the study was to investigate factors influencing the parturient woman's decision to accept or decline the HIV antibody test in the antenatal clinic. Eighty-eight women attending an antenatal clinic, in a central London hospital, for an appointment at 28-32 weeks of pregnancy were given a structured face to face interview. Results indicated that 36% (n = 32) had elected to be tested. Reasons for declining included assumption of no risk, being in a stable relationship, not wanting to think about HIV when pregnant and not wanting to know if HIV positive. Reasons for accepting included fears for health of the baby and fears for own health. 52% (n = 46) had discussed the test with their partner, most of whom had agreed with the woman's decision or left the decision to her. Only 31% of the women were aware they had been automatically tested for syphilis. Knowledge about vertical transmission was poor. Anxiety levels of those tested and those not tested were not significantly different nor did either group differ over time. The groups did not differ on demographic variables, transmission knowledge or perceived likelihood of infection. Most women elected not to be tested and reasons around the decision are very individualistic and varied. HIV testing does not appear to cause anxiety when it is offered on a voluntary basis. Knowledge of routine testing and of vertical transmission is poor and should be the focus of health education intervention. PMID- 7849117 TI - Bacterial vaginosis in a district genitourinary medicine department: significance of vaginal microbiology and anaerobes. AB - The aim of this study was to correlate the significance of vaginal microbiology, in particular its anaerobic component, to the presence of bacterial vaginosis (BV), and to review the clinical criteria used in the diagnosis of this condition. Ninety-two female patients who received routine STD screening were studied. After routine history, presence and character of vaginal discharge and vaginal pH were noted, an amine test performed, and a wet stain observed microscopically. Routine Gram stain smears and cultures were prepared. BV was diagnosed clinically in 28 (30%) of our sample, and Gardnerella vaginalis was cultured in 41 patients (45%). Both clue cells and anaerobes were closely associated with each other and both mutually exclusive with the presence of lactobacilli on Gram stain (P < 0.001). BV was found to be strongly associated with the presence of clue cells on the wet film, anaerobes and G. vaginalis. In conclusion, bacterial vaginosis is not only strongly associated with the presence of G. vaginalis in the vaginal flora, but more strongly with the presence of anaerobes. The study suggests that the microaerophile G. vaginalis is a commensal organism in a significant proportion of sexually active women. If the aerobic status of the healthy vagina is disrupted, anaerobes (including Gardnerella) will flourish, producing the clinical picture of bacterial vaginosis. PMID- 7849119 TI - High cumulative incidence of genital herpes amongst HIV-1 seropositive heterosexuals in south London. AB - The cumulative incidence of sexually transmitted diseases (STD) in a cohort of 51 (35 female, 16 male) HIV-1 seropositive STD clinic attenders who had acquired HIV 1 infection via heterosexual transmission was investigated through a retrospective review of the case notes. The women were followed up for a mean 11.6 months and the men for 18 months. Thirty-one (88%) of the women and 13 (81%) of the men were of sub-Saharan African origin. Approximately half of the subjects were first diagnosed as HIV-1 positive with CD4 counts < 200 x 10(6)/1 and a quarter with CD4 counts < 50 x 10(6)/1. STDs detected in women were: genital herpes 15 (43%), candida 12 (34%), bacterial vaginosis 9 (25%), and in men: genital herpes 6 (38%), non-gonococcal urethritis 4 (25%). No cases of gonorrhoea were detected. At the time of first diagnosis of genital herpes at the clinic, the mean CD4 count in women was 275 x 10(6)/1 and in men 285 x 10(6)/1. Genital herpes was the AIDS defining diagnosis in 3 of the women. The recognized risk of HIV transmission via genital lesions should be stressed in HIV-1 positive subjects with genital herpes. The incidence of other STD was low--both knowledge of HIV status and safer sex counselling may limit unsafe sexual behaviour and should be evaluated further as a strategy for limiting the spread of HIV-1 infection. PMID- 7849118 TI - A preliminary evaluation of a prototype western blot confirmatory test kit for syphilis. AB - A prototype Western blot kit was evaluated as a confirmatory test for syphilis using 131 sera characterized by other serological tests for syphilis. There were 114 treponemal sera (including 94 cases of early syphilis, 83 of which were untreated) and 17 non-treponemal problem sera (11 gave false positive reactions on screening with the TmpA recombinant antigen enzyme immunoassay (EIA), 3 gave false positive fluorescent treponemal antibody absorbed (FTA-abs) tests, and 3 false positive Captia Syphilis G EIA results). Based on the manufacturer's criteria of reactivity in multiple bands for designating a positive result the Western blot test gave a sensitivity of 99.1% (113/114) and a specificity of 88.2% (15/17) when indeterminate reactions were scored positive and 98.2% (112/114) and 100% (17/17) when indeterminate reactions were scored negative. Sensitivity was high in both treated and untreated infection. Corresponding sensitivities for the TPHA and FTA-abs when equivocal reactions were scored negative were 97.5% (111/114) and 99.1% (113/114). The high sensitivity of the FTA-abs in this study is probably due to the large number of untreated primary infections. Our results with the Western blot, confirm earlier studies using 'in house' test systems and, support a role for a commercial Western blot test in the confirmatory diagnosis of syphilis. Further studies are required to confirm the high specificity and sensitivity of the kit in a larger series including a wider variety of non-treponemal cases as well as patients with untreated and treated infection. PMID- 7849120 TI - A comparison of AIDS-defining events and subsequent CDC stage IV events in IDUs and gay men. AB - The two major risk groups for acquisition of HIV in the UK are gay men and IDUs. Individuals from these risk groups vary in a number of respects in their life style, which have the potential to affect the course of their HIV disease. This study compares gay men and IDUs from the Lothian Region of Scotland with respect to their AIDS defining diagnosis and subsequent CDC (Centers for Disease Control) stage IV events. Comparisons were made between the two risk groups for their AIDS defining diagnosis by performing chi square tests, Mann-Whitney tests and logistic regression. Subsequent CDC stage IV events were analysed using ordinal logistic regression and Cox regression. 89 IDUs and 56 gay men were included in the analysis. Oesophageal candida was a commoner AIDS-defining diagnosis in IDUs than gay men and Kaposi's sarcoma was diagnosed more frequently in gay men than IDUs. Subsequently oesophageal candida was also commoner in IDUs and CMV retinitis was seen more frequently in gay men. The role of prophylaxis and differences in diet are discussed as possible causes of the observed differences in the incidence of oesophageal candida. The higher incidence of CMV retinitis in gay men probably reflects the high level of sexual acquisition of CMV. PMID- 7849121 TI - Prevalence and incidence of syphilis and its association with HIV-1 infection in a population-based study in the Kagera region of Tanzania. AB - Population-based prevalence and incidence studies on HIV-1 infection were started in the Kagera region of Tanzania in 1987. The prevalence and incidence of infection with Treponema pallidum was studied to enable development of better strategies for STD control. Serological diagnosis of a past or treated infection with Troponema pallidum was made by seropositivity only to TPHA testing while active syphilis was diagnosed by seropositivity to both VDRL and TPHA tests. Seroconversion was measured in 1989 by finding TPHA serologically positive individuals during the follow-up period among the initially seronegative study population of 1987. The overall prevalence of active syphilis in the total sample of adults in the region was found to be 5.9% while that of past syphilis was 13.5%. The association between the prevalence of HIV-1 infection and syphilis of both types was found to be highly significant. However, the association between one pre-existing infection and seroconversion in the other was present but not statistically significant. The overall incidence of syphilis based on seroconversion in a cohort of adults in the region was found to be 11.6 per 1000 person-years at risk. In view of these findings, syphilis is a significant health problem in the region with a high level of transmission and efforts should be made to control it. Intervention studies should use these base-line data and monitor changes in syphilis incidence which may indicate changes in sexual behaviour. Such indicators could also be useful for evaluating the impact of interventions directed at reducing the transmission of HIV, syphilis and other STDs in the region. PMID- 7849122 TI - Screening for tuberculosis in an east London HIV clinic. AB - A prospective study was carried out to assess the value of routine skin tuberculin testing and chest radiography in HIV seropositive patients, attending the Genitourinary Medicine (GUM) clinic between July 1991-May 1992. 144 consecutive HIV seropositive patients had tuberculin Tine tests and chest radiographs performed. Ten patients were treated for active tuberculosis (TB) on the basis of abnormal radiography with or without strongly positive (Grade 3/4) skin tuberculin tests. A further 10 patients received prophylaxis on the basis of abnormal chest radiography consistent with previous tuberculous infection or strongly positive tuberculin tests. Active or previous tuberculous infection was found in the UK born Caucasian homosexual population as well as in injecting drug users and patients who were born in areas of high TB prevalence. Screening for TB in HIV seropositive patients is important both for detecting asymptomatic tuberculous infection and for recognizing patients at risk for reactivation of latent TB. We showed a high pick-up rate with 20 out of 144 patients having treatment as a result of screening. PMID- 7849123 TI - Concomitant HIV and mycobacterial infection in Ireland, 1987-92. AB - A six-year retrospective review of concomitant HIV and mycobacterial infection in the Republic of Ireland is presented. A total of 42 culture proven mycobacterial infections were seen in 40 different HIV-infected patients. There were 24 infections with Mycobacterium tuberculosis (M.tb) and 18 infections with mycobacteria other than tuberculosis (MOTT), a significantly higher rate of MOTT infections in Ireland compared to a study from 1962-1981. The detection rate for all mycobacterial infections had an annual upward trend with a 4-fold increase between 1987 and 1992. In homosexuals, MOTT infections occurred more frequently than M.tb, while the reverse was true for IVDUs. Twenty per cent of the infections were seen in patients recently incarcerated. Relapse of tuberculosis occurred in 42.9% (3/7) of non-compliant patients, 2 of whom developed rifampin resistant strains of M.tb. No patient compliant to their regimen had a relapse in disease. The overall survival of patients after diagnosis of M.tb was significantly better than those with MOTT infections, with respective one-year survival rate of 79% and 36% (log rank test, P = 0.006). PMID- 7849124 TI - Screening for cervical abnormalities in women with anogenital warts in an STD clinic: an inappropriate use of colposcopy. AB - An audit of the use of colposcopy in women with anogenital warts was performed. Fifty women attending a clinic for sexually transmitted diseases in a District General Hospital with anogenital warts were examined by cervical cytology and colposcopy for cervical infection by human papillomavirus (HPV) or epithelial abnormality indicating cervical intraepithelial neoplasia (CIN) or both. Collated results showed a high prevalence of both conditions in these 50 women; 20 (40%) had evidence of cervical infection by HPV and 11 (22%) epithelial abnormalities consistent with CIN 1 or 2. However, neither CIN 3 nor invasive disease was detected. Colposcopy in this setting was shown to be a specific but insensitive tool and its role in the routine management of women with anogenital warts at our institution is not warranted. PMID- 7849125 TI - Sentinel surveillance of HIV-1 infection in Tamilnadu, India. AB - The objective was to determine the time trends in the prevalence of HIV infection and to evaluate appropriate preventive intervention in different population groups. Sentinel surveillance of HIV-1 infection by anonymous unlinked technique was carried out in Tamilnadu from December 1989 to March 1993. The sentinel population monitored were attendees of STD clinics, blood donors and antenatal mothers. The results of HIV seropositivity were compared for each 6-month period. During the study period there was 10-fold rise of HIV seropositivity among STD patients (1% to 10%), 2-fold rise among antenatal attendees (0.37% to 0.76%), and 3-fold rise in blood donors (0.24% to 0.72%). There was a steady increase in the incidence of HIV infection among those with high risk behaviour (STD attendees) as well as in the general population. This information is of value in planning and evaluation of preventive and control programmes in India. PMID- 7849126 TI - Transmission of trichuriasis in a sexual setting? PMID- 7849128 TI - Communication with general practitioners by hospital-based HIV units. PMID- 7849129 TI - An analysis of the Washington Conference Report on bioanalytical method validation. AB - The Washington Conference Report on bioanalytical method validation is analysed with respect to the requirements for precision and accuracy. It is shown that if the requirements are interpreted too literally, this could lead to disappointment in practice. A better approach is to separate the total measurement error into its constant (bias) and random (precision) components. To ensure that 95% of all methods fall within the acceptance interval of +/- 15% around the true value, would require, for example, the bias to be < or = 8% and the method precision to be < or = 8% relative standard deviation (RSD; n = 5). PMID- 7849127 TI - Feedback on the Tenth International Conference on AIDS/International Conference on STD (7-11 August 1994). PMID- 7849130 TI - Development and validation of a method for routine base composition analysis of phosphorothioate oligonucleotides. AB - A method for routine base composition determination of phosphorothioate oligonucleotides containing as many as 21 nucleobases has been developed and systematically evaluated in terms of factors contributing to assay precision and accuracy. Phosphorothioate internucleotide linkages were oxidized with a mixture of tetrahydrofuran-water-methylimidazole (16:4:1, v/v/v) which has been shown to be 97.3% effective. This step was followed by enzymolysis and HPLC quantitation of individual nucleobases. RSD for inter-day base composition analysis ranged from 1.1 to 1.3%, and inter-lot variation was 0.6-2.0%. Accuracy of the determined nucleobase ratio was independently confirmed through sequencing of the oxidized oligomer by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF/MS). PMID- 7849131 TI - Lysine vasopressin undergoes rapid glycation in the presence of reducing sugars. AB - Lysine vasopressin (LVP) readily reacts with reducing saccharides both in lyophilized preparations and in aqueous solution. Incubation of LVP with, for example, lactose over a pH range of 3.0-8.5 in phosphate buffer or simply in water, gives rise to a number of reaction products, some of which form rapidly (in a matter of hours) even in the frozen state. Reaction mixtures were analysed by reversed-phase HPLC and the structures of the products were deduced from the amino-acid composition of isolated components, by comparison with product profiles obtained with analogues under similar conditions and by FAB mass spectral analysis of derivatives isolated after reduction with cyanoborohydride. The primary products arise from the formation of Schiff's bases at one or both of the two amino functions. The alpha-amino group of the N-terminal cystine is considerably more reactive than is the epsilon-amino group of lysine and it is the N-terminal adduct which rapidly forms even at -20 degrees C. It is concluded that caution must be shown in using reducing sugars in formulations containing peptides and proteins, particularly the vasopressins and oxytocin. PMID- 7849132 TI - Development and validation of capillary electrophoresis assay for ribonuclease A. AB - A quick and reproducible capillary electrophoresis assay was developed and validated for bovine pancreatic Ribonuclease A (Rnase A). Effects of separation buffer pH and concentration as well as separation power were evaluated on Rnase A samples in phosphate buffered saline in the 5-100 micrograms ml-1 concentration range. The separation variables yielded significant influence on peak elution, with phosphate buffer (pH 2.5; 0.2 M) at separation power of 2 W providing an optimum peak at about 4 min. The peak sharpness and detection limit was further improved by a base/sample/acid injection technique. The optimized method showed good linearity with inter- and intraday RSD of peak area in the 2-5% range. Heat, as well as guainidine hydrochloride denatured samples, showed loss of enzymatic activity, changes in tyrosine fluorescence and abnormal electropherograms. The assay was also compared to a bicinchoninic acid assay that is routinely used for protein quantitation, and found to have greater sensitivity and reproducibility. PMID- 7849133 TI - Determination of protonation macro- and microconstants and octanol/water partition coefficient of the antiinflammatory drug niflumic acid. AB - The drug niflumic acid is an amphoteric substance with overlapping pKa values. The acid-base chemistry of the molecule has been characterized in terms of protonation macroconstants (with reference to stoichiometric ionizations) and microconstants (with reference to ionizations of individual species). The proton binding sites were assigned using 1H and 13C NMR spectroscopy. Due to the very poor water solubility of niflumic acid, the aqueous pKa values were determined from the apparent ionization constants in methanol-water solutions of various proportions by extrapolation to zero co-solvent using the Yasuda-Shedlovsky procedure. The kz tautomerization microconstant of the equilibrium unionized form<-->zwitterionic form was determined from mixtures of organic solvent (dioxane or methanol) with aqueous buffer (at the pH of isoelectric point) by UV spectroscopy, and used for calculation of the other protonation microconstants. The zwitterionic form of the molecule predominates over the uncharged form, the concentration being maximal at the isoelectric pH. The apparent partition coefficients (Papp) of niflumic acid were measured in octanol/water solution by the shake-flask method over a wide pH range. The lipophilicity profile (logPapp vs pH) shows a parabolic shape near its maximum at the isoelectric point. A relationship derived between Papp, PXH0(micropartition coefficient of the uncharged microspecies) and PX-(partition coefficient of the anion) is valid for amphoteric drugs, in cases where the partition of the unionized form and the ion pair partition of anion can be confirmed. The logP values of microspecies indicate the high lipophilicity of niflumic acid, which is consistent with its good skin penetration and absorption. PMID- 7849134 TI - Experimental design for the rapid selection of separation conditions for methyl and propyl parahydroxybenzoate, phenylephrine hydrochloride and chlorphenamine maleate by ion-pair liquid chromatography. AB - Methyl and propyl parahydroxybenzoate (MPHB, PPHB), phenylephrine hydrochloride (PE) and chlorphenamine maleate (CPM) are often combined as ingredients in cough syrups. Due to distinct chemical structures, pKa values among other chemical properties are different. This may result in a particular chromatographic behaviour on ion-pair reversed-phase liquid chromatographic (LC) systems. A face centred central composite design was applied to study the impact of four LC mobile phase parameters and parameter interactions on the retention of these four compounds. The mobile phase parameters studied were the concentration of methanol as organic modifier, the concentration of sodium dioctylsulphosuccinate (SDSS) as counter-ion, the concentration of dimethyloctylamine (DMOA) as competitive base and the pH. By means of the proposed design, mathematical regression models and response surface plots were calculated, which could predict the compounds' retention times with good statistical reliability. Adequate combination of the most relevant of these mobile phase parameters enabled complete chromatographic separations within short times of analysis. PMID- 7849135 TI - Positive ion EI mass spectra of 2,3,5-trisubstituted-1,5-benzothiazepines, diltiazem, clentiazem and their fat-soluble metabolites. AB - Diltiazem, clentiazem and their acidic and basic metabolites extractable with tert-butyl methyl ether, which are all 2,3,5-trisubstituted-1,5-benzothiazepines, were analysed by positive ion electron ionization (PIEI) mass spectrometry, and the structures of fragment ions and their fragmentation pathways were investigated. In all the mass spectra of these compounds, b1 ions ([R1 - CH = CH OR2]+) or b2 ions ([R1 - CH = CH - OH]+, b1 - CH2CO; R2 = COCH3) were seen as the base peaks or one of the major peaks (R1 and OR2 are the substituents at position 2 and 3, respectively). These spectra varied greatly with the nature of the side-chain at position 5: in the spectra of compounds with a 5-(2 dimethylamino) ethyl group, the a1 ion, [CH2 = N(CH3)2]+, was the base peak ion; in those with a 5-(2-monomethyl-amino)ethyl group (trifluoroacetyl(TFA) derivatives), no a1 ion peak was seen, but the a3 ion, [CH2CH2NCH3TFA]+, was one of the major peaks; in those of the derivatives bearing a 5-(2-amino) ethyl or carboxymethyl group, no peaks indicating the structures of the side-chain group at position 5 could be seen. GC-mass chromatography using fragment ions such as the a1, a3, b1 and b2 ions enables detection of the unchanged drug and most of its metabolites obtained by extraction with organic solvents under acidic or basic conditions followed by derivatization. PMID- 7849136 TI - A sensitive enzyme immunoassay for angiotensin II in serum. AB - A sensitive and specific enzyme immunoassay for measuring angiotensin II (AII) has been developed as a convenient alternative to a radioimmunoassay. An antiserum to AII was prepared using AII conjugated by carbodi-imide to rabbit serum albumin, and coated on to microwell plates. The labelled antigen was prepared from AII and horseradish peroxidase using the periodate method. This enzyme immunoassay was a simple two-step procedure: 0.1 ml of AII-extracted plasma was incubated for 1 h at 37 degrees C; and 1 ml of labeled AII was incubated for 1 h at 37 degrees C. Bound horseradish peroxidase activity was then determined using o-phenylenediamine as chromogen by measuring the absorbance at 492 nm. The lower detection limit of the assay was 3.5 pmol l-1. Between- and within-assay RSD values were 8.8-18.3% and 6.9-17%, respectively, for concentrations of 10-40 pmol l-1. The accuracy of the assay, determined by recovery and linearity experiments, was 89-106% for recovery and 91-126% for parallelism. The results obtained by the present ELISA method were well correlated with those obtained by an established radioimmunoassay (n = 10, r = 0.96, intercept = 0.9 and slope = 1.02). This assay is easy to perform, rapid and does not require radioisotopes; thus it could be widely applied in clinical laboratories. PMID- 7849137 TI - A selective fluorimetric method for the determination of some 1,4-benzodiazepine drugs containing a hydroxyl group at C-3. AB - A highly selective and sensitive fluorimetric method was developed for the determination of four 1,4-benzodiazepine drugs containing a hydroxyl group at carbon 3, namely oxazepam, lorazepam, cinolazepam and temazepam. The method is highly specific because other benzodiazepinee lacking the hydroxyl group at C-3 do not react similarly and hence do not interfere. The proposed method involves reduction of the target compound using Zno/HCl at room temperature with the formation of a highly fluorescent derivative within 15 min. The different experimental parameters were carefully studied and incorporated into the procedure. Under the described conditions, the proposed method is applicable over the concentration range of 0.1-1.2 micrograms ml-1 for both temazepam and cinolazepam, and 0.2-2.5 and 1-8 micrograms ml-1 for oxazepam and lorazepam respectively. The recoveries of the title compounds from spiked urine ranged from 90.0 to 92.0% and for serum from 94.1 to 95.4% with a limit of detection (S/N = 2) of 4 ng ml-1 for all drugs. The mechanism of the fluorimetric reaction is discussed. PMID- 7849138 TI - Mouse hepatic metabolites of ketoconazole: isolation and structure elucidation. AB - Oxidation, cleavage and degradation of the imidazole and piperazine rings, O dealkylation, and aromatic hydroxylation are the reported pathways of ketoconazole (KC) metabolism. Metabolites were examined in hepatic extracts from male Swiss Webster mice treated with KC (350 mg kg-1 po x 7 days) in a 0.25% gum tragacanth suspension at 10 ml kg-1. Livers were collected 24 h after the last dose and stored at -70 degrees C. A mixture of chloroform/methanol extracts of liver homogenates were dried under vacuum and methanol extracts of the residue were chromatographed by a series of preparative and analytical HPLC techniques. Structure assignments were made by NMR and MS/MS techniques. It was demonstrated that KC was biotransformed to a number of products. Nine were isolated and seven identified as exclusive products of the biotransformation of the 1 acetylpiperazine moiety of KC. This substituent was biotransformed to the following: piperazine (de-N-acetyl ketoconazole, DAKC), N-carbamylpiperazine, N formylpiperazine, 2,3-piperazinedione, 2-formamidoethylamine, ethylenediamine and amine. The 1H-NMR and MS data suggested that the remaining two metabolites were products resulting from the oxidation of the imidazole ring. PMID- 7849139 TI - An automated analytical method for the determination of felbamate in human plasma by robotic sample preparation and reversed-phase high performance liquid chromatography. AB - An automated analytical method for the determination of felbamate in human plasma is described. Sample cleanup and preparation was performed by means of a Zymate II laboratory robot and consisted of a liquid-liquid extraction of felbamate and the internal standard, primidone, from human plasma to dichloromethane. The dichloromethane was evaporated and reconstituted in a phosphate buffer. Separation was performed by reversed-phase high performance liquid chromatography using a 5 microns Hypersil ODS column (150 x 4.6 mm) and a mobile phase consisting of a mixture of phosphate buffer (pH = 6.5, 0.015 M) and acetonitrile (79:21, v/v). Quantitation was performed by measurement of the UV absorbance at a wavelength of 210 nm. The lower limit of quantitation was 0.100 micrograms ml-1 using 200 microliters of plasma. The mean absolute analytical recovery of felbamate was 75.2% (n = 28). The recovery of the internal standard, primidone was 74.7% (n = 10). The within-day precision was below 3.8% at all concentration levels, except at the lower limit of quantitation (18.3%). The within-day accuracy varied between -3.7 and +7.4%. The between-day precision was below 5.0% at all concentration levels. The between-day accuracy of the method varied between -5.7 and +1.6%. The selectivity of the method towards several other anti epileptic drugs has been demonstrated. PMID- 7849140 TI - Development and validation of a chiral LC method for analysis of the four stereoisomers of 1045U85 in plasma. AB - A method for analysis of the four stereoisomers of 1045U85 in rat plasma was developed and validated. The method involved liquid extraction of 1045U85 and an internal standard (propranolol) from plasma, followed by reaction with a chiral derivatizing reagent, GITC. The diastereoisomeric products were then separated by reversed-phase LC. The range of quantitation was 9.828-0.121 micrograms ml-1 for total 1045U85 (3.440-0.042 micrograms ml-1 for the RR and SS isomers, and 1.474 0.018 micrograms ml-1 for the RS and SR isomers). Specificity of the method for 1045U85 was demonstrated using spiked plasma samples as well as plasma samples from dosed animals. Extraction recovery of 1045U85 and propranolol was greater than 95%, and the derivatization reaction was shown to be complete. Accuracy (% bias) ranged from -2.6 to 3.9% for total 1045U85 and from -4.7 to 14.1% for the individual stereoisomers. Precision (% RSD) was 3.8-8.7% for total 1045U85 and 2.9-16.5% for the individual isomers. Plasma samples stored at -70 degrees C were stable for 19 weeks. The method has been used to determine plasma 1045U85 concentrations in nonclinical studies with this compound. PMID- 7849141 TI - A reproducible, simple and sensitive HPLC assay for determination of ofloxacin in plasma and lung tissue. Application in pharmacokinetic studies. AB - A high-performance liquid chromatographic method with fluorometric detection was developed for the analysis of ofloxacin in plasma and lung tissue. The detection was performed at 280 nm for excitation and 500 nm for emission. The procedure involves the addition of an internal standard followed by treatment of the samples with acetonitrile and dichloromethane. The proposed technique is reproducible, selective, reliable and sensitive. Linear detector response was observed for the calibration curve standards in the range of 0.1-5 micrograms ml 1 for plasma and 0.025-2.5 micrograms g-1 for lung tissue. The limit of quantitation is 5 ng ml-1 or 5 ng g-1. The accuracy of the method is good; that is, the relative error is < 10%. This method was applied to the pharmacokinetic study of ofloxacin in 24 chronic obstructive pulmonary disease patients. PMID- 7849142 TI - The intestinal absorption of Luxabendazole in rats. PMID- 7849143 TI - [Nutritional problems in cirrhotic patients. Evaluation of dietetic aspects]. AB - The aim of the study was to evaluate: a) the influence of the diagnosis of liver cirrhosis on the alimentary behaviour of cirrhotic patients; b) the compliance and the effect during observation-time of a personalized diet; c) the modifications, induced by the diet, of some clinical and biochemical parameters, specifically of these correlated to hepatic encephalopathy in 20 non-alcoholic cirrhotic patients. They were entered the study, in stage A-B of liver disease, according to Child-Pugh criteria. No patients received a previous specific dietetic prescription. After the collection of the alimentary intake before and after the diagnosis of liver disease, we prescribed normoprotein and hyposodium diets, reducing or increasing the caloric intake for the patients who were not at their ideal weight. From our study it stands out that the diagnosis induced all patients to reduce their caloric intake, especially of lipids. The appropriate dietetic prescription followed by short run controls led to a general improvement of the evaluated parameters, which was not kept during the following months; as a matter of fact, at the long run control all patients tended to return to their previous alimentary habits, neglecting, in the course of time, the diets they had been prescribed. We can, consequently, maintain that the cirrhotic needs a steady clinical and dietetic control since he seems to undervalue the prescribed therapies. PMID- 7849145 TI - [Observations on dietary intake of iron in young adults of the city of Bologna and evaluation of the risk of iron deficiency]. AB - The dietary iron intake was studied in 50 volunteers sample of young adults in Bologna neighbourhood; thirty men, mean age 28.9, and 20 women, mean age 30.4. A structured questionnaire was proposed individually by a skilled dietary interviewer. The mean dietary iron daily intake results similar to that found in western industrialised countries, as reported in previous studies, respectively 15.1 mg and 14.0 in men and women. This study reveals a lower percentage of animal origin dietary iron than in northern and central Europe in both sexes, as previously reported (male: 32.8%; female: 27.3%), furthermore the iron intake per kcal was markedly lower (male: 4.91/1000 kcal, female: 5.97) than the level of 7 mg/1000 kcal reported for those countries. The authors argue that the described dietary habit can lead to iron loss balance, mostly in women whose iron intake is far lower than one recommended by LARN (Recommended daily dietary allowances by National Nutrition Italian Institute). It is considered the increasing chance of iron therapy need in women, particularly during long-lasting hypocaloric diets. PMID- 7849146 TI - [Vitamin content of foods in relation to their different technological treatments]. PMID- 7849144 TI - [Chronic gastritis and prostaglandins. Results of endoscopic screening]. AB - An endoscopic screening was carried out during the period between July 1989 and December 1991 in the Municipality of Roccagorga (LT) in order to: a) evaluate the presence of various forms of gastritis and pre-cancerous lesions; 2) verify the effect of the administration of prostaglandins (Misoprostol) on the evolution of superficial chronic gastritis (CG). A total of 468 endoscopy were performed (17% of the population aged between 20 and 75 years old). 22% of the subjects examined were found to be endoscopically normal; 34% presented symptoms of mild esophagitis and 4% of moderate esophagitis. The prevalence of duodenal ulcer was 10.6% and gastric ulcer 3.4%. Gastric carcinoma was diagnosed in 6 patients (1.2%). 8.5% of patients were found to have atrophic CG and 15.3% superficial CG. Thirty-six patients with superficial CG were randomly divided into two groups: A) treated with Misoprostol 600 mg/day for 6 months; B) controls (placebo). The administration of Misoprostol did not influence the evolution of CG, whereas it caused a reduction in the incidence of type 1 intestinal metaplasia. Misoprostol also led to an improvement in dyspeptic symptoms. The results of the present study do not suggest a role of prostaglandins in the natural evolution of CG. PMID- 7849147 TI - [Hepatic Wilson's disease: clinical presentation and prognosis. Indications for liver transplantation]. AB - Wilson's disease is a hereditary disorder of biliary copper excretion. Most often the disease presents with hepatic and neurological involvement. In the hepatic forms, hypocerulo-plasminemia, the determination of eye copper and the dosage of copper in serum, urine and liver tissue are all leads to diagnosis. The presentation and the biochemistry may direct the diagnosis of the acute forms. Treatment differs according to the clinical patterns. Early diagnosis in the asymptomatic patient leads to chelating therapy to prevent copper overload. Chronic disease may benefit from chelation and liver transplant. Transplantation is the cure for fulminant forms. We report three young women with Wilson's disease; one had a fulminant form and was transplanted and the other two responded to chelation therapy. Family screening allowed the identification of an asymptomatic sibling. PMID- 7849148 TI - [Wilson's disease: physiopathology, therapeutic approach and case report]. AB - Wilson's disease is an hereditary recessive autosomal disorder which affects around five people per million inhabitants. The primary defect is localized in the liver and the disease is manifested by the accumulation of copper in tissues. The diminution of ceruloplasmin, which until a few years ago was mistakenly thought to be the pathogenetic cause of Wilson's disease, is an epiphenomenon of the underlying metabolic defect characterized by defective copper biliary excretion. There are four stages in the natural history of the disease: 1) an asymptomatic stage of hepatic copper accumulation; 2) dismission and redistribution of copper leading to hepatocellular necrosis and hemolysis; 3) extrahepatic accumulation of copper leading to the onset of cirrhosis and neurological damage; 4) stage of homeostasis following treatment but with possible irreversible neurological damage. Treatment of Wilson's disease takes the form of pharmacological, dietary and surgical therapy. Through the formation of copper and protein metal complexes D-penicillamine impoverishes copper deposits causing the reduction or disappearance of hepatic and neurological symptoms; a small percentage of patients treated develops a nephrotic syndrome requiring the compulsory suspension of the drug. In this case a valid alternative is triethylenetetramine dichlorohydrate (TETA) which provokes increased blood copper during copper diuresis. The response to pharmacological treatment is better the earlier treatment is started and the more regular its administration. Dietary intake of copper must be reduced in parallel avoiding foods with a high copper content. Liver transplant obviously leads to the "resolution" of the underlying metabolic problem in patients who develop fulminating hepatitis with hypercupremia and hemolysis and, of course, in cases of uncompensated cirrhosis which do not respond to chelating therapy.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7849149 TI - [Nutritional aspects in a case of short bowel syndrome complicated by acute renal failure]. AB - The short bowel syndrome is a multifactorial disease that requires an intensive treatment especially if complication develop. The authors report their experience in a patient who, affected by acute renal failure after extensive intestinal resection, underwent temporary jejunostomy. The treatment of choice in this patient was initially a careful hydroelectrolytic balance, as he was in good nutritional status but underwent a dialytic treatment and jejunostomy. Then we started the nutritional support and initially we adopted enteral nutrition in order to facilitate small bowel functional integrity, avoid gastric uremic lesions and bacterial translocation which could prelude to multiple organ failure. At surgery we tried to preserve the distal ileum which is very important in order to absorb biliary salts and nutritional mixtures. Cholecystectomy was associated due to gangrenous cholecystitis probably caused both by short bowel syndrome and prolonged artificial nutrition. Six months after surgery the patient underwent a decrease of the body weight and then authors verified the stabilization of the weight and general conditions. PMID- 7849150 TI - [Zinc deficiency syndrome during TPN]. AB - The zinc deficiency syndrome, also called enteropathic acrodermatitis, has been mostly observed in those pathologies of the gastroenteric system characterized by grave food shortages during long term TPN in association with inflammatory intestinal pathologies. The authors believe this to be caused of such syndrome, that in the case in question is demonstrated before the normal period described in the literature to be caused by both increased request related to TPN and a greater loss or less absorption due to intestinal phlogosis. The case described has been noted in a general surgery division in a young patient suffering from Crohn's disease for many years in treatment with medical therapy and now complicated by perianal abscess following burrowing on the outside subjected and therefore in treatment with artificial parenteral nutrition pre and post operative. Such pathology to be due when to begin a symptomatology characterized by consciousness alteration, diarrhoea, vesicular squamous cutaneous lesions around orifices, often infected by bacteria and mycosis in patients in treatment nutritional artificial continued for digestive apparatus diseases. The knowledge of this syndrome and its diagnosis lead, through integrative therapy, to its resolution in a short time. The authors describe the course of a clinical case occurred to then and ended with the patient's recovery. They underline the risks of ignoring this pathology. PMID- 7849151 TI - [Decrease of insulin resistance after splenectomy in a diabetic patient with liver cirrhosis and portal hypertension. Physiopathologic evaluation]. AB - Liver cirrhosis is characterized by an increased incidence of glucose intolerance, diabetes and insulin resistance. We report a cirrhotic man (41 years old) who developed glucose intolerance and diabetes with insulin resistance over a period of six years. This patient suffered from severe portal hypertension with oesophageal varices and a enormously increased spleen volume. The subject underwent prophylactic endoscopic sclerotherapy of oesophageal varices. Splenectomy was performed because of severe piastrinopenia with recurrent nose bleeding. During laparotomy, multiple liver biopsies confirmed diagnosis of liver cirrhosis. Intra-operatory exploration revealed a splenic vein thrombosis. For this reason the planned spleno-renal shunting was not performed and the patient was only submitted to splenectomy. Liver function improved in the month following splenectomy and concomitant decrease of insulin resistance was observed (with a reduction in daily insulin dosage from 126 to 10 I.U.). We propose the following explanations of this event: 1) A decrease of portal and pancreatic vein pressure may have induced a proportional decrease (as already reported) of glucagon secretion. 2) The ameliorated liver function may have induced an improvement of liver glucose, insulin and glucagon metabolism. 3) A reduction of insulin circulating level (proved by a decrease of C Peptide value) may have lessened the insulin receptor down-regulation. PMID- 7849152 TI - [Treatment of pylethrombosis with alteplase. Description of a clinical case]. AB - The authors report a case of venous pylethrombosis of the proximal splanchnic circuit treated with rt-PA (alteplase) for the first two days and later associated with high doses of heparin. rt-PA demonstrated a good level of efficacy with the partial resolution of the thrombus already after the first administration and in spite of the late commencement of therapy. PMID- 7849153 TI - Genetic basis of cancer of the pancreas: diagnostic and therapeutic applications. AB - Relatively little is known about the molecular basis of pancreatic cancer despite it being one of the most common cancers in the developed world. Recent studies have shown that in human pancreatic cancer there are abnormalities in the structure or function, or both, of several oncogenes, notably the c-erb B-2 proto oncogene and the Ki-ras oncogene. These genetic alterations will have both diagnostic and therapeutic implications. The Ki-ras gene is mutated at codon 12 in about 90% of pancreatic cancers and there is abnormal expression of the c-erb B-2 oncogene in nearly 20%, although mutational activation of the latter is not seen in human pancreatic adenocarcinoma. There is considerable evidence to support the hypothesis that neoplastic transformation requires many genetic events, and it is likely therefore that there are other molecular abnormalities in pancreatic cancer. The sequence of their activation and the agents responsible for that activation have not yet been elucidated, and both laboratory and animal experiments are needed to define which molecular events activate the neoplastic genotype and phenotype and how. PMID- 7849154 TI - Impending and actual pathological fractures in patients with bone metastases of the long bones. A retrospective study of 233 surgically treated fractures. AB - OBJECTIVE: Analysis of short-term and long-term complications after cemented osteosynthesis for pathological fractures. DESIGN: Retrospective study. SETTING: South Municipal Hospital and the Daniel den Hoed Cancer Centre, Rotterdam, The Netherlands. SUBJECTS: 199 patients consecutive surgically treated between 1978 to 1990 for 233 fractures (161 actual and 72 impending) caused by metastatic lesions of the femur, humerus and tibia. INTERVENTIONS: Local resection of the tumour was followed by endoprostheses (n = 52) and by internal plate osteosynthesis (n = 167); 14 fractures were treated with intramedullary nails. Bone cement was added in 211 cases (91%). MAIN OUTCOME MEASURES: Pain relief, mobilisation, complications. RESULTS: Pain relief was achieved in about 90%. 145 (76%) who were treated for fractures of the lower extremity were able to walk again. There were 13 local complications: 26 (11%) implanted devices failed (cumulative probability 40%, after 60 months). In 11 cases the fixation failed after 7 weeks. The failure rate was 16% in the subtrochanteric region treated with an angled blade (probability 70% after four years). The patients' survival rate was 55% after six months and 20% at two years. CONCLUSION: Despite the poor life expectancy, our results indicate that hemiarthroplasty or osteosynthesis with bone cement for treatment of pathological (impending) fractures is a safe way to restore limb function and to improve quality of life. PMID- 7849155 TI - Videothoracoscopic lung biopsy by a stapling technique. AB - OBJECTIVES: To describe initial experience with a new technique for obtaining lung biopsy specimens using video-thoracoscopy and Multifire Endo GIA (U.S. Surgical Corporation) stapler. DESIGN: Retrospective study. SETTING: Central hospital, Denmark. SUBJECTS: Nine patients with suspected pulmonary fibrosis. MAIN OUTCOME MEASURES: Diagnosis, morbidity, and mortality. RESULTS: The endoscopic method provided a specimen of lung tissue large enough to secure a reliable diagnosis in all cases. CONCLUSION: The thoracoscopic technique implies less surgical trauma than thoracotomy resulting in less postoperative pain and a better cosmetic result. In patients suitable for general anaesthesia the endoscopic method for obtaining lung tissue specimen seems to be the ideal method. PMID- 7849156 TI - Retroperitoneal paragangliomas: role of immunohistochemistry in the diagnosis of malignancy and in assessment of prognosis. AB - OBJECTIVE: To present our experience of 10 patients with extra-adrenal retroperitoneal paragangliomas, and assess prognostic tests. DESIGN: Retrospective study of casenotes. SETTING: University hospital, Italy. SUBJECTS: 10 Patients who presented with paragangliomas between 1970 and 1991. MAIN OUTCOME MEASURES: Histological and immunohistochemical results, and outcome. RESULTS: All tumours were completely resected and there was no operative mortality. Of the 8 patients who had no metastases at presentation 3 died of recurrence 3, 5, and 10 years later, respectively; 4 were alive and free of disease 2-7 years after diagnosis. The 2 patients with synchronous bone metastases at presentation died 1 and 4 years later. Immunohistochemical analysis of type I cells (chromogranin A and neurone-specific enolase) showed little correlation with progression of disease, but there was a correlation between the presence of type II cells (S100 protein) and good prognosis. CONCLUSIONS: Excision is the treatment of choice for paraganglioma. Immunohistochemical techniques may provide useful information about prognosis, in particular about those patients who are at increased risk of recurrence. Long term follow up is essential, because successful management of recurrence is dependent on early recognition. PMID- 7849157 TI - Fatal pulmonary embolism in an unselected series: the possible role of caval filters in prevention. AB - OBJECTIVE: To evaluate the possible benefit of inserting a caval filter for the prevention of pulmonary embolism (PE) in an unselected group of patients admitted to hospital. DESIGN: Analysis of clinical data collected prospectively. SETTING: University hospital, Sweden. SUBJECTS: 1391 patients who presented during 1987 435 with deep vein thrombosis (DVT), thrombus in the right atrium or the right ventricle or PE at necropsy; 366 patients shown to have DVT on phlebography; 44 shown to have PE on pulmonary scintigraphy; and 546 patients operated on for hip fractures. OUTCOME MEASURES: Clinical description of patients and groups of patients who died of PE who could possibly have benefitted from insertion of a filter. RESULTS: Of the 435 patients with DVT or PE or both, 141 had DVT in the femoral or iliac veins or in the inferior vena cava together with PE which contributed to the cause of death. Only 11 of these had been suspected clinically of having DVT in or below the inferior vena cava and only 1 of these was less than 80 years old and did not have malignant disease with distant metastases. Of the 366 patients with phlebographically confirmed DVT 8 died with PE that had contributed to the cause of death; 6 had incurable cancer and the remaining two were over 85 years. Of the 44 patients with scintigraphically confirmed PE 2 patients (aged 78 and 89) died of PE that had already been diagnosed clinically and none would have benefited from insertion of a filter after diagnosis. There were 9 PE deaths related to PE among 546 patients operated on for hip fractures, and all but one had potentially lethal coexisting disease or were over 80 years old. CONCLUSION: In this epidemiological survey only a few patients would have benefited from insertion of a caval filter. The results call for a restricted use of caval filters until benefit has been confirmed by prospective studies. PMID- 7849158 TI - Limb loss in association with vascular surgery--a five-year series of major lower limb amputation. AB - OBJECTIVE: To evaluate the type, timing and number of vascular reconstructions that preceded amputation; to compare the characteristics of amputees who had had reconstructions with those of amputees who had not, and to compare the results of amputation. DESIGN: Retrospective study of case notes. SETTING: University hospital, Sweden. SUBJECTS: All 219 patients who underwent amputation between 1987 and 1992. MAIN OUTCOME MEASURES: Incidence of amputations; presenting features, and type and results of vascular reconstructions. RESULTS: The number of amputations decreased after 1988, and that of vascular reconstructions increased. 56 of the 99 who had amputations after reconstruction (57%) had had their last procedure within a month. This group had had a mean of three operations, had worse run-off as assessed by angiography, and 2 of them (5%) had amputations after failed suprainguinal reconstruction for claudication alone. 68 of the total (31%) had amputations without first being assessed by a vascular surgeon. 52 (24%) required reamputation. CONCLUSION: Better objective methods are needed for the assessment of patients before primary as well as secondary vascular reconstructions. All patients should be seen by a vascular surgeon before amputation is recommended. PMID- 7849159 TI - Reversible adjustable gastric banding. Surgical technique. PMID- 7849160 TI - Abdominal aortic aneurysm and vertebral osteomyelitis. PMID- 7849161 TI - Retractile mesenteritis. PMID- 7849162 TI - Recurrence of transient osteoporosis of the hip. PMID- 7849163 TI - Surgical procedure to treat Budd-Chiari syndrome. PMID- 7849164 TI - Hyperglycaemia and survival after haemorrhage. AB - OBJECTIVE: To assess the relation between the degree of hyperglycaemia during a standard haemorrhage and survival. DESIGN: Prospective laboratory study SETTING: University department of surgery, Sweden MATERIAL: 5 groups of 8-12 adult male Sprague-Dawley rats. INTERVENTIONS: Different degrees of hyperglycaemia were achieved in the 5 groups of rats (which had been starved for 24 hours) by infusion of the same amount of 0.9% saline, or 5%, 10%, 20% or 30% glucose during a 48% standard haemorrhage over 60 minutes. Blood glucose concentration and packed cell volume were measured every 30 minutes, and mean arterial pressure was monitored constantly. MAIN OUTCOME MEASURE: Survival at 7 days. RESULTS: Increases in blood glucose concentrations during haemorrhage correlated with plasma refill as indicated by reductions in packed cell volume (r = 0.85, p < 0.0001). Both increases in blood glucose concentrations and reductions in packed cell volume were inversely related to blood pressure during haemorrhage (p < 0.0001). The more glucose that was infused, the higher the blood glucose concentration and the better the plasma refill during haemorrhage which correlated with improvement in the rate of survival at 7 days (p < 0.001). CONCLUSION: The ability to mount a hyperglycaemic response is an important prognostic factor in survival after experimental haemorrhage. PMID- 7849165 TI - Effect of experimental peritonitis and ischaemia on peritoneal fibrinolytic activity. AB - OBJECTIVE: Measurement of the fibrinolytic response of the peritoneum to experimental peritonitis and ischaemia. DESIGN: Controlled study SETTING: Academic surgical unit, UK MATERIAL: Male Wistar rats INTERVENTIONS: Peritoneal injuries were caused in four groups of male Wistar rats (n = 35 in each group): (1) control group ("open and close" laparotomy); (2) bacterial peritonitis (mixed faecal flora); (3) chemical peritonitis (10 mg/ml tetracycline) and; (4) ischaemic peritoneum (ligated peritoneal buttons). Peritoneal biopsy specimens were taken from five animals in each group at seven time intervals and plasminogen activating activity (PAA) measured by fibrin plate assay. RESULTS: Compared with the control group the three peritoneal injuries produced a uniform reduction in PAA during the first 6 and 12 hours: at 6 hours the median PAA was 0.029 IU/cm2 for bacterial peritonitis, 0.021 IU/cm2 for chemical peritonitis, and 0.05 IU/cm2 for ischaemic peritoneum compared with 0.112 IU/cm2 for the control group; p < 0.001, ANOVA. At 12 hours the median PAA was 0.024 IU/cm2 for bacterial peritonitis, < or = 0.014 IU/cm2 for chemical peritonitis, and 0.05 IU/cm2 for ischaemic peritoneum compared with 0.112 IU/cm2 for the control group; p < 0.001, ANOVA. There then followed a rebound peak in all groups, maximal at 4 7 days, before a return to baseline values at two weeks. CONCLUSION: Peritoneal fibrinolysis was appreciably inhibited after three different standardised peritoneal injuries. The data support the hypothesis that there is a single pathophysiological mechanism of adhesion formation. PMID- 7849167 TI - Primary hyperparathyroidism: incidence and clinical and biochemical characteristics. A demographic study. AB - OBJECTIVE: To give a demographic description of primary hyperparathyroidism (pHPT) in a region in which the incidence of operative treatment was low (2/100,000 inhabitants/year) and to describe the association between histology, biochemistry, and morbidity among the patients. DESIGN: Retrospective study. PATIENTS: 107 consecutive patients who were operated on for pHPT referred for surgery during an 11 year period in a population comprising one million people. RESULTS: The median weight of adenomas was 1,300 mg (range 200-13,500), weight o hyperplastic tissue removed was median 1,500 mg (range 100-23,800). Weight of abnormal parathyroid tissue correlated significantly with preoperative serum calcium concentration (r = 0.50, p < 0.001). Preoperatively serum immunoreactive parathyroid hormone concentration was correlated with serum calcium concentration (r = 0.39, p < 0.001) and with serum creatinine concentration (r = 0.52 p < 0.001). In a quarter of the patients the serum calcium concentration fell below 2.0 mmol/l after operation. In this subgroup the weight of pathological parathyroid tissue was significantly higher than among those who did not develop hypocalcaemia. Preoperative serum calcium concentration was unrelated to postoperative hypocalcaemia. CONCLUSION: Patients from an area in which few operations are done for pHPT had biochemically and clinically advanced disease compared with patients from comparable areas in which more operations are performed. There is a good correlation between biochemistry, organ involvement, and histology. The serum concentration of calcium preoperatively seems to underestimate the presence of advanced disease in patients in whom the bones are affected. PMID- 7849166 TI - Rupture of the diaphragm after blunt trauma. AB - OBJECTIVE: To analyse our cases of acute rupture of the diaphragm after blunt trauma to find out how to diagnose it earlier and manage it more promptly in future. DESIGN: Retrospective study of casenotes. SETTING: Division of general surgery, district hospital, Taiwan. PATIENTS: 50 Patients who presented with acute rupture of the diaphragm after blunt trauma during the 10 year period 1982 91. MAIN OUTCOME MEASURES: Morbidity and mortality. RESULTS: The left hemidiaphragm was injured in 43 cases (86%), and the right in 7 (14%). The most common cause was road traffic accidents. 48 Patients had associated injuries, mainly to the chest and abdomen, and pelvic fractures. 44 Ruptured diaphragms were diagnosed before operation by chest radiography or upper gastrointestinal contrast examination. The transabdominal approach was the most appropriate, because 23 patients had intra-abdominal visceral injuries as well. 20 Patients (40%) had complications, and the rate was 33% among those treated within 24 hours and 70% among those whose treatment was delayed longer than 24 hours (p = 0.067). There were 3 deaths (6%); one patient died of empyema of the right chest as a result of simultaneous perforation of a hollow viscus. 6 Patients were permanently disabled by head and spinal injuries, and pelvic fractures. CONCLUSION: The prognosis of repairing diaphragmatic hernias is good as the disability rate is low. The diagnosis should be kept in mind in all patients with chest injuries, pelvic fractures, or abdominal injuries with hypoxaemia, as this will result in earlier treatment and improve prognosis. The transabdominal approach is the most appropriate because it makes simultaneous abdominal injuries easier to treat. Correct operative management at an early stage will keep mortality to a minimum. PMID- 7849168 TI - Tonometric assessment of sigmoid perfusion during aortobifemoral reconstruction for arteriosclerosis. AB - OBJECTIVE: To assess the effect of inferior mesenteric artery reimplantation on perfusion of the mucosa of the sigmoid colon in patients undergoing aortobifemoral reconstruction for arteriosclerotic disease. DESIGN: Random control study. SETTING: University hospital. SUBJECTS: 8 Men and 2 women with peripheral vascular disease and angiographically patent superior and inferior mesenteric arteries. INTERVENTIONS: Patients were randomised to have the inferior mesenteric artery reimplanted in the Y-graft or not. Sigmoid perfusion was measured with a tonometer and expressed as the intramucosal pH (pHi) during operation (baseline) and for four days afterwards. MAIN OUTCOME MEASURES: Measurements of pHi, arterial blood gases, and acid base balance, and signs of ischaemia of the gut. RESULTS: In both groups the pHi was reduced after clamping the aorta, but returned to baseline on the first postoperative day. One patient had a cardiac arrest from which he was resuscitated and his pHi measurements were subsequently low. CONCLUSION: pHi does seem to reflect changes in the circulation of the sigmoid mucosa. Even if the inferior mesenteric artery is patent, reimplantation is only rarely indicated in patients undergoing aortobifemoral reconstruction. PMID- 7849169 TI - Prognostic importance of radical lymphadenectomy in curative resections for gastric cancer. AB - OBJECTIVE: To evaluate the effect of extensive lymphadenectomy on survival in patients with gastric cancer. DESIGN: Retrospective analysis SETTING: University Hospital, Norway. SUBJECTS: 183 patients with stomach cancer resected for cure during the time period 1980-90. INTERVENTIONS: 78 patients had an R1- and 105 patients and R2 resection. 124 patients were treated by total gastrectomy, 5 by proximal--and 54 by distal resection. MAIN OUTCOME MEASURES: Morbidity, mortality and long term survival. RESULTS: The morbidity was 33% (60/183), of which 39 (21%) were general complications (pneumonia, thrombosis, or cardiovascular disease). 14 patients died postoperatively (8%). By logistic regression analysis we found that splenectomy was the only variable associated with both morbidity and immediate postoperative mortality. Five year survival was 39% for patients who had undergone curative resections, 30% for patients who had had an R1 resection, and 47% for those who had had an R2 resection. By multivariate analysis (Cox) we found that N-classification (TNM), tumour diameter of less than 45 mm, type of lymph node dissection (R2) and operation period (after 1984) correlated with improved survival. CONCLUSION: Extensive lymph node dissection improves survival without increasing morbidity or postoperative mortality. PMID- 7849170 TI - Activity and activation of the complement system in patients being operated on for cancer of the colon. AB - OBJECTIVE: To find out if there was any local activation of complement in the vicinity of a colonic cancer, and any fluctuation in the function of the complement system during operation. DESIGN: Prospective study. SETTING: One university and two district hospitals in Denmark. SUBJECTS: 29 selected patients undergoing emergency and elective operations for colonic cancer. INTERVENTIONS: Measurements of systemic and local complement fixation capacity and complement activation in samples of serum or plasma taken before, during, and after operation. MAIN OUTCOME MEASURES: Changes in complement fixation capacity and complement activation during operation. RESULTS: Haemodilution during operation caused a significant reduction in the complement fixation capacity of serum and in the activation of the complement system as measured by generation of C3c. We were unable to confirm the presence of complement inhibitors during operation. Haemodilution caused a 30% reduction in fixation capacity of C3b (12/29 samples of serum had values more than 2SD below the mean of the reference range compared with 4/29 before operation). The activity of C4 was reduced by 25% during operation and the capacity of the complement system to fix C3b and C4b was restored to baseline nine days postoperatively. Concentration of C3d was significantly higher in serum from tumour venous blood compared with that from peripheral blood during operation. CONCLUSION: The presence of complement activation products in the general circulation reflects local activation of the complement system in the vicinity of the tumour, but this may have been influenced by tissue necrosis or subclinical infection. Haemodilution causes a significant reduction in the capacity of the complement system during operation, whereas inhibitory factors associated with the cancer or operation and anaesthesia could not be demonstrated. We found no correlation between complement activity and clinical data. PMID- 7849171 TI - Peutz-Jeghers syndrome associated with bilateral synchronous breast carcinoma in a 30-year-old woman. PMID- 7849172 TI - Caecocolonic intussusception that prolapsed through the anus in an adult. PMID- 7849173 TI - Stricture of the bile duct after blunt abdominal injury: report of a case successfully managed by percutaneous biliary drainage. PMID- 7849174 TI - Cystic insulinoma: a rare islet cell tumour of the pancreas. PMID- 7849175 TI - Retractile mesenteritis involving the colon. PMID- 7849176 TI - Presence of multiple fucosyltransferases in rat Sertoli cells and spermatogenic cells. AB - Differential expression of fucosyltransferases (FTs) on Sertoli cell and germ cell surfaces and their function as ectoenzymes may be important in the process of spermatogenesis. To determine the glycosidic linkage specificity of FTs present in cultured Sertoli cells and in germ cells, we quantified FT activities by thin-layer chromatography using both high and low molecular weight acceptors in the presence of GDP-[14C]-L-fucose. Analysis of the acceptor substrate specificity of the FTs indicated that alpha(1-2), alpha(1-3), alpha(1-4)-FTs are expressed as demonstrated by fucose incorporation into phenyl-beta-D-galactoside, 2'-fucosyllactose, and lacto-N-fucopentaose-I, respectively. In Sertoli cells, the ratios of the three FTs examined were the same for whole-cell extracts and samples of purified plasma membranes. Higher relative FT activity was observed in plasma membranes from mixed germ cells than in Sertoli cell membranes. Furthermore, alpha(1-3)-FT and alpha(1-4)-FT activities were higher in mixed germ cell membranes. Spermatogenic stage specificity of FT expression was assessed in purified populations of germ cells. With calculation on a per-cell basis, all three alpha-FTs exhibited a quantitative decrease during the transition between pachytene spermatocytes and round spermatids. The decrease in alpha(1-3)-FT activity was particularly significant. In rat germ cells, all three alpha-FT activities associated with the cell surface in pachytene spermatocytes and round spermatids were 34-53% and 52-53%, respectively, of the total cell FT activity.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7849177 TI - Calculated optimal cooling rates for ram and human sperm cryopreservation fail to conform with empirical observations. AB - The permeability coefficient to water (Lp) and its associated activation energy (Ea) were measured for ram (8.47 microns/min/atm at 25 degrees C, 1.06 kcal/mol) and human (2.89 microns/min/atm at 30 degrees C, 1.93 kcal/mol) spermatozoa. By use of these figures, predictive water loss curves were calculated, from published equations, for different cooling rates from 100 degrees C/min to 100,000 degrees C/min. The calculated curves show that ram spermatozoa cooled at even the fastest rate would be in osmotic equilibrium by -20 degrees C, and human spermatozoa cooled at rates up to 10,000 degrees C/min would be in equilibrium by -15 degrees C. If the nucleation temperature for spermatozoa is taken to be between -20 degrees C and -30 degrees C, then ram and human spermatozoa cooled at these rates would apparently not exhibit any intracellular freezing. There is a significant discrepancy between these calculated optimal cooling rates and the published empirically derived optimal rates of 50 degrees C/min for ram and 10 degrees C/min for human. The failure of ram and human spermatozoa to conform with the established and previously successful model for prediction of optimal cooling rates suggests that damage sustained at high cooling rates may be unrelated to intracellular ice formation. PMID- 7849178 TI - An unusual nucleoporin-related messenger ribonucleic acid is present in the germ cells of rat testis. AB - An mRNA with a substantial similarity to the rat p62 mRNA that encodes a nucleoporin was cloned from the rat testis. A probe derived from a unique sequence in the nucleoporin-related (NPR) cDNA revealed a novel mRNA of 1.3 kb, different from the 2.7-kb transcript attributed to the p62 gene. This 1.3-kb transcript was not detected in Sertoli cells; it was found primarily in the haploid germ cells of the adult testis. The DNA sequencing revealed that the central region of the NPR cDNA sequence was identical to the 3' portion of the p62 cDNA containing heptad repeat sequences. However, the 5' region and the extreme 3' region of the NPR cDNA sequence were different from the p62 cDNA. Interestingly, the extreme 3' untranslated region (UTR) contained a 212-bp inverted repeat of a sequence located in the middle of the NPR cDNA that is identical to the p62 sequence. The inverted repeats of the NPR sequence could potentially hybridize, leading to the formation of circular transcripts. Using antibodies specific for the C-terminal regions of p62, a 26-kDa protein was detected from NPR cDNA hybrid-arrested translational products, and a 28-kDa protein was detected from the testis germ cell extracts but not from Sertoli cell extracts. PMID- 7849179 TI - Heparin-induced capacitation but not intracellular alkalinization of bovine sperm is inhibited by Rp-adenosine-3',5'-cyclic monophosphorothioate. AB - The objective of this study was to investigate the importance of cAMP during capacitation of bovine sperm. The competitive antagonist of cAMP, Rp-adenosine 3'5'-cyclic monophosphorothioate (Rp-cAMP), blocked heparin-induced capacitation (p < 0.05). The effect of Rp-cAMP on heparin-induced capacitation was reversed by 8-bromo-cAMP. The maximal inhibitory effect on capacitation occuroff when Rp-cAMP was added at the start of sperm incubation. These results support an important role for cAMP-dependent protein kinases during heparin-induced capacitation of bovine sperm. Further support for a role for protein phosphorylation during capacitation came from the use of the protein phosphatase inhibitor, okadaic acid. Okadaic acid had no affect on heparin-induced capacitation of bovine sperm (p > 0.05); however, bovine sperm were capacitated by okadaic acid in the absence of heparin (p < 0.05). The relationship of cAMP to capacitation-associated changes in sperm intracellular pH (pHi) was investigated using image analysis of bovine sperm. The pHi of sperm increased during capacitation, and Rp-cAMP did not affect the change in pHi. We conclude that heparin-induced capacitation of bovine sperm involves an increase in cAMP and a protein phosphorylation event but that these do not induce the increase in pHi associated with capacitation. PMID- 7849180 TI - Adrenergic receptors on cultured rat epididymal cells: regulation of Cl- conductances. AB - Adrenergic regulation of epididymal Cl- currents was studied by the whole-cell patch-clamp technique using various alpha- and beta-receptor agonists and antagonists in primary cultured rat cauda epididymal cells. Cl- currents could be activated with varying frequency by noradrenaline (primarily alpha- and beta 1 adrenoceptor-selective agonist, 1-5 microM), isoprenaline (nonselective beta adrenoceptor agonist, 5 microM), salbutamol (beta 2-adrenoceptor-selective agonist, 2 microM), and phenylephrine (alpha 1-adrenoceptor-selective agonist, 1 2 microM). Noradrenaline alone elicited Cl- current activation in 85% of the cells examined. In the presence of phentolamine (nonselective alpha-adrenoceptor antagonist, 15 microM), noradrenaline elicited Cl- current activation in 63% of the cells examined, whereas noradrenaline-induced activation was observed in 33% of the cells examined in the presence of both atenolol and butoxamine (beta 1- and beta 2-adrenoceptor antagonists, respectively, 10 microM). In 27% of single cells examined, a second current activation in response to salbutamol was observed after the first response to phenylephrine. When the order of stimuli was reversed, dual activation was also observed in 22% of the single cells examined, indicating the presence of both alpha- and beta-adrenoceptors in single epididymal cells. Profiles of time- and voltage-dependent Cl- current upon activation by different adrenoceptor agonists exhibited characteristics similar to those previously reported for Ca2+ and cAMP-activated Cl- currents, suggesting that regulation of epididymal Cl- conductances could be mediated by different adrenoceptor subtypes involving Ca2+ and cAMP as intracellular second messengers. PMID- 7849181 TI - Gonadal growth and hormone concentrations in photoregressed Siberian hamsters: pinealectomy versus photostimulation. AB - In Siberian hamsters, long and short durations of nightly melatonin secretion are associated with testicular regression and development, respectively; surprisingly, the absence of a nightly melatonin signal induced by pinealectomy is less effective than a short (4-6 h) melatonin duration for promoting gonadal development. We compared the patterns of serum FSH and prolactin concentrations underlying pinealectomy-induced and photostimulated testicular growth in juvenile hamsters. Pinealectomy in photoinhibited hamsters on Day 18 produced significant gonadal development compared to that in short-day controls by Day 23. By Day 28, however, testes weights of pinealectomized hamsters were significantly lower than those of intact hamsters transferred to a long photoperiod. Pinealectomy was associated with significant elevations in serum FSH and prolactin concentrations over baseline by Day 21, but peak values were attenuated compared with those induced by exposure to long days. FSH titers of pinealectomized animals were significantly lower than those of photostimulated animals between Days 21 and 30 but were significantly greater on Days 35 and 40; prolactin values were comparable in pinealectomized and photostimulated hamsters between Days 21 and 25 but were significantly lower in the former group thereafter. Blunted elevation of FSH and prolactin secretion may underlie the slower rates of gonadal maturation observed in pinealectomized, juvenile hamsters. The neuroendocrine systems of pinealectomized hamsters appear to be in a state intermediate between those characteristic of hamsters kept in long and in short day lengths. PMID- 7849182 TI - Ovarian follicular development in prepubertal heifers is influenced by level of dietary energy intake. AB - Objectives were twofold: 1) to determine the chronology of development of dominant ovarian follicles during the peripubertal period in heifers and 2) to determine whether feeding a diet with low energy content that delays onset of puberty alters chronology of dominant ovarian follicular development in peripubertal heifers. Ten heifers of composite breeding (1/4 Angus, 1/4 Hereford, 1/4 Red Poll, 1/4 Pinzgauer) were randomly assigned, at 8 mo of age, to receive a diet designed to produce 0.9 (n = 5) or 0.3 (n = 5) kg body weight gain per day for the duration of the experiment. To characterize changes in size of ovarian follicles, real-time linear ultrasonography of ovaries was conducted in all heifers every other day until puberty occurred. Blood samples were collected weekly to determine concentrations of progesterone and 17 beta-estradiol. Determination of time of puberty was based on increased concentrations of progesterone, ultrasound depiction of ovulation, and subsequent presence of a corpus luteum. Size of the dominant ovarian follicles differed prior to puberty (p < 0.03); diameter of the dominant ovarian follicle was greater in all heifers as the first ovulation approached as compared to earlier in prepuberty. Heifers fed the greater amount of energy exhibited larger dominant ovarian follicles at a younger age in comparison to heifers fed the lower amount of energy.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7849184 TI - Characterization of T lymphocytes and antigen-presenting cells in the murine male urethra. AB - The male lower urogenital tract is exposed to sexually transmitted pathogens and is therefore a strategic site of immune defense. To further define the immunodynamics of this region, we studied the histology, immune cell distribution, and draining lymph nodes of the murine male lower urogenital tract. The external surface of the foreskin was covered by skin composed of keratinized stratified epithelium containing numerous hair follicles and sebaceous glands. Immunologically the penile foreskin was characterized by the presence of few T lymphocytes and macrophages. Numerous Langerhans cells, however, were detected within the epithelium. The penile urethra was composed of stratified columnar epithelium, with a meatus lined by keratinized squamous epithelium preceding the opening proper. The most abundant immune cells of the penile urethra were macrophages. In young adult, virgin males, these were found primarily underlying the urethral epithelium, but in older, mated mice, they were usually intraepithelial in location, and were more abundant. Langerhans cells could not be specifically identified in the urethral mucosa. T lymphocytes were found underlying and occasionally within the epithelium of the urethral mucosa, with CD4+ cells more abundant than CD8+ cells. The majority of lymphocytes observed around the urethra were positive for the integrin beta 7 alpha M290, which is selectively expressed by mucosal lymphocytes, providing indirect evidence that the urethra is part of the common mucosal system. Lymphocytes expressing the gamma delta T cell receptor and IgA-positive plasma cells were not detected. The primary draining nodes for the vas deferens and urethra were the lumbar nodes. Lymphatic drainage from the rectum also involved the lumbar nodes. Information obtained in this study should help to elucidate optimal genital tract vaccination strategies for defense of the male urogenital tract against sexually transmitted pathogens. PMID- 7849183 TI - Rat ovarian granulosa cell as a site of endothelin reception and action: attenuation of gonadotropin-stimulated steroidogenesis via perturbation of the A kinase signaling pathway. AB - Endothelins (ETs) are a family of vasoactive peptides that may be involved in granulosa cell (GC) luteinization or follicular maturation. However, the precise role of ET in ovarian physiology remains unknown. We have investigated whether the rat GC is a site of ET reception and have characterized the antigonadotropic effect of ET in cultured GC from immature rats. Two major ET binding species (52 and 30 kDa) were observed after cross-linking of GC membranes with radiolabeled ET-1, although the smaller protein may represent a degradative product. Unlabeled ET-1, ET-2, or ET-3 were equipotent in displacing radiolabeled ET-1 from these putative ET receptors, with EC50s of 0.3-0.7 x 10(-9) M. Similarly, ET-1, ET-2, and ET-3 were equipotent (EC50s of about 10(-10) to 10(-9) M) in inhibiting the FSH-supported accumulation of progesterone. ET-1 (10(-7) M) also inhibited (> 90%) FSH-supported estrogen accumulation. Maximum progesterone inhibition (> 90%) by ET-1 (10(-7) M) was achieved throughout the range of FSH does and cell densities tested and by 48 h or 72 h of culture. ET-1 was not cytotoxic in the dose range tested. Forskolin-stimulated progesterone accumulation was similarly inhibited by ET-1, suggesting that ET-1 inhibits cAMP-mediated (e.g., FSH or forskolin-stimulated) progesterone accumulation. ET-1 inhibited (74%) the FSH stimulated accumulation of cAMP, suggesting that it acts at sites related to cAMP generation or degradation. In addition, ET-1 inhibited 8-bromo-cAMP-generated progesterone accumulation (60%), suggesting that it also acts at sites distal to cAMP generation.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7849185 TI - Ontogeny of granulosa cells in the ovary: lineage-specific expression of transforming growth factor beta 2 and transforming growth factor beta 1. AB - The differentiation of ovarian somatic cells into granulosa, interstitial, and thecal lineages, and the ovarian growth factor(s) potentially associated with the cytodifferentiation of granulosa cells during the perinatal period were investigated using cell type-specific protein markers. Ovaries collected from prenatal (Days 12-15 of pregnancy) and postnatal (Days 1-30) female hamsters were processed for immunohistochemical localization of transforming growth factor (TGF) beta (TGF beta 1, beta 2, and beta 3). Plasma levels of FSH, LH, progesterone, and estradiol-17 beta were detected by RIA. Prenatal hamster ovaries contained numerous mitotic oocytes and a few somatic cells. Only a fraction of somatic cells expressed barely detectable TGF beta 2 activity. Plasma FSH levels were quite detectable on postnatal Day 1 and increased gradually to reach a peak on Day 25, whereas LH did not increase until Day 12 and reached a plateau by postnatal Day 20. On postnatal Day 1, TGF beta 2 immunoreactivity was localized only in certain cells closely apposed to primordial oocytes. On postnatal Day 4, flattened, TGF beta 2-positive cells encircled individual oocytes, forming the very first cohort of primordial follicles. By Days 7 and 8, primary and early secondary follicles with intense TGF beta 2-positive cuboidal granulosa cells appeared. Subsequently, in large preantral follicles TGF beta 2 was expressed only in mural granulosa cells. On Day 13, TGF beta 1 and beta 2 immunoreactivities appeared for the first time in the interstitial cells. TGF beta 1 was localized in cells closely apposed to follicles, but TGF beta 2 activity was restricted to scattered cell clusters. Subsequently, the entire interstitium was positive for TGF beta 1 protein. These results suggest that differentiation of somatic cells into granulosa cells is the first event in ovarian morphogenesis; once the finite number of granulosa cells is selected, the residual cells differentiate into interstitium. Whether ovarian TGF beta 2 and TGF beta 1 are physiologically important in granulosa and interstitial cell differentiation needs further evaluation. PMID- 7849186 TI - Cyclic and postnatal developmental changes of testin in the rat seminiferous epithelium--an immunohistochemical study. AB - Testin is an authentic Sertoli cell secretory protein consisting of two molecular variants designated testin I (M(r) 35 000) and testin II (M(r) 37 000). N Terminal amino acid sequence analysis revealed that testin I is identical to testin II except that testin II has three extra N-terminal amino acids of threonine-alanine-proline (TAP). Earlier studies by immunoflorescence microscopy have shown that testin is detected in the seminiferous epithelium consistent with localization in the junctions between Sertoli cells as well as Sertoli-germ cells, and that it appears to be a component of junctional complexes in the testis. In the present study, we have examined the localization of testin in different stages of the spermatogenic cycle of the adult rat testis when germ cells migrate from the basal portion of the seminiferous epithelium to the tubular lumen. In stages I-IV, testin was localized mainly in the basement laminae in the junctional complexes between adjacent Sertoli cells as well as between Sertoli cells, spermatogonia, and pachytene spermatocytes. When elongated spermatids were embedded into the seminiferous epithelium in stage VII of the cycle, testin was detected predominantly on the concave side of the elongated spermatids, but relatively few testin reaction products were seen in the round spermatids. In the beginning of stage VIII of the spermatogenic cycle, intense testin immunoreactive substances were detected around the heads of the elongated spermatids; these substances were virtually undetectable in late stage VIII after the release of the mature sperm into the tubular lumen, suggesting that testin may be a novel marker to divide stage VIII into stages VIIIa and VIIIb.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7849187 TI - Hormonal regulation of meiotic maturation in the hamster oocyte involves a cytoskeleton-mediated process. AB - Maturation of the mammalian oocyte involves hormone-induced meiotic cell cycle progression from prophase I to metaphase II and extrusion of the first polar body (PB). In this study, the effects of gonadotrophins on meiotic cell cycle progression in cultured hamster oocytes were analyzed with respect to changes in cumulus cell-oocyte interactions and the oocyte cytoskeleton. Cumulus-oocyte complexes were obtained from large antral follicles (> or = 700 microns in diameter) of eCG-primed animals and were cultured in the presence or absence of gonadotropins alone (FSH, hCG, LH) or in combination (FSH + hCG or FSH + LH). Oocytes were analyzed using conventional, digital, and confocal fluorescence microscopy to monitor chromatin, actin, and tubulin organization under different culture conditions. Most oocytes (83%) cultured with FSH alone progressed to and arrested at metaphase II and extruded the first PB; in contrast, meiotic progression and PB extrusion were impaired (45-85%) in all other groups. The presence of cumulus cells associated with the oocyte was found necessary for progression to metaphase I and for first PB emission. Completion of meiotic maturation in the presence of FSH alone was correlated with enhanced cortical actin polymerization in the oocyte and the retraction of actin-containing transzonal cumulus processes. The results demonstrate that gonadotropins exert specific effects on meiotic progression, PB emission, cumulus-oocyte interactions, and oocyte cytoskeletal organization during in vitro maturation of hamster oocytes, indicating that the hormonal control of meiosis involves cytoskeletal changes in both the somatic and germ cells. PMID- 7849188 TI - Experimentally induced cryptorchidism increases apoptosis in rat testis. AB - Although surgical induction of cryptorchidism in the rat is known to cause infertility due to disruption of spermatogenesis, the exact cellular mechanism responsible for the degenerative changes in cryptorchid testes is unclear. Using a sensitive autoradiographic method for the detection of apoptotic DNA fragmentation, we have investigated the effect of experimentally induced cryptorchidism on apoptotic cell death in testes of immature rats. Bilateral or unilateral cryptorchidism decreased the weight of affected testes within 4 days; these decreases (24-27%) became significant (P < 0.05) at 7 days after the operation. Testes of sham-operated animals contained predominantly high molecular weight DNA (> 15 kb), whereas DNA cleavage into low molecular weight ladders characteristic of apoptosis was increased by induction of bilateral cryptorchidism in a time-dependent manner, i.e., 2.0-, 2.8-, and 4.2-fold (p < 0.05) at 2, 4, and 7 days after operation, respectively. In unilaterally cryptorchid animals, sham-operated testes also contained predominantly high molecular weight DNA, whereas induction of cryptorchidism of the contralateral testes increased DNA cleavage into low molecular weight fragments 3.0-, 2.8-, and 3.9-fold (p < 0.05) at 2, 4, and 7 days after the operation, respectively. In situ analysis of DNA fragmentation in testes of unilaterally cryptorchid rats at 7 days after the operation indicated that germ cells, mainly primary spermatocytes were affected and that the percentage of seminiferous tubules containing labeled cells increased in the operated testis as compared to the contralateral control in the same animal.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7849189 TI - Melatonin influences sex-specific prenatal mortality in meadow voles. AB - Meadow voles exhibit seasonal changes in litter size, ovulation rates, and prenatal mortality. To investigate the proximate bases of seasonal changes in reproductive effort, adult female voles, maintained in long photoperiods (14 h of light/day), were injected daily with 10 micrograms melatonin 2 h before light offset to extend the duration of the nighttime melatonin pulse. At parturition the number, sex, and weight of offspring were assessed. The number of ovarian corpora lutea (CL), an index of potential litter size, was used to calculate rates of prenatal survival (i.e., pups per CL). Prenatal survival rates were reduced in female but not male pups of dams that had been injected before blastocyst implantation (Days 1-6 of pregnancy) with melatonin as compared with saline. Melatonin injections initiated after blastocyst implantation (Days 7-21 of pregnancy) did not affect prenatal survival, nor were birth weights of pups affected by either pre- or postimplantation melatonin treatment. We conclude that sex-specific prenatal survival is a labile feature of vole reproduction that may be under proximate control of photoperiod and melatonin before blastocyst implantation. PMID- 7849190 TI - Rhesus monkey oocyte maturation and fertilization in vitro: roles of the menstrual cycle phase and of exogenous gonadotropins. AB - Our objectives were to improve the efficiency of rhesus monkey oocyte maturation and fertilization in vitro and to determine the influence of menstrual cycle phase and exogenous gonadotropins on these processes. Immature oocytes were recovered from antral follicles of ovaries excised from unstimulated animals (n = 14). The highest yield and quality was associated with oocytes obtained from early follicular phase ovaries, and more of these oocytes underwent germinal vesicle breakdown (GVBD; 55%) and matured to metaphase II (MII; 40%) than did oocytes from late follicular (GVBD, 28%; MII, 9%) or luteal (GVBD, 13%; MII, 10%) phase ovaries. Exogenous human (h) FSH and hLH improved GVBD and MII levels for oocytes recovered from late follicular phase ovaries and increased GVBD, but not MII, for oocytes from luteal phase ovaries. MII levels for oocytes from early follicular phase ovaries were adversely affected. Early follicular phase oocytes underwent GVBD faster and attained MII sooner than did those from either late follicular or luteal phase ovaries. Whereas exogenous gonadotropins did not significantly affect oocyte fertilization, follicular phase oocytes tended to be fertilized at a higher rate (p = 0.07). These results demonstrate that higher maturation levels are obtained with oocytes from early follicular phase ovaries and that gonadotropins influence oocyte performance in a cycle phase-dependent manner. PMID- 7849191 TI - Estradiol and androgen modulate chicken luteinizing hormone-releasing hormone-I release in vitro. AB - Hypothalamic slices (1 mm) including medial basal hypothalamus and preoptic areas (MBH-POA) were taken from adult male Japanese quail, placed in a short-term perifusion system, and exposed to estradiol or androgen. Release of chicken LHRH I (cLHRH-I) was measured by an enzyme immunoassay specific for cLHRH-I. In separate experiments, MBH-POA slices were exposed short-term to 5 alpha dihydrotestosterone (5 alpha-DHT, 10(-7) M) and testosterone (T, 10(-7) M), and short- or long-term to 17 beta estradiol (E2, 10(-9) M). Release of both basal and stimulated cLHRH-I (15-min exposure to 10(-6) M norepinephrine [NE]) was monitored. Basal cLHRH-I release during perfusion was episodic throughout the experimental periods. During no treatment, there was a mean (+/- SEM) pulse interval of 21.27 +/- 1.03 min, pulse duration of 13.98 +/- 0.59 min, pulse duration of 13.98 +/- 0.59 min, pulse amplitude of 4.12 +/- 0.13 pg/5 min, and pulse frequency of 2.93 +/- 0.12/h. Mean cLHRH-I pulse amplitude significantly (p < 0.05) increased with challenge by NE to 25.03 +/- 3.09 pg/5 min. Short-term E2 exposure significantly (p < 0.01) potentiated NE-induced cLHRH-I release. Neither T nor 5 alpha-DHT affected baseline or NE-stimulated cLHRH-1 release. Pretreatment with E2 (10(-9) M) for 14 h in static culture before perifusion significantly (p < 0.05) reduced the NE-induced cLHRH-I release. These results suggest that a hypothalamic LHRH-I pulse-generating mechanism is located within the MBH-POA. Further, these data provide evidence for E2 modulation of cLHRH-I release, which varies with exposure. PMID- 7849192 TI - Follicle-stimulating hormone priming of rhesus monkeys enhances meiotic and developmental competence of oocytes matured in vitro. AB - The objective of this study was to determine the effects of FSH priming of rhesus monkeys upon meiotic and developmental capacity of oocytes in vitro. FSH-primed monkeys (n = 9) received injections of porcine FSH for 6-7 days. Germinal vesicle stage oocytes (n = 402) were obtained from dissected follicles. All oocytes were cultured for 36-40 h, inseminated, and incubated until developmental arrest. Greater (p < or = 0.001) percentages of cumulus-enclosed oocytes from FSH-primed vs. nonstimulated monkeys completed meiotic maturation (74 vs. 41%), activated/fertilized (85 vs. 61%), and cleaved from the 2-4-cell (79 vs. 38%) through the morula (29 vs. 1%) stages. Blastocysts (4%) were obtained only from FSH-primed monkeys. Compared with their cumulus-enclosed counterparts, denuded oocytes were compromised (p < or = 0.05) in completing nuclear maturation and cleaving in vitro. The meiotic and developmental capacity of denuded oocytes from FSH-primed monkeys exceeded (p < or = 0.01) those of denuded oocytes from nonstimulated monkeys. Denuded oocytes from FSH-primed monkeys were more (p < or = 0.01) competent to cleave beyond 8 cells than cumulus-enclosed oocytes from nonstimulated monkeys. Meiotic and developmental competence was similar between oocytes with or without cytoplasmic vesicles. Thus, FSH priming of monkeys enhances nuclear and cytoplasmic maturation of oocytes in vitro, and resulted in production of the first in vitro-matured/in vitro-fertilized primate blastocysts in vitro. PMID- 7849193 TI - Alterations in endogenous gonadotropin secretion and pituitary responsiveness to gonadotropin-releasing hormone in adult ewes, following indirect selection in prepubertal male lambs. AB - Indirect selection to improve reproductive performance in the female, through use of a physiologically related trait in prepubertal males, the LH response to a GnRH challenge, has created two lines of sheep with altered pituitary gland sensitivity to both physiological and pharmacological doses of GnRH. These lines also exhibit correlated between-line differences in female reproductive performance during the first, and at the beginning of the second, breeding season. This study was designed to determine whether the observed between-line differences in female reproductive performance were related to between-line differences in endogenous gonadotropin secretion during the luteal and follicular phases of the estrous cycle and whether the between-line difference in the LH response to a GnRH challenge was maintained in adult females. The results indicated that, despite similar mean gonadotropin and steroid concentrations during the luteal and follicular phases of the estrous cycle, significant between line differences in LH pulse amplitude were present during the follicular phase (high line > low line). In addition, the results indicated that the between-line difference in the LH response to a GnRH challenge was maintained in adult ewes, being most apparent during the follicular phase, when the magnitude of the difference was similar to that in prepubertal female lambs. Therefore, in addition to showing maintenance of the between-line difference in the selected characteristic in postpubertal females, the results demonstrate that adult ewes from the two lines differ in additional, unselected but physiologically related traits and provide a model system with which to study steroidal regulation of gonadotropin secretion in the ewe. PMID- 7849194 TI - Hormonal pattern of the pheromonal restoration of cyclic activity in aging irregularly cycling and persistent-estrus female rats. AB - This study reports the hormonal pattern of pheromonal restoration of cyclic activity (PRCA) in irregularly cycling (IC) and in anovulatory persistent-estrus (PE) aging female middle-aged Wistar rats. Hypothalamic content of LHRH and plasma levels of LH, FSH, estradiol (E2), and progesterone (P) were measured by RIA methods, and prolactin (PRL) was examined by ELISA in 1) normal four-day cycling rats, 2) saline-treated IC and PE rats, and 3) IC and PE rats treated with sprays of male urine (50 microliters every 10 min for 1 h on only one day, at a distance of 1 cm from the nostrils). Group 1 showed low levels of LHRH and high levels of LH, FSH, E2, P, and PRL in the afternoon of proestrus (PR). In group 2, the pattern was not cyclical and the levels of the hormones were higher than basal for the cyclic rats, except for P, which was lower. Group 3 showed a depletion of the hypothalamic LHRH and an increase in plasma LH, FSH, E2, Pm, and PRL. FSH, E2, and P showed the strongest rise, leading to an elevated ratio of FSH to LH. Four-day estrous cycles reappeared in urine-treated rats on the succeeding days. The cyclic behavior of the PRCA hormones was, qualitatively, the same as in the normally cycling rats. According to the results, the origin of the PRCA effect is an olfactory input to the hypophysiotropic area of the hypothalamus.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7849195 TI - Contribution of the fetal adrenal to circulating immunoactive inhibin in the chicken embryo. AB - High concentrations of immunoactive inhibin are observed in the plasma of male and female chicken embryos. The exact nature and the source of this material remain obscure. In a previous study we presented evidence that the fetal gonads are unlikely to be the main source of circulating inhibin (Biol Reprod 1993; 49:549-554). Here we demonstrate that the fetal adrenal may account for the major portion of circulating immunoactive inhibin in the chicken embryo. A comparison of the inhibin content of different fetal organs shows that, expressed per milligram of tissue, the adrenal ranks second. Only the testis has a higher inhibin content, while the inhibin content of the fetal ovary is considerably lower than that of the fetal adrenal. Suppression of endogenous ACTH secretion by administration of dexamethasone results in a marked decrease of plasma inhibin. Maximal suppression (down to 24% and 25% of the control values in male and female embryos, respectively) was observed with the lowest dose of dexamethasone tested (1 microgram/egg). Dexamethasone (100 microgram/egg) reduced testicular weight and testicular inhibin content to approximately 50% of the control value. It is unlikely, however, that this contributed significantly to the fall in circulating immunoactive inhibin. In fact, ovarian inhibin content was unaffected, but even so, a comparable drop in circulating inhibin was observed in female embryos. Dexamethasone caused only marginal changes in plasma FSH. Administration of a synthetic peptide with ACTH activity (Synacthen) in vivo did not produce measurable changes in circulating inhibin. Isolated and cultured fetal adrenal cells, however, produced immunoactive inhibin, and this production was increased fivefold after stimulation with synthetic ACTH.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7849196 TI - Apoptosis in bovine granulosa cells in relation to steroid synthesis, cyclic adenosine 3',5'-monophosphate response to follicle-stimulating hormone and luteinizing hormone, and follicular atresia. AB - Apoptosis is a process of selective cell deletion implicated as a mechanism underlying the process of ovarian follicular atresia. The aims of this study were 1) to test the hypothesis that granulosa cell death during follicular (> or = 4 mm diameter) atresia in cows occurs by apoptosis and 2) to define relationships between the occurrence and degree of granulosa cell apoptosis, cAMP response to FSH or LH, extant aromatase activity, and other previously established biochemical and morphometric indices of granulosa cell function and follicular atresia in this species. Granulosa cells and follicular fluid from individual follicles 4-18 mm in diameter were collected from luteal-phase cow ovaries. Follicles were classified by morphometric criteria as "healthy" (n = 45) or atretic (n = 34). Apoptosis in granulosa cells from each follicle was inferred from detection of internucleosomal DNA cleavage by 3'-end radiolabeling; it was quantitated both subjectively from intensity of oligonucleosome labeling (apoptosis [AP] score = 0, 1, 2, or 3) and objectively by beta-counting of low molecular weight gel fragments (labeling index; LI). Extant aromatase activity (ng estradiol produced/10(6) cells/3 h) and cAMP response (pmol/10(6) cells) to different doses of FSH or LH (1-10,000 ng/ml) was determined for granulosa cells from most healthy follicles (n = 39). Apoptosis was detected in granulosa cells from all atretic follicles as well as from 76% of healthy follicles, from 80% (16 of 20) of follicles with follicular fluid estradiol to progesterone ratios > 1, and from 71% (10 of 14) of follicles with extant aromatase activity (> 2 ng/10(6) cells/3 h). For healthy and atretic follicles, degree of DNA fragmentation was inversely related to the number of granulosa cells recovered (as percentage maximum by follicle size). In healthy follicles, FSH stimulated cAMP synthesis is a dose-dependent manner in granulosa cells from all follicles examined (> or = 4 mm), but only 36% of these had appreciable aromatase activity. The cAMP response to FSH (per cell) increased with follicle size from 4-7 mm in diameter and remained high in granulosa cells from follicles > or = 8 mm with aromatase activity; in cells without aromatase activity, cAMP response to FSH decreased with increasing follicle size > or 8 mm. The cAMP response to LH was generally low or undetectable in granulosa cells from 4-8-mm follicles; it then increased linearly with increasing follicle diameter > or = 8 mm, but to a greater degree in cells with aromatase activity than in cells without.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7849197 TI - Effects of testosterone on spermatogenic cell populations in the adult rat. AB - The aim of this study was to investigate the progression of germ cell populations through the rat spermatogenic cycle when spermatogenesis was suppressed by LH withdrawal through the use of a combination of testosterone (T) and estradiol (E) and then reinitiated by the administration of high doses of T. Adult Sprague Dawley rats received 3-cm T and 0.4-cm E silastic implants for 6, 8, or 12 wk to suppress spermatogenesis followed by high-dose T (24-cm implants) for up to 12 wk to reinitiate spermatogenesis. The number of spermatogonia, primary spermatocytes, and round spermatids per testis was established by stereological techniques, and the elongated spermatid number was determined by the testicular content of nuclei resistant to homogenization in Triton X-100. Suppression for 6 12 wk resulted in moderate and significant (p < 0.05) reductions in the numbers of type A and type B spermatogonia (to 44-59% of control levels), preleptotene (68-72% of control), and leptotene/zygotene spermatocytes (62-79% of control) as well as in the numbers of stage I-VII (56-69% of control) and stage VIII-XIV (35 43% of control) pachytene spermatocytes. Round spermatids were suppressed to 29 45% of control levels (p < 0.05) while elongated spermatids were undetectable. The hourly production rates of germ cells (calculated using published time divisors) were used to study the cellular conversions through spermatogenesis (based on the ratios of the hourly production rates) and revealed that T withdrawal consistently abolished the conversion of round to elongated spermatids. The duration of suppression (6, 8, or 12 wk) had no effect on the degree to which germ cell populations or conversions were reduced. In response to high-dose T administration, spermatogonial and spermatocyte numbers and production rates (up to stage I-VII pachytene) remained suppressed, while stage VIII-XIV pachytene spermatocytes showed an increase of borderline significance. On the other hand, round and elongated spermatid numbers and production rates increased significantly (to 81% and 78% of control, respectively) and their conversion was normalized, i.e., the spermiogenic process was restored to a level consistent with the numbers of earlier germ cells proceeding through the cycle. These data suggest that, in the presence of low T levels, spermatogenesis proceeds at approximately 65% of normal levels between the spermatogonial and round spermatid stages, irrespective of the duration of T-induced suppression. This is followed by a precipitous decline in elongated spermatid number that is attributed to the disappearance of round spermatids.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7849198 TI - Gonadotropin secretion in ovariectomized Chinese Meishan and hybrid large white gilts; responses to challenges with estradiol benzoate, gonadotropin-releasing hormone, or porcine follicular fluid. AB - Castrated Meishan (MS) and hybrid Large White (hLW) gilts were used in a series of challenge experiments to establish differences in the control of gonadotropin secretion. Acutely ovariectomized gilts (72 h) were injected i.m. with 10 micrograms/kg estradiol benzoate (EB) and serially bled for evaluation of estradiol clearance from the blood and patterns of LH and FSH release. Estradiol was more rapidly metabolized from the circulatory system of the acutely ovariectomized MS gilts than from the hLW gilts; as a consequence, hLW gilts had higher concentrations of estradiol than MS gilts at 24-32 h (p < 0.05) and 48-60 h (p < 0.01) post-EB treatment. The hLW but not the MS gilts exhibited a classic negative/positive LH response to EB; MS gilts responded with a random release of large episodes of LH. Plasma FSH concentrations were consistently greater (p < 0.05) in acutely ovariectomized MS gilts than in hLW gilts. Both breeds demonstrated a slight negative FSH response to EB and then exhibited increased variability in plasma FSH with time after treatment. Mean plasma LH was immediately elevated in chronically ovariectomized (> 14 days) hLW and MS gilts given 1 microgram/kg of GnRH i.m., but the magnitude of the LH response was greater (p < 0.01) in the hLW gilts. Comparable differences (p < 0.01) in FSH secretion were also observed, indicating the presence of greater pools of releasable FSH and LH in the hLW gilts, or a greater sensitivity to GnRH.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7849199 TI - Partial characterization of a sex-steroid binding protein in the spotted seatrout (Cynoscion nebulosus). AB - A sex-steroid binding protein (SBP) that binds both testosterone and estradiol-17 beta was identified in the plasma and ovarian interstitial fluids of the spotted seatrout, Cynoscion nebulosus. Scatchard analysis revealed a single binding component with dissociation constants of 4.89 +/- 0.19 and 3.13 +/- 0.11 nM and binding capacities of 423 +/- 25 and 482 +/- 24 nM for testosterone and 17 beta estradiol respectively (n = 5). Competition studies demonstrated that the seatrout SBP had a high affinity for a range of estrogens and androgens; much lower affinity for 11-ketotestosterone, progesterone, and pregnenolone; and even lower affinity for cortisol and the maturation-inducing steroid, 17 alpha, 20 beta,21-trihydroxy-4-pregnen-3-one. The rates of steroid association and dissociation were very rapid with a t1/2 of less than 30 sec for ligand association and 90 sec for ligand dissociation. Testosterone binding activity precipitated between 40 and 60% ammonium sulphate saturation and eluted as a single peak with an estimated molecular mass of 150 kDa on Sephacryl S-200. Electrophoresis of plasma on native PAGE over a range of acrylamide concentrations gave a molecular mass estimate of 135 kDa. The migration of 17 beta-estradiol binding activity on native PAGE was identical to that of the testosterone binding activity. Steroid binding activity was destroyed by exposure to EDTA or dithiothreitol (DTT), or to temperatures above 50 degrees C. The SBP found in the ovarian interstitial fluids was similar to the plasma binding protein in terms of saturability, affinity, specificity, association and dissociation rates, stability, and molecular weight. PMID- 7849200 TI - Changes in the expression of the L-type voltage-dependent calcium channel during pregnancy and parturition in the rat. AB - The L-type voltage-dependent calcium channel (L-VDCC) is assumed to be a critical component of excitation-contraction coupling in smooth muscle. Using pregnant rat myometrium, we examined the hypothesis that parturition is associated with significant changes in the expression of the alpha 1 subunit of the L-VDCC at the mRNA or protein level. The binding of radiolabeled dihydropyridine, which correlates with the total number of calcium channels in the membrane, was increased by 14 days' gestation, in comparison to that in nonpregnant controls. The elevation in binding capacity persisted through labor and fell postpartum. Northern and RNA dot-blot analysis demonstrated the highest level of expression on Days 20 and 21, with a 3- to 10-fold decrease during parturition. We believe these studies are most consistent with a one-day lag time between mRNA and protein expression, and generally support a modest increase in L-VDCC expression in pregnancy and labor. Reverse transcriptase polymerase chain reaction was used to examine changes in isoform expression in Motif IV, a region of the alpha 1 subunit known to be alternatively spliced. These studies revealed the presence of multiple isoforms in rat myometrium, with a predominance of IVS3B. Interestingly, a marked increase in the ratio of S3B:S3A was noted at parturition. In summary, these data demonstrate that the number of L-type calcium channels, although increased in pregnancy, do not change prior to, or with the onset of, myometrial contraction. Intriguingly, mRNA expression was markedly decreased at parturition. The change in isoform expression during labor is of unknown, but potential, physiologic significance. PMID- 7849201 TI - [Quality assurance in nursing: nursing standard. Nausea, gagging and vomiting during emetogenic cytostatic therapies. Report of research into the development and introduction of nursing standards]. AB - This report documents the introduction of standard-setting in the haemato oncological reverse-isolation unit of the Kanton hospital, Basle. The topic is the prevention or reduction of nausea, choking and vomiting, and the treatment of patients who are receiving prolonged chemotherapy. The objective was quality assurance in nursing care. The definition of the desired outcome was the well being and safety of patients. In addition the wish of the staff to increase their security in dealing with antiemetics was taken into consideration. The authors describe the basic problems they encountered in their strategies and actions for standard setting. By extensive use of measurement and evaluation it was possible, in cooperation with medical leadership, to develop instructional leaflets and checklists. Approximation to the intended outcome was achieved. The well being of patients and satisfaction of the safety-needs of staff and patients reached a high level. The report shows that the introduction of nursing standards requires great effort and a high level of commitment of the entire team. It also shows that the effort is worthwhile for patients and staff. PMID- 7849202 TI - [Admission to a ward for terminal care as a status passage]. AB - In the last few years clinics exclusively for patients suffering from AIDS have been developed in Switzerland, specialising in terminal care. The institution in which the research here reported was carried out, admitted drug-dependent patients with AIDS. Admission to the unit, henceforth referred to as unit for the dying, is a very special event, which triggers off a variety of behavioural manifestations. The research shows that it is a case of 'status passage' as described by Glaser and Strauss (1971), which is experienced differently by each individual. In spite of individual differences, similar conditions, similar factors, which influence patients, similar coping mechanisms were observed. To end the paper, concrete suggestions are offered for the care of drug dependent patients suffering from AIDS, suggestions at the level of individual nurses, of the nursing profession and of the structure of the organisation. PMID- 7849203 TI - [Morning care of patients with Alzheimer's dementia: a theoretical model based on direct observation]. AB - Five hospitalized patients in different stages of Alzheimer-type dementia were monitored by unstructured, direct observations during morning care. Orem's model of nursing as a compensation for the patient's lack of self-care capabilities was used as a frame of reference for an analysis of the behaviours of patients and nurses during morning care. A 12-step classification system was developed to be used as a guide to understand and determine abilities essential for performance of morning care for demented patients. The quantitative assessment showed that none of the patients was able to manage morning care independently, but there was a wide variation in their highest level of performance. PMID- 7849204 TI - [Verbal communication and behavior during meals of 5 hospitalized patients with Alzheimer's disease]. AB - Five institutionalized patients with Alzheimer-type dementia were observed (video recorded) during meals. The aim was to assess their meal behaviour and social interaction. The results showed that when the patients ate without the participation of staff, the two least demented patients became 'caregivers' in the group and helped the three most demented patients to eat. When two mental health nurses joined the group, the patients dropped their roles as helpers. The conversation in the group could be characterized as incomplete, with short sentences and a lot of breaks. Sixty-three per cent of all comprehensible utterances concerned food and eating and almost all conversation concerned the present. PMID- 7849205 TI - [Relationships in nursing: active and inactive sexuality in nursing staff and in old residents in nursing homes]. AB - More awareness now exists of the issue of active and non-active sexuality as a result of the demographic changes and the increasing number of old people in residential and nursing home care. In this connection it is often assumed that sexuality in old age is a non-topic. The reasons for the misinterpretation of facts are manyfold, among them is the silence, surrounding the topic. This contribution deals with the recovery of sexuality of the very old and the correlation between residents' and their carers' active and non-active sexuality. PMID- 7849206 TI - [Synergetic hospital organization--a chance for nursing]. AB - In their work as counselors in the field of organisational psychology and staff development, the authors are constantly in search of ideas which are relevant to hospital work. They became aware of the concept of 'Fraktal factory', arising from reports of peoples' experiences. The concept refers to the synergistic organisation of decentralised, interdisciplinary, selfregulating units- 'Fraktale'. They found the concept convincing, it seems to represent an important principle for hospitals. It is a holistic concept. The concept should be adapted to nursing and introduced into the hospital. Because the concept is worth exploring and promising, since it is patient-centered and focuses on nursing, the authors hope that this paper will arouse curiosity among readers. They offer the concept for discussion and hope to encourage venturing into new territory. They hope it will stimulate experiments of adaptation and transplantation. PMID- 7849207 TI - [The nursing situation in the old and new parts of the Federal Republic of Germany: a comparison of requirements, obstacles and nursing autonomy]. AB - Differences with regard to demands, obstacles and elbow room, affecting nursing activities in general hospitals are examined. An instruments measuring various facets was devised (TAA KH). The results reveal that in all three areas there are significant differences between activities of nursing staff in East and West German Hospitals. The differences are being discussed against the background of the situation in the new Bundeslander. PMID- 7849208 TI - [10 years of the journal Atencion Primaria]. PMID- 7849209 TI - [The editorial process in the journal Atencion Primaria]. PMID- 7849210 TI - [Cheklist of the journal Atencion Primaria]. PMID- 7849211 TI - [Profile of the consultants of the journal Atencion Primaria and their assessment of the review process]. PMID- 7849212 TI - [Information on methodological aspects in articles of the journal Atencion Primaria]. PMID- 7849213 TI - [Studies on service utilization in the journal Atencion Primaria]. PMID- 7849214 TI - [Criteria for the development of a formulary of drugs in a basic health area and impact on prescription]. AB - OBJECTIVE: To promote rational prescription in Primary Care by elaborating a restricted list of medicines in a PC, the implementation of the list and the evaluation of its influence. DESIGN: Controlled intervention study. SETTING: Intervention group: Castelldefels Health Centre. CONTROL GROUP: Moli Nou HC in same health sector. PARTICIPANTS: Doctors from the PC teams of both centres. INTERVENTIONS: Initially the prescription for 1992 of the intervention group was analysed. The main therapeutic groups prescribed for on the initiative of the General Practitioners (GP) of the Castelldefels HC were identified and the intervention was then carried out on them. The PC team from the intervention group, chose the drugs by consensus, on the basis of pharmaceutical advice. MEASUREMENTS AND MAIN RESULTS: Castelldefels HD presented worse indicators than the rest of the Sector's. It was observed that the GPs decided 63.4% +/- 3.9% of their therapeutic prescriptions. The groups most prescribed for on GP initiative were systemic (J) and respiratory apparatus (R) anti-infection therapies. The intervention was verified with Macrolids, Beta-lactamics (excluding Cephalosporins) and Quinolones. In neither of the two HDs were statistically significant differences (p < 0.05) in the consumption of the selected antibiotics between the two periods observed. CONCLUSIONS: This process is aimed at altering GPs' attitudes, it is essential that they participate in the choice of medicines in order to keep them involved; and that the ongoing records of the chosen drugs are verified, with the evaluation of their influence then being just one more tool in this process. PMID- 7849215 TI - [Job satisfaction and stress among general physicians in the public health system]. AB - OBJECTIVE: To determine: 1) the level of job satisfaction and job stress among general practitioners of National Health Service, and 2) the most common sources of stress of their job. DESIGN: Descriptive study based in a meal survey with bivariate and multivariate analysis of data. SETTING: Primary Care Centers of the Valencian Health Service. SUBJECTS: 216 general practitioners were questioned. Of these 127 answered on time (102 male; age 39.55 years; response rate of 58.80%). MEASUREMENTS AND MAIN RESULTS: The Font Roja-AP Questionnaire (to evaluate job satisfaction and stress) and the Tabarca Inventory (to determine sources of stress) were used. Social relationship at work, intrinsic job satisfaction, job distension and variety at work were in hierarchy order the principal reasons of job satisfaction. On the other hand, interruptions of family life, emergency calls, monotony and practice administration and the doctor-patient communication aspects were in hierarchy order the principal reasons of job stress. CONCLUSIONS: The general practitioners work yield job satisfaction. Moderate job stress has been observed among general practitioners. The most important sources of stress were interruptions of family life and other conditions which disturb intimacy. PMID- 7849216 TI - [Food habits among children in a district of the island of Gran Canaria]. AB - OBJECTIVE: To find out the characteristics of the diet of a population-group of young children and to quantify their caloric and nutrient intake. DESIGN: A descriptive study of a crossover type by means of a questionnaire on the frequency of food consumption. Stratified random sampling. SETTING: A Primary Care Centre. PATIENTS AND OTHER PARTICIPANTS: 264 healthy children aged from 2 to 8, representative of a District. MEASUREMENTS AND MAIN RESULTS: The children studied had overall sufficient caloric intake ("calories consumed/calories recommended" index of 1 +/- 0.2), with an excess of proteins (16.6 +/- 1.8% of calories) and lipids (36.3 +/- 4% of calories, mainly of animal origin) to the detriment of carbohydrate intake (47.7 +/- 5% of the caloric intake). There was an important percentage (42%) of children whose iron intake was deficient. Only 9% of children had a poor calcium intake. The vitamin intake was adequate. CONCLUSIONS: The variability of alimentary customs between zones means that we must identify the dietetic habits of the population group (or even individuals) we are serving, especially for the paediatric age group. We propose systematic Primary Care use of questionnaires on food consumption to enable the detection and correction of nutritional dangers. PMID- 7849217 TI - [Precancer and skin cancer. Clinico-therapeutic approximation]. PMID- 7849218 TI - [Anticholinergic agents with gastrointestinal selectivity: are they really selective?]. PMID- 7849219 TI - [Underreporting of adverse reactions to drugs: is it due to primary care or hospital care?]. PMID- 7849220 TI - [Insulin-induced lipoatrophy in primary care]. PMID- 7849221 TI - [Pregnancy and hepatitis B immunization]. PMID- 7849222 TI - DNA binding of a spermine derivative: spectroscopic study of anthracene-9 carbonyl-N1-spermine with poly[d(G-C).(d(G-C)] and poly[d(A-T).d(A-T)]. AB - The binding of polyamines, including spermidine (1) and spermine (2), to poly[d(G C).d(G-C)] was probed using spectroscopic studies of anthracene-9-carbonyl-N1 spermine (3); data from normal absorption, linear dichroism (LD), and circular dichroism (CD) are reported. Ligand LD and CD for transitions located in the DNA region of the spectrum were used. The data show that 3 binds to DNA in a manner characteristic of both its amine and polycyclic aromatic parts. With poly[(dG dC).(dG-dC)], binding modes are occupied sequentially and different modes correspond to different structural perturbations of the DNA. The most stable binding mode for 3 with poly[d(G-C).d(G-C)] has a site size of 6 +/- 1 bases, and an equilibrium binding constant of (2.2 +/- 1.1) x 10(7) M-1 with the anthracene moiety intercalated. It dominates the spectra from mixing ratios of approximately 133:1 until 6:1 DNA phosphate: 3 is reached. The analogous data for poly[d(A T).d(A-T)] between mixing ratios 36:1 and 7:1 indicates a site size of 8.3 +/- 1.1 bases and an equilibrium binding constant of (6.6 +/- 3.3) x 10(5) M-1. Thus, 3 binds preferentially to poly[d(G-C).d(G-C)] at these concentrations. PMID- 7849224 TI - NMR study of collagen-water interactions. AB - A proton magnetic resonance study of different cross-linked collagens was performed as a function of water content and temperature. Collagens from three connective tissues (calf, steer, and cow) were chosen according to the different number of nonreducible multivalent cross-links, which increases during the life of animal. Samples were hydrated under five well-defined water activities (Aw) ranging from 0.44 to 0.85. The transverse and cross-relaxation times of water protons were studied as a function of temperature from -20 up to 100 degrees C. From the temperature dependence of relaxation rates, the dynamics of water molecules can be described according to different processes: exchange of protons at the higher temperatures and dipole-dipole interactions that prevail at the lower temperatures. The exchange processes are analyzed as a function of the residence lifetime of water molecules at the protein interface and of the transfer of spin energy from water protons to macromolecule protons. The proton dipole-dipole interactions are related to the relaxation parameters of protein and water protons. All the relaxation parameters showed specific behavior for the 0.44 water activity for every tissue. The collagen tissue from calf also showed distinct behavior in comparison with other tissues. PMID- 7849223 TI - Mixed conformation in C alpha, alpha-disubstituted tripeptides: x-ray crystal structures of Z-Aib-Dph-Gly-OMe and Bz-Dph-Dph-Gly-OMe. AB - We report here the synthesis and molecular structure in the solid state of fully protected tripeptides containing C alpha, alpha-diphenylglycine (Dph), namely Z Aib-Dph-Gly-OMe (Aib: C alpha, alpha-dimethylglycine) and Bz-Dph-Dph-Gly-OMe. The molecular conformation around the Dph residue, containing two bulky substituents, is fully extended, while the Aib residue, containing two smaller groups on the C alpha atom, adopts the typical 3(10)/alpha-helical conformation. Gly residues, without substituents on the C alpha atom, show different conformational preferences. Each residue seems to behave, from a conformational point of view, independently from the presence of the other residues, and thus mixed local conformations (folded and extended) are present in the crystals. The nonconventional peptide synthesis, using the Ugi reaction, is also reported. PMID- 7849225 TI - Direct observation of cell wall glucans in whole cells of Saccharomyces cerevisiae by magic-angle spinning 13C-NMR. AB - Intact cells of Saccharomyces cerevisiae were examined as an aqueous paste by 13C nmr spectroscopy with direct polarization and magic-angle spinning. The spectra obtained were highly resolved, showing numerous resonances in the 60-105 ppm range that were assigned to carbons of a liquid-like domain of the cell wall glucan. Assignments were confirmed by running the spectrum of S. cerevisiae in which the cell wall glucans were labeled with [13C] by feeding the cell [13C]galactose. The spectra indicate that the glucan in the cell wall of intact S. cerevisiae assumes a helical conformation and suggest that strain 17A fed with galactose preferentially incorporates the resulting glucose into beta (1-->3) linkages. PMID- 7849226 TI - Kinked structures of isolated nicotinic receptor M2 helices: a molecular dynamics study. AB - The pore-lining M2 helix of the nicotinic acetylcholine receptor exhibits a pronounced kink when the corresponding ion channel is in a closed conformation [N. Unwin (1993) Journal of Molecular Biology, Vol. 229, pp. 1101-1124]. We have performed molecular dynamics simulations of isolated 22-residue M2 helices in order to identify a possible molecular origin of this kink. In order to sample a wide range of conformational space, a simulated annealing protocol was used to generate five initial M2 helix structures, each of which was subsequently used as the basis of 300 ps MD simulations. Two helix sequences (M2 alpha and M2 delta) were studied in this manner, resulting in a total of ten 300 ps trajectories. Kinked helices present in the trajectories were identified and energy minimized to yield a total of five different stable kinked structures. For comparison, a similar molecular dynamics simulation of a Leu23 helix yielded no stable kinked structures. In four of the five kinked helices, the kink was stabilized by H bonds between the helix backbone and polar side-chain atoms. Comparison with data from the literature on site-directed mutagenesis of M2 residues suggests that such polar side-chain to main-chain H bonds may also contribute to kinking of M2 helices in the intact channel protein. PMID- 7849227 TI - Thermal unfolding equilibria in homodimeric chicken gizzard tropomyosin coiled coils. AB - CD studies are presented on thermal unfolding of coiled-coil homodimers of two genetic variant chains of chicken gizzard tropomyosin (CG-Tm). The experiments include the effects of cross-linking both isoforms and the dependence on protein concentration of unfolding in both reduced isoforms, variables not examined in extant work. The general shapes of the unfolding curves for singly cross-linked species depend on whether the cross-link is at C190 (its site on one isoform) or at C36 (its site on the other). These curves are compared with extant ones for various cross-linked species of rabbit tropomyosin. The comparison supports the view that the unfolding behavior of cross-linked species results from a complex interaction of strain at the cross-link, local variations in structural stability, and loop entropy. The observed concentration dependence of the transition temperature for the uncross-linked (reduced) species of CG-Tm is very small (2.9 degrees C) for one variant homodimer and unobservably small (< 2 degrees C) for the other in the 100-fold concentration range (approximately 0.01 1.0 mg/mL) accessible here. These experimental values of delta Tm are much smaller than are predicted from extant values of the van't Hoff transition enthalpies, calling the latter into question. PMID- 7849228 TI - Predicting immunoglobulin-like hypervariable loops. AB - A two-stage method is developed to search the conformational space of small protein segments for low energy structures. Central features of the method are efficient procedures for generating small, eight-backbone atom, local moves in Cartesian coordinates and for introducing geometric constraints in adaptable Monte Carlo procedures. This allows natural implementation of an adaptive simulated annealing algorithm, which achieves an effective trade-off between speed and acceptance ratio. The method is applied to the calculation of various immunoglobulin loops. We also develop data base derived rules for identifying constraint condition, and show that the incorporation of an identified side-chain constraint allows a 1.2 A all-backbone atom rms deviation prediction of a 9 residue long L1 loop. PMID- 7849229 TI - Peptide libraries: determination of relative reaction rates of protected amino acids in competitive couplings. AB - In the solid phase preparation of synthetic peptide libraries, equimolarity of the resultant peptides in the mixture simplifies the identification of active compounds. Two primary methods for the preparation of combinatorial peptide mixtures are currently used. In the first method, the starting resin is divided into equal aliquots, individual amino acids are coupled to each aliquot, and the resin is then recombined. This process is repeated for each position. However, due to the physical process, each resin bead contains only one peptide sequence. Statistically, for mixtures of longer sequences, an ever-increasing amount of resin is necessary to ensure complete representation of each peptide in the library. Thus, each peptide will be represented in the library if a sufficient number of resin beads are used. In addition, the concentration of each peptide in the library depends on both the number of mixture positions in the library and the amount of resin used. In the second method, mixtures of amino acids are coupled simultaneously at each addition step. The proportion of each amino acid in the reaction mixture is varied inversely to its reaction rate such that, ideally, an equimolar mixture of each peptide is synthesized. An advantage of this method over the previous method is that each peptide is ensured to be represented in the library, although not necessarily in equimolar amounts. It is known that not only do the coupling rates of each amino acid vary, but the coupling rates of individual amino acids also change when coupled to different amino acid resins.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7849230 TI - A pharmacokinetic evaluation of HIV protease inhibitors, cyclic ureas, in rats and dogs. AB - The pharmacokinetics of a series of novel cyclic, non-peptide inhibitors of HIV protease were studied in rats or dogs after intravenous and oral administration. Six symmetrically substituted cyclic urea compounds (XK234, XM311, XM320, XM321, XM323, and XM412), which effectively inhibited HIV virus replication, with IC90 values of 0.03-1.0 microM (0.017-0.76 microgram mL-1), were evaluated. Plasma concentrations were measured in rats and dogs using specific and sensitive HPLC methods. In rats, the maximum plasma concentrations of 0.21-1.88 micrograms mL-1 were detected within 1 h of oral administration of 10 mg kg-1 of the compounds. The elimination half-lives ranged from 1.25 to 3.3 h in rats and the absolute oral bioavailability ranged from 18 to 100%. In dogs, the maximum plasma concentration and absolute oral bioavailability were 4.37 micrograms mL-1 and 48%, 1.07 micrograms mL-1 and 16%, and 1.48 mg ML-1 and 38% for XK234, XM311, and XM323, respectively. The data demonstrated that the maximum plasma concentrations of these cyclic ureas were several times higher than the IC90 for inhibition of viral replication after single doses of 10 mg kg-1 in rats and dogs. With this combination of high potency against virus replication and good oral bioavailability, these cyclic ureas represent a new class of compounds that are suitable for development as therapeutic agents for the treatment of HIV associated diseases. PMID- 7849231 TI - The effect of competitive and non-linear plasma protein binding on the stereoselective disposition and metabolic inversion of ibuprofen in healthy subjects. AB - The stereoselective disposition and metabolic inversion of ibuprofen were studied in 12 healthy subjects under conditions of competitive and non-linear plasma protein binding. Each subject received each of four oral treatments according to a Latin-square design: 300 mg R(-)-ibuprofen, 300 mg S(+)-ibuprofen, 300 mg R(-)( )+300 mg S(+)-ibuprofen, and 300 mg R(-)(-)+600 mg S(+)-ibuprofen. For a given treatment, the partial clearance of S(+)-ibuprofen was greater than that of R(-) ibuprofen for all stereoisomeric drug species. Likewise, the unbound partial clearances of S(+)-ibuprofen were greater for most stereoisomeric drug species. There was also less difference among treatment groups when partial clearances were referenced to unbound as opposed to total plasma concentrations of enantiomer. The unbound intrinsic clearance and fractional inversion of R(-) ibuprofen were unchanged across the four treatments, and chiral inversion was systemic, averaging 69%. In conclusion, stereoselective differences exist for the partial and composite clearances of R(-)- and S(+)-ibuprofen even when corrected for differences in plasma protein binding. However, differences among treatment groups for a particular elimination pathway are largely due to ibuprofen's non linear binding. PMID- 7849232 TI - The influence of chronic lobular hepatitis on pharmacokinetics of cefoperazone--a novel galactose single-point method as a measure of residual liver function. AB - Cefoperazone is a semisynthetic cephalosporin antibiotic containing a piperazine side chain, which results in antipseudomonal activity. Unlike the other cephalosporins, it is mainly cleared by the liver (60-80%) and it may be more sensitive to changes in the liver function and/or plasma protein binding than other cephalosporins, which are not primarily cleared by the liver. In order to study the influence of chronic lobular hepatitis on the pharmacokinetics of cefoperazone, a dose of 1 g of cefoperazone was administered to 11 normal, healthy volunteers and 16 subjects with chronic lobular hepatitis. In each volunteer or patient, a novel galactose single-point (GSP) method, the galactose elimination capacity (GEC) test, and the modified galactose elimination capacity (MGEC) test were also performed as a measure of residual liver function. Cefoperazone was administered intravenously over a period of 3-5 min. Blood and urine samples were collected at appropriate intervals after drug administration and stored at -30 degrees C until high-pressure liquid chromatographic (HPLC) analysis. The cefoperazone hepatic clearance, mean residence time, and renal clearance in hepatitis patients were significantly different from those of normal healthy volunteers, whereas the plasma protein binding was unaltered between the two groups. Urinary excretion of cefoperazone showed a highly significant increase in patients, 23.95 +/- 5.06% and 37.54 +/- 13.61% for normal men and hepatitis patients respectively. Hepatic clearance and fraction excreted in urine significantly correlated with values of GSP and MGEC respectively (p < 0.05). These results suggest (i) cefoperazone kinetics was significantly altered in patients with chronic lobular hepatitis; (ii) GSP, a novel simple, clinically useful quantitative liver function test, can predict the cefoperazone hepatic clearance in patients with liver dysfunction. PMID- 7849233 TI - Relative bioavailability of two oral formulations of navelbine in cancer patients. AB - A study was carried out in 14 cancer patients to assess the relative bioavailability of two oral formulations of navelbine. A single 130 mg oral dose of the drug was given according to a randomized two-way crossover design as two capsules: one contained the drug in powder (formulation A, reference); another contained the drug in solution (formulation B). A 7 d washout period separated each dose. Navelbine was rapidly absorbed after administration of either formulation and exhibited a biphasic concentration decay pattern. The peak plasma level was reached within 2 h of administration in most patients. Formulation B resulted in better navelbine absorption with respect to peak plasma concentration (Cmax) and area under the plasma concentration-time curves (AUC) than did formulation A as ascertained by analysis of variance (ANOVA). The relative bioavailabilities (solution versus powder) were, respectively, 286.0% and 268.0% as estimated from experimental (0-72 h) and extrapolated (0-infinity) AUC. PMID- 7849234 TI - Variability in the disposition of chlorzoxazone. AB - Chlorzoxazone is 6-hydroxylated by cytochrome P450 2E1 (CYP 2E1), which bioactivates many toxic and carcinogenic molecules. Seventeen volunteers of varying age, ethnicity, and gender received a 250 mg tablet of chlorzoxazone and their blood and urine were sampled frequently for 8 h. V/F = 42 +/- 21 L and CL/F = 412 +/- 120 mL min-1. Comparison of these values with a study by other investigators using a suspension dosage form suggested that relative Ftablet approximately 0.7. The fraction excreted in the urine as 6-hydroxychlorzoxazone (fe,6-OH) was 0.39 +/- 0.20 and that portion of the total CL accounted for by CYP 2E1-mediated metabolism (CL6-OH) was 163 +/- 95 mL min-1. Thus, while V/F and CL/F varied by factors of less than five, fe,6-OH varied 16-fold and CL6-OH varied 28-fold. These results suggested that there was considerable inter individual variability in the metabolism of chlorzoxazone to 6 hydroxychlorzoxazone. This variability will significantly affect the construction of physiologically based pharmacokinetic models that use the 6-hydroxylation of chlorzoxazone as a marker for an individual's CYP 2E1 phenotype. PMID- 7849235 TI - Relationship between plasma and bone concentrations of cefuroxime and flucloxacillin. Three different parenteral administrations compared in 30 arthroplasties. AB - (i) The objective was to determine the range of bone levels of cefuroxime and flucloxacillin achieved after one intravenous (IV) administration of different dosages of cefuroxime and flucloxacillin. (ii) Six groups of five patients participated in the study. The first three groups (A-C) received respectively 1500 mg, 1000 mg, and 500 mg cefuroxime intravenously and the second three groups (D-F) received 2000 mg, 1500 mg, and 1000 mg flucloxacillin intravenously. (iii) Parenteral administration of cefuroxime and flucloxacillin resulted in measurable bone concentrations in all patients. (iv) Large inter-individual variation in bone concentration was observed. (v) The bone concentrations of IV cefuroxime were higher (1500 mg, p = 0.0057; 1000 mg, p = 0.0260) than those of flucloxacillin. The bone concentrations of cefuroxime and flucloxacillin were dose dependent. PMID- 7849236 TI - Pharmacokinetic profile of conjugated verrucarol urinary metabolites in dogs. AB - The pharmacokinetics and renal excretion of a trichothecene mycotoxin, verrucarol, were studied in six mongrel dogs following IV administration (0.4 mg kg-1). The fraction of verrucarol excreted intact in the urine ranged from 0.9% to 2.7% of the administered dose. The fraction of verrucarol metabolites excreted in the urine was 32-60% for verrucaryl glucuronides and 32-47% for verrucaryl sulphates. These urinary conjugated metabolites were analysed quantitatively following their enzymatic hydrolysis. The half-life of verrucarol calculated from the urinary data of its conjugated metabolites was not significantly different from the half-life calculated from the plasma data of the parent compound. PMID- 7849237 TI - Plasma pharmacokinetics and urinary and biliary excretion of a new potent tripeptide HIV-1 protease inhibitor, KNI-272, in rats after intravenous administration. AB - The pharmacokinetic (PK) characteristics of KNI-272, a potent and selective HIV-1 protease inhibitor, were evaluated in rats after intravenous (IV) administration. The effect of dose on KNI-272 plasma kinetics, and the urinary and biliary elimination kinetics of KNI-272, were examined. After IV administration of 10.0 mg kg-1 KNI-272, the mean terminal elimination half-life, t1/2 lambda zeta, was 3.49 +/- 0.19 (SE) h, the total plasma clearance, CLtot, was 15.1 +/- 1.2 mL min 1 and the distribution volume at steady state, Vd,ss, was 3790 +/- 280 mL kg-1. On the other hand, after 1.0 mg kg-1 IV administration, t1/2 lambda zeta was 3.04 +/- 0.11 h, CLtot was 15.9 +/- 0.2 mL min-1, and Vd,ss was 6950 +/- 600 mL kg-1. The PK parameters of KNI-272 after IV administration showed that the disposition of KNI-272 in the rat plasma is linear within the dose range from 1.0 to 10.0 mg kg-1. Using an equilibrium dialysis method, the plasma binding of KNI-272 was measured in vitro. The free fractions were 17.7 +/- 0.6%, 12.1 +/- 1.5%, and 13.8 +/- 1.4% at the total concentration ranges of 9.898 +/- 0.097 microgram mL-1, 0.888 +/- 0.008 microgram mL-1, and 0.470 +/- 0.55 microgram mL-1, respectively. The percentages of the dose excreted into the urine and bile as the unchanged form were 1.20 +/- 1.06% and 1.61 +/- 0.32% at 1.0 mg kg-1 dose, and 0.164 +/- 0.083% and 1.42 +/- 0.26% at 10.0 mg kg-1 dose, respectively. The renal clearance (CLR) and the biliary clearance (CLB) were calculated to be 0.191 and 0.256 mL min-1 for 1.0 mg kg-1, and 0.0248 and 0.215 mL min-1 for 10.0 mg kg-1, respectively. When comparing these values with the CLtot values, the urinary and biliary excretion of KNI-272 are minor disposition routes. PMID- 7849238 TI - Zn2+ inhibits the anion transport activity of band 3 by binding to its cytoplasmic tail. AB - Zn2+ can induce a conformational change of Band 3 with concomitant inhibition of its anion transport activity of human erythrocyte membrane vesicles only from the cytoplasmic side. The Zn2+ inhibition exhibits a dose-dependent manner with an apparent half maximal concentration of 50 microM ZnCl2 and can be reversed by 0.5 mM EDTA, but not by 1 mM dithiothreitol. The Zn2+ effect is specific and no similar inhibitory action could be observed by other divalent cations (Cu2+, Mn2+, Mg2+ or Sr2+). PMID- 7849239 TI - Action of neurohypophysial granule Lys-Arg endopeptidase on synthetic polypeptides comprising the processing sequence of provasopressin-neurophysin. AB - Neurohypophysial granule Ca(2+)-dependent endopeptidases have been allowed to act on synthetic polypeptides derived from the N-terminal sequence of bovine provasopressin-neurophysin, namely vasopressinyl-glycyl-lysyl-arginyl-alanylamide and vasopressinyl-glycyl-lysyl-arginyl-alanyl-methionyl-serinamide+ ++. Membrane bound enzymes have been used at pH 5.5 for 16 hr at 37 degrees C. Products have been identified by high-pressure liquid chromatography (HPLC) and by mass spectrometry performed on substances isolated by HPLC. With both substrates, vasopressinyl-Gly-Lys-Arg(OH) has been identified as a product confirming the Lys Arg specificity previously observed on small peptide fluorogenic substrates. Cleavage yields, however, appear low suggesting that some factors are missing, for example a targeting action of the precursor neurophysin domain to the granule membrane. PMID- 7849240 TI - A proper transmembrane Ca2+ gradient is essential for the stimulation of adenylate cyclase activity by stimulatory GTP-binding protein. AB - Stimulatory GTP-binding Protein (Gs) and adenylate cyclase prepared from bovine brain cortices were co-reconstituted into asolectin vesicles with or without 1000 fold transmembrane Ca2+ gradient. The results showed that both basal activity and Gs-stimulated activity of adenylate cyclase were highest in proteoliposomes with a transmembrane Ca2+ gradient similar to physiological condition (1 microM Ca2+ outside and 1 mM Ca2+ inside) and lowest when the transmembrane Ca2+ gradient was in the inverse direction. Such a difference could be diminished following dissipation of the transmembrane Ca2+ gradient by A23187. Comparable conformational changes of Gs in proteoliposomes were also observed when Gs was labeled with the fluorescence probe, acrylodan. These results may indicate that a proper transmembrane Ca2+ gradient is essential not only for higher adenylate cyclase activity but also for its stimulation by Gs. PMID- 7849241 TI - Role of cell membrane Na,K-ATPase for survival of human lymphocytes in vitro. AB - Lymphocytes are primordial immune cells with variable life times. Besides genetic programming, extracellular factors interacting with cell surface receptors might alter cell survival. We investigated whether the activity of the membrane embedded Na,K-ATPase (EC3.6.1.37) or sodium pump (NKA) plays a role for cell survival since this ubiquitous system establishes the vital transmembrane Na and K gradients as well as the resulting high intracellular K/Na ratio required for macromolecule synthesis; furthermore, the system exposes an extracellular inhibitory receptors for cardioactive steroids and palytoxin. Isolated human lymphocytes were incubated in vitro and their viability assessed by exclusion of trypan blue. Various incubation conditions were compared; in RPMI-1640 medium cell viability was preserved for 30 h at 37 degrees C. Externally added ouabain, a hydrophilic cardioactive steroid, blocked the [86Rb]potassium uptake at nanomolar concentrations. Despite pump inhibition ouabain did not alter lymphocyte survival, even at 10 mM for 30 h. By contrast, the hydrophilic toxin palytoxin, the most potent animal poison described so far, killed all cells within 2 h at 10 nM; this toxin is known to act via the sodium pump and to provoke deadly cation-leaks by unmasking a channel component. Intracellular Na increased and K decreased as measured by atomic absorption spectrometry in presence of palytoxin; cell swelling was seen by electron microscopy. Ouabain protected the cells from the toxic effect of palytoxin. The results reveal a pivotal role of NKA integrity for lymphocyte survival. PMID- 7849243 TI - Cyclosporine for nephrotic syndrome--isn't it time for a collaborative trial? PMID- 7849242 TI - Coxsackievirus B3 entry into the host cell interferes with G-protein-mediated transmembrane signalling. AB - In the present work we used various cell lines in order to study the possible effect of coxsackievirus B3 (CVB3) entry on the adenylyl cyclase transmembrane signalling system. A significant decrease (by about 10-20%) was found in forskolin-augmented as well as in A1F-4- and GTP gamma S-sensitive adenylyl cyclase activity in plasma membranes isolated from HeLa, HEp-2, Vero and green monkey kidney cells shortly (up to 60 min) preincubated with CVB3 (5 PFU/cell). Moreover, the ability of G-proteins derived from plasma membranes of infected cells to reconstitute AC activity in the cyc- mutant of S49 cells was also reduced. Content of G-protein subunits, however, remained unchanged after CVB3 attachment. Functional alterations in the G-protein-mediated adenylyl cyclase signalling system were accompanied by a marked decrease (by about 20-40%) of intracellular cAMP levels in virus-affected cells. These findings demonstrate clearly that CVB3 may affect functioning of the G-protein regulated adenylyl cyclase transmembrane signalling system in virus-sensitive cells as early as during the first period of its contact with the cellular plasma membrane. PMID- 7849244 TI - Cyclosporine in the treatment of idiopathic nephrosis. AB - Within the past decade, there have been numerous reports on the use of cyclosporine in idiopathic nephrosis. In this review, the results of both uncontrolled and controlled studies of the therapeutic effects of cyclosporine in steroid-sensitive/dependent idiopathic nephrosis and in steroid-resistant idiopathic nephrosis are analyzed. Cyclosporine is efficient in up to 80% of patients with steroid-sensitive/dependent idiopathic nephrosis. Most patients, however, relapse when the drug is withdrawn, thus necessitating prolonged treatments. Although cyclosporine is less efficient in patients with steroid resistant idiopathic nephrosis, a few studies seem to indicate that this drug may be successful in some patients, especially if combined with corticosteroids. There is no evidence that cyclosporine can prevent the recurrence of nephrotic syndrome on the graft after renal transplantation. However, in patients in whom disease has recurred, high doses of cyclosporine may be effective alone or in combination with plasma exchanges. The main worrisome side effect of cyclosporine is chronic nephrotoxicity, which should be differentiated from acute or "functional" toxicity. Follow-up studies including pretreatment and posttreatment renal biopsies show a lack of correlation between structural damage and renal function, suggesting that a histologic examination of the renal parenchyma is the only reliable way of evaluating chronic cyclosporine nephrotoxicity. PMID- 7849245 TI - Unexpected encephalopathy in chronic renal failure: hyperammonemia complicating acute peritonitis. AB - A woman with mild chronic renal insufficiency was being treated with glucocorticoids for a presumed chronic inflammatory disease. She developed peritonitis arising from a pelvic abscess, which was drained without complications. Unexpectedly, she became obtunded, and eventually, the neurologic dysfunction was linked to hyperammonemia in spite of normal liver function tests. Hyperammonemia was only transiently controlled in spite of protein restriction, repeated hemodialysis, and the use of biochemical means to reduce ammonia. A recurrent pelvic abscess was drained, and hyperammonemia disappeared. A review of ammonia and nitrogen metabolism indicates that bypassing the liver with shunting of ammonia into the systemic circulation should be added to the causes of symptomatic hyperammonemia. Treatment requires the elimination of the bacteria. PMID- 7849246 TI - Endothelin stimulates mitogen-activated protein kinase activity in mesangial cells through ETA. AB - Accumulating evidence suggests that endothelin (ET) contributes to the pathophysiology of such disorders as acute renal failure, cyclosporine-mediated renal and vascular toxicity, and perhaps even glomerular inflammation. The postreceptor signaling pathways that mediate the actions of ET in these pathophysiologic conditions may include activation of kinase cascades. Thus, the effects of ET isopeptides on p42 and p44 mitogen-activated protein (MAP) kinase activity in rat glomerular mesangial cells were examined. ET-1 activated both p42 and p44 MAP kinases with similar dose responses and different kinetics. The threshold for kinase activation was 10(-9) M ET-1. ET-1 stimulated p42 and p44 MAP kinases with similar rapid (5 min) but different sustained activation of p42 (3 to 6 h) and p44 (1 to 2 h). Endothelin-3 (ET-3) also activated both isoforms of MAP kinase but with a threshold at 10(-7) M. Compared with ET-1, ET-3 stimulated only a rapid increase of p42 MAP kinase activity. We further investigated which ET receptors are coupled to MAP kinase activation. BQ-123, an ETA blocker, completely blocked the responsiveness of the MAP kinase to either ET 1 or ET-3. In Chinese hamster lung fibroblasts transfected with ETA or ETB cDNA, both receptors showed a rapid stimulation of MAP kinase in response to ET-1. These results suggest that ET can activate MAP kinases through both ET receptors but act exclusively through ETA in glomerular mesangial cells. PMID- 7849247 TI - Preferential uptake of intermediate-density lipoproteins from nephrotic patients by human mesangial and liver cells. AB - Hyperlipidemia of nephrotic origin could potentially cause glomerular injury as well as increase the risk of atherosclerosis. The precise interaction of human lipoproteins abnormal in lipid and protein composition, with lipoprotein receptors has not been clearly defined. This study examines receptor-mediated uptake and intracellular cholesterol metabolism of apolipoprotein (apo)B,E containing intermediate-density lipoprotein (IDL) and apoB-100 containing low density lipoprotein (LDL), isolated from patients with the nephrotic syndrome (N = 6), in human glomerular mesangial and HepG2 cells. In the patients, serum IDL and LDL cholesterol levels were significantly increased as compared with those of healthy subjects. The IDL of nephrotic patients contained 80% more cholesterol than the IDL of healthy controls. No differences in lipid/protein composition were found in the LDL density range. Therefore, nephrotic and control LDL showed identical affinities for receptor-mediated uptake. In contrast, the IDL of nephrotic patients was taken up by mesangial cells and HepG2 with higher affinity than the LDL. Intracellular sterol synthesis was suppressed more effectively and cholesterol esterification rate was enhanced 2.2-fold by nephrotic IDL as compared with control IDL. These data indicate that hypercholesterolemia of nephrotic origin cannot be explained by reduced ligand binding for LDL. ApoE containing IDL of patients with the nephrotic syndrome were avidly taken up by glomerular mesangial cells and could therefore play the predominant role in the development of glomerulosclerosis and atherosclerosis associated with this disorder. PMID- 7849248 TI - Uptake of atrial natriuretic peptide and production of cGMP in cultured human glomerular endothelial cells. AB - Interactions between human glomerular endothelial cells and atrial natriuretic peptide (ANP) were studied with 125I-alpha-human-ANP binding and intracellular accumulation of cGMP. Uptake for alpha-hANP (1-28 or 5-28) by homogeneous cultures of human glomerular endothelial cells was dose and time dependent with optimal uptake occurring after 30 min of incubation at 37 degrees C. Scatchard analysis of the specific binding data with a two-compartmental model identified both high (Kd = 0.3 nM)- and low (Kd = 10 nM)-affinity receptors, with a binding site density of 12,000 and 18,060 receptors per cell, respectively. alpha-hANP markedly stimulated glomerular endothelial cell-associated cGMP. After a 2-min incubation, cGMP increased 1.3-fold (from 17.88 +/- 1.29 to 23.33 +/- 3 pmol/mg of protein), in the presence of 1 nM ANP, to more than threefold (from 21 +/- .1 to 80.5 +/- 14.5 pmol/mg of protein) with 1 microM ANP (P < 0.05). In contrast, a 10 microM concentration of the clearance receptor C-ANP4-23 increased cGMP by 1.6 +/- 0.6 fold. ANP stimulation of intracellular cGMP was 100 times more sensitive in human glomerular endothelial than in mesangial cells. In comparison, higher doses of bradykinin were necessary to evoke similar responses in glomerular endothelial cells. In the presence of 10 microM bradykinin, cellular cGMP increased by 1.75 +/- 0.6-fold versus control cells. However, unlike ANP, bradykinin-stimulated cGMP synthesis was significantly inhibited by prior treatment with oxyhemoglobin (10(-5) M), an inhibitor of soluble guanylate cyclase, and NG-nitro-L-arginine (NO2Arg), a specific inhibitor of endothelial derived relaxing factor (EDRF).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7849249 TI - HS-142-1, a potent antagonist of natriuretic peptides in vitro and in vivo. AB - To determine whether HS-142-1 (HS), a potent atrial natriuretic peptide (ANP) receptor antagonist, also inhibits the effects of brain natriuretic peptide (BNP), urodilatin (URO), and C-type natriuretic peptide, in vitro studies were carried out, demonstrating that HS inhibited production of cGMP by rat fetal lung fibroblast cells induced by ANP, BNP, URO, and C-type natriuretic peptide. Acute clearance studies were conducted in euvolemic Munich-Wistar rats under inactin anesthesia to characterize the effects of HS in vivo. In response to ANP, BNP, or URO (4 micrograms/kg priming dose plus 0.5 micrograms/kg per minute for 20 min), urine flow, absolute sodium excretion rates, and fractional sodium excretion exhibited similar increases (four- to fivefold) in vehicle-treated rats; these responses were, however, completely abolished by prior HS treatment. The tendency for GFR to rise during the infusion of natriuretic peptides (NP) was also blocked after HS. By contrast, HS did not block the renal effects of L-arginine, a precursor of nitric oxide, or of furosemide. Furthermore, the inhibition of endogenous NP by HS was associated with small but significant reductions in GFR and absolute and fractional sodium excretion in normal rats under euvolemic but not hydropenic conditions. These studies provide evidence that the observed effects of HS in vivo and in vitro are mediated exclusively by receptors of NP. Together, these data support the view that HS is a highly specific ligand for NP receptors, capable of antagonizing the renal effects not only of exogenous ANP, but also those of BNP and URO. PMID- 7849250 TI - Increased susceptibility to thiazide-induced hyponatremia in the elderly. AB - Hyponatremia is a common cause of morbidity in the elderly, and thiazide diuretics are often implicated. Eleven healthy young volunteers, eight healthy old volunteers, and five elderly patients with a history of thiazide-induced hyponatremia were studied to determine susceptibility to thiazide-induced hypoosmolality in age. Each of the healthy subjects ingested a water load (20 mL/kg) after 3 days of hydrochlorothiazide (HCTZ) (100 mg/day) or placebo. Although there were no differences in minimum Uosm between young and old, the healthy old had lower hourly free water clearances (CH2O) as compared with the young and a greater decline in serum osmolality in response to water loading (P < 0.05). HCTZ impaired minimum urine osmolality and CH2O and delayed recovery of serum osmolality after the water load in both healthy young and old (P < 0.005, placebo versus HCTZ), but the impairment in the latter two parameters was greater in the healthy elderly (P < 0.05, young versus old). Vasopressin levels were not different between healthy young and old (1.9 +/- 0.3 versus 2.0 +/- 1.0 pm with placebo; 3.0 +/- 0.7 versus 4.4 +/- 1.0 with HCTZ). Five of the young subjects were restudied after the addition of ibuprofen (400 mg thrice daily) to the thiazide and placebo regimens. Creatinine clearance was not changed, but free water clearance and serum osmolality after water loading were significantly reduced to a degree similar to that seen in the elderly subjects on the thiazide regimen (P < 0.05), suggesting an important role for renal prostaglandins in the defense against hyponatremia. PMID- 7849251 TI - Influence of gender on renal thiazide diuretic receptor density and response. AB - The influence of gender and gonadectomy on (1) the density of the renal thiazide sensitive ion transporter, as quantitated by the ability of renal membranes to bind (3H)metolazone, and (2) the changes in the urinary excretion of electrolytes caused by maximal bendroflumethiazide (BFTZ) in Sprague-Dawley rats was determined. The density of the thiazide receptor was twofold higher (P < 0.001) in females than in males. Orchiectomy increased thiazide receptor significantly in one of two studies (P < 0.01). Ovariectomy decreased thiazide receptor by more than 20% (P < 0.01) in both studies. The rates of the urinary excretion of sodium and chloride after BFTZ and the increases in the urinary excretion of sodium, chloride, and ammonium caused by BFTZ were greater in intact females than in intact males; BFTZ decreased the urinary excretion of calcium 50% in intact females, but not in intact males. Regression analysis of the thiazide receptor (in intact and gonadectomized animals) versus the urinary excretion of electrolytes before and after BFTZ yielded a model in which one-third of the variation in thiazide receptor could be related to the change in the excretion of calcium and ammonium produced by BFTZ, raising the possibility that the density of the thiazide receptor might be related to calcium or acid-base homeostasis. It was concluded that the renal excretion of sodium, chloride, calcium, and ammonium are, in part, controlled by gender and sex hormones via their regulation of the renal density of the thiazide diuretic receptor. PMID- 7849253 TI - Endogenous dopamine regulates phosphate reabsorption but not NaK-ATPase in spontaneously hypertensive rat kidneys. AB - Dopamine's modulatory actions on signal transduction in the spontaneously hypertensive rat (SHR) proximal tubule are blunted; therefore, it was predicted that dopamine does not regulate phosphate (Pi) reabsorption in SHR. To test this hypothesis, dopamine production was inhibited with carbidopa (10 mg/kg ip) 18 h before and during clearance measurements of chronically denervated SHR and Wistar Kyoto (WKY) rat kidneys. Dopamine excretion decreased 80% from SHR and 85% from WKY rats. Pi excretion decreased 60 to 67%. Plasma Pi and calcium, inulin clearance, and Na excretion did not change. Citrate excretion, which reflects proton secretion by proximal tubules, decreased 72% from WKY rats. Citrate excretion was significantly lower from SHR (5 +/- 10 pmol/min) than from WKY rats (73 +/- 11 pmol/min) and was not altered by carbidopa. Carbidopa, injected 18 and 1 h before kidneys were collected, increased NaK-ATPase in cortical basolateral membranes from WKY rats (27%) but not in membranes from SHR. After the incubation of renal cortical minceates for 15 min with L-DOPA (10(-5) M), there was no change in brush border membrane vesicle uptake of 32Pi, (3H)glucose, or (14C)citrate. Incubation with carbidopa (10(-4) M) increased 32Pi uptake by 11% (P < 0.001) and (3H)glucose uptake by 9% (P = 0.02). (14C)citrate uptake was not increased by carbidopa but was higher in SHR (977 +/- 2 pmol/10 s.mg) than in WKY rats (823 +/- 43 pmol/10 s.mg; P = 0.04). In summary, dopamine produced in WKY rat and SHR proximal tubules decreases Pi uptake by using a signaling process distinct from those that regulate NaK-ATPase and the antiporter.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7849252 TI - Renal vasoconstriction with U-46,619; role of arachidonate metabolites. AB - Thromboxane A2 (TxA2) or its stable mimetic U-46,619 can increase the generation of arachidonate metabolites. Therefore, these studies were designed to investigate the role of prostaglandins, TxA2, and leukotrienes in the renal vascular response to U-46,619. Anesthetized rats were studied during a basal period and during an intra-aortic infusion of vehicle or U-46,619 (1 micrograms/kg per minute). U-46,619 reduced the GFR and the RBF without changing the mean arterial pressure or the femoral vascular resistance. All of the effects of U-46,619 were blocked by pretreatment with the TxA2/prostaglandin H2 receptor antagonist SQ-29,548. Pretreatment with the cyclo-oxygenase inhibitor indomethacin did not modify the renal vascular response to U-46,619. However, pretreatment with the TxA2 synthesis inhibitor UK-38,485 or with the leukotriene D4/E4 antagonist LY-163,443 markedly blunted the U-46,619-induced increase in renal vascular resistance and the decrease in GFR. These results indicate that the renal vascular response to U-46,619 is receptor mediated and is promoted by TxA2 and leukotriene D4/E4. PMID- 7849254 TI - Angiotensin 1-7 has a biphasic effect on fluid absorption in the proximal straight tubule. AB - The effect of angiotensin 1-7 (Ang 1-7) on the proximal tubule has not been well studied. It was hypothesized that Ang 1-7 has a biphasic effect on fluid absorption in the isolated rat proximal straight tubule. Proximal straight tubules were perfused at a rate of 5.81 +/- 0.44 nL/mm per minute and absorbed fluid at 0.98 +/- 0.10 nL/mm per minute. Bicarbonate absorption was 80.1 +/- 11.6 pmol/mm per minute. When 10(-12) M Ang 1-7 was added to the bath, fluid absorption increased to 1.47 +/- 0.10 nL/mm per minute (P < 0.013) and bicarbonate increased to 115.0 +/- 12.8 pmol/mm per minute (P < 0.004). Ang 1-7 had no effect on either the maximum rate of bicarbonate absorption (P > 0.90) or bicarbonate permeability (P > 0.60). Next, 10(-8) M Ang 1-7 was used. During the control period, fluid absorption was 0.90 +/- 0.09 nL/mm per minute. When 10(-8) M Ang 1-7 was added, fluid absorption decreased to 0.62 +/- 0.04 nL/mm per minute (P < 0.05). DuP 753, an AT1 receptor antagonist, blocked both effects induced by Ang 1-7, whereas PD 123319, an AT2 receptor antagonist, did not block the stimulatory effect. From these data, it was concluded that Ang 1-7 binds AT1 receptors and has a biphasic effect on fluid absorption, and at physiologic levels, the heptapeptide induces the stimulation of bicarbonate absorption. PMID- 7849255 TI - Evidence that an angiotensin-converting enzyme inhibitor has a different effect on glomerular injury according to the different phase of the disease at which the treatment is started. AB - In rats with streptozotocin-induced diabetes, the effect of an angiotensin converting enzyme (ACE) inhibitor on the evolution of glomerular injury according to the time at which the treatment is started with respect to the onset of the disease was studied. Three groups of animals were used, a control Group 1 and two groups of diabetic rats treated with insulin (Groups 2 and 3). The latter were monitored until urinary protein excretion reached 40 to 50 mg/24 h (on average, 23 wk after the induction of the diabetes). At this time, Group 2 continued to receive insulin alone, whereas Group 3 was also given the ACE inhibitor moexipril for 8 more wk. Untreated diabetic rats showed a moderate increase in systolic blood pressure that was normalized by moexipril administration. Urinary protein excretion progressively increased during the 8-wk follow-up in untreated diabetics that, at the end of the study, developed moderate glomerular sclerosis. Moexipril treatment lowered urinary protein excretion to a normal range and completely prevented glomerular injury. Three other groups of rats were similarly treated, except that moexipril treatment was started later on (when proteinuria reached 100 to 200 mg/24 h, on average, 32 wk after the induction of diabetes), and were monitored for another 8 wk. Untreated and treated diabetics had comparable blood glucose levels throughout. Systolic blood pressure, significantly increased in untreated diabetic rats, was effectively controlled by moexipril administration.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7849256 TI - Decreased glomerulosclerosis in aging by angiotensin-converting enzyme inhibitors. AB - To evaluate the effects of angiotensin-converting enzyme inhibition on renal aging, enalapril was administered in the drinking water to three groups of CF1 mice at doses of 20 mg/L (Group A), 10 mg/L (Group B), and 5 mg/L (Group C). These experimental groups were compared with 20 CF1 mice not receiving enalapril (Group D). At 2 yr, total body weight was 48.1 +/- 7.5 g in Group A, 47.7 +/- 7.1 g in Group B, 47.6 +/- 4.6 g in Group C, and 35.1 +/- 5.4 g in Group D. The ratio of kidney to total body weight, in percentages, was 1.8 +/- 0.3, 1.6 +/- 0.3, 1.9 +/- 0.2, and 1.5 +/- 0.1 in Groups A, B, C, and D, respectively. Morphometric studies of the kidneys revealed the glomerular diameter to be 86.7 +/- 18.0 microns, 96.9 +/- 6.3 microns, 91.1 +/- 11.4 microns, and 106.8 +/- 9.3 microns in Groups A, B, C, and D, respectively. The number of glomeruli per square millimeter of renal cortex was 9.6 +/- 3.7, 12.3 +/- 2.7, 12.4 +/- 8.6, and 3.2 +/- 1.5 in Groups A, B, C, and D, respectively. The mesangial area per glomerulus, in percentages, was 11.6 +/- 4.8, 13.9 +/- 2.9, 14.2 +/- 3.1, and 20.6 +/- 1.9 in Groups A, B, C, and D, respectively. The percentage of glomeruli with sclerosis was 0.1 +/- 0.1, 0.3 +/- 0.1, 0.6 +/- 0.2, and 11.6 +/- 1.9 in Groups A, B, C, and D, respectively.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7849257 TI - Tubular fluid concentrations and kidney contents of angiotensins I and II in anesthetized rats. AB - Previous micropuncture studies have reported nanomolar concentrations of angiotensin II in proximal tubular fluid and have indicated that angiotensin II or a precursor may be secreted into the tubular lumen. Further experiments were performed to determine if proximal tubular fluid angiotensin I concentrations are also greater than plasma and kidney levels and to estimate the degree of intrarenal compartmentalization of the angiotensin peptides. Free-flow proximal tubular fluid samples were collected in micropipets and were pooled for each animal. At the end of each experiment, a blood sample was collected and the micropunctured left kidney was harvested and homogenized in methanol. The angiotensin I concentration in proximal tubular fluid samples averaged 6.1 +/- 1.2 pmol/mL, whereas the angiotensin II concentration averaged 8.1 +/- 1.6 pmol/mL (N = 13). HPLC analysis of a separate sample pooled from collections in five rats indicated that the immunoreactive angiotensin I and angiotensin II primarily represented authentic angiotensin I and II. Plasma concentrations of angiotensin I and angiotensin II averaged 0.39 +/- 0.09 and 0.15 +/- 0.03 pmol/mL, respectively. The kidney contents of angiotensin I and angiotensin II were 1.28 +/- 0.24 and 0.97 +/- 0.17 pmol/g of kidney, respectively. These findings indicate that proximal tubular fluid contains nanomolar concentrations of angiotensin I as well as angiotensin II. These high tubular fluid concentrations, which greatly exceed the plasma and kidney levels, likely reflect net secretion of the angiotensin peptides by proximal tubule cells.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7849258 TI - Linkage disequilibrium between the CA microsatellite D16S283 and PKD1. PMID- 7849259 TI - Lidocaine for the alleviation of pain associated with subcutaneous erythropoietin injection. PMID- 7849260 TI - The role of nuclear receptors in steroid hormone production. AB - Epidemiological studies implicate steroid hormones as important factors in the development of neoplasia, and hormonal manipulation constitutes an important treatment arm in cancer therapy. Recent studies demonstrate a key role for nuclear receptor proteins in the expression of genes encoding the cytochrome P450 enzymes responsible for steroid hormone biosynthesis. Two orphan nuclear receptors, SF-1 and NGFI-B, regulate steroid hydroxylase transcription; the gene encoding SF-1 is also essential for adrenal and gonadal development. These results highlight the importance of specific nuclear receptors in regulating the enzymes that make essential steroid hormones and in the differentiation of the primary steroidogenic tissues. Ultimately, these nuclear receptors may provide new targets for the design of novel therapies for hormone-dependent cancers. PMID- 7849261 TI - Definition of the cellular mechanisms which distinguish between hormone and antihormone activated steroid receptors. AB - Steroid hormones are key regulatory molecules required for the coordinated regulation of the events associated with growth, differentiation and maintenance of cellular homeostasis. A large number of clinical abnormalities have been shown to be associated with defects in sex steroid hormone production or in the way the cell responds to these hormonal stimuli. As a consequence of the need to modulate the action of the sex steroids, several antihormones, compounds which oppose the action of the natural hormones, have been developed. These antihormones have found widespread application in the treatment of breast and prostate cancers, endometriosis and uterine fibroids. Of late, considerable progress has been made in defining the precise molecular mechanism of action of steroid hormones and their corresponding antihormones. It is anticipated that this information will impact the discovery and development of novel antihormones with improved therapeutic profiles. PMID- 7849262 TI - Factors influencing nuclear receptors in transcriptional repression. AB - Members of the steroid receptor superfamily, like other transcription factors, can function as transcriptional inducers as well as repressors of transcription. The mechanisms by which repression is achieved seem to be specific for the factors and regulatory sequences involved. Silencing activity is conferred by the DNA bound v-ERBA, which is able to repress the activity of a complete or of a minimal promoter. Removal of the T3 or RA ligands converts the activated form of TR or RAR into a silencing conformation. Ligand-free TR, RAR or v-ERBA synergize with the DNA-bound negative protein 1 (NeP1) in a specific silencer sequence. In contrast to silencing, competitive repression is seen for specific negative hormone response elements. These elements are characterized by the presence of binding sites for other transcription factors. PMID- 7849264 TI - Genomic cross-talk between the estrogen receptor and growth factor regulatory pathways in estrogen target tissues. AB - Cell proliferation and differentiation are modulated by both estrogens and growth factors. Even though these two kinds of effectors interact with receptors localized in different compartments of the cell, their nuclear end points are often on the same genes. We review here the first evidence for transcriptional interference between these two regulatory pathways which might be essential in understanding the control of cell proliferation and invasion in human estrogen responsive cancers. PMID- 7849263 TI - Negative transcriptional regulation by nuclear receptors. AB - Steroid and thyroid hormones, and vitamins A and D bind to nuclear receptors, which act as ligand-modulated transcription factors. In many cases, ligand activated nuclear receptor binds to positively acting hormone response elements (p-HREs) to induce gene transcription. However, ligand-activated receptors also repress transcription of specific genes and several mechanisms that account for negative regulation have recently emerged. One major form of negative regulation is based on transcriptional interference between nuclear receptors and other transcription factors, such as AP-1. In this case, the liganded receptor prevents AP-1 or other positively acting transcription factors from fruitful interaction with the transcription initiation complex. A second form of negative regulation is based on binding of nuclear receptors to specialized negative HREs (n-HREs). Binding of unliganded receptor to such an element results in constitutive activation, which is terminated by the binding of ligand. While transcriptional interference with AP-1 has been described for many members of the nuclear receptor family, negative regulation through n-HREs so far has been shown only for one of the thyroid hormone receptors. However, this type of negative regulation is likely to be widespread. PMID- 7849265 TI - Steroid receptor variants and their potential role in cancer. AB - Variant forms of steroid receptors that possess altered structure have been described in a number of human cancers. This is particularly true for tumors of the breast, which frequently contain a variety of defective estrogen receptors. Evidence for the existence of steroid receptor variants in human tumors is summarized along with what is known regarding the functional behavior of these aberrant receptors. This article also discusses the implications that steroid receptor variants have for the diagnosis and treatment of tumors of the breast and other human malignancies. PMID- 7849266 TI - Cell cycle control by steroid hormones. AB - Steroid hormones have well documented stimulatory and inhibitory effects on target cell proliferation. These effects are steroid- and target cell-specific and are mediated by cell cycle phase-specific actions. The molecular mechanisms by which steroids control rates of cell cycle progression are, however, not well defined. Recent advances in our understanding of cell cycle control by proto oncogenes, tumor suppressor genes and cyclin dependent kinases provide models for further delineating the molecular basis of proliferation control by steroids. Transcriptional activation of c-fos, c-myc and cyclin D1 by estrogens and progestins in breast cancer cells and inhibition of expression of these genes by antiestrogens provide a paradigm for further understanding cell cycle control by steroids. PMID- 7849267 TI - The role of androgen in the regulation of programmed cell death/apoptosis in normal and malignant prostatic tissue. AB - Cells possess within their repertoire of epigenetic programs the ability to undergo a process of cellular suicide, termed programmed cell death. This programmed cell death process involves an epigenetic reprogramming of the cell that results in an energy-dependent cascade of biochemical and morphologic changes within the cell (also termed apoptosis), resulting in its death and elimination. Although the final steps (i.e. DNA and cellular fragmentation) are common to cells undergoing programmed death, the activation of this death process is initiated either by sufficient injury to the cell induced by various exogenous damaging agents (e.g. radiation, chemicals, viruses, etc) or by changes in the levels of a series of endogenous signals (e.g. hormones and growth/survival factors). As an illustrative example, the role of androgen as a cell type specific endogenous regulator of the programmed death of normal and neoplastic prostatic cells will be presented. PMID- 7849268 TI - Oscillations in rat liver cytosolic enzyme activities of the urea cycle. AB - Diurnal rhythms were studied in three rat liver enzymes of the urea cycle: arginase, arginosuccinate synthetase and arginosuccinase. In animals synchronized to a 12:12 h light-dark cycle these enzymes were determined at 8 different time points under three different feeding schedules: 24 h of fasting, ad libitum feeding and restricted feeding. Under the three experimental conditions maxima of enzyme activities occurred during the dark period. In all cases the maximum activity of arginosuccinase preceded the one of arginase and these in turn the one of arginosuccinate synthetase. On the other hand, the hepatic protein level was maximal during the light period and decreased to its lowest level during the dark period. The restriction of food between 08.00 h and 14.00 h induced an important phase shift of hepatic protein rhythm and arginosuccinase activity. Our results suggest that the diurnal rhythms of cytosolic enzymes of the urea cycle are not only dependent on the light-dark cycle, but also on the synchronizing and masking effect of food intake. PMID- 7849269 TI - Body temperature of the armadillo Chaetophractus villosus (mammalia, dasypodidae). AB - Body temperature of the armadillo Chaetophractus villosus (n = 17) was studied during a period of 15 days. Deep rectal temperature (TB) was recorded at 9 am, 1 pm and 5 pm. Temperature in the laboratory was kept between 24.6 degrees C and 26.0 degrees C. We found two main different profiles of thermal behaviour in our animals, namely: a) one with high variation, mainly due to the daily cycle. b) the other with middle or low variation, with no predominance of the daily cycle. There were great TB differences between hours (P < 0.01). Morning temperatures were lower than the other ones. This is what could be expected in a non diurnal animal like C. villosus. PMID- 7849270 TI - Characterization of extracellular pH drop due to the activation of the secretory process by acetylcholine in the bovine adrenal medulla. AB - A progressive and reversible decrease of external pH accompanied the catecholamine release elicited by acetylcholine in decorticated bovine adrenal glands perfused with buffer-free Locke solution adjusted to an initial pH of 7.4. Both the secretory response as well as the extracellular acid shift promoted by the cholinergic agonist were antagonized by hexamethonium plus atropine, Mg2+ and verapamil. Experiments performed to assess the effects of the reduction of external pH on acetylcholine-induced release of catecholamines revealed that increasing the extracellular concentration of H+ significantly and reversibly reduced this secretory response. These findings are consistent with the idea that adrenomedullary activation of secretion by acetylcholine could be associated with a transient acidification of the extracellular fluid. This release of protons, arising mainly from the chromaffin granules, may be involved in a local automodulatory mechanism of the regulated secretory process. PMID- 7849271 TI - In vitro and in vivo effects of HgCl2 on synaptosomal ATP diphosphohydrolase (EC 3.6.1.5) from cerebral cortex of developing rats. AB - The aim of the present investigation was to evaluate the in vitro (10-500 microM) and in vivo (1-21 subcutaneous injections of 2.5 mg/kg each) effects of HgCl2 on the ATP diphosphohydrolase activity (EC 3.6.1.5; apyrase) of synaptosomes from cerebral cortex of rats at different ages (5, 11, 18 and 25 days of life). The in vitro results showed that HgCl2 (from 10 to 500 microM) inhibited the hydrolysis of both substrates by the synaptosomal enzyme at all ages studied. In contrast, HgCl2 injected in vivo did no affected the normal ontogeny of ATP and ADP hydrolysis. The hydrolysis of both nucleotides increased at the same rate as a function of age in control and HgCl2-treated rats (the specific activity of enzyme increased about 5-fold from the first week of postnatal life of weaning). The results of the present study demonstrated that in vitro HgCl2 inhibited the enzyme, but was ineffective when tested in vivo. Probably the absence of an in vivo effect is due to the low permeability of blood-brain barrier to inorganic forms of mercury. PMID- 7849272 TI - Kinetics and inhibition by some aminoacids of lactating rat mammary gland arginase. AB - Some kinetic and regulatory properties of lactating rat mammary gland arginase were studied. At pH 7.4, i.e. at near-physiological conditions, there was evidence of inhibition by excess of substrate, with a Km value of 9.5 mM, slightly lower than the value of 18 mM observed at pH 9.8 (maximum enzyme activity). A study was also made of the effects of proline, ornithine, lysine and certain branched-chain aminoacids on enzyme activity: lactating rat mammary gland arginase was strongly and competitively inhibited by lysine, ornithine and valine, with Ki values of 1.2 mM, 1.1 mM and 3.6 mM, respectively. Other aminoacids (proline, isoleucine and leucine) also inhibited lactating rat mammary gland arginase, although to a lesser extent. PMID- 7849273 TI - Characterization of a natural hemagglutinin in the serum of a freshwater crab Parathelphusa hydrodromus (Herbst). AB - A naturally occurring hemagglutinin (HA) was detected in the serum of the freshwater crab Parathelphusa hydrodromus using mammalian erythrocytes (RBC) as indicator cells. The serum gave the highest HA titer with rabbit RBC. In cross adsorption tests, this RBC type completely adsorbed all HA activities from serum. An analysis of the physico-chemical properties of HA showed it to be specifically dependent on the presence of Ca2+ for its activity, irreversibly sensitive to EDTA, stable between pH 7.5 and 10.0, and heat-labile. Further studies demonstrated that the HA is proteinaceous as it was precipitable by conventional deproteinizing agents, and susceptible to the action of proteases and 2 mercaptoethanol. HA-inhibition assays performed with 44 carbohydrates revealed that the serum HA was specific for non-reducing terminal glucose with alpha 1-2 glycosidic linkage. Thus this agglutinin appears to be unique among all the known crustacean agglutinins. PMID- 7849274 TI - Age-dependent reduction of the response of rat cardiac muscle to the phosphodiesterase inhibitor milrinone. AB - This study aimed to investigate whether milrinone effect on cardiac muscle contractility undergoes to age-related changes. Experiments were carried out on papillary muscles isolated from right ventricle of Brown Norway rats belonging to two different age groups: 2 month old and 18 month old. The effect of milrinone (10-100 microM) on rat cardiac muscle in vitro preparations was characterized by a reduction of peak developed tension and of contraction duration. Furthermore, the recovery of contractility after a contractile cycle, i.e. the mechanical restitution was faster in the presence of milrinone than in control conditions. All these effects were reduced in preparations from 18 month old rats compared to preparations from 2 month old rats. The decrease of milrinone effect on the mechanical restitution was particularly pronounced. The reduction of the milrinone effects is likely connected with the reduction of the maximal effect of adrenergic stimulation, although the molecular basis of this link is not yet clearly understood. PMID- 7849275 TI - Comparison of macrophage phospholipid radiolabelling methods for measuring phospholipase A2 inhibition. AB - Rat peritoneal macrophages activated by ionophore A 23187, were labelled after introduction in the culture medium of 1-0-stearoyl 2-0-[3H] arachidonylglycero-3 phosphocholine (as unique source of tritiated arachidonic acid), or [3H] arachidonic acid which was esterified by cells in phospholipids and triglycerides or remained non esterified. With either cell-labelling method, stimulated macrophages produced tritiated nonesterified fatty acids and eicosanoids which were isolated from cell and medium lipids. When introduced into the culture medium at 1, 5 or 10 microM, the membrane phospholipid analogue 1,2 di-O hexadecylglycerophosphocholine (dihexadecyl-GPC), but not the lysolecithin analogue 1-0-octadecyl 2-0-methylglycero phosphocholine, lowered phospholipase A2 activity with either labelling method. Dihexadecyl-GPC had an inhibitory effect on the release of arachidonic acid and eicosanoids. Moreover, this effect, as measured by tritiated nonesterified fatty acid formation, was greater in activated cells labelled with tritiated phospholipid (IC50 6 microM) than with [3H] arachidonic acid (IC50 60 microM). This is attributable to the inhibitory effect of dihexadecyl-GPC on endogenous phospholipase A2 and the endogenous enzyme excreted together with lysosomes into the medium. It may be concluded that radioactive phospholipid labelling is a sensitive method for measuring phospholipase A2 activity and assessing the effects of potential phospholipase inhibitors. PMID- 7849276 TI - Carbohydrates of pigeon milk and their changes in the first week of secretion. AB - The carbohydrate content of pigeon crop secretion called pigeon milk (PM) was in the range of 0.9-1.5%. Sugars of trichloroacetic acid soluble (TCA-S) fraction increased by 67% between day-1 and day-5 of secretion while those of TCA- insoluble (TCA-P) fraction remained fairly constant. Sialic acids constituted 5 9% of carbohydrates. The proportion of lipid- and protein-bound sialic acids was 51% and 31% respectively; the former increased from 41% to 68% between day-1 and day-5 whereas the latter decreased from 45% to 21% during the corresponding period. Some of the sugars of PM were fucose (40%), glucosamine (31%), galactose (12%), mannose (9%) and glucose (8%). The free sugars whose content was very low (0.05%) included fucose, mannose, glucose and some unidentified oligosaccharides. The proportion of lipid- and protein-bound sugars was 31% and 63% respectively; the former decreased by 7% from day-1 to day-5 while the latter increased by 11% during the same period. Gel chromatography of PM confirmed the presence of sialic acids and glucosamine; the latter existed both in free and bound form. The nature of changes in the carbohydrate composition of PM in the first week of secretion was more quantitative than qualitative. PMID- 7849277 TI - Structural and ultrastructural evidence regarding immunologically mediated pathogenesis in mucosal lichen planus. AB - Tissue samples from six patients suffering from lichen planus (L. P.), with oral and genital localization were examined by light and transmission electron microscopy, in order to better define the structural and ultrastructural changes that are correlated with L. P. and fit with immunologically mediated pathogenesis theory. Many of the classical histopathological features of L. P. were found: the hydropic degeneration of basal keratinocytes, presence of colloid bodies and heavy chronic chorionic inflamatory cell infiltrate. There were also observed several differences from skin localization of L. P. consisting in more frequent parakeratosis, obvious atrophy of the epithelium, pathological presence of granular layer. Ultrastructural studies confirm and clarify the light microscopic picture: basal lamina is frequently broken, basal keratinocytes are degenerated, presenting thickening, clumping and disorders of orientation of tonofilaments. There are many Langerhans cells. The inflammatory infiltrate is composed of interacting cells: many T-lymphocytes and activated macrophages, few B lymphocites and plasma cells. PMID- 7849278 TI - Typical and atypical carcinoid tumors of lung: two distinct clinicomorphologic entities. AB - Thirty-six cases of bronchopulmonary carcinoid tumor were reviewed in order to identify the clinicomorphologic criteria whereby typical and atypical carcinoids can be classified as two distinct entities. This study indicates that bronchial typical carcinoids are tumors with very low malignancy, more often centrally located and occurring in relatively young patients. The prognosis is good, with a five year-survival rate of about 73%, although regional nodal metastases may occasionally develop. Atypical carcinoids are more frequently peripheral tumors, occurring in comparatively old patients and differing from typical carcinoids by a less favourable prognosis, with a five year-survival rate of about 25% and a higher incidence of nodal metastases. The morphological study of these tumors reveals the following criteria as most reliable for distinguishing between the two types of bronchial carcinoid: increased mitotic activity, cellular pleomorphism and tumor necrosis, which are best correlated with the agressiveness of atypical carcinoids. PMID- 7849280 TI - Aspects of ankylosing spondylarthritis immunopathogenesis correlated with some immunoseric- and synovial parameters in the investigation of histopathological and electronmicroscopic alterations of the articular cartilage correlated with some immunoseric and synovial parameters. AB - Eighteen biopsies of articular cartilage taken intraoperatory from patients with Ankylosing Spondylarthritis (AS) and from others with traumatisms (controls) were investigated using histopathological (HE, VG, PAS-Alcian, Gomori, Safranin 0), electronmicroscopic and histoenzymamologic techniques. Histopathologically, the synovitis in AS is characterized by abundant synovia lymphoplasmocytic infiltrates associated with aspects of vascular hyperplasia and fibrosis. At the pannus synovia-cartilage junction we found the invasive synovia lymphoplasmocytic infiltrates. The proteoglycan (PG) depletion is confirmed histopathologically by diminishing the Safranin 0 staining, then ultrastructurally by the existence of collagen revealing areas, whereas biochemically, by the presence of glycosaminoglycans (GAG) in serum and synovial fluid (SF). The morphological data were related to some immunological parameters involved in pathogenesis. In this way, we found pathological values of the immune circulating complexes (ICC) (serum, mean = 73.5 U; SF mean = 81.80 U) and of anti Collagen II antibodies (serum mean = 410 U; SF mean = 436 U). The reactive protein C acting in the phase (CRP) showed high pathological values both in serum (mean = 5.01 mg%) and in SF (mean = 3.6 mg%) of the patients with AS, emphasizing the inflammatory characteristics of the rheumatic disease. The presence of ICC, anticollagen II antibodies and GAS as well in synovia suggests that the inflammatory articulation in AS is a local potential antigen of collagen and proteoglycan nature. PMID- 7849279 TI - Histoenzymological and ultrastructural investigations regarding the role of the endogenous peroxidase at the pulmonary level in cardiogenic pulmonary hypertension. AB - We found optically and ultrastructurally endogenous peroxidase in 90 intraoperatory pulmonary biopsies taken from patients with valvular cardiopathies and different degrees of pulmonary hypertension. The enzymatic activity increases proportionally to the pulmonary hypertension and it reaches its maximum in severe cases of hemosiderosis. Ultrastructurally we found two reaction types namely: 1) in peroxisomes of circulating monocytes turning into tissue ones, in medium or slight pulmonary hypertension (PHT) and 2) (as granular reactions on the nuclear membrane and endoplasmic reticle in alveolar macrophages, granular pneumocytes in aggravating and severe medium PHT. The presence of both these two types of reaction in the same cell demonstrates the passing stages from circulating macrophages to tissue ones attesting a transitional process of the phagocytic cells. PMID- 7849281 TI - Aspects of immunopathogenesis of rheumatoid arthritis correlated with some immunological parameters in histopathological and electronmicroscopical investigations of the articular cartilage. AB - The histopathological (H. E., V. G., PAS-Alcian, Safranine 0, Gomori) and electron-microscopical investigations were carried out on twenty samples of articular cartilage taken during operations from patients with Rheumatoid Arthritis (R. A.) and from others with traumatism, as controls. Histopathologically, the rheumatoid synovial membrane is characterized by synovitis with abundant perivascular lymphoplasmocytic infiltrates. At the pannus synovia-cartilage junction we found the invasive and destructive inflammatory infiltrates penetrating and eroding the cartilage. The histopathological characteristics of the rheumatoid articular cartilage lie in alteration of tinctorial activity, affection of reticuline collagen network and the presence of superficial and deep cartilaginous fissures. The histopathological alterations were confirmed ultrastructurally. Immunologically we found pathological serum values regarding the immune circulating complexes (I. C. C.) (mean = 104 +/- 1.04 U), anticollagen II antibodies (mean = 538 +/- 5 U), reactive Protein C (mean = 16.75 +/- 1.95 mg%) and orosomucoid (mean = 151.1 +/- 4.91 mg%), in seropositive R. A. The corroboration of histopathological, electronmicroscopical and immunological data show the inflammatory and autoimmune feature of this rheumatic disease. PMID- 7849282 TI - Retroperitoneal malignant fibrous histiocytoma without histological atypias. AB - A case of a 36-year-old woman suspected of hepatic hydatid cyst with dyseptic symptoms, hepatomegalia, profound pains in the right hypochondrium is presented. During the operation a 15/12/17 cm well-incapsulated tumour is extirpated. The tumour stretched from the upper right renal pole behind the right hepatic lobe as far as the diaphragm and while sectioning it was grey and orange. Histopathologically we found a fibrous histiocytoma with zones of storiform fascicular pattern alternating with areas of histocytic cells with vacuolar-foamy cytoplasm, rich in lipids and without atypias or mitoses. We report the frequency, histological aspects of the fibrous histiocytomas as well as some particularities of their retroperitoneal location. PMID- 7849283 TI - Mammary carcinosarcoma with osteochondrosarcomatous differentiations. AB - The case of a 77-year-old woman with a 6/5/4.5 cm, mobile, hard, white-yellowish tumour associated with axillary adenopathy, with a progressive evolution in the upper external frame of the right breast is presented. The histopathological examination, carried out after the radical mammectomy, revealed zones with plates of slightly differentiated carcinomatous cells forming keratose pearls next to dense mixofibrochondrosarcomatous proliferations. The scarcity of these tumors as well as the mammary sarcomas and histogenesis questions are discussed. PMID- 7849284 TI - Voluminous solitary non-Hodgkin extraganglionary lymphoma of thigh. AB - The case of a 36-year-old woman is presented. She had a voluminous tumour inside the 1/3 average part of the right thigh at 12 cm from the inguinal region. Apart from some local pains, she had a normal haematological formula, normal spleen, liver and lymph nodes. As the tumour of 5.5 x 5 x 4.5 cm was well incapsulated between the sartorius muscle and the great adductor tendon it was easily extirpated and presented a whitish-light yellow section. The histological cellular aspect was pleiomorphic with round, ovalar cells; some were big and clear cells of centroblast-type with several mitoses and giant multinucleated cells and collagenic bundles in between. The nodular Hodgkin sclerosis is not confirmed immunohistochemically because of the negative reaction for antigen Kil (CD30) so that the diagnosis was lymphoma with lymphoma with big B cells by CD20 reaction. We also found positive T cells at CD43 that might be reactive lymphocytes. The tumour ranks a rare malignant lymphoma and for the first time, an extraganglionar lymphoma in thigh was found. We have not met such a location in the literature. PMID- 7849285 TI - [Morphopathologic organ correlations in endogenous Cushing syndrome in the dog]. PMID- 7849286 TI - The effect of early hypoxy upon the development of rats and mice. II. Foetal effects. AB - The late, foetal effect of temporary hypoxy--performed by uterine vascular clamping--during the preimplantation period (day 2, 3 and 4 of pregnancy) was controlled in rats. The main detected effects were: lowering of the number of implantation sites and of the mean number of living foetuses; lowering of the mean foetal weight: increased percentage of resorptions and partial retardation of skeletal development. No structural anomalies were registered. PMID- 7849287 TI - The effect of ethanol upon early development in mice and rats. XIX. The late effect of acute preimplantation intoxication with beer and cognac, on the background of chronic consumption, in mice. AB - The effect upon late foetal development of acute preimplantation intoxication with beer and cognac, on the background of chronic consumption was investigated in mice (controlled on day 19 of pregnancy), by using the following criteria: mean number of embryos/animal, number of resorptions, mean foetal and placental weight, changes of internal organs (Wilson's sections), skeletal development. The results showed that both beverages applied had a noxious foetal effect, manifested by: a decrease of the mean number of embryos/animal (cognac), an increased late mortality (beer), a decrease of the mean foetal and placental weight (both beverages) and the presence of some structural anomalies (especially after beer consumption). The more marked effect of beer and the correlation of late effects with preimplantation changes are discussed. PMID- 7849288 TI - Ultrastructural correlation between follicular dendritic cells and the frequency of virus-like particles during the lymph nodes reaction of SIV/HIV 2 infected cynomolgus monkeys. AB - Lymph nodes from 18 SIV/HIV2 infected monkeys developing a severe AIDS-like disease were studied by electron microscopy. The lesions were correlated with the histopathologic staining and the anti-SIVp28 immunostaining. The investigation of follicular dendritic cells (FDC) and associated retroviral particles was focused on the light zones of germinal centres during the follicular hyperplasia, fragmentation atrophy and depletion. FDCs were mostly developed in the first two stages, while the highest amount of retroviruses was found in the two middle stages. During the last stage of follicular depletion FDCs were still present but deprived of dendrites and no viral particles were seen around. Associated lesions were small haemorrhages, binucleated FDCs, viral phagocytosis by macrophages and reticular paracrystalline inclusions. PMID- 7849289 TI - Long-term repopulation of irradiated mice with limiting numbers of purified hematopoietic stem cells: in vivo expansion of stem cell phenotype but not function. AB - Hematopoietic stem cells were isolated from normal adult mouse bone marrow based on surface antigen expression (Thy-1.1(low)Lin(neg)Ly-6A/E+) and further selected for low retention of rhodamine 123. This population of cells (Rh-123low) could mediate radioprotection and long-term (greater than 12 months) repopulation after transplantation of as few as 25 cells. Transfer of five genetically marked Rh 123low cells in the presence of 10(5) normal bone marrow cells resulted in reconstitution of peripheral blood by greater than 10% donor cells in 64% (30 of 47) of recipient mice. Of 46 animals surviving after 24 weeks, 10 had over 50% donor-derived cells in peripheral blood. Two general patterns of long-term reconstitution were observed: one in which many donor-derived cells were observed 5 to 6 weeks after reconstitution and another in which donor-derived cells were rare initially but expanded with time. This result suggests that two classes of long-term repopulating hematopoietic stem cells exist, differing in their ability to function early in the course of transplantation. Alternatively, distinct anatomic sites of engraftment may dictate these two outcomes from a single type of cell. As an approach to measure the extent of self-renewal by the injected cells, recipients of five or 200 stem cells were killed 8 to 13 months after the transplants, and Thy-1.1(low)Lin(neg)Ly-6A/E+ progeny of the original injected cells were isolated for a second transplant. While a numerical expansion of cells expressing the cell surface phenotype of stem cells was observed, along with activity in the colony-forming unit-spleen assay, the expanded cells were vastly inferior in radioprotection and long-term reconstitution assays when compared with cells freshly isolated from normal animals. This result demonstrates that in stem cell expansion experiments, cell surface antigen expression is not an appropriate indicator of stem cell function. PMID- 7849290 TI - Leukocyte integrin CD11b promoter directs expression in lymphocytes and granulocytes in transgenic mice. AB - The human leukocyte integrin subunit CD11b is expressed predominantly on myelomonocytic cells. To identify CD11b promoter sequences important for myelomonocytic gene expression and to assess the utility of the CD11b promoter for expressing heterologous genes in vivo, we generated transgenic mice with a human CD4 reporter gene driven by CD11b promoter constructs composed of 1.5, 0.3, or 0.1 kb of DNA sequence 5' to the transcription start site. Using flow cytometry to detect the human CD4 reporter on murine leukocytes, two of three 1.5 kb CD11b promoter founder lines showed surface expression of the human CD4 transgene in granulocytes and lymphocytes. The transgene expression observed in lymphocytes was inappropriate relative to the normal pattern of CD11b expression. Of the eight 0.3-kb or 0.1-kb founder lines, only one 0.1-kb founder line showed transgene expression. The overall pattern of transgene expression among the 11 founder lines does not parallel expression of the endogenous CD11b gene. These studies indicate that additional CD11b regulatory elements will be required to express a reporter gene in vivo in a lineage-specific pattern that mimics the endogenous CD11b gene. PMID- 7849291 TI - Posttranscriptional regulation of macrophage tissue factor expression by antioxidants. AB - Tissue factor (TF) expression by cells of monocyte/macrophage lineage represents an important mechanism underlying the initiation of fibrin deposition at sites of extravascular inflammation. Recent evidence suggests a role for oxidant stress in the signalling pathway of various cell types by virtue of its ability to induce DNA binding of various transcription factors, including nuclear factor kappa B and AP-1. The effect of antioxidant treatment on lipopolysaccharide (LPS)-induced TF expression was examined in murine peritoneal macrophages and human monocytes. Both pyrrolidine dithiocarbamate, an oxidant scavenger, and N-acetyl-cysteine, a precursor of the endogenous antioxidant glutathione, inhibited stimulation of macrophage procoagulant activity by LPS. Northern blot analysis showed that neither of these agents reduced LPS-stimulated TF mRNA accumulation, thereby suggesting a posttranscriptional mechanism for the effect. Immunofluorescence studies of human monocytes using polyclonal anti-TF antibody showed that N-acetyl cysteine treatment prevented the characteristic plasmalemmal localization of TF antigen that occurs in response to LPS. Western blot analysis showed that N acetyl-cysteine reduced the accumulation of the 47-kD mature glycoprotein in LPS treated cells, a finding consistent with the results of the immunofluorescence studies. Furthermore, these conditions did not result in an accumulation of the less mature forms of TF. When considered together, these data suggest that antioxidants exert their effects by impairing translation and/or by causing degradation of newly translated protein. The effect of antioxidants on tumor necrosis factor appeared to be species specific, with no effect on LPS-induced tumor necrosis factor in murine cells, but with inhibition in human monocytes. The posttranscriptional effect of antioxidants on TF expression data suggests a novel mechanism whereby these agents might modulate monocyte/macrophage activation. PMID- 7849292 TI - Cytokine-mediated regulation of transferrin synthesis in mouse macrophages and human T lymphocytes. AB - Transferrin (Tf) plays an important role during immunologic activation by donating iron to activated lymphocytes. Therefore, synthesis by lymphomyeloid cells has been investigated. Mouse macrophages and macrophage cell lines synthesized Tf, with levels being markedly increased by gamma-interferon (gamma IFN) and, to a lesser extent, by interleukin-1 beta (IL-1 beta), IL-6, and tumor necrosis factor alpha (TNF alpha). Tf was also produced by phytohemagglutinin stimulated human T cells and two T-cell lines and was increased by IL-2. Even after appropriate activation, none was synthesized by human macrophages or monocytic cell lines or by mouse T cells, T-cell lines, or thymus cells. In both species, B-lineage cell lines were negative. Tf was also synthesised by macrophages from congenitally hypotransferrinemic mice and was responsive to gamma-IFN, but levels were lower than those from normal controls. Synthesis by human and murine hepatoma cells was increased by IL-6 but unaffected by IL-1, TNF alpha, or gamma-IFN. Iron decreased synthesis by hepatoma cells but had no effect on the lymphomyeloid cells. Tf mRNA levels paralleled protein synthesis, suggesting that regulation was pre-translational. Thus, Tf synthesis by lymphomyeloid cells is regulated differently from hepatic synthesis, which is consistent with the suggestion that Tf may act in a paracrine (mouse) or autocrine (human) manner on activated lymphocytes. PMID- 7849293 TI - ILA, the human 4-1BB homologue, is inducible in lymphoid and other cell lineages. AB - We recently identified a gene that is induced by lymphocyte activation (ILA). The sequence of the full-length 1.4-kb cDNA characterized ILA as a new member of the nerve growth factor/tumor necrosis factor (NGF/TNF) receptor family and the human homologue of the murine T-cell-specific receptor 4-1BB. The present study demonstrates ILA mRNA isoforms at 4.4, 4.0, and 1.8 kb in poly-A+ RNA from activated, but not from resting human peripheral blood T lymphocytes. A reverse transcriptase-polymerase chain reaction (RT-PCR) assay was used to study tissue distribution and regulation of ILA expression. The gene was induced in T lymphocytes by phytohemagglutinin (PHA), phorbol myristate acetate (PMA), and antibody to CD3, in B lymphocytes by PMA and antibodies to cell surface Ig, and in blood monocytes by interleukin-1 beta (IL-1 beta), lipopolysaccharide (LPS), and PMA. In T lymphocytes, ILA mRNA was detectable 1.5 hours after stimulation, reached maximal levels at 8 hours, and declined to background levels by 48 hours. Induction of ILA mRNA required protein synthesis and was primarily due to increased transcription. Actinomycin D reduced ILA mRNA levels in activated lymphocytes 50% within 30 minutes, demonstrating a relatively short half-life of this mRNA. Analysis of nonlymphoid cells showed that ILA mRNA was not detectable in resting cells. However, in contrast to the lymphoid-specific expression of the murine 4-1BB gene, ILA was detected in nonlymphoid cells, including epithelial and hepatoma cells after stimulation with IL-1 beta. ILA was not detectable in several brain derived cell lines. The ILA cDNA encodes a 30-kD protein as demonstrated by in vitro translation, and this protein is immunoprecipitated by antisera that were raised against ILA peptides or a glutathione-S-transferase fusion protein. Flow cytometry showed expression of ILA protein on a subset of activated T or B lymphocytes. In conclusion, activation-dependent expression of ILA is found not only in T lymphocytes, but also in B lymphocytes, monocytes, and diverse nonlymphoid cell types. PMID- 7849294 TI - Lymphomagenesis in the SCID-hu mouse involves abundant production of human interleukin-10. AB - Both human (hu) and viral (v) interleukin-10 (IL-10) appear to be important cofactors in the survival and growth of lymphoblastoid cell lines infected with Epstein-Barr virus (EBV). When mice with severe combined immune deficiency (SCID) are injected with human peripheral blood lymphocytes (PBL) from normal individuals who are seropositive for EBV, the majority of hu-PBL-SCID mice will develop an EBV-associated lymphoproliferative disease (EBV-LPD) of human B-cell origin, not unlike some cases of EBV-LPD that are seen in immunocompromised individuals. The role of huIL-10 or vIL-10 in this chimeric mouse model of EBV LPD is unknown. In the present study, we show that hu-PBL-SCID mice that develop EBV-LPD have significant elevation of serum huIL-10 levels compared with mice that do not develop EBV-LPD (P = .005). vIL-10 was undetectable in all animals. The EBV+ tumor samples express transcript for huIL-10 and huIL-10 receptor, express huIL-10 protein by immunohistochemical staining, and show specific binding of recombinant (r) huIL-10. In vitro analysis of the functional consequences of rhuIL-10 binding to IL-10 receptors on fresh EBV+ tumor cells shows that rhuIL-10 can prevent programmed cell death as well as promote proliferation and can do so at concentrations of huIL-10 found in vivo. Thus, huIL-10 production by EBV+ tumor cells may contribute directly to their malignant outgrowth in the hu-PBL-SCID mouse by two autocrine mechanisms: prevention of programmed cell death and proliferation. The implications of such findings with regard to EBV-LPD in humans is discussed. PMID- 7849295 TI - A clinical analysis of two indolent lymphoma entities: mantle cell lymphoma and marginal zone lymphoma (including the mucosa-associated lymphoid tissue and monocytoid B-cell subcategories): a Southwest Oncology Group study. AB - The objectives of this study were (1) to determine the clinical presentation and natural history associated with two newly recognized pathologic entities termed mantle cell lymphoma (MCL) and marginal zone lymphoma (MZL), including the mucosa associated lymphoid tissue (MALT) and monocytoid B-cell subcategories, and (2) to determine whether these entities differ clinically from the other relatively indolent non-Hodgkin's lymphomas with which they have been previously classified. We reviewed the conventional pathology and clinical course of 376 patients who had no prior therapy; had stage III/IV disease; were classified as Working Formulation categories A, B, C, D, or E; and received cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) on Southwest Oncology Group (SWOG) studies no. 7204, 7426, or 7713. All slides were reviewed by the three pathologists who reached a consensus diagnosis. Age, sex, performance status, bone marrow and/or gastrointestinal involvement, failure-free survival, and overall survival were compared among all the categories. We found that (1) MCL and MZL each represent approximately 10% of stage III or IV patients previously classified as Working Formulation categories A through E and treated with CHOP on SWOG clinical trials; (2) the failure-free survival and overall survival of patients with MZL is the same as that of patients with Working Formulation categories A through E, but the failure-free survival and overall survival of the monocytoid B-cell patients were higher than that of the MALT lymphoma patients (P = .009 and .007, respectively); and (3) the failure-free survival and overall survival of patients with MCL is significantly worse than that of patients with Working Formulation categories A through E (P = .0002 and .0001, respectively). In conclusion, patients with advanced stage MALT lymphomas may have a more aggressive course than previously recognized. Patients with MCL do not have an indolent lymphoma and are candidates for innovative therapy. PMID- 7849296 TI - Clinical and molecular characterization of a rare syndrome of acute promyelocytic leukemia associated with translocation (11;17). AB - Analysis of a variant translocation t(11;17) in a case of acute promyelocytic leukemia (APL) led to discovery of a novel zinc finger gene, PLZF, fused to the retinoic acid receptor-alpha (RAR alpha) gene. We reviewed the clinical and molecular features of five additional patients with t(11;17)-associated APL. The clinical course of three patients was characterized by early death and three experienced disseminated intravascular coagulation. Morphologically all of the patients fell in a unusual morphologic spectrum of APL, with features intermediate between M2 and M3 AML. All six patients had PLZF-RAR alpha gene fusion as detected by reverse transcription/polymerase chain reaction assay, Southern blotting, or pulsed-field gel electrophoresis. Five of the six patients failed to achieve complete remission after initial chemotherapy or differentiation therapy with all-trans retinoic acid (ATRA). A sixth patient responded to initial chemotherapy, but on relapse failed to respond to ATRA. When tested in vitro, cultured cells from three of the patients failed to differentiate in response to ATRA. APL associated with t(11;17) and fusion of the PLZF and RAR alpha genes is a discrete clinico-pathologic syndrome with a distinctly worse prognosis than t(15;17) APL. PMID- 7849297 TI - The pro region of human neutrophil defensin contains a motif that is essential for normal subcellular sorting. AB - Human defensins (human neutrophil peptides) HNP 1-3 are 29-30 amino acid antibiotic and cytotoxic peptides highly abundant in the cytoplasmic granules of polymorphonuclear leukocytes. The peptides are produced from 94 amino acid (aa) prepropeptides by proteolytic cleavage of the signal sequence and stepwise removal of the 44-45 aa anionic propiece. To study the role of the propiece, we constructed five in-frame deletions in preproHNP-1 cDNA between the signal peptidase site and the amino-terminus of the mature defensin region (aa 21-64). The wild type HNP-1 cDNA and the deletion mutants were ligated into the pBabe-Neo retroviral vector, expressed in GP+E86 packaging derivative of NIH 3T3 cells, then transduced into the 32D cl3 granulocytic cell line. For each construction and both cell lines, we measured the accumulation of the various defensin forms in cells and media by 24-hour labeling or pulse-chase with 35S-cysteine- and immunoprecipitation/sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Deletions in the amino-terminal two-fifths of the propiece, delta 21 28 and delta 21-38, had only minor effects on defensin biosynthesis in both cell lines and did not interfere with the accumulation of mature defensin in the granules of 32D cl3 cells. Deletions in the carboxyterminal three-fifths of the propiece (delta 21-51 and delta 21-64) diminished net defensin synthesis, blocked constitutive secretion of prodefensin in both cell lines, and interfered with defensin accumulation in cytoplasmic granules of 32D cl3 cells. These effects were reproduced by the smaller deletion delta 40-51, which contains highly conserved secondary structure. The propiece segment 40-51 appears to be essential for the subcellular trafficking and sorting of HNP-1 defensin. PMID- 7849298 TI - Functional reconstitution of the phagocyte NADPH oxidase by transfection of its multiple components in a heterologous system. AB - The phagocyte NADPH oxidase system, as previously defined by cell-free reconstitution, is comprised of five essential components, three of which are produced during late phagocytic differentiation--namely, two cytosolic proteins, p47- and p67-phox--and the large subunit of cytochrome b558, gp91-phox. To confirm that these are the only phagocyte-specific components necessary for oxidase activity in whole cells, the recombinant NADPH oxidase was reconstituted in a heterologous cell line. An undifferentiated multipotent leukemic cell line, K562, which expresses endogenous Rac and the small subunit of the flavocytochrome b558 (p22-phox), was cotransfected with episomal expression vectors containing cDNAs for the three other oxidase components. After 4 days of selection, the complete oxidase system was functionally reconstituted in transfected cells stimulated with phorbol myristate acetate or calcium ionophore. These easily transfected cells provide an ideal model system in which several oxidase components can be genetically manipulated and readily expressed. This system can be used to test the effects of mutations associated with any of the genes affected in chronic granulomatous disease and will facilitate studies on structure-function relationships within several oxidase components. This system will also aid in delineation of upstream regulators functioning through various signaling pathways. PMID- 7849299 TI - Identification of two novel deletion mutations in glucose-6-phosphate dehydrogenase gene causing hemolytic anemia. AB - Among over 50 distinct mutations causing glucose-6-phosphate dehydrogenase (G6PD) deficiency, only two deletion mutations have so far been reported. Using nonradioisotopic single-strand conformation polymorphism analysis, we found two additional deletion mutations in two Japanese G6PD-deficient patients with nonspherocytic hemolytic anemia. Case no. 1 had a 3-nucleotide deletion in exon 6 predicting a deletion of a serine at amino acid 188 or 189, which caused a class 1 variant G6PD Tsukui. Case no. 2 had a 3-nucleotide deletion in exon 5 predicting a deletion of a lysine at residue 95, which caused a class 2 variant G6PD Urayasu. The 188th serine, which might be deleted in G6PD Tsukui, is located close to the putative G6P binding site. The 188th serine is also involved in the amino acid substitution in G6PD Mediterranean, but the kinetics of these two variants are totally different. The residue with an amino acid deletion in G6PD Urayasu was distant from the substrate binding sites and was located in a region with low sequence homology among species. The different properties of variants having mutations in exons 5 and 6 suggest that these two exons code distinct functional domains of the enzyme. PMID- 7849300 TI - Development of a marrow transplant regimen for acute leukemia using targeted hematopoietic irradiation delivered by 131I-labeled anti-CD45 antibody, combined with cyclophosphamide and total body irradiation. AB - In an attempt to decrease the relapse rate after bone marrow transplantation (BMT) for advanced acute leukemia, we initiated studies using 131I-labeled anti CD45 antibody (BC8) to deliver radiation specifically to hematopoietic tissues, followed by a standard transplant preparative regimen. Biodistribution studies were performed in 23 patients using 0.5 mg/kg trace 131I-labeled BC8 antibody. The BC8 antibody was cleared rapidly from plasma with an initial disappearance half-time of 1.5 +/- 0.2 hours, presumably reflecting rapid antigen-specific binding. The mean radiation absorbed doses (cGy/mCi131I administered) were as follows: marrow, 7.1 +/- 0.8; spleen, 10.8 +/- 1.4; liver, 2.7 +/- 0.2; lungs, 2.1 +/- 0.1; kidneys, 0.7 +/- 0.1; and total body, 0.4 +/- 0.03. Patients with acute myelogenous leukemia (AML) in relapse had a higher marrow dose (11.4 cGy/mCi) than those in remission (5.2 cGy/mCi; P = .001) because of higher uptake and longer retention of radionuclide in marrow. Twenty patients were treated with a dose of 131I estimated to deliver 3.5 Gy (level 1) to 7 Gy (level 3) to liver, with marrow doses of 4 to 30 Gy and spleen doses of 7 to 60 Gy, followed by 120 mg/kg cyclophosphamide (CY) and 12 Gy total body irradiation (TBI). Nine of 13 patients with AML or refractory anemia with excess blasts (RAEB) and two of seven with acute lymphocytic leukemia (ALL) are alive disease-free at 8 to 41 months (median, 17 months) after BMT. Toxicity has not been measurably greater than that of CY/TBI alone, and the maximum tolerated dose has not been reached. This study demonstrates that with the use of 131I-BC8 substantially greater doses of radiation can be delivered to hematopoietic tissues as compared with liver, lung, or kidney, which may improve the efficacy of marrow transplantation. PMID- 7849301 TI - Differential CD26-mediated activation of the CD3 and CD2 pathways after CD6 depleted allogeneic bone marrow transplantation. AB - Patients who have undergone allogeneic bone marrow transplantation (allo-BMT) are susceptible to a variety of opportunistic infectious complications in the months to years after engraftment. Impaired in vitro T-cell functions have been documented in these patients, and these T-cell dysfunctions contribute to the prolonged immune deficiency after allo-BMT. In the present study, we examined the expression of CD26 as well as the reconstitution of CD26-mediated T-cell costimulation via the CD3 and CD2 pathways at various times in patients aged greater than 18 years after CD6-positive, T-cell depleted allo-BMT. We found that the percentage of CD26- and CD3-positive cells, as well as the levels of expression of both antigens, was lower than in normal controls during the first 4 months after CD6-depleted allo-BMT. Subsequently, the amount of lymphocytes expressing CD3 and CD26 and the quantitative surface expression of CD3 and CD26 were not significantly different in patients and normal controls. Functional studies showed that CD26-mediated T-cell proliferation via the CD3 pathway was considerably improved and almost reached normal levels by 1 year, whereas recovery of CD26-mediated T-cell proliferation via the CD2 pathway was delayed for at least 2 years after CD6-depleted allo-BMT. As CD26 involvement in the regulation of human thymocyte activation is restricted preferentially to the CD3 pathway--unlike its involvement with both CD3 and CD2 pathways of peripheral T cells--our results suggest that the different effects of CD26-mediated costimulation via the CD3 and CD2 pathways after CD6-depleted allo-BMT may be a reflection of peripheral T-cell immaturity in those individuals, similar to that seen in mature medullary thymocytes or cord T lymphocytes. PMID- 7849302 TI - Absence of breast cancer cells in a single-day peripheral blood progenitor cell collection after priming with cyclophosphamide and granulocyte-macrophage colony stimulating factor. AB - The effect of priming on occult tumor cell involvement of peripheral blood (PB) and PB progenitor cell (PBPC) collections is poorly characterized. Using sensitive immunocytochemistry (ICC) and tumor clonogenic assays (TCA) specific for epithelial-derived tumor cells, hematopoietic specimens were analyzed for PBPC and occult tumor cell involvement in 28 patients with chemotherapy-sensitive stage IIIB or IV breast cancer. Before PBPC priming, tumor was detected by ICC in PB of 1 of 23 (4%) patients and in bone marrow (BM) harvests of 4 of 27 (15%) patients. Fifteen days after cyclophosphamide and granulocyte-macrophage colony stimulating factor (GM-CSF) priming, 2 of 28 (7%) patients had ICC-positive PBPC collections. The median amplification of CD34+ PBPC during this time was over 19 fold (range, < 1 to 199). One patient had pretreatment tumor involvement of both PB and BM. One patient grew tumor colonies in TCA; the PB and BM were ICC- and TCA-positive, but the PBPC collection was ICC-positive and TCA-negative. After cytoreduction with conventional-dose chemotherapy, patients with advanced breast cancer and histologically negative BM biopsy specimens have rare tumor cell involvement of PB and BM. Despite effective PBPC priming with cyclophosphamide and GM-CSF, clonogenic breast cancer cells were not found in the PBPC collection performed on day 15. PMID- 7849303 TI - Monoclonal gammopathies and hepatitis C virus infection. PMID- 7849304 TI - Interleukin-6 (IL-6) autoantibodies and blood IL-6 measurements. PMID- 7849305 TI - Macedonian (delta beta) zero thalassemia has the same molecular basis as Turkish inversion-deletion (delta beta) zero thalassemia. PMID- 7849306 TI - Oral pilocarpine hydrochloride for the treatment of refractory xerostomia associated with chronic graft-versus-host disease. PMID- 7849307 TI - Hematologic abnormalities in Fanconi anemia. PMID- 7849308 TI - Interleukin-6 in human multiple myeloma. PMID- 7849309 TI - Leukemic cell growth in SCID mice as a predictor of relapse in high-risk B lineage acute lymphoblastic leukemia. AB - Mice with severe combined immunodeficiency (SCID) provide a model system to examine the in vivo homing, engraftment, and growth patterns of normal and malignant human hematopoietic cells. The relation between leukemic cell growth in this model and the treatment outcome in patients from whom cells were derived has not been established. Leukemic cells from 42 children with newly diagnosed high risk B-lineage acute lymphoblastic leukemia were inoculated intravenously into CB.17 SCID mice. Mice were killed at 12 weeks or when they became moribund as a result of disseminated leukemia. All mice were necropsied and subjected to a series of laboratory studies to assess their burden of human leukemic cells. Twenty-three patients whose leukemic cells caused histopathologically detectable leukemia in SCID mice had a significantly higher relapse rate than the 19 patients whose leukemic cells did not (estimated 5-year event-free survival: 29.5% v 94.7%; 95% confidence intervals, 11.2% to 50.7% v 68.1% to 99.2%; P < .0001 by log-rank test). The occurrence of overt leukemia in SCID mice was was a highly significant predictor of patient relapse. The estimated instantaneous risk of relapse for patients whose leukemic cells caused overt leukemia in SCID mice was 21.5-fold greater than that for the remaining patients. Thus, growth of human leukemic cells in SCID mice is a strong and independent predictor of relapse in patients with newly diagnosed high-risk B-lineage acute lymphoblastic leukemia. PMID- 7849310 TI - Neurologic complications after allogeneic marrow transplantation for sickle cell anemia. AB - Seven of 21 patients with sickle cell anemia developed neurologic complications 5 to 243 days (median, 33 days) after allogeneic marrow transplantation. Among these 7 patients, indications for transplantation included either a past history of stroke (4 patients) or recurrent severe vaso-occlusive events (3 patients). All received marrow from an HLA-identical sibling after preparation with busulfan and cyclophosphamide, and in 4 patients with antithymocyte globulin. Five of 6 patients developing seizures received anticonvulsant and supportive treatment with resolution of neurologic abnormalities. Three patients experienced intracranial bleeding, which was fatal in two. Of the 14 patients free of neurologic complications, 4 patients had experienced stroke before transplantation. However, among all patients with prior stroke, the incidence of intracranial hemorrhage was 38% (3/8), whereas none of the 13 patients without prior stroke developed posttransplant intracranial bleeding (P = .026). We conclude that patients with sickle cell anemia are at increased risk for neurologic complications after marrow ablative therapy and that patients with prior stroke are at increased risk for intracranial hemorrhage. Transplantation of patients before the onset of overt stroke may reduce this risk. PMID- 7849311 TI - Deletions and rearrangement of CDKN2 in lymphoid malignancy. AB - Recurrent abnormalities of the short arm of chromosome 9, including translocations and interstitial deletions, have been reported in both leukemia and lymphoma. The pathologic consequences of these abnormalities remain unknown. The cyclin-dependent kinase 4 inhibitor (CDKN2) gene, which maps to 9p21, has been implicated by the finding of a high frequency of biallelic deletions in leukemic cell lines. We have determined the incidence of structural abnormalities affecting CDKN2 by DNA blot in a panel of 231 cases of leukemia and lymphoma and 66 cell lines derived from patients with lymphoid malignancies with defined cytogenetic abnormalities. Structural alterations of CDKN2 were seen in 20 (8.3%) of all fresh cases and 10 (15.1%) of all cell lines. Biallelic CDKN2 deletions were seen in 11 of 53 (21%) cases of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). There was no association with any particular cytogenetic abnormality. Biallelic deletions were also found in high-grade and transformed non-Hodgkin's lymphoma (NHL) of both B- and T-cell lineages. In two cases of transformed NHL, analysis of sequential samples showed loss of CDKN2 with transformation. Neither deletions nor rearrangements of the CDKN2 gene were seen in any of the 119 leukemias of mature B or T cells analyzed. Biallelic deletions of CDKN2 were observed in 6 of 13 NHL cell lines. Three of the 6 cases had undergone transformation from low- to high-grade disease: in 2 of these cases it was possible to show that the CDKN2 deletions were present in fresh material from the patient and were therefore not an artifact of in vitro culture. Rearrangements of CDKN2 were seen in 2 cases (4%) of BCP-ALL, in 1 case of B-NHL, and in 1 Burkitt's lymphoma cell line and suggest the presence of a "hot spot" for recombination in the vicinity of the CDKN2 gene. These data indicate that the loss of CDKN2 expression may be involved in the pathogenesis of a subset of BCP ALL, some high-grade NHL, and in the transformation of NHL from low- to high grade disease. CDKN2 deletions and rearrangements occurred in the absence of detectable cytogenetic changes of chromosome 9p in 25 of 30 (83%) cases. Finally, of 10 cases of BCP-ALL that produced overt, transplantable leukemia in mice with severe combined immunodeficiency (SCID), seven showed biallelic CDKN2 deletions. In contrast, none of 11 cases that failed to engraft showed biallelic CDKN2 deletions. BCP-ALL cases that lack CDKN2 expression may have a particular propensity to grow in SCID mice. PMID- 7849312 TI - Molecular basis of the Kell (K1) phenotype. AB - K1 (K, Kell) is a strong immunogen; its antibodies can cause severe reactions if incompatible blood is transfused and may cause hemolytic disease of the newborn in sensitized mothers. K1 is a member of the Kell blood group system, which is complex, containing over 20 different antigens. Some of the antigens are organized in allelic pairs of high and low prevalence whereas others are independently expressed. K1, which is present in 9% of the population, is antithetical to the high-prevalence K2 (k) antigen. We have determined the molecular basis of the K1/K2 polymorphism by sequencing the 19 exons of the Kell gene (KEL) of a K1/K1 person. Polymerase chain reaction was performed on genomic DNA isolated from peripheral blood and the amplified products were either directly sequenced or subcloned and sequenced. Comparisons of K1/K1 and K2/K2 DNA showed a C to T base substitution in exon 6 that predicts a threonine to methionine change at amino acid residue 193. This amino acid substitution occurs at a consensus N-glycosylation site (Asn. X. Thr) and probably prevents N glycosylation, leading to a change in phenotype. The C to T substitution creates a Bsm I restriction enzyme site, which was tested in 42 different samples to confirm that this base change identifies the K1/K1 genotype. This test differentiates genotypes, K1/K1, K2/K2, and the K1/K2 heterozygote and should prove useful in the prenatal diagnosis of K1-related hemolytic disease of the newborn. PMID- 7849313 TI - Pharmacokinetic study of anti-interleukin-6 (IL-6) therapy with monoclonal antibodies: enhancement of IL-6 clearance by cocktails of anti-IL-6 antibodies. AB - The use of inhibiting cytokine-binding-proteins (CBPs) such as soluble cytokine receptors and anticytokine antibodies is considered for the treatment of cytokine dependent diseases. The pleiotropic cytokine interleukin-6 (IL-6) is a target for immunointervention in numerous pathologic situations, including multiple myeloma, B-cell lymphoma, and rheumatoid arthritis. An antitumor response was obtained in the treatment of a patient with multiple myeloma. A controversial issue is to evaluate whether the carrier effect of the CBPs might limit their efficiency in blocking the target cytokine. We analyzed the pharmacokinetics of radiolabeled IL 6 in mice treated with various combinations of anti-IL-6 antibodies. We show that injection of one or two antibodies led to the stabilization of the cytokine. Conversely, simultaneous treatment with three anti-IL-6 antibodies, binding to three distinct epitopes, induced the rapid uptake of the trimeric immune complexes by the liver and the elimination of IL-6 from the central compartment. The use of cocktails of three antibodies binding simultaneously to a cytokine thus provides a new means of enhancing the clearance of the target molecule and should help in the design of antibody-based clinical trials by overcoming the problem of the accumulation of the cytokine in the form of monomeric immune complexes. PMID- 7849314 TI - Recombinant interleukin-2 infusions and decreased IgG2 subclass concentrations. AB - The administration of low doses of recombinant interleukin-2 (rIL-2) in vivo to patients with malignant neoplasms has been demonstrated to selectively increase the number of circulating natural killer (NK) cells in these patients. Recent evidence from SCID mouse models suggests that IgG subclass levels can be influenced by the presence and activity of NK cells. Therefore, we sought to examine the effect of rIL-2 infusions on human serum IgG subclass concentrations. We determined serum IgG subclass concentrations in 27 cancer patients receiving low-dose rIL-2 by daily continuous intravenous infusion. Eleven of these patients had active, metastatic, nonhematologic tumors; 16 patients had received IL-2 when they were in a minimal residual disease state after autologous or allogeneic bone marrow transplantation. Samples obtained before beginning IL-2 therapy and 8 to 10 weeks into therapy were tested. Treatment with IL-2 resulted in an increase in the percentage of CD56+ NK cells from 18% to 54% (P = .0001). A significant decrease in geometric mean IgG2 concentration from 2,017 micrograms/mL to 1,655 micrograms/mL was noted over this time interval (P = .03). Furthermore, the geometric mean IgG2 concentration after treatment was significantly lower than that of healthy controls (P = .026). In contrast, no significant changes in serum IgG1, IgG3, or IgG4 were noted during r-IL2 infusions. Our data suggest that rIL 2 treatment selectively decreases serum IgG2 concentrations. We speculate that increased NK cells mediate downregulation of human serum IgG2. PMID- 7849315 TI - The growth factor requirements of STRO-1-positive human bone marrow stromal precursors under serum-deprived conditions in vitro. AB - Factors that regulate the growth and development of primitive bone marrow stromal cell precursors are not well defined. We have examined 25 purified recombinant growth factors for their ability to initiate and support clonogenic growth of fibroblast colony-forming cells (CFU-F) from adult human bone marrow. Assays were performed using bone marrow mononuclear cells (BMMNC) enriched in CFU-F by magnetic-activated cell sorting (MACS) using the monoclonal antibody (MoAb) STRO 1. A serum-deprived assay was developed to avoid components of fetal calf serum (FCS) that may mask or otherwise modify the response of CFU-F to exogenously added factors. L-ascorbate and the glucocorticoid dexamethasone were found to be essential for CFU-F colony development under serum-deprived conditions. Importantly, clonogenic growth of CFU-F in this culture system was absolutely dependent on an exogenous source of growth factor. Platelet-derived growth factor BB (PDGF) and epidermal growth factor (EGF) demonstrated the greatest ability to support colony growth. Colony formation was dose-dependent, with half-maximal colony numbers at approximately 0.2 ng/mL for either factor and plateau numbers at concentrations in excess of 1.0 ng/mL. Simultaneous addition of PDGF and EGF had no effect on the number of colonies initiated but resulted in dose-dependent increases in mean colony diameter that were significant (P < or = .05) when compared with the effect of either factor alone or with the size of colonies elicited in control cultures by 20% FCS. Fluorescence-activated cell sorting (FACS) of BMMNC using MoAbs to the alpha chain of the PDGF receptor and to the EGF receptor in combination with the Moab STRO-1 demonstrated constitutive expression of both receptors by greater than 90% on CFU-F. Receptors for insulin like growth factor-1 (IGF-1) and nerve growth factor (NGF) were also detected on STRO-1+ CFU-F, but in vitro both IGF-1 and NGF did not support colony growth. This report demonstrates the development of a simple, reproducible, and stringent culture system for the growth and assay of stromal precursors under serum deprived conditions and represents an important prerequisite for future studies of the role of growth factors in the regulation of stromal cell proliferation, differentiation, and development. PMID- 7849316 TI - Marrow accessory cell infection and alterations in hematopoiesis accompany severe neutropenia during experimental acute infection with feline immunodeficiency virus. AB - Severe neutropenia and bone marrow (BM) morphologic abnormalities occur during experimentally induced primary infection with feline immunodeficiency virus (FIV), a lentivirus biologically similar to human immunodeficiency virus (HIV). To further characterize the mechanisms involved in this acute infection model of lentivirus-induced BM suppression, peripheral blood counts, histologic BM studies, and BM culture assays were performed on 12 cats that underwent necropsy at regular intervals postinoculation (PI) with FIV Petaluma. Plasma viremia developed at week 3 PI and neutropenia was initially detected at week 6 PI. Low neutrophil counts, but normal hematocrits and platelet counts, persisted through week 12 PI. Infected BM mononuclear cells and megakaryocytes were identified by in situ hybridization assays for FIV nucleic acids in BM sections of cats that underwent necropsy at weeks 4 to 12 PI, correlating with detection of soluble FIV p24 antigen and identification of infected mononuclear and macrophage cells in BM buffy-coat cell cultures from these cats. At weeks 1.5 to 4 PI, the mean frequencies (number per 10(5) BM mononuclear cells) of erythroid progenitors (erythroid colony-forming units [CFU-E] and erythroid burst-forming units [BFU-E] and granulocyte/macrophage progenitors (CFU-granulocyte/macrophage [CFU-GM]) were increased to 508 +/- 74, 143 +/- 24, and 110 +/- 17, respectively (n = 5 cats) as compared with controls (172 +/- 24, 86 +/- 26, and 44 +/- 10; n = 3 cats; P < .02), and the percentages of progenitors in the DNA-synthetic phase of the cell cycle were equivalent to controls. In contrast, the progenitor frequencies at weeks 6 to 12 PI were significantly decreased (72 +/- 16, 43 +/- 6, and 19 +/- 4, respectively; n = 7 cats; P < .01), and these progenitors were more frequently in S-phase. Autologous serum significantly inhibited (P < .05) the growth of CFU-GM in 6 of 9 cats and failed to support the maximal growth of BFU-E in 4 of 9 cats studied at weeks 4 to 12 PI, whereas no such abnormalities were observed in colony assays containing autologous sera from control cats (n = 3) or cats studied at weeks 1.5 or 3 PI (n = 3). In comparison, sera from FIV-infected cats did not inhibit the growth of normal, allogeneic progenitors. However, FIV serum frequently failed to support maximal in vitro growth of normal CFU-GM as compared with uninfected allogeneic sera, further suggesting a lack of progenitor growth promoting substances in infected cat sera.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7849317 TI - Identification of hematopoietic stem cell subsets on the basis of their primitiveness using antibody ER-MP12. AB - Monoclonal antibody ER-MP12 defines a novel antigen on murine hematopoietic stem cells. The antigen is differentially expressed by different subsets in the hematopoietic stem cell compartment and enables a physical separation of primitive long-term repopulating stem cells from more mature multilineage progenitors. When used in two-color immunofluorescence with ER-MP20 (anti-Ly-6C), six subpopulations of bone marrow (BM) cells could be identified. These subsets were isolated using magnetic and fluorescence-activated cell sorting, phenotypically analyzed, and tested in vitro for cobblestone area-forming cells (CAFC) and colony-forming units in culture (CFU-C; M/G/E/Meg/Mast). In addition, they were tested in vivo for day-12 spleen colony-forming units (CFU-S-12), and for cells with long-term repopulating ability using a recently developed alpha thalassemic chimeric mouse model. Cells with long-term repopulation ability (LTRA) and day-12 spleen colony-forming ability appeared to be exclusively present in the two subpopulations that expressed the ER-MP12 cell surface antigen at either an intermediate or high level, but lacked the expression of Ly-6C. The ER-MP12med20- subpopulation (comprising 30% of the BM cells, including all lymphocytes) contained 90% to 95% of the LTRA cells and immature day-28 CAFC (CAFC-28), 75% of the CFU-S-12, and very low numbers of CFU-C. In contrast, the ER-MP12hi20- population (comprising 1% to 2% of the BM cells, containing no mature cells) included 80% of the early and less primitive CAFC (CAFC-5), 25% of the CFU-S-12, and only 10% of the LTRA cells and immature CAFC-28. The ER-MP12hi cells, irrespective of the ER-MP20 antigen expression, included 80% to 90% of the CFU-C (day 4 through day 14), of which 70% were ER-MP20- and 10% to 20% ER MP20med/hi. In addition, erythroblasts, granulocytes, lymphocytes, and monocytes could almost be fully separated on the basis of ER-MP12 and ER-MP20 antigen expression. Functionally, the presence of ER-MP12 in a long-term BM culture did not affect hematopoiesis, as was measured in the CAFC assay. Our data demonstrate that the ER-MP12 antigen is intermediately expressed on the long-term repopulating hematopoietic stem cell. Its level of expression increases on maturation towards CFU-C, to disappear from mature hematopoietic cells, except from B and T lymphocytes. PMID- 7849318 TI - Granulocyte-macrophage colony-stimulating factor signals for increased glucose uptake in human melanoma cells. AB - While the primary targets for granulocyte-macrophage colony-stimulating factor (GM-CSF) are hematopoietic precursors and mature myeloid cells, GM-CSF receptors (GMR) are also found on normal tissues including placenta, endothelium, and oligodendrocytes as well as certain malignant cells. The function of GMR in these nonhematopoietic cells is unknown. We studied the function of GMR in human melanoma cell lines. Six of seven cell lines tested (clones 1-5 and 3.44 of SK MEL-131, SK-MEL-188, SK-MEL-23, SK-MEL-22, and SK-MEL-22A) expressed mRNA encoding the membrane-bound and soluble isoforms of the alpha subunit of the GMR. Melanoma cell lines in early stages of differentiation expressed the largest quantities of alpha-subunit mRNA. Although five of these lines expressed trace levels of mRNA encoding the beta subunit of the GMR, Scatchard analysis of equilibrium binding data derived from three of the cell lines showed that they expressed only low-affinity GMR. Clones 3.44 and 1-5 of SK-MEL-131, and SK-MEL 188 cells expressed receptors with a dissociation constant (kd) for GM-CSF in the following ranges: 0.7 to 0.8, 1.2 to 1.8, and 0.4 to 0.8 nmol/L, respectively. GM CSF stimulated glucose uptake in four of the melanoma cell lines expressing the alpha subunit, presumably through facilitative glucose transporters, as uptake was blocked by cytochalasin B but not cytochalasin E. Stimulation of glucose uptake was transient, with maximum stimulation occurring at approximately 30 minutes in the presence of 1 nmol/L GM-CSF. GM-CSF stimulated glucose uptake 1.4- to 2.0-fold but did not stimulate cell proliferation. These results suggest a metabolic role for the low-affinity GMR in melanoma cell lines and indicate that the alpha subunit of the GMR can signal for increased glucose uptake in nonhematopoietic tumor cells. PMID- 7849319 TI - Genomic structure, chromosomal localization, and conserved alternative splice forms of thrombopoietin. AB - Thrombopoietin (TPO), the ligand for c-mpl, is a novel cytokine comprising an amino terminal domain with homology to erythropoietin and a glycosylated carboxyl terminal domain that does not bear overall homology to other known proteins. We report the cloning of cDNAs encoding the porcine and murine TPO and the characterization of the human TPO gene. The cDNA for an additional splice form (TPO-2) with a four-amino-acid deletion within the erythropoietin-like domain has been isolated and is conserved between humans, pigs, and mice. Species comparison of TPO shows that the amino terminal erythropoietin-like domain is highly conserved, while the carboxyl terminal domain is less conserved. Recombinant murine TPO and human TPO are each able to activate both the murine and human c mpl receptors, indicating an absence of strict species specificity. Human TPO is encoded by a single gene consisting of six exons and located on chromosome 3q27 28. PMID- 7849320 TI - Tumor necrosis factor (TNF)-alpha directly inhibits human erythropoiesis in vitro: role of p55 and p75 TNF receptors. AB - Two tumor necrosis factor receptors (TNFRs) with molecular weights of 55 kD (TNFR p55) and 75 kD (TNFR-p75) have recently been identified and cloned. In previous studies, TNFR-p55 has been shown to exclusively mediate bidirectional effects of TNF-alpha on committed bone marrow granulocyte-macrophage progenitor cells, whereas both TNFR-p55 and TNFR-p75 can mediate inhibition of primitive progenitors requiring multiple cytokines to proliferate. We show here that TNF alpha potently and directly inhibits the in vitro growth of committed erythroid progenitor cells in response to multiple cytokine combinations, and that TNF alpha-induced inhibition of burst-forming unit-erythroid colony formation is mainly mediated through TNFR-p55, although TNFR-p75-mediated inhibition could be observed on progenitors responsive to erythropoietin alone. Moreover, at low TNF alpha concentrations (2 ng/mL), TNF-alpha stimulates interleukin-3-dependent in vitro growth of committed granulocyte-macrophage progenitor cells, whereas it potently inhibits erythroid progenitor cell proliferation, showing that one concentration of TNF-alpha can simultaneously and bidirectionally modulate interleukin-3-dependent growth of committed granulocyte-macrophage (stimulation) and erythroid progenitor cells (inhibition). PMID- 7849321 TI - Functionally distinct human marrow stromal cell lines immortalized by transduction with the human papilloma virus E6/E7 genes. AB - A replication-defective recombinant retrovirus containing the human papilloma virus E6/E7 genes (LXSN-16 E6E7) was used to immortalize stromal cells from human marrow. The E6/E7 gene products interfere with the function of tumor-suppressor proteins p53 and Rb, respectively, thereby preventing cell cycle arrest without causing significant transformation. Twenty-seven immortalized clones designated HS-1 to HS-27 were isolated, four of which are characterized in this report. Two cell lines, HS-5 and HS-21, appear to be fibroblastoid and secrete significant levels of granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), macrophage-CSF (M-CSF), Kit ligand (KL), macrophage-inhibitory protein-1 alpha, interleukin-6 (IL-6), IL-8, and IL-11. However, only HS-5 supports proliferation of hematopoietic progenitor cells when cocultured in serum deprived media with no exogenous factors. Conditioned media (CM) from HS-5 promotes growth of myeloid colonies to significantly greater extent than a cocktail of recombinant factors containing 10 ng/mL of IL-1, IL-3, IL-6, G-CSF, GM-CSF, and KL and 3 U of erythropoietin (Epo). Two additional clones, HS-23 and HS-27, resemble "blanket" cells, with an epithelioid morphology, and are much larger, broader, and flatter when compared with HS-5 and HS-21. These lines secrete low levels of growth factors and do not support proliferation of isolated progenitor cells in cocultures. CM from HS-23 and HS-27 also fail to support growth of myeloid colonies. Both HS-23 and HS-27 express relatively high levels of VCAM-1, yet HS-27 is the only line that supports the formation of "cobblestone" areas by isolated CD34+38lo cells. We hypothesize that HS-5, HS-21, HS-23, and HS-27 represent functionally distinct components of the marrow microenvironment. PMID- 7849322 TI - Light microscopic distribution of some cholinergic markers in the rat and rabbit locus coeruleus and the nucleus angularis grisea periventricularis of the domestic pig (Sus scrofa): a correlative electron microscopic investigation of cholinergic receptor proteins in the rabbit. AB - Cholinergic modulation of locus coeruleus (LC) neurons evokes a variety of neuronal and behavioural effects. In an attempt to understand the LC cholinergic circuit, several markers has been investigated and compared. (Immuno) histochemical and autoradiographic methods have been used on rat, rabbit, and pig tissue. To identify the boundaries of the LC in each of these species, sections through the entire brainstem have been stained for tyrosine hydroxylase. The results indicate that the pig does not possess a LC proper that conforms to the accepted features of this cell group. However, in this location fusiform cells reminiscent of LC interneurons are still present. This group of fusiform neurons has been named the nucleus angularis grisea periventricularis (NAGP). LC cells of the rat and rabbit show strong acetylcholinesterase (AChE) activity. In the pig the NAGP is markedly free from AChE staining. Muscarinic binding sites are densely distributed over the rabbit LC and adjacent region. The rat and rabbit LC neurons synthesise both muscarinic (mAChR) and nicotinic receptor protein (nAChR). In the pig NAGP region mAChR and nAChR positive cell bodies are almost absent, while some nAChR immunoreactive dendrites are present. The light microscopic data in the rabbit have been confirmed by electron microscopic analysis. It is concluded that the general concept of a noradrenergic LC that is present throughout mammals is questionable. At present, choline acetyltransferase immunoreactive terminals that closely correspond to the other cholinergic components in the rat or rabbit LC have not been observed. However, in these species the cholinergic sensitivity of LC cells is mediated via both muscarinic and nicotinic receptors on somata and dendrites. PMID- 7849323 TI - Gene expression of neuroreceptors in the locus coeruleus of the rat. PMID- 7849325 TI - Dopaminergic innervation of rat locus coeruleus: a light and electron microscopic immunohistochemical study. AB - Dopaminergic innervation of the rat locus coeruleus (LC) was immunohistochemically studied by using monoclonal antibody directed against dopamine (DA) at the light- and electron-microscopic levels. A dense plexus of DA immunoreactive (IR) varicose fibers was found not only in the cell body area of the LC but also in the dendritic area. Three hundred and forty DA-IR terminal boutons were observed. They were distributed in a wide range of diameters of 0.1 1.8 microns but most of them were large (mean value: 0.98 micron). Sixty-nine percent formed an asymmetric synapse. There were many axo-spinous connections. Small dendrites less than 0.3 micron in diameter displaying synaptic specialization were mostly dendritic spines (75%). Most of the target dendrites seemed to be noradrenergic in nature. It is suggested that dopaminergic innervation may play a powerful role in control mechanisms of activity of NA containing neurons of the LC. PMID- 7849324 TI - Effects of phospholipase A2 inhibitors on the antidepressant-induced axonal regeneration of noradrenergic locus coeruleus neurons. AB - In previous experiments, we have shown that antidepressants such as desipramine (DMI) can induce axonal regeneration of noradrenergic locus coeruleus neurons. In this article, we suggest that phospholipase A2 is involved in the molecular mechanism of the antidepressant-induced regeneration of brain noradrenergic axons. The effects of the PLA2 inhibitors, mepacrine (MEP) or 4-bromphenacyl bromide (BPB), upon the DMI-induced regeneration of noradrenergic axons in the rat cerebral cortex were assessed by either histofluorescence or immunohistochemistry using an antibody to dopamine-beta-hydroxylase. Symmetrical sites of the frontal cortex in both hemispheres were pretreated with 6 hydroxydopamine (6-OHDA). Then, the same cortical site of one hemisphere was infused with DMI by means of osmotic minipumps for more than 2 weeks, while the corresponding cortical site of the other hemisphere was infused with DMI plus MEP or BPB. It was found that the PLA2 inhibitors could attenuate the DMI-induced regeneration of noradrenergic axons. Thus, if axonal retraction or degeneration of brain noradrenergic neurons is involved in the pathogenesis of clinical depression, elucidating the malfunction of the PLA2 systems may provide substantial evidence to aid in our understanding of the cause of depression at the molecular level. PMID- 7849327 TI - Locus coeruleus noradrenergic neurons as a micturition center. AB - The micturition reflex arch is composed of an afferent pathway from the urinary bladder to the pontine micturition center via the pelvic nerve and spinal cord. The efferent pathway projects from the center to the bladder through the sacral parasympathetic center of intermediolateral column cells. The pontine micturition center is thought to be noradrenergic (NA) neurons in the locus coeruleus (LC) due to the following observations: (1) LC stimulation induces bladder contraction in cats, and this response is blocked by intrathecal application of alpha 1 adrenergic antagonist (prazosin), but not the alpha 2- nor beta-adrenergic antagonist. Although this contraction is not observed after NA depletion with reserpine, with subsequent i.v. injection of L-dopa a NA precursor induces recurrence of the response. (2) The micturition reflex induced by bladder distention is similarly reversed with alpha 1-adrenergic antagonist and chemical destruction of NA cells by injecting 6-hydroxydopamine in the LC. However, subsequently applied alpha 1-adrenergic agonist induces the contraction due to bladder distention. (3) LC stimulation elicits spike generation of sacral intermediolateral cells. Microiontophoretically applied alpha 1-adrenergic antagonist inhibits the LC stimulation-induced spikes of the neuron, which is not antidromically activated by pelvic nerve stimulation. However, spikes in neurons activated antidromically were not affected by the drug. This indicates that the former and latter neurons are interneuron and parasympathetic projecting neurons, respectively. The existence of NA terminals from the LC and alpha 1-adrenergic receptors in the intermediolateral column cells supports the concept that NA cells in the LC are units constituting the micturition center. PMID- 7849326 TI - Anatomical evidence for the presence of glutamate or enkephalin in noradrenergic projection neurons of the locus coeruleus. AB - This paper reviews the anatomical evidence for the presence of glutamate (GLU) in noradrenergic neurons of the nucleus locus coeruleus (LC) and adjacent nuclei in the dorsolateral pontine tegmentum (DLPT) that project to the spinal cord, cerebellum, or cerebral cortex. Additionally, the evidence for the existence of methionine-enkephalin (ENK) in noradrenergic neurons of the DLPT that project to the spinal cord of the cat is reviewed. In these studies, we have combined the retrograde transport of either Fast Blue (FB), rhodamine labeled latex microspheres (MS), or rhodamine labeled dextran and indirect immunofluorescence histochemistry to determine whether the neurons that contain tyrosine hydroxylase (TH) and project to these terminal fields also contain GLU or ENK. The neurons of the cat that project to the spinal cord, cerebellum, and neocortex were observed in the nucleus LC and Kolliker-Fuse (KF) nucleus. They were also present, to a lesser extent, in the nucleus subcoeruleus (SC) and nuclei parabrachialis medialis (PBM) and lateralis (PBL). In the rat the majority of the neurons that project to the neocortex and hippocampus were located in the nucleus LC. Our data revealed a major proportion of these neurons to be immunostained for both GLU and TH (cat, rat), or ENK and TH (cat). Functional implications of such colocalized neurochemicals within individual LC projection neurons are discussed. PMID- 7849328 TI - Subcellular localization and quantitative analysis of Toxoplasma gondii target antigens of specific immunoglobulins G, M, A, and E. AB - The target antigens of specific immunoglobulins G, M, A, and E from patients with acquired acute toxoplasmosis were determined using immunocytochemistry. The relative repartition of these antigens in four cellular compartments of Toxoplasma (membrane complex, apical area, rhoptries, and dense granules) was quantitatively evaluated. Rhoptry antigens mainly react positively with IgA. Membrane, submembrane area (membrane complex), and rhoptry antigens are immunodominant for IgA and IgM. Apical area antigens are recognized by IgM two times more than IgG and IgA. IgE recognized only rhoptry antigens. The localization of pathogenetically antigenic components and their identification by the immune system appeared to be of importance for selection of immunodominant or recombinant antigens. Such localization would improve laboratory diagnosis of serious congenital toxoplasmosis or in immunocompromised patients with toxoplasmic complications after cyst reactivation. PMID- 7849329 TI - A computer-assisted stereological quantification program: OpenStereo. AB - At present, the stereological assessment of histological sections is made possible by the use of manual counting techniques which estimate measurement parameters. These methods are tedious, time-consuming, and subject to operator error. This paper describes a UNIX-based computer program, OpenStereo, which was developed to facilitate the quantitative investigation of innervation and vascularity from histological sections. We designed OpenStereo to reduce operator error and increase the efficiency of stereological point counting for volume estimation and intercept counting for surface area analysis. The program was written in the C language for the Sun Workstation and uses the XView graphics user interface. Digital images, obtained by a variety of modalities, may be processed using stereological point counting, interceptions, planimetry, or thresholding techniques. The program displays selected images in a random fashion for analysis or processing and records the number of manually selected points or interceptions. Delineation of the reference space provides the computer with the data necessary to calculate volume or surface densities. The efficiency of OpenStereo was demonstrated by performing a pilot study on the quantification of innervation in the normal human colon and ileum. This stereological package benefits from the features of the X-windowing environment and has proved to be suitable for what has hitherto been a tedious and time-consuming task. PMID- 7849330 TI - Intersection of first order Laue zone lines along the [100] direction in an FCC material. AB - An analytical result is given for the wavelength at which two or more first order Laue zone (FOLZ) lines intersect at a single point on the positive x axis when a face centred cubic crystal is observed in the convergent beam mode with the beam axis parallel to the [100] direction. The position of the intersection along the x axis is also given. The method uses the kinematic approximation of electronic diffraction and the exact hyperbolic form of the FOLZ lines, so that the accuracy is good even for lines that intersect at small angles. PMID- 7849331 TI - Three-dimensional structure of lung elastin demonstrated by scanning electron microscopy/stereo-pair images. AB - The aim of this study was to expose the inflated 3-D structure of lung elastin. Formic acid digestion followed by freeze-drying unveiled the lamellar framework. The 3-D structure of elastin was well preserved within the alveolar septa and ducts, as demonstrated by scanning electron microscopy/stereo-pair photography. Elastin fibers are seen in the alveolar septa, which are continuous with the lamellae. The removal of collagen fibers and cells by formic acid was visualised as a function of time: The optimum was 48 hours. Transverse sections still retained some collagen fibrils and partially digested cells in addition to elastin as shown by transmission electron microscopy (TEM). Formic acid digestion followed by critical point drying caused damage to the lamellar structures and they appeared to collapse. Sodium hydroxide digestion combined with freeze-drying did not preserve the 3-D lamellar structure of elastin, but converted it into flat ribbonlike bands. The main structures remaining following alkali treatment were identified by TEM as collagen fibrils well preserved in their original locations. PMID- 7849332 TI - Effect of calcium-channel blockers on cyclosporine clearance and use in renal transplant patients. AB - OBJECTIVE: To determine the effect of calcium-channel blockers (CCBs) on cyclosporine dose, clearance, and cost, and their effect on kidney graft function and survival in patients who underwent kidney transplant. DESIGN: A total of 176 adults receiving 177 transplants were studied retrospectively. Patients were stratified as follows: no CCB (n = 57), diltiazem (n = 13), nifedipine (n = 37), and verapamil (n = 70). Patients received cyclosporine 3-4 mg/kg by continuous infusion for 5 days followed by cyclosporine 10 mg/kg/d po to maintain initial whole blood concentrations of 300-400 ng/mL. Clearance of intravenously administered cyclosporine was calculated following at least 48 hours of the same dose by continuous infusion. The amount and cost of cyclosporine used during the first 10 days of oral therapy were also calculated. RESULTS: Patients receiving diltiazem, but not verapamil or nifedipine, had decreased clearance of intravenously administered cyclosporine compared with that of the mean control group. The mean clearance of intravenously administered cyclosporine +/- SD in patients receiving no CCB was 5.1 +/- 1.5 mL/min/kg, diltiazem was 3.7 +/- 0.8 mL/min/kg, nifedipine was 6.4 +/- 1.9 mL/min/kg, and verapamil was 5.2 +/- 2.2 mL/min/kg. The amount and cost of 10 days of oral cyclosporine therapy was decreased in the verapamil group (5.7 +/- 1.5 g and $257 +/- 69) compared with that of the control group (6.7 +/- 1.6 g and $304 +/- 72) (p < 0.001). There was no significant difference among the groups with respect to immediate graft function, 1-year serum creatinine concentration, or 1-year graft survival. CONCLUSIONS: Diltiazem decreased the clearance of intravenously administered cyclosporine. Although verapamil did not decrease the clearance of intravenously administered cyclosporine, it allowed a significant reduction in oral cyclosporine cost without apparent adverse effects on graft function. Further work is needed to determine the effect of CCBs on cyclosporine pharmacokinetics, especially with respect to their metabolism by gut and hepatic cytochrome P-450 enzymes, and their effect on patient outcome. PMID- 7849333 TI - Evaluating the accuracy of citations in drug promotional brochures. AB - OBJECTIVE: To evaluate the accuracy of statements cited in 3 x 5 inch promotional cards for the 50 most frequently prescribed drugs. MEASUREMENTS: The 50 most frequently prescribed drugs were identified in the April 1992 issue of Pharmacy Times. File cards were requested from the pharmaceutical companies. References in the file card were retrieved and cited statements identified. Criteria used to evaluate reference accuracy were: type of study design, use of peer review journals, retrievability of references in area libraries, and reference documentation as no error, major error, or minor error. Referenced statements were classified as correct, incorrect, misleading, or taken from the abstract, discussion, or conclusion section of a study. RESULTS: Of the 50 most frequently prescribed products, 21 file cards were obtained. One hundred forty-two cited references were retrieved (average +/- SD per file card 6.9 +/- 8.4). Three hundred thirty-four cited statements were verified (average per file card 15.9 +/ 24.7). Forty-two percent of references were human controlled trials, 17 percent not available, 11 percent review articles, 10 percent manufacturer information, 8 percent human uncontrolled, 4 percent nonhuman controlled, 3 percent retrospective, 2 percent tertiary literature, 1 percent epidemiologic studies, 1 percent prospective, and 1 percent editorial. Thirty-three percent of references were found in peer-review journals. Of all cited references, 73 percent were retrievable. Thirty-nine references were not retrievable: 24 were not held by local libraries and 15 were manufacturers' information. Eighty-five percent of references contained no errors in reference documentation. For accuracy of statements, 46.1 percent were correct, 29 percent not available, 15.3 percent misleading, 4.2 percent incorrect, and 5.4 percent were cited from the abstract, discussion, or conclusion section of the study. CONCLUSIONS: Most references cited in pharmaceutical promotional brochures referenced controlled studies that are retrievable. However, incorporation of more adequately controlled studies, more references from peer review journals, and careful evaluation of referenced statements by the pharmaceutical company, journals' editorial board. Food and Drug Administration, and healthcare professionals may be beneficial. PMID- 7849334 TI - Fatal neutropenia and thrombocytopenia associated with ticlopidine. AB - OBJECTIVE: To report the first case of ticlopidine-associated neutropenia resulting in sepsis and death. CASE SUMMARY: An 83-year-old Filipino man was started on ticlopidine 250 mg bid. By the seventh week of therapy his absolute neutrophil count (ANC) had dropped to 2700 from 7600 x 10(6) cells/L. The ticlopidine was stopped. Six days later, he was admitted to the hospital. He died 18 hours later of gram-negative sepsis. DISCUSSION: Although ticlopidine therapy was discontinued four days after the patient's ANC was 2700 x 10(6) cells/L, the ANC dropped to and remained at 0 until his death eight days later. This may be associated with the patient's decreased clearance of ticlopidine given his age and impaired renal function. This is the first reported case of moderate or severe neutropenia in a nonwhite patient and the first reported case of sepsis and death caused by ticlopidine. CONCLUSIONS: Healthcare professionals must be aware of the possibility of severe neutropenia and death caused by ticlopidine, even when the manufacturers' monitoring guidelines are followed. PMID- 7849335 TI - Malabsorption of digoxin tablets, gel caps, and elixir in a patient with an end jejunostomy. AB - OBJECTIVE: To report a case of malabsorption of digoxin from tablets, gel caps, and elixir in a patient with an end jejunostomy. CASE SUMMARY: A 69-year-old man with 18 cm of functioning jejunum following a surgical end jejunostomy was receiving oral digoxin. The patient presented on referral for short bowel syndrome, secretory diarrhea, and malabsorption. He was receiving digoxin tablets 0.75 mg/d with a serum digoxin concentration of 0.5 ng/mL. Attempts to achieve therapeutic digoxin serum concentrations of approximately 1.0 ng/mL by administration of digoxin in the form of liquid-filled gel caps and elixir were unsuccessful. DISCUSSION: Variable results have been presented in the literature regarding the ability to achieve therapeutic concentrations of digoxin following oral administration in patients with malabsorption syndromes. Several studies have suggested that changing the form of administered digoxin from tablet to elixir or liquid-filled gel caps may improve absorption in patients with small intestine malabsorption. Such changes in oral dosage form failed to achieve therapeutic digoxin serum concentrations in this case. CONCLUSIONS: The markedly diminished length and the lack of continuity of this patient's small intestine and colon likely resulted in severe malabsorption of orally administered digoxin. Some patients with end jejunostomies may require intravenous forms of medication because of inadequate absorption of orally administered medications. PMID- 7849336 TI - Adenosine use in pregnant women with supraventricular tachycardia. AB - OBJECTIVE: To review a case experience and published reports of treatment of supraventricular tachycardia with adenosine in pregnant women. DATA SOURCES: Published reports and clinical experience. DATA SYNTHESIS: Seven pregnant women with supraventricular tachycardia treated with adenosine have been described in the literature. We describe an eighth patient. Treatment has terminated the dysrhythmia in all cases, and no adverse maternal or fetal effects have been reported. CONCLUSIONS: Based on theoretical considerations and on limited published experience, adenosine appears to be safe and effective for treatment of supraventricular tachycardia in pregnant patients. PMID- 7849337 TI - Ifosfamide extravasation. AB - OBJECTIVE: To report a case in which a local reaction is attributed to an ifosfamide extravasation. Previously, extravasated ifosfamide has been considered a nonirritant. CASE SUMMARY: A 54-year-old woman with a non-Hodgkin's lymphoma in stage IV B developed a local reaction in her right arm after an ifosfamide extravasation. No pressure was prescribed, no bandaging was applied on the affected area, and the limb was elevated to the heart level. In addition, chondroitinsulfatase 150 turbidity-reducing units was administered subcutaneously around the area. This procedure was repeated 12 hours later, resulting in a satisfactory decrease in the inflammatory signs and pain. DISCUSSION: The local reaction in the patient's arm cannot be attributed to the hypertonicity of the infusing solution or to the vehicle of the infusate. The antidote used was chondroitinsulfatase, an enzyme similar to hyaluronidase. It enhances the systemic uptake of the drug from the tissue. CONCLUSIONS: Extravasated ifosfamide is a potential irritant. General measures applied after its extravasation can be potentiated strongly by local subcutaneous administration of chondroitinsulfatase or hyaluronidase, repeated if necessary. PMID- 7849338 TI - Efficacy of fluoxetine in trichotillomania. PMID- 7849339 TI - Lidocaine in status epilepticus. PMID- 7849340 TI - Rifabutin: a review with emphasis on its role in the prevention of disseminated Mycobacterium avium complex infection. AB - OBJECTIVE: To discuss the mechanism of action, in vitro and in vivo activity, pharmacokinetics, clinical trials, adverse effects, drug interactions, and dosage guidelines of rifabutin. DATA SOURCES: Pertinent literature published between 1982 and 1993 was identified via a MEDLINE search. Published proceedings of selected conferences were also reviewed. STUDY SELECTION: Selected basic science, microbiologic, and pharmacokinetic articles were evaluated. Because only limited data regarding rifabutin were available in the literature, all clinical trials involving the use of rifabutin in the prevention of Mycobacterium avium complex (MAC) infection in AIDS patients were reviewed. DATA SYNTHESIS: Rifabutin is a rifamycin derivative that was approved recently for the prevention of disseminated MAC disease in patients with advanced HIV infection. The drug has in vitro and in vivo activity against gram-positive bacteria, gram-negative bacteria, and mycobacteria. Two prospective, randomized, double-blind, placebo controlled, multicenter trials demonstrated that rifabutin decreased the progression to MAC bacteremia in AIDS patients by about 50 percent. Adverse effects that resulted in the discontinuation of rifabutin prophylaxis occurred in 16 percent of patients. Rifabutin induces hepatic enzymes to a lesser extent than does rifampin, but dosage adjustment of drugs that are known to interact with rifampin may be required. CONCLUSIONS: Rifabutin is the only drug shown to be effective in the prevention of MAC bacteremia in AIDS patients; therefore, it should be made available as a formulary agent. It may be reasonable to delay initiation of rifabutin prophylaxis until CD4 lymphocyte counts are less than 75 50/mm3. PMID- 7849341 TI - New macrolide antibiotics: usefulness in infections caused by mycobacteria other than Mycobacterium tuberculosis. AB - OBJECTIVE: To compare the pharmacology, in vitro activity, and clinical use of the new macrolide antibiotics, azithromycin and clarithromycin, in the treatment of infections caused by mycobacteria other than Mycobacterium tuberculosis. DATA IDENTIFICATION: An English-language literature search using MEDLINE (1987-1994), Index Medicus (1987-1994), Program and abstracts of the 31st (1991) and 32nd (1992) Interscience Conference on Antimicrobial Agents and Chemotherapy, and bibliographic reviews of related textbooks, review articles, and professional society publications. STUDY SELECTION: 105 articles were selected. In vitro and in vivo reports on the pharmacokinetics, microbiology, pharmacology, and effectiveness of clarithromycin and azithromycin were assessed to compare their effectiveness and safety. Emphasis was placed on the use of these new drugs in treating infections caused by Mycobacterium avium complex, Mycobacterium chelonae, and Mycobacterium fortuitum infections. RESULTS: A review of the in vitro activity of the new macrolides revealed moderate to very good activity against many strains of mycobacteria other than M. tuberculosis. Early clinical trials show promising results in pulmonary infections, lymphadenitis, cutaneous infections, and disseminated infections. CONCLUSIONS: The new macrolides, azithromycin and clarithromycin, show great promise for treating infections caused by these acid-fast bacteria. Clarithromycin is recommended as a component of combination therapy for the treatment of M. avium complex infections in patients with AIDS. The development of resistance in patients, particularly when these agents are used alone, has been reported. PMID- 7849342 TI - Management of bacterial urinary tract infections in adults. AB - OBJECTIVE: To provide a comprehensive review of the diagnosis and therapeutic management considerations in patients with urinary tract infections (UTIs). DATA SOURCES: A MEDLINE search was used to identify pertinent English language literature, including reviews. Infectious disease textbooks were used for background information. STUDY SELECTION: Clinical trials evaluating drug therapy in a variety of patient populations with UTIs were reviewed. DATA EXTRACTION: Background information was obtained from comprehensive reviews. Drug dosing strategies and efficacy comparisons were extracted from the investigations in this area. DATA SYNTHESIS: Information was processed to provide general guidelines and resources for practitioners to use in managing UTIs. CONCLUSIONS: There are a number of useful antibiotics for the management of UTIs. The distinctions between infection severity and underlying risk factors within a given population influence the appropriateness of drug selection and duration of treatment. PMID- 7849343 TI - Oxygen transport goals in the resuscitation of critically ill patients. AB - OBJECTIVE: To discuss the limitations of conventional monitoring techniques of shock and examine more recent monitoring techniques that are used to titrate therapies to attain supranormal oxygen transport goals. DATA SOURCES: Review articles and investigations published since 1973. STUDY SELECTION: Articles were selected if they examined the monitoring or treatment of shock. Emphasis was placed on finding investigations involving humans that used innovative methods to assess and treat inadequate tissue perfusion. DATA EXTRACTION: Data were extracted primarily from original investigations and review articles published in or translated into English. DATA SYNTHESIS: The conventional monitoring of shock often fails to detect inadequate tissue perfusion, which may lead to inadequate resuscitation of patients, resulting in increased morbidity and mortality. Attainment of supranormal values for oxygen transport variables has been associated with improved outcomes, especially in patients with hypovolemic shock or septic shock. Additionally, interventions used to increase these variables to supranormal values have resulted in improved survival in high-risk preoperative patients with hypovolemic or septic shock, but not in severely ill postoperative patients with multiple complications. CONCLUSIONS: Efforts to increase oxygen transport variables to supranormal values cannot be recommended routinely for all critically ill patients. Preoperative patients in early stages of hypovolemic or septic shock may benefit from therapies titrated to achieve supranormal goals, but patients in later stages of illnesses may be harmed by such attempts. Questions remain regarding how quickly and how long the oxygen transport variables should be elevated. The most effective and least toxic therapeutic interventions for increasing the variables need to be determined. PMID- 7849344 TI - Meta-analysis of controlled trials of drug therapy in mild chronic asthma: the role of inhaled corticosteroids. AB - OBJECTIVE: To determine the role of inhaled corticosteroids in the treatment of mild chronic asthma. SOURCE OF STUDIES: Searches of MEDLINE and Index Medicus for English language literature dealing with asthma and inhaled corticosteroids. DESIGN: All retrieved articles were subjected to predetermined criteria for inclusion in the meta-analysis. Inclusion criteria centered around randomized, double-blind studies reporting objective clinical endpoint(s) for subjects with mild chronic asthma who were treated for more than seven days. Studies that were included were not allowed to have any predetermined exclusion criteria. RESULTS: The literature search identified 129 articles, of which 41 satisfied some but not all of the criteria for inclusion. Five articles met all the criteria and were subjected to meta-analysis. The total number of subjects was 141. Peak expiratory flow rate (PEFR) was used as the objective endpoint for effect size calculation. Subjecting these five studies to quality review revealed a range of 0.607-0.741, with 1 as the highest attainable quality and 0 the lowest. Reported results for the different studies were found to be homogenous, thus allowing for the calculation of overall effect size. Inclusion of children in some of the studies added variance to the reported studies, but not to the point at which studies would be considered heterogenous. Effect sizes ranged between 0.41 and 0.89, and the overall weighted average effect size for PEFR was 0.59, with the calculated 95 percent confidence interval at 0.32 to 0.84. A tabulated display of binomial effect size for included trials provided ranges of success rates for treatment versus control values. Results of the studies were judged robust, as 92 studies reporting no significant effects are needed to turn the finding of the meta analysis insignificant. CONCLUSIONS: Based on the results of the meta-analysis, the existing literature suggests a role for inhaled corticosteroids in the treatment of mild chronic asthma. PMID- 7849345 TI - Meta-analysis and the scientific research that precedes it. PMID- 7849346 TI - Documenting pharmaceutical care: creating a standard. AB - OBJECTIVE: To examine the need for a standardized, systematized approach to document patient pharmacotherapy, workable in all pharmacy practice settings, and to propose a model to meet the identified needs. DATA SOURCE: A MEDLINE search was conducted, in addition to an assessment of current practices and a review of known sources of pharmacotherapy/pharmaceutical care evaluation and documentation methodology. CONCLUSIONS: Pharmacy lacks a universally accepted, standardized, systematized approach to document the evaluation of a patient's pharmacotherapy. An approach is presented that distills the concepts of pharmaceutical care into a manageable documentation format and provides a customization of the medical history and physical examination/subjective-objective-assessment-plan system to meet the unique needs of pharmacy. This approach provides a convenient format for notes for all pharmacists, applicable in any practice setting. It provides a starting point for decisions on what pharmacy wants and accepts as a standard to provide continuity of pharmaceutical care to patients, uniform communication with healthcare colleagues, appropriate instruction to students, data analysis to demonstrate the value of services, and needed guidance to software vendors, medical records departments, and third-party payers. PMID- 7849347 TI - Optimizing oxygen delivery in critical illness. PMID- 7849348 TI - Genesis of clinical pharmacokinetic/pharmacodynamic concepts: E.K. Marshall, Jr.'s role. PMID- 7849349 TI - Reversal of ranitidine-induced hypergastrinemia by cimetidine. PMID- 7849350 TI - Possible interaction between metronidazole and carbamazepine. PMID- 7849351 TI - Rifampin-induced severe thrombocytopenia in a patient with pulmonary tuberculosis. PMID- 7849352 TI - Amphotericin B for visceral leishmaniasis resistant to pentavalent antimonial drugs in AIDS. PMID- 7849353 TI - Bullous eruption induced by tranexamic acid. PMID- 7849354 TI - Adverse effects associated with dexamethasone, lorazepam, and granisetron. PMID- 7849355 TI - Neonatal fibrinogen depletion caused by sodium valproate. PMID- 7849356 TI - Sertraline overdose. PMID- 7849357 TI - Lack of nephrotoxicity with the administration of amphotericin B in a lipid emulsion. PMID- 7849358 TI - Severe bleeding in postoperative patients with infections. PMID- 7849359 TI - Acute hepatitis caused by tenoxicam. PMID- 7849360 TI - Sterilization of talc USP for intrapleural use. PMID- 7849361 TI - Anaphylactic shock caused by triamcinolone acetonide. PMID- 7849362 TI - Cholestasis: hepatocellular reaction to trimethoprim/sulfamethoxazole. PMID- 7849363 TI - Comment: Isoniazid-induced psychosis. PMID- 7849364 TI - Comment: Single daily dosage of lithium carbonate. PMID- 7849365 TI - Comment: Heparin infusion rates. PMID- 7849366 TI - Measurement of anterior and posterior circulation flow contributions to cerebral blood flow. An ultrasound-derived volumetric flow analysis. AB - Ultrasound-derived volumetric flow analysis may be useful in answering questions of basic physiological interest in the cerebrovascular circulation. Using this technique, the authors have sought to describe quantitatively the complete concurrent flow relations among all four arteries supplying the brain. The aim of this study of normal subjects was to determine the relative flow contributions of the anterior (internal carotid arteries) and posterior (vertebral arteries) cerebral circulation. Comparisons between the observed and theoretically expected anterior and posterior flow distribution would provide an opportunity to assess traditional rheological conceptions in vivo. Pulsed color Doppler ultrasonography was used to measure mean flow rates in the internal carotid and vertebral arteries in 21 normal adults. The anterior circulation (internal carotid arteries bilaterally) carried 82% of the brain's blood supply and comprised 67% of the total vascular cross-sectional area. These values demonstrate precise concordance between observations in vivo and the theoretically derived (Hagen-Poiseuille) expected flow distribution. These cerebrovascular findings support the traditional conception of macroscopic blood flow. Further studies using ultrasound-derived volumetric analysis of the brain's arterial flow relations may illuminate the vascular pathophysiology underlying aging, cerebral ischemia, and dementias. PMID- 7849367 TI - Critical neck position as an independent risk factor for posterior circulation stroke. A magnetic resonance angiographic analysis. AB - The purpose of this study was to compare the effects of critical neck angulation (rotation and hyperextension) on vertebral artery perfusion in symptomatic and control populations and to determine whether this represents a risk factor for ischemic stroke. In a cross-sectional study, 64 symptomatic individuals with well documented brainstem ischemic events (average age, 70.9 yr) and 37 control subjects (average age, 66.3 yr) were evaluated using a dynamic magnetic resonance angiography technique designed to mimic activities of daily living. Abnormalities of perfusion at the atlantoaxial and atlantooccipital junction and distal vertebral artery were recorded and scored independently by two neuroradiologists. Volume flow analysis was also recorded at the basilar artery, and distal and proximal vertebral arteries. Symptomatic subjects displayed a consistent pattern (56.4%) of contralateral hypoperfusion at the atlantoaxial and atlantooccipital junction and distal segments (grades 3 and 4) (p < 0.001). Unsuspected hypoplasia was noted in 13% of the symptomatic subjects with a right-sided preponderance (88%), suggesting developmental susceptibility. Occlusion was noted in all subjects with contralateral neck rotation. Postpositional ischemia was present (68%) and correlated with female gender (p < 0.001), severity of stenosis (p < 0.001), vascular risk factors (p < 0.001), and microinfarction on magnetic resonance images (p < 0.05). Flow analysis showed low basilar artery perfusion (< 25 ml/min) in 63.6%, and unsuspected steal with neck motion in 4 subjects.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7849368 TI - Comparison of magnetic resonance imaging and histology in collagenase-induced hemorrhage in the rat. AB - Complex changes in the appearance of blood on magnetic resonance images (MRIs) complicate interpretation of intracerebral hemorrhage. In this study serial MRIs of intracerebral hemorrhage were obtained at 1.5 T, using a recently developed model for brain hemorrhage, and the MRI findings were compared with histological findings. Hemorrhages were induced in 24 adult rats by the stereotactic injection of 0.5 unit of bacterial collagenase into the caudate/putamen. Initially, there was hypointensity seen on both T1- and T2-weighted images. Conversion to hyperintensity began on both T1- and T2-weighted images around 10 hours, when red blood cell lysis was observed histologically. By 24 hours, complete conversion to marked hyperintensity had occurred. Calculated T2 values increased twofold to fivefold after lysis, indicating that T2 effects dominate the conversion to hyperintensity seen after red blood cell lysis. At 24 hours there was a rim of intact red blood cells around the lesion, which was hypointense on MRI at a time when iron stains were negative. Fresh blood appears hypointense on T1- and T2 weighted images both at the early stages of a bleed and at later stages when rebleeding occurs. Collagenase-induced hemorrhage is a useful animal model to follow the evolution of paramagnetic effects of blood on MRI. PMID- 7849369 TI - Vexing problems of diagnostic magnetic resonance imaging (MRI) involves the appearance of bleeding. PMID- 7849370 TI - Tomographic electroencephalography/magnetoencephalography. Dynamics of human neural network switching. AB - New developments in multimodal registration of electroencephalography (EEG), magnetic resonance imaging (MRI), and positron emission tomography (PET) are presented as a method to create a tomographic EEG. Three-dimensional information about the x,y,z location of the sources of event-related potentials is corroborated through the use of experimental design and coregistration with MRI and PET. Once the three-dimensional location of event-related potential dipole sources is identified and corroborated, pseudoinverse procedures are used to derive a new EEG voltage sequence from each of the dipoles. Each derived EEG dipole time series is analogous to recording EEG from a deeply implanted electrode and constitutes a four-dimensional tomographic EEG (i.e., three dimensional space plus time). EEG coherence and phase analyses are then performed on the dipole-derived time series to study the temporal and spatial dynamics of neural network switching during voluntary finger movements. The purpose of this article is to demonstrate a new method to exploit the time domain dynamics of neural network switching in behaving human subjects. PMID- 7849371 TI - Muscle computed tomography features of motor neuron disease in late-onset GM2 gangliosidosis. AB - Late-onset GM2 gangliosidosis, a rare inherited neuronal storage disease, is characterized by a variety of clinical manifestations. The common clinical picture comprises neuromuscular, spinocerebellar, extrapyramidal, cognitive, and psychiatric abnormalities. Details of the extent of muscle involvement have never been reported. Eight patients with this syndrome were evaluated for the existence and extent of motor neuron disease using routine electrodiagnosis and systematic evaluation of skeletal musculature by computed tomography. Motor neuron disease was present in each and every patient regardless of the clinical manifestations and to a degree beyond that suspected on neurological examination. Muscle imaging disclosed a diffuse wasting and fatty replacement of muscles with predilection of pelvic and thigh muscles, and especially the quadriceps group. It seems that progressive motor disability in this syndrome is mainly due to motor neuron disease, as manifested by muscle atrophy, which can be easily demonstrated by muscle computed tomography. PMID- 7849372 TI - Magnetic resonance imaging of cauda equina syndrome in ankylosing spondylitis: a case report. AB - A case of ankylosing spondylitis associated with massive dural ectasia is presented. Computed tomography and magnetic resonance imaging characteristics are shown, and possible causes are discussed. PMID- 7849373 TI - Infratentorial cerebral cryptococcosis. AB - In a nonimmunocompromised patient with cerebral cryptococcosis, unique magnetic resonance findings included abnormalities limited to the posterior fossa and cerebellar hemispheric edema, gyriform enhancement of the vermis and cerebellar hemispheres, and infratentorial plaquelike enhancement. Magnetic resonance findings in central nervous system cryptococcosis are discussed. PMID- 7849374 TI - Patients who have been advised to have immediate or urgent discectomies because of low back pain. PMID- 7849375 TI - Multiple malignant meningiomas following systemic chemotherapy for Hodgkins lymphoma: a three-dimensional magnetic resonance imaging analysis. PMID- 7849376 TI - Contrast-enhanced magnetic resonance imaging of the lumbosacral roots in the dysimmune inflammatory polyneuropathies. AB - The diagnosis of acute Guillain-Barre syndrome and chronic inflammatory demyelinating polyradiculoneuropathy is based on clinical characteristics, abnormalities on nerve conduction studies, and nerve biopsy specimens indicating demyelination. Inflammation and edema are also common findings in nerve specimens. Immunotherapy is helpful in these dysimmune conditions. Occasionally the diagnosis is difficult to make, particularly when electrophysiological testing or nerve biopsy findings are not characteristic. The authors found contrast enhancement of lumbosacral roots in patients with chronic inflammatory demyelinating polyradiculoneuropathy and Guillain-Barre syndrome, but not in those with other demyelinating neuropathies. Contrast-enhanced magnetic resonance imaging could be a useful tool in the diagnosis of the dysimmune inflammatory neuropathies. PMID- 7849377 TI - Serial electrocardiographic findings in acute myocarditis. AB - The purpose of the present study was to clarify the characteristic findings of electrocardiogram (ECG) in 11 patients with acute myocarditis. ST elevation without reciprocal ST depression was one of the conspicuous findings in the acute stage. Total QRS amplitudes at the acute stage were significantly decreased as compared to those before illness and during the convalescent stage. Abnormal Q waves were present in 7 patients and disappeared in a short period. The number of leads showing Q waves was inversely correlated to left ventricular (LV) ejection fraction (r = -0.87, p < 0.01). Conduction disturbances were present in 7 patients. Second degree and advanced AV block was transient while bundle branch block remained over months. Corticosteroid treatment was effective for patients who had edematous myocardial thickening and AV conduction disturbances. As the serial ECG findings in acute myocarditis are so characteristic, and this help to differentiate it from acute myocardial infarction (AMI). PMID- 7849378 TI - Diaphragmatic electrical activity during controlled and assisted mechanical ventilation in conscious human subjects. AB - Breathing during mechanical ventilation was analyzed in 8 conscious healthy volunteers by application of intermittent positive pressure ventilation through a mouthpiece. In controlled mechanical ventilation (CMV), the respiratory rate and tidal volume were fixed at 110 and 120% of the subject's corresponding spontaneous breathing parameters. The diaphragmatic electromyogram (EMGdi) decreased significantly but become synchronous with the rhythm of the CMV. In assisted mechanical ventilation (AMV), the EMGdi response developed prior to and during the inspiratory phase of AMV. Application of an unexpected mechanical breath elicited the EMGdi. As the triggering sensitivity was decreased, the EMGdi prior to and during a mechanical breath was augmented, however, its rate of rise was unaffected. Our results suggest that the EMGdi during mechanical ventilation in conscious subjects is initiated by the respiratory center, however, this activity is modulated strongly by input from the pulmonary afferents and from the cerebral cortex. PMID- 7849379 TI - Hypercalcemia caused by PTH-rP associated with lung metastasis from urinary bladder carcinoma: an autopsied case. AB - We analyzed the parathyroid-related protein (PTH-rP) content in tissue specimens obtained from a 61-year-old man with hypercalcemia associated with lung metastasis from urinary bladder carcinoma using radioimmunoassay and immunohistochemistry. Radioimmunoassay showed that the PTH-rP content was higher in metastatic lung tumor tissue than in non-tumorous lung tissue. Immunohistochemical analysis revealed the presence of PTH-rP in tumor cells. Furthermore, proliferation of osteoclasts was found in bone marrow at autopsy. The results suggest that PTH-rP induced humoral hypercalcemia of malignancy in a patient with urinary bladder cancer. PMID- 7849380 TI - Japanese family with a deficiency of lecithin:cholesterol acyltransferase (LCAT). AB - We present findings in the ninth known Japanese family with lecithin:cholesterol acyltransferase (LCAT) deficiency. A 54-year-old man (proband) and his 58-year old brother presented with corneal opacity. Both subjects showed a marked decrease in serum high density lipoprotein (HDL)-cholesterol and in the cholesteryl ester ratio. Although apo A-I and A-II were low, apo E tended to be high. Serum LCAT activity and mass were not detectable. Urinary examination showed microhematuria or proteinuria. Renal function was normal and no anemia was demonstrated, but blood smears showed poikilocytosis with target cells. The serum LCAT activity of the proband's three sons, obligate heterozygotes of LCAT deficiency, was about one-half the normal level, and HDL-cholesterol and apo A-I levels were low normal. PMID- 7849381 TI - Hypersensitivity pneumonitis induced by inhalation of mushroom (Pholiota nameko) spores. AB - We describe the hypersensitivity pneumonitis of a 49-year-old woman who had been cultivating the edible mushroom 'Pholiota nameko' for three years. Her clinical manifestations and laboratory findings including transbronchial lung biopsy (TBLB) and bronchoalveolar lavage fluid (BALF) were consistent with those of other forms of hypersensitivity pneumonitis. Counter-immunoelectrophoresis determined the causative antigen to be the spores of Pholiota nameko. The indoor cultivation method appeared to play a major role in the occurrence of the hypersensitivity pneumonitis. PMID- 7849382 TI - Myasthenia gravis associated with Addison's disease. AB - Idiopathic Addison's disease developed in a 52-year-old female with a 15-year history of myasthenia gravis. The association of myasthenia gravis with other autoimmune diseases is well known, however an association with Addison's disease is rare. It was speculated that the development of Addison's disease in this patient might have been due to common immunological abnormalities underlying these two diseases. We report this case and briefly discuss the pathogenetic mechanism of this association. PMID- 7849383 TI - Pulmonary hyalinizing granuloma with Castleman's disease. AB - A case of pulmonary hyalinizing granuloma (PHG) with Castleman's disease in a 43 year-old man is presented. He was asymptomatic, but the disease was recognized due to a routine chest roentgenographic study. Anemia, multiple lymphadenopathy, hypoalbuminemia and polyclonal hypergamma-globulinemia were observed. Histological examination of cervical lymph nodes revealed the plasma cell type of Castleman's disease. The diagnosis of PHG was confirmed by video-assisted thoracoscopical lung biopsy, and the immuno-histochemical staining of lamellar fibrosis for types I and III collagen was positive. PMID- 7849384 TI - Primary retroperitoneal synovial sarcoma. AB - We present a patient with primary retroperitoneal synovial sarcoma which showed a monophasic fibrous pattern, the fourth such case to be described, and a review of the literature. Synovial sarcoma cells in the present case were stained positive for cytokeratin and epithelial membrane antigen (EMA), of which histology was differentiated from other spindle cell sarcoma with similar light microscopic features. Retroperitoneal synovial sarcoma is usually treated surgically, however only one of 16 cases identified in the literature survived five years after resection. Due to the high fatality rate, physicians should be alerted to the possibility of this disorder in the differential diagnosis of an abdominal mass. PMID- 7849385 TI - Successful treatment by surgical removal of bone metastasis producing PTH: new approach to the management of metastatic parathyroid carcinoma. AB - A 62-year-old woman had primary hyperparathyroidism due to parathyroid carcinoma. In spite of surgical removal of the enlarged parathyroid gland, intractable hypercalcemia persisted. 99mTc-methoxyisobutylisonitrile scanning revealed bone metastatic lesions, although conventional 201T1-chloride scanning failed to demonstrate those lesions. Octreotide inhibited parathyroid hormone (PTH) secretion, although various means such as bisphosphonates, calcitonin and hydration were effective to reduce serum calcium level to some extent but failed to reduce PTH secretion at all. The CT-guided transcutaneous tumor marking facilitated the subsequent orthopedic surgery for successful removal of the metastatic focus of PTH secretion from the iliac bone. PMID- 7849386 TI - Postpartum exacerbation of HTLV-I associated myelopathy/tropical spastic paraparesis followed by an episode of painless thyroiditis. AB - A 28-year-old woman noticed a progressive gait disturbance after her first delivery. At the age of 32, the gait disturbance improved during her second pregnancy, but became worse after delivery and eventually resulted in a scissoring gait. At the age of 34, she became transiently thyrotoxic and was diagnosed as having painless thyroiditis and HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP). The findings of this case suggest that the postpartum exacerbation of HAM/TSP was probably due to a rebound phenomenon after immunosuppression during pregnancy, and that the immunological abnormalities associated with HAM/TSP might have played some role in the development of painless thyroiditis. PMID- 7849387 TI - Purulent meningitis after endoscopic injection sclerotherapy for esophageal varices. AB - A 57-year-old man with liver cirrhosis developed alpha-hemolytic streptococcal meningitis following endoscopic injection sclerotherapy for esophageal varices. Central nervous system infection is uncommon as a complication of sclerotherapy, however, when such an infection does develop, it is usually intractable. We therefore emphasize the importance of immediate antibiotic therapy right after the onset of inflammatory symptoms in order to prevent the development of undesired infectious complications following sclerotherapy. PMID- 7849388 TI - Rapidly progressive pulmonary alveolar proteinosis in a patient with chronic myelogenous leukemia. AB - A 46-year-old man with chronic myelogenous leukemia (CML) was admitted to our hospital because of high fever. The chest radiographs showed bilateral groundglass-like infiltrates in the perihilar region. Transbronchial lung biopsy (TBLB) and autopsy revealed PAS-positive granular materials characteristic of pulmonary alveolar proteinosis (PAP). He had received interferon-alpha since the time of CML diagnosis. Busulfan had never been administered. Altered cell mediated immunity was thought to be closely related to the development of PAP. PMID- 7849389 TI - T cell abnormalities in mixed connective tissue disease complicated with Klinefelter's syndrome. AB - We report a 28-year-old Japanese with Klinefelter's syndrome who developed mixed connective disease (MCTD) and Sjogren syndrome. Previously being well, he presented with Raynaud's phenomenon, dry eye, fever and polyarthralgia. Clinical examinations revealed anti-nRNP autoantibody, leukopenia and lung fibrosis. Then he was found to have Klinefelter's syndrome. Flow cytometric analysis showed a relative increase of peripheral CD8+ T lymphocytes carrying either HLA-DR or CD57. Lymphocyte IL-2 production induced in vitro by concanavalin A was decreased. Such T cell abnormalities may be implicated in the development of autoimmune disease in Klinefelter's syndrome. PMID- 7849390 TI - Hepatic myelopathy: an unusual neurological complication of advanced hepatic disease. AB - Encephalopathy is widely known as one of the neurological complications of chronic hepatic disease. Recently, the occurrence of progressive myelopathy in patients with advanced hepatic disease has been well documented and differentiated from encephalopathy. We describe a 76-year-old man with decompensatory liver cirrhosis due to hepatitis C virus infection who suffered from progressive paraplegia. Postmortem examination revealed demyelination of the lateral column of the spinal cord, especially of the thoracic segment. No evidence of spontaneous portosystemic shunts was found. These findings suggest that the patient had been affected with hepatic myelopathy, which is a rare complication of liver cirrhosis. PMID- 7849391 TI - Successful delivery in a pregnant women with crescentic IgA nephropathy. AB - A 27-year-old Japanese female developed nephrotic syndrome and impaired renal function during pregnancy. A renal biopsy performed at 21 weeks of gestation revealed crescentic IgA nephropathy. She was treated with steroid pulse therapy followed by conventional steroid therapy. Although the nephrotic syndrome was persistent, the impaired renal function did not deteriorate after the treatment. A live infant was delivered by cesarean section at 37 weeks of gestation. After the delivery, both the nephrotic syndrome and renal insufficiency improved gradually. The indications for renal biopsy and treatments for active IgA nephropathy during pregnancy are discussed. PMID- 7849392 TI - Intrapulmonary lymph nodes. AB - We report two cases of intrapulmonary lymph nodes detected by a chest roentgenogram or CT scan. The first patient was a 61-year-old fisherman referred complaining of cough and hemosputum. Chest roentgenogram showed a subpleural small nodular shadow at the superior segment of the right lower lobe. Thoracotomy showed a small anthracotic lymph node. The other case was a 68-year-old female patient admitted for further examination of a subpleural small nodular shadow at the latero-basal segment of the left lower lobe detected on a chest CT scan. Thoracoscopic surgery revealed that the black nodule was an anthracotic lymph node. The appearance of an intrapulmonary lymph node on radiological examination is rare, however, it should be considered in the differential diagnosis of a solitary or multiple peripheral pulmonary nodules in adults. A small nodular shadow should be resected if malignancy is suspected though not proven. Subpleural intrapulmonary lymph node warrants thoracoscopic surgery. PMID- 7849393 TI - Treatment of a Japanese patient with familial amyloidotic polyneuropathy with orthotopic liver transplantation. AB - A 28-year-old male patient with familial amyloidotic polyneuropathy (FAP) underwent a liver transplantation from a heart-beating cadaveric donor in Sweden. He had suffered from the disease for 2.5 years. It took 5.5 hours to carry out the operation without blood transfusion. After the liver transplantation, serum amyloidgenic variant transthyretin (TTR) levels became extremely low and diarrhea stopped after the 7th day. On day 13, the patient was discharged from the hospital and one month after the transplantation, his general condition remained quite good. This is the first case of a Japanese patient with congenital metabolic disorders as well as FAP to receive a liver transplantation from a heart-beating cadaveric donor. PMID- 7849394 TI - Rapid and efficient construction of yeast artificial chromosome contigs in the mouse genome with interspersed repetitive sequence PCR (IRS-PCR): generation of a 5-cM, > 5 megabase contig on mouse chromosome 1. AB - We have developed a new technique for the generation of YAC contigs in the mouse genome that is based on the ability to detect overlapping clones by hybridization of shared IRS-PCR products. As a demonstration of the technique, a 5-cM, > 5 megabase contig was developed on the distal half of mouse Chromosome (Chr) 1, spanning the region from Lamb2 to At3. The contig covers roughly 5% of the genetic distance of the chromosome and is comprised of more than 80 clones; 71 probes were assigned physical order to the chromosome, of which 59 were new markers generated in this study. Eight of the new probes were shown to be polymorphic between C3H/HeJ-gld and M. spretus. Three probes were mapped on a [(C3H/HeJ-gld x M. spretus) x C3H/HeJ-gld] interspecific backcross to integrate the physical map with a high-resolution genetic map of the region. PMID- 7849395 TI - Ifg, Gli, Mdm1, Mdm2, and Mdm3: candidate genes for the mouse pg locus. AB - Various genes that mapped to the distal end of Chromosome (Chr) 10 were considered as possible candidates for the mouse pygmy (pg) locus. Probes derived from Ifg, Gli, Mdm1, Mdm2, and Mdm3 (Mdm2 and Mdm3 are genes that are coamplified with Mdm1 on the same double minute chromosomes in 3T3DM cells) were used for Southern analysis of DNA from wild-type mice and various pg mutants. In addition, the chromosomal locations of Ifg, Gli, Mdm1, Mdm2, and Mdm3 were determined by interspecific backcross analysis with progeny derived from matings of [(C57BL/6J x Mus spretus)F1 x C57BL/6J] mice. The mapping data indicate that the Mdm loci are linked to each other and to Ifg, pg, and Gli in the distal region of mouse Chr 10. Both the mapping data and the Southern analysis confirm that Mdm1, Mdm2, Mdm3, Ifg, and Gli are distinct from pg. PMID- 7849396 TI - Linkage of phosphoribosylpyrophosphate synthetases 1 and 2, Prps1 and Prps2, on the mouse X chromosome. AB - The X Chromosome (Chr) genes for phosphoribosylpyrophosphate synthetases 1 and 2, Prps1 and Prps2, were mapped on the mouse X Chr with interspecific backcrosses between C57BL/6 (B6) and M. spretus (S). Southern analysis showed that Prps1 mapped between Plp and DXWas31, a mouse X Chr region that is homologous to Xq21 24 on the human X Chr while Prps2 mapped between DXWas31 and Amg, a region that is homologous to the map position of PRPS2 on Xp22 of the human X Chr. Additionally, other restriction fragments highlighted by PRS II showed autosomal segregation. In situ hybridization and FISH analysis of metaphase chromosome spreads prepared from lymphocytes of B6 or S male mice confirmed that there were in fact two different locations on the X Chr, X F1-2 and X F2-3 for Prps1 and 2 respectively, as well as two autosomal sites for Prps-like genes. PMID- 7849397 TI - Characterization of six new loci within the swine major histocompatibility complex class III region. AB - A search for new potential coding sequences was conducted within two overlapping cosmid genomic DNA clusters of about 170 and 45 kb from the swine major histocompatibility complex class III region. The sequences were detected with various probes, including pools of swine cDNA, homologous and heterologous genomic sequences, and synthetic oligonucleotides. The 170 kb cluster was centered on the tumor necrosis factor genes (TNF), and the 45 kb cluster contained the heat-shock protein 70 genes (HSP70). The TNF cluster revealed the presence of five new genes: lymphotoxin beta, BAT1, BAT2, BAT3, and a sequence related to DNA-binding factors. No sequence homologous to B144 was found in the TNF cluster, although other unidentified coding sequences may be present in this cluster. The HSP70 cluster contained a gene identified as BAT6, that is, tRNA valyl synthetase. These results provide new evidence that the genomic maps of these various genes in the TNF and HSP70 sub-regions are similar in swine and human. PMID- 7849398 TI - Tissue-specific expression of Ran isoforms in the mouse. AB - Ran genes encode a family of well-conserve small nuclear GTPases (Ras-related nuclear proteins), whose function is implicated in both normal cell cycle progression and the transport of RNA and proteins between the nucleus and the cytoplasm. Previous studies of Ran proteins have utilized cell-free systems, yeasts, and cultured mammalian cells. We have now characterized patterns of Ran gene expression in the mouse. Serum starvation suppressed Ran gene transcription in mouse 3T3 cells. Ran mRNA reappeared in cells within 3 h after refeeding. A single Ran mRNA species was detected at low levels in most somatic tissues of the adult mouse. In testis, this Ran mRNA was abundant, as were other larger transcripts. Analysis of testis-derived Ran cDNA clones revealed the presence of two transcripts, one specifying an amino acid sequence identical to that of human Ran/TC4 and one specifying an amino acid sequence 94% identical. Northern blotting and reverse transcriptase-PCR assays with oligonucleotide probes and primers specific for each transcript demonstrated that the isoform identical to Ran/TC4 was expressed in both somatic tissues and testis, while the variant form was transcribed only in testis. The existence of tissue-specific Ran isoforms may help to rationalize the diverse roles suggested for Ran by previous biochemical studies. PMID- 7849399 TI - Use of porcine interspersed repeat sequences in PCR-mediated genotyping. AB - PCR primers derived from porcine short and long interspersed repeat sequences were used to amplify DNA samples isolated from individual members of three generation pig reference pedigrees. Subsequent high-resolution gel electrophoresis of both SINE and LINE-PCR products allowed direct visualisation of polymorphisms that segregated in a Mendelian manner. Additional polymorphisms were detected by Southern blotting of the gels described above followed by hybridization with simple sequence DNA. Genotyping by interspersed repeat-PCR exploits the natural architecture of the pig genome and allows the typing of polymorphisms by utilizing pre-existing sequence information. PMID- 7849400 TI - Evolutionary conservation and genomic organization of XAP-4, an Xq28 located gene coding for a human rab GDP-dissociation inhibitor (GDI). AB - After the development of efficient methods for the construction of transcription maps of defined genomic regions, the rate-limiting step in the analysis of the coding potentials of these regions is the elucidation of function of the novel genes and the examination of their possible involvement in hereditary diseases localized to the region. This can be greatly facilitated by the detection of sequence homology to a gene of known function. XAP-4 is one of the genes identified in the G6PD region of the human Xq28 by direct cDNA selection. The rapid assembly of this gene and the determination of its function was possible because of its sequence homology with the bovine smg p25A/rab3A GDP dissociation inhibitor (GDI). Sequence comparison with other GDIs in the databases has revealed that XAP-4 belongs to one of at least two distinct classes of mammalian rab GDIs. The rab GDIs, which play an important role in the regulation of cellular transport, are highly evolutionarily conserved, as are several other genes identified in the neighborhood of XAP-4. This genomic region is very gene dense, and all the cDNA clones from the approximately 2.5-kb-long transcript of XAP-4 map to a single 7.5-kb genomic EcoRI fragment. The genomic organization of XAP-4 has been examined to determine the distribution of the exonic sequences within this short segment of genomic DNA. It was found that, similar to several other genes from the region, XAP-4 is split into exons of average size, which are interrupted by very short introns. PMID- 7849401 TI - The cDNA sequence and chromosomal location of the human SOX2 gene. PMID- 7849402 TI - Zfp30, a KRAB domain containing zinc finger protein gene, maps to mouse chromosome 7. PMID- 7849403 TI - Anchorage of an unassigned linkage group to pig chromosome 10 with P1 clones. PMID- 7849404 TI - Isolation of dinucleotide repeats from a pig chromosome 1-specific DNA library. PMID- 7849405 TI - The mouse scurfy (sf) mutation is tightly linked to Gata1 and Tfe3 on the proximal X chromosome. PMID- 7849406 TI - Localization of mouse imprinted gene U2af1-rs1 to A3.2-4 band of chromosome 11 by FISH. PMID- 7849407 TI - Mapping of the gene for rat protein phosphatase 2C alpha (PP2C1) to chromosome 6. PMID- 7849408 TI - Location of the mouse mast cell protease 7 gene (Mcpt7) to chromosome 17. PMID- 7849409 TI - Co-management in eye care. A personal perspective. AB - Co-management is a relatively new health care delivery system. It represents a coordinated approach to the delivery of eye care involving the local primary care provider (optometrist) and the regional secondary and tertiary center. The history, philosophy, and future of co-management are discussed, as are keys to the development of a successful co-management team. PMID- 7849410 TI - Protocols for co-management. AB - Co-management by optometrists and ophthalmologists requires a written expression of the protocol for examination, treatment, and follow-up of patients. The protocol should also describe how and when information is to be shared between practitioners. To facilitate the communication process, standard forms should be adopted for use by all practitioners. Example protocols and sample forms are provided for the most common types of clinical situations in which co-management is required: postoperative care of cataract patients; treatment of glaucoma patients; and preoperative and postoperative management of radial keratotomy patients. PMID- 7849411 TI - How to make co-management work. PMID- 7849412 TI - Co-management of refractive eye surgery. AB - An onslaught of publicity about refractive surgery has led to considerable patient interest in this corrective procedure. Regardless of the optometrist's cautious view of refractive surgery, it is here to stay. We may not be providing appropriate care to our patients if we discuss only its disadvantages. It is imperative that we, as primary eye care providers, educate ourselves as to the advantages and disadvantages of refractive surgery so we can better educate our patients. It is our responsibility to help them decide if they are, indeed, candidates for refractive surgery. This paper provides basic knowledge to familiarize the practicing optometrist with radial keratotomy and excimer laser photorefractive keratectomy. Patient selection, preoperative evaluation and counseling, and postoperative care are discussed. Communication between the co managing optometrist and refractive surgeon is imperative. PMID- 7849413 TI - Co-management of patients with diabetes. AB - Co-management of the diabetic patient emphasizes interdisciplinary care between optometry and ophthalmology, and between optometry and the patient's primary physician. For the optometrist and the patient's primary physician, the emphasis is on written communication with regard to the ocular health of the patient's eyes. The optometrist also participates in educating patients about the complications related to diabetes mellitus, as well as reinforcing medical compliance and encouraging lifestyle changes for better health. By providing this scope of care, optometry becomes an integral part of the health care team. Between ophthalmology and optometry, the success of co-managing diabetic patients will be dependent on several factors, including demonstrating expertise in managing diabetic retinopathy, making timely and appropriate referrals based on results from national clinical trials, and developing a trusting relationship built over time. This paper emphasizes the multi-dimensional role the optometrist plays in the co-management of the diabetic patient with the patient's primary physician and with the ophthalmologist in treating and managing diabetic retinopathy. PMID- 7849414 TI - Co-management of patients with hypertension. AB - Information provided by doctors of optometry to the primary care providers of patients with hypertension provides one of the few objective means of assessing the status of these patients. The optometrist may also be the first to suspect primary or secondary hypertension in the course of a comprehensive eye examination. In this paper the pathophysiology of essential, malignant, and secondary hypertension is reviewed. The treatment and management of the systemic and ocular effects of hypertension are discussed along with the pivotal role that doctors of optometry play in co-managing patients with hypertension. PMID- 7849415 TI - Co-management of patients with glaucoma. AB - Glaucoma is a condition that challenges even the most experienced clinicians. Diagnosis may be straightforward and relatively simple, or difficult and trying. Management options include medication, laser, and surgery, alone or in combination. The care of patients with this chronic condition can be successfully delivered by a thoughtfully created glaucoma cooperative management team that includes providers who can address the various stages of glaucoma therapy based on the needs of the patient. Communication among team members is a key to success. Described in this paper is a potential model for the development and implementation of a successful glaucoma co-management team. PMID- 7849416 TI - Co-management of cataract postoperative care. AB - Cataract extraction is a common ophthalmic surgical procedure. Many, if not most, patients will require it at some point in their lives. Cataract postoperative care is now routinely co-managed by many optometrists and ophthalmic surgeons. Postoperative management of the cataract patient in the optometrist's office is beneficial to the patient, and allows involved providers to practice to the full extent of their training and expertise. This paper sets forth a clinical perspective on co-management of cataract postoperative care. Included are suggested protocols for examination intervals and examination components, as well as expected clinical findings and potential complications. PMID- 7849417 TI - A general approach for identifying and cloning peptide synthetase genes. AB - A wide variety of bioactive peptides are synthesized nonribosomally by large multienzyme complexes employing the thiotemplate mechanism. Based on the known and highly conserved structures of several genes encoding multifunctional peptide synthetases, we developed a universal polymerase chain reaction (PCR) approach for amplifying, cloning and identifying parts of putative peptide synthetase genes. We showed, by cloning fragments of peptide synthetase genes from the phaseolotoxin-producing strain Pseudomonas syringe pv. phaseolica and from Bacillus licheniformis, which produces the branched peptide antibiotic bacitracin, that this approach is applicable. It gives a new and potentially general access to the biosynthetic genes of many nonribosomally synthesized peptides. PMID- 7849419 TI - A practical synthesis of optically pure and fully protected L-gamma carboxyglutamic acid derivatives and its application in peptide synthesis. AB - The optically active and fully protected gamma,gamma-di-t-butyl N-Fmoc-L-gamma carboxyglutamate was synthesized from the relatively inexpensive D-serine. The overall yield of the synthesis was about 30%. Our studies review that, under TFA and various acidic conditions, L-Gla and its derivatives were stable with no decarboxylation. Finally, gamma,gamma-di-t-butyl N-Fmoc-L-gamma-carboxyglutamate was successfully used in peptide synthesis by Fmoc strategy on solid phase. PMID- 7849418 TI - Primary structure of a novel human salivary acidic proline-rich protein. AB - Human salivary acidic proline-rich proteins (PRPs) form a significant fraction of the total salivary protein and fulfill several biologically important roles in the oral cavity. Five commonly occurring PRP polymorphisms, Db, Pa, PIF, Pr2 and Pr1, have been identified, their structures determined, and several uncommon polymorphisms (frequencies < 1:100) have been reported. Most PRPs occur as protein pairs, because of an unusual, limited but well-controlled post translational cleavage. We now describe an additional uncommon polymorphism, found in the saliva of one of 127 individuals examined in a recent study, identified by high performance anion-exchange liquid chromatography. By analogy with previous terminology, we designate this protein pair as PRP-5, for the primary 150-residue polypeptide gene product, and PRP-6, for the secondary 106 residue cleavage product. Amino acid analysis of intact PRP-6 and sequence determination of PRP-6 chymotryptic peptides, residues 15-24 and 26-35, show a single difference in PRP-6, compared to the most similar, characterized PRP, PRP 4, in that residue 30 is histidine in PRP-6, rather than arginine as in PRP-4 and in all the other sequenced PRPs. This substitution may have implications for the resistance of this polymorphic variant to degradation by trypsin-like enzymes originating from the oral microflora. PMID- 7849420 TI - Preliminary experimental anticancer activity of cecropins. AB - The cecropins are a group of peptides that were first isolated from the hemolymph of the giant silk moth, Hyalophora cecropia. In preliminary studies, these novel peptides were shown to be active against several bacteria and mammalian lymphomas and leukemias in vitro. The mechanism of action of the cecropins is thought to involve pore formation at the cytoplasmic membrane. The potential anticancer activity of cecropin B, cecropin P1 and Shiva-1 was investigated against a panel of mammalian cell lines in vitro. Cell lines showed a range of sensitivities to cecropin B (IC50 3.2 to > 100 microM), and two cell lines with the multidrug resistant phenotype were sensitive to the peptide. In vitro cecropin B activity was virtually complete within one hour. Preliminary in vivo studies showed that cecropin B increases the survival time of mice bearing murine ascitic colon adenocarcinoma cells. Future studies will address structure/activity relationships of similar peptides in order to optimize antitumor activity. PMID- 7849421 TI - Characterization of a linear pentapeptide containing two consecutive beta-turns. AB - The contiguous occurrence of two beta-turns is examined using molecular mechanics calculations. A tripeptide can take up special conformations known as beta-turns resulting in the reversal of the chain. There are two major classes of beta turns, called type I beta-turn and type II beta-turn. In the specific case described here, the third peptide unit forms a part of a second turn resulting in the formation of a two-turn motif. In the case of dihydropteridine reductase, this motif is involved in cofactor binding. This study examines the energetic and conformational preferences for chain-reversed motifs. Energy minimizations were carried out on models of pentapeptides with four different sequences for residues 2 through 5: (i) GGGG, (ii) AGGA, (iii) AGAG and (iv) AAAA. For each of the above sequences, all four possible combinations of type I and type II beta-turns were considered. Out of the four possible combinations, the (II, II) combination is the most planar one. The (I, I) combination is the least planar. For the all-Gly model and the all-Ala model, the most favored conformation energetically is a type I-type I combination. On the other hand, the sequence AGGA favors a type II type I combination, and the sequence AGAG prefers a type II-type II combination. A computer search for double-turn motifs at the Brook-haven Protein Data Bank revealed that the (I, I) combination occurs with the highest frequency, and the (I, II) combination has the next highest frequency.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7849422 TI - [Differential diagnosis of cone dystrophies]. AB - Electrophysiological and psychophysical findings recorded in 70 patients with three hereditary diseases of the cone system,--blue cone monochromatism, cone-rod dystrophy and selective cone dystrophy--were compared. Blue cone monochromatism is distinguished from the other two diseases by a reduction of visual acuity since childhood, without progression and with a sex-linked mode of inheritance. In addition, nystagmus is generally observed only in the time shortly after birth and the green and red cones are found to be missing on spectral sensitivity measurements. Cone-rod dystrophy can be distinguished from the blue cone monochromatism by a reduction in visual acuity later in life with progression of the symptoms. Spectral sensitivity measurements reveal reduced function of all three cones in cone-rod dystrophy and a single cone mechanism in selective cone dystrophy. Moreover, in cone-rod dystrophy the ERG reveals a reduction in the amplitudes of the photopic system and often mild involvement of the scotopic part. Measurement of the spectral sensitivity and the ERG can thus help in the diagnosis of these three hereditary diseases. PMID- 7849423 TI - [Biochemical and histochemical analysis of age related lipid deposits in Bruch's membrane]. AB - In histochemical studies the age-related deposition of different lipids in Bruch's membrane has been seen. This is important for the pathogeneses of age related macular degeneration due to changes in diffusion characteristics. Because the specificity of histochemical results is limited, a correlation of histochemical lipid analysis with biochemical methods was performed. The macular Bruch's membrane of 27 donors (age 1-97 years) was analyzed. The results of this analysis demonstrated that the increasing histochemical staining for lipids in Bruch's membrane corresponded with an increasing amount of lipids extracted from Bruch's membrane in biochemical analysis. This lipid deposition progressed exponentially with age. However, a large variation in the type of lipid deposited could be observed, with predominant deposition of phospholipids in some eyes and of neutral lipids in others. Furthermore, the phospholipids extracted were differentiated into 50% phosphatidylcholine, 30% phosphatidylethanolamine and 20% phosphatidylinositol and phosphatidylserin. The deposition of lipids, especially neutral lipids, in Bruch's membrane may change its diffusion characteristics. This appears to be important for the pathogenesis of age-related pigment epithelium detachments. The composition of the phospholipids extracted from Bruch's membrane supports, furthermore, the concept that the material deposited is the result of metabolic limitations in the degradation of photoreceptor outer segment material. PMID- 7849424 TI - [Macular drusen. Changes in the retinal pigment epithelium and angiographic characteristics as prognostic markers]. AB - Drusen in the macular area may precede other manifestations of age-related macular disease associated with severe visual loss. To identify fundus changes that might be predictive of advanced age-related maculopathy, we examined 79 patients with drusen for up to 3 years. Fundus photographs and fluorescein angiograms were independently analysed by two readers in a masked fashion using a standardized grading scheme. Fourteen patients (17.7%) developed a new exudative or nonexudative lesion involving the fovea. Delayed choroidal perfusion on the fluorescein angiogram, interpreted as an indicator for diffuse thickening of Bruch's membrane and relative atrophy of the choriocapillaris, was observed in 12 patients, 5 of whom developed geographic atrophy of the retinal pigment epithelium during follow-up (P < 0.009). Additional predictive characteristics included focal hyperpigmentations (P < 0.005) and focal extrafoveal areas of atrophy of the retinal pigment epithelium within 1600 microns of the center of the fovea (P < 0.031). These ocular features allow identification of patients with macular drusen at high risk for the development of complicating macular lesions. PMID- 7849425 TI - [Pathogenesis and therapy of central serous retinopathy]. AB - There is no consensus in the literature on the etiology and therapy of central serous retinopathy. We conducted a retrospective study to find out whether patients treated with argon laser coagulation (ALK) experienced long-term visual acuity improvement. We were also concerned to find whether choroidal perfusion was involved in the etiology. PATIENTS: In all, 28 patients (4 women/24 men) with RCS confirmed by angiography were analyzed. All patients were followed up from 1988 to 1992. Patients with chronic recurrent RCS were not considered. Angiography was performed to examine the type and localization of the leakage and also the choroidal perfusion. Patients who were treated with ALK were compared with patients who were not. RESULTS: Only 9 patients were treated with carefully directed ALK. Their mean visual acuity was 0.5 (STD 0.09) before therapy. After treatment the mean visual acuity was improved to an average of 0.8 (0.23). The follow-up time was up to 56 weeks. The patients without ALK had an initial visual acuity of 0.6 (0.21) which improved to 0.8 (0.22) during an observation period of 60 weeks. By the end of the study the visual acuity was the same in both groups. In 46% of all patients delayed choroidal perfusion was seen on angiography. CONCLUSION: There was no difference in visual acuity between patients treated with and without ALK. The angiographic examinations suggest general changes in choroidal perfusion in patients with RCS. PMID- 7849426 TI - [Central serous chorioretinopathy. Studies of the site of the lesion with indocyanine green]. AB - Indocyanine green angiographies of 33 patients with central serous chorioretinopathy (CSC) were examined in order to find out whether the location of ICG exudation was correlated with other findings. Areas of delayed choroidal filling at the site of the hot spot were found in 27 patients (82%). The hot spot was usually located at the margin of such areas. Furthermore, it seemed correlated to a larger ciliary artery in 19 patients (60.6%). A detachment of the pigment epithelium was detected in 18% and showed a characteristic early hypo- and late hyperfluorescence. There is evidence that the exudation of indocyanine green indicates a primary choroidal disorder as the cause of CSC. Many clinical features, for example pigment epithelial detachments, are easier to explain with this hypothesis. A correlation of the hot spot with variation of choroidal filling has to be interpreted with caution. Yet, it seems feasible that the border between areas of different speed of filling is especially vulnerable and might therefore decompensate in the case of diseased regulation of the choroidal vessels, as has been postulated for CSC. PMID- 7849427 TI - [Exudation of indocyanine green from subretinal neovascularization and its significance]. AB - Owing to its tight binding to protein, exudation of indocyanine green from subretinal new vessels would not normally be expected, but it has been demonstrated. We investigated 102 subretinal new vessels to find out how often exudation develops and to understand the reason for it. Exudation was found in 29 (28.4%) of the cases examined; 37 (36.6%) were stained, which means that these membranes became hyperfluorescent but not lighter than other, definitively non exuding, structures on the fundus. In 26 (25.5%) no hyperfluorescence was seen in the late phase, and in 10, or 9.8%, neovascularization remained occult. The correlation of indocyanine green exudation with retinal blood or lipid deposits was significant (r = 0.77, p = 0.0001). Histological examinations showed a correlation of lipid deposits with a severe disintegration of retinal vessels. This finding, in combination with others, indicates that the exudation of indocyanine green reflects severe destruction of vessel walls, which does not seem to occur consistently in all neovascular membranes. The exudation of indocyanine green might be of prognostic value. PMID- 7849428 TI - [Protein composition of the vitreous body in proliferative diabetic retinopathy. An analysis with 2-D-electrophoresis]. AB - Gradient SDS-polyacrylamide gel electrophoresis is a useful technique for characterization of soluble human vitreous protein. However, this technique is limited in the case of suboptimal discrimination power. In this study, we used 2 D electrophoresis to analyse the protein composition of proliferative diabetic retinopathy (PDR) intraocular fluid (n = 10), and compared it with normal vitreous (n = 10) and serum (n = 10). In normal vitreous, the protein content consisted mainly of albumin, transferrin, alpha 1-antitrypsin, IgG, and prealbumin as confirmed by the comparison with protein standards. Compared to vitreous controls, all PDR samples were shown to have lower amounts of transferrin, alpha 1-antitrypsin, and prealbumin. However, the amounts of IgG were higher than in the controls. This reflects a shift to a serum-like protein profile, indicating a blood-retinal barrier breakdown. However, we also detected in PDR vitreous three protein spots in a low-molecular-weight range (5-10 kDa) none of which could be found in native vitreous or in serum. Therefore, additional local protein synthesis appears to be present in the pathogenesis of PDR. 2-D electrophoresis permits precise characterization of the soluble vitreous proteins which may be associated with the fibrovascular proliferative vitreoretinal response. PMID- 7849429 TI - [Anticardiolipin antibodies in vascular occlusions of the eye]. AB - Elevated levels of anticardiolipin antibodies (ACA) have recently been found to be associated with occlusive diseases such as myocardial or cerebral infarction or venous thrombosis. In a prospective study anticardiolipin antibodies (both IgG and IgM) were measured by ELISA in 140 patients with acute vascular occlusions of the eye. Patients with clinical evidence for lupus erythematodes, HIV infection or elevated concentrations of antinuclear antibodies (IIFT with HEp-2 as antigen, LD Diagnostika, Heiden, FRG) were excluded. Elevated concentrations of IgG-ACA and IgM-ACA were found in 9% of the cases, with no correlation with the type of ocular vascular occlusion (retinal artery occlusion, retinal vein occlusion, anterior ischemic optic neuropathy). These results indicate that the anticardiolipin syndrome with elevated concentration of anticardiolipin antibodies may also have a causal role in some patients with occlusive eye diseases, whereas in most patients the concentrations were within normal ranges. PMID- 7849431 TI - [Retinal photocoagulation with a pulsed, frequency-doubled Nd:YAG laser (532 nm)]. AB - The small difference in wavelength between an argon laser (514 nm) and a frequency-doubled Nd:YAG laser (532 nm), together with the advantage of the solid state technology, makes the Nd:YAG laser likely to play a major role in retinal photocoagulation in the near future. For technical reasons all frequency-doubled Nd:YAG lasers work in a quasi-continuous mode, emitting a burst of highly repetitive short laser pulses during the exposure time desired. We investigated the side effects due to high peak irradiances of those short laser pulse trains (Crystal Focus Nd:YAG laser, Emerald; pulse duration 1-10 microseconds, repetition rate 13 KHz) in rabbits in comparison with a standard argon laser system (Zeiss, Visulas, Argon II). The energy necessary for blanching the retina was similar in both cases. As opposed to the argon laser system, subretinal bubbles were regularly visible ophthalmoscopically with the Nd:YAG system, when average powers as high as 200 mW were used. The ED50 power for bubble formation is about 2-3 times above the ED50 power for blanching. Thermal calculations show that this bubble formation effect is likely to be related to the peak power of the short pulses. The hemorrhage threshold is similar in both systems. However, light microscopically there is no difference between the two laser systems. Panretinal photocoagulation (300-500 microns, 100-200 ms) in patients with proliferative diabetic retinopathy produced such bubbles about once per 1000 lesions. PMID- 7849430 TI - [Retinal vasculitis and antiphospholipid antibodies]. AB - Antiphospholipid antibodies (APAb) are often found in systemic lupus erythematosus (LE) (secondary antiphospholipid syndrome), leading to arterial or venous thrombosis. In primary antiphospholipid syndrome other LE-associated symptoms are not detectable. We present the clinical course and therapy of three patients with this rarely reported disease, discussing immunopathology and therapy. Three young patients (28, 29 and 31 years) were seen at the university eye clinic, presenting severe occlusive vasculitis with vitreal haemorrhages and/or thrombosis. The first patient did not respond to any therapy (various immunosuppressives, plasma-pheresis, laser coagulation) and ended up with defective light perception in both eyes. The second patient also had light perception as final outcome in spite of acetylsalicylic acid, steroids and immunosuppression. The third patient established complete reperfusion on an arteriovenous occlusion after haemodilution and acetylsalicylic acid. Antibodies directed against phospholipids interfere with the blood clotting system in many ways (activation and aggregation of thrombocytes, endothelial function, coagulation cascade). The optimal therapy of this severe disease is unclear, suggesting that acetylsalicylic acid seems to be important, while the effect of immunosuppression or steroids is uncertain. PMID- 7849432 TI - [Photocoagulation in the edematous and non-edematous retina with the cw-laser of different wavelengths]. AB - The impact of wavelength upon the laser power required in photocoagulation of oedematous and non-oedematous retinal areas was investigated in a restricted clinical study. The following laser systems were applied: an argon laser (514 nm), a diode-pumped frequency-doubled Nd:YAG laser (532 nm) and a diode laser (810 nm). All lasers had broadly similar properties as regards beam characteristics, beam conduction and application optics. Twenty-five eyes of 25 patients with diabetic retinopathy were included in the study. Each eye was treated with each laser in areas of edema and no edema. Apart from the wavelength, laser power was the only variable permitted. The power required for photocoagulation at 514 nm and 532 nm was identical under every aspect of the study. In comparison with 514 nm or 532 nm photocoagulations, 810 nm photocoagulations required 6.0 +/- 0.9-fold higher power settings in nonedematous retina and 5.75 +/- 1.0 fold higher power settings in edematous retina. At every wavelength investigated, retinal edema raised the average laser power needed by more than 20%. The extent of this effect seems to decline with longer wavelengths. PMID- 7849433 TI - [Selective occlusion of subretinal neovascularization with photodynamic therapy]. AB - Conventional photocoagulation of subretinal membranes induces a non-selective thermal necrosis of retinal and choroidal layers with extensive collateral damage. Hence, this modality is of limited value for the treatment of lesions close to or underneath the fovea. Photodynamic therapy uses systemic administration of a primarily non-toxic photosensitizer with localized light activation of the dye by subthermal light intensities. It provides intraluminal vascular occlusion by means of localized endothelial damage. Enhanced selectivity for neovascularization is achieved by the use of carrier molecules with increased receptor density on proliferating endothelial cells, e.g. low-density lipoproteins (LDL). Benzoporphyrin derivative (BPD), currently in phase I clinical trials, was complexed with LDL. BPD-LDL was used for photodynamic occlusion of the choriocapillary layer in the rabbit model. Subretinal photothrombosis and collateral damage to neural retina, retinal pigment epithelium, Bruch's membrane and large choroidal vessels were documented by ophthalmoscopy, angiography and light and electron microscopic histology. Homogenous vascular occlusion without retinal destruction was induced with light doses as low as 10 J/cm2. Selective neovascular occlusion by photodynamic therapy may allow occlusion of subretinal membranes while preserving retinal integrity and visual function. PMID- 7849434 TI - [Iris neovascularization, increased intraocular pressure and vitreous hemorrhage as risk factors for invasion of the optic nerve and choroid in children with retinoblastoma]. AB - A review of 289 eyes enculeated for retinoblastoma to evaluate prognostic factors for involvement of the choroid or optic nerve revealed choroidal invasion in 67 eyes (22%) and optic nerve invasion in 84 eyes (27%) due to retinoblastoma. Intraocular pressure (IOP) > or = 22 mmHg was found in 85 eyes prior to enucleation. A total of 118 eyes (38% showed histopathologic evidence of the development of glaucoma: 90 of them with iris neovascularisation and 28 with angle closure configuration. Patients with elevated IOP, iris neovascularisation and angle closure configuration had a significantly higher risk of optic nerve (P < 0.005) and choroidal (P < 0.002) involvement. On the other hand, optic nerve invasion due to retinoblastoma was significantly more frequent in eyes with elevated IOP (P < 0.02) and iris neovascularisation or angle closure configuration (P < 0.01). Risk factors for choroidal invasion of retinoblastoma were raised IOP (P < 0.04) and iris neovascularisations or angle closure configuration (P < 0.01) (univariant analysis). Raised IOP, iris neovascularisations and vitreous haemorrhage remained significant in the multivariant analysis. This study emphases the importance of IOP, iris neovascularisation and angle closure configuration as risk factors for outspreading invasion due to retinoblastoma. PMID- 7849435 TI - [Risk factors of pseudophakic detachment]. AB - The increase of pseudophakic retinal detachments has raised the question about its risk factors. According to the literature, complicated cataract surgery rarely contributes to pseudophakic retinal detachment. Nevertheless, we noted a high proportion of defects in the capsular barrier among our patients. We therefore reevaluated our charts for perioperative and epidemiologic risk factors for pseudophakic retinal detachment. PATIENTS: Seventy-six patients with pseudophakic retinal detachment after extracapsular cataract operation with intraocular lens implantation were referred to the Ophthalmology Department of Freiburg University between 1986 and 1991. Their case records were analyzed for possible risk factors for retinal detachment. RESULTS: When retinal detachment developed, posterior lens capsule was not intact in 52/76 eyes (68%), the highest rate published so far. In 37 eyes capsular rupture occurred during cataract surgery, in 16 eyes followed by vitreous prolapse and in 9 eyes with persistent vitreous incarceration. Three eyes had vitreous prolapse via zonula. In 10 eyes YAG laser capsulotomy preceded detachment, and in 2 eyes capsular rupture occurred during an aspiration procedure for secondary cataract. The high proportion of intraoperative capsular ruptures is understandable if we assume a 2% risk of intraoperative capsular rupture, followed by a 20-fold increase in retinal detachment. The latency between cataract surgery and retinal detachment was 22 months after uncomplicated surgery, after YAG laser capsulotomy 13.5 and after intraoperative capsular rupture 10 months (medians). CONCLUSION: Vitreal complications in cataract surgery facilitate the development of retinal detachment. The incidence of defect posterior capsules and vitreal complications among patients with pseudophakic retinal detachments can be explained by assuming a 10- to 20-fold increase in retinal detachments after these complications. In cases of capsular or zonular rupture, all means, including prophylactic vitrectomy of vitreal strands, should be used to avoid permanent vitreous traction. However, the rate of retinal detachments after YAG laser capsulotomies only minimally surpassed the rate after uncomplicated cataract surgery. The risk for retinal detachment is not determined so much by the capsular defect itself. It is determined rather by the circumstances in which it occurred and by the grade of vitreal disturbance. PMID- 7849436 TI - [Risk of retinal detachment in pseudophakia and axial myopia]. AB - The incidence of retinal detachment on axial myopic pseudophakic eyes after Nd:Yag laser capsulotomy or intraoperative complications varies in the literature. In this study we analysed the incidence of retinal detachment in 136 pseudophakic myopic eyes (axial length > or = 26.0 mm) with and without capsulotomy and after intraopertive complications. These results were compared with those published in the literature and those obtained in a control group of 136 pseudophakic eyes with an axial length of less than 26.0 mm. Both groups were followed up for 2 years following operations in 1989 and 1990. The incidence of retinal detachment in eyes with axial myopia > or = 26.0 mm was 3.6% (5/136), without capsulotomy 3.3% (3/90) and with capsulotomy 2.5% (1/40). Intraoperative defects of the posterior capsule occurred in 6 cases, and in 1 case retinal detachment (1/6) developed. No retinal detachment occurred in the control group. The risk of retinal detachment does not seem to be significantly higher after uncomplicated extracapsular cataract extraction in eyes with axial myopia than in myopic eyes in which cataract extraction has not been performed. The combination of capsulotomy and axial myopia does not seem to increase the risk of retinal detachment. However, intraoperative complications do increase the risk of retinal detachment. Retinal detachment is three times as likely to develop in pseudophakic myopic eyes as in eyes with normal axial length. PMID- 7849437 TI - [Follow-up examinations of papillary morphology with laser scanning tomography]. AB - The object of this study was to investigate the perceptibility of changes in the topography of the optic nerve head during follow up with laser scanning tomography (LST), with a minimum observation period of 24 months. METHODS: We evaluated the changes in cup and rim area, cup volume, and mean and maximum cup depth in 50 eyes (8 control eyes, 21 glaucomatous eyes, 21 eyes in which glaucoma was suspected by LST over a mean follow-up time of 36 +/- 10 (range 24-49) months and compared them with the results of computerized static perimetry (Octopus). Changes were considered to be significant if they were larger than three times the maximum deviation measured in one parameter and larger than the maximum deviation in one other parameter [27]. RESULTS: Among 10 eyes that showed increasing cup values, 5 initially presented with striking disc cups, and no pathologic function tests; in none of these eyes was functional loss revealed by perimetry during the follow-up period. Of the 5 glaucomatous eyes in which progression was found on optic disc morphometry, 4 had increasing defects revealed by computerized static perimetry (Octopus 500). CONCLUSION: The results confirm the value of LST. In 6 eyes in which LST revealed a significant increase in the optic cup values, perimetry did not demonstrate progression of the functional loss. Therefore, LST should be used in the follow up of all patients with glaucoma or suspected glaucoma, in addition to conventional computerized perimetry. PMID- 7849438 TI - [Changes in the immune status in patients with basal cell carcinoma of the eyelids of various TNM stages]. AB - Various lymphocyte populations/subpopulations--Leu-4+ (CD3+), Leu-2+ (CD8+), CD4+/CD8+ ratio, Leu-14+ (CD22+), Leu-M5+ and HLA-DR+--were studied in 104 patients with basal cell carcinoma (BCC) of the eyelid in different TNM stages by Coulter EPICS flow cytometry preoperatively. For comparison, an age-matched control group of 60 clinically healthy individuals (30 male and 30 female) was used. The mean percentage of CD4+ T-lymphocytes was significantly decreased in T3N0M0 and T4N0M0 stages. In all TNM stages, especially in T3N0M0 and T4N0M0, the CD8+ T-lymphocyte subpopulation was significantly larger than in the control group. In all TNM stages the CD4+/CD8+ ratio was significantly lower than that of the control group. The degree of immune imbalance correlated directly with tumor size. The immunosuppression may be one factor in the development of BCC of the eyelid. Age- or genetic-related depression of cell-mediated immunity and increased exposure to carcinogenic agents, especially UV light, may play a part. PMID- 7849439 TI - [Photodynamic therapy of eyelid basalioma after topical administration of delta aminolevulinic acid]. AB - Delta-aminolevulinic acid (ALA) induced Protoporphyring IX photodynamic therapy (PDT) is a new method in the therapy of cutaneous malignancies. Topical application prevents photosensibilization of normal skin. Promising results in the treatment of superficial basal cell carcinomas have been reported. To evaluate the efficiency of this method in the therapy of basal cell carcinomas of the lid, 10 patients were treated by PDT 5 h after application of ALA. The lesions were irradiated by an argon-ion-laser-pumped dye laser at a wavelength of 630 or 635 nm and at cumulative radiant exposures of 50 and 100 J/cm2. After 5-8 weeks follow-up, the basal cell carcinomas were excised to assess histologic changes. In the first few days after PDT the lesions seemed clinically to regress, due to erythematous swelling, but after a few weeks all tumours showed the same configuration they had before irradiation. Histological examination revealed small areas of necrotic cells in all irradiated basal cell carcinomas, surrounded by residual tumour formations. The reason for the poor results may be limited penetration of ALA or light. Although ALA-induced Protoporphyrin-IX PDT is a promising approach in the therapy of dermal lesions, it is not yet an acceptable alternative method in the treatment of basal cell carcinomas of the lid. PMID- 7849440 TI - [Hereditary optic atrophy]. PMID- 7849442 TI - Octreotide versus terlypressin in acute variceal hemorrhage in liver cirrhosis. Emergency control and prevention of early rebleeding. AB - Sixty patients with endoscopically confirmed active variceal bleeding entered a randomized controlled clinical trial aimed at comparing the efficacy of octreotide vs. terlypressin in the control of acute variceal hemorrhage (period I, 24 h) and in the prevention of early rebleeding (period II, 6 days). Of the sixty 30 received octreotide (period I, 100 micrograms bolus followed by continuous intravenous infusion at 25 micrograms/h; period II, 100 micrograms t.i.d. subcutaneously), and 30 received terlypressin (period I, 2 mg intravenous bolus every 4 h; period II, 2nd day, 2 mg every 6 h; from 3th to 7th days, 1 mg every 6 h). Control of bleeding was achieved in 23 (76.6%) patients receiving octreotide and in 16 (53%) treated with terlypressin (NS); none of these patients suffered rebleeding during treatment. No significant difference in mortality was observed between the two groups during the hospitalization period. Complications due to therapy were lower with octreotide than with terlypressin (P < 0.01). Under the same effectiveness conditions the cost/benefit ratio must be taken into account. PMID- 7849444 TI - Effect of the new somatostatin analogue SMS 201-995 on exogenously used insulin. AB - Somatostatin and somatostatin analogues are inhibitors of insulin, glucagon, and growth hormone secretion. However, it has not been determined whether it is somatostatin or its analogues which affect these hormones when used concomitantly. The effect of the somatostatin analogue SMS 201-995 on exogenously infused insulin was observed in ten healthy volunteers. The study was carried out on two occasions with at least a 1-week interval. Each subject was infused with saline throughout the study and insulin at a rate of 40 mU/kg per hour between 60 160 min of the study (step A) or SMS 201-995 in a 75 micrograms IV bolus following at a rate of 75 micrograms/h for 160 min and insulin at the same rate and duration (step B). Hyper-insulinemia and SMS 201-995 significantly suppressed C-peptide secretion, but the degree of C-peptide suppression was greater in the SMS 201-995 infused step than in the insulin-only infused step. Blood glucose levels decreased markedly throughout the infusion of insulin with or without SMS 201-995. In step B, the decrease in blood glucose was greater than in step A. Insulin levels in step B increased to higher levels than in step A (from 81.1 +/- 7.7 to 363.9 +/- 22.7 mmol/l and from 82.7 +/- 8.6 to 229.0 +/- 23.4 mmol/l, respectively). These results show that SMS 201-995 increases the level of exogenously infused insulin. This is probably due to the impaired clearance of exogenous insulin. PMID- 7849443 TI - Comparative long-term experience with immunoadsorption and dextran sulfate cellulose adsorption for extracorporeal elimination of low-density lipoproteins. AB - Two low-density lipoprotein (LDL) apheresis methods allowing a specific extracorporeal removal of atherogenic lipoproteins from plasma were compared concerning their efficacy and safety in the long-term therapy of severe familial hypercholesterolemia. Five patients were treated with immunoadsorption (IMA) at weekly intervals over 3 years each, and three patients received weekly therapy with dextran sulfate cellulose adsorption (DSA) for up to 2 years. The mean plasma volume processed per session to decrease total cholesterol to a target level of 100-150 mg/dl at the end of LDL apheresis was significantly lower in DSA than in IMA: 143% vs. 180% of the individual plasma volume. Both LDL apheresis procedures achieved a mean acute reduction of plasma LDL cholesterol by more than 70%. The average interval concentrations of plasma LDL cholesterol obtained without concomitant lipid-lowering medication were 151 +/- 26 mg/dl compared to 351 +/- 65 mg/dl at baseline in the IMA-treated patients and 139 +/- 18 mg/dl compared to 359 +/- 48 mg/dl at baseline in the DSA-treated patients. Two patients from the DSA group died after 2 years of study participation due to a stroke and a sudden cardiac death several days after the last plasma therapy. Treatment-related side effects were infrequent. Long-term therapy with IMA and DSA was associated with symptomatic improvement of coronary artery disease and mobilization of tissue cholesterol deposits. Analysis of coronary angiograms after 3 years of weekly LDL apheresis with IMA revealed in five patients nearly identical atherosclerotic lesions without definite regression or progression. PMID- 7849441 TI - Lipoproteins and their functions. PMID- 7849446 TI - Paracrine interactions regulating renal microcirculatory function. PMID- 7849445 TI - Controlled trial of high- versus low-dose aspirin treatment after percutaneous transluminal angioplasty in patients with peripheral vascular disease. AB - Percutaneous transluminal angioplasty of aortoiliac and femoropopliteal atherosclerotic lesions can provide long-lasting hemodynamic improvement. High dose aspirin is commonly prescribed as reocclusion prophylaxis, but low doses would be preferable because of fewer adverse effects. We performed a double blind, randomized, controlled clinical trial in patients with peripheral vascular disease with lesions appropriate for angioplasty. We compared the efficacy and side effects of two doses of aspirin (50 mg vs. 900 mg daily) during a period of 12 months after angioplasty. A total of 359 patients were evaluated: 175 were randomly assigned to treatment with 900 mg aspirin daily and 184 to 50 mg aspirin daily. Thirty-nine patients developed restenosis at the angioplasty site; the cumulative percentage of event-free survival after 1 year (patency rate) was 85% in 900 mg group and 84% in 50 mg group. An equivalence test showed the two groups equivalent with respect to restenosis rates (P = 0.0003 for an equivalence region of < 10% difference. Nine patients (5%) in the 900 mg group had serious gastrointestinal side effects (peptic ulcer, 8; erosive gastritis requiring transfusion, 1) compared to two ( peptic ulcer) in the 50 mg group (P = 0.03). The results of our study show that a dose of 50 mg aspirin a day is as effective as 900 mg for the prevention of restenoses after lower limb angioplasty, and that severe gastrointestinal side effects are less frequent. PMID- 7849447 TI - Vasoactive hormones: modulators of renal function. PMID- 7849448 TI - Molecular mechanisms in renin control. PMID- 7849449 TI - Tubular actions of diuretics (overview). PMID- 7849450 TI - Molecular cloning and characterization of the renal diuretic-sensitive electroneutral sodium-(potassium)-chloride cotransporters. AB - cDNAs encoding the two major electroneutral sodium-chloride transporters present in the mammalian kidney, the bumetanide-sensitive Na(+)-K(+)-Cl- symporter and thiazide-sensitive Na(+)-Cl- cotransporter, were isolated and their functional activity characterized in Xenopus laevis oocytes [2]. Although they differ in sensitivities to bumetanide and thiazides and have different requirements for potassium, these approximately 115-kDa proteins share about 60% sequence similarity and exhibit a topology featuring 12 potential membrane-spanning helices flanked by large hydrophilic domains at the NH2- and COOH-termini. These molecules, together with the Na-Cl cotransporter from the flounder urinary bladder, which exhibits a significant homology suggestive of common ancestry, define a new family of electroneutral Na(+)-(K+)-Cl- cotransporters. Northern blot analysis and in situ hybridization indicate that these transporters are expressed predominantly in kidney with an intrarenal distribution consistent with their recognized functional localization. The kidney-specific distribution of transcripts encoding these cotransporters suggest that other, probably related, genes encode non-renal Na(+)-(K+)-Cl- cotransporters. PMID- 7849451 TI - 11 beta-Hydroxysteroid dehydrogenase: a relevant determinant of gluco- and mineralocorticoid-actions. PMID- 7849452 TI - Atrial natriuretic peptide and endothelin: modulators of renal function. PMID- 7849453 TI - Endogenous ouabain: physiological activity and pathophysiological implications. PMID- 7849454 TI - Clinical problems of diuretic treatment. PMID- 7849455 TI - The possible role of chemotactic cytokines in renal disease. PMID- 7849456 TI - Cytokines and signal transduction. AB - Cytokines are signaling molecules that coordinate cellular interactions in immune and hematopoietic systems. During the past 5 years many cytokines and their receptors have been identified and cloned. With a few exceptions, cytokine receptors do not contain any known signaling domains and therefore, in order to trigger a specific cellular response, new and unusual features of signaling pathways must be assumed. A major advance in the field has come with the discovery of new family of cytoplasmic protein tyrosine kinases that associate with occupied cytokine receptors and make them competent for intracellular signal generation. This review describes some general characteristics of cytokine signaling. PMID- 7849457 TI - Molecular mechanisms of transplant rejection. PMID- 7849458 TI - Impact of the reperfusion injury on acute and chronic rejection events following clinical cadaveric renal transplantation. PMID- 7849459 TI - Hemodialysis: 70 years. PMID- 7849460 TI - Resistance of diuretics. PMID- 7849461 TI - Molecular and cell biology of primary hyperoxaluria type 1. PMID- 7849462 TI - Genetic aspects of renal dysfunction: Alport's syndrome. PMID- 7849463 TI - Genetics of hypertension: the pheochromocytoma model. PMID- 7849464 TI - [Imaging methods in diagnosis of malignant lymphoma]. AB - Modern diagnostic imaging has improved the evaluation of malignant lymphomas during the last years. Most of the invasive examinations were replaced by non invasive tomographic imaging. The most important examinations for the evaluation of lymph nodes are nowadays ultrasound, computed tomography and magnetic resonance imaging. The sequence of their use is depending on the region of examination. The immediate use of the method of choice for a certain body region instead of a protracted step-for-step diagnostic has led to a distinct shortening of diagnostics, diminishing of radiation dose exposure and cost reduction. PMID- 7849465 TI - Clinical significance of sonographic findings in outpatient clinics. AB - In the literature substantial controversy exists about the clinical significance of abdominal screening procedures. Therefore, the aim of our prospective study was to determine the clinical relevance and the differences of sonographic findings in both symptomatic and asymptomatic screening outpatients. We therefore systematically analyzed the sonographic findings in 200 consecutive patients of a medical outpatient unit. The patients were divided into 2 subgroups: group I consisted of 128 patients without specific clinical symptoms in the abdomen (screening group); group II included 72 patients with abdominal symptoms and therefore well-defined sonographic requests. The consequences drawn from the sonographic results were analyzed separately for both patient groups. All findings were subdivided into relevant, prospectively relevant or not relevant, depending on their individual influence on the patients' course. In all cases the entire abdomen and basal parts of the thorax were examined. In the 1st group (n = 128/93 findings) 6 findings (6.5%) were relevant, 24 (26%) prospectively relevant and 63 not relevant (67.5%). In contrast, the 2nd group (n = 72/68 findings) contained 13 relevant (19%), 27 prospectively relevant (40%) and 28 not relevant sonographic findings (41%). The differences between group I and II were statistically significant for the relevant findings (2p < 0.05) and the not relevant findings (2p < 0.01). In conclusion, abdominal ultrasonography provides- even for the screening of the outpatient population--in up to 30% additional clinically acute or prospectively relevant information. Therefore, it completes the physical examination adding a substantial amount of clinical information to the medical record of outpatients. PMID- 7849466 TI - Colour Doppler ultrasound in the diagnosis of transplant renal artery stenosis. AB - The validity of colour Doppler ultrasound (CDU) in the detection of transplant renal artery stenosis (TRAS) was investigated. 93 patients presenting with deteriorating hypertension underwent CDU. Seven out of 93 patients (8%) were excluded from the study because of incomplete visualization of the transplant vessels. The CDU diagnosis of TRAS was made when all of the following criteria were present: 1. local increase in flow velocity exceeding 150% of the values found in other sections of the transplant artery and 2. marked turbulences in the artery distally of a region with local flow increase. 86 CDU examinations obtained in 86 patients [52 male, 34 female; mean age 45.7 +/- 12.6 years; examined on average 28.8 months (1-156) after transplantation] were compared with 40 angiographies. Patients showing stenosis in the CDU (n = 12) or receiving combined antihypertensive therapy with 3 or more drugs (n = 28) had an angiography performed. Angiography confirmed 11 out of the 12 arterial stenoses that had been found with CDU and detected one segment artery stenosis of 30-50% that was not detected by CDU. In 4 stenosed arteries, peak velocities were higher than the maximum velocity measurable with the pw-Doppler (higher than 350 cm/s). Peak velocities measured by CDU within 8 stenoses exceeded the flow speeds obtained elsewhere in the artery by 193 +/- 35% (286 +/- 82 cm/s). Using the criteria of stenosis as defined in this paper, CDU may be employed as screening method to detect TRAS with a sensitivity of 92% and a specificity of 96%. PMID- 7849467 TI - [Densitometry in suspected preclinical osteoporosis: quantitative computerized tomography versus dual energy roentgen absorptiometry]. AB - The bone mineral density of 85 patients with suspicion of a preclinical osteoporosis was measured at the lumbar spine by using quantitative computed tomography (QCT) in single-energy technique (SEQCT) and dual-energy technique (DEQCT) as well as by using dual-energy X-ray absorptiometry (DEXA). Additionally, the bone density of 63 of these patients was measured at the left femoral neck using DEXA. DEQCT und DEXA of the lumbar spine showed only a moderate correlation (R = 0.75) and differed considerably concerning the classification of the patients as normals or individuals with a mineral deficit when compared with age-matched normals (relative mineral deficit). The DEXA proved to be susceptible to degenerative alterations of the lumbar spine. Because of the extremely low dose of radiation and the good reproducibility the DEXA could nevertheless be recommended as a method for the long-time progress control especially for younger patients. SEQCT and DEQCT showed a very strong correlation (R = 0.98). The SEQCT with its lower dose of radiation should be sufficient for a long-time progress control and in many cases also for the initial diagnostics. Significant but only moderate correlations were found between the bone density at the femoral neck and the DEXA or DEQCT results (R = 0.68 respectively R = 0.63) for the lumbar spine, so that the linear regression did not render any useable approximations. Sufficiently exact information about the mineralization status of a certain skeletal site can only be obtained by direct measurement. PMID- 7849468 TI - [Comparison of CT and MRI methods in diagnosis of tumors of the para- and retropharyngeal space and temporal bone]. AB - The aim of this paper was to compare the diagnostic value of computed tomography (CT) and magnetic resonance imaging (MRI) in the evaluation of malignant tumors of the temporal bone, of paragangliomas of the glomus tympanicum and jugulare as well as of malignant tumors of the para- and retropharyngeal space. 67 patients with tumors of the temporal bone--28 cases with malignant tumors and 39 cases with paragangliomas--were examined with MRI and CT. MRI had true-positive findings in nearly 93, CT in 89% of the patients with malignant tumors of the temporal bone. MRI is therefore recommended as the primary imaging investigation of malignant tumors of the temporal bone. Whereas the temporal bone is best visualized by high-resolution CT with thin slices, the tumor extension- especially cranial spread into the middle and posterior cranial fossa and caudal spread into the infratemporal fossa--is better detected on MRI. Enhanced T1 weighted spin-echo images with fat-signal suppression are most suitable for this purpose. Using 3D sequences, partial volume effects can be avoided with an attainable slice thickness of 0.8-1.0 mm. Furthermore, arbitrary slices--very helpful when studying the complex anatomy of the skull base--can be calculated from a 3D data set. MRI had true-positive findings in 97, CT in nearly 90% of the patients with paragangliomas. Furthermore, the response of paragangliomas to radiotherapy can be more accurately assessed on MR--independent of and before volumetric changes.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7849469 TI - [Simplified percutaneous transluminal angioplasty by a new kind of guide wire- initial experiences]. AB - A new guide wire for angioplasty of peripheral vessels was developed and tested in 20 patients. 24 occlusions mainly of the crural arteries were reopened, and 21 high-grade stenoses were treated. The use of the guide wire down to the foot is easy, cannulation times are short, and success rates of cannulation higher than with previous techniques. PMID- 7849470 TI - [Computer assisted analysis of the morphology of cutaneous capillaries in human intravital microscopy]. AB - Reproducibility of capillaroscopic data is studied by a computer-assisted interactive quantification method. Determination of capillary tortuosity and capillary density is a quantitative method with a variation coefficient below 7%, while determination of erythrocyte column diameter has to be considered as a semiquantitative method. Problems arising during interactive evaluation as in case of bundles of capillaries or massive capillary dilatation are discussed in the paper. PMID- 7849471 TI - [Texture analysis: a new method for evaluating ultrasound imaged lesions of the breast]. AB - Echogenicity and echostructure in sonomammography are essential criteria to determine the malignancy of a breast tumor. Looking for a correlation between echostructure of an ultrasound image and its histopathology a texture analysis was performed. Ultrasonic examinations were carried out by means of a 7.5-MHz linear scanner under standardized conditions. 71 mammasonographic findings were documented by video tape, each tumor in 2 dimensions. In a second step 'the region of interest', that means the whole tumor area, was marked and statistically analyzed by a dedicated computer system. The values of 23 first- and second-order statistical texture parameters were compared with the histopathology of the tumor. They include grey level histogram, Fourier analysis and cooccurrence matrix. The most important results were obtained in the histogram analysis. An obvious distinction could be worked out concerning carcinomas, adenomas, mastopathic tumors, and fat necrosis. Except the difference between carcinomas and adenomas this distinction was statistically significant. Fourier analysis and coocurrence matrix significantly separate fibrocystic lesions, fat necrosis, scars, and cystic structures from malignant tumors. Furthermore the maximum value method was used to compare the different parameters with regard to their capability of discriminating benign and malignant tumors. The extreme values of 100% were mostly observed in the case of seromas and scars. A significant difference was found by histological grading of carcinomas, too. Highly differenciated carcinomas show capability of results comparable to those of adenomas. By means of a computer texture analysis program it is possible to find a correlation between echostructure and histopathology of breast tumors.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7849472 TI - [Comparison of computerized tomography and B-image ultrasound in imaging diagnosis of the mediastinum]. AB - 40 patients with suspected mediastinal tumors were independently examined with computed tomography (CT) and sonography. The findings were confirmed by bronchoscopy, mediastinoscopy or surgery. In the assessment of the upper and middle mediastinum, sonography reaches a high sensitivity. On the contrary, in the evaluation of the anterior and posterior mediastinum, sonography is clearly inferior to CT. 90% of the tumors demonstrated by CT could be assessed with sonography. The most frequent tumors can be diagnosed with ultrasound. The evaluation of tumors in the paravertebral and retrosternal space is limited. Sonography of the mediastinum is a noninvasive, well-reproducible and cost effective imaging modality that provides important information in cases of unclear X-ray and CT findings. The preliminary results encourage to a more frequent use of mediastinal sonography. PMID- 7849473 TI - Diagnostic evaluation and surgical management of the aberrant right subclavian artery. AB - A case of dysphagia and dyspnea secondary to compression of the esophagus and the trachea by an aberrant right subclavian artery is presented. As the pathology of the aberrant right subclavian artery is extremely diverse, the diagnosis without radiologic investigation is hardly feasible. Conventional angiography of the aortic arch may be avoided by 3-dimensional magnetic resonance angiography, that is a suitable noninvasive method to diagnose and visualize the vascular pathology and the postoperative results after corrective vascular surgery. With the use of a Gore-Tex prosthesis the right aberrant subclavian artery was successfully translocated to the ascending aorta through a mid-sternal, transmediastinal approach. In contrast to previous reports the retro-esophageal vascular segment was kept in situ. The literature is reviewed with the reference to the diagnostic procedure and the treatment of dysphagia lusoria. PMID- 7849474 TI - Curriculum crossroads: which direction should nursing take? PMID- 7849475 TI - Health care professionals' recognition of illness in infants: a New Zealand pilot study of Baby Check. PMID- 7849476 TI - Nursing education. PMID- 7849477 TI - The curriculum revolution: what do all those buzz words really mean? PMID- 7849478 TI - International collaboration: New Zealand nurses demonstrate the value of working together to achieve academic excellence. PMID- 7849479 TI - New Zealand Holistic Nurses Inc. conference. "Caring: the healing essence of nursing". PMID- 7849480 TI - Enabling choice: public health nurses' perceptions of their work with children and families. PMID- 7849481 TI - "An exemplar from the past: Florence Nightingales influence on a New Zealand nurse's practice". PMID- 7849482 TI - Learning to walk the talk. Critical reflections on curriculum development at Whitirea Community Polytechnic from 1985-1993. PMID- 7849484 TI - Progress in evaluation of the potential of antisense technology. PMID- 7849483 TI - Time brings change. PMID- 7849485 TI - Improved anti-herpes simplex virus type 1 activity of a phosphodiester antisense oligonucleotide containing a 3'-terminal hairpin-like structure. AB - We synthesized a series of 20-mer antisense phosphodiester oligonucleotides constituting of a 5'-dodecameric sequence, complementary to the acceptor splice junction of herpes simplex virus type 1 (HSV-1) pre-mRNAs IE4 and IE5, flanked in 3' by octameric sequences adopting hairpin-like structures of different stabilities. The presence of the minihairpins in 3' protected the 20-mer phosphodiester oligonucleotides against serum nuclease degradation, this protection being well correlated to the reported melting temperatures of the minihairpins, and to the gel mobilities of the 20-mer oligonucleotides. While no protection was observed using a linear 8-mer, the addition in 3' of the most stable minihairpin--H8--increased more than eightfold the nuclease resistance of the linear antisense dodecamer. We analyzed the effect of such a protection on the anti-HSV-1 antisense activities of the oligonucleotides. When bearing H8 in 3', the antisense dodecamer was 10 times more active than in the absence of 3' flanking sequence, while a linear 20-mer control containing the antisense sequence was only 3 times more active. This work provides the basis for a further rational design of phosphodiester antisense oligonucleotides, taking advantage of the specific properties conferred by their conformations. PMID- 7849486 TI - Antisense c-myc oligonucleotide cellular uptake and activity. AB - Previously described cell membrane transport mechanisms are unable to account completely for oligodeoxynucleotide cellular uptake. These charged macromolecules enter cells by an incompletely defined mechanism and downregulate gene expression in either the cytoplasm or nucleus. Thus, the goal of this research was to study the mechanism of phosphodiester oligonucleotide cellular uptake in Rauscher Red 5 1.5 erythroleukemia cells. An antisense c-myc oligodeoxynucleotide (21 bases) demonstrated biological activity in these cells using two types of proliferation assays and Northern blot analysis, and was internalized as visualized by confocal laser microscopy. Oligonucleotide uptake appeared to be a complex process consisting of surface binding and internalization. Cellular internalization accounted for up to 40% of total uptake and was partially dependent on both a trypsin-sensitive component and cellular energy. Uptake in these cells was nonspecific and did not appear to be due to receptor-mediated endocytosis. Therefore, because oligonucleotide cellular uptake in other cell types apparently involves an endocytic mechanism, the primary mechanism of oligonucleotide internalization may be cell line dependent. PMID- 7849487 TI - Reduction in replication of the human immunodeficiency virus type 1 in human T cell lines by polymerase III-driven transcription of chimeric tRNA-antisense RNA genes. AB - Inhibition of human immunodeficiency virus type 1 (HIV-1) replication was demonstrated by using tat- and rev-directed antisense oligoribonucleotides 68 and 69 nucleotides in length. In this study, human T-lymphoid cells were transduced with a murine amphotropic retroviral vector containing a polymerase III-driven chimeric gene consisting of the human tRNA(imet) sequence and the short tat- and rev-directed antisense sequences that had been shown before to inhibit HIV-1 replication. Pools of transduced, G418-resistant human T-lymphoid Jurkat or CEM cells showed reduced replication of HIV-1 in the presence of antisense-containing chimeric transcripts, but not with sense sequence-containing transcripts. These results demonstrate that short inhibitory antisense RNA transcripts can be stably expressed endogenously using polymerase III promoters, which can reduce replication of HIV-1. The approach described in this work combines the advantages of short and, usually, synthetic oligonucleotides with the stable intracellular expression of inhibitory genes for HIV-1 in target cells. Considering the small size of the described chimeric polymerase III genes, it appears feasible to combine multiple antiviral genes with the currently available retroviral vectors as gene delivery systems. PMID- 7849488 TI - Use of partially phosphorothioated "antisense" oligodeoxynucleotides for sequence dependent modulation of hematopoiesis in culture. AB - To distinguish between sequence-dependent effects and non-specific cytotoxicity of phosphorothioate antisense oligonucleotides (AS-oligos), we introduced AS oligos blocking expression of 2Hs, the Homo sapiens cell division controller cdc2 kinase, its hematopoietically expressed homolog CHED, and the acetylcholine hydrolyzing enzyme butyrylcholinesterase (BCHE) into primary murine bone marrow (BM) culture. Antisense oligonucleotides were fully phosphorothioated (Ts) or prepared with three phosphorothioate groups at their 3' termini (S3). Each of these oligos could cause reductions in colony counts either as a result of its sequence-dependent biological capacity or due to sequence-independent cytotoxicity. The Ts and S3 forms of the matching sense oligo, S-BCHE, served for comparison. The S3 forms of AS-2Hs, AS-BCHE, and S-BCHE caused more limited drops in colony counts than their Ts counterparts, reflecting lower cytotoxicity. When incubated with electroblotted BM proteins, Ts but not S3 oligos intensively labeled two protein bands. Moreover, 5'-end 32P-labeled (Ts) S-BCHE labeled nuclear proteins in situ in small, mitotic cells, suggesting correlation between oligo-protein interactions and the sequence-independent cytotoxicity of Ts AS oligos. Extension of the apparently nontoxic AS-CHED by two adenosine residues at the 3' end, creating a potential for intramolecular hydrogen bond formation, resulted in increased toxicity. These findings recommend the use of nonlooped, partially phosphorothioated oligos for the modulation of hematopoiesis. PMID- 7849489 TI - Large-scale synthesis, purification, and analysis of oligodeoxynucleotide phosphorothioates. AB - Synthesis of oligonucleotides has been carried out on 1-, 2-, and 5-mmol scales using an appropriately modified automated, commercially available DNA synthesizer. The reaction cycles were optimized to obtain efficient coupling (> or = 97%). The synthesized oligonucleotide was purified by preparative reversed phase liquid chromatography, followed by detritylation and desalting to obtain the oligonucleotides in the Na+ form. The purified oligonucleotides were characterized by 31P NMR, mass spectrometry, capillary gel electrophoresis, and ion-exchange high-performance liquid chromatography. By using these protocols, a 25-mer oligodeoxyribonucleotide can be synthesized on a 1-, 2-, or 5-mmole scale to obtain approximately 2.4, 4.8, or 12 g of purified product. PMID- 7849490 TI - Complement activation and hemodynamic changes following intravenous administration of phosphorothioate oligonucleotides in the monkey. AB - Rapid intravenous infusion of GEM 91, a 25-mer phosphorothioate oligonucleotide complementary to the gag site of HIV, in the monkey produces transient decreases in peripheral total WBC and neutrophil counts, hemoconcentration, and a brief increase followed by a prolonged decrease in arterial blood pressure. These changes are preceded by and are likely mediated by activation of C5 complement. These effects are dose and infusion rate dependent and can be avoided by administering GEM 91 by slow intravenous infusion. Similar hemodynamic effects are produced with rapid intravenous infusion of other phosphorothioate oligonucleotides varying in length from 20- to 33-mer, and are, therefore, not sequence specific but a property of this chemical structure. PMID- 7849491 TI - Retroviral inhibition by antisense oligonucleotides determined by intracellular stability. AB - A 15-mer oligodeoxyribonucleotide was found to be efficient toward the Friend retrovirus only when modified or encapsulated in liposomes. The nonmodified oligomer was inefficient. We have measured the intracellular stability of this 15 mer when encapsulated or modified and we have observed a direct relationship between the intracellular stability of the oligonucleotides and their antiretroviral efficiency. PMID- 7849492 TI - Influence of base composition on membrane binding and cellular uptake of 10-mer phosphorothioate oligonucleotides in Chinese hamster ovary (CHRC5) cells. AB - A key problem in antisense therapeutics is the relatively poor cell uptake of oligonucleotides and subsequent transport to the cytoplasm and nucleus. Although the chemical characteristics of oligonucleotides seem likely to affect their uptake by cells, little is known about this issue. In this article we explore the effect of base composition on oligonucleotide uptake. We show that phosphorothioate homo-G oligomers have a distinctly greater cellular uptake than other phosphorothioate homooligomers. This is probably due to a greater initial association with the plasma membrane, because homo-G oligomers show the greatest binding to liposome membranes, when tested at physiological ionic strength. Under different buffer conditions appreciable differences in membrane binding to liposomes were detected for the various homooligonucleotides. PMID- 7849493 TI - Intracellular susceptibility to ribozymes in a tethered substrate-ribozyme provirus model is not predicted by secondary structures of human immunodeficiency virus type 1 RNAs in vitro. AB - We have assessed the sensitivity of different sites in HIV-1 genomic RNA to ribozymes. Ribozymes targeted to sequences in U5, Pol, Env, RRE, or R were positioned into nef of an infectious HIV-1 provirus. When these proviral DNAs were introduced into HeLa CD4+ cells, recombinant viruses that contain ribozymes tethered to genomic RNA or viral mRNAs were produced. The growth kinetics of ribozyme-containing viruses in CD4+ lymphocytes (MT4 cells) were distinctly delayed when compared to control viruses. On the basis of the ability of a particular ribozyme to inhibit virus replication, we inferred intracellular ribozyme-sensitive sites. We found that although ribozyme sensitivity in vitro could be correlated with predicted secondary structures of target RNAs, such in vivo correlations could not be made when using the HIV provirus model. We conclude that both Zuker algorithm computer modeling of substrate RNA secondary structures and in vitro cleavage efficiencies cannot be reliably used to determine HIV-1 ribozyme sensitive sites in vivo. PMID- 7849494 TI - Computerized analysis of ambulatory monitoring in the quantification of sinoatrial disease. AB - A computer program was written to allow quantitative beat-by-beat analysis of 24 h tapes acquired during standard ambulatory monitoring. Compared with a control group, subjects with sinoatrial disease were found to have significantly more tachy-brady events, more heart rate variability, more beat-to-beat variability and had fewer beats within a normal heart rate range. This technique, complementary to conventional analysis of 24-h tapes, may be useful in detecting more frequent but less severe abnormalities of heart rhythm in sinoatrial disease, strengthening the diagnostic power of ambulatory monitoring and allowing quantification of a further range of heart rhythm abnormalities. PMID- 7849495 TI - Autonomic cardiovascular reflexes in pregnancy. A longitudinal study. AB - Cardiovascular reflexes were studied in 22 healthy women before they were pregnant, once during each pregnancy trimester and after delivery to evaluate the effect of pregnancy on autonomic control of haemodynamics. The Valsalva manoeuvre, the deep breathing test, the orthostatic test and the isometric handgrip test were used to assess changes in autonomic nervous function. We found that pregnancy altered the heart rate response in the Valsalva manoeuvre, the deep breathing test and the orthostatic tests. The deep breathing difference (p = 0.03) and max/min ratio (p = 0.03) decreased in pregnancy, whereas standing heart rate increased (p < 0.0001). Both the systolic and diastolic blood pressure increased after standing up during pregnancy. The circulatory responses to isometric exercise were not affected by pregnancy. The results show that parasympathetic responsiveness is decreased in pregnancy and that it returns to normal after delivery. PMID- 7849496 TI - Phaeochromocytoma: intraoperative changes in blood pressure and plasma catecholamines. AB - The aim of this study was to assess the relationship between changes in plasma catecholamine concentrations and intra-arterial blood pressure (BP) measured simultaneously during resection of phaeochromocytoma (n = 14). Arterial plasma concentrations of noradrenaline (NA), adrenaline (A) and dopamine (DA) were measured by a radio-enzymatic method. Arterial NA concentrations (pmol/ml; median and Wilcoxon 95% CI) were 71.8 (46,162) before induction of anaesthesia, 113.0 (79,231) after intubation, 375.0 (285,931) during tumour handling and 32.5 (18,88) following tumour removal. Simultaneous mean BP values (mmHg; Mean +/- SEM) were 119 +/- 8, 114 +/- 7, 159 +/- 7 (p = 0.0001) and 72 +/- 6 (p < 0.0001) respectively. At the time of tumour handling there was a weak correlation between plasma NA and A combined and mean BP (r = 0.583, p = 0.029) and a stronger correlation between log plasma NA and A combined and pulse pressure (r = 0.749, p = 0.008). The very large rises in plasma catecholamine concentrations and in BP are likely to have been causally related. Individual patients maintained a constant ratio of NA to A in plasma from pre-induction to tumour handling (r = 0.916, p < 0.0001). The maintenance of a constant NA:A ratio suggests that the pattern of catecholamine synthesis and release may be a characteristic of the individual tumour. PMID- 7849497 TI - Immaturity of the myenteric plexus is the aetiology of meconium ileus without mucoviscidosis: a histopathologic study. AB - The most common aetiology of meconium ileus is a deficiency in trypsin activity caused by cystic fibrosis. The pathogenesis of meconium ileus without mucoviscidosis is less well understood, although a number of causative factors have been suggested. The symptoms and clinical course of nine patients with meconium ileus without mucoviscidosis were reviewed, and the myenteric plexus of a surgical specimen of intestine was examined histologically and cytometrically. The nuclei of the intramural ganglion cells were much smaller than were seen in normal newborn infants. The nuclear areas resembled those seen in fetuses of 5-6 months gestational age, but the number of ganglion cells approached normal. This immaturity of the ganglia was observed both in the contracted distal ileum and dilated proximal ileum. Patients with an ileostomy passed solid faeces for about 1 to 2 months postoperatively, after which time the faeces became watery. The intramural ganglia were mature at the time of ileostomy closure. We conclude that immaturity of the myenteric plexus in the ileum and colon seems to be the main aetiologic factor in meconium ileus without mucoviscidosis. PMID- 7849498 TI - Sympathetic suppression attenuates anomalous responses to morphine in unexplained pain after cholecystectomy. AB - Anomalous responses to morphine are common in patients with unexplained pain in the upper abdomen after cholecystectomy and may be linked to activation of the sympathetic nervous system. The hypothesis that sympathetic suppression would attenuate anomalous responses to morphine was tested by a randomized, cross-over trial using a standard challenge with morphine, with and without pretreatment with clonidine (300 micrograms orally, 1 h prior to the administration of morphine). In 13 of the 15 patients who completed the study, pre-treatment with clonidine decreased plasma concentrations of noradrenaline, dopamine and adrenaline by 56, 15 and 25% respectively. This was associated with a significant reduction in morphine-induced pain (p = 0.02) and nausea (p = 0.04) and attenuated increases in plasma aspartate aminotransferase (AST) activity (p = 0.03). Clonidine attenuates anomalous responses to morphine, perhaps through effects on sympathetic nervous activity or plasma concentrations of catecholamines. PMID- 7849499 TI - Functional dysautonomia: a valid clinical entity or pseudo-science? PMID- 7849501 TI - Differentiation and patterning in Dictyostelium. AB - Dictyostelium development is orchestrated by diffusible signals. Progress has been made in understanding how cAMP signaling triggers post-aggregative development and in defining the number of cell types that eventually differentiate. Ammonia is an unusual signal that may act by alkalinizing acidic vesicles. A chlorinated signal, differentiation-inducing factor (DIF), may be universal amongst the slime moulds. The first genes have been cloned using restriction enzyme mediated integration (REMI) insertional mutagenesis; one encodes a novel cytosolic protein essential for activation of adenylyl cyclase. PMID- 7849500 TI - Establishment of cell type specific gene transcription during sporulation in Bacillus subtilis. AB - Asymmetric cell division during the process of sporulation in the bacterium Bacillus subtilis generates dissimilar progeny that exhibit distinct programs of gene transcription. Recent work reveals a partner switching mechanism that governs the activity of the sporulation regulatory protein sigma F and that may be responsible for the establishment of cell type specific gene transcription. PMID- 7849502 TI - Transcription factors in plant growth and development. AB - The target DNA sequences of several classes of plant transcription factors, including basic leucine zipper (bZIP) proteins and Myb-related factors, have been characterized in vivo as well as in vitro. The bZIP proteins, for example, act at ACGT elements, the flanking nucleotides determining their binding specificities. Overexpression, co-suppression, and antisense technology studies of factor genes in transgenic plants have uncovered the roles of bZIP, homeodomain, and MADS box factors in plant growth and development; for example, ectopic expression of pMADS1 alone in early Petunia development is sufficient for homeotic conversion of sepals into petaloid organs. PMID- 7849503 TI - Cell fate and cell morphogenesis in higher plants. AB - The differentiation of plant cells depends on the regulation of cell fate and cell morphogenesis. Recent studies have led to the identification of mutants and the cloning of genes that influence these processes. In several instances, the genes encode products with homeodomains or Myb or Myc DNA-binding domains. PMID- 7849504 TI - Photosensory perception and signal transduction in plants. AB - Genetic and molecular studies are beginning to unravel the complexities of the signaling circuitry that plants use to sense and transduce information concerning the prevailing light environment. The past year has witnessed definition of discrete photosensory roles for phytochromes A and B, the cloning of a gene encoding the first apparent blue-light photoreceptor from any organism, the cloning of genes encoding additional members of the COP/DET/FUS class of light responsive master regulators, and evidence that G proteins, Ca2+/calmodulin, and cGMP may be signaling intermediates in phototransduction. PMID- 7849505 TI - Perception and response in plant disease resistance. AB - Plants express sophisticated mechanisms for recognizing pathogens. The functionally defined repertoire of non-self perception is large; the number and nature of subsequent molecular events required for resistance is unknown. Recent cloning of disease resistance genes, and genetic identification of loci required for their function, allows dissection of the structure, evolution, and deployment within populations of pathogen-perception mechanisms. Roles for reactive oxygen species and programmed cell death in resistance have also been suggested recently. New results document a role for salicylic acid as a lynchpin in the establishment and maintenance of the 'effector functions' of disease resistance, and strategies for engineered plant protection are moving closer to reality. PMID- 7849506 TI - Molecular genetics of Drosophila immunity. AB - Insects resist bacterial infections through the induction of both cellular and humoral immune responses. The cellular response involves the mobilization of hemocytes, whereas the humoral response utilizes antibacterial peptides that are synthesized in the fat bodies and secreted into the circulating hemolymph. Recent studies suggest that the induction of the humoral response involves Rel containing regulatory proteins, Dif and dorsal, which are related to mammalian NF kappa B. These regulatory proteins function as sequence-specific transcription factors that induce the expression of immunity genes, including cecropin and diptericin. In mammals, NF-kappa B has been implicated in both lymphocyte differentiation and the acute-phase response. The finding that insect and mammalian immunity involve related transcription factors offers the promise that genetic studies in Drosophila might lead to the identification of novel components mediating mammalian immunity. PMID- 7849507 TI - Promoter analysis meets pattern formation: transcriptional regulatory genes in sea urchin embryogenesis. AB - Analyses of spatial and temporal gene control mechanisms in the sea urchin embryo have identified several important trans-regulatory factors, including some that are related to known developmental control genes of the fly and mouse. Recent advances in gene perturbation technologies, including the use of antisense oligonucleotides to target mRNAs in early-stage embryos, as well as the injection of mRNAs into zygotes to express genes ectopically, have made it possible to test the functions of such factors directly. PMID- 7849508 TI - Genetic and epigenetic control in neural crest development. AB - The neural crest is a fascinating structure of the vertebrate embryo; its ontogeny includes a transient period during which its component cells undergo an epithelio-mesenchymal transition and become migratory. This phase was shown recently to be controlled by the 'Slug' gene which belongs to the 'Snail' family of Drosophila transcription factors. After homing to specific sites in the embryo, the crest-derived cells produce a large variety of phenotypes. Recent advances have shown that during migration most crest cells exhibit various degrees of pluripotentiality, some being already committed to a single and definite fate. Moreover, several lines of evidence point to the existence of totipotent stem cells in the neural crest, the progeny of which become progressively diversified through a combination of intrinsic and extrinsic influences. The latter have been documented by the disruption of several neurotrophin genes, which results in severe deficiencies of selected subsets of neural crest derivatives. The neural crest has also been shown to play an important role in the development of the vertebrate head and hypobranchial region. The genetic control of this process depends on the activity of developmental genes, among which the vertebrate Hox genes are essential, particularly at the rhombencephalic level. PMID- 7849509 TI - The regulation of kidney development: new insights from an old model. AB - The embryonic kidney is an excellent model system in which to address many fundamental issues in developmental biology. Inductive interactions are required for proliferation and differentiation of the ureter epithelium and kidney mesenchyme. Recent studies implicate a receptor-type tyrosine kinase as a target of inductive signals in the developing ureter. In the mesenchyme, the early induction response requires at least two transcription factors, WT1 and Pax-2. Through the integrated application of in vitro culture models and gene targeting methods, the molecular mechanisms underlying kidney morphogenesis are becoming clearer. PMID- 7849510 TI - Gene regulation and differentiation in vertebrate ocular tissues. AB - Molecular biological techniques have contributed greatly to the study of vertebrate ocular tissues. The specification of ocular tissues has been shown to be closely related to the expression of transcription factors encoded by genes such as Pax6 and microphthalmia. Lens-specific expression of the delta 1 crystallin gene is controlled by factors, such as delta EF1, binding to its enhancer sequences. Retinal activity of the glucocorticoid hormone receptor is regulated by its binding with another transcription factor. Degeneration of photoreceptors in a retinal disease, retinitis pigmentosa, can be caused by the introduction of a mutated opsin gene into mice. In addition, the process of transdifferentiation in ocular tissues has been described at the level of gene expression. PMID- 7849511 TI - Transcriptional mechanisms in anterior pituitary cell differentiation. AB - Development of the anterior pituitary gland involves the establishment of five distinct cell lineages which are each characterized by the expression of specific trophic hormone genes. Recent studies of the thyrotrope, somatotrope, and lactotrope cell types have investigated the molecular decisions responsible for the commitment and differentiation of these cell types and have characterized the regulatory mechanisms that govern cell-specific expression of individual hormone genes. In particular, elucidation of the molecular basis of heritable dwarf phenotypes lacking particular pituitary cell lineages, such as the Snell, Jackson, and little dwarf mice, and studies of the regulation of trans-acting factors, including Pit-1, involved in pituitary cell restricted gene activation have begun to delineate the pathways responsible for development of this organ. PMID- 7849512 TI - Vintage reds and whites: combinatorial transcription factor utilization in hematopoietic differentiation. AB - Pluripotent hematopoietic stem cells can differentiate into a number of distinct specialized cell types; however, no single lineage-specific master regulators have been identified that can activate individual patterns of gene expression. Recent evidence suggests that such lineage determination is regulated by a combinatorial matrix of regulatory proteins with overlapping tissue specificities which cooperate to define individual cell types. PMID- 7849513 TI - Bone and cartilage differentiation. AB - Recent progress in the study of regulation of bone and cartilage differentiation has come from the isolation, cloning, and expression of genes encoding bone morphogenetic proteins (BMPs). BMPs initiate cartilage and bone formation in a sequential cascade. Their pleiotropic effects on chemotaxis, mitosis, and differentiation are based on concentration-dependent thresholds. The existence of multiple members of the BMP family raises issues concerning functional redundancy. Current work in progress in different laboratories has revealed that BMP-2 or BMP-4 gene knockout by homologous recombination results, surprisingly, in embryonic lethality. Cartilage and bone differentiation during endochondral development involves a continuum of steps: initiation, promotion, maintenance, modeling, and termination. The signaling factors for initiation and maintenance are being defined at the molecular level, and future studies will focus on the gene regulation of initial signaling molecules such as BMPs. Critical progress in the determination of the role of BMPs in bone development has been accomplished by systematic study of skeletal mutations such as short ear and brachypodism in mice. The accelerating pace of advance in this area augurs well for the resolution of the molecular basis of morphogenesis of bone and cartilage. PMID- 7849515 TI - Differentiation and gene regulation. PMID- 7849514 TI - Muscle: the regulation of myogenesis. AB - The study of myogenesis in the embryo is a rapidly expanding field. In this context, the consequences of mutating different members of the MyoD family, together with an increasing number of observations that point to the importance of the MEF2 or RSRF family as myogenic regulators, and the identification of Pax 3 as a marker of early myogenic cells, have advanced our understanding of the molecular embryology of skeletal muscle. Novel cardiac regulatory factors such as Nkx-2.5 and GATA-4, in addition to MEF2 isoforms, are also beginning to be identified. At the molecular level, crystallographic studies have led to a structural model of the actinomyosin complex and also to information about how MyoD contacts DNA. PMID- 7849516 TI - Neuronal and glial cell biology. PMID- 7849517 TI - The molecular machinery for fast and slow neurosecretion. AB - Recent studies indicate that the molecular machinery for synaptic vesicle docking and fusion consists of a triad of botulinum/tetanus neurotoxin substrates (synaptobrevin, syntaxin, SNAP-25) that are homologues of proteins required for constitutive secretion. Proposed low-affinity Ca2+ sensors that regulate exocytosis remain to be identified, although recent studies on synaptotagmin suggest that it, along with other proteins, could play this role. Regulated peptide secretion from dense-core granules has been found to utilize a similar machinery for docking/fusion, and recent studies indicate that this pathway involves a pre-docking step that is regulated by a higher affinity Ca2+ sensor. PMID- 7849518 TI - Genetic analysis of neurotransmitter release at the synapse. AB - The recent application of genetics to the study of synaptic mechanisms has examined the in vivo significance of individual synaptic proteins and has tested hypotheses that were derived from biochemical observations on these proteins. In the case of synapsin I and Rab3A, the phenotypes of mice lacking these proteins was startlingly mild; only subtle alterations in transmission were observed. Whereas in synaptotagmin mutants of flies and nematodes, transmission was severely curtailed, though not abolished. A detailed analysis of the phenotype has led to a hypothesis that this protein stabilizes the docking of vesicles at release sites. The analysis of additional synaptic proteins, Unc-18/Rop and the cysteine string protein, has indicated that these are important players in synaptic mechanisms and may soon illuminate their function at the synapse. PMID- 7849519 TI - Cytoskeletal reorganization underlying growth cone motility. AB - Recent studies have implicated cytoskeletal dynamics as an important component in directing neuronal outgrowth. By using modern imaging techniques to observe the kinetics of individual cytoskeletal elements in living cells, these results have converged upon a common theme: functional coupling between the intracellular cytoskeleton and extracellular substrates, and regulation thereof, appears to be crucial in controlling neuronal migration. PMID- 7849520 TI - Inhibitory factors controlling growth cone motility and guidance. AB - Recent advances in the identification of factors that inhibit axon extension lead us to suggest that there exist at least two functionally distinct categories of inhibitory factors: those that inhibit the motile apparatus of the growth cone, and those that destabilize interactions of the growth cone with the substratum. These two types of inhibitory factors could play an important role in growth cone guidance. PMID- 7849521 TI - Neuronal intermediate filaments: new progress on an old subject. AB - Neurofilaments (NFs) are the major intermediate filaments in most mature neurons. Genetic approaches have now proven that NFs are an essential determinant for radial growth of axons. NF phosphorylation most probably plays an important role in this function. Further, forced over-expression of NF subunits in transgenic mice yields NF misaccumulation in motor neurons and, subsequently, causes motor neuron dysfunction. This has important implications for human motor neuron diseases because similar accumulations are nearly universally found in the early stages of many motor neuron disorders. PMID- 7849522 TI - Organelle transport and sorting in axons. AB - Recent advances of the past year in the field of organelle transport have documented the existence of numerous kinesin-related proteins and the presence of multiple conventional kinesins within neurons. Biochemical and genetic mutant analyses indicate that different kinesin superfamily members transport different organelles. In addition to microtubule-based systems, actin filaments and myosin motors are associated with organelle transport in axons. The great diversity of motor proteins suggests that they may play a role in sorting, in addition to transport. PMID- 7849524 TI - Gene targeting and synaptic plasticity. AB - Gene targeting is revealing new molecular functions by creating very specific developmental, physiological and behavioral perturbations, and providing new insights into biochemical pathways underlying synaptic plasticity. Recent studies of mice carrying mutations in genes thought to be involved in modulating synaptic transmission have been subject to integrated biochemical, physiological and behavioral analyses. PMID- 7849523 TI - Glial cell lineage and development. AB - Recent studies on the development of glial cells are making rapid progress in two major directions. While the factors that control gliogenesis during the perinatal period are becoming more clearly characterized, so too is the relationship between gliogenesis and the patterning of the embryonic central nervous system as a whole. PMID- 7849525 TI - Disease, transplantation and regeneration. PMID- 7849526 TI - The molecular mechanisms of neuronal apoptosis. AB - During the past year, apoptosis has been recognized as a process that is perpetually poised to be initiated--often from the cytoplasm rather than from the nucleus--unless it is suppressed by survival factors. Suspected mediators of apoptosis that have recently been investigated include the cysteine protease interleukin-1 beta-converting enzyme, free radicals and cell cycle kinases. Known inhibitors of programmed cell death, such as Bcl-2 and its homologues, have been further studied, and the results suggest that cell death may be regulated by multiple pathways. With the recent identification of the Drosophila gene reaper, which appears to play a role in the initiation of apoptosis, another genetic system for studying cell death has become available. PMID- 7849527 TI - Apolipoprotein E and Alzheimer's disease. AB - The past year has seen widespread confirmation that the epsilon 4 allele of the apolipoprotein E gene is a major risk factor for Alzheimer's disease. The epsilon 4 allele also appears to correlate with life expectancy. This allele has been found to be present in over 50% of Alzheimer patients, regardless of whether or not they have a family history of dementia. It is not yet clear how the epsilon 4 allele mediates its actions; however, recent evidence suggests that apolipoprotein E4 may be responsible for the accelerated formation of beta pleated amyloid from soluble beta-amyloid peptide, as is seen in the neuritic plaques of Alzheimer patients, as well as interacting with intraneuronal microtubular transport mechanisms. PMID- 7849528 TI - Amyloid beta-protein precursor: new clues to the genesis of Alzheimer's disease. AB - Research into the cellular processing and functional properties of the amyloid beta-protein precursor (beta PP) and its secreted derivatives is rapidly accelerating and drawing interest from many investigators outside the field of Alzheimer's disease pathobiology. Recent in vitro studies suggest multiple activities for the major secreted product, beta PPs, including protease inhibition, growth promotion, neuroprotection and stimulation of a signal transduction pathway. Surprisingly, the hydrophobic amyloid beta-protein fragment is also constitutively secreted. Its generation occurs in part during the endocytosis of cell-surface beta PP molecules. Processing of beta PP via amyloidogenic versus non-amyloidogenic pathways is under complex regulation by various first and second messengers. Analyses of beta PP missense mutations and of the effects of apolipoprotein E genotype lend new support to the hypothesis that accelerated amyloid beta protein deposition plays a pivotal role in the genesis of Alzheimer's disease. PMID- 7849529 TI - Trophic factors. AB - The various neurotrophic factors influence a wide range of cell functions in the developing, mature and injured nervous system. Recent studies have provided valuable insights on the receptors that mediate these effects and on the intracellular events that follow the binding of the ligand. Although growth factors were known to be expressed by non-neuronal cells in the targets and pathways of neuronal projections, it is now clear that the neurons themselves can also be a source of these molecules. A better understanding of the mechanisms of action of trophic factors on the survival and differentiation of neurons, coupled with advances in methods for the delivery of these molecules to the nervous system have provided an impetus for exploring their use as aids to the protection and regeneration of the injured nervous system. PMID- 7849530 TI - In vivo and ex vivo gene transfer to the brain. AB - The use of gene transfer techniques to express novel proteins within different cellular populations has provided insights into the function and plasticity of the brain. Recently, this technique has been successfully used to explore physiological processes within the CNS and to intervene in neurodegenerative disease and cancer. Progress in manipulating transgene products in vivo and in achieving cell-specific targeting of genetic material offers promise for enhancing the usefulness of this technique and its therapeutic potential for treating human disorders of the CNS. PMID- 7849531 TI - Grafting immortalized neurons to the CNS. AB - The ability to transplant an unlimited supply of clonally related neural progenitors that, in the brain, have the capacity to differentiate into neurons and glia in an anatomically and, perhaps, functionally appropriate manner, may not only facilitate developmental inquiries, but may also circumvent the limitations of primary fetal tissue for neural transplantation. These types of transplants also make possible new strategies for gene therapy and repair of the CNS, including replacement of degenerated cells, engineering donor cells to be resistant to toxins, delivery of missing metabolic or other gene products, over expression of molecules, and substitution of alternate metabolic pathways. PMID- 7849532 TI - Clinical application of cell transplantation and neurotrophic factors in CNS disorders. AB - Cell transplantation and administration of neurotrophic factors are now being explored as new therapeutic strategies to restore and preserve function in the diseased human central nervous system. Neural grafts show long-term survival and restore function in patients with Parkinson's disease, but the symptomatic relief needs to be increased. Cell transplantation also seems justified in patients with Huntington's disease and, possibly, in demyelinating disorders. Clinical trials with neurotrophic factors have been initiated in amyotrophic lateral sclerosis, dementia and Huntington's disease, and may later be started in Parkinson's disease and after acute brain insults. However, it remains to be shown if neurotrophic factors can rescue damaged cells in the brain and spinal cord of patients with these disorders. PMID- 7849533 TI - Neuronal and glial cell biology. PMID- 7849534 TI - Disease, transplantation and regeneration. PMID- 7849535 TI - The impact of early training on premenarchal and early menarchal athletes: a conference report. PMID- 7849536 TI - The impact of early training on young female athletes: an Olympic Committee perspective. PMID- 7849537 TI - Mood changes in pregnant women following an exercise session and a prenatal information session. PMID- 7849538 TI - Contraceptive advertising in the United States. PMID- 7849539 TI - Prenatal care use at an inner-city university hospital: why so low? PMID- 7849540 TI - Community health nurses' perceptions, knowledge, and involvement in abortion services. PMID- 7849541 TI - Bone mineralization in children and adolescents with a milk allergy. AB - To evaluate the correlation between dietary calcium intake and mineralization of the immature skeleton 55 children and adolescents aged 5-14 years (mean, 9.5 years) with a positive radioallergosorbent test (RAST) for serum antibodies to cow's milk protein were evaluated. Bone mineral density (BMD) in the lumbar spine and proximal femurs were measured by dual energy X-ray absorptiometry. BMD at each site for each subject was converted to an age-adjusted Z score based on our own series of 95 normal pediatric controls. Calcium intake was determined using a detailed food frequency questionnaire administered by a nutritionist during a 30 40-min interview. Dietary adjustments to the condition varied and resulted in a wide range of calcium intakes. Calcium supplements were taken by 22% of the subjects and were included in the determination of daily calcium intake. The group of 55 subjects was divided into quartiles based on calcium intake (mean +/- S.E mg calcium/day): Group 1, 409 +/- 21, Group 2, 663 +/- 16, Group 3, 950 +/- 32, Group 4, 1437 +/- 124. Bone density Z scores in the proximal femur serially increased across the calcium intake groups (mean +/- S.E.): Group 1, -0.16 +/- 0.31; Group 2, 0.05 +/- 0.33; Group 3, 0.44 +/- 0.24; Group 4, 0.79 +/- 0.41 (P = 0.03). A similar pattern was found with lumbar spine BMD Z scores: Group 1, -0.16 +/- 0.27; Group 2, 0.10 +/- 0.21; Group 3, 0.18 +/- 0.20; Group 4, 0.30 +/- 0.25 (P = 0.05). These data add further to the evidence that dietary calcium intake is important for optimal mineralization of the growing skeleton. PMID- 7849542 TI - The effect of fluoride therapy on blood chemistry parameters in osteoporotic females. AB - To determine the potential adverse effects, if any, of long-term fluoride ingestion in humans, samples were collected from 25 adult females taking daily doses of fluoride (mean, 23 mg elemental F) for the treatment of osteoporosis and from 38 osteoporotic female controls. Patients in the fluoride group had been receiving therapy for approximately 18 months with a mean duration of 4.2 years and had serum fluoride values of at least 10 mumol/l. Laboratory analyses for fluoride were conducted on plasma, urine and drinking water samples collected from each panelist. Blood was also collected for blood chemistry analyses and plasma lymphocytes were examined for the frequency of sister chromatid exchange (SCE). Plasma and urine fluoride levels were significantly different between the two groups, while water fluoride was not. The SCE frequency, a measurement of potential genotoxicity, did not differ between the two groups. Of the blood chemistry parameters measured, albumin, alkaline phosphatase, sodium, chloride, the albumin/globulin (A/G) ratio, indirect bilirubin, lactate dehydrogenase (LDH), and gamma-glutamyl transferase (GGT) were found to be significantly different between the two groups (P < or = 0.05). However, none of the mean group values were outside stated normal ranges for any of these parameters. We conclude that the risk of developing adverse systemic effects from the ingestion of fluoride, at dosages and for a duration comparable with that of our panel, is minimal. PMID- 7849543 TI - 1,25-Dihydroxyvitamin D3 receptors in peripheral blood mononuclear cells from patients with primary and secondary hyperparathyroidism. AB - A decreased number of calcitriol (1,25(OH)2D3) receptors has been observed in parathyroid glands of uremic animals. In humans, studies carried out in surgically removed parathyroid glands have shown that calcitriol binding is higher in primary than in secondary hyperparathyroidism. Since specific receptors for calcitriol have been described in peripheral blood mononuclear cells (PBMC), we have investigated the specific uptake of 3H-labelled 1,25(OH)2D3 in PBMC of 12 women with primary hyperparathyroidism (PHP), 8 women with hyperparathyroidism secondary to chronic renal failure (SH), 9 women with renal transplant (RT), and 23 healthy women. The median dissociation constant (Kd) was similar in all three groups of patients and in healthy women (mean +/- S.D. (range): PHP, 1.2 +/- 1.0 (0.2-4) x 10(-10) M; SH, 0.6 +/- 0.4 (0.2-1.2) x 10(-10) M; RT, 1.1 +/- 0.5 (0.4 1.9) x 10(-10) M; controls, 1.0 +/- 0.6 (0.3-2.6) x 10(-10) M). However, the maximal binding capacity (Nmax) was significantly enhanced in PHP (3.9 +/- 1.9 (1.3-7.6) fmol/10(7) cells vs. 2.3 +/- 0.9 (1.1-4.4) fmol/10(7) cells in controls; P = 0.0006) and decreased in SH (0.8 +/- 0.5 (0.2-1.6) fmol/10(7) cells vs. 2.3 +/- 0.9 (1.1-4.4) fmol/10(7) cells in controls; P = 0.0001), whereas no changes were seen in RT (2.3 +/- 0.7 (1.2-3.3) fmol/10(7) cells vs. 2.3 +/- 0.9 (1.1-4.4) fmol/10(7) cells in controls). In three patients with PHP who were subjected to parathyroidectomy, the calcitriol number came down to normal. Changes of calcitriol receptors in primary and secondary hyperparathyroidism could magnify the consequences of disturbances in serum concentration of calcitriol itself and might play an important role in the development of secondary hyperparathyroidism in uremia. PMID- 7849544 TI - The effect of fluoridated drinking water on axial bone mineral density--a population-based study. AB - Bone mineral density (BMD) of the spine and femoral neck was measured in a random stratified sample of 3222 perimenopausal women aged 47-59 years. A total of 969 women had used fluoridated drinking water (1.0-1.2 mg/l) for over 10 years. These women were compared with 2253 women with low levels of fluoride in drinking water (< 0.3 mg/l). BMD of the spine was significantly higher in the fluoride group than in the non-fluoride group (1.138 +/- 0.165 vs. 1.123 +/- 0.156 g/cm2, P = 0.026). Femoral neck BMDs did not differ between the groups. When the BMD values were adjusted for confounding factors (age, weight, menopausal status, calcium intake, physical activity level, deliveries, alcohol consumption and estrogen use), the differences between the groups increased (P < 0.001 for the spine and P = 0.004 for the femoral neck, respectively). There was no significant difference between the groups in the prevalence of self-reported fractures sustained during 1980-1989. We propose that the fluoridation of drinking water has a slight increasing effect on axial BMD in women in low fluoride areas. PMID- 7849545 TI - Primary cultures of human bone-derived cells produce parathyroid hormone-related protein: a study of 40 patients of varying age and pathology. AB - Parathyroid hormone-related protein (PTHrP), a mediator of hypercalcemia of malignancy, has been detected in many tumours and in some normal foetal and adult tissues. PTHrP has potent effects on bone turnover in vivo and in vitro. In this study we cultured cells derived from explants of bone obtained from 40 subjects (age range 2-88 years). Immunoreactive PTHrP (iPTHrP) was detected by immunoradiometric assay (IRMA) in conditioned medium from 25 of 40 cultures of bone-derived cells. PTHrP mRNA was detected in bone-derived cells by reverse transcriptase-linked polymerase chain reaction (RT-PCR). The identity of PCR products was confirmed by Southern blotting. Local production of PTHrP in vivo may be important in the regulation of bone growth and remodelling. PMID- 7849546 TI - The effect of alendronate on renal tubular reabsorption of phosphate. AB - We report the effects of alendronate on phosphate homeostasis in two patients. In a woman with postmenopausal osteoporosis, the infusion of alendronate (7.5 mg intravenously daily for 4 consecutive days) was not associated with secondary hyperparathyroidism despite a reduction in serum calcium. This was associated with a rise in serum phosphate and TmP/GFR. This response contrasted with those observed in 14 other patients with osteoporosis, in whom PTH rose significantly following the infusion of alendronate in association with a significant fall in serum phosphate and TmP/GFR. The second patient, a woman with Paget's disease, was treated with intravenous alendronate (10 mg daily for 5 consecutive days) on two occasions for relapse of disease activity. On the first occasion there was a 150% rise in serum PTH associated with a fall in serum phosphate and TmP/GFR. On the second occasion, when the rise in serum PTH was less marked, there was a rise in serum phosphate and TmP/GFR. We conclude that alendronate may increase renal tubular reabsorption of phosphate, but that this effect is usually offset by secondary hyperparathyroidism. PMID- 7849547 TI - A rapid, quantitative assay for measuring alkaline phosphatase activity in osteoblastic cells in vitro. AB - Alkaline phosphatase (ALP) is the most widely recognized biochemical marker for osteoblast activity. Although its precise function is poorly understood, it is believed to play a role in skeletal mineralization. The aim of this study was to develop an assay suitable for measuring the activity of this enzyme in microtiter plate format. Using the well-characterized osteoblast-like cell line Saos-2, this paper describes an optimized biochemical assay suitable for measuring ALP activity in tissue culture samples. We have determined that a p-nitrophenyl phosphate substrate concentration of 9 mM provides highest enzyme activities. We have found that cell concentration, and hence enzyme concentration, affects both the kinetics and precision of the assay. We also tested several methods of enzyme solubilization and found that freeze-thawing the membrane fractions twice at -70 degrees C/37 degrees C or freeze-thawing once with sonication yielded highest enzyme activities. The activity of the enzyme decreased by 10% after 7 days storage. This assay provides a sensitive and reproducible method that is ideally suited for measuring ALP activity in isolated osteoblastic cells, although sample preparation and storage can influence results. PMID- 7849548 TI - Stimulation of interleukin-4 of cell proliferation and mRNA expression of alkaline phosphatase and collagen type I in human osteoblast-like cells of trabecular bone. AB - Interleukin-4 (IL-4) potently inhibits bone resorption by preventing the differentiation of osteoclast precursors to osteoclasts. To elucidate the role of IL-4 in bone formation, we studied the effects of human IL-4 on human osteoblast like cells obtained from trabecular bone, which showed increased osteocalcin production in response to 1,25-(OH)2D3 in more than 10 passages. IL-4 stimulated the proliferation of osteoblast-like cells in a concentration-dependent manner, showing the minimal and maximal stimulatory effects at 10 pg/ml and 100-1000 pg/ml, respectively. IL-4 also stimulated the expression of alkaline phosphatase mRNA (1.7-fold) and the enzyme activity to the same extent at 10-100 pg/ml. Furthermore, IL-4 stimulated collagen type I mRNA expression in human osteoblast like cells. The cytokine did not affect osteocalcin production in a short culture period (3 days). These in vitro findings suggest that IL-4, a bone-resorption inhibitory cytokine produced by activated T cells in bone marrow, may exert an anabolic effect on osteoblast-like cells in trabecular bone through a paracrine mechanism. PMID- 7849550 TI - Further studies on the "de novo" process of alpha 1,4-alpha 1,6 glucopolysaccharides--corn starch biogenesis. AB - Starch biogenesis in corn endosperm from Flint, Sugary, Waxy, as a function of the grain filling/period was studied. We have differentially identified the initiation from the elongation process. After incubating under unprimed conditions, two glucose radiolabelled protein bands of 39,5 and 36 kDa were obtained. UDP(14C)Glc was the preferred glucosyl donor but also ADP(14C)Glc was. It was additionally found that more than one glucose was transferred to the protein or to the alpha 1,4-glucan linked to protein from UDPGlc. These results were supported by the fact that the glucosylated protein from UDPGlc liberates maltooligosaccharides after alpha- or beta-amylase treatment. The elongation activity in the first steps related to the glucan linked to protein is different from starch synthase. Therefore, we are proposing a model for starch biogenesis where two new transglucosylating enzyme activities are necessary to prepare the primer for starch synthase. PMID- 7849549 TI - Memorial issue for Rosalia Frydman. PMID- 7849551 TI - Soy protein has no hypocholesterolemic action in mice because it does not stimulate fecal steroid excretion in that species. AB - We compared the effects of dietary soy protein isolate (SPI) and casein on plasma cholesterol level and fecal steroid excretion in rats, mice and hamsters. In rats, compared with casein, SPI significantly stimulated fecal steroid excretion in 9 out of 12 experiments with or without dietary cholesterol, whereas it suppressed plasma cholesterol level in 5 experiments and tended to suppress that, though not significantly, in 4 experiments. In mice, on the contrary, no significant difference was observed between the effects of casein and SPI on either the fecal steroid excretion or plasma cholesterol level in most of 12 experiments in which three different strains were tested. High-molecular-weight fraction of undigested residue of SPI exhibited marked hypocholesterolemic and steroid excretion-stimulating effects in rats and hamsters, whereas it showed only mild effects in mice. The species-dependent difference indicated the existence of inverse correlation between fecal steroid excretion and plasma cholesterol level and supported the view that in species like rat and hamster, but not mice, SPI lowers plasma cholesterol level by stimulating fecal steroid excretion. PMID- 7849552 TI - The in vitro biosynthesis of functional nodulation factors (Nod Rm) produced by Rhizobium meliloti 1021. AB - Rhizobium meliloti associates symbiotically with alfalfa by forming root nodules in which the bacteria reduce atmospheric N2 into products useful to both organisms. Nod factors are signal molecules, lipooligosaccharides, produced by the bacteria that trigger nodule formation in the plant host. Nod Rm-1 consists of a beta-1,4-N-acetyl glucosamine tetrasaccharide from which the N-acetyl group at the non reducing end is replaced by a fatty acid and the N-acetyl glucosamine at the reducing end is sulfated at position 6. By in vitro incubation of electroporated cells in the presence of [35S]PAPS or UDP-[14C]GlcNAc a labelled compound has been obtained with the properties of the in vivo produced Nod Rm-1 factor, as judged by HPLC, TLC and HPTLC techniques. The [14C]GlcNAc labelled compound has also hair root deformation activity on alfalfa plantlets indicating that a functional Nod Rm-1 factor has been synthesized in vitro. PMID- 7849553 TI - Heme oxygenase: the physiological role of one of its metabolites, carbon monoxide and interactions with zinc protoporphyrin, cobalt protoporphyrin and other metalloporphyrins. AB - In 1991, we postulated that carbon monoxide, which is formed endogenously from heme catabolism catalyzed by heme oxygenase and shares some of the chemical and biological properties of nitric oxide, may play a role similar to that of nitric oxide as a widespread signal transduction mechanism for the regulation of cell function and communication. We review the experimental evidence that tests this postulate. Carbon monoxide appears to be involved in the neurophysiological phenomenon of long-term potentiation, which appears to play a key role in memory and learning. Zinc protoporphyrin, an inhibitor of heme oxygenase, prevents induction of long-term potentiation. Zinc protoporphyrin is an endogenous substance, the levels of which are increased in iron deficiency states and in lead poisoning, and by inhibiting heme oxygenase may modulate long-term potentiation and memory. It has been shown that, when cobalt protoporphyrin is injected into the medial nuclei of the rat hypothalamus, weight loss occurs. These nuclei contain heme oxygenase, and we postulate that weight loss is due to cobalt protoporphyrin induction of heme oxygenase and increased formation of carbon monoxide, which serves as a signal transduction mechanism in the medial hypothalamus to suppress appetite. PMID- 7849554 TI - Evidence for the presence of Mn(II) in a peanut peroxidase. An EPR study. AB - The characteristics of the paramagnetic centers of the main cationic isozyme of peanut peroxidase are analyzed using electron paramagnetic resonance. Two main paramagnetic species have been detected. The EPR spectrum of the native cationic peanut peroxidase shows features which correspond to those of high spin ferric heme iron. A second paramagnetic center has been identified as manganese (Mn2+). The EPR spectra of the reduced enzyme and its fluoride, cyano, carbon monoxide, thiolate and hydroxy derivatives have been studied. The signal attributed to Mn(II) disappeared after dialysis against 50 mM EDTA, which removed the Mn ions, as it was confirmed by atomic absorption spectroscopy. The disappearance of the Mn signal after the formation of the cyano, thiolate and hydroxy complexes suggest a transfer of electrons from the Mn(II) ions. The significance of manganese in the catalytic cycle of cationic peanut peroxidase discussed. PMID- 7849555 TI - Cobaltous chloride-mediated induction of rat hepatic tryptophan 2,3-dioxygenase: implications for the use of the enzyme to probe the hepatic free heme pool. AB - Subcutaneous administration of CoCl2, a well recognized inhibitor of hepatic heme synthesis, to rats results in the functional stimulation of total (holo- + apo) tryptophan 2,3 dioxygenase (TDO), a hemoprotein and the key rate-limiting enzyme in the oxidative metabolism of tryptophan to formylkynurenine. Because basal holo TDO activity is not altered, TDO stimulation appears to be entirely due to CoCl2 mediated increase of its apoprotein. This apoTDO increase was blocked by conventional inhibitors of protein synthesis (actinomycin D, cycloheximide), thereby revealing that such CoCL2-mediated apoprotein increase truly reflected TDO induction. To determine whether the CoCl2-mediated TDO induction involved the action of its natural physiological inducers (glucocorticoids) or was due to direct CoCl2-regulation of the TDO gene, rats were adrenalectomized before CoCl2 administration. In adrenalectomized rats, CoCl2 failed to induce TDO, but induction was completely restored on administration of the glucocorticoid hydrocortisone, but not of adrenaline. These findings reveal that CoCl2-mediated TDO induction is indirect and entails glucocorticoid participation. In addition, because CoCl2 lowered the % heme saturation of TDO [= 100(holo TDO activity/total (apo+holo) TDO activity] largely by increasing the apoTDO protein levels rather than by affecting the basal holo-TDO levels (as expected from its inhibition of heme synthesis), these findings question the widely accepted use of the relative intrahepatic % heme saturation of TDO as a reporter of the hepatic "free" heme pool. PMID- 7849557 TI - A role for polyamines in the control of ppGpp levels in Escherichia coli. AB - As an approach to understand the involvement of polyamines in the variation of intracellular guanosine 5'-diphosphate 3'-diphosphate (ppGpp) levels, kinetic studies with several polyamine-requiring relA and spoT Escherichia coli mutants have been carried out. The accumulation and turnover of the nucleotide have been followed under conditions of aminoacid depletion or energy source starvation. The results obtained strongly suggest an important role of the polycations mainly in the degradation of ppGpp, and also in its synthesis mediated by ppGpp synthetase I (PSI). PMID- 7849556 TI - Protoporphyrinogen accumulation in cultured hepatocytes treated with the diphenyl ether herbicide, acifluorfen. AB - Diphenyl ether (DPE) herbicides such as acifluorfen inhibit both the plant and mammalian forms of protoporphyrinogen oxidase, a heme biosynthetic enzyme. Only small amounts of protoporphyrin accumulated in primary cultures of chick embryo and rat hepatocytes treated with acifluorfen and the porphyrin precursor, 5 aminolevulinic acid. However, there was a large accumulation of the porphyrin precursor, protoporphyrinogen, which was detected after oxidation to protoporphyrin by an E. coli membrane enzyme. In contrast, conventional methods of porphyrin analysis which depend on quantitative autoxidation of protoporphyrinogen failed to detect this accumulation of protoporphyrinogen. This is the first demonstration that protoporphyrinogen can accumulate to high levels and remain stable in liver cells. In addition, we found that the effect of a protoporphyrinogen oxidase inhibitor such as acifluorfen on the regulation of heme synthesis in hepatocyte cultures differed from that of an iron chelator. PMID- 7849558 TI - Regulation of putrescine uptake in Leishmania mexicana promastigotes. AB - Putrescine uptake of Leishmania mexicana promastigotes is tightly regulated by polyamine intracellular concentrations. This uptake, markedly stimulated after parasite treatment with alpha-difluoromethylornithine (DFMO) for 48 to 72 hrs., was strongly repressed by exposure of Leishmania cultures to exogenous putrescine or its derivative 1,4-dimethylputrescine. In contrast, spermidine, spermine, diaminopropane and cadaverine were unable to decrease putrescine transport. Both, the uptake induction as well as its specific feedback repression by increased levels of endogenous putrescine requires protein synthesis since they were abolished after addition of cycloheximide for several hours. Our results seem to indicate that putrescine transporter is a stable and specific protein which can be reversibly inactivated by a relatively unstable repressor. PMID- 7849559 TI - Photodynamic therapy of tumors: effects of hematoporphyrin derivative on normal rat intestine. AB - Hematoporphyrin derivative (HpD) is a complex mixture of dicarboxylic porphyrins in addition to dimers, oligomers and aggregates of variable sizes. The ability of this mixture (and enriched preparations thereof) to be retained by tumors and to sensitize them to destruction by light has led to worldwide studies of the treatment modality called photodynamic therapy (PDT). Understanding how PDT affects normal tissues surrounding the tumor is of crucial importance. Prior studies have documented that normal intestinal blood flow can be disrupted by HpD PDT. In addition, mucosal and submucosal damage to normal rat jejunum was observed following HpD PDT. The present study was designed to correlate the above observed changes with local levels of porphyrins. Three groups of Fischer 344 rats were injected with 0 (controls), 10 or 20 mg HpD/kg body weight. Twenty-four hours after the drug was injected, jejunal segments were excised and blood samples taken. Jejunal contents were obtained by saline perfusion and analyzed for porphyrins alongside the jejunal homogenates and the bloods. Jejunal segments of animals injected with 10 or 20 mg HpD/kg b.w. had porphyrin levels some 4- and 9-fold above controls (controls m +/- S.D. = 0.25 +/- 0.12 micrograms/g wet weight). For each injected dose the jejunal perfusates contained 2- and 3-fold higher levels of porphyrins (in transit) as the controls (controls, m +/- S.D. = 1.48 +/- 0.66 micrograms/g w.w.). In the general circulation, only 0.6% or 0.4% of the respective injected doses remained. After HpD i.v. injections, high levels of porphyrins were found in the small intestine and in transit.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7849560 TI - Decrease in spermidine content during logarithmic phase of cell growth delays spore formation of Bacillus subtilis. AB - Bacillus subtilis 168M contained a large amount of spermidine during the logarithmic phase of growth, but the amount decreased drastically during the stationary phase. The extracts, prepared from B. subtilis cells harvested in the logarithmic phase, contained activity of arginine decarboxylase (ADC) rather than the activity of ornithine decarboxylase. In the presence of alpha difluoromethylarginine (DFMA), a specific and irreversible inhibitor of ADC, the amount of spermidine in B. subtilis during the logarithmic phase decreased to about 25% of the control cells. Under these conditions, spore formation of B. subtilis 168M delayed greatly without significant inhibition of cell growth. The decrease in spermidine content in the logarithmic phase rather than in the stationary phase was involved in the delay of sporulation. Electron microscopy of cells at 24 hrs. of culture confirmed the delay of spore formation by the decrease of spermidine content. Furthermore, the delay of sporulation was negated by the addition of spermidine. These data suggest that a large amount of spermidine existing during the logarithmic phase plays an important role in the sporulation of B. subtilis. PMID- 7849561 TI - Characterization of a hemA/hemE mutant of E. coli and regulation of hemE. AB - Uroporphyrinogen III is the committed intermediate common to heme and siroheme biosynthesis in E. coli. Uroporphyrinogen III decarboxylase is the first enzyme at the branch point which commits to heme synthesis. A hemin-permeable hemA mutant which could grow on 5-aminolevulinic acid (ALA) or hemin, was mutagenized to give a double mutant, 10L2-1. The second mutation which was identified as hemE because it was mapped to 90.1 min. by F' and Hfr mapping and P1 transduction, accumulated uroporphyrin and had no uroporphyrinogen decarboxylase activity. This mutation could be complemented with a plasmid harboring the hemE gene of Synechococcus. The complemented strain could grow on ALA and accumulated coproporphyrin and protoporphyrin but not uroporphyrin. The E. coli hemE gene was cloned by transducing 10L2-1 with an E. coli genomic library in lambda gt11. hemE with upstream regions of various sizes was cloned in front of a promoterless CAT gene. Good growth on chloramphenicol (25-75 micrograms/ml) depended on a promoter within 152 bp upstream of the hemE structural gene start of translation site. In addition, this construct could complement the hemE requirement of 10L2-1 as well as allow it to grow on chloramphenicol. Addition of hemin did not inhibit this growth and therefore it appears that it does not affect the hemE promoter. The hemE structural gene alone allowed good growth on 10 micrograms/ml but poor growth on 25 micrograms/ml chloramphenicol, suggesting that there is a weak promoter within hemE for a downstream ORF. Quantitation of CAT protein in these strains showed a weak promoter within hemE, a promoter 152 bp upstream of hemE and another promoter within 1.3 kb upstream of hemE. The 1.3 kb region contains an ORF 40 bp upstream of hemE, thus suggesting that hemE is part of an operon. PMID- 7849562 TI - Ornithine decarboxylase--a predictor for tumor chemosensitivity. AB - The activity of ornithine decarboxylase (ODC) was determined in P388 murine leukemia cells treated with adriamycin (ADR) and methotrexate (MTX). Some of the cell lines were resistant to ADR, MTX or their combinations. A similar pattern was found between the cytotoxicity and the suppression of ODC activity in these cell lines in terms of drug concentrations. In a cell line resistant to one drug, a relatively high concentration of that drug was required to inhibit ODC activity. This effect was independent of the sensitivity of the cells to the other drug. A similar correlation between arrest of growth and the inhibition in the induction of ODC was also observed in human epithelial carcinoma cells. In this case too, the growth of multidrug resistant cells was not affected by vinblastine, neither was the induction of ODC. On the other hand, both the growth and the induction of ODC were inhibited by vinblastine in drug-sensitive cells. These findings suggest that ODC measurements might be used for predicting the chemosensitivity of tumor cells. PMID- 7849563 TI - Hepatic uptake, transport and metabolism of alkylated bilirubins in Gunn rats and Sprague-Dawley rats. AB - We studied the metabolism and biliary excretion of four novel analogs of bilirubin in homozygous Gunn rats and Sprague-Dawley rats. All four compounds closely resemble bilirubin in constitutional structure but two of them contain strategically-placed geminal dimethyl substituents. These substituents destabilize, by steric buttressing, preferred ridge-tile conformational isomers and weaken intramolecular hydrogen bonding. The two analogs which lack geminal dimethyl substituents behaved like bilirubin itself--after intravenous administration they were metabolized to monoglucuronides and diglucuronides in Sprague-Dawley rats and not excreted significantly in bile in Gunn rats. The corresponding gem-dimethyl compounds--which, counter-intuitively, are much more polar than bilirubin--were, nevertheless, not excreted efficiently in bile Gunn rats. But, surprisingly, in Sprague-Dawley rats they were each metabolized predominantly to a single glucuronide metabolite, apparently a monoglucuronide. Thus, apparently minor constitutional changes, provoking subtle alterations of three-dimensional structure and hydrogen bonding, can have marked effects on the metabolism and hepatic processing of bilirubins in vivo. PMID- 7849564 TI - Pretreatment with the polyamine analog 1,19-bis-(ethylamino)-5,10,15 triazanonadecane (BE-4-4-4-4) inhibits etoposide cytotoxicity in U-251 MG (NCI) human brain tumor cells. AB - We studied whether pretreatment of U-251 MG human brain tumor cells with the polyamine analog 1,19-bis-(ethylamino)-5,10,15-triazanonadecane (BE-4-4-4-4) affected the cytotoxicity of the topoisomerase II inhibitor etoposide. We found that BE-4-4-4-4 protected cells from the cytotoxic effects of etoposide. Possible mechanisms for this protection may be related to enhanced DNA-nuclear matrix association in analog-treated cells. PMID- 7849565 TI - Expression of branching enzyme II of maize endosperm in Escherichia coli. AB - A cDNA clone encoding maize branching enzyme II (BEII) has been independently isolated from a maize endosperm cDNA library. The deduced protein sequence of maize BEII was compared with that of BE from diverse sources. The gene encoding mature BEII of maize endosperm has been expressed in E. coli using the T7 promoter. The expressed BEII was purified to near homogeneity so that amylolytic activity and bacterial BE could be completely eliminated from the BE preparation. The expressed enzyme showed very similar properties to those of BEII purified from developing maize endosperm. This result confirmed our earlier report that BEII had a lower rate of branching amylose and the rate of branching amylopectin was twice that of branching amylose. This study also showed a greater advantage of purifying BEII from the bacterial expression system than from developing maize endosperm. Most importantly, this study has established a useful tool to study the structure-function relationships of the maize BE using site-directed mutagenesis. PMID- 7849566 TI - The presence in Trypanosoma cruzi microsomes of alpha(1,2), alpha(1,3) and alpha(1,6) mannosidase activities not involved in protein-linked Man9GlcNAc2 processing. AB - Trypanosoma cruzi microsomes were found to possess membrane-bound alpha(1,2), alpha(1,3) and alpha(1,6) mannosidase activities that had an almost neutral optimum pH value, did not require CaCl2 for activity and were inhibited by swainsonine but not by deoxymannojirimycin. A mannosidase activity that degraded p-nitrophenylmannoside and that was inhibited by swainsonine was also present in the parasite microsomes. Experiments performed with intact cells showed that processing of protein-linked Man9GlcNAc2 was inhibited by deoxymannojirimycin but not by swainsonine. It was concluded that the activities detected were not involved in protein-linked Man9GlcNAc2 processing. PMID- 7849567 TI - Evidence for degradation of mRNA encoding alpha-L-iduronidase in Hurler fibroblasts with premature termination alleles. AB - Mutations in the gene encoding alpha-L-iduronidase (IDUA) are the cause of Hurler syndrome. Fibroblasts from patients homozygous for nonsense IDUA alleles have much reduced mRNA detectable by Northern analysis, as has been observed in many other instances of premature translation termination. Yet RT-PCR (reverse transcription followed by PCR amplification) showed a normal level of a segment covering exons 1 and 2 in Hurler cells homozygous for alleles bearing the nonsense mutations, Q70X or W402X. The 3' end of the segment was between exons 2 and 4. The results indicate that the nonsense RNA was degraded to fragment(s), independent of the position of the mutation (exon 2 or exon 9, respectively). Treatment of the cells with cycloheximide resulted in some increase of intact mRNA, suggesting that translation is required for mRNA degradation. PMID- 7849568 TI - Ionic factors affecting the association of tyrosine hydroxylase with chromaffin granules in the adrenal medullary cell. AB - Chromaffin cells were treated with digitonin in medium containing various ions and the efflux of tyrosine hydroxylase from these permeabilized cells was then determined to elucidate a possible influence of cytoplasmic ionic environment on the association of this enzyme with the chromaffin granule. The enzyme efflux was observed with a distinct lag during exposure to low concentrations of digitonin in the medium containing isotonic sucrose. In contrast, a larger extent of the enzyme efflux was observed without any notable delay in the presence of isotonic NaCl. The results were thought to indicate the possibility that the dissociation of soluble enzyme from the granule surface within the permeabilized cells might occur in the presence of NaCl. Furthermore, the interaction between tyrosine hydroxylase and isolated chromaffin granule membranes was directly examined, and this interaction was shown to be inhibited by NaCl. However, the enzyme-granule membrane interaction was also inhibited by KCl and choline chloride. It therefore seems possible to consider that the inhibitory action of NaCl on the association of soluble enzyme with the granule may not be due to the specific action of Na+, but presumably due to the non-specific chaotropic effect of Cl-. On the other hand, the enzyme efflux was markedly reduced by the presence of Ca2+ in the permeabilizing medium, but the enzyme-granule membrane interaction was not affected by Ca2+ at the same concentrations.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7849569 TI - The stability of angiotensin receptors and angiotensin converting enzyme in post mortem brain. AB - Quantitative in vitro autoradiography was used to assess the post mortem stability of angiotensin II receptors and angiotensin converting enzyme in adult sheep brainstems. There was no significant loss of angiotensin II receptor binding in brainstems stored for up to 24 h at 23 degrees C or for 8 h at 23 degrees C followed by 64 h at 4 degrees C. There was no significant decrease in angiotensin converting enzyme binding in the same nuclei after up to 48 h at 23 degrees C or after 8 h at 23 degrees C followed by up to 64 h at 4 degrees C. Interpretation of neurochemical studies of human brain tissue obtained at autopsy requires assessment of the post mortem stability of the molecules being studied. Our results indicate that angiotensin II receptors and angiotensin converting enzyme are remarkably stable in sheep brainstems after post mortem delays in excess of those usually encountered in hospital autopsies. PMID- 7849570 TI - 1-Methyl-4-phenylpyridinium (MPP+)-induced cell death in PC12 cells: inhibitory effects of several drugs. AB - 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), an inducer of parkinsonism, causes degeneration of nigro-striatal dopaminergic neurons by producing its neurotoxic metabolite, 1-methyl-4-phenylpiridium ion (MPP+), by monoamine oxidase B in glial cells. We used PC12 (rat pheochromocytoma cell line) as a model cell line of dopamine-containing neurons and investigated the effects of various drugs on MPP(+)-induced cell death in PC12 cells. To estimate the cell death, we measured lactate dehydrogenase (LDH) activity leaked into the culture medium from damaged cells. When PC12 cells were treated with MPP+ at 0.3, 1.0 and 3.0 mM for 24 h, MPP+ increased the leakage of LDH and the leakage by 1.0 and 3.0 mM MPP+ was significant compared to the control. High K+ (50 mM KCl) significantly inhibited both MPP(+)-induced leakage of LDH and [3H]MPP+ uptake into the cells, suggesting that high K+ inhibits MPP(+)-induced cell death by inhibition of MPP+ uptake. NGF, dibutyryl cAMP (diBu-cAMP), cycloheximide (CHX) and aurintricarboxylic acid (ATA) significantly inhibited MPP(+)-induced leakage of LDH but did not inhibit [3H]MPP+ uptake, suggesting that these drugs inhibit MPP(+)-induced cell death at other sites than the one of MPP+ uptake. PMID- 7849571 TI - Immunological identification of two proteoglycan fragments derived from neurocan, a brain-specific chondroitin sulfate proteoglycan. AB - Neurocan is a brain-unique chondroitin sulfate proteoglycan (CSPG) whose expression and proteolytic cleavage are developmentally regulated. One of the proteolytic products (C-terminal half) is known to be a CSPG with a 150 kDa core glycoprotein (CSPG-150). To identify the N-terminal half of neurocan, we raised an anti-neurocan polyclonal antibody (PAb 291) using a synthetic peptide whose amino acid sequence matched a part of the N-terminal half of neurocan. Western blots showed that PAb 291 recognized two CSPGs, one with a 220 kDa core glycoprotein (CSPG-220, namely neurocan) and one with a 130 kDa core glycoprotein (CSPG-130) isolated from young rat brains. CSPG-130 was co-purified along with CSPG-220 by PAb 291-immunoaffinity column chromatography. The amino acid sequence of the N-terminus of the immunopurified CSPG-130 was exactly the same as the N terminal sequence of CSPG-220. These results suggest that not only the C-terminal half (CSPG-150) but also the N-terminal half (CSPG-130) of CSPG-220 exists in a CSPG form in rat brain. Using PAb 291 and monoclonal antibody 1G2 (MAb 1G2) which recognizes CSPG-150 in addition to CSPG-220, we found that the contents of CSPG 130 and CSPG-150 in the rat brain reached maximum levels around the time of birth. Both CSPG-130 and 150 were observed, while CSPG-220 was hardly detectable in extracts from the adult rat brain. Immunohistochemical investigation showed that the PAb 291 antigen had a similar distribution pattern to the MAb 1G2 antigen.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7849572 TI - Comparison of the superfused efflux of preaccumulated D-[3H]aspartate and endogenous L-aspartate and L-glutamate from rat cerebrocortical minislices. AB - Because the validity of the use of preaccumulated isotopic excitatory amino acids (EAAs) to index the depolarization-evoked release of endogenous EAAs has been questioned, we compared the K(+)-evoked efflux of preaccumulated D-[3H]aspartate from rat cerebrocortical minislices with that of endogenous L-aspartate and L glutamate. Release of all EAAs increased with the rate of superfusion. Using the most rapid rate (1.6 ml/min), transient elevations in [K+] caused a concentration dependent increase, with 50 mM K+ evoking a 33-, 23- and 93-fold increase in the efflux of D-[3H]aspartate, L-aspartate and L-glutamate, respectively; this efflux was Ca(2+)-dependent and tetrodotoxin insensitive. Under polarized conditions (5 mM K+), 1 mM kainic acid increased the efflux of preaccumulated and endogenous EAAs. These elevations were not blocked by the competitive kainate receptor antagonist 6,7-dinitroquinoxaline-2-3-dione (DNQX) and were not affected by removing Ca2+ ions. We conclude that in superfused cortical minislices, the efflux of preaccumulated D-[3H]aspartate provides a robust and reliable index of the release of endogenous L-aspartate and L-glutamate. PMID- 7849573 TI - Effects of thyroxine and its related compounds on cerebral GABA receptors: inhibitory action on benzodiazepine recognition site in GABAA receptor complex. AB - The effects of thyroxine and its related derivatives on gamma-aminobutyric acid (GABA) receptors in the rat brain were examined. D-Thyroxine strongly inhibited [3H]flunitrazepam binding to benzodiazepine receptor in crude synaptic membrane from the rat brain. The Scatchard analysis of the [3H]flunitrazepam binding in the presence of D-thyroxine indicated the decreases in the affinity and maximum number of binding site. Furthermore, D-thyroxine inhibited the enhancing effect of flunitrazepam on GABA-stimulated 36Cl- influx into membrane vesicles, although GABA-stimulated 36Cl- influx alone was not affected by D-thyroxine. On the other hand, the effects of thyroxine and its related derivatives on cerebral GABAB receptor binding were not noted. These results suggest that D-thyroxine may be a drug which is able to modulate the function of GABAA receptor complex via the inhibitory action on benzodiazepine recognition site. PMID- 7849574 TI - Evidence for cholinergic vagal afferents and vagal presynaptic M1 receptors in the ferret. AB - The distribution of muscarinic receptor binding was examined in the ferret brainstem vagal nuclei using the non-selective ligand [3H]quinuclidinyl benzilate and the relatively M1 receptor-selective ligand [3H]pirenzepine. The highest density of receptor sites are found in the subnucleus gelatinosus and lower levels in the other subnuclei of the nucleus of the tractus solitarius and in the area postrema and dorsal motor nucleus of the vagus nerve. Dense binding was also seen in the adjacent hypoglossal nucleus. Following unilateral cervical nodose ganglion excision binding in the subnucleus gelatinosus was attenuated ipsilateral to the lesion compared with the contralateral side. In contrast, [3H]pirenzepine binding was only seen in the subnucleus gelatinosus and in no other region at this level of the brainstem. This binding was reduced in the subnucleus as a whole by 52% ipsilateral to a cervical vagotomy. In the more rostral parts of the subnucleus gelatinosus, binding was undetectable ipsilateral to the lesion but more caudally, appreciable levels of binding persisted. This distribution parallels the known rostro-caudal variation in cross-over of vagal afferent fibres in the ferret dorsal vagal complex and indicates a presynaptic localization of [3H]pirenzepine binding sites on vagal afferent terminals. The distribution of binding of the high affinity choline uptake site blocker, [3H]hemicholinium-3, was also examined in the ferret brainstem using autoradiography. High densities of [3H]hemicholinium-3 binding were seen in the hypoglossal nucleus, the subnucleus gelatinosus and in the area postrema, with lower levels in the dorsal motor nucleus of the vagus, the trigeminal nucleus and other subnuclei of the nucleus of the tractus solitarius.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7849575 TI - Evidence for biosynthesis and catabolism of monoamines in the sea pansy Renilla koellikeri (Cnidaria). AB - The biosynthesis of catecholamines and indoleamines was investigated in the sea pansy Renilla koellikeri by radiochemical screening of tissue samples exposed in vivo to labelled amino acid precursors and analysed by high-performance liquid chromatography coupled with electrochemical detection. Incubation of sea pansy tissues in [3H]tyrosine resulted in substantial accumulation of radioactivity recovered in chromatograms coeluting with tyrosine and 4-hydroxy-3-methoxy mandelic acid and, to a lesser extent, with 3,4-dihydroxy-phenylalanine, dopamine, norepinephrine, epinephrine, normetanephrine and 3,4-dihydroxyphenyl acetic acid. The catecholamine synthesis inhibitor alpha-methyl-p-tyrosine effectively reduced several of these [3H]tyrosine by-products formed as well as endogenous stores of these amines. Incubations in [3H]tryptophan resulted in large amounts of radioactivity associated with liquid chromatographic peaks coeluting with tryptophan and 5-hydroxytryptophan and lesser amounts with 5 hydroxytryptamine, N-acetyl-5-hydroxytryptamine and 5-hydroxy-3-indole acetic acid. The indoleamine synthesis inhibitor p-chlorophenylalanine reduced the amounts of products formed and depleted stores of the endogenous indoleamines. Enzyme activities which appear to involve tyrosine hydroxylase (EC 1. 12. 16. 2), tryptophan hydroxylase (EC 1. 14. 16. 4) and phenylethanolamine N methyltransferase (EC 2. 1. 1. 28) were also detected in rachidial tissues by HPLC analysis of reaction products (hydroxylases) and by a radioenzymatic assay (methyltransferase). The sea pansy being a representative of the earliest invertebrates possessing a nervous system, these results support the hypothesis that vertebrate-like enzymatic pathways for the biosynthesis and degradation of monoamine neurotransmitters were conserved throughout evolution. PMID- 7849577 TI - Effect of anions on the uptake and release of gamma-aminobutyric acid by isolated synaptic plasma membranes. AB - The influence of various anions on the uptake and release of gamma-aminobutyric acid (GABA) was investigated in synaptic plasma membrane (SPM) vesicles isolated from sheep brain cortex. We observed that substitution of Cl- by various anions greatly reduces [3H]GABA accumulation by SPM vesicles. The magnitude of the effect is about 30, 85, 95 and 100% when Cl- is replaced by Br-, NO3-, CH3COO- and SO4(2-), respectively. However, no effect was observed when these anions were added together with Cl-, which indicates that they do not inhibit the [3H]GABA uptake mechanism by SPM vesicles. On the other hand, we observed that [3H]GABA release, either by homoexchange or induced by K+ depolarization, is maximal in the presence of Cl- or Br-, whereas the other anions (NO3-, CH3COO- and SO4(2-)) caused a 50% reduction in the two processes of [3H]GABA release. We also observed that the basal release of [3H]GABA is not greatly altered by Br- and NO3-, but it is greatly enhanced by CH3COO- and SO4(2-) in substitution of Cl-. In contrast to these alterations in [3H]GABA movements, the membrane potential is not significantly affected by any of the anions tested. The results confirm the idea that GABA uptake implies Cl- co-transport and they demonstrate that the maximal release of [3H]GABA through its carrier (homoexchange or K+ depolarization induced release) requires the presence of small anions (Cl- or Br-) at the opposite side of the membrane from where the neurotransmitter is translocated. Furthermore, it appears that CH3COO- and SO4(2-) uncouple the system by inducing basal release, whereas it remains coupled in the presence of Cl-, Br- and NO3-. PMID- 7849576 TI - Inhibition of type A monoamine oxidase by 2(N)-methyl-6,7-dihydroxyisoquinolinium ions. AB - In the human brain, monoamine-derived 6,7-dihydroxy-1,2,3,4 tetrahydroisoquinolines and 1,2,3,4-tetrahydroisoquinolines have been identified and their enzymatic methylation into N(2)-methylisoquinolines has been also confirmed. N-methylated 6,7-dihydroxyisoquinolines were found to be oxidized into 6,7-dihydroxy-N-methylisoquinolinium ions. The effects of the isoquinolinium ions on type A and B monoamine oxidase were examined, using enzyme samples isolated from human brain synaptosomal mitochondria. 1,2-Dimethyl-6,7 dihydroxyisoquinolinium ion (N-methylsalsolinium ion) and 2-methyl-6,7 dihydroxyisoquinolinium ion (N-methylnorsalsolinium ion), were found to be potent inhibitors of type A monoamine oxidase. The inhibition was competitive to the substrate, while the isoquinolinium ions were much weaker inhibitors of type B and the inhibition was non-competitive to the substrate. Isoquinolinium ions without catechol structure, N(2)-methylisoquinolinium ion and 1,2 dimethylisoquinolinium ion also inhibited both type A and B monoamine oxidase. 1,2-Dimethylisoquinolinium was the most potent inhibitor among examined isoquinolines, followed by the N-methylsalsolinium ion. The activity-structure relationship of the isoquinolines with and without catechol structure was examined in terms of potency and selectivity of inhibition to type A and B monoamine oxidase. Catechol structure was found to increase the selectivity of inhibition to type A, as shown by comparison of N-methylsalsolinium ion with 1,2 dimethylisoquinolinium ion. N-Methylsalsolinium ion inhibited type A MAO more selectively than 1,2-dimethylisoquinolinium ion, which inhibited type A and type B with almost the sam values of the inhibitor constant.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7849578 TI - Activities of 3':5' cyclic nucleotide phosphodiesterases in the superior cervical ganglion of rat: characterization, compartmentalization and observations in young and old animals. AB - We investigated the presence and features of "low Km" 3'-5' cyclic nucleotide phosphodiesterase activity in the homogenates and extracts of rat superior cervical ganglion. The DEAE chromatographic elution profile of a Triton X-100 extract showed two peaks of cAMP phosphodiesterase activity eluted at 280 and 600 mM sodium acetate and two peaks of cGMP phosphodiesterase activity eluted at 300 and at 500 mM sodium acetate. The activity was poorly stimulated by calcium calmodulin and neither stimulated or inhibited by cGMP. Both cGMP PDE peaks were inhibited by zaprinast, with IC50's of 1.4 microM and 0.28 microM: their Km values were 4.4 and 3.8 microM, respectively. These features, together with cGMP binding activity, indicate that both enzymes belong to the phosphodiesterase V family. The Km values of the first and second cAMP phosphodiesterase peaks were 1.7 and 3.8 microM. Although both peaks displayed a cAMP specific hydrolysis, only the second peak was inhibited by RO 20-1724, with an IC50 of 8 microM. Preganglionic denervation indicated that the bulk of phosphodiesterase activity is localized in ganglion cells. In order to investigate possible effects of aging on the ganglionic function, phosphodiesterase activity was assayed in the ganglia of young (3 months) and old (25 months) male Fisher rats. The chromatographic profiles and kinetic features revealed no significant differences between young and old rats. PMID- 7849579 TI - Max Perutz's achievements: how did he do it? PMID- 7849580 TI - Polar zippers: their role in human disease. AB - Ascaris hemoglobin consists of 8 subunits, each of which contains a C-terminal peptide with the sequence Glu-Glu-Lys-His repeated 4 times. When plotted on a beta-strand, this sequence leads to alternate lysines and glutamates on one side of the strand, and alternate glutamates and histidines on the other side, suggestive of a polar zipper that links the subunits together. A computer search of the protein database showed that the same or similar sequences also occur in other proteins. Some contain long repeats of Asp-Arg or Glu-Arg, among them the small nuclear ribonucleo-U1 70K protein, which is an autoantigen in systemic lupus erythematosis. These repeats appear to constitute the dominant epitopes in the autoimmune reaction. Single chains with Asp-Arg repeats may form alpha helices in which alternate positively charged ridges and negatively charged grooves compensate each other. Several separate chains with Asp-Arg repeats could compensate each other's charges optimally by zipping together to beta-sheets. Several homeodomains of Drosophila, as well as the human transcription factor SP1, contain repeats of glutamines. Molecular modeling, circular dichroism, and electron and X-ray diffraction studies of a synthetic poly(L-glutamine) showed that it forms beta-sheets held together by hydrogen bonds between the main-chain and side-chain amides. Published data suggest that the function of these glutamine repeats consists of joining essential transcription factors bound to distant segments of DNA.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7849581 TI - Control of nucleation of protein crystals. AB - Control of nucleation may be needed to obtain a reliable supply of large protein crystals, when standard techniques give many small or twinned crystals. Heterogeneous nucleation may be controlled by the use of fine filters, with the elimination of airborne contaminants by working under paraffin oil. The area of contact with the supporting vessel also has an important effect. A heterogenous nucleant for lysozyme (identified earlier) has been shown to be effective for carboxypeptidase G2. Control of homogeneous nucleation (previously demonstrated by dilutions of a nucleating sample after various times of incubation) may also be achieved by incubating a sample at 1 temperature, where nucleation can occur, and changing the temperature to conditions where there is growth but no nucleation. PMID- 7849582 TI - The three-dimensional structures of mutants of porphobilinogen deaminase: toward an understanding of the structural basis of acute intermittent porphyria. AB - Mutations in the human gene for the enzyme porphobilinogen deaminase give rise to an inherited disease of heme biosynthesis, acute intermittent porphyria. Knowledge of the 3-dimensional structure of human porphobilinogen deaminase, based on the structure of the bacterial enzyme, allows correlation of structure with gene organization and leads to an understanding of the relationship between mutations in the gene, structural and functional changes of the enzyme, and the symptoms of the disease. Most mutations occur in exons 10 and 12, often changing amino acids in the active site. Several of these are shown to be involved in binding the primer or substrate; none modifies Asp 84, which is essential for catalytic activity. PMID- 7849583 TI - Role and mechanism of the maturation cleavage of VP0 in poliovirus assembly: structure of the empty capsid assembly intermediate at 2.9 A resolution. AB - The crystal structure of the P1/Mahoney poliovirus empty capsid has been determined at 2.9 A resolution. The empty capsids differ from mature virions in that they lack the viral RNA and have yet to undergo a stabilizing maturation cleavage of VP0 to yield the mature capsid proteins VP4 and VP2. The outer surface and the bulk of the protein shell are very similar to those of the mature virion. The major differences between the 2 structures are focused in a network formed by the N-terminal extensions of the capsid proteins on the inner surface of the shell. In the empty capsids, the entire N-terminal extension of VP1, as well as portions corresponding to VP4 and the N-terminal extension of VP2, are disordered, and many stabilizing interactions that are present in the mature virion are missing. In the empty capsid, the VP0 scissile bond is located some 20 A away from the positions in the mature virion of the termini generated by VP0 cleavage. The scissile bond is located on the rim of a trefoil-shaped depression in the inner surface of the shell that is highly reminiscent of an RNA binding site in bean pod mottle virus. The structure suggests plausible (and ultimately testable) models for the initiation of encapsidation, for the RNA-dependent autocatalytic cleavage of VP0, and for the role of the cleavage in establishing the ordered N-terminal network and in generating stable virions. PMID- 7849584 TI - Protein crystallography and infectious diseases. AB - The current rapid growth in the number of known 3-dimensional protein structures is producing a database of structures that is increasingly useful as a starting point for the development of new medically relevant molecules such as drugs, therapeutic proteins, and vaccines. This development is beautifully illustrated in the recent book, Protein structure: New approaches to disease and therapy (Perutz, 1992). There is a great and growing promise for the design of molecules for the treatment or prevention of a wide variety of diseases, an endeavor made possible by the insights derived from the structure and function of crucial proteins from pathogenic organisms and from man. We present here 2 illustrations of structure-based drug design. The first is the prospect of developing antitrypanosomal drugs based on crystallographic, ligand-binding, and molecular modeling studies of glycolytic glycosomal enzymes from Trypanosomatidae. These unicellular organisms are responsible for several tropical diseases, including African and American trypanosomiases, as well as various forms of leishmaniasis. Because the target enzymes are also present in the human host, this project is a pioneering study in selective design. The second illustrative case is the prospect of designing anti-cholera drugs based on detailed analysis of the structure of cholera toxin and the closely related Escherichia coli heat-labile enterotoxin. Such potential drugs can be targeted either at inhibiting the toxin's receptor binding site or at blocking the toxin's intracellular catalytic activity. Study of the Vibrio cholerae and E. coli toxins serves at the same time as an example of a general approach to structure-based vaccine design. These toxins exhibit a remarkable ability to stimulate the mucosal immune system, and early results have suggested that this property can be maintained by engineered fusion proteins based on the native toxin structure. The challenge is thus to incorporate selected epitopes from foreign pathogens into the native framework of the toxin such that crucial features of both the epitope and the toxin are maintained. That is, the modified toxin must continue to evoke a strong mucosal immune response, and this response must be directed against an epitope conformation characteristic of the original pathogen. PMID- 7849585 TI - Influenza virus neuraminidase: structure, antibodies, and inhibitors. AB - The determination of the 3-dimensional structure of the influenza virus neuraminidase in 1983 has served as a platform for understanding interactions between antibodies and protein antigens, for investigating antigenic variation in influenza viruses, and for devising new inhibitors of the enzyme. That work is reviewed here, together with more recent developments that have resulted in one of the inhibitors entering clinical trials as an anti-influenza virus drug. PMID- 7849586 TI - Comparison of the intermediate complexes of human growth hormone bound to the human growth hormone and prolactin receptors. AB - The crystal structures of complexes of human growth hormone (hGH) with the growth hormone and prolactin receptors (hGHR and hPRLR, respectively), together with the mutational data available for these systems, suggest that an extraordinary combination of conformational adaptability, together with finely tuned specificity, governs the molecular recognition processes operative in these systems. On the one hand, in the active 1:2 ligand-receptor complexes, 2 copies of the same receptor use the identical set of binding determinants to recognize topographically different surfaces on the hormone. On the other hand, comparing the 1:1 hGH-hGHR and hGH-hPRLR complexes, 2 distinct receptors use this same set of binding determinants to interact with the identical binding site on the ligand, even though few residues among the binding determinants are conserved. The structural evidence demonstrates that this versatility is accomplished by local conformational flexibility of the binding loops, allowing adaptation to different binding environments, together with rigid-body movements of the receptor domains, necessary for the creation of specific interactions with the same binding site. PMID- 7849587 TI - Quantification of tertiary structural conservation despite primary sequence drift in the globin fold. AB - The globin family of protein structures was the first for which it was recognized that tertiary structure can be highly conserved even when primary sequences have diverged to a virtually undetectable level of similarity. This principle of structural inertia in molecular evolution is now evident for many other protein families. We have performed a systematic comparison of the sequences and structures of 6 representative hemoglobin subunits as diverse in origin as plants, clams, and humans. Our analysis is based on a 97-residue helical core in common to all 6 structures. Amino acid sequence identities range from 12.4% to 42.3% in pairwise comparisons, and, despite these variations, the maximal RMS deviation in alpha-carbon positions is 3.02 A. Overall, sequence similarity and structural deviation are significantly anticorrelated, with a correlation coefficient of -0.71, but for a set of structures having under 20% pairwise identity, this anticorrelation falls to -0.38, which emphasizes the weak connection between a specific sequence and the tertiary fold. There is substantial variability in structure outside the helical core, and functional characteristics of these globins also differ appreciably. Nevertheless, despite variations in detail that the sequence dissimilarities and functional differences imply, the core structures of these globins remain remarkably preserved. PMID- 7849588 TI - Viral cell recognition and entry. AB - Rhinovirus infection is initiated by the recognition of a specific cell-surface receptor. The major group of rhinovirus serotypes attach to intercellular adhesion molecule-1 (ICAM-1). The attachment process initiates a series of conformational changes resulting in the loss of genomic RNA from the virion. X ray crystallography and sequence comparisons suggested that a deep crevice or canyon is the site on the virus recognized by the cellular receptor molecule. This has now been verified by electron microscopy of human rhinovirus 14 (HRV14) and HRV16 complexed with a soluble component of ICAM-1. A hydrophobic pocket underneath the canyon is the site of binding of various hydrophobic drug compounds that can inhibit attachment and uncoating. This pocket is also associated with an unidentified, possibly cellular in origin, "pocket factor." The pocket factor binding site overlaps the binding site of the receptor. It is suggested that competition between the pocket factor and receptor regulates the conformational changes required for the initiation of the entry of the genomic RNA into the cell. PMID- 7849589 TI - Electrostatic effects in the control of glycogen phosphorylase by phosphorylation. AB - Electrostatic effects are important in the initial activation mechanism of glycogen phosphorylase by phosphorylation. Analysis of the electrostatic surface potential of glycogen phosphorylase with the program GRASP shows that in the unphosphorylated state, the N-terminal 20 residues, which include a number of basic amino acids, are located close to a position on the surface of the molecule that is highly acidic. Upon phosphorylation by phosphorylase kinase at Ser 14, the N-terminal residues change their position and conformation so that the Ser-P is directed away from the acidic patch and to an intersubunit site where 2 arginines bind the phosphate. This recognition site is created through tertiary and quaternary structural changes that accompany the activation mechanism. PMID- 7849590 TI - The beginnings of structural biology. Recollections, special section in honor of Max Perutz. PMID- 7849591 TI - Proteolytic enzymes past and present: the second golden era. Recollections, special section in honor of Max Perutz. PMID- 7849592 TI - Sequence determinants of the capping box, a stabilizing motif at the N-termini of alpha-helices. AB - The capping box, a recurrent hydrogen bonded motif at the N-termini of alpha helices, caps 2 of the initial 4 backbone amide hydrogen donors of the helix (Harper ET, Rose GD, 1993, Biochemistry 32:7605-7609). In detail, the side chain of the first helical residue forms a hydrogen bond with the backbone of the fourth helical residue and, reciprocally, the side chain of the fourth residue forms a hydrogen bond with the backbone of the first residue. We now enlarge the earlier definition of this motif to include an accompanying hydrophobic interaction between residues that bracket the capping box sequence on either side. The expanded box motif--in which 2 hydrogen bonds and a hydrophobic interaction are localized within 6 consecutive residues--resembles a glycine based capping motif found at helix C-termini (Aurora R, Srinivasan R, Rose GD, 1994, Science 264:1126-1130). PMID- 7849593 TI - Probing the catalytic roles of n2-site glutamate residues in Escherichia coli glutamine synthetase by mutagenesis. AB - The contribution of metal ion ligand type and charge to catalysis and regulation at the lower affinity metal ion site (n2 site) of Escherichia coli glutamine synthetase (GS) was tested by mutagenesis and kinetic analysis. The 2 glutamate residues at the n2 site, E129 and E357, were changed to E129D, E129H, E357H, E357Q, and E357D, representing conservative and nonconservative alterations. Unadenylylated and fully adenylylated enzyme forms were studied. The Mn(2+)-KD values, UV-cis and fluorescence emission properties were similar for all mutants versus WTGS, except E129H. For kinetic determinations with both Mn2+ and Mg2+, nonconservative mutants (E357H, E129H, E357Q) showed lower biosynthetic activities than conservative mutants (E129D, E357D). Relative to WTGS, all the unadenylylated Mn(2+)-activated enzymes showed reduced kcat/Km values for ATP (> 7-fold) and for glutamate (> 10-fold). Of the unadenylylated Mg(2+)-activated enzymes, only E129D showed kinetic parameters competitive with WTGS, and adenylylated E129D was a 20-fold better catalyst than WTGS. We propose the n2 site metal ion activates ADP for departure in the phosphorylation of glutamate by ATP to generate gamma-glutamyl phosphate. Alteration of the charge density at this metal ion alters the transition-state energy for phosphoryl group transfer and may affect ATP binding and/or ADP release. Thus, the steady-state kinetic data suggest that modifying the charge density increases the transition-state energies for chemical steps. Importantly, the data demonstrate that each ligand position has a specialized spatial environment and the charge of the ligand modulates the catalytic steps occurring at the metal ion. The data are discussed in the context of the known X-ray structures of GS. PMID- 7849594 TI - Structure-function relationship in the globular type III antifreeze protein: identification of a cluster of surface residues required for binding to ice. AB - Antifreeze proteins (AFPs) depress the freezing point of aqueous solutions by binding to and inhibiting the growth of ice. Whereas the ice-binding surface of some fish AFPs is suggested by their linear, repetitive, hydrogen bonding motifs, the 66-amino-acid-long Type III AFP has a compact, globular fold without any obvious periodicity. In the structure, 9 beta-strands are paired to form 2 triple stranded antiparallel sheets and 1 double-stranded antiparallel sheet, with the 2 triple sheets arranged as an orthogonal beta-sandwich (Sonnichsen FD, Sykes BD, Chao H, Davies PL, 1993, Science 259:1154-1157). Based on its structure and an alignment of Type III AFP isoform sequences, a cluster of conserved, polar, surface-accessible amino acids (N14, T18, Q44, and N46) was noted on and around the triple-stranded sheet near the C-terminus. At 3 of these sites, mutations that switched amide and hydroxyl groups caused a large decrease in antifreeze activity, but amide to carboxylic acid changes produced AFPs that were fully active at pH 3 and pH 6. This is consistent with the observation that Type III AFP is optimally active from pH 2 to pH 11. At a concentration of 1 mg/mL, Q44T, N14S, and T18N had 50%, 25%, and 10% of the activity of wild-type antifreeze, respectively. The effects of the mutations were cumulative, such that the double mutant N14S/Q44T had 10% of the wild-type activity and the triple mutant N14S/T18N/Q44T had no activity. All mutants with reduced activity were shown to be correctly folded by NMR spectroscopy. Moreover, a complete characterization of the triple mutant by 2-dimensional NMR spectroscopy indicated that the individual and combined mutations did not significantly alter the structure of these proteins. These results suggest that the C-terminal beta-sheet of Type III AFP is primarily responsible for antifreeze activity, and they identify N14, T18, and Q44 as key residues for the AFP-ice interaction. PMID- 7849595 TI - Identification of amino acid residues involved in the binding of Huperzine A to cholinesterases. AB - Huperzine A, a potential agent for therapy in Alzheimer's disease and for prophylaxis of organophosphate toxicity, has recently been characterized as a reversible inhibitor of cholinesterases. To examine the specificity of this novel compound in more detail, we have examined the interaction of the 2 stereoisomers of Huperzine A with cholinesterases and site-specific mutants that detail the involvement of specific amino acid residues. Inhibition of fetal bovine serum acetylcholinesterase by (-)-Huperzine A was 35-fold more potent than (+) Huperzine A, with KI values of 6.2 nM and 210 nM, respectively. In addition, (-) Huperzine A was 88-fold more potent in inhibiting Torpedo acetylcholinesterase than (+)-Huperzine A, with KI values of 0.25 microM and 22 microM, respectively. Far larger KI values that did not differ between the 2 stereoisomers were observed with horse and human serum butyrylcholinesterases. Mammalian acetylcholinesterase, Torpedo acetylcholinesterase, and mammalian butyrylcholinesterase can be distinguished by the amino acid Tyr, Phe, or Ala in the 330 position, respectively. Studies with mouse acetylcholinesterase mutants, Tyr 337 (330) Phe and Tyr 337 (330) Ala yielded a difference in reactivity that closely mimicked the native enzymes. In contrast, mutation of the conserved Glu 199 residue to Gln in Torpedo acetylcholinesterase produced only a 3-fold increase in KI value for the binding of Huperzine A.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7849596 TI - Structural studies of the engrailed homeodomain. AB - The structure of the Drosophila engrailed homeodomain has been solved by molecular replacement and refined to an R-factor of 19.7% at a resolution of 2.1 A. This structure offers a high-resolution view of an important family of DNA binding proteins and allows comparison to the structure of the same protein bound to DNA. The most significant difference between the current structure and that of the 2.8-A engrailed-DNA complex is the close packing of an extended strand against the rest of the protein in the unbound protein. Structural features of the protein not previously noted include a "herringbone" packing of 4 aromatic residues in the core of the protein and an extensive network of salt bridges that covers much of the helix 1-helix 2 surface. Other features that may play a role in stabilizing the native state include the interaction of buried carbonyl oxygen atoms with the edge of Phe 49 and a bias toward statistically preferred side chain dihedral angles. There is substantial disorder at both ends of the 61 amino acid protein. A 51-amino acid variant of engrailed (residues 6-56) was synthesized and shown by CD and thermal denaturation studies to be structurally and thermodynamically similar to the full-length domain. PMID- 7849597 TI - Solution structure of the DNA-binding domain of the heat shock transcription factor determined by multidimensional heteronuclear magnetic resonance spectroscopy. AB - The solution structure of the 92-residue DNA-binding domain of the heat shock transcription factor from Kluyveromyces lactis has been determined using multidimensional NMR methods. Three-dimensional (3D) triple resonance, 1H-13C-13C 1H total correlation spectroscopy, and 15N-separated total correlation spectroscopy-heteronuclear multiple quantum correlation experiments were used along with various 2D spectra to make nearly complete assignments for the backbone and side-chain 1H, 15N, and 13C resonances. Five-hundred eighty-three NOE constraints identified in 3D 13C- and 15N-separated NOE spectroscopy (NOESY) heteronuclear multiple quantum correlation spectra and a 4-dimensional 13C/13C edited NOESY spectrum, along with 35 phi, 9 chi 1, and 30 hydrogen bond constraints, were used to calculate 30 structures by hybrid distance geometry/stimulated annealing protocol, of which 24 were used for structural comparison. The calculations revealed that a 3-helix bundle packs against a small 4-stranded antiparallel beta-sheet. The backbone RMS deviation (RMSD) for the family of structures was 1.03 +/- 0.19 A with respect to the average structure. The topology is analogous to that of the C-terminal domain of the catabolite gene activator protein and appears to be in the helix-turn-helix family of DNA-binding proteins. The overall fold determined by the NMR data is consistent with recent crystallographic work on this domain (Harrison CJ, Bohm AA, Nelson HCM, 1994, Science 263:224) as evidenced by RMSD between backbone atoms in the NMR and X-ray structures of 1.77 +/- 0.20 A. Several differences were identified some of which may be due to protein-protein interactions in the crystal. PMID- 7849598 TI - A common structural motif incorporating a cystine knot and a triple-stranded beta sheet in toxic and inhibitory polypeptides. AB - A common structural motif consisting of a cystine knot and a small triple stranded beta-sheet has been defined from comparison of the 3-dimensional structures of the polypeptides omega-conotoxin GVIA (Conus geographus), kalata BI (Oldenlandia affinis DC), and CMTI-I (Curcurbita maxima). These 3 polypeptides have diverse biological activities and negligible amino acid sequence identity, but each contains 3 disulfide bonds that give rise to a cystine knot. This knot consists of a ring formed by the first 2 bonds (1-4 and 2-5) and the intervening polypeptide backbone, through which the third disulfide (3-6) passes. The other component of this motif is a triple-stranded, anti-parallel beta-sheet containing a minimum of 10 residues, XXC2, XC5X, XXC6X (where the numbers on the half cysteine residues refer to their positions in the disulfide pattern). The presence in these polypeptides of both the cysteine knot and antiparallel beta sheet suggests that both structural features are required for the stability of the motif. This structural motif is also present in other protease inhibitors and a spider toxin. It appears to be one of the smallest stable globular domains found in proteins and is commonly used in toxins and inhibitors that act by blocking the function of larger protein receptors such as ion channels or proteases. PMID- 7849599 TI - Three-dimensional model and quaternary structure of the human eye lens protein gamma S-crystallin based on beta- and gamma-crystallin X-ray coordinates and ultracentrifugation. AB - A 3-dimensional model of the human eye lens protein gamma S-crystallin has been constructed using comparative modeling approaches encoded in the program COMPOSER on the basis of the 3-dimensional structure of gamma-crystallin and beta crystallin. The model is biased toward the monomeric gamma B-crystallin, which is more similar in sequence. Bovine gamma S-crystallin was shown to be monomeric by analytical ultracentrifugation without any tendency to form assemblies up to concentrations in the millimolar range. The connecting peptide between domains was therefore built assuming an intramolecular association as in the monomeric gamma-crystallins. Because the linker has 1 extra residue compared with gamma B and beta B2, the conformation of the connecting peptide was constructed by using a fragment from a protein database. gamma S-crystallin differs from gamma B crystallin mainly in the interface region between domains. The charged residues are generally paired, although in a different way from both beta- and gamma crystallins, and may contribute to the different roles of these proteins in the lens. PMID- 7849600 TI - Discovering structural correlations in alpha-helices. AB - We have developed a new representation for structural and functional motifs in protein sequences based on correlations between pairs of amino acids and applied it to alpha-helical and beta-sheet sequences. Existing probabilistic methods for representing and analyzing protein sequences have traditionally assumed conditional independence of evidence. In other words, amino acids are assumed to have no effect on each other. However, analyses of protein structures have repeatedly demonstrated the importance of interactions between amino acids in conferring both structure and function. Using Bayesian networks, we are able to model the relationships between amino acids at distinct positions in a protein sequence in addition to the amino acid distributions at each position. We have also developed an automated program for discovering sequence correlations using standard statistical tests and validation techniques. In this paper, we test this program on sequences from secondary structure motifs, namely alpha-helices and beta-sheets. In each case, the correlations our program discovers correspond well with known physical and chemical interactions between amino acids in structures. Furthermore, we show that, using different chemical alphabets for the amino acids, we discover structural relationships based on the same chemical principle used in constructing the alphabet. This new representation of 3-dimensional features in protein motifs, such as those arising from structural or functional constraints on the sequence, can be used to improve sequence analysis tools including pattern analysis and database search. PMID- 7849601 TI - Multiple protein structure alignment. AB - A method was developed to compare protein structures and to combine them into a multiple structure consensus. Previous methods of multiple structure comparison have only concatenated pairwise alignments or produced a consensus structure by averaging coordinate sets. The current method is a fusion of the fast structure comparison program SSAP and the multiple sequence alignment program MULTAL. As in MULTAL, structures are progressively combined, producing intermediate consensus structures that are compared directly to each other and all remaining single structures. This leads to a hierarchic "condensation," continually evaluated in the light of the emerging conserved core regions. Following the SSAP approach, all interatomic vectors were retained with well-conserved regions distinguished by coherent vector bundles (the structural equivalent of a conserved sequence position). Each bundle of vectors is summarized by a resultant, whereas vector coherence is captured in an error term, which is the only distinction between conserved and variable positions. Resultant vectors are used directly in the comparison, which is weighted by their error values, giving greater importance to the matching of conserved positions. The resultant vectors and their errors can also be used directly in molecular modeling. Applications of the method were assessed by the quality of the resulting sequence alignments, phylogenetic tree construction, and databank scanning with the consensus. Visual assessment of the structural superpositions and consensus structure for various well-characterized families confirmed that the consensus had identified a reasonable core. PMID- 7849602 TI - A quantitative methodology for the de novo design of proteins. AB - We have developed a general quantitative methodology for designing proteins de novo, which automatically produces sequences for any given plausible protein structure. The method incorporates statistical information, a theoretical description of protein structure, and motifs described in the literature. A model system embodying a portion of the quantitative methodology has been used to design many protein sequences for the phage 434 Cro and fibronectin type III domain folds, as well as several other structures. Residue sequences selected by this prototype share no significant identity with any natural protein. Nonetheless, 3-dimensional models of the designed sequences appear generally plausible. When examined using secondary structure prediction methods and profile analysis, the designed sequences generally score considerably better than the natural ones. The designed sequences are also in reasonable agreement with a sequence template. This quantitative methodology is likely to be capable of successfully designing new proteins and yielding fundamental insights about the determinants of protein structure. PMID- 7849603 TI - Malate dehydrogenase: a model for structure, evolution, and catalysis. AB - Malate dehydrogenases are widely distributed and alignment of the amino acid sequences show that the enzyme has diverged into 2 main phylogenetic groups. Multiple amino acid sequence alignments of malate dehydrogenases also show that there is a low degree of primary structural similarity, apart from in several positions crucial for nucleotide binding, catalysis, and the subunit interface. The 3-dimensional structures of several malate dehydrogenases are similar, despite their low amino acid sequence identity. The coenzyme specificity of malate dehydrogenase may be modulated by substitution of a single residue, as can the substrate specificity. The mechanism of catalysis of malate dehydrogenase is similar to that of lactate dehydrogenase, an enzyme with which it shares a similar 3-dimensional structure. Substitution of a single amino acid residue of a lactate dehydrogenase changes the enzyme specificity to that of a malate dehydrogenase, but a similar substitution in a malate dehydrogenase resulted in relaxation of the high degree of specificity for oxaloacetate. Knowledge of the 3 dimensional structures of malate and lactate dehydrogenases allows the redesign of enzymes by rational rather than random mutation and may have important commercial implications. PMID- 7849604 TI - On the evolution of alternate core packing in eightfold beta/alpha-barrels. AB - Two sequence-related subfamilies of flavin-binding beta/alpha-barrels have been identified (the type I and type II proteins) that differ in the nature of residue packing in the core of the barrel domain. Similar observed differences in the packing of internal amino acid side chains in beta/alpha-barrels have previously been used to argue that these domains have evolved convergently toward a stable structural framework. Using structural alignments of flavin-binding barrel proteins, we demonstrate that simple genetic alterations may be responsible for switching the nature of side-chain packing observed in beta/alpha-barrels. The implication is that the 2 structural classes of beta/alpha-barrel cores can arise divergently from an ancestral barrel framework and that convergent evolution to a stable fold need not be invoked to account for the emergence of 2 classes of beta/alpha-barrel core. PMID- 7849605 TI - Characterization of aminopeptidase N from Torpedo marmorata kidney. AB - A major antigen of the brush border membrane of Torpedo marmorata kidney was identified and purified by immunoprecipitation. The sequence of its 18 N terminal amino acids was determined and found to be very similar to that of mammalian amino-peptidase N (EC 3.4.11.2). Indeed aminopeptidase N activity was efficiently immunoprecipitated by monoclonal antibody 180K1. The purified antigen gives a broad band at 180 kDa after SDS-gel electrophoresis, which, after treatment by endoglycosidase F, is converted to a thinner band at 140 kDa. This antigen is therefore heavily glycosylated. Depending on solubilization conditions, both the antigen and peptidase activity were recovered either as a broad peak with a sedimentation coefficient of 18S (2% CHAPS) or as a single peak of 7.8S (1% CHAPS plus 0.2% C12E9), showing that Torpedo aminopeptidase N behaves as an oligomer stabilized by hydrophobic interactions, easily converted into a 160 kDa monomer. The antigen is highly concentrated in the apical membrane of proximal tubule epithelial cells (600 gold particles/microns2 of brush border membrane) whereas no labeling could be detected in other cell types or in other membranes of the same cells (basolateral membranes, vacuoles or vesicles). Monoclonal antibodies prepared here will be useful tools for further functional and structural studies of Torpedo kidney aminopeptidase N. PMID- 7849607 TI - Freeze-fracture and thin section study of the rough ER-Golgi interface in the pancreatic acinar cell. Resemblance between the intramembranal architecture of the outermost Golgi cisterna and the post-rough ER vesicular and tubular elements. AB - Post-ER membranous structures are clearly observed in pancreases fixed with aldehydes and subsequently with reduced osmium. Close to the transitional rough ER, clusters of vesicles of approximately 56 nm diameter are consistently present. In some cells, tortuous tubules appear enmeshed by the approximately 56 nm vesicles and by irregular, vesicular formations. In freeze-fracture replicas, the membranes of the bulges and tubules that protrude from the transitional rough ER differ from those of the donor compartment. These protrusions are herein designated as the budding chamber of the transitional rough ER. Quantitative and qualitative observations performed previously and in the present study show that the P and E freeze-fracture faces of the outermost Golgi cisternal membrane possess patterns of texture that are unique among membranes. The P-face exhibits a very high density of intramembranous particles of dimensions among the smallest yet described; E-faces show rugosities and an unusually high density of intramembranous particles of normal size. The membranes of the budding chamber, the putative transport vesicles of approximately 56 nm diameter, the sinuous tubules and the vesicles of irregular size and shape exhibit P and E fracture faces with textures indistinguishable from those of the corresponding P and E faces of the outermost Golgi cisterna. PMID- 7849606 TI - Effects of suramin, a polyanionic drug inducing lysosomal storage disorders on tooth germs in vitro. AB - Suramin, a potent inhibitor of lysosomal enzymes, is commonly employed as a tool for inducing experimental mucopolysaccharidosis and lipidosis. The effects of the drug on embryonic mouse molars were analysed. Presecretory ameloblasts and odontoblasts were loaded with lysosome-like vacuoles. Staining with MC22-33F, an antibody to choline phospholipids and sphingomyelin, was completely reversed in the suramin-treated germs, in that it stained only presecretory ameloblasts (versus odontoblasts and some pulpal cells in the control group), according to a developmentally regulated pattern. The suramin-induced cytoplasmic changes were reminiscent of the features of mucopolysaccharidoses and lipidoses. The basement membrane, separating the enamel organ from the dental papilla, displayed suramin induced patches, and in predentin collagen fibrillogenesis was found to be disturbed. Furthermore, autoradiography was employed to reveal uptake and distribution of [3H] suramin in the cells and predentin. Finally, a suramin induced disturbance of the metabolism of sulphated macromolecules was found. The results imply that suramin effects in vitro on tooth germs can be used as a useful experimental model with to study both the action of the drug as well as cell and extracellular matrix perturbations in a mucopolysaccharidosis-like condition. PMID- 7849608 TI - Cellular localization of polyamines: cytochemical and ultrastructural methods providing new clues to polyamine function in ram spermatozoa. AB - Polyamine binding sites have been localized in ram spermatozoa using biochemical and cytochemical tools. Incubating the cells with 14C-spermine and determining its distribution after sonication and differential centrifugation, revealed that 60% of the radioactive spermine was localized in the head, 21.5% in the tail and about 9% in the plasma membrane. A polyamine specific cytochemical staining by the formaldehyde-fluorescamine method, revealed that most of the polyamines were localized in the midpiece, where the cell mitochondria are located, and in the acrosome region. Two additional studies used electron microscopy, employing polycationic colloidal gold and spermine-ferritin as cytochemical markers. The most sensitive and specific method was the staining of the cells with ferritin spermine whose synthesis is described in this study. The outer membrane was the preferential site for spermine binding which was densely distributed in a highly orderly pattern. There was a sparse distribution of spermine binding sites on the plasma membrane surrounding the acrosome and none on the post acrosomal region. The role of spermine in the acrosome reaction and Ca2+ fluxes in sperm cells is discussed. PMID- 7849609 TI - Detection and cartography of the fluorinated antimalarial drug mefloquine in normal and Plasmodium falciparum infected red blood cells by scanning ion microscopy and mass spectrometry. AB - Due to the presence of fluorine atoms in its molecule, the antimalarial drug mefloquine (MQ) can be easily detected in normal and Plasmodium falciparum infected red blood cells (RBC) by scanning ion microscopy and mass spectrometry. The P falciparum infected RBC exhibited intense distribution of MQ inside the parasite. The main compartments of the parasite which accumulate the drug were the food vacuole and the cytoplasm. The correlation between fluorine (19F-) and phosphorus (31P-) as well as probes for the DNA synthesis (BrdU and IdU) emissions shows that the parasite nucleus is also accessible to the drug. This study demonstrates that SIMS technique on smear preparations is an efficient approach for the direct detection and cartography of fluorinated antimalarial drugs in normal and P falciparum infected RBC, without radioactive labelling. PMID- 7849610 TI - The cytoskeleton of mammalian spermatozoa. AB - The mammalian spermatozoa are endowed with a unique cytoskeleton which consists both of ubiquitous and specific proteins, some of them arising from gene haploid transcription. In the head, a dense perinuclear layer is made of basic proteins (calicin, cylicin, etc) associated with calmodulin and actin remnants. In the flagellum, the axonemal microtubules are mainly composed of glutamylated tubulin isoforms; the periaxonemal outer dense fibers and fibrous sheath are considered as related cytoskeletal structures on the basis of some common polypeptides. PMID- 7849611 TI - Generation of nitric oxide inhibits formation of superoxide in macrophages during activation. AB - We have studied the production of nitric oxide (NO) and superoxide by murine peritoneal macrophages during activation. The production of NO was induced by activation of cells with recombinant interferon-gamma (rIFN-gamma) and lipopolysaccharide (LPS). Phorbol 12-myristate 13-acetate (PMA)-induced formation of superoxide also increased during activation. However, NO released by the activated macrophages exerted the inhibitory effect on the superoxide formation in the same cells. This fact is supported by the increased production of superoxide when the cells were treated with NG-monomethyl-L-arginine (NGMMA) in addition to stimulation with rIFN-gamma and LPS. The production of superoxide was also inhibited by treatment with sodium nitroprusside (SPN), which spontaneously released nitric oxide in vitro, and at the same time there was increased adenosine diphosphate (ADP)-ribosylation of 37 kDa proteins of the cytoplasm. The 3-aminobenzamide (3-AB) treatment, which decreased ADP-ribosylation, partially reversed SNP-induced inhibition of superoxide generation in macrophages. The above data provide evidence that NO decreases superoxide formation possibly via ADP-ribosylation. PMID- 7849612 TI - Influence of triiodothyronine and insulin on the synthesis of glycerolipids in rat hepatocytes. AB - The short-term effect of T3 and insulin on glycerolipid synthesis from [1-14C] acetate was studied in hepatocytes from both euthyroid and hypothyroid rats. In these conditions fatty acid and cholesterol synthesis were also investigated. Within 4 h after T3 addition to euthyroid cells, a small but significative stimulation of the label incorporation into total lipids was observed. The increase was restricted to the neutral lipids, the glycerophospholipid synthesis being almost unaffected by the hormone. On the contrary, neutral lipid synthesis as well as that of the major glycerophospholipids were greatly enhanced by T3 in hypothyroid cells. Besides fatty acid synthesis, insulin stimulated acetate incorporation into all the lipid fractions. The stimulation was more pronounced in hepatocytes from hypothyroid animals. PMID- 7849613 TI - Expression of human acylphosphatase in Escherichia coli affects intracellular calcium levels. AB - In vitro experiments demonstrated the ability of acylphosphatase to hydrolyze the phosphorylated intermediate that is formed during the activity of Na+, K(+)- and Ca(2+)-ATPases of mammalian cells membranes. In order to investigate the effect of this enzyme on intracellular cation levels, a synthetic gene for human muscle acylphosphatase has been expressed in E. coli strains BL21 and JM101. Intracellular total steady-state calcium concentration, as measured by isotopic exchange, was significantly higher in transformed cells as compared to controls and the rising was dependent on the level of acylphosphatase expression. Accordingly also free intracellular calcium concentration, as measured by Fura-2 fluorescence, increased in transformed cells. On the other hand, phosphate levels were not affected by the expression of acylphosphatase, while sodium and rubidium levels increase in transformed cells. Intracellular pH resulted to be slightly affected by the expression of acylphosphatase, cytoplasm of transformed JM101 bacteria being more alkaline (pH 7.45) as compared to control cells (pH 7.40). On the basis of these results, it can be suggested that acylphosphatase acts in vivo by regulating the cation transport in E. coli. PMID- 7849614 TI - N-ethylmaleimide inhibits platelet aggregation and potentiates hydrogen peroxide formation induced by thrombin. AB - The effect of NEM pretreatment on hydrogen peroxide accumulation and aggregation in non stimulated and activated human platelets was studied. It was shown that low concentrations of NEM potentiate hydrogen peroxide formation induced specifically by thrombin. The cooperative effect of NEM with thrombin is dose dependent and reaches the maximum at 5 microM NEM. Thrombin is particularly effective at low concentrations (0.02-0.1 U). Extracellular Ca2+ significantly increases the NEM effect. Moreover NEM inhibits aggregation both in PRP and in washed platelets, exhibiting the greatest activity in washed platelets stimulated by thrombin. PMID- 7849615 TI - Angiotensin II up-regulates the expression of type A endothelin receptor in human vascular smooth muscle cells. AB - Using vascular smooth muscle cells, the effect of angiotensin II on endothelin receptor regulation was examined. Vascular smooth muscle cells cultivated from human pulmonary artery exhibited high affinity receptors for endothelin-1. When the cells were exposed to angiotensin II, the number of receptors was found to be increased without any change in their affinity. The ligand binding was effectively displaced by BQ123, a selective antagonist for type A endothelin receptor, but not by S6c, a selective ligand for type B receptor, in both control and angiotensin II-treated cells. The level of mRNA coding for the type A receptor was elevated in the latter. These results indicate that angiotensin II up-regulates type A endothelin receptors in human vascular smooth muscle cells through an increase in their corresponding mRNA, suggesting a link between the renin-angiotensin and the endothelin systems. PMID- 7849616 TI - Immunization of mice with proteins reacted with malonic dialdehyde (MDA): comparison between autologous and heterologous modified proteins. AB - In previous experiments, rabbits were injected with heterologous proteins reacted with MDA, and produced antibodies cross-reacting with other MDA-modified proteins (MPr), but not with the corresponding native ones (Pr). It was concluded that these antibodies (AbAIP) recognized epitopes including 1-amino-3-imino-propene (AIP) bridges resulting from reactions of MDA with primary amino groups of proteins. In the present work, mice were injected with autologous MDA-modified albumin (MAI) or with heterologous MPr. Mice immunized with MAI developed an immune response leading to an increased production of AbAIP, which clearly indicates that such a response may occur even with an autologous MPr. PMID- 7849617 TI - Effect of dietary vitamin E supplementation on macrophage metabolism during ageing. Study in rats fed fat-rich diets during ageing. AB - The effect of dietary vitamin E supplementation upon macrophage metabolism and function was examined in aged rats fed a balanced or a polyunsaturated-rich diet. The following parameters were studied: number of cells in the intraperitoneal cavity, maximal activity of hexokinase, citrate synthase, glucose-6-phosphate dehydrogenase, glutathione peroxidase and phosphate-dependent glutaminase. The consumption of glucose and the production of lactate, hydrogen peroxide and thiobarbituric reactive substances were measured in control ONCO-BCG injected rats. The results indicated that vitamin E has no significant effect on the values of the parameters studied in the macrophages of rats fed a balanced diet both for 3 (mature) or 17 months (aged). This antioxidant did not provoke any response on the changes caused by ageing the animals. However, several of the metabolic and functional alterations in macrophage induced by the polyunsaturated rich diets were reversed by the inclusion of vitamin E in the diet. These changes were associated with macrophage migration capacity, citrate synthase and glucose 6-phosphate dehydrogenase activities and the content of lipid peroxides. The findings suggest that vitamin E has a beneficial effect for macrophage metabolism and function, but the effects are confined to particular circumstances. PMID- 7849619 TI - Prediction of protein secondary structure from circular dichroism spectra using artificial neural network techniques. AB - An approach to predict protein secondary structure is presented using circular dichroism (CD) spectra as input to two types of artificial neural networks (ANNs): (i) a three-layer backpropagation network and (ii) a hybrid self organisation to backpropagation network. The dataset comprised the CD spectra of 22 proteins in the 178-260 nm wavelength range whose secondary structures were known. A total of 22 networks were trained by each method, using the jackknife technique for testing the prediction on each protein in turn. The performance, measured in terms of root mean square residuals and Pearson product-moment correlation coefficients, compares well with that obtained by other statistical and ANN methods, and is likely to improve with the growth of the dataset. PMID- 7849618 TI - Oxidative stress and mitochondrial dysfunction in neurodegeneration. AB - In the last 4 years much progress has been made in the understanding of mitochondrial disorders. Point-mutations, deletions and depletion of the mitochondrial genome are associated with disorders like Leber's disease, MERRF (Myoclonus Epilepsia with Ragged Red Fibers), MELAS (mitochondrial Myopathy, Encephalopathy, Lactic acidosis and Stroke-like episodes) and several others. Recently, mitochondrial dysfunctions have been also related to neurodegenerative disorders like Parkinson's disease and to aging. Since the brain depends mostly on mitochondrial energy supply, mitochondrial dysfunctions may affect the nervous system more severely than other tissues causing or worsening diseases and playing a role in the biological deterioration of aging. Furthermore, the mitochondrial energy supply is associated with the production of highly reactive oxygen species. Ninety-five percent of the molecular oxygen is metabolized within the mitochondria by the electron-transport chain so that mitochondria are highly exposed to oxidative stress which may damage selected neuronal populations. Oxygen radicals created during respiration induce mitochondrial dysfunction which accelerates the production of more deleterious species of oxygen. The latter step further increases mitochondrial malfunction, thus intensifying and perpetuating the cycle. These two mechanisms combined may lead to cell death in brain and other tissues with high metabolic rate. Therefore, in neurodegenerative disorders such as Parkinson's disease mitochondrial dysfunction and oxidative stress may cause or worsen the clinical features. PMID- 7849620 TI - Membrane topology of N-terminal residues of cytochromes P-450 2B4 and 1A2. AB - The paper describes the reactivity of fluorescein isothiocyanate towards the N terminus of cytochromes P450 2B4 and 1A2 in solution, in the natural membrane of microsomes and in proteoliposomes (cholate and ultrasonic). The results obtained indicate, that the N-terminus of microsomal or proteoliposomal cytochromes P-450 2B4 and 1A2 spans the membrane only once and faces the vesicles interior. It was suggested that of major importance in orientation of N-terminal residues in the membrane is not the hydrophobic segment itself but rather the positively charged fragment, following it. PMID- 7849622 TI - Delayed appearance of the catalytic activity by immunization of a rabbit compared with the hapten binding. AB - Polyclonal antibodies catalyzing the hydrolysis of carbonate ester were generated by immunizing a rabbit with hapten(4-nitrophenyl phosphate II) conjugated to keyhole limpet hemocyanin. The hydrolytic activity of IgG purified from antisera exhibited plateu one month later than the simple hapten-binding. The affinity of IgG with substrate increased even after the hapten-binding reached plateu. These suggest a strategy to generate good polyclonal catalytic antibodies and the day to fuse spleen cell with myeloma cell to get good monoclonal catalytic antibodies. PMID- 7849621 TI - Tryptophanase from Escherichia coli: catalytic and spectral properties in water organic solvents. AB - In water-methanol and water-dimethylformamide (DMF) (1:1 v/v) solutions tryptophanase from E.coli retains its abilities to form a quinonoid complex with quasisubstrates and to catalyze the decomposition of S-o-nitrophenyl-L-cysteine (SOPC). Both the KM and Vmax values decrease in water-organic media. The affinities of tryptophanase for L-alanine, L-tryptophan, oxindolyl-L-alanine and indole in aqueous methanol are decreased, the effect being stronger for the more hydrophobic substances. In a water solution tryptophanase catalizes the reaction of SOPC with indole to form L-tryptophan while in water-organic solvents only decomposition of SOPC is observed. PMID- 7849623 TI - In vitro translation of an intact mRNA coding for a poly(U), poly(C) specific ribonuclease isolated from six-day-old larvae of Ceratitis capitata by a modified extraction procedure. AB - Intact ribonucleic acid was prepared from six-day-old larvae of Ceratitis capitata, by enriching the guanidinium thiocyanate extraction procedure with a specific mixture for the active ribonuclease inhibition. RNA obtained by this means was then used as a source for the identification of mRNA coding for poly(U), poly(C) specific ribonuclease. The isolated poly(A+) RNA was translated in a cell-free protein synthesizing system. The presence of a poly(U), poly(C) ribonuclease among the newly synthesized products was detected by immunoprecipitation with anti-rabbit polyclonal antibodies against poly(U), poly(C) ribonuclease. PMID- 7849624 TI - Regulation of cell growth and the c-myc proto-oncogene expression by phorbol ester 12-0-tetradecanoyl phorbol-13-acetate (TPA) in the androgen-independent human prostatic JCA-1 cells. AB - The proliferation of the human prostatic cancer JCA-1 cells showed a complex response to different concentrations of TPA. Whereas cells exposed for 24 h had growth reduction which was proportional to the concentration of TPA added to the culture media, they showed resistance to low (0.016 and 0.16 nM) but not high (> or = 1.6 nM) doses of TPA after 72 h. Growth-inhibited, treated cells also displayed a distinct cell morphology compared with the controls. Since c-myc expression has previously been shown to be correlated with cellular proliferation, we determined changes in its steady-state level in control and treated cells by Northern analysis. Following a 24h, 48h, and 72h treatment, with 16 nM TPA, c-myc mRNA was suppressed by 91%, 83%, and 78%, respectively, in good agreement with the extent of growth reduction observed. At the low dose of TPA (0.16 nM), however, the c-myc mRNA expression remained inhibited by 85% even though cell growth was only reduced by 10-14%. No difference in the total amount of c-myc protein could be detected between control and treated cells by Western analysis. PMID- 7849625 TI - An inhibitory factor in rat thymus which interferes with binding of cytosol Ah receptor to xenobiotic responsive element. AB - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is known to induce aryl hydrocarbon hydroxylase in several tissues in the rat. This effect of TCDD is mediated by the Ah receptor. However, TCDD does not significantly enhance aryl hydrocarbon hydroxylase activity in the rat thymus. Analysis of 3H-TCDD bound Ah receptor on sucrose gradients revealed the presence of radioactivity sedimenting at 8-9S and 5-6S in the cytosol and nuclei of thymus respectively. Incubation of rat thymic cytosol with TCDD increased protein kinase C dependent phosphorylation, which reached saturation levels at high concentrations of TCDD, but the TCDD bound receptor did not appreciably retard 32P-labeled XRE-3 as determined by electrophoretic mobility shift assay. Incubation of rat hepatic cytosol with TCDD also increased protein kinase C dependent phosphorylation in a concentration dependent manner as well as retarded the mobility of 32P-labeled XRE far more than that observed with thymic cytosol. The ability of the Ah receptor to bind to XRE was temperature dependent. Incubation of thymic cytosol either with okadaic acid or with sodium fluoride did not increase the binding of the Ah receptor to XRE. On mixing hepatic cytosol with thymic cytosol prior to the electrophoretic mobility shift assay, the binding of the hepatic Ah receptor to XRE was reduced in a concentration-dependent manner. A similar effect was observed when renal cytosol was used instead of hepatic cytosol. Thymic cytosol also reduced the binding of the hepatic glucocorticoid receptor to its cognate responsive element. Thymic cytosol did not alter the topology/integrity of XRE. These data suggest that the thymus contains a factor(s) which interferes with the binding of AhR to its cognate responsive element. PMID- 7849626 TI - Changes in alanine turnover rate due to nutritional and genetic obesity in the rat. AB - The changes in alanine turnover were determined in Zucker rats, which were either genetically obese (fa/fa) or rendered obese by dietary treatment (cafeteria fed). The whole body rate of alanine turnover was higher in genetically obese rats than in rats in which obesity was induced by diet (cafeteria). This is possibly due to variations in the rate of the amino acid incorporation into proteins, since the rate of whole body alanine degradation is the same for both groups. Thus, the different pattern followed by alanine turnover rate in these types of obese animals reflects the differences in the nitrogen economy of these animals, pointing to a higher alanine utilization in the genetically obese animals and a conservative management of alanine in the cafeteria-fed animals. PMID- 7849627 TI - Two major groups of vitellogenin cDNA clones from Oreochromis aureus (Steindachner). AB - cDNA libraries were constructed using livers of male and female Oreochromis aureus that were stimulated with estradiol. Restriction map analyses of vitellogenin (Vg) cDNA clones indicated 4 subgroups with related restriction patterns, represented by pOAVg2 (from female) and pOAVg50, 71 & 87 (from male) fish. With the exception of pOAVg2, all other clones obtained from female fish resembled pOAVg50. There are no internal repeats within these cDNA clones. Southern blot cross-hybridisations distinguished pOAVg87 (group A) from pOAVg2, 50 and 71 (group B). The existence of these 2 major groups of Vg cDNAs was further confirmed by dot blot hybridisations and hybrid melting assays under varying stringencies. The difference of melting temperature, Tm between the 2 groups suggests a 7% intraspecific divergence in the Vg gene family. PMID- 7849628 TI - Effects of the antisense myb expression on hemin- and erythropoietin-induced erythroid differentiation of K562 cells. AB - In order to elucidate the role of c-myb gene in erythroid differentiation of K562 cell induced by hemin (Hm) and erythropoietin (Epo), we constructed recombinant plasmid that could produce antisense myb RNA after induction with dexamethasone. During treatment with Hm, K562 cells constitutively expressed c-myb mRNA, and 50% of them began to synthesize hemoglobin (Hb). Expression of antisense myb RNA reduced the amount of c-myb mRNA, and the percentage of Hb-synthesizing cells was decreased to 20%. In the presence of Epo, c-myb mRNA declined and 20% of K562 cells synthesized Hb regardless of antisense myb RNA expression. It is suggested that constitutive expression of c-myb mRNA is necessary for Hm-induced differentiation, and that a decrease in the amount of c-myb mRNA induced by antisense myb RNA expression suppresses Hm-induced differentiation. The amount of c-myb mRNA in K562 cells was reduced during the differentiation induced by Epo. Expression of GATA-1 mRNA was almost constant during Hm-induced differentiation, but increased during Epo treatment. It is supposed that the mechanism of Hm induced differentiation is distinguished from that of Epo-induced differentiation in K562 cells. PMID- 7849630 TI - The role of age on the cholesterol-metabolizing enzymes and lipid levels in chick plasma and liver microsomes after cholesterol enriched diet cessation. AB - Chicks of two age groups (11 and 21 days-old) were fed a cholesterol enriched diet administered either from hatching or for only 6 hours (9:00-15:00). Afterwards, the cholesterol was removed from the diet and we analysed hepatic Acyl-coenzyme A:cholesterol acyltransferase (ACAT) and 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase activities, plasma cholesterol levels and hepatic microsomal cholesterol content up to a day and a half. The treatments raised plasma and microsomal cholesterol levels in both age groups, increases in the older group exceeding those of the younger chicks. After removal of the cholesterol diet, both groups recovered by the middle of the next day, reaching values similar to those of control-chick groups. The ACAT activity showed a relationship with the microsomal cholesterol levels although did not return to similar levels than those of control microsomes. This correlation was not observed in HMG-CoA reductase. In general, differences in returning to the control values depended on the developmental stage of the chick. PMID- 7849629 TI - Production and characterization of a monoclonal antibody specific for the E1 component of the pyruvate dehydrogenase complex. AB - The monoclonal antibody F7F10 against the E1 component of the pigeon breast muscle pyruvate dehydrogenase complex has been produced. The dissociation constant of the E1-mAb F7F10 complex was determined to be 5.93 x 10(-8)M. The cross-reaction of the mAb with the E1 components of the pyruvate dehydrogenase complexes from various species (including human) was established. The competitive solid-phase immunoenzyme assay of the E1 component and PDC concentrations has been developed. PMID- 7849631 TI - Effect of carboxyatractylate on transmembrane electrical potential of plant mitochondria in different metabolic states. AB - The effects of carboxyatractylate (CAtr) on delta psi in sunflower hypocotyl and pea stem mitochondria were compared. In sunflower mitochondria, (1) CAtr at higher concentration increased delta psi in the presence of palmitate and delta psi in metabolic state 3; (2) ]1 microM CAtr did not prevent delta psi decrease, induced by ADP addition (in contrast to pea mitochondria); (3) The ATP-generated delta psi was small and was insensitive to 40 microM CAtr. Under the same conditions, in pea mitochondria generation of delta psi by ATP was inhibited by 1 microM CAtr. PMID- 7849632 TI - Biotin holocarboxylase synthetase: purification from rat liver cytosol and some properties. AB - The purification of biotin holocarboxylase synthetase (EC 6.3.4.10) from rat liver cytosol to a much higher degree of purity than previously reported, is described. The specific enzymatic activity of the final preparation is increased about 7,000 fold over the starting material. The purified preparation elutes from a gel-filtration column in a volume consistent with a molecular size of 100 kDa and examination by SDS-PAGE reveals one major band of M(r) 50 kDa. This suggests that the native synthetase may exist as a dimer of similar weight subunits. PMID- 7849633 TI - Evidence for superoxide radical production by a simple flavoprotein: glucose oxidase. AB - Nitroblue tetrazolium was reduced to blue formazan during the oxidation of glucose by glucose oxidase. The rate of blue color formation was dependent on the concentrations of glucose, nitroblue tetrazolium and glucose oxidase. The rate of the reaction was negligible below pH 8.4, but sharply increased with increasing pH. The reduction of nitroblue tetrazolium was inhibited by superoxide dismutase, consistent with the participation of superoxide anion radical in the reaction. PMID- 7849634 TI - Effect of cations and anthelmintics on enzymes of respiratory chains of the cestode Hymenolepis diminuta. AB - The enzymes involved in the catabolism of malate namely fumarate reductase, NADH oxidase, "malic" enzyme, succinate dehydrogenase and fumarase as well as NADPH:NAD transhydrogenase, which is involved in the electron transport chain, were studied in Hymenolepis diminuta, a rat intestinal tapeworm. Among cations, K+ had no effect on any enzyme whereas Ca2+ and Mg2+ showed an increase or decrease of varying degrees of different enzyme activities. Most of the compounds, which have been synthesized by the Central Drug Research Institute, Lucknow (India) and found to possess some anthelmintic properties, strongly inhibited the above enzymes except malic enzyme. PMID- 7849635 TI - Assessment of the interaction between calmodulin and casein kinase II. AB - Calmodulin is an in vitro substrate for casein kinase II and is also reported to inhibit casein kinase II activity in rat liver nuclear extracts. Here we demonstrate that in the presence or absence of Ca2+, calmodulin did not significantly alter either in vitro casein kinase II activity or autophosphorylation of its beta-subunit. In contrast, Ca2+ inhibited in a dose dependent manner both casein kinase II activity and casein kinase II-catalysed calmodulin phosphorylation. These data indicate that calmodulin does not directly inhibit casein kinase II activity, but casein kinase II is sensitive to physiologic Ca2+ concentrations. PMID- 7849636 TI - A novel method for evaluation of carbohydrate-binding activity: enzyme-linked carbohydrate-binding assay (ELCBA). AB - A highly sensitive method for detection of the carbohydrate-binding activity of proteins is described. The method is based on interactions of carbohydrate binding proteins, immobilized on a solid phase, with an enzyme-labeled soluble polysaccharide (peroxidase conjugated glycosaminoglycans-heparin, chondroitin sulfate or hyaluronic acid. Binding capacity was measured spectrofotometrically after enzymatic reaction with chromogenic substrate. The reliability of the assay was tested by use of two heparin-binding proteins-i) fibronectin (soluble) and ii) heparin-binding protein purified from the human brain (water-insoluble). Binding of heparin was dependent on metal ions, detergents and urea. The assay is believed to be applicable for the identification and characterization of a variety of carbohydrate(glycosaminoglycan)-binding proteins, especially, when traditional methods can not be applied (e.g., when proteins are water-insoluble). PMID- 7849637 TI - Iron chelators hydroxyurea and bathophenanthroline disulfonate inhibit DNA synthesis by different pathways. AB - We previously showed that thrombin-stimulated DNA synthesis in CCL 39 cells was inhibited by hydroxyurea (HU) and bathophenanthroline disulfonate (BPS) (Proc. Natl. Acad. Sci. USA, in press). A clear difference exists between these two inhibitors. Inhibition mediated by HU was immediate and must be present in the culture medium. BPS was equally effective when it was present in the medium or after preincubation, but it required at least 12 h to achieve maximal effect. The permeable form 1,10 phenanthroline had the same inhibitory effect in short-term incubations that BPS. Moreover, 1,10 phenanthroline was cytotoxic in long-term incubations indicating that the site of BPS inhibition was outside the cell. Further, long-term incubations with HU did not affect the ability of the cell to reinitiate DNA synthesis after removal of the chelator. PMID- 7849638 TI - Calorimetric investigation of the NABH4-modified bacteriorhodopsin in purple membrane from Halobacterium halobium. AB - Comparative differential scanning calorimetric study of intact purple membranes from Halobacterium halobium and when 50% of bacteriorhodopsin molecules were cut off by NaBH4 in the dark shows that two peaks beneath the overall endotherms correspond to a process of bacteriorhodopsin denaturation. These results suggest a different structural organization of two populations of bacteriorhodopsin in intact dark-adapted purple membranes. PMID- 7849640 TI - Hydrated electron-induced inactivation of tyrosinase in aqueous solution by exposure to cobalt-60 gamma-rays. I. Cresolase activity. AB - Tyrosinase (0.2 mg/ml of 0.1 M phosphate buffer solution, pH 6.5) which has cresolase and catecholase activities was irradiated with 60Co gamma-rays. The cresolase activity was measured at varying radiation doses under various atmospheric conditions. D0 was found to be 350 Gy in N2-saturated solution. The OH radical has been shown to be the main species involved in radiation-induced enzyme inactivation. However, in this study, OH radical scavengers, t-BuOH and MeOH, had no effect. O2 which acts generally as an enhancer of OH-induced enzyme inactivation also had little effect, but N20 ae aq scavenger, and Cu++ markedly inhibited the inactivation indicating that e aq is the main species involved in inactivating the cresolase activity, reducing Cu++ as the active center. PMID- 7849639 TI - On the 'active' molecules of DNA-polymerase beta in aging rat brain. AB - DNA polymerase beta, a 38kD protein is essentially considered to be a repair enzyme at least with respect to some forms of DNA damage. Through northern and western blotting, it was found that mRNA and immunologically reactive molecules of DNA-polymerase beta are reduced by 30% and 20% respectively in old rat brain as compared to the young. However, activity gel assay and immunotitration revealed a 50% reduction in the activity in old brain. These data are taken to indicate accumulation of catalytically inactive molecules of DNA-polymerase beta in rat brain with age. PMID- 7849641 TI - Hydrated electron-induced inactivation of tyrosinase in aqueous solution by exposure to cobalt-60 gamma-rays. II. Catecholase activity. AB - Tyrosinase (0.2 mg/ml) was irradiated with 60Co gamma-rays. The catecholase activity was measured at varying radiation doses under various atmospheric conditions. D0 was found to be 1.25 kGy and hit number to be 2 in N2-saturated solution. OH radical scavengers, t-BuOH and MeOH, had no effect. O2 which is an enhancer of OH-induced enzyme inactivation had little effect. But N2O as a e aq scavenger and Cu++ markedly protected against the inactivation indicating that e aq was the main species to inactivate the enzymatic activity. By Ultrogel chromatography, it was found that the enzymatic activity was lost when this enzyme dissociated into its subunits. Thus, it was concluded that the radiation induced inactivation was due to the reduction of Cu++ as the active center and the chelater with e aq followed by the dissociation. PMID- 7849642 TI - Calprotectin-like protein is related to soluble organic matrix in calcium oxalate urinary stone. AB - Soluble organic matrix was extracted with 0.1 M EDTA from calcium oxalate monohydrate urinary stone (CaOx), purified by SDS-polyacrylamide gel electrophoresis and transferred to polyvinylidene difluoride membranes for the NH2-terminal amino acid sequence analysis. A protein at 30 kDa showed complete homology with calprotectin (20 amino acids in the NH2-terminal), so we termed this a calprotectin-like protein. Calprotectin which was extracted from human granulocytes had inhibitory activity in calcium oxalate monohydrate crystal growth in vitro. This study suggested that, calprotectin-like protein detected in CaOx is thought to be a potent inhibitor of crystal growth and may therefore be important in the etiology of CaOx formation. PMID- 7849643 TI - Isolation of intact transition protein 4 from boar late spermatid nuclei. AB - Boar transition protein 4 was extracted with acid from the late spermatid nuclei, and separated from the transition protein-degrading proteases by ion-exchange chromatography on Fractogel EMD SO3- 650 (M). The transition protein was further purified by HPLCs on Nucleosil 300 7C18 and Diol-200. The circular dichroic spectra of the protein with and without dithiothreitol showed that the protein had beta-form predominantly. Although sodium dodecyl sulfate affected the tertially structure of the protein, the beta-form was well retained. These indicate that the protein has a structure-forming potential for the beta structure. PMID- 7849644 TI - A polymerase chain reaction on human alphoid DNA produces a characteristic ladder of bands. AB - A polymerase chain reaction (PCR) was performed on the tandemly repeated human alphoid DNA sequence. A characteristic ladder of bands was produced which differed by 171 (or 340) base pairs. This laddering phenomenon occurs because the two oligonucleotides can bind within the same monomer or in neighbouring monomers. In the latter case a larger PCR product is produced which is 171 bp or a multiple of 171 base pairs greater in size. The alphoid DNA PCR is very sensitive because a repeated sequence is amplified. Hence it could have applications in archaeology or forensic science. PMID- 7849645 TI - Vitamin A preserves the cytotoxic activity of adriamycin while counteracting its peroxidative effects in human leukemic cells in vitro. AB - Previous results from our laboratory gave evidence that safe doses of vitamin A were very effective in protecting rats from adriamycin-induced oxidative stress and lethal cardiotoxicity (Tesoriere, L. et al. (1994) J. Pharmacol. Experim. Ther. 269, 430-436). This was an incentive also to evaluate whether or not vitamin A affected the antitumor activity of adriamycin. K562 human erythroleukemia cells were exposed to adriamycin or to adriamycin plus vitamin A. Presence of 2.5 to 15 microM all-trans retinol in the cell culture did not impair the cytotoxicity of adriamycin. Rather, an enhanced cell death was observed when cell colony was exposed to both compounds. Additional assays showed that all trans retinol counteracted the lipoperoxide formation, assayed as malondialdehyde, induced in cell cultures by the redox cycling activity of adriamycin. These data strongly encourage a new therapeuthical approach with safe doses of vitamin A as an adjuvant in cancer chemotherapy. PMID- 7849647 TI - Identification and characterization of capsaicin-hydrolyzing enzymes purified from rat liver microsomes. AB - To elucidate the metabolic pathway of capsaicin (CAP), CAP-hydrolyzing enzymes, involved in the initial step of hydrolysis, were purified from rat liver microsomes and were characterized. CAP-hydrolyzing enzymes, whose activity was assayed by HPLC, were found to be located in the lumen of endoplasmic reticulum (ER). The enzymes were extracted from microsomes with Triton X-100 and purified by DEAE-cellulose, Sephadex G-200 (superfine), and isoelectrofocusing (IEF) chromatography. The enzymes were eluted from a gel filtration column as peaks with relative molecular mass of 60,000 and 180,000; IEF using Rotofor Cell showed that pIs of these enzymes are around 5.6 and 6.1, respectively. Total CAP hydrolyzing activity of enzyme pI 5.6 was much greater than that of enzyme pI 6.1. With several lines of criteria, these fully characterized enzymes were identified as previously known hydrolase pI 5.6 and hydrolase pI 6.1. PMID- 7849646 TI - Regulation of thymidylate synthase in regenerating rat liver after partial hepatectomy. AB - Level of thymidylate synthase (TS) mRNA elevated about 6-fold compared with the normal in 24 h-regenerating rat liver after partial hepatectomy. This elevation of TS mRNA level was coupled with that of the activity. After 24h, the TS mRNA level began to decline steeply and returned to the normal level at 72h, when TS activity remained at the maximal level. alpha-Adrenergic regulation of liver regeneration after partial hepatectomy, which was shown in our previous paper, was found to be occurred at mRNA level of TS. The administration of cycloheximide resulted in the decreases of both TS activity and TS mRNA level while actinomycin D had no effect. This suggested that the increase of TS mRNA in regenerating liver required the de novo synthesis of some activator protein(s). PMID- 7849648 TI - Ca(2+)-loading modulates potencies of cyclosporin A, Mg2+ and ADP to recouple permeabilized rat liver mitochondria. AB - We studied the relative potencies of cyclosporin A and endogenous effectors (Mg2+ and ADP) to recouple rat liver mitochondria permeabilized by different Ca(2+) loading in a P(i)-containing medium. Recoupling efficiency of cyclosporin A dramatically decreased at high Ca(2+)-loading (approx. 100 nM of Ca2+/mg protein and more). Mitochondria permeabilized by high Ca2+ were recoupled with approximately equal efficiency by higher cyclosporin A concentrations or by adding 1-5 mM Mg2+ together with low concentrations of cyclosporin A while potentiating effect of ADP on the cyclosporin A recoupling potency was insignificant. Mg2+ ions at concentrations of 3 mM and higher also prevented the carboxyatractylate-induced reversion of cyclosporin A recoupling effect. The data point to competitive relationships between cyclosporin A and/or Mg2+ ions and Ca2+ ions for the site(s) regulating permeability state of the pore. PMID- 7849649 TI - Deficient nucleation during co-polymerization of mammalian MAP2 and tobacco tubulin. AB - To obtain information on the functional domains of tubulin from a dicot plant, we investigated the interactions of tobacco tubulin with MAP2 from bovine brain supernatant. Taxol-stabilized tobacco and bovine brain microtubules had similar binding capacities for MAP2 (1 mol MAP2 per 8-9 mol tubulin). However, MAP2 dissociated from tobacco microtubules more readily than from bovine brain microtubules and induced the polymerization of tobacco tubulin into aberrant helical ribbon polymers, rather than microtubules. Ribbon assembly was partially suppressed by 50 mM KCl. Abundant tobacco microtubules formed when MAP2-induced nucleation was by-passed with microtubule seeds. Thus, deficient nucleation of tobacco tubulin assembly by MAP2 reflects distinct properties of the polymerization and regulatory domains of plant and animal tubulins. PMID- 7849650 TI - Saturated fatty acid, but not cholesterol, regulates apolipoprotein AI gene expression by posttranscriptional mechanism. AB - The aim of the present study was to investigate the regulation of the apoAI gene by dietary saturated fat and cholesterol. Saturated fatty acids and cholesterol raise low density- and high density lipoprotein particles in humans. Increased LDL is attributed to the down-regulation of LDL-receptor gene, but the mechanism of increased plasma HDL levels is unknown. To study the mechanism of HDL elevation by saturated fat, male rats and male mice were employed as animal models, since they also raise their plasma HDL levels when fed high lipid diets. Animals were divided in four groups and fed the following diets: control (5% corn oil); high cholesterol (0.5%); high fat (20% coconut oil); and high fat plus cholesterol diets. The high cholesterol diet did not alter plasma and HDL cholesterol levels. However, the high fat diet increased HDL levels by 20% in rats and 55% in mice. A combination of saturated fat and cholesterol diet raised plasma HDL levels by 36 and 67% in rats and mice, respectively. Plasma apoAI levels increased parallel to HDL concentrations. Mechanism of HDL elevation by saturated fat was investigated. Hepatic and intestinal apoAI mRNA did not change with any of the test diets in mice. Rat hepatic apoAI mRNA was also unchanged by the high cholesterol diet, but was decreased on high fat and fat-cholesterol combination diets. These results suggest that transcriptional regulation of the apoAI gene was not responsible for increased plasma apoAI and HDL. The translational efficiency of apoAI on isolated polysomes was also measured, and it was found that apoAI synthesis increased about 20% on high fat and fat cholesterol combination diets. This partially explains the elevated levels of plasma HDL. Additional regulation through impaired catabolism of HDL particles by high fat diet feeding may be another pathway for increased HDL levels. Unlike apoAI mRNA, the mRNA of other HDL apoproteins, apoAII and apoAIV, were increased by high fat and combination diet feeding. These results suggest that saturated fatty acids regulate plasma HDL levels by translational and posttranslational mechanisms. PMID- 7849651 TI - Improvement in the binding of cobrotoxin to microtiter plates by glutaraldehyde at neutral pH. AB - The coating of the wells of microtiter plates with cobrotoxin in Tris (pH 9.8) or PBS (pH 7.2) buffer was assessed by enzyme-linked immunoassay (ELISA). It was found that the poor binding in neutral buffer was improved by adding glutaraldehyde (GA), and the bound amount reached the same extent as that measured with alkali buffer. The optimal concentration of GA was approx. 0.02%. A decrease in optical density was observed with GA concentration higher than 0.02%. This may result from the modification of cobrotoxin by GA, which induced a decrease in the antigenicity of the cobrotoxin as revealed by competitive immunoassay. This study implies that the coating of physiological samples with GA for ELISA may be carried out with physiological buffers without the need to change the buffer to one of alkaline pH. PMID- 7849652 TI - Preparation method of highly-purified antibodies from antisera by using polyvinylidene difluoride membrane. Application to fatty acid binding protein in rat liver. AB - A simple method for preparation of highly-purified antibodies from antiserum was developed by using antigen-blotted polyvinylidene difluoride transfer membrane as an affinity matrix: The antigen was purified by SDS-polyacrylamide slabgel electrophoresis. Purified antibody preparations, which had been eluted from the Gly-HCl buffer (pH 2.5)-pretreated affinity matrix, by treatment with 1,4 dioxane, were more effective to obtain specifically stained band in immunoblot analysis than antiserum or immunoglobulin fractions purified by already reported methods. Antigen-blotted membranes were repeatedly available without remarkable release of antigen or decrease of antigenicity. This method was also applied to the examination of cross-reacting proteins with rat liver fatty acid binding protein in the cytosol fraction. PMID- 7849653 TI - Expression and purification of a truncated macrophage colony stimulating factor in Kluyveromyces lactis. AB - A truncated human macrophage colony stimulating factor (M-CSF) cDNA encoding amino acid residues from 3 to 149 of the native M-CSF was obtained by using polymerase chain reaction. When inserted into plasmid pCXJ1 and psPHO5 and introduced into Kluyveromyces lactis, it directs the the secretory expression of the biologically active dimeric form of M-CSF. Through a four-step purification protocol, i.e. ammonium sulfate salting out, DEAE-cellulose column chromatography, hydrophobic chromatography on phenyl-sepharose and Mono Q fast protein liquid chromatography, the recombinant truncated M-CSF was purified to homogenerity and show its apparent molecular mass at 21KDa on reduced SDS-PAGE, with a specific activity of 1.21 x 10(7) units/mg protein. PMID- 7849654 TI - Ballistic movement: muscle activation and neuromuscular adaptation. AB - Movements that are performed with maximal velocity and acceleration can be considered ballistic actions. Ballistic actions are characterized by high firing rates, brief contraction times, and high rates of force development. A characteristic triphasic agonist/antagonist/agonist electromyographic (EMG) burst pattern occurs during ballistic movement, wherein the amount and intensity of antagonist coactivation is variable. In conditions of low-grade tonic muscular activity, a premovement EMG depression (PMD; or silent period, PMS) can occur in agonist muscles prior to ballistic contraction. The agonist PMD period may serve to potentiate the force and velocity of the following contraction. A selective activation of fast twitch motor units may occur in ballistic contractions under certain movement conditions. Finally, high-velocity ballistic training induces specific neuromuscular adaptations that occur as a function of the underlying neurophysiological mechanisms that subserve ballistic movement. PMID- 7849655 TI - Heat strain in the Canadian Forces chemical defence clothing: problems and solutions. AB - The Canadian Forces chemical defence protective clothing can induce an overwhelming strain on one's ability to regulate body temperature. Recently a number of investigations have been completed at the Defence and Civil Institute of Environmental Medicine that focused initially on understanding the interaction of metabolic rate, ambient temperature, and ambient vapour pressure on the severity of heat strain associated with wearing the protective clothing. This paper presents a summary of these initial studies together with an overview of different attempts to reduce heat strain during exercise in a hot environment. Factors such as improved aerobic fitness or a period of dry heat acclimation have little if any benefit on tolerance time while wearing the clothing during light or moderate exercise. The best solution to the problem of heat strain remains the use of microclimate conditioning (personal cooling), and these techniques have been successful for Naval and Air Force personnel. For our Land Forces, however, microclimate conditioning is not feasible until a lightweight high-energy power source is developed. PMID- 7849656 TI - Endocrine responses to overreaching before and after 1 year of weightlifting. AB - Nine elite male junior weightlifters (mean age 17.6 +/- 0.3 yrs) performed weightlifting tests before (Test 1) and after (Test 2) 1 week of increased training volume (overreaching) and repeated the protocol after 1 year of their training program. Strength increased by Year 2 (p < 0.05) but did not change during either week of increased training volume. The 1-week overreaching stimulus resulted in attenuated exercise-induced testosterone concentrations during Year 1, but augmented exercise-induced testosterone concentrations during Year 2. Testosterone concentrations at 7 a.m. decreased for only Year 1. For both years, the 1-week overreaching stimulus increased cortisol at 7 a.m, indicative of the increased training volumes. Testosterone/cortisol was not affected by increased training volume for either year. One year of chronic weightlifting and prior exposure to the overreaching stimulus appears to decrease the detrimental effects of stressful training on the endocrine system. PMID- 7849657 TI - Hematological, electrolyte, and biochemical alterations after a 100-km run. AB - Seven well-trained male long-distance runners were studied during a 100-km road race. Hematologic parameters, plasma electrolytes, glucose, lactate, urea, and creatinine content in plasma and the activity of the enzymes gamma glutamyltransferase and creatinine kinase were determined before and after the race. A slight increase in hematocrit was found after the race, although the red blood cell count and hemoglobin concentration remained unchanged. Further, a significant rise in the number of white blood cells, lymphocytes, and neutrophils was found after the race. Postrun concentrations of plasma sodium and potassium increased significantly from 142 +/- 7 to 161 +/- 7 mmol.L-1, and from 4.22 +/- 0.37 to 5.15 +/- 0.46 mmol.L-1 (p < 0.05), respectively. Plasma concentrations of lactate (1.29 +/- 0.31 vs. 3.57 +/- 1.22 mmol.L-1), urea (6.09 +/- 1.0 vs. 8.35 +/- 1.35 mmol.L-1), creatinine (73.4 +/- 3.5 vs. 117.6 +/- 19.4 mumol.L-1), plasma creatine kinase (91.1 +/- 25.1 vs. 2843 +/- 2341 IU.L-1), and gamma glutamyltransferase (20.28 +/- 1.88 vs. 24.14 +/- 4.09 IU .L-1) increased significantly (p < 0.05) after the run. It was concluded that during ultralong distance races, acute renal dysfunction and muscle damage could contribute to the observed hypernatremia and hyperkalemia. PMID- 7849658 TI - Blood pressure responses to a progressive step test in normotensive males and females. AB - This study documents the blood pressure responses to a progressive step test adapted from the Canadian Aerobic Fitness Test (CAFT). Subjects were administered the first five stages of the CAFT in a progressive and discontinuous manner. Mean heart rate, SBP, and delta SBP increased linearly with exercise intensity, while mean diastolic blood pressure remained stable. The variables that contributed most to delta SBP (Stage 3) in males were age and degree of participation in physical activity, and in females the variables were body weight and degree of participation. Criteria for the detection of an exaggerated (mean delta SBP + 1 SD) and highly exaggerated (mean delta SBP + 2 SD) SBP response were defined. Resting normotensive individuals who demonstrate an excessive exercise blood pressure response seem to do so at the lowest levels of stepping intensities. This step test protocol appears to be a useful and practical procedure for assessing the exercise blood pressure response in higher risk individuals. PMID- 7849659 TI - Entrained breathing and oxygen consumption during treadmill walking. AB - Entrainment of the breathing rhythm to that of the rhythm of limb movement during exercise has been shown to decrease oxygen consumption for cycling at a moderate workload. This study examined the effect of entrainment on oxygen consumption during treadmill walking at two workloads. For each workload, 8 subjects performed two exercise protocols consisting of walking on a treadmill for 8 min. For the first protocol they received no instructions, but for the second protocol they were instructed to coordinate one breath per auditory cue which was provided during the last 4 min of exercise. The auditory cue was transmitted as a click via headphones. It was derived from a foot switch and was designed to synchronize breathing to the walking pace at a respiratory frequency close to that observed in the first protocol. Entrainment and oxygen consumption were compared between the protocols for the last 4-min segments for each workload. These comparisons showed that the presence of the auditory cue significantly increased entrainment from 29 to 74%, but oxygen consumption was not significantly changed. PMID- 7849660 TI - Prolonged recovery from eccentric versus concentric exercise. AB - In order to determine whether exercise mode affects recovery energy expenditure, 7 active men (average age 25 yrs) performed a control rest and three submaximal exercise bouts in counterbalanced order in separate weeks. The bouts, designed to involve three levels of eccentric muscular activity, included 60% VO2max jog (60 J), 60% downhill (-5%) jog (60 DH), 60% cycling (60 C), and a control session. Following a 24-hr period of regulated activity and diet, subjects exercised for 60 min. VO2 and RER were assessed during 48 hrs of regulated recovery. Total energy use was elevated following 60 C and 60 DH versus control, and fat energy use was elevated following 60 J, 60 DH, and 60 C versus control. For combined trials, the total energy use was higher at 1, 2, and 9 hrs postexercise. These results do not support the hypothesis that eccentric muscular activity affects the magnitude of recovery energy expenditure. PMID- 7849661 TI - Twitch analysis as an approach to motor unit activation during electrical stimulation. AB - The mechanical twitch in response to increasing electrical stimulus intensity, delivered both over the motor point and motor nerve, was recorded in the first dorsal interosseous (FDI) and the adductor pollicis (AP), and only over the motor point in the soleus (Sol), lateral (LG), and medial (MG) gastrocnemius muscles of human subjects. The relationship between intensity of electrical stimulation (ES) and twitch torque showed a positive linear regression in all muscles. In the FDI and AP the relationship was not significantly different when ES was applied at the motor point or over the motor nerve. At small intensities of activation, ES induced larger twitch torques in the MG and LG, which contain a roughly equal proportion of slow and fast motor units (MUs) compared to the Sol, which is composed mainly of slow type fibres. Moreover, the relationship between ES intensity and twitch time-to-peak is best fitted in all muscles by a power curve that shows a greater twitch time-to-peak range in its initial part for muscles containing a larger proportion of fast MUs (LG, MG) than for muscles mainly composed of slow MUs (Sol). In conclusion, these results induced by ES at the motor point and/or over the motor nerve confirm the concept of a reversed sequence of MU activation, as compared to voluntary contractions, and document this viewpoint in muscles of different function and composition. The reversed sequence of MU activation is more clearly evident during motor point ES. PMID- 7849662 TI - Measurement of left ventricular function during arm ergometry using the VEST nuclear probe. AB - A chest-mounted left ventricular (LV) nuclear probe (VEST) for use during arm and leg ergometry is presented, with a discussion of the validity and reproducibility of LV function measures at rest and exercise. During both arm and leg ergometry in trained subjects, transient changes in LV function/volumes were observed. LV ejection fraction and relative end-systolic and end-diastolic volumes were 25 to 30% less with the arms versus the legs, agreeing with data from other studies using conventional techniques. At peak exercise with both limbs, LV ejection fraction and relative LV end-systolic volume increased, followed by immediate postexercise normalization. The effect was greatest with the arms and reflects the effect of high intramuscular and arterial pressures generated during arm cranking, leading to increased LV afterloading. The VEST permits rapid and noninvasive assessment of LV function during arm exercise, avoiding the limitations of other techniques. PMID- 7849663 TI - Validation of the sensormedics (S2900Z) metabolic cart for pediatric exercise testing. AB - The accuracy of many microprocessor controlled exercise testing systems has not been established, particularly for testing children. A metabolic cart (Sensormedics S2900Z) was validated against a reference system (Douglas bag) in children. The systems were tested using 10 active, healthy children (age 11.6 +/- 2.3 yrs) during physiological steady state at two exercise intensities, submaximal walking and running. Eight children performed a high ventilatory flow (HVF) protocol, running for 11 min. All 10 performed a low ventilatory flow (LVF) protocol, walking for 11 min. In both, gas samples were measured after 6 to 7 and 10 to 11 min into the Douglas bag, and after 8 to 9 min by the test system. There was minimal evidence of bias for VO2 at either ventilation rate. Greater variability was noted for FeCO2 and VCO2. In conclusion, the Sensormedics S2900Z appears to be adequate for testing children. PMID- 7849664 TI - Digital syndactyly observed in the foot. PMID- 7849665 TI - Stabilizing suspension procedure involving multiple tendon transfers in a patient with multiple sclerosis. AB - Patients afflicted with multiple sclerosis develop weaknesses of the lower extremity resulting in drop foot, making ambulation very difficult. A review of the literature by the authors failed to reveal any cases or manuscripts discussing the podiatric management of patients with this disease. This manuscript offers a review of the disease, common principles regarding tendon transfers, a case report, and unique surgical approach consisting of a stabilizing suspension procedure involving multiple tendon transfers. At 1 year following correction, the patient was pleased with the results and ambulatory status. PMID- 7849666 TI - Dynamic unilateral distraction fixation: surgical management of tibial pilon fractures. AB - The tibial pilon fracture is a severe injury that can result in disastrous complications. Articulated unilateral external fixation provides an alternate method for the surgical treatment of intra-articular fractures of the distal tibia. This technique provides early mobilization of the ankle joint, stabilizes the fracture site, and through distraction prevents collapse and displacement of the fracture fragments. PMID- 7849667 TI - The effect of fibrin sealant on the strength of tendon repair of full thickness tendon lacerations in the rabbit Achilles tendon. AB - The influence of fibrin sealant on healing was investigated in the suture of Achilles tendons of 24 rabbits. The Achilles tendon cut through was anastomosed with a 4-0 prolene suture alone in one group and fibrin sealant was applied to the cut surfaces of the tendon prior to suture repair in the second group. After 17 and 27 days, five animals in each group were sacrificed. The repaired Achilles tendons were retrieved and the tensile strength of the repaired tendons measured using an Instron. One rabbit in each group was sacrificed at 3 weeks and 6 weeks and the repaired tendons were harvested and fixed for histologic study. At 17 and 27 days there was no significant difference between the tensile strength of the control and fibrin sealant groups. Histologically there was no distinct difference of the repair process of the tendons between the two groups. PMID- 7849668 TI - Osteochondroma of the subtalar joint. AB - Osteochondromas are benign, cartilage-capped, bone tumors that are relatively painless. At times, however, they may restrict normal biomechanical foot function and significantly reduce the activity level of the patient. A detailed discussion of this lesion, along with a case report of a subtalar joint osteochondroma are presented. PMID- 7849669 TI - The inverted Z bunionectomy: quantitative analysis of the scarf and inverted scarf bunionectomy osteotomies in fresh cadaveric matched pair specimens. AB - Quantitative analyses of the Scarf/Z and inverted Scarf/Z bunionectomy osteotomy procedures utilizing two-screw fixation were performed in fresh cadaveric specimens. Eighteen trials (nine matched pair feet) were used for direct comparison. Ultimate strength and failure areas were examined. Trial results revealed a strong statistically significant positive effect. The inverted Z approach was found, on average, 1.6 times stronger in resisting simulated weightbearing forces on the capital fragment to failure than that of the traditional Z bunionectomy osteotomy. PMID- 7849670 TI - Management of pedal puncture wounds. AB - Puncture wounds of the foot are a commonly encountered traumatic entity. Their management, however, is often inadequate and can lead to serious secondary complications. A comprehensive knowledge of proper treatment protocol should be mandated for any clinician who treats the lower extremity. PMID- 7849671 TI - Recurrence of aneurysmal bone cyst of the fourth metatarsal. AB - Aneurysmal bone cyst is a benign solitary lesion of unknown etiology. Its radiographic and histologic appearance can overlap with those tumors of malignant origin. It is imperative that clinical data, radiographs, and operative and pathological findings be correlated to ensure an accurate diagnosis. Aneurysmal bone cysts occur only 7% of the time in the foot. Recurrence rates are reported to be less than 12%. A case report of recurrence of aneurysmal bone cyst in the foot is reviewed, in addition to the etiology, differential diagnosis, and treatment alternatives. PMID- 7849672 TI - Elastofibroma of the forefoot. AB - Elastofibroma is an uncommon soft tissue lesion that most often presents as a mass in the lower scapular region of elderly female subjects. The authors report an elastofibroma arising in the right forefoot of a 63-year-old woman. Pain over the plantar aspect of the head of the third metatarsal preceded the formation of a tender mass. Although rare, elastofibroma should be considered in the differential diagnosis of painful conditions and tumors of the forefoot. PMID- 7849673 TI - Fluoroscopy-assisted plantar fasciotomy and calcaneal exostectomy: a retrospective study and comparison of surgical techniques. AB - A retrospective analysis of fluoroscopy-assisted plantar fasciotomy/calcaneal exostectomy is presented. The study included 34 patients whose symptoms were all improved to some degree by the procedure. On a five-point scale, the average improvement of preoperative symptoms was 3.2. There were a total of eight complications. The time it took to return to normal activities and until the pain became less than preoperatively was found to be decreased when compared with traditional methods. This technique, using a single, plantar medial, small incision should be considered as an option in the treatment of recalcitrant plantar fasciitis/heel spur syndrome. PMID- 7849674 TI - Squamous cell carcinoma of the great toe. AB - Nail bed malignancies are rare entities. Most nail bed malignancies are squamous cell carcinomas. The correct diagnosis is often delayed because nail bed malignancies are frequently mistaken for benign or infectious processes. This case involved a painful glomus tumor of the nail bed which complicated the diagnosis and perhaps initiated the development of a malignancy. The importance of a biopsy for chronic nonhealing lesions is stressed. The diagnosis, treatment, and prognosis are reviewed. PMID- 7849675 TI - Malignant eccrine neoplasms of the foot. AB - Eccrine cancers are uncommon, but potentially recurrent, metastatic and fatal. Rarely, they are primary foot lesions. The literature records 46 foot cases, with age and sex given for 41. Various eccrine cancer types (most on the sole), affected all races, males predominating. Average age at diagnosis was approximately 55. A podiatric facility recorded eight cases among approximately 30,000 skin biopsies, during 15 years. Seven arose in women. Five arose in the great toe area. Three are porocarcinomas. Five are "adenocarcinomas" varying in degree of differentiation. None of the eight patients presented recurrence or metastasis during follow-up 0.5-13.4 years. Of the combined 49 literature and podiatric cases, 28 (57.1%) arose in men, mostly between ages 41 and 70. Most were slow growing, long standing, and mildly symptomatic. No clinical features distinguished eccrine cancers from other pedal tumors. PMID- 7849676 TI - Polymetatarsia as an etiology for Tailor's bunion deformity: a surgical approach. AB - Congenital pedal deformities are well documented within the literature. The following article reviews a case history of a 4-year-old girl with a unique case of polymetatarsia and the complications associated with the resultant deformity. The history, case presentation, surgical treatment rendered, and follow-up care are presented. A review of the literature is also provided. PMID- 7849677 TI - Foot granular cell myoblastoma. AB - Granular cell myoblastoma is a benign tumor of undetermined origin. It is rarely diagnosed clinically and frequently discovered only as an incidental finding on physical examination. The authors present a 5-year follow-up review of a foot granular cell myoblastoma treated by local excision. A review of the literature is included. To the authors' knowledge this is only the second such case reported. PMID- 7849678 TI - Endoscopic decompression for intermetatarsal nerve entrapment--the EDIN technique: preliminary study with cadaveric specimens; early clinical results. AB - The authors have developed an endoscopic approach to the surgical treatment of Morton's neuroma. This technique is based on the premise that the condition is primarily a nerve entrapment disease. As with other endoscopically assisted procedures, the authors believe that this technique will be less traumatic, allowing an earlier return to normal activity, with less patient discomfort than with traditional surgical techniques. PMID- 7849679 TI - Podiatric imaging quiz. PMID- 7849680 TI - Radiography of articular disorders in the foot. AB - The author reviews various pedal articulations, as well as certain clinical manifestations with which these may be pathologic. Pertinent anatomy is described. Individual as well as multiple articular disorders in the foot are illustrated. PMID- 7849681 TI - New protocols for perioperative management of podiatric patients taking oral anticoagulants. PMID- 7849682 TI - The activity of the International Brain Research Organization (IBRO) in Hungary. PMID- 7849683 TI - Rapid synthesis of a glycine-rich protein in the cerebral cortex of the rat during activity. AB - A glycine-rich protein was previously discovered (Rojik and Feher, 1976) in the nervous system, which proved to be neuron-specific and in its appearance highly dependent on the actual intensity of neural activity. It was named by us neuragin. Time relations and regulation of neuragin synthesis were examined by the glycine labelling method in the cerebral cortex of the rat. During activation of the somato-sensory area, 2 min stimulation sufficed to provoke the appearance of neuragin in the neurons. The newly synthesised protein persisted in the nerve cells at least for 6 hours after stimulation. Phorbol-12-monoacetate strongly enhanced, sphingosin depressed the synthesis of neuragin. It is concluded, that neuragin is an immediate early gene product, similar to proteins encoded by genes c-fos and c-jun. PMID- 7849684 TI - Low-dose X-irradiation reduces neuronal and glial cell populations in the juxtaglomerular region of rat olfactory bulb. AB - Rats were subjected to fragmented, low-dose, whole body X-ray irradiation from last prenatal to third postnatal week of life. Consequences of the irradiation were examined at the cellular and synaptic level and evaluated by light- and electron microscopy. The fate of several cell types of the glomerular layer was assessed by semi-quantitative morphometry. All known neuronal and glial cell subtypes and varieties of synaptic connections of this layer were spared. X irradiation, however, had a marked influence on the composition of the juxtaglomerular cell population even at the youngest examined, two week old rat pups and this impact still persisted, without recovery, at six weeks of age. Density (and so, absolute number) of the small periglomerular neurones and astrocytes was depressed to 52-55% and 32-48% of control, respectively, while the density of the superficial tufted cells and the rest of glial cells remained at the control level. These results suggest that the small periglomerular neurones may primarily be responsible for the shrinkage of this layer. This means, in the same time that, selective depression of the development of a superficial interneuron (in addition to the deeply situated granule cells) could be achieved. PMID- 7849685 TI - Laryngeal-phonatory dysfunction in closed-head injury. PMID- 7849686 TI - Laryngeal dysfunction in dysarthric speakers following severe closed-head injury. AB - The laryngeal function of 19 severely closed head-injured subjects with a perceptible dysarthria was assessed using electrolaryngography and a computerized airflow/air pressure analysis system (Aerophone II). Variables measured included parameters of the Lx waveform (Fo, duty cycle and closing time) as well as aerodynamic parameters such as subglottal pressure, glottal resistance, average phonatory sound pressure level, phonatory flow rate and ad/abduction rate. Values were compared to those recorded from a non-neurologically impaired control group matched for age and sex, and correlated with the findings of a perceptual speech analysis. The findings are discussed in relation to the effects of a severe closed-head injury on laryngeal function. The clinical implications of the findings for the assessment and treatment of vocal dysfunction in head-injured subjects are also discussed. PMID- 7849687 TI - The Children's Orientation and Amnesia Test: educational status is a moderator variable in tracking recovery from TBI. AB - The Children's Orientation and Amnesia Test (COAT) is an objective, standardized means of assessing cognitive functioning in children and adolescents who are in the early stages of recovery from traumatic brain injury. The COAT is composed of 16 items that assess general orientation, temporal orientation, and memory. This study was designed to determine if children who are receiving special education services perform more poorly on the COAT than children who are in the regular classroom. It was found that children receiving special services performed significantly more poorly, and 13% of them were classified in the impaired range, as compared to 3% of the students in the regular classroom. The results provide important reference data for interpreting COAT scores of children with traumatic brain injuries who have either premorbid learning disabilities or other special service needs. PMID- 7849688 TI - Brain-injured persons in an altered state of consciousness: measures and intervention strategies. AB - We evaluated the states of consciousness of seven persons who had sustained a severe head injury, and describe the behavioural manifestations associated with four treatment strategies. The subjects were between the ages of 19 and 55 and were recruited from both acute and long-term care facilities; all were in an altered state of consciousness. The severity of the injury was measured by time in coma, the scores on the Glasgow Coma Scale [1] and the Coma Near Coma Scale [2]. Structured interventions consisted of visual, auditory, olfactory, gustatory and tactile stimulation; behaviour was measured using the Disability Rating Scale [3, 4] and a portion of the Levels of Cognitive Functioning Scale [5]. Sensory motor indications were recorded using a questionnaire developed by Freeman [6] and a quality-of-life instrument, developed for use with individuals having multiple disabilities [7], was adapted for the purpose of this study. Our results suggest that the use of structured interventions in the first 24 months following severe head injury is associated with a trend towards improved auditory and visual skills performance, manual performance, swallowing and language. Whereas initially no subject had any form of verbalization, by the final evaluation five subjects had some form of communication, either verbal or non-verbal. PMID- 7849689 TI - Late outcome of mild head injury: results from a controlled postal survey. AB - There is insufficient information about the long-term sequelae of mild head injury (postconcussional symptoms, PCS). Therefore, a questionnaire-based investigation was carried out in patients 1-5 years after mild head injury (MHI) and in non-concussed subjects in order to study the nature of long-term complaints after MHI. A three-factor model of residual subjective and psychological complaints that contained a dysthymic factor, a vegetative/bodily complaints factor, and a cognitive performance factor were identified in the patient population. Three rating scales were constructed from the relevant items or factors, and were used to compare the MHI patients with non-concussed controls. It was found that the profile of distresses and discomforts mentioned by a population of MHI patients 1-5 years after the trauma was similar to that of a non-concussed control population. These symptoms were indistinguishable from those encountered in ordinary everyday life. These symptoms were significantly more severe in the MHI patients. Stepwise regression analysis in the patient population indicated that a number of parameters were statistically of predictive importance: comorbidity, sex, and neurological complication at the time of the trauma. The results support the hypothesis that MHI may not ever be completely reversible. PMID- 7849690 TI - Clinical use of amantadine in brain injury rehabilitation. AB - We retrospectively reviewed the charts of 12 subjects with brain injury who were treated with amantadine. Ten of the 12 subjects exhibited some improvement in cognitive and/or physical function while on amantadine. Areas most consistently showing improvement included focused and sustained attention and concentration, orientation, alertness, arousal, processing, time, and psychomotor speed, mobility, vocalization, agitation, anxiety and participation in therapy. Two of the three subjects with severe agitation showed dramatic resolution of the agitation. Eight of nine low-arousal subjects displayed an increased level of responsiveness. Areas with inconsistent response included memory, assaultiveness, and confusion. No response was seen in depression or sexual inappropriateness. Possible side-effects of amantadine were noted in five of the 12 subjects, and included pedal oedema, hypomania, generalized seizure, and visual hallucinations. This work suggests amantadine may play a role in neurobehavioural recovery of brain injury, and demonstrates the need for more in-depth study. PMID- 7849691 TI - Thromboembolic infarcts occurring after mild traumatic brain injury in a paediatric patient with Noonan's syndrome. AB - Noonan's syndrome is a genetic concurrence of multiple morphological abnormalities typified by short stature, webbed neck, cardiovascular abnormalities, and characteristic facies. Numerous neurological conditions have also been associated with Noonan's syndrome, including cerebrovascular pathology. This paper describes the case of a 15-year-old female on our paediatric rehabilitation service who, in a motor vehicle accident, suffered a mild traumatic brain injury (TBI) which was followed by multiple thromboembolic infarcts of the posterior circulation. Full work-up resulted in the diagnosis of Noonan's syndrome and the demonstration of significant posterior circulation congenital anomalies. Traumatic vasculopathy, superimposed on the developmentally hypoplastic posterior vessels, was suggested as an aetiology of this patient's stroke. A review of the limited literature associating thromboembolic infarcts with antecedent TBI, and linking Noonan's syndrome to various neurological problems, is discussed. This paediatric rehabilitation case represents a fascinating new association between thromboembolic infarcts and TBI in the setting of a previously undiagnosed genetic syndrome. PMID- 7849692 TI - Optimizing outcome through cognitive therapy and advocacy: a case study. AB - When the medical model of rehabilitation is used to formulate outcome goals for survivors of traumatic brain injury, pertinent factors weighed typically include premorbid personality and background, current levels of adaptive functioning and physical and neuropsychological impairments. The independent living model utilizes the client's goal and strengths to focus rehabilitation. This case study illustrates how the independent living approach helped a survivor of brain injury achieve his outcome goal; living in his own apartment. PMID- 7849693 TI - Hypotensive effects of thioridazine in an elderly patient with traumatic brain injury. AB - Neuroleptics have been used to help control agitation, restlessness, and hostility in patients with traumatic brain injury. However, there are many reported side-effects with the use of neuroleptics after brain injury, including memory and other cognitive impairments, as well as slowed neural recovery. Alpha 1 adrenergic blockade with resultant hypotensive and sedating effects has also been reported. This is a case report of a 70-year-old gentleman with traumatic brain injury and cardiovascular disease. Thioridazine was used to control severe behavioural problems but had to be discontinued secondary to marked hypotension. This case illustrates the need for awareness of the significant alpha-1 receptor interaction of some neuroleptics, especially in the elderly population with pre existing heart disease. PMID- 7849694 TI - Expression of the Kallmann syndrome gene in human fetal brain and in the manipulated chick embryo. AB - Kallmann syndrome is an inherited disorder characterized by an abnormality in olfactory system development. The gene for the X-linked form of this disorder (KAL) maps to Xp22.3 and encodes a protein sharing homologies with molecules involved in neuronal migration and axonal pathfinding. Here we report the expression pattern of the KAL gene in various parts of the human fetal brain. We found KAL transcripts in granule cells of the olfactory bulb and the cerebellum, in the dorsomedial thalamus and in the developing cerebral cortex. To determine whether or not signals from the olfactory nerve are required for KAL expression in the olfactory bulb, we analyzed chick embryos in which the olfactory placode was surgically removed. Those embryos lacking an olfactory nerve had a histologically abnormal bulb which nevertheless expressed the KAL gene at high levels. These findings indicate that, while the development of the proper cytoarchitecture of the olfactory bulb requires the innervation by olfactory axons, the expression of KAL is independent of such developmental processes. PMID- 7849696 TI - A transcript map of the Down syndrome critical region on chromosome 21. AB - A catalogue of the genes encoded by chromosome 21 would provide a framework for assigning roles in the etiology of Down syndrome (DS) to individual genes. We have begun generating such a catalogue, starting with a 1.2 Mb region surrounding the marker D21S55. Our efforts utilized the yeast artificial chromosome (YAC) and cosmid-clone based high resolution physical maps that we have constructed of this region. Direct-selection of fetal brain cDNAs with YAC DNA was used to isolate transcribed sequences. The selected cDNA fragments were analyzed by limited DNA sequence analysis, Northern blot hybridization and screening of cDNA libraries. The cDNA fragments were assigned positions on the physical map by hybridization to a collection of cosmid clones. The accurate determination of map positions for individual cDNA fragments allowed us to determine sources of variability in the cDNA selection procedure. The combined analysis and mapping was used to estimate the completeness of our mapping efforts and to identify procedures that would facilitate large-scale transcript mapping. The transcribed sequence map that we have assembled will allow the importance to DS of genes in this region to be examined and will aid in the design of strategies for larger scale efforts. PMID- 7849695 TI - Prevention of dystrophic pathology in mdx mice by a truncated dystrophin isoform. AB - The C-terminal domain of dystrophin is alternatively spliced to produce a variety of tissue and developmental stage-specific isoforms. Recent studies suggest that the C-terminal domain binds to the dystrophin-associated glycoprotein complex (DGC) in muscle, but little is known about the functional significance of the alternative splicing or what role individual isoforms may play in specific tissues. The major dystrophin transcript in brain lacks exons 71-74, and encodes an isoform not observed in skeletal muscle. To explore the capacity of this truncated isoform to function in muscle, we have generated transgenic mice expressing a murine dystrophin mini-gene missing exons 71-74. Uniform expression of this construct on a mutant mdx mouse background results in normal muscle morphology and physiology, and prevents the development of muscular dystrophy. These mice also display normal expression and localization of the DGC, suggesting that the alternatively spliced exons are not required for dystrophin function in skeletal muscle. An additional line of mice was analyzed that had a mosaic pattern of expression. These mice display a markedly milder phenotype than mdx mice, despite the expression of dystrophin in only half the muscle fibers. These results indicate that viral delivery of dystrophin to a simple majority of fibers in a muscle group would greatly reduce the dystrophic pathology associated with Duchenne muscular dystrophy. PMID- 7849697 TI - Screening of genomic DNA to identify mutations in the gene for Bruton's tyrosine kinase. AB - Mutations in the gene for Bruton's tyrosine kinase (Btk) are responsible for X linked agammaglobulinemia (XLA). Thus far, mutations in this gene have been identified based on alterations in Southern or Northern blot analysis or cDNA sequence. To permit detection of mutations in genomic DNA, we designed PCR primers to flank each of the 19 exons of Btk with splice sites. Two overlapping PCR products were employed for exons longer than 230 base pairs. Single strand conformation polymorphism (SSCP) analysis was used to screen PCR products from 30 unrelated families presumed to carry a Btk mutation. It was possible to amplify DNA in every reaction from every patient, indicating that large deletions in Btk are uncommon. Twenty three different mutations were found in 25 unrelated families, including one family in whom DNA was available from a carrier but not an affected patient. Seven mutations were single base pair substitutions resulting in premature stop codons scattered throughout the gene. Small insertions or deletions causing frameshifts and secondary premature stop codons constituted an additional seven mutations. One patient had a point mutation in the start codon and one patient had a mutation in a splice donor site. Point mutations resulting in amino acid substitutions were seen in nine patients. Northern blot analysis of RNA from three patients with premature stop codons showed an absence of Btk transcript whereas four patients with amino acid substitutions had normal amounts of transcript of normal size. These studies document the considerable variability in the Btk mutations causing XLA and they demonstrate an approach that will be useful for carrier detection as well as mutation identification. PMID- 7849698 TI - Variants of the heavy neurofilament subunit are associated with the development of amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder primarily affecting motor neurons. The etiology of the majority of cases remains unknown. Recent findings from several laboratories suggest a role for neurofilaments in the development of motor neuron disorders. The C-terminal region of the human neurofilament heavy subunit (NEFH) contains a unique functional domain consisting of 43 repeat motifs of the amino acids Lys-Ser-Pro (KSP). This C-terminal region of NEFH forms the sidearm projections which cross-link the neurofilaments. Previously, we have demonstrated polymorphism in the C-terminal region of the human NEFH: an allelic variant of a slightly larger molecular size, containing an additional KSP phosphorylation motif. Novel mutations in this region were found in five ALS patients. We propose that changes in the KSP-repeat domain may affect the cross-linking properties of the heavy neurofilament subunit and perhaps contribute to the development of neurofilamentous swellings in motor neurons, a hallmark of ALS. PMID- 7849700 TI - Haplotype analysis of MEN 2 mutations. AB - Multiple endocrine neoplasia type 2 (MEN 2) is a dominantly inherited cancer syndrome which affects thyroid C cells, and with variable frequency, the adrenal medulla, parathyroid and enteric autonomic ganglia. The syndrome is due to germline mutation in the receptor tyrosine kinase gene, RET. We have recently shown an unexpected correlation between one particular RET mutation, cys634- >arg, and the probability of parathyroid involvement in families with MEN 2A. Here we use haplotype analysis in the families to show that this correlation is not explained by a single founder chromosome which carries both the cys634-->arg mutation and a separate allele conferring susceptibility to parathyroid abnormality, but is probably due to the cys634-->arg mutation itself. The results also indicate that new mutations to MEN 2 are not infrequent. PMID- 7849699 TI - Deficiency of the human mitochondrial transcription factor h-mtTFA in infantile mitochondrial myopathy is associated with mtDNA depletion. AB - Recent studies show that patients presenting with cytochrome oxidase (COX) deficiency in infancy may have reduced mitochondrial DNA (mtDNA) in muscle. The human mitochondrial transcription factor A (h-mtTFA) may be an important regulator of both transcription and replication of mtDNA. h-mtTFA levels were investigated in cell lines which were either free of mtDNA (rho 0) or temporarily depleted by treatment with dideoxycytidine (ddC), and in tissue from three patients with mtDNA depletion and cytochrome oxidase deficiency. h-mtTFA was compared with other mitochondrial proteins such as pyruvate dehydrogenase and porin by Western blotting. The ratio of mtDNA and h-mtTFA mRNA to reference nuclear probes was measured by dual labelling of dot blots. The ratio of mtDNA to nuclear DNA in skeletal muscle was low in muscle in the three patients and in other tissues in one. h-mtTFA was low in cells depleted either permanently or transiently of mtDNA, and this reduction in h-mtTFA roughly paralleled mtDNA levels. Similarly, treatment of rho 0 cell lines with ddC induced a reduction in mtDNA as well as h-mtTFA protein. The relationship between h-mtTFA and mtDNA levels suggests that they may be causally linked. MtDNA depletion was accompanied by an increase in the level of h-mtTFA RNA in the cell lines but low levels in the patient. This suggests that either h-mtTFA regulates mtDNA levels, or that h mtTFA expression may be regulated by a feedback mechanism initiated by MtDNA Depletion. PMID- 7849701 TI - The phospholipase C beta 3 gene located in the MEN1 region shows loss of expression in endocrine tumours. AB - Oncogenesis of tumours related to multiple endocrine neoplasia type 1 (MEN1) is associated with somatic deletions involving the MEN1 locus, suggesting inactivation of a tumour suppressor gene in this region. Identification of meiotic cross-overs in MEN1 families has placed the MEN1 locus centromeric of D11S807. An extended deletion mapping was performed in 27 primary parathyroid tumours, and identified D11S427 as the closest centromeric flanking marker. Through physical mapping using newly isolated cDNA clones, we estimated the distance between the flanking markers D11S807 and D11S427 to be less than 900 kb. One of these cDNA clones showed expression of a 4.4 kb message in multiple tissues, including those affected in MEN1, while in five endocrine tumours no transcript was detected. Sequence characterization showed that this gene encodes for the phospholipase C beta 3, a key enzyme in signal transduction. PMID- 7849703 TI - High resolution fluorescence in situ hybridization to linearly extended DNA visually maps a tandem repeat associated with facioscapulohumeral muscular dystrophy immediately adjacent to the telomere of 4q. AB - Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant neuromuscular disorder. The FSHD locus has been linked to the most distal genetic markers on the long arm of chromosome 4. An EcoRI fragment length polymorphism segregates with the disease in most FSHD families. Within the EcoRI fragment lies a tandem array of 3.2 kb repeats. Deletions of integral copies of this repeat have been associated with the disease. The 3.2 kbp repeat has recently been shown to cross-hybridize to several regions of heterochromatin in the human genome and DNA sequence analysis reveals strong homology to a class of heterochromatin repeats, LSau. In this report, we demonstrate that the 3.2 kbp tandem repeat lies adjacent to a subtelomeric sequence, which is within 5-14 kb of the telomeric repeat (TTAGGG)n. Direct visual fluorescence hybridization to linearly extended strands of DNA enabled the visualization of this subtelomeric sequence as a short string of signals at the end of a longer string of signals from the differentially labeled 3.2 kbp tandem repeat. Furthermore, in support of our data showing that the 3.2 kbp repeat lies in close proximity to the telomere of 4q, we demonstrated the lack of hybridization of total human DNA to this same region. Our results indicate that the tandem array of 3.2 kbp repeats, disrupted in FSHD, lies immediately adjacent to the telomere of 4q and that the gene responsible for FSHD is likely located proximal to the tandem repeat. PMID- 7849702 TI - Structural and mutational analysis of the xeroderma pigmentosum group D (XPD) gene. AB - Individuals affected by the autosomal recessive disease xeroderma pigmentosum (XP) are acutely sensitive to sunlight and predisposed to skin cancer on exposed areas. Cells cultured from XP patients are both UV sensitive and defective in the nucleotide excision repair of damaged DNA. These cellular phenotypes are amenable to experimental strategies employing complementation, an approach previously used to demonstrate the correction of XP-D phenotypes following the introduction of the XPD (ERCC2) gene. In the present study, we have characterized the genomic organization of the XPD (ERCC2) gene and found it to be comprised of 23 exons. These data were helpful in evaluating the functional integrity of alleles in two XP-D cell lines. In cell line GM436 a C-->G transversion was found at nucleotide position 1411 in the XPD (ERCC2) cDNA, a change expected to result in a Leu461Val substitution. Cell line XP67MA carries a C-->T transition in genomic DNA at nucleotide position 2176 in exon 22, introducing the termination codon TAG at amino acid 726. The latter would be expected to produce a protein truncated by 34 amino acids. Although expression of the normal XPD cDNA could be shown to correct the UV sensitivity phenotype in XP-D cells, cDNA constructs bearing either of the two mutations failed to yield complementation. These results confirm the role of ERCC2 in XP-D and illustrate the power of utilizing cellular phenotypes to evaluate the significance of single nucleotide substitutions. PMID- 7849704 TI - Characterization and expression of cDNA encoding coproporphyrinogen oxidase from a patient with hereditary coproporphyria. AB - Hereditary coproporphyria (HCP) is an acute hepatic porphyria with autosomal dominant inheritance, but with a variable degree of clinical expression. Molecular cloning, sequencing and expression of the defective gene for coproporphyrinogen oxidase (CPO) in a patient with HCP were carried out. Enzyme assays revealed that CPO activity in EBV-transformed lymphoblastoid cells from the proband and one of her sisters was approximately 50% of normal. Nucleotide sequence analysis of CPO cDNAs isolated from the proband's cells demonstrated three base substitutions, and three accompanying amino acid substitutions. An A514-->C transition causing a Asn172-->His substitution occurred in one allele, while two other transitions, G265-->A and G580-->A, caused Gly89-->Ser and Val194 ->Ile substitutions, respectively, in the other allele. The A514-->C and the G580 ->A transitions are known genetic polymorphisms. Transfection of CPO cDNA into Escherichia coli demonstrated that cDNA with the G265-->A transition produced a protein with less than 5% of normal enzyme activity. These findings indicate that the G265-->A transition, involving the highly conserved glycine residue at the 89th position, is responsible for the CPO defect in the patient and accounts for the partial deficiency of CPO activity in this pedigree. PMID- 7849705 TI - A high resolution physical map of 2.5 Mbp of the Down syndrome region on chromosome 21. AB - The region surrounding D21S55 in band 21q22 of human chromosome 21 has been implicated in the etiology of Down syndrome (DS). In this paper, we report the construction of a high resolution map of a 2.5 Mb region around the marker D21S55. Characterization of YAC clones by accurate size determination, end isolation and marker assignment was used to build a refined YAC-based map. The YAC clones were then used to isolate 284 cosmid clones, covering 2.3 Mb, from a chromosome 21-specific cosmid library. The cosmid clones were ordered into overlapping groups and a restriction map of each group was determined. The groups of cosmids were then ordered and oriented with respect to the YAC-based map. This high resolution map provides the framework for further analysis of the region by transcribed sequence mapping and sequence determination. PMID- 7849706 TI - A heat shock gene at 14q22: mapping and expression. AB - Heat shock proteins (HSP) belong to a family of highly homologous proteins that are encoded by several genes and function as protein chaperones. A number of HSP genes have been described in the major histocompatibility complex (MHC) on chromosome 6. We have cloned and mapped one chromosome 14 HSP gene (HSPA2) using a genomic probe (pH2.3) derived from one of the HSP genes present in the MHC, which was previously shown to also detect sequences on chromosome 14. Screening of a chromosome 14-specific cosmid library yielded one relevant clone that contains an HSP-like sequence, showing a high degree of identity with the HSP genes from the MHC and with HSP70.2 (Hspa2) in the mouse. This new HSP gene is expressed abundantly in muscle, heart, oesophagus and brain, and to a lesser extent in testis. Its localization to 14q22 was established by using a somatic cell hybrid panel and FISH analysis. A pentanucleotide repeat motif, showing seven alleles, was also identified in the cosmid clone. PMID- 7849707 TI - Loss of mutation at the FMR1 locus through multiple exchanges between maternal X chromosomes. AB - The mutation observed in the fragile X syndrome, an X-linked inherited disorder causing mental retardation, is almost exclusively an expanded CGG repeat in the first exon of the FMR1 gene. Here we describe a daughter of a female carrier, who inherited the fragile X premutation chromosome based on haplotype analysis using flanking markers. However, the CGG repeat sequence and the intragenic polymorphic marker FMRb showed the normal maternal alleles, while two other intragenic markers, FMRa and FRAXAC2 and other, more distant markers, showed the risk haplotype. Since FMRa and FRAXAC2 are located in between the markers CGG and FMRb, this results in patches of normal and fragile X sequences in the FMR1 gene of the daughter. This observation is very likely due to gene conversion. As this daughter received a normal CGG repeat region, we expect that her risk to have affected offspring is the same as the population risk. The observed phenomenon would therefore represent a back mutation at the FMR1 locus. PMID- 7849708 TI - 9q34 loss of heterozygosity in a tuberous sclerosis astrocytoma suggests a growth suppressor-like activity also for the TSC1 gene. AB - Tuberous sclerosis is an autosomal dominant disease whose characteristic feature is the development of multiple hamartomas in a variety of organs and tissues. Two major loci have been identified so far: TSC1 on chromosome 9q34 and TSC2 on chromosome 16p13.3. Loss of heterozygosity at 16p13.3-associated markers has been recently observed in hamartomatous lesions of some tuberous sclerosis patients. Here we report the first evidence of loss of heterozygosity at the TSC1 critical region in a giant cell astrocytoma of a familial tuberous sclerosis case. Segregation analysis showed that the 9q34 haplotype lost carried the putative normal TSC1 gene. These data support the hypothesis of both a germline and somatic loss-of-function mutation for the development of tuberous sclerosis hamartomas and suggest a tumor-suppressor-like activity also for the TSC1 gene product. Finally, the possible significance of a second small region of loss of heterozygosity at 9p21, found in the same astrocytoma, is discussed. PMID- 7849709 TI - The tuberous sclerosis gene on chromosome 9q34 acts as a growth suppressor. AB - We have previously demonstrated allele loss in hamartomas from patients with tuberous sclerosis for markers spanning the tuberous sclerosis gene on chromosome 16q13.3 (TSC2). Germline deletions in the TSC2 gene have been shown in 5% of patients with tuberous sclerosis (TSC). These data support our hypothesis that the TSC2 gene acts as a growth suppressor gene, analogous to the traditional tumour suppressor gene. We now report a TSC hamartoma showing allele loss for markers on chromosome 9q34 in the region of the TSC1 gene. We studied six hamartomas from four sporadic and two familial cases of TSC, none of which showed allele loss for markers on chromosome 16p13.3. The hamartomas were paraffin embedded sections of three renal angiomyolipomas, two giant cell astrocytomas, and a cardiac rhabdomyoma. Eight markers were analysed, comprising from centromeric to telomeric ASS-D9S64-D9S149-ABO-D9S150-DBH-D9S66-D9S67++ +. One angiomyolipoma showed allele loss for the markers ABO, DBH and D9S66, but not for D9S149 or D9S67. The patient was not informative for D9S150. The family structure did not permit the phase of the disease and marker alleles to be determined. These finding support the hypothesis that the TSC1 gene on 9q34, like the TSC2 gene, acts as a growth suppressor. The data would place the TSC1 gene between D9S149 and D9S67. Mapping of allele loss in hamartomas may help in the refinement of the location of the TSC1 locus. PMID- 7849710 TI - Identification of two mutant alleles of transcobalamin II in an affected family. AB - Transcobalamin II (TC II) deficiency is a rare autosomal recessive disease leading to cobalamin (Cbl; Vitamin B12) deficiency characterized by failure to thrive, megaloblastic anemia, impaired immunodefence and neurological manifestations. By means of Southern blotting and sequence analysis of TC II cDNA amplified from fibroblasts of an affected child and his parents, we have identified two mutant TC II alleles, one with a gross deletion and the other with a 4 nucleotide deletion. Both the mutations caused TC II mRNA and protein deficiency and hence defective plasma transport of Cbl and the development of Cbl deficiency in the affected child. The present study has identified molecular defects that cause TC II deficiency and lead to intracellular Cbl deficiency in humans. PMID- 7849711 TI - MTS1/CDKN2 gene mutations are rare in primary human astrocytomas with allelic loss of chromosome 9p. AB - Human astrocytomas frequently have allelic losses of chromosome 9p, suggesting the presence of a 9p astrocytoma tumor suppressor gene. The MTS1 (or CDKN2) gene on chromosome 9p encodes a cell-cycle regulator and is deleted in approximately 80% of astrocytoma cell lines. To determine whether MTS1 is the tumor suppressor gene involved in human astrocytoma formation in vivo, we have analyzed chromosome 9p allelic loss and the MTS1 gene in 30 primary astrocytomas. Deletion mapping demonstrated 15 cases with allelic loss of chromosome 9p, with all losses either flanking or involving the MTS1 gene. Direct analysis of the MTS1 gene, however, revealed only a single missense mutation in a high-grade tumor that had lost the second allele. The low frequency of MTS1 mutations in primary astrocytomas with allelic 9p loss suggests that MTS1 may be more important for in vitro than in vivo astrocytoma growth, and that another 9p tumor suppressor gene may be involved in astrocytoma formation in vivo. Analysis of the MTS1 gene also demonstrated two intragenic polymorphisms, one in exon 2 and one in the 3' untranslated region, that can be used to assay allelic loss directly at MTS1. PMID- 7849712 TI - Detection of a novel RYR1 mutation in four malignant hyperthermia pedigrees. AB - Malignant hyperthermia (MH) is a potentially fatal autosomal dominant disorder of skeletal muscle and is triggered in susceptible people by all commonly used inhalational anaesthetics and depolarizing muscle relaxants. To date, six mutations in the skeletal muscle ryanodine receptor gene (RYR1) have been identified in malignant hyperthermia susceptible (MHS) and central core disease (CCD) cases. Using SSCP analysis, we have screened the RYR1 gene in affected individuals for novel MHS mutations and have identified a G to A transition mutation which results in the replacement of a conserved Gly at position 2433 with an Arg. The Gly2433Arg mutation was present in four of 104 unrelated MHS individuals investigated and was not detected in a normal population sample. This mutation is adjacent to the previously identified Arg2434His mutation reported in a CCD/MH family and indicates that there may be a second region in the RYR1 gene where MHS/CCD mutations cluster. PMID- 7849713 TI - A proposed new contiguous gene syndrome on 8q consists of Branchio-Oto-Renal (BOR) syndrome, Duane syndrome, a dominant form of hydrocephalus and trapeze aplasia; implications for the mapping of the BOR gene. AB - The analysis of a de novo 8q12.2-q21.2 deletion led to the identification of a proposed previously undescribed contiguous gene syndrome consisting of Branchio Oto-Renal (BOR) syndrome, Duane syndrome, hydrocephalus and trapeze aplasia. This is the first reported localization of the genes responsible for Duane syndrome and this dominant form of hydrocephalus. In contrast, we report a new localization for the gene responsible for BOR syndrome which is more telomeric to an initial placement. Linkage analysis of affected families consistently mapped the gene responsible for BOR and Branchio-Oto (BO) syndromes to within the deletion. Using new algorithms, a YAC contig was constructed and used to localize the breakpoint of another chromosomal rearrangement associated with BO syndrome to a 500 kb interval within the deletion. The 8q12.2-q21.2 deletion suggests that reduced dosage of the relevant genes is sufficient to cause Duane syndrome, BOR syndrome and this dominant form of hydrocephalus. PMID- 7849714 TI - Linkage of a locus for autosomal dominant familial spastic paraplegia to chromosome 2p markers. AB - 'Pure' autosomal dominant familial spastic paraplegia (SPG) is a neurodegenerative disease which clinically manifests as spasticity of the lower limbs. Dominantly inherited SPG is known to be clinically heterogenous and has been classified into late-onset and early-onset types, based on the age of onset of symptoms. We tested five autosomal dominant SPG families for genetic linkage and established linkage to chromogene 2p markers (Z(theta) = 3.65) with evidence of genetic locus heterogeneity. Three late-onset SPG families and one early-onset SPG family had high posterior probability of linkage (P > 0.94) to chromosome 2p, while the fifth family (a very early-onset family) was not linked to chromosome 2 and showed high probability of linkage to chromosome 14q. These data provide a basis for a classification of SPG according to chromosome location rather than age of onset of symptoms. PMID- 7849715 TI - Polycystic ovaries and premature male pattern baldness are associated with one allele of the steroid metabolism gene CYP17. AB - Fourteen Caucasian families with 81 affected individuals have been assessed in which polycystic ovaries/male pattern baldness (PCO/MPB) segregates as an autosomal dominant phenotype (1). The gene CYP17, coding for P450c17 alpha (17 alpha-hydroxylase; 17/20 lyase) on chromosome 10q24.3 is the rate-limiting step in androgen biosynthesis. We have identified a new single base change in the 5' promoter region of CYP17 by heteroduplex analysis. This creates an additional SP1 type (CCACC box) promoter site, which may cause increased expression. This base change also creates a recognition site for the restriction enzyme MspA1 allowing a simple screening procedure. There is a significant association between the presence of this base change (A2) and the affected state for consecutively identified Caucasian women with PCO as compared either to consecutively matched controls (P = 0.03) with an odds ratio for those with at least one A2 allele of 3.57, or to a random population (P = 0.02) with an odds ratio of 2.50. Within the fourteen families, members with PCO or MPB have a significant association with the occurrence of at least one A2 allele compared to their normal relatives, with an odds ratio of 2.20 (P = 0.05). The base change does not cosegregate with the affected phenotype within the families showing association, demonstrating that this mutation of CYP17 does not cause PCO/MPB. Variation in the A2 allele of the CYP17 gene is a significant factor modifying the expression of PCO/MPB in families where it has been demonstrated to segregate as a single gene disorder, but it is excluded as the primary genetic defect. PMID- 7849716 TI - Identification of a novel paternally expressed gene in the Prader-Willi syndrome region. AB - We have isolated a novel gene from the Prader-Willi syndrome (PWS) smallest region of deletion overlap in proximal human chromosome 15q. IPW (Imprinted gene in the Prader-Willi syndrome region) was isolated using the direct selection method and yeast artificial chromosomes localized to the deletion region. IPW is spliced and polyadenylated but its longest open reading frame codes for only 45 amino acids, suggesting that it functions as an RNA, similar to H19 and XIST. The RNA is widely expressed in adult and fetal tissues and is found in the cytoplasmic fraction of human cells, which is also the case for the H19 non translated RNA, but differs from the XIST RNA which is found predominantly in the nucleus. Using a sequence polymorphism, exclusive expression from the paternal allele in lymphoblasts and fibroblasts was demonstrated; monoallelic expression was found in fetal tissues. IPW is located about 150 kb distal to SNRPN, the only other known gene in the deletion interval, and about 50 kb proximal to the breakpoint of a translocation which defines the distal end of the PWS region and the proximal end of the Angelman syndrome (AS) region. As is the case with SNRPN, PWS patients with 15q11-q13 deletions do not express IPW, whereas expression is normal in Angelman syndrome patients. Lack of expression of IPW may contribute to the PWS phenotype directly. Alternatively, the mRNA product of IPW may play a role in the imprinting process, acting either on genes located proximally in the PWS region or distally in the AS region. PMID- 7849717 TI - Characterization of a cystathionine beta-synthase allele with three mutations in cis in a patient with B6 nonresponsive homocystinuria. AB - We used SSCP to survey reverse transcribed-PCR amplified cystathionine synthase cDNAs from patients with homocystinuria. In a single CBS allele, we identified one synonymous and two missense mutations in a portion of the cDNA encoded by a single 135 bp exon which also encodes K119, the putative site of cofactor, pyridoxal 5'-phosphate, binding. The patient, a B6-nonresponsive homocystinuric of Irish descent, is homozygous for a G-->A transition at cDNA position 374, a G- >A transversion at position 393, and a G-->A transition at position 453 resulting in R125Q, E131D and P145P, respectively. Family studies confirmed that all three mutations are present in cis and none were present in 54 Irish and 58 North American controls. R125 is conserved in rat CBS while E131D is conserved in rat CBS, and a related enzyme, O-acetylserine(thiol)-lyase, from a variety of plant and bacterial species. Expression studies showed that both R125Q and E131D, either individually or together, inactivate CBS. The apparently simultaneous appearance of more than one mutation in a single exon suggests they may have arisen by a gene conversion event or by nonhomologous recombination. PMID- 7849718 TI - Identification of a new frameshift mutation (1801delAG) in the ALD gene. PMID- 7849719 TI - Alternative splicing as the result of a type II procollagen gene (COL2A1) mutation in a patient with Kniest dysplasia. PMID- 7849721 TI - Unique mutations of Bruton's tyrosine kinase in fourteen unrelated X-linked agammaglobulinemia families. PMID- 7849720 TI - RET proto-oncogene mutations in inherited and sporadic medullary thyroid cancer. PMID- 7849722 TI - Two new mutations affecting the donor splice site of COL3A1 IVS37 and causing skipping of exon 37 in patients with Ehlers-Danlos syndrome type IV. PMID- 7849723 TI - Missense mutations are frequent in the gene for X-chromosomal adrenoleukodystrophy (ALD). PMID- 7849724 TI - Novel small mutations along the DMD/BMD gene associated with different phenotypes. PMID- 7849725 TI - A novel homozygous nonsense mutation in the LAMC2 gene in patients with the Herlitz junctional epidermolysis bullosa. PMID- 7849726 TI - Six microsatellite polymorphisms at candidate and confirmed tumour suppressor gene loci. PMID- 7849727 TI - A common insertion/deletion polymorphism in the Prader-Willi syndrome minimal critical region. PMID- 7849728 TI - Tetranucleotide repeat polymorphism at the D8S492 locus. PMID- 7849729 TI - The same polymorphism identified by the DXS571(B) and DXS1105 loci. PMID- 7849730 TI - A Bg/II polymorphism in the COL4A6 gene. PMID- 7849731 TI - Dinucleotide repeat polymorphism at the NF2 gene. PMID- 7849732 TI - GA repeat polymorphism at the PRM2 male fertility locus. PMID- 7849733 TI - Single nucleotide polymorphism in exon 2 of the BCP gene on 7q31-q35. PMID- 7849734 TI - Detection of a RsaI polymorphism within the human galactokinase gene (GK2) by PCR SSCP. PMID- 7849735 TI - Polymorphism of the HLA90 new class I gene. PMID- 7849736 TI - Human male fertility--Y-linked genes and spermatogenesis. AB - Using a positional cloning approach, we have isolated a new gene family, the Y located RNA Recognition Motif genes (YRRM), which constitutes a candidate for AZF, the 'azoospermia factor' located principally within band Yq11.23, and thought to be important in the control of human spermatogenesis. The YRRM gene family has at least 15 members, more than one of which are transcribed, some of which are pseudogenes. RNA in situ hybridization to adult human testis tissue indicates that gene expression of the YRRM family is confined to germ cells, notably spermatogonia and/or primary spermatocytes. Similar patterns of hybridization are seen for a second gene family, TSPY, clustered mainly on the short arm of the human Y chromosome. Both YRRM and TSPY show Y chromosome conservation in several mammalian species. PMID- 7849737 TI - Genetic deafness--progress with mouse models. AB - Genetic deafness is relatively common, accounting for about half of the 1 in 1000 children born with a significant hearing impairment. Heterogeneity is a particular problem when searching for genes for deafness in humans, and the mouse may prove to be a valuable model not only for investigating the nature of the deafness once the gene is known, but also for finding the gene by positional cloning. Several genes causing syndromic deafness have been identified in humans, but the largest group in the population have autosomal recessive deafness, and identification of homologous genes in the mouse may be the only route to these genes. Progress with positional cloning of the shaker-1 mouse mutation is described. PMID- 7849738 TI - Molecular basis for three X-linked immune disorders. AB - Gene defects causing three X-linked human immunodeficiencies, agammaglobulinemia (XLA), hyper-IgM syndrome (HIGM), and X-linked severe combined immunodeficiency (SCID), have been identified. These represent the first human disease phenotypes associated with three gene families already recognized to be important in lymphocyte development and signaling: XLA is caused by mutations of a B-cell specific intracellular tyrosine kinase; HIGM by mutations in the tumor necrosis factor-related CD40 ligand, through which T cells deliver helper signals by direct contact with B-cell CD40; and SCID by mutations in the gamma chain of the lymphocyte receptor for interleukin-2. The great variety of patient mutations in all three genes represent both a challenge for genetic diagnosis and a resource for dissecting molecular domains and physiologic functions of the gene products. PMID- 7849739 TI - Sex determination. AB - The cloning of the 'testis determining gene', SRY, promised a revolution in the understanding of sex determination in humans. The failure to isolate further genes involved in sex determination has been a disappointment. The biology of SRY, however, has kept the field exciting. The discoveries of sex reversing SRY mutations with variable penetrance, but with full expressivity, rapid SRY sequence evolution and circular Sry transcripts could not have been predicted. PMID- 7849740 TI - Molecular genetics of oculocutaneous albinism. AB - Albinism is a group of genetic disorders characterized by deficient synthesis of melanin pigment. In oculocutaneous albinism (OCA) the pigment deficiency involves the skin, hair, and eyes, whereas in ocular albinism (OA) the defect involves principally the visual system. Type I (tyrosinase-deficient) OCA results from deficient catalytic activity of tyrosinase, which catalyzes at least three steps in the melanin biosynthetic pathway. Type II (tyrosinase-positive) OCA results from abnormalities of the 'P' polypeptide, which may be a melanosomal tyrosine transporter. At least some forms of OA appear to represent mild presentations of types I and II OCA. The causes of several other forms of albinism have not yet been identified. Recent application of molecular genetic techniques to the study of these disorders has led to greatly improved knowledge of their molecular pathogenesis and relationships, and paves the way to improved diagnosis, carrier detection and prenatal diagnosis, and even to eventual treatment. PMID- 7849741 TI - The molecular genetics of tuberous sclerosis. AB - Tuberous sclerosis (TSC) is an autosomal dominant trait characterized by the widespread development of benign tumours classified as hamartoma, and is often associated with seizures and mental retardation. The patchy distribution and focal nature of the growths suggests that they might result from inactivation of a tumour suppressor gene by a two-hit process. Over the last 2 years, studies designed to investigate both germline and somatic TSC mutations have lent support to this hypothesis. Analysis of TSC-associated hamartomas has shown loss of heterozygosity for the regions of chromosomes 9 and 16 known to harbour TSC genes, consistent with the occurrence of somatic 'second-hit' mutations. Parallel investigations using pulse field gel electrophoresis have identified constitutional deletions representing 'first-hit' mutations at 16p13.3, leading to the rapid identification of one of the causative genes, TSC2. Intriguingly, the TSC2 product, tuberin, has an area of sequence homology with the GTPase activating protein rap1GAP, suggesting a possible mechanism for its role in regulating cellular growth. PMID- 7849742 TI - Role play in X-inactivation. AB - Initiation of X-inactivation is known to depend on the presence of a unique region or locus known as the X-inactivation center, or Xic, defined by the study of chromosomal rearrangements. Its mode of action is currently unknown but is the scene of much research effort. This review explores the recent literature concerning the definition of Xic and its relationship both to Xist and to another genetic entity thought to play a role in the initiation of X-inactivation, the X controlling element, or Xce. PMID- 7849743 TI - DNA methylation and cancer. AB - Changes in the pattern of DNA methylation have been a consistent finding in cancer cells. The mostly descriptive nature of these studies and the fact that both hypo- and hypermethylation have been observed at various loci have made it difficult to assess whether these changes are causally involved in the transformation process or whether they reflect the altered physiology of rapidly dividing cancer cells. It is clear, however, that DNA methylation plays an important role in the generation of mutations in human tumors. The high incidence of C-to-T transitions found in the p53 tumor-suppressor gene is attributed to the spontaneous deamination of 5-methylcytosine residues. The multiple observations linking DNA methylation to cancer can be resolved in a model proposing that the high rate of mutation at CpG dinucleotides is due in part to methyltransferase facilitated deamination. Support for a role of DNA methyltransferase as a mutator enzyme is provided by work with a prokaryotic DNA methyltransferase under S adenosyl-methionine methyl-donor limiting conditions. Methyl-donor limiting conditions might arise in early stages of tumor development, leading to high rates of methyltransferase-mediated CpG mutagenesis, as seen in human tumors. Such a mechanism is consistent with the frequently reported methionine auxotrophy of cancer cells and with the tumorigenic effects of methyl-deficient diets. Methyl deficiency in tumor cells is also consistent with the commonly observed global hypomethylation of tumor cell DNA, despite normal or even high levels of DNA methyltransferase expression. PMID- 7849744 TI - Somatic gene therapy for cystic fibrosis. AB - There is considerable potential to ameliorate the pulmonary disease in cystic fibrosis (CF) using somatic gene therapy. Even low levels of expression of the gene in airways epithelium may be beneficial. Adenoviral vectors, DNA-liposome complexes, adeno-associated viral vectors and DNA-ligand complexes have been used effectively in vitro and have been tested in animals to varying extent. Adenoviral vectors and DNA-liposome complexes are being used to deliver the CF gene to patient airways in phase I clinical trials. Transient correction of the electrophysiological defect in human CF nasal epithelium has been achieved. Major goals are (i) to demonstrate that expression of the CF gene in airways epithelium will ameliorate lung disease in CF patients, and (ii) to achieve long-term expression of the introduced gene either through a single delivery with persistent expression or through the ability to use a delivery system repetitively with safety and efficacy. PMID- 7849745 TI - Molecular genetics of Charcot-Marie-Tooth disease and related neuropathies. AB - Collectively, the inherited disorders of peripheral nerves represent a common group of neurologic diseases. Charcot-Marie-Tooth neuropathy type 1 (CMT1) is a genetically heterogeneous group of chronic demyelinating polyneuropathies with loci mapping to chromosome 17 (CMT1A), chromosome 1 (CMT1B), the X chromosome (CMTX) and to another unknown autosome (CMT1C). CMT1A is most often associated with a tandem 1.5 megabase (Mb) duplication in chromosome 17p11.2-12, or in rare patients may result from a point mutation in the peripheral myelin protein-22 (PMP22) gene. CMT1B is associated with point mutations in the myelin protein zero (P0) gene. The molecular defect in CMT1C is unknown. X-linked Charcot-Marie-Tooth neuropathy (CMTX) is associated with mutations in the connexin32 gene. Charcot Marie-Tooth neuropathy type II (CMT2) is an axonal neuropathy, also of undetermined cause. One form of CMT2 maps to chromosome 1p36 (CMT2A). Dejerine Sottas disease, also called hereditary motor and sensory neuropathy type III (HMSNIII), is a severe, infantile onset demyelinating polyneuropathy syndrome that may be associated with point mutations in either the PMP22 gene of the P0 gene. Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder that results in a recurrent, episodic demyelinating neuropathy. HNPP is associated with a 1.5 Mb deletion in chromosome 17p11.2-12 and may result from reduced expression of the PMP22 gene. CMT1A and HNPP are apparent reciprocal duplication/deletion syndromes originating from unequal crossover during germ cell meiosis. PMID- 7849746 TI - Genes conserved in yeast and humans. AB - Evolutionary conservation of homologous gene products from distantly related organisms provides an information resource of great value for elucidating protein structure and function. Sequence similarities also serve as molecular cross references between diverse organisms that offer different, or complementary, experimental approaches for analyzing gene expression and biochemistry in normal and abnormal states. There are now countless examples of information about a protein from one species contributing to the understanding of biological phenomena or disease in another species. Such connections are often unanticipated and surprising, but there is an opportunity to make them more systematically as concerted genome sequencing projects progress. In the present review we focus on connections between yeast and human proteins and their functional implications. We present several 'case studies' as well as survey results derived from comprehensive sequence comparisons among all yeast and human proteins currently present in the public databases. PMID- 7849747 TI - A randomized-control study of active and passive treatments for chronic low back pain following L5 laminectomy. AB - The professional literature contains relatively few randomized-control studies that have assessed the efficacy of physical therapy approaches to the management of patients with chronic low back pain (CLBP). The purposes of this study were: 1) to investigate the effects of physical agents, joint manipulation, low-tech exercise, and high-tech exercise on objective measures of CLBP; 2) to track the length of CLBP relief; and 3) to determine treatment cost-effectiveness. Two hundred-fifty subjects (68 females, 182 males; ages 34-51 years) with CLBP following an L5 laminectomy were randomly assigned into five separate groups for a treatment period of 8 weeks. Chronic low back pain status was measured by modified-modified Schober, Cybex Liftask, and Oswestry procedures. Results revealed that: 1) only low-tech and high-tech exercise produced significant improvements (p < .05) in CLBP, 2) the mean period of CLBP relief ranged from 1.6 weeks (control) to 91.4 weeks (low-tech exercise), and 3) low-tech exercise was most cost-effective. It was concluded that: 1) low-tech and high-tech exercise were the only effective treatments for CLBP, 2) low-tech exercise produced the longest period of CLBP relief, and 3) low-tech exercise was the most cost effective form of treatment. Clinically, low-tech exercise may be the treatment method of choice for the effective management of chronic low back pain. PMID- 7849748 TI - The differential effects of external ankle support on postural control. AB - Ankle supports are commonly used in an attempt to decrease the risk of ankle injury during sport. However, their use may also impair postural control, which is an integral component of sports participation. The aim of this study was to investigate the effects of three different ankle supports (tape, brace, and elastic bandage) on postural control in 24 normal subjects with a mean age of 24.8 years (+/- 4.4). Two measures were used to evaluate postural control in one legged stance with the eyes closed: variability of mediolateral ground reaction force (acquired from a force platform) and frequency of foot touchdowns by the nonsupport leg (assumed to indicate ability of the subject to maintain one-legged stance posture). Both measures revealed a differential effect for ankle support on postural control. The use of an elastic bandage had no significant effect on postural control (p > 0.05), while the use of tape or a brace had a significant detrimental effect (p < 0.05). While wearing the tape or a brace, subjects were less steady and touched down more frequently. Restriction of ankle movement was offered as a possible explanation for the results, since postural control was impaired only by the ankle supports which limited ankle motion. These findings may have implications regarding impaired athletic performance. PMID- 7849749 TI - Assessment of quadriceps muscle performance by a hand-held dynamometer and an isokinetic dynamometer. AB - Assessment of muscle performance is an integral component of patient evaluation. The primary purposes of this study were to examine the relationship between isokinetic dynamometer isokinetic peak force values and hand-held dynamometer isometric peak force values when assessing quadriceps muscle performance in subjects with orthopaedic knee dysfunctions (N = 21) and to test for differences in muscle performance between injured and noninjured lower extremities using a hand-held dynamometer and an isokinetic dynamometer. An analysis of variance was used to compare injured and noninjured extremities for both testing devices. A Pearson product moment correlation was used to examine the relationship between the hand-held dynamometer and isokinetic dynamometer values. No significant difference between extremities at 0 degrees (p = 0.1224) or 60 degrees (p = 0.8267) was revealed when testing with the hand-held dynamometer. The isokinetic dynamometer, however, revealed a significant difference between extremities at 60 degrees/sec (p = 0.0041). Correlations between the two devices were significant, ranging from r = 0.57 to 0.80. We concluded that these correlations were misleading because more force was generated by the quadriceps muscles tested than a tester of average strength could resist. Further research is needed to validate the use of the hand-held dynamometer by a tester of average strength. PMID- 7849750 TI - Interdevice reliability and validity assessment of the Nicholas Hand-Held Dynamometer. AB - The Nicholas Hand-Held Dynamometer (HHD) has been shown to have excellent interday and intraday reliability when using the same HHD. Since clinics may have more than one HHD with which to evaluate patients, it would be of value to know if two identical HHDs measure the same variable consistently. The purpose of this investigation was to assess interdevice reliability of the Nicholas HHD as well as to determine its validity. Thirty healthy female subjects between the ages of 20 and 56 years (mean age = 28.4) were tested for hamstring strength. Three measurements of maximum hamstring contractions were obtained using the first HHD (Device A). The average of these three measurements was compared with the average of three measurements obtained after a brief rest using a second HHD (Device B). Measurements from the two HHDs were also compared with measurements obtained from a Kin-Com isokinetic dynamometer. The Kin-Com measurements were used as criteria to determine validity of the HHD. An intraclass correlation coefficient (ICC) calculated to determine reliability between the two HHDs was low (ICC = .58). Pearson product-moment correlation coefficients were calculated between the Kin Com and each of the two HHDs. These values were .85 and .83 for Device A and B, respectively. Analysis of variance showed no significant difference between the Kin-Com and Device A but a significant difference between the Kin-Com and Device B (p < .001). Measurements obtained from two identical HHDs may be significantly different and should not be compared. PMID- 7849751 TI - Clinical implications of secondary impingement of the shoulder in freestyle swimmers. AB - Swimming has become a popular recreational activity as well as a highly competitive sport in the United States. The repetitive nature of swimming can predispose the shoulder to mechanical impingement and microtrauma, which may lead to laxity, rotator cuff fatigue, and subsequent secondary impingement. Improper stroke mechanics can place the swimmer's shoulder at further risk. The purpose of this paper is to describe the pathology of secondary impingement in freestyle swimmers and to discuss the clinical implications for rehabilitation of swimmers with the pathology. A thorough subjective and objective evaluation is necessary to design a successful rehabilitation program. The rehabilitation program for swimmers with secondary impingement includes modification of training, flexibility, range of motion, strengthening, and mobilization as indicated. Functional and proprioceptive training may also be useful techniques in the rehabilitation of swimmer's shoulder. Improper stroke mechanics can also have clinical implications on swimmer's shoulders with secondary impingement. The clinical implication of secondary impingement in freestyle swimmers suggests that the primary goal of rehabilitation is to promote equilibrium of the shoulder complex while accounting for the demands of the sport. PMID- 7849752 TI - The effect of medical exercise therapy on a patient with chronic supraspinatus tendinitis. Diagnostic ultrasound--tissue regeneration: a case study. AB - There is an increased focus on the importance of using active exercise regimes for treating dysfunction in the musculoskeletal system. However, we have little exact knowledge on how to dose and grade exercises or the effect of exercise on the regeneration of low metabolic tissue structures in vivo. This case study deals with both topics and emphasizes the use of exercise only when treating a 73 year-old patient with a 1-year history of shoulder pain. His evaluation indicated chronic supraspinatus syndrome. Different treatment methods had no effect, and medical exercise therapy was tried as a last resort. The patient recovered after 21/2 months with four treatments per week. Diagnostic ultrasound taken before treatment and after a 51/2-month period showed that the supraspinatus tendon had regenerated. These findings are encouraging, supporting the possibility of tendon repair with biomechanical stresses from exercise. To our knowledge, it has never been shown in vivo that it is possible for a low metabolic structure to regenerate using exercise only. Instead of having surgery with an uncertain outcome, today the patient is free of symptoms and living a normal life enjoying his sporting activities nearly 4 years after he finished the treatment. PMID- 7849753 TI - Rescue of a maize mitochondrial cytochrome oxidase mutant by tissue culture. AB - The maize NCS6 mitochondrial mutation is a partial deletion of the cytochrome oxidase subunit 2 gene (cox2) that survives heteroplasmically in the plant. Mutant mitochondria segregate from normal mitochondria during somatic development giving rise to defective sectors on the plants, including areas of kernel abortion on the ears. Embryos from NCS6 kernels can be rescued by tissue culture. Slowly growing Type II callus derived from one of these embryos has been shown by PCR analysis to be homoplasmic for the mutation, carrying only the defective mitochondrial cox2 gene. Most of the rescued embryos were heteroplasmic for normal and mutant genes and heteroplasmy was maintained in the callus cultures. However, when suspension cultures were initiated from heteroplasmic calli, normal cells were shown to have a selective advantage. When the homoplasmic cox2 mutant callus cultures were placed on regeneration medium, plantlets did not regenerate. Heteroplasmic calli were capable of regeneration under the same conditions. These studies suggest that the functioning of mitochondrial cytochrome oxidase is not essential for growth as callus, but is required for the differentiation and development of plants. PMID- 7849754 TI - Expression of the S-locus receptor kinase multigene family in Brassica oleracea. AB - The S-receptor kinase (SRK) gene which is implicated in the self-incompatibility system of Brassica oleracea is one member of a large and complex family of similar sequences. Genomic and cDNA clones were isolated for the authentic, S linked SRK29 gene and its DNA sequence determined. Reverse transcriptase PCR (RT PCR) was used to detect the expression of SRK29 and other members of the family in stigma, leaf and root tissues. The SRK was found to be stigma-specific whereas, for instance, K3 transcripts appeared in all three tissues. The RT-PCR analysis also demonstrated the existence of partially processed intermediates for several of the kinase transcripts and, in the case of SRK29, a product apparently resulting from the splicing of a cryptic intron. RFLP analysis of an F2 family segregating for the S29 allele was used to show S-linkage for the SRK and possibly for the K2 sequence. The K8 kinase probe also revealed a minor RFLP which segregated with the S-locus. PMID- 7849755 TI - The barley 60 kDa jasmonate-induced protein (JIP60) is a novel ribosome inactivating protein. AB - The N-terminal region of a 60 kDa, jasmonate-induced protein of barley leaves (JIP60) is shown to be homologous to the catalytic domains of plant ribosome inactivating proteins (RIP). Western blotting of leaf extracts and in vitro reconstitution experiments indicate that JIP60 is synthesized as a precursor which is processed in vivo. This is in keeping with in vitro translation experiments indicating that a deletion derivative of the N-terminal region, but not the putative precursor, strongly inhibits protein synthesis on reticulocyte ribosomes. The inhibition of ribosome function is associated with depurination of 26S rRNA, characteristic of plant RIPs. This indicates that JIP60 is a novel ribosome-inactivating protein requiring at least two processing events for full activation. JIP60 derivatives do not significantly inhibit in vitro protein synthesis on wheat germ ribosomes. These and other results suggest that JIP60 may be involved in plant defence. PMID- 7849756 TI - The forever young gene encodes an oxidoreductase required for proper development of the Arabidopsis vegetative shoot apex. AB - In plant development, leaf primordia are formed on the flanks of the shoot apical meristem in a highly predictable pattern. The cells that give rise to a primordium are sequestered from the apical meristem. Maintenance of the meristem requires that these cells be replaced by the addition of new cells. Despite the central role of these activities in development, the mechanism controlling and coordinating them is poorly understood. These processes have been characterized in the Arabidopsis mutant forever young (fey). The fey mutation results in a disruption of leaf positioning and meristem maintenance. The predicted FEY protein shares significant homology to a nodulin and limited homology to various reductases. It is proposed that FEY plays a role in communication in the shoot apex through the modification of a factor regulating meristem development. PMID- 7849757 TI - The promoter of the barley aleurone-specific gene encoding a putative 7 kDa lipid transfer protein confers aleurone cell-specific expression in transgenic rice. AB - This paper describes the aleurone-specific gene Ltp2 from barley, which encodes a putative 7 kDa non-specific lipid transfer protein. As shown by Northern and in situ hybridization analyses, the Ltp2 transcript is present in barley aleurone cells shortly after the initiation of aleurone cell differentiation. The expression of Ltp2 increases until grain mid-maturity, but the mRNA is absent from mature grains. The Ltp2 transcript is undetectable in the embryo and vegetative tissues, confirming the aleurone specificity of the Ltp2 gene. The ability of the isolated 801 bp Ltp2 promoter to direct aleurone-specific expression in immature barley grains is demonstrated by particle bombardment experiments. In these experiments, the activity of the Ltp2 promoter is 5% of the activity of the strong constitutive Actin1 promoter from rice, as quantified by GUS activity measurements. In stably transformed rice plants containing the Ltp2 promoter-Gus construct, the specificity of the Ltp2 promoter is confirmed in vivo by the presence of GUS activity exclusively in the aleurone layer. This study demonstrates the conserved nature of the regulatory signals involved in aleurone specific gene transcription in cereal grains. PMID- 7849758 TI - Promoter tagging with a promoterless ipt gene leads to cytokinin-induced phenotypic variability in transgenic tobacco plants:implications of gene dosage effects. AB - Tobacco plants have been transformed with a T-DNA construct harboring a promoterless cytokinin-synthesizing ipt gene close to the right T-DNA border. Eighteen out of 85 transgenic clones displayed phenotypic alternations typical for an enhanced cytokinin production. Northern blot analysis confirmed the transcriptional activation of the introduced gene by tagged plant promoters. The concentration of cytokinins, expressed as zeatinriboside equivalents, was increased up to sevenfold in transgenic tissues. These increases in cytokinin levels resulted in major developmental changes. Transgenic clones exhibited to different levels traits of a general cytokinin-syndrome, i.e. reduced root growth, reduced apical dominance, reduced leaf surface, reduced growth of the stem and retarded leaf senescence or displayed localized and developmentally specific cytokinin-induced alterations in otherwise normally developing plants. These traits were in particular a simultaneous break of dormancy in all axillary buds before or at the onset of flowering or the reorientation of the developmental pathway of secondary meristems or terminally differentiated cells. This indicates that endogenously produced cytokinins not only influence different growth parameters but have the potential to alter differentiation pattern. The results show that stably inherited developmental alterations due to a general or localized cytokinin overproduction can be obtained by the promoter-tagging approach. The investigation of gene dosage effects in homozygote plants readdresses the question of threshold levels for cytokinin effects on the developmental program of plants. PMID- 7849759 TI - Analysis of the cucumber malate synthase gene promoter by transient expression and gel retardation assays. AB - Recently it has been demonstrated that the single-copy malate synthase (MS) and isocitrate lyase (ICL) genes from cucumber are regulated by nutritional status in cucumber cell cultures. In this paper a new cucumber mesophyll protoplast transient expression system is described in which electroporated MS promoter-GUS reporter gene constructs exhibit the same pattern of expression as the endogenous MS gene. Both the electroporated MS-GUS constructs and the endogenous gene are expressed when protoplasts are cultured for 48 h on a non-metabolizable carbon source such as mannitol or 3-methylglucose, and repressed when cultured on a utilizable carbon source such as sucrose, glucose or fructose. A series of deletion mutants identified a region from position -248 to -125 relative to the start of transcription that is essential for expression of the MS-GUS construct under the different metabolic conditions. A 191 bp fragment spanning this region was fused, in both orientations, to the CaMV 35S core promoter. A pattern of metabolic regulation similar to that of the intact MS promoter was observed for these promoter fusion constructs which strongly suggests the presence of enhancer element(s) within this region. Comparison of the 191 bp region with other MS and ICL promoter sequences revealed a region of homology, designated RT. A gel retardation assay was used to assess binding of the 191 bp fragment to whole cell protein extracts from cell cultures expressing MS. Both the unlabelled 191 bp fragment and a synthetic oligonucleotide of RT compete specifically for the demonstrated binding activity. PMID- 7849760 TI - Complementary deletions in expressed potato U2snRNA gene variants support the hypothesis that stem-loop IIb is dispensable for splicing. AB - A polymerase chain reaction (PCR) strategy designed to amplify DNA sequences between closely linked U2snRNA genes has generated extensive coding and 5' regulatory sequence information on the potato U2snRNA multigene family. Two of the U2snRNA coding sequences isolated differed substantially from normal U2snRNAs by containing both complementary deletions and regions of novel sequence. However, sequences such as Sm-binding sites and loops of stem-loops III and IV, which are some of the most highly conserved regions in U2snRNA, remain highly conserved in these genes. The complementary deletions would effectively remove stem-loop IIb which has been shown in yeast to be unnecessary for pre-mRNA splicing. Transcripts from one of the genes have been detected by reverse transcriptase-PCR (RT-PCR) in total RNA. These novel U2snRNA genes represent the first reported example of naturally occurring structural variants and provide support for the proposed non-essential role of U2snRNA stem-loop IIb. PMID- 7849761 TI - Molecular characterization of two Brassica napus genes related to oleosins which are highly expressed in the tapetum. AB - Two highly homologous Brassica napus flower cDNA clones, Sta 41-2 and Sta 41-9, were isolated and characterized. These clones were shown to correspond to genes expressed in the tapetum from the early uninucleate microspore stage to the dinucleate stage. The predicted Sta 41-2 and Sta 41-9 proteins possessed characteristics similar to oleosins such as a polar N-terminal domain, a large relatively conserved hydrophobic domain and a long C-terminal domain which consisted of four different groups of repeats. In addition, like oleosins, the Sta 41-2 and Sta 41-9 proteins have a basic pI, lack a signal peptide and are found in a tissue which accumulates lipids in small lipid bodies. PMID- 7849762 TI - Expression of extracellular matrix proteins and the role of fibroblasts and macrophages in repair processes in ischemic porcine myocardium. AB - In the experimental model of coronary microembolization in pig hearts, the processes of wound healing and scar formation were studied. Methods employed were: electron microscopy, immunohistochemistry using monoclonal antibodies (against fibronectin, laminin, collagen I, III, and VI, chondroitin sulfate, and vimentin), and in situ hybridization with radioactively labeled RNA (histones, fibronectin) or cDNA (acidic fibroblast growth factor) probes. The following time course for expression of various proteins and their mRNAs was established: Mitotic activity was significant at 3 d as well as expression of fibronectin mRNA. Cellularity comprising blood borne cells and macrophages was high. At 7 d, fibronectin, laminin and collagen VI accumulation were pronounced, vimentin positive cells were numerous. At 4 weeks, collagen expression was prominent, but interstitial cells were still present. It is concluded that healing after myocardial necrosis passes through the classical phases of wound healing, i.e., granulation tissue formation and final scar formation. Different extracellular matrix proteins show a differing time course of expression, tumor necrosis factor alpha (TNF-alpha) and acidic fibroblast growth factor (aFGF) produced by macrophages may be involved in inflammatory processes and angiogenesis. Scar formation is not yet completed at 4 weeks after injury. PMID- 7849763 TI - Changes in the microvascular network during cardiac growth, development, and aging. AB - Quantitative changes in the terminal vascular bed of the mammalian heart were assessed during postnatal development and aging. The most striking feature is a considerable formation of new capillaries in the early postnatal period, accompanied by a moderate formation of new arterioles. On the other hand, coronary arterioles seem to disappear at a higher rate than capillaries in the senescent heart. We proposed a three-dimensional structural model of tissue capillary supply, defined as capillary domain area times capillary segment length. This so called capillary supply unit increases as a function of age and body growth. It is very similar in size and shape (length to width ratio) to cardiac myocytes. PMID- 7849764 TI - Mechanical factors involved in the growth of the heart and its blood vessels. AB - Various proteins of cardiac myocytes are preprogrammed at a very early stage of heart development, but functional load (stretch, pressure) plays an important role in their expression under both physiological and pathological circumstances. Mechanical factors are also important in growth of vessels, particularly with respect to hypertrophy or hyperplasia of vascular smooth muscle. Their effect on growth of endothelial cells is less clear. Although they have been studied in cell culture, little is known about their involvement in capillary growth in vivo. Their possible role is considered in capillary growth in the normal adult heart where it was elicited by long-term administration of various vasodilators, by long-term bradycardia, or by increased inotropic action. Here the mechanical stimuli may act either by increased shear stress (resulting from increased velocity of flow in long-term dilatation) or by increasing vessel wall tension (in conjunction with increased diameters and/or stretch produced by increased inotropism). While the role of growth factors in the development of myocytes has been established, it is still questionable in capillary growth. It is also possible that various growth factors exert their effect on vessel growth by their vasoactive activity. PMID- 7849766 TI - Bibliography of cellular and molecular biology research. PMID- 7849765 TI - Cardiac muscle and its blood supply: palaeophysiological notes. PMID- 7849767 TI - Growth of the Heart and its Blood Vessels. Symposium proceedings from the 32nd International Congress of Physiological Sciences. Glasgow, Scotland, August 1-6, 1993. PMID- 7849768 TI - Cardiac phenotypic markers expressed in early stages of both cardiac and skeletal muscle development. AB - We have examined changes in the expression of chicken myosin heavy chain (MHC) mRNAs in the heart and skeletal muscles during normal development and in regenerating adult muscles. cDNA clones isolated from adult heart and regenerating skeletal muscle libraries revealed more than 98% sequence homology in the 3' untranslated regions. Using specific cDNA probes we have detected ventricular MHC transcripts in the heart and in early developmental stages of fast as well as slow skeletal muscles. The expression of ventricular MHC mRNA in skeletal muscles is especially significant since, in contrast to mammals, the avian ventricular and slow MHC mRNAs are encoded by different genes. PMID- 7849769 TI - Seamless care: the odyssey of Mrs. H. PMID- 7849770 TI - The PPI for drugs: a five-year trend. PMID- 7849771 TI - Managing chaos. AB - TQM/CQI. Patient-centered care. Critical paths. Reengineering. Downsizing, rightsizing, networking, merging. It is any wonder health care executives are feeling shell-shocked? Yet the reality is that there's no avoiding change, only managing it. And those executives shaping the flow of change are keeping their organizations in the game. Some stories from the front. PMID- 7849772 TI - Help employees become orderly--without orders. PMID- 7849773 TI - Back from bankruptcy. PMID- 7849774 TI - CEO summit--the leadership perspective. Roundtable discussion, Part 2. PMID- 7849775 TI - The urgent care crunch. Medicaid managed care tackles emergency use--with mixed results. AB - With so many state Medicaid programs all rushing to implement managed care programs, it's clear Medicaid managed care is here to stay. The issues involved in making these programs work, it turns out, are more practical than theoretical. And some states are doing better than others. PMID- 7849776 TI - Rural priorities. Hospital links and managed care contracts top the list. AB - CEOs of rural hospitals know that integrating their services is essential to survival. What's not clear is whether the steps many are now taking--hiring primary care doctors and partnering with other hospitals--will secure their future. Results from an H&HN survey on rural integration. PMID- 7849777 TI - Milwaukee--three hospital systems lead the way to integration in 'Brew City'. PMID- 7849778 TI - The top 1%--and counting. Happier patients signal hospital's recovery. PMID- 7849779 TI - Scared straight? PMID- 7849780 TI - The Cardinal's rule. PMID- 7849781 TI - Home-grown reform. PMID- 7849782 TI - Juicing up the Freedom Trail. Boston partners break ground for a data highway. PMID- 7849783 TI - Person to person--someone who knows, just a phone call away. PMID- 7849784 TI - How markets evolve. PMID- 7849785 TI - A trip to our health care future. PMID- 7849787 TI - Preparing graduate students to write for publication. AB - Students can write successfully for publication when the teacher provides appropriate guidelines, builds confidence, and rewards all efforts. This author describes how she has successfully introduced publication criteria into graduate school papers. PMID- 7849786 TI - Motivating clinical nurses to write for publication. AB - Clinical nurses know what works, what doesn't, and how to trouble shoot clinical problems. Yet, many hesitate to put their ideas into manuscript form. This nursing administrator shares successful strategies in motivating clinical nurses to write for publication. PMID- 7849788 TI - How textbook proposals are evaluated. PMID- 7849789 TI - Developing effective editorial boards for hospital-based newsletters and magazines. AB - Editorial boards can be of tremendous help to a busy editor of a hospital-based newsletter or magazine. This article shows you how to develop the role of the editorial board member, make certain all members know and can achieve the editor's expectations, and chair a board that shares with you a commitment to excellence in publishing. These strategies apply to other in-house publications, such as school of nursing and association newsletters as well. PMID- 7849790 TI - The hyphen: an illusive punctuation mark. AB - When you use the principles of hyphenation, you communicate your ideas clearly to the reader. By using hyphens correctly, authors can demonstrate their writing expertise to editorial board members. By commenting on hyphen problems during a review, board members can demonstrate their attention to detail to the author and editor. PMID- 7849791 TI - Blind peer review: tips for authors, reviewers, and editors. AB - Most nursing journal editors use peer review to help them make decisions about which manuscripts to publish. Blind review, masking the identities of authors and/or reviewers, is applied to keep the process fair and to limit biases. PMID- 7849792 TI - Creating a nursing service newsletter. AB - Developing an in-house newsletter requires making a considerable number of decisions to develop the right design for your publication. This nurse author and editor has national and international communication and publication experience. In this article, she shares her perspectives on the newsletter development process with a focus on the all-important design aspects. PMID- 7849793 TI - A special issue on fluency disorders. PMID- 7849794 TI - Improving the effectiveness of stuttering intervention: the journey continues. AB - This article explores a number of roads on the journey to improving stuttering intervention effectiveness. Roads discussed on this journey include: (1) revisiting the research-clinic paradigm; (2) improving definitions and descriptions of stuttering through standardized measurements, norms, and categorization; (3) developing and describing prognostic profiles; (4) documenting outcomes through improved designs and clinician preparation; (5) recognizing the merits and potential pitfalls of specialization; (6) embracing a global community, and (7) investing in future researchers and clinicians committed to improving treatment effectiveness. PMID- 7849795 TI - Of what value is a measure of the stutterer's fluency? AB - The fluency of the stutterer is discussed in terms of how this has contributed to information on stuttering, measurement of efficacy of therapy and possible therapeutic implications. Much research on physiological aspects of stuttering has relied on analysis of fluent tokens and the validity of this is questioned. Use of largely perceptual measures of the quality of fluency after therapy is evaluated and the therapeutic implications of these findings are discussed. PMID- 7849797 TI - Stuttering in childhood: a five-year longitudinal study in progress. AB - The actual state of research in childhood stuttering is presented and certain points open to criticism are discussed. We want to find answers to some of the open questions by means of a longitudinal study that starts at an early stage. In this study the prognostic validity of various dimensions of behaviour can be determined with regard to the development of stuttering. Thus, the conditions for the development of a valid and reliable instrument for early diagnosis are created that enable the specialist to estimate the probability of chronicity and to determine whether to treat or not to treat childhood stuttering. Furthermore, the study aims to develop a screening procedure which is easy to use for the persons in the child's surroundings (parents, teachers, physicians) so that stuttering children can be referred to a specialist at an earlier stage. PMID- 7849796 TI - The rise and fall of operant programs for the treatment of stammering. AB - In the sixties and seventies operant technology was used for the development of stammering treatment programs. Initial successes could not be maintained, which led to a marked decline. Some of the reasons for this are: lower effectivity than originally stated; limited clinical relevance; rigid structure which is uninspiring for the therapist; little room for individualizing the programs despite heterogeneity of clients. More recent treatments reduce these shortcomings with higher flexibility and use of cognitive techniques. PMID- 7849798 TI - A case of acquired stuttering. AB - This case study of acquired stuttering confirms the reality of acquired or neurogenic stuttering. It further shows that the syndrome can exist in its own right. It is not simply a secondary psychological consequence of brain damage but a direct result of the cerebral lesion. PMID- 7849799 TI - Stuttering therapy in 1837 and a young boy's dramatic experience. AB - This is a historical account of the first known case of stuttering therapy in Norway. In his autobiography, school administrator and politician Nils Hertzberg relates how he in 1837 as a 10-year-old boy travelled on horseback, skis and by boat across Norway from west to east and back in order to receive therapy from a travelling German speech teacher C.F. Bansmann. The article provides extracts from the exciting and dramatic journey, describes Bansmann's method and offers some comments on stuttering and stuttering therapy. PMID- 7849800 TI - The importance of zinc and metallothionein in brain. PMID- 7849801 TI - Patterns of cellular uptake and effects on cell survival using antimetallothionein oligodeoxyribonucleotide conjugates in vitro. AB - Synthetic oligodeoxyribonucleotides (ODNs) offer the potential for the sequence specific modulation of viral and cellular gene expression. However, several problems such as efficient delivery into cells, metabolic stability and delivery to specific cellular targets may limit their usefulness. Studies were designed to demonstrate that the covalent conjugation of an 18-mer ODN complementary in sequence to mRNA ODN with various polypeptide ligands, including poly(L-lysine), phosphomannan and asialo-orosomucoid, elicits a pattern of enhanced yet differential uptake into Chang and V79 cells in culture. Viability of cells exposed to conjugated ODNs was measured using a colorimetric assay (MTT). The ODNs covalently linked to poly(L-lysine) reveal an increased efficiency of antisense-directed cell killing from concentrations greater than 3 microM to less than 100 nM. Finally, poly(L-lysine) is also cytotoxic, particularly at extremes of molecular weight. Hence, these studies indicate that synthetic ODNs conjugated to peptides may offer enhanced cellular uptake leading to more efficient antisense activity. However, the cytotoxicity of ODN conjugates may limit their usefulness as research tools or therapeutic agents. PMID- 7849802 TI - Brain metallothionein gene expression and regulation. AB - Metallothionein (MT) gene expression in the brain has been most thoroughly studied using rodents. Although MT is considered to be a 'housekeeping' protein even in the brain, the basal MT mRNA expression level is not always high. Differences in the responses of rats and mice have made it difficult to interpret the data. Moreover, the response to inducers is not always apparent, probably because the brain is protected by the blood-brain barrier and initial responses to inducers in peripheral tissues modulate their accumulation in the brain. A relatively high content of MT protein in the brain might be sufficient to elicit minute alterations in the level of inducers. Nonetheless, regulation of MT gene expression in the brain seems to be important in e.g. maintaining the levels of trace elements and controlling redox potentials. The localization and utilization of trans elements such as MTF-I and MEP-I in the brain will provide new aspects for study. The high homology among MT isoforms with respect to nucleotide as well as amino acid sequences has made it difficult to obtain cDNA probes or antibodies capable of distinguishing MT isoforms. Thus, their cross-reactivity might make changes in MT mRNAs appear minimal when MT isoforms are differently regulated. The rapid developments in methodology permitting sensitive, rapid, high resolution analysis could clarify the background of tissue- and cell-specific gene regulation as well as differential induction. PMID- 7849803 TI - Induction of metallothionein in astrocytes by cytokines and heavy metals. AB - Immunohistochemical staining of human and rat brains for metallothionein (MT) using a monoclonal anti-MT antibody (MT45) revealed that protoplasmic astrocytes, which are densely localized in the gray matter, contain high levels of MT. Human U373MG astrocytoma cells were stimulated with interleukin (IL)-1 or heavy metals to produce MT. When expression of MT in U373MG cells was analyzed by Northern blotting or indirect immunofluorescence using the MT45 antibody, it was found that IL-1 (> or = 10 U/ml), CdCl2 (50 microM) and high concentrations of ZnCl2 (500 microM) induced marked biosynthesis of MT.IL-6 (up to 3,000 U/ml) and lower concentrations of ZnCl2 (10-50 microM), however, showed little inducing activity. Hippocampal astrocytes in primary culture produced a relatively high basal level of MT. The MT level increased in response to addition of IL-1 (> or = 10 U/ml), ZnCl2 (50 microM) and CdCl2 (5 microM). However, the increase induced by IL-6 (1,000 U/ml) was not very marked. The in vivo induction of MT in the brain by cytokines is not fully understood. However, our data and other indirect evidence suggest that IL-1 may be a potent stimulator of MT induction in astrocytes. Furthermore, the astrocytoma cell line, U373MG, is a suitable in vitro system to analyze the expression of MT in astrocytes. PMID- 7849804 TI - Glial metallothionein. AB - The metal-binding protein, metallothionein (MT) has been found to be primarily produced by astrocytes in the rat and human brain. This review discusses the relationship of glial MT to the distribution of metals in the brain, possible roles of MT in the regulation of glial enzymes and other glial proteins, and the possible role of a subset of MT-immunoreactive glia, the Gomori-positive astrocytes, in defending against toxic metals that enter the brain via circumventricular organs. The possible involvement of MT-containing astrocytes in degenerative brain disorders in also briefly discussed. PMID- 7849805 TI - Etiology and pathogenesis of human neural tube defects: insights from mouse models. AB - Research into neural tube defects (NTDs) is now entering a rapid phase as advances in experimental embryology and genetics, together with new insights from clinical epidemiology, provide testable hypotheses of the etiology and pathogenesis of these defects. Especially important have been contributions from the study of mouse mutants. The embryologic mechanisms responsible for upper and lower NTDs appear to be distinct, correlating with genetic evidence that distinguishes these phenotypes. The complex genetic etiology of NTDs may result from the effects of several modifier genes acting on a Mendelian trait of major effect, although no candidates are readily apparent for either type of gene. Clues to etiology have come from the preventive effect of nutritional supplements, especially those involved in one-carbon metabolism. More generally, research on NTDs has yielded major insights into how genetic predisposition can interact with environmental influences to modulate the incidence and severity of congenital malformations. PMID- 7849806 TI - The p53 tumor suppressor gene and pediatric brain tumors. AB - Mutations of the p53 tumor suppressor gene are common in astrocytomas that occur in adults but are rarely found in astrocytomas or medulloblastomas of children. This difference may contribute to the overall better prognosis of astrocytomas in children and potentially make pediatric astrocytomas and medulloblastomas more sensitive to antitumor therapy. PMID- 7849807 TI - Neuromuscular disorders in childhood. AB - The understanding of the molecular genetics of inherited neuromuscular disorders has unfolded rapidly in recent years. Identification of the genetic defects involved has enhanced diagnosis, prognosis, carrier detection, and prenatal diagnosis and has provided a basis for rational treatment strategies. This review provides an update on the most common neuromuscular disorders that present in childhood, eg, spinal muscular atrophy, muscular dystrophies, and myotonic disorders, and includes information on molecular genetics, pathogenesis, natural history, and experimental therapeutic strategies. PMID- 7849808 TI - Seizure disorders in children. AB - During the past year, a number of issues concerning the diagnosis and management of seizure disorders in children were addressed in large clinical studies and in carefully developed position papers. These issues included the syndrome of benign familial neonatal convulsions, the treatment and prognosis of infantile spasms, the prevention of febrile seizures with oral diazepam, the treatment of status epilepticus, and the identification of predictors of outcome of childhood epilepsy that may impact therapeutic decisions. Although the findings of some of these studies were controversial, each presents data that can be useful in the clinical assessment and treatment of children with these disorders. PMID- 7849809 TI - Early childhood wheezing. AB - This review touches on what is being learned about wheezing in infants, how it differs from wheezing in later childhood, and what has been relearned about its natural history. Wheeze is a common symptom with a number of different causal mechanisms and has a better prognosis in infants than in older children. The current ability to measure the lung function of infants has clearly shown the harmful effects of exposure to tobacco smoke. These effects begin in utero and continue during infancy and childhood. Improved viral isolation techniques have confirmed the important role of infections with respiratory syncytial virus, rhinovirus, and adenovirus in wheezing episodes. In later childhood, allergen sensitization and allergen exposure become of increasing importance. PMID- 7849810 TI - Antibiotic drug allergy in children. AB - Cutaneous reactions to penicillin-type antibiotics are usually caused by IgE mediated reactions directed toward the beta-lactam ring (in penicillin, ampicillin-amoxicillin, and cephalosporins). These allergic reactions may be reliably diagnosed (96% to 99% of the time) with a battery of skin tests derived from penicillin. A few individuals have been identified in Spain, and now Canada, who react to side chains of the beta-lactam antibiotics (and not the beta-lactam ring). Nonallergic cutaneous or systemic reactions to trimethoprim sulfamethoxazole (TMP-SMX) are now an emerging problem among HIV-infected patients. Life-threatening reactions have been described in HIV-infected infants who were rechallenged with TMP-SMX. New 10-day and 48-hour desensitization procedures have been used successfully in some TMP-SMX-reactive patients. Stevens Johnson syndrome and Lyell's syndrome (toxic epidermal necrolysis) are the most serious of the antibiotic-associated cutaneous reactions. These reactions may be caused by an immune reaction similar to graft-versus-host syndrome. Corticosteroids have been shown to be helpful in the management of Stevens Johnson syndrome. Although the mortality of toxic epidermal necrolysis is usually high, several children with this disorder have been successfully treated in a burn unit. PMID- 7849811 TI - Food hypersensitivity in children. AB - A variety of investigations of food hypersensitivity have been published over the past 18 months. These studies have focused on specific immunopathogenic, clinical, diagnostic, and prophylactic issues directly related to this allergic disorder. Whereas several of the reports have confirmed previous findings, significant pieces of new information have emerged. This review provides a practical summary of these scientific publications specifically related to food allergy. PMID- 7849812 TI - Chronic granulomatous disease: newly defined molecular abnormalities explain disease variability and normal phagocyte physiology. AB - Chronic granulomatous disease (CGD) typically presents as recurrent abscess formation beneath the skin and in the mononuclear phagocyte system. Common infecting organisms are staphylococci and enteric bacteria; Aspergillus organisms are a major threat. All CGD cases analyzed to date have revealed a defect in one of four proteins, each encoded on a separate gene. These four proteins are the major constituents of an enzyme complex that transfers electrons from NADPH to oxygen, creating microbicidal (yet tissue-toxic) oxidants. Recent research has defined the gene abnormalities in CGD and set the stage for gene therapy and pharmacologic modulation of host defense and inflammation. PMID- 7849813 TI - Clinical and immunologic studies of common variable immunodeficiency. AB - Common variable immunodeficiency is a complex primary immuno-deficiency disease that has as its hallmark subnormal amounts of at least two of the three main serum immunoglobulin isotypes. About 45% of cases are diagnosed before the patients reach 21 years of age, but the time of diagnosis may be delayed until even the sixth or seventh decade of life. The main clinical manifestations include sinopulmonary or gastrointestinal infections, autoimmunity, and neoplasia. The molecular defects of this disease are unknown and may involve intrinsic B-cell or T-cell defects, or both. At present, the mainstay of treatment is intravenous immunoglobulin, but experimental methods have shown that other in vivo methods might ultimately be found to ameliorate this immune deficiency disease. PMID- 7849814 TI - A 1-month-old boy with jaundice, thrush, and respiratory distress. PMID- 7849815 TI - The evolving role of clinical genetics in medicine. Commentary. PMID- 7849816 TI - Genetics of craniofacial disorders. AB - Due to the many recent and complementary advances in developmental biology and molecular genetics, we are learning much about the genetics of craniofacial disorders. In particular there is new information regarding craniosynostosis and orofacial clefting, which are among the more common birth defects. The pathogenesis of craniosynostosis, as well as the newest developments in the study of the common craniosynostotic syndromes, is discussed in this review. Genes and chromosomal regions implicated in orofacial clefting are reviewed. Lastly, insights are given into the pathogenesis of common craniofacial malformations as provided by animal models of human disease. PMID- 7849817 TI - Genetic disorders of copper metabolism. AB - In this review we discuss four genetic disorders of copper metabolism. Wilson's disease and Indian childhood cirrhosis result from the toxic effects of copper accumulation in the liver. Menkes' disease and, most likely, occipital horn syndrome result from copper deficiency secondary to disturbances in copper transport. The recent cloning and sequencing of the genes defective in Wilson's disease and Menkes' disease provide the molecular basis for understanding the causes of the two major disorders of copper transport in humans. Mutations that result in Wilson's and Menkes' diseases were shown to disrupt the function of two related P-type copper transporting ATPases. Genetic analysis demonstrates that Wilson's disease and, probably, Menkes' disease are caused by a number of different mutations within a single gene (allelic heterogeneity), and that this occurrence likely explains the clinical heterogeneity of both diseases. The possibility that different mutations within the same gene account for the similar phenotypes of Wilson's disease and Indian childhood cirrhosis on the one hand and for Menkes' disease and occipital horn syndrome on the other are discussed. PMID- 7849818 TI - Genetic basis of DiGeorge and velocardiofacial syndromes. AB - DiGeorge syndrome and velocardiofacial syndrome have been shown to be associated with microdeletions of chromosome 22q11. More recently, 22q11 deletions have also been detected in individuals with some types of conotruncal cardiac defects as well as conotruncal anomaly face syndrome. Fluorescence in situ hybridization of metaphase chromosomes using cosmid probes from the DiGeorge chromosomal region has been shown to be an efficient method for the detection of 22q11 deletions in at-risk patients, families, and pregnancies. This review summarizes recent cytogenetic, molecular, and phenotypic studies of patients with DiGeorge syndrome and velocardiofacial syndrome as well as recent efforts to identify genes within 22q11 that may play a role in the development of the phenotypic features observed in these disorders. PMID- 7849819 TI - Current approaches to genetic metabolic screening in newborns. AB - Genetic metabolic screening in newborn infants includes both specific testing for clinical indications in sick neonates and routine newborn screening. The decision of which sick neonates should have metabolic testing is based on the clinical phenotype and the results of general laboratory analyses, with particular attention to hypoglycemia, metabolic acidosis, and hyperammonemia. Metabolic tests include analyses for amino acids and organic acids and a carnitine profile. Routine newborn screening should be performed on all neonates prior to hospital discharge but no later than the 3rd day of life. The disorders covered by newborn screening vary among the states and among countries but virtually always include phenylketonuria and congenital hypothyroidism and often include sickle cell disease and galactosemia. Other metabolic disorders that may be included in newborn screening are maple syrup urine disease, homocystinuria, biotinidase deficiency, and congenital adrenal hyperplasia. PMID- 7849820 TI - Preimplantation genetic diagnosis. AB - Preimplantation genetic diagnosis now represents an alternative reproductive option for parents at high risk of having offspring affected with certain genetic diseases. Progress in the past year has included increasing reliability in embryo sexing by both polymerase chain reaction and fluorescent in situ hybridization techniques; delivery of babies free of specific diseases such as cystic fibrosis, Lesch-Nyhan syndrome, and Tay-Sachs disease; and successful development of molecular techniques for detecting common diseases such as fragile-X syndrome. In addition, sperm separation in combination with preimplantation genetic diagnosis appears to be an exciting advance in yielding more in vitro fertilization female embryos for transfer and subsequent pregnancy in families at risk for X-linked diseases. Accumulated world experience can now be reviewed to provide couples considering preimplantation genetic diagnosis with observed pregnancy rates and accuracy of diagnosis. PMID- 7849822 TI - [Nursing expertise, an investment]. PMID- 7849823 TI - [Nurse practitioners in Ontario; for renewed partnership]. PMID- 7849821 TI - Office laboratory procedures, economics of practice, patient and parent education, and urinary tract infection. AB - This review highlights recent advances in four major areas that are relevant to office practice: office laboratory procedures, economics of practice, adolescent risk-taking behavior in terms of sexually transmitted diseases, and urinary tract infections. Who should be screened for diseases and where these screening tests should be done are addressed, keeping the practicing pediatrician in mind. Next we review current office economics, including whether professional courtesy should be continued, how our practices are going to be increasingly influenced by guidelines developed by the American Academy of Pediatrics, the Clinical Laboratory Improvement Amendments, and the new Clinton Health Plan if it survives Congress, and finally how all of these issues will affect our expected income in the years ahead. As pediatricians strive to retain adolescent patients in their practices, they will need to find appropriate ways of counseling these patients concerning risk behaviors that could result in sexually transmitted diseases or HIV infections. Should we leave the comfortable confines of our offices to participate in these counseling programs for adolescents, and are there lessons from existing successful International Health Programs that we can use? Finally, urinary tract infections (UTIs) continue to be a common cause of childhood infections with possible serious long-term sequelae. Can we do a better job of diagnosing UTIs, has improved treatment become available, and is prevention of recurrences possible? Once the diagnosis has been made, how can we best evaluate these children with UTIs for underlying urologic abnormalities? It is our hope that the practicing pediatrician will be better prepared to face these issues having read this review. PMID- 7849824 TI - [Our hospitals need some reengineering of the way of doing things]. PMID- 7849825 TI - [Reform of health care systems--a world wide trend]. PMID- 7849826 TI - [Emphasizing the contribution of nurses]. PMID- 7849827 TI - [Nurse practitioner in neonatology; a plus for families]. PMID- 7849828 TI - [Private practice; diversified and personalized services]. PMID- 7849829 TI - [Teaching to asthma patients the precious competence of nurses]. PMID- 7849830 TI - [Breast self examination: a method, a priority, a challenge]. PMID- 7849831 TI - [Hip arthroplasty. Preparing the return home]. PMID- 7849832 TI - [Cancer and AIDS. Promoting communication]. PMID- 7849833 TI - [Managing a crisis of psychiatric emergency]. PMID- 7849834 TI - [The genogram, a choice tool in traumatology]. PMID- 7849835 TI - [Rehabilitation of brain-damaged patients. Taking one's place within the pluridisciplinary team]. PMID- 7849836 TI - [The welfare of the couple during all the stages of maternity]. PMID- 7849837 TI - [Total parenteral nutrition at home. Convincing results]. PMID- 7849838 TI - [For the quality of life of our elderly]. PMID- 7849839 TI - [Neurolinguistic power and programming]. PMID- 7849840 TI - [Relaxation and visualization; means to relieve pain]. PMID- 7849841 TI - Nursing expertise. The challenge, the stakes ... the theme of a very special convention! PMID- 7849842 TI - [Bioethics. Discussing and understanding in order to care better]. PMID- 7849843 TI - [Evaluating the moral judgement of a sexually delinquent population]. PMID- 7849844 TI - [The nursing sciences, a priority for the Quebec Fund for Health Research]. PMID- 7849845 TI - [Richard Morin: "The patient first!"]. PMID- 7849846 TI - Time and nursing. A method of autonomy and control. PMID- 7849847 TI - Use of multiple causes of death in the analysis of occupational cohorts--an example from the oil industry. AB - OBJECTIVES: To examine the efficacy of routine examination of multiple causes of death occurring on death certificates in cohort studies, with an example from the oil industry. METHODS: The underlying and multiple causes were coded for all notified deaths from a cohort of 35,000 men employed at eight oil refineries in the United Kingdom. Matrices of the frequencies of underlying causes by contributory causes were analysed for the total population and by subgroups defined by refinery, occupation, age, and calendar period of death. RESULTS: Over 75% of the 10,128 certificates had two or more causes but this varied by disease. Many ratios of mentions of total to underlying causes were similar to those of England and Wales. Ratios for cancer of the larynx and pneumonia were lower, indicating possible over-reporting of these diseases as the underlying cause. Investigation of an excess of pneumonia deaths at one refinery indicated possible miscoding of the underlying cause or the wrong position of pneumonia on some certificates, particularly in combination with malignancy and stroke. CONCLUSIONS: Routine analysis of multiple causes of death can provide useful additional information in cohort studies. PMID- 7849848 TI - Neurophysiological assessment of divers with medical histories of neurological decompression illness. AB - OBJECTIVE: To examine the possibility that subclinical damage may persist after clinical recovery from neurological decompression illness. METHODS: The neuraxes of 71 divers with medical histories of neurological decompression illness and 37 non-diver controls were examined by recording the somatosensory evoked potentials produced on stimulation of the posterior tibial and median nerves. RESULTS: Although the tests gave some objective support for the presence of "soft" residual neurological symptoms and signs, no evidence was given for the presence of subclinical damage. CONCLUSIONS: The contention that neurological damage persists after full clinical recovery from the neurological decompression illness was not supported. PMID- 7849849 TI - Effect of bis (tributyl tin) oxide on permeability of the blood-brain barrier: a transient increase. AB - OBJECTIVES: To study the effect of bis (tributyl tin) oxide (TBTO) on permeability of the blood-brain barrier. METHODS: Electron microscopy and an x ray microanalyser with lanthanum chloride as a tracer were used, and blood tin concentrations were determined with an atomic absorption spectrophotometer. Adult male wistar rats received 0.05 ml/kg body weight of TBTO orally. RESULTS: A transient increase in paracellular permeability at the blood-brain barrier was found 2 h after the dose of TBTO. Electron dense lanthanum deposits penetrated tight junctions of the endothelia and permeated the subendothelial space. The x ray microprobe data showed an accumulation of TBTO at the tight junctions at 2 h. Leakage of tracer did not occur at 4 h, but oedematous changes in the surrounding glial cells were prominent between 4 and 8 h and had almost returned to normal by 24 h. By atomic absorption analysis, it was seen that blood tin concentrations rapidly increased at 1 h and rose to a maximum peak at 8 h, then gradually decreased to reach zero at 24 h. CONCLUSIONS: Accumulated TBTO at tight junctions could have caused the temporary replacement of calcium ion by tin, which induces a transient increase in paracellular permeability throughout the blood-brain barrier. PMID- 7849850 TI - Exposure to benzene and urinary concentrations of 8-hydroxydeoxyguanosine, a biological marker of oxidative damage to DNA. AB - OBJECTIVES: Benzene is an established animal and human carcinogen. The mechanism of benzene toxicity, particularly its leukaemogenic effect, is not fully understood. The modified base 8-hydroxy-deoxyguanosine (8-OHdG) is a sensitive marker of the DNA damage due to hydroxyl radical attack at the C8 of guanine. This damage, if left unrepaired, has been proposed to contribute to mutagenicity and cancer promotion. We conducted this biomonitoring study with the aim of evaluating the association between excretion of 8-OHdG and level of exposure to benzene and other aromatic compounds among occupationally exposed people. METHODS: A random sample of 65 filling station attendants from Rome, Italy was studied for personal exposure to benzene, toluene, and xylenes, and excretion of 8-OHdG. Information about age, length of employment, smoking habits, and diagnostic exposure to x rays was collected by questionnaire. An average yearly level of exposure to benzene and methylbenzenes was calculated for each filling station attendant on the basis of about seven repeated personal samples collected during one year. A spot sample of 20 ml of urine was collected from each worker. Concentrations of 8-OHdG were determined by high performance liquid chromatography (HPLC) with coupled columns. RESULTS: A mean (SD) concentration of 1.36 (0.49) mumol of 8-OHdG/mol of creatinine was measured. A significant correlation was found between urinary 8-OHdG and exposure to benzene (r = 0.34). In a multiple regression analysis relating the concentration of urinary 8-OHdG with the age, length of employment, smoking, diagnostic exposure to x rays and personal exposure to benzene, an increase of 0.15 mumol/mol creatinine in urinary 8-OHdG/unit increase in the natural logarithm of the average yearly benzene concentration was estimated. CONCLUSION: This study shows a dose-response effect between personal exposure to benzene and urinary 8-OHdG concentration; further studies are needed to clarify the biological significance of 8-OHdG as a marker of cancer risk. PMID- 7849851 TI - Ocular and nasal irritation in operatives in Lancashire cotton and synthetic fibre mills. AB - OBJECTIVES: To document the prevalence of work related ocular (eyeWRI) and nasal (noseWRI) irritation in workers in spinning mills of cotton and synthetic textile fibres and to relate the prevalence of symptoms to atopy, byssinotic symptoms, work history, and measured dust concentrations in the personal breathing zone and work area. METHODS: A cross sectional study of 1048 cotton workers and 404 synthetic fibre workers was performed. A respiratory questionnaire was given to 1452 workers (95% of the total available population). Atopy was judged by skin prick tests to three common allergens. Work area cotton dust sampling (WAdust) was carried out according to EH25 guidelines in nine of the 11 spinning mills included in the study. Personal breathing zone dust concentrations were assessed with the IOM sampler to derive total dust exposure (PTdust) and a concentration calculated after the removal of fly (Pless). RESULTS: 3.7% of all operatives complained of symptoms of byssinosis, 253 (17.5%) complained of eyeWRI and 165 (11%) of noseWRI. These symptoms did not relate to atopy or byssinosis, or correlate univariately with any measure of cotton dust exposure (noseWRI v WAdust r = 0.153, PTdust r = 0.118, eyeWRI v WAdust r = 0.029, PTdust r = 0.052). Both of these symptoms on logistic regression analysis were related to being of white origin (P < 0.001), female sex (P < 0.001), and younger age (P < 0.001). With regression analysis, there was a negative relation between dust concentration and prevalence of symptoms. CONCLUSION: Work related ocular and nasal irritation are the most common symptoms complained of by cotton textile workers. There was no relation between these symptoms and atopy, byssinosis, or dust concentration. It is likely that they relate to as yet unidentified agents unrelated to concentration of cotton dust. PMID- 7849852 TI - Effects on health of a change from a delaying to an advancing shift system. AB - OBJECTIVES: Shift work can lead to a range of problems for some people that seem to result from the disturbance of the circadian system, and can broadly be classified as: disturbances of sleep, impaired physical and psychological health, and disturbed social and domestic life. The main attempt to try to reduce these problems has focused on the design of the shift system, and the identification of the most problematic features of the shift system. One such feature is believed to be the direction of shift rotation. Systems that advance are thought to be more problematic than those that delay. The present study examines the change in the direction of shift rotation from a delaying to an advancing system on health and wellbeing. METHODS: Self reported measures of tolerance to shift work were taken two months before and six months after the change. These included sleep difficulties, gastrointestinal problems, psychological ill health, chronic fatigue, social and domestic disruption, job satisfaction, and satisfaction with the shift system. RESULTS: The change from a delaying to an advancing system resulted in an increase in sleep difficulties between successive afternoon shifts, but a decrease in social disruption. There was little evidence of impaired health on the advancing compared with the delaying system. CONCLUSIONS: The increase in sleep difficulties was thought to result from the undesired adaptation of the circadian system to night work, as a result of the afternoon shifts now following a series of night shifts, whereas previously they followed a series of morning shifts. The decrease in social disruption was thought to result from the specific sequence of the shifts and the discontinuous nature of the shift system, in particular, the long week-end off every third week. Lack of reported health related differences are explained in terms of the relatively unharmful nature of the shift system in question, and the relatively short time span over which the study was conducted. PMID- 7849853 TI - Questionnaire for the identification of back pain for epidemiological purposes. AB - OBJECTIVES: To design a questionnaire for the identification and assessment of severity of back pain for epidemiological purposes, and gain preliminary experience of its use. METHODS: A group of specialists, experienced in the epidemiology and clinical assessment of back pain, designed the questionnaire, and tested it individually. It was also given cross sectionally by interview to a population of male coal mine workers. RESULTS: The questionnaire comprised a maximum of 12 questions on the presence, radiation, frequency, and severity of back pain with reference to difficulty with specific activities, interference with normal work, and absence from work. 471 coal miners answered the questionnaire (66% of those invited). 56% (265 men) of the responders reported pain or ache in the back during the previous 12 months, and the incidence of first ever attacks during the same period was reported to be 34%. 69% reported having had back pain at some time. The responses to the questionnaire were partially validated by comparison with certified sickness absence for two days or more attributed to back pain. In men who were symptomatic in the previous 12 months, for the question relating to absence from work because of back pain, the sensitivity was 82% and specificity was 84%. CONCLUSION: The questionnaire is easy to administer and generates clear cut data that could be useful for epidemiological or screening purposes. Preliminary, limited, studies of its validity are reasonably encouraging, although further validation is required. It is hoped that researchers will find the questionnaire useful, will extend its validation, and continue to develop it. PMID- 7849854 TI - Reproductive effects of sodium borates on male employees: birth rate assessment. AB - OBJECTIVES: The purpose of the study was to investigate potential reproductive effects of sodium borates on occupationally exposed male employees at a large mining and production facility in the Mojave Desert of California. METHODS: The standardised birth ratio (SBR) was used to assess fertility of the male employees. Live births were the measured end point, and the rate of female to male offspring was also assessed. Data were collected through a questionnaire after a series of on site introductory and explanatory meetings with the employees. Initial non-responders were followed up by telephone. Medical insurance records were assessed for those who declined to participate. RESULTS: The questionnaire was a good method of ascertainment for live births. There was no evidence of selection bias in the results. There was a highly significant excess of offspring fathered by the male employees. There was no evidence of a relation between exposure and this excess of offspring, nor were there any temporal differences during the period of observation (> 30 years). Also, there was an excess of the percentage of female offspring fathered by these male employees. This excess of female offspring was not significant. There was no evidence of an exposure relation to sodium borates with this excess of female offspring nor were there any temporal differences. CONCLUSION: Under the conditions studied, there were no adverse reproductive effects of high borate doses as reported from oral ingestion studies in animals. PMID- 7849856 TI - Survey of antimony workers: mortality 1961-1992. AB - The mortality of a census population and a prospective cohort of men employed on an antimony smelter in the north east of England was followed up from 1961-1992. The workers studied were exposed to a variety of agents including antimony and its oxides, arsenic and arsenic oxides, sulphur dioxide, and polycyclic aromatic hydrocarbons. The regional mortality rates were used to calculate expected deaths and a group of zircon sand workers employed on the site were used as a comparison group. For the census population of men working on the smelter before 1961 a significant increase in deaths from lung cancer was found (32 observed v 14.7 expected, P < 0.001). A similar excess was seen among maintenance men (12 observed v 5.3 expected P = 0.016). No such excess was found in the cohort recruited after 1960 (5 observed v 9.2 expected, maintenance workers 3 observed v 2.8 expected). There was evidence of a minimum latency period of around 20 years between first exposure and death from lung cancer. No evidence was found for a correlation between length of time worked and mortality from lung cancer. The results show that an increased risk of lung cancer existed in the workers employed before 1961, but it was not possible to attribute this excess to any particular agent. Mortality analysed by five year calendar periods of first exposure show a lessening of effect after 1955. Although the power of the study is clearly less for more recent periods of exposure the absence of any excess in the population after 1960 is encouraging. PMID- 7849855 TI - Postural stability of workers exposed to lead. AB - OBJECTIVE: To detect, with a computerised postural sway measurement system, any significant deviation of postural sway parameters among lead workers compared with a control group. METHODS: Postural stability was investigated with a computerised postural sway measurement system in 60 workers exposed to lead with a duration of exposure of 84 (range 3-366) months and 60 controls. Sway parameter data were collected with an Advanced Mechanical Technology computerised biomechanics platform system. RESULTS: The mean current blood lead concentration was 36.0 (range 6.4 to 64.5) micrograms/dl for the exposed workers and 6.3 (range 3.1 to 10.9) micrograms/dl for the 14 controls. There was no significant difference between the groups for the postural sway parameters obtained when the eyes were open. Significant differences were found for Xs, Ys (SDs of the coordinates of the centre of pressure); Xm, Ym (mean deviation of the coordinates of the centre of pressure); Rm (average displacement of Xi, Yi, from Xo, Yo); L (length of sway path); Vel (mean velocity of the centre of pressure along its path); Ao (area included within the path of the centre of pressure); Ae (95% confidence elliptical area). The Romberg ratios (the relation between eyes closed and open) for the Vel, L, Ao and Ae of the exposed workers were also significantly different from the controls. CONCLUSION: The study showed that workers exposed to lead had significantly poorer postural stability than the controls. Lead may affect certain parts of the whole sensory neural axis resulting in postural instability when the visual input is cut off. Based on current blood lead concentrations, we were not able to obtain any significant association with the postural sway parameters. PMID- 7849857 TI - Asbestos fibres and man made mineral fibres: induction and release of tumour necrosis factor-alpha from rat alveolar macrophages. AB - OBJECTIVES: Mounting evidence suggests that asbestos fibres can stimulate alveolar macrophages to generate the potent inflammatory and fibrogenic mediator, tumour necrosis factor-alpha (TNF-alpha), and that this may play an important part in the onset and development of airway inflammation and lung fibrosis due to asbestos fibre inhalation. Little is known, however, about the ability of other mineral fibres to initiate formation and release of TNF-alpha by alveolar macrophages. Therefore the effects of different fibres (crocidolite, chrysotile A, chrysotile B, two man made mineral fibres (MMVF 21 and MMVF 22), a ceramic fibre (RCF 1), and a silicon carbide whisker fibre (SiCwh)) on formation and release of TNF-alpha by rat alveolar macrophages were examined. METHODS: Cells were isolated and incubated at 37 degrees C with the different fibres, or with culture medium alone (controls), and the amounts of TNF-alpha messenger RNA (mRNA) in the cells and TNF-alpha bioactivity released into the culture medium were measured at different time points. RESULTS: Significantly (P < 0.05 v control) increased amounts of TNF-alpha mRNA were found in cells exposed to crocidolite, chrysotile A, chrysotile B, MMVF 21, RCF 1, or SiCwh for 90 minutes, and significantly (P < 0.05 v control) increased activities of TNF-alpha were found in the medium of macrophages exposed to crocidolite, chrysotile A, chrysotile B, or MMVF 21 for four hours. CONCLUSION: These observations suggest that not only natural mineral fibres but also certain man made mineral fibres are able to induce the formation and release of TNF-alpha by alveolar macrophages in vitro. PMID- 7849858 TI - Polypropylene production workers and colorectal cancer in Germany: a brief report. AB - OBJECTIVE: A retrospective cohort study of 640 male polypropylene production workers in Germany was performed to evaluate the reported association between colorectal cancer and polypropylene. METHOD: The follow up period was 1956 to 1990. Expected numbers of cancers were derived from incidence rates adjusted for age and calendar year from the Saarland cancer registry. RESULTS: Three colorectal cancers were identified compared with 4.0 expected (standardised incidence ration (SIR) = 0.75, 95% confidence interval (95% CI): 0.15-2.19). For total cancers there were 27 cases in the cohort compared with 35.4 expected (SIR = 0.76, 95% CI: 0.50-1.11). DISCUSSION: These results do not support earlier reports of a link between polypropylene production and colorectal cancer, but are consistent with a number of recent investigations of polypropylene production workers that have reported no association with risk of colorectal cancer. Due to the small size of this and other similar studies, however, a small to moderate increase in risk cannot be ruled out. PMID- 7849859 TI - Absence of risk of colorectal cancer among workers at a UK polypropylene production plant. PMID- 7849860 TI - Isotretinoin induced rubber glove dermatitis. PMID- 7849861 TI - Deposition and retention of inhaled fibres: effects on incidence of lung cancer and mesothelioma. AB - A review of the literature on chronic inhalation studies in which rats were exposed to mineral fibres at known fibre number concentrations was undertaken to examine the specific roles of fibre length and composition on the incidences of both lung cancer and mesothelioma. For lung cancer, the percentage of lung tumours (y) could be described by a relation of the form y = a + bf + cf2, where f is the concentration of fibre numbers and a, b, and c are fitted constants. The correlation coefficients for the fitted curves were 0.76 for > 5 microns f/ml, 0.84 for > 10 microns f/ml, and 0.85 for > 20 microns f/ml. These seemed to be independent of fibre type. It has been shown that brief inhalation exposures to chrysotile fibre produces highly concentrated fibre deposits on bifurcations of alveolar ducts, and that many of these fibres are phagocytosed by the underlying type II epithelial cells within a few hours. Churg has shown that both chrysotile and amphibole fibres retained in the lungs of former miners and millers do not clear much with the years since last exposure. Thus, lung tumours may be caused by that small fraction of the inhaled fibres that are retained in the interstitium below small airway bifurcations where clearance processes are ineffective. By contrast, for mesothelioma, the (low) tumour yields seemed to be highly dependent upon fibre type. Combining the data from various studies by fibre type, the percentage of mesotheliomas was 0.6% for Zimbabwe (Rhodesian) chrysotile, 2.5% for the various amphiboles as a group, and 4.7% for Quebec (Canadian) chrysotile. This difference, together with the fact that Zimbabwe chrysotile has 2 to 3 orders of magnitude less than tremolite than Quebec chrysotile, provides support for the hypothesis that the mesotheliomas that have occurred among chrysotile miners and millers could be largely due to their exposures to tremolite fibres. The chrysotile fibres may be insufficiently biopersistent because if dissolution during translocation from their sites of deposition to sites where more durable fibres can influence the transformation or progression to mesothelioma. PMID- 7849862 TI - Mortality among employees at a plastics and resins research and development facility. AB - OBJECTIVES: The study was undertaken to update a previous study of employees from a resins and plastics research and development facility and to further examine the mortality of these employees with particular emphasis on deaths due to pancreatic cancer. METHODS: This retrospective cohort study examined mortality from 1962 to 1992 for 257 men who were employed for at least one year during a 14 year period from 1962 to 1975 at a plastics and resins research and development facility. During the operative period, the primary activities involved applications and process development for polypropylene, polystyrene, epoxy resins, and to a lesser extent high density polyethylene. RESULTS: The cohort was young and was followed up for an average of 26 years. Although mortality for all causes among employees who worked at least one year at this facility was low (standardised mortality ratio (SMR) 0.74), the death rate from cancer was moderately higher than that of the general population (14 observed and 9.4 expected deaths). There were four observed and 0.5 expected deaths from pancreatic cancer among men who worked at this facility for at least one year, which resulted in a statistically increased SMR of 8.88 (95% confidence interval 2.42-22.74). All cases of pancreatic cancer had "laboratory" jobs, and their ages at death were relatively young compared with deaths in the general population from pancreatic cancer. Lung cancer mortality was high but not significant with seven observed and 3.5 expected deaths. There were no deaths due to non-malignant respiratory disease (1.9 expected). CONCLUSIONS: The increased cancer mortality was entirely due to excess deaths from pancreatic and lung cancers. No causative agent or process for these cases of pancreatic cancer has been identified. This study shows no increased colorectal cancer mortality as was found among another group of workers involved in the manufacture of polypropylene. PMID- 7849863 TI - Malignant mesothelioma: attributable risk of asbestos exposure. AB - OBJECTIVES: To evaluate a case-control study of malignant mesothelioma through patterns of exposure to asbestos based upon information from telephone interviews with next of kin. METHODS: Potential cases, identified from medical files and death certificates, included all people diagnosed with malignant mesothelioma and registered during 1975-1980 by the Los Angeles County Cancer Surveillance Program, the New York State Cancer Registry (excluding New York City), and 39 large Veterans Administration hospitals. Cases whose diagnosis was confirmed in a special pathology review as definite or probable mesothelioma (n = 208) were included in the analysis. Controls (n = 533) had died of other causes, excluding cancer, respiratory disease, suicide, or violence. Direct exposure to asbestos was determined from responses to three types of questions: specific queries as to any exposure to asbestos; occupational or non-vocational participation in any of nine specific activities thought to entail exposure to asbestos; and analysis of life-time work histories. Indirect exposures were assessed through residential histories and reported contact with family members exposed to asbestos. RESULTS: Among men with pleural mesothelioma the attributable risk (AR) for exposure to asbestos was 88% (95% confidence interval (95% CI) 76-95%). For men, the AR of peritoneal cancer was 58% (95% CI 20-89%). For women (both sites combined), the AR was 23% (95% CI 3-72%). The large differences in AR by sex are compatible with the explanations: a lower background incidence rate in women, lower exposure to asbestos, and greater misclassification among women. CONCLUSIONS: Most of the pleural and peritoneal mesotheliomas in the men studied were attributable to exposure to asbestos. The situation in women was less definitive. PMID- 7849864 TI - Genetic polymorphism for glutathione-S-transferase mu in asbestos cement workers. AB - OBJECTIVE: To investigate whether a lack of glutathione-S-transferase mu (GSTM1) activity was related to an increased risk for adverse outcome after asbestos exposure. METHODS: A study was made of 78 male former asbestos cement workers, with retrospective cohort data on exposure, radiographical findings, and lung function. Venous blood samples were obtained for the analysis of GSTM1 polymorphism by the polymerase chain reaction technique. Chest x ray films were classified according to the International Labour Organisation (ILO) 1980 classification. Vital capacity (VC) and forced expiratory volume during 1 s (FEV1) were determined. Individual estimates of asbestos exposure were calculated, and expressed as duration of exposure, average exposure intensity, and cumulative dose. Data on smoking were obtained from interviews. RESULTS: The lung function in the study group was reduced, compared with reference equations. 23% of the workers had small opacities > or = 1/0, 29% circumscribed pleural thickenings, 14% diffuse thickenings, and 12% obliterated costophrenic angles. 54% of the workers were GSTM1 deficient. They were comparable with the other workers in age, follow up time (median 30 years), and duration of exposure (median 18 years), but had a slightly higher cumulated dose (median 18 v 10 fibre years) than the others. Neither in radiographical changes nor lung function variables were there any differences between the different GSTM1 groups. The findings were similar when smoking habits and estimated asbestos exposure were taken into account. CONCLUSIONS: We could not show that lack of GSTM1 activity was related to an increased risk for radiographical or lung function changes in a group of asbestos cement workers, followed up for a long period after the end of exposure. PMID- 7849865 TI - Distribution of urinary hippuric acid concentrations by ALDH2 genotype. AB - OBJECTIVES: To clarify the relation between the genetic polymorphism of ALDH2 (low Km aldehyde dehydrogenase) and toluene metabolism. METHODS: The study subjects were 253 toluene workers (192 men and 61 women with an age range of 18 66). The genotypes of ALDH2 were classified by artificial restriction fragment length polymorphism into the homozygous genotype of normal ALDH2 (NN), the homozygous genotype of an inactive ALDH2 (DD), and the heterozygous genotype of normal and inactive ALDH2 (ND). The concentrations of hippuric acid (HA), the main metabolite of toluene, was determined in urine specimens of 253 toluene workers. The HA measurements in previous occupational health examinations were also referenced. The HA concentrations corrected for creatinine (HA/C) were compared with the biological exposure index (BEI) for toluene, which is 2.5 g/g creatinine. To estimate the toluene exposures, urinary o-cresol concentrations were also determined and compared with another BEI for toluene--that is, 1.0 mg urinary o-cresol/g creatinine. RESULTS: Incidence of each genotype in the toluene workers was almost the same as that in non-exposed controls who lived in the same area as the toluene workers. The incidence of each of the three genotypes also did not differ by smoking habit. Mean urinary HA concentrations were not significantly different in the groups with the different genotypes of ALDH2. The HA concentrations of > 70% of the 890 total samples were < 1.0 g/l. The number of urine samples > 3.0 g/l was 28 (5.4%) in the NN group and 19 (6.4%) in the ND group. No urine samples in the DD group were > 3.0 g/l HA. The distribution of urinary HA in the DD group was significantly different from those in both the NN and ND groups (P < 0.05). Seven (4.9%) of the 136 total specimens in the NN group and four (4.7%) of the 82 total specimens in the ND group exceeded the BEI. There were, however, no urine specimens that exceeded the BEI in the DD group. The maximum HA concentration after correction for creatinine in the DD group was 1.86 g/g creatinine. The percentages of urine specimens in which o-cresol concentrations exceeded this BEI were 14.3% in the NN group, 9.1% in the ND group, and 15.4% in the DD group. Therefore, the exposure rate for all three genotypic groups of workers was almost the same. CONCLUSIONS: The HA concentrations of toluene workers with ALDH2 DD genotype were lower than those of the NN and ND genotypes when they were exposed to relatively high concentrations of toluene. The exposures of the DD group were suspected to be underestimates because they were based on the BEI for the NN genotype. PMID- 7849866 TI - Factors in the sociocultural environment of child labourers: a study in a small scale leather goods industry in Calcutta. AB - OBJECTIVES: During a study of the occupational health of the child workers in several small leather workshops, investigations were also made of the sociocultural factors that made it necessary for the children, aged between 7 and 14 years, to work. The psychosocial effects of the same factors were also investigated. METHODS: Personal interviews were carried out with a prepared questionaire, and the findings were compared between the working children and a control group of the same number of non-working children from the neighbourhood, matched for age, sex, and religion. RESULTS: It was found that the foremost cause of taking up employment by the children was poverty. The overall effects found were deprivation of education and lowering of aspirations, that indicated a blunting of mental faculties. CONCLUSION: Prolonged, monotonous work in childhood that precludes education and healthy recreation, is harmful to the children. PMID- 7849867 TI - Disorders of the neck and upper limbs in women in the fish processing industry. AB - OBJECTIVE: The aim was to study the association between personal factors and physical and psychosocial work environment factors and disorders of the neck or upper limbs among women in the fish processing industry. METHODS: A cross sectional study was performed on 206 women in the fish processing industry and 208 control women. Several physical and psychosocial work environment factors were evaluated. Subjective complaints about the neck or upper limbs were assessed by questionnaire and by a clinical examination. RESULTS: The study showed a high prevalence (35%) of diagnoses in the neck or shoulders of the exposed women. All prevalence odds ratios (POR's) were substantially higher in young women. There was a pronounced dose-response relation between disorders of the neck or shoulders and duration of employment for women < 45 years old. When studying 322 former workers, the proportion who claimed musculoskeletal complaints as the reason for leaving was highest among the older women. Muscular tension, stress or worry, work strain, and the largest fraction of the work time spent with highly repetitive work tasks were clearly associated with disorders of the neck or shoulders. The measurements of the wrist movements also showed that the work was performed almost without any pauses and that the median flexion and extension velocity was high (41 degree/s). The results of observation showed good agreement with the measurements of wrist motion. CONCLUSION: Work in the fish processing industry is a risk factor for disorders of the neck and upper limbs. Due to the homogenity of the physical work load in the exposed group, we could not show any associations between the objective measurements and disorders. In cross sectional studies the risk may be underestimated due to a healthy worker effect. PMID- 7849868 TI - Controlled two year follow up of rehabilitation for disorders in the neck and shoulders. AB - OBJECTIVE: To evaluate the effects of an early, active, and multidisciplinary rehabilitation programme for neck and shoulder disorders. METHODS: Primary health care and industrial health care of a nonrandomised, controlled, cohort was followed up over two years in a geographically defined area. The cohort consisted of working people who consulted a physician about disorders of the neck or shoulders from 1 August 1988 to 31 October 1989. Criteria for acceptance; not chronic symptoms, patients had sick leave of no more than four weeks. Disorders were not caused by trauma, infections, malignancy, rheumatic diseases, abuse, or pregnancy. 107 people qualified for the study, 87% were followed up for two years. They were divided into two groups. One group obtained active, multidisciplinary rehabilitation for eight weeks that comprised physical training, information, education, social interaction, and work place visits. Controls were given traditional treatment; physiotherapy, medication, rest, and sick leave. The main outcome measures were: average number of days of sick leave for the two years after rehabilitation, subjective pain on a visual analogue scale, and ratings on seven subscales of the sickness impact profile. RESULTS: At 12 and 24 months of follow up effects of the active rehabilitation programme did not differ from traditional treatment in any of the outcome measures. New work task (P < 0.05) or changed work place (P < 0.001) during the follow up period were associated with decreased sick leave, independent of treatment. CONCLUSIONS: Active, multidisciplinary rehabilitation of neck and shoulder disorders was not more effective than traditional treatment. Changed work conditions were associated with decreased sick leave, independent of type of treatment provided. PMID- 7849869 TI - Non-differential misclassification of exposure always leads to an underestimate of risk: an incorrect conclusion. PMID- 7849870 TI - Use of the prevalence ratio v the prevalence odds ratio as a measure of risk in cross sectional studies. PMID- 7849871 TI - Airways obstruction, coal mining, and disability. PMID- 7849872 TI - Airways obstruction, coal mining, and disability. PMID- 7849873 TI - The pediatrician and cancer prevention. Accepting the present, changing the future. PMID- 7849874 TI - Comparisons of alcohol and other drug problems among Minnesota adolescents in 1989 and 1992. AB - OBJECTIVES: To measure alcohol and other drug use patterns, adverse consequences of substance use, other high-risk behaviors, and their personal and environmental correlates. DESIGN AND SUBJECTS: The survey was administered in 1989 and 1992 to Minnesota public school students in grades 6, 9, and 12. A comparison sample of school districts that participated in both years consisted of 81% of the state's school districts. District samples were weighted to reflect the proportion of actual enrollment by grade among participating districts. RESULTS: Although alcohol and other drug use declined markedly during the 3-year period studied, the proportion of students who reported at least three adverse consequences of their use was identical in 1989 and 1992: 1% of sixth graders, 7% of ninth graders, and 16% of 12th graders. Alcohol was the primary substance of abuse among students, regardless of age or level of substance involvement. The students with three or more adverse consequences of substance use were defined as "problem users" and compared with other students their age. The most commonly reported consequences of use were tolerance, blackouts, violence, and school or job absenteeism. The problem users were approximately two to seven times more likely to report parental alcohol or other drug problems, physical abuse, and sexual abuse than were students their age with fewer consequences or no history of use. They were also two to 15 times more likely than other students to report such correlates as low self-esteem, emotional distress, antisocial behavior, and suicide attempts. The greatest differences were seen among the youngest students. CONCLUSION: Primary health care workers, social service providers, educators, and other front-line personnel who have contact with youths outside the home need to recognize and respond to behavioral and emotional indicators of risk among adolescents. PMID- 7849875 TI - A longitudinal study of prenatal marijuana use. Effects on sleep and arousal at age 3 years. AB - OBJECTIVE: To test the hypothesis that sleep disruptions would be evident in 3 year-old children with a history of prenatal marijuana exposure. DESIGN: A prospective study using stratified random sampling beginning in the fourth month of pregnancy. Marijuana and other substance use were assessed by interviews at multiple time points. Offspring were followed up through age 3 years with multidomain assessments at fixed time points, including electroencephalographic sleep studies in the newborn period and at age 3 years. SETTING: Primary care, prenatal clinic at a university hospital. SUBJECTS: The sample included 18 children with prenatal marijuana exposure (mean [+/- SD] age, 39.0 +/- 4.4 months) and 20 control children (mean [+/- SD] age, 39.7 +/- 4.4 months). The two groups were similar in relationship to maternal age, race, income, education, or maternal use of alcohol, nicotine, and other substances in the first trimester. MAIN OUTCOME MEASURE: Sleep variables from polysomnographic recordings at age 3 years. RESULTS: Children with prenatal marijuana exposure showed more nocturnal arousals (mean [+/- SD], 8.2 +/- 5.3 vs 3.2 +/- 4.6; P < .003), more awake time after sleep onset (mean [+/- SD], 27.4 +/- 20.0 vs 13.7 +/- 12.4 min; P < .03), and lower sleep efficiency (mean [+/- SD], 91.0 +/- 3.8 vs 94.4 +/- 2.1; P < .03) than did control children. CONCLUSION: Prenatal marijuana exposure was associated with disturbed nocturnal sleep at age 3 years. PMID- 7849876 TI - The impact of very low-birth-weight infants on the family is long lasting. A matched control study. AB - OBJECTIVE: To test the hypothesis that parental stress associated with long-term morbidity of very low-birth-weight infants (VLBWIs) is long lasting. DESIGN: Matched case-control study. SETTING: High-risk newborn follow-up program, Winnipeg, Manitoba. PARTICIPANTS: Parents of 96 Manitoban VLBWIs born from July 1986 through June 1990, compared with parents of full-term controls matched for age, sex, race, domicile, singleton or multiple pregnancy, and birth order. MAIN OUTCOME MEASURES: Mailed questionnaire, including Stein's Impact on Family Scale, positive impact of parenthood, and attitudes toward treating VLBWIs. RESULTS: Families were demographically similar. The parents of VLBWIs had higher scores for financial burden, familial/social impact, personal strain, and mastery (P < .0001). The parents of VLBWIs experienced more impact when children had a functional handicap or low adaptive developmental quotient. Scores were highest when the adaptive developmental quotient was 70 to 85. High scores were associated with low family income and less parental education. Impact did not change over time. Only half of the parents in each group felt that "doctors should try to save every baby." The parents of VLBWIs felt more strongly that cost should never enter into the decision to treat a tiny baby (P < .005). The families of VLBWIs expressed a stronger desire for more children (P < .01), but control families were more likely to have given birth again (46.3% vs 28.2%). CONCLUSIONS: The birth and upbringing of a VLBWI is associated with more long term stress, even for well-educated nuclear families whose health care is financed by government. Caregivers need increased awareness of the needs of these families so that their medical and social needs are met effectively. Support services should be targeted toward low income, poorly educated parents whose children have functional handicaps. PMID- 7849877 TI - Variations in pediatric pneumonia and bronchitis/asthma admission rates. Is appropriateness a factor? AB - OBJECTIVE: To explore through a pilot study the relationship between appropriateness (medical necessity) and variations in pediatric hospital admission rates across several communities in the Boston (Mass) area for two common pediatric conditions with extremely variable admission rates: pneumonia and bronchitis/asthma. DESIGN: We identified five communities in the greater Boston area with high, average, and below-average ratios of observed to expected admissions for the study conditions. Diagnosis-specific, criteria-based utilization review instruments were developed by community-based pediatricians and applied by trained nurse reviewers to medical records. ADMISSIONS STUDIED: All admissions for pneumonia (diagnosis related group [DRG] 91) and bronchitis/asthma (DRG 98) of study area residents younger than 18 years to participating hospitals during fiscal year 1986. OUTCOME MEASURES: For each area, we calculated age-adjusted admission rates, age-adjusted observed to expected ratios, and rates of inappropriate admissions. We tested the hypothesis that admission rates and inappropriateness rates were directly related. RESULTS: We deemed 9.4% of pneumonia admissions and 4.4% of bronchitis/asthma admissions inappropriate. Rates of inappropriate admissions were not significantly associated with admission rates in this local pilot study for either study condition at P < .05. However, in one community both rates were high for both conditions. Feedback of findings to the key local hospital there resulted in sharp decreases in admission rates for DRGs 91 and 98 in subsequent years. CONCLUSIONS: Our results suggest that higher pediatric admission rates may not be associated with higher rates of inappropriateness. Further research is needed, with a larger number of communities, to differentiate practice patterns more precisely and explore patient and family preferences. PMID- 7849878 TI - Explanation for false-positive urine cultures obtained by bag technique. AB - OBJECTIVE: To test whether a urine bag technique, previously shown in circumcised male infants 1 month to 1 year of age to yield no false-positive cultures, would give similar results in newborns (females and circumcised and uncircumcised males). DESIGN: Prospective study in which periurethral and urine specimens were obtained from healthy newborns. After the periurethral specimen was obtained, the perineum was washed and a urine bag applied. The urine bag was removed immediately after voiding and the urine was cultured. SETTING: Normal newborn nursery and pediatric hospital. SUBJECTS: Ninety-eight healthy full-term newborns (49 female and 49 male) admitted to the normal nursery during a 4-month period. MAIN RESULTS: Isolation of a pathogen from the bag urine reflected periurethral flora. In 20 (95%) of the 21 urine specimens from which a pathogen was isolated, the same pathogen was detected on the periurethra. Sixteen of the 21 urine cultures were falsely positive (> 10(4) colony-forming units of pathogen per milliliter). In 50 (98%) of the 52 urine samples that yielded no growth, the periurethral culture was also negative. In the remaining 25 urine samples in which nonpathogens were detected, the periurethra yielded nonpathogens or no growth. Thus, if a pathogen was isolated from a bag urine sample, the same pathogen was detected on the periurethra 95% of the time. Conversely, if the bag urine sample was negative for a pathogen, the periurethral culture was negative 100% of the time. The presence of a pathogen on the periurethra was more common in female than male neonates (16 of 49 vs four of 49; P = .004), and none of the 14 circumcised male neonates had a pathogen detected on their periurethra or in their urine. CONCLUSION: This study explains the finding of false-positive cultures with the bag technique. Pathogens detected in bag urine samples reflected pathogens on the periurethra. Until a bag collection technique that avoids contamination by periurethral flora can be developed, urethral catheterization and suprapubic aspiration remain the methods of choice for obtaining a urine specimen in female and uncircumcised male neonates. PMID- 7849879 TI - Barriers to wearing bicycle safety helmets in The Netherlands. AB - OBJECTIVE: To explore behavioral factors that determine whether children (aged 7 to 13 years) wear bicycle safety helmets. DESIGN: Cross-sectional survey. SETTING: Three Dutch primary schools in Breda, Maastricht, and Terneuzen, the Netherlands. PARTICIPANTS: Two hundred fifty-nine children aged 7 to 13 years. INTERVENTION: Wearing a bicycle safety helmet for 6 consecutive weeks. RESULTS: Information about experiences with the bicycle safety helmet was gathered via questionnaires. Wearing a bicycle safety helmet was described as inconvenient, time-consuming, and uncomfortable. Children also perceived negative reactions from their social environment. CONCLUSIONS: Planned health promotion activities will be essential for the introduction of bicycle safety helmets to be successful. These activities should focus particularly on developing a comfortable bicycle safety helmet, creating facilities to store bicycle safety helmets, and changing negative social norms regarding wearing a bicycle safety helmet. PMID- 7849880 TI - Nephrogenic diabetes insipidus. A personal perspective. AB - To summarize these ideas that all center around time and variations, we might think of the genes as constituting a biological memory that serves at once to connect individuals with other people and with the past. The genes also provide a plan to construct and maintain an individual homeostatic memory that mediates experiences in the context of an ontogenetic memory that preserves individuality through time and change to set on health and disease a personal stamp. It is the mission of medicine to understand the individuality of these memories and of the elements that constitute them and, where necessary, to adjust the environment to homeostatic limitation. It is my hope that this account of this often colorful but hapless and stricken family might give substance to these thoughts. PMID- 7849881 TI - Nurses' perception of beeper calls. Implications for resident stress and patient care. AB - OBJECTIVES: To describe beeper calls made by nurses to physicians and to compare the nurses' ratings of the urgency of the beeper calls with the physicians' responses to the calls. DESIGN: Nurses were asked to complete beeper logs for all calls made to physicians. Nurses also recorded the physician's response to the call. Nurses assessed each call as routine (answer needed in 12 to 24 hours), urgent (answer needed soon to accomplish patient care), or an emergency (patient assessment needed immediately). SETTING: A university-affiliated children's hospital in Salt Lake City, Utah. RESULTS: Nurses recorded 849 beeper calls. Of this number, 30 (4%) were judged to be an emergency, 275 (32%) were perceived to be urgent, and 471 (55%) were considered to be routine. The recorded physician response for 597 calls is as follows: 60 calls (10%) resulted in physician assessment of the patient; 211 calls (35%) resulted in verbal orders given over the telephone; 136 calls (23%) resulted in other action taken; and 190 calls (32%) resulted in no action taken. While calls that were judged to be an emergency were more likely to result in physician assessment of the patient than were other calls (nine [45%] of 20 vs 49 [9%] of 541 calls) (P < .001), nearly half (43%) of the calls that resulted in physician assessment of the patient had been judged to be routine. Calls that were perceived to be urgent or routine did not significantly differ from the percentage of calls that resulted in no action taken by the physician (52 [27%] of 193 vs 118 [34%] of 348 calls). CONCLUSIONS: Nurses' ratings of the urgency of beeper calls are not good predictors of physician response to the call. Unless nurses' and physicians' perceptions of the urgency of beeper calls are similar, delaying response to routine calls cannot be assumed to be a safe and effective way to decrease unnecessary interruptions to resident activities. PMID- 7849882 TI - Radiological case of the month. Miliary pulmonary neuroblastoma. PMID- 7849883 TI - Picture of the month. Infantile Crohn's disease. PMID- 7849884 TI - Pathological case of the month. Cardiac fibroma. PMID- 7849885 TI - Metered-dose inhalers with spacers vs nebulizers for pediatric asthma. AB - OBJECTIVE: To determine whether the administration of beta-agonists by metered dose inhaler (MDI) with a spacer device is as effective as the administration of beta-agonists by nebulizer for the treatment of acute asthma exacerbations in children. DESIGN: Randomized trial with two arms. SETTING: Urban pediatric emergency department (ED) in Bronx, NY. PATIENTS: Convenience sample of 152 children 2 years and older with a history of at least two episodes of wheezing presenting to the ED with an acute asthma exacerbation. INTERVENTIONS: Patients were randomly assigned to receive standard doses of a beta-agonist (albuterol) by an MDI with spacer or by a nebulizer. Dosing intervals and the use of other medications were determined by the treating physician. MEASUREMENTS/MAIN RESULTS: Baseline characteristics and asthma history were recorded. Asthma severity score, peak expiratory flow rate in children 5 years or older, and oxygen saturation were determined at presentation and before admission or discharge. The groups did not differ in age, sex, ethnicity, age of onset of asthma, or asthma severity score at presentation. There were no significant differences between the groups in outcomes, including mean changes in respiratory rate, asthma severity score, and peak expiratory flow rate, oxygen saturation, number of treatments given, administration of steroids in the ED, and admission rate. Patients given MDIs with spacers required shorter treatment times in the ED (66 minutes vs 103 minutes, P < .001). Fewer patients in the spacer group had episodes of vomiting in the ED (9% vs 20%, P < .04), and patients in the nebulizer group had a significantly greater mean percent increase in heart rate from baseline to final disposition (15% vs 5%, P < .001). CONCLUSIONS: These data suggest that MDIs with spacers may be an effective alternative to nebulizers for the treatment of children with acute asthma exacerbations in the ED. PMID- 7849886 TI - Theophylline does not shorten hospital stay for children admitted for asthma. AB - OBJECTIVE: To determine if the use of intravenous theophylline, in the form of aminophylline, when added to systemic corticosteroids and aerosolized beta 2 agonists, enhances the improvement of children with acute asthma exacerbations. DESIGN: A double-blind, placebo-controlled, randomized, clinical trial. SETTING: The University of Maryland Medical Center, Baltimore, an urban primary- and tertiary-care pediatric medical center. PATIENTS: Forty-two children, aged 2 to 18 years, admitted to the hospital for acute exacerbations of asthma. METHODS: Patients were randomized to receive either intravenous theophylline to maintain a serum level greater than 55 mumol/L or a placebo infusion. All patients received methylprednisolone and nebulized albuterol. A clinical severity score was assessed twice daily. RESULTS: The mean length of stay for the treatment and control groups was 52.3 +/- 32.3 hours and 48.2 +/- 26.6 hours, respectively (t = 0.45, P = .65). The rate of improvement of clinical scores was similar. CONCLUSION: These data suggest that the addition of theophylline to albuterol and corticosteroids does not enhance improvement of children admitted to the hospital with asthma. PMID- 7849887 TI - Outcome and cost at a children's hospital following resuscitation for out-of hospital cardiopulmonary arrest. AB - OBJECTIVE: To determine the outcome and cost for children resuscitated following out-of-hospital cardiopulmonary arrest. DESIGN: Retrospective case series. SETTING: An organized prehospital emergency medical system within Birmingham, Ala, in a county with 150,493 children under the age of 15 years. PATIENTS: Sixty three pediatric victims of out-of-hospital cardiopulmonary arrest of any cause presenting to the emergency department of a children's hospital. INTERVENTION: Standard resuscitative techniques were performed for all patients until resuscitative efforts were discontinued in the hospital emergency department or successful resuscitation was achieved. MAIN OUTCOME MEASURES: Successful resuscitation, survival to hospital discharge, neurological outcome, final disposition, and cost of hospital care. RESULTS: Of 63 children with out-of hospital cardiopulmonary arrest treated in the emergency department of a children's hospital, 60 were pulseless and apneic on arrival, 18 (28.6%) were successfully resuscitated and admitted to the intensive care unit, and six (9.5%) were discharged from the hospital. Five of the survivors had severe neurological deficits and one appeared normal. On follow-up, two patients had died (1 month and 7 months after discharge), three were in a vegetative state, and one was normal. The normal patient had successful defibrillation prior to arrival at the emergency department. The average inpatient charge was $10,667 per patient for those who died and $100,000 for those discharged. CONCLUSIONS: Aggressive treatment does not lead to intact survival for victims of out-of-hospital cardiopulmonary arrest who present to the pediatric emergency department with a preterminal rhythm and absence of spontaneous circulation. Resuscitation efforts in the emergency department are commonly successful but lead to death or severe neurological sequelae at discharge with extremely high cost of care. PMID- 7849888 TI - Severe thrombocytopenia as a presenting manifestation of Kawasaki disease. PMID- 7849889 TI - Minocycline-induced rash in an 18-year-old patient. PMID- 7849890 TI - How to improve teaching on the hospital wards. PMID- 7849891 TI - [Neuroblastoma: is systemic screening possible?]. PMID- 7849892 TI - [Post-natal weight gain in the premature: the reference curves of Dancis (1948) can still be used]. AB - BACKGROUND: Post-natal growth curves for low birth-weight infants published in 1948 by Dancis et al are still used in many neonatal units. The aim of this study is to determine whether these curves are still valid or not. POPULATION AND METHODS: Thirty or more infants whose birthweights were 1000 +/- 125, 1250 +/- 125, 1500 +/- 125, 1750 +/- 125, 2000 +/- 125, 2250 +/- 125 and 2500 +/- 125 g were included in the study from September 1989 to September 1992. Inclusion criteria were: gestational age (GA) less than 37 weeks, absence of intra-uterine growth retardation, enteral feeding during the first post-natal week, absence of severe post-natal disease. The curves of weight were compared to those obtained by Dancis. RESULTS: The six curves established for those infants having a birthweight from 1250 +/- 125 to 2500 +/- 125 g were quite similar to Dancis' curves. The number of infants weighing 1000 +/- 125 g at birth was not sufficient to be included in the study. CONCLUSIONS: The curves established by Dancis from low birth-weight infants of all types (including intra-uterine growth retardation) are still valid to follow post-natal growth of appropriate weight for GA premature infants. PMID- 7849893 TI - [Pain symptomatology in premature infants]. AB - BACKGROUND: Assessing pain in premature babies is difficult because of their limited capacities to communicate. The aim of this study was to recognize manifestations of acute and chronic pain or, on the contrary, of well-being state, and to validate a "pain scale" for premature babies. POPULATION AND METHODS: Premature babies less than 28 days of age (most of them less than 32 weeks of gestational age) were carefully observed during their stay in a neonatal intensive care unit by nurses, physicians, physiotherapists and a psychiatrist. All signs and symptoms were collected during situations a priori painful and compared to the behavior of the well-being states. Photographs and videofilms were also analysed. RESULTS: Five items, scored from 0 to 4, were established, based on facial activity, movements and posture of the body, quality of sleep, relationship with the examiner, and efficacy of measures of comforting. These items permitted to describe four patterns corresponding to 1: well-being status, 2: acute pain, 3 and 4: durable pain or discomfort either through clinical picture of irritability or motionlessness. A strict concordance of scores for the five items between the different examiners was found in 80% of the 50 babies studied. The sensibility of the scale (studied in 12 babies) appeared accurate (77% of variation of the scores during hospitalization). CONCLUSIONS: An objective assessment of pain and discomfort in premature babies can be made using a "pain scale" useful for care and therapeutic decisions. PMID- 7849894 TI - [Comparative evaluation of clinical and ultrasonographic screening of hip dislocation in Breton and Languedoc populations]. AB - BACKGROUND: Congenital dislocation of the hip varies greatly in incidence among different regions. This work is aimed at comparing results of clinical investigation and ultrasonography of the hip in Languedoc-Roussillon and Brittany. POPULATION AND METHODS: Two thousand eight hundred and twelve and 2,809 neonates admitted to Nimes and Vannes hospitals respectively, were enrolled in a prospective study. Clinical examinations were made according to the protocol established by the "Groupe d' etudes en orthopedie pediatrique". Ultrasound investigations were performed in every risk case. RESULTS: No dislocation occurred in the 4946 neonates without risk factors. In the 675 neonates with risk factors, 213 ultrasonographic examinations were abnormal, more frequently in the Brittany group (P < 0.001); nine dislocations were observed. A familial history of hip dysplasia (P < 0.001) and the addition of two risk factors (P < 0.001) were more frequent in Brittany. One hundred and six cases required treatment, more frequently in Brittany (P < 0.001). CONCLUSIONS: Some clinical risk factors and delayed ossification or hip dysplasia at ultrasound examination are significantly more frequent in Brittany. Clinical examination with selective ultrasonography is a reliable method, allowing early diagnosis and treatment of delayed dislocations. PMID- 7849895 TI - [Screening of hemoglobinopathies and molecular analysis of beta-thalassemia in Central Tunisia]. AB - BACKGROUND: Previous investigations have permitted to locate 16 beta-thalassemic mutations in different samples of the Tunisian population. One of them (IVS I nt 2: T--G) had been found only in the central region of Tunisia. Our research was carried out in this part of the country to estimate the prevalence of this mutation and to establish a prenatal diagnosis using appropriate probes. POPULATION AND METHODS: One thousand one hundred and five blood samples taken from 1987 to 1990 from healthy blood donors and 346 samples taken from 1985 to 1992 from patients were analysed. Detection of hemoglobinopathies was carried out by means of specific hematological tests and different electrophoretic and chromatographic techniques. Mutations were detected by means of the usual techniques of molecular biology. RESULTS: Sickle cell anemia and beta-thalassemia were the most frequent in the samples studied. The molecular analysis carried out on eight patients native of the Essouassi-El-Djem region point out that all these patients carry the same point mutation (IVS I nt 2: T-G) detected for the first time in 1988 in a patient native of the same region. One of these patients, aged 43, who did not suffer from anemia and did not show the usual symptoms of beta O thalassemia, had one hemolytic attack at the age of 17. CONCLUSIONS: The high number of persons carrying Hb S and beta-thalassemia trait increase the risk of appearance of homozygous forms. The presence of the same mutation IVS I nt 2: (T G) in all beta O-thalassemic patients from Essouassi-El Djem region may indicate that it may have its origin there. The heterogeneity of clinical phenotype of these patients shows the difficulty of establishing a unique strategy of prenatal diagnosis by DNA analysing which can be applied in all cases. PMID- 7849896 TI - [Necrotizing tracheobronchitis in ventilated newborn infants]. AB - BACKGROUND: Necrotizing tracheobronchitis is a severe complication observed in some mechanically ventilated neonates. CASE REPORT: A twin premature (GA = 31 weeks), weighing 1,500 g required oral endotracheal intubation for mechanical ventilation because he suffered from respiratory distress syndrome. He was given indomethacin on day 4 for patent ductus arteriosus. Progressive weaning of ventilation on day 9 was dramatically complicated by hypoxia, respiratory acidosis and right pneumothorax. Immediate endoscopy showed total obstruction of trachea by necrotic secretions the suction of which was followed by rapid improvement of the respiratory condition. Bacterial examination of secretions showed coagulase-negative staphylococcus. The patient was given steroids + antibiotics. Prolonged ventilation resulted in bronchopulmonary dysplasia and the patient was only extubated at week 12 after a normal endoscopic control. CASE REPORT: A premature girl (GA = 32 weeks), weighing 1,800 g required oral endotracheal intubation for mechanical ventilation because she suffered from respiratory distress syndrome. The respiratory condition worsened on day 3, requiring tracheography which showed distal tracheal obstruction. Immediate endoscopy showed thin, adherent and necrotic membranes which were removed by suction. The patient was given steroids +antibiotics and was extubated on day 14 after a normal endoscopic control. CONCLUSIONS: This iatrogeneous complication must be recognized in a ventilated infant when the respiratory condition dramatically worsens. Emergency bronchoscopy permits endotracheal suction of necrotic secretions. PMID- 7849897 TI - [Exophthalmos in children caused by vascular orbital neoformation]. AB - BACKGROUND--Exophthalmos or proptosis may be a result of several causes; when unilateral, it leads to search a variety of orbital tumors. CASE 1--A 2 month-old baby presented with a right exophthalmos which developed within a few days. Computed tomography showed infiltration of the orbit by a mass. Surgical biopsy showed capillary hemangioma. The patient was given prednisone 2 mg/kg/day for 2 months; exophthalmos disappeared within 10 days and the child was normal 7 years later. CASE 2--A 13 year-old boy was examined because he had developed left exophthalmos within 2-3 weeks. Ultrasonography and computed tomography showed an orbital tumor compressing the eye and the optic nerve. This tumor was excised and histological examination showed that it was a thrombotic arterial aneurysm. CONCLUSIONS--Vascular lesions can be responsible for a rapidly developing orbital tumor. Their diagnosis can be difficult and must be made in order to avoid aggressive surgery. PMID- 7849898 TI - [CHARGE association]. AB - BACKGROUND: The spectrum of CHARGE association includes coloboma, heart disease, choanal atresia, retarded growth and development and/or CNS anomalies, genital anomalies and/or hypogonadism and ear anomalies and/or deafness. CASE REPORT: A 4 1/2 month-old boy was admitted suffering from microphthalmia. His weight was 6 kg (-1 SD), height 60 cm (-2 SD) and his head circumference was 44 cm (+ 2 SD). He had hypotonia. Examination showed low-set ears, micrognathia, coloboma, left choanal atresia and genital hypoplasia. His heart was normal. CONCLUSION: The CHARGE association must be recognized early since it may be complicated by respiratory and feeding difficulties which can be lethal. PMID- 7849899 TI - [Angelman syndrome]. AB - The Angelman syndrome is a neurological disorder characterized by constant features: severe mental retardation, easily provoked laughter, ataxia, absent speech, seizures. Most cases are sporadic but familial cases have been reported. About 60 to 70% of cases are due to an interstitial deletion on the maternally inherited chromosome 15 in the region q11-q13. Rare cases result from paternal disomy. In 30% of patients, neither maternal by inherited deletion, nor paternal disomy, can be found. In this category of patients recurrence risk for sibs is high and molecular mechanisms are not completely known. They appear to be more complex than previously suggested. It is clear that this syndrome is a genetically heterogeneous group. The main example of genomic imprinting in human pathology, Angelman syndrome is now a model in research for understanding molecular mechanisms underlying imprinting. PMID- 7849900 TI - [Treatment of central precocious puberty with sustained-release triptorelin]. AB - Central precocious puberty is defined as the appearance of morphological and biological changes induced by the early maturation of the hypothalamic-pituitary gonadal system before eight years of age in girls and ten years of age in boys. This early onset of the gonadotropin-releasing hormone pulse generator activation leads to secretion of gonadal steroids and therefore to the development of secondary sexual characteristics. The aim of medical treatment is to suppress the secretion of sex hormones. A dramatic improvement has been achieved with the development of gonadotropin releasing hormone agonists which induce a reversible suppression of gonadotropin secretion. Since 1986, triptorelin (Decapeptyl) (D Trp6-LHRH) has been available for this indication as a sustained-release formulation allowing an intramuscular injection of 3.75 mg every 4 weeks. Results published up to now concern 352 children (325 girls and 27 boys). The pituitary gonadal suppressive effect has been confirmed. The complete suppression of gonadal secretions induced a rapid regression of secondary sexual characteristics as early as the 3rd month of therapy, and decreased the growth rate acceleration which normalizes during the 3rd year of therapy. The progression of bone maturation clearly slowed down at the end of the first year of treatment so the final height prognosis significantly improved. Whatever length of the treatment period, the reversibility of the suppressive effect of triptorelin has been demonstrated. Puberty resumed 3 to 9 months after stopping the treatment. Tolerance of the medication was excellent. The rare side effects were minor and never led to treatment discontinuation: headaches (8% of the cases), hot flushes (12% of the cases). The percentage of drop out was very low. PMID- 7849901 TI - [Force-feeding of infants in North Cameroon. A harmful tradition-- preventive approach]. AB - Repeated infant force-feeding is a widespread custom among mothers in the district of Tokombere in North Cameroon. It is started in neonates and maintained until approximately one year of age, using mostly hot water. The authors describes the complications of this practice, the most severe one being aspiration pneumonia which can cause death. The traditional and cultural aspects of infant force-feeding in this area are discussed. The author believes that these aspects have to be taken into account in any preventive action directed towards the renunciation of this harmful practice. PMID- 7849902 TI - [How to measure disability in children? Different methodologies, values and applications]. AB - Infantile mortality data are insufficient for perinatal care evaluation. Long term morbidity, particularly child impairment prevalence, needs to be assessed regularly. In this paper different surveys on child impairment registration published in the literature are examined: cohort studies, follow-up studies on "at risk" children, cross sectional surveys and morbidity registers. Study designs and case ascertainment are analysed as well as case validation and reference population. The consistency of the results is discussed. In France, most of the studies on childhood impairment are follow-up studies of at risk children, not concerning a geographically defined population, and there is a need for larger epidemiological studies in order to better assess perinatal morbidity and the quality of perinatal cares. PMID- 7849903 TI - [Severe postoperative hyponatremia: role of prolonged fasting and perfusion of hypotonic solution]. PMID- 7849904 TI - [Laxative abuse: a cause of rectal bleeding not to be missed in children]. PMID- 7849905 TI - Microemulsions of perfluorinated and semi-fluorinated compounds. AB - Perfluorocarbons combine high gas dissolving capacities with extreme chemical and biological inertness: they are good oxygen carriers in artificial blood and in liquid breathing. However fluorocarbons are highly hydrophobic molecules. To solve the problem of their transport, it is necessary to use the perfluorocarbons as an oil-in water emulsion (O/W). To avoid harsh treatment to form such emulsions and in order to have injectable "blood substitutes", microemulsions seem particularly attractive since they are fluid, transparent, thermodynamically stable microheterogeneous systems. Microemulsions, contrarily to classical emulsions, are formed spontaneously by adding suitable surfactants (or a surfactant+a cosurfactant) in appropriate proportions to a non miscible mixture of water and oil. Biocompatible O/W microemulsions are difficult to obtain because of: 1) the existing segregation between perfluorinated and hydrogenated chains, resulting, in some cases in heterogeneities or gelation phases; 2) the toxicity of some components; 3) the possible harmfulness of the dispersed system, etc... We'll discuss all the parameters involved of the microemulsification process, the nature of products, the phase diagrams, and the phase behaviors. This study will outline certain guidelines necessary for the formation of microemulsions of perfluorinated (or almost completely fluorinated) oils with perfluorinated (or partially fluorinated) surfactants. PMID- 7849906 TI - Fluorocarbon blood substitutes in Russia. PMID- 7849908 TI - Pharmacokinetics and side effects of perfluorocarbon-based blood substitutes. AB - Perfluorochemicals are fluorine-saturated carbon-based molecules which demonstrate utility in the areas of imaging and oxygen delivery. In general, these molecules are biologically inert and, therefore, do not pose toxicologic risk from metabolic degradation. Intravenous (i.v.) perfluorocarbon (PFC) emulsions are cleared from the blood through a process involving phagocytosis of emulsion particles by reticuloendothelial macrophages (RES) and ultimate elimination through the lung in expired air. RES phagocytosis of PFC emulsion particles leads to characteristic, predictable, and reversible biological effects that are a consequence of a normal host-defense mechanism. This mechanism is characterized by dose-related stimulation of macrophages and subsequent release of intracellular products (particularly metabolites of the arachidonic acid cascade and cytokines) which are responsible for most of the biological effects associated with i.v. PFC emulsions (i.e., cutaneous flushing and fever at lower doses, and macrophage hypertrophy and recruitment at higher doses). These biological effects are reversible, and do not result in any permanent tissue alteration, even with prolonged exposure at relatively high doses. The rate of PFC elimination from the RES is proportional to the vapor pressure of the PFC, inversely proportional to molecular weight and positively influenced by lipophilicity. This dose-dependent respiratory excretion occurs with no evidence of metabolic products. Repeated administration of high doses of PFC emulsion may lead to a saturation of the RES-mediated clearance capacity, resulting in a redistribution of PFC to non-RES tissues and ingestion by resident or mobile macrophages. This condition is benign with respect to the integrity of the surrounding parenchyma, as well as to the macrophages themselves. Increased pulmonary residual volume (IPRV) due to pulmonary gas (air) trapping, a reversible side effect, has been observed with i.v. doses of PFC emulsion in some animal species. The gross morphological change associated with IPRV is not accompanied by any histological alteration other than the appearance of vacuolated macrophages (characteristic of the normal clearance mechanism) and some minor, increased interalveolar cellularity. Animal lungs affected by IPRV have a normal, pale pink appearance with no visible lesions or signs of edema. The degree of IPRV is dependent on species, PFC dose, and type of PFC administered; PFCs with higher vapor pressures produce the most severe cases of IPRV in sensitive species. Species sensitivity depends upon physiological and morphological characteristics. There is no evidence indicating that IPRV occurs in humans. Although i.v. PFC emulsions may elicit minor untoward effects, these effects are reversible and, at clinically relevant doses, do not pose a toxicologic risk. PMID- 7849907 TI - Quantitative pO2 imaging in vivo with perfluorocarbon F-19 NMR: tracking oxygen from the airway through the blood to organ tissues. AB - The physiological redistribution of perfluorocarbon (PFC) compounds to liver, spleen, bone marrow, and lung after intravenous (i.v.) or intraperitoneal (IP) administration of PFC emulsions affords the unique opportunity for non-invasive monitoring of oxygenation status of these organs and tissues utilizing fluorine (F-19) nuclear magnetic resonance (NMR) imaging techniques. PFCs also may be introduced directly into the pulmonary airways by procedures such as liquid ventilation, intratracheal instillation, or aerosol inhalation. Considerations of importance when establishing methodology for accurate quantitation of oxygen partial pressure (pO2) in vivo using F-19 NMR include: 1.) error analysis of the calibration curves which relate pO2 to the measured PFC F-19 relaxation rate, 2.) optimization of the NMR pulse sequence for efficient oxygen sensitive data acquisition and, 3.) fluorine signal independence from emulsion aqueous phase bioconstituents. The porcine model was investigated at 0.14T following i.v. or IP administration of the PFC emulsion containing perfluorotributylamine (FC-43) to demonstrate the capability for tracking oxygen with F-19 NMR from the lung through the blood to selected organ tissues. Quantitative pO2 projection images and isobaric contour graphs were derived for the liver, spleen, and lungs as a function of inspired oxygen. Blood pO2 levels in aorta, pulmonary artery, and hepatic vein were monitored simultaneously with NMR imaging for correlative analysis. PMID- 7849909 TI - Functional MR imaging of a metabolite of 17O2. PMID- 7849910 TI - Cardiovascular applications of fluorocarbons in regional ischemia/reperfusion. AB - Potential cardiovascular therapeutic uses for perfluorochemicals include oxygen delivery distal to an occluding balloon during high risk coronary angioplasties, treatment for acute myocardial infarction with or without concomitant reperfusion, cardioplegia, and preservation of donor hearts for transplant. Infusions of oxygenated perfluorochemicals during brief coronary occlusions, as occurs with angioplasties, preserves cardiac ultrastructure and cardiac function. Fluosol is currently approved in the U.S. for angioplasty procedures. Experimental studies have suggested that perfluorochemicals reduce myocardial infarct size during permanent coronary occlusion or temporary coronary occlusion. One school of thought suggests that these agents work by reducing reperfusion injury. By inhibiting neutrophil function, including adherence to endothelial cells and release of toxic substances, perfluorochemicals may preserve the endothelium and prevent no-reflow. However, one might argue that any agent which reduces infarct size by any mechanism would result in less neutrophil infiltration and smaller no-reflow areas. One pilot study suggested that intracoronary Fluosol administered at the time of reperfusion, reduced infarct size and improved regional ventricular function in patients. However, preliminary results of a large multicenter study in which this agent was given along with thrombolysis, were largely negative. Whether perfluorochemicals will become an important adjunctive agent along with reperfusion for acute myocardial infarction remains to be determined. PMID- 7849911 TI - Cardiovascular applications of fluorocarbons: current status and future direction -a critical clinical appraisal. AB - Alteration of normal blood flow to the heart may result in myocardial ischemia or infarction. Perfluorochemical emulsions offer a potential means to improve oxygenation of the heart during periods of hypoxia. The small particle size and linear disassociation curve of perfluorochemicals may result in greater oxygen delivery than blood particularly in severely diseased or damaged atherosclerotic vessels. Intracoronary Fluosol given during PTCA reduces the myocardial ischemia which occurs during balloon inflation. Although Fluosol does not prevent myocardial dysfunction during prolonged balloon inflations, new concentrated perfluorochemicals have increased oxygen delivery capacity and may have greater benefit. Experimentally, during coronary occlusions, perfluorochemicals promote higher oxygen tension in areas of ischemia and result in infarct size reduction. Reduction of oxygen free radicals has been proposed as the mechanism by which Fluosol exerts its ability to reduce infarct size. Clinical studies with Fluosol and thrombolytic therapy for treatment of acute myocardial infarctions are ongoing to assess ability to preserve myocardial function. Perfluorochemical cardioplegia can deliver oxygen during periods of cardiac arrest and may improve immediate post CPB myocardial function particularly in those patients with pre existing left ventricular dysfunction. The oxygen-carrying capacity of perfluorocarbons and its unique properties offer great advantages to improve the treatment of cardiovascular diseases. PMID- 7849912 TI - Perfluorochemical emulsions and radiation therapy. PMID- 7849913 TI - Combination of perfluorochemical emulsions and carbogen breathing with cancer chemotherapy. AB - Over the past ten years several laboratories have explored the use of perfluorochemical emulsions (PFCE) and carbogen (95% O2/5% CO2; C) or oxygen breathing as an adjuvant to radiation therapy and/or chemotherapy in solid tumor model systems. The rationale for the use of PFCE and C or oxygen breathing in this therapeutic setting is that solid tumor masses contain areas of hypoxia which are therapeutically resistant. Since x-rays and many chemotherapeutic agents require oxygen to be maximally cytotoxic and most normal tissues are well oxygenated, the additional oxygen put in circulation by the PFCE/C should not increase the normal tissue toxicities produced by the various therapies. Several anticancer agents are dependent on oxygen to be cytotoxic, these drugs such as the iron-chelating peptide bleomycin are enhanced in antitumor activity by the co administration of a PFCE/C. The antitumor alkylating agents especially cyclophosphamide, BCNU and melphalan show increased tumor cell killing without a concomitant increase in bone marrow toxicity when administered with PFCE/C. Enhanced activity was also observed when topoisomerase II inhibitors such as adriamycin and etoposide were co-administered with PFCE/C. Positive effects, although smaller, were observed when antimetabolites such as 5-fluorouracil and methotrexate were co-administered with PFCE/C. PMID- 7849914 TI - Full-tidal liquid ventilation with perfluorocarbon for prevention of lung injury in newborn non-human primates. AB - Hyaline membrane disease (HMD), the most common life-threatening respiratory disorder of newborns, is associated with lung injury manifested by alveolar proteinaceous edema. The cause of the disease is thought to be elevated alveolar surface tension due to surfactant deficiency at birth. Treatment with exogenous surfactant may be unsuccessful due to problems in distribution of the surfactant, or inhibition of the surfactant by alveolar proteinaceous edema. Liquid ventilation with oxygen-saturated perfluorocarbon liquid has been proposed as a method to eliminate alveolar surface tension; little is known about the interfacial tension between perfluorocarbon liquids and the lung lining layer. Premature and term newborn monkeys were treated from birth with a pressure limited, time-cycled liquid ventilator using oxygenated perfluorocarbon liquids (APF-145 and perflubron). Adequate gas exchange was achieved, and pilot experiments suggest long-term survival without adverse sequelae. Although many questions remain, liquid ventilation is a promising tool for the prevention and treatment of lung injury in newborns. PMID- 7849915 TI - Perfluorocarbon associated gas exchange (PAGE): gas ventilation of the perfluorocarbon filled lung. AB - BACKGROUND: Throughout most of the second half of this century, progress in respiratory life support was dominated by modernization of the mechanical ventilator. We have now entered an era in which the fundamental physiology of lung function can be manipulated to improve lung performance in hope of reducing morbidity and mortality and thereby decreasing the cost of intensive care. MAIN FINDINGS: Despite its almost alien technology, perfluorocarbon tidal liquid breathing is an effective means to support respiration in normal and surfactant deficient lungs. A second, technique, perfluorocarbon associated gas exchange (PAGE), has recently been shown effective in normal lungs and in several animal models of lung disease. Both techniques appear to improve pulmonary function when pulmonary surface tension is elevated. CONCLUSIONS: PAGE improves lung function and poses opportunities to reduce pulmonary morbidity and diminish the cost of intensive care. PMID- 7849916 TI - Non-invasive physiology: 19F NMR of perfluorocarbons. AB - Ever since it was shown that the 19F NMR spin-lattice relaxation rates (R1) of perfluorocarbon (PFC) emulsions are highly sensitive to oxygen tension (pO2), there has been a developing interest in the use of PFCs to probe tissue physiology. Oxygen is required for efficient function by most tissues and hypoxia leads to rapid cellular dysfunction and damage. In addition, hypoxic tumor cells are refractory to radiotherapy. Thus, the opportunity to measure tissue oxygen tension non-invasively may be significant in understanding mechanisms of tissue function and in clinical prognosis. PFC NMR parameters are also sensitive to temperature, facilitating NMR thermometry with potential applications in hyperthermia studies. I will review the development of experimental techniques, applications to specific tissues and discuss the challenges and opportunities presented by 19F NMR of perfluorocarbons. PMID- 7849917 TI - Pharmacokinetics and tolerance of weekly OXYGENT CA infusions in the dog. AB - This study determined the OXYGENT CA (90% w/v perflubron emulsion, Alliance Pharmaceutical Corporation) dose necessary to achieve a 3-4% fluorocrit, and the tolerance of this dose administered once per week for four weeks to dogs. This study simulated OXYGENT CA use as a radiosensitizing agent. Six adult dogs were administered 6 ml/kg OXYGENT CA once per week for 4 weeks. Blood samples were collected following infusion, until fluorocrits were < or = 0.5%. One week after the fourth infusion, three dogs were necropsied. Liver biopsies were obtained from the remaining three dogs which were monitored 12 additional weeks. All dogs achieved fluorocrits > 3.0% (3.5-5.1%) with the 6 ml/kg dose. A 3 ml/kg dose did not provide a fluorocrit > 3.0%. Serum bilirubin concentrations were elevated at 24-hour sampling times and declined within 72 hours. Elevations in ALT, SAP, and bile acids were noted. Splenic and hepatic microvasculature fibrosis occurred in the long-term study dogs. Thrombocytopenia occurred in 5/6 dogs, necessitating exclusions of one dog from 2 infusions. However, 3/5 thrombocytopenic dogs had titers for Ehrlichia sp., which elicits thrombocytopenia. Therefore, we cannot conclude the effect of OXYGENT CA on platelets. PMID- 7849918 TI - Enhanced oxygen delivery by perflubron emulsion during acute hemodilution. AB - A high-concentration 90% w/v perflubron (perfluorooctyl bromide [PFOB]) emulsion (Oxygent HT) is being evaluated as an oxygen carrier for use during surgery. This study was done to assess oxygen delivery by Oxygent HT during acute normovolemic hemodilution. Anesthetized mongrel dogs, instrumented with femoral and pulmonary artery catheters, were hemodiluted to a hematocrit of 25% with 3:1 (v/v) of Ringers-lactate (R-L). Dogs were then ventilated with 100% O2 and hemodiluted to a Hct approximately 11% with 1.5 (v/v) of colloid (autologous plasma and 5% albumin). Dogs then received either 3.3 mL/kg Oxygent HT (n = 5) or 3.3 mL/kg R-L (n = 4), and were monitored for 3 hours. Total oxygen delivery (DO2), blood oxygen content, cardiac output, mixed venous PO2, and mixed venous Hb saturation was higher in Oxygent HT treated dogs compared to the R-L controls. The percentage of total DO2 contributed by perflubron-dissolved oxygen was about 8 10% and accounted for 25-30% of total oxygen consumption (VO2). The percentage of VO2 contributed by Hb-carried oxygen was significantly higher in R-L controls (46 +/- 4%) than in the treated dogs (15 +/- 3%), indicating that the availability of the perflubron-dissolved oxygen allowed for a reserve of oxygen to remain available in the red blood cells. PMID- 7849919 TI - Influence of perflubron emulsion particle size on blood half-life and febrile response in rats. AB - Perfluorochemical (PFC) emulsions are particulate in nature and, as such, can cause delayed febrile reactions when injected intravenously. This study investigated the influence of emulsion particle size on intravascular retention and on body temperature changes in unrestrained conscious rats. Concentrated (60% to 90% w/v) emulsions based on perflubron (perfluorooctyl bromide [PFOB]) with mean particle sizes ranging from 0.05 microns to 0.63 microns were tested. Rats were fitted with a chronic jugular catheter and an abdominal body temperature telemetry unit. Fully recovered, conscious rats were monitored for 24 hours after infusion (dose = 2.7 g PFC/kg). Emulsion blood half-life (T1/2) was determined from blood perflubron levels measured by gas chromatography. Emulsions with a particle size of 0.2-0.3 microns caused fevers (6 to 8 hour duration) which peaked at 1-1.5 degrees C above normal (approximately 37.5 degrees C). Fevers could be blocked by i.v. treatment with either cyclooxygenase inhibitors (ibuprofen) or corticosteroids (dexamethasone). Both intensity and duration of the temperature response, quantified by area under the temperature curve, was decreased significantly for emulsions with a particle size < or = 0.12 micron. Blood T1/2 varied inversely with particle size, and was 3 to 4 fold longer for emulsions with a mean particle size < or = 0.2 micron. Thus, smaller emulsion particles more effectively evaded the reticuloendothelial system, which resulted in longer intravascular retention, less macrophage activity, and reduced febrile responses. PMID- 7849920 TI - Room temperature stable perfluorocarbon emulsions with acceptable half-lives in the reticuloendothelial system. AB - Prolonged room temperature stability (i.e. zero particle growth) can be achieved for concentrated emulsions of perflubron (perfluorooctyl bromide) or perfluorodecalin via addition of a secondary high molecular weight, lipophilic fluorocarbon component. Due to their enhanced lipophilic character, the secondary fluorocarbon components have acceptable half-lives in the organs of the reticuloendothelial system. PMID- 7849921 TI - Improved control over particle sizes and stability of concentrated fluorocarbon emulsions by using mixed fluorocarbon/hydrocarbon molecular dowels. AB - The use of a surfactant system consisting in equimolar amounts of egg yolk phospholipids and of a mixed fluorocarbon/hydrocarbon amphiphile (C8H17CH = CHC8F17) allows the preparation of concentrated (90% w/v, i.e. 47% v/v) emulsions of perfluorooctyl bromide (perflubron), with average particle sizes ranging from 0.12 to 16 microns post-sterilization, depending on the surfactant/fluorocarbon ratio. Emulsion droplet diameters varied linearly as a function of the emulsifier's concentration, thus allowing easy pre-determination of the emulsion's average particle size. Excellent stability was observed for the dowel containing emulsions for at least 6 months at 40 degrees C over the whole domain of particle sizes investigated. PMID- 7849922 TI - Biodistribution and excretion of a mixed fluorocarbon-hydrocarbon "dowel" emulsion as determined by 19F NMR. AB - To investigate the biodistribution, possible metabolism and excretion of mixed fluorocarbon-hydrocarbon "dowel" molecules used as stabilizers of fluorocarbon emulsions, we have prepared a 25% w/v emulsion of such a molecule, and quantitatively evaluated, by means of 19F NMR, its behavior in the blood and reticuloendothelial system (RES) of rats. C6F13CH = CHC10H21 (F6H10E) was emulsified using egg yolk phospholipids (EYP). The emulsion (F6H10E/EYP: 25/6% w/v) was injected intravenously into 33 Sprague Dawley female rats at a 3.6 g/kg body weight dose of F6H10E. The animals were sacrificed at regular intervals of time. 24 hours after the injection, 70% of the injected dose was located in the liver, 17% in the spleen, 4% in the lungs, 2% in the kidneys and 2% in the blood. The half-time retention of the dowel molecule in the liver was estimated to be 25 +/- 5 days. None of the 33 treated animals died prior to the planned sacrifice date. The dowel molecule F6H10E proved to be well tolerated, and excreted reasonably fast, without metabolism. This appears to warrant the use of such molecules as stabilizers in injectable fluorocarbon emulsions destined to serve as oxygen carriers, contrast agents or drug delivery systems. PMID- 7849923 TI - Pulmonary gas trapping differences among animal species in response to intravenous infusion of perfluorocarbon emulsions. AB - In animals, increased lung volume and a concomitant failure of lungs to collapse normally upon autopsy can occur following intravenous injection of higher vapor pressure perfluorocarbons (PFCs) administered as emulsions. Responses vary considerably depending on the PFC, dose and animal model. The study objective was to examine animal species differences with respect to this apparent pulmonary gas trapping (PGT) phenomenon which has not been observed in human clinical trials. A dose-related increase in postmortem lung volume following treatment with either a concentrated perflubron emulsion or Fluosol was observed. It was most pronounced in pigs, rabbits and monkeys, and essentially nonexistent in mice and dogs. No clear effects on arterial blood gases were seen in most species, but PaO2 levels were reduced transiently in monkeys given the highest PFC doses. Reversibility of pulmonary effects occurred more rapidly with perflubron emulsions than with Fluosol. Vacuolated mononuclear cells, reflecting the presence of PFC particles in the lung, and alveolar distention varied between species, but no lesions or edema were observed. Species differences in collateral ventilation, airway morphology and pulmonary intravascular macrophages may influence their sensitivity and contribute to the interspecies differences in response to intravenously administered PFC emulsions. PMID- 7849924 TI - Proposed mechanism of pulmonary gas trapping (PGT) following intravenous perfluorocarbon emulsion administration. AB - PURPOSE: To investigate various hypotheses and identify the most likely mechanism preventing the complete collapse of test animal lungs at sacrifice subsequent to intravenous injection of certain perfluorocarbon emulsions. PROTOCOL: Literature data were reviewed, experimental data were extracted from completed studies and new data were generated in an attempt to delineate reasons why, in certain animals, lungs fail to collapse normally at necropsy if previously injected with certain perfluorocarbon emulsions. The proposed hypothesis involved gas osmosis through endogenous pulmonary surfactant-liquid bridges (micro-bubbles). RESULTS: The observed effect of incomplete lung collapse upon necropsy was found to correlate with perfluorocarbon vapor pressure. Results indicated that failure to collapse could be attributed to the formation of intra-alveolar micro-bubbles induced by the normal pulmonary elimination of perfluorocarbon vapor. These micro bubbles result in a phenomenon which could be characterized by the term, pulmonary gas trapping. Reduction of the perfluorocarbon concentration gradient across the bubble films by exposure to a perfluorocarbon vapor-containing atmosphere was found to reduce the effect in-vivo and prevent gas osmosis bubble growth in-vitro. CONCLUSION: Experimental observations are consistent with the proposed theory of perfluorocarbon-related gas osmosis through micro-bubbles that prevent complete lung collapse as observed upon opening the thoracic cavity of test animals. PMID- 7849925 TI - Phagocytosis of a fluorescently labeled perflubron emulsion by a human monocyte cell line. AB - We hypothesized that fluorocarbon-based lipid emulsions are phagocytosed by monocytes and that many of the in vivo side effects related to the infusion of these particulate emulsions are due to release of cytokines by these monocytes. To clarify whether these emulsions are actually phagocytosed we attempted to measure by flow cytometry the apparent uptake of a fluorescently labeled high concentration (90%, w/v) perflubron (perfluorooctyl bromide [PFOB]) emulsion by a differentiated human monocyte cell line. A fluorescent chromophore (Zynaxis Cell Science) was used to label the egg yolk phospholipid in a perflubron emulsion. This phospholipid label was used to track the perflubron emulsion during overnight incubation with the human monocyte (THP-1) cell line which had been differentiated, by exposure to PMA, into macrophage-like cells. Our results indicate that after 24 hours of incubation with the labeled perflubron emulsion, 64.9% (+/- 11.0) of differentiated THP-1 cells had cell-associated emulsion (ingested and/or membrane bound) whereas 24.4 (+/- 6.8%) of the control cells had cell-associated emulsion. We speculate that this technique may be a useful method to track the intravascular persistence and extravascular distribution of such emulsions, and that the degree of uptake of the emulsion by macrophages in this assay may correlate with its in vivo half life. PMID- 7849926 TI - Influence of perflubron on the creation of oxygen free radical products in mesenteric artery occlusion shock. AB - The influence of a temporary occlusion of the superior mesentery artery on the generation of oxygen free radical products was tested in controls and after administration of perflubron. The occlusion time lasted for 90 min and a reperfusion time of 150 min was chosen until examination of tissue samples took place. The content of thiobarbituric acid reactive substances (TBARS), glutathione (GSH) and myeloperoxidase (MPO) was determined in homogenized tissue samples. A protective effect of antioxidants or radical scavengers was tested in form of alpha-tocopherol and allopurinol. A highly significant increase of TBARS was found in the operated control group, still higher under perflubron (perfluoroocytylbromide, PFOB). However, under alpha-tocopherol as well as under allopurinol the effect of radical products could be diminished below the values of controls. GSH and MPO were not significantly changed under PFOB as compared to the operated control group. PMID- 7849927 TI - Perfluorodecalin emulsion tested for biocompatibility in macrophages by means of a magnetometric method. AB - The effect of a stable perfluorodecalin (FDC) emulsion, based on addition of 0.2 0.5% (W/V) of perfluoroperhydrophenanthrene and 4% egg yolk lecithin was tested for its influence on Kupffer cells in vivo by means of a magnetometric procedure in rats. It was also compared with the effect of a perfluoro-chemical emulsion (PFC) of the first generation (FluosolR-DA, FDA). While doses of 0.1 g/kg body weight of both PFCs caused a small increase of activity in these cells (as measured by an increase in a ratio factor r after magnetization), doses of 1 g/kg b.wt. led to a significant retardation of intracellular movements after FDC and FDA for two and four days, respectively. A dose of 3 g/kg b.wt. of FDC effected a significant depression for 8 days, whereas after the same dose of Fluosol-DA the intracellular motility remained depressed for as long as 32 days. PMID- 7849928 TI - The effect of moderate hemodilution with Fluosol on cytochrome P4502D6 activity in the rat. AB - Desmethylimipramine (desipramine, DMI) is predominantly 2-hydroxylated to 2 hydroxydesipramine, and the remainder is N-demethylated to didesmethylimipramine (DDMI) in both rats and man. DMI 2-hydroxylation is mediated by the same cytochrome P-450 isoenzyme (P4502D6) in rats and man. Fluosol hemodilution has previously been shown to influence the activity of P4502B1 and P4502B2, the cytochrome P-450 isoenzymes induced by phenobarbital in rats. In this study, DMI was used as a model substrate to investigate the influence of moderate Fluosol hemodilution on P4502D6 activity in rats. DMI total body clearance was not influenced by Fluosol hemodilution. This was an anticipated outcome since phenobarbital had a negligible effect on DMI metabolism, and Fluosol and phenobarbital affect the same isoenzymes. DMI Vdss was increased at 0.5 hour after hemodilution, but decreased from 24-72 hours. The decreased Vdss is most likely due to increased concentrations of alpha-1-acid-glycoprotein. Thus, Fluosol hemodilution is not expected to influence the hepatic P4502D6 activity in man. However, Fluosol may have marked influences on the apparent volumes of distribution of basic drugs that bind to alpha-1-acid-glycoprotein. PMID- 7849930 TI - Lung functions after intravenous or intraperitoneal administration of perfluorooctyl bromide (PFOB) or perfluorotributylamine (FTBA) emulsions. AB - The biomechanical and oxygen transfer functions of lungs of animals administered intravenous or intraperitoneal fluorocarbon emulsions containing either perfluorotributylamine or perfluorooctyl bromide 4 to 7 days earlier were tested in a porcine and a canine model. Lung fluorocarbon content was measured by 19F NMR spectroscopy. The existence of fluorocarbon in the lung tissue produced no measurable effects on lung compliance variables in vivo or ex vivo nor on steady state oxygen transfer from air to blood over a wide range of inspired oxygen partial pressures. PMID- 7849929 TI - Perfluorocarbon distribution to liver, lung and spleen of emulsions of perfluorotributylamine (FTBA) in pigs and rats and perfluorooctyl bromide (PFOB) in rats and dogs by 19F NMR spectroscopy. AB - Perfluorocarbon emulsion (FCE) particles are reported to be taken up by the reticuloendothelial system (RES) and ultimately eliminated by the lung. This distribution provides an opportunity to measure oxygen partial pressure in vivo with fluorine-19 magnetic resonance imaging (19F MRI). Since the MR image signal to-noise ratio is directly proportional to the fluorine concentration in the tissue, a greater concentration of perfluorocarbon (PFC) in the tissue will result in a greater confidence in the oxygen image and reduce measurement time. It was postulated that the biodistribution of PFC administered in emulsion form may depend on species RES or FCE composition. The distribution of an emulsion (Oxypherol-E.T.) containing perfluorotributylamine (FTBA) 5 days after administration to pigs (11 g FTBA/kg body weight i.p.) and rats (19 g FTBA/kg i.p.) and an emulsion (Oxygent) containing perfluorooctyl bromide (PFOB) 7 days after administration to dogs (11 g PFOB/kg i.v.) and 5 days after administrations to rats (19 g PFOB/kg i.p.) was analyzed by F-19 NMR spectroscopy of tissue samples. PFC concentrations in spleen are 2 to 3 times those in liver. This pattern appears to be independent of PFC emulsion or species. In contrast, lung PFC content was less than that in the liver and showed a dependence upon both species and PFC emulsion. PMID- 7849931 TI - Effect of perfluorochemicals on liver detoxication enzymes. PMID- 7849932 TI - Mixed fluorocarbon/hydrocarbon molecular dowels help protect concentrated fluorocarbon emulsions with large size droplets against coalescence. AB - Mixed fluorocarbon/hydrocarbon amphiphiles, the so-called molecular dowels, have previously been reported to strongly stabilize concentrated (90% w/v, i.e. 47% w/v) submicronic size perfluorooctyl bromide emulsions emulsified by egg yolk phospholipids. The dowel molecules, used in equimolar amounts with phospholipids, enable the preparation of emulsions with large-sized particles which are impossible to obtain with phospholipids alone. We report here that molecular dowels (C6F13C10H21, F6H10) also hinder droplet coalescence induced by mechanical stress in sterilized emulsions with average particle sizes ranging from ca 1 to 16 microns. In contrast, the addition of equimolar amounts of perfluorodecyl bromide was found to have little influence on these emulsions' resistance to mechanical stress. This is consistent with the view that mixed fluorocarbon/hydrocarbon dowels are held in the interfacial film and reinforce its cohesion with the fluorocarbon phase. PMID- 7849933 TI - Amphiphilic sugar phosphates with single or double perfluoroalkylated hydrophobic chains for use in oxygen and drug delivery systems. AB - New anionic amphiphiles with a phosphate ester junction between the fluorophilic lipophilic tail and the sugar-based hydrophilic head were synthesized and evaluated. The single hydrophobic chain surfactants 1 a, b and 2a allowed the preparation of stable and fine highly concentrated emulsions of perfluorodecalin or perfluoroocytl bromide, either when used alone or in conjunction with egg yolk phospholipids (EYP). Surfactants 3d, 5d, 6d and 6e, with two hydrophobic chains, one fluorinated the other not, gave liposomal structures, and displayed encapsulation properties for carboxyfluorescein. The phosphodiesters tested cause no significant inhibition of the growth and viability of Namalva cell cultures (0.1-1 g/L range). Single chain phosphodiesters manifest no detectable hemolytic activity (at 100 g/L for 1a) whereas double chain compounds do moderately (ca 20% hemolysis at 20 g/L). The maximum tolerated dose compatible with the survival of all of a series of 10 intravenously injected mice is in 130 mg/kg body weight range. PMID- 7849934 TI - The elimination peculiarities of perfluorocarbon emulsions stabilized with egg yolk phospholipid. AB - In order to examine the elimination rate of Perfluorodecalin (FDC) emulsions stabilized with different emulsifiers--yolk phospholipid (EYP) and procsanol P 268 (analog of Pluronic F-68)--we performed controlled trials on excretion of FDC in exhaled air, elimination from blood and accumulation in the liver. Adult Wistar rats were injected intravenously with FDC emulsions stabilized with different emulsifiers at a dose of 11.5 g FDC per kg body weight. The concentration of FDC in blood, exhaled air and liver tissue was examined by means of the gas chromatography method. The circulation time in blood for the emulsion stabilized with EYP was much longer comparatively to the emulsion containing the synthetic emulsifier procsanol P-268. The injection of EYP dispersions prolonged the circulation time of lipid-stabilised FDC emulsions. The rate of PFC elimination in exhaled air from such an emulsion and the rate of its accumulation in liver during the initial period after injection are reduced compared to the procsanol-stabilized emulsion. These data are interpreted as the result of a reduction of phagocytic activity of blood monocytes toward the lipid-coated particles of the emulsion. The circulation time of PFC emulsion can be prolonged by using lipid emulsifier and additional injections of EYP dispersion. PMID- 7849935 TI - Oxidative assessment of phospholipid-stabilized perfluorocarbon-based blood substitutes. AB - Methods based on the HPLC separation with subsequent UV detection and spectrofluorimetry have been developed to monitor the formation of oxidative decomposition products of phospholipids in perfluorocarbon emulsions. Catalytic, as well as emulsion oxidative stability studies have been conducted utilizing egg yolk phospholipid (EYP) and perfluorocarbons of varied compositions/purity in order to assess their effect on susceptibility to oxidation. Our studies indicate that phospholipid composition, degree of unsaturation, perfluorocarbon purity and the presence of oxygen and trace metals have a significant effect on the formation of oxidative decomposition products. A combination of methods has proven useful in monitoring the levels of oxidative decomposition products of phospholipids in phospholipid-stabilized perfluorocarbon-based blood substitutes. Such an approach has proven beneficial in the development of pharmaceutical agents of potentially higher quality and storage stability. PMID- 7849936 TI - Effect of perfluorochemical emulsion on lipoproteins of plasma blood. AB - The effect of perfluorocarbons (PFC, Perfluorodecalin/Fogalin) on the lipoprotein level in plasma was studied. The PFC emulsion (FCE) was injected i.v. at a dose of 6 g PFC per kg of body weight into male Wistar rats weighing 250-280 g. The lipoproteins were separated by preparative centrifugation. It was found that PFCs influence the metabolism of lipoproteins. The greatest depletion of cholesterol level occurs in the HDL fraction of lipoproteins 3 and 24 hrs after injection. There is no relationship between the level of cholesterol in plasma and cholesterol lipoproteins. The content in lipoproteins, however, amounts to half the level of the cholesterol of plasma 72 hrs after injection. Based on these facts it is possible to conclude that when PFCs leave the cells of organs, they are carmed in the blood stream as a complex which contains at least PFCs, cholesterol and triglycerides. PMID- 7849937 TI - Effects of buffer pH and phosphate concentration on the droplet size and EYP hydrolysis of perflubron/EYP emulsions. AB - Oil-in-water emulsions containing perflubron (perfluorooctyl bromide; PFOB) and stabilized with egg yolk phospholipid (EYP) have potential applications as contrast agents and oxygen carriers. In this study, the effects of buffer pH and total phosphate concentration on the emulsion droplet size and EYP hydrolysis were evaluated. 90% w/v perflubron emulsions with NaH2PO4-Na2HPO4 buffers of different pH (4.7-8.7) and phosphate concentrations (30 and 60 mM) were prepared with a high-pressure homogenizer. Emulsions were stored at 40 degrees C and tested at 0, 1, 2 and 3 months. The pH dropped quickly in emulsions with pH 8.7 buffer whereas acidic and neutral buffered emulsions exhibited minor pH drops. The concentration of free fatty acids (FFA) vs emulsion pH can be fitted to a parabolic curve with a minimum at about pH 6.0. The droplet growth rates in emulsions with the pH 4.7 buffer were about 2.5 times of those in emulsions with the pH 8.7 buffer. Total phosphate concentration had only a minor effect. This study emphasizes the importance of the careful selection of buffer pH and capacity to control EYP hydrolysis and possibly emulsion droplet size. PMID- 7849938 TI - Effects of formulation, processing and storage parameters on the characteristics and stability of perflubron emulsion. AB - In this study, the effects of formulation, processing and storage parameters on perflubron (perfluorooctyl bromide; PFOB) emulsions were investigated. Emulsions with varying concentrations of perflubron and egg yolk phospholipid (EYP) were prepared with different processing parameters and placed at different storage temperatures. Their characteristics and stability were compared. The emulsion droplet growth rate was nearly proportional to the perflubron percentage in the range of 15-110% w/v. The initial droplet size of perflubron emulsions was inversely proportional to the concentration of EYP until a certain lower limit of droplet size was reached. The initial droplet size and droplet growth rate of perflubron emulsion were strongly dependent upon the processing parameters. The logarithmic value of the droplet growth rate decreased linearly with l/T in the range of 5-40 degrees C. The formulation and processing parameters are the key variables to be optimized to achieve better emulsion characteristics and stability. PMID- 7849939 TI - Analysis of Ostwald ripening in fluorocarbon emulsions by sedimentation field flow fractionation. AB - The Ostwald ripening mechanism has been studied using sedimentation field-flow fractionation (SdFFF). It has been shown that significant partitioning between different sized droplets occurs for two component disperse phase emulsions, when one of the components is virtually insoluble in the continuous phase. PMID- 7849941 TI - Application of fluorocarbon emulsions as components of cosmetics and medical ointments. AB - Localization and accumulation of perfluorochemicals (PFCs) in the skin and internal organs of rats after prolonged surface application of the concentrated PFC emulsion, fluorogel, have been studied by electron microscopy and gas chromatography. The PFC concentration in skin was about 0.03-0.04 mg per 1 g of tissue. Few aggregates of emulsion particles were detected in derma. The oxygen dependent favorable effect of fluorogel treatment of thermic burned skin and wound surface was found. PMID- 7849940 TI - Concentrated emulsions of perflubron in aqueous media. AB - Flocculation of o/w emulsions consisting of a perfluorochemical (PFC) emulsified by either phospholipids or decaglyceroldioleate (10-2-O) was assessed both by direct observation and through photon correlation spectroscopy (PCS) and viscoelasticity measurements in unsteady oscillatory flow. Flocculation gives rise to emulsion instability but can be prevented (a) by the addition of a negatively charged surfactant to either phosphatidylcholine (PC) or 10-2-O, respectively the zwitterionic phospholipid and the nonionic surfactant used as primary emulsifiers, or (b) by using a saccharide solution as the continuous phase. The study indicates that both electrostatic (Coulombic) repulsive forces and hydration (steric) forces play a role in preventing flocculation. Various minor components of the egg yolk phospholipids (EYP) used in commercial emulsion preparation probably stabilize the emulsion by increasing both electrostatic and hydration repulsion. PMID- 7849942 TI - Effect of lipid absorption by perfluorochemical emulsions in the bloodstream and perspectives of its clinical application. AB - Studies concerning lipid absorption by perfluorochemical particles (PFC) during circulation in the blood stream have been reported in experimental animals. We studied the cholesterol absorption from high density lipoproteins (rats) and erythrocyte membrane [1] and composition of the absorbed lipids [2]. The aim of present investigation is to clarify the influence of the PFC chemical structure and synthetic emulsifier on the composition of the absorbed lipids. The perspectives of clinical application of the effect of the lipid absorption by PFC particles is discussed. PMID- 7849943 TI - Central hemodynamics and blood flow distribution during infusion of perflubron emulsion or its vehicle: effects in anesthetized dogs. AB - Mongrel dogs were anesthetized and prepared for hemodynamic monitoring and the measurement of blood flow distribution using radionuclide-labelled microspheres (15 +/- 2 microns). Four dogs were infused with a perflubron emulsion (E) (90% w/v perflubron containing egg yolk phospholipid as a stabilizer) and five dogs were infused with the vehicle (V) (same composition without the perfluorocarbon). Both infusions were given at the dose of 3 ml/Kg over a 30-minute period. Measurements of blood pressures and cardiac output were made before, at 12 minutes of the infusion and at 5, 30 and 60 minutes post-infusion. Blood flow distribution was determined before, at the 15th minute of the infusion and at 2 and 60 minutes post-infusion. One dog infused with V exhibited a hypotensive reaction and urticaria; this was excluded from the group statistics. Neither group showed statistically significant hemodynamic changes during or after the infusion, although both E and V groups showed transient elevation of the stroke volume. Blood flows were raised consistently to the heart and renal cortex and transiently to some skeletal muscles by E treatment. PMID- 7849945 TI - Tumor oxygen tension: measurement using Oxygent as a 19F NMR probe at 4.7 T. AB - We have used Oxygent (an emulsion of perflubron [PFOB]) to measure pO2 in a Dunning prostatic adenocarcinoma non-invasively using 19F NMR spectroscopy. We have confirmed a linear relationship between the spin-lattice relaxation rate (R1) and pO2 and we have assessed the effect of temperature. R1 of the individual resonances of Oxygent is considerably more sensitive to changes in pO2 than other PFC emulsions, whilst being considerably less sensitive to interference from temperature variation. Oxygent has two well resolved resonances (delta delta approximately 18ppm) and these were both exploited to estimate tumor pO2 = 47 +/- 5 torr. PMID- 7849944 TI - Tumor oxygenation after 1) carbogen and/or perflubron emulsion administration in tumor xenografts 2) carbogen administration in patients. AB - This study examines the changes in tumor pO2 distribution assessed by polarography (KIMOC 6650, Eppendorf) in 1) two human tumor xenografts after carbogen inhalation with or without a perflubron (perfluorooctylbromide) emulsion (Oxygent, Alliance Pharmaceutical corp.) and in 2) human head and neck carcinomas after carbogen inhalation. Mice bearing HRT18 or NA11+ tumors were restrained and their body temperature was kept constant. Perflubron emulsion (4 ml/kg) was injected i.v. in the mice. In patients, oxygenation of the head and neck metastatic lymph nodes was assessed before and/or during carbogen exposure. The distribution of pO2 values shifted upwards during carbogen exposure in both animals and patients while the proportion of low pO2 values decreased. The maximal effect was obtained with patients after 1 to 6 minutes of carbogen exposure, but 4 patients still maintained very low pO2s. Carbogen plus 4 ml/kg perflubron emulsion was more efficient than carbogen alone for increasing hypoxic tumor pO2 in animals. If the animals data could be extrapolated to humans, then the effect of carbogen on tumor oxygenation should be increased by perflubron emulsion administration. PMID- 7849946 TI - Oxygenation of human tumor xenografts in nude mice by a perfluorochemical emulsion and carbogen breathing. AB - Human solid tumors (prostate carcinomas PC-3 and DU-145, breast carcinoma MX-1, cervical carcinoma ME-180, small cell lung carcinoma SW2, and glioblastoma T98G) were grown as xenografts in nude mice. Using the Eppendorf pO2 histograph microelectrode system, the oxygen profiles of the tumors were determined while the animals breathed air or carbogen (95% O2/5% CO2), and after administration of the perfluorochemical emulsion Oxygent-CA (8 ml/kg) under air breathing and carbogen breathing conditions. Under normal air breathing with or without Oxygent CA administration the mean oxygen tensions were between 4.9 and 9.3 mmHg and each tumor had severely hypoxic regions where the pO2 was less than 5 mmHg. The severely hypoxic regions comprised 41-71% of the oxygen tension measurements under normal air breathing conditions. Carbogen breathing alone increased the mean oxygen tensions to 10.9-23.9 mmHg. Administration of Oxygent-CA and carbogen breathing increased the mean oxygen tensions over the levels of carbogen breathing alone to varying degrees. The highest mean oxygen tensions were 40.8 mmHg in the T98G glioblastoma and 24.5 mmHg in the ME-180 cervical carcinoma. Investigation of the use of Oxygent-CA/carbogen to increase the oxygenation of clinical tumors is warranted. PMID- 7849947 TI - Oxygenation during perfluorocarbon associated gas exchange in normal and abnormal lungs. AB - Perfluorocarbon-associated gas exchange (PAGE) has been proposed for the treatment of lung diseases characterized by high alveolar surface tension. Perflubron (perfluorooctyl bromide, LiquiVent, Alliance Pharmaceutical Corp.) is a high purity medical grade perfluorocarbon suitable for PAGE. We studied PAGE using perflubron in normal piglets and in animal models of pulmonary disease (meconium aspiration syndrome, oleic acid infusion and gastric acid aspiration as models of ARDS, and neonatal respiratory distress syndrome). All animals were studied under anesthesia. PAGE was instituted by intratracheal instillation of a volume of perflubron (generally 30 ml/kg) that approximates a normal functional residual capacity of the lung. Arterial blood gases were measured at 15 minute intervals. FiO2 during PAGE was 1.0. In normal piglets, PaO2 fell from 543 torr (during conventional gas breathing) to 363 torr (during PAGE). However, in models of lung disease, PAGE significantly enhanced PaO2. PMID- 7849948 TI - Long-term partial liquid ventilation (PLV) with perflubron in the near-term baboon neonate. AB - PURPOSE: The feasibility and safety of continuous long-term (4-5 day) partial liquid ventilation (PLV) using perflubron was demonstrated in newborn baboons. PLV, a potential therapy for adult and neonatal respiratory distress syndrome (RDS), is conventional mechanical ventilation (CMV) with the lung filled to about functional residual capacity with perfluorochemical liquid. PROTOCOL: As a pilot trial for a larger preclinical study focused on the safety of extended duration PLV, three near term baboons were studied. The animals were delivered by cesarean section, anesthetized, intubated and placed on CMV. The animals were given intratracheal perflubron (30 ml/kg) and maintained on PLV for 96 hours. The transition back to gas ventilation occurred, after draining, over the fifth day (hrs 96-120). RESULTS: Two of the animals were born with normal pulmonary function, while the third developed respiratory distress prior to PLV. All the animals were adequately supported with PLV using moderate ventilator settings and low concentrations of oxygen. Perflubron distribution was enhanced by periodic rotation of the animals. Preliminary histology show vacuolated alveolar macrophages and no evidence of edema or other significant changes in the lungs. Pulmonary function in the RDS animal, after PLV treatment, showed normal gas exchange and lung mechanics. CONCLUSIONS: Three near term baboons, one with clinical RDS, tolerated 4 days of PLV followed by 1 day of CMV without complications using practical clinical management methods. PMID- 7849949 TI - Lung management with perfluorocarbon liquid ventilation improves pulmonary function and gas exchange during extracorporeal membrane oxygenation (ECMO). AB - We investigated whether pulmonary function and gas exchange would improve with liquid perfluorocarbon ventilation (LV) during ECMO for severe respiratory failure. Lung injury was induced in 11 young sheep 15.1 +/- 3.7 kg in weight utilizing right atrial injection of 0.07 cc/kg oleic acid followed by saline pulmonary lavage. When (A-a)DO2 > or = 600 mmHg and PaO2 < or = 50 mmHg with FiO2 = 1.0, ECMO was instituted. Animals were then ventilated with either standard ECMO "lung rest" gas ventilator settings (ECMO, n = 5) or with "total" liquid ventilation at standard ventilator device settings (LIQ-ECMO, n = 6) utilizing perflubron (perfluooctyl bromide, Liquivent; Alliance Pharmaceutical Corp.). After 3 hours on ECMO, pulmonary physiologic shunt decreased (ECMO = 88 +/- 11% vs LIQ-ECMO = 31 +/- 1%; p < .001) and pulmonary compliance increased (ECMO = 0.50 +/- 0.06 cc/cmH2O/kg vs. LIQ-ECMO = 1.04 +/- 0.19 cc/cmH2O/kg; p < .001). The ECMO flow rate required to maintain the PaO2 in the 50-80 mmHg range was decreased significantly (ECMO = 116 +/- 14 ml/kg/min vs. LIQ-ECMO = 14 +/- 5 ml/kg/min; p < .001). In this model requiring extracorporeal support for severe respiratory failure, lung management with liquid ventilation improves pulmonary function and gas exchange. PMID- 7849950 TI - Neonatal endotracheal tubes: variation in airway resistance with different perfluorochemical liquids. AB - To evaluate the effect of the physical properties of density and viscosity on airway resistance, three perfluorochemical fluids (PFCs) were used: FC-75, Liquivent, and APF-140. Using two different endotracheal tubes (ETT) (3.0mm ID and 4.0mm internal diameter (ID)), the three fluids were studied at steady state flow conditions over a range that approximated peak flow required for liquid ventilation of neonatal lambs (0.005-0.02 l/sec). The slope of airway resistance (Raw)-flow curves and absolute values of Raw for the 3 PFC liquids were higher for the 3.0 ETT compared to the 4.0 ETT. The 3.0 ETT demonstrated resistance changes that were dependent on flow, density and viscosity. The 4.0 ETT showed a resistance-flow relationship that was relatively less dependent on flow, density and viscosity. PMID- 7849951 TI - Fluorinated phospholipid-based vesicles as potential drug carriers: encapsulation/sustaining of drugs and stability in human serum. AB - The release of entrapped 5(6)-carboxyfluorescein from fluorinated vesicles in a buffer or in human serum is considerably less than that from hydrogenated liposomes. The presence of a fluorinated core inside the liposomal membrane definitely reduces its permeability. In some cases, the stability of liposomes made from fluorinated phospholipids alone is better than that of egg phosphatidylcholine cholesterol 1/1 vesicles, which are among the least permeable and most stable hydrogenated liposomes. PMID- 7849953 TI - Novel injectable fluorinated contrast agents with enhanced radiopacity. AB - Novel emulsions containing iodinated fluorinated radiopaque (IFR) molecules were prepared and evaluated as injectable contrast agents with prolonged intravascular persistence. Various stable IFR/egg yolk phospholipid emulsions were produced, heat-sterilized, and tested as to their radiopacity, shelf-stability and in vivo tolerance. No significant change in mean particle sizes was observed over a 3 month storage period at 40 degrees C. Intravenous injection of an emulsion of a 0.39 g/kg bw dose of a typical IFR, C6F13CH = CIC6H13 (F6H6IE) in rabbits led to high contrast in the liver and spleen. The same radiopacity of the liver was achieved with 7 times less IFR than perfluorooctyl bromide. Histological examination after 24 h, and blood analysis after 24, 48 h and 7 days, demonstrated normal functioning of the liver, even when high concentrations of IFR were present. The neat IFR was tolerated i.p. in mice at a 45 g/kg bw dose. Emulsified IFR was tolerated in rats and mice i.v. at a 8 g/kg bw dose. The iodinated fluorinated molecule tested appears promising for the formulation of new contrast agents for diagnosis. PMID- 7849952 TI - Utility of a perfluorochemical liquid for pulmonary diagnostic imaging. AB - The use of neat perfluorochemical liquid (PFC) as an alternative respiratory medium has gained increasing attention for assessment and treatment of the immature or injured lung. In vitro and in vivo plain film and computed tomographic (CT) studies were performed on small and large animals to evaluate the use of perfluorooctylbromide (perflubron) as a bronchographic contrast agent and to quantitate the distribution and elimination of this fluid from the lung following total liquid ventilation or during gas breathing after tracheal instillation of small quantities of this liquid. The results demonstrate the utility of a highly radiopaque PFC liquid in combination with diagnostic imaging techniques to visualize small airways anatomy, identify regional and gravity dependent differences in distribution/elimination of the fluid, ventilation, and track PFC liquid following therapeutic application. PMID- 7849954 TI - Preclinical and clinical studies on lymph node imaging using perflubron emulsion. AB - A perflubron emulsion is being developed as a contrast agent to enhance lymph nodes on computed tomography (CT) images. The emulsion is administered by percutaneous injection into the drainage field of the lymph nodes to be imaged. A series of preclinical studies was conducted to investigate the efficacy of the perflubron emulsion for enhancement of lymph nodes on CT images. The effects of dose (0.10 to 0.50 mL), application of massage, and route of administration were investigated in healthy New Zealand white rabbits. Results of these studies demonstrated that doses as low as 0.15 mL were efficacious for consistent enhancement of axillary lymph nodes on CT images after subcutaneous injections in the forepaw. Application of massage to the injection site decreased the time for maximum nodal enhancement from approximately 7 days to 2 days postinjection. A pilot study conducted in 18 healthy, male volunteers indicated dose-related enhancement of axillary lymph nodes on CT images following subcutaneous injections of the emulsion in the hand. Other than mild, transient injection-site discomfort, no clinically significant side effects were observed. These data demonstrate that the perflubron emulsion is safe and can enhance axillary lymph nodes on CT images following injections in the hand. PMID- 7849955 TI - Intracellular and extracellular transport of perfluoro carbon emulsion from subcutaneous tissue to regional lymphatics. AB - The aim of this study was to examine the transport mechanism of colloidal particles from subcutaneous tissue to lymphatics. The mechanism of lymph transport was studied in leg prenodal lymphatics of anesthetized rabbits using Imagent LN (60% W/V perfluorooctyl bromide [PFOB] emulsion). Extracellular (dispersed particles) and intracellular (phagocytosed particles by macrophages) PFOB transport was measured in lymph fluid after 0.1ml injection of fluorescently labeled PFOB emulsion into the dorsal skin of the rabbits' foot. Samples were collected from cannulated lower leg prenodal lymphatics. Particles of PFOB emulsion were observed by using a fluorescent technique. The foot/leg were moved passively in a rotary direction at 0.3Hz. Extracellular and intracellular PFOB could be determined in the lymph samples. These findings indicate that both intracellular and extracellular transport mechanisms play a role in the uptake of colloidal particles from interstitial tissue to lymphatics. PMID- 7849956 TI - Monitoring of pO2 by spin-spin relaxation rate 1/T2 of 19F in a rabbit abscess model. AB - The purpose of this study was to confirm the relationship of T1 and T2 relaxation rate vs. pO2 in vivo of 19F MR signal measured from intracellular perflubron. Our work to date has demonstrated that 1/T2 is more sensitive to pO2 than 1/T1 in the in vitro environment. The advantage of 1/T2 vs. 1/T1 is the speed of measurement and sensitivity. Seven alternating T1 and T2 measurements were obtained during a continuous acquisition using the TTISS pulse sequence. An abscess model was used for the in vivo experiments where rabbits were infused with 5ml/kg Oxygent HT 10 days prior to scanning. The abscess model was used because it has been shown that perflubron accumulates in macrophages located in the abscess wall. This technique thus provided signal from the intracellular milieu. The results of this study proved that pO2 monitoring by measuring T2 of 19F is feasible and can be used in lieu of the T1 measurement. Given that the T2 measurement is much more rapid than the T1 measurement and that T2 changes are more sensitive than T1 changes with alterations in pO2, T2 should prove to be practical and useful for monitoring transient rapid changes in pO2. PMID- 7849957 TI - Normothermic preservation of "multiple organ blocks" with a new perfluorooctyl bromide emulsion. AB - To evaluate the efficiency of fluorocarbon emulsions as oxygenating media for the normothermic preservation of organs (multiple organ blocks, MOB), a new perfluorooctyl bromide (perflubron) emulsion was compared with a mixture of modified Krebs solution and blood. The fluorocarbon emulsion used (90% w/v of fluorocarbon) contained a low amount of egg yolk phospholipid (EYP, 2% w/v) and was stabilized by a mixed fluorocarbon-hydrocarbon amphiphile C6F13C10H21 (F6H10). Blood of 4 rat MOBs was replaced with a 36% w/v fluorocarbon emulsion which has been complemented with albumin and electrolytes (EMOBs). 5 MOBs were perfused with a mixture of blood and albumin-containing Krebs solution (KBMOBs). Lactate, amylase and creatine kinase were lower (p < 0.05) at 60 and 120 min in EMOBs than in KBMOBs, PMID- 7849958 TI - Organ preservation without extreme hypothermia using an Oxygen supplemented perfusate. AB - All methods of organ preservation depend upon hypothermia to depress metabolism during storage. Yet, hypothermia may represent the rate-limiting factor in organ preservation. A new perfusate has been developed which supports organ preservation without extreme hypothermia. The perfusate consists of a complex fluid supplemented with an oxygen carrying perfluorocarbon emulsion, Oxygent (Alliance Pharmaceutical Corp,). The perfusate was used to preserve canine kidney autografts using pulsatile preservation at 32 degrees C and static storage at 25 degrees C. Upon autografting the dogs produced urine within minutes of reperfusion. These results indicate the new perfusate may have significant potential in organ preservation without extreme hypothermia. PMID- 7849960 TI - Reducing magnetic susceptibility differences using liquid fluorocarbon pads (Sat Pad): results with spectral presaturation of fat. PMID- 7849959 TI - Postmortem organ salvage using an Oxygen supplemented perfusate. AB - The world-wide shortage of organs for clinical transplantation is caused by the limited existing donor pool of heartbeating cadavers. Attempts to expand into the nonheartbeating cadaver population have been hindered by warm ischemic damage. We evaluated if a new Oxygent (Alliance Pharmaceutical Corp.) supplemented perfusate could be used to salvage canine kidneys postmortem. The kidneys preserved in the Oxygent perfusate could be maintained in situ for time points ranging from one eight hours postmortem; enough time to declare death and obtain consent for organ donation. In contrast, the control kidneys yielded abnormal histologic findings and impaired flow dynamics. These results suggest that new perfusate may have significant potential to expand the existing organ donor pool. PMID- 7849961 TI - Double-tailed perfluoroalkylated glycolipids as components for drug delivery and targeting systems. Preliminary biocompatibility results. AB - Vesicles are being investigated as drug carriers, especially for enhancing the therapeutic effectiveness of the drug while minimizing its side effects. Drug targeting can be achieved if there is a specific recognition of the vesicle's outer wall by specific cells. With these objectives in mind new glycolipids fitted with fluorinated, hydrogenated or mixed, single and double-tails, containing either a gluco- or a galactopyranose residue in their hydrophilic head, were synthesized and their ability to achieve self-organized supramolecular systems was assessed. Replacement of hydrogen by fluorine in these glycolipids was found to enhance biological tolerance. Thus, a fluorinated single-tailed glycolipid displayed no action on red blood cells at concentrations as high as 50 g/l while its hydrogenated analog was hemolytic at 5 g/l. 100% of survival was obtained one month after intravenous or intraperitoneal injection into mice of isotonic dispersions of single and double-tailed glycolipids at a dose of 500 mg/kg. These glycolipids were innocuous on Namalva cell cultures at a concentration of 0.1 g/l. PMID- 7849962 TI - Efficacy of Imagent BP at 1.5ml/kg in a rabbit liver tumor model. AB - We have shown using a Vx2 rabbit model that 3 and 5ml/kg of perflubron emulsion were highly effective in imaging liver tumors. The results from preliminary clinical trials suggested that should the infusion rate be increased, a 1.5ml/kg may be efficacious. This study determined whether 1.5ml/kg given as a bolus IV would be efficacious to image liver tumors using a Vx2 rabbit model. Vx2 tumors were implanted in 5 NZW rabbits, CT of the liver was performed during held expiration at 80kV and 800mAS, before and shortly after 1.5ml/kg Imagent BP (ImBP), again at 30 minutes and 3 days. Regions of interest (ROIs) were drawn over the CT image of the spleen, liver, inferior vena cava, and tumor, CT# obtained and average enhancement of each tissue calculated at each time point. 4 animals had tumors .5cm or greater. Precontrast, tumors were faintly seen on CT. Blood was brighter than liver shortly after infusion and isointense with liver at 30 minutes. Tumors did not enhance following contrast. Except for the liver and spleen, all tissues returned to baseline on the 3rd day. Therefore a clinical trial to determine the efficacy of 1.5ml/kg ImBP to image the liver is warranted. PMID- 7849963 TI - The use of Imagent BP as a blood pool contrast agent to visualize and quantitate liver tumor burden. AB - The accurate quantitation of liver tumor burden and visualization of lesions in three dimensions (3D) can assist in treatment planning and can allow monitoring of therapy. Previous attempts have used CT and standard contrast media. Because the iodinated agents rapidly diffuse into tumors, usually effacing, and at time enhancing tumor edges, they decrease accuracy and make image segmentation difficult. CT portography suffers from flow related artifacts and does not allow the distinction of tumors from hemangiomas. Blood pool contrast is ideal in this setting since it enhances liver, liver vessels and hemangiomas, but not tumors, 'physiologically' splitting the image into normal and abnormal tissues. This ongoing study assesses the feasibility of this technique to visualize tumor and presents a scheme to automatically quantitate tumor volume. It utilized a rabbit VX2 liver tumor model and CT scanning shortly after the infusion of 3 ml/kg perflubron emulsion. Cut sections of the frozen carcass served as gross pathologic correlation. Images were imported onto a Sparc workstation, 3D reformatted and tumor and liver volume calculated. Histograms of pixel intensity clearly separated tumors from liver and liver from surrounding structures allowing the easy demarcation of tumor and liver margins. PMID- 7849965 TI - Blood substitutes and related products: the fluorocarbon approach. Vth International Symposium on Blood Substitutes. San Diego, California, March 17-10, 1993. Proceedings. Part 3. PMID- 7849964 TI - Characterization and mechanism of side-effects of Oxygent HT (highly concentrated fluorocarbon emulsion) in swine. AB - Perfluorooctyl bromide is an oxygen-carrying perfluorocarbon presently under development as an artificial blood substitute (Oxygent HT). Intravenous (i.v.) Oxygent HT elicits a mild side-effect profile in man characterized by early onset headache and nausea and delayed onset fever. Early onset flushing has also been observed. Species of Artiodactyla are sensitive to particulate injections and demonstrate a transient pulmonary hypertensive response thought to be associated with the large number of pulmonary intravascular macrophages found in these species. Because of this sensitivity, we chose the swine as a model for further investigations. In anesthetized and conscious swine, i.v. Oxygent HT transiently increased mean pulmonary artery pressure (mPAP) and caused flushing. Both effects peaked at 30 min post injection and were resolved by 2 hrs. Plasma thromboxane B2 (TxB) increased in response to Oxygent HT. Oxygent HT-induced changes in mPAP, flush, and plasma TxB were blocked by aspirin and ibuprofen. Dexamethasone and SQ 29,548 (thromboxane receptor antagonist) blocked the mPAP increase. In conscious swine, Oxygent HT caused a febrile response which was blocked by ibuprofen or dexamethasone. Thus, both early- and late-onset effects of Oxygent HT in swine are blocked by interference with the arachidonic acid cascade. These findings suggest that the 2-phase "flu-like" syndrome induced by Oxygent HT is secondary to the release of products of the arachidonic acid cascade and may be effectively prophylaxed in man with corticosteroids or long plasma half-life cyclooxygenase inhibitors. PMID- 7849966 TI - Difficulties in demonstrating efficacy of blood substitutes. AB - Currently, the fear of infectious disease transmission by allogenic blood transfusions has spurred interest in developing a blood substitute FDA approval requires that a sponsor demonstrate that the substitute is effective. The challenge in designing efficacy studies in man is proving that the substitute offers significant advantages over conventional therapies for acute blood loss. This task is complicated by the oxygen reserve and the response to hemodilution following treatment of acute blood loss in man. Paradoxically, the technique that relies on these protective physiologies-isovolemic perioperative hemodilution many offer the best experimental model to establish efficacy of a blood substitute in man. PMID- 7849967 TI - Perfluorocarbons as blood substitutes: the early years. Experience with Fluosol DA-20% in the 1980s. AB - Clinical testing of perfluorocarbons (PFC) as blood substitutes began in the early 1980's in the form of Fluosol DA-20% (FDA), a mixture of perfluorodecalin and perfluorotripropylamine emulsified with Pluronic F68. We have treated 55 patients (Treatment (T) = 40; Control (C) = 15) with intravenous infusions of 30 cc/kg of FDA as part of either a randomized, clinical trial or a humanitarian protocol. All patients were Jehovah's Witnesses who refused blood transfusion and were severely anemic (mean hemoglobin = 4.6 g/d). FDA successfully increased dissolved or plasma oxygen content (P1O2 in ml/dl), but not overall oxygen content (T group: P1O2 baseline = 1.01 +/- .27, P1O2 12hrs = 1.58 +/- .47 [p = < .0001, t-test]; P1O2 12 hrs: T = 1.58 +/- .47, C = 1.00 +/- .31, p = < .0002, t test). This effect persisted for only 12 hours post infusion, and had no apparent effect on survival. FDA is an ineffective blood substitute because of low concentration and short half-life. Improved emulsion design may resolve these problems, thereby producing a more effective agent. Our discussion will include a review of our data plus a summary of other reports of FDA efficacy as a blood substitute. PMID- 7849968 TI - Improvement in circulatory and oxygenation status by perflubron emulsion (Oxygent HT) in a canine model of surgical hemodilution. AB - To examine the effect of a low dose of Oxygent HT on hemodynamics and oxygen transport variables in a canine model of profound surgical hemodilution, two groups of adult anesthetized splenectomized beagles were hemodiluted with Ringer's solution to Hb 7 g/dL. The treated group received 1 mL/kg Oxygent HT (90% w/v perflubron emulsion [perfluorooctyl bromide], Alliance Pharmaceutical Corp.) and both groups (7 controls and 10 treated) were further hemodiluted using 6% hydroxyethyl starch until cardiorespiratory decompensation occurred. Pulmonary artery catheterization data and oxygen transport variables were recorded at Hb decrements of 1 g/dL breathing room air. There was no difference among groups during initial hemodilution. However, in the Oxygent HT group there was a statistically significant improvement in mean arterial pressure, CVP, cardiac output, PvO2, SvO2, DO2, and pulmonary venous admixture shunt during profound hemodilution to Hb levels of 6, 5, and 4 g/dL. A low dose of Oxygent HT offered benefit in improving hemodynamics and oxygen transport parameters even under air breathing conditions in a model of surgical hemodilution. This effect was most apparent at lower levels of Hb. PMID- 7849969 TI - Use of current generation perfluorocarbon emulsions in cardiac surgery. AB - The development of novel perfluorocarbon emulsions that contain higher concentrations of perfluorochemicals than previous emulsions has renewed interest in the use of this class of erythrocyte substitute in cardiopulmonary bypass (CPB). Perfluorocarbons have the potential to increase the oxygen content of the perfusate and thus increase the capacity of the heart-lung machine to deliver oxygen to the body during CPB. Increasing the capacity of the heart-lung machine to deliver oxygen to the body has important implications for the conduct of cardiac operations. For example, adding perfluorocarbons to the pump prime solution may allow larger volumes of blood to be withdrawn from the patient immediately prior to bypass for transfusion after bypass. Lowering the acceptable hematocrit during CPB with the use of perfluorocarbons may also decrease the need for homologous transfusions of erythrocytes in neonates or anemic adults who undergo CPB. PMID- 7849970 TI - Fluorocarbon emulsions--the stability issue. AB - Long-term room temperature stability of ready-to-use concentrated fluorocarbon emulsions is necessary in order to fully exploit the therapeutic potential of fluorocarbons. Consequently, considerable efforts have been directed at investigating the physical nature of such emulsions, the mechanisms which lead to their degradation and the means of counteracting these. The particles which constitute typical fluorocarbon/egg yolk phospholipid emulsions have been identified to be surfactant-coated fluorocarbon droplets and lipid vesicles. Better understanding has been gained on the formation, structure and evolution of these particles during processing and storage. This has led to optimized formulations and processing, better control of emulsion characteristics and significantly improved stability. Molecular diffusion (Ostwald ripening or transcondensation) has been shown to be the maun mechanism of degradation when particles are less than 1 micron in diameter, even for the highly concentrated (volume fraction of fluorocarbon up to 50%) second generation fluorocarbon emulsions. Significant emulsion stabilization has been accomplished by adding fluorochemicals which are both less volatile and less water soluble, and nevertheless have an organ dwell time acceptable for intravascular use. The rate of molecular diffusion can also be reduced by decreasing the fluorocarbon/water interfacial tension; this was effectively achieved with appropriate, well-defined fluorinated surfactants. A further, novel means of stabilizing fluorocarbon-in water emulsions makes use of mixed fluorocarbon-hydrocarbon amphiphiles which act as molecular dowels to reinforce the adhesion between the fluorocarbon phase and the lipophilic zone of the surfactant film. Both long-term room temperature stability, and particle-size control over a large range of diameter, have been achieved by applying this principle. All in all it can be said that the challenge of producing injectable fluorocarbon emulsions with long-term room temperature particle size stability has been met. PMID- 7849971 TI - A metallic hemiarthroplasty resurfacing prosthesis for the hallux metatarsophalangeal joint. AB - Two-hundred seventy-nine arthritic hallux metatarsophalangeal joints treated surgically with a metallic resurfacing hemiarthroplasty over a 40-year period were reviewed. The implant, which is made available in three evenly graded sizes, is designed to replace only the articular surface of the proximal phalanx, with minimal resection of bone stock. The pathologic indications for surgery included classical hallux rigidus, rheumatoid arthritis, and degenerative changes associated with hallux valgus and bunion deformity. Follow-up at 8 months to 33 years after surgery revealed good or excellent clinical results in 95%. The time to follow-up was in excess of 5 years in 101 (36%) of the procedures, beyond 10 years in 62 (22%), and longer than 20 years in 23 (8%). Unlike other available surgical options for this debilitating condition, biomechanics of the hallux metatarsophalangeal joint remained unaffected and problems associated with prosthetic wear or mechanical failure were not encountered. PMID- 7849972 TI - A review of ankle arthrodesis: predisposing factors to nonunion. AB - The purpose of this study was to review 15 years of experience with ankle fusions, specifically addressing the underlying etiology of ankle pathology, incidence of nonunion, and associated predisposing conditions that can lead to nonunion. Seventy-eight ankle fusions, performed between 1975 and 1990, were reviewed for this study. The average follow-up was 4 years. Patients with nonunion were evaluated separately to look at the predisposing factors that may have lead to nonunion. Factors associated with nonunion included fracture type, evidence of avascular necrosis, infection, major medical problems, and open injuries. Factors that were not associated with nonunion included age, past history of subtalar or triple arthrodesis, and technique. PMID- 7849973 TI - Treatment of the atypical lesser toe deformity with basal hemiphalangectomy. AB - Eighty-six lesser toe basal hemiphalangectomies were performed in 52 patients. The surgical technique included an oblique dorsal incision, resection of 8 mm of bone, and an extensor tenotomy. Minimum follow-up was 2 years (range 2-6/1/2 years). Sixty percent of the patients had total relief of pain. Twenty-nine percent stated that they would not have the surgery again, and we categorized these patients as dissatisfied. An extensor tenotomy increased the satisfaction rate and was found to decrease the radiographic sagittal angulation of the toe. The preoperative diagnosis was significant to the outcome of the surgery. Patients with metatarsophalangeal joint synovitis and rheumatoid toe deformities had high rates of satisfaction; those with transverse deviation, metatarsalgia, and hammertoes with metatarsophalangeal joint subluxation/dislocation had lower rates of satisfaction. Seventy percent of the dissatisfied patients were dissatisfied because of persistent flexion deformity of the PIP joint or pain under the metatarsal head. We now add a PIP fusion if any flexion deformity, even a mild deformity, is present at the PIP joint and a plantar metatarsal condylectomy for metatarsalgia. PMID- 7849974 TI - Forefoot arthroplasty and changes in plantar foot pressures. AB - The aim of this study was to determine how effective forefoot arthroplasty is at reducing the pressures under the forefoot. The EMED F pressure measuring system was used. Fifteen patients (23 feet) were included in the study. All patients had foot pressure studies performed before and after surgery. Our results show a significant increase in total pressure and pressure-time integral under the foot after surgery. This increase was most marked under the first metatarsal head region (P < .005). However, the midmetatarsal region showed a slight decrease in pressure, but this was not significant. Symptomatically, 13 patients felt improved by the operation. The results suggest that the procedure is successful because it transfers the pressure to areas better able to tolerate it, rather than reduces the total pressure. PMID- 7849975 TI - Intramedullary screw fixation of lateral malleolus fractures. AB - A biomechanical evaluation of intramedullary versus buttress plate and lag screw fixation of lateral malleolus fractures is combined with a clinical evaluation of 44 patients with lateral malleolus fractures who underwent intramedullary screw fixation. The biomechanical study was performed in experimentally produced, Weber B, supination-eversion ankle fractures. The fractures were fixed with one of the two above fixation methods and then placed under a torsional load to failure. Sixteen cadaver ankles were tested as compared with native bone. The intramedullary screw provided 66.5% the resistance of torsion, and the buttress plate and lag screw provided 61.5% the resistance to torsion. There was no statistical difference between these two groups. The 44 fractures treated with an intramedullary screw were reviewed retrospectively. There was one failure of fixation, and one prominent hardware problem. Time to full weightbearing averaged 7.2 weeks. These results suggest that intramedullary screw fixation of noncomminuted lateral malleolus fractures provides stable fixation with good clinical results. This technique has the advantages of providing dynamic intramedullary fixation with limited surgical dissection and no subcutaneous hardware. PMID- 7849976 TI - Foot and ankle problems in rheumatoid arthritis. AB - The purpose of this study was to examine the prevalence of foot and ankle problems in 99 patients with clinically proven rheumatoid arthritis. Patients were recruited from outpatient rheumatology clinics; no attempt was made to select patients on the basis of the severity of their disease, duration of disease, or symptom constellation. Each patient was examined by an investigator utilizing a predesigned protocol to assess their functional status, functional capacity, and overall joint involvement. Ninety-three of 99 patients had complaints referable to the foot or ankle at some time since diagnosis of rheumatoid arthritis. Ankle problems were paramount in 42%, forefoot difficulties in 28%, and equal ankle and forefoot problems in another 14%. Only four patients had had any treatment involving foot orthotic devices or special shoe wear. The prevalence of foot and ankle symptoms was related to the duration of systemic illness, but was present in > 50% of patients at any time after diagnosis of rheumatoid arthritis. Patients with longstanding rheumatoid arthritis have a high prevalence of foot and ankle symptoms. Unlike previous reports, the present study found a high prevalence of ankle and hindfoot symptoms, as opposed to forefoot complaints. Despite this finding, the patients had been treated infrequently by either conservative nonoperative management directed at accommodating footwear or surgical intervention to favorably alter their foot and ankle mechanics. PMID- 7849977 TI - Anatomic study of arthroscopic debridement of the ankle. AB - To this date, there have been no published studies correlating gross intra articular anatomy and the compartments of the ankle that can be instrumented under arthroscopic visualization. The purpose of this study was to demonstrate which areas of intra-articular surface were accessible to the standard portals using a technique that allows direct anatomic correlation. Six fresh cadaver specimens and 12 fresh-frozen, below-knee amputations were used in this study. The 18 ankles were divided into six groups using only one arthroscopic portal site and one instrumentation site per group. Arthroscopic curettes were used to debride only the visualized talar, tibial, and fibular articular cartilage surfaces. After debridement, excision of the distal tibiofibular joint and the talus was performed. The total area of articular cartilage removed with each combination of arthroscope and instrument portal sites was noted, photographed, and recorded graphically. Use of the various combinations of the anteromedial, anterolateral, and posterolateral portals allowed complete access to all surfaces of the tibial plafond, anterior and posterior rims, and the talar dome. Areas that were not accessible by any portal combination were the distal half of the anterior colliculus of medial malleolus, the majority of the lateral talar articular surface, and the inferior half of the lateral malleolar articular surface. PMID- 7849979 TI - Irreducible dislocation of the fifth metatarsophalangeal joint: a case report. AB - Metatarsophalangeal joint dislocations are unusual in children and usually occur in the hallux. We are reporting a case of irreducible traumatic dislocation of the fifth metatarsophalangeal joint. At open reduction, the metatarsal head was incarcerated under the flexor digitorum longus. After returning the flexor digitorum longus tendon to its anatomical position, the metatarsophalangeal joint reduced and was stable. PMID- 7849978 TI - Closed posteromedial dislocation of the tibiotalar joint without fracture or diastasis: a case report. AB - Tibiotalar dislocation without fracture is an unusual injury. Seventy-three cases have been reported in the literature. Closed posteromedial dislocation of the tibiotalar joint without fracture or diastasis is a very rare phenomenon. Eight cases have been reported. A case of this unique injury is presented, along with a literature review of purely ligamentous ankle dislocations. The proposed mechanism and classification of these injuries are summarized. PMID- 7849980 TI - Irreducible proximal interphalangeal dislocation of the fourth toe: a case report. AB - Dislocation of the interphalangeal joints of the lesser toes is an uncommon injury, and complex (irreducible) dislocation has rarely been reported. All previous reports note that, during open reduction, the volar plate is interposed within the joint, thereby blocking reduction. In this case, the medial collateral ligament was the primary obstruction to reduction. Clinically, these dislocations are difficult to appreciate. It is recommended that x-ray studies be performed so that this diagnosis is not overlooked. PMID- 7849981 TI - Treatment of displaced talus fractures: an arthroscopically assisted approach. PMID- 7849982 TI - Temperature as a variable in reversed-phase high-performance liquid chromatographic separations of peptide and protein samples. I. Optimizing the separation of a growth hormone tryptic digest. AB - Peptide and protein samples are often complex mixtures that contain a number of individual compounds. The initial HPLC separation of such samples typically results in the poor resolution of one or more band pairs. Various means have been suggested for varying separation selectivity so as to minimize this problem. In this study of a tryptic digest of recombinant human growth hormone, the simultaneous variation of temperature and gradient steepness was found to be a convenient and effective means of varying selectivity and optimizing the separation. The use of computer simulation greatly facilitated this investigation. PMID- 7849984 TI - Comprehensive study on binding capacity of human immunoglobulin G to Avid AL affinity gel. AB - Avid AL is an affinity chromatographic gel based on a synthetic ligand which has been designed for the purification of immunoglobulins. The binding capacities of the gel for human IgG were investigated under different conditions; various salts; salt concentrations; different buffer systems with pH ranging from 3.8 to 10.0; and, tissue culture supernatant supplemented with 20% serum. At a similar ionic strength, the binding capacity changed according to the salting out effect of the ions used. Kinetic parameters of the affinity adsorption showed that a strong salting out effect significantly decreased the dissociation constant. Avid AL gel purified IgG from human serum with a capacity of 26.2 mg/ml gel using binding buffer containing sodium sulfate. Recombinant Protein A gel was used as a control. In this study it also exhibited enhanced binding capacity with a high salt concentration binding buffer. PMID- 7849983 TI - Temperature as a variable in reversed-phase high-performance liquid chromatographic separations of peptide and protein samples. II. Selectivity effects observed in the separation of several peptide and protein mixtures. AB - Changes in band spacing as a function of temperature and/or gradient steepness were investigated for four peptide or protein samples. Reversed-phase HPLC in a gradient mode was used to separate tryptic digests of tissue plasminogen activator and calmodulin. Additionally, a synthetic peptide mixture and a storage protein sample from wheat were studied. Simultaneous changes in gradient steepness and temperature were found to provide considerable control over band spacing and sample resolution. The effects of temperature and gradient steepness on selectivity in these systems appear to be complementary. Simultaneous optimization of both temperature and gradient steepness thus represents a powerful and convenient means of controlling band spacing and separation. Because of the complexity of these sample chromatograms, computer simulation proved to be a useful tool in both interpreting these experiments and in optimizing final separations. PMID- 7849985 TI - Retention mechanism and implications for selectivity for a group of dihydropyridines in ionic micellar liquid chromatography. AB - The retention behaviour of a group of dihydropyridines in micellar liquid chromatography was studied using sodium dodecyl sulphate and hexadecyltrimethylammonium bromide as surfactants in the mobile phase containing 5% of n-butanol and a C18 column. When the surfactant concentration in the mobile phase is increased, a tendency to change from a three partition equilibria mechanism to direct transfer of solutes from micelles to the stationary phase is observed for both surfactants. This progressive change in the retention mechanism is explained through the large micellar phase-water partition coefficients of these compounds and the increase produced in the fraction of solute molecules in the micellar phase due to the increase in the volume of this phase originating from the increase in surfactant concentration. As a result, the selectivity coefficients show a tendency to match the ratio of the stationary phase to micellar phase partition coefficients of these compounds, constituting further proof of the progressive change in the retention mechanism when the surfactant concentration is increased. PMID- 7849986 TI - Correlation of structure and retention behaviour in reversed-phase high performance liquid chromatography. II. Methionine-enkephalin-related glycoconjugates. AB - Reversed-phase high-performance liquid chromatographic elution data for methionine-enkephalin-related glycoconjugates were analysed as a function of the identity and position of the sugar-peptide linkage. It was shown that binding to the column could be correlated with the degree of sugar moiety protection. Replacement of either the phenylalanine or methionine residue in the peptide backbone of the glycoconjugates with its D-enantiomer leads to a considerably stronger retention on a reversed-phase column. The dependence of retention times on the methanol concentration in the mobile phase suggested that, under the conditions studied, there are different retention mechanisms for glycopeptides containing unprotected sugar moieties in the molecule. PMID- 7849987 TI - Purification of (-)-epigallocatechin from enzymatic hydrolysate of its gallate using high-speed counter-current chromatography. AB - Epigallocatechin gallate (EGCG) was hydrolyzed at various concentrations of tannase under pH 6.0 at 35 degrees C, and the reaction mixtures were separated by high-speed counter-current chromatography with a two-phase solvent system composed of hexane-ethyl acetate-water (1:13:20). The best results were obtained when 2 mg/ml of the enzyme buffer solution was added to 0.3 M EGCG buffers at a rate of 0.1 ml/min. Using 10 mg of the enzyme, 342 mg of epigallocatechin were obtained at a purity of 99.1%. PMID- 7849988 TI - Creativity and caring, hand and hearts.... PMID- 7849989 TI - Nursing and medication. Part two. Polypharmacy and older people: what can nurses do? PMID- 7849990 TI - Hepatitis C: the virus that won't go away. PMID- 7849991 TI - Ethical events: an every day dilemma. PMID- 7849992 TI - Just who do we restrain? PMID- 7849993 TI - Diabetes education: an important part of diabetes care. PMID- 7849995 TI - Specialisation in nursing. PMID- 7849994 TI - Behind closed doors: the power of nurses boards in Australia. PMID- 7849996 TI - A night to remember. PMID- 7849997 TI - Reiki--healing and dealing. PMID- 7849998 TI - Live and let die. PMID- 7849999 TI - Nursing and the law. Courts decide on delays in breast cancer diagnosis. PMID- 7850000 TI - Nurses and medication--Part 3. Knowledge and how we use it. PMID- 7850001 TI - The role of mental health nurses in chronic pain management. PMID- 7850002 TI - Coping with a tax audit. PMID- 7850003 TI - Erythropoietin and testicular steroidogenesis: the role of second messengers. AB - It has been demonstrated that erythropoietin (EPO) influences rat and human Leydig cell steroidogenesis, stimulating testosterone production through a direct and specific receptor-mediated mechanism. The aim of this study was to investigate the mechanism by which recombinant human erythropoietin (rHuEPO) exerts its stimulatory effect on rat Leydig cells. Recombinant human EPO did not induce, at any dose tested (10(-10) to 10(-13) mol/l), an increase in either cAMP or cGMP, suggesting that in Leydig cells the effect of rHuEPO does not involve the adenylate or guanylate-cyclase systems. The role of transmembrane calcium flux in rHuEPO-stimulated steroidogenesis was studied by evaluating the effect of calcium channel blocker, verapamil, and by the 45Ca2+ uptake method. Verapamil did not influence rHuEPO-induced testosterone secretion and rHuEPO did not modify calcium recycling, indicating that calcium transmembrane flux is not involved in the rHuEPO effect. The protein kinase C inhibitor staurosporine (10, 30, 100 and 300 nmol/l) inhibited rHuEPO-stimulated testicular steroidogenesis in a dose dependent manner. This indirect evidence suggests that the stimulatory effect of rHuEPO on rat Leydig cells may involve protein kinase C activation. PMID- 7850004 TI - Augmentation of thyrotropin-induced iodide uptake in FRTL-5 cells by immunoglobulins containing blocking thyrotropin-receptor antibodies under NaCl depleted conditions. AB - We have found recently that Graves' immunoglobulins (Igs) are more active under NaCl-free conditions to increase iodide uptake in FRTL-5 thyroid cells. The present study was designed to examine the effect of blocking-type thyrotropin (TSH)-receptor antibodies (TR-abs) in the same assay. FRTL-5 cells were incubated with crude Ig fractions from 13 patients with primary hypothyroidism having blocking TR-abs and 100 mU/l bovine TSH in NaCl-free Hanks' balanced salt solution (HBSS) supplemented with 274 mmol/l sucrose (HBSS(-)-sucrose) to keep isotonicity for 3 days, followed by the determination of 60 min of 125I uptake in the cells. Thyrotropin alone increased the uptake to 3.3- to 5.2-fold of the basal. When the highest concentration (250 ml serum equivalent (eq.)/l) of the Ig was used, the TSH-stimulated 125I uptake was decreased to 0-42% in 11 of the 13 cases. When the lower concentrations (0.4-50 ml serum eq./l) were used, however, 125I uptake was enhanced (1.4- to 11.4-fold) unexpectedly in all 13 cases. Such an enhancement was specific to blocking TR-abs, because the effect was duplicated by the purified IgG but not by Igs from 10 healthy control subjects or from three TR-ab-negative hypothyroid patients. When Graves' Igs, instead of TSH, were used as a stimulator, the similar stimulatory effect of the Ig with blocking activity was observed on the 125I uptake induced by three Graves' Igs but not on the response to one Graves' Ig. These Igs alone displayed no stimulating activity. When isotonic 5H medium was used instead of HBSS(-)-sucrose, effects of these 13 Igs were only inhibitory on the TSH-stimulated 125I uptake.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7850005 TI - Neuroendocrine regulation of growth hormone. AB - This short review is focused on the neuroendocrine regulation of growth hormone (GH) pulsatile secretory pattern and GH gene expression. The neuronal network involved in the central control of GH includes extrahypothalamic neurons such as the noradrenergic and cholinergic systems, which regulate the two antagonistic neurohormonal systems: somatostatin (SRIH) and GH-releasing hormone (GHRH). Intrahypothalamic Proopiomelanocortin- and Galanin-containing interneurons also participate in the regulation of SRIH and GHRH neuronal activity, which also is dependent on sex steroids and GH and/or insulin-like growth factor I (IGF-I) feedback. cAMP (controlled mainly by GHRH and SRIH), thyroid and glucocorticoid hormones. IGF-I and activin are among the factors that regulate GH gene expression at the transcriptional level and may play a role in somatotroph differentiation and proliferation during ontogeny as well as physiological and pathological states such as acromegaly. PMID- 7850006 TI - Persistence of somatostatinergic tone in acromegaly. AB - It is a matter of debate whether hypothalamic somatostatin (SRIH) secretion in acromegaly is preserved and still regulated by the physiological feedback mechanisms of growth hormone (GH) and insulin-like growth factor I. To gather further information on this, the reproducibility of plasma GH changes induced by growth hormone-releasing hormone (GHRH) administration was evaluated in 15 acromegalic patients. There was a highly significant correlation between the peak/basal ratio (P/B) GH response in the 15 patients administered GHRH on two separate occasions (r = 0.99, p < 0.001). The test was performed also before and after the administration of drugs able to inhibit or stimulate hypothalamic SRIH release, by activating (pyridostigmine) or inhibiting (pirenzepine) cholinergic pathways, respectively. The GHRH-induced GH response (P/B = 2, range 1.1-26.1) was increased significantly by pyridostigmine pretreatment in 30 patients (P/B = 2.6, range 1.3-34.8; p = 0.0045). In nine out of 30 patients an increase of greater than 2 SD of within-subject GHRH variability was observed in response to GHRH plus pyridostigmine when compared to GHRH alone. An inverse correlation (r = -0.37, p < 0.05) was observed between GH response to GHRH alone and after pyridostigmine pretreatment. On the contrary, no change of GHRH-induced GH response was observed in 12 patients after pirenzepine pretreatment (P/B = 1.9, range 1.1-5 and P/B = 2, range 1.3-6 without and after pirenzepine pretreatment, respectively). These data suggest that in acromegaly the somatostatinergic tone does not seem to fluctuate, and that it can be inhibited often by cholinergic pathway activation but not increased further by cholinergic suppression. PMID- 7850008 TI - Quadriceps and hand-grip strength in adults with childhood-onset growth hormone deficiency. AB - The effects of chronic growth hormone (GH) deficiency on muscle size and strength of postural (quadriceps) and non-postural (hand-grip) muscle groups, as well as on vertical jump capacity, were evaluated in six adults with childhood-onset GH deficiency. Data obtained were compared to those recorded in an age-, sex- and exercise-matched healthy control group. Thigh muscle plus bone cross-sectional area (CSAM+B) of the dominant quadriceps was significantly lower (p < 0.001) than in controls, while the CSAM+B/(Body height)2 ratio was similar to that of controls. The maximum voluntary contraction (MVC) of the quadriceps of patients was significantly lower (p < 0.002) than in controls, while no differences existed in the quadriceps force expressed per unit area (MVC/CSA) between patients and controls. As far as hand-grip was concerned, the CSAM+B of the dominant forearm was significantly lower (p < 0.003) than in controls, while the CSAM+B/(Body height)2 ratio was no different. The hand-grip MVC of patients was significantly lower (p < 0.004) than in controls, while no differences existed in the MVC/CSA ratio. It is noteworthy also that no difference existed in the hand grip to quadriceps MVC ratio of the two groups. Furthermore, no differences were found in the vertical jump capacity, because both delta Height and delta Height/Body weight of patients were not significantly different from those of controls. In conclusion, our study suggests that GH deficiency seems to reduce the size and strength of postural and non-postural muscle groups to the same extent.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7850007 TI - Effect of 15-day treatment with growth-hormone-releasing hormone alone or combined with different doses of arginine on the reduced somatotrope responsiveness to the neurohormone in normal aging. AB - It is well known that both spontaneous and growth hormone-releasing hormone (GHRH)-stimulated GH secretion undergo an age-related decrease; in addition, there is supportive evidence that the GH hyposecretory state of aging is of hypothalamic origin. The aims of the study in 35 normal elderly subjects (20 males and 15 females aged 65-89 years) were to verify whether the low somatotrope responsiveness to GHRH (1 microgram/kg) can be primed by a daily GHRH treatment and whether the potentiating effect of both high intravenous (0.5 g/kg) and low oral (8 g) doses of arginine (ARG) on GH response to GHRH is maintained with time. In group A (N = 14) the GH response to GHRH on day 1 (AUC: 373.5 +/- 78.5 micrograms.l-1.h-1) was unchanged after 7 (3720 +/- 38 micrograms.l-1.h-1) and 15 days (377.9 +/- 63.8 micrograms.l-1.h-1) of daily GHRH administration. In group B (N = 6) the GH response to GHRH co-administered with iv ARG on day 1 (1614.2 +/- 146.2 micrograms.l-1.h-1) was higher (p < 0.05) than that of GHRH alone (group A) and persisted unchanged after 7 (1514.7 +/- 366.5 micrograms.l-1.h-1) and 15 days (1631.7 +/- 379.1 micrograms.l-1.h-1) of treatment. In group C (N = 15) the GH response to GHRH co-administered with oral ARG on day 1 (950.6 +/- 219.4 micrograms.l-1.h-1) was higher (p < 0.03) than that of GHRH alone (group A) but lower (p < 0.05) than that to GHRH plus iv ARG (group B).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7850010 TI - Bone mineral density in middle-aged women with Turner's syndrome. AB - Bone mineral density (BMD), bone mineral content and body composition were determined in 47 middle-aged (mean age 47.9 +/- 1.1 years) women with Turner's syndrome. Bone mineral density was measured in the forearm, femoral neck and total body. The women investigated had a BMD lower than the normal mean. When expressed as Z scores (individual values compared to normal reference data matched for age, weight and sex), the median Z score of the total body was -1.23. When comparing women with the karyotype 45,X and mosaic women, the latter showed a higher BMD in all sites of measurement. Duration of hormonal replacement therapy (HRT) differed significantly between the mosaic and the 45,X women, with a longer duration in the mosaic group (20.7 +/- 2 vs 12.1 +/- 2.6 years; p < 0.01). The duration of HRT was found to be the more important factor to maintain bone mass, not the karyotype. Bone mineral density increased with years of HRT but not until after > 20 years of HRT could a significant difference be shown between the women with HRT < or = 20 years and those with HRT > 20 years. No correlation was found between BMD and body weight, body fat or percentage body fat. Whether the osteopenia found in women with Turner's syndrome is similar to that found postmenopausally or is a specific form related to the chromosome aberration remains to be investigated further. The present data support a relation to estrogen deficiency. PMID- 7850009 TI - Bone turnover and bone mineral density in young adult patients with panhypopituitarism before and after long-term growth hormone therapy. AB - We examined the effects of biosynthetic growth hormone (GH) on biochemical indices of bone turnover and on bone mineral density in a group of GH-deficient adults. Thirteen patients (eight males and five females) aged 24 +/- 5 years (range 16-35) were studied before and 12 and 24 months after GH treatment (0.1 IU.kg-1 day-1, 6 days a week). Serum levels of insulin-like growth factor I (IGF I), calcitonin, parathyroid hormone, alkaline phosphatase, intact osteocalcin, fasting urinary hydroxyproline/creatinine ratio and bone mineral density (BMD), measured at the lumbar spine by dual-photon absorptiometry, were evaluated. After 12 months of treatment, IGF-I, alkaline phosphatase, osteocalcin and the fasting urinary hydroxyproline/creatinine ratio increased significantly. However, after 24 months of therapy, serum levels of osteocalcin decreased to pretreatment values while IGF-I, fasting urinary hydroxyproline/creatinine ratio and alkaline phosphatase remained elevated significantly. No changes were found in parathyroid hormone and calcitonin plasma levels or in BMD either after 12 or 24 months of treatment. These data demonstrate that GH, at the dosage that we used, activates bone turnover during 24 months of therapy in adults with panhypopituitarism, even if a downward trend for osteocalcin became apparent at 24 months. However, this activation in bone turnover was not accompanied by an increase in BMD. We can hypothesize that GH, at the relatively high dosage used, may stimulate osteoclastic activity to a greater extent than osteoblastic activity. It is probable that the dose of GH replacement therapy in adults plays a key role. PMID- 7850011 TI - Thyroid cytotoxic antibodies in atrophic and goitrous autoimmune thyroiditis. AB - It is unknown whether in chronic lymphocytic thyroiditis the goitrous (Hashimoto's thyroiditis) and atrophic forms (primary myxedema) are variants of the same disease or different pathogenic entities. Conventional thyroid-related autoimmune parameters are unable to separate both diseases serologically. It is assumed that cellular and humoral cytotoxic events induce gland atrophy and thus should be detectable more often in non-goitrous than goitrous autoimmune thyroiditis. We determined antibody-dependent cell-mediated cytotoxicity in 67 patients with autoimmune thyroiditis, using a 51chromium-release assay against human thyroid cells. Thyroid volume had been measured by ultrasonography. Other thyroid-specific antibodies, like TSH binding-inhibiting antibodies, TSH function blocking antibodies, thyroglobulin antibodies and thyroid peroxidase antibodies, were determined. Cytotoxic antibody activity was 20.5% (median, range 0-54.5%) in patients with autoimmune thyroiditis and 8.3% (median, range 0-18.4%) in controls (p < 0.0001). Analysis of cytotoxicity regarding thyroid size showed a high incidence of cytotoxic antibodies in atrophic disease (median thyroid volume 6 ml), where cytotoxic antibodies were detectable in 80% versus 39% (x2 = 9.6; p < 0.0001) in goitrous disease (median thyroid volume 36 ml). The specific lysis of 30% (median; 95% confidence limit 23.9-32.9) in non-goitrous thyroiditis patients was significantly higher than in goitrous patients (16.9%; 95% confidence limit 13.2-20.4) (p = 0.0006).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7850013 TI - Intrasellar bony spine, a possible cause of hypopituitarism. AB - A 39-year-old male patient with long-standing pituitary deficiency is reported. The onset of hypopituitarism was probably at about the age of 12 years, but diagnosis was not made until 6 years later. Since then he has received substitutive hormonal treatment and was referred with complaints suggestive of growth hormone deficiency. Retrospective study of a skull radiography performed at the age of 18 years revealed a calcified lesion in the sellar region. Additional radiological examinations showed the presence of a 9-mm intrasellar bony spine. Magnetic resonance examination showed a ventrally extending arrow shaped bone deformation in continuity with the dorsum sellae, consisting of a hyperintense structure comparable with the intensity of the bone marrow of the dorsum and clivus. Computed tomography scanning confirmed in detail the morphology of the bony spine. This deformity probably represents the non regressed cephalic segment of the notochord. Only in four reports has the existence of this congenital abnormality been described, but this is the first one in which hypopituitarism can be regarded as a complication of the intrasellar spine. PMID- 7850012 TI - Abnormal calcitonin basal levels and pentagastrin response in patients with chronic renal failure on maintenance hemodialysis. AB - Hypercalcitoninemia has been reported in renal failure. Using a specific monomeric calcitonin (CT) immunoassay, we measured CT levels in 154 hemodialyzed patients. The relationship between CT and serum intact parathyroid hormone (PTH), gastrin, alkaline phosphatases, phosphate and calcium was studied. The pentagastrin test was performed in 26 patients exhibiting basal hypercalcitoninemia. Basal CT levels over 5.7 pmol/l (20 ng/l) were found in 25.3% of the patients and values higher than 26 pmol/l (90 ng/l) in 7.8%. Although CT is cleared by hemodialysis, post-dialysis CT levels either were unchanged or increased as compared with pre-dialysis values. This suggests that hypercalcitoninemia is not related to a decreased renal clearance, and that hemodialysis induces a specific regulatory pathway. None of the parameters studied were found to explain high CT levels. Of the patients with hypercalcitoninemia, 11.5% exhibited abnormal CT response to pentagastrin but no relationship between CT and phosphate, calcium and PTH levels was evidenced. Our findings confirm high CT monomer levels in renal failure. As there was no correlation with parameters classically involved in CT regulation, its physiological significance remains unclear. Abnormal CT response to pentagastrin raises the problem of its specificity as a tumoral marker with regard to medullary thyroid carcinoma. PMID- 7850014 TI - Reduction in goiter size by 131I therapy in patients with non-toxic multinodular goiter. AB - A retrospective follow-up study of 131I treatment was performed in 10 females (median age 48 years, range 40-74 years) with non-toxic multinodular goiter. The median dose of 131I given was 20 mCi (range 14-65 mCi). Thyroid volume was measured by ultrasonography. The median follow-up period was 26 months (range 12 68 months). Nine patients had a reduction of goiter size: thyroid volume decreased from 88 +/- 14.9 ml (mean +/- SEM) to 49 +/- 10.9 ml 1 year after 131I treatment. The relative decrease of goiter size was 48% after 1 year (N = 9) and 59% after 2 years (N = 5). One patient did not respond and was referred for operation. Side effects were mild spontaneously resolving radiation thyroiditis in one patient and subclinical hypothroidism in four patients. In conclusion, 131I treatment of non-toxic goiter is an effective treatment at the expense of post-radiation (subclinical) hypothyroidism. PMID- 7850015 TI - Induction of luteinized unruptured follicles in the rat after injection of luteinizing hormone early in pro-oestrus. AB - The cause of formation of luteinized unruptured follicles (LUF) is unknown. Formation of LUF was studied after injection of a varying small dose of luteinizing hormone (LH) with or without subsequent injection of gonadotrophin releasing hormone (GnRH); in addition, the effect of suppression of prolactin on LUF formation was studied. Luteinization without ovulation occurred in virtually all graafian follicles, if 0.5-1.0 microgram of LH was injected some hours before the presumed endogenous LH surge (suppressed by Nembutal); with increasing doses of LH progressively increasing numbers of ovulations were observed. If an early pro-oestrus 1 microgram of GnRH was given 4 h after 1 microgram of LH, formation of LUF was partly prevented; if the interval between LH and GnRH was 8 h or more, the great majority of graafian follicles developed into LUF. If early in pro oestrus 1 microgram of LH was given and 8 h later 0.1 microgram of a potent GnRH analogue, about 50% of the follicles became LUF; in similarly treated rats, suppression of prolactin by ergocryptine reduced but did not prevent LUF formation. The data support the idea that deficient LH secretion in the period before ovulation may be involved in the formation of LUF. PMID- 7850016 TI - Electrotonic clusters in the dendritic arborization of abducens motoneurons of the rat. AB - Following reconstruction with high spatial resolution of the 3-D geometry of the dendritic arborizations of two abducens motoneurons, we simulated the distribution of electronic voltage over the whole dendritic tree. Here, we demonstrate that the complex stochastic electronic structure of both motoneurons can be reduced to a statistically significant small set of well discriminated clusters. These clusters are formed by dendritic branches belonging to different dendrites of the neuron but with similar electronic properties. A cluster analysis was performed to estimate quantitatively the partition of the branches between the dendritic clusters. The contents of the clusters were analysed in relation to their stability under different values of specific membrane resistivity (Rm), to their remoteness from the soma and their location in 3-D space. The cluster analysis was executed in a 2-D parameter space in which each dendritic branch was described by the mean electrotonic voltage and gradient. The number of clusters was found to be four for each motoneuron when computations were made with Rm = 3 k omega.cm2. An analysis of the cluster composition under different Rm revealed that each cluster contained invariant and variant branches. Mapping the clusters upon the dendritic geometry of the arborizations allowed us to describe the cluster distribution in terms of the 3-D space domain, the 2-D path distance domain and the total surface area of the tree. As the cluster behaviour reflects both the geometry and the changes in the neuronal electrotonic structure, we conclude that cluster analysis provides a tool to handle the functional complexity of the arborizations without losing relevant information. In terms of synaptic activities, the stable dendritic branches in each cluster may process the synaptic inputs in a similar manner. The high percentage of stable branches indicates that geometry is a major factor of stability for the electrotonic clusters. Conversely, the variant branches introduce the conditions for mechanisms of functional postsynaptic plasticity. PMID- 7850017 TI - The nitric oxide--cyclic GMP pathway and synaptic depression in rat hippocampal slices. AB - The ability of exogenous nitric oxide (NO) to modify synaptic transmission was investigated in area CA1 of the rat hippocampal slice. The NO donors S-nitroso-N acetylpenicillamine (SNAP) and S-nitrosoglutathione (SNOG) depressed field excitatory postsynaptic potentials evoked by low frequency stimulation of the Schaffer collateral-commissural pathway. Upon washout of the NO donors, synaptic transmission rapidly returned to control levels. A similar reversible synaptic depression was produced by SNAP when tetanic stimulation (100 Hz; 1 s) was delivered in its presence. The effect of SNAP was not mimicked by its precursor or breakdown product and was blocked by haemoglobin, indicating that the effect involved NO. Roussin's black salt, a photolabile NO donor, also depressed transiently field excitatory postsynaptic potentials following photolysis. The depression was induced rapidly following a flash of UV light (20 s duration) focused onto the slice using a confocal microscope. The depressant effect of the NO donors on synaptic transmission was mimicked by zaprinast, a specific cGMP phosphodiesterase inhibitor. Zaprinast depressed to a similar extent both the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate and N-methyl-D-aspartate receptor-mediated components of excitatory postsynaptic currents without affecting passive membrane properties, indicating a presynaptic locus of action. SNAP, SNOG and zaprinast all elevated cGMP levels in rat hippocampal slices. Immunocytochemical staining revealed that the cGMP accumulation was mainly in a network of varicose fibres running throughout the CA1 region, consistent with a presynaptic site of action of NO. We conclude that NO, possibly through activation of guanylate cyclase, may be involved in transient presynaptic depression in the CA1 region of the hippocampus. PMID- 7850018 TI - Plasticity of NMDA receptor expression during mouse cerebellar granule cell development. AB - A period of hypersensitivity to N-methyl-D-aspartate (NMDA) has been described during the early development of different types of neuron. Since activation of NMDA receptors can also induce rapid neuron death, the hypersensitivity to NMDA may be tightly controlled. In the present study we show that mouse cerebellar granule neurons become transiently hypersensitive to NMDA between days 10 and 14 after plating in a culture medium containing 30 mM K+. The NMDA sensitivity is higher when cells are cultured in the presence of an NMDA receptor antagonist [30 mM K+ plus 100 microM 3-((+/-)-2-carboxypiperazine-4-yl)-propyl-1-phosphonic acid (CPP)], and no hypersensitivity is observed when cells are cultured in the continuous presence of NMDA (12.5 mM K+ plus 100 microM NMDA). The high NMDA sensitivity in control cells is associated with a higher density of NMDA receptors than that measured in NMDA-treated cells, suggesting that the sensitivity to NMDA may be partly controlled by activity-dependent NMDA receptor down-regulation. We also examined the level of NMDA-zeta 1 mRNA and found no correlation between this parameter and the transient pattern of NMDA sensitivity. Such NMDA receptor plasticity may be of importance in the central nervous system, protecting developing cells from excitotoxicity at critical developmental stages. PMID- 7850019 TI - Dynamic changes in the composition of the AP-1 transcription factor DNA-binding activity in rat brain following kainate-induced seizures and cell death. AB - Kainate, a potent excitatory and neurotoxic agent, has also proved useful in studies on other glutamate-driven phenomena, such as neuronal plasticity. Long term effects of kainate are apparently dependent on its influence on the expression of various genes, including those encoding the AP-1 transcription factor, consisting of proteins belonging to the Fos and Jun families. In our studies we analysed c-fos, fos B, c-jun, jun B and jun D mRNA levels as well as a functional feature of AP-1, its DNA-binding activity, in the rat brain following systemic injection of kainate. Two phases of elevated AP-1 DNA-binding activity were observed in the hippocampus and entorhinal cortex, and were correlated with period of seizures (2 and 6 h after kainate injection) and neuron damage (48-72 h). At 72 h after kainate treatment DNA fragmentation, believed to be diagnostic of apoptotic processes typical of programmed cell death phenomena, was noted. Two and six hours after the treatment, AP-1 consisted predominantly of Fos B, c-Fos, Fra-2 and Jun B, while at 72 h Jun D constituted the major AP-1 component in place of Jun B, and no c-Fos was detected. Only a slight AP-1 increase was seen 24 h after kainate treatment. In the sensory cortex, only the late phase of AP-1 elevation was detected. Contrary to AP-1, no effect of kainate on levels of two other transcription factors, CREB/ATF (cAMP-responsive element binding proteins) and OCT (octamer element DNA-binding activity) was seen.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7850020 TI - Ultrastructure and GABA immunoreactivity in layers 8 and 9 of the optic tectum of Xenopus laevis. AB - This study presents an ultrastructural analysis of layers 8 and 9 in the optic tectum of Xenopus laevis. Retinotectal axons were labelled with horseradish peroxidase and tectal cells were labelled with antibody to GABA. Four distinct axonal and dendritic structures were identified. GABA-negative axon terminals formed asymmetric synapses and were categorized as type a-1 (which included retinotectal axons), characterized by medium size synaptic vesicles and pale mitochondria, and type a-2 (non-retinotectal) with large vesicles and dense mitochondria. GABA-negative dendrites (type d) contained dense mitochondria, microtubules in the dendritic shafts, and dendritic spines devoid of microtubules. GABA-positive structures contained small synaptic vesicles and dense mitochondria. Some dendrites (type D) were not only postsynaptic but were also presynaptic elements, as defined by the presence of vesicles and distinct synaptic clefts with symmetric specializations. GABA-positive presynaptic structures were mostly located in vesicle-filled, bulbous extensions of dendritic shafts and usually terminated onto dendritic spines. Some type D dendrites were the middle element in serial synapses, with input from either GABA-positive or GABA-negative structures and output to GABA-negative structures. Retinotectal terminals were identified as one of the synaptic inputs to GABA-positive processes. Glia were characterized by granular cytoplasm and large mitochondria, often displaying a crystalline matrix structure. These results indicate that GABA positive neurons are a prominent component of circuitry in the superficial layers of the tectum of Xenopus and that, as in mammals, they participate in serial synaptic arrangements in which retinotectal axons are the first element. These arrangements are consistent with complex processing of visual input to the tectum and a central role for inhibitory processes in the shaping of tectal responses. PMID- 7850021 TI - Cortical magnification theory fails to predict visual recognition. AB - The sense of form is poor in indirect view. Yet the cortical magnification theory asserts that the disadvantage can be made up by scaling the image size according to the spatial variation in the mapping of the retina onto the cortex. It is thus assumed that all visual information passes through a functionally homogeneous neural circuitry, with the spatial sampling of input signals varying across the visual field. We challenge this notion by showing that character recognition in the visual field cannot be accommodated by any concept of sole size scaling but requires increasing both size and contrast of the target being viewed. This finding is formalized into a hyperbolic law which states that target size multiplied by log contrast is constant across the visual field. We conclude that the scalar cortical magnification theory fails for character recognition since the latter depends on multidimensional pattern representations in higher, i.e. striate and prestriate, cortical areas. PMID- 7850022 TI - Development of tonotopy in the inferior colliculus II: 2-DG measurements in the kitten. AB - The development of size and tonotopy in the inferior colliculus of the kitten was studied using the [14C]2-deoxyglucose technique and tone stimulation with 2 and 15 kHz at a maximum 110 dB sound pressure level. At 2 days of age, frequency specific labelling cannot be detected. Two kilohertz labelling is distinctly visible in the rostral and central inferior colliculus at day 6; 15 kHz labelling occurs first at day 11. In the rostral and central inferior colliculus, 2 kHz labelling starts at a ventral and central position and shifts dorsalwards and to a more lateral location between postnatal days 6 and 21. Such a shift is not seen in the caudal inferior colliculus. There, the focus of 2 kHz labelling remains rather constant; only the extension of the labelling increases in the older animals. In all parts of the inferior colliculus, 15 kHz labelling starts at a ventromedial position and shifts to a more lateral location while extending also more dorsalwards as the age increases. These changes in 15 kHz labelling continue up to 3 months. In addition to the ventromedial-to-dorsolateral shift and expansion of labelling, there is also a rostral-to-caudal gradient of maturation, in that in older animals frequency-specific labelling reaches farther caudalwards. The reported changes in frequency representation in the inferior colliculus can be explained on the basis of a shift in frequency input and input sensitivity to the laminae of the inferior colliculus, mainly due to maturational changes within the cochlea and/or as a consequence of the increasing size of the inferior colliculus. PMID- 7850023 TI - Distribution of nicotinic receptors in the human hippocampus and thalamus. AB - Neuronal nicotinic acetylcholine receptors consist of different subunits, alpha and beta, with different subtype arrangement corresponding to distinct pharmacological and functional properties. The expression of alpha 3, alpha 7 and beta 2 mRNA in the human brain was studied by in situ hybridization and compared to [3H]nicotine, [3H]cytisine and [125I]alpha-bungarotoxin binding in contiguous sections. The beta 2 probe showed a strong hybridization signal in the granular layer of the dentate gyrus and in the CA2/CA3 region of the hippocampus and in the insular cortex, and a signal of lower intensity in the subicular complex and entorhinal cortex. The alpha 3 probe showed strong hybridization in the dorsomedial, lateral posterior, ventroposteromedial and reticular nuclei of the thalamus, and a weak signal in the hippocampal region and in the entorhinal, insular and cingular cortex. The amount of alpha 7 mRNA was high at the level of the dentate granular layer and the CA2/CA3 region of the hippocampus, in the caudate nucleus and in the pulvinar and ventroposterolateral nuclei of the thalamus. [3H]Nicotine and [3H]cytisine binding appeared to be identical in anatomical distribution and relative intensity. It was high in the thalamic nuclei, the putamen and in the hippocampal formation in the subicular complex and the stratum lacunosum moleculare. The level of [125I]alpha-bungarotoxin binding was particularly high in the hippocampus and in the pyramidal cells of the CA1 region, but was relatively low in the subicular complex. Our data indicate that in the human brain nicotinic receptor subtypes have discrete distributions, which are in part different from those of other species. PMID- 7850024 TI - The survival of transected axonal segments of cultured Aplysia neurons is prolonged by contact with intact nerve cells. AB - Axonal segments transected from their cell body in vivo commonly undergo degeneration within 3-4 days (Wallerian degeneration). In lower vertebrates and invertebrates, however, some transected axonal segments survive for long periods ranging between 30 and 200 days. To circumvent the technical complications of studying the mechanisms underlying long-term survival of transected axons in vivo, we developed an in vitro system. We found previously that isolated axonal segments of cultured Aplysia neurons preserved their morphological integrity for an average duration of 7.6 days (range 2-14 days) and maintain their passive and excitable membrane properties. This survival occurred in the absence of de novo protein synthesis. In the present study we examined the influence of homologous neurons on the survival of transected axonal segments. We found that the average survival time of transected axons was doubled when co-cultured in physical contact with intact homologous neurons (average 15.3 days, range 2-27 days). During this period, the transected axons extended neurites, maintained normal passive and excitable membrane properties, formed electrotonic junctions with the intact neurons and maintained normal free intracellular Ca2+ levels. Consistent with these observations, electron micrographs of the transected axon revealed that the cytoskeletal elements of the axon appeared normal even 20 days after transection. In contrast, the mitochondria and smooth endoplasmic reticulum appeared damaged. As the prolonged survival was conditional on physical contact between the transected axon and the surrounding intact neurons, we suggest that the prolongation of survival time is promoted by the direct transfer of material from the intact neurons to the transected axon. However, co-culture of transected axons with homologous neurons did not fully mimic in vivo conditions, in which transected axons can survive for several months. PMID- 7850025 TI - Inhibition of posttraumatic microglial proliferation in a genetic model of macrophage colony-stimulating factor deficiency in the mouse. AB - Activation and proliferation of microglia are common cellular hallmarks in many different pathological processes of the central nervous system. Although a number of colony-stimulating factors enhance microglial proliferation in vitro, little is known about the endogenous mitogens. In the present study we show a strong and selective inhibition of microglial proliferation in the facial nucleus of osteopetrotic (op/op) mice, with a genetic deficiency in biologically active macrophage colony-stimulating factor (MCSF). Posttraumatic activation of adjacent axotomized neurons and reactive astrocytes was not affected, emphasizing the specificity of MCSF as a microglial growth factor. PMID- 7850026 TI - Relationship between lateral inhibitory connections and the topography of the orientation map in cat visual cortex. AB - The functional and structural topography of lateral inhibitory connections was investigated in visual cortical area 18 using a combination of optical imaging and anatomical tracing techniques in the same tissue. Orientation maps were obtained by recording intrinsic signals in regions of 8.4-19 mm2. To reveal the inhibitory connections provided by large basket cells, biocytin was iontophoretically injected at identified orientation sites guided by the pattern of surface blood vessels. The axonal and dendritic fields of two retrogradely labelled large basket cells were reconstructed in layer III. Their axonal fields extended up to 1360 microns from the parent somata. In addition to single basket cells, the population of labelled basket cell axons was also studied. For this analysis anterogradely labelled basket axons running horizontally over 460-1280 microns from the core of an injection site in layer III were taken into account. The distribution of large basket cell terminals according to orientation preferences of their target regions was quantitatively assessed. Using the same spatial resolution as the orientation map, a frequency distribution of basket cell terminals dependent on orientation specificity could be derived. For individual basket cells, the results showed that, on average, 43% of the terminals provided input to sites showing similar orientation preferences (+/- 30 degrees) to those of the parent somata. About 35% of the terminals were directed to sites representing oblique-orientation [+/- (30-60) degrees], and 22% of them terminated at cross-orientation sites [+/- (60-90) degrees]. Furthermore, the possible impact of large basket cells on target cells at different distances and orientation preferences was estimated by comparing the occurrence of orientation preferences with the occurrence of basket terminals on the distance scale. It was found that a basket cell could elicit iso-orientation inhibition with a high impact between 100-400 and 800-1200 microns, strong cross-orientation inhibition at approximately 400-800 microns, and oblique-orientation inhibition between 300 500 and 700-900 microns from the parent soma. The non-isotropic topography of large basket axons suggests a complex function for this cell class, possibly including inhibition related to orientation and direction selectivity depending on the location of the target cells and possible target selectivity. PMID- 7850027 TI - Cholera toxin beta subunit induces the differentiation of human medulloblastoma cell line DEV in a neuronal pathway. AB - Medulloblastomas are primitive neuroectodermal tumours that are thought to arise from multipotent precursor cells in the cerebellum. Medulloblastoma cells may be undifferentiated or exhibit glial, neuronal or ependymal characteristics, suggesting that they may conserve their ability to differentiate in appropriate circumstances. Medulloblastoma cell lines may thus provide models to study the commitment and differentiation of multipotent CNS progenitor cells. A human medulloblastoma cell line, DEV, has previously been shown to differentiate in an astrocytic pathway after infection by the retrovirus HTLV-1. In this study immunofluorescence flow cytometry shows that cholera toxin beta subunit (CT beta), which binds to the ganglioside GM1, induces a twofold increase in the number of DEV cells differentiating towards a neuronal pathway, as shown by the increased proportion and labelling intensity of cells stained by an anti neurofilament antibody. Immunocytochemistry shows that after 3 days in culture with CT beta, DEV cells develop processes which stain positive for neurofilaments and MAP-1. This suggests that CT beta induces DEV cells to express a more neuronal phenotype. PMID- 7850028 TI - Differential expression of bcl-2 and bax mRNA in axotomized dorsal root ganglia of young and adult rats. AB - Bcl-2 and Bax have recently been identified as putative repressor and effector proteins respectively, in the cell death program of growth factor-deprived haematopoietic cell lines. Overexpression of bcl-2 in neuronal cell culture prevents apoptosis induced by removal of neurotrophic factors. In the present in vivo study the expression of bcl-2 and bax mRNA has been investigated in dorsal root ganglia of young and adult rats using polymerase chain reaction. A high constitutive expression was observed for both genes in control ganglia. Unilateral transection of the sciatic nerve led to a dramatic decrease in bcl-2 mRNA levels in ganglia of young animals within 5 days following nerve lesion and a partial recovery thereafter. In contrast, the decline in bcl-2 mRNA was much less pronounced in axotomized ganglia of adults. The amount of bax transcripts did not change significantly in ganglia of both young and adult rats up to 20 days after nerve injury. The decrease in bcl-2 expression in dorsal root ganglia may be part of the molecular mechanism leading to neuronal cell death after axotomy-induced deprivation of neurotrophic factors. The age-dependent decline in the ratio of bcl-2 to bax gene products may explain the greater susceptibility of immature neurons to apoptosis. PMID- 7850029 TI - Inhibition of the classical and alternative pathways of the human complement system by glycosaminoglycan polysulfate. AB - Glycosaminoglycan polysulfate (GAGPS) concentration-dependently inhibited the activation of the classical and alternative pathways of the human complement system in vitro. Concentrations of > or = 0.2 mg/ml GAGPS prevented the cleavage of C4 by human aggregated gammaglobulin as evidence of inhibition of the classical pathway. At concentrations of > or = 0.15 mg/ml a concentration dependent inhibition of the cleavage of factor B, the major step in the activation of the alternative pathway, was seen in the presence of inulin. Concentrations < 0.05 mg/ml did not have a measurable effect on either pathway. The lysis of sheep red blood cells, which is mediated largely by the classical pathway, was significantly inhibited at 3.84 mg/ml GAGPS, with a mean inhibition of 45.7%. On the other hand, the same concentration of GAGPS almost completely inhibited the lysis of rabbit red blood cells, which is mediated by the alternative pathway of complement. Our results suggest that the inhibition by GAGPS is an early event in the activation of complement, occurring before the assembly of the C3 convertases of either pathway. The possible use of this drug in acute life-threatening situations where complement is thought to have a pathogenic role is discussed. PMID- 7850030 TI - The prick test and specific IgE (RAST and MAST-CLA) compared with the oral challenge test with milk, eggs and nuts. AB - In spite of the development of numerous in vivo and in vitro diagnostic techniques for food allergy, the oral challenge test (OCT) is still the "gold standard". Consequently, we have compared it with some of the more recent techniques. We studied 36 patients with a medical history compatible with food allergy (to milk, eggs or nuts) and 11 patients without food allergy (6 nonatopic and 5 with acarid allergy). A prick test, specific IgE (RAST and MAST-CLA) and an OCT with the suspected food were performed in all patients. The following parameters were calculated for all patients overall and for each of the three allergic groups separately: sensitivity, specificity and match with the OCT. We also studied the RAST-MAST-CLA correlation and the variability of the MAST-CLA. The prick test was the most sensitive (95%) and the MAST-CLA (13% divergence in two measurements) the most specific (92%). The RAST and the MAST-CLA (68% match) gave similar results, with an acceptable match (75% and 77%, respectively) with the OCT. The medical history could only suggest the diagnosis (39% false positives). After comparing the results with those in the literature, it is suggested that greater attention should be paid to the limitations of these techniques compared with the OCT. PMID- 7850031 TI - Responses of lymphocytes to Epstein-Barr virus in patients with primary immunodeficiencies. AB - Several reports have demonstrated that the responses of B-cells to Epstein-Barr virus (EBV) are variable in common variable immunodeficiency (CVID). In this study in patients with selected primary immunodeficiencies, i.e., Bloom's syndrome, Wiskott-Aldrich syndrome or IgA deficiency, the responses of peripheral blood mononuclear cells (PBMCs) to EBV were investigated. In the two patients with Bloom's syndrome, PBMCs stimulated with EBV showed decreased proliferation and immunoglobulin production, suggesting a mild abnormality of B-cells. In patients with Wiskott-Aldrich syndrome, the responses were variable. In the patient with IgA deficiency, PBMCs responded normally to EBV in proliferation, whereas PBMCs responded poorly to EBV in IgA production, suggesting an abnormality only in the IgA production mechanism. PMID- 7850032 TI - The effect of chronic exposure to formaldehyde, phenol and organic chlorohydrocarbons on peripheral blood cells and the immune system in humans. AB - The aim of this study was to evaluate immunological, hematological and biochemical parameters in subjects chronically exposed to inhaled formaldehyde (F), phenol (Ph) and isomers of organic chlorohydrocarbons (Chc) released from Ksylamit. Twenty-two office workers had been exposed for 6 months to vapors of Ksylamit, used for protection of felt plates inside the office building. The concentration of Ksylamit vapor was measured at the end of the 6-month period and the level of Ph and F in the air inside the building was 1.3 mg/m3 and 0.8 mg/m3, respectively. Most of the workers had ailments due to the irritant effect of inhaled Ksylamit, but no remarkable increase in morbidity was found during the 6 months of exposure and in a 3-year follow-up. Morphological parameters of blood and the number of natural killer (NK) cells in the group of exposed subjects were within the range observed in healthy subjects matched for age and sex. The number of T-lymphocytes and NK cell cytotoxicity were significantly decreased. Phytohemagglutinin (PHA)- and alloantigen-induced lymphocyte proliferation was diminished. Some biochemical parameters suggested liver damage, although these parameters did not correlate with the levels of Ph and methanol excreted in the urine. Eight subjects with the highest levels of Ph in the urine had decreased erythrocyte and T-helper lymphocyte numbers, and increased numbers of eosinophils and monocytes. The results obtained prove that the functions of both the immune and hematopoietic systems could be affected by chronic exposure to these toxic substances. PMID- 7850033 TI - Atopic sensitization in children of Somali immigrants in Italy. AB - Children of immigrants are known to be at greater risk for developing allergic manifestations than the population in general. In this study we observed children of Somali origin living in Italy in order to find plausible explanations for the high risk of allergic disease in immigrants. Fifty-two children aged 0-14 years (mean = 6.7 years) were examined during the spring season. The mothers of the children were asked to fill in a questionnaire on symptoms and signs of atopic diseases and the family history of atopy. In addition, a physical examination and skin tests were performed. All families used mattresses, pillows and/or blankets made of wool, known to favor the growth of mites. In the majority of these children's families we found at least five people cohabitating in the same room. Skin prick tests were most frequently positive for Dermatophagoides pteronyssinus. Seventy-four percent (14/19) of those with symptoms were positive to D. pteronyssinus. Only 14% (2/14) of those positive to D. pteronyssinus were positive to Lolium perenne. Thirty-seven percent (19/52) had atopic symptoms and 15% (5/33) of those without symptoms were positive to D. pteronyssinus (p < 0.0001 compared to those with symptoms). Sensitization to food allergens occurred less frequently as compared to common inhalant allergens (p < 0.0001). A high prevalence of atopic diseases among children of Somali immigrants in Italy might be attributed to contact with the new environment and poor socioeconomic conditions that promote, for example, the growth of mites. However, further studies are needed to document these differences. PMID- 7850034 TI - Interstitial pneumonitis induced in guinea pigs by Triatoma infestans antigens. AB - Data concerning the experimental induction of hypersensitivity pneumonitis in guinea pigs with a Triatoma infestans antigen are presented. Glycoproteins obtained from the chitinous structures of T. infestans (79 kd + 11 kd) were aerosolized daily to guinea pigs during 7 weeks. The presence of specific antibodies (IgG and IgE) was detected by serological techniques; histopathological studies of the lungs showed interstitial infiltrates of macrophages and T-cells. Single non-necrotizing granulomas were seen at the seventh week of the experiment. The results from this animal model suggest that this hypersensitivity pneumonitis is a typical delayed-type reaction due to chronic contact with the heterologous glycoproteins of T. infestans. PMID- 7850035 TI - Schnitzler's syndrome: report of a case with bone osteolysis. AB - A case of chronic urticaria with macroglobulinemia (Schnitzler's syndrome) is described. To our knowledge, this is only the second case reported in the literature with osteolysis and the presence of cryoglobulins in sera. The characteristics of the previous 21 cases of this syndrome are reviewed. The pathogenesis of this peculiar entity is discussed. PMID- 7850036 TI - Vestibular bibliography. PMID- 7850037 TI - Dynamic platform sway measurement in Meniere's disease. AB - Fourteen patients in the latent phase of Meniere's disease and 14 control subjects were tested on a moving platform apparatus as part of a protocol of investigations for Meniere's disease. Subjects were tested under 3 different visual conditions (eyes open, eyes closed, sway feedback) and 2 proprioceptive conditions (fixed platform and ankle stabilization). There was a significant interaction between subject group and visual condition, Meniere's patients had a larger RMS sway amplitude than controls with their eyes open and closed, but this difference was abolished by sway feedback. Loss of either visual or proprioceptive sensory information increased sway amplitude, indicating that both cues influence postural control, and in different ways, but patients were able to use these cues to maintain upright posture almost as effectively as controls. More patients than controls lost balance with ankles stabilized and eyes closed, but the difference was not statistically significant (P = 0.0516). There was no detectable relationship between clinical ratings of disease severity and sway scores. The dynamic platform tests described in this report are more suitable for tests involving comparisons between groups of subjects rather than for diagnostic testing of individuals. PMID- 7850038 TI - Reorientation of poststimulus nystagmus in tilted humans. AB - Recent studies indicate that the direction of postrotatory nystagmus and optokinetic afternystagmus reorients toward earth-horizontal in tilted subjects. To further examine this phenomenon in humans, we studied 8 adults (4M, 4F) with no history of neurologic or otologic disease. Vestibular stimulation consisted of yaw off-vertical axis rotation (OVAR) trapezoids with eyes open in the dark at 60 degrees/s constant velocity with a tilt angle of 30 degrees and a deceleration at 100 degrees/s2 to a stop in either the right-ear-down or the left-ear-down position. The optokinetic stimulus consisted of 5 degrees wide black and white stripes projected against a cylindrical visual surround 1 m in diameter rotated at a constant velocity of 30 degrees/s. The projector, visual surround, and subject were all tilted by 30 degrees; subjects were placed either in the right ear-down or left-ear-down position. Eye position was measured using the magnetic scleral search coil technique. Each trial was scrutinized for the presence of reorientation of nystagmus in the subject's roll plane by looking for vertical nystagmus in the appropriate direction. Results indicated that reorientation of postrotatory nystagmus following OVAR was variable but often present. Reorientation of optokinetic afternystagmus was neither as consistent nor as robust as that seen following OVAR. These findings confirm that humans exhibit a predilection for eye rotations in the earth-horizontal plane.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7850039 TI - Morphometric studies of type I and type II hair cells in the gerbil's posterior semicircular canal crista. AB - The existence of separate subtypes of type I vestibular hair cells according to morphological criteria in situ was investigated. Gerbils were anesthetized and perfused with mixed aldehydes. The crista ampullaris of the posterior canal was dissected, fixed in osmium, dehydrated, and embedded in epon. Five-micron sections were cut orthogonal to the long axis of each crista. Measurements were made on camera lucida drawings of individual cells located in the apical, middle, and basal 1/3 of the crista. Measurements for each hair cell included the circumference, greatest width of the body, length, width of the apical surface (cuticular plate region, P), width at narrowest portion of the neck (NW), neck width to plate ratio (NPR), length at a point 2 times NW from the apical surface (L2N). Type I hair cells were subgrouped into three classes (long -1, intermediate -i, and short -s) based on a subjective determination of neck length. Statistical comparisons were made between type I (n = 612) and type II (n = 74) hair cells and the type I subtypes (l, i, s). Statistically significant differences were found between type I and II hair cells for NPR, width, and length, but not perimeter. Thus, as in pigeons, NPR distinguishes type I and type II hair cells in the gerbil crista. While type I hair cells are wider and longer than type IIs, the circumference is the same, due to the restricted neck in type I hair cells. The L2N statistic separates three subtypes of type I hair cells.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7850040 TI - Quantitative distribution of amino acids in the rat vestibular nuclei. AB - The normal concentrations of 12 amino acids in the vestibular nuclei of rats were quantitatively measured using microdissection of freeze-dried brain sections combined with high performance liquid chromatography (HPLC) analysis. Both excitatory amino acids, aspartate and glutamate, showed only small variation across the vestibular nuclei. The distribution of glutamine tended to parallel that of glutamate. The inhibitory amino acids, gamma-aminobutyrate (GABA) and glycine, were much more concentrated in some regions than in others. GABA tended to be more concentrated than glycine in dorsal and rostral nuclei, while glycine tended to be more concentrated than GABA in ventral and caudal nuclei. The distribution of taurine was comparable to that of GABA, suggesting a close relationship with GABA function. Asparagine, serine, threonine, arginine, alanine and tyrosine had relatively low concentrations without significant differences among vestibular nuclei. Our results suggest that (1) different parts of the vestibular nuclear complex may receive similar amounts of excitatory amino acid afferents, (2) there is predominance of GABA or glycine as an inhibitory transmitter in different parts of the vestibular nuclear complex, and (3) there may be a close functional relationship between taurine and GABA within the vestibular nuclear complex. These results provide data basic to further research on the details of amino acid functions in the normal and abnormal vestibular system, as well as studies of plasticity in this system. PMID- 7850041 TI - Dynamics of directional plasticity in the human vertical vestibulo-ocular reflex. AB - Directional plasticity of the human vestibulo-ocular reflex (VOR) was studied in 10 subjects. The adaptation paradigm coupled 0.25 Hz, 19 degrees/s vertical pitch vestibular rotations with 28 degrees/s horizontal optokinetic oscillations. Electro-oculographic recordings in the dark were taken at 0.05, 0.1, 0.25, 0.5, and 1 Hz pitch rotations before and after training and at 15-minute intervals during 0.25 Hz adaptation. Peak head velocity was kept at 19 degrees/sec for frequencies above 0.1 Hz, while constant amplitude was maintained at +/- 24 degrees for 0.05 and 0.1 Hz. In all subjects, directional training produced slow phase horizontal VOR eye movements that were not present during vertical rotations before adaptation. During the 2-hour training period, the cross-axis VOR gain at 0.25 Hz increased up to 0.16. Adaptive VOR gain was highest at the lowest frequency and reached a tuned peak at the 0.25 Hz training frequency. Cross-axis VOR phase remained around 0 degrees at higher frequencies and lagged at lower frequencies. In all subjects, the cross-axis VOR gain was diminished when subjects were exposed to 0.25 Hz pitch rotations paired with a stationary visual field. The dynamics of the vertical VOR remained constant throughout the experiment. These results are further evidence that the frequency response characteristics of adaptive cross-axis VOR gain are similar in humans and cats, while phase behavior is less complex in humans. The high adaptive gain at low frequencies implicates otolith contributions during cross-axis adaptation. PMID- 7850043 TI - Effects of head position on posture during altered visual and proprioceptive orientation: preliminary report. PMID- 7850042 TI - Comparison of different exercise programs in the rehabilitation of patients with chronic peripheral vestibular dysfunction. AB - The purpose of this study was to evaluate the effects of two exercise programs on balance performance in patients with chronic peripheral vestibular dysfunction and to assess whether these exercise programs induce adaptive modifications of the vestibulo-ocular reflex (VOR). Patients were randomly assigned to one of two groups. (1) Those in the Rehab (Reh) group (n = 11) received a comprehensive exercise program that consisted of balance retraining and goal-directed eye-head exercises under combinations of varied visual and somatosensory sensory conditions. Patients received 45-minute training sessions, three times per week for 12 weeks, and were instructed on a custom home exercise program. (2) Those in the Home group (n = 12) were instructed to perform the Cooksey-Cawthorne eye-head exercises at home, on a daily basis, for 12 weeks. In addition, after completion of the exercise program and a follow-up period, 7 of the participants in the Home group (here defined as the A group) chose to enter the Reh program (here defined as the B group). Balance performance was assessed by measuring the peak-to-peak magnitude and total amount of anterior-posterior body sway, and of horizontal (shear) ground reaction force during six test conditions, in which visual and somatosensory orientation cues were reduced or altered by rotation of the visual surround or support surface in proportion to the subject's sway, and in which vision was eliminated (eyes closed). The VOR response to step chair rotations of 60 degrees/s and 120 degrees/s, and the optokinetic reflex (OKN) response to 60 degrees/s constant velocity optokinetic stimuli were recorded. Left-right difference in VOR gain, VOR time constant, and OKN gain were determined. These tests were performed 1 day prior to start of treatment (TD 1), 6 weeks after start of treatment (TD 2), at the end of the 12-week treatment period (TD 3), and 5 months after end of treatment (TD 4). The findings revealed a significant improvement in standing balance performance under dynamic conditions for patients in the Reh program (Reh and B groups) but not for patients performing the eye head exercise (Home or A groups). Thus, even in patients with chronic vestibular dysfunction, compensation for the loss or disruption of peripheral vestibular inputs can be effectively induced by exercises that provide sensory feedback appropriate for behavioral changes involving sensory substitution or sensory motor reorganization.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7850044 TI - Long-term outcome of operative treatment of focal atrial tachycardia. AB - BACKGROUND: This study examined the long-term clinical outcome of patients with focal atrial tachycardia who were treated surgically. Focal atrial tachycardia is a relatively rare arrhythmia that is often difficult to control with conventional medical therapy. Therapeutic modalities are not well defined because of the scarcity of long-term data of treated patients, including pathologic findings. STUDY DESIGN: Nine patients, six men and three women, ranging in age from 16 to 50 years (mean of 34 +/- 14 years), underwent operative treatment for focal atrial tachycardia. The average rate of tachycardia was 167 +/- 22 beats per minute. All patients were treated with antiarrhythmic drugs (mean 2.9 drugs per patient). Concomitant operative procedures were performed upon four patients, including division of the accessory atrioventricular pathway for the Wolff Parkinson-White syndrome in two patients, plication of the right atrium for idiopathic right atrial dilatation in one patient, and a closure of the atrial septal defect in one patient. Focal ablation was performed in all instances. RESULTS: There was no early or late death nor postoperative complications. Atrial tachycardia disappeared and there were no episodes of recurrent tachycardia postoperatively during the mean follow-up period of 67 +/- 38 months. Histopathologic findings from four patients revealed a sinus node-like structure, diffuse chronic epimyocarditis, focal myocarditis, and fascicular disarray lesions. CONCLUSIONS: Excellent long-term result were obtained in patients with focal atrial tachycardia who were treated operatively. Early operative intervention is preferable before the occurrence of impaired ventricular function. From the histopathologic findings, operative therapy should be selected in patients with diffuse atrial lesions. PMID- 7850045 TI - The outcomes of elective laparoscopic and open cholecystectomies. AB - BACKGROUND: The demand for evidence of effectiveness for medical care has prompted the development of epidemiologic approaches to relating the outcomes of care to treatment. This study compares the outcomes of care for patients undergoing the newly introduced laparoscopic cholecystectomy with the results from conventional open cholecystectomies. METHODS: Consecutive cases of elective cholecystectomy from 35 hospitals (all of the metropolitan and selected rural hospitals in Minnesota) were enrolled in the study. Patients were interviewed on admission to establish baseline symptoms and functional status and to confirm risk factors. Their medical records were abstracted to yield information on risk factors, treatment, and hospital complications. To establish outcomes, patients were sent a questionnaire about their symptoms and functional status six months postoperatively. RESULTS: Of 3,448 patients studied, 2,490 (72 percent) had a laparoscopic procedure, including 195 cases that were converted to open cholecystectomies. Functional status data were obtained on 2,481 cases (76 percent). Laparoscopic operation was associated with more operative complications (odds ratio 3.02, p < 0.001), but with fewer general complications (odds ratio 0.32, p < 0.001). The mean time to return to work was 15 days for laparoscopic cases compared to 31 days for open procedures (p < 0.001). The only functional outcome difference between the two procedures was that patients who underwent laparoscopic cholecystectomies were more likely than those with conventional cholecystectomies to be able to perform their usual activities at follow-up evaluation (p < .001). There was evidence of a learning curve; the more laparoscopic procedures a surgeon performed, the fewer the operative (p < 0.01) and general (p < 0.0001) complications. There was no indication that the availability of laparoscopic operation was associated with more operations being performed. CONCLUSIONS: Laparoscopic operation seems to represent a significant advance in getting patients back to a normal life sooner. More attention needs to be given to which patients are most likely to benefit from cholecystectomy of either type. Epidemiologic approaches can be useful in assessing the effectiveness of care. Partnerships between providers and researchers can produce useful effectiveness data by supplementing available clinical records with more detailed outcome data. PMID- 7850046 TI - Techniques in the composite reconstruction of extensive thoracoabdominal tumor resections. AB - BACKGROUND: This report illustrates the unique problems of reconstructing thoracoabdominal wall defects coexisting with diaphragmatic defects. STUDY DESIGN: Two patients with extensive primary chest wall tumors (chondrosarcoma and desmoid tumor) underwent aggressive resection of the hemithorax, hemidiaphragm, and anterior chest wall for cure. The combined chest and abdominal wall defect was greater than 625 cm2 in both cases. RESULTS: Functional restoration of these massive thoracoabdominal defects was accomplished by use of polypropylene-methyl methacrylate prostheses and vascularized tissue coverage. The requirements for rigidity, protection, and esthetic contouring of the chest wall are satisfied by this reconstruction. This technique also offers the flexibility and durability that the abdominal wall requires. Repair of the diaphragm using this technique is secure and simple. CONCLUSIONS: Our report confirms the principle that, with modern thoracic and plastic operative techniques, the extent of tumor resection should not be compromised because of concern over the ability to reconstruct the defect. PMID- 7850047 TI - Vaginal wall bipedicled flap and other techniques in complicated urethral diverticulum and urethrovaginal fistula. AB - BACKGROUND: Repair of a urethral diverticulum in females may be a rather simple operation or it may represent an operative challenge, depending on the site of the lesion and previous treatment. Thirty women operated upon during a 15-year period and with a variety of complicating factors, such as proximal location of diverticula or the presence of a urethrovaginal fistula, were reviewed. A new procedure using a transverse bipedicled vaginal flap to cover the urethral repair was used routinely. STUDY DESIGN: The long-term results were evaluated by clinical, endoscopic, and urodynamic methods. A follow-up postal survey was obtained reporting the presence of urethral pain, incontinence, frequency of micturition, postoperative sexual complaints, and subsequent operations. RESULTS: Repeated operations were rather common. The end result of operative repair was satisfactory in all but three patients, two of whom underwent multiple operations (four and seven times, respectively). These patients were left with residual symptoms of incontinence and recurrent urethral syndrome. However, the majority of patients who were operated upon repeatedly were cured. One patient who had impaired detrusor contractility had a relative urethral stricture. CONCLUSIONS: The successful treatment of complicated diverticula and fistula requires some basic technical steps during repair. When recurrence develops, it is important to interpret carefully urethral pressure profiles, cystometry, and other functional tests. PMID- 7850049 TI - Burn injury stimulates multiple proteolytic pathways in skeletal muscle, including the ubiquitin-energy-dependent pathway. AB - BACKGROUND: Burn injury is associated with increased muscle protein breakdown. However, the role of different intracellular proteolytic pathways in burn-induced muscle proteolysis is not known. STUDY DESIGN: A 30 percent total body surface area burn injury was inflicted on rats. Total and myofibrillar proteolysis was determined in incubated extensor digitorum longus muscles as release of tyrosine and 3-methylhistidine, respectively. Lysosomal proteolysis was assessed by using the lysosomotropic agents leupeptin and methylamine. Calcium-dependent proteolysis was determined by incubating muscles in the absence or presence of calcium or by blocking the calcium-dependent proteases calpain I and II. Energy dependent proteolysis was determined in muscles depleted of adenosine triphosphate (ATP) by 2-deoxyglucose and 2,4-dinitrophenol. Muscle ubiquitin messenger RNA (mRNA) was determined by Northern blot analysis to assess ATP ubiquitin-dependent proteolysis. RESULTS: Calcium-dependent total protein breakdown was stimulated in muscles from burned rats. However, the sensitivity to calcium in vitro was not increased after burn. The lysosomal and energy-dependent components of total protein breakdown were doubled in muscles from burned rats and the energy-dependent myofibrillar protein breakdown was increased almost seven-fold. Ubiquitin mRNA was increased in muscles from burned rats. CONCLUSIONS: Burn injury stimulates multiple proteolytic pathways in skeletal muscle. The ubiquitin-energy-dependent pathway may be particularly important for the breakdown of myofibrillar proteins. PMID- 7850050 TI - A technique for the use of cryosurgery to assist hepatic resection. AB - BACKGROUND: Wedge or other nonanatomic hepatic resections, performed in an attempt to spare functional parenchyma, often are not accomplished with clear resection margins and may be complicated by hemorrhage from the depth of the resection. STUDY DESIGN: The current study describes a technique of cryoassisted hepatic resection that allows for controlled resection with well-defined margins. The early experience in managing 16 tumors in 13 patients is reported. RESULTS: A cryoprobe is inserted into the tumor and freezing performed to a predetermined resection margin using ultrasound control. The ice ball, so formed, is then maintained and excised. The management of these 13 patients was associated with one intraoperative and two postoperative complications, including a death of a patient with cirrhosis who had infected ascites and died as a result of hepatic failure. CONCLUSIONS: Cryoassisted hepatic resection seems to be safe and allows resection with good tumor clearance and maximal preservation of functional parenchyma. PMID- 7850048 TI - The role of cefoxitin prophylaxis in chronic pilonidal sinus treated with excision and primary suture. AB - BACKGROUND: Treatment of chronic pilonidal sinus with excision and primary suture is followed by a relatively high proportion of wound infections. The role of preoperative antibiotic prophylaxis in improving results is not clear. STUDY DESIGN: One hundred fifty-three patients with chronic pilonidal sinus were operated on with radical excision and primary suture and randomized to receive a single dose antibiotic prophylaxis of 2 g cefoxitin intravenously (n = 78) or no prophylaxis (n = 75). RESULTS: The most common complications consisted of partial, slight separation of wound edges with slight discharge. In the group with cefoxitin, 34 patients (44 percent) had complications compared with 32 patients (43 percent) in the group without prophylaxis. Fifty-four patients (69 percent) healed within four weeks in the group with cefoxitin, whereas 48 (64 percent) healed within four weeks in the group without prophylaxis. After a follow-up period of six to 30 months, two patients in each group had not healed. Including these, two patients (3 percent) had recurrences in the group with cefoxitin and five patients (7 percent) in the group without prophylaxis (p = 0.41). CONCLUSIONS: The immediate and short-term results after excision and primary suture for chronic pilonidal sinus are not influenced significantly by a single dose prophylaxis of 2 g cefoxitin. PMID- 7850051 TI - Immediate transverse rectus abdominis musculocutaneous flap reconstruction after mastectomy. AB - BACKGROUND: This study examines the early and long-term outcomes of immediate transverse rectus abdominis musculocutaneous (TRAM) reconstruction of the breast after mastectomy. STUDY DESIGN: The records of all patients undergoing mastectomy and immediate TRAM breast reconstruction between December 1989 and October 1993 were reviewed retrospectively using hospital and breast care center databases. RESULTS: Fifty-three patients underwent a total of 73 immediate TRAM breast reconstructions. Reconstruction was successfully completed in all patients, using 46 pedicle flaps and 27 free tissue transfers. There were no flap losses or cardiopulmonary complications. Overall, the complication rate was 26 percent (29 percent for pedicle TRAM and 22 percent for free TRAM flaps). The median follow up period among the 53 patients was 22.6 months (range of three to 48 months). All patients employed preoperatively resumed their occupations postoperatively. CONCLUSIONS: Our experience indicates that immediate TRAM breast reconstruction is a safe and viable option for patients seeking reconstruction at the time of mastectomy. PMID- 7850052 TI - A rational approach to the use of hepatic transplantation in the treatment of metastatic neuroendocrine tumors. AB - BACKGROUND: Gastrointestinal neuroendocrine tumors are slow growing, and metastases are often limited to the liver. Whereas in asymptomatic patients, observation alone may be reasonable, in patients with neuroendocrine tumors and unresectable hepatic metastases, transplantation of the liver may be beneficial. We have developed a protocol in which patients with multiple hepatic metastases are initially treated with chemotherapy and embolization to control symptoms and inhibit tumor growth. Hepatic transplantation is reserved for patients in whom tumor progresses or symptoms of hormone production or mass effect persist. STUDY DESIGN: This is a retrospective review of eight patients with neuroendocrine tumor metastases who were referred to the Mount Sinai Hospital for evaluation for hepatic transplantation. RESULTS: Of the eight patients, three have undergone transplantation; all are alive, with no evidence of tumor recurrence at 12 to 30 months. In two patients, symptoms have been controlled by embolization of the hepatic artery or chemotherapy, or both; another has had massive hepatomegaly as a result of tumor progression, with wasting and portal hypertension, and currently awaits transplantation. Two patients died as a result of progressive disease, soon after referral. CONCLUSION: Transplantation of the liver may be an important treatment modality for a selected group of patients with neuroendocrine tumors unresponsive to conventional therapy. PMID- 7850053 TI - The role of pancreaticoduodenectomy for locally recurrent or metastatic carcinoma to the periampullary region. AB - BACKGROUND: The efficacy of operative resection of metastatic lesions to the liver, lung, and brain is well established. However, the appropriate management of metastatic or locally recurrent malignancies to the periampullary region is less well established. STUDY DESIGN: A retrospective review of The Johns Hopkins Hospital experience with pancreaticoduodenectomy for metastatic or locally recurrent periampullary lesions was performed. RESULTS: From 1988 to 1993, 27 patients with a past history of malignancy underwent pancreaticoduodenectomy. In six patients (22 percent), the lesion was determined to be from a metastasis or a local recurrence, and in 21 patients (78 percent), the lesion was a new primary. Patients with metastatic or locally recurrent lesions were younger (51.3 compared to 67.1 years of age) and presented with a shorter interval from their initial neoplasm (33 compared to 120 months). Of the six patients undergoing pancreaticoduodenectomy for a metastatic or locally recurrent lesion, three patients are alive an average of 38 months and three patients died an average of 11 months postoperatively. This compares favorably with the survival rate of the new primary group in which 12 patients are alive a mean of 22 months and nine patients died a mean of 14 months postoperatively. CONCLUSIONS: These results suggest that patients with metastatic or locally recurrent lesions in the periampullary region from a previously treated neoplasm should be considered candidates for pancreaticoduodenectomy. PMID- 7850054 TI - Biologic distinctions and therapeutic implications of sarcomatoid metaplasia of epithelial carcinoma of the breast. AB - BACKGROUND: Malignant sarcomatoid metaplasia of epithelial carcinoma of the breast (carcinosarcoma) is diagnosed at an annual rate of two cases per 107 women in the United States of America. It seems that these tumors behave differently than other carcinomas or sarcomas of the breast. STUDY DESIGN: The University of Texas M. D. Anderson Cancer Center experience (1947 to 1991) treating 50 patients (mean age of 50 years, range of 25 to 76 years) was retrospectively reviewed. The five-year overall survival and disease-free survival rates were compared and prognostic factors were identified. RESULTS: The overall survival rate of 43 percent was lower than had been expected for carcinoma of the breast. No patient with stage IV disease survived five years. Tumor size and stage at diagnosis had the strongest impact on outcome. The impact of axillary lymph node status on prognosis was less than expected. Hormonal receptor levels were positive in only 12.5 percent of the tumors tested. Mastectomy with adjuvant chemotherapy or radiotherapy, or both, was superior to mastectomy alone and to wide local excision with or without adjuvant therapy, particularly for patients with stage II disease. If complete surgical resection is possible, the surgical approach for treatment of recurrent disease is better than any other modality. CONCLUSIONS: Carcinosarcoma behave biologically differently than conventional carcinoma of the breast in that sarcomatoid characteristics dominate the clinical course. These biologic distinctions should direct the treatment toward a multimodality approach that includes mastectomy and sarcoma-oriented adjuvant chemotherapy and radiotherapy. PMID- 7850055 TI - Reclosure of the open abdomen. AB - BACKGROUND: The open abdomen technique for the treatment of diffuse peritonitis has gained acceptance. Our approach has been to use the zipper technique with daily irrigations. Once the abdominal problem has resolved, the mesh and zipper are removed. Surgeons are reluctant to reoperate on patients with such prior treatment because of the anticipation of a hostile abdomen. Our study is a retrospective review of 12 patients who were treated with the open abdomen technique. At a later date, they underwent elective reoperation. STUDY DESIGN: The charts of 12 patients were reviewed. After initial injury, the patients were in the surgical intensive care unit. Reoperations were performed nine months (mean) after discharge from this facility. The reasons for reoperation were closure of enteric fistula (five patients) and closure of an ostomy (seven patients). The abdominal wall was reconstructed in nine patients. In the other three patients, the abdomen was entered through a lateral incision and the bowel was reanastomosed. RESULTS: All of the patients survived. There were five complications. Two patients had ischemic skin grafts successfully treated by hyperbaric oxygen therapy (HBO). Two patients had ischemic skin flaps that were covering mesh. They responded to HBO with minimal slough of superficial tissue. One patient had a low output fistula that closed after two weeks of total parenteral nutrition. CONCLUSIONS: A history of an open abdomen is not a contraindication to later operation. Bowel continuity can be restored and abdominal wall reconstruction can be performed safely. This can be done as early as three to four months after recovery from the original injury. PMID- 7850056 TI - Emergency abdominal operations in the patient with acquired immunodeficiency syndrome. AB - BACKGROUND: We have previously shown high morbidity and mortality rates in patients with acquired immunodeficiency syndrome (AIDS) who require emergency abdominal operations. In a larger series of patients, we have investigated the reasons for these findings and have hypothesized that they are primarily the result of starvation and decreased resistance to infection. STUDY DESIGN: A retrospective review of the clinical records of patients at Montefiore Medical Center and its two associated municipal hospitals was done during a six year period. RESULTS: Postoperative morbidity and mortality rates of 50 and 38 percent, respectively, were documented and seem to be related to immunosuppression and the malnourished condition of these patients. CONCLUSIONS: Patients who meet the criteria for the diagnosis of AIDS have increased morbidity and mortality rates after emergency abdominal operations. This, however, should not exclude these patients from operation when it is indicated because many will survive and benefit from the operative procedure. Attention to nutritional support and the early diagnosis and treatment of associated infectious complications may result in decreased morbidity and mortality rates subsequent to the emergency abdominal operations. PMID- 7850057 TI - A prospective evaluation of CA15-3 in stage I carcinoma of the breast. AB - BACKGROUND: Carcinoma of the breast is characterized by a variable course with prognosis dependent on disease stage at presentation. Paradoxically, some patients with early malignancy demonstrate disease progression within a short time. The role of tumor markers in the management of carcinoma of the breast is controversial. While CA15-3 is the most widely used tumor marker in carcinoma of the breast, its role in the management of patients with early disease is controversial. STUDY DESIGN: Since 1986, all patients presenting to our unit with carcinoma of the breast have had serial CA15-3 levels measured. This study evaluates the role of serial CA15-3 levels in the management of a consecutive series of 168 patients with Stage I disease at presentation. RESULTS: The mean preoperative CA15-3 levels at presentation were significantly elevated in patients with Stage I disease compared with patients with benign disease. Sixteen patients had either locoregional (five patients) or metastatic recurrence (11 patients). CA15-3 levels were not elevated in patients with locoregional disease and were significantly elevated in patients with bony metastases and gave a mean lead time of 6.3 months over bone scintigraphy. CONCLUSIONS: Serial CA15-3 measurements are an efficient and cost-effective method of monitoring disease progression and have advantages over conventional investigations in patients with early carcinoma of the breast. PMID- 7850058 TI - Frequency, technical aspects, results, and indications of major hepatectomy after prolonged intra-arterial hepatic chemotherapy for initially unresectable hepatic tumors. AB - BACKGROUND: Major hepatectomy after prolonged intra-arterial hepatic chemotherapy (IAHC) is extremely rare, because IAHC usually fails to reduce the tumor volume sufficiently or obtain a long duration of response, or both, and because it impairs hepatic function. The present report was done to study the frequency, feasibility, and results of hepatectomy following IAHC. STUDY DESIGN: This retrospective study consisted of 14 patients treated with at least six courses of IAHC (mean of 17.6, median of 13, range of six to 48 courses) for hepatic tumors: colorectal metastases (n = 9), apudoma metastases (n = 4), and hepatoblastoma (n = 1). Systemic chemotherapy was associated in eight cases during (n = 5) or after (n = 3) IAHC. Initially, multiple hepatic tumors were unresectable in ten cases. They eventually became resectable, but were associated with extensive extrahepatic sites of involvement in four cases. All patients underwent curative major hepatectomy after a careful and specific morphologic and functional hepatic assessment. Right portal vein embolization was performed preoperatively upon three patients, resulting in 38, 44, and 77 percent hypertrophy of the left lobe before hepatectomy. Hepatectomy was also performed upon three patients with hepatic arterial thrombosis induced by IAHC, after a careful workup of the neoarteriovascularization of the liver. RESULTS: These 14 cases only represented 5.8 percent of the 239 patients in whom a catheter was inserted for IAHC, and 4.2 percent of the 335 patients who had hepatectomy for carcinoma. Postoperatively, there was no mortality and no clinical hepatic insufficiency. However, ten complications occurred in eight patients (three of them resulted in reoperation). Histologic examination revealed substantial modifications of the hepatic parenchyma because of IAHC. Results concerning survival were very encouraging: five of the nine patients with metastases of the colon and rectum are free of disease, with a mean follow-up period of 36 months after the beginning of IAHC. CONCLUSIONS: The decision to perform a major hepatectomy after prolonged IAHC is difficult and must be based on an output morphologic assessment with computed tomographic portography and a careful evaluation of functional liver impairment because of IAHC (the therapeutic strategy proposed by Makuuchi for hepatectomy in patients with cirrhosis, based on indocyanine green clearance and volume to resect, is very useful for this purpose). Hepatectomy is technically difficult to perform following IAHC because of a flabby parenchyma and unusually high pressure in the small central hepatic veins. This drawback is circumvented by using techniques, such as preoperative hypertrophy of the future remaining liver, a transparenchymatous approach of vasculobiliary structures, and intermittent clamping of the hepatic pedicle or vascular isolation of the liver. Postoperative complications occurred more frequently than after major hepatectomy in other clinical settings (p < 0.05). However, as this therapeutic approach greatly increases survival, it should not be neglected by clinicians, although indications for its use are very rare. PMID- 7850059 TI - Long-term outcome of operative treatment of focal atrial tachycardia. PMID- 7850060 TI - The outcomes of elective laparoscopic and open cholecystectomies. PMID- 7850061 TI - An inexpensive, quick, and easily learned technique for closure of abdominal trocar wounds after laparoscopy. PMID- 7850062 TI - A technique for full thickness closure of laparoscopic trocar sites. PMID- 7850063 TI - A simple endoscopic technique for nasoenteric feeding tube placement. PMID- 7850064 TI - Acute acalculous cholecystitis. PMID- 7850065 TI - Rationale for routine axillary dissection in carcinoma of the breast. PMID- 7850066 TI - Jass' classification revisited. PMID- 7850067 TI - Video-assisted thoracoscopic T2 sympathectomy for hyperhidrosis palmaris. PMID- 7850068 TI - Carcinomas of the breast with endocrine differentiation: a review. AB - The occurrence of endocrine differentiation in some mammary carcinomas seems well established, but pathologists continue to debate its significance. Contemporary thinking suggests that endocrine tumours of the breast do not constitute a single clinicopathological entity with a consistent histogenesis but rather that endocrine differentiation represents a pathway of neoplastic development available to a range of breast cancers. This pattern of differentiation occurs in tumours with vastly different morphological appearances, such as: ductal carcinoma in situ, mucinous carcinoma, a variant of lobular carcinoma, and low grade invasive ductal carcinoma. Although such tumours share some characteristics with intestinal endocrine neoplasms, the typical pattern of intestinal carcinoid virtually never occurs in mammary lesions. Conventional microscopy permits the diagnosis in most cases. Specialized techniques (histochemistry, immunohistochemistry, and electron microscopy) can serve as the basis for diagnosis in the absence of the appropriate morphological features. Although the system of nomenclature proposed by the World Health Organization for use with endocrine tumours in other organs can be used for endocrine tumours of the breast, only a minority of lesions will fit the established criteria. Most lesions are classifiable in the conventional categories of mammary carcinomas. No special prognostic significance is attached to these tumours at the present time. PMID- 7850069 TI - PIP/GCDFP-15 gene expression and apocrine differentiation in carcinomas of the breast. AB - The frequency and the significance of apocrine differentiation in carcinomas of the breast are uncertain, because of the lack of reliable and reproducible criteria for morphological diagnosis. The 15 kDa glycoprotein of cystic breast disease (GCDFP-15) is regarded as a specific functional marker of apocrine cells. Expression of the prolactin-inducible protein (PIP)/GCDFP-15 gene was investigated by Northern blot analysis and in situ hybridization in breast cancer cell lines and in an unselected series (33 cases) of primary carcinomas of the breast. On the same cases, histological assessment of apocrine differentiation and immunocytochemical detection of GCDFP-15 were also performed and correlated with follow-up data. The presence of PIP/GCDFP-15 mRNA was a feature of a relatively high number of cases, but was incompletely correlated with histological and immunocytochemical evidences of apocrine differentiation. Expression of the PIP/GCDFP-15 gene was significantly associated with relapse free survival, and may represent a novel variable of functional and prognostic relevance. PMID- 7850070 TI - Oxytocin inhibits proliferation of human breast cancer cell lines. AB - In this study we show that treatment of MDA-MB231 hormone-independent human breast cancer cells with oxytocin (OT) or with the OT analogue F314 induces significant growth inhibition together with a change in cell phenotype. In MCF7 and T47D human breast cancer cells, OT inhibits oestrogen-induced cell growth. In these same cells, OT administration significantly enhances the inhibitory effect of tamoxifen on cell proliferation. MDA-MB231, MCF7 and T47D cells all express mRNA specific for the OT receptor. These data suggest that it may be possible to inhibit breast cancer growth using OT and OT analogues. PMID- 7850071 TI - Characterization of human papillomavirus type 16 activity in separate biopsies from a carcinoma of the cervix uteri. AB - Human papillomavirus (HPV) 16-specific nucleic acid sequences were analysed in separate biopsies taken from a patient with a poorly differentiated squamous cell carcinoma of the uterine cervix. Biopsies were obtained from histopathologically normal epithelium adjacent to the carcinomatous epithelium, the primary carcinoma and a metastatic lymph node. Signals characterizing viral DNA and oncogene transcription were obviously differentiation dependent as shown by in situ hybridization of viral nucleic acids and immunofluorescence of epithelial differentiation specific proteins. In histologically normal parts of the epithelium viral DNA was amplified at the transition from basal to maturing cells, whereas E6/E7 genes were actively transcribed mainly in maturing epithelial cells following the basal cell layer. Some of the cells in the primary carcinoma and in the metastatic lymph node expressed involucrin at increased levels. Signals for viral DNA and HPV 16-specific E6/E7 transcripts decreased in intensity during differentiation in an inverse relationship to the observed involucrin increase in those cells. The absence of Ki67 in cells expressing large amounts of involucrin as revealed by immunostaining, support the inverse correlation between differentiation of cancer cells, HPV 16 replication and E6/E7 transcription. The changes in cytokine expression may indicate an HPV 16 associated disruption of normal cytokine expression pattern in the carcinoma. PMID- 7850073 TI - Immunohistochemical metallothionein expression in colorectal adenocarcinoma: correlation with tumour stage and patient survival. AB - Metallothioneins (MTs), a set of ubiquitous low-molecular-weight proteins essential for the protection of cells against heavy metal ion toxicity, were demonstrated immunohistochemically using a monoclonal antibody (E9) against a conserved epitope of I and II isoforms in a series of 109 colorectal adenocarcinomas. In a semiquantitative analysis strong MT expression in the majority of tumour cells was observed in 34 (31%) cases, 24 (22%) tumours showed a focal MT positivity, and 51 (47%) almost completely lacked MT expression. These differences in MT expression were statistically significantly (P < 0.05) associated with the tumour stage (Dukes classification) and the lymph node involvement at the time of operation (pN stages). However, in contrast to previous findings obtained on a variety of tumours, MT positivity was associated with a favourable clinical outcome in colonic carcinoma, which may indicate their different biological behaviour. Survival curves of cases with MT-positive and MT negative status differed from each other in a univariate analysis (Mantel Haenszel: 8.9, P < 0.05) but lost significance when a multivariate analysis was carried out by means of the Cox proportional regression model with Dukes' stages as a stratification factor. It is concluded that immunohistochemically demonstrated MT expression is significantly associated with tumour stages but does not represent an independent prognostic variable in colorectal cancer. However, it may provide important information about some of the biological mechanisms underlying progression in colorectal cancer. PMID- 7850072 TI - Expression of p53 protein in laryngeal squamous cell carcinoma and dysplasia: possible correlation with human papillomavirus infection and clinicopathological findings. AB - In order to evaluate the expression of p53 protein in 28 premalignant and 40 malignant squamous cell proliferations of the larynx and its relationship to tobacco consumption, human papillomavirus infection and differentiation grade of the lesions, p53 expression was examined by means of a microwave post-fixation immunohistochemical method using the PAb 240 and PAb 1801 monoclonal antibodies. HPV infection was assessed by non-isotopic in situ hybridization (NISH) and polymerase chain reaction (PCR). A large proportion of carcinomas (77.5%) and dysplasias (61%) expressed p53. No difference was found between differentiation grades of the lesions regarding p53 detection (P > 0.1), but moderate or intense p53 expression was more frequent in the carcinomas (P < 0.05). A statistical correlation was found between cigarette consumption and both p53 detection and p53 staining intensity (P < 0.05 in each case). HPV study revealed HPV 16 and 18 infection only in carcinomas. The frequency was 28% and the physical state of the virus as demonstrated by NISH was integration into the genome. We observed an inverse relationship between HPV infection and p53 expression (P = 0.006). Our findings suggest that p53 overexpression is a common and early event which increases in frequency with progression of laryngeal squamous cell carcinoma. The expression of p53 is influenced by tobacco and high-risk types of HPV. PMID- 7850074 TI - Angiocentric lymphoma with granulomatous panniculitis in the skin expressing natural killer cell and large granular T-cell phenotypes. AB - We investigated three patients suffering from angiocentric lymphoma with granulomatous panniculitis in the skin. All three patients presented with multiple purple subcutaneous nodules. Immunohistologically, the lymphoma cells in all three patients expressed CD2 (T-11), CD56 (neural cell adhesion molecule), and Mik-beta 1 (interleukin-2 beta receptor). CD3s (CD3, Leu-4)-positive lymphoma cells were found in two patients. A pore-forming protein (perforin) was detected in the lymphoma cells of all three patients. Perforin-possessing lymphoid cells were focally scattered in 2 of 15 patients with CD56-negative cutaneous lymphomas who served as controls. By the Southern blot method, one patient showed a rearranged T-cell receptor (TcR)beta gene in the biopsied specimen, and the other two patients had germ-line configurations of TcRs and immunoglobulin heavy chain genes. One patient had serum anti-human T-cell lymphotropic virus (HTLV)-I antibody, but showed no integration of its proviral DNA. Ultrastructurally, membrane-bound azurophilic granules were detected in the atypical lymphoid cells of all three patients. Angiocentric lymphoma with panniculitis in three patients showed the characteristics of natural killer and large granular T-cells. The histological features might be due to the characteristics of the neoplastic cells with azurophilic granules and perforin. PMID- 7850075 TI - "Varicoid change" of bile canaliculi in rat liver at an early phase of ischaemia reperfusion injury. AB - To elucidate early changes and the mechanism of ischaemia-reperfusion liver injury, we investigated three-dimensional microstructural changes of cellular actin filaments in rat livers using confocal laser scanning microscopy. The liver tissues of a reperfusion group were examined 12 h after removal of a vascular clamp. Fixed tissues were stained with fluorescein-labelled phalloidin to obtain stereoscopic images of the actin filaments and these were compared with histological findings. The images of bile canaliculi showed that multiple abnormal minute diverticula arose from the canalicular membranes and fused with one another, resulting in irregular dilation of the bile canaliculi. These changes were observed after 15 min of ischaemia and reperfusion in which no significant necrosis was seen. The frequency and degree of these changes were strictly dependent on the periods of ischaemia (15-60 min). We called these bile canacilular lesions "varicoid changes". The liver of an ischaemia group taken after persistent clamping without reperfusion did not show these changes. Our findings suggest that the varicoid change in the bile canaliculi is probably due to alterations in the actin polymerization-depolymerization cycle and is a pathognomonic change of ischaemia-reperfusion liver injury. PMID- 7850076 TI - Immunohistological detection of the beta subunit of prolyl 4-hydroxylase in rat and mini pig lungs with radiation-induced pulmonary fibrosis. AB - Polyclonal and monoclonal antibodies to the beta subunit of prolyl 4-hydroxylase, the protein disulphide isomerase, were used to compare the pulmonary cells in 13 normal and in 20 fibrotic rat and mini-pig lungs made fibrotic by X-ray irradiation, using the ABC immunoperoxidase technique. In normal lungs, prominent staining of Clara cells and type II pneumocytes and weaker reactivity with alveolar macrophages, fibroblasts, endothelial and smooth muscle cells were detectable. In pulmonary disease, in which interstitial fibrosis was the characteristic feature, the immunoreactivity was increased in both the epithelial and interstitial cells. Type I pneumocytes remained negative. In the early stages of disease (3 to 4 weeks after irradiation) when little morphological alteration was seen, capillary endothelial cells had already become immunoreactive. These results underline the complex involvement and interaction of different lung cell populations in the process of pulmonary fibrogenesis. PMID- 7850077 TI - Endothelial cell heterogeneity in experimentally-induced rabbit atherosclerosis. Demonstration of multinucleated giant endothelial cells by scanning electron microscopy and cell culture. AB - We investigated the aortic endothelial cells of cholesterol-fed rabbits, using scanning electron microscopy and a cell culture technique. Rabbits were given a 1% cholesterol diet intermittently for up to 40 weeks. In these animals, the area of endothelial cells was increased and the cells showed polymorphism in relation to the progression of atherosclerosis. In animals fed the cholesterol diet for 12, 28 and 40 weeks, the average area of the endothelial cells was 436 +/- 15, 762 +/- 153, and 836 +/- 165 microns2, respectively. In the cholesterol-fed 40 week group, in particular, giant endothelial cells, measuring more than 1200 microns2, accounted for 14% of the population. In animals fed a standard diet there was no significant difference in endothelial cell morphology between control 0-week and control 40-week groups; in both, the luminal surface of the thoracic aorta formed a homogeneous sheet covered by small rhomboidal endothelial cells, the area of most being less than 400 microns2. Primary cultured endothelial cells harvested from those control groups were mononuclear typical small cells with a centrally located nucleus; the proportion of binucleated cells was less than 2% and no multinucleated giant cells with three or more nuclei were detected. Endothelial cells from the cholesterol-fed groups, however, contained larger numbers of binucleated cells, with the number increasing in proportion to the duration of cholesterol feeding. The major distinguishing feature of the endothelial cells in the cholesterol-fed groups was the presence of multinucleated giant cells with three or more nuclei; these accounted for 2.3% and 3.3% of the total cell population in the cholesterol-fed 28- and 40-week groups, respectively. No bromodeoxyuridine uptake was found in the nuclei of the cultured multinucleated giant cells. Heterogeneity of endothelial cells, with the concomitant appearance of multinucleated giant cells, emerges with the progression of diet-induced atherosclerosis. The morphological alterations of endothelial cells observed in the present study intimately reflect changes in their function associated with the progression of atherosclerotic lesions. PMID- 7850078 TI - Solid variant of aneurysmal bone cyst: a case report with bilateral involvement of the distal femoral metaphyses. AB - An extremely rare case of bilateral, symmetrical involvement of distal femoral metaphyses by the solid variant of aneurysmal bone cyst (ABC) in a boy aged 13 years is described. Although there is no difference between the conventional ABC and the solid variant in terms of clinical and radiological presentation, the lesion is solid, composed of fibrohistiocytic cells with abundant giant cells and/or areas of florid, heterotopic ossification, while aneurysmal channels are sparse or absent. The lesion needs to be differentiated from giant cell tumour of bone, when the osteoclastic component predominates, while fibrous dysplasia, osteoblastoma and even osteosarcoma need to be excluded any time ossification is prominent. Careful evaluation of the clinical, radiological and pathological findings is necessary. PMID- 7850079 TI - Gaucher's disease, type I (adult type), with massive involvement of the kidneys and lungs. AB - A 33-year-old Japanese male, first diagnosed as having Gaucher's disease at the age of 3 years, died of renal and pulmonary failure. Autopsy findings disclosed the proliferation of Gaucher's cells in the liver, bone marrow, lymph nodes, kidneys and lungs. Electron-microscopical findings suggested that the Gaucher's cells observed in the renal glomeruli might be derived from circulating macrophages. PMID- 7850081 TI - [Sexuality at the hospital]. PMID- 7850080 TI - Leiomyomatosis with vascular invasion. A unified pathogenesis regarding leiomyoma with vascular microinvasion, benign metastasizing leiomyoma and intravenous leiomyomatosis. AB - Three uterine leiomyomas with vascular invasion (LWVI), two of which were associated with pulmonary leiomyomatous nodules, and a case of intravenous leiomyomatosis (IVL) invading the vena cava and extending to the right atrium, are described. Despite their histological benignity, these lesions have a strong tendency to metastasize and are closely related to the so-called benign metastasizing leiomyoma (BML). From a clinical point of view, the pulmonary nodules of LWVI are stable or slowly-growing. The IVL was a "worm-like" tumour that presented as a cardiac mass. On the basis of their histological and immunohistological features, a unified histogenetic view of LWVI, IVL and BML of the uterus is proposed. LWVI and BML may be the same pathological entity and microscopic vascular invasion may represent the metastatic mechanism of BML. Alternatively, LWVI may be the initial stage of IVL. In rare instances, IVL may be associated with distant parenchymal (pulmonary) metastases. LWVI seems to be the precursor of both BML and IVL. PMID- 7850082 TI - [Problems presented by sexuality in nursing care]. PMID- 7850083 TI - [What approach to sexuality for holistic nursing care?]. PMID- 7850085 TI - [The touching being]. PMID- 7850084 TI - [Relations between men and women in the hospital]. PMID- 7850086 TI - [Encounters with sexuality]. PMID- 7850087 TI - [Nursing education. Integration into the training course]. PMID- 7850088 TI - [Multidisciplinarity and nursing diagnosis. Partnership, limits and connections between the fields of exercise]. PMID- 7850089 TI - [Admission to training for nurses aides and pediatric nurses aides]. PMID- 7850090 TI - There's no going back--so, I've been forced to move forward. PMID- 7850091 TI - Who cares about nurses? PMID- 7850092 TI - Confrontation--if it's non-direct, it's ineffective! PMID- 7850093 TI - Revolution looks at clinical practice. Oppression--how nurses can overcome it. PMID- 7850094 TI - Revolution looks at education. The guide for true education--life experience. PMID- 7850095 TI - Putting nursing on the media map. PMID- 7850096 TI - Revolution looks at clinical practice made and betrayed in America: the experiences of a disabled nurse. PMID- 7850097 TI - Piece of mind meeting the challenges of change. PMID- 7850098 TI - Putting out fires. PMID- 7850099 TI - Healthcare reform: a revolutionary nursing perspective. PMID- 7850100 TI - Juggling--how nurses can keep everything going at once. PMID- 7850102 TI - Salary status and comp time--do they illegally take money out of your pocket? PMID- 7850103 TI - A caregiver's guide to personal growth & empowerment. PMID- 7850101 TI - Alaska: living a wilderness dream. PMID- 7850104 TI - We're staying in "the kitchen!". PMID- 7850105 TI - Nurses united can create change. PMID- 7850107 TI - Don't be a doormat: personal empowerment in nursing. PMID- 7850106 TI - Sisters helping sisters. PMID- 7850108 TI - Under the influence: the myth of professional codependency. PMID- 7850109 TI - What nurses need to know about legal, ethical, and political issues. PMID- 7850110 TI - Toxic encounters of the carcinogenic kind. PMID- 7850111 TI - PCAs & CTAs. Are they the beginning of the end for nursing? PMID- 7850112 TI - Nursing support of epilepsy self-management. AB - Self-management techniques for epilepsy can encompass any treatment or behavior that may enhance seizure control, minimize side effects and risks, promote adaptation, and enhance quality of life. Nursing support of self-management involves assessing a variety of factors, but, ultimately, nurses' promotion of responsibility and their offer of support and care may make the most difference in the success of any self-management approach. PMID- 7850113 TI - Epilepsy self-management: suggestions for lifestyle modifications. PMID- 7850114 TI - Nursing assessment of complex partial seizures. PMID- 7850116 TI - How to describe a seizure. A guide for patients and caregivers. PMID- 7850115 TI - Seizurelike phenomena in children and young adults. PMID- 7850117 TI - Homelessness and epilepsy: overcoming the barriers to health care. PMID- 7850118 TI - Epilepsy in the elderly. PMID- 7850119 TI - New-onset childhood seizures: parents' concerns and needs. PMID- 7850121 TI - [Care planning and nursing documentation]. PMID- 7850120 TI - [The nursing process as an instrument for the measurement of quality in the hospital. An active model for in hospital continuing education]. PMID- 7850122 TI - [An aid for home care. Easyslide: sliding instead of lifting]. PMID- 7850123 TI - [Burns and scalds in children. Their care causes great psychological and physical stress to patients and caregivers]. PMID- 7850124 TI - [Work in a hospice--report on experiences]. PMID- 7850125 TI - [The status of nursing personnel. Psychosomatics and cooperation in a general hospital]. PMID- 7850126 TI - [Psychohygiene. Self care in psychiatry]. PMID- 7850127 TI - [Fracture fixation with polyester. Primary care with polyester in selected forms of fractures]. PMID- 7850128 TI - [Organizational flaws. Better structuring will increase the nurses' motivation]. PMID- 7850129 TI - [Model "Integration Services". The integration of unemployed mentally disabled in the Bodensee-Upper Swabia region]. PMID- 7850130 TI - [Community psychiatry. The "incurable"--touchstone for community psychiatry]. PMID- 7850132 TI - [Care legislation. More protection for the ones concerned from the new care legislation?]. PMID- 7850131 TI - [Care of mental patients. The schizophrenic patient in the hospital and in a nursing home]. PMID- 7850134 TI - [Too many hospital infections]. PMID- 7850133 TI - [Hostility to foreigners. Model of conflict solving in nursing schools]. PMID- 7850135 TI - [Lump sum payments per case. There were no gray zones in the accounting]. PMID- 7850136 TI - [Liability legislation. Care and liability in pediatrics]. PMID- 7850137 TI - [The premature infant. Stimulation by stable parent-child contact]. PMID- 7850138 TI - [Diabetes and environmental protection. Modern aids for drug administration facilitate therapy]. PMID- 7850140 TI - [Wheelchairs fitted like tailor-made suits]. PMID- 7850139 TI - [Decubitus ulcer from a socio-medical viewpoint]. PMID- 7850141 TI - [Prevention of falls--a nursing task]. PMID- 7850142 TI - [Confirming the demented patient in his being]. PMID- 7850143 TI - [Quality of care--spirit of the age or chance?]. PMID- 7850144 TI - Prevention of coronary heart disease in 1994: evidence for intervention. PMID- 7850145 TI - Prevention of cardioembolic stroke. PMID- 7850146 TI - Hypertension and retinal vessels. PMID- 7850147 TI - Recognition, etiology, and clinical implications of pulsus bisferiens. PMID- 7850148 TI - The value of bedside examination in an era of high technology--Part 4. PMID- 7850149 TI - Thromboembolic complication of ascending aortic synthetic graft. PMID- 7850150 TI - Papillary fibroelastoma of the cardiac valves. PMID- 7850151 TI - Indications for external cardioversion/defibrillation. PMID- 7850152 TI - Indications for diagnostic tests in the evaluation of stroke. PMID- 7850153 TI - Positron emission tomographic imaging of the cardiovascular system: an emerging clinical tool. PMID- 7850154 TI - Treatment of patent ductus arteriosus. PMID- 7850155 TI - Indications for cardiac transplantation. PMID- 7850156 TI - Indications for surgical treatment of aortic valve stenosis. PMID- 7850157 TI - Left ventricular thromboembolism after myocardial infarction. PMID- 7850158 TI - Emotions and coronary heart disease. PMID- 7850159 TI - Recognition and management of valvular pulmonic stenosis. PMID- 7850160 TI - Mechanisms in current management of ventricular tachycardia in children. PMID- 7850161 TI - Diseases of the aortic root. PMID- 7850162 TI - Recognition and management of atrial septal defect. PMID- 7850163 TI - Cardiovascular complications of AIDS. PMID- 7850164 TI - Current management of supraventricular tachycardia in children. PMID- 7850165 TI - Coronary disease in elderly patients: myocardial infarction and myocardial revascularization. PMID- 7850166 TI - Guidelines for the management of patients with acute ischemic stroke: a synopsis. A Special Writing Group of the Stroke Council, American Heart Association. PMID- 7850167 TI - A test of the model-free formulas. Effects of anisotropic rotational diffusion and dimerization. AB - The effects of anisotropy of rotational diffusion and extent of dimerization on the performance of the simple and extended model-free formulas are investigated. Numerically exact 15N NMR R1, R2, and NOE data are simulated for cylindrically symmetric species and also for mixtures of spherical monomers and dimers with the same internal dynamics. The relevant internuclear vectors are assumed to move in isotropic deflection potentials fixed at different orientations in the molecule and to exhibit a single relaxation time in their internal correlation functions. The simple model-free formula is fitted to these simulated data in order to obtain the best-fit order parameter and internal relaxation time for each nucleus. Fitting is accomplished by the standard data-analysis protocol, in which a single common global correlation time is adjusted, and also by an alternative protocol, in which the global correlation time is adjusted separately for each nucleus. The extended model-free formula is likewise fitted to these same data. With noise-free data, the simple model-free formula and standard protocol yield remarkably good best-fit internal motion parameters up to moderate anisotropies (r = D parallel/D perpendicular = 2.0), but some or many of the NMR relaxation data are not fitted well even for quite modest anisotropies (r = 1.3). The extended model-free formula yields an improved fit to the NMR data, but predicts substantial amplitudes of nonexistent slow internal motions (tau approximately greater than 0.2 ns) for many of the nuclei for all r > or = 1.3. The simple model-free formula with the alternate protocol yields even better internal motion parameters than the standard protocol and also an excellent fit to the NMR relaxation data. The best-fit global correlation time for each nucleus corresponds very closely to the theoretical correlation time defined herein. Knowledge of these times would allow one not only to estimate the anisotropy of diffusion but also in favorable cases to infer the existence of slow internal motions. Inclusion of typical statistical errors in R1, R2, and NOE, or modest exchange contributions to R2, seriously degrades the performance of the simple model-free formula with either protocol, especially in regard to the internal relaxation times, which can exhibit very large deviations from their input value even for spherical diffusors. When the fraction of monomers existing as dimers lies in the range 0.1 < or = fd < or = 0.8, none of the three model-free approaches tested yields reliable internal motion parameters. PMID- 7850168 TI - Spectroscopic imaging of circular voxels with a two-dimensional Fourier-series window technique. AB - Spatial localization with the spectroscopic imaging technique is normally implemented with the Fourier-transform approach, yielding rectangular voxels, with potentially significant cross-voxel contamination. Multidimensional Fourier series window (FSW) is an alternate approach that generates single voxels of predetermined shape, with minimal out-of-voxel contamination. The spatial location of the voxel is shifted by means of postacquisition processing. A two dimensional circular voxel is introduced, which for many in vivo applications is a good match of the region of interest. Phantom images illustrate the spatial distribution of signal intensity within the circular FSW voxels. Phantom spectroscopic studies show excellent spatial localization, with no detectable out of-voxel contamination. The circular FSW voxel approach is implemented in human and animal model studies, demonstrating the technique's utility. This arbitrary shape approach can be extended to three dimensions, defining, for example, cylinders, spheres, or ellipsoids. PMID- 7850169 TI - Sensitivity optimization of echo times and data sampling times for spin-echo spectroscopy. PMID- 7850170 TI - Field dispersion in water-macromolecular proton magnetization transfer. PMID- 7850171 TI - Proton resonance assignments in oligosaccharides containing multiple monosaccharide residues of the same type. AB - A technique is described for assisting the resonance assignment process in oligosaccharide proton NMR spectra, where multiple residues of the same type generate extreme resonance overlap in the spectrum. The approach involves the modification of a conventional HOHAHA experiment with constant-time acquisition in t1, which effectively proton decouples the C-1 protons of residues whose resonances overlap, thus affording a significant increase in effective resolution in that dimension. For a sufficiently long spin-lock time, complete one dimensional subspectra are obtained essentially free of cross talk from adjacent resonances. Further simplification of the assignment process is illustrated by incorporation of the constant-time modification into a three-dimensional HOHAHA HOHAHA experiment. PMID- 7850172 TI - A relaxation-matrix analysis of distance-constraint ranges for NOEs in proteins at long mixing times. AB - Long-mixing-time data (tau m > 200 ms) from NOE spectra have largely been ignored as a source of protein structural information due to the effects of spin diffusion on calculated interproton distances when using the two-spin approximation. An effective approach for incorporating spin-diffusion effects in an average way into refinements is to choose distance bounds based on distributions of distances observed in NOE back calculations on homologous proteins from a protein structure database. We have determined distributions of interproton distances characteristic of newly observed NOE cross peaks for the proteins crambin, PTI, and echistatin at long mixing times. A relaxation-matrix analysis was used to model the effects of spin diffusion. Constraint ranges were constructed from the interproton distance distributions which can be used in standard protein-refinement programs based on the two-spin approximation. Back calculations are also used to analyze constraint ranges typically used for protein structure determinations based on NOE spectra at shorter mixing times. PMID- 7850173 TI - Spectral lineshape determination by self-deconvolution. AB - A data-processing method is described for the determination of spectral lineshapes using deconvolution of the data with an initial estimate of the same spectrum, referred to as self-deconvolution. The method is demonstrated using computer-simulation studies and experimental data, and is shown to accurately determine amplitude and phase lineshape distortions which may be caused by field inhomogeneity and gradient eddy-current effects. The results indicate that the method is robust in the presence of noise and errors in the initial spectral estimate. Once the spectral lineshape is determined it can be incorporated into a parametric spectral-analysis procedure, thereby reducing the number of parameters to be determined and improving the accuracy of the fit. A proposed application of the method is for spatially resolved in vivo NMR studies where local susceptibility effects and gradient eddy-current effects cause significant deviation of the spectral lineshape from a Lorentzian lineshape. PMID- 7850174 TI - Automated proton spectroscopic image processing. AB - An automatic data processing and display protocol for proton magnetic resonance spectroscopic imaging is described. The spectroscopic images are generated using the fitted peak areas of phased metabolite resonances using the Levenberg Marquardt algorithm. This automated spectroscopic image processing is tested and evaluated using phantom and human brain data. This algorithm is robust, simple to use, and minimizes user bias in processing and quantifying serial changes of metabolite levels in brain tissue. PMID- 7850175 TI - Position-dependent internal motions and effective correlation times for magnetization transfer in DNA. AB - An effective correlation time that accounts for position dependence of the combined local angular motions and collective twisting and bending deformations, as well as for anisotropic uniform rotation, is defined in terms of the magnetization-transfer rate and expressed in terms of molecular parameters. Application to measured magnetization-transfer rates from H6 to H5 of cytosine in cases where all other relevant data, including the uniform rotational diffusion coefficients, are known, suggests that the amplitude of local angular motion, as well as that due to collective deformations, is significantly greater for a penultimate base pair than for base pairs near the center of the molecule, and that such amplitudes might be approximately transferable from one molecule to another. Protocols are suggested for using estimated ratios of effective correlation times in the initial calibrations of internuclear distances and in the subsequent structure-refinement process. PMID- 7850176 TI - Water suppression in 1H MASS NMR spectra of lipids and biological membranes. PMID- 7850177 TI - Sequential backbone assignment in 13C-labeled DNA by the 1H, 13C, 31P triple resonance experiment, HCP-CCH-COSY. PMID- 7850178 TI - The impact of direct refinement against 13C alpha and 13C beta chemical shifts on protein structure determination by NMR. PMID- 7850179 TI - Simultaneous collection of two transverse 15N relaxation pathways in isotopically labeled proteins. PMID- 7850180 TI - Dynamic nuclear polarization with nitroxides dissolved in biological fluids. AB - The most widely used free radicals for dynamic nuclear polarization (DNP) experiments or related Overhauser imaging are nitroxides. The DNP parameters in biological fluids were measured in order to provide guidelines for the design of new nitroxides, adapted to the biological applications of DNP. Eighteen nitroxides were studied at a concentration of 1 mM. Extrapolation at complete electron paramagnetic resonance saturation and proton longitudinal-relaxation time measurements enable calculation of the coupling factor between nitroxide free electrons and water protons. In deoxygenated phosphate-buffered solutions, the NMR signal enhancement by DNP ranged from -36.3 to -6.7, and the coupling factor ranged from 0.31 to 0.03. Nitroxides with a long side chain yield poor enhancement, although their relaxivity is far greater than that of nitroxides with small chains. In a 1 mM albumin solution, the loss in enhancement factor is mainly caused by the fact that proton relaxation occurs via interactions, not only with the dissolved free radicals but also with the albumin macromolecules. In serum, the enhancement factor is lower than that in an albumin solution, because of the higher protein concentration in serum. In red-blood-cell suspensions, the enhancement factor was further decreased. Two effects contribute to this decrease: first, the increased viscosity due to the presence of red blood cells, and second, the susceptibility effects of the paramagnetism of deoxyhemoglobin. The high sensitivity to oxygen of DNP in phosphate-buffered solution is also greatly reduced when nitroxides are dissolved in blood.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7850181 TI - Tailored correlation spectroscopy for the enhancement of fingerprint cross peaks in peptides and proteins. AB - A new experimental mixing scheme for band-selective Hartmann-Hahn transfer between the HN and H alpha resonances of peptides and proteins is presented. This form of tailored correlation spectroscopy (TACSY) allows enhancement of the sensitivity of specific (HN-H alpha)-fingerprint signals compared to broadband TOCSY experiments. The design criteria as well as experimental applications of the multiple-pulse sequence CABBY-1 are presented. PMID- 7850182 TI - Development and optimization of three-dimensional spatial EPR imaging for biological organs and tissues. AB - The development and optimization procedures for obtaining high-quality three dimensional spatial electron-paramagnetic-resonance images of large lossy samples at L band are described. Strategies for selecting optimized parameters for projection acquisition, instrumentation, and algorithms for correcting drifts in microwave frequency and inaccuracies in the static and gradient magnetic fields are described. Image reconstruction was performed using a two-stage filtered back projection method with spectral deconvolution. With this instrumentation, correction algorithms, and image reconstruction method, spatially accurate 3D images of radical distribution were observed in complex phantoms using 0.5 mM nitroxide labels. The results indicate that high-quality images of lossy samples, including biological organs and tissues of up to 25 mm in size, could be obtained in a reasonable time with submillimeter resolution. PMID- 7850183 TI - Exact vs approximate methods for simulation of 3D NOE-NOE spectra. AB - An exact full matrix analysis of 2D NOESY spectroscopy has been extended to 3D homonuclear NOE-NOE spectroscopy and applied to the simulation of NOE-NOE spectra of the Dickerson dodecamer d(CGCGAATTCGCG)2 and a tandem GA mismatched decamer deoxynucleotide duplex d(CCAAGATTGG)2. The exact method has been compared with the approximation method based on Taylor expansions. It has been found that the approximations using one or two terms in the Taylor expansion series are generally inadequate for simulations of 3D NOE-NOE volumes and fail at very short mixing times, depending on the motional properties of the biomolecule in question. Specifically, the first-order approximation fails at tau c tau m > or = 1.8 x 10(-10) s2 for both the dodecamer and the decamer if an RMS error in the volumes of < 50% is desired. PMID- 7850184 TI - A hybrid-hybrid matrix method for 3D NOE-NOE data analysis. AB - A hybrid-hybrid matrix method is described that quantitatively analyzes 3D NOE NOE NMR data. Experimental 3D data are merged with simulated 3D data to create a hybrid 3D NOE-NOE spectrum. This is then deconvoluted into a 2D hybrid NOESY spectrum. The deconvoluted, 2D hybrid NOESY spectrum can then be merged with other 2D NOESY experimental data along with additional simulated 2D data as necessary to create a hybrid-hybrid 2D NOE volume matrix. This hybrid-hybrid volume matrix is then used with the complete relaxation program, MORASS, to calculate a rate matrix, and the resulting distances taken from the off-diagonal cross-relaxation rates can then be utilized in a distance geometry or restrained molecular-dynamics refinement of the structure. This process is repeated until a satisfactory agreement between the calculated and observed 3D volumes is obtained. This hybrid-hybrid matrix method retains computational efficiency and utilizes the resolution of the 3D data set while retaining any information content of the available 2D data. The initial tests of the deconvolution algorithm give high correlation results even with the introduction of random error into the 3D data set. Our results suggest that the hybrid-hybrid matrix method for analysis of 3D NOE-NOE spectra may provide a viable tool in the refinement of large molecules. PMID- 7850185 TI - Improved water suppression for localized in vivo 1H spectroscopy. PMID- 7850186 TI - Multidimensional NMR in lipid systems. Coherence transfer through J couplings under MAS. PMID- 7850188 TI - Identification of protein-mediated indirect NOE effects in a disaccharide-Fab' complex by transferred ROESY. PMID- 7850187 TI - Lipoprotein-lipid quantification by neural-network analysis of 1H NMR data from human blood plasma. PMID- 7850189 TI - [One world is ending, another is beginning]. PMID- 7850190 TI - [Control of onchocerciasis vectors in West Africa: description of the logistics adapted for a large-scale public health program]. AB - The Onchocerciasis Control Programme (OCP) in West Africa, launched in 1974, includes 11 participating countries and covers more than one million square kilometres. The aim of the OCP is to control blinding onchocerciasis (river blindness) which is caused by the savannah strain of Onchocerca volvulus transmitted by the Simulium damnosum complex. There is no effective macrofilaricide, so vector control to prevent the transmission of the parasite remains the method of choice, despite the availability of ivermectin, a drug which controls ocular morbidity. The potential value of vector control has been demonstrated by the original programme: 14 years activity has eliminated the disease as a public health problem in the areas included. This strategy requires adapted logistical support involving (i) widespread insecticide coverage (27,000 km of river are treated by the OCP during the rainy season), (ii) frequent (weekly) application of larvicide and (iii) prolonged intervention due to the life-span of the worm in the human reservoir, estimated to be approximately 14 years. We describe the vector control operations and their organisation 20 years after the initiation of the OCP. The OCP can be divided into 5 areas of logistic activity. The first covers activities involving insecticide and fuel management for the OCP as a whole: assessment of the requirements for the following year, ordering from insecticide and petrol suppliers, stocking fuel and insecticide at the depots covering the area. The second activity is the treatment of rivers with insecticide. This includes treating the ground with larvicide, the aerial operations run by an independent company supplying 12 helicopters on contract to the OCP, and use of satellite beacons for retransmitting of hydrological data. The third activity is monitoring the impact of larvicides on both the target (adult and larval S. damnosum) and on other fauna (fish, crustaceans and other insects). The fourth activity is field data collection and its processing. This involves a data transmission network to facilitate stock management insecticide application and entomological and hydrological surveillance using computer systems. The fifth activity is the coordination of vector control operations, technical and administrative staff and estimations of the funds available to the Vector Control Unit. The logistic aspects of other large-scale-insect-control programmes world-wide are considered, and the possibility of using the OCP as a model for such programmes (both public health and agricultural) is assessed. PMID- 7850191 TI - [Epidemiological surveillance and obstetrical dystocias surgery in Senegal]. AB - Maternal morbidity and mortality remain major problems of public health in developing countries. Having long been neglected, maternal health is now being included among the priorities of a large number of countries. The rate of maternal mortality in Senegal is 850 per 100,000 live births, among the highest in the world. The main causes of maternal mortality in Africa are obstructed labour and uterine rupture, hypertensive disorders of pregnancy, puerperal infection and haemorrhage. An epidemiological survey of obstetric disorders was initiated in 1992 in Senegal to characterise the requirements for surgical coverage during pregnancy and delivery. In 1992, the national rate of caesarean section was low (0.66% of estimated births). However, rates differed greatly between regions, and between rural and urban areas. The indications for caesarean section were classified into three groups, each corresponding to a different public health issue. The rate of maternal mortality associated with surgery was high: 4.7%, of which 29% during surgery and 71% post op. Perinatal prognosis was also poor, with a mortality rate of approximately 30%. There are only 18 reference obstetrics units functioning, and they give a very uneven coverage of the country. These finding have led to new guidelines to improve the quality and cover of maternal care over the coming years. PMID- 7850192 TI - [Pregnancies complicated by hemorrhage and birth of low birth weight infants in Cotonou (Benin)]. AB - The effect of bleeding during pregnancy on the outcome remains unclear. Nevertheless, some of these pregnancies go to term, raising the question of the effects on the new-born infant. The data concerning a possible correlation with low birth weight are ambiguous. Furthermore, there are few studies of this issue in developing countries. We studied 2168 women giving birth to single children chosen at random in two maternity services in Cotonou (Benin) in 1990. Data was collected by two trained midwives interviewing the women and from the medical files 24 hours after delivery. One hundred and thirty seven mothers (6.2%) reported bleeding during pregnancy. Multivariate statistical analysis indicated that this was associated with preterm birth of low birth weight infants: OR = 4.09 (2.2-7.6) for bleeding during the first trimester, OR = 2.29 (1.1-6.9) during the second and OR = 4.79 (2.1-11.9) during the third. Only bleeding during the third trimester correlated with a significant retardation of intrauterine growth [OR = 2.33 (1.4-7.3)] according to model fitting. Thus, despite possible bias in this retrospective study, bleeding during pregnancy appears to be a predictor of low birth weight in Cotonou (West Africa). PMID- 7850193 TI - [Bamako school age children and their diet from street vendors]. AB - Eating outside the home is very common in African cities. Food is bought from street vendors and eaten on the street. A large proportion of these consumers are school children, but little is known about what they buy, and the reasons why they make the choices they do. We therefore surveyed 494 second and sixth year primary school children in 1993. They were all enrolled at schools or Muslim colleges in both affluent and underprivileged areas of Bamako (Mali). The language used for the survey was Bambara. Almost all the children had money, mostly given by either or both of their parents and in most cases supplemented by odd jobs. The richest group of children were those in the sixth year in the more privileged areas. However, within a district or a (school) class, there was no correlation between the family's socio-economic group (SEG) and money available to the child. The proportions of children in each area, SEG and class buying the following classes of food were nearly identical; drinks, ice cream, groundnuts, fruit, cooked meals, uncooked meals, and sweets. The amount of money available correlated with the purchase of cooked or uncooked meals and drinks. The amount spent on food correlated with the money available, and the relationship is particularly clear for cooked and uncooked meals. The independence of the children in buying food represents a large part of the total daily food budget of the family. Their true diet and its nutritional value should therefore be quantified. Strategies targeting these children to help improve their diet would have a favorable effect on nutrition, because of their autonomy. Any such strategy should involve the street vendors so as to improve the quality of their products. PMID- 7850194 TI - [An innovative program for public health training at the University of Geneva. Program during employment centered on the student and oriented to the population's health needs]. AB - Switzerland's first Master degree course in public health was launched in the autumn of 1990 at the Geneva University School of Medicine. It is a 3 year, part time course, which is learner-centred and community-oriented. The aim of the course is to prepare students to use a multi-disciplinary approach to plan, implement and evaluate activities intended to solve public health problems. Throughout the course, studies plan, implement and evaluate projects concerning health problems they have encountered in their work as health professionals. The curriculum includes individual and group work, discussions and seminars with teachers and students, and brainstorming sessions with specially trained facilitators. The students can thus identify and fulfil individual educational objectives while working on community-related health projects. Priority health needs of individuals and communities are thus the pivotal points of the novel approach to public health training. PMID- 7850195 TI - [The sampan dwellers of the Vi Da district (Hue, 1993). Results of a survey preliminary to humanitarian aid intervention]. AB - This survey is a preliminary step in a cooperative health-care programme, run by the association Le Pelican. It was conducted in July 1993 among the sampan dwellers in the district of Vi Da (Hue), Vietnam. The People's Committee of the town of Hue hopes to improve the living conditions of the inhabitants of the district. The work of the association is part of a wider project of integrated cooperation (Cites unies developpement) for the community of sampan dwellers. The survey describes the demography, the state of children's health, the attitudes and behaviour of women and heads of the household towards maternity, contraception, disease and the health-care system. The Vi Da community is young: 40.5% of the inhabitants are under 15 years of age. The main health problems involve mothers and children: 56% of children aged between 5 and 59 months suffer from malnutrition; 71% of those between 0 and 15 years of age have never been vaccinated. The use of contraceptives is inadequate. Health-care services, however, are numerous and are mainly in the private sector. Any health-care project undertaken in this district to improve the state of children's health will have to reinforce the immunisation coverage and set up health education programmes dealing with nutrition and family planning. This will require a better knowledge of the mentality of the sampan dwellers, of their socio-cultural environment and their attitudes to illness and health-care. PMID- 7850196 TI - [Leishmaniasis and AIDS]. PMID- 7850197 TI - Balancing the drug-resistance equation. PMID- 7850198 TI - Origin and evolution of DNA associated with resistance to methicillin in staphylococci. AB - The gene mediating resistance to methicillin in staphylococci (mecA) and its flanking sequences (mec DNA) make up a chromosomal DNA locus that is unique to methicillin-resistant bacteria; no equivalent locus exists in methicillin susceptible cells. The origin of mec DNA is not known, but evidence supports horizontal transfer of mec DNA between different staphylococcal species and of the mecA gene between different Gram-positive genera. PMID- 7850199 TI - Resistance to aminoglycosides in Pseudomonas. Aminoglycoside Resistance Study Groups. AB - In a study involving 1996 isolates from approximately 143 hospitals in 27 countries, the incidence of multiple mechanisms of resistance to aminoglycosides in Pseudomonas species was much higher than in previous studies. The two most common single mechanisms of resistance [permeability and aminoglycoside acetyltransferase (6')-II] were also most commonly involved in multiple mechanisms. This incredible heterogeneity of mechanisms suggests continued and diverse selection pressures. PMID- 7850200 TI - Epidemiology of tetracycline-resistance determinants. AB - Resistance to tetracycline is generally due either to energy-dependent efflux of tetracycline or to protection of the bacterial ribosomes from the action of tetracycline. The genes that encode this resistance are normally acquired via transferable plasmids and/or transposons. Tet determinants have been found in a wide range of Gram-positive and Gram-negative bacteria and have reduced the effectiveness of therapy with tetracycline. PMID- 7850201 TI - Extrachromosomal resistance in gram-negative organisms: the evolution of beta lactamase. AB - beta-Lactamases are the major defense used by bacteria to overcome the effects of penicillins, cephalosporins and related beta-lactam antibiotics. In the antibiotic era, the enzymes have evolved to become more prevalent, to appear in new hosts, to be expressed at higher levels, to be acquired by plasmids and to change catalytic properties to increase affinity for what were meant to be nonhydrolysable substrates or to reduce affinity for beta-lactamase inhibitors. PMID- 7850202 TI - Origin and molecular epidemiology of penicillin-binding-protein-mediated resistance to beta-lactam antibiotics. AB - Resistance to beta-lactam antibiotics in some naturally transformable bacterial pathogens has arisen by interspecies recombinational events that have generated hybrid penicillin-binding proteins with reduced affinity for the antibiotics. This type of resistance is of particular concern in pneumococci, in which it is increasing worldwide. PMID- 7850203 TI - Detection and surveillance of antimicrobial resistance. AB - The clinical microbiology laboratory is strategically positioned to recognize changing patterns in bacterial resistance to antimicrobials. This requires the application of accurate testing methods and a methodological survey of drug resistance patterns among clinically important bacteria. This information can be assembled into comprehensive international databases, using a common format to facilitate monitoring. PMID- 7850205 TI - Benefit and risk in the beta-lactam antibiotic-resistance strategies of Streptococcus pneumoniae and Staphylococcus aureus. PMID- 7850204 TI - Molecular structures of penicillin-binding proteins and beta-lactamases. AB - In the past, new antibacterial agents have been selected either from natural sources or by 'trial and error' modification of existing antibacterials. Future therapeutic strategies are likely to depend on increased knowledge of existing drug targets and the search for new targets. The machinery for the assembly of bacterial-cell-wall peptidoglycan is an ideal place to look. PMID- 7850206 TI - Bacterial resistance to the cyclic glycopeptides. AB - Cyclic-glycopeptide antibiotics, such as vancomycin and teicoplanin, have been almost uniformly active against pathogenic Gram-positive bacteria since their discovery in the 1950s. Resistance is now emerging among enterococci and staphylococci by acquisition of novel genes or by mutation, respectively. The mechanism of resistance for enterococci appears to be synthesis of an altered cell-wall precursor with lower affinity for the antibiotics. PMID- 7850207 TI - Expression of resistance to methicillin. AB - Methicillin-resistant staphylococci have an additional low-affinity penicillin binding protein, PBP2a (PBP2'), encoded by the mecA gene. The typical heterogeneity seen in the expression of resistance to methicillin and in levels of resistance depends on the concerted action of chromosomally encoded genes, including fem and aux, that are also present in the genome of susceptible staphylococci. PMID- 7850208 TI - Molecular mechanisms of drug resistance in fungi. AB - Failures of treatment in fungal infections have drawn attention recently to the problem of antifungal resistance and its underlying mechanisms. The number of fungal isolates that are resistant to the orally active azole antifungals, especially fluconazole, is growing. Amphotericin-B-resistant isolates have been recovered during treatment of patients with candidiasis, and resistance to flucytosine is so common that this antifungal is no longer recommended as a single-drug therapy. PMID- 7850209 TI - Drug resistance in viruses. AB - The mechanisms of action of antiviral drugs and of drug resistance are known in remarkable detail, partly because X-ray crystallographic structures are known for many target viral proteins. Resistance usually involves amino acid substitutions in the target protein that prevent drug binding or prevent an enzyme from accepting the drug as a substrate. This information allows more effective use of available drugs and aids the development of new drugs. PMID- 7850210 TI - Microbial multidrug-resistance ABC transporters. AB - Multidrug resistance in tumor cells is often caused by the increased efflux of a wide variety of drugs, mediated by P glycoprotein, a member of the superfamily of ATP-binding cassette (ABC) transporters. The genes encoding members of this superfamily have also been isolated from drug-resistant microorganisms, and the role of microbial ABC transporters in drug resistance is being investigated. PMID- 7850211 TI - Mycobacterium tuberculosis: drug-resistance mechanisms. AB - Tuberculosis has resurged during the past decade in many industrialized countries, and strains of Mycobacterium tuberculosis that are resistant to one or more of the main antituberculous drugs are emerging. The molecular basis of mycobacterial drug resistance is now beginning to be understood. Resistance derives from mutations in chromosomal genes leading to overproduction, alteration or loss of the drug target. PMID- 7850212 TI - Resistance to drugs targeting protein synthesis in mycobacteria. AB - Many antibiotics exert their effects by interfering with protein synthesis. Studies of the molecular mechanisms of antibiotic resistance in clinical strains of mycobacteria have revealed mutations in ribosomal RNAs. This type of acquired resistance was previously unknown in bacterial pathogens and was made possible because mycobacteria have only a single set of rRNA genes. PMID- 7850213 TI - Antimicrobial resistance: prognosis for public health. AB - Antimicrobial resistance poses a significant threat to public health worldwide, with certain infections already being untreatable with antibiotics. Increasing resistance is resulting from antimicrobial use coupled with various epidemiological factors that enhance transmission of drug-resistant organisms, and the problem is likely to worsen. Control of antimicrobial resistance is feasible, but will be difficult. PMID- 7850214 TI - [Microbiological identification of coagulase-negative staphylococci and the present status of their sensitivity to antibiotics]. AB - Reliable laboratory diagnosis of coagulase-negative staphylococci and subsequent assessment of the MIC of these strains is part of the essential routine work of clinical laboratories with regard to the rising incidence of nosocomial coagulase negative staphylococci infections, in particular in specialized departments concerned with important clinical issues. PMID- 7850215 TI - [Drug resistance in M. tuberculosis in Prague 1987-1992]. AB - In 1987-1992 in Prague drug resistance of M. tuberculosis to four standard antituberculotics (isoniazide, streptomycin, rifampicin, ethambutol) was recorded in 39 patients, i.e. in 1.5-5% of patients with bacillary tuberculosis. Initial resistance was found in 25, secondary resistance in 13 subjects, in one patient both types of resistance were observed. In both groups men and patients born before 1941 predominated. In patients with initial resistance findings rated as small or medium-sized predominated, while in secondary resistance half the findings were medium-sized or extensive; an extrapulmonary form was recorded in one female patient. In the group of patients with an initially resistant M. tuberculosis monoresistant strains predominated and the highest ratio was accounted for by strains resistant to isoniazide; in patients with secondary resistance strains with combined resistance to two or more drugs predominated, however in all instances a combination of isoniazide with other antituberculotics was involved. With regard to the changing epidemiological situation as regards tuberculosis (in particular the arrested decline of the incidence of bacillary tuberculosis and the increase of drug resistance of M. tuberculosis), the authors recommend further monitoring and epidemiological analysis of the incidence of strains with initial and secondary resistance, systematic external checks of laboratory technique used for testing the sensitivity to antituberculotics and its centralization as well as the introduction of analyses of restrictive fragments of the DNA genome (RFLP method) to monitor the spread of tuberculous mycobacteria in the population. PMID- 7850216 TI - [External control of drug sensitivity determination in mycobacteriologic laboratories in the Czech Republic]. AB - In 1992 and 1993 an external control of sensitivity assessment of coded strains of M. tuberculosis to five basic antituberculotics was made: isoniazide, streptomycin, pyrazinamide, ethambutol and rifampicin. In 1992 from 11 participating laboratories an erroneous result was recorded in 9 (3 laboratories made two mistakes, 6 laboratories one mistake), two laboratories did not provide complete results. Unsatisfactory results were obtained during external controls in 1993. Of 15 participating laboratories four laboratories made one mistake, two laboratories two mistakes, four laboratories three mistakes. Five laboratories (i.e. one third) made more than three mistakes. Analysis of the results revealed a low reproductibility of results of drug sensitivity tests. To eliminate these shortcomings it will be necessary to make systematic external controls with subsequent solution of the shortcomings, restriction of the number of laboratories making these examinations to those who will systematically produce correct results. And it will be also necessary to test the sensitivity tests to antituberculotics in resistant strains in the National reference laboratory for mycobacteria. PMID- 7850217 TI - [Transstadial transmission of Francisella tularensis by Ixodes ricinus ticks infected during the nymphal stage]. AB - The degree of infection of nymphs of Ixodes ricinus which finished their feeding on experimentally infected mice on the day of their death from tularaemia represented more than 10(7) cells of Francisella tularensis per tick after feeding. The high degree of positivity was preserved in ticks also during one month of metamorphosis. Transstadial transmission of the agent from the stage of nymph to the stage of imago was confirmed in adults either by cultivation or by experiments attempting to transmit the infection to white mice, even after more than a year after infection of nymphs or more than a year after metamorphosis. Some of the ticks which did not transmit the infection while feeding were found to be positive subsequently. Results of quantitative examination of the degree of infection indicate also the possibility of reproduction of the agent in imagines after feeding on hosts. Incompletely engorged nymphs which fed repeatedly on mice after being collected from their host dead from tularaemia, were able to transmit the infection during interrupted feeding. Further possibilities of transmission were indicated by findings of consumption of infected ticks by hosts or by elimination of F. tularensis in faeces of infected nymphs and adults. PMID- 7850218 TI - [Defects in cellular immunity in patients with dermatophytosis]. AB - The authors examined in a group of 24 patients with epidermophytosis, refractory to general and local antimycotic treatment, persisting for 2-4 years, the immunity profile and compared the results with those in a group of healthy subjects. Epidermophytosis was diagnosed on the basis of the clinical picture, microscopic and cultivation examinations. The authors revealed in the patients with epidermophytosis a defect in the cellular immunity component, while there was no defect in the humoral component. They revealed also a shift in the proteins of the inflammatory phase which confirmed the long-term inflammatory process of the disease. In the conclusion the authors recommend to examine in patients with prolonged epidermophytosis refractory to general and local antimycotic treatment the immunological profile, and if there is a defect of cellular immunity despite antimycotic treatment to administer also immunostimulating preparations. PMID- 7850219 TI - [Geographic aspects in the epidemiology of multiple sclerosis]. AB - The Czech Republic is one of the countries with a high and heterogeneous prevalence of multiple sclerosis with the highest prevalence in the zone beneath the Ore Mountains (Krusne hory) and with a maximum in the territory of Teplice. The focus of the disease is consistent with the area with a generally higher health risk and polluted environment. The adverse exogenous component alters significantly immune mechanisms and participates in the provoking and trigger effect; however, its individual factors are difficult to identify as key or specific factors. It is assumed that global factors, long-term exposure and susceptibility of genetically predisposed subjects are involved. PMID- 7850220 TI - [Distribution of Salmonella typhimurium phage types isolated from various sources in the Slovak Republic 1992-1993]. AB - The author assessed phagotypes of Salmonella typhimurium strains isolated in 1992 and 1993 from patients with salmonellosis (n = 1,099) from foods (mainly home pig slaughtering) (n = 10), surface water (n = 1) and one case of a nosocomial infection. In the reference laboratory for phagotyping of Salmonellae a total of 1,111 strains were examined -376 in 1992 and 735 in 1993. During this period phagotypes 2b dominated (27.81%), 1 (26.28%) and 1 variant (25.02%), whereby in 1993 among the examined strains phagotypes 1 and 1 variant predominated (37% and 36.8% resp.). All strains isolated from foodstuffs in 1993 belonged to these two phagotypes. Types of 12.8% of the total number of examined strains could not be identified. PMID- 7850221 TI - [Indications for vaccination against invasive meningococcal disease in Olomouc]. AB - Problems connected with the decision about indication of vaccination in connection with the increase of invasive meningococcal disease are discussed. The epidemiological situation in the Olomouc district, where a local outbreak of invasive meningococcal diseases occurred, is briefly described and factors in favour of and against the indication of vaccination are discussed. PMID- 7850222 TI - [The new epidemiologic situation in the Czech Republic caused by the C:2a:P1.2 (P1.5) strain of meningococci]. AB - A new epidemiological situation for invasive meningococcal disease developed in the Czech Republic in 1993. The investigation of meningococcal noncapsular antigens revealed that the new strain Neisseria meningitidis C:2a:P1.2 (P1.5) is the causative agent. This strain has never been found in the Czech Republic before, at least not since 1973 (Czech meningococci have been sero/subtyped since). The investigation of the relationships by ET-typing revealed that this Neisseria meningitidis C:2a:P1.2 (P1.5) belongs to the ET-37 clone. In spring 1993 this new meningococcal clone caused an unusual increase of morbidity in two districts in one region of the Czech Republic and during the next winter/spring season (1993/1994) it spread to all regions of the country. This new strain causes severe and frequently atypical clinical manifestations, with the highest morbidity and fatality rates in the age group of 15-19 years (20% fatality in 1993). PMID- 7850223 TI - [150 years since the birth of R. Koch--his life and work]. AB - In December 1993 150 years have elapsed since the birth of Robert Koch. Koch began his research activities already as a rural physician. Later, from 1880 he worked in the Imperial Health Institute in Berlin, from 1885 he was as professor in charge of the Institute of Hygiene of the Medical Faculty of Berlin University. Greater opportunities for research were offered to him in the Institute for Infectious Diseases in Berlin. R. Koch laid the foundations of scientific microbiology, his activities were, however, also closely linked with epidemiology. His discoveries include evidence of B. anthracis, V. cholerae and in particular M. tuberculosis (1882). He studied also the etiology of wound infections. He enriched microbiology by new cultivation, staining and microscopic techniques, by using vapour during sterilization as well as investigations of the effect of new disinfectants. A major part of his research was devoted to tropical diseases which he studied during six expeditions. Koch was not only concerned with laboratory research, he implemented also many epidemiological field projects. Many scientists who later became famous worked with him. In 1905 Koch was awarded the Nobel Prize. R. Koch died on May 27, 1910. PMID- 7850224 TI - [Serologic detection of microbial diseases--present status and perspectives]. AB - The cost of serological diagnostic products amounts to more than a quarter of total laboratory material expenses. The major problem in serological diagnostics is correct interpretation of the presence of specific antibodies. Aspects influencing diagnostic conclusions drawn from serological finding include: 1. Features of infectious agents and pathogenesis of infection. 2. Principle of serological assay. 3. Condition of antigen used in the assay. 4. Individual reactivity of the patient. 5. Temporal data and data on the course of the disease. Modern serological methods such as ELISA and indirect immunofluorescence have, compared to classical techniques (i.e. complement fixation test, agglutination, immunoprecipitation and neutralization), a number of advantages. Nevertheless, they also have drawbacks of and classical methods should be used at least in selected cases for a number of years in future. Novel approaches such as immunoblotting, body fluid antibody detection, IgA and IgE determination and low avidity antibody detection are gaining importance and promise new insights. PMID- 7850225 TI - [Comparison of results of the fluorescent method in the determination of atherogenic lipids and the data of biochemical methods]. AB - Devices based on assessment of fluorescence of special "probes" incorporated in lipoprotein particles of the blood were developed at Research Institute of Physicochemical Medicine of the Ministry of Health of the Russian Federation. The resultant value is considered to reflect the sum of total cholesterol and triglycerides. The present study was aimed at elucidation of the relationship between the fluorescent and enzymatic methods, the enzymatic method realized by the Centrifikhem autoanalyzer. Coronary angiography during which blood for analysis by the two methods was collected was carried out in 182 patients aged 26 to 68 (mean age 49). Analysis of correlations revealed a direct relationship of the fluorescent value with the sum of total cholesterol and triglycerides, with triglycerides, with total cholesterol, and an inverse relationship with high density lipoproteins. Using multifactorial regression analysis, the level of fluorescent parameter could be predicted only on the basis of triglyceride level and ratio of total cholesterol to high-density lipoproteins. Using the linear regression equation it is possible, if the fluorescent parameter value is available, to calculate triglyceride level. No relationship of the fluorescent parameter or triglycerides with the dissemination of coronary atherosclerosis, which is characteristic of total cholesterol sum, was detected. PMID- 7850226 TI - [A method of determination of cholesterol contents on the surface of the human skin and prospects of its use. I. Atherosclerosis]. AB - Proceeding from published data on lipid content and composition in human skin and on the possible relationship between cholesterol level in skin biopsy specimens and status of blood vessels, the authors measured cholesterol content in skin layers available for external extraction in patients with atherosclerosis with different types of dyslipoproteinemias. Effective conditions of extraction were developed permitting after external rapid atraumatic treatment extraction of the maximally possible amount of cholesterol, 1.5 to 1.6 mkg from 1 cm2 of the palm skin surface, this being a constant value for each examinee (coefficient of variations after 3-4 repetitions 5%). Though slight, but statistically reliable increase of the amount of surface-extractable cholesterol was observed in atherosclerosis patients. This parameter did not correlate with the blood serum concentration of lipid components. A correlation (r = 0.54, p < 0.001) was observed with an only serum lipoprotein parameter, the so-called dyslipoproteinemia coefficient representing the sum of "atherogenic" parameters (cholesterol+triglycerides) divided by alpha-lipoprotein cholesterol. Measurements of surface-extractable skin cholesterol may be used as an available discriminant of atherosclerosis; the method seems to find application in other diseases as well. PMID- 7850227 TI - [A method of determination of cholesterol contents on the surface of the human skin and prospects of its use. II. Psoriasis]. AB - A noninvasive method for cholesterol extraction from the surface layers of the epidermis is suggested. Levels of cholesterol and its fractions were measured in extracts obtained from the foci of psoriasis and apparently intact skin of 105 patients with psoriasis. Cholesterol levels were found noticeably increased, mainly at the expense of its free fraction in involved foci and in apparently intact skin. A conclusion is made on the good informative value of the suggested method. PMID- 7850228 TI - [Use of the method of transcutaneous bilirubinometry in hyperbilirubinemia in the newborn]. PMID- 7850229 TI - [Molecular bases of the fluorescence method in the determination of binding capacity of serum albumin]. AB - A fluorescent method for assessment of albumin capacity to bind low-molecular metabolites, toxins, or drugs in blood serum, making use of fluorescent probe K 35, was recently suggested. The paper presents results of investigation of molecular basis of the method and of principles of interaction between fluorescent test molecules with albumin molecules in the blood serum. Molecules of fluorescent probe K-35 in blood serum plasma or serum are binding to albumin centers transporting low-molecular ligands (metabolites, toxins, drugs, etc.). Virtually the total intensity of K-35 fluorescence is due to the very molecules of the probe which are situated in these albumin centers. K-35 occupies two types of albumin centers, both of them equally contributing to total fluorescence intensity. Appearance of metabolites filling albumin centers and competing with K 35 probe results in reduction of the probe fluorescence. It is observed both in simulation experiments and in disease. It is possible that, besides the competitive mechanism, other mechanisms of blocking albumin centers in disease exist, to which K-35 is similarly sensitive. K-35 probe may be also used to measure effective albumin concentration. PMID- 7850230 TI - [Albumin binding capacity and blood lipids during the development of acute myocardial infarct]. AB - Excellent reproducibility of rapid fluorescent methods for assessment of cholesterol and triglycerides, effective and total concentrations of albumin permits monitoring these parameters over the course of development of acute myocardial infarction. Manifest changes of cholesterol and triglycerides and of albumin binding reserve estimated as the ratio of effective to total albumin concentrations multiplied by 100% were observed in acute myocardial infarction and even in a single anginal attack. Total albumin concentration changed on days 3-4 only in infarction. Time course of the parameters was related to the disease severity. PMID- 7850231 TI - [Correctness and reproducibility of the fluorescent method in the determination of mass concentration of human serum albumin]. AB - Intraseries reproducibility and correctness of measuring total concentration of albumin by fluorescent method in control sera, patients' sera, and in solutions of isolated albumin were under study. For comparison albumin concentrations in the same samples were measured by the bromocresol purple method. The characteristics of the fluorescent method were as follows: intraseries relative random error of a single measurement was 0.4%, relative mean quadratic deviation from declared values of albumin concentrations in control sera 2.9%, as shown by analysis of control sera and solutions of isolated albumin. Albumin liganding with nonesterified fatty acids did not change the results of measurements of total albumin concentration. Total error of the fluorescent method in analysis of patients' sera was 5%. Analytical characteristics of the fluorescent method are not inferior to those of bromocresol method. PMID- 7850232 TI - [Fluorescent method of determining mass concentration of human serum albumin]. AB - Fluorescent method for measuring mass (total) albumin concentration in human blood serum is suggested. Fluorophore K-35 previously suggested for measuring the effective concentration of albumin is recommended. Total albumin concentration is measured in acid pH range in the presence of nonionic detergent. Conditions under which the effects of factors impeding albumin assay virtually do not manifest were found. The resultant values of total albumin concentration coincide with the values determined by the bromocresol purple method. PMID- 7850233 TI - [The present and the future of noninvasive diagnosis]. PMID- 7850234 TI - [Effects of haloperidol therapy on dynamics of serum albumin binding capacity in patients with schizophrenia]. AB - Time course of blood serum albumin binding capacity was studied by the fluorescent method in schizophrenics, including those treated with haloperidol. Effective and total albumin concentrations were measured and binding reserve estimated, which was equal to ratio of effective to total albumin concentrations multiplied by 100%. Effective albumin concentrations and albumin binding reserve were found markedly reduced in the patients vs. healthy donors. Drastic changes of albumin binding reserve from one examination to another and a trend to increase of effective concentration of albumin were characteristic of patients administered haloperidol. In the patients administered no haloperidol albumin binding reserve was as a rule unchanged and effective albumin concentration had a trend to reduction. PMID- 7850235 TI - [Characteristics of the method and reagents in fluorescent determination of effective and total concentration of serum albumin]. AB - The characteristics of fluorescent essay of total and effective albumin concentrations by Zond-Albumin kit (experimental lot) were as follows: intraseries reproducibility in measurements not more than 1.6%, the error in serum dosage being mainly responsible for the total error. After unsealing the ampules the reagents may be stored at 5 degrees C for at least a week. Fluorescence intensity recorded in measurements in the majority of samples is stable for at least 50 min after addition of reagents. Measured values of total albumin concentration coincide with the results of measuring mass albumin concentration by bromocresol blue method, coefficient of linear correlation r = 0.98. PMID- 7850236 TI - [Methodology of bilirubin studies]. PMID- 7850237 TI - [Determination of hyaluronidase activity by the rivanol clot method]. AB - A method for hyaluronidase activity measurement in various biologic samples is suggested, based on rivanol capacity to form a clot with hyaluronic acid inversely proportional to this acid depolymerization under the effect of hyaluronidase. This method sensitivity is ten times higher than that of the mucin clot method; any colorimetric or fluorometric method can be used for detection. The method has been adapted to measurements of commercial hyaluronidase preparations and of blood serum hyaluronidase activity. PMID- 7850238 TI - [Urinary lactose determination]. AB - The authors suggests a modified method for nonchromatographic measurement of urinary lactose. The minimal detectable lactose volume is 0.5 g/l. Eighty-four children, mostly babies, with lactose intolerance were examined, breast-fed or formula-fed with lactose-containing mixtures. Lactosuria was detected in 27.4% of the examinees. Urinary lactose levels were (mean +/- m) 0.69 +/- 0.02 g/l. No lactosuria was detected by this method in 29 babies without lactose tolerance (control group). PMID- 7850239 TI - [Determination of uric acid in blood and urine by volt-amperometry]. PMID- 7850241 TI - [Method of storage and transportation of bacterial culture using paper disks]. AB - A method for bacterial culture storage and transportation is suggested consisting in impregnation of filter paper disks with broth culture and drying. Bacterial cultures can be stored in this mode for at least a year at 4 degrees C. PMID- 7850240 TI - [Bacteremia in patients at a cardiological clinic]. AB - The author analyzes the problems arising in the differential diagnosis of bacteremias in cardiovascular patients. He analyzes a relationship between infective endocarditis clinical symptoms and the presence of bacteremia. PMID- 7850242 TI - [Accreditation of clinical diagnosis laboratories]. PMID- 7850243 TI - [Outside control of the quality of coagulation studies]. PMID- 7850244 TI - [Necessity of structural changes in the system of training personnel for laboratory diagnosis]. PMID- 7850245 TI - [Erythrocyte sedimentation rate in clinical practice]. AB - Describes the principal mechanisms of red cell sedimentation rate in accordance with the available literature data. Characterizes the factors enhancing and inhibiting red cell sedimentation rate. Presents three methods for evaluation of red cell sedimentation rate: Panchenkov's micromethod, rapid method, and fractionated test. Discusses the most incident errors occurring in determination of red cell sedimentation rate and the clinico-diagnostic significance of this parameter in a number of diseases. PMID- 7850246 TI - [Noninvasive methods in the diagnosis of occupational diseases]. AB - Author's and reported data on the noninvasive methods used in the diagnosis of professional exposures and occupational diseases are reviewed. Noninvasive diagnostic methods include laboratory, physiological, morphological, allergological, etc. methods. Special attention is paid to laboratory methods. Urine, saliva, hairs, nails, teeth, exhaled air, bronchoalveolar lavage fluid, car wax can be used as biosubstrates in which inorganic and organic exogenic compounds, their metabolites or products forming as a result of xenobiotic interaction with cells or molecules of target organ are determined. The significance of laboratory methods for the diagnosis of occupational intoxications and detection of toxic substances in depot is discussed. PMID- 7850247 TI - [Diagnostic value of gas chromatographic study of exhaled air]. AB - The authors analyze the problem of collection and concentration of exhaled air samples and its gas chromatographic measurement. A simple method for collection, transportation, and gas chromatographic analysis of alveolar air is suggested. The results indicate changes in the alveolar air composition during various diseases. PMID- 7850248 TI - Use of probabilistic methods to understand the conservatism in California's approach to assessing health risks posed by air contaminants. AB - Many state and federal agencies have prepared risk assessment guidelines, which describe methods for quantifying health risks associated with exposure to vapors and particulates emitted from point and area sources (e.g., California Air Pollution Control Officers Association [CAPCOA] under the Air Toxics "Hot Spots" Act [Assembly Bill 2588] and the U.S. Environmental Protection Agency [EPA] under the Clean Air Act). In general, these guidelines recommend or require the use of upperbound "point" estimates for numerous exposure parameters. This methodology yields a single risk estimate, which is intended not to underestimate the true risk and may significantly overstate it. This paper describes a risk assessment of a facility's airborne emissions using a probabilistic approach, which presents a range and distribution of risk estimates rather than a single point estimate. The health risks to residents living near a food processing facility, as estimated using techniques recommended by California AB2588, are compared to the results of a probabilistic analysis. Polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) were identified as the emitted chemicals of concern. The point estimate method recommended by CAPCOA resulted in estimates that were greater than the 99.99th percentile risk predicted by the probabilistic analysis. As shown in other assessments of persistent airborne chemicals, secondary or indirect exposure pathways (i.e., ingestion of beef, ingestion of cow's milk, and ingestion of mother's milk) rather than inhalation, were the greatest contributors to risk. In this analysis, the probability distributions for the cancer potency factor and ingestion of cow's milk had the largest impact on the results of the 33 exposure factors considered. PMID- 7850249 TI - Formation of esterified fatty acids in rats administered 1-butanol and 1 pentanol. AB - The esterification of fatty acids by ethanol via a nonoxidative pathway has been well documented and has been implicated in toxic effects in animals and humans. The administration of 1-butanol (1 ml/kg, ip) to rats resulted in the formation of butyl esters of palmitate, stearate and oleate in the liver but not in measurable quantities in lung or pancreas. 1-Pentanol (amyl alcohol) administration (0.25 ml/kg, ip) did not result in esterification of fatty acids in any tissue. The data suggest that chain length may be important in the ability of alcohols to esterify fatty acids in vivo. PMID- 7850250 TI - A semi-micro method for fibrinogen determination essentially unaffected by turbidity. AB - A semi-micro method (BR BLUE) is presented using Coomassie Brilliant Blue G-250 color reagent for the determination of fibrinogen on potentially turbid specimens. It is compared with the reference Clauss method using the automated MLA Electra 1000C Automatic Coagulation Timer and the semi-automated Mechrolab Clot Timer. Correlation is excellent (r = 0.97). The BR BLUE method is also seen to be reasonably precise and linear. PMID- 7850251 TI - Enhanced expression of catalytic subunit isoform PP1 gamma 1 of protein phosphatase type 1 in malignant fibrous histiocytoma. AB - The expression of the three catalytic subunits of protein phosphatase (PP) type 1 and 2A, PP1 alpha, PP1 gamma 1, and PP2AC, was examined in malignant fibrous histiocytoma using immunohistochemical analysis. The percentage of cells stained positively with antiserum against PP1 catalytic subunit isoform PP1 gamma 1 was significantly higher in tumorous region than in non-tumorous region of malignant fibrous histiocytoma. Furthermore, tumorous region showed markedly high S-phase fraction in the cell cycle, as compared to non-tumorous region. These results suggest that PP1 gamma 1 is involved in the accelerated growth of tumor cells in malignant fibrous histiocytoma. PMID- 7850252 TI - Direct transfer of copper from metallothionein to superoxide dismutase: a possible mechanism for differential supply of Cu to SOD and ceruloplasmin in LEC rats. AB - Copper (Cu) and zinc (Zn)-binding superoxide dismutase (Cu,Zn-SOD) is synthesized always in a form of holo-protein in the liver of LEC rats, a genetically disordered mutant strain in Cu metabolism which accumulates Cu in a form bound to metallothionein (MT). On the other hand, ceruloplasmin (Cp) is synthesized in the liver and excreted into the blood plasma mostly as an apo-protein before the onset of acute hepatitis, and then holoform at the onset of jaundice. Thus, Cu is supplied differentially between Cp and SOD, and at different times, i.e., before and at the onset of acute hepatitis. Availability of Cu to apo-SOD was examined to explain the mechanisms for the differential supply of Cu among three different Cu forms; i) cuprous ion bound to glutathione, ii) free cupric ion, and iii) cuprous ion bound to MT. Cu was transferred to SOD from the three Cu complexes though MT-bound Cu was a less efficient Cu source to apo-SOD. The results indicate that SOD is always present in a holo-form in LEC rats because even MT bound Cu can be supplied to SOD, while Cp is present in an apo-form because Cu is sequestered to MT and not available in free ionic forms in LEC rats before the onset of acute hepatitis. PMID- 7850253 TI - Induction of metallothionein synthesis by bismuth in cultured vascular endothelial cells. AB - Metallothionein synthesis induced by bismuth nitrate was characterized using a cell culture system. It was found that bismuth (1-10 microM) significantly increased the intracellular accumulation of metallothionein in bovine aortic endothelial cells without an exhibition of cytotoxicity and a change of either general protein synthesis or proliferative DNA synthesis after a 24-h incubation. A low increase in the metallothionein accumulation was observed in bovine aortic smooth muscle cells; however, porcine kidney epithelial LLC-PK1 cells, human Chang liver cells and two human hepatoma cell lines (HLF cells and Hep-G2 cells) did not respond to bismuth. Other cations including cobalt, lead and zinc at 10 microM failed to induce metallothionein in endothelial cells, although cadmium at 1 microM was a strong inducer. Bismuth accumulated highly in endothelial cells but very slightly in LLC-PK1 cells and Chang liver cells. The present data suggest that bismuth is a selective inducer of metallothionein of vascular endothelial cells and this cell type particularly responds to the cation. PMID- 7850254 TI - Changes in ATP after cyclosporin A treatment in a renal epithelial cell line in the rat studied by 31P-NMR spectroscopy. AB - Experiments reported in this paper provide evidence that 31P-NMR spectroscopy can detect mitochondrial toxicity produced by cyclosporin A (CsA) in cultured rat renal cells cast in agarose threads. The effects observed in the normal rat kidney epithelial cell line NRK-52E include dose-dependent increases in the beta ATP signal at CsA concentrations from 2.5-25 micrograms/ml. At a CsA concentration of 100 micrograms/ml, there is a severe decrease in the beta-ATP signal with a concomitant increase in the inorganic phosphate (P(i)) signal. Effects observed in NRK-52E cells perfused with 100 micrograms/ml CsA mimic those previously observed by 31P-NMR spectroscopy using a surface coil over exposed kidneys of rats given chronic oral doses of 5 and 25 mg/kg/day CsA for periods of up to 90 days. These observations support the hypothesis that mitochondrial toxicity contributes to induction of CsA nephrotoxicity. PMID- 7850255 TI - Relationship between leukotriene B4 and prostaglandin I2 in patients with sepsis. AB - To examine the roles of leukotriene B4 (LTB4) and prostaglandin I2 (PGI2), the metabolites of arachidonic acid found in patients with sepsis, we measured the serum levels of LTB4 and a stable metabolite of PGI2, 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), in 22 patients with sepsis. Results were analyzed in relation to patients' survival. The serum levels of both LTB4 and 6-keto-PGF1 alpha were significantly higher in patients who died than in those who survived, thus serving as indicators of illness severity. There was a significant correlation between LTB4 and 6-keto-PGF1 alpha levels. The present study suggests that LTB4, a potent leukocyte activator, induces damage to vascular endothelial cells in patients with sepsis, resulting in the excessive production of PGI2 and, consequently, serious illness. PMID- 7850256 TI - Immunocytochemical localization of desferrioxamine in the kidney, liver and brain of the developing and adult mouse: implications for drug processing and therapeutic mechanisms. AB - The iron chelator, desferrioxamine, has been shown to interfere with hydroxyl radical formation, which mediates tissue damage in several disease states. In this study, young and adult mice were given intraperitoneal injections of desferrioxamine and sacrificed after 1, 24 or 72 hr, and adult rats were given intraventricular injections and sacrificed after 24 or 72 hr. Immunohistochemical experiments, that utilized an anti-desferrioxamine antiserum, were performed to localize the cellular distribution of the drug in the kidney, liver and brain. In the kidney, the findings were as follows: 1) at 0 days, there was heterogeneous distribution of desferrioxamine, which suggests that there are functional differences between nephrons in the immature kidney; 2) with increasing age, the degree of staining decreased, which suggests that the efficiency of renal clearance of desferrioxamine increases with maturity; 3) punctate staining was superimposed onto diffuse staining, which suggests that the drug can get taken up in pinocytotic vesicles during tubular reabsorption; and 4) staining was present at 72 hr, which suggests a prolonged clearance period. In the liver, there was an absence of staining at 24 and 72 hr and only diffuse staining at 1 hr, which suggests a rapid processing of the drug by the liver. In the normal mouse brain, the drug was found localized to the choroid plexus and ependymal cells at all ages, and the staining decreased with increasing time following injection. These results indicate that there are differences in the way that desferrioxamine is processed by cells in different tissues and indicate possible therapeutic mechanisms. PMID- 7850257 TI - Effect of S-carboxymethylcysteine lysine salt on mucociliary clearance in rabbits with secretory cell metaplasia. AB - A single intratracheal instillation of porcine pancreatic elastase (PPE, 100 U/Kg) induces in rabbits bronchial secretory cell metaplasia as well as emphysematous changes. The mucus hypersecretion and the marked reduction of ciliated cells matched by a high percentage of atypical cilia are responsible for the delayed mucociliary clearance in this model. S-Carboxymethylcysteine lysine salt (SCMC-LYS, 0.35 g/Kg b.w.), given per os daily for 10 days starting 2 days before elastase administration, significantly ameliorated the mucociliary clearance. The pharmacological treatment did not modify the degree of secretory cell metaplasia and the percentage of atypical cilia, or prevent the alveolar wall destruction. At TEM examination, the morphological aspects of secretion occurring in bronchial tree of PPE-treated animals were rarely visible in the PPE + SCMC-LYS treated group. The beneficial effect of SCMC-LYS on mucociliary clearance may be ascribed to an antisecretagogue effect of this drug through elastase inhibition and to a reduction of mucus viscosity. PMID- 7850258 TI - Effect of PAF-antagonists on aeroallergen-induced bronchial eosinophilia in guinea pigs: a therapeutic approach. AB - Aeroallergen-induced eosinophilia in actively sensitized guinea pigs was used as a marker of bronchial inflammation in this study. Drugs were administered p.o. therapeutically, i.e., four hours after aeroallergen challenge. Allergic bronchial eosinophilia in guinea pigs was sensitive to dexamethasone. Thus, the therapeutic approach appears to be a reliable, predictable, and sensitive for the evaluation and selection of potential bronchial anti-inflammatory compounds. PAF antagonists (WEB-2086, WEB-2170, and E-6123) and a 5-lipoxygenase inhibitor (E 6080) did not influence allergen-induced eosinophil infiltration in the bronchoalveolar lavage fluid. These observations seem to suggest that therapeutic administration of PAF antagonists and leukotriene synthesis inhibitors exert little or no inhibitory effect on the progression of late-phase allergic bronchial inflammation in this model. PMID- 7850259 TI - Cerebral protective effects of VA-045, a novel apovincaminic acid derivative, in mice. AB - The cerebral protective effects of VA-045, a novel apovincaminic acid derivative, were investigated in mice under conditions of normobaric hypoxia, histotoxic anoxia by potassium cyanide (KCN), and complete ischemia. VA-045 and thyrotropin releasing hormone (TRH) showed a significant protective effect on normobaric hypoxia. The duration of action of the protective effect of VA-045 was longer than that of TRH. VA-045 but not TRH significantly prolonged the survival time following administration of KCN. VA-045 and TRH showed a positive effect on complete ischemia, and the duration of the protective effect of VA-045 was longer than that of TRH. Beneficial effects of VA-045 for treating cerebral hypoxia, anoxia and ischemia will be discussed. PMID- 7850260 TI - Combined testosterone treatment in pubertal and adult periods induces male specific acetohexamide reductase activity in liver microsomes of female rats. AB - The influence of testosterone treatment on acetohexamide reductase activities in liver microsomes and cytosol of female rats was examined. Acetohexamide reductase activity in liver microsomes was much lower in female rats than in male rats. Combined testosterone treatment in pubertal and adult periods induced male specific acetohexamide reductase activity in liver microsomes of female rats. However, testosterone treatment only during puberty or during adulthood was without effect. Testosterone secreted from the testes during puberty appeared to have a significant effect similar to neonatal imprinting in the induction of acetohexamide reductase activity in liver microsomes of female rats. The combined testosterone treatment, or testosterone treatment only during puberty or during adulthood had no effect on acetohexamide reductase activity in liver cytosol of female rats. PMID- 7850261 TI - Introduction to bone marrow transplant symposium held at the Albert Einstein Cancer Center at Bronx, NY, USA, March 23 to 25, 1994. PMID- 7850263 TI - Clinical outcome of peripheral blood stem cell support. AB - Two clinical results of peripheral blood stem cell support are commonly considered: (1) the effect on hematopoietic recovery and (2) the effect on the underlying malignancy. The dynamics of hematopoietic recovery after autologous bone marrow transplantation and after autologous peripheral blood stem cell transplantation in a clinical setting are similar if no exogenous cytokines are administered and the peripheral stem cells are collected while their numbers are not deliberately increased (mobilised). If mobilized peripheral stem cells are transplanted, hematopoietic recovery is accelerated. In some circumstances, patients who receive peripheral stem cell transplantation may experience an improved progression-free survival after high-dose therapy when compared with similar patients who receive autologous bone marrow transplantation. Explanations for such a survival advantage might include (1) a lower likelihood of occult tumor cells capable of restoring disease in peripheral stem cell autograft products than in bone marrow harvests, (2) a greater number of cytotoxic effector cells capable of destroying occult tumor cells in the peripheral stem cell collections than in bone marrow harvests, and (3) a different and advantageous pattern of immunologic recovery following autologous peripheral stem cell transplant compared to autologous bone marrow transplant. PMID- 7850262 TI - Update of results of autologous bone marrow transplantation in lymphoma. AB - A substantial proportion of patients with Hodgkin's disease and non-Hodgkin's lymphoma will fail to achieve a complete remission with initial chemotherapy or will relapse after attaining a complete remission. The results of conventional salvage chemotherapy regimens for these patients have been disappointing. This has led to the use of high-dose therapy regimens which can be administered with the use of hematopoietic rescue (bone marrow transplantation). The use of bone marrow transplantation for patients with relapsed and refractory lymphoma has increased rapidly. Data from the North American Autologous Bone Marrow Transplant Registry indicate that approximately 40% of autologous bone marrow transplants are being performed for patients with lymphoma. Several large series of transplantation for Hodgkin's disease and non-Hodgkin's lymphoma have been published in the last two years. The results of these series vary widely due to differences in patient selection and pre-transplant prognostic factors. Differences in supportive care and preparative regimens prior to transplant may also account for the wide range of outcomes reported after transplantation. Although these differences make it impossible to compare results of one series with another, it is clear that a significant proportion of patients can achieve long term disease free survival following high dose therapy with marrow transplantation. It is also important, however, to note that this form of therapy can be associated with substantial morbidity and mortality. Transplant-related mortality exceeds 20% in some series. However, greater experience, better patient selection, and advances in supportive care, such as hematopoietic growth factors, are allowing many institutions to perform transplantation with mortality rates under 5%. PMID- 7850264 TI - High-dose therapy with stem cell support in solid tumors. AB - We describe some issues of ongoing studies and results in metastatic and high risk breast cancer. Caution should be used to not over interpret the outcomes of these data given the patient selection. In other tumors with lesser developed studies, such as with ovarian cancer, non seminomatous germ cell tumors (NSGC), childhood sarcoma, melanoma and limited small cell carcinoma, promising outcomes in small phase II studies are identified and proposed or potential studies comparing high-dose therapy to conventional are outlined. High-dose therapy with either peripheral blood stem cell support (PBSC) or autologous bone marrow transplantation (ABMT) in Phase II studies on a diverse array of solid tumors shows exciting promise of long-term, disease-free survival. Comparative studies in early-stage patients are urgently needed to confirm these outcomes. PMID- 7850265 TI - Hemopoietic stem cells: sources and applications. AB - Classically hemopoietic stem cells to be used for transplantation or autologous reinfusion have been harvested from the bone marrow which has remained the major source of stem cells for allogeneic transplantation. However, pluripotent stem cells also circulate in peripheral blood under physiological conditions and can be "mobilized" to appear in very large numbers in peripheral blood by treatment with cytotoxic chemotherapy, hemopoietic growth factors, or both. These cells are now being used widely for autologous stem cell support. They have the advantage of very rapid hemopoietic reconstitution, thereby shortening the posttransplant period of pancytopenia. Fetal liver cells, another classic source of stem cells, are currently used only infrequently. However, there is a growing interest in the use of umbilical cord blood which is rich in stem cells and easily accessible. Cord blood stem cells have been used successfully for pediatric transplants even across major histocompatibility barriers. Technology has been developed which may permit sufficient in vitro expansion so that these cells can also be used for transplants in adults. Furthermore, there is evidence that these cells may be preferable to marrow or even mobilised peripheral blood stem cells for the purpose of gene transfer. PMID- 7850266 TI - Allogeneic marrow transplantation for chronic myeloid leukemia. PMID- 7850268 TI - Molecular heterogeneity in retinitis pigmentosa. More mutations. PMID- 7850267 TI - Bone marrow transplantation for acute lymphoblastic leukemia (ALL). AB - Advances in the treatment of childhood acute lymphoblastic leukemia (ALL) have been striking while results have been less impressive in adults who develop this disease. Obvious differences in a patient's ability to withstand cytotoxic therapy may account, in part, for these findings, but the biologic behaviour of the disease in the two age groups appears to be different; relapses are more frequent and cures less common in adults. In fact, age alone appears to be the most important prognostic factor in ALL. The demonstration of the efficacy of bone marrow transplantation in advanced disease as well as the marked improvements in supportive care and the development of effective high-dose cytotoxic preparative regimens, especially those which use total body irradiation, however, have paved the way for transplantation in first complete remission. Formerly, most adult ALL patients who underwent bone marrow transplant did so in relapse, or in second or subsequent remission. In most studies 40-50% of first remission adult patients attain long-term disease-free survival after allogeneic and autologous bone marrow transplant. Relapses are considerably higher in the autologous transplant group when compared to the allogeneic group, but the latter population may experience increased morbidity and mortality due to graft-versus-host disease and opportunistic infection. These differences may reflect the beneficial graft-versus-leukemia effect in the allograft as well as infusion of autologous leukemia cells in the autograft but neither transplant subtype appears superior. Compared to more conventional approaches, however, transplantation may offer improved disease-free survival, although patient selection appears to be significantly influence outcome. These many inherent biases must be noted when comparing markedly different approaches, e.g. transplant versus conventional therapy. The challenge of demonstrating which therapy is superior for adult ALL patients can only be addressed in a well designed, prospective, randomized trial. PMID- 7850269 TI - Thr4Lys rhodopsin mutation is associated with autosomal dominant retinitis pigmentosa of the cone-rod type in a small Dutch family. AB - A mother and daughter with autosomal dominant retinitis pigmentosa (adRP) were found to carry a cytosine-to-adenine transversion mutation at codon 4 of the rhodopsin gene. This mutation predicts a substitution of lysine for threonine at one of the glycosylation sites in the rhodopsin molecule (Thr4Lys). Both patients presented with a similar phenotype including a tigroid pattern of the posterior pole and a regional predilection for degenerative pigmentary changes in the inferior retina with corresponding visual field defects. The electroretinographic pattern was suggestive of RP of the cone-rod type. This report documents the clinical findings associated with this defined mutation of the rhodopsin gene. PMID- 7850270 TI - Autosomal dominant retinitis pigmentosa. A mutation in codon 181 (Glu-->Lys) of the rhodopsin gene in a Japanese family. AB - The PCR/restriction endonuclease digestion (RE) assay and PCR/SSCP analysis of the rhodopsin gene in 13 Japanese families with autosomal dominant retinitis pigmentosa (ad RP) revealed a G-A substitution of the first nucleotide of codon 181, replacing Glu (GAG) with Lys (AAG), in one family. The proband showed an early onset of symptoms in childhood with a diffuse loss of rod and cone function and a relatively good preservation of cone function, corresponding to the type with relatively rapid progression to blindness (type I category of ad RP). PMID- 7850271 TI - The blinding mechanisms of incontinentia pigmenti. AB - The ocular and cerebral abnormalities associated with incontinentia pigmenti, an X-linked dominant disease with characteristic cutaneous features, are far worse than the name would indicate. Although some patients have normal vision, total blindness or permanent visual deficiency may occur. Retinal vascular abnormalities, involving the periphery as well as the macula, appear to represent the primary disease process in the eye. Retinal detachment may then ensue, due to mechanisms that seem analogous to those of retinopathy of prematurity. Optic nerve atrophy and occipital lobe infarction are additional causes of severe visual dysfunction in some patients. For the first time, neonatal infarction of the macula is documented in this disease. The purpose of this report is to describe the visually disabling ocular and cerebral manifestations in five selected cases of incontinentia pigmenti. PMID- 7850272 TI - Wolfram syndrome. A report of four cases and review of the literature. AB - This is a report of four new cases of Wolfram syndrome in three families and a review of the literature. The ophthalmologic, urologic, otologic, psychiatric and endocrine findings of the syndrome are discussed as well as their pathophysiology. Two recent reports with features atypical of the Wolfram syndrome are discussed. The genetics of this syndrome are also discussed. PMID- 7850273 TI - A family with optic atrophy and congenital hearing loss. AB - A 37-year-old woman had optic atrophy in both eyes and low-tone hearing disturbance of both ears noted after 34 years of age. Her visual acuity was 0.5 in the right eye and 0.6 in the left. The visual fields of both eyes showed slight progressive concentric narrowing. Hearing loss was gradually progressive. Her 13-year-old daughter also had optic atrophy in both eyes and low-tone hearing loss in both ears after 11 years of age. Her visual acuity was 0.8 in the right eye and 1.0 in the left. Her visual fields showed slight concentric narrowing. She had enlarged blind spots in both eyes. The mother and her daughter had deuteranomaly. Family history showed that the father, one brother and three sisters of the mother had congenital hearing loss. No other cause for the optic nerve atrophy and hearing disturbance could be found except heredity. PMID- 7850274 TI - Genetic isolate and preserved para-arteriole retinal pigment epithelium. AB - Preserved para-arteriole retinal pigment epithelium (PPRPE) is an uncommon form of retinitis pigmentosa, with a very peculiar funduscopic appearance. To our knowledge no patient under age ten, affected by PPRPE, has been reported in the literature. The authors present here a seven-year-old boy, whose fundus examination is consistent with the diagnosis of PPRPE. The case report confirms that PPRPE starts early in childhood, and additionally supports the hypothesis of an autosomal recessive inheritance of this condition, since the proband's family lives in a 'genetic isolate'. PMID- 7850275 TI - Professor Geoffrey Duncan Chisholm. PMID- 7850276 TI - Leiomyoma of the spermatic cord. PMID- 7850277 TI - A ureteric stone in a child causing retention of urine. PMID- 7850278 TI - Renal actinomycosis complicated by renoduodenal fistula and diabetes mellitus. PMID- 7850279 TI - The importance of biopsy in primary testicular failure. PMID- 7850280 TI - Incomplete bladder duplication. PMID- 7850281 TI - Solitary testicular plasmacytoma. PMID- 7850282 TI - Koro presenting after prostatectomy in an elderly man. PMID- 7850283 TI - Renal arteriovenous malformation presenting as haematuria in pregnancy. PMID- 7850284 TI - Malakoplakia of the testis. PMID- 7850285 TI - Laptops, infertility and testicular cancer. PMID- 7850286 TI - Seminal vesicle cyst, renal agenesis and infertility. PMID- 7850287 TI - Gastric carcinoma presenting with testicular metastasis. PMID- 7850288 TI - Urinary incontinence due to unilateral vaginally ectopic single ureters. PMID- 7850289 TI - Destruction of the vesicoureteric plexus for the treatment of hypersensitive bladder disorders. PMID- 7850290 TI - Prognostic assessment of renal cell carcinoma. PMID- 7850291 TI - Metachronous torsion of the appendix testis. PMID- 7850292 TI - Erectile function following transurethral prostatectomy. AB - OBJECTIVE: To determine the true incidence and possible aetiology of impotence following transurethral prostatectomy. PATIENTS AND METHODS: Over a 9-month period 268 patients who were about to undergo transurethral prostatectomy were interviewed about their sexual function. Full details of each operation were recorded including size of prostate, operative time, grade of surgeon and the occurrence of capsular perforation. The interviews were repeated by letter or telephone 3 months after operation. RESULTS: Of the 268 men interviewed, 246 (91.8%) were suitable for inclusion in the study. Pre-operatively, 137 (55.7%) were fully potent, 43 (17.5%) could achieve a partial erection and 66 (26.8%) were impotent. Of the fully potent patients, 20 (14.6%) became partially potent and four (2.9%) became impotent post-operatively. Of those who were partially potent before operation, 16 (37.2%) became impotent post-operatively. Overall, the risk of impotence was 28.1% if the prostate capsule was breached at operation but only 10.0% if it was not (P < 0.01). CONCLUSION: In fully potent men the risk of impotence after transurethral prostatectomy is fairly low, but it is higher in men who already have a degree of erectile failure. The risk of impotence is related to the incidence of capsular perforation at the time of surgery. PMID- 7850293 TI - Radical radiotherapy for localized adenocarcinoma of the prostate. A report of 191 cases. AB - OBJECTIVE: To assess the results of radiotherapy in the treatment of localized prostate cancer. End points for assessment were survival, local control, development of metastases, and the toxicity of therapy. MATERIALS AND METHODS: The case notes of 191 patients who were treated with radical radiotherapy between 1982 and 1992 were reviewed. The pathology of 130 patients was reviewed by a single pathologist. A multivariate analysis was performed to identify significant prognostic factors with regard to survival and relapse. RESULTS: One-hundred and eighty-two patients were assessable. The minimum length of follow-up was one year (median = 40 months). The actuarial cause-specific 5 and 10 year survival rates were 63% and 35% respectively. Local progression occurred in 41% of patients with 37% developing metastases. Multivariate statistical analysis demonstrated that T stage and Gleason Score were significant predictors for survival. Late complications were usually mild, with only 4% developing serious bladder toxicity. CONCLUSION: Radical radiotherapy has a role in the curative treatment of prostate cancer. Survival is significantly related to T stage at the time of presentation, and to the Gleason Score of the tumour. Survival in this series was not as good as the best surgical series, but it is still not clear which patients should receive radiotherapy and which surgery as their primary management. PMID- 7850294 TI - Salvage radical prostatectomy in the management of locally recurrent prostate cancer after 125I implantation. AB - OBJECTIVE: To define the role of salvage prostatectomy in patients who have locally recurrent prostate cancer following pelvic lymph node dissection and 125I implantation. PATIENTS AND METHODS: Over 1000 patients underwent 125I implantation for localized prostate cancer at the Memorial Sloan Kettering Cancer Center between 1970 and 1986. Salvage radical prostatectomy was performed in a highly selected group of 10 patients with locally recurrent disease. RESULTS: Three of the 10 patients had organ-confined residual prostate cancer following salvage radical prostatectomy. The remaining seven patients had extra-prostatic disease including four patients with positive surgical margins. Two patients with organ-confined disease and one with extracapsular tumour had no evidence of locally recurrent or metastatic disease and continue to have undetectable prostate-specific antigen (PSA) levels at 50, 44, and 31 months following salvage radical prostatectomy. After a mean follow-up of 30 months, the remaining seven patients had a rising PSA level consistent with locally persistent and/or metastatic disease (median 5 ng/mL; range 1.0-144). This PSA elevation occurred within 20 months of salvage radical prostatectomy (median 6 months). Two of these patients developed clinically evident bone metastases. CONCLUSION: Salvage radical prostatectomy, although technically feasible in highly selected patients, should not be widely advocated as an effective treatment option for patients with locally recurrent prostate cancer after 125I implantation. PMID- 7850296 TI - Statistical power: a measure of the quality of a study. PMID- 7850295 TI - Quality of life 12 months after radical prostatectomy. AB - OBJECTIVE: To evaluate the impact of radical prostatectomy (RP) upon quality of life (QOL) in patients with prostate cancer. PATIENTS AND METHODS: Seventy-nine patients with prostate cancer were recruited to evaluate the impact of RP upon QOL. The patients comprised two groups: the first group (n = 51) was evaluated 12 months or longer after RP; and the second group (n = 28) was evaluated 1 month prior to RP. All patients completed two previously reported QOL measures: the Functional Living Index Cancer (FLIC) and Profile of Mood States (POMS), and a series of questions which evaluated bladder, bowel and sexual function. RESULTS: Comparison of patients before RP with those after RP at 12 month follow-up revealed significant (P < 0.05) deterioration in sexual function, continence and hardship scores following RP while tension scores improved significantly. Although 10 other subscale parameters were analysed, no other differences were observed. Of the 51 post-RP patients, 46 (90%) stated that given a choice they would have their surgery again. CONCLUSION: The results reported show that RP has minimal overall impact upon patient QOL. Although minimal voiding and bowel dysfunction was reported, many patients were dissatisfied with post-operative sexual function. PMID- 7850297 TI - Magnetic resonance imaging for the diagnosis of prostate cancer metastatic to bone. AB - OBJECTIVE: To examine the role of magnetic resonance imaging (MRI) in the evaluation of osseous metastasis in patients with prostate cancer. PATIENTS AND METHODS: A series of 36 patients with known prostate cancer, who were undergoing MRI and an isotope bone scan, were studied. RESULTS: Of 19 positive bone scans, MRI was read as negative for metastasis in one. Of eight equivocal scans, two MR images were interpreted as positive and six as negative. Of nine negative scans MRI was positive in one. Further MRI demonstrated additional metastatic lesions that were not shown by bone scintigraphy in six patients. MRI clearly indicated the areas of spinal cord compression in five patients with spinal metastases and associated myelopathy. CONCLUSION: MRI is helpful in the diagnosis of metastatic prostate cancer, especially when other radiographic examinations are inconclusive or spinal cord compression is suspected. PMID- 7850298 TI - The long-term results of skin inlay urethroplasty. AB - OBJECTIVE: To report the results of a 10-year follow-up of 73 patients who underwent skin-inlay urethroplasty for the treatment of strictures that failed to respond to a trial of endoscopic surgery. PATIENTS AND METHODS: The 10 year follow-up of 48 patients with patch urethroplasties and 25 with tube urethroplasties of pedicled preputial, penile and scrotal skin is reported. RESULTS: The patients with patch urethroplasties tended to do well in the medium term whatever the source of skin, although there was a steady annual attrition rate after 4 years of about 5%/year requiring revision. The 25 patients with tube urethroplasties did less well, particularly those with scrotal skin tubes. The patients with preputial/penile tube urethroplasties did rather better but, in general, all these tube urethroplasties seem to narrow uniformly with time. Urethrotomy was never curative when a stricture recurred in relation to a urethroplasty. CONCLUSION: If the initial result is satisfactory, then patch urethroplasties tend to do well in the medium term whatever the source of the flap. No matter how good the initial result, scrotal skin tube urethroplasties do badly; preputial/penile skin performs better but tube urethroplasties tend to narrow down nonetheless. In the long term--more than 10 years--all skin inlays seem to have a tendency to deteriorate. PMID- 7850299 TI - Impotence following pelvic fracture urethral injury: incidence, aetiology and management. AB - OBJECTIVE: To evaluate the potency status of patients undergoing delayed perineal repair following a pelvic fracture urethral injury to determine the incidence and aetiology of impotence. PATIENTS AND METHODS: Long-term potency (> 6 months post operatively) was subjectively evaluated in 92 patients and correlated with their pre-operative and intra-operative findings. The management of their impotence was aso reviewed. Thirty original pelvic radiographs were assessed independently to determine if the pattern of bony injury was associated with the development of impotence. RESULTS: Fifty-seven patients (62%) remained impotent in the long term with a median follow-up of 48 months (range 12-128) and the operation did not render any potent patient impotent. Self-injection with vasoactive agents was successful in 24 of 27 (89%), suggesting a neurogenic aetiology in the majority. Bilateral pubic rami fracture was also associated with a high incidence of impotence. CONCLUSION: Disruption of the cavernosal nerves lateral to the prostatomembranous urethra behind the symphysis pubis is the most likely cause of impotence in this injury. PMID- 7850300 TI - The importance of accurate assessment and conservative management of the open bladder neck in patients with post-pelvic fracture membranous urethral distraction defects. AB - OBJECTIVE: To review the pre-operative assessment of bladder neck competence and assess the success of non-operative management of the bladder neck in patients with pelvic fracture membranous urethral distraction defects. PATIENTS AND METHODS: A series of four patients with long-standing post-pelvic fracture urethral distraction defects and open bladder necks demonstrated on pre-operative investigation are presented. RESULTS: All four patients were managed by perineal urethroplasty without surgery to the bladder neck. All patients were continent post-operatively despite the injury having ablated the distal sphincter mechanism. CONCLUSION: We believe that the majority of patients can be managed successfully by a non-operative approach to the bladder neck, sparing them the unnecessary operative morbidity of an abdomino-perineal repair, which should be reserved for those with obviously scarred or distorted bladder necks. PMID- 7850301 TI - Anti-bacterial activity of the fluid contents of spermatoceles and epididymal cysts. AB - OBJECTIVE: To show that the fluids obtained from spermatoceles and epididymal cysts are not infected, even though they may be present for long periods, and that these fluids have bactericidal activity. MATERIALS AND METHODS: Sixteen patients, 13 with a spermatocele and three with an epididymal cyst, were included in the study. Protein, glucose, chloride, inorganic phosphorus, calcium and magnesium contents were measured and cultures of the fluids were carried out. Bactericidal activity against the Escherichia coli NTCC 10418 clone was tested in different dilutions. RESULTS: Biochemical analysis showed that the protein, glucose and ionic content of the fluids was lower than that of serum, except for chloride. Microbiological cultures were negative for all samples. A significant bactericidal effect was obtained with 1/1 dilution and no reproduction was seen with this dilution. CONCLUSION: These findings indicate that the fluids within spermatoceles and epididymal cysts do not become infected under normal circumstances. PMID- 7850302 TI - Emphysematous pyelonephritis in diabetic patients. AB - OBJECTIVE: To determine the clinico-pathological profile of patients with emphysematous pyelonephritis (EPN). PATIENTS AND METHODS: The records of 22 diabetic patients who presented with EPN were reviewed. RESULTS: EPN occurred predominantly in female diabetic patients without evidence of ureteric obstruction. The ages of the patients and the duration of the diabetes were variable. EPN occurred in insulin-dependent as well as non-insulin-dependent patients. The patients presented following a prodromal illness of urinary sepsis, with an acute severe illness with symptoms and signs on the affected side. Dehydration and ketoacidosis were common. The diagnosis was made by recognizing gas in the kidney on an X-ray or ultrasound. Eighteen patients were subjected to emergency nephrectomy. CONCLUSIONS: EPN is an uncommon, life-threatening condition characterized by the production of intraparenchymal gas. We believe that vigorous resuscitation and emergency nephrectomy is the treatment of choice. PMID- 7850303 TI - Treatment of catheter-associated Candiduria with fluconazole irrigation. AB - OBJECTIVE: To examine the safety and efficacy of fluconazole in patients with a permanent nephrostomy or suprapubic catheter in the prevention of candiduria. PATIENTS AND METHODS: Twenty patients with a nephrostomy or suprapubic catheter who had at least two positive urine cultures with a minimum of 15,000 col/mL Candida counts were studied. The catheters were irrigated with fluconazole solution prepared as 1 mg/mL with normal saline. Repeated urine cultures were obtained. RESULTS: In 17 patients Candida was eradicated from the urine by the third to sixth day of irrigation. No side-effects were noted. CONCLUSION: Fluconazole as an irrigant is effective and safe in the treatment of catheter associated candiduria, which can be eliminated without changing the catheter. PMID- 7850304 TI - Absolute concentration of urinary endogenous beta-glucuronidase determined by an ELISA method as a sensitive but non-specific indicator for active renal parenchymal damage. AB - OBJECTIVE: To demonstrate that the absolute concentration, instead of the activity, of urinary endogenous beta-glucuronidase is a better indicator for active renal parenchymal damage. MATERIALS AND METHODS: Urine samples were obtained from 143 adult patients comprising 60 control subjects with no evidence of urinary tract disease and 83 patients with serum creatinine > 1.5 mg/dL. The absolute concentration of urinary endogenous beta-glucuronidase was determined by an enzyme-linked immunosorbant assay (ELISA) method recently developed by us. The maximal velocity of the enzyme was determined by the enzyme kinetic method. The bacterial beta-glucuronidase and bilirubin in the urine were also detected. RESULTS: The urinary beta-glucuronidase activity was affected by certain inhibitors (D-glucaro-1, 4-lactone), intrinsic substrates (conjugated bilirubin) and bacterial beta-glucuronidase present in the urine. Its concentration, determined by the ELISA method, was not interfered with by such factors. When those urine samples which were contaminated with bacteria and/or bilirubin were excluded, the beta-glucuronidase concentration (X ng/mumol creatinine) was significantly correlated with its maximal velocity (Y nmol/min/mumol creatinine): Y = 0.003 + 0.103X. Contrary to blood urea nitrogen, which increases with the increase in serum creatinine, the urinary beta-glucuronidase activity and its concentration reached a peak at a serum creatinine of 1.6-3.0 mg/dL and declined at higher serum creatinine levels. Episodic elevation of serum creatinine due to acute insult to the kidney or flare up of disease activity was often preceded by an increase in the level of urinary beta-glucuronidase. CONCLUSION: The absolute concentration of the urinary beta-glucuronidase was not affected by several factors in the urine which interfere with its activity, and was a sensitive indicator for renal parenchymal damage, particularly in the early stage when the disease is active. PMID- 7850305 TI - Clam enterocystoplasty and pregnancy. AB - OBJECTIVE: To assess the course and outcome of pregnancy in patients who have undergone clam enterocystoplasty. PATIENTS AND METHODS: A retrospective study was carried out of 19 pregnancies in 18 women aged from 21 to 36 years who had undergone clam enterocystoplasty. RESULTS: Urinary tract infection was common but renal function remained normal with prompt treatment with antibiotics. No other adverse antenatal factors were identified and all pregnancies had a normal fetal outcome. Vaginal delivery was a safer option for these patients, even in those who had undergone an anti-incontinence procedure in addition to enterocystoplasty. CONCLUSION: Careful antenatal monitoring by both an obstetrician and a urologist resulted in a successful pregnancy and vaginal delivery in these patients. PMID- 7850306 TI - The application of continent urinary stomas to bladder augmentation or replacement in the failed exstrophy reconstruction. AB - OBJECTIVE: To determine the application and success of continent urinary stomas in the failed bladder exstrophy reconstruction. PATIENTS AND METHODS: A total of 35 patients underwent construction of a continent urinary stoma during bladder replacement or bladder augmentation between 1987 and 1993. The continent stoma was constructed with appendix (19 patients), tapered ileum (2), Benchekroun (12), Indiana (1) and Mainz type stoma (1). RESULTS: Three patients required revision of their continent stoma, one for incontinence and two for difficulty in catheterization. Overall, 95% experienced daytime continence on an intermittent catheterization regimen, while 90% were dry at night. The upper tract remained normal in 34 of 35 patients. CONCLUSIONS: While the Benchekroun technique is reliable in producing continence, difficulty with catheterization has been a chronic problem due to stomal stenosis. Our positive experience with using the appendix as a catheterizable conduit into either the bladder template or bowel segment has led us to prefer this method of continent stoma construction in the patient with a failed exstrophy. In the absence of an appendix, our preference is a tapered ileal segment. The failed exstrophy reconstruction can be salvaged with a continent stoma and substitution or augmentation cystoplasty in most patients, thus avoiding urinary diversion. PMID- 7850307 TI - Written information for transurethral resection of the prostate--a national audit. AB - OBJECTIVES: To assess the use and content of written information relating to transurethral resection of the prostate (TURP). MATERIALS AND METHODS: All 328 full members of the British Association of Urological Surgeons (BAUS) were requested to submit any information sheets or specialized consent forms given to patients about to undergo TURP. They were asked to record when the information was given and whether this was recorded in the notes. The sheets were analysed with reference to a nominally comprehensive list of topics suitable for inclusion in such sheets. RESULTS: One-hundred and eleven replies were received (34%) which represents 44% of urological departments. Of those replying, only 56 used information sheets for TURP. The overall comprehensiveness of the information was surprisingly poor, with 12% omitting to mention retrograde ejaculation and 19% failing to discuss the need for a catheter. CONCLUSION: The written information given to patients about to undergo TURP appears inadequate. There is a need for a nationally accepted information sheet that can be edited locally. PMID- 7850308 TI - Clinical presentation and pathophysiology of meatal stenosis following circumcision. AB - OBJECTIVE: To describe the clinical presentation and pathophysiology of meatal stenosis occurring after circumcision. PATIENTS AND METHODS: The clinical presentation and operative findings are reported in 12 children who presented with meatal stenosis over a period of 3 years. RESULTS: The cardinal symptoms of meatal stenosis were penile pain at the initiation of micturition (12 of 12), narrow, high velocity stream (8 of 12) and the need to sit or stand back from the toilet bowl to urinate (6 of 12). Following surgical correction with meatotomy there was no recurrence of stenosis after a mean follow-up of 13 months. Traumatic meatitis of the unprotected post-circumcision urethral meatus and/or meatal ischaemia following damage to the frenular artery at circumcision are suggested as possible causes of meatal stenosis. CONCLUSION: Preservation of the frenular artery at circumcision, or the use of an alternative procedure (preputial plasty), may be advisable when foreskin surgery is required, to avoid meatal stenosis after circumcision. PMID- 7850309 TI - Distal penile hypospadias repair in children, with complete mobilization of pendulous urethra and triangular glandular flap. AB - OBJECTIVE: To present a technique for repair of distal hypospadias. PATIENTS AND METHODS: Sixteen children (average age 6.6 years) were treated between January 1985 and January 1991. The procedure is described. RESULTS: One child developed a mild meatal stenosis and another had a small urethral fistula; both responded to treatment. Results were excellent in the remaining 14 patients. CONCLUSION: This simple operative procedure was successful in the majority of patients and there were only two minor complications. PMID- 7850310 TI - Adult circumcision under local anaesthetic. PMID- 7850311 TI - The use of a single deep inferior epigastric artery (DIEA) myocutaneous flap for primary cover of large skin defects following bilateral groin dissection. PMID- 7850312 TI - Single-step procedure for the radical resection of an adenocarcinoma in the deep male urethra. PMID- 7850313 TI - Current status of the 'STING': an American perspective. PMID- 7850314 TI - Ten year experience with subureteric Teflon (polytetrafluoroethylene) injection (STING) in the treatment of vesico-ureteric reflux. PMID- 7850315 TI - Percutaneous cryosurgery for renal tumours. AB - OBJECTIVE: To evaluate the use of percutaneous cryosurgery in the treatment of renal tumours. MATERIALS AND METHODS: A cryoprobe using liquid nitrogen was designed. The tolerance of renal cancer cells to cooling was tested. Freezing tests on two extirpated kidneys involved with hypervascular tumour were performed in water at 40 degrees C. A clinical trial of percutaneous cryosurgery was carried out in two patients with advanced renal carcinoma. RESULTS: The cooling function of the new probe was similar to that of a conventional probe. The tolerance test on renal cancer cells showed that the cooling temperature should be below -20 degrees C to render them necrotic. Freezing tests on two nephrectomized kidneys with hypervascular renal cancer suggested that embolization of the renal artery might be advisable before treatment. The clinical trial in two patients with advanced renal carcinoma showed that the whole kidney, including the tumour, became necrotic and shrunken post operatively. The patients' Karnofsky performance scale showed a marked improvement 3 months after the operation, but their general condition gradually deteriorated. Patient 1 died 10 months and patient 2 died 5 months after the procedure. CONCLUSION: Percutaneous cryosurgery was performed successfully in two patients with hypervascular renal tumours. Cryo-immunological activity was assumed to have contributed to the temporary improvement in their condition. These results suggest that percutaneous cryosurgery might be useful as minimally invasive treatment in a limited number of patients with advanced renal carcinoma. PMID- 7850316 TI - Renal cell carcinoma extending into the vena cava: surgical approach, technique and results. AB - OBJECTIVE: To describe the technique and results of a thoraco-abdominal approach to removing the caval thombi in patients with renal cell carcinoma extending into the vena cava. PATIENTS AND METHODS: Between 1970 and 1990 35 patients presenting with renal cell carcinoma extending into the vena cava were treated at the Department of Urology, Innsbruck. Twenty-three of these patients underwent radical tumour nephrectomy including cavotomy and thrombectomy or caval resection. A transabdominal approach had been used in this department for radical tumour nephrectomy including cavotomy and thrombectomy or caval resection until 1987. Since 1988, a thoraco-abdominal approach has been employed. In group I patients the approach was via the seventh intercostal space, whereas in group II and III patients the thoraco-abdominal incision was made through the fifth intercostal space. In the present study the anatomy of the thoraco-abdominal approach is described. RESULTS: Tumour staging and grading yielded stage T3b in 15 patients (grade I, 1; grade II, 6; grade III, 8); another eight patients with stage T3b were found to have metastatic disease (N1, 6; N2, 2; M1, 3). On the basis of the extension of the caval thrombus the patients were classified as follows: group I, 16; group II, 3; group III, 4. In T3b N0 M0 patients the 5-year survival rate was 62.5%, while in patients with positive lymph nodes the mean survival rate was 15.5 months. CONCLUSION: Our results suggest that the thoracoa abdominal approach is the method of choice for the safe removal of renal cell carcinomas associated with caval thombi. If resection of the caval tumour is complete, prognosis is dependent on known factors, such as tumour invasion, nodal involvement and distant metastases rather than the extension of the tumour thrombus. An aggressive approach is not warranted in patients with nodal involvement and/or distant metastases, as it does not improve survival. PMID- 7850317 TI - The influence of age on treatment choice and survival in 735 patients with renal carcinoma. AB - OBJECTIVE: To determine whether age is related to treatment choice and survival in patients with renal carcinoma. PATIENTS AND METHODS: In this retrospective study 735 patients with renal carcinoma, diagnosed between 1982 and 1990 in one of the hospitals connected to the Rotterdam Cancer Registry, were evaluated with respect to treatment choice and survival. RESULTS: Nephrectomy was performed less often in elderly patients, both with and without distant metastases. The resection rate for patients aged 70 years and older was 63% against 82% for younger patients (P < 0.001). Crude 5-year survival rates for patients aged 20 59, 60-69 and 70+ were 54, 38 and 22% respectively. For patients with tumours restricted to the kidney (Robson stage 1), corrected survival rates were 80, 70 and 48% respectively. The overall post-operative mortality was 3.8% and was not related to age (P = 0.73). CONCLUSION: Treatment choice and outcome in patients with renal carcinoma were affected by age. As the proportion of patients aged 70 years and older, now 38%, will inevitably increase in the next decades, more attention is needed with respect to contra-indications for surgical treatment in the elderly. PMID- 7850318 TI - Bladder mast cell expression of high affinity oestrogen receptors in patients with interstitial cystitis. AB - OBJECTIVE: To investigate the role of oestrogens in the pathophysiology of interstitial cystitis (IC), specifically with respect to activated bladder mast cells (MC), as well as urine concentrations of MC-derived histamine and methylhistamine, all of which are increased in patients with IC. This goal appeared important because IC is a bladder disorder which occurs almost exclusively in women, and is characterized by polyuria, nocturia and pelvic pain, which worsen perimenstrually. PATIENTS AND METHODS: Biopsies from six patients with IC and four control patients were analysed blindly for the presence of oestrogen receptors (OR) using both custom-made and commercially available antibodies against OR. RESULTS: Bladder MC alone were shown to express high affinity OR and there was a higher number of such cells present in patients with IC compared with controls. The identity of MC in the bladder was documented with immunohistochemistry for tryptase. OR were also identified in human MC (HMC-1), a MC line kept in culture. These steps were necessary because of the unique finding that only MC express OR, in spite of the inflammatory infiltrate present. CONCLUSION: These findings may help to explain why IC occurs primarily in women, why IC and other associated symptoms tend to be worst at the midcycle, and may also suggest that prognostic usefulness of staining bladder biopsies for OR. These results are particularly interesting because oestradiol has been shown to augment MC histamine secretion in response to the neuropeptide, substance P, which may be released in certain neuroinflammatory disorders which have a high prevalence in women, such as IC and irritable bowel syndrome. PMID- 7850319 TI - Proliferating cell nuclear antigen cyclin in human transitional cell carcinoma. AB - OBJECTIVES: To confirm the value of the proliferating cell nuclear antigen (PCNA) labelling index in relation to histological grade, stage and prognosis. MATERIALS AND METHODS: Tissue specimens from 56 patients (49 men, 7 women; mean age 65 years [range 34-86]) with newly diagnosed transitional cell carcinoma of the urinary bladder were stained by an avidin-biotin peroxidase method using an anti PCNA monoclonal antibody. Immunohistochemical analysis was performed on ethanol fixed, paraffin-embedded tissue sections obtained by endoscopic biopsy or transurethral resection (TUR). The PCNA labelling index was determined by counting the number of PCNA-labelled cells in the tissue sections. RESULTS: Grade 1 tumours averaged 5.1 +/- 3.0% labelling versus 10.9 +/- 5.2% in grade 2 tumours, and grade 3 tumours had a PCNA labelling index of 21.8 +/- 10.4%. The average labelling indices for superficial tumour (37 patients) and invasive tumour (19 patients) were 7.5 +/- 5.3% and 20.8 +/- 10.0%, respectively. A distant metastatic bladder tumour showed an average labelling index of 42.3%. To analyse survival, tumours with PCNA indices above and below the median level (12%) were compared. Those patients with an index of < 12% (the mean of all of the PCNA values) had a worse prognosis than those with an index of > 12%. The mean PCNA labelling indices in recurrent and non-recurrent tumours were 6.4 +/- 0.7% and 8.2 +/- 1.7%, respectively, statistically not significant. CONCLUSION: The higher PCNA labelling index may indicate biological malignancy. These results suggest that measurement of the PCNA labelling index in bladder cancer may prove to be an objective and quantitative assay of biological aggressiveness and provide significant prognostic information, though it does not help to select patients at high risk of recurrence in superficial tumours. PMID- 7850320 TI - Spindle and giant cell carcinoma of the urinary bladder: a clinicopathological light microscopic and immunohistochemical study. AB - OBJECTIVE: To evaluate the cellular nature and biological behaviour of spindle and giant cell carcinoma (SGCC) of the urinary bladder. The clinicopathological, light microscopic and immunohistochemical features of seven patients are reported. PATIENTS AND METHODS: Paraffin-embedded tissue was available from each patient for microscopic and immunohistochemical studies. There were five men and two women, ranging in age from 48 to 79 years. Clinical histories and follow-up information were obtained by review of the patients' charts. The clinical outcome was compared with that of transitional cell carcinoma (TCC) and small cell carcinoma (SCC). RESULTS: The tumours were large, polypoid and frequently ulcerated. They diffusely permeated the bladder musculature or the perivesical fat. On microscopic examination five tumours were composed mainly of interlacing sheets of spindle cells and occasional giant cells; two comprised giant cells only. Foci of identifiable TCC (papillary or in situ) were present in four tumours. Immunohistochemistry demonstrated that SGCCs exhibit a phenotype indicative of an epithelial nature. CONCLUSIONS: The median survival (11 months) of the seven patients indicates that SGCCs have a poor prognosis and they are more aggressive than TCCs of the same stage. The unfavourable clinical course is similar to the rapidly fatal outcome of small cell carcinomas of the bladder. The prolonged survival periods of three patients who received additional chemotherapy suggest that this treatment may be profitable. PMID- 7850321 TI - Expression of retinoblastoma gene product and p53 protein in bladder carcinoma: correlation with Ki67 index. AB - OBJECTIVES: To determine whether loss of the tumour suppressor gene retinoblastoma (Rb) and increased expression of the p53 protein were associated with increased tumour cell growth fraction. PATIENTS AND METHODS: Tumours from 105 patients (72 men, 33 women; median age 69 years, range 35-89) with newly diagnosed primary transitional cell bladder carcinoma were studied. Tumour samples were taken by means of cystoscopic resection. Expression of the retinoblastoma (Rb) and p53 gene products was assessed immunohistochemically in 98 of the carcinomas. The proportion of cells expressing the Ki67 antigen (Ki67 index which is a measure of growth fraction) was determined in 64 cases. RESULTS: p53 protein was detectable in 50% and Rb protein in 82% of the tumours. Staining for p53 and lack of staining for Rb protein were associated with muscle-invasive growth and high tumour grade (G3). The Ki67 index varied over a wide range (1 47%), but there were significant differences between mean indices for poorly differentiated (G3) and well or moderately differentiated (G1/G2) tumours, and between indices for muscle-invasive and the remaining tumours. The mean Ki67 indices for Rb-negative tumours and p53-positive tumours were approximately twice those for Rb-positive and p53-negative tumours. Only 10% of the tumours expressed high levels of p53 protein and failed to express Rb. CONCLUSION: These observations are consistent with the hypothesis that loss of Rb and mutation and overexpression of p53 are associated with an increased tumour cell growth fraction and that such changes may play a role in the de-regulation of cell proliferation in transitional cell carcinoma of the bladder. PMID- 7850322 TI - Analysis of early failures after intravesical instillation therapy with bacille Calmette-Guerin for carcinoma in situ of the bladder. AB - OBJECTIVE: To analyse the clinical and therapeutic consequences of early treatment failure after bacille Calmette-Guerin (BCG) instillation therapy for carcinoma in situ of the bladder. PATIENTS AND METHODS: A total of 115 patients with carcinoma in situ (Tis) of the bladder were treated by intravesical instillation of living BCG vaccine (Immun BCG Pasteur F). Twenty five patients had primary Tis and 90 had secondary Tis with synchronous or prior superficial papillary tumours. All papillary tumours were resected before instillation of BCG. All patients completed one series of 6 weekly instillations of 120 mg BCG. RESULTS: Twenty-two of 25 patients (88%) with primary Tis responded completely, with negative cytology and cystoscopy findings within a median follow-up period of 44 months. Three of the 25 (12%) had cytological evidence of disease within 9 months of therapy and were considered to be early treatment failures. One patient had muscle-invasive bladder cancer, one had Tis and invasive cancer of the prostatic urethra, and the last, in whom a second BCG course also failed, had Tis of both ureters. Seventy of 90 patients (78%) with secondary Tis had a complete response after treatment with BCG, with repeated negative cytology and cystoscopy examinations within a median follow-up time of 40 months. Twenty of the 90 (22%) with secondary Tis had positive cytology within 9 months after BCG therapy and were considered early treatment failures. Five of these 20 had a cystectomy, three for persistent Tis of the bladder and two for a solid urothelial carcinoma of the prostate. The remaining 15 early failures received a second course of BCG. Four of these 15 patients responded and the remaining 11 failed the second course. The 11 failures included two patients with multifocal T1 G3 bladder cancers. four with invasive bladder cancer, two with solid urothelial carcinomas of the prostatic urethra, and three with Tis of the upper urinary tract. CONCLUSIONS: According to these data, early treatment failure after 6 weekly instillations of 120 mg Immun BCG Pasteur F is an alarming signal which requires immediate re-assessment of the patient to exclude a muscle-invasive bladder cancer or an extravesical carcinoma in situ, either in the upper urinary tract or in the prostatic urethra. PMID- 7850323 TI - Low-dose bacille Calmette-Guerin (BCG) therapy in superficial high-risk bladder cancer: a phase II study with the BCG strain Connaught Canada. AB - OBJECTIVE: To evaluate low-dose bacille Calmette-Guerin (BCG) therapy, with the Connaught Canada strain, in patients with superficial transitional cell carcinoma (STCC) of the urinary bladder. PATIENTS AND METHODS: Between September 1990 and December 1992 25 patients were entered into a phase II study to evaluate the feasibility, response and toxicity of BCG immunotherapy for patients with high risk STCC. Therapy consisted of six, weekly instillations of 27 mg (3 x 10(8) colony-forming units) of the BCG strain Connaught Canada. Maintenance therapy was administered monthly for 1 year with the same dosage. RESULTS: Of 25 eligible patients, 84% had complete responses after the initial cycle with low-dose BCG and had stable disease. Four patients had no response, three of whom subsequently underwent radical cystectomy. The mean length of follow-up was 30.8 months (25 36). Toxicity included profound local reactions such as severe dysuria, frequency and gross haematuria. No systemic infections, except fever, were seen; none of the patients needed isoniazid. All reactions were treated symptomatically. CONCLUSIONS: The results of this study suggest that low-dose BCG with the strain Connaught Canada can be successfully used in the treatment of patients with high risk STCC. Toxicity was not reduced substantially by the lower dosage of BCG used. PMID- 7850324 TI - The persistence of bacille Calmette-Guerin in the bladder after intravesical treatment for bladder cancer. AB - OBJECTIVE: To determine the incidence of bacille Calmette-Guerin (BCG) bacilli persisting in the urinary tract of patients treated previously with intravesical BCG for carcinoma in situ or multiple Ta.T1 transitional cell carcinoma. PATIENTS AND METHODS: One-hundred and twenty-five patients were treated at the Freeman Hospital, Newcastle upon Tyne, UK over an 8-year period, 90 of whom submitted early morning urine samples for culture for acid-fast bacilli at varying intervals following BCG treatment. The records of all patients were reviewed to determine the incidence of caseating granulomata containing acid-fast bacilli together with the incidence of toxicity and the outcome of treatment. RESULTS: Five patients were found to have persisting acid-fast mycobacteria in their urine or bladder up to 16.5 months after completing intravesical instillations of BCG. In one patient this probably accounted for bladder symptoms that required palliative cystectomy. In four patients the 'infection' was not severe. Two patients were treated with antituberculous chemotherapy without complication. Three years after intravesical BCG therapy 36 of 69 patients (52%) had remained tumour free. CONCLUSION: BCG organisms can persist in the urinary tract for at least 16.5 months after the completion of intravesical BCG instillation therapy. PMID- 7850325 TI - Superficial bladder cancer: for how long should a tumour-free patient have check cystoscopies? AB - OBJECTIVE: To determine the probability of a patient with superficial bladder cancer developing a recurrent tumour after having remained tumour free for 2 or more years. PATIENTS AND METHODS: One-hundred and seventy-nine patients with Ta or T1 tumours at diagnosis, a minimum follow-up of 3 years and a minimum of 2 years remaining tumour free were identified. Thirteen patients had more than one episode that was eligible for inclusion and there were therefore 192 tumour-free episodes for analysis. Survival curves of the probability of being recurrence free against time were constructed for the whole group, for subgroups of Ta and T1 tumours and for subgroups with characteristics at diagnosis suggesting a good, intermediate and poor prognosis. RESULTS: The probability of a patient developing a recurrence after 2, 5 and 10 years of being tumour free was 43, 22 and 2% respectively. No patient had a recurrence after remaining tumour free for 12 years. No patient who had been tumour free for at least 2 years progressed to muscle invasion or metastases. There was no significant difference in the probability of recurrence between Ta and T1 tumours after 2 years of remaining tumour free. CONCLUSION: The optimum length of cystoscopic follow-up for patients with superficial bladder cancer is unknown, but patients continue to develop recurrences even after many years of being tumour free. If a patient is to discontinue cystoscopic follow-up, then alternative methods of assessment should be applied. PMID- 7850326 TI - Results of radiotherapy on ureteric obstruction in muscle-invasive bladder cancer. AB - OBJECTIVE: To evaluate the effect of radiotherapy on ureteric obstruction due to muscle-invasive bladder cancer. PATIENTS AND METHODS: Retrospective evaluation of the records of 574 patients with muscle-invasive bladder cancer revealed 90 patients (16%) with ureteric obstruction; the obstruction was bilateral in 24%. The effect of radiotherapy was assessed in 55 patients with 68 obstructed kidneys. Six patients with eight obstructed kidneys required percutaneous nephrostomy or ureteric catheters in addition to radiotherapy. RESULTS: Drainage improved in 20% of kidneys and the diverting catheter was withdrawn permanently in one (17%) of the diverted patients. The median survival was 11 months. Irradiation was followed by significant complications in 37 patients (67%). CONCLUSION: The results of this study raise doubts about the assumed beneficial effect of irradiation on ureteric obstruction due to muscle-invasive bladder cancer. The short median survival of 11 months confirms that ureteric obstruction is a poor prognostic factor in muscle-invasive bladder cancer. PMID- 7850327 TI - Health-related quality of life after cystectomy: bladder substitution compared with ileal conduit diversion. A questionnaire survey. AB - OBJECTIVE: To compare the health-related quality of life after bladder substitution with that following ileal conduit diversion. PATIENTS AND METHODS: Sixty-seven male patients with bladder cancer completed the questionnaire; 38 had undergone bladder substitution and 29 ileal conduit diversion; the median follow up was 1.0 year (range 0.5-3.0) and 4.8 years (range 1.1-15.2), respectively. Semi-structured qualitative interviews were conducted and analysed, and the questionnaire was developed based upon these results. RESULTS: Both day- and night-time urinary leakage occurred more frequently following bladder substitution (18% against 10%, and 21% against 3%). Nevertheless, urinary leakage affected conduit patients more severely and they scored higher on a leakage distress scale. Furthermore, 58% of the ileal conduit but only 21% of the bladder substitution patients gave urinary leakage as their main concern (P = 0.04). Ileal conduit patients did not retain their body image as well as those with bladder substitution. The frequency of both sexual and non-sexual physical contacts decreased in the majority of the conduit patients but only in a minority of the bladder substitute patients. Global satisfaction was high and similar in both groups. CONCLUSION: These results show that the health-related quality of life is retained to a higher degree after bladder substitution and supports the use of this procedure as the standard method of diversion after cystectomy for bladder cancer. PMID- 7850329 TI - Use of the rectus abdominis myocutaneous flap in treating advanced carcinomas of the penis. AB - OBJECTIVE: To examine the methods used to obtain skin closure after radical surgery for carcinomas of the penis, with special reference to the rectus abdominis myocutaneous flap. PATIENTS AND METHODS: Over a 20 year period, 21 patients underwent surgery for carcinomas of the penis. Seven had advanced tumours, requiring radical surgery for complete local tumour control. The resulting wounds were repaired with scrotal skin transfer in three patients and with a rectus abdominis myocutaneous flap in the other four. RESULTS: These methods of repair were a 100% reliable, all wounds being healed within 10 days. CONCLUSIONS: Scrotal skin transfer is a simple and effective method of achieving wound closure. Where removal of the scrotum is required along with curative or palliative surgery, and after ilio-inguinal lymphadenectomy, a rectus abdominis myocutaneous flap is useful for skin closure. PMID- 7850328 TI - Does neoadjuvant cisplatin-based chemotherapy improve the survival of patients with locally advanced bladder cancer: a meta-analysis of individual patient data from randomized clinical trials. Advanced Bladder Cancer Overview Collaboration. AB - OBJECTIVES: To assess whether neoadjuvant or concurrent platinum-based chemotherapy improves the survival of patients with locally advanced bladder cancer, and to determine whether there is any evidence that chemotherapy is more or less effective within well-defined subgroups of patients. PATIENTS AND METHODS: A formal meta-analysis (overview) was carried out using updated individual data from 479 patients (301 deaths) from four randomized trials comparing local definitive treatment alone with neoadjuvant or concurrent single agent cisplatin followed by local definitive treatment. Further summary data were available from a similar randomized trial of cisplatin and doxorubicin in 325 patients (127 deaths). RESULTS: Combined analysis of the individual patient data gave an overall hazard ratio of 1.02 in favour of local therapy alone (P = 0.845, 95% confidence interval = 0.81-1.26), representing a 2% increase in the relative risk of death with the use of chemotherapy. When this analysis was supplemented by data from the only trial for which individual patient information was not available, the hazard ratio was 0.91 in favour of chemotherapy (P = 0.328, 95% confidence interval = 0.75-1.10), representing a 9% reduction in the relative risk of death. The only prognostic factor for which the evidence suggested a differential treatment effect (interaction) across groups was age (chi-square test for trend = 3.833, P = 0.05), with younger age groups (< 60 years) exhibiting a possible effect in favour of chemotherapy. CONCLUSIONS: Despite a meta-analysis of all known randomized trials, there is still insufficient information to obtain a definitive answer to the question of whether neoadjuvant cisplatin-based chemotherapy improves the survival of patients with locally advanced bladder cancer. Such chemotherapy cannot therefore be currently recommended for routine use and any planned clinical trial should include a 'no chemotherapy' control arm. PMID- 7850330 TI - The role of histamine in human penile erection. AB - OBJECTIVE: To investigate the relaxant action of histamine on human corpus cavernosum in vitro and the erectile response caused by the intracavernous injection of histamine in patients with psychogenic impotence. PATIENTS AND METHODS: Human corpus cavernosum (HCC) tissue was cut into strips of approximately 2 cm and suspended in a cascade bioassay. The strips were then superfused with oxygenated and warmed Krebs solution and precontracted with noradrenaline (3 microM). Glyceryl trinitrate, acetylcholine and histamine were injected as a single bolus in the absence or in the presence of mepyramine and cimetidine. For the in vivo studies, histamine (30-60 micrograms) was injected intracavernously as a single bolus into the right corpus cavernosum 1 cm from the balamo-preputial sulcus. Similar protocols were carried out for papaverine (50 mg). The erectile response was divided into four grades: no response, tumescence, partial and full erection. RESULTS: In vitro studies demonstrated that histamine (3-100 micrograms) caused dose-dependent relaxation of the HCC strips which was significantly inhibited by cimetidine (5-10 microM). The histamine H1 receptor antagonist mepyramine (1 microM) potentiated histamine-induced relaxation. The co infusion of both mepyramine and cimetidine did not abolish histamine-induced relaxation. When injected intracavernously in humans, histamine (30 micrograms) caused full erection in 13% of the patients, whereas 87% had partial erection or tumescence. A higher dose of histamine (60 micrograms) caused full erection in 26% of the patients and 74% had partial erection or tumescence. Papaverine induced full erection in the majority of patients (66%). In contrast to papaverine, the duration of erection induced by histamine was markedly shorter (mean 200 and 6.5 min, respectively). The penile erections induced by papaverine were associated with complications such as pain, haematoma and priapism. Histamine did not induce any complications. Treatment of eight male patients with psychogenic impotence with the histamine H1 receptor antagonist astemizol (10 mg orally once daily for 1 week) did not affect histamine-induced erectile responses. CONCLUSION: These results indicate that histamine may play a role in human penile erection. The erection-promoting action of histamine is probably due to H2 receptor activation, although another histamine receptor, possibly H3, also seems to be involved. This study suggests that histamine could be a valuable tool in the diagnosis of erectile dysfunction. PMID- 7850331 TI - A novel anti-seminoma monoclonal antibody (M2A) labelled with technetium-99m: potential application for radioimmunoscintigraphy. AB - OBJECTIVE: To study the potential usefulness of monoclonal antibody (mAb) M2A specific for seminoma to image tumour nodules in a preclinical nude mouse model. MATERIALS AND METHODS: MAb M2A was labelled with technetium-99m (99mTc) following reduction and was administered intraperitoneally to nude mice bearing subcutaneous HEY cell xenografts against which the antibody was originally raised. Biodistribution and gamma scintigraphy studies were performed 24 h after administration of 99mTc-M2A. RESULTS: Biodistribution studies showed specific targeting of 99mTc-M2A to HEY tumours in comparison with control mAb 99mTc-6E8 and 99mTc-2G3 which do not bind to HEY cells. Subcutaneous HEY cell tumours (0.5 1.0 g) were successfully imaged using gamma-scintigraphy following administration of 99mTc-M2A. CONCLUSION: The results of this study indicate the potential usefulness of 99mTc-M2A as a clinical reagent for imaging seminoma metastases. PMID- 7850332 TI - Persistent polyuria after posterior urethral valves. AB - OBJECTIVE: To assess urinary concentrating ability, urine production and glomerular filtration rates in a cohort of boys with previously treated posterior urethral valves. PATIENTS AND METHODS: Urinary concentrating capacity was assessed in 51 boys aged 5.4-9.9 years with previously treated posterior urethral valves. They all completed urinary frequency/volume charts, permitting calculation of 24 h urine volumes. The osmolality of an overnight urine collection was measured and, if < 800 mOsm/kg (n = 40), an intramuscular injection of desamino-cys-1-8-D-arginine vasopressin was given to determine the maximum concentrating ability. The glomerular filtration rate (GFR) was estimated from the plasma clearance of 51Cr-ethylenediamine tetra-acetic acid following a single intravenous injection. RESULTS: The mean 24 h urine volume was 1025 +/- 448 (SD) mL. The mean overnight urine flow rate was 28.4 +/- 17.9 mL/h. Urinary concentrating capacity was impaired (< 800 mOsm/kg) in 30 (59%) of the boys and < 300 mOsm/kg in eight (16%). The mean GFR was 81 +/- 38 mL/min/1.73 m2SA. Significant correlations were noted between the GFR, the maximum urine concentration and the 24 h urine volume. CONCLUSION: Persistent polyuria after valve ablation occurs in boys with posterior urethral valves. This has implications both in terms of urinary continence and on-going renal impairment. PMID- 7850333 TI - Reducing trauma whilst removing long-term indwelling balloon catheters. PMID- 7850334 TI - Burch colposuspension facilitated by means of the Ferguson speculum. PMID- 7850335 TI - Metachronous transitional cell carcinoma of the urachus and bladder. PMID- 7850336 TI - Localized amyloidosis of the urethra. PMID- 7850337 TI - Renal cell carcinoma presenting with orbital metastases. PMID- 7850338 TI - An unusual rhabdoid-like tumour of the kidney in childhood. PMID- 7850339 TI - 'Open' percutaneous ultrasonic lithotripsy for failed anatrophic nephrolithotomy. PMID- 7850340 TI - A rare cause of epididymo-orchitis. PMID- 7850341 TI - Massive bladder calculus as a complication of a titanium prostatic stent. PMID- 7850342 TI - Carcinoma of the bladder presenting during pregnancy. PMID- 7850343 TI - Renal cell carcinoma during pregnancy. PMID- 7850344 TI - Inflammatory pseudotumour of the epididymis. PMID- 7850345 TI - An unusual JJ stent story. PMID- 7850346 TI - Bladder function in healthy volunteers: ambulatory monitoring and conventional urodynamic studies. PMID- 7850347 TI - Written consent about sexual function in men undergoing transurethral prostatectomy. PMID- 7850348 TI - Incontinence treated with Teflon. PMID- 7850349 TI - Electron crystallography of organic and biological molecules--techniques and comparison to X-ray crystallographic results. AB - In this review, it is shown how ab initio analyses of molecular crystal structures can be carried out with electron diffraction intensities and high resolution, low-dose, electron micrographs, dispelling the long-held myth that such determinations are not possible. The results for small organics, polymethylene compounds, various polymers, and even intregral membrane proteins, are in good agreement with independent X-ray crystal structure determinations, which, however, were not needed to solve the crystallographic phase problem from the electron scattering data. The concept of electron crystallography benefits from the utility of electron micrographs for providing phase information, in addition to the standard 'direct' methods used nowadays by all crystallographers. PMID- 7850350 TI - Testing the quality of electron microscope mapping data for DNA molecules with sequence-specific ligands. AB - A procedure for the testing of Electron Microscope (EM) mapping data for DNA molecules with site-specific bound ligands is suggested. The difficulty of distinguishing DNA molecule ends on electron micrographs indicates that their true orientations are not known. This in turn presents problems in obtaining correct maps relating to their alignment, and complicates checking the maps' validity. For these reasons a computer simulation of the EM study of double stranded DNA molecules with site-specific bound ligands was carried out. The knowledge of the true orientations of the simulated DNA molecules allowed us to examine their final orientations after alignment. We used the number of improper oriented molecules as the quantitative measure of the map quality. Detailed investigation based on this parameter permitted us to invent the criterion for the map validity, and to suggest the procedure for the testing of alignment of real DNA molecules. This procedure implies multiple randomization of initial orientations of the DNA molecules and minute analysis of the final maps. Most of the molecular, statistical and experimental parameters inherent to EM investigation of site-specific binding, such as the number of specific binding sites (N), the mean number of bound ligands (A), the length of the DNA molecules (L), the specific/non-specific ratio of binding (K), together with the standard deviation of DNA molecule lengths (HL) were tested for their influence upon the quality of EM mapping data. An empirical equation for the ultimate values of these parameters has been found, allowing us to predict the success of EM mapping. PMID- 7850351 TI - Antibody penetration into LR-White sections. AB - The purpose of this investigation is to study the ability of antibodies to penetrate sections of LR-WHITE resin. The methods used in this study were the following: (1) Reembedding of sections labeled with immunogold (1 nm) and peroxidase/DAB/gold chloride, (2) tilting of ultrathin sections treated with immunogold (1 nm), (3) immunolabeling of cylindrical structures embedded in LR WHITE, (4) application of primary and secondary antibodies on opposite sides of ultrathin sections. Fibrin and human pituitary tissue was embedded in LR-WHITE and treated with anti-fibrinogen or anti-ACTH respectively (ACTH = Adrenocorticotropic hormone). No indication of antibody penetration into the section were found with either of the methods, contrary to findings in earlier publications. The significance of this result is that antigens cannot be demonstrated in the interior of LR-WHITE sections with post-embedding techniques. Furthermore, LR-WHITE resin may be used for quantitative immunoelectron microscopy, and the resin may be used for double immunogold labeling since the application of immunoreagents on opposite sides of the sections is completely safe. PMID- 7850352 TI - Conformation, order-disorder conformational transitions and gelation of non crystalline polysaccharides studied using electron microscopy. AB - Direct imaging of polysaccharides using transmission electron microscopy (EM) is an important alternative to physical characterization of non-crystalline polysaccharides in solution. The polymer nature of stiff-chain polysaccharides is quite apparent from direct visualization of the electron micrographs, despite the fact that commonly employed preparation techniques reduce the resolution limit to about 1-2 nm. Electron microscopy has recently been used to study polysaccharides with emphasis both on quantitative properties like contour length, end-to-end distance and chain stiffness, and on qualitative structural features such as cyclization at the macromolecular level. The structural richness observed for polysaccharides of the beta-D0glucan family after a denaturation-renaturation treatment of the specimen, in particular, illustrates the unique potential of EM as a tool for obtaining conformational information about carbohydrate macromolecules. Examples of the latter also include the recent discoveries of cyclic beta-D-glucan and l-carrageenan structures. The EM technique provides information that is not only complementary to what can be obtained using other physical techniques, but also offers important insight otherwise masked by the averaging implicit in most physical techniques used to study aqueous polysaccharide solutions. PMID- 7850353 TI - Neuroligand receptor heterogeneity among astroglia. AB - Astroglia are remarkedly diverse cells with respect to their pharmacological responsiveness and the processes regulated by neuroligand receptors. The results of single cell analyses indicate that astroglia continue to diversify in vitro. For example, the two daughter cells of a single division can exhibit qualitatively distinct responses to neuroligand application. These findings indicate that in contrast to most cells that "lock" their neuroligand receptor phenotype early in development, astroglia exhibit unusual plasticity. It is possible that this plasticity is necessary for immature astrocytes to respond to a changing neuronal environment during development. Interestingly, the increase in astroglial calcium following addition of neuroligands tends to originate from a localized area of the cell and then spreads as a wave that moves through the cell in a nondecremental manner. In situations in which astroglia are connected by gap junctions, the wave of calcium in one cell readily moves into the second without any obvious decrease in magnitude. Furthermore, astroglial calcium responses occur in an "all-or-none" manner reminiscent of neuronal action potentials. That is, the magnitude of an astroglial cell's calcium response appears relatively independent of the concentration of the ligand used or the density of receptors present on the cell. However, the probability of an astroglial cell responding to a given neuroligand is related to the density of receptors expressed and the concentration of the neuroligand applied. These characteristics suggest that, like neurons, signals received by an astrocyte are integrated and that when a threshold is reached the cell responds with a localized response that then propagates through that cell and into adjacent cells in a nondecremental manner. In neurons this is accomplished via depolarizations leading to action potentials and release of neurotransmitters. In astrocytes, distant signaling appears to occur via an "all-or-none" release of calcium, which then propagates through the cell and neighboring cells as a calcium wave. Our recent findings that neuroligands can modulate the opening and closing of astrocytic gap junctions suggest that specific pathways of astrocytic communication may exist. Overall, it is becoming evident that neuronal-glial signaling may be far more complex than previously imagined. PMID- 7850354 TI - Astroglial modulation of synaptic transmission. AB - Brain astrocytes appear as a class of cells with the capacity to produce integrated responses to multiple stimuli. The cells interact dynamically with neurons, sense and support synaptic transmission. The anatomy of the cells, their formation of an electrically coupled syncytium with long-distance, slow speed transfer of information within the syncytium together with their well-developed capacity for cell volume regulation, and thereby an indirect influence on extracellular volume, has made us put forward the possibility that this syncytium constitutes an extraneuronal system for excitability control. PMID- 7850355 TI - Glial cell heterogeneity in the mammalian spinal cord. AB - The vertebrate spinal cord is comprised of a complex array of different populations of neurons and axon tracts. Recent studies suggest that this complex neuronal cytoarchitecture is complemented by a similarly complex glial cytoarchitecture. Cultures of neonatal rat spinal cord contain multiple different classes of astrocytes. These distinct classes of astrocytes have particular morphologies and arise from separate precursors that proliferate in response to different mitogens. It seems likely that the individual classes of astrocytes will have regional localization and will be involved in specific functions in the intact spinal cord. In contrast to the significant diversity seen among astrocytes, spinal cord oligodendrocytes in the embryonic animal appear to be a relatively homogenous population of cells that proliferates in response to known growth factors at particular stages of maturation. An important future challenge in glial cell biology is to define clearly the functional roles of individual populations of astrocytes in the developing adult, and injured spinal cord. Such information may ultimately lead to the ability to modulate astrocytic function at a cellular level during aberrant development and following injury to the adult spinal cord. PMID- 7850356 TI - Astroglial 5-HT1a receptors and S-100 beta in development and plasticity. AB - The work described in this article is concerned with the role of the 5-HT1a receptor in mediating the neurotrophic effects of serotonin, principally through the release of the substance S-100 beta from astroglial cells. These receptors are also present in astrocytes of the mature brain and may play a role in the synaptic plasticity necessary for certain experience-driven brain changes, such as memory or learning. The presence of these receptors on astroglial cells of the adult brain also has interesting implications for the mechanism of action of many psychotropic drugs acting through the serotonergic system. PMID- 7850357 TI - Glial heterogeneity and developing neurotransmitter systems. AB - Evidence from the developing serotonergic system provides support for the working hypothesis that an important function of receptors expressed by developing glia may be to mediate the effects of neurotransmitters on growth and differentiation of the neurons that utilize them, by regulating the production of glial-derived neurotrophic factors. Regional heterogeneity of glial expression may reflect the specific roles played by these receptors within different compartments of a developing neurotransmitter system. During the construction of neural pathways, the specificity of these neurotransmitter-mediated neuronal-glial interactions would require appropriate spatiotemporal expression of glial receptors and neurotrophic factors, as well as specificity of these factors for neurons of appropriate neurotransmitter phenotypes. PMID- 7850358 TI - Heterogeneity of expression of neuropeptide genes by astrocytes: functional implications. AB - A specific subset of neuropeptides are expressed in astrocytes, with specificity in terms of both brain region and gene, as well as with specific developmental patterns: the overall pattern of expression is thus heterogeneous. These neuropeptides have been demonstrated to have a number of trophic effects, including regulation of cell number, of length of axons and dendrites, and of neuronal phenotype. The developmental regulation of expression of neuropeptides in astrocytes further supports functional roles for the neuropeptides as trophic modeling factors. Not all the trophic effects have to be stimulatory and evidence suggests that opioid peptides may function to prune dendrites or decrease cell numbers in order to modulate or shape the nervous system. In addition to roles during development, preliminary experiments suggest that astrocyte neuropeptide expression turns back on in the adult brain following injury, suggesting that the neuropeptides may play a role in supporting survival or recovery of damaged neurons. The heterogeneity of neuropeptide expression in astrocytes must therefore contribute to the establishment and maintenance of the network of communication among neurons and glia in the nervous system in ways we have yet to understand fully. PMID- 7850359 TI - Region-specific neuroastroglial interactions in neuronal morphogenesis and polarity: from homeogenic induction to cellular cytomechanics. AB - Because of several studies on neuronal differentiation, it has been possible to produce a list of adhesion molecules, cytoskeletal elements, and transacting factors that participate in the determination of neuronal shape and polarity. Most of these proteins are ubiquitous, and this lack of regional specificity is unlikely to be compensated for by editing mechanisms, such as alternative splicing and post-translational modifications. In this context it is quite difficult to understand the regional specificity of neuroneuronal or neuroastroglial interactions. For this reason, we are interested in the study of homeoproteins, a class of transcription factors endowed with regional specificity, which regulate the synthesis of several morphoregulatory molecules, including cell and substrate adhesion molecules. We propose a model in which specific neuroastroglial and neuroneuronal interactions result from the homeoprotein-dependent regulation of the quantities and of the topological organization of such ubiquitous morphoregulatory molecules. Moreover, we extend this model by proposing that some homeoprotein isoforms could act not only according to a classic intracrine mode, but also through a paracrine mechanism. PMID- 7850360 TI - Heterogeneity among astrocytes in reactive gliosis. AB - Reactive gliosis has been considered to be the major cause of regenerative failure of the mature mammalian central nervous system (CNS). It is classically defined by increased glial fibrillary acidic protein expression. However, the response to injury is not uniform throughout the CNS. This heterogeneity is becoming more apparent as other markers for reactive astrocytes emerge from recent studies. These molecules may be more relevant markers of the functional state of reactive astrocytes and may help us understand the events leading to failure of regeneration in the CNS. PMID- 7850361 TI - Cells on the edge: boundary astrocytes and neurons. AB - The caudate-putamen nucleus (neostriatum) is organized as a mosaic of two compartments that during development are cordoned off by astrocytes and associated glycoconjugates. There are complex interactions between these boundary astrocytes and neurons during pattern formation in the neostriatal mosaic, with distinct classes of neurons (such as NADPH-d/NOS cells) residing within boundary as well as nonboundary sites. An hypothesis is presented that implicates glial cells, different classes of neurons, synaptic activity, and neurotoxicity in the shaping of normal cytoarchitectonic and connectional arrangements in the neostriatum. Within such a scenario, special glial cells and neurons are on the edge between compartments, living and dying. PMID- 7850362 TI - Lung development. AB - Human lung development is divided into five stages: embryonic, pseudoglandular, canalicular, saccular, and alveolar. The boundaries between these stages are not sharp; rather, overlap occurs between various gestational ages and individuals. The anatomic and morphological characteristics of each stage are described; general principles of lung development and cytodifferentiation of type I and type II pneumocytes are discussed. The complex phenomenon of lung development incorporates two processes--lung growth and lung maturation. Although these processes are developmentally related, they appear to be separately controlled. Lung growth seems to be influenced primarily by physical factors such as intrathoracic space, lung liquid volume and pressure, and amniotic fluid volume among others. Special attention is given to fetal lung liquid dynamics and the effects of its manipulation on lung growth, particularly by tracheal occlusion. Lung maturation has two components--structural and biochemical (ie, surfactant). Structural lung maturation appears to be regulated by physical factors. Physical factors that produce hypoplasia produce structurally immature lungs, whereas physical factors that produce hyperplasia produce structurally mature lungs. Biochemical maturation appears to be hormonally regulated by several endocrine organs (pituitary, adrenal, thyroid) and a host of endocrine factors including corticotropin, cortisol, thyroid hormones, and others. PMID- 7850363 TI - Congenital lung cysts. AB - Congenital cystic adenomatoid malformation (CCAM), pulmonary sequestration, congenital lobar emphysema (CLE), and bronchogenic cysts are all congenital malformations of the lung that present in imaging studies as abnormal air, air/fluid, or fluid-filled cysts. The embryology, histology, clinical presentation, and treatment of these lesions are discussed based on world literature and our experience with 22 operative resections of congenital lung cysts over the past 10 years. The roles of prenatal diagnosis and fetal surgery in the management of certain lung cysts are considered. Computed tomography has emerged as an extremely useful tool in the differential diagnosis of these lesions. Surgical excision by segmentectomy or lobectomy for intrapulmonary lesions and simple excision for extralobar sequestrations and bronchogenic cysts are safe and have a low incidence of complications. Asymptomatic patients with CLE may not require resection. Overall, with accurate diagnosis and preoperative planning these rare but fascinating anomalies can be treated safely and effectively, with excellent results. PMID- 7850364 TI - Tracheal reconstruction. AB - Treatment of stenosing malformations of the pediatric airway has progressed from dilatation and occasional localized resection to radical resection or extended tracheoplastic reconstruction. Current preoperative evaluation includes high contrast radiography, bronchography, often magnetic resonance imaging (MRI) or computed tomography (CT), and intraoperative bronchoscopy. Cardiopulmonary bypass may be essential for complicated reconstructions involving the carina and bronchi, but most other stenoses can be corrected without bypass. Balloon dilatation directed toward forceful posterior split of complete cartilage rings has shown recent promise in small infants. Segmental resection with anastomosis is preferred for localized lesions. Incision tracheoplasty with interposition cartilage grafting is the current choice for long stenoses. PMID- 7850365 TI - Tracheomalacia. AB - Tracheomalacia describes a generalized or localized weakness of the trachea that results in excessive narrowing of the tracheal lumen during expiration or whenever intrathoracic pressure increases. Severe forms of tracheomalacia are characterized by life-threatening apneic spells, inability to extubate the airways, and episodic pneumonia. Aortopexy has proved to be an effective method of treatment for most of these conditions when seen in children. When aortopexy fails to prevent tracheal obstruction, a support applied to the external circumference of the trachea can be useful to prevent airway collapse. PMID- 7850366 TI - Mediastinal tumors--airway obstruction and management. AB - Large mediastinal massess can cause compression of surrounding mediastinal structures. Patients may have symptoms of airway obstruction or cardiovascular compromise. The additive effects of anesthetics, paralysis, and positioning during biopsy can lead to acute airway obstruction and death. In some cases, tissue diagnosis can be achieved and treatment initiated without general anesthesia. When general anesthesia is necessary, specific measures should be taken to avoid disaster or immediately alleviate obstruction should it occur. Some patients at greatest risk will require pretreatment of the mass before tissue diagnosis. This article reviews these issues and provides a useful algorithm for managing patients with mediastinal masses. PMID- 7850367 TI - Chest wall tumors in infants and children. AB - Chest wall tumors are infrequent in infants and children, but a high proportion of these tumors are malignant. They present most frequently as a palpable mass, and less frequently with pain or respiratory distress. Radiographic evaluation should include chest radiographs followed by computed tomographic (CT) scan. In most cases an initial incisional biopsy is performed because of the significant risk of malignancy. The most frequent tumors are the malignant small round cell tumors (Ewing's sarcoma/primitive neuroectodermal tumor [PNET] family) followed by rhabdomyosarcoma, osteosarcoma, chondrosarcoma, and a spectrum of other sarcomas. Initial treatment with chemotherapy, particularly for the malignant small round cell tumors and osteosarcoma, may facilitate resection by decreasing the size of the tumor as well as its vascularity and friability. Cure requires successful local control and adjuvant chemotherapy and is particularly difficult to achieve in children presenting with metastases. PMID- 7850368 TI - Thoracoscopy in infants and children. AB - Thoracoscopy is a rapidly advancing technique in the diagnosis and treatment of children. Miniaturization of instrumentation and improved optics now allow extensive intrathoracic procedures to be performed in infants as small as 2 kg. Procedures such as lung biopsy and resection, biopsy or removal of mediastinal masses, esophageal surgery, and even patent ductus arteriosus closure can now be performed safely with minimally invasive techniques. PMID- 7850369 TI - Chlorinated dioxins and related compounds. Proceedings of the 13th International Symposium. Vienna, Austria, 20-24 September 1993. PMID- 7850370 TI - The Dutch PCB/Dioxin Study. Development of a method for the determination of dioxins, planar and other PCBs in human milk. AB - A method for the determination of dioxins, planar PCBs and other PCBs in human milk is described. The work is part of a big Dutch project, (seven institutes participates) in which 400 human milk samples from two areas (Rotterdam and Groningen) taken at two different times (10 and 42 days) after delivery had to be analysed for planar PCBs, dioxins and other PCBs (1st sampling) and only other PCBs (2nd sampling). Planar compounds are determined with GC/HRMS, other PCBs with GC/ECD. As type of analytes for 1st and 2nd sampling are different the method was focussed on these analytes. After fat extraction, clean up was carried out on GPC and alumina columns. Only in case of analysis of planar compounds and other PCBs, chromatography on porous graphitised carbon was carried out after which GC-HRMS (planar compounds) and GC/ECD (other PCBs) was performed; otherwise GC/ECD after alumina clean up was performed. The method is validated through recovery experiments with standards (other PCBs, labelled planar compounds), comparison of results for other PCBs obtained with the two different clean-up procedures, reproducibility of "quality control samples" for planar compounds blanc chemicals. PMID- 7850371 TI - Secondary formation of PCDD/F during the thermal stabilization of sewage sludge. AB - In the City of Nuremberg, from 1972 to 1992 the sewage sludge used to be thermally stabilized in a modified Porteous process. In recent years the impact of this process on the concentration of various persistent contaminants in the sludge has been studied. In the process part the organic material in the sludge is decomposed and to the same extent an increase of the concentration of persistent components is found in the processed sewage sludge. The enrichment factors for heavy metals and PCB show a modest variation between 1.15 and 1.63 with a mean value around 1.3. In contrast to these data, for PCDD/F enrichment factors up to 8 are found with a strong variation between the congeners, and the highest enrichment factors to be found for tetra- and pentachlorinated dioxins. The thermal stabilization of sewage sludge seems to be a source of PCDD/F due to their secondary formation in the process. PMID- 7850372 TI - Transfer of PCDD/PCDF from contaminated soils into carrots, lettuce and peas. AB - In a field experiment, the PCDD/PCDF transfer pathways from soil into carrots, lettuce and peas has been investigated. PCDD/PCDF contamination levels in soil varied between 5 ng I-TEq/kg on the control plot and 56 ng I-TEq/kg on the contaminated plot. PCDD/PCDF levels in carrots were threefold higher in the contaminated plot than in the control plot, which was a result of a tenfold increase in the PCDD/PCDF levels of the peel. PCDD/PCDF levels in lettuce and peas were not higher when grown on the contaminated plot and were much lower than in carrots, which indicates that the PCDD/PCDF in lettuce and peas from both plots are of atmospheric origin. PMID- 7850373 TI - Dioxins in U.S. food and estimated daily intake. AB - Congener-specific analyses for polychlorinated dioxins and dibenzofurans were performed on eighteen dairy, meat, and fish samples obtained from a supermarket in upstate New York. Dioxin toxic equivalents (TEqs) on a whole or wet weight basis for these food samples ranged from 0.02 to 1.5 parts per trillion (ppt). Data on American food consumption rates were used to estimate a U.S. range of dioxin intake from food. Based on these first congener-specific dioxin analyses of U.S. food, U.S. average daily intake of "International" dioxin toxic equivalents for an adult weighing 65 kilograms (kg) was estimated to be between 18 to 192 picograms TEq or 0.3 to 3.0 picograms per kilogram of body weight. Our previous results for cow's milk, human breast milk, and soy-based infant formula were used to calculate intake for infants. The relatively high level of dioxins commonly reported in human breast milk from America contributes from 35 to 53 picograms of dioxin toxic equivalents per kilogram of body weight to the nursing infant per day in its first year of life. This value greatly exceeds the U.S. Environmental Protection Agency estimated dose which would lead to one excess cancer per one million people of 0.006 pg of TCDD per kg of body weight per day over a seventy year lifetime or similar reference doses used by some other countries of up to 10/pg/kg/day over a 70 year lifetime. PMID- 7850374 TI - The Dutch PCB/Dioxin Study. Contents of dioxins, planar and other PCBs in human milk from the Rotterdam and Groningen area. AB - In two areas (Groningen and Rotterdam): individual human milk samples (24 hr.) were obtained 10 and 42 days after delivery from about 200 mothers. In all samples non-planar PCBs, including some monoorthochlorine substituted PCBs were determined. All first samples, and a smaller number of the second samples were analysed for dioxins and coplanar PCBs. The obtained results are in the same order of magnitude as earlier Dutch results and do in general not differ from the situation in neighbouring countries. No differences could be observed between the analytical results of both areas. PMID- 7850375 TI - Intake and fecal excretion of PCDDs, PCDFs, HCB and PCBs (138, 153, 180) in a breast-fed and a formula-fed infant. AB - Intake and fecal excretion of PCDDs, PCDFs, HCB and PCBs (IUPAC Nos. 138, 153, 180) were measured in a breast-fed and a formula-fed infant at the age of 1 and 5 months. As expected, the intake of these compounds was clearly higher in the breast-fed infant. In this baby an almost complete absorption was observed for lower chlorinated PCDDs and PCDFs and also for HCB and PCBs, whereas for hepta- and octachlorinated PCDDs and PCDFs fecal excretion was considerably higher (from 20% up to nearly 100% of the intake). Due to low concentrations in diet and feces of the formula-fed infant an evaluation was possible only for a few compounds at the age of 5 months. These values were in the same range when compared with those of the breast-fed infant. For collection of feces new cotton diapers were used which were pre-extracted in order to reduce the levels of polychlorinated compounds. Unexpectedly, after washing the tissue a much higher contamination was observed which made a calculation of fecal excretion rates in the formula-fed infant at the age of 1 month impossible. PMID- 7850376 TI - PCB metabolism, persistence, and health effects after occupational exposure: implications for risk assessment. AB - Analysis of the kinetics and congener selectivities for PCB metabolism in occupationally exposed workers shows that the lipid PCB concentrations required for the induction of P4502B cytochromes must be > 20 mg/kg; for inducing P4501A and the associated toxic effects, > 600 mg/kg. The observed kinetic behavior indicates that the reported statistical associations between serum PCB levels and certain disease states in the general population (lipid PCBs generally 0-2 mg/kg) probably arise from correlations with the factors that control steady-state xenobiotic levels in human serum (notably, P450 activity and serum lipids) rather than from novel toxic activities of the PCBs. PMID- 7850377 TI - Lymphodepletion of the thymus cortex in rats after single oral intubation of 2,3,7,8-tetrachlorodibenzo-p-dioxin. AB - Atrophy of the thymus and thymic lymphodepletion occurs after exposure to sublethal doses of TCDD. Previous studies using high doses of TCDD (150 micrograms/kg) have indicated a preferential lymphodepletion of the thymus cortex on day 4 after a single oral intubation. Here we describe the effects of a single oral intubation of lower dose levels of TCDD (1, 5, and 25 micrograms/kg) on thymic weights and thymocyte subpopulations in Wistar rats on day 4 after exposure. A single administration of 1 micrograms/kg TCDD induced a significant reduction in the number of immature CD4+CD8+ double-positive (DP) thymocytes. At this time point the numbers of mature CD3high medullary thymocytes were not affected at any dose level tested. We conclude that also lower dose levels of TCDD induce thymic atrophy via a preferential lymphodepletion of the thymus cortex. PMID- 7850378 TI - Lethality and EROD-inducing potency of chlorinated chrysene in chick embryos. AB - Chrysene was non-specifically chlorinated and the toxic potency of the mixture formed was studied. The chlorinated mixture was considerably more potent than the parent compound in terms of embryolethality and EROD and AHH induction in a 2 week test in chick embryos. The chlorinated chrysene caused anomalies, including edema and beak defects, similar to those previously found after treatment of chick embryos with coplanar PCBs. Chlorinated chrysene was also much more potent than chrysene as an inducer of EROD in a 72-hour test in chick embryos in ovo and in chick embryo liver in vitro. It seems that the mechanism of toxicity of chlorinated chrysene in chick embryos is similar to that of the coplanar PCBs and other Ah receptor ligands. The effects of the chlorinated mixture were mainly accounted for by 6- chlorochrysene and 6,12-dichlorochrysene. PMID- 7850379 TI - Effect on tissue vitamin A levels in the rat following subchronic exposure to four individual PCB congeners (IUPAC 77, 118, 126, and 153). AB - The present study was carried out to investigate the effect on tissue vitamin A levels in rats exposed to 3,3',4,4'-tetraCB (CB-77), 2,3',4,4',5-pentaCB (CB 118), 3,3',4,4',5-pentaCB (CB-126), and 2,2',4,4',5,5'-hexaCB (CB-153). The obtained results show that hepatic vitamin A levels are reduced both in male and female rats following dietary exposure to individual PCB congeners for 13 weeks. However, there are pronounced potency differences between congeners. Compared to TCDD, the hepatic vitamin A reducing potencies of CB-126, CB-77 and CB-153, are 0.05, 0.0001 and 0.00001, respectively, in male rats. Compared to male rats, female rats are equally sensitive to hepatic vitamin A reduction both by TCDD and dioxinlike CBs. Effects on renal and pulmonary vitamin A levels vary between CBs and between sexes. PMID- 7850380 TI - Levels of PCBs and some organochlorine pesticides in the human population of selected areas of the Slovak Republic. I. Blood. AB - Fifty samples of human blood collected in 1992 from the general human population living in five selected areas of the Slovak Republic (the Michalovce, Velky Krtis and Nitra District, Myjava area and Bratislava) were analysed for polychlorinated biphenyls (IUPAC Nos. 28, 52, 77, 101, 105, 114, 118, 123, 126, 138 (+163), 153, 156, 157, 167, 169, 180 and 189) and some organochlorine pesticides (HCB, gamma HCH, p,p'-DDE and p,p'-DDT). PCB levels (the sum of the congeners analysed) in serum lipids averaged for all the samples analysed were 1.79 micrograms.g-1 (range: 0.53-9.20 micrograms.g-1, median: 1.33 micrograms.g-1), HCB 5.38 micrograms.g-1 (0.16-23.20 micrograms.g-1, 4.27 micrograms.g-1), gamma-HCH 0.012 microgram.g-1 (< 0.01-0.18 microgram.g-1), p,p'-DDE 6.05 micrograms.g-1 (1.30 34.80 micrograms.g-1, 4.39 micrograms.g-1) and p,p'-DDT 0.27 microgram.g-1 (< 0.01-0.79 microgram.g-1, 0.23 microgram.g-1). About three times higher levels of PCBs were found in the samples from the district where PCB formulations had been produced (the Michalovce District). PMID- 7850381 TI - Dioxin and PCB levels in blood and human milk in relation to living areas in The Netherlands. AB - Dioxins and polychlorinated biphenyls (PCBs) are ubiquitous toxic compounds in the environment. Negative influences of these compounds on the health status of human beings have been described. Especially susceptible might be the fetus, which is exposed in utero, and the newborn breast-fed infant, since both are exposed to relatively high levels of dioxins and PCBs during a critical period of organ growth and development. We investigated PCB levels in 406 maternal plasma samples as well as PCB and dioxin levels in 172 human milk samples with relation to living area of women living for at least five years in the western industrialized part of the Netherlands or the northern more rural part. The western part was further subdivided into one urban and two highly industrialized areas. After correction for covariates, we found significantly higher levels of PCB 118 in maternal plasma as well as significantly higher levels of the dioxin TEQ and of ten individual dioxin and PCB congener levels in human milk in the western more industrialized areas of the Netherlands compared to the northern more rural part. We did not find significant differences in planar, mono-ortho or di-ortho PCB-TEQ levels in human milk between all different areas. We conclude that significantly higher levels of a number of dioxin and PCB congeners are found in women living in industrialized areas compared to women living in rural areas in the Netherlands. PMID- 7850382 TI - Concentrations and profiles of PCDDs and PCDFs in human mammary carcinoma tissue. AB - PCDD/PCDF concentrations in eight mammary carcinoma tissue samples obtained after surgical excision were similar to those found in two healthy breast glandular tissue samples from autopsy material. These levels agree well with mean concentrations in human adipose tissue from German adults. An analogous consistency was found for the congener profiles of the normalized concentrations, also in comparison with mothers' milk from Germany. In spite of similar congener profiles the concentrations in four axillary adipose tissue samples corresponding to the carcinoma samples were about 40% lower. This discrepancy was not found in one tissue pair from a healthy breast. PMID- 7850383 TI - Effects of highly toxic organochlorine compounds retained in human body on induction of sister chromatid exchanges in cultured human lymphocytes. AB - In this study, we investigated the effect of mixture of the organochlorine compounds, which very resembled their contamination of healthy Japanese people in its composition, on the induction of sister chromatid exchanges (SCEs) in human whole-blood cultures in order to clarify their genotoxicity as a whole. The following results were obtained. Regardless of the presence or absence of 7,8 benzoflavone (ANF) in the blood culture system, we could observe a fairly good dose-response relationship between the concentration of the mixture of organochlorine compounds and the induction of SCEs/cell. In particular, we found that 50% effective concentration of the mixture of the organochlorine compounds was considered to be only about 3 times greater level over the average concentration in the healthy people, namely 70ppt as 2,3,7,8-TCDD, in the absence of ANF and about 8 times more than that in the presence of ANF. PMID- 7850384 TI - PCDD/PCDF in humans, a 1993-update of background data. AB - 70 blood samples--collected in 1993 in Germany--have been analysed for PCDD/PCDF. For all persons involved, no certain expose, except for food consumption, has been reported. The levels measured show a decrease of PCDD/PCDF compared to previous data on blood collected mainly in 1989 and in 1992. This trend for the dioxin values in blood corresponds well to the observations reported for human milk. PMID- 7850385 TI - Elevated dioxin blood levels in Russian chemical workers and their children following maternal exposure. AB - Elevated dioxin levels in children of female workers with elevated dioxin body burden following workplace exposure has not been previously reported. We previously reported elevation of polychlorinated dibenzo-p-dioxins, particularly 2,3,7,8-TCDD, in Russia male and female chemical production workers' blood. Exposure is thought to have occurred in the early 1960s and blood was drawn in 1991. Among those with elevated dioxin levels were women with grown children. Since dioxins can be transferred transplacentally and by nursing, it was decided to see if a relationship existed between blood dioxin levels in mothers and their children. Individual samples were obtained from factory office workers, production workers and their now adult offspring. A pooled blood sample (n = 100) from adult Ufa residents was obtained for comparison. Samples were analyzed for polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) and coplanar polychlorinated biphenyls (CoPCBs). Office workers, production workers and workers' children 2,3,7,8-TCDD (TCDD) blood levels ranged from 11 to 273 parts per trillion (ppt) on a lipid basis, while the pooled blood sample (n = 100) from adult Ufa residents had a TCDD level of 12 ppt. Elevated TCDD was detected in all adult children of female production workers tested while two adult children of a male production worker had dioxin levels similar to the general population of Ufa. All children of workers had been nursed by their mothers for the first year of life and none have worked at a chemical plant. The data suggest that relatively large amounts of TCDD were transferred from mother to child approximately 18 to 28 years prior to blood collection. A sample of 2,4, D amine salt produced at this factory was also analyzed to determine if its dioxin congeners might be contributing to dioxin contamination. 2,3,7,8-TCDD was not detected in the 2,4-D (detection limit of 0.02 ppb), although other dioxins were present, including some with 2,3,7,8- chlorine substitution. PMID- 7850386 TI - Comparison of dibenzodioxin levels in blood and milk in agricultural workers and others following pentachlorophenol exposure in China. AB - Substantial amounts of sodium pentachlorophenol (Na-PCP) salts have been sprayed in certain areas in central China since the 1960s for control of snail-borne schistosomiasis. A sample of Na-PCP used in the area of concern was analyzed and showed 2,3,7,8-substituted dibenzodioxin (PCDD) and dibenzofuran (PCDF) congeners as well as some non-2,3,7,8-substituted congeners. Dibenzodioxin analysis of two pooled blood samples from 100 persons living in sprayed areas and a pooled sample from 26 individuals who had direct contact with the Na-PCP showed elevations of PCDD/F congeners found in the Na-PCP. Total PCDD/Fs ranged from 631 to 1252 parts per trillion (ppt) lipid in the blood of those exposed to Na-PCP, while two general population age-matched pooled blood samples from 50 persons each had total PCDD/Fs of 147 and 178 ppt. Toxic equivalents calculated with International Toxic Equivalency Factors (I-TEqs) ranged from 9 to 16.3 ppt in the blood samples from exposed persons while the general population blood I-TEqs were 4.8 and 6.4 ppt. A pooled breast milk sample from 50 women living in the sprayed areas was compared with a pooled sample from 50 women living in unsprayed areas. Total PCDD/Fs was low in both exposed and general population samples (134 and 42 ppt lipid, respectively), however, the women living in sprayed areas had considerably higher PCDDs, 129 ppt versus 34 ppt. The mothers exposed to Na-PCP had a I-TEq of 5.4, which was about double that of the mothers from the general population, 2.6 ppt, lipid. Although human PCDD and PCDF tissue levels in China are low compared with those in more industrialized countries, the higher levels in exposed persons are cause for concern. PMID- 7850387 TI - Subchronic (13-week) toxicity of heptachlorodibenzo-p-dioxin in male Sprague Dawley rats. AB - A 13-week oral toxicity study with 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HpCDD) was performed in Sprague-Dawley rats. Rats received HpCDD at five different dose levels or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) at one dose level. The doses were divided into 4 daily loading doses and 6 biweekly maintenance doses. At the end of the 13-week dosing period half of the rats were scheduled for necropsy and the other half after another 13-week off-dose period. This preliminary report contains only data from male rats during the 13-week main study period. At the two highest doses of HpCDD and in the TCDD dosage group the body weight or body weight gain was reduced. Mortality was 15, 50 and 5%, respectively. Wasting syndrome was the primary cause of death, but some rats died of hemorrhage without wasting, which may be related to the dose-dependent decrease in platelet counts. Phosphoenolpyruvate carboxykinase (PEPCK), the rate limiting enzyme of gluconeogenesis, was decreased only at the two highest dose levels of HpCDD and in the TCDD group, all of which also showed mortality. Ethoxyresorufin O-deetylase (EROD) was induced dose-dependently in all treated groups. Serum total thyroxine (T4) concentrations were decreased beginning at the middle dose of HpCDD. The study demonstrates that the toxicity observed after subchronic exposure to HpCDD is very similar to that of TCDD. Most importantly, most of the effects after subchronic and acute dose exposure are identical, confirming the validity of 0.007 as the toxic equivalency factor for HpCDD. PMID- 7850388 TI - Early development of Yu-Cheng children born seven to twelve years after the Taiwan PCB outbreak. AB - In Taiwanese children born seven to twelve years after their mothers' or fathers' intoxication of heat-degraded polychlorinated biphenyls (PCBs) (Yu-Cheng mothers or fathers), we measured the development and behavioral problems in 1991-2. The development was assessed with the Chinese Child Developmental Inventory (CCDI), and the behavioral problems with Rutter's Child Behavior Scale A. Children of Yu Cheng mothers had delayed development on several subscales of CCDI and on the combined general development score. Girls were more affected than boys in their development. Children of Yu-Cheng fathers did not score differently from unexposed controls on this measurement. In Rutter's scale, the scores in Yu-Cheng mothers' children and Yu-Cheng fathers' children were not different from those of their unexposed controls. We conclude that children born seven to twelve years after mothers' exposure to degraded PCBs had delayed development, but they did not show more behavior problems when compared with unexposed controls. PMID- 7850389 TI - Cognitive development in Yucheng children. AB - We have been following up the biological and mental development of children exposed prenatally to polychlorinated biphenyls and their contaminants (Yucheng children). When we started this 12-year follow-up study in August 1985, 118 Yucheng children we assigned a non-exposed child matched by sex, age, locality of residence, mother's age, socio-economic status of the family. This article reports the cognitive aspect of the development of Yucheng children as compared to their matched controls. A consistent tendency which indicates that Yucheng children score lower in each kind of measurement tool at each age level has been observed. This seems to imply that congenitally exposure to PCBs and their contaminants has long-term adverse effects on the cognitive development of human being. PMID- 7850390 TI - Disordered behavior in the early-born Taiwan Yucheng children. AB - Behavioral problems were evaluated in Taiwanese children who were born between July 1978 and June 1985 to women who had consumed rice oil that was contaminated by heat-degraded polychlorinated biphenyls (PCBs). One hundred and eighteen such children, referred to as 'the early-born Yucheng children', and matched controls were followed with the Chinese version of Rutter's Child Behavior Scale A annually from 1985 to 1991. At any fixed age, the early-born Yucheng children had mean Rutter behavior scores 1.75 to 2.40 points higher (14-38% worse) than that of their controls. The effects were similar in the health, habit, and behavioral subscores and persistent as the children aged. PMID- 7850391 TI - Laboratory results for selected target organs in 138 individuals occupationally exposed to TCDD. AB - Blood specimens for dioxin congener analysis and clinical laboratory studies were recently obtained for 138 employees who had been potentially exposed to 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) following a 1953 trichlorophenol autoclave accident. Results for 34 clinical tests were regressed on three exposure measures (current TCDD concentration, log TCDD concentration back-calculated to the time of exposure, and chloracne status). Age, smoking status and body-mass-index were included as additional explanatory factors in the analyses. Positive associations were found between each of the exposure measures and both serum thyroxine (T4) and thyroxine binding globulin (TBG). Additional exposure-response associations were detected relative to several immune system parameters, erythrocyte sedimentation rate, platelet count and serum alkaline phosphatase. These data will be specifically helpful in interpreting the results of additional morbidity and mortality studies conducted within the same target population. PMID- 7850392 TI - Recent measures to further reduce dioxin impact on man and the environment in the Federal Republic of Germany. AB - During last year's Dioxin symposium at Tampere/Finnland a report was given on the legislative actions of the German Federal Government to reduce dioxin release into the environment (1). Since then, further progress has been made, especially to regulate chemicals and to establish orientation values for PCDD/F in cow's milk. An international dioxin symposium and hearing was held in Berlin in November 1992, which focused on the scientific base for legislative and other governmental action to minimize dioxin burden on man and the environment. Measurements from different media including breast milk indicate a decrease in dioxin release into the environment during the last several years in Germany. PMID- 7850393 TI - Mutagenic and carcinogenic risk of oxygen containing chlorinated C-3 hydrocarbons: putative secondary products of C-3 chlorohydrocarbons and chlorination of water. AB - Oxygen containing C-3 chlorohydrocarbons are secondary products of C-3 chlorohydrocarbons formed during oxidation at air, in the metabolism of pesticides and by chlorination of drinking water. These compounds are mutagenic, genotoxic and carcinogenic. 2-Chloroacroleins are extremely strong mutagens and genotoxins and form 1,N2-cyclic deoxyguanosine adducts. The role of such adducts in mutagenicity and carcinogenicity is discussed. PMID- 7850394 TI - Rapid-rate transcranial magnetic stimulation and ECT. PMID- 7850395 TI - The significance of clinical EEG abnormalities in depressed patients treated with ECT. AB - Standard pretreatment clinical electroencephalograms (EEGs) were abnormal in 18.6% of 140 consecutive patients with Research Diagnostic Criteria (RDC) endogenous major depression. The patients were randomized to unilateral or bilateral and low- and high-dosage electroconvulsive therapy (ECT) conditions. Clinical features, short-term treatment response, and the rate and timing of relapse were contrasted in patients with normal and abnormal clinical EEG examinations. Psychotic depression was more common among abnormal EEG (61.5%) than normal EEG (38.9%) patients. Otherwise, the two groups were equivalent in a variety of demographic, clinical, and pharmacological variables. Patients with abnormal EEG findings tended to show a poorer rate of response to unilateral ECT, but a strong rate of response to bilateral ECT. Rates and timing of relapse were equivalent in the two groups. Other than the suggestion that bilateral ECT may be preferable in patients with clinical EEG abnormalities, little evidence was found that such abnormalities characterize discrete subgroups or have preductive utility with respect to ECT outcome. PMID- 7850396 TI - Asymmetric bilateral right frontotemporal left frontal stimulus electrode placement: comparisons with bifrontotemporal and unilateral placements. AB - The asymmetric bilateral stimulus electrode placement described by Swartz was used to treat four patients, ages 60, 75, 75, and 80 years, who had previously received electroconvulsive therapy with other placements. After the course, each showed full remission with no overt cognitive dysfunction and no decrement in mini-mental state score. Three patients had shown substantial confusion during previous treatments, one with bifrontotemporal brief pulse and two with sine wave, at least one of whom received unilateral treatment. Remission was maintained at followup 2-4 months later. These cases further suggest that this new placement is clinically useful. PMID- 7850397 TI - An exploratory evaluation of ECT in haloperidol-treated DSM-IIIR schizophreniform disorder. AB - In a double-blind, prospective study, 30 consecutive treatment-naive adult men with first-onset psychosis and DSM-IIIR provisional schizophreniform disorder (without good prognostic features) were randomized into true electroconvulsive therapy (ECT) and sham ECT groups. Both groups received haloperidol in a fixed dose of 15 mg at night. The ECT schedule comprised six bilateral, sinusoidal wave treatments administered on alternate days, thrice a week. Weekly ratings for the first 6 weeks showed an absence of significant difference between the groups in the number of patients responding and in the rate of attenuation of psychosis; severity of depression, while less in the true ECT group after the first 3 weeks, did not differ between the groups at any subsequent time point. Clinical ratings were repeated at 6 months, and social functioning was assessed; again, no group differences emerged. It is concluded that ECT does not meaningfully improve response in unselected schizophreniform disorder that is treated with an adequate dose of neuroleptic. PMID- 7850398 TI - Consent to electroconvulsive therapy: investigation of the validity of a competency questionnaire. AB - A valid consent is a necessary precondition to the administration of electroconvulsive therapy (ECT). However, the assessment of mental competence to consent may be both complicated and controversial because neither case law nor statutes provide a clear description of the necessary mental abilities. The closest approximation in the literature is that derived from judicial commentary on the relevant case law and summarized into four standards. We designed a 15 item questionnaire to define and test the content or essential elements of each of these standards, and surveyed lawyers and health care professionals with known expertise or interest in the field to investigate the content validity of the questionnaire. Of the 15 items, 12 were rated important or essential to the assessment of competence to consent to ECT by > or = 67% of the lawyers and 11 were so rated by > or = 67% of the health professionals. Ten items were rated as important or essential by > or = 67% of both groups. Only two items were not so endorsed by > or = 67% of one of the groups. We conclude that the questionnaire has a satisfactory content validity and may be considered a general guideline for assessing competence to consent to ECT. PMID- 7850399 TI - What do rodents and test tubes teach us about ECT? PMID- 7850401 TI - Convalescence and ECT. PMID- 7850400 TI - ECT in combined multiple system atrophy and major depression. PMID- 7850403 TI - Circulation and hemodynamics. PMID- 7850402 TI - Hormones, autacoids, neurotransmitters, and growth factors. PMID- 7850404 TI - Renal mechanisms of salt sensitivity in hypertension. PMID- 7850405 TI - The sodium pump in hypertension. AB - There is increasing evidence that the sodium pump plays a role in essential hypertension. Recent publications have focused on intrinsic alterations in pump activity, external modification of pump activity by circulating inhibitors, and endothelial mediation of endogenous inhibitor effects on the vascular response. Hence, this review focuses on these areas. Although there is intriguing evidence that alterations in sodium pump activity might contribute to the pathogenesis of hypertension, in at least some sodium-sensitive models and some patients with essential hypertension, the evidence remains circumstantial and areas of substantial controversy exist. PMID- 7850406 TI - Human angiotensin receptor subtypes. AB - The rapid expansion of our knowledge of angiotensin receptors has been led by the development of subtype-specific angiotensin II receptor antagonists and by the cloning and sequencing of the AT1 receptor in angiotensin II. Although some actions of angiotensin II have been attributed to AT2 subtype receptors, the importance of these binding sites remains elusive. Nonpeptide, AT1-selective antagonists, such as losartan, block virtually all of the well-known effects of angiotensin II in mammalian cells. The effects of losartan are now being confirmed by the rapidly developing class of nonpeptide, AT1-selective angiotensin II receptor antagonists. In rodents, subtypes of the AT1 receptor have been cloned and designated AT1A and AT1B, but they have not been functionally distinguished. Such isoforms have not been identified for human AT1 receptors. Importantly, it now appears that the AT2 receptor has been cloned. The angiotensin receptors undergoing intense study are those in fetal tissue, brain, endothelial cells, and fibroblasts. Angiotensin II-induced growth and cardiovascular hypertrophy are the focus of broad-based research efforts. The clinical relevance of angiotensin II receptor subtypes is unknown, but there is growing evidence that AT1-selective agents are effective inhibitors of the angiotensin system in humans. PMID- 7850407 TI - Genetics and molecular biology of hypotension. AB - Major strides in the molecular biology of essential hypertension are currently underway. This has tended to obscure the fact that a number of inherited disorders associated with low blood pressure exist and that these diseases may have milder and underrecognized phenotypes that contribute importantly to blood pressure variation in the general population. This review highlights some of the gene products that, if abnormal, could cause hypotension in some individuals. Diseases due to abnormalities in the catecholamine enzymes are discussed in detail. It is likely that genetic abnormalities with hypotensive phenotypes will be as interesting and diverse as those that give rise to hypertensive disorders. PMID- 7850408 TI - The angiotensin I-converting enzyme gene polymorphism: implication in hypertension and myocardial infarction. AB - The angiotensin I-converting enzyme gene is one of the major genes of the renin angiotensin and kallikrein-kinin systems and is a candidate gene for several cardiovascular diseases for which a genetic predisposition has been established. Based on analysis of the level of the enzyme in plasma, a genetic polymorphism of its expression has been well characterized. Use of a DNA marker on the angiotensin I-converting enzyme gene has shown that the gene polymorphism is located within the angiotensin I-converting enzyme gene itself. This review summarizes the results of various studies of this polymorphism in cardiovascular diseases and the hypotheses that can be proposed to explain this effect. PMID- 7850409 TI - What can the molecular genetics of hypertensive rats teach us about the genetics of hypertension in humans? AB - Recent progress in molecular genetics has raised expectations that the application of powerful new techniques to established animal models of hereditary hypertension may provide important new insights in the genetic basis of human hypertension. Whereas these methods provide exciting opportunities, we shall have to revise many traditional and established strategies used in hypertension research to recognize their full potential. Although it is probably naive to anticipate the quick identification of genes involved in the pathogenesis of human hypertension from this research, these methods, if applied wisely, are likely to render important conceptual insights into the nature not only of hypertension and cardiovascular disease but of polygenic disorders in general. PMID- 7850410 TI - Dopamine action and metabolism in the kidney. AB - Dopamine is one of the major natriuretic hormone. It acts as an autocrine or paracrine factor to inhibit Na+ transport in several tubular segments. Na+,K(+) ATPase is an important target protein for dopamine. Studies of the tubular effects of dopamine have provided new information about the coupling of dopamine to intracellular signaling systems and about the molecular mechanism for dopamine interaction with other hormones. Several lines of evidence now suggest that abnormalities of the renal dopamine system can lead to salt-sensitive hypertension. PMID- 7850411 TI - Molecular and cellular biology of vasopressin and oxytocin receptors and action in the kidney. AB - The molecular cloning and characterization of receptors for [Arg8] vasopressin and oxytocin were recently accomplished. These receptors form a subfamily among the large number of guanine nucleotide-binding regulatory protein (G protein) coupled receptors with seven transmembrane domains. The molecular cloning of the human V2 receptor was rapidly followed by the identification of mutations in the V2 receptor gene segregating with the clinical phenotype in families with X linked nephrogenic diabetes insipidus. These naturally occurring mutations will be useful to identify critical functional regions of the vasopressin V2 receptor. Carrier detection and early diagnosis of affected male infants are available and can avert the physical and mental retardation that are the consequences of episodes of dehydration. Together with the recent cloning of the vasopressin regulated water channels in the apical membrane of the collecting tubule, these developments will enable direct investigation of the mammalian concentrating mechanism. PMID- 7850412 TI - Transforming growth factor-beta and the pathogenesis of glomerular diseases. AB - Transforming growth factor-beta (TGF-beta) is a cytokine that is important in embryogenesis, development, carcinogenesis, and tissue repair. TGF-beta is unique among cytokines in its widespread actions on the regulation of extracellular matrix. In a model of acute mesangial proliferative glomerulonephritis, it was shown that overproduction of TGF-beta is the cause of pathologic matrix accumulation in the nephritic glomeruli. TGF-beta acted to increase matrix production, inhibit matrix degradation, and modulate matrix receptors in the glomerulonephritic rats. Elevated expression of TGF-beta was also found in other experimental glomerular diseases, including diabetic nephropathy. Studies of humans with glomerulonephritis and diabetic nephropathy also strongly implicated TGF-beta in the pathogenesis of glomerular matrix build-up. Recently, the proteoglycan decorin was shown to neutralize TGF-beta. When injected into glomerulonephritic rats, decorin markedly suppressed pathologic matrix deposition in the glomeruli. Thus, decorin offers hope as a treatment for progressive kidney diseases caused by the overproduction of TGF-beta. PMID- 7850413 TI - The mechanisms of regulation of vitamin D metabolism in the kidney. AB - Recently, the 24-hydroxylase enzyme of 25-hydroxyvitamin D3 was purified from rat and chick kidney, and its complementary DNA was cloned. The length of the rat 24 hydroxylase gene is about 15 kbp with 12 exons. Cloning of the 24-hydroxylase gene made it possible to examine the mechanism of regulation of vitamin D metabolism at the gene level. Expression of renal 24-hydroxylase mRNA is regulated by a balance of plasma parathyroid hormone and 1 alpha,25 dihydroxyvitamin D3 levels, whereas intestinal 24-hydroxylase mRNA is regulated mainly by plasma 1 alpha,25-dihydroxyvitamin D3. This article reviews recent progress in understanding the molecular aspects of vitamin D metabolism. PMID- 7850414 TI - Physiologic and pathophysiologic roles of endothelin in the kidney. AB - Endothelin is an important modulator of renal function via its binding to abundant receptors in renal tissue and by the ability of renal endothelial and epithelial cells to synthesize and release endothelin. In the kidney, endothelin may function as a paracrine-autocrine factor in the regulation of renal blood flow, glomerular hemodynamics, and sodium and water homeostasis. Recent evidence suggests that circulating endothelin may play an important role in renal regulation in cardiorenal states of endothelin activation. Endothelin is a potent renal vasconstrictor that has dual actions on glomerular filtration rate due to its ability to preferentially constrict efferent arterioles preserving glomerular filtration. Furthermore, endothelin modulates sodium excretion and water balance at the level of the proximal tubule and medullary collecting ducts, respectively, by mechanisms that are still unclear. In addition, endothelin stimulates the renin-angiotensin-aldosterone system and atrial natriuretic peptide release and inhibits arginine vasopressin-mediated water reabsorption in the inner medullary collecting duct. Recent studies using specific receptor antagonists have demonstrated a pathophysiologic role for endothelin during renal ischemia, cyclosporine-induced toxicity, and chronic renal failure. This review highlights recent research that supports an important role for endothelin as a locally produced vasoactive and natriuretic peptide in the regulation of renal hemodynamic and excretory functions. PMID- 7850415 TI - Endothelin peptides and compensatory growth of renal cells. AB - Endothelins are paracrine or autocrine peptides that regulate diverse aspects of renal function. In addition to their potent vasoconstrictor activity, recent evidence suggests that endothelin-1 is a growth factor for renal cells. Different forms of renal injury markedly upregulate endothelin-1 secretion, which is postulated to contribute to compensatory renal growth. Similar roles have been hypothesized for other vasoactive peptides, such as angiotensin II and arginine vasopressin. New information has recently emerged regarding pathways of mitogenic signaling linking activation of endothelin receptors to changes in gene expression. ETA receptor subtypes activate downstream effectors, such as protein kinase C, protein tyrosine kinases of the src gene family, and mitogen-activated protein kinases. These cytosolic effectors in turn lead to altered programs of gene expression by activating, among others, AP-1 and serum response factor transcription factors. In addition, recent studies in organisms amenable to genetic analysis, such as Drosophila, Dictyostelium, and yeast, are providing important clues to effector mechanisms employed by vasoactive peptide receptors in higher organisms. Information on the molecular mechanisms for mitogenic signaling by endothelin receptors might be used to gain insight into the pathogenesis of compensatory renal growth and the development of novel therapeutic strategies. PMID- 7850416 TI - Endothelin in kidney disease. AB - The role of endothelin in renal physiology and pathophysiology continues to be the subject of intense current research. Further insight into the mechanisms of interaction of endothelin in the kidney has provided a better understanding of its effects on renal hemodynamics and tubular function. Of interest is the emerging role of endothelin as a potential physiologic osmotic regulator of sodium and water reabsorption in the renal medulla. Increasing evidence implicates endothelin in the pathophysiology of progressive glomerulosclerosis, postischemic renal failure, cyclosporine-induced nephrotoxicity, and radiocontrast-induced nephropathy. The recent finding of elevated plasma endothelin levels in patients with the hepatorenal syndrome is particularly exciting and implicates a potential role for endothelin in the pathophysiology of the renal failure that occurs in patients with this syndrome. PMID- 7850417 TI - Endothelin, endothelin receptors, and endothelin antagonists. AB - Endothelin is a peptide with potent biologic effects in vascular and nonvascular cells. Its effects are mediated by two receptors, ETA and ETB, and possibly also by a third receptor, ETC. In vascular smooth muscle cells, endothelin causes profound contraction and also has proliferative effects, mainly through activation of ETA but also through ETB receptors. Activation of endothelin receptors on vascular smooth muscle explains the profound vasoconstriction observed in isolated blood vessels as well as with infusion of the peptide in vivo. Endothelial cells can express ETB receptors linked to the formation of nitric oxide or prostacyclin. Activation of these receptors leads to the transient vasodilation observed with intravascular infusion of the peptide. In vascular smooth muscle, activation of endothelin receptors stimulates phospholipase C, with concomitant formation of inositol triphosphate and diacylglycerol. These events lead to the release of intracellular calcium and initiation of contraction. In addition, endothelin can activate voltage-operated calcium channels via Gi proteins, thereby increasing influx of extracellular calcium. The later phenomenon may explain the ability of calcium antagonists to inhibit endothelin-induced contractions. Normally, circulating endothelin levels, as well as production of the peptide in isolated blood vessels, are rather low due to the absence of stimuli and the presence of potent inhibitory mechanisms. Important stimulators of endothelin production are thrombin, angiotensin II, arginine vasopressin, and transforming growth factor-beta, as well as certain cytokines and physicochemical factors such as hypoxia.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7850418 TI - Arteriolar structure and its implications for function in health and disease. AB - Vascular remodeling is a general term describing any change in blood vessel structure caused by hemodynamic changes, such as flow and pressure, injury, or disease. It also encompasses development and vascularity. This review focuses on the implications of remodeling from both structure and function of isolated arteries and on how a remodeled vascular bed responds to vasoactive stimuli. Essential, genetic, experimental, and pulmonary hypertension, endothelial dysfunction in atheroma, vascular surgery, subarachnoid hemorrhage, congestive heart failure, coronary collateralization, ischemia, and pregnancy are among the examples discussed in this review. Research efforts should be directed toward understanding the processes of cell-cell interaction underpinning these changes in structure and function. Much could be gained from better measurement of vascular structure and full stimulus-reactivity relationships under in vivo conditions in a variety of vascular beds and models of animal and human hypertension. Mathematical models of the average vascular structure drawn from experimental data aid clear thinking when discussing the remodeling process. PMID- 7850419 TI - Allosteric activation of latent p53 tetramers. AB - BACKGROUND: The DNA-binding activity of p53 is essential to its function as a tumour suppressor. Point mutations that abolish this activity have been found to occur frequently in the p53 genes of human cancer cells. Wild-type p53 protein assembles into oligomers with latent DNA-binding activity that can be activated in vitro by phosphorylation of a carboxy-terminal regulatory region, catalyzed by protein kinase C or casein kinase II. We have investigated the mechanism underlying this post-translational regulation of p53. Specifically, we have asked the following questions. First, whether the carboxy-terminal regulatory site contributes to p53's ability to form tetramers. Second, whether the latent DNA binding activity of p53 can be activated in vivo. And third, whether the activation of p53 is reversible. RESULTS: Biophysical molecular-sizing analysis shows that both latent and activated forms of p53 are tetramers. Using a novel method, we have further established that p53 remains tetrameric when bound to DNA. We have also found that p53 can indeed be activated in vivo: p53 prepared from cells can be separated into activated and latent forms. Finally, we generated a monoclonal antibody specific for the casein kinase II target site in the carboxy-terminal regulatory region of p53, and used it to demonstrate the allosteric inhibition of in vitro and in vivo activated forms of p53. CONCLUSIONS: p53 protein assembles naturally as a tetramer that can be converted between latent and activated forms by a concerted, allosteric transition. The highly purified, reconstituted system that we have developed, in which the DNA binding activity of p53 can be reversibly regulated, should facilitate the discovery of agents that can modulate the DNA-binding activity of p53- particularly those that can activate mutant p53 proteins and that may have potential in the design of anti-cancer drugs. PMID- 7850420 TI - Cip1 blocks the initiation of DNA replication in Xenopus extracts by inhibition of cyclin-dependent kinases. AB - BACKGROUND: Cip1 is a 21 kD protein that interacts with and inhibits cyclin dependent kinases (cdks). Expression of Cip1 is induced by the tumour suppressor p53, and tumour cells have greatly reduced levels of Cip1. As cdks are required for normal progression through the cell cycle, their inhibition by Cip1 may mediate the ability of p53 to block cell proliferation. Cip1 has also been shown to inhibit the DNA polymerase delta auxiliary factor PCNA (proliferating cell nuclear antigen), which is required for replication-fork elongation, and this could be an alternative mechanism by which p53-induced Cip1 blocks cell proliferation. RESULTS: We have investigated the effect of Cip1 protein on chromosomal DNA replication, using cell-free extracts of Xenopus eggs that initiate and complete chromosome replication under normal cell-cycle control. Cip1 protein strongly inhibited an early stage of DNA replication in this system, and this inhibition was not complemented by extracts that had been affinity depleted of cdks. In contrast, Cip1 did not inhibit the elongation of replication forks that had accumulated in the presence of aphidicolin. Cip1 inhibition of DNA replication was fully rescued by addition of cyclins A or E, but not cyclin B, cdk2 or PCNA. CONCLUSIONS: Our results suggest that Cip1 specifically blocks the initiation of DNA replication by inhibition of a cyclin-dependent kinase (cdk2), but has no major effect on the elongation of preassembled replication forks. The ability of cyclin A or cyclin E to rescue the Cip1 inhibition suggests that these cyclins may play a direct role in the initiation of replication in the Xenopus system. PMID- 7850421 TI - Three-dimensional solution structure of the pleckstrin homology domain from dynamin. AB - BACKGROUND: The pleckstrin homology (PH) domain is a region of approximately 100 amino acids, defined by sequence similarity, that has been found in about 60 proteins, many of which are involved in signal transduction downstream of cell surface receptors; the function of PH domains is unknown. The only clue to the function of PH domains is the circumstantial evidence that they may link beta gamma subunits of G proteins to second messenger systems. Knowledge of the three dimensional structures of PH domains should help to elucidate the roles they play in the proteins that contain them. RESULTS: Using homonuclear and heteronuclear magnetic resonance spectroscopy, we have determined the solution structure of the PH domain of the GTPase dynamin, one of a number of proteins that have PH domains and interact with GTP. The fold of the dynamin PH domain is composed of two antiparallel beta-sheets, which pack face-to-face at an angle of approximately 60 degrees. The first beta-sheet comprises four strands (residues 13-58) from the amino-terminal half of the protein sequence; the second beta-sheet contains three strands (residues 63-99). A single alpha-helix (residues 102-116) flanks one edge of the interface between the two sheets, parallel in orientation to the second sheet, in an alpha/beta roll motif similar to that of the B oligomer of verotoxin 1 from Escherichia coli. CONCLUSIONS: The structure of the dynamin PH domain is very similar to the recently reported structures of the pleckstrin and spectrin PH domains. This shows that, despite the low level of sequence similarity between different PH domains, they do have a characteristic polypeptide fold. On the basis of our structure, the suggestion that PH domains engage in coiled-coil interactions with G protein beta gamma subunits seems unlikely and should be re evaluated. PMID- 7850422 TI - Human cortical areas selectively activated by apparent sound movement. AB - BACKGROUND: Positron emission tomography (PET) measures cerebral blood flow, an indicator of neural activity. PET has been used successfully to identify visual association areas in the human brain, which are involved in the analysis of different aspects of visual stimuli. However, comparable studies have not yet been carried out for the human auditory system. RESULTS: We have attempted to identify human cortical areas that are selectively activated during sound movement analysis. Using PET, we have identified cortical areas that appeared to be selectively activated while human subjects attended to the position of a moving sound image compared to when they attended to a stationary sound image. The areas are in the right insula, adjacent to the right posterior cingulate, and in the cerebellum. CONCLUSIONS: We suggest that the insula may be acting as an auditory association cortex involved in sound movement analysis, analogous to area V5 in the visual system. PMID- 7850423 TI - Switching neurons are integral members of multiple oscillatory networks. AB - BACKGROUND: The stomatogastric ganglion of the crab Cancer borealis contains the neurons that generate several different behaviors, such as the fast pyloric rhythm and the slower gastric-mill rhythm. It has previously been shown that many stomatogastric ganglion neurons can switch between pyloric- and gastric-timed activity. However, the question remained whether these neurons really are integral members of several central-pattern-generating networks, or just passive followers that only change their activity patterns in response to a switch determined by other neurons. RESULTS: To address this question, we perturbed the activity of the 'pyloric' ventricular dilator neuron and the 'gastric' lateral gastric neuron during ongoing pyloric and gastric rhythms. In the absence of ongoing gastric rhythms, these neurons can fire in pyloric time, and perturbing them can reset the pyloric rhythm. During robust gastric activity, the lateral gastric and ventricular dilator neurons can fire in gastric time, and perturbing them can reset the gastric rhythm. CONCLUSIONS: When stomatogastric ganglion neurons change their firing patterns, they also function as part of the circuitry that generates the new rhythm with which they are firing, demonstrating that individual neurons can be used as part of multiple pattern-generating circuits. PMID- 7850424 TI - Mouse development. Winged-helix in axial patterning. AB - Analysis of HNF-3beta mutant mice demonstrates that the HNF-3beta transcription factor is an important regulator of the gastrulating mouse embryo. PMID- 7850425 TI - Cell division. Septins in common? AB - Two apparently quite distinct processes, cytokinesis in animal cells and in budding yeast cells, have been shown to involve proteins of the same family, the septins, suggesting that the two may not be so different after all. PMID- 7850426 TI - Molecular evolution. Dissolving the barriers. AB - The crystal structure of lysin, a protein involved in abalone fertilization, together with evolutionary sequence analysis, provides clues to lysin's non enzymatic mode of action and possible role in speciation. PMID- 7850427 TI - Cell-cell interactions. Receiving signals in the nematode embryo. AB - Two molecules involved in an inductive cell-cell interaction in the C. elegans early embryo have been identified. The apx-1 gene seems to encode the ligand and glp-1 the receptor responsible for the induction. PMID- 7850428 TI - Retinal synapses. Glutamate receptors for signal amplification. AB - The localization of metabotropic glutamate receptors in retinal bipolar cells supports the view that these receptors are involved in the synaptic amplification that allows the detection of dim-light stimuli. PMID- 7850429 TI - Lampbrush chromosomes. Asymmetric loops. AB - Although the study of lampbrush chromosomes has proved highly informative over the years, some aspects of their structure remain strangely enigmatic. PMID- 7850430 TI - Evolution. Archaea and eukaryotes versus bacteria? AB - The recent discovery of homologs of the eukaryotic transcription factor TATA binding protein in archaea has been taken as support for the view that archaea and eukaryotes have a close phylogenetic relationship. PMID- 7850431 TI - Membrane traffic. Call for the COPs. AB - Vesicles are the vehicles of membrane traffic in cells. A new complex of cytosolic proteins that is required for vesicle formation at the endoplasmic reticulum, dubbed COPII, has been identified. PMID- 7850432 TI - T-cell activation. Transcriptional regulation in activated T cells. AB - Assembly of the activated T-cell transcription factor, NF-AT, from two different types of subunit is sensitive to immunosuppressive drugs and is a striking example of gene regulation by convergent intracellular signals. PMID- 7850433 TI - Protein folding. Folding helpers and unhelpful folders. AB - Recent studies have provided new insights into the mode of action of protein disulphide isomerases in the catalysis of protein folding. PMID- 7850435 TI - Translational regulation. Y the message is masked? AB - Much mRNA in Xenopus oocytes is translationally dormant for months until meiotic maturation and fertilization. This masking has been found to be coupled to transcription and mediated by the Y-box protein FRGY2. PMID- 7850434 TI - Synapse development. Up the junction. AB - alpha-Dystroglycan has been suggested to be the receptor for agrin, an extracellular glycoprotein that signals postsynaptic differentiation at the neuromuscular junction, but it may not have the necessary specificity. PMID- 7850436 TI - Synthetic proteins. Designer proteins. AB - Attempts to synthesize de novo proteins with particular properties should improve our understanding of the long-range cooperative interactions that are so crucial to the structure and function of proteins. PMID- 7850437 TI - Replication initiation. A new controller in Escherichia coli. AB - A new factor involved in the sequestration of recently active replication origins in Escherichia coli, SeqA, has been discovered and appears to be a multifaceted negative regulator of replication initiation. PMID- 7850438 TI - T-cell regulation. Tails of phosphorylation and T-cell activation. AB - How do quantitative differences in T-cell signal transduction lead to qualitatively different responses? Recent work demonstrates that even well established regulatory paradigms are open to question. PMID- 7850439 TI - Programmed cell death. A rich harvest. AB - The identification of genes that affect programmed cell death in Drosophila puts this organism at the forefront of cell-death research. PMID- 7850440 TI - Sport, science and medication. PMID- 7850441 TI - Equine echocardiography. PMID- 7850442 TI - Models for assessing the relationship between drug concentration and drug effect in performance horses. AB - The actions of most drugs are dependent upon achieving adequate plasma concentrations. Plasma concentrations are influenced by the degree to which a drug is absorbed, distributed, metabolized and excreted. Pharmacokinetic assessment reflects changes in these variables as a function of time. Pharmacodynamics refers to specific drug effects or mechanisms of drug action. Individual drug pharmacokinetics provides information on which to base a therapeutic dose, route of administration and dosing interval. However, not all drug actions temporally correlate with plasma kinetics. To resolve this discrepancy, pharmacodynamic models of drug action have been developed. In this review several pharmacodynamic models of anti-inflammatory and central nervous system effects are discussed in relationship to individual drug pharmacokinetics in the horse. The use of appropriate statistical models can minimize error and maximize the detection of drug effects over time. Data are presented showing the value of pharmacodynamic models in assessing and predicting the onset, peak and duration of drug action. Penetration of drugs into inflamed tissue or the brain may not temporally correlate with plasma kinetics. Therefore, drug kinetics in tissues or compartments associated with a particular effect may be a better predictor of efficacy than plasma concentrations. Recent studies have shown that exercise can affect drug disposition and influence both pharmacokinetics and pharmacodynamics. In competitive athletes, plasma or urine concentrations of drugs are determined to regulate use. Some jurisdictions are advocating the establishment of specific drug thresholds based upon plasma or urine concentrations. However, drug effects may occur during low or undetectable plasma concentrations. Urine concentrations are often dissociated in time from those in plasma. Therefore, the use of appropriate pharmacodynamic models, and the exercising horse, can complement plasma pharmacokinetics in determining drug efficacy and drug thresholds. PMID- 7850443 TI - Equine echocardiography--sound advice at the heart of the matter. AB - Echocardiography is an extremely versatile tool for both the equine clinician and physiologist. There are three useful forms of echocardiography, B mode, M mode and Doppler. Together they provide complementary information on cardiac disease and haemodynamic status. B mode is used to image the cardiac chambers, valves, myocardium and pericardium. M mode allows determination of motion of cardiac structures; it is superior to B mode for timing of events and it is used to make precise measurements of the heart. Doppler echocardiography can assess intracardiac blood flow and its velocity. Echocardiography has applications in all forms of equine cardiac disease. In this article the principles of, and imaging techniques used in, B mode, M mode and Doppler echocardiography in the horse are reviewed. Normal findings and abnormalities seen in association with valvular lesions, congenital cardiac disease, myocardial and pericardial diseases are discussed. Recent developments in echocardiographic techniques for assessment of ventricular function are described. PMID- 7850444 TI - The effectiveness of copper oxide powder as a component of a sustained-release multi-trace element and vitamin rumen bolus system for cattle. AB - Copper oxide powder administered in the form of two experimentally produced sustained-release rumen boluses significantly increased blood and liver copper concentrations in growing sheep. It was estimated that 7% of the copper released was stored in the liver. In two farm observation trials administration of two standard production boluses significantly increased blood copper concentrations in out-wintered suckler cows during late pregnancy and early lactation, and in growing cattle at grass in the summer over periods of at least 170 and 123 days, respectively. PMID- 7850445 TI - Detection of Chlamydia psittaci (ovis) antigen in tissue sections and McCoy cells using streptavidin-biotin and the IMAGEN staining method. AB - Two procedures for identifying chlamydial antigen in infected McCoy cells and tissue sections are described. Both the streptavidin-biotin method and the IMAGEN test clearly detected chlamydial antigen in ovine placental tissue sections and in infected McCoy cells before they could be detected by conventional stains. The streptavidin-biotin method is lengthy, but specific and sensitive, and the slides can be kept indefinitely for later examination. By contrast, the IMAGEN test is a single step procedure which requires fluorescent microscopy and slides can only be kept for up to 1 week before examination. PMID- 7850446 TI - The use of long-acting oxytetracycline for the treatment of ovine footrot. AB - The use of long-acting oxytetracycline for the treatment of ovine footrot was investigated under different experimental conditions. In sheep with artificially induced footrot housed under dry conditions, treatment with long-acting oxytetracycline produced a cure in 6/6 affected feet (a cure rate of 100%); foot bathing in zinc sulphate produced a cure in 2/8 affected feet (a cure rate of 25%). This difference was statistically significant (P < 0.05). In sheep with naturally occurring footrot, housed under dry conditions, treatment with long acting oxytetracycline produced a cure in 8/9 affected feet (a cure rate of 89%); foot-bathing in zinc sulphate produced a cure in 7/10 affected feet (a cure rate of 70%). This difference was not statistically significant. In sheep with naturally occurring footroot, kept under field conditions, treatment with a combination of long-acting oxytetracycline and foot-bathing in zinc sulphate produced a cure in 49/52 affected feet (a cure rate of 94%); treatment by foot bathing alone produced a cure in 39/51 affected feet (a cure rate of 77%). This difference was statistically significant (P < 0.05). PMID- 7850447 TI - Effects of luteolytic doses of prostaglandin F2 alpha and cloprostenol on concentrations of progesterone, luteinizing hormone, follicle-stimulating hormone, glucose, insulin, growth hormone, thyroxine, prolactin and cortisol in jugular plasma of lactating dairy cows. AB - Three groups of five lactating dairy cows in the mid-luteal phases of oestrous cycles were given an injection (at time 0 h) of the naturally-occurring prostaglandin F2 alpha (PGF2 alpha) or cloprostenol (a synthetic analogue of PGE2 alpha) at doses recommended for inducing luteolysis, or injection vehicle. Concentrations of glucose and hormones in jugular plasma were measured from 26 h before to 12 h after the injections and the significance (P < 0.05) of the effects of the prostaglandins on these concentrations was determined. Both prostaglandins induced falls in progesterone concentration and rises in luteinizing hormone concentration; neither influenced follicle-stimulating hormone. PGF2 alpha increased glucose concentration; neither prostaglandin influenced insulin concentration. Both prostaglandins increased growth hormone concentration and resulted in declining thyroxine concentration. PGF2 alpha increased prolactin and cortisol concentration. There were, however, no significant differences between the effects of the two prostaglandins on any hormone (or glucose) concentration. PMID- 7850448 TI - Preliminary evidence for the enterohepatic circulation of progesterone in the pig. AB - In two gilts, following doses of either 47.7 or 64.6 mumol progesterone, a secondary increase in steroid concentration in portal and mesenteric blood plasma occurred 35-40 min after dosing or 10-15 min after an intravenous (i.v.) dose of cholecystokinin. It is suggested that this increase is splanchnic blood progesterone concentration indicates that the steroid undergoes enterohepatic circulation. In five ovariectomized gilts given single i.v. doses of 47.7 mumol progesterone, the steroid was cleared from the circulating plasma bi exponentially; the mean half-lives (t 1/2) of the two components were 2.47 (+/- 0.36) and 33.5 (+/- 6.63) min. The t 1/2 of the first component was compatible with the liver being a principal organ of clearance. PMID- 7850449 TI - Peripheral blood concentrations of plasma steroids and a metabolite of prostaglandin F2 alpha in pregnant cows vaccinated against foot and mouth disease. AB - Blood samples were collected from 82 pregnant cows at 6-h intervals to determine the effects of vaccination against foot and mouth disease (FMD) on plasma concentrations of progesterone, total unconjugated oestrogens, total corticosteroids and 13,14-dihydro-15-keto-prostaglandin F2 alpha (PGFM). Twenty two (26.8%) cows showed a strong post-vaccinal reaction in the form of a significant (P < 0.05) elevation in rectal temperature, accompanied by significant (P < 0.01) increases in plasma progesterone and corticosteroid concentrations for 36-42 h after vaccination. Seven (8.5%) cows returned to oestrus within 5-6 days when vaccinated during the first month of pregnancy and nine (10.9%) gave birth prematurely within 72-80 h when vaccinated during the last month of gestation. The importance of post-vaccinal reactions on embryonic mortality and premature birth is emphasized. It is suggested that cows in early and late pregnancy are most susceptible to adverse effects of vaccination against FMD. PMID- 7850450 TI - Stability of the gp53 gene of a bovine viral diarrhoea virus isolated at different times from a persistently infected steer. PMID- 7850451 TI - Metabolic and structural changes in Pseudomonas aeruginosa, Achromobacter CDC and Agrobacterium radiobacter cells injured in parenteral fluids. AB - The long term metabolic changes of three oxidase positive microorganisms (Pseudomonas aeruginosa, Agrobacterium radiobacter and Achromobacter CDC) all isolated from aquatic environment, were defined after they were inoculated in three parenteral fluids: Lactated Ringer's solution, Sodium Chloride 0.9% and Dextrose 5%. The number of microorganisms introduced into the parenteral products was adjusted to 10(5) bacteria/ml and left at room temperature (20-22 degrees C) for 30 days. Their enzymatic and protein profile as compared with their initial characteristics after they were grown in broth, were measured using API 20NE batteries of tests and gel electrophoresis. In L-R and NaCl 0.9% fluids, P. aeruginosa and Ag. radiobacter lost the ability to hydrolyse urea while Ac CDC retained this ability. In Dextrose 5% fluid the microorganisms lost most of their metabolic characters. The protein patterns in SDS-PAGE of samples prepared from cells of the tested microorganisms showed marked differences (in P. aeruginosa) to minor differences (in Ag. radiobacter and Ac CDC) while new proteins with M(r) > 66KDa revealed Ag. radiobacter cells. The gelatinolytic zymogram shows also differences between bacterial cells grown in nutrient broth and those that remained in parenteral fluids. These changes reflect the stress of the tested bacteria in an unfavorable condition. The alterations of injured bacteria could render them unable to grow on routine, for sterilization testing, culture media. PMID- 7850452 TI - Semiautomated inspection versus fully automated inspection of lyophilized products. AB - The development of fully automated inspection systems for parenteral products has created a situation of high expectations regarding productivity and quality improvements. However, not all products and production situations are suited for automation. A guideline for inspection and automation strategies will be discussed, structuring the field of lyophilized products according to the critical decision parameters. PMID- 7850453 TI - Archiving requirements for electronic pharmaceutical manufacturing documents and associated executable software. AB - Many pharmaceutical manufacturers are currently evaluating the feasibility of electronic batch record (EBR) and electronic document management (EDM) systems. Considerable effort has been invested in the design of the batch record files and electronic signature devices and procedures. Much less consideration has been given to the potential need for pharmaceutical manufacturers to be able to re create the operational software environment necessary to review archived documents at some future date. The paper discusses methods, policies, and equipment that can be used to fulfill this function. PMID- 7850454 TI - Lyophilization of biotechnology products. AB - In this review the lyophilization of biotechnology products is discussed. It is emphasized that the final quality of a protein product is determined by an interplay between the proper choice of excipients and the freeze-drying process. A crystalline matrix after freeze-drying is detrimental for the protein product. A glassy amorphous state is a prerequisite for stability, however a glassy state as such will not assure sufficient stability. The glass temperature which defines the state of the freeze-dried cake can be influenced by the moisture content and the choice of excipients. PMID- 7850456 TI - Foreign FDA pre-approval inspections: requirements/preparation. PMID- 7850455 TI - Prediction of lyophile collapse temperature by dielectric analysis. AB - A new method for predicting lyophile collapse temperatures based upon dielectric analysis (DEA) of frozen two component systems is presented. The method, called the take off frequency model (TOF), relies both on the inherent ability of DEA to detect molecular motion and on the abrupt change in viscosity experienced by a frozen sample undergoing a glass-liquid transition. Collapse temperatures for binary glass forming systems (an antibiotic, sucrose, trehalose, or sorbitol, with water) were in good agreement with the values reported in the literature. DEA was easily able to detect glass transitions poorly defined by differential scanning calorimetry (DSC). Conservative lyophilization cycles for simple systems can be quickly determined on the basis of the TOF model. PMID- 7850457 TI - Improved parenteral formulations for traditional antiepileptics. PMID- 7850458 TI - Cytokine receptor alterations during HIV infection in the human central nervous system. AB - Cytokines are potent factors mediating interactions between the immune and nervous systems. Cytokines released by macrophages/microglia, the predominant immune cell within the brain, have been proposed to modulate neuronal survival and death. In human immunodeficiency virus-encephalitis (HIVE), cytokines could modulate neurologic damage if nervous system cells possessed appropriate receptors. We hypothesized that the populations of neurons vulnerable to the toxic effects of cytokines in HIVE might contain specific receptors for these molecules. We examined the distribution of cytokine receptors in the human brain utilizing fluorescent-labeled cytokines combined with confocal laser microscopy imaging. Phycoerythrin-conjugated interleukin-1 beta and phycoerythrin Avidin/biotin conjugated transforming growth factor beta 1 labeled dendritic processes of neurons in the neocortex. Labeling was abolished by pre-incubation with unlabeled cytokines. In cases with moderate HIVE, an average 35% increase in intensity of labeling was observed compared to cases without HIVE or with cases with severe HIVE. The patterns of interleukin 2 labeling were not altered in HIVE. These results suggest that neurons susceptible to cytokine-mediated damage during the progression of HIVE display abnormal patterns of cytokine receptor labeling. PMID- 7850459 TI - Increased N-methyl-D-aspartate (NMDA) activity in the mouse spinal cord following morphine does not mediate opioid withdrawal. AB - N-Methyl-D-aspartate (NMDA) receptors have been proposed to play a role in opioid tolerance and dependence. The present study was designed to determine whether the increased NMDA activity in the spinal cord, unmasked by naloxone in morphine pretreated mice, reflects activity leading to opioid withdrawal. Behavioral responses to intrathecal injections of NMDA were inhibited by pretreatment (2 h) with morphine (10 mg/kg i.p.), but enhanced following morphine when naloxone was injected together with NMDA. Although injected at doses that inhibited NMDA activity, the excitatory effects of morphine on NMDA-induced behaviors were prevented by dizocilpine (MK-801), a phencyclidine (PCP) ligand, but not by 3 ((+/-)-2-carboxypiperazin-4-yl)-propyl-1 phosphonic acid (CPP), a competitive NMDA antagonist. MK-801 also inhibited naloxone-induced withdrawal jumping, however, just as CPP failed to affect morphine-induced changes in MMDA-induced behaviors, CPP also failed to inhibit withdrawal jumping. Together these data indicated that withdrawal from acute opioid dependence correlates with, but is not mediated by enhanced NMDA activity. PMID- 7850460 TI - Radioautographic demonstration and localization of glucagon receptors in duck brain. AB - The discovery of glucagon biosynthesis and receptors within mammalian brain has led one to suspect a neurotransmitter role for glucagon. In order to address this hypothesis in birds, we investigated the existence of glucagon receptors in duck brain by radioligand binding on fresh tissue sections and radioautography. Specific high-affinity [125I]glucagon binding sites similar to those in the liver were demonstrated in the avian brain. Mapping of these putative glucagon receptors revealed a discrete distributional pattern. Most of the [125I]glucagon binding capacity in duck brain is concentrated within the telencephalon, mainly in components of motor and limbic systems. Specific labeling densities were associated with avian equivalents of the mammalian pyramidal system (hyperstriatum accessorium; archistriatum intermedium and tractus occipitomesencephalicus) and extrapyramidal system (paleostriatum augmentatum, paleostriatum primitivum and lobus parolfactorius), as well as several limbic structures (hippocampal formation, nucleus taeniae and the caudal part of the archistriatum). Few glucagon-reactive foci were detected in the diencephalon (the nucleus dorsomedialis of hypothalamus, the two circumventricular organs, organum vasculosum of the lamina terminalis and median eminence and the nucleus habenularis medialis). These findings suggest that glucagon might be involved in the central control of somatic motricity and basic behaviors and point therefore to glucagon as a new neuroactive messenger in avian brain. The extensive difference between the distribution of glucagon binding sites observed in duck brain and that previously reported in rat brain suggests that glucagon does not subserve the same physiological role(s) in avian and mammalian brains. PMID- 7850461 TI - Attenuation of a voltage-dependent sodium current by GABA (identified neurons, buccal ganglia, Helix pomatia). AB - The action of systemically applied GABA on voltage-dependent currents of the identified neurons B1-B4 in the buccal ganglia of Helix pomatia were investigated by conventional voltage clamp techniques. In the B4 neuron, superfusion with sodium-free solution or addition of tetrodotoxin to the bath medium abolished the voltage dependent inward current. This voltage dependent sodium current was reduced with GABA application. Muscimol exerted the same effect as GABA whereas administration of baclofen had no effect. Voltage-dependent sodium and calcium currents of the neurons B1-B3 remained unchanged with GABA application. It is concluded that GABA is capable of reducing voltage-dependent sodium currents of distinct neuronal individuals via a GABAA receptor-like structure. PMID- 7850462 TI - Effects of dihydrexidine, a full dopamine D-1 receptor agonist, on delayed response performance in chronic low dose MPTP-treated monkeys. AB - Monkeys exposed to low doses of the neurotoxin 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) over long periods of time develop cognitive deficits without severe parkinsonian motor signs. In the present study we assessed the effects of the selective and full dopamine D-1 receptor agonist dihydrexidine on delayed response deficits in chronic low dose (CLD) MPTP-treated monkeys. Dihydrexidine caused a dose-dependent improvement in task performance, that could be blocked by the D-1 receptor antagonist SCH-23390. In addition to reducing the number of mistakes made during delayed response performance, dihydrexidine also improved task persistence. These data suggest that dihydrexidine may be useful in treating cognitive as well as motor deficits of parkinsonism. PMID- 7850463 TI - Effects of dopaminergic blockade upon carotid chemosensory activity and its hypoxia-induced excitation. AB - The effects of domperidone, antagonist of D2 receptors, on arterial chemoreceptor activity were studied in spontaneously breathing and pentobarbitone anesthetized cats, in which recordings of chemosensory impulse activity were obtained simultaneously from both cut carotid (sinus) nerves. Intravenous injections of domperidone 50 micrograms/kg produced a maintained increase in the basal frequency of chemosensory discharges, after which hyperoxic tests (breathing 100% O2 for 30 s) evoked larger falls in the rate of chemosensory impulses. Chemosensory responses evoked by hypoxic hypoxia (100% N2 tests) and by cytotoxic hypoxia (i.v. injections of NaCN) reached higher impulse rates after domperidone treatment. The effects of domperidone reveal that a resting release of dopamine from glomus cells maintains a low level of basal chemosensory activity under normoxic conditions. Domperidone turns off such restraining dopaminergic control and enhances the transient chemosensory responses to hypoxic stimuli. Present data support a modulatory role for dopamine within the chemoreceptor process, but not its participation as excitatory transmitter between glomus cells and sensory nerve endings. PMID- 7850464 TI - Sciatic nerve regeneration navigated by laminin-fibronectin double coated biodegradable collagen grafts in rats. AB - Biodegradable type I collagen tube grafts filled longitudinally with laminin and fibronectin double coated collagen fiber bundles (L-F grafts) were implanted to promote sciatic nerve regeneration in rats. Grafts filled with uncoated collagen fibers were used as control. A 1 cm defect on the right sciatic nerve was filled with a graft in the manner of bridging. Thirty days after implantation, several newly developed nerve fasciculi were found at the middle portion of the L-F grafts in contrast to no developed nerves in the controls. After 60 days, the middle and distal portions of both grafts included well-developed nerve tissues with prominent myelinated and unmyelinated nerve fibers surrounded by perineural cells, but the control distal portion showed fewer nerve fibers. All artificial collagen elements were completely degraded and absorbed at 30 days, and new nerve tissues surrounded by an epineurium successfully connected the proximal stump to the distal stump of the initially separated nerve. Descending and ascending action potentials were evoked in all grafts at 60 days. These results indicated that laminin and fibronectin may promote the growth of axons in biodegradable collagen grafts, which guided nerve regeneration well and allowed the formation of epineurium. PMID- 7850465 TI - The bisexual brain: sex behavior differences and sex differences in parthenogenetic and sexual lizards. AB - The parthenogenetic lizard Cnemidophorus uniparens alternates in the display of male-like and female-like sexual behavior, providing a unique opportunity for determining the neuronal circuits subserving gender-typical sexual behavior within a single sex. Here we report a 6-fold greater [14C]2-fluoro-2-deoxyglucose uptake in the medial preoptic area of C. uniparens displaying male-like behavior in comparison with C. uniparens displaying female-like receptivity. The ventromedial nucleus of the hypothalamus showed greater 2DG accumulation in receptive C. uniparens than in courting C. uniparens. When a related sexual species (C. inornatus) was compared to the unisexual species, the anterior hypothalamus in C. inornatus males exhibited significantly greater activity. PMID- 7850466 TI - High extracellular potassium concentrations stimulate oxidative metabolism in a glutamatergic neuronal culture and glycolysis in cultured astrocytes but have no stimulatory effect in a GABAergic neuronal culture. AB - Rates of deoxyglucose accumulation and of CO2 production from [U-14C]glucose, or from [U-14C]lactate or [2-14C]pyruvate (as a determination of tricarboxylic acid (TCA) cycle activity) were determined in primary cultures of either astrocytes, cerebellar granule cell neurons (utilizing glutamate as their transmitter) or cerebral cortical interneurons (utilizing GABA as their transmitter) during control ('resting') conditions and during exposure to an elevated extracellular potassium concentration, mimicking functional activity. The elevation of the extracellular potassium concentration increased the rate of deoxyglucose accumulation, but not of TCA cycle activity in astrocytes and both deoxyglucose accumulation and TCA cycle activity in cerebellar granule cells, but had no stimulatory effect in cerebral cortical neurons. Based on these observations it is suggested that the increase in energy metabolism in the CNS in vivo during functional activity mainly reflects increased active accumulation of potassium ions and extrusion of sodium ions in neurons receiving excitatory input and in adjacent astrocytes in order to re-establish pre-stimulus ion distribution across cell membranes. PMID- 7850467 TI - A permissive role of corticosterone in an opioid form of stress-induced analgesia: blockade of opiate analgesia is not due to stress-induced hormone release. AB - The 100 inescapable tail-shock paradigm produces three sequential analgesic states as the number of shocks increases: an early opioid analgesia (after 2 shocks) that is attenuated by systemic naltrexone, a middle analgesia (after 5-40 shocks) that is unaffected by systemic naltrexone, and a late opioid analgesia (after 80-100 shocks) that is attenuated by systemic naltrexone. In order to determine whether the absence of adrenal hormones would affect any of these analgesias, we tested adrenalectomized (ADX) versus sham-operated control rats 2 weeks post-surgery. Pain threshold was assessed using the tail-flick (TF) test. ADX attenuated both the early (2 shock) and late (80-100 shock) opiate analgesias and failed to reduce the naltrexone-insensitive analgesia after 5-40 shocks. We demonstrated that a loss of adrenomedullary catecholamines does not underlie the ADX-induced attenuation of opioid analgesia since sympathetic blockade using systemic chlorisondamine (6 mg/kg) failed to reduce analgesia at any point in the shock session. It was further shown that stress levels of adrenal hormones are not critical since (a) analgesia was unaffected when animals were tested 48 h after ADX, (b) 2 shocks do not produce a surge in corticosterone (CORT) over and above levels observed in animals restrained and TF tested in preparation for shock, and (c) basal CORT replacement in drinking water fully restored analgesia in ADX rats. These experiments demonstrate that basal CORT, rather than adrenomedullary substances, is critical to the expression of analgesia. The function of CORT here is not linked to a shock-induced surge of the steroid. CORT appears to play a permissive role in the expression of analgesia. Potential effects of the absence of corticosteroids on neurotransmitter biosynthesis important in analgesia production are discussed. PMID- 7850468 TI - Lithium chloride-induced anorexia, but not conditioned taste aversions, in rats with area postrema lesions. AB - Area postrema (AP) lesions were produced by vacuum aspiration in adult male Sprague-Dawley rats. Consistent with previous findings, when water-deprived rats were allowed to drink novel flavored fluids immediately before treatment with LiCl (3 mEq/kg, i.p.), sham-operated and non-operated control rats demonstrated a pronounced aversion to the fluids whereas rats with AP lesions did not decrease fluid consumption significantly. However, in a 30-min test period after overnight food deprivation, rats with AP lesions reduced food intake significantly and to an equivalent degree as control animals when pretreated with LiCl (3 mEq/kg, i.p. or i.v.). These and other results are consistent with the traditional view that AP mediates the sensation of nausea produced by LiCl treatment (hence the loss of conditioned taste aversions after AP lesions), but suggest that neither nausea nor AP is necessary for the marked disinclination to eat that is induced in rats by acute administration of LiCl. PMID- 7850469 TI - Tonotopic organization of human auditory association cortex. AB - Neuromagnetic studies of responses in human auditory association cortex for tone burst stimuli provide evidence for a tonotopic organization. The magnetic source image for the 100 ms component evoked by the onset of a tone is qualitatively similar to that of primary cortex, with responses lying deeper beneath the scalp for progressively higher tone frequencies. However, the tonotopic sequence of association cortex in three subjects is found largely within the superior temporal sulcus, although in the right hemisphere of one subject some sources may be closer to the inferior temporal sulcus. The locus of responses for individual subjects suggests a progression across the cortical surface that is approximately proportional to the logarithm of the tone frequency, as observed previously for primary cortex, with the span of 10 mm for each decade in frequency being comparable for the two areas. PMID- 7850470 TI - Trophic mechanisms regulate mitotic neuronal precursors: role of vasoactive intestinal peptide (VIP). AB - While trophic support from targets depends on innervation, recent evidence suggests that local VIP promotes survival of sympathetic neuroblasts prior to target interactions, during the period of neurogenesis. Developmental studies now indicate that VIP expression peaks at embryonic day 15.5 (E15.5) in sympathetic ganglia in vivo, decreasing 3-fold by birth. The expression pattern in vivo paralleled the time course of ganglion neuroblast mitosis and peptide promotion of survival in culture. In contrast, nerve growth factor (NGF) exhibited a reciprocal trophic relationship, primarily supporting older neurons that were unresponsive to VIP. To define relationships of trophism to mitosis, serial time lapse photography was employed to document the fate of neuroblasts produced by cytokinesis in vitro. In the absence of trophic factors, up to 80% of newly born cells died by 48 h, while virtually all neuroblasts survived in response to VIP plus NGF. In addition, trophic factors elicited multiple rounds of precursor division and an increase in absolute cell number, indicating that both trophic and mitogenic mechanisms contribute to proliferation. In aggregate, these observations suggest that VIP is expressed locally during a critical fetal period, providing trophic support to dividing ganglion neuroblasts prior to the action of target-derived NGF. PMID- 7850471 TI - Increased responsiveness of pontine reticular formation neurons associated with audiogenic seizure susceptibility during ethanol withdrawal. AB - Susceptibility to audiogenic seizures (AGS) is observed during ethanol withdrawal (ETX). The pontine reticular formation (PRF) is implicated in the propagation pathway for AGS during ETX. The present study examined the changes in single PRF neuronal firing patterns produced by ethanol and during ETX following repeated intragastrically administered ethanol. Microwire electrode bundles were implanted into PRF and single neuronal responses in freely moving rats were examined. During initial ethanol administration the animals were stuporous, and spontaneous and acoustically-evoked PRF neuronal firing were reduced significantly. During ETX the animals were susceptible to AGS and displayed agitated and irritable behavior. At this time a significant increase in spontaneous and acoustically evoked PRF neuronal firing was observed. Repetition-induced response attenuation (habituation) of PRF neuronal responses was significantly diminished during ETX, leading to an exaggerated acoustic startle response, which may be a physiological basis for AGS. Previous reports indicate that ethanol enhances the effects of GABA and decreases the effects of glutamate. The PRF neuronal firing increases during EXT in the present study may involve the down-regulation of GABAA receptors and supesensitivity of glutamate receptors reported to occur during ETX, which could contribute to AGS susceptibility. The PRF neuronal firing increases observed in the present study in concord with previous observation of AGS blockade by PRF microinjections during ETX further support an important role of this brain region in the propagation of AGS during ethanol withdrawal. PMID- 7850472 TI - Developmental modulation of blood-brain-barrier glucose transport in the rabbit. AB - Blood-brain barrier (BBB) glucose transport rates were measured using the intracarotid injection method in newborn, 14-day-old suckling, 28-day-old weanling and adult rabbits, and compared with membrane transporter density. Light microscope immunochemistry confirmed the presence of the GLUT1 glucose transporter isoform in these rabbits. Quantitative electron microscopic immunogold analyses of GLUT1-immunoreactive sites per micrometer of capillary membrane indicated GLUT1 density increased with age, and correlated with in vivo measurements of Vmax. Maximal transport velocities (Vmax) of glucose transfer (an indicator of the activity and relative number of transporter proteins) increased significantly (P = 0.05) with age: in neonates Vmax = 0.61 mumol.min-1.g-1, in sucklings Vmax = 0.68 mumol.min-1.g-1, in weanlings Vmax = 0.88 mumol.min-1.g-1, and in adults Vmax = 1.01 mumol.min-1 g-1. Cerebral blood flow (CBF) rates, increased with age from 0.19 and 0.26 ml.min-1.g-1 in neonates and sucklings to 0.51 (weanlings) and 0.70 (adults) ml.min-1.g-1. Non-linear regression analyses indicated the half-saturation constant (Km) for glucose transport ranged from 13 mM in adult rabbits to 19 mM in 14-day-old sucklings: differences in Km were not significant. Age-related changes in the Permeability-Surface Area product (PS +/- S.E.) of both water and glucose were also seen. At all ages studied, the diffusion component (Kd) of glucose uptake was not distinguishable from zero. We conclude developmental up-regulation of the rabbit BBB glucose transporter is characterized by no changes in transporter affinity, and provide the first demonstration of increased membrane transporter proteins correlating with an age related increase (65%) in glucose transporter maximal velocity. PMID- 7850473 TI - Calcium waves in gray matter are due to voltage-sensitive glial membrane channels. AB - The retina is the most accessible piece of central gray matter in the vertebrate brain. Its wide dynamic operational range makes it the ideal neuronal network to study its excitability. Spreading depression waves in the retina are accompanied by strong intrinsic optical signals (IOS) and thus can be measured non-invasively with optical methods. Additionally, incubation with fluorescent dyes allows to follow calcium fluxes in parallel. The IOS can be divided into red and green scatter of light. We show that during spreading depression the red scatter signal precedes the green scatter signal and that the calcium signal matches the red scatter signal. Incubation of the retina with barium chloride leads to a reversible depression of red scatter and calcium signal whereas the green scatter signal is hardly effected. The wave propagation velocity is reduced, too. This supports the idea that the early red scatter signal is a direct visualisation of glial membrane potential and that glia cells in the chicken retina are involved in the control of extracellular calcium. PMID- 7850475 TI - On the mechanism of antiepileptic peptides appearance in the cerebrospinal fluid. AB - Intraventricular injection of cerebrospinal fluid obtained from cats with electroshock seizures resulted in suppression of generalized picrotoxin-induced seizures in rats. Antiepileptic action of cerebrospinal fluid was abolished by partial bilateral midbrain destruction that included the region of colliculi superii. Electrical stimulation of cerebellum in cats with such destructions caused the appearance of a pronase-sensitive antiepileptic substances in cerebrospinal fluid. PMID- 7850474 TI - Activity of the hypothalamic pituitary adrenal axis and sympathoadrenal system during food and water deprivation in the rat. AB - It has been previously shown that chronic water deprivation or hypertonic saline intake, osmotic stress models with concomitant decrease in food intake, decrease hypothalamic CRH mRNA levels and ACTH responses to acute stimulation. To determine the contribution of food restriction to the effects of osmotic stimulation, the function of the hypothalamic pituitary adrenal axis was analyzed in rats subjected to food deprivation, water deprivation or their combination for 60 h. In all three groups, basal levels of plasma corticosterone were increased, while ACTH and catecholamines were unchanged. Basal plasma vasopressin levels were normal in food deprived rats, but significantly increased in water deprived and simultaneously food and water deprived rats. In contrast to the 25% reduction of plasma ACTH responses to 30 min immobilization by water deprivation, food deprivation had no inhibitory effect and prevented the decreased ACTH responsiveness caused by water deprivation. In control rats, plasma corticosterone levels increased 22.5-fold 30 min after immobilization, and this response was significantly potentiated in the water deprived, food deprived and combined food and water deprived groups. The elevation in plasma catecholamines in response to acute immobilization was also enhanced in both water deprived and food deprived rats. In situ hybridization studies showed a 35% increase in VP mRNA levels in the PVN after water deprivation, whereas food deprivation caused a slight decrease and prevented the stimulatory effect of water deprivation. CRH mRNA in the PVN was reduced by 27% after food deprivation and by 67% after water deprivation, but simultaneous food and water deprivation caused a significantly smaller reduction similar to that in food deprivation alone.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7850476 TI - [7-D-ALA]-angiotensin-(1-7): selective antagonism of angiotensin-(1-7) in the rat paraventricular nucleus. AB - Microiontophoretic application of both, the octapeptide angiotensin II (Ang II) and its N-terminal heptapeptide angiotensin-(1-7), [Ang-(1-7)], has been shown to increase the firing rate of rat hypothalamic paraventricular neurones. In the present microiontophoretic study, the effect of the angiotensin analogue [7-D Ala]-Ang-(1-7) on Ang II- and Ang-(1-7)-induced firing rate increase of paraventricular neurones has been tested. While the response to Ang II was unchanged, the response to Ang-(1-7) was effectively blocked by [7-D-Ala]-Ang-(1 7). The results indicate that the Ang-(1-7)-induced excitation of paraventricular neurones may be mediated by a distinct Ang-(1-7)-receptor and that [7-D-Ala]-Ang (1-7) is a selective antagonist of this receptor. PMID- 7850478 TI - Thermoregulation and hypothalamic histamine turnover modulated by interleukin-1 beta in rats. AB - To clarify the involvement of hypothalamic histamine in thermogenic response provoked by high ambient temperature, or interleukin-1 beta (IL-1 beta), changes in rectal temperature and histamine turnover were investigated. Rectal temperature was maintained normally after exposure to high ambient temperature, but elevated by IL-1 beta. In spite of these different responses of body temperature, hypothalamic histamine turnover was increased in each treatment. The results suggest that hypothalamic histaminergic neurons are activated not only peripherally by high ambient temperature, but also centrally by IL-1 beta as endogenous pyrogen. PMID- 7850477 TI - Characterization of a new angiotensin antagonist selective for angiotensin-(1-7): evidence that the actions of angiotensin-(1-7) are mediated by specific angiotensin receptors. AB - In this study we describe a new angiotensin antagonist [Asp1-Arg2-Val3-Tyr4-Ile5 His6-D-Ala7, (A-779)] selective for the heptapeptide angiotensin-(1-7) [Ang-(1 7)]. A-779 blocked the antidiuretic effect of Ang-(1-7) in water-loaded rats and the changes in blood pressure produced by Ang-(1-7) microinjection into the dorsal-medial and ventrolateral medulla. In contrast, A-779 did not change the dipsogenic, pressor, or myotropic effects of angiotensin II (Ang II). Also, A-779 did not affect the antidiuretic effect of vasopressin or the contractile effects of angiotensin III, bradykinin, or substance P on the rat ileum. In the rostral ventrolateral medulla, the pressor effect produced by Ang-(1-7) microinjection was completely blocked by A-779 but not by AT1 or AT2 receptor antagonists (DUP 753 and CGP 42112A, respectively). Conversely, the pressor effect produced by Ang II was not changed by A-779 but was completely blocked by DUP 753. Binding studies substantiated these observations: A-779 did not compete significantly for 125I-Ang II binding to adrenocortical membranes at up to a 1 microM concentration. Low affinity binding was also observed in adrenomedullary membranes with an IC50 greater than 10 microM. Our results show that A-779 is a potent and selective antagonist for Ang-(1-7). More importantly, our data indicate that specific angiotensin receptors mediate the central and peripheral actions of Ang-(1-7). PMID- 7850479 TI - Effects of sigma ligands on rat cerebellar Purkinje neuron firing: an iontophoretic study. AB - The electrophysiological responses of rat cerebellar Purkinje neurons to selective sigma ligands applied iontophoretically was examined in urethane anesthetized male Sprague-Dawley rats. 1,3-Di-o-tolylguanidine (DTG), dextrallorphan (DEX), (+)-pentazocine((+)-PENT), (+)-3-(3-Hydroxyphenyl)-N propylpiperidine ((+)-3-PPP), and the novel diamine BD1008, were ejected from multibarrel pipettes onto individual Purkinje cells. In some neurons, cell firing was inhibited following ejections of all compounds. These inhibitory effects were dose dependent and occurred without changes in spike amplitude or duration, thus ruling out local anesthetic effects as a mechanism. (+)-3-PPP and DEX increased firing rate in 27% and 14% (n = 15, n = 14, respectively) of cells studied. The results of this study indicate that sigma ligands significantly alter the spontaneous firing of Purkinje neurons, consistent with previous work suggesting motor effects of sigma ligands via the rubro-cerebellar circuitry. PMID- 7850480 TI - Evidence for reciprocal connections between the dorsochiasmatic area and the hypothalamo neurohypophyseal system and some related extrahypothalamic structures. AB - In the preceding article, a dorsochiasmatic area (DCh) was described that projects to both paraventricular (PVN) and supraoptic (SON) nuclei. The main afferents of the DCh, revealed by local injections of retrograde tracers, are the hypothalamic PVN and SON, lateral septal nuclei (LSV and SHy), bed nuclei of the stria terminalis (BST), anteroventral third ventricle region, particularly the median preoptic nucleus (MnPO), the subfornical organ, medial preoptic areas, arcuate hypothalamic nucleus, ventromedial hypothalamic nuclei, paraventricular thalamic nucleus, and, more caudally, several structures of the posterior hypothalamus and mesencephalon. The relations between DCh and BST, LSV, SHy, or MnPO appeared reciprocal. In view of their reciprocal relationships with the hypothalamo-neurohypophyseal system and some of their related extrahypothalamic structures, the DCh might be involved in the regulation of the vasopressin (AVP) and/or oxytocin (OT) systems, or in reproductive behavior. PMID- 7850481 TI - A three-dimensional reconstruction of the human hypothalamus. AB - A previous three-dimensional reconstruction of the rat hypothalamus revealed an organization of nuclei into three major clusters. This clustering may relate to the presence of three hypothalamic anlagen in the embryo and to a restriction of marker proteins and transcription factors to specific regions of the hypothalamus during development. To see if a similar clustering was apparent in the human hypothalamus, a reconstruction of the hypothalamus from a male cadaver was prepared. The reconstruction showed a clustering of nuclei into three anterior posterior groups. With reference to the well-defined human supraoptic nucleus, the suprachiasmatic and lateral mammillary nuclei were proportionately smaller in this single human specimen than would be expected from data in the rat. A high degree of homology between hypothalamic structures in the rat and human were generally observed. PMID- 7850482 TI - Behavioral and electrophysiological correlates of the quinolinic acid rat model of Huntington's disease in rats. AB - The influence of bilateral intrastriatal injection of quinolinic acid (QA, 300 nmol) was studied in male Wistar rats. Behavioral and electrophysiological experiments were conducted in 15 lesioned plus 15 vehicle-injected (control) animals. With respect to control animals, QA-lesioned rats showed marked, statistically significant alterations from both the behavioral (greater motor activation in response to d-amphetamine, place-learning deficit in the Morris water maze), and the electroencephalographic (reduced voltage amplitude and EEG power at the level of frontal cortex) points of view. In addition, a significant loss in body weight and a marked striatal gliosis (GFAP staining) were observed in lesioned rats. Conversely, QA-lesioned rats did not show modifications in posttetanic potentiation (P.T.P.) or long-term potentiation (L.T.P.) in CA1 hippocampal area. The present results confirm that QA lesions of rat striatum may be regarded as a suitable model of Huntington's disease (HD). PMID- 7850483 TI - Acoustic prepulses can facilitate the startle reflex in rats: discrepancy between rat and human data resolved. AB - Small changes in the sensory environment, called prepulses, prior to a startle eliciting stimulus can inhibit or facilitate the startle reaction. Previous studies reported that at large intervals between prepulse and startle stimulus the prepulse facilitates the startle reaction, possibly by means of an orienting response. This was, however, only observed in humans and not in rats, and was consequently proposed to measure unique brain functions. In the present study with rats, the prepulse intensity was decreased from 85 to 81 dB, which resulted in decreased prepulse inhibition. Prepulse facilitation was now observed at large intervals (> 800 ms), which suggests that this facilitation was masked by inhibition in previous studies. These results solve the discrepancy between rat and human data and indicate that similar mechanisms are involved. PMID- 7850485 TI - Autoradiographic analysis of second-messenger and neurotransmitter receptor systems in the exo-focal remote areas of postischemic rat brain. AB - We studied the chronological changes of protein kinase C (PKC) and muscarinic acetylcholine receptor binding activities of the rat brain which were determined by using [3H]phorbol 12,13-dibutyrate (PDBu) and [3H]quinuclidinyl benzilate (QNB) autoradiographic methods, respectively, after 90 min of right middle cerebral artery (MCA) occlusion and after such occlusion, followed by different periods of recirculation. After the ischemic insult followed by 3 h of recirculation, [3H]PDBu binding sites were found to be significantly decreased in the cerebral cortex and lateral segment of the caudate putamen, both supplied by the occluded MCA; thereafter, the binding sites decreased progressively in those ischemic foci. On the contrary, there was no alteration on day 1, but 3 days after ischemic insult, a significant decrease of [3H]QNB binding sites was first detected in those ischemic foci. Moreover, 3 days after ischemic insult, both [3H]PDBu and [3H]QNB binding sites were concurrently reduced in the ipsilateral thalamus and 1 week after the ischemia, in the substantia nigra, in which both areas had not been directly affected by the original ischemic insult. These alterations of PKC in the postischemic brain areas developed concurrently with 45Ca accumulation, which was detected in our previous study. These results suggest that postischemic alterations of second-messenger (PKC) and neurotransmitter receptor systems were involved not only in the ischemic foci due to ischemia-induced energy failure, but also in the exo-focal remote areas prior to the histologic changes where neuronal damage might be caused by transsynaptic delayed degeneration. PMID- 7850484 TI - Distribution and regulation of estrogen-2-hydroxylase in the quail brain. AB - The anatomical distribution and endocrine regulation of the estrogen-2 hydroxylase activity were investigated in the brain of adult male and female Japanese quail. Significant levels of enzymatic activity were detected in all brain regions that were studied, but the highest levels were observed in preoptic and hypothalamic brain nuclei that are known to contain high levels of aromatase activity. These data are consistent with previous results suggesting that the placental aromatase is also responsible for the estrogen-2-hydroxylase activity. However, there is a marked sex difference and a control by T of aromatase activity in the quail brain, and no such difference in 2-hydroxylase activity could generally be detected except in the VMN. Further studies will be needed to know whether the previously published conclusions concerning the human placenta also apply to the brain. The present data are consistent with the idea that estrogens formed locally in the brain by testosterone aromatization could affect reproduction by interfering with the catecholaminergic transmission after being metabolized into catechol-estrogens. PMID- 7850486 TI - Autoradiographic characterization of 125I-neurotensin binding sites in human entorhinal cortex. AB - The laminar and rostro-caudal distribution of 125I-neurotensin binding sites is described in human entorhinal cortex using quantitative autoradiography. Specific binding was most prominent over the cell clusters of layer II of the entorhinal cortex throughout its rostro-caudal extent. Dense binding was also observed in the adjacent presubiculum and cortical amygdaloid transition area, whereas minimal binding was detected in the hippocampus and dentate gyrus. 125I Neurotensin may serve as a selective probe for neurotensin receptor alterations and layer II-specific cytoarchitectural disturbances in the entorhinal cortex in neuropsychiatric diseases associated with abnormalities of the mesial temporal lobe. PMID- 7850487 TI - How do oligodendrocytes ensheath and myelinate nerve fibers? AB - Oligodendrocyte precursor cells were cultured from newborn rat brain and studied their differentiation and proliferation. They have identified type-1, type-2, and type-3 oligodendrocytes based on the expression of characteristic marker molecules that frequently used to stage oligodendrocyte development. The type-3 oligodendrocytes were observed to send but tentative that locate axons prior to myelination. These processes terminate in lamellipodia, which eventually enwrap the axon and begin the myelination process with several steps. At the first stage, ruffling is immediately induced at the lamellipodia with filopodia made of oligodendrocyte processes, and the axon is contacted several times; then process retraction occurs to reform the filopodial and lamellipodial parts prior to the onset of the myelination. Second, after filopodial movements and lamellipodial ruffling occur again, their morphology is dramatically changed to become three thick filopodia that anchor to the axon. Finally, lamellipodial ruffling parts ripple, the angle between the position of the resting filopodium and the axon change, depending on the start of axonal movement, and the lamellipodia turn around the axon like a transverse wave with one stroke of the brush, as observed on the video screen, and their rolling membrane changes to the bursting form within minutes in real time. PMID- 7850489 TI - Corpus callosum surface area across the human adult life span: effect of age and gender. AB - This magnetic resonance (MR) imaging study analyzed and provides normative data on the midsagittal surface area of the corpus callosum (CC) across the human adult life span in 200 normal volunteers. Using MR imaging scans, CC midsagittal surface area was quantified, along with midsagittal intracranial surface area and total intracranial volume (measures of cranial size). Results demonstrate that when head size is controlled, no major changes associated with normal aging are evident in the CC during the more active years of adult life span (up through 65). Overall, females had significantly larger CC relative to total intracranial volume. Results are discussed in terms of potential gender differences in CC size and the clinical application of this normative data. PMID- 7850488 TI - IGF-I and IGF-I24-41 but not IGF-I57-70 affect somatic and neurobehavioral development of newborn male mice. AB - Insulin-like growth factor (IGF-I) is a trophic factor for both neurons and glial cells. Its presence in developing and adult nervous system suggests an important role for this peptide in the development of neural circuitries. Neonatal male mice of the CD-1 outbred strain were injected intracerebroventricularly with either recombinant IGF-I, synthetic IGF-I fragment 24-41 or IGF-I fragment 57-70 on postnatal days (PND) 2, 4, and 7. Physical traits such as body weight gain, body length, and tail length were recorded daily from PND2 to PND13. Sensorimotor development was scored according to a modified Fox's scale. The ultrasonic vocalization pattern on PND8 and homing performance on PND10 were also recorded. Measures for body weight gain and tail length of the pups were significantly increased following treatment with the whole IGF-I peptide. However, neither IGF I nor the smaller fragments affected mice sensorimotor development. IGF-I and IGF I24-41 but not IGF-I57-70 increased the rate of ultrasonic calls of the pups measured on PND8. These data provide evidence that IGF-I regulates somatic growth and behavioral development when administered in newborn mice and that different portions of the peptide can exert different effects. PMID- 7850490 TI - Localization of androgen receptor within peptidergic neurons of the rat forebrain. AB - This study tested for the presence of androgen receptor-immunoreactivity in somatostatin, galanin, vasopressin, corticotropin-releasing hormone, and oxytocin neurons in the rat forebrain. The brains of adult male Sprague-Dawley rats were fixed with 4% paraformaldehyde. Androgen receptor was visualized in coronal sections using nickel intensification of diaminobenzidine, and the neuropeptides were identified using a brown diaminobenzidine reaction product. Androgen receptor was localized to the nuclei of neurons in the septum, amygdala, cortex, hippocampus, and hypothalamus. The majority of somatostatin-containing neurons in the periventricular hypothalamic nucleus also contained androgen receptor. Androgen receptor was also found within galanin-expressing cells in the bed nucleus of the stria terminalis and in the amygdala. Androgen receptor was not observed in corticotropin-releasing hormone, vasopressin, or oxytocin neurons in all areas examined. The data suggest that androgens may be capable of directly regulating somatostatin-expressing neurons of the periventricular nucleus of the hypothalamus and galanin-containing neurons of the bed nucleus of the stria terminalis and amygdala. PMID- 7850491 TI - Reperfusion following focal stroke hastens inflammation and resolution of ischemic injured tissue. AB - Previously, we described cellular changes following Permanent Middle Cerebral Artery Occlusion (PMCAO) in spontaneously hypertensive rats. Ischemic changes following PMCAO included a time-related focal pan necrosis, inflammatory cell infiltration, gliosis, and eventual loss of necrotic tissue post PMCAO. We have now characterized changes which occur after Temporary Middle Cerebral Artery Occlusion (TMCAO; 80 or 160 min) followed by reperfusion and compared these changes to those which occur following PMCAO. TMCAO with reperfusion results in cortical infarcts which vary in size in an occlusion-time-dependent manner. After 1 h of reperfusion, ischemic changes were observed histologically, including microhemorrhages and the beginning of a slight inflammatory infiltration in and around the meningeal vasculature. This infiltrate consisted primarily of neutrophils, which by 6 h of reperfusion was significant with infiltration from deep blood vessels into brain tissue, including the presence of some monocytes adhering within blood vessels. Neutrophil infiltration occurred sooner and to a greater extent in reperfused tissues than in permanently occluded tissues, where it only began at 12 h post PMCAO. As occurred following PMCAO, increased Glial Fibrillary Acidic Protein (GFAP) immunoreactivity indicating astrogliosis was first observed at 12 h postTMCAO. Over 1-3 days of reperfusion, a heavy macrophage infiltrate was observed in the reperfused tissues in addition to a continued influx of neutrophils. Following 5 days of reperfusion, the lesion was completely replaced with inflammatory cells, of which macrophages predominated. Unlike PMCAO, which resulted in focal spots of neutrophil accumulation, neutrophils were more distributed throughout the infarcted cortex following TMCAO.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7850492 TI - Qualitative or quantitative: so what is your religion? PMID- 7850493 TI - Murder Board: some postmortem thoughts on instrument construction. AB - The Murder Board provides a mechanism by which educational and psychosocial instruments developed for use in nursing research can be systematically reviewed to identify errors or flaws in construction. The information for this review is based on a small field-test of the tool administered to a sample of respondents representative of the population for whom the instrument was designed. Only eyewitness evidence obtained from this sample can reveal certain types of errors that would not be detected at any other stage of development. The board can use this evidence to comprehensively review each item and the instrument's structure and format to recommend appropriate revisions. This process should produce a draft version of an instrument that is free of structural flaws. PMID- 7850494 TI - Development of an Agitated Behavior Rating Scale for discrete temporal observations. AB - Agitation is a commonly encountered clinical problem, particularly among institutionalized geriatric patients. Agitation is particularly difficult to study because it is manifested in a variety of ways and may occur intermittently across the 24-hour day. Existing ratings scales offer rich behavioral descriptions of agitated behavior but fail to take into account the real-time component of when such behaviors occur. In this article we report the development of an agitated behavior rating scale based on discrete, intermittent real-time observation. Results indicated high levels of interobserver agreement among three trained observers. Percentage agreement exceeded 85% and kappa coefficients were statistically significant at the .001 level for the most general categories of agitation. More specific categories of agitation yielded slightly lower, but still acceptable percentage agreements and kappas. These findings suggest that such a rating scale may have utility in the study of agitation and related phenomena across the 24-hour day. PMID- 7850495 TI - Development of a pediatric skill self-efficacy scale. AB - The Pediatric Skill Survey (PSS) is a self-report measure of self-efficacy for nursing skills needed when caring for patients under 18 years old. Potential item stems were derived from a frequency analysis of case presentations in an emergency department. Expert judges later assessed content sampling of items. Initial use of the PSS with 93 subjects showed an internal consistency estimate of .98 across 47 items. Significant known groups discrimination was found between three groups, from lay person to expert nurse, supporting validity. Subsequent study with a sample of 125 nurses showed significant positive correlations between knowledge of pediatric care, attitude toward pediatric patients, and PSS scores, offering further support for the construct validity of the scale. PMID- 7850496 TI - Preserving qualitative meaning in instrument development. AB - This article presents the process through which qualitative meaning can be preserved in instrumentation. Examples illustrating this process are taken from the development of the Index of Readiness, a scale designed to assess and evaluate individual appraisal of readiness to initiate health behavior change. The generation of scale items from qualitative data and the initial steps taken to assess instrument reliability and validity as a way of preserving the meaning inherent in qualitatively generated data are described. The creation of measurement scales that reflect the uniqueness of individual experience and meet criteria for psychometric testing challenges nurse researchers to continue to devise more effective ways of representing and investigating the complexities of human experience. The use of qualitative data for instrument development is an important aspect of such scale development. PMID- 7850497 TI - Development of the Serenity Scale. AB - Serenity is a sustained inner peace. Nurses can use knowledge about serenity to help clients cope with harsh circumstances. The Serenity Scale is a 40-item self report, summated scale that evaluates clients' serenity status. Critical attributes, identified by serenity experts, served as the theoretical framework. Sixty-five items were given to 542 male and female subjects age 20 to 95 (73% Caucasians and 27% minority) from varying income and educational levels yielding an alpha of .93. Forty items (SS.V2) were extracted for further analysis. The alpha coefficient was .92 with item-to-total correlations ranging from .25 to .67. Item means ranged from 2.6-3.7 (grand mean = 3.4). A principal components factor analysis with varimax rotation revealed nine factors explaining 58.2% of the variance. Limitations are that SS.V2 has not been tested with an independent sample and subjects with low educational levels had difficulty with some items. PMID- 7850498 TI - Development and psychometric evaluation of the Resilience Scale. AB - This study describes the development and initial psychometric evaluation of the 25-item Resilience Scale (RS) in a sample of 810 community-dwelling older adults. Principal components factor analysis of the RS was conducted followed by oblimin rotation indicating that the factor structure represented two factors (Personal Competence and Acceptance of Self and Life). Positive correlations with adaptational outcomes (physical health, morale, and life satisfaction) and a negative correlation with depression supported concurrent validity of the RS. The results of this study support the internal consistency reliability and concurrent validity of the RS as an instrument to measure resilience. PMID- 7850499 TI - The right to know and the right to privacy: confidentiality, HIV and health care professionals. PMID- 7850500 TI - Nursing ethics or ethics in nursing: a German perspective. PMID- 7850501 TI - Freedom of speech in the NHS. PMID- 7850502 TI - Dissatisfaction: with professional relationships, with the status quo and with health care in general. PMID- 7850503 TI - Knowledge for ethical care. AB - Knowledge needed for ethical care must be constructed in the relationship between professional and patient who strive together to understand what meaning the disease factors have within the experience of the individual patient. Three kinds of knowledge are described. The first two, descriptive knowledge and abstract knowledge, are part of the more comprehensive and complex inherent knowledge. The reality of human experience and meaning is profoundly more complex than the scientific approach of fragmentation for purposes of dissection and diagnosis. In order to develop descriptive, abstract and inherent knowledge as outlined here, three moves need to be made: the move from dominance to collaboration, the move from abstraction to context, and the move from beneficence to nurturance. PMID- 7850504 TI - Guilt and nursing practice: implications for nurse education and the climate of care. AB - This paper considers the influence of guilt within nursing practice. The author draws on her experience as a nurse tutor to show how guilt has implications for the well-being of both nurses and patients. It is suggested that nurses' experience of guilt, and the fear that they may be considered guilty, are indicative of a moral climate that rests predominantly upon rules. While rules fulfil a requirement for professional and organizational accountability, they need not be perceived as statements about the trustworthiness of nurses, or as a disciplinary threat. Nurses need to feel trusted to bring judgement to their practice. PMID- 7850505 TI - Confidentiality and personal integrity. AB - This paper uses the social theory of Erving Goffman in order to argue that confidentiality should be understood in relation to the mundane social skills by which individuals present and respect specific self-images of themselves and others during social interaction. The breaching of confidentiality is analysed in terms of one person's capacity to embarrass another, and so to expose that person as incompetent. Respecting confidentiality may at once serve to protect the vulnerable from an unjust society, and yet also protect the guilty from just accusation. Ethical reasoning about confidentiality must therefore recognize the dangers of prejudice and violence inherent in decisions to breach or to respect confidentiality. Case studies are used to illustrate the efficacy of this account, culminating with analyses of three examples from the UKCC document Confidentiality. PMID- 7850506 TI - Breast cancer patients' perceived participation in health care: how do patients themselves and nurses assess this participation? AB - The purpose of this study was to compare breast cancer patients' perceived participation in their own care with nurses' perceptions of such participation. Both groups reported that patients are able and willing to take part in their own care more actively than allowed under the present health care system. Nurses also reported that they do provide patients with opportunities for participation. PMID- 7850507 TI - 'Nursing development units'. PMID- 7850508 TI - Can nursing survive? A view through the keyhole. AB - Nursing in the United Kingdom is undergoing massive retrenchment. An increasing number of nurses are unable to obtain employment following qualification and agency nursing and short-term contracts are becoming the norm. Amalgamations of colleges of nursing have resulted in redundancies of nurse teachers and a significant reduction in student nursing places. The profession of nursing in the UK is in a state of crisis from which it may never recover. Nurses have generated and facilitated this situation in their self-interested quest for professional status. Essentially, nurses have turned their backs on many nursing skills and allowed others to take on the role. British nursing may find its survival through its health care assistants. Nurses in other countries should take note and take steps to safeguard the profession on an international level. PMID- 7850509 TI - Cases of conscience: casuistic analysis of ethical dilemmas in expanded role settings. AB - In the absence of a well articulated conceptual framework for nursing ethics, this article argues for a theory of applied ethics--casuistics--used within a clinical reasoning model, to analyse the complicated issues presented in three cases involving adolescents receiving treatment for abuse through a rural alternative learning centre. The clinical nurse specialist, as an independent practitioner within the community, is presented with many ethical challenges arising from cultural diversity. The inherent independent nature of such practice environments combined with the pluralism which exists in today's multicultural society demands that professional nurses working in these circumstances develop and utilize an ethical framework for the analysis of patient care in situations that involve moral conflict. PMID- 7850510 TI - The nurse's challenge in coping with ethical dilemmas in occupational health. AB - This paper discusses the occupational health nurse's dilemmas by illustrating two cases faced by nurses in occupational health practice and setting out their analysis according to a decision-making model. The counter-interests, which may offend the principles of conserving professional occupational ethics among service consumers and employers as well as fellow professionals, are emphasized. This paper also describes the complex problems involved in the worker's safety and the safeguarding of their autonomy, while preserving interpersonal relations among the various people concerned. PMID- 7850511 TI - Ethics and research in nursing. AB - Considering the importance of research in the development of nursing, we examine the ethical principles governing nurses' investigative activity, as well as the different codes regulating biomedical investigation with human beings, amongst which are the Nuremberg Code, the Declaration of Human Rights, and the Declaration of Helsinki. From the perspective of the central points of the article reference is made to different codes proposed by international nursing associations, as well as reviewing the Deontological Code of Spanish Nursing. The ethical principles a nurse has to bear in mind in research are analysed, with respect to patients, society and the profession. Finally, we refer to certain ethical aspects to be considered in the elaboration and development of a research project, as well as publication of the results. PMID- 7850512 TI - HIV and AIDS: the nursing response and some ethical challenges. AB - AIDS has challenged many concepts and practices within nursing. Because of the serious implications attending a positive diagnosis, and because patients with AIDS have become articulate and well informed, familiar principles have been exposed to renewed scrutiny. Anomalies and dilemmas have been revealed. Results from a recent Institute of Medical Ethics survey carried out by the author have illustrated some of the theoretical concepts. Confidentiality has assumed new dimensions. Partnership and mutual empowerment are seen as keys to sound practice involving the patient in decision-making. A vital ingredient relates to the preparation of professionals; they need to be aware of those attitudes and prejudices within themselves which potentially stand in the way of caring well. PMID- 7850513 TI - Torture survivors: a challenge to nursing practice. AB - Why should all nurses and student nurses receive instruction in the subject of torture, its purpose, methods and sequelae on body and soul? One reason is because torture is an atrocity, the most perverted and digusting act that exists. Some nurses meet torture survivors and their families in their private lives and at work. Many countries have ratified codes and declarations in relation to torture, and are therefore obliged to educate some professional groups in the subject. This article describes how the subject 'Torture' is dealt with at the School of Nursing in Aalborg, Denmark. Aspects of how the course is planned, the placement of the subject, teaching objectives, content of the lessons, teaching methods and teaching materials are mentioned. This article also underlines why it is so important to educate student and qualified nurses about torture. The conclusion is that nurses can help to alleviate the effects of torture in a merciless and unfeeling world. PMID- 7850514 TI - To feed or to nourish? Thoughts on the moral significance of meals in hospital. AB - This paper explores the issue of the serving of food in hospital from both a moral and a philosophical point of view. The concepts of 'having a meal' and of 'feeling nourished by food' are examined; it is suggested that the former is a necessary condition for the latter. The implications of this for nursing care are considered and it is argued that there is a moral imperative for us to try and serve 'meals', rather than simply 'food' to patients. The importance of this is highlighted by current concerns about malnutrition in hospital. PMID- 7850515 TI - Comments on the ICN position statements regarding human rights. PMID- 7850516 TI - A comment on Ultrasound unsound, by Beverley Lawrence Beech and Jean Robinson, Association for Improvements in the Maternity Services (AIMS), February 1994. PMID- 7850517 TI - When water won't work. PMID- 7850518 TI - Crisis in long-term care nursing leadership. PMID- 7850519 TI - Practical steps to "getting published". PMID- 7850520 TI - Pet therapy. PMID- 7850521 TI - LTC law: extended coverage for psychological injury. PMID- 7850522 TI - Therapeutic options in the treatment of congestive heart failure. Part I. PMID- 7850523 TI - Reimbursement: how does it relate to your staffing? PMID- 7850524 TI - Groin dissection in malignant melanoma. AB - BACKGROUND: There is controversy about the extent of groin dissection necessary (whether superficial or radical) and about its utility when the deep nodes are affected. METHODS: A total of 198 groin dissections (1977-1991) were reviewed; 94 (48%) were superficial and 104 (52%) were radical dissections. Of 72 patients with palpable positive inguinal nodes, 31 (43%) had involvement of the deep nodes; of 39 patients with nonpalpable, histologically positive inguinal nodes, seven (18%) had or later manifested involvement of the deep nodes. RESULTS: The mean number of positive nodes (median) in the group with clinically palpable disease was six (two), and in the group with occult disease the number was two (one). The estimated overall (disease-free) 5-year and 10-year survival rates for patients with negative nodes were 73% (67%) and 64% (58%), respectively, and for those with positive nodes they were 36% (27%) and 30% (23%), respectively. Survival was significantly poorer for patients with positive nodes (p < 0.0001). The respective 5-year and 10-year survival rates for patients with positive nodes and involvement of the inguinal nodes only were 41% (33%) and 36% (29%), and for those with involvement of the inguinal and deep nodes the rates were 28% (17%) and 19% (13%). Survival was significantly poorer for patients with deep node involvement (p = 0.006). CONCLUSIONS: The survival rates after therapeutic groin dissection are substantial and unattainable with any other treatment at the present time. Incontinuity dissection of the deep nodes is advisable in the presence of palpable inguinal nodes, since the incidence of deep node involvement is considerable and the survival rate appreciable after removal of involved deep nodes. PMID- 7850525 TI - Malignant melanoma in children. AB - BACKGROUND: Cutaneous melanoma is an uncommon malignancy in children and for this reason, there is little information available regarding the timing and patterns of recurrence in children with this disease. This study reviews the experience at a single institution (Duke University Melanoma Clinic) in treating children with malignant melanoma. METHODS: Eighty-five patients < or = 18 years of age with malignant melanoma have been treated. All but three patients were over the age of 10; 73% of them were > 14. As for adults, treatment consisted of wide local excision of all primary lesions with primary closure or split-thickness skin graft, as needed. In addition, 22 patients underwent dissection of regional lymph nodes. Patients whose tumors had aggressive pathologic characteristics were treated with an adjuvant immunotherapy protocol. Patients with recurrence at distant sites were offered combination chemotherapy. RESULTS: Patients and pathologic characteristics of sex, race, primary site, histologic type, tumor thickness, and Clark level were similar to those observed in adults. Actuarial survival rates (79% versus 77% at 5 years) of the pediatric and adult Stage I melanoma patients were also not significantly different. Children had a greater incidence of recurrence after initial treatment, although recurrence tended to happen after a longer disease-free interval than for adults. Half of the 79 children who were first seen with Stage I disease have suffered a relapse, but more than one-third were disease free for > or = 5 years after initial treatment. Of the 18 patients who were disease free for > or = 7 years, 12 (67%) ultimately had recurrent disease, including five patients who had recurrences > 13 years after initial diagnosis. CONCLUSIONS: The early age at which malignant melanoma may occur and the significant potential for very late recurrence mandate that pediatricians and other primary care physicians consider the diagnosis of melanoma even in young patients with new skin lesions and that patients treated for melanoma be carefully followed for a lifetime. PMID- 7850526 TI - Gastrointestinal tumors in children: an analysis of 39 cases. AB - BACKGROUND: Gastrointestinal tumors are relatively uncommon in infants and children, and the histologic diagnoses differ from those seen in an adult practice. Furthermore, the clinical presentation of such tumors is quite variable. METHODS: We reviewed the records of 39 pediatric patients who had been treated for tumors of the alimentary tract at our hospital over the past 20 years. The symptoms, physical findings, treatments, and outcomes are tabulated and discussed. RESULTS: Non-Hodgkin's lymphoma was the predominant diagnosis. It was found in 22 children, and the survival rate was 60%. Other malignant tumors found in this pediatric series included colorectal carcinoma in four patients and gastric leiomyosarcoma in one. The outcomes of these patients were poor; four of the children have died, and one girl remains alive with extensive disease. Benign lesions included neurogenic tumors (n = 5), inflammatory pseudotumors (n = 3), hemangiomas (n = 2), teratoma and carcinoid (n = 1 each). These tumors were ultimately cured, with one exception, after surgical resection. CONCLUSIONS: Gastrointestinal tumors in children cover a broad spectrum of benign and malignant varieties and stem from conditions that differ significantly from those observed in adults. While treatment varies according to diagnosis, most patients respond best to complete resection of the primary tumor. PMID- 7850527 TI - Small bowel cancer: a 30-year review. AB - BACKGROUND: Small bowel cancer is a relatively rare tumor with an incidence of 2,700 new cases and 900 deaths per year. The influence of stage on survival has been reported only once previously. Patterns of recurrence are unreported. METHODS: All cases of small bowel cancer treated at our hospital over a 30-year period (1960-1989) were reviewed. RESULTS: The site of most cancers was the duodenum (46%), followed in frequency by the jejunum (33%) and the ileum (21%). Adenocarcinoma was the most common histology (63%), followed in frequency by lymphoma (15%), leiomyosarcoma (13%), carcinoid tumors (6%), and miscellaneous (3%). Analysis of stage distribution by site showed a decrease in stages I and II with more distal locations. Associated cancers occurred in 11%, but none were seen in the group with carcinoid tumors. Actuarial 10-year survival rates were 24% for those with adenocarcinoma (all stages) 75% for stage I, 25% for those with stage II, and 0% for stage III. A subgroup of 10 patients who underwent a pancreaticoduodenectomy (one stage I, seven stage II, two stage III) had a 30% 10 year survival rate. Those patients with lymphoma had a 12% 10-year survival rate, and those with leiomyosarcoma had a 20% 10-year survival rate. A 100% 10-year survival rate was observed in those with carcinoid tumors. Peritoneal carcinomatosis was the most common failure pattern (33%), followed in frequency by local recurrence in 23% and abdominal wall recurrence in 15%. CONCLUSIONS: A correlation exists between the pathologic stage and the survival rate for adenocarcinoma. The most common recurrence pattern for adenocarcinoma was carcinomatosis, followed in frequency by abdominal wall recurrence. Leiomyosarcoma preferentially metastasizes to the liver. PMID- 7850529 TI - Improved survival with adjuvant immunotherapy after surgical resection in a murine model. AB - BACKGROUND: Adoptive immunotherapy has met with limited success in the treatment of bulky metastatic disease. The purpose of this study was to determine whether lymphocytes stimulated in vitro could improve survival when given as an adjuvant to surgical resection in animals harboring microscopic metastatic disease. METHODS: Lymphocytes from nodes draining the primary tumor (DLN lymphocytes) were stimulated in vitro with phorbol 12,13-dibutyrate and ionomycin and used as adjuvant immunotherapy after surgical resection of the primary tumor. Mice with advanced P-815 footpad tumors and disseminated microscopic metastases underwent amputation of the tumor-bearing extremity and were randomized to various adjuvant treatments. RESULTS: Mice treated with adjuvant immunotherapy using stimulated DLN lymphocytes demonstrated significantly improved survival, showing that DLN lymphocytes stimulated in vitro can abrogate metastases that are invading multiple organs simultaneously. Mice successfully treated with adjuvant immunotherapy demonstrated long-term (80 days) in vivo antitumor activity by rejecting subsequent tumor challenge. In addition, stimulated DLN lymphocytes provided in vivo antitumor activity to naive mice. CONCLUSIONS: Adjuvant immunotherapy after resection in the face of residual microscopic tumor burden may prove to be a useful application of adoptive immunotherapy. PMID- 7850528 TI - Activation of T lymphocytes for the adoptive immunotherapy of cancer. AB - BACKGROUND: Adoptive immunotherapy of malignancy involves the passive transfer of antitumor-reactive cells into a host in order to mediate tumor regression. Based on animal models, the transfer of immune lymphoid cells can eradicate widely disseminated tumors and establish long-term systemic immunity. Critical for successful adoptive immunotherapy is the ability to isolate large numbers of immune cells. For clinical therapy, it will require the development on in vitro methods to promote the sensitization and propagation of tumor-reactive cells. However, this is a formidable task since human cancers are postulated to be poorly immunogenic because of their spontaneous origins. RESULTS: Human lymphoid cells for ex vivo activation and subsequent adoptive transfer have been derived from different sources, including peripheral blood, tumor, and lymph nodes. Peripheral blood lymphocytes can be incubated with interleukin 2 to generate lymphokine-activated killer (LAK) cells, which nonspecifically lyse autologous and allogeneic tumor cells in vitro. LAK cell therapy represented the earliest attempt to treat advanced human cancers, with encouraging results documented in patients with renal cell cancer and melanoma. From that experience, the use of more immunologically specific cellular agents with potentially greater therapeutic efficacy has been investigated. One approach uses tumor-infiltrating lymphocytes, which have been characterized experimentally to be more specific in tumor reactivity compared with LAK cells. Other techniques have involved the use of lymphoid cells derived from lymph nodes draining tumors or primed by tumor vaccines. In vitro activation of these cells with tumor antigen or anti-CD3 monoclonal antibody results in the generation of T cells that mediate the rejection of poorly immunogenic tumors in animal studies. These alternate methods are currently being evaluated in clinical studies. CONCLUSIONS: Experimentally, cellular therapy is a potent method to eradicate progressive tumors. Initial clinical studies have demonstrated that this form of therapy is technically feasible and can result in meaningful antitumor responses. Advances in this area will require improved methods to sensitize, isolate, and expand tumor-reactive T cells for adoptive transfer. PMID- 7850530 TI - Effect of growth hormone on tumor and host in an animal model. AB - BACKGROUND: The relative effects of growth hormone on tumor versus host growth and protein metabolism are not known. This study examines the influence of recombinant rat growth hormone (r-rGH) on host and tumor growth, host body composition, and protein synthesis of tumor and host in tumor-bearing rats. METHODS: After left flank implantation of methylcholanthrene-induced sarcoma, 28 Fischer rats with palpable tumor were treated with s.c. saline or 1 mg/kg/day r rGH for 11 days. At death, fractional protein synthetic rates (FSRs) of tumor, liver, and gastrocnemius muscle were determined. In a separate experiment, 27 tumor-bearing rats received saline or 1 mg/kg/day r-rGH for 2 weeks. Tumor and host growth and host body composition were analyzed. RESULTS: Animals treated with r-rGH had significantly higher liver FSR than did controls (233 +/- 27%/day vs. 110 +/- 4%/day, respectively). No significant differences were associated with growth hormone administration with respect to tumor growth, host composition, or FSR of tumor or muscle. CONCLUSIONS: Growth hormone stimulates liver protein synthesis, without changing tumor growth, protein synthesis, or host composition in this rat sarcoma model. Further investigation of growth hormone as an anticachectic agent is warranted. PMID- 7850531 TI - Effect of systemic insulin on protein kinetics in postoperative cancer patients. AB - BACKGROUND: Cancer cachexia is a significant cause of postoperative morbidity and mortality in patients with tumors of the upper gastrointestinal tract. Standard parenteral nutrition (TPN) has failed to alter this. The anabolic effect of insulin has been well documented, and its positive effect on protein economy in cancer patients has been recently demonstrated. This study examines the effect of high-dose insulin and parenteral nutrition on protein kinetics in postoperative cancer patients. METHODS: Eleven patients underwent surgery for pancreatic, esophageal, or gastric carcinoma. Postoperatively, patients received standard TPN for 4 days (1 g/kg/day amino acids, 1,000 kcal/day dextrose, 100 g/day lipid), and hyperinsulinemic parenteral nutrition for 4 days (same as standard TPN plus 1.44 U/kg/day regular human insulin) in a crossover design. All patients received both treatments, and the order of treatment was determined randomly. Euglycemia was maintained during insulin infusion via a variable 30% dextrose infusion. Patients underwent protein metabolic studies after each treatment period and rates of whole body and skeletal muscle protein synthesis, breakdown, and net balance were determined by radioisotopic tracer methods using 14C-leucine and 3H phenylalanine. RESULTS: Compared with standard TPN (STD), hyperinsulinemic TPN (INS) resulted in a significant increase in skeletal muscle protein synthesis (INS: 52.04 +/- 10.22 versus STD: 26.06 +/- 6.71 nmol phe/100 g/min, p < 0.05) and net balance of protein (INS: 7.75 +/- 4.61 versus STD: -15.10 +/- 6.44 nmol phe/100 g/min, p < 0.01), but no difference in skeletal muscle protein breakdown (INS: 44.29 +/- 11.54 versus STD: 41.17 +/- 5.89 nmol phe/100 g/min). Whole-body net balance of protein also significantly increased with insulin-based TPN, compared with standard TPN (INS: 0.04 +/- 0.05 versus STD: -0.08 +/- 0.07 mumol leu/kg/min, p < 0.05), but no difference in whole-body protein synthesis (INS: 2.52 +/- 0.15 versus STD: 2.49 +/- 0.15 mumol leu/kg/min) or whole-body protein breakdown (INS: 2.48 +/- 0.16 versus STD: 2.58 +/- 0.19 mumol leu/kg/min) was observed. Patients received significantly more calories during the hyperinsulinemic TPN period than during the standard TPN period. There was no difference in total, essential, or branched-chain amino acids, and no difference in serum free fatty acids, triglycerides, or cholesterol was observed between the two treatment periods. CONCLUSION: High-dose insulin in conjunction with hypercaloric parenteral nutrition causes improved skeletal muscle protein synthesis, skeletal muscle protein net balance, and whole-body protein net balance compared with standard TPN in postoperative cancer patients. PMID- 7850532 TI - Interstitial fluid pressure in breast cancer, benign breast conditions, and breast parenchyma. AB - BACKGROUND: Interstitial fluid pressure (IFP) in rodent malignant tumors is reportedly much higher than in surrounding normal tissue. We hypothesized the same may be true in human invasive breast tumors. METHODS: We measured IFP in the operating room in 25 patients undergoing excision breast biopsy under local anesthetic for diagnostic purposes. RESULTS: In patients with invasive ductal carcinomas IFP was 29 +/- 3 (SE) mm Hg, compared with -0.3 +/- 0.1 mm Hg in those with normal breast parenchyma (p < 0.001), 3.6 +/- 0.8 mm Hg in those with benign tumors (p < 0.003), -0.3 +/- 0.2 mm Hg in those with noninvasive carcinomas (p = 0.034), and 0.4 +/- 0.4 mm Hg in those with other benign breast conditions (p = 0.002). There was a direct correlation between IFP and tumor size (R2 = 0.3977; p = 0.021). No correlation was found between IFP and nuclear grade, angiolymphatic invasion, systemic blood pressure, metastasis to lymph nodes, or estrogen and progesterone receptors. CONCLUSIONS: IFP measurements may facilitate radiographic or ultrasound localization of small or nonpalpable malignant tumors in those patients undergoing needle aspiration cytology or stereotactic core needle biopsy. PMID- 7850534 TI - Surgeon's role in the management of solitary renal cell carcinoma metastases occurring subsequent to initial curative nephrectomy: an institutional review. AB - BACKGROUND: Solitary metastases from a primary renal cell carcinoma (RCC) occur in < 10% of patients with metastatic RCC. To date, the benefit of surgically resecting such apparently solitary lesions has not been well documented. MATERIALS AND METHODS: Forty-one patients (25 men, 16 women) with metastatic renal cell carcinoma treated by surgical excision of solitary metastases (1970 1990) were retrospectively reviewed. They comprised 9% of patients with metastatic hypernephroma seen during this period. All patients had undergone previous curative nephrectomy with a median disease-free interval of 27 months. Patients with skeletal, spinal cord, and lymph node metastases were excluded. RESULTS: Metastases were intrathoracic (n = 20), intracranial (n = 7), and intraabdominal or in the extrapleural chest wall soft tissue (n = 10). Three patients had metastases to the thyroid gland and one had a solitary metastasis to an index finger. Median follow-up was 3.2 years. Complete resection was possible in 36 patients (88%) with a single lesion excised in 23 of these 36 patients (64%). There was no operative mortality. Predicted survival from the date of complete resection of metastases was 77%, 59%, and 31% at 1, 3, and 5 years, respectively, with a median survival of 3.4 years. One patient is alive without evidence of recurrent tumor 93 months from the first of 12 complete surgical resections. Varying adjuvant therapy was used in 50% of the patients. An increased histological tumor grade of the metastatic lesion relative to the original RCC was the only significant prognostic indicator identified. Disease free interval and number of resected lesions were not significantly associated with patient survival. CONCLUSION: A small fraction of renal cell carcinoma patients are candidates for potentially curative surgical resection of solitary metastatic lesions. Excision of such lesions may contribute to prolonged survival in selected instances. PMID- 7850533 TI - Relationships of Na+ and K+ concentrations to GRP, CGRP, and calcitonin immunoreactivities and Na+,K(+)-ATPase (NKA) inhibitory activity in human breast cyst fluid. AB - BACKGROUND: Although the etiology of gross cystic disease of the breast is unknown, elevated cyst concentrations of potassium (K+) (> 60 mM/L) may be related to symptoms. The purpose of this study was to clarify the mechanism(s) of K+ accumulation in breast cysts. METHODS: We assayed cyst fluids for factors known to exert effects on K+ transport, namely, endogenous digitalis-like inhibitors of Na+,K(+)-ATPase (NKA) and the neuropeptides gastrin-releasing peptide (GRP), calcitonin (CT), and calcitonin gene-related peptide (CGRP). RESULTS: Cyst fluid K+ was directly correlated with cyst volume, cyst NKA inhibitory activity (in ouabain equivalents), and cyst concentrations of calcitonin, GRP, and CGRP. Cyst fluid Na+ was inversely correlated with cyst fluid K+, cyst NKA inhibitory activity, cyst volume, and cyst fluid concentrations of calcitonin, GRP, and CGRP. NKA inhibitory activity correlated directly with GRP and CGRP. Immunocytochemistry localized GRP to breast cyst lining cells and areas of ductal and lobular epithelial hyperplasia in biopsies of 15 of 15 cysts and in 5 of 5 breast carcinomas, but not in (0 of 5) normal breast biopsies. Specificity of GRP staining was demonstrated by total abolition of reactivity after adsorption with synthetic GRP, but not after adsorption with synthetic substance P, neurokinin A, or neurokinin B. CONCLUSIONS: We conclude that both the concentrations of endogenous digitalis-like factors and the neuropeptides calcitonin, GRP, and CGRP in human breast cyst fluids are related to the concentrations of K+ and Na+ in breast cysts and to cyst volume. PMID- 7850535 TI - Radical forequarter amputation with hemithoracectomy and free extended forearm flap: technical and physiologic considerations. AB - BACKGROUND: A radical forequarter amputation with partial chest wall resection (one to four ribs) has been reported for benign and malignant lesions involving the shoulder and chest wall region. Concerns about reconstruction and postoperative pulmonary function have previously limited more extensive chest wall resections. The current report describes the first case in which a complete unilateral anterior and posterior chest wall resection and pneumonectomy (hemithoracectomy) accompany a forequarter amputation. A novel reconstructive technique used the full circumference of the forearm tissue with an intact ulna as a free osseomyocutaneous flap. METHODS: In this case, a 21-year-old patient presented with an extensive recurrent desmoid tumor that involved the shoulder, brachial plexus, subclavian vein, and chest wall from the lateral sternal border to the midportion of the scapula and down to the eighth rib. The operative technique involved removal of the entire right hemithorax from the midline sternum to the transverse process posteriorly, down to the ninth rib inferiorly. Due to the absence of a rigid hemithorax, the uninvolved ipsilateral lung was also removed. The forearm flap was prepared before final separation of the specimen and division of the subclavian vessels. RESULTS: Postoperatively, the patient maintained excellent oxygenation without atelectasis or fever and was extubated on the 15th postoperative day. As expected after pneumonectomy, significant decreases from preoperative to immediate postoperative values were noted for the vital capacity (VC) (from 4.87 L to 1.29 L), forced 1-s expiratory volume (FEV1) (from 3.77 L to 1.02 L), and inspiratory capacity (IC) (3.33 l to 0.99 l). Rehabilitation included a specially designed external prosthesis to provide cosmesis and prevent scoliosis. By the 15th postoperative week the patient had returned to normal social and physical activities, with a gradual improvement in all respiratory parameters: VC 1.52 L, FEV1 1.29 L, IC 1.04 L. There has been no evidence of tumor recurrence at 1 year. CONCLUSIONS: This report provides evidence that a complete hemithoracectomy, pneumonectomy, and forequarter amputation can be safely performed for selective tumors involving the shoulder region with extensive chest wall invasion. Reconstruction may be achieved with an extended forearm osseomyocutaneous free flap with an excellent functional outcome. PMID- 7850536 TI - Stereotactic core needle biopsy of mammographic breast lesions as a viable alternative to surgical biopsy. AB - BACKGROUND: Stereotactic needle biopsy technique has received considerable attention as a possible alternative to surgical biopsy of nonpalpable breast lesions. The exact role of this procedure in the management of mammographic breast lesions has not yet been accurately defined. METHODS: Data have been collected prospectively on 416 patients over an 8-month period (January 1992 through August 1992). Of 416, 356 patients underwent only stereotactic breast biopsy with a 14-gauge needle. Sixty patients underwent stereotactic breast biopsy followed by surgical biopsy. Based on mammographic findings before biopsy, lesions were classified as benign (24%), likely benign (49%), malignant (2%), likely malignant (6%), and indeterminate (19%). The number of core biopsy specimens obtained from each patient ranged from one to six. RESULTS: The specimen was considered adequate in 98% of cases. Complications were minimal. The tissue diagnosis was benign in 92% and malignant in 8% of patients. In those patients undergoing surgical and stereotactic biopsy, 57 of 60 had matching histopathological results, representing an agreement rate of 95% (p < 0.001). The three patients whose histopathological results did not match had malignant diagnoses on stereotactic biopsy that were subsequently not identified in the modified radical mastectomy specimen because the entire focus of malignancy was removed by the several passes made by the core needle during biopsy. No patient had a negative stereotactic biopsy result in whom malignancy was later detected by surgical biopsy. CONCLUSIONS: This study indicates excellent agreement between surgical and stereotactic needle biopsy findings. Stereotactic biopsy with a 14 gauge needle could obviate the need for surgical biopsy in certain women with radiologically benign, likely benign, and indeterminate lesions. PMID- 7850537 TI - Importance of image-guided stereotactic biopsy to confirm diagnosis in an oncological setting. AB - BACKGROUND: In current practice, the neurosurgical community relies heavily on computed tomography (CT) and magnetic resonance imaging (MRI) for making the diagnosis of brain lesions, especially when surgically inaccessible. However, the specificity of these neuroimaging modalities remains limited, and errors in diagnosis are frequent. In an attempt to ascertain how often the diagnosis based on imaging studies is proved wrong by biopsy, we reviewed the findings from 100 consecutive stereotactic biopsies performed in an oncological setting. METHOD: The records of 100 consecutive stereotactic biopsies were postoperatively reviewed. The preoperative clinical and radiologic differential diagnoses were compared with diagnosis made on tissue retrieved by biopsy. RESULTS: In 19% of patients, the preoperative clinical and radiological diagnoses and postoperative diagnosis were different, and reliance on brain imaging data alone would have led to an incorrect tentative diagnosis and the wrong choice of treatment. CONCLUSIONS: The high rate of discrepancy between clinical and radiological diagnoses on the one hand and biopsy-proven diagnosis on the other hand is a compelling reason to establish tissue diagnosis. Stereotactic biopsies of brain lesions are relatively safe and should be performed in cases where tissue characteristics affect prognosis, where therapy carries an inherent risk, and in those patients under treatment for cancer or immune deficiencies in whom there is an unusually broad differential diagnosis. PMID- 7850538 TI - Acute metabolic effects of human recombinant tumor necrosis factor beta in the rat. AB - BACKGROUND: Cancer cachexia is associated with several alterations in host metabolism, including hypoaminoacidemia and an increase in gluconeogenesis (GLC) and lipolysis. Tumor necrosis factor beta (TNF beta), a lymphokine released by mitogen-activated T lymphocytes and several cancer cell lines, causes an increase in lipolysis in 3T3L1 adipocytes. Since little is known about the metabolic effects of TNF beta in vivo, we examined its acute effects in the rat. METHODS: Twenty-eight male Fischer rats were injected intraperitoneally with TNF beta (250 micrograms/kg) or saline (CTL), and after 4 h, isolated hepatocytes were obtained (by in situ collagenase liver perfusion [n = 12]) or aortic blood was collected (n = 16). Hepatocytes were incubated with 10 mM alanine (ALA) or 10 mM lactate (LAC), and glucose production was measured. Rates of GLC (nmol glucose/10(6) cells/min) were determined by linear regression. Plasma lactate, glucose, insulin, and amino acids (AA) (nmol/ml) were measured, and values were expressed as means +/- SEM. Comparisons between groups were made by unpaired t test or Mann Whitney U test, and significance was defined as p < 0.05. RESULTS: TNF beta caused a 130% increase in gluconeogenesis from alanine (2.7 +/- 0.5 vs 1.2 +/- 0.2 nmol glucose/10(6) cells/min, TNF vs CTL), and a 60% increase from lactate (7.5 +/- 1.0 vs 4.6 +/- 0.5 nmol glucose/10(6) cells/min, TNF vs CTL). Plasma insulin levels in TNF treated rats were 1.2 +/- 0.2 ng/ml compared to 1.1 +/- 0.2 ng/ml in CTL. Total amino acid levels in TNF treated rats were 3,175 +/- 111 nmol/ml compared to 3,190 +/- 103 nmol/ml in CTL. CONCLUSION: In vivo TNF beta causes an increase in hepatic gluconeogenesis from alanine and lactate with no change in plasma insulin or amino acids. PMID- 7850539 TI - Functional morbidity of hyperthermic isolated regional perfusion of the extremities. AB - BACKGROUND: Isolated regional perfusion (IRP) of an extremity is a major operation. The therapeutic value for stage I melanoma is still controversial and is presently being investigated in a prospective, randomized study by the European Organization for Research and Treatment of Cancer. So far there are no reliable data available concerning the morbidity of IRP. Therefore, we performed a prospective, randomized study on this topic. METHODS: In a prospective study, a group of 97 patients with a stage I melanoma localized on an arm or leg were randomized for IRP with melphalan followed by wide excision (WE) and fasciotomy or for WE only. Morbidity was evaluated on the basis of the following parameters: duration of hospitalization, postoperative pain, postoperative performance, and grade of perfusion toxicity. At 12-month follow-up, a physical diagnostic examination was performed to measure the mobility of the joints, and the circumference and volume of the treated and untreated extremities. RESULTS: All the parameters, including the physical diagnostic examination, could be evaluated in 83 of the 97 patients (8 patients died of metastatic disease and 1 patient died of another disease before they could be investigated; 2 patients were in too poor physical condition due to metastases to be examined, and 3 patients were unable to participate for nonmedical reasons). Age and sex distribution were comparable in the various patient groups. Treatment mortality was 0%. There were no complications except for urine retention (one patient) and wound dehiscence (one patient). After IRP + WE of the lower limb, the period of hospitalization was an average of 1.9 days longer (p = 0.01) than for WE on the limb only. This difference was absent for the arm. Naturally after perfusion, there was a significant difference in toxic reactions (edema and pain) between the IRP + WE patients and the WE-only patients. However, at 12-month follow-up, the difference in morbidity between IRP + WE and WE-only patients was no longer present: Morbidity of joints and circumference of the limb were the same. A number of subjective complaints were encountered fairly often after IRP + WE (e.g., pricking sensations or pain during changes in the weather), which can possibly be explained by fibrosis caused by perfusion. These complaints were not quantified further because they did not hinder the patients' functioning. CONCLUSIONS: In a long term, IRP with fasciotomy does not cause any additional morbidity. Immediately after the operation, there was more morbidity as a result of the perfusion, which caused a 2-day-longer period of hospitalization in the patients with lower-limb perfusion compared with those who underwent WE only. These findings are in contrast to those in the literature, in which 25% limitation of motion in the ankle joint after perfusion is mentioned. One explanation may be that we always performed fasciotomy after perfusion to prevent (sub)clinical compression syndrome and avoid late fibrosis. PMID- 7850540 TI - Complete hepatic venous isolation and extracorporeal chemofiltration as treatment for human hepatocellular carcinoma: a phase I study. AB - BACKGROUND: We performed a phase I study of a novel system of complete hepatic venous isolation and extracorporeal chemofiltration in patients with unresectable hepatocellular carcinoma (HCC) to determine (a) whether systemic exposure to doxorubicin could be limited after high-dose hepatic arterial infusion (HAI), and (b) the hepatic maximum tolerated dose (MTD) of doxorubicin. METHODS: Ten patients with biopsy-proven HCC were treated with 20-min HAI of doxorubicin (17 total treatments). Two patients were treated with doxorubicin 60 mg/m2, three patients were treated at 90 mg/m2, and five patients received 120 mg/m2. A newly developed dual-balloon vena cava catheter was advanced from the femoral vein, and the balloons were inflated to isolate and capture total hepatic venous outflow. The hepatic venous blood was pumped through extracorporeal carbon chemofilters before return of the blood to the systemic circulation. RESULTS: Peak systemic doxorubicin levels were an average 85.6% lower than were peak prefilter levels (p < 0.01). Because all catheters were placed percutaneously and because the chemofiltration markedly limited systemic chemotherapy exposure, patients were discharged 1 day after 16 of the 17 treatments. The hepatic and systemic MTD of doxorubicin in this treatment protocol was 120 mg/m2. CONCLUSIONS: This novel system of complete hepatic venous isolation and chemofiltration limits systemic chemotherapy toxicity and will allow use of higher doses of chemotherapeutic agents to treat HCC. PMID- 7850541 TI - Prostate cancer imaging with a new monoclonal antibody: a preliminary report. AB - BACKGROUND: Optimal treatment of prostate cancer depends on accurate staging. Computed tomography (CT) and magnetic resonance imaging have severe limitations, and standard bone scanning can show only destructive osseous metastases. A radiolabeled antibody specific to prostatic adenocarcinoma could theoretically find evidence of soft-tissue metastases and lymph node involvement. METHODS: An immunoconjugate (CYT-356) consisting of a murine monoclonal antibody against human prostatic adenocarcinoma bound to a linker-chelator and radiolabeled with indium 111 was administered intravenously to seven patients with documented Stage D adenocarcinoma of the prostate. Planar imaging was done on days 1, 2, and 3 after injection. The CYT-356 scans were compared with standard technetium Tc99m sulfur colloid bone scans and CT scans. RESULTS: Optimal imaging results were obtained on the 72-h scans. All patients had lesions on both the 99mTc-sulfur colloid bone scan and the CYT-356 scan. The location of the lesions correlated to a great extent. Two patients had positive lesions biopsied, and both biopsies showed the presence of metastatic prostatic carcinoma. There were no side effects from administration of the antibody. CONCLUSION: In this preliminary study, CYT 356 scanning appears to be a promising agent to accomplish specific staging of prostatic carcinoma. PMID- 7850542 TI - Protective effect of doxorubicin in vitamin C or dimethyl sulfoxide against skin ulceration in the pig. AB - BACKGROUND: Accidental extravasation of doxorubicin leads to skin necrosis and significant morbidity. Based on our previous work in the rat, we hypothesized that the free radical scavengers dimethyl sulfoxide (DMSO) and vitamin C prevent doxorubicin-induced skin ulcers in white swine. METHODS: Fifteen white swine were anesthetized and injected with 0.5 mg of doxorubicin (1 mg/ml) intradermally delivered in saline, 10% DMSO, 20% DMSO, vitamin C (1 mg/ml), or vitamin C in 20% DMSO. Presence of skin ulceration and ulcer size, in the two greatest dimensions, was determined weekly for 3 weeks. RESULTS: Delivery of doxorubicin in DMSO and/or vitamin C lowered the ulcer incidence from 87% to 27% (p < 0.0001) when compared with delivery in saline. CONCLUSION: We conclude that the free radical scavengers DMSO and vitamin C are capable of lowering the incidence of doxorubicin-induced skin ulcers and could significantly lessen the morbidity associated with doxorubicin extravasation. PMID- 7850543 TI - Comparison of charges related to radiotherapy for soft-tissue sarcomas treated by preoperative external-beam irradiation versus interstitial implantation. AB - BACKGROUND: We compared treatment-related charges associated with external beam irradiation and interstitial implantation for soft-tissue sarcoma of the extremity. METHODS: Charges related to radiotherapy in 35 patients with soft tissue sarcoma of the extremity were reviewed. Preoperative external beam irradiation (EB) delivering 50 Gy in 25 fractions with 6 MV photons was administered to 12 of the patients evaluated. The remaining 23 patients were treated with interstitial implantation (IR) as the only radiotherapeutic intervention. The anatomic distribution of the sarcomas treated by IR included 14 lower-extremity (LE) and nine upper-extremity (UE) lesions. The average length of iridium wire used for IR was 78 cm. Because LE lesions tend to be larger, the average length equaled 109.5 cm as compared with the 47 cm for UE implants. RESULTS: The radiotherapeutic approach represented the only difference in treatment-related charges because the operative procedure of wide local excision was performed in each group. No difference in perioperative complications was observed between the two treatment approaches. Charges were stratified according to hospital-based and professional services. Radiotherapy-based hospital charges for the administration of EB averaged $6,515 compared with $4,050 for IR (p < 0.0001). Professional services also were significantly different, totaling $4,390 for EB and $3,240 for IR (p < 0.0001). The total of these charges for radiotherapy procedures and professional fees equaled $10,905 for EB compared with $7,290 for IR (p < 0.0001). Incorporating the necessary operating-room time for implant placement ($750) and five additional hospital days ($1,800), the costs associated with IR totaled $9,840; using chi-square analysis, the cost for IR remained significantly (p < 0.0001) less expensive than the $10,905 associated with EB. Because a large component of the radiotherapy cost for IR is related to the length of iridium 192 wire required, charges were stratified according to the location of the tumor. The total charge for IR of the UE equaled $9,345 compared with $10,335 for LE implants. Chi-square comparison for both UE and LE implants continued to show significant differences (p < 0.0001) when related to EB therapy. CONCLUSION: Cost-analysis comparison of brachytherapy versus external beam irradiation found lower charges for patients undergoing adjuvant irradiation with brachytherapy for soft-tissue sarcoma. To optimize the cost-benefit ratio, prospective studies are necessary to define the application of these radiotherapeutic approaches based on clinical criteria. PMID- 7850544 TI - Loss of blood group antigen A in non-small cell lung cancer. AB - BACKGROUND: Many human tumor cells display alterations in blood group antigen expression, and the loss of antigen A expression by non-small cell lung cancer (NSCLC) in blood group A patients has recently been associated with decreased survival. METHODS: To confirm this finding, we performed a retrospective study of 62 NSCLC patients undergoing potentially curative resection between August 1987 and December 1991 who were blood group A and had paraffin-embedded primary lung cancer tissue suitable for immunohistological analysis of antigen A expression. Twenty-seven patients expressed antigen A in their tumors, whereas 35 had loss of antigen expression. Disease-free survival (DFS) curves were calculated for stage I (n = 26) and IIIA (n = 25) patients. RESULTS: The two groups of patients with or without antigen A expression did not have significantly different DFS. A proportional hazards regression analysis identified no significant difference in the DFS of stage I patients with or without antigen A, but stage IIIA patients who had preservation of antigen A had significantly shorter DFS than did those who lost antigen A (p = 0.0002). CONCLUSIONS: The loss of expression of antigen A by primary tumor cells was not a significant adverse prognostic factor in DFS in our series, and we would recommend further studies to define clearly the clinical importance of antigen A expression in pulmonary carcinoma. PMID- 7850545 TI - Decrease of glutaminase expression by interferon-gamma in human intestinal epithelial cells. AB - BACKGROUND: Glutaminase, the principal enzyme of glutamine hydrolysis, breaks down glutamine to supply energy and intermediates for cell growth and is present in high concentrations in replicating tissues such as intestinal epithelium and malignant tumors. In the host with cancer, glutaminase activity in the gut mucosa diminishes as the tumor grows, but the regulation of this response is unknown. Because cytokines may regulate the altered glutamine metabolism that is characteristic of the host with cancer, we studied the effects of cytokines on gut mucosal glutaminase expression in vitro using the human enterocytic Caco-2 cell line. METHODS: Differentiated confluent cells were incubated with interleukin (IL)-1, IL-6, tumor necrosis factor, or interferon-gamma (IFN-gamma). After a 12-h incubation, glutaminase-specific activity and kinetic parameters (maximal enzyme activity [Vmax] and enzyme affinity [Km]) were determined. Glutaminase protein concentration was determined by Western blot analysis using a rabbit antirat polyclonal antibody. Total cellular RNA was extracted for Northern hybridization and radiolabeled with a glutaminase cDNA probe. RESULTS: Of the cytokines studied, only IFN-gamma altered glutaminase activity. Kinetic studies indicated a decrease in activity secondary to a 25% decrease in Vmax with no change in Km, consistent with a reduction in the number of glutaminase molecules rather than a change in enzyme affinity. Glutaminase protein was decreased 50% in IFN-gamma-treated cells when compared with controls. This decrease was dose independent and was associated with a concomitant 75% decrease in glutaminase messenger RNA levels. These reductions in message and protein translated into a 60-80% decrease in functional glutaminase-specific activity. CONCLUSIONS: This IFN-gamma-mediated decrease in glutaminase activity may be one mechanism by which gut glutamine metabolism is diminished as the tumor grows and becomes the principal organ of glutamine use. PMID- 7850547 TI - Prophylactic mastectomy: an unnecessary procedure. PMID- 7850548 TI - Management of the contralateral breast. PMID- 7850549 TI - Preventive mastectomy. PMID- 7850550 TI - Rationale for elective contralateral mastectomy with immediate bilateral reconstruction. AB - BACKGROUND: Women with breast cancer treated by mastectomy with immediate breast reconstruction can get exceptionally good results if the reconstruction is performed with autogenous tissue using the transverse rectus abdominis myocutaneous (TRAM) flap. Bilateral reconstruction with TRAM flaps is also possible, but only if both breasts are reconstructed at the same time. To avoid the possibility of subsequently developing contralateral malignancy and having to undergo assymetrical reconstruction with a different technique, some patients have chosen the alternative of bilateral mastectomy with bilateral immediate reconstruction. This is only reasonable if the incidence of failure in bilateral breast reconstruction is very low. METHODS: We prospectively studied reconstructive outcomes in 100 patients who had breast cancer and who underwent bilateral mastectomy and reconstruction (using implants as well as TRAM flaps). We also reviewed the histologic findings in 88 prophylactically removed high-risk breasts. RESULTS: Successful outcomes were initially achieved in 95 patients; of the 5 failures, two were successfully reconstructed with alternative techniques for an overall success rate of 97%. Of the 63 patients reconstructed with bilateral TRAM flaps, all but one (98%) were successful on the first try. TRAM flap reconstructions were significantly more likely to be successful than were those based on implants (p = 0.05). Previously unsuspected invasive cancer was found in 3 patients (3.4%), whereas carcinoma in situ was found in 5 patients (5.7%) and in another 18 patients (20%) cellular atypia was present. CONCLUSIONS: Bilateral breast reconstruction has a low incidence of failure, particularly if TRAM flaps are used. For selected patients, elective contralateral mastectomy with immediate bilateral reconstruction is a reasonable treatment alternative provided that the necessary expertise is available and the patients clearly understand the risks. PMID- 7850546 TI - Cytokine-mediated gene therapy for cancer. AB - BACKGROUND: Significant interest has been generated in the gene therapy of cancer. One strategy involves tumor-directed cytokine gene transfer and its effects on tumor immunobiology. METHODS: The authors review the current literature pertaining to cytokine gene therapy of cancer and provide a description of gene transfer methods currently being evaluated. RESULTS: Several cytokine gene transfer models have been described involving at least 12 different cytokines. The introduction of cytokine genes into experimental animal tumors improves their ability to be recognized and destroyed by the host immune system. Certain cytokines will regulate phenotypic properties such as major histocompatibility complex antigens, immunosuppressive peptides, protooncogenes or endogenous cytokine production. Cytokine-transduced tumors attract an inflammatory exudate in vivo that generally results in tumor destruction. The nature of the infiltrate (lymphocytic, mononuclear, granulocytic) cannot always be predicted from the known biological properties of each cytokine. Untransduced bystander tumor cells are usually also destroyed. Some, but not all, cytokine transductions result in the generation of systemic major histocompatibility complex-restricted, tumor immunity. It has been hypothesized that the local continuous production of cytokines by tumor cells provides an optimal microenvironment for antigen recognition and the generation of T-cell immunity. CONCLUSIONS: These experimental observations hold promise for the clinical application of genetically engineered tumor vaccines. PMID- 7850551 TI - Insurance coverage of patients with breast cancer in the 1991 commission on cancer patient care evaluation study. AB - BACKGROUND: Trends in the care of patients with cancer are monitored annually by the Commission on Cancer of the American College of Surgeons. In 1991 a patient care evaluation study of breast cancer was conducted, which among other questions examined the correlation of health insurance with type or quality of care delivered for breast cancer on a national basis. METHODS: The tumor registry system of the American College of Surgeons was used to obtain data on patients with breast cancer diagnosed in 1983 and 1990. Trends in diagnosis and treatment were correlated with the type of insurance or lack of insurance. RESULTS: Data were obtained from hospitals in 50 states on a total of 41,651 patients. The largest number of patients were covered by Medicare. Fewer than 5% were considered medically indigent. Medically indigent patients presented with higher stage disease and did not participate in a trend toward downstaging, which occurred between the two study years. The treatment of medically indigent patients appeared to be appropriate and comparable with better insured patients. Insurance type (health maintenance organization vs. private) did not affect stage, treatment, or outcome. Decisions to use controversial therapies, such as chemotherapy for stage I disease, did not appear to be financially driven. CONCLUSION: A nationwide pattern of care study for breast cancer indicates that medically indigent patients present with more advanced disease compared with better insured patients, but once the diagnosis is made, treatment and outcome have little to do with insurance type. PMID- 7850552 TI - Radiotherapy for parotid cancer. AB - BACKGROUND: Parotid malignancies represent a heterogeneous group of tumors primarily managed by surgical extirpation. Moderately high recurrence rates are seen after surgery alone, and postoperative radiotherapy has been used for patients with higher risks for local failure. METHODS: To assess the role of radiotherapy in the management of patients with malignant tumors of the parotid gland, the records of 68 patients receiving megavoltage therapy at our institution from 1966 to 1989 were reviewed. Patients were placed into three groups for analyses. Group I was composed of 41 patients receiving radiotherapy following total gross removal of parotid cancer by surgical procedures, varying from excisional biopsy through total parotidectomy. Radiation dose for this group ranged from 4,995 to 6,500 cGy. Group II was composed of 10 patients treated with radiotherapy after incisional biopsy or excision with positive margins. These patients received radiation doses of 4,000-9,470 cGy. Group III was composed of 17 patients receiving radiotherapy for a postsurgical local recurrence. Their radiation dose ranged from 4,300 to 8,400 cGy. RESULTS: Two of the 41 patients from group I developed a local recurrence. Two of these patients also developed distant metastases, one concurrent. Two of 10 group II patients failed locally, whereas three developed distant metastases. Only nine of the 17 patients in group III were controlled locally, and four patients developed distant dissemination. CONCLUSION: Total gross excision of parotid cancer, sparing facial nerve if possible and followed by regional radiotherapy, provides excellent rates of local control and survival with modest toxicity. Patients presenting postoperatively with gross residual tumor or recurrence after surgery should be considered for trials of more aggressive treatment with combined chemotherapy or altered fractionation schemes of irradiation. PMID- 7850553 TI - Long-term effects of radiotherapy administered in childhood for the treatment of malignant diseases. AB - BACKGROUND: The use of radiotherapy for the treatment of childhood malignancy has improved long-term survival significantly, and many treated children now survive well into adulthood. As a consequence, long-term effects of childhood irradiation are being seen with increasing frequency. METHODS: The medical records of 236 patients who had been treated for malignant disease with radiotherapy during childhood were examined to determine the long-term effect of the radiation on their growth and development. RESULTS: Mean treatment dose was 35.5 Gy; mean age at treatment was 7.2 years; and mean follow-up was 14.5 years. Adjuvant chemotherapy was given to 82%. Some degree of bone deformity (usually with overlying soft-tissue hypoplasia) was seen in 40%; 21% developed some type of endocrine deficiency; 30% developed atrophic skin changes; and 7% developed second malignancies. The incidence of bone deformity and hormonal deficiency increased with the radiation dose; the incidence of second malignancy was independent of dose. Bone deformities were more common when radiation was administered before the age of 2 years. CONCLUSIONS: The consequences of radiotherapy in childhood are significant and must be considered when planning treatment. Even when treatment is essential, families should be informed of the possibility of growth disturbance to prevent subsequent misunderstanding. PMID- 7850555 TI - Age as a prognostic factor in the malignant melanoma population. AB - BACKGROUND: The incidence of malignant melanoma is increasing faster than any other cancer, and the state of Florida has one of the highest incidence of melanoma in the United States. This increased incidence is thought to be due to the intense sunlight exposure and ultraviolet radiation exposure in the elderly population. With the increased emphasis on issues of aging, it is appropriate to study the role of age as a prognostic factor for malignant melanoma in the Florida population. METHODS: A retrospective, computer-aided search identified 442 consecutively registered patients with malignant melanoma at the Cutaneous Oncology Program. All patients had stage 1 or 2 disease (cutaneous disease only) at diagnosis. Prognostic variables analyzed included the most powerful factors for stage 1 and 2 melanoma, tumor thickness, ulceration, and Clark level of invasion. Other prognostic variables included in the analysis were the clinical variables of sex and primary site (axial vs. extremity). The population was divided into patients < or = 65 and > 65 years of age. RESULTS: Significant disease-free survival differences were encountered in the older population, with only 55% of the elderly population being disease free at 5 years compared with 65% for the younger population (p = 0.0073). However, a greater percentage of patients with melanoma who were > 65 years of age had ulcerated lesions (17.5% vs. 12.9%) and a greater percentage of thick lesions at diagnosis (67.2% vs. 62.7%). Both of these prognostic factors would bias the older population with a poorer survival. A stepwise regression analysis of the entire population was performed, treating age as a continuous variable. Surprisingly, increasing age along with tumor thickness were the only significant predictors for disease-free survival. After inclusion of these two prognostic variables, none of the other prognostic factors, including Clark level, ulceration, sex, and primary site, added to the prognostic model. CONCLUSIONS: From this analysis, it is apparent that geriatric patients with melanoma have a worse prognosis than a younger control population, even after the correction for the more commonly cited prognostic factors. This information should be used in mathematical modeling to identify high-risk populations who are candidates for perhaps more aggressive primary or adjuvant therapies. PMID- 7850554 TI - Partial splenectomy in children: an alternative for splenectomy in the pathological staging of Hodgkin's disease. AB - BACKGROUND: The more accurate staging of Hodgkin's disease in children is achieved with a staging laparotomy and splenectomy. A disadvantage of the splenectomy is the high risk for an overwhelming postsplenectomy sepsis (OPSI). Therefore, the partial splenectomy was introduced as an alternative to splenectomy in the staging of Hodgkin's diseases in children. METHODS: During the period 1982-1988, 12 children with Hodgkin's disease underwent a staging laparotomy with partial splenectomy. All patients were preoperatively vaccinated with Pneumococcus vaccine. The first three patients received 44 Gy locoregional radiotherapy, whereas nine patients received 25 Gy locoregional radiotherapy and two courses of MOPP/ABVD (mitoxin, oncovin [vincristine], procarbazine, prednisone/adriamycin, bleomycin, vinblastine, decarbazine). RESULTS: The morbidity was negligible. The pathological stage changed in three patients (25%). During a median follow-up of 6 years (range 4-10), no OPSI was diagnosed. One patient developed a secondary leukaemia. CONCLUSIONS: Staging laparotomy for Hodgkin's disease is being performed with less frequency because the majority of patients are treated with chemotherapy and low-dose radiation therapy. After splenectomy and chemotherapy regimens with alkylating agents, there is an increased risk for secondary acute leukemia. With partial splenectomy an adequate staging of the disease can be achieved, allowing a more tailored therapy so that systemic chemotherapy will not be used as frequently, resulting in a lower treatment morbidity without decreasing survival. PMID- 7850556 TI - Clinical applicability of human in vivo localized phosphorus-31 magnetic resonance spectroscopy of bone and soft tissue tumors. AB - BACKGROUND: Magnetic resonance imaging (MRI) is of restricted value for the in vivo characterization of tumor types. The applicability of phosphorus-31 (31P) magnetic resonance spectroscopy (MRS) in the diagnosis of bone and soft tissue tumors is unknown. METHODS: A total of 191 consecutive patients (85 females and 106 males; mean age 41 years, range 1-80) with a well-defined bone or soft tissue tumor on MRI were analyzed for additional 31P spectroscopy. Histology and/or cytology was obtained from all tumors. Because of low sensitivity of the 31P nucleus and the contamination of surrounding tissue, only large, superficially located tumors accessible to the surface coil could be accepted for MRS. RESULTS: Twenty-one patients (11%) could be included in the study. From this remaining group only 12 studies (57%) produced spectra with well resolved phosphorus peaks and an acceptable signal-to-noise ratio. However, these spectra did not allow differentiation between the benign and malignant nature of the lesions. The other 9 studies showed spectra with poor signal intensities and/or poorly defined peaks, making tumor differentiation impossible. CONCLUSION: Only 6% of the bone and soft tissue tumors produced well defined spectra, which implies that localized 31P MRS cannot be considered as a routine technique in the diagnostic and treatment evaluation of bone and soft tissue tumors. PMID- 7850557 TI - Ulcerative colitis and coexisting colorectal cancer: recurrence rate after restorative proctocolectomy. AB - BACKGROUND: The association between mucosal ulcerative colitis (MUC) and adenocarcinoma is well established. METHODS: Records of patients who had undergone restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) from 1983 through 1992 were examined. Of these, 604 had MUC and 27 (4.3%) had MUC with coexisting cancer. Patients were surveyed annually for recurrent disease. Pouch function and quality of life were evaluated with a questionnaire and physical examination. RESULTS: The duration of disease was longer (p = 0.001) in patients with cancer (16.1 +/- 8.0 years) than in those without cancer (9.1 +/- 7.1 years), although the mean age at diagnosis of MUC was the same. Of the 27 patients, 20 had colon cancer and seven had rectal cancer. Multicentricity was found in seven (25.9%) patients. Using the TNM staging classification, 14 patients (51.8%) had stage 1 cancer, eight (29.6%) had stage 2, four (14.8%) had stage 3, and one (3.8%) had stage 4. The patient with stage 4 cancer died 5 months after surgery and was excluded from the follow-up analysis. During a mean follow-up time of 4.3 +/- 2.6 years, cancer recurred in two of the remaining 26 patients (7.7%). In one patient, a local recurrence was found 8 months after surgery, and distant metastases were found in the other patient 35 months after surgery. Both recurrences were in patients with colon cancer. Two of the 26 patients died; one death was related to cancer recurrence (3.8%). Pouch function is good to excellent in all surviving patients. CONCLUSIONS: Restorative proctocolectomy for patients with MUC and coexisting colorectal cancer can be performed with a favorable prognosis and function. It is appropriate for curative intent, given that an adequate margin without tumor is obtained. PMID- 7850558 TI - Breast cancer in a county hospital population: impact of breast screening on stage of presentation. AB - BACKGROUND: Indigent patients in a county hospital setting typically present with breast cancer at a later stage than do patients in the private sector. In the early 1980s, 50% of all breast cancers diagnosed in our county hospital were stages III and IV. This contrasted markedly with the findings of an American College of Surgeons study, which showed < 15% of breast cancers diagnosed as stages III and IV. METHODS: Recognizing this disparity, we instituted a breast screening project in the county teaching hospital targeted at women who routinely received medical care in the county hospital clinics. Between 1985 and 1992, 14,567 mammograms were performed. RESULTS: Two hundred eighty-nine breast biopsies were performed and 76 cancers were identified (26%). Ninety-five patients advised to have surgical consultation for biopsy declined further evaluation. The stage distribution of cancers diagnosed was as follows: stage 0, 20%; stage I, 43%; stage II, 28%; stage III, 8%; and stage IV, 1%. This compares favorably with National Cancer Data Base statistics for 1988. In contrast, symptomatic nonscreened patients diagnosed at the county hospital in 1992 presented at a significantly more advanced stage: stage 0, 1%; stage I, 14%; stage II, 45%; stage III, 26%; and stage IV, 13%. CONCLUSIONS: Mammographic screening has lowered the stage of cancers diagnosed in the screened indigent population. However, a significant percentage of patients are presenting to our hospital with stage III and IV disease. Problems identified in the screening project included noncompliance with recommendations for follow-up of abnormal studies and noncompliance with appointments. In order to broaden the impact of our breast screening project, we have instituted outreach programs with community based clinics and the American Cancer Society. PMID- 7850559 TI - The impact of patterns of nodal metastasis on modifications of neck dissection. AB - BACKGROUND: Radical neck dissection (RND) is standard treatment for cervical metastasis from head and neck cancer. Although effective, RND produces significant morbidity. In an effort to reduce this morbidity, modifications of RND have been developed. These modifications can be comprehensive yet spare some or all of the nonlymphatic structures removed in RND, or they can remove less than all the lymph node groups removed in RND and are termed selective neck dissections. We have reviewed the literature regarding the patterns of nodal metastasis from head and neck cancer to define the indications for these modifications of RND. METHODS: A review of the literature concerning patterns of nodal metastasis from head and neck cancer was performed. Using this information, recommendations on the use of modifications of neck dissection were formulated. RESULTS: In squamous cancers, with clinically negative neck supraomohyoid neck dissection is an adequate node sampling procedure for oral cavity and oropharyngeal lesions, and lateral (jugular) neck dissection for primary lesions of the hypopharynx, and larynx. In the clinically positive neck comprehensive neck dissection with preservation of the spinal accessory nerve is oncologically sound. CONCLUSIONS: Nodal metastasis of head and neck cancer occurs in predictable patterns. Based on these patterns of nodal metastasis, recommendations for the use of modifications of neck dissection are presented. PMID- 7850560 TI - Costs and benefits of picture archiving and communication systems. AB - A picture archiving and communication system (PACS) is an electronic and ideally filmless information system for acquiring, sorting, transporting, storing, and electronically displaying medical images. PACS have developed rapidly and are in operation in a number of hospitals. Before widespread adoption of PACSs can occur, however, their cost-effectiveness must be proven. This article introduces the basic components of a PACS. The current PACS cost-analysis literature is reviewed. Some authors conclude that the PACS would pay for itself, while others find the PACS much more expensive. Explanations for these differences are explored. Almost all of these studies focus on direct costs and ignore indirect costs and benefits. The literature characterizing the indirect costs of PACS is reviewed. The authors conclude that there is a need for uniform, well-defined criteria for the calculation of the costs and savings of PACSs. PMID- 7850562 TI - Changes in physicians' computer anxiety and attitudes related to clinical information system use. AB - STUDY OVERVIEW: Interns' anxiety about computer use ("computer anxiety") and their attitudes toward medical computer applications were determined by a standardized questionnaire. Participants were surveyed before and after three months of differential exposure to three clinical information systems (CISs), including one with provider-entered encounters. POPULATION: Fifty-one interns completed both surveys. Their average age was 27 years. Thirty-three percent were female, 7% were African American, and 8% were foreign graduates. RESULTS: The most common previous exposures to computers were for literature searching and retrieval of patient information (both 92%). Factors that commonly emerged as predictive of anxiety about computer use included self-rated skills, typing ability, and computer attitudes. Factors predictive of attitudes toward computers included self-rated skills, typing ability, maximal frequency of prior computer use, computer ownership, and computer anxiety. Factors that were not predictive of computer anxiety or attitudes toward computers included age, gender, and physician input of data. CONCLUSION: Identification of markers for negative psychological reactions to computer use may allow development of interventions to improve acceptance of computer base patient records (CBPRs). PMID- 7850561 TI - MEDLINE: the options for health professionals. AB - The bibliographic database MEDLINE, produced by the National Library of Medicine (NLM), is a computerized index to the world's biomedical literature. The database can be searched back to 1966 and contains 6.8 million records. The various means of access are divided, for the purposes of this article, into three categories: logging onto a remote host computer by telephone and modem or by the Internet; subscribing to part or all of the database on compact disc (CD-ROM); and leasing the data on a transport medium such as magnetic tape or CDs for loading on a local host computer. Decisions about which method is preferable in a given situation depend on cost, availability of hardware and software, local expertise, and the size of the intended user population. Trends include increased access to the Internet by health professionals, increased network speed, links from MEDLINE records to full-text databases or online journals, and integration of MEDLINE into wider health information systems. PMID- 7850563 TI - Information needs of health care professionals in an AIDS outpatient clinic as determined by chart review. AB - OBJECTIVE: To examine the information needs of health care professionals in HIV related clinical encounters, and to determine the suitability of existing information sources to address those needs. SETTING: HIV outpatient clinic. PARTICIPANTS: Seven health care professionals with diverse training and patient care involvement. METHODS: Based on patient charts describing 120 patient encounters, participants generated 266 clinical questions. Printed and on-line information sources were used to answer questions in two phases: using commonly available sources and using all available medical library sources. MEASUREMENTS: The questions were divided into 16 categories by subject. The number of questions answered, their categories, the information source(s) providing answers, and the time required to answer questions were recorded for each phase. RESULTS: Each participant generated an average of 3.8 clinical questions per chart. Five categories accounted for almost 75% of all questions; the treatment protocols/regimens category was most frequent (24%). A total of 245 questions (92%) were answered, requiring an average of 15 minutes per question. Most (87%) of the questions were answered via electronic sources, even though paper sources were consulted first. CONCLUSIONS: The participating professionals showed considerable information needs. A combination of on-line and paper sources was necessary to provide the answers. The study suggests that present-day information sources are not entirely satisfactory for answering clinical questions generated by examining charts of HIV-infected patients. PMID- 7850564 TI - Potential identifiability and preventability of adverse events using information systems. AB - STUDY OBJECTIVE: To evaluate the potential ability of computerized information systems (ISs) to identify and prevent adverse events in medical patients. DESIGN: Clinical descriptions of all 133 adverse events identified through chart review for a cohort of 3,138 medical patients were evaluated by two reviewers. MEASUREMENTS: For each adverse event, three hierarchical levels of IS sophistication were considered: Level 1--demographics, results for all diagnostic tests, and current medications would be available on-line; Level 2--all orders would be entered on-line by physicians; and Level 3--additional clinical data, such as automated problem lists, would be available on-line. Potential for event identification and potential for event prevention were scored by each reviewer according to two distinct sets of event monitors. RESULTS: Of all the adverse events, 53% were judged identifiable using Level 1 information, 58% were judged identifiable using Level 2 information, and 89% were judged identifiable using Level 3 information. The highest-yield event monitors for identifying adverse events were "panic" laboratory results, unexpected transfer to an intensive care unit, and hospital-incurred trauma. With information from Levels 1, 2, and 3, 5%, 13%, and 23% of the adverse events, respectively, were judged preventable. For preventing these adverse events, guided-dose algorithms, drug-laboratory checks, and drug-patient characteristic checks held the most potential. PMID- 7850565 TI - Grand challenges in medical informatics? PMID- 7850566 TI - Standardized coding of the medical problem list. PMID- 7850567 TI - Toward standard classification schemes for nursing language: recommendations of the American Nurses Association Steering Committee on Databases to Support Clinical Nursing Practice. AB - The American Nurses Association (ANA) Cabinet on Nursing Practice mandated the formation of the Steering Committee on Databases to Support Clinical Nursing Practice. The Committee has established the process and the criteria by which to review and recommend nursing classification schemes based on the ANA Nursing Process Standards and elements contained in the Nursing Minimum Data Set (NMDS) for inclusion of nursing data elements in national databases. Four classification schemes have been recognized by the Committee for use in national databases. These classification schemes have been forwarded to the National Library of Medicine (NLM) for inclusion in the Unified Medical Language System (UMLS) and to the International Council of Nurses for the development of a proposed International Classification of Nursing Practice. PMID- 7850568 TI - Evaluation of user acceptance of a clinical expert system. AB - OBJECTIVE: To measure the attitudes of physicians and nurses who use the Health Evaluation through Logical Processing (HELP) clinical information system. DESIGN: Questionnaire survey of 360 attending physicians and 960 staff nurses practicing at the LDS Hospital. The physicians' responses were signed, permitting follow-up for nonresponse and use of demographic data from staff files. The nurses' responses were anonymous and their demographic data were obtained from the questionnaires. MEASUREMENTS: Fixed-choice questions with a Likert-type scale, supplemented by free-text comments. Question categories included: computer experience; general attitudes about impact of the system on practice; ranking of available functions; and desired future capabilities. RESULTS: The response rate was 68% for the physicians and 39% for the nurses. Age, specialty, and general computer experience did not correlate with attitudes. Access to patient data and clinical alerts were rated highly. Respondents did not feel that expert computer systems would lead to external monitoring, or that these systems might compromise patient privacy. The physicians and nurses did not feel that computerized decision support decreased their decision-making power. CONCLUSION: The responses to the questionnaire and "free-text comments" provided encouragement for future development and deployment of medical expert systems at LDS Hospital and sister hospitals. Although there has been some fear on the part of medical expert system developers that physicians would not adapt to or appreciate recommendations given by these systems, the results presented here are promising and may be of help to other system developers and evaluators. PMID- 7850569 TI - Machine learning for an expert system to predict preterm birth risk. AB - OBJECTIVE: Develop a prototype expert system for preterm birth risk assessment of pregnant women. Normal gestation involves a term of 40 weeks, but because 8-12% of the newborns in the United States are delivered prior to 37 weeks' gestation, problems associated with prematurity continue to plague individuals, families, and the health care system. DESIGN: A knowledge-base development methodology used machine learning, statistical analysis, and validation techniques to analyze three large datasets (18,890 subjects and 214 variables). The dependent (i.e., decision) variable studied was weeks of gestation at delivery, with dichotomous coding of preterm delivery (prior to 37 weeks) and full-term delivery (37+ weeks). RESULTS: Machine learning with a program named Learning from Examples using Rough Sets (LERS) induced 520 usable rules that were entered into a prototype expert system. The prototype expert system was 53-88% accurate in predicting preterm delivery for 9,419 patients. CONCLUSION: The prototype expert system was more accurate than traditional manual techniques in predicting preterm birth. PMID- 7850570 TI - Developing optimal search strategies for detecting clinically sound studies in MEDLINE. AB - OBJECTIVE: To develop optimal MEDLINE search strategies for retrieving sound clinical studies of the etiology, prognosis, diagnosis, prevention, or treatment of disorders in adult general medicine. DESIGN: Analytic survey of operating characteristics of search strategies developed by computerized combinations of terms selected to detect studies meeting basic methodologic criteria for direct clinical use in adult general medicine. MEASURES: The sensitivities, specificities, precision, and accuracy of 134,264 unique combinations of search terms were determined by comparison with a manual review of all articles (the "gold standard") in ten internal medicine and general medicine journals for 1986 and 1991. RESULTS: Less than half of the studies of the topics of interest met basic criteria for scientific merit for testing clinical applications. Combinations of search terms reached peak sensitivities of 82% for sound studies of etiology, 92% for prognosis, 92% for diagnosis, and 99% for therapy in 1991. Compared with the best single terms, multiple terms increased sensitivity for sound studies by over 30% (absolute increase), but with some loss of specificity when sensitivity was maximized. For 1986, combinations reached peak sensitivities of 72% for etiology, 95% for prognosis, 86% for diagnosis, and 98% for therapy. When search terms were combined to maximize specificity, over 93% specificity was achieved for all purpose categories in both years. Compared with individual terms, combined terms achieved near-perfect specificity that was maintained with modest increases in sensitivity in all purpose categories except therapy. Increases in accuracy were achieved by combining terms for all purpose categories, with peak accuracies reaching over 90% for therapy in 1986 and 1991. CONCLUSIONS: The retrieval of studies of important clinical topics cited in MEDLINE can be substantially enhanced by selected combinations of indexing terms and textwords. PMID- 7850571 TI - Predicting length of stay for psychiatric diagnosis-related groups using neural networks. AB - OBJECTIVE: To test the effect of diagnosis on training an artificial neural network (ANN) to predict length of stay (LOS) for psychiatric patients involuntarily admitted to a state hospital. DESIGN: A series of ANNs were trained representing schizophrenia, affective disorders, and diagnosis-related group (DRG) 430. In addition to diagnosis, variables used in training included demographics, severity of illness, and others identified to be significant in predicting LOS. RESULTS: Depending on diagnosis, ANN-predictions compared with actual LOS indicated accuracy rates ranging from 35% to 70%. The validity of ANN predictions was determined by comparing LOS estimates with the treatment team's predictions at 72 hours following admission, with the ANN predicting as well as or better than did the treatment team in all cases. CONCLUSIONS: One problem in traditional approaches to predicting LOS is the inability of a derived predictive model to maintain accuracy in other independently derived samples. The ANN reported here was capable of maintaining the same predictive efficiency in an independently derived cross-validation sample. The results of ANNs in a cross validation sample are discussed and the application of this tool in augmenting clinical decision is presented. PMID- 7850572 TI - Medical librarianship and medical informatics: a call for the disciplines to join hands to train tomorrow's leaders. PMID- 7850573 TI - Toward data standards for clinical nursing information. Iowa Intervention Project Group. PMID- 7850575 TI - Hepatocellular dysfunction occurs earlier than the onset of hyperdynamic circulation during sepsis. AB - Studies indicate that hepatocellular dysfunction occurs at 2 h after cecal ligation and puncture (CLP, i.e., sepsis model) despite the increased cardiac output (CO) and hepatic perfusion. It, however, remains unknown whether hepatocellular function is depressed earlier than the onset of hyperdynamic circulation in sepsis. To determine this, rats were subjected to sepsis by CLP. At .5, 1, 1.5, or 2 h after CLP, CO was measured by dye dilution. Hepatocellular function (i.e., maximum velocity of indocyanine green clearance and the efficiency of the active transport) was determined using an in vivo indocyanine green clearance technique. Microvascular blood flow was measured by laser Doppler flowmetry. To determine whether there is any association between hemodynamics and prostaglandins (PGs), plasma levels of PGE2 and PGI2 were measured by radioimmunoassay. The results indicate that hepatocellular function decreased significantly as early as 1.5 h after CLP. Cardiac output and microvascular blood flow in the liver and small intestine, however, increased and vascular resistance decreased at 2 h after CLP. Thus, hepatocellular dysfunction occurs earlier than the occurrence of hyperdynamic circulation during sepsis. Although circulating PGE2 levels were not altered, plasma PGI2 increased significantly at 2 h after CLP. The elevated circulating PGI2 levels, therefore, may be partially responsible for the decreased vascular resistance and increased tissue perfusion at 2 h after CLP. Our findings also suggest that cellular dysfunction, observed in the very early stage of sepsis, is not due to any hyperdynamic circulation/hypermetabolism-related events, but may be associated with the release of proinflammatory cytokines. PMID- 7850574 TI - Tumor necrosis factor in sepsis: mediator of multiple organ failure or essential part of host defense? AB - Tumor necrosis factor-alpha (TNF) exerts numerous influences which, in association with severe infection, subserve both detrimental as well as beneficial host responses. The current review addresses recent insights into the structure and function of this pleiotropic cytokine, with a particular emphasis upon cellular and organ system consequences of sepsis-induced TNF activity. A comparison of responses elicited by endotoxin or TNF administration are discussed as are mechanisms of endogenous TNF regulation, such as soluble receptors, anti inflammatory cytokines, and counter-regulatory responses. A review of past and future clinical strategies for altering TNF activity during sepsis is also provided. PMID- 7850576 TI - Effect of anti-tumor necrosis factor alpha on leukocyte adhesion in the liver after hemorrhagic shock: an intravital microscopic study in the rat. AB - Tumor necrosis factor (TNF) plays a well known role during the development of multiple organ failure, in part due to its role for the expression of adhesion molecules on endothelial cells, thereby contributing to inflammatory reactions. The purpose of this study was to investigate the effects of TNF on leukocyte endothelial interactions in the liver as a key organ during the systemic inflammatory response syndrome. In Sprague-Dawley rats (n = 6/group) hemorrhagic shock was induced by reduction of the mean arterial blood pressure (MAP) to 40 mmHg for 45 min; resuscitation was initiated by retransfusion of shed blood (60%) and Ringer's lactate. At 1 and 5 h after resuscitation, intravital microscopy of the liver was performed after injection of acridine orange as marker of leukocytes in sham-control animals and in shock animals pretreated with anti-TNF monoclonal antibody (2 mg/kg b.w. TN3; Celltech, Slough, UK) or NaCl .9% 2 h prior to shock induction, respectively. At constant systemic hemodynamic conditions in all groups (e.g., normal MAP), sinusoidal diameters and sinusoidal blood flow were comparably decreased to approximately 75% of control values in all shock groups. Significant differences were observed particularly in respect to permanent adherent leukocytes with 31.8 +/- 4.7% in the shock/NaCl group and 20.7 +/- 2.6% (mean +/- S.E., p < .05) in the shock/TN3 group 5 h after resuscitation following hemorrhagic shock. Consistently higher adhesion rates were observed in the portal regions compared to pericentral regions of the liver lobules.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7850577 TI - Calcitonin gene-related peptide release in endotoxicosis may be mediated by prostaglandins. AB - Three cyclo-oxygenase inhibitors (ibuprofen, indomethacin, and high dose aspirin) and two inhibitors of thromboxane biosynthesis (imidazole and low dose aspirin) were used to evaluate the role of prostaglandins and thromboxane in the release of calcitonin gene-related peptide (CGRP) during endotoxicosis. Endotoxin (lipopolysaccharide B from Salmonella Enteritidis, 5 mg/kg, intravenously) was administered to rats lightly anesthetized with ether during injection. After 3 h, endotoxin significantly elevated plasma CGRP levels by 3-fold. Ibuprofen (50 mg/kg, subcutaneously), indomethacin (10 mg/kg, subcutaneously) and high dose aspirin (100 mg/kg, intraperitoneally (i.p.)), but not imidazole (30 mg/kg, i.p.) or low dose aspirin (15 mg/kg, i.p.), significantly blocked endotoxin-induced CGRP elevations, suggesting that a prostaglandin, but not thromboxane, served as a mediator of CGRP release during endotoxicosis. Because endotoxin-induced production of prostaglandins is greatly diminished in endotoxin-tolerant rats (following multiple exposures to low dose endotoxin), we tested whether endotoxin induced CGRP release also becomes diminished in tolerant rats. Accumulation of plasma CGRP was greatly diminished in endotoxin-tolerant rats exposed to endotoxin (5 mg/kg, intravenously), consistent with a mediator role for prostaglandins in the CGRP release during endotoxicosis. PMID- 7850578 TI - Leukocyte margination during hemorrhagic shock correlates to preshock margination and is reduced by fucoidin. AB - Systemic and pulmonary circulation kinetics for 51Cr-erythrocytes and 111In leukocytes were measured in rats during experimental hemorrhagic shock and normotension with or without pretreatment with the antirolling agent fucoidin. Leukocyte margination was expressed as transit factors (white blood cell transit time/red blood cell transit time) for polymorphonuclear and mononuclear cells. There was an increased pooling of leukocytes in the pulmonary and systemic vascular beds during shock with a maximum after 60 min when the transit factors had increased 2.90-3.72 times in the pulmonary vascular bed and 2.00-3.52 times in the systemic vascular bed for mononuclear and polymorphonuclear cells, respectively. High preshock pooling levels lead to a more pronounced increase in pooling during shock. Pretreatment with fucoidin significantly reduced the pooling increase in the systemic vascular bed. Granulocyte oxidative activity (nitro blue tetrazolium test) invariably increased during shock and was not affected by fucoidin. PMID- 7850579 TI - Endotoxin induces organ-specific endothelial cell injury. AB - Endothelial cell (EC) injury is observed in clinically important pathological processes, including bacterial endotoxemia. We hypothesized that such pathological processes may exhibit target organ heterogeneity due to organ specific heterogeneity of endothelial cells. To test this hypothesis, endothelial cells of aorta (AO), pulmonary artery (PA), left ventricle (LV), and right ventricle (RV) were cultured from individual sheep and exposed to bacterial endotoxin. Marked heterogeneity in endotoxin-induced cytotoxicity was observed. AOEC were the most sensitive, followed by PAEC, LVEC, and RVEC. This cytotoxicity was manifested as programmed cell death (apoptosis). All cells were able to express both interleukin-6 and endothelin-1 (ET-1) transcripts. Following exposure to bacterial endotoxin, interleukin-6 transcripts accumulated in all cells, whereas ET-1 expression was constant or slightly decreased. These data suggest that organ-specific heterogeneity of EC responsiveness to endotoxin is a potential determinant of organ-specific resistance to endotoxin and other mediators of injury. PMID- 7850580 TI - MEGX (monoethylglycinexylidide): a novel in vivo test to measure early hepatic dysfunction after hypovolemic shock. AB - A quantitative liver test based on the formation of the lidocaine metabolite monoethylglycinexylidide (MEGX), was used to evaluate the effect of hemorrhagic shock at 40 mmHg for 90 min on Sprague-Dawley rats. After 2 h of stabilization, lidocaine was injected (2 mg/kg). A second group received volume resuscitation with Ringer's lactate over 1 h (15 mL/kg) after shock, and after 1 h of stabilization lidocaine was administered. These groups were compared to control animals. Blood samples were drawn at 0 time (baseline), prior to lidocaine injection, and at 10, 15, 30, and 60 min after lidocaine injection. MEGX values in shocked animals were significantly lower than in the control group; in animals receiving volume resuscitation, levels were higher than the shocked animals without resuscitation, but did not reach control levels. Thus, shock produced a significant depression of hepatocyte function, which was partially reversed by Ringer's lactate resuscitation. The MEGX test appears to be a suitable tool for clinical evaluation and therapeutic intervention after shock. PMID- 7850582 TI - Going monthly. PMID- 7850583 TI - Chromosomal defects and outcome in 1015 fetuses with increased nuchal translucency. AB - In 1015 fetuses undergoing first-trimester karyotyping because of increased nuchal translucency thickness, the incidence of chromosomal abnormalities increased with both maternal age and nuchal translucency thickness. The observed numbers of trisomies 21, 18 and 13 in fetuses with nuchal translucency thicknesses of 3 mm, 4 mm, 5 mm and > or = 6 mm were approximately 3 times, 18 times, 28 times and 36 times higher than the respective numbers expected on the basis of maternal age. The incidences of Turner syndrome and triploidy were 9 fold and 8-fold higher but the incidence of other sex chromosome aneuploidies was similar to that of an unselected population of women undergoing first-trimester fetal karyotyping for maternal age. In the chromosomally normal group, the incidence of structural defects, mainly cardiac, diaphragmatic, renal and abdominal wall, was approximately 4%, which is higher than would be expected in an unselected population. The rates of fetal loss in the groups with nuchal translucency thickness of 3 mm and 4 mm were 2% and 4%, respectively, which is similar to the 2.3% rate of fetal loss observed in a group of fetuses with normal nuchal translucency thickness undergoing chorion villus sampling. For fetal nuchal translucency thickness of > or = 5 mm, the rate of fetal loss was 13%. PMID- 7850581 TI - Activation of Kupffer cells and neutrophils for reactive oxygen formation is responsible for endotoxin-enhanced liver injury after hepatic ischemia. AB - The potential role of reactive oxygen species generated by Kupffer cells and neutrophils was investigated in a model of endotoxin-enhanced liver injury after hepatic ischemia. Male Fischer rats were subjected to 20 min ischemia and reperfusion of up to 24 h; .5 mg/kg Salmonella enteritidis endotoxin was injected at 30 min of reperfusion. The animals developed severe liver injury resulting in 50% hepatocellular necrosis at 24 h. Isolated Kupffer cells and neutrophils from the postischemic liver generated 10-fold more superoxide than cells from control livers. Treatment with gadolinium chloride (GdCl3) selectively reduced the capacity of Kupffer cells to generate superoxide by 65% and attenuated liver injury by 73% at 4 h and 58-69% at 24 h. Monoclonal antibodies against neutrophil adhesion molecules (CD11/CD18) had no effect on the early injury but reduced hepatocellular necrosis by 90-95% at 24 h. The antioxidant Trolox and the iron chelator deferoxamine attenuated liver injury by 71 and 80%, respectively. It is concluded that Kupffer cells are mainly responsible for the initial injury, and neutrophils are the dominant cytotoxic cell type during the later phase. Reactive oxygen generated by both cell types is critical for this pathogenesis. PMID- 7850584 TI - The implementation of first-trimester scanning at 10-13 weeks' gestation and the measurement of fetal nuchal translucency thickness in two maternity units. AB - The aim of this prospective screening study was to evaluate the implementation of an additional ultrasound examination, incorporating the measurement of fetal nuchal translucency thickness, at 10-13 weeks' gestation in two maternity units providing routine antenatal care. During the 1 year prior to the introduction of the first-trimester scan, the major indication for fetal karyotyping was maternal age > or = 35 years and only two out of the total of 11 cases of trisomy 21 were identified. In the first 5 months of the study, 70% of the women delivering in these hospitals attended for measurement of fetal nuchal translucency thickness and the measurement was obtained in all cases. This was achieved without an increase in the number of sonographers or ultrasound machines. The incidence of fetal nuchal translucency thickness > or = 2.5 mm was 3.6% (63 of 1763), and this group included three of the four fetuses with trisomy 21. The findings of this study demonstrate the feasibility of introducing scanning at 10-13 weeks' gestation and the measurement of fetal nuchal translucency thickness in routine maternity units. The sensitivity and specificity of this method of screening are at present being evaluated in a large multicenter study. PMID- 7850585 TI - First-trimester nuchal edema as a marker of aneuploidy. AB - Targeted ultrasonographic screening for nuchal fluid accumulation during the first trimester (9-13 weeks) seems to be a recommendable method for the detection of Down's syndrome and other chromosomal anomalies in pregnant women. It compares favorably with current methods of maternal serum screening performed during the second trimester. Using a 4-mm cut-off value, the detection rate of aneuploidy among our population was found to be 57.1%, with a false-positive rate of 0.7% and a positive predictive value of 72.7%. Chromosomal analysis should be considered for fetuses with nuchal translucency equal to or greater than 4 mm in the first trimester. PMID- 7850586 TI - Does gender have an impact on the sonographic detection of second-trimester fetuses with Down's syndrome? AB - The biometric and structural sonographic features of 95 second-trimester fetuses with Down's syndrome were evaluated to determine whether affected male fetuses differed from affected females. There were 54 male and 41 female fetuses with Down's syndrome studied. A shortened femur was identified in 28/54 (52%) males compared with 19/41 (46%) affected females (NS). A thickened nuchal fold was identified in 19/54 (35%) of males vs. 20/41 (49%) of females. Renal pyelectasis was seen in 7/54 (13%) males and 8/41 (19%) females. A heart defect was seen in 8/54 (15%) males and 7/41 (17%) females. Ventriculomegaly was identified in 6/54 (11%) males and 3/41 (7%) females with Down's syndrome. There were no statistically significant differences in the incidence of the sonographic findings when male and female Down's fetuses were compared. Our data show that the criteria for evaluation of sonographic markers for the identification of second-trimester fetuses with Down's syndrome should be the same in male and female fetuses. PMID- 7850587 TI - Fifth digit measurement in normal pregnancies: a potential sonographic sign of Down's syndrome. AB - The objective of the study was to obtain measurements of the fetal fifth finger, as a basis for further studies and for future comparison with fetuses with Down's syndrome. The study group included 173 karyotypically normal fetuses at 15-23 weeks' gestation. Routine biometric measurements were obtained on all, including biparietal diameter (BPD), femoral length (FL) and humeral length (HL), and the length of the fetal fifth finger. Linear growth of the fifth finger was observed across the range of gestational ages (GA), and a linear correlation was shown to exist between the length of the fifth finger and gestational age (y = -7.804 + 0.9079 x GA; r = 0.923; p < 0.0001), biparietal diameter (y = -3.7010 + 0.3043 x BPD; r = 0.913; p < 0.0001), femoral length (y = -0.0983 + 0.3406 x FL; r = 0.926; p < 0.0001), and humeral length (y = -1.3453 + 0.3982 x HL; r = 0.929; p < 0.0001). These results provide normative data of the length of the fetal fifth finger across a range of gestational ages. These data may provide an additional screening parameter for the prenatal detection of Down's syndrome. PMID- 7850588 TI - Continuous wave Doppler velocimetry of the main-stem uterine arteries: the transvaginal approach. AB - The purpose of the study was (1) to establish the efficacy of the transvaginal approach for continuous wave Doppler velocimetry of the main-stem uterine arteries in normal pregnancy and (2) to provide reference values for the flow velocity waveform indices of the main-stem uterine arteries in normal pregnancy. In a cross-sectional study from 16 to 40 weeks of pregnancy, 201 healthy normal women were examined by transvaginal continuous wave Doppler, and flow velocity waveforms were obtained from the main branch of the uterine artery on both sides. Nomograms were compiled for the systolic: diastolic ratio, pulsatility index and resistance index. Values for all variables declined during the course of pregnancy until 22 weeks' gestation, and then remained stable to term. Intra- and interobserver variations were 5% and 8%, respectively, and the examination time was < 5 min. Flow velocity waveform indices declined during pregnancy, indicating a decrease of resistance in the uteroplacental circulation. Our results are comparable to those obtained transvaginally by pulsed wave Doppler, previously reported in the literature. The transvaginal approach for continuous wave Doppler velocimetry of the main-stem uterine arteries is a simple, quick, accurate, safe, cheap and highly reproducible method, and is therefore suitable for evaluating the uteroplacental circulation. PMID- 7850589 TI - Ultrasonic demonstration of local myometrial thickening in early intrauterine pregnancy. AB - In a group of women in the first and early second trimesters of pregnancy, local thickening of a limited region of the myometrium was observed ultrasonically. This prospective study aimed to evaluate the incidence and nature of this phenomenon. Local myometrial thickening was observed in 72 women out of 5521 examined (1.3%). Twenty-two were given ritodrine hydrochloride 10 mg by mouth, and 46 were monitored for up to 60 min without treatment. The local myometrial thickening in the ritodrine hydrochloride-treated group disappeared in 21 out of 22 women (95.5%) compared with the observed group, where the phenomenon disappeared in only 37 women (80.4%). Local myometrial thickenings probably represent transient uterine contractions; they tend to appear early in pregnancy, are prolonged, and may respond to ritodrine hydrochloride. PMID- 7850590 TI - Differentiation between adenomyoma and leiomyoma with transvaginal ultrasonography. AB - The clinical utility of transvaginal ultrasonography in the differentiation of adenomyoma from leiomyoma was evaluated in 147 patients who had been scheduled for surgery due to symptomatic uterine masses. In all subjects, ultrasonographic images obtained preoperatively were correlated postoperatively with surgicopathological findings. Pathological findings showed that 110 patients proved to have fibroids, while 30 had adenomyomata. For the diagnosis of adenomyoma, transvaginal ultrasonography attained a sensitivity of 80%, a specificity of 94.3%, a positive predictive value of 85.7% and a negative predictive value of 90.9%, compared with a sensitivity of 94.3%, a specificity of 80%, a positive predictive value of 90.9% and a negative predictive value of 85.7% for leiomyoma diagnosis. Further to assess which characteristic used in ultrasonography was useful in the differential diagnosis, five characteristics were analyzed and compared by chi 2 test. These were position, number, margin and echogenicity of the uterine masses and the presence or absence of hypoechoic spaces (lacunae). Margin, echogenicity, mass number and lacunae were significantly different between both conditions. A stepwise logistic regression procedure revealed that margin, lacunae and echogenicity were good parameters for differentiating adenomyoma from leiomyoma. If we selected the features of distinct margin and absence of hypoechoic lacunae within the masses for analysis, leiomyoma could be correctly predicted in 97% of patients. PMID- 7850591 TI - The role of color Doppler in diagnosis of endometriomas. AB - The aim of this study was to characterize the appearance of the vascular pattern of endometriomas in terms of color Doppler and to verify the role of Doppler flow indices in differentiating endometriomas from other pelvic masses. Twenty patients with suspected endometriosis were referred for evaluation and surgical management of adnexal masses and/or infertility problems. Before surgery, transvaginal sonography was performed using an Ultramark 9 (ATL) Ultrasound system. The color Doppler was used for evaluation of the vascular color distribution. Flow parameters (resistance index (RI) and pulsatility index (PI) were obtained using pulsed Doppler. A total of 24 masses were identified in the 20 patients studied. Sixteen masses proved to be endometriomas, with a mean size of 3.5 +/- 0.4 cm. Of confirmed endometriomas, 81% had a regular internal surface and 63% showed the characteristic homogeneous low-level echoes filling the cyst. Eleven of 16 (69%) endometriomas showed flow by color Doppler. The flow was characteristically limited, with few spots of vascular color seen in each mass. Cases that showed dense vascularity with color Doppler proved not to be endometriomas. The mean +/- SE of the RI and PI for the endometriomas were 0.59 +/- 0.02 and 0.95 +/- 0.1, respectively. All endometriomas showed an RI of > 0.5 with a range of 0.5-0.74, while the PI was 0.59-1.59. No significant differences between flow indices for endometriomas and other benign cystic lesions were noted. Scattered vascularity, one feature of adnexal endometriomas, may help to differentiate them from other lesions of dense vascular distribution, such as corpora lutea or ovarian neoplasms. PMID- 7850592 TI - Trisomy 18: first-trimester nuchal translucency with pathological correlation. AB - Diagnosis of trisomy 18 was made following prenatal screening at 11 weeks' gestation for ultrasonographically detected nuchal translucency and subsequent chorionic villus sampling. An intact fetus was therapeutically aborted and pathological examination was undertaken. We conclude that, although the etiology of nuchal translucency remains unclear, it does not appear to be lymphatic or cardiac in origin. PMID- 7850593 TI - Fetal yawning. AB - Incidental fetal yawning movements can rarely be observed during real-time ultrasonographic examination. In this report we document repetitive fetal yawning movements in a 27-week fetus over a 7-min period. Each episode lasted for 4-6 s, and the intervals between them varied from 21 to 195 s. This case demonstrated that fetal yawning, a complex involuntary behavioral reflex, is present in its full extent during the second half of pregnancy. PMID- 7850594 TI - Fetal nuchal translucency: a need to understand the physiological basis. PMID- 7850596 TI - Prenatal diagnosis of a congenital astrocytoma: a case report and literature review. AB - Congenital intracranial tumors are very rare. We report an endovaginal ultrasonographic diagnosis of an anaplastic astrocytoma at 31 weeks' gestation. Other means, such as antenatal magnetic resonance imaging and fetal blood sampling were not shown to have any diagnostic advantage. A detailed literature review of the topic is provided. PMID- 7850597 TI - The uterine biophysical profile. PMID- 7850595 TI - First-trimester diagnosis of hydrolethalus syndrome. AB - At 12 weeks of gestation, a combination of atypical hydrocephalus with absent mid line structures and club foot was detected during transvaginal ultrasound examination. These findings were diagnostic of hydrolethalus syndrome and were confirmed after subsequent termination of the pregnancy. This is the first known case of first-trimester prenatal diagnosis of hydrolethalus syndrome. PMID- 7850598 TI - First-trimester Down's syndrome screening using nuchal translucency: a prospective study in patients undergoing chorionic villus sampling. AB - The value of the measurement of nuchal translucency thickness for predicting fetal Down's syndrome and other aneuploidies was prospectively evaluated at 8-15 weeks of gestation in 1819 consecutive pregnancies scheduled for karyotyping by chorionic villus sampling. In 43 cases, a chromosomal unbalanced aberration was found. Two teams of ultrasonologists who examined patients attending either National Health Service (Series 1) or private practice clinics (Series 2) were involved in the study. The same type of ultrasound machine and standardized approach were used in both study groups. In those cases in which the maximum subcutaneous thickness of the translucency was 3 mm or greater, the incidence of chromosomal aberration was 18.6% compared to 1.7% in the cases in which this was below 3 mm. The sensitivity, specificity and relative risk for all aneuploidies were 30%, 96% and 10.83, respectively, and no difference was found between trisomy 21 and other types of aneuploidy. The sensitivity and specificity and relative risk were significantly higher at 9-10 weeks than between 11 and 15 weeks. The results were concordant in the two series; however, the overall values for sensitivity (20% vs. 39%), specificity (94% vs. 98%) and relative risk (4.13 vs. 24.20) were clearly higher in the group of private patients. The results obtained confirm the potential application of the measurement of nuchal translucency thickness for fetal aneuploidy screening before the end of the first trimester and suggest that a multiplicity of individual, structural and organizational factors may interact and play a crucial role in determining the actual efficiency of ultrasound screening programs. PMID- 7850599 TI - School behavior of children in kinship care. AB - This paper is based on the first comprehensive study of the health and educational status of children in kinship care, an increasingly frequent arrangement where children are placed in the care of relatives, mostly following neglect or abuse. Questionnaires were completed by teachers of 75% of the 374 school-age children in kinship care in one city, and additional information was obtained from caseworkers, caregivers, and school records. Compared to classroom peers, children in kinship care had poor study habits and attention and concentration skills. Other common problems included overactive, aggressive, and attention-seeking behavior. Most children had average or better relationships with teachers and peers. Multivariate analyses yielded several predictors that explained a modest amount of the variation in the children's school behavior. There was poor to moderate concordance in the assessments of teachers, caregivers, and caseworkers concerning various school related behaviors. Schools, caseworkers, and pediatricians should pay special attention to children in kinship care and ensure that this high-risk group of children receives necessary services. PMID- 7850600 TI - The "no man's" land of home weekends for children in residential care. AB - Home Weekends are the main channel of contact between children in placement and their parents. This practice is of special interest because of both the hopes it raises and the risk it entails. The present research examines public welfare agency practice in this domain. Interviews were held with 45 social workers (from 32 agencies) who were responsible for case-managing 74 families with children in residential care (n = 105). Findings clearly indicate that the practice of home weekends is characterized by the following: an absence of professional access to the children and their parent(s) and neglect in assuring the well-being of children; a lack of differential patterns of children's visits or intensity of social worker-parent contact in relation to parents' dysfunctioning; and a lack of implementation of family-oriented intervention. It was also found that, for 50% of the children, the well-being score while at home does not manifest serious distress. This raises the question of whether the conditions obligate placement in a residential setting. Implications for research and practice are discussed. PMID- 7850601 TI - Emotional and cognitive adjustment in abused children. AB - Research on the impact of maltreatment on children has increased in the last years, as there is a need to design appropriate treatment strategies. Social, cognitive, and emotional areas may be affected in these children. This research is aimed to study the psychological functioning of child victims, particularly in their emotional and cognitive adjustment. Nineteen children (10.3 years old) with case histories of at least 2 years of physical and emotional parental abuse and a group of 26 nonmaltreated children (9.4 years old) matched in socio-economic characteristics and coming from the same community area were compared in depressive symptomatology and attributional style by using the standardized measures from Kovacs' Children's Depression Inventory (CDI) and Kaslow's Children Attributional Style Questionnaire (CASQ). General and detailed statistical analyses on the emotional and cognitive areas assessed showed significant differences between groups. Child victims showed greater feelings of sadness, lower self-esteem and self-worth, and they perceived the aversive events in their lives as unpredictable which generated helplessness. This is a result of their lack of control of those aversive events. Results are contrasted with those obtained by other researchers who used similar methodology and are discussed in terms of the learned helplessness' model proposed and developed by Seligman, Kaslow, Alloy, Peterson, Tanenbaum, and Abramson (1984). Implications for the child abuse victims' emotional and cognitive rehabilitation are also analyzed and discussed. PMID- 7850603 TI - Punishments: what predicts adult approval. AB - We surveyed 449 parents to assess: (a) the prevalence of different types of physical and emotional punishment during their childhoods: (b) the prevalence of current parental approval of these types of punishments, and (c) risk factors for current approval of physical and emotional punishments. Parents in waiting rooms of pediatric clinics were asked to complete an anonymous questionnaire about their childhood punishment experiences and their current approval of various types of punishment. Reported experiences and approval were as follows: 24% experienced and 6% approved of uncommon punishments (e.g., burned), 45% experienced and 17% approved of common punishments (e.g., shaken), and 94% experienced and 88% approved of very common punishments (e.g., spanked). Having experienced each type of punishment was a highly significant risk factor for currently approving of that type of punishment (p < .01 for each). Race, income, and education were not significant risk factors for approval of different types of punishment. Many parents have experienced harsh types of punishment during their childhoods. Efforts at identifying and educating parents who approve of harsh and/or abusive types of punishment should focus on those who have experienced harsh punishment rather than on particular racial or socioeconomic groups. PMID- 7850602 TI - Perceptual responses to infant crying after EEG biofeedback assisted stress management training: implications for physical child abuse. AB - The adult's perception of infant crying determines whether it is a source of stress and may be an antecedent to physical child abuse. The study had clients listen to infant crying and used stress management training to change their perceived arousal, anxiety, and evaluation of the crying. Fifteen nonparental female clients were randomly assigned to three groups who either had pretraining without stress, pretraining while listening to infant crying, or listened to yoked infant crying without pretraining. During the second stage all clients had stress management training while listening to infant crying. The clients' perceived anxiety and arousal elicited by crying were significantly diminished after stress management training and anxiety measures were strongly correlated with both perceived arousal and the clients' evaluation of infant crying. Although this is the first experiment applying biofeedback assisted stress management training to the perceptual responses and physiological arousal associated with infant crying, these results with inexperienced clients have implications for the prevention and treatment of parental stress and should encourage further research treating physical child abuse as a stress-related disorder. PMID- 7850604 TI - Detection of intrafamilial child abuse: children at intake at a children's observation home in India. AB - Cross-cultural studies have brought awareness that child abuse is a global problem. This study sought to assess whether the abuse of children by caregivers/parents is a phenomenon that is prevalent in Indian society, where social workers and other human service professionals traditionally have not been sensitive to its occurrence. Interviews with 515 children brought to a Children's Observation Home in Bombary resulted in self-reports of physical violence from approximately 50% of the sample, and of these, over two-thirds reported the use of abusive violence. In addition, over 60% of the children who had run away from home cited violence by parents as the primary reason for their leaving, suggesting that this may be one of the variables adding to the numbers of street children in India. Feelings about perpetrators and implications of findings are discussed. PMID- 7850605 TI - Treatment of adolescent sexual offenders: theory-based practice. AB - The treatment of adolescent sexual offenders (ASO) has its theoretical underpinnings in social learning theory. Although social learning theory has been frequently cited in literature, a comprehensive application of this theory, as applied to practice, has not been mapped out. The social learning and social cognitive theories of Bandura appear to be particularly relevant to the group treatment of this population. The application of these theories to practice, as demonstrated in a program model, is discussed as a means of demonstrating how theory-driven practice methods can be developed. PMID- 7850606 TI - Child sexual abuse: several brief interventions with young perpetrators. AB - Clinicians are expected to treat very young perpetrators and victims of sexual abuse, often with limits on the number of sessions they may offer, the family members they may see, and the compromising circumstances of day care and housing arrangements affecting the safety and welfare of the children referred for treatment. Using specific case examples, this paper offers several therapeutic principles and their practical application to demonstrate brief and effective interventions that are sufficiently flexible to meet the challenges and needs of victimized and perpetrating children within the constraints imposed by shelters, foster and day care and other protective settings. PMID- 7850607 TI - A survey of health care and child protective services provider knowledge regarding the toe tourniquet syndrome. AB - Recent efforts to increase public awareness of child abuse may result in an increased number of inappropriate reports of suspected child abuse. The authors believe that digital hair strangulation should be included among the conditions that may be confused with child abuse. Digital hair strangulation (toe tourniquet syndrome) occurs primarily in infants and is characterized by a constricting band of foreign material that becomes tightly wrapped around a digit or digits (most often the toes). The consensus in the medical literature is that this condition is not the result of intentional injury. As no reference to the toe tourniquet syndrome exists in the child abuse literature, it was hypothesized that child welfare workers would be more likely than physicians and public health nurses to misinterpret this condition as resulting from intentional injury. A survey was conducted to test this hypothesis. Professionals from the fields of medicine, nursing, and child welfare were provided with a history and photographic findings of a child with a typical case of the toe tourniquet syndrome. Participants were surveyed regarding their interpretation of the described injuries. More than 50% of all respondents indicated that they would report this case as suspected abuse. Child welfare workers responded that the injuries were suggestive of abuse (83%), significantly more often than public health nurses did (45%), (chi 2 = 4.55, p = .03).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7850608 TI - Spare the rod and spoil the child. Is this a sensible justification for the use of punishment in child rearing? AB - This paper examines the validity of the well-used proverb Spare the rod and spoil the child. To do this, the original form of the proverb from the Bible is compared with the modern form, and some significant differences are highlighted. The definition of punishment is considered, and the differences between punishment and corporal punishment are examined. Punishment is explored in some detail with attention given to the criteria that need to be satisfied in order for punishment to be effective. Discrepancies in the literature concerning these criteria are pointed out, making punishment a complex issue. The negative effects of punishment are significant with links to social problems such as teenage delinquency and violence. Reference is made to cultures where corporal punishment has been banned and the effects of this action. Given the problems associated with punishment programs, especially those being used in families, alternatives to punishment are discussed. Finally, an alternative form of the proverb to the current adaptation is offered. PMID- 7850609 TI - Child-rearing violence. AB - In 1989, a national, random sample of 801 adults was questioned about the punishment they received as children and the way they discipline their own offspring. Analysis revealed that verbal and physical discipline are not substitutes, but, instead, are commonly used together. Parents who yell frequently are the ones most likely to hit frequently, and vice versa. In addition, both physical and verbal violence appear to be transgenerational. Respondents who were spanked (yelled at) frequently as children are more prone to frequently spank (yell at) their own children. Still, most people are able to break out of the transgenerational cycle of punitive child rearing. This outcome may be found particularly among those who consider themselves to have been abused. PMID- 7850610 TI - The investigation of child sexual abuse: an interdisciplinary consensus statement. PMID- 7850611 TI - Sibling incest in a clergy family: a case study. AB - A case study is presented of a female adult survivor of childhood sexual abuse where the perpetrator was her older brother. The children belonged to a clergy family where the father was a clergyman in a mainstream Christian church. The family dynamics are described, emphasizing the physically absent father, the emotionally distant mother, and the surrogate parent status of the perpetrator. The victim's adult years are described, revealing recurrent failures both socially and in the workplace, and a general dissatisfaction with life. Her several attempts to seek appropriate help are described. Eventually, one of these proved successful, and the victim's emotional outlook was transformed into that of a survivor. She is now able to view the world from a contented and achieving aspect. Her experiences of disclosing the abuse to her parents and confronting the church hierarchy are described. Concern is expressed at the perceived inappropriateness of some of the professional assistance the victim was offered as she came to terms with her experience of sibling incest. PMID- 7850612 TI - Predicting child abuse potential across family types. AB - The present study was conducted to explore whether stress, family resources, and social support are correlates of the child abuse potential of mothers, and whether prediction functions differ across families with children with disabilities and families with no children with disabilities. The design and analyses were correlational. Statistically and practically significant relationships were found. Stress in family functioning appears to be an important predictor of child abuse potential, and it is suggested that interventions might be designed to target related features of family functioning. PMID- 7850613 TI - Should this child be removed from home? Hypothesis generation and information seeking as predictors of case decisions. AB - Two vital aspects of the investigative process in child abuse and neglect (CAN) cases are (a) generating as many plausible hypotheses as possible and (b) seeking out as much uncontaminated information as possible. Alternatively, unwarranted assumptions about the nature of CAN cases can impair investigative decision making. We examined whether the numbers of (a) unwarranted assumptions, (b) hypotheses generated, and (c) requests for additional information concerning a hypothetical reported case of CAN predicted level of agreement with a premature decision to remove a child from home among a group of CAN professionals. As expected, lower levels of agreement with the intervention were associated with (a) less unwarranted assumptions, (b) a greater number of hypotheses generated, and (c) more requests for information concerning the case. Compared with a group of undergraduates, a significantly greater percentage of CAN professionals requested information, and a significantly smaller percentage of professionals made unwarranted assumptions. Interestingly, however, no significant difference in mean level of agreement with the intervention was observed between professionals and undergraduates. Directions for future research are discussed. PMID- 7850614 TI - A survival analysis of the revictimization of children: the case of Colorado. AB - This paper reports the results of a survival analysis of patterns of revictimization of children with records of confirmed cases of maltreatment in Colorado during the 4-year period 1986-1989. The study examined the cases of 24,507 children in that state's Child Abuse and Neglect Registry for evidence of their revictimization. Hazard rates for repeat offenses were highest immediately after the initial incident of abuse or neglect. Risk of revictimization was greater for younger children and for females, but those relationships were strongly mediated by the form of maltreatment. The rate of revictimization of physically neglected children exceeded that for other major types of maltreatment. Although abused and neglected children were most at risk immediately after their incident of abuse or neglect, they remained at greater risk of mistreatment for years thereafter. PMID- 7850615 TI - Testing the measurement properties of risk assessment instruments in child protective services. AB - This study examined a population of children alleged to be at risk of abuse and the adult allegedly abusing the child for the purpose of identifying variables that were predictive of the child's risk of being abused. The study population consisted of 72 Brooklyn, New York children and the alleged adult abuser. These cases were investigated in the Child Protective Services office in Bedford Stuyvesant by 12 workers who volunteered to participate in the research effort. The worker assigned to a case filled out the standard New York City case recording instrument (called the Child Protective Services Review Document, CPSRD for short), the Magura-Moses Child Well-Being Scales, and the Beck and Jones List of Problems and Conditions. In addition, the worker also evaluated the degree of risk of abuse that the child was exposed to from the alleged abuser using a supplemental scale created for this study. Our hypotheses were that variables from each of the instruments would be predictive of the case decision-making by protective service workers regarding the abuse to which a child was exposed, that the data from the Magura-Moses scales would have predictive value for a minority population, and that the data from the CPSRD would reflect unique dimensions of this population. The data from the 72 cases supported each of these hypotheses. PMID- 7850616 TI - Maternal hyperthyroidism and child physical abuse. PMID- 7850617 TI - Personal history of childhood abuse among clinicians. PMID- 7850618 TI - Physiological responses to child stimuli in mothers with and without a childhood history of physical abuse. AB - The present study investigated changes in heart rate, skin conductance, and self reported affect in response to child stimuli in mothers with and without a childhood history of physical abuse. The stimuli were videotape presentations of a smiling and crying infant. During baseline periods (prior to videotape presentations), mothers without a childhood history of abuse displayed a significant reduction in skin conductance, which was not observed in mothers with a childhood history of abuse, suggesting that mothers without a history of abuse habituated to the experimental setting. Although the two groups of mothers did not differ in self-reported affect or in heart rates in response to the crying and smiling infant, mothers with a childhood history of abuse showed increases in skin conductance while viewing the smiling infant, but not while viewing the crying infant. In contrast, mothers without a childhood history of abuse showed increases in skin conductance during the presentation of the crying infant, but not while viewing the smiling infant. Similarities between the skin conductance results for mothers with and without a childhood history of abuse and skin conductance data reported for physically abusive and at-risk mothers are discussed. PMID- 7850619 TI - A new era of nursing practice and scholarship in Australia. PMID- 7850620 TI - Nursing as textually mediated reality. AB - Nursing and nursing practice both construct and are in turn constructed by the context in which they operate. Texts plays a central part in that construction. As such, nursing and nursing practice can be considered to represent a reality that is textually mediated. This paper explores the notion of nursing as a textually mediated reality and offers the reader the possibility of engaging in reflection on what implications this has for nursing and their own nursing practice. The analyses provided draw on aspects of the work of both Foucault and Derrida. Foucault's notion of discourse provides a vehicle for the exploration of nursing as textually mediated, as does Derrida's concept of binary oppositions. The paper thus illustrates some of the possibilities afforded nursing by poststructural analyses. In particular it does this by exploring one of the central textual constructions, impacting on the way that nursing and nursing practice are conceptualized, the mind/body binary opposition. PMID- 7850621 TI - A hermeneutic study of the concept of 'focusing' in critical care nursing practice. AB - A phenomenological hermeneutic study of the lifeworld of critical care nursing was undertaken, from which emerged the concept of 'focusing'. Focusing is defined as empathizing concern for the critically ill person and his/her family amid the high technology of the intensive care unit. When nurses focus on the patient and the patient's family they are able to empathize with the personal dimensions of caring. The study used a phenomenological hermeneutic approach to describe the nature of the lived experience of clinical nursing practice in a high technology environment. PMID- 7850622 TI - Nursing the postmodern body: a touching case. AB - Using touch as a medium for exploring the ways in which it is constructed by nurses, the body is here characterized by a plethora of competing and co-existing terms: disobedient, obedient, mirroring, stigmatized, sinful, post-mortem, sanitized, angelic, desexualized, dangerous, dominant, dominating, deceitful, submissive, disciplined, postmodern and communicative. We have tried to be provocative by juxtaposing contradictory messages and evoking conflicting emotions, and we hope that the reader will not assume that we believe everything we write, or that everything may be taken only at face value. There are as many messages and meanings in the paper as each reader thinks there are. PMID- 7850623 TI - Florence Nightingale and the women's movement: friend or foe? AB - The historical analysis of the complex and often contradictory views of Florence Nightingale regarding the rights of women is explored in this paper. Feminism and nursing are often viewed as contradictory and antithetical. The relationship between the two is examined through the link between Florence Nightingale and her contemporary, Barbara Leigh-Smith Bodichon. Leigh-Smith was founder and primary financier of The English Women's Journal that provided a public platform for the major feminist writings of the period. Its offices in Langham Place formed the administrative centre of the Society for Promoting the Employment of Women. Bodichon and her colleagues were often referred to as the 'Langham Place Group'. Unexplored prior to this study was the fact that Leigh-Smith and Nightingale were first cousins. Utilizing techniques of internal and external criticism, primary and secondary sources were surveyed relating to Nightingale and Leigh-Smith. The views of both women on the subjects of the rights of women, women's suffrage, the employment status of women, and the societal place of women are compared and contrasted. The legacy of both Leigh-Smith and Nightingale to twentieth century feminism, the status of women, and the profession of nursing is then elaborated. The exploration of the views of both Nightingale and Leigh-Smith is important to gain a clearer understanding of the existing relationship between nursing and feminism. In keeping with the aims of feminist inquiry, women's experiences, specifically those of Nightingale and Leigh-Smith, are the major 'objects' of investigation. The concluding interpretation provides a synthesis that is emancipatory as well as knowledge generative. PMID- 7850624 TI - Confronting 'reality': nursing, science and the micro-politics of representation. AB - In an age where previous frames of reference lose their certainty nurses are finding themselves rethinking their relations to the 'real'. In this paper I interrogate an empirical 'text' of a local nursing cultural practice through a poststructural critique of the ways in which language, discourses, representation and experience intersect to construct 'reality' for us with specific consequences. I do this in an attempt to disclose the micro-politics at work in the processes of signifying and thus representing nursing to a world of potential students. The discourses of science and caring find themselves exposed in particular representational technologies and practices that mark nursing's collusion with the 'truths' of science at the expense of those we loosely name 'caring'. This cultural theoretical work constitutes a provisional and historical fragment of analysis designed to trouble the relations we often unwittingly sustain with dominant 'regimes of truth'. PMID- 7850625 TI - Emergency department assessment of the adult trauma patient. AB - Trauma is recognized as a leading killer in the United States today. The development of trauma care systems and traumatology, as a response to this public health problem, has led to the evolution of the role of the trauma nurse. Assessment of the trauma patient is a challenging and demanding role for trauma nurses and is vitally important because the detection of potentially life threatening injuries and development of standards of care for the resuscitation and management of the trauma patient are based on the initial assessment. The authors address the role of the nurse from preparation for the trauma patient's arrival to continuous monitoring and documentation responsibilities. PMID- 7850626 TI - Who will care for the trauma patient under healthcare reform? PMID- 7850627 TI - Assessment and initial management of the pregnant trauma patient. AB - The pregnant trauma patient with a blunt or penetrating injury presents a unique and challenging clinical situation. Two patients must be treated simultaneously: the mother and fetus. The author reviews the assessment changes of pregnancy, which can both mask and mimic injury. The unique injuries that occur in this patient population are described, including abruptio placentae, preterm labor, fetomaternal hemorrhage, and uterine and fetal trauma. Successful resuscitation of the pregnant trauma patient requires early and frequent collaboration with the obstetrical staff. Within a team approach, the dual assessment of mother and fetus can render prompt identification and treatment of injuries. Diagnostic tests, including laboratory data, radiographic exams, and abdominal and obstetrical procedures, are reviewed. PMID- 7850628 TI - Regulatory bodies and healthcare reform. PMID- 7850629 TI - "Nurses: charting a course for the future". PMID- 7850630 TI - Ethics. PMID- 7850631 TI - A conversation with Kaye Challinger. Interview by Marie Manthey. PMID- 7850632 TI - Substitution of technical workers for professional nurses: a challenge to nursing ethics and client advocacy. PMID- 7850634 TI - Writing up your research. PMID- 7850633 TI - LPNs and the ethics of healthcare reform. PMID- 7850635 TI - Resource costs of capitation maintenance care in Britain. AB - The aims of this study were to examine variations in the resource cost of maintenance care for children under capitation by the area in which the dentist worked, the gender of the dentist, the number of years that the dentist had been qualified and the social class mix of the practice locality. Data were analysed from those collected during a clinical trial of capitation and fee-for-service payment systems that took place between 1986 and 1989. The costs of restorative/surgical treatment were over twice as high in Grampian than in Bromley. The costs of all treatment provided were 46 per cent higher in Salford than in Bromley. The date of qualification of the dentist was the only factor significantly associated with the cost of preventive treatment provided, with more recent graduates offering more preventive care than older dentists. The difficulties of using uniform national capitation rates are discussed. PMID- 7850636 TI - The demographic and social variation in the prevalence of dental enamel opacities in north Wales. AB - The variation in the prevalence of developmental defects of enamel in areas of North Wales with low levels of fluoride in the drinking water was studied. Significant differences in the prevalence of diffuse opacities were found for the ten county districts in the study area. In addition, there was an association between area deprivation, as measured using the Townsend index, and diffuse opacity prevalence. The prevalence of subjects with one or more diffuse opacities was lower in more deprived electoral wards than those less deprived. For demarcated opacities and hypoplastic defects in the ten county districts, the prevalences were not significantly different and there was no association with area deprivation. PMID- 7850637 TI - Use of linear multiple regression analysis on dental survey data. AB - The use of multiple regression analysis in dental research has increased greatly in recent years. However, in most cases insufficient or no details are given to assess the validity of the results obtained through this statistical approach. Since multiple regression is the method of choice when dealing with three or more variables, provided the assumptions are fulfilled, this study reports the use of this technique on caries data from a random sample of schoolchildren from Andalucia, Spain. Linear multiple regression was used to analyse caries experience, expressed as dmft or DMFT, a quantitative dependent variable. The explanatory or independent variables considered for each age group were gender, type of area, social class and province, following the basic survey method recommended by the World Health Organization. Laborious data transformation procedures had to be employed to comply with necessary assumptions for this statistical technique. The difficulties encountered may be partly due to the fact that all the independent variables considered in the study were categorical or qualitative variables. In the process of ensuring valid results, several helpful statistics were identified. In addition, statistically significant influences on the dependent variable studied were easily detected, as well as the order of importance of the independent variables included in the model. However, the complex data transformation procedures required to validate assumptions in this study suggested that in some instances it could prove extremely difficult to use linear multiple regression on survey data. PMID- 7850638 TI - A study of the dietary fluoride supplementation prescribing pattern of south Glamorgan dentists. AB - Following the inclusion of dietary fluoride supplements in the Dental Practitioners Formulary on 1st January 1993, the aims of this study were to observe the fluoride supplementation prescribing pattern of South Glamorgan general dental practitioners and relate it to the latest caries prevalence data. The analysis was carried out on the prescribers and recipients of the prescriptions using post codes to locate all members of both groups into one of 26 dental planning areas (DPA) within the district. As the age of a minority of recipients could not be substantiated, an assumption that they were all 14 years or under was used to calculate a prescription to population ratio for each DPA. These ratios were correlated against the latest available caries prevalence data for each DPA to ascertain any relationship between the level of fluoride supplement prescription and the caries prevalence within South Glamorgan. Data were collected via the Prescription Pricing Division of Welsh Health Common Services Authority for the six month period, 1st January to 30th June 1993. Of 623 prescriptions dispensed within South Glamorgan, 581 were issued by dentists working in the District for patients living in the District. Of the 163 dentists registered within South Glamorgan FHSA, (boundary coterminous with the DHA) 49 made one or more prescription. Of these, 10 dentists wrote 20 prescriptions or more, totalling 401, during the study period, i.e. 6 per cent of the dentists made 69 per cent of the prescriptions. The correlation of the number of prescriptions issued per DPA (according to the dentists' location) with whole time equivalents in that DPA was 0.58 (P < 0.002).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7850639 TI - Dental fear in an urban Swedish child population: prevalence and concomitant factors. AB - In order to establish normative data on the dental subscale of children's fear survey schedule (CFSS-DS), measuring child dental fear, and to study the influence of general fears, parental fears and socio-economic correlates on children's dental fear levels, a questionnaire was sent to parents of a representative sample of 4,505 children aged 4-6, and 9-11-years-old in Goteborg, Sweden. The questionnaire contained the CFSS-DS, a short form of the CFSS measuring general fears, Corah's dental anxiety scale (DAS) (measuring parents' dental fear) and specific questions on parents' employment and the native language in the family. A total of 3,204 responses was received. The overall mean score on CFSS-DS was 23.1, and 6.7 per cent of the children were found to be fearful. Dental fear decreased with increasing age and was positively correlated to general fears. Three variables: age, general fears and maternal dental fear, were found to have a significant impact on the variance of CFSS-DS. PMID- 7850640 TI - The relative contribution of dental services to the changes and geographical variations in caries status of 5- and 12-year-old children in England and Wales in the 1980s. AB - The aim of this study was to assess the relative contribution of dental services to the changes and geographical variations in caries status of 5- and 12-year-old children in England and Wales in the 1980s. A secondary aim was to assess the association between caries experience and social factors. An ecological study analysing data at a district health authority level in England and Wales was conducted. Twenty-eight, 43 and 34 per cent of the variations in 5-year-old dmft in 1985, 1987 and 1989 respectively were explained by dental service activity indicators and 53, 62 and 57 per cent by social factors. Twenty-nine per cent of the variation in 12-year-old DMFT in 1988 was explained by dental service activity indicators and 46 per cent by social factors. PMID- 7850641 TI - A comparison of orthodontic screening methods used in school dental inspections. AB - The validity of two currently used orthodontic screening programmes was investigated and compared to an objective measure of need for orthodontic treatment. The results indicate that existing orthodontic screening methods underestimate the numbers of children with severe malocclusions. The use of a more objective measure of orthodontic treatment need is recommended. PMID- 7850642 TI - Productivity in dental care for children. Factors influencing the time spent delivering dental care. AB - The cost of dental services is related to their productivity. The purpose of the study was to identify factors influencing productivity, measured as time spent providing dental care per child under care, per year, in public dental clinics. The time was expected to vary with characteristics of the patients, the personnel and the clinics. Time spent by dentists and dental hygienists delivering dental care for children aged three to 18 years was obtained from 137 public dental clinics. The data showed substantial variation in productivity between clinics. Multiple regression analysis revealed that the time spent per child was associated with interval between examinations, proportion of male dentists, ratio of dental assistants to dentists, proportion of child treatment time given by dental hygienists and proportion of all treatment time spent on child patients. These variables explained 43 per cent of the variance in the total time spent by dentists and hygienists and 41 per cent of the variance in dentists' time. Individual dentists and hygienists may reduce the mean time spent per child by extending recall intervals. On an administrative level, dentists' time per child may be reduced by employing more dental assistants or dental hygienists and allowing dentists to treat patient groups other than children. It is concluded that productivity in dental care for children in the public dental services may be influenced in several ways, both by clinical and administrative decisions. PMID- 7850643 TI - Correlates of toothbrushing in preschool children by their parents in four ethnic groups in The Netherlands. AB - A previous study among Amsterdam 5-year-old children showed that on average, the older the child at the onset of toothbrushing and the less frequent the toothbrushing, the more life time caries experience it had. The aim of the present study was to assess correlates of these two caries risk factors, in four ethnic groups. A further aim was to evaluate the putative role of correlates as intervening variables between ethnicity and caries risk factors. Questionnaire data were available from the Amsterdam study, in which a stratified sample of 103 Turkish, 258 Moroccan, 59 Dutch and 56 Surinamese parents were interviewed at home in their mother tongue. Results showed 69 per cent of the Turkish, 45 per cent of the Moroccan, 17 per cent of the Dutch and 11 per cent of the Surinamese parents had commenced brushing their child's teeth only after its second birthday or even never at all. Moreover, many parents had not brushed their child's teeth every day. Almost all potential correlates in six domains, namely parental habits, attitudes, evaluative beliefs, behavioural beliefs, perceived role of the child and that of the partner, were found to be related crudely to the risk factors. Large differences in score patterns on the correlates were observed between ethnic groups. Multiple logistic regression analyses showed substantial parts of the differences in risk factor scores between the Turkish group and a combined Dutch and Surinamese reference group could be attributed to the intervening role of the correlates, as could only minor parts of the difference in risk factor scores between the Moroccan group and the reference group.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7850644 TI - The role of traditional healers in the treatment of toothache in Tanga Region, Tanzania. AB - The study was conducted in five villages in each of two districts in the Tanga Region of Tanzania. Seventy-three traditional healers and 408 villagers of 14 years and above (selected through systematic random sampling) were interviewed. Most of the traditional healers had practised for more than ten years and the majority had been trained by their father or grandfather. Sixty per cent of the traditional healers claimed, that they treated dental patients with an average of three patients per month. A large variety of local herbs was used and about 40 per cent of the traditional healers claimed that they would refer the client to a modern health facility, if their treatment did not work. Half of the villagers interviewed had experienced toothache and 60 per cent of those who had experienced toothache within the last two years had sought treatment from traditional healers, where they had all been treated with local herbs. Relief was obtained for more than six months for 40 per cent of the patients, who sought this service. The establishment of modern emergency oral care in rural health centres and dispensaries did not influence the villagers' use of the traditional healers. PMID- 7850645 TI - Congenital biliary tract dilatation in infancy and childhood--74 cases experience. AB - This report presented a twelve-year experience from 1981 to 1992. Seventy-four cases of congenital biliary tract dilatation were at diagnosed an age of 6 days to 16 years. Twenty-two cases were infants. There were 54 females and 20 males. The ratio of female to male was 2.7:1. The classic triad of abdominal pain, jaundice and a palpable mass was seen in eleven cases (14.9%). Most children suffered from abdominal pain (50/74), vomiting (45/74), anorexia (42/74) and jaundice (34/74). Prolonged jaundice was the main symptom in infancy (15/22). A long common pancreatico-biliary channel was seen in six cases (6/47); the bile amylase level was elevated in five cases (5/20), one patient had a complex union with obstructive jaundice. All these cases were diagnosed by preoperative sonography accurately (100%). According to the Todani's classification, type Ia was the most common (40/74), followed by type IV-A (25/74) and type Ic (8/74). Cholelithiasis (13/74), perforation (9/74), and atresia/stenosis of distal choledochus (8/74) were the most common associated conditions. Cyst excision with biliary tract reconstruction was performed in all cases. Reoperation was needed in ten cases. Two cases died postoperatively due to sepsis and cholangitis induced hepatic failure. PMID- 7850646 TI - Frozen preservation of human amnion and its use as a burn wound dressing. AB - A method of freezing and sterilizing the human amnion enabled it to be stored at 60 degrees C for more than six months. The membranes were obtained from twenty four cesarean section mothers without a history of endometritis, premature rupture of their membranes or a positive serology. The elongation and break strength of the membranes were evaluated before and after storage. The membranes as prepared have been utilized on twenty-two wounds of ten burn patients. The results indicate that amnion is quite safe and effective as a biological dressing using this preservation method. PMID- 7850647 TI - Resectional therapy for a giant cavernous hemangioma of the liver. AB - Twelve patients with cavernous hemangiomas of the liver were treated by surgical resection from 1982 to 1991. There were three male and nine female patients. Their ages ranged from 31 to 62 with a mean of 49. All except one with gall bladder polyp had abdominal pain. Preoperatively, dynamic computerized tomographic scans performed on three patients produced accurate diagnoses, while angiography was correct in only 2 out of 7 patients. The indications for operation were suspected hepatoma in five, symptomatic pain in three, intraperitoneal hemorrhage resulting from biopsy in one, intrahepatic stone with suspicion of cholangioma in one, abdominal mass mimicking a gastric leiomyosarcoma in one and incidental laparotomy in a final patient. Surgical treatment resulted in no operative mortalities apart from one delayed death from cirrhotic decompensation occurring four months postoperatively. Morbidity included one patient with a postoperative hemorrhage and one with bile leakage, however, both of them were discharged uneventfully. During the follow up period from 6 to 72 months, no more abdominal pain attacked in those three patients with preoperative symptomatic pain. Three patients developed multiple recurrent hemangiomas. No identifiable causes were readily apparent. We conclude that the preoperative differentiation between hemangioma and hepatoma in a hepatic lesion is very important. When necessary, such as a giant symptomatic hemangioma of the liver can be safely resected without significant complications. PMID- 7850648 TI - Echocardiographic study of Ebstein's anomaly. AB - This report analyze the M-mode, two-dimensional (2-D) Doppler and contrast echocardiographic features of 8 patients with Ebstein's anomaly. The diagnosis was confirmed by cardiac catheterization in all cases. M-mode echocardiograms showed: dilated right ventricular cavity (29-59 mm) in 7 patients (88%), abnormal septal motion in 6 patients (75%), delayed closure of tricuspid valve in 4 patients (50%), increased excursion of anterior tricuspid leaflet (20-32 mm) in 6 patients (75%). Two-dimensional echocardiogram revealed: apical displacement of septal tricuspid leaflet (10-43 mm) in all cases (100%), elongated anterior tricuspid leaflet with whip-like motion in 7 patients (88%), tethering of septal tricuspid leaflet in 1 case (13%). The Doppler studies revealed tricuspid regurgitation in 4 of the 5 cases studied (80%) and atrial septal defect flow pattern in all 5 cases studied (100%). Contrast study showed right to left shunt through the atrial septal defect in all 5 cases studied (100%). We conclude that echocardiography is a useful diagnostic tool in detecting Ebstein's anomaly. PMID- 7850649 TI - Vibrio vulnificus infection--report of 8 cases and review of cases in Taiwan. AB - Vibrio vulnificus infection, which is a rare and fatal disease, can be categorized clinically as either primary septicemia or wound infection. The clinical presentation of patients with primary septicemia can vary from fever alone to a more severe illness including high-grade bullous lesions, hypotension, and shock. Wound infection typically results from either injury to the skin in a marine environment or contact of a preexisting wound with sea water. We reported eight cases with Vibrio vulnificus infection in Chang gung Memorial Hospital and reviewed ten other cases previously reported with details in Taiwan. Fourteen patients presented with primary septicemia, and four with wound infection. Thirteen patients had alcoholism or chronic liver disease, two had peptic ulcer disease, one was steroids abuser, and one patient had thalassemia and chronic liver disease. Overall mortality was 55.6% (ten patients). Patients with hypotension within 48 hours of admission had higher mortality than normotensive patients (77% vs. 0%, P = 0.007). Patients with chronic liver disease or liver cirrhosis also had tendency to a higher mortality than not (64% vs. 25%, P = 0.274). Chronic liver diseases and liver cirrhosis are common disease in Taiwan. They take a high risk for Vibrio vulnificus infection. Clinician should keep in mind of this potentially fatal infection in these patients reporting a history of recent raw oyster consumption and presented with sepsis and characterized skin lesions. Prompt empirical antibiotics treatment and aggressive surgical treatment may be lifesaving for this acute and fatal disease. PMID- 7850650 TI - [Clinical observation of Henoch-Schonlein purpura-focus on gastrointestinal manifestation and endoscopic findings]. AB - During the 5.5-year period from January 1988 to June 1993, there were 40 cases of Henoch-Schonlein purpura diagnosed in Chang Gung Memorial Hospital, Taipei. The diagnosis criteria is defined as a typical skin rash, which pathologic examination shows leukocytoclastic vasculitis, accompanied by any two of these major manifestations of the disease, namely gastrointestinal, renal and joint involvement. Their medical records were reviewed with respect to the clinical symptoms, laboratory findings, roentogenologic findings, endoscopic findings, and morbidity. There are 21 women and 19 men with age raging from 10 to 63 years old (mean age 35.9 years old). The male to female ratio was 1:1.1 and about 80% of the patients were at the age of fifteen or older. There was no special season distribution in this series. The main clinical features were purpuric skin rashes, 40 cases (100%), followed by gastrointestinal symptoms, 25 cases (62.5%), renal involvement, 21 cases (52.5%) and joint involvement, 19 cases (47.5%). The major gastrointestinal symptoms were abdominal pain (25 case) and bleeding from gastrointestinal tract (10 cases), and minor symptoms included vomiting (7 cases), diarrhea (1 cases) and acute pancreatitis (2 cases). Gastrointestinal endoscopy was performed in 5 cases and all had hyperemic mucosa and scattered hemorrhagic purpura in the stomach and duodenum. The characteristic hemorrhagic erosive duodenitis were observed in 3 cases. These findings may alert the gastroenterologists to take into consideration of this disease earily and thus avoid unnecessary laparotomy and complications. PMID- 7850651 TI - [The analysis of plain film presentation and bone age of achondroplasia]. AB - Achondroplasia is the most common type of inheritant dwarfism. The diagnosis is mainly depended on clinical and plain film presentation. This study mainly focus on the characteristic presentation of plain film in achomdroplasia. We try to find the most consistent presentation and explain it through the development and growth of bone. The presentation in our 16 cases is as follows: Metaphyseal flaring 100% (16/16), Concave backs of vertebral body 100% (4/4), Short & wide tubular bone of hand & foot 85% (12/24). Square iliac bone 78% (11/14), Flare anterior end of ribs 76% (10/13), Decrease interpeduncular distance of lower L spines 64% (9/14), Proimal < distal tubular bone 33% (5/15). Disproportionately long fibular bone 8% (1/13). We also analyze the heritant characteristics and conclude that most of achondroplasia are caused by mutation. The heritant trait is only 6%. According to bone age study, we found high percentage (31%) of delayed bone maturation. PMID- 7850652 TI - Imaged thoracic resection of a huge mediastinal tumor--role of extended incision and the use of conventional instruments. AB - Intrathoracic lesions are usually removed through conventional thoracotomy. The long incision and the spreading of the rib usually results in much pain and interference of chest wall mechanics. Today, with the development of imaged thoracic surgery (combination of thoracoscope and video optics), major procedures can be performed through small incisions. However, indications are greatly limited due to lack of suitable instrumentation and restricted space of the trocar channel especially when a huge intrathoracic tumor is encountered. In this selected report, we demonstrate a successful procedure using extended incision and conventional instruments in imaged resection of a huge cystic intrathoracic tumor. The procedure offers the benefit of safe, easy and fast manipulation. The patient had an uneventful postoperative course and was discharged on the fourth postoperative day. PMID- 7850653 TI - Successful treatment of hereditary progressive dystonia--a case report. AB - Hereditary progressive dystonia or Segawa disease is a very rare disease. Diagnosis depends on typical clinical features with remarkably good response to levodopa and normal laboratory findings. Here, we report on a unique case of Segawa disease with a fixed equinovarus foot. The patient was a twenty one year old female with the typical clinical manifestations since eight years of age who became wheel-chair dependent at the age of fifteen. The dystonia responded well to levodopa except for the foot deformities. The foot deformities were successfully corrected by use of the Ilizarov apparatus and she ambulated freely at follow up. Since several similar foot deformities appeared in the early stage of a progressive neurological degenerative disease, the treatable Segawa disease should be added to the differential diagnosis when facing a patient with pes equinovarus. PMID- 7850654 TI - Ectopic ACTH syndrome with nocardiosis--a case report. AB - A 25-year-old man was admitted with chief complaints of multiple ecchymoses over face and both arms after a trivial trauma since one month before entry. Physically, he was thin without moon face, buffalo hump, or purple striae, while extensive fungus infection was present. Mild hyperglycemia, hypokalemic alkalosis were also found. Chest x-ray revealed multiple cavitary nodular lesions over bilateral lung fields. Needle biopsy from a rib lesion showed small cell carcinoma with strongly positive ACTH stain. The patient's basal cortisol level was greater than 62 micrograms/dl and failed to be suppressed by both low and high dose dexamethasone. The 24 hours urine free cortisol, 17 KS, and 17 OHCS were 8454 micrograms/24h, 49.8 mg/24h, and 50.8 mg/24h respectively. His plasma ACTH level was 725 pg/ml and remained high (1210 pg/ml) after high dose dexamethasone suppression. On the 10th day after admission, the patient's general condition got worse rapidly. Fever, dyspnea developed with progression of the lung lesions. Nocardia infection was proved. He expired three days later in spite of antibiotics and ketoconazole treatment. PMID- 7850655 TI - Extramedullary plasmacytoma of the head and neck. AB - Extramedullary plasmacytoma (EMP) is an uncommon malignant plasma cell neoplasm which usually presents as soft tissue mass in the head and neck. We retrospectively reviewed 7 cases with EMP of the head and neck between 1978 and 1992. All patients were male. Their ages ranged from 27 to 66 years. M-protein was identified in 5 patients (IgG-kappa in 3, IgG-lambda in 1 and Lambda light chain in 1). All but one were treated with local irradiation. Three patients received chemotherapy. All patients have been alive for 37+ to 116+ months since the diagnosis of EMP. One patient had a cervical node recurrence 9 years after local irradiation and the other one who refused local irradiation but received chemotherapy developed multiple myeloma 5 years later. Based on our experience and the review of the literature, it is recommended that irradiation to the primary sites and the involved cervical nodes is the treatment of choice. Additional chemotherapy may be considered in patients with disease progression, recurrence, or dissemination. The M-protein is a useful parameter to assess tumor control or disease progression. PMID- 7850656 TI - Gout with aseptic loosening of cementless total hip arthroplasty--a case report. AB - One case of gouty patient with aseptic loosening of cementless total hip arthroplasty was reported. Mechanical and biological factors may both play some roles in this ollsening hip. From both cup and stem, no direct evidence of loosening was found from pathologic aspect. Further study may need to define relationship between gout and loosening of total hip arthroplasty. PMID- 7850657 TI - [Clinical experience of automated peritoneal dialysis]. AB - For uremic patients on continuous ambulatory peritoneal dialysis who are complicated with peritonitis, hernia or burn out of meticulous procedure, automated peritoneal dialysis (APD) is a new alternative therapy. We started our APD program by continuous cyclic peritoneal dialysis (CCPD) method from October, 1991 and this study included 3 CAPD patients. Our studies showed high dose CCPD was better than CAPD in ultrafiltration and urea clearance with similar weekly creatinine clearance and weekly KT/V urea. During the one year treatment course, there was no signs of fluid overload. We performed once to twice day time exchange by low volume dialysate (1500-1600ml) There was no events of abdomen discomfort due to increase intraabdominal pressure or recurrent hernia in susceptible patient. The decrease in day time exchange frequency obviously reduced patients'loading. One patient changed to high dose CCPD due to underdialysis after stand CCPD therapy. Two patients returned to hemodialysis due to severe peritonitis and technique method, but careful assessment of dialysis adequacy with PET test and KT/V evaluation is mandatory. PMID- 7850658 TI - [Proximal interphalangeal joint dorsal dislocations without fractures--four cases report]. AB - Four patients with proximal interphalangeal joint (PIP) dorsal dislocation without fracture had been treated at Chang Gung Memorial Branch (Kaohsiung and Keelung) Hospital from June 1987 to Jan. 1989. All four cases were open dislocations, only one patient received immediate diagnosis and treatment, while the other 3 cases were delayed diagnosis and treatment. Open reduction, repair of the ruptured ligaments and joint capsule, reinsertion of the disrupted volar plate were given in these 4 patients. The patient with immediate surgical treatment received rehabilitation program, the other three patients with delay surgical management did not receive rehabilitation program. The rehabilitation program included early active exercises of the PIP joint, started from the second week postoperatively. The rehabilitation period was about three to six months. The prompt diagnosis, reduction, institution of appropriate treatment and rehabilitation might result in better function of the PIP joint after dorsal dislocation. PMID- 7850659 TI - [Floating shoulder (ipsilateral scapular neck and clavicle fracture)--two cases report]. AB - Fracture of either clavicle or scapular neck alone are generally stable and have satisfactory results by conservative treatment. However, displaced scapular neck and ipsilateral clavicle fractures are relatively unstable. Those sequelae as drooping shoulder and limited range of motion may develop if treated conservatively. Surgical intervention either fixation of clavicle alone or fixation of clavicle and scapular neck simultaneously can achieve stable reduction of the fractures and prevent those sequelae. We present two cases of floating shoulder treated surgically with excellent results. PMID- 7850660 TI - Supraphysiological levels of magnesium in cardioplegic arrest solutions: is there cause for concern? PMID- 7850661 TI - Time varying loading of the pulmonary circulation: a model to describe hemodynamic observations in the stiff left atrial syndrome. AB - OBJECTIVE: To develop a mathematical model that could explain the following observations: that right heart failure can develop in association with no other cardiac abnormality than a severe reduction in the compliance of the left atrium; and that patients with this syndrome have systolic pulmonary hypertension with left atrial v waves in the absence of either mitral regurgitation or left ventricular dysfunction. DESIGN: A model of the pulmonary circulation was designed with a time varying terminal hydraulic load, which was varied between a noncompliant left atrium during systole and a compliant left ventricle/left atrium combination during diastole. Using representative parameters and a pulmonary arterial flow wave as input, pressures in the pulmonary artery and left atrium and right ventricular power output were calculated. RESULTS: Pulmonary arterial and left atrial systolic pressures are increased as left atrial compliance is reduced. The time varying change in terminal load results in an increase in systolic pressures, whereas diastolic pressures remain normal. A decrease in left atrial compliance increases both the nonpulsatile and pulsatile components of pulmonary input impedance, whereas only the nonpulsatile component of right ventricular power output is increased. CONCLUSIONS: The time varying pulmonary load model of the pulmonary circulation, in the presence of a reduced left atrial compliance results in pulmonary, and left atrial pressures similar to those observed in patients with the stiff left atrial syndrome. The resulting increase in right ventricular power output could be an important factor in the development of right heart failure. PMID- 7850662 TI - Thrombolytic therapy in cardiogenic shock: effect of increased aortic pressure and rapid tPA administration. AB - OBJECTIVES: To investigate the effect of an increase in aortic pressure combined with rapid tissue plasminogen activator infusion on hemodynamic stability and patency of the infarct-related artery in patients with acute myocardial infarction complicated by profound hypotension or cardiogenic shock. BACKGROUND: Thrombolytic therapy improves mortality in relatively stable patients with acute myocardial infarction but not in patients with cardiogenic shock. Recent canine studies have demonstrated that a moderate increase in low aortic pressure improves thrombolysis. Conceivably, then, decreased thrombolytic efficacy in cardiogenic shock is due, at least in part, to a low aortic pressure impairing delivery of the thrombolytic agent. PATIENTS AND METHODS: For patients presenting within 6 h of an acute myocardial infarction complicated by profound hypotension or cardiogenic shock, an inotropic agent was rapidly administered to increase the systolic aortic pressure to approximately 110 mmHg, and 100 mg of tissue plasminogen activator was administered intravenously over 45 to 60 mins. RESULTS: Eight consecutive patients meeting the study criteria were treated over 18 months. In six of eight patients, the inotropic agent increased systolic blood pressure over 10 mins, from a mean of 64 +/- 12 mmHg to 102 +/- 12 mmHg. In the two patients whose blood pressure did not increase, early angiography in one demonstrated occlusion of the infarct-related artery, and both of the patients died. In the other six patients there was clinical and hemodynamic evidence of early reperfusion, and infarct-related arteries were patent on angiography. These six patients survived at least 30 days, with four having a favourable clinical outcome and two having a functional limitation due to heart failure. CONCLUSIONS: These results are consistent with experimental data indicating that an increase in aortic pressure combined with rapid tissue plasminogen activator infusion may increase thrombolytic efficacy when an acute myocardial infarction is complicated by profound hypotension or cardiogenic shock. PMID- 7850663 TI - Coexistence of hypothyroidism and myocardial infarction. AB - OBJECTIVE: To assess the coexistence of overt hypothyroidism and acute myocardial infarction (MI) in respect of clinical and biological manifestations and outcome. DESIGN: Retrospective study of patients with coincident untreated or uncontrolled hypothyroidism presenting to Notre-Dame Hospital with acute MI. Each patient's MI was matched with two controls for date of admission (within three years) of MI, age, sex, diabetes mellitus and number of previous MIs. SETTING: All patients were admitted to Notre-Dame Hospital, which is a secondary and tertiary care institution. PATIENTS: From 1975 to 1990, 5691 patients were seen at the authors' institution with acute MI, of whom 17 had simultaneously an untreated or uncontrolled hypothyroidism. Hypothyroidism was defined as thyroid-stimulating hormone levels greater than 40 mU/L associated with low or normal levels of serum thyroxine. RESULTS: Chest pain was documented in each case. Electrocardiogram location of the MI was inferior in 10 (59%) patients and in 14 (41%) controls, anterior in seven (41%) patients and in 20 (59%) controls. There was a trend towards higher creatine kinase peak levels in patients with hypothyroidism (1409 +/- 1145 U/L versus 943 +/- 788 U/L). The Killip index was similar in the two groups (1.8 +/- 1 versus 1.8 +/- 1), as was the incidence of arrhythmias (seven of 17 versus 11 of 32). There was no significant difference in mortality between the two groups (18% [three of 17] versus 12% [four of 34]). However, the incidence of residual ischemia was greater in patients with hypothyroidism (12 of 17 versus 10 of 34, P < 0.008). CONCLUSIONS: Hypothyroidism is not associated with an unfavourable effect on the clinical course of acute MI. However, patients with hypothyroidism seem to have an increased incidence of residual ischemia. PMID- 7850664 TI - Evaluation of myocardial infarction therapy at a Canadian tertiary referral hospital. AB - OBJECTIVE: To evaluate the appropriateness of acute and postmyocardial infarction (MI) treatment. DESIGN: A retrospective chart review. SETTING: Tertiary care teaching hospital. PATIENTS: All patients admitted with a potential MI or who experienced an MI during their hospital stay from November 18, 1991 to September 20, 1992. RESULTS: For acute treatment, thrombolytics, acetylsalicylic acid (ASA) and intravenous beta-blockers were used in 82%, 96% and 39% of eligible patients with a median time delay of 1.4, 4.4 and 1.8 h, respectively. For post-MI treatment, ASA, oral beta-blockers, warfarin and angiotensin-converting enzyme inhibitors were used in 93%, 68%, 50% and 71% of eligible patients, respectively. CONCLUSIONS: ASA use was considered acceptable while the other therapies were underused. The time delays in the initiation of therapies were also considered longer than desirable. Ongoing audit may aid in improving the quality of care in future patients with an MI. PMID- 7850665 TI - Effects of modified St Thomas' Hospital solution on coronary artery endothelium dependent relaxation in the isolated rat heart. AB - Addition of magnesium to a preservation solution such as St Thomas's Hospital solution has been shown to improve myocardial preservation. High concentration of magnesium can affect coronary artery endothelial-dependent relaxation. Isolated rat hearts were studied in the Langendorff apparatus to investigate whether magnesium-enriched hyperkalemic cardioplegic solution (HCS) could alter coronary endothelial function. Hearts in group 1 (n = 8) were perfused for 30 mins with a standard hyperkalemic cardioplegic solution (potassium chloride 24 mmol/L). Hearts in group 2 (n = 8) were perfused with modified St Thomas' Hospital solution (MST) containing 16 mmol/L of magnesium chloride and 24 mmol of potassium chloride. The endothelium dependent and endothelium independent relaxation of the coronary arteries were respectively assessed by infusing 5 hydroxytryptamine (5-HT) (1 x 10(-6) mol/L) and sodium nitroprusside (SNP) (1 x 10(-5) mol/L) before and after perfusion of cardioplegic solutions. Hearts in group 2 showed a reduction of the 5-HT-induced coronary flow increase following the MST exposure (before, 8.66 +/- 0.86 mL/min; after, 5.66 +/- 0.97 mL/min, P < 0.01) whereas hearts in group 1 were not significantly affected (before, 8.00 +/- 0.68 mL/min; after, 6.99 +/- 1.02 mL/min, not significant), suggesting endothelial dysfunction in the former. Coronary flow response to SNP was not affected in either group.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7850666 TI - Acute hemodynamic effects of drugs acting on the renin-angiotensin system in acute heart failure. AB - OBJECTIVE: To determine the role of the renin-angiotensin system in a model of acute heart failure. METHODS: Placebo or drugs (Ro 44-9375, a renin inhibitor; captopril, an angiotensin-converting enzyme [ACE] inhibitor; or DuP 532, an angiotensin II receptor [AT1] antagonist) were given to anesthetized splenectomized dogs (n = 12 for each group) for 50 mins after a volume load (dextran 70, 25 mL/kg over 10 mins) during rapid right ventricular pacing at 250 beats/min. Total vascular compliance and capacitance were determined from mean circulatory filling pressure-blood volume curves during transient circulatory arrests induced by acetylcholine. Cardiac index was measured by thermal dilution. RESULTS: Compared with the untreated group, all three drugs significantly reduced systemic pressure and total peripheral resistance while increasing arterial compliance. Captopril alone increased cardiac index (25 +/- 11 versus -23 +/- 13 mL/kg/min) and reduced pulmonary capillary wedge pressure (16.6 +/- 0.7 versus 21.9 +/- 1.0 mmHg). None of the drugs altered the mean circulatory filling pressure, total vascular compliance or capacitance, stressed or unstressed blood volumes, or central blood volume. CONCLUSION: The renin-angiotensin system is not strongly implicated in the hemodynamic manifestations of this model of acute heart failure. These drugs had effects on the arterial but not the venous side of the circulation. Captopril alone reduced pulmonary capillary wedge pressure, perhaps by nonangiotensin effects. PMID- 7850667 TI - Atypical retrograde atrial activation in 'typical' atrioventricular nodal reentrant tachycardia. AB - Atrioventricular nodal reentrant tachycardia (AVNRT) can be cured by radiofrequency catheter ablation by selective ablation of the slow or the fast pathway. Retrograde fast pathway ablation is performed anterosuperiorly at the apex of Koch's triangle, whereas slow pathway ablation is performed at the base of Koch's triangle near the coronary sinus ostium. A patient with otherwise typical slow-fast AVNRT who demonstrated earliest retrograde atrial activation at the proximal coronary sinus rather than the usual His bundle recording position is described. Loss of retrograde fast pathway conduction occurred after radiofrequency ablation at the base of Koch's triangle, suggesting an atypical location of the fast pathway. This supports recent evidence that the retrograde fast pathway may be located near the coronary sinus ostium in some patients with otherwise typical AVNRT. PMID- 7850668 TI - The Victoria Declaration--a unifying force. AB - The Victoria Declaration, the policy document which resulted from the First International Heart Health Conference--'Bridging the Gap: Science and Policy in Action'--is an historic document. Advances in cardiovascular disease prevention, intervention and research as well as in heart health promotion have been frequent and significant. At the same time, a lack of appreciation of the need for a coordinated effort between clinicians, researchers, epidemiologists, community health professionals and others in the health field has meant that we have not been able to capitalize on the opportunity for greater success. The Victoria Declaration highlights the fact that a comprehensive approach to cardiovascular disease prevention needs to expand partnerships well beyond the health sector into many areas of policy development both within and outside government and in the private and voluntary sector, among others. The key message of the declaration is that our best effort will be a unified, systematic effort that marries the preventive, clinical and research approaches with those of policy makers, governments, private sector and others. It is imperative that health professionals recognize this. The declaration outlines a comprehensive framework for cardiovascular disease prevention, advocating a public health approach, targeted towards the population at large and focusing on the reduction of the major risk factors. It suggests a number of key strategies and advocates a research agenda. The declaration is a document that has international scope and recognizes that global partnerships are necessary to assist developing countries (that are now experiencing increasing rates of cardiovascular disease) in the fight against this disease. PMID- 7850669 TI - Promoting dietary change. AB - The discouraging failure rate of counselling patients for dietary change suggests that traditional methods require some reconsideration. These have been frequently based on generalized assumptions regarding patients' health values, their need for knowledge, level of literacy, and ability to translate abstract concepts into daily food. Similarly, both patient and counsellor often insufficiently examine the environmental context of the dietary changes to determine whether or not they are feasible. This brief overview examines ways in which nutrition counselling can be enhanced to ensure that patients are enabled to develop a heart-healthy diet through active problem solving and directed development of self-efficacy in the skills they will need for lasting change. PMID- 7850670 TI - How can we help patients to initiate change? AB - This paper presents guidelines to help patients initiate change in risk behaviours for coronary artery disease. Two questions are explored. These address the clinical method and session content, respectively. How might we best conduct the interview, so that the patient's motivation for changing risk behaviour is enhanced? What is the optimal focus for counselling, so that the patient can feel that the activity of exploring or modifying their risk behaviour is meaningfully connected with their personal goals and life priorities? Specific guidelines are presented to guide practitioners in fostering a patient-centred clinical method. Practitioner tasks for structuring session content are derived from motivational theory and the transtheoretical model of readiness for change. PMID- 7850671 TI - Cardiovascular disease prevention: talking occurs at all levels--does understanding? AB - The magnitude of the health problems posed by cardiovascular disease is well known and represents a major public health challenge. Traditionally programmes of prevention have had a 'lifestyle' orientation, focusing on individual behaviours. Ironically, it may well be that profound societal changes, notably the agricultural and industrial revolutions, have largely been responsible in the most fundamental sense for the modern epidemic of cardiovascular disease. Thus attempts to deal with individually expressed behaviours alone may not be the most effective way to prevent the development of cardiovascular disease in our society. Ultimately, it will be the creation of social environments in which healthy behaviours are the norm that will have the most profound effect on the community's cardiovascular health. Misunderstandings abound. Politicians, while speaking favourably about the importance of prevention, do not match their rhetoric with resources. Many health professionals mistake 'risk-factor identification' with 'prevention'. Private industry has often confused or distorted public understanding in the process of marketing products deemed to have cardiovascular benefits. The public's awareness of many of the basic epidemiological realities concerning the prevention of cardiovascular disease is often sadly lacking. In spite of the misunderstandings, preventive approaches have played a significant role in the reduction of cardiovascular disease, a role that should become more prominent in the future. PMID- 7850672 TI - Why do we behave the way we do? AB - Changing high risk behaviours involves progress through six stages of change: precontemplation, contemplation, preparation, action, maintenance and termination. Stage-matched programs for cardiovascular disease prevention can produce much higher participation rates than traditional action-oriented programs (80 to 85% versus 1 to 5%). The amount of success following intervention is directly related to the state of change participants are in before intervention. Helping people progress through the stages involves matching particular processes and principles of change to particular stages of change. PMID- 7850673 TI - Why don't they stay changed? AB - The multifactorial nature of cardiovascular disease means that preventive efforts often stress a variety of complex behavioural capabilities (eg, increasing physical activity, changing eating habits, quitting smoking, practising stress reduction techniques). A variety of theoretical models have been suggested to help explain and predict health behaviours; however, social cognitive theory provides one of the most comprehensive frameworks for understanding human behaviour. Important constructs of social cognitive theory that relate to the initiation and maintenance of behaviour change are reviewed here, including perceived threat, behavioural capability, expectancies, interdependence and environmental influence. Suggestions about how these constructs may be applied in health practice are provided. PMID- 7850674 TI - What do we really know about secondary prevention after myocardial infarction? AB - Secondary prevention following acute myocardial infarction begins at the time of the in initial hospitalization. An aggressive approach should focus on appropriate lifestyle changes as well as pharmacotherapy. Smoking cessation, increased physical activity and lipid lowering are key lifestyle objectives, while beta blockade and aspirin should be routinely prescribed for all patients following acute myocardial infarction, unless there are specific contraindications. Improvement in survivorship, prevention of nonfatal reinfarction, regression of atheromatous disease as well as a better quality of life are all proven benefits of secondary prevention. PMID- 7850676 TI - Stress and cardiovascular disease risk behaviours: implications for health behaviour change. AB - This brief paper presents an integrative framework helpful in understanding the relationships between stress and cardiovascular disease risk behaviours. Key concepts such as cardiovascular reactivity, type A behaviour and hostility, ways of coping with both life and illness-related stressors, and the challenges associated with changing risk behaviours can support a patient's behaviour change efforts if communicated in a personally salient manner. Assessing the determinants of health behaviour change facilitates tailoring of interventions and can more precisely identify a patient's needs for referral to a psychologist with expertise in health behaviour issues. PMID- 7850677 TI - An experimental model of osteoarthritis in rabbit. AB - BACKGROUND: From both a microscopic and a metabolic view, experimental animal models are very important for study of the pathogenesis of osteoarthritis. A new, different operative procedure was used in rabbit models, and the pathologic findings were evaluated. METHODS: Twelve New Zealand white rabbits were divided into six groups; eight were used as animal models and four, for drug efficacy study. Transection of the anterior cruciate and medial collateral ligaments on the left knee joint, and sham-operation were performed on the right knee joint. Rabbits were sacrificed post surgery from 4, 6, 8 and 12 weeks. Eight parameters from gross to microscopic findings were used in order to evaluate osteoarthritic changes. Indomethacin and aspirin were chosen for the drug efficacy experiment; the two rabbits of each group were sacrificed at the end of the sixth week post surgery. RESULTS: According to pathological findings, this operative procedure can produce osteoarthritic changes, visible both microscopically and macroscopically. There were osteoarthritic changes in the fourth week post surgery group and, obviously, in the eighth week; these persisted until 12th weeks post-surgery. Neither indomethacin nor aspirin showed any effect in preventing osteoarthritis progression. CONCLUSIONS: Transection of the anterior cruciate and medial collateral ligament rabbit model can produce osteoarthritic lesions in the knee joint. This model can be used for further biochemical and metabolic studies. PMID- 7850678 TI - Intestinal lengthening experience in short-bowel swine. AB - BACKGROUND: Traditional therapy for short-bowel syndrome is long-term, expensive and inconvenient; it is often associated with high morbidity and mortality. Thus, there has been increasing interest in the surgical management of this syndrome. Intestinal lengthening is attractive not only because of tapering of the dilated intestine, but also for preserving the intestine that is tapered. The purposes of this study were (a) to develop a reproducible surgical technique for intestinal lengthening and (b) to assess the response of the lengthened jejunum to a short gut situation. METHODS: Fourteen pigs weighing 13-20 kg were chosen for the study. The animals were divided into three groups: Group I: two pigs received a 20 cm jejunum lengthening only; Group II: six pigs received an 80% bowel resection only; Group III: six pigs received an 80% bowel resection, followed by a 20 cm loop lengthening in the residual jejunum four to seven weeks later. All were observed for a period from 4 to 28 weeks. RESULTS: All lengthened loops, of either primary lengthening (Group I) or delayed lengthening (Group III) functioned well and showed no clinical leakage. Three pigs in Group II (bowel resection only) died of malnutrition at the 5th, 10th and 19th postoperative week, respectively. Only one pig in Group III died, 67 days after bowel lengthening, from intestinal obstruction. During sacrificing laparatomy, two pigs in Group III were found to have side to side enteroenteral fistulae between the lengthened loops. The lengthened bowel was found to be normal histologically. CONCLUSIONS: These results proved that intestinal lengthening is technically feasible, and may be useful for patients suffering from surgical short-bowel syndrome and who have not been completely weaned off parenteral feeding. PMID- 7850679 TI - The influence of sham feeding on gastric acid and pepsin secretion in the Chinese with duodenal ulcer and liver cirrhosis. AB - BACKGROUND: This study was conducted to evaluate gastric acid and pepsin output in the Chinese patients with liver cirrhosis and duodenal ulcers. METHODS: In a period of one year and three months, we prospectively assayed the acid and pepsin responses to sham feeding in 10 healthy males, 20 males with duodenal ulcers, and 11 males with liver cirrhosis. RESULTS: Although basal and sham feeding stimulated acid outputs were higher in duodenal ulcer patients (2.7 +/- 0.3 and 3.7 +/- 0.3 mEq/h, mean +/- SEM) than in normal subjects (1.6 +/- 0.4 and 2.9 +/- 0.6 mEq/h) and in patients with liver cirrhosis (1.8 +/- 0.4 and 2.1 +/- 0.7 mEq/h), it did not reach statistical significance. Both basal and sham feeding stimulated pepsin outputs were significantly higher in duodenal ulcer patients (11.2 +/- 2.1 and 9.5 +/- 2.2 mg/h) than in normal subjects (2.4 +/- 0.5 and 4.3 +/- 1.2 mg/h) and in patients with liver cirrhosis (3.6 +/- 1.4 and 3.9 +/- 1.2 mg/h) (p < 0.05). The serum gastrin and pepsinogen I concentration in basal and sham feeding conditions demonstrated no statistically significant difference among three groups. CONCLUSIONS: Basal and sham feeding stimulated acid outputs in the Chinese were lower in normal subjects and duodenal ulcer patients as compared with those in the Occidentals. High basal pepsin output may play an important role in the pathogenesis of duodenal ulcers in the Chinese. PMID- 7850680 TI - Acute intermittent porphyria: clinical analysis of nine cases. AB - BACKGROUND: Acute intermittent porphyria (AIP) is an uncommon disorder, characterized by a variety of nonspecific symptoms and signs. Many patients have undergone prolonged medical care for the condition without accurate diagnosis; some have even received unnecessary operation. Here the clinical features of nine cases are presented. METHODS: Nine patients with AIP were diagnosed and treated at this hospital during the period for 1986 to 1993. The medical records of these patients were reviewed, and diagnosis of AIP in all cases was confirmed by positive Watson-Schwartz test. In three cases, further confirmation was done with erythrocyte porphobilinogen (PBG) deaminase activity measurement. Patients with photosensitivity were excluded. RESULTS: All patients presented initially with abdominal pain; two had been operated upon for acute abdomen. Neurological presentations at diagnosis were motor and/or sensory polyneuropathy (6/9), autonomic dysfunction (6/9), mental change (5/9) and seizure (4/9). Two cases had hyponatremia. One patient died of intractable seizures. CONCLUSIONS: AIP is a frequently forgotten old disease; if not correctly recognized, repeated and unnecessary surgery may occur. However, the diagnosis is easy when the possibility of this disorder is kept in mind. PMID- 7850681 TI - Thyroid cancer in children and adolescents. AB - BACKGROUND: Thyroid cancer in children and adolescents has rarely been reported in Taiwan. The purpose of this study is to realize the characteristics of thyroid cancer of children and adolescents. METHODS: From 1971 to 1992, a total of 726 patients with cancer of thyroid were treated at Veterans General Hospital-Taipei. Of these, 37 were below the age of 21, and were followed 1 to 21 years with an average of 7.4 years. RESULTS: Only one patient with thyroid cancer had the history of previous radiation therapy for head and neck tumor. Neck mass was the most common mode of presentation and 36% had associated cervical adenopathy. Histologically, papillary cancer was found in 29 patients, follicular cancer in 7 and medullary cancer in 1. There was no undifferentiated cancer. Twenty-three patients had lymph node metastases. Eight patients developed distant metastases, especially to the lung, and most of them were male. Recurrence after initial surgical treatment was found in 12 patients, without significant association with the surgical procedure. The major operative complication was hypoparathyroidism. Disease-related mortality occurred in only one case (2.8%). CONCLUSIONS: Well differentiated carcinomas of the thyroid in children and young adults are rare in Taiwan and are mostly papillary carcinomas not related to previous neck irradiation. Before the age of puberty, boys were predominant in this series. The rate of distant metastasis was higher in males. The prognosis after surgical treatment is excellent. PMID- 7850682 TI - Allen score in clinical diagnosis of intracranial hemorrhage. AB - BACKGROUND: Allen score is a validated weighted linear score for clinical distinction between hemorrhagic and ischemic stroke. As the prevalence of hemorrhagic stroke differs between Caucasian and Chinese populations, and the predictive value of any diagnostic score depends greatly on the prevalence of disease being considered, we tried to verify prospectively this score among the Chinese living in Taiwan. METHODS: From 1 April to 31 August 1993, all patients with acute stroke syndrome, who visited the emergency room at Veterans General Hospital-Taichung, were studied prospectively. Clinical features were recorded thoroughly to calculate the Allen score. The diagnosis was all confirmed by computed tomography (CT) of the head. RESULTS: Totally 255 stroke cases were identified. The types of the stroke were cerebral infarction in 186 subjects (73%), cerebral hemorrhage in 64 subjects (25%), and subarachnoid hemorrhage in 5 subjects (2%). Seventy-five cases were excluded because of the lack of clinical details for calculation. Thus, 180 patients were included. When a cut-off of 4 or 24 was taken into account, the sensitivity of Allen score for diagnosing a hemorrhage was 67%, specificity 100%, accuracy 93%, positive predictive value 100%, and negative predictive value 91%. CONCLUSIONS: Although Allen score can be used for epidemiological studies of incidence and outcome in stroke as well as for a first bedside screening to decide the priority of patients for CT, it is not safe enough as a guide for anticoagulant or thrombolytic therapy. Its validity should be verified before use in a given population other than the Caucasian. PMID- 7850683 TI - Perinatal characteristics of low birthweight infants in postdate pregnancies. AB - BACKGROUND: Early literature discussed postdate pregnancy in relation to difficult delivery of mothers with an excessively large fetus; more recent reports imply that the risk of perinatal death exists especially for the small, growth-retarded fetus. However there is little in the literature concerning low birthweight infants in postdate pregnancies. METHODS: A 6-year retrospective review of 135 low birthweight infants with 40 or more weeks' gestation was conducted. Among the subjects, 19 cases had a gestational age greater than 42 weeks (Group 1), 26 cases, between 41 and 42 weeks (Group 2), and 90 cases, between 40 and 41 weeks (Group 3). Assess was made of the outcomes of low birthweight infants in postdate pregnancies, comparing Group 1 with Group 2 and Group 3. RESULTS: Group 1 infants had significantly higher rates of chromosomal (21.1%) and congenital (31.6%) abnormalities and perinatal mortality (21.1%) than either Group 2 or Group 3 infants. Also, in Group 1 there were two cases of polyhydramnios and they both had abnormal karyotypes. CONCLUSIONS: The outcome of low birthweight infants in postdate pregnancies appears to be worse than predicted. This finding could offer for managing the cases which have a high frequency of abnormal karyotype (21.1%), especially when combined with polyhydramnios. PMID- 7850684 TI - Varicella-zoster virus infection in children with malignancy. AB - BACKGROUND: Immunocompromised children are potentially threatened by infections, among which, the highly contagious chickenpox infection is the most common. In the past six months, there has been a spate of five chickenpox infections in children with malignancy, all of whom were receiving chemotherapy at that time. METHODS: The cases of 17 children with malignancies, who suffered from varicella zoster infection during a period of chemotherapy at Taichung Veterans General Hospital were reviewed. RESULTS: The diagnoses of their neoplasms were 12 acute lymphoblastic leukemia (ALL), 2 lymphoma, 3 solid tumors. The mean age was 6.8 +/ 4.0 year-old (range 3 to 15 year-old). The average duration from chickenpox skin eruption to admission was 3.3 +/- 1.8 days. Four patients suffered from abdominal pain and three of them died soon; three of them suffered from back pain and one died later. Seven of these 11 patients had impaired liver function (GOT > 45 U/L), of whom 4 died later. There were seven patients with pneumonitis, of whom five died later. Among 12 patients with ALL, 3 had absolute lymphocyte counts (ALC) < 500/mm3, but only 1 died later; 9 had ALC > 500/mm3, of whom 4 had pneumonitis, and all died later. Four patients developed disseminated intravascular coagulopathy, and three of them died later. Seven patients were prescribed acyclovir within three days after first skin eruption, none of these died. Ten patients were prescribed acyclovir three days or more after first skin eruption and five of them died later. Five patients were prescribed intravenous immunoglobulin (IVIG) within three days after first skin eruption, and none of them died; of the seven patients prescribed IVIG three days or more after first skin eruption, three died later. CONCLUSIONS: Abdominal pain and disseminated intravascular coagulopathy (DIC) were signs of visceral dissemination. Severe liver function impairment, pneumonitis and DIC were the principal causes of death. Early administration of acyclovir and intravenous immunoglobulin (IVIG) can probably effectively prevent the dissemination of varicella-zoster virus (VZV). While varicella-zoster immunoglobulin (VZIG) was unavailable, IVIG was still valuable in treating VZV infection. PMID- 7850685 TI - Krukenberg tumor in pregnancy with delivery of a normal baby: a case report. AB - Successful termination of a pregnancy and delivery of a normal infant in a young woman with Krukenberg tumor is reported. This association has rarely been described previously. The persistent gastrointestinal symptoms mimicking the early nausea and vomiting of pregnancy mask the presentation of a tumor in the stomach. Growth of the fetus leading to abdominal distension masks the presence of the metastatic ovarian tumor in the pelvic cavity. Thus, early diagnosis of the tumor may be delayed. We emphasize the importance of differentiation between physiological morning sickness and unusual persistent gastrointestinal symptoms in pregnant women. Persistent unusual gastrointestinal symptoms need careful evaluation by panendoscopic examination. PMID- 7850686 TI - Intraductal mucin-hypersecreting papillary adenocarcinoma of the pancreas: a case report. AB - A 68-year-old male was admitted with jaundice and abdominal fullness. Abdominal ultrasonography and computed tomography (CT) scan showed a diffusely dilated main pancreatic duct (MPD) with microcystic lesions over the pancreatic head and dilatation of the biliary tract. Duodenoscopy revealed mucin secretion at the orifice of the papilla of Vater. Findings of endoscopic retrograde cholangiopancreatography (ERCP) were compatible with a mucinous tumor of pancreas invading the common bile duct. The patient was treated with a modified Whipple's operation. Pathological diagnosis was papillomatosis with papillary adenocarcinoma of the pancreas. PMID- 7850687 TI - Adult respiratory distress syndrome and late death following imipramine overdose: a case report. AB - Adult respiratory distress syndrome (ARDS) after tricyclic antidepressant (TCA) overdose has been reported, but has not received as much attention in the literature as hemodynamic instability, cardiac arrhythmias or seizures. This report concerns a 33-year-old female who ingested a large amount of imipramine in an attempted suicide. She developed deep coma, hypotension, cardiac dysrhythmias and seizures. Although she survived initially, ARDS developed and she died of severe hypoxia nine days later. Her lung injury may have been the result of a variety of factors including prolonged hypotension, aspiration pneumonia, sepsis or a direct action on the lung parenchyma by imipramine. The literature pertaining to etiology, epidemiology, pathophysiology and management of TCA induced lung injury has been reviewed. In one series of severe TCA overdose, an ARDS rate of 9% was reported. The risk of developing pulmonary edema and ARDS should be considered in severe TCA-poisoned patients. To try to prevent this complication, early intubation should be considered to avoid aspiration, and cautious volume loading, plus judicious use of alpha-adrenergic agonists, is indicated to prevent protracted hypotension. PMID- 7850688 TI - Bowel perforation--a fatal complication following renal transplantation: a report of two cases. AB - From May 1983 to January 1993, 162 patients received renal transplantation at Taichung Veterans General Hospital. Two patients developed bowel perforation after this surgery. One was proved at 21 days and another, at 13 days after renal transplantation. Both patients died as a direct result of the perforation. From a review of literature, the average incidence is 2.7%, and the average mortality rate is 56.5%. Because of this high mortality rate, a high clinical suspicion, prompt and adequate surgical intervention, reduction of immunosuppressive agents and effective antibiotic coverage should contribute to a decline in mortality. PMID- 7850689 TI - Right ventricular myxoma in a 12-year-old child: a case report. AB - Cardiac myxoma especially of the right ventricle, is rare in children. A 12-year old boy with right ventricle myxoma is reported. His heart murmur was found incidentally when he visited the Outpatient Department (OPD) because of upper respiratory infection symptoms. There was no exertional dyspnea, no palpitation, no syncope and no skin lesion. The echocardiogram revealed a heart tumor of about 4 x 3 cm in the right ventricle (RV) extending to the right atrium (RA). The tumor grew from the interventricular septum, resulting in an RV outlet and inlet obstruction. Magnetic resonance image (MRI) revealed a well-defined mass in the RV ventricle, with good enhancement after injecting a contrast medium. The patient received right atriotomy and total excision of the tumor with repairing of the interventricular septum base. Pathology revealed myxoma with gelatinous whitish color and central hemorrhage. At post-operative follow-up, the patient's condition was good. PMID- 7850690 TI - Epidemiology of bone loss with aging. AB - Lifespans worldwide continue to get progressively longer as we learn more about the science of aging, adopt more healthy lifestyles, and develop better technology to promote successful longevity. Unfortunately, with advanced age comes bone loss and an increased risk for skeletal fractures. Much is known about age-related changes affecting bone metabolism, but also much is yet to be explained. Obviously, becoming more knowledgeable about our skeletal system is a continuing project. Through a better understanding of the mechanisms involved in aging and bone loss, effective prevention and treatment of this major public health problem can be provided. PMID- 7850691 TI - Age-related osteoporosis. AB - Osteoporosis is an important public health problem. Over the next few years the health-care demands of osteoporosis and hip fractures are expected to increase ten-fold. In this article, the pathogenesis and classification of age-related osteoporosis are analyzed. Treatment options are examined and a rational management plan for this entity is discussed. PMID- 7850692 TI - Hip fracture. AB - One of the major factors contributing to a deterioration in the quality of life and independence of older adults is osteoporosis and hip fracture. Recent advances in our knowledge of the causes of hip fracture are providing new and effective approaches to the prevention of this disabling condition. Because hip fracture is a leading cause of disability, significant efforts have been directed to the development of strategies for the more effective rehabilitation and treatment of the fracture patient. PMID- 7850693 TI - Drug-induced bone disease. AB - Drugs can cause accelerated bone loss as well as disturbances in serum calcium levels. This article focuses on chemically induced bone diseases that commonly affect the elderly and result in either osteoporosis, osteomalacia, hypercalcemia or hypocalcemia. Also discussed are drugs that increase the risk of falls, putting those patients with osteoporosis at a greater risk for future. PMID- 7850694 TI - Treatment of osteoporosis in the elderly. AB - Fracture risk is adversely related to bone density, wherever it is measured. Women should be screened by bone densitometry around the time of the menopause and treated with calcium or hormones if the density is low. Women with vertebral compression should be treated with calcitriol if calcium absorption is low, with hormones if urine calcium is high, and with calcitriol and hormones if both abnormalities are present. It is uncertain whether newer treatments offer any advantages over this regimen. Vitamin D is indicated in household individuals or others with low levels of 25 OHD to prevent loss from secondary hyperparathyroidism and perhaps also to improve muscle power. PMID- 7850695 TI - Intracapsular fractures of the proximal femur. AB - Intracapsular fractures in the geriatric population are the result of progressive osteopenia, resulting in weakening of the bone. Minor trauma results in fracture of the weakened femoral neck. Most commonly, this process occurs in patients whose osteopenia is secondary to senile osteoporosis. The fact that the femur is osteopenic means that fixation may be difficult to achieve. However, reduction is relatively easy to obtain because of the absence of communication and the minimal displacement. PMID- 7850696 TI - Clinical presentation and treatment of arthritis in the aged. AB - Arthritis is a common condition among older individuals; osteoarthritis is the most common. Other frequently encountered conditions are rheumatoid arthritis, polymyalgia rheumatica, gout, and pseudogout. The clinical presentation of these disorders may differ from those seen in younger patients. Therapeutic modalities, such as physical therapy, medications, and surgery should be modified sometimes to accommodate age-related changes in body mechanics and function. PMID- 7850697 TI - Lumbar spinal stenosis. Diagnosis, management, and treatment. AB - Spinal stenosis presents with the patient complaining that walking a certain distance causes leg pain or leg weakness. The underlying cause is narrowing of the spinal canal, resulting in nerve root compression. The resulting claudication or leg pain is actually vascular in origin. The nerve roots cannot receive the necessary blood supply because of the mechanical compression, and that restriction is the cause of the leg pain and why the characteristic claudication leg pain presents in a fashion similar to the claudication symptoms seen with peripheral vascular disease. If the problem is severe enough, the treatment is decompression of the appropriate nerve roots. Usually decompression can be performed without any instrumentation or fusion. For certain conditions, however, these additional surgical modalities are necessary to provide the patient with a lasting good result. Several medical, social, psychological, and nutritional factors should be evaluated preoperatively. The goal of the surgery is to allow the patient to walk longer distances and, therefore, to be a more functional member of society. With appropriate treatment and preoperative medical evaluation, we find that roughly 85% of patients are significantly helped with surgical treatment, 12% feel that they are not significantly better, and 3% feel they are worse. The incidence of serious postoperative complications has been surprisingly low. PMID- 7850698 TI - Infections of the bone, joint, and bursa. AB - Infections of the skeletal system, specifically bone, joint, and bursa, cause major morbidity as well as substantial number of deaths in older patients. In this article, the discussion focuses on the cause, pathogenesis, microbial causes, diagnosis, treatment, and available preventive interventions of septic arthritis, prosthetic joint infection, setic bursitis, and osteomyelitis in elderly patients. PMID- 7850699 TI - Paget's disease of the bone. AB - Paget's Disease of the bone is the second most common bone disease affecting the older population. Many of its symptoms are often erroneously attributed to the aging process. Its diagnosis is relatively simple. Means are now available to arrest the progress of the disease and restore a normal bone architecture. PMID- 7850700 TI - Malignant skeletal neoplasms in the geriatric patient. AB - Malignant neoplasms of the geriatric skeleton are either primary or metastatic in nature. The vast majority are metastatic to the skeleton from carcinomas. Rarely, a primary skeletal malignancy, usually a chondrosarcoma or a malignant fibrous histiocytoma, develops in the geriatric patient. This article discusses the presentation, evaluation, and management of these patients. Illustrative cases are presented. PMID- 7850701 TI - Primary hyperparathyroidism. AB - Primary hyperparathyroidism is not rare. It is particularly common after the age of 50 and may affect up to 3% of postmenopausal women. It is commonly found as a result of blood tests performed for other reasons and is therefore often asymptomatic. Surgical treatment is recommended for patients with renal stone disease, plasma calcium above 3 mmol/L and accelerated bone loss (e.g., bone density < 3 standard deviations below the young normal mean). There is considerable debate about whether mild asymptomatic disease should be treated, but if there is rapid bone loss, either surgical or medical therapy with hormones or bisphosphonates is indicated. PMID- 7850702 TI - The relationship of macroscopic shape of superficial esophageal carcinoma to depth of invasion and regional lymph node metastasis. AB - BACKGROUND: There has been considerable controversy with regard to surgical strategies for the treatment of superficial esophageal carcinoma, which is characterized by tumor confined within the epithelium (EP), muscularis mucosae (MM), or submucosa (SM). The relationships among macroscopic shape, depth of invasion, and lymph node involvement in superficial tumors were investigated to devise therapeutic strategies for patients with such disease. METHODS: Thirty three patients with superficial primary esophageal cancer underwent esophagectomy with regional lymph node dissection (3 EP, 6 MM, and 24 SM). Tumors were divided into two types according to macroscopic characteristics: (1) tumors with elevated components and (2) flat or depressed tumors without an elevated component. RESULTS: Tumors with an elevated component (n = 19) showed invasion of the deep layer, and a high incidence of lymph node metastasis. Conversely, tumors without an elevated component (n = 14) showed varied depths of invasion, and, with one exception, had no lymph node involvement. CONCLUSIONS: The existence of an elevated component in superficial esophageal cancer is an important macroscopic feature suggesting submucosal invasion and a high probability of lymph node involvement. More intensive treatment should be adopted for such tumors, whereas localized resection may be feasible for tumors without an elevated component. PMID- 7850703 TI - 5-Fluorouracil/leucovorin/interferon alpha-2a in patients with advanced colorectal cancer. Effects of maintenance therapy on remission duration. AB - BACKGROUND: A Phase II study of combination treatment with 5-fluorouracil (5-FU), leucovorin (LV), and interferon alpha-2a (IFN) in patients with previously untreated metastatic colorectal cancer was previously reported by the authors. Therapy was on an outpatient basis and consisted of LV 60 mg orally every 8 hours days 1-3, IFN 18 x 10(6) IU subcutaneously days 1-3, and bolus 5-FU 750 mg/m2 intravenously days 2-3. Treatment was repeated every 14 days, until a maximum of 8 courses was administered. A response rate of 54% [95% confidence interval (CI), 34-72%] was observed. However, remission duration after cessation of therapy was short, with a median duration of 5 months (range, 2 to 13+ months). METHODS: Subsequent to the above study, patients on this induction treatment who achieved remission received maintenance therapy: the above described 3-day regimen every 6 weeks until progression, for a maximum of 2 years. RESULTS: Fifty-three patients were enrolled in the induction regimen and 18 out of 29 patients who achieved remission received maintenance treatment. In 50 assessable patients 3 complete recoveries and 26 partial recoveries were observed for a response rate of 58% (CI, 43-72%). Median remission duration of patients receiving maintenance therapy was 9.4 months (CI, 8.4-10.3 months) compared with 4.7 months (CI, 3.2-6.2 months) for patients without maintenance therapy. Median overall survival of all patients was 16.6 months. Toxicity of maintenance therapy was confined to WHO grade 2. CONCLUSIONS: The high response rate of this 5-FU/LV/IFN regimen holds true in a larger group of patients. The group that received maintenance treatment had a remission duration of just over 9 months, the maintenance regimen added little toxicity. PMID- 7850704 TI - Prognostic significance of clinically false positive cervical lymph nodes in patients with laryngeal carcinoma. AB - BACKGROUND: A significant proportion of clinically positive palpable cervical lymph nodes in patients with head and neck cancer are histologically benign. The biologic and prognostic significance of this reactive lymph node enlargement has not been fully clarified. METHODS: In this study, the incidence of clinically positive microscopically negative cervical lymph nodes in a series of 902 patients who had neck procedures as a part of their primary treatment for N0-2 laryngeal cancer was analyzed and survival rates of 342 patients with true negative lymph nodes (N0- necks) were compared with those of 106 patients with clinically false positive lymph nodes (N1-2b- necks). In 86 patients with false positive lymph nodes, a histopathologic analysis was performed to determine the histomorphologic pattern of the enlarged lymph nodes and to evaluate which parameters, if any, correlated with 5-year patient survival. RESULTS: Overall actuarial survival did not differ significantly in the two groups. However, the actuarial survival curves in the false positive group were clearly better compared with those of the true negative group with more advanced laryngeal cancers, particularly T4 lesions (P < 0.05). Interestingly, the analysis of pattern of recurrence showed a higher incidence of distant metastases in false positive patients with advanced stage laryngeal cancer than in true negative subjects. In addition, the histologic examination of 375 enlarged hyperplastic cervical lymph nodes from 86 neck specimens showed the prevalence of sinus histiocytosis in the false positive group and its favorable prognostic significance. No statistically significant differences with regard to the number and size of enlarged lymph nodes were found. On the contrary, lymph node location seems to have a prognostic impact on survival and the reactive benign enlargement of a digastric lymph node is a possible poor prognostic factor. CONCLUSIONS: Survival of patients with clinically false positive, histologically benign hyperplastic cervical lymph nodes who have more advanced laryngeal carcinoma is higher than clinically negative patients, suggesting that the presence of palpable benign nodes may be a sign of the host's immune activation, with favorable prognostic significance. PMID- 7850705 TI - Systemic relapse of patients with osteogenic sarcoma. Prognostic factors for long term survival. AB - BACKGROUND: A retrospective study of long term outcome after the development of metastases from osteosarcoma was performed, with emphasis on the impact of different treatment strategies and the identification of prognostic factors. METHODS: From 1975 to 1993, a population-based series of 60 patients with distant metastases (relapse) from high grade, extremity-localized osteosarcoma was treated at The Norwegian Radium Hospital. Six patients relapsed after surgery alone, 28 patients relapsed after primary chemotherapy of low potency, and 26 patients after modern, intensive chemotherapy. Lung metastases were present in 88% of the patients, 52% had bilateral lesions, and the median number of lesions was three (range, 1-25 lesions). Forty-seven percent of patients had complete surgical excision of all identifiable metastatic nodules and 54% of these had additional second line chemotherapy defined as adequate. Adequate chemotherapy included further dose escalations of methotrexate in approximately half of the patients, usually from 8 to 12 g. The rest were exposed to novel agents such as cisplatin, etoposide, and ifosfamide. Of the operated patients, 43% had additional thoracotomies after subsequent relapses. RESULTS: The projected 5-year survival rate from the first metastatic event was 24% for all patients and 50% for patients who underwent complete metastasectomy. In a multivariate analysis, the factors with independent predictive value for improved overall survival were the presence of a solitary metastasis, the accomplishment of complete metastasectomy, and the administration of adequate salvage chemotherapy. CONCLUSIONS: Complete metastasectomy is mandatory for long term survival of patients with metastatic osteosarcoma, and repeated lung resections are necessary in nearly half the patients. Second line chemotherapy and following primary treatment with modern intensive chemotherapy protocols may improve survival further. PMID- 7850706 TI - Telomerase activity and oncogenesis in giant cell tumor of bone. AB - BACKGROUND: Benign giant cell tumor of bone (GCT) is a primary skeletal neoplasm with an unpredictable pattern of biologic aggressiveness and cytogenetic findings characterized by telomeric associations and telomeric reduction. The role of maintaining telomeric integrity is performed by telomerase. To determine if telomerase activity is present, cell extracts from fibroblasts and tumor cells from five patients with GCT were analyzed and compared with HeLa (a positive control cell line). METHODS: Telomerase activity was detected by visualizing the extension of radioactive telomeric repeats on DNA sequencing gels. Telomere reduction was assessed using southern blot analyses of the restriction enzyme Hinf I digested DNA with a radio-labeled telomere probe. RESULTS: Telomerase or telomerase-like activity was detected in the cell extracts from HeLa and tumor cells. However, GCT telomerase activity varied and was less than that observed in HeLa, but no activity was detected from fibroblasts. In addition, telomere reduction was seen in DNA isolated from both HeLa and GCT but not in fibroblasts or age-matched controls. CONCLUSION: Telomere reduction and telomerase activity may be oncogenic sustaining events required to maintain the transformed phenotype seen in GCT. PMID- 7850707 TI - Leukemic meningitis in B-cell prolymphocytic leukemia. A clinical, pathologic, and ultrastructural case study and a review of the literature. AB - BACKGROUND: Leukemic meningitis is rare in B-chronic lymphocytic leukemia (CLL) and B-prolymphocytic leukemia (PLL); a MEDLINE search for reports published 1960 and after disclosed only nine prior reports. A patient with stable Rai Stage II CLL/PL developed mental status changes. Lumbar puncture revealed a lymphocytic pleocytosis with prolymphocytes containing intracytoplasmic inclusions. METHODS: The patient's cerebrospinal fluid lymphocyte population was analyzed by immunophenotyping and electron microscopy. RESULTS: The studies revealed a clonal population of B prolymphocytes, with typical immunophenotypic and ultrastructural characteristics. The patient was treated with intrathecal chemotherapy with eventual resolution of the cerebrospinal fluid pleocytosis and return to his normal neurologic status. Prior studies also have revealed the efficacy of intrathecal chemotherapy. CONCLUSION: Leukemic meningitis in CLL or PLL is responsive to treatment with intrathecal chemotherapy. PMID- 7850708 TI - Topotecan in chronic lymphocytic leukemia. AB - BACKGROUND: Topotecan is one of a new class of agents that targets topoisomerase I (Topo I) and stabilizes the DNA-topo1 complex, ultimately resulting in cell death. The rationale for the use of topotecan in chronic lymphocytic leukemia (CLL) is based on the finding that levels of Topo I are elevated in the lymphocytes of patients with this disease. METHODS: Twelve patients with CLL were treated with topotecan to assess its clinical efficacy; in addition, DNA-protein cross-linking was measured after exposure of the cells to topotecan, in an attempt to correlate potential anti-CLL effects with this parameter. The median age of the patients was 63 years; all had received prior therapy with fludarabine and four (33%) were resistant to fludarabine. Four patients (33%) had also received therapy with chlorambucil, and three of them were resistant to this agent. Seven patients (58%) were Rai stage I-II and five (42%) were Rai stage III IV. Topotecan was given as a 30-minute infusion at a daily dose of 2 mg/m2 for 5 days, and courses were repeated monthly. Cells were obtained from the patients before treatment and exposed to 2 microM topotecan or control in vitro. In addition, cells were obtained from patients after they received the first dose of topotecan and protein-bound DNA was measured with the same technique. RESULTS: No patient responded to therapy with topotecan (95% confidence interval, 0-27%). Nonhematologic toxicity was mild and thrombocytopenia occurred in four of eight patients whose conditions could be evaluated. One patients died of myocardial infarction and another died of fungal pneumonia. DNA-protein cross-linking was detected in all nine patients whose cells were assessed in vitro, with levels of cleavable complex ranging from twofold to 7.5-fold that of the control cells. Only two of eight patients with evaluable conditions had increased cross-linking detectable in circulating cells after the first dose of topotecan, which was consistent with the drug's lack of effect in vivo. CONCLUSIONS: Although exposure of cells from patients with CLL to topotecan in vitro at 2 microM resulted in detectable protein-DNA cross-linking, this effect was not seen in patients who received a bolus dose of 2 mg/m2, and no remissions were noted in 12 patients. PMID- 7850709 TI - Cellular schwannoma. A clinicopathologic, DNA flow cytometric, and proliferation marker study of 70 patients. AB - BACKGROUND: A clinicopathologic study of 70 cases of cellular schwannoma was performed to assess their distribution, response to therapy, and rate of recurrence relative to modern prognostic indicators. METHODS: Seventy-one cellular schwannomas from 70 patients were retrieved from the files of the Mayo Clinic Tissue Registry. The significance of mitotic index, proliferative marker staining (proliferating cell nuclear antigen and MIB1), immunochemical p53 expression, and DNA ploidy were assessed relative to tumor behavior, particularly recurrence. All parameters were subject to statistical analysis (Student's t test). RESULTS: Cellular schwannomas represented 4.6% of benign peripheral nerve tumors operated on at the Mayo Clinic. In 15% of the cases, an initial diagnosis of malignancy had been made. The median patient age was 47.7 years (range, 15-80 years) and the female-to-male ratio was 1.6:1. The principle tumor locations were the para- and intraspinal regions, including the sacrum (64%), extremities (25%), and intracranial space (8%). All tumors consisted primarily of hypercellular, compact, Antoni A tissue. Mitoses (< or = 4/10 hPF]) were observed in 71% of the cases. Foci of necrosis were noted in 11% of cases. Ultrastructural studies and immunohistochemistry clearly demonstrated features of schwannian differentiation. Surgery was the treatment in all cases. Excision was intralesional to gross total in the majority; total resection with wide margins was undertaken in three tumors, each of which had initially been considered malignant. Follow-up in 47 patients (67%) ranged from 1 to 29 years (mean, 7.7 years) and revealed recurrences in 11 patients (23.4%): no patient experienced metastasis or died of tumor. Although no correlation existed between recurrence and DNA ploidy, percent S-phase determinations, proliferation marker (PCNA, MIB1) staining, or the frequency of p53 immunoreactivity, a statistically significant correlation (P < 0.001) was observed, however, between recurrence and mitotic indices. CONCLUSION: Proliferation indices, as defined by immunochemical analysis, are not useful predictors of recurrence in cellular schwannoma. In lesions not completely resected, tumor recurrence is significantly correlated with mitotic count. The significant overall frequency of recurrence in this series is attributable to a high proportion of intraspinal and intracranial tumors. Our study confirms the benign nature of cellular schwannoma and underscores the necessity of distinguishing them from malignant peripheral nerve sheath tumors, lesions that often require adjuvant therapy. PMID- 7850710 TI - Frequent incidence of extrapulmonary sites of initial metastasis in patients with liposarcoma. AB - BACKGROUND: The vast majority of soft tissue sarcomas spread initially to the lungs and then to other sites. The lung has been the most carefully monitored organ system during routine surveillance for a metastasis. Liposarcoma is one of the most common soft tissue sarcomas and has been noted to have extrapulmonary sites of initial metastasis. This study was undertaken to investigate both the frequency and distinguishing features of initial extrapulmonary metastasis in patients with liposarcoma. METHODS: A review of 60 patients with liposarcoma treated at the Massachusetts General Hospital (MGH) from 1971 to 1990 was performed. Survival and regression analyses were used to analyze disease free intervals and prognostic factors. RESULTS: Metastatic disease occurred in 37% of patients and local failure in 17%. Among the subset of patients who underwent primary definitive surgery at the MGH, the incidence of local failure was 3%. An unusually high incidence of extrapulmonary site of first metastasis was found. Isolated extrapulmonary disease was the site of initial metastasis in 59% of patients. In contrast to patients with an initial pulmonary metastasis, patients with an initial extrapulmonary metastasis had a statistically significant (P = 0.001) longer disease free interval from diagnosis to first metastasis. CONCLUSIONS: Liposarcoma, in comparison with other soft tissue sarcomas, has a different pattern of metastatic spread, with a tendency toward extrapulmonary sites. In addition, patients with extrapulmonary metastases have a longer disease free interval compared with patients with pulmonary metastasis. PMID- 7850711 TI - Atypical fibroxanthoma versus benign and malignant fibrous histiocytoma. A comparative study of their proliferative activity using MIB-1, DNA flow cytometry, and p53 immunostaining. AB - BACKGROUND: MIB-1 was found to be detectable in formalin fixed, paraffin embedded materials with microwave treatment using Ki-67 monoclonal antibody, and immunostaining has been widely documented as a useful marker of proliferation. Because atypical fibroxanthoma (AFX) is regarded as a fibrohistiocytic tumor with an intermediate potential, the proliferative activity of AFX was compared with that of benign and malignant fibrous histiocytomas. METHODS: Thirty-eight soft tissue tumors including atypical fibroxanthoma (n = 5), benign fibrous histiocytoma (FH) (n = 17) and malignant fibrous histiocytoma (MFH) (n = 16) were examined using immunohistochemistry to determine MIB-1, DNA flow cytometry, and p53 (PAb 1801) immunostaining. RESULTS: The mean of the MIB-1 labeling index (MIB 1 LI), defined as the percentage of positive cells for more than 500 cells, was determined in an increasing order as follows: FH, 3.3 +/- 1.8; AFX, 12.2 +/- 6.3; and MFH, 21.5 +/- 10.2. However, the MIB-1 LI of each case in AFX was considerably scattered, and the MIB-1 LI of AFX and MFH overlapped each other. A DNA analysis revealed that the proliferative index (S+G2+M fraction) showed no significant correlation with the MIB-1 LI, and an aneuploid pattern was present in only five (42%) of 12 cases of MFH. p53 positivity was detected in 2 (40%) of 5 cases of AFX and 6 (38%) of 16 cases of MFH. CONCLUSIONS: Although AFX shows a lower degree in the MIB-1 LI than MFH, the MIB-1 LI shows a limited value in relation to the biologic activity of fibrohistiocytic tumors. Aneuploidy demonstrates a malignant potential in fibrohistiocytic tumors. PMID- 7850712 TI - Inadequate adherence to radiotherapy in Latina immigrants with carcinoma of the cervix. Potential impact on disease free survival. AB - BACKGROUND: Radiation therapy plays an important role in the loco-regional control of carcinoma of the cervix. Strict adherence to the radiation protocol, without the introduction of time breaks, has been shown to favorably affect loco regional control and survival, making adherence a crucial variable for optimal outcome. Because carcinoma of the cervix is a common disease among Latinas, with survival rates worse than those of other ethnic groups in this country, the pattern of adherence to the prescribed radiation treatment among Latina patients seen at Los Angeles County Hospital were studied. METHODS: The records of 69 consecutive Latina patients with cervical cancer who received radiation therapy at Los Angeles County Hospital were reviewed. Semi-structured interviews in a successive group of 30 similar patients were conducted to acquire preliminary information about their psychosocial characteristics. RESULTS: The results demonstrate inferior rates of optimal adherence to radiation treatment among Latina immigrant patients when compared with the rates reported in the literature for the general population of cervical cancer patients in United States (16 vs. 63%). Furthermore, a large subset of patients (20%) in the series elected to discontinue treatment without a medical reason. When a comparable group of Latina patients was interviewed, potential practical, psychologic, and cultural barriers to optimal care were identified. CONCLUSIONS: The results from this exploratory study support the need for further studies to document the pattern of adherence to radiotherapy in the rest of the country among this minority population. The results suggest that an intervention to improve information and adherence to radiation therapy may be necessary to assure Latinas a chance for rates of cure comparable with the national standards. PMID- 7850713 TI - Peripheral neurotoxicity of taxol in patients previously treated with cisplatin. AB - BACKGROUND: Taxol is a new anticancer drug that acts as a tubulin polymeration enhancer. Its major toxicities are myelosuppression, hypersensitivity, and mucositis, but it also induces peripheral nerve damage. The use of taxol has recently been proposed for platinum-resistant cancers, but in these cases there is a possibility of cumulative toxicity in the peripheral nervous system. METHODS: Twenty-two patients affected by a relapse of cisplatin-treated ovarian cancer were examined clinically and neurophysiologically to determine the evolution of taxol-induced peripheral somatic and autonomic neurotoxicity and the possible cumulative effect of a combination of taxol and cisplatin. Each patient was examined before, during, and after taxol treatment (using a dose of 135 or 175 mg/m2 in 3 hours every 3 weeks). RESULTS: No patients were excluded from the study because of unacceptable toxicities of any kind. The serial examinations demonstrated that taxol induced onset of (or worsening of preexisting) neuropathic symptoms and signs in almost all the patients. The features were those of a distal, symmetrical, sensory polyneuropathy due to an axonopathy. Motor nerves and the autonomic nervous system were unaffected. Taxol neurotoxicity appeared early in the course of the treatment (i.e., after three courses) and was not severely disabling. In most cases after the early onset of peripheral neuropathy, stabilization of this side effect occurred. CONCLUSIONS: Considering the low doses of taxol used in this study, the sensory nerve damage was unexpectedly severe. It appears that a cumulative, but not dose-limiting, neurotoxic effect occurs using taxol in patients previously treated with cisplatin. PMID- 7850714 TI - The Functional Assessment of Cancer Therapy (FACT) scale. Development of a brain subscale and revalidation of the general version (FACT-G) in patients with primary brain tumors. AB - BACKGROUND: This report describes the development and validation of a brain subscale for the Functional Assessment of Cancer Therapy (FACT) scale, and the revalidation of the subscales of the general version (FACT-G), which measure physical, social, family, emotional, and functional well-being and the quality of the relationship with the physician. METHODS: 101 patients with primary brain tumors, after giving informed consent, participated in the last two phases of a four-phase validation process: item generation, item reduction, validation, and reliability testing. In the validation phase, FACT-G subscale and total scores as well as the brain subscale scores were correlated with other tests of mood, response, bias, and quality of life (QOL). Test-retest reliability testing was performed with 46 patients who had primary brain tumors. RESULTS: Validity and reliability coefficients were high for the FACT-G and brain subscale, except for the comparison with a second QOL measure (FP-QLI) and the Karnofsky Performance Status (KPS). The lower scores were the result of inherent differences in the two QOL instruments and the relatively high performance status of the brain tumor patients, which restricted the KPS score range. CONCLUSION: The FACT-G has good psychometric properties supporting its broad generalizability and the brain subscale tests substantially different QOL issues than the core instrument. Use of this scale with the addition of the brain subscale provides a well rounded view of the various aspects of QOL from the patient's perspective. With modifications and further psychometric testing, the brain subscale may have broader applicability to subpopulations of patients with other brain disorders. PMID- 7850715 TI - Lack of T-cell receptor gene rearrangements in cells involved in Langerhans cell histiocytosis. AB - BACKGROUND: Studies using X-chromosome inactivation assays have recently provided evidence in support of a clonal origin of cells affected by Langerhans cell histiocytosis (LCH). A search for more specific clonal markers has led to the investigation for T-cell receptor (TCR) gene rearrangements in cells affected by LCH. METHODS: Conventional southern blot analysis was used to investigate the possibility of clonal TCR gene rearrangements in tissues affected by LCH wherever possible, otherwise, a polymerase chain reaction (PCR)-based technique was employed for amplification of rearranged joint (J) and variable (V) segments of the TCR-gamma gene including the N-region. 32P-labeled PCR products were then resolved using nondenaturing polyacrylamide gel electrophoresis. RESULTS: The results using the PCR-based technique showed a lack of clonal rearrangement of the TCR-gamma gene in affected tissues of eight patients with different stages of LCH. Southern blot analyses performed on two of these samples confirmed germline configurations at both the TCR-C-beta and delta-2 gene loci. CONCLUSIONS: There is no evidence of clonal TCR gene rearrangement in cells involved by LCH. The search for a more specific clonal marker to address whether "'LCH cells" represent a neoplastic clonal transformation of cells with differentiation toward Langerhans cell phenotype continues. PMID- 7850716 TI - Angiotropic large cell lymphoma presenting as thrombotic microangiopathy (thrombotic thrombocytopenic purpura). AB - BACKGROUND: Angiotropic large cell lymphoma is a rare lymphoproliferative disorder that affects vessels of almost all organs. Therefore, many different signs and symptoms can be observed and may delay a rapid diagnosis in these patients. However, no association between angiotropic large-cell lymphoma and thrombotic microangiopathy (TMA) has been reported so far. METHODS: The case report describes a 69-year-old female Caucasian who presented with fever, neurologic symptoms, microangiopathic hemolytic anemia, thrombocytopenia, and hyaline thrombi within small vessels. TMA was diagnosed and intense treatment, including plasma exchange and corticosteroid therapy, was initiated. Nevertheless, the patient died 3 days after admission. A postmortem examination including immunohistochemistry and molecular studies was performed. RESULTS: Autopsy revealed angiotropic large cell lymphoma with tumor cell aggregates in small vessels of the brain, myocardium, lungs, liver, small and large intestines, mesenterium, kidneys, and lymph nodes. Immunohistochemical analysis of the tumor cells showed positive reactions with B-cell markers, but negative T-cell and epithelial cell markers. Molecular studies using polymerase chain reaction with primers for the rearranged immunoglobulin heavy chain and the T-cell receptor beta chain gene confirmed the diagnosis of a monoclonal B-cell disorder. CONCLUSION: TMA can occur in association with angiotropic large cell lymphoma and, furthermore, can be its sole clinical manifestation. PMID- 7850717 TI - Carboplatin hypersensitivity in children. A report of five patients with brain tumors. AB - BACKGROUND: Carboplatin, which is used in the treatment of several childhood tumors, increasingly has been reported to cause hypersensitivity reactions, the majority reported in adults. Five cases of children with primary brain tumors who were treated with carboplatin and developed acute allergic reactions are presented. METHODS: The clinical history of each patient is described, as is the schedule, cumulative dose, and number of infusions of carboplatin, type of reaction, and retreatment. RESULTS: Four of the five patients had histologically proven low grade astrocytic tumors; three had juvenile pilocytic astrocytomas, and one had a mixed oligoastrocytoma. One patient with neurofibromatosis type I had radiographically-defined bilateral optic nerve gliomas. Three patients had prior chemotherapy, one with cisplatin. All five patients developed hypersensitivity reactions such as urticaria, facial erythema, and facial swelling after multiple infusions of carboplatin. Two were retreated with carboplatin after receiving antihistamines, but still developed a reaction. Carboplatin therapy was discontinued in all patients. CONCLUSION: The purpose of this report is to heighten awareness of this potentially serious complication of carboplatin in children so that potentially dangerous retreatment is avoided. As use of a weekly schedule of carboplatin in children with low grade gliomas increases, with planned therapy extending for more than 50 weeks, more hypersensitivity reactions are anticipated. PMID- 7850718 TI - An open-label, multicenter study of polyethylene glycol-L-asparaginase for the treatment of acute lymphoblastic leukemia. AB - BACKGROUND: L-asparaginase has been a mainstay of therapy along with vincristine and prednisone in the treatment of acute lymphoblastic leukemia (ALL) in children for almost 30 years. Because L-asparaginase is a foreign protein, the potential exists for severe, dose-limiting hypersensitivity reactions. To reduce this toxicity, L-asparaginase has been linked with polyethylene glycol (PEG). METHODS: Patients with ALL in relapse were entered in a Phase II, open-label clinical trial (ASP-201A) to evaluate the toxicity and efficacy of PEG-L-asparaginase. PEG L-asparaginase has demonstrated potential low immunogenicity and a prolonged plasma half-life relative to native enzyme. PEG-L-asparaginase (2000 IU/m2 every 2 weeks) was used as single-agent induction therapy during an initial 14-day investigational window. Thereafter, the regimen consisted of PEG-L-asparaginase, vincristine, and prednisone. Patients also were allowed to receive doxorubicin and intrathecal chemotherapy beginning on day 14. All patients had been treated previously with one or more courses of native L-asparaginase; one of these patients was hypersensitive to L-asparaginase at enrollment. RESULTS: During the 14-day investigational window with PEG-L-asparaginase monotherapy, 22% of patients examined achieved a complete or partial remission. By completion of the 35-day induction period, 78% (or 14 of 18) of evaluated patients achieved complete or partial remission. Anaphylaxis did not occur during treatment. Mild urticaria and mild local allergic reactions occurred in five patients but did not cause discontinuation of treatment. The incidence of hyperglycemia and pancreatitis was less than expected from historic data published for previous studies with native L-asparaginase. CONCLUSIONS: As administered in this study, PEG-L-asparaginase can be given safely with a spectrum of toxicity similar to that of native L-asparaginase. Single-agent activity was documented in patients with ALL in bone marrow relapse. PMID- 7850719 TI - Follicular large cell lymphoma of the testis in a child. AB - BACKGROUND: A unique case of primary testicular lymphoma in a child is reported. METHODS: Tumor tissue was studied using immunohistochemical techniques and southern blot hybridization to detect immunoglobulin and bcl-2 gene rearrangement and in situ hybridization for the Epstein-Barr virus (EBV) genome. RESULTS: Light microscopy revealed a lymphocytic infiltrate with a follicular pattern. Immunohistochemical staining revealed lambda light chain restriction and gene rearrangement studies revealed a clonal rearrangement of the immunoglobulin heavy chain, confirming a clonal neoplastic process. Immunostaining failed to detect bcl-2 protein expression, and no evidence of bcl-2 gene rearrangement was noted on southern blot analysis. In situ hybridization for EBV nucleic acid in tumor tissue was negative. CONCLUSIONS: To the authors' knowledge, this is the first report of a case of a primary testicular lymphoma with follicular histology in a child. Despite the follicular histology, no evidence of bcl-2 expression or gene rearrangement was detected. PMID- 7850720 TI - Report of the consensus workshop on screening and global strategy for prostate cancer. PMID- 7850721 TI - The World Health Organization's histologic classification of bone tumors. A commentary on the second edition. AB - BACKGROUND: The World Health Organization's histologic classification of bone tumors was revised in 1993. METHODS: The first edition was reviewed by an international panel of pathologists from nine countries and modified to incorporate advances made in the twenty years since it appeared. RESULTS: The framework and concept of the classification remain the same (i.e., based on histologic criteria in terms of differentiation shown by the tumor cells via conventional light microscopy supplemented by immunohistochemistry). New entities not described in the first edition include, for example, benign and malignant fibrous histiocytomas, well differentiated osteosarcoma, round-cell osteosarcoma, clear cell chondrosarcoma, primitive neuroectodermal tumor of bone, osteofibrous dysplasia, and giant cell reparative granuloma. CONCLUSION: The revised and expanded classification reflects advances in our knowledge, but is similar in concept and framework to the original version to allow comparisons between data collected in the past and future. PMID- 7850722 TI - The effects of cyclosporine on the pharmacokinetics of doxorubicin in patients with small cell lung cancer. PMID- 7850723 TI - Myelopathy after intrathecal chemotherapy: a case report with unique magnetic resonance imaging changes. PMID- 7850724 TI - Collaboration in nursing education. PMID- 7850725 TI - Feelin' groovy. PMID- 7850726 TI - A candle in the wind. PMID- 7850728 TI - Breaking free. PMID- 7850729 TI - [Liberating oneself by knowledge]. PMID- 7850727 TI - Tattoos: fashion statement or health risk? PMID- 7850730 TI - [Living in a remote region with a chronically ill child]. PMID- 7850731 TI - We're all human. PMID- 7850732 TI - Babble busting. PMID- 7850733 TI - Multidisciplinary teaching: the wave of the future. PMID- 7850734 TI - Medical workstations for applied imaging and graphics research. AB - We present a medical workstation for the efficient implementation of research ideas related to image processing and computer graphics. Based on standard hardware platforms the software system encompasses two major components: A turnkey application system provides a functionally kernel for a broad community of clinical users working with digital imaging devices, including methods of noise suppression, interactive and automatic segmentation, 3D surface reconstruction and multi-modal registration. A development toolbox allows new algorithms and applications to be efficiently implemented and consistently integrated with the common framework of the turnkey system. The platform is based on an elaborate object class structure describing objects for image processing, computer graphics, study handling and user interface control. Thus expertise of computer scientists familiar with this application domain is brought into the hospital and can be readily used by clinical researchers. PMID- 7850735 TI - Computerized localization of brain structures in single photon emission computed tomography using a proportional anatomical stereotactic atlas. AB - An accurate identification of cerebral structures is necessary to perform quantification of single photon emission computed tomography (SPECT). We have developed an anatomical localization system that accounts for individual brain shapes and sizes by using the Talairach proportional grid system. The locations of the commissural lines, which define the stereotactic coordinate system, are calculated from the external landmarks provided by the canthomeatal line. This is validated on MRI images. When applied to SPECT data, the use of a neuroanatomical atlas data along with the automaticity of the processing guarantees a high degree of objectivity and inter-observer reproducibility. PMID- 7850736 TI - Comparison of spiral CT and conventional CT in 3D visualization of facial trauma: work in progress. AB - Spiral computed tomography (SCT) differs from conventional CT (CCT) in that regions of the body can be rapidly imaged via continuous scanning. This is accompanied by simultaneous advancement of the patient, thus allowing volumetric data acquisition of up to 60 cm in less than a minute. Thus motion is minimized and slice misregistration is minimized when multiplanar and three dimensional reconstructions are performed. This paper compares the utility of SCT and CCT in facial trauma. A total of six patients were studied with either CCT or SCT of the face after trauma. SCT scans were obtained using a Siemens Somatom Plus-S CT scanner (2 mm thick collimation and 3 mm/sec table feed for 32 s). Three dimensional (3D) and multiplanar reconstruction images of the facial bones were generated after appropriate thresholds were selected by the radiologist; similar images generated with a CCT (GE quick 9800) were compared using a three point scale with kappa analysis. SCT is able to generate axial and reformatted images of comparable quality to CCT (k = 0.47-0.89) in less than half the time to perform an examination (26 min vs 63 min). SCT can rapidly produce (3D) and multiplanar reformatted images of facial trauma with minimal motion, or misregistration artifact when compared to CCT. PMID- 7850738 TI - Use of general purpose mechanical computer assisted engineering software in orthopaedic surgical planning: advantages and limitations. AB - Two surgical plans were developed for an appropriately complex reconstructive orthopaedic surgery case. One plan was developed with customary methods using two dimensional (2D) radiographs. The second plan was developed with general purpose mechanical computer assisted engineering (MCAE) software using x-ray computed tomography (CT) data. The limitations of each method are identified. To create a surgical plan using three-dimensional (3D) medical datasets and MCAE software, five necessary steps were identified: (a) data reduction; (b) contour extraction; (c) 3D model creation; (d) extraction of mass properties; (e) model idealization. The principal limitation of general purpose MCAE software is the lack of pre processing modules with which to address the unique requirements of medical image datasets. PMID- 7850737 TI - CT scans through metal scanning technique versus hardware composition. AB - OBJECTIVE: Streak artifact on CT scans of metal containing areas has been a long standing problem. Although several artifact reducing methods have been used to improve image quality, most have been limited by requiring specialized equipment or lengthy complex calculations that are not automated. Others have shown that increasing the beam energy results in increased thickness of metal that may be imaged by CT without severe image degradation. We have studied the image quality of bone surrounding metal both with titanium and cobalt-chrome prostheses using various scanning techniques. METHODS: In a double blind fashion, 28 radiology residents and attendings were surveyed as to the best technique for imaging bone detail surrounding metal. A series of images was arranged of an implanted titanium prosthesis, a cobalt-chrome prosthesis and a pelvis repaired with stainless steel pelvic reconstruction plates. Scans were performed using three techniques: 120 kVp, 170 mA, 2 s, 360 degrees rotation, 140 kVp, 140 mA, 3 s, 360 degrees rotation, 140 kVp, 140 mA, 4 s, 420 degrees rotation. RESULTS: Titanium was superior to cobalt-chrome (p < .0001 Wilcoxon Signed Rank Test). No advantage was noted for higher kVp or increased scan arc of 420 degrees compared to the standard 360 degrees. CONCLUSION: Titanium allows improved bone detail surround the metal than CT cobalt-chrome. We have found no advantage to using either high kVp or a 420 degrees scan arc to improve the image quality of bone surrounded by metal. PMID- 7850739 TI - Visualization and quantitative analysis of talocrural joint kinematics. AB - The three dimensional (3D) in vivo kinematic behavior of the ankle joint was evaluated using spiral volumetric CT scanning of a normal adult foot. The CT data were reconstructed and interpolated to create an isotropic 3D data volume. These data were rendered, visualized, segmented into their bony elements, labeled, and exported to disk using Mayo Analyze software. The labeled 3D CT datasets were analyzed to determine relative orientation, translation, and rotation of the tibia-talus, tibia-calcaneus and calcaneus-talus. Using these results, the 3D motion characteristics during normal adult foot flexion/extension were described quantitatively. PMID- 7850740 TI - Interactive segmentation of cerebral gray matter, white matter, and CSF: photographic and MR images. AB - Digital photography of postmortem brain slices was compared with magnetic resonance imaging (MRI) for morphological analysis of human brain atrophy. In this study, we used two human brains obtained at autopsy: a cognitively defined nondemented control (70-yr-old male) and a demented Alzheimer's disease (AD) subject (82-yr-old female). For each of two brains, interactive manual image segmentation was performed by two observers on two image sets: (a) four coronal T1-weighted MR images (5 mm slices); and (b) four digitized photographic images from comparable rostrocaudal levels. Microcomputer image analysis software was used to measure the areas of three segmented cerebral compartments--gray matter (GM), white matter (WM) and CSF--for both image types. Resegmentation error was defined as the absolute difference between the areas derived from two segmentation trials divided by the value from trial 1 and multiplied by 100. This yielded the percent difference between the area measurements from the two trials. We found intra-observer agreement was better (error rates 1-18%) than inter observer agreement (3-70%) with best agreement for WM and least for CSF, the smallest object class. MRI overestimated GM area relative to digitized photographs in the control but not the AD brain. The results define limitations of manual image segmentations and comparison of MRI with pathologic section photographic images. PMID- 7850741 TI - CT, MR, and SPECT findings in a general paresis. AB - CNS changes in a case with general paresis were investigated by X-ray computed tomography (CT), Magnetic resonance (MR), and single photon emission computed tomography (SPECT). CT and MR showed a mild degree of diffuse cortical atrophy and the dilatation of lateral ventricles with no signs of ischemic lesions or inflammations. On the other hand, SPECT using 123I-N-isopropyl-p-iodoamphetamine (123I-IMP demonstrated marked reduction of the cerebral blood flow especially in the bilateral frontal and temporal cortices. Moreover, the reduction of the blood flow was significantly improved after the antisyphilitic therapy, correlated with the improvement of the mental disorders. These observations suggested that the SPECT is a useful method to evaluate the brain dysfunctions, and to assess the effect of antisyphilitic therapy in the patients with general paresis. PMID- 7850742 TI - Primary intraosseous calvarial meningioma. AB - A case of primary intraosseous calvarial meningioma is documented by computed tomography and conventional radiography of the resected specimen. The lesion involved the frontal bone and expanded the diploic space. The process was radiodense with an internal radiating pattern that was perpendicular to the plane of the calvarium. PMID- 7850743 TI - CT demonstration of a giant adrenal endothelial cyst of the angiomatous subtype. AB - Adrenal cysts are uncommon lesions with only approximately 300 having been reported to date. Histologically, they are heterogeneous in nature with angiomatous endothelial cysts being quite rare. The computed tomography of a woman with a very large cyst of this variety displayed thin walls with a few septations and foci of soft tissue within. The possibility of a large cystic mass originating from the adrenal gland must be considered in the diagnosis when a large abdominal mass is encountered. PMID- 7850744 TI - Identification of the chromosome 12 translocation breakpoint region of a pleomorphic salivary gland adenoma with t(1;12)(p22;q15) as the sole cytogenetic abnormality. AB - Cell line Ad-312/SV40, which was derived from a primary pleomorphic salivary gland adenoma with t(1;12)(p22;q15), was used in fluorescence in situ hybridization (FISH) analysis to characterize its translocation breakpoint region on chromosome 12. Results of previous studies have indicated that the chromosome 12 breakpoint in Ad-312/SV40 is located proximally to locus D12S8 and distally to the CHOP gene. We here describe two partially overlapping yeast artificial chromosome (YAC) clones, Y4854 (500 kbp) and Y9091 (460 kbp), which we isolated in the context of a chromosome walking project with D12S8 and CHOP as starting points. We present a composite long-range restriction map encompassing the inserts of these two YAC clones and show by FISH analysis that both YACs span the chromosome 12 breakpoint as present in Ad-312/SV40 cells. Subsequently, we have isolated cosmid clones corresponding to various sequence-tagged sites (STSs) mapping within the inserts of these YAC clones. These included cRM51, cRM69, cRM85, cRM90, cRM91, cRM110, and cRM111. In FISH studies, cosmid clones cRM85, cRM90, and cRM111 appeared to map distally to the chromosome 12 breakpoint, whereas cosmid clones cRM51, cRM69, cRM91, and cRM110 were found to map proximally to it. These results assign the chromosome 12 breakpoint in Ad 312/SV40 to a DNA region of less than 165 kbp. FISH evaluation of the chromosome 12 breakpoints in five other pleomorphic salivary gland adenoma cell lines indicated that these are located proximally to the one in Ad-312/SV40, at a distance of more than 0.9 Mbp from STS RM91. These results, while pinpointing a potentially critical region on chromosome 12, also provide evidence for the possible involvement of 12q13-q15 sequences located elsewhere. PMID- 7850745 TI - Translocation (1;16) identified by chromosome painting, and PRimed IN Situ labeling (PRINS). Report of two cases and review of the cytogenetic literature. AB - We used the molecular cytogenetic in situ techniques chromosome painting and PRimed IN Situ labeling (PRINS) to elaborate the cytogenetic observations in two cases of the rare aberration der(16)t(1;16), which occurs in a wide variation of hematologic and nonhematologic malignancies [1-3]. Review of the literature showed that, in contrast to the chromosome 1 breakpoint, the breakpoint on chromosome 16 is associated with diagnosis as well as patient age. PMID- 7850746 TI - Involvement of natural killer cells in chronic myeloid leukemia. AB - We assessed the involvement of natural killer (NK) cells in chronic myeloid leukemia (CML). We adopted the MAC (morphology antibody chromosomes) method, which allows simultaneous assessment of cell morphology, immunophenotype, and chromosome aberrations in the same mitotic or interphase cells. We examined three patients with CML in chronic phase and two patients with the disease in blast crisis. Patients in the chronic phase of the disease showed no involvement of NK cells, but involvement was detected in one of the patients in blast crisis. In this patient, a proportion of the B cells and lymphoid stem cells was also neoplastic, whereas mature postthymic T cells were normal. PMID- 7850747 TI - The clonal nature of mediastinal germ cell tumors and acute myelogenous leukemia. A case report and review of the literature. AB - The clonal identity of a mediastinal germ cell malignant tumor and acute myelogenous leukemia is described in an 11-year-old boy in whom both tumors presented simultaneously. The relationship between these two histologically distinct malignancies is discussed in relation to this patient and 34 previously reported patients. PMID- 7850748 TI - Deletion 20q in association with Philadelphia chromosome positive acute lymphoblastic leukemia. A report of two cases. AB - Cytogenetic deletions involving the long arm of chromosome 20 are thought to be characteristic of myeloid disorders. We report clinical and cytogenetic observations of two adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia: one with a smaller 20q deletion that was the sole cytogenetic abnormality in a persisting remission clone, the other with a larger 20q deletion that was a late addition to the leukemic clone at disease relapse following allogeneic bone marrow transplantation. PMID- 7850749 TI - Selection of adrenal tumor cells in culture demonstrated by interphase cytogenetics. AB - Solid tumors often consist of an admixture of cell populations with different genome constitutions. Karyotyping of this material is complicated by the low mitotic index. Even when chromosome studies are feasible, altered representation of the original cell populations after cell cultivation is possible. We report a human adrenal carcinoma that exhibited a normal karyotype after cultivation but was shown to be highly aneuploid when investigated by fluorescence in situ hybridization (FISH) in direct preparations of uncultured cells with six different centromeric probes. The high frequencies of trisomy for the investigated chromosomes in these interphase cells indicate that most of the tumor cells were in the triploid range. Strong selection for disomic cells was detected in interphase preparations after one and two subcultures and was even stronger in the corresponding metaphase preparations. Trisomy for chromosome 15 appeared to be maintained independent of triploidy and might play a role in cultured cell survival. The number of chromosome 17 centromeres was not increased in polyploid cells, suggesting loss of this chromosome in the original cells of the tumor. PMID- 7850750 TI - Structural instability of a transmissible end-to-end dicentric chromosome in a xeroderma pigmentosum fibroblast clone. AB - Cytogenetic analysis was performed in a fibroblast clone (XP9UV25) selected for anchorage-independent growth from an XP strain of normal origin and characterized by the presence of clonal chromosome rearrangements. A dicentric chromosome involving the 5p and 16q telomeric regions was observed in XP9UV25 cells at the fifth passage from colony isolation and at successive passages. The specific anomaly was present with increasing frequency (from 22 to 60% of mitoses) during culture propagation, undergoing rearrangements that gave rise to: 1) (5;16) dicentrics with deletions or duplications of the intercentromeric region; 2) homodicentrics for chromosomes 5 or 16, either end-to-end associations or rearranged; and 3) derivative 5p+ and 16q+ monocentric chromosomes. The frequency of other anomalies involving other chromosomes was negligible. These findings represent the first demonstration that a telomeric association leads to a variety of balanced and unbalanced chromosome rearrangements. These rearrangements may result from asymmetric interchanges between sister chromatids, "bridge-breakage fusion" events during cell division, breakage and reunion of isochromatids, and breakage followed by healing of the ends. The type of anomaly and the sequence of karyotypic changes we observed in the XP9UV25 clone and their mechanisms of origin may be the same as those occurring during transformation from diploidy to aneuploidy in neoplastic cells. PMID- 7850751 TI - Mutational activation of ras genes is absent in pediatric osteosarcoma. AB - Activation of ras oncogenes is found in human cancers; overall it is observed in 15% of all neoplasms. The purpose of this study was to assess the extent of involvement of ras oncogenes in osteosarcoma. Tumor samples from a series of 49 pediatric patients diagnosed with osteosarcoma and treated at our institution were evaluated. Paraffin-embedded tumor samples from diagnostic biopsies, from tumor en bloc resection tissue after neoadjuvant chemotherapy, and samples from metastases were examined in search of point mutations in H, K, and N-ras genes at codons 12 and 61 by means of polymerase chain reaction (PCR), slot-blotting, and radioactive labeled specific DNA probes. A total of 92 archival samples were studied. No point mutations activating these genes were found. These findings suggest that the activation by point mutations at codons 12 and 61 of the H, K, and N-ras genes does not play a role in the pathogenesis of human osteosarcoma. Since no point mutations in codons 12 and 61 were detected, it was not possible to establish any correlation between the ras genes and clinical or histologic findings. PMID- 7850752 TI - Chromosomal characteristics of tumorigenic cells derived from a spontaneous uterine leiomyosarcoma of the Chinese hamster. AB - A tumorigenic cell line (CHAUT) derived from a spontaneous uterine leiomyosarcoma of the Chinese hamster was established, and two clones (CHAUT-C and CHAUT-G) were characterized cytogenetically by both G- and C-band techniques. In both clones, all cells analyzed (53 in the C clone and 65 in the G clone) were distributed within a diploid range (24-26) with a modal number of 25. Their karyotypes were also characterized by four common changes; translocation of heterochromatic segment onto chromosome 2, tetrasomy of chromosome 10, monosomy of X chromosome, and one to three additional marker chromosomes of unknown origin. PMID- 7850753 TI - Clonal evolution of an immunoblastic type non-Hodgkin's lymphoma with der(6)t(1;6)(q11;p11) as its primary cytogenetic abnormality. AB - Recurrent pleural effusions from a 45-year-old man who was diagnosed as having non-Hodgkin's lymphoma of immunoblastic type were studied cytogenetically. The majority of the metaphases were tetraploid, but there were also lymphoma cells observed with pseudodiploid chromosome constitutions. Cytogenetic analysis by G banding revealed the existence of at least two cell populations. The karyotype of the minor pseudodiploid clone, which exhibited partial trisomy of 1q11qter and monosomy of 6p11pter as sole abnormalities, was 46,XY,der(6)t(1;6)(q11;p11). The karyotype of the major clone was 92,XXYY,-1,der(6)t(1;6)(q11;p11)x2, +9. The ancestral diploid clone, carrier of the balanced translocation involving chromosomes 1 and 6, was not observed even in the first pleural effusion harvest. The high proportion of tetraploid cells in the recurrent effusions was an indication that these cells were favorably selected in the environment of the somatic cavity. Our cytogenetic findings suggest that partial trisomy of 1q may be a crucial secondary chromosomal abnormality in highly malignant non-Hodgkin's lymphoma. This genetic imbalance was predetermined from the primary abnormality and may be responsible for further tumor progression, as suggested from the clonal evolution in this particular case and, therefore, may be associated with the aggressive biologic behavior of malignant cells. PMID- 7850754 TI - Satellite I DNA in transformed rat cells. AB - P93-50, a 93-basepair (bp) repetitive DNA sequence from rats, was hybridized to transformed sublines of rat endothelial origin. The sequence hybridized at or near the centromeres of most but not all chromosomes in two transformed cell lines and three single-cell derived cultures. The hybridization signal was also frequently present at the telomeres. These cell lines have a highly aberrant karyotype including dicentric and multicentric chromosomes; however, even though this sequence labeled the centromere regions of some chromosomes, it did not hybridize with the telomere regions of the cell line XC, which rarely shows any dicentrics. Apparently, the telomere signals represent prematurely separating, inactive, terminal centromeres. The p93-50 sequence does not influence the timing of centromere separation, nor it is necessary for formation of heterochromatin. PMID- 7850755 TI - Elevated frequency of a SstI polymorphism of the Ets-1 oncogene in non-Hodgkin's lymphoma patients. AB - We studied the frequency of a SstI polymorphism of the Ets-1 oncogene in 100 patients with non-Hodgkin's lymphoma, 44 patients with Hodgkin's disease, 49 patients with chronic myeloid leukemia, and 100 controls. There was no difference in the genotype frequency between the controls and patients with either Hodgkin's disease or chronic myeloid leukemia. In contrast, there was a highly significant difference in the distribution of the three genotypes between the patients with non-Hodgkin's lymphoma and the controls (X2 = 10.76, 2df, p = 0.004) with the C2 allele being more frequent in the lymphoma patients. Molecular cloning indicated that the polymorphic SstI site lay 304 bp from exon 7. This is the second association of the SstI polymorphism of the Ets-1 oncogene with a lymphoid disorder and suggests that the presence of the C2 allele is associated with a predisposition to develop a lymphoid malignancy. PMID- 7850756 TI - Loss of heterozygosity on the short arm of chromosome 17 in uterine cervical carcinomas. AB - DNA samples from 26 cervical carcinoma and normal tissue pairs were studied by restriction fragment length polymorphism (RFLP) analysis to determine the frequency of loss of heterozygosity (LOH) on 17p. Allelic loss in the p13.1 region of chromosome 17, known to contain the TP53 locus, was not detected in any of 10 informative cases. Instead, LOH was detected on 17p13.3 in eight (40%) of 20 informative cases with at least one of two 17p13.3 markers. Examination of the intragenic region of p53 in the same samples using polymerase chain reaction (PCR)-RFLP analysis showed no LOH in the gene (none of 16 informative individuals). PMID- 7850757 TI - Myelodysplastic syndrome in a child with constitutional trisomy 8 mosaicism and normal phenotype. AB - Trisomy 8 is a frequently acquired cytogenetic abnormality in myeloid malignancies, but may also represent a constitutional chromosome abnormality with a wide phenotypic variation. We report a case of myelodysplastic syndrome (MDS) that developed in a child with trisomy 8 mosaicism and normal phenotype. Bone marrow (BM) cells all showed trisomy 8 with additional clonal abnormalities in most cells. Based on the present case and a review of previously published cases of myeloid malignancies in patients with trisomy 8 mosaicism, it appears likely that the malignant cells developed from the trisomic cell population, suggesting that constitutional trisomy 8 may be a predisposing condition to myeloid malignancies. Trisomy 8 in malignant cells is usually considered an acquired abnormality, but this implies a risk of ignoring a constitutional trisomy 8 mosaicism. Examination for constitutional trisomy 8, despite a normal phenotype, may therefore be warranted in hematologic malignancies with trisomy 8 of BM cells to evaluate further the possible association and to preclude erroneous use of trisomy 8 as a tumor marker. PMID- 7850758 TI - Characterization of chromosome 8 abnormalities by fluorescence in situ hybridization in childhood B-acute lymphoblastic leukemia/non-Hodgkin lymphoma. AB - Using fluorescence in situ hybridization (FISH), we studied chromosome 8 abnormalities in 30 children with mature B-cell acute lymphoblastic leukemia (B ALL) or B-cell non-Hodgkin lymphoma (B-NHL). FISH was performed on metaphase spreads and interphase nuclei with a whole chromosome 8 painting probe. Fifteen patients were studied retrospectively after metaphases from the malignant cell specimen had already been G-banded. When interphase nuclei were examined, FISH was able to confirm t(8;14)(q24;q32) in all nine patients positive by previous G banding. FISH, however, was positive in metaphase spreads from only seven patients. Another 15 patients were included in a prospective study. In six of them (40%), a translocation involving chromosome 8 was shown by a split small segment (8q24-8qter) on interphase nuclei. Analysis of metaphase spreads showed only three positive cases each by FISH or G-banding, respectively, with corresponding results in two patients. By interphase FISH, trisomy of chromosome 8 also was detectable. In three patients shown by G-banding to have trisomy, interphase FISH study showed high scores of three chromosome 8 signal positive cells. There was no cross-hybridization to other chromosomes interfering with FISH analysis. FISH analysis on interphase nuclei using a whole chromosome 8 hybridization probe will supplement and can be more sensitive than metaphase cytogenetic techniques for detection of chromosome 8 rearrangements in B-ALL/NHL. PMID- 7850759 TI - First report of t(8;21)(q22;q22) in a case of de novo acute monoblastic leukemia. AB - Here we describe the case of a 30-year-old man with a diagnosis of de novo acute monoblastic leukemia (FAB M5a), whose karyotype analysis revealed the presence of the translocation (8;21)(q22;q22) as the sole chromosome anomaly. In spite of the rather good prognosis patients suffering from acute leukemia and carrying this translocation are supposed to have, our patient had a very poor outcome, including an early relapse resistant to any treatment and meningeal localization. Death occurred within 5 months from diagnosis. To our knowledge this is the first report of t(8;21)(q22;q22) in de novo acute monoblastic leukemia. PMID- 7850760 TI - Sister chromatid exchange analysis in acute leukemia patients. AB - This study was made to show the effects of acute leukemia (AL) and cytostatic drug therapy on chromosomes by sister chromatid exchange (SCE) analysis. Metaphase preparations from peripheral blood lymphocytes (PBL) of 15 patients [13 with acute nonlymphocytic leukemia (ANLL) and one with acute lymphocytic leukemia (ALL), and one with Hodgkin's disease (HD)] were harvested before and after treatment. Mean SCE frequency in the cells was 12.07 +/- 0.15 before therapy and was 14.04 +/- 0.32 after therapy as compared with 7.87 +/- 0.60 in controls. SCE values of patients with AL were significantly higher than those of controls, and this was more conspicuous in the cells that had undergone anticancer treatment. PMID- 7850762 TI - Involvement of chromosome 7 in Wilms tumor. AB - Cytogenetic and molecular analysis of Wilms tumors have led to the identification of two regions on the short arm of chromosome 11 (11p13 and 11p15) involved in tumor development. Recent studies have provided evidence that an additional locus on 16q is also involved. Further molecular testing may reveal additional loci associated with the development or progression of this tumor. Reports of single chromosome abnormalities in tumors generally pinpoint regions of interest that may be involved in the etiology of the tumor. We present an additional case of Wilms tumor with an isochromosome 7q as the sole cytogenetic change, resulting in loss of 7p and gain of 7q material. PMID- 7850761 TI - Intermediate lymphocytic lymphoma with both t(14;19)(q32.3;q13.1) and t(3;22)(q27;q11.2). AB - Chromosome translocations involving various chromosomes sites, including the sites of immunoglobulin loci (14q32,2p12,22q11) represent recurrent aberration in non-Hodgkin lymphoma (NHL). We report a novel case of intermediate lymphocytic lymphoma (ILL) with both t(14;19)(q32.3;q13.1) and t(3;22)(q27;q11.2). The t(14;19)(q32.3;q13.1) and t(3;22) (q27;q11.2) may represent reciprocal recombinations between immunoglobulin (Ig) H chain gene (14q32.3) and bcl 3(19q13.1) and between Ig lambda chain gene (22q11.2) and bcl-6 (3q27), respectively. PMID- 7850763 TI - Serendipity of Philadelphia chromosome. PMID- 7850764 TI - Lung cancer pathology in smokers, ex-smokers and never smokers. AB - The histologic distribution of lung cancer is markedly different in smokers and non-smokers. It is not known whether the histology among former smokers varies according to the number of years since quitting. Using data from a large case control study of lung cancer, we found that for both men and women, the proportion of adenocarcinomas increased with the number of years since quitting smoking. Among long-term quitters (> 25 years), the proportion of adenocarcinomas was similar to that in never smokers. These findings have implications for studies of environmental tobacco smoke and lung cancer. PMID- 7850765 TI - Induction of apoptosis in chronic myelogenous leukemia lymphocytes by hydroxyurea and adriamycin. AB - The nature of the cytotoxic effects of the anticancer drugs hydroxyurea, adriamycin, cisplatin and interferon, was studied on lymphocytes obtained from chronic myelogenous leukemia (CML) subjects prior to the commencement of chemotherapy. These drugs appeared to mediate their cytotoxic effects by the process of apoptosis as observed from the morphological changes, i.e., cell shrinkage, chromatin condensation, cell membrane blebbing, and also from the cellular damage and DNA fragmentation into oligonucleosomal ladder of 180-bp multiples, which are all characteristics of apoptotic cell death. The effect was much more marked by hydroxyurea and adriamycin. Maximum sensitivity was seen at 24 h post treatment. Untreated CML lymphocytes cultured for 24 h also showed some apoptosis. PMID- 7850766 TI - Cellular accumulation of antineoplaston AS21 in human hepatoma cells. AB - Antineoplaston AS2-1 is a mixture of sodium salts of phenylacetic acid (PAA) and phenylacetylglutamine (PAG) in the ratio 4:1. The uptake of both compounds has been examined in human hepatoma cell line, Hep G-2. The accumulation of PAA was characterized by temperature sensitivity, saturability and energy dependency. Organic anions (probenecid, p-aminonohippuric acid and stilbene) inhibited PAA uptake suggesting the involvement of organic anion system in PAA transport. PAG cellular uptake exhibited dependency on metabolic energy, since the accumulation was sensitive to lowered temperature as well as to replacement of sodium ions by choline in the incubation medium. In contrast, the process showed tolerance to lithium ions as a substitute to sodium ions. This finding, together with the strong inhibition of PAG accumulation by histidine and glutamine, indicates that system N, known to be specific for hepatic tissue and the glutamine-preferring amino acid transport system, mediates PAG uptake. We conclude that PAG, through competition with glutamine for the same membrane carrier, may reduce glutamine transport leading to intracellular glutamine depletion. The physiological consequence of this biochemical event could be critical to cancer cells and therefore might contribute to the mechanism of antineoplaston AS2-1 action. PMID- 7850767 TI - The usefulness of severe combined immunodeficiency (SCID) mice to study human carcinogenesis. AB - In the present study, we engrafted normal colonic epithelial and histologically diagnosed colonic adenomas from a familial adenomatous polyposis (FAP) patient into severe combined immunodeficient (SCID) mice and subsequently examined them histologically and molecular biologically. Successful engraftment and metastasis was observed. The facts that human normal colonic epithelium and adenomatous polyps can take in SCID mice indicates the possibility that this human SCID mouse system will be useful for investigating the dynamics of human carcinogenesis in various tissues. PMID- 7850768 TI - Chromophore-enhanced laser-tumor tissue photothermal interaction using an 808-nm diode laser. AB - A diode laser was used to irradiate tumor tissue, with indocyanine green as the chromophore. The 808-nm wavelength radiation falls within the absorption peak of the chromophore (about 780 nm). The preliminary results in this report revealed clear and significant coupling of this laser and indocyanine green in laser tissue photothermal interaction. The chromophore targeted tissue showed laser damage while peripheral tissues remained intact. Without the chromophore, this laser inflicted no apparent tissue damage in the non-contact mode with irradiance up to 1755 J/cm2. PMID- 7850769 TI - The effects of tumour growth on circulating amino acids in the late pregnant rat. AB - The implantation of a rapidly-growing tumour--the AH-130 Yoshida ascites hepatoma -to late pregnant rats resulted in important changes in both the maternal and fetal amino acid concentrations. Increased concentrations of most amino acids- glycine, alanine, threonine, serine, proline, glutamate+glutamine, valine, leucine, isoleucine, phenylalanine, tyrosine and lysine--are found in the fetal circulation, the concentration of total and essential amino acids being clearly higher than in the non-tumour bearing controls. In the maternal circulation, the presence of the tumour also caused increases in the concentration of glycine, lysine, glutamate+glutamine and arginine. Conversely, tumour-bearing rats had lower concentrations of threonine, serine, aspartate+asparagine, valine, leucine, phenylalanine and histidine. These results support the described increased fetal availability of amino acids during tumour growth (Carbo, N., Lopez-Soriano, F.J. and Argiles, J.M. (1994). In the late pregnant rat, tumour growth results in an increased availability of fetal amino acids. Biochem. J., in press) and allow us to suggest that important changes in placental amino acid transport systems must be induced by tumour burden. PMID- 7850770 TI - Sulofenur cytotoxicity and changes in cytosolic calcium and mitochondrial membrane potential in human colon adenocarcinoma cell lines. AB - Sulofenur treatment (12.5 microM-1 mM) of colon adenocarcinoma cell lines resulted in dose- and time-dependent cell killing. LYc5 cells were viable longer than GC3/c1 cells. Each concentration resulted in elevation of cytosolic calcium [Ca2+]i) for both cell lines. At lower doses, elevation was delayed for LYc5 cells. GC3/c1 cells after 1 mM treatment in Ca(2+)-free HBSS showed no rise of [Ca2+]i. GC3/c1 cells after carbonyl cyanide-m-chlorophenylhydrazone rapidly lost rhodamine 123 fluorescence from mitochondria; after 1 mM sulofenur, fluorescence faded slowly. Following treatment, cells became rounded, blebs formed and the cells died. Results suggest that elevated [Ca2+]i plays an important role in sulofenur cytotoxicity. PMID- 7850771 TI - Inhibition of protein kinase C by a synthetic peptide corresponding to cytoplasmic domain residues 828-848 of the human immunodeficiency virus type 1 envelope glycoprotein. AB - This report describes the inhibition of protein kinase C (PKC) by a synthetic peptide corresponding to a viral sequence expressed in mammalian cells. The peptide corresponds to cytoplasmic domain residues 828-848 of the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (gp41), and it inhibits Ca(2+)- and phosphatidylserine (PS)-dependent phosphorylation of synthetic peptide substrates and histone by purified PKC with IC50 values ranging from 9 to 32 microM. Although previously described pKC-inhibitory synthetic peptides corresponding to sequences expressed in mammalian cells are also effective against the phosphorylation of synthetic peptide substrates, they fail to affect PKC-catalysed phosphorylation of potent protein substrates such as histone. This may limit their usefulness as inhibitors of PKC-catalysed protein phosphorylation in cellular systems. PKC activation is a major contributing factor in multidrug resistance (MDR) in cancer. Our observation that the synthetic peptide gp41(828-848) inhibits pKC-catalysed phosphorylation of a protein substrate suggests the potential value of expressing the viral sequence gp41(828-848) in cancer cells as a novel in vitro model system of MDR reversal. PMID- 7850772 TI - Biodistribution of haematoporphyrin analogues in a lung carcinoma model. AB - In an attempt to identify novel compounds useful for the optimization of Photodynamic Therapy (PDT), the tissue localization of new synthetic porphyrins was compared with Photofrin II in nude mice xenografted with a human small cell lung cancer (POVD). Three haematoporphyrin analogues were selected for this study based on prior in vitro photosensitivity screening of a series of 15 such derivatives, as well as on the basis of improved localization in C6 gliomas in mice. Two of the porphyrins yielded better tumour:normal lung ratios than Photofrin II and, of these two, one (P13) is known to exhibit good photosensitization properties both in vitro and in vivo, and is therefore a good candidate as a lead compound for the development of porphyrins suitable for the photodynamic treatment of lung tumours. PMID- 7850773 TI - Binding affinities of highly repetitive DNA components for a nuclear scaffold protein from rat-ascites hepatoma cells. AB - Separate samples of a self-ligated tandem dimer of a highly repetitive DNA component (369-bp HindIII fragment) from rat-ascites hepatoma nuclei were digested with different restriction enzymes that cleave only once in the monomer. The resulting 369-bp sequence-permuted monomers showed anomalously slow gel electrophoretic mobility. Of them, the XmnI fragment had the slowest mobility. This suggests that bending of the helix axis is the strongest in this fragment. Our previous work has shown that such a repetitive bent DNA has selective affinities for two nuclear scaffold proteins from rat liver that have molecular weights of 123,000 and 130,000 Hibino et al. (1992) Biochem. Biophys. Res. Commun., 184, 853-858; Hibino et al. (1993) Biochim. Biophys. Acta, 1174, 162 170). In the present experiment, it has been found that the nuclear scaffold fraction from rat-ascites hepatoma cells does not contain these proteins, but does have a repetitive bent DNA-binding protein that has a molecular weight of about 230,000. These results imply that there is some difference in the structure of nuclear DNA attachment region between rat liver and the hepatoma. PMID- 7850774 TI - Effect of cadmium on human ovarian cancer cells with acquired cisplatin resistance. AB - Cadmium (Cd) dichloride is a compound that has teratogenic, mutagenic, and carcinogenic properties. Recent reports have suggested the possibility that this compound may also have tumor suppressive properties in some settings. For these reasons, we have studied the subcellular pharmacological profile of elemental cadmium in human ovarian cancer cells, when administered as cadmium dichloride. The cell lines A2780 and A2780/CP70 were used, which are well characterized with respect to their cellular response to platinum-based compounds. Cd was measured in all experiments with the use of atomic absorbance spectrometry with Zeeman background correction. In both cell lines, there were direct relationships between; drug dose and cellular accumulation of drug; cellular accumulation of drug and DNA damage levels; and DNA damage levels and cytotoxicity. These cell lines differed in that the cisplatin-resistant A2780/CP70 cell line, was also comparatively resistant to cadmium dichloride. This enhanced cellular resistance appeared to be mediated through decreased drug accumulation, and increased cellular tolerance to higher levels of DNA damage. Total genomic DNA repair and cytosolic inactivation of drug appeared not to differ substantively between these two cell lines. PMID- 7850775 TI - Increased levels of laminin in ascitic fluid of patients with ovarian cancer. AB - Laminin is a component of the extracellular matrix and is associated with tumor cell metastasis. Present studies show that the ovarian cancer cell lines produce significant amounts of laminin (54-140 ng/ml) in culture. Since ovarian cancer is associated with ascites production, laminin levels were then determined in ascites and serum. The results indicate that the ascites from patients with serous adenocarcinoma of the ovary had higher levels of laminin than the normal peritoneal fluid (P < 0.0001). However, the serum levels of laminin did not differ significantly between the control population and ovarian cancer patients. PMID- 7850776 TI - CEA-mediated homotypic aggregation of human colorectal carcinoma cells in a malignant effusion. AB - This study was performed to clarify the role of carcinoembryonic antigen (CEA) in the aggregation of colorectal carcinoma (CRC) cells in malignant effusions. We analysed freshly purified CRC cells from one patient, which expressed CEA (98% positive cells) on the surface and formed huge cell aggregates in the patient's ascites. The carcinoma cells expressed Sialyl Lewis A (82%), Sialyl Lewis X (92%) and the beta 1 integrin subunit (78%) but did not express the pair-ligands for these molecules. Cell aggregation was completely inhibited by anti-CEA mAb. The decreased CEA expression induced by phosphatidylinositol-specific phospholipase C (PI-PLC) treatment led to decreased cell aggregation. We also examined the correlation between the degree of cell aggregation and CEA expression using smears of ascites fluid from 27 patients with colorectal cancer. There was a significant correlation between the degree of cell aggregation and CEA expression by CRC cells. The present study provided the first evidence that CEA molecules mediate the homotypic aggregation of CRC cells in malignant effusions. PMID- 7850777 TI - Induction of teratocarcinoma F9 cell differentiation with cis-diammine dichloroplatinum(II) (CDDP). AB - cis-Diammine dichloroplatinum(II) (CDDP) is the salt of a platinum compound which has been noted to have a wide spectrum of activity against malignant disorders. We have studied the effects of CDDP on embryonal carcinoma F9 cell differentiation. In the presence of this agent in vitro, the cells showed rapid morphological changes, a marked increase in the mRNA expression of various differentiation markers accompanied by a loss of tumorigenicity. These results indicate that the differentiation of F9 cells is induced with CDDP. PMID- 7850778 TI - Intracellular Ca2+ mediates the cytotoxicity induced by bepridil and benzamil in human brain tumor cells. AB - The effects of bepridil and benzamil, known Na(+)-Ca2+ exchange blockers, on the growth of human brain tumor cells were evaluated using SK-N-MC human neuroblastoma and U-373 MG human astrocytoma cells as model cellular systems. These drugs induced cytotoxicity in both cells in a dose-dependent manner. Agonist (2% fetal bovine serum) alone induced a rapid increased intracellular Ca2+ concentration and then it returned to the basal level. However, the pretreatments of these drugs resulted in a more sustained high intracellular Ca2+ concentration mobilized by an agonist. Moreover, BAPTA/AM, an intracellular Ca2+ chelator, significantly blocked the cytotoxicity induced by these drugs. These results suggest that bepridil and benzamil act as effective inhibitors of in vitro growth of human brain tumor cells and that intracellular Ca2+ may be involved in the mechanism of actions of these agents. PMID- 7850779 TI - Expression of variant dihydrofolate reductase with decreased binding affinity to antifolates in MOLT-3 human leukemia cell lines resistant to trimetrexate. AB - Various alterations of the dihydrofolate reductase (DHFR) gene are involved in resistance. In order to understand the mechanism that induce such gene alterations in human leukemia cells, we studied the expression products of DHFR gene in trimetrexate (TMQ)- and/or methotrexate (MTX)-resistant sublines derived from a MOLT-3 human leukemia cell line. A 200-fold TMQ-resistant subline (MOLT 3/TMQ200) expressed the mutated DHFR mRNA, with a base change (T-->C) at the second position of codon 31, as well as the wild type gene. A MTX-resistant subline derived from MOLT-3/TMQ200 (MOLT-3/TMQ200-MTX500) showed a further increase in the expression of the mutated DHFR mRNA, compared to MOLT-3/TMQ200, with a marked decrease of expression of the wild type DHFR mRNA, which is confirmation of amplification of the mutated DHFR gene. By contrast, a 10,000 fold MTX-resistant subline (MOLT-3/MTX10,000) over-expressed the wild type DHFR mRNA, which is confirmation of amplification of the wild type gene. Increased levels of the DHFR enzyme in these sublines were proportional to expression levels of the DHFR mRNA. The DHFR enzyme expressed in MOLT-3/TMQ200-MTX500 cells showed a 40-fold increase in the Ki values for both MTX and TMQ, compared with values for the wild type DHFR expressed in both MOLT-3/MTX10,000 and its parent cell line. These findings suggest that the altered DHFR gene, which was introduced in MOLT-3 cells by exposure to TMQ, gave rise to a variant enzyme with reduced affinity to antifolates, and that complex DHFR alterations confer drug resistant phenotypes in antifolate-resistance. Structural difference between the antifolates could be important in the introduction of the differential DHFR gene alterations in the antifolate resistance. PMID- 7850780 TI - Lack of correlation of N-myc gene amplification with prognosis in localized neuroblastoma: a Pediatric Oncology Group study. AB - Multiple copies of N-myc proto-oncogene are only rarely detected in localized neuroblastomas (NBs), and the prognostic relevance of amplification in this subset of patients is not clear. We analyzed a series of 850 children with NB admitted to a Pediatric Oncology Group NB Biology Study and identified six patients with localized NBs harboring N-myc gene amplification. Three patients whose tumors showed favorable histology by Shimada classification and low-risk histological features according to the Joshi classification have remained disease free, whereas two of three patients with unfavorable histology tumors have developed recurrent disease. Although earlier studies have indicated that N-myc amplification is associated with diploid DNA content, flow cytometric analysis revealed that only two of the localized tumors contained stem lines with diploid DNA content. Loss of chromosome 1p was not detected by fluorescence in situ hybridization in the two tumors examined. N-myc protein was detected by immunohistochemical studies in four of the five NBs analyzed. However, N-myc protein was not visualized in one of the tumors with stroma-rich histology, and Western blot analysis revealed only low levels of N-myc protein expression in another NB with favorable histology. These studies indicate that the presence of N-myc amplification in localized NBs does not necessarily portend an adverse outcome. Furthermore, the biological features of this subset of N-myc-amplified NBs appear to differ from those of more advanced N-myc-amplified tumors. PMID- 7850781 TI - Amplification at 12q13-14 in human malignant gliomas is frequently accompanied by loss of heterozygosity at loci proximal and distal to the amplification site. AB - We have recently reported that a subset of human malignant gliomas shows amplification and overexpression of multiple genes from chromosomal segment 12q13 14, including CDK4, SAS, and MDM2. In the present study we have performed an allelotyping for 16 polymorphic loci spanning both arms of chromosome 12 in a series of 136 gliomas. Allelic deletions were found in 50% (7 of 14) of the malignant gliomas with 12q13-14 amplification and involved loci located on 12q proximal and distal to the amplification site. In contrast, the incidence of allelic loss on chromosome 12 was significantly lower in gliomas without 12q13-14 amplification [14% (11 of 79) in the WHO grade III and IV gliomas, 9% (4 of 43) in the WHO grade I and II gliomas]. The frequent association between 12q13-14 amplification and loss of alleles from 12q is in line with a model suggesting chromosome breakage and deletion as important events in the development of gene amplification. PMID- 7850782 TI - Androgens induce resistance to bcl-2-mediated apoptosis in LNCaP prostate cancer cells. AB - We describe an in vitro model for prostate cancer treatment that suggests a potential benefit for combined androgen ablation and cytotoxic chemotherapy. Androgen treatment of the LNCaP hormone-dependent human prostate cancer cell line induces increased expression of the BCL-2 protein. Increased levels of this protein are known to mediate inhibition of apoptosis. LNCaP cells, however, did not undergo apoptosis in response to androgen withdrawal. Etoposide exerts its cytotoxicity on LNCaP and other cells by inducing apoptosis. In vitro etoposide cytotoxicity was diminished 83% in the presence of either 10(-8) M dihydrotestosterone or 10(-9) M R1881 in LNCaP cells. The interaction between androgen and etoposide was mediated through the BCL-2 protein, since bcl-2 antisense oligonucleotides blocked the protective effect of androgens on etoposide cytotoxicity. PMID- 7850783 TI - Enhancement of hyperthermic killing in L5178Y cells by protease inhibitors. AB - We have investigated the effect of protease inhibitors on hyperthermic cell killing using cultured mammalian cells (L5178Y) and found that protease inhibitors were potent hyperthermia sensitizers. At 37 degrees C, phenylmethylsulfonyl fluoride (PMSF), a serine protease inhibitor, was not cytotoxic at the concentration of 400 micrograms/ml for up to 6 h. When cells were exposed to PMSF (200-400 micrograms/ml) during heating at 43 degrees C, significant potentiation of hyperthermic cell killing was observed. Other protease inhibitors, such as chymostatin and diisopropylfluorophosphate (both are serine protease inhibitors); (2S,3S)-trans-epoxy-succinyl-L-leucylamido-3 methylbutane ethyl ester (cysteine protease inhibitor) and pepstatin-A (aspartate protease inhibitor) showed similar effects. However, when cells were heated at 43 degrees C in the presence of cycloheximide (a protein synthesis inhibitor) together with PMSF, hyperthermic enhancement by PMSF decreased markedly. A decrease in potentiating the effect of PMSF was also noted with thermotolerant cells. These facts suggest that protease inhibitors may exert their hyperthermic cell killing by inhibiting proteases and ubiquitin, which are necessary to degrade denatured proteins induced by heat. PMID- 7850784 TI - Cloning and characterization of a mouse gene with homology to the human von Hippel-Lindau disease tumor suppressor gene: implications for the potential organization of the human von Hippel-Lindau disease gene. AB - The human von Hippel-Lindau disease (VHL) gene has recently been identified and, based on the nucleotide sequence of a partial cDNA clone, has been predicted to encode a novel protein with as yet unknown functions [F. Latif et al., Science (Washington DC), 260: 1317-1320, 1993]. The length of the encoded protein and the characteristics of the cellular expressed protein are as yet unclear. Here we report the cloning and characterization of a mouse gene (mVHLh1) that is widely expressed in different mouse tissues and shares high homology with the human VHL gene. It predicts a protein 181 residues long (and/or 162 amino acids, considering a potential alternative start codon), which across a core region of approximately 140 residues displays a high degree of sequence identity (98%) to the predicted human VHL protein. High stringency DNA and RNA hybridization experiments and protein expression analyses indicate that this gene is the most highly VHL-related mouse gene, suggesting that it represents the mouse VHL gene homologue rather than a related gene sharing a conserved functional domain. These findings provide new insights into the potential organization of the VHL gene and nature of its encoded protein. PMID- 7850785 TI - Camptothecin and taxol: discovery to clinic--thirteenth Bruce F. Cain Memorial Award Lecture. AB - Camptothecin and taxol are secondary metabolites found, respectively, in the wood bark of Camptotheca acuminata, a native of China, and Taxus brevifolia, found in the northwest Pacific coastal region of the United States. The compounds were isolated guided by bioassay on various extracts and chromatographic fractions. Their unique and hitherto unknown structures were elucidated by nuclear magnetic resonance, mass spectrometry, and X-ray analysis. Both compounds have unique mechanisms of antitumor activity; camptothecin uniquely inhibits an enzyme, topoisomerase I, involved in DNA replication. Taxol binds to a protein, tubulin, thus inhibiting cell division. Taxol has been called the best new anticancer agent developed from natural products, showing particular efficacy against ovarian cancer. Camptothecin and analogues singly or combined with cisplatin show efficacy against solid tumors, breast, lung, and colorectal, which hitherto have been unaffected by most cancer chemotherapeutic agents. PMID- 7850786 TI - Hepatic glycerol metabolism in tumorous rats: a 13C nuclear magnetic resonance study. AB - Cancer cachexia contributes to the demise of a significant number of cancer patients, and severe loss of adipose tissue is a prominent component of this syndrome. One of the products of fat catabolism is glycerol, and its turnover is elevated in the cancerous state. Since glycerol is also one of the most important gluconeogenic substrates, its role in the augmented and abnormal gluconeogenesis of cancer hosts needs to be defined. In the present study, we examined hepatic glycerol metabolism in livers of Fischer 344 rats bearing s.c. nonmetastatic adenocarcinoma R3230AC. Five weeks after tumor inoculation, the liver was removed and perfused with 5 mM [2-13C]glycerol while 13C nuclear magnetic resonance spectroscopy was performed. In the livers of tumorous rats, we found: (a) lipogenesis from glycerol was augmented; (b) the rate of hepatic glycerol uptake was unchanged; (c) glucose production from glycerol was not altered; and (d) conversion of glycerol 3-phosphate to dihydroxyacetone phosphate remains the rate limiting step. Therefore, it appears that, in cancer hosts, diminished glycerol clearance is not due to reduction in hepatic glycerol uptake or metabolism, and the abnormal gluconeogenesis involves the pathway prior to the entry of glycerol. The exaggerated lipolysis is probably used for the pathological hepatomegaly, and the availability of the cytosolic hydrogen acceptor remains the rate-limiting factor for glycerol metabolism. PMID- 7850787 TI - Purification and characterization of the platelet-aggregating sialoglycoprotein gp44 expressed by highly metastatic variant cells of mouse colon adenocarcinoma 26. AB - A platelet-aggregating sialoglycoprotein with a molecular weight of 44,000 (gp44) was immunochemically purified from highly metastatic mouse adenocarcinoma cells. The rat monoclonal antibody (mAb) 8F11 used in the purification procedure has been generated previously against NL-17 cells derived from the mouse colon 26 cell line, mAb 8F11 inhibits NL-17 cells from inducing platelet aggregation and suppresses their experimental metastasis to the lung. The purified gp44 induced mouse platelet aggregation in a dose-dependent manner without any plasma component. This aggregation was completely inhibited by mAb 8F11. The gp44 was partially characterized by sequential enzymatic hydrolysis of carbohydrates and was found to be O-glycans enriched. When gp44 was sequentially treated with N glycanase and neuraminidase, it lost platelet aggregation activity. Further treatment with O-glycanase resulted in a loss of the reactivity to mAb 8F11. These results suggest that sialylated carbohydrate chains of gp44 are involved in the induction of platelet aggregation and may play an important role in the colonization of NL-17 cells in the lung. PMID- 7850788 TI - Translocation of protein phosphatase 1 catalytic subunits during 1,25 dihydroxyvitamin D3-induced monocytic differentiation of HL-60 cells. AB - To elucidate the roles of protein phosphatases type 1 (PP1) and type 2A (PP2A) in 1,25-dihydroxy-cholecalciferol [1,25(OH)2D3]-induced differentiation of HL-60 cells into monocytes, we examined the enzyme activity and the protein and gene expressions of PP1 and PP2A in these cells. Calyculin-A augmented the 1,25(OH)2D3 induced differentiation of the cells. Treatment of the cells with 1,25(OH)2D3 led to a decrease in PP1-like activity in the cytosol fraction, with a concomitant increase in the membrane and nuclear PP1-like activity, as determined when protein phosphatase activity was assayed using myosin light chain as substrate in the presence of 5 nM okadaic acid. Western blot analysis with antibodies specific for PP1 catalytic subunit isozymes (PP1 alpha, PP1 gamma, and PP1 delta) showed that all three PP1 isozymes were expressed but were differentially distributed in each cellular fraction. Subcellular redistribution of PP1-like activity during 1,25(OH)2D3-induced differentiation was mainly attributed to PP1 gamma and PP1 alpha proteins. In contrast, the localizations of PP1 delta and PP2A catalytic and regulatory subunits were not significantly affected by 1,25(OH)2D3 treatment. The gene expressions of PP1 alpha and PP1 gamma appeared to be constant during processes of monocytic differentiation. The correlation between phenotypic and functional changes of HL-60 cells on the one hand and subcellular redistribution of PP1-like activity on the other suggest that the translocations of PP1 alpha and PP1 gamma isozymes may contribute to the 1,25(OH)2D3-induced monocytic differentiation of HL-60 cells. PMID- 7850789 TI - Beta-2 microglobulin is mitogenic to PC-3 prostatic carcinoma cells and antagonistic to transforming growth factor beta 1 action. AB - Previous studies have identified a M(r) 12,000 protein in rat prostatic stromal cell-conditioned medium with growth stimulatory activity to human prostatic carcinoma cells as a direct match with beta 2-microglobulin (beta 2-m). The present study was conducted to characterize the activities of human beta 2-m directly, using commercially available, purified human beta 2-m. Beta 2-m was assayed for growth stimulatory activity to human PC-3 prostatic carcinoma cells and rat PS-1 prostatic stromal cells and for antagonistic activity to transforming growth factor beta 1 (TGF-beta 1)-induced growth inhibitory actions. Beta 2-m acted to stimulate [3H]thymidine incorporation in PC-3 cells in a linear, concentration-dependent and saturable manner in serum-free medium. Beta 2 m stimulated cell proliferation and significantly decreased population doubling times in both PC-3 and PS-1 cell lines. At half-maximal concentrations of TGF beta 1 and lower, beta 2-m acted in a concentration-dependent, antagonistic manner, acting to stimulate growth-inhibited PC-3 cells to fully neutralize TGF B1 activity. In contrast, cells exposed to maximum activity TGF-beta 1 concentrations were refractory to beta 2-m action, regardless of the concentration tested. This represents the first report to demonstrate a growth stimulatory activity of B2-m with carcinoma/epithelial cells and to show beta 2-m antagonistic activity to TGF-B1 growth-induced inhibition. Beta 2-m has been shown previously to associate with hormone/growth factor receptors. Together, these data suggest that beta 2-m may play a role in modulating cell proliferation, possibly through modification of ligand/receptor kinetics. Owing to the elevation of both beta 2-m and TGF-beta 1 in many dysplastic-neoplastic conditions, beta 2-m may be relevant to mechanisms of abnormal proliferation disorders and in modulating TGF-beta 1 mechanisms of actions. PMID- 7850790 TI - Fetus-specific CYP3A7 and adult-specific CYP3A4 expressed in Chinese hamster CHL cells have similar capacity to activate carcinogenic mycotoxins. AB - To assess whether CYP3A4 and CYP3A7 have a similar capacity to activate carcinogenic mycotoxins, we established cell lines stably expressing human CYP3A4 and CYP3A7, which are adult- and fetal-specific forms of cytochrome P450 in human livers, respectively. Each cDNA was introduced into CR-119 cells which had been established by introducing guinea pig NADPH-cytochrome P450 reductase cDNA into Chinese hamster lung cells. The cell lines (4-line and 7-line) stably expressed the mRNA and the protein corresponding to CYP3A4 and CYP3A7, respectively. The concentration-response for aflatoxin B1 (AFB1) cytotoxicity in 4-line and 7-line, respectively, was compared. 4-10 and 7-40 cells were approximately 17- and 20 times more sensitive to AFB1 than the parental CR-119 cells, respectively. In addition, the sensitivities to AFB1 of both 4-10 and 7-40 cells were enhanced approximately seven times by the addition of 10 microM alpha-naphthoflavone, a known activator of CYP3A enzyme, while the sensitivities were suppressed approximately four times by the addition of 100 microM troleandomycin, which forms a metabolite intermediate complex with CYP3A enzyme. Moreover, both cell lines showed approximately 10 and 2 times higher sensitivity to sterigmatocystin and aflatoxin G1 than CR-119 cells, respectively. These results indicate that CYP3A4 and CYP3A7 have essentially similar capacities to activate AFB1, sterigmatocystin, and aflatoxin G1 to produce toxic metabolites. PMID- 7850791 TI - Behavior of crocidolite asbestos during mitosis in living vertebrate lung epithelial cells. AB - Asbestos has been described as a physical carcinogen in that long thin fibers are generally more carcinogenic than shorter thicker ones. It has been hypothesized that long thin fibers disrupt chromosome behavior during mitosis, causing chromosome abnormalities which lead to cell transformation and neoplastic progression. Using high-resolution time lapse video-enhanced light microscopy and the uniquely suited lung epithelial cells of the newt Taricha granulosa, we have characterized for the first time the behavior of crocidolite asbestos fibers, and their interactions with chromosomes, during mitosis in living cells. We found that the keratin cage surrounding the mitotic spindle inhibited fiber migration, resulting in spindles with few fibers. As in interphase, fibers displayed microtubule-mediated saltatory movements. Fiber position was only slightly affected by the ejection forces of the spindle asters. Physical interactions between crocidolite fibers and chromosomes occurred randomly within the spindle and along its edge. Crocidolite fibers showed no affinity toward chromatin and most encounters ended with the fiber passively yielding to the chromosome. In a few encounters along the spindle edge the chromosome yielded to the fiber, which remained stationary as if anchored to the keratin cage. We suggest that fibers thin enough to be caught in the keratin cage and long enough to protrude into the spindle are those fibers with the ability to snag or block moving chromosomes. PMID- 7850792 TI - Bioactivation of aromatic amines by recombinant human cytochrome P4501A2 expressed in Ames tester strain bacteria: a substitute for activation by mammalian tissue preparations. AB - The most widely used bioassay in genetic toxicology is the Ames test, which combines a bacterial mutagenicity assay (reversion of Salmonella typhimurium histidine-auxotrophic tester strains) with an exogenous bioactivation system (hepatic postmitochondrial supernatant or "S9"). The enzymatic activities of S9 prepared from the tissues of experimental animals are difficult to control. We show that the requirement for S9 can be obviated by the engineered expression of enzymes of bioactivation within the bacterial cell. With this strategy, reactive metabolites are produced inside the bacterial cell, proximate to the genetic target. Species boundaries can be crossed, and chimeric or mutant enzymes can be studied. We have constructed an Ames tester strain, expressing both aromatic amine N-acetyltransferase and human cytochrome P4501A2, which detects aromatic amine mutagenicity in the absence of S9. PMID- 7850793 TI - Cyclophosphamide metabolism in children. AB - The alkylating agent cyclophosphamide is a prodrug which is metabolized in vivo to produce both therapeutic and toxic effects. Cyclophosphamide metabolism was investigated in 36 children with various malignancies. Concentrations of cyclophosphamide and its principal metabolites were measured in plasma and urine using a quantitative high-performance TLC method. The results indicated a high degree of inter-patient variation in metabolism. In contrast to previous adult studies on urinary metabolites, plasma carboxyphosphamide concentrations did not support the existence of polymorphic metabolism. Plasma concentrations of dechlorethylcyclophosphamide and carboxyphosphamide were correlated in individual patients, suggesting that the activity of both aldehyde dehydrogenase and cytochrome P450 enzyme(s) determine carboxyphosphamide production in vivo. The presence of ketocyclophosphamide in plasma was strongly associated with dexamethasone pretreatment and was also accompanied by a high clearance of the parent drug. Interpatient differences in metabolism reflect individual levels of enzyme expression and may contribute to variation in clinical effect. PMID- 7850795 TI - Expression of the messenger RNAs for luteinizing hormone-releasing hormone (LHRH) and its receptor in human ovarian epithelial carcinoma. AB - Recently we reported the presence of specific high affinity binding sites for luteinizing hormone-releasing hormone (LHRH) and its analogues (Kd = 1.5 or 1.7 nM) in the human epithelial ovarian cancer cell lines EFO-21 and EFO-27. The proliferation of these cell lines was inhibited by nM concentrations of a LHRH agonist. This study was performed to ascertain whether these ovarian cancer cell lines produce LHRH and whether the high affinity LHRH binding site found previously was identical to the pituitary LHRH receptor. Significant amounts of immunoreactive LHRH were found in the extracts of both the EFO-21 cell line (449 +/- 56 fmol/10(6) cells) and the EFO-27 line (409 +/- 76 fmol/10(6) cells). LHRH bioactivity of these extracts, assessed in terms of release of luteinizing hormone by rat pituitary cells, was comparable to that of authentic LHRH. EFO-21 and EFO-27 cells expressed the mRNAs for both human LHRH and human LHRH receptor as assessed by reverse transcriptase-PCR using oligonucleotide primers according to published sequences. In addition, in eight of eight biopsy samples of human epithelial ovarian cancers we detected mRNA for LHRH, six of these specimens expressed the mRNA representing the LHRH receptor. These data support the concept that human epithelial ovarian cancers might have a local system based on LHRH to regulate cell proliferation. It is still obscure at present whether LHRH produced locally has a stimulatory, inhibitory, or no impact on the proliferation of ovarian cancer cells. However, exogenous LHRH agonists seem to have clear antiproliferative activity, probably mediated through LHRH receptors. This finding might provide the base for novel approaches in the therapy of epithelial ovarian cancer. PMID- 7850794 TI - Nonlinear pharmacokinetics of cyclophosphamide in patients with metastatic breast cancer receiving high-dose chemotherapy followed by autologous bone marrow transplantation. AB - The pharmacokinetics of cyclophosphamide has been evaluated in 15 patients with metastatic breast cancer undergoing high-dose chemotherapy with alkylating agents followed by autologous bone marrow transplantation. Each patient received two courses of chemotherapy: 4 g/m2 of cyclophosphamide by 90-min infusion prior to peripheral blood progenitor cell collection (the first course) and 6 g/m2 of cyclophosphamide with 800 mg/m2 of thiotepa by 96-h constant infusion before marrow and stem cell reinjection (the second course). In the first course, plasma cyclophosphamide concentration-time data of 9 of 15 patients were fit by a one compartment model with Michaelis-Menten saturable elimination in parallel with first-order renal elimination. The mean (SD) Vmax and Km values were 1.47 (0.89) microM/min and 575 (347) microM, respectively. The first course data of the remaining six patients were fit using first-order elimination only. In the second drug course, plasma cyclophosphamide disposition curves of 13 of 15 patients demonstrated a decline in concentration following attainment of an initial steady state. The plasma cyclophosphamide disposition data of these patients were fit by a one-compartment pharmacokinetic model, in which the decline of plasma cyclophosphamide concentration after reaching the initial steady state was modeled as being due to an increase in the clearance rate of cyclophosphamide. The mean (SD) initial and final clearance rates were 51 (16) ml/min and 106 (48) ml/min, respectively. Michaelis-Menten elimination was not apparent in the second course because the plasma concentration of cyclophosphamide was much lower. The mean renal clearance rate was 17 ml/min in the first course and 16 ml/min in the second course. Urinary excretion of cyclophosphamide accounted for 17% and 23% of the total dose administered in the first and the second course, respectively. No change in cyclophosphamide clearance rate was apparent in a patient who was taking phenytoin, but a change was present in a patient who was taking phenobarbital. A drug interaction between cyclophosphamide and thiotepa may explain the smaller initial clearance rate for cyclophosphamide during the second drug course. PMID- 7850796 TI - Inhibition of AIDS-Kaposi's sarcoma cell proliferation following retinoic acid receptor activation. AB - Retinoids, a group of natural and synthetic vitamin A analogues the receptors of which belong to the superfamily of steroid receptors, can exert profound effects on growth and/or differentiation of embryonic and neoplastic cells. Kaposi's sarcoma (KS), previously a rare multicentric neoplasm, has become epidemic with HIV infection, although the etiology of KS remains obscure. In the present study, the effects of two potent retinoids, all-trans-retinoic acid (RA) and 13-cis-RA, on the expression of retinoic acid receptor alpha and the growth of AIDS-related KS (AIDS-KS) cells were examined. The proliferation of AIDS-KS cells was significantly inhibited by RA and 13-cis-RA in a dose-dependent manner with 50% inhibitory concentration of 1.4 x 10(-10) M and 4.7 x 10(-9) M, respectively, which correlate with their potency. Growth inhibition was time dependent with maximal inhibition of 90% after 3 days of treatment with 10(-8) M RA. Growth inhibition by RA was further potentiated by forskolin (1 microM), an intracellular cyclic AMP-inducing agent. Moreover, RA treatment blocked the proliferative effect of oncostatin M and tumor necrosis factor alpha, two major KS autocrine growth factors. The effects of RA were accompanied by a dramatic increase in nuclear staining for retinoic acid receptor alpha and in the relative number of strongly positive retinoic acid receptor alpha nuclei. Finally, RA induced morphological changes as KS cells became more flattened, better spread, and more adhesive to the substrate. These results suggest that retinoids inhibit proliferation of AIDS-KS cells and further support their utility as therapeutic agents in AIDS-KS. PMID- 7850797 TI - Biological characterization of a novel antitumor quinolone. AB - A-84441, a potent new antitumor quinolone, was active in vitro and in vivo against murine and human tumors. A-84441, a prodrug, was comparable in potency to the parent compound with an IC50 range of 0.03-0.49 microgram/ml against a panel of murine and human tumor cell lines. The parent compound bound mammalian DNA in a magnesium-dependent manner and caused inhibition of DNA and RNA synthesis. A 84441 produced a significant increased life span and cures in three lines of i.p. implanted murine tumors. A-84441 was active against seven of nine solid tumors including s.c. murine tumors and human tumor xenografts. The compound appeared to be more active when administered i.v. compared to i.p. injection. Antitumor efficacy was little effected by treatment schedule, although multiple divided dosing was generally more effective than single dose treatment. A-84441 was over 10-fold-more active against murine leukemic cells than against normal murine bone marrow cells. The acute toxicity of A-84441 following single or multiple dosing ranged between 11 and 50 mg/kg dependent on schedule of administration when given by i.v. or i.p. route. The agent had no apparent toxicity or efficacy when administered p.o. PMID- 7850798 TI - Identification of a point mutation in the folate receptor gene that confers a dominant negative phenotype. AB - UM-SCC-38 cells, a squamous cell carcinoma cell line of the head and neck, express limited amounts of folate receptor alpha antigen which is not capable of binding either folic acid or 5-methyltetrahydrofolic acid. Three distinct mutations in the open reading frame of the folate receptor were identified. We now show that the three mutants are nonfunctional with respect to folic acid binding because the protein products do not bind folate. Additionally, a study of MA104 cells (a receptor-positive cell line) transfected with each mutant was done. Expression of one mutant, FR-67, results in a dominant negative phenotype because folate binding is significantly reduced although membrane antigen is significantly increased. Coexpression of FR-67 and the normal protein in MA104 cells also results in large, bright clusters of receptor protein inside the cell around the nucleus when visualized using indirect immunofluorescence. These clusters are not found in cells that express either normal or FR-67 protein alone. In conclusion, this study provides the first evidence of a mutant folate receptor protein capable of affecting normal receptor function in a dominant negative manner. PMID- 7850799 TI - Differential effects of N-(4-hydroxyphenyl)retinamide and retinoic acid on neuroblastoma cells: apoptosis versus differentiation. AB - Retinoids exert various important biological effects in the control of normal growth, differentiation, and fetal development. While retinoic acid (RA) has entered clinical trials as a differentiation-promoting agent, it is only recently that the synthetic retinoid N-(4-hydroxyphenyl)retinamide (HPR) has been shown to be of potential clinical interest in cancer chemoprevention and treatment. Since thus far no data exist on the effects of HPR on neural crest cell-derived tumors, we have examined its in vitro effects on neuroblastoma (NB) cell lines and found that at relevant pharmacological concentrations it induces a dose-dependent growth inhibition. The antiproliferative effects of HPR were, in six of six cell lines tested, drastically more potent that those induced by an equimolar dose of RA. Time course growth analysis showed that HPR at 3 x 10(-6) M induces a very rapid (24-72 h) fall in thymidine uptake (> 90%), whereas at 3 x 10(-7) M it exhibits cytostatic effects. In contrast to RA, HPR did not show morphological changes typical of NB cell maturation nor did it induce the expression of any cytoskeletal protein associated with neuronal differentiation. DNA flow cytofluorimetric analysis revealed that HPR did not induce an arrest in a specific phase of the cell cycle while triggering apoptosis. This phenomenon was evidenced both by the visualization of "DNA ladders" on gel electrophoresis and by a quantitative assay for evaluating programmed cell death based upon the labeling of DNA breaks with tritiated thymidine. With the latter method, apoptotic cells were detectable as early as 3-6 h after treatment of NB cells with 10(-5) M HPR, while more than 50% of cells were apoptotic by 24-72 h following exposure to 3 x 10(-6) M HPR. In contrast, RA induced a low rate of apoptosis in NB cells only after 3-5 days. Time lapse photomicroscopy showed that NB cells treated with HPR underwent a death process highly reminiscent of apoptosis, with progressive condensation of the cytoplasm around the nucleus and intense cell shrinkage. The cells then rounded up and detached from the plate. Furthermore, propidium iodide staining of the DNA showed that a high proportion of cells treated with HPR displayed a small and brightly staining nucleus; chromatin appeared aggregated into dense masses in the nuclear periphery, a typical feature of apoptotic cells. In conclusion, our study demonstrates that contrary to the differentiation-promoting activity of RA, HPR dramatically suppresses NB cell growth by inducing programmed cell death.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7850800 TI - Efficacy of the quinocarmycins KW2152 and DX-52-1 against human melanoma lines growing in culture kand in mice. AB - Quinocarmycin monicitrate (KW2152) and its analogue, DX-52-1, demonstrated specificity for melanomas in the National Cancer Institute in vitro human tumor cell line drug screen. In contrast to most cell lines, a 50% reduction in tumor cell burden (as measured protein) at the end of a 48-h drug incubation was produced in five of eight melanoma lines by KW2152 concentrations (LC50s) ranging from 0.49 to 10.93 microM and by DX-52-1 concentrations ranging from 0.71 to 7.33 microM. Using the COMPARE algorithm, the patterns of differential cytotoxicity for both agents at the LC50 level of effect most closely resembled those for actinomycin D, mithramycin, and Adriamycin. In in vivo studies, both KW2152 (40 mg/kg/day) and DX-52-1 (90 mg/kg/day) caused partial and complete regressions of staged s.c.-implanted LOX IMVI melanoma xenografts following i.p. administration on days 5, 9, and 13 and produced tumor growth delays of 231 and 181%, respectively (P < 0.001). Activity was augmented by more prolonged therapy. Statistically significant growth inhibition of SK-MEL-2, UACC-62, UACC-257, and M14, but not SK-MEL-5 and MALME-3M, melanoma xenografts also was observed following every fourth or seventh day i.p. treatments. Based on these findings, DX-52-1 has been selected by the National Cancer Institute for development to clinical trial especially against melanomas. This agent represents one of the first to be selected for preclinical development based on disease-panel specificity discovered in the National Cancer Institute cancer drug screen. PMID- 7850801 TI - Effect of inhibitors of poly(ADP-ribose) polymerase on the induction of GRP78 and subsequent development of resistance to etoposide. AB - We have recently demonstrated that cell lines deficient in poly(ADP-ribose) synthesis due to deficiency in the enzyme poly(ADP-ribose) polymerase (PADPRP) or depletion of its substrate NAD+ overexpress GRP78. Furthermore, this overexpression of GRP78 is associated with the acquisition of resistance to topoisomerase II-directed drugs such as etoposide (VP-16); (S. Chatterjee et al., Cancer Res., 54: 4405-4411, 1994). Thus, our studies suggest that interference with NAD+-PADPRP metabolism could provide an important approach to (a) define pathways of GRP78 induction, (b) study the effect of GRP78 on other cellular processes, (c) elucidate the mechanism of GRP78-dependent resistance to topoisomerase II targeted drugs, and (d) modulate responses to chemotherapy in normal and tumor tissues. However, in the in vivo situation, it is impractical to interfere with NAD+-PADPRP metabolism by mutational inactivation of PADPRP or by depletion of its substrate NAD+. Therefore, we have examined several inhibitors of NAD+-PADPRP metabolism including 3-aminobenzamide, PD128763, and 6 aminonicotinamide for their ability to reproduce the results obtained with cell lines deficient in NAD+-PADPRP metabolism relative to the induction of GRP78 and subsequent development of resistance to VP-16. Our studies show that 6 aminoicotinamide treatment is highly effective in the induction of GRP78 and subsequent development of resistance to VP-16, whereas treatment with 3 aminobenzamide or PD128763 does not induce GRP78 and thus does not result in VP 16 resistance. PMID- 7850802 TI - Effect of L-10B-p-boronophenylalanine-fructose and the boron neutron capture reaction on mouse brain dopaminergic neurons. AB - Radiation damage to the dopamine tracts caused by enriched L-10B-p boronophenylalanine (L-10BPA)-fructose and the boron neutron capture reaction was investigated using the mouse model. Following various treatments with L-10BPA and neutron irradiation of the head, the brain was perfusion fixed and removed; 50 microns frozen sections were cut. Dopaminergic neurons were visualized using immunohistochemistry for tyrosine hydroxylase. The administration of L-10BPA had no permanent effect on dopaminergic tracts. Neutron capture therapy with L-10BPA caused a reduction in tyrosine hydroxylase immunohistochemical activity within 4 h of irradiation, but by 48 h, this reduction reversed. No damage was observed at 120 h postirradiation. PMID- 7850803 TI - Effect of the extent of chelate substitution on the immunoreactivity and biodistribution of 2IT-BAT-Lym-1 immunoconjugates. AB - Trial therapy for lymphoma with the radiolabeled chelate-antibody conjugate 67Cu 2IT-BAT-Lym-1 has been promising. It is desirable to deliver therapeutic doses of radiometal using a minimum amount of 2IT-BAT-Lym-1 to minimize the risks of adverse patient reaction and antigenic response to antibody. This is readily accomplished by increasing the number of metal-binding sites (i.e., chelating agents) conjugated per antibody, but the ability of the antibody to bind antigen and target tumor cells in vivo must not be impaired by the conjugation reaction. To determine the maximum chelator:antibody ratio (c/a) of 2IT-BAT-Lym-1 at which functional integrity is preserved, immunoconjugates with a c/a of 1.3-23 were prepared and examined by radioimmunoassay and competitive antigen binding versus lightly iodinated Lym-1. The biodistribution in tumored mice of conjugates with c/a of 2.1, 4.3, 8.4, and 11.4 also was examined. Conjugates with c/a up to 5 exhibited no loss of immunoreactivity, and conjugates with c/a up to 11 retained 75% or greater immunoreactivity relative to unmodified Lym-1. All conjugates examined competed less effectively than did unmodified Lym-1 for antigen binding, but the effect at c/a 5 was slight. Tumor uptake declined with increasing c/a, but the effect was insignificant at c/a 2.1 and 4.3. Conjugates of c/a 4-5 were found to be optimal for the preparation of radioimmunoconjugate of high specific activity with minimal, if any, loss of functional integrity. PMID- 7850805 TI - Frequent microsatellite alterations on chromosome 3p in esophageal squamous cell carcinoma. AB - By the microsatellite assay, two types of genetic alterations, loss of heterozygosity (LOH) and replication error (RER), were examined using 7 dinucleotide repeat markers [D3S1317 (3p26); CI3-1169 (3p25); CI3-946 (3p25); D3S1255 (3p24.2-25); CI3-771 (3p21.3); CI3-1413 (3p14.1-14.3); and CI3-373 (3p13)] on the short arm of chromosome 3p as well as 3 markers [D2S123 (2p15-16), IFNA (9p22), and D16S408 (16q12.1-13)] on other chromosomes in 35 patients with esophageal squamous cell carcinoma. On 3p, LOH was detected in 34% (12 of 35) and RER was detected in 60% (21 of 35) at single or multiple loci. RER occurred at a similar frequency in all stages and did not correlate with clinicopathological characteristics. On the other hand, LOH at the 3p25 locus was more frequently detected in carcinomas with lymph node metastasis than in those without it (P < 0.05). The incidences of microsatellite alterations were low on the chromosomes other than 3p, except at D2S123, where the incidence of RER was 20%. These findings suggest that RER on 3p is an early event and that a tumor suppressor gene which is involved in the progression of esophageal squamous cell carcinoma may exist near the 3p25 locus. PMID- 7850804 TI - Treating tumor-bearing mice with low-dose gamma-interferon plus tumor necrosis factor alpha to diminish immune suppressive granulocyte-macrophage progenitor cells increases responsiveness to interleukin 2 immunotherapy. AB - Production of granulocyte-macrophage (GM) colony-stimulating factor by murine metastatic Lewis lung carcinoma cells (LLC-LN7) increases the number and distribution of GM progenitor cells that are suppressive to T cell responsiveness to interleukin 2 (IL-2). The presence of these GM suppressor cells can be diminished by treatment of LLC-LN7-bearing mice with low doses of 100 units IFN gamma plus 10 units tumor necrosis factor alpha (TNF-alpha). The aim of this study was to determine whether treatment of LLC-LN7-bearing mice with IFN gamma/TNF-alpha to diminish GM suppressor cell presence would increase the responsiveness to IL-2 immune stimulatory therapy (100-1000 IU, twice daily for 5 days). Treatment first with IFN-gamma/TNF-alpha and then also with low dose IL-2 increased both the numbers of CD4+ and CD8+ cells within the tumor and the levels of their expression of the p55 IL-2 receptor. These intratumoral T cells also had an increased cytolytic capacity toward autologous tumor cells and an increased capacity to proliferate and secrete IL-2. Such effects were observed to a lesser extent in mice that were treated with either IFN-gamma/TNF-alpha alone or with low doses of IL-2 only. The combination treatment regimen of IFN-gamma/TNF-alpha and then IL-2 was also significantly more effective at reducing the size of the primary tumor and the formation of metastatic lung nodules than were the individual treatments. These results show that treatment to minimize the presence of GM suppressor cells enhances the effectiveness of IL-2 to stimulate anti-tumor immune responses and to diminish tumor growth and metastasis. PMID- 7850806 TI - Overexpression of DAN gene product in normal rat fibroblasts causes a retardation of the entry into the S phase. AB - Differential screening-selected gene aberrative in neuroblastoma (DAN) gene (previously named N03 gene), whose expression is significantly reduced in transformed cells, has recently been demonstrated to have a tumor-suppressive activity in vitro. In order to investigate biological roles of DAN gene product in normal rat fibroblasts (3Y1), marker-selected transfectants that expressed the high amount of DAN gene product were generated from 3Y1 cell lines. These clones did not exhibit morphological changes compared with parental 3Y1 cells; however, they showed a decrease in growth rate and a remarkable reduction in saturation density. Cell cycle analysis revealed that the overexpression of DAN gene product causes the retardation of the entry into the S phase. These results suggest that DAN gene product may have an important role in regulation of the entry of cells into the S phase. PMID- 7850807 TI - High expression level of alpha 6 integrin in human breast carcinoma is correlated with reduced survival. AB - We recently reported that alpha 6 integrin mediates experimental metastasis in mice by functioning in the adhesion of tumor cells to the vascular endothelium. In the current study, we investigated the expression of human alpha 6 integrin in invasive breast carcinomas of 119 women. In 50% of the tumors alpha 6 integrin was expressed in the majority of the cells, and this expression was correlated with reduced survival time. By contrast, the 24% of patients with breast tumors devoid of alpha 6 integrin expression all survived. The tumors were also evaluated for clinical risk factors including histological grading and steroid receptor level. The combination of these factors with alpha 6 integrin expression was superior in predicting overall survival than considering the other factors alone. The correlation with decreased survival time was consistent, regardless of whether the tumors expressed the alpha 6 integrin A or B forms, which differ in their cytoplasmic domain. On the basis of this pilot study we consider alpha 6 integrin expression to be a novel prognostic marker for human breast cancer. PMID- 7850808 TI - Expression of mutant p21ras induces insulin-like growth factor 1 secretion in thyroid epithelial cells. AB - There is substantial evidence supporting the existence of insulin-like growth factor 1 (IGF-1) autocrine circuits in many tumor types, although the underlying inducing event has remained undefined. In order to address this matter, we have generated several immortalized human thyroid epithelial cell lines containing a zinc-inducible mutant H-ras gene and used these to investigate the relationship between expression of mutant p21ras and secretion of IGF-1. Induction of the transgene in the presence of zinc ions (Zn2+) was confirmed by Northern blot analysis and immunocytochemistry. IGF-1 levels in serum-free medium, stripped of binding proteins, were monitored using a sensitive radioimmunoassay. Expression of mutant p21ras in these cells, induced by Zn2+, resulted in an approximate 30 fold increase in the IGF-1 production rate, reaching a level exceeding that of human embryo fibroblasts. The data presented here suggest that an activating mutation of a ras oncogene may directly account for IGF-1 secretion in some human tumor cells. PMID- 7850809 TI - Molecular analysis of the cytokine network involved in cachexia in colon 26 adenocarcinoma-bearing mice. AB - Two clones, one cachexigenic (clone 20) and the other noncachexigenic (clone 5), from a murine colon adenocarcinoma, colon 26 cells, were used to analyze the involvement of immune reactions as well as the cytokine network in cachexia. Clone 20 induced cachexia in nude and SCID mice as well as in normal BALB/c mice, suggesting that lymphocytes played little, if any, role in the process. Both clones failed to express mRNA of interleukin (IL) 1 alpha, IL-1 beta, IL-6, and tumor necrosis factor alpha in vitro with or without the coculture of NIH3T3 cells or spleen cells. However, IL-6 mRNA was selectively detected at the tumor site of clone 20 but not at that of clone 5-bearing mice. In contrast, tumor necrosis factor alpha mRNA was detected at tumor sites and in spleens of only clone 5-bearing mice, suggesting a potential role of IL-6, but not tumor necrosis factor alpha, in inducing cachexia. Anti-IL-6 antibody partially reversed the weight loss induced by clone 20, whereas the continuous infusion of IL-6 failed to cause weight loss, despite being associated with an elevation of a serum acute phase protein. These results suggest that IL-6 is necessary but not sufficient for the induction of cachexia. Both clones expressed IL-6 mRNA in the presence of IL-1 in vitro, and mice bearing either clone expressed IL-1 beta mRNA at the tumor site. Moreover, IL-1 receptor antagonist (IL-1Ra) mRNA was detected at the tumor site of clone 5-bearing mice but not at that of clone 20-bearing mice, suggesting that IL-1Ra might block IL-1 activity to reduce IL-6 production in clone 5-bearing mice. However, the transfection of clone 20 with IL-1Ra cDNA failed to abolish its capacity to produce IL-6 and to cause cachexia. Collectively, additional factor(s) besides IL-1Ra and IL-1 beta may control IL-6 and some other cachexigenic factor production, thereby causing cachexia in this model. PMID- 7850810 TI - Characterization of the major sialyl-Lex-positive mucins present in colon, colon carcinoma, and sera of patients with colorectal cancer. AB - The expression of the mucin-bound sialyl-Lewisx epitope is increased in the tissue of most colorectal carcinomas and in the sera of about 30% of tumor patients. In colon cancer, a portion of the sialyl-Lex groups detectable with the monoclonal antibody AM-3 is located on MUC1 (C. Hanski et al., Cancer Res., 53: 4082-4088, 1993). In order to characterize the major colon carcinoma-associated sialyl-Lex-positive glycoprotein components, the tissue- and serum-derived antigens were investigated. The buoyant densities of the sialyl-Lewisx-positive antigens from tumor and normal colonic tissues and from sera of patients with colon carcinoma and healthy donors correspond to that of mucins (1.40 g/ml). The sialyl-Lex-positive mucins purified from both tissues elute under nonreducing conditions in the void volume of a Sepharose CL-2B column, indicating a molecular mass more than 2 x 10(7) daltons. They yield in immunoblot after SDS gel electrophoresis under reducing conditions a main band at an apparent M(r) 880,000. Radioactive labeling revealed that the band at M(r) 880,000 is the major protein component in sialyl-Lewisx-positive mucins both from tumor and normal colonic tissue. In sera of colon carcinoma patients, the sialyl-Lex moiety is also detectable mainly on a M(r) 880,000 glycoprotein band and, additionally, on a M(r) 140,000 molecule as well as on alpha 1-acid glycoprotein. Sera from healthy donors exhibited only a sialyl-Lex-positive glycoprotein with the apparent M(r) 140,000. Sandwich ELISA as well as immunoblots of mucins purified from the colon carcinoma cell line LS174T indicated that the sialyl-Lex moiety migrating in the M(r) 880,000 band is located on MUC2 protein core. Together, these data suggest that sialyl-Lex antigen in colon, colon carcinoma, and the sera of patients with this tumor is located on the MUC2 molecule, consisting of several subunits with an apparent M(r) 880,000, linked via disulfide bridges. The increase of sialyl-Lex expression in colon carcinomas appears to be mainly due to a more frequent transfer of sialyl-Lex moieties onto the mucin core in tumor tissue. PMID- 7850811 TI - Antiproliferative effect of spermine depletion by N-cyclohexyl-1,3-diaminopropane in human breast cancer cells. AB - Spermine is often the most abundant polyamine in human tumors such as breast carcinomas. However, its specific role in tumor biology is still uncertain, since inhibitors of ornithine decarboxylase such as alpha-difluoromethylornithine depress cell growth while leaving spermine content mostly unaffected. We have assessed the specific role of spermine in breast cancer cell growth using N cyclohexyl-1,3-diaminopropane (C-DAP), a potent spermine synthase inhibitor. In ZR-75-1 cells, C-DAP decreased net cell growth after 14 days by 65% at 50 microm, with an IC50 of about 5 microM, and was about 10 times more potent than N-(n butyl)-1,3-diaminopropane, another spermine synthase inhibitor. C-DAP acted as a specific inhibitor of spermine biosynthesis, since (a) it depleted spermine content while causing an equal or greater accumulation of spermidine on a molar basis, (b) it rapidly induced S-adenosylmethionine decarboxylase activity and the accumulation of its products due to relief of spermine-dependent inhibition of enzyme expression, and (c) exogenous spermine (1 microM) completely reversed C DAP-induced growth inhibition. C-DAP and related compounds were accumulated, at least in part, through a mechanism distinct from the polyamine transport system, while also blocking putrescine and spermidine uptake with various potencies. Reversibility of C-DAP-induced growth inhibition by exogenous spermine was progressively lost on prolonged treatment, in association with marked morphological changes. In 4 different human breast cancer cell lines (ZR-75-1, T47-D, MCF-7, and MDA-MB-231), relative growth sensitivity to C-DAP was inversely related to the extent of spermidine accumulation caused by spermine synthase inhibition, suggesting that spermidine overaccumulation can functionally replace spermine. Interestingly, C-DAP strongly potentiated growth inhibition caused by alpha-difluoromethylornithine in all cell lines tested by preventing conversion of residual spermidine to spermine, indicating that spermine synthesis limits alpha-difluoromethylornithine action and that under some critical threshold, spermidine cannot fulfill cellular needs for spermine. Thus, spermine plays specific and important functions in breast tumor growth, and spermine synthase inhibitors could markedly improve the therapeutic effectiveness of existing polyamine depletion strategies, especially in spermine-rich tumors. PMID- 7850812 TI - Abnormal patterns of D-type cyclin expression and G1 regulation in human head and neck cancer. AB - D-type cyclins are proto-oncogenic cell cycle regulators implicated in the pathogenesis of several types of cancer. Amplification of the cyclin D1 gene has been described in 30-50% of human head and neck squamous cell carcinoma (HNSCC). Using immunohistochemistry on archival specimens of human HNSCC and a mAb DCS-6, which is specific for cyclin D1, strong positivity was found in nuclei of 9 (17%) of 52, a moderately elevated signal in 16 (31%) of 52, and weak staining comparable with normal tissues in 27 (52%) of 52 patients. Immunoblotting analysis of five HNSCC-derived cell lines showed three distinct spectra of D-type cyclin proteins: cyclin D1 only (in UMSCC-2 and UMSCC-22b cell lines with 11q13 amplification), cyclins D1 and D3 (in HN5 and HN6), or cyclins D1, D2, and D3 (in UMSCC-1). Electroporation of neutralizing antibodies demonstrated requirement for cyclin D1 in cell cycle progression of all five HNSCC cell lines. Cyclin D2 was essential and showed a cooperative effect with cyclin D1 in positive regulation of G1 in UMSCC-1 cells. These data are consistent with the proposed oncogenic role of cyclin D1 in HNSCC and open up the way for immunohistochemical assessment of cyclin D1 aberrations in archival clinical specimens. It is also suggested that excessive levels of cyclin D1 alone or cooperative effects of several D-type cyclin proteins may lead to deregulation of G1 control in distinct subsets of human HNSCC. These results are discussed in the context of possible functional redundancy of D-type cyclins and the role of the D-type cyclin/p16-CDKN2/pRB pathway in tumorigenesis. PMID- 7850813 TI - Expression of selenium-dependent glutathione peroxidase in human breast tumor cell lines. AB - In estrogen receptor (ER)-positive breast cancer cell lines, very low expression of glutathione peroxidase-1 (GPX-1) activity and hgpx1 mRNA has been observed. Such cell lines have been used as models in studies of resistance to redox cycling anticancer drugs. In particular, large increases in GPX-1 activity levels by expression of transfected GPX-1 cDNA have been shown to confer some resistance to such drugs. It has never been determined that such low GPX-1 expression is a common feature of breast cancer. Based on previous limited surveys of breast cancer cell lines, it has been suggested that there may be an inverse correlation between ER status and GPX-1 production. Here we report the results from a larger survey of breast cancer cell lines, including six recently isolated cell lines. A near absence of hgpx1 mRNA expression was observed in 3 of 13 ER-negative cell lines; 1 of 4 ER-positive cell lines had high production of GPX-1. Both observations weaken the proposed inverse correlation between ER status and GPX-1 production. We have evidence to suggest that one cell line, COH-BR-5 (ER negative), lacked hgpx1 gene expression prior to culture. This is based on the finding of stable hgpx1 gene expression during serial culture of ER-negative breast cancer cell lines newly isolated from malignant effusion and absence of hgpx1 mRNA expression in COH-BR-5. Expression of hgpx2 mRNA (producing GPXGI, the GI tract GPX) was detected in several long and newly established, ER-negative breast cancer cell lines. Cell lines, COH-BR-5 and MDA-MB-175, expressed only hgpx2 mRNA. The hgpx2 mRNA was detected in COH-BR-5 and COH-BR-7 at low passage number, suggesting that hgpx2 gene expression occurs in breast cancer malignant effusion. Thus, studies of the role of GPX in redox drug resistance may account for changes in hgpx2 gene expression. Phospholipid hydroperoxide GPX activity was not found to be generally elevated above normal tissue levels in newly established breast cancer-derived cell lines. PMID- 7850815 TI - Workshop on eukaryotic DNA repair genes and gene products. PMID- 7850814 TI - Induction of M(r) 92,000 type IV collagenase expression in a squamous cell carcinoma cell line by fibroblasts. AB - A previous investigation (Matsumoto et al., J. Oral Pathol. Med., 18: 498-501, 1989) has shown that the in vitro invasion of a collagen gel by squamous cell carcinoma can be substantially augmented in the presence of fibroblasts. Therefore, we undertook a study to determine if the production of collagenase(s) by a squamous cell carcinoma cell line, UM-SCC-1, was up-regulated by fibroblasts. Cocultivation of UM-SCC-1 cells with MDA-TU-138 fibroblasts, both established from the oral cavity, resulted in a dose-dependent increase in the activity of a M(r) 92,000 gelatinase as shown by zymography. Augmented M(r) 92,000 gelatinase activity was a consequence of the stimulation of the UM-SCC-1 cells by a soluble, fibroblast-derived factor since this effect could be reproduced with fibroblast-conditioned medium but not with glutaraldehyde-fixed fibroblasts. The increased M(r) 92,000 gelatinolytic activity could be accounted for by an increase in M(r) 92,000 type IV collagenase (MMP-9) protein, as demonstrated by Western blotting for this metalloproteinase. Trypsin treatment of the fibroblast-conditioned medium abolished its ability to increase MMP-9 secretion by UM-SCC-1 cells. Furthermore, fractionation of the fibroblast conditioned medium revealed a M(r) 3,000-10,000 soluble factor(s) which was responsible for the augmented production of MMP-9 by UM-SCC-1 cells. To determine if the increased production of MMP-9, in response to the fibroblasts, was a consequence of increased promoter activity, UM-SCC-1 cells were transiently transfected with a chloramphenicol acetyltransferase reporter driven by the MMP-9 promoter and plated on plastic or on a monolayer of MDA-TU-138 fibroblasts. A 4-5 fold stimulation of MMP-9 promoter activity was observed with UM-SCC-1 cells plated with the MDA-TU-138 fibroblasts, when compared with similarly transfected cells recultured on plastic. In conclusion, we have demonstrated that MMP-9 expression in a squamous cell carcinoma cell line is augmented by a fibroblast derived protein(s). This finding indicates a role for stromal cells in the regulation of MMP-9 expression in squamous cell carcinoma. The ability of fibroblasts to regulate MMP-9 expression in tumor cells in vitro may explain the observation that the amount of M(r) 92,000 type IV collagenase mRNA in tumor cells is highest at the tumor:stromal interface of resected squamous cell carcinoma. PMID- 7850816 TI - Changes in left ventricular mass and filling after renal transplantation are related to changes in blood pressure: an echocardiographic and pulsed Doppler study. AB - To examine changes in left ventricular (LV) mass and function (diastolic and systolic) after successful renal allograft transplantation (RT), we prospectively studied 30 patients (19 men, 11 women, aged 37 +/- 13 years) by M-mode, two dimensional and pulsed Doppler echocardiography at the time of surgery and 10 +/- 1.8 months later. At the time of transplantation all patients had been undergoing dialysis (4 peritoneal dialysis, 26 hemodialysis) for 2.5 +/- 3.2 years. A hematocrit of < or = 30% was present in 26 patients. After RT the mean hematocrit increased from 26 +/- 4 to 40 +/- 7 (p < 0.01), whereas systolic, diastolic and mean blood pressure (BP) remained unchanged. The LV mass index (LVMI) decreased from 201 +/- 56 to 171 +/- 41 g/m2, (p < 0.01); LV diastolic diameter corrected by body surface area (LVDDI) decreased from 298 +/- 38 to 279 +/- 35 (p < 0.01) and the LV end-diastolic volume index (LVEDVI) from 72 +/- 18 to 63 +/- 15 (p < 0.01). There were no changes in LV fractional shortening or LV end systolic wall stress. Peak late transmitral velocity (A wave) decreased from 77 +/- 16 to 68 +/ 12 cm/s (p < 0.01) with no changes in other Doppler-derived indexes of diastolic function. No fistula patency influence on changes in LV mass and function was found. After RT, BP decreased in 21 patients from 150 +/- 20 to 132 +/- 15 (p < 0.001; group I) and increased in 9 patients from 130 +/- 14 to 153 +/- 16 (p < 0.05, group II). Patients in group I suffered a reduction in LVMI (p < 0.001), LV end-diastolic diameter (p < 0.05), LVDDI (p < 0.001); LV end-diastolic volume (p < 0.05); LVEDVI (p < 0.01); cardiac index (p < 0.05), and peak late transmitral velocity (p < 0.01), but no changes in group-II patients were observed. We concluded that BP is a major determining factor with regard to changes in LV hypertrophy and function following RT. LV mass and volumes can be expected to decrease after RT in patients with BP reduction. PMID- 7850817 TI - Probability of supraventricular tachycardia recurrence in pediatric patients. AB - Supraventricular tachycardia (SVT) in pediatric patients is usually associated with a better prognosis than that in adults. However, late recurrence of SVT has been recently described. A total of 90 patients who had their initial SVT episode before 15 years of age were retrospectively studied (2-228 follow-up months; median, 215 months). Concomitantly congestive heart failure was present in 14 (16%) patients, and a cerebrovascular accident occurred in 1 patient. Intravenous verapamil was most frequently used to convert the initial SVT episodes without adverse effects, even in those younger than 1 year of age (9 patients). Older children could also be converted spontaneously or by vagal maneuvers. Patients with SVT recurrence were associated with an older age at initial SVT episodes (p < 0.001). By Kaplan-Meier actuarial analysis, the chance of remaining SVT-free during the follow-up was much lower in patients with initial SVT after 5 years of age than in patients with initial attacks before the age of 1 and between the age of 1 and 5 (p = 0.02 and 0.04, respectively). Even though, about 40% of the patients whose initial attacks occurred during infancy had recurrences 5 years later. Only those who had the initial attacks during the prenatal period remained free from SVT recurrences. Patients with initial SVT episodes during infancy have a longer period without SVT attacks and a lower chance of recurrences; nonetheless, a substantial number of them had recurrence at later childhood except those with initial SVT attacks during the prenatal period.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7850818 TI - Postoperative antiarrhythmic effects of diltiazem in patients undergoing coronary bypass grafting. AB - Hemodynamic problems resulting from cardiac arrhythmias often occur in patients undergoing coronary bypass grafting in the early postoperative period. Therefore, in this study the antiarrhythmic effects of the calcium channel antagonist diltiazem were evaluated in coronary bypass grafting. Forty patients were randomly assigned either to a therapy with diltiazem or nitroglycerin. Hemodynamic measurements were established by Swan-Ganz catheter, and long-term ECG analyses were performed preoperatively and 1, 3 and 5 days after operation. There were significantly fewer ventricular arrhythmias (Lown class IV) in the diltiazem groups than in the nitroglycerin groups (p < 0.05). Supraventricular tachycardias were significantly more often observed in the nitroglycerin groups on all 3 days (p < 0.05). As a result, the calcium channel antagonist diltiazem is recommended as a standard adjunct to perioperative medication in cardiac surgery. PMID- 7850819 TI - Direct and indirect cost of percutaneous transluminal coronary angioplasty. AB - A prospective study of 53 patients employed in the 6-month period before coronary angioplasty was performed to determine the direct and indirect costs of lag time in work resumption. The total direct costs calculated were $273,480; indirect costs for this sample were $150,944. When these costs are generalized to all patients in the US undergoing uncomplicated percutaneous transluminal coronary angioplasty, the costs are more than $1.2 billion. This study demonstrated that even in patients with a high a priori probability of work return, delay in work resumption results in a greater cost to the individual and society through absence from the labor force. PMID- 7850821 TI - Cilazapril plus hydrochlorothiazide: improved efficacy without reduced safety in mild to moderate hypertension. A double-blind placebo-controlled multicenter study of factorial design. AB - In this multicenter, placebo-controlled, double-blind, 4 x 3 factorial design study, 1,162 patients randomized into 12 parallel groups received either placebo (n = 97), cilazapril (CLZ 0.5, 5, or 10 mg; n = 288 total), hydrochlorothiazide (HCTZ 12.5 or 25 mg; n = 198 total), or one of the six possible combinations of the two drugs (n = 579 total) given orally once daily for 4 weeks. The mean decrease from baseline in predose (i.e., 24 h postdose) sitting diastolic blood pressure (SDBP) was statistically significantly (p < 0.01) greater for all combinations studied compared to placebo, as well as to their respective monotherapy components. Synergistic antihypertensive effects were noted for the 5/12.5 mg CLZ/HCTZ combination therapy. The normalization (SDBP < or = 90 mm Hg) rate of the 5/12.5 mg CLZ/HCTZ combination was essentially additive with respect to the component monotherapies. The tolerability profile of the CLZ/HCTZ combination was similar to its respective components and comparable to placebo. The CLZ/HCTZ group reported low serum potassium (K+) and high serum uric acid less frequently than the HCTZ group. Therefore, the CLZ/HCTZ combination (5 mg/12.5 mg) is an option for hypertensive patients not responding to single drug CLZ therapy. PMID- 7850820 TI - Comparative hemodynamic effects of intravenous digoxin and enoximone in severe chronic heart failure. AB - In order to compare the acute hemodynamic effects of digoxin (0.01 mg/kg) and enoximone (1 mg/kg), a phosphodiesterase inhibitor inotropic agent, in severe chronic congestive heart failure, 8 patients (male, mean age 56.7 years, sinus rhythm) were investigated with a randomized cross-over study. Peak effect of enoximone (30 min) in comparison to that of digoxin (90 min) resulted in a similar reduction of left-ventricular filling pressure (-27 vs. -28%) and mean pulmonary artery pressure (-23 vs. -24%). Pulmonary (-39 vs. -16%; p < 0.01) and systemic vascular resistance (-27 vs. -4%; p < 0.001) were significantly lowered by enoximone. Cardiac index (+30 vs. +6%; p < 0.001) and heart rate (+11 vs. -3%; p < 0.05) were increased significantly more by enoximone than by digoxin. Since enoximone resulted in an enhancement of cardiac performance greater than that produced by digoxin, enoximone could be a useful and powerful substitute for digoxin in the acute therapy of severe chronic congestive heart failure with sinus rhythm. PMID- 7850822 TI - Thrombolytic therapy of acute myocardial infarction alters collagen metabolism. AB - The objective of the study was to monitor collagen metabolism after thrombolytic therapy. Sequential measurements of serum aminoterminal type-III procollagen propeptide (S-PIIINP) and carboxyterminal type-I procollagen propeptide (S-PICP) were made in 62 patients suspected of acute myocardial infarction and receiving thrombolytic therapy. Regardless of whether acute myocardial infarction was confirmed or not, S-PIIINP increased (94-120%) 4 h after streptokinase therapy (p < or = 0.02), and decreased during the next 20 h with median values at 24 h still above the baseline (p < 0.02). With confirmed acute myocardial infarction, S PIIINP increased from 24 h towards a plateau reached at day 2-3 (p < 0.01), with values still elevated at 6 months. No similar biphasic pattern was found for S PICP, but patients with acute myocardial infarction had S-PICP above baseline at 1, 2, and 6 months (p < 0.05). A less pronounced S-PIIINP increase was noted with tissue-plasminogen activator than with streptokinase. Thrombolytic therapy induces collagen breakdown regardless of whether acute myocardial infarction is confirmed or not. With confirmed acute myocardial infarction collagen metabolism is altered for at least 6 months. Furthermore, fibrin-specific and nonspecific thrombolytic agents appear to affect collagen metabolism differently. PMID- 7850823 TI - Relationship between plasma level of brain natriuretic peptide and myocardial infarct size. AB - To investigate the clinical significance of plasma brain natriuretic peptide (BNP) measurement in patients with acute myocardial infarction (MI), circulating levels of BNP, atrial natriuretic peptide, creatine kinase (CK), and hemodynamic parameters were serially determined in 24 patients with a first episode of acute MI. Plasma BNP (mean +/- SEM) gradually increased and peaked 21 h after the onset (from 13.7 +/- 2.2 to 23.0 +/- 3.3 fmol/ml; p < 0.001). A significant correlation was found between the increase in plasma BNP level and both the peak CK level (r = 0.83; p < 0.05) and the MI size (r = 0.74; p < 0.05). The increase in plasma BNP in the acute phase was found to be a significant predictor of left ventricular (LV) function evaluated in the convalescent phase (LV ejection fraction, r = -0.63; p < 0.05, LV end-diastolic pressure, r = 0.56; p < 0.05). In conclusion, in patients with acute MI, increases in plasma BNP concentration during the early phase reflect MI size, and thereby may predict later LV function. PMID- 7850824 TI - Cardiopulmonary exercise capacity in healthy normals of different age. AB - Sixty-nine healthy normals from the 3rd to the 6th decade were stressed to exhaustion by means of a cardiopulmonary exercise test on a bicycle ergometer. Peak VO2, VCO2 and ventilation differed significantly between the four decades: peak VO2 (mean +/- SD) was 3,393 +/- 516; 3,061 +/- 444; 2,817 +/- 801 and 2,589 +/- 687 ml/min (p < 0.001). The mean value for respiratory gas exchange ratio (R) at ventilatory threshold (VT) was 0.86 and for ventilatory equivalent O2 (EqO2) 0.24. Mean VO2 at VT was 1,662 +/- 521; 1,462 +/- 308; 1,474 +/- 559 and 1,268 +/ 232 ml/min (p < 0.05). The VO2 of the four age groups at VT was between 47 and 49% of peak VO2 (n.s.), and both parameters correlated significantly (r = 0.67, p < 0.001). The average increase of VO2 in relation to work rate (ml/W/min) was 11.5 +/- 1.2 for the total exercise and was below VT lower (9.4 +/- 1.9) than above VT (12.9 +/- 1.2) (p < 0.001). PMID- 7850825 TI - Persistence of normal right ventricular Doppler filling pattern early after tricuspid valve excision. AB - Two patients with acute tricuspid bacterial endocarditis in which a normal right ventricular Doppler filling pattern was demonstrated early following valvectomy are reported. After surgery, on pulsed Doppler examination, the sample volume positioned at the right atrioventricular level revealed a normal M-shaped filling pattern. A pathologic monophasic pattern was documented a few months later. Our findings suggest that early after surgery the preserved gradient throughout ventricular diastole leads to a passive and active filling similar to normal. Only at a later stage is the grossly dilated right atrium unable to maintain active filling, and the 'A' wave disappears despite the fact that sinus rhythm is maintained. Tricuspid valve diastolic motion represents a product of the several factors that determine atrioventricular gradient, but the valve itself appears not to be involved in the generation of a normal filling pattern. PMID- 7850826 TI - Pericardial mesothelioma with intracardiac invasion into the right atrium. PMID- 7850827 TI - Role of percutaneous cardiopulmonary bypass and other support devices in interventional cardiology. AB - Percutaneous cardiopulmonary bypass support has a role to play in the management of the high-risk coronary angioplasty patient. This article discusses the basic principles of cardiopulmonary bypass, technique, indications, and complications of this new addition to interventional cardiology. In addition, the role of other support devices during high-risk coronary interventions is also discussed. PMID- 7850828 TI - Interventional strategies for managing acute myocardial infarction. AB - The management of acute myocardial infarction has evolved greatly with the development of interventional cardiology and thrombolytic therapy. Interventional strategies in the setting of thrombolytic therapy include immediate, delayed, and elective PTCA. Randomized trials suggest no benefit to these approaches; however, primary PTCA without adjunctive lytics when compared to lytic therapy alone may improve both survival and costs. Newer catheter-based technology may also enhance outcomes in patients with acute myocardial infarction. PMID- 7850829 TI - Adjunctive thrombolytic agents with coronary interventional techniques. AB - Thrombolytics are used in a variety of interventional procedures, including direct lytic therapy, and in conjunction with PTCA, directional atherectomy and intracoronary stenting. The dosage and variety of thrombolytics is controversial. This article examines all potential uses of thrombolytics and reports on major trials using thrombolytics in these situations. PMID- 7850830 TI - Excimer laser coronary angioplasty. AB - Excimer laser angioplasty has evolved from a difficult experimental procedure to a more refined intervention with flexible catheters, well-defined indications, and consistent results for certain lesion types such as aortoostial stenosis, total occlusions, and certain saphenous vein graft lesions. This article reviews the current clinical results with excimer laser angioplasty, discusses the procedural technique and indications, and emphasizes the need for rigorous comparison of excimer laser angioplasty with alternative approaches for patients with coronary artery disease. PMID- 7850831 TI - Rotational ablation. The Rotablator catheter. AB - High-speed rotational ablation addresses specific limitations inherent in conventional methods of percutaneous revascularization. The Rotablator system represents an alternative mechanism to achieve restoration of luminal dimensions by removing atherosclerotic plaque. This article summarizes results, identifies indications, and discusses potential applications of rotational ablation in the treatment of coronary artery disease. PMID- 7850832 TI - Transluminal extraction coronary atherectomy. AB - The TEC is a forward-cutting atherectomy catheter that has the unique potential to excise and aspirate atheroma, especially intraluminal thrombus. This device has been under clinical investigation for more than 6 years and received final marketing approval by the FDA for the treatment of lesions in the coronary vasculature in 1993. In the US TEC Multicenter Registry, the overall clinical and lesion successes were favorable. The success rates were similar for both native coronary vessels and saphenous vein bypass grafts. Importantly, the procedural success rates were maintained even in the presence of several unfavorable angiographic features, such as ostial location, intraluminal thrombus, and total occlusion. Further insights into the mechanisms of action of the TEC were made from studies using percutaneous angioscopy and intravascular ultrasound. Angioscopy clearly demonstrated that the TEC was indeed able to remove intraluminal thrombus, especially loosely adherent red thrombus, in a population of patients with unstable coronary syndromes. However, the TEC frequently leaves behind multiple intimal disruptions which not only create a possible nidus for restenosis but also explain the frequent hazy angiographic appearance of the vessel after TEC atherectomy. As is true for all new interventional devices, the specific niche for the TEC in interventional cardiology will best be determined in randomized clinical trials. There are several areas in which the TEC appears promising. First, this device may have a role in the management of patients with diffusely diseased saphenous vein grafts. Second, the TEC may be an effective primary therapy in lesions with intraluminal thrombus. Treatment with the TEC may then be followed by an adjunctive therapy to maximize the final vessel diameters. Finally, the TEC may be valuable in the treatment of lesions in patients with high-risk unstable coronary syndromes. PMID- 7850833 TI - Reopening of chronic coronary occlusions by low-speed rotational angioplasty. AB - Total occlusions are found in 10% to 20% of patients undergoing coronary angioplasty. The low-speed rotational angioplasty system (ROTACS) was developed as an addition to conventional guidewire techniques in chronic occlusions. It can be employed if the passage of the obstructed vascular segment with a conventional guidewire fails. The results in 200 patients presented here indicate that angioplasty expands the option of nonsurgical coronary revascularization. PMID- 7850834 TI - Indications for and applications of the Gianturco-Roubin coronary stent. AB - The Gianturco-Roubin coronary stent is approved for and effective in the management of acute or threatened closure after unsuccessful coronary intervention. Factors critical to successful stenting include patient and lesion selection, preprocedure identification of patients in potential need of stenting, selection of stent-compatible ancillary equipment, appropriate antiplatelet and anticoagulant therapy, postdeployment stent dilatation, and careful sizing of stents. Further refinements of technique and adjunctive drug therapy should continue to improve results and avoid acute complications. Published clinical experience and potential future applications are discussed. PMID- 7850835 TI - Indications and use of the Palmaz-Schatz coronary stent. AB - Restenosis prevention has been the 'holy grail' of contemporary interventional cardiology. Even though balloon angioplasty has become the standard treatment for ischemic syndromes, it is still plagued by a definite incidence of restenosis. This recidivism has prompted the search for newer, catheter-based modalities of treatment to address this issue. The proliferation of newer devices for intervention has increased the number of options for the interventional cardiology; however, until recently, none has had a significant impact on restenosis. The randomized trials (STRESS and BENESTENT) have both shown a significant reduction in angiographic restenosis with the Palmaz-Schatz stent in de novo coronary lesions. Nonrandomized trials suggest additional benefit in saphenous vein bypass grafts. PMID- 7850836 TI - Wiktor coronary stent. AB - The Wiktor stent is a unique balloon-expandable tantalum coil stent currently undergoing clinical trials to determine the efficacy and safety of the device for reducing restenosis and for salvaging a failed angioplasty (bailout). This article discusses the stent in detail, the procedure, possible complications, and its advantages and disadvantages. PMID- 7850837 TI - Current status of the Strecker stent. AB - Knitted flexible tantalum stents proved to be a valuable adjunct to percutaneous transluminal angiplasty (PTA) in the case of insufficient PTA results, and their use was established in the distal aorta, the iliac, the femoro-popliteal, the renal, and the coronary arteries. Recently, long arterial occlusions were defined as new indications for primary stenting; stent indications were further extended to the subclavian, the carotid, and the splanchnic arteries. Due to higher incidence of acute and late complications after stent treatment of small diameter arteries, patients have to be selected thoroughly. Newly designed drug-releasing stents tested in animal experiments promised to be suitable to diminish the incidence of late restenosis due to intinal hyperplasia, thus providing better long-term patency. PMID- 7850838 TI - Structural design, clinical experience, and current indications of the coronary Wallstent. AB - Based on data described previously, the wallstent is a versatile stent that, by virtue of its longitudinal flexibility and low profile, can be deployed with a high degree of success in complex lesions of both native coronary arteries and bypass vein grafts. This article discusses its structural design, the experimental studies of thrombogenicity and polymeric coating, early and late clinical experience with the wallstent, clinical evaluation of the less shortening wallstent, and the current indications of the coronary wallstent PMID- 7850839 TI - Current status of biodegradable stents. AB - Coronary angioplasty remains limited by abrupt closure and restenosis. Metallic stents are useful for suboptimal PTCA results or threatened closure and can reduce restenosis in de novo lesions. However, they are permanent devices that are used to treat a short-term problem and have only limited potential for local drug delivery. Several catheters have been designed for specific delivery of drugs or gene products. Unfortunately drug delivery efficiency and long-term retention remain problematic. To overcome these limitations and provide a scaffold for the remodeling vessel as well as a vehicle for sustained local drug delivery, bioabsorbed stents have been proposed as an alternative. This article describes the limitations of the current metallic stents, reviews the initial animal studies of polymeric stents, and proposes the biodegradable stent as a local drug delivery device to prevent restenosis and acute closure post-PTCA. PMID- 7850840 TI - Polymeric endoluminal paving. A family of evolving methods for extending endoluminal therapeutics beyond stenting. AB - This article briefly reviews the background and rationale for the development of polymer paving. The process of endoluminal paving is described both in its generic form as well as in three experimental embodiments. Several experimental studies with two forms of paving, solid paving and gel paving, are reviewed. Finally, the envisioned future clinical role for both solid and gel paving is described. PMID- 7850841 TI - Aluminum uptake and inhibition of enamel dissolution by sequential treatments with aluminum solutions. AB - The effects of sequentially applied solutions containing aluminum (Al) on enamel uptake and inhibition of acid dissolution were investigated. Following 10 consecutive 5-min treatments with seven Al solutions varying in concentration from 0.15 to 2.0 mmol/l, the subsequent acid dissolution of enamel was progressively reduced from 0 to over 70%. Teeth treated with 1.5 mmol/l Al from 1 to 30 consecutive 5-min periods demonstrated a stepwise increase in the reduction of enamel acid dissolution ranging from about 10 to 90%. Following the same treatment regimen, the amount of Al deposited in the enamel varied from 2,500 ppm after a single 5-min application to approximately 9,000 ppm after 20 or 30 consecutive treatments. These experiments showed that teeth repeatedly exposed to low concentrations of Al solutions (i.e. < 2 mmol/l) progressively accumulated significant amounts of Al in the surface enamel, which was associated with a concomitant decrease in the acid dissolution rate of enamel. PMID- 7850842 TI - Fluoride release and effect on enamel softening by fluoride-treated and fluoride untreated glass ionomer specimens. AB - The effect of fluoride application on fluoride release and enamel protection was studied using conventional and light-activated glass ionomers and composite. The specimens prepared from the materials were tested as (1) freshly mixed, (2) aged (29 days), (3) aged and fluoride treated, and (4) aged, fluoride treated, and aged (29 days). For fluoride application, the specimens were immersed in 1.2% NaF solution for 10 min and washed. After handling, the specimens were glued on polished bovine enamel slabs and immersed in lactic acid (pH 5.0) for 3 h. The microhardness of the enamel was measured before and after the acid immersion. Freshly mixed glass ionomers significantly prevented enamel softening. The effect disappeared (conventional glass ionomer) or decreased (light-activated glass ionomer) during aging, but was reestablished by fluoride application. After the subsequent 4 weeks of aging, no significant protective effect could be seen for either of the glass ionomers. The fluoride release, which was greatly increased by fluoride application, was still elevated after 4 weeks of aging for both materials. PMID- 7850843 TI - A microbiological study of recurrent dentinal caries. AB - A cross-sectional microbiological study of recurrent (secondary) dentinal caries was conducted. Freshly extracted human teeth containing amalgam restorations judged to be clinically intact were scrubbed with chlorhexidine soap and soaked in povidone-iodine solution. The teeth were then split to remove the fillings and examined for dentinal caries. Of 54 teeth examined, 22 (40%) were free of dentinal caries in the restored site. The remainder were assigned to arbitrary groups of questionable (15), initial (8) and active caries (9), based on the amount of dentinal decay observed. Comparison of pre-extraction bite-wing radiographs with the in situ findings revealed the sensitivity for secondary caries detection to be only about 50%. In contrast, the specificity for absence of caries was 73%. There was considerable variation in the numbers and types of micro-organisms found in dentine samples from lesions of comparable severity. Facultatively, anaerobic streptococci were the most numerous and most prevalent micro-organisms in the affected dentine, but no single species was significantly associated with recurrent caries. Mutans streptococci were found in 40% of sites with any degree of caries and in only 3 of the 9 sites with the most caries. Homofermentative lactobacilli were present in 18 of the 54 dentine samples, including 4 from caries-free sites. While the prevalence and numbers of lactobacilli increased with the degree of caries, they occurred in less than half of the affected dentine samples. Actinomyces occurred in 15 of 32 affected sites but only in 2 of the 9 most active sites. Their numbers never exceeded 3 x 10(3) CFU/mg.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7850844 TI - Mucin-sulphatase activity of some oral streptococci. AB - Mucin-sulphatase activity, measured using a 35S-[SO4(2-)]-labelled colonic mucin substrate, was detected in whole cells of Streptococci isolated from the human oral cavity. The highest levels of sulphatase activity were found in all strains of Streptococcus salivarius, Streptococcus mitis and in half of the strains of Streptococcus mutans tested. Little or no activity was detected in 9 of the 11 Streptococcus oralis strains examined, in the 4 Streptococcus constellatus strains, and in the 3 Streptococcus anginosus isolates tested. The highest enzyme levels were obtained from the two fresh Streptococcus gordonii isolates. This is the first report of such activity in oral microorganisms. Streptococcal mucin sulphatase may contribute to the destruction of salivary mucins and mitigate their protective functions in the oral cavity, and be a determinant in the development of dental caries. PMID- 7850845 TI - Lysozyme and lactoperoxidase inhibit the adherence of Streptococcus mutans NCTC 10449 (serotype c) to saliva-treated hydroxyapatite in vitro. AB - Lysozyme, lactoperoxidase and salivary peroxidase inhibit the metabolism and growth of mutans streptococci, but any possible effects on the adherence of these bacteria are unknown. In this study the effects of lysozyme and lactoperoxidase on the adhesion of 3H-labelled Streptococcus mutans (NCTC 10449, serotype c strain) to saliva-coated hydroxyapatite were studied at pH 5.0 and 7.0. Human whole saliva was either lysozyme-depleted and centrifuged, or sterilized and dialysed to achieve no detectable lysozyme and peroxidase activities; this modified saliva was used to form experimental pellicles. The incorporation of lysozyme (50-200 micrograms/ml) to the pellicle caused a significant (p < 0.01) reduction in the adherence of S. mutans without any loss of bacterial viability. Pretreatment of either saliva-coated apatite or S. mutans cells with lysozyme did not change the results but lysozyme bound more readily to bacteria than to the experimental pellicles. Also, lactoperoxidase (10-200 micrograms/ml) reduced significantly (p < 0.001) the adherence of S. mutans but, in contrast to lysozyme, in a dose-dependent way. The strongest inhibition of adhesion was found when both saliva-coated apatite and bacteria were pretreated with lactoperoxidase. This enzyme bound to experimental pellicles in preference to streptococci. A non-specific protein control, albumin, did not block the inhibition by lysozyme or lactoperoxidase. The inhibition of adherence of a serotype c strain of S. mutans to saliva-coated hydroxyapatite is a novel antibacterial mechanism for both lysozyme and lactoperoxidase. PMID- 7850846 TI - Fluoride inhibits the antimicrobial peroxidase systems in human whole saliva. AB - Fluoride (F-) ions at concentrations present in vivo at the plaque/enamel interface (0.05-10 mM) inhibited the activities of lactoperoxidase (LP), myeloperoxidase (MP) and total salivary peroxidase (TSP) in a pH- and dose dependent way. The inhibition was observed only at pH < or = 6.5 and with F- concentrations > or = 0.1 mM. At pH 5.5 LP activity was inhibited by 85% and MP by 34% with 10 mM F-. TSP activity was also inhibited only at low pH (5.5) by approximately 25%. Furthermore, the generation of the actual antimicrobial agent in vivo, hypothiocyanite (HOSCN/OSCN-), of the oral peroxidase systems was inhibited by F-, again at low pH (5.0-5.5) both in buffer (by 45%) and in saliva (by 15%). This inhibition was observed only with the highest F- concentrations studied (5-10 mM). Fluoridated toothpaste (with 0.10 or 0.14% F) mixed with saliva did not inhibit TSP or HOSCN/OSCN- generation. This may have been due to the 'buffering' effect of toothpaste which did not allow salivary pH to drop below 5.9. We conclude that the F- ions in acidic fluoride products, e.g. in gels or varnishes (but not in toothpastes), may have the potential to locally inhibit the generation of a nonimmune host defense factor, HOSCN/OSCN/SCN-, produced by oral peroxidase systems. The possible clinical significance of this finding remains to be shown. PMID- 7850847 TI - Effect of chlorhexidine treatment followed by stannous fluoride gel application on mutans streptococci in margins of restorations. AB - The effect of antimicrobial treatment on the numbers of mutans streptococci (MS) in plaque from margins of restorations and in saliva was studied. Nineteen persons with well-restored dentitions and > 0.5 x 10(6) MS per ml saliva were treated with 1% chlorhexidine (CHX) gel in individually designed applicators 5 min/day for 9 days. Ten of the subjects continued the treatment with 0.4% stannous fluoride (SnF2) gel and the remaining 9 with a placebo gel for another 14 days. Plaque samples from margins of selected restorations and stimulated saliva were collected at baseline, after the completion of each gel treatment and then again at regular intervals up to 24 weeks. The CHX gel treatment suppressed MS in the margins of restorations as well as in saliva. Additional treatment with the SnF2 gel prolonged this suppression compared with CHX treatment alone. In the CHX-SnF2 group, the number of MS in margins of amalgam and composite restorations was still significantly lower at the end of the study compared with the baseline. In the CHX placebo group, the margins of amalgam restorations, mainly placed in premolars and molars, were recolonized somewhat faster than the margins of composite restorations in the front teeth. PMID- 7850848 TI - In situ remineralization of root surface lesions using a fluoride chewing gum or fluoride-releasing device. AB - The in situ remineralization of early root surface lesions was studied using a fluoride-releasing device (FRD) or a fluoride chewing gum. Root specimens with subsurface lesions were mounted in removable lower appliances in 6 adult subjects. Test groups chewed five sticks/day (0.1 mg F/stick) or one FRD (0.5 mg F/day release rate) was mounted in the midline of the appliance. A fluoride-free dentifrice was used three times/day for each 21-day control and the two test regimens. Separate root lesions were used to measure fluoride uptake or changes in mineral content by quantitative microradiography. Comparable values for percent remineralization for both FRDs and F gum were higher than controls, and the F uptake for FRDs exceeded both the F gum and controls (p = 0.05). PMID- 7850849 TI - Dissolution of various calcium fluoride preparations in inorganic solutions and in stimulated human saliva. AB - The aim of the present study was to examine the dissolution of various preparations of calcium fluoride in inorganic solutions and in human saliva. Calcium fluoride was prepared by mixing either 0.25 or 0.02 mol/l calcium chloride with 0.5 or 0.04 mol/l sodium fluoride. After preparation, the salts were washed in 1 mmol/l calcium chloride solution and in distilled water. A commercial product, calcium fluoride Suprapur (Merck), was used for comparison. The solubility of the salts was examined in distilled water, in a 2-mmol/l sodium phosphate solution, and in whole human saliva, produced by chewing paraffin. It was found that the calcium fluoride ion product after suspension for 1-3 h in distilled water ranged closely around 10(-10.7) for all salts. In the phosphate solution, the commercial product dissolved slowly, the ratio between dissolved fluoride and calcium ranged from 4 to 7, in buffered solutions approaching 2. The supernatant was not saturated by the salt. Our two calcium fluoride salts dissolved quickly and made the phosphate-containing solutions supersaturated with respect to fluorapatite, leading to fluorapatite formation, and because of compensating calcium fluoride dissolution, this led to increasing fluoride concentrations in saliva of up to around 85-95 ppm. The results of this study indicate that calcium fluoride of less than Suprapur standard may dissolve quickly in saliva, unless the dissolution is retarded by a physical barrier, like a forming pellicle. PMID- 7850850 TI - Effect of water rinsing after toothbrushing on fluoride ingestion and absorption. AB - This investigation was done to determine the bioavailability of fluoride (F) after toothbrushing associated with different water rinsing procedures. Eight adult subjects participated in four experiments, conducted with a randomised, crossover design: (A) 2 min brushing with an F dentifrice, followed by three quick (3 x 2 s) rinses, each with 10 ml of water; (B) brushing as in A followed by one long-lasting (1 min) rinse with 5 ml of water combined with the toothpaste saliva mixture; (C) brushing as in A followed by expectoration but without any water rinse afterwards; and (D) ingestion of the toothpaste as a slurry with 100 ml of de-ionized water. Blood samples were collected before and frequently for 6 h after each experiment and analyzed for F content. The area under the plasma F concentration vs. time curves (AUC) was calculated and the degree of F absorption estimated. AUC values obtained in experiment D were assumed to represent 100% F bioavailability. The plasma values recorded during experiment A were not significantly greater than the baseline values, indicating almost no F absorption when 3 quick water rinses were performed after toothbrushing. The degrees of F absorption after one long-lasting water rinse (B) were 7.6 +/- 4.2% and with no water rinse after toothbrushing (C) 23.8 +/- 13.5%, respectively. The results showed that the degree of F absorption after toothbrushing using an F toothpaste is strongly related to the mode of water rinsing. PMID- 7850851 TI - The effect of normal pulsed Nd-YAG laser irradiation on pits and fissures in human teeth. AB - The effects of normal pulsed Nd-YAG laser irradiation on the acid resistance of human dental enamel of pits and fissures, the cleaning of the pit and fissure contents and fluoride uptake into deep pits and fissures were examined. The acid resistance of the pit and fissure enamel was evaluated by the amount of dissolved calcium per square millimeter of the surface area. The pit and fissure enamel treated with laser irradiation obtained an acid resistance 30% higher than that of the unlased controls. The cleaning effect of laser irradiation on the pit and fissure contents was compared with chemicomechanical and mechanical methods. The laser irradiation was found to clean the pits and fissures to a greater depth without alterating the shape of pits and fissures, compared with the other two methods. The distribution of calcium, phosphorus and fluoride in the enamel of the pits and fissures was then measured by electron probe microanalyzer. At the entrance and in the deep part of the pits and fissures, the fluoride content of the enamel treated with acidulated phosphate fluoride after laser irradiation was higher than that of the enamel treated with acidulated phosphate fluoride alone. These results thus suggest that Nd-YAG laser irradiation might be effective in increasing the acid resistance of the pit and fissure enamel, while removing the pit and fissure debris contents and increasing the fluoride uptake into the pit and fissure enamel. PMID- 7850852 TI - Consumption of sweet snacks and caries experience of primary school children. AB - With the aim of evaluating the relationship between consumption of sweet snacks (sugars) and caries prevalence, a secondary analysis was performed on data obtained in an epidemiological study of 5-, 8- and 11-year-old children, all participants of Regional Institutions for Youth Dentistry. The children's primary and permanent teeth were examined mainly by visual examination. Parents completed a questionnaire on the child's toothbrushing habits, use of fluoride tablets and fluoride toothpaste, consumption of sweet snacks, level of education of the mother as an indicator of the socio-economic status of the family and country of birth of the mother as an indicator of ethnicity. The various oral hygiene habits were combined into one variable. Firstly the crude relationship between consumption of sweet snacks and caries experience was evaluated, subsequently oral hygiene habits, socio-economic status and ethnicity were taken into account. Mean dmfs scores of 5- and 8-year-old children who consumed sweet snacks between meals more than 5 times a day (according to parents' reports) were significantly higher than mean dmfs scores of children with a lower reported sweet snack consumption. Multivariate analysis confirmed this result. Only 4.2% of the children were in the group with such a high sweet snack consumption. A number of parents probably underestimated the sweet snack consumption of their children. As the validity of the data on sweet snack consumption was questionable, the actual influence of this factor might be larger than the results of this study show. PMID- 7850853 TI - The role of actin filaments in the organization of the endoplasmic reticulum in honeybee photoreceptor cells. AB - Close to the bases of the photoreceptive microvilli, arthropod photoreceptors contain a dense network of endoplasmic reticulum that is involved in the regulation of the intracellular calcium concentration, and in the biogenesis of the photoreceptive membrane. Here, we examine the role of the cytoskeleton in organizing this submicrovillar endoplasmic reticulum in honeybee photoreceptors. Immunofluorescence microscopy of taxol-stabilized specimens, and electron microscopic examination of high-pressure frozen, freeze-substituted retinae demonstrate that the submicrovillar cytoplasm lacks microtubules. The submicrovillar region contains a conspicuous F-actin system that codistributes with the submicrovillar endoplasmic reticulum. Incubation of retinal tissue with cytochalasin B leads to depolymerization of the submicrovillar F-actin system, and to disorganization and disintegration of the submicrovillar endoplasmic reticulum, indicating that an intact F-actin cytoskeleton is required to maintain the architecture of this domain of the endoplasmic reticulum. We have also developed a permeabilized cell model in order to study the physiological requirements for the interaction of the endoplasmic reticulum with actin filaments. The association of submicrovillar endoplasmic reticulum with actin filaments appears to be independent of ATP, Ca2+ and Mg2+, suggesting a tight static anchorage. PMID- 7850855 TI - Developmental expression of transforming growth factor-alpha and epidermal growth factor receptor proteins in the human pancreas and digestive tract. AB - This study was designed to localize transforming growth factor alpha (TGF-alpha) and epidermal growth factor receptor (EGFR) expression in the developing human gastrointestinal tract and pancreas. Immunohistochemical techniques using specific antibodies against human TGF-alpha and EGFR were performed on digestive tissues of fetuses from 9 to 10 to 24 weeks of gestation, children and adults. In fetuses, TGF-alpha and EGFR proteins were expressed in all epithelial tissues studied with a good correlation and from an age as early as 9 to 10 weeks of gestation, except for TGF-alpha in the esophagus. The strongest TGF-alpha immunostaining was noted in the stomach and the proximal colon. Unexpectedly, immunoreactive gut endocrine cells were observed with the two antibodies used. Relatively numerous in fetuses, they decreased in number with age and were rare in adults particularly along the colon. Enteroglucagonsecreting cells were shown to express TGF-alpha, while some gastrin, somatostatin and pancreatic glucagon cells were immunostained with EGFR antibodies. The presence of TGF-alpha and its receptor in digestive tract epithelium and pancreatic tissues early in fetal life suggests a functional role for TGF-alpha during the developmental process of the digestive system. We demonstrate that TGF-alpha is also produced by endocrine cells and might have an additional mode of action other than paracrine, at least during fetal life. PMID- 7850854 TI - Heterogeneous histochemical reaction pattern of the lectin Bandeiraea (Griffonia) simplicifolia with blood vessels of human full-term placenta. AB - Bandeiraea simplicifolia lectin (BS-I) stains vascular endothelium in various species. In humans, less than 10% of the specimens studied exhibit a reaction with BS-I. In the present histochemical study, the reactivity of BS-I with placental blood vessels and its correlation with the blood group from mother and newborn child was investigated. Acetone-fixed cryosections of representative tissue segments of human full-term placenta and umbilical cord were stained with BS-I. The staining pattern of tissues from patients with different blood groups was identical, although the reaction of BS-I in the placenta was heterogeneous. BS-I did not react with the umbilical cord. Vascular smooth muscle cells at the insertion site of the umbilical cord into the chorionic plate, and endothelium deeper in the chorionic plate, became progressively stained. The endothelial cells and tunica muscularis of smaller arteries and veins in stem villi lost their reactivity in parallel with decreasing vessel size. Arterioles and venules reacted heterogeneously. Capillaries, trophoblastic basement membranes, especially epithelial plates, and sometimes the syncytiotrophoblast were labelled in several terminal villi. The data indicate that 1) the placenta binds BS-I to fetal endothelium independent of the blood group, 2) cell-surface antigens on placental endothelial cells are expressed heterogeneously and 3) cell-surface glycans are constituted in an organ-specific manner on human endothelial cells. PMID- 7850856 TI - Localization of FMRFamide- and ACEP-1-like immunoreactivities in the nervous system and heart of a pulmonate mollusc, Achatina fulica. AB - Immunohistochemical localization of two neuropeptides possibly involved in the regulation of cardiac activity in a pulmonate mollusc, Achatina fulica Ferussac, was studied. On the ventral surface of the right cerebral ganglion, more than 50 neurons with diameters of 30-50 microns showed immunoreactivity to the antiserum of the neuropeptide FMRFamide. Many were also immunoreactive to an antiserum raised against Achatina cardio-excitatory peptide-1 (ACEP-1). Although FMRFamide like immunoreactive neurons occurred in all components of the subesophageal ganglia, identifiable ACEP-1-like immunoreactive neurons were located only in the visceral ganglion and the right parietal ganglion. In the heart, FMRFamide- and ACEP-1-like immunoreactive fibers were restricted to the atrium and the aortic end of the ventricle, consistent with morphological observations of cardiac innervation. The present results suggest that FMRFamide- and ACEP-1-like peptides are involved in regulating the heart beat of this snail. PMID- 7850857 TI - Antibodies to quinolinic acid and the determination of its cellular distribution within the rat immune system. AB - Antibodies to quinolinic acid were produced in rabbits with protein-conjugated and gold particle-adsorbed quinolinic acid. Quinolinic acid immunoreactivity was below detection limits in carbodiimide-fixed rat brain. In contrast, strong quinolinic acid immunoreactivity was observed in spleen cells with variable, complex morphology located predominantly in the periarterial lymphocyte sheaths. In the thymus, quinolinic acid immunoreactivity was observed in cells with variable morphology, located almost exclusively in the medulla. Lymph nodes and gut-associated lymphoid tissue contained many, strongly stained cells of similar complex morphology in perifollicular areas. Immunoreactivity in liver and lung was restricted to widely scattered, perivascular cells and alveolar cells respectively. Additional stained cells with complex morphology were observed in bronchus-associated lymphoid tissue, in skin, and in the lamina propria of intestinal villi. Follicles in all secondary lymphoid organs were diffusely stained, ranging from mildly to moderately immunoreactive in spleen, to intensely immunoreactive in gut-associated lymphoid tissue. These results suggest that quinolinic acid is an immune system-specific molecule. Two hypothetical schemes are proposed to account for high levels of quinolinic acid in specific cells of the immune system. PMID- 7850858 TI - Postnatal reorganization of actin filaments and differentiation of intercellular boundaries in the rat aortic endothelial cells. AB - Postnatal change in the distribution of actin filaments in endothelial cells was studied in the rat aorta by use of rhodamine-phalloidin staining and confocal laser scanning microscopy. Endothelial cells of the rat aorta possessed two populations of actin filament bundles, namely, peripheral bands at the cell border and stress fibers running longitudinally in the cytoplasm. Aortic endothelial cells of the neonatal rat contained only stress fibers, whereas those of the 10-day-old rat developed both peripheral bands and stress fibers. After 20 days of age, aortic endothelial cells had predominantly peripheral bands with occasional stress fibers around the branch orifices. During postnatal development the length density of stress fibers in aortic endothelial cells decreased, whereas individual stress fibers in endothelial cells were shortened. Electron microscopic observation revealed that the high intercellular boundaries of aortic endothelial cells at birth decreased in height and developed cytoplasmic interdigitations after 20 days of age. The occurrence of peripheral bands at the cell border is thought to be closely related to formation of cytoplasmic interdigitation which strengthens the mechanical connection between endothelial cells against increasing transmural pressure. Expression of stress fibers in aortic endothelial cells of the neonatal rat is supposed to be affected by longitudinal elongation of the developing aorta, whereas their postnatal decrease is thought to be correlated with the change of fluid shear stress loaded on the aortic endothelium. PMID- 7850859 TI - The presence of opioidergic pinealocytes in the pineal gland of the European hamster (Cricetus cricetus): an immunocytochemical study. AB - By use of antibodies raised against leu-enkephalin and met-enkephalin immunoreactive, opioidergic bi- and multipolar cells were demonstrated in the pineal gland of the European hamster. Ultrastructural analysis of these opioidergic cells revealed them to be pinealocytes. Processes emerged from the cell bodies and terminated in club-shaped swellings containing many small clear and some larger granular vesicles. Some of the terminals made synapse-like contacts with non-immunoreactive pinealocytes. The presence of the opioidergic pinealocytes strongly indicates that the pineal gland of the European hamster, in addition to its pinealopetal nervous regulation, is regulated by intrapineal peptidergic pinealocytes via a synaptic mechanism. A possible paracrine role of the opioidergic cells must also be considered. PMID- 7850860 TI - Leucokinin and diuretic hormone immunoreactivity of neurons in the tobacco hornworm, Manduca sexta, and co-localization of this immunoreactivity in lateral neurosecretory cells of abdominal ganglia. AB - Because leucokinins stimulate diuresis in some insects, we wished to identify the neurosecretory cells in Manduca sexta that might be a source of leucokinin-like neurohormones. Immunostaining was done at various stages of development, using an antiserum to leucokinin IV. Bilateral pairs of neurosecretory cells in abdominal ganglia 3-7 of larvae and adults are immunoreactive; these cells project via the ipsilateral ventral nerves to the neurohemal transverse nerves. The immunoreactivity and size of these lateral cells greatly increases in the pharate adult, and this change appears to be related to a period of intensive diuresis occurring a few days before adult eclosion. Relationships of these neurons to cells that are immunoreactive to a M. sexta diuretic hormone were also investigated. Diuretic hormone and leucokinin immunoreactivity are co-localized in the lateral neurosecretory cells and their neurohemal projections. A median pair of leucokinin-immunoreactive, and a lateral pair of diuretic hormone immunoreactive neurons in the larval terminal abdominal ganglion project to neurohemal release sites within the cryptonephridium. The immunoreactivity of these cells is lost as the cryptonephridium is eliminated during metamorphosis. This loss appears to be related to the change from the larval to adult pattern of diuresis. PMID- 7850861 TI - Immunocytochemical localization of POMC-derived peptides (adrenocorticotropic hormone, alpha-melanocyte-stimulating hormone and beta-endorphin) in the pituitary, brain and olfactory epithelium of the frog, Rana esculenta, during development. AB - Developmental stages of Rana esculenta, starting with the posterior limb-bud stage (stage 26) up to a few days after metamorphosis, were examined immunohistochemically to localize cells and fibers producing some POMC-derived peptides, namely, alpha-MSH, ACTH and beta-END. Anti ACTH and anti alpha-MSH revealed a positive reaction in the pars intermedia during all stages of development included in this study, whereas no immunoreactivity in this pituitary zone was ever evidenced with anti beta-END. In the pars distalis strongly positive cells were seen with anti ACTH and anti beta-END, while anti alpha-MSH yielded weakly positive cells. Interestingly, these peptides were colocalized in the same cells. Immunoreactivity for alpha-MSH was no longer present in the pars distalis during metamorphic climax and postmetamorphosis. In the brain of premetamorphic tadpoles, belonging to stages 26 to 30, a few neurons in the posterior telencephalon showed a positive reaction only with anti alpha-MSH, but from stage 31 (prometamorphosis) onwards, ACTH and beta-endorphin-like peptide producing cells, together with alpha-MSH-immunoreactive cells, were seen in this region and in the anterior preoptic area and infundibulum. This situation persisted in the subsequent stages of development. Anti alpha-MSH also revealed weakly positive cells in the olfactory epithelium in premetamorphic tadpoles; strong immunoreactivity with anti alpha-MSH was seen in olfactory epithelium cells in animals during prometamorphosis, metamorphic climax and postmetamorphosis. The possible significance of these findings is briefly discussed. PMID- 7850862 TI - A large proportion of pelvic neurons innervating the corpora cavernosa of the rat penis exhibit NADPH-diaphorase activity. AB - Nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase histochemistry, which indicates the presence of neural nitric oxide synthase, the enzyme responsible for the generation of nitric oxide, was used in combination with retrograde labelling methods to determine, in whole-mounts and sections of rat major pelvic ganglia, whether neurons destined for the penile corpora cavernosa were able to produce nitric oxide. In whole-mount preparations of pelvic ganglia, among the 607 +/- 106 retrogradely labelled neurons innervating the penile corpora cavernosa, 84 +/- 7% were NADPH-diaphorase-positive, 30 +/- 7% of which were intensely histochemically stained. In serial sections of pelvic ganglia, out of a mean count of 451 retrogradely labelled neurons, 65% stained positively for NADPH-diaphorase. An average of 1879 +/- 363 NADPH-diaphorase positive cell bodies was counted in the pelvic ganglion. In the major pelvic ganglion, neurons both fluorescent for Fluorogold or Fast Blue and intensely stained for NADPH diaphorase were consistently observed in the dorso-caudal part of the ganglia in the area close to the exit of the cavernous nerve and within this nerve. This co existence was much less constant in other parts of the ganglion. In the rat penis, many NADPH-diaphorase-positive fibres and varicose terminals were observed surrounding the penile arteries and running within the wall of the cavernous spaces. This distribution of NADPH-diaphorase-positive nerve cells and terminals is consistent with the idea that the relaxation of the smooth muscles of the corpora cavernosa and the dilation of the penile arterial bed mediated by postganglionic parasympathetic neurons is attributable to the release of nitric oxide and that nitric oxide plays a crucial role in penile erection.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7850863 TI - Ultrastructural and immunocytochemical study of skin fibroblasts from normal and sialidosis patients. AB - The objectives of this study were to analyze morphologically, morphometrically and immunocytochemically the lysosomal compartment of normal fibroblasts and of fibroblasts with neuraminidase deficiency. The immunocytochemical analyses consisted of quantifying the distribution of saposins and beta-galactosidase in the lysosomes of these cells to test the hypothesis that neuraminidase deficiency is associated with an impairment in the transport of these proteins to the lysosomal compartment. To test this idea, cultured skin fibroblasts of patients with or without sialidosis were prepared for electron microscopy and probed with antibodies against lysosomal beta-galactosidase and lysosomal saposins. The lysosomes of the affected cells had an abnormal accumulation of incompletely digested membranes which was associated with a significant lowering in the density of antigenic sites per lysosome. However, due to a significant increase in the number of lysosomes per affected cell, the total number of antigenic sites in control and neuraminidase deficient cells was similar. This presumably compensatory effect indicates that although the rate of production of beta galactosidase and saposins remains unchanged, the transport of these molecules to the lysosomes is somehow affected. Our data also indicate that in the fibroblasts, lysosomes require a normal concentration of the three enzymes to maintain neuraminidase activity and sphingolipid degradation. PMID- 7850864 TI - Investigation of the early mineralisation on collagen in dentine of rat incisors by quantitative electron spectroscopic diffraction (ESD). AB - The earliest crystallites in dentine appear as chains of "dots" in ultra-thin sections viewed by transmission electron microscopy. These dots rapidly coalesce along the longitudinal directions of the collagen microfibrils to form needle like structures that coalesce preferentially in lateral directions to form ribbon like or plate-like crystallites. This morphological interpretation is supported by line-scans of the corresponding zero-loss filtered electron spectroscopic diffraction patterns, which demonstrate the crystalline structure of the dentine mineral (apatite). The intensity ratio of the Debye-Scherrer rings of the characteristic Bragg-reflections (002 to 300, together with 1 or 2 unresolved reflections) shows a maximum in the region of early chain-like and needle-like crystallites, decreasing with maturation of the dentine mineral to the ribbon plate-like crystallites. Detailed investigations using line-scans of the zero loss filtered electron spectroscopic diffraction patterns through the dentine zone show that the intensity ratio found near the mineralisation front is repeated 3-5 times at distances of about 10-20 microns. This may represent a circadian pattern of mineralisation corresponding to light microscopically visible incremental lines in dentine. PMID- 7850865 TI - Distinction of apoptotic and necrotic cell death by in situ labelling of fragmented DNA. AB - The occurrence and spatial distribution of intracellular DNA fragmentation was investigated by in situ 3' end labelling of DNA breaks in K562 cells treated in such a way to cause either apoptotic or necrotic cell death. The localisation of DNA breaks was examined by confocal laser microscopy and compared with the electron-microscopic appearance of the cells. In addition, the number of cells with fragmented DNA was counted and compared with the number of dead cells, as determined by the nigrosin dye exclusion test. Apoptosis was induced by cultivation of the cells in the presence of actinomycin D. Cells undergoing apoptosis were characterised by massive intracellular DNA fragmentation that was highly ordered into successive steps. Cells in early stages of the apoptotic process had DNA breaks diffusely distributed in the entire nucleus, except the nucleolus, with crescent-like accumulations beyond the nuclear membrane. In the more advanced stages, the nucleus was transformed into many round bodies with intense labelling. Intracellular accumulations of fragmented DNA corresponded exactly to electron-dense chromatin seen in the electron microscope, whereas diffuse DNA breaks had no morphological correlate at the ultrastructural level. In necrosis induced by ionomycin, NaN3, or rapid freezing combined with thawing, no DNA fragmentation occurred at the onset of cell death, but appeared 24 h later. This fragmentation was not characterised by a unique morphology, but represented the breakdown of the chromatin in the configuration remaining after cell death. Therefore, apoptosis is characterised by DNA fragmentation that proceeds in a regular orderly sequence at the beginning of cell death, and can be detected by in situ 3'end labelling of DNA breaks. PMID- 7850866 TI - Characterization of the fibrillar layer at the epithelial-mesenchymal junction in tooth germs. AB - A characteristic layer containing numerous fibrils is associated with the basement membrane of the inner enamel epithelium during the early stages of odontogenesis. However, its nature is not well understood. In this study, the layer was examined with high-resolution electron microscopy and immuno histochemical staining. Tooth germs of monkeys (Macaca fuscata) were studied and each fibril in the layer was found to be a tubular structure, 8-9 nm in width, resembling a "basotubule", the tubular structure previously observed in various basement membranes. The space between the fibrils was filled with a network formed by irregular anastomosing strands with an average thickness of 4 nm; these strands resembled the "cords" forming the network in the lamina densa of basement membranes. After immunoperoxidase staining, fine threads immunoreactive for laminin staining were seen winding along the strands of the network, and 1.5-nm wide filaments, immunoreactive for type IV collagen, took the form of a network arrangement. The 5-nm-wide ribbon-like structures associated with the strands were identified as heparan sulfate proteoglycan by immunostaining. These results are similar to those obtained for the cord network of the lamina densa. The "fibrillar layer" therefore represents a highly specialized lamina fibroreticularis of the basement membrane of the inner enamel epithelium, and rich in basotubules. PMID- 7850867 TI - Chorionic gonadotropin-like proteins in the obplacental giant cells of the rabbit. AB - Obplacental giant cells are enlarged cells, found following implantation, in the antimesometrial region of the rabbit uterus. They probably originate from trophoblastic knobs that traverse the uterine epithelium during early implantation. Little is known about their function. In this study, trophoblast, placental, paraplacental and obplacental tissues at days 7-15 post-coitum, and enzyme-isolated giant cells at day 15 were studied by two-dimensional gel electrophoresis, followed by immunoblotting and light-microscopic immunohistochemistry, for the presence of human chorionic gonadotropin-like proteins. Immunostaining was performed by using anti-human chorionic gonadotropin antibodies. In gel electrophoresis of obplacental tissue and isolated giant cells, two proteins of human chorionic gonadotropin-like antigenicity at 26 kDa with pIs equivalent to pH 6.4 and 6.6 were found; they were absent in the placenta, paraplacenta, day-7 blastocyst and day-8 trophoblast. The onset of synthesis of these proteins could be observed when day-8 trophoblastic tissue was cultured in vitro for 24 h. In immunohistochemistry, only the obplacental giant cells showed a positive reaction, indicating that the production of chorionic gonadotropin occurs in this cell type. PMID- 7850868 TI - Glutamate immunoreactivity is enriched over pinealocytes of the gerbil pineal gland. AB - Mammalian pinealocytes have been shown to contain synaptic-like microvesicles with putative secretory functions. As a first step to elucidate the possibility that pinealocyte microvesicles store messenger molecules, such as neuroactive amino acids, we have studied the distributional pattern of glutamate immunoreactivity in the pineal gland of the Mongolian gerbil (Meriones unguiculatus) at both light- and electron-microscopic levels. In semithin sections of plastic-embedded pineals, strong glutamate immunoreactivity could be detected in pinealocytes throughout the pineal gland. The density of glutamate immunolabeling in pinealocytes varied among individual cells and was mostly paralleled by the density of immunostaining for synaptophysin, a major integral membrane protein of synaptic and synaptic-like vesicles. Postembedding immunogold staining of ultrathin pineal sections revealed that gold particles were enriched over pinealocytes. In particular, a high degree of immunoreactivity was associated with accumulations of microvesicles that filled dilated process terminals of pinealocytes. A positive correlation between the number of gold particles and the packing density of microvesicles was found in three out of four process terminals analyzed. However, the level of glutamate immunoreactivity in pinealocyte process endings was lower than in presumed glutamatergic nerve terminals of the cerebellum and posterior pituitary. The present results provide some evidence for a microvesicular compartmentation of glutamate in pinealocytes. Our findings thus lend support to the hypothesis that glutamate serves as an intrapineal signal molecule of physiological relevance to the neuroendocrine functions of the gland. PMID- 7850869 TI - Localization of follicle-stimulating hormone (FSH) immunoreactivity and hormone receptor mRNA in testicular tissue of infertile men. AB - Testicular biopsies from 82 oligo- or azoo-spermic male patients were subjected to immunostaining using anti-human FSH antibodies. Histological evaluation showed normal spermatogenesis (nspg) in 7 (FSH: (2.7 +/- 0.7), mixed atrophy (ma) in 63 (FSH:L 5.3 +/- 0.5), and bilateral or unilateral Sertoli Cell Only syndrome (SCO) in 12 (FSH: 21.7 +/- 3.5) patients. For the relationship between FSH values and testicular histology, see Bergmann et al. (1994). FSH immunoreactivity was found exclusively in Sertoli cells and in some interstitial cells. Seminiferous epithelium showing normal or impaired spermatogenesis displayed only weak immunoreactivity compared to intense immunoreaction, i.e. large and numerous vesicles in Sertoli cells of SCO tubules in biopsies showing mixed atrophy or SCO. In addition, h-FSH receptor mRNA was demonstrated by in situ hybridization using biotinylated cDNA antisense oligonucleotides. Hybridization signals were found within the seminiferous epithelium exclusively in Sertoli cell cytoplasm associated with normal spermatogenesis and in epithelia showing different signs of impairment, including SCO. It is concluded that: (1) Sertoli cells are the only cells within the seminiferous epithelium expressing FSH receptors; (2) the accumulation of FSH immunoreactivity in Sertoli cells of SCO tubules appears to be a sign of impaired Sertoli cell function. PMID- 7850871 TI - Ultrastructural localization of rDNA and rRNA by in situ hybridization in the nucleolus of human spermatids. AB - The ultrastructural localization of rDNA and rRNA within the nucleolus of human spermatids was investigated by in situ hybridization at steps 1 and 2. Two different digoxigenin-labeled human probes from the rRNA transcription unit were used. Identification of hybrids was performed with immunogold techniques. Comparative observations in the Sertoli cell nucleolus as controls revealed that rDNA was predominantly visualized in the threads of the dense fibrillar component, while rRNA was detected over both the fibrillar component and the granular component. Within the nucleolus of round spermatids in the same sections of seminiferous tubules, rDNA labeling was localized over the spherical or stranded dense fibrillar components. rRNA labeling was found not only over these components but also in the adjacent nucleoplasm rich in ribonucleoprotein particles. These results are consistent with the view that the round spermatid nucleolus is transcriptionally active. PMID- 7850870 TI - Lectin-histochemical analysis of glycans in ovine and bovine near-term placental binucleate cells. AB - Chorionic binucleate cells (BNC) occur in several ruminants including cow, deer, goat and sheep. They migrate through the chorionic tight junction to fuse with uterine epithelial cells and discharge their granules into maternal connective tissue. We have compared the BNC of near-term, resin-embedded, ovine and bovine placentae using 15 biotinylated lectins and an avidinperoxidase revealing system. There was pronounced conservation of saccharides between the two species. Several sub-types of N-glycan were present, with highly branched structures being abundant, as shown by Galanthus nivalis, Pisum sativum and Phaseolus vulgaris (leuko) agglutinins. Among the non-reducing terminal saccharides conserved were GalNAc alpha 1,3(Fuc alpha 1,2)-Gal beta 1,4GlcNAc beta 1-, GalNAc alpha 1,6Gal beta 1-, Gal beta 1-, Gal beta 1,4GlcNAc- and Gal beta 1,3GalNAc alpha 1- shown by Dolichos biflorus, Wisteria floribunda, Erythrina cristagalli, and Maclura pomifera agglutinins, respectively. Arachis hypogaea and Glycine max agglutinins tended to bind to bovine BNC at different stages of maturity, while fucosyl residues detectable by Tetragonolobus purpureus and Ulex europaeus-1 agglutinins were not observed in either species. The only major difference related to sialyl residues, with alpha 2,3-linked sialic acid being present in bovine (Maackia amurensis, Limax flavus) and alpha 2,6 sialic acid being present in ovine (Sambucus nigra agglutinin) cells. This conservation of glycan may be related to glycosylation of peptide hormones in the granules, and may thus be important in the targeting of these hormones to their receptors. PMID- 7850872 TI - Ultrastructure of cultured human orbital fibroblasts. AB - The fine structure of cultured human orbital fibroblasts was investigated by transmission electron microscopy. One culture was derived from a patient with severe Graves' ophthalmopathy, the other from a donor without inflammatory orbital disease. Despite their known differences in metabolism, orbital fibroblasts from either source revealed no ultrastructural differences. The cells had extensive thin cytoplasmic processes. The perinuclear areas contained multiple assemblies of Golgi membranes, modest amounts of rough endoplasmic reticulum, intermediate filaments, and lysosome-like structures. Glycogen deposits were noted both in the perinuclear cytoplasm and in the thin processes. These ultrastructural features of orbital fibroblasts are the same as those of fibroblasts from other anatomic regions. PMID- 7850873 TI - The melanin-concentrating hormone: from the peptide to the gene. AB - Melanin-concentrating hormone (MCH) is a cyclic peptide originally isolated from chum salmon pituitaries, then structurally characterized from rat hypothalami. In the fish, MCH induces melanin concentration within the melanophores and may inhibit ACTH secretion in vitro and under stressful conditions in vivo. In the rat, MCH modulates ACTH release in vivo and oxytocin secretion in vitro. However, on the basis of neuroanatomical features, that is, cell bodies almost exclusively confined to the lateral area of the hypothalamus and the zona incerta, while fibers are observed throughout whole rat or human brains, this peptide appears to participate as a neurotransmitter/neuromodulator in the control of goal-oriented behaviors and/or general arousal in mammals. The knowledge of structural and regulatory features of the MCH precursor, mRNA, and genes at the cellular and molecular levels has recently made great progress. (1) The cells expressing MCH and associated peptides have been defined conjointly using radioimmunoassay, immunocytochemistry, and in vitro and in vivo molecular hybridization techniques. (2) The organization of the precursor deduced from cDNA cloning has been established and led to the discovery of two novel putative peptides named NEI and NGE. (3) The regulation of MCH mRNA and peptide production has been explored during the course of development in rodent and human and under a variety of paradigms (neurogenic or osmotic stress, hormonal stimuli, etc.). (4) The structure of the MCH genes has been determined in salmon, rat, mouse, and human and revealed striking exon-intron organization differences between fish and mammals. Strong homology, with a likely functional implication, was found between salmon MCH mRNA and 7SL RNA, a structural RNA involved in protein translocation. Furthermore, a variant gene that may encode slightly different MCH was found exclusively in primates. (5) Chromosomal assignment of the authentic and variant MCH genes in rat and human indicates that these genes may be good candidates involved in neurodegenerative or psychiatric disorders. Based on the framework of these studies, a working model of MCH regulation/function in mammalian brain is finally proposed. PMID- 7850874 TI - The role of the hypothalamic-pituitary-adrenocortical system during inflammatory conditions. AB - Infections and injury are often accompanied by the production of large quantities of proinflammatory mediators such as cytokines and eicosanoids. These substances have been shown to efficiently activate the hypothalamic-pituitary-adrenocortical (HPA) system. The glucocorticoid hormones secreted from the adrenal cortex seem to be crucial for survival because they have an inhibitory influence on inflammatory processes, which, if uncontrolled, may become toxic for the host. Furthermore, these steroid hormones are known to support thermogenesis by inducing or repressing key enzymes of carbohydrate, lipid, and protein metabolism, and thus may also facilitate energy mobilization during fever, which usually accompanies infectious diseases. Finally, a number of studies suggest that glucocorticoids attenuate debilitating symptoms of inflammatory mediators, such as sleepiness, loss of appetite, and suppression of reproductive functions. One can assume that glucocorticoids exert similar behavioral effects during inflammatory conditions, which are seen in infectious diseases. Corticotropin releasing hormone (CRH), the major hypothalamic component of the HPA system, is a putative mediator of the central effects of cytokines and autacoids because it inhibits growth, reproduction, and food intake. In contrast, CRH decreases sleep duration. Vasopressin, another hypothalamic peptide of the HPA system, counteracts fever and sickness behavior and is thought to support recovery from inflammatory diseases. Apparently, a well-balanced, concerted action of proinflammatory mediators, glucocorticoids, and hypothalamic peptide hormones provides not only an efficient principle for combating microorganisms and support of tissue repair but also for self-protection of the host during the stress of inflammation. Therefore, an impairment of the HPA system under inflammatory conditions often has severe pathological consequences, for example, in patients suffering from Addision's disease and arthritis. PMID- 7850875 TI - The neuropathology of the trisomy 16 mouse. AB - The purpose of this review is to describe the neuropathology of mouse trisomy 16 and to compare that pathology with the pathologic features observed in individuals with Down syndrome (DS) trisomy 21 (Ts21). Additionally, we will compare the neuroanatomic, neurochemical, and neurophysiologic abnormalities observed in both DS and in mouse trisomy 16 (Ts16). We discuss strategies that have been used to circumvent the failure of trisomy 16 mice to survive into the postnatal period: the creation of chimeras, the use of transplantation of fetal trisomic nervous tissue into normal hosts, and the generation of mice with partial Ts16. We compare the results with those observed in DS and in fetal mouse Ts16. Like individuals with DS, mice with trisomy 16 have triplication of a constellation of genes that have remained together in the same order for roughly 80 million years. As more of these genes have been identified and localized to specific regions of human chromosome 21 and mouse chromosome 16, efforts have been made to create transgenic mice that carry single of these genes in excess. In this review, we also discuss the comparative pathology observed in these transgenic mice. PMID- 7850876 TI - Chronic muscular pain: aetiology and pathogenesis. AB - The conclusion is that no one single mechanism can explain FMS and is thus in that sense a compromise. FMS in some patients may start in the muscle, in other patients in the brain. The combination of peripheral and central factors is the key to the pathogenesis of FMS as long as FMS is defined as a pain syndrome. PMID- 7850877 TI - Muscle function and origin of pain in fibromyalgia. AB - It may be concluded that both peripheral and central mechanisms may operate in the pathophysiology of both impaired muscle function and pain in FM. These mechanisms may in part be attributable to physical deconditioning and disuse of muscle secondary to the characteristic pain and fatigue so often seen in FM. Most likely the initiation of this condition is multifactorial and the combination of peripheral and central factors that constitute a vicious circle may perpetuate the condition into a chronic state. PMID- 7850878 TI - Neurobiology of the myofascial trigger point. AB - The clinical phenomenon of the MTrP is accessible to any clinician who takes the time to learn to palpate skeletal muscle gently and carefully, and who is willing to learn the functional anatomy necessary to understand the regional spread of MTrPs through functional muscle units (Travell and Simons, 1992). Yet despite the years of clinical study of MPS, the pathophysiology of the central feature, the trigger point, has remained elusive. Many investigators have contributed to the general understanding of the mechanisms of pain perception, but we owe a particular debt of gratitude to Dr Seigfried Mense of Heidelberg for his pursuit of the study of pain originating in muscle lesions. However, Dr Mense would be the first to caution us against the direct transference of the results obtained with an inflammatory lesion produced in the experimental animal to the pain of MTrPs in the clinic patient. Notwithstanding that, researchers in the field of pain have given us an understanding of the basis for the hyperalgesia, allodynia and the previously difficult-to-understand finding of referred pain zones that we see daily in our patients. Finally, the interesting initial observations of Hubbard and Berkoff (1993), suggesting that the muscle spindle may be associated with the trigger point, open yet another door in our understanding of the nature of MPS. PMID- 7850879 TI - Neuromediator and hormonal perturbations in fibromyalgia syndrome: results of chronic stress? AB - Since the first comprehensive description of the symptoms of FMS by Yunus et al (1981), numerous investigations have confirmed that FMS is a clinical entity. However, the aetiology of the syndrome is still not fully elucidated. It seems, however, logical to place the origin of the disorder in the muscle. Muscle pain, especially at the muscle-tendon junctions, fatigue and stiffness are the first symptoms. A malfunction of energy metabolism has been detected in part of the muscle fibres. However, it has to be considered that the muscle is not an isolated entity. Its activity is controlled by segmentally arranged motor units of the ventral horn of the spinal cord in response to proprioceptive afferent signals arising in the muscle spindles or in other sensory elements including nociceptors. Together with supraspinal descending inputs, the spinal motor neurone pool is the common final pathway for segmental and suprasegmental inputs, making the motor system extremely powerful for adaptive adjustments but also vulnerable if deficits occur in either of these input levels. A second, recently discovered abnormality seen in FMS is a lowered serotonin level in peripheral and most likely also central structures. The underlying mechanism seems to be defective absorption of the precursor amino acid tryptophan from the gut. Serotonin is involved centrally in the regulation of the sleep pattern, and at the spinal level it acts as a 'gain setter' of motoneurone excitability and suppresses signal transmission of noxious stimuli in dorsal horn neurones. Either of these two disturbances, muscle energy depletion or serotonin deficiency, could by itself evoke many of the symptoms of FMS, and their combined appearance will perpetuate the disease. Depressed levels of somatomedin C, caused by a deficit of stage 4 sleep-dependent release of GH, might represent an additional factor in preventing proper development or repair of myoskeletal structures. Malabsorption of certain amino acids, possibly due to a genetic disorder of gut transport mechanisms, may constitute an additional deleterious factor. The abnormalities found in the HPA and HPT axis may be seen as an attempt of the organism to restore homeostasis. The stimulus eliciting this counter-regulatory reaction may be pain or other afferent signals which normally do not reach the central nervous system. It is doubtful whether the unspecific activation of the HPA axis in a non inflammatory disease is beneficial.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7850880 TI - Fibromyalgia syndrome: a pain modulation disorder related to altered limbic function? PMID- 7850881 TI - Chronobiological influences on fibromyalgia syndrome: theoretical and therapeutic implications. AB - A review of the evidence from diurnal physiological, seasonal environmental and prospective studies of social-behavioural functions suggest that a chronobiological theoretical model provides a comprehensive basis for the dynamics of central nervous system mechanisms, the assessment and the management of patients with fibromyalgia. The chronobiological model stresses the importance of temporal variation and the factors that influence and govern recurrent patterns of biological functions and behaviour that determine health and illness. Finally, the theory allows for an integrated study of brain, behaviour and somatic functions over time and emphasizes that such a comprehensive approach is core to any therapeutic intervention. PMID- 7850882 TI - Psychological aspects of fibromyalgia syndrome: a component of the dysfunctional spectrum syndrome. PMID- 7850883 TI - The concept of affective spectrum disorder: relationship to fibromyalgia and other syndromes of chronic fatigue and chronic muscle pain. PMID- 7850884 TI - Myofascial pain. AB - MFP is a regional muscle pain disorder characterized by localized muscle tenderness and pain and is the most common cause of persistent regional pain. The affected muscles may also display an increased fatiguability, stiffness, subjective weakness, pain on movement and slightly restricted range of motion that is unrelated to joint restriction. MFP is frequently overlooked as a diagnosis because it is often accompanied by signs and symptoms in addition to pain, coincidental pathological conditions, and behavioural and psychosocial problems. Chronic pain characteristics often precede or follow the development of MFP. Evaluation of MFP includes locating the trigger points and muscles involved as well as recognition of the contributing factors. Management of the syndrome naturally follows with muscle exercises, therapy to the trigger points, and reduction of all the contributing factors. The short-term goal is to restore the muscle to normal length and posture and full joint range of motion with exercises and trigger point therapy. The long-term goals include reducing the symptoms and their negative effects while helping the patient return to normal function without the need for future health care. The difficulty in managing MFP lies in the critical need to match the level of complexity of the management programme with the complexity of the patient's situation. Failure to address the entire problem, through a team approach if needed, may lead to failure to resolve the pain and perpetuation of a chronic pain syndrome. PMID- 7850885 TI - Physical medicine and rehabilitation approaches to the management of myofascial pain and fibromyalgia syndromes. AB - In summary, we have presented the physical medicine and rehabilitation medicine approaches for treating patients with fibromyalgia and the myofascial pain syndromes. The importance of approaching these patients from a holistic and multidisciplinary standpoint has been stressed, paying attention to the physical, emotional, spiritual and behavioural components of the presentation. Although fibromyalgia and the myofascial pain syndromes are two distinct conditions, they often overlap, and when they do the myofascial component should be treated first. However, the clinician should remember that pain, tissue dysfunction and disability from pain are all separate issues and should be treated as such. Treatment in all cases should be individualized and comprehensive. It is imperative to make the patient an active participant in his care and to establish mutually agreed upon goals at the outset of treatment. It is important to establish an adequate and appropriate home exercise programme to supplement formal treatment. A good home exercise programme should stress both stretching and strengthening. Formal treatment programmes should not be geared to pain relief alone but rather to restoration of function, and return to functioning lifestyles. The clinician has available a wide array of modalities and tools to control pain, but the major goal of all treatment programmes is to restore individuals to functional lifestyles and to promote both physical and emotional flexibility, balance and 'wellness'. It is often necessary to involve the family unit as an inherent and critical part of the treatment team, particularly with the patient who continues to be dysfunctional despite apparently appropriate treatment. Although treatment always starts at the tissue level, a good treatment programme must always be holistic in nature and treat the tissues, the patient as a whole, and his or her environmental stressors and contingencies as well. PMID- 7850886 TI - Controlled trials of therapy in fibromyalgia syndrome. AB - Many different interventions have been studied in the therapy of fibromyalgia syndrome (Tables 1 and 2). While most have been effective, in general these trials have been short term. Furthermore, important or substantial improvement, when it has been assessed, occurs in only small proportions of patients. Long term, comparative trials of both efficacy and toxicity are necessary. Trials such as these require large numbers of patients (compared with placebo-controlled trials, which are generally impractical in long-duration trials due to the large numbers of dropouts in the placebo arm) and therefore are expensive and difficult to accomplish. Two other approaches offer potential solutions to the problem of adequate long-term comparative trials: (a) N-of-1 trials and (b) meta-analysis. N of-1 trials have the advantage of random assignment, double-blinding and multiple potential comparisons in the same patient. Meta-analysis involves combining the results of studies, which individually may have conflicting results and lack adequate statistical power, to reach an overall result with sufficient statistical power to make meaningful conclusions, especially with respect to comparative efficacy. Peluso and colleagues (1993) have performed a recent meta analysis of available therapies in fibromyalgia syndrome and found that the effect-size (a standardized measure of the efficacy of a given therapy) of several non-medication therapies such as electroacupuncture exceeded that of traditional medication therapies. Unfortunately, lack of uniformity in the use of outcome measures across included trials and the small numbers of comparable non medication trials makes definitive conclusions regarding relative efficacy of therapies difficult. Nevertheless, application of meta-analytic methods such as these should facilitate future comparisons of different interventions. Ideally, future clinical trials in fibromyalgia syndrome should employ the same outcome measures to permit application of these methods. Few trials have assessed improvement in functional status. Functional status measures such as the HAQ (Fries et al., 1980), the Fibromyalgia Impact Questionnaire (Burckhardt et al, 1991) or similar instruments should be employed in future studies of therapy in fibromyalgia. Given that individual modalities appear to confer relatively modest benefit on average. Combination approaches are reasonable, although randomized, blinded trials to assess these approaches are methodologically complex. Several preliminary studies which have addressed this approach appear promising (see Chapter 12; Goldenberg et al, 1993). Finally, no studies have yet assessed the comparative cost-efficacy of available treatments. Controlled trials which address the cost-efficacy of commonly employed, but unproven treatments such as physiotherapy chiropractic manipulation and injection techniques are urgently needed. PMID- 7850887 TI - Education programmes for fibromyalgia patients: description and evaluation. AB - A firm theoretical basis for patient education in rheumatic disease care has been built up over the past 10 to 15 years. Education in self-management has enabled patients to control symptoms and become partners in care with their health providers. Education for fibromyalgia patients has come to the foreground during the last 5 years as health professionals have come to understand the syndrome better and recognize the role that stress plays in the exacerbation of symptoms. A few controlled trials of various strategies, such as aerobic conditioning and cognitive-behavioural techniques, have been reported recently. All have shown significant benefits to patients with fibromyalgia. Only one controlled trial has studied the effects of a self-management education programme alone. The results of this programme were positive. Self-efficacy and life quality were enhanced. This programme and an uncontrolled programme that integrated many strategies have shown some of the first positive long-term indications that patients who are treated intensively for even a short time can continue to improve as they practice self-management techniques. There is still a need for further documentation of non-drug treatment strategies and especially further research into who is helped by which strategies, the optimal length of time for a programme, and the need for ongoing treatment. PMID- 7850888 TI - An intuitive person-centred perspective on fibromyalgia syndrome and its management. PMID- 7850890 TI - Microtubule-stabilizing activity of microtubule-associated proteins (MAPs) is due to increase in frequency of rescue in dynamic instability: shortening length decreases with binding of MAPs onto microtubules. AB - The role of microtubule associated proteins (MAPs) on the dynamic instability of microtubules was examined under a dark-field microscope using bovine brain tubulin purified by DEAE-Sepharose column chromatography. In the absence of MAPs, the transition from the shortening phase to the growing phase (the rescue) occurred rarely both in self-assembled microtubules and seeded ones, especially at the plus end. Even under the conditions unfavorable to stabilize microtubule, the addition of a small amount of crude MAPs or purified microtubule associated protein 2 (MAPs) to the microtubules allowed them to undergo the rescue. At increased concentrations of MAPs or MAP2, both the length change required for a rescue during shortening phase ("shortening length") and for a catastrophe (transition from the growing to the shortening phase) ("growth length") decreased. Under these conditions, the rescue often occurred at the same site where previous rescues occurred. Distribution of immunofluorescent MAP2 antibodies along individual microtubules showed that MAP2 molecules bound onto microtubules by forming discrete clusters. The number of MAP2 molecules per cluster was estimated to be between 25 and 60. Because both the "shortening length" and the distance between MAP2 clusters in a microtubule decreased with increased MAPs concentration, we suggest that the MAP2 clusters may form the specific site at which the shortening of the microtubule readily stops. MAP2 possibly regulates the dynamic instability by stopping the shortening, which is a prerequisite for the rescue. PMID- 7850889 TI - Characean cells as a tool for studying electrophysiological characteristics of plant cells. AB - Characean cells have contributed significantly to various areas of plant cell biology such as cell motility and membrane transport. Since characean cells are very large, various kinds of operations can easily be applied to them. Development of techniques of intracellular perfusion and permeabilization of plasma membrane has facilitated studies on functions of the plasma membrane and the vacuolar membrane (or tonoplast) which is specific to plant cells. The present article is aimed at reviewing the contribution of characean cells to the study of electrophysiological characteristics of plant membranes. Our attention was mainly focused on experiments using plasma membrane-permeabilized cells and intracellularly perfused cells. PMID- 7850891 TI - Retarded fibronexus formation and cell attachment on type V collagen. AB - We previously found that type V collagen repressed the attachment and spread of aortic smooth muscle cells. The present study was carried out to investigate the effects of type V collagen on the formation of fibronectin and F-actin filaments of human dermal fibroblasts in relation to cell attachment and spread, using an immunofluorescent technique and morphometry. The number and area of the cells attached to type V collagen at 1 and 3 hours after seeding were significantly lower than those of cells on other substrates, including collagen types I, III and IV, and bovine serum albumin. However, there was no significant difference in the attachment and spread among the cells on these substrates after 24 hours. Cultured fibroblasts exhibited two patterns of fibronectin; one was a clear, linear fibronectin localized mainly in the cellular margins, and the other was a granular or flocculent fibronectin found in the perinuclear areas. The former was stained in non-permeabilized cells, but not in trypsin-treated cells (cell surface fibronectin). In contrast, the latter was not detected in nonpermeabilized cells, but was found in trypsin-treated cells (perinuclear fibronectin). Most of the cells cultured on type V collagen did not form either linear cell surface fibronectin or F-actin filaments at 3 hours. In contrast, many cells on collagen types I, III, and IV developed both cell surface fibronectin and F-actin filaments, the distributions of which were partially coincident. Colocalization of linear cell surface fibronectin and F-actin filaments was found in cells on all of the substrates after 24 hours. Perinuclear fibronectin showed similar patterns, and was not colocalized with F-actin filaments on different substrates at 3 and 24 hours of culture. Solid-phase substrates induced a better cellular attachment at 3 hours than serum adhesive factors. The administration of monensin, which inhibits the secretion of protein products, decreased the intensity of the fluorescence of cell surface fibronectin in fibroblasts, which was observed in a clear line. These results suggest that the retardation of the initial attachment and spread of fibroblasts on type V collagen is related to an inhibition in the formation of the fibronexus, a close transmembranous association of individual fibronectin fibers and F-actin filaments. PMID- 7850892 TI - Transforming growth factor beta 1 selectively increases gene expression of the serine/threonine kinase receptor 1 (SKR1) in human hepatoma cell lines. AB - Human hepatoma cell lines (Hep 3B-TS, PLC/PRF/5, and Hep G2), sensitive to growth inhibition by transforming growth factor beta 1 (TGF-beta 1), express TGF-beta receptors type I, type II, and type III. We report that TGF-beta 1 protein selectively increased steady-state levels of the mRNA for the serine/threonine kinase receptor 1 (SKR1), a member of the TGF-beta superfamily receptor genes in these cells, whereas TGF-beta 1 had little effect on expression of the TGF-beta receptor type II gene. This increase of SKR1 mRNA in Hep 3B-TS cells could be detected by Northern blot analysis within 3 h of addition of TGF-beta 1 to the cells, and enhanced message levels peaked at 12 h as long as TGF-beta 1 was present in the culture medium. Hep 3B-TR cells which were resistant to TGF-beta 1 due to lack of both TGF-beta receptors type I and type II, expressed SKR1 mRNA, but it was not induced by TGF-beta 1 protein. The increased expression of SKR1 mRNA in the cells was actinomycin D-sensitive and was not dependent on new protein synthesis. The results indicate that TGF-beta 1 selectively induces SKR1 message at a transcriptional level by a positive regulator. PMID- 7850893 TI - Effect of Ca2+ on morphogenesis of HVJ (Sendai virus) virion in LLC-MK2 cells: suppression of viral production. AB - Production of HVJ (Sendai virus) virion is suppressed in the infected LLC-MK2 cells in the low Ca2+ condition. To clarify this phenomenon, the effect of Ca2+ on HVJ morphogenesis was examined under normal and low Ca2+ conditions. The HVJ production was observed in standard medium (containing 1.8 mM Ca2+) within 24 hr after infection and increased with the culture time. Indirect immunofluorescent staining with an anti-HVJ envelope antibody showed that the viral glycoproteins, HANA (HN) and F proteins, were synthesized within 10 hr after infection, diffused to the cell surface, and then many patches strongly stained with this antibody were formed on the cell surface. In contrast, when the infected cells were cultured in low Ca2+ medium, viral glycoproteins were synthesized as in the case of standard medium. However, the glycoproteins were almost all accumulated in the Golgi apparatus, suggesting that expression of viral glycoproteins at the cell surface was suppressed, and the patches were hardly seen on the cell surface. When the low Ca2+ medium was replaced by standard medium, the accumulated viral glycoproteins were rapidly diffused and expressed on the cell surface, HVJ production was restored and patches formed on the cell surface. By confocal laser scanning microscopy, the results were seen more clearly; Ca2+ is necessary for the expression of viral glycoproteins at the cell surface. By electron microscopy under normal conditions, groups of viral budding sites were seen collected in restricted areas, corresponding to the patches observed on immunofluorescent staining, but the budding sites were not seen on the cells cultured in low Ca2+ medium.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7850894 TI - Further analysis of the effect of Ca2+ on morphogenesis of HVJ (Sendai virus) in LLC-MK2 cells: effects on phosphorylated M protein associated with viral morphogenesis. AB - Previously we have reported that Ca2+ concentration in culture medium affects the morphogenesis of HVJ from infected cells. We further investigated the effects of Ca2+ on HVJ morphogenesis in LLC-MK2 cells, focusing on M (matrix) protein which plays an important role in the assembly of viral components. On culture in standard medium (containing 1.8 mM Ca2+), most of the M protein accumulated on the apical surface in patches. On double immunofluorescent staining with anti-M protein monoclonal antibody and polyclonal antibody against HVJ glycoproteins, M protein and viral glycoproteins were observed in the same patches at the cell surface. By contrast, in low Ca2+ medium, M protein was evenly dispersed over the cell surface, especially in the regions of cell-cell contact, and was not seen in patches. Immunoblot analysis for M protein in the infected cells showed that the total amount of M protein was almost the same irrespective of Ca2+ concentration in the culture medium. But, there was a distinct difference in the forms of M protein found in the cells: most of the M protein in the cells cultured in standard medium was of the non-phosphorylated form, whereas the phosphorylated form of M protein was distinctly increased in the cells cultured in low Ca2+ medium. These results suggest that Ca(2+)-deficiency in the medium blocks dephosphorylation of phosphorylated M protein necessary for patch formation, resulting in disturbance of viral morphogenesis. PMID- 7850895 TI - Immunohistochemical localization of estrogen receptors in the submandibular gland tumors of female rats. AB - The localization of estrogen receptors (EsR) in the tumor tissues of submandibular glands was examined in female rats, using the indirect immunoperoxidase method in combination with the in situ hybridization technique. Tumors were experimentally produced by 9,10-dimethyl-1,2-benzanthracene (DMBA), and the tumor tissues were fixed with formalin or paraformaldehyde and then embedded in paraffin. In the DMBA-induced submandibular gland tumors, immunoreactivity to EsR-peroxidase conjugate was found in nuclei of the tumor cells which occupied the peripheral rim of the tumor cell nests. In contrast, the reactivity in the normal submandibular glands without tumor was mostly confined to nuclei of the duct cells. When EsR mRNA expression was analyzed in the tumor tissue by in situ hybridization with a cDNA probe, its distribution was identical with that of immunoreactivity to EsR. These data suggest that the ductal cells of the submandibular gland are responsive to ovarial steroids, and that estrogens may play an important role in the maintenance of growth of the submandibular gland tumors. PMID- 7850896 TI - tsJT16, a cell cycle ts mutant of rat fibroblast defective in early G0/G1 transition, fails to induce G1-cyclin and cdk2 genes after serum stimulation at the nonpermissive temperature. AB - tsJT16 is a cell-cycle temperature-sensitive (ts) mutant derived from rat fibroblasts whose functional defect appears soon after the growth stimulation from G0 phase. In addition to c-fos, c-myc and ornithine decarboxylase gene, 7 primarily inducible genes, c-jun, KC, JE, 2F1, 2A9, egr-1, and egr-2, were further shown to be expressed after serum stimulation at both permissive and nonpermissive temperatures. However, expression of secondarily inducible genes, cyclin D1 and D3 and cdk2, was ts and was cycloheximide sensitive. Expression of cyclin C was not inhibited by cycloheximide but it was ts. Failure in expression of G1 cyclins and Cdk2 is suggested to be a causal event for inability of growth induction of tsJT16 at the nonpermissive temperature. PMID- 7850897 TI - [Artificial lenses in surgery of traumatic cataracts due to perforating injuries of the eye]. AB - In this work longdated anatomical and functional results of artificial lens implantation in traumatic cataracts after perforation of the eye in the group of 44 eyes (43 patients) aged between 3-54 years are evaluated (in the years 1985 89). Average period of observation was 6.3 years. Saving capsula, the artificial intraocular lens was implanted into the posterior eye chamber. In the years 1985 86 also the pupilar models (T03 Fyodorv-Zacharov) were used. In absent of capsular support, the artificial intraocular lens was implanted into the anterior eye chamber and also the posterior-chamber models with polypropylene haptics were successfully applicated (less number of negative changes was achieved). The visual acuity 6/36 and better was constated in 79.5% eyes (before operation only in 13.7%) during the last examination of the observed patients. Best results were achieved after implantation into the posterior eye chamber (90% of the eyes had visual acuity 6/6-6/12). PMID- 7850898 TI - [Intraocular lens implantation in traumatic cataracts caused by intraocular foreign bodies]. AB - The authors reports about the group of 17 patients in whom an IOL was implanted in eyes with traumatic cataract caused by IOFB. In 8 patients varied the interval between IOFB removal and IOL implantation from 5 months to 5 years. In 7 patients was IOFB removal and IOL implantation performed in one procedure. In one patient was IOFB not removed and in one patient was IOFB removed 1 month after IOL implantation. In two patients was IOL implanted in AC, in all other patients in the bag or in the sulcus. Per- and postoperative complications are discussed. We lost one patient from the observation. The follow-up period of 16 patients varied between 6-56 months. The final visual acuity in 10 patients reached 0.8-1.0. Visual acuity only of light perception is at patient, after repeated vitrectomies for retinal detachment. PMID- 7850899 TI - [The CO2 laser in ophthalmology. I. Physical and biological properties and indications for the 20-C CO2 laser made by Pfizer Laser Systems]. AB - The authors describe physical and biological properties of a CO2 laser operating in the infrared area (wave length 10,600 m). The authors discuss the use of this laser in ophthalmology and draw attention to its advantages as well as shortcomings. They describe the apparatus 20-C of Pfizer Laser Systems, incl. safety measures required for operation of the CO2 laser. PMID- 7850900 TI - [The CO2 laser in ophthalmology. II. Use of the CO2 laser in facial skin disorders]. AB - The authors present an account on results of CO2 laser therapy in facial skin and conjunctival affections during the period between 1990 and 1993. In the evaluated group, comprising 60 patients with an observation period of 18 months, this method was used 82 times, incl. four where it was used repeatedly. In the technique of the procedure simple vaporization markedly predominates over combined operations or laser incisions (continual regime). The defect after vaporization heals by tissue which has the same colour as surrounding skin, in a very small minority with slight local depigmentation without a tendency of major scarring and with a satisfactory cosmetic effect. The authors discuss indications of CO2 lasers in ophthalmology. The method is recommended in strictly defined affections of the skin and conjunctivae. PMID- 7850901 TI - [Opacification of the posterior capsule after IOL implantation and its therapy using a picosecond Nd-YAG laser]. AB - In a group of 1700 patients after operation of cataract with implantation of IOL the authors found opacification of the posterior capsule in 765 instances (45%). Treatment was provided with a Nd-YAG laser using a picosecond regime. The authors discuss the causes of opacification, successful surgery and its complications. PMID- 7850902 TI - [Fibrin reaction after implantation of posterior chamber intraocular lenses]. AB - One of the complications after implantation of posterior chamber intraocular lenses is fibrin reaction. The authors analyse group of 653 patients--659 eyes after the operation of cataract with implantation of posterior chamber IOL operated in 1991-1992 at Postgraduate School of Medicine, Ophthalmology Department in Bratislava. The fibrin reaction was found out in 33 cases (5%). This reaction started between the first and third day after the operation. From this group of 33 patients, 14 (43%) were treated for glaucoma, 11 (33%) had diabetes mellitus and 3 (9%) overcome uveitis in past years. In all cases after the treatment came to the complete loss of fibrin. Finally visual acuity was 5/5 to 5/10. PMID- 7850903 TI - [Ocular manifestations of sarcoidosis]. AB - The authors describe two patients with endogenous uveitis. When investigating the aetiology of the inflammation systemic sarcoidosis was diagnosed. The authors emphasize the necessity of interdisciplinary collaboration during care of patients suffering from this disease. PMID- 7850904 TI - [A case of Creutzfeldt-Jakob syndrome with dominant ocular symptoms]. AB - The authors present a rare case of a 46-year-old man with Creutzfeldt-Jacob's disease, its causal agent being an unconventional virus (prion). Ocular symptoms were the first which made the patient see a doctor. The course of the disease with a fatal outcome caused great diagnostic difficulties among a number of specialists. PMID- 7850905 TI - [Changes in visual fields after a single dose of alcohol]. PMID- 7850906 TI - [Coatel--2% hydroxypropylmethylcellulose (OPSIA)]. PMID- 7850907 TI - [Deep pre-endothelial stromal hemorrhage caused by sleeping with aphakic daily wear contact lenses in place]. PMID- 7850908 TI - [The sutureless technic in cataract surgery]. PMID- 7850909 TI - [Nooptropic agents and their action mechanisms in relation to neuropathology in senile dementia. II. Disorders of membrane integrity and neuron metabolism]. AB - The author discusses several newer aspects concerning neurodegenerative processes in nerve cells of aging brain on the level of membrane integrity and neuronal metabolism disturbances: aggressive impact of free radicals and excitatory amino acids, loss of calcium homeostasis, deposition of amyloid proteins. Perspective nootropic agents are presented which were synthetized with the aim to regulate these deficits and first clinical experience with their administration in senile dementia patients is evaluated. PMID- 7850910 TI - [Diagnosis of behavior disorders according to the ICD-10]. AB - The author defines the character and symptoms of behavioural disorders in childhood and adolescence. The material is classified according to the concept of continuity and discontinuity of psychiatric symptoms or syndromes and diagnostic entities from childhood to adult age. PMID- 7850911 TI - [Heroin addiction--a new type of drug dependence in Slovakia (personal experience)]. AB - The authors present their initial experience with patients reporting contact with heroin. For the authors this is a new type of dependence. They present a group of 33 patients (only two women), mean age 26 years, hospitalized at two psychiatric clinics in Bratislava. The majority of patients were single, and had only elementary education. Only in 10 patients the diagnosis of fully developed dependence on heroin confirmed, in 12 patients sign of dependence were lacking. The authors draw attention to the discrepancy between subjective data of the patients and objectively assessable signs of dependence. Most frequently heroin was inhaled, only in five patients i.v. administration of the drug was recorded. For treatment available psychopharmaceutical preparations were used (anxiolytics, neuroleptics). Opium administration was not necessary. PMID- 7850912 TI - [Homicidal activity directed against parents (forensic-psychiatric aspect)]. AB - The authors present an account of four men where orders were given to examine their mental state because of murderous activity focused on a parent. In three instances murder was involved, in one case attempted murder. Three of the subjects were youths 13-19 year old, one was 61-year-old at time of murder. In three instances the activity occurred in a state of affect, incl. one case of simple affect of anger and mild drunkenness, in another case (except simple affect of fear) a short-out activity, and in the last case a pathic affect with impaired consciousness at the climax. In one case (the 13-year-old boy) the parent was killed during sleep obnubilation. The temporary mental disorder at the time of the crime led in three of the murders to severe impairment of differentiating and control abilities. In another of the men (61 years old) in the impaired control and differentiating abilities in addition to the affect of anger and simple drunkenness--slight impairment of cognitive functions participated. The authors emphasize the exceptional character of aggression in cases of murderous activities focused on parents. They compare their own experience with data in the literature and draw attention to the frequent occurrence of major forensic mental disorders. The diagnosis of mental disorders must respect general diagnostic principles. An important part is played by auxiliary examination methods. PMID- 7850914 TI - [Emotional disorders in medieval medicine]. PMID- 7850913 TI - [Occurrence of deviant tendencies in phalloplethysmographic and vulvoplethysmographic examinations in sexually dysfunctional patients (case reports)]. AB - The author demonstrates on four case-histories the presence of sexual deviant trends as the cause of sexual dysfunctions in conventional heterosexual relations in men and women and the irreplaceable part played by vulvo- or phalloplethysmography used for their detection. In a man treated for some time on account of impaired erectile potency and in a woman who visited the surgery with her husband and presented complaints diagnosed as secondary frigidity and anorgasmy, PPG or VPG examination revealed a homosexual orientation. Both these patients knew of their homosexual orientation but did not tell anybody. The mentioned male patient intentionally dissimulated homosexuality, the woman attempted in vain to achieve heterosexual adaptation. In two young men with primary disorders of erectile potency PPG examination revealed sadomasochistic tendencies. In the first one the impaired erectility created the impression of "debutant's failure" when starting a partnership, in the second one it seemed to be due to adverse psychosocial factors. During an interview following the examination both described spontaneously and in detail erotic dreams and masturbation fantasies with sadomasochistic contents. They were not aware of the association of their specific sexual motivation structure. It was typical for all four patients that they never disclosed previously their deviant sexual tendencies and only the specific situation during the PPG or VPG examination, which they had voluntarily after previous instruction, they were motivated to confess their problems. PMID- 7850915 TI - Phase II study of a new combined primary chemotherapy regimen, intravenous methotrexate and vincristine and intraarterial adriamycin and cisplatin, for locally advanced urinary bladder cancer: preliminary results. AB - A phase II study of a new combination therapy was performed using intraarterial (i.a.) cisplatin and Adriamycin in combination with i.v. methotrexate and vincristine for 27 patients with invasive urinary bladder carcinoma of stages T2 3NOMO, and the therapeutic effects were assessed. Methotrexate (20 mg/m2) was given i.v. on days 1,15, and 22, and vincristine (0.7 mg/m2) was injected i.v. on day 2 before i.a. infusion therapy and on days 15 and 22. The i.a. chemotherapy was performed after both superior gluteal arteries had been embolized using 3- or 5-mm stainless-steel coils. A mixture of cisplatin (50-70 mg/m2) and Adriamycin (20 mg/m2) was infused i.a. via both internal iliac arteries over a period of 20 30 min. Angiotensin II (mean dose, 21 micrograms) was simultaneously infused i.a. in 15 of 27 patients. In 24 of the 27 patients, at least 2 cycles of full-dose chemotherapy were completed. The dose was decreased in the remaining 3 patients because of their poor health status and advanced age. Among the 27 patients, 9 and 14 had complete (CR) and partial responses (PR), respectively; 3 manifested no change (NC), and 1 had progressive disease (PD). The objective response rate (CR+PR) was 85.2%. Among the 27 patients staged T2-3 NOMO, 6 (CR, 1; PR, 5) underwent total cystectomies and 18 (CR, 8; PR, 8; NC, 2) had transurethral resection of a bladder tumor (TUR-Bt) or partial resections following chemotherapy. The remaining 3 diminished-dose patients had no surgery. Of the 27 patients, 22 were alive after a median follow-up period of 21+ (range, 7-48+) months. No significant side effect was observed except for lower extremity paresthesias in 5 patients (18.5%). These results point to the effectiveness of this therapy and to the possibility of urinary bladder preservation in patients with invasive, advanced urinary bladder cancers. PMID- 7850916 TI - D-19575--a sugar-linked isophosphoramide mustard derivative exploiting transmembrane glucose transport. AB - D-19575 is a glucose derivative of ifosfamide mustard with a broad spectrum of antitumor activity in animal models. In comparison with ifosfamide, D-19575 is less toxic and is better tolerated by tumor-bearing animals, achieving a better therapeutic efficacy. D-19575 is directly cytotoxic in vitro--in contrast to ifosfamide--and it is possible to modulate this cytotoxicity by inhibition of transmembrane glucose transporters. Correspondingly, renal reabsorption of filtered D-19575 could be blocked by pre- and cotreatment with phlorizin, resulting in a higher urinary excretion of the unchanged drug. The toxicity to white blood cells, colony-forming units (CFU-C), and spleen-cell colony-forming units (CFU-S) is considerably lower for D-19575 as compared with ifosfamide. In conclusion, D-19575 is a new alkylating cytotoxic agent with increased antitumor selectivity, probably caused by an active transmembrane transport mechanism. PMID- 7850917 TI - Cytotoxicity and cellular accumulation of a new cis-diammineplatinum (II) complex containing procaine in murine L1210 cells sensitive and resistant to cis diamminedichloroplatinum (II). AB - The emergence of drug resistance during tumor chemotherapy is one of the main problems associated with cancer treatment, particularly with cisplatin (cis-DDP). In the hope of overcoming this problem, various cis-DDP-derived compounds have been synthesized, and their pharmacological activity was compared with that of cis-DDP. In this paper we report on studies on the cytotoxic activity induced by cis-diamminechloro-[2-(diethylamino)ethyl-4-aminobenzoate, N4]- chlorideplatinum(II) monohydrochloride monohydrate (DPR), a new complex of platinum containing procaine. All experiments were carried out on murine leukemic cells, which were either sensitive (L1210) or resistant (L1210/DDP) to cis-DDP. A tetrazolium dye (MTT) assay conducted 5 days after a 2-h exposure of cells to both drugs was utilized to determine the resistance factor (RF) of L1210/DDP cells as compared with the sensitive wild-type cells. Drug accumulation and efflux, together with the amount of platinum bound to DNA, were also investigated. The activity of DPR on sensitive cells was not significantly different from that of cis-DDP. Conversely, DPR was 4.3 times more effective than cis-DDP on resistant cells. A decreased drug accumulation is one of the mechanisms of resistance to cis-DDP of L1210/DDP cells. However, DPR accumulation was not significantly different in sensitive and resistant L1210 cells. Under culture conditions that yielded similar intracellular platinum concentrations, treatment with DPR produced significantly greater DNA platination than did treatment with cis-DDP in both cell lines. No difference in efflux was observed between L1210 and L1210/DDP cells exposed to either cis-DDP or DPR. Our results show that in parental cells, DPR is as potent as cis-DDP on a molar basis, and it is also minimally cross-resistant with cis-DDP in L1210/DDP cells. A direct implication of our results is that DPR could be useful in those human tumors showing a mechanism of resistance similar to that of L1210/DDP cells. PMID- 7850918 TI - Resistance to oxidants associated with elevated catalase activity in HL-60 leukemia cells that overexpress multidrug-resistance protein does not contribute to the resistance to daunorubicin manifested by these cells. AB - PURPOSE: It has been recognized that enhanced antioxidant defenses can contribute to the resistance of cancer cells displaying multidrug resistance (MDR) that arises in conjunction with the overexpression of P-glycoprotein (Pgp). The purpose of this study was to determine if the defenses against oxidant stress in MDR human leukemia cells (HL-60/AR) that overexpress multidrug-resistance associated protein (MRP), but not Pgp, contribute to the mechanism of drug resistance in this cell line. METHODS: HL-60/AR cells were evaluated in comparison with wild-type cells with respect to sensitivity to the oxidants hydrogen peroxide (H2O2) and tert-butyl hydroperoxide (t-BuOOH), the activities and amounts of the antioxidant enzymes catalase and glutathione peroxidase (GSH Px), and the effects that manipulation of the activities of these enzymes may have on cellular sensitivity to the oxidants and to daunorubicin. We also evaluated the ability of the cells to generate daunorubicin semiquinone free radical as measured by electron spin resonance (ESR) spectroscopy. RESULTS: HL 60/AR cells were > 10-fold resistant to the cytotoxic effects of the H2O2 or t BuOOH as compared with parental, drug-sensitive HL-60 cells. This phenomenon could be attributed largely to elevated activity and protein levels of catalase in HL-60/AR cells. Furthermore, inhibition of catalase by 3-amino-1,2,4-triazole (AT) diminished the resistance of HL-60/AR to these oxidants by > 80% or > 50%, respectively. Despite these findings, AT was incapable of causing sensitization of HL-60/AR cells to the cytotoxic effects of daunorubicin. We found that the activity and amount of selenium-dependent glutathione peroxidase (GSH-Px) was no greater in HL-60/AR cells than in HL-60 cells. Cultivation of cells in selenium deficient medium caused a marked reduction in GSH-Px activity in HL-60/AR cells and a profound inhibition of GSH-redox cycling manifested by a decrease in baseline hexose monophosphate shunt activity (HMPS) and markedly blunted stimulation of the HMPS by the oxidant t-BuOOH in both wild-type and resistant cells. These variations in GSH-Px activity and GSH-redox cycling, however, were not associated with an alteration in cellular sensitivity to daunorubicin. The failure of catalase inhibition or selenium manipulation of GSH-Px activity to affect daunorubicin cytotoxicity was not due to the inability of these cells to produce free-radical species of daunorubicin, since ESR studies revealed that the generation of daunorubicin semiquinone free radical by HL-60/AR cells was equal to and, in fact, 3-fold that obtained with HL-60 cells. CONCLUSIONS: In comparison with parental HL-60 cells, MRP-overexpressing HL-60/AR cells have demonstrable alterations in antioxidant defenses that are manifested by cellular resistance to the cytotoxic effects of H2O2 and t-BuOOH and by elevated protein levels and activity of catalase. Whether these alterations are epiphenomena or are related to overexpression of MRP remains to be determined. However, it does appear that the enhanced antioxidant defenses observed in HL-60/AR cells do not contribute to the resistance to daunorubicin manifested by this cell line. Although HL-60/AR cells generate daunorubicin semiquinone free radical to an extent equal to or greater than that observed in HL-60 cells, the failure of alterations in GSH-Px activity or inhibition of catalase to change the sensitivity of HL-60/AR cells to daunorubicin suggests that the cytotoxicity of daunorubicin in these cells in not mediated through H2O2 or other peroxide species detoxified by these enzymes. PMID- 7850919 TI - Cytotoxic and biochemical implications of combining AZT and AG-331. AB - We have reported that noncytotoxic concentrations of 3'-azido-3'-deoxythymidine (AZT) increase the cytotoxicity of ICI D1694, a folate-based thymidylate synthase (TS) inhibitor, with increasing AZT incorporation into DNA. We postulated that the inhibition of TS by ICI D1694 would decrease 5'-deoxythymidine triphosphate (dTTP) pools, which compete with AZT triphosphate (AZT-TP) as a substrate for DNA polymerase. Furthermore, the inhibition of TS would increase the activity of both thymidine kinase (TK) and thymidylate kinase (TdK). Each of these consequences of TS inhibition would favor more incorporation of AZT into DNA. Thus, we reasoned that other TS inhibitors should also result in increased AZT incorporation into DNA and, perhaps, in increased cytotoxicity. N6-[4-(Morpholinosulfonyl)benzyl]-N6 methyl-2,6-diaminobenz[ cd]indole glucuronate (AG-331) differs from ICI D1694 in that it is a de novo designed lipophilic TS inhibitor, it does not require a specific carrier for cellular uptake, and it does not undergo intracellular polyglutamation. This potent TS inhibitor causes minimal cytotoxicity in MGH-U1 human bladder cancer cells. A 24-h exposure to 5 microM AG-331 causes almost complete TS inhibition but only 35% cell kill. The combination of AZT and AG-331 in MGH-U1 cells resulted in an enhanced antitumor effect relative to that of each agent alone; 50 microM AZT, noncytotoxic alone, increased the cell kill of induced by AG-331 from 35% to 50%. Biochemical studies of this combination revealed that simultaneous treatment with 5 microM AG-331 plus 1.8 microM [3H] AZT produced as much as a 68% +/- 7% increase in AZT incorporation into DNA. This observation was associated with an increase in DNA single-strand breaks, measured as comet tail moment, of up to 6.6-fold. These studies support our original premise that TS inhibition favors increased incorporation of AZT into DNA and that the combination causes more cell kill than either drug alone in MGH-U1 cells. PMID- 7850920 TI - A pharmacologically guided phase I study of carboplatin in combination with methotrexate and vinblastine in advanced urothelial cancer. AB - Carboplatin is an alternative for cisplatin in the treatment of urothelial cancers. A pharmacologically guided phase I study of carboplatin in combination with methotrexate (30 mg/m2) and vinblastine (4 mg/m2) was conducted in ten patients by increment of the area under the plasma concentration versus time curve (AUC) for ultrafilterable carboplatin using the Calvert formula. The maximal tolerated AUC was 5 mg ml-1 min, with neutropenia being the dose-limiting toxicity. There was a significant linear correlation between the percentage of decrease in neutrophil count and the carboplatin AUC. Determination of the glomerular filtration rate by the isotopic method allowed us to adapt the dose of carboplatin given to patients suffering from urothelial cancer, who frequently have impaired renal function. The recommended AUC for phase II study is 4 mg ml-1 min. PMID- 7850921 TI - A phase I and pharmacokinetics study of 2-chlorodeoxyadenosine in patients with solid tumors. AB - Preclinical studies of 2-chlorodeoxyadenosine (2-CdA) against solid tumors in the human tumor cloning assay and evidence that 2-CdA is active against slow-growing or resting tumor cells have stimulated interest in the clinical activity of this agent against solid tumors. This study sought to estimate the maximum tolerated dose, dose-limiting toxicity, and plasma and urine pharmacokinetics accompanying the intravenous administration of 2-CdA by 120-h continuous infusion in patients with solid tumors. Treated patients were also assessed for other toxicities of therapy and for antitumor response. A total of 23 patients received 35 courses of treatment given at doses of 3.5, 5.3, 6.5 and 8.1 mg/m2 per day by continuous intravenous infusion for 5 days and repeated every 28 days. Blood and urine specimens were collected before, during, and after drug infusion. The dose limiting toxicity at 8.1 mg/m2 per day manifested as granulocytopenia in 2 of 5 patients (3 of 7 courses of treatment) and as thrombocytopenia in 3 of 5 patients (3 of 7 courses of treatment). At the dose levels of 6.5 and 8.1 mg/m2 per day, recovery from thrombocytopenia was often delayed. Severe lymphocytopenia (< 1,000/microliters) was observed at all dose levels of 2-CdA. Dose-related anemia and leukopenia were observed and were infrequently severe. Non-hematological toxicities were confined to mild-to-moderate nausea, vomiting, fatigue, and anorexia. Fever of 37 degrees-40 degrees C was induced during drug infusion in 19 patients. No antitumor response was observed. Average plasma concentrations at steady-state (Cpss) ranged from 3 ng/ml at the initial dose level to 13 ng/ml at the dose level of 8.1 mg/m2 per day. Both the Cpss and the area under the plasma concentration-time curve (AUC) were proportional to the dose. A relationship was observed between the percentage of change in absolute neutrophil count and the AUC. Renal excretion accounted for only 18% of the elimination of 2-CdA over the 5-day infusion period. The maximum tolerated dose for 2-CdA given by 5-day continuous infusion was 8.1 mg/m2 per day in this study. The recommended dose on this schedule for phase II studies is 6.5 mg/m2 per day. Granulocytopenia and thrombocytopenia were dose-limiting. No antitumor activity was observed during this study. On the basis of the plasma concentrations of 2-CdA observed, it is unlikely that this schedule of drug administration will permit achievement of the concentrations consistent with antitumor activity observed in preclinical studies. PMID- 7850922 TI - Subcellular localisation of the antitumour drug mitoxantrone and the induction of DNA damage in resistant and sensitive human colon carcinoma cells. AB - Cellular uptake and subcellular localisation of the antitumour agent mitoxantrone were studied in a human colon-carcinoma cell line and a mitoxantrone-resistant subline showing features consistent with an atypical multidrug-resistance phenotype involving altered topoisomerase II. Flow cytometry indicated a reduced uptake of mitoxantrone in the resistant line. Confocal microscopy indicated that mitoxantrone-associated fluorescence was primarily found within discrete cytoplasmic inclusions and around the periphery of the nucleus, with low levels being observed within the nucleus. The frequency of cytoplasmic inclusions was reduced in mitoxantrone-resistant cells as compared with parental cells. Fluorescence in cytoplasmic inclusions persisted throughout a 24-h post-treatment period in both cell lines. The results suggest that the persistence of mitoxantrone in cells is a determinant for the continuous induction of DNA damage, perhaps through chronic topoisomerase II trapping, and that modified sequestration may contribute to clinically relevant moderate levels of non classic multidrug resistance. PMID- 7850923 TI - Cyclocreatine in cancer chemotherapy. AB - Cyclocreatine, an analog of creatine, is an efficient substrate for creatine kinase, but its phosphorylated form is a poor phosphate donor in comparison with creatine phosphate. Cyclocreatine was not very cytotoxic upon 24 h of exposure of human SW2 small-cell lung cancer cells to concentrations of up to 5 mM. However, combinations of cyclocreatine (0.5 mM, 24 h) with each of four antitumor alkylating agents, cis-diamminedichloroplatinum(II), melphalan, 4 hydroperoxycyclophosphamide, and carmustine, resulted in additive to greater-than additive cytotoxicity toward exponentially growing SW2 cells. The greatest levels of synergy were seen at higher concentrations of 4-hydroperoxycyclophosphamide and carmustine as determined by isobologram analysis. In vivo cyclocreatine (0.5 or 1 g/kg) was more effective if given i.v. rather than i.p. The longest tumor growth delays, up to 10 days, were produced by extended regimens of cyclocreatine. Cyclocreatine was an effective addition to therapy with standard anticancer agents including cis-diamminedichloroplatinum(II), cyclophosphamide, Adriamycin, or 5-fluorouracil. No additional toxicity was observed when 10 days of cyclocreatine treatment was given with full standard-dose regimens of each drug. The resultant increases in tumor-growth delay were 1.7- to 2.4-fold as compared with those obtained for each of the drugs alone. These results indicate that cyclocreatine may be an effective single agent and an effective addition to combination chemotherapy regimens. PMID- 7850924 TI - Population pharmacokinetics of hydroxyurea in cancer patients. AB - The pharmacokinetics of hydroxyurea (HU) were investigated in cancer patients after intravenous infusion or oral administration. On the basis of the minimal value of the objective function (MVOF) and prior knowledge of the disposition of HU in animals and man, the data were best described by a one-compartment pharmacokinetic model with parallel Michaelis-Menten metabolism and first-order renal excretion. The computer program NONMEM (nonlinear mixed effects model) was used to perform the nonlinear regression and provide estimates of the population parameters. For the combined intravenous and oral data set, these parameters were estimated to be: maximal elimination rate (Vmax), 0.097 mmol h-1 l-1; Michaelis constant for HU elimination (KM), 0.323 mmol/l; renal clearance (ClR), 90.8 ml/min; volume of distribution (Vd), 0.186 x (body weight) + 25.4 l; absorption rate constant (Ka), 2.92 h-1; and availability to the systemic circulation (F), 0.792. The principal findings of the investigation are that HU undergoes nonlinear elimination in cancer patients and that HU is reasonably well absorbed following oral administration. PMID- 7850926 TI - Inhibition of intestinal P-glycoprotein and effects on etoposide absorption. AB - P-glycoprotein (Pgp) actively pumps a number of antineoplastic drugs, such as etoposide, out of cancer cells and causes multidrug resistance. Pgp is also expressed at the brush-border membrane of the small intestine under normal physiological conditions. We hypothesized that inhibition of intestinal Pgp might decrease the efflux of etoposide from the blood into the intestinal lumen, thereby, increasing the bioavailability of etoposide. The absorption of etoposide was studied using everted gut sacs prepared from rat jejunum and ileum. The addition of C219, a monoclonal antibody of Pgp, at 100 ng/ml or of 0.2 M 5' adenylylimidodiphosphate, a nonhydrolyzable adenosine triphosphate (ATP) analog, increased the absorption of etoposide. Quinidine, an antiarrythmic agent, has been demonstrated to circumvent multidrug resistance in cell lines, possibly by interfering with Pgp function. Adding quinidine at 1 mg/ml to the everted gut sac increased the absorption of etoposide. In vivo absorption of etoposide was also studied by intraluminal perfusion of the drug in the small intestine of anesthetized rats. Intravenous infusion of quinidine at either 1 or 2 mg/h increased the serum level of etoposide in a dose-dependent manner. Intravenous infusion of etoposide at 0.2 mg/h resulted in luminal exsorption of the drug in the small intestine. The intestinal clearance of etoposide was 41.7 +/- 7.2 ml kg 1, which decreased to 18.4 +/- 3.9 ml kg-1 with the infusion of quinidine at 1 mg/h. The present data confirm that intestinal Pgp mediates the efflux of etoposide and that the use of Pgp-inhibiting agents such as quinidine may increase the bioavailability of etoposide. PMID- 7850925 TI - Molecular characterization of the in vivo alkylating agent resistant murine EMT-6 mammary carcinoma tumors. AB - The expression of several early-response genes and genes associated with malignant disease was assessed in the EMT-6/parent tumor and the EMT-6/CTX and EMT-6/CDDP in vivo resistant tumor lines growing as tumors or as monolayers in culture. In the absence of treatment the levels of mRNA for the genes c-jun, c fos, c-myc, Ha-ras and p53 were increased in the EMT-6/CTX and EMT-6/CDDP as compared with the EMT-6/parent tumor, whereas the expression of erb-2 was similar in all three tumors. Although the cells from each of the three tumors show increased expression of early response genes after exposure to cisplatin (CDDP; 100 microM, 2 h) or 4-Hydroxyperoxycyclophosphamide (4-HC; 100 microM, 2 h) in culture, in mRNA extracted from tumor tissue these changes are absent or very small. Both C-jun and erb-2 were detectable in liver. There was increased expression of both of these genes in the livers of tumor-bearing animals as compared with non-tumor-bearing animals. The highest expression of both c-jun and erb-2 occurred in the livers of animals bearing the EMT-6/CDDP tumor. Treatment of the animals with CDDP or cyclophosphamide, in general, resulted in increased expression of both genes at 6 h post treatment. The increased expression of these genes may impart metabolic changes in the tumors and/or hosts that contribute to the resistance of these tumors to specific antitumor alkylating agents. PMID- 7850927 TI - 5-Fluorouracil and low-dose leucovorin in metastatic colorectal cancer: a pilot study. AB - A total of 56 consecutive patients with metastatic colorectal cancer received treatment with 5-fluorouracil (5-FU) given at 425 mg/m2 by rapid intravenous infusion, immediately preceded by leucovorin (LV) given at 20 mg/m2, with cycles being repeated every 4 weeks. Of 48 evaluable patients undergoing this treatment, a tumor response was observed in 16 (33%); a complete response, in 2 (4%); and a partial response, in 14 (29%). The median survival was 8.5 months for all patients and 16.5 months for responders. An improvement in symptoms was seen in 9 (26%) of 34 symptomatic patients. In all 15 (27%) of 44 evaluable patients showed an improvement in performance status. The most significant toxicity attributable to the treatment was mucositis of grade 3 or 4, seen in 27% of the patients. Altogether, 2 patients (3.5%) were hospitalized for treatment-related toxicity. We conclude that the combination of 5-FU and low-dose LV is active in advanced colorectal cancer and is associated with acceptable toxicity. PMID- 7850928 TI - Antitumor activity of cis-malonato[(4R,5R)-4,5-bis(aminomethyl)-2- isopropyl-1,3 dioxolane]platinum(II), a new platinum analogue, as an anticancer agent. AB - The in vitro and in vivo antitumor activity of a new antitumor platinum complex, cis-malonato[(4R, 5R)-4,5- bis(aminomethyl)-2-isopropyl-1,3 dioxolane]platinum(II) (SKI2053R, NSC D644591), were evaluated and compared with those of cisplatin (CDDP) and carboplatin (CBDCA) using murine tumors. SKI 2053R was highly active in vitro against both L1210 murine leukemia and its CDDP resistant subline, L1210/DDP; the relative resistances were 20.0-, 14.5-, and 2.7 fold for CDDP, CBDCA, and SKI 2053R, respectively. SKI 2053R showed activity comparable with or superior to either CDDP or CBDCA in mice implanted with L1210. In mice implanted with L1210/DDP, as compared with CBDCA, SKI 2053R showed high values for the percentage of treated survivors relative to controls and for numbers of cured mice, whereas CDDP had virtually no activity. In mice implanted with P388, all three drugs were highly active, but the intensity of activity was shown to be ranked in the following order: SKI 2053R > CDDP > CBDCA. The antitumor activity of SKI 2053R against Lewis lung carcinoma was comparable with that of both CDDP and CBDCA. The antitumor activity of SKI 2053R was further investigated against two human tumor xenografts, KATO III (stomach adenocarcinoma) and WiDr (colon adenocarcinoma), implanted s.c. in nude mice and was compared with that of CDDP. In SKI 2053R-treated groups, the time required for a mean tumor weight of 1,000 mg was 33.1 days in KATO III xenografts and 35.0 days in WiDr xenografts as compared with 30.2 and 27.2 days in CDDP-treated groups, respectively. SKI 2053R achieved growth-inhibition rates comparable with those of CDDP against KATO III (65% versus 59%) and WiDr xenografts (64% versus 54%) on day 35. These results indicate that SKI 2053R is an attractive candidate for further development as a clinically useful anticancer drug. PMID- 7850929 TI - Nitric oxide mediates the blood flow response to intravenous adenosine in the rabbit. AB - The objective of this study was to determine if nitric oxide mediates the effects of exogenously administered adenosine on peripheral blood flow. An intravenous infusion of adenosine (1.0 mumol/kg/min) into male New Zealand white rabbits caused an increase in blood flow, measured using radiolabeled microspheres, throughout the gastrointestinal tract, as well as in the heart and kidneys. Prior administration of nitro-L-arginine methyl ester (L-NAME) 10 mg/kg i.v. completely blocked the hyperemic effect of adenosine on all organs studied. Administration of L-arginine (300 mg/kg bolus and 50 mg/kg/min infusion) together with L-NAME restored the hyperemic effect of adenosine. This phenomenon was specified to the L-arginine/nitric oxide pathway in that a similar pressor response induced by phenylephrine (1.5 micrograms/kg/min) did not block the effects of adenosine. We conclude that the peripheral vasodilator response to intravenously administered adenosine in the rabbit is mediated by nitric oxide. PMID- 7850930 TI - Monophosphoryl lipid A protects against endotoxic shock via inhibiting neutrophil infiltration and preventing disseminated intravascular coagulation. AB - The major objective of the present study was to determine the effects of a partial structure of the lipid A moiety of gram-negative lipopolysaccharide, monophosphoryl lipid A (MLA), on endotoxin-induced mortality and disseminated intravascular coagulation (DIC) in rats. A second objective was to examine the role of polymorphonuclear neutrophil invasion to visceral organs, including lung, liver, heart, and kidney in the pathogenesis of the compromised multiorgan function which occurs in endotoxic shock. Finally, a third aim was to determine if the potential protective effects of MLA might be mediated via inhibiting neutrophil invasion to various visceral organs. Male Sprague-Dawley rats (220-260 g) were fasted over night and used the following day. In control rats, endotoxin (S. abortus equi LPS, 15 mg/kg, i.v.) produced a 89% mortality at 48 hr following its administration, and gross pathological and laboratory signs of DIC at 3 hr after injection. The latter included increased serum fibrin(ogen) degradation products (FDP, 24.00 +/- 7.81 vs. 0 micrograms/ml, P < .05), prothrombin time (PT, 16.20 +/- 1.12 vs. 13.03 +/- 0.20 sec, P < .05), and activated partial thromboplastin time (APTT, 32.70 +/- 3.83 vs. 20.11 +/- 0.60 sec, P < .05), and decreased plasma fibrinogen (233.2 +/- 41.6 vs. 406.3 +/- 23.2 mg/dl, P < .05) as well as evidence of gross visceral hemorrhage. Pretreatment with MLA (5 mg/kg) for 24 hr produced a marked reduction in endotoxin-induced mortality at 48 hr (0% versus 89% in controls) and inhibited all of the manifestations of DIC produced by endotoxin.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7850931 TI - Renal interleukin-1 expression during endotoxemia and gram-negative septicemia in conscious rats. AB - Endotoxin-induced cytokines such as interleukin-1 (IL-1) and tumor necrosis factor (TNF) are thought to contribute to the proinflammatory effects of endotoxin in gram-negative infections. Using a conscious rat model of sepsis, induced by intravenous challenge with LD95 doses of endotoxin (n = 24) or live Escherichia coli (E. coli) (n = 24), we examined frozen sections of kidney at various intervals for evidence of IL-1 alpha and TNF alpha expression. A transient glomerular endothelial IL-1 alpha expression was demonstrated at 30 and 90 min after initiation of the sepsis in both endotoxin and E. coli-treated animals using immunohistochemistry. The endothelial IL-1 alpha expression as determined by immunohistochemistry occurred at the same time as IL-1 alpha mRNA expression, as determined by Northern blot analysis. The glomerular endothelial IL-1 alpha expression coincided with a slight but significant increase in the number of the glomerular polymorphonuclear leukocytes as identified by naphthol AS-D chloroacetate esterase enzyme histochemical reaction. Glomerular endothelial IL-1 alpha expression was virtually absent by 180 and 360 min. No TNF alpha expression was detected in the renal tissues at any time interval. Neither alpha naphthyl acetate esterase-positive nor acid phosphatase-positive monocytes/macrophages were identified in the glomeruli. Our findings provide direct in vivo evidence that the IL-1 alpha gene product is expressed locally in the kidney by glomerular endothelial cells in this septic rat model. PMID- 7850932 TI - Ventricular dysfunction in norepinephrine-induced cardiomyopathy. AB - Cardiac dysfunction resulting from norepinephrine-induced cardiomyopathy has not been fully investigated. This study evaluates acute and chronic changes in systolic and diastolic function at three levels of norepinephrine (NE)-induced injury. Rabbits were infused with saline or 2, 4, or 6 micrograms/kg/min NE for 90 min. Ventricular function was assessed immediately after infusion or at 48 hr using the isolated non-ejecting heart preparation. Hearts were perfused at 10 ml/min/g with Krebs-Henseleit buffer. After baseline measurements, hearts were perfused with NE (10(-10) to 10(-7) M). Steady state left ventricular pressure (LVP), +dP/dt, and -dP/dt were recorded at baseline and each NE concentration. NE infusion acutely depressed baseline LV systolic function. Decreases in LVP and +dP/dt were inversely related to dose of infused NE. By 48 hr, LVP and +dP/dt improved slightly in all NE groups but improvement was significant only in hearts from rabbits infused with 4 micrograms NE. Systolic function of hearts from animals infused with 6 micrograms NE remained depressed. Diastolic (-dP/dt) function was impaired following NE infusion when compared to saline treated hearts and did not improve within 48 hr. Although baseline function is depressed, myopathic hearts increased ventricular function the same amount as normal hearts at 10(-7) M NE. These findings demonstrate a) impairment in LV systolic and diastolic function acutely after NE infusion, b) improvement in systolic function within 48 hr, c) ability to increase contractility in response to NE is not impaired, and d) recovery of systolic function precedes improvement in diastolic function. PMID- 7850933 TI - Protective effects of a cyclic nitrone antioxidant in animal models of endotoxic shock and chronic bacteremia. AB - Evidence of a role for oxygen-derived free radicals in the pathophysiology of endotoxic shock has been found in animal models. However, the importance of free radicals in chronic models of bacterial infection has not been examined. In this study a novel nitrone radical spin trap is described and its activity in animal models of endotoxic shock and chronic bacteremia were explored. MDL 101,002 is a cyclized variant of alpha-phenyl N-tert-butyl nitrone (PBN), an established spin trap. MDL 101,002 can react with free radicals to form persistent adducts as demonstrated by electron paramagnetic resonance (EPR) spectroscopy. This agent is about 10 times more potent than PBN as an in vitro antioxidant and scavenger of hydroxyl radicals. In a rat endotoxic shock model MDL 101,002 (3-30 mg/kg, i.p.) administered 30 min prior to endotoxin (30 mg/kg, i.p.) treatment reduced mortality in a dose-dependent manner. Peroxide-enhanced chemiluminescence in hepatic homogenates from endotoxin treated rats was elevated indicating that oxidative stress and antioxidant depletion was increased. Importantly, treatment with MDL 101,002 (30 mg/kg, i.p.) 30 min prior to, and 120 min following endotoxin, minimized the increase in chemiluminescence. MDL 101,002 also reduced mortality in a model of chronic bacteremia employing implantation of infected fibrin clots into the peritoneal cavity of gentamicin-treated leukopenic rats. MDL 101,002 (2.5 mg/kg/hr) increased survival from 24% to 52% in these rats. These data are consistent with a role for free radicals in the pathophysiology of endotoxic shock and suggest free radicals are also important mediators in chronic models of sepsis. PMID- 7850934 TI - Human responses to bacterial endotoxin. AB - The literature concerning human responses to bacterial endotoxin, in particular to the purified lipopolysaccharide derivative, has been critically reviewed and summarized. Papers selected for review are those that reported studies of human subjects in a normal state of health administered defined doses of either intravenous or aerosol inhaled material. Emphasis was placed on cardiovascular, pulmonary, metabolic, and inflammatory parameters. The information detailed here can be applied to understanding the pathophysiology of human consequences to spontaneous, clinical diseases induced by this highly inflammatory and ubiquitous substance. PMID- 7850935 TI - Comparison of low-dose dobutamine-gradient-echo magnetic resonance imaging and positron emission tomography with [18F]fluorodeoxyglucose in patients with chronic coronary artery disease. A functional and morphological approach to the detection of residual myocardial viability. AB - BACKGROUND: There have been conflicting reports of whether substantial myocardial thinning alone as an indirect sign of myocardial scarring is sufficient evidence to exclude the presence of viable myocardium in patients with previous myocardial infarction and persisting regional left ventricular akinesia. Demonstration of a dobutamine-induced contraction reserve in postischemic viable but akinetic myocardium may serve as a direct indicator of myocardial viability. In the present study, end-diastolic wall thickness at rest and dobutamine-induced systolic wall thickening assessed by magnetic resonance imaging (MRI) were compared with corresponding [18F]fluorodeoxyglucose uptake as assessed by positron emission tomography (FDG-PET). METHODS AND RESULTS: Thirty-five patients with myocardial infarction (infarct age, > 4 months) and regional akinesia or dyskinesia assessed by left ventriculography underwent rest and dobutamine MRI studies (10 micrograms dobutamine.min-1.kg-1) and FDG-PET followed by segmental analyses of end-diastolic wall thickness, systolic wall thickening, and FDG uptake in corresponding short-axis tomograms. Two definitions of viability, as assessed by MRI, of a segment akinetic at baseline were used: (1) end-diastolic wall thickness of > or = 5.5 mm (the mean minus 2.5 SD of a healthy control group [n = 21]) and (2) evidence of dobutamine-induced systolic wall thickening > or = 1 mm. Segments were graded as viable by FDG-PET if FDG uptake was > or = 50% of the maximum uptake in a region with normal wall motion as assessed by left ventriculography. Preserved end-diastolic wall thickness in akinetic regions was found in 17 of 35 (48%) patients at rest, and functional recovery within the infarct region was found in 19 of 35 (54%) patients during dobutamine infusion. Viability of the infarct region was indicated by FDG-PET in 23 of 35 patients (66%), yielding a diagnostic agreement between FDG uptake and myocardial morphology in 29 of 35 (83%) and between dobutamine-induced contraction reserve and FDG-PET in 31 of 35 (89%). Of 2200 segments, 482 (22%) were akinetic at rest. Of these akinetic segments, 234 (48%) had preserved end-diastolic wall thickness, 251 (52%) had a dobutamine-induced contraction reserve, and 299 (62%) were graded as viable by FDG-PET. Correlations of FDG uptake with end-diastolic wall thickness at rest (r = .48) and with dobutamine-induced wall thickening (r = .42) were similar. Comparison of segmental MRI and FDG-PET gradings indicated that dobutamine-induced wall thickening was a better predictor of residual metabolic activity (sensitivity, 81%; specificity, 95%; positive predictive accuracy, 96% than was end-diastolic wall thickness (sensitivity, 72%; specificity, 89%; positive predictive accuracy, 91%). However, grading a segment as viable if at least one of both MRI parameters fulfilled viability criteria improved the sensitivity (88%) of MRI for FDG-PET-assessed metabolic activity without a major decrease in specificity (87%) or positive predictive accuracy (92%). CONCLUSIONS: Viable myocardium is characterized by preserved end-diastolic wall thickness and a dobutamine-inducible contraction reserve. Both parameters should be taken into account to maximize the sensitivity of MRI in the detection of regions with signs of viability on FDG-PET images. PMID- 7850936 TI - Residual 201Tl activity in irreversible defects as a marker of myocardial viability. Clinicopathological study. AB - BACKGROUND: The objective of the present study was to characterize the relation between the residual 201Tl activity in irreversible perfusion defects and the extent of irreversible myocardial damage indicated by the volume fraction of myocardial interstitial fibrosis in patients with chronic coronary artery disease. METHODS AND RESULTS: Stress planar 201Tl scintigraphy with tracer reinjection at rest was performed in 37 patients with > or = 75% stenosis of the left anterior descending coronary artery, and anteroseptal 201Tl activity was quantified by computer-assisted placement of regions of interest from the serial myocardial images. During coronary artery bypass grafting (performed within 6 +/- 3 weeks after scintigraphy), two transmural biopsy specimens were taken from the anterior wall of the left ventricle and the amount of interstitial fibrosis was assessed by use of light microscopic morphometry. A wide spectrum of interstitial fibrosis was obtained, ranging from 15 vol% to 60 vol%. Interstitial fibrosis was similar in patients with reversible (n = 11) or irreversible (n = 15) tracer defects in conventional stress-redistribution images. However, interstitial fibrosis was significantly lower in patients who had enhanced regional 201Tl activity after tracer reinjection compared with those who did not have enhancement of tracer activity after reinjection (28 +/- 8 vol%, n = 7, versus 41 +/- 12 vol%, n = 8; P = .031). The correlation between relative poststenotic 201Tl activity and interstitial fibrosis after tracer reinjection was significantly improved compared with conventional redistribution images (r = .622 versus r = -.851, n = 15; P < .01). CONCLUSIONS: The present data demonstrate that the level of regional 201Tl activity in redistribution and, in particular, reinjection images is significantly related to the mass of preserved viable myocytes in poststenotic left ventricular myocardium. Therefore, the residual 201Tl activity provides information about viability within irreversible perfusion defects and may itself serve as marker of myocardial viability. PMID- 7850937 TI - Valve repair improves the outcome of surgery for mitral regurgitation. A multivariate analysis. AB - BACKGROUND: Mitral valve repair has been suggested as providing a better postoperative outcome than valve replacement for mitral regurgitation, but this impression has been obscured by differences in baseline characteristics and has not been confirmed in multivariate analyses. METHODS AND RESULTS: The outcomes in 195 patients with valve repair and 214 with replacement for organic mitral regurgitation were compared using multivariate analysis. All patients had preoperative echocardiographic assessment of left ventricular function. Before surgery, patients with valve repair were less symptomatic than those with replacement (42% in New York Heart Association functional class I or II versus 24%, respectively; P = .001), had less atrial fibrillation (41% versus 53%; P = .017), and had a better ejection fraction (63 +/- 9% versus 60 +/- 12%, P = .016). After valve repair, compared with valve replacement, overall survival at 10 years was 68 +/- 6% versus 52 +/- 4% (P = .0004), overall operative mortality was 2.6% versus 10.3% (P = .002), operative mortality in patients under age 75 was 1.3% versus 5.7% (P = .036), and late survival (in operative survivors) at 10 years was 69 +/- 6% versus 58 +/- 5% (P = .018). Late survival after valve repair was not different from expected survival. After surgery, ejection fraction decreased significantly in both groups but was higher after valve repair (P = .001). Multivariate analysis indicated an independent beneficial effect of valve repair on overall survival (hazard ratio, 0.39; P = .00001), operative mortality (odds ratio, 0.27; P = .026), late survival (hazard ratio, 0.44; P = .001), and postoperative ejection fraction (P = .001). CONCLUSIONS: Valve repair significantly improves postoperative outcome in patients with mitral regurgitation and should be the preferred mode of surgical correction. The low operative mortality is an incentive for early surgery before ventricular dysfunction occurs. PMID- 7850938 TI - Increased early mortality in women undergoing cardiac transplantation. AB - BACKGROUND: To evaluate factors that explain sex differences affecting mortality after cardiac transplantation, a retrospective analysis of adult patients undergoing orthotopic cardiac transplantation was undertaken at the Columbia Presbyterian Medical Center. METHODS AND RESULTS: The study population consisted of 379 patients (75 women, 304 men) > or = 18 years of age who survived for > or = 48 hours after undergoing orthotopic cardiac transplantation between March 1985 and March 1992. The following were analyzed: incidence of death and treated rejection episodes, donor and recipient cytomegalovirus (CMV) matches, use of OKT3 induction therapy, and donor and recipient HLA mismatches. Women 49 +/- 12 years old and men 47 +/- 12 years old were characterized by differences in race and diagnosis. Women were more likely to be nonwhite (P < .01) and have idiopathic cardiomyopathy than were men (P < .01). A trend toward an increase in first-year rejection frequency was seen in women compared with men (P = .08). Overall actuarial survival was significantly reduced in women after transplantation (P < .05). At 36 months, female actuarial survival was 64 +/- 7% versus 76 +/- 3% for men (P < .05). The majority of patients in this study did not receive CMV prophylaxis. Univariate analysis revealed that only CMV(+) donor status and the use of OKT3 induction therapy affected survival in women. Multivariate analysis revealed a marked reduction in survival in female recipients of CMV(+) donors given OKT3 induction therapy. At 36 months, only 25% of women were still alive compared with 86% of women with neither risk factor (P < .001). Even without OKT3 induction there was markedly reduced survival in women with mismatched CMV status, ie, CMV(-) recipients of CMV(+) donors; 17% survival after 36 months versus 86% in women who were CMV(+) recipients (P < .05). Although at this institution during the study time period, CMV prophylaxis was not routinely employed and OKT3 induction was selectively used in higher-risk patients, conclusions regarding differences in outcome that are sex dependent are valid. CONCLUSIONS: (1) Women are at risk for reduced actuarial survival up to 3 years after cardiac transplantation. (2) Univariate analysis shows that women are selectively at risk for death when receiving hearts from CMV(+) donors and after receiving OKT3 induction therapy. (3) Multivariate analysis reveals that women are at even greater risk for death when receiving hearts from CMV(+) donors in conjunction with OKT3 induction therapy. (4) In the absence of OKT3 use, the greatest risk of death occurs in CMV(-) women transplanted with CMV(+) donor hearts. (5) When female to male survival curves are compared, factors that influenced survival in women did not appear to be problematic in men. PMID- 7850939 TI - Sensitive detection of abnormal aortic architecture in Marfan syndrome with high frequency ultrasonic tissue characterization. AB - BACKGROUND: Aneurysmal dilation of the aorta with subsequent rupture or dissection occurs frequently in patients with Marfan syndrome and is the primary cause of morbidity. These complications are related to the altered composition and disorganized structure of the aortic media. Our goal was to use high frequency ultrasonic tissue characterization to identify these structural changes in abnormal aorta from patients with Marfan syndrome. We measured integrated backscatter and anisotropy of backscatter of ultrasound from specimens of aorta from patients with Marfan syndrome undergoing aortic root replacement and compared these values with those from aortic specimens of patients without clinical aortic pathology. METHODS AND RESULTS: Aortic tissue was obtained at the time of surgery from 11 patients with Marfan syndrome undergoing repair of an aortic aneurysm or dissection. Normal tissue was obtained at the time of autopsy from 8 patients without evidence of aortic disease. Acoustic microscopy at 50 MHz was performed to measure integrated backscatter from each specimen. The magnitude of ultrasonic anisotropy of backscatter for each tissue type was determined as an index of the three-dimensional (3D) organization of the vessel matrix. The collagen content of each specimen was determined with a hydroxyproline assay. Marfan aortas exhibited less backscatter than did normal aortas (-40.9 +/- 2.9 versus -32.6 +/- 2.2 dB for patients with Marfan syndrome and healthy subjects, respectively, P < .0001). No significant difference in collagen concentrations was observed between normal and Marfan aorta (262.7 +/- 52.7 versus 282.4 +/- 41.8 mg/g tissue for normal and Marfan aortas, respectively, P = .42), despite the large difference in backscatter. Histological analysis revealed striking differences in both the amount and organization of the elastin in the aortic aneurysm segments from patients with Marfan syndrome compared with normal aorta. Normal aorta was characterized by well-formed elastin fibers arranged in a lamellar pattern. The media from aneurysms in Marfan aorta exhibited a profound decrease in elastin content that was associated with loss of the highly aligned and ordered lamellar arrangement. The directional dependence of scattering, or ultrasonic anisotropy, also differed dramatically between the two tissue types. Backscatter from normal aorta decreased substantially when the media was insonified parallel compared with perpendicular to the principal axis of the elastin fibers. Marfan aorta exhibited a much smaller directional dependence of scattering. Normal aortas manifested a 14-fold greater ultrasonic anisotropy than did Marfan aortas (24.1 +/- 3.7 versus 12.4 +/- 3.3 dB for normal and Marfan aortas, P < .0001), which is indicative of the profound extent of matrix disorganization in Marfan syndrome. CONCLUSIONS: These data show that high frequency ultrasonic tissue characterization sensitively detects changes in vessel wall composition and organization that occur in the aorta of patients with Marfan syndrome. Aortic segments from these patients manifested a significant decrease in integrated backscatter compared with normal aorta (approximately 8 dB, or greater than a 6-fold decrease in scattering). A 15-fold reduction in the ultrasonic anisotropy of Marfan tissue was observed, which suggests a marked disorganization of the 3D architecture of these aortas. These data support the hypothesis that high-frequency ultrasonic tissue characterization may be useful for identifying abnormalities of vessel wall composition, architecture, and material properties. PMID- 7850940 TI - Sex differences in perioperative and long-term cardiac event-free survival in vascular surgery patients. An analysis of clinical and scintigraphic variables. AB - BACKGROUND: Little information is available regarding the occurrence of perioperative and late cardiac events in women with vascular disease. The current study was performed to examine whether sex-specific differences exist in these outcomes in a large population of vascular surgery patients and to determine the value of clinical and dipyridamole thallium variables in predicting myocardial infarction and cardiac death. METHODS AND RESULTS: Preoperative dipyridamole thallium imaging was performed in 567 vascular surgery patients, including 380 men and 187 women. The incidence of nonfatal myocardial infarction and cardiac death was noted during the perioperative period and during a follow-up period of 50 +/- 5 months. Fixed and reversible thallium perfusion abnormalities were more common in men than in women (P < .001 and P = .004, respectively). Perioperative cardiac event rates were similar in men and women, 8.4% and 7.5%, respectively (P = .07). A transient thallium defect was associated with an increased risk of cardiac events by 3.9-fold in men (CI, 1.5 to 10.2) and 5.5-fold in women (CI, 1.4 to 22). Various clinical factors also were predictive of events but demonstrated substantial sex differences. For example, dipyridamole-induced ST segment depression was strongly associated with perioperative events in men but not in women. There were 22 nonfatal myocardial infarctions and 29 cardiac deaths in men during the follow-up period, with comparable event rates noted for women. Cardiac event-free survival rates also were similar for men and women (P = .40). Multivariate analysis demonstrated that a history of heart failure was an important prognostic variable for both sexes, as was a fixed thallium defect. Significant sex differences in the predictive value of other clinical factors for late cardiac events was apparent. CONCLUSIONS: The present study demonstrates that (1) thallium perfusion defects are more common in men; (2) transient thallium defects are associated with perioperative myocardial infarction and cardiac death in both sexes; (3) long-term survival rates after vascular surgery are similar between men and women; (4) a fixed perfusion defect is predictive of late cardiac events in women, with a trend noted in men; and (5) sex-specific differences were noted with regard to the prognostic value of various clinical risk factors. Therefore, dipyridamole thallium plays a significant role in the assessment of perioperative and long-term prognosis for both male and female vascular surgery patients. On the basis of these observations, modifications in risk stratification based on sex may be appropriate for men and women with vascular disease. PMID- 7850941 TI - Differential effects of chronic oral antihypertensive therapies on systemic arterial circulation and ventricular energetics in African-American patients. AB - BACKGROUND: A comprehensive evaluation of arterial load characteristics and left ventricular energetics in systemic hypertension has been limited by the need for invasive techniques to access instantaneous aortic pressure and flow. As a consequence of this methodological limitation, no data exist on the effects of long-term antihypertensive therapy on global arterial impedance properties and indexes of myocardial oxygen consumption (MVO2). Using recently validated noninvasive techniques, we compared in hypertensive patients the effects of chronic oral treatment with ramipril, nifedipine, and atenolol on arterial impedance and mechanical power dissipation as well as indexes of MVO2. METHODS AND RESULTS: Sixteen African-American subjects with systemic hypertension were studied with a randomized, double-blind, crossover protocol. Instantaneous central aortic pressure and flow, from which arterial load characteristics can be derived, were estimated from calibrated subclavian pulse tracings (SPTs) and continuous-wave aortic Doppler velocity in conjunction with two-dimensional (2D) echocardiographic measurements of the aortic annulus, respectively. To derive ventricular wall stress and indexes of MVO2, left ventricular short- (M-mode) and long-axis (2D echo) images were acquired simultaneously with SPTs. Data were collected at the end of a 2-week washout period (predrug control) and after 6 weeks of treatment with each agent. Although all three agents reduced diastolic blood pressure to the same extent, different effects on mean and systolic pressures and vascular impedance properties were noted. Nifedipine reduced total peripheral resistance (TPR; 1744 +/- 398 versus 1290 +/- 215 dyne-s/cm5) and increased arterial compliance (ACL; 1.234 +/- 0.253 versus 1.776 +/- 0.415 mL/mm Hg). This improvement in arterial compliance was not entirely accounted for by the reduction in distending pressure. Ramipril also decreased TPR (1740 +/- 292 versus 1437 +/- 290 dyne-s/cm5) and increased ACL (1.214 +/- 0.190 versus 1.569 +/- 0.424 mL/mm Hg), but with this agent, the change in arterial compliance was explained solely on the basis of a reduction in distending pressure. Atenolol, in contrast, did not affect either TPR or ACL. In agreement with the compliance results, nifedipine and ramipril significantly lowered the first two harmonics of the impedance spectrum, but atenolol did not. None of these agents resulted in a significant change in characteristic impedance or in the relative amplitude of the reflected pressure wave. Total vascular mechanical power and percent of oscillatory power remained unaltered with all antihypertensive treatments. Only ramipril and nifedipine reduced the integral of both meridional and circumferential systolic wall stresses, indicating that MVO2 per beat was reduced with these agents. Stress-time index, a measure of MVO2 per unit time, decreased significantly with ramipril but not with nifedipine because of an increase in heart rate noted in 10 of 16 patients (mean increase, 10 beats per minute). Thus, a reduction in MVO2 coupled with unchanged total vascular mechanical power suggests improved efficiency of ventriculoarterial coupling with ramipril and with nifedipine in the subset of patients in whom heart rate remained unchanged. In contrast, there was no evidence of a reduction in wall stress, stress integral, or stress-time index with atenolol. CONCLUSIONS: The noninvasive methodology used in this study constitutes a new tool for serial and simultaneous evaluation of arterial hemodynamics and left ventricular energetics in systemic hypertension. In this study, we demonstrate the differential effects of chronic antihypertensive therapies on systemic arterial circulation and indexes of MVO2 in African-American subjects. Consideration of drug-induced differential responses of arterial load and indexes of MVO2 with each drug may provide a more physiological approach to the treatment of systemic hypertension in indivi PMID- 7850942 TI - Permanent pacemaker selection and subsequent survival in elderly Medicare pacemaker recipients. AB - BACKGROUND: Dual-chamber pacemakers have been in use for more than 15 years. Although they may confer a physiological advantage over single-chamber ventricular pacemakers, they are more expensive and have a generally shorter service life than single-chamber devices. We carried out the present study to identify patient subgroups who were preferentially receiving greater or lesser proportions of dual-chamber devices and to determine whether the selection of different types of pacemakers was associated with differences in mortality. METHODS AND RESULTS: We analyzed a 20% random national sample of all Medicare beneficiaries aged 65 years or older who underwent initial placement of a permanent pacemaker and were discharged in 1988, 1989, or 1990 (n = 36,312). The minimum follow-up for vital status was 1 year. The relation of pacemaker type to patient and provider characteristics was determined using logistic regression analysis. The relation between pacemaker type and mortality was determined using the Cox proportional hazards method. The proportion of dual-chamber systems that were received increased from 27.2% in 1988 to 37.0% in 1990 (P < .001). Dual chamber pacemaker recipients were younger (P < .001) than ventricular pacemaker recipients. Other independent correlates of dual-chamber pacemaker selection included male sex (odds ratio and 95% confidence intervals, 1.18 and 1.12 to 1.24, respectively), atrioventricular block (1.59 and 1.51 to 1.67), congestive heart failure (1.14 and 1.08 to 1.20), atrial fibrillation (0.36 and 0.34 to 0.39), and the presence of a major noncardiac diagnosis (0.86 and 0.83 to 0.89). Nonmedical predictors of dual-chamber pacemaker selection included Medicaid eligibility (0.78 and 0.71 to 0.86), implantation in the western United States (1.19 and 1.10 to 1.29), implantation by a rural provider (0.70 and 0.65 to 0.76), hospitalization in a 500-bed-or-larger hospital (1.20 and 1.13 to 1.28), hospitalization in a private hospital (1.19 and 1.10 to 1.28), or hospitalization in a hospital with a catheterization laboratory (1.47 and 1.38 to 1.56). Dual chamber pacemaker selection was an independent predictor of survival at 1 year (0.82 and 0.77 to 0.87) and at 2 years (0.82 and 0.77 to 0.87) after controlling for potentially confounding patient-level and hospital-level characteristics. CONCLUSIONS: The present study describes important variations in the clinical practice of cardiac pacing, many of which are not based on clinical characteristics. Furthermore, the selection of a dual-chamber pacemaker is associated with increased survival. These results underscore the need for prospective, outcome-based clinical trials of pacemaker mode selection. PMID- 7850943 TI - Cost of initial therapy in the Electrophysiological Study Versus ECG Monitoring trial (ESVEM). AB - BACKGROUND: Patients randomized to either serial electrophysiological testing (EPS) or serial Holter monitoring (HM) to guide antiarrhythmic therapy for life threatening ventricular arrhythmias had equivalent rates of mortality and arrhythmia recurrence in the ESVEM study. This report analyzes the effects of EPS, HM, and clinical factors on the charges for initial evaluation and management of patients with life-threatening ventricular arrhythmias. METHODS AND RESULTS: Ten of 14 clinical centers participating in ESVEM provided bills from the initial hospitalization for randomized patients. Predictors of charges (1991 dollars) were analyzed by linear regression after logarithmic transformation. Initial hospital charge data were obtained for 286 patients randomized in ESVEM (88% of patients eligible for this substudy, 59% of all ESVEM patients). Patients with charge data were somewhat more likely to be older, to be female, and to have failed previous antiarrhythmic drug therapy at study entry and were less likely to have a drug predicted effective after randomization. Mean overall hospital charges were $35,986 (SD, $32,628) with a median of $24,532 (interquartile range, $16,126 to $43,593). Prerandomization patient characteristics generally had insignificant effects on charges, with the exception of presentation with resuscitated sudden death (28% increase in charges, P = .01) and heart failure (26% increase in charges, P = .02). Patients randomized to EPS had higher mean charges for evaluation ($42,002 versus $29,970, P = .0015) as well as more drug trials (3.0 versus 2.1, P = .0001) and a longer hospital stay (19.6 versus 13.9 days, P = .0007). In a multivariate regression model, failure to find an effective drug (P = .0001), the number of drug trials (P = .0001), and resuscitated sudden death as the presenting arrhythmia (P = .0001) were the only independent predictors of higher initial charges. CONCLUSIONS: (1) Initial hospital charges are significantly higher for EPS-guided than HM-guided therapy. (2) The higher charges for EPS-guided therapy were due to a greater number of drug trials and a lower probability of finding an effective drug. (3) Failure to find an effective drug, a larger number of drug trials, and a history of resuscitated sudden death independently predict higher charges. PMID- 7850944 TI - Characteristics of the ventricular insertion sites of accessory pathways with anterograde decremental conduction properties. AB - BACKGROUND: Accessory pathways (APs) with anterograde decremental conduction properties referred to as Mahaim fibers have recently been recognized as originating from the right lateral atrium. Little information is available about their distal insertion. The purpose of this study was to determine the different kinds of APs involved and the characteristics of their distal insertion site. METHODS AND RESULTS: Twenty-one patients (mean age, 28 +/- 13 years) with reciprocating tachycardia or atrial fibrillation were studied. Right-sided atrial and/or ventricular endocardial mapping during tachycardia identified different types of APs. (1) Seventeen patients had long APs originating from the right lateral atrium and coursing several centimeters to the right ventricle. In 10 patients, the AP terminated in or close to the right bundle-branch system (atriofascicular AP) and in 7, the AP terminated in the anterior right ventricle (atrioventricular AP). Patients with atriofascicular APs had narrower QRS complexes (133 +/- 10 versus 165 +/- 26 milliseconds, P = .02) and narrower initial r wave in leads V2 through V4 during maximal preexcitation than patients with atrioventricular APs. In addition, they had earlier His-bundle and right bundle-branch retrograde activation, ie, shorter V-His (16 +/- 5 versus 37 +/- 9 milliseconds, P < .01) and V-right bundle intervals (3 +/- 5 versus 25 +/- 6 milliseconds, P < .01). In 6 patients, minimal preexcitation not readily apparent was present in sinus rhythm despite the appearance of a narrow QRS complex. A wide distal insertion site of 0.5 to 2 cm in diameter consistent with arborization of the AP was found in 10 patients. The distal application of radiofrequency current produced a change in the preexcitation pattern in 4 patients and ablated the AP in 2 patients. In the other patients, radiofrequency current was applied more proximally and successfully ablated the AP bundle (n = 9) or AP proximal insertion (n = 6). No recurrence was observed during a follow up period of 12 +/- 10 months. (2) Four patients had short paratricuspid atrioventricular APs; in one, the decremental conduction property was acquired as demonstrated by two electrophysiological studies performed 7 years apart. Radiofrequency ablation was successfully accomplished in all 4 patients at the tricuspid annulus. CONCLUSIONS: Different types of APs account for tachycardias previously called Mahaim fibers. Long and short atrioventricular APs are observed in 81% and 19%, respectively. Long APs often have a distal arborization and may have either a fascicular or ventricular insertion. Radiofrequency current is more efficient when applied to the AP bundle or AP proximal insertion rather than to the distal insertion in patients with long APs. PMID- 7850945 TI - Characterization of atrioventricular nodal behavior and ventricular response during atrial fibrillation before and after a selective slow-pathway ablation. AB - BACKGROUND: The presence of atrioventricular nodal dual-pathway physiology in patients with atrioventricular nodal reentrant tachycardia (AVNRT) provides an opportunity to characterize the effect of a selective slow-pathway ablation on the ventricular rate during atrial fibrillation (AF). This may have important clinical implications for the nonpharmacological management of AF with a rapid ventricular rate. METHODS AND RESULTS: Selective radiofrequency catheter ablation of the atrioventricular nodal slow pathway was performed with a stepwise approach in patients with documented sustained AVNRT. The AV nodal conduction properties and refractoriness and the ventricular rate during induced AF were assessed at baseline and under autonomic blockade before and after a selective slow-pathway ablation in 18 patients (mean age, 34 +/- 8 years). Sustained AVNRT was induced with a mean cycle length of 339 +/- 58 ms. A slow-pathway ablation was successfully achieved with 5 +/- 4 applications of radiofrequency energy. The shortest cycle length of 1:1 AV conduction and the AV nodal effective refractory period significantly prolonged after ablation (367 +/- 53 versus 403 +/- 55 ms, P < .0001, and 258 +/- 55 versus 292 +/- 74 ms, P < .05, respectively). Selective slow-pathway ablation significantly prolonged the mean (526 +/- 93 versus 612 +/- 107 ms, P < .0001), the shortest (378 +/- 59 versus 423 +/- 73 ms, P < .0001), and the longest (826 +/- 150 versus 969 +/- 226 ms, P < .01) cycle lengths of the ventricular response to AF. Significant slowing of the ventricular rate during AF occurred in 13 patients (72%), including all eight patients in whom AV nodal dual pathway physiology was abolished. Five patients did not have a significant change in the ventricular rate during AF; a persistent dual AV nodal pathway physiology was demonstrable in four of these patients. Loss of dual-pathway physiology after ablation had a sensitivity of 77%, specificity of 80%, and positive predictive value of 91% for slowing the ventricular rate during AF. CONCLUSIONS: In patients undergoing a slow-pathway ablation for control of AVNRT, selective slow-pathway ablation may cause a significant decrease in the ventricular rate during AF. These effects are primarily due to the prolongation of AV nodal conduction properties and refractory period of the residual AV nodal transmission system. These findings may have important therapeutic implications for the nonpharmacological treatment of AF, particularly in patients with underlying dual AV nodal physiology. PMID- 7850946 TI - Termination of atrioventricular nodal reentrant tachycardia by premature stimulation from ablating catheter. A reliable guide to identify site for slow pathway ablation. AB - BACKGROUND: Slow-pathway ablation is currently used more frequently to control atrioventricular nodal reentrant tachycardia (AVNRT). However, in patients with the common type of AVNRT, successful ablation of the slow pathway can be difficult and time-consuming. We tested a simple method to predict a site for slow-pathway ablation in patients with AVNRT of the common variety. METHODS AND RESULTS: Twenty patients with symptomatic common AVNRT (13 women and 7 men; mean age, 41 +/- 21 years) were included in the study. Once the AVNRT had a stable cycle length (+/- 10 ms) for at least 20 cycles, single extrastimuli were delivered from the ablating catheter tip beginning with 20 ms less than the tachycardia cycle length and decrementing by 10 ms until tachycardia terminated or loss of capture occurred at the pacing site. The pacing protcol was performed systematically in a stepwise fashion at four adjacent sites starting from the posterior/inferior interatrial septum near the tricuspid annulus and moving progressively more anteriorly. The pacing protocol was then repeated in the same sequence, followed by delivery of radiofrequency current at each site to determine its effect at sites where AVNRT could not be terminated with a pacing protocol. AVNRT could be terminated in the anterograde direction from at least one site in 19 patients. Tachycardia could be terminated at two or more adjacent sites in 5 patients. The longest atrial coupling interval at the site of tachycardia termination was 67 +/- 27 ms (range, 30 to 130 ms) less than the AVNRT cycle length. Resetting of subsequent His bundle depolarization (H2), producing an H-H2 interval prolongation of 26 +/- 24 ms (range, 10 to 80 ms), occurred in 17 patients before termination of the tachycardia. In 18 of the 19 patients, the slow pathway was successfully ablated at the site at which AVNRT was terminated at the longest atrial coupling interval. CONCLUSIONS: Termination of tachycardia in the anterograde direction at the longest atrial coupling interval by extrastimuli delivered from the ablating catheter can be helpful for identification of an optimal site for slow-pathway ablation in patients with the common variety of AVNRT. PMID- 7850948 TI - Role of calcium/calmodulin-dependent protein kinase II in the regulation of vascular smooth muscle cell migration. AB - BACKGROUND: The migration of vascular smooth muscle cells (VSMCs) is a key event in the pathogenesis of many vascular diseases. We have previously shown that VSMC migration in response to platelet-derived growth factor (PDGF) is suppressed when cultured cells are growth-arrested and induced to differentiate. The present study was undertaken to elucidate the mechanism of this suppression. METHODS AND RESULTS: While both proliferating and growth-arrested VSMCs upregulated expression of the immediate early response genes, c-fos and JE (monocyte chemoattractant protein 1), growth-arrested VSMCs exhibited much smaller changes in intracellular calcium in response to PDGF and failed to activate the calcium/calmodulin-dependent protein kinase II (CaM kinase II). Blocking calcium calmodulin interactions (50 mumol/L W7) or the activation of CaM kinase II (10 mumol/L KN62) in proliferating cells blocked their migration by more than 90%, whereas inhibition of protein kinase C activation had no significant effect on migration. Pretreatment of growth-arrested VSMCs with the calcium ionophore ionomycin resulted in an approximately 2.5-fold activation of CaM kinase II and increased migration of growth-arrested cells to 84 +/- 6% that of proliferating cells. These effects of ionomycin were blocked by inhibitors of CaM kinase II. Constitutively activated (ie, calcium/calmodulin-independent) CaM kinase II introduced by gene transfection into growth-arrested cells significantly increased migration toward PDGF from < 20% to > 70% that of proliferating cells. CONCLUSIONS: These results demonstrate that activation of CaM kinase II is required for VSMC migration, that its activation in response to PDGF is suppressed in growth-arrested VSMCs, and that this suppression of CaM kinase II activation is responsible, in large part, for the failure of growth-arrested VSMCs to migrate toward PDGF. PMID- 7850947 TI - Hyperdynamic circulation and cardiovascular risk in children and adolescents. The Bogalusa Heart Study. AB - BACKGROUND: Hyperdynamic circulation has been reported to be associated with adverse levels of insulin, blood pressure, adiposity, and lipoproteins in the adult population. Whether this putatively insulin-mediated association also occurs in early life is not known. This aspect was examined in 2229 children and adolescents 8 to 17 years old living in Bogalusa, La. METHODS AND RESULTS: Individuals were categorized as hyperdynamic (pulse pressure and heart rate in the upper quartile of the race-sex-age distribution), intermediate, and hypodynamic (pulse pressure and heart rate in the bottom quartile). Systolic blood pressure was significantly greater with a hyperdynamic circulation in both sexes (P < .0001), and several measures of obesity were greater with a hyperdynamic circulation. Hyperdynamic circulation was associated with statistically significant increases in triglyceride (P < .05) and fasting insulin (P < .01) in boys independently of age, race, and obesity. A decreasing trend with HDL cholesterol (P = .06) was also observed in boys. A significant association with total cholesterol (P < .05) was observed only in girls. In the analysis stratified by percent body fat, many of these features still occurred in obese individuals (top quartile) but not in lean individuals (bottom quartile). Further, when a subset of this cohort (n = 1074) was followed over a 3-year period, the above trend persisted significantly in boys. CONCLUSIONS: The present study demonstrates that a hyperdynamic state as defined is associated with increased insulin levels and an adverse cardiovascular risk in early life. PMID- 7850949 TI - Effects of 15-deoxyspergualin on experimental autoimmune giant cell myocarditis of the rat. AB - BACKGROUND: The benefits of immunosuppressive therapy for human myocarditis are controversial. The effects of a new immunosuppressant agent, 15-deoxyspergualin (DSG), on rats with experimental autoimmune myocarditis (EAM), an animal model of human giant cell myocarditis, were examined. METHODS AND RESULTS: Lewis rats were immunized with cardiac myosin in Freund's complete adjuvant on day 0. In the first experiment, the effective doses of DSG required to prevent EAM were investigated. Rats were placed into one of five groups: the control group (A) was administered saline from days 1 to 10; group B, 0.3 mg/kg per day of DSG; group C, 1.0 mg/kg per day of DSG; group D, 3.0 mg/kg per day of DSG, and group E, 10.0 mg/kg per day of DSG. Rats were killed on day 28. The heart weight/body weight ratios of the rats of groups D and E were significantly lower than that of the control group. Macroscopic and microscopic scores for myocarditis decreased in groups D and E. In the next experiment, the effects of delayed administration of DSG in preventing autoimmune myocarditis were studied. Two groups of rats received 3.0 and 10.0 mg/kg per day of DSG from days 6 to 15, respectively. Two other groups of rats received the same doses of DSG from days 11 to 20. No preventive effect of delayed DSG treatment was observed. The effects of long term, delayed initiation therapy then were evaluated. Rats were administered 10.0 mg/kg per day of DSG from days 6 to 25. The heart weight/body weight ratio and macroscopic and microscopic scores of the rats so treated significantly decreased compared with the controls. CONCLUSIONS: It was demonstrated that DSG can prevent the development of cardiac myosin-induced autoimmune myocarditis. PMID- 7850950 TI - Fish oil treatment decreases superoxide anions in the myocardium and coronary arteries of atherosclerotic monkeys. AB - BACKGROUND: This experiment sought to determine the effects of fish oil on superoxide anion production in the myocardium and coronary arteries of atherosclerotic monkeys. Recent evidence indicates that dietary supplementation with fish oil preserves normal vasomotion of atherosclerotic coronary arteries and reduces damage to the myocardium after ischemia and reperfusion, although the mechanisms remain unclear. METHODS AND RESULTS: Adult male cynomolgus monkeys were fed an atherogenic diet with (n = 15) or without (n = 15) half the fat calories from fish oil. After 12 months, chemiluminescence of lucigenin was used to measure superoxide anion production in coronary arteries and myocardium after 1 hour of ischemia and 2 hours of reperfusion. The signals were calibrated with known quantities of xanthine and xanthine oxidase. Superoxide anion production in ischemic myocardium was (mean +/- SEM, nmol/mg dry wt per minute) 1 +/- 1 and 4 +/- 1 in monkeys fed fish oil and not fed fish oil, respectively (P < .05). Superoxide anion production in coronary arteries not exposed to ischemia and reperfusion was (nmol/mg dry wt per minute) 4 +/- 1 and 8 +/- 2 in monkeys fed fish oil and not fed fish oil, respectively (P < .05). Superoxide anion production in coronary arteries was (nmol/mg dry wt per minute) 5 +/- 2 and 16 +/ 3 in monkeys fed fish oil and not fed fish oil after ischemia and reperfusion, respectively (P < .05). CONCLUSIONS: Dietary supplementation with fish oil reduced vascular superoxide anion production and prevented the increase in vascular and myocardial superoxide anion production that accompanied ischemia and reperfusion. These phenomena may underlie some of the beneficial cardiovascular effects of fish oil. PMID- 7850951 TI - Evidence that angiotensin II is present in human monocytes. AB - BACKGROUND: The purpose of the present study was to determine whether human monocytes and polymorphonuclear leukocytes contain angiotensins I and II. METHODS AND RESULTS: Human mononuclear and polymorphonuclear leukocytes were isolated from blood. To identify angiotensins in human leukocytes, we performed immunocytochemistry using both alkaline phosphatase and fluorescence methods. With light microscopy immunocytochemistry with alkaline phosphatase, prominent staining of angiotensin II was observed in mononuclear leukocytes. Angiotensin I was also demonstrated in mononuclear leukocytes, but the signal was less pronounced than for angiotensin II. Polymorphonuclear leukocytes showed very little staining for angiotensin II. Fluorescence immunocytochemistry also demonstrated angiotensin II in mononuclear leukocytes. Angiotensins I and II in homogenate of leukocytes were quantified by radioimmunoassay. The concentration of angiotensins I and II in mononuclear leukocytes was 355 +/- 216 (mean +/- SEM) and 2331 +/- 106 fmol/mg protein, respectively, and the concentration in polymorphonuclear leukocytes was 36 +/- 10 and 336 +/- 120 fmol/mg protein. CONCLUSIONS: These findings suggest that human mononuclear leukocytes contain large amounts of angiotensin II and lesser amounts of angiotensin I. Human polymorphonuclear leukocytes contain small amounts of angiotensin I and II. PMID- 7850952 TI - Opposing effects of plasma epinephrine and norepinephrine on coronary thrombosis in vivo. AB - BACKGROUND: It is well known that plasma catecholamines and myocardial infarction have a close relation and that coronary artery thrombosis is a major cause of myocardial infarction. In addition, epinephrine is known to be a prothrombogenic agent in vivo. However, the role of the other major circulating catecholamine, norepinephrine, in the development of coronary thrombosis is somewhat uncertain, although the role of norepinephrine is often considered analogous to the role of epinephrine. Therefore, the present study was designed to investigate the effect of norepinephrine and its interaction with epinephrine on coronary thrombosis. METHODS AND RESULTS: To compare the effects of epinephrine and norepinephrine on coronary thrombosis, we analyzed the frequency of cyclic blood flow reductions (CFRs) in an anesthetized canine model of coronary thrombosis (n = 25). Three experiments were used in the present study. In the first experiment with epinephrine infusion, plasma epinephrine was elevated from 0.46 +/- 0.25 to 27.7 +/- 1.85 nmol/L. The frequency of CFRs increased by more than 60%, from 7.1 +/- 0.5 to 11.5 +/- 0.7 in 40 minutes (P < .01). The second experiment included three experimental periods: control, norepinephrine infusion, and norepinephrine infusion plus epinephrine infusion. Norepinephrine was infused to raise plasma norepinephrine from 1.3 +/- 0.2 to 32.4 +/- 4.3 nmol/L. The frequency of CFRs in the dogs was markedly reduced, from 7.89 +/- 0.42 to 2.41 +/- 1.08 in 40 minutes (P < .01), whereas arterial pressure was elevated from 88 +/- 3 to 118 +/- 5 mm Hg (P < .01). However, when epinephrine infusion was added to the norepinephrine infusion, the frequency of CFRs increased from 2.41 +/- 1.08 to 7.74 +/- 1.12 in 40 minutes (P < .01). In the third experiment, a servocontrol device was used during the norepinephrine infusion to prevent rises in coronary arterial pressure. As a result of the norepinephrine infusion, the frequency of CFRs was reduced from 7.47 +/- 0.71 to 0.83 +/- 0.65 in 40 minutes (P < .01), even though the coronary arterial pressure was not altered. CONCLUSIONS: The present study demonstrated that infusion of epinephrine stimulated coronary artery thrombosis, whereas infusion of norepinephrine inhibited coronary artery thrombosis. In addition, the inhibitory effect of norepinephrine on coronary thrombosis is independent of increases in coronary arterial pressure. Therefore, the present findings suggest that epinephrine and norepinephrine have opposing effects on coronary thrombosis in dogs. PMID- 7850953 TI - Effect of coronary artery reperfusion on transmural myocardial remodeling in dogs. AB - BACKGROUND: The effects of reperfusion after coronary occlusion on transmural remodeling of the ischemic region early and late after nontransmural infarction must importantly affect the recovery of regional function. Accordingly, analysis of local volume and three-dimensional strain was performed using a finite element method to determine regional remodeling. Systolic and remodeling strains were measured using radiographic imaging of three columns (approximately 1 cm apart) of four to six gold beads implanted across the left ventricular posterior wall in 6 dogs. METHODS AND RESULTS: After a control study, infarction was produced by 2 to 4 hours of proximal left circumflex coronary artery occlusion followed by reperfusion. Follow-up studies were performed at 2 days, 3 weeks, and 12 weeks with the dogs under anesthesia and in closed-chest conditions. Biplane cineradiography was performed to obtain the three-dimensional coordinates of the beads. At 2 days, end-systolic strains were akinetic with loss of normal transmural gradients of shortening and thickening. Remodeling strains (RS) were determined by use of a nonhomogeneous finite element method by referring the end diastolic configuration during follow-up studies to its control state at matched end-diastolic pressures and heart rates. Tissue volume at 2 days increased substantially, more at the endocardium (30 +/- 7%) than at the epicardium (5 +/- 12%, P < .01); the increase was associated with an average RS in the wall thickening direction of 0.18 +/- 0.15 (P < .01) with all other RS near zero. At 12 weeks systolic function partially recovered, with normal wall thickening in the epicardium (radial strain, 0.081 +/- 0.056 [control] versus 0.113 +/- 0.088 [12 weeks]) but with dysfunction in the endocardium (0.245 +/- 0.108 [control] versus 0.111 +/- 0.074 [P < .01] [12 weeks]). This inability of the inner wall to recover function may be related to increased transmural torsional shear and negative longitudinal-radial transverse shear in the inner wall. Volume loss occurred at 12 weeks in the endocardium (-36 +/- 16%) corresponding to transmural gradients in longitudinal RS and both transverse shear RS. Negative longitudinal RS was greater at the endocardium (-0.20 +/- 0.10) than at the epicardium (-0.06 +/- 0.05, P < .01). CONCLUSIONS: These results indicate the presence of marked subendocardial edema 2 days after reperfusion following 2 to 4 hours of coronary occlusion. At 3 months after reperfusion, however, there was volume loss in the inner wall due to shrinkage along the myofiber direction with reduced transmural function and loss of longitudinal shortening, while both tissue volume and function recovered completely in the outer wall. PMID- 7850954 TI - Testosterone relaxes rabbit coronary arteries and aorta. AB - BACKGROUND: Until menopause, women appear to be protected from coronary heart disease. Evidence suggests that estrogen may play a role in the protection of the cardiovascular system by exerting a beneficial effect on risk factors such as cholesterol metabolism and by a direct effect on the coronary arteries. To date there has been no evidence linking testosterone with the occurrence of coronary heart disease. Testosterone may affect the cardiovascular system directly, thus partially explaining the difference in the incidence of coronary artery disease in men and premenopausal women. The purpose of this study was to assess the direct effect of testosterone and a number of testosterone analogues on rabbit coronary arteries and aorta in vitro. METHODS AND RESULTS: Rings of coronary artery and aorta of adult male or nonpregnant female New Zealand White rabbits were suspended in organ baths containing Krebs solution; isometric tension then was measured. The response to testosterone was investigated in prostaglandin F2 alpha (PGF 2 alpha)- and KCl-contracted rings. The effects of endothelium and nitric oxide synthase, prostaglandin synthetase, and guanylate cyclase inhibition on testosterone-induced relaxation were investigated. The effects of ATP sensitive potassium channels and potassium conductance were also assessed. Relaxing responses in the presence of aromatase inhibition and testosterone receptor blockade were performed. The relaxing responses to the testosterone analogues etiocholan-3 beta-ol-17-one, epiandrosterone, 17 beta-hydroxy-5 alpha androst-1-en-3-one, androst-16-en-3-ol, and testosterone enanthanate were measured. Testosterone relaxed rabbit coronary arteries and aorta. There was no significant difference between the relaxation effect of testosterone with or without endothelium. Similar results were obtained from male and nonpregnant female rabbits. The relaxing response of testosterone in the coronary artery was significantly greater than in the aorta. The relaxing response of testosterone in the coronary artery was significantly reduced by the potassium channel inhibitor barium chloride but not by the ATP-sensitive potassium channel inhibitor glibenclamide. The relaxing response to testosterone was greater in PGF 2 alpha contracted rings compared with KCl-contracted rings. Inhibitors of nitric oxide synthase, prostaglandin synthetase, and guanylate cyclase did not affect relaxation induced by testosterone. Inhibition of aromatase and testosterone receptors did not affect relaxation. Testosterone did not shift the rabbit coronary arterial calcium concentration-dependent contraction curves, whereas verapamil did. There were, however, significant differences in the relaxing response to testosterone compared with testosterone analogues. Testosterone was the most potent relaxing agent, suggesting that there may be a structure-function relation in the relaxing response. CONCLUSIONS: Testosterone induces endothelium independent relaxation in isolated rabbit coronary artery and aorta, which is neither mediated by prostaglandin I2 or cyclic GMP. Potassium conductance and potassium channels but not ATP-sensitive potassium channels may be involved partially in the mechanism of testosterone-induced relaxation. The in vitro relaxation is independent of sex and of a classic receptor. The coronary artery is significantly more sensitive to relaxation by testosterone than the aorta. Testosterone is a more potent relaxing agent of rabbit coronary artery than other testosterone analogues. PMID- 7850955 TI - Hyperhomocysteinemia-induced vascular damage in the minipig. Captopril hydrochlorothiazide combination prevents elastic alterations. AB - BACKGROUND: Previous attempts in animals failed to reproduce the metabolic, pathological, and clinical situations encountered in homocystinuric patients. Minipigs on a methionine-rich caseinate-based diet, however, have a special long lasting postprandial plasma accumulation of methionine, the metabolic precursor of homocysteine. We hypothesized that these minipigs develop hyperhomocysteinemia in the long term. Angiotensin-converting enzyme (ACE) inhibition prevents atherogenic alteration of viscoelastic functions of arterial pulsatility and compliance and reduces fragmentation of vascular elastic laminae in the minipigs. We consequently analyzed the therapeutic effects of the captopril hydrochlorothiazide combination against the typical hyperhomocysteinemia-induced alterations of vascular elastic features. METHODS AND RESULTS: Thirty-two Gotingen minipigs were randomized as control diet-fed (C), captopril (25 mg/d)/hydrochlorothiazide (12.5 mg/d)-treated C (C+Cp), caseinate-based diet-fed (M), and M+Cp minipigs. After 4 months, M and M+Cp animals had hyperhomocysteinemia (9.64 +/- 4.10 mumol/L, n = 16) compared with C and C+Cp minipigs (5.67 +/- 1.14 mumol/L, n = 16) (P < .05). In the M group, one minipig died from thromboembolic syndrome, and one had pulmonary infarction. M minipigs presented with systolic-diastolic hypertension and extended reactive hyperemia, as well as a mega-artery syndrome in hyperpulsatile arteries due to expanded volumetric compliance, curtailed stiffness, strengthened vascular tension, and prevalence of the viscous wall component. In their arterial tree, hypertrophic endothelial cells covered a thickened subendothelial space. Major elastic lamina dislocations were observed, as well as hypertrophy and reorientation of smooth muscle cells, resulting in the settlement of spreading pathways for medial cells between muscular laminae. In C+Cp and M+Cp animals, serum and lung ACE activity were inhibited by 74% and 40%, respectively. Although the treatment with captopril-hydrochlorothiazide did not modify the hyperhomocysteinemia per se, the therapeutic effects of the drug combination are made evident by the absence of death and ischemic diseases in the M+Cp group. Specifically, the drug combination prevented diastolic hypertension and improved aortic blood flow by normalizing peripheral resistances, abolished the vascular hyperpulsatile characters, and restrained the fragmentation and the splitting of elastic fibers in capacitance arteries. In contrast, the drugs slightly prevented systolic and mean hypertension. In addition, the aortic stiffness and stress response remained altered and vascular smooth muscle cell hypertrophy was still observed in the M+Cp group. CONCLUSIONS: In minipigs, the present methionine-rich caseinate-based diet induced hyperhomocysteinemia, which reproduces the metabolic and histopathological situation found in homocysteic patients. Our results show that hyperhomocysteinemia-induced vascular alterations favor the viscous component of the wall rheology to the detriment of the elastic component. Furthermore, they extend to hyperhomocysteinemia the therapeutic effects characteristically shared by ACE inhibitors in association with hydrochlorothiazide against the atherogenic activation of elastinolytic processes. PMID- 7850956 TI - Thrombolysis and reocclusion in experimental jugular vein and coronary artery thrombosis. Effects of a plasminogen activator inhibitor type 1-neutralizing monoclonal antibody. AB - BACKGROUND: Thrombolytic therapy for acute myocardial infarction is often complicated by reocclusion of the initially reperfused artery. Platelets have been shown to play an important role in this process. We determined the contribution of plasminogen activator inhibitor type 1 (PAI-1), stored in the alpha-granules of platelets, to thrombolysis resistance and to reocclusion. METHODS AND RESULTS: In a rabbit jugular vein thrombosis model, the effect of a PAI-1-neutralizing monoclonal antibody (CLB-2C8) on thrombolysis and thrombus growth was assessed. The effect on reperfusion, reocclusion, and duration of vessel patency was studied in a canine model of coronary artery thrombosis superimposed on a high-grade stenosis and endothelial damage. In the rabbit jugular vein model, the intravenous administration of 1 mg/kg anti-PAI-1 antibody significantly enhanced the endogenous thrombolysis from 5.5 +/- 1.3% in the animals treated with a nonspecific monoclonal antibody (control) to 13.7 +/- 2.6% in the animals treated with the anti-PAI-1 antibody. Thrombus growth was reduced significantly, from 41.3 +/- 2.6% in the control animals to 22.8 +/- 2.8% in the animals treated with the anti-PAI-1 antibody. In combination with a single bolus injection of recombinant tissue-type plasminogen activator (rTPA; 0.25 mg/kg), the anti-PAI-1 antibody reduced thrombus growth significantly, from 21.5 +/- 2.7% in the animals treated with rTPA alone to 12.2 +/- 2.6% in the animals treated with rTPA and the antibody. No additional effect of the anti-PAI-1 antibody was observed on rTPA-induced thrombolysis. In the canine coronary artery thrombosis model, the administration of a suboptimal dose of rTPA (0.45 mg/kg) induced reperfusion in 7 of the 8 dogs after 19.5 +/- 8.2 minutes. Reperfusion was followed by reocclusion in all animals after 3.3 +/- 2.6 minutes. Administration of the anti-PAI-1 antibody in combination with rTPA significantly reduced time to reperfusion (8.1 +/- 5.2 minutes) and delayed the occurrence of reocclusion to 11.6 +/- 12.5 minutes. CONCLUSIONS: Administration of the anti-PAI-1 antibody (CLB-2C8) results in increased endogenous thrombolysis and inhibition of thrombus growth in a venous thrombosis model in rabbits and facilitated reperfusion and reduction of reocclusion in a canine model of coronary artery thrombosis. PMID- 7850957 TI - Administration of wine and grape juice inhibits in vivo platelet activity and thrombosis in stenosed canine coronary arteries. AB - BACKGROUND: Moderate daily consumption of alcoholic beverages is a negative risk factor for the development of atherosclerosis and coronary artery disease (CAD), especially in France and other Mediterranean areas where red wine is regularly consumed with meals. Platelets contribute to the development of atherosclerosis, CAD, and acute arterial thrombus formation. METHODS AND RESULTS: Anesthetized dogs were prepared with the Folts model of mechanically stenosed coronary arteries and intimal damage. Periodic acute platelet-mediated thrombus formation occurred, causing cyclic flow reductions (CFRs) in coronary blood flow. The CFRs were eliminated by the administration of 1.62 +/- 1.12 mL/kg red wine intravenously (IV) and 4.0 mL/kg intragastrically (IG). The CFRs were abolished by 2.04 +/- 1.42 mL/kg of grape juice IV and 10 mL/kg IG. White wine did not have significant results in eliminating the CFRs, either IV (2.0 mL/kg) or IG (4.0 mL/kg), decreasing the slopes of the CFRs only slightly. CONCLUSIONS: Pure ethanol has been shown to inhibit platelet aggregation in vitro, ex vivo, and in vivo, although a blood alcohol content (BAC) of > or = 0.2 g/dL is usually required. The BAC of dogs administered the red wine-saline solution intravenously was 0.028 g/dL, much less than is usually necessary for platelet inhibition with pure ethanol. Because red wine and grape juice, but not white wine, abolished the CFRs, this suggests there are compounds present in red wine and grape juice that are not present or are present in a lower concentration in white wine. Wine and grape juice contain a wide variety of naturally occurring compounds, including fungicides, tannins, anthocyanins, and phenolic flavonoids (including flavonols and flavones). These compounds have shown platelet inhibition in vitro by a variety of proposed mechanisms. Perhaps the biological activity of these compounds can explain the platelet-inhibitory properties of red wine and grape juice that are observed without high levels of ethanol. PMID- 7850958 TI - Papillary muscle displacement causes systolic anterior motion of the mitral valve. Experimental validation and insights into the mechanism of subaortic obstruction. AB - BACKGROUND: Systolic anterior motion (SAM) of the mitral valve in hypertrophic cardiomyopathy (HCM) has generally been explained by a Venturi effect related to septal hypertrophy, causing outflow tract narrowing and high velocities. Patients with HCM, however, also have primary abnormalities of the mitral apparatus, including anterior and inward or central displacement of the papillary muscles, and leaflet elongation. These findings have led to the hypothesis that changes in the mitral apparatus can be a primary cause of SAM by altering the forces acting on the mitral valve and its ability to move in response to them. Despite suggestive observations, however, it has never been prospectively demonstrated that such changes can actually cause SAM. METHODS AND RESULTS: To test this hypothesis in vivo, anterior papillary muscle displacement was created in 7 dogs studied by echocardiography, with controlled cardiac output and heart rate. In all 7 dogs, papillary muscle displacement caused SAM, with an outflow tract gradient (33 +/- 19 mm Hg) and mitral regurgitation in 6. As in patients with HCM, the mitral valve was displaced anteriorly and the coaptation point shifted toward the insertion of the leaflets, creating longer distal residual leaflets that moved anteriorly. CONCLUSIONS: Primary changes in the mitral apparatus can cause SAM without septal hypertrophy. In this model, SAM appears to be determined by the ability of the leaflets to move anteriorly (papillary muscle displacement causing slack and increased residual leaflet length) and their interposition into the outflow stream by anterior displacement, determining the direction of this motion. Geometric factors observed in HCM and in patients with SAM without HCM can therefore play a primary role in causing SAM. PMID- 7850959 TI - Comparison of valvular resistance, stroke work loss, and Gorlin valve area for quantification of aortic stenosis. An in vitro study in a pulsatile aortic flow model. AB - BACKGROUND: Valvular resistance and stroke work loss have been proposed as alternative measures of stenotic valvular lesions that may be less flow dependent and, thus, superior over valve area calculations for the quantification of aortic stenosis. The present in vitro study was designed to compare the impacts of valvular resistance, stroke work loss, and Gorlin valve area as hemodynamic indexes of aortic stenosis. METHODS AND RESULTS: In a pulsatile aortic flow model, rigid stenotic orifices in varying sizes (0.5, 1.0, 1.5 and 2.0 cm2) and geometry were studied under different hemodynamic conditions. Ventricular and aortic pressures were measured to determine the mean systolic ventricular pressure (LVSPm) and the transstenotic pressure gradient (delta Pm). Transvalvular flow (Fm) was assessed with an electromagnetic flowmeter. Valvular resistance [VR = 1333.(delta Pm/Fm)] and stroke work loss [SWL = 100.(delta Pm/LVSPm)] were calculated and compared with aortic valve area [AVA = Fm/(50 square root of delta Pm)]. The measurements were performed for a large range of transvalvular flows. At low-flow states, flow augmentation (100-->200 mL/s) increased calculated valvular resistance between 21% (2.0 cm2 orifice) and 66% (0.5-cm2 orifice). Stroke work loss demonstrated an increase from 43% (2.0 cm2) to 100% (1.0 cm2). In contrast, Gorlin valve area revealed only a moderate change from 29% (2.0 cm2) to 5% (0.5 cm2). At physiological flow rates, increase in transvalvular flow (200-->300 mL/s) did not alter calculated Gorlin valve area, whereas valvular resistance and stroke work loss demonstrated a continuing increase. Our experimental results were adopted to interpret the results of three clinical studies in aortic stenosis. The flow-dependent increase of Gorlin valve area, which was found in the cited clinical studies, can be elucidated as true further opening of the stenotic valve but not as a calculation error due to the Gorlin formula. CONCLUSIONS: Within the physiological range of flow, calculated aortic valve area was less dependent on hemodynamic conditions than were valvular resistance and stroke work loss, which varied as a function of flow. Thus, for the assessment of the severity of aortic stenosis, the Gorlin valve area is superior over valvular resistance and stroke work loss, which must be indexed for flow to adequately quantify the hemodynamic severity of the obstruction. PMID- 7850960 TI - Splanchnic venous pressure-volume relation during experimental acute ischemic heart failure. Differential effects of hydralazine, enalaprilat, and nitroglycerin. AB - BACKGROUND: Vasodilator drugs have variable effects on veins and arteries. However, direct measurements of their effects on the splanchnic veins, perhaps the most important volume reservoir, have not been reported. We assessed the effect of acute heart failure and the subsequent administration of hydralazine, enalaprilat, and nitroglycerin on the splanchnic venous pressure-volume relation in intact dogs. METHODS AND RESULTS: Experimental acute ischemic heart failure was induced in 19 splenectomized dogs by microsphere embolization of the left main coronary artery. Embolization was repeated until left ventricular end diastolic pressure (LVEDP) reached 20 mm Hg and cardiac output decreased by 50%. The splanchnic vascular pressure-volume relation was determined by radionuclide plethysmography during the control stage, after acute heart failure had been established, and after administration of a vasodilator (hydralazine, enalaprilat, or nitroglycerin) at a dose sufficient to reduce mean aortic pressure by approximately 20%. Induction of acute heart failure was associated with a decrease in the splanchnic vascular volume from 100% to 86 +/- 2% and an increase in LVEDP from 6 +/- 1 to 21 +/- 1 mm Hg (P < .001). There was a parallel leftward shift of the splanchnic vascular pressure-volume curve. After the administration of hydralazine, enalaprilat, and nitroglycerin, the splanchnic vascular volumes increased from 86% to 88 +/- 3%, 96 +/- 3%, and 113 +/- 3%, respectively (P = NS, P < .01, and P < .001, respectively, versus heart failure). After drug administration, the LVEDPs were 18 +/- 2, 16 +/- 1, and 13 +/- 1 mm Hg (P = NS, P < .05, and P < .001, respectively, versus heart failure). CONCLUSIONS: Acute heart failure was associated with a parallel leftward shift of the splanchnic venous pressure-volume relation (venoconstriction). Splanchnic (systemic) venoconstriction may in part explain the increased LVEDP during acute heart failure by displacement of blood to the central compartment. Subsequently administered enalaprilat and, to a greater degree, nitroglycerin produced splanchnic venodilation, thereby lowering LVEDP. Hydralazine had no significant effect on the splanchnic veins and only a modest effect on LVEDP. In this model, splanchnic capacitance changes appear to modulate change in left ventricular preload. PMID- 7850961 TI - Disparate effects of early pressure overload hypertrophy on velocity-dependent and force-dependent indices of ventricular performance in the conscious baboon. AB - BACKGROUND: The effects of early pressure overload on left ventricular (LV) chamber mechanics in the primate heart are poorly understood. METHODS AND RESULTS: To test the hypothesis that early LV pressure overload hypertrophy is associated with depression of velocity-dependent indices of LV systolic (LV dP/dt) and diastolic function (time constant of relaxation, tau) but unchanged systolic elastance (Ees), we studied six conscious baboons instrumented with LV micromanometers and LV dimension and wall thickness sonomicrometers. Loading conditions were altered by pharmacological angiotensin II generation both before and 12 weeks after producing renovascular hypertension (2 kidney, 1 clip). The LV systolic pressure (149 +/- 11 [SD] versus 114 +/- 5 mm Hg) and LV mass (125 +/- 25 versus 91 +/- 20 g) were greater 12 weeks after than before (both P < .05). Both Ees and Ees normalized for LV mass were similar before versus 12 weeks after (23.0 +/- 9.6 versus 22.3 +/- 9.8 mm Hg/mL and 26.5 +/- 14.5 versus 19.8 +/- 12.5 mm Hg/mL, respectively; both P = NS). At matched LV systolic and diastolic pressures, LV fractional shortening was similar (18.6 +/- 6.8% versus 21.6 +/- 4.9%), but the time constant of LV isovolumic relaxation was significantly longer (42.3 +/- 5.3 versus 31.4 +/- 7.0 ms, P < .05) and LV dP/dt and Vcf were significantly less (1891 +/- 352 versus 2342 +/- 284 mm Hg/s and 0.9 +/- 0.4 versus 1.1 +/- 0.3 circ/s, respectively; both P < .05) 12 weeks after than before. CONCLUSIONS: In conscious baboons with systemic arterial hypertension and early LV hypertrophy, there is depression of velocity-dependent indices of LV contraction and relaxation but unaltered force-dependent measures of contractility. PMID- 7850962 TI - Balloon dilatation of porcine pulmonary arteries decreases endothelium-dependent relaxations and increases vasoconstriction to aggregating platelets. AB - BACKGROUND: Balloon dilatation of muscular coronary arteries disrupts endothelium and smooth muscle and allows platelet aggregation and adherence and cell proliferation, which can lead to restenosis. Balloon dilatation of the more distensible pulmonary artery is commonly performed, but the extent of damage to endothelium and its effect on the release of endothelium-derived nitric oxide (EDNO) and prostacyclin has not been studied. METHODS AND RESULTS: We dilated distal pulmonary arteries of intact ex vivo porcine lungs (n = 20; balloon dilated [BD] group) using similar-sized adjacent vessels as controls with (E+group) and without (E- group) endothelium. Isolated rings were studied in vitro. Aggregating platelets caused constrictions of quiescent rings from the BD (27.4 +/- 8% of constriction to 80 mmol/L KCl) and E- groups (24 +/- 5%), which were inhibited by pyrilamine, a histamine blocker (11 +/- 4%; P < .05), and an intact endothelium (8 +/- 5%; P < .05). Constrictions to histamine and KCl were similar in the BD and E- groups. In rings with increased tone, platelets caused endothelium-dependent relaxations in the E+ group (70 +/- 6% relaxation), which were significantly (P < .05) inhibited in the BD group (20 +/- 7%), by L-nitro arginine (EDNO blocker, 17 +/- 7%) and in the E- group (21 +/- 9%). Balloon dilatation markedly reduced endothelium-dependent relaxations to 5 hydroxytryptamine, thrombin, acetylcholine, and the calcium ionophore A23187, but relaxations to sodium nitroprusside were unaffected. CONCLUSIONS: Despite the distensibility of the pulmonary artery, balloon dilatation significantly damages the pulmonary endothelium, decreases EDNO production, impairs vasodilation, and favors platelet-induced vasoconstriction. PMID- 7850963 TI - Direct measurements of endothelium-derived nitric oxide release by stimulation of endothelin receptors in rat kidney and its alteration in salt-induced hypertension. AB - BACKGROUND: Stimulation of endothelin subtype B (ETB) receptors has been proposed to induce release of endothelium-derived nitric oxide (EDNO). METHODS AND RESULTS: To obtain direct evidence of its release and its alteration in deoxycorticosterone acetate (DOCA)-salt hypertension, EDNO released from renal vessels by ET stimulation was assayed by a highly sensitive chemiluminescence method. Kidneys were isolated from DOCA-salt and control rats, and renal perfusion pressure (RPP) and EDNO (by hydrogen peroxide-luminol chemiluminescence) in the perfusate were monitored simultaneously during perfusion of ET-1, ET-3, an ETA receptor antagonist (BQ-123), and an ETB receptor agonist (BQ-3020). In control rats, ET-1 and ET-3 dose-dependently increased both RPP and NO release. Although the vasoconstricting effects of ET-1 were greater, their NO-releasing effects were comparable. The increase in NO release by ETs was inhibited by NG-monomethyl-L-arginine. After 10(-6) mol/L BQ-123 treatment, ET-1 decreased RPP and increased NO release in control kidneys. DOCA-salt rats responded to these agents with much less NO release. BQ-3020 at up to 10(-10) mol/L caused vasodilation (RPP, 10(-11) mol/L, -5.4 +/- 1.7%, P < .01) associated with increased NO release in control kidneys (+9.0 +/- 2.7 fmol.min-1.g-1 kidney wt, P < .01). However, in DOCA-salt kidneys, BQ-3020 caused renal vasoconstriction (RPP, +5.4 +/- 2.4%, P < .01 versus control) and a much smaller NO release (+1.1 +/- 0.4 fmol.min-1.g-1 kidney wt, P < .01 versus control). Northern blot analysis revealed that renal ETB mRNA was significantly decreased in DOCA-salt rat kidneys compared with controls (0.36 +/- 0.13 versus 1.00 +/- 0.23, P < .05). CONCLUSIONS: These results suggest that ET-1 and ET-3 release EDNO via ETB receptors in renal vessels. ETB-mediated NO release was reduced in DOCA-salt rats, which may modulate renal function and thus blood pressure regulation in DOCA-salt hypertensive rats. PMID- 7850964 TI - Reentrant arrhythmias in the subacute infarction period. The proarrhythmic effect of flecainide acetate on functional reentrant circuits. AB - BACKGROUND: The Cardiac Arrhythmia Suppression Trial has shown that flecainide was associated with an increased incidence of sudden cardiac death in postinfarction patients. The exact mechanism(s) of the proarrhythmic effects of flecainide remain unclear. We performed a detailed analysis of the electrophysiological and proarrhythmic effects of flecainide in a well characterized model of reentrant arrhythmias in the subacute phase of myocardial infarction. METHODS AND RESULTS: Sixteen dogs were studied 4 days after ligation of the left anterior descending coronary artery. Isochronal mapping of ventricular activation showed that flecainide facilitated both the induction and sustenance of ventricular tachycardia, especially at shorter basic cycle lengths. Flecainide had negligible effect on the length of the arc of functional conduction block but markedly depressed conduction of the common reentrant wave front that was usually oriented parallel to fiber axis. Whole heart mapping was analyzed in combination with basic measurements of the effects of flecainide on conduction and refractory properties of both normal and ischemic myocardia using a high-resolution cross electrode consisting of four orthogonal arms, each comprised of 16 poles with an interelectrode spacing of 500 microns. The electrode was especially designed to study the effects of the drug on anisotropic conduction as determined by a linear regression of activation time and distance in each direction. Flecainide resulted preferentially in more marked rate dependent depression of conduction in ischemic compared with normal myocardium. On the other hand, the effect of flecainide on refractoriness in both normal and ischemic myocardia was negligible. CONCLUSIONS: Because flecainide caused no significant change in refractoriness in both normal and ischemic myocardia, there was no difference in the dimension of the potential reentrant pathway, that is, the continuous line of functional conduction block, around which the reentrant wave fronts circulate. Yet, flecainide resulted in significant rate-dependent slowing of conduction preferentially in ischemic myocardium. The additional slowing of conduction of the common reentrant wave front coupled with minimal changes in the length of the reentrant pathway allowed additional time for the wave front to reexcite normal myocardium on the proximal side of the arc of block. After flecainide, reentry could be induced in hearts in which reentry could not be induced during control. The same proarrhythmic mechanism explains the propensity of nonsustained figure-8 reentrant tachycardias to become sustained after flecainide. PMID- 7850965 TI - Comparison of upper limit of vulnerability and defibrillation probability of success curves using a nonthoracotomy lead system. AB - BACKGROUND: An upper limit to the strength of shocks that induce fibrillation during the vulnerable period, the upper limit of vulnerability (ULV), has been shown to exist in both humans and animals. The purpose of this study was to compare ULV and defibrillation (DF) probability of success curves for a clinically useful nonthoracotomy lead system. METHODS AND RESULTS: Sixteen pentobarbital-anesthetized pigs were studied. Single-capacitor biphasic waveforms with both phases 5.5 ms in duration were used for ULV and DF testing. A right ventricular catheter electrode served as first-phase cathode and a superior vena cava catheter electrode coupled with a cutaneous R2 patch electrode served as common first-phase anodes. A pacing catheter was placed in the right ventricle to deliver a train of 15 S1 stimuli at a pacing interval of 250 to 300 ms. A ULV shock was delivered on the peak of the T wave as measured from the surface ECG; if ventricular fibrillation was induced, a DF shock was delivered after 10 seconds of fibrillation. Shock voltages were determined by an up-down protocol. Ventricular fibrillation was induced an average of 53 times in each animal. The composite data indicate that below V97, that is, the voltage that leaves the animal in normal sinus rhythm 97% of the time when delivered on the peak of the T wave or the voltage that defibrillates 97% of the time, ULV is lower than DF. ULV and DF became significantly correlated at V80 and maximally correlated at V97. Even at V97, however, ULV and DF differed by more than 100 V in 2 of the 16 animals. CONCLUSIONS: ULV approximately equaled DF at V97. This is fortunate because it is clinically important to set the device voltage at the uppermost portion of the probability of success curve. Estimating DF V97 from ULV V97 would reduce the number of fibrillation inductions needed to establish defibrillation shock strength requirements. However, the large difference between ULV V97 and DF in a few animals indicates that further improvement and testing of algorithms for determining ULV V97 must be developed before the technique is used clinically. PMID- 7850966 TI - History of the Council on Epidemiology and Prevention, American Heart Association. The pursuit of epidemiology within the American Heart Association: prehistory and early organization. PMID- 7850967 TI - Images in cardiovascular medicine. Coarctation of the aorta and ventricular septal defect. PMID- 7850968 TI - Repairing the mitral valve. PMID- 7850969 TI - Cardiac involvement in mitochondrial diseases, and vice versa. PMID- 7850970 TI - Amyloidosis. PMID- 7850971 TI - Ultrasonic characterization of the aortic architecture in Marfan patients. PMID- 7850972 TI - Improvement of age-related impairment in left ventricular diastolic filling with verapamil in the normal human heart. PMID- 7850973 TI - A 67-year-old man with increasingly frequent angina. PMID- 7850974 TI - N-terminal proatrial natriuretic peptide and brain natriuretic peptide are stable for up to 6 hours in whole blood in vitro. PMID- 7850975 TI - Potential iatrogenic component to coronary artery restenosis. PMID- 7850976 TI - Guidelines for clinical use of cardiac radionuclide imaging. A report of the American Heart Association/American College of Cardiology Task Force on Assessment of Diagnostic and Therapeutic Cardiovascular Procedures, Committee on Radionuclide Imaging, developed in collaboration with the American Society of Nuclear Cardiology. PMID- 7850977 TI - Cardiovascular health at the crossroads: outlook for the 21st century. Presented at the 67th Scientific Sessions of the American Heart Association November 4, 1994 Dallas, Texas. PMID- 7850978 TI - Tissue endothelin-1 immunoreactivity in the active coronary atherosclerotic plaque. A clue to the mechanism of increased vasoreactivity of the culprit lesion in unstable angina. AB - BACKGROUND: The pathomorphological substrate of complicated coronary atherosclerotic lesions underlying unstable angina is characterized by a localized chronic inflammatory process. Functionally, coronary lesions associated with unstable angina demonstrate an enhanced vasoreactivity. Endothelin-1 is a potent vasoconstrictor peptide produced not only by endothelial cells but also by macrophages and polymorphonuclear leukocytes, the cell types characteristic of inflammation. METHODS AND RESULTS: By use of immunohistochemical techniques, we examined the presence of endothelin-1 in coronary atherosclerotic plaque tissue obtained by directional coronary atherectomy of primary lesions from 50 consecutive patients. The tissue specimens of 43 of 50 patients (86%) demonstrated endothelin-1-like immunoreactivity. Endothelin-1-like immunoreactivity preferentially localized to macrophage-rich areas, to hypercellular regions rich in microvessels, and to plaque areas with evidence of prior hemorrhage. Double-immunolabeling revealed that both macrophages (HAM56 positive) and intimal smooth muscle cells (alpha-actin positive) demonstrated cytoplasmic immunostaining for endothelin-1. Semiquantitative analysis of endothelin-1-like immunostaining revealed significantly (P < .005) higher staining grades in active (1.86 +/- 0.15, n = 40) compared with nonactive lesions (0.78 +/- 0.35, n = 10): endothelin-1 staining grades were significantly (P < .001) lower in patients with stable angina (0.69 +/- 0.19, n = 13) than in patients with crescendo angina (1.82 +/- 0.30, n = 11), with angina at rest (2.08 +/- 0.21, n = 12), or with angina after myocardial infarction (2.0 +/- 0.26, n = 14). CONCLUSIONS: Endothelin-1 immunostaining of atherosclerotic tissue localizes predominantly with plaque components indicative of chronic inflammatory processes. The increased tissue endothelin-1-like immunoreactivity in active coronary atherosclerotic lesions may provide a clue to the mechanisms of increased vasoreactivity of the culprit lesion in acute ischemic syndromes, which is the clinical substrate of the active coronary atherosclerotic plaque. PMID- 7850979 TI - Rapid angiographic progression of coronary artery disease in patients with elevated lipoprotein(a) AB - BACKGROUND: The mechanisms underlying rapid angiographic progression of coronary artery disease are still unknown. Intravascular thrombosis with or without plaque rupture may be involved. METHODS AND RESULTS: In a prospective study in 79 patients with coronary artery disease and at least one coronary diameter stenosis > or = 50%, possible risk factors for rapid progression were investigated. Quantitative coronary angiography was performed twice at a mean time interval of 66 +/- 25 days. Rapid progression of coronary disease defined as (1) an increase > 10% in stenosis severity in at least one stenosis > or = 50%, (2) occurrence of a new stenosis > or = 50%, or (3) occlusion of a formerly patent vessel was found in 21 patients (27%). Between patients with rapid progression and those without, there were no significant differences in sex distribution, age, smoking history, frequency of hypertension or diabetes mellitus, and serum LDL cholesterol, HDL cholesterol, and apolipoprotein B concentrations. In contrast, serum lipoprotein(a) [Lp(a)] concentrations > or = 25 mg/dL were found in 14 of 21 patients (67%) with rapid progression of coronary artery disease but in only 19 of 58 (33%) in the group without progression (P = .007). The respective median Lp(a) concentrations were 66 mg/dL (range, 2 to 139) and 13 mg/dL (range, 2 to 211; P = .01). CONCLUSIONS: Lp(a) appears to be a risk factor for the rapid angiographic progression of coronary artery disease. The pathophysiological link between Lp(a) and rapid progression may be an interference with thrombolysis through the partial structural homology of Lp(a) with plasminogen. PMID- 7850980 TI - Molecular variant of angiotensinogen gene is associated with coronary atherosclerosis. AB - BACKGROUND: A positive association was previously reported between angiotensin converting enzyme (ACE) gene polymorphism and several cardiovascular diseases, such as myocardial infarction, left ventricular hypertrophy, and restenosis after percutaneous transluminal coronary angioplasty. Plasma ACE activity and carotid wall thickening measured by ultrasonography were related, and it was postulated that long-term exposure to high levels of plasma ACE could be involved in structural changes of the arterial wall. In addition, angiotensinogen gene mutation was recently reported to be associated with essential hypertension and preeclampsia. There exists a possibility that the renin-angiotensin system plays an important role in the progress of cardiovascular diseases in humans. Therefore, we examined the association between the molecular variant of the angiotensin gene and coronary atherosclerosis. METHODS AND RESULTS: This study included 82 patients who had coronary atherosclerosis and 160 control subjects; all study participants were Japanese. All patients with coronary atherosclerosis had at least one coronary artery with > 25% luminal diameter obstruction on average according to multiple coronary angiographic views. Angiotensinogen gene molecular variants were designated AA, Aa, and aa. The a allele indicated thymine cytosine transition at nucleotide 704 in exon 2. Genomic DNA was extracted from peripheral blood leukocytes. Polymerase chain reaction was performed to amplify the concerned region of the angiotensinogen gene. After restriction enzyme digestion, it was possible to distinguish the molecular variant of the angiotensinogen gene. The frequencies of these genotypes were 7.3%, 26.8%, and 65.9% in the patients and 18.8%, 31.9%, and 49.3% in the control subjects for the AA, Aa, and aa alleles, respectively. There was an excess in the a allele among patients (P < .01). CONCLUSIONS: We found a significant association between coronary atherosclerosis and a molecular variant of the angiotensin gene. The results suggested that the molecular variant of the angiotensinogen gene could be a new risk factor for coronary atherosclerosis. PMID- 7850981 TI - Cardiac involvement in mitochondrial diseases. A study on 17 patients with documented mitochondrial DNA defects. AB - BACKGROUND: Mutations of mitochondrial DNA have been demonstrated as causes of human mitochondrial diseases. While these disorders typically involve multiple organs, the effect of mitochondrial mutations on the heart has not been systematically studied. METHODS AND RESULTS: We studied mitochondrial mutations and cardiac changes in 17 patients with Kearns-Sayre syndrome; ocular myopathy; myoclonus epilepsy with ragged red fibers (MERRF); and mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS). Cardiac involvement was evaluated by chest radiograph, ECG, His-bundle electrogram, and echocardiogram. All 3 patients with Kearns-Sayre syndrome had large deletions of mitochondrial DNA and disturbances in cardiac conduction. ECG abnormalities were found in 2 of 6 patients with ocular myopathy who showed large deletions of mitochondrial DNA. All 3 patients with MERRF had an A-to-G mutation at nucleotide position 8344; 2 had cardiomegaly, asymmetrical septal hypertrophy, and diffuse hypokinesis of the left ventricle. One patient with asymmetrical septal hypertrophy developed dilated cardiomyopathy 2 years later. All 5 patients with MELAS had an A-to-G mutation at nucleotide position 3243, and 2 had symmetrical left ventricular hypertrophy with or without abnormal wall motion. CONCLUSIONS: The clinical features of cardiac involvement in mitochondrial diseases vary in the different subgroups of these disorders. Particular mitochondrial mutations can cause characteristic cardiac abnormalities. PMID- 7850982 TI - A novel variant of transthyretin, 59Thr-->Lys, associated with autosomal dominant cardiac amyloidosis in an Italian family. AB - BACKGROUND: Amyloidosis is a disorder of protein metabolism characterized by extracellular accumulation of abnormal protein fibrils. Different proteins form the fibrils in different forms of the disease, and the condition can be acquired or hereditary. Involvement of the heart is quite common, producing a serious and usually fatal cardiomyopathy. Cardiac amyloidosis is often diagnosed late, and cardiac biopsy together with proper histological examination is essential. Contrary to previous perceptions, there is much recent evidence of effective treatment for several different types of systemic and cardiac amyloidosis, including the most common hereditary form caused by mutations in the transthyretin gene. Chemical and genetic typing of amyloid is therefore of considerable clinical importance. METHODS AND RESULTS: Seven members in two generations of an Italian family presented with cardiac disease inherited as an autosomal dominant and were found to have systemic amyloidosis. Angina pectoris like pain, an unusual feature in cardiac amyloidosis, was a prominent symptom, possibly related to partial obliteration of the distal coronary arteries by amyloid infiltration. There were also cases of sudden cardiac death. Peripheral and autonomic neuropathy, which are the usual features of hereditary amyloidosis, were present in only two cases, and a diagnosis of acquired, immunoglobulin light chain (AL type) amyloidosis was suspected in the index case before the family history emerged. In fact, the amyloid fibrils were composed of transthyretin, and the two affected individuals from whom DNA was available were both heterozygotes for a single base change in exon 3 of the transthyretin gene, encoding substitution of Lys for the wild-type Thr residue at position 59 in the mature protein. This mutation has not previously been reported. CONCLUSIONS: We have identified a novel mutation in the transthyretin gene encoding 59Thr-->Lys associated with autosomal dominant hereditary systemic amyloidosis in an Italian kindred in whom cardiac involvement was the major feature. This family illustrates the difficulty in diagnosis of cardiac amyloid, the variable clinical phenotype in hereditary amyloidosis even within a family, and the importance of precise fibril typing for correct management in this condition. PMID- 7850983 TI - Local lesion-related factors and restenosis after coronary angioplasty. Evidence from a quantitative angiographic study in patients with unstable angina undergoing double-vessel angioplasty. AB - BACKGROUND: Restenosis rates are high when coronary angioplasty is performed in patients with unstable angina. The relative contributions of local and systemic factors to this excess risk of restenosis are unclear. To assess these, we compared changes in minimal lumen diameter and the incidence of restenosis, determined by quantitative coronary angiography, after coronary angioplasty at culprit and nonculprit lesions dilated in the course of a single procedure in patients with unstable angina. METHODS AND RESULTS: We identified 67 consecutive patients with unstable angina in whom two lesions, in different vessels, were dilated during the same procedure. Lesions were designated as culprit or nonculprit on the basis of the location of ECG changes during chest pain combined with assessment of the angiographic characteristics of the lesions. With these criteria, 43 patients had identifiable culprit lesions. Stenosis severity before and immediately after angioplasty and at follow-up was assessed with quantitative angiography. Angiographic follow-up was performed in 91% (39 patients) of this subgroup. Culprit lesions were more severe (P < .02) than nonculprit lesions. The late loss at culprit lesions (0.87 +/- 0.75 mm) was significantly (P < .01) greater than the equivalent value for nonculprit lesions (0.33 +/- 0.69 mm). With a categorical definition (> 50% stenosis at follow-up), restenosis occurred at 67% of culprit lesions and at 32% of nonculprit lesions (P < .01). CONCLUSIONS: The greater loss in minimal lumen diameter and the consequent higher rate of restenosis at culprit compared with nonculprit lesions suggest that local "lesion related" factors are an important determinant of the high rate of restenosis when coronary angioplasty is performed in patients with unstable angina. PMID- 7850984 TI - Intermittent transdermal nitroglycerin therapy. Decreased anginal threshold during the nitrate-free interval. AB - BACKGROUND: Intermittent transdermal nitroglycerin therapy is effective in the treatment of stable angina and prevents the development of tolerance. Previous investigations have suggested that removal of nitroglycerin patches may be associated with a decrease in anginal threshold. This study examines the effect of nitroglycerin patch removal on anginal threshold in a group of patients with stable angina. METHODS AND RESULTS: Twelve patients with stable angina were enrolled in a randomized, double-blind, placebo-controlled, crossover study. These patients had reproducible treadmill walking times and were taking no other long-acting antianginal medications or vasodilators. They received 0.8 mg/h transdermal nitroglycerin or wore a matching placebo patch for 5 to 7 days and then crossed over to the other treatment arm of the study. Transdermal nitroglycerin was applied at 8:00 PM and removed at 8:00 AM each day. On the last day of each treatment period, patients underwent treadmill exercise testing at 8:00 AM (before patch removal) and at 2, 4, and 6 hours after patch removal. The primary end point was the treadmill walking time until moderate angina (P2). Other end points included the treadmill walking time until onset of angina (P1), the amount of ST segment depression at P1 and P2, and treadmill walking time until the development of 1 mm ST depression. Heart rate, systolic blood pressure, and the rate-pressure product were determined at rest before exercise and at P1 and P2. At 8:00 AM P1 and P2 were not significantly affected by active nitroglycerin compared with placebo, indicating the development of tolerance. Removal of the active transdermal nitroglycerin patch was associated with a significant decrease in the time to P1 at 2, 4, and 6 hours after patch removal compared with placebo. There was also a decrease in the time to P2 after active patch removal that was statistically significant compared with placebo at 2 and 4 hours and was of borderline significance at 6 hours. There were no differences in heart rate, blood pressure, or amount of ST segment depression at either P1 or P2 after active compared with placebo patch removal. CONCLUSIONS: In patients with stable angina pectoris, intermittent transdermal nitroglycerin therapy is associated with a decrease in anginal threshold for 4 to 6 hours after patch removal. Although the cause of this phenomenon remains uncertain, it may be due to counterregulatory responses that develop during nitroglycerin patch application. PMID- 7850985 TI - Influence of diabetes mellitus on early and late outcome after percutaneous transluminal coronary angioplasty. AB - BACKGROUND: Although patients with diabetes mellitus constitute an important segment of the population undergoing coronary angioplasty, the outcome of these patients has not been well characterized. METHODS AND RESULTS: Data for 1133 diabetic and 9300 nondiabetic patients undergoing elective angioplasty from 1980 to 1990 were analyzed. Diabetics were older and had more cardiovascular comorbidity. Insulin-requiring (IR) diabetics had diabetes for a longer duration and worse renal and ventricular functions compared with non-IR subjects. Angiographic and clinical successes after angioplasty were high and similar in diabetics and nondiabetics. In-hospital major complications were infrequent (3%), with a trend toward higher death or myocardial infarction in IR diabetics. Five year survival (89% versus 93%) and freedom from infarction (81% versus 89%) were lower, and bypass surgery and additional angioplasty were required more often in diabetics. In diabetics, only 36% survived free of infarction or additional revascularization compared with 53% of nondiabetics, with a marked attrition in the first year after angioplasty, when restenosis is most common. Multivariate correlates of decreased 5-year survival were older age, reduced ejection fraction, history of heart failure, multivessel disease, and diabetes. IR diabetics had worse long-term survival and infarction-free survival than non-IR diabetics. CONCLUSIONS: Coronary angioplasty in diabetics is associated with high success and low complication rates. Although long-term survival is acceptable, diabetics have a higher rate of infarction and a greater need for additional revascularization procedures, probably because of early restenosis and late progression of coronary disease. The most appropriate treatment for these patients remains to be determined. PMID- 7850986 TI - Relation between thallium uptake and contractile response to dobutamine. Implications regarding myocardial viability in patients with chronic coronary artery disease and left ventricular dysfunction. AB - BACKGROUND: Both thallium scintigraphy and dobutamine echocardiography have been used to assess myocardial viability. However, thallium uptake and the inotropic response to dobutamine are expressions of different cellular phenomena. The present study was undertaken to investigate the relation between the two methods in patients with chronic coronary artery disease and left ventricular dysfunction to derive insights into the mechanisms related to myocyte viability. METHODS AND RESULTS: Thirty patients (28 men and 2 women; age, 59 +/- 10 years) with chronic coronary artery disease and impaired left ventricular systolic function at rest (mean ejection fraction, 32 +/- 9%) were included in the study. Patients underwent transesophageal echocardiography during incremental doses of dobutamine from 2.5 to a maximum of 40 micrograms.kg-1.min-1 and single photon emission computed tomographic thallium scintigraphy using a stress-redistribution reinjection protocol. The left ventricle was divided into 16 segments for analysis of echocardiographic and thallium images. Segmental myocardial contractile function was graded as normal, hypokinesis, akinesis, or dyskinesis at each incremental dose of dobutamine. Thallium uptake in each myocardial segment was graded on a 5-point scale from 0 (absent) to 2 (normal) for each of the stress, redistribution, and reinjection images. A segment was considered viable if the assigned thallium score was 1 or higher (normal uptake or only mild to moderate defect) in any of the stress, redistribution, or reinjection images. Among 472 myocardial segments available for analysis, 311 had resting wall motion abnormalities, of which 56% (173/311) showed contractile improvement with dobutamine (usually first observed at < or = 10 micrograms.kg-1.min-1) and 84% (262/311) were considered viable by thallium scintigraphy (P < .0001). Of the 262 segments considered viable by thallium, 167 (64%) had a contractile improvement with dobutamine; in contrast, only 6 of the 49 segments (12%) considered nonviable by thallium had a positive dobutamine response (P < .0001). Furthermore, a positive inotropic response to dobutamine was significantly related to the magnitude of thallium uptake: the proportion of segments with a positive dobutamine response rose with increasing magnitude of thallium uptake (P < .001). The disagreement between the two tests was related primarily to segments considered viable by thallium that did not show contractile improvement with dobutamine. CONCLUSIONS: These findings demonstrate the existence of a relation between thallium uptake and the inotropic response to dobutamine in patients with chronic coronary artery disease and left ventricular dysfunction. However, the proportion of segments showing a positive response to dobutamine is significantly lower than those with thallium uptake, suggesting that the cellular mechanisms responsible for a positive inotropic response to adrenergic stimulation require a higher degree of myocyte functional integrity than those responsible for thallium uptake. PMID- 7850987 TI - The detection of 3-methylglutarylcarnitine and a new dicarboxylic conjugate, 3 methylglutaconylcarnitine, in 3-methylglutaconic aciduria. AB - Two patients, diagnosed with 3-methylglutaconic aciduria, who presented with diverse clinical and metabolic manifestations, were studied. Glycine conjugation as a possible detoxification mechanism in these two patients yielded negative results. Carnitine conjugates were however detected. 3-Methylglutarylcarnitine was observed in the urine of both patients, while one of the patients excreted detectable quantities of 3-methylglutaconylcarnitine, a previously unknown metabolite. The presence of this metabolite in urine samples from one patient and the apparent correlation between administered carnitine and the conjugate excretion profile seems to indicate that carnitine may play an important role in future therapeutic programmes. PMID- 7850988 TI - Incidence of the apolipoprotein B-3500 mutation in Denmark. AB - A total of 5000 consecutively samples newborn screening cards were anonymously selected for screening for the apolipoprotein B-3500 (apo B-3500) mutation, which causes familial defective apolipoprotein B-100 (FDB). The mutation was found in 5 of 5000 Danish children, of whom 2 were twins. This indicates a lower prevalence of this mutation in Danes than that reported in the UK, Germany, USA, Austria, Canada and especially Switzerland. Haplotype studies suggest that Caucasian subjects with the apo B-3500 mutation have a common founder. The apparently lower prevalence in Denmark than in Switzerland and Central Europe may indicate that the mutation was brought from these areas to Denmark after the initial settling of Denmark. In 101 unrelated Danish subjects with familial hypercholesterolemia, diagnosed on clinical and biochemical criteria including tendon xanthomata, 2 were heterozygous for the apo B-3500 mutation (2%). PMID- 7850989 TI - Effect of a 6-month storage on human serum fructosamine concentration. PMID- 7850990 TI - Determinants of serum 1,25-dihydroxyvitamin D concentration in healthy premenopausal subjects. AB - Concentrations of serum phosphate and parathyroid hormone (PTH) are well known regulators of the production of 1,25-dihydroxyvitamin D (1,25-(OH)2D) and acidosis is known to affect the serum concentration of 1,25-(OH)2D. However, the factors that play a role in the regulation of serum 1,25-(OH)2D concentration in healthy subjects have not been fully evaluated. The associations of ionised calcium, pH, serum concentration of phosphate, PTH, 25-hydroxyvitamin D (25-OHD) and serum 1,25-(OH)2D were examined in 296 healthy premenopausal women (age range 17-40 years). Calculation of partial correlation coefficients showed that serum 1,25-(OH)2D was significantly correlated with phosphate (r = -0.148, P < 0.01), pH (r = 0.221, P < 0.001) and PTH (r = 0.136. P < 0.01). Ionised calcium was not related to serum 1,25-(OH)2D. When the results were stratified according to quartiles based on serum 1,25-(OH)2D concentration, significant trends (by analysis of variance) were seen in phosphate, pH, age, albumin and 25-OHD. Stepwise multiple regression analysis showed that phosphate and pH were the major contributors of serum 1,25-(OH)2D levels. There was a small contribution from PTH and 25-OHD. The results suggest that in young healthy premenopausal women plasma phosphate and pH may be important determinants of serum 1,25-(OH)2D concentration. PMID- 7850991 TI - Vitamin, trace element and peroxide status in HIV seropositive patients: asymptomatic patients present a severe beta-carotene deficiency. AB - We have investigated whether nutritional status and peroxidation process are associated with the degree of development of HIV infection. This was done by measuring the status of vitamins (E, A and beta-carotene), of antioxidant trace elements (zinc, selenium) and lipid peroxide levels (lipid hydroperoxides and thiobarbituric acid reactants) in HIV-seropositive patients at CDC II and CDC IV stages and in comparison with normal subjects. There was a decrease in vitamin and trace element levels related to the severity of disease. The most dramatic decrease, however, was seen for carotenoids (0.94 +/- 0.46 mumol/l) and beta carotene (0.24 +/- 0.14 mumol/l vs. 0.56 +/- 0.29 mumol/l) whose stage II levels were only half the normal value. Paradoxically, lipid peroxidation was higher at stage II than at stage IV. This can be attributed to an overproduction of oxygen radicals by polymorphonuclears in stage II. This deficiency in antioxidant status, often found in patients suffering from peroxidative diseases, may have important consequences on cellular immunity. Furthermore, the concomitant overproduction of free radicals may also affect HIV multiplication. PMID- 7850992 TI - A screening method for abnormally high lipoprotein(a) concentrations by agarose lipoprotein electrophoresis. AB - A routine electrophoretic method detecting plasma lipoprotein(a) (Lp(a)) is described. Plasma lipoproteins were electrophoresed using an agarose gel film containing cations which retard migration of beta-, prebeta- and alpha-bands. When present, the Lp(a)-band was detected between prebeta- and alpha-bands. This extra-band lipoprotein has been demonstrated to be Lp(a), by an immunofixation technique using anti-Lp(a) antibodies. This original procedure allows a distinct separation of Lp(a) from prebeta even after samples have been stored at 4 degrees C for several days, or in cases of hyperlipemic samples with increased prebeta lipoproteins. The reliability of this detection test has been tested in comparison with an Lp(a) electroimmunoassay. Both these techniques have been performed on 719 randomly selected subjects. With electrophoresis, the Lp(a) positive subjects accounted for 34.2% of the subjects and although this method does not distinguish between different levels of positivity (depending on the sample), the presence of Lp(a)-band was always perceptible at concentrations that belong to the upper 15th percentile of values as determined by electroimmunodiffusion; inversely, all Lp(a)-positive plasma was measurable. In consequence, since it is reliable and relatively inexpensive, this detection test on modified agarose gel appears very useful for revealing the presence of abnormally high values of Lp(a) in populations. PMID- 7850993 TI - Copper, zinc-superoxide dismutase and hydrogen peroxide: a hydroxyl radical generating system. AB - Because superoxide (O2-.) is a mediator of inflammation, Cu,Zn-superoxide dismutase (Cu,Zn-SOD) has been employed as an anti-inflammatory compound. However, Cu,Zn-SOD can increase intra- and extracellular H2O2. This may react with the Cu atom of SOD in a Fenton-type reaction producing the hydroxyl radical (.OH). With a non-physiological concentration of H2O2 (0.8 mmol/l) to stimulate chemiluminescence (CL) at a level < 2 mV, it was observed that the addition of Cu,Zn-SOD (100 micrograms/ml) yielded an increase of 204.7 +/- 78.2 mV (P < 0.05). This increase in CL depended on the concentrations of H2O2 and Cu,Zn-SOD and was only seen with luminol (reacts with O2-. and .OH) but not with lucigenin (reacts with O2-.). No CL was observed when Cu,Zn-SOD was heat inactivated, or when Mn-SOD was used. Dissipators of H2O2, copper chelators and .OH scavengers attenuated this CL. In electron paramagnetic resonance, with the use of the spin trap dimethylpyrroline-N-oxide (DMPO), it was demonstrated that, in the reaction between H2O2 and Cu,Zn-SOD, .OH was generated. The oxidation of keto methylthiobutyric acid (KMB) to ethylene, assessed by gas chromatography, demonstrated that H2O2/Cu,Zn-SOD-generated .OH can react with KMB and not only with the SOD molecule itself. We conclude that H2O2 reduces SOD-bound Cu2+ to Cu1+ which, in reaction with H2O2 catalyses its reduction to OH. Whether this 'pro-inflammatory' reaction occurs in vivo remains to be established. PMID- 7850994 TI - The use of HPLC to evaluate the variations of blood coronary adenosine levels during percutaneous transluminal angioplasty. AB - Although it is well established that adenosine is released during acute ischemia, little is known of the behaviour of adenosine levels following treatment of coronary lesion by percutaneous transluminal coronary angioplasty (PTCA). Using high performance liquid chromatography, we measured intracoronary adenosine levels before and 5 min after PTCA in ten patients with one-vessel disease and a significant (> 70%) coronary stenosis. Adenosine levels decrease in all patients after PTCA. Nevertheless, more studies are now necessary to evaluate the possible predictive value (with regard to restenosis) of coronary adenosine levels after PTCA. PMID- 7850995 TI - Abnormal glycine betaine content of the blood and urine of diabetic and renal patients. AB - In normal human plasma the concentrations of the renal osmolyte, glycine betaine, are usually between 20 and 70 mumol/l, in adult males (median 44 mumol/l) higher than in females (34 mumol/l). Concentrations are lower in renal disease (median 28 mumol/l) and normal in diabetes. Urinary excretion of glycine betaine shows no sex difference and is frequently elevated both in renal disease and in diabetes (medians: normal, 6.2, renal 12.3 and diabetes, 39.7 mmol/mol creatinine). The elevation in diabetes does not strongly correlate with known renal disease, nor with either urinary microalbumin or plasma creatinine. There is no correlation with glycated haemoglobin. The positive correlation with the excretions of another renal osmolyte, sorbitol, was highly significant in diabetic subjects. In the diabetic group there was also a significant negative correlation between plasma glycine betaine and urine microalbumin. PMID- 7850996 TI - A competitive dual-label time-resolved immunofluorometric assay for simultaneous detection of carbonic anhydrase I and II in cerebrospinal fluid. AB - Carbonic anhydrase (CA) is functionally an important enzyme in the central nervous system (CNS) where it is involved in the control of acid-base balance and regulation of the production of cerebrospinal fluid (CSF). Isoenzyme II (CAII) is the most widely distributed CA in the CNS being specifically present in CNS glial tissue and therefore it is expected to be leaked to CSF in degenerative CNS diseases. A competitive dual-labeled time-resolved immunofluorometric assay was developed for simultaneous quantification of human CAI (HCA I) and II (HCA II) in CSF. HCA I was measured to determine the blood contamination in the samples. This solid-phase immunoassay is based on competition between europium (Eu3+)- or samarium (Sm3+)-labeled antigen and the sample antigens for polyclonal rabbit antibodies which are attached to microtiter-plate wells precoated with sheep anti rabbit IgG. The subsequent immunoassay, including the separation of free and bound HCA I and II, requires only one incubation step, after which an enhancement solution dissociates Sm3+ and Eu3+ ions from the labeled HCA I and II, respectively, into a solution where they form highly fluorescent chelates. Spectra of the fluorescent chelates in the microtitration strip wells were run on time-resolved fluorometers equipped with filters for Eu3+ (613 nm) and Sm3+ (643 nm), the fluorescence from each sample being inversely proportional to the concentration of antigens. The detection limit of the HCA II assay was 0.3 micrograms/l and that of the HCA I assay was 5.2 micrograms/l. The intra- and inter-assay imprecisions (C.V.s) were 8.0% and 8.8% for HCA I and 6.3% and 4.8% for HCA II, respectively.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7850997 TI - Urinary excretion of homocitric acid and methylhomocitric acid in propionic acidaemia: minor metabolic products of the citrate synthase aldol condensation reaction. AB - The identity of two formerly novel citric acid analogues, homocitric acid and methylhomocitric acid, in urine samples from patients with propionic acidaemia was confirmed by gas chromatography and mass spectrometry. Authentic reference substances were synthesized using a Reformatskii reaction. Homocitric acid and methylhomocitric acid were detected as minor metabolites in the urine samples from propionyl coenzyme A carboxylase deficient individuals. It was shown that these substances can be formed by the citrate synthase condensation reaction of alpha-ketoglutarate with acetyl coenzyme A and propionyl coenzyme A, respectively. PMID- 7850998 TI - Hepatobiliary complications in adults receiving nutrition support. AB - Hepatobiliary dysfunction in patients receiving nutrition support is frequent. Other reasons for elevated enzyme levels including drugs, recent anesthesia and surgery or sepsis often coexist. Liver test abnormalities in adults are usually milder than in children and frequently self-limited and are 10 times more likely to occur with total parenteral nutrition (TPN) than tube enteral nutrition. Patients on short-term TPN usually have mild-to-moderate elevations in transaminase and alkaline phosphatase levels and steatosis or portal triaditis on biopsy. Patients who are infected while on TPN are at greater risk of developing steatosis and intrahepatic cholestasis. Strategies to correct abnormalities include alteration of the caloric mix in the TPN, cyclic infusions, metronidazole, enteral nutrition and inclusion of L-glutamine in the TPN formula. Patients on long-term home parenteral nutrition may develop persistent elevations in liver tests and steatohepatitis. Both acalculus and calculus cholecystitis occur with increased frequency in patients on long-term TPN. Biliary sludge precedes calcium bilirubinate stones: predisclosing factors include nil per os, prior ileal resection and use of narcotics or anticholinergics. PMID- 7850999 TI - Intestinal manometry in man: a historical and clinical perspective. AB - The historical background and current status of manometry of the small intestine are reviewed. The evolution of technology for the assessment of small intestinal motor activity in man is described and advances in physiology and pathophysiology highlighted. Technological advances over the past several decades have permitted the extensive study of intestinal motility in man and have led to both a greater understanding of intestinal motor physiology and an increased awareness of the breadth of intrinsic variability. Though motor patterns have been described in various disease states, the definition of the clinical utility of intestinal manometry must await further prospective studies, which should, in particular, compare manometry with other available and less invasive tests. PMID- 7851000 TI - NSAID-induced peptic ulcer disease: a critical review of pathogenesis and management. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) initiate gastroduodenal ulceration and promote complications such as bleeding and perforation. Age greater than 60 years, a prior history of ulcer disease, and concomitant corticosteroid use are important risk factors for ulcer development. NSAIDs interfere with mucosal defense via direct toxic effects in addition to cyclooxygenase inhibition and subsequent depletion of endogenous prostaglandins. While all NSAIDs are ulcerogenic, drugs which avoid topical injury and do not inhibit mucosal prostaglandins appear to have lesser risk of toxicity. Although NSAID injury requires luminal acid, prophylactic use of H2 receptor antagonists has been disappointing, preventing duodenal injury only. Greater acid suppression with proton pump inhibition appears promising. Prostaglandins are effective for prevention of NSAID-induced gastroduodenal injury, but are not well tolerated. Recent evidence suggests NSAID ulcers heal rapidly with proton pump inhibitors compared to H2 receptor antagonists in those patients who require continued NSAID therapy. PMID- 7851001 TI - Osteoporosis in chronic liver disease: pathogenesis, risk factors, and management. AB - This article reviews osteoporosis (OP) in adults with chronic liver disease. OP in this setting is characterized in general by low bone turnover. The pathogenesis is unclear but is probably not related to vitamin D abnormalities. Patients at high risk of OP include those with evidence of cirrhosis, hypogonadism, overt calcium malabsorption, steroid therapy and choleostatic liver disease (particularly primary biliary cirrhosis). OP is best managed by adequate calcium intake, regular weight bearing exercise, and the avoidance of alcohol and tobacco smoking. There is probably no reason for vitamin D supplementation. Hormonal replacement therapy when necessary is indicated in males and should be considered in females. Finally, liver transplantation has the potential to improve or stabilize OP in the median term, although it is associated with significant short-term deterioration. PMID- 7851002 TI - Leukocyte-endothelial cell interactions: implications for the pathogenesis and treatment of gastrointestinal disease. AB - Evidence implicating leukocytes as mediators of tissue injury in different disease processes is accumulating rapidly. The sequestration and activation of neutrophils have been shown to be key components in the pathophysiology of chronic inflammatory bowel diseases, and in gastrointestinal lesions following hemorrhagic shock, ischemia-reperfusion, and ingestion of nonsteroidal anti inflammatory drugs, or ethanol. Leukocyte-endothelial cell interactions also appear to be a target for the action of various drugs proven to be useful in the treatment of gastrointestinal inflammatory disorders. This review focuses on the alterations in leukocyte-endothelial cell interactions in the aforementioned conditions. PMID- 7851003 TI - Gallstones and acute pancreatitis--mechanisms and mechanics. AB - The observation that necrotizing pancreatitis and gallstones can be associated is more than 300 years old [1]. Since the beginning of our century, numerous investigations have addressed the question as to how gallstones cause pancreatitis. Despite this effort and many excellent clinical and experimental studies, few pathophysiological issues in gastroenterology have remained so controversial and even fewer have found advocates with such incompatible views and uncompromising convictions. We will review the past and present theories regarding the pathophysiology of gallstone-induced pancreatitis and outline the therapeutic consequences implied by these concepts. PMID- 7851004 TI - Is vitamin E depleted in Crohn's disease at initial diagnosis? AB - We measured serum and red blood cell concentrations of vitamin E and serum lipid concentrations in 13 inpatients at the initial diagnosis of Crohn's disease and compared them with those of 12 healthy controls. Although the serum concentrations of vitamin E were significantly lower in the patients with Crohn's disease than in the controls, the red blood cell concentrations of this vitamin did not differ between the two groups. The serum concentrations of total lipids and total cholesterol were decreased in the patients with Crohn's disease. A significant correlation was found between the red blood cell concentration of vitamin E and the serum vitamin E/serum total lipids ratio in both the groups. There was no correlation between the Crohn's disease activity index and serum or red blood cell levels of vitamin E. These findings suggest that the lowered serum vitamin E levels in patients with Crohn's disease are a symptom of hypolipidemia, and that vitamin E deficiency may not actually become a serious problem in patients diagnosed with Crohn's disease. PMID- 7851005 TI - Effects of anti-CD3 monoclonal antibodies on functional activity of lymphocytes: studies in vivo and in vitro. AB - Lymphocyte functional activity was tested in 38 renal transplant recipients receiving induction treatment with various anti-CD3 MoAbs, i.e. OKT3, T3.G2a (an IgG2a anti-CD3 MoAb) or T3.A (an IgA anti-CD3 MoAb of the same idiotype). During treatment with OKT3 and T3.G2a, lymphocyte response to phytohaemagglutinin-P (PHA), as determined with the use of a whole-blood lymphocyte culture technique, decreased significantly. However, during treatment with T3.A PHA response was not affected. Using a conventional lymphocyte culture technique, PHA response was unchanged during treatment with all three MoAbs, indicating that the immunosuppressive effect of OKT3 and T3.G2a is probably dependent upon the presence of MoAb in culture medium and is reversible. In addition, we tested in vitro inhibition of aspecific mitogen- or antigen-induced lymphocyte stimulation by OKT3, T3.A and T3.G2a. It appeared that at low concentrations (< 25 ng/ml) T3.G2a and OKT3 exerted a stronger immunosuppressive effect than T3.A. However, at higher concentrations T3.A, OKT3 and T3.G2a were equally immunosuppressive. We conclude that the immunosuppressive effect of T3.A is caused by blindfolding. At low concentrations T3.G2a exerts its immunosuppressive effect mainly through modulation of the CD3 and/or T cell receptor complex, as a result of interaction with Fc receptors on monocytes. At higher concentrations blindfolding of the CD3/T cell receptor complex may contribute to immunosuppression. PMID- 7851006 TI - The immunosuppressive drug thalidomide induces T helper cell type 2 (Th2) and concomitantly inhibits Th1 cytokine production in mitogen- and antigen-stimulated human peripheral blood mononuclear cell cultures. AB - Thalidomide is an effective immunomodulatory drug in man, but its mechanism of action remains unclear. We hypothesized that, in addition to its reported inhibitory effects on production of monocyte-derived tumour necrosis factor-alpha (TNF-alpha), thalidomide might be effective at the level of Th immunoregulation. In a comparative study with the immunosuppressant cyclosporin A, we have demonstrated a potent and specific effect of thalidomide on cytokine production relating to the distinct Th1 and Th2 subsets. It induced and enhanced the production of IL-4 and IL-5 and, at the same dose (1000 ng/ml), significantly inhibited interferon-gamma (IFN-gamma) production in phytohaemagglutinin (PHA) stimulated human peripheral blood mononuclear cell (PBMC) cultures. Stimulation of PBMC with recall antigen (streptokinase:streptodornase (SKSD)) at 144 h in the absence of thalidomide resulted in a predominantly Th1 response, with the production of IFN-gamma and IL-2. Thalidomide switched this response from a Th1 to a Th2 type. The effect was most pronounced at 1000 ng/ml thalidomide, where inhibition of IFN-gamma and enhancement of IL-4 production was maximal. In unstimulated cultures thalidomide alone induced IL-4 production. Cyclosporin A, in contrast, inhibited both Th1 and Th2 cytokine production by PHA-stimulated PBMC. Time course data from thalidomide-treated cultures revealed that the augmented IL-4 production diminished as the culture time increased, whereas IFN gamma production was significantly increased. This response might be due to activation-induced apoptosis of Th2 cells or the induction of Th2 cell anergy, in the continued presence of stimulating agents, with the emergence of IFN-gamma secreting Th1 cells when Th2 antagonism declines. The effects of thalidomide and related compounds may enhance our understanding of the mechanisms of T helper cell selection, offer the possibility of controlled therapeutic switching between Th1 and Th2 responses, and may lead to a rational approach for the treatment of some T cell-mediated immunological disorders. PMID- 7851007 TI - Antibody and clinical responses in volunteers to immunization with malaria peptide-diptheria toxoid conjugates. AB - Twenty residue peptides from the 185-200-kD and 45-kD merozoite surface antigens of the malaria parasite Plasmodium falciparum were covalently linked to diphtheria toxoid as a carrier and used to immunize human volunteers with aluminium hydroxide as an adjuvant. Significant antibody levels were elicited by two boosting injections. The antibodies reacted with acetone-methanol fixed merozoite membranes in an immunofluorescence assay, but no inhibition of merozoite reinvasion could be detected in in vitro cultures containing the antibodies. Antibody levels against the immunizing peptides declined markedly within 77 days after the third injection. No hypersensitivity was observed against the peptides. However, the volunteers developed hypersensitivity against diphteria toxoid, and in particular a pronounced type III (Arthus) hypersensitivity after three injections with the toxoid. This effect might appear to limit the use of peptide-diphtheria toxoid conjugates for human immunization. Several biochemical, haematological and immunological tests done on the volunteers showed no other adverse effects from the immunizations. PMID- 7851008 TI - The affinity of IgG antibodies to gag p24 and p17 in HIV-1-infected patients correlates with disease progression. AB - The affinity of anti-gag antibody was studied for up to 9 years (1984-1993) in sera from 15 HIV-1+ patients with haemophilia. On the basis of their 1993 clinical status patients were divided into two groups: (i) patients who remained asymptomatic (n = 9); and (ii) those who progressed to AIDS between late 1987 and 1993. The affinity constants of antibody for p24 and p17 were determined by a double isotope fluid-phase radioimmunoassay; and the relationships between antibody affinity and titre, patient clinical course, CD4 cell counts and p24 antigenaemia were analysed. The affinity of p24- and p17-specific antibody was up to 100 times greater in asymptomatic patients than in patients who progressed to AIDS. Patients who developed AIDS either lost or failed to develop high-affinity antibodies early in the infection. Asymptomatic patients maintained high-affinity antibodies for several years; however, in some of these patients the affinity of anti-p24 and p17 antibodies subsequently fell later in the study period. The presence of low-affinity antibody and progressive reduction in the titre of specific antibody were earlier predictors of disease onset than CD4 cell counts. The failure to either develop or maintain high affinity gag-specific antibody suggests an early impairment of T helper function in individuals who progressed to AIDS. The presence of antibody of high affinity could be essential in controlling virus replication and the onset of AIDS. PMID- 7851009 TI - Comparison of activation marker and TCR V beta gene product expression by CD4+ and CD8+ T cells in peripheral blood and lymph nodes from HIV-infected patients. AB - Since lymphoid organs constitute the site of active and progressive HIV disease, analysis of their lymphocytes may provide more accurate information on T cell abnormalities than that obtained from studying peripheral blood lymphocytes. The objective of this study was to compare the expressions of activation markers and T cell receptor (TCR) V beta gene products by CD4+ and CD8+ T cells in lymph nodes (LN) and peripheral blood (PB) from healthy individuals and asymptomatic HIV-infected patients to determine whether anomalies that could be identified at the HIV replication site could support the hypothesis of T cell activation by HIV encoded antigens or superantigens. CD4+ and CD8+ T cells in paired LN and PB obtained from six healthy controls and five asymptomatic HIV-infected individuals were analysed by flow cytometry, using anti-CD38, anti-HLA-DR and 13 anti-V beta MoAbs that cover, approximately, 45% of the T cell repertoire. Analysis of T cell activation marker expression indicated that the percentages of CD4+ and CD8+ T cells bearing CD38 or CD38 and HLA-DR molecules were higher in patients than in controls and, in patients, higher in LN than in PB. Comparison between the V beta repertoires of CD4+ and CD8+ T cells in LN and PB showed that, in each healthy individual, a limited number of V beta families expressed by CD4+ or CD8+ T cells had different repartition in LN and PB, whereas in each HIV+ patient, more V beta families exhibited different distributions and these differences recurred among certain V beta segments, such as V beta 5.3 and V beta 21 in the CD4+ T cell population and V beta 5.2/5.3, V beta 12 and V beta 21 in the CD8+ T cell population. Taken together, these data argue for a skewed TCR repertoire in HIV infection and sustained activation of T cells by HIV-encoded antigens at the site of HIV replication, and further demonstrate that a high proportion of CD4+ T cells are in an activation state that may, indirectly, participate in their functional abnormalities. PMID- 7851010 TI - Efficacy of HIV-specific and 'antibody-independent' mechanisms for complement activation by HIV-infected cells. AB - Previous studies in this laboratory have shown that efficient activation of complement (C) on HIV isolates and HIV-infected cells requires the binding of specific anti-HIV antibodies, while other investigators have observed 'antibody independent' C activation. In an attempt to clarify these disparate findings, we investigated the effect of several variables on C activation by HIV-infected cells using flow cytometric analysis of C3 deposition. Antibody-mediated C activation using pooled sera from infected persons or human MoAbs directed against the V3 region of gp120 was always substantially higher than activation without antibody. Normal human serum (NHS) from a subset of HIV antibody-negative donors did, however, induce low levels of C3 deposition. Differences in C3 activation between the various NHS did not correlate with total haemolytic C levels or mannose-binding protein (MBP) levels. IgM isolated from NHS that induced high levels of C activation was at least partly responsible for the 'antibody-independent' C activation. Although there appeared to be a correlation between NHS that induced C activation and the presence of anti-blood type B IgM, absorption of anti-B did not abrogate the C3 deposition. Additionally, MoAb to the B antigen did not induce C3 deposition. These studies show that IgM in sera from HIV-uninfected donors can induce C3 deposition on HIV-infected cells, but that specific antibody-dependent C activation is substantially more efficient. Therefore, 'antibody-independent' C activation on HIV-infected cells may, in some cases, be more accurately described as HIV-cross-reactive antibody-dependent C activation. PMID- 7851011 TI - Tumour necrosis factor-alpha (TNF-alpha) synthesis is associated with the skin and peripheral nerve pathology of leprosy reversal reactions. AB - Leprosy may be complicated by episodes of increased cell-mediated immunity towards Mycobacterium leprae (reversal reactions) which result in severe local immunopathology in skin lesions and peripheral nerves. Using in situ hybridization and MoAb techniques we have demonstrated TNF-alpha mRNA and TNF alpha protein in macrophages infiltrating leprosy skin and peripheral nerve. Levels of TNF-alpha mRNA are significantly increased in reactional skin and nerve, particularly in borderline tuberculoid patients. TNF-alpha mRNA and TNF alpha protein levels are higher in reactional nerves then reactional skin. In both reactional skin and nerve TNF-alpha mRNA is more abundant than TNF-alpha protein; this may reflect the rapid turnover of TNF-alpha protein in an immunologically dynamic situation, such as is seen in reversal reaction. Our findings emphasize the importance of documenting both mRNA and protein production when assessing the role of cytokines in pathology. The leprosy reversal reaction may be regarded as a useful model of tissue immunopathology in which TNF-alpha is generated as part of the host response to infection, but also produces local tissue damage. PMID- 7851012 TI - Theileria annulata induces abberrant T cell activation in vitro and in vivo. AB - The protozoan parasite of cattle, Theileria annulata, causes a severe lymphoproliferative disease, developing initially in the draining lymph node, which is often fatal in naive animals. Infection of macrophages with T. annulata leads to an augmentation of their antigen-presenting capability in vitro and infected cells can induce proliferation of autologous resting T cells from naive animals. This inappropriate activation of T cells may play an important role in the failure of the host to mount an effective immune response in vivo. To investigate this hypothesis we characterized further the response of T cells from naive cattle to infected cells in vitro, and also examined the development of the immune response in lymph nodes draining the sites of T. annulata infection. Both CD4+ and CD8+ T cells from naive peripheral blood mononuclear cells (PBMC) were induced to proliferate and express the activation markers IL-2R and MHC class II when cultured with infected cells. This effect was seen in both 'naive' and 'memory' T cells, and was dependent upon contact with infected cells. In vitro, infected cells are therefore capable of activating T cells irrespective of their antigen specificity or memory status. In draining lymph nodes, although large numbers of IL-2R+ cells developed following infection, these activated cells were only associated with areas of parasite-induced proliferating cells, and subsequently disappeared from the node. Cells expressing IL-2R were not present in recognized sites for T cell development. Germinal centres were severely affected, losing T cell-dependent zones followed by a total destruction of morphology. T cell function is therefore severely disrupted within draining nodes. This study has shown that parasitized cells supply sufficient signals in vitro to activate T cells irrespective of specificity. T cells also are not stimulated in a conventional manner in vivo, and this may play an important role in preventing an effective immune response from being generated. PMID- 7851013 TI - Linkage of IgA deficiency to Gm allotypes; the influence of Gm allotypes on IgA IgG subclass deficiency. AB - IgA deficiency (IgAD) is the most common immunodeficiency, characterized by an arrest in B cell differentiation. It has a sporadic occurrence or variable inheritance pattern, and is also linked to the HLA genes. IgA deficiency is sometimes associated with IgG subclass deficiency. In this study the Gm allotypes, as genetic characteristics of the IgG1, IgG2 and IgG3, were analysed in 83 Caucasian IgAD individuals. Half of the patients presented with IgG4 < 0.01 g/l compared with 5% (P < 0.001) in a healthy population. Three of the 83 had significantly low IgG2 and four had significantly low IgG3 levels. Gm allotype frequencies in IgAD deviated compared with a normal population. Of the 83 patients, 44 (53%) showed homozygous G2 m(",") expression on the IgG2 locus (33% in controls, P < 0.01). In IgAD the Gm(a,",g) haplotype was more frequent (43%) compared with controls (31%, P < 0.01). The Gm homozygous phenotype Gm(a,",g/a,",g) was most common, found in 20 of 83 patients (24%, P < 0.05) compared with controls (14%). On the other hand the Gm(f,n,b) haplotype of IgAD was rare (28%) compared with controls (45%, P < 0.001). The low IgG4, < 0.01 g/l, found in 50% of the patients, was even more frequent (56-69%) among the G2 m(",") phenotypes. IgG subclass levels were given for different Gm phenotypes of the IgAD group and compared with controls. Significantly low IgG4 was revealed in the Gm(a,",g/a,",g) phenotype (P < 0.01) and significantly low IgG2 in the Gm(a,",g/f,",b) phenotype (P < 0.01). The Gm(a,",g/f,",b) phenotype contained the three patients found with IgG2 levels < -2 s.d., and the four patients with IgG3 levels < -2 s.d. were present among those with the homozygous Gm(a,",g/a,",g) phenotype; both phenotypes with G2 m(",") on the IgG2 locus. The 'compensatory' increase of IgG was significant for both IgG1 and IgG3 in all Gm phenotypes, but in the Gm(a,",g/f,",b). Thus, the susceptibility of IgAD with the additional IgG antibody deficiencies, down-regulated IgG4 and IgG2/IgG3, is associated with Gm allotypes, especially the homozygous G2 m(",") expression on the IgG2 locus. PMID- 7851014 TI - A prospective study of CD45 isoform expression in haemophagocytic lymphohistiocytosis; an abnormal inherited immunophenotype in one family. AB - In a prospective study, CD45 isoform expression on T lymphocytes was analysed in seven patients with haemophagocytic lymphohistiocytosis (HLH) and their family members. Six patients, their parents and seven healthy age-matched controls showed the normal pattern of three subpopulations of CD45R expression. In one patient, his mother and one of his healthy brothers only two subpopulations could be identified, which might indicate that the maturation from a CD45RA/RO double positive to a CD45RO single-positive phenotype does not occur in these individuals. It is not clear if this finding had any impact on the development of HLH in this patient and if the pattern of CD45RA and RO expression observed in this family might represent a predisposition to HLH. In another patient a marked increase of the CD45RO single-positive T cell population was observed during a period of increased disease activity. The clinical relevance of this observation and whether CD45RO expression could serve as a marker for disease activity, or in selected individuals as a susceptibility marker for HLH, remain unknown. PMID- 7851015 TI - Secretion of immunoglobulins and plasma proteins from the colonic mucosa: an in vivo study in man. AB - There are no available data on immunoglobulins and albumin outputs into the normal human colon. We thus measured the intracolonic secretion rates of IgA, IgG, IgM, secretory component (SC) and plasma proteins (albumin (Alb), orosomucoid (Oro), transferrin (Transf) and alpha 2-macroglobulin (alpha 2-M)). Using a pancolonic perfusion technique in 10 healthy volunteers (six females, four males, mean age 24 years), concentrations and outputs of Alb, immunoglobulins, SC, Oro, Transf and alpha 2-M were measured in the rectal effluents by immunoradiometric assay. Monomeric (m) and polymeric (p) IgA distribution was analysed by sucrose density ultracentrifugation. The secretion of polymeric IgA (p-IgA) was 153 micrograms/min, i.e. 220 mg/day, exceeding that of other immunoglobulins (m-IgA 8.5 micrograms/min; IgG 33.5 micrograms/min; IgM 17 micrograms/min) and of non-immunoglobulin proteins (Alb 104 micrograms/min; Oro 9 micrograms/min; Transf 7 micrograms/min; alpha 2-M 4.5 micrograms/min). p IgA was entirely linked to SC (secretory IgA) and 12% of SC was in free form. About 62% of total IgA was IgA2. For each protein, a relative coefficient of excretion (RCE) was calculated (colon to serum concentration ratio expressed relative to that of Alb). The p-IgA, IgM and m-IgA RCE were 277, 6 and 2.2 times higher than the values predicted from their molecular weight. RCE of non immunoglobulin proteins also exceeded the values expected from a passive seepage from the vascular compartment. The intracolonic clearance of Alb extrapolated to 24 h was only 3.7 ml/day. These results show the high local production and/or the facilitated transport to the colonic lumen of p-IgA, and are in very good agreement with the distribution of plasma cells in the colonic mucosa. PMID- 7851016 TI - Non-lymphoid and lymphoid cells in acute, chronic and relapsing experimental colitis. AB - In rodents, intracolonic administration of ethanol 30% induces an acute colitis, while administration of 2,4,6-trinitrobenzene sulphonic acid (TNBS) in ethanol induces a longer lasting colitis. In the acute and chronic stages of experimental colitis, lymphoid and non-lymphoid cells were studied in the colon by immunohistochemistry. During the acute inflammation a high damage score of the colon was observed, which was related to an increase in the number of macrophages and granulocytes. Also a change in distributional patterns of macrophage subpopulations was found. The chronic stage of TNBS-ethanol-induced colitis was characterized by an increase in the number of lymphocytes, especially T cells. These data suggest that macrophages and granulocytes are important in the acute phase of experimental colitis, while lymphocytes play a pivotal role in the chronic stage. As most inflammatory bowel disease (IBD) patients have relapses during the chronic disease, we attempted to induce a relapse during experimental colitis by giving a second i.p. or s.c. dose of TNBS. This resulted in increased damage scores of the colon, new areas of ulceration and a further increase in macrophage numbers. No effect on the number of granulocytes was seen. These results indicate that it is possible to mimic relapses in experimental colitis by a second administration of TNBS, and suggest that the rats had been sensitized by the first dose of TNBS, given into the colon. PMID- 7851017 TI - CD4+ T cell subsets defined by isoforms of CD45 in primary biliary cirrhosis. AB - Primary biliary cirrhosis (PBC) is an autoimmune condition characterized by destruction of the intrahepatic bile ducts. Autoreactive CD4+ T cells have been reported both in the peripheral circulation and in the mononuclear cell infiltrate in the affected portal tracts. In this large study we have used two- and three-colour flow cytometry to determine the phenotypes of the CD4+ T cell subsets in the peripheral blood and liver-infiltrating lymphocytes of PBC patients (n = 43), normal controls (n = 19) and patients with alcoholic cirrhosis (n = 15), according to a novel classification based on the simultaneous expression of different isoforms of CD45. In PBC patients the proportion of peripheral blood CD4+ cells possessing the CD45ROhighRA- 'memory' phenotype was significantly increased, and the CD45RO-RAhigh 'naive' population was significantly decreased, compared with the two control groups. No significant differences in peripheral blood CD4+ T cell subsets were seen between patients with pre-cirrhotic and cirrhotic PBC. A similar, but more marked, shift towards the CD45ROhighRA- 'memory' phenotype was seen in the liver-infiltrating CD4+ T cells in PBC patients compared with alcoholic cirrhotics. Cells within the CD4+ memory subpopulation were further subgrouped according to expression of CD45RB, the level of expression of which has been associated with functional differences in the memory subset. In peripheral blood no differences were seen between PBC patients and controls with respect to the proportion of CD45ROhighRBhigh and CD45ROhighRBdim memory subsets. A statistically significant difference in the distribution of these memory subsets, with an increased memory-2/memory-1 ratio was observed in the liver-infiltrating CD4+ T cells of PBC patients compared with those from alcoholic cirrhotic patients. The potential implications of this observation are discussed. PMID- 7851018 TI - Expression of MHC antigens by intestinal epithelial cells. Effect of transforming growth factor-beta 2 (TGF-beta 2). AB - The effect of interferon-gamma (IFN-gamma) and TGF-beta 2 on expression of MHC antigens by the human intestinal epithelial cell line HT-29 was examined by immunohistochemistry and flow cytometry. Untreated HT-29 cells constitutively expressed HLA-ABC but little HLA-DR. Expression of both molecules was increased by IFN-gamma (100 U/ml, 24 h). TGF-beta 2 at concentrations > or = 0.5 ng/ml given before or simultaneously with IFN-gamma, inhibited the IFN-induced expression of HLA-DR. Small increases in HLA-ABC expression by IFN-gamma were further increased by pretreatment with TGF-beta 2, while a strong induction of HLA-ABC was inhibited by the TGF-beta 2 pretreatment. Our results suggest that the inhibitory action of the TGF-beta 2 on both HLA-ABC and HLA-DR correlates with the degree of induction following IFN-gamma treatment. Since TGF-beta 2 is present in milk and is produced by gut epithelial cells, one of its possible functions may be to regulate expression of HLA antigens in the neonatal intestine and/or diseased intestine. PMID- 7851019 TI - Low serum levels of dehydroepiandrosterone may cause deficient IL-2 production by lymphocytes in patients with systemic lupus erythematosus (SLE). AB - The principal cause of IL-2 deficiency, a common feature of both murine lupus and human SLE, remains obscure. Recent studies of our own as well as others have shown that dehydroepiandrosterone (DHEA), an intermediate compound in testosterone synthesis, significantly up-regulates IL-2 production of T cells, and that administration of exogenous DHEA or IL-2 via a vaccinia construct to murine lupus dramatically reverses their clinical autoimmune diseases. Thus, we have examined serum levels of DHEA in patients with SLE to test whether abnormal DHEA activity is associated with IL-2 deficiency of the patients. We found that nearly all of the patients examined have very low levels of serum DHEA. The decreased DHEA levels were not simply a reflection of a long term corticosteroid treatment which may cause adrenal atrophy, since serum samples drawn at the onset of disease, which are devoid of corticosteroid treatment, also contained low levels of DHEA. In addition, exogenous DHEA restored impaired IL-2 production of T cells from patients with SLE in vitro. These results indicate that defects of IL-2 synthesis of patients with SLE are at least in part due to the low DHEA activity in the serum. PMID- 7851020 TI - Expression of the B cell repertoire in lpr mice; abnormal expansion of a few VHJ558 germ-line genes. AB - Analysis of the VH gene repertoire of the J558 family was done in lipopolysaccharide (LPS)-stimulated resting cells and in vivo activated cells derived from C57Bl/6-lpr mice (IghCb). Using a restriction fragment length polymorphism (RFLP) based on digestion with the restriction enzyme Pstl, the expression of the subfamilies of the J558 family of VH genes could be determined. The J558 subfamily repertoire of resting B cells of the lpr mice was similar to that of the normal mice, while the J558 repertoire of the in vivo-activated cells was altered: analysis and sequencing of the IgM-expressed J558 repertoire of a sick female mouse showed that 50% of the J558 genes were represented by a single VH gene rearrangement, showing that its expansion was monoclonal. Furthermore, this same rearrangement made up to 90% of the J558 repertoire in the IgG2a+ population, showing that it had been preferentially selected, expanded and switched. However, compared with its IgM counterpart, it showed no evidence of somatic hypermutation. PMID- 7851021 TI - The effect of free and liposome-encapsulated clodronate on the hepatic mononuclear phagocyte system in the rat. AB - Clodronate, encapsulated within small unilamellar vesicles (SUVc) will deplete hepatic macrophages after intravenous injection. Functional studies, using probes to evaluate hepatic Fc and C3b uptake, showed a close correlation between the inhibition of receptor-mediated uptake and the depletion of hepatic macrophages. Twenty milligrams of clodronate encapsulated within SUVc produced > or = 90% inhibition of uptake and clearance of Fc- and C3b-coated erythrocytes and a comparable reduction of hepatic macrophage numbers. Inhibition of macrophage receptor-mediated uptake of these erythrocytes was closely related to the reduction in macrophage numbers. Repopulation of macrophages within the liver took place over 2 weeks. At 1 week after depletion, although repopulation was taking place, receptor-mediated function remained suppressed. In a preliminary experiment, treatment of rats with adjuvant arthritis with 20 mg clodronate encapsulated in SUV suppressed the inflammation and reversed the course of the disease, while treatment with 20 mg free clodronate in saline or 20 mg clodronate in multilamellar vesicles (MLVc) did not. PMID- 7851022 TI - Characterization of CD4+ T helper cells in patients with Kawasaki disease (KD): preferential production of tumour necrosis factor-alpha (TNF-alpha) by V beta 2- or V beta 8- CD4+ T helper cells. AB - KD is an acute febrile illness in children characterized by coronary arteritis accompanied by aneurysm and thrombotic occlusion. The etiology of KD is unknown. It has been recently reported that KD is associated with the selective expansion of V beta 2+ and V beta 8.1+ T cells in peripheral blood lymphocytes (PBL), by studying the T cell receptor (TCR) repertoire of in vitro activated T cells. KD may therefore be caused by a superantigen [1-3]. To understand better the immunopathology of KD, we investigated TCR V beta 2 and V beta 8.1 expression on both the T cells of freshly isolated PBL and T cell clones (TCC) from patients with KD. Cytokine production by TCC was also studied. Blood samples were obtained from patients with acute (n = 20) and convalescent (n = 20) KD, age-matched children with non-infectious diseases (n = 18), and healthy adults (n = 20). Among these four groups, there were no significant differences in the percentages of either V beta 2+ or V beta 8.1+ T cells of freshly isolated PBL. The same was true for the CD4+ or CD8+ T cell subsets. One hundred and five TCC (98 CD3+ CD4+ CD8- and seven CD3+ CD4- CD8+) established from the affected skin, lymph node or PBL of six patients with KD were also negative for either V beta 2 or V beta 8.1 TCR. Sixty-eight of 105 TCC (65%) produced detectable levels (> 5 pg/ml) of TNF alpha (6-1016 pg/ml), in the absence of any stimuli. In contrast, only 11 (10%) of 105 TCC or 7 (7%) of 97 TCC produced detectable levels of IL-2 or IL-6, respectively, in the absence of any stimuli. Stimulation with phytohaemagglutinin (PHA) and phorbol myristate acetate (PMA) induced most TCC to produce higher amounts of TNF-alpha, IL-2 and IL-6. These results suggest that CD4+ T helper cells expressing TCR-beta other than V beta 2 or V beta 8 receptor, primarily through TNF-alpha production, are involved in the immunopathology of KD. PMID- 7851023 TI - Passive dual immunization against tumour necrosis factor-alpha (TNF-alpha) and IL 1 beta maximally ameliorates acute aminonucleoside nephrosis. AB - Rats receiving a single dose (10 mg/100 g) of aminonucleoside of puromycin (PAN) develop heavy proteinuria and acute interstitial nephritis (AIN). Whole isolated glomeruli from rats injected with PAN secreted both TNF-alpha and IL-1 beta cytokines. TNF-alpha secretion was first and maximally detected on day 3, whereas IL-beta activity was found on day 7, when rats were heavily proteinuric and AIN developed. In vivo treatment with either anti-TNF-alpha or anti-IL-1 beta antibodies produced a drastic and simultaneous reduction in both levels of proteinuria and intensity of interstitial cell infiltrate. These effects improved when both antibodies were administered together. Our studies demonstrate the effectiveness of immunosuppressive therapy against these two cytokines in rats with PAN-induced nephrosis. PMID- 7851024 TI - Relationship between facilitated allergen presentation and the presence of allergen-specific IgE in serum of atopic patients. AB - Allergen presentation to allergen-specific T cells can be facilitated when IgE allergen complexes are endocytosed by antigen-presenting cells (APC) after binding to the low-affinity Fc epsilon R type II (CD23). Here we present a study on the relative capabilities of sera of atopic patients to mediate facilitated antigen presentation (FAP). To this aim FAP was studied in an in vitro model in which CD23-expressing Epstein-Barr virus (EBV)-B cells act as APC to T lymphocyte clones (TLC) that are specific for Der p 2, a major allergen of housedust mite Dermatophagoides pteronyssinus (Dp). Der p 2 is immune-complexed by preincubation in sera from atopic patients, containing allergen-specific IgE. If EBV-B cells are preincubated with these complexes before using the cells as APC, the allergen specific TLC proliferate at 100-1000-fold lower allergen concentration than required for T cell activation after presentation of uncomplexed allergen. The relative capability of various sera to mediate FAP was correlated with total serum IgE, and especially with Der p 2-specific serum IgE. In the model used, a high FAP capacity could be demonstrated only in sera with a total serum IgE concentration above approximately 2 micrograms/ml or with Der p 2-specific IgE above approximately 100 ng/ml. Maximal FAP, i.e. the ability to induce maximal proliferation of the TLC, was obtained in the presence of more than +/- 600 ng Der p 2-specific IgE/ml. At 100-600 ng/ml Der p 2-specific IgE the level of FAP was correlated with the concentration of allergen-specific IgE, whereas at lower concentrations FAP was low or absent. All tested sera from eczema patients, all having serum anti-Der p 2-IgE concentrations > 600 ng/ml, showed a high FAP capacity, whereas all tested sera from atopic patients without eczema, which had serum anti-Der p 2-IgE levels < 600 ng/ml, showed no or a low FAP capacity. The association of high FAP capacity with eczema may reflect a functional role of FAP in the pathogenesis of atopic dermatitis. PMID- 7851027 TI - IgG-associated primary glomerulonephritis in children. AB - Ten children with IgG-associated primary diffuse mesangial proliferative glomerulonephritis are presented. All cases showed diffuse global IgG deposits in the mesangium. IgG was the sole immunoglobulin deposited in the mesangium in 8 patients and was the predominant immunoglobulin in 2. C3 was also present in 8 patients. Light microscopy revealed variable diffuse and global mesangial proliferation in all cases, with additional focal segmental glomerular sclerosis in one. On electron microscopy, electron-dense deposits in the mesangium were identified in all patients. Clinically, 4 patients presented with the steroid resistant nephrotic syndrome, and 6 had proteinuria and hematuria. At the latest follow-up, renal function was normal in all patients, 6 showed clinical remission and 4 had slight proteinuria and/or hematuria. These data suggest that there is a clinicopathologic entity, IgG-associated glomerulonephritis, characterized by diffuse mesangial proliferation, predominant mesangial IgG deposition, variable clinical presentation, and a relatively benign course. PMID- 7851028 TI - The P1 blood group and the severity of diarrhea-associated hemolytic uremic syndrome. AB - Thirty-one children with diarrhea-associated hemolytic uremic syndrome were retrospectively studied to determine if expression of the P1 blood type was related to the severity of the acute illness or to the prognosis. No differences were found in the clinical variables studied in the patients who were P1 positive compared to the patients who were P1 negative. The clinical variables studied included the age, hemoglobin, white blood cell count (WBC), and presence of central nervous system involvement at presentation, the duration of elevated WBC, thrombocytopenia, hemorrhagic colitis, and anuria, and the follow-up incidence of proteinuria, hypertension and decreased GFR. Expression of the P1 phenotype does not appear to exert a protective influence in patients with D+ HUS. PMID- 7851026 TI - Cytokine production by normal human monocytes: inter-subject variation and relationship to an IL-1 receptor antagonist (IL-1Ra) gene polymorphism. AB - Monocytes from different individuals show variable cytokine production in response to a variety of stimuli. We wished to determine the sets of conditions (cytokine combinations) that would enable us to demonstrate stable inter individual differences in the production of IL-1 alpha, IL-1 beta, IL-1Ra, on-6 and tumour necrosis factor-alpha (TNF-alpha) by monocytes. We assessed the ability of a number of recombinant human cytokines (granulocyte-macrophage colony stimulating factor (GM-CSF), interferon-gamma (IFN-gamma), TNF-alpha, IL-4, IL-6, transforming growth factor-beta (TGF-beta), IL-10 and IL-1Ra)) to stimulate or inhibit the production of one or more of these monocyte products. GM-CSF was found to stimulate the production of all five of these cytokines in a highly reproducible manner. TNF-alpha also up-regulated production of IL-1 alpha, IL-1 beta, IL-1Ra and IL-6 by monocytes, but the variability in the results of cells cultured from the same individuals on different occasions was greater. Other cytokines either stimulated production of only some of the five cytokine products tested, or stimulated the production of some cytokine products while inhibiting production of others. This was especially evident when cytokines were used in combination with GM-CSF: IFN-gamma down-regulated production of IL-1Ra while up regulating the production of IL-1 alpha/beta, IL-6 and TNF-alpha, while IL-4 had the exact opposite effect. Polymorphisms in regions of cytokine genes that affect transcription may account for some of the interindividual variation in cytokine production. We have shown that a stable estimate of cytokine production phenotype can be obtained when monocytes collected on at least two separate occasions are stimulated by GM-CSF in vitro. We have looked for a relationship between IL-1 production and an 86-bp variable repeat polymorphism in intron 2 of the IL-1Ra gene. A less common allele of this polymorphism (allele 2) was associated with increased production of IL-1Ra protein, and also reduced production of IL-1 alpha protein by monocytes. PMID- 7851025 TI - Unaltered thyroid function in mice responding to a highly immunogenic thyrotropin receptor: implications for the establishment of a mouse model for Graves' disease. AB - Grave's disease (GD) is a common disorder characterized by the presence of autoantibodies to the thyrotropin receptor. In the past, the exceedingly low expression of the thyrotropin receptor on thyrocytes has not allowed its purification in quantities sufficient to investigate the establishment of an animal model for this disease. In this study, we have purified the 398-amino acid, extracellular region of the human thyrotropin receptor (TSH-R.E) from insect cells using recombinant baculovirus, and explored its immunopathogenic properties in H-2b,d,q,k,s strains of mice. The receptor preparation was highly immunogenic since it elicited strong specific proliferative T cell responses as well as IgG responses in all strains tested. In addition, hyperimmunization with TSH-R.E induced (i) serum antibodies that blocked the binding of 125I-TSH to its receptor, a common feature of GD autoantibodies; and (ii) IgG that reacted with a synthetic peptide (residues 32-54) from the N-terminus of the receptor, a region implicated in the binding of thyroid stimulating antibodies. In SJL animals only, a weak antibody response to two other thyroid antigens, thyroglobulin and thyroid peroxidase, was also observed. The presence of these antibodies, however, was not accompanied by a detectable alteration in thyroid function as assessed by the measurement of serum TSH, T4 and iodine levels. Also mononuclear infiltration of the thyroid gland or morphological changes compatible with an activation state of thyrocytes were not apparent in TSH-R-challenged mice. In contrast, mice treated with the anti-oxidant aminotriazole showed a dramatic increase in serum TSH levels and an activated follicular epithelium. These data demonstrate that a highly immunogenic TSH-R.E in mice does not necessarily provide a proper stimulus for the induction of a hyper- or hypothyroid status as defined by hormonal or histological criteria. Main reasons for the inability to induce receptor-specific antibodies that affect thyroid function such as those generated in GD are likely to be the inappropriate folding of the recombinant extracellular domain of the receptor, or the xenogeneic nature of the autoantigen. PMID- 7851029 TI - A proposed method for the noninvasive evaluation of renal asymmetry in a living related donor candidate. AB - This report proposes an adjunctive technique for the evaluation of asymmetry of renal size and function of undetermined etiology, discovered during the assessment of two living-related donor candidates. The method utilizes the observation of renal functional reserve measurement as demonstrated by oral protein loading in patients with normal and diseased kidneys. Renal function was measured as timed Ccr and estimation of differential GFR by technetium-99m diethylenetriaminepentaacetic acid (99mTcDTPA) scintigraphy. A comparison of renal function before and after protein loading in two such patients demonstrated the anticipated increase in GFR. No change in differential GFR as determined by renal scan in one patient was interpreted as supportive evidence for bilaterally normal parenchymal function. Follow-up of both donors shows continued normal renal function. PMID- 7851030 TI - Three cases of malignant hypertension: the roles of endothelin-1 and the renin angiotensin-aldosterone system. AB - We experienced three cases of malignant hypertension. Plasma endothelin-1 (ET-1) was extremely high in all patients on admission (12.1 +/- 1.0 pg/ml, normal 1.5 +/- 0.5 pg/ml), and changed in parallel with the serum creatinine level. In one patient, during the recovery period, serum creatinine increased 1 mg/dl over a one-week period just after the increase of plasma ET-1 (14.2 pg/ml), while plasma renin activity (PRA) and plasma aldosterone concentration (PAC) were stable. In contrast, the decline of renal dysfunction was larger in patients with high PRA and PAC. These data suggest that increased plasma ET-1 and an enhanced renin aldosterone-angiotensin system act together in a vicious cycle to deteriorate renal function in patients with malignant hypertension. PMID- 7851031 TI - The impaired control of plasma renin activity in hypertensive patients with end stage renal disease due to chronic glomerulonephritis. AB - In twelve hypertensive patients with end-stage renal disease (ESRD) due to chronic glomerulonephritis (CGN), the mechanisms of renin and aldosterone regulation were studied by exogenously infused angiotensin II, captopril, and upright posture. The results were compared to those obtained in ten patients with unilateral renovascular hypertension (RVH), eleven patients with essential hypertension (EH), and in eleven normal subjects (NS). Exogenously infused angiotensin II (5.0 ng/kg/min) failed to decrease the plasma renin activity (PRA) in the ESRD group but significantly decreased the PRA in the RVH, EH, and NS groups. The plasma aldosterone concentration (PAC) in the ESRD group and in the other control groups significantly increased after the addition of exogenous angiotensin II. An oral dose of 50 mg of captopril failed to increase the PRA in the ESRD group. However, it significantly raised the PRA in the RVH, EH, and NS groups. The plasma aldosterone concentration was significantly reduced by captopril in the ESRD group, and similar results were obtained in the other three groups. The ratio between the PRA before and after being in an upright posture for 4 hours in the ESRD group was lower than that in the three other groups. Meanwhile, there was no difference in the PAC ratio between the ESRD group and the control groups. Thus, we conclude that, in hypertensive patients with ESRD due to CGN, PRA regulation is different from that in the other three groups, although there were no differences in the regulation of the PAC among the four groups, suggesting that renin production in the ESRD group is somewhat autonomous. PMID- 7851032 TI - The influence of ACE-inhibition on myocardial mass and diastolic function in chronic hemodialysis patients with adequate control of blood pressure. AB - The objectives of this study were to evaluate the specific effect of the ACE inhibitor lisinopril on myocardial mass and diastolic function in uremic patients using a protocol designed to leave blood pressure unchanged. Nineteen hemodialysis patients (7 males; mean age: 55 +/- 13 years; mean time on dialysis: 44 +/- 35 months) received lisinopril for 6 months in addition to their preexistent antihypertensive treatment regimens (mean: 1.4 +/- 0.8 drugs). Doses of antihypertensive drugs were adjusted to keep both systolic and diastolic blood pressure stable. Nine patients were withdrawn from lisinopril treatment after 43 +/- 33 days because of hypotension (n = 4), withdrawn consent (n = 3), stroke (n = 1) and cough (n = 1). Seven of them were further studied as controls. Ten patients received 6.4 +/- 4 mg lisinopril as a mean for 6 months. Mean myocardial mass, calculated by M-mode echocardiography, was 324 +/- 103 g before, and 313 +/ 79 g after 6 months of lisinopril treatment. In the control patients, myocardial mass was 318 +/- 110 g initially, and after 6 months, it was 334 +/- 159 g. Early and late transmitral diastolic flow velocities were not significantly influenced by lisinopril. Throughout the study, both the systolic and diastolic 24-h mean blood pressure levels remained stable (systolic: before: 145 +/- 19 mmHg, at 6 months: 147 +/- 17 mmHg; diastolic: before: 87 +/- 12 mmHg, at 6 months 87 +/- 10 mmHg). Thus, no specific effect of lisinopril on regression of myocardial hypertrophy or improvement of diastolic function could be observed within a 6 month period in this small group of hemodialysis patients.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7851033 TI - Clinical profile and outcome of primary hyperparathyroidism accompanied by chronic renal failure. AB - We encountered 5 cases of primary hyperparathyroidism (PHPT) accompanied by chronic renal failure over the past 4 years. Neither hypocalcemia nor hyperphosphatemia was found in the past records. The parathyroid hormone (PTH) levels in these cases were extraordinarily higher than those in usual patients suffering from renal failure. The manifestation of PHPT-developed insidiously together with the decline of renal function. Serum 1,25(OH)2D3 levels were lower than normal range in all cases, and which in turn might accelerate the progression of PHPT in a similar way as the development of secondary hyperparathyroidism. Parathyroidectomy (PTX) was done successfully in 4 cases, and the pathology of the biggest gland was adenoma but hyperplasia was found in other glands simultaneously. These results revealed the polymorphism of parathyroid glands in case of complication with renal failure. Furthermore, the interruption of postoperative 1 alpha(OH)D3 treatment induced the relapse of hyperparathyroidism (HPT). The case which refused PTX was treated by oral pulse therapy with 1,25(OH)2D3. The calcium/intact PTH sigmoidal curve examined 3 years later revealed that the set point shifted to right and upward despite therapy. It suggested that functional parathyroid mass became larger and the sensitivity to calcium became less under continuous stimuli on parathyroid glands. According to these results, PHPT accompanying with renal failure is resistant to medical therapy, and surgical treatment is a possibility. In this occasion, total PTX with autograft transplantation is better than simple adenectomy because even the glands not responsible to clinical manifestation of PHPT can have some pathological abnormalities.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7851034 TI - Variable blood pump flow rates and the effect on recirculation. AB - There has been a movement in the dialysis community towards higher blood pump flow rates (QB) during dialysis. However, the effects of increased QB on recirculation and consequently the impact on clearances have not been well quantified for clinically relevant QBS. We studied the effect of QB on recirculation in 16 patients in a prospective fashion. Blood pump speeds of 200, 250, 300, 350, 400, 450, and 500 cc/min were studied in a randomized order. For QBS of 350 cc/min and greater, 14-gauge needles were used; at lower QBS, 16-gauge needles were used. The needles were positioned at least 5 cm apart. Recirculation studies were done after stabilization of QB during the first 15 minutes of dialysis with a dialysate temperature of 37 degrees C and minimal transmembrane pressure. Recirculation was calculated using the three-needle technique. All patients had an angiogram performed upon completion of the study. Effective clearances were calculated to demonstrate the effect of QB on Recirculation rates increased with increased QB (r = 0.43). Recirculation was 12.1% +/- 1.2 (Mean +/- SEM) at a QB of 200 cc/min versus 23.8% +/- 3.0 at a QB of 500 cc/min (p < 0.05). Venous pressures increased with increasing QBS, 120.0 mmHg +/- 7.3 at a QB of 200 cc/min to 204.2 mmHg +/- 9.1 at a QB of 500 cc/min. Bleeding from needle puncture sites only occurred with use of the 14-gauge needles (p = 0.02). Effective dialyzer urea and B12 clearances for six different dialyzers increased at a considerably lower rate beyond a QB of 300 cc/min.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7851035 TI - Glomerular lesions in juvenile cystinosis: report of 2 cases. AB - We report glomerular lesions in 2 siblings presenting a juvenile cystinosis. Kidney biopsy in one of them showed focal, segmental, mesangial proliferative and hyalinosis lesions, and the second showed segmental juxtahilar hyalinosis in one third of glomeruli. Neither of the 2 patients displayed a Toni-Debre-Fanconi syndrome. In one of the patients, cystine crystals were found by means of electronic microscopy. The first patient developed chronic renal failure and a kidney transplantation was performed. No recurrence of the cystine deposits was observed in the graft. Pedigree of the described family seems to be in accordance with an autosomal dominant pattern of inheritance. PMID- 7851036 TI - A case of renal sarcoidosis showing central necrosis and abnormal expression of angiotensin converting enzyme in the granuloma. AB - We describe a 66-year-old man who developed renal failure related to granulomatous renal sarcoidosis without systemic manifestations. Renal failure was severe enough to require hemodialysis transiently. Renal biopsy of this patient revealed the central necrosis of the granuloma which is usually absent in sarcoid granuloma. Serum level of angiotensin converting enzyme (ACE) was not helpful for diagnosis in this patient because serum ACE level is often elevated in the condition of chronic renal failure. Immunohistochemical detection of ACE was of diagnostic value in this patient. Subsequent course in which glucocorticoid was used for therapy was consistent with the diagnosis. This is the first report of identification of ACE in renal sarcoid granuloma. PMID- 7851037 TI - Ultrasonographic unilateral hydronephrosis with bladder outlet obstruction. AB - Renal ultrasonography plays an important role in the evaluation of azotemic patients. Knowledge of its limitations is crucial for the proper evaluation of obstructive uropathy. Two cases are presented in which screening ultrasonography detected unilateral hydronephrosis despite lower urinary tract obstruction. Both patients had markedly asymmetrical renal function, with the hydronephrosis found in the better functioning kidney. The importance of searching for asymmetry of renal function in the azotemic patient with atypical ultrasonogram findings is emphasized. Other clinical factors which would heighten suspicion for obstructive uropathy and lead to further investigation despite a minimally abnormal or even normal renal ultrasonogram are also discussed. PMID- 7851038 TI - Superior vena cava syndrome from central venous hemodialysis. PMID- 7851039 TI - Membranous nephropathy and endometriosis. PMID- 7851040 TI - Is folate and vitamin B12 supplementation necessary in chronic hemodialysis patients with EPO treatment? PMID- 7851041 TI - Bence Jones proteinemia. PMID- 7851042 TI - Beneficial effect of low molecular weight heparin ("fragmin") on proteinuria of proliferative glomerulonephritis. PMID- 7851043 TI - Renal transplantation: donor with renal stone disease. PMID- 7851044 TI - Lobar pilocytic astrocytomas of the cerebral hemispheres: I. Diagnosis and nosology. AB - This study provides neuropathological and neuroradiological observations on 11 cases of lobar pilocytic astrocytomas of the cerebral hemispheres, reappraising potential diagnostic caveats. These tumors may show variable degrees of contrast enhancement on computed tomography, as well as gadolinium uptake on magnetic resonance imaging, making them indistinguishable from malignant gliomas. Histopathologically, although typically pilocytic, they may exhibit areas of increased cellular density with protoplasmic and multinucleated glial elements (pilo-protoplasmic astrocytoma). The presence and particularly the abundance of distinct gliodegenerative structures, i.e. eosinophilic granular bodies (EGBs) and to a lesser degree Rosenthal fibers, in conjunction with collateral clinical, histologic and imaging parameters may facilitate oncotypic diagnosis. Mixed pilocytic and fibrillary astrocytomas are recognized, while malignant change may also rarely occur in longstanding lobar pilocytic astrocytomas. PMID- 7851045 TI - Lobar pilocytic astrocytomas of the cerebral hemispheres: II. Pathobiology- morphogenesis of the eosinophilic granular bodies. AB - This study provides new immunocytochemical observations on the so-called eosinophilic granular bodies (EGBs), seen predominantly (but not exclusively) in pilocytic astrocytomas. Using combined immunohistochemical and immunoelectron microscopic approaches on formalin-fixed, paraffin-embedded tissues, we have demonstrated that (1) EGBs exhibit pronounced reactivity with antibodies to serine protease inhibitors alpha-1-antichymotrypsin and alpha-1-antitrypsin; by immunoelectron microscopy, the reaction product is localized either in the form of diffuse floccular densities, or larger conglomerates of amorphous, globular material; (2) an antiserum to ubiquitin-protein conjugates, codistributes in the EGBs at the light microscopic level, while ultrastructurally is either localized in diffuse, finely granular deposits, and/or fragmented filamentous particles; and (3) that a monoclonal antibody to beta-amyloid precursor protein (beta-APP) stains smaller EGBs. The detection of serpin-like and beta-APP-like staining in EGBs may be a reflection of acute phase reactant activity in response to tumor produced proteases. We postulate that EGBs contain complexes of serpins and hitherto unknown protease(s), which are in turn probably degraded via ubiquitin mediated mechanism(s). Although EGBs typify pilocytic astrocytomas, they may be exceptionally present in malignant astrocytomas, calling for cautious interpretation of their biologic as well as prognostic import. PMID- 7851046 TI - Intracranial malignant fibrous histiocytoma: characterization of GFAP-positive cells in the tumor. AB - A case of malignant fibrous histiocytoma (MFH) arising in the cerebellopontine angle of a 57-year-old woman was reported. The immunohistochemical and electron microscopic findings indicated distinct fibrohistiocytic nature and myofibroblastic differentiation of this peculiar tumor. Immunohistochemistry disclosed that the tumor cells expressed monocyte/macrophage markers including CD 68, MAC 387, and alpha-1-antichymotrypsin. In addition, the neoplasm contained scattered glial fibrillary acidic protein (GFAP)-positive cells which made small nests in some areas. These GFAP-positive cells had bundles of densely packed intermediate filaments and scanty organellae in the cytoplasm, as demonstrated by an immunostained-semithin and serial-ultrathin section method. By immunostaining of MIB-1 and GFAP, and silver nucleolar organizer region (AgNOR) impregnation on serial sections, the GFAP-positive cells were not labeled by MIB-1 and their AgNOR counts averaged 1.13/nucleus. Thus, these GFAP-positive cells seem to have lower proliferating activity than neoplastic astrocytes. It is concluded that they may be nonneoplastic astrocytic cells involved by MFH. PMID- 7851047 TI - Quantitative evaluation of nucleolar features on cytologic material in brain tumor diagnosis. AB - Nucleolar-related features were quantified in toluidin blue-stained smears from 36 brain tumors in order to improve our knowledge of the nucleolar frequency, size and margination. It was observed that low-grade astrocytic tumors had high percentages of nucleolated cells but the nucleoli were mostly single with maximum nucleolar diameter smaller than 2.00 microns. The percentages of marginated nucleoli were also low, ranging between 3.00% and 30.00% (only one case had a higher percentage). The high-grade tumors, i.e. anaplastic astrocytomas and glioblastomas, did not significantly differ from low-grade astrocytomas in their percentages of nucleolated nuclei, but they showed a higher number of nuclei having three or more nucleoli and the mean nucleolar diameter was in general bigger than 2.00 microns. Glioblastomas had marginated nucleoli much more frequently than anaplastic astrocytomas, the percentage in all but one case being higher than 30.00%. The percentage of marginated nucleoli was much higher in glioblastomas than in metastases, while the nucleoli were bigger in the latter group. A wide range of values for most of the nucleolar-associated parameters was observed in the remaining non-astrocytic brain tumors. Our results, showing differences in nuclear number, size and margination in different brain tumors, lead us to consider it worthwhile to investigate nucleolar-related features and their relationships using a quantitative approach. PMID- 7851048 TI - A case of dissection of intracranial cerebral arteries with segmental mediolytic "arteritis". AB - The intravital diagnosis of intracranial arterial dissection is not always possible due to atypic and non-specific clinical and radiological presentations. The postmortem pathological examination of cerebral blood vessels is therefore necessary to establish or confirm the presence of a dissecting aneurysm of intracranial arteries. Most of the described cases showed no significant underlying vascular pathology. Here we present the case of a 24-year-old women who died 5 days after admission to the hospital for a rapidly developing right sided hemisyndrome. Neuroradiological examination had revealed ill-defined bifrontal hypodense lesions and angiographic findings were compatible with a dissection of the left extracranial internal carotid artery with embolic subocclusion of both anterior cerebral arteries. The pathological evaluation ruled out a thromboembolic occlusion of cerebral arteries and an extracranial internal carotid artery dissection but showed an extended dissecting process of variable age in the anterior circulation of the circle of Willis. The dissected vessels showed pathological changes characteristic of segmental mediolytic "arteritis" [Slavin and Gonzalez-Vitale 1976]. To our knowledge this is the first report on intracranial arteries being affected by this pathologic entity. Our case illustrates the importance of a postmortem examination of dissecting aneurysms of intracranial arteries. Careful serial section studies of dissected intracranial arteries in young subjects should be performed and may allow for a better understanding of the vascular pathology underlying the dissection processus. PMID- 7851049 TI - Solitary brain metastasis as only recurrence of a carcinoma of the bladder. AB - A case of solitary brain metastasis from a transitional carcinoma of the bladder occurring 20 months after resection is presented. The patient underwent gross total removal followed by external irradiation and intravenous chemotherapy. The tumor in this quite unusual occurrence had a very characteristic aspect, both operatively and at pathologic examination. We believe that these patients should be managed aggressively whenever possible. PMID- 7851050 TI - Muscle mitochondrial abnormalities. Ageing, inflammation or both? PMID- 7851051 TI - Future of prodrugs in antiviral therapy. PMID- 7851052 TI - Sumatriptan clinical pharmacokinetics. AB - Sumatriptan is a novel serotonin 1 (5-hydroxytryptamine 1; 5-HT1)-like agonist which has been shown to be effective in the treatment of acute migraine. Single dose pharmacokinetic studies reflect the way that sumatriptan will be used in routine practice, but relatively few studies have been published. Bioavailability is high (96%) following subcutaneous injection, but low (14%) following oral administration because of first-pass metabolism. Absorption is rapid after subcutaneous injection, with peak concentration reached in 10 minutes. After oral administration, multiple peak concentrations are observed, but a concentration that is 75% of the final peak concentration is usually reached within 45 minutes. Less than 20% of the drug is protein bound. The volume of distribution is greater than total body water at 170L. Total plasma clearance is rapid, with an elimination half-life of around 2 hours. There is one major metabolite (an indole acetic acid analogue) which is excreted in the urine as the free acid and its ester glucuronide conjugate. The pharmacokinetic profile of sumatriptan is not significantly affected by an acute migraine attack (absorption phase), old age or gender. Pharmacokinetic studies in individuals with hepatic and renal disease have not been published; however, care should be taken when sumatriptan is administered to patients with liver disease until such information is available. No significant interaction was found between sumatriptan and propranolol, flunarizine, pizotifen or alcohol (ethanol). PMID- 7851054 TI - Antibody-directed enzyme prodrug therapy. AB - A 2- or 3-stage system can overcome some of the limitations of antibody-based attempts to restrict the action of cytotoxic agents to tumour sites. These systems use the antibody to direct an enzyme, which is unique to extracellular locations in humans, to tumour sites. The tumour-located enzyme is used to activate a subsequently administered prodrug. As with any antibody-based system, the main limitation lies in the distribution of the antibody or antibody conjugate. However, in contrast to drugs or radioisotopes, an enzyme can be inactivated in nontumour tissues or subjected to rapid clearance without toxic effects. The conjugation of an enzyme to an antibody increases its immunogenicity and may require the administration of immunosuppressive agents or the development of nonimmunogenic fusion proteins. A small scale pilot clinical trial has shown the general feasibility of this approach. PMID- 7851053 TI - Pharmacokinetics of cardiovascular drugs in children. Inotropes and vasopressors. AB - Infants and children with congenital or acquired heart disease and children with systemic disease often require pharmacological support of their failing circulation. Catecholamines may serve as inotropic (enhance myocardial contractility) or vasopressor (elevate systemic vascular resistance) agents. Noncatecholamine inotropic agents, such as the cardiac glycosides or the bipyridines, may be used in place of, or in addition to, catecholamines. Developmental changes in neonates, infants and children will affect the response to inotropic or pressor therapy. Maturation of the gastrointestinal tract, liver and kidneys alters absorption, metabolism and elimination of drugs, although there are few clear examples of this among the vasoactive drugs considered in this review. Changes in body composition affect the volume of distribution (Vd) and clearance (CL) of drugs. Developmentally based pharmacodynamic differences also affect the responses to both therapeutic and toxic effects of inotropes. These pharmacodynamic differences are based in part upon developmental changes in myocardial structure, cardiac innervation and adrenergic receptor function. For example, the immature myocardium has fewer contractile elements and therefore a decreased ability to increase contractility; it also responds poorly to standard techniques of manipulating preload. Available data suggest that dopamine and dobutamine pharmacokinetics are similar to those in adults. Wide interindividual variability has been noted. A consistent relationship between CL and age has not been demonstrated, although one investigator demonstrated an almost 2-fold increase in the CL of dopamine in children under the age of 2 years. The CL of dopamine appears to be reduced in children with renal and hepatic failure. Fewer data are available regarding the pharmacokinetics of epinephrine (adrenaline), norepinephrine (noradrenaline) and isoprenaline (isoproterenol). Digoxin pharmacokinetics have been extensively evaluated in infants and children. The Vd for digoxin is increased in infants and children. Children beyond the neonatal period display increased CL of digoxin, approaching adult values during puberty. Although it was previously thought that children both needed and tolerated higher serum concentrations of digoxin than adults, more recent studies indicate that adequate clinical response can be achieved with serum concentrations similar to those aimed for in adults, with decreased toxicity. Evaluation of studies of digoxin pharmacokinetics is complicated by the presence of an endogenous substance with digoxin-like activity on radioimmunoassay. Limited studies of amrinone pharmacokinetics in infants and children indicate a dramatically larger Vd, and a decreased elimination half-life in older infants and children, compared with values observed in adults. PMID- 7851057 TI - 96th Annual meeting of the American Society for Clinical Pharmacology and Therapeutics. San Diego, California, March 15-17, 1995. Abstracts. PMID- 7851055 TI - Pharmacokinetic contributions to postantibiotic effects. Focus on aminoglycosides. AB - The postantibiotic effect (PAE) refers to a period of time after complete removal of an antimicrobial during which there is no growth of the target organism. The PAE appears to be a feature of most antimicrobial agents and has been documented with a variety of common bacterial pathogens. Various factors influence the presence or duration of the PAE including the type of organism, type of antimicrobial, concentration of antimicrobial, duration of antimicrobial exposure, antimicrobial combinations, and inoculum and medium used. beta-Lactams demonstrate a PAE against Gram-positive cocci, but produce only a short PAE with Gram-negative bacilli. Antimicrobial agents that inhibit RNA or protein synthesis have a PAE against Gram-positive cocci and Gram-negative bacilli. In vivo studies of aminoglycosides suggest that area under the plasma concentration-time curve is the pharmacokinetic parameter that best correlates with clinical efficacy. This is thought to be due to the concentration-dependent killing and PAE possessed by these antimicrobials. Animal and human studies have reported that once-daily administration of aminoglycoside is as effective as, or more effective than, and possibly less toxic than traditional multiple daily administration. PMID- 7851058 TI - Diving physiology and pathophysiology. AB - Divers have worked at 500 m depth in the sea and have reached 700 m in simulated chamber dives. A prerequisite for this has been extensive physiological studies of the body's reactions to pressure and pressure changes. This paper reviews such physiological and pathophysiological studies with emphasis on recent developments. PMID- 7851056 TI - Pharmacokinetic optimisation of the treatment of peptic ulcer in patients with renal failure. AB - The pathogenesis of peptic ulceration is not yet clear. It could be due to an imbalance between acid secretion and mucosal defensive and/or protective mechanisms, but the association between Helicobacter pylori and peptic ulceration has questioned this hypothesis. Therefore, drugs inhibiting acid secretion and/or eradicating H. pylori are of major interest. Peptic ulcer disease is often associated with renal failure. For the selection of the proper dosage of these agents their pharmacokinetic properties and alterations in pharmacokinetics in various disease states, including renal failure, should be known. As histamine H2 receptor antagonists and pirenzepine are mainly eliminated by the renal route their elimination is dependent on creatinine clearance. Consequently, their elimination will be impaired in patients with renal insufficiency, which makes dosage reduction mandatory in these patients. No dosage supplementation is necessary after any type of dialysis because the drugs are removed in insignificant amounts by the various blood purification procedures. Misoprostol and proton pump inhibitors, such as omeprazole, lansoprazole and pantoprazole, are primarily eliminated by nonrenal routes. Therefore no dosage adjustments are necessary in patients with renal insufficiency. Bismuth salts, sucralfate and antacids should be avoided in patients with renal failure because of the accumulation of their cations and the associated risk of toxic reactions. For most agents more long term experience from comparative and double-blinded studies is needed to define better their clinical efficacy and tolerability in patients with renal failure. PMID- 7851059 TI - Effect of physical activity on the day-to-day variation in serum digoxin concentration. AB - Physical exercise has been found to increase digoxin binding in working skeletal muscle along with a concomitant decrease in serum digoxin concentration. In a recent study on healthy volunteers, moderate physical activity during maintenance digoxin treatment was shown to decrease the renal excretion of digoxin secondary to this redistribution of the drug, thereby affecting the body content of digoxin. In the present study the influence of changes in everyday physical activities, carried out during a 10-h period after ingestion of the daily maintenance digoxin dose, on the steady-state serum digoxin concentration (24 h after the last dose) was studied in 10 digoxin-treated outpatients (61-81 years of age). Compared to normal daily activity, complete bed rest for 10 h after ingestion of the maintenance dose did not affect the steady-state serum digoxin concentration. The lack of such an influence may be explained either by a low degree of everyday physical activity in the investigated patients or to a compensatory increase in the renal excretion of digoxin during the night preceding the serum digoxin measurement. Thus, standardization of physical activity 1-2 h before blood sampling is adequate when analysing the serum digoxin concentration in elderly outpatients. PMID- 7851060 TI - Normal limits of the derived vectorcardiogram in Caucasians. AB - The derived vectorcardiogram (dVCG) can be obtained from three orthogonal leads X, Y, Z, which are synthesized from the conventional 12-lead ECG by one of a number of mathematical techniques. The application of the dVCG in routine cardiological practice has the advantage of not requiring extra recording electrode other than those used for the conventional 12 electrocardiographic leads, and offers the simultaneous availability of additional dVCG diagnostic information. In this study, the dVCGs were obtained using the inverse Dower method from 1555 apparently healthy Caucasian individuals (884 men and 671 women) and were analysed to determine the age and sex dependent normal ranges of vector measurements in a Caucasian population. The vectorcardiographic parameters measured included the directions of inscription of the QRS vector loops, the magnitude of initial 20 and 30 ms QRS vectors and the direction of the initial 20 ms QRS vector. The maximal spatial QRS vector magnitude, as well as the maximal QRS and T vector magnitudes in the frontal, horizontal, and right sagittal planes, were observed to decrease significantly with advancing age in both sexes (P < 0.001) and were significantly larger in men in all age groups (P < 0.001). The observations from the current study illustrate the significant age and sex dependent differences in the normal ranges of dVCG parameters. These are of potential importance for diagnostic applications. PMID- 7851061 TI - Weight carrying effects on treadmill exercise response in persons without heart disease. AB - To evaluate the effect of weight carrying on dynamic exercise response, 12 normal subjects were studied during treadmill exercise using ear densitography in two ways: (1) no weight, (2) 10 kg weight in one hand. Although there were no significant differences in diastolic time (DT), tension-time index [TTI: systolic blood pressure x heart rate (HR) x left ventricular ejection time (LVET)] was significantly higher throughout the weight carrying exercise compared to dynamic exercise. The amount of change (delta) in TTI was significantly larger in the initial stage (control to 1 min) of weight carrying exercise compared to dynamic exercise, but there were no significant differences in the later stages (1-3 min and 3-6 min). A prolongation in LVET was observed despite increasing HR during the first minute of exercise in both type of exercise, but LVET was longer at any given HR in weight carrying compared to dynamic exercise. Thus, despite higher TTI throughout the weight carrying exercise, delta TTI was larger only in the initial stage which was caused by prolongation of LVET resulting from disproportionate increase in venous return of early exercise. PMID- 7851062 TI - Fatty acid exercise scintigraphy after percutaneous transluminal coronary angioplasty. AB - We performed a sequential fatty acid exercise-rest scintigraphy in 18 patients with an initially successful percutaneous transluminal coronary angioplasty (PTCA) to study the concordance of trends in symptoms, exercise tolerance and myocardial metabolism. Eleven patients stopped the exercise because of angina pectoris in the preoperative test; 2 days after PTCA this number decreased to two, but again increased to eight 3 months later. Exercise time (9.7 +/- 0.6 min, mean +/- SEM) and maximum exercise heart rate (128 +/- 4 beats min-1) were at least as good immediately after the operation as originally (8.8 +/- 0.6 min and 121 +/- 4 beats min-1, respectively). After 3 months both parameters were significantly (P < 0.05) better (10.3 +/- 0.6 min and 136 +/- 4 beats min-1, respectively) than originally. Some relative improvement in washout was noticed in 61% 2 days and in 56% of cases 3 months after PTCA. Fatty acid exercise uptake was more homogeneous in 72% of cases immediately after angioplasty and in 44% 3 months later. The trend in fatty acid uptake, exercise characteristics, and also in symptoms was most favourable among the eight patients with a dilatated left anterior descending coronary artery. Although the gamma camera technique possibly underestimated the effects of angioplasty, the impaired fatty acid metabolism could be linked with persistent symptoms after the operation. We conclude that most patients can safely participate in a symptom-limited (maximal) ergometry test already 2 days after PTCA, and that postoperatively myocardial perfusion and metabolism improve rapidly. However, this advantage is eventually lost to some degree, even if exercise tolerance continues to improve. PMID- 7851064 TI - Triglycerides in diabetes: time for action? PMID- 7851063 TI - High hydrostatic pressures in traumatic joints require elevated synovial capillary pressure probably associated with arteriolar vasodilatation. AB - Three out of the four Starling pressures were determined at arthroscopy of traumatic effusions of the knee. The range of the joint fluid hydrostatic pressure Pjoint was 5-83 cmH2O (0.5-8.1 kPa, 4-61 mmHg), that of the colloid osmotic pressure difference COPplasma-COPjoint 0-21.7 cmH2O. In 11 of 15 cases the sum Pjoint+COP difference exceeded 32.6 cmH2O (3.19 kPa, 24 mmHg), a high estimate of average capillary pressure at the level of the heart. The number of 'exceeding' cases was 8/15 if only 80% of the COP difference was considered effective. Pjoint and the COP difference oppose filtration of fluid from plasma into joints, indicating that mean capillary pressure, the only Starling pressure not determined, was elevated unless the effusions were being resorbed back into the blood. The findings can be explained by tamponade compensated by arteriolar vasodilatation, suspected to be metabolically mediated. PMID- 7851065 TI - Charles-Edouard Brown-Sequard: double-hyphenated neurologist and forgotten father of endocrinology. AB - This year is the Centenary of the death of Brown-Sequard who, although remembered today only for his eponymous syndrome, was as well known in the Victorian medical world as Robert Maxwell was to newspaper readers in the past decade. His position in the history of endocrinology is paradoxical; a good case can be made for saying that he invented the doctrine of internal secretion. Yet, the excesses of the organotherapy movement he founded at the end of his life discredited endocrinology and probably delayed the discovery of insulin. PMID- 7851066 TI - Growth factors and diabetic neuropathy. AB - A variety of soluble growth factors influence the peripheral nervous system. Although of considerable importance during development and growth, they appear also to be implicated in tissue maintenance in adult life and, particularly, during nerve regeneration. In addition, cell-surface and extracellular connective tissue matrix molecules are intimately involved in regeneration. So far, the possible participation of such growth factors in the causation of diabetic neuropathy is only speculative, but there are indications that their use could be of value in treatment. PMID- 7851067 TI - Cholesterol rich apo B containing lipoproteins and smoking are independently associated with macrovascular disease in normotensive NIDDM patients. AB - A cross-sectional study of macrovascular disease (MVD) and associated metabolic and other risk factors was conducted in 87 normotensive NIDDM patients. MVD was assessed by Rose questionnaire, 12 lead resting ECG, duplex scanning of carotid and peripheral vessels, and ankle:brachial systolic blood pressure ratio. Fasting serum total cholesterol, total triglycerides, LDL cholesterol, HDL cholesterol, apolipoproteins AI and B, lipoprotein (a), HbA1, plasma glucose, insulin, and C peptide responses to a carbohydrate rich meal, body mass index (BMI), waist-hip ratio, urinary albumin excretion rate, blood pressure, smoking and family history were assessed as possible 'risk factors'. Apolipoprotein:lipid ratios were calculated to estimate lipoprotein composition. Thirty-six patients had demonstrable MVD. The presence of MVD was associated with higher total triglycerides (p < 0.05), BMI (p < 0.05), systolic blood pressure (p < 0.01), a lower apo B:non HDL cholesterol ratio (p < 0.001), and smoking (p < 0.005) but no other measures. Multiple regression analysis revealed smoking and a low apo B:non HDL cholesterol to be independently associated with MVD. The low apo B:non HDL cholesterol suggests a high cholesterol content of apo B containing lipoproteins. This lipoprotein abnormality is not a feature of NIDDM, but when present in these patients may be particularly atherogenic. PMID- 7851068 TI - Serum lipoprotein levels and plasma concentrations of insulin, intact and 32, 33 split proinsulin in normoglycaemic relatives of patients with type 2 diabetes. AB - Type 2 diabetes is associated with abnormal lipoprotein levels and altered plasma concentrations of insulin, intact and 32, 33 split proinsulin. To investigate whether these are early features of the disease, we studied 36 normoglycaemic first-degree relatives of patients with Type 2 diabetes (13 European, 15 of Asian (Indian-subcontinent), and 8 of Afro-Caribbean origin) and 36 control subjects with no family history of diabetes. Relatives and controls were matched for age (mean +/- S.E. 33 +/- 2 vs 34 +/- 2 years), body mass index (23.7 +/- 0.5 vs 23.7 +/- 0.6 kg m-2), sex (17 M, 19 F) and ethnic origin. After an overnight fast, blood was sampled for measurement of serum lipids, plasma glucose and insulin, intact and 32, 33 split proinsulin by specific immunoradiometric assays. Relatives and controls had similar fasting concentrations of glucose (5.0 +/- 0.1 vs 4.9 +/- 0.1 mmol l-1), total cholesterol (4.51 +/- 0.13 vs 4.54 +/- 0.17 mmol l-1), HDL-cholesterol (1.21 +/- 0.06 vs 1.10 +/- 0.05 mmol l-1), LDL-cholesterol (2.84 +/- 0.14 vs 2.96 +/- 0.14 mmol l-1) and triglyceride (median (range) 0.78 (0.44-2.45) vs 0.83 (0.41-4.03) mmol l-1). Fasting levels of insulin (50.4 (18.9 174.0) vs 51.6 (10.0-118.0) pmol l-1, intact proinsulin (2.8 (0.1-15.0) vs 2.1 (0.6-6.4) pmol l-1 and 32, 33 split proinsulin (2.0(0-23.7) vs 1.6 (0.3-6.0) pmol l-1) were not significantly different between relatives and controls.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7851069 TI - Ethnic differences in secretion, sensitivity, and hepatic extraction of insulin in black and white Americans. AB - Hyperinsulinaemia and abnormalities in hepatic insulin extraction commonly coexist in ethnic groups with severe insulin resistance. Therefore, we compared the effects of ethnicity on glucose/insulin/C-peptide dynamics, hepatic insulin extraction, and insulin sensitivity in healthy black (n = 32) and white (n = 30) Americans. Standard oral glucose tolerance test (OGTT) and tolbutamide-modified, frequently sampled, intravenous glucose tolerance (FSIVGT) tests were performed in each subject. Insulin sensitivity index (S1)) was calculated using the MINIMOD method described by Bergman et al. Basal and post-stimulation hepatic insulin extraction were calculated by the molar ratios of C-peptide and insulin concentrations during the basal steady state and areas under the post-stimulation hormone curves, respectively. Apart from a slightly greater mean serum glucose peak response after oral glucose in the whites, mean glucose levels were identical in the blacks and whites during both stimulations. In contrast, serum insulin levels at basal and during both stimulations were significantly greater (2-3 fold) in the blacks than whites. However, the corresponding C-peptide responses were identical in both groups. The basal and postprandial hepatic insulin extraction were 33% and 45% lower in the blacks when compared to whites, respectively. The mean S1 was significantly (p < 0.02) lower in the blacks (4.93 +/- 0.46) than the whites (7.17 +/- 0.88 x 10(-4).min-1 (mU l-1)-1). We conclude that ethnicity may be a major determinant of the mechanism of peripheral hyperinsulinaemia and insulin insensitivity in black and white Americans. PMID- 7851070 TI - Human red cell membrane fluidity and calcium pump activity in normolipidaemic type II diabetic subjects. AB - Red cell membrane cholesterol, 1,6-diphenyl-1,3,5-hexatriene (DPH) and 1-[(4 trimethylammonium)phenyl]-6-phenyl-1,3,5-hexatriene (TMA-DPH) anisotropies and basal and calmodulin-stimulated calcium pump activities were compared in 16 normolipidaemic Type 2 (non-insulin-dependent) diabetic patients and 20 normolipidaemic control subjects using the Mann-Whitney U-test. Serum cholesterol, membrane cholesterol, and membrane DPH and TMA-DPH anisotropies were similar in the two groups but both basal and calmodulin-stimulated calcium pump activities were reduced in the diabetic group: basal activity (median (inter quartile range), mumol mg-1 h-1) 1.66 (1.18-1.97) vs 2.09 (1.90-2.50), p < 0.005 and calmodulin-stimulated activity 4.19 (3.07-5.48) vs 5.53 (4.70-6.88), p < 0.006. Although there were no correlations between glycaemic control and membrane anisotropy and between glycaemic control and calcium pump activity, the reduction in calcium pump activity is most likely due to a direct effect of diabetes on the calcium pump protein itself. PMID- 7851071 TI - Application of OpSite film: a new and effective treatment of painful diabetic neuropathy. AB - The aim of the study was to assess the effect of application of OpSite dressings on the pain and quality of life in 33 patients with chronic diabetic neuropathy. The effect of OpSite was compared with no treatment. After a run-in period of 2 weeks, OpSite was applied to one of the painful legs for 4 weeks. This was followed by another period of 4 weeks when OpSite was switched to the opposite leg. Pain was assessed by visual analogue scale and the primary analysis variable was within patient difference in pain between OpSite leg and no treatment leg at week 4 corrected for baseline. Secondary variables were paracetamol pill ingestion and the quality of life dimensions, sleep, mobility, contact discomfort, appetite, and mood. Changes in these variables from baseline to weeks 4 and 8 were analysed. There was a significantly greater reduction in pain in the OpSite treated limbs than the control limbs (p < 0.001). By week 4 paracetamol intake also declined significantly (p = 0.034) and patients experienced a significant improvement in contact discomfort, sleep, mood, appetite, and mobility (p < 0.002 for all 5 variables). OpSite appeared to alleviate the pain associated with diabetic painful neuropathy and thus improved patients' quality of life. PMID- 7851072 TI - Hypertension in Diabetes Study. III. Prospective study of therapy of hypertension in type 2 diabetic patients: efficacy of ACE inhibition and beta-blockade. AB - The Hypertension in Diabetes Study (HDS) is an ongoing, multicentre, prospective randomized intervention trial of therapy of hypertension (> or = 160 and/or > or = 90 mmHg) in Type 2 diabetic patients. It compares tight blood pressure control (aim: < 150/85 mmHg) versus less tight control (aim: < 180/105 mmHg) and, within the tight control group, an ACE inhibitor, captopril, versus a beta blocker, atenolol. We report the efficacy, side-effects of treatment, biochemical responses and incidence of hypoglycaemia in 755 patients (mean age 57 years, blood pressure 150/94 mmHg) followed for 2 years. At 2 years, blood pressure was 143/84 in the tight control and 156/90 mmHg in the less tight control group (p < 0.0001). Blood pressure reduction, adherence to therapy, incidence of side effects and of hypoglycaemia were similar on captopril and on atenolol. Patients on atenolol had a greater increase in body weight (+2.3 vs +0.7 kg, p < 0.01) and a non-significant trend to a greater increase in triglyceride than patients on captopril. A large blood pressure difference between the tight control and less tight control groups was obtained, with captopril and atenolol having similar hypotensive effects. The study has the potential to determine whether strict blood pressure control reduces the incidence of diabetic complications and whether ACE inhibitor or beta-blocker therapy is clinically advantageous. PMID- 7851073 TI - The N-acetyltransferase (NAT) gene: an early risk marker for diabetic nephropathy in Japanese type 2 diabetic patients? AB - A point mutation in the N-acetyltransferase gene (NAT2) leads to the recessive trait for the slow acetylator phenotype, which is suggested to be associated with microalbuminuria in Type 1 diabetic patients. Our study was designed to elucidate whether the NAT2 gene polymorphism would be a marker for diabetic nephropathy. The genotype distribution was studied in Japanese Type 2 diabetic patients with established nephropathy (n = 43), with microalbuminuria (n = 24), with normoalbuminuria (n = 18), non-diabetic patients with kidney disease (n = 62), and healthy control subjects (n = 51). The different alleles of the NAT2 gene were identified by restriction fragment length polymorphism analysis: the gene was amplified from genomic DNA (obtained from blood) and digested with restriction enzymes. The genotype was classified by the specific pattern of each allele (M1, M2, M3) in the agarose electrophoresis and ethdium bromide fluorescence. Alleles M1, M2, and M3 of NAT2 gene were found in 42.4% of all subjects (40.0% in all diabetic patients and 44.2% in all non-diabetic controls). The prevalence of the genotype, encoding the slow acetylator phenotype, was 7.0% in diabetic patients with established diabetic nephropathy, 20.8% in microalbuminuric diabetic patients, 0% in normoalbuminuric diabetic patients, 6.5% in non-diabetic patients with kidney disease, and 7.8% in healthy control subjects. The differences in the prevalence were non-significant. The results suggest that the N-acetyltransferase gene polymorphism may not be a genetic risk marker for diabetic nephropathy in Japanese Type 2 diabetic patients.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7851074 TI - Occupational hydrocarbon exposure and diabetic nephropathy. AB - Exposure to hydrocarbons has been implicated in the pathogenesis of glomerulonephritis but its role in the development of diabetic nephropathy remains unknown. Three groups of patients with Type 1 diabetes of over 10 years duration were studied. Group 1 comprised 45 patients (23 F) with no diabetic nephropathy (urinary albumin excretion (AER) < 30 mg 24 h-1), group 2 comprised 37 patients (17 F) with incipient diabetic nephropathy (AER between 30-300 mg 24 h-1), and group 3 comprised 31 patients (15 F) with overt diabetic nephropathy (AER > 300 mg 24 h-1). The groups were comparable for age, sex, duration of diabetes, recent glycaemic control, social class, and residential area. Patients were assessed blindly by a validated questionnaire and interview for hydrocarbon exposure, consumption of tobacco, analgesic agents, and alcohol. Exposure scores to hydrocarbons derived from the questionnaire were significantly higher in patients with incipient and overt diabetic nephropathy with smoking adjusted odds ratios of 3.6 and 5.2, respectively. The consumption of alcohol, analgesic agents, tobacco, and smoking habits were similar in the three groups. In conclusion, hydrocarbon exposure may be a key environmental factor in the development of diabetic nephropathy in patients with Type 1 diabetes. PMID- 7851075 TI - Relationships between diabetes duration, metabolic control and beta-cell function in a representative population of type 2 diabetic patients in Sweden. AB - To clarify whether metabolic control and beta-cell function deteriorate with increasing duration of diabetes, we investigated in a cross-sectional study Type 2 diabetic patients in an area-based population. Type 2 diabetic patients (n = 231: 112 males, 119 females) were identified by age at onset > or = 35 years, fasting levels of C-peptide > 0.04 nmol l-1, and absence of islet cell antibodies. Body weight was slightly elevated (BMI 26.8 +/- 0.3 kg m-2), however 76/210 (36%), had normal weight (BMI < 25 kg m-2). Fasting blood glucose rose significantly during the first 10 years of known diabetes from 8.2 +/- 0.3 mmol l 1 in patients with 0-5 years of duration to 9.9 +/- 0.7 mmol l-1 in those with 5 10 years of duration, p < 0.01 and HbA1c from 6.4 +/- 0.2 to 7.4 +/- 0.4%, p < 0.05. Fasting C-peptide levels decreased after 10 years duration from 0.90 +/- 0.06 nmol l-1 during 5-10 to 0.69 +/- 0.08 nmol l-1 during 10-15 years of diabetes, p < 0.05. The proportion of insulin treated patients increased from 13% (12/94) with 0-5 years of duration to 33% (13/39) with 10-15 years and 60% (18/30) with more than 15 years of duration. In conclusion in Type 2 diabetic patients without signs of autoimmunity, metabolic control, and beta-cell function deteriorate with increasing duration of diabetes, leading to common but not inevitable occurrence of 'secondary failure'. PMID- 7851077 TI - An approach to manageable datasets in diabetes care. British Diabetic Association. AB - A proposal is made to help the implementation of the British Diabetic Association dataset for diabetes care in those sites of care where information technology has yet to be established, or is in need of modification. A stepped approach is suggested and priorities identified. PMID- 7851076 TI - Insulin loss at the injection site in children with type 1 diabetes mellitus. AB - A simple filter paper technique is described for demonstrating and measuring insulin loss at the injection site in children with type 1 diabetes mellitus. Using this technique in a cohort of 19 children during a 7-day period, measurable fluid was demonstrated at the injection site in 68% of children at least once and was present following 23% of all injections. In nearly 80% of cases the insulin loss probably represented less than 1 unit but could on occasions be 2 units or more or up to 18% of the injected dose. Insulin losses were observed following injections given by children themselves and by parents. There was no significant relationship between insulin dose and insulin loss. Insulin losses at the injection site are frequent and, although usually small in amount, are a potential source of blood glucose variability. PMID- 7851078 TI - Wine and type 2 diabetes. PMID- 7851079 TI - Two modes of mental representation and problem solution in syllogistic reasoning. AB - In this paper, the theory of syllogistic reasoning proposed by Johnson-Laird (1983, 1986; Johnson-Laird & Bara, 1984; Johnson-Laird & Byrne, 1991) is shown to be inadequate and an alternative theory is put forward. Protocols of people attempting to solve syllogistic problems and explaining to another person how they reached their conclusions were obtained. Two main groups of subjects were identified. One group represented the relationship between classes in a spatial manner that was supplemented by a verbal representation. The other group used a primarily verbal representation. A detailed theory of the processes for both groups is given. PMID- 7851080 TI - Phonological awareness and visual skills in learning to read Chinese and English. AB - It is well known that phonological awareness is closely related to reading skill in children who are learning to read an alphabetic script such as English. In this study, the relationship between phonological awareness and reading skill was also investigated in children living in Hong Kong and Taiwan who were learning to read Chinese. This is because children from Taiwan learn a phonological script, known as Zhu-Yin-Fu-Hao, before they are taught to read any Chinese characters. In addition, a high proportion of Chinese characters contain a "phonetic" component which might be used by Chinese readers when they are recognising Chinese words. Consequently, the performance of 137 8-year-old primary children from Britain, Hong Kong and Taiwan on tests of phonological awareness, visual skills and reading ability was examined. Although there were significant correlations between Chinese reading and phonological awareness, the results of a series of regression analyses did not support the view that differences in phonological awareness per se are a primary cause of differences in reading ability amongst children learning to read Chinese. In contrast, performance on the phonological awareness tests (rhyme and phoneme detection) was significantly related to the reading ability of British children even after the effects of IQ and vocabulary had been partialled out. The results also showed that a test of visual skills (visual paired associates learning) was significantly related to the reading ability of the children in Hong Kong and Taiwan, but not to the reading of the British children. In addition, the nature of rhyme and phoneme deletion skills differed in children from Britain and Hong Kong. Whereas British children found it more difficult to delete the first phoneme from an initial consonant blend (e.g., deleting /s/ from star) than from a word which contained a single consonant before the vowel (e.g., deleting /s/ from sit), children from Hong Kong showed exactly the opposite pattern. In addition, performance on a phoneme deletion test appeared to be strongly influenced by whether or not the child had learnt an alphabetic script in the language in which they were being tested. PMID- 7851081 TI - Can overconfidence be used as an indicator of reconstructive rather than retrieval processes? AB - In a recent paper Wagenaar (1988) suggested that overconfidence can be used as an indicator of reconstructive processes which allow responses based on inference to be distinguished from responses based on retrieval. The ecological models (Bjorkman, in press; Gigerenzer, Hoffrage, & Kleinbolting, 1991; Juslin, 1993a, 1993b, 1994) provide a more positive view of the calibration of reconstructive responses. In this paper we compare these two views and argue that overconfidence cannot be considered a reliable indicator of reconstructive processes since people may be well calibrated for tasks that require inference, provided that tasks are selected in offunbiased manner. Instead, we discuss two different models: the response-independence model which is appropriate to retrieval, and the response-dependence model which applies to inference. These two models predict different distributions of solution probabilities and they therefore provide a criterion by which we can distinguish between direct retrieval and reconstruction. In two empirical studies modelled after Experiment 1 in Wagenaar's (1988) paper it is shown that calibration can be very similar and quite reasonable both for tasks that are dominated by inference and tasks that are dominated by retrieval processes. In Experiment 2 we show that the two conditions nevertheless differ in regard to the distributions of solution probabilities in the manner predicted by the two response models presented in the paper. It is proposed that the issue of which is the most appropriate interpretation of solution probabilities is neglected, and that the criterion should be of interest also to applications outside the domain of calibration research. PMID- 7851082 TI - Molecular epidemiology of gastric colonization by Enterococcus faecalis in a surgical intensive care unit. AB - We applied restriction endonuclease analysis of genomic DNA using pulsed field gel electrophoresis (PFGE) to study gastric colonization with Enterococcus faecalis among patients hospitalized in the surgical intensive care unit (SICU). Isolates were obtained by culturing prospectively the gastric contents of 140 patients in the SICU. In addition, cultures of respiratory specimens were obtained daily and cultures of blood, normally sterile body fluids, wounds, and urine were obtained when indicated clinically. A total of 177 isolates were obtained from 45 patients. Concentrations of E. faecalis in gastric fluid ranged from 1 x 10(2) colony forming units (CFU)/ml to greater than 5 x 10(7) CFU/ml (mean 8.0 x 10(6) CFU/ml). Overall, 33 different DNA types were identified by PEGE. In examining strain variation among isolates obtained from multiple anatomic sites over time, we found that the same DNA type was recovered from gastric aspirates, sputum, and wounds in a given patient and that these strains were carried over time. In general, given individuals were colonized with their own unique DNA type; however, one DNA type (type C) was shared by 11 different patients, and seven DNA types were shared by two individuals each. These results demonstrate the potential importance of gastric colonization as a reservoir for nosocomial strains of E. faecalis in an SICU setting. PMID- 7851083 TI - Prevalence of important pathogens and antimicrobial activity of parenteral drugs at numerous medical centers in the United States, I. Study on the threat of emerging resistances: real or perceived? Fluoroquinolone Resistance Surveillance Group. AB - Forty-three medical centers participated in a national (United States) surveillance study of parenteral antimicrobial agents as empiric therapy of pathogens isolated from blood, skin wounds, respiratory tract, and urine (> 8500 strains, 200 per laboratory). All laboratories tested each organism by the same reagent disks and/or Etest (AB Biodisk, Solna, Sweden) strips. Quality control results validated all laboratories for analyses. The most common isolates were Escherichia coli (1648), Staphylococcus aureus (1408), Pseudomonas aeruginosa (1003), Klebsiella species (792), and the enterococci (684). Among the tested drugs the percent susceptible rates observed were ofloxacin (83.4%), ciprofloxacin (82.0%), and cefuroxime (62.9%) tested against all organisms; cefazolin (54.7%) and ceftazidime (76.7%) tested against all nonfastidious aerobes; gentamicin (91.2%), imipenem (95.3%), ticarcillin-clavulanate (78.2%), and ceftriaxone (66.2%) tested against Gram-negative organisms only; and vancomycin (97.9%) and erythromycin (49.2%) tested against Gram-positive aerobes. Several drug-resistant species appear to be emerging or increasing in the United States: (a) vancomycin-resistant enterococci (7.9%, mostly Enterococcus faecium); (b) oxacillin-resistant S. aureus (21.0%); (c) third-generation cephalosporin resistant Enterobacteriaceae, including E. coli and Klebsiella species with extended-spectrum beta-lactamases (approximately 1.3%-8.6%); (d) penicillin resistant Streptococcus pneumoniae (17.8%); and (e) ciprofloxacin-resistant P. aeruginosa (14.9%). Fluoroquinolone resistance among the enteric bacilli was confirmed in 60 of 66 referred strains (0.8% of total strains), and cross resistance was high among ciprofloxacin, ofloxacin, lomefloxacin, fleroxacin, and norfloxacin (98.3%-100%). Seventeen strains of fluoroquinolone-resistant enteric bacilli (0.2% of total) also harbored an ESBL and resistance to aminoglycosides. Clonal spread within medical centers was observed with the ESBL-producing Klebsiella pneumoniae. This national clinical isolate data base continues to demonstrate broad fluoroquinolone efficacy (ofloxacin > ciprofloxacin) against hospital-based pathogens and many strains of emerging resistant bacteria. Continued US surveillance studies are urged to monitor emerging antimicrobial resistance and to guide interventions to minimize its occurrence. PMID- 7851084 TI - Etest for antifungal susceptibility testing of yeasts. AB - Comparison [+/- 1 dilution between minimum inhibitory concentrations (MICs)] of fluconazole and flucytosine Etest MICs of 10 candidate quality control yeast isolates and 78 clinical isolates demonstrated good agreement (> or = 90%) with the reference method (National Committee for Clinical Laboratory Standards document M27-P). This study suggests that the Etest is a promising alternative method for antifungal susceptibility testing in the clinical laboratory, but that further evaluations are needed. PMID- 7851085 TI - Comparison of the ProSpecT and Color Vue enzyme-linked immunoassays for the detection of Cryptosporidium in stool specimens. AB - Two enzyme-linked immunosorbent assays, the ProSpecT (Al-exon, Sunnyvale, CA, USA) and the Color Vue (Seradyn, Indianapolis, IN, USA) were compared for their ability to detect Cryptosporidium in 236 formalin-fixed stool specimens using the Merifluor C/G (Meridian, Cincinnati, OH, USA) stain as the reference method. The initial sensitivities of the ProSpecT and the Color Vue were 96.0% and 76.0%, which upon repeat testing of all discrepancies remained at 96.0% for the ProSpecT and decreased to 72.0% for the Color Vue. There were 25 (11%) specimens positive by the reference method. Initially, there were five false positive specimens by the ProSpecT, only one of which remained positive on retesting. The specificity of the Color Vue was 100% for the initial and repeated results, whereas the ProspecT had an initial specificity of 97.6% that increased to 99.5% upon repeat testing. The enzyme-linked immunosorbent assays offered the advantages of objectivity, batch testing, and, in the case of the ProSpecT, an acceptable sensitivity. PMID- 7851086 TI - Increased in vitro activity of ceftriaxone by addition of tazobactam against clinical isolates of anaerobes. AB - A total of 461 clinical strains of anaerobes were tested using a broth microdilution test to determine the activity of the combination of ceftriaxone and tazobactam and other antimicrobials against these isolates. Ceftriaxone was combined with tazobactam in ratios of 1:1, 2:1, 4:1, and 8:1 and twofold dilutions of ceftriaxone in constant concentrations to tazobactam of 2, 4, 8, 16, and 32 micrograms/ml. Against beta-lactamase-producing strains of the Bacteroides fragilis group, B. capillosus, and Prevotella species all combinations of ceftriaxone and tazobactam showed enhanced in vitro activity and were eight- to 2048-fold more active than ceftriaxone alone. By comparison ceftriaxone and tazobactam showed superior or equal activity to ampicillin and sulbactam, piperacillin and tazobactam, amoxicillin and clavulanate, ticarcillin and clavulanate, and metronidazole against these same strains. Against beta-lactamase nonproducing strains of Porphyromonas, Fusobacterium, Clostridium, Eubacterium, Peptostreptococcus, and Veillonella parvula the addition of tazobactam produced no appreciable enhanced ceftriaxone activity. Fixed concentrations of tazobactam at 2 and 4 micrograms/ml appear to be most suitable for susceptibility testing and are within the pharmacologic profile of this inhibitor. Pharmacologic and toxicity studies will be needed to define the role of ceftriaxone and tazobactam in infectious diseases. PMID- 7851087 TI - In vitro activity of CP-99,219, a novel 7-(3-azabicyclo[3.1.0]hexyl) naphthyridone antimicrobial. AB - The in vitro activity of CP-99,219 was compared with that of ciprofloxacin and sparfloxacin against 814 clinical bacterial isolates using a microdilution method with brain-heart infusion broth. CP-99,219 was the most potent agent tested against methicillin-resistant, ciprofloxacin-susceptible staphylocci (minimum inhibitory concentration [MIC]90 < or = 0.25 microgram/ml). CP-99,219 was 32-fold and fourfold more potent than ciprofloxacin and sparfloxacin, respectively, against Streptococcus pneumoniae, including strains resistant to penicillin G and erythromycin (MIC90 < or = 0.25 microgram/ml). CP-99,219 was also the most potent agent tested against S. pyogenes and Enterococcus faecalis (MIC90 < or = 0.5 microgram/ml). The activity of CP-99,219 against Enterobacteriaceae was comparable to that of sparfloxacin, with 90% of Escherichia coli, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Citrobacter freundii, C. diversus, Helicobacter pylori, and K. oxytoca being inhibited by < or = 0.5 microgram/ml. Serratia marcescens, Morganella morganii, and Pseudomonas aeruginosa were less susceptible, with MIC90 values to CP-99,219 of 4, 2, and 2 micrograms/ml, respectively. The MIC90 for Bacteroides fragilis was 0.39 microgram/ml for CP-99,219 compared with 12.5 micrograms/ml for ciprofloxacin. CP 99,219 was highly bactericidal at 1 x to 4 x MIC against both Gram-positive and Gram-negative organisms; its activity was similar in nutrient, trypticase soy, and cation-supplemented Mueller-Hinton broths. The spectrum and potency observed with CP-99,219 warrant further testing with this novel quinolone. PMID- 7851088 TI - Dual infections with Staphylococcus aureus and Streptococcus pyogenes causing toxic shock syndrome. Possible synergistic effects of toxic shock syndrome toxin 1 and streptococcal pyrogenic exotoxin C. AB - We describe a 35-year-old woman with clinical, microbiologic, and serologic findings suggesting that the patient developed toxic shock syndrome as a result of dual infections caused by toxin-producing strains of Staphylococcus aureus and Streptococcus pyogenes. Certain aspects of the pathogenesis of this toxin-related syndrome are reviewed. PMID- 7851089 TI - Tracing adverse food reactions without equipment. PMID- 7851090 TI - Smoking and asthma. PMID- 7851091 TI - New therapies for asthma. AB - Asthma is an inflammatory disease. Therefore, effective doses of antiinflammatory agents, particularly inhaled steroids, should have prominent place in the hierarchy of treatment, even in mild asthma. Suppression of airway inflammation may result in reduction of the need for bronchodilators, and perhaps the morbidity and mortality of asthma. PMID- 7851092 TI - The role of T-cell receptors in health and disease. AB - The progress made in the last several years in understanding the biology of the human T-cell receptor has enabled the start of the formidable task of deciphering the mechanisms that result in the pathogenesis of several important disease states in man. The ability to clone T-cells, and to identify TCR utilization by genetic techniques, has greatly enhanced our ability to diagnose T-cell malignancy and follow its response to treatment. The phenomenon of superantigen activation of TCR has improved our understanding of certain disorders associated with infections in humans. We are now prepared to use new knowledge to begin to dissect the role of T-cells in initiating and perpetuating human autoimmune disease. However, several impediments to progress must first be overcome. One of the most problematic is our failure to identify autoantigens that are relevant to specific disease states. Experimental approaches to the analysis of TCR in humans are complicated by the high degree of genetic variability present in our outbred population. We also currently lack an accurate understanding of the structural basis of TCR/MHC interactions, and we therefore have difficulty translating the relationship of linear TCR gene sequence data to three-dimensional structure. Further progress in understanding the role of the TCR in normal human immune recognition and in disease states will be made when science is successful in bypassing these obstacles. PMID- 7851093 TI - Antineutrophilic cytoplasmic antibodies (ANCA) and vasculitis. PMID- 7851094 TI - Asthma: diagnosis and management of nocturnal symptoms. AB - An approach to asthma evaluation and treatment that seriously considers the strong nocturnal predilection for exacerbations of asthma is necessary for proper care of most asthmatics. Appreciation of the chronopharmacology of medications that may improve nocturnal asthma is essential. Controlled-release theophylline preparations, such as Uniphyl, which achieve peak blood levels 10-12 hours after dosage, should be administered immediately after the evening meal to give greatest efficacy between 3 and 6 AM when airflow reaches its nadir. Oral corticosteroids should be administered around 3 PM to achieve peak pulmonary antiinflammatory efficacy between 3 AM and 6 AM corticosteroid-induced decreases in inflammatory cell infiltration in lungs clearly being associated with improvement in lung function. Future developments of high-potency inhaled corticosteroid medications or sustained-action inhaled anticholinergic agents may add to the therapeutic armamentarium in the battle against asthma, the nocturnal affliction. PMID- 7851095 TI - Asthma: the feline connection. PMID- 7851096 TI - Asthma: causes and treatment. PMID- 7851097 TI - Eosinophil as a therapeutic target in allergic disease. AB - The eosinophil appears to be a key cell in the development of active symptoms in both allergic diseases and asthma. Its involvement in inflammation seems to be mediated in part by release of its mediators ECP, MBP, EPO, and EDN. Therefore, the eosinophil and its inflammatory mediators would make ideal targets for pharmacological manipulation. In designing therapeutics to modify eosinophil participation, it will be helpful to keep the pharmacologic regulation as eosinophil-specific as possible. In this way, The function of other granulocytes is not affected and the patient is still able to fight infections. PMID- 7851098 TI - Assisting clients of community mental health centers to secure SSI benefits: a controlled evaluation. AB - The entire caseloads of three Community Mental Health Centers were screened on variables normally assessed in the SSI application process. These data were then used to classify each individual as Possibly Eligible for SSI benefits, or as Probably Not Eligible. The Possibly Eligible subjects were randomly assigned to either the Experimental condition, in which subjects were helped to apply for SSI, or the Control condition, in which no intervention was provided. Results showed that the Experimental subjects were almost twice as likely to secure SSI benefits as the Control subjects. The usefulness of the screening form was supported in that control subjects were almost five times more likely to be awarded SSI, compared with subjects who had been classified as Probably Not Eligible. PMID- 7851099 TI - Two modes of case management: assessing their impact. AB - This is a study of two strategies of case management-Community Treatment Teams (CTTs) and Intensive Case Management Teams (ICMTs). A random sample of 30 cases from the CTT group were matched with 30 cases from the ICMT group using 4 criteria. Data were collected from case records and verified with case managers. The analysis revealed that although the CTTs engaged in more case management activities, there were few significant differences in the outcomes of the two approaches. The results are discussed in relation to a possible "ceiling effect" of case management, cost effectiveness, and limitations in the sample. PMID- 7851100 TI - A community ability scale for chronically mentally ill consumers: Part II. Applications. AB - The authors describe uses for a 17-item instrument that efficiently measures the functioning level of chronically mentally ill persons living in the community. The Multnomah Community Ability Scale is designed to be completed by case managers who work with chronically mentally ill consumers. The instrument is sensitive to differences among individuals within this special population of consumers and is easy to complete. Community mental health program staff can be trained to use the scale reliably. The scale has been used to compare levels of severity between urban and rural community mental health program clients. The authors discuss the application of the Multnomah Community Ability Scale to a capitated payment system for severely mentally ill, involuntary clients. PMID- 7851101 TI - Predictors of burden among lower socioeconomic status caregivers of persons with chronic mental illness. AB - This study uses a stress-coping-support framework to examine the predictors of caregiver burden with a sample of 103 lower social class family caregivers of persons with chronic mental illness. Results of multiple regression analyses show that the greater the frequency of client behavioral symptoms and the lower the amount of perceived support from family members, the higher the level of overall caregiver burden. Examination of the predictors of specific types of burden family disruption, stigma, strain, and dependency-reveal that different constellations of variables predict different types of burden. The need for mental health agencies to address caregiver and client concerns is addressed. Implications are presented for practice and future research. PMID- 7851102 TI - Violent and destructive behavior among the severely mentally ill in rural areas: evidence from Arkansas' community mental health system. AB - A comparison of rates of violence among admissions to the Arkansas State Hospital system between urban and rural areas tested the hypothesis that thresholds for admission to the hospital were greater in rural than in urban areas. Data on violent and destructive behavior were recorded from the medical records of 609 patients. Logistic regression was used to model the presence or absence of violent behavior in urban and rural admissions controlling for selected demographic and clinical characteristics. Results indicated that rural patients showed increased likelihood of violent and destructive behavior prior to admission supporting the hypothesis that barriers to mental health services in rural areas may be creating differential thresholds of service access and utilization. The increased rate of violence was particularly evident in those using substances prior to admission in rural areas suggesting that community management of the violent, substance abusing patient may be particularly difficult for rural areas. PMID- 7851103 TI - The response of an assertive community treatment program following a natural disaster. AB - A newly forming model treatment program for seriously mentally ill adults was dramatically affected by a natural disaster in September 1989. Hurricane Hugo rendered the offices of the Assertive Community Treatment Program uninhabitable, its vehicles marginally driveable, and its resources virtually nonexistent. In the three months following the storm, however, not a single psychiatric rehospitalization took place. Although the authors cannot claim that the program model was solely responsible for this outcome, this paper illustrates the service system elements that contributed to the program's effectiveness in the wake of one of the nation's most severe natural disasters. PMID- 7851105 TI - Scientific knowledge and social consensus. PMID- 7851104 TI - Rehabilitative day treatment vs. supported employment: I. Vocational outcomes. AB - Day treatment remains a core component in many community mental health programs for persons with severe mental disorders throughout the United States. Many other mental health centers are moving away from day treatment toward psychosocial and vocational rehabilitation programs. Empirical research directly comparing these two systems of organizing outpatient services is needed. In this study the authors compared a rehabilitative day treatment program in one small city with a similar program in a nearby city that changed from day treatment to a supported employment model. Clients who were enrolled in community support services during a baseline year prior to the change and during a follow-up year after the change (71 in the program that changed and 112 in the other) were evaluated during both intervals. In the program that changed, competitive employment improved from 25.4% to 39.4% for all clients, and from 33.3% to 55.6% for those clients who had been regular attenders of day treatment during the baseline. Hours worked and wages earned similarly improved after the program change. For all work variables, clients who had not worked during the baseline year accounted for the improvements in outcome. Meanwhile, employment remained stable in the day treatment program. No negative outcomes were detected. These results indicate that eliminating day treatment and replacing it with a supported employment program can improve integration into competitive jobs in the community. PMID- 7851106 TI - Moricizine and quality of life in the Cardiac Arrhythmia Suppression Trial II (CAST II). AB - The Cardiac Arrhythmia Suppression Trial II (CAST II) was a double-masked placebo controlled randomized trial that compared the survival effects of moricizine to placebo in postmyocardial infarction arrhythmia patients. The quality-of-life outcome measures were designed prospectively for CAST and were previously shown to have high reliability and clinical discriminative validity. The CAST quality of-life instrument detected significant differences between moricizine and placebo. In particular, moricizine was most strongly associated with inferior social activity and satisfaction scores (p = .014) and lower scores for overall contentment with life (p = .007). Moreover, the quality-of-life measures improved significantly for both the moricizine and placebo treatment groups after entry into the clinical trial. These results indicate that the CAST quality-of-life instrument is sensitive for assessing pharmacological therapies in the treatment of heart disease. PMID- 7851107 TI - Simulation as a design tool for phase I/II clinical trials: an example from bone marrow transplantation. AB - We discuss the design and analysis of a proposed phase I/II clinical trial in bone marrow transplantation whereby dose modifications that decrease the risk of one complication increase the risk of another. Trials of this type are carried out to determine whether a dose can be found that balances the risks of each complication. Three different scenarios describing potential relationships between each risk and the treatment dose are postulated. The scenarios encompass both favorable situations in which several acceptable doses exist and unfavorable situations in which no acceptable dose exists. The operating characteristics of three sequentially developed trial designs were examined by simulation under each dose-response scenario. The first design was derived from seemingly reasonable rules, but simulations showed that performance fell far short of what was desired, thus motivating modifications. Subsequent designs showed improved performance characteristics compared to the original design. Without close examination of the operating characteristics, the original design would have been implemented, leading to high risk of an erroneous conclusion. PMID- 7851108 TI - A Bayesian approach to establishing sample size and monitoring criteria for phase II clinical trials. AB - Thall and Simon propose a Bayesian approach to phase II clinical trials with binary outcomes and continuous monitoring. The efficacy theta E of an experimental treatment E is evaluated relative to that of a standard treatment S based on data from an uncontrolled trial of E, an informative prior for theta S, and a noninformative prior for theta E. The trial continues until E is shown with high posterior probability to be either promising or not promising, or until a predetermined maximum sample size is reached. Operating characteristics are evaluated under fixed values of the success probability of E. In this paper, we propose two extensions of this decision structure, describe sample size and monitoring criteria, and provide numerical guidelines for implementation. The first extension gives criteria from early termination of trials unlikely to yield conclusive results, based on the marginal (predictive) distribution of the observed success rate. The second extension allows early termination only if E is found to be not promising compared to S. Operating characteristics of each of these designs are evaluated numerically over a range of design parameterizations. We also examine the effects of intermittent monitoring on the design's properties. An application of this approach to a leukemia biochemotherapy trial is described. PMID- 7851109 TI - Is double data entry necessary? The CHART trials. CHART Steering Committee. Continuous, Hyperfractionated, Accelerated Radiotherapy. AB - There is some controversy over the need for double data entry in clinical trials. In particular, does the number and types of errors identified with this approach justify the extra effort involved? We report the results of a study carried out to address this question. Our main outcome measure was the frequency and types of errors involved in the entry of data for the CHART (continuous, hyperfractionated, accelerated radiotherapy) trials. Data were reentered for a sample of 44 patients by a data manager other than the one making the initial entry. The second entry was then compared with the first entry. The error rate for the two entries combined was 14 per 10,000 data items (fields) (95% confidence interval 10, 19). The error rate for the initial entry alone was 15 per 10,000 fields (95% confidence interval 9.5, 22), and the vital/important error rate (defined as any error on a principal outcome measure or a major error on any other endpoint or variable) was 2.5 per 10,000 fields (95% confidence interval 0.68, 6.4). On this evidence double data entry is not performed for the CHART trials. PMID- 7851110 TI - Power considerations for testing an interaction in a 2 x k factorial design with a failure time outcome. AB - We examine the power and sample size requirements for testing an interaction in the situation of a 2 x k factorial design with time to failure as the outcome of interest. Using the distribution of a general test statistic, based on weighted residual sum of squares for testing a general interaction in a 2 x k factorial experiment, we describe the relationship between the power of the test and the size of the sample. In a simulation study, we evaluate the behavior of three commonly used estimators as methods for estimating the parameters of the test statistic. These are the Mantel-Haenszel (MH) method, a method (O/E) based on the ratio of the observed to expected number of events, and the maximum likelihood (MLE) method. We show that in most cases nominal test sizes and appropriate powers are attained using the MLE and MH methods, whereas the O/E method yielded test sizes and powers less than expected. With both large baseline hazard rates and large differences in relative hazard rates, the difference between the simulated and asymptotic powers for all three methods become larger; however, the size of this difference is small and unlikely to seriously affect the use of either the MLE or MH methods. The proposed methods could also be used to calculate the power and sample size for testing a treatment-covariate interaction in a stratified data analysis. PMID- 7851111 TI - The Ottawa Stroke Trials Registry Collaborative Group and the development of the Ottawa Stroke Trials Registry (OSTR). PMID- 7851112 TI - The Nambour Skin Cancer and Actinic Eye Disease Prevention Trial: design and baseline characteristics of participants. AB - The Nambour Skin Cancer and Actinic Eye Disease Prevention Trial (the Nambour Trial) is a field trial conducted in an unselected adult population in Australia. Using a randomized 2 x 2 factorial design, the principal aim is to evaluate whether regular use of high-protection sunscreen and/or dietary supplementation with beta-carotene (30 mg daily) can alter the incidence rates of basal cell carcinomas and squamous cell carcinomas of the skin over a minimum follow-up time of 4.5 years. Changes in the incidence of solar keratoses and actinic eye disease and the rate of photoaging after intervention will also be investigated. In 1992, 1626 participants between the ages of 25 and 75 years were enrolled, all of whom had been randomly selected from residents of the southeastern Queensland township of Nambour for an earlier skin cancer prevalence survey. This paper describes the background to the trial and its design, with respect to evaluation of effects on actinic skin disease, and documents the baseline characteristics of participants recruited into the Nambour Trial. PMID- 7851113 TI - Pseudomonas aeruginosa corneal ulcer isolates distinguished using the arbitrarily primed PCR DNA fingerprinting method. AB - Infection of the eye by Pseudomonas aeruginosa can result in corneal inflammation (keratitis) and ulceration, and permanent decrease in vision if not successfully treated. We tested for diversity among P. aeruginosa strains from corneal ulcers by the sensitive and efficient 'RAPD' (for 'random amplified polymorphic DNA') fingerprinting method. This method uses single oligonucleotides of arbitrarily chosen sequence as primers in low-stringency PCR amplification, and results in strain-specific arrays of DNA fragments. Tests of 20 independent P. aeruginosa corneal ulcer isolates yielded 19 different arrays of products with each of three arbitrary primers, indicating that all but two of the strains differed from one another. Additional isolates from three patients (infected eye, contact lens or eye drops) yielded fragment patterns that were identical to those of the original isolate in each case. Thus, our results demonstrate considerable diversity among P. aeruginosa corneal ulcer isolates, and suggest that just one clone may predominate in typical infections. PMID- 7851114 TI - Distribution of cytokine proteins within epiretinal membranes in proliferative vitreoretinopathy. AB - This study reports on the immunohistochemical staining for cytokine proteins of 26 epiretinal membranes obtained from eyes undergoing surgery for the treatment of proliferative vitreoretinopathy. All specimens were investigated for the distribution of staining for interleukin-1 alpha (IL-1 alpha), interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF alpha), interferon-gamma (IFN gamma) and interleukin-2 (IL-2). The results showed that 22 of the membranes (85%) stained for TNF alpha not only intracellularly but also in the extracellular matrix. This contrasts with the findings that only 2 membranes stained for IL-1 alpha and that another 3 were positive for IL-1 beta. Staining for the cytokines IL-6 and IFN gamma was also observed in 9 and 7 membranes respectively. None of the specimens investigated stained with antibodies to IL-2 or control antibodies, and none of three normal retinas stained with any of the antibodies used. Pre-absorption of anti-cytokine antibodies with the corresponding human recombinant cytokines abolished staining of cells and extracellular matrix. The present findings support growing evidence that cytokine mediated pathways of inflammation are involved in the pathogenesis of proliferative vitreoretinopathy, and draw attention to the possibility that interaction between extracellular matrix-bound cytokine and inflammatory leucocytes or resident cells of the retina may promote the development and perpetuation of this condition. PMID- 7851115 TI - Glial-, neuronal- and photoreceptor-specific cell markers in rosettes of retinoblastoma and retinal dysplasia. AB - Previous studies have shown that a rosette formation represents an attempt to form embryonic retinal tissue, primarily rods and cones. To test the theories as to the origin and characteristics of retinoblastoma cells, we compared the characteristics of tumor rosettes with those of dysplastic rosettes seen in retinal dysplasia using the glial, neuronal and photoreceptor markers. Forty-four retinoblastoma and one retinal dysplasia specimens were analyzed by indirect immunohistochemistry, using specific antibodies against glial fibrillary acidic protein, S-100 protein, myelin basic protein, neuron-specific enolase, neurofilament, retinal S-antigen and retinal pigment epithelial antigen. In human retinoblastoma, all the glial, neuronal, retinal pigment epithelial, and photoreceptor cell markers, except for the neurofilament, were present in parts of rosette-forming tumor cells. However, their localization was different for each antigen and it was not clear whether each tumor cell possesses several antigens. These immuno-positive tumor cells were cytologically indistinguishable from other rosette-forming cells at the light microscopic level. In retinal dysplasia, neuron specific enolase and retinal S-antigen were diffusely expressed in the dysplastic rosettes, however, other antigen were not seen in those rosettes. The staining pattern by immunocytochemistry is totally different in tumor rosettes from dysplastic ones. We found varying localizations of different immunoreactivities within tumor rosettes. These results led us to suggest that tumor cells in the rosettes of retinoblastoma may have the ability to differentiate into neural and glial cells. To prove the theory that retinoblastoma cells may have originated from a primitive neuroectodermal cell capable of multipotentiality, further investigation is needed. PMID- 7851116 TI - Comparative antioxidant protection of cultured rabbit corneal epithelium. AB - Oxygen-free radicals may injure the epithelium of corneas in storage awaiting transplantation. This study compared the cytoprotective effects of several antioxidants against oxygen-free radical injury to rabbit corneal epithelial cells in vitro. Cultured rabbit corneal epithelial cells were exposed to oxygen free radicals generated by xanthine oxidase and hypoxanthine. The cytoprotective activities of various antioxidants on this system were compared using established morphologic criteria. The results demonstrated that purpurogallin at 1.0 mM delayed cell necrosis to 9.98 +/- 1.16 min compared with 2.96 +/- 0.67 min without antioxidant protection. This degree of protection was significantly different from that provided by ascorbate (1.0 mM), trolox (1.0 mM), superoxide dismutase + catalase, catalase (92,000 IU/L), mannitol (1.0 mM), and superoxide dismutase (24,200 IU/L) (p < 0.01). We concluded that purpurogallin effectively protects corneal epithelium from oxygen-free radical injury and may help prevent such injury in corneal preservation solutions. PMID- 7851117 TI - The collagen fibrillar network in the human pial septa. AB - The three-dimensional organization of the collagen fibrils in the human pial septa was studied by transmission electron microscopy and by scanning electron microscopy after cell maceration with sodium hydroxide. The collagen fibrils along the nerve fibers were loosely distributed thin filaments with a diameter ranging from 25 to 40 nm (mean, 32 +/- 6 nm). Most fibrils were oriented perpendicularly to the long axis of the nerve fiber. In the deeper stroma of the pial septa, collagen fibrils were well packed and the diameter was 40 +/- 6 nm (range, 35 to 50 nm). The scanning electron microscopic study demonstrated a smooth, fabric-like structure formed by wavy and loosely interwoven thin collagen fibrils. Under high magnification, multiple collagenous sheets were observed in the pial septa by scanning electron microscopy. In addition to the structure of loosely arranged thin fibrils on the surface layer adjacent to the nerve fibers, two distinct patterns of collagen fibril network were demonstrated in the deeper stroma. One exhibited fibrils with random distribution, and the other showed well packed, undirectionally oriented collagen. Small openings corresponding to elastic tissues were also observed. This collagen architecture may contribute to the flexibility and tensile strength of the pial septa required in the intraorbital portion of the optic nerve. PMID- 7851118 TI - Comparison of linear, multilinear and mask microdensitometric analyses of Scheimpflug images of the lens nucleus. AB - We wanted to determine the agreement among three methods currently used to measure the average density of the nucleus from a Scheimpflug video image of the lens, namely, the multilinear, linear and mask techniques. Using the NEI Scheimpflug Cataract Imaging System, video images of the lens were obtained from 49 eyes of 31 consecutive patients with predominantly nuclear opacities of varying severities. For each image, 3 separate determinations of the average nuclear density [in optical density units (odu)] were obtained by one analyst sequentially applying each of the three methods. Repeat measurements were obtained by the same analyst one week apart to evaluate reproducibility (using 95% error range), of each of the methods. Pairwise comparisons of the 3 methods were also done. Only the error due to outlining of the nucleus was assessed. Reproducibility of each method was excellent. The 95% error ranges were +/- 0.015 odu for the linear, +/- 0.013 odu for the multilinear, and +/- 0.017 odu for the mask methods. Very strong linear relationships were observed between the linear and multilinear methods (R2 = 0.99), between the linear and mask methods (R2 = 0.97), and between the multilinear and mask methods (R2 = 0.98). Simple linear regressions calibrating these three methods against each other would facilitate comparison of density measurements using any of these methods for analysis of Scheimpflug images of the lens nucleus. PMID- 7851119 TI - Effect of cytokines and prostaglandins on the growth of chick retinal pigment epithelial cells. AB - The effect of cytokines and prostaglandins on the growth of chick retinal pigment epithelial (RPE) cells was studied in vitro. The growth of RPE cells was evaluated by [3H]-thymidine uptake. Human recombinant interleukin-1 beta, interferon-beta and tumor necrosis factor-alpha stimulated the growth of RPE cells at 50-200 units/ml. Prostaglandins such as PGE1, PGE2 and PGF2 alpha suppressed RPE cell growth at 10(-5) approximately (-6)M. Indomethacin, an inhibitor of cyclooxygenase, did not affect the spontaneous RPE cell growth at 10(-7) approximately (-9) M. However, 10(-7) M indomethacin enhanced RPE cell growth stimulated by cytokines synergistically. The addition of 10(-6) M PGF2 alpha suppressed the enhanced growth of RPE cells which was induced with cytokines and indomethacin. Furthermore, RPE cells stimulated with cytokines produced PGE2. These results suggest that RPE cells produce prostaglandins which have a negative regulatory role in RPE cell growth. PMID- 7851120 TI - Enhancement of filtration surgery with cytosine arabinoside and reversal of toxicity with 2'-deoxycytidine. AB - Antifibrosis agents have improved the success of glaucoma filtration surgery, although undesired side effects are not readily reversible and may present a major limitation in the use of these agents. Our purpose was to study the efficacy of cytosine arabinoside (Ara-C) as an adjunctive antimetabolite in glaucoma surgery in the rabbit, and reversal of toxicity due to this agent with the competitive inhibitor 2'-deoxycytidine. Posterior lip sclerectomy was performed in rabbit eyes treated with 15 mg subconjunctival Ara-C daily for 7 d then every other day for 7 d. Mean intraocular pressure was lower in eyes treated with Ara-C compared with controls at all time points following filtration surgery. On the 10th postoperative day, the mean intraocular pressure of control eyes (25.0 +/- 1.9 mm Hg) had returned to baseline levels, whereas the intraocular pressure of eyes treated with Ara-C was significantly lower (16.0 +/- 1.7 mm Hg) (P < 0.001). Bleb survival was also prolonged in the Ara-C-treated eyes. The major ocular side effect of Ara-C was corneal toxicity, with epithelial defects in 40% of eyes after 8 daily injections of 15 mg Ara-C. Reversal of toxicity was enhanced with 2'-deoxycytidine, with complete resolution of epithelial toxicity after 6.5 +/- 1.7 d following daily topical 10% 2' deoxycytidine compared with 12.7 +/- 0.58 for control (P < 0.002). These results demonstrate that postoperative subconjunctival injection of Ara-C results in improved bleb function after filtration surgery in the rabbit. Recovery from corneal epithelial toxicity due to Ara-C is markedly enhanced with the competitive inhibitor 2'-deoxycytidine. PMID- 7851122 TI - Malpractice: punitive damages. PMID- 7851121 TI - Interphotoreceptor retinoid-binding protein derived peptide can induce experimental autoimmune uveoretinitis in various rat strains. AB - Experimental autoimmune uveoretinitis (EAU) is an intraocular inflammatory disease model induced by retinal specific antigens such as S-antigen and interphotoreceptor retinoid-binding protein (IRBP). The present study was aimed at testing the uveitogenicity of IRBP and an IRBP-derived peptide in various strains of rats with different RT1 (major histocompatibility complex in rats) haplotypes. Immunization with IRBP induced distinct EAU in LEW (RT1l), WKAH (RT1k) W/M (RT1k), LEJ (RT1j), and BUF (RT1b) rats. IRBP also induced a low grade of EAU in SDJ (RT1u), but no disease was detected in TO rats, another strain of the RT1u haplotype. IRBP-derived peptide R16 (aa 1177-1191) induced severe EAU in LEW rats and moderate disease in the WKAH and W/M strains. Immunization with R16 also induced low levels of inflammation in eyes of 75% and 20% of LEJ and BUF rats, respectively, but this peptide did not cause any disease in SDJ and TO rats. Injection of Bordetella pertussis had minimum or no effect on the induction of EAU by peptide R16 in this study. These data thus indicate that peptide R16 can bind to various RT1 molecules in addition to RT1l. Further, our observations support the notion that certain epitopes of IRBP could be uveitogenic in humans with different HLA haplotypes. PMID- 7851123 TI - The Latest in latex allergy. PMID- 7851124 TI - A dermatologic diary. Portrait of a practice. PMID- 7851125 TI - Telangiectases in human immunodeficiency virus-positive patients. AB - Telangiectases have been noted as a cutaneous manifestation of the acquired immunodeficiency syndrome and are characteristically distributed across the upper chest in a crescentic pattern between the clavicles. We describe the observation of diffuse upper body telangiectasia in a forty-seven-year-old, human immunodeficiency virus-seropositive man. Histopathologic examination revealed dermal telangiectasia with perivascular plasma cells. Although we are aware of the association between telangiectases and human immunodeficiency virus seropositive findings, we believe that this is the first documented observation of diffuse upper body telangiectasia in a human immunodeficiency virus seropositive patient. PMID- 7851126 TI - Embedded earrings. AB - Techniques used to pierce ears include needles, safety pins, sharpened studs, self-piercing kits, and spring-loaded guns. The spring-loaded gun requires minimal personnel training and because it is easy to use, it has a widespread popularity. We report twenty-six cases of embedded earrings following ear piercing with the spring-loaded gun. PMID- 7851127 TI - Excessive growth of eyelashes in patients with acquired immunodeficiency syndrome. AB - We report a new case of excessive growth of eyelashes in a patient seropositive for human immunodeficiency virus 1. The exact mechanism of this hypertrichosis is still unknown. Although this sign seems to occur late in the human immunodeficiency virus infection, we believe early recognition of this manifestation could lead, in some cases, to earlier diagnosis of the infection. PMID- 7851128 TI - Ulcerated necrobiosis lipoidica diabeticorum in a patient with a history of generalized granuloma annulare. AB - Granuloma annulare and necrobiosis lipoidica diabeticorum have rarely been reported in the same patient. We describe the unusual case of a woman with diabetes and a history of generalized granuloma annulare who noted leg ulcers that clinically represented ulcerated necrobiosis lipoidica diabeticorum and had histologic features of necrobiosis lipoidica diabeticorum and granuloma annulare. Her condition responded to treatment with antiplatelet agents. PMID- 7851129 TI - Cutaneous cryptococcosis with molluscum contagiosum coinfection in a patient with acquired immunodeficiency syndrome. AB - We report the first patient with acquired immunodeficiency syndrome in whom molluscum contagiosum and Cryptococcus neoformans were documented in the same cutaneous lesion. While cases of the co-occurrence of two pathologic entities in patients with acquired immunodeficiency syndrome have been reported, namely cytomegalovirus with herpes simplex virus and Kaposi's sarcoma with Histoplasma capsulatum, the findings in this patient are unique. The clinical presentation of cutaneous lesions caused by molluscum contagiosum and by Cryptococcus neoformans is reviewed. The findings in this case are more remarkable still given the often noted tendency of cutaneous cryptococcosis to masquerade as molluscum contagiosum. It may be that the lesions of molluscum contagiosum create a favorable environment for cryptococcal dissemination. Examination of a biopsy specimen is crucial to the diagnosis of skin lesions, often atypical or deceptive, in immunosuppressed patients. PMID- 7851130 TI - A case of trichorhinophalangeal syndrome, type I. AB - A single case of trichorhinophalangeal syndrome, type I, is reported. The patient manifested the complete triad of the syndrome: thin, sparse, slow-growing scalp hairs; a pear-shaped nose; and cone-shaped epiphysis in some interphalangeal articulations of both hands. In addition, tooth decay, pectus carinatum, lumbar scoliosis, and polycystic ovary were observed. This multisystemic disorder is apparently rare, but its prevalence is probably underestimated in the dermatologic literature. PMID- 7851131 TI - Seborrheic keratoses of the areola. AB - A patient noted the appearance of a few asymptomatic lesions on both areolae eighteen months after delivery of her last son. Histologic examination showed typical seborrheic keratosis. A brief review of the differential diagnosis of skin problems of the nipple and the areola is provided. PMID- 7851132 TI - Lichenoid drug eruption: crystal methamphetamine or adulterants? AB - Many drugs have been reported to produce an eruption that is clinically and histologically indistinguishable from lichen planus. I report a case of lichenoid drug eruption occurring after crystal methamphetamine abuse. To my knowledge, this is the first report of an illicit drug causing a lichenoid drug eruption. PMID- 7851133 TI - Key child care and other federal programs for infants and toddlers. PMID- 7851134 TI - The extended families of people with disabilities. PMID- 7851135 TI - People with disabilities and their families know what's best. PMID- 7851136 TI - [Comments on the contribution by J.-A. Ruggeberg: Ambulatory breast surgery- irresponsible procedure?]. PMID- 7851137 TI - [Risk of infection caused by homologous blood transfusion]. AB - Compared with other nosocomial infections, transfusion-associated infectious risks are of minor relevance in the Federal Republic of Germany today. The actual spectrum of measures for an optimal degree of safety of blood components comprises a careful donor selection, highly sensitive and specific screening assays for viral parameters, inactivation and quarantine procedures for plasmatic preparations. Further possible improvements, both in the blood bank and clinical setting are discussed with regard to the inevitable residual risks of hemotherapy. PMID- 7851138 TI - [Preoperative autologous blood donation and disposition. Possibilities and prerequisites]. AB - Preoperative blood deposit can help to avoid the risks of homologous blood transfusions. However, it is necessary that prerequisites concerning medicine standard, organisation, technical questions and administrative aspects have to be fulfilled. PMID- 7851139 TI - [Blood-saving surgery]. AB - Trauma, blood loss and autologous blood transfusions induce a variety of changes in the reactivity of patients' immune systems. In clinical studies the differentiation of these effects is difficult. Association between autologous blood transfusion and postoperative infection is highly likely. In surgical oncology blood transfusions are associated with poor prognosis, but probably this is more because of the circumstances that necessitate them. PMID- 7851140 TI - [Artificial blood substitutes ]. AB - The most important function of blood is gas transport. In the attempt to replace this function, two lines of investigation were followed. Gas transport using of hemoglobin involves saturable physicochemical mechanisms. The affinity of human "stroma-free" hemoglobin for oxygen is too high, hampering the release of oxygen in tissue. The binding of oxygen to stroma-free hemoglobin can be improved by coupling of hemoglobin to pyridoxal phosphate. By cross-linking with, for example, dialdehydes (particularly glutaraldehyde) the production of hemoglobin molecules of higher molecular weight and greater stability is possible. However, first trials in humans using these preparations fall short of expectations. The stability of the polymers and of the preparations was not as good as expected. Another possibility is the use of water-insoluble fluorocarbons (perfluorocarbons), which have a high capacity for physical gas transport. The disadvantage of using emulsions of these substances is the necessity for high partial oxygen pressure to attain sufficient gas transport. The complete insolubility in water impedes the use of the metabolic inert fluorocarbons, because they can only be eliminated via the lungs. Despite these problems the fluorocarbons have been extensively used in humans. In the USA the use of some emulsions is allowed for special indications. Extended clinical use of fluorocarbons and of hemoglobin derivates cannot be expected in the near future. Substitution of the blood hydrocolloid albumin has been practiced for many years, synthetic hydrocolloids being used to replace the colloid osmotic pressure of albumin and also to decrease the blood viscosity by hemodilution and hence improve flow. In Germany hydroxyethyl starch (HES) is the most-used hydrocolloid with the least side effects. Anaphylactic reactions restrict the use of dextran, and gelatin derivatives, because of their short half-life, are not of clinical importance in Germany. Hydrocolloids with a half-life of 3-6 h (dextran 40, middle-substituted HES) are preferred, while those with a half-life of about 20 30 h (dextran 60/70, highly substituted HES) are infrequently used. PMID- 7851141 TI - [Limited radical approach in differentiated thyroid gland cancers. A prospective study of 107 patients]. AB - From 1979 until 1987 a prospective study about limited radical therapy of 107 patients with differentiated cancer of the thyroid was performed. Nearly all of the tumors were occult papillary or encapsulated papillary and follicular carcinomas. The thyroid was not completely resected. Postoperative therapy consisted in TSH-suppression. After a follow-up of 7.5 (5-12) years one patient had died because of the tumor disease. Four patients had to be reoperated for lymph node metastases and then stayed free of disease as all other patients. PMID- 7851142 TI - [Growth and invasion in differentiated thyroid carcinoma. Function of different growth factors]. AB - Aggressiveness of follicular (FTC) and papillary thyroid cancer (PTC) varies widely. Tumorigenesis is associated with an imbalance of growth-promoting and growth-constraining factors. We investigated the effects of thyrotropin (TSH), epidermal growth factor (EGF) and transforming growth factor beta 1 (TGF-beta 1) on invasion and growth of 3 FTC- and 2 PTC-cell lines. Invasion (penetration through an 8 microns pore membrane, covered by Matrigel) and growth were measured using the MTT-method. EGF (10 ng/ml) and TSH in low concentrations (1 mU/ml) stimulated invasion and growth of FTC and PTC, whereas TGF-beta 1 (10 ng/ml) and TSH in high concentrations (100 mU/ml) were inhibiting. The parental cell line FTC133 was considerably more responsive to all growth factors than the metastatic clones. Invasion of FTC133 was enhanced by 42% (EGF) and 21% (TSH), invasion of FTC236 by 8% (EGF and TSH). Conversely, invasion of FTC133 was inhibited by 32% (TGF-beta 1) and 21% (TSH), invasion of FTC236 by 18% (TGF-beta 1) and 11% (TSH). TSH, EGF and TGF-beta 1 have an important impact on differentiated thyroid cancer cells and metastases may have developed by escaping from the normal control of growth factors. PMID- 7851143 TI - [Combined interventions in heart and thyroid surgery--an example of interdisciplinary cooperation]. AB - The anatomic closeness of heart and thyroid gland makes it feasible to operate on both organs simultaneously if required. Between January 1988 and February 1994 we did simultaneous procedures on heart and thyroid gland in 14 patients. We did not see any procedure-specific complications. The cumulative risk of the combined operation seems to be less than in the two stage procedure, because of the better exposure of the thyroid. The main advantage for the patient is the avoidance of a second intervention. Because of the high frequency of thyroid diseases liable for operation endocrinological diagnostics should be performed in all patients undergoing cardiac surgery. The indication for a simultaneous intervention should be made generously in order to avoid a second operation. PMID- 7851144 TI - [Immunocytologic detection of disseminated tumor cells in the peritoneal cavity and bone marrow in patients with pancreatic carcinoma]. AB - Despite radical surgical treatment, the prognosis of patients with pancreatic cancer is poor. The success of surgical treatment is often limited due to local recurrence and especially the development of metastases and peritoneal carcinosis by cells which have been seeded already at the time of operation. Immunocytological methods enabled the detection of disseminated cancer cells before their clinical manifestation as demonstrated by this study. Lavage samples from the peritoneal cavity and bone marrow samples from 34 patients with an adenocarcinoma of the pancreas were investigated with a panel of six different monoclonal antibodies against tumor-associated antigens (CEA, CA-19-9, 17-1A, C 54-0, Ra96) and cytokeratin, respectively. Additionally, 43 patients with benign diseases were investigated as a control group. By this method, micrometastases were detected either in the bone marrow or the peritoneal cavity in 76% of pancreatic cancer patients. The occurrence of stained cells in the peritoneal cavity and bone marrow samples correlated with the tumor stage and showed even in early stages (I and II) a detection rate of 43% (bone marrow) and 33% (peritoneal cavity), respectively. No unspecific reactions were found in the control group. The 1-year follow-up shows a significant correlation between tumor cell detection and the survival (p = 0.03). Our study demonstrates that in most patients pancreatic cancer is a disseminated disease at time of diagnosis. It underlines the need for adjuvant postoperative therapy concepts. PMID- 7851145 TI - [Surgical treatment of tracheal injuries]. AB - Traumatic and iatrogenic injuries of the trachea are rare. In case of suspected rupture of the trachea a bronchoscopy remains the 'gold standard' of diagnostic procedures. The injuries should be repaired as soon as possible through a right thoracotomy or a collar incision using resorbable sutures. In case of small lesions a conservative treatment may be discussed. Overall the prognosis of tracheal injuries is good. PMID- 7851146 TI - [Conventional or laparoscopic cholecystectomy in treatment of acute cholecystitis?]. AB - Elective laparoscopic cholecystectomy has become established as the procedure of choice for the treatment of symptomatic cholecystolithiasis while the application of this method for acute cholecystitis has been propagated with restrainment. In a prospective study 114 conventional (right subcostal incision) and 102 laparoscopic cholecystectomies for this indication were compared. The overall complication rate amounted 10.7% for conventional cholecystectomy and 8.9% for laparoscopic cholecystectomy. The rate of conversion was 9.2%. Due to the fact that intraoperative cholangiography was carried out in 60% of conventional cholecystectomies and in only one of laparoscopic procedures the arithmetic advantage of minimally invasive technique with respect to blood loss and operating time does not allow final conclusions. These patients however recovered clearly faster and could be discharged after an average of 5.2 +/- 4.2 postoperative days, while the hospitalisation after conventional operations amounted to 7.6 +/- 3.8 days (p < 0.001). PMID- 7851147 TI - [Results of a prospective study of laparoscopic appendectomy]. AB - Laparoscopic appendicectomy for acute appendicitis is being increasingly criticized, because of the possible complications, the technical effort required and the high costs. The results of the present prospective study performed between May 1992 and March 1994 on 222 appendectomies (110 conventional and 112 laparoscopic) are intended to serve as a tentative guide. The use of endoscopic stapling and cutting devices, as well as the observance of exclusion criteria make laparoscopic appendicectomy a safe operation. It can be employed routinely and shows certain advantages for the patient e.g. fewer disturbances of wound healing and shorter postoperative hospitalization. Although laparoscopic appendicectomy has brought us valuable experience, it is by no means the method of choice and for the time being, it is unlikely to replace conventional appendicectomy. PMID- 7851148 TI - [Standardized combined pancreas and liver explantation]. AB - Maximum use of organs from a single donor is mandatory as a result of the current organ shortage. In combined liver and pancreas allograft retrieval, it is vital that one remember the variability in the anatomy of vessels. Based on our experience, we describe a new technique of dividing the celiac trunk horizontally with subsequent arterial reconstruction, depending on the anatomical situation. Vascular division of the grafts can be performed either in situ or in an ex situ fashion in cases where cardiovascular function has deteriorated. PMID- 7851149 TI - [Laparoscopic abdomino-perineal rectum excision with high dissection of the inferior mesenteric artery. Simplification by intraoperative ventral fixation of the rectosigmoid]. AB - Between July 1992 and September 1993, 8 patients with adenomcarcinoma of the rectum were treated by laparoscopic-assisted abdomino-perineal excision of the rectum. Using an awl, it was possible to ventrally retract the sigmacolon and fix it to the ventral abdominal wall, simplifying the dissection of the inferior mesenteric artery. PMID- 7851150 TI - [Endoscopic, extraperitoneal adrenalectomy]. AB - Between March and June 1994 three adrenalectomies were performed via an endoscopic extraperitoneal approach. After creating a carbon dioxide retropneumoperitoneum three 10 mm trocars were introduced in the area of conventional lumbar incision. Via these ports adrenalectomy was performed. Time of operation amount to 215, 290 and 330 min. No postoperative complications were observed. Time of postoperative hospitalisation amount to 3, 4 and 7 days. The advantage of the extraperitoneal approach is that it decreases postoperative pain and allows more rapid recovery. PMID- 7851151 TI - [Partial portal vein and mesenteric vein thrombosis in familial protein S deficiency]. AB - Protein S, a vitamin-K dependent glycoprotein is a cofactor of protein-C system, which acts as an inhibitor of the plasmatic coagulation. Protein-S congenital deficiency results in recurrent venous thromboses, atypical locations in portal and mesenteric veins are possible. In our patient the partial thrombosis of the portal vein was diagnosed by computed tomography and angiography. Small bowel ischaemia due to mesenteric vein thrombosis required segmental resection. Post operatively the patient was heparinized and later phenprocoumon was applied to a long-term therapy. PMID- 7851152 TI - [Todani type I choledochal cyst--diagnosis and surgical therapy]. AB - Ultrasound, ERC and computed tomography are the main preoperative diagnostic procedures of common bile duct cysts. In individual cases the definitive diagnosis can be confirmed only intraoperatively. The high rate of complications and the risk of carcinoma requires a radical surgical treatment. PMID- 7851153 TI - [Homologous blood transfusion in severely burned Jehovah's witnesses]. PMID- 7851154 TI - [Formulating decisions in surgery. Comments on the contributions by Lorenz et al. and Sitter et al]. PMID- 7851155 TI - [Rectal carcinoma 35 years after total proctocolectomy for ulcerative colitis]. PMID- 7851156 TI - Fully automatic chromosome segmentation. AB - This paper is concerned with automatic segmentation of high resolution digitized metaphases. This includes automatic detection and rejection of interphase nuclei, stain debris, and other "noise"; automatic detection and segmentation of touching and overlapping chromosome clusters; and automatic rejection of cells which are evaluated as being incomplete, or incorrectly segmented, or where the cell is otherwise unsuitable for further analysis. In this paper, a rule-based approach is described which treats the cell as a whole rather than as a series of individual chromosomes or clusters. The rules adapt classification and segmentation parameters for each cell. Initially, different sets of parameters are chosen according to the staining method of the cells, and the goal of the segmentation. A chromosome number predictor is used to guide the adaptation of the parameters and to estimate the performance. The adaptation is iterative, and the self-adjustment will stop when either a satisfactory result is achieved or if the cell is rejected. The method was implemented on both a Sun workstation and a Cytoscan, a commercial machine for chromosome analysis. Seven hundred and thirteen cells from real data have been tested. A success rate of 90-95% has been achieved. The procedure has been implemented in an automatic aberration scoring system for routine use. PMID- 7851157 TI - Simultaneous detection of beta-galactosidase activity and surface antigen expression in viable haematopoietic cells. AB - The quantitation of intracellular beta-galactosidase activity has been described for viable cells. By using the fluorogenic substrate fluorescein-di-beta-D galactopyranoside (FDG) in conjunction with flow cytometry, the proportion of positive cells as well as the level of expression can be determined. In this paper we describe beta-galactosidase expression in lymphoid and myeloid cells from transgenic mice that widely express beta-galactosidase from an inserted lacZ transgene. Both foetal and adult haematopoietic tissues are able to express beta galactosidase. The intracellular fluorescence reflecting beta-galactosidase activity can be readily combined with fluorescently labelled antibodies against cell surface antigens. Thus, beta-galactosidase can be used as a marker in transplantation experiments to study the development of lymphoid and myeloid precursor cells. PMID- 7851158 TI - Reliable method for the simultaneous detection of cytoplasmic and surface CD3 epsilon expression by murine lymphoid cells. AB - During their development, T-cell precursors (pre-T cells) undergo a variety of changes with respect to their expression of specific surface proteins. Among the most critical of the surface markers acquired by developing T cells is the T-cell receptor (TCR)/CD3 complex. Prior to the assembly and transport of complete TCR/CD3 multimeric complexes to the plasma membrane, the individual constituent subunits are expressed in the cytoplasm (ER-Golgi). In order to study the expression of the T-cell receptor TCR/CD3 complex during pre-thymic T-cell differentiation, we have developed a flow cytometric technique for the simultaneous detection of surface (sCD3 epsilon) and cytoplasmic CD3 epsilon (cCD3 epsilon). This technique, which employs fixation in 1% paraformaldehyde and permeabilization with 1% saponin and 0.025% digitonin, features reliable internalization and low nonspecific binding of anti-CD3 epsilon in murine lymphoid cells, as well as tissue culture cell lines. The combination of saponin and digitonin treatment was also compatible with the staining of sCD3 and other lymphocyte surface antigens such as Thy1, CD4, CD8, B220, and IgM. In contrast, permeabilization of cells with the detergents Tween 20 and Triton X-100 was shown to remove surface-bound anti-CD3 epsilon. The present technique permitted the detection of discernible sCD3 epsilon and cCD3 epsilon double and single positive lymphocytes and may prove useful in defining bone marrow-resident pre-T cells. PMID- 7851159 TI - Flow cytometric quantitation of C-myc and P53 proteins in bovine papillomavirus type 1-transformed primary mouse fibroblasts. AB - Bovine papillomavirus type 1 (BPV-1)-transformed mouse fibroblast cell lines were analyzed via flow cytometry (FCM) for expression of p53 and c-myc proteins along with their DNA content. In comparison to the nontransformed control cell line, significantly elevated levels of both the p53 and the c-myc protein were present in some but not all of the transformed cell lines. Quantitation of p53 and c-myc proteins in cell lines containing BPV-1 DNA revealed that the tumorigenic cell lines expressed higher levels of both the p53 (P = 0.0034; Mann-Whitney U test) and the c-myc protein (P = 0.0039; Mann-Whitney U test) as compared to the nontumorigenic cell lines. On average, at least 9,000-10,000 p53 or c-myc protein molecules per cell were detected in the transformed tumorigenic cell lines. These results show that quantitative FCM can be reliably used to detect very low levels (3,000 molecules per cell) of specific protein, and FCM is a useful tool to study the virus-induced changes in the levels of nuclear proteins within a cell population and in tumorigenesis. PMID- 7851160 TI - Methodologies for the preservation of proliferation associated antigens PCNA, p120, and p105 in tumor cell lines for use in flow cytometry. AB - The retention of antigen expression of PCNA, p120, and p105 in two tumor cell lines (MOLT-4 and MDA-MD-175-VII) under various conditions of fixation was investigated using flow cytometric analysis. Four currently utilized procedures for fixation/permeabilization of intracellular antigens were compared for their ability to stain the nuclear antigens. A procedure using a brief incubation in a solution of lysolecithin in paraformaldehyde followed by fixation in ice-cold methanol prior to antibody staining was selected to evaluate reagent protocols aimed at preserving antigen expression. Holding samples overnight at 4 degrees C in 2.5% fetal bovine serum after the lysolecithin/paraformaldehyde and methanol fixation steps prior to staining with monoclonal antibodies resulted in no decline in the percentage of cells positively stained for all three markers with little decrease in intensity of fluorescence and no increase in DNA coefficient of variation (c.v.). Fixed/permeabilized MOLT-4 cells held longer than 24 h before staining were lower in PCNA fluorescence than freshly stained cells; holding samples of either cell line longer than 48 h resulted in decreased PCNA and p120 staining. Prefixing and holding cells in 50% methanol or 50% ethanol overnight before processing and staining severely depressed PCNA and p120 fluorescence. Prefixing either cell line in a range of concentrations (0.25-1.0%) of paraformaldehyde also resulted in reduced intensity of PCNA and p120 fluorescence along with increased DNA c.v. P105 staining appeared to be relatively unaffected by all prefixation/storage conditions tested, except for a decline of fluorescence when MDA cells were prefixed in 50% ethanol. Cells cryopreserved in liquid nitrogen for 1 week before processing showed < 5% loss of PCNA and p120 fluorescence compared to freshly processed cells, but p105 fluorescence dropped 29% in cryopreserved MDA cells. These results underscore the fact that specific protocols for the fixation and storage of biological samples prior to staining and analysis must be determined for the specific nuclear antigen marker under investigation. PMID- 7851161 TI - Comparative flow cytometric analysis of Ki-67 and proliferating cell nuclear antigen (PCNA) in solid neoplasms. AB - The proliferation associated antigens, Ki-67 and proliferating-cell nuclear antigen (PCNA), have been widely used in studies assessing the growth fraction in human malignancies. It remains unclear, however, whether these markers yield similar assessments of proliferative activity in any given neoplasm. In this study, we compared Ki-67 and PCNA expression in 93 malignant solid neoplasms using bivariate flow cytometric analysis of these antigens and DNA content. The growth fractions measured by Ki-67 and PCNA were compared and correlated with acridine orange (AO) analysis and tumor grade. Our results indicate a significant difference between Ki-67 and PCNA values in neoplasms of low and intermediate grade (P = 0.002); Ki-67 values were significantly lower than those obtained by PCNA in this group. No statistical difference between Ki-67 and PCNA values was found in high grade neoplasms (P = 0.38). Analysis of different cell cycle compartments indicates that the observed difference in the positivity of these markers was due to their differential expression in the G0/1 segment of the cell cycle. We conclude that Ki-67 may better reflect the proliferative activity in solid neoplasms than does PCNA. PMID- 7851162 TI - A knowledge-based system for the interpretation of flow cytometry data in leukemias and lymphomas. AB - Flow cytometry immunophenotyping and analysis of DNA ploidy and proliferative activity have become extremely helpful techniques for diagnosing and subclassifying hematopoietic cell populations in a modern, full-service hematopathology laboratory. The number of physicians with special training in the interpretation of these studies is limited. A knowledge-based computer system has been designed to aid in the interpretation of immunophenotyping and DNA flow cytometry results in hematopoietic disease. The system, known as "Professor Fidelio," is a heuristic classification system that reasons on the basis of defined diagnostic patterns. In this study, Fidelio was tested as a stand-alone system on 366 specimens from two large tertiary medical centers. Fidelio's interpretation was considered to be appropriate in all cases. In 300 of 366 (82%) specimens, the system's interpretation agreed with the diagnosis of record. Many of the disagreements could be traced to errors in the recording of the original diagnosis and minor differences in diagnostic criteria between Fidelio's knowledge base and the criteria in use at the medical centers. When used in a stand-alone mode, Fidelio's interpretation was less specific than the diagnosis of record in certain lymphoproliferative disorders that require morphologic information for subclassification. Professor Fidelio is one module in a workstation for the diagnostic hematology laboratory. This workstation is designed for interpretive reporting, education, and database functions for clinical research. Clinical and morphologic information are shared between Fidelio and the other modules for peripheral blood analysis, bone marrow morphology, and lymph node interpretation by means of a relational database. The system will be useful in hospitals that lack individuals specially trained in flow cytometry.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7851163 TI - Development of a method for measuring cell number: application to CNS primary neuronal cultures. AB - In the present work we further develop a method for counting cell number that is totally independent from the permeability or uptake conditions of the cells, from the state of activation of intracellular enzymes, and from cellular metabolism. We provide a visual characterization of the method and show that it is highly suitable for cells not growing as monolayers as well as for cultures containing numerous aggregates. We also extend the applicability of this method to CNS primary neuronal cultures and show its direct comparison with alternative means for cellular quantification. The technique is fast, does not require tedious procedures or long washes, and offers advantages such as a high sensitivity and no background. PMID- 7851164 TI - Management of perianal Crohn's disease. Results of a multicenter study in Italy. AB - PURPOSE: Management of perianal Crohn's disease is still controversial, and reports on large series are very few in the literature. The aim of this multicenter study was to investigate the outcome of both medical and surgical treatment in 225 patients. METHODS: Patients cared for at different institutions were followed up for a median of six years. Most of them had either anal fistula or an abscess (86 percent and 43 percent, respectively), but fissures were also present in 26 percent of the cases. Diarrhea and anal pain were the most common symptoms. Anal lesions preceded the onset of intestinal symptoms in 19 percent of cases. RESULTS: Medical treatment was curative only in 21 of 123 patients. Overall, medical and surgical treatment either cured or improved 62 percent of the cases. Fifty percent had an intestinal resection. Abscess drainage and fistulotomy were the most common anal surgeries. Rectovaginal fistulas (n = 30) required intestinal surgery in 36 percent and anal surgery in 20 percent of the cases, 50 percent with good results. Of 166 patients who had anal surgery, 97 (58 percent) had a positive outcome. Recurrence of anal disease requiring further surgery occurred in 24.5 percent of the cases. CONCLUSIONS: Limited surgeries seem to achieve satisfactory results in more than one-half of the patients affected by perianal Crohn's lesions, whereas medical treatment alone is curative in a small portion of them. PMID- 7851165 TI - Practice parameters for sigmoid diverticulitis. The Standards Task Force American Society of Colon and Rectal Surgeons. AB - It should be recognized that these guidelines should not be deemed inclusive of all proper methods of care or exclusive of methods of care reasonably directed to obtaining the same results. The ultimate judgment regarding the propriety of any specific procedure must be made by the physician in light of all of the circumstances presented by the individual patient. PMID- 7851166 TI - Randomized trial to determine the optimum level of pouch-anal anastomosis in stapled restorative proctocolectomy. AB - PURPOSE: This study was undertaken to identify the optimum level of stapled ileal pouch-anal anastomosis. METHOD: A prospective, randomized trial was completed to compare double-stapled ileoanal anastomosis placed at the top of anal columns (high, n = 26) with anastomosis at the dentate line (low, n = 21). RESULTS: There was no significant difference in the overall complication rate between operations (high, n = 7, vs. low, n = 8; P < 0.21). Pouch-anal functional score (scale 0-12; 0 = excellent, 12 = poor) was significantly better in the high anastomosis group (median (range): 2 (1-9) vs. 5.5 (1-12); P < 0.05). Incontinence occurred in only two patients randomized to high anastomosis compared with six in the low anastomosis group. Nocturnal soiling was reported in three patients after high anastomosis and in six patients after dentate line anastomosis. Both operations caused a significant but comparable reduction of maximum and resting pressure (31 percent after high anastomosis (P < 0.05); 23 percent after low anastomosis (P < 0.05)). However, a significant fall in functional length of the anal canal was only seen after a low pouch-anal anastomosis (P < 0.05). CONCLUSION: Stapled pouch-anal anastomosis at the top of anal columns gives better functional results compared with a stapled anastomosis at the dentate line. PMID- 7851167 TI - Effect of cisapride on distal colonic motility in the early postoperative period following left colonic anastomosis. AB - PURPOSE: This study was designed to investigate the modulatory effect of cisapride on colonic motility in the postoperative period. METHODS: A prospective, double-blind, randomized, placebo-controlled trial of 14 patients undergoing left colonic anastomosis was carried out. Manometric probes were positioned with transducers on either side of the anastomosis, and colonic activity was recorded continuously for a median of 98 (range, 72-144) hours using an ambulatory system. Quantitative indices of motility were calculated with an automated analysis program. RESULTS: Isolated waveform activity returned at a median of 1.8 (interquartile range, 1-3) hours and motor complex activity at 24 (interquartile range, 19-30) hours in the placebo group and at similar times in the cisapride group. All motility variables except mean amplitude increased significantly with time in both groups. In the cisapride group the motility index was significantly increased compared with the placebo group (P = 0.03), resulting from an increase in percentage duration of activity (P = 0.002). Activity index, mean amplitude of waveforms, and number of waves greater than 50 cm H2O did not differ between groups. In contrast to placebo, cisapride significantly increased the median number of waves greater than 13 cm H2O and percentage duration of activity distal to the anastomosis compared with proximally. The return of bowel sounds (median, 43, interquartile range, 24-48 hours vs. 67, 29-69 hours; P = 0.2) or first passage of flatus (78, 54-94 hours vs. 94, 81-105 hours; P = 0.1) did not differ between groups. CONCLUSIONS: Although cisapride may have a differential effect on the colon proximal and distal to an anastomosis and significantly increases some indices of motility in the early postoperative period, these are unlikely to be of any clinical relevance. PMID- 7851168 TI - Anorectal melanoma. A 64-year experience at Memorial Sloan-Kettering Cancer Center. AB - PURPOSE: Operative management of patients with anorectal melanoma is controversial. To formulate a rational approach to patients with this disease, we reviewed our experience from 1929 to 1993. METHODS: Records of all patients treated at our center with anorectal melanoma from 1929 to the present were reviewed. Survival analyses were graphically displayed using the Kaplan-Meier product-limit method, and distributions were compared using the log-rank test. Fisher's exact test was used to compare groups with small sample sizes. RESULTS: Survival for the entire group (n = 85) was poor, 17 percent at 5 years (median, 19 months). Among the 71 patients with resectable disease, the five-year, disease free survival distribution of patients who underwent abdominoperineal resection (APR) was more favorable than that of patients who underwent local procedures only, although this was not statistically significant (27 percent vs. 5 percent, APR vs. local procedures, respectively; P = 0.11). However, those who had an APR were more likely to survive long term than those who did not (P < 0.05). All ten long-term survivors were women. Nine had undergone APR, and one had a wide local excision. Of the nine survivors following APR, eight had negative and one had positive mesenteric nodes. Median size of the primary tumor in survivors following APR was 2.5 cm, compared with 4.0 cm for patients who did not survive long term following APR. CONCLUSIONS: APR should be considered in patients with localized anorectal melanoma, particularly those with smaller tumors and no evidence of nodal metastases. PMID- 7851169 TI - Adjuvant radiotherapy and anastomosis in rectal cancer--disturbing evidence from animal studies. AB - PURPOSE: Adjuvant radiotherapy is used increasingly in the management of rectal cancer. However, ionizing radiation is mutagenic, and, superimposed on a background of increased cellular proliferation as seen around anastomoses and in colorectal cancer patients, there is the potential for enhanced metachronous cancer risk. METHOD: The influence of preoperative irradiation on both carcinogenesis and cellular proliferation at colonic anastomoses was explored in 180 adult male F344 rats. Orthovoltage x-rays were delivered to the distal descending colon by parallel opposed fields. Ninety rats received 16 Gy in one fraction; the remainder received 36 Gy in two fractions one week apart. In each irradiation group 18 rats either acted as controls or one week after radiotherapy underwent distal colotomy and repair. RESULTS: We found the descending colon susceptible to radiation carcinogenesis; 26 colorectal tumors developed in the low-dose irradiation group and 47 in the high-dose group (P = 0.0008; Mann Whitney U test, 16 vs. 36 Gy). Preferential tumor development was seen in the anastomotic region. In those animals that underwent surgery and irradiation, among the low-dose irradiation group only 3 of 72 had tumors within the descending colon compared with 21 of 72 at the anastomotic site (McNemar's test chi-squared = 40.9; P < 0.001), and in the high-dose irradiation group 5 of 72 had tumors within the descending colon compared with 36 of 72 at the anastomotic site (McNemar's test chi-squared = 22.0; P < 0.001). Anastomotic crypt cell production rates were increased for at least three months following exposure to irradiation (16 Gy: f = 15.1, P < 0.005; 32 Gy: f = 9.4, P < 0.005). CONCLUSIONS: Radiation carcinogenesis is greatly enhanced at colonic anastomoses and may result from altered anastomotic proliferation. This has potentially disturbing implications in view of the increasing use of adjuvant radiotherapy for rectal carcinoma. PMID- 7851170 TI - Ileal pouch-anal anastomosis function following childbirth. An extended evaluation. AB - PURPOSE: Women undergoing ileal pouch-anal anastomosis (IPAA) are frequently within reproductive years and eager to bear children. Management issues have been raised regarding the effects of pregnancy and delivery on the pouch, particularly with respect to obstetric care. Our experience is updated to search for delayed sequelae of pregnancy and delivery and to establish whether other factors have an adverse effect on pouch function. These results are also compared with the outcome of pregnancy and delivery in patients with ileostomy or Kock pouch. METHODS: Records of 43 women who had a successful pregnancy and delivery following IPAA were reviewed, including 8 women who had more than 1 pregnancy. RESULTS: Pregnancy was generally well tolerated, with complications being managed nonoperatively. Stool frequency (P < 0.01), incontinence (P < 0.01), and pad usage (P < 0.05; sign rank test) were significantly increased during pregnancy, but prepregnancy function was restored following delivery. Vaginal delivery, multiple births, length of labor, and birth weight had no adverse permanent effect on subsequent pouch function. Longer follow-up after vaginal delivery (mean, 2.4 years) demonstrated no compromise of pouch function. CONCLUSIONS: Incidence of pouch-related complications in patients with IPAA compares favorably with incidence in patients with ileostomy or Kock pouch. Operative rate for complications was 0 percent in IPAA patients compared with 9 percent in patients with ileostomy and 19 percent in patients with Kock pouch. The cesarean section rate was higher in patients with IPAA than in those with ileostomy or Kock pouch, and this may be caused by uncertainty about how to manage delivery in patients with IPAA. Pregnancy and childbirth are well tolerated in women with IPAA, with a lower complication rate and a higher cesarean section rate than women with ileostomy or Kock pouch. Type of delivery should be influenced by obstetric considerations, with vaginal delivery avoided in patients with a noncompliant, rigid perineum. PMID- 7851171 TI - Pudendal neuropathy in evacuatory disorders. AB - PURPOSE: Aims of the present study were to assess frequency of pudendal neuropathy in patients with constipation and fecal incontinence, to determine its correlation with clinical variables, anal electromyographic assessment, and anal manometric pressures, and to determine usefulness of the pudendal nerve terminal motor latency assessment in evaluation of these evacuatory disorders. METHODS: From 1988 to 1993, 395 patients (constipated, 172; incontinent, 223) underwent pudendal nerve terminal motor latency, electromyography, and anal manometry. Pudendal neuropathy was defined as a pudendal nerve terminal motor latency greater than 2.2 ms. RESULTS: Patients were a mean age of 60.7 (range, 17-88) years. Overall incidence of pudendal neuropathy was 31.4 percent (constipated, 23.8 percent; incontinent, 37.2 percent; P < 0.05). Incidence of pudendal neuropathy dramatically increased after 70 years of age in both groups (22 percent vs. 44 percent; P < 0.05). Moreover, subjects with pudendal neuropathy were older than those without pudendal neuropathy (mean age, 67 vs. 57 years; P < 0.05). The presence of pudendal neuropathy was associated with decreased motor unit potentials recruitment in patients with incontinence (P < 0.01). Patients with and without pudendal neuropathy had a similar mean squeezing pressure in both groups. CONCLUSION: Pudendal neuropathy is an age-related phenomenon. Although pudendal neuropathy is associated with abnormal anal electromyographic findings in patients with incontinence, no association with anal manometric pressures was found. Pudendal nerve terminal motor latency assessment is a useful tool in the evaluation of patients with fecal incontinence, but its role in the assessment of constipated patients remains unknown. PMID- 7851172 TI - Serum gastrin levels and colorectal neoplasia. AB - PURPOSE: Confirmation of an association between elevated serum gastrin concentrations and presence of colorectal tumors would have important implications with regard to screening procedures and therapeutic strategies. METHODS: We compared fasting serum gastrin concentrations of patients with colorectal cancer (n = 91; mean age, 66 (range, 35-87) years), colorectal polyps (n = 89; mean age, 61 (range, 38-86) years), or a normal colonoscopy (n = 101; mean age, 62 (range, 34-82) years) in the period between 1983 and 1992. RESULTS: Median serum gastrin concentrations were, respectively, 20, 20, and 21 pmol/liter (not significant). We were unable to find a relation with histology of the polyp, presence or severity of dysplasia, and extent of cancer. CONCLUSIONS: This large study fails to show any difference in serum gastrin concentrations among the three studied groups. PMID- 7851173 TI - Immediate vs. salvage resection after local treatment for early rectal cancer. AB - PURPOSE: There is an increasing awareness of local procedures to treat early stage rectal cancer. Abdominoperineal resection (APR) or low anterior resection (LAR) has been recommended if adverse pathologic findings are encountered in the local excision specimen. No data compare the impact on survival of "immediate" resection for adverse features vs. "salvage" resection for clinical recurrence. METHODS: We reviewed retrospectively 155 patients who underwent initial curative treatment of invasive rectal cancer by excision (91), snare-cautery (44), and fulguration (20). RESULTS: Twenty-one patients underwent APR/LAR immediately after initial local treatment, whereas another 21 patients underwent salvage APR/LAR for local recurrence. The disease-free survival after APR/LAR was 94.1 percent for the immediate group and 55.5 percent for the delayed group (P < 0.05). CONCLUSION: This decreased survival observed after delayed resection supports the recommendation for immediate APR/LAR when adverse pathologic features are present in the excision specimen. PMID- 7851174 TI - Assessment of peripouch inflammation after ileoanal anastomosis using endoluminal ultrasonography. AB - PURPOSE: This study was designed to assess the impact of endoluminal transpouch ultrasonography in the investigation and management of inflammatory complications of pelvic pouches and to compare endoluminal transpouch ultrasonography to pouchography and computerized axial tomograph scanning. METHODS: A prospective evaluation was made of the presentation, investigation, treatment, and clinical outcome of 16 patients referred for endoluminal transpouch ultrasonography with dysfunctional pelvic pouches and no evidence of pouchitis on endoscopy. RESULTS: There were 5 normal and 11 abnormal examinations. Six patients had peripouch inflammatory phlegmons, four patients had peripouch abscesses, and one patient had a rectovaginal fistula. A total of nine patients had anastomotic leaks detected. Two patients had abscesses drained under ultrasound guidance and a pigtail catheter left in situ. Pouchography detected only 3 of 8 (38 percent) anastomotic leaks detected by endoluminal transpouch ultrasonography. Computerized axial tomograph scan detected 2 of 5 (40 percent) peripouch abscesses or phlegmon detected by endoluminal transpouch ultrasonography. Patients with peripouch sepsis had significantly thicker anal wall thickness (23.8 vs. 16.8 mm; P < 0.02) and external sphincter thickness (9.1 vs. 7.3 mm; P < 0.05) than pouches with no sepsis. CONCLUSIONS: Endoluminal transpouch ultrasonography appears to detect anastomotic leaks and peripouch sepsis and may guide the initial management of patients with dysfunctional pelvic pouches and an inconclusive clinical and endoscopic examination. PMID- 7851175 TI - Restorative proctocolectomy without diverting ileostomy. AB - PURPOSE: Restorative proctocolectomy (RPC) by abdominal colectomy and ileal pouch anal anastomosis (IPAA) in the setting of chronic ulcerative colitis (CUC) and familial adenomatous polyposis (FAP) has gained widespread popularity among surgeons and patients. Traditionally, temporary loop ileostomy has been established proximal to the ileal pouch in an effort to mitigate the effects of any suture line complications that may occur. This study compares functional results and complications encountered after RPC with mucosectomy with and without temporary ileostomy. METHODS: One hundred forty-three consecutive patients with either CUC or FAP underwent RPC including mucosectomy and ileal "J" reservoir. Proximal loop ileostomy was performed in 69 patients, and ileostomy was omitted in 74. Ileostomy was omitted if the patient was taking no immunosuppressives and less than 20 mg of prednisone daily in the month preceding surgery, the anastomosis was absolutely tension-free, and blood supply to the pouch was excellent. RESULTS: There were no perioperative deaths. There were two instances of pelvic abscess, one in the diverted group and one in the nondiverted group. Occurrence of IPAA suture line dehiscence was not significantly different between the two groups (ileostomy, 4/69 (6 percent), vs. no ileostomy, 6/74 (8 percent); P > 0.05). Comparison of 129 patients with colitis with and without diversion also failed to demonstrate a significant difference with regard to IPAA suture line dehiscence (ileostomy, 4/69 (6 percent) vs. 4/60 (7 percent); P > 0.05). Frequency of bowel movements and continence were the same in both groups and were comparable with results obtained without mucosectomy. Mean hospital stay at time of RPC for the nondiverted group was significantly longer (12 days vs. 10 days; P = 0.0004). Significantly fewer patients without an ileostomy were hospitalized for partial intestinal obstruction (ileostomy, 13/69 (19 percent), vs. no ileostomy, 3/74 (4 percent); P = 0.02), and significantly fewer required enterolysis (ileostomy, 7/69 (10 percent), vs. no ileostomy, 1/74 (1 percent); P = 0.04). On average, patients without an ileostomy spent significantly fewer total days in the hospital (17 vs. 24; P = 0.002). CONCLUSION: Restorative proctocolectomy with mucosectomy and without ileostomy is the procedure of choice for selected patients with FAP and CUC. Septic complications and functional results are similar to those seen in patients managed with a stoma. Anastomotic leakage, when it occurs, can be safely managed in most cases without surgery. RPC without ileostomy results in significantly fewer episodes of intestinal obstruction, fewer instances of re-exploration, and fewer total days in the hospital. PMID- 7851176 TI - Observer variability in the assessment of type and dysplasia of colorectal adenomas, analyzed using kappa statistics. AB - PURPOSE: The aim of this study was to establish the intraobserver and interobserver variability in the assessment of histologic type (tubular, villous, and tubulovillous) and grade of cytologic dysplasia (mild, moderate, and severe) in colorectal adenomas. METHODS: One hundred eighty-seven slides of adenomas were assessed twice by three experienced pathologists, with an interval of two months. Results were analyzed using kappa statistics. RESULTS: For agreement between first and second assessment (both type and grade of dysplasia), kappa values for the three specialists were 0.5345, 0.9022, and 0.4100, respectively. Agreement was better for type than for dysplasia. The strength of agreement was moderate for Observers A and C and almost perfect for Observer B. Agreement between all three observers was seen in 35.2 percent for both type and dysplasia in 61 percent for type and in 47.8 percent for dysplasia. The kappa values for Observer A vs. B and Observer C vs. B were 0.3480 and 0.3770, respectively (both type and dysplasia). Values for type were better than for dysplasia, but agreement was only fair to moderate. CONCLUSION: The interobserver agreement was moderate to almost perfect, but the intraobserver agreement was only fair to moderate. A simpler classification system or a centralization of assessments would probably increase kappa values. PMID- 7851177 TI - Laparoscopic-assisted vs. open resection. Rectopexy offers excellent results. AB - PURPOSE: Anterior resection +/- rectopexy effectively manages full-thickness rectal prolapse; however, morbidity is approximately 15 percent mainly because of the laparotomy wound. There has been no comparison of laparoscopic with laparotomy approaches to the repair of this disorder. The purpose of this paper is to compare an age/sex-matched series of laparoscopic-assisted (n = 8) with laparotomy (n = 10) resections/rectopexies. METHODS: A retrospective case review of laparoscopic-assisted (n = 8) vs. laparotomy (n = 10) resections/rectopexies from May 1989 to September 1993 was performed. Data collected included age, gender, technique, operative blood loss, operative time, length of bowel resected, length of hospital stay, return of bowel function, oral intake, and postoperative complications. RESULTS: No significant difference was noted in age, sex, length of bowel resected, mortality, significant morbidity, or recurrence (mean follow-up, 27.1 +/- 4.4 months) in either group. Estimated blood loss for the laparotomy group was greater than for the laparoscopic group (285.0 +/- 35.0 vs. 184.4 +/- 31.0 ml). Operative time was greater for the laparoscopic group (177.1 +/- 23.0 vs. 86.5 +/- 8.6 min). Length of stay (95.0 +/- 16.7 vs. 183.5 +/ 8.9 hours), time to passage of flatus (3.9 +/- 1.1 vs. 2.8 +/- 1.9 days), and resumption of oral intake (4.5 +/- 0.7 vs. 2.8 +/- 1.9 days) occurred earlier for the laparoscopic group. CONCLUSION: Therefore, laparoscopic-assisted resection/rectopexy effectively treats rectal prolapse without the morbidity of the laparotomy wound and significantly shortens hospitalization for this benign disease. PMID- 7851178 TI - Blood flow in colon anastomotic stricture formation. AB - PURPOSE: The influence of both blood flow and anastomotic technique on the development of anastomotic stricture formation was studied using a dog model. METHODS: Fifty-three dogs underwent distal colocolonic anastomosis with either an EEA (U.S. Surgical Corp., Norwalk, CT) circular stapler or a Czerny-Lembert two layered, handsewn anastomosis. Blood flow was measured by Laser Doppler Velocimetry using the Laserflo BPM2 (Vasamedics Inc., St. Paul, MN). The animals were separated into three blood flow groups: greater than or equal to 62.5 percent of normal blood flow, between 37.5 percent and 62.5 percent of normal blood flow, and less than or equal to 37.5 percent of normal blood flow. Each blood flow group had an anastomosis performed by either stapling or by hand sewing techniques. At six weeks, the anastomoses were opened longitudinally and fixed to determine the anastomotic index (AI). AI is defined as two times the anastomotic circumference over the proximal circumference plus the distal circumference. Blood flow groups and anastomotic technique groups were compared with an interaction variable for the outcome, AI using a two-way analysis of variance. RESULTS: The AI of the stapled anastomoses was found to be significantly higher than handsewn anastomoses (P < 0.006). There was no difference in AI between different blood flow groups and no correlation of observed histologic findings with AI. CONCLUSION: Clinically relevant ischemia does not directly influence stricture formation in either handsewn or stapled distal colonic anastomoses. PMID- 7851179 TI - Risk of residual rectal mucosa after proctocolectomy and ileal pouch-anal reconstruction with the double-stapling technique. Postoperative endoscopic follow-up study. AB - PURPOSE: This study was designed to assess the risk of retained rectal mucosa after proctocolectomy and ileal pouch-anal anastomosis with the double-stapling technique. METHODS: A total of 113 patients underwent proctocolectomy with an ileal pouch-anal reconstruction. In 57 patients the anastomosis between pouch and proximal anal canal was performed using the double-stapling technique. In 26 patients the procedure was carried out without a protecting ileostomy. Of the remaining 31 patients with a proximal ileostomy, 15 underwent endoscopy six weeks postoperatively. Circular biopsies were taken just distal from the pouch-anal anastomosis. RESULTS: Histologic examination revealed rectal mucosa in at least one biopsy in 7 of 15 patients. At follow-up (mean 18 months) no (distal) pouchitis was clinically noticed. In one patient with familial polyposis, a few polyps, distal of the anastomosis, had to be endoscopically removed. CONCLUSIONS: Double-stapled ileal pouch-anal anastomosis has a considerable risk of residual rectal mucosa, because of combined linear transection and circular stapling with bilateral dog-ear formation of rectal mucosa. Residual rectal mucosa did not seem to influence clinical results at follow-up. PMID- 7851180 TI - Laparoscopic suture rectopexy. AB - PURPOSE: This article describes a technique for laparoscopic suture rectopexy and assesses the postoperative results. METHODS: The rectum was fixed to the presacral fascia with five to six sutures. The procedure was performed using a laparoscope in four patients. RESULTS: There were no postoperative complications. In one patient a large enterocele was observed during the operation. This patient developed a recurrence about one month postoperatively. CONCLUSION: Laparoscopic suture rectopexy might be an alternative to open rectopexy for patients with isolated rectal prolapse. PMID- 7851181 TI - Enhancing cosmesis in laparoscopic colon and rectal surgery. AB - PURPOSE: The only unanimously accepted advantage of laparoscopic colon and rectal surgery, at present, is cosmesis. Techniques to enhance cosmesis in laparoscopic surgery are presented. METHOD: Careful and meticulous placement of laparoscopic ports and incisions enhance the cosmetic effect of the procedure. Determination of port sites is aided, in part, by preoperative assessment of natural skin folds and creases by a stomatherapist. Intraoperative techniques include placement of ports directly through the umbilicus, previous incisions, and natural skin folds and creases. RESULTS: These techniques have been practiced with no complications or added morbidity. Safety and good access during the procedure is not compromised. The cosmetic effect in laparoscopic surgery is enhanced. CONCLUSION: Techniques to enhance cosmesis in laparoscopic surgery can be practiced safely and efficiently. Surgeons should make an effort to focus on this benefit, when possible. PMID- 7851182 TI - Anal sphincteroplasty for incontinence after ileal pouch-anal anastomosis. Report of two cases. AB - PURPOSE: This report reviews two patients who underwent anal sphincteroplasty to improve continence after ileal pouch-anal anastomosis (IPAA). METHODS: A retrospective study of two patients was performed. RESULTS: Two patients underwent anal sphincteroplasty after IPAA for incontinence, one diagnosed preoperatively and one postoperatively. Both had had previous anal surgery. Satisfactory continence was achieved in both cases, despite modest changes in manometric studies. CONCLUSION: Anal sphincteroplasty should be considered after IPAA. The value of anorectal manometry in this situation is equivocal. PMID- 7851183 TI - Posttraumatic colonic polyps with skin heterotopia. Report of a case. AB - A case of posttraumatic colonic polyps with skin heterotopia is reported. A 35 year-old man was the victim of a grenade explosion, which caused evisceration and partial amputation of the right colon. Twenty-five months after the accident, hypochromic anemia developed because of three polyps in the ascending colon. Histology documented the presence of sebaceous glands and keratinized epithelium, suggesting a graft of skin fragments on the colonic mucosa. Such a skin heterotopia has never been reported. PMID- 7851184 TI - Human proximal duodenal ion and water transport. Role of enteric nervous system and carbonic anhydrase. AB - Intestinal ion transport is mediated by the interaction of enterocyte function, the enteric nervous system, humoral agents, and mucosal production of carbonic anhydrase. Our purpose was to examine the effect of the carbonic anhydrase inhibitor acetazolamide and inhibition of the enteric nervous system with the topical anesthetic lidocaine on basal and prostaglandin E2-stimulated ion and water transport and transmucosal electrical potential difference. At rest, mean basal (95% confidence intervals) net ion secretion into the human proximal duodenum was: Cl- 670 (288-1052), Na+ 818 (410-1225), K+ 32 (14-51) mumol/cm/hr. Basal net water transport was 30 (14.6-45.3) ml/hr, and the potential difference (PD) was 7.0 (3.6-10.9) mV, lumen negative. Intraluminal prostaglandin E2 increased the secretion of all ions, water, and the PD. After pretreatment with acetazolamide and luminal administration of lidocaine, basal ion transport was unchanged, but the response to luminal PGE2 was inhibited. It is concluded that: (1) at rest there is a net secretion of Na+, K+, Cl-, and water by the human proximal duodenum; and (2) PGE2-stimulated water electrolyte secretion is dependent in part upon mucosal carbonic anhydrase activity and the enteric nervous system. PMID- 7851185 TI - Effect of repeated boluses of intravenous omeprazole and primed infusions of ranitidine on 24-hour intragastric pH in healthy human subjects. AB - The aim of this study was to identify dosage regimens using intravenous omeprazole and ranitidine that would elevate and consistently maintain intragastric pH > 6 in the first 24 hr of therapy. In 19 healthy, fasting human subjects using continuous 24-hr gastric pH-metry, we studied two dosages of primed infusions of ranitidine (50 mg bolus followed by infusion of either 3 or 6 mg/kg body wt/24 hr) and six regimens of intravenous omeprazole (80-200 mg in 24 hr in two to five boluses). Only the two ranitidine infusions and high doses of omeprazole (> or = 160 mg/day as four or five boluses) raised the intragastric median pH above 5.4. There was no significant difference in the median intragastric pH after high dose ranitidine and high doses of omeprazole. Considerable interindividual variation in intragastric pH was observed after omeprazole therapy. The percentage of intragastric pH > 6.0 during the 24-hr study was lower after omeprazole (35-42%) than after high-dose ranitidine (58%). We conclude that it is possible to raise intragastric pH > 6.0 by use of either primed ranitidine infusion or by repeated boluses of omeprazole. However, maintenance of this high pH in the first 24 hr is difficult with both, more so with omeprazole. PMID- 7851186 TI - Increased mortality of acute upper gastrointestinal bleeding in patients with chronic obstructive pulmonary disease. A case controlled, multiyear study of 53 consecutive patients. AB - The etiology, clinical presentation, and mortality of acute upper gastrointestinal bleeding in patients with chronic obstructive pulmonary disease (COPD) were analyzed in a case-controlled study of 53 consecutive patients admitted from 1985 through 1990 to a university teaching hospital. The primary controls were 40 consecutive patients with acute upper gastrointestinal bleeding and without COPD admitted from June through November 1990 to the same hospital. COPD patients had a significantly increased mortality from gastrointestinal bleeding as compared to controls with gastrointestinal bleeding and without COPD (mortality in COPD = 32%, controls = 10%, odds ratio = 4.3, confidence interval of odds ratio = 1.22-14.8, P < 0.01, Fisher's exact test) and as compared to a second control group of 53 consecutive COPD patients without gastrointestinal bleeding (mortality in second controls = 11%, odds ratio = 3.7, confidence interval of odds ratio = 1.25-11.0, P < 0.02, chi square). The study COPD patients had a significantly greater likelihood of being older, smokers, alcoholics, and taking corticosteroids than the primary controls. However, an increased mortality was still present when controlling for these differences by population stratification (eg, mortality in patients > or = 60 years old: COPD = 36%, controls = 13%, odds ratio = 4.6, P < 0.05). The two groups had similar mean values of parameters of bleeding severity, such as lowest hematocrit and units of packed erythrocytes transfused. The increased mortality was correlated with COPD severity (eg, four of five patients with prior endotracheal intubation for COPD died, 13 of 48 COPD patients without prior intubation died, odds ratio = 10, P < 0.04, Fisher's exact test).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7851187 TI - Regional distribution of transforming growth factor-alpha and epidermal growth factor in normal and portal hypertensive gastric mucosa in humans. AB - This study was designed to evaluate the concentration and the regional distribution of TGF-alpha and EGF in normal and portal hypertensive human gastric mucosa. To this end we measured by RIA the gastric and duodenal concentration of TGF-alpha and EGF in subjects with chronic hepatitis, who had normal gastric endoscopic appearance, and in patients with liver cirrhosis with and without congestive gastropathy. Our results show that TGF-alpha concentration is significantly higher than EGF concentration in both the stomach and duodenum. No significant regional differences in the distribution of the two peptides were found. Moreover, the gastroduodenal tissue levels of TGF-alpha were comparable in subjects with and without hypertensive gastropathy. EGF gastric concentration was not altered in patients with congestive gastropathy. However, EGF duodenal tissue levels were significantly lower in patients with liver cirrhosis than in noncirrhotic subjects. We speculate that the higher level of TGF-alpha in the gastroduodenal mucosa may support the hypothesis that TGF-alpha and not EGF is the major physiological ligand for TGF-alpha/EGF receptor in the intact gut. Furthermore, the lower duodenal concentration of EGF in cirrhotics might partially explain the increased susceptibility of cirrhotic patients to duodenal ulcer. PMID- 7851188 TI - Products of neutrophil metabolism increase ammonia-induced gastric mucosal damage. AB - Recent studies have indicated that ammonia is involved in the pathophysiology of Helicobacter pylori-associated gastric mucosal damage. Helicobacter pylori associated chronic active gastritis is characterized by an invasion of neutrophils. We investigated the interrelationship among hypochlorous acid (oxidant produced by neutrophil), ammonia (product of Helicobacter pylori urease), and monochloramine (product of ammonia and hypochlorous acid) in the development of gastric mucosal damage in rats. Gastric mucosal lesions were produced by exposure of the gastric mucosa to ammonia, urea with urease, or urea with Helicobacter pylori in rats subjected to ischemia. Pretreatment with taurine (scavenger of hypochlorous acid) or antineutrophil serum significantly attenuated gastric mucosal lesions induced by the above test agents. Ammonia-induced gastric mucosal lesions were exacerbated in the presence of hypochlorous acid with concomitant generation of monochloramine. These results suggest that the ammonia, hypochlorous acid, and monochloramine triad may be important in Helicobacter pylori-mediated gastric mucosal damage. PMID- 7851189 TI - Irritant and protective action of urea-urease ammonia in rat gastric mucosa. Different effects of ammonia and ammonium ion. AB - The effects of urea-urease-ammonia on the rat gastric mucosa were examined and compared with those of NH4OH and NH4Cl. The mucosal application of urea with urease produced a reduction in potential difference (PD) in a dose-related manner for urea, and a significant drop was observed by > 0.1% urea in the presence of 100 units urease. Such PD reduction was also observed when the mucosa was exposed to either NH4OH (> 0.03%) or NH4Cl (> 1%); delta PD (20 mV) caused by 0.3% NH4OH and 3% NH4Cl was equivalent to that induced by 0.5% urea+urease (100 units). The combined oral administration of urea (approximately 6%) and urease (100 units) did not induce any macroscopic damage in the gastric mucosa. NH4Cl given orally had no or little effect on the mucosa at any dose levels even at 10%, while NH4OH given orally caused hemorrhagic lesions in the mucosa at the dose of > 0.3%. In contrast, both urea+urease and NH4Cl given prior to HCl/ethanol protected the gastric mucosa against damage in a dose-related manner, and a significant effect was obtained by urea at > 0.5% and by NH4Cl at > 1%. NH4OH was also effective in reducing the severity of HCl/ethanol-induced gastric lesions at lower dose (0.3%). The protective effect of urea+urease was attenuated significantly by prior administration of indomethacin or coadministration of hydroxyurea, while that of NH4Cl or NH4OH was mitigated by indomethacin.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7851190 TI - Spontaneous swallowing rate and emotional state. Possible mechanism for stress related gastrointestinal disorders. AB - Excessive spontaneous swallowing has been associated with a variety of common gastrointestinal symptoms including abdominal pain, heartburn, and bloating and may contribute to disorders such as hiatus hernia, duodenal ulcer, and irritable bowel syndrome. The present study investigated the hypothesis that changes in emotional state alter spontaneous swallowing rate. Subjects were 38 generally healthy undergraduates assigned to either a pleasant low arousal, neutral, or aversive high arousal condition. Each experimental session was divided into 30 min baseline and arousal manipulation periods. Spontaneous swallowing rate increased significantly with emotional arousal: for low, neutral, and high arousal groups, means were 7.9 +/- 1.9 (SE), 15.8 +/- 2.4, and 23.7 +/- 3.6 swallows/30 min, respectively. Other physiological and self-report measures, used to check the effectiveness of the arousal manipulation, varied appropriately with experimental procedures. These results indicate that changes in emotional state alter spontaneous swallowing rate in generally healthy individuals. Further research with patients is needed to establish whether stress-induced increases in swallowing rate produce or exacerbate clinically significant gastrointestinal symptomatology. PMID- 7851191 TI - Endoscopic detection of ectopic multiple minute sebaceous glands in the esophagus. Report of a case and review of the literature. AB - This case report describes a patient with a rare form of ectopic sebaceous glands. The patient was a 53-year-old woman complaining of prolapse of a polyp through the anus who was admitted for polypectomy of the rectal polyp. After polypectomy, esophagogastroduodenoscopy was performed to detect other lesions. Although she had no symptoms from an upper gastrointestinal series, such as dysphagia, heartburn, or epigastric pain, multiple yellow rounded elevated lesions arranged in rows, 0.5 mm in diameter and more than 100 in number were observed in the middle and lower esophagus. Histological examination of the biopsied specimens taken from the lesions endoscopically revealed a structure with the characteristics of a sebaceous gland including an excretory duct. PMID- 7851192 TI - Interleukin-2 receptor alpha and beta chain expression by circulating alpha beta and gamma delta T cells in inflammatory bowel disease. AB - The pathogenetic role of activated alpha beta and gamma delta T cells in inflammatory bowel disease (IBD) is not well defined. To elucidate this, interleukin-2 receptor (IL-2R) alpha and IL-2R beta single chain expression and coexpression by peripheral blood TCR alpha beta + cells and TCR gamma delta + cells was studied in 21 patients with ulcerative colitis (UC), 25 with Crohn's disease (CD), and 15 controls. The percentages of IL-2R alpha + beta-, IL-2R alpha-beta +, and IL-2R alpha + beta + TCR alpha beta + cells were increased in IBD patients with moderate and severe disease activity, as compared to controls (P < 0.01). In contrast, the percentages of IL-2R alpha-beta + and IL-2R alpha + beta + TCR gamma delta + cells were increased in patients with inactive UC (P < 0.01), but not in CD. The results suggest that activated alpha beta T cells are involved in the development of IBD. The differences in gamma delta T cell IL-2R expression between inactive UC and CD may correspond to a yet undefined etiopathogenetic difference between these two diseases. PMID- 7851193 TI - Safety and efficacy of controlled-release mesalamine for maintenance of remission in ulcerative colitis. Pentasa UC Maintenance Study Group. AB - This 12-month, double-blind, placebo-controlled study randomized 205 ulcerative colitis patients in remission to placebo or controlled-release mesalamine at 4 g/day for 12 months. Patients were stratified to either pancolitis or left-sided disease, based on previous diagnosis. Maintenance of remission was defined as a sigmoidoscopic index of < 5, less than five stools per day, and the absence of rectal bleeding. A significantly greater number of patients maintained remission on mesalamine 4 g/day than on placebo at each of five study visits, following the first one-month visit (P < 0.05). The estimated 12-month remission rates for the mesalamine group were 64% (38% for placebo, P = 0.0004). Baseline subgroups (disease location, time since last flare of active disease, and previous response to oral/rectal steroids or sulfasalazine) did not influence remission rates. Treatment-related adverse events were rare. Controlled-release mesalamine is a safe and efficacious single agent for maintaining remission of ulcerative colitis. PMID- 7851194 TI - Topical treatment of refractory distal ulcerative colitis with 5-ASA and sodium butyrate. AB - Nine patients with distal ulcerative colitis refractory to standard therapy were treated with intrarectal instillation of a sodium butyrate solution and 5-ASA. A marked clinical, endoscopical and, to a smaller extent, histological improvement was observed in seven of nine patients. The clinical improvement usually occurred within the second week of therapy, and thus earlier than in previous cases treated with butyrate alone. This preliminary experience suggests that the combined butyrate-5-ASA treatment may prove a useful therapeutic tool in refractory distal ulcerative colitis and possibly increase the effectiveness of the individual therapeutic regimens. PMID- 7851195 TI - Eosinophilic gastroenteritis presenting with colitis and cholangitis. AB - Eosinophilic gastroenteritis (EG) is a rare condition that most commonly affects the stomach and intestine. Large bowel involvement has also been described. We report a case of EG presenting with colitis and cholangitis. This is the first case of associated cholangitis demonstrated radiologically and histologically. Simultaneous biliary and gastrointestinal tract involvement suggest a common link between EG and hypereosinophilic syndrome (HES). However, HES requires high peripheral hypereosinophilia and several organs including gastrointestinal tract, lung, heart, infiltrated with eosinophils. The patient's condition improved with corticosteroids. PMID- 7851196 TI - Nonsteroidal antiinflammatory drug-induced colonic stricture. An unusual cause of large bowel obstruction and perforation. AB - Nonsteroidal antiinflammatory drugs (NSAIDs) are widely prescribed drugs that can result in gastroduodenal ulceration. Adverse effects upon the small and large intestine are now more often recognized. Small intestinal obstruction secondary to both mucosal diaphragms and broad-based stenoses is reported, but colonic strictures appear to be less common. A case of NSAID-induced colonic stricture leading to large bowel obstruction and secondary cecal perforation (previously unreported) is presented. Twelve additional cases of NSAID-induced colonic stricture are reviewed from the literature and its possible pathogenesis is discussed. PMID- 7851197 TI - Colonic lactate metabolism and D-lactic acidosis. AB - D-Lactic acidosis is seen in patients with intestinal bypass or short bowels in whom colonic produced D-lactate accumulates. An intestinal bypassed patient with D-lactic acidosis had higher fecal D-lactate (122.4 mmol/liter) and L-lactate (90.1 mmol/liter) than described before in humans. D-Lactate fluctuated between 0.5 and 3.1 mmol/liter in plasma (normal < 0.1 mmol/liter) and between 1.1 and 52.8 mmol/liter in urine (normal < 0.7 mmol/liter) within a few hours, indicating that the human organism do metabolize and excrete D-lactate. The patient with D lactic acidosis had a 10-fold increased DL-lactate production from glucose in fecal homogenates compared to 14 healthy controls and a patient with intestinal bypass, who did not have D-lactic acidosis. A 67% carbohydrate (starch)-enriched diet resulted in a minor elevation of fecal and plasma lactate, whereas 50 + 100 + 150 g of ingested lactose increased D-lactate in feces (84.0 mmol/liter) and plasma (2.3 mmol/liter) considerably in the patient with D-lactic acidosis. Intestinal prolongation (22 cm ileum) had a temporary effect on fecal and plasma D-lactate, but intestinal continuity was reestablished 26 months later because D lactic acidosis recurred (plasma 8.6 mmol/liter, urine 101.3 mmol/liter). Large amounts of lactulose (160 g/day) to 12 normal individuals increased D-lactate to 13.6 +/- 3.5 mmol/liter in feces, but never increased D-lactate in plasma or urine. The in vitro fermentation of glucose in fecal homogenates increased DL lactate, which disappeared after complete metabolization of the glucose. L Lactate was converted to D-lactate and vice versa, and both were degraded to the short-chain fatty acids acetate, propionate, and butyrate. An infrequent, but elevated ability of the colonic flora to produce lactate may be a prerequisite for D-lactic acidosis to occur and may explain why the syndrome is so seldom seen even in patients with intestinal bypass or short bowels. The suggestion that D lactate is not metabolized and hence accumulates is probably not valid. PMID- 7851198 TI - Role of T lymphocytes in secretory response to an enteric nematode parasite. Studies in athymic rats. AB - Athymic (nude) rats have been used to assess the role of thymus-dependent T cells in the control of the intestinal response following infection with the enteric parasite, Nippostrongylus brasiliensis. Tissues from infected rats were excised on days 4, 7, 10, and 21 postinfection (p-i) for physiological and morphological studies; uninfected (day 0) rats served as controls. In response to the worm burden, jejunal tissues displayed a secretory response, indicated by an elevated baseline short-circuit current (Isc) on days 7 and 10 p-i, and were more responsive to histamine than control tissues. Despite this enhanced secretory response, approximately 35% of the worm burden was still present on day 21 p-i (compared with expulsion of > 95% by day 14 p-i in normal rats). Mast cell activation and hyperplasia, increased goblet cell (implying increased mucus synthesis) and intraepithelial leukocyte numbers, and abnormalities in Isc responses after electrical stimulation of enteric nerves were identified following infection. These events in nude rats were attenuated or delayed in onset as compared with conventional immunocompetent rats. Our results support the postulate that thymus-dependent T cells regulate the timing and/or nature of the mucosal response to enteric parasitic infections. However, ion secretion was not altered in the absence of T cells and, therefore, is more likely to be a consequence of mast cell activation. PMID- 7851200 TI - Abnormal abdominal CT findings in a patient with giardiasis. Resolution after treatment. PMID- 7851199 TI - Influence of heated and nonheated partially hydrogenated dietary fats on ileal chyme fat and fatty acid composition of ileal mucosa in pigs. AB - In this study the effects of partially hydrogenated chemically processed fats (CPF) and non-CPF on the ileal chyme fat and the fatty acid (FA) profile of the ileal mucosa and the subcutaneous tissue were analyzed. Samples were collected via an ileocutaneous fistula. For three months pigs were fed a control meal or diets containing either non-CPF high on 16:0, non-CPF high on 18:2 n6, CPF with 50% trans-18:1 or 20% trans-18:1. The latter fat was used after heat treatment. With both CPF diets, the fat content in the ileal chyme was three times higher than with non-CPF. In contrast to subcutaneous tissue reflecting dietary composition, changes in FA profile of ileal mucosa were restricted. Each non-CPF resulted in an increase of the characteristic major dietary FA. Both CPF increased the mucosal trans-FA percentage from 0 to 12% on average, although dietary composition was different. This study suggests: (1) less effects of trans FA on the regulation of intraluminal fat load compared to saturated and cis polyunsaturated FA, and (2) higher mucosal incorporation of trans-FA with heated CPF. This may play a role in the development of epithelial lesions in the ileum, which are known following ingestion of these fats. PMID- 7851201 TI - Effect of wheat bran in treatment of chronic nonorganic constipation. A double blind controlled trial. AB - After a two-week basal period, 24 patients were randomly allocated to receive, with a crossover double-blind design, for two consecutive four-week periods, bran (20 g/24 hr) or placebo. The daily intake of water and dietary fibers was standardized. Symptomatology, oroanal transit time, bowel frequency, and stool weight were assessed in basal conditions and at week 4 and 8 of the treatment. Oroanal transit time decreased and bowel frequency and stool weight increased significantly during both bran and placebo administration in comparison with basal period. Bran treatment was more effective than placebo in improving bowel frequency and oroanal transit. During bran treatment oroanal transit time became normal only in patients with slow colonic transit and not in those with slow rectal transit. Neither the occurrence nor the severity of the most frequent accompanying symptoms of chronic constipation differed significantly between placebo and bran treatments. PMID- 7851202 TI - Microvascular structure of benign and malignant tumors of the colon in humans. AB - Studies of experimental tumors in rodents indicate that there are morphological abnormalities of the tumor microcirculation compared to normal tissues. The aim of this study was to examine the structure of the microvasculature in benign and malignant colonic tumors in humans using microvascular casting techniques. There were 15 adenocarcinomas, four benign sporadic adenomas, and three specimens from patients with familial adenomatous polyposis (FAP). A cast of the microvessels of these tumors was prepared by intraarterial administration of acrylic resin (Mercox) and the cast examined by scanning electron microscopy. Quantitative measures of the microvasculature were obtained from histological sections using stereological techniques in four carcinomas, two sporadic adenomas, and 12 adenomas from patients with FAP. Vascular casts of benign colonic adenomas showed that the microvasculature had a similar organization to normal colon. However, capillaries and venules were elongated and had increased diameters compared to normal. In adenomas greater than 3 mm in diameter, there was an increased density of microvessels in the spaces between tumor cells. Vascular casts of colonic carcinomas were characterized by a disorganized structure and increased density of microvessels. The organization of microvessels within carcinomas had a similar overall pattern to normal colon. However, the increased number and density of microvessels resulted in formation of nodular clusters of capillaries, formation of "sheets" of frequently anastomosing capillaries, or almost complete packing of the interstitial spaces of the tumor by capillaries in places. Most capillaries had a long and tortuous course and numerous capillary sprouts were identified. Tumor microvessels had greater mean diameters than normal. Extravasation of resin from microvessels in carcinomas was frequently seen. The vascular volume of carcinomas (23.1% +/- 12.2), sporadic adenomas (16.3% +/- 3.4), and adenomas > 3 mm diameter in patients with FAP (17.7% +/- 3.0) were significantly greater than in normal colon (11.0% +/- 4.2). This study indicates that there is an increased vascular density in benign and malignant tumors of the colon compared to normal colon. The presence of profusely anastomotic microvessels and frequent capillary sprouts is evidence of active neovascularization and suggests control of tumor growth could be achieved by modifiers of angiogenesis. PMID- 7851203 TI - Ecological study of association between Helicobacter pylori infection and gastric cancer in Taiwan. AB - The association between Helicobacter pylori infection and gastric cancer remains controversial. A community-based serosurvey was carried out in Taiwan to investigate the association. Serum IgG antibodies against Helicobacter pylori were examined in 728 subjects randomly selected from three townships with different gastric cancer mortality rates. The overall seropositivity of Helicobacter pylori was 54.7% (398/728) with no gender difference (males: 54.5%; females: 54.8%). The seroprevalence of Helicobacter pylori progressively increased with age in all three study townships. The age-specific seropositivity of Helicobacter pylori correlated well with age-adjusted gastric cancer mortality in the three townships. The difference in seropositivity was more profound in younger age groups. The ecological study in Taiwan suggests an association between Helicobacter pylori infection and gastric cancer. Helicobacter pylori infection in early childhood may be a key issue; in addition, a long induction time appears to be required for gastric carcinogenesis. PMID- 7851204 TI - Autoantibodies specific for villin found in patients with colon cancer and other colitides. AB - We have sought evidence for blood-borne autoantigens from the apical regions of the intestinal epithelial cell that are associated with specific gastrointestinal diseases. While a wide range of brush border-specific proteins are antigenic in various disease states, significantly increased levels of autoantibody to villin, a 95-kDa protein microvillar actin-binding protein, were identified by western blot in colon cancer patients' sera. Examination of a population with a range of colonic diseases showed that anti-villin antibody is most prevalent in patients with colon cancer at significantly higher (P < 0.005) levels than normal controls. We conclude that cryptic antigens within the brush border, specifically including villin, incite an active autoimmune response. The pathological significance of these antibodies remains to be determined. These anti-villin antibodies also may provide a unique noninvasive approach for the detection of gastrointestinal pathology. PMID- 7851205 TI - Aging. Increased responsiveness of colorectal mucosa to carcinogen stimulation and protective role of folic acid. AB - Recent investigations have demonstrated a protective role for folic acid in dysplasia and neoplasia, through an unknown mechanism. The current study was designed to evaluate whether the protective role of folic acid is due, in part, to its antiproliferative properties. In addition, because colorectal neoplasia is more common with increasing age, we have compared results in both old (22 months) and young (3 months) rats. Colorectal mucosal explants of rats treated with the known carcinogen methylazoxymethanol, were supplemented with folic acid. Ornithine decarboxylase was then measured as an index of cellular proliferative activity. We observed that supplemental folic acid suppressed carcinogen-induced ornithine decarboxylase activity by 64% in the old and 74% in the young rats. Furthermore, a similar phenomenon was observed for tyrosine kinase, which was measured for comparison. The suppression of hyperproliferative activity by supplemental folic acid may contribute to the protective effect of folic acid in colorectal neoplasia. PMID- 7851206 TI - Familial adenomatous polyposis and inflammatory bowel disease associated in two kindreds. AB - We describe two families in which some members are affected by familial polyposis syndrome: in one family a case of ulcerative colitis and in the other a case of Crohn's disease were found. This is the first report about this family association, but in our opinion the fact that two cases have been found in one series suggests that this association could be more frequent than reported so far. The research for a genetic pattern of inflammatory bowel disease could be addressed towards chromosome 5. PMID- 7851207 TI - Cholecystokinin and pancreatic polypeptide release in diabetic patients with and without autonomic neuropathy. AB - The present study was undertaken to investigate postprandial responses of cholecystokinin (CCK) and pancreatic polypeptide (PP) and their interrelationship in patients with diabetes mellitus (DM) with and without autonomic neuropathy (AN). Twenty-two patients with DM (seven with AN and 15 without AN) and 14 age matched healthy controls were studied. AN was diagnosed according to several tests of cardiovascular autonomic function. CCK and PP plasma levels were measured by specific radioimmunoassays before and at several time points after the oral administration of a test meal. Basal CCK plasma levels in DM patients were normal, whereas basal PP plasma levels were increased (139 +/- 18 vs 72 +/- 7 pg/ml; P < 0.01). Integrated postprandial CCK response was increased in DM patients (208 +/- 27 vs 110 +/- 14 pmol/liter/2 hr; P < 0.05), mainly due to the patients with AN. Postprandial PP response was increased in DM patients without AN (37,273 +/- 5241 vs 13,418 +/- 3299 pg/ml/2 hr; P < 0.001) but not in those with AN (8887 +/- 3461 pg/ml/2 hr). Moreover, PP response was closely (P < 0.002) correlated with the degree of AN. A direct and linear correlation between postprandial CCK and PP responses was found in healthy controls (r = 0.78; P < 0.005) but not in DM patients. We conclude that the CCK response to a meal is increased in diabetic patients with AN, whereas the PP response is increased only with an intact autonomic nervous system.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7851208 TI - Human polymorphonuclear leukocyte phagocytosis of crystalline cholesterol, bilirubin, and calcium hydroxyapatite in vitro. AB - We tested the hypothesis that human polymorphonuclear leukocytes (PMNs) phagocytize crystalline cholesterol, bilirubin, or calcium hydroxyapatite in vitro and in the process release oxygen metabolites and enzymes involved in the inflammatory process. Chemiluminescence (CL), elicited by the respiratory burst (release and activation of oxygen metabolites and enzymes) of PMNs during phagocytosis of a target particle, was used to quantitate PMN phagocytosis of each crystal. Significant CL (P < 0.05) was observed with cholesterol concentrations of 1.3-5.3 mg/ml and the dose-response was linear (r > or = 0.95). With bilirubin, significant CL was observed with concentrations of 0.07-0.33 mg/ml. The response to calcium hydroxyapatite was variable. Human PMNs phagocytize cholesterol, bilirubin, and to a lesser extent, calcium hydroxyapatite. PMN chemiluminescence was associated with phagocytosis, indicating that inflammatory substances are being released in the process. These results support the concept that crystals that occur in the gallbladder may initiate gallbladder inflammation. PMID- 7851209 TI - Toxic effects of cholelitholytic solvents on gallbladder and liver. A piglet model study. AB - We evaluated the toxic effects of four currently used chemolytic solvents- dimethyl sulfoxide (DMSO, 99%), ethyl propionate (EP, 99%), tetrasodium ethyl dimethyl tetraacetate (4Na-EDTA, 2%, pH 11), and methyl tert-butyl ether (MTBE, purity = 99.5%) in an animal model. Each solvent was tested in nine farm piglets (Landrace), weighing between 20 and 25 kg. A solvent-resistant catheter was inserted transhepatically into the gallbladder (GB) using sonographic guidance 24 hr prior to each experiment. Seventy-five milliliters of each solvent was infused over 3 hr into the gallbladder. The following day, a laparotomy was performed in order to assess for possible damage to the liver, GB, bile ducts (BD), or intestines. The GB and liver were resected and their histology examined. The following pathologic grades were assigned to GB, BD, and liver specimens to describe the tissue damage: normal (0), mild (1), moderate (2), and severe (3). We found that DMSO had the highest score on gallbladder and bile duct injury (49, 3), followed by EP (36, 2), EDTA (14, 1) and MTBE (16, 0), respectively; the difference in gallbladder damage was statistically significant. Very mild hepatocyte damage was present in the DMSO (2) and MTBE (2) groups. The administration of EP and EDTA resulted in no liver injury at all. Piglets within each treatment group suffered from varying degrees of tissue injury. No deaths were attributed to the administered solvents. We concluded that DMSO, EP, EDTA, and MTBE do not have serious local toxic effect on the GB, BD, and intestine; nor do they lead to severe hepatotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7851210 TI - Cholecystokinin-induced gallbladder contraction and muscarinic blockade with pirenzepine in man. PMID- 7851211 TI - Gallbladder emptying, plasma levels of estradiol and progesterone, and cholecystokinin secretion in liver cirrhosis. AB - Defective gallbladder emptying has been proposed as a possible accessory pathogenetic factor to explain the increased prevalence of gallstones in liver cirrhosis. In this study we have evaluated the fasting volume and the meal stimulated emptying of the gallbladder, the plasma levels of estradiol and progesterone, and the basal and postprandial secretion of cholecystokinin in Child A cirrhotic patients compared to normal subjects. Basal (42.2 +/- 27 vs 22.8 +/- 8.4 ml) (P < 0.002) and residual (8.4 +/- 8.7 vs 4.6 +/- 3.8 ml) (P < 0.05) gallbladder volumes were higher in cirrhotics but neither the integrated gallbladder response to meal nor the maximal percentage of emptying was significantly different. Circulating estradiol and progesterone was slightly increased in only 1/13 and 5/13 cirrhotics, respectively. In eight cirrhotics and seven normals taken from the overall populations, the secretion of cholecystokinin was also measured. The fasting plasma level of cholecystokinin was higher in the cirrhotics (6.71 +/- 5.08 vs 2.02 +/- 0.46 pmol/liter) (P < 0.01). The meal-stimulated integrated plasma cholecystokinin response also was greater in cirrhotics (438.5 +/- 615 pmol/liter/270 min) than in normals (153 +/- 170.4 pmol/liter/270 min), but this difference was not significant because of the small study population. In spite of a normal kinetics of postprandial emptying, cirrhotic patients show increased fasting gallbladder volume and increased plasma levels of basal and postprandial cholecystokinin. Circulating estradiol and progesterone do not seem to be responsible for the large gallbladder volume found in liver cirrhosis. PMID- 7851213 TI - A retrospective study of hepatitis C virus carriers in a local endemic town in Japan. A possible presence of asymptomatic carrier. AB - Chronic hepatitis, cirrhosis, and hepatocellular carcinoma are the accepted sequelae of chronic hepatitis C virus (HCV) infection. However, the real natural history of HCV infection is not still well understood. To approach this problem, we investigated 91 individuals positive for antibodies against HCV (anti-HCV), who have received annual liver function examination in a local town known to have had high carrier rates of hepatitis B virus (HBV) and HCV. Among the 91 anti-HCV positive individuals, 63 had undertaken the annual examination more than five times in the past 14 years. We analyzed retrospectively the past liver function test results of these 63 subjects and evaluated their present virological status by determining HCV genotypes and estimating quantity of HCV RNA in the sera. Among the 63 subjects, 50 (79.4%) had HCV RNA in the serum and 40 (80%) of the 50 subjects with HCV RNA had abnormal alanine aminotransferase or aspartate aminotransferase level more than once in their records. However, the other 10 (20%) had no abnormal levels during the period examined. Six of 50 (12%) had ultrasonographic findings suggestive of cirrhosis. Thus, HCV-infected individuals in this area did not seem to have progressive liver diseases. Considering the advanced ages of the individuals examined (mean 64 years old), we may have observed a stage in the natural history of HCV infection in which viremia persists in most individuals and the tendency to progress to serious chronic liver disease is mild. PMID- 7851214 TI - Multicenter, multiyear study of safety and efficacy of flexible sigmoidoscopy during pregnancy in 24 females with follow-up of fetal outcome. AB - Our objectives were to analyze the risks versus benefits of flexible sigmoidoscopy to the pregnant female and fetus. We retrospectively studied 24 consecutive pregnant patients admitted to four university hospitals during seven years who underwent 26 flexible sigmoidoscopies. Sigmoidoscopy indications included hematochezia in 11, diarrhea in 12, abdominal pain in 7, constipation in 2, and occult rectal bleeding in 1. Seven patients were in the first trimester of pregnancy, nine were in the second trimester, and eight were in the third trimester. Sigmoidoscopy provided helpful clinical information in all patients. Twelve patients had a lesion diagnosed by sigmoidoscopy, including reactivation of Crohn's colitis, reactivation of ulcerative colitis, infectious colitis, nonspecific colitis, bleeding internal hemorrhoids, pseudomembranous colitis, anastomotic ulcer, and newly diagnosed Crohn's colitis. In particular, nine of 11 patients with rectal bleeding had a lesion identified by sigmoidoscopy. No endoscopic complications occurred to any pregnant female. Two pregnant patients underwent repeat sigmoidoscopy without complications. Fetal outcome was ascertained in all but one pregnancy. Eighteen pregnant females delivered healthy infants (16 at full term, two at 35 or 36 weeks). Their mean Apgar scores were 8.8 +/- 0.4 SD at 1 min, and 9.0 +/- 0.4 SD at 5 min. One diabetic and hypertensive female suffered an involuntary abortion nine weeks after sigmoidoscopy, which appeared unrelated to the sigmoidoscopy. Four pregnancies were voluntarily aborted. This study suggests that flexible sigmoidoscopy does not induce labor or result in congenital malformations, that sigmoidoscopy is not contraindicated during pregnancy, and that sigmoidoscopy should be considered in medically stable pregnant patients with significant gastrointestinal bleeding.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7851212 TI - Autoimmune hepatitis. Evolving concepts and treatment strategies. PMID- 7851216 TI - Experimental oxygen-induced retinal detachment in the newborn Wistar rat. AB - We conducted an extensive histological study of the retinas of newborn rats that had been exposed to hyperoxic conditions. Our aim was to verify whether it is possible, using oxygen alone, to induce retinal detachment, a lesion that is characteristic of the more advanced stages of retinopathy of prematurity (ROP). Eight litters (total number of animals: 64) of newborn, albino Wistar rats were used. Four litters (32 rats) were exposed to 80% oxygen for the first ten days of life. Some of these rats were then removed to room-air environments where they were kept for two, three or four more weeks. The other four litters (32 rats) were maintained for the entire period in room-air. On the 11th, 25th, 32nd and 39th days of life rats from both the exposed and control groups were sacrificed and 5 micron sections of their in toto eyeballs were submitted to histological evaluation and immunohistochemical studies. Folding of the internal retinal layers was observed in some of the animals exposed to hyperoxia, as well as those kept in room air. These folds did not alter the overall thickness of the retina itself and were probably congenital. Retinal folds and microdetachments were seen in many of the retinas from the exposed group of rats. Extensive detachment was observed in one of the rats sacrificed after two weeks of room-air recovery, in two of those recovered for three weeks and in two exposed to four weeks of room air. The sections containing these areas of retinal detachment showed marked increases in glial fibrillary acidic protein (GFAP) in immunocytochemical studies, suggesting that Muller cells might play a role in the pathogenesis of retinal detachment. PMID- 7851217 TI - Astigmatism after penetrating keratoplasty. Role of the suture technique. AB - The Authors retrospectively evaluated the evolution of corneal astigmatism 6, 12 and 24 months after penetrating keratoplasty in 75 eyes by comparing 2 suture techniques: running suture (RS) in 14 cases vs interrupted suture (IS) in 61 cases. The mean keratometric astigmatism in patients with RS was 7.75 +/- 3.10 D at 6 months, 5.89 +/- 2.50 D at 12 months and 3.90 +/- 1.70 D at 24 months. In patients with IS these values were 4.82 +/- 4.00 D at 6 months, 2.81 +/- 1.60 D at 12 months and 2.77 +/- 1.34 D at 24 months. A significant lower astigmatism (P < 0.05) was noted after using IS at 6 and 12 months. At 24 months, however, this difference was no longer statistically significant (P > 0.3). The IS suture allowed a better control of the post-surgical astigmatism, and a more rapid recovery of the visual acuity. PMID- 7851215 TI - Peripheral neural circuits regulating IOP? A review of its anatomical backbone. AB - The peripheral nervous system is classically separated into a somatic division containing both afferent and efferent pathways and an autonomic division composed of efferents only. The somatic afferent division is divided in A- and B-neurons. The B-neurons are supposed to be autonomic afferents as part of a reflex system involved in homeostasis. Recent data obtained by neuronal tracing and immunohistochemical experiments concerning the eye related peripheral nervous system endorse the existence of these peripheral reflex systems. Somatic afferents of trigeminal origin synaptically innervate parasympathetic neurons in the pterygopalatine ganglion. This probably represents a pathway mediating autonomically regulated ocular activity in response to sensory stimulation. In addition, it has been hypothesized that trigeminal sensory nerve fibres have an efferent function in response to noxious stimuli e.g. the ocular injury response. Sympathetic nerve fibres originating in the superior cervical ganglion course through the trigeminal and pterygopalatine ganglion without forming direct synaptic contacts. These fibres, however, contain clusters of vesicles suggesting some kind of interneural communication. Parasympathetic nerve fibres of pterygopalatine origin course through the ciliary ganglion. These nerve fibre terminals also contain clusters of vesicles without direct synaptic contacts. Experimental data concerning the distribution of neuropeptides revealed a more detailed knowledge of the anterior eye segment innervation. These experimental data are subject to some debate. The pros and cons of different techniques are discussed. Neural circuits regulating IOP have long been postulated. The possible role of peripheral reflex systems in the regulation of IOP is discussed. PMID- 7851218 TI - Slowly progressive changes of the retina and retinal pigment epithelium in Briard dogs with hereditary retinal dystrophy. A morphological study. AB - Seven eyes from 2 generations of Briard dogs (5 weeks--7 years old) with congenital night blindness and (in the second generation) impairment of day vision to varying degrees, were examined by light and electron microscopy. Specimens from 4 locations were studied: the central area, the midperiphery of the tapetal area, the upper periphery and the lower periphery. Disorientation of rod outer segment disc membranes was seen in the 5-week-old dog. Large electron lucent inclusions were found in the RPE at 3.5 months of age. These inclusions occurred most frequently in the central and midperipheral-tapetal areas and seemed to increase in numbers and spread towards the periphery with increasing age. The content of these inclusions is not elucidated. Rod photoreceptor degeneration was apparent from 7 months of age and was most prominent in the peripheral areas. The cones were better preserved. The 7-year-old dog showed reduction of photoreceptors in the central and midperipheral-tapetal areas and almost complete photoreceptor degeneration in the periphery. This dog also showed severe changes of the inner retina in the peripheral fundus. It appears that these Briard dogs suffer from a very slowly progressive retinal degeneration, in which the photoreceptor degenerative changes do not correlate anatomically to the changes in the RPE cells. The disease seems to be different from the retinopathy described in the English Briards. It is not clear yet whether the lipid type of retinopathy found in American Briards is identical to the present disease. PMID- 7851219 TI - Effects of aldose reductase inhibition with tolrestat on diabetic retinopathy in a six months double blind trial. AB - To study the effects of the new aldose reductase inhibitor tolrestat on diabetic retinopathy, 31 diabetic patients with various degrees of retinopathy were randomly assigned to either tolrestat (200 mg once daily) or placebo treatment for six months. Separate morphological features of diabetic retinopathy were assessed by fundus photography and fluorescein angiography before and at the end of the study. The results showed some amelioration of clinical signs of diabetic retinopathy during aldose reductase treatment. Hard exudates, intraretinal hemorrhages and focal fluorescein leakage increased on average in the placebo and decreased in the tolrestat group. The difference was statistically significant for focal fluorescein leakage only. The permeability of the blood retinal barrier was determined by vitreous fluorophotometry before and at the end of the study. No change in permeability values was found. PMID- 7851220 TI - Analysis of diode, argon, and Nd: YAG peripheral iridectomy in cadaver eyes. AB - We compared semiconductor diode, neodymium (Nd): YAG and argon laser iridectomies performed in 14 cadaver eyes using Miyake videographic, histologic and scanning electron analysis. We found that the diode laser created an iridectomy in < 10 applications in blue, hazel and brown irides using 1000-1200 mW over 0.5 seconds. In hazel and blue irides the argon laser created iridectomies at parameters similar to the diode, but required multiple low energy burns in brown irides. Scanning electron microscopy showed pigment epithelial loss with the diode and Nd:YAG laser, and heaped up epithelium at the iridectomy site with the argon laser. Nd:YAG laser had the greatest iridectomy size. This study suggests a possible clinical advantage of diode versus argon laser iridectomies in reduced applications in brown irides and in preventing postoperative pigment occlusion. However, diode laser demonstrated no definite advantage over Nd:YAG laser. PMID- 7851221 TI - From the president: the results of the Diabetes Control and Complications Trial. PMID- 7851222 TI - AADE position statement: Diabetes Control and Complications Trial (DCCT). PMID- 7851223 TI - Guidelines for the practice of Adaptive Diabetes Education for Visually Impaired Persons (ADEVIP). Developed by the Visually Impaired Persons Specialty Practice Group. PMID- 7851224 TI - Increasing children's responsibility for diabetes self-care: the In Control study. AB - The purpose of this pilot study was to test the hypothesis that children can learn to become more independent in their own diabetes self-management without compromising their metabolic control. Twenty-four children (ages 8 to 12 years) with insulin-dependent diabetes mellitus (IDDM) were matched by age and race, then randomly assigned either to a 6-week, self-management education program (experimental) or to receive usual care (control). A questionnaire was administered to the parents to determine the frequency with which 35 diabetes management behaviors were performed and the degree to which children assumed responsibility for these behaviors. Glycohemoglobin levels were monitored at baseline and at posttreatment, 12 weeks after baseline. At the posttreatment, children in the experimental group were found to be assuming significantly more responsibility for their diabetes self-care than were children in the control group. No decrease in the frequency with which self-care behaviors were performed was observed, and metabolic control was maintained. The results suggest that a diabetes self-management education program for children ages 8 to 12 years can be effective in facilitating children becoming more responsible for their own diabetes management. PMID- 7851225 TI - An inpatient diabetes educator's impact on length of hospital stay. AB - This study assessed the impact of an inpatient diabetes education program on: 1) staff nurses' and patients' knowledge about diabetes, 2) hospital length of stay, and 3) patients' glycemic control. Over the course of 1 year, a certified diabetes educator updated nursing staff about diabetes care and education and coordinated a diabetes education program on two experimental medical units. Length of stay of insulin-requiring patients with diabetes and their diabetes knowledge and glycemic control were compared with two control medical units that received no structured diabetes education program. Results showed a significant difference in length of stay and patient knowledge between experimental and control units. Three conditions commonly associated with diabetes (diabetic ketoacidosis, osteomyelitis, foot ulcer) did not account for this difference in length of stay. There was no significant difference between the groups in glycemic control following discharge. While all groups showed improvement in their glycosylated hemoglobin values, only the change in the values of the total population and the control groups was significant. The findings suggest that a Certified Diabetes Educator can decrease length of stay in the hospital setting. PMID- 7851226 TI - Resistance training guidelines for individuals with diabetes mellitus. AB - Resistance/strength training is added to an exercise regimen to create a well rounded program that enhances muscular conditioning and improves health, physical fitness, and/or athletic performance. This article presents resistance training guidelines for individuals with diabetes mellitus, with and without vascular complications. The existing literature concerning exercise prescription and the acute and chronic physiological responses to resistive-type exercise is discussed. The educator is provided with principles that govern resistance training so that safe and effective programs can be prescribed for individuals with diabetes. PMID- 7851227 TI - Facilitating diabetes self-management. AB - The purpose of this study was to enhance sensitivity to and understanding of the perceptions of persons with diabetes by analyzing these individuals' unsolicited comments on structured questionnaires. Twenty of 66 adults with non-insulin dependent diabetes mellitus (NIDDM) who participated in a study to modify their eating habits wrote a total of 122 unsolicited comments on three different questionnaires. A systematic analysis of the content of these comments resulted in seven coding categories: personal philosophy; knowledge deficit; weight or blood sugar problems; diet, exercise, or medication problems; self-care activity; stress; and success. Further analysis resulted in a trilevel schema (survival, regulation, success) depicting how individuals learn to manage their diabetes. The problem-identification and seeking-help behaviors identified in the survival level gradually changed to learning to live with the regimen in the regulation level. Respondents whose activities were in the success level demonstrated more autonomy than persons in the other two levels. A health orientation rather than a problem orientation also was seen in the success level. Consequently, teaching strategies should be tailored to the client's level of self-care, with an emphasis on assisting them toward the success level. PMID- 7851228 TI - Modeling the effect of diabetes education on glycemic control. AB - The objective of this study was to identify the mechanisms by which diabetes education improves glycemic control. Study participants were 82 adult patients from a comprehensive outpatient diabetes education program who completed a research protocol at the outset of the program and again 6 to 12 months later. The research protocol included a glycosylated hemoglobin assay and self-reported frequency of two insulin administration events (shot skipping and dosage adjustment), self-monitoring of blood glucose (SMBG), and exercise. Those who did not improve any aspect of self-care reduced their mean glycohemoglobin from 9.7 to 9.0. Those who improved exercise or SMBG (but not both) reduced their glycohemoglobin from 10.9 to 9.6. Those who improved both exercise and SMBG and those who improved insulin administration had the largest improvement in glycemic control, from 12.5 to 9.6. These findings suggest that if diabetes education can help patients improve self-care behavior, it can bring about dramatic improvements in glycemic control. Improved insulin administration is the single most powerful way to improve glycemia, but improving other aspects of self-care also can produce substantial gains. PMID- 7851229 TI - Diabetes simulation: an effective method for teaching diabetes to medical students. PMID- 7851230 TI - Diabesity: the deadly pentad disease. AB - Insulin resistance and hyperinsulinemia are characteristic features not only of obesity and NIDDM, but are associated with the development of hypertension, hyperlipidemia, and atherosclerosis. DeFronzo et al has used the analogy that insulin resistance can be viewed as a large iceberg submerged just below the water. The physician recognizes only the tips of the iceberg--obesity, diabetes, hypertension, hypertriglyceridemia and low-HDL cholesterol, and atherosclerosis- which protrude above the surface, while the complete insulin-resistance syndrome may be missed. With the recognition that insulin resistance consists of a cluster of nutritional causes and biochemical abnormalities, it is important for the various subspecialties to work together closely to define the mechanism(s) responsible for the defects in insulin-mediated glucose metabolism and to discover effective strategies for prevention and treatment. PMID- 7851231 TI - Facing diabetes: taking charge. PMID- 7851232 TI - From the president: AADE moves to advanced practice model for diabetes education and care. PMID- 7851233 TI - Evolution of a Progressive Self-Directed Diabetes Education Model. PMID- 7851234 TI - Situational obstacles to adherence for adolescents with diabetes. AB - Twenty adolescents with insulin-dependent diabetes mellitus were interviewed to obtain samples of problem situations that create obstacles to dietary adherence. The resulting 57 situations were analyzed using a reliable coding system to determine the presence or absence of 28 stimulus features. A hierarchical cluster analysis was used to identify 10 relatively homogeneous categories of obstacles to dietary adherence: being tempted to stop trying; negative emotional eating; facing forbidden foods; peer interpersonal conflict; competing priorities; eating at school; social events and holidays; food cravings; snacking when home, alone, or bored; and social pressure to eat. Diabetes educators should consider an individual's ability to cope with this array of obstacles to adherence when individualizing treatment. Dietary intervention then can be personalized to address specific situational obstacles. PMID- 7851235 TI - Clinical accuracy of capillary blood glucose monitoring in hospitalized patients with diabetes. AB - This study evaluated the clinical accuracy of capillary blood glucose monitoring (CBGM) performed by nursing personnel on hospitalized patients with diabetes. We compared the results of 80 serum glucose samples obtained in a blinded fashion within 5 minutes of routine capillary glucose measurements performed during the course of clinical care. The CBGM results obtained by a diabetes nurse specialist during endocrine testing procedures were correlated with the serum results. Correlation of CBGM to serum glucose ranged from .74 to .99 depending on the method used. Visual and manual interpretation yielded the lowest correlation and variable accuracy results, per error grid analysis, with 1 in 4 patients having errors of sufficient magnitude that could lead to inappropriate therapy. Monitoring with the AccuChek II blood glucose meter produced the highest correlation and most accurate clinical readings. Bedside blood glucose monitoring of inpatients has a wide range of reliability depending on the method used. PMID- 7851236 TI - Patient perceptions of benefits and concerns following pancreas transplantation. AB - The purpose of this study was to assess patient perceptions of the impact of pancreas transplantation on various aspects of life, as well as perceptions of the benefits of and concerns with the procedure. All surviving adult patients who had received a pancreas transplant at a midwestern hospital and were at least 1 year posttransplant at the time of the study (N = 138) were sent a self-report questionnaire that included demographic data, questions about life satisfaction, quality of life, symptoms, and health impact. Patients with pancreas graft function reported less pain with healthcare treatment, fewer episodes of feeling physically ill, fewer dietary restrictions, less interference with family life, fewer health limitations in interpersonal relationships and leisure activities, and feeling good about themselves compared with those without graft function. A majority of patients with functioning grafts cited the following benefits: freedom from insulin reactions, normal blood sugars, freedom from insulin injections, freedom from a specialized diet, decreased chance of amputation, feeling better physically, more feelings of hope for the future, and more freedom and control over life. Major concerns posttransplant included side effects and the expense of immunosuppressive medications. PMID- 7851237 TI - Measuring attitudes and health beliefs among Mexican Americans with diabetes. AB - Adherence to the treatment regimen for patients with diabetes is of major concern to healthcare practitioners, particularly when dealing with the high-risk, low income, Mexican-American population. Assessing the attitudes and beliefs of this group is vital for planning effective and realistic intervention strategies. Therefore, we designed a culturally sensitive instrument to measure health beliefs and attitudes of low-income Mexican Americans with diabetes. The Health Belief Model (HBM) was used as a basis for this study because it is well accepted as a predictor of health-related behaviors. However, we found that the HBM was not an effective tool for assessing the health beliefs or attitudes of this patient population even after rigorous efforts to operationalize the HBM and after conducting extensive statistical analyses. Only two of the five subscales of the traditional HBM, barriers and benefits, were reliable. Scales to measure acculturation and fatalism were added to increase the cultural sensitivity of the tool. These added components were found to be an important variable in interpreting the results for low-income Mexican-American patients. PMID- 7851238 TI - Utilizing a 24-hour dietary recall and culturally specific diabetes education in Mexican Americans with diabetes. AB - Two objectives were established for this study: 1) to assess the impact of a culturally specific, intensive diabetes education program on dietary patterns, and 2) to assess nutrient consumption relative to the Recommended Dietary Allowances. The study population consisted of elderly Mexican Americans with diabetes living in Harlingen and Brownsville, Texas. The experimental group (n = 78) participated in an intense, 2-hour nutrition education session, while the control group (n = 74) did not. The education session was conducted for groups of eight subjects via videotapes and interactive discussion. All groups experienced significant weight loss except the women in the experimental group. After the education program, however, the experimental women had increased the percentage of calories consumed daily from carbohydrate. Mean calcium consumption was substantially less than the RDA in all groups, and inadequate amounts of ascorbic acid and vitamin A often were consumed. Intensive, frequent, long-term follow-up appears essential for more sustained results. PMID- 7851239 TI - Teach less, teach better at every opportunity. PMID- 7851240 TI - Sweetening our foods: blending sweeteners. PMID- 7851241 TI - Adapting diabetes education to the Tongan culture. PMID- 7851242 TI - Planning your meeting right from the start. PMID- 7851243 TI - The Comprehensive Diabetes Monitoring Instrument. PMID- 7851244 TI - Adapting a diabetes patient education program for use as a university course. AB - A study was conducted to determine if a patient education program, "Life With Diabetes," could be converted to an undergraduate course. The course consisted of seven 2-hour sessions with presentations by a physician, dietitian, psychologist, and clinical nurse specialists. Topics included definition, treatment, nutrition, monitoring, children, older adults, and patient empowerment. A total of 52 students (45 without diabetes, 7 with diabetes) have completed this one-credit course. A patient diabetes knowledge test and a 50-item Diabetes Attitude Survey were administered before and after the course. For the students without diabetes, mean knowledge posttest scores improved significantly, and significant changes were seen on the attitude subscales, with posttest scores moving closer to those of a national panel of diabetes experts. Students with diabetes scored closer to the national panel on the pretest and improved significantly only on the patient autonomy subscale. This course measurably improved knowledge and attitudes among undergraduates, suggesting that a patient education program can be adapted successfully to provide additional training opportunities for diabetes education programs. PMID- 7851245 TI - Perceptions of the importance placed on religion and folk medicine by non-Mexican American Hispanic adults with diabetes. AB - The high incidence of diabetes and diabetes-related complications in Hispanic adults in the United States continues to be of concern among healthcare providers. The underutilization of screening services and early treatment centers by Hispanic adults seems to contribute to the problem. This survey examined whether religious, spiritual, and folk medicine beliefs play a role in the participants' view of diabetes and treatment choices. One hundred four non Mexican-American Hispanic adults with diabetes were surveyed using a self-report questionnaire. Results showed that 78% of patients believed they had diabetes because it was God's will; 17% of patients reported using herbs to treat their diabetes. This survey demonstrates the importance of addressing religion and spirituality when dealing with the issues of disease and health in this population. PMID- 7851246 TI - Measuring the diabetes knowledge of nurses in long-term care facilities. AB - A knowledge test was developed by a local diabetes educators' group to evaluate the diabetes knowledge base of 59 nurses currently employed in four long-term care facilities in eastern North Carolina. The test contained items in the following categories: monitoring, medication, hypoglycemia, hyperglycemia, illness care, diet, exercise, foot care, and patient/family education. The results of the diabetes knowledge test were analyzed according to overall test scores as well as scores in each of the selected categories. The overall scores ranged from 42% to 89%, with a group mean of 67% (passing = 70% or higher). The scores in the individual categories ranged from 18.6% for monitoring and 23.8% for medications to 91.5% for patient/family education. PMID- 7851247 TI - The challenges of teaching clients with cerebrovascular accidents to manage their diabetes. AB - Cerebrovascular accident is a major cause of morbidity and mortality in adults, and occurs more frequently in persons with diabetes. The numerous resulting cognitive, perceptual, communicative, and motor disturbances present a challenge to the individual's ability to learn and carry out aspects of diabetes care and other personal care activities. Different educational strategies can be used depending on the impairments that are present and the needs of the individual. The major goal of these interventions is to help the individual achieve an optimal level of independence, emotional well-being, and overall quality of life. After a thorough assessment to identify the remaining abilities, the educator should collaborate with clients and their families to plan and implement ability enhancing and ability compensating strategies. PMID- 7851248 TI - The relationship between eating patterns and metabolic control in patients with non-insulin-dependent diabetes mellitus (NIDDM). AB - The most important element in the therapeutic plan of patients with non-insulin dependent diabetes mellitus (NIDDM) is dietary modification. Dietary instructions target patient behaviors in two areas: following an exchange-based diet and adhering to the same basic eating pattern every day. However, there is little empirical data that addresses the relationship between dietary instruction and metabolic control. Fifty patients with NIDDM were enrolled in an 8-week study to ascertain if either dietary approach was more predictive of improved metabolic control. The effect on metabolic control was determined by changes in HbA1c over a 2- to 3-month period. Patients added or deleted almost half of all prescribed exchanges, and added or deleted an average of one prescribed meal or snack per day. Deviations in prescribed eating patterns, particularly breakfast-skipping and snack additions and deletions, were related to poorer metabolic control. Maintaining consistent eating patterns should be further evaluated as an important component of dietary instruction for patients with NIDDM. PMID- 7851249 TI - Inside the diabetes experience: an educator's perspective. PMID- 7851250 TI - Progress toward achieving Healthy People 2000 objectives for diabetes patient education. American Association of Diabetes Educators: the role of change agents in creating and tracking change. PMID- 7851251 TI - The diabetes education experience of randomly selected patients under the care of community physicians. AB - The purpose of this study was to describe the diabetes education and nutritional counseling received by patients under the active care of community physicians. The study population consisted of 440 patients with diabetes from the practices of 68 primary care physicians in eight Michigan communities. Fifty-eight percent of the sample reported having received diabetes education, and the mean number of years since the most recent education was 4.15 years. Sixty-six percent reported having seen a dietitian. Patients who had received diabetes education scored higher on a basic diabetes knowledge test (70% correct vs 60%) than patients who had not received diabetes education. From 1981 to 1991, a decline was observed in the percentage of patients who reported having received diabetes education (70% to 58%). Although patient education is an integral part of comprehensive diabetes care, too few patients are receiving it. Furthermore, diabetes education often results in less-than-optimal levels of knowledge. The situation has deteriorated over the past 10 years, and patients who are not on insulin typically are the least well served. PMID- 7851252 TI - Use of carbohydrate counting for meal planning in type I diabetes. AB - Certain questions often arise regarding carbohydrate counting, such as: Why use carbohydrate counting? Where does one start? How much carbohydrate is prescribed? How does one balance the diet? How is carbohydrate counting taught to patients? Which patients are the best candidates for carbohydrate counting? This article provides possible answers to these questions based on clinical experience at the Vanderbilt University Medical Center Diabetes Research and Training Center, and the Diabetes Control and Complications Trial. PMID- 7851253 TI - Beliefs about smoking and diabetes care. AB - The purpose of this study was to address the following questions: 1) Do smokers with diabetes believe that cigarettes have favorable outcomes associated with diabetes management? 2) Do smokers with diabetes believe that quitting smoking negatively impacts diabetes management? 3) Do smokers with diabetes perceive significant others as being supportive of attempts to quit smoking? and 4) What is the relationship between these factors and attitude toward quitting smoking? Patients with insulin-dependent diabetes mellitus (IDDM) completed a measure of Attitude Toward Quitting Smoking, which assessed desire and confidence in ability to achieve cessation, and the Diabetes and Smoking Beliefs Questionnaire, which assessed beliefs regarding cigarettes and diabetes management. Smokers whose attitudes reflected less desire to quit and less confidence in doing so reported that cigarettes had utility in diabetes management, that quitting has negative effects on diabetes, and perceived significant others as only moderately supportive of attempts to quit smoking. Implications of these findings for diabetes education are discussed. PMID- 7851254 TI - An outpatient model of integrated diabetes treatment and education: functional, metabolic, and knowledge outcomes. AB - A cohort of 137 insulin-treated adults with diabetes was evaluated at enrollment in a diabetes education and care program; 69 completed follow-up evaluations (mean = 11.2 months) to ascertain clinical outcomes. Factors that predicted change in metabolic, functional, and knowledge status were identified. The metabolic status of this cohort also was compared with a similar group of patients from a health maintenance organization (HMO) in a neighboring state. The mean HbA1c decreased from 9.97% at enrollment to 7.53% at follow-up. Functional status scores did not improve from baseline to follow-up. The relationship between knowledge and metabolic control differed for subjects with diabetes of long duration and short duration. A predictor of improved HbA1c was baseline HbA1c. A predictor of improved symptom score included white race or Hispanic origin. Patients who attended this program had better metabolic outcomes than the comparison group of patients. PMID- 7851255 TI - A comparison of two intravenous insulin regimens among surgical patients with insulin-dependent diabetes mellitus. AB - We compared two intravenous insulin regimens among 58 consecutive surgical patients who required perioperative insulin infusions. Patients were randomized to either a standard glucose-insulin-potassium (GIK) infusion or a more complex, tailored two-pump protocol. Both methods provided similar overall glycemic control. However, the two-pump regimen resulted in a significantly greater proportion of finger-prick results in the target range both preoperatively (47.4% vs 60.1%) and postoperatively (52.0% vs 66.4%). The length of stay (15 vs 16 days), duration of infusion (15 vs 16 hours), and number of medical and nursing incidents (18% vs 20%) were similar. Although the two-pump protocol required more changes to the administration rate (2 vs 10), this method was preferred by the nursing staff over the GIK regimen, resulted in more stable glucose control, and is likely to be associated with fewer clinical errors. PMID- 7851256 TI - Nutrition basics for the pediatric patient with diabetes mellitus. PMID- 7851257 TI - Use of computer-assisted instruction in diabetes education. PMID- 7851258 TI - The following two poems describe the professional demands and responsibilities of being a diabetes educator. PMID- 7851259 TI - American Association of Diabetes Educators. White paper on healthcare reform. PMID- 7851260 TI - Can you ask? PMID- 7851261 TI - Home syringe disposal: practice and policy in Washington state. PMID- 7851262 TI - Accuracy of blood glucose monitoring for patients: what it is and how to achieve it. PMID- 7851263 TI - Changes in conceptions and attitudes during five years of intensified conventional insulin treatment in the Stockholm Diabetes Intervention Study (SDIS). AB - Previous studies have demonstrated that intensified treatment can result in lower blood glucose concentrations and retard microvascular complications. In the Stockholm Diabetes Intervention Study, 96 patients were followed for 5 years; 44 patients received intensified, conventional treatment and 52 patients received regular treatment. Changes in conceptions and attitudes that accompanied intensified treatment were evaluated with questionnaires and semistructured interviews. After education and personal tutoring, HbAlc was significantly lower in patients in the intensified treatment group compared with patients in the regular treatment group. Self-rated well-being and perceived ability to control the diabetes increased more in the patients in the intensified treatment group. Blood glucose testing became more important to the patients in the intensified treatment group, who used the blood glucose tests more frequently whenever necessary, and who acted on the test results. Microvascular complications were retarded or halted. PMID- 7851264 TI - A comparison of learning activity packages and classroom instruction for diet management of patients with non-insulin-dependent diabetes mellitus. AB - Forty patients were randomly assigned to receive either the individualized learning activity packages or classroom instruction. Effectiveness was evaluated on the basis of fasting plasma glucose, glycosylated hemoglobin, percent of ideal body weight, and knowledge and behavior scores. No significant differences were found between the groups at entry or at the 2-month follow-up. At the 5-month follow-up, the group that received the learning activity packages scored significantly higher on knowledge assessment, significantly increased their behavior score, and decreased their percent of ideal body weight. Patients who received classroom instruction increased their behavior score and exhibited significantly decreased glycosylated hemoglobin levels. Behavior and blood glucose levels were significantly correlated. Although the learning activity packages proved effective in increasing knowledge, no significant improvement was observed in blood glucose levels. PMID- 7851265 TI - Utilizing content analysis of counseling sessions to identify psychosocial stressors among patients with type II diabetes. AB - This qualitative, descriptive study identified specific individual and family psychosocial stressors that impact on the ability of patients with type II, non insulin-dependent diabetes mellitus to manage the self-care regimens recommended by healthcare professionals. A series of 2 to 12 counseling sessions was incorporated into a nationally recognized outpatient diabetes education program. Data collection consisted of in-depth interviews in which six patients with type II diabetes and their families discussed current problems associated with their diabetes. Content analysis identified the following themes and problem areas: patients' inner experience with diabetes, family stressors that affect patients with diabetes, coping strategies of type II diabetes patients, and psychopathology. Based on these findings, specific interventions that emphasize family involvement and support were developed for the healthcare team to use with patients with type II diabetes. PMID- 7851266 TI - Quality assurance of individual diabetes patient education. AB - Individual patient education is the most common means of communicating diabetes information and teaching self-care skills. Despite a considerable amount of literature regarding the outcome of group patient education, there is limited reference to the outcome of individual diabetes patient education or to quality assurance of the health messages delivered during this type of education. This study was designed to develop standardized educational messages for individual patient education delivered by diabetes nurse educators, test the immediate impact of these educational messages on patient knowledge, and identify any differences between diabetes nurse educators in their ability to influence patient knowledge. Overall, subjects demonstrated a significant improvement in knowledge immediately following an individual education session. The topic with the least improvement was diet. Significant differences in the patients' posteducation knowledge scores were observed between the three nurse educators in this study. No apparent patient factors accounted for this difference. PMID- 7851267 TI - The prognostic significance of urinary albumin in Polynesians with non-insulin dependent diabetes. AB - Polynesian (59 Maori and 30 Pacific Island) patients were identified from two diabetes clinic registers and followed for a mean of 4.8 years, in order to determine the prognostic significance of urinary albumin excretion. Events were defined as death or entry onto a renal replacement programme. Fourteen events occurred during the period of follow-up. Urinary albumin/creatinine ratio was treated as a continuous variable in a proportional hazards analysis. A 10-fold increase in albumin/creatinine ratio was associated with a 5-fold increase in the risk of an event (95% C.I. = 2.05-12.09). In conclusion, elevated urinary albumin/creatinine predicted mortality and renal morbidity in Maori and Pacific Island patients with non-insulin-dependent diabetes. PMID- 7851268 TI - The effect of an aldose reductase inhibitor (Epalrestat) on diabetic nephropathy in rats. AB - In order to clarify the possible contribution of the abnormal polyol pathway to the development of diabetic nephropathy, the effect of aldose reductase inhibitor on renal function and morphology was examined in streptozotocin (STZ)-induced diabetic rats. Six months after STZ injection, glomerular filtration rate and renal plasma flow showed marked decline with significant increase in nuclear-free mesangial area (MA) and relative mesangial area (RMA; MA per glomerular area) in diabetic rats. Oral administration of an aldose reductase inhibitor, Epalrestat, prevented renal hypofunction and mesangial expansion in diabetic rats without influencing the levels of blood glucose. These results suggest that the abnormal polyol pathway in diabetic rats is closely related to the development of mesangial expansion, a morphologic representative of diabetic glomerulopathy, and renal hypofunction. PMID- 7851270 TI - Indications of reduced pulmonary function in type 1 (insulin-dependent) diabetes mellitus. AB - Abnormalities of pulmonary function tests have been described in type 1 (insulin dependent) diabetes mellitus (IDDM). To better characterise such abnormalities and to verify whether these latter are associated with the presence of diabetic microvascular disease we compared 23 non-smoking patients who had IDDM with 24 non-smoking healthy control subjects strictly matched for sex, age, and body mass index. Compared with controls, diabetic patients had a reduced forced vital capacity (FVC) (87.5 +/- 13.1% vs. 96.4 +/- 13.6% of the predicted; P = 0.03) and forced expiratory volume in 1 s (FEV1) (90.5 +/- 17.7% vs. 101.2 +/- 13.2% of the predicted; P = 0.02). While within the group of patients the presence of retinopathy and autonomic neuropathy were not associated with modifications of pulmonary function tests, those with altered urinary albumin excretion rate (AER > or = 20 micrograms/min; range 21-589) (n = 7) had a significantly lower pulmonary diffusion capacity (DLCO) than the 16 normoalbuminuric subjects (62.6 +/- 7.2% vs. 88.7 +/- 20.1% of the predicted; P = 0.01). Moreover, in the group of patients, DLCO was inversely related with AER (r = -0.43; P = 0.04). In conclusion, IDDM is characterised by reduced FVC and FEV1, while a significant decrease in DLCO may be considered as selectively associated with renal disease. PMID- 7851269 TI - Glomerular hyperfiltration in young Polynesians with type 2 diabetes. AB - An increase in glomerular filtration rate (hyperfiltration) may be an important early event in the initiation of diabetic nephropathy but the prevalence of hyperfiltration appears to vary between different populations with type 2 diabetes. We have measured glomerular filtration rate using 51Cr EDTA clearance in 15 young Polynesians (mean age 32 years), 1-30 months after the initial diagnosis of type 2 diabetes and 15 control Polynesian subjects of comparable age and sex distribution. The mean glomerular filtration rate in the diabetic subjects (216 ml/min) was 57% greater than that of the controls (137.5 ml/min, P < 0.0001). About one-third of their excess in glomerular filtration rate could be accounted for by the marked obesity of the diabetic subjects, but even after correcting for body size the diabetic subjects still had a significantly higher mean glomerular filtration rate than controls (165.6 vs. 119.6 ml/min per 1.73 m2, P < 0.001); 73% of the diabetic subjects had hyperfiltration (> 140 ml/min per 1.73 m2). The diabetic subjects were normotensive but nonetheless had increased rates of albumin excretion (median 61 versus 9 mg/day, P < 0.001). We conclude that hyperfiltration is common in young Polynesians with recently diagnosed type 2 diabetes. Prospective studies are needed to determine whether this early abnormality of renal function heralds the later development of overt nephropathy. PMID- 7851271 TI - Glomerular clearance and tubular reabsorption of transferrin in microtransferrinuric patients with non-insulin-dependent diabetes. AB - Our objective was to determine the role of increased glomerular clearance (GC) or reduced tubular reabsorption (TR) of transferrin in producing microtransferrinuria. An infusion of L-arginine was used to inhibit TR of transferrin, permitting the determination of both GC and TR of transferrin in 64 patients with non-insulin-dependent diabetes mellitus (NIDDM), with or without microtransferrinuria. Thirty-one healthy volunteers served as control subjects. The GC of transferrin in NIDDM patients with microtransferrinuria did not differ significantly from that in healthy controls or in NIDDM patients with normal transferrin excretion rates (TfER). No correlation was found between TfER and GC of transferrin in any group of the subjects. However, the TR of transferrin was inversely correlated with TfER in healthy controls and in the NIDDM patients, with or without microtransferrinuria. When transferrin absorption was plotted against the filtered load of transferrin, the regression lines for the three subject groups were parallel. The regression line for NIDDM patients with microtransferrinuria was shifted to the right of those for healthy controls and NIDDM patients with a normal TfER. These findings suggest that microtransferrinuria in patients with NIDDM is caused by the impaired tubular reabsorption of transferrin. PMID- 7851272 TI - Impaired recovery in diabetic rat nerve following anoxic conduction block. AB - It is well documented that diabetic rats and subjects have a paradoxical resistance to ischemic conduction block although the nerves of diabetes are more susceptible to entrapment neuropathies. The aim of the present study was to further analyze the effect of anoxia on the diabetic nerve. Nerve conduction was measured in vitro in desheathed sciatic nerves from spontaneously diabetic rats (BB-Wistar) and age-matched controls. After onset of anoxia the compound action potential (CAP) decreased to 50% in 17 min in diabetic rat nerves and 8 min in normals. Following reoxygenation CAP recovered to 50% in 30 s in normal rat nerves and after 3 min the recovery was 92%. In nerves from diabetic animals 50% recovery took 4 min, but still after 12 min CAP was suppressed to a 60% level of the original. Longer periods of anoxia did not impair the recovery in normal nerve as it did in the diabetic ones. This defective recovery after anoxia in nerves from diabetic animals may be relevant for the understanding of the pathogenesis of entrapment neuropathies in diabetic subjects. PMID- 7851273 TI - Outcome of diabetic pregnancy and glucose intolerance in pregnancy: an audit of fetal loss in Newcastle General Hospital 1977-1990. AB - The outcome of pregnancy complicated by established diabetes or gestational glucose intolerance (diabetes mellitus or impaired glucose tolerance) is compared with the outcome of non-diabetic pregnancy. Between 1977 and 1990, 169 pregnancies in women with established diabetes and 61 pregnancies in women with gestational glucose intolerance were referred to the Newcastle General Hospital. The perinatal mortality (PNM) in women with established diabetes was 8.2/1000 and the viable fetal loss (sum of PNM, neonatal and infant loss) was 41/1000. The PNM in women with gestational glucose intolerance was 49.2/1000 and the viable fetal loss was 82/1000. The PNM in the background population was 11.6/1000. The fetal malformation rate was 17.3% for established diabetes, 9.8% in gestational glucose intolerance and 2.2% in the background population. Fetal abnormality remains the major cause of viable fetal loss in both established diabetes and gestational glucose intolerance. PMID- 7851274 TI - Relationship between insulin resistance and risk factors for cardiovascular disease in Japanese non-insulin-dependent diabetic patients. AB - To investigate whether a resistance to insulin-stimulated glucose uptake (IR) is associated with the risk factors (RF) for cardiovascular disease (CVD) in non insulin-dependent diabetic (NIDDM) patients, we determined the degree of IR in 135 adult NIDDM patients who had no advanced diabetic complications. The euglycemic (80 mg/dl) hyperinsulinemic clamp (insulin infusion rate 1.12 mU/kg per min) was performed and the average glucose infusion rate (GIR) during a steady-state euglycemia was determined as a measure of IR. Hypertension was more common among NIDDM patients with an increased IR and was highest in the group of patients with CVD. CVD-RF such as hypertension, hypertriglyceridemia, low HDL cholesterol and obesity tended to cluster in the NIDDM patients who had lower GIR values and higher fasting IRI levels. GIR values were compared between a set of groups extracted from the 135 NIDDM patients that were matched for age, sex, body mass index and HbA1c levels. The CVD-positive group had the significantly lower GIR value than the CVD-negative group (2.06 +/- 0.66 vs. 3.45 +/- 1.75, P < 0.005). The GIR value was also significantly lower in the hypertriglyceridemic group compared with the normotriglyceridemic group (2.50 +/- 1.36 vs. 4.03 +/- 1.82, P < 0.0005). However, there was no significant difference between the hypertensive and normotensive groups and between the high cholesterol or low HDL cholesterol groups and their respective control groups. In conclusion, these results suggest that IR contributes to the clustering of CVD-RFs which may accelerate the development of CVD in the subgroup of Japanese NIDDM patients. PMID- 7851275 TI - Improvement of glucose tolerance by bezafibrate in non-obese patients with hyperlipidemia and impaired glucose tolerance. AB - Glucose intolerance or diabetes mellitus, hyperlipidemia, obesity and hypertension may have a close interrelation based on insulin resistance. We selected 28 impaired glucose tolerance (IGT) patients with hyperlipidemia. The IGT patients demonstrated hypertriglyceridemia associated with hyperinsulinemia, a typical manifestation of insulin resistance. Administration of bezafibrate at 400 mg/day for 4 weeks to the IGT patients with hypertriglyceridemia resulted in an improvement of the plasma glucose level and insulin response to 75 g oral glucose loading associated with a concomitant decrease in non-esterified fatty acids. The ratio of the level of serum C-peptide to that of insulin after a 75 g oral glucose tolerance test (OGTT) was augmented after 4 weeks of bezafibrate administration. However, reduction of the cholesterol level with pravastatin did not alter these parameters. These results suggest that treatment to reduce the level of serum triglycerides, but not that of cholesterol, may have a beneficial effect for improving insulin resistance even in the non-obese subjects with IGT and decreasing the risk of coronary heart disease. PMID- 7851276 TI - Induction of insulin resistance by autoantibodies to insulin receptors following on an acute Coxsackie B4 infection. AB - We report a case of a young women who developed hyperglycemia shortly after Coxsackie B4 infection. Her clinical course was characterized by insulin resistance and the presence of anti-insulin receptor antibodies, without acanthosis nigricans. PMID- 7851277 TI - HIV infection and cocaine use in methadone maintained and untreated intravenous drug users. AB - In a survey of 424 intravenous drug users (IVDUs) of whom 107 were currently enrolled in a methadone maintenance program (MMP), we assessed risk behaviors for Human Immunodeficiency Virus (HIV) transmission and conducted HIV testing. We found that African Americans were over-represented in the HIV infected group and under-represented in the methadone maintenance treatment group. Furthermore, subjects in current methadone maintenance treatment reported fewer drug injections in the last 30 days, a reduced speedball (a heroin/cocaine mixture) injection frequency and reduced total cocaine and injected cocaine use. HIV infected subjects reported 20% more cocaine use and injected cocaine use than HIV negatives. However, this difference was due to African Americans reporting more cocaine use and at the same time being over-represented in the HIV infected group. Stratified analysis by ethnicity found significant MMP effects for all ethnic groups, but only one significant HIV status effect, and this was limited to African Americans. Cocaine injection frequency in African Americans was significantly higher for the HIV infected versus non-infected subjects. We conclude that i.v. cocaine use is a risk factor associated with HIV infection and that methadone maintenance treatment is associated with reducing this risk factor. Furthermore, African American cocaine users are at great risk for HIV infection, and increased efforts for engagement in treatment are necessary. PMID- 7851278 TI - A controlled comparison of buprenorphine and clonidine for acute detoxification from opioids. AB - We compared the short-term efficacy of a high-dose, 3 day regimen of buprenorphine to a standard 5-day course of clonidine in attenuating the signs and symptoms of the acute opioid abstinence syndrome during rapid detoxification from heroin in 25 men and women admitted to a closed inpatient research ward for this randomized, double-blind, parallel-group trial. Among the 18 completers, there were no significant differences between the buprenorphine and clonidine groups on five subjective and six physiological measures. However, clonidine lowered blood pressure and buprenorphine provided more effective early relief of withdrawal symptoms. PMID- 7851279 TI - The effect of repeated amphetamine administration on the proopiomelanocortin mRNA level in the rat pituitary: an in situ hybridization study. AB - The effect of single and repeated administration of amphetamine (5 mg/kg i.p., twice daily, 14 days) on the proopiomelanocortin (POMC) mRNA level was investigated in the rat pituitary. In situ hybridization histochemistry, using a 35S-d-ATP-labelled deoxyoligonucleotide probe and densitometric analysis of autoradiograms, showed that repeated administration of amphetamine moderately increased the POMC mRNA level (by approximately 16%) in the anterior and the intermediate lobes of the pituitary at 72, but not 2, hr after the last injection. Adrenalectomy (48 h after the last drug injection) increased the POMC mRNA level only in the anterior lobe of repeated saline- and amphetamine-treated rats by 59 and 67%, respectively. No significant changes in POMC mRNA level in either lobe were found following single administration of amphetamine. These results suggest that repeated amphetamine administration leads to a delayed and moderate increase in POMC biosynthesis in the rat pituitary. On the other hand, the responsiveness of the POMC pituitary system to adrenalectomy was not significantly altered in rats treated repeatedly with amphetamine. PMID- 7851280 TI - Suspected determinants of enrollment into detoxification and methadone maintenance treatment among injecting drug users. AB - Our primary aim in this study has been to evaluate selected conditions thought to influence the entry of injecting drug users (IDU) into detoxification and methadone maintenance programs, making use of a prospective study design to strengthen a cross-sectional investigation of these conditions. To begin our investigation, we analyzed cross-sectionally gathered data on 2879 IDUs who had been recruited through extensive community outreach efforts and who were interviewed at the time of recruitment. We then tested our hypotheses about suspected determinants of entry into treatment by analyzing prospectively gathered data on 1039 active drug users who had no recent history of being treated for drug problems. Among these 1039 IDUs (a subset of the initial cross sectional sample), 144 entered a detoxification program between their recruitment interview and their next follow-up interview, conducted about six months after recruitment (range: 3.5-9.5 months) and 64 entered a methadone maintenance program during that observation interval. Using multiple logistic regression analyses, we found that a recent drug overdose, relatively higher frequency of injecting drugs, and a history of prior arrest or treatment were independent predictors of entry into detoxification. Being married or living with a partner, being female, a lengthy duration of drug use (> 10 years), and a history of prior treatment were independent predictors of entry into methadone maintenance. These findings shed light on what appears to be a different profile of suspected determinants of entry into a detoxification treatment versus methadone maintenance treatment, and help to clarify some potential differences between treated and untreated drug users that ought to be considered when evaluating results of investigations with IDU participants recruited solely from treatment settings. PMID- 7851281 TI - Opiate detoxification of methadone maintenance patients using lefetamine, clonidine and buprenorphine. AB - Thirty-nine methadone maintenance patients were included in a 9-day, double blind, randomized, inpatient detoxification trial. Methadone was tapered to 10 mg/day and then patients were assigned to one of these 3 protocols: clonidine (0.3-0.9 mg/day), lefetamine (60-240 mg/day), buprenorphine (0.15-0.9 mg/day). Buprenorphine treatment was significantly superior to clonidine and to lefetamine (F = 3.96 df = 2, 29 P < 0.05) in controlling objective, subjective and psychological withdrawal symptomatology. Clonidine was more effective than lefetamine in suppressing withdrawal in the first 3 days of treatment (day 3: F = 4.10 df = 2, 30 P < 0.05), and this trend was apparent on the objective and psychological items. In addition to evaluations of the efficacy of the single drugs used, the study showed that tapering methadone to low doses before entering the pharmacologically assisted discontinuation phase was clinically acceptable in detoxification from long-term methadone treatment. PMID- 7851282 TI - Effects of morphine in postaddict humans: a meta-analysis. AB - The literature on assessment of abuse liability of opioid drugs in humans was reviewed, and meta-analysis (a statistical method designed to combine results of different studies) was performed to study a dose-effect relationship for some variables commonly used for the evaluation of the subjective and physiological effects of morphine. Thirty-five studies, published between 1964 and 1991, including the i.m. or s.c. administration of morphine to non-dependent subjects with prior history of opioid abuse, were selected. Logistic regression models were applied for categorically dependent variables, and linear regression models were used for quantitative dependent variables. The log-transformation of the dose of morphine, stratifying by studies, acted as predictor variable. A dose effect function was demonstrated. Doses producing an average effect across studies ranged from 7 mg (observers-reported 'liking') to 12 mg (subjects reported 'liking'). Average effect on pupil diameter decreases was obtained for a dose of 8 mg. Doses producing a 50% of maximum positive responses were 10 mg for subjects' opioid classification, and 20 mg for the ARCI-MBG scale. The heterogeneity between studies obtained, along with the large variability present in most of the variables, supports the usefulness of a concurrent assessment of several indexes when assessing the effects of morphine. PMID- 7851283 TI - Anabolic steroid users identified by needle and syringe exchange contact. AB - The increasing prevalence in the extent of misuse of anabolic-androgenic steroids has been well recognised in the United States and more recently in Great Britain. The injecting misuse of steroids carries with it considerable risks in relation to liver damage, lipid metabolism disturbance and the potential of HIV and viral hepatitis transmission. This study of 21 steroid users contacted at a needle and syringe exchange showed that 42.8% had abnormal liver function tests and 28.5% had lowered high-density lipoprotein concentrations. None of this group reported engaging in high risk behaviour through sharing injecting equipment. The group did contain a bisexual and a previous injecting amphetamine user. Needle and syringe exchanges offering health examination facilities will provide a valuable role in contacting steroid users who will then be in a position to make informed decisions about their own drug use and the potential harm from steroids. PMID- 7851284 TI - Effects of in-utero opiate exposure: new paradigms for old questions. AB - The purpose of this paper is to present an overview of existing research on prenatal opiate exposure, identifying limitations of past work and in so doing provide a useful paradigm for contemporary investigations. Initial opiate exposure research in the 70's and early 80's typically employed a bi-variate approach with little or no attention to multiple confounding factors. By the mid 80's most researchers recognized that not only biological but social and environmental risk factors must be considered and began to call for a multi factorial approach to investigate perinatal and developmental outcomes associated with prenatal opiate exposure. However, concurrent with this direction toward a multivariate approach, prenatal cocaine exposure became a priority and funding interest in the effects of opiates began to wane. Unfortunately, rather than employ the model emerging from the experience of opiate investigations, initial research directed at identifying effects of cocaine exposure often employed the same type of bi-variate approach, naive to the cumulative risks concomitant to maternal substance abuse. Subsequently, one is left with a sense of de ja vu as researchers investigating the effects of prenatal cocaine exposure begin to recognize the complexity of delineating the effects of prenatal drug exposure and the need to address multiple confounding factors. It is within this context that an overview of existing research on prenatal opiate exposure will be presented with the hope that the limitations of the past can be used to construct a useful paradigm for the future.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7851286 TI - [20 years of endoscopic papillotomy. Analysis of 2752 patients at Erlangen Hospital]. AB - Following the development and introduction of endoscopic papillotomy (EPT), 2752 procedures were performed at Erlangen University Hospitals between 1973 and 1993. All papillotomies were evaluated with regard to indications, technique, results, complications and mortality. To show the development process clearly, results for the periods 1973-1980 (A), 1981-1987 (B) and 1988-1993 (C) were summarised separately. The proportion of patients with common bile duct stones was 91% in group A, 60% in group B and 41% in group C. By contrast the number of papillotomies for malignant disease rose from 1% (A) to 26% (B) and 29% (C). More recent indications such as chronic pancreatitis (11%), biliary pancreatitis (5%) and others (for example sphincter of Oddi dysfunction) (11%) were first seen in group C. While the Erlangen standard papillotomy was used in almost all cases in group A (96%), the precut technique was used (mostly with needle knife) in one third of all papillotomies in groups B and C (32%). The success rate for EPT in all three periods was highest for common bile duct stones (from 96% for group A to 98% for groups B and C). For malignancies, the success rate was lower (89% in groups B and C). The complication rate fell significantly with time (P < 0.05) from 11% (A) to 7.6% (B) and 6.3% (C). Precut techniques did not increase the complication rate. While 71% of all complications were treated surgically in period A, the proportions fell to 28% (B) and then to 7.5% (C). Method-related mortality fell from 1.1% (A) to 0.4% (B) and 0.5% (C).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7851285 TI - Prenatal alcohol and offspring development: the first fourteen years. AB - This report summarizes findings from a prospective longitudinal study of the effects of prenatal alcohol exposure on a birth cohort of 500 offspring selected from 1,529 consecutive pregnant women in prenatal care by mid-pregnancy at two representative community hospitals. Effects of prenatal alcohol observable on size measures at birth were insignificant after 8 months. Morphometric analysis of facial features identified effects only at the very highest alcohol exposure levels. By contrast, dose-dependent effects on neurobehavioral function from birth to 14 years have been established using partial least squares (PLS) methods jointly analysing multiple measures of both alcohol dose and outcome. Particularly salient effects included problems with attention, speed of information processing, and learning problems, especially arithmetic. PMID- 7851287 TI - [Xanthogranulomatous pyelonephritis with phlegmonous abdominal wall infiltration. Diagnosis and assessment of extent via computerized tomography]. AB - A 34-year-old woman who 14 years previously had undergone a left nephrotomy for nephrolithiasis complained of pain in the left renal fossa which was reddened and painful on percussion. She had a fever of 38.2 degrees C. C-reactive protein was raised to 80 mg/l, the white cell count to 14,620/microliters (83% neutrophils). Protein and white cells were found in the urine together with a significant number of E. coli on urine culture. Plain film of the abdomen showed a staghorn calculus and ultrasonography demonstrated renal enlargement with a possible paranephritic abscess. The computed tomography diagnosis was xanthogranulomatous pyelonephritis, on the basis of renal enlargement, staghorn calculus, hypodense areas with typical density values (10-15 Hounsfield units), contrast enrichment and extrarenal extension of partly phlegmonous partly fused-together inflammatory changes. The abscessing parts were drained under computed tomography control. Starting 7 days pre-operatively the patient had been receiving ciprofloxacin (0.4 g daily) intravenously. A nephrectomy had to be performed subsequently. Antibiotic treatment was discontinued 2 weeks later and she was discharged symptom-free. The diagnosis of diffuse xanthogranulomatous Pyelonephritis was confirmed by histological examination of the surgical specimen. PMID- 7851288 TI - [A small outbreak of trichinosis caused by imported smoked ham]. AB - Three patients fell ill with diarrhoea 14 to 15 days after eating smoked ham. All had an increased white cell count (up to 16,200 microliters), eosinophilia (14 to 38%) and increased creatinkinase activity (357 up to 1905 U/l). Patient 1 (a 21 year-old woman) also had fever of around 40 degrees C; patient 2 (32-year-old woman) had a fever up to 39 degrees C, with muscle pains and swellings in the face. Patient 3 (38-year-old man) had no other symptoms. Because of eosinophilia and as five other family members in former Yugoslavia whence the ham had been imported, also had had fevers, trichinosis was soon considered as the cause. Serology in patients 1 and 2 was positive on admission, in patient 3 after one week. Mebendazole was administered, initially 50 mg/kg in three doses for 2 days. Drug blood levels were determined 1 and 4 hours after start of treatment and the dosage was then increased to 80-100 mg/kg daily. Duration of treatment ranged from 11 to 14 days. All patients were discharged symptom-free and there have been no sequelae. In Germany trichinosis typically occurs in small outbreaks. It is assuming increasing importance as an imported disease. PMID- 7851289 TI - [Monoethylglycinexylidide (MEGX)-test. A test for the assessment of prognosis before and after liver transplantation]. PMID- 7851290 TI - [Diagnosis of alcohol embryopathy]. PMID- 7851292 TI - [Duty to secrecy in a patient's unfitness for automobile driving]. PMID- 7851291 TI - [Cholesterol debate: evaluation of overeating and lack of exercise as health risk factors?]. PMID- 7851293 TI - [Tissue plasminogen activator following unsuccessful resuscitation in fulminant lung embolism?]. PMID- 7851294 TI - [Thyroid hormone resistance. Rare cause of recurrence following goiter resection]. PMID- 7851295 TI - [Hyperthermia in metastasizing breast carcinoma]. PMID- 7851296 TI - [The surgical treatment of intestinal prolapse (prolapsus recti) in fattening swine under practice conditions]. AB - The amputation of the prolapsed rectum of 102 pigs of a fattening unit was carried out by means of a 5-10 cm piece of a plastic hose inside and a ligation around the prolapse. The pressure necrosis due to the ligation leads to the amputation of the prolapse. The positive effect of this method on the performance of the pigs was demonstrated by comparing the 102 treated pigs with a group of pigs that were not treated and with the non-diseased control group. Additionally the influence of diarrhoea and coughing on the frequency of rectal prolapses was investigated. PMID- 7851297 TI - [Decrease of the lead burden of cattle within the last 20 years]. AB - After introduction of many measures in technical and hygienic fields, emission of lead was remarkably reduced within the last years. Whether these measures were followed by a real decrease of the actual lead burden of man and animals may be recognized by controlling the lead content of food. Further it was possible to quantify a biological effect as an indicator of lead burden by the activity of delta-aminolevulinic acid dehydratase in red blood cells of cows in the Hannover area and to compare actual results with those obtained twenty years ago in the same region using identical methods. Results show a remarkable decrease of lead caused inhibition of that enzyme. PMID- 7851298 TI - Antibody prevalence of caprine arthritis encephalitis virus (CAEV) in goats in Turkey. AB - In this study, a serological survey in goat herds for antibodies against Caprine Arthritis Encephalitis Virus (CAEV) in Turkey is described. 808 serum samples were collected from three state farms and seven private flocks in different regions of Turkey. The serologic examination was performed by Agar Gel Immunodiffusion (AGID) technique. 16 (1.9%) out of 808 sera deriving from two state farms (n = 14) and one private herd (n = 2) were found to be serologically positive. The findings are discussed with regard to the relatively low prevalence of CAEV in Turkey, age and race dependency and the kind of origin of the serologically screened animals. PMID- 7851299 TI - [Salmonella in broiler intestines in relation to flooring system]. AB - Broilers were reared on two flooring systems: conventional litter (wood shavings) and plastic floor ("trampoline") without litter. Female birds were housed over 49 d (20 birds per m2), males over 70 d (10 birds per m2). After slaughtering the guts were sampled and deep frozen. Guts of 84 birds from litter floor and 94 birds from plastic floor were examined for Salmonella. Totally, 20% of the guts were Salmonella negative. The plastic floor did not significantly diminish the occurrence of Salmonella. Also not significant in both flooring systems was the higher amount of negative samples after 49 d than after 70 days. Data show, that the amount of Salmonella in the guts of birds from plastic-floor might have been lower than those from litter-floor, in the samples from plastic-floor the amount of Salmonella after 49 days might have been lower than in those after 70 days rearing. The isolates were S. virchow and S. enteritidis. PMID- 7851300 TI - [The effect of birth weight on the early postnatal vitality of piglets]. AB - Investigations with 1248 newborn piglets in 7 farms showed a high significant influence of birth weight on parameters of early postnatal vitality. The duration between birth and first standing up was by two times, the time between birth and first udder contact by 3.5 times and the duration between birth and first colostrum intake was by 4 times longer in piglets with a low birth weight (< 800 g) in comparison with heavier piglets at birth (> 2200 g). The drop in rectal temperature up to 30 minutes after birth reached 4.5 Kelvin in lightweight piglets, whereas their litter mates with a high body weight at birth had a value of 0.85 K (p < 0.01). The birth weight of piglets belongs to the most important endogenous factors with influence on the vitality of newborn piglets and has a high prognostic value in relation to the risk of losses and the live weight development of neonates. PMID- 7851301 TI - The impact of live animal importation on the epizootiology of foot-and-mouth disease in Saudi Arabia. AB - Saudi Arabia imports annually more than 6 millions live ruminants for slaughter. The majority of these animals are imported from countries where foot-and-mouth disease (FMD) is enzootic. Serotypes of FMD virus not incorporated in the vaccine currently used in Saudi Arabia (e.g. SAT1 and SAT2) are prevalent in some of these exporting countries, and in others, the prevalent serotypes of FMD virus are not routinely typed. The previous exposure of imported animals to field FMD virus in the countries of origin has been confirmed by the detection of precipitating antibodies against virus infection associated (VIA) antigen and neutralizing antibodies against serotypes O, A, C and/or Asia1 of FMD virus in the sera of some imported animals. However, no isolation of FMD carrier virus could be made from 209 proband samples collected from sheep and goats imported from countries where FMD is enzootic. The significance of the obtained results is discussed. Particular emphasis has been placed on the possibility of importing either carrier animals which might act as potential source of infection or subclinically infected animals which might actively excrete FMD virus. In addition recommendations are made to reduce the risks of introducing exotic FMD virus strains to the Kingdom through live animal importation. PMID- 7851303 TI - [Bovine leukocyte adhesion deficiency: clinical picture and differential diagnosis]. AB - The pathological clinical and laboratory findings obtained in 50 calves and young cattle affected with Bovine Leukocyte Adhesion Deficiency are compared with those found in 114 calves and young cattle showing marked neutrophil leukocytosis of other origin (age: < 2 years; leukocyte count: > 30,000 per microl; percentage of lymphocytes: < 55%). PMID- 7851302 TI - [Detection of antibodies against the virus of enzootic bovine leukosis in serum and milk samples using an immunoblot]. AB - A method for detection of antibodies against the enzootic bovine leukemia virus in single serum and milk samples, as well as in pooled milk samples, is described. After the electrophoretical separation of the antigen proteins with SDS-PAGE, a transfer onto an immobilizing membrane is done, followed by immunodetection based on the reaction of the leukemia virus antibodies with antigen proteins. The antibody-antigen complex is visualized by a second, biotinylated antibody and peroxidase-avidin. This system is developed for verification of ELISA-results in surveillance of official admitted herds free of leukosis. The threshold for positive samples is tested by the European reference serum E-4, Copenhagen, the dilution 1:25,000 is recognized as positive. The detected antigen-antibody reactions are determined by scanning and comparison with the MW-markers. PMID- 7851304 TI - Inferior vena cava flow velocity waveforms relative to fetal behavioural states and sample site in normal term pregnancy. AB - Reproducibility and behavioural state dependency of flow velocity waveforms from the proximal and distal part of the fetal inferior vena cava were studied in a total of 27 normal pregnancies at 36-39 weeks of gestation. Within patient coefficients of variation in fetal inferior vena cava waveform recording were markedly higher for the proximal part compared with the distal part. This is also reflected by lower reliability values as a measure of the relative proportion of within patient and between patient variance components. No statistically significant changes in flow velocity values could be detected at proximal and distal level of the fetal inferior vena cava relative to fetal behavioural states. A marked difference in flow velocity values was, however, observed between the two measuring sites with the highest velocities at proximal level. Since a considerable variation in fetal inferior vena cava flow recording was established, a possible behavioural state related modulation may have been obscured by these waveform variabilities. PMID- 7851305 TI - Growth parameters in mid-trimester fetal Turner syndrome. AB - Growth failure is a consistent finding at birth in infants with Turner syndrome. However, the time of onset and pattern of growth deficiency is unknown. To determine the presence of growth failure in the second trimester in fetuses with Turner syndrome, second trimester fetuses that had a complete autopsy at the Central Laboratory for Human Embryology at the University of Washington were studied. A control group of specimens with normal findings was selected and compared with a study group with Turner syndrome documented by karyotype. Footlength and crown-rump length were measured directly with a ruler and femur, tibia, fibula, humerus, ulna and radius were measured from X-rays. Crown-rump length was used as the indicator of gestational age. Statistical comparisons between the normal and study groups were performed by multiple regression. Long bone measurements were made on 105 normal and 13 Turner fetuses. Footlength and the six long bones showed evidence of statistically significant growth failure. Fetuses with 45,X/46,XX mosaic Turner syndrome may demonstrate a lesser degree of growth retardation, at least for footlength, than those with a 45,X karyotype, but small numbers limited the analysis. We conclude that the growth failure consistently demonstrated in newborns with Turner syndrome begins early in gestation and is well-established by mid-pregnancy. PMID- 7851306 TI - Sodium in hand and pump expressed human breast milk. AB - Sodium content was analysed in the expressed breast milk from 30 mothers. Measurements were taken up to 24 days postpartum, during which time the mothers expressed manually or by means of a pump. Statistical analysis has confirmed not only the known decline in sodium levels postpartum but has also shown a significantly higher sodium content in manually expressed milk compared to that from pump expressed milk. This finding suggests that the method of expression may alter the sodium concentration in human breast milk, thus potentially reducing the amount of sodium supplementation required by some preterm infants. PMID- 7851308 TI - Immunohistochemical and morphometrical development of the dorsal root ganglion as a neural crest derivative: comparison with the fetal CNS. AB - The developmental difference between the dorsal root ganglion (DRG), paravertebral ganglion (PVG) and the central nervous system (CNS) in embryos and fetuses was investigated using immunohistochemical (neuron-specific enolase (NSE) and human natural killer-1 (HNK-1)) and morphometrical methods. NSE positive cells developed from 7 weeks of gestation in the DRG as early as the anterior horn cells of the spinal cord, while the pyramidal cells of the cerebral cortex matured after 20 weeks of gestation. HNK-1 positive granules were present until 14 weeks gestation in the spinal cord and until 26-27 weeks in the DRG and PVG. This early development of DRG cells may be closely related to the peripheral organ maturation during the embryonic or early fetal period. PMID- 7851307 TI - Ultradian and diurnal cyclicity in the sleep states of newborn infants during the first two postnatal days. AB - OBJECTIVE: The purpose of this study was to investigate both ultradian and diurnal cyclicity in the sleep states of newborn fullterm infants during the first 2 postnatal days. METHODS: The sleep of 31 healthy newborn infants was recorded continuously throughout the first 2 postnatal days, starting immediately after birth, using an automated Motility Monitoring System (MMS). The MMS consists of a pressure sensitive mattress pad connected to an amplifier and a small 24-h analog recorder. A single channel of analog signals produced by the infant's respiration and body movements was recorded and then scored in 30-s epochs for Active Sleep. Quiet Sleep, Active-Quiet Transition, Sleep-Wake Transition, and Wake. DATA ANALYSES: The 48 h of recording were divided into successive 12-h periods from 07:00 h to 19:00 h (day) and 19:00 h to 07:00 h (night), and all measures were derived for each day and night period. Both cross sectional and repeated measures analyses were used because all babies were not represented in all day/night periods. RESULTS: Day/night differences in state variables: On both days, there was greater Wakefulness, shorter Quiet Sleep Bout Lengths, shorter Mean Sleep Periods and shorter Longest Sleep Periods during the daytime. On day 1 only, there was less Quiet Sleep, shorter Quiet Sleep Bout Lengths and more Sleep-Wake Transition during the daytime. On day 2, repeated measures analyses revealed two additional day/night differences: less Quiet Sleep and more Sleep-Wake Transition during the daytime. Day/night differences in Quiet Sleep cyclicity: 28 sleep periods met the criteria for analysis of Quiet Sleep cyclicity, and only six of these occurred during the daytime. Seventeen of 28 analyzable sleep periods showed significant Quiet Sleep cyclicity. Only two of these occurred during the daytime. CONCLUSIONS: Contrary to the prevailing view of developing sleep rhythms, the results of this study suggest that newborn infants exhibit both ultradian ad diurnal cyclicity in their sleep patterns from the earliest postnatal period. PMID- 7851310 TI - Kinetic theory of living pattern. AB - The self-organization whereby developing organisms generate the patterns and spatial relationships of their parts has not been explained on any generally accepted theoretical basis. There is a wide gulf between physical scientists and experimental biologists in their expectations of the kind of theory that is best to pursue. Physical scientists incline towards the power of nonlinear dynamics to generate pattern and are trying evangelistically to interest biologists in this approach. PMID- 7851309 TI - Late neurological, cognitive and behavioural sequelae of prenatal exposure to coumarins: a pilot study. AB - Neurological, cognitive and behavioural development were assessed in a group of 21, 8- to 10-year old children whose mothers took coumarins during pregnancy. Findings were compared with those in a group of 17 control children. The study was performed to test whether it is feasible to carry out a reliable retrospective study of late effects of prenatal exposure to coumarins. This turned out to be the case. In this small pilot study, no statistical significant differences were found between the study and control group, nevertheless a few findings were remarkable. One child showed severe neurological abnormalities, which may be due to prenatal exposure to oral anticoagulants. The children with the lowest scores on the neurological assessment and the lowest IQ-scores, were found in the exposed group. Obviously, the number of children in this study is too small to conclude if there has been definite effects from coumarin, but these results indicate that a large follow-up study is required. In the present paper, we have shown that such a study is feasible. PMID- 7851312 TI - Noninfectious manifestations of human immunodeficiency virus infection. AB - Infection with HIV is associated with an array of noninfectious conditions of which the emergency physician should be aware. The knowledge of these complications and their differentiation from microbial conditions also common with HIV is essential in treating such patients in the emergency department. These complications involve every organ system: they are discussed in some detail and the most common are considered more closely from a target organ perspective. PMID- 7851311 TI - The epidemiology of the acquired immunodeficiency syndrome in the 1990s. AB - Since the recognition of AIDS in 1981, it has become a global pandemic afflicting more than 6 million people worldwide. To date, more than 22 million people are infected with HIV-1, the cause of AIDS, and more than 40 million people may be infected with HIV by the year 2000. In the United States, AIDS has become the leading cause of death in young men and the fourth leading cause of death in young women. HIV is primarily transmitted sexually, parenterally, and perinatally, with increasing evidence of heterosexual transmission in the United States and worldwide. Factors associated with transmission and susceptibility to HIV are discussed, and the natural history of HIV and means of intervention are detailed in this article. PMID- 7851313 TI - Adverse reactions to therapy for HIV infection. AB - Although chronic drug therapy with antiretroviral agents and chemoprophylaxis has led to longer survival without disease, high rates of adverse reactions to agents used to treat HIV infection have been reported. The incidence of adverse drug reactions in patients with HIV infection varies with the type of drug therapy, dosage, drug-to-drug interactions, and the stage of HIV infection. This article discusses recognition, treatment, and prevention of adverse reactions to specific drugs and classifications of drugs. PMID- 7851314 TI - HIV infections in children. AB - HIV infection in infants and children who acquire it early in life is quite different from HIV infection in adults. The immune deficiency that results occurs in an immunologically naive organism, resulting in a larger role for common pathogens in causing severe infections. The immune deficiency is superimposed on age-related changes in all parts of the immune system so that a CD4 count that would be comforting in an adult or older child is cause for concern in an infant. Manifestations of infection include susceptibility to common and opportunistic infection, but growth failure and neurocognitive delays are much more significant patterns of disease than in adults. Therapy is clearly effective in slowing progression of the disease and, in the case of treatment of the pregnant woman, capable of primarily preventing the infection. The emergency physician's role in the treatment of children with HIV infection includes early identification, management of infections and complications, and advocacy for children who are so often unable to advocate for themselves. PMID- 7851315 TI - Psychiatric issues and emergencies in HIV infection. AB - Emergency departments are frequently the entry point for patients infected with HIV. Psychiatric conditions may be the initial predominant presentation or an important concomitant factor. Because of the complexities of HIV infection, the serious medical nature of its associated psychiatric complications, the frequent presence of comorbid substance use and other behavioral disorders, and the multiple sites of treatment involved, psychiatrists, emergency physicians, and other professionals must work in collaboration in screening patients infected with HIV for mental disorders and in providing careful and rational care. PMID- 7851316 TI - Tuberculosis in the HIV-infected patient. AB - After decades of decline, tuberculosis has emerged as a global health challenge. In the setting of HIV immunocompromise, TB occurs frequently, early, and often atypically. New infections can take an accelerated course. The usual tests for diagnosing Mycobacterium tuberculosis infection are less sensitive when CD4+ counts are low. Increased prevalence of treatment failure, drug-resistant strains, and nosocomial transmission of multidrug-resistant TB are discussed as are new diagnostic tests that will accelerate the time to diagnosis and allow better epidemiologic tracking. Early recognition, isolation, appropriate therapy, and environmental controls that will protect staff and patients from the risk of exposure are also described. PMID- 7851317 TI - Risks for exposures to and infection with HIV among health care providers in the emergency department. AB - This article reviews the information available that is relevant to the risk of occupational infection with HIV, attempts to frame this evidence in perspective for emergency health care providers, and underscores the strategies that have been shown to be effective in reducing these risks. PMID- 7851318 TI - HIV and AIDS. Legal and ethical issues in the emergency department. AB - The treatment of individuals infected with HIV in the emergency department presents difficult and unique medical, social, legal, and ethical issues. These issues include: (1) informed consent for testing for HIV status, (2) mandatory testing of patients for HIV, (3) confidentiality of patients infected with HIV, (4) the duty to treat individuals infected with HIV, and (5) issues concerning health care workers infected with HIV. PMID- 7851319 TI - Biology of HIV-1 and treatment strategies. AB - Effective vaccines and treatments for HIV-1, the retrovirus responsible for AIDS, continue to be elusive. Many of the obstacles to more effective intervention can be traced to special properties of the virus itself. Although great progress has been made in our understanding of the biology of the virus, important gaps remain regarding how HIV-1 functions as an agent of disease. The poor track record of traditional approaches to date has also spurred the development and testing of novel strategies, such as gene therapy, for the treatment of HIV-1 disease. PMID- 7851320 TI - HIV testing. AB - Testing for HIV infection is not generally required for the appropriate treatment of medical emergencies. Current standard HIV tests rely on the detection of antibodies to the HIV virus and are among the most sensitive and specific tests used in medicine. Standard HIV tests can be unreliable for detecting infection in certain patients, such as individuals who have been recently infected and neonates born to mothers with HIV infection. Other methods for detecting HIV infection, such as viral culture, polymerase chain reaction (PCR) amplification of viral DNA or RNA, and detection of viral antigens have limited clinical applications. Testing for HIV infection requires facilities for effective counseling, access to appropriate medical referrals, and the ability to maintain strict patient confidentiality. PMID- 7851321 TI - Presentations and emergency department evaluation of HIV infection. AB - Patients with HIV infection may present with a wide variety of symptomatology, both related and unrelated to HIV infection. Evaluation should be conducted in an orderly fashion and should focus on the involved system, with particular attention to ruling out treatable infection, malignancy, or other HIV-related disease process. PMID- 7851322 TI - Infectious complications of HIV disease. AB - HIV disease is associated with a wide variety of infections caused by bacteria, viruses, parasites, and fungi. Although some infections occur only in patients with very low CD4 cell counts, others require only mild to moderate immunosuppression. This article discusses the opportunistic infections associated with HIV disease and reviews their clinical presentation, diagnosis, treatment, and prevention, with an emphasis on emergency department diagnosis and management. PMID- 7851323 TI - 4th Japan-U.S. Biostatistics Conference on the Study of Human Cancer. Tokyo, Japan, November 9-11, 1993. PMID- 7851324 TI - A two-stage validation study for determining sensitivity and specificity. AB - A two-stage procedure for estimating sensitivity and specificity is described. The procedure is developed in the context of a validation study for self-reported atypical nevi, a potentially useful measure in the study of risk factors for malignant melanoma. The first stage consists of a sample of N individuals classified only by the test measure. The second stage is a subsample of size m, stratified according the information collected in the first stage, in which the presence of atypical nevi is determined by clinical examination. Using missing data methods for contingency tables, maximum likelihood estimators for the joint distribution of the test measure and the "gold standard" clinical evaluation are presented, along with efficient estimators for the sensitivity and specificity. Asymptotic coefficients of variation are computed to compare alternative sampling strategies for the second stage. PMID- 7851325 TI - Analysis of cancer risk related to longitudinal information on smoking habits. AB - Radiation Effects Research Foundation (RERF) has followed the RERF Life Span Study (LSS) cohort consisting of atomic bomb survivors and unexposed subjects for more than 40 years. The information on their lifestyles, including smoking habits, has been collected in the past 25 years through two mail surveys of the entire LSS cohort and three interview surveys of a subcohort for the biennial medical examination program. In the present study an attempt was made to consolidate the information of smoking habits obtained from the five serial surveys, and then a risk analysis was conducted to evaluate the effect of updating the smoking information on the smoking-related risk estimates for lung cancer. The estimates of smoking-related risk became larger and estimates of dose response became sharper by updating smoking information using all of the data obtained from the five serial surveys. Analyses were also conducted for cancer sites other than lung. The differences in risk estimates between the two approaches were not as evident for the other cancer sites as for lung. PMID- 7851326 TI - Corrected likelihood for proportional hazards measurement error model and its application. AB - Consider the case where the exact values of covariates in the proportional hazards model may not be observed but instead, only surrogates for them involving measurement errors are available. The maximum likelihood estimate based on the partial likelihood with the true covariate replaced by the observed surrogate is even asymptotically biased and may cause seriously misleading results in covariance analysis based on the partial likelihood. These facts are illustrated by Monte Carlo simulation. A correction to partial likelihood proposed by the first author is studied to gain insight into its merits and limitations in practical applications. The results indicate that when the "effective magnitude of the measurement error" as defined in this article is small, which is indeed the case for most applications, the method will be useful. Some other correction methods for the measurement error in censored survival models are also reviewed and discussed. PMID- 7851327 TI - Design and analysis of multilevel analytic studies with applications to a study of air pollution. AB - We discuss a hybrid epidemiologic design that aims to combine two approaches to studying exposure-disease associations. The analytic approach is based on comparisons between individuals, e.g., case-control and cohort studies, and the ecologic approach is based on comparisons between groups. The analytic approach generally provides a stronger basis for inference, in part because of freedom from between-group confounding and better quality data, but the ecologic approach is less susceptible to attenuation bias from measurement error and may provide greater variability in exposure. The design we propose entails selection of a number of groups and enrollment of individuals within each group. Exposures, outcomes, confounders, and modifiers would be assessed on each individual; but additional exposure data might be available on the groups. The analysis would then combine the individual-level and the group-level comparisons, with appropriate adjustments for exposure measurement errors, and would test for compatibility between the two levels of analysis, e.g., to determine whether the associations at the individual level can account for the differences in disease rates between groups. Trade-offs between numbers of groups, numbers of individuals, and the extent of the individual and group measurement protocols are discussed in terms of design efficiency. These issues are illustrated in the context of an on-going study of the health effects of air pollution in southern California, in which 12 communities with different levels and types of pollution have been selected and 3500 school children are being enrolled in a ten-year cohort study.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7851328 TI - Hierarchical regression for epidemiologic analyses of multiple exposures. AB - Many epidemiologic investigations are designed to study the effects of multiple exposures. Most of these studies are analyzed either by fitting a risk-regression model with all exposures forced in the model, or by using a preliminary-testing algorithm, such as stepwise regression, to produce a smaller model. Research indicates that hierarchical modeling methods can outperform these conventional approaches. These methods are reviewed and compared to two hierarchical methods, empirical-Bayes regression and a variant here called "semi-Bayes" regression, to full-model maximum likelihood and to model reduction by preliminary testing. The performance of the methods in a problem of predicting neonatal-mortality rates are compared. Based on the literature to date, it is suggested that hierarchical methods should become part of the standard approaches to multiple-exposure studies. PMID- 7851329 TI - Effect of air pollution on lung cancer: a Poisson regression model based on vital statistics. AB - This article describes a Poisson regression model for time trends of mortality to detect the long-term effects of common levels of air pollution on lung cancer, in which the adjustment for cigarette smoking is not always necessary. The main hypothesis to be tested in the model is that if the long-term and common-level air pollution had an effect on lung cancer, the death rate from lung cancer could be expected to increase gradually at a higher rate in the region with relatively high levels of air pollution than in the region with low levels, and that this trend would not be expected for other control diseases in which cigarette smoking is a risk factor. Using this approach, we analyzed the trend of mortality in females aged 40 to 79, from lung cancer and two control diseases, ischemic heart disease and cerebrovascular disease, based on vital statistics in 23 wards of the Tokyo metropolitan area for 1972 to 1988. Ward-specific mean levels per day of SO2 and NO2 from 1974 through 1976 estimated by Makino (1978) were used as the ward-specific exposure measure of air pollution. No data on tobacco consumption in each ward is available. Our analysis supported the existence of long-term effects of air pollution on lung cancer. PMID- 7851330 TI - Sampling strategies in nested case-control studies. AB - A stratified version of nested case-control sampling which we call "countermatching" is presented. This design uses data available for all cohort members to obtain a sample for collecting additional information in a case control substudy. Hitherto the only stratified sampling design for such studies has involved matching of controls to cases with respect to confounding variables. However, in some situations, rather than sampling to make controls as similar as possible to cases, we might wish to make them as different as possible. This is achieved by the counter-matched design. Statistical analysis of counter-matched studies is straightforward using existing computer software. We investigate the use of the design when a surrogate measure of exposure is available for the full cohort, but accurate exposure data is to be collected only in a nested case control study, and when exposure data are available for the whole cohort but data concerning important confounders are not. Asymptotic relative efficiency calculations indicate that a substantial efficiency gain relative to simple random sampling of controls can be expected in these situations. We also illustrate how the design might be implemented in practice. PMID- 7851331 TI - Reproducibility of dietary and other data from a self-administered questionnaire. AB - This study examined the reproducibility of information obtained from a questionnaire covering dietary and other information by comparing the answers to the questionnaires with answers to the same questions one year later. Answers from 191 men and 220 women, aged 40 to 65, in Fukuoka prefecture, Japan were compared. The surveys were conducted in November 1989 and November 1990. In the second survey, 97.2% of the first respondents answered. The concordance between the two responses was high, and the differences between the mean intakes from the two surveys were within 5% for 7 food items and within 15% for 14 food items among the 20 items about which the respondents were asked. The intraclass correlation coefficients varied from 0.30 for eggs to 0.62 for milk, with 16 items greater than 0.4. The differences in reproducibility between the sexes and two age categories were not significant. Close values also were obtained for the estimated consumption of salt. A substantially high reproducibility was observed on items regarding drinking and smoking; most of the kappa statistics and the intraclass correlation coefficients were between 0.5 and 0.9. The above reproducibility on individual food items was comparable to or better than those reported from other studies. The results of the present study thus indicate that the self-administered semiquantitative food intake questionnaire used for our cross-sectional study is useful for epidemiologic studies to assess the association between diet and various diseases. In particular, the present questionnaire is highly dependable regarding the overall group intake of foods.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7851332 TI - Risk ratio estimation in case-cohort studies. AB - In traditional (cumulative-incidence) case-control studies, the exposure odds ratio can be used as an estimator of the risk ratio only when the disease under study is rare. The case-cohort study is a recently developed useful modification of the case-control study. This design allows direct estimation of the risk ratio from a fixed cohort, but does not require any rare-disease assumption. This article reviews recent developments in risk ratio estimation procedures for the analysis of case-cohort data. In the crude analysis, it is shown that the empirical risk ratio estimator is not fully efficient, and the maximum likelihood estimation of the crude risk ratio is discussed. In the stratified analysis, several common risk ratio estimation procedures and standardization methods have been proposed for large strata. However, the Mantel-Haenszel risk ratio and its variance estimator are the only available methods for sparse data. PMID- 7851333 TI - Generalized Mantel-Haenszel procedures for 2 x J tables. AB - Generalization of Mantel-Haenszel procedure for 2 x J (J > 2) tables is reviewed. Included are generalized Mantel-Haenszel tests, estimators for a common odds ratio, and generalized Breslow-Day test for the homogeneity of odds ratios across the strata.-Environ Health Perspect 102(Suppl 8): 57-60 (1994) PMID- 7851334 TI - Meta-analysis in cancer epidemiology. AB - Meta-analysis has seen increasing use as a tool in epidemiology over the past five years. Although this method is relatively well accepted for use in clinical trials, its use has proved somewhat more controversial in epidemiology. If meta analysis is viewed as an evolutionary improvement over the review article, it may become more widely acceptable. Meta-analysis should incorporate the concern for study quality and differences in study design seen in classic review articles with the concern for rigor, objectivity, and quantitative precision characteristic of meta-analysis. Available tools for consideration of differences among studies are described with several examples from the literature. The extent to which various methods are used in published meta-analyses is described. Methods for assessing publication bias, and tools for combining dose-response data, are discussed also. Evaluation of risk factors and protective factors for cancer must be based on the weight of the evidence. Tools such as meta-analysis are essential if we are to interpret the vast number of completed studies in cancer epidemiology. PMID- 7851335 TI - Evaluation of cancer prevention strategies by computerized simulation model: methodological issues. AB - A computerized simulation model developed to evaluate the potential impact of primary and secondary prevention is discussed from methodologic perspectives. In the simulation model, named CANSAVE (Cancer Strategy Analysis and Validation of Effect), the natural history of cancer was modeled as a Markovian stochastic process from cancer-free state to death. The lung cancer death rate among Japanese males was projected for 50 years to the year 2041. The simulation showed that the age-adjusted death rate would increase and reach a peak of 166 per 100,000 in 1989 and then decrease to 148 in 2003. It then shows a tendency to increase again, up to 255 in 2028. This change may be attributed to a lower smoking initiation rate among those born in the 1930s. Promotion of mass screening programs exhibits a more prompt effect than antismoking efforts, but the reduction in annual deaths is expected to be only 11%, even if a 100% participation is realized by the year 2000. The reduction in smoking initiation rate, on the other hand, begins to show a visible effect very slowly. It was predicted that a 1% annual reduction in smoking initiation rate would result in a 20% decrease in the number of deaths in 2041. The smoking cessation program is in the middle with regard to promptness. The predicted reductions in lung cancer deaths in 2041 were 13, 47, and 66%, respectively, when the annual smoking cessation rate was increased from 0.46% (present status) to 1, 3, and 5%. The combined application of all three preventive measures seems essential to realize the most effective reduction in lung cancer deaths. PMID- 7851336 TI - ROC curve regression analysis: the use of ordinal regression models for diagnostic test assessment. AB - Diagnostic tests commonly are characterized by their true positive (sensitivity) and true negative (specificity) classification rates, which rely on a single decision threshold to classify a test result as positive. A more complete description of test accuracy is given by the receiver operating characteristic (ROC) curve, a graph of the false positive and true positive rates obtained as the decision threshold is varied. A generalized regression methodology, which uses a class of ordinal regression models to estimate smoothed ROC curves has been described. Data from a multi-institutional study comparing the accuracy of magnetic resonance (MR) imaging with computed tomography (CT) in detecting liver metastases, which are ideally suited for ROC regression analysis, are described. The general regression model is introduced and an estimate for the area under the ROC curve and its standard error using parameters of the ordinal regression model is given. An analysis of the liver data that highlights the utility of the methodology in parsimoniously adjusting comparisons for covariates is presented. PMID- 7851337 TI - Topoisomerase II enzymes and mutagenicity. AB - Topoisomerase II (topo II) enzymes maintain DNA structure by relieving torsional stress occurring in double-strand DNA during transcription and replication. Topo II causes transient breaks in both strands of DNA, allowing passage of one double helix through another, and probably acts as a structural protein in interphase cells, playing a role in the organisation of mitotic and meiotic chromosomes. A number of clinical anticancer drugs are thought to act on topo II enzymes to stabilise DNA-drug-topo II ternary complexes known as "cleavable complexes." These complexes may lead to illegitimate recombination events, as well as to the formation of other DNA lesions. Topo II-mediated genotoxicity is strongly dependent on the cell cycle status of the target cells. It is now apparent that some dietary components and environmental chemicals may act on topo II. Since the structural features of chemicals that lead to topo II interaction are not clear, it is currently not possible to predict such activity from chemical structure. For many years, the central dogma of chemical carcinogenesis has been that the most carcinogenic chemicals are those that can form a covalent bond with DNA, either directly or after metabolic activation. Topo II-directed drugs are not usually capable of forming covalent bonds with DNA and tend to have low mutagenicity in microbial assays. However, topo II-directed agents are potent cancerogens, inducing characteristic cytogenetic modifications. It is important to define the most sensitive tests to identify topo II-directed mutagens and to develop appropriate strategies for genotoxicity testing of such chemicals. PMID- 7851338 TI - Mutation spectra in Salmonella of complex mixtures: comparison of urban air to benzo[a]pyrene. AB - We used an ion-exchange procedure coupled to the Salmonella assay to fractionate the dichloromethane-extractable particulate organics from an urban air sample collected in Boise, Idaho. A resulting base/neutral fraction contained 81% of the mutagenic activity but only 36% of the mass of the unfractionated sample. Chemical analysis showed that polycyclic aromatic hydrocarbons (PAHs) accounted for much of the mutagenic activity of the air sample. Colony probe hybridization, PCR, and DNA sequence analysis were then used to determine the mutations induced by the complex mixtures and a model PAH, benzo[a]pyrene (BAP) in approximately 900 revertants of the frameshift hisD3052 allele and approximately 400 revertants of the base-substitution hisG46 allele. The majority (93-94%) of the mutations induced at the frameshift allele in strain TA98 by the whole or base/neutral fraction of the urban air sample was a hotspot 2-base deletion of a CG or GC within the sequence CGCGCGCG. The remaining mutations were complex frameshifts that consisted of -2 or +1 frameshifts associated with a flanking base substitution. BAP induced a somewhat similar pattern of mutations, with 70% being the hotspot mutation, 23% being complex frameshifts, and the remaining being deletions. The inferred base-substitution specificity associated with the complex frameshifts at the hisD3052 allele (primarily G.C-->T.A transversions) was consistent with the observation that this same transversion was the primary mutation induced by the whole urban air sample and BAP at the base-substitution allele in strain TA100. At the frameshift allele, adducts that promote correct incorporation/slippage could account for hotspot mutations, whereas those that promote misincorporation/slippage could account for complex frameshifts. At the base-substitution allele, a mixture of adducts or of adducts with multiple conformations could account for the observed proportion of transitions and transversions. Combined with the bioassay-directed chemical analysis, these results from the first mutation spectra of a complex mixture suggest that such spectra reflect the dominance of particular classes of chemical mutagens within the mixture. PMID- 7851339 TI - Statistical tests of significance in transgenic mutation assays: considerations on the experimental unit. AB - When significant animal-to-animal variability is present in binary response data, the usual statistical tests applied to such data do not always operate correctly. In transgenic mouse mutation data, some evidence of significant animal-to-animal variability already exists, suggesting that conventional statistical methods may not be appropriate. Here, we describe an alternative statistical method that treats the animal as the experimental (or statistically independent) unit, and contrast results of its application with those from methods that take the transgene as the experimental unit. Using data from two publications that report experimental results for individual animals, the transgene-based and animal-based analyses can yield very different interpretations of the experimental data. The performance of animal-based statistical methods should be improved by conducting future experiments with enough animals to adequately address animal-to-animal variability. PMID- 7851340 TI - Reduction of benzene toxicity by toluene. AB - BDF1 mice were exposed in inhalation chambers to benzene (900 ppm, 300 ppm) and/or toluene (500 ppm, 250 ppm) 6 hr per day, 5 days per week, for up to 8 weeks. Benzene alone induced a slight anemia after 4 and 8 weeks and a reduction of BFU-E and CFU-E numbers in the marrow. The coexposure to toluene reduced the degree of anemia. These results confirm previous studies where toluene was found to reduce benzene toxicity. This protective effect was most pronounced when DNA damage was studied in peripheral blood cells, bone marrow, and liver using the single cell gel (SCG) assay. With benzene alone, either with 300 or 900 ppm, a significant increase in DNA damage was detected in cells sampled from all three organs. Toluene alone did not induce a significant increase in DNA damage. The coexposure of benzene and toluene reduced the extent of DNA damage to about 50% of benzene alone. This result is considered a clear indication for a protective effect of toluene on the genetic toxicity of benzene. PMID- 7851341 TI - Role of oxygen radicals in the chromosomal loss and breakage induced by the quinone-forming compounds, hydroquinone and tert-butylhydroquinone. AB - The mechanisms by which two quinone-forming compounds, hydroquinone (HQ) and tert butyl-hydroquinone (tBHQ), induce chromosomal loss and breakage in a prostaglandin H synthase-containing V79 cell line have been investigated using the cytokinesis-block micronucleus assay with CREST antibody staining. Increased frequencies of CREST-positive micronuclei (indicating chromosome loss) and CREST negative micronuclei (indicating chromosome breakage) were observed following exposure of cells to HQ and tBHQ. The formation of micronuclei by HQ, but not tBHQ, was dependent on arachidonic acid supplementation, indicating activation by prostaglandin H synthase. Since the oxidation of hydroquinones can result in the generation of oxygen radicals, the contribution of oxygen radicals to the formation of chromosomal alterations induced by HQ and tBHQ was investigated. In the presence of a superoxide-generating system consisting of hypoxanthine and xanthine oxidase, a significant increase in micronucleated cells was observed. These induced micronuclei consisted exclusively of CREST-negative micronuclei and their formation was completely inhibited by pretreatment with catalase. Catalase also significantly inhibited the CREST-negative micronuclei induced by HQ and tBHQ. In addition, glutathione treatment inhibited both CREST-positive and negative micronuclei induced by these phenolic compounds. These results indicate that both chromosome loss and breakage are induced by these two quinone-forming agents. Reactive oxygen species contribute to the chromosomal breakage induced by HQ and tBHQ but the observed chromosomal loss appears to result from other mechanisms such as an interference of quinone metabolites with spindle formation. PMID- 7851342 TI - Cytogenetic and germ cell effects of phosphine inhalation by rodents: II. Subacute exposures to rats and mice. AB - Phosphine (PH3) is a highly toxic grain fumigant to which there is significant human workplace exposure. To determine the in vivo cytogenetic effects of inhalation of PH3, male F344/N rats and B6C3F1 mice were exposed to target concentrations of 0, 1.25, 2.5, or 5 ppm PH3 for 6 hr/day for 9 days over an 11 day period. Approximately 20 hr after the termination of exposures, blood was removed from the mice and rats by cardiac puncture and the lymphocytes cultured for analyses of sister chromatid exchanges and chromosome aberrations in rats and mice, and micronuclei (MN) in cytochalasin B-induced binucleated lymphocytes from mice. In addition, bone marrow (rats) and peripheral blood (mice) smears were made for the analysis of MN in polychromatic and normochromatic erythrocytes. No significant increase in any of the cytogenetic endpoints was found at any of the concentrations examined. These results indicate that concentrations of PH3 up to 5 ppm are not genotoxic to rodents when administered by inhalation for 9 days during an 11-day period as measured by several cytogenetic assays. To evaluate the effects of PH3 on male germ cells, a dominant lethal test was conducted in male mice exposed to 5 ppm PH3 for 10 days over a 12-day period and mated to groups of untreated females (2 females/male) on each of 6 consecutive 4-day mating intervals. None of the 6 groups of females exhibited a significant increase in percent resorptions. These results indicate that exposure to 5 ppm PH3 by inhalation does not induce dominant lethality in male mouse germ cells at steps in spermatogenesis ranging from late differentiating spermatogonia/early primary spermatocytes through mature sperm. PMID- 7851343 TI - Reciprocal mitotic recombination is the predominant mechanism for the loss of a heterozygous gene in Saccharomyces cerevisiae. AB - The loss of a functional copy of a heterozygous tumor suppressor gene represents an important step during neoplastic transformation. In order to learn more about the genetic events that lead to spontaneous and drug-induced loss of heterozygosity, a diploid Saccharomyces cerevisiae strain was constructed that allows the detection of the loss of a heterozygous gene by means of direct selection. The strain contains a single functional URA3 gene copy inserted at the ADE2 locus located on the right arm of chromosome 15. In addition, the chromosome contains two other phenotypic marker genes, HIS3 which is located distal from URA3, and PHO80 which is closely linked to the centromere. The homologous chromosome lacks all three marker genes. Loss of the heterozygous copy of URA3 can easily be detected by 5-fluoro-orotic acid resistance of the resulting clones. Simple phenotypic tests of the resistant clones further allows one to distinguish whether the loss of the URA3 gene copy occurred by crossing over, chromosomal loss, or point mutation and gene conversion. Loss of heterozygosity was found to be induced in a dose-dependent fashion by UV radiation and by several chemical agents. All the tested mutagens induced loss of heterozygosity predominantly by crossing over. PMID- 7851344 TI - Induction of genotoxic effects by chlorohydroxyfuranones, byproducts of water disinfection, in E. coli K-12 cells recovered from various organs of mice. AB - The genotoxic effects of three chlorohydroxyfuranones (CHFs), 3-chloro-4 (dichloromethyl)-5-hydroxy-2[5H]-furanone (MX), 3-chloro-4-(chloromethyl)-5 hydroxy-2[5H]furanone (CMCF) and 3,4,-dichloro-5-hydroxy-2[5H]furanone (MCA), which are formed as byproducts of water disinfection with chlorine, were investigated in bacterial differential DNA repair assays in vitro and in animal mediated assays in vivo. As indicators of DNA damage, E. coli K-12 strains were used that differ in their repair capacity (uvrB/recA vs. uvr+/rec+). Liquid incubation of the compounds without metabolic activation caused a pronounced reduction of the viability of the repair-deficient strain relative to the repair proficient wild-type strain. The order of potency of genotoxic activity in vitro (dose range 0.004-10 micrograms/ml) was MX > CMCF > MCA. Addition of mouse S-9 mix or bovine serum albumin to the incubation mixtures resulted in an almost complete loss of the activity of all three test compounds. In the animal-mediated assays, mixtures of the indicator bacteria were injected intravenously into mice which were subsequently treated with the test compounds (200 mg/kg b.w.). Two hours later, the cells were recovered from various organs and the relative survival frequencies determined. Under these conditions, all three compounds caused pronounced genotoxic effects, MX and CMCF being stronger genotoxins than MCA. The strongest effects were consistently found in the gastrointestinal tract, but statistically significant DNA damage was also observed in indicator cells recovered from lungs, liver, spleen and kidneys. In a further experiment, the effects of lower doses of MX (4.3, 13 and 40 mg/kg) were investigated. In these experiments dose-dependent effects were measured in all organs. CMCF and MA caused only marginal effects at 40 mg/kg except in the stomach where approximately a 50% reduction of relative survival frequency was observed with CMCF. The results of these animal-mediated assays indicate that (i) all three CHFs cause genotoxic effects in the living animal, and (ii) the potencies of the three compounds observed under in vivo conditions are not commensurate with their extremely high activities measured in vitro. One possible explanation for the weaker responses observed in the animal-mediated assays might be that CHFs are inactivated by non-specific protein binding. PMID- 7851345 TI - Enhancement of the mutagenicity of amino acid pyrolysates by phthalate esters. AB - The ability of phthalic acid, phthalic acid anhydride, and various phthalate esters to enhance the mutagenicity of many amino acid pyrolysates was observed with the Ames test (Salmonella typhimurium TA98), but not the SOS Chromotest. Phthalate enhancement of the mutagenicity of 4-nitroquinoline-1-oxide, 2 nitrofluorene, and benzo[a]pyrene was not observed with either test. The mutagenicity-enhancing ability may be related to the induction of enzymes such as P450IIB, that metabolize amino acid pyrolysates. By quantitative structure activity relationship (QSAR) analysis, a good correlation was observed between the mutagenicity-enhancing activity of phthalates and their octanol-water partition coefficients. PMID- 7851346 TI - The rodent dominant-lethal assay. PMID- 7851347 TI - Traditional test protocols. PMID- 7851348 TI - 26th Annual meeting of the Environmental Mutagen Society. St. Louis, Missouri, March 12-16, 1995. Abstracts. PMID- 7851349 TI - Trans-oesophageal echocardiographic assessment of left ventricular systolic function: the anaesthesiologist's view. PMID- 7851350 TI - Use of EEG spectral edge as index of equipotency in a comparison of propofol and isoflurane for maintenance of general anaesthesia. AB - Propofol and isoflurane were compared for haemodynamic stability and recovery time as main anaesthetic agents for maintenance in a total of 43 ASA I and II patients in uncomplicated operations lasting at least 30 min. The premedication (oral diazepam), induction (thiopentone-fentanyl-suxamethonium) and maintenance protocol (N2O-O2 2:1 litre min-1, fentanyl and vecuronium in incremental doses) were identical for all patients. In one group of 20 patients, propofol was used in continuous intravenous (i.v.) infusion (starting dose 3 mg kg-1 h-1), while in the second group of 23 patients, isoflurane was administered in a starting concentration of 1%. To improve the equipotency of the two agents in all cases the dose of the main anaesthetic was titrated to keep the EEG 90% spectral edge frequency (SEF-recorded by processed EEG monitor) between 8 and 12 Hz. Mean blood pressure (BP) and heart rate (HR) deviations of +/- 20% from the baseline were recorded. The incidence of mean blood pressure deviations/case in the propofol group was less than half of those occurring in the isoflurane group (0.45 vs. 0.96 P = 0.04). The mean duration of blood pressure deviation from baseline value was 5.5 min in the propofol group vs. 16.8 min in the isoflurane group (P = 0.01). The recovery intervals were significantly shorter in the propofol group (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7851351 TI - Total intravenous anaesthesia with sufentanil-midazolam for major abdominal surgery. AB - Haemodynamic and endocrine stress responses were compared during total intravenous anaesthesia with sufentanil and midazolam or fentanyl and midazolam in patients undergoing elective major abdominal surgery. Twenty-two ASA I and II patients were allocated randomly to receive sufentanil (induction 1.5 micrograms kg-1 plus infusion 1.5 micrograms kg-1 h-1) or fentanyl (induction 10 micrograms kg-1 plus infusion 10 micrograms kg-1 h-1) supplemented with 0.15 microgram kg-1 sufentanil or 1 microgram kg-1 fentanyl as necessary. Midazolam was infused to obtain plasma concentrations of 500-600 ng ml-1. Ventilation was with oxygen enriched air. The opioid infusion was reduced post-operatively by half and benzodiazepine effects were reversed by titration with flumazenil. Mean arterial pressure, heart rate and cardiac index decreased in both groups after induction (cardiac index: sufentanil 4.94 +/- 0.45 to 2.99 +/- 0.18 litre min-1; fentanyl 4.97 +/- 0.45 to 3.71 +/- 0.36 litre min-1), but all returned to baseline during surgery. With sufentanil; mean arterial pressure was lower throughout the study period, and heart rate was lower intra-operatively. Oxygen uptake decreased in both groups after induction (sufentanil 289 +/- 29 to 184 +/- 21 ml min-1; fentanyl 318 +/- 32 to 216 +/- 32 ml min-1) and remained low with sufentanil until flumazenil was given. Adrenaline concentrations increased in both groups but there was no intergroup difference. The median noradrenaline concentration was lower intra-operatively with sufentanil (0.47 nmol litre-1 (range 0.06-6.77)) than with fentanyl (0.73 nmol litre-1 (0.07-4.58)). Cortisol, glucose and lactate concentrations increased in both groups. Bradycardia occurred in four patients with sufentanil and in three with fentanyl. There were two cases of marked thoracic rigidity with sufentanil and one with fentanyl. PMID- 7851352 TI - Analgesia for outpatient surgery: placebo versus naproxen sodium (a non-steroidal anti-inflammatory drug) given before or after surgery. AB - One hundred and eighty patients scheduled for day-care surgery were allocated randomly to one of three groups to receive naproxen sodium 1100 mg 1 h prior to surgery, naproxen sodium 1100 mg immediately after surgery, or placebo. The pre surgery naproxen sodium group had significantly lower pain scores 1 h post operatively and at discharge than the placebo group. At discharge both treatment groups were better than placebo. At 24 h post-operatively only the post-operative naproxen sodium group had lower pain scores. There was no difference in post operative analgesic requirements until discharge between the groups, but at 24 h post-operatively the placebo group had required significantly more analgesics than the treatment groups. A questionnaire concerning general acceptability of anaesthesia/analgesia showed similar results. Our conclusion is that naproxen is better than placebo for treatment of post-operative pain. The time of administration pre- or post-operatively is important for the immediate post operative pain, but we found no support for the existence of 'pre-emptive analgesia'. PMID- 7851353 TI - Sustained release metoclopramide for prophylaxis of post-operative nausea and vomiting. AB - Oral metoclopramide may be given as a premedicant to reduce post-operative nausea and vomiting, but there is little evidence that it is effective. We studied the anti-emetic action of a sustained release formulation of metoclopramide (Gastromax 30 mg) in 39 fit women undergoing inpatient laparoscopy under general anaesthesia with a standardized anaesthetic technique in a double-blind placebo controlled trial. No benefit was demonstrated. (Incidences: nausea: 13 of 20 patients [placebo] and 13 of 19 [metoclopramide]; vomiting: 13 of 20 and 12 of 19.) PMID- 7851354 TI - Technical problems and side effects associated with continuous intrathecal or epidural post-operative analgesia in patients undergoing hip arthroplasty. AB - Fifty-five patients undergoing hip arthroplasty under spinal anaesthesia (4 ml of 0.5% plain bupivacaine) were randomized to receive post-operative analgesia either using an intrathecal or an epidural catheter. Associated technical problems and side effects were studied. In both groups per-operative analgesia was achieved with intrathecal 0.5% plain bupivacaine, 4 ml. In the intrathecal infusion group a bolus dose of 100 micrograms morphine was injected through a spinal 28 gauge catheter followed by a 24 h infusion of 200 micrograms morphine (8.3 micrograms h-1). In the epidural infusion group a bolus dose of 2 mg of morphine was injected before the epidural 24 h infusion was started (morphine 200 micrograms h-1 + 0.25% bupivacaine 4 ml h-1). There were 10 catheter failures (two could not be inserted) in the intrathecal group and one in the epidural group. Three epidural catheter infusions failed due to other technical problems. The number of side effects was 21 in the remaining spinal group (n = 20) and 18 in the 20 epidural group patients with successful infusions. One patient in the spinal catheter group developed postdural puncture headache. For post-operative pain relief the patients in the epidural group needed less supplementary intramuscular oxycodone (five doses/four patients) than the spinal group (17 doses/nine patients) (P < 0.05). PMID- 7851355 TI - Heart transplantation under coumarin therapy: friend or foe? AB - Thirty-six patients were included in a retrospective study of the effect of pre operative anticoagulant therapy on peri-operative blood loss and haemostatic changes after heart transplantation. Eleven patients (group H) had received intravenous heparin for at least 3 weeks before cardiac transplantation. Twelve patients (group P) had been transplanted when fully anticoagulated with phenprocoumon. A control group of 13 patients (group C) had undergone bypass grafting of their coronary arteries with no pre-operative anticoagulant therapy. Post-operative drainage from the chest drains was 700 ml (median) in group H, 425 ml in group P, and 360 ml in group C (group H vs. group C: P < 0.05). After heparinization for cardiopulmonary bypass, activated clotting time was 462 s (median) in group H, 1500 s in group P, and 727 s in group C (P < 0.003 vs. groups H and P). Post-operatively, patients in group P were given more units of fresh frozen plasma (median 2.5 units; P < 0.01), prothrombin complex concentrate (median 1000 I.U.; P < 0.05) and vitamin K (median 10 mg; P < 0.05) than groups H and C. Heart transplantation under full phenprocoumon therapy does not increase the likelihood of complications caused by peri-operative bleeding. PMID- 7851356 TI - Neuromuscular and cardiovascular effects of neostigmine and methyl-atropine administered at different degrees of rocuronium-induced neuromuscular block. AB - The neuromuscular and cardiovascular effects of neostigmine, 40 micrograms kg-1, and methyl-atropine, 7 micrograms kg-1, administered at different degrees of rocuronium-induced (600 micrograms kg-1) neuromuscular block were evaluated. In one group of patients spontaneous recovery was awaited (Group A; n = 20). Neostigmine and methyl-atropine were administered 2 minutes after rocuronium (Group B; n = 20) or at 25% twitch recovery (Group C; n = 20). Neuromuscular transmission was monitored mechanomyographically. Data are presented as mean (SD) [95%-CI]. The initial rate of recovery (time until a TOF ratio of 0.2) in group B, i.e. 14.2 (4.5) [12.1-16.3] min, was significantly faster than in group C, i.e. 28.7 (5.3) [26.3-31.1] min. However, the time until clinically sufficient recovery (time until a TOF ratio of 0.7) was similar for groups B, i.e. 29.3 (9.5) [24.9-33.7] min and group C, i.e. 31.8 (5.6) [29.2-34.4] min, both significantly different from that of group A, i.e. 53.2 (14.5) [46.5-59.9] min. The increase in heart rate following neostigmine/methyl-atropine was more pronounced in the group reversed at 2 min after rocuronium (P < 0.01). PMID- 7851357 TI - Attendance of the anaesthesiologist to the patient. National recommendations for standard of anaesthetic practice. AB - The national recommendations for standard of anaesthetic practice in six countries of the European Community are compared with respect to the attendance of the anaesthesiologist to the patient. These standards apply to anaesthesia, major regional anaesthesia and sedation administered by anaesthesiologists. The attendance to the patient varies from strict continuous presence of the anaesthesiologist to observation of the patient by a non-medical assistant and the anaesthesiologist taking care of another anaesthetized patient. Items which all standards should mention are defined. PMID- 7851358 TI - An evaluation of a time-saving anaesthetic machine checkout procedure. AB - Although it is generally acknowledged that a pre-use checkout of the anaesthetic machine significantly improves patient safety, an evaluation of such procedures is uncommon. Previous studies have shown that anaesthetic personnel using different check routines are unable to detect the majority of pre-set technical malfunctions. We have shown that it is possible to develop an effective and time saving check procedure by integrating seven simple steps into one continuous flow procedure, where the settings and results of one step are used in the following step to optimize step interaction. The method is a 'core' procedure adapted to machines sold after 1980 according to the current ISO standard (presently undergoing revision). A user inquiry demonstrated that this pre-use check has been easily adopted in departments of anaesthesia. Moreover, the inquiry showed that most departments would not accept a checkout procedure which required more than 5-6 min. A study on nurse anaesthetists performing this procedure in the operating suite showed an average checking time of approximately 3 min. A performance test was undertaken by activating four different malfunctions in an anaesthetic machine training simulator. Twelve of 17 nurse anaesthetists rapidly identified all faults, whereas five nurses missed one or two faults. Our study suggests that our check procedure (the seven point check) provides a time-saving method for effective pre-use control of the anaesthetic machine. PMID- 7851359 TI - Long-term sedation with propofol and green discolouration of the liver. AB - Propofol has been reported to cause discolouration of urine and hair. A case of green discolouration of the liver is reported in a 56-year-old man after long term sedation with propofol in the intensive care unit. After discontinuation of propofol the discolouration of the liver disappeared. This phenomenon is due to metabolism of propofol which may lead to a phenolic green chromophore which is conjugated in the liver and excreted in the urine. PMID- 7851360 TI - Speaking from the heart: cardiovascular components of stress rating changes and the relative reactivity of physiological and psychological variables. AB - The first part of the experiment compared the relative reactivity of various cardiovascular measurements and self-reported assessment of mental arithmetic, an active coping stress task. It was found that the self-reported stress rating was more responsive (student's t = 9.4) than the physiological measurements. Among the cardiovascular indices, heart rate was the most responsive (student's t = 6.5), followed by the interval between R-wave and the maximal systolic pressure (student's t = 5.0). The second part of the study used a multiple regression to examine the cardiovascular components of change in stress rating following mental arithmetic. Both resting (psychophysiological "trait" variables) and change under stress (psychophysiological "state" variables) were used to predict change in stress rating. Stress rating increase were associated with greater maximal systolic pressure rate of rise (finger dP/dt) at baseline and less heart rate increase during mental arithmetic, yielding a multiple r of 0.67. The dual autonomic nature of active coping stress response is discussed. The shortcomings of using a correlate of a correlate are noted. PMID- 7851361 TI - Continuous monitoring of lactate during exercise in humans using subcutaneous and transcutaneous microdialysis. AB - We have evaluated the possibility of monitoring the plasma lactate concentration in human volunteers during cycle ergometer exercise using subcutaneous and transcutaneous microdialysis. In transcutaneous microdialysis, the relative increase in dialysate lactate concentration exceeded that of plasma lactate concentration by a factor of 6 during exercise due to exercise-induced lactate secretion in sweat. During exercise the subcutaneous microdialysis dialysate lactate concentration underestimated the plasma lactate concentration possibly due to diffusion limitation or adipose tissue lactate production. While it was demonstrated that microdialysis can be used for on-line lactate monitoring, neither subcutaneous nor transcutaneous dialysate lactate concentration were linearly related to the plasma lactate concentration during exercise, and it was found therefore that it was not possible to monitor directly plasma lactate concentration during exercise. PMID- 7851362 TI - Enhanced endurance in trained cyclists during moderate intensity exercise following 2 weeks adaptation to a high fat diet. AB - These studies investigated the effects of 2 weeks of either a high-fat (HIGH-FAT: 70% fat, 7% CHO) or a high-carbohydrate (HIGH-CHO: 74% CHO, 12% fat) diet on exercise performance in trained cyclists (n = 5) during consecutive periods of cycle exercise including a Wingate test of muscle power, cycle exercise to exhaustion at 85% of peak power output [90% maximal oxygen uptake (VO2max), high intensity exercise (HIE)] and 50% of peak power output [60% VO2max, moderate intensity exercise (MIE)]. Exercise time to exhaustion during HIE was not significantly different between trials: nor were the rates of muscle glycogen utilization during HIE different between trials, although starting muscle glycogen content was lower [68.1 (SEM 3.9) vs 120.6 (SEM 3.8) mmol.kg-1 wet mass, P < 0.01] after the HIGH-FAT diet. Despite a lower muscle glycogen content at the onset of MIE [32 (SEM 7) vs 73 (SEM 6) mmol.kg-1 wet mass, HIGH-FAT vs HIGH-CHO, P < 0.01], exercise time to exhaustion during subsequent MIE was significantly longer after the HIGH-FAT diet [79.7 (SEM 7.6) vs 42.5 (SEM 6.8) min, HIGH-FAT vs HIGH-CHO, P < 0.01]. Enhanced endurance during MIE after the HIGH-FAT diet was associated with a lower respiratory exchange ratio [0.87 (SEM 0.03) vs (SEM 0.02), P < 0.05], and a decreased rate of carbohydrate oxidation [1.41 (SEM 0.70) vs 2.23 (SEM 0.40) g CHO.min-1, P < 0.05].(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7851363 TI - Effects of hydration state on plasma testosterone, cortisol and catecholamine concentrations before and during mild exercise at elevated temperature. AB - This investigation examined the influence of pre-exercise hydration status, and water intake during low intensity exercise (5.6 km.h-1 at 5% gradient) in the heat (33 degrees C), on plasma testosterone (TEST), cortisol (CORT), adrenaline (A), and noradrenaline (NA) concentrations at baseline (BL), pre-exercise (PRE), and immediately (IP), 24 h (24 P), and 48 h postexercise (48 P). Ten active men participated in four experimental treatments. These treatments differed in pre exercise hydration status [euhydrated or hypohydrated (HY, -3.8 (SD 0.7)% body mass)] and water intake during exercise (water ad libitum or no water intake during exercise, NW). There were no significant changes in TEST, CORT, or A concentrations with time (BL, PRE, IP, 24 P, and 48 P), or among treatments. However, significant increases from BL and PRE plasma NA concentrations were observed at IP during all four treatment conditions. In addition, HY+NW resulted in significantly higher plasma NA concentrations at IP compared to all other treatments. These results suggest that moderate levels of hypohydration during prolonged, low intensity exercise in the heat do not influence plasma TEST, CORT, or A concentrations. However, plasma NA appears to respond in a sensitive manner to these hydration and exercise stresses. PMID- 7851364 TI - Muscle energetics in short-term training during hypoxia in elite combination skiers. AB - Four well-trained combination skiers were studied through pre- and post-training for the effects of short-term intermittent training during hypoxia on muscle energetics during submaximal exercise as measured by Phosphorus-31 nuclear magnetic resonance and maximal aerobic power (VO2max). The hypoxia and training in the cold was conducted in a hypobaric chamber and comprised 60-min aerobic exercise (at an intensity equivalent to the blood lactate threshold), using a cycle ergometer or a treadmill twice a day for 4, consecutive days at 5 degrees C, in conditions equivalent to an altitude of 2000 m (593 mm Hg). No change in VO2max was observed over the training period, while in the muscle energetics during submaximal exercise, the values of phosphocreatine/(phosphocreatine+inorganic phosphate) and intracellular pH were found to be significantly increased by training during hypoxia. During recovery, the time constant of phosphocreatine was found to have been significantly reduced [pre, 27.9 (SD 6.7) s; post, 22.5 (SD 4.7) s, P < 0.01]. The observed inhibition of phosphocreatine as well as that of intracellular pH changes after training during hypoxia and quicker recovery of phosphocreatine in submaximal exercise tests, may indicate improved oxidative capacity (i.e. a high adenosine 5' triphosphate formation rate) despite the short-term hypoxia training. PMID- 7851365 TI - Diameter and blood velocity changes in the saphenous vein during thermal stress. AB - Although volume, pressure or flow in superficial veins have been studied extensively, little is known about venous blood velocity during thermal stress. Most authors have suggested that the velocity is decreased in the dilated superficial veins during heat stress to facilitate heat loss, and is increased during cooling as the vein is constricted. Duplex ultrasound has been used to study saphenous cross sectional area (CSA) and mean maximal venous blood velocity (BV) in ten healthy volunteers (age 22-31 years). Compared with unstressed mean values, 4.8 (SD 2.6) mm2, CSA increased to 9.3 (SD 2.1) mm2 (P < 0.005) during heat stress and decreased to 2.1 (SD 1.9) mm2 (P < 0.005) during cold stress. These results are consistent with previous studies, but the absolute CSA of the saphenous vein has never been estimated during thermal stress. The BV increased from 0.07 (SD 0.02) m.s-1 to 0.29 (SD 0.11) m.s-1 (P < 0.005) during warming. During cooling, BV tended to decrease: 0.05 (SD 0.03) m.s-1 (N.S). We would suggest that heat loss during thermal stress can be facilitated by the rapid turnover of warm blood, and not (as usually suggested) by the prolonged cooling of each blood sample in the dilated superficial veins. PMID- 7851366 TI - A method for estimating bicarbonate buffering of lactic acid during constant work rate exercise. AB - A method to estimate the CO2 derived from buffering lactic acid by HCO3- during constant work rate exercise is described. It utilizes the simultaneous continuous measurement of O2 uptake (VO2) and CO2 output (VCO2), and the muscle respiratory quotient (RQm). The CO2 generated from aerobic metabolism of the contracting skeletal muscles was estimated from the product of the exercise-induced increase in VO2 and RQm calculated from gas exchange. By starting exercise from unloaded cycling, the increase in CO2 stores, not accompanied by a simultaneous decrease in O2 stores, was minimized. The total CO2 and aerobic CO2 outputs and, by difference, the millimoles (mmol) of lactate buffered by HCO3- (corrected for hyperventilation) were estimated. To test this method, ten normal subjects performed cycling exercise at each of two work rates for 6 min, one below the lactic acidosis threshold (LAT) (50 W for all subjects), and the other above the LAT, midway between LAT and peak VO2 [mean (SD), 144 (48) W]. Hyperventilation had a small effect on the calculation of mmol lactate buffered by HCO3- [6.5 (2.3)% at 6 min in four subjects who hyperventilated]. The mmol of buffer CO2 at 6 min of exercise was highly correlated (r = 0.925, P < 0.001) with the increase in venous blood lactate sampled 2 min into recovery (coefficient of variation = +/- 0.9 mmol.l-1). The reproducibility between tests done on different days was good. We conclude that the rate of release of CO2 from HCO3- can be estimated from the continuous analysis of simultaneously measured VCO2, VO2, and an estimate of muscle substrate. PMID- 7851367 TI - Efficacy of a home-based training program for older adults using elastic tubing. AB - The purpose of this study was to investigate the efficacy of, and the adherence to, a 12-week home-based progressive resistance training program for older adults utilizing elastic tubing. Sixty-two adults (mean age, 71.2 years) qualified to participate in the study. Subjects were randomly assigned to either the exercise (E) (n = 31) or non-exercise (NE) group (n = 31). Pre- and post-testing included isokinetic (1.05 rad.s-1) concentric/eccentric knee extension/flexion strength testing and flexibility measures of the hip, knee, and ankle. The E group trained three times per week, performing one to three sets of 10-12 repetitions for each of 12 resistance exercises. The exercises involved muscles of both the lower and upper body. Within the E group, 25 of the 31 subjects (80.6%) completed the study. Of the E subjects completing the study adherence to the three training sessions per week was 90% (range 72%-100%). Training resistances used during workouts increased significantly with the average estimated increase being 82% (P < 0.001). The E group also demonstrated significant (P < 0.05) increases in isokinetic eccentric knee extension (12%) and flexion (10%) strength. No other significant changes were observed between E and NE groups. These results suggest that home-based resistance training programs utilizing elastic tubing can serve as a practical and effective means of eliciting strength gains in adults over the age of 65. PMID- 7851368 TI - Influence of training status on maximal accumulated oxygen deficit during all-out cycle exercise. AB - The influence of training status on the maximal accumulated oxygen deficit (MAOD) was used to assess the validity of the MAOD method during supra-maximal all-out cycle exercise. Sprint trained (ST; n = 6), endurance trained (ET; n = 8), and active untrained controls (UT; n = 8) completed a 90 s all-out variable resistance test on a modified Monark cycle ergometer. Pretests included the determination of peak oxygen uptake (VO2peak) and a series (5-8) of 5-min discontinuous rides at submaximal exercise intensities. The regression of steady state oxygen uptake on power output to establish individual efficiency relationships was extrapolated to determine the theoretical oxygen cost of the supramaximal power output achieved in the 90 s all-out test. Total work output in 90 s was significantly greater in the trained groups (P < 0.05), although no differences existed between ET and ST. Anaerobic capacity, as assessed by MAOD, was larger in ST compared to ET and UT. While the relative contributions of the aerobic and anaerobic energy systems were not significantly different among the groups, ET were able to achieve significantly more aerobic work than the other two groups, while ST were able to achieve significantly more anaerobic work. Peak power and peak pedalling rate were significantly higher in ST. The results suggested that MAOD determined during all-out exercise was sensitive to training status and provided a useful assessment of anaerobic capacity. In our study sprint training, compared with endurance training, appeared to enhance significantly power output and high intensity performance over brief periods (up to 60 s), yet few overall differences in performance (i.e. total work) existed during 90 s of all-out exercise. PMID- 7851369 TI - Variable resistance all-out test to generate accumulated oxygen deficit and predict anaerobic capacity. AB - A supramaximal variable resistance test over varying time intervals was evaluated as an instrument for the assessment of a number of anaerobic parameters, including the accumulated oxygen deficit (AOD). Eight active men [age, 22 +/- 1 (SEM 1) years, peak oxygen uptake, 53.1 (SEM 2.1) ml x kg-1 x min-1] completed three randomly ordered all-out sprints of 45-, 60- and 90-s duration. Two incremental pretests consisting of three 5-min stages at power outputs of 45, 135, 225 W and 90, 180, 270 W were performed to establish individual efficiency relationships [r = 0.996 (SEE 1.1) ml x kg-1 x min-1]. These relationships were used to estimate energy demand (millilitres per kilogram of oxygen equivalents in 15-s time intervals) during the supramaximal tests. The AOD for the 45 [47.6 (SEM 1.5) ml x kg-1], 60 [49.0 (SEM 1.8) ml x kg-1] and 90 s [49.6 (SEM 1.7) ml x kg 1] tests were significantly different only for the 45 and 90-s tests. Evaluation of the 90-s test indicated that maximal or near-maximal (98%) anaerobic energy release was achieved in 60 s, with the AOD beginning to plateau after this time. No significant differences among tests were found for peak power, time to peak power and peak pedalling rate. Differences in mean power, total work and relative power decrement were related to the length of the test.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7851370 TI - Effects of growth hormone on rat skeletal muscle after hindlimb suspension. AB - To examine the effects of growth hormone (GH) on the preferential atrophy of the soleus muscle (SOL) occurring after hindlimb suspension (HS), two groups of male rats received daily injections of 2 IU.kg-1 body mass of recombinant human growth hormone (rhGH). Rats were either suspended by the tail for 21 days (HS-GH, n = 5) or nonsuspended (C-GH, n = 5). The effects of rhGH treatment on SOL and extensor digitorum longus muscles (EDL) were compared in two groups of animals receiving daily injections of saline, either suspended by the tail (HS-SA, n = 5) or nonsuspended (C-SA, n = 5). The results showed that the SOL hypertrophy in response to rhGH administration was mostly observed in C rats (+33%, P < 0.01). This increase in muscle mass was correlated with a concomitant increase in the size of type I fibres (+21%, P < 0.05). Although SOL mass decreased during HS in rhGH treated animals (-44%, P < 0.001), the mean normalized mass of this muscle did not significantly differ between C-SA and HS-GH groups. A statistically significant increase in the absolute mass of EDL occurred with rhGH treatment in C-GH (+12%, P < 0.05). The HS-induced decrease in the percentage distribution of type I fibres in SOL was unaffected by the rhGH treatment. In addition, a decrease in the citrate synthase activity in the whole SOL was observed in the two groups of tail-suspended rats (-31%, P < 0.05; -21%, P < 0.05 in SA and GH animals, respectively).2+ f1p4 PMID- 7851371 TI - Influence of muscle activation dynamics on reaction time in the elderly. AB - The aim of this investigation was to determine whether age-related changes in the dynamics of muscle activation were, in part, responsible for longer reaction times (RT) in the elderly. A group of 12 young (mean age, 20.6 years) and 12 elderly (mean age, 64.3 years) women performed a series of ballistic forearm supination movements in response to an auditory stimulus while using a simple reaction time test. Surface electromyographic waveforms from biceps brachii (agonist) and pronator teres (antagonist) muscles were recorded, together with the angle-time curves representing the motion of the forearm, on to an IBM compatible microcomputer. The results showed that an age-related increase (P < 0.05) in motor reaction time (MRT) contributed to longer RT in the elderly. In addition, the longer (P < 0.05) MRTs in the elderly were associated with a significantly slower rate (P < 0.05) of biceps brachii muscle activation and a significantly increased proportion (P < 0.05) of the initial biceps brachii muscle burst required to initiate the movement. This data suggested that an important part of the slowing of motor behaviour, commonly observed with increasing age, may be due to either decreases in the ability of aged skeletal muscle to rapidly generate tension or to a reduction in motor drive. PMID- 7851372 TI - Hyperammonaemia in relation to high-intensity exercise duration in man. AB - Adenine nucleotide (AN) degradation has been shown to occur during intense exercise in man and in the horse, at or close to the point of fatigue. The aim of the study was to compare plasma ammonia concentration ([NH3]) as a result of intense exercise with plasma [lactate]. Plasma glutamine concentration ([Gln]) was also measured pre- and post-exercise. On separate occasions, nine healthy subjects (two females) exercised on a motorised treadmill for periods of between 30 s and 210 s, at 5.6 m.s-1 (0% incline). On one occasion, running at the same speed, two subjects ran at +4% incline whilst one other subject ran at +7% incline. Blood samples were taken and plasma was analysed for [lactate], [NH3] and [Gln]. Subjects showed varying degrees of AN degradation as indicated by plasma [NH3]. A comparison of plasma [NH3] with that of plasma [lactate] indicated a marked increase in AN degradation, corresponding to a [lactate] of around 14 mmol.l-1 in plasma. The data further support the hypothesis that there is a critical intramuscular pH below which there is a stimulus to AN degradation during intense exercise, possibly as a result of a substantial reduction in the kinetics of adenosine diphosphate (ADP) rephosphorylation provided by phosphocreatine, resulting in an increase in [ADP]. PMID- 7851373 TI - Alkaline phosphatase isozymes of serum and urine and urinary protein in young men before and after running 3 km. AB - Urine samples were collected from seven healthy male students 1 h before (control fraction) and 5-15 min (5-15 min fraction), 1 h (1-h fraction) and 3 h (3-h fraction) after running 3 km at a perceived exertion equal to approximately 15-17 Borg's scale. Venous blood was also collected from the subjects 1 h before and 1 h after the run. Urine was studied by measuring protein excretion, patterns of sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) of proteins, total alkaline phosphatase (ALP) excretion, intestinal alkaline phosphatase (IAP) excretion and ALP isozyme analysis by PAGE. Serum ALP was studied by measuring the total ALP activity and isozyme analysis by PAGE. The following results were observed: firstly, an increase was seen in the excretion of total protein, total ALP and IAP after the exercise. Statistical significance was seen in the first two of these parameters; secondly, albumin was the only detectable protein band in the control, 5-15 min and 3-h fraction by SDS-PAGE; thirdly, no significant changes were seen in total ALP activity and ALP isozymes in the serum; and fourthly, three to five ALP bands (bands 1, 2, 3, 4 and 5, from the cathodal side) were detected in the zymograms of urinary ALP. Bands 1-3 were high molecular mass ALP. Bands 4 and 5 were intestine-like and liver-like ALP, respectively. An increase of ALP activity of high molecular mass ALP and/or decrease of that of band 5 or appearance of band 4 were seen in the 1-h fraction, in comparison to the control fraction.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7851374 TI - Spectral analysis of electromyogram in lumbar muscles: fatigue induced endurance contraction. AB - In the last few years, epidemiological studies have shown correlations between the low endurance capacity of the erector spinae muscle and low back pain (LBP). In this study, the function of the erector spinae muscle and localized muscle fatigue in LBP were investigated in both LBP patients and control subjects without LBP, using surface multi-channel electromyograms (EMG). Four positions (L1, L2, L4, L5) were chosen as representative locations for the different functions of the erector spinae muscle. Median frequency (fm) parameters of an EMG power density spectrum were monitored to quantify localized muscle fatigue. This research indicated a statistically significant difference (P < 0.05) in fm parameters between the LBP patients and the control subjects. The integrated electromyogram (iEMG) signals of LBP patients were considerably higher than for the control subjects during endurance isometric contraction. Our research suggested that human fatiguing erector spinae muscle, in submaximal voluntary contractions tests, induced a different firing order of motor unit spikes between two groups. PMID- 7851375 TI - Attenuation of the cutaneous blood flow response during combined exercise and heat stress. AB - Skin blood flow (SkBF) was measured in six male subjects using laser-Doppler velocimetry, with zero-gradient auditory canal temperature (Tac) used as an index of body core temperature (Tc). Subjects performed incremental, upright cycling commencing at 40% peak power (Wpeak: 10 min), increasing every 4 min by 5% Wpeak thereafter. Trials were conducted in hot (ambient temperature (Ta) 36.7 +/- 0.2 degree C, relative humidity (rh) 46.1 +/- 3.2%; mean +/- S.D.), and neutral environments (Ta 19.6 +/- 0.3 degree C, rh 50.2 +/- 1.4%). SkBF increased with Tac in all subjects. Attenuation of SkBF occurred at the same Tac, relative SkBF and cardiac frequency (fc) between environments, but at a lower exercise intensity (40.8 +/- 0.8% versus 55.8 +/- 3.0% Wpeak) in the hot environment (p < 0.05). Data indicate that Tc thresholds for SkBF attenuation may exist. However, it is suggested that attenuation thresholds coincided with a reduced central blood volume, which may occur at a critical level of cutaneous blood pooling. PMID- 7851376 TI - Identification of the proteolytic thrombin fragments formed after cleavage with rat mast cell protease 1. AB - We have previously identified rat mast cell protease 1 (RMCP-1), a chymotrypsin like secretory granule serine protease, as a potent inactivator of thrombin. The present study outlines the cleavage pattern obtained after degradation of thrombin by RMCP-1. The cleavage sites in thrombin were identified by N-terminal amino acid sequence analysis of recovered thrombin fragments. Incubation of thrombin with RMCP-1 resulted in the rapid formation of a 37-kDa fragment, due to cleavage of the Phe1G-Gly1F bond in the thrombin A chain (numbering of amino acid residues according to topological equivalencies with chymotrypsinogen). Further incubation resulted in cleavage of the Trp148-Thr149 bond in the B chain, along with the formation of fragments of 27 kDa and 15 kDa. When the RMCP-1/thrombin mixtures were incubated further, successive degradation of the 37-kDa, 27-kDa and 15-kDa fragments was observed, along with cleavage of the Tyr117-Ile118 bond in the B chain and the formation of fragments of 12, 9 and 6 kDa. No residual thrombin activity was detected after the degradation process had proceeded to this stage. Heparin was shown to markedly enhance the rate of thrombin degradation by RMCP-1. PMID- 7851377 TI - Characterization of high-density apolipoprotein particles A-I and A-I:A-II isolated from humans with cholesteryl ester transfer protein deficiency. AB - The cholesteryl ester transfer protein (CETP) plays an important role in metabolism of high-density lipoprotein and reverse cholesterol transport in humans. The two major classes of high-density lipoprotein particles are those containing apolipoprotein A-I (LpA-I) and those containing both apoA-I and apoA II (LpA-I:A-II). We isolated and characterized the apoA-I-containing lipoprotein particles from three subjects with homozygous CETP deficiency (CETP-D) and compared the results with those from normolipidemic control subjects. Plasma concentrations of apoA-I in both LpA-I and LpA-I:A-II were significantly elevated in CETP-D subjects. Both LpA-I and LpA-I:A-II from these subjects were larger and contained more cholesteryl ester per particle than control particles. In CETP-D, subpopulations of LpA-I and LpA-I:A-II with an unusually large size (Stokes diameters 13.8 nm and 12.6 nm, respectively) not detected in normal subjects were isolated. The molar ratio of apoA-I to apoA-II in LpA-I:A-II isolated from CETP-D subjects was higher (mean 2.4) than those of controls (mean 1.4). ApoE was primarily associated with LpA-I:A-II in CETP-D subjects. A subclass of LpA-I with pre-beta migration on agarose electrophoresis was increased in CETP-D subjects. Both LpA-I and LpA-I:A-II from CETP-D subjects bound with higher affinity but less capacity to HepG2 cells compared with control particles, and were internalized to a lesser extent than control particles. These data suggest that the absence of CETP in humans significantly affects the plasma concentration, size, composition, and cellular interaction of both major classes of apoA-I containing lipoprotein particles. PMID- 7851378 TI - Activin A and retinoic acid synergize in cyclooxygenase-1 and thromboxane synthase induction during differentiation of J774.1 macrophages. AB - The murine macrophage cell line J774.1 was used to study the development of prostanoid biosynthesis under the influence of activin A and retinoic acid. Treatment of cells with 3 nM activin A for 48 h increased the biosynthesis of the prostaglandins E2, D2, F2 alpha and thromboxane A2 more than fourfold due to an induction of cyclooxygenase-1 while cyclooxygenase-2 was unaffected. Transforming growth factor-beta acted in a similar way. Retinoic acid, when present alone, was without effect on the total cyclooxygenase products and only slightly changed the pattern of prostanoids. However, when coincubated with activin A, retinoic acid specifically induced the synthesis of thromboxane-A-synthase-specific mRNA and induced an increase in enzyme activity with a synergistic effect on cyclooxygenase-1 protein and mRNA. JunB, but not c-jun, mRNA expression was found under these conditions in addition to a transient c-fos mRNA increase. The combination of activin A and retinoid acid may be regarded as a differentiation model to study the development of cell-specific prostanoid patterns in macrophages and possibly other differentiating cells. PMID- 7851379 TI - Periplasmic sulphide dehydrogenase (Sud) from Wolinella succinogenes: isolation, nucleotide sequence of the sud gene and its expression in Escherichia coli. AB - Wolinella succinogenes contains a periplasmic sulphide dehydrogenase when grown with formate and polysulphide as catabolic substrates. The isolated enzyme catalyzes the reduction of dimethylnaphthoquinone with sulphide at high values of both apparent Km and turnover number. The active enzyme consists of two identical subunits (14 kDa) and amounts to approximately 1% of the soluble cell protein. Prosthetic groups such as flavin, haem or molybdenum are missing. The corresponding gene (sud) encodes a signal peptide together with the mature subunit that consists of 129 amino acid residues including one single cysteine. The sud gene is expressed from a plasmid in Escherichia coli. The resulting enzyme catalyzes sulphide oxidation with dimethylnaphthoquinone and is located in the periplasm of E. coli. PMID- 7851380 TI - Identification and partial purification of (Ca2+ or Mg2+)-ATPase in renal brush border membranes. AB - The protein responsible for the (Ca2+ or Mg2+)-ATPase activity in brush-border membranes from pig kidney tubular cells was characterized to distinguish this enzyme from the N-ethylmaleimide-sensitive Mg(2+)-ATPase, also present in renal brush borders. Both enzymes are clearly different in their pH optimum and their sensitivity to divalent cations, nucleoside 5'-triphosphates and inhibitors. Solubilization of the (Ca2+ or Mg2+)-ATPase from brush-border membrane vesicles was accomplished with Nonidet P-40 or dodecylmaltoside. However, simultaneous inactivation of the enzyme was inevitable. A tenfold enrichment of the ATPase activity was obtained by chromatofocusing of Nonidet-P-40-solubilized brush borders. A similar degree of purification was achieved by ion-exchange chromatography of dodecylmaltoside-solubilized preparations. From the SDS/polyacrylamide gels of partially purified (Ca2+ or Mg2+)-ATPase, a few protein bands could still be tentatively identified as responsible for the enzyme activity. Labeling of solubilized brush-border preparations with several radioactive ATP analogues also revealed that a protein band of molecular mass 90 kDa is the most probable candidate for the catalytic peptide of the (Ca2+ or Mg2+)-ATPase. Finally, immunoprecipitation as well as semi-dry blotting with antibodies generated against partially purified enzyme preparations, confirmed that a 90-kDa component is a reasonable candidate for the (Ca2+ or Mg2+)-ATPase in renal brush-border membranes. PMID- 7851381 TI - Benzoyl-coenzyme-A 3-monooxygenase, a flavin-dependent hydroxylase. Purification, some properties and its role in aerobic benzoate oxidation via gentisate in a denitrifying bacterium. AB - A new variant of aerobic benzoate degradation has been found in a denitrifying bacterium in which benzoyl-CoA is the first intermediate [Altenschmidt, U., Oswald, B., Steiner, E., Herrmann, H. & Fuchs, G. (1993) New aerobic benzoate oxidation pathway via benzoyl-coenzyme A and 3-hydroxybenzoyl-coenzyme A in a denitrifying Pseudomonas sp, J. Bacteriol. 175, 4851-4858)]. The initial reaction is catalyzed by benzoate-CoA ligase (AMP-forming), converting benzoate into benzoyl-CoA. The next step is 3-hydroxylation of benzoyl-CoA to 3-hydroxybenzoyl CoA catalyzed by a flavin-nucleotide-dependent monooxygenase, benzoyl-CoA 3 monooxygenase. This novel enzyme has been purified and studied. It is specific for NADPH and requires the presence of a flavin nucleotide for activity; both FAD or FMN function similarly well as cofactor. Only benzoyl-CoA, but not benzoate, is hydroxylated. The protein is a monomer of M(r) 65,000 and is induced when cells are grown aerobically with benzoate. 3-Hydroxybenzoyl-CoA is further hydroxylated para to the hydroxyl group affording 2,5-dihydroxybenzoate (gentisate). This reaction requires another monooxygenase, 3-hydroxybenzoyl-CoA 6 monooxygenase, which is unspecific specific with respect to the pyridine nucleotide. Cells contain a second 6-monooxygenase activity which acts on free 3 hydroxybenzoate. Based on these and other data, the outlines of the new aerobic benzoate pathway have been deduced. The proposed intermediates are benzoyl-CoA, 3 hydroxybenzoyl-CoA, gentisate, maleylpyruvate, fumarylpyruvate and fumarate plus pyruvate. PMID- 7851382 TI - Re-face specificity at C14a of methylenetetrahydromethanopterin and Si-face specificity at C5 of coenzyme F420 for coenzyme F420-dependent methylenetetrahydromethanopterin dehydrogenase from methanogenic Archaea. AB - Coenzyme F420-dependent methylenetetrahydromethanopterin dehydrogenase from methanogenic Archaea catalyzes the reversible transfer of a hydride ion from C14a of N5,N10-methylenetetrahydromethanopterin to C5 of coenzyme F420. In this study, we report that this hydride transfer proceeds stereospecifically from the Re face at C14a to the Si face at C5. The results were obtained by using chirally 3H labelled N5,N10-methylenetetrahydromethanopterin generated via Re-face-specific H2-forming N5,N10-methylenetetrahydromethanopterin dehydrogenase and by analyzing reduced coenzyme F420 via Si-face-specific F420-reducing hydrogenase. PMID- 7851383 TI - Identification of a novel UDP-GalNAc:GlcNAc beta-R beta 1-4 N acetylgalactosaminyltransferase from the albumen gland and connective tissue of the snail Lymnaea stagnalis. AB - Both the albumen gland, one of the female accessory sex glands, and connective tissue of the freshwater snail Lymnaea stagnalis contain N acetylgalactosaminyltransferase activity, capable of transferring GalNAc from UDP GalNAc in beta 1-4 linkage to the terminal GlcNAc residue of GlcNAc beta-R. The albumin gland enzyme was partially purified by affinity chromatography on UDP hexanolamine-Sepharose 4B. Using GlcNAc beta 1-2Man alpha 1-6(GlcNAc beta 1-2Man alpha 1-3)Man beta 1-4GlcNAc beta 1-4GlcNAc or GlcNAc beta 1-OMe as substrates, the enzyme showed an absolute requirement for Mn2+ with an optimum concentration of 12.5-50 mM. The optimal pH was approximately pH 7.0. The enzyme activity was independent of the Triton X-100 concentration in the range 0.25-2.5%, and no activation effect was found. The more labile connective tissue microsomal enzyme, subjected to the same optimization procedure, gave comparable results. Both enzyme activities have similar substrate specificities towards GlcNAc or GlcNAc beta 1-OMe, and towards oligosaccharides or glycopeptides with a non-reducing terminal beta-GlcNAc unit, but cannot act on GlcNAc alpha 1-OMe. Saccharides with non-reducing terminal Gal or GalNAc residues, and free GalNAc, Gal or Glc residues are not acceptors. Product analysis was carried out for albumen gland N acetylgalactosaminyltransferase and four acceptors having GlcNAc beta 1-R as the terminal non-reducing unit, and for connective tissue N acetylgalactosaminyltransferase with GlcNAc beta 1-OMe as acceptor. In all instances, products with GalNAc beta 1-4-linked to GlcNAc were obtained, showing that the connective tissue and the albumen gland activities are probably from one enzyme. This enzyme activity can be identified as UDP-GalNAc:GlcNAc beta-R beta 1 4 N-acetylgalactosaminyltransferase, and is probably involved in the biosynthesis of N,N'-diacetyllactosediamine-containing glycoproteins, like hemocyanin, in the snail L. stagnalis. PMID- 7851384 TI - Cloning and expression in insect cells of two pancreatic lipases and a procolipase from Myocastor coypus. AB - The physiological role of pancreatic lipases has traditionally been assigned solely to triacylglyceride metabolism, while the digestion of phospholipids requires the presence of the pancreatic phospholipase A2, a 14-kDa enzyme unrelated to pancreatic lipases. However, in the guinea pig, it was observed that the pancreatic phospholipase A2 was absent and that a guinea pig pancreatic lipase-related protein 2 (GPL-RP2) was responsible for phospholipase activity, in contrast to the situation observed in other mammalian species. As the guinea pig is a member of the hystricomorph rodents, it was of interest to investigate if other species within this evolutionary suborder display similar characteristics. The coypu (Myocastor coypus) also a member of the hystricomorph rodents, was chosen for further investigations. The cDNAs encoding two pancreatic lipases and a procolipase from the coypu were cloned, expressed and characterized. One lipase, CoPL-RP2, was identified as belonging to the RP2 subfamily, while the second, CoPL, was found to belong to the classical pancreatic lipase subfamily. Enzymic characterization and sequence data suggest a role for coypu colipase as a specific cofactor for CoPL, while this coypu colipase cannot be an important cofactor for CoPL-RP2 in vivo. Also, the new lipase cDNA sequences were used in a phylogentic analysis to reinvestigate the taxonomical position of the hystricomorph rodents (e.g. coypu and guinea pig) with respect to the myomorph rodents (e.g. rat and mouse). PMID- 7851385 TI - Molecular structure and mechanism of action of the crotoxin inhibitor from Crotalus durissus terrificus serum. AB - An antivenom protein has been identified in the blood of the snake Crotalus durissus terrificus and proved to act by specifically neutralizing crotoxin, the main lethal component of rattlesnake venoms. The aim of this study was to purify the crotoxin inhibitor from Crotalus serum (CICS), and to analyze its mechanism of action. CICS has been purified from blood serum of the Crotalus snake by gel filtration on Sephadex G-200, ion-exchange chromatography on DEAE-Sephacel, and FPLC gel filtration on a Superose 12 column. It is an oligomeric glycoprotein of 130 kDa, made by the non-covalent association of 23-25-kDa subunits. Two different subunit peptides were identified by SDS/PAGE, however, their N-terminal sequences are identical. They are characterized by the absence of methionine residues and a high content of acidic, hydrophobic and cysteine residues. The neutralizing effect of purified CICS towards the neurotoxic effects of crotoxin has been demonstrated in vivo by lethality assays. CICS binds to the phospholipase subunit CB of crotoxin, but not to the acidic chaperon subunit CA; it efficiently inhibits the phospholipase activity of crotoxin and its isolated CB subunit and evokes the dissociation of the crotoxin complex. The molecular mechanism of the interaction between CICS and crotoxin seems to be very similar to that of crotoxin with its acceptor. It is, therefore, tempting to suggest that CICS acts physiologically as a false crotoxin acceptor that would retain the toxin in the vascular system, thus preventing its action on the neuromuscular system. PMID- 7851386 TI - Determining elasticities from multiple measurements of flux rates and metabolite concentrations. Application of the multiple modulation method to a reconstituted pathway. AB - A recently developed method to determine elasticities by multiple measurements of steady-state flux rates and metabolite concentrations [Giersch, C. (1994) J. Theor. Biol. 169, 89-99] is applied to a reconstituted metabolic pathway. The pathway is the section of glycolysis converting glycerate-3-phosphate to pyruvate. The elasticities of the pathway enzymes are determined from the dependence on effector concentrations of measured steady-state flux rates and steady-state metabolite concentrations. To verify assumptions regarding the dependence of reaction rates on metabolites, flux control coefficients calculated from enzyme elasticities are compared with those estimated by means of the usual enzyme titration. The proposed method is shown to allow experimental determination of enzyme elasticities but requires, like other experiments in metabolic control analysis, a high level of reproducibility and experimental accuracy which may be difficult to attain. PMID- 7851387 TI - Cloning and primary structure of murine 11 beta-hydroxysteroid dehydrogenase/microsomal carbonyl reductase. AB - Screening of a mouse liver lambda gt 11 cDNA library with a rat liver 11 beta hydroxysteroid dehydrogenase cDNA (11 beta-HSDr1A) and subsequent screening with an isolated mouse probe, resulted in the isolation and structure determination of a mouse cDNA encoding an amino acid sequence which is very similar to human and rat 11 beta-hydroxysteroid dehydrogenases (78% and 86% similar, respectively), and also to other known vertebrate 11 beta-hydroxysteroid dehydrogenase structures. Open-reading-frame analysis and the deduced amino acid sequence predict a protein with a molecular mass of 32.3 kDa which belongs to the superfamily of the short-chain dehydrogenase proteins. The amino acid sequence contains two potential glycosylation sites. These data are in agreement with information on the glycoprotein character of the native enzyme. This kind of post translational modification seems to be a determining factor concerning the equilibrium of the catalyzed 11 beta-dehydrogenation/11-oxo reduction step [Obeid, J., Curnow, K. M., Aisenberg, J. & White, P.C. (1993) Mol. Endocrinol. 7, 154-160; Agarwal, A.K., Tusie-Luna, M.T., Monder, C. & White, P.C. (1990) Mol. Endocrinol. 4, 1827-1832]. After in vitro transcription/translation of the mouse cDNA, immunoprecipitation with anti-(microsomal carbonyl reductase) serum and N terminal sequence analysis of the purified protein confirms the identity of microsomal 11 beta-hydroxysteroid dehydrogenase with the previously described, microsomal-bound xenobiotic carbonyl reductase [Maser, E. & Bannenberg, G. (1994) Biochem. Pharmacol. 47, 1805-1812], and points to an involvement of the 11 beta HSD1A isoform in the reductive phase-I metabolism of xenobiotic compounds, besides its endocrinological functions. The alignment and comparison to other hydroxysteroid dehydrogenase forms of the same protein superfamily allows the identification of important residues in the 11 beta-HSD primary structure. PMID- 7851388 TI - Platelet-derived growth factor stimulates de-novo synthesis of mitogen-activated protein kinase in renal mesangial cells. AB - Platelet-derived growth factor (PDGF) BB is a potent mitogen for renal mesangial cells and stimulates a biphasic mitogen-activated protein kinase (MAP kinase) activation. A rapid increase in activity (maximal at 10 min) is followed by a lower persistent level of activity which is maximal at 4-6 h. The second peak of MAP kinase activity is markedly attenuated by the protein synthesis inhibitor cycloheximide and, consequently, is paralleled by a marked de-novo synthesis of p42 and p44 MAP kinases, as measured by immunoprecipitation of [35S]methionine labeled mesangial cells and by a 700% increase in total MAP kinase protein, as detected by Western-blot analysis. A 30-min treatment with PDGF-BB is sufficient to induce pronounced de-novo synthesis of MAP kinase. However, for maximal induction of MAP kinase synthesis, PDGF is required to be present for at least 4 h. In addition, an increased de-novo synthesis of MAP kinase kinase, the upstream activator of MAP kinase, is observed in response to PDGF stimulation. We propose that PDGF-induced de-novo synthesis of MAP kinase and MAP kinase kinase is important for the potent mitogenic activity of this growth factor. PMID- 7851389 TI - Molecular cloning and sequence of two novel P-type adenosinetriphosphatases from Plasmodium falciparum. AB - We have identified two novel P-type ATPase genes from Plasmodium falciparum and report the full-length nucleotide and derived amino acid sequence of the ATPase2 gene from P. falciparum (PfATPase2). PfATPase2 is phylogenetically remote from the different members of prokaryotic and mammalian P-type ATPases but shares features with a putative membrane-spanning Ca2+ ATPase involved in ribosome function in yeast. PfATPase2 is expressed during the intraerythrocytic life cycle of the parasite and appears to be required in the late stages of its asexual development. We also present the partial sequence of another malarial gene displaying sequence similarity with the family of P-type transporting ATPases (PfATPase4). We have analysed the organisation of the genes encoding the P-type ATPases of P. falciparum and show that they are a highly dispersed gene family. PMID- 7851390 TI - Copper binding to rabbit liver metallothionein. Formation of a continuum of copper(I)-thiolate stoichiometric species. AB - Circular dichroism and ultraviolet absorption spectral data have been used to probe the binding mechanism for formation and the structure of the copper(I) thiolate binding clusters in rabbit liver metallothionein during addition of Cu+ to aqueous solutions of Zn7-metallothionein 2 and Cd5Zn2-metallothionein 2. Mammalian metallothionein binds metals in two binding sites, namely the alpha and beta domains. Spectral data which probe the distribution of Cu(I) between the two binding domains clearly show that both the site of binding (alpha or beta), and the structures of the specific metal-thiolate clusters formed, are dependent on temperature and on the nature of the starting protein (either Zn7-metallothionein or Cd5Zn2-metallothionein). CD spectra acquired during the addition of Cu+ to Zn7 metallothionein show that Cu+ replace the bound Zn(II) in a domain-distributed manner with complete removal of the Zn(II) after addition of 12 Cu+. Spectral and metal analyses prove that a series of Cu(I)-metallothionein species are formed by a non-cooperative metal-binding mechanism with a continuum of Cu(I):metallothionein stoichiometries. Observation of a series of spectral saturation points signal the formation of distinct optically active Cu(I) thiolate structures for the Cu9Zn2-metallothionein, Cu12-metallothionein, and the Cu15-metallothionein species. These data very clearly show that for Cu(I) binding to Zn7-metallothionein, there are several key Cu(I):metallothionein stoichiometric ratios, and not just the single value of 12. The CD spectra up to the Cu12-metallothionein species are defined by bands located at 255(+) nm and 280(-) nm. Interpretation of the changes in the CD and ultraviolet absorption spectral data recorded between 3 degrees C and 52 degrees C as Cu+ is added to Zn metallothionein show that copper-thiolate cluster formation is strongly temperature dependent. These changes in spectral properties are interpreted in terms of kinetic versus thermodynamic control of the metal-binding pathways as Cu+ binds to the protein. At low temperatures (3 degrees C and 10 degrees C) the spectral data indicate a kinetically controlled mechanism whereby an activation barrier inhibits formation of ordered copper-thiolate structures until formation of Cu12-metallothionein. At higher temperatures (> 30 degrees C) the activation barrier is overcome, allowing formation of new Cu(I)-thiolate clusters with unique spectral properties, especially at the Cu9Zn2-metallothionein point. The CD spectra also show that a Cu15-metallothionein species with a well-defined, three-dimensional structure forms at all temperatures, characterized by a band near 335 nm, indicating the presence of diagonal Cu(I).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7851391 TI - Solvent-induced structural distortions of horse metmyoglobin. AB - Structural and dynamic constraints produced by the surrounding solvent on the aquometmyoglobin molecule were investigated by means of circular dichroism and Fourier-transform infrared spectroscopies, tritium/hydrogen exchange kinetics and small-angle neutron-scattering experiments. Formamide and ethanol were chosen as cosolvents because they are known to increase and decrease protein activity, respectively. The CD measurements in the Soret region show that no changes occur in the heme molecular structure nor in the protein near the heme. The results of proton-exchange kinetics experiments indicate that the conformational dynamics of aquometmyoglobin is only marginally affected by the cosolvents. However, the small-angle neutron-scattering spectra strongly suggest that these cosolvents induce some distortions of the tertiary conformation. According to the ultraviolet CD and Fourier-transform infrared data, the alteration of the tertiary conformation results from changes in both the number of intrachain hydrogen bonds and the structures of beta turns of type I' for formamide and of type II for either of the two cosolvents. The use of several techniques allows the present approach to demonstrates that the myoglobin structure is extremely sensitive to its environmental conditions. PMID- 7851393 TI - Analysis of the vhoGAC and vhtGAC operons from Methanosarcina mazei strain Go1, both encoding a membrane-bound hydrogenase and a cytochrome b. AB - DNA encompassing the structural genes of two membrane-bound hydrogenases from Methanosarcina mazei Go1 was cloned and sequenced. The genes, arranged in the order vhoG and vhoA as well as vhtG and vhtA, were identified as those encoding the small and the large subunits of the NiFe hydrogenases [Deppenmeier, U., Blaut, M., Schmidt, B. & Gottschalk, G. (1992) Arch. Microbiol. 157, 505-511]. Northern-blot analysis revealed that the structural genes formed part of two operons, both containing one additional open reading frame (vhoC and vhtC) which codes for a cytochrome b. This conclusion was drawn from the homology of the deduced N-terminal amino acid sequences of vhoC and vhtC and the N-terminus of a 27-kDa cytochrome isolated from Ms. mazei C16. VhoC and VhtC contain four tentative hydrophobic segments which might span the cytoplasmic membrane. Hydropathy plots suggest that His23 and His50 are involved in heme coordination. The comparison of the sequencing data of vhoG and vhtG with the experimentally determined N-terminus of the small subunit indicate the presence of a 48-amino acid leader peptide in front of the polypeptides. VhoA and VhtA contained the conserved sequence DPCXXC in the C-terminal region, which excludes the presence of a selenocysteine residue in these hydrogenases. Promoter sequences were found upstream of vhoG and vhtG, respectively. Downstream of vhoC, a putative terminator sequence was identified. Alignments of the deduced amino acid sequences of the gene clusters vhoGAC and vhtGAC showed 92-97% identity. Only the C-termini of VhoC and VhtC were not similar. PMID- 7851392 TI - 1H and 13C NMR assignments and structural aspects of a ferrocytochrome c-551 from the purple phototrophic bacterium Ectothiorhodospira halophila. AB - Two-dimensional nuclear magnetic resonance was used to assign the 1H and 13C resonances of ferrocytochrome c-551 from Ectothiorhodospira halophila, a halophilic phototrophic purple bacterium. This 78-residue protein belongs to a small subgroup of class I cytochromes c together with the analogous cytochromes c 551 from E. halochloris and E. abdelmalekii. A nearly complete assignment of 13C resonances was obtained at natural abundance using a gradient-enhanced 1H detected heteronuclear single quantum coherence experiment (HSQC). This was found to be extremely useful for the unambigous assignment of side chain protons. The secondary structure of the protein was determined from analyses of short- and medium-range nuclear Overhauser enhancements (NOE), amide proton exchange and 13C alpha chemical shifts. Three helices could be identified which are well conserved among the class I cytochromes c. There is some evidence for two other regions of less well defined helical structure. From a preliminary analysis of long-range NOE it is shown that in the E. halophila cytochrome c-551 the general cytochrome c fold is well conserved, including the three conserved helices (residues 2-8, 41 50, 63-76), the regions around the heme ligands (Cys14-Ser15-Ser16-Cys17-His18, Met55) and the omega loop (residues 18-28). In addition, three variable segments of the protein are discussed in detail, one of those including a cis-proline, a feature so far unique in the cytochrome c family. Structural alignments of the E. halophila cytochrome c-551 with two other Pseudomonas cytochrome c5 homologs (Azotobacter vinelandii cytochrome c5 and Chlorobium limicola cytochrome c-555) are provided which are based on sequence similarities and secondary structure alignments. PMID- 7851394 TI - Purification from placenta, amino acid sequence, structure comparisons and cDNA cloning of human glutaredoxin. AB - Glutaredoxin is generally a glutathione-dependent hydrogen donor for ribonucleotide reductase and also catalyses general glutathione (GSH)-disulfide oxidoreduction reactions in the presence of NADPH and glutathione reductase. A Glutaredoxin from human placenta was purified to homogeneity, as judged by SDS/PAGE and IEF (12 kDa). Purification was monitored by the activity with hydroxyethyl disulfide as a substrate. Values of pI for glutaredoxin were obtained by IEF; the pI of the protein shifted from 7.3 in its fully reduced state to 9.0 in the oxidized state after treatment with excess hydroxyethyl disulfide. The glutaredoxin preparation showed GSH-dependent hydrogen-donor activity with recombinant mouse ribonucleotide reductase, it exhibited dehydroascorbate reductase activity as well as hydroxyethyl-disulfide-reducing activity. The amino acid sequence (residues 3-104) of glutaredoxin was determined by peptide sequencing and residues 1, 2 and 105 by cDNA sequence analysis. The glutaredoxin sequence comprised the classical active site for glutaredoxins Cys22-Pro-Tyr-Cys25- and three additional half-cystine residues; two of these in positions 78 and 82. The sequence was similar to other known mammalian glutaredoxins (about 80% identities), with important differences such as one additional Cys residue (Cys7) and no Met residue. The sequence of human glutaredoxin was compared to that of Escherichia coli glutaredoxin with known three-dimensional structure in solution to identify conserved residues and predict a structure from alignment. In particular the GSH-binding site of glutaredoxin was conserved between all molecules. A cDNA that encodes the entire glutaredoxin gene (grx) and flanking sequences was isolated from a human spleen cDNA library. The nucleotide sequence of this cDNA (0.8 kb) was determined, including the complete grx gene. PMID- 7851395 TI - Disulfide bonds and glycosylation in fungal peroxidases. AB - Four conserved disulfide bonds and N-linked and O-linked glycans of extracellular fungal peroxidases have been identified from studies of a lignin and a manganese peroxidase from Trametes versicolor, and from Coprinus cinereus peroxidase (CIP) and recombinant C. cinereus peroxidase (rCIP) expressed in Aspergillus oryzae. The eight cysteine residues are linked 1-3, 2-7, 4-5 and 6-8, and are located differently from the four conserved disulfide bridges present in the homologous plant peroxidases. CIP and rCIP were identical in their glycosylation pattern, although the extent of glycan chain heterogeneity depended on the fermentation batch. CIP and rCIP have one N-linked glycan composed only of GlcNAc and Man at residue Asn142, and two O-linked glycans near the C-terminus. The major glycoform consists of single Man residues at Thr331 and at Ser338. T. versicolor lignin isoperoxidase TvLP10 contains a single N-linked glycan composed of (GlcNAc)2Man5 bound to Asn103, whereas (GlcNAc)2Man3 was found in T. versicolor manganese isoperoxidase TvMP2 at the same position. In addition, mass spectrometry of the C terminal peptide of TvMP2 indicated the presence of five Man residues in O-linked glycans. No phosphate was found in these fungal peroxidases. PMID- 7851396 TI - Identification and localisation of a synaptosomal membrane prolyl endopeptidase from bovine brain. AB - Prolyl endopeptidase, which has long been recognised for its importance in the degradation of several neuropeptides such as thyroliberin, luteinising hormone releasing hormone, angiotensin, substance P and neurotensin, has been widely characterised as a cytosolic enzyme. However, in this paper, we report the presence of a prolyl endopeptidase activity in the particulate fractions of bovine brain, which is distinct from that in the cytoplasm. This previously uncharacterised activity was found to reside in the synaptosomal membranes, a location which is highly significant for the inactivation of neuropeptides in brain. Following vigorous salt washing and osmotic shock, the prolyl endopeptidase activity was released from the membranes by treatment with the detergent Triton X-100, and was partially purified by gel filtration on a Sephacryl S-200HR column. This prolyl endopeptidase activity was shown to have a molecular mass (87 kDa) higher than the cytosolic prolyl endopeptidase but, from initial investigation, appears to demonstrate a similarly broad substrate specificity towards proline-containing neuropeptides. The partially purified enzyme was inhibited by certain thiol-protease inhibitors and was also found to be sensitive to the metal chelator 1,10-phenanthroline. PMID- 7851397 TI - Conversion of phenol derivatives to hydroxylated products by phenol hydroxylase from Trichosporon cutaneum. A comparison of regioselectivity and rate of conversion with calculated molecular orbital substrate characteristics. AB - This study describes the regioselective hydroxylation and the rates of conversion of a series of fluorinated phenol derivatives by phenol hydroxylase from the yeast Trichosporon cutaneum. The natural logarithm of the kcat value for the conversion of the phenolic substrates correlates with the calculated energy of the reactive electrons in the highest occupied molecular orbital of the substrate (r = 0.85). This observation supports the hypothesis that at physiological pH (7.6) and 25 degrees C, in the absence of monovalent anions, the nucleophilic attack of the electrons in the highest occupied molecular orbital of the substrate on the C(4a)-hydroperoxyflavin enzyme intermediate is of major importance in determining the overall rate of catalysis. Results from 19F-NMR analysis of the incubation mixtures demonstrate for phenols with two identical ortho substituents, that the ortho position which becomes preferentially hydroxylated is the one with the highest density of the reactive electrons in the highest occupied molecular orbital. A halogen substituent at a meta position decreases the chances for hydroxylation at the adjacent ortho position further than expected on the basis of the calculated reactivity. This result indicates a contribution of a protein/substrate dipolar interaction, influencing the time averaged orientation of the substrate with respect to the reactive C(4a) hydroperoxyflavin intermediate. PMID- 7851398 TI - Inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase and citrate synthase by sulfoxides and sulfones of substrate-analogue CoA-thioether derivatives. AB - Sulfoxides and sulfones were prepared by specific oxidation of 3-hydroxy-3 methylglutaryl-CoA-analogue CoA-thioether derivatives and their kinetic properties were determined with 3-hydroxy-3-methylglutaryl-CoA reductase. The oxidized CoA-thioether derivatives with a hydroxyl group at C3 were powerful competitive inhibitors, their Ki values being much smaller than the Km for 3 hydroxy-3-methylglutaryl-CoA. Sulfoxides and sulfones of substrate analogues of citrate synthase were also prepared. When tested in the appropriate reaction with citrate synthase, the sulfoxide and sulfone derivatives were competitive inhibitors, but their Ki values were greater than the Km values of the corresponding unmodified substrates. PMID- 7851399 TI - Kinetic properties and ligand binding of the eleven-subunit cytochrome-c oxidase from Saccharomyces cerevisiae isolated with a novel large-scale purification method. AB - A novel, large-scale method for the purification of cytochrome-c oxidase from the yeast Saccharomyces cerevisiae is described. The isolation procedure gave highly pure and active enzyme at high yields. The purified enzyme exhibited a heme a/protein ratio of 9.1 mmol/mg and revealed twelve protein bands after Tricine/SDS/PAGE. N-terminal sequencing showed that eleven of the corresponding proteins were identical to those recently described by Taanman and Capaldi [Taanman, J.-W. & Capaldi, R.A. (1992) J. Biol. Chem. 267, 22,481-22,485]. 15 of the N-terminal residues of the 12th band were identical to subunit VIII indicating that this band represents a dimer of subunit VIII (M(r) 5364). We conclude that subunit XII postulated by Taanman and Capaldi is the subunit VIII dimer and that cytochrome-c oxidase contains eleven rather than twelve subunits. We obtained the complete sequence of subunit VIa by Edman degradation. The protein contains more than 25% of charged amino acids and hydropathy analysis predicts one membrane-spanning helix. The purified enzyme had a turnover number of 1500 s-1 and the ionic-strength dependence of the Km value for cytochrome-c was similar to that described for other preparations of cytochrome-c oxidase. This was also true for the cyanide-binding characteristics of the preparation. When the enzyme was isolated in the presence of chloride, more than 90% of the preparation showed fast cyanide-binding kinetics and was resistant to formate incubation, indicating that chloride was bound to the binuclear center. When the enzyme was isolated in the absence of chloride, approximately 70% of the preparation was in the fast form. This high content of fast enzyme was also reflected in the characteristics of optical and EPR spectra for cytochrome-c oxidase purified with our method. PMID- 7851400 TI - Characterization of activators and inhibitors of protein kinase C mu. AB - In order to investigate regulatory mechanisms and to identify potential substrates of a novel member of the protein kinase C (PKC) family, PKC mu, specific antibodies have been raised against unique amino- and carboxy-terminal regions. PKC mu kinase activity was studied upon immunoprecipitation from stably transfected cell lines as well as from the A549 carcinoma cell line expressing the endogenous PKC mu gene. Cell fractionation revealed that PKC mu is predominantly found in the particulate fraction, suggesting an association with the membrane or membrane-bound structures. In vitro kinase assays with immunoprecipitated PKC mu demonstrated a Ca2+ independent enhancement of constitutive autophosphorylation activity by phosphatidylserine. Despite a limited in vitro phorbol ester response, an apparent phorbol ester activation of PKC mu was observed when cell cultures, instead of immunoprecipitated enzyme, were treated with either phorbol 12-myristate 13-acetate or 1,2 dioleoyl-sn glycerol. Both in vitro autophosphorylation and substrate phosphorylation of myelin basic protein and histone III were enhanced under these conditions. However, long-term treatment with the phorbol ester did not result in downregulation of PKC mu protein levels and kinase activity. Studies with several protein kinase inhibitors revealed a novel sensitivity profile of PKC mu, with no inhibition by calphostin C, reduced sensitivity to staurosporine but, compared to other PKCs, an approximately 60-fold higher sensitivity to the selective PKA inhibitor H89. Together, the data presented here show that localization of PKC mu and regulation of its kinase activity differ from that of other PKCs suggesting a novel function of PKC mu in intracellular signal pathways. PMID- 7851401 TI - Significant amounts of glycogen are synthesized from 3-carbon compounds in astroglial primary cultures from mice with participation of the mitochondrial phosphoenolpyruvate carboxykinase isoenzyme. AB - The incorporation was studied of the gluconeogenic substrates lactate, alanine, aspartate and glutamate into glycogen of astroglial primary cultures derived from mouse brain. The incorporation was inhibited by 3-mercaptopicolinate, an inhibitor of one of the characteristic gluconeogenic enzymes, phosphoenolpyruvate carboxykinase. Only the mitochondrial isoenzyme of phosphoenolpyruvate carboxykinase was detectable in the astroglial primary cultures. After the incubation of glucose-starved cells with medium containing a mixture of [6 3H]glucose and [U-14C]glucose, the newly synthesized glycogen showed a 3H/14C ratio which was approximately 15% less than the isotope ratio for the medium. The decrease of the isotope ratio was not significantly inhibited by 3 mercaptopicolinate, indicating a cycling of approximately 15% of the glucose to the level of the triose phosphates before its incorporation into astroglial glycogen. During the initial phase of glycogen resynthesis, the contribution of the gluconeogenic substrates appeared to be higher. This was in agreement with the accumulation of fructose 2,6-bisphosphate during refeeding. A participation of gluconeogenic substrates in glycogen metabolism was also detectable when the glycogen content was not changing significantly. PMID- 7851402 TI - Processing of the 2S storage protein pronapin in Brassica napus and in transformed tobacco. AB - The 2S protein napin in Brassica napus is synthesized as a proprotein from which an N-terminal an an internal propeptide are removed. In order to investigate the mechanism of 2S storage-protein processing, N-terminal sequences were determined for the light and heavy chains of all major napin isoforms isolated. Mutants of a napin gene, with deletions of different portions of the propeptides, were transformed into tobacco and napin protein was isolated. Napin light and heavy chains were separated and their N-terminal amino acid sequences determined. Further, the C-terminal residues of one napin isoform isolated from B. napus and one mutant napin isolated from tobacco were deduced from molecular-mass determinations of the constituents chains. Analyses suggested that the two propeptides are exposed at the surface of the proprotein. The light chain is processed to the correct length independent of the amino acid sequence in the N terminal propeptide and the processing site. The internal propeptide is attacked by endoproteases. Aminopeptidases and carboxypeptidases then digest portions of the propeptide to the extent allowed by the primary and the three-dimensional structures, often resulting in 2S protein chains with partly frayed ends. PMID- 7851403 TI - A seven-iron ferredoxin from the thermoacidophilic archaeon Desulfurolobus ambivalens. AB - A seven-iron ferredoxin was isolated from aerobically grown cells of the hyperthermoacidophilic archaeon Desulfurolobus ambivalens (DSM 3772). The protein is monomeric, with an apparent molecular mass of 15 kDa and contains 7 iron atoms/molecule. The N-terminal sequence shows a large similarity (70% identity) with that of the ferredoxin isolated from the archaeon Sulfolobus acidocaldarius. The EPR characteristics in both the native (oxidized) and dithionite-reduced states of this protein allowed an unequivocal identification of a [3Fe-4S]1+/0 center, with a reduction potential of -270 +/- 20 mV, at pH 7.5. The protein also contains a [4Fe-4S]2+/1+ center with a very low reduction potential (Eo = -540 mV, pH 7.0), which yields a rhombic EPR spectrum upon reduction with sodium dithionite at high pH. The reduction potentials of both centers are slightly pH dependent between pH 6 and 9. The [3Fe-4S] ferredoxin center is able to accept electrons from pyruvate oxidase and NADH oxidase isolated from D. ambivalens. This ferredoxin is present in large amounts (at least 130 mg/kg wet cells), which allowed the unequivocal observation of oxidized [3Fe-4S] clusters in intact D. ambivalens cells. PMID- 7851404 TI - A fluorescent interleukin-8 receptor probe produced by targetted labelling at the amino terminus. AB - Interleukin-8 is the most extensively characterised member of the structurally related chemotactic and pro-inflammatory proteins collectively called chemokines. It binds to two closely related members of the seven transmembrane chemokine receptor family found on a variety of leukocyte cell types. In order to study the interaction of interleukin-8 with its receptors, and their distribution, we have produced a fluorescently labelled protein as an alternative to the radioactive 125I-interleukin-8 ligand. Interleukin-8 is naturally produced as two forms, a 72 residue polypeptide by monocytes and a 77-residue form produced by endothelial cells which has an extension of five amino acids at the amino terminal. Both forms are active at nanomolar concentrations, implying that chemical modification to the amino terminus of the 72-residue form will not destroy activity. The 72 residue interleukin-8 sequence starts with a serine residue, which can be oxidised under mild conditions to give a reactive glyoxylyl function which is then reacted with a nucleophilic fluorescein derivative. The site-specifically labelled protein was easily isolated by reverse-phase HPLC. The dissociation constant of the fluorescently labelled interleukin-8 from its receptors on neutrophils was measured by displacement of 125I-interleukin-8 and found to be 10 nM compared to 1 nM for the unmodified protein. The modified protein is highly active in in vitro bioassays using human neutrophils, giving an EC50 of 7 nM in chemotaxis and an EC50 of 0.62 nM for shape change. The binding of the fluorescent protein to neutrophils can also be measured by fluorescent automatic cell sorter (FACS) analysis, and can be competed by unlabelled interleukin-8. The amino-terminal modification of interleukin-8 has produced a reagent which is useful for the quantification of interleukin-8 receptor expression, and will also be useful in monitoring the fate of the ligand after receptor binding. PMID- 7851405 TI - Stereoselectivity of microbial lipases. The substitution at position sn-2 of triacylglycerol analogs influences the stereoselectivity of different microbial lipases. AB - In the present study, the stereoselectivity of purified lipases from Candida rugosa, Chromobacterium viscosum, Pseudomonas species and Rhizopus arrhizus towards triacylglycerols in comparison to various structural analogs were investigated. Different triacylglycerol analogs with distinct polarities at position sn-2 of the glycerol backbone (1,3-diacyl-2-X-glycerol, where 2-X = 2 acyloxy, 2-alkyloxy, 2-deoxy-2-alkyl, or 2-deoxy-2-phenyl) were synthesized. Substrate hydrophobicity and steric requirement was modified by variation of the alkyl and acyl chain length. Hydrolysis of these substrates demonstrated that minor structural variations at C2 of triacylglycerol strongly affect the stereoselectivity of the lipases tested. It was noteworthy that the variation of substrate structure did not only affect the quantity of stereoselectivity expressed as percentage enantiomeric excess, but also resulted in a reversal of stereopreference in some cases. Replacement of the acylester in position 2 of glycerol by a non-ester-linked aliphatic moiety shifted the preference of Chromobacterium viscosum lipase from sn-3 to sn-1. Lipases from Chromobacterium viscosum. Pseudomonas species and Rhizopus arrhizus exhibited sn-3 preference with 2-deoxy-2-phenyl analogs, while towards substrates with a 2-deoxy-2-alkyl moiety sn-1 stereobias was recorded. Candida rugosa lipase was rather insensitive to substrate variations concerning the polarity at position 2 of the glycerol backbone. However, variation of the acyl chain length significantly influenced stereoselectivity of this lipase. PMID- 7851406 TI - Cloning and expression patterns of two members of a novel protein-kinase-C related kinase family. AB - The cDNA clones for two members of a novel protein kinase family were isolated and sequenced. These protein-kinase-C-related kinases, PRK1 and PRK2, display extensive identity to each other, revealing non-kinase domain similar regions. HR1 and HR2. HR1 contains a motif repeated three times (HR1a-c), while HR2 shows similarity to the amino-terminal sequence of protein-kinase-C epsilon and eta isotypes. Both PRK1 and PRK2, expressed in COS 1 cells, are autophosphorylated in immunoprecipitates, indicating intrinsic kinase activity. PRK1 and PRK2, as well as a third member of this family, PRK3, show distinct patterns of expression in adult tissues. PMID- 7851407 TI - The C-terminal domain of alpha-spectrin is structurally related to calmodulin. AB - An alignment of amino acid sequences suggests that the spectrin domain, which contains two EF-hand calcium-binding motifs, is structurally related to calmodulin. It is possible to align approximately 160 residues at the C-terminus of alpha-spectrin with the entire calmodulin sequence. We have expressed this domain in Escherichia coli and purified it. Circular dichroic and nuclear magnetic resonance spectroscopy show that the protein is folded and mostly helical. The conformation of the protein, as monitored spectroscopically, is sensitive to calcium at 0.1-1.0 mM. Equilibrium dialysis shows that there are two binding sites within this domain, with affinities in the 0.5 mM range. The domain can be split into N-terminal and C-terminal halves which fold independently. Only the N-terminal subdomain binds calcium. These data suggest that the C-terminus of alpha-spectrin has a domain with a calmodulin fold and two calcium-binding sites. Sequence alignments suggest that the related domains in alpha-actinin, and possibly in dystrophin, may share the same calmodulin-like structure. However, only non-muscle alpha-actinins appear to have one or two EF-hand(s) with the calcium-binding consensus sequence, and a strict consensus is not found in the muscle alpha-actinins or dystrophins. PMID- 7851408 TI - The contribution of glucose cycling to the maintenance of steady-state levels of lactate by hepatocytes during glycolysis and gluconeogenesis. AB - When hepatocytes from fasted rats were incubated with 10 mM glucose, there was a linear accumulation of lactate and pyruvate for about 80 min after which steady state concentrations of these metabolites became established. The rate of glycolysis, determined with [6-3H]glucose, was constant over the entire incubation period and was 50% greater than that calculated from carbon balance studies. This suggests that one-third of the glycolytic products formed were recycled to glucose. To enable study of the factors associated with the generation and maintenance of the lactate steady state and to measure accurately the carbon balance, incubations were performed using supraphysiological concentrations of glucose (20-80 mM). Under these conditions the initial rate of lactate accumulation and its concentration at steady state were shown to be dependent on the concentration of extracellular glucose. Rates of glycolysis were also measured using 40 mM [6-3H]glucose and [U-14C]glucose added alone, or in combination with a steady-state lactate concentration (3 mM). There was no effect on the rate of glycolysis determine with [6-3H]glucose, even when lactate was present in the medium. The difference in rates between measurements with the two isotopes reflect the apparent degree of glucose recycling which in the absence and presence of added lactate increased from 0.26 to 0.54 mumol C3 equivalents min-1.g-1 respectively. Identical studies employing [U-14C]lactate showed that glucose and CO2 were the major products of lactate metabolism under steady-state conditions and that the formation of lactate from [U-14C]glucose exactly balanced the rate of lactate removal as a result of oxidation and gluconeogenesis. These studies provide evidence for the concomitant operation of glycolysis and gluconeogenesis, even in the presence of high glucose concentrations. They also demonstrate that lactate steady states are achieved not by the cessation of glycolysis but rather by the removal of lactate and pyruvate at a rate equal to that of their production. PMID- 7851409 TI - Preferred DNA-binding-sites of polyomavirus large T-antigen. AB - Polyomavirus large T-antigen is a multifunctional protein. Its essential function in virus infection is to control the synthesis of viral RNA and DNA. For this activity specific DNA binding is necessary. Large T-antigen can bind to several sites in the regulatory region of viral DNA, consisting of clustered GRGGC nucleotide motifs. Since large T-antigen also regulates the activity of cellular genes and cellular DNA synthesis, it seemed possible that there are alternative, as yet unrecognized, binding sites. To identify sites preferred by large T antigen, double-stranded polynucleotides with random sequence were used. These polymers had a 31-bp central segment synthesized from a mixture of all four nucleotides and flanking segments of defined sequence. They were subjected to several cycles of binding to large T-antigen with intervening PCR amplification. Individual polynucleotides with affinity for large T-antigen were then isolated by cloning and their nucleotide sequences were determined. The majority of the polynucleotides contained two or three GRGGC motifs separated by between five and eight variable nucleotides. This result suggests that there are not any alternative high-affinity binding sites of large T-antigen. By comparing all the individual binding motifs an extended consensus sequence was observed. The dinucleotide TG was predominant immediately 5' to the binding pentanucleotide. On the 3'-side, at position +2, C residues were very rare. Although the pentanucleotide motif is the same as in polyomavirus DNA, the extended consensus sequence is not observed in viral DNA. In semi-quantitative experiments, binding of purified large T-antigen to a few of the selected DNA molecules was tested. Stable complexes were formed with DNA substrates containing two or three binding motifs in tandem. Binding to DNA with only one complete motif was weaker, but significantly stronger than non-specific association. This result has implications for the number of large T-antigen binding sites in cellular DNA. When mutant bc1081 large T-antigen, that is defective in specific DNA binding, was used in selection of polynucleotides, a different result was obtained. Neither bc1081 nor wild-type large T-antigen bound strongly to these polynucleotides. However, the presence of the motif TTCGGCTT, or part of it, in five of the six isolated polynucleotides suggested that the T-antigen selection was specific. PMID- 7851410 TI - Amino acid phosphatase activity of alkaline phosphatase. A possible role of protein phosphatase. AB - Alkaline phosphatase (ALP) hydrolyzed phosvitin and amino acid phosphates demonstrating nonisotropy at different pH. Orthovanadate, a protein phosphatase inhibitor, more specifically inhibited the serine and tyrosine phosphatase activities of ALP than that of threonine phosphatase at concentrations > 0.1 mM or 0.01 mM, respectively. Calyculin A and okadaic acid at increased concentrations increased ALP amino acid phosphatase activity. Bisphosphonates, such as disodium-1-hydroxy-1-aminopropylidine-1,1-diphosphonate (APD) and ethane 1-hydroxy-1,1-diphosphonate (HEBP), at increased concentrations, inhibited ALP amino acid phosphatase activity. These results suggest that ALP may function as a protein phosphatase. In terms of protein kinase inhibitors, N-[2 (methylamino)ethyl]-5-isoquinolinesulfonamide, N-(6-aminoheyxl)-5-chloro-1 naphthalenesulfomide hydrochloride and 4',5,7-trihydroxyisoflavone had little effect on ALP amino acid phosphatase activity. Staurosporine slightly enhanced ALP serine and threonine phosphatase activities at a concentration of 0.1 mM. These results suggest that protein phosphatase activity does not depend on the protein kinase activity of ALP, since duality between the former and the latter is not supported. ALP may function less as a protein kinase than as a protein phosphatase. The coupling mechanism of phosphate dynamics may be regulated indirectly. PMID- 7851411 TI - Kinetics of beta-1,3 glucan interaction at the donor and acceptor sites of the fungal glucosyltransferase encoded by the BGL2 gene. AB - Formation of branched glucan, glucan-glucan cross links, and glucan-chitin cross links most likely involves the action of fungal wall glucanases and transglycosylases. We developed an HPLC assay using radiolabeled substrates in order to study the kinetics of interaction of donor and acceptor molecules with a glucosyltransferase present in the cell walls of both Saccharomyces cerevisiae and Candida albicans. Purified transferase first forms an activated intermediate from a donor beta-1,3 glucan, releasing free disaccharide. The activated intermediate is transferred, in the presence of an appropriate acceptor beta-1,3 glucan, yielding a linear glucan containing a beta-1,6 linkage at the transfer site [Yu, L., Goldman, R., Sullivan, P., Walker, G. & Fesik, S. W. (1993) J. Biomol. NMR 3, 429-441]. An apparent Km of 0.41 mM for the acceptor site was determined using laminaritetraose as the acceptor. An apparent Km of 31 mM for the donor site was determined using increasing concentrations of laminaripentaose, and monitoring formation of laminaribiose. The enzyme functioned as a glucanase at low concentrations of acceptor molecules, with excess H2O competing for reaction at the activated donor site, thus resulting in hydrolysis. However, as the concentration of acceptor increased, the reaction shifted from hydrolysis to glucosyltransfer. The reaction appeared specific for beta-1,3 glucan as acceptor, in as much as no transfer was detected when either hexa-N-acetyl-chitohexaose or maltooligosaccharides were used as acceptors. The roles of such an enzymic activity in cell wall metabolism is discussed in terms of repair, cross linking and incorporation of newly synthesized chains of beta 1,3 glucan into the previously existing cell wall structure. PMID- 7851412 TI - Role of tyrosine kinase in the regulation of myogenin expression. AB - Using an affinity-purified anti-myogenin antibody, three stages of mouse myoblast C2C12 cells during myogenesis could be identified: proliferating myoblasts as myogenin-negative mononucleated cells, differentiating myoblasts as myogenin positive mononucleated cells, and myotubes as myogenin-positive multinucleated cells. We found differential effects of genistein, an inhibitor of protein tyrosine kinase, on myogenic cells during these three stages. Genistein severely inhibited myotube formation and myogenin production in differentiating myoblasts by inhibiting the transcription of the myogenin gene in a dose-dependent manner. We also found that genistein inactivated mitogen-activated protein kinase (MAP kinase) accompanied by suppression of myogenin expression. In contrast, genistein failed to inactivate MAP kinase and eliminate myogenin from myotubes. The results suggest that protein-tyrosine kinase plays a role in the transcriptional regulation of myogenin through the MAP kinase cascade during myogenesis. Furthermore, genistein inhibited the transactivation of the myosin heavy chain gene by constitutively expressed myogenin. Therefore, it is suggested that protein-tyrosine kinase is involved in the post-translational regulation of myogenin as well as in transcriptional regulation during myogenesis. PMID- 7851413 TI - Stathmin is a major substrate for mitogen-activated protein kinase during heat shock and chemical stress in HeLa cells. AB - Stathmin is a ubiquitous, highly conserved 19-kDa cytoplasmic protein whose expression and phosphorylation are regulated in relation to cell proliferation, differentiation or activation, in many biological systems. In this report, we show that stathmin undergoes major phosphorylation in HeLa cells submitted to heat or chemical stress. Heat-shock-induced stathmin phosphorylation was very rapid, as maximal incorporation of phosphate was observed at 5 min. Phosphorylation of stathmin might, therefore, occur as a very early step in the intracellular response to heat shock. The sites of phosphorylation of stathmin involved during the stress response were identified as mostly Ser25 and, to a lesser extent, Ser38. These sites are both followed by a proline residue, and known to be good substrates in vitro for mitogen-activated protein kinase (MAP kinase) and p34cdc2 kinase, respectively. In lysates from heat-shocked cells, an increased stathmin-kinase activity, distinct from the histone-H1-kinase activity, was found to phosphorylate stathmin mostly on Ser25, the main site for MAP-kinase in vitro. This stathmin-kinase coeluted quantitatively with the stress-activated MAP-kinase from an FPLC MonoQ column. Furthermore, a stathmin kinase activity was precipitated from lysates of heat-shocked HeLa cells by an anti-(MAP-kinase) serum. Together, these results indicate that the phosphorylation of stathmin by MAP-kinase is likely to be a significant component of the signalling array controlling the cellular response to stress, and they further underline the general involvement of stathmin in intracellular signalling. PMID- 7851414 TI - Evolution of transthyretin in marsupials. AB - The evolution of the expression and the structure of the gene for transthyretin, a thyroxine-binding plasma protein formerly called prealbumin, was studied in three marsupial species: the South American polyprotodont Monodelphis domestica, the Australian polyprotodont Sminthopsis macroura and the Australian diprotodont Petaurus breviceps. The transthyretin gene was found to be expressed in the choroid plexus of all three species. In liver it was expressed in P. breviceps and in M. domestica, but not in S. macroura. This, together with previous studies [Richardson, S. J., Bradley, A. J., Duan, W., Wettenhall, R. E. H., Harms, P. J., Babon, J. J., Southwell, B. R., Nicol, S., Donnellan, S. C. & Schreiber, G. (1994) Am. J. Physiol. 266, R1359-R1370], suggests the independent evolution of transthyretin synthesis in the liver of the American Polyprotodonta and the Australian Diprotodonta. The results obtained from cloning and sequencing of the cDNA for transthyretin from the three species suggested that, in the evolution of the structure of transthyretin in vertebrates, marsupial transthyretin structures are intermediate between bird/reptile and eutherian transthyretin structures. In marsupials, as in birds and reptiles, a hydrophobic tripeptide beginning with valine and ending with histidine was found in transthyretin at a position which has been identified in eutherians as the border between exon 1 and intron 1. In humans, rats and mice, the nine nucleotides, coding for this tripeptide in marsupials/reptiles/birds, are found at the 5' end of intron 1. They are no longer present in mature transthyretin mRNA. This results in a change in character of the N-termini of the subunits of transthyretin from hydrophobic to hydrophilic. This change might affect the accessibility of the thyroxine-binding site in the central channel of transthyretin, since, at least in humans, the N termini of the subunits of transthyretin are located in the vicinity of the channel entrance [Hamilton, J. A., Steinrauf, L. K., Braden, B. C., Liepnieks, J., Benson, M. D., Holmgren, G., Sandgren, O. & Steen, L. (1993) J. Biol. Chem. 268, 2416-2424]. PMID- 7851415 TI - The role of an enolase-related molecule in plasminogen binding to cells. AB - The alpha isoform of enolase is a candidate plasminogen receptor on U937 monocytoid cells [Miles, L. A., Dahlberg, C. L., Plescia, J., Felez, J., Kato, K. & Plow, E. F. (1991) Biochemistry 30, 1682-1691]. In the present study, an enolase-related molecule was detected on the surfaces of peripheral blood monocytes and neutrophils by fluorescence-activated cell sorting. A mRNA transcript encoding a unique membrane form of an enolase-related molecule was not detected by Northern-blotting and primer-extension analyses, consistent with the cell-surface protein being authentic alpha-enolase. Both the alpha and beta isoforms of purified enolase, bound plasminogen with an affinity similar to that of the cell surface. Moreover, immunopurified alpha-enolase enhanced plasminogen activation by tissue plasminogen activator and blocked the binding of plasminogen to alpha 2-antiplasmin, mimicking functions arising from the association of plasminogen with cells. The interaction of the enolase isoforms with plasminogen was dependent upon recognition of the C-terminal lysyl residue of the enolases by the lysine-binding sites of plasminogen, as the interaction was blocked by (a) peptides with C-terminal lysine residues and (b) an antibody to the C-terminal aspect of enolase. A monoclonal antibody was developed, characterized and utilized to quantify the enolase molecules present on the surface of U937 cells. A substantial number of molecules, 1.8 x 10(6)/cell, was present, accounting for approximately 10% of the plasminogen-binding capacity of these cells. These studies clearly establish the role of enolase as a cell-surface plasminogen binding site with profibrinolytic functions. PMID- 7851416 TI - Characterization of 45-kDa/54-kDa HSP27 kinase, a stress-sensitive kinase which may activate the phosphorylation-dependent protective function of mammalian 27 kDa heat-shock protein HSP27. AB - Heat-shock protein 27 (HSP27) is a major target of phosphorylation upon cell stimulation with a variety of agents and has been suggested to have a phosphorylation-regulated function at the level of actin filaments. Here we investigated comparatively the mechanisms of HSP27 phosphorylation by oxidative stresses, exposures to tumor necrosis factor (TNF), heat shock and growth factors. Extracts of Chinese hamster or human cells exposed to H2O2, xanthine/xanthine oxidase, menadione or TNF contained up to 15-fold more HSP27 kinase activity than comparable extracts obtained from control cells. Induction of HSP27 kinase activity by TNF or H2O2 was completely inhibited by first treating the cells with the antioxidant N-acetyl-L-cysteine, suggesting that generation of reactive oxygen metabolites was the key triggering element of this induction. In contrast, prior treatment with acetylcysteine had no or little effect on the induction by thrombin, serum and heat shock. The kinase activity in extracts of cells stimulated by heat shock, H2O2, sodium arsenite, TNF or growth factors was identified by in-gel renaturation and purified approximately 8000 fold by sequential chromatography. In all cases, the induced kinase activity was entirely associated with two polypeptides of 45 kDa and 54 kDa, identified as mitogen-activated-protein kinase-activated protein (MAPKAP) kinase-2 based on its reactivation in vitro by 42/44-kDa MAP kinases, its antigenic properties and its substrate specificity. The 45/54-kDa HSP27 kinase may play an important role in the cell response to oxidative stress. Overexpression of the wild-type HSP27 but not of a nonphosphorylatable form of human HSP27 in Chinese hamster cells conferred resistance to actin fragmentation by oxidative stress generated by H2O2. It is concluded that activation of the 45/54-kDa HSP27 kinase is a common mechanism of HSP27 phosphorylation to which converge both oxyradical-dependent and oxyradical-independent pathways and which may participate in a homeostatic response to stress at the level of actin microfilament. PMID- 7851417 TI - Interaction studies between elongation factor Tu and anthraniloyl-fluorescent analogues of guanyl nucleotides. AB - A fluorescent analogue of GDP, the 3'-O-anthraniloyl-GDP (anl-GDP) was demonstrated to bind to the elongation factor Tu (EF-Tu) with an affinity even higher than that of the parent nucleotide. As a consequence of the binding, an increase in fluorescence anisotropy and an emission band arising from non radiative energy transfer among the protein intrinsic fluorophores and the labelled nucleotide were observed. Therefore, it was possible to study the exchange kinetics and the equilibrium between the protein-bound labelled GDP and the natural nucleotide through modifications, occurring during the course of the reaction, of fluorescence anisotropy and non-radiative energy transfer. In this way, it was also easily proven that, in the presence of aurodox (N methylkirromycin), an antibiotic impairing EF-Tu biological function, the exchange kinetics between the protein-bound labeled GDP and the natural nucleotide was faster. Moreover, it was also found that the labelled nucleotide is recognized as a substrate by pyruvate kinase, being converted by this enzyme, in the presence of phosphoenolpyruvate, into anl-GTP. Pyruvate kinase is also able to convert, in the presence of phosphoenolpyruvate, the complex EF-Tu.anl GDP into the complex EF-Tu.anl-GTP. The fluorescence properties of the 3'-O anthraniloyl-labeled guanyl nucleotides and their feature as excellent acceptors of fluorescence arising from protein intrinsic fluorophores, may make these compounds useful for structural and binding studies on guanosine-nucleotide binding proteins. PMID- 7851418 TI - Metabolic pathway for biosynthesis of poly(3-hydroxybutyrate-co-4 hydroxybutyrate) from 4-hydroxybutyrate by Alcaligenes eutrophus. AB - Various aerobic Gram-negative bacteria have been examined for their ability to use 4-hydroxybutyrate and 1,4-butanediol as carbon source for growth. Alcaligenes eutrophus strains H16, HF39, PHB-4 and Pseudomonas denitrificans 'Morris' were not able to grow with 1,4-butanediol or 4-hydroxybutyrate. From A. eutrophus HF39 spontaneous primary mutants (e.g. SK4040) were isolated which grew on 4 hydroxybutyrate with doubling times of approximately 3 h. Tn5::mob mutagenesis of mutant SK4040 led to the isolation of two phenotypically different classes of secondary mutants which were affected in the utilization of 4-hydroxybutyrate. Mutants exhibiting the phenotype 4-hydroxybutyrate-negative did not grow with 4 hydroxybutyrate, and mutants exhibiting the phenotype 4-hydroxybutyrate-leaky grew at a significantly lower rate with 4-hydroxybutyrate. Hybridization experiments led to the identification of a 10-kbp genomic EcoRI fragment of A. eutrophus SK4040, which was altered in mutants with the phenotype 4 hydroxybutyrate-negative, and of two 1-kbp and 4.5-kbp genomic EcoRI fragments, which were altered in mutants with the phenotype 4-hydroxybutyrate-leaky. This 10 kbp EcoRI fragment was cloned from A. eutrophus SK4040, and conjugative transfer of a pVDZ'2 hybrid plasmid to A. eutrophus H16 conferred the ability to grow with 4-hydroxybutyrate to the wild type. DNA-sequence analysis of this fragment, enzymic analysis of the wild type and of mutants of A. eutrophus as well as of recombinant strains of Escherichia coli led to the identification of a structural gene encoding for a 4-hydroxybutyrate dehydrogenase which was affected by transposon mutagenesis in five of six available 4-hydroxybutyrate-negative mutants. Enzymic studies also provided evidence for the presence of an active succinate-semialdehyde dehydrogenase in 4-hydroxybutyrate-grown cells. This indicated that degradation of 4-hydroxybutyrate occurs via succinate semialdehyde and succinate and that the latter is degraded by the citric acid cycle. NMR studies of poly(3-hydroxybutyrate-co-4-hydroxybutyrate) accumulated from 4 hydroxy [1-13C]butyrate or 4-hydroxy[2-13C]butyrate as substrate gave no evidence for a direct conversion of 4-hydroxybutyrate into 3-hydroxybutyrate and therefore supported the results of enzymic analysis. PMID- 7851419 TI - Expression and functional characterization of chimeras between human and bovine vitamin-K-dependent protein-S-defining modules important for the species specificity of the activated protein C cofactor activity. AB - Vitamin-K-dependent protein S is an anticoagulant plasma protein functioning as a cofactor to activated protein C (APC) in the degradation of factors Va and VIIIa. The APC-cofactor function of protein S is species specific, as human protein S potentiates the anticoagulant activity of human but not that of bovine APC, whereas bovine protein S is a cofactor to APC from both species. To elucidate which modules in protein S determine the species specificity, in vitro mutagenesis was used to construct six recombinant chimeric molecules between human and bovine protein S. Wild-type human and bovine protein S and the chimeras were expressed in 293 cells and the recombinant proteins purified by monoclonal antibody affinity chromatography. The recombinant proteins were found to be post translationally modified, they bound C4b-binding protein and were functionally active as cofactors to APC. Chimeras having both the thrombin-sensitive region (TSR) and the first epidermal-growth-factor-(EGF)-like module of bovine origin expressed APC-cofactor activity similar to that of bovine protein S. Those chimeras, in which TSR or EGF1 derived from different species, manifested APC cofactor activity similar to that of human protein S, i.e. they did not express cofactor activity to bovine APC. These data indicate that sequence differences in the TSR and EGF1 of human and bovine protein S cause the species specificity of the APC-cofactor activity. The data support the concept that these two modules of protein S interact with APC on the surface of negatively charged phospholipids. PMID- 7851420 TI - A two-dimensional NMR study of bovine Cu, Co superoxide dismutase. Further assignments in the region surrounding the active site. AB - Bovine Cu, Co superoxide dismutase has been investigated by two-dimensional NMR with regard to the resonances arising from protons that surround the copper site. These protons have magnetic properties that are intermediate between those belonging to residues coordinated to the paramagnetic metal center and the diamagnetic residues. Nuclear Overhauser enhancement spectroscopy spectra have been recorded by using a new procedure and with different mixing times and different spectral widths, in order to observed dipolar connectivities between isotropically shifted and diamagnetic resonances. Scalar-correlated spectra were obtained with both correlation spectroscopy and total-correlation spectroscopy experiments. The original X-ray coordinates of the Cu, Co enzyme were used in order to obtain the appropriate interproton distances. The data allowed us to assign more than 20 new resonances to protons which cover a wide region around the copper ion, including two protons belonging to the catalytically important Arg141 residue. The results represent significant progress in the effort to elucidate the three-dimensional features of the region surrounding the active site of Cu, Zn superoxide dismutase in solution and a tool for a deeper investigation of the reaction mechanism of the enzyme. PMID- 7851421 TI - Presence of a closely related subgroup in the aldo-ketoreductase family of the mouse. AB - Aldose reductase (alditol:NAD(P)+ 1-oxidoreductase), an enzyme implicated in the pathogenesis of various diabetic complications, catalyzes the reduction of a variety of aldehydes. From a mouse kidney library, we isolated aldose reductase cDNA that encodes a 316-amino-acid protein with approximately 97% identity to rat lens aldose reductase, approximately 69% identity to the mouse vas deferens protein and also approximately 69% identity to mouse fibroblast growth-factor-1 regulated protein. RNA-blot analysis demonstrated abundant expression of the enzyme transcript in the testis, skeletal muscle and kidney. However, a very low level of the transcript was detected in the sciatic nerve and lens, where abundant expression and involvement of the enzyme in diabetic complications were documented in other animals species. The isolated cDNA was expressed in Escherichia coli and the recombinant protein was purified to homogeneity by affinity chromatography and chromatofocusing. The expressed enzyme demonstrated reductase activity for various aldo sugars but not for the steroids. The enzyme reaction with DL-glyceraldehyde was, however, competitively inhibited by progesterone or 17 alpha-hydroxyprogesterone. The results not only indicate a unique tissue distribution and enzyme attribute of mouse aldose reductase, but also the presence of a closely related subgroup within the aldo-oxidoreductase superfamily in mouse tissues. PMID- 7851422 TI - Functional consequences of proline mutations in the putative transmembrane segments 6 and 10 of the glucose transporter GLUT1. AB - Proline residues are thought to play a characteristic structural and/or dynamic role in various membrane proteins [Williams, K.A. & Deber, C.M. (1991) Biochemistry 30, 8919-8923]. By use of site-directed mutagenesis and functional expression of mutant glucose transporters in Xenopus oocytes, we investigated the effects of single proline substitutions in the putative helices 6 and 10 on GLUT1 mediated glucose transport. Proline residues of helix 6, that are conserved in all human glucose-transporter isoforms except for the human GLUT2, were mutated either to alanine or to the corresponding residues of GLUT2, i.e. to histidine (P187H), arginine (P196R) or phenylalanine (P205F). In addition, the three proline amino acids within the domain G382-P-G-P-I-P of helix 10 were individually replaced with either alanine or glutamine residues. In all cases, transport function was retained when each individual proline residue was replaced with alanine. Substitution of proline 196 by arginine (P196R), however, resulted in reduction of 2-deoxy-D-glucose uptake rates by approximately 70%. Since the amount of this mutant transporter protein in plasma membrane and total membrane preparations was found to be decreased, as detected by immunoblotting, no single proline residue seemed to play a critical role in maintaining the catalytic activity of GLUT1. However, structural changes introduced by incorporation of the neutral polar amino acid glutamine at each single proline position of helix 10 almost completely abolished 2-deoxy-D-glucose uptake. Thus, the specific chemical structure of the side chain of the substituted amino acid rather than the unique property of proline residues for cis-trans isomerization seemed to determine the consequences on glucose transport. PMID- 7851423 TI - Porcine aorta smooth-muscle myosin contains three species made of different combinations of two 17-kDa essential light-chain isoforms. AB - Porcine aorta myosin was reacted with a bifunctional cross-linking reagent, N,N' o-phenylenedimaleimide. The 17-kDa essential light chain (LC17) in each myosin head was intramolecularly cross-linked within a single myosin molecule. The 34 kDa cross-linked LC17 dimer was isolated and its peptide map, after lysylendopeptidase digestion, was obtained by reverse-phase HPLC. Based on the amino acid compositions of peptide fragments, the N-terminal Cys residues of LC17 subunits were assigned to be cross-linked to each other. To study the distribution of two LC17 isoforms, LC17nm and LC17gi [Hasegawa, Y., Ueda, Y., Watanabe, M. & Morita, F. (1992) J. Biochem. 111, 798-803], aorta myosin was reacted with 5,5'-dithiobis(2-nitrobenzoic acid) (Nbs2). The LC17 dimer cross linked with Nbs2 was resolved into three distinct bands on urea/PAGE using a 4% acrylamide gel. Densitometric analysis of the three band intensities showed that three pairs of LC17 isoforms in aorta myosin are present in the ratio of LC17nm LC17nm/LC17nm-LC17gi/C17gi-LC17g i = 22:46:32. This ratio is consistent with the random combination of two LC17 isoforms with myosin heavy chains. PMID- 7851424 TI - Characterization of the rat m3 muscarinic acetylcholine receptor produced in insect cells infected with recombinant baculovirus. AB - The m3 muscarinic acetylcholine receptor from rat heterologously produced in insect cells after infection with a recombinant baculovirus has an apparent molecular mass of approximately 75 kDa. Polyclonal antibodies raised against a carboxy-terminal nonapeptide that is unique to the m3 subtype can detect the receptors produced in the insect cells by Western blot and can also immunoprecipitate solubilized receptor. Immunofluorescence microscopy as well as electron microscopy revealed that the receptor was located intracellularly, visualized as a ring around the nucleus of the infected insect cells. Solubilization of the receptor was accomplished with digitonin which was added in increments (over 10 min) to a final concentration of 0.8% (mass/vol). The solubilized receptor is unstable when the ligand-binding site is not protected by a ligand. Here the low-affinity ligand propylbenzilylcholine (approximately 10 nM) has demonstrable protective ability during solubilization, but the usefulness of this ligand is limited by a very slow off rate. From the behaviour of the solubilized receptor during DEAE-Sephacel chromatography and lectin-affinity chromatography it can be deduced that the receptor produced in insect cells is heterogeneously glycosylated in the producing insect cells. PMID- 7851425 TI - Primary structure and tissue distribution of human 4-aminobutyrate aminotransferase. AB - cDNA encoding human 4-aminobutyrate aminotransferase (aminobutyrate:2 oxoglutarate aminotransferase) was prepared by polymerase chain reaction using mRNA from human neuroblastoma cells as the template and oligonucleotides synthesized on the basis of the information obtained from direct protein sequencing. The cDNA-deduced sequence enabled peptides, sequenced by automated Edman degradation, to be aligned for confirmation of the complete primary structure. The results are compared with the recently published sequence of the rat enzyme deduced entirely from DNA sequencing [Medina-Kauwe, L. K., Tillakaratne, N. J. K., Wu, J.-Y. & Tobin, A. J. (1994) J. Neurochem. 62, 1267 1275]. Although the sequences are almost identical for most of their length, they differ in a segment of 36 residues. Almost complete identity of the two sequences is established if it is assumed that a frame-shift error was introduced into the reported rat cDNA sequence. The human cDNA was used to probe for the presence of 4-aminobutyrate aminotransferase mRNA in human tissues and a significant transcript was found in heart, placenta and in tissues usually associated with the expression of this enzyme. PMID- 7851426 TI - Substitution of apolar residues in the active site of aspartate aminotransferase by histidine. Effects on reaction and substrate specificity. AB - In an attempt to change the reaction and substrate specificity of aspartate aminotransferase, several apolar active-site residues were substituted in turn with a histidine residue. Aspartate aminotransferase W140H (of Escherichia coli) racemizes alanine seven times faster (Kcat' = 2.2 x 10(-4) s-1) than the wild type enzyme, while the aminotransferase activity toward L-alanine was sixfold decreased. X-ray crystallographic analysis showed that the structural changes brought about by the mutation are limited to the immediate environment of H140. In contrast to the tryptophan side chain in the wild-type structure, the imidazole ring of H140 does not form a stacking interaction with the coenzyme pyridine ring. The angle between the two ring planes is about 50 degrees. Pyridoxamine 5'-phosphate dissociates 50 times more rapidly from the W140H mutant than from the wild-type enzyme. A model of the structure of the quinonoid enzyme substrate intermediate indicates that H140 might assist in the reprotonation of C alpha of the amino acid substrate from the re side of the deprotonated coenzyme substrate adduct in competition with si-side reprotonation by K258. In aspartate aminotransferase I17H (of chicken mitochondria), the substituted residue also lies on the re side of the coenzyme. This mutant enzyme slowly decarboxylates L aspartate to L-alanine (Kcat' = 8 x 10(-5) s-1). No beta-decarboxylase activity is detectable in the wild-type enzyme. In aspartate aminotransferase V37H (of chicken mitochondria), the mutated residue lies besides the coenzyme in the plane of the pyridine ring; no change in reaction specificity was observed. All three mutations, i.e. W140-->H, I17-->H and V37--H, decreased the aminotransferase activity toward aromatic amino acids by 10-100-fold, while decreasing the activity toward dicarboxylic substrates only moderately to 20%, 20% and 60% of the activity of the wild-type enzymes, respectively. In all three mutant enzymes, the decrease in aspartate aminotransferase activity at pH values lower than 6.5 was more pronounced than in the wild-type enzyme, apparently due to the protonation of the newly introduced histidine residues. The study shows that substitutions of single active-site residues may result in altered reaction and substrate specificities of pyridoxal-5'-phosphate-dependent enzymes. PMID- 7851427 TI - 13C-NMR studies of Corynebacterium melassecola metabolic pathways. AB - Coryneform bacteria are widely used to produce amino acids, in particularly glutamic acid, by fermentation. To study the metabolic fate of glucose as the carbon source, we developed a method to analyze intracellular extracts by NMR and HPLC. The intracellular metabolites represent the metabolic state of the cells. Glutamic acid was the major metabolic intermediate found in the extracts and its 13C isotopic enrichment reflected that of pyruvic acid. Thus, it was possible to determine the respective contributions of the two major glucose catabolic pathways during the exponential growth phase; glycolysis (55%) and the pentose phosphate pathway (45%). Absolute glutamate 13C enrichments resulting from the incorporation of [1-13C]glucose were determined to quantify the contribution of several metabolic pathways such as anaplerotic pathways (61%; phosphoenolpyruvate carboxylase, pyruvate carboxylase, malic enzyme), a single turn (32%) or multiple turns of the Krebs cycle and the glyoxylate shunt, to oxaloacetate synthesis. A previously described model was adapted to C. melassecola for these calculations. The Krebs cycle was active, whereas the glyoxylate shunt was inactive in exponentially growing cells of C. melassecola with glucose as the sole carbon source. The contributions of anaplerotic enzymes and pyruvate dehydrogenase to replenishing the Krebs' cycle were determined to be 38% and 62%, respectively. PMID- 7851428 TI - Inhibition by modified oligodeoxynucleotides of the expression of type-1 plasminogen activator inhibitor in human endothelial cells. AB - Antisense phosphodiester and phosphorothioate oligodeoxynucleotides (23-residue or 24-residue oligodeoxynucleotides) were constructed for sequences of type-1 plasminogen-activator-inhibitor mRNA to assess their capability to modulate type 1 plasminogen-activator-inhibitor-mediated fibrinolysis. Antisense oligodeoxynucleotides were targeted at the mRNA sequence coding a signal peptide, at a part of the reactive center Ile342-Pro349, and at an internally translated segment Asn265-Leu272. The effect of antisense oligonucleotides on the concentration of type-1 plasminogen activator inhibitor in conditioned media and human endothelial cells was determined by the activity test with fibrin as a substrate, and by immunoprecipitation after metabolic labelling of cells with [35S]methionine. Three phosphorothioate oligodeoxynucleotides were specifically inhibitory while phosphodiester oligodeoxynucleotides with the same sequence did not show any activity. Phosphorothioate oligodeoxynucleotides 2, 4 and 6 inhibited the synthesis of type-1 plasminogen activator inhibitor in endothelial cells in a time-dependent and concentration-dependent manner. These data suggest that antisense oligodeoxynucleotides may be useful in the design of antithrombolytic therapeutics. PMID- 7851429 TI - Subcellular distribution of serine acetyltransferase from Pisum sativum and characterization of an Arabidopsis thaliana putative cytosolic isoform. AB - The intracellular compartmentation of serine acetyltransferase, a key enzyme in the L-cysteine biosynthesis pathway, has been investigated in pea (Pisum sativum) leaves, by isolation of organelles and fractionation of protoplasts. Enzyme activity was mainly located in mitochondria (approximately 76% of total cellular activity). Significant activity was also identified in both the cytosol (14% of total activity) and chloroplasts (10% of total activity). Three enzyme forms were separated by anion-exchange chromatography, and each form was found to be specific for a given intracellular compartment. To obtain cDNA encoding the isoforms, functional complementation experiments were performed using an Arabidopsis thaliana expression library and an Escherichia coli mutant devoid of serine acetyltransferase activity. This strategy allowed isolation of three distinct cDNAs encoding serine acetyltransferase isoforms, as confirmed by enzyme activity measurements, genomic hybridizations, and nucleotide sequencing. The cDNA and related gene for one of the three isoforms have been characterized. The predicted amino acid sequence shows that it encodes a polypeptide of M(r) 34,330 exhibiting 41% amino acid identity with the E. coli serine acetyltransferase. Since none of the general features of transit peptides could be observed in the N terminal region of this isoform, we assume that it is a cytosolic form. PMID- 7851430 TI - A reactive, surface cysteine residue of the class-II fructose-1,6-bisphosphate aldolase of Escherichia coli revealed by electrospray ionisation mass spectrometry. AB - The state of post-translational modification of the class-II fructose-1,6 bisphosphate aldolase (FBP-aldolase) purified from Escherichia coli was examined by electrospray ionisation mass spectrometry (ESI-MS). The mass was larger than that expected from the known DNA sequence by approximately 80 +/- 6 Da, suggesting the presence of a covalent modification on the protein. Phosphorylation (+ 80 Da), a known modification in an FBP-aldolase from Bacillus subtilis and a suspected modification in this E. coli aldolase, was ruled out as the extra mass was readily removed by treatment with dithiothreitol. Purification of aldolase by a protocol which omitted 2-mercaptoethanol from all buffers resulted in the purified protein having the expected mass (39016 Da). The extra mass was therefore established as a covalent adduct of the protein with 2 mercaptoethanol (+ 76 Da). Reduction and alkylation studies, followed by isolation of tryptic peptides, established that the site of attachment was Cys36. Although no significant effect of the modification on the activity of the protein was observed, the study underlines the ease with which a protein can be modified covalently by a simple and mild purification procedure; such labelling, which may not always be benign, would be undetectable without the routine use of mass spectrometric analysis. PMID- 7851431 TI - Calorimetric investigation of thermal stability and ligand-binding characteristics of disulfide-bond-cleaved ribonuclease T1. AB - A combination of differential titration calorimetry and differential scanning calorimetry was used to study the effect of disulfide bond cleavage and reaction with iodoacetamide of ribonuclease T1 on both the binding of nucleotides and the thermal stability of the free enzyme species. Although guanosine monophosphates still bind to the active site of the modified protein the transition temperature of unfolding and the transition enthalpy decrease drastically indicating a relatively loose structure. The calorimetric data presented in this study suggest a cooperative linkage between the site of the disulfide bonds, the ligand-binding site, and the general thermodynamic stability of the enzyme. PMID- 7851432 TI - Site-specific N-terminal auto-degradation of human serum albumin. AB - Human serum albumin prepared by blood fractionation for clinical purposes was found to degrade when stored at or above 30 degree C. Mass spectrometry and N terminal sequencing of the protein identified degradation corresponding to the loss of the first two residues, aspartic acid and alanine. The reaction was shown to be dependent upon temperature and the N-terminal alpha-amino group. In addition, comparison with serum albumins derived from other species showed that the instability of the N-terminus was specific to the human albumin sequence. An intact aspartyl-alanyl dipeptide, purified from degraded albumin solutions, differed substantially from a synthetic dipeptide on amino acid analysis, N terminal sequencing and NMR. It is suggested that the released dipeptide may be cyclic, implying a novel cleavage mechanism. PMID- 7851433 TI - Electron spin resonance and electron nuclear double resonance studies of flavoproteins involved in the photosynthetic electron transport in the cyanobacterium Anabaena sp. PCC 7119. AB - The flavins of ferredoxin-NADP+ reductase (FNR) and flavodoxin from the cyanobacterium Anabaena PCC 7119 were obtained in their semiquinone states at pH 7 by photoreduction of the pure proteins in the presence of EDTA and 5 deazariboflavin. For FNR, the ESR signal of the FAD semiquinone was centred at g = 2.005 with linewidths 2.0 mT in H2O and 1.48 mT in D2O. These data are in agreement with those reported for other neutral flavin semiquinones. The linewidths were the same when measured either at X-band (9.35 GHz) or at S-band (4 GHz), indicating that line broadening is due to unresolved nuclear hyperfine couplings, caused in part by exchangeable protons. When the substrate, NADP+, was added to the semiquinone form of the protein no changes in the linewidth or shape of the spectra were detected, but a decrease in the ESR signal due to the FNR semiquinone was observed, consistent with the reduction of NADP+ to NADPH by reduced FNR and, subsequent displacement of the equilibrium. No changes in the shape or linewidth of the FNR ESR signals were observed when photoreduction of FNR was performed in the presence of either flavodoxin or ferredoxin. Electron nuclear double resonance (ENDOR) spectroscopy of FNR semiquinone from Anabaena PCC 7119 provided further information about the interactions of the flavin radical with protons. A group of signals, with couplings of 5-9.5 MHz, is attributed to protons on C6 and on 8-CH3 of the flavin ring. No change in these hyperfine couplings was detected when the protein was studied in D2O, but the coupling Aiso attributed to protons on 8-CH3 decreased from 8.12 MHz to 7.72 MHz in the presence of NADP+. The decrease in the electron spin density distribution on this part of the flavin ring system was attributed to binding of the substrate, polarising the electron density distribution of the flavin towards the pyrimidine ring. A second group of signals was observed, with hyperfine couplings less than 3 MHz, some of which disappeared when the protein was transferred into D2O. Effects of NADP+ binding to the protein were also observed in these weak couplings. These signals are attributed to displaced water protons, or to exchangeable protons from amino acid residues on the protein near the flavin binding site, involved in substrate stabilization.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7851434 TI - Properties of the catalytic domain of sdc25p, a yeast GDP/GTP exchange factor of Ras proteins. Complexation with wild-type Ras2p, [S24N]Ras2p and [R80D, N81D]Ras2p. AB - The catalytic domain of the Saccharomyces cerevisiae SDC25 gene product, including the last 550 C-terminal residues (Sdc25p-C), was produced as an Escherichia coli recombinant protein fused with glutathione S-transferase. The highly purified (greater than 95%) stable fusion protein, obtained by affinity chromatography, was very active in enhancing the dissociation rate or the GDP/GTP exchange of the GDP complex of Ras2p or human H-ras p21. This activity was further increased (three times) by glutathione S-transferase cleavage with thrombin. The stimulation of the guanine nucleotide release by Sdc25p-C was stronger for Ras2p.GDP than Ras2p.GTP, an effect that was less pronounced in the case of the p21 complexes. The association rate of the Ras2p.GDP (GTP) complex was also enhanced by Sdc25p-C. Monovalent and divalent salts inhibit the nucleotide-releasing activity of Sdc25p-C. Retention phenomena occurring on gel filtration chromatography hindered the use of highly purified Sdc25p-C to study the formation of stable complexes with Ras2p. For this purpose, Sdc25p-C was produced as a non-glutathione-S-transferase fusion protein via pTTQ19. Upon partial purification, this product yielded a 54-kDa truncated form of Sdc25p-C (truncated Sdc25p-C) showing the same specific activity as the 64-kDa Sdc25p-C protein. On gel filtration, truncated Sdc25p-C and nucleotide-free Ras2p (or p21) formed a stable 1:1 stoichiometric complex that was dissociated by increasing concentrations of GDP. The properties of this complex were analyzed by using the mutant [S24N]Ras2p, the homologue of [S17N]p21 known to induce a dominant negative phenotype, [R80D, N81D]Ras2p, a recessive negative mutant insensitive to the truncated form of Sdc25p-C in vitro. The complex with [S24N]Ras2p was greater than 100-fold less sensitive to the dissociating effect of GDP, whereas [R80D, N81D]Ras2p was unable to form a stable complex with truncated Sdc25p-C. These results strongly suggest that the residues R80 and N81 are situated in or closely associated with the Ras2p specific site binding Sdc25p. PMID- 7851435 TI - Characterisation of a protease from Escherichia coli involved in hydrogenase maturation. AB - The large subunits of nickel-containing hydrogenases are synthesised in a precursor form which, after nickel incorporation, is processed by proteolytic cleavage at the C-terminal end. The protease involved in processing of HycE, the large subunit of hydrogenase 3 from Escherichia coli, was purified by three chromatographic steps to apparent homogeneity. Its gene was identified by using a hybridisation probe generated by PCR with oligonucleotide primers the sequence of which was derived from the N-terminal and internal amino acid sequences. Determination of the nucleotide sequence showed that the gene is located distally and as a hitherto uncharacterised gene within the hyc operon, coding for hydrogenase 3 components. It was designated hycI. The HycI protease has a molecular mass of 17 kDa and is a monomer. Its cleavage reaction is not inhibited by conventional inhibitors of serine and metalloproteases, which correlates with the fact that the sequence does not contain signature motifs characteristic of serine-, metallo-, cysteine- or acid proteases. Homologous genes are present in other transcriptional units coding for hydrogenases. PMID- 7851436 TI - Horse liver alcohol dehydrogenase can accept NADP+ as coenzyme in high concentrations of acetonitrile. AB - The coenzyme specificity of horse liver alcohol dehydrogenase assayed in mixtures of acetonitrile and buffer, 0.01 M Tris/HCl pH 7.4, was investigated. The enzyme could accept NADP+ as coenzyme if it was first bio-imprinted with NADP+, i.e. precipitated from an aqueous buffer with 1-propanol in the presence of NADP+ dried, and then assayed in a system with less than 10% buffer. When assayed in a system with 25% buffer, no activity with NADP+ as coenzyme was observed. The activity was measured with a coenzyme regeneration assay with cinnamoyl alcohol and octylaldehyde as substrates. Other methods to prepare a binary complex of horse liver alcohol dehydrogenase and NADP+, i.e. if the enzyme was immobilized on silica and NADP+ added afterwards or if it was deposited on Celite together with NADP+, failed to show any bio-imprinting effect. The activity of horse liver alcohol dehydrogenase bioimprinted with NADP+ and assayed in acetonitrile/buffer mixtures with less than 10% buffer showed the same or higher activity than an enzyme preparation prepared by bio-imprinting with NAD+. The hypothesis is that the conformation of the active site of horse liver alcohol dehydrogenase is modified to one that is complementary to the ligand present during precipitation and drying. This is possible because of the restricted motility of the enzyme conformation in high concentrations of organic solvent. In the presence of more than 10% buffer the mobility increases in such a way that the imposed conformation with activity towards NADP+ disappears. PMID- 7851437 TI - Phosphoglycerate-kinase-glyceraldehyde-3-phosphate-dehydrogenase interaction. Molecular mass studies. AB - When rabbit muscle phosphoglycerate kinase (PGK; a 48-kDa monomeric protein) and glyceraldehyde-3-phosphate dehydrogenase (GraPDH; a 145-kDa homotetrameric protein) are present together in solution in the proportion of 1 mol PGK/1 mol GraPDH monomer (total protein 0.2-1.0 mg/ml), an 80--82-kDa protein species is observed by gel-penetration (dilution factor) method and by the conventional procedure of elution from a gel column. Individually, PGK and GraPDH do not exhibit any self association or dissociation in the concentration range employed. Electrophoresis of the 80-82-kDa peak eluted from the gel column shows a single protein band with mobility intermediate between those of GraPDH and PGK. In titration experiments by the gel-penetration method, plots of dilution factor of PGK (or GraPDH) activity versus GraPDH (or PGK) concentration shows two linear portions intersecting at approximately 1 mol GraPDH monomer/1 mol PGK. From the molecular-mass values and the titration experiments, it has been suggested that, in solution, these enzymes form a complex consisting of 1 molecule of PGK and one monomeric subunit of GraPDH (expected molecular mass 84 kDa). Its dissociation constant has been estimated to be equal to or less than 13 nM. The complex is dissociated in the presence of KCl or NADH, with approximately half dissociation at 0.1 M salt or 0.25 mM NADH. At 0.1 M KCl, the complex is completely dissociated by adding ATP, NADH or 3-phosphoglycerate. AMP, ADP, NAD+, glyceraldehyde-3-phosphate, phosphate ions and fructose-1,6-bisphosphate reverse the effect of KCl. PMID- 7851438 TI - Fatty acid binding to bovine serum albumin prevents formation of intermediate during denaturation. AB - Urea-induced denaturation of defatted BSA and BSA containing six mol palmitic acid/mol protein (fatted BSA) has been studied by the techniques of UV difference spectroscopy and fluorescence spectroscopy. The notable differences between the two transitions are a shift in the transition of fatted BSA to a higher urea concentration and a three-state denaturation transition in defatted BSA compared to an apparent two-state denaturation transition in fatted BSA. The stable denaturation intermediate in defatted BSA occurs at 4.5-5.0 M urea, a urea concentration at which denaturation in fatted BSA has not yet started. These results are further supported by the difference spectral results obtained at 4.5 M urea in the two albumin preparations. The occurrence of denaturation intermediate only in defatted BSA and the presence of the two strong fatty-acid binding sites in domain III lead us to conclude that this domain is relatively unstable in the absence of fatty acids and is responsible for the formation of intermediate. PMID- 7851439 TI - Expression and purification of the high-affinity phosphate transporter of Saccharomyces cerevisiae. AB - The plasma membrane high-affinity phosphate permease of Saccharomyces cerevisiae has been overproduced as a stable membrane-bound chimeric protein in Escherichia coli. Construction of a chimera between the permease and a peptide containing 10 consecutive histidine residues allowed selective binding of the chimera to a chelating column charged with Ni2+, and elution with imidazole in a high state of purity. Approximately 5 mg purified His10-permease was obtained from 3 g (wet mass) cells. The purified phosphate permease chimera catalyzes uncoupler sensitive phosphate transport after reconstitution into proteoliposomes. PMID- 7851440 TI - Structure, stability and biological properties of a N-terminally truncated form of recombinant human interleukin-6 containing a single disulfide bond. AB - A mutant species of the 185-residue chain of human interleukin-6 lacking 22 residues at its N-terminus and with a Cys-->Ser substitution at positions 45 and 51 was produced in Escherichia coli. The 163-residue protein des-(A1-S22)-[C45S, C51S]interleukin-6, containing a single disulfide bridge, formed inclusion bodies. Mutant interleukin-6 was solubilized in 6 M guanidine hydrochloride, subjected to oxidative refolding and purified to homogeneity by ammonium sulfate precipitation and hydrophobic chromatography. The purity of the mutant species was established by electrophoresis, isoelectrofocusing and reverse-phase HPLC and its structural identity was checked by N-terminal sequencing of both the intact protein and several of its proteolytic fragments. Electrospray mass spectrometry analysis of mutant interleukin-6 gave a molecular mass of 18,695 +/- 2 Da in excellent agreement with the calculated value. Circular dichroic, fluorescence emission and second-derivative ultraviolet absorption spectra indicated that mutant interleukin-6 maintains the overall secondary and tertiary structure, as well as stability characteristics, of the recombinant wild-type human interleukin 6. The urea-induced unfolding of mutant interleukin-6, monitored by circular dichroic measurements in the far-ultraviolet region, occurs as a highly cooperative process with a midpoint of denaturation at 5.5 M urea. The data of the reversible unfolding of mutant interleukin-6 mediated by urea were used to calculate a value of 20.9 +/- 0.4 kJ.mol-1 for the thermodynamic stability of the protein at 25 degrees C in the absence of denaturant. The biological activity of mutant interleukin-6 was evaluated in vitro by the hybridoma proliferation assay, and in vivo by measuring thrombopoiesis in monkeys. Dose/response effects of the mutant were comparable or even higher than those of the wild-type protein. Overall the results of this study show that mutant interleukin-6 is a biologically active cytokine, which could find practical use as a therapeutic agent. PMID- 7851441 TI - A putative digestive cysteine proteinase from Drosophila melanogaster is predominantly expressed in the embryonic and larval midgut. AB - Plant seeds have biodefense systems for protection against insects. One of these systems may be based on the occurrence of phytocystatins, cysteine proteinase inhibitors of plant origin, that probably inhibit insect cysteine proteinases involved in digestive functions. To elucidate a molecular mechanism for this biodefense phenomenon, we isolated a gene encoding a putative digestive cysteine proteinase from Drosophila melanogaster, a suitable model species. The cloned genomic DNA fragment contained a sequence encoding a cysteine proteinase. The mature enzyme from the encoded protein, termed Drosophila cysteine proteinase-1, consisted of 218 amino acid residues. Drosophila cysteine proteinase-1 showed 67% similarity in its amino acid sequence to a lobster cysteine proteinase-3 contained in the digestive juice. This enzyme also showed significant similarities to cysteine proteinases of animal origin such as cathepsins H and L, and to proteinases of plant origin such as rice oryzains alpha and beta. In situ hybridization studies for the embryo showed that the mRNA for Drosophila cysteine proteinase-1 was predominantly expressed in the midgut. Larval alimentary organs, such as the salivary gland and the midgut including the gastric caeca, also expressed the mRNA at significant levels. These observations, suggesting that Drosophila cysteine proteinase-1 is a digestive cysteine proteinase which can be used as a model target of phytocystatins, will hopefully lead to new strategies for the regulation of pest insects. PMID- 7851442 TI - Integral cytochrome-c oxidase. Preparation and progress towards a three dimensional crystallization. AB - A new rapid procedure for the preparation of monodispersed highly active cytochrome-c oxidase from bovine heart is described. The crucial step is the separation of cytochrome-c oxidase from cytochrome-c reductase by selective solubilization in the non-ionic detergents Triton X-100 or lauryl beta-D maltoside. The enzyme is purified by subsequent anion-exchange chromatography. The preparation is finished within two days yielding approximately 60% of the oxidase present in mitochondria. The enzyme has a heme alpha/protein ratio of 9.7 +/- 0.5 nmol/mg, approximately equal to the theoretical value of 9.77 nmol/mg based on a molecular mass of 204.696 kDa for the protein monomer. SDS/PAGE of the preparation reveals the presence of the well-known thirteen protein components. Quantitative Edman degradation of the enzyme exclusively releases the known ten N terminal residues; three of the thirteen protein components are blocked at the N terminus. The preparation is highly active with maximal turnover numbers of approximately 600 s-1, identical to the maximal activity found in the mitochondrial membrane under these conditions. No g = 12 signal and no adventitious copper signal are observed in the EPR spectrum. The enzyme exhibits a fast monophasic reaction with cyanide. Determination of the metal contents of the enzyme indicates the stoichiometric presence of three copper ions besides two iron, one magnesium and one zinc ion in relation to the 94 sulfur atoms of the protein monomer. Gel-filtration experiments show a monodispersed dimeric association to form a complex of approximately 500 kDa. The phosphorus content 44 +/- 6.8 atoms/dimer, results from 59% cardiolipin, 23% phosphatidylethanolamine and 18% phosphatidylcholine, indicating a stable lipid shell, different from other previously described preparations. Crystals have been obtained from these preparations and are investigated for their suitability for X-ray work. PMID- 7851443 TI - Affinity labeling of a sulfhydryl group in the cardiacglycoside receptor site of Na+/K(+)-ATPase by N-hydroxysuccinimidyl derivatives of digoxigenin. AB - Na+/K(+)-ATPase from pig kidney is inactivated by protein-reactive N hydroxysuccinimidyl derivatives of digoxigenin. Like digoxigenin, its protein reactive derivatives N-hydroxysuccinimidyl digoxigenin-3-methylcarbonyl-epsilon aminocaproate (HDMA), 3-amino-3-deoxydigoxigenin hemisuccinimide succinimidyl ester (ADHS), 3-iodoacetylamino-3-deoxydigoxigenin (IAD) and digoxigenin-3-O succinyl-[2-(N-maleimido)]ethylamide (DSME) inhibited the sodium pump in the presence of Na+, Mg2+ and ATP. At 37 degrees C, half-maximal inhibition of Na+/K(+)-ATPase was seen by HDMA at 0.47 microM, by ADHS at 5.8 microM, by IAD at 8 microM and by DSME at 94 microM. Thus, all compounds bind to the cardiac steroid receptor site of Na+/K(+)-ATPase. Affinity labeling of the alpha subunit by 'front door' or 'back door' phosphorylation was only seen with HDMA or ADHS in the range 0.1 microM. Excess of ouabain protected against affinity labeling. All the other protein-reactive derivatives of digoxigenin labeled the enzyme independent of the formation of a phosphointermediate at much higher concentrations. This labeling was not suppressed by an excess of ouabain. Tryptic hydrolysis of the HDMA-modified Na+/K(+)-ATPase gave peptides of the apparent molecular masses 20, 12.5 and 11.2 kDa. The 11.2-kDa and 12.5-kDa peptides started amino-terminally with Asp68, and the 20-kDa peptide with Asp24. Thus, the HDMA-labeled peptides originate from the cardioactive steroid-binding site formed by the first and second transmembrane helix. N-Hydroxysuccinimidyl esters such as HDMA are normally thought to modify lysine and arginine residues covalently. Since such residues do not exist in the putative cardiac glycoside-binding site, the possibility of a thioester formation of the digoxigenin derivatives HDMA and ADHS with Cys104 in the H1 transmembrane domain was tested. In fact, hydroxylaminolysis led to the release of the covalently bound HDMA, and the formation of a free sulfhydryl group. This could be labeled by [2-14C]ICH2COOH. We therefore propose, consistent with a recent conclusion from a site-directed mutagenesis experiment [Canessa, C. M., Horisberger, J.-D., Louvard, D. & Rossier, B. C. (1992) EMBO J. 11, 1681-1687], that a cysteine residue (probably Cys104) participates in the structure and function of the cardiac glycoside binding. PMID- 7851444 TI - An increase in phosphorylation of microtubule-associated protein 2 accompanies dendrite extension during the differentiation of cultured hippocampal neurones. AB - Hippocampal neurones, from embryonic rats, were cultured for different times and the extension of dendrite-like processes was analysed morphologically and by immunofluorescence, using microtubule-associated protein 2 (MAP2) as a marker. Simultaneously, the changes in phosphorylation in MAP2 were analyzed and a correlation between dendrite sprouting and an increase in MAP2 phosphorylation was found. Phospho-MAP2 was cleaved by Staphylococcus aureus V8 protease limited proteolysis and its phosphopeptide pattern was compared to that obtained with two protein kinases (calcium/calmodulin-dependent kinase and protein kinase C) in vitro. An involvement of calcium/calmodulin-dependent protein kinase in the phosphorylation of MAP2, occurring simultaneously with dendrite extension during neuronal differentiation in vitro, is suggested. PMID- 7851445 TI - Probing protein structure by solvent perturbation of NMR spectra. A comparison with photochemically induced dynamic nuclear polarization techniques applied to native alpha-lactalbumin. AB - We have suggested elsewhere the use of surface mapping by spin label probes (Esposito et al., 1992). According to this approach, soluble nitroxides are added to a protein solution. Resonances of protons that are accessible to the nitroxide are broadened and bleached out of the spectrum, while resonances in the protein interior remain unaffected. This approach is, in principle, complementary to another technique, photochemically induced dynamic nuclear polarization, which maps the position of aromatic protons on the protein surface. A detailed comparison between the two techniques is necessary for a confident use of the more recent suggested nitroxide perturbation approach. In the present study, we show that the results obtained by the two techniques for the native state of bovine alpha-lactalbumin are fully consistent and may therefore be combined for the study of protein surfaces. PMID- 7851446 TI - Probing protein structure by solvent perturbation of NMR spectra. Photochemically induced dynamic nuclear polarization and paramagnetic perturbation techniques applied to the study of the molten globule state of alpha-lactalbumin. AB - We have characterized the high-temperature molten globule state of bovine alpha lactalbumin by a combined use of photochemically induced dynamic nuclear polarization and nitroxide surface perturbation. Both techniques are extremely well suited to follow the progressive increase of exposed surfaces in the native state and the appearance of partially or completely unfolded species. Our results suggest that the molten globule state obtained at high temperature and pH 7, and the state obtained at pH 2 are not only thermodynamically but also structurally very similar. PMID- 7851447 TI - Import and insertion of proteins into the mitochondrial outer membrane. AB - Nuclear-encoded proteins destined for insertion into the mitochondrial outer membrane, follow the same general pathway for import as proteins that are translocated to interior compartments within the organelle. This observation is true both for beta-barrel-type proteins and for proteins that contain hydrophobic alpha-helical transmembrane segments. In this review, we describe what is known about the various steps leading to protein insertion into the outer membrane, and discuss the energetics that favor vectorial translocation into and across this membrane. The selection of the outer membrane during import may involve a lateral release of the translocating polypeptide from the import machinery so that the appropriate domains of the protein become embedded in the lipid bilayer. One type of topogenic domain that can guarantee such selection of the outer membrane is a signal-anchor sequence of the type characterized for the bitopic protein Mas70p. It is suggested that a signal-anchor sequence selective for the mitochondrial outer membrane causes abrogation of polypeptide translocation and triggers the release of the transmembrane segment into the surrounding lipid bilayer, prior to any possibility for the commitment of translocation to the interior of the organelle. Specific structural features of the signal-anchor sequence specify its orientation in the membrane, and can confer on this sequence the ability to form homo-oligomers and hetero-oligomers. Strategies other than a signal-anchor sequence may be employed by other classes of proteins for selection of the outer membrane. Of note is the ability of the outer-membrane import machinery to catalyze integration of the correct set of proteins into the outer-membrane bilayer, while allowing proteins that are destined for integration into the bilayer of the inner membrane to pass through unimpeded. Again, however, different proteins may employ different strategies. One model proposes that this can be accomplished by a combination of a matrix-targeting signal and a distal stop-transfer sequence. In this model, the formation of contact sites, which is triggered when the matrix-targeting signal engages the import machinery of the inner membrane, may prevent the outer-membrane translocon from recognizing and responding to the downstream stop-transfer domain. This allows the transmembrane segment to pass across the outer-membrane, and subsequently integrate into the inner membrane. PMID- 7851448 TI - A novel EF-hand Ca(2+)-binding protein from abdominal muscle of crustaceans with similarity to calcyphosine from dog thyroidea. AB - The amino acid sequence of a novel EF-hand Ca(2+)-binding protein from the abdominal muscle of the crayfish, Orconectes limosus, has been elucidated by tandem mass spectrometry and automated Edman degradation. The name CCBP-23 (23 kDa crustacean Ca(2+)-binding protein) is proposed. The protein can also exist as a disulfide-linked homodimer. The sequence of the monomeric form spans 200 residues with an acetylated N-terminal Ser and reveals four EF-hand domains. The 174-mass-unit difference between the calculated average molecular mass of 22,669.6 Da deduced from the sequence and the obtained electrospray ionization mass spectroscopy (ESI-MS) mass of 22,844 Da has not yet been explained. Partial sequence analysis (137 residues) of CCBP-23 from the lobster, Homarus americanus, showed a sequence identity of 74% with the crayfish protein. Homology searches revealed a 44% sequence identity of CCBP-23 from crayfish to calcyphosine, a Ca(2+)-binding protein from dog thyroidea (Lefort et al., 1989). Although CCBP-23 also shows a 44% identity to R2D5 antigen (Nemoto et al., 1993), we believe that both proteins represent two distinct subgroups within the family of EF-hand proteins. PMID- 7851449 TI - Trends in cerebrovascular mortality in western and eastern Europe. PMID- 7851450 TI - Frontal stroke syndromes. AB - The frontal lobe is the largest lobe of the brain, and it is thus commonly involved in stroke. Moreover, almost one in five strokes is limited to the prerolandic areas. This high frequency of anatomical involvement is in sharp contrast with the apparent rarity of clinical frontal dysfunction in stroke. It is remarkable that frontal behavioral syndromes have been rather uncommonly reported in patients with stroke as compared to patients with other diseases, such as brain tumor. This fact is paradoxical, because an acute process (stroke) is expected to yield more clinical dysfunction than a more chronic disease (tumor). A volume effect may be the main factor leading to this phenomenon. Another interesting aspect of frontal strokes is the contribution of so-called 'silent' strokes, the recurrence of which may nevertheless lead to intellectual decline and compromise recovery from another stroke with more specific neurologic dysfunction. The contribution of stroke to understanding of frontal lobe dysfunction is important, because of the focal nature of this disease, and great opportunity for clinical-topographic classification correlations. One of the first modern attempts to develop a clinical-topographic classification of frontal lobe lesions came from the school of Luria, who tried to delineate three main types of frontal lobe syndromes (premotor syndrome, prefrontal syndrome, medial frontal syndrome). Recent anatomic correlates using MRI make it possible to improve this classification. We suggest considering six main clinical-anatomic frontal stroke syndromes: (1) prefrontal; (2) premotor; (3) superior medial; (4) orbital-medial; (5) basal forebrain; (6) white matter. Finally, another fascinating topic relates to frontal lobe symptomatology due to stroke sparing the frontal cortex or white matter. This occurs mainly in three instances: lenticulo-capsular stroke, caudate stroke, and thalamic stroke. Studies using blood flow or metabolism measurements suggest that diaschisis (frontal lobe dysfunction from a remote lesion) may play a role. We believe that this is more likely to be related to dynamic interruption of complex circuitry than to static frontal lobe deactivation. PMID- 7851451 TI - Migrainous stroke and the antiphospholipid antibodies. AB - The pathogenesis of migrainous stroke is controversial. The possibility that a number of migraine-related strokes is associated with the presence of antiphospholipid antibodies, a condition predisposing to coagulopathy, has been suggested. We investigated the prevalence of lupus anticoagulant and anticardiolipin antibodies in patients with migrainous stroke. In 6 out of 16 patients with migrainous cerebral infarction, the presence of antiphospholipids antibodies was detected. In such patients, the presence of other risk factors for stroke was significantly lower (chi 2 = 5.6; p = 0.01) with respect to patients with negative results for antiphospholipid antibodies. These results suggest that antiphospholipid antibodies associated with migraine may be an important marker for ischemic stroke. PMID- 7851452 TI - Sleep problems in multiple sclerosis. AB - Twenty-eight consecutive patients with multiple sclerosis (MS) were clinically evaluated to determine the presence of sleep-related disorders. There were 12 males and 16 females aged between 22 and 67 with disability ranging between 1.5 and 8.5 on Kurtzke extended disability status score (EDSS). Fifteen patients (54%) reported sleep-related problems. These included difficulties initiating sleep and/or frequent awakenings due to spasms or discomfort in the legs (8 patients), difficulty in initiating or maintaining sleep (3), habitual snoring (4) and nocturia (1). All-night oximetry was performed and the tracings analysed for the number of dips in oxygen saturation (SaO2) or more than 4%. Three patients showed significant sleep-related oxygen desaturation (> 5 dips of > 4% SaO2/h). Subsequent polysomnography performed in 2 of the 3 patients with significant oxygen desaturation confirmed the presence of sleep apnoea. MRI analysis of brain stem regions showed abnormalities in 20/22 cases. The 3 patients showing nocturnal oxygen desaturation had MRI brain stem lesions, but their locations were variable and their general appearance not different from that seen in the 17 without sleep apnoea. Sleep disturbance in MS is common but poorly recognised. It is usually due to leg spasms, pain, immobility, nocturia or medication. It is much less commonly associated with nocturnal respiratory insufficiency. PMID- 7851453 TI - Influence of clinical variables on neuropsychological performance in multiple sclerosis. AB - The effects of age, educational level, duration and course of the disease, physical disability and mood status on several cognitive functions (short- and long-term memory, frontal functions, attention, language and visuospatial skills) have been evaluated in 42 multiple sclerosis (MS) patients. The Hamilton Depression Rating Scale (HDRS) scores and a secondary progressive disease course significantly influenced neuropsychological performance. Factorial analysis revealed that indexes of (1) frontal function impairment, (2) long-term verbal memory and language function impairment, and (3) visuospatial short- and long term memory and visuoperceptive function impairment accounted for 85% of the variance in neuropsychological performance. Only the first factor was significantly related to the presence of depressive symptomatology, as assessed by the HDRS. These results indicate that both the course of the disease and the presence of affective disorders must be taken into account when evaluating the natural history of cognitive impairment in MS and suggest that depressive symptomatology and cognitive dysfunction in MS are related to the involvement of at least partially overlapping anatomofunctional circuits. PMID- 7851454 TI - Colonic transit time in nonidiopathic Parkinson's syndrome. AB - Constipation is well known to be a frequent symptom in idiopathic Parkinson's disease. In this study, colonic transit time was measured in 16 patients with nonidiopathic Parkinson's syndrome (non-IPS). These patients all had lacunar infarcts in the caudate, putamen, or globus pallidus, as a cause of the disease, as demonstrated by MRI. In comparison with the control group there was only a slightly longer transit time with, on the whole, a normal transit time (about 59 h). In only five cases was the transit time significantly decreased. Our results suggest that colonic transit is only prolonged in patients with idiopathic PD, whereas it is normal in non-IPS. This seems to be cause by a multi-degenerative process in the idiopathic disease. PMID- 7851455 TI - Multiple sclerosis with very late onset: report of six cases and review of the literature. AB - Multiple sclerosis (MS) usually starts in young adulthood. However, the disease may appear late or very late in life. We report 6 cases with onset after the age of 59 years and review the literature. As in early onset disease, the diagnosis is mainly clinical. Laboratory findings and paraclinical evidence may support the diagnosis of clinical data are not sufficient. In elderly patients clinical history and laboratory data should be thoroughly appraised to exclude conditions more common in old age such as vascular diseases. PMID- 7851456 TI - Pregnancy in a patient with Wilson's disease treated with D-penicillamine and zinc sulfate. A case report and review of the literature. AB - A case of successful pregnancy in a patient with Wilson's disease treated with D penicillamine and zinc sulfate is presented. Experience with D-penicillamine, triethylene tetramine dihydrochloride (trien) and zinc salts during pregnancy is reviewed and discussed. PMID- 7851457 TI - Myotonia induced by potassium repletion in a diabetic patient with secondary hypokalemic paralysis. AB - In a woman suffering from insulin-dependent diabetes mellitus, hypokalemic paralysis developed acutely following an episode of diabetes decompensation. During the treatment of this episode, as soon as serum potassium levels were restored to normal values, a marked increase in muscular excitability with an electromyographic picture of myotonia was observed. The patient showed signs of chronic muscle denervation that accounted for an increased sensitivity to potassium-induced depolarization and contraction and that might have been responsible for the appearance of myotonia during potassium repletion. PMID- 7851458 TI - Ageusia associated with thalamic plaque in multiple sclerosis. AB - Ageusia and the cheirooral syndrome developed in a patient with a relapse of multiple sclerosis. Magnetic resonance imaging revealed an area of demyelination in the thalamus. This lesion presumably affected the most medial part of the ventralis posterior nucleus, where taste information is located. Given the proximity of the taste area and somatosensory representation of the hand and oral cavity in the ventralis posterior nucleus, we propose that a diagnosis of thalamic lesion should be considered when ageusia occurs with the cheirooral syndrome. PMID- 7851459 TI - Role of diltiazem in ischemia-reperfusion injury of the intestine. AB - It is well recognized that reperfusion causes tissue damage in excess of that produced by ischemia alone. The present study was designed to test this and to evaluate the role of the calcium antagonist, diltiazem (400 micrograms/kg body weight administered intravenously over 95 min), in ischemia-reperfusion injury of the intestine. Intestinal ischemia was produced by occlusion of the superior mesenteric artery (SMA) with interruption of the collateral flow for 30 min. Reperfusion was established by declamping the SMA for 1 h, and mucosal injury was assessed using a grading scale from 0 to 5. The severity of mucosal damage increased significantly after 1 h of reperfusion, from a mean grade of 2.1 in the ischemia group to 3.8 in the ischemia-reperfusion group (p < 0.01). Diltiazem was effective in the amelioration of histologic changes of reperfusion injury and reduced the degree of mucosal injury from a mean grade of 3.8 in the ischemia reperfusion group to 2.5 in the diltiazem group (p < 0.05). This study strongly suggests that calcium ions are involved in the pathogenesis of ischemia reperfusion injury and that diltiazem attenuates this injury by preventing the intracellular calcium influx that occurs during reperfusion. PMID- 7851460 TI - Interrelationship of oxygen supply by hepatic artery and portal vein: rapid analysis of ischemia-reflow-induced changes in hepatic oxygenation in experimental and clinical subjects by tissue near-infrared spectroscopy. AB - The rapid changes in extracellular oxygenation and intracellular oxidation during ischemia and reflow were measured in deep liver tissue by a novel method combining tissue near-infrared spectroscopy with multicomponent curve-fitting analysis. This method enabled us to make real-time measurements of oxygen saturation (SO2) and amount (THB) of hemoglobin in the liver sinusoid as parameters of extracellular oxygenation state and of redox transition of cytochrome aa3 as intracellular oxidation state. Clamping of the hepatic artery in rabbit decreased the THB with a transient fall of SO2. Clamping of the portal vein decreased both SO2 and THB. The decreases of SO2 and THB caused by Pringle's maneuver were larger than the sum of decreases by hepatic artery and portal vein. These changes in SO2 were correlated with intramitochondrial oxidation state as measured by cytochrome aa3. These results indicate the presence of an interrelationship of oxygen supply by hepatic artery and portal vein. This method was clinically applied during and after clamping of hepatic artery and portal vein in 19 cases of hepatic resection with or without chronic hepatic diseases. The decrease in SO2 values before and after clamping (SO2D) and the slope of SO2 recovery (SO2R) after release were calculated. SO2D and SO2R values of the portal vein in cirrhotics were significantly higher and lower, respectively, than those in the normal liver. These data indicate that the present method provides a rapid and reliable method of quantifying hepatic oxygenation during liver surgery and its perioperative management. PMID- 7851462 TI - Effect of vagotomy on cholecystokinin release and gallbladder contraction in patients with complicated duodenal ulcer. AB - In this prospective study, we investigated gallbladder (GB) contraction and plasma cholecystokinin (CCK) levels in response to food intake before and 1 month after vagotomy in 27 patients with complicated duodenal ulcer. Highly selective vagotomy (HSV) was carried out in 6 patients, truncal vagotomy and pyloroplasty (TVP) in 4, truncal vagotomy and antrectomy (TVA) in 7, selective vagotomy and pyloroplasty (SVP) in 5 and selective vagotomy and antrectomy (SVA) in another 5 patients with pyloric stenosis. The results of our studies indicated that (1) basal plasma CCK levels increased significantly after vagotomy, (2) none of the vagotomy operations altered the integrated CCK response, (3) unlike HSV, SVA and TVA, SVP and TVP decreased GB emptying and (4) antrectomy significantly enhanced CCK release after food intake. We concluded from these findings that the operative procedure of HSV, SVA or TVA to circumvent bile stasis-related postvagotomy cholelithiasis is superior to SVP or TVP in the surgical treatment of complicated duodenal ulcer. PMID- 7851461 TI - Histomorphological changes of organs, in particular the liver, in a study of endotoxin tolerance in an animal model. AB - We studied the histomorphological changes of organs in an animal model of endotoxin tolerance (ETT). ETT was induced by pretreating pigs with increasing doses of endotoxin (ET) before challenging them with a continuous lethal ET infusion. In the ETT group the survival time was prolonged significantly versus controls, so that in the ETT group on an average double the ET challenge dose was administered. In this histomorphological study the lung, kidney, and intestine of almost all animals (ETT group n = 12, controls n = 11) showed about the same unspecific histological shock features. In the liver, however, we diagnosed partly disseminating, partly confluent, but obviously ET-induced, neutrophil liver cell necrosis in 10/12 ETT pigs and in 10/11 controls. We conclude that ETT in our model was not a protective factor against serious liver cell injury after ET administration. Our results may indicate that the ETT phenomenon can be overcome by raising the ET challenge dosage. PMID- 7851463 TI - Conjunctival oxygen tension measurements for assessment of tissue oxygen tension during pulmonary surgery. AB - Conjunctival oxygen tension (PcjO2) and routine cardiorespiratory parameters were measured in 8 patients during pulmonary surgery. In each patient we found a close relationship between PcjO and arterial blood oxygen tension (PaO2), and for all patients the correlation coefficient was 0.962. The mean values of the ratio between PcjO2 and PaO2 in each patient were ranging between 0.46 and 0.55. We conclude that PcjO2 measurements represent a useful and reliable method for evaluation of peripheral oxygenation and perfusion during pulmonary surgery. Furthermore, the method has been found useful for estimation of arterial blood oxygen tension in hemodynamically stable patients during anesthesia. PMID- 7851464 TI - Effect of 15-deoxyspergualin on accelerated rejection in rat heart transplantation. AB - The effect of 15-deoxyspergualin (DSG) on accelerated rejection was evaluated using a rat heart transplantation model. Lewis rats (LEW, RT1l) served as the organ recipient and Brown Norway rats (BN, RT1n) as the donor. In the accelerated rejection model, the LEW recipient was sensitized with BN skin and BN heart was transplanted 7 days later; the heart graft was rejected within 2 days (n = 7). Histologically, the graft showed coagulation necrosis and hemorrhage throughout the myocardium. DSG (2.5 mg/kg/day) was administered to the recipient under the following three protocols: group 1: during the sensitization period (7 days); group 2: from 3 days after the sensitization to 2 days after grafting (7 days), and group 3: immediately after heart transplantation. The mean graft survival period in groups 1, 2, and 3 was 4.3 +/- 0.8 days (n = 7, p < 0.01 vs untreated host), 11.7 +/- 2.1 days (n = 7, p < 0.001, vs. untreated host), and 2.0 +/- 0 days (n = 6), respectively. The rejected grafts in groups 1 and 3 histologically showed coagulation necrosis and hemorrhage. By contrast, in group 2, the major histological change was interstitial lymphocyte infiltration and there were few findings such as coagulation necrosis or hemorrhage. In the complement-dependent cytotoxicity test, serum obtained at the second posttransplant day from the recipients treated in group 1 showed a high cytotoxicity level, although the cytotoxicity level of serum obtained from the recipients treated in group 2 was consistently low.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7851465 TI - Measuring progression of diabetic nephropathy. PMID- 7851466 TI - Effect of 5-hydroxytryptamine antagonists on cholera toxin-induced secretion in the human jejunum. AB - In rats, the combined administration of the 5-HT2 antagonist ketanserin and the 5 HT3 antagonist tropisetron inhibits cholera toxin-induced intestinal secretion. We investigated whether these agents and the 5-HT3 antagonist ondansetron can inhibit cholera toxin-induced secretion in the human jejunum using a segmental perfusion technique. In a first control period the subjects' jejunums were perfused continuously with a plasma-like electrolyte solution. In a second control period they either received a combination of tropisetron plus ketanserin, or tropisetron or ondansetron alone. Cholera toxin 6.25 micrograms was then administered intrajejunally and the experiments were continued for 4 h. Net water movements during the 4th hour after CT administration minus net water movement during the first control period was used for further calculation and was referred to as net luminal gain. In perfusion studies with tropisetron plus ketanserin resp. ondansetron the net luminal gain of water (+ 161 +/- 26 resp. 189 +/- 28 ml 30 cm-1 h-1, mean +/- SEM) was significantly higher compared to perfusion studies with cholera toxin alone (+ 94 +/- 30). Treatment with tropisetron did not change the CT-induced net luminal gain of water (+ 108 +/- 41). Movements of sodium, chloride, bicarbonate and potassium paralleled the movement of water. In agreement with these observations we found a deterioration of clinical parameters after the end of the perfusion studies in four of five subjects treated with CT 25 micrograms plus ketanserin and tropisetron.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7851467 TI - Postprandial apolipoprotein B100 and B48 metabolism in familial combined hyperlipidaemia before and after reduction of fasting plasma triglycerides. AB - Hepatic VLDL overproduction in familial combined hyperlipidaemia (FCH) may delay the clearance of atherogenic apolipoprotein (apo) B containing particles. We investigated if normalization of fasting plasma triglycerides (TG) by hypolipidaemic treatment results in improved metabolism of apo B48 and apo B100 in six male subjects with FCH and compared them to six normolipidaemic controls. The FCH patients were studied before (TG, 5.2 +/- 1.2 mmol l-1; mean +/- SEM) and after therapy (TG, 2.1 +/- 0.3 mmol l-1) with either simvastatin (n = 4) or combined therapy with gemfibrozil (n = 2). The postprandial changes of apo B100 and apo B48 were studied after a single oral fat meal (24 h; 50 gram fat m-2). Changes in triglyceride rich particles (TRP; d < 1.006 g ml-1) and remnant fractions (REM; d:1.006-1.019 g ml-1) of apo B were quantitated by scanning silverstained SDS-PAGE (4-15%). Apo B48 in fasting TRP in untreated and treated FCH was 15% and 14% of total apo B, and 6% in controls (P < 0.05). In controls, postprandial B48 increased maximally at 4 h by 81% in TRP and by 137% in REM compared to baseline. In treated FCH, the postprandial apo B48 pattern normalized in TRP compared to the untreated state. Postprandial apo B100 in controls decreased in TRP and REM by 33% and 18% (P < 0.05). In untreated and treated FCH, postprandial apo B100 remained unchanged vs. baseline in TRP and in REM suggesting hypersecretion of VLDL. The elimination of B100--assessed as area under the curve--in TRP (32.5 +/- 3.6 au.h; mean +/- SEM) and REM fractions (33.2 +/- 3.1 au.h), improved significantly after treatment (21.0 +/- 2.8 and 20.4 +/- 3.3 au.h, respectively). The apo B48 clearance in TRP fractions was improved after treatment (4.3 +/- 1.4 au.h vs. 2.9 +/- 1.2 au.h; P = 0.06), but not in REM fractions (2.8 +/- 1.0 au.h vs. 1.8 +/- 0.5 au.h; NS). In conclusion, in FCH subjects with apo B100 hypersecretion and increased fasting plasma apo B48 levels, reduction of fasting plasma TG improved, but did not normalize, TRP apo B48 and B100 metabolism. However, therapy normalized postprandial apo B100 remnant metabolism. Impaired postprandial apo B metabolism may be instrumental in the development of premature atherosclerosis in FCH subjects. PMID- 7851468 TI - Enhancement of transforming growth factor beta 1 expression in the rat pancreas during regeneration from caerulein-induced pancreatitis. AB - Synthesis of extracellular matrix components is enhanced in the rat pancreas during regeneration from caerulein-induced pancreatitis. To study the involvement of transforming growth factor beta 1 (TGF beta 1), one of the most potent modulators of the extracellular matrix, in the process of pancreatic regeneration we examined the expression of this gene on the transcript and protein level. Pancreatic RNA was extracted from rats killed 0 h, 12 h, 24 h, 2, 3 and 7 days after induction of caerulein pancreatitis. Transcript levels for TGF beta 1 were measured by slot-blot analysis and mRNA in situ hybridization. Total amount of TGF beta 1-protein was measured using a radioligand binding assay. TGF beta 1 protein was increased twofold after 24 h and 48 h and returned to control values 7 days after induction of pancreatitis, TGF beta 1-mRNA reached maximal values (3 fold over controls) after 2 days. The largest amount of TGF beta 1-mRNA was found in pancreatic acinar cells and in stromal cells. In summary, expression of TGF beta 1 in acinar and stromal cells of the rat pancreas is enhanced during regeneration from caerulein-induced pancreatitis, which may indicate an involvement of TGF beta 1 in the regulation of extracellular matrix regeneration in the rat pancreas after caerulein-induced pancreatitis. PMID- 7851469 TI - Effect of experimental non-insulin requiring diabetes on myocardial microcirculation during ischaemia in dogs. AB - To examine whether chronic high blood glucose may influence myocardial microcirculation during acute myocardial ischaemia in the dog, a noninsulin requiring diabetes was induced by the streptozotocin-alloxan method. Seventy-five days later, myocardial ischaemia was provoked by occluding the left anterior descending coronary artery for 2 h and microcirculation regulation was assessed in the ischaemic and non-ischaemic myocardium by the radioactive microsphere method. Diabetic dogs were compared with normal dogs. Diabetic dogs had higher blood glycated haemoglobin (2.66 +/- 0.4%) and fructosamine (397 +/- 62 mumol l 1) than control dogs (0.66 +/- 0.2, P < 0.004 and 229 +/- 13, P < 0.03, respectively). Haemodynamic data in the two groups were not different at any time. The size of the ischaemic zone was similar in both groups. During the 2 h ischaemia in the ischaemic zone subendocardial (P = 0.22) and subepicardial (P < 0.05) blood flow slightly increased in control dogs whereas there was a 63% (P < 0.02) and 35% (P = 0.06) reduction respectively in diabetic dogs. In the non ischaemic zone, blood flow of controls tended to increase (P < 0.006 in the subepicardium and P < 0.06 in the subendocardium) whereas in diabetic dogs blood flow tended to decrease (P = 0.03 in the subendocardium and in the subepicardium). This first investigation on myocardial microcirculation in diabetic dogs during ischaemia suggests that one of the possible causes of increased mortality rate from ischaemic cardiac disease in diabetics might be related to a paradoxical and unfavourable pattern of myocardial blood flow during ischaemia. PMID- 7851470 TI - Hepatic uptake and intestinal absorption of bile acids in the rabbit. AB - The existence of transporters for bile acids (BA) in liver and intestine has been well documented, but information is still needed as to their respective transport capacity. In the present investigation, we compared the hepatic and intestinal transport rates for BA, using perfused livers and intestines. The livers and intestines were separately perfused and dose-response curves (0.25-10 mM) for tauroursodeoxycholate, taurocholate and taurodeoxycholate were obtained. The intestinal and mesenteric concentration and bile acid pattern were also evaluated in six non-fasting rabbits. Taurocholic, tauroursodeoxycholic and taurodeoxycholic acid ileal absorption showed saturation kinetics in the intestine as in the liver; the maximal uptake velocity for each bile acid in the liver was tenfold higher than the respective maximal transport velocity in the intestine; the Km values obtained in the liver were of the same order of magnitude, i.e. in the millimolar range. Taurocholic, tauroursodeoxycholic and taurodeoxycholic acid transport differences in the liver paralleled those in the intestine. Although the intestine was not homogeneously filled, the bile acid concentration in the ileal content fell into the range of the Km for the three studied bile acids, while the portal blood total bile acid concentration was inferior to the observed Kms of liver uptake. Therefore, both the hepatic and intestinal systems do not operate at their maximal transport rates at the prevailing concentrations in portal blood and luminal content, and the hepatic transport occurs at its highest efficiency (below the Km values) in physiological conditions. PMID- 7851471 TI - Diurnal variations in the plasma concentrations of mevalonic acid in patients with abetalipoproteinaemia. AB - Previous studies have demonstrated that changes in the rates of cholesterol biosynthesis can be evaluated by the determination of plasma concentrations of sterol intermediates, including mevalonic acid and lathosterol and that, in normal human subjects, a diurnal rhythm exists in which the highest concentrations of sterol intermediates are observed at night. The factors responsible for this diurnal rhythm in cholesterol synthesis are, however, unknown. To test the hypothesis that the nocturnal increase in cholesterol biosynthesis is attributable to a reduced rate of hepatic uptake of chylomicron remnants at night as compared to higher rates of uptake during the daytime in response to alimentary lipaemia, we have examined the diurnal rhythm of mevalonic acid in six normal volunteers and three patients with phenotypic abetalipoproteinaemia. The latter patients do not absorb appreciable amounts of dietary cholesterol and are unable to synthesize chylomicron particles. Plasma concentrations of mevalonic acid exhibited a diurnal rhythm in the normal subjects, and the highest plasma concentrations were observed between 24.00 hours/04.00 hours. A similar rhythm was observed in the plasma of patients with abetalipoproteinaemia. These results suggest that the nocturnal increase in cholesterol biosynthesis which occurs in humans is not attributable to reduced hepatic uptake of chylomicron remnants at night; further studies are needed to better define those factors which influence the periodicity of cholesterol biosynthesis in humans. PMID- 7851472 TI - Silicon and aluminium and their inter-relationship in serum and urine after renal transplantation. AB - The present study was undertaken to establish the relationship between serum and urine silicon and improve renal function and examine whether the increased urinary excretion of aluminium observed after successful renal transplantation was associated with silicon. The changes in silicon and aluminium concentrations in serum and urine were measured in 15 patients for a period of up to 17 days following a first renal transplant. Serum silicon, unlike aluminium, progressively decreased with improving renal function and was significantly positively correlated with serum aluminium but not with the silicon excretion. The urine excretion of aluminium peaked between 4-8 days post-transplantation and was highly significantly positively correlated with urine silicon. The individual patient fractional excretion profiles of aluminium and silicon were variable but in general gave significant positive correlations suggesting that the elements may be cleared by the kidney through a common mechanism or as a chemical species, possibly an hydroxyaluminosilicate. If soluble silicon can chemically interact with aluminium in vivo it may, as in the biosphere, be important in the control of aluminium toxicity and eventual detoxification. Thus, elevated serum silicon concentrations may help to alleviate aluminium toxicity in end-stage renal disease and assist in the rapid clearance of aluminium seen after kidney transplantation. PMID- 7851473 TI - Antiparkinsonian activity of talipexole in MPTP-treated monkeys: in combination with L-dopa and as chronic treatment. AB - We examined whether or not the antiparkinsonian activity of talipexole (B-HT 920, 6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]-azepine) could be optimised by combination with L-3,4-dihydroxyphenylalanine (L-dopa). Additionally, the effects of chronic treatment with talipexole on motor behavior were investigated using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated and normal common marmosets. Administration of MPTP (0.5 mg/animal i.v. once or twice) to marmosets induced persistent parkinsonian motor deficits. The antiparkinsonian activity of talipexole (40 micrograms/kg s.c.) was significantly enhanced by its combination with L-dopa (30 mg/kg i.p.). This may further support the postulated postsynaptic dopamine D2 receptor agonist properties of talipexole. Chronic treatment with talipexole (a daily dose of 40 micrograms/kg s.c. for 21 days) did not lead to tolerance to the antiparkinsonian activity in MPTP-treated animals. No obvious dyskinesia was seen throughout the chronic treatment. In contrast, in normal marmosets, talipexole at a dose of 80 micrograms/kg which is a dose sufficient to induce hyperactivity did not increase motor activity during the treatment repeated for 21 days. These results suggest that talipexole is a selective dopamine D2 receptor agonist drug of potential use in the treatment of Parkinson's disease. PMID- 7851474 TI - Thermoregulatory effects of resiniferatoxin in the rat. AB - When administered acutely, the vanilloid (capsaicin) receptor agonist resiniferatoxin induces marked hypothermia in the ferret, rat and mouse. The aim of this study was to further characterise the thermoregulatory effects of resiniferatoxin in the rat in an attempt to understand the mechanism by which resiniferatoxin induces this hypothermic effect. Three doses of resiniferatoxin were administered (50, 100, 200 micrograms/kg s.c.) in separate animals at an ambient temperature (Ta) of 20 degrees C but there was no apparent dose-related effect on the decrease in colonic temperature over this range. Resiniferatoxin (50 micrograms/kg s.c.) decreased whole body oxygen consumption when measured below thermoneutrality (Ta = 20 degrees C) but not at thermoneutrality (Ta = 29 degrees C); likewise there was no hypothermic response to resiniferatoxin when measured at a Ta of 29 degrees C. Operant responding for radiant heat in a cold environment (-8 degrees C) was also measured in resiniferatoxin-treated (50 micrograms/kg s.c.) rats. These experiments showed that resiniferatoxin-treated rats attempted to defend body temperature by lever pressing for more radiant heat. However, this was not sufficient to reverse the hypothermia. Two repeat doses, 1 week apart, had little or no effect on colonic temperature, oxygen consumption or operant responding in the cold. Resiniferatoxin (50 micrograms/kg s.c.) also produced hypothermia (Ta = 20 degrees C) in neonatally capsaicinized adult rats. The exact site and mode of action is still under investigation, but it is postulated that resiniferatoxin activates, and then destroys or desensitizes warm thermoreceptors. PMID- 7851475 TI - Inhibition of either angiotensin-converting enzyme or neutral endopeptidase induces both enzymes. AB - Synthesis of angiotensin-converting enzyme is induced during its chronic inhibition. Like angiotensin-converting enzyme, neutral endopeptidase (EC 3.4.24.11) is a plasma membrane peptidase. We studied changes of the two enzymes in lung, kidney and serum in a coronary ligation model of experimental congestive heart failure, and during chronic inhibition of the enzymes. Coronary-ligated rats (n = 19) and sham-operated controls (n = 18) were given SCH 34826 [(S)-N-[N [1-[[(2,2-dimethyl-1,3-dioxolan-4-yl) methoxy]carbonyl]-2-phenylethyl]-L phenylalanine]-beta-alanine], a specific neutral endopeptidase inhibitor (n = 13), captopril (n = 12), or vehicle (n = 12) for 4 days, and exsanguinated. Pulmonary angiotensin-converting enzyme was induced both by captopril (52% compared to vehicle) and by SCH 34826 (21%). Serum angiotensin-converting enzyme was induced by captopril (44%). Neutral endopeptidase was induced in lung by captopril (73%), and in kidney by SCH 38426 (32%). Compared to controls, the relative heart weight of rats with heart failure was increased by 29%, and the plasma level of atrial natriuretic peptide elevated by 74%, but enzyme activities were not different. We conclude that, in the rat, separate inhibition of either angiotensin-converting enzyme or neutral endopeptidase induces both enzymes, and that the induction varies in different tissues. Alterations in the substrates of the two enzymes, e.g. in bradykinin, might cause these changes. PMID- 7851476 TI - Antibodies against intercellular adhesion molecule 1 protect against myocardial ischaemia-reperfusion injury in rat. AB - In this study we have assayed the pathophysiological role of intercellular adhesion molecule (ICAM-1), a cytokine-inducible adhesion molecule, in a model of ischaemia reperfusion in the rat. Anaesthetized rats were subjected to occlusion (1 h) of the left main coronary artery followed by reperfusion (1 h). Sham myocardial ischaemia-reperfusion rats (Sham MI/R) were used as controls. Myocardial ischaemia plus reperfusion in untreated rats decreased survival rate, produced a marked myocardial necrosis, increased serum creatine phosphokinase activity, and cardiac myeloperoxidase activity (a marker enzyme commonly used to assess polymorphonuclear leukocyte accumulation). Furthermore, rats subjected to myocardial ischaemia-reperfusion showed an increased pressure rate index, studied as a quantitative means for assessing myocardial oxygen demand. Treatment with monoclonal anti-rat ICAM-1 (1 mg/kg i.v.), 3 h before occlusion of the left main coronary artery, significantly lowered serum creatine phosphokinase activity, blunted leukocyte accumulation and protected the myocardium from injury subsequent to ischaemia and reperfusion injury. These investigations have revealed that ICAM-1 is a critical adhesion molecule in the pathogenesis of ischaemia-reperfusion injury. In addition these results suggest that the use of monoclonal antibodies raised against ICAM-1 can represent a useful tool for the prevention of ischaemia-reperfusion damage. PMID- 7851477 TI - Comparative effects of selective kappa-opioid receptor agonists on dopamine levels in the dorsal caudate of freely moving rats. AB - Microdialysis was utilized to evaluate the effects of selective kappa-opioid receptor agonists on dopamine levels in the dorsal caudate of conscious rats. Subcutaneous administration of equivalent antinociceptive doses of spiradoline- (+/-)-(5 alpha, 7 alpha, 8 beta)-3, 4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1 oxaspiro[4,5]dec-8-yl] benzeneacetamide--(U62066; 12 mg/kg), BRL 52656--(2S)-1 [(4- trifluoromethylphenyl)acetyl]-2-[(1-pyrrolidinyl)methyl]piperidine--(2 mg/kg) and enadoline--(-)-(5 beta, 7 beta, 8 alpha)-N-methyl-N-[7-(1- pyrrolidinyl)-1-oxaspiro[4,5]dec-8-yl]benzo[b]furan-4-acetamide-- (CI-977; 0.1 mg/kg) produced similar, statistically significant decreases in dorsal caudate dopamine levels; BRL 53001--(2S)-2- (dimethylaminomethyl)-1-[(5,6,7,8-tetrahydro 5-oxo-2-naphthyl)ace tyl] piperidine--(12 mg/kg) was, however, without effect. At a higher dose (36 mg/kgP, BRL 53001 also caused a significant reduction in dopamine levels. BRL 52974--4-(1-pyrrolidinylmethyl) 5-[(3,4 dichlorophenyl)acetyl]-4,5,6,7-tetrahydroimidazo[4,5-c] pyridine, a selective kappa-opioid receptor agonist with limited ability to cross the blood brain barrier or produce antinociceptive effects, had no effect on dopamine levels at 10 mg/kg s.c. Overall, these findings suggest that selective kappa-opioid receptor agonists decrease dopamine levels in the dorsal caudate of rats via a central locus of action. Furthermore, compared to other kappa-opioid receptor agonists, BRL 53001 appears to have a reduced propensity to decrease dopamine levels at equianalgesic doses. PMID- 7851478 TI - Evidence that nor-binaltorphimine can function as an antagonist at multiple opioid receptor subtypes. AB - This study examined the influence of acute and repeated administration of the kappa-opioid receptor antagonist, nor-binaltorphimine, upon opioid-induced antinociception as measured by the tail-pressure test. A single intracerebroventricular (i.c.v.) injection of nor-binaltorphimine (30 micrograms) administered 1, 10 or 30 days prior to algesiometric testing prevented the analgesic effect of the kappa-opioid receptor agonist, (5 alpha, 7 alpha, 8 beta) (-)-N- methyl-N-(7-(1-pyrrolidinyl)-1-oxaspiro(4,5)dec-8-yl)benzenacet amide (U69593). The analgesic effect of the mu-opioid receptor agonist, [D-Ala2,N methyl-Phe4,Gly5-ol]enkephalin (DAMGO), and the delta-opioid receptor agonist, [D Pen2,D-Pen5]enkephalin (DPDPE), was not modified. In contrast, when nor binaltorphimine was administered repeatedly (twice daily i.c.v. administration of 30 micrograms nor-binaltorphimine for 10 days), the analgesic effect of DAMGO, DPDPE as well as U69593 was abolished. In the case of mu- and delta-opioid receptor agonists, this abolition was apparent when testing occurred 1 or 2, but not 5 days after termination of nor-binaltorphimine treatment. This treatment regimen also resulted in a long-lasting antagonism (e.g. 20 days) of U69593 induced analgesia. These data show that, depending on the treatment regimen employed, nor-binaltorphimine can function as a selective kappa-opioid receptor antagonist, or as an antagonist at multiple opioid receptor subtypes. Further, they demonstrate that nor-binaltorphimine functions as a long-lasting kappa opioid receptor antagonist in vivo. PMID- 7851479 TI - Inhibition by omega-conotoxin GVIA of adrenal catecholamine release in response to endogenous and exogenous acetylcholine. AB - Effects of the N-type voltage-dependent Ca2+ channel (VDCC) blocker, omega conotoxin GVIA, and the L-type VDCC blockers, nifedipine and verapamil, on adrenal catecholamine release were examined in anesthetized dogs. These blockers were infused into the adrenal gland through the phrenicoabdominal artery. Splanchnic nerve stimulation at 1 and 3 Hz produced frequency-dependent increases in epinephrine and norepinephrine output determined from adrenal venous blood. Infusion of omega-conotoxin GVIA (0.4 micrograms/min) significantly inhibited the splanchnic nerve stimulation-evoked increases in epinephrine and norepinephrine output. Furthermore, increases in epinephrine and norepinephrine output induced by intraarterial injection of acetylcholine (3 micrograms) into the adrenal gland also were inhibited by omega-conotoxin GVIA (0.4 micrograms/min). Further inhibition of splanchnic nerve stimulation- or exogenous acetylcholine-induced increases in catecholamine output was observed even after the cessation of omega conotoxin GVIA infusion. Neither nifedipine (1 microgram/min) nor verapamil (10 micrograms/min) affected the splanchnic nerve stimulation-evoked increases in catecholamine output, whereas they inhibited the exogenous acetylcholine-evoked catecholamine release. These results suggest that N-type VDCCs located in adrenal medullary cells may contribute to the release of adrenal catecholamines in response to endogenous and exogenous acetylcholine in the dog. PMID- 7851480 TI - Binding of bromine-substituted analogs of methylphenidate to monoamine transporters. AB - We synthesized the o-, m- and p-bromo derivatives of dl-threo-methylphenidate from the corresponding bromophenylacetonitriles by modification of the literature synthesis of methylphenidate (Panizzon, Helv. Chim. Acta 1944, 27, 1748). In in vitro binding assays all three dl-threo bromo compounds had higher affinities than methylphenidate for dopamine transporter sites labeled with [3H]2 beta carbomethoxy-3 beta-(4-fluorophenyl)tropane ([3H]WIN 35,428; IC50 = 13, 4, 20 and 82 nM for o-, m-, and p-bromo compounds, and unsubstituted methylphenidate, respectively). They also bound more strongly than methylphenidate to norepinephrine reuptake sites labeled with [3H]nisoxetine (IC50 = 32, 20, 31 and 440 nM, respectively), but were weak ligands (IC50 > or = 1 microM) at the serotonin transporter labeled with [3H]paroxetine. In addition, the bromine substituted derivatives demonstrated similar activity to methylphenidate in vivo in rodents in terms of inhibition of heart uptake of [3H](-)-norepinephrine, elevation of striatal extracellular dopamine, and stimulation of locomotor activity. PMID- 7851481 TI - Thrombin inhibitors and anti-coagulants on thrombin-induced embolisation in rabbit cranial vasculature. AB - 111Indium-labelled platelets were continuously monitored in the cranial vasculature of anaesthetised rabbits and thrombin inhibitors and anti-coagulants were tested on the sustained platelet accumulation induced by intracarotid injection of thrombin (90 U/kg). Pretreatment, commencing 30 min prior to thrombin, with a 1-h intracarotid infusion of D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone (PPACK; 0.25-1.0 micrograms/kg per min), unfractionated heparin (Multiparin; 5-20 U/kg bolus + 0.75-3.0 U/kg per min infusion) or low molecular weight heparin (Fragmin; 2.4-9.6 U/kg per min) produced dose-related reductions in platelet accumulation. Continuous infusion of acetyl-D-phenylalanyl prolyl-boroarginine (DuP-714 ester; 30 micrograms/kg per min) for 30 min induced marked accumulation of platelets in the pulmonary circulation in the absence of thrombin. Bolus intracarotid injection, 1 min before thrombin, of Hirulog (0.05 0.2 mg/kg), PPACK (10-30 micrograms/kg), Multiparin (25-100 U/kg), Fragmin (150 U/kg) or DuP-714 ester (15-30 micrograms/kg) caused significant reductions in platelet accumulation. When injected 1 min after thrombin, Hirulog (1 mg/kg), PPACK (100 micrograms/kg), Fragmin (150 U/kg) and DuP-714 ester (30 micrograms/kg) had no significant effect and Multiparin (100 U/kg) increased platelet accumulation. The results demonstrate that pretreatment with a range of thrombin inactivators, acting via different mechanisms, can inhibit thrombin induced cerebral thromboembolism in the rabbit. PMID- 7851482 TI - Enhancement of thrombolytic efficacy of tissue-type plasminogen activator by adjuvants in the guinea pig thrombosis model. AB - Reocclusion following thrombolysis is a major limitation of thrombolytic therapy with recombinant tissue-type plasminogen activator (rt-PA). We investigated the effects of vapiprost ((1R-(1 alpha(Z),2 beta,3 beta,5 alpha))-7-(5-((1,1' biphenyl)-4-yl-methoxy)- 3-hydroxy-2-(1-piperidinyl)cyclopentyl)-4-heptenoic acid, a thromboxane A2 receptor antagonist); argatroban ((2R,4R)-4-methyl-1-[N2 (3-methyl-1,2,3,4-tetrahydro-8-quinolinyl)sulfon yl] - L-arginyl)]-2-piperidine carboxylic acid, a specific thrombin inhibitor) and MK-886 (3-[1-(4-chlorobenzyl) 3-t-butyl-thio-5-isopropylindol-2-yl]-2,2- dimethylpropanoic acid, a specific leukotriene biosynthesis inhibitor) on the thrombolytic efficacy of rt-PA. The guinea pig femoral artery was thrombotically occluded by photochemical reaction between rose bengal and green light. Thirty min after the occlusion, rt-PA was administered and the time (T1) for reopening of the vessel and the frequency of reocclusion (Fro) 24 h after thrombolysis were monitored. With rt-PA alone, T1 was 28 +/- 7 min (n = 10) and Fro was 70%. T1 was reduced to 9 and 20 min by a combination of rt-PA with vapiprost and argatroban respectively. Fro was reduced by all three adjuvants. Histological observations revealed extensive adherence of polymorphonuclear leucocytes to the damaged endothelium at the site of thrombolysis. It is concluded that thromboxane A2, thrombin and leucocytes are involved in reocclusion after thrombolysis. PMID- 7851483 TI - Suramin interferes with auto/paracrine insulin-like growth factor I-controlled proliferative loop on human lung cancer cell lines. AB - Human non-small cell lung cancer (N-SCLC), a common malignancy generally unmanageable by conventional cytotoxic chemotherapy, represents a major world health burden. Suramin, a polyanionic drug which appears to interfere with growth factor/receptor interaction, has recently been shown to be cytostatic for small cell lung cancer cells; it may also be effective for N-SCLC. As insulin-like growth factor I (IGF-I) is a known progression agent for N-SCLC, we have examined the effects of suramin on the 'IGF-I system' in a panel of human N-SCLC cell lines. Colorimetric and thymidine incorporation assays were used to assess cell chemosensitivity whereas a radio-receptor assay was employed to evaluate IGF I/receptor binding. Suramin reversibly reduced, in a concentration- and time dependent manner, the growth of each N-SCLC cell line examined either cultured in serum-containing or serum-free medium. Furthermore, suramin caused a concentration-related inhibition of labeled IGF-I peptide specific binding on all cell lines studied. Suramin caused a significant reduction in the Bmax values with only weak variations in the affinity constants (Kd). We hypothesize that suramin interference with IGF-I mitogenic activity is a pathway by which this drug produces its effect in vitro. These data indicate further studies on the mechanism of action and pharmacology of suramin in vivo are warranted. PMID- 7851484 TI - The antiparkinsonian drugs budipine and biperiden are use-dependent (uncompetitive) NMDA receptor antagonists. AB - N-Methyl-D-aspartate- (NMDA-) evoked [3H]acetylcholine release in rabbit caudate nucleus slices was inhibited by the antiparkinsonian drugs budipine (1-tert-butyl 4,4-diphenylpiperidine) and biperiden (1-bicyclo[2.2.1.]hept-5-en-2-yl-1-phenyl-3 piperidino propanol) yielding functional Ki values of 4.6 and 8.8 microM. In contrast to the competitive antagonist 2-amino-5-phosphonopentaonate, budipine and biperidene significantly reduced both the apparent KD and the Emax value of NMDA. Moreover, they displaced [3H]MK-801 specifically bound to membranes of the same tissue, although with low affinity (IC50: 38 and 92 microM). It is concluded that budipine and biperiden are use-dependent (uncompetitive) antagonists at the NMDA receptor, binding to the receptor-linked ion channel, but probably not to the MK-801 binding site. NMDA antagonism may contribute to the antiparkinsonian effects of budipine. PMID- 7851485 TI - [3H]L-694,247 labels the 5-HT1D beta receptor in pig caudate membranes. AB - This study, carried out in pig caudate membranes, characterises the radioligand binding site labelled with [3H]L-694,247 (2-[5-[3-(4-methylsulphonylamino)benzyl 1,2,4-oxadiazol-5-yl ]-1H-indole-3 - yl]ethylamine). The affinities of 27 standard compounds are consistent with binding to a 5-HT1D recognition site. In addition the results indicate that, under the assay conditions described, [3H]L 694,247 specifically labels the 5-HT1D beta recognition site since ketanserin and ritanserin display a low affinity consistent with their activities at this subtype of the 5-HT1D receptor. PMID- 7851486 TI - Visualization by [3H]resiniferatoxin autoradiography of capsaicin-sensitive neurons in the rat, pig and man. AB - [3H]Resiniferatoxin autoradiography revealed high densities of binding sites in rat dorsal root ganglia as well as in the superficial dorsal horn of the spinal cord, known to contain the cell bodies and central terminals, respectively, of capsaicin-sensitive, sensory neurons. This binding was fully displaced by non radioactive resiniferatoxin and was absent following administration of high, neurotoxic doses of capsaicin. The binding thus has the characteristics expected for the vanilloid (capsaicin) receptor. High density, specific resiniferatoxin binding was also observed in pig spinal cord and dorsal root ganglia. Finally, similar high density binding was detected in the dorsal horn of human spinal cord obtained post-mortem. We conclude that [3H]resiniferatoxin autoradiography may afford a novel neurochemical tool to identify capsaicin-sensitive neurons in the central as well as in the peripheral nervous system, to explore the ontogeny of these neurons, and to detect changes in vanilloid (capsaicin) receptor expression under pathophysiological conditions. PMID- 7851487 TI - Binding of [3H](+)-PN200-110 to aortic membranes from normotensive and spontaneously hypertensive rats. AB - We report here the quantitative evaluation of binding density (Bmax) of [3H](+) PN200-110 in aortic membranes obtained from spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. At both 4 and 13 weeks of age, there were no significant differences in Bmax and the dissociation constants (Kd) of [3H](+)-PN200-110 binding between SHR and WKY rat aortas. Irrespective of strain, the Kd increased and the Bmax decreased with age. These results suggest that the number of Ca2+ channels in aortas of SHR and WKY rats are not significantly different, even when hypertension is established in SHR. PMID- 7851488 TI - d-Fenfluramine improves hepatic insulin action in streptozotocin-diabetic rats. AB - We have examined the effect of chronic (21 days) oral administration of the serotoninergic anorectic drug d-fenfluramine (5 mg/kg) in a rat model of non insulin-dependent diabetes (without obesity), as induced by injection of a low dose (45 mg/kg) of streptozotocin at 6 weeks, and characterized by marked hyperglycaemia and hepatic and peripheral insulin resistance. The following parameters were assessed: (1) basal blood glucose and insulin levels, and (2) basal and insulin-stimulated in vivo glucose production and glucose utilization, using the insulin-clamp technique in conjunction with isotopic measurement of glucose turnover. In the d-fenfluramine-treated diabetic rats, postabsorptive basal plasma glucose levels were decreased (7.8 +/- 0.3 mM as compared to 14.9 +/ 0.1 mM in the untreated diabetic rats) while the basal plasma insulin levels were unchanged. A similar reduction of the basal plasma glucose levels was observed in the pair-fed untreated diabetic group (8.3 +/- 0.2 mM). Basal glucose turnover was reduced by 45% (P < 0.01) in the d-fenfluramine-treated diabetic rats as well as in the pair-fed untreated diabetic rats. The impaired suppression of hepatic glucose output by insulin, caused by diabetes, was totally reversed by d-fenfluramine, while pair-feeding did not modify hepatic insulin resistance. The whole body insulin-mediated glucose uptake in the diabetic rats was also significantly improved by d-fenfluramine treatment. Such an effect was also found in the pair-fed untreated group.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7851489 TI - [Pro34]peptide YY is a Y1-selective agonist at peptide YY/neuropeptide Y receptors. AB - We have investigated binding and functional effects of a new peptide YY analogue, [Pro34]peptide YY, at Y1 and Y2-like subtypes of receptors for peptide YY and neuropeptide Y. In binding studies [Pro34]peptide YY had a similarly high affinity as peptide YY to human Y1-like receptors in SK-N-MC cells, a human neuroblastoma cell line of presumed neurogenic origin, and HEL cells, a human cell line derived from a patient with Hodgkin's disease. In functional studies [Pro34]peptide YY stimulated Ca2+ elevations in both Y1-like receptor cell lines with similar potency and efficacy as peptide YY. In contrast to peptide YY [Pro34]peptide YY was 1000-fold less potent in binding to Y2-like receptors in porcine splenic membranes and lacked agonistic effects in another Y2-like receptor-mediated model system, i.e. inhibition of [3H]serotonin release from rat cerebral cortical slices. Thus, [Pro34]peptide YY is a highly Y1-selective full agonist of peptide YY/neuropeptide Y receptors. [Pro34]peptide YY could be useful for studying the importance of Y receptor subtypes in mediating peptide YY physiological actions. PMID- 7851490 TI - [N-methylnorleucine-(28,31)]cholecystokinin-(26-33) (SNF 8702) activity at a cloned rat CCKB receptor. AB - [N-methyl-Nle 28,31)]cholecystokinin-(26-33) (SNF 8702) is a highly selective ligand for the CCKB type of receptor present in the vertebrate central nervous system. Radioligand binding data showing that SNF 8702 binding affinity is reduced by the GTP analog guanylyl-imidodiphosphate suggest that SNF 8702 is an agonist but the ability of SNF 8702 to activate CCKB receptors has not been demonstrated. The present study shows that SNF 8702 is a highly potent agonist at rat CCKB receptors expressed on COS-7 cells and that these receptors are coupled to the mobilization of intracellular calcium. The A50 measured for SNF 8702 induced calcium mobilization (66 pM) is over 6-fold less than that of cholecytstokinin octapeptide (420 pM). Data are also presented showing that SNF 8702 has high binding affinity for these receptors with a Kd value (760 pM) consistent with previous measurements using guinea pig brain tissue preparations. PMID- 7851491 TI - Forskolin-induced up-regulation and functional supersensitivity of dopamine D2long receptors expressed by Ltk- cells. AB - Mouse fibroblast Ltk- cells, stably expressing the human dopamine D2long receptor, were grown in the presence of forskolin (100 microM) for 4 or 16 h. The 16 h treatment resulted in a significant up-regulation of the dopamine D2long receptors by 43-96% as measured with [3H]raclopride with no change in the Kd value. A significant increase in the maximal inhibition of acute forskolin stimulated cAMP accumulation by dopamine (0.1 nM-3 microM) was found both at 4 and 16 h. No such D2long-receptor-coupled response to dopamine could be detected in wild-type, untransfected, Ltk- cells with or without forskolin treatment. Furthermore, basal cAMP levels as well as the maximal response to acute forskolin stimulation decreased in the D2long receptor expressing cells with the treatment, by 33% and 23% respectively. The results indicate that persistent maintenance of high cAMP levels in transfected Ltk- cells may lead to adaptive quantitative and functional changes of the dopamine D2long receptor reminiscent of receptor supersensitivity induced by chronic antagonist treatment in vivo where the receptor targeted is inhibitorily coupled to adenylyl cyclase, as is the D2long receptor. This may provide a model for studying mechanisms underlying dopamine D2 receptor up-regulation and receptor supersensitivity, not readily induced in cell lines. PMID- 7851492 TI - The neuroactive steroid 3 alpha-hydroxy-5 beta-pregnan-20-one is a two-component modulator of ligand binding to the GABAA receptor. AB - Neuroactive steroids allosterically inhibit [35S]t-butylbicyclophosphorothionate ([35S]TBPS) and enhance [3H]flunitrazepam binding to the GABAA receptor complex. In the presence of 5 microM GABA, 3 alpha-hydroxy-5 beta-pregnan-20-one (3 alpha, 5 beta-P) inhibits [35S]TBPS binding with high- (IC50 21-32 nM) and low- (IC50 24 63 microM) affinity components in bovine cortical, cerebellar, and hippocampal membranes. The percentage of high-affinity sites ranges from 53% in cortex to 65% in cerebellum and hippocampus. However, 3 alpha, 5 beta-P is a single-site inhibitor in thalamus (IC50 43 nM). In the absence of GABA, similar affinities for the high- and low-affinity components were detected, although the percentages of high-affinity sites were reduced. Similarly, 3 alpha, 5 beta-P enhances [3H]flunitrazepam binding with high- (EC50 44-58 nM) and low- (EC50 2-13 microM) affinity components which account for 71-77% and 23-29% of the sites, respectively, in cortex, cerebellum and hippocampus. 3 alpha, 5 beta-P is a single-site enhancer in thalamus (EC50 80 nM). In contrast to 3 alpha,5 beta-P, 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha,5 alpha-P) is a single site modulator of [35S]TBPS and [3H]flunitrazepam binding in all regions examined. These data provide pharmacological evidence consistent with receptor heterogeneity for neuroactive steroids. PMID- 7851493 TI - ABT-200, a norepinephrine uptake inhibitor, blocks Ca2+ signals in chromaffin cells. AB - We previously described inhibition by racemic (+/-)-(1'R*,3R*)-3-phenyl-1- [1',2',3',4'-tetrahydro-5',6'-methylenedioxy-1'- napthalenyl-methyl]-pyrrolidine methanesulfonate (ABT-200), and its two constituent enantiomers, SS,ABT-200 and RR,ABT-200, of nicotine-stimulated but not histamine-stimulated catecholamine release from bovine adrenal chromaffin cells. To test the hypothesis that this inhibition reflects a blockade of Ca2+ influx, we used fura-2 loaded chromaffin cells to investigate cytosolic Ca2+ signals. We found that SS,ABT-200 inhibited nicotine- and K(+)-stimulated Ca2+ signals, both of which depend on Ca2+ influx. However, the early phase of the histamine-stimulated Ca2+ signals, which depends on Ca2+ mobilization from intracellular stores, was unaffected. We also examined ion flux through the nicotinic receptor by measuring 86rubidium+ (86Rb+) efflux from preloaded mouse midbrain synaptosomes. We found that SS,ABT-200 partially inhibited nicotine-stimulated 86Rb+ efflux, suggesting that it blocks ion flux through the nicotinic receptor directly. These data support a model in which ABT 200 blocks nicotine-stimulated catecholamine release by inhibiting cation flux through multiple channels. PMID- 7851494 TI - Exendin-4 and exendin-(9-39)NH2: agonist and antagonist, respectively, at the rat parietal cell receptor for glucagon-like peptide-1-(7-36)NH2. AB - Exendin-4 is a novel peptide from Heloderma suspectum venom which is 53% homologous with glucagon-like peptide-1 GLP-1-(7-36)NH2, a stimulant of cAMP dependent H+ production in rat parietal cells. It was the aim of the present study to determine whether this effect of GLP-1-(7-36)NH2 is shared by exendin-4, and whether the responses to either peptide are blocked by exendin-(9-39)NH2, a competitive specific exendin receptor antagonist. In enriched rat parietal cells H+ production was measured indirectly by [14C]aminopyrine accumulation. cAMP production was determined by radioimmunoassay. [125I]GLP-1-(7-36)NH2 was prepared using chloramine T followed by high pressure liquid chromatography (HPLC) purification. Exendin-4 (10(-12) - 10(-8) M) stimulated [14C]aminopyrine accumulation in a concentration-dependent manner (EC50 = 7.6 x 10(-11) M). At the maximally effective concentration (10(-9) M) exendin-4 was as effective as GLP-1 (7-36)NH2 reaching 70-80% of the response to 10(-4) M histamine. Likewise, exendin-4 (10(-11) - 10(-7) M) stimulated parietal cell cAMP production up to 2.8 fold. Maximal stimulation by exendin-4 of [14C]aminopyrine accumulation was not affected by ranitidine (10(-4) M), but was concentration-dependently reduced by exendin-(9-39)NH2 (10(-11) - 10(-7) M). At the maximal concentration, exendin-(9 39)NH2 completely abolished the responses to 10(-9) M exendin-4 and to 10(-9) M GLP-1-(7-36)NH2 while not altering stimulation by 10(-4) M histamine. Binding of [125I]GLP-1-(7-36)NH2 to enriched parietal cells was displaced by exendin-4 (Ki = 4.6 x 10(-10) M) as well as by exendin-(9-39)NH2 (Ki = 4.0 x 10(-9) M).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7851495 TI - Heterocyclic amino alcohols related to ifenprodil as sigma receptor ligands: binding and conformational analyses. AB - The interaction of a novel series of heterocyclic amino alcohols with the sigma receptor site was assessed using radioligand binding and computerized molecular modelling. All heterocyclic amino alcohols, like the structurally related ifenprodil, fully inhibited the specific binding of [3H]R(+)-3-(3-hydroxyphenyl) N-(1-propyl)piperidine ([3H]3-PPP) to rat cerebral cortical membranes. All compounds recognised two populations of binding sites labelled by [3H]3-PPP and the proportion of sites in the high affinity state was 60-80% of the total sites. Some of the heterocyclic amino alcohols also displayed similar affinity for alpha 1-adrenoceptors labelled by [3H]prazosin, where the pattern of inhibition appears to be stereospecific, unlike that seen with the binding of [3H]3-PPP. The amino alcohols had negligible affinity for sites labelled by the N-methyl-D-aspartate channel ligand, [3H]-(N-1-[thienyl]cyclohexyl)piperidine. Quantitative conformational analyses indicated that the heterocyclic amino alcohols and ifenprodil fitted well to a sigma receptor site model; low energy conformers could be superimposed like other potent sigma receptor ligands with confidence to the sigma receptor model. Our results define a new class of sigma receptor ligands and extend the understanding of the molecular requirements for drugs active at the sigma receptor. PMID- 7851496 TI - Regulation of serotonin 5-HT2C receptors in the rat choroid plexus after acute clozapine treatment. AB - We studied the effects of acute clozapine and haloperidol treatments on 5-HT2C receptor binding characteristics and 5-HT2C receptor-mediated phosphoinositide hydrolysis in the rat choroid plexus. Scatchard analysis (with [3H]mesulergine) showed that acute clozapine treatment (10 and 25 mg/kg) decreased the density (Bmax) of 5-HT2C receptors by 20-25% with no marked change in the affinity (Kd). Quantitative autoradiography was in accordance with homogenate binding studies showing that acute clozapine treatment, unlike haloperidol (0.5 mg/kg), decreased the number of both agonist ([125I](+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2 aminopropane, [125I]DOI) and antagonist ([3H]mesulergine) labeled 5-HT2C receptor binding sites. The decrease was more robust with the higher dose of clozapine. For comparison, both doses of clozapine, unlike haloperidol, decreased equally the density of 5-HT2A receptors in the frontal cortex by about 45%, whereas none of the treatments altered dopamine D2 receptor characteristics in the striatum. The Kd value of 5-HT2A receptors was significantly increased after the dose of 25 mg/kg of clozapine. These clozapine treatments failed to decrease the maximal 5 HT2C receptor-mediated phosphoinositide hydrolysis response. The higher dose of clozapine increased 5-HT-induced phosphoinositide hydrolysis response, but also decreased significantly the basal levels of phosphoinositide hydrolysis. Haloperidol did not significantly affect the 5-HT2C receptor-mediated phosphoinositide hydrolysis. To summarize, the present data show that a single injection of clozapine is able to reduce the density of 5-HT2C receptors but fails to cause functional desensitization of 5-HT2C receptors in the rat choroid plexus. PMID- 7851497 TI - Tiagabine, SK&F 89976-A, CI-966, and NNC-711 are selective for the cloned GABA transporter GAT-1. AB - gamma-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian brain. The synaptic action of GABA is terminated by rapid uptake into presynaptic terminals and surrounding glial cells. Molecular cloning has revealed the existence of four distinct GABA transporters termed GAT-1, GAT-2, GAT-3, and BGT-1. Pharmacological inhibition of transport provides a mechanism for increasing GABA-ergic transmission, which may be useful in the treatment of various neuropsychiatric disorders. Recently, a number of lipophilic GABA transport inhibitors have been designed and synthesized, which are capable of crossing the blood brain barrier, and which display anticonvulsive activity. We have now determined the potency of four of these compounds, SK&F 89976-A (N-(4,4 diphenyl-3-butenyl)-3-piperidinecarboxylic acid), tiagabine ((R)-1-[4,4-bis(3 methyl-2-thienyl)-3-butenyl]-3- piperidencarboxylic acid), CI-966 ([1-[2-[bis 4 (trifluoromethyl)phenyl]methoxy]ethyl]-1,2,5,6-tetrahydro-3- pyridinecarboxylic acid), and NNC-711 (1-(2-(((diphenylmethylene)amino)oxy)ethyl)-1,2,4,6-tetrahydro 3- pyridinecarboxylic acid hydrochloride), at each of the four cloned GABA transporters, and find them to be highly selective for GAT-1. These data suggest that the anticonvulsant activity of these compounds is mediated via inhibition of uptake by GAT-1. PMID- 7851498 TI - Identification of a region of the human endothelin ETA receptor required for interaction with bosentan. AB - Bosentan (Ro 47-0203, 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2- methoxy-phenoxy) 2,2'-bipyrimidin-4-yl]-benzenesulfonamide) is a new non-peptidic mixed antagonist of endothelin receptors whose binding activity was two orders higher for the endothelin ETA receptor than that for the endothelin ETB receptor. To identify which region of the human endothelin ETA receptor interacts with bosentan, we created various chimeric endothelin receptors containing domains from the endothelin ETA and ETB receptors in Chinese hamster ovary cells and studied the effect of bosentan on the binding of endothelin-1 to the chimeric receptors. We found that the chimeric endothelin ETB receptor containing domains from the endothelin ETA receptor, the second extracellular region including the proximal transmembrane region (B-region) revealed an affinity toward bosentan which was similar to that of the endothelin ETA receptor. In contrast, the chimeric endothelin ETA receptor, containing the B-region of the endothelin ETB receptor, reduced the binding affinity to the level of the endothelin ETB receptor. Since bosentan competes with endothelin-1 for binding to the endothelin ETA receptor, this receptor antagonist seems to interact with the (140-144) KLLAG sequence located at the carboxylterminus of the second transmembrane region of the endothelin ETA receptor, required for the natural ligand binding. PMID- 7851499 TI - Pharmacological dissociation of glutamatergic metabotropic signal transduction pathways in cortical astrocytes. AB - Using cultured cortical astrocytes we demonstrate differential activation of metabotropic signal transduction pathways with 1-aminocyclopentane-trans-1S3R dicarboxylic acid (1S3R-ACPD) and the glutamate transport inhibitor trans-2,4 pyrrolidine dicarboxylic acid (trans-2,4-PDC). Phosphoinositide hydrolysis was more potently stimulated by 1S3R-ACPD than by L-trans-2,4-PDC; however, L-trans 2,4-PDC was far more efficacious than 1S3R-ACPD at inhibiting cyclic AMP accumulation. The metabotropic receptor antagonist (+)-alpha-methyl-4 carboxyphenylglycine ((+)-MCPG) inhibited 1S3R-ACPD stimulation of phosphoinositide hydrolysis but not its ability to inhibit cyclic AMP accumulation thereby demonstrating a means to pharmacologically dissociate these two metabotropic signal transduction pathways in astrocytes. (+)-MCPG produced similar antagonism of the metabotropic agonist properties of L-trans-2,4-PDC. The metabotropic effects of L-trans-2,4-PDC could not be reduced with enzymatic treatment of the cultures to remove extracellular glutamate, suggesting that these effects are not secondary to the ability of this compound to inhibit glutamate uptake. Taken together the findings indicate the presence of multiple glutamatergic signal transduction pathways in astrocytes and suggest a similarity in the pharmacophores for metabotropic receptors and glutamate transporters. PMID- 7851500 TI - Changes in brain microvessel endothelial cell monolayer permeability induced by adrenergic drugs. AB - Brain microvessel endothelial cell monolayers have been shown to be a suitable blood-brain barrier in vitro system to study adrenergic regulation of permeability. We tested adrenergic drugs on bovine brain microvessel endothelial cell monolayer permeability to a biomembrane impermeant molecule, sodium fluorescein. Endogenous catecholamines noradrenaline and adrenaline were tested as well as the alpha-adrenoceptor agonist phenylephrine, the beta-adrenoceptor agonist clenbuterol and the alpha-adrenoceptor antagonist prazosin. Results showed an alpha-adrenoceptor mediated increase and a beta-adrenoceptor mediated decrease in monolayer permeability. Both alpha- and beta-adrenoceptor mediated changes in permeability were abolished by inhibiting fluid-phase pinocytosis, either by vincristine or by avoiding bovine brain microvessel endothelial cell's energy utilization. The reverse transport (i.e., from brain to blood side) was also influenced by adrenergic drugs; alpha- or beta-adrenoceptor stimulation induced a permeability-reducing effect. We conclude that alpha-adrenoceptor stimulation increases bovine brain microvessel endothelial cell monolayer permeability and that beta-adrenoceptor stimulation has the opposite effect. Reverse transport results obtained with beta-adrenoceptor stimulation seem controversial and deserve further study. These results also support in vivo findings that demonstrated adrenergic influences on blood brain barrier permeability. PMID- 7851501 TI - Characterization of YM022: its CCKB/gastrin receptor binding profile and antagonism to CCK-8-induced Ca2+ mobilization. AB - We investigated the antagonistic activity of (R)-1-[2,3-dihydro-1-(2'- methylphenacyl)-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3- (3-methylphenyl) urea (YM022), a benzodiazepine derivative, at CCKB/gastrin receptors. This compound potently inhibited [125I]CCK-8 binding to rat brain CCKB/gastrin receptors with a Ki value of 0.26 nM, but it showed weak affinity for rat pancreas CCKA receptors (Ki = 270 nM). Selectivity for CCKB/gastrin receptors was 1000-fold greater than that for CCKA receptors. Changes in intracellular free Ca2+ concentration ([Ca2+]i) in response to CCK-8 were measured in a rat anterior pituitary cell line GH3 by fura-2 fluorometry. CCK-8 (1-100 nM) dose-dependently increased [Ca2+]i in these cells, whereas YM022 had no effect on baseline [Ca2+]i even at the highest concentration of 100 nM. YM022 inhibited the mobilization of [Ca2+]i elicited by 10 nM CCK-8 in a concentration-dependent manner with an IC50 value of 4 nM. In conclusion, YM022 is an extremely potent and highly selective antagonist of CCKB/gastrin receptors. This compound is therefore useful for studying the physiological and pharmacological roles of CCKB/gastrin receptors. PMID- 7851502 TI - Staurosporine induces tyrosine phosphorylation of a 145 kDa protein but does not activate gp140trk in PC12 cells. AB - Staurosporine, a protein kinase C inhibitor, induces neurite outgrowth in PC12 cells similarly to nerve growth factor (NGF). Since NGF neurotropic effects are transduced by the 'trk' gene product 140 kDa tyrosine kinase receptor, gp140trk, we investigated the role of gp140trk and tyrosine phosphorylations in staurosporine neurotropic effects. A direct correlation between staurosporine neurotropic effects and a novel stimulation of tyrosine phosphorylation of a 145 kDa protein (p145) with the following characteristics has been discovered: (1) Staurosporine specifically induced, among indolcarbazoles-K252a derivatives, in a dose-dependent manner (5-100 nM), p145 tyrosine phosphorylation and neurite outgrowth. (2) Staurosporine-induced p145 tyrosine phosphorylation was selective compared to other neurotropic compounds such as 8-Br-cAMP, acidic and basic fibroblast growth factors and NGF. (3) Staurosporine stimulation of p145 tyrosine phosphorylation gradually increased during the first 8 h of staurosporine treatment coinciding with the initiation of neurotropic effects. (4) K252a, a selective inhibitor of NGF actions, and several tyrphostins did not block staurosporine-induced p145 tyrosine phosphorylation and neurotropic effects. (5) Staurosporine stimulation of p145 tyrosine phosphorylation and neurotropic effects are independent of PKC. (6) Staurosporine did not activate gp140trk-NGF receptor in PC12 cells. The present study proposes staurosporine as a pharmacological tool to study the role of tyrosine phosphorylation pathway(s), such as p145 phosphorylation, in the action of neurotropic agents. PMID- 7851503 TI - (Rp)-8-pCPT-cGMPS, a novel cGMP-dependent protein kinase inhibitor. AB - In the present study, the inhibitory effect of the cGMP analog (Rp)-8-(para chlorophenylthio)guanosine-3',5'-cyclic monophosphorothioate ((Rp)-8-pCPT-cGMPS) on the cGMP-dependent protein kinase-mediated protein phosphorylation in intact human platelets was investigated. In vitro phosphorylation experiments with the substrate kemptide demonstrated an inhibition of the cGMP-dependent protein kinase by (Rp)-8-pCPT-cGMPS with a Ki of 0.5 microM. In intact human platelets, (Rp)-8-pCPT-cGMPS antagonized the activation of the cGMP-dependent protein kinase by 8-pCPT-cGMP without affecting cAMP-dependent protein kinase or cGMP-regulated phosphodiesterases. The data obtained suggest that (Rp)-8-pCPT-cGMPS may be a useful tool for studying the role of cGMP in vitro and in intact cells. PMID- 7851504 TI - Facilitatory effects of somatostatin on reduced uptake of 2-deoxyglucose in cerebral cortical and hippocampal slices from aged rats. AB - The aim of the present study was to determine whether or not the reduction of 2 deoxyglucose uptake by the cerebral cortical slices in aged rats (22-23 months old) was attenuated by somatostatin or carbachol. In 8-week-old rats, somatostatin and carbachol produced concentration-dependent increases in 2 deoxyglucose uptake. 2-Deoxyglucose uptake of the cortical slices in 22-23-month old rats was significantly facilitated by treatment with 0.1-1 microM somatostatin or 1-100 microM carbachol. Metabolic responses to somatostatin or carbachol were quite similar in young and aged rats. The present results demonstrated that 2-deoxyglucose uptake by the cerebral cortex was facilitated by somatostatin and carbachol in both young and old rats. PMID- 7851505 TI - Effects of moxonidine, an imidazoline antihypertensive agent, on second messenger systems in rat brain. AB - Moxonidine, an imidazoline, binds to alpha 2-adrenoceptors and imidazoline receptors. We sought to determine the effects of moxonidine on accumulation of cAMP, cGMP, and phosphoinositide turnover in minislices of cerebral cortex and brainstem. In cerebral cortex, but not in brainstem, moxonidine inhibited the stimulated production of cAMP, an effect blocked by alpha 2-adrenergic antagonist rauwolscine. It also increased the hydrolysis of phosphoinositide above 100 microM in cerebral cortex and failed to alter accumulation of cGMP in both regions. We conclude that moxonidine is a typical alpha 2-adrenergic agonist inhibiting cAMP production in cerebral cortex, but not in brainstem, its interaction with I1 imidazoline sites in brainstem did not regulate second messenger systems, and moxonidine increased phosphoinositide turnover in cerebral cortex by unknown mechanisms. PMID- 7851506 TI - Synaptic connectivity of serotonin graft efferents in the suprachiasmatic and supraoptic nuclei of the hypothalamus. AB - We have previously reported that a cell suspension from the rostral part of the embryonic raphe grafted to the basal hypothalamus of 5,7-dihydroxytryptamine denervated rats produced incomplete serotonin (5-HT) re-innervation of the suprachiasmatic nucleus (SCN) as opposed to hyper-innervation of the supraoptic nucleus (SON). We took advantage of this experimental model to investigate whether the graft-derived, 5-HT fibres retained normal ultrastructural features, and, particularly, a normal density of synaptic junctions, irrespective of the extent of target re-innervation. The intrinsic features of immunostained, graft derived 5-HT axonal varicosities in both the SCN (ventral portion) and the SON were essentially similar to those exhibited by the respective endogenous innervation. Analysis of well-preserved varicosities in uninterrupted series of thin sections allowed us to evaluate directly the proportions of junctional to non-junctional 5-HT varicosities in both regions. Synaptic incidences were also remarkably conserved after grafting (45.5% in the SCN versus 38.5% in the SON; 48% and 38% in normal rats, respectively). Synapses were primarily reestablished on dendritic shafts, which also were identified as the major post-synaptic targets of the normal 5-HT innervations. We noted, however, a tendency toward increased numbers of symmetrical versus asymmetrical synapses in both the SCN and SON of grafted rats. Thus, irrespective of whether hypo- or hyper-innervation patterns developed post-grafting, the transplanted 5-HT neurons essentially retained normal ultrastructural features in their target territories, with a normal incidence of synaptic junctions. The data provide further support to the hypothesis that the innervation territory is the major determinant of the frequency with which ingrowing 5-HT fibres make synaptic junctions. PMID- 7851507 TI - Ibotenic acid lesions of the striatum reduce drug-induced rotation in the 6 hydroxydopamine-lesioned rat. AB - Lesions of the dopaminergic nigrostriatal tract produce a range of motor and sensorimotor deficits. One of the simplest and most reliable is the rotational response of the animal following activation with drugs that stimulate the dopaminergic network, most notably amphetamine and apomorphine. Consequently, the rotation test has been extensively used in assessing the success of treatments designed to restore dopaminergic function, including neural transplants. The present study investigates whether rotation induced by 6-hydroxydopamine lesions of the nigrostriatal bundle in rats is modified by additional lesions in the neostriatum. It was found that apomorphine-induced rotation can be reduced by ibotenic acid lesions of the dopamine-deafferented striatum, and that the extent of the reduction was proportional to the size of the lesions. In contrast, such lesions produced a non-significant reduction in amphetamine-induced rotation, although the correlation between the extent of the reduction and the size of the lesion was again apparent. Since the pattern of change was similar in direction, albeit smaller in magnitude, than the previously reported effects of intrastriatal transplantation in rats with similar nigrostriatal lesions, rotation tests alone do not provide an unequivocal test of graft survival and function. PMID- 7851508 TI - Differential ascending projections from neurons in the cat's lateral cervical nucleus. AB - Extracellular microelectrode recordings were made from single cells of the lateral cervical nucleus (LCN) in cats anaesthetized with chloralose and paralysed with gallamine triethiodide. The cells were tested for antidromic activation from the contralateral medial lemniscus and the contralateral tectum. Seventy-two LCN units were recorded which projected to one or both targets. Sixty (83%) projected through the medial lemniscus, and of these 36 (50% of the total) also projected to the tectum, whereas 24 (33%) projected through the medial lemniscus only; 12 (17%) projected only to the tectum. Twenty-nine units (40%) were excited by moving hairs of the coat but not by pinch of the skin, and 9 (31%) of these projected to the tectum, 11 (38%) through the medial lemniscus and 9 (31%) to both targets. Forty units (56%) were excited by hair movement and noxious pinch, and 3 (7%) of these projected to the tectum, 10 (25%) through the medial lemniscus and 27 (68%) to both targets. Three units (4%) had no discernible receptive fields and they all projected through the medial lemniscus, but not to the tectum. Of the 12 units projecting only to the tectum, 11 had receptive fields completely or partially on the trunk. Units projecting either through the medial lemniscus only, or through the medial lemniscus and also into the tectum, had receptive fields more widely distributed: these included small fields on the fore- and hind feet, on the limbs and also, a minority, on the trunk. Units with glove- or stocking-like receptive fields projected through the medial lemniscus. The results show that while most LCN cells project through the medial lemniscus, those excited by hair movement alone preferentially project either to the tectum or through the medial lemniscus, but not by both routes. The differences in receptive field properties of the differently projecting units are discussed in terms of the possible functions of the spinocervical system. PMID- 7851509 TI - Sensory interactions in the anterior ectosylvian cortex of cats. AB - Sensory interactions, namely, the responses of single cells to stimulations originating from the two sides of the body or from the two visual fields, or from more than one sensory modality (namely, visual, auditory and somatosensory), were evaluated within the anterior ectosylvian cortex (AEC) of cats. Results showed that responses of single neurons to a stimulus of one modality can be enhanced or inhibited by the presentation of another stimulus of either the same or another modality. This facilitatory or inhibitory modulation seems to depend upon temporal and/or spatial relationships between the stimuli. These results, taken together with those previously obtained in our laboratory and by others, suggest that neurons in the AEC may be involved in integrating inputs from various modalities and possibly linking sensory input with action. PMID- 7851510 TI - The force constraint strategy for stance is independent of prior experience. AB - The purpose of this study was to examine the effect of prior experience concerning direction of a postural perturbation on the balance response of cats to translations of their support surface. Previous work has shown that, when cats are translated in many directions in the horizontal plane, they respond by exerting active forces with each paw in only two directions, termed the force constraint strategy. This study examined whether the force constraint strategy could be modified based on predictability of the direction of translation and whether this strategy is used by the naive animal with no prior experience of platform translation. Four cats were trained to stand quietly on the force platform using positive reinforcement, and then were implanted with chronically indwelling electrodes for recording electromyographic (EMG) activity. The first experiment concerned the response of the naive cats to their first exposure to platform translation and consisted of translations presented randomly in four different directions in the horizontal plane. The second experiment consisted of two complete sets of 16 directions of translation (15 trials per direction), with the direction of translation randomized in one set and serially ordered in the other, to make the direction of translation unpredictable or predictable, respectively. Forces exerted by the cat, EMG activity, and platform position were recorded during the 1-s trials. The use of the force constraint strategy was independent of prior experience with direction of translation, as was the amplitude of the response.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7851511 TI - Relations among motor unit types, generated forces and muscle length in single motor units of anaesthetized cat peroneus longus muscle. AB - The active length-tension curves of identified single motor units (MUs) belonging to peroneus longus muscle (PL) of anaesthetized adult cats were obtained by eliciting isometric single twitches and tetani. The recorded responses were evaluated by measuring the peak tension amplitude and the tension-time area at muscle lengths extending throughout the physiological length range of the muscle (mean 5.5 mm, standard deviation +/- 0.8). The muscle lengths at which each tested MU developed its maximal twitch (Ltw) and tetanic (Lte) tensions were determined and compared with the muscle length (Lo) at which the stimulation of all the alpha-axons, innervating PL and contained in L7 ventral root, developed their maximal twitch tension. The mean of single MU Ltw values was at Lo +1.08 +/ 1.1 mm. Slow MUs showed the longest values of Ltw (Lo +1.6 +/- 1.0 mm). Single MUs stimulated at tetanic frequencies presented their Lte at values shorter than Lo (Lo - 2.8 +/- 1.7 mm). Slow MUs had the shortest Lte (Lo - 3.4 +/- 1.5 mm). For all the units Lte was shorter than Ltw. Ltw and Lte were, respectively, negatively and positively correlated with the developed tension. Optimal length values also appeared to be related to the MU types. The possibility is discussed that the muscle and tendon compliances and the high non-linearities to the applied forces are the main factors which can determine the differences among Lo, Ltw and Lte values. The relationships between MU type and optimal length values are suggested to be, at least partly, an epiphenomenon due to the different contraction strengths of the various MU types.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7851513 TI - Functional organisation of corticonuclear pathways to motoneurones of lower facial muscles in man. AB - EMG responses were recorded from lower facial muscles (depressor labii inferioris or depressor anguli oris) of 12 normal subjects after magnetic stimulation of the motor cortex. Using a figure-of-eight stimulating coil, the largest responses were obtained from points around 8-10 cm lateral to the vertex. Usually they were bilateral and had the same latency (11-12 ms) on both sides of the face. Patients with complete Bell's palsy had no response in muscles on the same side as the lesion, indicating that the ipsilateral component to cortical stimulation was not the result of recrossing in the periphery of nerve fibres from the contralateral side. Single-unit studies showed that cortical stimulation produced two phases of motoneuronal facilitation: a short-latency (central motor delay from contralateral cortex to the intracranial portion of the facial nerve, 7.6 ms), short-duration (1- to 2-ms duration peak in the post-stimulus time histogram) input, which was more commonly evoked by contralateral than ipsilateral stimulation; and a longer latency (central delay > 15 ms), long-duration input evoked equally well from either hemisphere. The former may represent activity in a predominantly contralateral oligosynaptic corticobulbar pathway; the latter, a polysynaptic indirect (e.g. cortico-tegmento-nuclear) bilateral pathway to lower facial muscles. PMID- 7851512 TI - Responses of lateral thalamic neurons to algesic chemical stimulation of the cat knee joint. AB - In order to gain insight into the representation of articular pain of the knee at the supraspinal level, recordings were made from lateral thalamic neurons receiving input from afferent fibres of the knee joint in chloralose anaesthetized cats. Dorsoventral penetrations were made through the ventral posterior lateral nucleus (VPL) using high intensity electrical stimulation of the medial articular nerve (MAN), which contains a high proportion (80%) of A delta and C afferent fibres. All recording sites were verified histologically. Close retrograde injections (300 microliters over 6 s) into geniculate artery of KCl (2 x isotonic), bradykinin (BK, 2.6 or 26 micrograms) and capsaicin (200 microM) were used to test the response properties of thalamic neurons. Of the 50 MAN-positive units tested, 20 showed a response to intra-arterial KCl; of these 20, 12 had a response to BK; 8 of these 12 units were additionally tested with capsaicin and all responded. KCl and capsaicin injections had similar mean response latencies (4.5 and 6.8 s), whereas BK had a longer mean latency (18.6 s). The mean peak response was greatest for capsaicin (168 impulses/s), then KCl (87.5 imp/s) and least with BK (36.4 imp/s). The mean response duration was longest with capsaicin (118 s), followed by BK (67.5 s) and least with KCl (27.9 s). Most of these were convergent wide dynamic range (WDR) neurons with a deep receptive field in the knee joint and hindlimb muscle and/or cutaneous distal hind limb digit, located to the dorsal or ventral periphery of the lateral division of the VPL, the VPL1. In addition, 8 neurons showed inhibitory responses to KCl and/or BK injections. The background activity of VPL1 neurons activated by saphenous nerve stimulation was inhibited by the nociceptive articular stimulus with a magnitude and time course which mirrored the excitatory responses in the periphery of VPL1. These results support the concept that the lateral thalamus plays an important role in mediating discriminative aspects of joint pain. PMID- 7851514 TI - The responses of neurons in the temporal cortex of primates, and face identification and detection. AB - The ability of a human observer to detect the presence of a briefly flashed picture of a face can depend on the picture's spatial configuration, that is on whether its features are rearranged (jumbled) or are in their normal configuration. The face-detection effect (FDE) is found under conditions of backward masking, when the presence of a face can be detected with shorter masking intervals when it is in the normal than when in the rear-ranged configuration. A similar effect is found when the subject is asked to classify the face as rearranged or not - the face-classification effect (FCE). Part of the interest of the FDE and the FCE is that they show how the configuration of a stimulus can be an important factor in the perceptual processing which leads to detection and classification of the stimulus. To analyse these effects we recorded from single neurons in the cortex in the superior temporal sulcus of macaques when they were shown (in a visual fixation task) normal and rearranged faces under backward masking conditions shown in experiments 2 and 3 to produce, with the same apparatus, the FCE, and also to produce comparable effects on the identification of which face was present (called hereafter the face identification effect), and also of the clarity of the face. We found in experiment 1 that there are some face-selective neurons which respond to faces only, or better, when the features in the faces are in their normal configuration rather than rearranged. We also showed in this experiment that the difference in the response to the normal as compared to the rearranged faces became greater when the masking stimulus was delayed more. Thus, at intermediate delays, there are more neurons active for the normal than for the rearranged face. We therefore propose that the FDE, the FCE, and the face-identification effect arise because the total number of neurons activated by faces in their normal configuration is greater than that activated by rearranged faces, because of the sensitivity of some face-selective neurons to the spatial arrangement of the features. The experiments also show that backward visual masking does produce abrupt termination of the firing of neurons in the temporal cortical visual system, so that the duration of a neuronal response is very short when visual stimuli can just be perceived. PMID- 7851515 TI - Dyscoordination of pinch and lift forces during grasp in patients with cerebellar lesions. AB - Effects of cerebellar lesions on the production of isometric pinch force and the coordination of pinch and lift force were examined. Twenty-one patients, mostly with degenerative cerebellar disorders, and ten healthy controls lifted an instrumented test object using the precision grip of thumb and index finger. The load of the object could be varied to study the adaptation of pinch force generation. The results were: (1) Cerebellar patients were able to adapt their pinch force levels to the different object loads. (2) Patients showed a longer latency between the onset of pinch force and onset of life force than controls. The level of pinch force at the start of lift force was elevated. (3) Patients were able to use sensorimotor memory about object load to adapt force output based on previous experience through repetitive testing, but they were significantly less efficient than healthy controls. (4) The temporal profile of pinch force rate of change featured an irregular pattern characteristic for a lack of sufficient anticipatory parameterization. PMID- 7851516 TI - The relative activation of muscles during isometric contractions and low-velocity movements against a load. AB - Surface electromyographic (EMG) and motor unit activity were measured in human arm muscles during isometric contractions and during movements against an elastic load. The direction of force applied proximal to the wrist and movement direction of the wrist were varied in a horizontal plane. During isometric contractions the direction in which the largest EMG activity was measured corresponded to the direction in which motor units had the smallest recruitment threshold, for each muscle. The same was found for movements against an elastic load. However, this direction was different for isometric contractions and for movements. Because the magnitude and sign of these changes varied for different muscles, this resulted in a different relative activation of muscles for the two conditions. The amplitude of the surface EMG during contractions against an elastic load was generally significantly larger than that for isometric contractions against the same load. For m. brachioradialis isometric conditions yielded occasionally increased EMG activity. The change in EMG activity could be attributed completely to changes in motor unit recruitment thresholds leading to proportionate changes in the number of recruited motor units. However, the initial firing rate of motor units at recruitment was the same under both conditions and, therefore, did not contribute to changes in amplitude of surface EMG activity. PMID- 7851517 TI - The movement-induced modulation in discriminability between cutaneous nonpainful stimuli depends on test stimulus intensity. AB - The purpose of this study was to find out whether the finger movement-induced modulation of cutaneous discrimination thresholds varies with the intensity level of the test stimulation in various movement conditions. The effect of active and passive finger movement on cutaneous sensitivity to nonpainful electrical stimulation of threshold and suprathreshold intensity was studied in human subjects. The detection threshold and the just-noticeable amplitude difference (discrimination threshold) at two suprathreshold intensities (3 x and 10 x detection threshold) were determined using a forced-choice paradigm before and after (controls) or during finger movement. In one condition the stimuli were applied just prior to the movement. The finger was actively or passively moved at the frequency of 1.5 Hz or 3 Hz, and the test stimuli were applied to the moving finger, except in one condition to the contralateral finger. The contralateral condition was used to rule out vigilance- and attention-related mechanisms as a cause of sensitivity changes. Active as well as passive movement of the finger produced a significant increase in the detection threshold during the movement. Also just prior to the movement the detection threshold was increased. Suprathreshold discrimination thresholds in the moving finger were not significantly changed during or just prior to the active movement, whereas during passive movement the discrimination threshold to suprathreshold level stimulation was significantly decreased. When test stimuli were applied to the finger contralateral to the actively moving finger, neither the detection threshold nor the discrimination between stimuli of suprathreshold intensities were significantly changed.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7851518 TI - Human neuronal interlimb coordination during split-belt locomotion. AB - Human interlimb coordination and the adaptations in leg muscle activity were studied during walking on a treadmill with split belts. Four different belt speeds (0.5, 1.0, 1.5, 2.0 m/s) were offered in all possible combinations for the left and right leg. Subjects adapted automatically to a difference in belt speed within 10-20 stride cycles. This adaptation was achieved by a reorganization of the stride cycle with a relative shortening of the duration of the support and lengthening of the swing phase of the "fast" leg and, vice versa, in support and swing duration on the "slow" leg. The electromyogram EMG patterns were characterized by two basic observations: (1) onset and timing of EMG activity were influenced by biomechanical constraints. A shortening of the support phase on the faster side was related to an earlier onset and increase in gastrocnemius activity, while a coactivation pattern in the antagonistic leg muscles was predominant during a prolonged support phase on the slower side. (2) A differential modulation of the antagonistic leg muscles took place. An increase in ipsilateral belt speed in combination with a constant contralateral belt speed was associated with an almost linear increase in ipsilateral gastrocnemius and contralateral tibialis anterior EMG activity, while the contralateral gastrocnemius and ipsilateral tibialis anterior EMG activity were little affected. It is concluded that a modifiable timing within the stride cycle takes place with a coupling between ipsilateral support and contralateral swing phase. The neuronal control of this coupling is obviously based on ipsilateral modulation of leg extensor EMG by proprioceptive feedback and an appropriate central (e.g. spinal) modulation of contralateral tibialis anterior EMG activity. PMID- 7851519 TI - Influence of transcranial magnetic stimulation on the execution of memorised sequences of saccades in man. AB - Memorised sequences of saccades are cortically controlled by the supplementary motor area (SMA), as shown in animal experiments and in humans with isolated SMA lesions. We applied transcranial magnetic stimulation (TMS) in eight healthy subjects executing memorised sequences of saccades. Sequences of three targets were presented. Then, upon a go-signal, the subjects had to execute the appropriate sequences. Ten to fifteen sequences were performed in each experiment, and the number of errors were counted. The number of errors increased significantly if TMS was given 80 ms before or 60 ms after the go-signal, with the stimulation coil overlying the SMA. There was no significant increase in errors if different stimulation intervals were chosen (160 ms and 120 ms before the go-signal; 100 ms, 140 ms or 240 ms after the go-signal), if the coil was positioned inappropriately (e.g. over the occipital cortex), or if the stimulator output was too low. We conclude that TMS can interfere specifically with the function of the SMA during a critical time interval close to the go-signal. PMID- 7851520 TI - Orientation of Listing's plane in normals and in patients with unilateral vestibular deafferentation. AB - The parameters characterizing Listing's plane have been determined in a group of normal subjects, and in patients who have had unilateral vestibular deafferentation on the right or left side. All patients were well compensated. There was no statistically significant difference in the orientation of Listing's plane between either of these groups: Listing's plane was approximately perpendicular to the horizontal stereotaxic plane and showed a systematic temporal tilt, i.e., it tilted right for the right eye, and left for the left eye. We also found a considerable intersubject variability in the orientation of Listing's plane. The effect of this variability on the interpretation of three dimensional eye position and velocity data is discussed. PMID- 7851521 TI - A common topology of proteins catalyzing ATP-triggered reactions. AB - A protein fold, six parallel beta strands surrounding the central alpha helix, is likely to be a common structure in protein families known to have a typical set of nucleotide binding consensus sequence motifs A and B and to catalyze ATP triggered reactions. According to this ATP-triggered protein fold, the conserved Glu (or Asp), which acts as a general base to activate a water molecule for an in line attack of the gamma-phosphate, is at the exit of the second beta strand. The fifth beta strand may be involved in propagation of conformational change triggered by ATP hydrolysis. PMID- 7851522 TI - The prothymosin alpha gene is specifically expressed in ectodermal and mesodermal regions during early postimplantation mouse embryogenesis. AB - Prothymosin alpha (ProT alpha) is a highly acidic nuclear protein, once believed to have an extracellular immunoregulatory role but more recently implicated in cell proliferation and/or differentiation. Several recent studies have revealed that ProT alpha mRNA is present during embryogenesis. However, these studies did not investigate the spatial distribution of ProT alpha mRNA in the embryo. Here we present a detailed study of the spatial distribution of ProT alpha mRNA during the early stages of postimplantation development (6.5-12.5 dpc) of the mouse. Three findings are of particular interest. First, ProT alpha mRNA levels increase during the early postimplantation stages (6.5-8.5 dpc) of mouse embryogenesis. Second, ProT alpha mRNA is not uniformly distributed in the mouse embryo, but is present in a spatially specific manner. Third, we have observed that the mouse ProT alpha gene is expressed almost exclusively in ectodermal and mesoderm derived structures, and not in cells which give rise to the definitive endoderm. PMID- 7851523 TI - Cold lability of the mutant forms of Escherichia coli inorganic pyrophosphatase. AB - The variants of Escherichia coli pyrophosphatase carrying the substitutions Glu20 ->Asp, His136-->Gln or His140-->Gln are inactivated, in contrast to the wild-type enzyme, at temperatures below 25 degrees C: their activity measured at 25 degrees C decreases with decreasing the temperature of the stock enzyme solution. The inactivation is completely reversible and is explained by cold-induced dissociation of these hexameric enzymes into less active trimers. PMID- 7851524 TI - HOQNO interaction with cytochrome b in succinate:menaquinone oxidoreductase from Bacillus subtilis. AB - 2-n-Heptyl 4-hydroxyquinoline-N-oxide (HOQNO) inhibits the succinate:quinone oxidoreductase activity of isolated and membrane-bound succinate:menaquinone oxidoreductase of B. subtilis. The inhibition pattern resembles closely that observed for alpha-thenoyltrifluoroacetone and carboxins in the mitochondrial succinate:ubiquinone oxidoreductase: ca. 90% of the activity is highly sensitive to HOQNO (Ki ca. 0.2 microM for the isolated enzyme) whereas the rest 10% proves to be resistant to the inhibitor. HOQNO binding is shown to perturb the absorption spectrum of the ferrous di-heme cytochrome b of the B. subtilis succinate:quinone oxidoreductase both in the alpha and Soret bands. In addition, the inhibitor is shown to bring about a negative shift of Em of the low-potential heme b. It is suggested that HOQNO interacts with a menasemiquinone binding site near the low-potential heme and suppresses the MQ.(-)-to-MQH2 step of the quinone reductase reaction but allows partly for the MQ-to-MQ.- transition to occur; dismutation of MQ. formed in the latter reaction to MQ and MQH2 may account for the 10% of the enzyme activity insensitive to HOQNO. PMID- 7851525 TI - Rapid kinetics of membrane potential generation by cytochrome c oxidase with the photoactive Ru(II)-tris-bipyridyl derivative of cytochrome c as electron donor. AB - Yeast iso-1-cytochrome c covalently modified at cysteine-102 with (4-bromomethyl 4'-methylbipyridine)[bis(bipyridine)]Ru2+ (Ru-102-Cyt c) has been used as a photoactive electron donor to mitochondrial cytochrome c oxidase (COX) reconstituted into phospholipid vesicles. Rapid kinetics of membrane potential generation by the enzyme following flash-induced photoreduction of Ru-102-Cyt c heme has been measured and compared to photovoltaic responses observed with Ru(II)(bipyridyl)3 (RuBpy) as the photoreductant [D.L. Zaslavsky et al. (1993) FEBS Lett. 336, 389-393]. At low ionic strength, when Ru-102-Cyt c forms a tight electrostatic complex with COX, flash-activation results in a polyphasic electrogenic response corresponding to transfer of a negative charge to the interior of the vesicles. The initial rapid phase is virtually identical to the 50 microsecond transient observed in the presence of RuBpy as the photoactive electron donor which originates from electrogenic reduction of heme a by CuA. CuA reduction by Ru-102-Cyt c turns out to be not electrogenic in agreement with the peripheral location of visible copper in the enzyme. A millisecond phase (tau ca. 4 ms) following the 50 microsecond initial part of the response and associated with vectorial translocation of protons linked to oxygen intermediate interconversion in the binuclear centre, can be resolved both with RuBpy and Ru 102-Cyt c as electron donors; however, this phase is small in the absence of added H2O2. In addition to these two transients, the flash-induced electrogenic response in the presence of Ru-102-Cyt c reveals a large slow phase of delta psi generation not observed with RuBpy. This phase is completely quenched upon inclusion of 100 microM ferricyanide in the medium and originates from a second order reaction of COX with the excess Ru-102-Cyt c2+ generated by the flash in a solution. PMID- 7851526 TI - The antitumor action of seminal ribonuclease and its quaternary conformations. AB - It has been previously shown that the antitumor action of bovine seminal ribonuclease (BS-RNase) is dependent on its dimeric structure. However, two distinct quaternary structures, each in equilibrium with the other, have been described for the enzyme: one in which the two subunits exchange their N-terminal ends, the other with no exchange. Antitumor activity assays, carried out on homogeneous quaternary forms of the enzyme, as well as on dimeric mutants of bovine pancreatic RNase A, reveal that another structural determinant of the antitumor activity of BS-RNase is the exchange of N-terminal ends between subunits. PMID- 7851527 TI - Self-aggregation of purified and membrane-bound erythrocyte CD38 induces extensive decrease of its ADP-ribosyl cyclase activity. AB - The transmembrane glycoprotein CD38 is a bifunctional enzyme that catalyzes at its ectocellular domain both the synthesis and the hydrolysis of cyclic ADP ribose (cADPR). The complete reaction, converting NAD+ to nicotinamide and ADP ribose, reproduces an NAD+glycohydrolase (NADase) reaction. CD38 purified from human erythrocyte membranes has been recently shown to undergo stable oligomerization induced by either NAD+ or beta-mercaptoethanol. We demonstrate that oligomerization is also triggered by reduced glutathione (GSH) and that the GSH-induced self-aggregation of purified CD38 is accompanied by extensive and comparable decrease of its ADP-ribosyl cyclase and NADase activities. GSH-induced oligomerization of CD38 and strong enzyme inactivation take place also in situ on erythrocyte membranes. PMID- 7851528 TI - Effect of the C-terminal proline repeats on ordered packing of squid rhodopsin and its mobility in membranes. AB - Negative stain electron microscopy and saturation transfer electron spin resonance spectroscopy have been used to compare the lattice ordering and in plane membrane mobility of full-length and C-terminally cleaved squid rhodopsin. The C-terminus of squid rhodopsin contains a negatively charged region followed by 9-10 repeats of a proline-rich sequence, not found in rhodopsins other than those of cephalopod invertebrates, but similar proline repeats are found in other, unrelated membrane proteins. We find that the proline repeats cluster the rhodopsins into small groups, interfering with two-dimensional crystallization and maintaining their mobility in the membrane. PMID- 7851529 TI - Ferredoxin-dependent CO2 fixation in bean sprouts. AB - Extracts of bean sprouts are capable of reducing ferredoxin and of catalyzing the incorporation of bicarbonate and acetyl coenzyme A into an organic compound that is likely to be pyruvate, in a reaction that requires reduced ferredoxin. The rate of the reaction, the first known for which ferredoxin appears to serve as the direct reductant for CO2 fixation in a higher plant, depends on the concentrations of both ferredoxin and bicarbonate, with half-maximal rates being observed at ferredoxin and bicarbonate concentrations of 0.8 microM and 200 microM, respectively. PMID- 7851530 TI - Prodigiosin 25-C uncouples vacuolar type H(+)-ATPase, inhibits vacuolar acidification and affects glycoprotein processing. AB - Prodigiosin 25-C inhibited the accumulation of 3-(2,4-dinitroanilino)-3'-amino-N methyldipropylamine and acridine orange in the acidic compartments of baby hamster kidney cells with little perturbation of cellular ATP levels. In rat liver lysosomes, prodigiosin 25-C inhibited the proton pump activity with an IC50 of approximately 30 nM, but did not affect ATPase activity up to 1 microM. It also delayed the transport of vesicular stomatitis virus G protein and induced a drastic swelling of Golgi apparatus and mitochondria. These results indicate that prodigiosin 25-C raises the pH of acidic compartments through inhibition of the proton pump activity of vacuolar type H(+)-ATPase, thereby causing the functional and morphological changes to the Golgi apparatus. PMID- 7851531 TI - Isolation and identification of a mu-calpain-protein kinase C alpha complex in skeletal muscle. AB - A mu-calpain-PKC complex was isolated from rabbit skeletal muscle by ultracentrifugation and by anion-exchange chromatography. The PKC associated to mu-calpain was stimulated by calcium, phosphatidylserine and diacylglycerol, and corresponds to a conventional PKC (cPKC). This complex presents an apparent molecular mass close to 190 kDa and is composed of one mu-calpain molecule and of one cPKC molecule. Using monoclonal antibodies specific for the different cPKC isoforms, the isoenzyme associated to mu-calpain was identified as cPKC alpha. Immunofluorescence staining reveals a co-localization of mu-calpain and cPKC alpha on the muscle fibre plasma membranes. PMID- 7851532 TI - Fluorescence spectra of bacteriorhodopsin and the intermediates O and Q at room temperature. AB - An unequivocal answer is given to the question of why the reported fluorescence spectra of bacteriorhodopsin (bR568) have been different from one another. The inconsistency is shown to arise from the accumulation of the fluorescent intermediates O and Q (KN) by cw excitation light. Their fractions in the photo stationary states depend on the excitation power and the suspension pH. We report the intermediate-free fluorescence spectrum of bR568 obtained with a weak excitation source (632.8 nm, 5.3 x 10(15)-1.9 x 10(16) photons cm-2.s-1) and a near-IR sensitive intensified photodiode array system. The fluorescence maxima of the spectra, F(lambda) and f(nu), are located at 755 +/- 10 nm and 12700 +/- 200 cm-1, respectively. The spectrum of O is identical to that of the deionized purple membrane bR605 (Fmax = 750 +/- 5 nm, fmax = 13,000 +/- 100 cm-1). Q (KN) exhibits a blue-shifted spectrum more than that of bR568 (Fmax < 720 nm, fmax > 13,400 cm-1). PMID- 7851533 TI - Quinacrine mustard and lipophilic cations inhibitory to both vacuolar H(+)-ATPase and F0F1-ATP synthase. AB - Various lipophilic cations, such as quinacrine mustard and dequalinium, which are known to inhibit mitochondrial F1-ATPase, strongly inhibited vacuolar H(+)-ATPase purified from bovine adrenal chromaffin granules. Quinacrine mustard bound irreversibly to vacuolar H(+)-ATPase subunit A, and the 115 kDa accessory polypeptide and dithiothreitol had no effect. The binding was competitively inhibited by chlorpromazine and quinacrine, and these compounds specifically reduced the amount of labeling of subunit A. Quinacrine mustard also prevented the binding of [alpha-32P]ATP to subunit A but had no effect on the binding of [3H]N-ethylmaleimide to either subunit A or the 115 kDa accessory polypeptide. These results suggest that the binding site of quinacrine mustard in subunit A is not related to the N-ethylmaleimide-binding site(s), which is important for activity. PMID- 7851534 TI - A human de-ubiquitinating enzyme with both isopeptidase and peptidase activities in vitro. AB - Some enzymatic and physicochemical properties of a human ubiquitin-specific isopeptidase are reported. The enzyme was purified to homogeneity from red blood cells and its specificity towards polymeric ubiquitin substrates suggests a de ubiquitinating activity capable of cleaving 'head-to-tail' polyUb chains as well as isoamide 'branched' Ub dimers. KM values show a 10 fold preference for the cleavage of branched Ub dimers over head-to-tail Ub dimers. The enzymatic activity can be strongly inhibited by various peptides containing either of the cleavage site sequences found in Ub polymers, but not by unrelated peptides. The enzyme is monomeric under reducing conditions and exhibits a globular shape with an average diameter of 9 nm, an S20,w value of 5.2 S and a molar mass of 110 kDa +/- 10%. Because the enzyme cleaves both peptide-linked and isopeptide-linked Ub moieties from substrates, we propose to name it de-ubiquitinase rather than isopeptidase. PMID- 7851535 TI - Squamous cell carcinoma antigen is a potent inhibitor of cysteine proteinase cathepsin L. AB - A squamous cell carcinoma antigen (SSCA), which is a member of the serpin family of proteinase inhibitors, was purified from sera of cancer patients. It did not inhibit serine proteinases. However, it non-competitively inhibited human cathepsin L with a Ki of 0.064 nM, but not cathepsins B and H among cysteine proteinases. These results indicated that SCCA is a non-functional serpin that inhibits cathepsin L in cancer cells. PMID- 7851536 TI - Changes in subcellular and zonal distribution of glucokinase in rat liver during postnatal development. AB - Subcellular and zonal distribution of glucokinase in rat liver during postnatal development was examined immunohistochemically. Before day 11 after birth, only some hepatocytes were immunostained, and a positive immunostaining was found in the cytoplasm but not in the nucleus. No zonal distribution of glucokinase was observed in livers of such pups. From day 15, at which time a dietary change from milk to laboratory chow begins to take place, glucokinase immunoreactivity increased; this increase was associated with increases in glucokinase activity and in glucokinase protein, and also the immunostaining was observed mainly in the nuclei. At day 21, the glucokinase immunoreactivity was found almost exclusively in the perivenous zone. At day 30, an intense immunostaining was seen both in the perivenous zone and in the periportal zone, being slightly predominant in the former. The present results indicate that dramatic changes in the distribution of glucokinase in developing rat liver may be related to dietary change. PMID- 7851537 TI - Dual effects of microwaves on single Ca(2+)-activated K+ channels in cultured kidney cells Vero. AB - Using the patch voltage-clamp method, possible effects of millimetre microwaves (42.25 GHz) on single Ca(2+)-activated K+ channels in cultured kidney cells (Vero) were investigated. It was found that exposure to the field of non-thermal power (about 100 microW/cm2) for 20-30 min greatly modifies both the Hill coefficient and an apparent affinity of the channels for Ca2+(i). The data suggest that the field alters both cooperativity and binding characteristics of the channel activation by internal Ca2+. The effects depend on initial sensitivity of the channels to Ca2+ and the Ca2+ concentration applied. PMID- 7851538 TI - Viral Q beta RNA as a high expression vector for mRNA translation in a cell-free system. AB - Dihydrofolate reductase (DHFR) mRNA was inserted into Q beta phage RNA instead of its coat protein cistron. Translation of this recombinant mRNA in the Escherichia coli cell-free system resulted in the synthesis of DHFR, which was two orders of magnitude higher than that in the case of translation of the control DHFR mRNA. Additionally, it resulted in a significantly enhanced synthesis of Q beta replicase as compared with its synthesis when the original Q beta RNA was used. PMID- 7851539 TI - Mitochondrial presequences can induce aggregation of unfolded proteins. AB - We have studied the interactions between various synthetic peptides and two model unfolded proteins, reduced alpha-lactalbumin and reduced and carboxymethylated alpha-lactalbumin. We found that mitochondrial presequences could induce aggregation of the unfolded alpha-lactalbumins but not of the native alpha lactalbumin. The presequence-induced aggregation of unfolded alpha-lactalbumin was dependent on electrostatic interactions and on the amphiphilicity of the presequences. Since positive charge and amphiphilicity are necessary for the targeting function of mitochondrial presequences, presequence-induced aggregation may be responsible for the instability of mitochondrial precursor proteins and may need to be inhibited by binding factors in the cytosol. PMID- 7851540 TI - Binding of progastrin fragments to the 78 kDa gastrin-binding protein. AB - The non-selective gastrin/cholecystokinin receptor antagonists proglumide and benzotript inhibit colon carcinoma cell proliferation by binding to the 78 kDa gastrin-binding protein (GBP) (Baldwin, Proc. Natl. Acad. Sci. USA, 91 (1994) 7593-7597). However, although most colon carcinoma cell lines synthesize progastrin, production of mature amidated gastrin17 has not been observed. In order to define the structural requirements for the binding of gastrin to the GBP the affinities of various fragments of amidated and C-terminally extended gastrin17 for the GBP have been measured. The results indicate that the GBP recognizes both N- and C-termini of gastrin17. Moreover since C-terminal amidation is not a prerequisite for binding of gastrin to the GBP, the GBP is a potential target for the autocrine effects of progastrin. PMID- 7851541 TI - Primary liver tumours in children. AB - An overview is presented of current management strategies in primary hepatic tumours in children. Recent advances include research in the genetic and molecular properties, especially of hepatoblastoma, the application of pre operative chemotherapy, and the development of pre-surgical staging. Problem areas include management of relapse, chemotherapeutic drug resistance and multifocality. Hepatocellular carcinoma continues to have a much worse outcome than hepatoblastoma. PMID- 7851542 TI - A case of squamous cell carcinoma complicating hidradenitis suppurativa. AB - A case of extensive squamous cell carcinoma arising in widespread perianal and inguinal hidradenitis suppurativa is used to illustrate the pathological features which influence management. The surgical pathology, with wide extension along subcutaneous sinuses, frequently leads to the view that it is incurable. A planned surgical approach, using both immediate frozen section and delayed paraffin histology to assess clearance margins allowed complete surgical excision in two stages. Colostomy is not a necessary part of management and healing by granulation is an acceptable alternative to extensive reconstruction procedures. Radiotherapy and chemotherapy, sometimes used in palliation mode, are not likely to be beneficial. PMID- 7851543 TI - Is there still a place for abdominoperineal resection of the rectum? AB - During the past two decades, low anterior resection (LAR) with colo-rectal or colo-anal anastomosis has replaced abdominoperineal resection (APR) as the primary surgical therapy for rectal cancer. Several studies, although not prospectively randomized, have shown that the outcome after LAR with deep anastomosis and APR is comparable concerning mortality, local recurrence rate and survival. Adequate clearance of the tumour, and not the surgical procedure performed, is the determinant factor influencing the outcome. Whereas most tumours in the upper third and mid-rectum are amenable to a sphincter-saving procedure (SSP), the lower third of the rectum is of debate in this respect. Small tumours (T1) in the lower third can be treated by peranal local excision. Low grade tumours with a T2 or T3 stage located above 3 cm from the dentate line are treated by SSP. There is still a place for for advanced tumours (T3 and T4) below 5 cm from the anal verge, in case of deficiency of the anal sphincter, and when the sphincter complex is infiltrated by the tumour. Preoperative staging measures are essential for patients selection in relation to height of the tumour above the anal canal, depth of tumour invasion into the rectal wall, and presence or absence of regional lymph node metastases. Biology of rectal cancer and its implication on surgery, preoperative staging of rectal cancer, technique and results of the main three surgical options, and the advent of laparoscopy are discussed in this article. PMID- 7851544 TI - Parotid surgery. PMID- 7851545 TI - Interleukin-2 (IL-2) augments host cellular immune reactivity in the perioperative period in patients with malignant disease. AB - Major surgery impairs cellular and humoral immunity, in particular natural cytotoxicity, and this may facilitate the dissemination of tumour cells in the peri-operative period. Recombinant interleukin-2 (rIL-2) has been used to modulate peri-operative immune function. Eighteen patients were randomized to receive either rIL-2 or placebo for three days, as a subcutaneous injection, prior to surgical resection for colorectal cancer. Natural cytotoxicity (natural killer (NK) and lymphokine-activated killer (LAK) cell activity), monocyte phagocytosis and immune cell surface activation marker (CD14+HLA-DR) expression were assessed during therapy and for up to 21 days after surgery. rIL-2 therapy enhanced both NK and LAK cell-mediated cytotoxicity and augmented circulating lymphocyte CD16+ and CD56+ cell subset populations. Circulating monocyte phagocytosis was also increased. Hence, rIL-2 may be used to enhance immune function in the peri-operative period in patients undergoing curative cancer surgery. PMID- 7851546 TI - How should the axilla be treated in breast cancer? Why I favour axillary node sampling in the management of breast cancer. PMID- 7851547 TI - Prognostic value of insulin-like growth factor-1 receptors in patients with colon/rectal cancer: correlation with plasma prolactin. AB - Prognostic value of IGF-1 receptors (IGF-1R) was evaluated and compared with circulating prolactin (PRL) in 59 patients with Dukes B or C colon/rectal cancer. IGF-1R was estimated by radioligand binding assay and PRL was estimated by immunoradiometric assay. Eighty-five percent (50/59) of patients had IGF-1R- tumours while IGF-1R positivity was observed in only 15% (9/59) of patients. None of the clinicopathological parameters showed any association with IGF-1R status. No significant difference was observed in overall survival period between patients with IGF-1R+ tumours and those with IGF-1R- tumours. However, a significant difference in overall survival time was observed between patients with PRL < 20.0 and > 20.0 ng/ml plasma (X2 = 4.70, df = 1, P < 0.05). In bivariate analysis, patients with IGF-1R- tumours and concomitant hyperprolactinemia had unfavourable prognosis compared to their counterpart (X2 = 4.21, df = 1, P < 0.05). We conclude that there was a trend of better overall survival in patients with IGF-1R+ tumours, and PRL < 20.0 ng/ml plasma when compared to patients with IGF-1R- tumours, and PRL > 20.0 ng/ml plasma. Further, IGF-1R negativity in conjunction with hyperprolactinemia could be used as an indicator of unfavourable prognosis in patients with Dukes B or C colon/rectal cancer. PMID- 7851548 TI - SMS 201.995 (Sandostatin) enhances in-vitro effects of 5-fluorouracil in colorectal cancer. AB - 5-fluorouracil (5-FU) is still the most effective cytotoxic agent for the treatment of human colorectal cancer. Response rates, however, vary between 5 20%. One attempt to improve the effect of 5-FU is through biomodulation. We have previously found the somatostatin analogue, SMS 201.995 (Sandostatin, Sandoz), to inhibit both the in-vitro and in-vivo growth of some human colon cancer cell lines. It may act specifically by means of receptors on the surface of tumour cells, or by reducing the concentration of some growth factors. We report that, when 5-FU at 0.125 and 0.25 micrograms/ml was combined with SMS 201.995 at 10( 12) x 2 to 10(-8) x 2M, an enhanced inhibition of in-vitro growth of two human colorectal cancer cell lines (C170 and LIM 1215) was achieved. Effects were measured using [3H]-thymidine uptake and by a colorimetric assay of cellular respiration (MTT, Promega, Sydney). SMS 201.995 alone has minimal inhibitory effects, whilst 5-FU alone shows inhibition as low as 39.6% of control. When 5-FU was then combined with SMS 201.995, a 10-30% inhibition occurred compared to the 5-FU control. The combination of 5-FU and SMS 201.995 may be a useful method of improving response to human colorectal cancer therapy. PMID- 7851549 TI - Liver resection for colorectal liver metastases. AB - The management of patients with colorectal liver metastases is still controversial. Recent evidence suggests benefit for resection of localized metastases within a single lobe of the liver. A series of 49 patients undergoing liver resection for localized liver metastases is presented. Resection involved right hepatectomy (23), left hepatectomy (8) and segmental excision (18). The median age was 62 (range 40-77). Patients have been followed for a period of up to seven years. The overall median survival was 24 months. The actuarial 3-year survival was 57.9%. There was no significant correlation of survival with the degree of differentiation or Dukes staging of the primary tumour. This series adds further weight to the evidence supporting resection in selected patients with colorectal liver metastases. PMID- 7851550 TI - Mastectomy and immediate breast reconstruction: oncological considerations and evaluation of two different methods relating to 88 cases. AB - The authors consider 88 cases of mastectomy and immediate breast reconstruction mainly performed using the skin expander plus prosthesis method or latissimus dorsi myocutaneous flaps. At the same time, 53 patients underwent contralateral mastopexy for symmetry. The mean follow-up was 21 months (range 2-102). Progressive disease was observed in nine cases: one patient presented scar relapse, one axillary relapse, two contralateral tumor, two contralateral tumor and distant metastasis, three distant metastases and one death from distant metastasis. Reconstruction complications were capsular contracture in 12 cases, infection in nine, skin necrosis in two, skin expander breakage in three and implant dislocation in one. The final result was judged good in 54 cases, fair in nine, poor in 11 and unevaluable in 14. In conclusion immediate breast reconstruction does not seem to interfere with the disease or oncological therapy. After analysing separately, and comparing the results and complications of the two main techniques used, latissimus dorsi seems to be the most reliable method in the majority of cases but skin expanders can be a good technique in patients with small and firm breasts and without complicating risk factors. PMID- 7851551 TI - Long-term prognosis of breast cancer: an analysis of 462 patients in a general hospital in south east Netherlands. AB - In this study the long-term prognosis was analysed of all 462 consecutive female breast cancer patients who were diagnosed and carefully staged between 1970 and 1980 in a 600-bed community hospital in Eindhoven, south east Netherlands. Follow up of recurrence and causes of death was obtained until 1 January 1993. Observed survival rates at 5, 10 and 20 years were 66%, 45% and 32%, respectively, and the corresponding breast cancer-specific survival rates were 71%, 54% and 44%. The yearly risk for a recurrence of breast cancer after treatment steadily decreased from 10% the first year to 1% after 10 years. In a multivariate survival analysis both tumour size and nodal status appeared to be equally important prognostic factors in the first 5 years after diagnosis. After 5 years only tumour size had independent prognostic value, which was not significant any more after 10 years. In patients with a tumour size < or = 2 cm and without lymph node involvement at diagnosis, the risk for a recurrence was found to be negligible after 10 years. Those patients may be considered cured, although a search for early diagnosis of a second primary breast cancer in this group is still advisable. PMID- 7851552 TI - Pre-operative localization of non-palpable lesions in breast cancer by charcoal suspension. AB - The use of preoperative localization procedures for non-palpable breast lesions (NPBL) is becoming more and more widespread, increasing the detection of early breast cancers. From October 1987 to July 1992, at our Institution, 253 patients (pts) with clinically non-palpable lesions underwent surgical treatment. Of the 253 pts, the lesions have been localized in 95 cases by a needle system, and in the other 158 cases by a dye injection of a 3% sterile charcoal suspension using stereotactic method (118 cases) or sonography (40 cases). The patients' mean age was 53 years (range 30-75). Mammography revealed regular opacities in 133 cases, clustered microcalcification in 75, diffuse microcalcification in 24, opacities with irregular borders in nine and opacities with internal microcalcifications in 12. The histological findings showed benign breast disease in 175 cases (69.2%), borderline breast disease in 23 (9.1%) and malignancy in 55 (21.7%). The benign/malignant/borderline lesions ratio was 3.2:1. The majority (70%) of these malignant lesions were small cancers (less than 1 cm in diameter) and without lymph-node involvement. The biopsy cost (benign/malignant/borderline ratio, patients discomfort and cosmetic result) has been acceptable. PMID- 7851553 TI - How should the axilla be treated in breast cancer? Why I favour axillary node clearance in the management of breast cancer. PMID- 7851554 TI - Laparoscopy and laparoscopic ultrasound for staging of upper gastrointestinal tumours. AB - Conventional imaging studies are often not sensitive enough to allow accurate preoperative staging of intra-abdominal tumour spread. Laparoscopy and laparoscopic ultrasound appear to be suitable to improve staging of gastrointestinal tumors. Within a 10-month period 40 patients with upper GI tract cancer underwent laparoscopy for intra-abdominal staging. Additionally laparoscopic ultrasound was performed on 20 of these patients using a flexible echo-endoscope equipped with a curved array transducer (5/7.5 MHz). By laparoscopy additional information compared to conventional staging was obtained in 16 patients (40%). Laparoscopy revealed peritoneal carcinomatosis and liver metastases in seven and four patients, respectively. M1-lymph nodes were detected in four patients. Laparoscopic ultrasound was able to image otherwise inaccessible regions of the abdominal cavity and induced a change of staging in seven of 20 patients in whom laparoscopy was uneventful. Ultrasound also proved to be valuable for localization of M1-lymph nodes. In summary, combination of laparoscopy and laparoscopic ultrasound improved staging in 23 of 40 patients (57%). Consequently surgery was abandoned in 16 patients due to incurable or non resectable disease, while down-staging occurred in seven patients, who subsequently underwent resection. Laparoscopy is capable of improving staging of intra-abdominal malignancy by detection and subsequent biopsy of small lesions. Laparoscopic ultrasound can replace the lack of tactile sensitivity in laparoscopy, thus enabling the detection of non-superficial lesions. PMID- 7851555 TI - Amplification of HER-2/neu gene in human gastric adenocarcinomas: correlation with primary site. AB - Adenocarcinomas of the proximal stomach including the gastroesophageal junction are extremely virulent cancers which are increasing rapidly in incidence. Stage for-stage proximal gastric cancers have a worse prognosis than do tumors of the body or antrum of the stomach. To further explore biological differences based on site, we studied 80 patients with locally advanced primary tumours of the proximal (n = 40) and distal stomach (n = 40) for amplification of the HER-2/neu proto-oncogene. None of 40 patients with proximal lesions had overexpression of HER-2/neu, whereas four of 40 (10%) distal adenocarcinomas had a 16-24-fold gene amplification (P = 0.04). In the adenocarcinomas from two patients, gene rearrangements were found in addition to amplification. HER-2/neu gene product p185 over-expression was found only in the amplified cases. All four patients with distal tumors and amplification had rapid progression of disease (median survival: 4.3 months). While it is unclear why HER-2/neu amplification is seen only in distal tumors, these data further support the hypothesis that biological differences between proximal and distal lesions are present. As is the case for other tumours, HER-2/neu amplification is associated with a poor prognosis for the individual patient. PMID- 7851556 TI - The effect of intravenous and intra-tumoural chemotherapy using a monoclonal antibody-drug conjugate in a xenograft model of pancreatic cancer. AB - In order to investigate the efficacy of the intra-tumoural administration of an anticancer drug-monoclonal antibody conjugate in athymic nude mice bearing xenografts of a human pancreatic carcinoma, we examined the clearance of the murine monoclonal antibody A7 from the xenografts after intravenous or intra tumoural administration and measured the antitumour effect of neocarzinostatin conjugated to MAb A7 following intravenous or intra-tumoural injection. Compared with 125I-labelled normal mouse IgG, a larger amount of 125I-labelled A7 remained in the tumour after both intravenous and intra-tumoural injection, and a significantly larger amount of 125I-labelled A7 remained in the tumour after intra-tumoural injection than that after intravenous injection. Moreover, a larger amount of 125I-labelled A7-NCS localized in the tumour after intra tumoural injection than that after intravenous injection. Neocarzinostatin conjugated to MAb A7 showed greater activity against human pancreatic cancer than neocarzinostatin alone after both intravenous and intra-tumoural administration. Tumour growth was suppressed completely by the intra-tumoural administration of A7-NCS at a dose that did not suppress tumour growth via the intravenous route. These observations suggest that the intra-tumoural injection of neocarzinostatin conjugated to MAb A7 offers promise in treating pancreatic carcinoma. PMID- 7851557 TI - The University of Massachusetts technique of radical retropubic prostatectomy. AB - A modified technique of radical retropubic prostatectomy is described which takes advantage of combining the antegrade dissection of prostate described by Skinner and the early control of prostatic vasculature as publicized by Walsh. Integration of both techniques of radical retropublic prostatectomy has resulted in improved exposure and minimal blood loss. The average blood loss with this technique was 500 ml in contrast to the average blood loss of 1100 ml while performing over 300 radical retropubic prostatectomies by the standard technique. The average operating times have been 150 minutes. Because of improved exposure and reduced blood loss, it is easy to teach this technique of radical prostatectomy to the surgeon in training (resident or the registrar) without any compromise to the primary goal of surgery which is to remove all tumour. No intra operative complications were encountered during the performance of this modified technique of radical retropubic prostatectomy. PMID- 7851558 TI - A randomized trial of postoperative adjuvant chemotherapy in non-small cell lung cancer (the second cooperative study). The Study Group of Adjuvant Chemotherapy for Lung Cancer (Chubu, Japan). AB - A prospective randomized trial (the second cooperative study) was conducted from July 1985 to December 1987 to investigate the benefits of postoperative adjuvant chemotherapy in patients for whom non-small cell lung cancer had been resected completely. Patients were randomly assigned either to a chemotherapy group (group A) treated postoperatively with CDDP (66 mg/m2 x 1), ADM (26 mg/m2 x 1) and UFT (8 mg/kg/day) during 6 months, or to a control group (group B) which had undergone surgery only. Three hundred and thirty-three resected cases were registered. Among them, 24 cases (7.2%) were excluded, because of incomplete resection (15), pathologically benign tumour (3), small cell lung cancer (2) and other factors (4). Three hundred and nine cases were eligible: 155 cases in group A (p-Stage I 93, II 19, III 43) and 154 in group B (I 109, II 10, III 35). The 5 year survival rate in group A was 61.8%, and that in group B 58.1%. The 5-year disease-free survival rate for each group was 61.8% and 57.4%, respectively. There were no significant differences in the 5-year survival between the two groups. However, since a significant difference was observed between the two groups regarding pathological lymph node metastasis (pN), the prognostic factors were adjusted using Cox's proportional hazard model. Thereafter the adjusted survival rate and disease-free survival rate for group A became significantly higher than for group B (P = 0.044 and P = 0.036, respectively). Thus, from these results, it is concluded that the role of surgery for non-small cell lung cancer still remains of primary importance, and postoperative adjuvant chemotherapy is effective to improve the results of surgery and prolong life of patients with non small cell lung cancer. PMID- 7851560 TI - Clinical trials--a new section in the European Journal of Surgical Oncology. PMID- 7851559 TI - Malignant peripheral nerve sheath tumors in patients with and without neurofibromatosis. AB - Malignant peripheral nerve sheath tumors (MPNST) are rare. They account for 10% of all soft tissue sarcomas. The incidence of MPNST in patients with neurofibromatosis type 1 (NF-1) is 4%. A retrospective study was undertaken to evaluate the prognosis of patients with MPNST and NF-1 vs patients with MPNST alone. Twenty-two patients with MPNST were diagnosed. The MPNST was diagnosed with NF-1 in 11 patients (50%). Treatment was defined as curative in 20 patients (90%), non-curative in one patient (5%), and one patient received no treatment. The median disease-free survival (DFS) was 14 months (range 0-153 months). The median overall survival 24 months (range 1-153 months). There were three patients with isolated local failures (14%), four patients with local and distant failures (18%), and seven patients with isolated distant failures (32%). There was no statistical difference between patients with and without NF-1. Five patients with NF-1 developed a second MPNST (45%), none of the patients without NF-1 did (P = 0.018). A statistically worse survival was found when the duration of the first symptoms had been longer than six months. Patients with MPNST have a poor prognosis with a high risk for local and distant failures (> 50%). There is no statistical difference in the final outcome for MPNST with or without NF-1, but patients with NF-1 have a high risk for developing a second MPNST. PMID- 7851561 TI - Malignant lymphoma of the rectum treated preoperatively with hyperthermia and radiation. AB - A 58-year-old Japanese woman with primary malignant lymphoma of the rectum was treated preoperatively with radiation and intraluminal hyperthermia, after which abdominoperineal rectal amputation (Miles' operation) was done. The rectal tumor disappeared and there were no lymphoma cells in the resected specimens. The postoperative course was smooth and she is being followed in the outpatient department. At this writing, five years after the surgery, she remains well. PMID- 7851562 TI - Duodenal leiomyosarcoma as a cause of retroperitoneal sepsis. AB - The case of a patient with a duodenal leiomyosarcoma presenting with sepsis is presented. The necrotic centre of the tumour communicated with the lumen of the duodenum without causing duodenal obstruction. Resection of the duodenum with tumour offers the only chance of cure. PMID- 7851563 TI - Leiomyosarcoma of the inferior vena cava presenting as Budd-Chiari syndrome. Vena cava replacement under veno-venous bypass and liver hypothermic perfusion. AB - We report the first case of leiomyosarcoma of the middle and upper part of the vena cava successfully treated by surgical resection, complete vena cava replacement and disobliteration of the hepatic veins under veno-venous bypass and liver hypothermic perfusion as described in "ex situ, in vivo liver surgery". PMID- 7851565 TI - Why clinical trials? PMID- 7851564 TI - Parenchymal leiomyoma of the breast. Report of a case and clinicopathological review. AB - We describe a 42-year-old woman with a solid breast mass of smooth muscle cell origin. Breast leiomyoma is an extremely rare benign tumour, with only 11 cases reported thus far. Various explanations have been offered with regard to its origin, such as hamartoma, embryonal migration from the nipple tissue, multipotent mesenchymal cells or the presence of myoepithelial cells originating from the breast ducts. The differential diagnosis for breast leiomyoma usually includes benign fibrous breast lesions, but leiomyosarcoma should definitely be ruled out. Surgical treatment consists of tumour excision with free margins. We discuss the tumour's clinical, pathological and immunohistochemical features, and review the current literature. PMID- 7851566 TI - Small bowel melanoma: extended survival with surgical management. AB - Small intestinal melanoma is rare, and primary vs metastatic origin is often unclear. A patient with the longest reported survival (21 years) after resection of a melanoma in the small intestine is presented, and the debate regarding primary small bowel melanoma is reviewed. Multiple resections of neck recurrence (or second primaries) in this patient with prolonged survival validates the aggressive pursuit and excision of localized melanoma when possible. PMID- 7851567 TI - Metastasis of malignant melanoma to a transitional cell carcinoma of the urinary bladder. AB - A case of malignant melanoma metastatic to a transitional cell carcinoma of the urinary bladder in a 28-year-old female is reported. This is the sixth reported case involving malignant melanoma metastasis in another neoplasm. The pertinent literature is reviewed. PMID- 7851568 TI - How we do it--manage early breast cancer in a pre-menopausal patient. 3- Assessment of patient from presentation to preliminary decision on management. PMID- 7851569 TI - The genetic basis of colorectal cancer--clinical implications. AB - Colorectal carcinomas demonstrate extensive molecular genetic alterations throughout the genome. The genetic changes in cancer of the colon and rectum are among the best understood of any common human cancer. The genetic abnormalities include both dominant-acting oncogenes (Ki-ras, c-src) and tumor-suppressor genes which undergo inactivation or loss (APC, DCC, p53). The evolution of the cancer is a complicated and multistep process. At the various steps of this phenomenon we can recognize specific molecular genetic alterations. These particular genetic changes may be useful as improved markers to predict those patients who have an aggressive cancer of the colon, with occult metastases or increased metastatic capability and this selection of patients could lead to improved surgical and medical management. PMID- 7851570 TI - Surgically induced ovulation in the polycystic ovary syndrome: wedge resection revisited in the age of laparoscopy. AB - OBJECTIVE: To provide an up-to-date comprehensive review of published data on laparoscopic methods of ovulation induction in the polycystic ovary syndrome (PCOS). Areas to be considered include the historical background of these procedures, their outcomes as reported in the literature, and their potential adverse effects. Through the careful review of these issues, some recommendations for clinical use and further study are offered. DESIGN: Relevant studies were identified through a the search of a computerized bibliographic database of holdings in the National Library of Medicine as well as the manual scanning and cross-referencing of relevant medical journals. RESULTS: Twenty-nine relevant studies were identified in the English language literature. These studies consist almost exclusively of uncontrolled case series. Pregnancies after laparoscopic ovulation induction procedures have been reported in an average of 55% of treated subjects (range 20% to 65%). Potential advantages of laparoscopic ovulation induction over gonadotropin therapy may include possible cost savings, serial repetitive ovulatory events resulting from a single treatment, no increased risk of ovarian hyperstimulation or multiple gestation, and the prospect for a higher live birth rate owing to a seemingly lower incidence of miscarriage. Reported adverse effects include a high rate of intra-abdominal adhesion formation and a single case of iatrogenic premature menopause due to postoperative ovarian atrophy. CONCLUSIONS: The available circumstantial evidence suggests that laparoscopic procedures designed to induce ovulation may be of value in the PCOS subject who, despite an exhaustive trial of clomiphene citrate therapy, remains anovulatory and is unable or unwilling to undergo gonadotropin therapy. However, because of the risks of postoperative ovarian adhesions, carefully constructed controlled trials must be performed before these procedures can be viewed as efficacious and safe. PMID- 7851571 TI - From microsurgery to laparoscopic surgery: a progress. PMID- 7851572 TI - Prognostic factors for successful expectant management of ectopic pregnancy. AB - OBJECTIVE: To determine the independent ability of initial hCG titers, trend of hCG titers, and ultrasonographic findings in the prediction of successful expectant management in ectopic pregnancy (EP). DESIGN: Case-control study. SETTING: University hospital. PATIENTS: Sixty-seven patients with EP managed expectantly, 49 of whom (73%) had a spontaneous resolution, whereas 3 (5%) underwent medical treatment, and 15 (22%) eventually underwent surgical treatment. RESULTS: Univariate analysis showed that the initial hCG titer, the trend in hCG titers between first and second sample, and ultrasonographic visualization of absence of an ectopic gestational sac were significant predictors of a successful expectant management. Using receiver operating characteristic curve analysis, an hCG titer < 1,000 mIU/mL was chosen as the optimal cutoff for this prediction, identifying 88% of women destined to have spontaneous resolution of the EP. Multivariate analysis showed that both initial hCG titer and trend in hCG titers but not ultrasonographic visualization of an ectopic gestational sac were independent predictors of a successful or failed expectant management. CONCLUSION: Expectant management of EP is successful in the majority of patients with initial hCG titer < 1,000 mIU/mL. PMID- 7851573 TI - Laparoscopic prostaglandin injection in ectopic pregnancy: success rates according to endocrine activity. AB - OBJECTIVE: To investigate the clinical performance of local prostaglandin treatment of ectopic pregnancies (EPs) in relation to their biologic activity as determined by preoperative serum hCG levels. DESIGN: Prospective study over a 2 year period of 108 patients with 127 tubal pregnancies. SETTING: A department of obstetrics and gynecology in a central county hospital. PATIENTS: One hundred eight patients who presented with a clinical diagnosis of EP. INTERVENTIONS: Patients with EP were treated with laparoscopy-guided injection of prostaglandin F2 alpha in the surrounding tubal wall and the corpus luteum-bearing ovary. All members of the staff participated. MAIN OUTCOME MEASURES: Success rate, hospitalization cost, and convalescence period. RESULTS: Seven laparotomies (7.5%) were performed postoperatively due to increasing hCG levels or ruptures with circulatory reactions. All except one had an initial (preoperative) hCG value > 1,000 mIU/mL (conversion factor to SI unit, 1.00). The mean hospitalization period was 2.7 days and 90% of the medically treated patients returned home on the first postoperative day. The mean convalescence period was 18 days. CONCLUSION: The procedure is simple and carries an acceptable success rate in cases with hCG levels < 1,000 mIU/mL. The approach demands minimal technical resources and it may reduce health care costs substantially. PMID- 7851574 TI - Effects of two different doses of leuprolide acetate depot on uterine cavity area in patients with uterine leiomyomata. AB - OBJECTIVE: To compare the effects of two different doses of a monthly depot injection of a GnRH agonist (GnRH-a) on uterine cavity area in patients with uterine leiomyomata. DESIGN: Prospective, randomized study. SETTING: Hospital department of obstetrics and gynecology. PATIENTS: Thirty-six premenopausal women, 25 to 52 years of age, with uterine leiomyomata. INTERVENTION: Leuprolide acetate (LA) depot, 1.88 or 3.75 mg, was administered SC every 4 weeks for 24 weeks. MAIN OUTCOME MEASURE: Uterine cavity area before and after treatment was assessed by hysterosalpingography. RESULTS: The 1.88- and 3.75-mg LA depots significantly reduced uterine cavity area by 40.8% and 40.2%, respectively. No significant difference was observed between the two groups. CONCLUSION: Monthly injection of 1.88 or 3.75 mg LA depots appears to reduce uterine cavity area to a similar extent in patients with uterine leiomyomata. PMID- 7851575 TI - An expanded polytetrafluoroethylene barrier (Gore-Tex Surgical Membrane) reduces post-myomectomy adhesion formation. The Myomectomy Adhesion Multicenter Study Group. AB - OBJECTIVE: To evaluate the effects of the expanded polytetrafluoroethylene barrier (PTFE), Gore-Tex Surgical Membrane, in reducing postmyomectomy adhesion formation. DESIGN: Multicenter randomized clinical trial. INTERVENTIONS: Twenty seven women having myomectomy with at least two incisions on the uterine fundus and posterior uterine wall of similar length were enrolled in the study. At laparotomy, the two incision sites were randomly assigned to be covered with PTFE or were left uncovered. A second-look laparoscopy to evaluate adhesion formation and to lyse adhesions was done from 2 to 6 weeks after the myomectomy. Adhesions were scored using a 0- to 11-point scoring system. RESULTS: At laparoscopy, 15 of 27 incisions covered with PTFE (55.6%) and only 2 of 27 uncovered sites (7.4%) were completely free of adhesions. The mean adhesion score at the PTFE sites was significantly lower (1.88 +/- 0.46; SEM) than at the control sites (7.55 +/- 0.57). CONCLUSION: The PTFE barrier is effective in reducing postmyomectomy adhesion formation. PMID- 7851576 TI - Pregnancy in women with Kallmann's syndrome. AB - OBJECTIVE: To induce of ovulation and pregnancy in women with Kallmann's syndrome. DESIGN: Retrospective study. PATIENTS: Three women with hypogonadotropic hypogonadism and anosmia with a desire for pregnancy. INTERVENTIONS: Investigation of hypothalamic-pituitary-ovarian function and induction of ovulation by pulsatile GnRH or intramuscular human pituitary gonadotropins (hPG) or hMG with hCG. MAIN OUTCOME MEASURES: Successful induction of ovulation as measured by serum P levels and successful pregnancy. RESULTS: Ovulation was induced successfully in all three patients on more than one occasion and nine pregnancies occurred. Gonadotropin-releasing hormone was given IV by an electronically timed syringe driver. A total of 12 pulsatile GnRH cycles resulted in two pregnancies, 6 of these cycles being in one patient who did not ovulate or conceive with this therapy. Ovulation occurred in 10 of 16 hMG or hPG cycles, with conception in 7 of these. Gonadotropin usage was higher in these women compared with women with hypogonadotropic hypogonadism without anosmia (2,850 compared with 2,100 IU per treatment cycle), and the follicular phase was longer. CONCLUSIONS: All three women conceived and had children after induction of ovulation. The success rate of these therapies in Kallmann's syndrome appears to be high in spite of very few reports in the literature. PMID- 7851577 TI - Dysmenorrhea is related to the number of implants in endometriosis patients. AB - OBJECTIVE: To determine whether the symptoms of endometriosis were related to the number and/or location of endometrial implants and the number and/or location of adhesions. DESIGN: Prospective, double-blind study. PATIENTS: Seventy consecutive female surgical patients undergoing diagnostic and operative laparoscopy for pain, infertility, or both. INTERVENTIONS: Patients completed a self-administered questionnaire one day before laparoscopy. MAIN OUTCOME MEASURES: The number, type, and location of endometrial implants and the number, type, and location of adhesions were evaluated during laparoscopy. These were compared with the type and severity of endometriosis symptoms as reported by patients. RESULTS: The total number of ectopic endometrial implants was associated directly with the intensity of dysmenorrhea experienced by patients in the 60 days before operative laparoscopy (n = 47). Patients with low pain scores had significantly fewer implants than patients with high pain scores. CONCLUSIONS: The intensity of menstrual pain is related to the number of endometrial implants in patients with endometriosis. PMID- 7851578 TI - Short-term Lupron or danazol therapy for pelvic endometriosis. AB - OBJECTIVE: To compare the efficacy of a 3-month trial of leuprolide acetate (LA; Lupron; TAP Pharmaceuticals, Deerfield, IL) versus danazol (Danocrine; Scenofi Winthrup Pharmaceuticals, New York, NY) therapy on laparoscopically proven endometriosis. DESIGN: Endometriosis severity was assessed at the time of laparoscopy and patients were randomized to receive 0.1 mg SC LA (n = 22) or 800 mg danazol orally (n = 18) daily for 3 months. A second laparoscopy and/or laparotomy was performed to assess the change in the extent of endometriosis and for surgical therapy. SETTING: Private practice at a university-affiliated hospital. PATIENTS: Forty patients with mild, moderate, or severe endometriosis. Ten patients were excluded. INTERVENTION: Three-month treatment randomly assigned to either LA or danazol. MAIN OUTCOME MEASURES: Prospective measurement of American Fertility Society endometriosis scores and size of ovarian endometriomata before and after therapy via laparoscopy. RESULTS: The mean endometriosis score including adhesions decreased significantly from 36 +/- 4.9 to 29 +/- 5.0 (mean +/- SEM) with LA and from 34 +/- 6.4 to 29 +/- 6.5 with danazol. The mean laparoscopic endometriosis score not including adhesions decreased from 27 +/- 3.5 to 22 +/- 3.4 with LA and 22 +/- 3.5 to 19 +/- 3.1 with danazol. Seven of 18 (39%) endometriomata responded to LA and 6 of 15 (40%) endometriomata responded to danazol. CONCLUSION: We conclude that both danazol and LA will reduce endometriosis scores after a 3-month course of therapy. Larger clinical trials are needed to compare short courses of therapy with the more established 6-month trials. A 3-month versus a 6-month course of therapy offers obvious benefits including decreased cost and decreased side effects. PMID- 7851579 TI - 17 beta-Estradiol: oral or parenteral administration in hyperandrogenic women? Metabolic tolerance in association with cyproterone acetate. AB - OBJECTIVE: To compare the metabolic effects of two different administration routes of estrogen associated with cyproterone acetate (CPA) in young women. DESIGN: Randomized and prospective study. SETTING: University medical and research center. PATIENTS: Sixty-five premenopausal young women with clinical hyperandrogenism. INTERVENTIONS: A high dose of CPA was administered, associated with either transdermal (group T) or oral (group O) 17 beta-E2. MAIN OUTCOME MEASURES: Glucose tolerance, plasma lipid level, coagulation and fibrinolysis parameters, and angiotensinogen, before and at 6 and 12 months during treatment. RESULTS: At 12 months, fasting blood glucose and basal insulin levels were significantly lower in group O than in group T. The increase in angiotensinogen was greater in group O, however, without modification in arterial blood pressure. No significant difference between the two groups was observed in lipids, coagulation, and fibrinolysis. CONCLUSION: Natural estrogens associated with CPA have no patent deleterious metabolic effect. However, the choice of oral estrogen administration seems to be better among patients with disorders such as hyperandrogenism or obesity with potential hyperinsulinism. PMID- 7851580 TI - Effects of low-dose estrogen oral contraceptives on weight, body composition, and fat distribution in young women. AB - OBJECTIVE: To determine prospectively whether the use of low-dose estrogen oral contraceptives (OC) is associated with changes in weight, body composition, or fat distribution. DESIGN: Anthropometric measurements were performed in 49 healthy young (16 to 21 years old) women before commencement of OC use (30 micrograms ethinyl estradiol [EF2] plus 75 micrograms gestodene) and after three and six treatment cycles. Thirty one age- and weight-matched women who were not using OC served as controls. SETTING: Outpatient gynecological clinic of Hadassah Medical Center, a tertiary level hospital, and the "Shilo" voluntary service for the prevention of unwanted pregnancy. MAIN OUTCOME MEASURES: Anthropometric measurements included body mass index (BMI), waist-to-hip girth ratio, and body composition (the percentage of body fat and water), estimated by mean of infrared interactance. RESULTS: In the group of OC users, baseline BMI, percent fat, percent water, and waist-to-hip girth ratio were 21.1 +/- 0.32 (kg/m2), 23.8% +/- 0.63%, 57.4% +/- 0.39%, and 0.73 +/- 0.01, respectively, and did not change significantly after six cycles (20.6 +/- 0.41 [kg/m2], 23.9% +/- 0.57%, 58.1% +/- 0.49%, and 0.72 +/- 0.03, respectively). These measurements were not significantly different when compared with the nonusers. Fifteen OC users (30.6%) gained weight (> 0.5 kg). Weight gain was due to a significant accumulation of fat (from 22.5% +/- 1.1% to 25.6% +/- 0.74%), whereas the percentage of body water remained stable. The waist-to-hip girth ratio also was not changed significantly. Similarly, 11 nonusers (35.4%) gained weight because of similar nonabdominal fat accumulation. Ten OC users (20.4%) lost weight (57 kg +/- 1.51 to 55.4 +/- 1.47 [mean +/- SEM]) and 6 nonusers (19.3%) also lost weight (59 kg +/- 1.42 to 57.3 +/- 1.92). In both groups the loss of weight was not associated with significant change in body composition. CONCLUSIONS: The use of low-dose OC (EE2 plus gestodene) was not associated with overall impact on weight, body composition, or fat distribution. However, when weight gain did occur during OC use, it was due to increase in body fat and not in volume of body water, and it was not associated with changes in fat distribution. PMID- 7851581 TI - Total and unbound cytosolic estrogen and progesterone receptors in myometrium and fibroid after gonadotropin-releasing hormone agonist treatment. AB - OBJECTIVE: To study the changes in bound and unbound cytosolic estrogen receptor (ER) and progesterone receptor (PR) in fibroid and myometrium after treatment with gonadotropin-releasing hormone agonists (GnRH-a). DESIGN: Prospective randomized study. SETTING: A tertiary institutional hospital. PATIENTS: Thirty premenopausal women with normal regular menstrual cycles and uterine fibroids. INTERVENTIONS: Patients were randomized to receive buserelin acetate for 3 months (n = 20) or no treatment (n = 10) before hysterectomy. MAIN OUTCOME MEASURES: Bound and unbound ER and PR. RESULTS: In nontreated women, values of unbound ER and PR in fibroid were higher than in myometrium. There were no differences in total receptors. The total and unbound ER in myometrium was higher in treated than in nontreated women. There were no differences in fibroid. CONCLUSIONS: The higher content of unbound hormone receptors in fibroid correlates with an exacerbation of the hormone dependence of this tissue compared with myometrium. The increase of total and unbound ER in myometrium after treatment suggests a higher level of synthesis or a lower level of degradation of receptors in this tissue. PMID- 7851582 TI - Elevated follicular fluid angiotensin II and pregnancy outcome. AB - OBJECTIVE: To assess whether a relationship exists between follicular fluid (FF) angiotensin II (AII) concentration and pregnancy outcome or earlier fecundity parameters and whether correlations exist among FF AII concentrations and P, E2, T, androstenedione (A), or various ratios of these. DESIGN: Retrospective study in which hormone concentrations in FF samples were measured. SETTING: In vitro fertilization clinic-Assisted Reproductive Technology Program, Rush Medical Center. PATIENTS: Twenty-six female patients underwent ovarian stimulation for IVF. INTERVENTION: Leuprolide acetate was combined with hMG and FSH for ovarian stimulation. MAIN OUTCOME MEASURE: Follicular fluid aspirates were collected and oocytes were recovered 34 to 36 hours after hCG injection. The patients proceeded to undergo IVF and ET. Follicular fluid hormones were measured using standard RIA. Angiotensin II and steroid hormone concentrations in FF were compared for pregnant versus nonpregnant women using the Student's t-test and rank-sum test. Pearson multiple-correlation analysis was performed to calculate correlation coefficients among AII concentrations and steroid concentrations in FF aspirates. RESULTS: Mean FF concentration of AII was significantly lower in samples from women showing clinical pregnancies (112.2 +/- 13.9 pg/mL [107.3 +/- 13.3 pmol/L]) compared with samples from women who did not achieve pregnancy (217.1 +/- 23.8 pg/mL [207.5 +/- 22.7 pmol/L]) (mean +/- SE). A negative correlation was observed between FF concentrations of AII and P. Correlations of AII with E2, T, A, or with ratios of these did not show significance. CONCLUSION: These data suggest that high AII concentration at time of oocyte recovery may indicate poor pregnancy outcome in women undergoing ovarian stimulation for IVF. These data corroborate previous results in animal models showing that AII predisposes follicles to undergo atresia-like conditions. PMID- 7851583 TI - Integrins as markers of uterine receptivity in women with primary unexplained infertility. AB - OBJECTIVE: To assess uterine receptivity in women with unexplained infertility using integrin cell adhesion molecules as markers. DESIGN: Prospective, controlled study design. PATIENTS: Eighty-seven nulliparous women with unexplained infertility and 32 fertile and infertile parous controls. MAIN OUTCOME MEASURE: Immunohistochemical staining for alpha 1, alpha 4, and beta 3 integrin subunits in endometrial biopsies obtained during the window of implantation (days 20 to 24), using the semiquantitative HSCORE by two observers in a blinded fashion. RESULTS: All endometrial biopsies from parous controls contained positive immunostaining for the alpha 1, and beta 3 integrin subunits in glandular epithelium. Some samples from parous controls were missing the alpha 4 subunit. In contrast, compared with parous controls, biopsies from women with unexplained infertility had reduced significantly beta 3 expression, with similar expression of alpha 1 and alpha 4. Two distinct defects in integrin expression were identified: "out-of-phase" samples that lacked beta 3 because of histologic lag (type I defects) and "in-phase" endometrium that still failed to express this integrin (type II defects). These subclassifications accounted for 26% and 39% of the total unexplained infertility group, respectively. CONCLUSIONS: Abnormal endometrial integrin expression was a frequent finding in women with unexplained infertility. These data suggest that defective uterine receptivity may be an unrecognized cause of infertility in this population of women. PMID- 7851584 TI - Factors related to preferences in gamete donor sources. AB - OBJECTIVE: To survey fertile and infertile individuals concerning attitudes about donor insemination and ovum donation and to analyze whether gender, experience with infertility, and religion influences: [1] preference for choosing gamete donor over adoption or child-free living; [2] choice of selecting a known or anonymous donor; or [3] choice of disclosure or nondisclosure to any offspring. DESIGN: Patients in an infertility clinic and obstetrics and gynecology practice were asked to complete surveys. PARTICIPANTS: Three hundred nineteen individuals who completed surveys. MAIN OUTCOME MEASURES: A 14-item questionnaire (created for this study) with a demographic information section. RESULTS: No gender differences were observed for preference to use donor gametes, to adopt, or to live child free within the infertility group. In the obstetrics and gynecology group, men preferred adoption more than women and were less likely to use a donor. Choice of whether to use a donor, which donor source, and whether to disclose the use of a donor was influenced by gender, experience with infertility, and religion. CONCLUSIONS: Gender, experience with infertility, and religion influence an individual's choice in family building options as well as what information will be shared with the child. There is a wider acceptance of using known donor sources than has heretofore been seen and these options should be explored. PMID- 7851585 TI - Endometrial blood flow response to hormone replacement therapy in women with premature ovarian failure: a transvaginal Doppler study. AB - OBJECTIVE: To evaluate the endometrial blood flow response to hormone replacement therapy (HRT) in women with premature ovarian failure who plan to enter an oocyte donation program. DESIGN: Transvaginal color Doppler ultrasound examinations were performed in women with ovarian failure before and during a cycle of standard HRT and in those with normal menstrual cycles. Blood flow response was assessed by visualization of arterial wave forms in the endometrial region. The transvaginal color flow mapping system was used. Resistance indexes were calculated for analysis and correlated with plasma E2 and P concentrations. PATIENTS: Eighteen women with ovarian failure (study group), and 12 volunteers with normal ovarian cycles (control group). RESULTS: Data for resistance indexes were divided into five phases according to the day of hormonal cycle: 0, pretreatment phase; I, early follicular phase (days 5 to 7); II, late follicular phase (days 11 to 13); III, early luteal phase (days 17 to 21); and IV, late luteal phase (days 23 to 25). All women with ovarian failure demonstrated continuous forward end-diastolic flow velocities at phase I, whereas none showed this pattern during the pretreatment period (phase 0). Women with ovarian failure in the early follicular phase had a significantly higher resistance index (0.85 +/- 0.1; mean +/- SD) than that in the late follicular phase (0.57 +/- 0.1), and the resistance index in the early luteal phase (0.67 +/- 0.1) was significantly higher than that of the late follicular phase. There was no difference in the resistance index between early and late luteal phases. A similar pattern of lower resistance index around midcycle was observed in the control group. However, a comparison of the resistance indexes between ovarian failure and control patients revealed a significant difference between values in the early follicular phase only (0.85 +/ 0.1 versus 0.68 +/- 0.1). In the late follicular phase and during the entire luteal phase, the mean resistance index did not differ between the study and control groups. CONCLUSIONS: The observed data suggest that standard HRT in women with premature ovarian failure enables restoration of endometrial blood flow to normal. This may imply uterine receptivity for oocyte donation. PMID- 7851586 TI - The effect of endometriosis, its stage and activity, and of autoantibodies on in vitro fertilization and embryo transfer success rates. AB - OBJECTIVES: To analyze IVF cycle parameters, including pregnancy rates (PR), in women with and without endometriosis and to evaluate the effect of the stage and activity of endometriosis and of autoantibodies. DESIGN: A retrospective analysis of 237 consecutive IVF cycles (193 patients), 119 in women with and 118 without endometriosis. The endometriosis group was further subdivided according to the stage and activity of the disease and autoantibody positivity. SETTING: Hospital based and freestanding IVF programs with the same IVF team. PATIENTS: One hundred ninety-three women of reproductive age undergoing IVF; 84 had prior diagnosis of endometriosis, and 109 had other indications for IVF. Within the endometriosis group, 40 did and 44 did not have evidence of active disease. Autoantibodies were measured in 50 patients. INTERVENTIONS: The IVF protocol was standard with GnRH agonist administered from the midluteal phase of the preceding cycle. Variables included the method of ET and the use of corticosteroids. MAIN OUTCOME MEASURES: Number of follicles produced, number of eggs retrieved, fertilization rates, number of embryos transferred, and PR per transfer. RESULTS: There was no difference between groups in the response to stimulation, number of oocytes retrieved, number fertilized, and number cleaved. The overall PR was 27% per transfer; it was similar in women with and without endometriosis (29% and 25%, respectively). There was also no difference in PR according to the stage or activity of the disease. However, PR in autoantibody-positive and -negative patients were significantly different (22.9% and 45.7%, respectively). Among autoantibody-positive patients treated with corticosteroids, 8 of 10 conceived. CONCLUSIONS: This study confirms previous reports that IVF success rates are comparable in women with and without endometriosis regardless of the activity and stage of the disease. However, our study also indicates that autoantibodies may affect adversely implantation of embryos and that this effect can be overcome by administration of corticosteroids. PMID- 7851587 TI - Elevated luteinizing hormone on the day of human chorionic gonadotropin administration does not reduce cycle fecundity in a low-dose flare-up in vitro fertilization protocol. AB - OBJECTIVE: To determine if elevated LH at the time of hCG administration occurs and adversely affects success in a low-dose gonadotropin-releasing hormone analogue (GnRH-a) flare-up protocol in hMG-stimulated IVF cycles. DESIGN: Pearson correlation matrix analysis of hormonal, gamete, and clinical data derived from 203 consecutive IVF cycles was performed. All patients were treated with low-dose GnRH-a (250 micrograms SC leuprolide acetate) and hMG. In 203 consecutive IVF cases, serum was obtained on the day of hCG administration and assayed for E2, LH, and P. These data were correlated with peak E2, number of follicles, oocytes, embryos, and conceptions. Additionally, patients with elevated LH were compared with the nonelevated LH group. RESULTS: Twenty six women had LH > 35 mIU/mL (mean +/- SEM; 51.1 +/- 1.9) and five pregnancies (cycle fecundity 19.2% per retrieval). One hundred seventy-seven patients had LH < 35 mIU/mL (16.3 +/- 0.5) and 25 pregnancies (cycle fecundity 14.1%). There were no differences in the mean P (1.0 +/- 0.1 ng/mL, conversion factor to SI unit, 3.81) and E2 (1,672 +/- 144 pg/mL, conversion factor to SI unit, 3.671) of the former group compared with the P (1.1 +/- 0.07 ng/mL) and E2 (1,456 +/- 69 pg/mL) of the latter group. There was no correlation with the number of follicles, oocytes, embryos, pregnancies, E2, or P to LH concentration (rmax = 0.132). CONCLUSION: In a low-dose, GnRH suppression, IVF induction protocol, elevated LH occurs in a small subset (13%) of women at the time of hCG administration. This event does not appear to alter cycle fecundity nor induce premature luteinization. PMID- 7851588 TI - Hyperestrogenism induced by menotropins alone or in conjunction with luprolide acetate in in vitro fertilization cycles: the impact on hemostasis. AB - OBJECTIVE: To evaluate coagulation parameters during IVF cycles with elevated E2. DESIGN: Prospective clinical study. SETTING: Human volunteers in an IVF clinic. PATIENTS: Infertile women undergoing IVF procedures. INTERVENTIONS: Coagulation factors were measured in blood along with E2 and P after singular hMG or leuprolide acetate (LA) plus hMG up to 14 days after hCG. MAIN OUTCOME MEASURES: Plasma coagulation factors. RESULTS: Some coagulation factors were statistically but not clinically elevated after LA-hMG-induced hyperestrogenism. For the most part, this was not correlated with E2. CONCLUSION: This study suggests that endogenous E2 increases due to fertility drugs cause a molecular activation of some coagulation factors, which do not result in an increased thrombosis. PMID- 7851589 TI - Low-dose glucocorticoids after in vitro fertilization and embryo transfer have no significant effect on pregnancy rate. AB - OBJECTIVE: To determine the effect on pregnancy rate (PR) of low-dose glucocorticoid treatment in cycles without micromanipulation. DESIGN: Randomized, prospective, double-blinded, placebo-controlled trial. SETTING: One university based tertiary infertility center and two private infertility centers. PATIENTS: All patients receiving standard stimulation IVF-ET or transfer of cryopreserved embryos at the participating facilities from January to September 1993 were asked to participate in this study. Patients having micromanipulation were excluded from this study. INTERVENTIONS: Participating patients were randomized to either 16 mg oral 6-alpha-methylprednisolone for four evenings starting the evening of retrieval or the evening before thawing cryopreserved embryos or to placebo administered in an identical fashion. Both groups were treated with 250 mg oral tetracycline four times per day starting with initiation of the study medication and continuing for 4 days. Cryopreservation and stimulation cycles were managed according to pre-established protocols for all patients. A clinical pregnancy was confirmed by an appropriately rising hCG titer and a gestational sac on ultrasound. RESULTS: A total of 206 stimulation patients and 61 cryopreservation patients were randomized and had an ET. Patient characteristics were similar between groups. The clinical pregnancy and implantation rates between placebo and glucocorticoid groups were 35.9% versus 40.8% and 12.8% versus 11.7% for stimulation cycles and 30.3% versus 25% and 9.9% versus 7.4% for cryopreservation cycles, respectively. None of these differences were statistically significant. CONCLUSIONS: Glucocorticoid plus antibiotic treatment at these doses for transfers of nonmicromanipulated embryos does not appear to have a significant effect on pregnancy or implantation rates. PMID- 7851590 TI - Tubal versus uterine transfer of cryopreserved embryos: a prospective randomized trial. AB - OBJECTIVE: To compare pregnancy rates after fallopian tubal and uterine transfer of cryopreserved embryos. DESIGN: Prospective randomized trial with assignment to treatment groups by a random number table. SETTING: University of Iowa Hospitals and Clinics, a tertiary care academic institution. PATIENTS: Forty patients with patent fallopian tubes and at least three cryopreserved embryos. INTERVENTIONS: Cryopreserved embryos were thawed and transferred to the fallopian tube by laparoscopy or to the uterus by a transcervical catheter. MAIN OUTCOME MEASURES: Clinical and ongoing pregnancy rates. RESULTS: Tubal transfer of cryopreserved embryos resulted in statistically higher clinical (68% versus 24%) and ongoing pregnancy rates (58% versus 19%) when compared with uterine transfer. CONCLUSIONS: Tubal transfer of cryopreserved embryos is highly effective and offers an improved pregnancy rate when compared with uterine transfer of embryos. This method of transfer should be considered in patients with patent fallopian tubes and at least three cryopreserved embryos. PMID- 7851591 TI - High levels of sperm-associated antibodies impair human spermoolemma interaction after subzonal insemination. AB - OBJECTIVE: To investigate the impact of sperm-associated antibodies in the fertilization process beyond the zona pellucida in human oocytes. DESIGN: Subzonal insemination (SUZI) was performed with antibody-coated spermatozoa from patients with autoimmune infertility. Sperm parameters and antibody binding were analyzed after Percoll selection and were compared with SUZI outcome. PATIENTS: Patients (n = 29) with an immunobead test higher than 60% for immunoglobulin (Ig)G, IgA, or both classes were included in the study (38 attempts). Twenty-six patients had previous IVF failures, and the semen characteristics for three were unsuitable for IVF. RESULTS: Diploid fertilization occurred in 52.6% of cycles and 16.0% of oocytes (n = 263). The fertilization rate was inversely correlated to the proportion of spermatozoa coated with IgG in the Percoll-selected sperm suspension. Three of the 16 attempts in which > 90% of the spermatozoa were coated with IgG resulted in a low diploid rate of 4.1%. Fertilization was obtained in 18 of the 22 attempts in which < 90% of spermatozoa were IgG coated, with a diploid fertilization rate of 22.8%. Association of both classes of antibodies (IgG and IgA) further impaired the fertilization rate. Twenty ETs gave four pregnancies: one biochemical, one ongoing, and two giving birth to healty babies (1 singleton and 2 twins). CONCLUSIONS: Subzonal insemination is a potential solution for achieving fertilization in cases of IVF failure because of sperm autoimmunity. However, IgG inhibits in a dose-dependent manner the fusion of gametes' membranes. Though the level of IgA antibodies does not appear as critical as that of IgG antibodies, association of both classes of Igs impairs the probability of fertilization. PMID- 7851592 TI - Use of postseparation sperm parameters to determine the method of choice for sperm preparation for assisted reproductive technology. AB - OBJECTIVE: To evaluate strict sperm morphology after preparation of semen specimens using three different sperm separation techniques, since strict morphology correlates well with IVF. DESIGN: Semen from 30 men were analyzed before and after sperm separation using mini-Percoll gradient, direct swim-up, and SpermPrep filtration column (ZBL, Inc., Lexington, KY) methods. SETTING: Assisted Reproductive Technology laboratory at Sinai Hospital of Baltimore. MAIN OUTCOME MEASURES: Primary end points measured were percent morphologically normal sperm and percent improvement in sperm morphology, using Kruger strict criteria. Secondary factors determined were percent motility, improvement in motility, hypoosmotic swelling, improvement in hypoosmotic swelling, and 24- and 48-hour sperm survival under simulated IVF conditions. RESULTS: Mini-Percoll produced specimens with significantly greater normal sperm morphology, morphology improvement, motility, hypoosmotic swelling, and survival than obtained with the other two separation methods. For 25 of 30 specimens, mini-Percoll yielded the greatest number of morphologically normal, motile sperm that survived for 24 hours. In four instances, mini-Percoll was associated with an increased percentage of acrosomal abnormalities despite an overall improvement in morphology. Hypoosmotic swelling scores were lower in two subjects after mini Percoll sperm separation and in three subjects for each of the other methods. CONCLUSIONS: Data suggest that mini-Percoll is superior to swim-up or SpermPrep for producing specimens with enhanced morphology, motility, and in vitro survival. However, no single separation technique is always superior, and methodology may induce damage to the acrosome or sperm membranes. Sperm specimens should be evaluated individually to determine the best separation method before actual ART cycles. The technique that yields the most morphologically normal, motile sperm that survive in culture should be used for ART procedures. PMID- 7851593 TI - Relevance of acrosome function in the evaluation of semen in vitro fertilizing ability. AB - OBJECTIVES: To determine whether or not acrosome evaluation can enhance the prediction of IVF results when associated to conventional semen parameters. DESIGN: Acrosome reaction, sperm concentration, motility, and morphology were recorded in 131 semen samples from patients undergoing an IVF attempt. MAIN OUTCOME MEASURES: Spontaneous acrosome loss after a 24-hour incubation in B2 medium and after induction by calcium ionophore A23187 and phorbol ester, phorbol 12-myristate 13-acetate 4-O-methyl ether (TPA). RESULTS: Statistically significant differences between fertilization failures and successes were found for concentration, viability, spontaneous and induced acrosome reaction, and most parameters of motility and morphology. However, none of the parameters could predict > 64% of IVF results when studied alone. A progressive discriminant analysis allowed to predict up to 83% of IVF results, by classifying sperms through their normal forms, rapid motility, spontaneous acrosome loss, enlarged heads, multiflagellar forms, vitality, linear motility, and acrosome response to TPA. The other parameters, including concentration and response to calcium ionophore, had no additive value. CONCLUSION: The study of acrosome function, through spontaneous acrosome loss and response to TPA, is of great interest in clinical practice when associated to some parameters of motility and morphology. However, it appears that response to calcium ionophore, one of the most studied parameters, is of poor practical interest. PMID- 7851594 TI - Levels of CA-19.9, CA-125, and CA-195 in seminal plasma and in vitro fertilization rates. AB - OBJECTIVE: To assess the relationship between carbohydrate tumor markers in seminal plasma and fertilization rates in IVF cycles. DESIGN: Prospective study. SETTING: Academic tertiary hospital. PATIENTS: Forty-six consecutive couples subjected to IVF in which at least one oocyte was obtained. MAIN OUTCOME MEASURES: Determination of CA-19.9, CA-125, and CA-195 in seminal plasma 1 week before IVF. RESULTS: CA-125 was higher in the group without fertilization (321 +/ 198 U/mL, mean +/- SD) than in the group in which at least one oocyte was fertilized (155 +/- 165 U/mL), whereas CA-19.9 and CA-195 were similar in both groups. However, at the cutoff 66%, lower values of CA-19.9 were found in the fertilization group rate < 66% (707 +/- 1,217 versus 1,069 +/- 1,084) and of CA 195 (67 +/- 44 versus 218 +/- 274). No correlation was found between tumor marker levels and fertilization rates. CONCLUSION: CA-125 seems to be an indicator of sperm fertilization capacity, whereas the importance of CA-195 and CA-19.9 will require further studies. PMID- 7851595 TI - Sperm morphology analysis (strict criteria) in male infertility is not a prognostic factor in intrauterine insemination with husband's sperm. AB - OBJECTIVE: To assess the prognostic value of strict sperm morphology analysis in intrauterine insemination with husband's sperm (IUI) cycles performed because of male infertility. DESIGN: Prospective study. SETTING: Academic tertiary hospital. PATIENTS: Seventy-four consecutive couples subjected to 271 IUI cycles because of male infertility. MAIN OUTCOME MEASURE: Strict morphology analysis 1 month before the beginning of IUI following the criteria of Kruger et al. RESULTS: Pregnancy and no pregnancy couples were similar regarding strict normal forms (2.85% +/- 2.07% versus 3.13% +/- 2.63%), slightly amorphous forms, and the morphology index (11.79 +/- 6.06 versus 12.04 +/- 7.13). Pregnancy rates (PRs) were similar when normal forms were <4% (39.1%) or > 4% (35.7%). The PR, although higher in the group with morphology index > 10% (41.4%) than in the group < 10% (33.3%), lacked statistical significance. In pure male infertility group, mean values of morphology were similar in pregnancy and nonpregnancy group. A not significant trend was detected toward higher PRs in morphology index > 10% (50.0%) than in the group < 10% (33.3%). CONCLUSION: Strict morphology analysis 1 month before the beginning of IUI is not a useful prognostic factor in IUI performed because of male infertility. PMID- 7851596 TI - Clinical relevance of sperm morphology assessment using strict criteria and relationship with sperm-mucus interaction in vivo and in vitro. AB - OBJECTIVE: To determine the relationship of the differentiated morphological pattern of semen samples according to strict criteria and sperm-mucus interaction in vivo and in vitro. PATIENTS: One hundred sixty-three randomly chosen couples with long-standing infertility (median duration of infertility 4 years, range 1 to 19 years). SETTING: Outpatient clinic of the fertility unit at the Women's University Hospital of the University of Heidelberg, Heidelberg, Germany. MAIN OUTCOME MEASURES: Sperm morphology assessment using strict criteria (Tygerberg or Norfolk classification) parallel to standard methods of sperm analysis: Evaluation of the cervical factor of patients' female partners, including a microbial screening of genital secretions of both partners; Examination of sperm migration ability in vivo under hormonally controlled conditions for the cervical mucus (CM) quality and in vitro with the crossed sperm-CM penetration test performed with CM of patients' partners, as well as with CM and spermatozoa of donors; Determination of the selection capacity of CM with regard to sperm morphology by means of a biological model; Prospective analysis of the differentiated morphological pattern with respect to couples' subsequent fertility within 6 months. RESULTS: Using stict criteria, amorphous sperm heads were the most frequently found sperm anomaly (severely amorphous forms: median, 28%; range, 4% to 62%). The morphology index offered a median of 45% (range, 7% to 80%). Results correlated significantly with routine sperm analysis, including standard morphology. The morphological pattern differed significantly in samples offering adequate or inadequate ability to penetrate CM in the standardized sperm CM penetration test or in the postcoital test, with the percent of severely amorphous heads as the most important parameter. Neck and tail defects did not play an important role. During passage of mucus columns in vitro, the rate of pathological spermatozoal forms was reduced significantly, from a median of 65% to a median of 38%. Better functional capacity of spermatozoa with normal head morphology also was reflected by a significantly higher pregnancy rate under natural conditions of conception. CONCLUSIONS: Sperm morphological properties, determined with strict criteria, are important factors for sperm ability to penetrate the mucus barrier at the uterine cervix before reaching the site of fertilization, but sperm morphology is only one among other parameters determining the complex phenomenon of sperm-mucus interaction. PMID- 7851597 TI - Acrobeads test: a new diagnostic test for assessment of the fertilizing capacity of human spermatozoa. AB - OBJECTIVE: To determine the effectiveness of the Acrobeads test for predicting the outcome of IVF. DESIGN: Human spermatozoa express the CD46 molecule (membrane cofactor protein) on their heads after the acrosome reaction. CD46-positive spermatozoa formed a sperm-bead complex with immunobeads coated with anti-CD46 monoclonal antibody. In the Acrobeads test, fertilizing capacity was determined by assessing sperm-bead agglutination. SETTING: Department of Obstetrics and Gynecology, Osaka University Hospital. PARTICIPANTS: Thirty-seven donors of proven fertility and 88 male partners of infertile couples. MAIN OUTCOME MEASURES: We carried out the Acrobeads test and a sperm penetration assay (SPA) using zona-free hamster oocytes within 3 months before IVF and we then analyzed the results in relation to IVF outcome. RESULTS: The sensitivity of the Acrobeads test and SPA was 100% and 88%, respectively, whereas the specificity was 43% and 52%, respectively. The negative predictive value of the Acro-beads test was 100%, whereas that of the SPA was 73%. These results indicate that there was no significant difference between these two tests in terms of predicting IVF outcome. CONCLUSION: We suggested that the Acrobeads test be used to evaluate the fertilizing capacity of human spermatozoa because we should avoid using the SPA to prevent cruelty to animals. PMID- 7851598 TI - Fertility in cases of hypergonadotropic azoospermia. AB - OBJECTIVE: To review the outcome of reconstructive microsurgery in men with hypergonadotropic azoospermia. DESIGN: A retrospective study on patients with hypergonadotropic azoospermia who underwent scrotal exploration and bypass microsurgery. SETTING: Male infertility microsurgery clinic affiliated with a tertiary university hospital. PATIENTS: Thirty-one hypergonadotropic azoospermic men with evidence of spermatogenesis on testicular biopsy. INTERVENTIONS: Microsurgical exploration of the testes, operative sperm aspiration, and bypass procedures: vasoepididymostomy or vasovasostomy. MAIN OUTCOME MEASURES: Intraoperative aspirated sperm, postoperative ejaculated sperm, proof of fertilizing ability (fertilizations), and pregnancies. RESULTS: Sperm were aspirated intraoperatively in all cases and were detected in postoperative ejaculations in 87%. Of the 14 patients with long-term follow-up data, 6 achieved pregnancies (8 children), and 3 more demonstrated the capacity for fertilization at IVF. CONCLUSIONS: The observation of a high serum FSH in men with azoospermia does not rule out the possibility of obstruction and the capacity for fertility. Caution should be exercised particularly if unilateral testicular atrophy is present. A testicular biopsy should be performed to detect possible spermatogenesis and, if present, then a microsurgical bypass can lead to a successful pregnancy. PMID- 7851599 TI - Increased reactive oxygen species formation in semen of patients with spinal cord injury. AB - OBJECTIVES: To evaluate reactive oxygen species production of semen samples and Percoll-washed spermatozoa from men with spinal cord injuries and to determine if there is a relationship between this reactive oxygen species production and sperm motility. PARTICIPANTS: Semen samples from healthy volunteers and infertile patients were collected by masturbation. INTERVENTIONS: Semen samples from men with a spinal cord injury were obtained by electroejaculation or by masturbation after treatment with physostigmine. MAIN OUTCOME MEASUREMENTS: Motility was measured using the CellSoft computer-assisted analysis system (Cryo Resources Ltd., Montgomery, NY). Luminol-amplified chemiluminescence was used to measure reactive oxygen species production. RESULTS: Semen samples and Percoll-washed spermatozoa from men with a spinal cord injury produced reactive oxygen species at much higher frequency and levels than equivalent preparations from infertile men or healthy volunteers. There was an inverse relationship between the percentage of motility and reactive oxygen species production in Percoll-washed spermatozoa from men with a spinal cord injury. CONCLUSION: Semen samples and Percoll-washed spermatozoa from men with spinal cord injury produce high levels of reactive oxygen species that may be related to the low sperm motility and infertility observed in these men. PMID- 7851600 TI - The effect of three hormone replacement regimens on bone density in the aged ovariectomized rat. AB - OBJECTIVE: To investigate the effects of estrogen (E) alone or with cyclic, continuous, or interrupted P regimens on bone density in an aged rat model. DESIGN: Randomized controlled trial. ANIMALS: Twenty 12-month-old female Sprague Dawley rats were sham operated (intact control) and 100 were ovariectomized (OVX). INTERVENTION: Four groups of 20 OVX rats were implanted with silastic capsules containing 5% E2 (wt/wt) in cholesterol. All rats in the intact control (group 1), OVX (group 2), and the first of the OVX plus E groups (group 3) were injected subcutaneously daily for 6 months with corn oil (vehicle). Three other groups of rats with E capsules received daily injections of norethindrone in corn oil, according to the following dosage schedules: 6 micrograms norethindrone/rat per day for 2 of every 4 weeks (cyclic; group 4); 3 micrograms norethindrone/rat per day every day (continuous; group 5); or 3 micrograms norethindrone/rat per day for 3 of every 6 days (interrupted; group 6). MAIN OUTCOME MEASURES: Bone mineral content (BMC) and bone mineral density (BMD) in the femur and vertebrae were measured by dual-energy roentgenogram absorptiometry. RESULTS: The OVX rats (group 2) receiving corn oil alone had the lowest BMD. Intact controls (group 1), E plus cyclic P (group 4), and E and interrupted P (group 6) were all similar and had significantly greater bone density in the vertebrae than the OVX controls. In contrast, vertebral BMD with E alone (group 3) and continuous E and P (group 5) was not significantly different from the OVX group. Femur BMD was significantly lower in the OVX group compared with the other five groups, which did not differ significantly from each other. CONCLUSION: In this experimental model, compared with OVX controls, combined hormone replacement therapy with E and cyclic or interrupted P resulted in the best vertebral BMD whereas continuous E and P resulted in the worst BMD. In the femurs, E alone and E plus P had equal effects on BMD. PMID- 7851601 TI - A simple approach to intracytoplasmic sperm injection. AB - OBJECTIVE: To describe a simple injection apparatus and method for performing intracytoplasmic sperm injection in a clinical IVF program. DESIGN: A prospective clinical trial of intracytoplasmic sperm injection. SETTING: A private office based fertility program. PATIENTS: Five couples undergoing IVF-ET with intracytoplasmic sperm injection as a treatment for male factor infertility. INTERVENTIONS: Intracytoplasmic sperm injection was performed at room temperature (23.5 to 24.5 degrees C) in a simple zwitterion-buffered medium. MAIN OUTCOME MEASURES: Fertilization rates, cleavage rates, clinical pregnancy rates, implantation rates. RESULTS: Intracytoplasmic sperm injection was performed on 44 fresh oocytes from five patients. Twenty-three oocytes fertilized (52.3%) and 22 zygotes cleaved (95.7%). Three of five patients became pregnant (60%), resulting in the live birth of one normal male infant, one continuing singleton pregnancy, and one continuing twin gestation (46XX, 46XY). The implantation rate was 23.5%. CONCLUSION: Intracytoplasmic sperm injection can be performed successfully in a simple medium at room temperature using commercially available microtools. PMID- 7851602 TI - In vitro retrieval of epididymal sperm: a new approach to achievement of pregnancy for post-testicular azoospermia. AB - OBJECTIVE: To determine the efficacy of in vitro retrieval of epididymal sperm for pregnancy induction for obstructive azoospermia patients. DESIGN: Patients were divided into three groups as follows: [1] ductal obstruction with previous epivasostomy (group I); [2] ductal obstruction with previous epididymitis (group II); and [3] ductal obstruction without previous epivasostomy or epididymitis (group III). SETTING: A university teaching hospital. PATIENTS: Twenty infertile males with obstructive azoospermia. INTERVENTIONS: Epididymides were detached surgically just after harvest of oocytes from corresponding wives and severed into three pieces (caput, corpus, and cauda). Each piece was dissected and squeezed in Ham's F-10 medium to retrieve the sperm. After completion of sperm preparation, IVF of their wives' oocytes and zygote intrafallopian transfer followed. RESULTS: Overall pregnancy rate by in vitro retrieval of epididymal sperm was 35% (7 of 20). The rate for group I was 0%, or 0 of 6; for group II the rate was 0%, or 0 of 3; and for group III it was 63.6%, or 7 of 11. CONCLUSIONS: In vitro retrieval of epididymal sperm can be a new method for inducing pregnancy in surgically incorrectable obstructive azoospermia. PMID- 7851603 TI - The life span of sperm motility and pattern in cumulus coculture. AB - OBJECTIVE: To study the effect of cumulus cell coculture on human sperm motility, life span, and patterns. DESIGN: Controlled prospective study of 50 normal semen samples. Sperm motility and forward grade was observed in droplets of Ham's F-10 media with cumulus cell coculture and compared with sperm in droplets of Ham's F 10 only. SETTING: The Egyptian IVF-ET Center. MAIN OUTCOME MEASURES: Sperm motility, life span, and forward progressive pattern. RESULTS: The time course of loss of sperm motility in cumulus coculture was significantly slower than without cumulus. Also, the percentage of motile sperm with linear progressive motility of grade 4,3 was significantly higher in cumulus coculture. CONCLUSION: Cumulus cell coculture has a positive effect on prolongation of sperm motility life span and its forward progression. PMID- 7851604 TI - Profound luteinizing hormone suppression after stopping the gonadotropin releasing hormone-agonist leuprolide acetate. AB - OBJECTIVE: To compare levels of serum LH during continued use of leuprolide acetate (LA) with levels during the first week after discontinuing LA. DESIGN: Prospective controlled study. SETTING: Clinical assisted conception program. PATIENTS: Women undergoing controlled ovarian stimulation for assisted conception were randomized to receive LA according to "short" or "ultrashort" protocols. The alternative protocol was used then in a second cycle. Each patient was thus her own control. MAIN OUTCOME MEASURES: Serum LH over time. RESULTS: When LA was stopped after 5 days of administration, LH levels fell profoundly when compared with levels when LA was continued. CONCLUSION: Loss of LH after stopping LA is likely to be clinically important in ovarian stimulation regimens that use pure FSH with LA in ultrashort protocols. The fall in LH lasts at least 1 week and may be explainable by persistent suppression of endogenous GnRH by LA during this time. PMID- 7851605 TI - Tubal ostium membranes and their relation to infertility. AB - OBJECTIVE: To define the clinical significance of tubal ostium membranes. DESIGN: Retrospective multivariate stepwise logistic regression analysis. SETTING: Algemene Kliniek Sint--Jan, Brussels, Belgium. PATIENTS: Three thousand forty-six hysteroscopies on 2979 patients, including 172 with infertility, over a 9-year period. MAIN OUTCOME MEASURES: Presence of tubal ostium membranes, age, infertility, endometrial thickness, and hormonal environment. RESULTS: Tubal ostial membranes were present in 74 (2.5%) patients: they were unilateral in 30 (42.1%) and bilateral in 44 (57.9%). Their presence was independent from hormonal state and from endometrial thickness. The incidence of ostial membranes was significantly higher (9.9%) in patients referred for infertility for unilateral (3.5%) as well as for bilateral presence (6.4%). Only the bilateral form was age dependent. CONCLUSIONS: Tubal ostium membranes may be one of the unknown limiting factors affecting female fertility and thus reducing the monthly fecundity rate. The present data suggest that bilateral and unilateral tubal ostium membranes may have a different clinical significance. The unilateral form is unrelated to age, hormonal state, or endometrial thickness and can be congenital. This form is most clearly related to infertility. The bilateral form is less related to infertility, is found in women of older age, and can be acquired. Further prospective analysis is needed to clarify the pathogenesis and pathophysiology of tubal ostium membranes. Tubal ostium membranes should routinely be looked for when performing a hysteroscopic examination in infertile women. PMID- 7851606 TI - The role of follicle-stimulating hormone in the depletion of follicular reserve: menopause in a woman with hypogonadotropic hypoestrogenic amenorrhea: a case report. AB - OBJECTIVE: To investigate the role of FSH in the depletion of follicular reserve in a human being. DESIGN: Prospective evaluation of a very rare case. SETTING: Academic research environment. PATIENT: A 43-year-old woman with primary hypogonadotropic hypoestrogenic amenorrhea, with very low levels of plasma FSH throughout her life. INTERVENTIONS: Pulsatile GnRH was administered IV at the dose of 4 micrograms every 90 minutes for 20 days. Blood samples were collected every 3 to 4 days. MAIN OUTCOME MEASURES: Plasma levels of E2, FSH, and LH. RESULTS: During the 20 days of treatment there was no increase in E2 plasma levels. On the contrary, FSH and LH levels began to rise after 3 days and reached postmenopausal levels within 20 days. CONCLUSIONS: Depletion of follicular reserve may occur also when the levels of FSH are very low throughout a woman's life. Thus FSH seems only able to rescue follicles from atresia without interfering with the onset of menopause. PMID- 7851607 TI - Massive deep vein thrombosis in a patient with antithrombin III deficiency undergoing ovarian stimulation for in vitro fertilization. AB - OBJECTIVE: To present the first report of a thromboembolic complication in early pregnancy after ovarian hyperstimulation for IVF in a patient with AT III deficiency who was treated successfully and subsequently delivered a healthy male infant at 32 weeks of gestation. DESIGN: Case report. SETTING: Hospital-based clinic for reproductive medicine. PATIENT: A 28-year-old woman who consulted our IVF clinic with a 3.5-year history of primary infertility. INTERVENTIONS: Intravenous heparin therapy. RESULTS: The patient responded adequately to heparin therapy and was discharged home on SC heparin. A primary cesarean section was performed at 32 weeks of gestation because of poor fetal growth and transverse lie. CONCLUSIONS: We stress the importance of obtaining a thorough personal and family history before initiation of ovarian hyperstimulation. Measuring activity of AT III, protein C, and protein S in patients with a suspicious history of thromboembolic episodes occurring at an early age may lead to the implementation of appropriate prophylactic measures, preventing potentially life-threatening complications. PMID- 7851608 TI - A tenaculum improves ovarian accessibility during difficult transvaginal follicular aspiration: a novel but simple technique. AB - OBJECTIVE: To evaluate the use of a cervical tenaculum to improve ovarian access during oocyte retrieval. DESIGN: Description of a new technique. SETTING: Normal human volunteer in an academic research environment. PATIENT: An infertile woman undergoing controlled ovarian hyperstimulation and ultrasound-guided oocyte retrieval. Access to her right ovary was obstructed by her uterus. INTERVENTIONS: During the retrieval procedure, a tenaculum was applied to the patient's cervix and downward traction was applied. RESULTS: The ovary became closer to the vaginal wall. CONCLUSION: Applying downward cervical traction with a tenaculum can bring an ovary closer to the vaginal wall, avoiding possible uterine injury and facilitating oocyte collection. PMID- 7851609 TI - Efficacy of flutamide versus spironolactone. PMID- 7851610 TI - Condoms for the collection of semen samples. PMID- 7851611 TI - Oocytes--will travel? PMID- 7851612 TI - Discriminatory zone for human chorionic gonadotropin--level of certainty? PMID- 7851613 TI - Metabolic activity of cultured skin grafts cryopreserved in different forms. AB - Cultured epidermal cells in the form of coherent sheets have been used for the treatment of skin defects. Metabolic activity of fresh and in liquid nitrogen cryopreserved keratinocyte suspensions and three forms of coherent cultured skin sheets were compared with the aim to find the most appropriate form of skin cultures for cryopreservation. Keratinocytes cultured from cryopreserved suspensions formed a confluent layer in 8-10 days after thawing, showing 95% activity of the fresh confluent cultures. Cryopreserved cultured epidermal sheets attached to the bottom of the dish as well as recombined human/pig skin (RHPS) reached more than 70% of the metabolic activity of fresh grafts following 24 h regeneration in the incubator after thawing. Cultured epidermal sheets detached from the dish and mounted on tulle grass reached only 28% of the fresh graft metabolic activity under the same conditions. PMID- 7851614 TI - Evidence for teratogenicity of thalidomide using congenic and recombinant inbred rat strains. AB - Teratogenic properties of thalidomide were tested in two systems of laboratory rat strains carrying the mutant lx allele that determines the polydactyly-luxate syndrome. In agreement with our previous experiments, we have confirmed that the response of foetuses basically depends on their genotype. Foetuses of LEW/BN, +/+ genotype remained unaffected following 500 or 3 x 500 mg/kg thalidomide doses (43 and 56 foetuses, respectively). In LEW/BN, +/lx foetuses these doses elicited 24% and 87% hind feet polydactyly (14/59 and 53/61 foetuses, respectively), which was highly significant when compared with 84 vehiculum-treated and 235 untreated controls (P < 0.001). However, in 48 SHR/RI 2, lx/lx foetuses both pairs of limbs were affected in an opposite way after the 500 mg/kg thalidomide dose: hind feet oligodactyly (94/96 limbs) and increased front feet polydactyly occurred (in comparison with 70 controls, P < 0.001). The mutant lx allele as well as modifying genes are involved in the response to thalidomide. PMID- 7851615 TI - Chromosome 11 participation in acute lymphoblastic leukaemia in Sprague-Dawley rats. AB - Five cases of spontaneous acute lymphoblastic leukaemias (ALL) of Sprague-Dawley (SD) inbred rats have been studied cytogenetically. Chromosome studies were performed on direct preparations of the lymphomas using common cytogenetic methods. For detailed karyology, G-banded preparations were used. The chromosome numbers of metaphase cells in all leukaemias were near diploidy, the majority of metaphases being pseudodiploid with 1-2 stable marker chromosomes. The most frequent change involved chromosome 11, where the translocation form of trisomy 11 or 11q+ aberration was observed. Chromosome 11 abnormalities were found in all five leukaemias studied, suggesting to be a nonrandom change. 11 q11-q12 is supposed to be the critical region involved in the genesis or progression of SD ALL. These results are in agreement with our previous observations in nine cases of SD ALL (Sladka et al., 1988). PMID- 7851616 TI - Immunomodulatory properties of 9-(2-phosphonomethoxyethyl)-adenine (PMEA). AB - PMEA was found to influence the immune system of the mouse and rat in vivo in different ways. PMEA administered after injection of parental splenocytes to F1 recipients reduced the development of local graft-versus-host reaction (GVHR). However, PMEA treatment of donors of splenocytes had no influence on GVHR. Modifications in the immune system triggered by PMEA were confirmed in the rat model by evaluation of subsets of white blood cells isolated from peripheral blood by a set of monoclonal antibodies. Enhanced formation of nitric oxide (NO) was found in both unconditioned and LPS-stimulated macrophage cultures on day 14 of the drug treatment of rats. PMID- 7851617 TI - Mathematical modelling of immunotherapy in HIV infection. AB - The effect of active or passive immunotherapy on HIV infection was simulated using a mathematical model of CD4+ lymphocyte depletion. Permanently effective active immunotherapy increased CD4+ lymphocyte counts to a steady-state level depending on the intensity of the therapy. Active HIV immunization effective for one or more years increased CD4+ lymphocyte counts during the treatment period and prolonged survival substantially; this prolongation exceeded the time interval of therapy duration. Intensive passive immunotherapy by anti-HIV antibodies led to a temporary increase of CD4+ lymphocyte numbers and an apparent prolongation of survival. PMID- 7851618 TI - Nuclear and nucleolar kinetics in multinucleate osteoclasts in the chick development and after the hormonal treatment. AB - This study demonstrates the changes in the number of nuclei, number of nucleolar silver-stained granules, and the incidence of the morphological types of nucleoli in the chick osteoclast ontogeny and after the parathormone and calcitonin treatment. The number of cell nuclei was increased during the ontogeny and after the parathormone treatment. The number of silver-stained nucleolar granules decreased during the ontogeny. Parathormone and calcitonin did not influence the number of silver-stained granules, and an insignificant effect on the number of nuclei was detected after the calcitonin application. The compact nucleoli and/or nucleoli with nucleolonema prevailed in all the investigated developmental stages of the chick. The nucleoli in multinucleate osteoclasts are active from the morphological point of view. A relationship between the nucleolar function and the number of nuclei in one cell could be possible. PMID- 7851619 TI - [A case of unilateral primary adrenal nodular hyperplasia with elevated plasma adrenocorticotropin (ACTH)]. AB - A 57-year-old woman was admitted to our hospital with occipital headache and nausea. She had severe hypertension (192/122mmHg), hypokalemia (2.8mEq/l) and fasting hyperglycemia (127 mg/dl). Further examination revealed elevated plasma ACTH (124pg/ml) and cortisol (26.5 mu g/dl) with a lack of diurnal rhythm. Plasma ACTH or cortisol did not increase by injection of corticotropin releasing hormone (CRH). Rapid ACTH test resulted in an exaggerated response of plasma cortisol. Abdominal MRI scan showed a left adrenal tumor. Since the bilateral adrenal venous blood sampling revealed a significant increase of cortisol on the left, left adrenalectomy was performed. Histological examination of the resected adrenal gland revealed marked cortical hyperplasia. Postoperative investigations revealed that despite a small dose of steroid replacement for only 20 days, plasma ACTH level was decreased for a period of 6 months. Both plasma ACTH and cortisol increased by a CRH injection 38 days after surgery. CRH test during bilateral inferior petrosal sinus sampling indicated that this patient had no functioning pituitary tumor. Although the exact mechanism of high plasma ACTH level in this case was unknown, these findings suggest that any substance secreted from primary adrenal nodular hyperplasia adrenal nodular hyperplasia may stimulate pituitary ACTH production. This is a very rare case of Cushing's syndrome due to unilateral primary adrenal nodular hyperplasia with elevated plasma ACTH. PMID- 7851620 TI - [Studies on the hormone-binding function of thyroid hormone-binding proteins by heat treatment]. AB - Thyroxine-binding globulin (TBG), a major thyroid hormone-binding protein, is denatured by heat and subsequently loses its binding activity. This study aimed to investigate changes in the function of thyroid hormone-binding proteins utilizing a method of heat treatment. The first aim of this study was to examine how the relationship between thyroid hormones and binding proteins changes with heat treatment at 56 degrees C in serum from normal subjects. When approximately half of the native TBG was denatured by heat, the mean percentage of T4 bound to thyroxine-binding prealbumin (TBPA), measured by a single immunoprecipitation method, was increased from 15.3% to 25.7% and the percentage of T4 bound to albumin was increased from 4.7% to 7.5%. Serum free T4 concentration were increased to 166.0 +/- 17.1% (Mean +/- SD) from the basal value. By heating at 58 degrees C, T4 bound to TBPA was denatured, but T4 bound to albumin showed a significant increase, and serum free T4 concentrations were increased to 396.0 +/ 62.1%. Because T4 binding ratios of TBPA and albumin were increased after TBG denaturation, free hormone concentrations did not increase very greatly. The second aim of this study was to examine the properties of TBG in patients with non familial partial deficiency of TBG (NFPD-TBG). When the serum sample of NFPD TBG was heated, the half time of NFPD-TBG was 14.1 +/- 5.5 min, which was significantly shorter than that of normal TBG (45.1 +/- 7.0 min, P < 0.001). Isoelectric focusing (IEF) of NFPD-TBG showed that the pIs were not different from those of normal TBG. When serum from NFPD-TBG was mixed with normal serum, the half time was still shorter than the normal serum samples. The data suggest that the molecular structure of NFPD-TBG is not abnormal, but a certain factor which alters the heat stability of TBG exists in the serum from NFPD-TBG. PMID- 7851621 TI - [Effective treatment with constant subcutaneous infusion of octreotide in a patient with acromegaly associated with diabetic pre-coma and diabetes insipidus]. AB - A 58-year-old woman was admitted to our hospital for impaired consciousness, hyperglycemia and bitemporal hemianopsia. She was diagnosed as having NIDDM one year ago and was treated with diet and glibenclamide (1.25 mg/day) for 6 months. However, she stopped her medical treatment one month ago and then polydipsia and general fatigue were manifested. She was admitted to a hospital five days ago at which time hyperglycemia (405 mg/dl) and anemia (Hb8.0g/dl) were detected. She was transferred to our hospital for control of blood glucose and further examination of bitemporal hemianopsia. She showed typical acromegalic features including enlargement of the nose, lips and tongue, increased heel pad and acral growth. Conscious disturbance was cured by the infusion of saline and the administration of insulin. Endoscopy revealed an active gastric ulcer (A1). Endocrine data disclosed increased GH levels in plasma and urine, whereas plasma IGF-1 levels were low. Plasma GH paradoxically increased following the administration of TRH. A water deprivation test showed an impaired increase in urinary osmolarity, indicating partial central diabetes insipidus (DI). MRI with Gd-contrast revealed a macroadenoma which progressed toward suprasella. She was diagnosed as having acromegaly, partial DI and probable hyperosmolar hyperglycemic nonketotic diabetic pre-coma. Polyuria (5-101/day) due to partial DI was controlled by the administration of DDAVP (10 micrograms/day). The constant subcutaneous administration of octreotide (240 micrograms/day) resulted in normal plasma GH levels and a marked shrinkage of the pituitary tumor. The pituitary tumor was finally removed by the transsphenoidal approach following treatment with octreotide for 4 months. HE staining of the pituitary tumor showed atrophic and acidophilic cells surrounded by hyaloid connective tissue. After the surgery, plasma GH levels were normalized and complications were cured. In conclusion, this is a very rare case of acromegaly associated with diabetic pre coma and partial DI, and effectively treated with constant subcutaneous infusion of octreotide. PMID- 7851622 TI - [A case of malignant pheochromocytoma treated with a combination of cyclophosphamide, vincristine, and dacarbazine (CVD). A review of the Japanese literature of malignant pheochromocytoma treated with a combination of CVD]. AB - A 49-year-old woman had a right adrenalectomy for pheochromocytoma in April 1989. In May 1990 she underwent an operation to remove paraaortic lymph nodes, and the lymph nodes showed pheochromocytoma. Twenty-two months after the first operation, metastases to the left cervical nodes, lung, and liver occurred. Her blood pressure was 172/104 mmHg; fasting plasma glucose (FPG), 342 mg/dl; urinary noradrenaline (NA), more than 2000 micrograms/day; and plasma NA, 17.28 ng/ml. Treatment with the CVD regimen (cyclophosphamide, 750 mg/m2 on day 1; vincristine, 1.4 mg/m2 on day 1; dacarbazine, 600 mg/m2 on days 1 and 2, every 21 days) was begun on February 14, 1991. After 3 cycles of the CVD regimen her blood pressure was 140/82 mmHg; FPG, 157 mg/dl; urinary NA, 917 micrograms/day 1; and plasma NA, 4.54 ng/ml. The size of the metastatic lesions in the liver had decreased. Treatment with the CVD regimen was continued until May 1992. After that she did not go to the hospital for about 2 months. Metastatic lesions progressed gradually and treatment with the CVD regimen was repeated again. She was admitted to the hospital on February 17, 1993 because of appetite loss and nausea. Her blood pressure was 188/94 mmHg; FPG, 197 mg/dl; HbA1c, 9.5%; urinary NA, 18265.3 micrograms/day; and plasma NA, 47.20 ng/ml. She was treated with the CVD regimen in 2 repeated cycles (28th cycle of treatment with the CVD regimen) but there was no effect. She died following hemoptysis on March 15, 1993.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7851623 TI - [Adrenergic receptors and nephrone]. AB - It is well known that the renal nerve plays an important role in the regulation of renal functions such as sodium and water reabsorption in the tubules as well as in the pathogenesis of essential hypertension. The renal sympathetic nerves innervate to the basement membranes of almost all nephron segments. Specific adrenergic receptors and intracellular signal transduction systems are located in these nephron segments. By the recent progress of molecular biological techniques, at least three alpha 1-, three alpha 2- and three beta-adrenergic and five dopaminergic receptors have been identified and characterized. Using micromethods such as microperfusion, micropuncture techniques and the reverse transcription and polymerase chain reaction (RT-PCR) methods applied to the microdissected tubules, more detailed localizations and functions of these adrenergic and dopaminergic receptors are being classified. Future studies in this field may provide further information concerning the physiological and pathophysiological roles of these receptors in the kidney. PMID- 7851624 TI - [A case of isolated ACTH deficiency with dementia]. AB - We encountered a patient with siolated ACTH deficiency accompanying dementia. A 69-year old man was admitted because of abdominal pain. A decrease of serum Na level (114mEq/l) due to increased urinary Na excretion suggested the existence of adrenal insufficiency. While serum cortisol and urinary 17-OHCS, 17-KS excretions were reduced, plasma ACTH level remained below the normal range. Since daily ACTH injections increased both serum cortisol level and urinary 17-OHCS excretion, the patient was diagnosed as having isolated ACTH deficiency. The severity of dementia was measured by using the Hasegawa Dementia Scale. Both cerebral blood flow and metabolism, assessed with Positron Emission Computed Tomography (PET), decreased even after the start of 20mg/day cortril administration. An increase of the cortril supplement dose to 30mg/day attenuated the reduction of cerebral blood flow with the improvement of dementia from score point "1" to "27" (Hasegawa scale). The present case raised the possibility that loss of glucocorticoid may involve the development of dementia, resulting from decreased cerebral blood flow and metabolism. PMID- 7851625 TI - [A five-year follow-up of two different 131I treatment methods for Graves' disease and the factors affecting the outcome]. AB - We employed two different methods of 131I treatment for Graves' disease in 285 patients and compared the results between the two. (We also analyzed the factors affecting the treatment outcome.) A single dose of 131I adjusted to the patients' thyroid weight was administered to 180 patients in group 1, while a relatively lower dose of 131I (approximately 30Gy) was given repeatedly to 105 patients in group 2. A 5-year follow-up showed that in group 1, 34% of the patients were euthyroid, 11% hypothyroid, 11% subclinical hypothyroid and 44% still remained hyperthyroid. In group 2, 43% of the patients were euthyroid, 5% hypothyroid, 35% subclinical hypothyroid and 17% hyperthyroid. The factors affecting the outcome of the treatment in group 1 patients were their thyroid weight, the duration of the disease and TRAb levels. No significant correlation was observed between the efficacy of 131I treatment and the patients' sex, age, 24hr 131I-uptake, effective half life of administered 131I or titers of antithyroid antibodies. We conclude that the repeated low dose administration of 131I provides the best outcome in a 5-year follow-up. However, we suggest that an adjusted dose of 131I in relation to the patients' thyroid weight should be employed to obtain a faster therapeutic response. PMID- 7851626 TI - A compendium of reviews in biochemistry and molecular biology published in the second half of 1993. AB - 1. A compendium of reviews and mini-reviews in Biochemistry and Molecular Biology published in the second half of 1993 is presented. In all 1063 titles are listed from 127 different publications. 2. This compendium presents the references Journal by Journal. Keyword and author cross-reference indexes are not included but are available in the computer database that is the companion to this paper version. The electronic form contains details of reviews published since 1990 as listed in this and earlier compendia. Anyone wishing to receive this database should contact the author: it can be distributed either via Internet or on MS-DOS formulated floppy disks in either Reference Manager or Medline format. Please contact the author for details of the number of pre-formatted floppy disks required. PMID- 7851627 TI - Tyrosine protein kinase inhibition and cancer. AB - The various aspects of the research on tyrosine protein kinase inhibition and its connections with cancer are presented. The emphasis was made on the theoretical low toxic side effects of specific tyrosine protein kinase inhibitors. Particularly, the strategy of finding peptidic substrate-derived inhibitors or modulators is discussed, with an almost complete compendium of the tyrosine protein kinase peptidic substrates published so far. A series of data has been gathered that may serve as a basis for the discovery of selective and specific tyrosine protein kinase inhibitors by screening on molecular and cellular models. The potential of SH2 domain-interfering agents are also presented as a promising route to new anticancer compounds. PMID- 7851628 TI - Biochemistry and molecular biology of drug-metabolizing sulfotransferase. AB - Sulfation is an important conjugation reaction in the metabolism of various xenobiotics and endogenous compounds and is catalyzed by sulfotransferase (ST) present in cytosols. The cloning studies on STs have provided the basis for the understanding of the ST multigene family. STs are classified into hydroxysteroid (or alcohol), aryl (or phenol), estrogen, flavonol and polysaccharide STs and recent developments in the molecular characterization of these isoforms are reviewed. Regulation and localization of ST isoforms in various tissues are characterized at the molecular level by virtue of the specific antibodies and the corresponding cDNA probes. The recent developments are summarized. ST inhibitors are potent tools for the study on ST multiplicity and for the characterization of the enzyme structure. It also appears to be important to understand exogenous and endogenous ST inhibitors in clinical environment. The recent developments are reviewed. PMID- 7851629 TI - Molecular mechanism of RNA phage morphogenesis. AB - Recent progress on the molecular mechanism of RNA phage morphogenesis is described. Functional studies, both in vivo and in vitro, are correlated with the latest structural studies on phages, their capsids and the assembly initiation RNA stem-loop. PMID- 7851630 TI - Cell surface glycoconjugates as modulators of embryo attachment to uterine epithelial cells. AB - Attachment of mammalian embryos to the uterine wall involves the coordinated development of both the embryo and the uterine epithelium to an attachment competent state. This coordination is achieved directly or indirectly through the actions of ovarian steroids. Acquisition of attachment competence is proposed to reflect two processes. The first is the loss of non-adhesive glycoproteins at the cell surface of embryos, e.g. zona pellucida subunits, as well as uterine epithelial cells, e.g. mucin glycoproteins. The second process is the functional expression of complementary adhesion-promoting molecules at these cell surfaces. A series of studies indicates that heparan sulfate proteoglycans and their corresponding binding sites can play an important role in the initial stage of embryo attachment to the uterine surface. PMID- 7851631 TI - Purification of a cytosolic enzyme from human liver with phospholipid hydroperoxide glutathione peroxidase activity. AB - Phospholipid hydroperoxide glutathione peroxidase (PHGPx) is a selenoprotein which inhibits peroxidation of microsomes. The human enzyme, which may play an important role in protecting the cell from oxidative damage, has not been purified or characterized. PHGPx was isolated from human liver using ammonium sulphate fractionation, affinity chromatography on bromosulphophthalein glutathione-agarose, gel filtration on Sephadex G-50, anion exchange chromatography on Mono Q resin and high resolution gel filtration on Superdex 75. The protein was purified about 112,000-fold, and 12 micrograms was obtained from 140 g of human liver with a 9% yield. PHGPx was active on hydrogen peroxide, cumene hydroperoxide, linoleic acid hydroperoxide and phosphatidylcholine hydroperoxide. The molecular weight, as estimated from non-denaturing gel filtration, was 16,100. The turnover number (37 degrees C, pH 7.6) on (beta-(13 hydroperoxy-cis-9, trans-11-octadecadienoyl)-gamma-palmitoyl)-L-alpha phosphatidylcho line was 91 mol mol-1 s-1. As reported for pig PHGPx, activity of the enzyme from human liver on cumene hydroperoxide and on linoleic acid hydroperoxide was inhibited by deoxycholate. In the presence of glutathione, the enzyme was a potent inhibitor of ascorbate/Fe induced lipid peroxidation in microsomes derived from human B lymphoblastic AHH-1 TK +/- CHol cells but not from human liver microsomes. Human cell line microsomes contained no detectable PHGPx activity. However, microsomes prepared from human liver contained 0.009 U/mg of endogenous PHGPx activity, which is 4-5 times the activity required for maximum inhibition of lipid peroxidation when pure PHGPx was added back to human lymphoblastic cell microsomes.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7851632 TI - Alanine aminopeptidase of guinea-pig brain: a broad specificity cytoplasmic enzyme capable of hydrolysing short and intermediate length peptides. AB - Alanine aminopeptidase is reported to be a broad specificity aminopeptidase acting on peptides of different lengths. In this study we wish to define the properties of the activity from guinea-pig brain and compare these properties with previous findings. Alanine amino-peptidase was purified from cytoplasm of guinea-pig brain by a four-step procedure involving chromatography on DE-52, hydroxylapatite, Sephacryl S-200 and DEAE-Sephacryl. Relative molecular mass was determined by chromatography on Sephacryl S-200 column and subunit size determined by SDS-PAGE under denaturing conditions. Cations which reactivate the enzyme were determined with EDTA treated enzyme. Substrate specificity was determined by TLC and kinetic parameters were derived from Lineweaver-Burk plots. A 216-fold purification was achieved by the above procedures. The purified enzyme was found to consist of one polypeptide chain with a relative molecular mass of 104,000. Its activity was inhibited by chelating agents, sulphydryl reactive agents, puromycin, bestatin and amastatin but stimulated over 6-fold by dithiothreitol. Some dipeptides and all tripeptides and longer peptides containing up to 16 amino acids tested were hydrolysed provided neither Glp or Pro occurred at the N-terminus or that Pro did not occur in the penultimate position from the N-terminus. The enzyme preferred bulky non-polar residues at the N-terminal and penultimate positions and was found to hydrolyse three dipeptidyl methyl coumarin amides used in detecting dipeptidyl aminopeptidases. Alanine aminopeptidase is thus a broad specificity amino-peptidase acting on short and intermediate length peptides whose affinity for substrates increases with increasing peptide length. Its properties are well suited to a role in peptide turnover in brain cytoplasm. PMID- 7851633 TI - Pancreatic islet hypertrophy in spontaneous maturity onset obese-diabetic CBA/Ca mice. AB - Mature male CBA/Ca mice develop a spontaneous mild diabetes-obesity syndrome which is characterized by hyperglycaemia, hyperinsulinaemia and insulin resistance, and resembles human Type II diabetes mellitus. Immunocytochemical staining of pancreas sections for insulin showed that the pancreas from mature obese mice possessed significantly enlarged islets compared to those from age matched control (lean) mice. The pancreatic insulin content was significantly greater in 24-week-old obese mice (1.78 +/- 0.14 mU/mg) compared with lean controls (0.92 +/- 0.09 mU/mg). This increase was still apparent at 48 weeks of age. We conclude that, unlike most other rodent models of Type II diabetes, there is no chronic degeneration of beta cells in these mice, so that circulating insulin levels remain high throughout their life. We suggest, therefore, that the male CBA/Ca mouse represents a valuable model for investigating maturity onset diabetes. PMID- 7851634 TI - The phosphodiesterase secreted by prestalk cells is necessary for Dictyostelium morphogenesis. AB - Dictyostelium discoideum secretes a cyclic nucleotide phosphodiesterase to control cAMP levels during development. Three promoters control expression of the gene--one during vegetative growth, one during aggregation, and one which constrains phosphodiesterase synthesis to prestalk cells. In this report we show that the expression of phosphodiesterase (PDE) in prestalk cells is necessary for morphogenesis. A gene that codes for a specific glycoprotein inhibitor of the phosphodiesterase (Kd = 0.1 nM) was fused to the prestalk-specific promoter of the PDE gene. Transformants carrying multiple copies of this construct secreted inhibitor in 100-fold excess after the aggregation process had occurred. The first effect seen was an elongated tip, followed by a block in slug formation and an inability to culminate. Stalk and spores cells are produced but morphogenesis is uncoupled from cellular differentiation. Overproduction of inhibitor during earlier stages delayed aggregation, but did not affect fruiting body formation. A phosphodiesterase mutant was transformed with a plasmid that expresses PDE only during aggregation and not in prestalk cells. The defect in aggregation was rescued, but the defect in later development was not. The combined results indicate that PDE expression in prestalk cells is critical to morphogenesis. To ask whether the inhibitor gene under its normal regulation had a role in aggregation or later morphogenesis, it was destroyed by homologous recombination. The loss of the gene did not prevent development under the conditions used. PMID- 7851635 TI - Parthenogenesis in Urechis caupo (Echiura). I. Persistance of functional maternal asters following activation without meiosis. AB - A peptide (P23) isolated from sperm acrosomal protein initiates development in eggs of the marine worm Urechis caupo (Echiura). However, in these earlier experiments the eggs were exposed continuously to P23 and did not cleave unless they were provided with a sperm centrosome. The present study reports that parthenogenetic cleavage can be induced when the eggs are exposed to P23 for 1.5 to 2 min in seawater at pH 8 followed by acidifying the seawater to pH 7 or washing off the peptide at pH 7 or 8. The mechanism of parthenogenesis induction was studied by comparing the behavior of maternal and paternal centrosomes (microtubule organizing centers), chromosomes, nuclei and nucleoli in fertilized eggs, P23-activated eggs that failed to cleave, and P23-activated eggs that cleaved, using bright-field, phase-contrast, and fluorescence microscopy following anti-tubulin and bis-benzimide staining. Parthenogenetic cleavage to mostly diploid embryos occurred in eggs that underwent germinal vesicle breakdown without polar body formation. The centrosomes used for cleavage were the persistent maternal centrosomes that did not cycle through meiosis. When cytochalasin B was used to suppress polar body formation without inhibiting the meiotic cycles, eggs did not subsequently cleave even though all four maternal centrosomes were retained. When fertilized eggs were transferred to pH 7 seawater at 1.5 to 2 min after insemination, they underwent a partial activation like the P23-activated eggs and did not form polar bodies. Subsequent cleavage was very abnormal due to the presence of multiple asters formed by the persistant active maternal centrosomes. These results show that maternal centrosomes are normally inactivated by a maternal mechanism associated with meiotic cycling. PMID- 7851636 TI - 3D analysis of cell movement during normal and myosin-II-null cell morphogenesis in dictyostelium. AB - To gain insights into the possible guidance mechanisms used by Dictyostelium cells as they undergo morphogenesis, we have used time-lapse computational optical-sectioning microscopy to visualize and quantify the three-dimensional (3D) trajectories of both normal (Ax2) and myosin-II-null cells. To accomplish this, we typically collected 30-60 time-lapse 3D images every 2-3 min at the earliest multicellular stage, the mound. These time-lapse data were used to generate 3D movies of morphogenesis and to construct 3D trajectories for individual cells. In contrast to previous 2D time-lapse cinematography studies which revealed predominantly spiral trajectories of Ax2 cells in the mound, we have found a complex assortment of motile behaviors: some cells jiggled in place; others appeared to follow either linear or spiral trajectories; some cells reversed their directions; and others apparently converted from one motile behavior to another. These results suggest that a number of different, potentially competing cell-guidance mechanisms are operative in the mound. To assess one molecular mechanism underlying this assortment of motile behaviors, we have examined cell locomotion in a mutant, namely, in myosin-II-null cells which never develop beyond the mound. Previous studies had shown that these cells can crawl, albeit somewhat slowly, on a 2D substrate. We also found, at the earliest stages of myosin-II-null mound formation, some directed cell locomotion. But later, as the mound condensed into a tightly packed cell conglomerate, extended cell trajectories disappeared, and instead virtually all of the cells jiggled in place. Thus, our results suggest that myosin-II is absolutely essential for normal 3D ameboid locomotion. PMID- 7851637 TI - Interactive cellular modulation of chondrogenic differentiation in vitro by subpopulations of chick embryonic calvarial cells. AB - The embryonic chick calvarium normally develops into an intramembranous bone without an intermediate cartilage stage, although cartilage-like calvarial cells have been observed in calcium-deficient chick embryos (Dev. Biol. 115, 215, 1986; Dev. Biol. 133, 221, 1989). To analyze the cellular basis of calvarial development, Incubation Day 14 embryonic chick calvarial cells were fractionated by Percoll gradient isopycnic centrifugation; after 12 days in monolayer culture, a subpopulation of cells (fraction F) was observed to differentiate into a rounded cellular morphology with refractile extracellular matrix. The cartilaginous nature of the extracellular matrix produced by fraction F cells was strongly suggested by the immunodetection of aggrecan and type II collagen, and Alcian blue staining. The other calvarial cell fractions (C, D, E) showed predominantly osteoblastic morphology, expressed alkaline phosphatase activity, and elaborated a collagen type I extracellular matrix. These findings suggest that a "chondrocyte-like" subpopulation of cells exist in the embryonic calvarium. To investigate how cellular interactions may influence the expression of osteogenic versus chondrogenic phenotypes by calvarial cells in vitro, the following cell type combinations were tested in high-density (20 x 10(6) cells/ml) micromass cultures: (1) total, unfractionated calvarial cells; (2) Percoll fractions (C to F) of calvarial cells; and (3) a highly chondrogenic cell type, Hamburger-Hamilton stage 23/24 chick limb bud mesenchymal cells. The micromass cocultures were set up either by mixing and plating two cell types to form the initial, single micromass or by plating the two cell types as separate, side-by-side cultures in the same culture well. The effects of interactions between cocultured calvarial and limb mesenchymal cells upon their respective differentiation fates were separately analyzed, on the basis of the number of Alcian blue-staining cartilage nodules in limb mesenchymal cells and [35S] sulfate incorporation in both cell types. In cocultures with unfractionated or "osteoblast-like" fraction C and D calvarial cells, limb mesenchymal cells had decreased chondrogenesis. In separate cocultures with "chondrocyte-like" fraction F cells, limb mesenchymal cells exhibited enhanced chondrogenesis. Conditioned media from fraction C and D cells, and from fraction F cells, inhibited and enhanced limb mesenchymal cell chondrogenesis, respectively. Q35S]Sulfate incorporation was greater in (1) unfractionated and fractionated calvarial cells cocultured separately with limb mesenchymal cells, compared to calvarial cells cultured alone, and (2) fraction F cells, compared to other fractions or unfractionated calvarial cells. Interestingly, [35S]sulfate incorporation in fraction F cells was decreased when cocultured with fraction C, D, and E cells.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7851638 TI - Evidence that MIF plays a role in the development of pigmentation patterns in the frog. AB - A ventrally localized melanization-inhibiting factor (MIF) may play an important role in the expression of dorsal-ventral pigment patterns of amphibians. In efforts to purify this putative MIF, ventral skin conditioned medium (VCM) from Rana forreri was partially fractionated and used to immunize mice. A monoclonal antibody that has the ability to block the activity of MIF was isolated, and an immunoaffinity matrix was prepared by cross-linking the antibody to protein G Sepharose. The fraction of VCM that bound to the affinity matrix decreased the number of melanized cells in the Xenopus laevis neural tube explant assay, but did not reduce significantly the number of cells that emigrated. The monoclonal antibody was used for immunohistochemical studies on R. pipiens skin. Strong staining with the antibody was observed beneath the basement membrane, in mucous glands, and in the subcutaneous tissue of the ventral skin. A weak staining was also observed in the ground substances of both ventral and dorsal skin. These results confirm that a monoclonal antibody has been secured against at least one of the MIF constituents and that it is useful as a probe in detecting the distribution of MIF in tissues. The results of its use in this study support the hypothesis that MIF plays a role in the expression, development, and maintenance of the dorsal-ventral pigmentation patterns of frogs. PMID- 7851639 TI - Competition for factors and cellular resources as a principle of pattern formation in Hydra. I. Increase of the potentials for head and bud formation and rescue of the regeneration-deficient mutant reg-16 by treatment with diacylglycerol and arachidonic acid. AB - The mutant strain reg-16 of Hydra magnipapillata has less capacity to regenerate a head than the wild-type strain 105 when examined in a standard test. The present comparative study with various strains of Hydra shows: (1) The head forming potential of reg-16 and also of a widely used strain of Hydra vulgaris is severely impaired by the presence of a just-emerging or latent bud. (2) Periodic treatment with dioctanoylglycerol (DAG), a known activator of protein kinase C (PKC), plus arachidonic acid (AA), the mother compound of the eicosanoid signal substances, enabled reg-16 and H. vulgaris to insert additional tentacles into their original whorl while the export of cells by budding was reduced. (3) On the other hand, during the period of daily treatment with DAG+AA, potentials for head and bud formation were stored. Gastric segments excised from pretreated animals formed more tentacles than untreated wild-type 105 and even formed supernumerary head structures; in addition, segments excised from all body regions quickly resumed budding in spite of starvation and while they regenerated a head. (4) With continued treatment supernumerary tentacles were elicited in all strains although with high frequency only in Hydra magnipapillata, wt105. However, while wt105 formed supernumerary head structures preferentially at ectopic sites, reg 16, H. vulgaris, and Hydra oligactis instead increased the number of tentacles in the apical head, which occasionally split into two heads. (5) The treatment with DAG+AA caused the budding zone to shift closer to the foot end. (6) In H. vulgaris a pulse treatment with a high dose of DAG frequently caused a mirror image duplication of the budding zone; in wt105 mere excessive feeding over 2-3 weeks may have the same effect. The hypothesis is proposed that a regenerating head and a beginning bud compete for hormone-like factors, which enable the cells to increase positional value, and for precursor cells. Periodic treatment with activators of PKC plus AA leads to an augmentation of these resources, and head structures and buds can be produced simultaneously. Traditional terms are reinterpreted correspondingly: the high level of "head inhibition" in reg-16 is interpreted as a low level of resources, in particular, of head-promoting factors, and the low head activation level as a low ability to make use of resources. PMID- 7851640 TI - Competition for factors and cellular resources as a principle of pattern formation in Hydra. II. Assistance of foot formation by heads and buds and a new model of pattern control. AB - In Hydra long-range interactions between head, bud, and foot formation take place in addition to short-range interactions which are recognized as induction phenomena, occurring when transplants are placed into an environment of disparate positional value. Here the long-range promotion of foot formation is analyzed. The data show: (1) While head regeneration and the onset of budding are mutually inhibitory, in particular in Hydra vulgaris and strain reg-16 of Hydra magnipapillata, fully developed heads and advanced buds cooperatively support foot formation in both the bud and the parent. Utilizing these interdependences H. vulgaris can be caused to form ectopic feet and to regenerate feet at both ends of excised segments. (2) The foot-promoting activity returns late in head regeneration, as late as the apparent long-range "head inhibition" determined in transplantation studies. (3) While periodic treatment with diacylglycerol (DAG) increases the capacities to form heads and buds, the potency to form feet is transiently reduced. (4) When treatment with DAG is finished the elevated capacities to form heads and buds subside, in reg-16 and H. vulgaris there followed a phase of ectopic foot formation. (5) The foot does not promote head regeneration. Based on the results of this and previous studies the following hypotheses are proposed: (1) Heads and buds compete for resources, such as precursor cells and soluble head-promoting factors that are distributed in the interstitial spaces. (2) The ability to make use of these resources is associated with positional value and decreases down the body column. The decreasing capability is attributed to a decreasing complement of receptors for the head promoting factors. (3) Feet are made by body regions which are the losers in the competition for these factors. (4) Superiority in the ability to compete for the locally available factors enables transplants to develop head structures, and inferiority causes them to form a foot. (5) Depletion of the head-promoting factors in the whole body column is a significant component of the "head inhibition potential" and mediates the assistance of heads and buds in foot formation. (6) A surplus of resources causes supernumerary head structures and delays or prevents foot regeneration. These interpretations have reference to a new receptor-based model of pattern control and are contrasted with prevailing hypotheses. PMID- 7851641 TI - Extracellular matrix protein fibulin-2 is expressed in the embryonic endocardial cushion tissue and is a prominent component of valves in adult heart. AB - Fibulins-1 and -2 are two recently characterized extracellular matrix proteins of a novel protein family. They are found in many tissues in the adult stage, but several differences in their expression patterns were noted in cultured cells and adult tissues. Fibulin-1 is particularly well expressed in the endocardial cushion tissue (ECT) during embryogenesis and we therefore compared the expression patterns of fibulin-1 and -2 in the developing mouse heart. Antibodies against mouse fibulin-1 and -2 were used in immunofluorescence, and the expression of mRNAs were studied with synthetic oligonucleotides by in situ hybridization. A striking codistribution of fibulin-1 and -2 was seen at all stages of the development of the endocardial cushion tissue. Fibulin-2 was found to be a more specific marker for the embryonic ECT than fibulin-1, which was also transiently expressed in cardiac muscle. Immunofluorescence showed that the fibulins remained expressed in valves of the heart in the adult stage. The results suggest a role of the two fibulins in the development of the ECT and in the maintenance of the tensile strength of the cardiac valves. PMID- 7851642 TI - Light and developmental regulation of the gene con-10 of Neurospora crassa. AB - The gene con-10 of Neurospora crassa is expressed preferentially during conidiation and following illumination of vegetative mycelia with blue light. In this study we have examined the segmental locations of the genetic elements associated with con-10 that are responsible for light and developmental expression. A translational fusion was prepared between the initial segment of con-10 and Escherichia coli lacZ. Deletions were then introduced into the con-10 upstream region associated with this translational fusion. Each construct was integrated at the his-3 locus of N. crassa by transformation and homologous recombination. Photoinduction of mycelia containing the translational fusion with the intact upstream region revealed a two phase stimulus-response curve. Exposure to light for as little as 5 sec induced a transcriptional response. Following this initial induction, a period of 15 min in the dark or light was required for appearance of a second phase response. Only a brief light treatment was necessary for induction of the second phase response. Deletions within the upstream region altered normal light and developmental expression of constructs containing the con-10-lacZ translational fusion. The deleted segments appear to contain a mycelial repression site, two conidiation activation sites, and two dark repression sites. A repeated 17-bp sequence acted as a transcriptional enhancer. One copy of this enhancer is in the upstream region. The second copy, with the opposite orientation, is located in the first con-10 intron. The enhancer was required for proper mycelial and conidial expression of the con-10-lacZ fusion. The initial 10 bp of this enhancer sequence were sufficient to restore conidial expression to a deletion construct lacking both copies of the 17-bp repeat. Proteins were detected in extracts of mycelia and conidia that specifically bound to the enhancer sequence in vitro. Our findings suggest that conidiation-specific and mycelial-specific expression of con-10 requires the action of several factors acting independently and/or in concert at distinct sites located in the regulatory regions for con-10. PMID- 7851643 TI - The ovarian tumor protein isoforms of Drosophila melanogaster exhibit differences in function, expression, and localization. AB - The Drosophila melanogaster ovarian tumor (otu) gene, required for normal proliferation and differentiation of the female germ-line, encodes two cytoplasmic protein isoforms, 98 and 104 kDa. Mutants with defects in this gene are typically grouped into one of three phenotypic classes: quiescent (germ cells do not proliferate), oncogenic or tumorous (germ-line cells proliferate uncontrollably), and differentiated (germ-line cells initiate but do not complete differentiation). Analysis of transformants expressing only one of the otu isoforms showed that the 104-kDa isoform (otu-104) can rescue all classes of otu mutants, whereas only differentiated mutants are rescued to a significant extent by the 98-kDa isoform (otu-98). Western analysis of protein extracts prepared from ovaries of various developmental stages indicated that otu-104 predominates in predifferentiated stages, while otu-98 is prevalent in differentiated egg chambers. Immunolocalization experiments demonstrated that otu protein is present in the cytoplasm of oogonial stem cells that populate third instar larvae and in all germ-line-derived cells until late in oogenesis. In stage 10 egg chambers, otu protein shifts to the subcortical region of nurse cells. This type of analysis also showed that upon formation of a 16-cell syncytium otu-104, but not otu-98, preferentially accumulates in the developing oocyte cytoplasm. The otu mutant protein does not show this pattern of enhanced accumulation, nor does it occur in ovaries of egalitarian and Bicaudal-D mutants, which are defective in oocyte determination. Thus, these studies indicate that the 104-kDa isoform is required for normal proliferation of female germline cells and perhaps for oocyte differentiation. The 98-kDa isoform appears to be dispensable but can provide an otu function needed for the completion of oocyte maturation. PMID- 7851644 TI - Restricted distribution of tetraploid cells in mouse tetraploid<==>diploid chimaeras. AB - Tetraploid mouse embryos were produced by electrofusion at the 2-cell stage, cultured overnight, and aggregated with normal diploid embryos to produce tetraploid<==>diploid (4n<==>2n) chimaeric conceptuses. At 7 1/2 days the 4n<==>2n chimaeras were usually smaller and developmentally retarded compared to control diploid<==>diploid chimaeras. At 12 1/2 days the 4n<==>2n chimaeras had heavier placentas but there was no significant difference in fetal size. Tetraploid cells showed a restricted tissue distribution at both developmental stages studied: 4n cells were commonly present in both the primitive endoderm and the trophectoderm lineages but they rarely contributed to the primitive ectoderm lineage. The overall similarity in the distribution of tetraploid cells at 7 1/2 and 12 1/2 days implies that whatever causes the restricted tissue distribution operates largely before 7 1/2 days. There was no evidence for excessive embryonic losses of 4n<==>2n chimaeras. So, if the restricted distribution of 4n cells was a result of cell selection, the mechanism is more likely to involve loss of 4n cells from the primitive ectoderm early in development rather than selective death of conceptuses with tetraploid cells in this lineage. Alternatively, 4n cells may be preferentially allocated to the trophectoderm and primitive endoderm rather than the primitive ectoderm layer at the blastocyst stage. PMID- 7851645 TI - Mesenchymal and neuronal cell expression of the p75 neurotrophin receptor gene occur by different mechanisms. AB - The p75 neurotrophin receptor serves as a receptor for all known neurotrophins, including NGF, BDNF, NT-3, and NT-4/5. The expression pattern of p75 is known to be widespread and extends outside the nervous system, suggesting that neurotrophins may have functions beyond neuronal cell survival and differentiation. To investigate the expression of p75, a human minigene was constructed that contained the full-length receptor cDNA directed by its own promoter and 4 kb of 5' upstream sequence. This minigene was used to generate transgenic mice and was found to be expressed in selective neuronal populations such as the cerebellar external granular layer. Expression of the transgene was not observed in sensory or sympathetic ganglia or in the basal forebrain. Transection of the sciatic nerve revealed that the human transgene was appropriately upregulated after nerve injury, indicating that sequences responsible for proper induction during nerve regeneration reside in the minigene construct. In contrast, the p75 transgene was found to be extensively expressed in mesenchymal cells during development, closely mimicking the in vivo pattern of expression. The detection of p75 receptors in the mesenchyme implies that neurotrophins are likely to exert effects during morphogenesis of mesodermal tissues and that separate signals are likely to direct neuronal versus nonneuronal expression of the p75 gene. PMID- 7851646 TI - Transcriptional activation of the matrix metalloproteinase gene stromelysin-3 coincides with thyroid hormone-induced cell death during frog metamorphosis. AB - A full-length cDNA was isolated for a thyroid hormone response gene in the metamorphosing frog intestine and shown by sequence analysis to be the frog homolog of the mammalian extracellular matrix metalloproteinase stromelysin-3 (ST3). Northern hybridization indicated that ST3 gene expression is differentially activated in tadpole tissues during metamorphosis. In the small intestine, in situ hybridization localized high levels of ST3 mRNA to fibroblast like cells during thyroid hormone-induced metamorphosis. ST3mRNA was undetectable in the intestine prior to metamorphosis, while high levels were present at the metamorphic climax. At this time, primary intestinal epithelial cells are known to undergo cell death and replacement by secondary epithelial cells, arguing that ST3 is involved in the modification of the extracellular matrix during apoptosis. ST3mRNA was also expressed at high levels during tadpole tail resorption, but not in premetamorphic tail or developing hindlimb, further supporting a role for ST3 when tissue remodeling is accompanied by large-scale cell death. Premetamorphic tadpoles treated with thyroid hormone showed a similar but compressed time course of ST3 gene regulation, suggesting that thyroid hormone controls ST3 gene expression during metamorphosis. In contrast, during embryogenesis, ST3 was expressed before endogenous thyroid hormone is detectable, indicating that ST3 can also be regulated independently of thyroid hormone. These findings implicate that ST3 participates in the modification of the extracellular matrix during matamorphic apoptosis, but Northern analyses using heterologous probes raise the possibility that additional matrix metalloproteinases may also be involved. PMID- 7851647 TI - Early determination of nasal-temporal retinotopic specificity in the eye anlage of the chick embryo. AB - The retinotectal projection of the chick is established between Embryonic Days 3 and 13 (E3 to E13). Fate mappings of the eye anlage by local injections of the fluorescent dyes DiI and DiA revealed that the anteroposterior axis of the optic vesicle corresponds to the nasotemporal axis of the retina. To investigate possible alterations in retinotopic specificity after ablating parts of the early eye anlage, we resected either most of the presumptive temporal or a large part of the presumptive nasal half of the eye anlage around stage 11 of the Hamburger Hamilton scale (40-45 hr). After such treatment, the axes are restored in the healed optic vesicle. In the healing process the wound is closed by cells moving in from surrounding areas. After early posterior (i.e., temporal) ablation, the projection from the restored temporal half-retina onto the optic tectum was examined in embryos (E13 to E17) and juvenile chicken (P16) by retrograde and anterograde labeling of ganglion cells and their axons with DiI and DiASP. Normally, only a small fraction of ganglion cells from the temporal retina (between 6.4% on E13 and 0.08% on P16) projects onto the caudal part of the tectum. In experimental embryos and juvenile chicken this fraction is significantly increased (up to 80%). Retrograde double-labeling from the rostral and the caudal tectum reveals that temporal cells project onto either the rostral or the caudal tectum, but not via collaterals upon both areas. The ganglion cells with "displaced nasal" identity within the temporal retina that were backlabeled from the caudal tectum were to a large extent segregated into distinct clusters, indicating their derivation from few or possibly even single progenitor cells. Likewise, ablation of the anterior half of the optic vesicle led to clusters of rostrally projecting cells of "displaced temporal" identity within the restored nasal retina. In these experiments the dorsal-ventral retinotectal relationship remained intact. The simplest, though not exclusive interpretation of the findings is that positional information is imposed as a temporal-to-nasal step function already on the multipotent progenitors of the ganglion cells in the eye anlage by stage 11 or earlier. The positional values remain stable when during the healing of the optic vesicle cells of one specification become surrounded by cells of another specification. PMID- 7851649 TI - Neurite branch development of an identified serotonergic neuron from embryonic Helisoma: evidence for autoregulation by serotonin. AB - Previous studies have shown that in select neurons, neurite outgrowth can be regulated by the same neurotransmitter that is synthesized and released by those neurons. However, it is not known whether such an autoregulatory mechanism is utilized during the normal course of nervous system development in either invertebrates or vertebrates. In the present study, we tested this hypothesis on the first pair of identified serotonergic neurons to be expressed in embryos of the pulmonate gastropod, Helisoma trivolvis. Embryonic neurons C1 (ENC1) elaborate a stereotyped pattern of neurite outgrowth prior to the differentiation of subsequent serotonergic neurons. Embryos were treated with either p chlorophenylalanine (pCPA) or 5-hydroxytryptophan (5-HTP) to lower or raise embryonic serotonin content, respectively. High-performance liquid chromatography with electrochemical detection was used to measure the effects of these treatments on serotonin content, and serotonin immunohistochemistry was carried out to quantify the extent of neurite outgrowth of ENC1. Embryonic serotonin content was significantly reduced at both 24 and 48 hr after treatment with 0.02% pCPA, whereas dopamine levels were unchanged. Although the proximal neurite outgrowth of ENC1 appeared unaffected by the pCPA treatment at both of these time points, the distal outgrowth in the target cell region appeared more profuse. This effect on outgrowth was quantified by counting the number of neurite branch points, which was significantly increased both 24 and 48 hr after pCPA treatment. In contrast, 5-HTP treatment resulted in an increase in embryonic serotonin content and a significant decrease in the number of ENC1 branch points. Treatment with dopamine had no effect on the pattern of ENC1 neurite outgrowth. Together, these results support the hypothesis that a neuron may utilize its own transmitter in an autoregulatory fashion to regulate neurite formation during embryonic development. PMID- 7851648 TI - Genetic control of adult pigment stripe development in zebrafish. AB - Adult zebrafish stripes are formed from stripes of gold iridophores alternating with stripes of black melanocytes lying beneath silver stripes. Analysis of defects in pigment pattern development caused by sparse (spa, rose (ros), and leopard (leo) single and double mutant combinations suggests that spa+ and ros+ functions are required for development of separate populations of pigment cells in the adult and that leo+ functions to control assembly of melanocytes into stripes. Thus, between 2 and 3 weeks of zebrafish development, spa-dependent melanocytes differentiate throughout the flank, followed by leo-dependent assembly of these cells into stripes. Beginning at 3 weeks of development, a distinct ros-dependent population of melanocytes differentiates in the stripe. Both early and late differentiating melanocytes then affect the formation of the silver stripes, ensuring registration of melanocyte and iridophore stripes. PMID- 7851650 TI - Cloning, characterization, and development expression of a rat lung alveolar type I cell gene in embryonic endodermal and neural derivatives. AB - We report here the identification and characterization of a novel gene, T1 alpha, expressed in high abundance in adult rat lung, fetal lung, and early fetal brain. T1 alpha was identified by a monoclonal antibody previously shown to be specific for an antigen expressed by alveolar epithelial type I cells. The cDNA for T1 alpha is 1.85 kb and identifies a single mRNA species of the same size on Northern blots of adult rat lung. The longest open reading frame of the cDNA is 498 bases which would encode a protein of approximately 18 kDa. The protein has a putative membrane spanning domain near the C-terminus but lacks consensus sequences for N-glycosylation. Northern blots and RT-PCR show high expression of T1 alpha in adult lung, with marginally detectable expression in adult brain, intestine, and kidney. RT-PCR analysis shows expression of T1 alpha in freshly isolated type I cells (50-60% purity) but not in highly purified type II cells or other lung cells. We believe therefore that T1 alpha is primarily if not uniquely expressed in alveolar type I cells in the adult rat. Polyclonal antisera against a 16-amino-acid peptide identified in the deduced sequence reacts with the apical membranes of adult type I cells in lung tissue sections but does not label other cell types. The above antiserum as well as the original monoclonal antibody recognize a single approximately 18-kDa protein derived from bacterial expression of a construct containing the T1 alpha open reading frame. By RT-PCR T1 alpha is detected in rat lung from Day 13.5 onward, but is detected by in situ hybridization earlier in lung, brain and neural derivatives, and foregut. Expression is down-regulated in all but lung tissues as development proceeds. PMID- 7851651 TI - Production of sweat gland cholinergic differentiation factor depends on innervation. AB - Sympathetic neurons innervating sweat glands undergo a target-directed developmental switch in neurotransmitter properties. Using cultured sympathetic neurons as a bioassay for cholinergic differentiation factors, we and others found that extracts containing soluble proteins from developing and adult footpads caused the same changes in transmitter properties in sympathetic neurons in vitro that the target does in vivo. In the present studies, using footpads from Tabby mutant mice that lack sweat glands, we found that the presence of sweat glands is correlated with the presence of cholinergic differentiation activity in footpad extracts. We examined the conditions necessary for secretion of differentiation activity from primary cultures of sweat gland cells. Surprisingly, sweat gland cells cultured alone do not produce or secrete cholinergic differentiation activity. When grown in the presence of sympathetic neurons, however, gland cells induce cholinergic function, increase vasoactive intestinal peptide content, and reduce catecholamine production in the neurons. Medium conditioned by sweat gland/neuron cocultures has a similar effect on the transmitter properties of cultured sympathetic neurons, indicating that the target influence on phenotype is mediated by a secreted factor(s). The innervation-dependence of cholinergic differentiation factor production provides evidence that reciprocal interactions between neurons and sweat glands are necessary for acquisition of the mature transmitter phenotype. PMID- 7851652 TI - Cloning of tropomodulin cDNA and localization of gene transcripts during mouse embryogenesis. AB - Tropomodulin (Tmod) is a tropomyosin-binding protein involved in the structuring of actin filaments. This report describes Tmod expression in distinct patterns during embryonic development in a wider variety of adult and embryonic vertebrate tissues than previously reported. Identical Tmod cDNAs were cloned from mouse brain, skeletal muscle, heart, and hematopoeitic cells. Genomic blotting demonstrates that Tmod is encoded by a single gene, which has a 1077-bp open reading frame that is highly homologous to that of the human erythrocyte. The spatial and temporal expression of the Tmod gene was examined during mouse embryogenesis using in situ hybridization. Tmod mRNA is present by 9.5 days postcoitum (p.c.) in the developing rostral somites, coincident with expression of contractile protein genes in myotomes, suggesting that Tmod may play an important role in sarcomeric thin filament organization in skeletal muscle. While the expression of Tmod mRNA in cardiac muscle is earlier than that in skeletal muscle, its appearance in the heart also coincides with the expression of genes for thin filament proteins and correlates with initial myocardial contractions at 8.0 days p.c. Tmod mRNA is not detected in developing smooth muscle of the gut, but Tmod mRNA is expressed in hematopoeitic cells in yolk sac and developing liver. The sensory ganglia and epithelia of the inner ear express Tmod mRNA as do other sensory neurons such as those in the olfactory epithelium. Expression levels in the brain are much lower prenatally than postnatally. These findings show that Tmod expression in many cell types is developmentally regulated, suggesting that the interaction of actin filaments with this tropomyosin binding protein is an important process in tissue and cell differentiation. PMID- 7851653 TI - Maintenance of metaphase in colcemid-treated mouse eggs by distinct calcium- and 6-dimethylaminopurine (6-DMAP)-sensitive mechanisms. AB - In mouse eggs, the arrest at meiotic metaphase II is released by the fertilization-induced increase in intracellular calcium. When eggs treated with the microtubule inhibitor colcemid are fertilized or exposed to the calcium ionophore A23187, normal calcium increases occur, but the eggs remain at metaphase. However, when colcemid-treated eggs are fertilized or A23187-treated and then exposed to the protein kinase inhibitor 6-dimethylaminopurine (6-DMAP), they enter interphase. Although colcemid-treated eggs require a calcium signal and exposure to 6-DMAP, colcemid-treated embryonic cells are released from metaphase by treatment with 6-DMAP, but not by exposure to A23187. These results suggest that two distinct mechanisms maintain metaphase: one is the calcium sensitive mechanism involving cytostatic factor, which normally maintains metaphase II arrest in eggs; the other mechanism, which may require the activity of 6-DMAP-sensitive kinases, maintains metaphase in the absence of spindle assembly in both mitotic cells and eggs. PMID- 7851654 TI - Sorting of the domain-specific acrosomal matrix protein AM50 during spermiogenesis in the guinea pig. AB - We previously identified an insoluble 50-kDa acrosomal matrix protein (AM50) localized to the ventral region of the guinea pig sperm apical segment. AM50 is converted to a 42-kDa polypeptide and released during matrix dispersion in acrosome-reacting sperm. This study examines the sorting pathways and assembly processes which generate the domain-specific distribution of AM50 in the acrosome. AM50 was expressed during early acrosome development and localized to the matrix of proacrosomal granules and the acrosomal vesicle. Initial sorting of AM50 occurred in Golgi phase spermatids, where it became concentrated in the matrix surrounding the acrosomal granule. AM50 remained restricted to the apical segment of acrosome phase spermatids and was finally sorted to the ventral matrix of the apical segment in maturation phase spermatids. By reducing SDS-PAGE testicular AM50 exhibited a slightly higher M(r) of 52 kDa than the 50-kDa form of cauda epididymal spermatozoa. Nonreducing SDS-PAGE demonstrated that testicular and epididymal AM50 were assembled into homomeric complexes of 480 and 450 kDa respectively. Cauda epididymal sperm apical segments contained a second disulfide-cross-linked homomeric complex of 520 kDa composed of a 68-kDa subunit. These studies indicate that AM50 is first assembled into a disulfide-cross-linked complex and subsequently processed into mature AM50. These data also suggest that disulfide-linked complexes of different structural proteins may assemble into distinct acrosomal matrix compartments. PMID- 7851655 TI - Regulation of the Xenopus labial homeodomain genes, HoxA1 and HoxD1: activation by retinoids and peptide growth factors. AB - Vertebrate homologues of Drosophila labial are likely to play key roles in anteroposterior axis formation. However, little is known about the regulation of these genes during vertebrate development. Here we examine the expression and regulation of the Xenopus labial homeodomain genes, HoxA1 and HoxD1. HoxA1 was expressed around the dorsoventral circumference of the trunk in neurula embryos, with later expression in spinal cord, midbrain, hindbrain, and endolymphatic duct. By mid gastrula, HoxD1 was predominantly expressed in dorsolateral and ventral ectoderm, with a gap in expression at the dorsal midline. By neurula, ventral expression had declined with most expression restricted to dorsolateral mesoderm and ectoderm. Retinoic acid strongly induced HoxA1 and HoxD1 throughout the ectoderm and mesendoderm of gastrula stages, while in older embryos retinoids induced ectopic expression of these genes in more limited regions. Induction by retinoids was independent of protein synthesis. Surprisingly, HoxA1 was expressed at high levels in isolated animal caps in the absence of retinoic acid. The peptide growth factors bFGF and activin A strongly induced expression of HoxD1, but not HoxA1, in animal caps; however, RNA accumulated only many hours after the application of these factors. Overexpression of thyroid hormone receptor (c-erbA) prevented induction of HoxD1 by retinoic acid in animal caps. c-erbA also ablated expression of HoxD1 in whole embryos, suggesting a role for endogenous retinoids in the regulation of HoxD1 expression. Dominant interfering activin and FGF receptors prevented expression of HoxD1 in vivo, implicating these factors in the normal induction of HoxD1. Our data indicate that induction of labial-like homeodomain genes is complex and may require many factors. PMID- 7851656 TI - Differentiation of hippocampal progenitor cells in vitro: temporal expression of intercellular coupling and voltage- and ligand-gated responses. AB - Mechanisms regulating the expression of intercellular coupling, development of membrane excitability, and cellular responsiveness to neurotransmitters during neuronal ontogeny are largely unknown. To define the temporal relationship among these properties during neurogenesis, murine embryonic hippocampal progenitor cells immortalized with a temperature-sensitive allele of the SV40 large T antigen were examined during successive stages of neuronal differentiation in vitro using patch clamp, dye coupling, and Ca2+ imaging techniques. Electrotonic and dye coupling between untreated neuroblasts were frequent in cells maintained at the temperature (39 degrees C) nonpermissive for T-antigen expression. However, as neuroblasts differentiated into neurons under the influence of interleukin-7 added alone or concurrently with transforming growth factor-alpha after basic fibroblast growth factor, both junctional conductance and the extent of dye coupling progressively decreased. Voltage-dependent inward currents were present within 2 to 6 days after differentiating treatments began. During intermediate developmental stages (3 to 5 days in culture), cells became responsive to GABA (> or = 100 microM) but not to glutamate, glycine, or to acetylcholine (< or = 1 mM), as indicated by [Ca2+]i measurements and patch clamp recordings. In contrast, voltage- and ligand-gated responses but not electronic coupling were frequently observed in mature neuronal primary cultures. Together, these results indicate that certain cytokines may orchestrate the progressive expression of functional neuronal phenotypes in vitro, in which the gradual disappearance of intercellular coupling parallels the onset of voltage-dependent responses and both of which precede the expression of neurotransmitter chemosensitivity. PMID- 7851657 TI - Microtubules are a general component of mRNA localization systems in Drosophila oocytes. AB - Some of the spatial cues which direct early patterning events in Drosophila embryogenesis are maternal mRNAs localized in the oocyte during oogenesis. For example, Bicaudal-D, fs (1) K10, and orb RNAs are transiently localized at the anterior oocyte margin in mid oogenesis, and oskar RNA is localized at the posterior oocyte margin beginning in mid oogenesis. Using inhibitors of cytoskeletal function, we find that microtubules, but not microfilaments, are required for localization of these mRNAs during oogenesis, results similar to those described earlier for bicoid RNA. However, the RNAs show a differential sensitivity to microtubule inhibitors. Anterior localization of Bicaudal-D, fs (1) K10, and orb RNAs is completely disrupted following even mild drug treatments. bicoid RNA localization is intermediate in its response to microtubule drugs, while oskar RNA localization is much more resistant. In addition, the localized RNAs respond differently to taxol, a microtubule stabilizing agent. The differences among these RNAs suggest that factors other than microtubules are required to maintain the positions of localized RNAs in the oocyte. Microtubules are also required for the preferential accumulation of these transcripts in the previtellogenic oocyte, consistent with the idea that these mRNAs are transported by a microtubule-dependent mechanism to the oocyte. PMID- 7851658 TI - Mouse oocytes inhibit plasminogen activator production by ovarian cumulus and granulosa cells. AB - Following the preovulatory surge of gonadotropins, the compact layer of cumulus cells in the antral follicle secretes a hyaluronic acid-enriched extracellular matrix and undergoes a morphological change referred to as cumulus expansion. It has been previously shown that a soluble factor(s) produced by the oocyte is required, in combination with FSH, to promote this process. Since such matrix is sensitive to proteases we have now studied the effect of the oocyte on another gonadotropin-controlled follicle cell function, i.e., the synthesis of plasminogen activator (PA). Our data indicate that isolated cumulus cells secrete uPA in the medium and that FSH or dbcAMP increases this production. The presence of the oocyte or the oocyte-conditioned medium greatly reduces uPA synthesis induced by FSH and dbcAMP in cumulus cells by modulating the abundance of its mRNA. The ability of the mouse oocyte to produce such a factor(s) is dependent upon its stage of development, with fully grown oocytes but not growing oocytes or two-cell embryos being able to inhibit uPA synthesis. A preliminary characterization of this factor suggests that it is a heat-unstable protein with an apparent molecular weight above 100 kDa. Thus, the mouse oocytes appear to promote preovulatory matrix accumulation that occurs just prior ovulation by modulating the gonadotropin action on both the synthesis and the degradation of specific matrix component. PMID- 7851659 TI - A fat body-derived protein is selectively sulfated during transit to ovarian follicles in the stick insect Carausius morosus. AB - A monoclonal antibody raised against ovarian follicles of the stick insect Carausius morosus reacted with two related polypeptides of 157 and 85 kDa in both the ovary and the hemolymph. In vitro cultured fat body proved capable of releasing the 157-kDa polypeptide into the culture medium and processing it to the lower-molecular-weight polypeptide of 85 kDa. This was further demonstrated by in vitro exposure to [35S]methionine. Under the same culturing conditions, ovarian follicles proved incapable of synthesizing and/or secreting the 85-kDa polypeptide. However, in vivo [35S]methionine-labeled ovarian follicles released both polypeptides when cultured in vitro for up to 24 hr. Vitellogenin polypeptides were labeled in vivo following exposure to [3H]glucosamine, while 157- and 85-kDa polypeptides were labeled only in ovarian follicles exposed in vivo to sodium [35S]sulfate. Under in vitro conditions, the 157-kDa polypeptide could be labeled with sodium [35S]sulfate only if ovarian follicles were cocultured with fat body. No sulfation occurred in fat body or ovarian follicles cultured separately. These experiments suggest that the 157-kDa polypeptide is a fat body-derived polypeptide that is sulfated upon transfer to the ovarian follicle. PMID- 7851660 TI - A protein of the sea urchin cortical granules is targeted to the fertilization envelope and contains an LDL-receptor-like motif. AB - Cortical granules of eggs contain a population of heterogeneous proteins that are sequestered selectively within the cortical granule during oogenesis and that participate in the block to polyspermy during the fertilization reaction. To begin to understand the targeting mechanism of proteins to this organelle, we have identified cDNA clones that encode proteins of the cortical granule. Here we characterize the protein encoded by the cDNA, SFE 9, which is packaged specifically into the spiral lamellae of the cortical granules in the sea urchin Strongylocentrotus purpuratus. The SFE 9 protein showed a molecular mobility in PAGE of 150 kDa, close to the estimated 128 kDa predicted by cDNA sequence, and contained three regions of distinct repeating sequence. Each type of repeat sequence was of different length, frequency, and amino acid composition, but each type showed a high degree of conservation within a repeat type. A fourth region of sequence showed similarity to the low-density lipoprotein (LDL)-receptor motif. The N-terminal 2/3 of the protein contained an abundance of cysteine residues with regular and conserved spacings. Upon fertilization, SFE 9 was secreted and was rapidly incorporated into the fertilization envelope. The integration of SFE 9 into the fertilization envelope was complete within 5 min post-fertilization and was mediated by ovoperoxidase-catalyzed cross-linking. Incorporation of SFE 9 into the fertilization envelope was not uniform. Instead, it concentrated to the microvillar casts both in normal and in ovoperoxidase inhibited fertilization envelopes. Thus, SFE 9 shows molecular heterogeneity within the fertilization envelope and the targeted integration is independent of ovoperoxidase activity. The strong repeat regions and the LDL-receptor motif of SFE 9 are postulated to be used in specific protein-protein interactions that occur either during traflicking to the cortical granules during biogenesis or to the fertilization envelope during the fertilization reaction. PMID- 7851661 TI - Peripheral axonal pathway and cleaning behavior are correlated in Drosophila microchaetes. AB - The notum of Drosophila is covered with evenly spaced small mechanosensory bristles (microchaetes). Four groups of microchaetes can be distinguished on the basis of the pathways followed by the axons of their neurons. In three of the four groups, the axons extend along fibrous processes, the prospective tendons of the adult indirect flight muscles, formed by the epithelial cells. We show that the subdivision into four fasciculation groups is correlated to differences in the cleaning behavior elicited by stimulating the microchaetes. PMID- 7851662 TI - Induction of early stages of kidney tubule differentiation by lithium ions. AB - Kidney tubules develop by a mesenchyme-epithelium transition, normally induced by ureteric bud through a mechanism that remains obscure. Murine nephrogenesis in vitro has always required heterologous inducing cells. We have discovered that Li+ can elicit the early stages of epithelial differentiation in isolated nephrogenic mesenchyme. We have made detailed comparisons of the timing of morphoregulatory molecule expression between Li(+)-mediated induction and the traditional in vitro method using induction by spinal cord. Both followed the same program of early morphoregulatory molecule expression, though Li(+)-induced samples failed to progress into the later parts of the nephrogenic process. Mesenchymes induced by Li+ showed more DNA synthesis than controls, though less than those induced by spinal cord. Discovery of a chemical means to activate differentiation in the absence of heterologous tissue offers a new basis for studying molecular mechanisms regulating the early events of nephrogenesis, as well as for investigating transduction of inductive signals that initiate the process. PMID- 7851663 TI - Evolution of cell lineage and pattern formation in the vulval equivalence group of rhabditid nematodes. AB - During the formation of the vulva in many nematode hermaphrodites or females, pattern formation, induction, and cell specification can readily be studied at a single-cell level. Nematodes thus allow an evolutionary analysis of developmental processes. We have analyzed cell lineages and pattern formation in the vulva equivalence group of six rhabditid nematodes of the genera Oscheius, Rhabditella, Rhabditoides, Pelodera, and Protorhabditis. The comparison of these species with four previously analyzed species of this family reveals evolutionary modification at several levels. The number of vulva precursor cells (VPCs) differ among species. Of the three particular cell lineages (1 degree, 2 degrees, and 3 degrees) generated by the vulva precursor cells in Caenorhabditis, two (2 degrees and 3 degrees) are altered, whereas the third lineage (1 degree) is conserved among the analyzed species. While most vulval lineages are invariant, we observe variability of the 3 degrees lineage in Pelodera with respect to the number of precursor cells adopting this fate and the number of progeny formed. In two species, the 3 degrees lineage generates an asymmetrical set of cells, oriented by the gonad. In Protorhabditis we frequently find animals with an additional or altered set of VPCs forming vulval tissue. PMID- 7851664 TI - Developmental regulation of Fos-protein during proliferative growth of the otic vesicle and its relation to differentiation induced by retinoic acid. AB - This work studies Fos protein expression in the otic vesicle and the developing cochleovestibular ganglion (CVG), focusing on the possible role of Fos in the regulation of cell proliferation and differentiation during otic development. Fos was detected as a product of 56-62 kDa in otic vesicles and CVG lysates. Expression was transient and stage-dependent. Maximal levels occurred at stage 20 in the otic vesicle and at Day 4 in the CVG. Another wave of Fos expression occurred after Day 7 of development, out of the early proliferative period. Fos immunoreactivity was localized in cell nuclei of otic epithelium and CVG. Fos was readily induced by mitogens like serum and bombesin and this induction was inhibited by 25 nM retinoic acid, an inhibitor of cell proliferation in the otic vesicle.c-fos antisense oligonucleotides inhibited growth in the otic vesicle in parallel with a reduction in Fos expression. High levels of Fos protein were not sufficient, however, to sustain growth of isolated otic vesicles in the absence of mitogens. Incubation with retinoic acid (24 hr) induced differentiation of sensory hair-cells in parallel with inhibition of cell proliferation. Contrary to retinoic acid, Fos inhibition by antisense did not induce differentiation. The results suggest that Fos is part of the signaling mechanisms regulating normal development of the inner ear. Regulation of Fos may be required for controlling of the transition between cell proliferation and differentiation. PMID- 7851665 TI - Neural tube and notochord promote in vitro myogenesis in single somite explants. AB - We have developed an in vitro assay for examining the neural tube/notochord influence on somite myogenesis. No cells committed to myogenesis (operationally defined as immunopositive staining for myosin heavy chain after a 48-hr culture period) are present in the most caudal somites (I-V) of stage 8-11 chicken embryos, whereas by stage 14-15, the most caudal somites occasionally produce differentiated muscle cells when cultured alone. To test for responsiveness to neural tube, one somite of each pair was cultured in contact with a piece of neural tube; as a control, the contralateral somite was cultured alone to test for prior myogenic commitment of somitic cells. Using this assay, we show that neural tube induces myogenesis in single somite explants, that close somite neural tube proximity is required, and that the interaction can occur in defined medium. Neural tube induces myogenesis in the most recently formed somites and in segmental plate mesoderm, indicating that somite segmentation is not a prerequisite for neural tube mediated myogenesis in vitro. The assay was also used to determine whether continued exposure to neural tube is required for increasing myogenic cell numbers in somites which already contain cells committed to myogenesis. Since somites containing committed cells exhibit a fourfold increase in the number of myogenic cells when cocultured with neural tube, continued in vitro exposure to neural tube either recruits additional somite cells into the myogenic lineage, and/or it stimulates proliferation of existing myogenic cells. Consistent with this finding, the most rostral neural tube retains its inductive properties as evidenced by the induction of nascent myogenesis in the most caudal somites. Parallel studies of notochord mediated myogenesis indicate that the notochord promotes myogenesis within somites II VIII, but not within somite I or the segmental plate. This observation suggests either a qualitative or quantitative difference in the mechanism by which the neural tube and notochord communicate with the youngest somite and presomitic mesoderm. PMID- 7851666 TI - Cloning of cDNAs for the precursor protein of a low-molecular-weight subunit of the inner layer of the egg envelope (chorion) of the fish Oryzias latipes. AB - cDNA clones for L-SF, the precursor of a low-molecular-weight subunit (ZI-3) of the inner layer of the Oryzias latipes egg envelope were isolated from Lambda ZAP cDNA libraries constructed from the poly(A)+ RNA of the liver of spawning female fish and estrogen-treated male fish. Among them, a clone, L-SF41, is 1473 bp long and contains an open reading frame encoding a signal peptide of 19 amino acids and L-SF protein of 420 amino acids. L-SF protein seems to be glycosylated, judging from the result of the glycanase digestion. L-SF protein contains a domain similar to ZP-domains in ZP3 of some mammalian species. Northern blot analysis employing XhoI-SmaI fragments of the cloned cDNA as probes revealed that expression of the L-SF gene occurred exclusively in the livers of spawning female fish and estrogen-treated male fish and that there was no mRNA encoding L-SF in the ovary of the spawning female fish. PMID- 7851667 TI - BAEP studies in children with attention deficit disorder. AB - Brainstem auditory evoked potentials (BAEPs) were performed on 114 children with attention deficit disorder (ADD). Prolonged latencies of waves III and V and longer brainstem transmission time interval of waves I-III and I-V were observed in the study group compared with normal controls. A significant asymmetry of wave III latency between the ears was found in children with ADD, but not observed in the control group. The authors conclude that children with ADD have brainstem dysfunction. BAEPs, an objective electrophysiological test, may contribute to the diagnosis of ADD, distinguishing these children from the normal population. PMID- 7851668 TI - The effects of non-nutritional factors on growth in cerebral palsy. AB - This study was designed to evaluate the effects of non-nutritional factors alone on the growth of children with cerebral palsy (CP). 20 children with hemiplegic CP, normal stature and normal triceps skinfold measurements had 16 different anthropometric measures performed on each side of the body (affected vs unaffected). All measures of breadth, circumference and length were significantly smaller on the affected side compared with the unaffected side. Skinfold measurements had a tendency to be larger on the affected side. These results suggest that non-nutritional factors related to disease severity have a significant influence on the growth of children with CP, even in the absence of malnutrition. PMID- 7851669 TI - Podiatric disorders among children with Down syndrome and learning disability. AB - This study investigated podiatric pathology in seven- to 14-year-old children with Down syndrome (DS) and non-Down syndrome learning-disabled and non-learning disabled age-matched controls. Several conditions, including pes planus, fissures, split toenails, increased plantar flexed first ray and a wide hallucal cleft were found to be more common in the DS group. Pes cavus and foot rigidity were more common in the non-DS learning-disabled group. In all groups the majority of children wore laced shoes, which were most ill-fitting among children with a learning disability. Approximately one-third in each group had abnormal foot-pressure prints. Greater care and professional awareness of podiatric pathology in children with learning disability is recommended. PMID- 7851670 TI - Selective injury of the globus pallidus in children with post-cardiac surgery choreic syndrome. AB - Occasionally children undergoing cardiac surgery using cardiopulmonary bypass with deep hypothermia and cardiac arrest develop a postoperative syndrome of acute chorea. The authors report the neuropathological findings in two such children surgically treated for congenital heart disease. Examination of the brain showed neuronal loss, reactive astrocytosis and degeneration of myelinated fibers (without frank necrosis) in the globus pallidus, primarily the outer segment, with sparing of other regions commonly susceptible to hypoxic-ischemic necrosis. The localization and relative mildness of the brain damage suggest a susceptibility of the globus pallidus to injury in this setting and implicate disruption of pallidal pathways in the pathogenesis of post-cardiac surgery choreic syndrome. PMID- 7851671 TI - Development of prospective control of catching moving objects in preterm at-risk infants. AB - Healthy term infants and infants classified as neurologically at-risk because of low birthweight and preterm birth were tested longitudinally between 20 and 48 weeks on the ability to use visual information predictively. Reaching for an object moving at different speeds was assessed; the object was occluded from view by a screen during the last part of its approach. At each infant's first reaching session, gaze anticipated the reappearance of the moving toy; however, onset of reaching and prospective control of gaze and hand varied considerably between the normal and at-risk groups. In addition, some at-risk infants geared their actions not to the time but to the distance that the toy was from the catching place, causing problems with faster-moving toys. The two children who anticipated least well were the only two of the at-risk group who were later diagnosed as having cerebral palsy. PMID- 7851672 TI - Frontal and central lobe focal dysplasia: clinical, EEG and imaging features. AB - The authors studied 11 patients with developmental malformations and seizures originating from the frontal and central regions. Patients with centrally located seizures had primary involvement of the face or mouth; clonic activity involving the limb was also seen. Seizures among those with frontal lesions were primarily unilateral or bilateral tonic motor. Secondary generalized tonic-clonic seizures preceded by focal manifestations occurred infrequently in those with central localization, but were not rare in the frontal group. MRI revealed abnormalities in 10 patients, nine of whom underwent surgical resection with good results. Focal cortical dysplasia may be the underlying epileptogenic abnormality in young patients with clinical features suggestive of central or frontal cortical involvement. PMID- 7851673 TI - Correlation of cervical auscultation with physiological recording during suckle feeding in newborn infants. AB - Pharyngeal swallows during infant suckle-feeding are associated with a characteristic sequence of sounds audible by stethoscope or by an accelerometer or microphone held over the larynx. In rhythmically feeding term-born neonates, the delineating acoustic elements are discrete sounds which precede and succeed pharyngeal swallows. Digital signal processing shows similarities in morphological detail between the discrete sounds preceding swallows and between those succeeding swallows; those succeeding swallows are more variable in temporal relation to swallows, amplitude and morphological detail. Variations in the pattern of interswallow respiration, including apnea, are correlated with variations in the discrete sounds. Specification of physiological correlates of these internal feeding sounds increases the utility of cervical auscultation as a method of investigation and of clinical observation of feeding. PMID- 7851674 TI - Cerebral palsy and muscle transformation. PMID- 7851675 TI - 'A simple, effective and well-tolerated treatment regime for West Syndrome'. PMID- 7851676 TI - An unusual myasthenic syndrome developing in children who presented with infantile myopathy with type I fibre-specific hypertrophy. PMID- 7851677 TI - A multicentre comparative trial of sodium valproate and carbamazepine in paediatric epilepsy. The Paediatric EPITEG Collaborative Group. AB - The long-term efficacy and adverse-event profiles of sodium valproate and carbamazepine in children with newly diagnosed primary generalised or partial epilepsy were compared at 63 outpatient clinics. Children with two or more generalised tonic-clonic or partial seizures in the previous six months were randomised to oral sodium valproate (N = 130) or oral carbamazepine (N = 130) and followed for three years as outpatients. Dosages were increased as needed until seizures were controlled or toxicity developed. Sodium valproate and carbamazepine were equally effective in achieving high levels of seizure control in both primary generalised seizures and partial seizures with or without generalisation. Adverse events were mostly mild, few necessitating drug withdrawal. Those particularly associated with valproate were weight increase, alopecia and appetite increase, and with carbamazepine, rashes, somnolence, diplopia and abnormal gait/ataxia. PMID- 7851678 TI - Sulphatide in islets of Langerhans and in organs affected in diabetic late complications: a study in human and animal tissue. AB - Sulphatide has been found in rat islets of Langerhans and anti-sulphatide antibodies have been demonstrated in patients with insulin-dependent diabetes mellitus. Using a specific monoclonal antibody, Sulph I, directed against sulphatide, we investigated the in situ distribution of this glycolipid immunohistochemically; furthermore, the sulphatide concentration was determined in several organs and cells by thin-layer chromatography. The islets of Langerhans in all species examined, mouse, rat, pig, and monkey were intensively stained but exocrine tissue remained unlabelled. The sulphatide concentration in human islets was 150 +/- 46 pmol/100 islets. The only glycolipid-antigen detected was sulphatide. Regarding other tissues, sulphatide was found to be located in distal tubules in the kidney, peripheral nerves, distinct scattered spot-like structures in the choreoid layer of the eye, the ovum, and peripheral granulocytes. Sulph I injection in mice showed homing to kidney tubules, Lung, heart, liver, adrenal, spleen, lymph node and thymus were not stained by Sulph I. Thus, the distribution of sulphatide shows an association with organs known to be affected in diabetes, either initially or in late complications. PMID- 7851679 TI - Culture duration and conditions affect the oscillations of cytoplasmic calcium concentration induced by glucose in mouse pancreatic islets. AB - The pattern of the increase in cytoplasmic Cai2+ that glucose produces in beta cells has been reported to be highly variable. Here, we evaluated the influence of the culture duration (1-4 days) and conditions (5-10 mmol/l glucose) on Cai2+ in normal mouse islets stimulated by glucose. After 1 day of culture in 10 mmol/l glucose, a rise of the glucose concentration from 3 to 15 mmol/l induced a triphasic change of Cai2+ in the islets. A small initial decrease was followed by a large peak increase and then by regular fast oscillations (approximately 2.5/min). When the culture was prolonged to 2, 3 and 4 days, the initial decrease became inconsistent and the peak occurred earlier, whereas the oscillations decreased in frequency, increased in duration and eventually disappeared; on day 4 the Cai2+ rise was sustained. After culture in 5 mmol/l glucose, the pattern of Cai2+ changes induced by 15 mmol/l glucose was different. The initial decrease was very pronounced, the first peak was delayed and clearly separated from the subsequent oscillations. These were of a mixed type (fast Ca2+ transients on top of slow ones) after 1 day, and of a slow type only after 4 days. These alterations in the Cai2+ oscillations triggered by glucose could not be ascribed to desynchronization of the signal between different regions of the islets. In conclusion, culturing normal mouse islets in 5 or 10 mmol/l glucose for 1-4 days, markedly alters the characteristics of the changes in Cai2+ produced by glucose.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7851680 TI - Arterial hypertension and microalbuminuria in IDDM: the Italian Microalbuminuria Study. AB - Arterial hypertension and poor glycaemic control are central to the development of microalbuminuria in insulin-dependent diabetes mellitus (IDDM). Recent consensus has established sensitive criteria for their detection and treatment, although the proportion of patients who may benefit is unclear. Between 1988 and 1990, we measured urinary albumin to creatinine concentration ratio (A/C) in 3,636 adult out-patients with IDDM of more than 3 years duration, serum creatinine under 133 mumol/l and who were not undergoing antihypertensive treatment. A/C indicating microalbuminuria (> or = 2.38/2.96 mg/mmol, male/female) was found in 620 of 3,451 patients without proteinuria, and associated with hypertension (blood pressure > or = 140 and/or 90 mmHg; p = 0.0016; rate: 39.6%), independent of diabetes duration (p = 0.0082) and male gender (p = 0.0350; relative risk = 1.16; 95% confidence interval: 1.01-1.32). Hypertension was less common among those with normal A/C (27.5%, p < 0.0001) but was positively related with diabetes duration. Of the 1,015 patients with A/C > or = 2.0 mg/mmol 529 were reexamined. Glycated haemoglobin levels exceeded 3 SD above the mean of normal in 84.3% of the 198 microalbuminuric patients (AER = 20 200 micrograms/min), but were comparably poor (79.2%) in normoalbuminuria. Duration of diabetes was inversely related to glycated haemoglobin only in microalbuminuria (0.05 < p < 0.1). Intervention to lower blood pressure remains mainly restricted to those patients with long-term diabetes and slower development of kidney disease. Near-normalisation of glycaemia remains the priority for the majority of patients with microalbuminuria. PMID- 7851682 TI - Insulin-mediated and glucose-mediated glucose uptake following hemipancreatectomy in healthy human donors. AB - Healthy humans undergoing hemipancreatectomy for the purpose of donation to a family member with IDDM have previously been demonstrated to maintain serum glucose values equal to matched control subjects during short-term glucose infusion despite significant decrements in glucose- and arginine-induced insulin secretion. In order to determine whether humans compensate for hemipancreatectomy by increasing insulin- or glucose-mediated glucose uptake, we measured glucose turnover and insulin sensitivity by three protocols. Insulin-mediated glucose uptake was measured during sequential infusions of insulin at rates of 0.25, 1.0, and 10.0 mU.kg-1.min-1 in 12 donor subjects and 12 matched control subjects maintained at euglycaemia. Both groups displayed similar increases in rates of glucose disappearance and similar decreases in rates of hepatic glucose production. Glucose-mediated uptake was calculated as the difference between the rates of glucose disappearance measured during a hyperglycaemic clamp performed at identical rates of insulin infusion and was also found to be similar in both donor subjects and control subjects. Both groups also had indistinguishable measures of insulin sensitivity and glucose effectiveness as determined by the minimal model technique. Therefore, donor subjects appear to compensate for diminished insulin secretion following hemipancreatectomy by an unidentified mechanism since neither insulin- nor glucose-mediated glucose uptake are increased. PMID- 7851681 TI - Effect of sustained physiologic hyperinsulinaemia and hyperglycaemia on insulin secretion and insulin sensitivity in man. AB - Two study protocols to examine the effects of chronic (72-96 h) physiologic euglycaemic hyperinsulinaemia (+ 72 pmol/l) and chronic hyperglycaemic (+ 1.4 mmol/l) hyperinsulinaemia (+ 78 pmol/l) on insulin sensitivity and insulin secretion were performed in 15 healthy young subjects. Subjects received a three step euglycaemic insulin (insulin infusion rates = 1.5, 3, and 6 nmol.kg-1.min-1) clamp and a hyperglycaemia (6.9 mmol/l) clamp before and after chronic insulin or glucose infusion. Following 4 days of sustained euglycaemic hyperinsulinaemia whole body glucose disposal decreased by 20-40%. During each insulin clamp step, the defect in insulin action was accounted for by impaired non-oxidative glucose disposal (p < 0.01). Chronic euglycaemic hyperinsulinaemia did not alter insulin mediated suppression of hepatic glucose production. Following insulin infusion the ability of hyperglycaemia to stimulate insulin secretion was significantly diminished. Following 72 h of chronic glucose infusion (combined hyperglycaemic hyperinsulinaemia), there was no change in whole body glucose disposal. However, glucose oxidation during each insulin clamp step was significantly increased and there was a reciprocal decline in non-oxidative glucose disposal by 25-39% (p < 0.01); suppression of hepatic glucose production by insulin was unaltered by chronic hyperglycaemic hyperinsulinaemia. Chronic glucose infusion increased the plasma insulin response to acute hyperglycaemia more than twofold. These results demonstrate that chronic, physiologic hyperinsulinaemia, whether created by exogenous insulin infusion or by stimulation of endogenous insulin secretion, leads to the development of insulin resistance, which is characterized by a specific defect in the non-oxidative (glycogen synthetic) pathway. These findings indicate that hyperinsulinaemia should be considered, not only as a compensatory response to insulin resistance, but also as a self-perpetuating cause of the defect in insulin action. PMID- 7851683 TI - Insulin sensitivity is related to the fatty acid composition of serum lipids and skeletal muscle phospholipids in 70-year-old men. AB - Recent data indicate that peripheral insulin sensitivity may be influenced by dietary fat quality and skeletal muscle phospholipid fatty acid composition. During a health survey of 70-year-old men insulin sensitivity was measured by the euglycaemic hyperinsulinaemic clamp technique and the fatty acid composition of the serum cholesterol esters was determined (n = 215) by gas liquid chromatography. In a subsample the fatty acids of the skeletal muscle phospholipids and triglycerides were determined after fine needle biopsy from m. vastus lateralis (n = 39). The peripheral insulin sensitivity was significantly and negatively correlated to the proportion of palmitic (r = -0.31, p < 0.001), palmitoleic (r = -0.25, p < 0.001) and di-homo-gamma-linolenic (r = -0.33, p < 0.001) acids and positively to the content of linoleic (r = 0.28, p < 0.001) acid in the serum cholesterol esters. There was an even stronger negative relationship to the proportion of palmitic acid in the skeletal muscle phospholipds (r = 0.45, p < 0.004). The fatty acid composition was also significantly related to insulin sensitivity in a stepwise multiple regression analysis in the presence of other clinical variables, which were associated with insulin action in univariate analysis. Thus, more than 51% of the variation of the insulin sensitivity was explained by an equation containing body mass index, serum triglyceride concentration and the content of palmitic acid in the skeletal muscle phospholipids. It is concluded that the fatty acid composition in serum and of the phospholipids of skeletal muscle may influence insulin action in elderly men. PMID- 7851684 TI - Autonomic neuropathy and transcutaneous oxymetry in diabetic lower extremities. AB - Transcutaneous oxygen tension is a useful method with which to assess the functional status of skin blood flow. The reduced values observed in diabetic patients have been interpreted as a consequence of peripheral vascular disease. However, diabetic patients show lower transcutaneous oxygen tension values than control subjects with equivalent degrees of peripheral vascular disease, suggesting that additional factors are involved. Since the autonomic nervous system influences peripheral circulation, we studied the relationship between autonomic neuropathy and foot transcutaneous oxymetry in non-insulin-dependent diabetic (NIDDM) patients without peripheral vascular disease. The following age matched patients were selected and evaluated: control subjects, C, (n = 20), NIDDM patients without autonomic neuropathy, D, (n = 16) and with autonomic neuropathy, DN, (n = 20). All diabetic patients showed lower transcutaneous oxygen tension values than control subjects, while no differences were observed between the diabetic patients with and without autonomic neuropathy. In addition the saturation index that increases in the presence of autonomic neuropathy does not correlate with foot TcPO2. In conclusion autonomic neuropathy does not influence foot TcPO2 and therefore it is unlikely that it contributes to development of foot lesions during induction of foot skin ischaemia. PMID- 7851685 TI - Asymptomatic peripheral nerve dysfunction and vascular reactivity in IDDM patients with and without microalbuminuria. AB - Abnormal vascular reactivity has been implicated in the aetiology of diabetic microvascular disease and we have previously demonstrated enhanced contractility of hand veins to noradrenaline in insulin-dependent diabetic (IDDM) patients with microalbuminuria. We have now assessed the possible contribution of subclinical peripheral nerve dysfunction to exaggerated vascular reactivity in micro albuminuric patients. Twenty-five IDDM patients (15 with microalbuminuria), none of whom had symptomatic neuropathy, and 10 control subjects were studied. Vasoconstrictor responses were measured in dorsal hand veins using noradrenaline and phenylephrine. Conduction in median, peroneal and sural nerves was assessed using electrophysiology, and autonomic function using standard cardiovascular reflex tests. The noradrenaline dose causing 50% vasoconstriction was significantly lower in the microalbuminuric diabetic subjects compared with normoalbuminuric (3.6(1.7) mean (SEM) ng/min vs 20.1(6.0) ng/min, p = 0.0002) and non-diabetic subjects (35.1(5.0) ng/min; p < 0.0001). However, reactivity to phenylephrine did not differ between the groups. Median nerve motor conduction velocity was significantly slower in microalbuminuric (48.4(1.4) m/s) than in normoalbuminuric (52.7(1.2) m/s, p = 0.04) and non-diabetic subjects (56.7(0.9) m/s, p = 0.0001). In the diabetic group overall, there was a strongly positive linear correlation between vascular response to noradrenaline and conduction velocity in both the median nerve (r = 0.62, p = 0.0009) and peroneal nerve (r = 0.53, p = 0.006). There was no correlation between phenylephrine-induced responses and motor conduction velocity in either nerve, nor were indices of autonomic function correlated with vascular reactivity to either agent.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7851686 TI - Betel-nut chewing and diabetes in Papua New Guinea and elsewhere. PMID- 7851687 TI - The 29th Minkowski Prize winner 1994 Thomas Mandrup-Poulsen, Gentofte, Denmark. PMID- 7851688 TI - The role of interleukin-1 in the pathogenesis of insulin-dependent diabetes mellitus. PMID- 7851689 TI - 1994 Castelli Pedroli Prize, 9th Camillo Golgi Lecture John E. Tooke, Exeter, United Kingdom. PMID- 7851690 TI - The genetics of non-insulin-dependent diabetes mellitus: tools and aims. PMID- 7851691 TI - S15261, a new compound for the treatment of the insulin resistance syndrome. AB - A new oral agent, S15261 (the L-isomer of 3-[2-[2-[4-[2-[alpha-fluorenyl acetyl amino ethyl] benzoyloxy] ethyl amino] 1-methoxy ethyl] trifluoromethyl-benzene), has been developed for the treatment of the so-called "insulin resistance syndrome". In obese, insulin-resistant ageing Sprague-Dawley rats, chronic treatment with S15261 (0.5-2.5 mg.kg-1.day-1 twice per day, for 14 days) resulted in dose-dependent decreases in plasma insulin (43%), and triglyceride levels (36%), and in an increase of the glucose disposal rate during an intravenous glucose tolerance test (IVGTT) (48.5%). An increase in peripheral insulin sensitivity produced by S15261 was revealed by the glucose clamp technique. Thus, the glucose infusion rate was increased by 20% whilst steady-state insulin levels decreased by 15%. At the higher doses S15261 led to a decrease in body weight (3%), plasma glucose (13%) and blood pressure (8 mm Hg) in mildly hypertensive animals. At the doses used to achieve these results, the compound has no hypoglycaemic activity in normoglycaemic animals. Acute administration of S15261 directly into the portal vein provoked a marked increase in glucose disappearance rate during an intravenous glucose tolerance test (60%) and also in the pancreatic response to the glucose challenge. Thus, acute administration of the compound has a direct effect on glucose metabolism. These data suggest that S15261 could be a useful agent for the treatment of the insulin resistance syndrome. PMID- 7851692 TI - The feto-placental glucose steal phenomenon is a major cause of maternal metabolic adaptation during late pregnancy in the rat. AB - The aim of this study was to determine the extent to which a feto-placental glucose steal phenomenon contributes to the process of maternal metabolic adaptation to late pregnancy. Glucose metabolism was studied in virgin control, pregnant rats and virgin rats with a phlorizin-induced model of the feto placental glucose steal phenomenon. Whole body glucose kinetics and glucose uptake into individual tissues were measured in anaesthetised rats basally and during hyperinsulinaemic euglycaemic clamps. The basal glucose metabolism of the pregnant rats was closely mimicked by the phlorizin-treated rats. Basal plasma glucose was 39% and 38% lower (p < 0.0001 for both); hepatic glucose production was 21% and 26% higher (p < 0.05 for both); and plasma glucose clearance was 109% and 104% higher (p < 0.0001 for both) in the pregnant and phlorizin-treated rats, respectively, compared to the control rats. Basal glucose uptake into peripheral tissues was lower in both the pregnant and phlorizin-treated compared to the control rats, being most evident in heart (p < 0.01 for both) and brown adipose tissue (p < 0.001 for both). In the clamp studies, impairment of glucose uptake into skeletal muscle was observed in both the pregnant and phlorizin-treated rats compared to the control rats. In conclusion, the feto-placental glucose steal phenomenon is a major contributing factor to postabsorptive glucose metabolism in late pregnancy. This phenomenon also contributes to the impairment of maternal insulin-stimulated peripheral glucose uptake. PMID- 7851695 TI - [Magisterial conference "Miguel F. Jimenez". Science and anti-science in clinical nutrition]. PMID- 7851693 TI - Immunoneutralization of endogenous glucagon with monoclonal glucagon antibody normalizes hyperglycaemia in moderately streptozotocin-diabetic rats. AB - The role of glucagon in diabetic hyperglycaemia has been a matter of controversy because of difficulties in the production of selective glucagon deficiency. We developed a high-capacity (40 nmol/ml), high-affinity (0.6 x 10(11) l/mol) monoclonal glucagon antibody (Glu-mAb) and gave i.v. injections (4 ml/kg) to rats in order to study the effect of selective glucagon deficiency on blood glucose. Controls received a mAb against trinitrophenyl. Glu-mAb completely abolished the hyperglycaemic effect of 2.86 nmol/kg glucagon in normal rats (p < 0.05, n = 6). In moderately hyperglycaemic rats injected with streptozotocin as neonates (N STZ), Glu-mAb abolished a postprandial increase in blood glucose (from 11.2 +/- 0.7 mmol/l to 17.3 +/- 1.8 mmol/l in controls vs 10.5 +/- 0.9 mmol/l to 9.3 +/- 1.0 mmol/l; cross-over: n = 6, p < 0.05). No significant effect of Glu-mAb treatment was observed in more hyperglycaemic N-STZ rats (cross-over, n = 4) and in severely hyperglycaemic rats injected with STZ as adults (n = 6), but after insulin treatment of the latter, at doses partially restoring blood glucose levels (12.7 +/- 4.3 mmol/l), Glu-mAb administration almost normalized blood glucose (maximal difference: 6.0 +/- 3.8 mmol/l; cross-over: n = 5, p < 0.05). In conclusion, our results provide strong additional evidence for the hypothesis that glucagon is involved in the pathogenesis of diabetes. The hormone plays an important role in the development of STZ-diabetic hyperglycaemia, but glucagon neutralization only leads to normoglycaemia in the presence of insulin. PMID- 7851694 TI - Pancreatic Reg/pancreatic stone protein (PSP) gene expression does not correlate with beta-cell growth and regeneration in rats. AB - The Reg/pancreatic stone protein (PSP) gene is postulated to be an important regulator of pancreatic beta-cell growth. To investigate this hypothesis, we analysed the expression of the Reg/PSP gene following a 90% pancreatectomy and after chronic glucose infusion, two well-defined models of pancreatic beta-cell growth. There was a rapid induction of the Reg/PSP gene in the remnant pancreas after a 90% pancreatectomy in rats during the period of marked growth of the exocrine and islet tissue. However, a similar rapid, but smaller, induction of the Reg/PSP gene was observed in sham-operated rats and in non-surgical control rats in which there was no enhanced pancreatic growth. Furthermore, there was no pancreatic Reg/PSP gene induction in a model of selective beta-cell growth, the chronic glucose-infused rat. Thus, it is unlikely that Reg/PSP is a beta-cell specific growth factor, even though the function of this important pancreatic gene is still unknown. PMID- 7851696 TI - [Sensitivity, specificity, and predictive values of fine-needle biopsy in thyroid cancer]. AB - One-hundred and eleven patients were studied with the objective of exploring the diagnostic usefulness of the fine needle aspiration (FNA) biopsy in cases with cancer of the thyroid gland. The mean age of the total sample was 42.4 years, with 89 percent females. A thyroid gland FNA was done in all cases as well as a surgical intervention for the establishment of a definitive diagnosis (i.e., gold standard). The cytologic diagnosis was done by the same expert pathologist in all cases. The diagnostic accuracy was obtained using a 2 x 2 table. Sensitivity was found to be 72 percent and specificity 91 percent, with 85.5 percent of diagnostic accuracy. Taking into account a 30 percent prevalence in our sample, predictive values were found to be 81 percent for positive and 87 percent for negative. It is concluded that FNA is better than the gold standard in the following points: it is easy to do, it has lower risk, and it has lower discomfort and financial cost. FNA showed a better utility to identify the absence of cancer. This is a procedure which is recommended for use in hospitals similar to the General Hospital of Mexico S.S. as part of the presurgical diagnosis in cases with clinical suspicion of thyroid gland malignancy. PMID- 7851697 TI - [Surveillance of the clinical course of 6,030 surgical wounds]. AB - This report describes a 4 year prospective study of postoperative wound infections, utilizing a program of wound surveillance. Surgical wounds after 6030 operations of a general surgery service were surveyed by the authors and a specialist nurse, daily and in the follow up clinic for 30 days. Results were reported to all the surgeons monthly. The rates of infections demonstrated a decline over the years of surveillance. In the first year there was a 6.37 percent incidence of infection and the fourth year 4.7 percent. This represents an improvement in hospitalization days and expenses. PMID- 7851698 TI - [Electroretinography in non-insulin dependent diabetic patients]. AB - The objective of this study was to determine the amplitude and temporal changes of flash electroretinogram, in nondependent insulin diabetic patients without diabetic retinopathy. Electroretinograms (Cadwell Quantum 84, Colliere) were obtained in thirty two healthy people and thirty two non-dependent insulin diabetic patients. We found decreasing time of a and b waves, in 26 diabetic patients, which suggests early retinal changes. There were no significant changes in amplitude and oscillatory potentials. The abnormalities on waves a and b were present 6.6 years after an set of diabetes; however, a relationship was not found between electroretinogram changes and duration of diabetes. In conclusion, there are decreasing times in the electroretinogram of non-dependent insulin diabetic patients before funduscopic changes are evident. Suggesting that electroretinogram may be useful to know and to follow-up early funduscopic changes in diabetic patients. PMID- 7851699 TI - [Effect of iron deficiency on attention capacity among school children]. AB - The effect of iron deficiency on the attention span was studied in 169 school children between 6 to 11 years of age. All were studied by hematological procedures and psychological methods in order to know the nutritional status for iron and their capacity of attention. Then were treated with iron sulfate for 12 weeks, and the hematological and psychological studies were repeated. Results shown iron deficiency anemia in 17.1 percent of the children, and iron deficiency, without anemia, in 14.7 percent. After treatment of the school children the scores and time required in a visual attention test improved. Also there was a favorable change in the scores obtained by one the subtests of the WISC Test. Findings are discussed and it is mentioned that a program for combating iron deficiency anemia through food fortification most be implemented. PMID- 7851700 TI - [New perspective in liaison psychiatry. Experience at the Pediatric Hospital of the National Medical Center Siglo XXI]. AB - In hospitalized and chronically ill children, the prevalence of psychopathology is very high. It is necessary that in its prevention, diagnosis and treatment not only professionals of the mental health disciplines intervene but also that the pediatricians, nurses and the family of the patient himself participate actively. Consultation Liaison Child Psychiatry activities at the Pediatric Hospital of the National Medical Center "Siglo XXI" are described. Its goal is to incorporate the mental health professional to the team of hospital care and promote that pediatricians gain a greater conscience of psychological and social factors that are crucial for the sick child. PMID- 7851701 TI - [Usefulness of liver biopsy in the study of the pediatric patient. Review of 145 cases]. AB - There were reviewed 145 cases of children in which hepatic biopsy was done at the Hospital Infantil del Estado de Sonora, from 1978 to 1990. The larger age group were infants and preschool children (74.3 percent) males being predominant; signs and symptoms were related with hepatic illness, as well as the admission diagnoses. The indication of biopsy was for confirmation of liver disease in more than 50 percent, 37.1 percent for unknown diagnoses and 20.6 percent to look for liver disease by a systemic illness. The most usual procedure was percutaneous biopsy with Vim-Silverman needle in 111 cases (76.5 percent), in 23 percent, the biopsy was done by major surgical method. Nine percent of the children needed open surgical method after percutaneous biopsy. The time from the admission to biopsy performance in patients with neonatal hepatitis vs biliary atresia was 14 days. In other type of illness the time was 25 days. The morbidity was 1 percent. There was no mortality. The histopathologic diagnosis of liver diseases was done in 96 cases (66.7 percent) by this method in 31 children (21.3 percent) with investigation of jaundice (neonatal hepatitis vs biliary atresia). The diagnostic mistake in tissues obtained by percutaneous needle, was statistically significant (p < 0.05). Average hospitalization stay was less than two months in 70 percent of the cases. PMID- 7851703 TI - [Magisterial conference "Dr. Ignacio Chavez" 1993. Society and health: the commitment of the Mexican physician]. PMID- 7851702 TI - [Symposium: world summit on childhood]. PMID- 7851704 TI - [Deficits in gynecologic education in the examination technique of suspected sex offenses]. PMID- 7851705 TI - [Fathers as birth partners--current aspects]. PMID- 7851706 TI - [Partnership practice management]. PMID- 7851707 TI - [Tumor cell seeding caused by hysteroscopy?]. AB - 154 patients suffering from endometrial carcinoma who underwent CO2-hysteroscopy pretherapeutically, were examined as to whether hysteroscopy lead to tumour cell spread to the peritoneal cavity and worsened the prognosis of the patients. For that purpose, both fallopian tubes of 118 women were investigated thoroughly by histology for intratubarian spread of tumourous cells. Only in one of the 118 patients a single tumour cell complex was detected inside the ampullar part of a fallopian tube. Comparing the investigated patients with data from the literature in terms of five-year survival rates and frequency of relapses, our collective showed the same outcome as those from the literature. These results prove, that the prognosis of endometrial carcinoma is not worsened by CO2-hysteroscopy. PMID- 7851708 TI - [Risk of hematogenous metastasis of cancer of the uterine cervix]. AB - Metastasis development in cervical cancer was analysed retrospectively to determine whether haematogenic metastases occurred with higher frequency in younger women than in older women. Based on clinical and morphologic data, parameters for the identification of a high-risk group for the development of haematogenic metastases were established. The data of 533 patients who underwent therapy at the University Women's Hospital Berlin-Charlottenburg from 1970 to 1984 were evaluated. 11.8% of these patients developed haematogenic metastases. No significant difference was found in the 5-year risk for development of haematogenic metastases between different age groups. Furthermore, no increase in the incidence of haematogenic metastases was found in women under 35 years in the course of time. The influence of pretreatment characteristics for the development of haematogenic metastases was assessed in 185 patients who underwent surgery for cervical cancer from 1979 to 1984. Univariate as well as multivariate regression analysis of histopathologic characteristics in the surgical specimens revealed blood vessel invasion, tumour grading, dissociated tumour growth, and number of mitoses as important parameters for the occurrence of haematogenic metastases. In this study group, patient age strongly influenced the occurrence of haematogenic metastases. In contrast, prognostic parameters for the development of local recurrence of the disease were derived from morphologic data which described the locoregional spread of the tumour (staging, tumour growth beyond the cervix, involvement of the corpus uteri, and lymph node involvement).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7851709 TI - [Prenatal determination of lung maturity from amniotic fluid--indications and new methods]. AB - Although fetal lung maturity determination is carried out more and more rarely in the German-speaking area, a reliable information about the degree of lung maturity is still very important in the care of high-risk pregnancies. The side effects and costs of a postpartal surfactant administration can be avoided if lung maturity is proved. Indications for determination of fetal lung maturity are the threatening preterm delivery and the premature rupture of membranes before the 34th week of gestation and uncertain gestational age. Furthermore, in preeclampsia resp. in diabetes mellitus, which is difficult to control, premature delivery may be necessary. To improve lung maturity testing we introduce a new "sequence scheme" containing three lung maturity tests which are easy to carry out (in the following sequence: Amniostat-FLM ultrasensitive, counting of the lamellar bodies in amniotic fluid, surfactant/albumin ratio with TDx-FLM). The principle of this scheme is, that if any of these three tests indicates lung maturity, the sequence is terminated and no further test is performed. Only if all three tests indicated immaturity, the child was at risk for RDS. In 87 amniotic fluid samples with 7 RDS-cases, we achieved high predictive values for lung maturity (specificity 90%, sensitivity 100%, predictive value of positive test 47%, predictive value of negative test 100%). In 62% only one test was needed for lung maturity determination. It is possible to use other combinations in such a scheme (e.g. the L/S ratio). This might lead to equal or perhaps better results. An advantage of this suggested "sequence scheme" is that it can be performed in any clinic. PMID- 7851710 TI - [Quantitative determination of fetal fibronectin in cervical smears: a new marker for evaluating the risk of premature labor]. AB - There is a well-known correlation between ascending infection and preterm labour. Nevertheless, up to now an exact method to identify patients which are at high risk for preterm labour does not exist. Fetal fibronectin is an extracellular matrix protein, which is produced by fetal membranes. High concentrations are present in amniotic fluid, but not in cervical secretions in uncomplicated pregnancies (only in 3-4%). If there is an inflammatory mediated damage to fetal membranes (amnion/chorion) or a mechanical disruption caused by preterm contractions, fetal fibronectin should be released into the cervix and vagina. A prospective clinical study measuring quantitatively the content of fFN in cervicovaginal secretions in patients with preterm labour (n = 43), preterm rupture of membranes (n = 15) and 20 controls was undertaken. In 16 patients frequent specimen could be obtained over a period of several weeks. 14 of the 34 patients with preterm labour, which could be observed until delivery, delivered before term (< 37. WOP). In 13 fFN was present in a concentration > 75 ng/ml (sensitivity: 92.4%). 13 patients were negative for fFN and only one of these patients delivered before term (92% chance of term delivery in absence of fFN in cervicovaginal fluids). In 8 patients with beta-adrenergic treatment fFN was present. All patients delivered before term. The 15 patients with PROM had very high concentrations of fFN with a medium concentration of 967.3 ng/ml. 18 of the 20 control patients were negative for fFN (< 75 ng/ml), 2 had a slightly elevated concentration of 84 and 85 ng/ml.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7851711 TI - [Contraception in patients with type I diabetes: a survey of 808 women of reproductive age]. AB - In-depth advice about contraception is important for type I diabetic women since special medical aspects have to be considered and because pregnancy should be planned. The actual contraceptive practice in diabetic women living in Germany had not been investigated before. METHODS: In December 1992 type I diabetic women of 16 to 46 yrs of age who had consecutively participated in a diabetic treatment and teaching programme (n = 1028) were mailed a multiple-choice questionnaire about reproductive and contraceptive issues. 409 non-diabetic women were also questioned and served as a control group. RESULTS: 808 diabetic women (age 32[7] yrs, duration of diabetes 14[8] yrs) returned the questionnaire. The percentage of women using a method of contraception was comparable between diabetic and control women (76 vs. 72%). Of these, fewer diabetic women used oral contraceptives (OC) (33 vs. 57%). The OC-using diabetic women were younger than those using other methods (27[5] vs. 33[7] yrs), however 63% had at least one of the contraindications for OC-use (smoking, hypertension, proteinuria, retinopathy, poor metabolic control) and 18% were using high-dose preparations. More diabetic than control women used IUDs (19 vs. 12%) and more diabetic women were sterilised (19 vs. 9%). Compared to controls diabetic women had had sterilisation at a younger age (31[5] vs. 36[4] yrs) and more sterilised women were childless (29 vs. 14%). Methods of lower efficacy (condom, diaphragma, spermatocides) were used by 26% of diabetic women (controls 20%), p < 0.05. Nearly half of the diabetic women had received contraceptive advice exclusively by gynaecologists. 22% of all pregnancies were unplanned (controls 17%); 0 > 0.05). CONCLUSION: More diabetic women should use methods of contraception with high efficacy. However, when prescribing OCs more attention must be payed to special contraindications. Sterilisation should be recommended more cautiously to diabetic women without advanced diabetic complications. Contraceptive advice to diabetic women must be given by gynaecologists and diabetologists. PMID- 7851712 TI - [A rapid method for diabetes screening in pregnancy]. AB - Gestational diabetes affects about 3% of pregnancies in German-speaking countries. Roughly one third of these pregnancies develop a requirement of insulin. In unrecognised and hence untreated pregnancies, perinatal morbidity and mortality are increased 20-fold. Gestational diabetes is asymptomatic and only 60% of patients have risk factors for the condition; thus, general screening with oral glucose tolerance testing is necessary to detect all cases. Most antenatal medical care is provided by gynaecologists in practice and by general practitioners who do not have a sophisticated laboratory at their immediate disposal. General screening requires a test that is simple, inexpensive and quick but nonetheless meets high quality standards. A new microcuvette rapid test fulfills these requirements; the results are ready within a few minutes' time. We performed parallel blood glucose measurements with a standard enzymatic method and with the rapid test in 500 unselected pregnant women undergoing an oral glucose tolerance test at our obstetric clinic. The mean fasting, 1-hr and 2-hr values were 77,128 and 106 mg/dl, respectively, as measured by the enzymatic test and 75,129 and 107 mg/dl as measured by the rapid test. The results of the reference enzymatic method and the rapid test agreed at a high level of significance (r = 0.98; p < 0.0001). PMID- 7851714 TI - In memoriam Lev G. Leibson (1900-1994). PMID- 7851713 TI - [HELLP syndrome and manifestation of type I diabetes mellitus in pregnancy]. AB - HELLP syndrome (haemolysis, elevated liver function tests and low platelets) is a multiorganic disease and has been described in combination with pre eclampsia/eclampsia, but even without symptoms of gestosis. There are signs, that HELLP syndrome represents an "acute status of autoimmunity". Since immune mechanisms play a fundamental role together with other factors in the development of type I diabetes mellitus, a combination of autoimmune reactions could explain the development of type I diabetes during an altered immune status. We report on the course of a pregnancy complicated by HELLP syndrome, which developed type I diabetes mellitus in the same pregnancy. A subsequent pregnancy with adequate diabetes therapy was uncomplicated and without recurrence of HELLP syndrome. PMID- 7851715 TI - Testosterone levels and the free running rhythm of feeding activity in Japanese quail in darkness. AB - Castrated male Japanese quail were reared in total darkness for 7 months. In order to mimic changes in concentration of plasma testosterone during sexual development, the birds were implanted on three occasions with increasing numbers of testosterone-filled capsules. The feeding activity of each bird was recorded and concentrations of plasma testosterone were measured before and after capsules were implanted. The concentration of testosterone was around 0.05 ng/ml and the period of the free running feeding rhythm was 22.5 hr before testosterone-filled capsules were implanted. The free running period lengthened after testosterone filled capsules were implanted in 79% of the cases (N = 66), with a direct relationship between the concentration of plasma testosterone and the length of the free running period of the feeding rhythm. A direct relationship between the variation of the amount of feeding activity and the variation of the period of the free running rhythm was also established. During a seasonal breeding cycle, this change in circadian organization would lead to a slower advance of feeding activity, allowing the dawn chorus to precede the daily onset of feeding activity as well as result in a better adjustment of daily foraging time. PMID- 7851716 TI - Changes in plasma levels of 17 beta-estradiol after administration of an analogue of luteinizing hormone releasing hormone (LHRH-A) and pimozide in Diplectrum formosum (Teleostei: Serranidae). AB - Gonadotropin secretion in teleosts is known to be stimulated by gonadotropin hormone releasing hormone (GnRH) and inhibited by dopamine. This study has investigated the effects of administration of pimozide (PIM) alone or in combination with an analogue of GnRH on plasma 17 beta-estradiol (17 beta-E) levels and the gonadosomatic index. Adult Diplectrum formosum were treated with a gonadotropin-releasing hormone analogue [des-Gly10 D-Ala6 Pro9 N-ethylamide (LHRH A); 50, 70, and 100 ng/g body wt] alone or in combination with pimozide (PIM), a dopamine antagonist (0.5, 1.0, and 5.0 micrograms/g body wt). LHRH-A alone caused a dose-dependent increase in plasma 17 beta-E levels. A single injection of PIM (0.5 or 5.0 micrograms/g) 12 hr previous to a single injection of 100 ng/g body wt of LHRH-A increased 17 beta-E concentrations compared with fish receiving PIM alone; however, 1 microgram/g PIM did not change 17 beta-E plasma levels. Simultaneous administration of PIM (0.5, 1.0, and 5.0 micrograms/g body wt) and 100 ng/g body wt of LHRH-A at an interval of 12 hr (30% of the total dose of both PIM and LHRH-A was administered in the first injection and 70% in the second injection) significantly increased plasma 17 beta-E concentrations. The magnitude of this increase was at least threefold higher than those of fish receiving a single injection of PIM, 12 hr before a single injection of LHRH-A. LHRH-A or PIM alone or combined was ineffective in causing ovulation. PMID- 7851717 TI - Cloning, expression, and characterization of a recombinant gilthead seabream growth hormone. AB - cDNA clones coding for the gilthead seabream (Sparus aurata) growth hormone (sbGH) were isolated from a pituitary expression library using a flounder cDNA probe. The nucleotide sequence of a GH cDNA clone containing an insert of 896 nucleotides was determined. The cDNA encoded a polypeptide of 204 amino acids including a signal peptide of 17 amino acids and contained a 5' and a 3' untranslated region of 48 and 233 nucleotides, respectively. The mRNA determined by Northern blot was approximately 1 kb. Amino acid sequence homologies of 97.1% with red seabream GH, 88.9% with the tuna GH, and 67% with the coho salmon GH was found. Transient expression of a sbGH cDNA was done in HeLa cells by induction with a vaccinia virus system, and the expressed GH was detected by immunofluorescence and immunoprecipitation with a specific antibody to the native sbGH. The sbGH cDNA was expressed in Escherichia coli by using the pGEX-3X and the pET-3a expression systems. The recombinant sbGH expressed in the pET-3a system was similar, if not identical, to the native hormone when analyzed by homologous radioimmunoassay and receptor binding assay. PMID- 7851718 TI - Purification and characterization of 17 alpha,20 beta-dihydroxy-4-pregnen-3-one binding protein from plasma of rainbow trout, Oncorhynchus mykiss. AB - A 17 alpha,20 beta-dihydroxy-4-pregnen-3-one (17 alpha,20 beta-DP) (the natural maturation-inducing hormone of salmonid fish) binding protein (DBP) was purified from rainbow trout plasma. It had an apparent molecular weight of 110 kDa on native PAGE and was composed of two subunits with molecular weights of 50 and 55 kDa on SDS-PAGE. Enzymatic digestion of sugar chains converted both subunits to a single peptide with a molecular weight of 42.5 kDa. Scatchard analysis of 17 alpha,20 beta-DP binding to purified DBP showed the presence of a single binding site with a Kd of 21 nM and Bmax of 5 nmol/mg of protein. The affinities of various steroids were estimated by the displacement of [3H]17 alpha,20 beta-DP binding in the decreasing order of 17 alpha,20 beta-DP, testosterone, 17 alpha hydroxyprogesterone, progesterone, estradiol-17 beta, 17 alpha,20 beta,21 trihydroxy-4-pregnen-3-one, and cortisol. We conclude that DBP is a sex-hormone binding globulin in rainbow trout. PMID- 7851719 TI - Prolactin, growth hormone, and luteinizing hormone-beta subunit gene expression in the cephalic and caudal lobes of the anterior pituitary gland during embryogenesis and different reproductive stages in the chicken. AB - Messenger RNA (mRNA) levels of prolactin (PRL), growth hormone (GH), and luteinizing hormone (LH)-beta subunit in the cephalic and caudal lobes of the anterior pituitary gland of the chicken during embryonic development and different reproductive stages were determined by Northern blot analysis and are related to hormone levels in plasma and each lobe. Steady-state levels of 1.4-kb transcript of PRL of the cephalic and caudal lobes increased on Days 18 and 20 of incubation, respectively. The levels were greater in the cephalic lobe than in the caudal lobe on Days 18 and 20 of incubation. Levels of PRL in each lobe show similar changes to those of mRNA levels. GH mRNA levels of both lobes started to increase on Day 16 of incubation but the levels were higher in the caudal lobe than in the cephalic lobe on Days 16-20 of incubation. Levels of GH in the cephalic lobe increased discontinuously, while those in the caudal lobe increased continuously on days of incubation. LH-beta mRNA was not detected in embryos. Levels of PRL mRNA increased approximately 18-, 20-, and 3-fold in hens at 1 and 3 weeks of egg incubation and brooding stages in the hen, relative to prelaying, respectively. These levels were higher in the cephalic lobe than in the caudal lobe at all stages except for prelaying stages. Levels of PRL in each lobe displayed essentially similar changes to the mRNA levels. GH mRNA levels did not significantly vary during the cycle but were higher in the caudal lobe than in the cephalic lobe. There was no difference in LH-beta mRNA levels between the two lobes but the levels were higher at prelaying and laying stages than at incubation and brooding stages.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7851720 TI - Plasma androgen levels, spermatogenesis, and secondary sexual characteristics in two species of plethodontid salamanders with dissociated reproductive patterns. AB - In the summer of 1991 (late May to early September), I measured seasonal levels of plasma androgens in two species of plethodontid salamanders to assess the temporal relationship of elevated plasma androgen levels with spermatogenic events and with sexual behavior. In both species, spermatogenesis occurs in the spring and summer. In one species, Plethodon jordani, mating occurs in the fall. In the other species, Desmognathus ochrophaeus, the mating season is prolonged, occurring both in the fall and in the spring. In P. jordani, plasma testosterone (T) levels were lowest in June and highest in late August, such that elevated plasma T levels coincided with the development of secondary sexual characteristics and the time when mating behavior occurs. Plasma dihydrotestosterone (DHT) levels for P. jordani were lowest in June and rose significantly in mid July when spermiation began. In D. ochrophaeus, plasma T and DHT levels were lowest during June and July and highest in late August. Elevated T and DHT levels coincided with spermiation and with the period when mating behavior occurs. Data for these two salamander species indicate that maximally elevated plasma androgens were temporally dissociated from the peak of spermatogenesis; maximal androgen levels were more closely associated with spermiation and the development of secondary sexual characteristics. PMID- 7851721 TI - Melatonin activity rhythms in eyes and cerebral ganglia of Aplysia californica. AB - In this study, we used a sensitive and specific radioimmunoassay to detect a substance which appears to be melatonin, an acetylation and methylation product of serotonin, in the eyes and central nervous system of the opisthobranch mollusc Aplysia californica. This identification was confirmed in the eyes by HPLC with fluorimetric detection. Melatonin activity was high in the eyes during the day and in the cerebral ganglia during the night. Only small amounts of melatonin were present at midday or midnight in the pedal ganglia. A single 1-hr exposure to light in the middle of the dark phase resulted in a sharp increase of melatonin in the eyes, whereas no such activity was detectable in cerebral and pedal ganglia. Eyes maintained in culture exhibited a diurnal rhythm of released melatonin activity over a 3-day period. These results suggest that melatonin is produced in A. californica in a rhythmic pattern different from that associated with pineal melatonin production in vertebrates. PMID- 7851722 TI - Hormonal regulation of final maturation of striped bass oocytes in vitro. AB - An in vitro culture system was developed to investigate hormonal control of final oocyte maturation (FOM) in striped bass (Morone saxatilis). Isolated ovarian fragments exposed to human chorionic gonadotropin (hCG), dibutyryl cAMP, or forskolin produced significant amounts of 17 alpha,20 beta-dihydroxy-4-pregnen-3 one (DHP) and the oocytes underwent germinal vesicle breakdown (GVBD). Slight increases in 17 alpha,20 beta,21-trihydroxy-4-pregnen-3-one (20 beta-S) production were also observed. Production of testosterone and estradiol-17 beta was relatively high at the beginning of in vitro treatment with hCG but decreased as production of DHP increased and GVBD was initiated. Inhibitors of protein transcription (actinomycin-D), translation (cycloheximide), and steroidogenesis (trilostane) completely blocked hCG-induced DHP and 20 beta-S production and the associated GVBD. FOM, assessed from the progress of GVBD, proceeded in trilostane treated but not in cycloheximide-treated follicle-enclosed oocytes when DHP or 20 beta-S was added to the cultures. Structure-activity experiments revealed that DHP and 20 beta-S were more potent at inducing GVBD than 14 other structurally similar C21 steroids that were tested. These results demonstrate that FOM in striped bass is induced by gonadotropin-mediated production of a delta 4 steroid through an adenylate-cyclase pathway which requires protein synthesis. DHP and 20 beta-S are implicated as final oocyte maturation-inducing steroid hormones in striped bass. PMID- 7851724 TI - Temperature-dependent sex determination in the snapping turtle: manipulation of the embryonic sex steroid environment. AB - In certain reptiles with temperature-dependent sex determination (TSD), estrogens act as a signal for female differentiation. Because aromatase produces estrogens from androgens, this enzyme plays a pivotal role in TSD. Whether androgens act as the signal for male differentiation in TSD species in not yet clear. We manipulated the hormonal environment in eggs of the common snapping turtle (Chelydra serpentina) to determine the effects of an estrogen (estradiol 17 beta), an aromatase inhibitor (fadrozole; CGS 16949A), and androgens (testosterone and dihydrotestosterone) on sex determination in this TSD species. Test solutions were applied topically to representative eggs (total tested = 1054 from 27 clutches) and incubated at two male-producing temperatures (24 and 26.5 degrees) and at a predominantly female-producing temperature (29 degrees). In this species, application of an estrogen induced female development at all temperatures tested. In contrast, the aromatase inhibitor had no effect at the male-producing temperatures, but induced male development at the predominantly female-producing temperature. At this temperature, aromatase inhibitor plus testosterone had a similar male-producing effect, but when applied alone, testosterone failed to augment male production. Dihydrotestosterone had a similar effect, in contrast to its reported androgenic effects in other TSD species. In the snapping turtle, male differentiation may not be androgen dependent; rather, it may proceed in the absence of female differentiation. In this species, female development is clearly estrogen-dependent and is altered by aromatase inhibition at female-producing temperatures. Our results not only provide additional evidence that sex steroids mediate gonadal differentiation in TSD species, but also suggest caution with respect to generalizations about the proximal mechanisms of TSD in reptiles. PMID- 7851723 TI - Molecular cloning of a cDNA encoding the prepro-salmon gonadotropin-releasing hormone of the red seabream. AB - Complementary DNA fragments encoding the prepro-salmon gonadotropin-releasing hormone ([Trp7, Leu8]GnRH, sGnRH) of the red seabream Pagrus major were amplified from mRNA of the olfactory bulbs using a reverse transcriptase-polymerase chain reaction (RT-PCR), and the full-length cDNA was cloned from a cDNA library using the PCR-amplified cDNA as a probe. The cDNA consisted of 442 bp, including an open reading frame of 270 bp which encoded the prepro-sGnRH (90 amino acid residues). The prepro-sGnRH had the same architecture as that reported in other species. It was composed of a signal peptide, sGnRH and a GnRH-associated peptide (GAP), which was connected to sGnRH by a Gly-Lys-Arg sequence. The prepro-sGnRH of the red seabream had 90% amino acid identity to the prepro-sGnRH from an African cichlid Haplochromis burtoni which belongs to the same suborder as the red seabream; however, identity was lower to the prepro-sGnRH from Atlantic salmon Salmo salar (74%) and masu salmon Oncorhynchus masou (70%). The GnRH peptide itself and the Gly-Lys-Arg sequence in the prepro-GnRH are highly conserved among vertebrates. The red seabream GAP also shows significant amino acid identity to the GAPs of the African cichlid (89%), Atlantic salmon (74%), and masu salmon (67%), but exhibits no significant identity to chicken or mammalian GAP. PMID- 7851725 TI - Sulfate conjugates of catecholamines in the allantoic fluid of the chicken embryo. AB - In addition to free dopamine (DA), norepinephrine (NE), and epinephrine (E), the allantoic fluid of the 13-day-old chicken embryo contains sulfate conjugates of these three catecholamines (CAs). The concentration of DA sulfate is relatively low, while NE and E sulfates occur at levels similar to those of the free fractions. The comparatively low concentration of free CAs in the amniotic fluid, seen in a previous study, is confirmed. However, the amniotic barrier for sulfated CAs is much stronger, possibly absolute. Though some technical difficulties remain to be resolved, the chicken embryo may become a useful model for the study of the prenatal functions of CA conjugates. PMID- 7851726 TI - Atrial natriuretic factor in the freshwater turtle Pseudemys scripta: a partial characterization. AB - The presence of natriuretic and vasorelaxant materials in the atria and ventricles of a Chelonian reptile, the freshwater turtle Pseudemys scripta, was verified and the active substance partially characterized. Crude atrial and ventricular extracts were acutely natriuretic and diuretic when administered to anesthetized rats increasing sodium excretion 23.5 +/- 7.9 and 5.11 +/- 18 microM Na/10 min/mg extract, respectively. Although atrial extracts were relatively more natriuretic than ventricular extracts, the total natriuretic content of ventricular extracts was approximately twofold greater. Moreover, partially purified atrial extracts were found to relax precontracted isolated rat aortic ring segments and exhibited immunoreactivity to mammalian ANP antisera. Also, the natriuretic and immunoreactive substance was purified further by size exclusion chromatography and a molecular weight of 3-5 kDa was determined. Using the bovine adrenal glomerulosa ANP receptor, this partially purified natriuretic substance displayed an apparent binding affinity similar to that of mammalian ANP. Finally, in order to demonstrate that this reptile is physiologically responsive to ANP, synthetic rat ANP (10 micrograms/kg) was shown to decrease arterial pressure in conscious turtles from a control value of 37.2 +/- 5.2 to 30.3 +/- 2.7 mm Hg. These data demonstrate that unlike other non-Chelonian reptiles, both the atria and the ventricles of this Chelonian reptile synthesize and store substantial levels of biologically active ANP-like materials, and further, that ANP is a highly conserved and primitive cardiac hormone. PMID- 7851727 TI - Insulin-like growth factor II in the horse: determination of a cDNA nucleotide sequence and expression in fetal and adult tissue. AB - Horse cDNA for insulin-like growth factor II (IGF II) has been isolated. cDNA was synthesized from bulk mRNA and subsequently PCR-amplified and sequenced. Like its human counterpart, the mature horse IGF II peptide contains 67 amino acids with only two substitutions, isoleucine instead of valine in position 35 and asparagine instead of serine in position 36. The nucleotide homology was 92.1% between horse and human and 87.8% between horse and mouse. The isolated cDNA hybridized to multiple transcripts in fetal and adult tissues, thus confirming earlier reports on developmental expression of this gene in the horse. PMID- 7851728 TI - Cortisol-induced hepatic vitellogenin mRNA in Oreochromis aureus (Steindachner). AB - Cortisol triggers rapid but transient transcription of the silent vitellogenin (Vg) gene in male Oreochromis aureus, producing short-lived Vg mRNA. Implantation of cocoa butter containing cortisol at 0.8, 8, 20, and 40 micrograms/g fish body wt induced hepatic Vg mRNA within 1 or 2 hr. Implantation of cortisol at the lowest of these dosages (0.8 micrograms/g body wt) produced a transient surge in serum cortisol within 1 hr. This is equivalent to a 30-fold increase over that of the resting male fish in which the endogenous cortisol levels measured 10.5 +/- 2.39 and 11.4 +/- 3.1 ng/ml, respectively, for fish kept communally or singly. Although sham implantation with cocoa butter also resulted in the elevation of serum cortisol, the rise was much more gradual, only reaching a peak after 6 hr. Thus, parameters like the treatment regime, sampling time intervals after implantation, and the interaction between these two factors can significantly affect the serum cortisol concentrations (P = 0.001). Although implantation of cocoa butter with or without cortisol increased serum cortisol, albeit unsynchronized, Vg mRNA was detected only in the hormone-treated group. The profile of Vg mRNA accumulation appeared to coincide with that of serum cortisol, further suggesting the activating effect of exogenous cortisol on Vg gene. Compared with an earlier study on estradiol-induced Vg gene expression, the action of cortisol was more rapid, but transient. This is reflected in the rapid clearance of the cortisol-induced Vg mRNA and, hence, the lack of plasma Vg protein during cortisol treatment. PMID- 7851729 TI - Gas chromatographic-mass spectrometric (GC-MS) analysis of gonadal steroids in plasma of the male African catfish, Clarias gariepinus: effects of castration or treatment with gonadotropin releasing hormone analogue. AB - To identify testicular steroids that may be involved in the feedback mechanisms of the hypothalamus-pituitary-gonad axis in African catfish, Clarias gariepinus, steroids, which are known to be produced by the testis in vitro, were identified and quantified in blood plasma before and after castration using gas chromatography followed by mass spectrometry. Before castration 20 testicular steroids were detected. Quantitatively dominant steroids were testosterone (16.9 +/- 4.3 ng/ml), androstenedione (12.0 +/- 3.9 ng/ml), and 11-ketotestosterone (6.7 +/- 1.8 ng/ml). After castration, only these steroids showed a strong decrease in plasma, indicating that they are of testicular origin. Assuming that steroids involved in the feedback to the pituitary are under gonadotropic control, fish were injected with two doses of a salmon gonadotropin releasing hormone analogue (sGnRHa). The lower sGnRHa dose (0.25 microgram/kg body weight) increased plasma GTH-II levels in the same range as those induced by castration, resulting in a significant increase in plasma levels of testosterone, androstenedione, and 11-ketotestosterone. After injection of a higher dose of sGnRHa (5.0 micrograms/kg body weight), there was a greater increase in plasma GTH-II level, as well as a significant increase in most of the other steroids studied. The decreased levels of testosterone, androstenedione, and 11 ketotestosterone after castration and the significant increase in these steroids following moderate GTH stimulation, suggest that one or more of these steroids plays a role in the feedback mechanism within the hypothalamus-pituitary-gonad axis. PMID- 7851730 TI - Steroid 5 alpha-reductase activity in the harderian glands of male and female Syrian hamster (Mesocricetus auratus). AB - The activity of the enzyme steroid 5 alpha-reductase in Harderian glands of adult syrian hamsters was assessed by measuring the conversion of testosterone (T) to 5 alpha-dihydrotestosterone (DHT). The optimal conditions for this reaction were determined in vitro using whole gland homogenates and [3H]testosterone as substrate. Enzyme activity was maximal at pH 5.5. The Michaelis-Menten constant of the Harderian enzyme for T was 4.6 +/- 1.2 x 10(-6) M in females and 4.2 +/- 0.39 x 10(-6) M in males, estimated by Eadie-Hofstee plots. On the basis of relative maximum velocity values, there was 9 or 10 times more 5 alpha-reductase in females (2.8 +/- 0.67 nmol/mg protein/hr) than in males (0.289 +/- 0.029 nmol/mg protein/hr). Consistently, glands of intact male hamsters had lower 5 alpha-reductase activities than those of females. Castration of males significantly increased the enzymatic activity, which within 4 weeks reached female-like values. The levels of 5 alpha-reductase mRNA also increased with castration. There was a direct correlation between activity and mRNA levels of the enzyme in castrated male glands. Further, the administration of T or DHT to ovariectomized hamsters led to intact male values in the enzymatic activity of the gland. The sex differences in 5 alpha-reductase activity may be of relevance to the differential regulation exerted by androgen upon the physiology of male and female glands. The results are consistent with the view that 5 alpha dihydrotestosterone is the active androgen in the Harderian gland. PMID- 7851731 TI - Time course of release of pheromonally active gonadal steroids and their conjugates by ovulatory goldfish. AB - Previous studies have demonstrated that ovulatory goldfish synthesize and release a variety of steroids into the water, where some of them function as sex pheromones. Among the steroids which have been measured are free androstenedione, testosterone, 17 alpha,20 beta-dihydroxy-4-pregnen-3-one (17,20 beta-P), 17 alpha,20 beta,21-trihydroxy-4-pregnen-3-one (17,20 beta,21-P), 17 alpha-hydroxy-4 pregnene-3,20-dione (17-P), 11-deoxycortisol (17,21-P), and 17 alpha,20 alpha dihydroxy-4-pregnen-3-one (17,20 alpha-P), glucuronidated testosterone, 17,20 beta-P, and 17,20 beta,21-P, and sulfated 17,21-P, 17,20 beta-P, and 17,20 beta,21-P. This study reports the changes in the amounts of these steroids released into the water, at 3-hr intervals, by 12 female goldfish injected with human chorionic gonadotrophin (HCG). Eight fish ovulated. The amounts of steroids released into the water were significantly higher in the fish which ovulated than in those which did not. The peak rate of release (ng per hour) of free androstenedione (91), glucuronidated testosterone (143), and sulfated 17,21-P (33) occurred at ca. 4 hr postinjection; free 17-P (163) and free 17,21-P (217) at ca. 6 hr.; free 17,20 beta-P (58) and free 17,20 beta,21-P (58) at ca. 7.5 hr; and glucuronidated 17,20 beta-P (96), glucuronidated 17,20 beta,21-P (264), sulfated 17,20 beta-P (64) and sulfated 17,20 beta,21-P (153) at ca. 9 hr. Amounts of all of the steroids were at their lowest between 12 and 15 hr and, in the ovulated fish, had risen significantly again between 18 and 21 hr. The amounts of glucuronidated testosterone, 17,20 beta-P and 17,20 beta,21-P, and of sulfated 17,20 beta-P and 17,20 beta,21-P, in water exceeded those of free steroid. Elevated levels of free and glucuronidated steroids were also found in the blood plasma of HCG-injected fish. Considerably more androstenedione than testosterone was released into the water. Assessment of the "pheromonal effectiveness" of each steroid indicated that the free and sulfated forms of 17,20 beta-P and 17,20 beta,21-P, and androstenedione were the most important pheromonal steroids released by female goldfish. PMID- 7851732 TI - The oxidative stress response in Bacillus subtilis. AB - Bacillus subtilis undergoes a typical bacterial stress response when exposed to low concentrations (0.1 mM) of hydrogen peroxide. Protection is thereby induced against otherwise lethal, challenge concentrations (10 mM) of this oxidant and a number of proteins are induced including the scavenging enzymes, catalase and alkyl hydroperoxide reductase, and a putative DNA binding and protecting protein. Induced protection against higher concentrations (10-30 mM) of hydrogen peroxide is eliminated in a catalase-deficient mutant. Both RecA and Spo0A influence the basal but not the induced resistance to hydrogen peroxide. A regulatory mutation has been characterized that affects the inducible phenotype and is constitutively resistant to high concentrations of hydrogen peroxide. This mutant constitutively overexpresses the proteins induced by hydrogen peroxide in the wild-type. The resistance of spores to hydrogen peroxide is partly attributable to binding of small acid soluble proteins by the spore DNA and partly to a second step which coincides with the depletion of the NADH pool, which may inhibit the generation of hydroxyl radicals from hydrogen peroxide. PMID- 7851733 TI - The use of arbitrarily primed PCR (AP-PCR) to develop taxa specific DNA probes of known sequence. AB - A rapid polymerase chain reaction (PCR) method to obtain taxa-specific DNA probes has been developed. The oligonucleotide probes derived from the sequences of species-specific (or other taxa) random amplified polymorphic DNA (RAPD) fragments. The methodology was applied to design probes for the halophilic archaeal species Haloferax mediterranei. With this technique, DNA probes of known sequence can be generated easily and without any previous knowledge about the properties of the microorganisms. PMID- 7851734 TI - Role of the exosporium in the stability of the Bacillus sphaericus binary toxin. AB - The persistence of toxicity of the Bacillus sphaericus 1593 binary toxin was compared when produced in B. sphaericus, inside the exosporium, or in a recombinant B. thuringiensis strain, outside the exosporium. The stability of the toxin crystal was affected by temperature and quality of the water, but not by the location of the production in the bacterial cell. PMID- 7851735 TI - Transcriptional analysis of the Clostridium cellulovorans endoglucanase gene, engB. AB - An endoglucanase gene, which was shown to be identical to the previously sequenced engB gene [Attwood et al. (1993) Abstr. Ann. Meet. Am. Soc. Microbiol.], was isolated from a Clostridium cellulovorans genomic library. Because of the lack of transcriptional information concerning engB we examined its expression in C. cellulovorans and in the heterologous hosts Escherichia coli and C. acetobutylicum following transformation of engB. Northern analysis suggested that both E. coli and C. acetobutylicum produced several transcripts of various sizes. C. cellulovarans produced a single transcript of 1600 bp with the relative amount of engB mRNA from cellulose-grown cells being much greater than that from cellobiose-grown cells. Primer extensions showed that engB was transcribed from a single transcription initiation site in C. cellulovorans preceded by sequences similar to promoter sequences found in Gram-positive bacteria. Primer extensions from both E. coli and C. acetobutylicum strains containing the engB gene showed multiple transcription initiation sites, none of which corresponded to the site determined in C. cellulovorans. We conclude that transcriptional control of the engB gene is less stringent in heterologous backgrounds and postulate that expression of the engB gene in C. cellulovorans is increased in the presence of cellulose. PMID- 7851736 TI - Cloning and nucleotide sequence analysis of the Lactobacillus delbrueckii ssp. lactis DSM7290 cysteine aminopeptidase gene pepC. AB - A genomic library of Lactobacillus delbrueckii ssp. lactis DSM7290 in the low copy number vector pLG339, was screened for the presence of peptidase genes. Using the chromogenic substrate gly-ala-beta-naphthylamide, which is not a substrate for any of the recently cloned peptidases of DSM7290, and the multiple peptidase deficient Escherichia coli strain CM89, allowed the isolation of clones, which contained the equivalent hydrolytic activity. To identify genes encoding the conserved catalytic active site of cysteine proteases, partial nucleotide sequencing with a degenerate oligonucleotide was performed on recombinant plasmids isolated from such clones. This allowed to identify two out of nine clones to carry the Lactobacillus pepC gene. A total of 2026 nucleotides were determined, and sequence analysis revealed a gene with strong homology to the recently cloned Lb. helveticus (73.2%) and Lactococcus lactis (51.03%) pepC genes, and the derived protein showed homology with the active site of a large number of cysteine proteases. The predicted open reading frame consists of 449 codons, coding for a protein of 50,909 Da. The enzyme is functional and extremely overexpressed in E. coli. PMID- 7851737 TI - Cryptic plasmids from Lactobacillus helveticus and their evolutionary relationship. AB - Three different cryptic plasmids from Lactobacillus helveticus have been identified and their DNA sequences determined. Analysis and comparisons of their primary structures revealed stretches of DNA with considerable homology. Thus, large portions of the plasmid non-coding sequences were conserved at 80-90% identity between the different plasmids identified so far in L. helveticus. Nevertheless, different plasmids found in a same host strain utilise different genes of replication, probably acquired during evolution from different replicons from Gram-positive bacterial origins. A remnant structure of such a possible genetic integration of a foreign replication gene into one of the plasmids of L. helveticus was identified. PMID- 7851738 TI - Characterization and expression of the pepN gene encoding a general aminopeptidase from Lactobacillus helveticus. AB - An aminopeptidase N (pepN) gene was detected by DNA hybridization from an industrially important Lactobacillus helveticus strain using part of the L. helveticus CNRZ32 pepN gene as the probe. One of five hybridization positive clones was characterized in more detail. A subcloned 3.7 kb fragment, positive in hybridization and encoding aminopeptidase activity, was sequenced and analyzed. Only one open reading frame (ORF) of 2532 base pairs with a coding capacity for a 95.9 kDa protein could be found. The deduced amino acid sequence of the 95.9 kDa protein showed homology to PepN proteins from other lactic acid bacteria and carried the conserved catalytic and zinc binding sites of the neutral zinc metallo-peptidase family confirming the identity of the pepN gene. A 2.75 kb transcript and two transcription start sites were identified with mRNA analyses. Expression of pepN in L. helveticus, studied as the function of growth, revealed a high level of pepN transcripts throughout the growth, in contrast to the steady state levels of other peptidase mRNAs from L. helveticus analyzed in our laboratory. PMID- 7851739 TI - Inconsistency between the fimbrilin gene and the antigenicity of lipopolysaccharides in selected strains of Porphyromonas gingivalis. AB - Immunochemical specificity of lipopolysaccharide and the molecular property of the gene encoding the fimbrilin (fimA) of Porphyromonas gingivalis strains were examined using 'fimbriated' strains 381 and HG564 and 'non-fimbriated' strains 381FL and W50. Lipopolysaccharide from strains 381, 381FL and HG564 reacted with monoclonal antibody raised to lipopolysaccharide from strain 381 to give a fused precipitin band by the immunodiffusion test. However, silver staining and Western blotting of lipopolysaccharide clearly revealed a difference in profile of bands between strains 381 and 381FL. On the other hand, lipopolysaccharide from W50 formed another precipitin band and reacted with the antibody, but only at higher concentrations of lipopolysaccharide. The fimA genes in these strains were amplified by polymerase chain reaction and cloned. Sequencing of the fimA gene revealed that the fimA(W50) was almost identical to fimA(HG564), but a notable difference was observed at the start codon of the open reading frame, while the fimA(381FL) was considerably different from fimA of other strains and its open reading frame was found to be missing. These results indicate that the molecular structure of the fimA genes of these strains is not homologous, indicating that molecular modifications in the fimA gene should occur during in vitro passages and maintenance of strains of P. gingivalis in laboratories. PMID- 7851740 TI - Zinc content of the Bacillus anthracis lethal factor. AB - We present evidence that the anthrax toxin lethal factor binds multiple zinc atoms. Results from atomic adsorption spectroscopy indicate that lethal factor contains approximately three zinc atoms per toxin molecule. Lethal factor treated with EDTA and o-phenanthroline contained a similar number of zinc atoms, indicating that all three zinc atoms are tightly bound to the protein. Lethal factor contains the highly conserved zinc-binding consensus sequence, HExxH, that is present in all known zinc metalloproteases. In addition, lethal factor contains an inverted form of this motif, HxxDH, which may also be involved in zinc binding. Using a large array of protease model substrates, however, we were unable to detect an endogenous protease activity for lethal factor. PMID- 7851741 TI - The phylogenetic structure of the genus Acinetobacter. AB - 16S rDNA sequence analysis was performed on the type strains of all validly described Acinetobacter species and five unnamed Acinetobacter strains. The phylogenetic analyses confirm that Acinetobacter is a coherent genus within the gamma subclass of Proteobacteria and that the species are phylogenetically well defined. A. calcoaceticus, A. lwoffii, A. johnsonii and A. haemolyticus form one cluster of closely related species, the pair A. junii and A. baumannii forms a second cluster. A. radioresistens stands phylogenetically isolated. The study reveals that three undescribed strains can be assigned to individually described species, while strains DSM 30009 and DSM 590 may represent two novel Acinetobacter species. PMID- 7851742 TI - Cyclic AMP in ruminal and other anaerobic bacteria. AB - An examination of cAMP levels in predominant species of ruminal bacteria and other anaerobic bacteria was conducted. Cellular cAMP concentrations of glucose grown cultures of Butyrivibrio fibrisolvens 49, Prevotella ruminicola D31d, Selenomonas ruminantium HD4 and D, Megasphaera elsdenii B159, Streptococcus bovis JB1, Bacteroides thetaiotaomicron 5482, and Clostridium acetobutylicum ATCC 824 were determined at various times during growth by a competitive binding radioimmunoassay procedure. The results were compared to those for Escherichia coli NRRL B3704. The levels of cAMP ranged from undetectable for B. thetaiotaomicron to approximately 15 pmol/mg cell protein for P. ruminicola D31d. Varying the growth substrate in a manner previously shown to elicit regulatory response did not alter the level of cAMP in these organisms. In general, cAMP concentrations present in these organisms were much lower than the 6-25 pmol/mg cell protein observed for E. coli. The levels of cAMP in P. ruminicola were consistently higher than levels in other anaerobes, particularly during the early exponential and stationary phases of growth. Based on these data it seems unlikely that cAMP is involved in regulation of substrate catabolism in the anaerobic bacteria examined except in P. ruminicola where it may have an unknown regulatory function. PMID- 7851743 TI - Mutations which reduce levels of pyruvate dehydrogenase in Schizosaccharomyces pombe cause a requirement for arginine or glutamine. AB - Forty-four mutants of Schizosaccharomyces pombe were isolated which required supplementation with arginine or glutamine. These mutants appear to define three genes, provisionally named agg1, agg2 and agg3 (arginine, glutamine requiring). Mutants in all three genes were found to have reduced levels of pyruvate dehydrogenase compared to wild-type. PMID- 7851744 TI - Expression and sequence of outer surface protein C among North American isolates of Borrelia burgdorferi. AB - The expression of outer surface protein C (OspC) was determined for North American Borrelia burgdorferi isolates HB19, DN127cl9-2, 25015 and both low and high culture passage B31. A monoclonal antibody detected the presence of OspC protein in only two isolates, while polyclonal antiserum identified this protein in all five isolates. The ospC gene was cloned and sequenced for isolates HB19, DN127cl9-2 and 25015, and compared with the published ospC sequences of other Lyme disease spirochetes. Both the nucleotide and amino acid sequences were found to vary as much among isolates from the same geographic area as between isolates of different species. PMID- 7851745 TI - Impairment of Na+,K(+)-ATPase activity following enterotoxigenic Campylobacter jejuni infection: changes in Na+, Cl- and 3-O-methyl-D-glucose transport in vitro, in rat ileum. AB - Unidirectional fluxes of Na+, Cl- and 3-O-methyl-D-glucose (3-MG) were measured in vitro across Campylobacter jejuni live culture-infected and control rat ileal short-circuited tissues by the Ussing Chamber technique. Net secretion of Na+ and enhanced secretion of Cl- ions was observed in the infected animals (P < 0.001, n = 6) as compared to the net absorption of Na+ and marginal secretion of Cl- ions in the control animals. There was a significant decrease in the mucosal-to serosal fluxes of 3-MG in C. jejuni-infected rat ileum. The specific Na+,K(+) ATPase activity when measured biochemically in the membrane-rich fraction of enterocytes was found to be significantly lower (58%) in the infected group as compared to the control group (P < 0.001). Our results therefore suggest that infection with an enterotoxigenic C. jejuni inhibits the Na+,K(+)-ATPase activity in rat enterocytes. The impairment of Na+,K(+)-ATPase activity thus appears to induce a secondary change in Na+,Cl- and 3-MG transport in vitro in rat ileum. PMID- 7851746 TI - Isolation and characterization of a Bacillus subtilis secA mutant allele conferring resistance to sodium azide. AB - A mutation has been isolated in the Bacillus subtilis secA gene (secA10) which allows cell growth and residual protein translocation in the presence of 1.5 mM sodium azide. Besides conferring resistance to sodium azide, the corresponding SecA10 mutant protein, in which glutamic acid at position 338 has been changed to glycine, seems to possess a secretion defect even in the absence of azide. In addition, the secA10 mutant protein was found to be recessive to wild-type secA with regard to azide resistance. Our results strongly suggest that, like the situation in Escherichia coli, the B. subtilis SecA protein is a main target for the lethal action of sodium azide. PMID- 7851747 TI - Characterization of a chitinase gene (chiA) from Serratia marcescens BJL200 and one-step purification of the gene product. AB - The nucleotide sequence of the chiA gene from Serratia marcescens strain BJL200 was determined. The gene was found to encode a protein of 563 amino acid residues, with a typical N-terminal signal peptide of 23 residues, that is cleaved off during export. The gene exhibited striking differences with two previously characterized chiA genes of S. marcescens in the region corresponding to amino acid residues 410-467 of the gene product. Periplasmic fractions of an Escherichia coli strain harbouring the cloned gene were used as starting material for the development of a fast, one-step purification protocol for the chitinase that is based on hydrophobic interaction chromatography. PMID- 7851748 TI - Cell surface appendages of lactobacilli. AB - Seventeen vaginal isolates of lactobacillus were negatively stained using 1% phosphotungstic acid and examined by transmission electron microscopy. One or two flagella were observed in a polar or, less frequently, sub-polar position on 14 of the 17 isolates. The structures, measuring 12 nm in diameter and up to 12 microns long, were seen on cells cultured in both solid and liquid MRS medium. Fimbriae, measuring 3.5 nm in diameter and 0.1 micron to 1.0 micron in length, extended from the cell surface of 15 of the 17 lactobacillus isolates. Production of fimbriae was maximal when the lactobacilli were cultured on solid medium in an anaerobic atmosphere. Fimbriation significantly increased adhesion of lactobacilli to vaginal epithelial cells in vitro. PMID- 7851749 TI - Methionine-321 in the C-terminal alpha-helix of catabolic ornithine carbamoyltransferase from Pseudomonas aeruginosa is important for positive homotropic cooperativity. AB - Pseudomonas aeruginosa has a pair of distinct ornithine carbamoyltransferases. The anabolic ornithine carbamoyltransferase encoded by the argF gene catalyzes the formation of citrulline from ornithine and carbamoylphosphate. The catabolic ornithine carbamoyltransferase encoded by the arcB gene promotes the reverse reaction in vivo; although this enzyme can be assayed in vitro for citrulline synthesis, its unidirectionality in vivo is determined by its high concentration at half maximum velocity for carbamoylphosphate ([S]0.5) and high cooperativity toward this substrate. We have isolated mutant forms of catabolic ornithine carbamoyltransferase catalyzing the anabolic reaction in vivo. The corresponding arcB mutant alleles on a multicopy plasmid specifically suppressed an argF mutation of P. aeruginosa. Two new mutant enzymes were obtained. When methionine 321 was replaced by isoleucine, the mutant enzyme showed loss of homotropic cooperativity at physiological carbamoylphosphate concentrations. Substitution of glutamate 105 by lysine resulted in a partial loss of the sigmoidal response to increasing carbamoylphosphate concentrations. However, both mutant enzymes were still sensitive to the allosteric activator AMP and to the inhibitor spermidine. These results indicate that at least two residues of catabolic ornithine carbamoyltransferase are critically involved in positive carbamoylphosphate cooperativity: glutamate 105 (previously known to be important) and methionine 321. Mutational changes in either amino acid will affect the geometry of helix H2, which contains several residues required for carbamoylphosphate binding. PMID- 7851751 TI - Enhanced expression of Plasmodium falciparum heat shock protein PFHSP70-I at higher temperatures and parasite survival. AB - The effect of various body temperatures, encountered during malaria fever, on the synthesis of Plasmodium falciparum heat-shock protein called PFHSP70-I and parasite growth rates among five different isolates are described. The results show that after the exposure of parasites at 39 degrees C for 30 min the amount of PFHSP70-I in all five isolates increased markedly and significantly, whereas parasite growth rates and the amount of total blood stage antigens remained almost unaffected. This indicates that the PFHSP70-I gene responds to heat-shock by producing higher amounts of PFHSP70-I protein, presumably to protect the parasite from being killed during malaria fever. PMID- 7851750 TI - High correlation between Chagas' disease serology and PCR-based detection of Trypanosoma cruzi kinetoplast DNA in Bolivian children living in an endemic area. AB - The detection of Trypanosoma cruzi kinetoplast DNA by polymerase chain reaction (PCR) amplification is a potentially powerful tool for the parasitological diagnosis of Chagas' disease. We have applied this technique in a field situation in Bolivia, where 45 children from a primary school were subjected to serological testing, buffy coat analysis and PCR diagnosis. 26 of the 28 serology-positive individuals were also positive by PCR. In addition, two serology-negative children gave a positive result by PCR, including one who was positive in the buffy coat test. These results suggest that PCR detection of T. cruzi DNA in blood can be a very useful complement to serology in Chagas' disease diagnosis in Bolivia. PMID- 7851753 TI - Discovery and genetic definition of the Drosophila Antennapedia complex. PMID- 7851752 TI - Gene sequence and analysis of protein domains of EGB, a novel family E endoglucanase from Fibrobacter succinogenes S85. AB - The endoglucanase gene (endB) of Fibrobacter succinogenes S85 encodes a protein of 555 amino acids (EGB) with a M(r) of 62,500. EGB shows homology with cellulases belonging to family E. Residues involved in the catalytic activity of CelD from Clostridium thermocellum are also found in EGB. Structure predictions suggest that EGB, like CelD, comprises a large alpha-helical catalytic domain plus a beta-strand domain of unknown function located in the N-terminal part of the protein. Construction of a phylogenetic tree of family E catalytic domains revealed that EGB is closest to a cellodextrinase from Butyrivibrio fibrisolvens. PMID- 7851754 TI - Rates of spontaneous mutation in bacteriophage T4 are independent of host fidelity determinants. AB - Bacteriophage T4 encodes most of the genes whose products are required for its DNA metabolism, and host (Escherichia coli) genes can only infrequently complement mutationally inactivated T4 genes. We screened the following host mutator mutations for effects on spontaneous mutation rates in T4: mutT (destruction of aberrant dGTPs), polA, polB and polC (DNA polymerases), dnaQ (exonucleolytic proofreading), mutH, mutS, mutL and uvrD (methyl-directed DNA mismatch repair), mutM and mutY (excision repair of oxygen-damaged DNA), mutA (function unknown), and topB and osmZ (affecting DNA topology). None increased T4 spontaneous mutation rates within a resolving power of about twofold (nor did optA, which is not a mutator but overexpresses a host dGTPase). Previous screens in T4 have revealed strong mutator mutations only in the gene encoding the viral DNA polymerase and proofreading 3'-exonuclease, plus weak mutators in several polymerase accessory proteins or determinants of dNTP pool sizes. T4 maintains a spontaneous mutation rate per base pair about 30-fold greater than that of its host. Thus, the joint high fidelity of insertion by T4 DNA polymerase and proofreading by its associated 3'-exonuclease appear to determine the T4 spontaneous mutation rate, whereas the host requires numerous additional systems to achieve high replication fidelity. PMID- 7851755 TI - Suppressor analyses of temperature-sensitive cbp1 strains of Saccharomyces cerevisiae: the product of the nuclear gene SOC1 affects mitochondrial cytochrome b mRNA post-transcriptionally. AB - The induction of mitochondrial function is dependent upon both nuclearly encoded and mitochondrially encoded gene products. To understand nuclear-mitochondrial interactions, we must first understand gene-specific interactions. The accumulation of mitochondrial cytochrome b (COB) RNA is dependent upon Cbp1p, encoded by the nuclear gene CBP1. Thus, respiration is dependent upon Cbp1p. In this study, suppressors of temperature-sensitive cbp1 (cbp1ts) strains were selected for restoration of respiratory capability at the restrictive temperature Ts+). One nuclearly encoded suppressor, extragenic to CBP1, is recessive with respect to the wild-type suppressor allele and is unlinked to other known genetic loci whose gene products are necessary for expression of COB mRNA. The suppressor, called soc1 for Suppressor of cbp1, suppresses several other cbp1ts alleles but does not operate via a bypass mechanism. Molecular analyses indicate that soc1 allows the steady-state level of COB mRNA to increase at high temperature but has little or no effect on the levels of COB pre-mRNA. These data have led us to propose that the product of the nuclear gene SOC1 is required for normal turnover of COB mRNA. PMID- 7851756 TI - Requirement for RGR1 and SIN4 in RME1-dependent repression in Saccharomyces cerevisiae. AB - RME1 is a zinc-finger protein homolog that functions as a repressor of the meiotic activator IME1. RME1 is unusual among yeast repressors in two respects: it acts over a considerable distance (2 kbp) and it can activate transcription from a binding site separated from its natural flanking region. To identify genes required for RME1 to exert repression, we have selected mutants with improved RME1-dependent activation. One rare mutant was defective in RME1-dependent repression of an artificial reporter gene as well as the native IME1 gene. The mutation permits sporulation of a/a diploids, which express RME1 from its natural promoter, and of a/alpha diploids constructed to express RME1 from the GAL1 promoter. The mutation also causes temperature-sensitive growth and a methionine or cysteine requirement. Analysis of a complementing genomic clone indicates that the mutation lies in a known essential gene, RGR1. Prior studies have indicated a functional relationship between RGR1 and SIN4 (also called TSF3); we have found that a sin4 null mutation also causes a defect in RME1-dependent repression and a methionine or cysteine requirement. The rgr1 and sin4 mutations do not cause a reduction of RME1 polypeptide levels. The defect in RME1-dependent repression may result from effects of sin4 and, presumably, rgr1 on chromatin structure. PMID- 7851757 TI - Use of a chromosomal inverted repeat to demonstrate that the RAD51 and RAD52 genes of Saccharomyces cerevisiae have different roles in mitotic recombination. AB - An intrachromosomal recombination assay that monitors events between alleles of the ade2 gene oriented as inverted repeats was developed. Recombination to adenine prototrophy occurred at a rate of 9.3 x 10(-5)/cell/generation. Of the total recombinants, 50% occurred by gene conversion without crossing over, 35% by crossover and 15% by crossover associated with conversion. The rate of recombination was reduced 3,000-fold in a rad52 mutant, but the distribution of residual recombination events remained similar to that seen in the wild type strain. In rad51 mutants the rate of recombination was reduced only 4-fold. In this case, gene conversion events unassociated with a crossover were reduced 18 fold, whereas crossover events were reduced only 2.5-fold. A rad51 rad52 double mutant strain showed the same reduction in the rate of recombination as the rad52 mutant, but the distribution of events resembled that seen in rad51. From these observations it is concluded that (i) RAD52 is required for high levels of both gene conversions and reciprocal crossovers, (ii) that RAD51 is not required for intrachromosomal crossovers, and (iii) that RAD51 and RAD52 have different functions, or that RAD52 has functions in addition to those of the Rad51/Rad52 protein complex. PMID- 7851758 TI - The yeast translational allosuppressor, SAL6: a new member of the PP1-like phosphatase family with a long serine-rich N-terminal extension. AB - The allosuppressor mutation, sal6-1, enhances the efficiency of all tested translational suppressors, including codon-specific tRNA suppressors as well as codon-nonspecific omnipotent suppressors. The SAL6 gene has now been cloned by complementation of the increased suppression efficiency and cold sensitivity caused by sal6-1 in the presence of the omnipotent suppressor sup45. Physical analysis maps SAL6 to chromosome XVI between TPK2 and spt14. The SAL6 gene encodes a very basic 549-amino acid protein whose C-terminal catalytic region of 265 residues is 63% identical to serine/threonine PP1 phosphatases, and 66% identical to yeast PPZ1 and PPZ2 phosphatases. The unusual 235 residue N-terminal extension found in SAL6, like those in the PPZ proteins, is serine-rich. The sal6 1 mutation is a frameshift at amino acid position 271 which destroys the presumed phosphatase catalytic domain of the protein. Disruptions of the entire SAL6 gene are viable, cause a slight growth defect on glycerol medium, and produce allosuppressor phenotypes in suppressor strain backgrounds. The role of the serine-rich N terminus is unclear, since sal6 phenotypes are fully complemented by a SAL6 allele that contains an in-frame deletion of most of this region. High copy number plasmids containing wild-type SAL6 cause antisuppressor phenotypes in suppressor strains. These results suggest that the accuracy of protein synthesis is affected by the levels of phosphorylation of the target(s) of SAL6. PMID- 7851759 TI - Protein-protein interactions in the yeast pheromone response pathway: Ste5p interacts with all members of the MAP kinase cascade. AB - We have used the two-hybrid system of Fields and Song to identify protein-protein interactions that occur in the pheromone response pathway of the yeast Saccharomyces cerevisiae. Pathway components Ste4p, Ste5p, Ste7p, Ste11p, Ste12p, Ste20p, Fus3p and Kss1p were tested in all pairwise combinations. All of the interactions we detected involved at least one member of the MAP kinase cascade that is a central element of the response pathway. Ste5p, a protein of unknown biochemical function, interacted with protein kinases that operate at each step of the MAP kinase cascade, specifically with Ste11p (an MEKK), Ste7p (an MEK), and Fus3p (a MAP kinase). This finding suggests that one role of Ste5p is to serve as a scaffold to facilitate interactions among members of the kinase cascade. In this role as facilitator, Ste5p may make both signal propagation and signal attenuation more efficient. Ste5p may also help minimize cross-talk with other MAP kinase cascades and thus ensure the integrity of the pheromone response pathway. We also found that both Ste11p and Ste7p interact with Fus3p and Kss1p. Finally, we detected an interaction between one of the MAP kinases, Kss1p, and a presumptive target, the transcription factor Ste12p. We failed to detect interactions of Ste4p or Ste20p with any other component of the response pathway. PMID- 7851760 TI - The mutator gene swi8 effects specific mutations in the mating-type region of Schizosaccharomyces pombe. AB - The swi8+ gene of Schizosaccharomyces pombe appears to be involved in the termination step of copy synthesis during mating-type (MT) switching. Mutations in swi8 confer a general mutator phenotype and, in particular, generate specific mutations in the MT region. Sequencing of the MT cassettes of the h90 swi8-137 mutant revealed three altered sites. One is situated at the switching (smt) signal adjacent to the H1 homology box of the expression locus mat1:1. It reduces the rate of MT switching. The alteration at the smt signal arose frequently in other h90 swi8 strains and is probably caused by gene conversion in which the sequence adjacent to the H1 box of mat2:2 is used as template. This change might be generated during the process of MT switching when hybrid DNA formation is anomalously extended into the more heterologous region flanking the H1 homology box. In addition to the gene conversion at mat1:1, two mutations were found in the H3 homology boxes of the silent cassettes mat2:2 and mat3:3. PMID- 7851762 TI - Neurospora mutants affecting polyamine-dependent processes and basic amino acid transport mutants resistant to the polyamine inhibitor, alpha difluoromethylornithine. AB - Polyamines (spermidine and spermine) are required by living cells, but their functions are poorly understood. Mutants of Neurospora crassa with enhanced or diminished sensitivity to interference with polyamine synthesis, originally selected to study the regulation of the pathway, were found to have unexpected defects. A group of four non-allelic mutations, causing no interference with polyamine synthesis, each imparted spermidine auxotrophy to a genotype already partially impaired in spermidine synthesis. Strains carrying only the new mutations displayed unconditional delay or weakness at the onset of growth, but grew well thereafter and had a normal or overly active polyamine pathway. These mutants may have defects in vital macromolecular activities that are especially dependent upon the polyamines-activities that have not been identified with certainty in studies to date. Another group of mutants, selected as resistant to the polyamine inhibitor difluoromethylornithine (DFMO), had normal activity and regulation of ornithine decarboxylase, the target of the drug. All but one of thirty mutants were allelic, and were specifically deficient in the basic amino acid permease. This mechanism of DFMO resistance is unprecedented among the many DFMO-resistant cell types of other organisms and demonstrates that DFMO can be used for efficient genetic studies of this transport locus in N. crassa. PMID- 7851761 TI - Nonhomologous synapsis and reduced crossing over in a heterozygous paracentric inversion in Saccharomyces cerevisiae. AB - Homologous chromosome synapsis ("homosynapsis") and crossing over are well conserved aspects of meiotic chromosome behavior. The long-standing assumption that these two processes are causally related has been challenged recently by observations in Saccharomyces cerevisiae of significant levels of crossing over (1) between small sequences at nonhomologous locations and (2) in mutants where synapsis is abnormal or absent. In order to avoid problems of local sequence effects and of mutation pleiotropy, we have perturbed synapsis by making a set of isogenic strains that are heterozygous and homozygous for a large chromosomal paracentric inversion covering a well marked genetic interval and then measured recombination. We find that reciprocal recombination in the marked interval in heterozygotes is reduced variably across the interval, on average to approximately 55% of that in the homozygotes, and that positive interference still modulates crossing over. Cytologically, stable synapsis across the interval is apparently heterologous rather than homologous, consistent with the interpretation that stable homosynapsis is required to initiate or consummate a large fraction of the crossing over observed in wild-type strains. When crossing over does occur in heterozygotes, dicentric and acentric chromosomes are formed and can be visualized and quantitated on blots though not demonstrated in viable spores. We find that there is no loss of dicentric chromosomes during the two meiotic divisions and that the acentric chromosome is recovered at only 1/3 to 1/2 of the expected level. PMID- 7851763 TI - The Neurospora transposon Tad is sensitive to repeat-induced point mutation (RIP). AB - RIP (repeat-induced point mutation) efficiently mutates repeated sequences in the sexual phase of the Neurospora crassa life cycle. Nevertheless, an active LINE like retrotransposon, Tad, was found in a N. crassa strain from Adiopodoume. The possibility was tested that Tad might be resistant to RIP, or that the Adiopodoume strain might be incompetent for RIP. Tad elements derived from the Adiopodoume strain were found to be susceptible to RIP. In addition, strains lacking active Tad elements, including common laboratory strains and strains representing seven species of Neurospora, were found to have sequences closely related to Tad but with numerous mutations of the type resulting from RIP (G:C to A:T). Even the Adiopodoume strain showed Tad-like elements with mutations characteristic of RIP. Results of crossing of an Adiopodoume transformant with progeny of Adiopodoume suggest that the Adiopodoume strain is proficient at RIP. We conclude that Tad is an old transposable element that has been inactivated by RIP in most strains. Finding relics of RIP in both heterothallic and homothallic species of Neurospora implicates RIP across the genus. PMID- 7851764 TI - REMI-RFLP mapping in the Dictyostelium genome. AB - A set of 147 Dictyostelium discoideum strains was constructed by random integration of a vector containing rare restriction sites. The strains were generated by transformation using restriction enzyme-mediated integration (REMI) which results in the integration of linear DNA fragments into randomly distributed genomic restriction sites. Restriction fragment length polymorphism (RFLP) was generated in a single genomic site in each strain. These REMI-RFLP strains were used to confirm gene linkages previously supported by two other physical mapping techniques: yeast artificial chromosome (YAC) contig construction, and megabase-scale restriction mapping. New linkages were uncovered when two or more hybridization probes identified the same RFLP fragments. Probes for 100 genes have marked 53% of the RFLPs, representing greater than 22 Mb of the 40 Mb Dictyostelium genome. Alignment of these and other large fragments along each chromosome should lead to a complete physical map of the Dictyostelium genome. PMID- 7851765 TI - Selective lineage specification by mab-19 during Caenorhabditis elegans male peripheral sense organ development. AB - The action of the gene mab-19 is required for specification of a subset of Caenorhabditis elegans male peripheral sense organ (ray) lineages. Two mab-19 alleles, isolated in screens for ray developmental mutations, resulted in males that lacked the three most posterior rays. Cell lineage alterations of male specific divisions of the most posterior lateral hypodermal (seam) blast cell, T, resulted in the ray loss phenotype in mab-19 mutant animals. Postembryonic seam lineage defects were limited to male-specific T descendent cell divisions. Embryonic lethality resulted when either mab-19 mutation was placed over a chromosomal deficiency encompassing the mab-19 locus. The earliest detectable defect was aberrant hypodermal cell movements during morphogenesis. From these data, it is inferred that both mab-19 alleles described are hypomorphs, and further reduction of mab-19 function results in embryos that are unable to complete morphogenesis. Thus, mab-19 may play a larger role in developmental regulation of hypodermal cell fate, including sensory ray development in males. Body morphology mutations, passage through the dauer stage, and heat or CdCl2 treatment suppressed mab-19 male phenotypes. A model is presented in which all three types of suppression result in a physiological stress response, which in turn leads to correction of the mab-19 defect. PMID- 7851766 TI - Assessing the viability of mutant and manipulated sperm by artificial insemination of Caenorhabditis elegans. AB - We describe a protocol for artificial insemination of Caenorhabditis elegans which we used to evaluate the viability of sperm from different strains and of sperm activated in vitro. Worms can be artificially inseminated with almost 100% success. Both male and hermaphrodite sperm can be used for insemination. Sperm from a sterile hermaphrodite [fem-3(q23ts)] were found to be viable. As with normal mating, male sperm inseminated into hermaphrodites artificially outcompete the hermaphrodite's own sperm, even though they have not been ejaculated with seminal fluid. Spermatozoa that were activated in vitro from spermatids by the weak base triethanolamine were viable. In contrast, spermatozoa activated in vitro by protease treatment were not. PMID- 7851767 TI - Molecular polymorphism in the period gene of Drosophila simulans. AB - The threonine-glycine (Thr-Gly) repeat region of the period (per) gene of eight natural populations of Drosophila simulans from Europe and North Africa was analyzed by polymerase chain reaction, DNA sequencing and heteroduplex formation. Five different length alleles encoding 21, 23, 25 and two different kinds of 24 Thr-Gly pairs in the uninterrupted repeat were found. In the 3' region flanking the repeat 6 nucleotide substitutions (3 synonymous, 3 replacement) were observed in three different combinations that we called haplotypes I, II and III. The complete linkage disequilibrium observed between the haplotypes and these length variants allowed us to infer from the repeat length, the DNA sequence at the 3' polymorphic sites. The haplotypes were homogeneously distributed across Europe and North Africa. The data show statistically significant departures from neutral expectations according to the Tajima test. The results suggest that balancing selection might have played a role in determining the observed levels and patterns of genetic diversity at the per gene in D. simulans. PMID- 7851768 TI - The Drosophila homeotic mutation Nasobemia (AntpNs) and its revertants: an analysis of mutational reversion. AB - The homeotic gene Antennapedia (Antp) controls determination of many different cell types in the thorax and abdomen of Drosophila melanogaster. The spontaneous mutant allele Nasobemia (AntpNs) and its revertants have been widely used to infer normal Antp gene function but have not themselves been thoroughly characterized. Our analysis reveals that AntpNs consists of an internal 25-kb partial duplication of the Antp gene as well as a complex insertion of > 40 kb of new DNA including two roo transposons. The duplication gives the mutant gene three Antp promoters, and transcripts from each of these are correctly processed to yield functional ANTP proteins. At least two of the promoters are ectopically active in the eye-antenna imaginal discs, leading to homeotic transformation of the adult head. A molecular and genetic description of several AntpNs revertants shows them to be diverse in structure and activity, including a restoration of the wild type, rearrangements separating two of the AntpNs promoters from the coding sequences, and protein nulls and hypomorphs affecting expression from all three of the promoters. Finally, one revertant has a suppressing lesion in the osa locus far away from Antp. These features explain the unusual homozygous viable nature of AntpNs, suggest a mechanism by which its homeotic transformation occurs, and exemplify the diversity of ways in which mutational reversion can take place. PMID- 7851769 TI - Dosage compensation of the period gene in Drosophila melanogaster. AB - The period (per) gene is located on the X chromosome of Drosophila melanogaster. Its expression influences biological clocks in this fruit fly, including the one that subserves circadian rhythms of locomotor activity. Like most X-linked genes in Drosophila, per is under the regulatory control of gene dosage compensation. In this study, we assessed the activity of altered or augmented per+ DNA fragments in transformants. Relative expression levels in male and female adults were inferred from periodicities associated with locomotor behavioral rhythms, and by histochemically assessing beta-galactosidase levels in transgenics carrying different kinds of per-lacZ fusion genes. The results suggest that per contains multipartite regulatory information for dosage compensation within the large first intron and also within the 3' half of this genetic locus. PMID- 7851770 TI - Identification of mutations in three genes that interact with zeste in the control of white gene expression in Drosophila melanogaster. AB - Three previously described genes, enhancer of yellow, 1, 2 and 3, are shown to cooperate with the zeste gene in the control of white gene expression. The mutations e(y)1u1, e(y)3u1, and to a lesser extent e(y)2u1, enhance the effect of the zeste null allele zv77h. Different combinations of e(y)1u1, e(y)2u1 and e(y)3u1 mutations with several other z alleles also enhance the white mutant phenotype, but only to levels characteristic of white alleles containing a deletion of the upstream eye enhancer. Loss of zeste protein binding sites from the white locus does not eliminate the effect of e(y)1u1 and e(y)3u1 mutations, suggesting that the products of these genes interact with some other nucleotide sequences. Combinations of either e(y)1u1 or e(y)2u1 mutations with e(y)3u1 are lethal. The products of these three genes may represent, together with zeste, a group of proteins involved in the organization of long-distance interactions between DNA sequences. PMID- 7851771 TI - Neutral and non-neutral evolution of Drosophila mitochondrial DNA. AB - To test hypotheses of neutral evolution of mitochondrial DNA (mtDNA), nucleotide sequences were determined for 1515 base pairs of the NADH dehydrogenase subunit 5 (ND5) gene in the mitochondrial DNA of 29 lines of Drosophila melanogaster and 9 lines of its sibling species Drosophila simulans. In contrast to the patterns for nuclear genes, where D. melanogaster generally exhibits much less nucleotide polymorphism, the number of segregating sites was slightly higher in a global sample of nine ND5 sequences in D. melanogaster (s = 8) than in the nine lines of D. simulans (s = 6). When compared to variation at nuclear loci, the mtDNA variation in D. melanogaster does not depart from neutral expectations. The ND5 sequences in D. simulans, however, show fewer than half the number of variable sites expected under neutrality when compared to sequences from the period locus. While this reduction in variation is not significant at the 5% level, HKA tests with published restriction data for mtDNA in D. simulans do show a significant reduction of variation suggesting a selective sweep of variation in the mtDNA in this species. Tests of neutral evolution based on the ratios of synonymous and replacement polymorphism and divergence are generally consistent with neutral expectations, although a significant excess of amino acid polymorphism within both species is localized in one region of the protein. The rate of mtDNA evolution has been faster in D. melanogaster than in D. simulans and the population structure of mtDNA is distinct in these species. The data reveal how different rates of mtDNA evolution between species and different histories of neutral and adaptive evolution within species can compromise historical inferences in population and evolutionary biology. PMID- 7851772 TI - Unraveling selection in the mitochondrial genome of Drosophila. AB - We examine mitochondrial DNA variation at the cytochrome b locus within and between three species of Drosophila to determine whether patterns of variation conform to the predictions of neutral molecular evolution. The entire 1137-bp cytochrome b locus was sequenced in 16 lines of Drosophila melanogaster, 18 lines of Drosophila simulans and 13 lines of Drosophila yakuba. Patterns of variation depart from neutrality by several test criteria. Analysis of the evolutionary clock hypothesis shows unequal rates of change along D. simulans lineages. A comparison within and between species of the ratio of amino acid replacement change to synonymous change reveals a relative excess of amino acid replacement polymorphism compared to the neutral prediction, suggestive of slightly deleterious or diversifying selection. There is evidence for excess homozygosity in our world wide sample of D. melanogaster and D. simulans alleles, as well as a reduction in the number of segregating sites in D. simulans, indicative of selective sweeps. Furthermore, a test of neutrality for codon usage shows the direction of mutations at third positions differs among different topological regions of the gene tree. The analyses indicate that molecular variation and evolution of mtDNA are governed by many of the same selective forces that have been shown to govern nuclear genome evolution and suggest caution be taken in the use of mtDNA as a "neutral" molecular marker. PMID- 7851773 TI - The effects of spontaneous mutation on quantitative traits. I. Variances and covariances of life history traits. AB - We have accumulated spontaneous mutations in the absence of natural selection in Drosophila melanogaster by backcrossing 200 heterozygous replicates of a single high fitness second chromosome to a balancer stock for 44 generations. At generations 33 and 44 of accumulation, we extracted samples of chromosomes and assayed their homozygous performance for female fecundity early and late in adult life, male and female longevity, male mating ability early and late in adult life, productivity (a measure of fecundity times viability) and body weight. The variance among lines increased significantly for all traits except male mating ability and weight. The rate of increase in variance was similar to that found in previous studies of egg-to-adult viability, when calculated relative to trait means. The mutational correlations among traits were all strongly positive. Many correlations were significantly different from 0, while none was significantly different from 1. These data suggest that the mutation-accumulation hypothesis is not a sufficient explanation for the evolution of senescence in D. melanogaster. Mutation-selection balance does seem adequate to explain a substantial proportion of the additive genetic variance for fecundity and longevity. PMID- 7851774 TI - Dosage compensation in sciarids is achieved by hypertranscription of the single X chromosome in males. AB - Dosage compensation refers to the process whereby females and males with different doses of sex chromosomes have similar amounts of products from sex chromosome-linked genes. We analyzed the process of dosage compensation in Sciara ocellaris, Diptera of the suborder Nematocera. By autoradiography and measurements of X-linked rRNA in females (XX) and males (XO), we found that the rate of transcription of the single X chromosome in males is similar to that of the two X chromosomes in females. This, together with the bloated appearance of the X chromosome in males, support the idea that in sciarids dosage compensation is accomplished by hypertranscription of the X chromosome in males. PMID- 7851775 TI - Analysis of autosomal polygenic variation for the expression of Haldane's rule in flour beetles. AB - Haldane's rule states that, in interspecific crosses, when hybrid viability or fertility is diminished more in one sex of the hybrids than in the other, the heterogametic sex is more adversely affected. We used quantitative genetic methods to investigate the genetic basis of variation for the expression of the viability aspect of Haldane's rule when Tribolium castaneum males are crossed to Tribolium freemani females. Using a half-sib design, we found significant genetic variance for the expression of Haldane's rule, i.e., variation among T. castaneum sires in the hybrid sex ratios produced by their sons. We also derived 23 independent lineages from the same base population by 8 generations of brother sister mating. From the same experiments, we also found heritable variation among surviving hybrid males in the incidence of antennal deformities. Upon inbreeding, the variance of both traits (hybrid sex ratio and proportion deformities) increased substantially but the means changed little. Because fitness within T. castaneum lineages declined substantially with inbreeding, we infer that hybrid male viability may have a different genetic basis than viability fitness within species. Deleterious recessive alleles held within species by mutation/selection balance appear not to be a major contributor to hybrid incompatibility. PMID- 7851776 TI - Sex-limited mitochondrial DNA transmission in the marine mussel Mytilus edulis. AB - Mitochondrial DNA (mtDNA) was thought to be inherited maternally in animals, although paternal leakage has been reported in mice and Drosophila. Recently, direct evidence of extensive paternal inheritance of mtDNA has been found in the marine mussel Mytilus. We give evidence that whereas female mussels are homoplasmic for a genome that is transmitted to eggs, male mussels are heteroplasmic for this genome and for a second genome that is transmitted preferentially to sperm. The results provide support for the existence of separate male and female routes of mtDNA inheritance in mussels. The two genomes show a base sequence divergence exceeding 20% at three protein coding genes, consistent with long term maintenance of the heteroplasmic state. We propose that the two genomes differ in fitness in males and females, possibly as a result of interaction with nuclear genes. PMID- 7851777 TI - Haplotypic divergence coupled with lack of diversity at the Arabidopsis thaliana alcohol dehydrogenase locus: roles for both balancing and directional selection? AB - We designate a region of the alcohol dehydrogenase locus (Adh) of the weedy crucifer, Arabidopsis thaliana, as "hypervariable" on the basis of a comparison of sequences from ecotypes Columbia and Landsberg. We found eight synonymous and two replacement mutations in the first 262 nucleotides of exon 4, and an additional two mutations in the contiguous region of intron 3. The rest of the sequence (2611 bp) has just three mutations, all of them confined to noncoding regions. Our survey of the hypervariable region among 37 ecotypes of A. thaliana revealed two predominant haplotypes, corresponding to the Columbia and Landsberg sequences. We identified five additional haplotypes and 4 additional segregating sites. The lack of haplotype diversity is presumably in part a function of low rates of recombination between haplotypes conferred by A. thaliana's tendency to self-fertilize. However, an analysis in 32 ecotypes of 12 genome-wide polymorphic markers distinguishing Columbia and Landsberg ecotypes indicated levels of outcrossing sufficient at least to erode linkage disequilibrium between dispersed markers. We discuss possible evolutionary explanations for the coupled observation of marked divergence within the hypervariable region and a lack of haplotype diversity among ecotypes. The sequence of the region for closely related species argues against the possibility that one allele is the product of introgression. We note (1) that several loss of function mutations (both naturally and chemically induced) map to the hypervariable region, and (2) the presence of two amino acid replacement polymorphisms, one of which causes the mobility difference between the two major classes of A. thaliana Adh electrophoretic alleles. We argue that protein polymorphism in such a functionally significant part of the molecule may be subject to balancing selection. The observed pattern of extensive divergence between the alleles is consistent with this explanation because balancing selection on a particular site maintains linked neutral polymorphisms at intermediate frequencies. PMID- 7851778 TI - A detailed RFLP map of cotton, Gossypium hirsutum x Gossypium barbadense: chromosome organization and evolution in a disomic polyploid genome. AB - We employ a detailed restriction fragment length polymorphism (RFLP) map to investigate chromosome organization and evolution in cotton, a disomic polyploid. About 46.2% of nuclear DNA probes detect RFLPs distinguishing Gossypium hirsutum and Gossypium barbadense; and 705 RFLP loci are assembled into 41 linkage groups and 4675 cM. The subgenomic origin (A vs. D) of most, and chromosomal identity of 14 (of 26), linkage groups is shown. The A and D subgenomes show similar recombinational length, suggesting that repetitive DNA in the physically larger A subgenome is recombinationally inert. RFLPs are somewhat more abundant in the D subgenome. Linkage among duplicated RFLPs reveals 11 pairs of homoelogous chromosomal regions-two appear homosequential, most differ by inversions, and at least one differs by a translocation. Most homoeologies involve chromosomes from different subgenomes, putatively reflecting the n = 13 to n = 26 polyploidization event of 1.1-1.9 million years ago. Several observations suggest that another, earlier, polyploidization event spawned n = 13 cottons, at least 25 million years ago. The cotton genome contains about 400-kb DNA per cM, hence map-based gene cloning is feasible. The cotton map affords new opportunities to study chromosome evolution, and to exploit Gossypium genetic resources for improvement of the world's leading natural fiber. PMID- 7851779 TI - Molecular evolution of the plant R regulatory gene family. AB - Anthocyanin pigmentation patterns in different plant species are controlled in part by members of the myc-like R regulatory gene family. We have examined the molecular evolution of this gene family in seven plant species. Three regions of the R protein show sequence conservation between monocot and dicot R genes. These regions encode the basic helix-loop-helix domain, as well as conserved N-terminal and C-terminal domains; mean replacement rates for these conserved regions are 1.02 x 10(-9) nonsynonymous nucleotide substitutions per site per year. More than one-half of the protein, however, is diverging rapidly, with nonsynonymous substitution rates of 4.08 x 10(-9) substitutions per site per year. Detailed analysis of R homologs within the grasses (Poaceae) confirm that these variable regions are indeed evolving faster than the flanking conserved domains. Both nucleotide substitutions and small insertion/deletions contribute to the diversification of the variable regions within these regulatory genes. These results demonstrate that large tracts of sequence in these regulatory loci are evolving at a fairly rapid rate. PMID- 7851780 TI - The maize NCS2 abnormal growth mutant has a chimeric nad4-nad7 mitochondrial gene and is associated with reduced complex I function. AB - The molecular basis of the maternally inherited, heteroplasmic NCS2 mutant of maize was investigated. Analysis of the NCS2 mtDNA showed that it closely resembles the progenitor cmsT mitochondrial genome, except that the mutant genome contains a fused nad4-nad7 gene and is deleted for the small fourth exon of nad4. The rearrangement has occurred at a 16-bp repeat present in the third intron of the nad4 gene and in the second intron of the nad7 gene. Transcripts containing exon 4 of the nad4 gene are greatly reduced in mtRNA preparations from heteroplasmic NCS2 plants; larger transcripts are associated with the first three nad4 exons. Identical 5' ends of the nad4 transcripts have been mapped 396 and 247 bp upstream of the start codon in mtRNAs from both NCS2 and related non-NCS plants. The putative transcription termination signal of nad4 is deleted in mutant DNA, resulting in the production of the unique longer transcripts. The complex transcript pattern associated with nad7 is also altered in the mutant. Both nad4 and nad7 encode subunits of complex I (NADH dehydrogenase) of the mitochondrial electron transfer chain. Oxygen uptake experiments show that the functioning of complex I is specifically reduced in mitochondria isolated from NCS2 mutant plants. PMID- 7851781 TI - Reversible changes in the composition of the population of mtDNAs during dedifferentiation and regeneration in tobacco. AB - Differences in the composition of the population of mtDNAs between green plants and calli of tobacco were detected by DNA filter hybridization analysis. The altered composition of the population of mtDNAs observed in calli returned to the composition typical of green plants during the process of regeneration. Quantitative assays revealed that the changes were associated with the differentiation and dedifferentiation of cells since the extent of the change in composition depended on the degree of differentiation of a population of cells. The sequence that accumulated in dedifferentiated cells was shown to be a product of recombination mediated by a 9-nucleotide repeated element, one of which is located at the 5' region of atp6. Although the recombinant sequence was not detected by a hybridization procedure in green plants, its presence was identified by a more sensitive polymerase chain reaction method. The recombination event was shown to result in a deletion that prevents reverse recombination. Therefore, the reversion from the altered composition to the normal state of the population of mtDNAs during regeneration is explained not by recombination but by the preferential amplification of subgenomic mtDNA molecules. PMID- 7851782 TI - Controlling the type I and type II errors in mapping quantitative trait loci. AB - Although the interval mapping method is widely used for mapping quantitative trait loci (QTLs), it is not very well suited for mapping multiple QTLs. Here, we present the results of a computer simulation to study the application of exact and approximate models for multiple QTLs. In particular, we focus on an automatic two-stage procedure in which in the first stage "important" markers are selected in multiple regression on markers. In the second stage a QTL is moved along the chromosomes by using the preselected markers as cofactors, except for the markers flanking the interval under study. A refined procedure for cases with large numbers of marker cofactors is described. Our approach will be called MQM mapping, where MQM is an acronym for "multiple-QTL models" as well as for "marker QTL-marker." Our simulation work demonstrates the great advantage of MQM mapping compared to interval mapping in reducing the chance of a type I error (i.e., a QTL is indicated at a location where actually no QTL is present) and in reducing the chance of a type II error (i.e., a QTL is not detected). PMID- 7851783 TI - A pleiotropic nonadditive model of variation in quantitative traits. AB - A model of mutation-selection-drift balance incorporating pleiotropic and dominance effects of new mutations on quantitative traits and fitness is investigated and used to predict the amount and nature of genetic variation maintained in segregating populations. The model is based on recent information on the joint distribution of mutant effects on bristle traits and fitness in Drosophila melanogaster from experiments on the accumulation of spontaneous and P element-induced mutations. These experiments suggest a leptokurtic distribution of effects with an intermediate correlation between effects on the trait and fitness. Mutants of large effect tend to be partially recessive while those with smaller effect are on average additive, but apparently with very variable gene action. The model is parameterized with two different sets of information derived from P element insertion and spontaneous mutation data, though the latter are not fully known. They differ in the number of mutations per generation which is assumed to affect the trait. Predictions of the variance maintained for bristle number assuming parameters derived from effects of P element insertions, in which the proportion of mutations with an effect on the trait is small, fit reasonably well with experimental observations. The equilibrium genetic variance is nearly independent of the degree of dominance of new mutations. Heritabilities of between 0.4 and 0.6 are predicted with population sizes from 10(4) to 10(6), and most of the variance for the metric trait in segregating population is due to a small proportion of mutations (about 1% of the total number) with neutral or nearly neutral effects on fitness and intermediate effects on the trait (0.1-0.5 sigma P).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7851784 TI - On the distribution of the mean and variance of a quantitative trait under mutation-selection-drift balance. AB - The distributions of the mean phenotype and of the genetic variance of a polygenic trait under a balance between mutation, stabilizing selection and genetic drift are investigated. This is done by stochastic simulations in which each individual and each gene are represented. The results are compared with theoretical predictions. Some aspects of the existing theories for the evolution of quantitative traits are discussed. The maintenance of genetic variance and the average dynamics of phenotypic evolution in finite populations (with Ne < 1000) are generally simpler than those suggested by some recent deterministic theories for infinite populations. PMID- 7851785 TI - Genetic and statistical analyses of strong selection on polygenic traits: what, me normal? AB - We develop a general population genetic framework for analyzing selection on many loci, and apply it to strong truncation and disruptive selection on an additive polygenic trait. We first present statistical methods for analyzing the infinitesimal model, in which offspring breeding values are normally distributed around the mean of the parents, with fixed variance. These show that the usual assumption of a Gaussian distribution of breeding values in the population gives remarkably accurate predictions for the mean and the variance, even when disruptive selection generates substantial deviations from normality. We then set out a general genetic analysis of selection and recombination. The population is represented by multilocus cumulants describing the distribution of haploid genotypes, and selection is described by the relation between mean fitness and these cumulants. We provide exact recursions in terms of generating functions for the effects of selection on non-central moments. The effects of recombination are simply calculated as a weighted sum over all the permutations produced by meiosis. Finally, the new cumulants that describe the next generation are computed from the non-central moments. Although this scheme is applied here in detail only to selection on an additive trait, it is quite general. For arbitrary epistasis and linkage, we describe a consistent infinitesimal limit in which the short-term selection response is dominated by infinitesimal allele frequency changes and linkage disequilibria. Numerical multilocus results show that the standard Gaussian approximation gives accurate predictions for the dynamics of the mean and genetic variance in this limit. Even with intense truncation selection, linkage disequilibria of order three and higher never cause much deviation from normality. Thus, the empirical deviations frequently found between predicted and observed responses to artificial selection are not caused by linkage-disequilibrium-induced departures from normality. Disruptive selection can generate substantial four-way disequilibria, and hence kurtosis; but even then, the Gaussian assumption predicts the variance accurately. In contrast to the apparent simplicity of the infinitesimal limit, data suggest that changes in genetic variance after 10 or more generations of selection are likely to be dominated by allele frequency dynamics that depend on genetic details. PMID- 7851786 TI - Substitution processes in molecular evolution. III. Deleterious alleles. AB - The substitution processes for various models of deleterious alleles are examined using computer simulations and mathematical analyses. Most of the work focuses on the house-of-cards model, which is a popular model of deleterious allele evolution. The rate of substitution is shown to be a concave function of the strength of selection as measured by alpha = 2N sigma, where N is the population size and sigma is the standard deviation of fitness. For alpha < 1, the house-of cards model is essentially a neutral model; for alpha > 4, the model ceases to evolve. The stagnation for large alpha may be understood by appealing to the theory of records. The house-of-cards model evolves to a state where the vast majority of all mutations are deleterious, but precisely one-half of those mutations that fix are deleterious (the other half are advantageous). Thus, the model is not a model of exclusively deleterious evolution as is frequently claimed. It is argued that there are no biologically reasonable models of molecular evolution where the vast majority of all substitutions are deleterious. Other models examined include the exponential and gamma shift models, the Hartl Dykhuizen-Dean (HDD) model, and the optimum model. Of all those examined, only the optimum and HDD models appear to be reasonable candidates for silent evolution. None of the models are viewed as good candidates for protein evolution, as none are both biologically reasonable and exhibit the variability in substitutions commonly observed in protein sequence data. PMID- 7851787 TI - Proportion of genes survived in offspring conditional on inheritance of flanking markers. AB - In mammalian genetics and perhaps in human genetics as well, it is an interesting question as to how many offspring are needed in order to have a desired chance of preserving part of the entire genome of an individual. A more practical and perhaps more important question is: given k children and DNA marker data on a particular region of interest, what proportion of one's genes has been actually passed on to his children? To answer this question, I define the concept of identity by descent proportion, or IBDP for short. The IBDP is defined to be the proportion of genetic material shared identical by descent by a group of relatives in a specified chromosomal region. I provide a novel approach to computing the mean and variance of IBDP for k (> or = 2) half-sibs based on marker data, thus providing a means to compute the mean and variance of proportion of genes survived. I first show that each chromosome in an offspring can be represented by a two-state Markov chain, with the time parameter being the map distance along the chromosome. On this basis, I will show that IBDP can be written as a stochastic integral and that the computation of the EIBDP can be reduced to evaluating an integral of some elementary functions. Numerical examples are provided to illustrate the calculation. PMID- 7851788 TI - Empirical threshold values for quantitative trait mapping. AB - The detection of genes that control quantitative characters is a problem of great interest to the genetic mapping community. Methods for locating these quantitative trait loci (QTL) relative to maps of genetic markers are now widely used. This paper addresses an issue common to all QTL mapping methods, that of determining an appropriate threshold value for declaring significant QTL effects. An empirical method is described, based on the concept of a permutation test, for estimating threshold values that are tailored to the experimental data at hand. The method is demonstrated using two real data sets derived from F(2) and recombinant inbred plant populations. An example using simulated data from a backcross design illustrates the effect of marker density on threshold values. PMID- 7851789 TI - The GCR1 gene of Saccharomyces cerevisiae is a split gene with an unusually long intron. PMID- 7851790 TI - Masquerade: a novel secreted serine protease-like molecule is required for somatic muscle attachment in the Drosophila embryo. AB - Diverse developmental processes, such as neuronal growth cone migration and cell shape changes, are mediated by the interactions of cells with the extracellular matrix. We describe here a secreted molecule encoded by the Drosophila masquerade (mas) gene. Total loss of mas function causes defective muscle attachment. This mutant phenotype suggests that mas normally acts to stabilize cell-matrix interaction and represents a novel functional and limiting component in the adhesion process. mas encodes a 1047-amino-acid preproprotein that is further processed by proteolytic cleavage to generate two polypeptides. The carboxy terminal polypeptide is highly similar to serine proteases and has an extracellular localization; however, it is unlikely to possess proteolytic activity, because the catalytic site serine has been substituted by a glycine residue. During embryonic development, the mas amino- and carboxy-terminal polypeptides are differentially localized. The mas carboxy-terminal polypeptide accumulates at all somatic muscle attachment sites, which corresponds well with the morphological defect seen in the mas mutants. Our findings demonstrate the involvement of an extracellular component in somatic muscle attachment. We propose that mas acts via its modified serine protease motif, either as a novel adhesion molecule and/or as a competitive antagonist of serine proteases, to stabilize muscle attachment. PMID- 7851791 TI - Dominant feminizing mutations implicate protein-protein interactions as the main mode of regulation of the nematode sex-determining gene tra-1. AB - The tra-1 gene is the terminal global selector of somatic sex in Caenorhabditis elegans: High tra-1 activity elicits female somatic development while low tra-1 activity elicits male development. Previous genetic studies defined a cascade of negatively interacting genes that regulates tra-1 activity in response to the primary sex-determining signal. Here, we investigate the last step in this regulatory cascade, by studying rare gain-of-function (gf) mutations of tra-1 that direct female somatic development irrespective of the upstream sex determining signal. These mutations appear to abolish negative regulation of tra 1 in male tissues. We identify the lesions associated with 29 of these mutations and find that all affect a short stretch of amino acid residues present in both protein products of the tra-1 gene. Twenty-six alleles are associated with single nonconservative amino acid substitutions. Two alleles affect tra-1 RNA splicing and generate messages that omit part or all of the exon encoding this short stretch. These results suggest that sexual regulation of tra-1 is achieved post translationally, by an inhibitory protein-protein interaction. The amino acid stretch altered by the tra-1(gf) mutations may define a site of interaction for negative regulators of tra-1. The stretch includes a potential phosphorylation site for glycogen synthase kinase 3 and may be conserved in the human gene GLI3, a homolog of tra-1 identified previously. PMID- 7851792 TI - A homeo domain protein lacking specific side chains of helix 3 can still bind DNA and direct transcriptional repression. AB - A series of mutations in the homeo domain of the yeast alpha 2 protein were constructed to test, both in vivo and in vitro, predictions based on the alpha 2 DNA cocrystal structure described by Wolberger et al. (1991). The effects of the mutations were observed in three different contexts using authentic target DNA sequences: alpha 2 binding alone to specific DNA, alpha 2 binding cooperatively with MCM1 to specific DNA, and alpha 2 binding cooperatively with a1 to specific DNA. As expected, changes in the amino acid residues that contact DNA in the X ray structure severely compromised the ability of alpha 2 to bind DNA alone and to bind DNA cooperatively with MCM1. In contrast, many of these same mutations, including a triple change that altered all the "recognition" residues of helix 3, had little or no effect on the cooperative binding of alpha 2 and a1 to specific DNA, as determined both in vivo and in vitro. These results show that the ability of a homeo domain protein to correctly select and repress target genes does not necessarily depend on the residues commonly implicated in sequence-specific DNA binding. PMID- 7851793 TI - DNA-dependent protein kinase: a potent inhibitor of transcription by RNA polymerase I. AB - DNA-dependent protein kinase (DNA-PK) comprises a catalytic subunit of approximately 350 kD (p350) and a DNA-binding component termed Ku. Although DNA PK can phosphorylate many transcription factors, no function for this enzyme in transcription has been reported thus far. Here, we show that DNA-PK strongly represses transcription by RNA polymerase I (Pol I). Transcriptional repression by DNA-PK requires ATP hydrolysis, and DNA-PK must be colocalized on the same DNA molecule as the Pol I transcription machinery. Consistent with DNA-PK requiring DNA ends for activity, transcriptional inhibition only occurs effectively on linearized templates. Mechanistic studies including single-round transcriptions, abortive initiation assays, and factor-independent transcription on a tailed template demonstrate that DNA-PK inhibits initiation (i.e., the formation of the first phosphodiester bonds) but does not affect transcription elongation. Repression of transcription involves phosphorylation of the transcription initiation complex, and rescue experiments reveal that the inactivated factor remains bound to the promoter and thus prevents initiation complex formation. We discuss the possible relevance of these findings in regard to the control of rRNA synthesis in vivo. PMID- 7851794 TI - p53-dependent repression of CDK4 translation in TGF-beta-induced G1 cell-cycle arrest. AB - Transforming growth factor beta 1 (TGF-beta 1) can cause a cell-cycle arrest in G1. Inhibition of cyclin-dependent kinase 4 (cdk4) synthesis plays a significant role in the mechanism by which this cytokine causes G1 growth arrest. Deregulated expression of cdk4 confers resistance to TGF-beta 1. Here, we show that TGF-beta 1 down-regulates cdk4 expression by inhibiting its translation. Moreover, mutant p53 confers resistance to TGF-beta 1 by interfering with the down-regulation of cdk4 in response to the cytokine. In contrast, we demonstrate that wild-type p53 represses the translation of CDK4. Regulation of cdk4 synthesis by both p53 and TGF-beta 1 is mediated by the 5'-untranslated region of the CDK4 message. Thus, regulation of CDK4 translation may be involved in control of G1 progression by p53. PMID- 7851795 TI - Mutations derepressing silent centromeric domains in fission yeast disrupt chromosome segregation. AB - The ura4+ gene displays phenotypes consistent with variegated expression when inserted at 11 sites throughout fission yeast centromere 1. An abrupt transition occurs between the zone of centromeric repression and two adjacent expressed sites. Mutations in six genes alleviate repression of the silent-mating type loci and of ura4+ expressed from a site adjacent to the silent locus, mat3-M. Defects at all six loci affect repression of the ura4+ gene adjacent to telomeres and at the three centromeric sites tested. The clr4-S5 and rik1-304 mutations cause the most dramatic derepression at two out of three sites within cen1. All six mutations had only slight or intermediate effects on a third site in the center of cen1 or on telomeric repression. Strains with lesions at the clr4, rik1, and swi6 loci have highly elevated rates of chromosome loss. We propose that the products of these genes are integral in the assembly of a heterochromatin-like structure, with distinct domains, enclosing the entire centromeric region that reduces or excludes access to transcription factors. The formation of this heterochromatic structure may be an absolute requirement for the formation of a fully functional centromere. PMID- 7851796 TI - The Saccharomyces cerevisiae Msh2 protein specifically binds to duplex oligonucleotides containing mismatched DNA base pairs and insertions. AB - The yeast Saccharomyces cerevisiae encodes four proteins, Msh1, Msh2, Msh3, Msh4, that show strong amino acid sequence similarity to MutS, a central component of the bacterial mutHLS mismatch repair system. MutS has been shown to recognize base pair mismatches in DNA in vitro. Previous studies have suggested that Msh2 is the major mismatch recognition protein in yeast. In this study, the 109-kD Msh2 polypeptide was overexpressed and purified to analyze its DNA-binding properties. This analysis demonstrated that Msh2 can bind selectively to duplex oligonucleotide substrates containing a G/T mismatch, 1- to 14-nucleotide insertion mismatches, and palindromic (12- to 14-nucleotide) insertion mismatches. A general trend was that the affinity of Msh2 for substrate was proportional to the size of the insertion mispair present (+14 PAL, +12 PAL > +14 > +8 > GT, +6, +4, +2, +1). Kinetic studies indicated that the specificity of Msh2 to mismatch substrates was a function of its ability to form stable complexes with mispair-containing duplex DNAs. These complexes decayed more slowly than Msh2 complexes formed with homoduplex DNA. PMID- 7851797 TI - Transient DNA breaks associated with programmed genomic deletion events in conjugating cells of Tetrahymena thermophila. AB - Thousands of programmed genomic deletion events occur during macronuclear development in Tetrahymena thermophila. Two of the deleted segments, called M and R, have been particularly well-characterized. Using ligation-mediated PCR, we have detected DNA strand breaks that correlate temporally and structurally with the deletion events in the M and R regions. The ends appear at positions that correspond precisely to boundaries of deleted sequences, as defined by observed chromosomal junctions found after deletion is complete. They occur exclusively during the known DNA rearrangement period in macronuclear development. The breaks are staggered by 4 bp in the complementary strands. Several alternative breaks were found at the end of one deleted region, consistent with multiple alternative chromosomal junctions detected previously. The free 5' ends generated at the breaks are phosphorylated. A purine residue always occurs at the free 3' ends, with an adenosine appearing in 11 of 12 cases. Patterns found in the detected break sites suggest rules that define the ends of the deleted segments within a transposon-like deletion mechanism. PMID- 7851798 TI - Integrating sex- and tissue-specific regulation within a single Drosophila enhancer. AB - We have investigated the integration of sex- and tissue-specific transcriptional regulation in Drosophila. A single copy of the o-r enhancer from yolk protein genes directs female- and fat body-specific transcription. It consists of four protein-binding sites: dsxA, which binds male (DSXM) and female (DSXF) proteins encoded by the doublesex gene; aef1, which binds the AEF1 repressor; bzip1, which binds the DmC/EBP activator encoded by the slbo gene; and ref1, which binds an unknown activator. Multimeric and mutated binding sites were used in protein binding, germ-line transformation, and genetic experiments to examine the independent and combinatorial activities of the proteins and DNA sites. DSXF activates from dsxA by sterically excluding AEF1 repressor from the aef1 site and synergistically activating transcription together with a protein at bzip1. Sex specificity in fat bodies arises from the opposite effect of DSXM, which represses activity of the protein at bzip1. Tissue specificity is regulated by all four DNA sites. Separately, bzip1 and ref1 activate transcription in ovarian somatic cells and all nongonadal tissues, respectively, whereas together they activate only in fat bodies. The aef1 site represses ectopic transcription in ovaries and dsxA antirepresses this activity in fat bodies. Thus, in the organism, ref1 and bzip1 act combinatorially to direct the fundamental tissue specificity, aef1 and dsxA modulate this tissue specificity, and dsxA adds sex specificity. PMID- 7851799 TI - Geriatric aspects on estrogen effects and sexuality. PMID- 7851800 TI - Low-dose estrogen in urogenital ageing. PMID- 7851801 TI - Urogenital ageing. PMID- 7851802 TI - Local oestrogen replacement for local symptoms in older community dwelling women. PMID- 7851803 TI - Human decidua-associated protein 200 levels in uterine fluid at hysteroscopy. AB - Hysterosocpic intrauterine findings and levels of human decidua-associated protein 200 (hDP 200) in the uterine fluid were recorded in 116 women investigated for infertility or recurrent abortions. The levels of hDP 200 were significantly higher in the presence of submucous myomas or endometrial polyps, and lower in the presence of intrauterine adhesions in comparison to those in normal uterine cavities. hDP 200, an immunoglobin secreted by the endometrium, may be involved in implantation and placentation and its level in the uterine cavity is influenced by the presence of intrauterine pathology. PMID- 7851804 TI - Mononuclear cell magnesium content remains unchanged in various hypertensive disorders of pregnancy. AB - Serum magnesium levels, as well as magnesium content of red blood cells and peripheral mononuclear cells, were examined in 31 pregnant women in their third trimester. Ten were preeclamptic; chronic hypertension was found in 10, and 11 were normotensive. Magnesium serum levels were 1.2 +/- 0.1, 1.2 +/- 0.1 and 1.3 +/- 0.1 mEq/l in the normotensives, chronic hypertensives and preeclamptics, respectively. Red blood cell magnesium concentration was 3.4 +/- 0.4, 3.7 +/- 0.7 and 3.5 +/- 0.5 mEq/l, and mononuclear magnesium content was 37.9 +/- 30.6, 27.6 +/- 15.9 and 30.2 +/- 25.7 fg/cell in the same groups, respectively. These changes were not statistically significant. The results do not support the hypothesis that magnesium deficiency is involved in the pathophysiology of preeclampsia. PMID- 7851805 TI - Blood levels of lipids, lipoperoxides, vitamin E and glutathione peroxidase in women with habitual abortion. AB - Plasma levels of triglycerides, cholesterol, cholesterol esters, phospholipids, lipoperoxides, vitamin E and erythrocyte glutathione peroxidase activity showed no significant differences between 40 women with habitual abortion and controls. However, the levels of free fatty acids (FFA), which are extremely cytotoxic compounds, were significantly higher in women with habitual abortion (HA) than in controls (16.8 +/- 6.7 vs. 8.6 +/- 3.7 mg/100 ml, p < 0.01, respectively). The high amounts of FFA in HA women during pregnancy were probably due to a continuous and/or excessive stress-dependent discharge into the blood of catecholamines from autonomic nerve endings. These catecholamines can induce a strong uterine vasoconstriction and placental ischemia-hypoxia which, in association with additional insults caused by reoxygenation, might lead to eventual miscarriage. PMID- 7851806 TI - Changes in white blood cells during parturition in mothers and newborn. AB - Following spontaneous delivery (n = 12) a pronounced increase in the maternal total white blood cell count was found (to [mean +/- SD]: 20 +/- 6 x 10(9) total leukocytes/l), which would be considered highly 'pathological' in nonpregnant women. The alteration was predominantly due to an increase in polymorphnuclear cells and band forms. Simultaneously, a drastic decrease in the percentage and the absolute number of lymphocytes was noticed in venous blood (from 32 to 5%, or [mean +/- SD]: from 2.7 +/- 0.7 to 1.1 +/- 0.3 x 10(9) total lymphocytes/l). In this decrease nearly all lymphocyte subtypes were involved, although to differing extents. Following elective caesarean delivery (n = 6), no leukocytosis was found, however the percentage and absolute number of lymphocytes was also decreased, although not as pronounced as after spontaneous delivery. Again not all the lymphocyte subpopulations were affected to the same degree, and the effect was especially obvious for the suppressor T cells and B cells. Following emergency caesarean delivery (n = 5), no obvious effect on the absolute number of lymphocytes or on the pattern of lymphocyte subpopulations was observed. However, the total number of white blood cells was clearly increased, as after spontaneous deliveries. The possible significance of these findings, also for therapeutic consequences during the perinatal period, is discussed. PMID- 7851807 TI - Cell-mediated immunity imbalance in pregnancy-induced hypertension. AB - Pregnancy is associated with modifications in the maternal immune system that may be involved in the absence of rejection of the fetoplacental graft characterized by the presence of paternal antigens. This active and specific tolerance towards the fetoplacental unit seems to be compromised in pregnancy-induced hypertension (PIH). To evaluate whether the immunological state in patients with PIH is altered with respect to normal pregnant women we studied 15 patients with PIH, 15 uncomplicated pregnant and 10 healthy nonpregnant women using monoclonal antibodies directed to specific lymphocyte antigen determinants, cytokines (TNF) and soluble molecules (sIL-2R, sCD8). The percentage of CD4 lymphocytes and of natural killer (NK) cells was significantly higher in PIH patients compared to controls (CD4: 42.9 +/- 10.5 vs. 32.7 +/- 12.5%; p < 0.05; NK: 14.7 +/- 6.3 vs. 8.3 +/- 3.4%; p < 0.01). However, these values did not differ when compared to normotensive nonpregnant controls (CD4: 53.1 +/- 5.9%; NK: 17.2 +/- 7.1%). In addition, the soluble IL-2 receptor (sIL-2R) was higher in PIH patients when compared to control patients (725.5 +/- 194.2 vs. 482.5 +/- 187.2 U/ml; p < 0.01). The immune response observed in normal pregnancies responsible for the tolerance towards the fetoplacental unit seems to be altered in PIH patients as suggested by higher levels of CD4 and NK cells, and sIL-2R. This may lead to a chronic rejection syndrome and be involved in the pathophysiology of PIH. PMID- 7851808 TI - Uterocervical reflex: description of the reflex and its clinical significance. AB - The effect of uterine distension on the cervix was studied in 16 women (mean age 38.4 years). Carbon dioxide was infused, in increments up to 50 ml, into a condom ended catheter introduced into the uterus. The response of uterine and cervical pressures to uterine distension was determined before and after anesthetizing the uterine body and the cervix, respectively. Upon slow uterine distension, the cervical pressure increased (p < 0.01), while the uterine pressure showed insignificant changes (p > 0.05). Rapid distension led to cervical pressure decrease (p < 0.01) and increase of uterine pressure (p < 0.01). The cervical pressure did not respond to slow or rapid inflation of the anesthetized uterus, neither did the anesthetized cervix respond to uterine inflation. A reflex relationship seems to exist between the uterine body when distended and the cervix, which we call 'uterocervical reflex'. The study demonstrates that the uterus behaves differently under physiologic and pathologic conditions. Upon slow uterine distension as in pregnancy, the uterus adapts by uterine dilatation and cervical tightening. In pathologic conditions which distend the uterus rapidly, the latter reacts with uterine contraction and cervical dilatation, discharging the uterine contents. Dysfunction of the uterocervical reflex may result in uterine and cervical disorders. The reflex may thus be included as a diagnostic tool in such disorders. PMID- 7851809 TI - Antiestrogenic effects of danazol on rabbit uterus. AB - To examine antiestrogenic effects of danazol through the receptor system and to clarify its direct effects on the endometrium in vivo, we applied danazol jelly directly into the rabbit uterine cavity and measured uterine estrogen, progesterone and androgen receptors (ER, PR and AR, respectively). Danazol significantly reduced ER, PR and AR (p < 0.05). Treatment with receptor-blocking agents (RU 486 and oxendolone) showed that the decrease in the ER level showed a closer association with that in PR than with AR. These results indicate that danazol directly administered into the uterine cavity is absorbed by the endometrial tissue and exerts its antiestrogenic effects possibly through PR in the cells. PMID- 7851810 TI - Etiology of serum CA-125 in patients with endometriosis treated with a gonadotrophin-releasing hormone agonist (Buserelin). AB - Fifty-six patients with pelvic endometriosis were treated with a buserelin dosage of 200 micrograms/day s.c. for 6 months. Scoring of the American Fertility Society (AFS) for endometriosis was performed by laparoscopy in all cases before and at the end of therapy. Serum CA-125 and estradiol levels were determined before the treatment, and monthly during therapy and follow-up (6 months; respectively). A slight positive correlation was found between serum CA-125 concentrations before treatment and AFS scores for adhesions only. Before treatment, serum CA-125 values also correlated slightly with total AFS scores of patients with adhesions. At the end of the 6-month therapy, no correlation was found between CA-125 concentrations and second-look AFS scores for implants and/or adhesions. Serum CA-125 and estradiol values were closely parallel to each other during and after therapy with the gonadotrophin-releasing hormone agonist buserelin. In conclusion, (1) adhesions may play a role in the elevation of serum CA-125 levels in endometriosis, and (2) a significant decrease in serum CA-125 values during the buserelin therapy may result from a rather different mechanism, such as ovarian suppression, other than the therapeutic effect of this agent. PMID- 7851811 TI - Release of 17-beta-oestradiol from a vaginal ring in postmenopausal women: pharmacokinetic evaluation. AB - Oestrogen-containing vaginal rings of various designs have been utilised in hormone replacement therapy. In contrast to the traditional 'homogeneous' design, rings designed with a steroid-containing core and outer polymer sheath provide a diffusion-controlled release rate which enables the delivery of low doses of drug. The aim of this investigation was to evaluate in vitro oestradiol release from a 'core' designed vaginal ring (Estring) and furthermore, to establish the in vivo concentration-time course of oestradiol, oestrone and total oestrone (unconjugated plus conjugated) in consecutive applications of such an oestradiol containing vaginal ring in postmenopausal women. Results indicate that the controlled release design of Estring produces stable, low systemic plasma concentrations of oestradiol and has an extended time period of release. PMID- 7851812 TI - Suppression of plasma insulin-like growth factor-1 levels in healthy, nulliparous, young women using low dose oral contraceptives. AB - Insulin-like growth factor-1 (IGF-1) levels were analyzed in 43 healthy, nulliparous women aged 19-25 years. Blood samples were drawn in a standardized way in follicular and luteal phases, for present users during cycle days 5-10 and 18-23, respectively. In each women, absolute levels and a difference in p-IGF-1 levels between the two menstrual cycle phases (delta IGF-1) were related to oral contraceptive (OC) use, height, weight, age, gonadotropin and serum sexual hormone binding globulin (s-SHBG) levels. In the follicular phase and cycle days 5-10, absolute values of p-IGF-1 did not significantly differ between present, former and never users of OCs, in contrast to a significant difference (p = 0.0013) in the luteal phase and cycle days 18-23 between present users and never users, after adjustment for age. delta IGF-1 was significantly negatively correlated to present OC use, compared with nonusers (p = 0.0002). delta IGF-1 did not significantly differ between former and never users. While height and weight were not significantly related to delta IGF-1, there was a significant negative correlation between age and delta IGF-1 (p = 0.05). Also, s-SHBG and p IGF-1 were significantly negatively related in the luteal phase and cycle days 18 23 after adjustment for age (p = 0.006), although this relationship disappeared after adjustment for present OC use. PMID- 7851813 TI - Sonohysterography versus hysteroscopy in the diagnosis of endouterine polyps. AB - The objective of this retrospective study was to evaluate the usefulness of abdominal and vaginal sonohysterography (SHG; considered both singly and in combination) for the diagnosis of uterine polyps. Fifty fertile women hospitalized for hysterectomy for benign gynecologic indications were enrolled. Main outcome measures were preoperative conventional vaginosonography, transabdominal and vaginal SHG, hysteroscopy and histologic evaluation of the surgical specimen. Conventional vaginosonography had a sensitivity of 33.3% and a specificity of 100%; the predictive values of abnormal and normal scans were 100 and 79.5%, respectively. Transabdominal SHG had a sensitivity of 75% and a specificity of 100%. The predictive value of an abnormal scan was 100%; that of a normal scan 91.2%. Vaginal SHG had a sensitivity of 58.3% and a specificity of 100%; the predictive value of an abnormal scan was 100%, that of a normal scan 86.1%. The combination of the two kinds of SHG had a sensitivity of 91.7% and specificity of 100%; the predictive value of an abnormal test was 100% and that of a normal test 96.9%. The sensitivity, specificity and predictive values of abnormal and normal hysteroscopic examination were all 100%. In conclusion, the presence of endouterine polyps can be effectively investigated by SHG; nevertheless, hysteroscopy is more sensitive, being capable of detecting even very small endouterine neoformations. PMID- 7851814 TI - Accuracy of pipelle endometrial sampling in endometrial carcinoma. AB - In this prospective study, we compared the histological results of Pipelle endometrial sampling (PES) with that of hysterectomy to examine whether endometrial sampling with the Pipelle device can accurately diagnose endometrial carcinoma. PES was performed in 26 patients with known endometrial carcinoma whose initial therapy consisted of hysterectomy. Discomfort and pain during the biopsy were reported to be mild by 22 patients, moderate by 3 patients and severe by only 1 patient. All of the samples were found to be adequate. Twenty-four of 26 PES confirmed endometrial carcinoma, a correlation of 95%, and the histological grade reported on PES agreed with that of hysterectomy specimens in 87.5% of the patients. On the other hand, the tumor grade in the specimens obtained at dilation and curettage correlated with hysterectomy specimens in 95% of the patients. We conclude that Pipelle is an accurate device in patients with endometrial carcinoma. PMID- 7851815 TI - Detection of human papillomavirus RNA in ovarian and endometrial carcinomas by reverse transcription/polymerase chain reaction. AB - The presence of human papillomavirus (HPV) type 16 and 18 transcripts was determined by reverse transcription/polymerase chain reaction (PCR) in ovarian and endometrial carcinoma tissue. HPV-16 DNA sequences were detected in 50.0% (9/18) of the ovarian carcinomas and in 44.4% (8/18) of endometrial carcinomas. HPV-18 DNA sequences were found in 16.7% (3/18) of both the ovarian and endometrial carcinomas. Using RNA-PCR analysis, we found 3 out of 9 (33.3%) of the HPV-16 DNA-positive and 1 in 3 (33.3%) of the HPV-18 DNA-positive ovarian carcinomas were transcriptionally active, contrary to the HPV-16 DNA-positive or HPV-18 DNA-positive endometrial carcinomas. The results suggest that HPV RNA may be detected in ovarian carcinomas though its biological significance remains to be elucidated. HPV RNA is not demonstrable in endometrial carcinoma using the current primer sets. Further investigations are necessary for a final conclusion. PMID- 7851816 TI - [Two applications of in vivo brain microdialysis: administration of high molecular-weight drugs through a microinjection tube and measurement of nitric oxide production]. AB - A brain microdialysis technique has made it possible to determine neurotransmitter levels in the targeted region of the brain of a freely moving rat. In this article, two kinds of application of the brain microdialysis are demonstrated. First, to study central nervous effects of large molecular weight substances that cannot cross the blood-brain barrier, we used a microdialysis probe equipped with a microinjection tube for administering the substance in the same region into which the probe had been inserted. We proved that interleukin-1 beta (1 ng) injected directly into the anterior hypothalamus elicited releases of NE, DA and 5-HT, as well as increases in their metabolites. Second, using a new method combining a brain microdialysis technique with measurement of nitrite/nitrate by the Griess reaction, we demonstrated that activation of N methyl-D-aspartate (NMDA) receptors in the cerebella of rats induces the release of nitric oxide (NO). Since L-NG-monomethyl-arginine (L-NMMA), which competitively blocks NO synthesis from L-arginine, significantly inhibited the release of nitrite/nitrate from the rat cerebellum, these results indicate that this new method is capable of measuring NO formation from L-arginine following the stimulation of NMDA receptors. PMID- 7851817 TI - [Antinociceptive effects of counterirritants]. AB - Counterirritants such as l-menthol, methyl salicylate, camphor, thymol and capsaicin are widely used in the treatment of mild pains and itches by topical application. However, little experimental research on counterirritants has been reported. In the present study, we investigated the antinociceptive effects and mechanisms of topically applied counterirritants, especially those of l-menthol. From the formalin test in mice, l-menthol (at a concentration of 1-30% in ethanol) showed a major effect in the early phase of pain response (0-5 min). In contrast, the antinociceptive effects of indomethacin (10 mg/kg, p.o.) were found only in the late phase of pain response (15-25 min). Furthermore, morphine (0.75 6 mg/kg, s.c.) dose-dependently inhibited both phases. l-Menthol-induced analgesia during the early phase was significantly blocked by naloxone and potentiated by bestatin. The antinociceptive effects of l-menthol were furthermore examined in dexamethasone-treated mice. l-Menthol also produced antinociceptive effects in the hot plate test of mice and hind paw pressure test of rats. l-Menthol showed mild surface and infiltrating anesthetic effects in guinea pigs. l-Menthol did not inhibit both carrageenin-induced paw edema of rats and the synthesis of prostaglandin E2 in vitro. Based on these findings, we proposed that l-menthol produces antinociceptive effects by activation of the endogenous opioid system and/or partially by local anesthetic actions without anti-inflammatory effects. PMID- 7851818 TI - [Effect of mesalazine, an agent for the treatment of idiopathic inflammatory bowel disease, on reactive oxygen metabolites and LTB4 formation]. AB - Mesalazine microgranules (Pentasa) were developed as a drug for idiopathic inflammatory bowel diseases such as ulcerative colitis and Crohn's disease. In this study, we examined the effect of mesalazine on radical scavenging, lipid peroxidation and the formation of LTB4. Mesalazine reduced the free radical 1,1 diphenyl-2-picrylhydrazyl with an IC50 value of 9.5 microM. It scavenged hydrogen peroxide and hypochlorite (IC50: 0.7 microM and 37.0 microM, respectively), but had no effect on superoxide. Lipid peroxidation in rat liver microsomes was inhibited by mesalazine (IC50: 12.6 microM). Mesalazine significantly inhibited (P < 0.01) gastric mucosal lipid peroxidation induced by ischemia and reperfusion in rats at a dose of 50 mg/kg, p.o. Mesalazine also inhibited the formation of LTB4 in rat peritoneal neutrophils (IC50: 44.9 microM). N-Acetyl-mesalazine, the metabolite of mesalazine, had no effect on radical scavenging and lipid peroxidation. Only a high concentration (1 mM) of the metabolite inhibited the formation of LTB4. These studies suggest that mesalazine inhibits cell injury in the inflamed mucosa by scavenging reactive oxygen metabolites and prevents the invasion of neutrophils by inhibition of LTB4 formation. PMID- 7851819 TI - [Effect of 5-[2-(diethylamino)ethyl]amino-5,11- dihydro[1]benzoxepino[3,4 b]pyridine trihydrochloride (KW-5805) on the biosynthesis of rat gastric mucus]. AB - The effect of 5-[2-(diethylamino)ethyl]amino-5,11- dihydro[1]benzoxepino[3,4 b]pyridine trihydrochloride (KW-5805) on the activity of an enzyme regulating gastric mucous aminosugar metabolism was studied in rats. Restraint and water immersion stress decreased the gastric mucosal glucosamine synthetase activity and induced gastric ulcers. The decrease of the enzyme activity reached a maximum at 1 hr and then returned to the non-stressed value. Pretreatment with KW-5805 at oral doses of 3 and 30 mg/kg inhibited the decrease of the enzyme activity and the gastric adherent mucus content and gastric ulceration induced by the stress. KW-5805 (30 mg/kg, p.o.) increased the enzyme activity in normal rats and also prevented the decrease of gastric mucosal N-acethylglucosamine kinase activity in the stressed rats. KW-5805 stimulated the activities of gastric mucosal. UDP-N acethylglucosamine 4-epimerase and UDP-galactosyltransferase in in vitro. These results suggested that the antiulcerogenic effect of KW-5805 might be due to the activation of an enzyme regulating the biosynthesis of gastric mucus resulting in the reinforcement of gastric mucosal defensive mechanisms. PMID- 7851820 TI - [Effect of bifemelane hydrochloride in rats on the improvement of the learning and memory impairments and prevention of neuronal damage following transient forebrain ischemia]. AB - Modified four-vessel occlusion in rats caused loss of the passive avoidance response (PAR) and impaired the radial maze performance (RMP). We investigated the effectiveness of bifemelane hydrochloride (bifemelane) in restoring these abilities. After the RMP test, the hippocampal neuronal density following cerebral ischemia was observed histologically and the effect of bifemelane on it examined. Bifemelane was intraperitoneally administered at a dose of 1, 3, 10 mg/kg or 30 mg/kg twice before ischemia and daily following cerebral ischemia. The control rats were given physiological saline in the same manner. At a dose of 10 mg/kg, i.p., bifemelane significantly restored the PAR, which had been lost as a result of 5-min ischemia. At the same dose, it significantly restored the RMP, which had been impaired by 15-min ischemia and prevented neuronal damage in the CA2 region of the anterior hippocampus and the CA1, CA2 and CA3 regions of the posterior hippocampus. The correlation between the memory score and the neuronal density in the CA1 region of the posterior hippocampus was statistically significant. These results suggest that bifemelane might prevent the neuronal damage induced by ischemia and restore impaired learning and memory capabilities following cerebrovascular disease. PMID- 7851821 TI - Withasteroids, a growing group of naturally occurring steroidal lactones. PMID- 7851822 TI - [The differential diagnostic value of skeletal, dental and soft-tissue analyses in the planning of orthodontic-oral surgical therapy. A retrospective study of treated patients with skeletal Angle class III]. AB - The study evaluated the orthodontic documentation gathered in the course of conducting combined surgical-orthodontic therapy on 45 skeletal angle class III patients. In 15 of the patients Le Fort I osteotomy of the maxilla was performed, in 15 sagittal split osteotomy of the mandible, and in the last 15 patients bimaxillary surgery. The purpose of the study was to evaluate by means of a retrospective analysis of cephalograms taken prior to surgery the role hard tissue, soft tissue, and dental cephalometric variables play in the choice of the type of surgery to be performed. Discriminate analysis was used to determine the ability of the individual parameters to predicate accurately the type of the surgery that had been carried out. The study revealed that the skeletal relationship diagnosed in the x-rays was suitable primarily in the differentiation of the monomaxillary and bimaxillary patients who had undergone surgery. Using discriminate analysis the accuracy to predict group membership was 75.6% for the skeletal parameters of the McNamara analysis and 67.5% for those of the Bergen analysis. Differentiation between the cases where surgery had been performed solely in the maxilla and those where surgery had been performed only in the mandible was most successful using the soft tissue parameters describing the position of the subnasale and the position of the lower lip in relation to the aesthetic line according to Ricketts. In addition, the arrangement of the lower incisors was more retrusive in the cases with isolated surgery in the maxilla. Discriminate analysis applying a combination of skeletal, dental, and soft tissue parameters had a capability to predict accurately in 93.3% of the patients the form of the chosen surgical procedure. PMID- 7851823 TI - [Can magnets or additional intermaxillary forces improve the mode of action of jumping-the-bite plates?]. AB - The use of accessory intermaxillary elastic traction or magnets during bite jumping appliance therapy marks a significant improvement in patient treatment. The use of interarch traction results in 100% mouth closure during the night, which is independent of the patient's sleeping position. During the night the guide pegs are subjected to almost no stress, which guarantees a quick adaptation. Additional intermaxillary traction does call for anchoring procedures in the maxillary anterior (torque springs) and mandibular molar region (clasps). According to the dental situation, the application of dynamic force can be withdrawn for a transitory period of time. Use of additional magnets in the anterior, depending on sleeping position, leads to complete mouth closure in up to 70 to 90% of the cases. Extensive measures in the mandibular and maxillary anterior areas must be considered when using this variant. In many cases the application of brackets is an absolute necessity. However, when the dental situation calls for it, magnets cannot be deactivated. All magnets in use today corrode very easily. It is, therefore, recommended that magnets used interorally be especially well shielded. Leaky capsules must considered especially problematic. Correct adjustment in the sagittal plane does not in any case guarantee stabilization. Only when a 3- or 4-stage bite has been reached, can it be said that a good adjustment in the neuromuscular masticatory pattern has been achieved. Depending on patient compliance, this period can be significantly drawn out. A functional analysis is not a suitable method for analyzing an extant stable result. With both of these modifications there is a tendency to greater dentoalveolar effect and diminished influence on the skull. The issue of whether magnets have no place in orthodontics, as Gianelly [3] claims, cannot be definitively answered, however, it can be said that intermaxillary traction, especially when force is applied by using super-elastic springs, is less expensive, demonstrates a better effectiveness, and it is much easier to use. PMID- 7851824 TI - [A retrospective examination of the acceptance of removable appliances]. AB - In order to study the subjective attitudes of patients and their parents to orthodontic treatment questionnaires were handed out to both groups. One hundred and forty five patient questionnaires and those answered by 114 parents formed the base of the study. The majority of the patients were only able to provide partial answers to precise questions about their treatment. Speech impairment, pressure, and salivation were given as being the most vexatious aspects of the treatment. The majority of the patients and the majority of parents favored removable appliances over fixed appliances. The patients' social environment did not negatively influence their attitude to orthodontic treatment. PMID- 7851825 TI - [Simultaneous electromagnetic articulography and video endoscopy. A case contribution to the objective diagnosis of the velopharyngeal sphincter]. AB - An objective examination of velopharyngeal sphincter function (VP) is possible using a variety of signal and pictorial methods to differing degrees. Video endoscopy and videofluoroscopy are the currently accepted clinical standard. With the help of a new concept described here it is possible both to analyze VP function in the midsagittal plane using electromagnetic articulography (EMA) and also to examine simultaneously the horizontal plane video endoscopically. This multidimensional analysis of VP function is presented in a case study of a healthy test person and the timing aspects of VP closure and transverse-sagittal ratio of VP port-diameters ist reported. PMID- 7851826 TI - [An in-vitro study of the bonding and fracture pattern of light-hardening, fluoride-releasing bonding materials in metal brackets]. AB - Three hundred bovine incisors, which were divided into 6 groups of 50 teeth each, were used in this study. Two types of metal brackets, 1 with a conventional foil mesh base and the other with a photo-etched Micro-Loc base, were adhered to the teeth with 3 different bonding agents, namely, Sequence, a fluoride-releasing, light-activated composite, Photac-Fil, a light-hardened glass ionomer cement, and, in the control group, Concise, a 2-component composite which hardens chemically. A universal testing machine was employed to test tensile bonding strength and the site of failure was visually determined and analyzed. The study showed that Sequence can be considered as a qualitatively equal alternative to Concise. Both composites demonstrate equal tensile bonding strength. The use of Photac-Fil, the light-hardened glass ionomer bonding agent, cannot be recommended. It possesses significantly less tensile bonding strength than the other 2 bonding agents. Sequence and Concise, which showed better results with the brackets with conventional foil mesh base than with the brackets with photo etched Micro-Loc base, had no significant differences in their failure sites. The interface of the composite with the bracket was the main failure site. Both composites demonstrated a significantly reduced rate of failure at the interface of the composite with the enamel, when they were used with the brackets with the Micro-Loc base. This differed from the failure site of Photac-Fil, when the photo etched base was used. With Photac-Fil the main site of failure came at the interface of the enamel with this glass ionomer cement.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7851827 TI - [An in-vitro study of 2 resins used in orthodontics for their cell toxicity]. AB - The aim of this study was to examine in vitro cell compatibility of the orthodontic base resins Orthocryl (Dentaurum) and Wil-o-dont (Wilde) using the method described by Heidemann and Lampert (1980). The acute local nonspecific cytotoxicity of these materials and that of their individual components were evaluated. Used were both a qualitative microscopic assessment of cytopathological changes occurring in human gingival fibroblasts cultured along side the specimens and a semiquantitative assessment of the zones of inhibited cell growth around the specimens. Whereas Orthocryl and its components exhibited no toxic influence on the growth of the cultured cells, substantial cytotoxicity was observed in the tests of Wil-o-dont. The monomer and the adhesive component of this resin were found to be particularly toxic under the conditions tested. On the basis of the results of the study Wil-o-dont can not be given a clean bill of health in relation to the cytotoxicity of the product. PMID- 7851828 TI - [Hardened anodized aluminum as a replacement material for bracket manufacture]. AB - Attention has been repeatedly drawn to the problem of corrosion and the risk of allergic reaction to nickel resulting from the use of stainless steel brackets. In the search for a suitable alternative, manufacturers have turned to thin coating technology using hardened anodized aluminium. Applying resistance to corrosion and abrasion as the criteria to be met, they have selected aluminium alloy type 6082 as the material of choice. Purpose of this study is to examine the physical suitability of this material. Using the above noted alloy, 60 prototype brackets were made with a hardened anodized surface. They were then subjected to the following 3 stress tests: first an abrasion test using a tooth polishing machine, second, a deformation test using a device designed to simulate torque movement, and, third, a corrosion test. The effects on the brackets resulting from the three types of stress were evaluated by light microscopy. A quantitative analysis of the corrosion test was performed by ICP spectrometry. The control group consisted of conventional stainless steel brackets. The light microscopic analysis revealed no evidence of surface damage or signs of deformation in the prototype brackets. The steel brackets, on the other hand, showed clear signs of wear and corrosion. The quantitative analysis of the corrosion solution revealed metallic ion wear of 1.75 ng x mm-2 x h-1 for the prototypes subjected to abrasion. The steel brackets showed at a factor of around 104.6 metallic ion wear of 183 ng x mm-2 x h-1. In addition to this, no Ni ions were found in the corrosion solution of the prototype brackets.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7851829 TI - [The practical aspects of using "superelastic" arch wires in the edgewise technic]. AB - Ever increasing refinements in orthodontic treatment and the corresponding increase in technical demands are challenges to both the dentist in his/her practice and to the manufacturers of orthodontic materials. One interesting development has been the introduction of "super-elastic" arch wires, which have now been on the market for some years. Such arch wires are characterized by an excellent "shape memory", various levels of super-elasticity, a remarkable hysteresis, and temperature sensitivity. On the basis of findings from temperature controlled tests of arch wires in a "Lloyd 1000 R" testing machine, the following conclusions can be drawn. Shape memory can, from a clinical point of view, be regarded as being a positive feature. "Super-elasticity" is of lesser value, because conventional activation of edgewise arches rarely reaches the level of deformation necessary for super-elasticity to be called into play. Hysteresis and temperature sensitivity make a biomechanical control of the arch wires difficult. Reducing active forces by chilling the archwire brings relief to sore teeth. Whether this possibly leads to an improvement in blood circulation in the periodontal tissue, which would be biologically advantageous, should be made the subject of further research. PMID- 7851830 TI - [Headgear-free molar distalization]. AB - The difficulty in treating dentoalveolar class II disharmonies is briefly outlined. An innovative treatment method is presented which makes possible a distalization without the use of headgear. In the treatment method bands are cemented on the first molars, next impressions are made of the upper and lower dental arch, and then the impressions are poured with plaster. Following this the models are mounted in centric relationship in an articulator and the bite is opened 2 mm to 3 mm, so that the molars can be moved without making occlusal contact. The apparatus, an acrylic splint, is constructed in such a fashion as to cover the palatal surfaces from 2nd premolar to 2nd premolar. In addition, the premolars are also covered occlusally and buccally and the canine tips and the incisal edges are covered labially. A headgear tube is attached at the buccal surface in the premolar region of the acrylic splint. This acrylic splint, which is itself retentive, is cemented using glass ionomer cement. Combining this apparatus with a modified Nance Button makes it possible to establish an anchoring segment which is able to retain its position in the face of molar distalization. Molar distalization is then performed using a 0.032 inch stainless steel wire, which is placed between the headgear tube of the acrylic splint and the headgear tube of the band of the first molar. Highly elastic nickel-titanium open coil springs are used as the force elements. PMID- 7851831 TI - [Ion channels of vascular smooth muscle and pharmacological effects of calcium antagonists and potassium channel openers]. PMID- 7851832 TI - Mutations in the transcriptional regulatory region of the precore and core/pregenome of a hepatitis B virus with defective HBeAg production. AB - Termination mutations in the precore open reading frame of hepatitis B virus (HBV) variants with defective hepatitis B e antigen (HBeAg) production have been demonstrated in both infected patients who have seroconverted to anti-HBe and those with fulminant hepatitis B. A donated plasma sample was found to be positive for the hepatitis B surface antigen, but negative for both HBeAg and anti-HBe. The HBV DNA titer in the plasma was estimated to be 32 pg/ml, and circulating virus-like particles were observed by electron microscopy. The entire nucleotide sequence of the virus was determined and at least 7 nucleotides were found to be unique when compared with previously reported sequences. These nucleotides created no termination codon in the precore/core, pol, preS/S and HBx open reading frames. The deduced amino acid substitutions were 28 Arg--Gln, 94 His--Tyr, 131 Val--Ile and 132 Phe--Tyr of HBx and 715 Met--Val and 789 Asp--Asn of pol. Furthermore, the precore and core/pregenome promoter contained altered 1764 A, 1766 T and 1768 A. Therefore, mutations in regions other than the precore open reading frame can cause defective HBeAg production. PMID- 7851833 TI - [Treatment of obesity as an insulin resistance]. AB - Insulin resistance or hyperinsulinemia should play an important role in the formation of obesity-associated complications such as hypertension, impaired glucose tolerance, hyperlipidemia etc.. Moreover, obesity is a major aggravating factor for the musculoskeletal disorders. Using the ratio of fasting plasma glucose per insulin (IRI) as a parameter of insulin resistance, I have attempted to know how the insulin resistance would be improved concomitant to the weight reduction of obese patients who mainly suffered from musculoskeletal diseases. The results clearly showed the vigorous weight reduction conducted the significant decrease of the insulin resistance as well as normalizations of blood pressures and several biochemical parameters. PMID- 7851834 TI - [A case of syndrome X whose hyperglycemia, hyperlipidemia and hypertension were improved as accompanying with decreased insulin resistance]. AB - A 60-year-old man was admitted to the Kyushu University Hospital because of poor glycemic control of diabetes mellitus. Although he had been treated with glicrazide and nifedipine for his diabetes and hypertension, the controls of the diseases were unsatisfactory. Plasma triglyceride level was 186 mg/dl. Furthermore, extreme insulin resistance was found by measuring glucose infusion rate with an euglycemic hyperinsulinemic clamp method. These findings were compatible to those seen in syndrome X. After admission, diet therapy of 1,800 Cal was started and his metabolic disorders such as hyperglycemia, hyperlipidemia, and hypertension were all improved. Moreover, euglycemic hyperinsulinemic clamp study also revealed a decreased insulin resistance after diet therapy. Our experience from the case suggested that insulin resistance may closely related with the metabolic disorders of the disease "syndrome X". PMID- 7851835 TI - [Severe thrombocytopenia during interferon-alpha therapy for chronic active hepatitis C associated with systemic lupus erythematosus]. AB - We herein report a case of chronic active hepatitis C which developed a severe thrombocytopenia during an interferon therapy. The case is a 34 year-old-female, who admitted for the inactive stage systemic lupus erythematosus based on the laboratory findings and the episodes of polyarthralgia. HCV-RNA was positive and the Ristology of the liver biopsy specimen showed the feature of chronic active hepatitis. Under the diagnosis of C type chronic active hepatitis, the natural interferon-alfa therapy was started. After administering the total dose of 366M units of the interferon, purpura developed and the total blood counts revealed pancytopenia, especially severe thrombocytopenia. However, by administering packed red blood cells, platelets and prednisolone, the pancytopenia promptly recovered. Involvement of an immunological mechanism is considered as a cause of the pancytopenia. However, anti-platelet antibody and platelet-associated antibody were both negative and the bone marrow tap revealed a hypoplastic marrow. Therefore, cytotoxic cytokines induced by the interferon was considered to be a factor which caused the pancytopenia in this patient. PMID- 7851836 TI - Drug-induced parkinsonism: a review. AB - The main clinical features, pathophysiology and underlying mechanisms of drug induced parkinsonism are reviewed. The clinical manifestations of drug-induced parkinsonism are often indistinguishable from idiopathic Parkinson's disease. However, some subtle differences may exist: for example drug-induced parkinsonism is often associated with tardive dyskinesias, bilateral symptoms and the absence of resting tremor, etc. Besides toxins (eg manganese, carbon monoxide or MPTP), many drugs are known to produce parkinsonism: dopamine blocking drugs (true neuroleptics used as antipsychotics: phenothiazines, butyrophenones, thioxanthenes but also sulpiride, "hidden" neuroleptics prescribed as anti-nausea or anti-vomiting drugs (such as metoclopramide and other benzamide derivatives), dopamine depleting drugs (reserpine, tetrabenazine), alpha-methyldopa, calcium channel blockers (flunarizine, cinnarizine, etc). The putative role of other drugs (eg fluoxetine, lithium, amiodarone) as well as the therapeutic management of this side effect are reviewed. PMID- 7851837 TI - Opioidergic control of the spinal release of neuropeptides. Possible significance for the analgesic effects of opioids. AB - Several neuropeptides play a key role in the transfer (substance P, calcitonin gene-related peptide, etc) and control (enkephalins, cholecystokinin, etc) of nociceptive messages from primary afferent fibres to spino-thalamic neurones in the dorsal horn of the spinal cord. This first relay in nociceptive pathways has been shown to be a major target for opioids such as analgesic drugs, and the effects of exogenous (mainly morphine) and endogenous opioids on the release of neuropeptides within the dorsal horn are reviewed here for a better understanding of the cellular mechanisms responsible for their antinociceptive action. Complex modulations of the in vitro (from tissue slices) and in vivo (in halothane anaesthetized rats whose intrathecal space was perfused with an artificial cerebrospinal fluid) release of substance P and calcitonin gene-related peptide by opioids have been reported, depending on the opioid receptor (mu, delta, kappa, and their subtypes) stimulated by these compounds. In particular, the inhibition by delta agonists of substance P release from primary afferent fibres, and that by the concomitant stimulation of mu and kappa receptors of the release of calcitonin gene-related peptide are very probably involved in the analgesic action of specific opioids and morphine at the level of the spinal cord. Furthermore, the negative modulation (through presynaptic opioid autoreceptors) by delta and mu agonists of the spinal release of met-enkephalin, and the complex inhibitory/excitatory influence of delta, mu and kappa receptor ligands on the release of cholecystokinin within the dorsal horn very likely also contribute to the antinociceptive action of these drugs and morphine. The reviewed data strongly support the existence of functional interactions between mu and kappa receptors within the spinal cord, and their key role in the analgesic action of non specific opiates (acting on mu, delta and kappa receptors) such as morphine. PMID- 7851838 TI - Drugs designed to maintain the transparence of the ocular lens. AB - Research into the biological basis of lens transparency has demonstrated the implication of lens sugar stress in the diabetic cataract whereas senile cataract is the result of natural degeneration which is enhanced by various external factors such as cosmic and ionizing rays, or oxidative processes. Drugs have been developed which are aimed at being effective on lens pathological physiology and metabolism, concurrently. Such molecules: aldose reductase inhibitors (ARIs: sorbinil, AD-5467, CT-112 and imirestat), acetyl salicylic acid (ASA), salicylate (SA) and sodium monomethyl trisilanol orthohydroxybenzoate (SMB, a prodrug for salicylate) have undergone pharmacodynamic, pharmacokinetic and/or clinical studies which are presented here. ARIs have shown efficacy in slowing down and preventing the progression of experimental sugar cataracts; sorbinil can partially reverse the very early morphological signs of sugar cataract. Sorbinil and imirestat have also demonstrated anti-oxidant properties. ARIs administration (per os or by topical instillation) generally results in lens levels compatible with concentrations that are efficient on biochemical mechanisms of cataract formation. However, at the present time, clinical evaluations are in progress and as yet, there is no confirmation of their efficacy in man. ASA and SA can prevent various mechanisms of lens protein denaturation; they inhibit AR and prevent, in vitro, the formation of some pigments found in the aged cataractous lens. Extrapolation of the ASA ocular pharmacokinetics results in animal to man, suggest that ASA administration per os could result in efficacious levels in the lens. This is also sustained by the observation of a reduced frequency of cataracts in ASA treated diabetic rheumatoid arthritis patients. SMB pharmacokinetic studies have shown small but persistent levels of the active principle in the lens. They suggest that the capsule slows down SA diffusion into the lens and that, on the contrary, lens epithelium facilitates its penetration. Preliminary results of pharmacodynamic studies are given. PMID- 7851839 TI - Differential inhibition of the pressor effects of natural pro-endothelins by phosphoramidon in rats. AB - The vasopressor responses of three natural endothelins (ET-1, ET-2, ET-3) and their precursors, pro-ETs, were studied in a pithed rat preparation, which allows the profile and the potency of vasoconstrictor agents to be determined in the absence of central control of the cardiovascular system. ET-1 was found to be 4- and 8-fold more potent in raising blood pressure than ET-2 and ET-3, respectively. The immediate precursors of these isopeptides, h-pro-ET-1 (human), p-pro-ET-1 (porcine), pro-ET-2 and pro-ET-3, produced significantly smaller pressor responses than their respective ETs, when measured either as peaks or as areas under the time-effect curve. Hence, the bioavailability of h-pro-ET-1, p pro-ET-1 and pro-ET-2, assessed on the basis of these two parameters, was approximately 50% of that of their corresponding ET, whereas the bioavailability of pro-ET-3 was only 25% that of ET-3. Phosphoramidon inhibits metallopeptidases, the enzymes that convert pro-ETs to ETs. The approximate i.v. doses of phosphoramidon reducing by 50% the pressor effects of the pro-ETs were 2.5, 0.625, less than 2.5 (this dose produced 75% inhibition) and 5 mg/kg i.v. for h pro-ET-1, p-pro-ET-1, pro-ET-2 and pro-ET-3, respectively. In conclusion, these results indicate that the rat may have more than one pro-ET converting enzyme, each specific for one of the natural pro-ETs studied, although the alternative explanation, that there is a single enzyme with different affinities for these pro-ETs, cannot be entirely dismissed. PMID- 7851840 TI - Changes in brain MAO activity and glycogen levels upon chronic alcoholization of three successive generations of rats. AB - Changes in neurobiological parameters were examined from early life (10 days post natal) until late adulthood (8 months post-natal) in three successive generations of alcoholized rats. The mean daily consumption of alcohol by the 2nd and 3rd generation rats (7.40 +/- 0.22 and 7.70 +/- 0.20 g ethanol/kg body weight, respectively) was significantly greater than that of the 1st generation alcoholized group (4.26 +/- 0.33 g/kg). Brain/body weight ratios of alcoholized rats, 10 days post-natal, were significantly greater than controls, with 1st generation alcoholized rats presenting significantly greater brain/body weight ratios than those of the 2nd or 3rd generation, which tended toward control weights and ratios. This difference between alcoholized rats and controls persisted, although to a lesser extent, at 8 months post-natal. Glycogen content in the brains of rats of all alcoholized generations was significantly lower than in controls at 10 days post-natal, with a reversal of this situation in later life for 2nd and 3rd generation rats, which presented significantly greater cerebral glycogen levels than control or 1st generation alcoholized rats (which had an equivalent cerebral glycogen content). In 10-day-old rat pups, monoamine oxidase (MAO) activity in brain tissues had a tendency (mostly non-significant) to be greater in alcoholized rats than in controls, with a reversal of this situation, ie a statistically significant decrease in MAO activity in the 2nd and 3rd alcoholized generations with respect to controls, in 8-month-old rats. MAO activity in adrenal glands of alcoholized rats was greater than in controls at 10 days post-natal, and this difference persisted at 8 months. PMID- 7851841 TI - Short-term effects of quinapril and nifedipine on early renal changes in streptozotocin-induced diabetes in rats. AB - The effects on renal function of quinapril, an angiotensin I converting enzyme (ACE) inhibitor, and of nifedipine, a dihydropyridine calcium antagonist, were studied in the early stages of diabetes in rats. Wistar rats received one injection of streptozotocin (STZ) to induce diabetes; the hyperglycaemia was then controlled with daily insulin therapy (2-3 units NPH insulin/rat). One week after STZ injection, rats were treated orally with quinapril (0.3 or 3 mg/kg/d) or nifedipine (30 mg/kg/day) for 1 week, after which renal functions were compared with those of untreated diabetic rats or non-diabetic control rats. At the end of these two weeks, diabetic rats had gained less weight and had developed renal hypertrophy and glomerular hyperfiltration (3.21 +/- 0.23 vs 2.36 +/- 0.09 ml/min for non-diabetic rats, mean +/- SEM, P < 0.01). Their urinary albumin excretion was higher, as was the urinary excretion of water, sodium, potassium, urea and glucose. One week treatment with quinapril or nifedipine had no significant effect on the increase in the glomerular filtration rate (respectively 2.97 +/- 0.18 and 2.99 +2- 0.15 ml/min). Quinapril and nifedipine differed with regard to their effects on urinary albumin excretion. Albuminuria was increased by nifedipine but not by quinapril (respectively 0.554 +/- 0.158 and 0.149 +/- 0.046 mg/day/100 g BW, P < 0.05). This difference between the effects of the dihydropyridine and the ACE inhibitor on albuminuria may be linked to different effects on the glomerular functions. PMID- 7851842 TI - Effects of triiodothyronine and dexamethasone on plasma and tissue angiotensin converting enzyme in the rat. AB - In order to identify tissue specific regulation of angiotensin converting enzyme (ACE), the effects of dexamethasone (0.04 mg sc per day for 7 days) and triiodothyronine (T3) (0.5 mg/kg sc per day for 10 days) on ACE activity were investigated in different tissues in male Wistar rats. ACE activity was measured by fluorimetry in the plasma, heart, lung and kidney. In the kidney, ACE activity was measured in the medulla, cortex and brush border of proximal tubular cells and 3H-ramiprilat binding was used to characterise the changes in brush border ACE activity. Dexamethasone elicited a significant increase in lung ACE activity and a significant decrease in plasma ACE activity, but did not alter enzyme activity in the other tissues studied. T3 produced a significant decrease in lung ACE activity and an increase in ACE activity in the plasma and heart. In the kidney, ACE activity was not modified in the medulla whereas in the cortex and brush border ACE activity was doubled. This increase in ACE activity corresponded to a similar increase in the maximum number of binding sites of 3H-ramiprilat, suggesting that the increase in activity corresponded to an increase in the ACE level. The increased heart and kidney ACE activity in response to T3 may contribute to the cardiovascular effects of thyroid hormones through increased local angiotensin II generation. These results show that under dexamethasone or T3, ACE activity can vary from one tissue to another, suggesting that the ACE regulatory mechanism acts differently in each tissue. PMID- 7851843 TI - The effect of different calcium antagonists and a calcium agonist on the metabolism of propranolol by isolated rat hepatocytes. AB - The influence of the dihydropyridine calcium entry blockers nicardipine, amlodipine, nifedipine, isradipine and of the dihydropyridine calcium entry promotor BAY K 8644 on the disappearance rate of propranolol by isolated rat hepatocytes was compared to the effect of diltiazem and verapamil, two non dihydropyridine calcium channel blockers and known inhibitors of hepatic cytochrome P450 mixed function oxidases. All compounds dose-dependently inhibited the disappearance rate of propranolol. Nicardipine and isradipine were more potent in inhibiting the disappearance rate of propranolol than the other dihydropyridines and than diltiazem and verapamil. The inhibitory effect of nicardipine on the disappearance rate of propranolol was not stereoselective and was not influenced by age. PMID- 7851844 TI - Effects of repeated intravenous administration of diazepam on food intake in rats. AB - Effects of repeated intravenous (i.v.) administration of diazepam on food intake were investigated in freely moving rats implanted with a chronic i.v. cannula. Diazepam (0.2 and 2 mg/kg) was automatically injected i.v. at 3-h intervals for 3 consecutive days. Food intake was measured twice daily, ie for the light phase (7 00-19 00) and dark phase (19 00-7 00). Food intake during the light phase was increased in a dose-dependent manner following diazepam. Each injection of diazepam provoked hyperphagia, followed by a compensatory hypophagia until the next diazepam injection. Body weight, however, was increased significantly in rats treated with diazepam. When diazepam (2 mg/kg) was automatically injected at 3-h intervals for 10 consecutive days, tolerance did not develop to the hyperphagia and body weight was increased significantly following diazepam injection. After cessation of diazepam injection, both food intake and body weight decreased. These findings suggest that such excessive i.v. treatment with diazepam induces hyperphagia showing no tolerance accompanied by an increase in body weight, thus resulting in a trend toward obesity in rats. PMID- 7851845 TI - Colorectal carcinoma metastatic to skeletal muscle. AB - Skeletal muscle is one of the most unusual sites of metastasis from any malignancy. We report on a case of skeletal muscle metastasis from colonic carcinoma, and review seven previously reported cases. The patient was a 66-year old man who exhibited a painful metastatic mass in the right major teres muscle six months after surgery for colonic carcinoma. He underwent three operations and one course of arterial infusion chemotherapy, but died of carcinoma after two years and seven months. In seven previous cases and in the present case (3 males and 5 females, aged between 30 and 75 years), the sites of the primary lesion and metastatic lesion in skeletal muscle were diverse. The interval between primary carcinoma and relapse ranged from synchronous to 5 years. Spontaneous pain in the recurrent region was a characteristic symptom. Surgical removal of the metastatic lesions relieved pain. Prognosis was considered poor. However, complete resection of the metastatic lesion at a time when no other recurrent lesions were present might have cured the patient. PMID- 7851846 TI - Synchronous colorectal carcinomas. AB - Eighteen (5.0%) out of 358 patients who underwent resection of a colorectal carcinoma during the period 1978 through 1990 had synchronous colorectal carcinomas, and were 5.6 years younger on average than those with a single carcinoma. The distance between synchronous lesions was less than 10 cm in 69.6% of all the patients in the study. Among the synchronous carcinomas there was a higher incidence of ascending colon involvement, mucinous carcinoma, family history of malignant diseases, multiple malignant neoplasms associated with other organs and benign neoplastic polyps of the colorectum, and it is suggested that hereditary oncogenic factors influence these carcinomas. The synchronous lesions were detected pre-operatively in 14 of 18 patients with synchronous carcinomas, and the most common reason why synchronous lesions were missed was that the lesions on the anal side prevented the lesions on the proximal side from being examined. The prognosis in the synchronous lesion group was worse than in the solitary lesion group. Since it is difficult to predict synchronous colorectal carcinomas, careful pre-operative examination, including that of other organs, is necessary, and intra-operative colonoscopy should be carried out when pre operative examination was insufficient. PMID- 7851848 TI - A family of five first degree relatives affected by Lynch II syndrome. AB - Hereditary non-polyposis colorectal cancer (Lynch syndromes) has been reported in the international literature over the last decade. We now present a case of a family with Lynch II syndrome, in which five first-degree relatives were affected by colorectal cancer; in addition, the two female patients had ovarian or breast cancer. PMID- 7851847 TI - An adapted program of colorectal cancer screening--7 years experience and cost benefit analysis. AB - The Czech program of colorectal cancer screening differs from most foreign programs in a number of points. The age interval of screened population was limited to 45 to 60 years. Screening was multicentric, with one reference center. More than 95% of the subjects screened were asymptomatic employees of various factories, boards and institutions. Total colonoscopy was the primary procedure in all Haemoccult-positive subjects. Some 109,213 subjects received 3 Haemoccult slides. Compliance was 83.1%, and Haemoccult was positive in 2.92% of the subjects. The diagnostic program revealed 347 (13.1%) cancers, 763 adenomas in 592 (22.2%) subjects, and other bleeding conditions in 1043 (39.2%) persons. Dukes A or B colorectal cancer was found in two-thirds of the screened subjects and in only one-third of non-screened symptomatic patients. Average diagnostic and therapeutic costs were almost the same in both groups. Gross national product savings realized by one asymptomatic subject were 315,540 Czechoslovak Crowns (approximately 18,560 US-dollars at the 1989 exchange rates). The adapted program was found to be effective, and its use in a population with a high incidence of colorectal neoplasia deserves consideration. PMID- 7851849 TI - Prognostic significance of the hepatitis B virus-DNA concentration in patients after orthotopic liver transplantation. AB - Hepatitis B virus-DNA was detected by polymerase chain reaction in 9 out of 10 patients after orthotopic liver transplantation. Three of these patients were at the same time positive for hepatitis B virus-DNA by dot-blot hybridization (hepatitis B virus-DNA > 1.5 pg/ml). In these three patients HBs-antigen (HBsAg) reappeared within a mean time of 12 weeks after orthotopic liver transplantation (range 7-18 weeks). Only two of the six polymerase chain reaction-positive and dot-blot-negative patients (hepatitis B virus-DNA between 0.4 fg/ml and 1.5 pg/ml) had recurrence of HBsAg within a mean time of 54 weeks (range 52-56 weeks). Passive immunoprophylaxis with anti-HBs antibodies (serum titers > 100 IU/l) did not prevent infection of the graft in the five reinfected patients. We conclude that a low concentration of serum hepatitis B virus-DNA after orthotopic liver transplantation, which is detectable only by polymerase chain reaction, indicates a delayed infection of the graft. PMID- 7851850 TI - Radiotherapy for hepatocellular carcinoma: clinicopathological study of seven autopsy cases. AB - The clinical value of radiotherapy for hepatocellular carcinoma (total tumor dose: 50-70 Gy) was evaluated in seven autopsied patients with nine tumors. A partial response as defined by the WHO criteria for chemotherapy was observed in three tumors (33%). Progressive and marked shrinkage of the noncancerous liver tissue within the irradiated field was also observed in all cases. Histological examination revealed viable cancer cells in all cases. These results indicate that local radiotherapy applying 50-70 Gy achieved some clinical benefit, but was not capable of curing hepatocellular carcinoma. PMID- 7851851 TI - Hepatic mitochondrial changes in experimental obstructive jaundice complicated by biliary infection. AB - The effects of biliary infection on the structural and functional changes in the liver in obstructive jaundice was studied using rats as experimental animals. Biliary infection with obstructive jaundice was induced in the animals by injecting Escherichia coli into the common bile duct through a nylon tube cannulated into the duct. This was followed by the clamping of the tube. For the controls, the tube was clamped in the absence of Escherichia coli. After 3, 7, 14 and 21 days, the animals were sacrificed, and some serum enzyme activities, histological changes in the liver, and the coupling efficiency of mitochondria isolated from the liver were investigated. The phosphorylating ability of hepatic mitochondria was more seriously affected when the obstruction was complicated by cholangitis. We suggest that, when associated with obstructive jaundice, biliary infection should be carefully treated prior to hepatectomy. PMID- 7851852 TI - Primary mixed hepatocellular carcinoma with carcinoid characteristics. A case report. AB - Primary hepatocellular carcinoma is a well known liver condition. Carcinoids are tumors arising mostly in the intestinal tract and/or in the lungs, and giving rise to a certain syndrome. They metastisize to other organs, especially the liver (1). Primary hepatocellular carcinoma with carcinoid features is an extremely rare tumor and only one such case has been reported so far (2). In this report we describe the case of a tumor of the liver with features both of primary hepatocellular carcinoma and carcinoid. PMID- 7851853 TI - Urinary gastrin output and serum gastrin in patients with liver cirrhosis. Urinary gastrin output in cirrhosis. AB - The aim of the present study was to examine the diurnal urinary gastrin output in cirrhotics and to clarify whether in patients with hepatorenal syndrome urinary gastrin output is reduced. Thirty-two cirrhotics and 25 age- and sex-matched, controls were studied. Cirrhotics were divided into 3 groups: (I: without ascites and normal serum creatinine; II: ascites and normal creatinine; III: ascites and increased creatinine). Mean fasting serum gastrin concentration was lower in the control group than in Group I, II (p < 0.01) or III (p < 0.001). In this latter group mean serum gastrin concentration was significantly higher (p < 0.001) than in the other two groups of cirrhotics. The mean 24 h urinary gastrin output was lower (p < 0.001) in Group III patients than in the other groups of subjects studied. Also in the controls urinary gastrin output was lower (p < 0.01) than in Groups I and II. These findings suggest that: a) in cirrhotics with normal serum creatinine the average serum gastrin levels over the course of the day are indeed higher than in normals and b) In cirrhotics with hepatorenal syndrome, impaired urinary gastrin output appears to contribute significantly to their hypergastrinemia. PMID- 7851854 TI - Successful treatment of primary sclerosing cholangitis with cyclosporine and corticosteroid. AB - A case of primary sclerosing cholangitis (PSC) successfully treated with cyclosporine is described. A 65-year-old man who presented with jaundice and anemia was diagnosed as having PSC, accompanied by pancreatic duct abnormalities. Cholangiography and pancreatography showed marked improvements following combined therapy with cyclosporine and methylprednisolone. Cyclosporine seems to be a promising drug for the treatment of patients with PSC. This report reasons that the same disease process affects both the pancreatic ducts and the bile ducts, and that stagnation of pancreatic juice may have a role to play in the pancreatic duct abnormalities. PMID- 7851855 TI - Variable loading cholangiomanometry and clinical applications. AB - We have designed a variable loading cholangiomanometric method, which permits a precise and objective evaluation of distal bile duct function. Normal resistance (R) values (1-7 units) and residual pressure (P) values (50-150 mm H2O) have been defined by this method. We have performed this procedure on 138 patients with cholelithiasis, and have found that 13 patients with cholecystolithiasis and 14 patients with choledocholithiasis have elevated R and P values in the distal bile duct. These patients also had morphological abnormalities in the distal bile duct. There was a high percentage of patients with abnormal pressure/flow curves at high flow rates among patients with morphologically dilated bile ducts. Division of pressure/flow curve patterns at low flow rates into three types made it possible to differentiate between functional and structural abnormalities. Patients in whom the residual P values were high and morphological defects of the distal bile duct. The possible application of these measurements in determining the need for additional surgery on the inferior bile duct, particularly papilloplasty, is discussed. PMID- 7851856 TI - Caustic sclerosing cholangitis. Report of four cases and a cumulative review of the literature. AB - We report on four patients of our own and another thirty-six from the literature, who developed almost identical and unusual clinical syndromes after surgical treatment of hydatid disease of the liver, with the aim of showing the extremely serious nature of the problem that can ensue. An association of four factors seems to be necessary to promote caustic sclerosing cholangitis: a) injection of a scolicidal agent (formalin, hypertonic saline, ethanol, silver nitrate or iodine solution) into the cyst cavity; b) a communication between the cyst and the biliary tree; c) a condition that prolongs the exposure of the biliary tree to the scolicidal; and d) a particular sensitivity to the scolicidal agent. While this last condition cannot be anticipated, we may justifiably conclude that surgeons should not inject a scolicidal solution into the hydatid cyst, but prevent intra-abdominal diffusion of the parasite by using hydrogen peroxide, gauze pads moistened by a scolicidal solution or by preoperative chemotherapy with albendazole. Caustic sclerosing cholangitis has an earlier onset of symptoms and a more rapidly progressive nature than primary sclerosing cholangitis. In foresight, serum alkaline phosphatase should be monitored and, when raised, a retrograde endoscopic cholangiogram and/or a liver biopsy should be performed. Digestive shunt surgery should be avoided and the possibility of liver transplantation has to be periodically evaluated. PMID- 7851857 TI - Effects of surgical trauma of laparoscopic vs. open cholecystectomy. AB - The effects of surgical trauma resulting from laparoscopic cholecystectomy and open cholecystectomy, were compared by assessing the postoperative acute phase alterations of selected plasma proteins, hormones and lymphocyte subpopulations in fifty-seven patients prior to elective cholecystectomy. Patients were prospectively randomized to undergo either laparoscopic cholecystectomy (n = 30) or open cholecystectomy (n = 27). Duration of operation and general anesthesia was similar in the two patient groups. The laparoscopic cholecystectomy patients had a shorter postoperative stay in hospital (3.1 (0.5) days vs. 7.1 (1.6) days; p < 0.001). In open cholecystectomy patients a significantly greater postoperative acute phase increase in plasma C-reactive protein (p < 0.001), cortisol (p < 0.05), and prolactin blood level (p < 0.001) was recorded. The postoperative acute phase decrease in the blood total-T-lymphocyte count (CD3 cells) and in the activated-lymphocyte count (OKDR cells) was significantly greater after open cholecystectomy (p < 0.05). These results, showing that acute phase responses are less marked after laparoscopic cholecystectomy than after open cholecystectomy, support the concept that the laparoscopic procedure is less traumatic. PMID- 7851858 TI - Isolated pancreatectomy for ductal carcinoma of the head of the pancreas. AB - Hepatic carcinoma recurrence in the early months after pancreatectomy for ductal carcinoma of the head of the pancreas is one of the major factors of the poor survival rate. Early hepatic recurrence might be caused by carcinoma cells entering the portal vein as a result of surgical manipulations. To deal with this problem, we devised a new operative procedure called "isolated pancreatectomy" in 1987. This method involves no-touch pancreatic resection combined with extensive retroperitoneal skeletonization. Both the feeding and draining vessels of the pancreatic carcinoma are ligated and divided prior to pancreatectomy. The confluence of the portal vein, the superior mesenteric vein, and the splenic vein is removed together with the pancreatic head. The wide surgical field thus obtained facilitates subsequent skeletonization of the retroperitoneum. We have experienced 71 cases of pancreatectomy for ductal carcinoma of the head of the pancreas among whom isolated pancreatectomy has been performed in 16 patients since 1987. In all cases, long-term survival was obtained in the patients undergoing curative and extended resection. The cumulative five-year survival rate for stages I and II was 40.7%, and that for stage III was 17.3%. After the introduction of isolated pancreatectomy, hepatic recurrence rates within six months and 12 months after pancreatectomy have dropped to 0% and 16.7%, respectively, from the 22.9% and 31.3% of the other pancreatectomy. The survival rate for the patients with stage III in isolated pancreatectomy significantly exceeded that obtained with other pancreatectomy. PMID- 7851859 TI - Early and late results of 100 consecutive total gastrectomies for cancer. AB - The authors present a case study of 100 patients who underwent total gastrectomy out of a total of 376 patients submitted to surgery for gastric cancer between 1970 and 1992. The majority of the neoplasms were located in the middle third of the stomach with histological characteristics of an epithelial type in 92% of the cases, 8 of which were classified Stage IA, 6 Stage IB, 14 Stage II, 24 Stage IIIA, 25 Stage IIIB, and 15 at Stage IV. An R2 total gastrectomy, which included the distal 2-3 centimeters of the esophagus and the proximal 2-3 centimeters of the duodenum, combined with omentectomy and level 1 and 2 lymphadenectomy, was always performed. Thirty-four of the operations were extended and splenectomy was performed in 27 of these. Digestive continuity was obtained in 37 cases with an esophago-jejunostomy on a Roux-en-Y loop. Recanalization of the duodenum was accomplished in accordance with the Moricca technique in 32 cases and the Mouchet Camey technique in 22 cases. Of the remaining 9, 5 underwent reconstructive surgery as described by Sweet-Allen, 2 as described by Nakayama, and the remaining 2 direct esophago-duodenostomy. The majority of the cases received total parenteral nutrition on the second postoperative day and this was maintained for the following eight days. Post-operative mortality, reported during the initial 30 days was 7%, overall morbidity 17%. A detailed protocol of clinical and diagnostic tests was established for follow-up studies conducted on a 4-month basis.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7851860 TI - Gallbladder cancer with double pancreatic ducts--a case report. AB - Various forms of anomalous pancreatic ducts may be encountered. We treated a patient with very rare courses of pancreatic ducts associated with gallbladder cancer. The patient, a 65-year-old female, attended our hospital with epigastric pain and general malaise. Abdominal sonography and a CT scan led to the diagnosis of gallbladder cancer. Endoscopic retrograde cholangiopancreatography revealed two main pancreatic ducts that followed a parallel course and joined the end of the common bile duct to form a common duct. The common duct opened at the ampulla of Vater. Thus, duplicated ducts of Wirsung served as the main pancreatic ducts, with no duct of Santorini. The embryonal mechanism and the clinical significance of double pancreatic ducts remains unknown, and our case is very rare. PMID- 7851861 TI - Ileal carcinoid tumors and intestinal ischemia. AB - Three patients with carcinoid tumors of the ileum are presented; two had severe intestinal ischemia, one with infarction of the small intestine. In all three cases, histopathological examination revealed elastic vascular sclerosis (EVS) in the mesenteric blood vessels. Intestinal ischemia in the presence of a carcinoid tumor is probably due to a combination of tumoral secretion products, vascular changes, mesenterial retraction and nodal involvement. Selective superior mesenteric artery arteriography is diagnostic. All the reported carcinoid tumors with ischemic manifestations are ileal and invaded the mesentery or had positive nodes or metastases; two-thirds had EVS, and one-third mesenterial vascular luminal narrowing. Intestinal ischemia may be the underlying cause of vague symptoms in patients with a carcinoid tumor. This tumor may be small and must be looked for during laparotomy, mild intestinal ischemia or mesenterial thickening are important signs. Early resection can prevent intestinal complications. An aggressive attitude, including debulking of metastases, is justifiable. PMID- 7851862 TI - Successful resection of a minute icteric hepatocellular carcinoma--case report. AB - A 38-year-old male was admitted to our department with jaundice. Imaging studies including ultrasonography, ERCP, PTC and computed tomography (CT) revealed a hilar lesion. Right hepatic lobectomy, caudate lobectomy, excision of CBD and restoration of biloenteric continuity was performed. Pathological examination showed an icteric hepatoma (1.2 x 0.8 x 0.8 cm in size) originating in the caudate lobe. The tumor thrombus occupied the common hepatic duct and the right intrahepatic duct. The postoperative course was fairly unremarkable, and the patient has remained in good health for four years after surgery without any sign of recurrence. PMID- 7851863 TI - Schistosomiasis of the colon and rectum. PMID- 7851864 TI - Prognostic implications of DNA ploidy and cell-cycle analysis in pancreatic and periampullary carcinoma. PMID- 7851865 TI - Cytokines and diabetes: the final step? Involvement of TNF-alpha in both type I and II diabetes mellitus. PMID- 7851866 TI - Vitamin E delays diabetes onset in the non-obese diabetic mouse. AB - Vitamin E was administered to non-obese diabetic (NOD) mice to determine if the selective destruction of pancreatic beta cells leading to Type 1 (insulin dependent) diabetes mellitus could be halted by virtue of this vitamin's free oxygen radical scavenger activity. Two groups of NOD mice were treated from 3 weeks of age until 30 weeks of age with either diet supplemented with vitamin E or control diet. Diabetes incidence was recorded as well as the degree of lymphocytic infiltration of the pancreas (insulitis) in animals which did not develop diabetes. Vitamin E did not reduce the incidence of diabetes by 30 weeks of age, however it did significantly delay the onset of the disease (p < 0.01- parallelism test). There were no differences in the degree of insulitis with respect to control mice. We conclude that antioxidant therapy with Vitamin E delays diabetes onset in NOD mice without having an apparent effect on the autoimmune process. PMID- 7851867 TI - Biological characterisation of [67Ga] or [68Ga] labelled DFO-octreotide (SDZ 216 927) for PET studies of somatostatin receptor positive tumors. AB - Radiolabelled analogues of Somatostatin (SRIF) were demonstrated to be useful for conventional gamma-camera imaging of SRIF receptor-positive tumors and their metastases. To evaluate the feasibility of positron emission tomography (PET) or SRIF receptor-positive tumors deferoxamine (DFO) was conjugated to octreotide via a succinyl linker to form a stable conjugate with the gallium isotopes 67Ga and 68Ga. This new octreotide analog, SDZ 216-927, binds specifically and with high affinity to SRIF receptors in vitro (pKi = 8.94 +/- 0.06) and exhibits SRIF like biological properties as demonstrated by the inhibition of growth hormone (GH) release from cultured pituitary cells. SDZ 216-927 was efficiently labelled with 67Ga without affecting high affinity binding to SRIF receptors. Biodistribution studies revealed that [67Ga]SDZ 216-927 was stable in vivo and rapidly cleared from the circulation, as indicated by the low amount of 67Ga detected in the blood four hours post injection (p.i.). SRIF receptor-positive tumors were clearly visualized 10 minutes p.i. in tumor bearing rats. The specificity of ligand binding in vivo was demonstrated i) by the high tumor/non-tumor ratio 4 hours p.i. (tumor/blood 22.3:1, tumor/muscle 64.5:1, tumor/liver 4.0:1, tumor/spleen 16.8:1) and ii) by a significantly lower uptake of radioactivity in the tumor after pretreatment of tumor bearing animals with an excess of unlabelled SDZ 216-927. SDZ 216-927, when labelled with the positron emitting isotope 68Ga, clearly imaged SRIF receptor-positive tumors using positron emission tomography (PET). Therefore quantitative SRIF receptor imaging with PET seems to be possible using this new radiopharmaceutical. PMID- 7851868 TI - Antisense oligodeoxynucleotides for in vivo targeting of corticotropin-releasing hormone mRNA: comparison of phosphorothioate and 3'-inverted probe performance. AB - Antisense DNA has been successfully used in vivo to selectively inhibit expression of proteins in the brain. However, stressful side effects after oligodeoxynucleotide (ODN) application have been observed, but not carefully characterized. An attempt was made to establish an animal model of reduced corticotropin-releasing hormone (CRH) activity, using antisense DNA corresponding to the start coding region of rat CRH mRNA with either 3'-3' inverted internucleotidic linkage or with all-phosphorothioate modification. Probes were injected intracerebroventricularly (i.c.v.) twice, 12-hours apart. After phosphorothioate sense ODN injection serum corticosterone levels were significantly elevated compared to vehicle (aCSF) or 3'-3' end inverted sense ODN controls. This increase was also apparent but less pronounced in phosphorothioate antisense treated animals compared with the corresponding sense group. After exposure to ether vapour, both phosphorothioate and inverted antisense ODN injected rats showed a markedly diminished stress induced corticosterone secretion compared to the corresponding sense or vehicle injected rats. These results indicate that a) stress induced corticosterone release is suppressed by i.c.v. CRH antisense treatment, b) phosphorothioate ODNs exert an unspecific, chronic stress-like activation of the HPA-axis and c) this effect is partly inhibited by phosphorothioate antisense directed against CRH mRNA. PMID- 7851869 TI - Identification of delta-iodolactone in iodide treated human goiter and its inhibitory effect on proliferation of human thyroid follicles. AB - There is evidence that iodoarachidonates are mediators of iodide in thyroid autoregulation, however, their occurrence in vivo has not yet been demonstrated. We therefore tried to identify delta-iodolactone (5-Hydroxy-6-iodo-8,11,14 eicosatrienoic delta-lactone, IL-delta) in thyroid tissue from a patient with Graves' disease treated with high doses of iodide. Lipids were extracted from thyroid tissue, purified by reversed phase chromatography and analyzed by gas chromatography--tandem mass spectrometry (GC-MSMS). The retention time in gas chromatography and fragmentation pattern in tandem mass spectrometry were determined with biochemically synthesized non-deuterated and deuterated IL-delta. According to retention time (13.44 min) and specific fragments (m/z 303, m/z 259) the occurrence of IL-delta could be demonstrated in the extract of iodide treated goiter. In vitro, potassium iodide (40 microM) as well as IL-delta (1.0 microM) significantly inhibited the proliferation of human thyroid follicular cells induced by phorbol ester TPA (12-O-tetradecanoylphorbol 13-acetate). These results demonstrate for the first time that Il-delta is present in iodide treated human thyroid. As cell proliferation is under negative control of IL-delta, a crucial role in thyroid involution following iodide treatment may be possible. PMID- 7851870 TI - Acute effect of low-calorie and low-carbohydrate diet on serum triiodothyronine response to glucose ingestion and its relation to glucose tolerance. AB - This study was conducted to elucidate the mechanism of glucose intolerance due to carbohydrate restriction. 15 non-diabetic patients, aged 51 +/- 3 yr, were placed under dietary condition-I (2,012 kcal/day; carbohydrate 299 g) for more than 3 days after admission and then condition-I was substituted by condition-II (1,156 kcal/day; carbohydrate 139 g) for 2 weeks. At the end of condition-I and -II, 75 g OGTT was performed. After the comparison between condition-I and -II, patients were subdivided into two groups, namely, glucose tolerance-improved (n = 8) and impaired (n = 7) groups. In the former, sigma glucose (mg/dl) during OGTT decreased from 898.1 +/- 28.0 to 738.5 +/- 36.0 (p < 0.05) and sigma IRI (microU/ml) decreased from 418.8 +/- 60.1 to 300.7 +/- 33.5 (p < 0.05) but sigma dT3 (ng/dl) increased from 11.3 +/- 14.7 to 70.3 +/- 15.1 (p < 0.05). In the latter, sigma glucose (mg/dl) increased from 774.6 +/- 46.6 to 867.1 +/- 50.1 (p < 0.05) and sigma IRI (microU/ml) increased from 323.4 +/- 47.8 to 400.8 +/- 47.8 (p < 0.05) but sigma dT3 (ng/dl) decreased from 45.3 +/- 7.1 to 20.0 +/- 14.7 although it did not reach a level of statistical significance. These results suggest that blunted serum T3-response to glucose ingestion is linked to the mechanism of glucose intolerance due to carbohydrate restriction. PMID- 7851871 TI - The effect of laparoscopic cholecystectomy on insulin sensitivity. AB - It is well known that there is impaired glucose tolerance after open abdominal surgery. We have investigated the effect on insulin sensitivity of laparoscopic cholecystectomy. Eight non-diabetic patients aged 51 +/- 3.5 years were studied pre and postoperatively. Insulin sensitivity measured by the short insulin tolerance test (ITT) was expressed as % disappearance of glucose per minute (KITT). Preoperative fasting blood glucose was 4.7 +/- 0.15 mmol/l compared with postoperative fasting blood glucose of 5.7 +/- 0.31 mmol/l (p = 0.02). Fasting insulin levels were 8.4 +/- 1.6 mU/l preoperatively compared to 30.0 +/- 9.3 mU/l postoperatively (p = 0.1 NS). KITT was 2.29 +/- 0.2% min-1 (range 1.0-3.03) preoperatively with 1.11 +/- 0.25% min-1 (range 0.13-1.97) postoperatively (p = 0.02). Hence marked insulin resistance is a consequence of major abdominal surgery irrespective of surgical technique. PMID- 7851872 TI - Circulating insulin-like growth factor I concentrations in clinically severe obese patients with and without NIDDM in response to weight loss. AB - Earlier studies have demonstrated decreased levels of circulating Insulin-Like Growth Factor-I (IGF-I) in patients with NIDDM and IDDM (Yde 1969; Rieu and Binoux 1985), with a return to normal in those diabetics who achieve improved metabolic control (Rieu and Binoux 1985; Ameil, Sherwin, Hintz, Gertner, Press and Tamborlane 1984) following insulin therapy. One method of improving metabolic control in clinically severe obese NIDDM patients is the gastric bypass procedure (GBP). This study revealed a significant decrease in serum IGF-I concentrations in clinically severe obese patients with NIDDM (obese NIDDM) (105 ng/dl +/- 11; n = 29) as compared with clinically severe obese patients with normal glucose tolerances (obese control) (143 +/- 11; n = 21) and lean controls (177 +/- 14; n = 19) (p < 0.001). Following a GBP, IGF-I levels increased in the NIDDM group (142 ng/dl +/- 13.0; n = 20) to the extent that no significant difference was seen between postoperative NIDDM, obese controls, and lean controls. Postoperative IGF-I levels in the obese controls (151 +/- 14; n = 9) revealed no difference from preoperative levels. Postoperative obese NIDDM and obese control had a 28% and 29% decrease, respectively, in weight, with no difference between the groups in respect to Body Mass Indices. The NIDDM postoperative group revealed reductions in levels of HbA1C, insulin, and glucose concurrent with elevations in IGF-I when compared with controls. We conclude that improvement in glucose control led to the increase in IGF-I levels. PMID- 7851873 TI - Calcium and prolactin secretion in humans: effects of the channel blocker, verapamil, in the spontaneous and drug-induced hyperprolactinemia. AB - The effects of the intravenous administration of a calcium channel blocker, verapamil (0.0833 mg/min for 2-3 h after a 5 mg bolus) on prolactin (PRL) and thyrotropin (TSH) circulating levels were assessed in 7 normal subjects and in 17 patients with hyperprolactinemia (11 with prolactinoma and 6 sulpriride-induced). In the normal group a non-significant increase in PRL levels occurred (mean +/- SEM = 11.7 +/- 2.9 micrograms/l verapamil vs. 8.5 +/- 1.4 micrograms/l saline). In this control group the peak response of PRL and TSH to TRH (thyrotrophin releasing hormone) during verapamil or saline was also determined: PRL = 112.0 +/ 27.0 micrograms/l on verapamil vs. 53.6 micrograms/l on saline, p = 0.02; TSH 7.1 +/- 0.7 microU/l on verapamil vs. 9.0 +/- 0.6 mU/l on saline, p = 0.01. In the hyperprolactinemic subjects verapamil induced opposite effects on PRL levels, the prolactinoma group exhibiting an increase in the mean values (168.5 +/- 22.3 micrograms/l vs. 150.8 +/- 23.6 micrograms/l on saline, p = 0.04) whereas in the sulpiride-induced there was a reduction in the mean PRL levels (61.1 +/- 13.8 micrograms/l vs. 78.5 +/- 19.3 micrograms/l on saline, p = 0.002). In both groups of hyperprolactinemic patients no effects on TSH levels were observed. The authors discuss the possibility that the divergent effects of verapamil in hyperprolactinemia of different etiologies could be related to the balance between dopamine and calcium channel effects on hypothalamus and/or pituitary. PMID- 7851874 TI - Association of an estrogen receptor variant with increased height in women. AB - There is an association between a B region allele (here called the B' allele) of the estrogen receptor (ER) and a history of spontaneous abortion in women with ER positive breast cancer, but no such association for women with ER negative tumors or women without breast cancer. In this study we compared the heights of women carrying the B and B' alleles. The B' allele was identified by polymerase chain reaction to amplify genomic DNA around the polymorphic region of the ER gene, followed by allele specific oligonucleotide hybridization. This analysis used DNA obtained from blood lymphocytes. Women carrying the B' allele were significantly taller than those carrying the wild type allele (B allele). Multiple linear regression also demonstrated that this association remained (p = 0.017), controlling for the effects of age and race. Since the B' ER allele results from a silent mutation, a second mutation, segregating with it, no doubt plays a role in producing the high incidence of spontaneous abortion we reported previously and the height difference we report here. This second mutation might lie within the estrogen receptor itself or within one of the genes nearby. PMID- 7851875 TI - Lipoprotein(a) in non-insulin-dependent diabetic patients with normo- and microalbuminuria. PMID- 7851876 TI - The effect of chronic angiotensin converting enzyme inhibition on circulating prolactin in systemic hypertension. PMID- 7851877 TI - The effect of acute reserpine administration on the uncoupling protein mRNA levels in the mouse brown adipose tissue. PMID- 7851878 TI - Cloning the human major histocompatibility complex in YACs. AB - To clone the human major histocompatibility complex (MHC), 53 YACs, with an average size of 490 kb, were isolated and characterized from the CEPH YAC library. These YACs were organized in a single large contig covering more than 4000 kb. Furthermore, a complete physical map of the previously uncloned HLA class I region was established from partial and/or total digestions of 15 YACs spanning 2000 kb. This resulted in the establishment of the first YAC contig that spans the entire MHC region and constitutes an essential step in the isolation of all of the genes present in the region. PMID- 7851879 TI - Mapping of the beta 2 subunit gene (GABRB2) to microdissected human chromosome 5q34-q35 defines a gene cluster for the most abundant GABAA receptor isoform. AB - The gamma-aminobutyric acid receptor (GABAAR) is a multisubunit Cl- channel that mediates most fast inhibitory synaptic transmission in the central nervous system. Molecular evolution has given rise to many genetic variants of GABAAR subunits, including alpha 1-6, beta 1-4, gamma 1-4, delta, and rho 1-2, suggesting that an enormous number of combinations of subunits are possible. Here we report that the beta 2 gene is located on chromosome 5q34-q35, defining a cluster comprising alpha 1, beta 2, and gamma 2 genes that together code for the most abundant GABAAR isoform. The fact that intron position is conserved in the beta 1-3 genes, taken together with the observation that chromosomes 4 and 15 also contain distinct alpha-beta-gamma gene clusters, strongly suggests that an ancestral alpha-beta-gamma cluster was duplicated and translocated to at least two different chromosomes. This organization of GABAAR gene clusters may have been preserved as linkage provides a mechanism for facilitating coordinate gene expression. PMID- 7851880 TI - Structure of the human 4-hydroxyphenylpyruvic acid dioxygenase gene (HPD). AB - 4-Hydroxyphenylpyruvic acid dioxygenase (HPD) is an important enzyme in tyrosine catabolism in most organisms. The activity of this enzyme is expressed mainly in the liver and developmentally regulated in mammals, and a genetic deficiency in this enzyme in humans and mice leads to hereditary tyrosinemia type 3. Using human HPD cDNA as a probe, a chromosomal gene related to HPD was isolated from human gene libraries. The human HPD gene is over 30 kb long and is split into 14 exons. The extract size and boundaries of exon blocks were determined, and all of the splice donor and acceptor sites conformed to the GT/AG rule. Analysis of the 5' flanking sequence of the gene suggests that expression of the gene is regulated by hepatocyte-specific and liver-enriched transcription factors, as well as by hormones. These features of the 5' flanking region of the gene are similar to those of other genes that are specifically expressed in hepatocytes and that are developmentally regulated. PMID- 7851881 TI - Gene structure prediction by linguistic methods. AB - The higher-order structure of genes and other features of biological sequences can be described by means of formal grammars. These grammars can then be used by general-purpose parsers to detect and to assemble such structures by means of syntactic pattern recognition. We describe a grammar and parser for eukaryotic protein-encoding genes, which by some measures is as effective as current connectionist and combinatorial algorithms in predicting gene structures for sequence database entries. Parameters of the grammar rules are optimized for several different species, and mixing experiments are performed to determine the degree of species specificity and the relative importance of compositional, signal-based, and syntactic components in gene prediction. PMID- 7851882 TI - Human mitochondrial HMG CoA synthase: liver cDNA and partial genomic cloning, chromosome mapping to 1p12-p13, and possible role in vertebrate evolution. AB - Mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase (mHS) is the first enzyme of ketogenesis, whereas the cytoplasmic HS isozyme (cHS) mediates an early step in cholesterol synthesis. We here report the sequence of human and mouse liver mHS cDNAs, the sequence of a HS-like cDNA from Caenorhabditis elegans, the structure of a partial human mHS genomic clone, and the mapping of the human mHS gene to chromosome 1p12-p13. The nucleotide sequence of the human mHS cDNA encodes a mature mHS peptide of 471 residues, with a mean amino acid identity of 66.5% with cHS from mammals and chicken. Comparative analysis of all known mHS and cHS protein and DNA sequences shows a high degree of conservation near the N terminus that decreases progressively toward the C-terminus and suggests that the two isozymes arose from a common ancestor gene 400-900 million years ago. Comparison of the gene structure of mHS and cHS is also consistent with a recent duplication event. We hypothesize that the physiologic result of the HS gene duplication was the appearance of HS within the mitochondria around the time of emergence of early vertebrates, which linked preexisting pathways of beta oxidation and leucine catabolism and created the HMG CoA pathway of ketogenesis, thus providing a lipid-derived energy source for the vertebrate brain. PMID- 7851883 TI - The human actin-regulatory protein cap G: gene structure and chromosome location. AB - Cap G (formerly called macrophage capping protein or gCap39) is a member of the gelsolin/villin family of actin-regulatory proteins. Unlike all other members of this family, Cap G caps the barbed ends of actin filaments, but does not sever them. This protein is half the molecular weight and contains half the number of repeat subunits (3 vs 6) of gelsolin and villin, suggesting that these two proteins may have arisen by gene duplication of the Cap G gene. To investigate this possibility we have cloned and sequenced the human Cap G gene (gene symbol CAPG). The gene is 16.6 kb in size, contains 10 exons and 9 introns, and is located on the proximal short arm of chromosome 2. The open reading frame is 6.9 kb, having 9 exons and 8 introns. This region contains 3 splice sites that are nearly identical to the human gelsolin gene, but shares only one with villin, indicating that CAPG is more closely related to gelsolin. Further comparisons of these three genes, however, indicate that the evolutionary steps resulting in human gelsolin and villin are likely to have been more complex than a simple tandem duplication of the Cap G gene. PMID- 7851884 TI - Molecular cloning of murine pig-a, a gene for GPI-anchor biosynthesis, and demonstration of interspecies conservation of its structure, function, and genetic locus. AB - Many membrane proteins are anchored to the cell membrane by glycosylphosphatidylinositol (GPI). The core structure and biosynthesis of the GPI anchor are well conserved in eukaryote cells. We previously cloned a human PIGA gene that participates in GPI anchor biosynthesis. We have now cloned complementary and genomic DNA of Pig-a, the murine homologue of PIGA, and compared its function and gene structure with those of PIGA. The deduced amino acid sequence of mouse PIG-A is 88% identical with that of human PIG-A. Transfection of Pig-a cDNA complemented the defects of both a PIG-A-deficient murine cell line and a PIG-A-deficient human cell line, demonstrating that functions of mouse and human PIG-A are conserved. Like human PIGA, the chromosomal Pig-a gene has six exons and spans approximately 16 kb. Moreover, Pig a was mapped to X-F3/4, which is syntenic to human Xp22.1, where PIGA is located. Thus, murine Pig-a provides a good animal model to study paroxysmal nocturnal hemoglobinuria, a disease caused by a somatic mutation of PIGA. Database analysis demonstrated that a yeast gene, SPT14, is homologous to Pig-a and PIGA and that these genes are members of a glycosyltransferase gene family. PMID- 7851885 TI - A streamlined random sequencing strategy for finding coding exons. AB - The random (shotgun) DNA sequencing strategy is used for most large-scale sequencing projects, including the identification of human disease genes after positional cloning. The principle of the method--sequence assembly from overlap- requires the candidate gene region to be partitioned into 15- to 20-kb pieces (usually lambda inserts), themselves randomly subcloned into M13 prior to sequencing with a 6- to 8-fold redundancy. Most often, a time-consuming directed strategy must be invoked to close the remaining gaps. Ultimately, computer-based methods are invoked to locate putative coding exons within the finished genomic sequence. Given the small average size of vertebrate exons, I show here that they can be detected from the computer analysis of the individual runs, much before completion of contiguity. However, the successful assessment of coding potential from the raw data depends on a combination of new sequence masking techniques. When the identification of coding exons is the primary goal, the usual random sequencing strategy can thus be greatly optimized. The streamlined approach requires only a 2- to 2.5-fold sequencing redundancy, can dispense with the subcloning in lambda and the closure of gaps, and can be fully automated. The feasibility of this strategy is demonstrated using data from the X-linked Kallmann syndrome gene region. PMID- 7851886 TI - Human chromosome 19p: a fluorescence in situ hybridization map with genomic distance estimates for 79 intervals spanning 20 Mb. AB - A physical map of human chromosome 19p has been constructed by fluorescence in situ hybridization of cosmids to metaphase chromosomes and sperm pronuclear interphases. The map spans approximately 20 Mb and was generated with 141 multiple, partially overlapping estimates of genomic distances for 79 intervals separating 80 sequentially ordered cosmid reference points. The average distance separating pairs of cosmids was 250 kb, with a range from 50 to 700 kb; 75% of the intervals were estimated to be less than or equal to 300 kb and only 8 intervals were between 500 and 700 kb. Cosmids positive for 33 genes or gene families and 5 polymorphic markers were included among the mapped elements. The fluorescence in situ hybridization map will be useful for furthering the integration of the physical and genetic maps of 19p and for placing newly identified markers within a few hundred kb of their neighbors. PMID- 7851887 TI - Cloning and molecular characterization of the Chinese hamster ERCC2 nucleotide excision repair gene. AB - The Chinese hamster ERCC2 nucleotide excision repair gene, encoding a presumed ATP-dependent DNA helicase, was cloned from the V79 cell line, and its nucleotide sequence was determined. The approximately 15-kb gene comprises 23 exons with a 2283-base open reading frame. The predicted 760-amino-acid protein is 98% identical to the human ERCC2/XPD (760 amino acids), 51% identical to the Saccharomyces cerevisiae RAD3 (778 amino acids), and 54% identical to the Schizosaccharomyces pombe rad15 (772 amino acids) proteins. The promoter region of the hamster ERCC2 gene contains a pyrimidine-rich stretch (42 nucleotides, 88% C+T) similar to sequences found in the promoter regions of two other nucleotide excision repair genes, a GC box, a putative alpha-Pal transcription factor binding site, and two CAAT boxes. There is no apparent TAATA box. No consensus polyadenylation sequence (AATAAA or its variants) was found within 663 bases 3' of the translation termination codon. PMID- 7851888 TI - Homozygosity mapping of the Werner syndrome locus (WRN). AB - Werner syndrome (WS) is an autosomal recessive disorder characterized by the early onset of several age-related diseases. The locus for this disease was recently mapped to 8p12. We studied 27 WS kindreds of mixed ethnic origins, 26 of which were consanguineous. In 24 of these families, the affected subject was given the diagnosis of "definite" WS and affected subjects in the remaining 3 pedigrees were given the diagnosis of "probable" WS. Affected subjects from each kindred were genotyped for 13 short tandem repeat polymorphic sites. Two-point linkage analysis yielded significant evidence for linkage to D8S137, D8S339, D8S87, PLAT, D8S165, and D8S166. The locus yielding a maximum lod score at the smallest recombination fraction was D8S339, suggesting that this marker is the closest to the WS gene (WRN locus) of those tested. D8S339 gave significant lod scores (Zmax > or = 3.0) for both Japanese and non-Japanese (mostly Caucasian) families, demonstrating that a single locus is responsible for WS in both groups. Multipoint analysis of these markers yielded a maximum lod score of 17.05 at a distance of approximately 0.6 cM from D8S339. The combined evidence from 2-point analysis, multipoint analysis, and analysis of regions of homozygosity in subjects from inbred pedigrees indicates that the WRN locus is between D8S131 and D8S87, in an 8.3-cM interval containing D8S339. PMID- 7851889 TI - Cloning of human genes encoding novel G protein-coupled receptors. AB - We report the isolation and characterization of several novel human genes encoding G protein-coupled receptors. Each of the receptors contained the familiar seven transmembrane topography and most closely resembled peptide binding receptors. Gene GPR1 encoded a receptor protein that is intronless in the coding region and that shared identity (43% in the transmembrane regions) with the opioid receptors. Northern blot analysis revealed that GPR1 transcripts were expressed in the human hippocampus, and the gene was localized to chromosome 15q21.6. Gene GPR2 encoded a protein that most closely resembled an interleukin-8 receptor (51% in the transmembrane regions), and this gene, not expressed in the six brain regions examined, was localized to chromosome 17q21.1-q21.3. A third gene, GPR3, showed identity (56% in the transmembrane regions) with a previously characterized cDNA clone from rat and was localized to chromosome 1p35-p36.1. PMID- 7851890 TI - Regional localization of human chromosome 15 loci. AB - One hundred forty-nine chromosome 15 loci were mapped by PCR with respect to chromosome breakpoints in three somatic cell hybrids retaining total or part of chromosome 15 and to a 10-Mb YAC contig. This chromosome was subdivided into 5 regions, yielding an average resolution of more than 1 sequence tagged site per megabase. The mapped loci included 18 genes, 60 cDNA-derived sequence tagged sites, and 69 microsatellites. In addition, the amount of chromosome 15 retained in line A15.1 has been defined. This work represents the first attempt at an integration of the human physical, expression, and genetic maps of chromosome 15. PMID- 7851891 TI - Genomic organization and chromosomal assignment of the human voltage-gated Na+ channel beta 1 subunit gene (SCN1B). AB - Voltage-gated sodium (Na+) channels are essential for the generation and propagation of action potentials in striated muscle and neuronal tissues. Biochemically, Na+ channels consist of a large alpha subunit and one or two smaller beta subunits. The alpha subunit alone can exhibit all of the functional attributes of a voltage-gated Na+ channel, but requires a beta 1 subunit for normal inactivation kinetics. While genetic mutations in the skeletal muscle Na+ channel alpha-subunit gene can cause human disease, it is not known whether hereditary defects in the beta 1 subunit underlie any inherited syndromes. To help explore this further, we have carried out an analysis of the detailed structure of the human beta 1 subunit gene (SCN1B) including the delineation of intron-exon boundaries by genomic DNA cloning and sequence analysis. The complete coding region of SCN1B is found in approximately 9.0 kb of genomic DNA and consists of five exons (72 to 749 bp) and four introns (90 bp to 5.5 kb). Using a 15.9-kb genomic SCN1B clone, we assigned the gene to the long arm of chromosome 19 (19q13.1-q13.2) by fluorescence in situ hybridization. An intragenic polymorphic (TTA)n repeat that is positioned between two tandem Alu repetitive sequences was also characterized. The (TTA)n repeat exhibits 5 distinct alleles and a heterozygosity index of 0.59. This information should be useful in evaluating SCN1B as a candidate gene for hereditary disorders affecting membrane excitability. PMID- 7851892 TI - Genetic map of the region around grizzled (gr) and mocha (mh) on mouse chromosome 10, homologous to human 19p13.3. AB - Grizzled (gr) is a recessive mouse mutation resulting in a gray coat color and reduced perinatal viability. Mocha (mh) is one of several recessive mouse mutants characterized by platelet storage pool disorder, pigment abnormalities, reduced fertility, kidney function deficiencies, and, in some mutants, inner ear and natural killer cell deficiencies. Murine platelet storage pool deficient mutants may be models for Chediak-Higashi and Hermansky-Pudlak syndromes in humans. The genes for gr and mh are very closely linked to each other (0 +/- 1.2 cM). However, their relative position with respect to molecular markers was previously unknown. Thus, genetic mapping of the gr locus will also yield information about the mh location. To map these two genes genetically, we have performed an intersubspecific backcross of grizzled mice with Mus musculus castaneus. In 539 progeny tested, we found no recombination between the gr gene, the gene for anti Muellerian hormone (Amh), and the microsatellite markers D10Mit7, D10Mit21, and D10Mit23. One recombination event for each of the flanking markers Basigin (Bsg) and D10Mit22 was identified. These closely linked markers should provide entry points for positional cloning of the gr and mh genes. The region linked to grizzled is homologous to a gene-rich region on human Chromosome 19p13.3. PMID- 7851893 TI - Cloning of human and mouse EBI1, a lymphoid-specific G-protein-coupled receptor encoded on human chromosome 17q12-q21.2. AB - A lymphoid-specific member of the G-protein-coupled receptor family has been identified by PCR with degenerate oligonucleotides. We have determined that this receptor, also reported as the Epstein-Barr-induced cDNA EBI1, is expressed in normal lymphoid tissues and in several B- and T-lymphocyte cell lines. While the function and the ligand for EBI1 remain unknown, its sequence and gene structure suggest that it is related to the receptors that recognize chemoattractants, such as interleukin-8, RANTES, C5a, and fMet-Leu-Phe. Like the chemoattractant receptors, EBI1 contains intervening sequences near its 5' end; however, EBI1 is unique in that both of its introns interrupt the coding region of the first extracellular domain. The gene is encoded on human chromosome 17q12-q21.2. None of the other G-protein-coupled receptors has been mapped to this region, but the C-C chemokine family has been mapped to 17q11-q21. The mouse EBI1 cDNA has also been isolated and encodes a protein with 86% identity to the human homolog. PMID- 7851894 TI - Chromosomal localization of three repair genes: the xeroderma pigmentosum group C gene and two human homologs of yeast RAD23. AB - The nucleotide excision repair (NER) disorder xeroderma pigmentosum (XP) is characterized by sun (UV) sensitivity, predisposition to skin cancer, and extensive genetic heterogeneity. Recently, we reported the cloning and analysis of three human NER genes, XPC, HHR23A, and HHR23B. The previously cloned XPC gene is involved in the common XP complementation group C, which is defective in excision repair of non-transcribed sequences in the genome. The XPC protein was found to be complexed with the product of HHR23B, one of the two human homologs of the Saccharomyces cerevisiae NER gene RAD23. Here we present the chromosomal localization by in situ hybridization using haptenized probes of all three genes. The HHR23A gene was assigned to chromosome 19p13.2. Interestingly, the HHR23B and XPC genes, the product of which forms a tight complex, were found to colocalize on band 3p25.1. Pulsed-field gel electrophoresis revealed that the HHR23B and XPC genes possibly share a MluI restriction fragment of about 625 kb. Potential involvement of the HHR23 genes in human genetic disorders is discussed. PMID- 7851895 TI - Gene organization of the pregnancy-specific glycoprotein region on human chromosome 19: assembly and analysis of a 700-kb cosmid contig spanning the region. AB - The pregnancy-specific glycoprotein (PSG) gene family consists of 11 closely related genes that form a subgroup of the carcinoembryonic antigen (CEA) gene family on 19q13.2. Using a high-resolution restriction fragment fingerprinting technique, we have assembled 256 cosmids from the PSG region into a single 700-kb contig. Fluorescence in situ hybridization to sperm pronuclei and cosmid walking experiments indicated that this PSG contig was directly telomeric of CGM8 at the telomeric end of the CEA subgroup gene cluster. Detailed restriction mapping and hybridization with gene-specific probes indicated that the order of the 11 Previously identified PSG genes is cen-PSG3-PSG8-PSG12-PSG1-PSG6-PSG7-+ ++PSG13 PSG2-PSG5-PSG4-PSG11-tel. The CEA subgroup gene CGM11 is located at the telomeric end of the PSG gene cluster. The PSG genes are all oriented in tandem with the 5' 3' direction of transcription from telomere to centromere. The detailed map also led to the identification of seven new CEA family genes in this region. One of these (CGM12), located between CGM8 and PSG3, is a member of the CEA subgroup. The remaining six (CGM13 through CGM18) are interspersed among the PSG genes and appear to form a third distinct subgroup within the CEA gene family. PMID- 7851896 TI - The pregnancy-specific glycoprotein (PSG) gene cluster on human chromosome 19: fine structure of the 11 PSG genes and identification of 6 new genes forming a third subgroup within the carcinoembryonic antigen (CEA) family. AB - The human pregnancy-specific glycoprotein (PSG) genes belong to the carcinoembryonic antigen (CEA) family, which in turn is a member of the immunoglobulin superfamily. We have analyzed a 700-kb cosmid contig spanning the PSG region on chromosome 19q13.2. The region contains 11 closely related PSG genes organized in tandem with a highly conserved structure and organization. Seven novel genes (CGM12 to CGM18) were found in the PSG region. CGM12 belongs to the CEA subgroup and appears to be a pseudogene. CGM13 to CGM18 forms a third new subgroup within the CEA gene family. The members of this new subgroup show 94-99% identity to each other but only 70-80% to other members of either the CEA or the PSG subgroups. They are composed of exons encoding two IgC-like domains and short hydrophilic carboxyl terminals similar to those of the PSGs. Unlike any of the known CEA family genes, however, they seem to lack the exon for an IgV-like N terminal domain. PMID- 7851897 TI - A high-resolution genetic map of mouse chromosome 5 encompassing the reeler (rl) locus. AB - Using interspecific crosses between BALB/c and Mus spretus (SEG) mice, the murine reeler (rl) gene was mapped to the proximal region of chromosome 5 between the hepatocyte growth factor gene (Hgf) and the D5Mit66 microsatellite. The following order was defined: (centromere)-Cchl2a/Hgf-D5Mit1-D5Nam1/D5-Nam2 -rl/D5Mit61 D5Mit72-Xmv45-Htr5a- Peplb-D5Nam3-D5Mit66. Estimated distances between reeler and the nearest flanking markers D5Nam1 and D5Mit72 are 1.5 and 1.0 cM, respectively (95% confidence level), suggesting that the region could be physically mapped using a manageable number of YAC clones. PMID- 7851899 TI - Use of somatic cell hybrids and fluorescence in situ hybridization to localize the functional serum amyloid A (SAA) genes to chromosome 11p15.4-p15.1 and the entire SAA superfamily to chromosome 11p15. AB - The serum amyloid A (SAA) superfamily consists of two acute phase genes, SAA1 and SAA2; a pseudogene, SAA3; and a constitutively expressed gene, SAA4. The SAA proteins, which are found associated with high-density lipoprotein, are believed to have an essential function. Chronic infection, inflammation, or trauma causes very high levels of the acute phase SAA proteins. This may result in the potentially fatal condition, amyloidosis, in which amyloid fibrils are deposited in the essential organs. Somatic cell hybrids have been used by several groups to map one or more of the SAA genes to chromosome 11p. We used FISH analysis and PCR amplification of DNA from 17 somatic cell hybrids carrying all or part of chromosome 11 as their only human component to fine map systematically the chromosomal location of the entire SAA superfamily. We demonstrate by these methods that the location of the entire SAA superfamily is at 11p15. Furthermore, we have demonstrated that SAA1, SAA2, and SAA4, i.e., all of the functional genes of the superfamily, map within this region to chromosome 11p15.4-p15.1. PMID- 7851898 TI - Chromosomal localization of the genes encoding the kinetochore proteins CENPE and CENPF to human chromosomes 4q24-->q25 and 1q32-->q41, respectively, by fluorescence in situ hybridization. AB - CENPE and CENPF are human kinetochore proteins of 312 and approximately 400 kDa, respectively. As part of an effort to characterize the functions of these two proteins, we have used their respective cDNAs to map their human chromosomal locations by fluorescence in situ hybridization. The gene that encodes CENPE, a kinetochore-associated motor protein that is postulated to segregate chromosomes during mitosis, maps to chromosome 4q24-->q25. The CENPF gene, which encodes a structural protein of the kinetochore, maps to chromosome 1q32-->q41 within close proximity to the genetic locus that is linked to Van der Woude syndrome. PMID- 7851900 TI - Human type I pituitary adenylate cyclase activating polypeptide receptor (ADCYAP1R): localization to chromosome band 7p14 and integration into the cytogenetic, physical, and genetic map of chromosome 7. AB - The gene encoding the human type I pituitary adenylate cyclase activating polypeptide receptor (ADCYAP1R1) was mapped to chromosome 7 by PCR analysis of genomic DNA from a human/rodent somatic cell hybrid mapping panel. This assignment was confirmed and the gene localized to chromosome band 7p14 by fluorescence in situ hybridization. A yeast artificial chromosome containing ADCYAP1R1 was identified in the CEPH "B" Mega-YAC library. This YAC includes two highly polymorphic dinucleotide repeat sequences that will facilitate genetic studies of the contribution of ADCYAP1R1 in disease states of the central nervous and neuroendocrine systems. PMID- 7851901 TI - Isolation and refined regional mapping of expressed sequences from human chromosome 21. AB - To increase candidate genes from human chromosome 21 for the analysis of Down syndrome and other genetic diseases localized on this chromosome, we have isolated and studied 9 cDNA clones encoded by chromosome 21. For isolating cDNAs, single-copy microclones from a chromosome 21 microdissection library were used in direct screening of various cDNA libraries. Seven of the cDNA clones have been regionally mapped on chromosome 21 using a comprehensive hybrid mapping panel comprising 24 cell hybrids that divide the chromosome into 33 subregions. These cDNA clones with refined mapping positions should be useful for identification and cloning of genes responsible for the specific component phenotypes of Down syndrome and other diseases on chromosome 21, including progressive myoclonus epilepsy in 21q22.3. PMID- 7851902 TI - Structure and chromosomal localization of the human PD-1 gene (PDCD1). AB - A cDNA encoding mouse PD-1, a member of the immunoglobulin superfamily was previously isolated from apoptosis-induced cells by subtractive hybridization. To determine the structure and chromosomal location of the human PD-1 gene, we screened a human T cell cDNA library by mouse PD-1 probe and isolated a cDNA coding for the human PD-1 protein. The deduced amino acid sequence of human PD-1 was 60% identical to the mouse counterpart, and a putative tyrosine kinase association motif was well conserved. The human PD-1 gene was mapped to 2q37.3 by chromosomal in situ hybridization. PMID- 7851903 TI - Familial migraine: exclusion of the susceptibility gene from the reported locus of familial hemiplegic migraine on 19p. AB - Genetic isolates are highly useful in analyses of the molecular background of complex diseases since the enrichment of a limited number of predisposing genes can be predicted in representative families or in specific geographical regions. It has been suggested that the pathophysiology and etiology of familial hemiplegic migraine (FHM) and typical migraine with aura are most probably the same. Recent assignment of FHM locus to chromosome 19p in two French families makes it now possible to test this hypothesis. We report here linkage data on four families with multiple cases of migraine disorder originating from the genetically isolated population of Finland. We were interested to discover whether the migraine in these families would also show linkage to the markers on 19p. We could exclude a region of 50 cM, flanking the reported FHM locus, as a site of migraine locus in our four families. It seems evident that locus heterogeneity exists between different diagnostic classes of migraine spectrum of diseases and also between different ethnic groups. PMID- 7851905 TI - The human intercellular adhesion molecule 3 (ICAM3) gene is located in the 19p13.2-p13.3 region, close to the ICAM1 gene. AB - The chromosomal location of the intercellular adhesion molecule 3 (ICAM3) gene, coding for a lymphocyte function-associated antigen (LFA)-1 counterreceptor and selectively expressed by human leukocytes, was analyzed by in situ hybridization with the cDNA coding sequence as a probe. This sequence mapped to the p13.2-p13.3 region of chromosome 19, close to the ICAM1 gene chromosomal location. PMID- 7851904 TI - Mapping of the human SAP1 (SRF accessory protein 1) gene and SAP2, a gene encoding a related protein, to chromosomal bands 1q32 and 12q23, respectively. AB - SAP1, SAP2, and ELK1 form a related subgroup of ETS-domain proteins that can form ternary complexes with the transcription factor SRF at the c-fos serum response element (SRE). SAP1 was identified by a genetic screen for proteins interacting with SRF expressed in yeast, and SAP2 by its homology with SAP1; ELK1 was previously identified by its homology to the ETS domain. cDNA probes were used to isolate cosmid and phage clones harboring genes encoding SAP1 and SAP2. These clones were subsequently used to map the genes to 1q32 and 12q23, respectively, by fluorescence in situ hybridization. PMID- 7851906 TI - Refined localization of the human TPR gene to chromosome 1q25 by in situ hybridization. PMID- 7851907 TI - Localization of the human fibromodulin gene (FMOD) to chromosome 1q32 and completion of the cDNA sequence. PMID- 7851908 TI - Mapping of the Tuple1 gene to mouse chromosome 16A-B1. PMID- 7851909 TI - Assignment of the human prostaglandin-endoperoxide synthase 2 (PTGS2) gene to 1q25 by fluorescence in situ hybridization. PMID- 7851910 TI - The human CHC1 gene encoding RCC1 (regulator of chromosome condensation) (CHC1) is localized to human chromosome 1p36.1. PMID- 7851911 TI - Assignment of the human transglutaminase 2 (TGM2) and transglutaminase 3 (TGM3) genes to chromosome 20q11.2. PMID- 7851912 TI - Macromolecular bioactivity: is it resonant interaction between macromolecules?- Theory and applications. AB - Biological processes in any living organism are based on selective interactions between particular biomolecules. In most cases, these interactions involve and are driven by proteins which are the main conductors of any living process within the organism. The physical nature of these interactions is still not well known. This paper represents a whole new view to biomolecular interactions, in particular protein-protein and protein-DNA interactions, based on the assumption that these interactions are electromagnetic in their nature. This new approach is incorporated in the Resonant Recognition Model (RRM), which was developed over the last 10 years. It has been shown initially that certain periodicities within the distribution of energies of delocalized electrons along a protein molecule are critical for protein biological function, i.e., interaction with its target. If protein conductivity was introduced, then a charge moving through protein backbone can produce electromagnetic irradiation or absorption with spectral characteristics corresponding to energy distribution along the protein. The RRM enables these spectral characteristics, which were found to be in the range of infrared and visible light, to be calculated. These theoretically calculated spectra were proved using experimentally obtained frequency characteristics of some light-induced biological processes. Furthermore, completely new peptides with desired spectral characteristics, and consequently corresponding biological activities, were designed. PMID- 7851913 TI - Long-term intramuscular electrical activation of the phrenic nerve: safety and reliability. AB - The safety and reliability of a system for long-term intramuscular electrical activation of the phrenic nerve was evaluated in seven dogs. In this system, electrodes are implanted bilaterally into the diaphragm without directly contacting the phrenic nerve using a laparoscope to direct placement. Five dogs underwent chronic bilateral intramuscular diaphragm stimulation (IDS) for 61 to 183 days at stimulus parameters selected to evoke at least 120% of the animal's basal ventilation. Two dogs maintained as controls did not undergo chronic stimulation. The safety and reliability of the system was evaluated in terms of tissue responses to the electrode, alterations in diaphragm muscle, pulmonary function, electrode reliability, and cardiac activation. (The efficacy of long term intramuscular activation of the phrenic nerve is addressed in a companion paper.) No adverse responses to the electrode or stimulation were found. The histochemistry of chronically stimulated diaphragm suggested transformation towards type I (oxidative metabolism) muscle fibers. Two IDS electrodes dislodged out of a total of 32 IDS electrodes implanted. Both electrodes dislodged within seven days of implant. All IDS electrodes had stable and repeatable recruitment properties. No IDS electrode mechanical failures were found and no electrode corrosion was observed. We conclude from these experiments that intramuscular activation of the phrenic nerve will present a minimal risk to human patients who are good candidates for clinical studies using this technique. PMID- 7851914 TI - Long-term intramuscular electrical activation of the phrenic nerve: efficacy as a ventilatory prosthesis. AB - The efficacy of a system for long-term intramuscular activation of the phrenic nerve as a ventilatory prosthesis was evaluated in seven dogs. (The safety and reliability of this system is addressed in a companion paper.) Five dogs underwent chronic bilateral intramuscular diaphragm stimulation (IDS) for 61 to 183 days at stimulus parameters selected to evoke at least 120% of the animal's basal ventilation. Two dogs maintained as controls did not undergo chronic stimulation. The ability of IDS to provide long-term ventilation without diaphragm fatigue was evaluated in terms of the ventilatory capacity of IDS, the effects of chronic IDS on diaphragm contractile properties, and the phrenic nerve recruitment properties of chronic IDS electrodes. Hemidiaphragms with electrodes placed within 2 cm of the phrenic nerve trunk could be completely activated by 25 mA pulses having a 100 microsecond pulse width. The tidal volume evoked by IDS in this study was 167% (+/- 48 s.d.) of that required for full-time basal ventilation without diaphragm fatigue. Evoked tidal volume increased after 8 to 9 weeks of chronic IDS for stimulus pulse intervals longer than 50 mS. Electrode recruitment properties were stable for both active and passive implanted electrodes. We conclude from these studies that with properly placed electrodes IDS is capable of providing reliable full-time ventilatory support without fatiguing the diaphragm. PMID- 7851915 TI - A three-dimensional microelectrode array for chronic neural recording. AB - This paper describes a 3-D microelectrode array for the chronic recording of single-unit activity in the central nervous system. The array is formed by a microassembly of planar silicon multishank microprobes, which are precisely positioned in a micromachined platform that resides on the surface of the cortex. Interconnects between the probes and the platform are formed using electroplated nickel lead transfers, implemented using automated computer control. All dimensions are controlled to +/- 1 micron and sank/probe separations as small as 100 microns are possible. Four-probe 16-shank prototype arrays have been tested chronically in guinea pig cortex. After three months in vivo, no significant tissue reaction has been observed surrounding these structures when they remain free to move with the brain, with normal appearing tissue between shanks spaced at 150 microns to 200 microns intervals. The array structure is compatible with the use of signal processing circuitry both on the probes and on the platform. A platform-based signal processing system has been designed to interface with several active probes, providing direct analog access to the recording sites, performing on-chip analog-to-digital conversion of neural activity, and providing simple binary-output recognition of single-unit spike events using a user-input threshold voltage. PMID- 7851916 TI - Hermite expansions of compact support waveforms: applications to myoelectric signals. AB - Nonstationary signals with finite time support are frequently encountered in electrophysiology and other fields of biomedical research. It is often desirable to have a compact description of their shape and of their time evolution. For this purpose, Fourier analysis is not necessarily the best tool. The Hermite Rodriguez and Associated Hermite basis functions are applied in this work. Both are based on the product of Hermite polynomials and Gaussian functions. Their general properties relevant to biomedical signal processing are reviewed. Preliminary applications are described concerning the analysis and description of: a) test signals such as a square pulse and a single cycle of a sinewave, b) electrically evoked myoelectric signals, and c) power spectra of either voluntary or evoked signals. It is shown that expansions with only five to ten terms provide an excellent description of the computer simulated and real signals. It is shown that these two families of Hermite functions are well suited for the analysis of nonstationary biological evoked potentials with compact time support. An application to the estimation of scaling factors of electrically evoked myoelectric signals is described. The Hermite functions show advantages with respect to the more traditional spectral analysis, especially in the case of signal truncation due to stimulation with interpulse intervals smaller than the duration of the evoked response. Finally, the Hermite approach is found to be suitable for classification of spectral shapes and compression of spectral information of either voluntary or evoked signals. The approach is very promising for neuromuscular diagnosis and assessment because of its capability for information compression and waveform classification. PMID- 7851917 TI - Combined statistical study of joint angles and ground reaction forces using component and multiple correspondence analysis. AB - The purpose of this research is to propose a general methodology to draw gait patterns when including hip, knee and ankle angle excursions in the sagital plane and the three components of the ground reaction force. The multidimensional signal analysis procedure is divided into three main stages: 1) describing the six signals of each step through sliding averages computed for successive time windows, 2) analyzing separately the six step-by-window tables obtained for each signal through principal component analysis to reduce the excessive quantity of data, and 3) analyzing the most informative time windows of the six signals at the same time. To emphasize both linear and nonlinear relationships between the respective time windows, the signal range within a window is cut into fuzzy modalities such as, "low" "medium" and "large." The resulting table is investigated using multiple correspondence analysis. The outcomes are gait patterns combining both time and space aspects. The factor planes obtained from multiple correspondence analysis constitute initial data models so that new data obtained from pathological gait can be directly projected onto them. Such an operation can be used to show how the rehabilitation of a particular subject evolves in relation to normal gait patterns. PMID- 7851918 TI - Improved beat-to-beat timing measurements of His-bundle signal. AB - A simplified bioelectric model of the atrioventricular (AV) junction is proposed to better understand the underlying biophysical generation of intracardiac His bundle signal and to analyze the effects of electrocatheter displacements on waveform morphology and estimation of AV node conduction time (AVCT). Based on this model, an inverse problem approach has been developed to estimate electrode displacements occurring in real recordings. A measurement correction method is proposed to improve estimation of AVCT. Results illustrate autonomic influences on AVCT, a phenomenon hardly measured with common techniques. PMID- 7851919 TI - Design and experimental evaluation of an intracavitary ultrasound phased array system for hyperthermia. AB - For evaluating the feasibility of treating prostate cancer, a 64-element linear ultrasound phased array applicator for intracavitary hyperthermia was designed and constructed. A 64-channel ultrasound driving system including amplifiers, phase shifters, and RF power meters was also developed to drive the array. The design of the array and driving equipment are presented, as are the results of acoustical field measurements and in vitro perfused phantom studies performed with the array. Several techniques for heating realistically sized tumor volumes were also investigated, including single focus scanning and two techniques for producing multiple stationary foci. The results show that the operation of the array correlated closely with the theoretical model. When producing a single stationary focus, the array was able to increase tissue temperature by 12 degrees C in vitro in perfused phantom. With some minor improvements in array design, intracavitary phased arrays could be evaluated in a clinical environment. PMID- 7851920 TI - Effects of strong pulsed magnetic fields on the cardiac activity of an open chest dog. AB - The heart of an open chest dog was stimulated by strong magnetic fields which were damped sinusoidal pulses with the one-cycle period of 1.47 ms. Stimulation effects were detected by electrocardiograph (ECG) and arterial blood pressure as a function of the strength of the field, the triggering point in the cardiac cycle, and the position of a stimulating coil. The threshold for arrhythmias was a minimum for the stimuli triggered at the apex of the T wave and on the P wave in the ECG. Premature ventricular and premature atrial contractions occurred according to whether the coil was placed over the ventricles or the atria. Ventricular defibrillation can not be attained by the magnetic stimulus with the flux density of 9.2 T which was the maximum field used. PMID- 7851921 TI - Two-point electrical-fluorescence recording from heart with optical fibers. AB - Optical recordings from frog myocardium, stained with a voltage-sensitive dye, have been made through a fiber optic system that uses fiber couplers to provide two excitation/detection paths and to separate excitation light from the fluorescence signal. The excitation light, from a green He-Ne laser (543 nm), is focused into a 100 microns-core fiber then is split 1:1 to two other fibers. Each of these two fibers transmits part of the excitation light through a fiber coupler (1:15 transmittance ratio) to the heart preparation which is stained with the voltage-sensitive dye RH237. The returning red fluorescence is split at the same fiber coupler (15:1 transmittance ratio) and is directed to a photomultiplier tube through a longpass filter. With this two-point mapping method, differences in action potential shape and timing have been observed. PMID- 7851922 TI - Live cell image segmentation. AB - A major requirement of an automated, real-time, computer vision-based cell tracking system is an efficient method for segmenting cell images. The usual segmentation algorithms proposed in the literature exhibit weak performance on live unstained cell images, which can be characterized as being of low contrast, intensity-variant, and unevenly illuminated. We propose a two-stage segmentation strategy which involves: 1) extracting an approximate region containing the cell and part of the background near the cell, and 2) segmenting the cell from the background within this region. The approach effectively reduces the influence of peripheral background intensities and texture on the extraction of a cell region. The experimental results show that this approach for segmenting cell images is both fast and robust. PMID- 7851923 TI - Magnetic backprojection imaging of the vascular lumen. AB - Current injected into a phantom model generated a magnetic field which was distorted above a simulated atherosclerotic lesion. The output of a Hall effect magnetic sensor was used in a backprojection to reconstruct the centroid of the simulated blood flow and thus localize the modeled atherosclerotic plaque region. PMID- 7851924 TI - Two-channel enhancement of a multifunction control system. AB - The enhancement of an existing myoelectric control system has been investigated. The original one-channel system used an artificial neural network to classify myoelectric patterns. This research shows that a two-channel control system can improve the classification accuracy of the pattern classifier significantly, thus improving the reliability of the prosthesis. PMID- 7851925 TI - Image-based display of activation patterns derived from scattered electrodes. AB - Presentation of electrophysiologic data, such as activation patterns, can take many forms, the most common of which are hand- or machine-drawn isochronal maps. We present an image-based method which provides accurate matching between electrophysiologic data and the anatomic sites from which the data were derived. This method is linear, simple, and straightforward to implement, and presents results in a format which is easy to understand and interpret. PMID- 7851927 TI - Detection of ECG characteristic points using wavelet transforms. AB - An algorithm based on wavelet transforms (WT's) has been developed for detecting ECG characteristic points. With the multiscale feature of WT's, the QRS complex can be distinguished from high P or T waves, noise, baseline drift, and artifacts. The relation between the characteristic points of ECG signal and those of modulus maximum pairs of its WT's is illustrated. By using this method, the detection rate of QRS complexes is above 99.8% for the MIT/BIH database and the P and T waves can also be detected, even with serious baseline drift and noise. PMID- 7851926 TI - Performance of filters for noise reduction in maxillary alveolar bone imaging. AB - Film-grain noise degrades image detail, hinders detection of subtle radiographic bone changes, and could thwart attempts to use dental radiographs of alveolar bone to detect osteoporosis. The purpose of this investigation was to quantify and compare the performance of various 1- and 2-D spatial and frequency domain filters in suppressing this noise. Estimates of noise-free bone profiles (scan lines) from each of five maxillary interdental areas were made by superimposing and averaging 16 identically exposed and digitized radiographs. The average mean absolute error and mean-squared error between the 80 initially noisy images and their respective noise-free profiles were calculated to provide an estimate of initial noise. Filter performance was measured as the change in these values after filtering the noisy images. Frequency domain analysis revealed that bone signal power spectra dominated at frequencies less than 2-3 cycles/mm and that some form of low-pass filtering would be applicable. The 2-D Butterworth low-pass filter provided the best performance, removing 57% of the film-grain noise when measured by mean absolute error, and over 80% when measured by mean-squared error. Surprisingly, the Lee, Lp mean, geometric mean, binomial, median, and simple neighborhood averaging filters offered comparable levels of performance. PMID- 7851928 TI - Phase and group-delay characteristics of signal-averaged electrocardiograms from patients with ventricular tachycardia. AB - Fourier analysis of the signal-averaged ECG (SAECG) has previously revealed significant differences in magnitude spectra that differentiate patients with ventricular tachycardia (VT) from those without VT. To determine additional distinguishing features in the frequency domain, we analyzed phase spectra of SAECG's of sinus beats from 57 patients with VT, 65 without VT, and 20 normal controls. Unwrapped phase spectra from SAECG's of the entire cardiac cycle were calculated with respect to three fiducial points: onset of the P and Q waves, and the negative of the slope of the phase (group delay) for frequencies in the band, which accounted for 97.5% of the energy in the vector magnitude of the Frank SAECG leads. Phase spectra of SAECG's from patients with VT differed from the non VT patients at frequencies > or = 21 Hz (p = 0.000039) for the P-wave fiducial, at frequencies > or = 60 Hz (p = 0.00085) for the Q-wave fiducial, and at frequencies < or = 62 Hz (p = 0.0035) for the 97.5% energy fiducial. Group delays in SAECG's from patients with and without VT differed from 10 to 26 Hz (p = 0.000016) for the P-wave fiducial, and from 14 to 24 Hz (p = 0.00000070) for the Q-wave fiducial. Group delays with respect to the Q-wave fiducial in the VT patients in the 14-24 Hz band were, on average, 9 ms and 5 ms longer than those of the non-VT's and normals, respectively. Thus, phase spectra of SAECG's contain previously undetected features that together with magnitude may be helpful in improving methods for stratifying the risk of VT. PMID- 7851929 TI - Nonlinear changes in brain's response in the event of injury as detected by adaptive coherence estimation of evoked potentials. AB - Injury-related changes in evoked potentials are studied with the aid of the coherence function, which effectively measures the degree of linear association between a pair of signals recorded during normal and abnormal states of the brain. The performance of an adaptive algorithm for estimating coherence function is studied, and the effects of additive noise on the estimated coherence function is discussed. Further, a linearity index is formulated and, through analysis and simulations, the index is shown to respond in a predictable manner to increasing nonlinearity while maintaining the robustness to the observation noise. Somatosensory evoked potentials are shown to be sensitive to injury resulting from acute cerebral hypoxia. We analyze the somatosensory evoked potentials recorded from anesthetized cats during inhalation of 8-9% oxygen gas mixtures and during recovery with 100% oxygen. Analyses of the experimental data show a very sharp drop in the magnitude coherence estimates during hypoxic injury and a corresponding rapid decline in the linearity index at the very early stages of the hypoxic injury. Thus, injury may lead to nonlinearities in the electrical response of the brain, and such measurements analyzed by the adaptive coherence estimation method may be used for diagnostic purposes. PMID- 7851930 TI - Evaluation of boundary element methods for the EEG forward problem: effect of linear interpolation. AB - We implement the approach for solving the boundary integral equation for the electroencephalography (EEG) forward problem proposed by de Munck [1], in which the electric potential varies linearly across each plane triangle of the mesh. Previous solutions have assumed the potential is constant across an element. We calculate the electric potential and systematically investigate the effect of different mesh choices and dipole locations by using a three concentric sphere head model for which there is an analytic solution. Implementing the linear interpolation approximation results in errors that are approximately half those of the same mesh when the potential is assumed to be constant, and provides a reliable method for solving the problem. PMID- 7851931 TI - Principal-component localization of the sources of the background EEG. AB - A method, based on principal components for localizing the sources of the background EEG, is presented which overcomes the previous limitations of this approach. The spatiotemporal source model of the EEG is assumed to apply, and the method involves attempting to fit the spatial aspects of this general model with an optimal rotation of a subset of the principal components of a particular EEG. The method is shown to be equivalent to the subspace scanning method, a special case of the MUSIC algorithm, which enables multiple sources to be localized individually rather than all at once. The novel aspect of the new method is that it offers a way of selecting the relevant principal components for the localization problem. The relevant principal components are chosen by decomposing the EEG using spatial patterns common with a control EEG. These spatial patterns have the property that they account for maximally different proportions of the combined variances in the two EEG's. An example is given using a particular EEG from a neurologic patient. Components containing spike and sharp wave potentials are extracted, with respect to a standard EEG derived from 15 normal volunteers. Spike and sharp wave potentials are identified visually using the common spatial patterns decomposition and an EEG reconstructed from these components. Four dipole sources are fitted to the principal components of the reconstructed EEG and these source account for over 88% of the temporal variance present in that EEG. PMID- 7851932 TI - A method for localizing EEG sources in realistic head models. AB - A computationally practical method for performing moving dipole calculations to localize EEG sources in realistic, boundary element (integral equation) type of head models is presented. This method makes use of a rapid method of solving the forward problem of calculating the EEG's produced by a dipole in a realistic head model. This rapid forward calculation method allows the use of standard Simplex search techniques to solve the inverse problem of localizing electrical sources in the brain from EEG's measured on the scalp. PMID- 7851933 TI - Transformation of multichannel magnetocardiographic signals to standard grid form. AB - Multichannel magnetocardiographic (MCG) recordings with fixed sensor arrays are not directly comparable with single-channel measurements carried out at standard grid locations. In addition, comparison of data obtained with different types of magnetometers is difficult. We present a method for transforming multichannel measurements to the standard-grid format. The minimum-norm estimate (MNE) of the source current distribution in the body is calculated, and the desired field components in standard grid points are then computed from the MNE. We measured three subjects with both a 24-channel and a single-channel instrument. The signals extrapolated from the multichannel measurements corresponded quite well to the single-channel data registered at the standard grid locations, especially in those grid points that were covered by the 24-channel device. The signal amplitude-weighted correlations between the extrapolated and directly measured signals were 0.73-0.87. In simulations with ideal measurement geometry but with a realistic amount of random noise in the signals, we obtained a 0.99 correlation. It was also found that the method is relatively tolerant to errors in the location and orientation of the multichannel magnetometer. For example, a simulated 20-mm displacement in the location of the sensor array caused only a 3% decrease in the correlation, and when it was rotated and tilted by 10 degrees C, the correlation decreased by 5%. The basic advantage of our extrapolation method is its physiologic nature: the method is based on the mathematical modeling of the source current distribution, rather than on direct constraints applied to the magnetic field. PMID- 7851934 TI - Evaluation of a long-range adaptive predictive controller for computerized drug delivery systems. AB - A closed-loop adaptive control system, based on the generalized predictive control law with a terminal matching condition, has been developed for computerized drug delivery. The control law is a minimization of the squares of prediction errors over a small future prediction horizon plus weighted square of the prediction error at steady-state. A control-relevant, long-range identification algorithm is used for on-line parameter estimation. Since the control and identification are mutually compatible, the system truly satisfies the approximate dual control criterion. The system has been applied to the control of mean arterial pressure (MAP) by automatic infusion of sodium nitroprusside in the presence of physical and physiological constraints. Experimental evaluation on six mongrel dogs, in an ethics-approved manner, included setpoint tracking and regulation of MAP in the presence of unpredictable disturbances. The system was found to be capable of inducing hypotension in an average of 2.44 +/- 0.31 min (mean +/- standard error of mean) after probing without any overshoots in mean arterial pressure. The nitroprusside infusion was also free of any ringing. When the subjects were not disturbed, 96.2% of mean arterial pressure remained within 5 mm Hg of the target pressure. A series of disturbances introduced in the presence and absence of closed-loop control affirms the robustness and effectiveness of this control system. PMID- 7851935 TI - An optimal control model for analyzing human postural balance. AB - The question posed in this study is whether optimal control and state estimation can explain selection of control strategies used by humans, in response to small perturbations to stable upright balance. To answer this question, a human sensorimotor control model, compatible with previous work by others, was assembled. This model incorporates linearized equations and full-state feedback with provision for state estimation. A form of gain-scheduling is employed to account for nonlinearities caused by control and biomechanical constraints. By decoupling the mechanics and transforming the controls into the space of experimentally observed strategies, the model is made amenable to the study of a number of possible control objectives. The objectives studied include cost functions on the state deviations, so as to control the center of mass, provide a stable platform for the head, or maintain upright stance, along with a cost function on control effort. Also studied was the effect of time delay on the stability of controls produced using various control strategies. An objective function weighting excursion of the center of mass and deviations from the upright stable position, while taking advantage of fast modes of the system, as dictated by inertial parameters and musculoskeletal geometry, produces a control that reasonably matches experimental data. Given estimates of sensor performance, the model is also suited for prediction of uncertainty in the response. PMID- 7851936 TI - Reverse genetics of negative strand RNA viruses. PMID- 7851937 TI - Carbonic anhydrase: an efficient enzyme and an elusive mechanism. PMID- 7851938 TI - Kinetic mechanism of yeast alcohol dehydrogenase activity with secondary alcohols and ketones. AB - The kinetic mechanism of yeast alcohol dehydrogenase (EC 1.1.1.1) activity with the redox pair 2-propanol/acetone has been probed in detail by the application of initial rate studies in the absence and in the presence of products, and a dead end inhibitor pyrazole. An overall steady-state random Bi Bi mechanism in both directions, with the formation of both abortive ternary complexes, enzyme.NADH.2 propanol and enzyme.NAD+.acetone has been observed. A complete list of steady state kinetic constants are also reported for the redox pair (S)-(+)-2-butanol/2 butanone. PMID- 7851939 TI - Phosphorylation of casein, fibrinogen and calmodulin by a glycoprotein protein kinase from monkey cerebellum: a casein kinase II-like enzyme. AB - A glycoprotein protein kinase was isolated from monkey cerebellum by polylysine Sepharose chromatography and affinity chromatography on Sepharose 4B coupled to the lectin, Concanavalin A. The protein kinase phosphorylated casein on serine and threonine residues and was stimulated by polylysine, polyarginine, spermine, histone, protamine and sphingosine, but was inhibited by heparin, poly (Glu, Ala, Tyr) and poly (Glu, Tyr). These characteristics were typical of casein kinase II. The protein kinase also phosphorylated fibrinogen and calmodulin and exhibited similar characteristics of stimulation by polylysine or polyarginine. The phosphorylation of fibrinogen (a glycoprotein), but not casein or calmodulin (non glycoproteins), was significantly inhibited by Concanavalin A. Unlike casein kinase II, the enzyme did not undergo autophosphorylation. The collective results suggested that the enzyme from monkey cerebellum was a casein kinase II-like protein kinase and that phosphorylation of a glycoprotein substrate (fibrinogen) by the kinase could be influenced by a carbohydrate binding lectin. PMID- 7851940 TI - Mechanism of the antioxidant effect of Bordetella pertussis extract. AB - In order to gain insight into the antioxidant effect of the cell extract from Bordetella pertussis (strain 18-323, phase I) pancreatic antioxidant enzymes, glutathione (GSH), lipid conjugated dienes, DNA strand breaks in islet cells and the in vitro ROM scavenging potential of the extract were studied in 18 hr-fasted mice after administration (i.v.) of the extract (1 mg/kg body wt) 1 hr before alloxan treatment. The antioxidant enzymes activities as well as the glutathione content, which were severely depleted in the alloxan group, were found to be significantly restored in the extract treated group at the end of 48 hr. Moreover, the extract arrested the two-fold increase in lipid conjugated dienes, the primary products of lipid peroxidation, and afforded significant protection against DNA strand breakage in islet cells of pancreas in alloxan diabetic mice. In addition, it caused a six-fold increase in serum insulin levels of normal mice in 15 min and also demonstrated an unique in vitro superoxide anion radical scavenging activity at a dose of 37.5 micrograms/ml in 10 min. B. pertussis extract thus appears to exert its antioxidant protection through stimulation of insulin release from pancreas and hitherto unobserved intrinsic superoxide anion radical scavenging ability. PMID- 7851941 TI - Effect of in vivo propranolol treatment on oxidative energy metabolism in rat liver and kidney mitochondria. AB - In vivo treatments with propranolol inhibited state 3 respiration in rat liver mitochondria with glutamate, pyruvate+malate, beta-hydroxybutyrate and succinate as substrates. The extent of inhibition was generally higher for the acute treatment. In the kidney mitochondria, the extent of inhibition of state 3 respiration for glutamate, pyruvate+malate and ascorbate+TMPD was equal in both acute and chronic treatments. However, the contents of cytochromes in both liver and kidney mitochondria remained unaffected by either of the drug treatments. The results suggest that prolonged use of the drug can have toxic effects on the respiratory activity of mitochondria even in the peripheral tissues, in addition to the target tissues. PMID- 7851942 TI - Biliary proteins from hepatic bile of rats fed curcumin or capsaicin inhibit cholesterol crystal nucleation in supersaturated model bile. AB - Following our earlier observations that curcumin and capsaicin are antilithogenic in mice and hamsters, attempts were now made to understand the manner in which these spice principles were acting. For this purpose, the hepatic biles of rats fed a control, lithogenic, and lithogenic diet supplemented with curcumin or capsaicin were subjected to gel filtration chromatography (sepharose-4B-Cl) and the LMW protein fractions were tested for their ability to influence cholesterol crystal growth in model bile. The LMW protein fraction from the lithogenic group bile shortened the nucleation time and increased the crystal growth rate and final crystal concentration. But with the LMW protein fractions from the biles of rats on the lithogenic group supplemented with curcumin or capsaicin, the nucleation times were prolonged and the crystal growth rates and final crystal concentrations were decreased. The LMW fractions were further purified into three different sugar specific proteins by affinity chromatography. A higher proportion of LMW proteins from the lithogenic group bile was bound to Con-A whereas higher proportions of LMW proteins from the groups fed with curcumin and capsaicin were respectively bound to wheat germ agglutinin and Helix pomatia lectin. The Con-A bound fraction obtained from the lithogenic group showed a pro-nucleating effect. In contrast, the WGA-bound fraction obtained from curcumin group or the Helix pomatia lectin bound fraction obtained from capsaicin group showed a potent antinucleating activity. PMID- 7851943 TI - A mechanistic approach into a diabetic serum factor-mediated release of beta glucuronidase in normal neutrophils. AB - The possible mechanism of diabetic serum factor (DSF)-mediated lysosomal degranulation has been investigated. It was observed that pertussis toxin, sodium fluoride and vanadate could significantly inhibit DSF-mediated beta-glucuronidase release, whereas atropine exhibited only a partial blockage against DSF. Since DSF can generate toxic free radicals, various free radical quenchers were tested in order to evaluate their contributions. Superoxide dismutase was found to be the most effective in inhibiting lysosomal release as compared to catalase and peroxidase. The mixtures of all the enzymes failed to exhibit any additive effect. Interaction of DSF with heparin, insulin and Con A revealed that heparin can completely block DSF-mediated lysosomal release. The implications of the observations are discussed. PMID- 7851944 TI - Thermodynamics of binding water and solute to powdered long-chain salts of fatty acids. AB - Hydration of powdered fatty acids and their salts has been studied both in presence and absence of neutral salts, sucrose and urea using the isopiestic vapour pressure technique. Moles of water vapour adsorbed per mole or kg of soaps like sodium palmitate, sodium stearate, sodium myristate and sodium laurate have been measured in presence and absence of salts and compared with that of detergents (SDS, CTAB, DTAB and MTAB). For each case of positive excess adsorption of water vapour and negative excess adsorption of inorganic salts, urea and sucrose to different soaps, the standard free energy change (delta G degrees) per kg of substrate in bringing the bulk mole fraction from zero to unity have been calculated using an appropriate thermodynamic equation and the values so obtained have been compared critically. PMID- 7851945 TI - Effect of experimental selenium deficiency and its supplementation on the candidacidal activity of neutrophils in albino rats. AB - The role of selenium in the diet of rats has been examined with respect to the neutrophil functions. Feeding of Se-deficient diet for 75 days resulted in reduction in candidacidal activity, superoxide production, oxygen consumption, glucose utilisation and glutathione peroxidase activity. Supplementing the diet with Se for 30 days resulted in partial restoration of all the activities. PMID- 7851946 TI - Studies on interfacial potentials and currents of urine-urea systems across urinary bladder membrane. AB - Interfacial potential of urine-urea mixture across urinary bladder membranes of goat has been studied by comparing membrane-solution resistance and current data. It has been found that interfacial potential of urine solution is higher as compared to urea solution and that of urine-urea system increases with increase in concentration of urea in urine. Current generated in the system decreases with decrease in concentration of urea in the urine. Implications of electro physiological studies in understanding the micturition process are discussed. PMID- 7851947 TI - Circadian rhythms of renal phosphohydrolases analysed by Cosinor method. AB - Rhythmometric analysis of hydrolytic enzymes of mouse kidney has been performed on circadian time scale using the F test. Significant rhythms were detected in glucose-6-phosphatase (G6Pase), inorganic pyrophosphatase (InPPase) and alkaline phosphatase (AlPase) on protein and fresh weight basis. Acrophase (time for peak activity) of G6Pase, InPPase and AlPase per mg protein was at 9.9 degrees (1.0 hr), 88.5 degrees (6.0 hr) and at 342.3 degrees (20 hr) respectively. ATPase, which did not show significant rhythm (mean +/- SD = 4.51 +/- 0.30), had a peak value at 32.1 degrees (2.14 hr) with an amplitude of 0.31 units on protein basis. However, G6Pase and AlPase oscillated with high amplitudes (0.18 and 0.71) across the mean value (mesor) of 0.68 +/- 0.3 and 1.43 +/- 0.46 units respectively and with a phase shift of 5 hr. Since G6Pase is a multicomponent and multifunctional enzyme having several overlapping enzyme activities (viz. InPPase), coordinated events of G6Pase, InPPase and ATPase in the regulation of daily renal functions have been mapped in the intact animals, along a physiologic time scale. PMID- 7851948 TI - Cytokines and tuberculosis. PMID- 7851949 TI - Primary lung cancer in non-tuberculous upper lobe lesions. AB - Tuberculosis is not only the commonest infectious disease of the lungs in India, but it is also the most commonly overdiagnosed entity whenever upper lobe lesions are seen on a chest roentgenogram. Over a two year period (1990-1992), 150 non tuberculous upper lobe lesions in high risk group patients (middle aged and elderly; chronic smokers) were investigated Sixty-two patients (41.3%) were found to have primary malignant tumours of whom 67.7% had squamous cell carcinoma. Routine screening for malignancy in high risk patients with non-tuberculous upper lobe lesions should be undertaken. PMID- 7851950 TI - Domestic smoke pollution and prevalence of chronic bronchitis/asthma in a rural area of Kashmir. AB - An increased prevalence of chronic bronchitis (12.21%) was observed in Gujjar females of a rural area of Kashmir valley in this study. Screening of adult population of two randomly selected village showed an overall prevalence rate of 7.7% for chronic bronchitis and 1.96% for asthma. This increased prevalence of chronic bronchitis was attributed to exposure to domestic smoke pollution, lower socio-economic status, illiteracy, poor housing conditions and overcrowding. PMID- 7851951 TI - Work place challenge: spirometric response in polyurethane (isocyanate) paint workers. AB - In industrialised countries, isocyanate is probably the most common cause of occupational asthma. The present study was conducted to see the effect on FEV1 in workers who were directly exposed to isocyanate. One hundred and fourteen workers of a rail coach factory who were involved in polyurethane paint spray were studied. Spirometry was done three times, first before starting the work, at two hours and then 6-8 hours after finishing the work to see immediate, late and dual responses. Positive response was considered when there was fall of 20% or more in forced expiratory volume in 1 second (FEV1) from base line. Sixteen per cent of the workers exposed to isocyanate developed immediate reaction, 10% developed late reaction and 6% developed dual reaction. Non-smokers were more prone to develop late and dual responses. PMID- 7851952 TI - Aggressive fibromatosis. PMID- 7851953 TI - Salmonella group-E (Senftenberg) lung abscess: a case report. AB - A male patient presented with complaints of fever, cough with expectoration, burning micturition and 5-6 semisolid motions per day for the past 6 days. Skiagram chest (PA view) revealed lung abscess in the left mid zone. There was no improvement, symptomatically and radiologically, after an empirical course of antibiotics (IV ampicillin and gentamycin). Sputum, urine and stool cultures grew salmonella group E organisms sensitive only to cefotaxime. The patient was treated with IV cefotaxime and responded well clinically, radiologically and bacteriologically. PMID- 7851954 TI - Filarial pleural effusion with constrictive pericarditis. PMID- 7851955 TI - Pneumocystis carinii pneumonia complicating Hodgkin's disease: a case report. AB - A case of Hodgkin's disease who developed Pneumocystis carinii pneumonia (PCP) is described. The diagnosis of P. carinii was confirmed on post-mortem lung biopsy. The rarity of its occurrence in our country is emphasised as is the need for high degree of suspicion and early institution of treatment. PMID- 7851956 TI - Associations of IgA and IgA-rheumatoid factor with disease features in patients with rheumatoid arthritis. AB - In previous studies we have shown that levels of IgM-rheumatoid factor (RF) in plasma and peripheral blood mononuclear cell supernatants are correlated with disease activity and response to second-line therapy in patients with rheumatoid arthritis (RA). The present studies were designed to examine whether IgA-RF levels are also correlated with clinical features of this disease. Two groups of RA patients were studied. Group I consisted of 87 patients in whom extensive clinical data had been collected. Group II included nine patients beginning treatment with gold or methotrexate who were studied during the first year of therapy. Measurement of IgM, IgA, IgM-RF and IgA-RF in culture supernatants and plasma was done by an ELISA method. These data were examined for correlations with clinical and laboratory features. Levels of IgA-RF in supernatants and plasma were found not to be correlated with disease features in the cross sectional analysis of Group I patients, while IgM-RF and total IgA levels did show significant clinical correlation. Treatment of Group II patients with gold or methotrexate was associated with significant decreases in plasma levels of total IgA and IgM-RF as well as a small but statistically significant decrease in plasma IgA-RF. Plasma levels of total IgM were not altered during therapy. These findings suggest that production of IgA but not IgA-RF is correlated with disease status in patients with RA. PMID- 7851958 TI - Regulation of B cell:T cell interactions: potential involvement of an endogenous B cell sialidase. AB - In light of the ability of B cells treated with neuraminidase to interact more effectively with T cells, the increased capacity of activated, but not small resting B cells, to interact with T cells could be associated with the level of sialylation on certain B cell surface molecules which influences the effectiveness of the physical interaction between B and T cells. The purpose of this study was to determine if activation of B cells altered sialylation via an endogenous sialidase which affected both the initial interaction between T and B cells and subsequent B cell-induced T cell proliferation. The competitive neuraminidase inhibitor, 2-deoxy-2,3-dehydro-N-acetylneuraminic acid (NeuAc2en), inhibited LPS-mediated enhancement of B cell conjugate formation with Ia-specific T cell clones as well as enhancement of their capacity to stimulate a mixed lymphocyte reaction. The addition of NeuAc2en during LPS stimulation did not affect the surface expression of Ia, LFA-1, ICAM-1 or mB7, suggesting that inhibition of LPS-mediated enhancement by the sialidase inhibitor was not due to changes in the level of expression of the major B cell adhesion or co-stimulatory molecules. Short term stimulation with phorbol myristate acetate (PMA) and ionomycin also enhanced the ability of resting B cells to form antigen specific T:B conjugates. However, activation of B cells with PMA and ionomycin or with LPS did not change the capacity of a sialic acid specific lectin to bind to the B cells, suggesting that activation was not associated with global changes in surface sialic acid content. B cell stimulation did not appear to increase the activity of the most prevalent B cell sialidase activity as measured in an in vitro assay system, suggesting that the major B cell sialidase may not be responsible for the alteration of B cell sialylation levels or the ability of activated B cells to interact more effectively with T cells. The possibility of intracellular compartmentalization of sialidase activity or that a minor B cell sialidase may play a role in the regulation of a B cells ability to interact with T cells are discussed. PMID- 7851957 TI - A toxic shock syndrome toxin-1 peptide that shows homology to amino acids 180-193 of mycobacterial heat shock protein 65 is presented as conventional antigen. AB - Peripheral blood mononuclear cells (PBMC) from the majority of adults (12 out of 18 subjects tested) showed an in vitro proliferative response to a 20 amino acid long peptide (peptide 1, a.a 18-37) derived from TSST-1. In contrast, thymocytes and PBMC from cord blood did not proliferate to this peptide. TSST-1 peptide 1 did not induce IL-1 beta mRNA in monocytes indicating that it does not behave as a superantigen. Proliferation of PBMC to peptide 1 could be blocked by anti-HLA DR, but not by anti-HLA DP or DQ monoclonal antibodies suggesting that HLA-DR molecules are the restriction elements for the recognition of this peptide by T cells. Studies with subjects of known HLA-DR types showed that all types tested are capable of responding to this peptide. Peptide 1 shows homology to a.a 180 193 of mycobacterial hsp 65 and was shown to stimulate the proliferation of T cell lines and T cell clone specific for the purified protein derivative (PPD) of Mycobacterium tuberculosis. This cross reactivity may confer on TSST-1 the potential to trigger self reactivity and may also contribute to the natural immunity against TSST-1. PMID- 7851959 TI - A 21-mer synthetic peptide of toxic shock syndrome toxin 1, TSST-1[58-78], activates T cells by binding to MHC class II and by an MHC unrestricted xenostimulatory pathway. AB - Toxic shock syndrome toxin-1 (TSST-1) is a "superantigen" which binds to MHC class II molecules and induces a polyclonal stimulation of T cells. In this communication by using a FACS technique and a 21-mer synthetic peptide from the primary sequence of TSST-1 (KGEKVDLNTKRTKKSQHTSEG), designated TSST-1(58-78), we demonstrated binding of the peptide only to cells bearing MHC class II. The proliferative effect of TSST-1(58-78) on human T cells was shown to be inhibited much more by anti-HLA-DR than by anti-HLA class I antibody. Furthermore, human monocytes were able to present TSST-1(58-78) to a mouse VSV specific T cell clone by a xenostimulatory mechanism. These data indicate this peptide to contain an active site of the TSST-1 holotoxin. PMID- 7851960 TI - Poly(vinyl alcohol) as a blocking agent in enzyme immunoassays. AB - We examined the blocking ability of poly(vinyl alcohol) (PVA) in enzyme immunoassays by coating polystyrene microtiter wells with PVA of different molecular weights (MW) and percent hydrolysis (%Hyd). Blocking ability was measured by the differences in non-specific binding of an anti-rabbit IgG horseradish peroxidase conjugate to coated and uncoated wells. PVA with a MW of 124,000-186,000 and > 99 %Hyd was the most effective in suppressing the binding of the conjugate. This PVA at 0.5% (w/v) was significantly better at reducing non specific binding than commonly used blocking agents and did not interfere with the specific binding of the conjugate to antigen-coated microtiter wells. PMID- 7851961 TI - Effect of lectins on mouse peritoneal macrophage phagocytic activity. AB - We studied the in vitro ability of lectin-treated murine peritoneal macrophages to attach and phagocytize particulate antigens. Glucose and mannose specific lectins such as Con-A and lentil lectin, as well as complex lactosamine residues specific lectins, such as Phaseolus vulgaris var. cacahuate and Phaseolus coccineus var. alubia, increased the macrophage phagocytic activity towards heterologous erythrocytes, whereas peanut agglutinin, a galactose-specific lectin, diminished the macrophage phagocytic activity. These results suggest that a galactose-N-acetyl-D galactosamine-containing structure could participate as negative modulator of the phagocytic activity. PMID- 7851962 TI - High cytokine serum levels in patients with autoimmune hemolytic anemia (AIHA). AB - In autoimmune diseases striking abnormalities of T and B cell activation and of cytokine production are present. In 14 patients with autoimmune hemolytic anemia (AIHA), idiopathic or in the course of: lymphoma, B hepatitis, carcinoma, drug therapy (alpha-methyldopa), systemic lupus erythematosus (SLE), and not yet submitted to immunosuppressive therapy, the PBL proliferative response to PHA and the IL1 alpha, IL2, IL4 and IL2R serum levels have been valued. While the stimulation index of PBL was strongly reduced in 10 cases (64 +/- 56 vs 138 +/- 45 in the control group), IL1 alpha, IL2 and IL2R were greatly increased in all the patients, and IL4 in 5 (IL1 alpha :199 +/- 268 pg/ml in patients vs 0.30 +/- 0.2 in controls; IL2:716 +/- 311 pg/ml vs 16 +/- 4; IL4:29 +/- 13 pg/ml vs 13 +/- 7; IL2R:1233 +/- 471 U/ml vs 256 +/- 114). Cytokine serum levels were not related with the associated disease, with the CD4+ and CD8+ cells absolute number or with PBL blastogenic in vitro response. The high serum levels of cytokines and IL2R suggest that in AIHA there exist a CD4+ lymphocyte hyperactivation (the low proliferative response of PBL might imply a temporary functional exhaustion of T lymphocytes) as in the other autoimmune diseases. PMID- 7851963 TI - Macrophage priming and activation during fibrosarcoma growth: expression of c myb, c-myc, c-fos, and c-fms. AB - Macrophages (M phi)3 function by a two-step process that includes priming (induction of cytokine and enzyme mRNA) and activation (production of effector molecules). The initial steps in M phi priming involve the expression of certain proto-oncogenes that regulate expression of other genes. Because tumor growth primes M phi to produce several suppressor monokines, we determined if cancer induced M phi expression of these proto-oncogenes. Unstimulated peritoneal M phi from tumor-bearing hosts (TBH) constitutively expressed the proto-oncogenes c fms, c-fos, c-myc, and c-myb, whereas normal host (NH) M phi had little or no expression of these proto-oncogenes. When M phi were given a 24-h adherence priming stimulus, NH M phi expressed c-fms and c-fos at levels equivalent to TBH M phi constitutive expression. Adherence had little or no effect on c-fms and c fos expression in TBH M phi or on NH and TBH M phi c-myc expression. c-myb expression was not induced in NH M phi during adherence and was strongly decreased in TBH M phi. Activation with a 1-h lipopolysaccharide-treatment increased NH and TBH M phi expression of c-fms, c-fos, and c-myc, with higher expression of these proto-oncogenes in TBH M phi. Activation failed to induce c myb expression in NH M phi and completely inhibited expression in TBH M phi. Because c-fms, c-fos, and c-myc are normally expressed early during M phi activation, our results suggest that tumor growth primes M phi by inducing expression of these proto-oncogenes. c-myb is expressed in immature M phi and is downregulated during M phi activation. These observations explain why NH M phi expression of c-myb was not induced and are consistent with reports that suggest TBH M phi have not reached full developmental maturity. The induction of M phi proto-oncogene expression during cancer may put M phi in a primed state, which leads to earlier and stronger production of adverse suppressor and cytotoxic molecules. PMID- 7851964 TI - Immune response to measles, mumps & rubella vaccine at 9, 12 & 15 months of age. AB - Seroconversion rates to measles, mumps and rubella (MMR) in children given MMR vaccine at 9, 12 and 15 months of age were assessed so as to recommend the optimum age for vaccination. A total of 164 infants were recruited, of whom 123 completed the study. Sera were tested pre-immunization and 4 wk after MMR vaccine, for the presence and titres of antibodies by the haemagglutination inhibition (HI) test and by enzyme-linked immunosorbant assay (ELISA). The pre immunization results showed that levels of maternal antibody detectable by HI had disappeared by 9 months in all infants in the case of measles, but not in the case of mumps or rubella. Evidence for subclinical infection with the three viruses was found in 19 to 31 per cent of infants by 15 months of age. The responses to measles antigen by both HI test and ELISA were better (> 95%) at 12 or 15 months than at 9 months (80%). Vaccine failure was low at 12 or 15 months. The response to mumps antigen by HI antigen was also higher (92%) at 12 months than at 9 months (75%). Vaccine failure was less frequent at 12 months than at 9 months. The ELISA was found to be unreliable for mumps virus antibody testing. Rubella vaccine evoked good seroresponse (> 92%) at 9, 12 and 15 months, both by HI test and ELISA. Thus a better response to the MMR vaccine was obtained at or after 12 months of age than earlier. Hence, a dose of MMR may be given optimally at 12 months for children not previously immunized with measles vaccine. For those already given measles vaccine, the MMR may be given at 12 or 15 months. PMID- 7851965 TI - Absence of HTLV-I infection in some Indian populations. AB - A total of 946 adults belonging to ten population groups of Uttar Pradesh and West Bengal were screened for HTLV-I using a gelatin particle agglutination test. The percentage of seroreactive cases varied from 0 to 5.8 per cent. The overall prevalence of seroreactivity was 2 per cent. Of the 19 seroreactive cases, 15 were subjected to Western blot analysis, none could be confirmed. HTLV-I infection is, therefore, absent in these populations. PMID- 7851966 TI - Changes in the virulence of Mycobacterium bovis (BCG Phipps) in carbon tetrachloride treated mice. AB - Mild grade of liver damage was produced in mice by repeated subcutaneous injection of carbon tetrachloride. These mice along with saline treated mice were challenged with an avirulent vaccine strain of BCG (Phipps), intravenously. The CCl4 treated, BCG challenged mice developed disease and died much earlier than the controls, indicating an increased susceptibility to the avirulent strain in mice with mild hepatitis. PMID- 7851967 TI - Evaluation of PCR based test for the detection of Mycobacterium tuberculosis in coded sputum specimens. AB - A test based on amplification of 169 bp DNA specific to Mycobacterium tuberculosis was evaluated in a trial, on 50 coded samples which included 25 sputum specimens from radiologically, clinically and bacteriologically proven patients of pulmonary tuberculosis and 25 control specimens. At the end of the trial the code was broken and the results of PCR test were compared with those obtained with Ziehl Neelsen staining and culture test. The test appeared highly sensitive reacting 100 per cent in either of the hands with concordance rate of 76 per cent; 3 of 25 control samples gave false positive results. PMID- 7851968 TI - A quantitative microbiological study of bacterial vaginosis. AB - A quantitative microbial study of vaginal secretions from 100 women with bacterial vaginosis (BV) and 50 healthy women matched for age, was undertaken. This was aimed at comparing the bacterial flora colonising the vagina of sexually active asymptomatic women with those with BV and correlating bacterial counts with presence of symptoms. Of the total 475 bacteria isolated anaerobes were predominant among controls and among patients aerobes and anaerobes had equal prevalences. The increased viable counts of all anaerobes (> 10(7) cfu/g) were related with symptoms. Mobiluncus mulieris could be isolated from one patient and Chlamydia trachomatis antigen was absent in all samples tested. Bacteroides, G. vaginalis and Ureaplasma urealyticum were found to be the most commonly occurring group in women with BV. Lactobacillus, and probably Coryneforms have a protective role in health, preventing disease. PMID- 7851969 TI - Red cell distribution width as a measure of severity of iron deficiency in iron deficiency anaemia. AB - Of the various red cell parameters used for distinguishing iron deficiency anaemia (IDA) from beta-thalassaemia trait BTT, red cell distribution width (RDW), which is an objective measure of the degree of anisocytosis, was examined by us for its discriminating value. RDW was measured in 55 patients of IDA and 56 patients of BTT at presentation with the help of an automated haematology analyser. The mean RDWs in IDA and BTT patients were 18.2 +/- 3.8 and 15.1 +/- 1.2 respectively (P < 0.001). In IDA, RDW showed an inverse relationship with the haemoglobin level (r = -0.543; P < 0.001), while no such correlation was observed in BTT patients. An inverse relation was also observed in IDA between RDW and transferrin saturation (TS). Patients with high RDW had low TS and vice versa. The latter finding, although statistically not significant, suggested that the degree of elevation of RDW in IDA could reflect the severity of iron deficiency. Our study revealed that red cell count, which was significantly higher in BTT patients (P < 0.001), the RDW, and the discriminant function (DF) calculated from these two parameters could be useful in distinguishing IDA from BTT. A RDW above 17.1 strongly suggests the presence of IDA. For RDW below 17.1 the DF can be applied for further discrimination. RDW has the advantage of being obtained directly from the analyser, while DF is a calculated value. PMID- 7851970 TI - Octreotide (SMS 201-995) as an antisecretory agent in cholera toxin & bile acid induced intestinal secretion in an in vivo animal study. AB - The effect of Octreotide (SMS 201-995), synthetic somatostatin analogue on small intestinal and colonic fluid secretion induced respectively by cholera toxin (CT) and deoxycholic acid (DCA) was investigated in rabbits using in vivo isolated loops. After exposure to CT and DCA, marked fluid accumulation was observed in the small intestinal and colonic loops, along with elevation of jejunal and colonic mucosal cyclic AMP concentrations. Octreotide inhibited CT and DCA induced small intestinal and colonic secretion, dose-dependently. This anti secretory effect was observed after both intramuscular and oral administration of octreotide. In contrast, octreotide did not affect the elevated mucosal cyclic AMP concentrations. These results suggest that octreotide inhibits CT and DCA induced intestinal secretion, and this anti-secretory effect is produced by affecting processes beyond cyclic AMP formation. PMID- 7851971 TI - Metabolic responses to episodes of partial dietary restriction in undernourished Wistar rats. AB - Wistar rat pups raised in large litters (LL) and small litters (SL) prior to weaning had access to ad libitum dietary intakes up to the age of 90 days. At 90 and again at 180 days they were partially diet restricted for a period of 15 days. Body weights, resting metabolic rates (RMR) and capacity for nonshivering thermogenesis (NST) was evaluated prior to, during and after the period of energy restriction. Responses were compared with 180 day rats from both groups who had been diet restricted for the first time at 180 days. Body weight losses were greater in the latter group. Groups of rats exposed to dietary restriction once, had higher body weights than rats of identical ages who had not been restricted. RMR decreased in all groups during restriction. However, reductions in NST were seen only in nutritionally deprived animals and in well-nourished controls who were partially restricted once. Changes in NST contribute to metabolic efficiency seen during episodic dietary restriction. PMID- 7851972 TI - Influence of dietary vitamin A deficiency on rat digestive & absorptive functions during diabetes mellitus. AB - Intestinal absorption of glucose and activities of amylases of intestinal and pancreatic origin were measured in animals vitamin A deficient, diabetic and combined state of vitamin A deficiency with diabetes. The vitamin A deficient diet caused a significant reduction in intestinal digestive and absorptive functions. On the other hand the digestive and absorptive functions were increased in the diabetic state. The combination of diabetes with vitamin A deficient diet caused a decrease in the digestive and absorptive functions along with blood glucose level in comparison to diabetic state alone. These findings suggest that the inhibition of digestive and absorptive functions observed in the combined state of vitamin A deficiency and diabetes may be due to the presence of vitamin A deficient diet. PMID- 7851973 TI - Effect of moderate & high loadings on the proteoglycans & water content of bovine knee joint articular cartilage. AB - Variations in proteoglycans and water content of the knee joint cartilage were found to occur when the joint was subjected to articulating motion under moderate and high loadings. It was found that at a moderate load of 150 kg there were an increase in the percentage of proteoglycans but the percentage decreased when the joint was articulated at a high loading of 300 kg. It has also been observed that the ratio of water content and the proteoglycans decreased at moderate load, whereas the ratio increased at high load. The observed changes in proteoglycans and water content in extracellular matrix with moderate and high loadings suggested that articular cartilage properties respond to mechanical stresses. PMID- 7851974 TI - Occupational cancer in developing countries. Introduction. PMID- 7851975 TI - Cancer. PMID- 7851976 TI - Other diseases. PMID- 7851977 TI - International and national measures for prevention and control. PMID- 7851978 TI - Strategies for the prevention of occupational cancer in developing countries. PMID- 7851979 TI - Transfer of hazardous industries. PMID- 7851980 TI - Burden of cancer in developing countries. PMID- 7851981 TI - Identification of occupational carcinogens. PMID- 7851982 TI - Occupational exposure to carcinogens in developing countries. PMID- 7851983 TI - Industrialization and health. PMID- 7851984 TI - Special exposure circumstances. PMID- 7851985 TI - Loss of immunoreactivity for glial fibrillary acidic protein (GFAP) in astrocytes as a marker for profound tissue damage in substantia nigra and basal cortical areas after status epilepticus induced by pilocarpine in rat. AB - Status epilepticus induced by pilocarpine in rats induces massive tissue damage comprising neurons and astrocytes (incomplete infarction) in substantia nigra pars reticulata (SNR) and in basal cortical areas (BCTX). Immunohistochemistry with a polyclonal antiserum and a monoclonal antibody to GFAP were used here to study the astroglial damage in these regions. Control sections showed a strong labeling for glial fibrillary acidic protein (GFAP) for both antibodies in SNR and BCTX. At 1 day after induction of seizures, labeling with the polyclonal antibodies showed diffuse increase within the lesioned areas and enhanced staining of astrocytes at the border zones. However, staining with the monoclonal antibody was abolished. At 3 days, labeling with both the polyclonal antiserum and the monoclonal antibody was severely reduced within the damaged regions. Reactive astrocytes in the surround of the infarct showed enhanced labeling with both antibodies. This combination of enhanced labeling with polyclonal antibodies and decreased labeling with the specific monoclonal antibody for GFAP can be taken as indicator for acute glial cell damage in seizures and related experimental conditions. PMID- 7851986 TI - Regulation of gene expression in mature oligodendrocytes by the specialized myelin-like membrane environment: antibody perturbation in culture with the monoclonal antibody R-mAb. AB - We have previously shown that the growth of oligodendrocyte progenitors in the presence of a monoclonal antibody (R-mAb) reacting with a cell surface component reversibly blocks their further differentiation at a specific, late progenitor stage of the lineage. This block is characterized by a nearly complete elimination of the onset of terminal differentiation at the level of RNA expression. In the present study, mature oligodendrocytes already expressing markers of terminal differentiation were exposed to R-mAb. This resulted in a retraction of cell processes and the formation of round, swollen cells, and a dose-dependent, antibody-specific partial reduction (30-50%) in the steady state levels of markers of terminal differentiation. Upon removing the perturbing antibody, all markers returned to control levels within 2 days. This inhibition was due to modulations of the levels of the specific mRNAs and proteins, not to cell loss. Total protein and levels of a marker of astrocytic differentiation were not affected by the treatment. Monoclonal antibody O1 did not cause the effects observed with R-mAb. We conclude that the response of terminally differentiating oligodendrocytes to the effects of R-mAb is different from that of oligodendrocyte late progenitors. Whereas the latter appears to operate through perturbation of the onset of gene expression (mRNA transcription and/or stability), the partial down-regulation of previously activated myelinogenic gene expression appears to be due to the loss of a normal, myelin-like, membrane environment needed for the stability of myelin mRNA and protein components. PMID- 7851987 TI - Developmental changes in the number, size, and orientation of GFAP-positive cells in the CA1 region of rat hippocampus. AB - Changes in extracellular potassium concentration as measured with ion-selective microelectrodes revealed abnormally large accumulations in the hippocampus during postnatal development. While rises in [K+]o during stimulation of the Schaffer collaterals were limited to about 12 mM in adult animals, identical stimulations elicited rises to levels as large as 18 mM in juveniles. Since astrocytes are believed to play an important role in K+ homeostasis, we studied the postnatal development of astrocytes in the CA1 region of rat hippocampus in four age groups using a polyclonal antibody against glial fibrillary acidic protein (GFAP). The main proliferation of GFAP-positive cells (GFAPpc) occurred in all laminae between postnatal days 8 and 16. The number of GFAP-positive astrocytes per unit area was reached in stratum lacunosum-moleculare and stratum oriens at about 2 weeks and in stratum radiatum at about 3 weeks of age. During further development -at the age of 24 days--the orientation of individual astrocytes in stratum radiatum became polar with an orientation almost perpendicular to stratum pyramidale. This was revealed by an analysis based on determination of the quotients between the angular orientation of the processes of single individual GFAP-positive cells. When the crossing points of all glial processes over vertical and horizontal grid lines were determined and respective quotients evaluated, the same development towards a perpendicular orientation of astrocytes was noted in stratum radiatum. The same approach revealed a transient orientation parallel to the fissure in stratum lacunosum-moleculare around day 24. Camera lucida drawings of GFAPpc in stratum radiatum revealed that astrocytes became larger during the first three postnatal weeks, followed by a reduction of various parameters (e.g., cell extension, branching pattern) until adulthood. The observed developmental changes of astroglial cells may contribute to the known delayed maturation of potassium regulation in rat hippocampus. PMID- 7851988 TI - Intracellular pH regulation in primary rat astrocytes and C6 glioma cells. AB - We used the pH-sensitive fluorescent dye BCECF to study intracellular pH (pHi) regulation in primary cultures of rat astrocytes and C6 glioma cells. Both cell types contain three pH-regulating transporters: 1) alkalinizing Na+/H+ exchange; 2) alkalinizing Na+ + HCO3-/Cl- exchange; and 3) acidifying Cl-/HCO3- exchange. Na+/H+ exchange was most evident in the absence of CO2; recovery from acidification was Na+ dependent and amiloride sensitive. Exposure to CO2 caused a cell alkalinization that was inhibited by DIDS, dependent on external Na+, and inhibited 75% in the absence of Cl- (thus mediated by Na+ + HCO3-/Cl- exchange). When pHi was increased above the normal steady-state pHi, a DIDS-inhibitable and Na(+)-independent acidifying recovery was evident, indicating the presence of Cl /HCO3- exchange. Astrocytes, but not C6 cells, contain a fourth pH-regulating transporter, Na(+)-HCO3- cotransport; in the presence of CO2, depolarization caused an alkalinization of 0.12 +/- 0.01 (n = 8) and increased the rate of CO2 induced alkalinization from 0.23 +/- 0.02 to 0.42 +/- 0.03 pH unit/min. Since C6 cells lack the Na(+)-HCO3- cotransporter, they are an inferior model of pHi regulation in glia. Our results differ from previous observations in glia in that: 1) Na+/H+ exchange was entirely inhibited by amiloride; 2) Na+ + HCO3-/Cl- exchange was present and largely responsible for CO2-induced alkalinization; 3) Cl-/HCO3- exchange was only active at pHi values above steady state; and 4) depolarization-induced alkalinization of astrocytes was seen only in the presence of CO2. PMID- 7851989 TI - Type II sodium channels in spinal cord astrocytes in situ: immunocytochemical observations. AB - The expression of sodium channel alpha-subunit isoforms in astrocytes in adult rat spinal cord and optic nerve was examined utilizing immunocytochemical methods with antibodies generated against conserved and subtype-specific sequences of the sodium channel. In adult rat spinal cord, astrocytes within the dorsal and ventral funiculi were immunolabelled with antibody SP20, which recognizes a conserved sequence within sodium channel types I, II, and III. In addition, astrocytes within these spinal cord white matter tracts were immunostained with antibody SP11-II, which recognizes sodium channel type II. Antibodies SP11-I and SP32-III, which are directed against subtype-specific sequences in sodium channel types I and III, respectively, did not label astrocytes in the dorsal and ventral funiculi of the spinal cord. In optic nerves, astrocytes were immunostained with antibody SP20. However, no detectable labelling of cells within the optic nerve was observed with antibodies SP11-I, SP11-II, and SP32-III. These observations demonstrate that sodium channel II is expressed by astrocytes in spinal cord white matter. Moreover, these data suggest that regional factors regulate the level of sodium channel isoform expression in astrocytes. PMID- 7851990 TI - Atrial natriuretic peptide-like (ANP-LIR) and ANP prohormone immunoreactive astrocytes and neurons of human cerebral cortex. AB - Atrial natriuretic peptide (ANP) represents a family of related peptides originally isolated from cardiac atria that have potent natriuretic, diuretic, and vasorelaxant properties. ANP has previously been localized in neurons of the rat brain in regions subserving cardiovascular functions and fluid/electrolyte balance and has been localized in astroglia of the canine brain. To determine whether ANP is present in astrocytes of the human brain and to validate the canine model for future studies, human brain tissue was obtained from autopsy cases with no brain damage or neurological or vascular disease. Human brains were obtained less than 3 h postmortem, and anterior cingulate and striate cortices were dissected following perfusion or immersion fixation. Immunohistochemical processing utilized antibodies against the processed form of ANP (ANP IV, ANP104 128) and against rat proANP (amino terminus) and the avidin-biotin-peroxidase technique. Isolated, strongly ANP-immunoreactive protoplasmic astrocytes were observed in all layers of the cingulate and striate cortex gray matter. ANP positive fibrous astrocytes were observed in the white matter. Additionally, distinctive immunopositive astrocytes were found both within and immediately subjacent to the glia limitans. Antibody against the prohormone stained only protoplasmic astrocytes and sublimitans astrocytes and processes. In addition to the astroglia, ANP was detected in scattered multipolar neurons in the cerebral gray matter. These results provide additional evidence for diversity of peptide localization in astrocytes and suggest roles for ANP in the local regulation of cerebral blood flow, blood-brain barrier permeability, or cerebrospinal fluid volume. PMID- 7851991 TI - Comparing perceptions of dental aesthetics in the USA with those in eleven ethnic groups. AB - The Standard DAI is an orthodontic index based on perceptions of dental aesthetics in the USA. The Standard DAI is a regression equation linking perceptions of the social acceptability of dental aesthetics with the objective intraoral measurements of ten occlusal traits. Since the Standard DAI is based on perceptions of dental aesthetics in the USA it can be used without modification only where perceptions of dental aesthetics are similar to those in the USA. This study was designed to determine whether perceptions of dental aesthetics of students in eleven diverse ethnic groups are similar to those of students in the USA. The same 25 stimuli (photographs of dental configurations, a subset of the 200 stimuli used in deriving the Standard DAI equation) were rated for dental aesthetics by Australian, Chinese, German, Japanese, Korean, Latvian, Native American, Singaporean Chinese, Singaporean Indian, Singaporean Malay, and Thai students. Their ratings were compared with the ratings of the same 25 stimuli by students in the USA. Spearman rank-order correlations ranged from 0.84 to 0.94. These correlations are sufficiently high to show that perceptions of dental aesthetics in all eleven ethnic groups are very similar to the perceptions of USA students. Therefore the Standard DAI can be used without modification in all eleven ethnic groups. PMID- 7851992 TI - Nutrition, diet and oral health. Report of an FDI Working Group. PMID- 7851993 TI - Prevalence of caries and dental care status of schoolchildren from urban and rural areas in Araraquara, SP, Brazil. AB - The research reported was carried out to assess the prevalence of caries and dental care status in schoolchildren from urban and rural areas in Araraquara, SP, Brazil. Schoolchildren from an urban area (1,472) and from a rural area (355), aged 7-12 years were examined by two examiners previously trained using the DMFT index. The results showed that the DMFT index was similar in both areas. At 12 years-of-age, the DMFT was 3.8 in urban schoolchildren and 4.0 in rural schoolchildren, considered moderate according to WHO classification. The dental care status was different in the urban and rural areas. In the urban area, 82.9 per cent of the decayed teeth were filled and in the rural area, only 22.1 per cent. The moderate prevalence of dental caries and the high proportion of filled teeth in the urban area suggest that the implementation of primary prevention programmes is necessary, in both, urban and rural populations. PMID- 7851994 TI - Pattern of caries experience among an elderly population in south India. AB - A study was carried out among a population aged 60 years or over in South India. The caries experience, as expressed by the DMFT index, was found to be a mean of 13.51, of which the 'missing' component was 10.98. The sample population had an average of 18.42 teeth present but not one of the 300 individuals interviewed and examined had a tooth filled. Details are given of the teeth most commonly carious and missing. Data are also provided on habits and oral hygiene measures and their effect on the oral health of the elderly in this region. PMID- 7851995 TI - The permanent first molar as an indicator for predicting caries activity. AB - Using a study population in Saudi Arabia, this study recorded the current caries experience in first permanent molars and sought to correlate it with age and overall caries experience. A strong relationship was found between the caries experience of the first permanent molar and the mean DMFT score for the study population, as was a relationship with age of the individual. It is suggested that such a correlation may be helpful in the prediction of caries progression for individuals or groups. PMID- 7851996 TI - A comparison of information recorded using the Thylstrup Fejerskov index, Tooth Surface Index of Fluorosis and Developmental Defects of Enamel index. AB - This study considers information recorded using three different indices of enamel defects/fluorosis. The comparisons were based on photographs of subjects taken in two areas with < 0.1 and with 0.7 ppm fluoride in their drinking water. The three indices used were the Thylstrup Fejerskov index, the Tooth Surface Index of Fluorosis (TSIF) and the Developmental Defects of Enamel (DDE) index. Each was scored by a different examiner. All three indices were able to detect significant differences in opacity/fluorosis prevalence between the two areas. However, it was clear from the results that information collected using these different enamel opacity/fluorosis indices was not directly comparable for individual teeth even though prevalences of defects were similar for two of the indices, the TSIF and the DDE index. PMID- 7851997 TI - A report on compulsory continuing dental education requirements for relicensure. AB - Thirteen FDI National Member countries were surveyed to determine their status relative to compulsory (mandatory) continuing education as a requirement for relicensure. Of the twelve which responded, three have compulsory CDE requirements. Other countries are in the process of considering it. PMID- 7851998 TI - The status of fluoride mouthrinse programmes in Japan: a national survey. AB - The purpose of this investigation was to determine the current status of fluoride mouthrinse programmes throughout Japan. Data collection and analysis took place in 1992. The focus of this study was on schools that were participating in the rinse programme at the time of the survey. Questionnaires were sent by mail to 49 dentist-members of the Association for the Promotion of Fluoride Use in Japan. These members gathered information from the schools and, when necessary, also from local government offices. Starting with a single prefecture in 1970, the rinse programme increased to 32 out of 47 prefectures by 1992. The total number of schools using fluoride mouthrinse was 1,183 (nursery schools and kindergartens 48 per cent, primary schools 46 per cent, and secondary schools 6 per cent). In nursery schools and kindergartens, 60 per cent of the participating schools adopted the daily method using 0.05 per cent NaF solution. In primary and secondary schools, 78 per cent adopted the weekly method using 0.2 per cent NaF solution. The costs for the rinse regimen were paid for by public funds of the prefectural and municipal governments in 71 per cent of the schools. Fifty-four per cent of the schools which first initiated the rinse programmes in their districts identified dentists and dental associations as the most influential in programme acceptance and implementation. Although the number of fluoride rinse programmes is increasing, it is still modest. These results suggest that cooperation between dental organisations, dental schools and prefectural governments can play very important roles in implementing school based rinse programmes. PMID- 7851999 TI - Social pharmacology: unresolved critical issues. AB - This article describes and analyzes decision-making by patients, physicians, and drug information providers about registered medical drugs. Based on a cognitive psychology perspective, cognitive variables (the individual's mediating system) are assumed to be critical factors determining both patient and physician behavior. The individual's psychological functioning is seen as a continuous reciprocal interaction between behavioral, cognitive, and environmental influences; i.e., an interactional paradigm is applied. The importance of research models including cognitive and situation variables to guide the search for appropriate research methods is stressed. An intensive research strategy with a small sample of respondents will often be necessary. Also, respondents should be asked to describe their reactions to specific medical situations. The drug information sender has to select a set of goals for disseminating information to patients. Among the goals most often selected are: message comprehension, receiver satisfaction, changes in knowledge, attitudes, and drug behavior, as well as health effects. More research is needed on how the patient's mediating system, the actual situation, and the perceived situation steer his search for the use of new drug information. A different set of factors influence the patient's decision to start a medicinal or drug treatment than the factors that influence his decision to continue a treatment. The latter factors include forgetfulness, misunderstandings, and the patient's interpretation of physiological signs. More cognitive-oriented research about drug compliance must be undertaken. In such studies the mediating systems of a group of patients could be considered before and after intervention. There are a great number of types of inappropriate (irrational) prescribing. However, a physician may prescribe rationally in one area but irrationally in another. Face-to-face education of physicians has been shown to be effective in reducing inappropriate prescribing in a number of studies. "Overprescribing" of benzodiazepine has been an issue of intensive professional debate during the last decades. The two groups who criticize and defend the existing use of benzodiazepines build their views on different assumptions about the interaction between mind and brain as well as making different value assumptions regarding the use of a psychotropic drug. There is a need for prescription studies where a cognitive and interactional perspective is combined with an information-processing and a normative perspective. The benzodiazepines dependency problem has provoked lively discussion among professionals and the general public. Long-term benzodiazepine use and personality disorders increase the risk of the patient becoming dependent. A great number of research models have been suggested for the analysis of prescription drug dependency and as guides to the treatment of dependency.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7852000 TI - Modifying the process of treatment to meet the threat of AIDS. AB - Treatment for drug users is unlikely to receive sufficient resources to expand to the level of treatment need. Moreover, there is indication that a substantial minority of injection drug users have never initiated needed treatment in spite of long histories of injecting drugs. Given the potential for that population to contract and spread AIDS, it is important that we explore street-based treatment alternatives derived from findings regarding the efficacy of outreach/intervention programs. Those programs were found both to reduce drug taking behaviors of injecting drug users and to prepare those users for clienthood. Additional strategies that need to be explored include: aftercare, behavioral counseling for sex partners of drug treatment clients, and partial (i.e., survival) treatment services for clients who cannot be accommodated within existing treatment capacity. PMID- 7852001 TI - Tennis elbow. Anatomical, epidemiological and therapeutic aspects. AB - Five studies of tennis elbow are presented. Epidemiological studies showed an incidence of tennis elbow between 1 and 2%. The prevalence of tennis elbow in women between 40 and 50 years of age was 10%. Half of the patients with tennis elbow seek medical attention. Local corticosteroid injections were superior to the physiotherapy regime of Cyriax. Release of the common forearm extensor origin resulted in 70% excellent or good results one year after operation and 89% at five years. Anatomical investigations and nerve conduction studies of the Radial Tunnel Syndrome supported the hypothesis that the Lateral Cubital Force Transmission System is involved in the pathogenesis of tennis elbow. PMID- 7852002 TI - The radial tunnel syndrome. AB - The authors present their experience with 35 cases of radial tunnel syndrome, which is caused by compression of the posterior interosseus nerve in the proximal dorsal forearm related to exertion. Chronic aching muscle pain is the problem. Real paralysis is very rare, and is usually considered as a separate entity. The syndrome is often confused with tennis elbow, although the patient may have both problems. The diagnosis remains clinical, and surgical decompression of the nerve in the region of the supinator will give relief in most cases. PMID- 7852003 TI - A method of closed reduction of posterior dislocation of the elbow. AB - A simple and safe method of closed reduction of fresh posterior dislocation of the elbow is described. The method does not require assistance, sedation, traction or significant manipulation. It has succeeded in 90% of dislocations within 24 h of injury. PMID- 7852004 TI - Incomplete rupture of the tendon of triceps brachii. A case report. AB - A 36 year old woman with a history of chronic renal failure secondary to acute glomerulonephritis sustained an injury to the tendon of the triceps brachii in her right arm. Magnetic resonance imaging showed an incomplete rupture of the tendon. The injury was successfully treated conservatively. PMID- 7852005 TI - Comminuted intra-articular fractures of the distal humerus. AB - Seventy-five intra-articular fractures of the distal humerus were treated from 1980 to 1991 in our hospital by open reduction and internal fixation with AO small and mini-fragment instrumentation. Muller's classification into C1, C2 and C3 types was used and the results graded by Burri and Lob's criteria after a minimum follow up of 1.6 years to a maximum of 12 years. Results were satisfactory in 77%, fair in 16% and poor in 7%. The correct indications are important together with anatomical reduction and postoperative physiotherapy. These results are encouraging compared with others previously reported. PMID- 7852006 TI - Osteoarthritis after the Eden-Hybbinette-Lange procedure for anterior dislocation of the shoulder. A 15 year follow up. AB - We have quantified the rate and severity of osteoarthritis after the Eden Hybbinette-Lange procedure. With a mean follow up of 15 years, 44/56 (79%) of operated shoulders showed osteoarthritic changes on radiographic review. Of the contralateral non-operated shoulders the rate of osteoarthritis was 8/60 (8%). Only shoulders in the operated group demonstrated severe osteoarthritis. In our hands the rate of osteoarthritis for the Eden-Hybbinette-Lange procedure is higher than for the Eden-Hybbinette procedure or for rival operations for recurrent dislocation. We recommend careful evaluation of the Eden-Hybbinette Lange procedure. The high rate of late osteoarthritis indicates that other operations with an equally low rate of redislocation may be of greater long term benefit to the patient. PMID- 7852007 TI - Secondary extradural spinal tumours in children. AB - Secondary extradural spinal tumours are very rare, but they comprise most of the extradural neoplasms seen in infancy and childhood. Thirty-nine patients with this type of secondary tumour were treated in our hospital between 1965 and 1991. The diagnosis was proved by biopsy in every case. Following surgical decompression, all 35 survivors had radiotherapy and/or chemotherapy. Their outcome is reported. PMID- 7852008 TI - The Nepalese patuka in the prevention of back pain. AB - The patuka is a special piece of cloth worn around the waist by heavy workers and mountain porters in Nepal. An investigation was carried out to study its role in preventing pain in the back. Observations of intra-abdominal pressure and the lumbosacral compression force confirmed that the patuka might be responsible for the low incidence of back pain in those wearing it. PMID- 7852009 TI - Total en bloc spondylectomy for solitary spinal metastases. AB - We have developed a technique for total en bloc spondylectomy through a posterior approach and now report our experience of 20 patients with a solitary or localised metastasis in the thoracic or lumbar vertebrae. There are two steps: an en bloc laminectomy, followed by en bloc resection of the vertebral body with an oncological wide margin and the insertion of a vertebral prosthesis. Pain was relieved in the 17 patients who could be assessed; 11 of the 15 patients with a neurological deficit were much improved, impending paralysis being prevented in 5 patients. There have been no local recurrences. Nine patients are at present alive with a mean follow up of 17.4 months. PMID- 7852010 TI - Complications of bone lengthening. AB - Bone lengthening is a surgical method which requires meticulous technique, continuous attention, and satisfactory cooperation on the part of the patient. The absence of common criteria makes it difficult both to classify the complications which arise, and to compare them with those of other authors. We report the complications in a group of 61 patients who were studied prospectively. Disorders of the lengthening callus accounted for 45% of all complications, and a further 33% arose in the joints. The remainder occurred in the bone, the apparatus and the soft tissues, of which the most common were stiffness of the joints, axial deviations and loosening of the pins, while articular subluxation, fractures with angulation and delayed consolidation occurred less frequently. In our study, the overall number of complications per lengthening process was 2.1. In bilateral lengthening, the rate was 1 per segment, while in unilateral cases the mean was 2.7. Problems which we defined as severe, requiring that the lengthening had to be halted, occurred in 1.8% of the total complications. The aetiology of the length discrepancy has an important role in the complications which occur in each segment. Over twice as many problems occur in asymmetrical lengthening procedures as in patients where lengthening is symmetrical. PMID- 7852011 TI - Valgus tibial osteotomy in a patient with benign dominant osteopetrosis (Albers Schoenberg disease). A case report. AB - Operation in osteopetrosis, or Albers-Schoenberg disease, needs careful technique because of the brittleness of the bone. We report a patient with autosomal dominant osteopetrosis (MIM 166600)18 and unicompartmental osteoarthritis of the knee which was treated by a valgus tibial osteotomy. Our experience, and a review of the literature, shows that external fixation is a valuable form of treatment because it is noninvasive and ensures perfect interfragmentary compression. PMID- 7852012 TI - Subcapital stress fracture of the femoral neck after total knee arthroplasty. AB - Although total knee arthroplasty is a valuable surgical technique, complications and problems do occur. Associated stress fracture of the femoral neck is relatively rare and we have only found eleven relevant reports. In this paper we present a case of bilateral total knee arthroplasty where three months after the second replacement, and without significant injury, the patient suffered a femoral neck fracture in the limb which had received the first new knee joint. PMID- 7852013 TI - The treatment of progressive coxa vara in children with bone softening disorders. AB - Fractures of the proximal femur frequently occur in children with osteogenesis imperfecta or fibrous dyplasia and may lead to progressive coxa vara and a "shepherds crook" deformity. We have found existing methods of fixation of the femoral neck in small children to be unsatisfactory. We have devised a method of fixation using a small signal arm nail. With a mean follow-up of 9.3 years there was a successful outcome in all 11 hips treated. PMID- 7852015 TI - The effect of shockwaves on mature and healing cortical bone. AB - It has been proposed that high energy shockwaves could be used to create microfractures in cortical bone. This quality might be exploited clinically to perform closed osteotomies and promote healing in nonunion (15). However, no study has previously documented the effect of shockwaves on cortical bone "in vivo". We report an investigation designed to demonstrate the effect of shockwaves on mature cortical and healing bone. An osteotomy was performed on the tibiae of 37 lambs; two weeks later the operation site was exposed to shockwaves. Three weeks later the lambs were killed and specimens of the bone examined histologically and radiographically. Shockwaves had no effect on the periosteal surface of mature cortical bone, but on the endosteal surface some new trabecular bone was seen. Healing of bone was delayed by the shockwave therapy. We conclude that there is currently little place for shockwave treatment in clinical orthopaedics. PMID- 7852014 TI - Surgical prevention of paralytic dislocation of the hip in cerebral palsy. AB - Paralytic dislocation of the hip in cerebral palsy may be prevented by soft tissue surgery and the results of two procedures are reported. Twenty hips were treated by adductor tenotomy alone and this was unsuccessful in every case. An alternative method was carried out in 42 hips in 25 patients. The procedure combined adductor tenotomy with release of the hip muscles including iliac crest resection, tenotomy of the rectus femoris, recession of the iliopsoas and, when necessary, either release or transposition of the knee flexors. This was much more successful in decreasing migration of the femoral head. PMID- 7852016 TI - Systemic diseases in age related cataract patients. AB - Age related cataract is the most common cause of blindness in the world. Most of these patients are elderly and are likely to have various associated systemic diseases. Higher mortality has been reported in patients undergoing cataract surgery. In order to determine the prevalence of associated systemic disease, we carried out a large eye camp based study in 6103 age related cataract patients. Seventeen percent of our patients had systemic problems. Pulmonary disease was seen in 4.3%, cardiovascular disease and hypertension in 4.1%, diabetes mellitus in 3.8%, skin disorder in 1.4%, orodental disease requiring tooth extraction in 3%, and other diseases were seen in 0.4% of the cases. Seventy eight patients (1.27%) had significant systemic complications post-operatively, 46% of whom required hospitalization in a tertiary care center. Thus, all patients undergoing cataract surgery should be evaluated for associated systemic diseases to prevent morbidity and mortality in the preoperative, operative and postoperative period. PMID- 7852017 TI - Fuch's heterochromic cyclitis and HLA histocompatibility antigens. AB - Genetic typing of class I major histocompatibility complex (MHC) antigens (HLA-A, -B and -C) was performed in 22 patients with Fuch's heterochromic cyclitis (FHC) and in a control group of 339 healthy subjects in order to ascertain whether there are any genetic factors that protect against or increase the risk of developing this disease. The frequency of only one HLA-antigen was found to differ significantly in the patients with FHC as compared with the normal subjects: HLA-A2 had a negative association with FHC (9.09% in FHC verus 47.47% in the control group; p < 0.01, Fisher's exact test with correction for the number of antigens studied) with an odds ratio of 0.11 (95% confidence limits 0.03 and 0.50). Other HLA antigens also showed a negative or positive association with FHC but not to a statistically significant level. Our results suggest a possible role for HLA genetic factors in the pathogenesis of FHC. PMID- 7852018 TI - Anatomical and functional choroidal lobuli. AB - The purpose of this paper is to clarify the controversy between anatomists and clinicians regarding the choroidal angioarchitecture. Vascular casts from 36 human and 10 Rhesus monkey eyes were studied using scanning electron microscopy (SEM). Both the human and monkey choriocapillaris (CC) are non-homogenous structures. They have patterns which change from the peripapillary to peripheral areas. Anatomically, the 'lobular' appearance of the CC exists only in part of the posterior pole. One or more collecting venules were found in the center of 86% of the anatomical lobules, while a central feeding arteriole was observed in 14%. Both major and minor feeding arterioles supply the CC areas which may be recognized as the choroidal functional vascular unit (CFVU) or functional lobule described in the past by Hayreh. Our vascular casts and SEM study show that the choroidal anatomical lobuli are not identical with those observed by angiographical study. Thus, two distinct models of choroidal lobuli, anatomical and functional, should be recognized. The CFVU seen on fluorescein (FA) and indocyanine green (ICG) angiographies as a lobular appearance is most likely caused by the pressure gradient of the blood flow. PMID- 7852019 TI - Pneumatic retinopexy with drainage of subretinal fluid. AB - Thirty bullous retinal detachments were treated with pneumatic retinopexy and drainage of subretinal fluid. Patient selection criteria were similar to pneumatic retinopexy. All the eyes were reattached after the first operation. In three (10%) eyes new breaks with retinal detachment developed within two months after the initial operation and were treated with scleral buckling. One of these three eyes developed proliferative vitreoretinopathy grade D3 two months after scleral buckling. Twenty-nine (96.7%) out of thirty eyes were eventually reattached. The follow-up period was at least nine months. Visual acuity was maintained or improved in 29 (96.7%) eyes. Complications developing due to subretinal fluid like extension of detachment, persistence of subretinal fluid, subretinal gas, reopened retinal breaks were not encountered. By applying cryotherapy to a reattached retina after drainage of subretinal fluid, retinal pigment epithelial dispersion is decreased and the so-called steamroller technique is avoided. Drainage of subretinal fluid did not prevent a good success rate and did not result in additional complications. PMID- 7852020 TI - Orbital-tuberculosis. AB - Three cases of orbital tuberculosis are presented, two as cold abscess in the orbit and one as a chronic indolent sinus. A simple clinical test like Fine Needle Aspiration Cytology (FNAC) can demonstrate some or all of the characteristic pathological features like caseating necrosis, epitheloid cells and Langhan's giant cells. Important corroborative evidence can be obtained from the Tuberculin test and a positive therapeutic trial. While there are many other causes or orbital swelling and abscess, tuberculosis should be considered an important differential diagnosis in endemic areas. Simple tests like the tuberculin reaction and Fine Needle Aspiration Cytology should be considered among the routine diagnostic investigations for orbital swellings. PMID- 7852021 TI - Trabecular aspiration: a new surgical approach to improve trabecular facility in pseudoexfoliation glaucoma. AB - The main reason for elevation of intraocular pressure in pseudoexfoliation glaucoma is due to secondary plugging of the intertrabecular spaces by pigment and fibrillous material. The aim of the present study was to introduce a new surgical concept to clean trabecular meshwork in pseudoexfoliative glaucoma. 'Trabecular aspiration' was performed under the operating microscope prior to extracapsular cataract extraction in half of the chamber angle circumference using a specially designed irrigation-aspiration device. The hand-held instrument has three outlets, one for aspiration (400 microns wide and 45 degrees horizontally angulated to meet the slope of the meshwork) and two openings (650 microns) for irrigation to maintain a deep anterior chamber and to keep the iris away from suction. Trabecular debris and pigment was cleared with a suction force of 100-200 mmHg. The effect of trabecular aspiration was cross-checked by analysing the aspirate. Pigment granules, fibrillous protein and other forms of trabecular debris were identified in the aspirate using light- and scanning electron microscopy. The morphological analysis of the trabecular aspirate clearly indicates the efficacy of 'trabecular aspiration' for removing pre- and intratrabecular debris. The clinical relevance of this new procedure looks promising, a clinical trial, recently initiated, is warranted. PMID- 7852022 TI - Excimer laser photoablative filtration surgery: histology and ultrastructure in 4 human cadaver eyes. AB - The purpose of this study was to verify the feasibility of ab externo layer-by layer excimer laser photoablative removal of limbal tissue down to the trabecular meshwork and to assess the damage caused by this procedure to the neighbouring structures. Excimer laser photoablation (193 nm) can remove layers of corneal tissue effectively with little or no damage to the adjacent areas. Previous experimental studies have demonstrated a decrease in outflow resistance after ab externo photoablative removal of juxtacanalicular tissue. We have performed ab externo photoablative removal of limbal tissue overlying the trabecular meshwork in four freshly enucleated eyes from our Eye Bank. The beam of an excimer laser (wavelength 193 nm; fluence 180 mJ/Sq.cm) was shaped using a metal mask with a rectangular opening of 1.2 x 2.5 mm. After removing the conjunctiva, photoablation was carried out at maximum surgical microscope magnification (40 x) until trabecular meshwork appeared at the bottom of the crater. Light microscopy showed that craters had smooth walls and their base reached the Schlemm's canal area; all structures appeared of normal morphology. Transmission electron microscopy showed a thin layer of amorphous material or pseudomembrane on the side walls of the crater; corneoscleral collagen fibers were abruptly interrupted and undistorted. At the bottom of the crater the trabecular meshwork and Schlemm's canal tissues appeared normal. PMID- 7852023 TI - The progressive outer retinal necrosis syndrome. AB - The progressive outer retinal necrosis (PORN) syndrome is a recently described clinical variant of necrotizing herpetic retinopathy in patients with the acquired immunodeficiency syndrome (AIDS). It is caused by varicellazoster virus infection of the retina. Its course and clinical features distinguish it from the acute retinal necrosis syndrome and CMV retinopathy. Early disease is characterized by multifocal deep retinal opacification. Lesions rapidly coalesce and progress to total retinal necrosis over a short period of time. Despite aggressive therapy with intravenous antivirial drugs, prognosis is poor; disease progression and/or recurrence is common, and the majority of patients develop no light perception vision. Total retinal detachments are common. Prophylaxis against retinal detachment using laser retinopexy has not been useful in most cases. PORN syndrome is an uncommon, but devastating complication of AIDS. PMID- 7852024 TI - Occlusion of the retinal vasculature after trabeculectomy with mitomycin C. AB - A 45-year-old male underwent a trabeculectomy with mitomycin C for a secondary glaucoma after complicated cataract surgery. Because of early bleb failure a needling procedure with subconjunctival injection of mitomycin C was performed. Five days postoperatively the patient developed an occlusion of both the arterial and venous retinal vasculature. A relation between the diffusion of mitomycin C into the vitreous cavity and the development of retinal toxicity is suggested. PMID- 7852026 TI - Portable scope, stand ideal for mission trips. PMID- 7852025 TI - Nuclear magnetic resonance spectroscopy. Principles and applications in neuroophthalmology. AB - Magnetic resonance spectroscopy is a valuable method for the non-invasive investigation of metabolic processes and can now be combined with conventional magnetic resonance imaging in patients. This article gives a brief introduction into the principles and physiological and clinical applications of in vivo proton magnetic resonance spectroscopy, surveys experiences in healthy volunteers and presents exemplary results in patients suffering from cortical blindness or visual field defects. The causes of visual loss include brain trauma, cerebral ischemia, and brain tumors. In traumatic, ischemic and neoplastic lesions, an important spectral finding is an elevated lactate resonance which has been explained by increased anaerobic glycolysis of ischemic brain tissue and macrophages invading necrotic tissue. In our investigations using a clinical spectroscopy protocol on a 1.5 T MR system, a significant lactate signal was absent in spectra obtained from the visual cortex of normal volunteers, even during photic stimulation with a stroboscope. Other spectral changes in the patients include a decreased N-acetyl-aspartate resonance which indicates a decreased number of viable neurons in the examined brain region. PMID- 7852027 TI - Gastric arteriolar and venular responses to nitrogenous and nonnitrogenous vasodilating agents in the rat. AB - We made in vivo microvascular observations to simultaneously compare the actions of various direct vasodilators on the resistance and capacitance vessels without confounding systemic hemodynamic effects. The responses of gastric submucosal arteriolar and venular diameters to the topical application of 10(-7) 10(-5), and 10(-3) M of the vasodilators nitroglycerin (NTG), sodium nitroprusside (SNP), hydralazine (HYD), and adenosine (ADN), and acetylcholine (ACh) were studied in 6 rats for each agent using in vivo microscopy. The basal diameters of arterioles, 37 +/- 2 microns (mean +/- SE), were maximally dilated to 86 +/- 2 microns by 10( 3) M ADN, NTG, SNP or ACh, while with 10(-3) M HYD dilation was just 55%. The basal diameters of venules, 36 +/- 2 microns, were maximally dilated only to 51 +/- 1 micron by 10(-3) M ADN, NTG or SNP, while those by 10(-3) M HYD and ACh were 60 and 71%, respectively. We observed that: (1) NTG and SNP were the strongest arteriolar and venular dilators, but at low dose (10(-7) M), NTG was more effective than SNP. (2) Gastric submucosal venules had considerably less dilating capacity than arterioles. (3) ADN was as effective as NTG and SNP for both arteriolar and venular dilation at 10(-3) M. It was less potent at lower concentrations. (4) ACh was as potent as ADN, NTG and SNP in dilating arterioles, but it was notably less potent in dilating venules. (5) HYD was the weakest arteriolar and venular dilator among all agents studied, and its action on venules was slightly greater than that on arterioles. PMID- 7852028 TI - L-arginine restores cholesterol-attenuated microvascular responses in the rat cremaster. AB - The role of L-arginine in the reversal of cholesterol-induced endothelial dysfunction was studied in the cremaster muscle microcirculation. In vivo television microscopy was used to measure microvascular diameters and macromolecular leakage. Male Sprague-Dawley rats were fed either a normal chow diet or a diet supplemented with 1% cholesterol and 0.5% cholic acid for 3 weeks prior to in vivo experimentation. The cholesterol diet caused a decreased third order arteriole dilator response to both acetylcholine and serotonin. This decreased responsiveness occurred in the presence of a higher plasma concentration of L-arginine and an increased ratio of L-arginine to its metabolite L-citrulline. The attenuation to both agonists was reversed by intravenous infusion of the nitric oxide precursor L-arginine (30-mg/kg bolus and 10-mg/kg/min continuous infusion). The cholesterol diet also decreased the postcapillary macromolecular leakage response to serotonin, and again this effect was reversed by L-arginine infusion. D-Arginine infusion had no restorative effect with either agonist in the cholesterol animals. Further experimentation with the nitric oxide production inhibitor N omega-nitro-L-arginine methyl ester demonstrated an inhibition of aretriolar dilation to acetylcholine, but there was no inhibition of dilation or macromolecular leakage to serotonin. Thus, it is probable that serotonin-induced leakage as well as dilation was not caused by stimulation of nitric oxide. These results suggest that L-arginine restores both nitric oxide-dependent and -independent dilation as well as macromolecular leakage in cholesterol-fed rats.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7852029 TI - Increased hyaluronan flux in canine paw lymph is induced by histamine and the histamine-releasing agent compound 48/80. AB - The present experiments investigated hyaluronan (HYA) flux from skin of pentobarbital anesthetized mongrel dogs when transcapillary fluid flux was increased by local intraarterial injection of histamine (50 micrograms) or Compound 48/80 (C48/80) (100 micrograms) inducing mast cell degranulation. A prenodal lymphatic draining the hindpaw was cannulated and the paw flexed passively at 50 times/min. Grand mean (n = 18) of control lymph flow and HYA concentration was 16 +/- (SD) 14 microliters/min and 8.8 +/- 2.3 micrograms/ml, respectively. Lymph flow increased 11- and 15-fold within 10 min after histamine and C48/80 injection, respectively, and returned to control values after 3 h for histamine while it did not return fully in the C48/80 group. HYA concentration decreased by 30 and 40% during the first hour after histamine and C48/80, respectively, while HYA flux increased 11-15 times control. Control experiments (saline vehicle) showed an unexpected and gradual increase in HYA concentration during the 8-hour experimental period, regardless of unchanged lymph flow. This increase became statistically significant at the end of the experimental period, suggesting either an increased synthesis or increased rate of release of bound HYA from the paw. The present data show that HYA is loosely bound and easily mobilized from the interstitial matrix and that histamine and C48/80 cause a release of bound HYA from the interstitium. An increase in HYA concentration towards the end of the 8-hour experimental period most likely represents an increased synthesis of HYA. PMID- 7852030 TI - Microvessel diameters of human colon adenocarcinoma during acute treatment with serotonin. AB - Modulation of tumor blood flow could be of clinical importance, especially when it is combined with radio- or chemotherapy. Serotonin (5-HT), a naturally occurring agent, selectively reduces tumor blood flow and consecutively inhibits the growth of many animal tumors. Therefore, we introduce a new preparation that allows the study of topically applied 5-HT (10(-8) to 10(-2) mol/l) in the microcirculation of a human colon adenocarcinoma. This tumor has been xenotransplanted subcutaneously under the dorsal surface of the ear in athymic nude mice. 5-HT was also tested in the normal skin. The microvascular diameters of large and small arterioles (A1-3) and venules (V1-4) as well as capillaries were measured via closed-circuit videomicroscopy. Normal skin arterioles and venules constricted at higher doses (> 10(-7) mol/l) of 5-HT. In human colon carcinoma, doses of 5-HT higher than 10(-7) mol/l caused constriction of these microvessels; yet, tumor arterioles constricted more than skin arterioles. Thus, 5-HT could selectively reduce blood flow of human colon adenocarcinoma. Based on these findings, we suggest that 5-HT can inhibit growth of human tumors by selectively constricting tumor arterioles. PMID- 7852031 TI - Effect of levofloxacin and ciprofloxacin injection on permeability of the tail vein in mice and skin microvasculature in rats. AB - We examined the effects of levofloxacin (LVFX) and ciprofloxacin (CPFX) on the permeability of the tail vein in mice and skin microvasculature in rats after a single intravenous and intracutaneous injection, respectively, with 125I-human serum albumin. In addition, the effect of an H1 histamine antagonist, diphenhydramine, on the hyperpermeability induced by quinolone injections was examined, and the injections were also performed into the tail vein of WBB6F1 (mast cell-deficient) mice. LVFX and CPFX significantly increased the permeability of the mouse tail vein at injection concentrations of 0.2% and 0.05% of more, respectively, and both quinolones increased the permeability of rat skin microvasculature by 0.5% or more. Diphenhydramine concomitantly injected with quinolones completely blocked the hyperpermeability induced by LVFX and CPFX at 0.5% in the mouse tail vein and rat skin microvasculature. Neither quinolone increased the tail vein permeability in WBB6F1 mice. These results suggest that LVFX and CPFX increase vascular permeability through the induction of histamine release from mast cells in rodents. PMID- 7852032 TI - Alteration of structural order of human erythrocyte ghost membrane by glucocorticoids and the influence of the glucocorticoid receptor antagonist RU 486. AB - High-dose pulse glucocorticoid therapy has been used successfully in the clinic in severe pathological conditions for about 20 years. The mode of glucocorticoid action after administration of such megadoses is inexplicable up to now. It is supposed that some effects may be due to membrane alterations. In the present in vitro experiments the effect of dexamethasone, of further glucocorticoids, and of the glucocorticoid receptor antagonist RU 486, on structural order of human erythrocyte ghost membranes was investigated by determining the steady-state fluorescence anisotropy of diphenylhexatriene (DPH). Dexamethasone was found to induce a significant decrease in membrane structural order at concentrations of about 10(-6) M in a concentration-dependent manner. We found a correlation between the uptake of dexamethasone by the ghost membranes and the decrease in the structural order. The other glucocorticoids tested, methylprednisolone and corticosterone, were also effective at concentrations of 10(-5) M or greater. We observed no change in membrane structural order with RU 486 up to a concentration of 10(-4) M. However, simultaneous incubation of RU 486 with dexamethasone caused a distinct interference of RU 486 with dexamethasone. Thus, the glucocorticoid induced membrane perturbation, the possibility to inhibit it by RU 486, and the inactivity of the structurally related progesterone, refer to relatively specific binding sites for the glucocorticoids in the membrane of erythrocyte ghosts. PMID- 7852033 TI - Protection of beta-thalassaemic erythrocytes from oxidative stress by propionyl carnitine. AB - Susceptibility to oxidative stress is increased in erythrocytes of patients with beta-thalassaemia due to the free alpha-chain pool and to the excess of iron. We have investigated the effect of L-propionylcarnitine concentrations on oxidative stress determined by lactoperoxidase-hydrogen peroxide-iodide and by xanthine oxidase-acetaldehyde on erythrocytes of patients with beta-thalassaemia (major and intermedia). L-propionyl carnitine protects the erythrocytes from oxidative stress as measured by cell lysis. The protection is concentration-dependent. L propionyl carnitine also stabilizes the cell membranes in which a latent peroxidative damage has been produced. These data suggest that L-propionyl carnitine may prove beneficial in protecting in vivo patients in which peroxidative damage of cell structure is increased as in the case of beta thalassaemic patients. PMID- 7852034 TI - Antiinflammatory effect of superoxide dismutase (SOD). Comparison between yeast and bovine SOD on some complement-mediated reactions in vitro and in vivo. AB - The effect of CulZn superoxide dismutases from yeast cells (SODy) and commercial SOD from bovine erythrocytes (SODb) on zymosan-induced inflammation in mice and on complement activity in normal human serum (NHS) was studied. Zymosan-induced oedema formation was moderately suppressed by SODb. The alternative pathway (AP) activity in mouse serum was strongly inhibited after i.p. treatment with SODy. Comparison between the two enzymes showed different mode of action on the classical pathway (CP) as compared to the AP of complement activation. The inhibitory effect caused by SODy was more pronounced and strongly time- and temperature-dependent. SODy affected several activation steps in the complement cascade, while the inhibition caused by SODb was mainly directed to C1 of the complement activity. The powerful action of SODy on AP activity may be attributed to the oligosaccharide moiety in the enzyme molecule from yeast origin. PMID- 7852035 TI - Histology of postmortem changes in rat livers to ascertain hour of death. AB - Postmortem changes in hepatic tissues of male rats kept at 3 different temperatures after death (room temperature at 23 degrees C, body temperature at 37.5 degrees C, and cool temperature at 5 degrees C) were examined in relation to the hour of death. The time of occurrence and the degree of histological postmortem changes in the liver were found to differ depending on the temperature at which the body was kept (5 degrees C < 23 degrees C < 37.5 degrees C). There was a reduced stainability of erythrocytes, atrophy of hepatocytes, sinusoidal dilatation and karyopyknosis of endothelial or Kupffer cells, after 48 h at 5 degrees C. These observations were made after 3-5 h in tissues of rats kept at 37.5 degrees C, as compared to 12 h at 23 degrees C. Atrophy of hepatocytes and sinusoidal dilatation were prominent in the subcapsular region. In epithelia of the interlobular bile ducts (IBD), swelling of nuclei and karyopyknosis with an eosinophilic cytoplasm were evident. Electron microscopy revealed that the former change was heterogeneity of nucleoplasm and peripheral localization of nuclear chromatin with coagulative cytoplasmic organelles, and the latter was atrophy of nuclei with cytoplasm, including disruption and disappearance of organelles. The time course of these findings in dead rats kept at different temperatures suggests that postmortem changes of epithelial nuclei of IBD progressed from swelling to karyorrhexis (disappearance) via karyopyknosis. The frequency of karyopyknosis with an eosinophilic cytoplasm of IBD epithelia (positive cells) at 37.5 degrees C increased rapidly up to 5 h after death, and decreased extensively after 12 h. At 37.5 degrees C, the frequency of positive cells increased constantly up to 24 h, in accordance with hour of death. At 5 degrees C, the frequency of positive cells increased slowly up to 48 h, and the majority of epithelia showed positive changes at 72 h. The frequency of cells positive for karyopyknosis and eosinophilic cytoplasm can serve as one marker for estimating the hour of death. PMID- 7852036 TI - Evaluation of calcitonin-gene related peptide on haemodynamics of isolated perfused rat kidney. AB - Outside the central nervous system, calcitonin-gene-related peptide (CGRP) plays an important role in the control of regional blood flow. The present authors studied the renal haemodynamic effects of CGRP in the model of isolated perfused rat kidney (IPRK). This experimental model avoids the complex feed-back mechanisms activated by any modification of renal perfusion pressure. It was found that the infusion of CGRP in the IPRK induced a marked decrease of perfusion pressure; this vasoactive effect is well measured by the glomerular morphometric analysis that shows a striking increase in the glomerular diameter and volume. PMID- 7852037 TI - Tumor blood flow measured using dynamic computed tomography. AB - RATIONALE AND OBJECTIVES: A method for measuring the tumor blood flow (TBF) by means of dynamic computed tomography (DCT) was devised and investigated. METHODS: Twenty-seven patients with superficial tumors underwent measurement of TBF by the new DCT method. For all of the 27 patients, the thermal clearance method was employed to measure the relative tumor blood flow (RTBF). For 16 patients, TBF was measured by oxygen-15-gas positron-emission tomography (PET). The TBF values measured by DCT were compared with the RTBF by the thermal clearance method and the TBF by PET. RESULTS: The results demonstrated a linear relationship. CONCLUSIONS: The newly devised DCT method yields reliable data in measuring TBF. PMID- 7852038 TI - Coronary microvascular responses after exposure to iodinated contrast media. AB - RATIONALE AND OBJECTIVES: Iodinated contrast media can cause a number of well described acute hemodynamic and vascular effects including vascular spasm, hypotension, and arrhythmias. Coronary microvessels were studied in vitro after high-dose exposure to an ionic, high-osmolar contrast agent diatrizoate meglumine in vivo. The aim of this study was to examine the endothelium-dependent and endothelium-independent vasodilator responses of the microvessels after previous contrast media administration in a clinically relevant setting. METHODS: Left coronary angiography was performed on six pigs using a cumulative dose of 60 mL (5 mL/injection) of diatrizoate meglumine. After 1 hour of reperfusion, epicardial coronary microvessels were studied in vitro in a pressurized, no-flow state with video microscopy. The vasodilators bradykinin, calcium ionophore A23187, and sodium nitroprusside were sequentially applied extraluminally after preconstriction. Serotonin and the thromboxane A2 analog U46619 were studied without preconstriction. RESULTS: Microvessels exposed to diatrizoate meglumine had normal relaxation responses to the endothelium-dependent vasodilators bradykinin and calcium ionophore A23187 when compared to control vessels. The vasoconstrictor responses to U46619 and serotonin were not significantly altered compared to control vessels. Responses to the endothelium-independent vasodilator sodium nitroprusside were not reduced or were slightly enhanced after exposure to contrast media. CONCLUSION: Coronary resistance vessels responses to the endothelium-dependent vasodilators bradykinin and calcium ionophore A23187 are not diminished after previous exposure to diatrizoate meglumine. The vasoconstrictor responses to U46619 and serotonin were similarly unaffected by previous exposure to contrast media. This suggests that, when used in clinically relevant amounts, diatrizoate meglumine does not cause functional endothelium or vascular smooth muscle impairment. PMID- 7852039 TI - Acute toxicity of lipiodol infusion into the hepatic arteries of dogs. AB - RATIONALE AND OBJECTIVES: The authors studied the acute toxicity of percutaneous transcatheter hepatic artery infusion of iodized poppy oil fatty acid ester (Lipiodol, Laboratoire Guerbet, Aulnay-sous-Bois, France). METHODS: Lipiodol dosages of 0, 0.25, 0.5, 1.0, and 2.0 mL/kg were infused into the hepatic arteries of 10 beagles. Enzymatic and radiographic alterations were assessed. RESULTS: After the infusion of Lipiodol, the dogs showed body weight loss and hypoalbuminemia attributable to decreased food intake, transient elevation of the aspartate transaminase and alanine transaminase, and continuous increase in alkaline phosphatase. The controls did not show any significant change. The radiographs obtained immediately after and 2 weeks after the infusion showed dose dependent accumulation of Lipiodol in the liver. After 2 weeks, histologic examination of livers and lungs showed dose-dependent (r = .9) retention of oily droplets in sinusoids and pulmonary capillaries. Interlobar pericholangitis was found in four dogs infused with Lipiodol. Pulmonary inflammatory reaction was observed with capillary oil embolism. Oil droplets also were found in the pancreas and the brain. CONCLUSIONS: Lipiodol infusion of the hepatic artery resulted in dose-dependent circulation and embolism of Lipiodol droplets via sinusoids and via pulmonary capillaries into the systemic circulation. PMID- 7852040 TI - Binary nature and radiographic identifiability of craniosynostosis. AB - RATIONALE AND OBJECTIVES: Two independent gold standards and diagnoses from three dimensional computed tomography (CT) images were used to examine the possibility that craniosynostosis is a binary abnormality that potentially may be diagnosed without error. METHODS: Surgical reports, histology of excised sutures, and three dimensional CT images were compared for 25 children undergoing surgical management of craniosynostosis. Surgical reports identified sutures as normal or abnormal. Histology reported suture closure on a 5-point scale. Four radiologists used three-dimensional CT images to diagnose sutures on a 6-point rated response scale. RESULTS: Sutures with histology 0, 1, or 2 were normal on surgical reports, and those with histology 3 or 4 were abnormal. Most readers achieved nearly perfect sensitivity and specificity. Reader confidence was unrelated to degree of pathology. CONCLUSION: Craniosynostosis appears to be binary in our sample. Surgical reports, pathology results, and three-dimensional CT images read by experienced viewers achieved nearly perfect agreement. PMID- 7852041 TI - The usefulness of a contrast agent and gradient-recalled acquisition in a steady state imaging sequence for magnetic resonance imaging-guided noninvasive ultrasound surgery. AB - RATIONALE AND OBJECTIVES: The ability of magnetic resonance imaging to detect small temperature elevations from focused ultrasound surgery beams was studied. In addition, the value of a contrast agent in delineating the necrosed tissue volume was investigated. MATERIALS AND METHODS: Gradient-recalled acquisition in a steady state (GRASS) T1-weighted images were used to follow the temperature elevation and tissue changes during 2-minute sonications in the thigh muscles of 10 rabbits. The effects of the treatment on the vascular network was investigated by injecting a contrast agent bolus before or after the sonication. RESULTS: The signal intensity decreased during the sonication, and the reduction was directly proportional to the applied power and increase in temperature. The signal intensity returned gradually back to baseline after the ultrasound was turned off. Injection of the contrast agent increased the signal intensity in muscle, but not in the necrosed tissue. The dimensions of the delineated tissue volume were the same as measured from the T2-weighted fast-spin-echo images and postmortem tissue examination. CONCLUSIONS: These results indicate that magnetic resonance imaging can be used to detect temperature elevations that do not cause tissue damage and that contrast agent can be used to delineate the necrosed tissue volume. PMID- 7852042 TI - Bayesian restoration of chest radiographs. Scatter compensation with improved signal-to-noise ratio. AB - OBJECTIVES: The authors introduce a Bayesian algorithm for digital chest radiography that increases the signal-to-noise ratio, and thus detectability, for low-contrast objects. METHOD: The improved images are formed as a maximum a posteriori probability estimation of a scatter-reduced (contrast-enhanced) image with decreased noise. Noise is constrained by including prior knowledge of image smoothness. Variations between neighboring pixels are penalized for small variations (to suppress Poisson noise), but not for larger variations (to avoid affecting anatomical structure). The technique was optimized to reduce residual scatter in digital radiographs of an anatomical chest phantom. RESULTS: The contrast in the lung was improved by a factor of two, whereas signal-to-noise ratio was improved by a factor of 1.8. Image resolution was unaffected for objects with a contrast greater than 2%. CONCLUSION: This statistical estimation technique shows promise for improving object detectability in radiographs by simultaneously increasing contrast, while constraining noise. PMID- 7852043 TI - Functional imaging of changes in human intrarenal perfusion using quantitative dynamic computed tomography. AB - RATIONALE AND OBJECTIVES: Quantitative dynamic computed tomography was used with perfusion imaging to characterize intrarenal variations in perfusion in normal and abnormal human kidneys. METHODS: Perfusion images were obtained from 14 normal and four abnormal kidneys, comprising a renal tumor, an infarcted renal allograft, and two kidneys in a patient with cyclosporin toxicity. RESULTS: Images demonstrating quantifiable intrarenal variations in perfusion were consistently obtained. Normal cortical and medullary perfusion were 4.7 mL/min/mL and 1.1 mL/min/mL, respectively, consistent with accepted normal ranges. The changes in the abnormal kidneys corresponded with known pathophysiology. CONCLUSION: Computed tomography perfusion imaging creates quantifiable images of renal perfusion with a spatial resolution currently higher than any other functional imaging technique. It offers the opportunity to characterize renal diseases by their relative effects on cortical and medullary perfusion. PMID- 7852044 TI - Hepatic interstitial laser photocoagulation. An investigation of the relationship between acute thermal lesions and their sonographic images. AB - OBJECTIVES: The relationship between hepatic interstitial laser photocoagulation (ILP) lesions and their acute ultrasound images was evaluated. In addition, the natural history of ILP lesions in normal pig liver was documented. METHODS: Eighteen pigs underwent laparotomy and ultrasound-monitored ILP. In part 1 of the study, 12 pigs each had four separate exposures (1.50 W for 60, 100, 300, and 500 seconds) and were divided into four groups according to when they were killed (0, 3, 7, and 21 days). In part 2 of the study, six pigs each had two sequential exposures (1.60 W for 1,000 and then 500 seconds) at separate hepatic sites. Survival time was 3 days. Necropsy and histologic examination were performed in all animals. In 0- and 3-day survivors, actual thermal lesions were compared with "early" (immediately after ILP) and "late" (1 hour after ILP) ultrasound images. RESULTS: In the 300-, 500-, and 1,000-second exposures of parts 1 and 2, thermal lesions were overestimated or approximated by early ultrasound and were underestimated or approximated by late ultrasound. Analysis of variance showed statistically significant differences between thermal lesions and their early and late ultrasound images (F = 18.6, P < .001, no interactions). Time-growth characteristics of ILP lesions were reasonably consistent on ultrasound; exceptions were identifiable 200 seconds into the exposure. In part 2, ultrasound changes were minimal in five of six 500-second (second sequential) technically satisfactory exposures. Thermal lesions were seen at necropsy. All lesions healed by formation of granulation tissue and collagen. CONCLUSIONS: During ILP, early ultrasound images frequently overestimate actual thermal lesions. Ultrasound monitored ILP of tumors may be most effective if, on early ultrasound, echogenic changes extend beyond the tumor margins. Late ultrasound images underestimate or approximate thermal lesions. Their value in clinical ILP should be investigated. It is unclear why ultrasound images of proven thermal lesions were not seen during 5 of 6 otherwise satisfactory 500-second ILP exposures performed immediately after 1,000-second exposures. PMID- 7852045 TI - Statistical concepts in the interpretation of serial bone densitometry. AB - The precision of a measurement can be expressed as the variance of multiple measurements. The coefficient of variation is a dimensionless expression of precision that is prevalent in the radiology literature. However, the coefficient of variation has important limitations. The question whether measured change is significant arises whenever any quantitative clinical parameter is followed over time. When serial bone mineral density measurements are made, change is commonly estimated as the slope of a line fitted to the serial data by linear regression. Confidence intervals for change based on this method usually assume that the precision error in measurement remains constant over time and that change is truly linear. Estimates of long-term precision may be elusive, and if constant, may vary for different individuals. If separate measurement precisions are known or are indeed constant, one can assess the level of statistical agreement of longitudinal data to linear, or other theoretical, models. PMID- 7852046 TI - The use of ultrasound mean acoustic attenuation to quantify bone formation during distraction osteogenesis performed by the Ilizarov method. Preliminary results in five dogs. AB - RATIONALE AND OBJECTIVES: Management of distraction during Ilizarov limb lengthening remains primarily clinical and empirical. Estimates of tissue acoustic attenuation were evaluated for their ability to quantify bone formation within the distraction gap. METHODS: Five dogs had tibias lengthened by the method of Ilizarov. Mean acoustic attenuation measurements at multiple positions across the distraction gap were compared with corresponding x-ray computed tomography attenuation measurements. RESULTS: Computed tomography and ultrasound attenuation displayed similar quantitative behavior across the gap. Linear correlation between them ranged from R2 = .878 to R2 = .131. Fibrous interzone width estimates based on computed tomography and ultrasound attenuation measurements were correlated, based on our preliminary data with R2 = .519. These estimates are independent of the width of distraction. CONCLUSIONS: Ultrasound parallels computed tomography as a measure of bone formation within the distraction gap. Future studies are needed to improve acoustic attenuation data acquisition techniques and to evaluate their potential as a tool for optimizing early distraction rates in patients at risk for rate-related complications. PMID- 7852047 TI - Chest mass in a patient with leukemia with hemoptysis. PMID- 7852048 TI - Cardiac allografts in rat recipients with simultaneous use of anti-ICAM-1 and anti-LFA-1 monoclonal antibodies leads to accelerated graft loss. AB - Cardiac allografts from Fisher rats underwent acute rejection in Wistar King Aptekman/Hokkaido (WKAH) recipient rats. ICAM-1 molecule was induced in grafted myocytes and interstitial cells during the rejection. LFA-1 (+) inflammatory cells heavily infiltrated into rejected allografts. Monoclonal antibodies to rat ICAM-1 or LFA-1 were administered intravenously to WKAH rats receiving Fisher cardiac allografts for 3-7 consecutive days after transplantation. Anti-LFA-1 treatment for 7 consecutive days prolonged allograft survival, and two of these obtained a long-term survival. While 2 out of 13 allografts survived more than 100 days in the anti-ICAM-1-treated groups, anti-ICAM-1 treatment did not affect allograft survival in the other recipients. Surprisingly, simultaneous use of both anti-ICAM-1 and anti-LFA-1 antibodies resulted in accelerated graft loss with interstitial edema, diffuse myocardial degeneration, vascular injury and scattered hemorrhage. Thus, beneficial effects on allograft survival were partially seen when recipients were given anti-ICAM-1 or anti-LFA-1 antibody alone. However, serious disadvantage in preventing rejection was clearly seen when both anti-ICAM-1 and anti-LFA-1 antibodies were used together. PMID- 7852049 TI - Expression of naloxone-resistant beta-endorphin binding sites on A20 cells: effects of concanavalin A and dexamethasone. AB - beta-Endorphin affects mononuclear cell proliferation, cytokine production and calcium uptake in a naloxone-resistant manner. The presence of naloxone insensitive binding sites for beta-endorphin have been demonstrated on murine EL4 thymoma cells, transformed human mononuclear cells and normal murine splenocytes. Since murine splenic B cells have been shown to express naloxone-resistant receptors for beta-endorphin in response to the mitogen, concanavalin A (Con A), the A20 B-cell lymphoma line was used to further study regulation of this site by Con A and dexamethasone. Analyses showed two sites: a high-affinity site, Kd1 = (8.7 +/- 2.3) x 10(-11) M and binding capacity (Bmax1) of (2.6 +/- 2.0) x 10(3) receptors/cell; and a low-affinity site, Kd2 = (2.2 +/- 0.8) x 10(-8) M with Bmax2 of (1.5 +/- 0.8) x 10(5) receptors/cell. Competition studies showed that N acetyl-beta-endorphin was approx. 5-fold and beta-endorphin6-31 10-fold less potent than beta-endorphin1-31. Neither beta-endorphin1-27 nor naloxone, morphine or other opioid receptor agonists displaced [125I]beta-endorphin. Con A (20 micrograms/ml) significantly increased the Bmax (3.5-fold; expressed per cell) and resulted in a loss of the higher-affinity site. However, the increased Bmax occurred in proportion to the Con-A-induced increase in protein/cell. Dexamethasone (Dex) also increased Bmax, primarily by increasing (2-3-fold) the number of lower affinity sites. In contrast to Con A, two binding sites persisted after treatment with Dex, which exerted a minimal effect on protein/cell. Therefore, binding/cell and binding/protein/cell were both significantly enhanced by Dex. The combined effects of Dex and Con A on binding failed to show additivity or synergy. When binding was analyzed per protein/cell, the effect of Con A appeared to dominate; the Dex-enhanced binding/protein/cell was no longer evident in the presence of Dex plus Con A. Thus, Dex and Con A may enhance binding by independent mechanisms. PMID- 7852050 TI - Side-effects of peptidoglycan monomer (PGM) treatment in mice. AB - The influence of single (4 mg/mouse) and multiple (1 mg/mouse per day for 5 consecutive days) injections of PGM on some hepatic enzymes, lipid peroxide generation in serum and liver, sialic acid concentration in serum and spleen and hepatic lysosomal membrane permeability was investigated. The studies performed showed that a single injection of PGM in vivo changed temporarily the permeability of lysosomal membranes, lipid peroxidation products and sialic acid concentration, and when administered in vitro modulated superoxide anion production and did not affect the activity of lysosomal membrane enzymes. Multiple injections of PGM did not cause significant changes in the examined parameters. Although the metabolic changes were time-limited and from the toxicological point of view, provoked transient effects, the results obtained may be of importance when using PGM in combined chemo-immunotherapy. PMID- 7852051 TI - Mercury induces in vivo and in vitro secretion of interleukin-1 in mice. AB - Macrophages from SJL and DBA mice incubated with mercuric chloride (HgCl2) in vitro for 24-72 h secreted an increased amount of interleukin 1 (IL-1) to the supernatant compared with control-incubated macrophages, as determined by a sensitive thymocyte proliferation assay. The increase of IL-1 activity showed a highly significant dose-response relationship, being close to that in controls at 10(-8) M, and maximal after incubation with 10(-5)-10(-6) M HgCl2 in both strains. At optimal concentrations of HgCl2 the IL-1 activity started to increase after 6 hrs incubation and reached a maximum after 48 h. Incubation with concentrations of HgCl2 higher than 10(-5) M resulted in a severely reduced IL-1 activity, which correlated with a reduced cell viability. Extracts of HgCl2 incubated macrophages representing cell-bound IL-1 showed no increase in IL-1 activity, irrespective of the concentration or incubation time. Topical application of HgCl2 in a mixture of acetone-olive oil on the external ear of SJL mice induced a dose- and time-dependent increase in IL-1 activity. A maximal increase was seen after application of 1% HgCl2 for 24 h with lower IL-1 activity after 48 and 72 h. Application of 5%, but not 1% or 0.1%, slightly increased the IL-1 activity in the contralateral ear treated with acetone-olive oil only, as compared with the activity in ears from animals given no mercury treatment, suggesting a systemic effect by application of 5% HgCl2.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7852052 TI - Suppression of experimental autoimmune encephalomyelitis by cannabinoids. AB - The effect of delta 8-THC on experimental autoimmune encephalomyelitis (EAE) was examined. delta 8-THC is an analogue of delta 9-THC, the psychoactive component of marijuana. It is more stable and less psychotropic than delta 9-THC and like the latter it binds to the brain cannabinoid receptor. Two strains of rats were inoculated for EAE, and delta 8-THC (40 mg/kg) was administered for up to 21 days. delta 8-THC significantly reduced the incidence and severity of neurological deficit in both rat strains. The beneficial influence of delta 8-THC only occurred on oral administration and not with parenteral injection. Serum corticosterone levels were twofold elevated in rats with EAE chronically treated with delta 8-THC. These results suggest that suppression of EAE by cannabinoids may be related to their effect on corticosterone secretion. PMID- 7852053 TI - An anti-IL-2 antibody increases serum half-life and improves anti-tumor efficacy of human recombinant interleukin-2. AB - We examined the ability of anti-human recombinant interleukin-2 (hu rIL-2) monoclonal antibody DMS-1.10 to increase serum half-life of hu rIL-2, and the effect of this complex on inhibition of tumor progression in a B16-F10 murine melanoma model. In C57B1/6 mice, intravenous (i.v.) injection of DMS-1.10 premixed with 1 x 10(4) units (U) of hu rIL-2 at a 1:1 molar ratio extended serum half-life greater than 10-fold (222 min) when compared to the same dose of hu rIL 2 alone (20 min). In a murine tumor model, multiple intraperitoneal (i.p.) injections of non-neutralizing DMS-1.10 premixed with hu rIL-2 at a 5:1 molar ratio reduced the growth rate of subcutaneous (s.c.) B16-F10 tumor in C57B1/6 mice by 64% when compared to PBS and irrelevant antibody treated controls. Although similar treatment with hu rIL-2 alone reduced tumor growth rate by 46%, it was significantly less effective than the premixed treatment. Results from a flow cytometry assay confirm B16-F10 does not have IL-2 receptors, precluding direct inhibition of tumor growth by hu rIL-2 treatments. We propose that therapeutic efficacy of hu rIL-2 is improved by prolonging the in vivo half-life with an anti-IL-2 antibody, thus augmenting hu rIL-2 bioactivity and enhancing the hosts immune response against tumor. PMID- 7852055 TI - Propellant-driven aerosols of functional proteins as potential therapeutic agents in the respiratory tract. AB - Aerosols of respirable-sized particles of functional proteins were delivered by volatile propellant from metered-dose aerosol canisters. The enzyme alkaline phosphatase and a monoclonal antibody were lyophilized with surfactant and suspended in the aerosol propellant dimethylether. As much as 20 micrograms of functional protein, assessed by enzyme function or antibody binding activity, was delivered per 40 microliters of released propellant. Up to 25% of the protein was of respirable size (< or = 4 microns mass median aerodynamic diameter) when aerosolized proteins were sampled with a Casella cyclone. Respirable particles were derived from visible surfactant/protein complexes suspended in the liquified propellant and from propellant-soluble, nonsedimentable, surfactant/protein molecules that are probably reverse micelles. 10-14 days of propellant exposure in dimethylether increased protein solubility in the propellant, increased the total protein aerosolized and maintained or increased the quantity of respirable sized protein molecules, as compared to the day aerosol vials were charged with propellant. Scanning electron microscopic studies of the respirable-sized protein/surfactant particles showed that they ranged in size from 0.07 to 3.25 microns in diameter, and they appeared to be chain aggregates of spherical subunits, 0.11 to 0.93 microns in diameter. This structural motif was common to both proteins. The possibility of delivering immunizing antigens, cytokines, passive antibodies and other therapeutic proteins to the respiratory tract using propellant-driven aerosols is discussed. PMID- 7852054 TI - Cocaine blunts human CD4+ cell activation. AB - Cocaine is reported to be immunotoxic. The biochemical mechanisms responsible for the immunopharmacological outcomes of cocaine in vivo and in vitro remain, however, to be fully elucidated. Our experimental data confirm that exposure of normal human T cells to micromolar concentrations of cocaine modulates T-cell responses to stimulation by a variety of stimuli, and indicate that cocaine impairs early activation events during CD4+ but not CD4- T-cell stimulation. Pre incubation of enriched CD4+ T-cell subpopulations that express the homing receptor CD62L with nanomolar concentrations of the endogenous opioid peptide beta-endorphin leads to a more severe impairment of activation than that noted following pre-incubation with micromolar concentrations of cocaine alone. These findings begin to elucidate the molecular and cellular mechanisms of the immunopathology of cocaine. Our data support the proposition that cocaine abuse may place cocaine-abuser HIV-seropositive individuals at increased risk of opportunistic infections. PMID- 7852057 TI - 10 year index. Volumes 20-29. PMID- 7852056 TI - In vitro effect of platelet-derived growth factor on fibroproliferation and effect of cytokine antagonists. AB - Platelet-derived growth factor (PDGF) stimulates fibroblast proliferation and increases collagen synthesis. Fibroproliferation, as assessed by tritiated thymidine uptake, was significantly stimulated by platelet-derived growth factor (8 ng/ml). Several drugs including dexamethasone (1 nM-20 microM), cysteamine (1.3-65 mM), N-acetylcysteine (0.6-15 mM), glutathione (1 microM-0.1 mM), glutathione peroxidase (0.1-1 Unit/ml), pentoxifylline (60 microM-36 mM), colchicine (0.025-250 nM) and aurothioglucose (1.15-23 microM) were assessed in the fibroproliferation assay for their ability to block the fibroproliferative effect of platelet-derived growth factor. Dexamethasone and aurothioglucose did not affect PDGF-stimulated fibroproliferation, while pentoxifylline, colchicine, cysteamine and N-acetylcysteine effectively reduced fibroproliferation stimulated by PDGF. The effect of pentoxifylline on PDGF stimulated fibroproliferation was compared to trapidil, theophylline and adenosine to assess mechanism of action. All four methylxanthines effectively inhibited PDGF stimulated fibroproliferation. Pentoxifylline was as effective as trapidil (IC50 = 129 microM and 141 microM, respectively), but pentoxifylline was more potent than theophylline (IC50 = 688 microM) and pentoxifylline was not as potent as adenosine (IC50 = 19 microM) in reducing PDGF-stimulated fibroproliferation. PMID- 7852058 TI - Patterns of postnatal weight changes in infants with very low and extremely low birth weights. AB - OBJECTIVE: To describe (1) short-term postnatal weight loss and gain patterns in infants with very low and extremely low birth weights and (2) the variables that may affect these weight change patterns. DESIGN: Descriptive, retrospective review. SETTING: University hospital in the intermountain western United States. SUBJECTS: Sixty-two charts of infants admitted to a university neonatal intensive care unit from July 1990 through November 1992 were reviewed. Infants who weighed 1000 grams or less were categorized as extremely low birth weight (ELBW) and infants weighing 1001 to 1500 grams were categorized as very low birth weight (VLBW). Each group was comprised of 31 infants. Fifty percent of the sample were male, and 50% were female. Eighty-five percent of the sample were Anglo-American, and 15% were non-Anglo-American. MEASURES: Data were collected on a three-part data collection tool and included demographic and treatment variables. RESULTS: A significant difference was found in the maximum percent weight lost between the two groups, with the ELBW group losing a mean of 14.77% of birth weight and the VLBW group losing a mean of 11.35% of birth weight (t = 2.45, p < 0.05). The day the infants reached their nadir weight was significantly different between the two groups. The ELBW group reached their nadir on day of life 7, and the VLBW group reached their nadir on day of life 6 (t = 2.00, p < 0.05). No significant difference was noted in the time to return to birth weight between the two groups, with a mean of 15 days to return to birth weight. Factors associated with postnatal weight changes were intraventricular hemorrhage, use of diuretics and steroids, day of life when nadir weight occurred, and maximum percent of weight lost. Many of the independent variables were significantly interrelated to each other (r = -0.90 to r = 0.91, p < 0.01 to p < 0.001). However, only the variables that correlated with time to return to birth weight were entered into the regression analysis. These variables included number of days diuretics were given before return to birth weight, maximum percent of weight lost, and day of life the infants reached their nadir weight. Number of days diuretics were given before return to birth weight correlated significantly with time to return to birth weight (r = 0.77, F = 26.66, p < 0.0001) although maximum percent of weight lost and day of life the infants reached their nadir weight had a minimal effect. CONCLUSIONS: Further research into the effects of diuretic therapy on weight changes in this population of infants may lead to interventions to minimize the negative effects of diuretics on return to birth weight. In addition, the older growth charts may not be applicable to this population of infants. Generation of new growth charts that provide growth curves based on these data could be useful in developing nutritional therapies that would promote growth and possibly decrease the length of hospital stay for these infants. PMID- 7852059 TI - Criteria in the selection of organ transplant recipients. AB - The purposes of this article are to describe the criteria used to select organ transplant recipients, to highlight the similarities and differences in these criteria, and to review the findings that support these criteria. Reports on criteria used in selecting heart, lung, liver, pancreas, and kidney recipients were reviewed in addition to reports on proposed approaches to allocating scarce health care resources. The conclusions are that criteria used for organ transplant recipient selection (other than medical criteria related to the diseased organ) vary from setting to setting, organ to organ, and are modified over time. No universal system has been adopted to guide recipient selection. PMID- 7852060 TI - Do-not-resuscitate status: conflict and culture brokering in critical care units. AB - OBJECTIVE: To describe the conflict that occurs during the process of consenting to do-not-resuscitate (DNR) status and the strategies used by critical care nurses to attempt to prevent, minimize, and/or resolve these conflicts. DESIGN: Grounded theory study. SUBJECTS: Twenty-two critical care nurses practicing in upstate New York in urban and rural, profit and nonprofit hospitals. METHOD: Semi structured, in-depth interviews were used to collect data. The interviews were audiotaped and transcribed. The transcribed data were analyzed with the continuous comparative method of grounded theory. Categories were identified and linked to a core category: conflict. RESULTS: Conflict occurred during the process of consenting to DNR status. Two major categories of conflict were intrapersonal (inner conflict in coming to terms with a DNR-status decision) and interpersonal (conflict that took place between individuals involved in consenting to a DNR status). Intrapersonal conflict occurred while determining the appropriateness of DNR for the patient and coming to terms with the meaning of DNR status. Interpersonal conflict occurred between family members, patients, and staff. Nurses descriptions of their role were reflective of a culture broker framework incorporating advocacy, negotiation, mediation, and sensitivity to patients' and families' needs. CONCLUSIONS: Critical care nurses play an active role in assisting patients and families with DNR-status decisions. To better understand the process of consenting to DNR status, additional studies need to focus on the experiences of patients, families, and other health care providers. PMID- 7852061 TI - Study of respiratory failure in organophosphate and carbamate poisoning. AB - OBJECTIVE: To study the clinical profile and cholinesterase levels of subjects of organophosphate and carbamate poisoning and to identify those subjects who would require ventilatory support. DESIGN: Prospective, observational study. SETTING: Intensive care unit of a tertiary care urban hospital. SUBJECTS: Fifty-two patients admitted with a diagnosis of organophosphate or carbamate poisoning. OUTCOME MEASURES: Subject survival and ventilator requirement. INTERVENTION: Treatment with atropine and pralidoxime and mechanical ventilation for patients with respiratory failure. Clinical features were monitored at every stage, and blood for plasma and red blood cell cholinesterase levels was collected on admission. RESULTS: According to the ingested poison, subjects were divided into four groups: organophosphates (13 subjects), mixed organophosphate and carbamate (18), carbamates (13), and a fourth miscellaneous group (8). Dyspnea and vomiting were the most common symptom and miosis and cyanosis were the most frequently observed signs. Plasma and red cell cholinesterase levels were lowest in the mixed poison group and highest in the carbamate group. Twenty-seven subjects developed Type I respiratory failure and 7 had Type II respiratory failure. Mechanical ventilation was required in 31 subjects. Overall 33 subjects survived. A scoring system, on a point scale of 16, was developed using miosis, unconsciousness, fasciculations, and plasma cholinesterase levels to predict ventilator requirement. CONCLUSION: This study helps to identify at an early stage those patients with organophosphate or carbamate poisoning who would ultimately require ventilatory support. We found miosis, unconsciousness, fasciculations, and a low plasma cholinesterase level to be of greatest predictive value. PMID- 7852062 TI - A comparison of nursing interventions for smoking cessation in adults with cardiovascular health problems. AB - OBJECTIVE: To examine the relative effectiveness of three different presentations of a smoking cessation program on the smoking behavior of adults with cardiovascular health problems. DESIGN: A 2 x 2 x 2 x 4 experimental design with stratification by sex, smoking history, and a cardiovascular event, and randomization to Individual, Group, Written, or No Intervention groups. SETTING: Six community hospital classrooms. SUBJECTS: 255 nonhospitalized adults. THEORETIC FRAMEWORK: Interaction Model of Client Health Behavior. MEASUREMENTS: Study Intake: Professional referral form, demographic questionnaire, smoking habits questionnaire, health history, perceived threat survey, perceived health status. Follow up: smoking cessation and health questionnaire, saliva thiocyanate testing. RESULTS: At 12-month follow-up, a nurse-client interaction was more effective than written self-help materials; however, smoking cessation rates were highest in the No Intervention control group, possibly related to having had coronary artery bypass graft surgery. Variables positively related to quitting were being male and married and having a higher income. With baseline factors considered, a quitter was most likely to be male and less than 48 years of age, have a high degree of perceived threat relative to medical diagnosis, and be in the individual intervention group. Only partial support for the study hypotheses was found. PMID- 7852063 TI - Use of epicardial pacing wires after coronary artery bypass surgery. AB - OBJECTIVE: To replicate a previous study that described the incidence and characteristics of patients after coronary artery bypass graft surgery who required the use of epicardial pacing wires and to explore the reasons for epicardial pacing wire use in this patient population. DESIGN: Ex post facto descriptive correlational. SETTING: Cardiothoracic intensive care and step down units of a 500-bed medical center. SUBJECTS: Convenience sample of 196 patients after coronary artery bypass graft surgery, 165 who did not use the epicardial pacing wires and 31 who used the epicardial pacing wires to augment cardiac output, diagnose dysrhythmias, suppress dysrhythmias, or treat heart block. Patients receiving other surgical techniques in combination with coronary artery bypass graft surgery were not included. PROCEDURE: Recording of demographic and clinical data for all of the sample population, with additional data collected when the epicardial pacing wires were used. DATA ANALYSIS: Independent t test and chi-square analysis were used to determine significance between the means and frequencies in the variables of the patients who used the epicardial pacing wires and those who did not. The significance level was set at 0.05. RESULTS: There were no statistically significant differences between the groups in terms of age or previous or recent myocardial infarction, which was opposite of the replicated study's findings. A statistically significant difference (p < 0.001) was found between the groups for the use of inotropic support, which was also opposite of the findings of that study. The group requiring epicardial pacing wire utilization demonstrated a greater need for diuretics in the preoperative phase than those who did not (p < 0.01), as well as a higher use of digitalis therapy before surgery (p < 0.01). Additionally, those who were paced experienced a greater cardiac output (p = 0.013) and cardiac index (p = 0.018) after pacing was initiated. CONCLUSIONS: The variation in findings between this study and the one replicated may be the result of variations in the patient populations, treatment practices, or preoperative condition. Replication of this study at a future date may reveal variables not identified here. PMID- 7852065 TI - Managing pain during mediastinal chest tube removal. AB - OBJECTIVE: To compare four analgesic regimens used in preparing patients for chest tube removal. DESIGN: Prospective, randomized, controlled multiple-group comparison. SETTING: Mid-atlantic university affiliated tertiary medical center. PATIENTS: 80 adult patients who underwent heart surgery and who had two mediastinal chest tubes. OUTCOME MEASURES: Subject's pain intensity rating on a 0 to 100 mm visual analog scale and subject's description of sensations blindly rated by six nurses. INTERVENTION: Before chest tube removal, subjects were medicated with either: (1) intravenous morphine sulfate (morphine), (2) intravenous morphine and subfascial angiocatheter lidocaine hydrochloride (lidocaine), (3) intravenous morphine and subfascial angiocatheter normal saline solution, or (4) subfascial angiocatheter lidocaine. RESULTS: Mean pain rating scores for groups 1, 2, 3, and 4 were 43.7 40.9, 36.4, and 38.1, respectively. Analysis of variance showed no significant difference between scores (p = 0.8948). The percentage of comments rated as "not bad at all" or "not bad" for groups 1, 2, 3, and 4 were 56%, 83%, 47% and 75%, respectively. Chi-square analysis showed a significant difference between ratings (p < 0.01). CONCLUSIONS: Blind ratings of subjects' descriptions of sensations suggest subfascial lidocaine may be useful in reducing discomfort during chest tube removal. PMID- 7852064 TI - Iron supplementation for acute blood loss anemia after coronary artery bypass surgery: a randomized, placebo-controlled study. AB - OBJECTIVE: To evaluate the use of oral iron replacement therapy as an effective treatment for acute surgically induced anemia. DESIGN: Double-blind, placebo controlled, randomized clinical trial. SETTING: Perioperative acute care hospital and a surgery clinic for a single cardiothoracic physician group. PATIENTS: One hundred twenty-eight men and postmenopausal women, 50 years of age or older, admitted for elective coronary artery bypass surgery over a consecutive 8-month period. OUTCOME MEASURES: Before surgery: serum iron, serum ferritin, hemoglobin and hematocrit. Six days after surgery: hemoglobin and hematocrit. Mean of 59 days after surgery: serum iron, serum ferritin, hemoglobin and hematocrit. INTERVENTION: Patients were randomized to one of four groups: control group; placebo group; low-dose group, 50 mg elemental iron + 60 mg ascorbic acid in a multi-vitamin daily; and usual-dose group, 200 mg elemental iron daily. RESULTS: One hundred twenty-one subjects completed the study: 100 men (82.6%) mean age 64.5 years and 21 women (17.4%), mean age 65.7 years. There were no statistically significant age or gender differences among groups. Statistical analysis revealed, except for side effects, no differences between or among groups for any variable measured during the last two time intervals. The mean hemoglobin and hematocrit of the entire sample at 6 days was 9.5 +/- 1.2 gm/dl and 28% +/- 2.3%, respectively. At a mean of 59 days later these values increased equally for all groups to a mean for the cohort of 13.6 +/- 1 gm/dl for hemoglobin and 40.6% +/- 3 for hematocrit. Serum iron and ferritin were within the normal range. The 200 mg group experienced significantly more side effects (p < 0.01). CONCLUSION: Thus the use of oral iron supplements for the treatment of acute blood loss anemia after uncomplicated coronary artery bypass surgery did not assist in restoring red blood cell mass or help maintain total body iron stores. PMID- 7852067 TI - Perceived needs of families of long-term critical care patients: a brief report. AB - OBJECTIVE: To determine if families of long-term critical care patients have needs different from those of families of short-term critical care patients. DESIGN: Ex post facto, descriptive, convenience sample. SETTING: Southeastern community-based medical centers. SUBJECTS: Twenty-six family members of patients in surgical intensive care units (SICU) for a minimum of 2 weeks. Age range was 20 to 73 years with a median of 48.19 years. INSTRUMENT: Molter's Critical Care Family Needs Instrument administered to a relative of a patient in the SICU for 2 weeks or more. RESULTS: The needs of families were very similar to the previously reported needs of families who had members in critical care units for short periods of time (3 to 4 days). The desire for information remained the number one need. CONCLUSION: These findings suggest that family needs remain constant and continue in a crisis mode regardless of the length of time a family member may be a patient in the SICU. Recognition of these continuing needs will assist nurses in relating to the families of long-term critical care patients. PMID- 7852066 TI - Outpatient cardiac rehabilitation in elderly patients. AB - Exercise as part of cardiac rehabilitation plays a role in minimizing disability associated with myocardial infarction and coronary artery bypass surgery. The beneficial effects have been documented primarily among middle-aged participants. The study of those aged 65 years or greater has received less attention. The purpose of this review article is to summarize available data regarding exercise training in elderly patients with heart disease and review issues and considerations for their participation, together providing a basis for inclusion of more elderly in cardiac rehabilitation. Both male and female elderly patients with heart disease can benefit from exercise through significant improvements in functional capacity and reduced myocardial work. Changes are similar in magnitude to those observed among younger participants. Because elders are the fastest growing U.S. population segment and have a twofold to threefold higher incidence of acute myocardial infarction than younger individuals, decreasing disability by including more elderly in cardiac rehabilitation has important public health implications. PMID- 7852068 TI - Rhodococcus equi: fatal pneumonia in a patient without AIDS. AB - Rhodococcus equi infections are being recognized with greater frequency in immunocompromised patients and the population infected with the human immunodeficiency virus (HIV). R. equi usually causes a progressive pneumonia that may or may not cavitate and is relatively refractory to antibiotic therapy. We report a case of fatal R. equi pneumonia in a normal host. PMID- 7852069 TI - Educating health care professionals in human immunodeficiency virus disease and policies: an ongoing challenge. PMID- 7852070 TI - Video colonoscope systems. PMID- 7852071 TI - Inadequately secured connections on ECMO tubing circuits. PMID- 7852072 TI - Liquid disinfecting and sterilization reprocessors used for flexible endoscopes. AB - In this issue, we evaluate three liquid disinfecting flexible endoscope reprocessors that can be used with a user-supplied liquid chemical germicide (LCG), primarily for high-level disinfection (HLD). Applying most of the same criteria and test methods, we also evaluated a fourth unit, presented separately, that is marketed as a liquid sterilizing reprocessor and must be used with manufacturer-supplied, single-use containers of LCG. Although the sterilizing unit can be used for rigid endoscopes, surgical instruments, and endoscopic accessories, we evaluated its application to the reprocessing of only flexible endoscopes. Our ratings are based on the following: (1) basic performance, such as compatibility with several different types of endoscopes and LCGs, inclusion of all essential reprocessing phases, and exposure of all endoscope surfaces to the LCG and rinse water; (2) safety, such as ensuring that essential reprocessing phases cannot be skipped or omitted, that personnel exposure to LCG vapors is minimized, and that the reprocessor is unlikely to contaminate the endoscope during reprocessing; and (3) human factors design, such as ease of use and installation. We did not perform microbiological testing to confirm HLD or sterilization by any of the evaluated reprocessors because, with a suitably clean endoscope that is in good condition, no evidence indicates that the LCGs used would not be effective on the surfaces that they contact; also, the results would be unique to the two flexible endoscopes that we used for our testing. We rated all four reprocessors Conditionally Acceptable. The units are Acceptable on the condition that users understand that they cannot be used to process the elevator cable channel of side-viewing duodenoscopes; additional conditions apply only to the liquid disinfecting units. However, if the conditions are met, all four units reduce the likelihood of using a contaminated endoscope on a patient and reduce personnel exposure to the LCG. Selection of a unit will be based on the needs and preferences of the individual healthcare facility. Our ratings also assume that these units will be used according to the manufacturers' instructions and the endoscope's operator's manual. Note that, although the evaluated liquid disinfecting units provide detergent-flushing, post-detergent water-rinse, and post-detergent water-rinse-removal phases, manual cleaning of endoscopes before automatic reprocessing is essential, regardless of which reprocessor is used. PMID- 7852073 TI - ECRI responds to FDA Safety Alert on Laerdal automated external defibrillators. AB - PROBLEM: On January 26, 1994, FDA issued a Safety Alert to directors of emergency medical services (EMS) and emergency healthcare provider organizations concerning automated external defibrillators (AEDs) manufactured by Laerdal Manufacturing Corp. The Safety Alert listed problems with three different Laerdal AED models: 1. Heartstart 1000 (Laerdal's fully automated unit): Failure to recognize and treat ventricular fibrillation. FDA did not provide a recommendation to prevent this problem, but requested that any deaths, serious injuries, or serious illnesses involving Laerdal defibrillators (or other devices) be reported. 2. Heartstart 1000s (a semiautomated version of the 1000): Delivery of a second, unnecessary shock after a normal sinus rhythm had been restored by a first shock. FDA recommended that users of this model check the patient for evidence of a pulse and breathing before allowing the machine to deliver a second or repeated shocks. 3. Heartstart 3000: Keypad malfunction, faulty battery connection, and defective optocoupler components. Other than recommending that all defibrillators, regardless of type or brand, be tested at the beginning of each shift and that they undergo all periodic maintenance recommended by the manufacturer, FDA did not provide specific recommendations to address these problems. CONCLUSIONS: ECRI has several concerns with the FDA's Safety Alert: It does not adequately characterize the frequency or severity of the problems listed and provides a specific recommendation for only one. The specific recommendation provided for the Heartstart 1000s instructs EMS systems using this model to abandon established, successful practices and to adopt a new procedure that contradicts the American Heart Association's (AHA) protocol for AED use and could cause confusion and an increased risk of operator shock. It has caused enough concern that some EMS systems have taken Laerdal AEDs out of service or have hesitated to place new units into service. Unless alternative defibrillators are used, this will prevent patients from receiving the potentially lifesaving therapy of early defibrillation and can lead to unnecessary loss of life. The FDA Safety Alert is intended to raise the awareness of safe and effective use of medical devices; it does not have the force of law. PMID- 7852074 TI - ECRI responds to FDA public health advisory on i.v. free-flow. AB - PROBLEM: In a Public Health Advisory issued on March 1, 1994 ("Avoiding Injuries from Rapid Drug or i.v. Fluid Administration Associated with i.v. Pumps and Rate Controller Devices"), FDA stated that it had received reports of injuries and deaths from uncontrolled, rapid infusion of medications and/or fluids associated with i.v. pumps and rate-control devices. The Advisory focuses on uncontrolled gravity flow, or what is commonly referred to as free-flow. However, it does not adequately describe free-flow protection mechanisms and makes suggestions that are misleading unwarranted, hazardous, or expensive to implement. One suggestion places patients at greater risk than the problem it is intended to prevent. CONCLUSIONS: ECRI recommends against purchasing electronic infusion devices (EIDs) that do not have infusion set-based free-flow protection, and we provide conditions for use of EIDs with unprotected infusion sets in this article. We strongly disagree with the FDA's suggestion to limit drug concentration and see no substantiation for its suggestions to place warning labels on EIDs, use limited-volume reservoir chambers, or change the regular inspection and preventive maintenance (IPM) schedule. The FDA Public Health Advisory is intended to be used only as guidance; it does not have the force of law. PMID- 7852075 TI - Fatal gas embolism caused by overpressurization during laparoscopic use of argon enhanced coagulation. AB - PROBLEM: ECRI recently investigated an incident in which a patient died from complications of a gas embolism caused by intra-abdominal overpressurization during a laparoscopic cholecystectomy. A Birtcher Medical Systems 6400 argon beam coagulator was used to coagulate bleeding on the liver bed during the incident. Shortly after application of argon enhanced coagulation (AEC), the patient's intra-abdominal pressure increased above the insufflator's alarm limit, activating an audible alarm. When the alarm was noticed, the intra-abdominal pressure displayed on the insufflator was 33 mm Hg. Concurrently, the patient began experiencing difficulties consistent with gas embolism; the embolism was later confirmed by autopsy. Since our initial investigation, we have also become aware of two other incidents during laparoscopic use of an AEC system (FDA 1993 [MDR File No. 67284]; Mastragelopulos et al. 1992 [using a Beamer One Argon Gas Cart--see below]) that resulted in gas embolism and mechanical lung damage. CONCLUSIONS: ECRI believes that the use of AEC during laparoscopic procedures presents patients with a significant risk of gas embolism from abdominal overpressurization and displacement of CO2 by argon gas. Therefore, AEC should be used only during laparoscopic procedures when no equal or superior modality of coagulation is available and when the associated patient risks and benefits have been fully examined. If clinicians decide to use AEC, they must exercise extreme caution during the procedure. PMID- 7852076 TI - Ambulatory telemetry arrhythmia monitoring systems. PMID- 7852077 TI - Responding to fires in areas of oxygen use. PMID- 7852078 TI - Fires from defibrillation during oxygen administration. PMID- 7852080 TI - Loose-lead alarms resulting from dried-out disposable electrodes. PMID- 7852079 TI - Errors in DuPont aca IV bilirubin analysis. PMID- 7852081 TI - Should vacuum pump effluent be treated? PMID- 7852082 TI - The use of Staphylococcus V8 protease in the structural determination of human hemoglobin variants: HB Valparaiso [alpha 88(F9)Ala-->Gly] example. AB - In human hemoglobin, enzymic cleavage with the protease from Staphylococcus aureus strain V8 (protease V8) is a convenient method for the study of variants that involve large peptides such as alpha T-9 and alpha T-12b. We report here on Hb Valparaiso [alpha 88(F9)Ala-->Gly], a new neutral variant with a slight increase in oxygen affinity, that was identified by use of this strategy. PMID- 7852083 TI - Hb Washtenaw [ beta 11(A8)Val-->Phe]: an electrophorectically silent, unstable, low oxygen affinity variant associated with anemia and chronic cyanosis. AB - Hb Washtenaw [beta 11(A8)Val-->Phe] is a new, low oxygen affinity variant with a previously undescribed substitution, identified in seven members over three generations of a Hungarian-American family. The hemoglobin is mildly unstable and the family members studied are clinically asymptomatic but mildly cyanotic, and some exhibit mild anemia. The index case had severe pulmonary hypertension and some of the family members had increased pulmonary vascular resistance on echocardiography. An association between the inheritance of this abnormal hemoglobin and the pathogenesis of primary pulmonary hypertension is suggested but the mechanism is unclear. PMID- 7852084 TI - Hb Fannin-Lubbock in five Spanish families is characterized by two mutations: beta 111 GTC-->CTC (Val-->Leu) and beta 119 GGC-->GAC (Gly-->Asp). AB - We have sequenced the amplified beta-globin genes of five, apparently unrelated, Spanish adults with a fast-moving hemoglobin variant, and observed a GGC-->GAC mutation at codon 119 which identified the abnormality as Hb Fannin-Lubbock or alpha 2 beta (2)119(GH2)Gly-->Asp. In addition, we found a GTC-->CTC change at codon 111 which leads to a Val-->Leu replacement at this location. Protein analysis of the beta A and beta X chains from one of these individuals confirmed that both mutations are located on the same chromosome. It is hypothesized that some other known variants may carry an additional mutation in one of their exons, resulting in a silent amino acid substitution which may have an effect on some physicochemical property. In the case of Hb Fannin-Lubbock, it appears likely that the Val-->Leu replacement at beta 111, rather than the Gly-->Asp replacement of beta 119, is the cause of the instability of the variant. The Hb Fannin Lubbock variant in these Spanish families had a normal oxygen affinity. PMID- 7852085 TI - Hb F-Sassari: a novel G gamma variant with a threonine residue at position gamma 75, characterized by mass spectrometric techniques. AB - The cord blood sample of a Caucasian newborn contained about 40% of an abnormal fetal hemoglobin. The mutated gamma chain was isolated using reversed phase high performance liquid chromatography and characterized by means of electrospray and fast atom bombardment mass spectrometric techniques as a G gamma-globin variant with an Ile-->Thr substitution at position gamma 75. The variant chain shows the same structure as the previously described Hb F-Charlotte that was demonstrated to be an A gamma variant with an Ile-->Thr substitution at position gamma 75 and an additional Ala-->Gly substitution at gamma 136. PMID- 7852086 TI - The high frequency of the Hb B2 variant in the Herero population: a founder effect? AB - The beta-globin gene cluster haplotype associated with the delta-globin variant Hb B2 was determined in Herero individuals from six different families, in order to establish whether founder effect was responsible for the high frequency of this variant in the population. The electrophoretic detection of Hb B2 was confirmed at the molecular level by polymerase chain reaction, followed by Cfo I digestion. The haplotype associated with the Hb B2 chromosome was determined in two families, and was shown to be the same. In the remaining four families the haplotypes could not be established conclusively, but were consistent with the haplotype observed in the other two families. The high gene frequency of Hb B2 is thus likely to have resulted form founder effect. PMID- 7852087 TI - Molecular characterization of beta-thalassemia in north Jordan. AB - We have studied the beta-thalassemia mutations in 91 chromosomes of 43 patients with beta-thalassemia major and five with Hb S-beta-thalassemia, aged 6 months to 24 years. Many are blood transfusion-dependent and are being treated at the major hospital, the Princess Basma Hospital, in Irbid, Jordan. As many as 13 different mutations have been identified; three Mediterranean mutations [IVS-I-110 (G-->A), IVS-II-I (G-->A), and IVS-II-745 (C-->G)] were present in 54% of the chromosomes tested, while six other Mediterranean alleles were found in 24% of the chromosomes, for a total of 78% of Mediterranean origin. Sixteen chromosomes carried mutations which were observed in Arabian, Southeast Asian/Indian, and Iranian/Egyptian or Black populations; four beta-thalassemia mutations remained unidentified. PMID- 7852088 TI - A new beta chain variant, Hb Tyne [beta 5(A2)Pro-->Ser]. PMID- 7852089 TI - Identification of Hb Zurich [alpha 2 beta 2(63)(E7)His-->Arg] by DNA analysis in a Brazilian family. PMID- 7852090 TI - Two rare hemoglobin variants: Hb Pyrgos [beta 83(EF7)Gly-->Asp] and Hb Legnano [alpha 141(Hc3)Arg-->Leu] found in Inner Mongolia, P. R. China. PMID- 7852091 TI - Hb Agenogi [beta 90(F6)Glu-->Lys] identified by DNA analysis. PMID- 7852092 TI - -(alpha)20.5 is the most frequent large deletion in the Puglia region of Italy. PMID- 7852093 TI - Two rare mutations [CD 30 (G-->C) and CDs 36/37 (-T)] in a Turkish thalassemia major patient from Bulgaria. PMID- 7852094 TI - Hb Ramona or alpha (2)24(B5)Tyr-->Cys beta 2. PMID- 7852095 TI - Distinct genetic subdivision in sympatric and sibling species of the genus Littorina (Gastropoda: Littorinidae). AB - The genetic structure of two sibling and sympatric species of the genus Littorina was compared using allozymic loci. The two species are biologically and ecologically well-known and mostly show similar life history characteristics. Three populations of L. mariae Sacchi & Rastelli and L. obstusata (L.) were studied in the Muros-Noya Ria (Galicia, NW Spain). In addition, four microgeographical subsamples taken from one of the populations were analysed for each species. Age, sex and genotypes for nine polymorphic loci were studied in 1250 snails of both species. L. mariae showed larger genetic population subdivision and lower heterozygosity levels for the loci studied than did L. obtusata. Heterozygote deficiencies were found in only a few cases in natural populations of both species, usually affecting the Lap-1 locus. No significant genetic differences among age or sex classes were found. These results may be explained by the lower effective population size in L. mariae than in L. obtusata. Known differences between these species in generation interval and population density during the winter can cause the different effective population sizes suggested. These life history characteristics appear to provide the most likely explanations for the differences in genetic differentiation and heterozygosity between the two species. A previously unknown L. mariae morph from exposed shores is tentatively suggested to be conspecific. PMID- 7852096 TI - Synaptic patterns of rye B chromosomes. IV. The B isochromosomes. AB - Pairing of B isochromosomes in rye was studied by surface spreading of synaptonemal complexes in pollen mother cells from plants containing one small iso-B (iso-BS), one large iso-B (iso-BL), two iso-BL, one iso-BS plus one standard B (iso-BS+stB), one iso-BS plus two standard Bs (iso-BS + 2 stB) and one iso-BL plus two standard Bs (iso-BL + 2 stB). The main characteristics of iso-Bs were as follows. (1) Their location in the surface-spread nuclei was peripheral. (2) Their period of pairing relative to that of the A-set was delayed. (3) The commonest pachytene configuration was a symmetrical hairpin loop, although they could also undergo nonhomologous synapsis. (4) Synapsis could start at the chromosome ends, at the putative centromeric region or at both regions more or less simultaneously. (5) The frequency of iso-BL bivalents was only 46 per cent rather than the 66 per cent predicted by the random-end-pairing model. Interchromosomal pairing was frequent in these configurations. (6) In pairing competition situations involving three and four doses of the short arm of the standard B (iso-BS+stB, iso-BS + 2 stB), a large predominance of self-synapsed iso-BS univalents (63 per cent and 80 per cent respectively) was found. On the other hand, there was no apparent pairing preference among four doses of the long arm of the standard B in the iso-BL + 2 stB combination. Similarities and differences between the synaptic behaviours of iso-Bs of Crepis capillaris and Secale cereale are discussed. PMID- 7852097 TI - Use of random PCR (RAPD) technology to analyse phylogenetic relationships in the Lolium/Festuca complex. AB - The RAPD PCR technique has been employed to investigate phylogenetic relationships between species of the genera Lolium and Festuca. Several decamer primers were used to generate patterns from groups of genotypes of several different species. The degree of band sharing was used to evaluate genetic distances between species and to construct a phylogenetic tree which is in good overall agreement with classical taxonomy, but contains a number of novel insights. The degree of homoplasy inherent in this approach has been investigated using Southern hybridization. These results are discussed in the context of current work in molecular biosystematics. PMID- 7852098 TI - Hybrid vigour against parasites in interspecific crosses between two mice species. AB - The resistance and susceptibility to the intestinal pinworm Aspiculuris tetraptera, a natural parasite of the house mouse Mus musculus, is experimentally analysed using both the F1 from wild-type mice of the two subspecies (M. m. domesticus and M. m. musculus) and the F1 from different laboratory inbred mice. The results show that: (i) the F1 from wild-type mice harbour a lower parasite load than the parental mice, suggesting a phenomenon of hybrid vigour; and (ii) the F1 from inbred mice harbour parasite loads similar to the resistant parent, suggesting that resistance is inherited as a dominant feature in these laboratory mice. This analysis supports the hypothesis that recombinations occurring between the two mouse genomes (i.e. M. m. domesticus and M. m. musculus) are responsible for the hybrid dysgenesis observed in the natural hybrid zone between the two mice subspecies. PMID- 7852099 TI - Sequence conservation of microsatellites between Bos taurus (cattle), Capra hircus (goat) and related species. Examples of use in parentage testing and phylogeny analysis. AB - A panel of 70 bovine microsatellites was tested for amplification from goat DNA. Forty-three could be successfully amplified by PCR, 20 of which were tested for polymorphism. Three were applied for parentage testing in goat families and their exclusion probability evaluated. Fourteen were cloned and sequenced from goat DNA, and goat and bovine sequences were compared to evaluate interspecific conservation. Correlation between the structure of the dinucleotide repeat and the number of alleles was studied and indicated that interruption(s) in the repeat could explain the difference in the levels of polymorphism between the two species. This study provides a valuable in vivo clue to the mechanism generating polymorphism in microsatellites. Sequence conservation was also observed for several microsatellites with two wild species of Bovidae, Nilgai (Boselaphus tragocamelus) and Himalayan Tur (Capra cylindricornis), and with one species of Cervidae, the fallow deer (Cervus dama). This study showed that an estimated 40 per cent of the microsatellites isolated from cattle will prove useful to study the caprine genome and to characterize economically important genetic loci in this species. Moreover, bovine microsatellites were shown to constitute very useful tools for the study of genetic diversity of the Artiodactyla. PMID- 7852101 TI - DOs who train in allopathic residency programs not 'disloyal'. PMID- 7852100 TI - Evolution in heterogeneous environments: genetic variability within and across different grains in Tribolium castaneum. AB - The course of adaptation to heterogeneous environments is influenced by the magnitude of genetic variation for ecologically important characters within each environment and the extent of genotype x environment interaction. Using the genetic correlation between the expression of characters in different environments as a measure of genotype x environment interaction is particularly useful for evolutionary interpretation. In this study, we estimated patterns of genetic variability and cross-environment genetic correlations for pupal weight and development time in two strains of the flour beetle Tribolium castaneum in five flours (wheat with brewer's yeast, wheat, rice, corn and oat). Wheat plus yeast is the standard medium in which the strains have been reared for hundreds of generations; other flours are novel environments. The results indicated moderate levels of genetic variation within the various flours for pupal weight but not for development time. Performance varied considerably across flours, with the highest performance for both strains found in the standard medium and the poorest in oat flour. The genetic correlations of pupal weight across flours in both strains were generally not significantly different from + 1. This suggests that evolution of body size in different flours cannot proceed independently, and that improved performance in the novel flours may produce declines in fitness in the standard environment. PMID- 7852102 TI - Atrophy of suboccipital muscles in patients with chronic pain: a pilot study. AB - Magnetic resonance imaging studies were performed in six patients with chronic head and neck pain and in five control subjects to determine whether irreversible atrophic changes resulting in destruction of muscle fibers have a role in patients with chronic pain specific to the cervical spine. Both groups of subjects had medical history obtained and underwent physical examination and proton density-weighted (PD-weighted) magnetic resonance imaging. Subjects with chronic pain had substantial restriction of motion. Axial proton density-weighted images of the rectus capitis major and minor muscles were examined. In the subjects with chronic pain, the muscles had high signal intensity, indicating replacement of dead suboccipital skeletal muscle with fatty tissue. This infiltration was not observed in the control subjects who were free of significant motion restrictions and had no history of recurring neck and head pain. Analysis of pixel intensity values confirmed this finding. The reduction in proprioceptive afferent activity in affected muscles may cause increased facilitation of neural activity that is perceived as pain. At least mean squares algorithm was used to define a linear estimating equation for each subject. Linear regression analysis, using an alpha level < .005, was used to determine how well each subject's data fit the estimating equation. This preliminary work indicates substantial infiltration of fatty tissue into suboccipital muscles of some subjects being treated for chronic head and neck pain. PMID- 7852103 TI - Medical liability, product liability, and the question of tort reform. AB - Physicians have identified malpractice reform as their first priority during the recent flurry of national reform initiatives. Their focus on malpractice, however, tends to obscure the relationship between malpractice and the systemic problems wracking our healthcare delivery system. Because malpractice has an impact on all three foci of comprehensive reform--quality, cost, and access--it is reasonable to expect healthcare reform to include some manner of tort reform. However, it is important to realize the tangential nature of the relationship and keep the focus of reform on the underlying issues of system reform. The authors define the areas of physician liability under tort law (both malpractice and product liability), point out the misperceptions that inform physician behavior, and review the individual reforms proposed. They identify the stakeholders and their positions on each proposal, while imploring a cooperative, systemwide approach to tort reform. PMID- 7852104 TI - Performances of candidates with osteopathic compared with allopathic subspecialty training on the American Osteopathic Board of Internal Medicine subspecialty certifying examinations 1984 to 1992. AB - The American Osteopathic Board of Internal Medicine has been examining various factors that may affect candidate performance on subspecialty certifying examinations. To see whether taking subspecialty training in an osteopathic compared with an allopathic institution could predict better performance on the certifying examinations, the authors analyzed examination performance for all candidates from 1984 through 1992. There was no significant difference between the mean scores for the two groups for any of the nine subspecialty certifying examinations. When the results from all nine examinations were pooled, the mean first-time examination takers' score for candidates in allopathic subspecialty programs (n = 201) was 78.3 and for those in osteopathic subspecialty programs (n = 153), 77.4 (P > 0.2). On the basis of these results, we cannot conclude that osteopathic subspecialty training is a factor that predicts better performance on the subspecialty certifying examination. PMID- 7852105 TI - Brain tumors in children: long-term survival after radiation treatment. AB - PURPOSE: To determine the cause of death in children who survive more than 5 years after radiation treatment of a brain tumor. METHODS AND MATERIAL: Nine hundred and twelve consecutive children with a primary brain tumor irradiated at the Princess Margaret Hospital or Toronto-Bayview Regional Cancer Center from 1958 to 1991, were evaluated for long-term outcome. RESULTS: Overall 10- and 20 year survival rates were 44% and 37%. Subsequent survival of 377 5-year survivors was, at an additional 10 and 20 years, 78% and 67%. Most (83%) deaths that occurred more than 5 years from diagnosis were a result of relapse of the original tumor. The 10-year survival rate subsequent to relapse was 9% when the first relapse occurred less than one year from diagnosis, 17% for 1-2 years, and 31% when the time to relapse was 3 years or greater. The cumulative actuarial incidence of, and death from, second malignant tumors at 30 years from diagnosis was 18% and 13%, respectively. CONCLUSIONS: Death later than 5 years from diagnosis of a brain tumor in children is common and is usually due to progressive disease in slowly evolving low grade tumors. Death from a second malignant tumor becomes more frequent than death from the original tumor after 15 years from diagnosis. PMID- 7852106 TI - Quality-adjusted survival analysis of malignant glioma. Patients treated with twice-daily radiation (RT) and carmustine: a report of Radiation Therapy Oncology Group (RTOG) 83-02. AB - PURPOSE: To quantify the quality of life of malignant glioma patients treated on a randomized Phase I/II trial of twice-daily radiation therapy (RT) and carmustine, using a modified quality adjusted survival (QAS) model, and to compare the QAS among assigned treatment arms. MATERIALS AND METHODS: The Radiation Therapy Oncology Group (RTOG) accrued 786 malignant glioma patients to a Phase I/II randomized dose escalation trial of twice-daily RT with carmustine from 1983 to 1989. Patients were randomized to one of four arms of hyperfractionated RT in 1.2 Gy twice daily (BID) fractions (64.8 Gy, 72.0 Gy, 76.8 Gy, or 81.6 Gy) or to either of two accelerated hyperfractionated RT arms in 1.6 Gy BID fractions (48.0 or 54.4 Gy). Although preliminary toxicity and survival data have been published, little information is available regarding the quality of these patients' lives during and following such therapy. QAS is a refinement of the methodology for assessing survival quality among breast cancer patients receiving adjuvant chemotherapy. The QAS method allows for inclusion of both improvement and decline in neurologic functional status. Patients were scored by the presence or absence of 15 neurologic signs and symptoms at on-study and at every follow-up. Within each category were gradations of severity, with the quality survival time (Q-TIME) adjusted according to any changes in these neurologic findings. The summation of all changes in signs and symptoms were weighted by 1/15th and incorporated into the QAS model as QAS = Q-TIME-TOX-RRX. TOX was the time spent with treatment-related toxicities, and RRX was the time spent in recovery from subsequent therapy. RESULTS: Of 747 evaluable patients, the average QAS time was 18.5 months. The average QAS for the hyperfractionated arms of 64.8 Gy, 72.0 Gy, 76.8 Gy, and 81.6 Gy were 15.6, 20.8, 10.0, and 13.7 months, respectively. For the accelerated hyperfractionated RT arms of 48.0 and 54.4 Gy, the average QAS times were 13.1 and 13.4 months. The QAS time of the 72.0 Gy arm was significantly longer than that of all other groups, except the 64.8 Gy arm. As expected, the QAS times were strongly discriminated by both age and Karnofsky Performance Scores (KPS) (p < 0.001). Younger patients and patients with high KPS benefited most from assignment to the 72.0 Gy arm; QAS time was not significantly longer in any treatment arm among patients over age 50 or with KPS scores of 80 or less. CONCLUSIONS: This quality-adjusted survival methodology can be successfully applied to malignant glioma patients and permits a quantitative assessment of the influence of investigational therapies on patient quality of life. This analysis confirms the potential benefit of intermediate dose (72.0 Gy) hyperfractionated RT for selected malignant glioma patients. PMID- 7852107 TI - Low grade gliomas: preliminary analysis of failure patterns among patients treated using 3D conformal external beam irradiation. AB - PURPOSE: The pattern of failure of low grade gliomas following radiotherapy is less well known than that of the high grade gliomas. Stereotactic histologic studies have suggested that tumor cells extend beyond imaging abnormalities, and that large margins would be required for radiotherapy target volumes to encompass all of the neoplasm. Our experience using computerized tomography (CT)- and magnetic resonance (MR)-planned irradiation of low grade gliomas was reviewed to determine the pattern of tumor recurrence, in an effort to clinically define the minimum margin required. METHODS AND MATERIALS: Forty-six patients with low grade supratentorial gliomas were treated between April 1985 and November 1992 using three-dimensional (3D) conformal CT- or MR-planned external beam radiotherapy. Fields were designed to encompass a target volume created by adding a margin to the tumor in three dimensions. Generally, patients were treated using shrinking fields with an initial target (tumor plus a 1 to 3 cm margin) treated to a dose of 45 to 50.4 (median 50.4) Gy, and a boost (tumor plus a 0 to 2 cm margin) treated to a total of 54 to 59.4 (median 59.4) Gy. Median follow-up was 32.9 months. RESULTS: There have been 11 failures; all of these occurred within the radiographic abnormality (either T2 prolongation or CT hypodensity) visualized at the time of treatment planning (i.e., all failures were within the boost volume). Median time to failure was 53 months. Because all failures were local, there was no relationship between the amount by which the tumor volumes were expanded to create target volumes and the eventual outcome. CONCLUSION: Despite pathologic data suggesting that low grade glioma cells can be found outside the MR T2-signal abnormality in many cases, our results demonstrate that conformal external beam radiotherapy, in which the high dose volume is limited, does not result in increased marginal or out-of-field failures. Until control of tumor within the radiographically abnormal volume can be achieved, the need for large fields to treat prophylactically microscopic disease beyond the visualized tumor volume is questionable. The use of conformal fields might be associated with reduced toxicity, and thereby allow delivery of higher total doses to the central tumor. PMID- 7852108 TI - Locally challenging osteo- and chondrogenic tumors of the axial skeleton: results of combined proton and photon radiation therapy using three-dimensional treatment planning. AB - PURPOSE: Tumors of the axial skeleton are at high risk for local failure. Total surgical resection is rarely possible. Critical normal tissues limit the efficacy of conventional photon therapy. This study reviews our experience of using combined high dose proton and photon radiation therapy following three dimensional (3D) treatment planning. METHODS AND MATERIALS: Between December 1980 and September 1992, 47 patients were treated at the Massachusetts General Hospital and Harvard Cyclotron Laboratory for primary or recurrent chordomas and chondrosarcomas (group 1, 20 patients), osteogenic sarcomas (group 2, 15 patients) and giant cell tumors, osteo-or chondroblastomas (group 3, 12 patients). Radiation treatment was given postoperatively in 23 patients, pre- and postoperatively in 17 patients, and 7 patients received radiation therapy as definitive treatment modality following biopsy only. The proton radiation component was delivered using a 160 MeV proton beam and the photon component using megavoltage photons up to 23 MV energy with 1.8-2.0 Cobalt Gray Equivalent (CGE) per fraction, once a day. Total external beam target dose ranged from 55.3 CGE to 82.0 CGE with mean target doses of 73.9 CGE (group 1), 69.8 CGE (group 2), and 61.8 CGE (group 3). RESULTS: Group 1 (chordoma and chondrosarcoma): Five of 14 patients (36%) with chordoma recurred locally, and 2 out of 5 patients developed distant metastasis, resulting in 1 death from disease. A trend for improved local control was noted for primary vs. recurrent tumors, target doses > 77 CGE and gross total resection. All patients with chondrosarcoma achieved and maintained local control and disease-free status. Five-year actuarial local control and overall survival rates were 53% and 50% for chordomas and 100% and 100% for chondrosarcomas, respectively. Group 2 (osteogenic sarcoma): Three of 15 patients (20%) never achieved local control and died within 6 months of completion of radiation treatment. Only 1 out of 12 patients who were controlled for more than 6 months failed locally, yielding a 5-year local control rate of 59% for 15 patients. Overall, 4 patients (27%) developed distant metastasis (two in patients with uncontrolled primary); 4 patients succumbed to their disease, 3 patients died of intercurrent disease, resulting in overall survival of 44% at 5 years. Group 3 (giant cell tumors, osteo- and chondroblastoma): One of 8 patients with giant cell tumor failed locally, 1 patient distantly, and all patients are alive. Three of 4 patients with osteo- or chondroblastoma are alive and well. One patient suffered local recurrence and died of disease. Local control rate and overall survival for this group of 12 patients was 76% and 87% and local control for patients with giant cell tumors 83% at 5 years. In the majority of cases radiotherapy was well tolerated. However, one patient with a large base of skull tumor developed retinopathy, one patient required enucleation of a previously blind eye, and another patient with sacral tumor developed chronic diarrhea. CONCLUSION: Combined proton and photon radiation therapy optimized by 3D treatment planning, allows the delivery of higher radiation doses to tumors of the axial skeleton, while respecting normal tissue constraints. High radiation doses can result in improved long-term local control. PMID- 7852109 TI - Survival outcome following isolated central nervous system relapse treated with additional chemotherapy and craniospinal irradiation in childhood acute lymphoblastic leukemia. AB - PURPOSE: An analysis of survival outcome following isolated central nervous system (CNS) relapse treated with craniospinal irradiation (CSI) and additional chemotherapy in children with acute lymphoblastic leukemia (ALL) was conducted. METHODS AND MATERIALS: Eighteen of 344 pediatric patients with ALL who attained initial complete remission on the St. Jude Children's Research Hospital "Study XI" prospective protocol (1984-1988) developed a CNS relapse as first adverse event. Median interval to isolated CNS relapse was 7.5 months (range = 2-40 months) after achieving initial complete remission. At diagnosis, 14 of the 18 children were categorized as "high risk" for subsequent leukemic relapse. Preventive cranial irradiation [PCI (18 Gy)] was delivered as planned to one of the 14 "high-risk" children. The other 13 "high-risk" patients experienced a CNS relapse during the first year of continuation therapy prior to week 52 of planned PCI. All four "low-risk" patients experienced a CNS relapse beyond the first year of continuation therapy; none were scheduled to receive PCI. Following isolated CNS relapse, all 18 patients were treated on a prospective contingency of "Study XI" trial consisting of intensified reinduction chemotherapy, weekly intrathecal methotrexate/hydrocortisone/Ara-C x 4-6 injections, craniospinal irradiation (cranium to 24.0 Gy and spine to 15.0 Gy at 1.5 Gy/fraction) and maintenance systemic therapy for a minimum of 1 year. RESULTS: Ten of 18 patients remain in continuous complete secondary remission at 17 to 50 months post-CNS relapse. Second sites of relapse in the remaining eight children were as follows: CNS in four, bone marrow in three, and bilateral testicular in one patient. Each of these eight patients died of progressive leukemia. At a median followup of 40 months post-initial CNS relapse, the 3-year secondary Kaplan-Meier survival and event-free survival are 72% and 56%, respectively. Minimal long-term neurotoxicity was associated with the treatment regimen. The most important prognostic factors predicting continuous secondary remission included white blood cell count at diagnosis (p = 0.05), and duration of initial remission (p = 0.04). CONCLUSION: This trial demonstrates that more than one-half of patients may be successfully salvaged with intensified chemotherapy and craniospinal irradiation without significant morbidity following an isolated CNS relapse, despite previous multiagent chemotherapy though virtually no prior PCI in childhood ALL. PMID- 7852110 TI - Local tumor control in rhabdomyosarcoma following low-dose irradiation: comparison of group II and select group III patients. AB - PURPOSE: To determine whether low-dose irradiation (i.e., approximately 40 Gy at 1.5-1.8 Gy/fraction), which is associated with > or = 90% local control in children with initially resected rhabdomyosarcoma and microscopic residual [Intergroup Rhabdomyosarcoma (IRS) group II disease], achieves comparable results in children with locally advanced rhabdomyosarcoma (IRS group III) left with microscopic disease after induction chemotherapy with or without delayed surgery. METHODS AND MATERIALS: Among 103 patients entered on five successive studies between 1968 and 1991, 24 had evidence of microscopic residual disease after initial surgical resection (IRS group II) and received low-dose irradiation. Initial chemotherapy was used in 79 with IRS group III disease. In 28 of these 79 group III patients, chemotherapy alone (n = 16) or in combination with delayed surgery (n = 12) reduced disease to microscopic levels prior to the start of radiotherapy based upon which they received low-dose irradiation. All have a minimum 2-year follow-up and median age of 4 years. Primary tumor sites among the 24 with group II disease included: orbit (5), parameningeal (2), nonparameningeal head and neck (3), genitourinary: nonbladder/prostate (5), extremity (4), and other (5). Irradiation dose ranged from 32-50 Gy, with a median and modal dose of 40 Gy. Primary tumor sites among the 28 with group III disease selectively treated with low-dose irradiation included: orbit (1), parameningeal (6), nonparameningeal head and neck (4), genitourinary: bladder/prostate (12) and nonbladder/prostate (1), extremity (1), and other (3). Irradiation dose ranged from 33-52 Gy, with a median and modal dose of 40 Gy. RESULTS: Local disease control has been maintained in 23 of 24 patients (96%) with group II disease. Local control occurred in eight of nine (89%) group II patients receiving < 40 Gy and in all 15 receiving > or = 40 Gy (p = 0.26). Twenty (83%) are alive and free of disease. Twenty-two of the 28 patients (79%) with group III disease treated with low-dose irradiation have maintained continuous local control of disease which was not statistically different from the group II patients (p = 0.08). Local control occurred in 7 of 11 (64%) group III patients receiving < 40 Gy vs. 15 of 17 (88%) receiving > or = 40 Gy (p < = 0.14). Nineteen (68%) are alive and free of disease. Survival in these group III patients is significantly worse than that of the group II patients, with 19 (68%) alive and free of disease (p = 0.04). CONCLUSION: Children with locally advanced rhabdomyosarcoma (IRS group III) who have only microscopic disease after induction chemotherapy with or without delayed surgery have a high likelihood of achieving local control with low-dose irradiation. For this group, data suggest treatment to a dose level of at least 40 Gy. PMID- 7852112 TI - Does pathologic node status affect local control in patients with carcinoma of the head and neck treated with radical surgery and postoperative radiotherapy? AB - PURPOSE: To evaluate the effect of pathologic lymph node status and nodal stage on local control at the primary site in patients with advanced squamous cell carcinomas of the head and neck, treated with radical surgery and postoperative irradiation. METHODS AND MATERIALS: Fifty-seven patients with advanced squamous cell carcinomas of the oral cavity, oropharynx, hypopharynx, larynx, and supraglottic larynx were analyzed. All patients underwent resection of the primary lesion, neck dissection, and postoperative radiotherapy. Minimum follow up was 2 years. The median dose to the primary tumor bed was 60.4 Gray (range 39.7-72.0). Besides pathologic nodal status (pN0 vs. pN+) and nodal stage, the following factors were analyzed for their impact on local control: age, gender, T stage, tumor grade, resection margins, interval from surgery to irradiation, dose to the primary site, and overall treatment time. RESULTS: The 3-year actuarial local control rate was 78%. When all patients were analyzed, nodal status (pN0 vs. pN+) did not affect control at the primary site (71% vs. 82%, p = 0.42). Nodal stage (pN0-N2a va. pN2b-N2c) was also not a significant factor for local control (74% vs. 82%, p = 0.57). When only patients with negative margins were analyzed, nodal status again did not impact on local control (79% vs. 90% for pN0 vs. pN+, p = 0.39). On univariate analysis, only tumor grade, margin status, and elapsed days were significant factors for local control. Local control was 85% for patients with negative margins vs. 60% for those with positive margins (p = 0.016). For patients with moderately and poorly differentiated tumors, local control was 86% as compared to 50% for patients with well-differentiated tumors (p = 0.007). When radiotherapy was completed within 50 days, local control was 93% as opposed to 63% for > 50 days (p = 0.016). On multivariate analysis, only margin status (p = 0.002) and tumor grade (p = 0.007) remained significant. CONCLUSION: We conclude that neither the presence of pathologically positive nodes nor nodal stage is a prognostically significant factor for local control in patients who have undergone radical surgery and postoperative radiotherapy for advanced squamous cell carcinomas of the head and neck. We do not recommend a change in treatment philosophy, such as an increase in dose to the primary site, based on the pathologic status of the neck. PMID- 7852111 TI - Hyperfractionated radiation in the treatment of squamous cell carcinomas of the head and neck: a comparison of two fractionation schedules. AB - PURPOSE: In 1984 we began treating patients with squamous cell carcinomas of the larynx and hypopharynx with hyperfractionated radiotherapy. Patients received 76.8 Gy in 1.2 Gy fractions twice daily, with a 4 h interfraction interval. In 1988, this schedule was modified in patients treated with shrinking field techniques. The dose per fraction was slightly reduced (while not changing the total dose), and the interfraction interval was increased to 6 h. The goal was to decrease toxicity while maintaining satisfactory local-regional control. This retrospective study analyzes the results of this schedule modification. METHODS AND MATERIALS: Two hundred thirty-six patients were included in the analysis. Distribution of patients by primary site and T stage was as follows: supraglottic larynx, 120 patients; hypopharynx, 70; true vocal cord, 24; and oropharynx, 22; T1, 5 patients; T2, 118; T3, 93; T4, 19; and Tx, 1. Ninety-nine patients presented with cervical nodal disease. Seventy-eight patients (group A), including 16 treated with induction chemotherapy, were treated throughout with 1.2 Gy fractions twice daily and a 4-h interfraction interval. Subsequently, 158 patients (group B), 57 of whom received chemotherapy, received 1.1 Gy fractions to 55 Gy, and then 1.2 Gy fractions to their boost volumes to 76.6 Gy. The interfraction interval was 6 h. Median follow-up was 91 and 35 months for group A and B, respectively. RESULTS: Two-year actuarial survival, local control, and ultimate local rates were 70%, 75%, and 85%, respectively. Differences between survival rates for group A and group B were not statistically significant, with 2 year rates of 66% and 72%, respectively. Overall local control rates at 2 years were 77% and 74%, respectively, for groups A and B (p = 0.22). However, there was a trend toward inferior results in group B patients with T3 disease (67% at 2 years compared to 76% in group A, p = 0.13). Confluent mucositis and persistent mucositis developed in 52% and 14% of group A patients, but only 37% and 4% of group B patients (p = 0.02 and p < 0.01, respectively). There was a near significant trend toward fewer late complications in group B who developed an 8% complication rate at 3 years compared to 15% of group A patients (p = 0.07). CONCLUSIONS: The net effect of reducing the dose per fraction to 1.1 Gy twice daily for fields covering gross disease and subclinical sites, and increasing the interfraction interval to 6 h was to reduce the incidence of both acute and late complications. Excellent overall local control rates (85%) for T2 lesions were achieved with both hyperfractionation regimens and we, therefore, continue to treat patients with T2 tumors with the modified schedule. The overall results in selected patients with T3 lesions was also satisfactory (69%), but as there was a trend towards poorer local control in patients treated with 1.1 Gy fractions, we recommend using 1.2 Gy for the entire treatment of these patients, while maintaining the 6 h interfraction interval to reduce the risk of late complications. PMID- 7852113 TI - Fractionated or single-dose total body irradiation in 171 acute myeloblastic leukemias in first complete remission: is there a best choice? SFGM. Societe Francaise de Greffe de Moelle. AB - PURPOSE: To evaluate the importance of fractionating total body irradiation (TBI) in patients receiving an allogenic bone marrow transplant (BMT) for an acute myeloblastic leukemia (AML) in first complete remission (CR1). METHODS AND MATERIALS: Between 1983 and 1990, 171 consecutive patients received either single dose TBI (STBI) (n = 65) or fractionated TBI (FTBI) (n = 106) after being conditioned with cyclophosphamide and before receiving a non-T-depleted Human Leucocyte Antigen (HLA)-identical marrow. Both groups were comparable except for date of BMT and diagnosis-to-BMT interval (D-BMT). RESULTS: After 63 months median follow-up, transplant-related mortality (TRM), probability of relapse, and 5-year disease-free survival (DFS) were 0.38 and 0.27 (p = 0.04), 0.29 and 0.26 (p = 0.22), 0.43 and 0.56 (p = 0.06), respectively, for STBI and FTBI. The supposed influence of the schedule of TBI disappeared in the multivariate analysis: TRM was enhanced by severe acute graft vs. host disease (p = 0.0002), early years of transplant (before January 1, 1987) (p = 0.0003), and longer D-BMT intervals (p = 0.038). Relapse was linked to early years of transplant (p < 0.00001), and the absence of chronic GVHD (p = 0.007). Longer DFSs were observed for later years of transplant (after January 1, 1987 and later) (p = 0.001), milder acute GVHD (p = 0.005), and shorter D-BMT intervals (p = 0.045). Important improvements of the results were made during the 7-year observation period: TRM, probability of relapse, and DFS were, respectively, 0.36, 0.28, and 0.46 for patients transplanted before January 1, 1987 vs. 0.21, 0.15, and 0.67 after that date. CONCLUSION: Our data strongly suggest that allogenic BMT is the best postremission treatment for AML in CR1, and the results are better when BMT shortly follows the achievement of remission. The schedule of TBI was of little importance compared with the improvements made in the management of patients undergoing BMT during the 1980s, and, therefore, reports concerning data prior to 1985 should be interpreted cautiously. PMID- 7852114 TI - In vitro radiation sensitivity of mouse lung fibroblasts isolated by flow cytometry. AB - PURPOSE: Recently, we have isolated two major fibroblast cells (Thy-1+, Thy-1-) from mouse LAF1 lung tissue using the anti-Thy-1 antibody expression and fluorescence activated cell sorter. To examine the possibility that x- or gamma ray-induced pulmonary fibrosis at the late stage of injury could arise from radioresistant cell subpopulations, the radiation sensitivities of Thy-1+ and Thy 1- cells were evaluated by the colony forming assay. METHODS AND MATERIALS: Cell survival curves, repair of potentially lethal damage (PLD) and sublethal damage (SLD), and cell-age response curves were obtained after Cs-137 gamma-ray irradiation. RESULTS: The cell survival curves measured after 0-10 Gy gamma-ray showed that Thy-1+ cells were slightly more radioresistant than Thy-1- cells. The D0, n, alpha, and beta values measured from the survival curves also confirmed this observation. After a single dose of 10 Gy, a small amount of PLD repair was observed in Thy-1- cells, while no PLD repair was found in Thy-1+ cells. Although the initial cell survival level of Thy-1- cells was lower, the final survival levels of Thy-1+ and Thy-1- cells became identical at 8 h after irradiation due to the PLD repair. After split-dose irradiation of 4 Gy followed by 4 Gy, a similar extent and rate of SLD repair was found in Thy-1+ and Thy-1- cells. Cell age response curves were obtained from irradiated G0/G1, S, and G2M cells separated by centrifugal elutriation and irradiated with 8 Gy gamma-ray. The results indicated that Thy-1+ and Thy-1- cells had a similar S resistant, and G1, G2M-sensitive radiation cell-age response curve. CONCLUSIONS: This study suggests that the selection of radioresistant lung fibroblast may not be responsible for the development of lung fibrosis in irradiated LAF1 mouse. PMID- 7852115 TI - Exogenous lactate interferes with cell-cycle control in Balb/3T3 mouse fibroblasts. AB - PURPOSE: Previous studies have shown that exogenous lactate may influence proliferation rates, radiation sensitivity, and postirradiation repair capacity of mammalian cells. In the present study, we addressed the question of potential underlying mechanisms and, therefore, examined effects of exogenous lactate on proliferation rates and cell-cycle distribution in immortal but nontumorigenic mammalian cells. METHODS AND MATERIALS: Cells were grown at 37 degrees C in an incubator with 5% CO2 and 95% air, in a culture medium supplemented or not with lactate at a 10 mM concentration. Daily, we changed the culture medium and counted cells per dish. On selected days, cell-cycle distribution was determined by flow cytometry. Balb/3T3 mouse fibroblasts were used. RESULTS: During the exponential phase of cell proliferation, mean population doubling time was significantly increased from 17.7 to 19.9 h, due to selective prolongation of G2/M. However, in density-inhibited cultures, exogenous lactate stimulated entry into S and proliferation to a significantly higher saturation density. CONCLUSIONS: These findings indicate that exogenous lactate interferes with mechanisms of cell-cycle control at two different points in the cell-cycle, depending on cell density and the resulting absence or presence of inhibition of cell proliferation. Interference with cell-cycle control may underly the modification by exogenous lactate of radiosensitivity and postirradiation repair capacity in mammalian cells. PMID- 7852116 TI - gamma-Interferon administration after 90yttrium radiolabeled antibody therapy: survival and hematopoietic toxicity studies. AB - PURPOSE: Hematopoietic toxicity is the dose-limiting factor for radioimmunotherapeutic regimens. Cytokines have been shown to decrease hematopoietic toxicity in animals exposed to whole-body irradiation. The purpose of this study was to investigate the effects of murine gamma-interferon (gamma IFN) on survival and hematopoietic toxicity in mice treated with high dose 90yttrium labeled anticarcinoembryonic antigen (CEA) monoclonal antibody. METHODS AND MATERIALS: Balb/c nu/nu mice were injected intravenously with 250 Ci 90Y T84.66 (a murine anti-CEA monoclonal antibody). Thirty thousand units of gamma IFN was administered i.v. 24 h later. Control mice received either 250 Ci 90Y T84.66 alone or 30,000 units gamma-IFN alone. Survival, antibody biodistribution, and bone marrow histologic studies were then performed. RESULTS: Only 7% of the animals treated with 90Y-T84.66 survived up to 40 days posttreatment, when the study was terminated. In contrast, 52% of the mice treated with both 90Y-T84.66 and gamma-IFN survived 40 days posttherapy. No toxic deaths were seen in the control group administered gamma-interferon alone. Histologic examination of the bone marrow of animals receiving 90Y-T84.66 and gamma-IFN showed cellular depletion of 40-70% of the hematopoietic cells by 48 h. Cell depletion was 50-70% and 20% by 72 h and 8 days posttherapy, respectively. The marrow of the 90Y T84.66-treated control group was depleted to a level of 50-80% at 48 h, and remained depleted at 90% at 72 h and 8 days posttherapy. No marrow cell reduction was seen in the gamma-IFN-only treated group. Biodistribution studies showed no alterations in antibody biodistribution or kinetics that could account for the changes in bone marrow toxicity after gamma-IFN. CONCLUSION: These results demonstrate that gamma-IFN can reduce the hematologic toxicity resulting from high dose radioimmunotherapy. Histologic studies of bone marrow suggest that gamma-IFN acts primarily to accelerate myelorestoration of the bone marrow. Further studies exploring the use of gamma-IFN as an adjunct to radioimmunotherapy are therefore warranted. PMID- 7852117 TI - Relative biological effectiveness of proton medical beam at Moscow synchrotron determined by the Chinese hamster cells assay. AB - PURPOSE: Assessment of relative biological effectiveness (RBE) of the proton medical beam at Moscow synchrotron. METHODS AND MATERIALS: The study was performed at Moscow proton medical facility (Institute for Theoretical and Experimental Physics). Relative biological effectiveness of the synchrotron proton beam was assessed at the entry of the unmodulated 179 MeV beam and in the center of spread out Bragg peak (SOBP), from measurements of the survival of Chinese hamster cells (clone 431). Gamma-radiation of 60Co was used as a reference source. RESULTS: According to the linear regression model, mean RBE values at 37% survival level were found to be 1.10 +/- 0.04 at the beam entry and 1.14 +/- 0.05 in the center of SOBP. Values of RBE obtained using the linear quadratic model for 10% and 37% survival levels were 1.09 and 1.07, respectively, at the beam entry and 1.07 and 1.08, respectively, in the center of SOBP. CONCLUSIONS: The data obtained indicate that (a) the RBE values at the entry of the unmodulated beam and at the center of the SOBP are in close agreement, with an average of about 1.10; (b) protons are radiobiologically somewhat more effective than 60Co gamma rays; and, (c) high pulse dose rate of the medical beam does not significantly affect biological effects of the beam. PMID- 7852118 TI - Pharmacokinetics and dose estimates following intrathecal administration of 131I monoclonal antibodies for the treatment of central nervous system malignancies. AB - PURPOSE: Treatment of malignant disease in the central nervous system (CNS) with systemic radiolabeled monoclonal antibodies (MoAbs) is compromised by poor penetration into the cerebrospinal fluid (CSF), limited diffusion into solid tumors, and the generation of anti-mouse antibodies. To attempt to avoid these problems we have treated patients with diffuse neoplastic meningitis with radioimmunoconjugates injected directly into the intrathecal space. METHODS AND MATERIALS: Tumor-specific MoAbs were conjugated to Iodine-131 (131I) (629-3331 MBq) by the Iodogen technique, and administered via an intraventricular reservoir. A clinical response rate of approximately 33% was achieved, with better results in more radiosensitive tumors. Here, we present detailed pharmacodynamic data on patients receiving this intracompartmental targeted therapy. RESULTS: Elimination from the ventricular CSF appeared biphasic, with more rapid clearance occurring in the first 24 h. Radioimmunoconjugate entered the subarachnoid space and subsequently the vascular compartment. From this information, the areas under the effective activity curves for ventricular CSF, blood, and subarachnoid CSF were calculated to permit dosimetry. Critical organ doses were calculated using conventional medical internal radiation dose (MIRD) formalism. Where available, S-values were taken from standard tables. To calculate the doses to CSF, brain, and spinal cord, S-values were evaluated using the models described in the text. CONCLUSION: A marked advantage could be demonstrated for the dose delivered to tumor cells within the CSF as compared to other neural elements. PMID- 7852119 TI - Sphincter preservation with preoperative radiation therapy and coloanal anastomosis. AB - PURPOSE: To determine if preoperative radiation therapy allows sphincter preservation in the treatment of rectal cancer. METHODS AND MATERIALS: Thirty patients with the diagnosis of invasive, resectable, primary adenocarcinoma of the rectum limited to the pelvis were enrolled on a Phase I/II trial of preoperative radiation therapy plus low anterior resection/coloanal anastomosis. By preoperative assessment, all patients had invasive tumors (2: T2 28:T3) involving the distal half of the rectum and required an abdominoperineal resection. The median tumor size was 4 cm (range: 1.5-6 cm) and the median distance from the anal verge was 4 cm (range: 3-7 cm). The whole pelvis received 46.8 Gy followed by a 3.60 Gy boost to the primary tumor bed. The median follow up was 43 months (range: 6-82 months). RESULTS: Of the 29 patients who underwent resection, 3 (10%) had a complete pathologic response and 24 (83%) were able to successfully undergo a low anterior resection/colonanal anastomosis. The incidence of local failure was crude: 17% and 4-year actuarial: 23%. The 4-year actuarial survival was 75%. One patient developed a partial disruption of the anastomosis and two developed rectal stenosis. Analysis of sphincter function using a previously published scale was performed at the time of last follow-up in 22 of the 24 patients who underwent a low anterior resection/coloanal anastomosis. Function was good or excellent in 77%. The median number of bowel movements/day was two (range: 1-6). CONCLUSIONS: This technique may be an alternative to an abdominoperineal resection in selected patients. Continued follow-up is needed to determine if this approach ultimately has similar local control and survival rates as an abdominoperineal resection. PMID- 7852120 TI - A prospective neurocognitive evaluation of children treated with additional chemotherapy and craniospinal irradiation following isolated central nervous system relapse in acute lymphoblastic leukemia. AB - PURPOSE: A prospective assessment of neurocognitive performance was conducted in children with acute lymphoblastic leukemia (ALL) following isolated central nervous system (CNS) relapse to evaluate the impact of additional systemic/intrathecal (IT) chemotherapy and craniospinal irradiation (CSI) upon long-term intellectual function. METHODS AND MATERIALS: Twenty-one children with ALL manifesting an isolated CNS relapse between 1984 through 1989 underwent serial evaluations of intellectual function. Neurocognitive function was measured by the full-scale intelligence quotient (FSIQ) as determined by the age appropriate Wechsler Intelligence Scale and by achievement in reading, math, and spelling as assessed by the Wide Range Achievement Test (WRAT). Intelligence testing was initiated following isolated CNS relapse after clearance of cerebrospinal fluid (CSF) cytology but prior to CSI and continued at annual intervals for a minimum of 4 years postmeningeal failure. Protocol treatment for isolated CNS relapse consisted of reinduction and maintenance systemic therapy, intrathecal (IT) triple-agent chemotherapy, and early CSI (cranium to 24 Gy and spine to 15 Gy at 1.5 Gy/fraction) as outlined on the institutional "Total XI" trial. RESULTS: All 21 children attained secondary CNS remission and underwent the planned additional systemic/IT chemotherapy and CSI. Fourteen of the 21 children remain in secondary continuous remission, while the remaining 7 experienced a second relapse and were removed from further neurocognitive assessment. For the eight female and six male long-term survivors, mean ages at original diagnosis and at CSI were 5.7 years (range = 0.6-16.2) and 7.0 years (range = 1.8-17.0), respectively. At a median follow-up interval of 4.6 years (ranges 1.7-6.8) post-CNS relapse, comparison of group mean initial to final FSIQs revealed no statistically significant difference between the two measures (94.5 vs. 95.9, respectively, n = 11, p = 0.52). None of the children are functioning in the mentally retarded range. Final FSIQ outcome directly correlated with initial FSIQ (p = 0.00005, n = 11), age at diagnosis (p = 0.009, n = 14), and age at CSI (p = 0.011, n = 14). In addition, change between initial and final FSIQ scores inversely correlated with age at diagnosis (p = 0.009) and age at CSI (p = 0.018) but not with baseline IQ score (p = 0.41). Initial FSIQ scores were not influenced by either age at diagnosis (p = 0.12) or age at CSI (p = 0.14). Final group mean (range) WRAT scores in reading, math, and spelling were measured to be 94.7 (68-132), 95.6 (69-126), and 93.7 (77-122), respectively (n = 13). Final reading and math scores directly correlated with both age at diagnosis (p = 0.01) and age at CSI (p = 0.009). Spelling outcome did not correlate with either age at diagnosis (p = 0.25) or age at CSI (p = 0.24). Nine children are placed in regular classrooms, while the remaining five require a mixed classroom environment. CONCLUSION: In our study, children with ALL experiencing an isolated CNS relapse tolerated additional systemic/IT chemotherapy and CSI without apparent deterioration of group serial intellectual scores. However, longitudinal analyses of group intellectual measures obscured the independent impact of initial FSIQ, age at original diagnosis, and age at CSI upon individual neurocognitive outcome. Early and more intensive psychoeducational stimulation may be needed in very young children presenting with low initial FSIQ scores who are treated with CSI and additional chemotherapy following isolated CNS relapse in ALL. PMID- 7852121 TI - Transforming growth factor alpha expression as a potential survival prognosticator in patients with esophageal adenocarcinoma receiving high-dose radiation and chemotherapy. AB - PURPOSE: Transforming growth factor alpha (TGFA) stimulates the growth and proliferation of cells, and its overexpression has been correlated with patient survival in a variety of tumors, including squamous carcinoma of the esophagus. This study was performed to investigate the influence of TGFA in patients with esophageal adenocarcinoma (EA) receiving high-dose radiation and chemotherapy (HDRCT). METHODS AND MATERIALS: Thirty-one patients with localized esophageal adenocarcinoma were enrolled in a Phase II study involving high dose radiation and concurrent 5-fluorouracil (5-FU)/mitomycin-C with or without esophagectomy. Twenty-seven pretreatment (tumor not available in 4) and 11 posttreatment (insufficient tumor in 20) specimens were immunostained using the avidin-biotin peroxidase technique. RESULTS: Fifteen of 27 (56%) pretreatment and 4 out of 11 (36%) postchemoradiation specimens had intense TGFA staining. Eight patients with intense and seven with little or no staining on pretreatment biopsy underwent esophagectomy. Median survival for the eight patients was 28 months, and for the seven patients 19 months (p = 0.4). Transforming growth factor alpha staining of posttreatment specimens that contained residual tumor also did not correlate with overall (p = 0.36) or disease-free (p = 0.17) survival. Among the 10 patients with both pre and posttreatment TGFA specimens, decreasing or negative TGFA expression was associated with a better median disease-free survival (32 vs. 13 months, p = 0.04) than persistently positive or increasing TGFA expression. CONCLUSION: There is frequent overexpression of TGFA in EA. Although pretreatment TGFA expression was not associated with survival, patients with tumors that persistently expressed or that increased TGFA expression had a worse prognosis. Posttreatment TGFA expression may serve as a prognostic marker in patients with EA treated with HDRCT. PMID- 7852122 TI - Results of radiotherapy and vitamin E in the treatment of Peyronie's disease. AB - PURPOSE: A retrospective analysis of 38 patients with Peyronie's disease treated with primary radiotherapy in the period of 1975-1993. METHODS AND MATERIALS: Important complaints were curvature of the penis during erection for 92% of the patients, painful erection for 68%, and problems with sexual intercourse for 37.5%. Average size of all indurated plaques was 2.5 cm. The average pretreatment duration of symptoms was 9.5 months. All 38 patients were irradiated with orthovoltage radiotherapy (200 and 250 kV photons) with a total dose of 9 Gy in 5 alternating days (regimen A). Because of minimal response, 16 patients were irradiated again with another 9 Gy in 5 days and finally received 18 Gy (regimen B). RESULTS: With regimen A, a satisfying improvement was achieved for the majority of the patients: 65% experienced less penile pain during erection, 40% reported less curvature of the penis, and 47% experienced an improvement of their sex life. With the higher dose of regimen B there was an additional improvement for a minority of the patients: 25% reported less pain during erection, 21% had less curvature, and 29% experienced an improved sex life. With regimen A, pain improvement was statistically significantly superior when compared to regimen B. For all other improvements (curvature, sexual intercourse, and induration) no dose-response relation could be demonstrated between regimen A and the higher dose regimen B. No patient experienced any radiation-induced morbidity. After evaluating regimen A and regimen B, the overall result was that 76% experienced less pain, 60% reported an improved sex life, and 48% had a diminished curvature during erection. CONCLUSION: From this analysis it can be concluded that the distressing symptoms of Peyronie's disease can be treated successfully with radiotherapy. Radiotherapy proves to be a safe, noninvasive treatment method without causing morbidity. Low-dose radiotherapy with only a few fractions is recommended for an effective treatment result. PMID- 7852123 TI - Base of skull and cervical spine chordomas in children treated by high-dose irradiation. AB - PURPOSE: To evaluate the outcome of children with base of skull or cervical spine chordomas treated by high dose irradiation. METHODS AND MATERIALS: Eighteen children, 4 to 18 years of age, with base of skull or cervical spine chordomas, received fractionated high-dose postoperative radiation using mixed photon and 160 MeV proton beams. The median tumor dose was 69 Cobalt Gray-equivalent (CGE) with a 1.8 CGE daily fraction. RESULTS: The median follow-up was 72 months. The 5 year actuarial survival was 68% and the 5-year disease-free survival (DFS) was 63%. The only significant prognostic factor was the location: patients with cervical spine chordomas had a worse survival than those with base of skull lesions (p = 0.008). The incidence of treatment-related morbidity was acceptable: two patients developed a growth hormone deficit corrected by hormone replacement, one temporal lobe necrosis, and one fibrosis of the temporalis muscle, improved by surgery. CONCLUSION: Chordomas in children behave similarly to those in adults: children can receive the same high-dose irradiation as adults with acceptable morbidity. PMID- 7852124 TI - Dosimetry and clinical implementation of dynamic wedge. AB - PURPOSE: Wedge-shaped isodoses are desired in a number of clinical situations. Physical wedge filters have provided nominal angled isodoses with dosimetric consequences of beam hardening, increased peripheral dosing, nonidealized gradients at deep depths, along with the practical consequences of filter handling and placement problems. Dynamic wedging uses a combination of a moving jaw and changing dose rate to achieve angled isodoses. The clinical implementation of dynamic wedge and an accompanying quality assurance program are discussed in detail. METHODS AND MATERIALS: The accelerator at our facility has two photon energies (6 MV and 18 MV), currently with dynamic wedge angles of 15 degrees, 30 degrees, 45 degrees, and 60 degrees. The segmented treatment tables (STT) that drive the jaw in concert with a changing dose rate are unique for field sizes ranging from 4.0 cm to 20.0 cm in 0.5 cm steps, resulting in 256 STTs. Transmission wedge factors were measured for each STT with an ion chamber. Isodose profiles were accumulated with film after dose conversion. For treatment planning purposes, dmax orthogonal dose profiles were measured for open and dynamic fields. Physical filters were assigned empirically via the ratio of open and wedge profiles. RESULTS: A nonlinear relationship with wedge factor and field size was found. The factors were found to be independent of the stationary field setting or second order blocking. Dynamic wedging provided more consistent gradients across the field compared with physical filters. Percent depth doses were found to be closer to open field. The created physical filters provided planned isodoses that closely resembled measured isodoses. Comparative isodose plans show improvement with dynamic wedging. CONCLUSIONS: Dynamic wedging has practical and dosimetric advantages over physical filters. Table collisions with physical filters are alleviated. Treatment planning has been solved with an empirical solution. Dynamic wedge is a positive replacement for physical filters, and a first step for commercial introduction of dynamic conformal therapy. PMID- 7852125 TI - The use of an electronic portal imaging device for exit dosimetry and quality control measurements. AB - PURPOSE: To determine ways in which electronic portal imaging devices (EPIDs) could be used to (a) measure exit doses for external beam radiotherapy and (b) perform quality control checks on linear accelerators. METHODS AND MATERIALS: When imaging, our fluoroscopic EPID adjusts the gain, offset, and frame acquisition time of the charge coupled device (CCD) camera automatically, to allow for the range of photon transmissions through the patient, and to optimize the signal-to-noise ratio. However, our EPID can be programmed to act as an integrating dosemeter. EPID dosemeter measurements were made for 20 MV photons, for different field sizes and thicknesses of unit density phantom material placed at varying exit surface to detector distances. These were compared with simultaneous Silicon diode exit dose measurements. Our exit dosimetry technique was verified using an anthropomorphic type phantom, and some initial measurements have been made for patients treated with irregularly shaped 20 MV x-ray fields. In this dosimetry mode, our EPID was also used to measure certain quality control parameters, x-ray field flatness, and the verification of segmented intensity modulated field prescriptions. RESULTS: Configured for dosimetry, our EPID exhibited a highly linear response, capable of resolving individual monitor units. Exit doses could be measured to within about 3% of that measured using Silicon diodes. Field flatness was determined to within 1.5% of Farmer dosemeter measurements. Segmented intensity modulated fields can be easily verified. CONCLUSIONS: Our EPID has the versatility to assess a range of parameters pertinent to the delivery of high quality, high precision radiotherapy. When configured appropriately, it can measure exit doses in vivo, with reasonable accuracy, perform certain quick quality control checks, and analyze segmented intensity modulated treatment fields. PMID- 7852126 TI - Three-dimensional conformal pancreas treatment: comparison of four- to six-field techniques. AB - PURPOSE: We compare practical conformal treatment approaches to pancreatic cancer using 6 and 18 MV photons and contrast those approaches against standard techniques. METHODS AND MATERIALS: A four-field conformal technique for treating pancreas cancer has been developed using nonopposed 18 MV photons. This approach has been extended to 6 MV photon application by the addition of one to two fields. These techniques have been optimized to increase sparing of normal liver and bowel, compared with opposed-field methods, to improve patient tolerance of high doses. In this study we compare these techniques in a simulated tumor model in a cylindrical phantom. Dose-volume analysis is used to quantify differences between the conformal, nonopposed techniques with conformal, opposed field methods. This model is also used to evaluate the effect of 1-2 cm setup errors on dose-volume coverage. RESULTS: Dose-volume analysis demonstrates that five-to-six field conformal treatments using 6 MV photons provides similar or better dose coverage and normal tissue sparing characteristics as an optimized 18 MV, four field approach when 1-2 cm margins are included for setup uncertainty. All approaches using nonopposed beam geometry provide significant reduction in the volume of tissue encompassed by the 30-50% isodose surfaces, as compared with four-field box techniques. CONCLUSIONS: Three-dimensional (3D) conformal treatments can be designed that significantly improve dose-volume characteristics over conventional treatment designs without costing unacceptable amounts of machine time. Further, deep intraabdominal sites can be adequately accessed and treated on intermediate energy machines with a relatively moderate increase in machine time. PMID- 7852127 TI - Asymmetric arc technique for posterior pharyngeal wall and retropharyngeal space tumors. AB - PURPOSE: Tumors of the posterior pharyngeal wall and nasopharyngeal cancer with retropharyngeal extension can partly encircle the cervical vertebrae. Treating the patient within spinal cord tolerance can cause a geographic miss. A simple technique has been developed to avoid this problem. METHODS AND MATERIALS: The standard fields for posterior pharyngeal wall and nasopharyngeal tumors are used up to 36-40 Gy. A planning computed tomography (CT) scan is taken during the second or third week of treatment with the patient fitted in a new shell ensuring that the cord is straight and parallel to the treatment couch. The asymmetric arc technique consists of two posterior arcs with closure of one jaw beyond the central axis. Each arc delivers the total dose to each ipsilateral side, while the median region of the U-shaped volume is treated by the summation of both arcs. RESULTS: We have treated 10 patients using asymmetric arcs in the last 3 years. This technique proved to be a versatile way of treating targets wrapped around the spine. The technique allows better individualization for target volume irregularities than the partial rotation with a central bar. PMID- 7852128 TI - Evaluation of linear accelerator radiosurgical techniques using biophysical parameters (NTCP and TCP). AB - PURPOSE: Several irradiation techniques are compared with regard to normal tissue complication probability and tumor control probability. METHODS AND MATERIALS: Normal tissue complication probability is calculated using a model based on the "critical element architecture." The probability of controlling an inhomogeneously irradiated tumor is calculated using a model that takes into account the heterogeneity of tumors (different radiosensitivity of clonogens within the tumor and the varying number of clonogens among patients with the same kind of tumor). The ratio of tumor control probability to normal tissue complication probability (therapeutic gain factor) at different levels of dose has been used as a score for the analysis of various irradiation techniques. RESULTS: The best irradiation techniques depends on many factors: irradiation genometry, irradiation field size, choice of the reference isodose, and it is dictated by the pathology of the lesions (noninfiltrating radioresistant tumors, infiltrating radioresistant tumors, noninfiltrating radiosensitive tumors, infiltrating radiosensitive tumors, arterovenous malformations). For the irradiation of the artero-venous malformations it is proposed to insert on the supplemental collimator a flattening filter to reduce the probability of inducing a poorly syncronized obliterative effect. CONCLUSION: We propose that for each kind of pathology to be treated radiosurgically, a proper irradiation strategy should be used. PMID- 7852130 TI - Single isocenter treatment planning for homogeneous dose delivery to nonspherical targets in multiarc linear accelerator radiosurgery. AB - PURPOSE: Conventional radiosurgery refers to single isocenter focused beam irradiation of small intracranial targets with a single collimator. Conventional radiosurgery is characterized by spherical-shaped isodose surfaces. Nonspherical targets require a different approach to avoid exposing a large volume of nontarget brain tissue to high dose, particularly for lesions larger than 25 mm. Multiple isocenters are frequently used to treat nonspherical large targets, but multiple isocenter treatments are associated with a relative dose inhomogeneity of approximately 100% within the target volume, and may be correlated with an increased rate of complications. The feasibility of conformally treating elongated targets to an approximately homogeneous dose using a single isocenter methodology will be demonstrated. METHODS AND MATERIALS: A prolate ellipsoid of revolution, 25 mm in diameter, 35 mm in length, positioned at five representative locations in a head phantom, was used as a target model. The alignment of the target was taken to be parallel in turn to each of the three principal axes of the head model (A/P, R/L, and C/C). Dose conformation is achieved by nonuniform arc weighting, selective limitation of the extent of individual arcs, and the use of different collimator apertures for the different arcs in accordance with the aperture size required to encompass the target for that arc. Treatment plans were selected based on considerations of dose-volume histograms and conformation of the 80% dose surface with the surface of the target. The goal was that the minimum target dose would not be less than 80% of the maximum dose. RESULTS: Practical treatment plans for which the minimum target dose exceeded 80% were obtained for the three orthogonal orientations of the target for the five target locations. Plan parameters were essentially independent of the target position, dependent only on target orientation. The 80% isodose contour surface enclosed on average 2.8 cm3 larger volume (range: 2.1-3.9 cm3) than the prescribed 11.45 cm3 target. The minimum dose to the target ranged from 80.1 to 84.5%, and the average dose to the target was 94.26%. The 80-to-50% dose volume enclosed an average of 14.8 cm3 of nontarget volume (range: 12.7-15.9 cm3). Average deviation in the principal planes of the 80% isodose lines from the surface of the target volume was 0.95 mm for the 25 mm dimension (range 0.0 to +1.9 mm) and 0.86 mm (range 0.0 to + 2.4 mm) for the 35 mm dimension. CONCLUSION: Standardized single isocenter treatment plans with the isocenter at the center of the target can achieve good conformation of the dose distribution to targets elongated along any of the principal axes, and located anywhere in the brain. PMID- 7852129 TI - Photoneutrons from high energy medical linear accelerators: measurement of the spectrum and dose using a miniature proportional counter. AB - PURPOSE: A new method of measuring photoneutron dose to the patient during treatment with high energy photon or electron beams is presented. This method has the advantage of providing not only the dose, but the microdosimetric spectrum at the same time. METHODS AND MATERIALS: A miniature cylindrical gas proportional counter (0.5 mm diameter by 0.5 mm height) has been used to measure scatter radiation from a 20 MV teletherapy photon beam. At atmospheric pressure, filled with propane base tissue equivalent gas, this counter simulates a unit density tissue region of approximately 0.9 microns. We present here single event microdosimetric spectra measured outside the primary beam 1.4 m from the target. This technique allows a single measurement to determine the scattered dose due to gammas and photoneutron contamination, as well as the quality factor of the photoneutrons. RESULTS: Spectral components from scattered photons and the photoneutrons are easily separated, and dose contributions can be estimated. The ratio of photoneutron dose measured by the proportional counter to photon dose at isocenter is 0.75 x 10(-4). CONCLUSIONS: Neutron dose was also measured using a bubble neutrometer. The proportional counter and neutrometer agree within experimental errors. This type of instrument is shown to be a viable technique for determination of exposure of patient and also personnel to photoneutrons, providing not only a dose determination, but also a spectrum that can be used to estimate quality factors for equivalent dose. Its main drawback is that it requires a lengthy (several hours) measurement because of low count rate of the neutrons. PMID- 7852131 TI - Radiation oncologists can assist head and neck cancer patients with smoking cessation. PMID- 7852132 TI - Echographic monitoring of response of extraocular muscles to irradiation in Graves' ophthalmopathy. AB - PURPOSE: Confirmation of the efficacy of orbital irradiation in Graves' ophthalmopathy is needed due to the unpredictable natural history of the disease, the variation in individual clinical presentations, the contribution of other simultaneous treatments, and the lack of controlled studies using objective criteria to classify and assess response over time. Orbital echography before and at select intervals following orbital irradiation is proposed as an objective parameter of tissue response to orbital irradiation over time. METHODS AND MATERIALS: From January, 1983 to September, 1993, 55 patients with progressive Graves' ophthalmopathy underwent 20 Gy retrobulbar irradiation. On retrospective review, standardized orbital echography was performed randomly prior to irradiation in 37 of the 55 patients to assess the acoustic characteristics of the extraocular muscles and to quantitate their individual and summed diameters. Twenty-one patients had at least one follow-up echographic evaluation at random intervals of 0 to 27.5 months following completion of irradiation. Twelve patients received steroids before or during irradiation, which were tapered in proximity to completion of radiation. Follow-up ranged from 2 to 65 months with the majority followed at least 6 months (18 patients). RESULTS: Of the 21 patients with serial studies, 18 showed an interval decrease in individual and summed muscle size over time and return of symmetry. Interval improvement was documented as early as the 1 month follow-up study, with continued improvement seen during the 3-9-month studies, with stability typically achieved within 12 months. One patient had further changes between the 21 and 27.5 month follow-up studies. Exacerbation of disease was, however, echographically demonstrated in three patients at 6.5, 8.5, and 13 months. Follow-up studies in two of these patients again revealed improvement, one following tapered steroids. The third patient required orbital decompression. CONCLUSION: Objective parameters of response are needed to document both the immediate and long-term outcome of orbital irradiation on the course of Graves' ophthalmopathy and confirm its efficacy. Serial echography is proposed as a new technique for providing parameters to judge response. PMID- 7852133 TI - Oral pilocarpine for radiation-induced xerostomia: integrated efficacy and safety results from two prospective randomized clinical trials. AB - PURPOSE: Pilocarpine hydrochloride administered in either a fixed-dose or in a dose-titration protocol three times a day for 12 weeks was evaluated for its ability to relieve symptoms of postradiation xerostomia and to improve saliva production. The studies were randomized, double-blind, placebo-controlled, multicenter clinical trials. A total of 369 patients who had received at least 40 Gy of radiation to the head and neck with clinically significant xerostomia were enrolled in the two studies. In the dose-titration study, 162 patients were enrolled and they received a thrice daily regimen of 2.5 mg tablets for first 4 weeks, 5.0 mg tablets for the second 4 weeks, and 10.0 mg tablets for last 4 weeks of a 12-week study. Patients in the titration study were allowed to down titrate following at least one dose escalation to alleviate bothersome side effects, if any. In the fixed dose study, 207 patients received either placebo, 5.0 mg, or 10.0 mg tablets t.i.d. for 12 weeks. METHODS AND MATERIALS: Patients were evaluated for symptomatic relief by responding to questionnaires using visual analog scales and categorical questions; and, for saliva production by sialometry. Questionnaires measured relief of intraoral dryness, improvement in overall condition (global response), oral discomfort, difficulty in speaking, chewing and swallowing, denture wearing, and usage of artificial saliva. Evaluations were conducted at baseline, and weeks 4, 8, and 12. RESULTS: There were statistically significant improvements in salivary flow in pilocarpine treatment groups vs. placebo. There was a significant improvement in the overall "global" condition of xerostomia associated with the use of pilocarpine in both studies. In the fixed-dose study, there were significant improvements in oral dryness, mouth comfort, ability to speak, and reduction in the use of oral comfort agents. The dose-titration study showed improvements in dryness that approached significance (p = 0.057) and a decreased use of oral comfort agents (p = 0.045). All pilocarpine dosages (2.5, 5.0, and 10.0 mg three times a day) were judged to be safe. Adverse experiences were those expected for a cholinergic agonist, with the most common being mild to moderate sweating. The incidence of these events increased by dose. CONCLUSION: It is concluded that in these studies pilocarpine produced clinically significant benefits with acceptable side effects and risks for the treatment of symptomatic postradiation xerostomia. The incidence of most adverse events increased with dose. Best results may require continuous treatment for more than 8 weeks with doses greater than 2.5 mg three times a day. A 5.0 mg thrice daily regimen produced the best clinical results when both efficacy and side effects were taken into consideration. There may be some patients who would experience some additional benefit by increasing the dose to 10 mg thrice daily. PMID- 7852134 TI - Brain tumors in children--lifetime for patients and investigators. PMID- 7852135 TI - Central nervous system relapse in children with acute lymphoblastic leukemia. PMID- 7852136 TI - How much is enough? The continuing evolution of therapy in childhood rhabdomyosarcoma and its refinement. PMID- 7852137 TI - Radical nonoperative management of early rectal cancer. PMID- 7852138 TI - Concurrent cisplatinum and radiation for advanced head and neck cancer. PMID- 7852139 TI - Concerns regarding technique using parallel-opposed high-energy electron beams for reirradiation of tumors near the spinal cord (recurrent Hodgkin's lymphoma) PMID- 7852140 TI - In response to Dr. Rajan et al. regarding The management of histologically unverified presumed cerebral gliomas with radiotherapy (IJROBP 28:405-413; 1994) PMID- 7852141 TI - The management of histologically unverified presumed cerebral gliomas with radiotherapy. PMID- 7852142 TI - Some common causes of treatment prolongation. PMID- 7852143 TI - Response to Dr. Schmidt-Ullrich et al.--Re: "Altered expression of epidermal growth factor receptor ..."; Schmidt-Ullrich et al., IJROBP 29:813-819; 1994. PMID- 7852144 TI - Radiotherapy in Vietnam: Regarding reflections on radiotherapy in Vietnam: political lessons still to be learned. IJROBP 28:773-775; 1994. PMID- 7852145 TI - In response to Janjan et al: Reflections on radiotherapy in Vietnam: political lessons still to be learned. IJROBP 28:773-775; 1994. PMID- 7852146 TI - In response to Janjan et al. PMID- 7852147 TI - Response to the letter of Dr. Cohen. PMID- 7852148 TI - In response to Flickinger et al. PMID- 7852149 TI - Response to the editorial of Pellegrini "Radiation prophylaxis of heterotopic ossification" IJROBP 30:743-744; 1994. PMID- 7852150 TI - Clarification regarding radiation-induced height impairment in pediatric Hodgkin's disease. PMID- 7852151 TI - Ultrasonographic detection of adrenal gland tumors in two ferrets. AB - Hyperadrenocorticism is recognized as a common medical condition in middle- to old-aged ferrets. Because diagnosis of adrenocortical tumors in ferrets, using results of adrenocorticotropic hormone stimulation or dexamethasone suppression tests, is unreliable, ultrasonography was used as an alternative to laparotomy for the detection of tumors in 2 ferrets. The diagnosis was confirmed by surgical excision and histologic examination of the adrenal gland. In a typical manifestation of the condition, clinical signs in 1 ferret included vulvar swelling and serous to mucopurulent vaginal discharge, which resolved after the adrenalectomy. PMID- 7852152 TI - Terfenadine toxicosis in dogs. AB - Terfenadine is an antihistamine that has been reported to be safe for use in human beings and animals. This report focuses on an index case of terfenadine toxicosis and several cases of terfenadine toxicosis reported to the National Animal Poison Control Center from 1987 through 1992. Adverse effects of terfenadine can be seen with dosages as low as 6.6 mg/kg of body weight. Any accidental exposure to terfenadine should be treated by inducing emesis and by administering activated charcoal, along with supportive care. PMID- 7852153 TI - Thymoma in dogs: 23 cases (1980-1991). AB - Medical records of 23 dogs in which thymoma was diagnosed between Jan 1, 1980 and Dec 31, 1991 were reviewed. All thymomas were located in the cranial mediastinum. Eleven dogs had megaesophagus, and myasthenia gravis was confirmed in 7 of these 11. One dog developed clinical signs of myasthenia gravis after removal of the thymoma. Concurrent, nonthymic neoplasms were found in 5 dogs, and 2 had hypercalcemia. Three dogs developed third-degree atrioventricular heart block, 1 of which had generalized myositis involving the cardiac muscle. None of the dogs had evidence of distant metastasis. Histologically, the predominant tumor types were differentiated epithelial type (9/23) and lymphocyte-rich type (6/23). Clear cells (large cells with nonstaining cytoplasm) comprised > or = 50% of the cell population in tumors from 5 dogs. Mast cells were detected histologically in 85% of the thymomas evaluated. Sixteen dogs were treated, and in 15 of these, surgery was the primary means of treatment. Six of the 9 dogs with megaesophagus that underwent surgery died or were euthanized within 1 week of diagnosis; whereas only 1 of the 4 dogs without megaesophagus that underwent surgery died within 1 week of diagnosis. Two dogs underwent surgery and received adjuvant chemotherapy. One dog died of complications associated with chemotherapy. One dog was treated with chemotherapy alone and survived 14 months. Seven dogs did not undergo treatment; 4 of these were euthanatized immediately after the mass was first discovered.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7852155 TI - Recurrent reproductive failure associated with porcine reproductive and respiratory syndrome in a swine herd. AB - An investigation of a case of recurrent reproductive failure in a swine herd was conducted. The subject farm (A) and a neighboring farm (B) had experienced an acute outbreak of porcine reproductive and respiratory syndrome in 1990. During 1992, farm A experienced recurrent episodes of conception failure, stillbirths, preweaning mortality, and sow mortality. Similar clinical findings were not evident on farm B. Evaluation of production records indicated that the problem was occurring in first-parity litters. It was learned that replacement gilts for farm A were being purchased from an outside source, whereas farm B raised its own replacement gilts. Indirect fluorescent antibody testing of gilts from both farms indicated a high prevalence of seronegative gilts on farm A vs a high prevalence of seropositive gilts on farm B. Although there is no correlation between indirect fluorescent antibody titers and immunity, it would appear that exposure to porcine reproductive and respiratory syndrome virus prior to breeding is essential to prevent reproductive disease. PMID- 7852154 TI - Eastern equine encephalomyelitis virus infection in swine. AB - In 1 of 2 outbreaks of eastern equine encephalomyelitis virus (EEEV) infection in swine, 280 of 350 pigs died. Histopathologic findings in the brain were typical of EEEV infection. In addition, multifocal necrosis and inflammation were seen in the myocardium. Follow-up investigation in 1 of the herds revealed antibody response to EEEV in surviving pigs and in adult swine. Growth retardation was noticed in surviving pigs. Histologic examination revealed mild lesions in the brain of the survivors. PMID- 7852156 TI - Use of a full-thickness autograft on the tarsus of an ostrich. AB - Full-thickness, cutaneous autografting was successfully performed on an adult female ostrich to heal a granulomatous wound on the right tarsus. With surgical techniques used in domestic species such as dogs and horses, skin grafting is an alternative in avian species when conventional wound closure is not appropriate. PMID- 7852157 TI - Use of naltrexone for treatment of psychogenically induced dermatoses in five zoo animals. AB - Naltrexone was used successfully in controlling self-mutilation behavior in 3 zoo animals from 2 families (Felidae and Sciuridae). It had no effect on 2 other zoo animals from 2 families (Canidae and Ursidae). Long-term administration of glucocorticoids was not satisfactory in controlling the behaviors, and concerns were raised about potential long-term adverse effects, especially with regard to fertility. Detrimental effects were not noticed in any of the zoo animals treated with naltrexone. Two males successfully sired healthy offspring. PMID- 7852158 TI - Periarticular hyperostosis and renal disease in six black lemurs of two family groups. AB - Proliferative periosteal disease was identified in 6 black lemurs (Eulemur macaco macaco) of 2 family groups. Bilaterally symmetric formation of periosteal new bone at the metaphyseal regions of major long bones was first detected at the stifle and tarsal areas and was detected later at the carpal areas. Bony changes were accompanied by progressive renal disease. The syndrome progressed for 6 to 16 months before the lemurs were euthanatized because of debility. Necropsy revealed changes confined to the skeleton and kidneys. Formation of new bone was detected at all affected joints, and chronic renal disease was evident in each lemur. A specific cause was not identified. Although indistinguishable histologically from hypertrophic osteoarthropathy, several important differences were apparent. Distribution of the periosteal new bone was in the metaphyseal rather than diaphyseal areas. Thoracic or gastrointestinal lesions, typically seen with hypertrophic osteoarthropathy, were not detected, and substantial renal disease was evident. A genetic component may be involved in the development of this condition. PMID- 7852159 TI - Characteristics and salaries of laboratory animal veterinarians. PMID- 7852161 TI - AVMA promotes use of public health veterinarians. PMID- 7852160 TI - National Board Examination Committee moves towards independence, approves examination fee increases. PMID- 7852162 TI - Human health. An important aspect of veterinary medicine. PMID- 7852163 TI - Computers: beyond the basics. PMID- 7852164 TI - Cats need friends, too. Examining aggressive behavior in the cat. PMID- 7852165 TI - Adverse reactions to diazepam. PMID- 7852166 TI - Up to speed on information superhighway. PMID- 7852167 TI - Drug compounding. PMID- 7852168 TI - Blastomycosis in a veterinarian. PMID- 7852169 TI - Microsporum canis vaccine. PMID- 7852170 TI - Love for animals and the veterinary profession. PMID- 7852171 TI - Transferring stereotypes about chemotherapy. PMID- 7852172 TI - What is your diagnosis? Transverse fracture of the proximal 4th sesamoid bone of the right front foot. PMID- 7852173 TI - ECG of the month. Recurrent nonclinical supraventricular tachycardia. PMID- 7852174 TI - Oligodendroglioma in a 15-month-old dog. PMID- 7852175 TI - Animal behavior case of the month. Increasing unwillingness to enter the owner's car. PMID- 7852176 TI - Some legal considerations in the management of a veterinary medical association. PMID- 7852177 TI - An echocardiographic and electrocardiographic study of cardiovascular function in hypothyroid dogs. AB - Echocardiograms and ECG were obtained for 11 hypothyroid dogs before and after levothyroxine supplementation (0.022 mg/kg of body weight, q 12 h for 64 +/- 12 days). Evidence of impaired left ventricular function was found in the dogs before treatment. A significant decrease in shortening fraction and velocity of circumferential fiber shortening, increase in left ventricular end-systolic diameter, and prolongation of preejection period was noted when comparing measurements before and after levothyroxine supplementation. Amplitude of the P and R waves was significantly higher after treatment than before. It was concluded that changes in cardiac function can be reversed in hypothyroid dogs. PMID- 7852178 TI - AML1 and Pebp2: the gene for a transcription factor is involved in recurring translocations in human acute myeloid leukemia. PMID- 7852179 TI - Intravenous administration of polyethylene glycol-modified tumor necrosis factor alpha completely regressed solid tumor in Meth-A murine sarcoma model. AB - Complete regression of solid tumors was achieved by plural intravenous (i.v.) administrations of polyethylene glycol (PEG)-modified tumor necrosis factor-alpha (TNF-alpha), prepared by covalently modifying natural human TNF-alpha with N succinimidyl succinate PEG. The anti-tumor efficacy of PEG-modified TNF-alpha (MPEG-TNF-alpha), in which 56% of the TNF-alpha-lysine residues were coupled with PEG, was compared with that of native TNF-alpha in the Meth-A murine fibrosarcoma model. MPEG-TNF-alpha and native TNF-alpha were given as i.v. injections twice a week for 2 weeks. The anti-tumor activity of MPEG-TNF-alpha was dose-dependent and was far superior to that of native TNF-alpha. Complete regression was observed in 3 of the 8 mice administered native TNF-alpha at the dose of 10,000 JRU (Japan reference unit), but 4 of the 5 remaining mice died during the therapeutic period. At 5,000 JRU of native TNF-alpha, no case of complete regression was observed. By contrast, complete regression was obtained in all 10 mice given 200 JRU of MPEG-TNF-alpha. No side-effects were observed at the dose of 500 JRU of MPEG-TNF-alpha, which was 2.5 times the minimal dose (200 JRU) of MPEG-TNF-alpha required for complete regression in all treated mice. MPEG-TNF alpha appears to have potential as a candidate anti-tumor therapeutic agent. PMID- 7852180 TI - High frequency of cancer patients with abnormal assembly of the T cell receptor CD3 complex in peripheral blood T lymphocytes. AB - Structural abnormality of T cell receptor (TCR)-CD3 complex on the cell surface was investigated in peripheral blood lymphocytes (PBL) from 55 cancer patients. In 24 of the 68 tests done on these patients, the CD3 zeta chain was not detected by immunoprecipitation with anti-CD3 epsilon monoclonal antibody (mAb), but was observed with anti-CD3 zeta mAb, suggesting that a high frequency of cancer patients possesses abnormal T cell receptor (TCR) complex in PBL. On the other hand, the total zeta chain was missing in several advanced cases. During follow up of several patients, the zeta chain became undetectable after two or three months of cancer progression. It appears that immunosuppressive status can be monitored by analyzing the TCR-CD3 complex on the cell surface of PBL. PMID- 7852181 TI - High detection rate of breast cancer by mass screening using mammography in Japan. AB - A trial of mass screening for breast cancer using both mammography and physical examination (independently) was carried out in women over 50 years of age in Tokushima Prefecture. Breast cancer was detected in eight of a total of 950 examinees by mammography alone, and no cases of breast cancer were detected by physical examination. The detection rate of breast cancer was 0.84%, which is very much higher than that obtained by conventional mass screening using physical examination alone. The detection rate increased especially in the sixth and seventh decades of life. All eight detected breast cancers were in the early stage. Based on these results, it is recommended to employ mammography in breast cancer screening for asymptomatic women aged over 50 years. PMID- 7852182 TI - Risk of lung cancer among cigarette smokers in relation to tumor location. AB - To evaluate the effect of cigarette smoking on lung cancer by tumor location and histological type, we compared the smoking history obtained from medical records of 605 patients with squamous cell carcinoma (194 males and 10 females) or adenocarcinoma (219 males and 182 females) of the lung and 183 patients with metastatic lung cancer (82 males and 101 females) who had been aged 40 years or over at the time of surgical resection at the Cancer Institute in Tokyo from 1973 1991. The tumors which developed in a main or segmental bronchus were classified as central type, and those in a subsegmental or more distal bronchi were categorized as peripheral type. Cases with adenocarcinoma were classified by a pathologist into two histological subtypes, papillary and tubular types, according to the WHO lung carcinoma classification. Risk of squamous cell carcinoma was strongly associated with cigarette smoking for both central (OR (odds ratio) = 10.3 in males and 4.4 in females) and peripheral sites (OR = 10.7 in males and 6.5 in females). There was no significant association between cigarette smoking and adenocarcinoma for any tumor site or histological subtype in both sexes. PMID- 7852183 TI - Morphogenesis of esophageal carcinoma induced by N-methyl-N'-nitro-N nitrosoguanidine in the house musk shrew, Suncus murinus (Insectivora). AB - The histological changes occurring in the esophageal mucosa of shrews (Suncus murinus) after N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) treatment were investigated sequentially. Six-week-old female shrews were given a 50 micrograms/ml MNNG solution as drinking water for 30 weeks, and 5 selected at random were killed at 10 and 20 weeks of age, and thereafter at 5-week intervals until 45 weeks of age. Controls were killed at 45 weeks of age. The MNNG-induced esophageal lesion in shrews began from basal cell hyperplasia at 20 weeks of age, followed by dysplasia occurring at 25 weeks of age, then progressed toward intraepithelial carcinoma to invasive squamous cell carcinoma at 35 weeks of age. Apparent sequential dysplasia-carcinoma transition was seen. Papillomas were seen from 25 weeks of age but there was no evidence of papilloma-carcinoma sequence. Five MNNG-untreated shrews killed at the end of the experiment were free of esophageal tumors. PMID- 7852184 TI - Chemopreventive effects of beta-carotene, alpha-tocopherol and five naturally occurring antioxidants on initiation of hepatocarcinogenesis by 2-amino-3 methylimidazo[4,5-f]quinoline in the rat. AB - Inhibitory effects of naturally occurring antioxidants on the initiation stage of hepatocarcinogenesis were studied. Group 1 rats were given a diet containing beta carotene (beta-CT, 0.02%), alpha-tocopherol (alpha-TP, 1.5%), glutathione (GLT, 5%), vanillin (VNL, 1%), quercetin (QCT, 1%) or ellagic acid (ELA, 1%), or 3 doses of diallyl sulfide (DAS, 200 mg/kg, i.g.) over an 8-day period. On day 7, the animals received a single dose of 2-amino-3-methylimidazo[4,5-f] quinoline (IQ, 100 mg/kg, i.g.), 12 h after two-thirds partial hepatectomy for initiation and 2 weeks thereafter, were placed on promotion regimen comprising phenobarbital (0.05% in diet) and a single dose of D-galactosamine (100 mg/kg, i.p.). Groups 2 and 3 were treated as described for Group 1, but without test material or IQ, respectively. Survivors were killed at week 11 and antioxidant influence was assessed by comparing values for preneoplastic glutathione S-transferase placental form-positive (GST-P+) foci between Groups 1 and 2. All lesions larger than 70 microns in diameter consisting of approximately 5 cells in cross section were counted. Numbers of GST-P+ foci/cm2 in Group 1 were: beta-CT, 7.99; alpha TP, 8.21; GLT, 9.71; DAS, 10.37; VNL, 10.57; QCT, 11.1; ELA, 12.5 (n = 11-15). All, except ELA, showed a significant decrease as compared with the Group 2 value of 14.54 (n = 15). Only beta-CT showed a significant decrease for the area value. This is the first report to show that beta-CT, alpha-TP, GLT, DAS, VNL, QCT exert inhibitory effects on initiation of hepatocarcinogenesis by the food carcinogen IQ, suggesting that these antioxidants might find application as chemopreventive agents. Furthermore, the current protocol proved practical for the assessment of chemopreventive agents within 11 weeks, a relatively short period. PMID- 7852185 TI - Activation of 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b] pyridine by cDNA expressed human and rat arylsulfotransferases. AB - Sulfation plays an obligatory role in the activation of N-hydroxy derivatives of carcinogenic arylamine (amide)s and heterocyclic amines. We found that the hepatic sulfotransferase-mediated covalent binding of 3H-labeled 2-hydroxyamino-1 methyl-6-phenylimidazo[4,5-b] pyridine (N-OH-PhIP) to calf thymus DNA was 3.3 and 12.9 times higher with human cytosol preparation than with male and female rat cytosol preparations, respectively, in the presence of 3'-phosphoadenosine 5' phosphosulfate. To assess the activating capacities of individual phenol sulfating sulfotransferases, five different forms, human ST1A2 and ST1A3 and rat ST1A1, ST1B1 and ST1C1, were expressed in heterologous cells. All five sulfotransferases mediated the activation of N-OH-PhIP to DNA-bound products. The extents of the binding, however, differed considerably among these forms. Human ST1A2 and ST1A3 mediated the activation of N-OH-PhIP at 5.2- and 6.2-fold higher rates than did rat ST1C1, a main N-hydroxy-2-acetylaminofluorene-activating sulfotransferase, in rat liver. Extents of the binding of N-OH-PhIP in human hepatic cytosols of different individuals were positively correlated with the contents of immunoreactive ST1A2/3. These results suggest a potential role of human liver sulfotransferases in N-OH-PhIP activation. In contrast, the low sulfotransferase-mediated activation of N-OH-PhIP in rat liver is consistent with the lack of PhIP hepatocarcinogenicity in this species. PMID- 7852186 TI - Rearrangement of bcl-2 is detectable in Hodgkin's disease by polymerase chain reaction. AB - The authors examined the occurrence of the t(14;18) chromosomal translocation in 44 cases of Hodgkin's disease (HD) using the polymerase chain reaction and Southern blot hybridization with non-radioactive oligonucleotide probes. DNAs were extracted from unfixed, fresh-frozen and formalin-fixed, paraffin-embedded biopsy specimens. Southern blot hybridization of the amplification product showed that, of 44 HD DNAs, three had a detectable t(14;18) breakpoint at the mbr (major breakpoint region), while none had a detectable t(14;18) breakpoint at the mcr (minor cluster region). Of the three cases positive for a t(14;18) breakpoint at the mbr, two were of lymphocyte predominance type, and the other was of mixed cellularity type. PMID- 7852187 TI - Linkage analysis of BRCA1 in Japanese breast cancer families. AB - We examined the involvement of BRCA1, which plays a major role in Western breast cancer families, in Japanese breast cancer families. Eleven families, in which at least three individuals within third degree relatives were affected by breast cancer, were collected. Five of them were early-onset breast cancer families, in which the average age at diagnosis was less than 45 years, and the other six were late-onset families. Ovarian cancer was observed in one patient in the early onset families. Using seven polymorphic markers on chromosome 17q21, D17S250, ERBB2, THRA1, D17S579, D17S588, GIP and NME1, linkage to BRCA1 was analyzed. Linkage was not detected in any single family. Assuming homogeneity in an inherited component that confines the susceptibility to breast cancer in all families, we summed the LOD scores of all families. The cumulative LOD score obtained was -1.86 for D17S588 at theta = 0.001, indicating no linkage with BRCA1. Since the proportion of families linked to BRCA1 is larger in Western early-onset breast cancer families than in late-onset ones, we also summed the LOD scores of five early-onset families. However, again a negative LOD score was obtained. These results suggest that BRCA1 is not a major breast cancer susceptibility gene in Japanese familial breast cancer. PMID- 7852188 TI - Prognostic significance of p53 and ras gene abnormalities in lung adenocarcinoma patients with stage I disease after curative resection. AB - We investigated the prognostic significance of p53 gene abnormalities and ras gene mutations in patients with curatively resected stage I lung adenocarcinoma. Formalin-fixed and paraffin-embedded tissues were obtained from 30 patients who had undergone curative resection for stage I lung adenocarcinoma. Abnormalities of the p53 gene were detected using polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE) analysis and immunohistochemistry and ras mutations were detected using PCR-restriction fragment length polymorphism (RFLP) analysis. Both univariate and multivariate analyses were performed to assess the relationship between the presence of abnormalities of these genes and the patients' disease-free survival. Eleven tumors (37%) had mutated p53 sequences and 11 (37%) showed p53 overexpression. A total of 15 tumors (50%) had p53 gene abnormalities and the concordance rate was 73%. Seven tumors (23%) showed mutated ras sequences. The univariate analysis revealed that the disease-free survival of patients with any p53 abnormality was shorter than that of those without abnormalities (P = 0.02, generalized Wilcoxon test), and survival of those with p53 protein overexpression was more significantly shorter (P = 0.003, generalized Wilcoxon test). Multivariate analysis using the Cox proportional hazards model indicated that the presence of p53 abnormalities was a significantly (P = 0.01) unfavorable prognostic factor. There was no significant correlation between the presence of ras mutation and survival. These results suggest that analysis of the p53 gene may be helpful for the selection of high-risk patients for clinical trials of adjuvant therapy for stage I lung adenocarcinoma. PMID- 7852189 TI - Alteration of the p53 tumor suppressor gene occurs independently of K-ras activation and more frequently in serous adenocarcinomas than in other common epithelial tumors of the human ovary. AB - To clarify the role of the p53 tumor suppressor gene in the development of human ovarian epithelial tumors and to study the association of p53 alterations with K ras activation, a series of 70 common epithelial ovarian tumors from Japanese patients was studied. These included 31 serous adenocarcinomas, 12 mucinous adenocarcinomas, 5 mucinous tumors of borderline malignancy, 13 endometrioid adenocarcinomas, and 9 clear cell carcinomas. Allelic loss, recognized at the polymorphic site in codon 72 of the p53 gene, was detected in 14 of 36 (39%) informative cases by restriction fragment length polymorphism analysis and by single-strand conformation polymorphism (SSCP) analysis of polymerase chain reaction (PCR)-amplified DNA fragments. Mutations in the highly conserved regions of the p53 gene were detected by SSCP analysis of PCR-amplified fragments. Mutations were found in 22 of 70 (31%) ovarian tumors, including 1 of 5 mucinous tumors of borderline malignancy. Mutations were subsequently characterized by direct sequencing. Single missense base substitutions were detected in 13 ovarian carcinomas and in one case of mucinous tumor of borderline malignancy. Short (1-8 bp) deletions and insertions were found in 8 cases. Mutations in the p53 gene occurred more frequently in serous adenocarcinomas (14/31, 45%) than in all nonserous types of malignant epithelial tumors combined (7/34, 21%; P = 0.032). Point mutations in K-ras were identified by dot blot hybridization analysis of PCR-amplified fragments with mutation-specific oligonucleotides and by direct sequencing. The overall frequency of K-ras mutations was 19/70 (27%). K-ras mutations were found in 12 of 17 (71%) mucinous tumors (8/12 mucinous carcinomas [67%] and 4/5 mucinous tumors of borderline malignancy [80%]), and occurred more frequently than in serous carcinomas (4/31, 13%; P = 0.00009) or in all nonmucinous types of ovarian epithelial tumors combined (7/53, 13%; P = 0.00002). These data suggest that different combinations of oncogenes and/or tumor suppressor genes may be involved in the genesis and development of histologically distinct categories of common epithelial tumors of the human ovary. PMID- 7852190 TI - Serum levels of laminin, type IV collagen and type III procollagen peptide as markers for detection of metastasis. AB - We investigated the clinical usefulness of serum laminin, type IV collagen and type III procollagen peptide (PIIIP) as markers for detection of metastasis in patients with primary or metastatic bone and soft part tumors. The subjects consisted of 28 patients with metastatic bone tumors, 18 with primary bone tumors (benign; 10, malignant; 8), 22 with primary soft part tumors (benign; 12, malignant; 10), 18 with cancer without metastasis (as controls to metastatic bone tumor) and 60 healthy controls. Elevated levels of serum laminin, type IV collagen and PIIIP were not associated with any specific histological subtype, tumor size or location, and were clearly related to evidence of metastasis. Mean serum concentrations of laminin, type IV collagen and PIIIP were significantly higher in patients with metastasis than in patients without metastasis. Positive correlations were observed among serum laminin, type IV collagen and PIIIP levels in tumor patients. The sensitivity values for laminin, type IV collagen and PIIIP in detecting metastasis were 83.7%, 83.3% and 80.5%, respectively, with specificity of 90.0%, 86.1% and 86.1%. When two of the three markers were evaluated in identical blood samples, combined sensitivity and specificity values exhibited further increases as compared to the sensitivity and specificity of each marker. The use of all three markers led to the best combined sensitivity and specificity. These findings suggest that the combination of these markers would be a valuable screening test in predicting metastasis. PMID- 7852191 TI - Synergistic antimetastatic effects of lentinan and interleukin 2 with pre- and post-operative treatments. AB - The antimetastatic activity of a combination of lentinan and interleukin 2 (IL-2) was evaluated against spontaneously metastatic 3-methylcholanthrene-induced DBA/2.MC.CS.T fibrosarcoma. Although pre-operative treatment with either IL-2 or lentinan alone exerted little effect on the reduction of lung metastasis colony numbers (7.1% or 28.4% reduction, respectively), the combination exhibited a synergistic effect (85% reduction). Furthermore, 3 of 13 mice given the pre operative combination treatment achieved complete cure, while no mice given saline did. Although the post-operative combination treatment also reduced the colony number (71% reduction), it caused little prolongation of survival and no mouse achieved complete cure. Synergistic effects were observed between pre- and post-operative treatments with lentinan and IL-2: 8 of 12 mice were completely cured. The anti-metastatic activity was abolished in mice treated simultaneously with antibodies to CD4 and CD8 antigens, whereas either CD4, CD8, or NK1.1 antibody alone was ineffective. Analysis of the cellular mechanism involved in the antimetastatic activity revealed the involvement of a tumor-associated antigen-specific delayed-type hypersensitivity response. These data suggest that the life-prolonging effect of the combination of lentinan and IL-2 is mediated by antigen-specific T cells and that the combination of pre- and post-operative therapy with lentinan and IL-2 may be effective to prevent cancer recurrence and metastasis after surgical resection. PMID- 7852192 TI - An in vivo study of hepatic and splenic interleukin-1 beta mRNA expression following oral PSK or LEM administration. AB - The effects of orally administered biological response modifiers (BRMs) in preventing postoperative micro liver metastasis of primary colorectal cancer were examined in experimental animals. The two BRMs tested were Krestin (PSK) and Lentinus edodes mycelia (LEM). In previous experiments, we found that oral administration of PSK or LEM suppressed liver metastasis and prolonged the survival period. We also found that these agents elevated the liver natural killer (NK) and liver macrophage activities. In the present study in vivo, using reverse transcriptase-polymerase chain reaction (RT-PCR), we examined whether or not the liver and spleen have cytokines which would induce NK cells and macrophages, and whether or not the liver and spleen have cytokines induced by NK cells or macrophages. We placed emphasis on the examination of interleukin (IL)-1 beta expression in the liver and spleen in vivo. Two to six hours after oral administration of PSK or LEM (1 g/kg) to mice, IL-1 beta levels in the liver and spleen rose, and they returned to their baseline levels 24 h later. These findings suggest two possibilities: (1) hepatic IL-1 beta is potentiated by these agents soon after administration, resulting in activation of liver NK cells or macrophages, or (2) these agents stimulate IL-1 beta production by liver macrophages, and the produced IL-1 beta activates liver NK cells or liver macrophages (Kupffer cells). The results of this in vivo study suggest that the potentiation of hepatic and splenic IL-1 beta by PSK and LEM is involved in the early phases of suppression of micro liver metastases of colorectal cancer. PMID- 7852193 TI - Differential effect of duocarmycin A and its novel derivative DU-86 on DNA strand breaks in HeLa S3 cells. AB - Duocarmycin A (DUMA) and DU-86, a semisynthetic derivative of duocarmycins (DUMs) and a possible active form of KW-2189, both showed potent cell growth-inhibitory and cell-killing activities against human uterine cervix carcinoma HeLa S3 cells. Both drugs showed similar profiles of inhibition of macromolecular synthesis and influence on cell-cycle distribution. Namely, they inhibited [3H]thymidine uptake at lower concentrations than [3H]uridine or [3H]leucine uptake, suggesting that the inhibition of DNA synthesis is the primary site of their actions. Furthermore, they induced the accumulation of cells in early S phase. However, a significant difference was observed between these drugs in terms of DNA fragmentation activity against HeLa S3 cells by using two independent methods, pulse-field gel electrophoresis and alkaline elution. DNA fragmentation was insignificant in the cells treated with DU-86, in contrast to the cells treated with DUMA. The analysis of DNA adducts in the cells revealed that DU-86 alkylated adenine quite selectively, while DUMA alkylated both adenine and guanine. These results suggest that the pyrrolidone ring of DUMA is responsible for its adduct formation with guanine and the subsequent DNA-fragmentation and inhibition of DNA synthesis, while DU-86 alkylated adenine and inhibited DNA synthesis through mechanisms other than DNA-fragmentation. PMID- 7852194 TI - Immunocytochemical reactivities of precursor cells and their progeny in the ear of a cichlid fish. AB - Cell types in the inner ear of the fish Astronotus ocellatus were examined for the immunocytochemical reactivity to 31 commercial antibodies. Nine showed positive reactivity: vimentin, S-100, caldesmon, calbindin, MAP-1, MAP-2, parvalbumin, neurofilament, and GAP-43. The cell types examined were: hair cells, support cells, hair cell precursors, eighth nerve neurons, and neuronal precursors. The pattern of reactivities among these cell types lead to the following conclusions. First, hair cells and eighth nerve neurons have a striking immunocytochemical similarity. Second, the precursor cells for hair cells and neurons did not share immunoreactivity with these mature progeny. Third, the only antibody to react with supporting cells also reacted with the proliferating precursors that give rise to new hair cells and supporting cells. Taken with other available data, these finding suggest that in the oscar ear, hair cell precursors and supporting cells are closely related, if not the same cell type. PMID- 7852195 TI - Dysgenesis of melanocytes and cochlear dysfunction in mutant microphthalmia (mi) mice. AB - In order to evaluate the cytological homology of intermediate cells and melanocytes, and to investigate the function of melanocytes in the inner ear, hearing acuity and cochlear pathology were studied in three strains of mice, namely, wild type mice (+/+), albino mice without melanin (c2J/c2J), and microphthalmia mice with no melanocytes (mibw/mibw). Our histochemical data indicated that intermediate cells showed cytological characteristics almost identical to those of melanocytes and that disorders of melanin and/or melanocytes were reflected in the stria vascularis of each mouse. While c2J/c2J presented the same normal hearing acuity and normal structure of the stria vascularis as +/+, the hearing acuity of mibw/mibw mutants was severely impaired. Their stria vascularis was abnormally thin, lacking intermediate cells. According to these results, lack of melanin has little influence on hearing acuity; however, the absence of intermediate cells or melanocytes causes severe hearing loss, presumably due to a strial dysfunction. PMID- 7852196 TI - Modeling the additivity of nonsimultaneous masking. AB - Thresholds were measured for detecting a brief 6-kHz sinusoidal signal preceded by a broadband noise masker (forward masking), followed by the masker (backward masking), or both preceded by and followed by the masker (combined masking). The masker-signal interval was systematically varied. Consistent with the literature, thresholds in the combined-masking condition were higher than would be predicted by an energy-sum of the effects of the individual forward and backward maskers. This is often referred to as 'excess' masking. The data were modeled by subjecting the amplitude of the stimuli to a power-law nonlinearity followed by a sliding temporal integrator ('window'). It was assumed that threshold corresponds to a fixed signal-to-noise ratio at the output of the window. The best fits to the data were obtained using a power less than unity (0.5 to 0.7), i.e. by a compressive nonlinearity. Generally good fits to the data were achieved, indicating that the model is able to account for the decay of forward and backward masking as well as the effects of combining pairs of maskers (excess masking). The temporal windows derived from the data are also able to predict thresholds in decrement and increment detection tasks, and to account for the longer-term effects of masker duration in forward masking. PMID- 7852197 TI - Noise-induced elevations of plasma endothelin (ET-3). AB - The endothelins (ETs) are a novel family of peptides which participate in hemodynamic homeostasis. Elevated levels of circulating ETs are evident in several stress related conditions and are associated with a variety of vascular pathophysiologies. The purpose of the current study was to test the possibility that plasma concentrations of endothelin increase following noise exposure using radioimmunoassay (RIA). No difference in plasma endothelin was detected in rats subjected to brief noise exposure (30 min of 100 dB SPL broad-band noise) compared to control animals. Statistically significant elevations in plasma endothelin (ET-3) were measured in animals exposed to prolonged noise exposure (90 min and 72 h of 100 dB SPL broad-band noise). These results suggest that hemodynamic alterations, and potential vascular pathophysiologies accompanying prolonged exposure to noise are mediated by endothelin. PMID- 7852198 TI - Up-regulation of GAP-43 (B50/F1) gene expression in vestibular efferent neurons following labyrinthectomy in the rat: in situ hybridization using an alkaline phosphatase-labeled probe. AB - Growth-associated protein (GAP)-43 plays a significant role in nerve regeneration and synaptic remodeling. We examined the profiles of GAP-43 mRNA expression in vestibular efferent neurons after labyrinthectomy in adult rats, and clearly demonstrated that labyrinthectomy increased GAP-43 expression in these neurons. This finding suggests the ability of vestibular efferent nerves to regenerate after nerve injury. PMID- 7852199 TI - Cell coupling in the supporting cells of Corti's organ: sensitivity to intracellular H+ and Ca+2. AB - The input capacitance of cell pairs or small groups can be used to gauge the degree of electrical coupling via gap junctions (Santos-Sacchi, 1991). In order to estimate junctional sensitivity to intracellular Ca+2 and H+ concentration, the input capacitance of supporting cell syncytia of the organ of Corti was measured with the whole cell voltage clamp technique, while directly modifying the cation concentrations via the patch pipette. Typically, a pH below 6.5 was capable of uncoupling Hensen cells. On the other hand, pCa levels as low as 3 were ineffective. PMID- 7852200 TI - Solvent-induced ototoxicity in rats: an atypical selective mid-frequency hearing deficit. AB - Most previous reports of ototoxicity following exposure to several volatile organic solvents have restricted testing to the low- and mid-frequencies (2-20 kHz) of the hearing range in the rat (0.25-80 kHz). We report here that inhalation exposure to styrene, mixed xylene, toluene, and 1,1,2 trichloroethylene resulted in hearing dysfunction only in the mid-frequency range and spared function at lower and higher frequencies. Adult male Long Evans rats were exposed via inhalation (whole body) in flow-through chambers. The following exposures were used: styrene, 1600 ppm; 1,1,2-trichloroethylene, 3500 ppm; toluene, 2500 ppm; mixed xylenes, 1800 ppm (N = 7-8 per group, 8 h/day for 5 days), and n-butanol, 4000 ppm (N = 10/group, 6 h/day for 5 days). Testing of auditory function was conducted 5 to 8 weeks after exposure using reflex modification audiometry (RMA). RMA thresholds were determined for frequencies from 0.5 to 40 kHz. Results indicated increased RMA thresholds for the mid frequency tones (e.g., 8 and 16 kHz), but not higher or lower tones, for all solvents except n-butanol. Toluene and xylene also increased thresholds at 24 kHz. These data indicate that for those solvents reported thus far to cause hearing loss, the deficit is restricted to mid-frequencies in rats. PMID- 7852201 TI - Expression of Na+,K(+)-ATPase alpha 1 subunit mRNA in the developing rat cochlea. AB - The distribution of Na+,K(+)-ATPase alpha 1 subunit mRNA was identified using in situ hybridization in the developing rat cochlea. The expression of alpha 1 subunit mRNA in stria vascularis (SV) was observed in all time points studied, 1 to 30 postnatal day (pnd) rats. The adult expression level was attained between 11 to 14 pnd. Surprisingly, alpha 1 subunit mRNA in spiral ligament (SL) and spiral limbus (SLi) was expressed in a more distinct time-dependent manner. At 7 pnd, the alpha 1 subunit mRNA expression was observed initially in the tissues of the SL. At 11 pnd, alpha 1 subunit expression appeared in SLi. Between 11 and 14 pnd, an adult-like pattern of Na+,K(+)-ATPase alpha 1 subunit mRNA expression was attained in the SL and SLi. These data suggest that the expression of Na+,K(+) ATPase alpha 1 subunit mRNA in these areas are closely related to the development of the rat EP, as its expression in the stria vascularis. PMID- 7852203 TI - Cell cycle of transdifferentiating supporting cells in the basilar papilla. AB - Mitosis of supporting cells has been shown to contribute to the cellular repopulation of the basilar papilla after acoustic trauma. In the present work we report data obtained with light and transmission electron microscopy after acoustic trauma in chicks. We report changes that occur in cell shape, surface morphology, intercellular junctions, nuclear shape and location, and cytoplasmic organization of supporting cells after trauma. The findings strongly suggest that supporting cells transdifferentiate and that the proliferative pattern is similar to interkinetic nuclear migration, as previously shown in the developing neural tube and basilar papilla. S-phase nuclei were positioned adjacent to the basement membrane, suggesting that interaction with the extracellular matrix may occur during the cell cycle. Supporting cells divided with the long axis of the spindle parallel to the reticular lamina and displayed no signs of intercellular communication during mitosis. This suggested to us that the fate of the progeny cells is determined prior to mitosis and that the progeny may be of identical phenotypic fate. Dividing cells had a smooth apical surface. The smooth surface may provide a marker to help identify dividing cells with scanning electron microscope analysis. PMID- 7852202 TI - Using an excitation-pattern model to predict auditory masking. AB - This paper evaluates the extent to which auditory masking can be reliably predicted from excitation patterns. For this purpose a quantitative model proposed by Glasberg and Moore [Hear. Res. 47, 103-138 (1990)] was used to calculate excitation patterns evoked by stationary sounds. Model simulations were performed for a number of masking experiments, reported in the literature, by calculating excitation patterns for the masker-alone as well as for the masker plus-target conditions. As a threshold criterion, a difference between the two patterns of 1 dB at any frequency was imposed. For narrow-band-noise masking patterns, the method yields a fairly precise prediction of experimental data. For other conditions, however, systematic deviations between model predictions and data are observed. For instance, the model does not reproduce the typical tip tail shape of psychophysical tuning curves. Furthermore, the nonlinearities in level dependence are not correctly described, and the model fails to reproduce a realistic two-tone masking curve. PMID- 7852204 TI - Belgian Waterslager canaries are afflicted by Scheibe's-like dysplasia. AB - Behavioral investigations of Belgian Waterslager canaries (BWCs) have demonstrated a congenital hearing impairment that primarily affects high frequencies. Research into the surface anatomy of the basilar papilla of these birds has pointed to the hair cells as the site of the lesion. Given that the basilar papilla and the vestibular organs both develop from the otocyst, we were interested in ascertaining whether the vestibular sensory epithelia also displayed abnormal hair cells. The inner ear of adult BWCs was examined by scanning electron microscopy. As expected, hair cells in the basilar papilla of BWCs were abnormal. As for the vestibular parenchyma, abnormal hair cells were detected in only one structure: the sacculus. Morphological abnormalities of the cochlea and sacculus are pathognomonic signs of Scheibe's dysplasia, the most common inner ear defect associated with congenital hearing loss. Our results suggest that BWCs are afflicted by this genetic disorder. PMID- 7852205 TI - Morphological gradients in sensory hair cells of the amphibian papilla of the frog, Rana pipiens pipiens. AB - The sensory hair cells of the amphibian papilla (AP) of the northern leopard frog were examined in a light-microscopic analysis. Hair cell length and cross sectional area were found to vary systematically along the rostro-caudal axis of the endorgan. The AP was readily divided into three morphological regions. Rostrally-located hair cells are tall, cylindrically-shaped cells with large cross-sectional areas and long stereocilia; caudally-located hair cells are short, goblet-shaped cells with small cross-sectional areas and short stereocilia. In the middle region, hair cells exhibit features intermediate to those of hair cells located at the AP extremes. The detailed pattern of changes in hair cell morphology along the endorgan correlates well with its observed tonotopy and may have implications for the intrinsic tuning of the AP. PMID- 7852206 TI - 2-Deoxyglucose uptake patterns in response to pure tone stimuli in the aged rat inferior colliculus. AB - The tonotopic map of the inferior colliculus (IC) of aged rats (25 months old) was examined to determine whether age-related changes known to occur in the cochlea are reflected in the 2-deoxyglucose (2-DG) uptake pattern of the IC. Because aged animals have hearing losses, auditory brainstem response thresholds were measured. Animals with threshold shifts of no greater than 30 dB relative to young animals were used. Animals were injected with radiolabeled 2-DG and stimulated with continuous pure tones presented at 70 dB above the behavioral thresholds for young animals at either 1, 4 or 32 kHz for one hour in a sound attenuated booth. The stimulus sound pressure levels were chosen to achieve comparable sensation levels between the young and aged animals. The tonotopic map of the IC in aged rats was different from that reported previously for young animals (Ryan et al., 1988), in that, the regions stimulated by 1 and 4 kHz were shifted towards the higher frequencies and the uptake areas were twice as broad for the aged animals as for the young animals. The observed 2-DG uptake patterns are consistent with an activation pattern of a high intensity stimulus and a loss of responsive elements in the cochlear apex. Similar broad and shifted bands of activated tissue may contribute to difficulties in auditory perception in aged humans with increased thresholds and sound amplification. PMID- 7852207 TI - Effects of conceptions of ability on anxiety, self-efficacy, and learning in training. AB - A field experiment of 76 employees studied the effects of induced conceptions of ability as either an acquirable skill or fixed entity on computer anxiety, computer efficacy beliefs, and the acquisition of declarative knowledge, drawing from social cognitive theory. The setting was an introductory microcomputer training course. The findings indicate that trainees in the acquirable skill condition experienced a significant decrease in computer anxiety between the pre- and posttraining assessments; however, trainees in the entity condition did not experience a significant change in computer anxiety. Also, trainees in the acquirable skill condition experienced a significant increase in computer efficacy beliefs, and trainees in the entity condition experienced a significant decrease in computer efficacy between the pre- and posttraining assessments. Contrary to expectations, the effects of the training intervention on the acquisition of declarative knowledge were not mediated by computer anxiety and computer efficacy beliefs. The significant results are consistent with deductions made from social cognitive theory. PMID- 7852208 TI - Bias against overweight job applicants in a simulated employment interview. AB - This study assessed whether moderately obese individuals, especially women, would be discriminated against in a mock employment interview. Potential confounding factors were controlled by having 320 Ss rate videotapes of a job interview that used the same professional actors appearing as normal weight or made up to appear overweight by the use of theatrical prostheses. Results suggested that bias against hiring overweight job applicants does exist, especially for female applicants. Bias was most pronounced when applicants were rated by Ss who were satisfied with their bodies and for whom perceptions of their bodies were central to self-concept. The decision not to hire an obese applicant was, however, only partially mediated by personality attributions. Implications and limitations of these results are discussed. PMID- 7852209 TI - Clinical application of recombinant erythropoietin in the perioperative period. AB - Recombinant human erythropoietin (EPO) therapy as an alternative to allogenic blood transfusion has been studied extensively in the perisurgical period. The potential benefits of EPO in this setting are twofold; EPO enhances autologous blood collection in advance of elective surgery and stimulates erythropoiesis perioperatively. Clinical evidence of the role of EPO therapy in these settings to minimize allogenic blood exposure is presented. PMID- 7852210 TI - Erythropoietin in obstetrics. AB - The physiology of maternal and fetal erythropoiesis in pregnancy shows that hematopoiesis, and the stimulation of hematopoiesis, take place separately in the two circulations. Erythropoietin appears the main regulator in both mother and fetus. The human placenta forms a manifest barrier to endogenous and recombinant erythropoietin, thus fulfilling the cardinal precondition for the use of recombinant erythropoietin in the treatment of maternal pregnancy anemia. The prevalence of maternal anemia in pregnancy and post partum is high; up to 95% of cases are due to iron deficiency, compounded post partum by blood loss during and after delivery. Use of rHuEPO for reversing pregnancy and postpartum anemia has given promising initial results. PMID- 7852211 TI - Regulation of erythropoietin production. New insights into molecular mechanisms of oxygen homeostasis. AB - EPO plays a key role in O2 homeostasis by regulating blood O2-carrying capacity. The EPO gene is expressed in fetal liver, whereas after birth the kidney becomes the predominant site of synthesis. Transgenic studies indicate that EPO expression in postnatal liver is repressed via DNA sequences that are distant from the gene. Expression in postnatal kidney is dependent upon sequences located between 6 kb and 14 kb 5' to the transcription initiation site. Additional sites of low-level EPO synthesis have been identified, but the functional significance of these observations is unknown at the present time. Modulation of transcription by changes in cellular O2 tension has been studied in the hepatic cell lines Hep3B and HepG2. A kidney-derived cell line in which EPO expression is regulated by O2 tension has not been established. A hypoxia-inducible enhancer, identified in the EPO 3'-flanking sequence, contains binding sites for several transcription factors, including HIF-1, a factor whose DNA-binding activity is induced by hypoxia. Binding of HIF-1 is required for EPO transcriptional activation in response to hypoxia. HIF-1 binding sites are also present in the EPO promoter, which may also play a role in hypoxia-inducible transcription. Binding sites for members of the nuclear hormone receptor superfamily are also present in both the promoter and enhancer. The hypoxia signal-transduction pathway leading to EPO transcriptional activation has not been established. Two hypothetical mechanisms of O2 sensing are oxy-deoxy conformational changes of a hemoprotein and the production of reactive O2 species from molecular O2. HIF-1 activity is induced in a variety of cell types, and in all cell types a single signal transduction pathway appears operative, but its nature is undefined. Moreover, genes encoding glycolytic enzymes are transcriptionally activated in hypoxic cells via a similar mechanism, including the binding of HIF-1 to promoter and enhancer elements. Thus, the molecular mechanisms by which EPO transcription is regulated may also be utilized to control the expression of other genes responsible for cellular and systemic O2 homeostasis. PMID- 7852212 TI - The molecular structure of human erythropoietin. AB - The molecular structure of EPO has been discussed, and the gradual emergence of information about EPO has been reviewed. The importance of certain regions of the molecule and of glycosylation to EPO's structure and function are clear. Although its nucleotide and amino acid sequences are known, its tertiary structure remains elusive. Antipeptide antibody and mutagenesis studies have increased our ability to study structure/function and certain spatial relationships. Undoubtedly, additional information will continue to become available in this exciting area, providing a better understanding of the mechanisms behind EPO's central role in erythropoiesis. PMID- 7852213 TI - Erythropoietin cell biology. AB - Erythropoietin (EPO) mediates its biologic actions in responsive cells through the 78 kDa cell surface form of the EPO receptor. The biosynthesis, activations, and destruction of EPO receptors are described. The binding of EPO to its receptor leads to the activation of a tyrosine protein kinase(s) that results in the phosphorylation of the receptor and other proteins. PMID- 7852214 TI - Clinical application of recombinant erythropoietin in renal dialysis patients. AB - The advent of erythropoietin (EPO) can be considered one of the major advances over the past 10 years in the treatment of end stage renal disease (ESRD) patients who are receiving chronic maintenance dialysis. Not only has it resulted in freedom from transfusion dependency and elimination of the attendant risks, but it also has led to a significant improvement in the quality of life these patients are able to achieve within the physical and emotional limitations imposed by the multiple metabolic abnormalities, concomitant medical problems of ESRD, and the dialysis process itself. PMID- 7852215 TI - Clinical application of recombinant erythropoietin in predialysis renal failure. AB - The benefits of EPO treatment, including improved exercise tolerance, amelioration of lassitude and fatigue, improved cognitive function, and enhanced quality of life in general, can be extended to symptomatic anemic chronic renal failure patients before their need for dialysis treatment. The favorable pharmacokinetics and erythropoietic response with weekly subcutaneous dosing of EPO make this treatment suitable and convenient for patients and health care providers alike. EPO treatment can be provided without undue concern about accelerating the deterioration of renal function, but patients require frequent follow-up and close monitoring while treatment is initiated and adjusted over the first 3 to 6 months, in order to promptly detect and treat any adverse reaction or failure to respond. PMID- 7852216 TI - Clinical application of recombinant erythropoietin in the anemia of chronic disease. AB - The anemia of chronic disease is a consequence of the abnormal production of cytokines associated with chronic inflammatory, infectious, and neoplastic disorders. rhEPO can correct the impaired erythropoiesis encountered with this syndrome in vitro and in the clinical setting. Although most patients with the anemia of chronic disease will not require specific intervention to increase their hemoglobin and hematocrit, certain subsets of patients may benefit from rhEPO therapy. These include patients with anemia sufficiently severe to require transfusion, and patients for whom autologous blood donation is precluded by anemia. PMID- 7852217 TI - The clinical application of recombinant erythropoietin in the HIV-infected patient. AB - Patients with HIV infection frequently develop clinically significant anemia, either as a manifestation of the HIV or as a result of therapy with medications such as zidovudine. Therapy with recombinant human erythropoietin can increase hemoglobin levels in these patients, decreasing transfusion requirements and improving some aspects of the quality of life. Once erythropoietin therapy is started, it is important to monitor patients carefully for the development of iron deficiency and erythrocytosis. PMID- 7852218 TI - Clinical application of recombinant erythropoietin in anemic cancer patients. AB - Anemia is common in cancer patients and may require treatment for symptomatic palliation. Transfusion has been the mainstay of therapy, but is not without risk. Because erythropoietin levels in cancer-related anemia are inadequate for the degree of anemia, recombinant human erythropoietin has been studied to treat the anemia. Results from these studies are encouraging. PMID- 7852219 TI - Erythropoietin after bone marrow transplantation. AB - The anemia associated with bone marrow transplantation is in part related to a relative erythropoietin deficiency. Recombinant human erythropoietin has been studied in different clinical situations. After allogenic bone marrow transplant, recombinant human erythropoietin has enhanced erythroid engraftment and in several studies, decreased transfusion requirement. PMID- 7852220 TI - Clinical application of recombinant erythropoietin in myelodysplasia. AB - This article attempts to summarize the current information regarding the clinical application of recombinant human erythropoietin in patients with myelodysplastic syndromes (MDS). To date, more than 300 MDS patients have been reported to be treated with recombinant human erythropoietin. The response patterns have been variable, but in general they range from 20% to 30%. The hormone has been shown to be safe and nontoxic. PMID- 7852221 TI - Diabetes mellitus--to predict or not to predict. PMID- 7852222 TI - Trace elements in health and disease. PMID- 7852223 TI - Pancreatic beta cell function in normoglycaemic offspring of diabetic parents. AB - The aim of the study was to look for any time-realted fluctuation in the pancreatic beta cell function in normal offspring of diabetic parents, over a period of three years. Serum insulin (IRI) and C-peptide (CP) responses to oral glucose were reevaluated three years after the initial study in 25 normoglycaemic offspring of conjugal Type 2 diabetic parents. The mean area under the curve of IRI (AUC IRI) response was higher than normal control value in the offspring at both time points (P < 0.01) and the two values did not differ much. The 2 hr IRI was also significantly higher (P < 0.05) than the control value. CP responses at both time points in the offspring did not differ from the mean control value. Wide fluctuations in the individual IRI were noted on follow-up despite similar plasma glucose response. Follow-up IRI was higher in 6, lower in 5 (+/- 25% of the initial) and remained unaltered in the other 4 offspring. The corresponding CP showed increased values in 3, decreased values in 5 and no change in 7 offspring. The fluctuations were nonuniform in nature among the individuals studied. Disparity between the IRI and CP responses were present in 5 offspring during the follow-up. This study thus shows that wide fluctuations in insulin responses occur even in the normoglycaemic offspring of diabetic parents. PMID- 7852224 TI - Cadmium and hypertension. AB - Hypertension is a very common and important disease of modern civilised life. There are comflicting reports about cadmium, a trace element in the genesis of essential hypertension. The present study was conducted to estimate the cadmium levels in whole blood in the normal group of thirty subjects who were normotensive and the same was compared to that of thirty hypertensive patients and the levels were found to be statistically significant (p < 0.05). PMID- 7852225 TI - Clinical and electrophysiological study of intermediate syndrome in patients with organophosphorous poisoning. AB - Intermediate syndrome (IS) developed in 38 of 214 cases with organophosphorous compound poisoning (OPCP). Neck muscle weakness, motor cranial nerve palsy, respiratory muscle paralysis, proximal limb weakness were the chief neurological signs developed 16-120 hours after consumption of the insecticide. Two patients had pyramidal tract signs. Mean duration of IS was 9.26 (+/- 4.84) days. Electrophysiological study (EPS) was done in 21 patients. 18 patients showed decremental response to repetitive stimulation at 3Hz 5 pulses and absence of post tetanic facilitation. Motor conduction studies were abnormal in on (prolonged distal latency and reduced conduction velocity), 'F' responses were abnormal in, sensory nerve conduction was abnormal in two, and simple repetitive response were observed in 11 patients. 4 patients died. In IS neuromuscular junctional dysfunction is the predominant factor. PMID- 7852226 TI - Effect of gugulipid on bioavailability of diltiazem and propranolol. AB - The effect of single oral dose of 1 gm gugulipid was studied on bioavailability of single oral dose of propranolol (40 mg) and diltiazem (60 mg) in 10 and 7 normal healthy male volunteers respectively. It was a randomised within group crossover study. Blood samples were collected at hourly intervals upto 8 hrs. Gugulipid significantly reduced (P < .01) peak plasma concentration (Cmax) and area under curve (AUC 0-8 hrs) of both the drugs in normal volunteers. Such interaction in patients receiving propanolol or diltiazem with gugulipid may lead to diminished efficacy or nonresponsiveness due to significant reduction in bioavailability. PMID- 7852227 TI - Serum magnesium levels in idiopathic epilepsy. AB - Fifty cases of idiopathic epilepsy and 25 age and sex matched normal healthy controls were studied. There was a significant fall in serum magnesium levels in idiopathic epilepsy on day one and 4 of the seizures (P < 0.01) as compared to controls, and was not decreased significantly on day 7 of the seizures (P < 0.05). The fall was maximum in status epilepticus and severe epilepsy than in mild and moderate epilepsy. Serum magnesium took less time to come back to normal in mild and moderate epilepsy than in other types. This shows that serum magnesium does have a prognostic significance. Lesser the fall in the magnesium levels, less frequent were the convulsions and vice versa. It is concluded that serum magnesium continues to be a sensitive early diagnostic index of idiopathic epilepsy. PMID- 7852228 TI - The effect of aspirin on neurodeficit and platelet aggregability in acute ischemic cerebral strokes. AB - We examined the role of aspirin in modifying platelet aggregability (PA) and neurodeficit (ND) in patients presenting within 48 hours of acute ischemic cerebral strokes of the carotid territory. 28 adult patients were studied at baseline and after 7 days of treatment with a single daily dose of aspirin 325mg (group A, n = 12) and 160 mg (Group B, n = 16). We also evaluated the neurologic outcome at the beginning and at the end of 7 days using a scoring system. There was no significant difference in the ND scores and in vitro PA between these two groups. PA, as measured in vitro, does not appear to have any significant role as a predictor of neurologic outcome in acute ischemic strokes. The change in ND scores of patients with ischemic cerebral strokes treated acutely with aspirin was not significant upto first 7 days therapy. PMID- 7852229 TI - A comparison of low vs standard dose intramuscularly administered hepatitis B vaccine. AB - In a randomised, controlled, single-blind trial we compared different doses of a yeast-derived recombinant hepatitis B vaccine: a low dose intramuscular (i.m.) regimen (using 2 micrograms at first followed by 1 microgram each at 1, 2 and 6 months) with the standard dose (10 micrograms each at 0, 1 and 6 months) for post vaccination anti-HBs seropositivity. At the end of 7 months, only 78% of volunteers on the low dose (n = 77) tested positive for anti-HBs whereas 100% of volunteers on the standard dose (n = 43) were seropositive. Therefore, low dose regimen is not satisfactory for primary HBV vaccination. PMID- 7852230 TI - Triglyceride and coronary heart disease. AB - The predictive association of triglyceride (TG) in coronary heart disease (CHD). In patients without CHD levels were elevated in those coronary risk factors, as compared to those without the risk factor the elevation of TG may occur in asymptomatic subjects before the onset of clinical manifestation of CHD. The high risk, asymptomatic subjects with high levels of TG may be on the "threshold" of the sysptomatic phase of CHD. The levels had a positive correlation with body mass index and increased with increasing number of coronary risk factors. PMID- 7852231 TI - Indigenous free radical scavenger MAK 4 and 5 in angina pectoris. Is it only a placebo? AB - Thirty patients were evaluated to study the effect of Maharishi Amrit Kalsh (MAK) 4 & 5 on Angina pectoris. The mean angina frequency per month was 8.87. Twelve lead ECG, computerized TMT and echo studies were done initially, at 6 months, and after 2 years in all cases. Ten grams of MAK 4 paste was given daily in two divided doses, each followed by a MAK 5 tablet, for six months. Vasodilator and antihypertensive drugs were continued on ethical grounds. Twenty-four patients (80%) out of the total 30 reported a significant improvement after 6 months of therapy. The mean angina frequency per month improved from 8.87 to 3.03. All patients reported a sense of well being. Five out of 11 hypertensive patients reported a fall in systolic blood pressure. Lipid profile showed a rise in HDL which was statistically insignificant. Improved exercise tolerance was observed in 10 cases (33.33%) after 6 months of therapy and this effect was sustained even at 2 years. ECG and echo studies were inconclusive. No side effects or drug interactions were seen. This beneficial effect observed is probably as a result of free radical scavenging property of MAK on 'Reactive Oxygen Species' or an inhibitory effect on lipid peroxidation; or by its inhibitory action on platelet aggregation or all these in synergism. PMID- 7852232 TI - Repeated blood donation effective in treating hyperlipidemia. AB - Effectiveness of repeated blood donation in lowering blood lipids has been studied. Ten patients of hyperlipidaemia who donated blood 300 ml every month for 3 months and received gemfibrozil 1200 mg/day (Group B) had nearly 2 fold greater fall in serum total cholesterol, LDL and triglyceride levels in comparison to 17 patients of group A who were treated with gemfibrozil alone in similar dose for the same period. HDL level remained almost unchanged. Thus, a non-pharmacological way of treating hyperlipidaemia has emerged from this study. Moreover donated blood will be available as by-product for use by others. This method may be especially suitable in obese persons. PMID- 7852233 TI - Thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome: the microangiopathic haemolytic anaemia's. PMID- 7852234 TI - Migraine. PMID- 7852235 TI - Intracoronary stents: an initial experience. PMID- 7852237 TI - Acquired pure amegakaryocytic thrombocytopenic purpura. PMID- 7852236 TI - Treatable dementia in an elderly woman. PMID- 7852238 TI - Choreoacanthocytosis. PMID- 7852239 TI - Dapsone syndrome. PMID- 7852240 TI - Osler Rendu Weber syndrome. PMID- 7852241 TI - Nephrotic syndrome in a HIV seropositive patient. PMID- 7852242 TI - The rational use of drugs in the treatment of acute diarrhoea. PMID- 7852243 TI - Enalapril precipitating an attack of asthmatic bronchitis. PMID- 7852244 TI - Hypoglycaemic--hemiplegia. PMID- 7852245 TI - Recurrence of Graves disease after 40 years. PMID- 7852246 TI - Acute myositis complicated by myoglobinuric acute renal failure. PMID- 7852247 TI - Cranial nerve palsy at high altitude. PMID- 7852248 TI - Spontaneous reversal of a tropine induced delirium in organophosphorous compound poisoning. PMID- 7852249 TI - High altitude cerebral oedema. PMID- 7852250 TI - More thoughts on enteric fever. PMID- 7852251 TI - Hyper parasitaemia due to plasmodium falciparum malaria. PMID- 7852252 TI - Relapse in patients on long-term fluoxetine treatment: response to increased fluoxetine dose. AB - BACKGROUND: Although several studies have examined the long-term efficacy of antidepressants, relatively little attention has been paid to the management of relapses or recurrences during continued antidepressant treatment. This study examined whether depressed patients who had recovered and then relapsed on fluoxetine 20 mg/day would benefit from an increase in fluoxetine dose. METHOD: Eighteen patients who relapsed on fluoxetine 20 mg/day during long-term treatment with fluoxetine as part of a placebo-controlled study had their fluoxetine dose raised to 40 mg/day and were followed for at least 1 month (mean time = 4.7 months). RESULTS: Twelve (67%) were full responders, 3 (17%) partial responders, and 3 (17%) dropped out because of side effects (e.g., insomnia and agitation). Of those patients who had either full or partial response (N = 15; 83%), 3 complete responders had a recurrence on 40 mg/day after a mean of 5.8 months and 1 partial responder had a recurrence 11 months later. Overall, 11 (61%) of 18 patients maintained their response during their follow-up while taking the higher dose of fluoxetine. CONCLUSION: An increase in dose of fluoxetine to 40 mg/day appears to be an effective strategy in the treatment of relapse among depressed patients who had initially responded to fluoxetine 20 mg/day. PMID- 7852253 TI - Rhinotillexomania: psychiatric disorder or habit? AB - BACKGROUND: Conditions once considered bad habits are now recognized as psychiatric disorders (trichotillomania, onychopagia). We hypothesized that nose picking is another such "habit," a common benign practice in most adults but a time-consuming, socially compromising, or physically harmful condition (rhinotillexomania) in some. METHODS: We developed the Rhinotillexomania Questionnaire, mailed it to 1000 randomly selected adult residents of Dane County, Wisconsin, and requested anonymous responses. The returned questionnaires were analyzed according to age, sex, marital status, living arrangement, and educational level. Nose picking was characterized according to time involved, level of distress, location, attitudes toward self and others regarding the practice, technique, methods of disposal, reasons, complications, and associated habits and psychiatric disorders. RESULTS: Two hundred fifty-four subjects responded. Ninety-one percent were current nose pickers although only 75% felt "almost everyone does it"; 1.2% picked at least every hour. For 2 subjects (0.8%), nose picking caused moderate to marked interferences with daily functioning. Two subjects spent between 15 and 30 minutes and 1 over 2 hours a day picking their nose. For 2 others, perforation of the nasal septum was a complication. Associated "habits" included picking cuticles (25%), picking at skin (20%), biting fingernails (18%), and pulling out hair (6%). CONCLUSION: This first population survey of nose picking suggests that it is an almost universal practice in adults but one that should not be considered pathologic for most. For some, however, the condition may meet criteria for a disorder-rhinotillexomania. PMID- 7852254 TI - Factors predicting the use of multiple psychotropic medications. AB - BACKGROUND: Recent studies have questioned the appropriateness of some types of psychotropic medication prescribing, especially by general practitioners. The purpose of this study is to investigate factors that predict prescribing of multiple psychotropic medications, a class that may represent more complicated cases. METHOD: This study analyzed data from the 1989 National Ambulatory Medical Care Survey (NAMCS). Multiple logistic regression methods were used to determine variables that predicted the provision or ordering of multiple psychotropic medications during a single office visit. RESULTS: Patients who visited psychiatrists were six times more likely to receive psychotropics in combination than patients visiting general practitioners. Patients diagnosed as manic were four times more likely to receive multiple psychotropics, and those diagnosed as schizophrenic were three times more likely Patients visiting physicians in the Northeast and South were significantly less likely to receive psychotropics in combination than patients in the Midwest. CONCLUSION: Although general practice physicians contribute to the use of multiple psychotropic medications, patients visiting psychiatric specialists are much more likely to be provided combination therapy. PMID- 7852255 TI - Gender differences in outpatient research subjects with affective disorders: a comparison of descriptive variables. AB - BACKGROUND: Gender may play an important role in the etiopathophysiology of psychiatric illness and has become a subject of increasing interest because of its possible effects on biological markers, treatment outcome, and prognosis. Intrigued by this issue and as part of our attempt to further characterize research subjects in San Diego, we evaluated male and female research subjects from our affective disorders clinical research center on a variety of measures. Based on epidemiologic data, we postulated that female and male subjects would be similar to epidemiologic samples and would differ in terms of comorbid diagnoses and that female subjects would be more likely to have had a history of previous treatment. METHOD: The demographic characteristics; coffee, tobacco, and alcohol consumption patterns; symptom patterns; and current and lifetime comorbid DSM-III R Axis I diagnoses of 124 female and 69 male outpatient research subjects were contrasted. RESULTS: Female research subjects had more comorbid problems with anxiety disorders, were more likely to have been previously treated, and were more likely to have a family history of psychiatric illness. CONCLUSION: Male and female research subjects were remarkably similar with respect to most characteristics assessed but, as postulated, differed in terms of their comorbid diagnoses and prior treatment history. PMID- 7852256 TI - Methadone withdrawal psychosis. AB - BACKGROUND: Methadone is a typical mu-opioid receptor agonist that is widely used for maintenance and detoxification treatment of opiate-dependent patients. Although methadone withdrawal syndrome is well described, it generally does not include psychosis. METHOD: Having observed new onset psychosis in a patient on methadone taper, the authors identified three other such patients by chart review. All met DSM-III-R criteria for opioid dependence. Distinctive features of their clinical presentation, pharmacotherapy received, and follow-up were recorded. RESULTS: Two patients had no history of psychosis, one patient had a psychotic episode 21 years prior to admission, and one patient was diagnosed with schizophrenia but remained asymptomatic for at least 1 year while treated with only methadone. Psychosis resolved spontaneously in one case, whereas the other cases required neuroleptic treatment. In one case, methadone resumption was required. None of the patients developed typical methadone withdrawal syndrome. CONCLUSION: The above results suggest that opioid taper may be a period of high risk for development of psychosis. This risk is probably higher in patients with preexisting CNS illness. Clinicians caring for patients in opioid withdrawal should be aware of this risk. Further research is required to evaluate whether methadone withdrawal psychosis represents a clinical manifestation of opioid agonist modulation of dopaminergic neurotransmission in the human brain. PMID- 7852258 TI - Duplicate publication. PMID- 7852257 TI - Comorbidity of axis I psychiatric disorders in bulimia nervosa. AB - BACKGROUND: The coexistence of other psychiatric disorders in patients with bulimia nervosa is of major clinical and theoretical interest. We therefore studied a group of consecutively evaluated bulimic patients. METHOD: The Structured Clinical Interview for DSM-III-R (SCID) was administered to a sample of 59 female patients with DSM-III-R-defined bulimia nervosa. RESULTS: The following frequencies of lifetime Axis I comorbid diagnoses were found (in decreasing frequency): any affective disorder (75%), major depressive disorder (63%), any anxiety disorder (36%), any substance abuse disorder (20%), social phobia (17%), generalized anxiety disorder (12%), and panic disorder (10%). In the 44 cases with an affective disorder, 27 (61%) had the onset of affective disorder, 27 (61%) had the onset of their affective disorder prior to the onset of their bulimia, 15 (34%) afterward, and 2 (5%) concurrently. In the 21 cases with any anxiety disorder, 15 (71%) had the onset of their anxiety disorder prior to the onset of their bulimia, 4 (19%) afterward, and 2 (10%) concurrently. CONCLUSION: These data confirm previous reports of a strong association between bulimia nervosa and affective illness, which in most cases precedes the eating disorder. In addition, a high frequency of anxiety disorders, particularly social phobia, is seen in bulimic patients. PMID- 7852259 TI - ECT for OCD. PMID- 7852260 TI - Paroxetine-molindone interaction. PMID- 7852261 TI - Recurrent manic episode 10 years after arteriovenous malformation resection. PMID- 7852262 TI - Molecular structure of a heme-copper redox center of the Escherichia coli ubiquinol oxidase: evidence and model. AB - Biochemical, spectroscopic, and molecular biological studies on bacterial respiratory oxidases in the last decade have greatly increased our understanding of a molecular structure of the metal centers which catalyze the dioxygen reduction chemistry. Based upon the latest physicochemical and molecular biological evidence and theoretical consideration of a folding mechanics of membrane proteins, we propose here the tertiary structure of the heme-copper metal center of the Escherichia coli bo-type ubiquinol oxidase, the cytochrome bo complex. The molecular mechanism of electron transfer-coupled proton pumping in the heme-copper respiratory oxidases is reviewed on the basis of this predicted model. PMID- 7852263 TI - Conformational changes of melittin upon insertion into phospholipid monolayer and vesicle. AB - Two model systems were used to study the conformational changes of melittin upon insertion into phospholipid. The first model system is phospholipid monolayers with different surface pressure. The second one is small unilamellar vesicles at above or below their phase transition temperature. The conformational changes of melittin upon insertion were elucidated by employing a combination of monolayer technique, fluorescence technique, CD, and FTIR. The results showed that melittin adsorbed on the lipid layer surface contains less alpha-helix than its counterpart inserted into the lipid layer. As the penetration depth of melittin increases, more ordered structures (alpha-helix) appear. A possible molecular mechanism underlying melittin insertion is proposed. PMID- 7852264 TI - Corn cystatin I expressed in Escherichia coli: investigation of its inhibitory profile and occurrence in corn kernels. AB - Corn cystatin I was expressed in Escherichia coli as a mature protein. It was purified by gel filtration on Sephadex G-50, ion-exchange HPLC, and reversed phase HPLC. The purified protein showed strong inhibitory activities against papain (Ki: 3.7 x 10(-8) M), and cathepsins H (Ki: 5.7 x 10(-9) M) and L (Ki: 1.7 x 10(-8) M), whereas it inhibited cathepsin B to a lesser extent (Ki: 2.9 x 10( 7) M). Western blot analysis using antibody raised against corn cystatin I revealed that in the corn kernel, the protein occurs with a molecular mass of approximately 13 kDa. Localization in the aleurone layer and embryo of the corn kernel was shown by immunostaining microscopy. PMID- 7852265 TI - Affinity labeling of the two species of Escherichia coli lysyl-tRNA synthetase with adenosine di- and triphosphopyridoxals. AB - Lysyl-tRNA synthetase (LysRS), a representative of the class 2 aminoacyl-tRNA synthetases, occurs as two species in Escherichia coli: LysRSs and LysRSu. To identify the ATP-binding site in this enzyme, we have applied affinity labeling with reactive adenine nucleotide analogs. Incubation of either enzyme species with adenosine di- or triphosphopyridoxal, followed by borohydride reduction, resulted in a time-dependent incorporation of the reagent, accompanied with the loss of both tRNA(Lys) aminoacylation, and lysine-dependent isotopic ATP-PPi exchange activities. LysRSu appeared less sensitive to adenosine triphosphopyridoxal than LysRSs. Complete inactivation with either reagent corresponded to the incorporation of about 2 mol of reagent per mol of dimeric enzyme. MgATP and ATP protected both enzyme species against the inactivation, suggesting that the modification occurs at the ATP-binding site. Sequence analysis of the labeled peptide isolated from the inactivated LysRSs and LysRSu revealed that bulk of the label was distributed among six lysyl residues at positions 25, 82, 114, 156, 364, and 505, with preference for Lys-114 and Lys 156. In LysRSs, Lys-132 and Lys-185 were also modified by both reagents, although these residues are not conserved in LysRSu. It is concluded that the folding of the LysRSs and LysRSu polypeptides and the relative locations of the identified lysyl residues with respect to the binding site for the two labels are very similar. PMID- 7852266 TI - Affinity labeling of Escherichia coli lysyl-tRNA synthetase with pyridoxal mono- and diphosphate. AB - Pyridoxal 5'-phosphate (PLP) and pyridoxal 5'-diphosphate (PLDP) were used to identify lysyl residues at the phosphate-binding locus in the lysS-encoded and the lysU-encoded lysyl-tRNA synthetases (LysRSs and LysRSu, respectively) from Escherichia coli. Incubation of LysRSs with either reagent, followed by borohydride reduction, resulted in a time-dependent covalent incorporation of the reagent, accompanied with the loss of both tRNA(Lys) aminoacylation and lysine dependent ATP-PPi exchange activities. By contrast, LysRSu activity was insensitive to prolonged incubation with either reagent, possibly reflecting a difference at the phosphate-binding locus in the two enzyme species. MgATP protected LysRSs against inactivation by PLP or PLDP. Complete inactivation of LysRSs corresponded to the incorporation of 2.6 +/- 0.1 mol of PLP or PLDP per mol of dimeric enzyme. Either reagent was found to label the same set of eight lysyl residues (Lys-25, Lys-82, Lys-114, Lys-132, Lys-156, Lys-185, Lys-364, and Lys-505) as adenosine di- or triphosphopyridoxal (see the preceding paper in this issue). These lysyl residues might represent the subsite for the phosphate moiety of ATP in LysRSs. None of the identified lysyl residues is located within the three sequence motifs considered as characteristic of the class 2 aminoacyl-tRNA synthetases. The present results are discussed on the basis of the crystalline structure of the closely related aspartyl-tRNA synthetase from Saccharomyces cerevisiae. PMID- 7852267 TI - Regulation of choline kinase R: analyses of alternatively spliced choline kinases and the promoter region. AB - The previous report described the cloning kinase R1 cDNA [Uchida, T. and Yamashita, S. (1992) J. Biol. Chem. 267, 10156-10162]. A new cDNA, for choline kinase R2, was isolated from rat liver cDNA libraries. This transcript was thought to be generated by alternative splicing. Ribonuclease protection analysis revealed the presence of a third choline kinase. Three transcripts were detected in all of the examined rat tissues at different levels. Southern blot analysis demonstrated a single copy of choline kinase R gene. The genomic DNA containing the first exon and its flanking regions of choline kinase R gene was isolated and characterized. A number of transcription start sites, determined by ribonuclease protection and primer extension analyses, were found. The most 3' site, 193 base pairs upstream of the initiation codon and common in liver and testis, was the main site in liver. Some transcription start sites were detected only in testis. Choline kinase R gene showed features not only of a typical housekeeping gene but also of a gene regulated through a variety of putative cis-acting motifs. 3 Methylcholanthrene and carbon tetrachloride increased all of three transcripts to various levels, and enhanced transcription from the same start site, which scarcely gave a detectable product in normal liver. PMID- 7852268 TI - Isolation and characterization of an N-acetyllactosamine-binding lectin from the mushroom Laetiporus sulfureus. AB - A hemagglutinating and hemolytic lectin (PSL) has been isolated from carpophores of the parasitic mushroom Laetiporus sulfureus by affinity chromatography on Sepharose. Its molecular weight, as determined both by gel filtration and by electrophoresis in non-denaturing conditions, is about 190,000 and its structure is tetrameric, with two distinct types of subunits (about 60,000 and 36,000). It appeared homogeneous on HPLC gel filtration but exhibited microheterogeneity on isoelectric focusing. Hapten inhibition assay indicated that the Laetiporus lectin is specific for N-acetyllactosamine residues and that hemagglutinating and hemolysis activities are supported by the same site. PMID- 7852269 TI - A novel oligosaccharide, xylosyl beta 1-4xylosyl beta 1-(4-methylumbelliferone), synthesized by cultured human skin fibroblasts in the presence of 4 methylumbelliferyl-beta-D-xyloside. AB - 4-Methylumbelliferyl-beta-D-xyloside (Xyl-MU) was added to the medium of cultured human skin fibroblasts. After incubation, the culture medium was pooled, concentrated with a lyophilizer, and dialyzed against distilled water. Then the Xyl-MU derivatives in the diffusate were purified by gel-filtration and HPLC. A novel Xyl-MU derivative was obtained, in addition to the previously reported Xyl MU derivatives, Xyl-MU-induced glycosaminoglycan (GAG-MU), SA-Gal-Xyl-MU, GlcA Xyl-MU, Gal-Gal-Xyl-MU, and Gal-Xyl-MU. This Xyl-MU derivative was subjected to carbohydrate composition analysis, enzyme digestion, Smith degradation and ion spray mass spectrometric analysis, and the results indicated that it was Xyl beta 1-4Xyl beta 1-MU. Although the quantity of Xyl beta 1-4Xyl beta 1-MU synthesized by human skin fibroblasts increased with incubation time, its production was independent of that of the GAG-MU. Xyl-Xyl-MU is different from the intermediates in the regular pathway of GAG-MU biosynthesis initiated by added Xyl-MU, posing an interesting question as to its significance in GAG biosynthesis. PMID- 7852270 TI - A spectrophotometric study on the interaction of thermolysin with chloride and bromide ions, and the state of tryptophyl residue 115. AB - The activity of thermolysin is greatly enhanced in the presence of high concentrations of neutral salts [Holmquist, B. and Vallee, B.L. (1976) Biochemistry 15, 101-107; Inouye, K. (1992) J. Biochem. 112, 335-340]. NaBr and NaCl are the most effective for the activation. An absorption difference spectrum with a peak around 293 nm, which is characteristic of the red-shift of a tryptophyl residue caused by charge effects, was observed on mixing of thermolysin with NaCl. As the peak disappeared in the presence of competitive inhibitors of the enzyme (phosphoramidon and zincov), it was considered to be derived from a tryptophyl residue (Trp 115) located in the active site of the enzyme. On the other hand, this peak was not observed on the mixing of thermolysin and NaBr, indicating that the slight difference in size between chloride and bromide ions is critical for the interaction with the tryptophyl residue. NaCl and NaBr exhibit comparable effects on the activation of thermolysin regardless of the considerable discrepancy in their effects on the absorptivity difference around 293 nm. This suggests that the interaction of salts with Trp 115 is not necessarily correlated with the activation of thermolysin. PMID- 7852271 TI - Cloning and nucleotide sequence of cDNA encoding a lipase from Fusarium heterosporum. AB - Fusarium heterosporum produces a solvent-tolerant lipase. A 1.3-kbp lipase cDNA was isolated from the cDNA library by colony hybridization with an oligonucleotide probe corresponding to the N-terminal amino acid sequence. Nucleotide sequence analysis showed an open reading frame of 999 bp, and the deduced amino acid sequence contained the N-terminal sequence determined by Edman degradation and the consensus pentapeptide (-Gly-X-Ser-X-Gly-), which is conserved in lipase, esterase, and serine protease. The mature lipase consisted of 301 amino acid residues with a molecular mass of 32.7 kDa, preceded by the putative signal peptide or preprosequence. The enzyme was homologous to lipases from Humicola lanuginosa (39% homology), Rhizomucor miehei (32%), Rhizopus delemar (32%), and Rhizopus niveus (32%), and to mono- and diacylglycerol lipase from Penicillium camembertii (38%). Comparison of this lipase with these homologous enzymes suggested that the catalytic triad was composed of Ser144, Asp198, and His256, and that the oxyanion hole was formed with Ser 82. PMID- 7852272 TI - Isolation and analysis of cDNA encoding a precursor of Canavalia ensiformis asparaginyl endopeptidase (legumain). AB - Recently, asparaginyl endopeptidase was purified to homogeneity from jack bean (Canavalia ensiformis) seeds, and its NH2-terminal amino acid sequence was determined for 25 residues [Abe, Y. et al. (1993) J. Biol. Chem. 268, 3525-3529]. On the basis of this sequence information, we searched for seed cDNAs encoding this enzyme. Seven clones were obtained and sequenced. By combining four of them, we obtained a cDNA for a precursor of the enzyme containing the reported NH2 terminal sequence. The other three clones seemed to be for precursors of its isozymes. When the deduced amino acid sequences of these enzyme precursors were compared with those in the GeneBank, EMBL, and NBRF databases, only one protein was found with a homologous sequence. It was a precursor of hemoglobinase from a blood fluke (Schistosoma mansoni). Significant homology was observed only in the range of sequence for the mature form. Although hemoglobinase and asparaginyl endopeptidase behave as cysteine proteinases, their protein natures are distinct from either papain-type proteinases or clostripain. Various plant seeds have been reported to contain asparaginyl endopeptidases. This may be the first report, however, that deals with the primary structure of such a proteinase. PMID- 7852273 TI - A novel beta-galactoside-binding lectin in adult rat kidney. AB - Two carbohydrate-binding proteins with subunit molecular weight of about 17,500 and 16,500, respectively, were isolated from Triton X-100 extracts of rat kidney using a lactose affinity column. They did not require Ca2+ for the carbohydrate binding nor reducing agents for maintaining their activity. The partial amino acid sequence of the 17.5-kDa protein (rkCBP-17.5), the main component, revealed that this protein is a novel member of a superfamily of beta-galactoside-binding animal lectins. The N-terminal amino acid sequence of the 16.5 kDa component (rkCBP-16.5) indicated that it is a fragment derived from the IgE-binding protein (IgEBP). Monoclonal antibodies to rkCBP-17.5 were prepared and used to examine the distribution of the lectin in various organs of adult rats. Immunoreactive protein with the same molecular weight was found in lung, spleen and liver, in lesser amounts in heart, and in trace amounts in brain and skeletal muscle. rkCBP 17.5 exhibits binding activity to various saccharides with the following order of affinity: N-acetyllactosamine > lactose > D-galactose > methyl alpha-D galactopyranoside > N-acetyl-D-galactosamine > methyl beta-D-galactopyranoside. It binds to Engelbreth-Holm-Swarm(EHS) tumor laminin and rat plasma fibronectin, but does not bind to human plasma fibronectin. PMID- 7852274 TI - Substrate-dependent change in the pH-activity profile of alkaline endo-1,4-beta glucanase from an alkaline Bacillus sp. AB - A neutral cellulase (BSC) from Bacillus subtilis and an alkaline cellulase (NK1) from alkalophilic Bacillus sp. N-4 show significant amino acid sequence homology. Despite the high homology, the pH-activity profiles of the two enzymes for carboxymethyl cellulose (CMC) hydrolysis are quite different; BSC shows a sharp optimum pH at 6, whereas NK1 shows its full activity in a broad range, from pH 6 to 10.5. For elucidation of the reasons for the difference in their pH-activity profiles, their activities were examined at various pHs using a series of cellooligosaccharides and their derivatives, cellotetraose (G4), cellopentaose (G5), cellohexaose (G6), cellopentaitol (G5OH), and cellohexaitol (G6OH), as substrates. The optimum pH of BSC was around 6 for all the cellooligosaccharides examined. On the other hand, the optimum pH of NK1 varied depending on the substrate, i.e., a sharp optimum at pH 6 with G4 and G5OH, and a broad optimum of pH 6 to 10.5 with G5, G6, and G6OH. Comparison of the kinetic parameters of the two cellulases at pH 7 and 9 using G6OH as a substrate revealed that NK1 showed similar values at both pHs, while BSC showed a greatly increased Km value for this substrate at pH 9. In addition, NK1 showed a greatly increased Km value for G5OH hydrolysis at pH 9. Both enzymes cleaved these substrates at the same position, which suggests the same productive binding mode of these substrates with both enzymes. All these observations suggest that the reduced enzyme activity of BSC in the alkaline pH range can be attributed to a decrease in the affinity of a subsite for the third glucose moiety from the scissile site of these substrates. PMID- 7852275 TI - Plasma alpha-1-antiproteinase from the Mongolian gerbil, Meriones unguiculatus: isolation, partial characterization, sequencing of cDNA, and implications for molecular evolution. AB - alpha-1-Antiproteinase (also called alpha-1-proteinase inhibitor or alpha-1 antitrypsin) with a molecular mass of 56 kDa was purified from plasma of the Mongolian gerbil, Meriones unguiculatus, to apparent homogeneity. It inhibited trypsin, chymotrypsin, elastase, and plasmin, but not kallikrein or thrombin. Eight cDNA clones coding for this protein were isolated from a liver cDNA library and sequenced. They contained the same coding regions consisting of a 24-residue signal peptide and a 382-residue mature protein. The reactive site sequence (P3 P3) was Val-Pro-Met-Ser-Ile-Pro, characteristic of alpha-1-antiproteinase of orthodox type [Suzuki, Y. et al. (1991) J. Biol. Chem. 266, 928-932]. A molecular phylogenetic tree of 11 orthologous inhibitors, constructed on the basis of the synonymous substitution rate, shows (i) that the reactive site region is highly conserved as compared to the other part of the molecule, which contrasts with the generally accepted view that the reactive site region of serpins is strongly hypervariable, and (ii) that the myomorphs (gerbil, rat, and two species of mouse, i.e. Mus domesticus and Mus caroli) and the caviomorph (guinea pig) fail to consist of a monophyletic order, which also contradicts the traditional taxonomy based on the morphology. In the present tree, the guinea pig joins the lagomorph (rabbit), and is rather widely separated from the myomorph branch. The result, however, supports the recent hypothesis based on the molecular evolution of several other proteins that the guinea pig does not belong to the same order as the myomorph, and the caviomorphs should be elevated in taxonomic rank and conferred an ordinal status distinct from the rodents. PMID- 7852276 TI - Blood coagulation factor Xa interacts with a linear sequence of the kringle 2 domain of prothrombin. AB - Prothrombin is a vitamin K-dependent plasma protein composed of several functional domains, which is proteolytically activated into thrombin by factor Xa in the presence of factor Va, Ca2+, and phospholipids. During the activation, prothrombin is cleaved into three fragments: fragment 1, containing a domain rich in gamma-carboxyglutamic acid residues and kringle 1 domain; fragment 2, containing the kringle 2 domain; and a protease catalytic domain, thrombin. Here we studied the interaction site for factor Xa in human prothrombin during the activation. The isolated fragment 2 inhibited the activation of prothrombin by either prothrombinase complex or factor Xa alone in a dose-dependent manner, whereas fragment 1 and diisopropylphosphate (DIP)-thrombin did not. Factor Xa directly bound to fragment 2 immobilized to microwell plates with a Kd of 9.0 x 10(-8) M, but not to fragment 1 or DIP-thrombin. Factor Xa also bound to immobilized prothrombin and prethrombin 1 with Kds of 2.0 x 10(-7) and 1.5 x 10( 7) M, respectively, suggesting that factor Xa interacts with the kringle 2 domain in these molecules. The binding of factor Xa to immobilized fragment 2 was Ca(2+) dependent with an optimal concentration at 6 mM. In the presence of Ca2+, the interaction was enhanced by phospholipids in a concentration-dependent manner. To localize the factor Xa-binding site in the kringle 2 domain, fragment 2 was digested with lysyl endopeptidase and then trypsin after reduction and S carboxymethylation. The resulting peptides were immobilized to microwell plates and assayed for factor Xa binding ability. The amino acid sequence of the peptide positive in the assay was determined to be residues His205 to Arg220. Factor Xa bound to a synthetic peptide corresponding to the residues His205 to Arg220 immobilized to microwell plates. The peptide inhibited factor Xa-catalyzed activation of prothrombin, but a peptide with the reversed sequence of His205 to Arg220 did not. These findings indicate that factor Xa interacts with at least a linear sequence, His205 to Arg220, in the kringle 2 domain of prothrombin during its activation into thrombin. PMID- 7852277 TI - Isolation, characterization, and primary structure of three major proteins obtained from Mytilus edulis sperm. AB - Acrosomal proteins from Mytilus edulis sperms were separated into 11 fractions by reverse phase HPLC. The three major proteins, named M3, M6, and M7, showed strong egg vitelline coat lysin and first polar body releasing activities. The amino acid sequences of these proteins were determined. M6 and M7 were composed of 180 amino acid residues and showed high sequence homology (76%), while M3 was composed of 149 residues and showed 26% homology with M6 and M7. The disulfide linkage motif of the three proteins was similar and resembled the carbohydrate recognition domain (CRD) of C-type lectin. The C-terminal half of these proteins showed sequence homology with CRD of C-type lectins, but no homology with vitelline coat lysins of other mollusks. The proteins bound to asialofetuin Sepharose in the presence of Ca2+ and were eluted with EDTA, indicating that they are Ca(2+)-dependent carbohydrate-binding proteins. PMID- 7852278 TI - Subtype switching of natriuretic peptide receptors in rat chondrocytes during in vitro culture. AB - Subtype switching of natriuretic peptide receptor (NPR) during in vitro culture of rat chondrocytes was demonstrated by polymerase chain reaction (PCR) analysis, receptor binding assay, and the cGMP formation method. NPR-B was the predominant form in the receptor guanylate cyclase family (i.e. NPR-A and NPR-B) in both rat xiphoid cartilage and in its cultured cells. However, the chondrocytes began to express NPR-C at high levels when cultured in vitro and NPR-C became the major form (maximal binding capacity: 450 fmol/mg of protein) of NPR in the cultured cells. The abundantly expressed NPR-C had no effect on adenylate cyclase activity or proliferation of chondrocytes. PMID- 7852279 TI - Coordinate modulation of melanogenesis and type I trimer collagen secretion by type I collagen substratum during reversible conversion between melanotic and amelanotic cells in mouse B16 melanoma. AB - Two clones, melanotic (M3) and amelanotic (A4) cells, were isolated from B16 mouse melanoma cells. The two clones exhibited distinct phenotypes in cell morphology, melanogenesis, and secretion of extracellular matrix, with preferential secretion of type I trimer collagen in A4 cells. Grown on type I collagen substratum, M3 cells were converted to cells exhibiting similar phenotypes to A4 cells. Subsequent culture of A4-like cells on plastic dishes resulted in the recovery of the initial M3 phenotypes. These results indicate that the reversible conversion between melanotic and amelanotic cells in B16 melanoma cells in vitro is controlled by type I collagen substratum and that modulation of cell shape, melanogenesis, and type I trimer collagen secretion during conversion were all coordinately and reversibly regulated. The results provide evidence that extracellular matrix can control the cell phenotypes in mouse B16 melanoma. Modulation of type I trimer collagen secretion by type I collagen substrate could be a useful model for studying the alpha 1(I) chain specific regulatory mechanism. PMID- 7852280 TI - Purification and characterization of galactocerebrosidase from human lymphocytes. AB - Galactocerebrosidase was purified about 22,600-fold using several hydrophobic column and gel filtration steps with a 4.8% recovery, from human lymphocytes. Its specific activity was 1.54 x 10(5) nmol/h/mg with tritium-labeled galactocerebroside as the substrate in the taurocholate system. The optimal pH for galactocerebroside was 4.2 in the taurocholate system and 4.6 in the cholate system. The Km values for galactocerebroside were 5 microM in the taurocholate system and 25 microM in the cholate system. The molecular weight of the purified enzyme was estimated to be 90 kDa by sodium dodecylsulfate polyacrylamide gel electrophoresis and gel filtration. However, 70, 50, 40, and 30 kDa bands were also recognized on SDS-PAGE. The N-terminal amino acid sequences of the 70 kDa molecule and the three 50 kDa molecules were the same as that of the 90 kDa molecule. The N-terminal amino acid sequences of the 40 and 30 kDa molecules were unique. A monoclonal antibody raised against the purified enzyme effectively immunoprecipitated galactocerebrosidase activity, and an affinity column prepared with this monoclonal antibody bound the 90 and 50 kDa proteins. These results suggest that this enzyme is probably processed from the 90 kDa protein. PMID- 7852281 TI - Ascorbate radicals in fresh cow's milk. AB - Using ESR, a weak signal identified as the ascorbate free radical was observed in fresh cow's milk. The signal was unchanged after storage at 5 degrees C for 24 h but disappeared after storage at 25 degrees C. A marked increase in the steady state ascorbate radical concentration was observed with the addition of H2O2 or xanthine; the increase was abolished in the presence of azide. Based on the xanthine-oxygen reductase activity and 2,2'-azino-di-(3-ethylbenzthiazoline-6 sulfonic acid) peroxidase activity, cow's milk contains 0.45 microM xanthine oxidase and 0.32 microM lactoperoxidase. The results suggest that H2O2- and xanthine-induced ascorbate radical formation was due to the ascorbate peroxidase activity of lactoperoxidase in cow's milk. PMID- 7852282 TI - Effects of sialic acids and the beta-drug adrenergic blocker, propranolol, on the dynamics of human alpha 1-acid glycoprotein: a fluorescence study. AB - The effect of propranolol on the dynamics of human alpha 1-acid glycoprotein (orosomucoid) (sialylated and asialylated) was studied. 2-p-Toluidinylnaphthalene 6-sulfonate (TNS) bound to the protein was used as a probe. The results were identical for all samples. Excitation at the red edge of the absorption spectrum of TNS leads to an important shift (15 nm) of the fluorescence emission maximum of the probe. This reveals that emission of TNS occurs before relaxation of the amino acid dipole has time to occur. Emission from a non-relaxed state means that TNS molecules are bound tightly to the protein, a result confirmed by polarization studies. Sialic acid residues and propranolol do not affect the rigidity of the binding site of TNS. PMID- 7852283 TI - Purification and characterization of diamine oxidase (histaminase) from rat small intestine. AB - Diamine oxidase (DAO) was purified to homogeneity from rat small intestine, and its biochemical and immunochemical properties were studied. DAO was suggested to be a dimer of a 92 kDa subunit, and its isoelectric point was found to be 6.0. Histamine, putrescine, N tau-methylhistamine, and cadaverine were good substrates, with Km values ranging from 9.4 to 16.0 microM. Spermine and spermidine were not substrates. Both an immunoprecipitation study and Ouchterlony's double diffusion test involving antiserum against the purified DAO showed that the immunological properties of the DAOs from rat small intestine, thymus, and placenta were identical. Among small intestinal DAOs from different species, this antibody reacted to the guinea pig enzyme as strongly as to the rat enzyme, but the reaction was much weaker to the mouse enzyme than to the rat enzyme. The DAOs from rabbit and dog small intestine, pig kidney, and human placenta showed no reactivity toward this antibody. PMID- 7852284 TI - Molecular cloning of a chicken lung cDNA encoding a novel protein kinase with N terminal two LIM/double zinc finger motifs. AB - Using the cDNA fragment of chicken c-sea receptor tyrosine kinase as a probe, we isolated from a chicken lung cDNA library overlapping cDNA clones encoding a novel protein kinase, which we termed LIM-kinase (LIMK). The predicted polypeptide of 642 amino acid residues contains remarkable structural features, composed of the N-terminal two tandemly arrayed LIM/double zinc finger motifs and the C-terminal unusual protein kinase domain. To our knowledge, a protein kinase containing the LIM motif in the molecule has not heretofore been described. The protein kinase domain of LIMK shares highly conserved residues with the known protein kinases, but LIMK is unique in that it contains the sequence DLNSHN in subdomain VIB and a short, highly basic insert sequence, which may function as a signal for nuclear localization, between subdomain VII and VIII in the protein kinase domain. Northern blot analysis revealed that the single species of LIMK mRNA of 3.8 kb is expressed predominantly in the lung, and faintly in the kidney, liver, brain, spleen, gizzard, and intestine. As the LIM motif is thought to be involved in protein-protein interactions by binding to another LIM motif, and is often present in the homeodomain-containing proteins involved in cell fate determination and in the oncogenic nuclear proteins (rhombotins), it is likely that LIMK is involved in developmental or oncogenic processes through interactions with these LIM-containing proteins. PMID- 7852285 TI - Further characterization of mitochondrial outer membrane: evidence for the presence of two endogenous sialylated glycoproteins. AB - The distribution of sialic acid-containing glycoproteins was investigated in highly purified mitochondrial membranes using labeled Sambucus nigra agglutinin as a detection system. Two sialylated glycoproteins were shown to be true components of the mitochondrial outer membrane. Relative to monoamine oxidase activity, these glycoproteins were found to be preferentially located in the "free" outer membrane fraction. As sialic acid is thought to be involved in molecular recognition, a role for these glycoproteins in mediating the interactions between mitochondria and other sub-cellular organelles is considered. PMID- 7852286 TI - Transport of envelope proteins of Sendai virus, HN and F0, is blocked at different steps by thapsigargin and other perturbants to intracellular Ca2+. AB - The effects of thapsigargin (Tg), a specific inhibitor of Ca(2+)-ATPase of the endoplasmic reticulum (ER), on replication of Sendai virus (HVJ) in BALB3T3 cells were examined. In the presence of Tg, the cells infected with HVJ did not release viral particles to the culture medium. Tg inhibited almost completely the expression of viral envelope proteins, HN and F0, on the cell surface, although it did not affect the synthesis of viral proteins. Two other inhibitors of Ca(2+) ATPase of the ER, 2,5-di(tert-butyl)-1,4-benzohydroquinone (BHQ) and cyclopiazonic acid (CPA), as well as Ca(2+)-ionophores such as A23187 and ionomycin, also inhibited the expression of HN protein on the cell surface. Tg seemed to inhibit the intracellular transport or maturation of the viral membrane proteins by perturbing intracellular distribution of Ca2+ ions. In the presence of Tg, HN protein remained sensitive to endoglycosidaseH (endoH) for 3 h after its synthesis. On the other hand, F0 protein became resistant to endoH and sensitive to neuraminidase even in the presence of Tg. These results indicate that the transport of HN protein is blocked at the ER or the cis-Golgi region, while that of F0 protein is blocked at the post-Golgi stage in the presence of Tg. PMID- 7852287 TI - Pseudopregnancy-dependent accumulation of cholesterol sulfate due to up regulation of cholesterol sulfotransferase and concurrent down-regulation of cholesterol sulfate sulfatase in the uterine endometria of rabbits. AB - The uterine endometria of rabbits induced into pseudopregnancy by intramuscular injection of 17 beta-estradiol, followed by intravenous injection of human chorionic gonadotropin, expressed cholesterol sulfate at a significantly high concentration. The highest concentration of cholesterol sulfate was observed 4 days after the injection of gonadotropin for formation of the corpus luteum, being 10 times higher than that in nonpregnant endometria, and 15.2% of the total cholesterol in the endometrium was converted to the sulfated form, whose percentage in nonpregnant endometrium was 3.2%. However, no significant change in the concentration of gangliosides was observed during the period of pseudopregnancy. In the pseudopregnant endometria, the activity of cholesterol sulfotransferase, a cytosolic thiol enzyme, was increased thirtyfold over that in the nonpregnant endometria, whereas cholesterol sulfate sulfatase, a microsomal enzyme, exhibited approximately one-tenth of the activity in nonpregnant endometria. Arylsulfatase C, but not arylsulfatases A and B, exhibited the same change in activity as cholesterol sulfate sulfatase. Thus, the striking increase in cholesterol sulfate after induction of pseudopregnancy was found to be due to the activation of cholesterol sulfotransferase and the simultaneous inhibition of cholesterol sulfate sulfatase. PMID- 7852288 TI - Simultaneous stereoinversion and isomerization at specific aspartic acid residues in alpha A-crystallin from human lens. AB - We characterized the primary structure of alpha A-crystallin from the lens of the human eye by detailed analyses of the amino acid sequence, mass, and stereoisomers, and found the biologically uncommon D- and beta-aspartic acid (Asp) residues in the protein. The stereoconfiguration of the Asp151 and Asp58 residues in alpha A-crystallin from old subjects (mean age: 80 years) was inverted to the D-isomer, and the residues were simultaneously isomerized to beta aspartyl residues, which may occur via a succinimide intermediate. This is thought to be the first observation of stereoinversion of amino acids in protein in vivo. It is noteworthy that similar stereoinversion was observed in the same residues of alpha A-crystallin from young subjects (age: 11 months), with simultaneous isomerization, although the extent of isomerization was low compared with that in the aged. The conversion may take place in the early life of the lens and the resulting isomers may accumulate with aging. We also found that terminal serine173 was cleaved in aged alpha A-crystallin. Since the cleavage was not observed in young alpha A-crystallin, it may result from the in vivo aging process. The present findings also make it necessary to revise the amino acid sequence of human alpha A-crystallin presented previously: human alpha A crystallin is composed of 173 (formerly reported as 172) amino acid residues, and the sequence from residues 153 to 155 is THA (formerly reported as -HT). PMID- 7852289 TI - Cycling of an 85-kDa lysosomal membrane glycoprotein between the cell surface and lysosomes in cultured rat hepatocytes. AB - We studied the endocytic transport of an 85-kDa lysosomal membrane glycoprotein (LGP85) from the cell surface to lysosomes in cultured rat hepatocytes. Fab' fragments of a monoclonal antibody against LGP85 (YA30 mAb) were conjugated with horseradish peroxidase (HRP) and then used as probes to monitor the endocytic transport of LGP85 from the plasma membrane to lysosomes. Continuous internalization and lysosomal transport of HRP-YA30 mAb Fab' occurred in the hepatic cells, resulting in its accumulation in the dense lysosomal fraction obtained from the cells on Percoll density centrifugation. The endocytic transport of HRP-YA30 mAb continued in the presence of the protein synthesis inhibitor, cycloheximide, indicating that LGP85 is cycled between the cell surface and lysosomes or endosomes, like other lysosomal membrane glycoproteins, lamp-1 and lamp-2, as reported previously [Akasaki et al. (1993) J. Biochem. 114, 598-604]. The half times (t1/2) of internalization and lysosomal transport of LGP85 were 32 min and 2.0 h, respectively. The kinetics of endocytic transport for LGP85 are very similar to those of lamp-1 and lamp-2. LGP85 possesses a short cytoplasmic tail whose amino acid sequence is quite different from those of lamp 1 and lamp-2. Therefore, these results suggested that continuous internalization from the cell surface and lysosomal transport of of endogenous LGP85 occur through a mechanism that can recognize this novel amino acid sequence, probably a Leu-Ile-containing motif, in normal hepatic cells of rat. PMID- 7852290 TI - Structure and expression of rat and mouse mRNAs for Zn-alpha 2-glycoprotein. AB - Rat and mouse cDNAs for Zn-alpha 2-glycoprotein (Zn alpha 2gp) were isolated from liver libraries (lambda gt11) and compared with the human one. The lengths of cDNA inserts analyzed were 1,233 and 1,273 nucleotides for rat and mouse, respectively. The deduced amino acid sequences suggested that rat and mouse Zn alpha 2gp proteins consist of 279 and 290 amino acid residues in the mature form, respectively. They have 59.4% (rat) and 58.6% (mouse) identities in amino acid sequence with the human counterpart, and between rat and mouse the identity is 88.5%. Among the three domains, domain B is best conserved; the identities are 74.7, 73.6, and 95.6% between human and rat, human and mouse, and rat and mouse, respectively. Four cysteine and eight tryptophan residues are all conserved, and two of the three asparagine residues that carry a glycan in the human protein are conserved. Analysis of rat tissues by Northern blot suggested that its mRNA is expressed in liver, and, to a much lesser extent in submandibular gland, lung, kidney, and stomach. A more detailed study by in situ hybridization demonstrated that some epithelial cells of renal tubules and the isthmus and the neck zone cells of gastric fundic glands express Zn alpha 2gp mRNA. PMID- 7852291 TI - Temperature modulated solubility-activity alterations for poly(N isopropylacrylamide)-lipase conjugates. AB - Chemical modification of proteins by use of functional polymers is expected to endow them with new properties without destroying their native functions, thus providing useful materials for application in different fields. We have synthesized poly(N-isopropylacrylamide) [poly(IPAAm)] co-oligomer with N,N dimethylacrylamide (DMAAm) and reactive end groups by telomerization of IPAAm. This co-oligomer exhibits a lower critical solution temperature (LCST) at 37 degrees C. Using this temperature-responsive semitelechelic co-oligomer, we prepared polymer-enzyme conjugates of lipase by covalent coupling via carboxyl end-groups. This bioconjugate exhibits a LCST at 37 degrees C, having rapid, reversible hydration-dehydration changes due to highly mobile free polymer end groups. The conjugate retained its native enzymatic activity below this critical temperature, above which it precipitated and its catalytic function was shut off. This conjugate can be readily separated from reaction mixtures as a precipitate by simple temperature changes after reaction and reused in cycles without denaturation. Such a modulated system is attractive for application as a novel bioreactor system. PMID- 7852292 TI - Direct expression of a synthetic gene in Escherichia coli: purification and physicochemical properties of human initiation factor 4E. AB - An artificial synthetic gene coding for human eIF-4E was cloned into an expression vector and direct expression was attempted in Escherichia coli [BL21(DE3) strain] under the control of T7 promoter. The active gene product which was induced in high yield (ca. 4 mg/100 ml) by isopropyl-beta-D thiogalactopyranoside was purified to homogeneity by a two-step chromatographic procedure with a good yield (ca. 74%), and was confirmed to be recombinant human eIF-4E by amino acid composition and sequence analyses, isoelectric focusing, and absorption spectral measurements. The identity of three-dimensional structures between the recombinant and native human eIF-4Es was confirmed by CD and fluorescence measurements. PMID- 7852293 TI - Increased retention of small chromosomes in a novel yeast mutant. AB - MSC201 and MSC202 are novel yeast mutant strains in which a 10-kb linear yeast artificial chromosome (YAC) was stably maintained in unselective medium during mitotic cell division. After culturing for 35 cycles of cell division, about 50% of MSC cells retain YAC3 DNA, compared to 0.001% of the wild-type AB1380 strain. Southern blot hybridization analysis with pBR322 DNA as the probe showed that in the MSC transformants, YAC DNA remained in a linear form free of cellular chromosomal DNA. The msc201 mutation was shown to be recessive by the rapid loss of the YAC in a diploid strain made by mating with AB1375, which has a genetic background similar to that of the MSC strain. Linear YAC DNA with a centromere was stabilized in MSC201 better than a linear construct lacking a centromere sequence. PMID- 7852294 TI - The synthetic pathway for glucosylsphingosine in cultured fibroblasts. AB - The synthesis of glucosylsphingosine (GlcSph), a glucosylceramide (GlcCer) analogue devoid of fatty acids, in cultured fibroblasts was studied by using conduritol beta epoxide (CBE), an inhibitor of beta-glucosidase, and 1-phenyl-2 decanoylamino-3-morpholino-1-propanol (PDMP), an inhibitor of glucosylceramide (GlcCer) synthase (glucosyltransferase). When CBE was added to the culture medium, the intracellular beta-glucosidase activity decreased, and both GlcCer and GlcSph accumulated in the cells. After the addition of PDMP, the concentration of GlcCer decreased, while the content of GlcSph increased. When CBE and PDMP were added together, the intracellular accumulation of GlcSph to decreased to less than when CBE alone was added. Based on these results, the synthetic pathway for GlcSph was thus considered to not only be through the glucosylation of sphingosine, but also through the deacylation of GlcCer. When GlcCer (d18:1, C12:0) was added to the culture medium, the intracellular accumulation of GlcSph (d18:1) was evident, and it was also more pronounced in the presence of CBE. In addition, when GlcCer (d18:0, C12:0) was used, apparent accumulation of GlcSph (d18:0) was also observed. In order to determine whether or not the deacylase of GlcCer is identical to acid ceramidase, a deacylase of ceramide, the same experiments were carried out using fibroblasts from two patients with Farber disease, in which acid ceramidase is genetically deficient. The accumulation of GlcSph in the Farber disease fibroblasts after the loading of GlcCer for 7 days was found to be one-fifth of the control level.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7852295 TI - Purification and characterization of dimeric dihydrodiol dehydrogenase from dog liver. AB - High NADP(+)-linked dihydrodiol dehydrogenase activity was detected in dog liver cytosol, from which a dimeric enzyme composed of M(r) 39,000 subunits was purified to homogeneity. The enzyme oxidized trans-cyclohexanediol, and trans dihydrodiols of benzene and naphthalene, the [1R,2R]-isomers of which were selectively oxidized. In the reverse reaction in the presence of NADPH as a coenzyme, the enzyme reduced alpha-dicarbonyl compounds, such as methylglyoxal, 3 deoxyglucosone, and diacetyl, and some compounds with a carbonyl group, such as glyceraldehyde, lactaldehyde, and acetoin. 4-Hydroxyphenylketones and ascorbates inhibited the enzyme. The results of steady-state kinetic analyses indicated that the reaction proceeds through an ordered bi bi mechanism with the coenzyme binding to the free enzyme, and suggested that the inhibitors bind to the enzyme NADP+ binary complex. The dimeric enzyme was detected in liver and kidney of dog, and was immunochemically similar to the dimeric enzymes from monkey kidney, rabbit lens, and pig liver. The sequences (total 127 amino acid residues) of eight peptides derived on enzymatic digestion of the dog liver enzyme did not show significant similarity with the primary structures of members of the aldo keto reductase and short chain dehydrogenase superfamilies, which include monomeric dihydrodiol dehydrogenases and carbonyl reductase, respectively. PMID- 7852296 TI - Exon recognition in vertebrate splicing. PMID- 7852297 TI - Reconstitution of human DNA repair excision nuclease in a highly defined system. AB - Xeroderma pigmentosum is a hereditary disease caused by defective DNA repair. Somatic cell genetics and biochemical studies with cell-free extracts indicate that at least 16 polypeptides are required to carry out the repair reaction proper, i.e. the removal of the lesion from the DNA by the dual incisions of the damaged strand. To find out if these proteins are necessary and sufficient for excision repair, they were obtained at a high level of purity in five fractions. The mixture of these five fractions reconstituted the excision nuclease (excinuclease) activity. Using the reconstituted excinuclease, we found that the excised fragment remains associated with the post-incision DNA-protein complex, suggesting that accessory proteins are needed to release the excised oligomer. PMID- 7852298 TI - Cell-type and amyloid precursor protein-type specific inhibition of A beta release by bafilomycin A1, a selective inhibitor of vacuolar ATPases. AB - Treatment of human 293 cells transfected with amyloid precursor protein (APP)K595N,M596L (the "Swedish" mutation) with a specific inhibitor of the vacuolar H(+)-ATPases, bafilomycin A1 (baf A), leads to a potent inhibition of the release of the A beta peptide. This is accompanied by a selective inhibition of beta-secretase activity. Surprisingly, baf A did not inhibit the production of A beta from either wild-type APP (WT APP) or from APPv7171 (the "Hardy" mutation), expressed in the same cell type. In contrast, the robust production of A beta from a human neuroglioma-derived cell line (HS683) transfected with WT APP, or from primary human mixed brain cultures (HMBC) expressing genomic WT APP, were also effectively inhibited by baf A. The inhibition of A beta production from the HMBC was also accompanied by the inhibition of beta-s-APP release. No inhibition of alpha-s-APP release was seen in any of the cell types tested. These results indicate that intracellular acidic processes are rate-limiting for beta secretase cleavage and A beta production from SW APP, but not WT APP, in the peripheral 293 cell line. Furthermore, such acidic processes also play a rate limiting role in A beta release from human central nervous system-derived cells, including HMBC. Differential trafficking of the SW APP into an acidic compartment conducive to beta-secretase cleavage and A beta release could be one explanation for the increased production of A beta observed on expression of this mutation. PMID- 7852300 TI - Na+,K(+)-ATPase in the choroid plexus. Regulation by serotonin/protein kinase C pathway. AB - In the choroid plexus, the ion pump Na+,K(+)-ATPase regulates the production of cerebrospinal fluid. We now report that incubation of choroid plexus with an activator of protein kinase C, phorbol 12,13-dibutyrate, strongly stimulates the phosphorylation of Na+,K(+)-ATPase and inhibits its activity. Similar effects were obtained with serotonin, which in the choroid plexus stimulates phosphoinositide turnover, thereby activating protein kinase C. Serotonin (10 microM) increased by about 10-fold the amount of phosphorylated Na+,K(+)-ATPase and significantly reduced its activity. Two-dimensional peptide mapping showed comigration of Na+,K(+)-ATPase phosphorylated by either phorbol 12,13-dibutyrate or serotonin in intact cells and by protein kinase C in vitro. These results demonstrate that first messengers can regulate the activity of Na+,K(+)-ATPase through a mechanism involving protein phosphorylation. Moreover, they provide a plausible mechanism for the demonstrated ability of serotonin to decrease cerebrospinal fluid production. PMID- 7852299 TI - Substrate recognition domain of the Gal2 galactose transporter in yeast Saccharomyces cerevisiae as revealed by chimeric galactose-glucose transporters. AB - The Gal2 galactose transporter takes up galactose in yeast. A homologous glucose transporter from the same organism, Hxt2, was selected, and various chimeras between these two transporters were constructed by making use of homologous recombination in Escherichia coli. Comparison of the galactose transport activities of three series of chimeras enabled us to positively identify a crucial substrate recognition region of 101 amino acids that lies close to the carboxyl terminus of the Gal2 transporter. PMID- 7852301 TI - ADP-ribosylation factor functions synergistically with a 50-kDa cytosolic factor in cell-free activation of human neutrophil phospholipase D. AB - Proteins in both the cytosol and plasma membrane are needed to reconstitute cell free phospholipase D activity from phagocytes (Olson, S., Bowman, E. P., and Lambeth, J. D. (1991) J. Biol. Chem. 266, 17236-17242); membrane factors include a small GTP-binding protein in the Rho family (Bowman, E., Uhlinger, D. J., and Lambeth, J. D. (1993) J. Biol. Chem. 268, 21509-21512). ADP-ribosylation factor (ARF) was recently implicated as the cytosolic factor, as it activates phospholipase D in HL-60 membranes. Herein, we show that ion exchange chromatography separates ARF from the major phospholipase D-stimulating cytosolic factor. Both bovine brain ARF and recombinant human ARF-1 stimulated a small amount of phospholipase D activity in the absence of cytosol (about 10% of the response seen with cytosol). With a high concentration of ARF-depleted cytosol, ARF did not further activate. However, at low cytosol, ARF caused marked activation. Thus, ARF synergizes with the cytosolic factor in phospholipase D activation. PMID- 7852302 TI - Insulin receptor signaling is augmented by antisense inhibition of the protein tyrosine phosphatase LAR. AB - Considerable evidence has shown that most physiologic responses to insulin require activation of the intrinsic tyrosine kinase of the insulin receptor. Biochemical studies have also supported the hypothesis that receptor kinase activity can be modulated by cellular protein tyrosine phosphatases (PTPases), which have not yet been identified. To test the hypothesis that the transmembrane PTPase LAR can modulate insulin receptor signaling in vivo, antisense RNA expression was used to specifically suppress LAR protein levels by 63% in the rat hepatoma cell line, McA-RH7777. Hormone-dependent autophosphorylation of the insulin receptor was increased by approximately 150% in the antisense-expressing cells at all insulin concentrations tested. This increase in autophosphorylation was paralleled by a 35% increase in insulin receptor tyrosine kinase activity. Reduced LAR levels did not alter non-hormone-dependent tyrosine phosphorylation nor basal insulin receptor tyrosine phosphorylation and kinase activity. Most significantly, reduced LAR levels resulted in a 350% increase in insulin dependent phosphatidylinositol 3-kinase activity. These studies provide unique in vivo evidence that LAR is involved in the modulation of insulin receptor signaling in intact cells. PMID- 7852303 TI - Thr-422 and Tyr-424 residues in the carboxyl terminus are critical for the internalization of the rat neurotensin receptor. AB - In order to identify the amino acid sequences responsible for the internalization of the cloned rat brain neurotensin receptor, we carried out site-directed mutagenesis of the cDNA encoding the receptor followed by expression of the receptor into mammalian COS 7 cells. In cells transfected with the full-length neurotensin receptor, 56% of iodinated neurotensin specifically bound to the cells after 60 min of incubation at 37 degrees C was internalized. Deletions made in the third intracellular loop did not affect receptor internalization. By contrast, internalization was reduced to 5% of total in cells in which almost all the carboxyl-terminal tail of the receptor had been deleted (R392stop). In order to determine which part of the tail was responsible for this effect, several Ser and Thr residues were deleted in the carboxyl cytoplasmic sequence of the receptor. Almost all of these receptors were internalized as efficiently as the wild type. Only the form of the neurotensin receptor truncated at Glu-421 (deletion of the last three residues, TLY) produced a significant decrease in the amount of ligand internalized. Finally, point mutations of Thr-422 and Tyr-424 residues to Gly led to an almost complete loss of ligand internalization demonstrating the involvement of these 2 residues in the internalization process. Replacement of the last three amino acids by the cytoplasmic endocytosis signal of the vesicular stomatitis virus did not restore the efficiency of neurotensin receptor internalization. These biochemical results were confirmed by confocal microscopic analysis. Cell transfected with the wild type receptor showed a temperature-dependent intracellular accumulation of a fluorescent analog of neurotensin, whereas cells transfected with a receptor truncated at the carboxyl terminus showed a clustering of the fluorescent peptide at the cell surface. PMID- 7852304 TI - Generation of the glycyl radical of the anaerobic Escherichia coli ribonucleotide reductase requires a specific activating enzyme. AB - The anaerobic ribonucleotide reductase from Escherichia coli contains a glycyl radical as part of its polypeptide structure. The radical is generated by an enzyme system present in E. coli. The reductase is coded for by the nrdD gene located at 96 min. Immediately downstream, we now find an open reading frame with the potential to code for a 17.5-kDa protein with sequence homology to a protein required for the generation of the glycyl radical of pyruvate formate lyase. The protein corresponding to this open reading frame is required for the generation of the glycyl radical of the anaerobic reductase and binds tightly to the reductase. The "activase" contains iron, required for activity. The general requirements for generation of a glycyl radical are identical for the reductase and pyruvate formate lyase. For the reductase, the requirement of an iron containing activase suggests the possibility that the iron-sulfur cluster of the enzyme is not involved in radical generation but may participate directly in the reduction of the ribonucleotide. PMID- 7852305 TI - Heat-inducible DNA binding of purified heat shock transcription factor 1. AB - The heat-induced expression of heat shock proteins, called the cellular stress response, is mediated by heat shock transcription factor 1 (HSF1). HSF1 exists in unstressed cells in an inactive form, which is converted to the DNA binding from upon exposure of cells to elevated temperature. We have developed a protocol for isolation of the non-DNA binding form of recombinant mouse HSF1, involving expression and affinity purification of HSF1 as a fusion with the glutathione S transferase protein in Escherichia coli, followed by specific protease cleavage to release pure HSF1 protein. We report here that the purified inactive HSF1 can be converted to the DNA binding form by heat treatment in vitro. Chemical cross linking analysis demonstrates that this conversion is accompanied by oligomerization of HSF1 from a monomeric to a trimeric native structure, similar to that observed for HSF1 in heat-shocked cells. These results indicate that elements residing in the HSF1 polypeptide are sufficient both for maintenance of this factor in the non-DNA binding from and for its heat-induced conversion to the DNA binding form and support a role for HSF1 as the "molecular thermostat" in eukaryotic cells, which senses adverse environmental conditions and activates the cellular stress response. PMID- 7852306 TI - Purification and characterization of REKS from Xenopus eggs. Identification of REKS as a Ras-dependent mitogen-activated protein kinase kinase kinase. AB - We have previously identified a protein factor, named REKS (Ras-dependent Extracellular signal-regulated kinase/Mitogen-activated protein kinase kinase (MEK) Stimulator), which is necessary for Ras-dependent MEK activation. In this study, we attempted to highly purify and characterize REKS. We have highly purified REKS by successive column chromatographies using a cell-free assay system in which REKS activates recombinant extracellular signal-regulated kinase 2 through recombinant MEK in a guanosine 5'-O-(thiotriphosphate) (GTP gamma S)-Ki Ras-dependent manner. REKS formed a stable complex with GTP gamma S-Ras; REKS was coimmunoprecipitated with GTP gamma S-Ki-Ras or GTP gamma S-Ha-Ras, but not with GDP-Ki-Ras or GDP-Ha-Ras by an anti-Ras antibody. REKS was absorbed to a GTP gamma S-glutathione S-transferase (GST)-Ha-Ras-coupled glutathione-agarose column but not to a GDP-GST-Ha-Ras-coupled glutathione-agarose column and was coeluted with GTP gamma S-GST-Ha-Ras by reduced glutathione. The minimum molecular mass of REKS was estimated to be about 98 kDa on SDS-polyacrylamide gel electrophoresis. REKS phosphorylated this 98-kDa protein as well as recombinant MEK. REKS was not recognized by any of the anti-c-Raf-1, anti-Mos, and anti-mSte11 antibodies. These results indicate that REKS is a Ras-dependent MEK kinase. PMID- 7852307 TI - Design of a ruthenium-cytochrome c derivative to measure electron transfer to the initial acceptor in cytochrome c oxidase. AB - A ruthenium-labeled cytochrome c derivative was prepared to meet two design criteria: the ruthenium group must transfer an electron rapidly to the heme group, but not alter the interaction with cytochrome c oxidase. Site-directed mutagenesis was used to replace His39 on the backside of yeast C102T iso-1 cytochrome c with a cysteine residue, and the single sulfhydryl group was labeled with (4-bromomethyl-4' methylbipyridine) (bis-bipyridine)ruthenium(II) to form Ru 39-cytochrome c (cyt c). There is an efficient pathway for electron transfer from the ruthenium group to the heme group of Ru-39-cyt c comprising 13 covalent bonds and one hydrogen bond. Electron transfer from the excited state Ru(II*) to ferric heme c occurred with a rate constant of (6.0 +/- 2.0) x 10(5) s-1, followed by electron transfer from ferrous heme c to Ru(III) with a rate constant of (1.0 +/- 0.2) x 10(6) s-1. Laser excitation of a complex between Ru-39-cyt c and beef cytochrome c oxidase in low ionic strength buffer (5 mM phosphate, pH7) resulted in electron transfer from photoreduced heme c to CuA with a rate constant of (6 +/- 2) x 10(4) s-1, followed by electron transfer from CuA to heme a with a rate constant of (1.8 +/- 0.3) x 10(4) s-1. Increasing the ionic strength to 100 mM leads to bimolecular kinetics as the complex is dissociated. The second-order rate constant is (2.5 +/- 0.4) x 10(7) M-1s-1 at 230 mM ionic strength, nearly the same as that of wild-type iso-1-cytochrome c. PMID- 7852308 TI - Excitation-transcription coupling mediated by zinc influx through voltage dependent calcium channels. AB - Electrical activity initiates a program of selective gene expression in excitable cells. Although such transcriptional activation is commonly attributed to depolarization-induced changes in intracellular Ca2+, zinc represents a viable alternative given its prominent role as a cofactor in DNA-binding proteins coupled with evidence that Zn2+ can enter excitable cells in a voltage-dependent manner. Here it is shown that Zn2+ entry into heart cells depends upon electrical stimulation and occurs via dihydropyridine-sensitive Ca2+ channels. The addition of extracellular Zn2+ to spontaneously depolarizing GH3 pituitary tumor cells induced the expression of a reporter gene driven by the metallothionein promoter, an effect that was prevented by exposure to dihydropyridine Ca2+ channel blockers. Thus, Zn2+ influx through L-type Ca2+ channels can mediate voltage dependent gene expression. PMID- 7852309 TI - Polarized distribution and delivery of plasma membrane proteins in thyroid follicular epithelial cells. AB - Thyroid follicular cells coordinate several oppositely located surface enzyme activities. Recent studies have raised questions about the basic mechanisms used to achieve thyroid surface polarity. We investigated these mechanisms in primary thyroid epithelial monolayers cultured on porous filters. In the steady state, most Na+/K(+)-ATpase and aminopeptidase N were available for surface biotinylation, and these proteins exhibited physiological distributions (basolateral and apical, respectively). Glycosylphosphatidylinositol-anchored proteins were also apically distributed. By pulse-chase, newly synthesized transmembrane proteins exhibited polarized surface delivery that was oriented similarly to that observed at steady state. Little time elapsed between acquisition of Golgi-specific processing and cell surface arrival. Interestingly, when either newly synthesized or steady state-labeled thyroid peroxidase was similarly analyzed, only approximately 30% of the enzyme was ever detected at the cell surface. Of this, the majority was localized apically. The data suggest that most thyroid peroxidase remains intracellular in these monolayers, consistent with the possibility of intracellular iodination activity in addition to apical extracellular iodination. Nevertheless, in filter-polarized thyrocytes, most newly synthesized plasma membrane proteins appear to be sorted in the Golgi complex for direct delivery to apical and basolateral domains. PMID- 7852310 TI - Effect of the FruR regulator on transcription of the pts operon in Escherichia coli. AB - The promoters of the pts operon of Escherichia coli are controlled by the cyclic AMP receptor protein (CRP) complexed with cAMP (CRP.cAMP). In addition, glucose stimulates pts operon expression in vivo. The pts promoter region has a fructose repressor (FruR)-binding site (the FruR box) that partially overlaps with one of the CRP.cAMP-binding sites. The effects of the pleiotropic transcriptional regulator FruR on pts operon expression were studied to determine whether the in vivo glucose effect on pts operon expression is mediated by FruR. In vitro, FruR can repress P1b transcription, which is activated by CRP.cAMP, and restore P1a transcription, which is repressed by CRP.cAMP. FruR can displace CRP.cAMP from its binding site in the presence of RNA polymerase even though FruR and CRP.cAMP can bind simultaneously to their partially overlapping binding sites in the absence of RNA polymerase. FruR had very little effect on the transcription of the P0 promoter, which is most important for regulation by glucose. Consistent with the in vitro results, pts P0 transcription did not increase as much in cells grown in the presence of fructose or in fruR- mutant cells as in cells grown in the presence of glucose. These results suggest that FruR alone does not mediate the in vivo glucose effect on pts operon expression. PMID- 7852311 TI - Calpain expression in lymphoid cells. Increased mRNA and protein levels after cell activation. AB - Although calpain is ubiquitously present in human tissues and is thought to play a role in demyelination, its activity is very low in resting normal lymphocytes. To determine the nature of calpain expression at the mRNA and protein levels in human lymphoid cells, we studied human T lymphocytic, B lymphocytic, and monocytic lines as well as peripheral blood mononuclear cells. Stimulation of cells with the phorbol ester phorbol myristate acetate and the calcium ionophore A23187 resulted in increased calpain mRNA and protein expression. Calpain mRNA expression is also increased in human T cells stimulated with anti-CD3. A dissociation between the increases of RNA and protein suggested that calpain could be released from the cells; the subsequent experiments showed its presence in the extracellular environment. 5,6-Dichloro-1b-D-ribofuranosylbenzimidazole, a reversible inhibitor of mRNA synthesis, reduced calpain mRNA levels by 50-67% and protein levels by 72-91%. Its removal resulted in resumption of both calpain mRNA and protein synthesis. Cycloheximide, a translational inhibitor, reduced calpain protein levels by 77-81% and calpain mRNA levels by 96% in activated THP-1 cells. Interferon-gamma induced calpain mRNA and protein in U-937 and THP-1 cells. Dexamethasone increased mRNA expression in THP-1 cells. Our results indicate that activation of lymphoid cells results in de novo synthesis and secretion of calpain. PMID- 7852312 TI - p70 phosphorylation and binding to p56lck is an early event in interleukin-2 induced onset of cell cycle progression in T-lymphocytes. AB - The cytoplasmic protein tyrosine kinase p56lck has been implicated as an effector of interleukin-2-induced cell division in T-lymphocytes, but little is known about physiological substrates for p56lck during these events. We have used p56lck fusion proteins to identify potential cytoplasmic signal transduction proteins that bind to p56lck in mitotically activated human peripheral blood lymphocytes and in constitutively dividing leukemic T-cell lines. In peripheral blood lymphocytes, we have observed an interleukin-2-dependent tyrosine phosphorylation of a 70-kDa protein and binding of tyrosine phosphorylated p70 to the SH2 domain of p56lck. A 70-kDa phosphoprotein was also observed to constitutively bind p56lck in leukemic T-cells. Affinity purification of p56lck associated p70 and sequencing of proteolytic fragments revealed identity to a 62 kDa protein that has been identified as a ras-GTPase activating protein. These results demonstrate a stimulation-dependent tyrosine phosphorylation of p70 and its interaction with p56lck and may provide a link between p56lck and GTPase mediated signal transduction pathways in activated T-lymphocytes. PMID- 7852313 TI - Glycan requirements of glycosylphosphatidylinositol phospholipase C from Trypanosoma brucei. Glucosaminylinositol derivatives inhibit phosphatidylinositol phospholipase C. AB - Glycosylphosphatidylinositol phospholipase C (GPI-PLC) from Trypanosoma brucei and phosphatidylinositol phospholipase C (PI-PLC) from Bacillus sp. both cleave glycosylphosphatidylinositols (GPIs). However, phosphatidylinositol, which is efficiently cleaved by PI-PLC, is a very poor substrate for GPI-PLC. We examined GPI-PLC substrate requirements using glycoinositol analogs of GPI components as potential inhibitors. Glucosaminyl (alpha 1-->6)-D-myo-inositol (GlcN(alpha 1- >6)Ins), GlcN(alpha 1-->6)Ins 1,2-cyclic phosphate, GlcN(alpha 1-->6)-2-deoxy Ins, and GlcN(alpha 1-->6)Ins 1-dodecyl phosphonate inhibited GPI-PLC. GlcN(alpha 1-->6)Ins was as effective as Man-(alpha 1-->4)GlcN(alpha 1-->6)Ins; we surmise that GlcN(alpha 1-->6)Ins is the crucial glycan motif for GPI-PLC recognition. Inhibition by GlcN(alpha 1-->6)Ins 1,2-cyclic phosphate suggests product inhibition since GPIs cleaved by GPI-PLC possess a GlcN(alpha 1-->6)Ins 1,2 cyclic phosphate at the terminus of the residual glycan. The effectiveness of GlcN(alpha 1-->6)-2-deoxy-Ins indicates that the D-myo-inositol (Ins) 2-hydroxyl is not required for substrate recognition, although it is probably essential for catalysis. GlcN(alpha 1-->6)-2-deoxy-L-myo-inositol, unlike GlcN(alpha 1-->6)-2- deoxy-Ins, had no effect on GPI-PLC; hence, GPI-PLC can distinguish between the two enantiomers of Ins. Surprisingly, GlcN(alpha 1-->6)Ins 1,2-cyclic phosphate was not a potent inhibitor of Bacillus cereus PI-PLC, and GlcN(alpha 1-->6)Ins had no effect on the enzyme. However, both GlcN(alpha 1-->6)Ins 1-phosphate and GlcN(alpha 1-->6)Ins 1-dodecyl phosphonate were competitive inhibitors of PI-PLC. These observations suggest an important role for a phosphoryl group at the Ins 1 position in PI-PLC recognition of GPIs. Other studies indicate that abstraction of a proton from the Ins 2-hydroxyl is not an early event in PI-PLC cleavage of GPIs. Furthermore, both GlcN(alpha 1-->6)-2-deoxy-Ins 1-phosphate and GlcN(alpha 1-->6)-2-deoxy-L- myo-inositol inhibited PI-PLC without affecting GPI-PLC. Last, the aminoglycoside G418 stimulated PI-PLC, but had no effect on GPI-PLC. Thus, these enzymes represent mechanistic subclasses of GPI phospholipases C, distinguishable by their sensitivity to GlcN(alpha 1-->6)Ins derivatives and aminoglycosides. Possible allosteric regulation of PI-PLC by GlcN(alpha 1-->6)Ins analogs is discussed. PMID- 7852314 TI - Regulation of inositol transport in Saccharomyces cerevisiae involves inositol induced changes in permease stability and endocytic degradation in the vacuole. AB - Uptake of inositol by Saccharomyces cerevisiae is mediated by a specific inositol permease encoded by the ITR1 gene. Removal of inositol from the growth medium results in an increase in ITR1 mRNA abundance. The increase in ITR1 mRNA is accompanied by an increase in de novo synthesis of the Itr1 permease leading to an increased capacity for uptake. When inositol is added to the growth medium inactivation of uptake activity occurs, and both transcription of ITR1 and uptake activity are repressed to a basal level of function. The transcriptional regulation of ITR1 depends on the INO2, INO4, and OPI1 genes. In addition, repression is also achieved by regulation of ITR1 expression at the post translational level. In this study, we show that there is a change in the stability of the Itr1 permease after the addition of inositol to the growth medium. Immunoblot analysis using a monoclonal antibody against an epitope attached to the Itr1 permease showed that the addition of inositol causes a dramatic increase in the rate of degradation of the permease. After the repressed (basal) level is achieved, turnover continues to be rapid. The increased rate of degradation was also observed in strains with mutations that block conjugation to ubiquitin. Degradation was not observed in strains defective in the END3/END4 endocytic pathway or in the production of vacuolar proteases (PEP4). Thus, inactivation of the Itr1 permease is accompanied by endocytic internalization followed by degradation in the vacuole. Inactivation may be a separate process that precedes and signals endocytic degradation. Since the end3/end4 mutations did not affect uptake activity under derepressed conditions, endocytosis is not required for normal inositol uptake. PMID- 7852315 TI - Regulation of the myoblast-specific expression of the human beta-enolase gene. AB - The muscle-specific beta-enolase gene is expressed in proliferating adult myoblasts as well as in differentiated myotubes. Through deletion-transfection analysis, we identified a 79-base pair enhancer from the beta-enolase gene that leads to high level expression of a reporter gene in myoblasts, but not in fibroblasts. Following myoblast differentiation into myotubes, the activity of the enhancer declined, indicating that beta-enolase gene expression in myotubes is mediated by other regulators, possibly the myogenic helix-loop-helix family of transcription factors. Electrophoretic mobility shift assays indicated that proteins present in myoblast nuclear extracts specifically bind to the 3' half of the 79-base pair enhancer. This region contains an ets DNA-binding motif which is required not only for high level activity in myoblasts, but also for repressing activity in fibroblasts. Furthermore, the beta-enolase myoblast-specific enhancer shows limited similarity to the myoblast-specific enhancer associated with the human desmin gene, suggesting that gene expression in adult myoblasts may be coordinately regulated. PMID- 7852316 TI - Tandem mass spectrometry and structural elucidation of glycopeptides from a hydroxyproline-rich plant cell wall glycoprotein indicate that contiguous hydroxyproline residues are the major sites of hydroxyproline O-arabinosylation. AB - Hydroxyproline-rich glycoproteins (HRGPs) occur in the extracellular matrix of land plants and green algae. HRGPs contain from 2 to 95% of their dry weight as carbohydrate, predominantly as oligoarabinosides and/or as heteropolysaccharides which are O-linked to the hydroxyproline residues. A glycosylation code that determines the presence or absence and extent of arabinosylation at each hydroxyproline residue is likely, as each HRGP has a unique arabinosylation profile. Previously we noted a positive correlation between the contiguity of hydroxyproline residues and the extent of HRGP O-arabinosylation (Kieliszewski, M., deZacks, R., Leykam, J.F., and Lamport, D.T.A. (1992) Plant Physiol. 98, 919 926); most arabinosylated hydroxyproline residues and the longer arabinofuranoside chains occur in HRGPs where Hyp residues occur as blocks of tetrahydroxyproline, while those with little or no contiguous Hyp exhibit very little Hyp arabinosylation. In order to test this Hyp contiguity hypothesis, we have for the first time determined the arabinosylation site specifics of an HRGP, namely the proline and hydroxyproline-rich glycoprotein (PHRGP) isolated from Douglas fir (Pseudotsuga menziesii). Pronase digests of PHRGP yielded a major peptide and three glycopeptides whose structures were determined directly from the unfractionated underivatized Pronase digest by tandem mass spectrometry using collisionally induced dissociation. We corroborated the peptide and glycopeptide structures by Edman degradation, neutral sugar analyses, hydroxyproline arabinoside profiles, and further mass spectrometric analyses after purification of the major peptide and glycopeptides by a combination of hydrophilic interaction and reverse phase column chromatography. Consistent with the Hyp contiguity hypothesis, the structural analyses indicate that while the sequence Ile-Pro-Pro-Hyp is never arabinosylated and Lys-Pro-Hyp-Val-Hyp is only occasionally monoarabinosylated at Hyp-5, the peptide containing contiguous Hyp, Lys-Pro-Hyp-Hyp-Val, is always arabinosylated at Hyp-3, mainly by a triarabinoside. We also obtained precise molecular masses for both intact and anhydrous hydrogen fluoride-deglycosylated PHRGPs (73.113 and 53.834 kDa) via matrix-assisted laser desorption/ionization time of flight mass spectrometry, representing the first HRGP to be analyzed by this method. PMID- 7852317 TI - Cell-mediated catabolism of aggrecan. Evidence that cleavage at the "aggrecanase" site (Glu373-Ala374) is a primary event in proteolysis of the interglobular domain. AB - A rat chondrosarcoma cell line and primary bovine chondrocytes have been used to study cell-mediated aggrecan catabolism. Addition of 1 microM retinoic acid to chondrosarcoma cultures resulted in aggrecan proteolysis with the release of greater than 90% of the cell layer aggrecan into the medium within 4 days. NH2 terminal sequencing of chondroitin sulfate-substituted catabolic products gave a single major NH2-terminal sequence of ARGNVILTXK, initiating at Ala374. This showed that the proteinase, commonly referred to as "aggrecanase," which cleaves the Glu373-Ala374 bond of the interglobular domain of aggrecan (Sandy, J. D., Neame, P. J., Boynton, R. E., and Flannery, C. R. (1990) J. Biol. Chem. 266, 8683 8685), is active in this cell system. Aggrecan G1 domain, generated by cleavage of the interglobular domain, was also liberated during catabolism and this was characterized with three antipeptide antisera. Anti-CDAGWL was used as a general probe for G1 domain. Anti-FVDIPEN was used to specifically detect G1 domain with COOH terminus of Asn341, the form which is readily generated by cleavage of aggrecan by a wide range of matrix metalloproteinases. Anti-NITEGE antiserum was used to specifically detect G1 domain with COOH terminus of Gln373, the form which is the expected product of "aggrecanase"-mediated cleavage of aggrecan. Western blot analysis indicated that a single form of G1 domain of about 60 kDa was formed. G1 domain of this size reacted with both anti-CDAGWL and anti-NITEGE but not with anti-FVDIPEN. Similar experiments with primary bovine chondrocyte cultures, treated with either retinoic acid or interleukin 1, showed that two forms of catabolic G1 domain, of about 62 and 66 kDa, were formed. Both of these forms reacted on Western blots with anti-CDAGWL and also with anti-NITEGE. It is suggested that cell-mediated catabolism of the aggrecan interglobular domain in these culture systems, whether promoted by retinoic acid or interleukin 1, primarily involves cleavage of the Glu373-Ala374 bond by aggrecanase. The accumulation of G1 domain with a COOH-terminal of Glu373 shows that such aggrecanase-mediated cleavage can occur independent of the cleavage of the Asn341 Phe342 bond by matrix metalloproteinases. PMID- 7852318 TI - A direct regulatory role for troponin T and a dual role for troponin C in the Ca2+ regulation of muscle contraction. AB - Troponin (Tn), containing three subunits: Ca2+ binding (TnC), inhibitory (TnI), and tropomyosin binding (TnT), plays a crucial role in the Ca2+ regulation of vertebrate striated muscle contraction. These three subunits function by interacting with each other and with the other thin filament proteins. Previous studies suggested that the primary role of TnT is to anchor the TnI.TnC complex to the thin filament, primarily through its interactions with TnI and tropomyosin. We propose here a new role for TnT. Our results indicate that, when TnT is combined with the TnI.TnC complex, there is an activation of actomyosin ATPase that is Ca(2+)-dependent. To determine whether the latter results from a direct effect of TnC on TnT or indirectly from an effect of TnC on TnI which is transmitted to TnT, we prepared a deletion mutant (deletion of residues 1-57) of TnI, TnId57 (Sheng et al. (1992) J. Biol. Chem. 267, 25407-25413), which interacts with TnC but not TnT. Both wild type (TnI.TnC.TnT) and mutant (TnId57.TnC.TnT) Tn complexes demonstrated equivalent activity in the Ca2+ regulation of actomyosin-S1 ATPase activity. Similarly, both TnI and TnId57 could equally reconstitute TnI-depleted skinned muscle fibers. Therefore, since TnId57 does not interact with TnT, these results suggest that TnT reconstitutes native Ca2+ sensitivity via direct interaction with TnC. Thus Ca2+ binding to TnC would have a dual role: 1) release of the ATPase inhibition by TnI and 2) activation of the ATPase through interaction with TnT. PMID- 7852319 TI - C-terminal post-translational proteolysis of plant lectins and their recombinant forms expressed in Escherichia coli. Characterization of "ragged ends" by mass spectrometry. AB - Electrospray mass spectrometry was used to accurately measure the molecular masses of single chain lectins from legume seeds and also of three recombinant lectins, expressed in Escherichia coli. The five single chain lectins, Erythrina corallodendron lectin, soybean and peanut agglutinins, Dolichos biflorus lectin, and Phaseolus vulgaris hemagglutinin E, all showed evidence of C-terminal proteolytic processing, in some cases to "ragged" ends, when their masses were compared to those expected from their cDNA sequences and their known carbohydrate chains. Recombinant forms of the lectins from E. corallodendron, soybean, and peanut also showed C-terminal trimming, but not to the same points as the natural forms. Discrepancies between the protein and cDNA sequences of the E. corallodendron lectin were resolved by combined liquid chromatography-mass spectrometry peptide mapping and protein sequencing experiments, and the presence of a second glycosylation site was demonstrated. Our data show that all of these lectins undergo C-terminal proteolytic processing of a readily attacked peptide segment. This trimming is frequently imprecise, and the resulting heterogeneity may be a major contributor to the appearance of isolectin forms of these proteins. PMID- 7852320 TI - The assembly and organization of the alpha 5 and alpha 7 helices from the pore forming domain of Bacillus thuringiensis delta-endotoxin. Relevance to a functional model. AB - The pore-forming domain of Bacillus thuringiensis insecticidal CryIIIA delta endotoxin contains two helices, alpha 5 and alpha 7, that are highly conserved within all different Cry delta-endotoxins. To gain information on the mode of action of delta-endotoxins, we have used a spectrofluorimetric approach and characterized the structure, the organization state, and the ability to self assemble and to co-assemble within lipid membranes of alpha 5 and alpha 7. Circular dichroism (CD) spectroscopy revealed that alpha 7 adopts a predominantly alpha-helical structure in methanol, similar to what has been found for alpha 5, and consistent with its structure in the intact molecule. The hydrophobic moment of alpha 7 is higher than that calculated for alpha 5; however, alpha 7 has a lesser ability to permeate phospholipids as compared to alpha 5. Binding experiments with 7-nitrobenz-2-oxa-1,3-diazole-4-yl (NBD)-labeled peptide demonstrated that alpha 7 binds to phospholipid vesicles with a partition coefficient in the order of 10(4) M-1 similar to alpha 5, but with reduced kinetics and in a noncooperative manner, as opposed to the fast kinetics and cooperativity found with alpha 5. Resonance energy transfer measurements between fluorescently labeled pairs of donor (NBD)/acceptor (rhodamine) peptides revealed that, in their membrane-bound state, alpha 5 self-associates but alpha 7 does not, and that alpha 5 coassembles with alpha 7 but not with an unrelated membrane bound alpha-helical peptide. Furthermore, resonance energy transfer experiments, using alpha 5 segments, specifically labeled in either the N- or C-terminal sides, suggest a parallel organization of alpha 5 monomers within the membranes. Taken together the results are consistent with an umbrella model suggested for the pore forming activity of delta-endotoxin (Li, J., Caroll, J., and Ellar, D. J. (1991) Nature 353, 815-821), where alpha 5 has transmembrane localization and may be part of the pore lining segment(s) while alpha 7 may serve as a binding sensor that initiates the binding of the pore domain to the membrane. PMID- 7852321 TI - COOH-terminal substitutions in the serpin C1 inhibitor that cause loop overinsertion and subsequent multimerization. AB - The region COOH-terminal to the reactive center loop is highly conserved in the serine protease inhibitor (serpin) family. We have studied the structural consequences of three substitutions (Val451-->Met, Phe455-->Ser, and Pro476- >Ser) found in this region of C1 inhibitor in patients suffering from hereditary angioedema. Equivalent substitutions have been described in alpha 1-antitrypsin and antithrombin III. The mutant C1 inhibitor proteins were only partially secreted upon transient transfection into COS-7 cells and were found to be dysfunctional. Immunoprecipitation of conditioned media demonstrated that in the intact, uncleaved form they all bind to a monoclonal antibody which recognizes specifically the protease-complexed or reactive center-cleaved normal C1 inhibitor. A second indication for an intrinsic conformational change was the increased thermostability compared to the normal protein. Furthermore, gel filtration studies showed that the Val451-->Met and Pro476-->Ser mutant proteins, and to a lesser extent Phe455-->Ser, were prone to spontaneous multimerization. Finally, a reduced susceptibility to reactive center cleavage by trypsin was observed for all three mutants, and the cleaved Val451-->Met and Pro476-->Ser mutants failed to adopt the conformation recognized by a cleavage-specific monoclonal antibody. Investigation of plasmas of patients with the Val451-->Met or Pro476-->Ser substitutions showed that these dysfunctional proteins circulate at low levels and are recognized by the complex-specific antibody. These results strongly indicate a conformational change as a result of these carboxylterminal substitutions, such that anchoring of the reactive center loop at the COOH terminal side is not achieved properly. We propose that this results in overinsertion of the loop into beta-sheet A, which subsequently leads to multimerization. PMID- 7852322 TI - Enzyme assembly after de novo synthesis in rabbit reticulocyte lysate involves molecular chaperones and immunophilins. AB - The folding kinetics of two luciferases were studied after synthesis in reticulocyte lysates to investigate whether molecular chaperones and/or folding catalysts are involved in the folding reactions. Two bacterial luciferases were used as model proteins: heterodimeric Vibrio harveyi luciferase (LuxAB), and a monomeric luciferase fusion protein (Fab2). Data indicate that folding of these enzymes to the native state occurs in the translation system, and that the extent of folding can be quantified. It was found that (i) folding of LuxAB and Fab2 can clearly be separated in time from synthesis, (ii) folding of Fab2 and LuxAB is slow because it involves either transient (Fab2) or permanent (LuxAB) interaction of polypeptides, (iii) preservation of the assembly competent state of LuxA and/or LuxB and folding of Fab2 depend on ATP-hydrolysis, (iv) folding of Fab2 and LuxAB is partially sensitive to cyclosporin A (CsA) and FK506, i.e. inhibitors of two distinct peptidylprolyl cis/trans-isomerases. Thus, bacterial luciferases provide a unique system for direct measurement of the effects of ATP dependent molecular chaperones on protein folding and enzyme assembly in reticulocyte lysates. Furthermore, these two luciferases provide the first direct evidence documenting the involvement of peptidylprolyl cis/trans-isomerases in protein biogenesis in a eukaryotic cytosol. PMID- 7852323 TI - Replication error rates for G.dGTP, T.dGTP, and A.dGTP mispairs and evidence for differential proofreading by leading and lagging strand DNA replication complexes in human cells. AB - We have determined the fidelity of DNA replication by human cell extracts in reactions containing excess dGTP. Replication errors were scored using two M13 DNA substrates having the replication origin on opposite sides of the lacZ alpha complementation gene. The data suggest that the average rates for replication errors resulting from G(template), T.dGTP, and A.dGTP mispairs are 25 x 10(-6), 12 x 10(-6), and 3 x 10(-6), respectively. The data also suggest that error rates for both the (+) and (-) strands differ by less than 2-fold when they are replicated either as the leading or lagging strand. This is in contrast to the 33 and 8-fold differences observed earlier for G.dTTP and C.dTTP mispairs on the (+) strand when replicated by the leading or lagging strand complex (Roberts, J. D., Izuta, S., Thomas, D. C., and Kunkel, T. A. (1994) J. Biol. Chem. 269, 1711 1717). Thus, the relative fidelity of the leading and lagging strand replication proteins varies with the mispair and sequence considered. Misincorporation of dGTP preferentially occurs at template positions where dGTP is the next correct nucleotide to be incorporated. This "next nucleotide" effect is characteristic of reduced exonucleolytic proofreading and suggests that these replication errors are normally proofread efficiently. Fidelity measurements performed in the absence or presence of dGMP, an inhibitor of proofreading exonuclease activity, suggest that the leading strand replication complex proofreads some mispairs more efficiently than does the lagging strand replication complex. PMID- 7852324 TI - Mutational analysis of the double-stranded RNA (dsRNA) binding domain of the dsRNA-activated protein kinase, PKR. AB - The interferon-induced, double-stranded RNA (dsRNA)-dependent protein kinase, PKR, is an inhibitor of translation and has antiviral, antiproliferative, and antitumor properties. Previously, the dsRNA binding domain had been located within the N-terminal region of PKR and subsequently shown to include two nearly identical domains comprising residues 55-75 and 145-166. We have undertaken both random and site-directed, alanine-scanning mutagenesis in order to investigate the contribution of individual amino acids within these domains to dsRNA binding. Here we identify 2 residues that were absolutely required for dsRNA binding, glycine 57 and lysine 60. Mutation of 2 other residues within the domain (lysine 64 and leucine 75) resulted in less than 10% binding (compared to wild type). We have also identified a number of other residues that influence dsRNA binding to varying degrees. Mutants that were unable to bind dsRNA were not active in vitro and possessed no antiproliferative activity in vivo. However, dsRNA binding mutants were partially transdominant over wild type PKR in mammalian cells, suggesting that binding of dsRNA activator is not the mechanism responsible for the phenotype of PKR mutants. PMID- 7852325 TI - Isoforms of Bet v 1, the major birch pollen allergen, analyzed by liquid chromatography, mass spectrometry, and cDNA cloning. AB - Bet v 1, the major allergen of birch pollen, displays a considerable degree of heterogeneity. Several charge variants have been detected by two-dimensional IgE immunoblots and isoelectric focusing techniques. This heterogeneity has been attributed to glycosylation (or other post-translational modifications) or to isogenes coding for Bet v 1 isoforms and/or allelic variants. However, until now, only limited structural data for Bet v 1 have been published. Recently, we described the expression, purification, and immunological properties of recombinant Bet v 1 (rBet v 1) produced in Escherichia coli as a non-fusion protein (Ferreira, F. D., Hoffmann-Sommergruber, K., Breiteneder, H., Pettenburger, K., Ebner, C., Sommergruber, W., Steiner, R., Bohle, B., Sperr, W. R., Valent, P., Kungl, A. J., Breitenbach, M., Kraft, D., and Scheiner, O. (1993) J. Biol. Chem. 268, 19574-19580). Here, we present a more detailed structural characterization of Bet v 1 by both cDNA cloning and mass spectrometry. Thirteen different cDNA clones coding for Bet v 1 isoforms were obtained by polymerase chain reaction amplification of birch pollen cDNA with a sequence-specific 5' terminal primer and a nonspecific 3'-terminal primer or by immunological screening of a birch pollen cDNA library. These isoforms are referred to as Bet v 1b to Bet v 1n, whereas the previously isolated Bet v 1 cDNA (Breiteneder, H., Pettenburger, K., Bito, A., Valenta, R., Kraft, D., Rumpold, H., Scheiner, O., and Breitenbach, M. (1989) EMBO J. 8, 1935-1938) is now referred to as Bet v 1a. High performance liquid chromatography and plasma desorption mass spectrometry of proteolytic fragments of purified natural Bet v 1 (nBet v 1) and rBet v 1a were used to (i) confirm the primary structure of all Bet v 1 isoforms and (ii) to investigate any possible postsynthetic modifications on rBet v 1a or on the natural mixture of isoallergens obtained from birch pollen. Except for the cleavage of initiating methionine, no postsynthetic modifications were found in either nBet v 1 or rBet v 1a. PMID- 7852326 TI - Functional interactions of gene 32, 41, and 59 proteins of bacteriophage T4. AB - Genes 41 and 59 of bacteriophage T4 are involved in DNA recombination as well as in DNA replication. The 41 protein has a DNA helicase activity. The 59 protein has been recently purified and found to have a specific affinity for both 32 protein (single-stranded DNA-binding protein) and 41 protein (Yonesaki 1994, J. Biol. Chem. 269, 1284-1289). We examined the effects of 59 protein on ssDNA dependent ATPase activity and DNA helicase activity of 41 protein in the presence or absence of 32 protein. The ATPase activity of 41 protein was strongly inhibited by 32 protein over a wide range of amounts from subsaturation to oversaturation of ssDNA. The 32 protein was also inhibitory toward DNA helicase activity. Addition of 59 protein effectively eliminated these inhibitory effects of 32 protein. Moreover, 59 protein facilitated 41 protein to overcome the barrier to initiate the unwinding reaction with a duplex flanking a single stranded DNA gap. Intriguingly, 32 protein at an amount optimal for saturation of ssDNA stimulated the overcoming of the barrier when 59 protein was present. For the best circumvention of this initiation barrier, only eight monomers of 59 protein/one DNA substrate molecule containing 2900 nucleotides of ssDNA were required. These results strongly suggest that 59 protein modulates 41 protein activities by forming a complex with 41 protein and that 41 protein can produce recombinogenic ssDNA with the aid of 32 and 59 proteins. PMID- 7852327 TI - Phosphorothioate oligodeoxynucleotides bind to basic fibroblast growth factor, inhibit its binding to cell surface receptors, and remove it from low affinity binding sites on extracellular matrix. AB - We studied the interactions of phosphorothioate oligodeoxynucleotides and heparin binding growth factors. By means of a gel mobility shift assay, we demonstrated that phosphodiester and phosphorothioate homopolymers bound to basic fibroblast growth factor (bFGF). Binding of a probe phosphodiester oligodeoxynucleotide could also be shown for other proteins of the FGF family, including acidic fibroblast growth factor (aFGF), Kaposi's growth factor (FGF-4) as well as for the bFGF-related vascular endothelial growth factor, VEGF. No binding to epidermal growth factor (EGF) was observed. In addition, using a radioreceptor assay, we have shown that phosphorothioate homopolymers of cytidine and thymidine blocked binding of not only 125I-bFGF, but also of 125I-PDGF to NIH 3T3 cells, whereas phosphodiester oligodeoxynucleotides were ineffective. The extent of blockade of binding was dependent on the chain length of the phosphorothioate oligodeoxynucleotide. Furthermore, we have examined the effects of 18-mer phosphorothioate oligodeoxynucleotides of different sequences on 125I-bFGF binding to low and high affinity sites on both NIH 3T3 fibroblasts and DU-145 prostate cancer cells. Despite the fact that we have observed inhibition of bFGF binding by the 18-mer phosphorothioate oligodeoxynucleotides for both the high and low affinity classes of bFGF receptor, the inhibition was sequence-selective only for the high affinity receptors. We have also demonstrated that phosphorothioate homopolymers of cytidine and thymidine release bFGF bound to low affinity receptors in extracellular matrix (ECM). Finally, the most potent phosphorothioate oligodeoxynucleotides used in these experiments (e.g. SdC28) were inhibitors of bFGF-induced DNA synthesis in NIH 3T3 cells. PMID- 7852328 TI - Differential inhibition by iodonium compounds of induced erythropoietin expression. AB - Diphenylene iodonium chloride suppresses the cobaltous chloride-induced expression of erythropoietin by Hep3B cells to about 50% at a concentration of 30 nM. At that concentration, it has no effect on the response to low oxygen. The related compound iodonium diphenyl chloride acts similarly but is a much less effective inhibitor. If, as reported, diphenylene iodonium chloride is a specific inhibitor of cytochrome b, it follows that the response to CoCl2 is dependent on that enzyme but the response to hypoxia is not. PMID- 7852329 TI - Site-directed mutagenesis of vacuolar H(+)-pyrophosphatase. Necessity of Cys634 for inhibition by maleimides but not catalysis. AB - A characteristic feature of the vacuolar H(+)-translocating inorganic pyrophosphatase (V-PPase) of plant cells is its high sensitivity to irreversible inhibition by N-ethylmaleimide (NEM) and other sulfhydryl reagents. Previous investigations in this laboratory have demonstrated that the primary site for substrate-protectable covalent modification of the V-PPase by 14C-labeled NEM maps to a single M(r) 14,000 V8 protease fragment (V8(14)K) (Zhen, R.-G., Kim, E. J., and Rea, P. A. (1994) J. Biol. Chem. 269, 23342-23350). Here, we describe site-directed mutagenesis of the cDNA encoding the V-PPase from Arabidopsis thaliana, its heterologous expression in Saccharomyces cerevisiae and single substitution of all 9 conserved Cys residues to either Ser or Ala. In all cases, except one, Cys mutagenesis exerts little or no effect on either the catalytic activity or susceptibility of the enzyme to inhibition by NEM. By contrast, and in complete agreement with the results of peptide mapping experiments, substitution of Cys634, the sole conserved cysteine residue encompassed by V8(14)K, with Ser or Ala generates enzyme that is insensitive to NEM but active in both PPi hydrolysis and PPi-dependent H+ translocation. The specific requirement for Cys634 for inhibition by NEM and the dispensability of all of the conserved Cys residues, including Cys634, for V-PPase function indicate that the inhibitory action of maleimides reflects steric constraints imposed by the addition of a substituted alkyl group to the side chain of Cys634 rather than direct participation of this amino acid residue in catalysis. PMID- 7852330 TI - Trp-145 is essential for the binding of 25-hydroxyvitamin D3 to human serum vitamin D-binding protein. AB - Chemical modification of specific amino acid residues in a protein has been a valuable tool in identifying amino acid residues that are responsible for ligand binding of a protein. In the present investigation, we targeted Trp and His residues in human serum vitamin D-binding protein (hDBP) by modifying them with specific chemical modifiers. We also evaluated the results of these modifications in the binding of 25-hydroxy[26(27)-3H]vitamin D3 ([3H]25-OH-D3) to hDBP. We observed a dose-dependent loss of binding activity by N-bromosuccinimide (specific for Trp). Similar results were observed with diethylpyrocarbonate (specific for His). Furthermore, loss of [3H]25-OH-D3-binding was protected by preincubation of hDBP samples with an excess of 25-hydroxyvitamin D3. These results strongly emphasized the importance of Trp (single residue at position 145) and 1 His residue (out of a total of 6) in the vitamin D sterol-binding by vitamin D-binding protein. PMID- 7852331 TI - Upstream stimulatory factor proteins are major components of the glucose response complex of the L-type pyruvate kinase gene promoter. AB - L-type pyruvate kinase (L-PK) gene transcription is induced by glucose through its glucose response element (GlRE) composed of two degenerated E boxes able to bind in vitro ubiquitous upstream stimulator factor (USF) proteins. Here we demonstrate in vivo, by transient transfections in hepatoma cells, that (i) native USF proteins synthesized from expression vectors can act as transactivators of the L-PK promoter via the GlRE, stimulating transcription without glucose and, therefore, decreasing the glucose responsiveness of the promoter; (ii) expression of the truncated USF proteins, able to bind the GlRE but devoid of the NH2-terminal activation domain, represses the activation of the L-PK promoter by glucose; and (iii) a similar repression of the glucose effect is observed upon expression of mutant USF proteins devoid of the basic DNA binding domain, able to dimerize with endogenous USF but not to bind the GlRE. We conclude that USF proteins are components of the transcriptional glucose response complex assembled on the L-PK gene promoter. PMID- 7852332 TI - The actin-binding properties of the Physarum actin-fragmin complex. Regulation by calcium, phospholipids, and phosphorylation. AB - The actin-binding properties of the actin-fragmin complex from Physarum polycephalum microplasmodia were investigated with respect to regulation by Ca2+, phospholipids, and phosphorylation of the actin subunit by the endogenous actin fragmin kinase. Fragmin possesses two high affinity actin-binding sites and probably also a third, low affinity site. Its nucleating and F-actin severing activities are inhibited by phosphatidylinositol 4,5-bisphosphate (PIP2). Actin fragmin specifically binds PIP2 which competes with actin for the Ca(2+) sensitive site. However, PIP2 cannot dissociate the actin-fragmin complex nor the actin2-fragmin trimer. Efficient F-actin nucleating activity by actin-fragmin is only observed with unphosphorylated actin-fragmin, in the absence of PIP2 and at high Ca2+ (> microM) concentrations. In the presence of PIP2, actin-fragmin only caps actin filaments when unphosphorylated. The results suggest that in the cell, hydrolysis of PIP2, concomitant with the increase of cytosolic Ca2+, could promote subcortical actin polymerization. PMID- 7852334 TI - The effect of the beta-D-xyloside naroparcil on circulating plasma glycosaminoglycans. An explanation for its known antithrombotic activity in the rabbit. AB - Beta-D-Xylosides are known to initiate or prime free glycosaminoglycan (GAG) chain synthesis in cell and tissue culture. As such, the effect of the venous antithrombotic beta-D-xyloside, naroparcil, was investigated on the plasma GAG profile in the rabbit after oral administration. Using dose-response experiments, we showed that antithrombin activity via antithrombin III and heparin cofactor II was increased in parallel with GAG plasma levels compared to control. A more detailed qualitative examination of plasma GAGs by cellulose acetate electrophoresis and ion-exchange chromatography, following oral administration of naroparcil at 400 mg/kg, revealed the presence of higher density charged molecules compared to control. The extracted GAGs were found to activate inhibition of thrombin by heparin cofactor II and contained approximately 25% of a dermatan sulfate-like compound (undetectable in control), which could be responsible for the antithrombotic effect. Using radiolabeled naroparcil, we found radiolabeled GAG fractions and the fact that naroparcil was a substrate for galactosyltransferase I, the second enzyme responsible for GAG chain polymerization, suggested that the compound could initiate in vivo the biosynthesis of antithrombotic free GAG chains. This is, to our knowledge, the first description of the in vivo effect of a beta-D-xyloside on GAG biosynthesis; furthermore, this is correlated with an antithrombotic action. PMID- 7852333 TI - Involvement of glutamic acid 23 in the catalytic mechanism of T4 endonuclease V. AB - Bacteriophage T4 endonuclease V has both pyrimidine dimer-specific DNA glycosylase and abasic (AP) lyase activities, which are sequential yet biochemically separable functions. Previous studies using chemical modification and site-directed mutagenesis techniques have shown that the catalytic activities are mediated through the alpha-amino group of the enzyme forming a covalent (imino) intermediate. However, in addition to the amino-terminal active site residue, examination of the x-ray crystal structure of endonuclease V reveals the presence of Glu-23 near the active site, and this residue has been strongly implicated in the reaction chemistry. In order to understand the role of Glu-23 in the reaction mechanism, four different mutations (E23Q, E23C, E23H, E23D) were constructed, and the mutant proteins were evaluated for DNA glycosylase and AP lyase activities using defined substrates and specific in vitro and in vivo assays. Replacement of Glu-23 with Gln, Cys, or His completely abolished DNA glycosylase and AP lyase activities, while replacement with Asp retained negligible amounts of glycosylase activity, but retained near wild type levels of AP lyase activity. Gel shift assays revealed that all four mutant proteins can recognize and bind to thymine dimers. The results indicate that Glu-23 is the candidate for stabilizing the charge of the imino intermediate that is likely to require an acidic group in the active site of the enzyme. PMID- 7852335 TI - Protein kinase C (PKC)-induced PKC down-regulation. Association with up regulation of vesicle traffic. AB - Phorbol esters cause long term activation of protein kinase C (PKC) and frequently the down-regulation of PKC protein levels in mammalian cells. Mammalian PKC-gamma, -delta, and -eta down-regulated in response to phorbol esters when expressed in Schizosaccharomyces pombe. However, PKC-epsilon does not down-regulate in S. pombe, in contrast to the behavior of this isotype in mammalian cells. Co-expression of PKC-gamma or -delta with PKC-epsilon in S. pombe renders PKC-epsilon susceptible to down-regulation. A protein kinase defective form of PKC-delta does not down-regulate efficiently in S. pombe but, like PKC-epsilon, is susceptible when co-expressed with PKC-gamma or full-length PKC-delta. Thus, down-regulation is a consequence of the catalytic function of certain PKC isotypes with other isotypes being affected in trans. PKC down regulation parallels a striking accumulation of vesicles in S. pombe, suggesting a direct relationship between these events. PMID- 7852336 TI - Human complement protein C2. Alternative splicing generates templates for secreted and intracellular C2 proteins. AB - Alternative splicing of the primary transcript for human complement protein C2 generates templates for translation of a secreted (C2 long) protein and an intracellular (C2 short) form in liver, bronchoalveolar macrophages, and fibroblasts. The approximate ratio of C2 long to C2 short mRNA is 2:1. The C2 short mRNA does not contain the 396-base pair encompassed by exons 2 and 3 of the full-length C2 long and thus lacks codons for the 5 carboxyl-terminal residues of the signal peptide. Synthesis of C2 in cells transfected with full-length RNA corresponding to each of the transcripts show that C2 long is secreted within a half-time of approximately 1 h and that C2 short is not secreted. Cell-free biosynthesis in the presence of microsomes demonstrate that this intracellular C2 protein (70 kDa) is apparently capable of traversing the membrane of the endoplasmic reticulum. Though the function of the intracellular C2 protein is unknown, it is abundant in all cell types that express the C2 gene. PMID- 7852337 TI - A signal for endoplasmic reticulum retention located at the carboxyl terminus of the plasma membrane Ca(2+)-ATPase isoform 4CI. AB - The plasma membrane Ca(2+)-ATPase isoform 4b (PMCA4CI) with truncations in the cytoplasmically exposed COOH-terminal tail was expressed in COS and HeLa cells and in Sf9 cells using the baculovirus system. The truncated protein terminating with the acidic sequence Glu1067-Arg1087 was retained within the endoplasmic reticulum (ER), whereas mutants lacking this sequence or having it at a distance from the COOH terminus were delivered to the plasma membrane. Although the truncated protein retained in the endoplasmic reticulum was still able to form a Ca(2+)-dependent phosphoenzyme, it underwent partial degradation. Substitution of glutamic and aspartic residue(s) in the acidic region promoted rescue of the protein to the plasma membrane. The results suggest that the sequence Glu1067 Arg1087 encodes a masked signal for ER retention and for the degradation of the protein. However, its presence at the COOH terminus was not sufficient to induce ER-retention and degradation; when the sequence was attached to the full-length PMCA protein, normal plasma delivery was observed. Evidently, ER retention and degradation required the presence of the sequence in its specific location within the PMCA structure. The degradation of the protein retained in the endoplasmic reticulum occurred through the proteolytic attack at cytoplasmically exposed residues (amino acid sequence 720-750) by a cytoplasmic PEST sequence-related protease different from calpain. PMID- 7852338 TI - cis-acting elements involved in the regulation of mouse Clara cell-specific 10 kDa protein gene. In vitro and in vivo analysis. AB - Transient transfection and murine germ line gene transfer analysis was used to determine the regions of DNA necessary to confer the appropriate level and cell specificity of the expression of the gene coding for the murine Clara cell 10-kDa protein, mCC10. To identify the cis-acting elements involved in the regulation of mCC10 gene, different lengths of the 5'-flanking sequence were ligated to the bacterial chloramphenicol acetyltransferase gene for transient transfection to H441 cells (human lung adenocarcinoma cell line). The corresponding sequences were also fused to the human growth hormone gene and transferred to the murine genome for an in vivo analysis of mCC10 promoter activity. The results of the transient transfection analysis identified the region from -166 to -124 of the 5' flanking region of the mCC10 gene as necessary for the expression of this gene in H441 cells. The transgenic mouse analysis confirmed that the 166 base pairs of 5' flanking DNA was sufficient to confer cell-specific expression. However, the transgenic mouse analysis also showed that, to achieve the full quantitative level of transgene (human growth hormone) expression, regions between -803 and 166 base pairs of the 5'-flanking sequences are required for maximum expression of mCC10 gene promoter activity. PMID- 7852339 TI - Endoproteolytic cleavage of its propeptide is a prerequisite for efficient transport of furin out of the endoplasmic reticulum. AB - The trans-Golgi network (TGN) proprotein convertase furin is synthesized in a zymogenic form and is activated by intramolecular, autoproteolytic cleavage of the propeptide from its precursor. To obtain insight in possible functions of the furin propeptide, we have studied biosynthesis, propeptide cleavage, biological activity, and intracellular localization of human and bovine furin. Analysis of autocatalytic cleavage site mutants of furin revealed that efficient propeptide cleavage requires the presence of the complete furin cleavage consensus sequence Arg-X-Lys-Arg. In studies of a mutant in which the P1 + P4 + P5 residues of the autoproteolytic cleavage site were substituted, no substrate processing activity could be demonstrated, indicating a complete block of maturation. In immunofluorescence analysis, this mutant was found in the endoplasmic reticulum (ER), suggesting ER retention of profurin. This ER retention, however, appeared saturable. Furin proteins encoded by oxyanion hole mutant N188A and negative side chain mutant D248L, which possess autoprocessing activity but lack substrate processing activity, were found in the Golgi and the ER, respectively. Finally, analysis of a furin mutant, in which all three potential sites for N-linked glycosylation were altered, revealed autocatalytic cleavage, substrate processing, and transport to the Golgi. Our results indicate that cleavage of the propeptide occurs in the endoplasmic reticulum and is necessary but not sufficient for transport of furin out of this compartment. PMID- 7852340 TI - Tumor necrosis factor-alpha-dependent activation of a RelA homodimer in astrocytes. Increased phosphorylation of RelA and MAD-3 precede activation of RelA. AB - Rel proteins are important intracellular mediators of cytokine-induced signal transduction. To understand how cytokines affect different cell populations in the brain, we have characterized Rel activation in astrocytes. A RelA homodimer is uniquely activated in cytokine-stimulated astrocytes. Cytokine-dependent phosphorylation of the RelA inhibitor MAD-3 occurred on discrete peptides prior to its dissociation from RelA. A transient hyperphosphorylation of RelA was also induced. Antioxidant treatment inhibited both RelA activation and phosphorylation of the RelA.MAD-3 complex. These results demonstrate that cytokine-dependent activation of the RelA homodimer involves phosphorylation of both RelA and its associated inhibitor. The sole activation of a RelA homodimer suggests that cytokines will activate a unique set of Rel-regulated genes in astrocytes. PMID- 7852341 TI - Effect of hemoglobin concentration on nucleation and polymer formation in sickle red blood cells. AB - We have used differential polarization imaging microscopy to measure the amount and orientation of aligned sickle hemoglobin polymer in quickly deoxygenated sickle red blood cells. Images of the angular orientation of the aligned polymer at each point in the cell allowed for determination of the inclination of individual domains, providing detailed information regarding the polymerization and elongation of sickle hemoglobin polymers ex vivo. We found that the number of aligned polymer domains increased with increasing mean cell hemoglobin concentration. Sickle and holly leaf-shaped cells contained single or few domains of aligned polymer, while more compact cells such as irreversibly sickled cells contained many domains. A new class of cells was discovered by examination of images of the angular orientation of aligned polymer, which contained a single central nucleation site, with growth of polymer occurring outward in all directions in a spherulite-like domain. PMID- 7852342 TI - Cloning and expression of glucocorticoid-induced genes in fetal rat lung fibroblasts. Transforming growth factor-beta 3. AB - Glucocorticoids have been shown to accelerate fetal lung type II cell maturation, and this effect appears, in part, to be mediated via fibroblasts. To identify glucocorticoid induced genes in fetal lung fibroblasts, we screened a cDNA library from cortisol-treated fetal lung fibroblasts with a subtracted cDNA probe which was enriched for sequences specific for cortisol-treated fetal lung fibroblasts. Fifty-seven clones were isolated from the cDNA library. One cDNA represented approximately 30% of the 57 clones. Analysis of DNA sequence homology suggested that this cDNA encodes the rat transforming growth factor-beta 3 (TGF beta 3). We found that TGF beta 3 mRNA was expressed in fetal lung fibroblasts but not epithelial cells. Expression of message in fetal lung fibroblasts was developmentally regulated. TGF beta 3 mRNA levels were low during the pseudoglandular stage (day 18), peaked during the early canalicular stage of lung development (day 19), then fell again at days 20 and 21 (term = 22 days). Exposure of fetal lung fibroblasts to cortisol increased TGF beta 3 mRNA expression in a time- and dose-dependent manner. Maternal administration of dexamethasone also enhanced mRNA expression of TGF beta 3 in fetal lung fibroblasts. These data suggest that glucocorticoids may mediate their stimulatory effect on lung maturation by inducing TGF beta 3 expression in fetal lung fibroblasts. PMID- 7852343 TI - Upstream mechanisms of glycogen synthase activation by insulin and insulin-like growth factor-I. Glycogen synthase activation is antagonized by wortmannin or LY294002 but not by rapamycin or by inhibiting p21ras. AB - This study was undertaken to define intracellular signaling pathways upstream to glycogen synthase activation. First, we examined the role of the two pathways of insulin signaling, Ras-dependent and wortmannin/LY294002-sensitive, in glycogen synthase activation. Although negative dominant Ras (Ras17N) induction in PC12 cells markedly decreased activities of mitogen-activated protein kinase (MAP) and pp90 S6 kinase in response to insulin or insulin-like growth factor I (IGF-I), activation of glycogen synthase by these agents was unaffected by negative dominant Ras induction. In contrast, wortmannin and 2-(4-morpholinyl)-8-phenyl-4H 1-benzopyran-4-one (LY294002), inhibitors of phosphatidylinositol 3-kinase, antagonized glycogen synthase activation in response to insulin or IGF-I. Next, we examined the contribution of pp70 S6 kinase, one of the wortmannin/LY294002 sensitive signaling molecules on glycogen synthase activation. Immunosuppressant rapamycin completely blocked activation of pp70 S6 kinase by insulin or IGF-I, but rapamycin alone or in combination with induction of negative dominant Ras failed to antagonize glycogen synthase activation by these hormones. These data suggest that 1) activation of Ras-MAP kinase is not necessary for stimulation of glycogen synthase and 2) activation of wortmannin/LY294002-sensitive pathway, independent of pp70 S6 kinase, plays a key role in glycogen synthase regulation in PC12 cells. PMID- 7852344 TI - Primer terminus stabilization at the phi 29 DNA polymerase active site. Mutational analysis of conserved motif KXY. AB - phi 29 DNA polymerase shares with other DNA-dependent DNA polymerases several regions of amino acid homology along the primary structure. A conserved amino acid motif, located in the C-terminal portion of the polypeptide and characterized by the amino acid sequence KK(K/R)Y, is conserved in the group of eukaryotic-type DNA polymerases. In the subgroup of DNA polymerases that have a protein-priming mechanism, this motif is restricted to the sequence KXY, X never being a positively charged amino acid. Residues Lys498 and Tyr500 form this conserved motif in phi 29 DNA polymerase. Mutant K498T, in which the positive charge of the motif has been eliminated, was strongly affected both in initiation (terminal protein-dAMP formation, using terminal protein as primer) and DNA polymerization reactions. Mutants K498R and Y500S were able to carry out the initiation reaction to a higher or similar extent, respectively, than wild-type phi 29 DNA polymerase but were affected in DNA polymerization reactions. All of the mutations severely affected the stable binding of the polymerase to a primer template DNA. In addition, all of the mutant polymerases analyzed in this work showed an unusually strong 3'-5' exonuclease activity both under polymerization or non-polymerization conditions. The results obtained suggest a role of the conserved residues of the KXY motif in stabilizing the primer terminus at the polymerization active site, the positive charge of residue Lys498 being critical for the synthetic activities of phi 29 DNA polymerase. PMID- 7852345 TI - Invariant chain induces a delayed transport from early to late endosomes. AB - Invariant chain associated with class II molecules is proteolytically processed in several distinct intermediates during its transport through the endocytic pathway. Using subcellular fractionation, early and late endosomal compartments were separated in human fibroblasts transfected with HLA-DR (4N5 cells) and supertransfected with invariant chain (4N5Ii cells) or invariant chain lacking most of the cytoplasmic tail (4N5 delta 20Ii cells). Early and late endosome membrane fractions were characterized by morphology and by analyzing the presence of the Rab5 and Rab7 GTPases as markers of early and late endosomes, respectively. The transfer of endocytosed horseradish peroxidase from early to late endosomes proceeded relatively rapid both in 4N5 and 4N5 delta 20Ii cells (t1/2 = 25 min), whereas this transfer was significantly delayed (t1/2 = 2 h) in 4N5Ii cells. Pulse-chase experiments showed that invariant chain and its degradation products were first observed in early endosomes and thereafter in late endosomes. Our results strongly suggest that invariant chain induces a retention mechanism in the endocytic pathway. PMID- 7852346 TI - The soluble exoplasmic domain of the type II transforming growth factor (TGF) beta receptor. A heterogeneously glycosylated protein with high affinity and selectivity for TGF-beta ligands. AB - The transforming growth factor (TGF)-beta type II receptor is a transmembrane serine/threonine kinase which is essential for all TGF-beta-induced signals. In several cell types TGF-beta 2 is as potent as TGF-beta or TGF-beta 3 in inducing cellular responses, yet TGF-beta 2 does not bind to the majority of expressed type II receptors. Here we characterized the properties of the soluble extracellular domain of the human TGF-beta type II receptor synthesized in COS-7 cells. Like the membrane-attached type II receptor, the soluble receptor contains complex N-linked oligosaccharides as well as additional sialic acid residues that cause it to migrate heterogenously upon SDS-polyacrylamide gel electrophoresis. 125I-TGF-beta 1 binds to and is chemically cross-linked to this protein. Unlabeled TGF-beta 1 inhibits the binding of 125I-TGF-beta 1 with an apparent dissociation constant (Kd) of approximately 200 pM, similar to the apparent Kd (approximately 50 pM) of the cell-surface type II receptor. TGF-beta 3 inhibits the binding of 125I-TGF-beta 1 to the soluble type II receptor with a similar dissociation constant, approximately 500 pM. In contrast, 125I-TGF-beta 2 cannot bind and be chemically cross-linked to the soluble type II receptor, nor does as much as a 125-fold excess of unlabeled TGF-beta 2 inhibit the binding of 125I-TGF beta 1 to the soluble receptor. This is the first demonstration of the binding affinities of the type II receptor in the absence of the other cell-surface molecules known to bind TGF-beta. Expressed alone in COS-7 cells the type II receptor also cannot bind TGF-beta 2; co-expression of type III receptor enables the type II receptor to bind TGF-beta 2. Thus, the type III receptor or some other component is required for transmission of TGF-beta 2-induced signals by the type II receptor. PMID- 7852347 TI - Mutation of a conserved amino acid residue (tryptophan 1173) in the tyrosine kinase domain of the IGF-I receptor abolishes autophosphorylation but does not eliminate biologic function. AB - The amino acid sequence of the tyrosine kinase domain of the insulin-like growth factor-I (IGF-I) receptor is 84% identical to the sequence of the analogous region of the insulin receptor. A naturally occurring mutation of the tryptophan residue at position 1200 of the insulin receptor to serine results in impaired beta subunit autophosphorylation of wheat germ agglutinin-purified receptors, severely impaired thymidine incorporation and moderately reduced glycogen synthesis; however, glucose uptake was unaffected. To study the importance of this residue in IGF-I receptor function, we mutated the analogous tryptophan residue at position 1173 of the IGF-I receptor to serine and overexpressed the mutant receptor in NIH-3T3 cells. In cell lines overexpressing this mutant IGF-I receptor, beta subunit autophosphorylation was severely reduced. Additionally, the overexpressed mutant receptors exhibited a dominant-negative effect on IGF-I stimulated autophosphorylation of endogenous mouse IGF-I receptors. Phosphorylation of insulin receptor substrate (IRS)-1 in intact cells by the mutant IGF-I receptors was similar to the level of IRS-1 phosphorylation seen in the parental NIH-3T3 cells, but there was no obvious dominant-negative effect on IRS-1 phosphorylation. Wheat germ agglutinin-purified mutant receptors were as active in phosphorylating poly-(Glu,Tyr) 4:1 as wild-type IGF-I receptors, suggesting that, in intact cells, additional factors are necessary in order for the IGF-I receptor to phosphorylate IRS-1. Thymidine incorporation was severely reduced in one clone overexpressing the mutant IGF-I receptor and abolished in a second clone. Glucose uptake in both clones was reduced to about half of that seen in a cell line over-expressing wild-type IGF-I receptors. Thus, we propose that the tryptophan residue at position 1173 of the IGF-I receptor is important in the regulation of autophosphorylation in vivo. This study again confirms that high levels of autophosphorylation are not required for mediation of all of the biologic activities of the IGF-I receptor. PMID- 7852348 TI - Protein O-glycosylation in yeast. The PMT2 gene specifies a second protein O mannosyltransferase that functions in addition to the PMT1-encoded activity. AB - The PMT2 gene from Saccharomyces cerevisiae was identified as FUN25, a transcribed open reading frame on the left arm of chromosome I (Ouellette, B. F. F., Clark, M. W. C., Keng, T., Storms, R. G., Zhong, W., Zeng, B., Fortin, N., Delaney, S., Barton, A., Kaback, D.B., and Bussey, H. (1993) Genome 36, 32-42). The product encoded by the PMT2 gene shows significant similarity with the dolichyl phosphate-D-mannose:protein O-D-mannosyltransferase, Pmt1p (EC 2.4.1.109), which is required for initiating the assembly of O-linked oligosaccharides in S. cerevisiae (Strahl-Bolsinger, S., Immervoll, T., Deutzmann, R., and Tanner, W. (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 8164 8168). The PMT2 gene encodes a new protein O-D-mannosyltransferase. Yeast cells carrying a PMT2 disruption show a diminished in vitro and in vivo O-mannosylation activity and resemble mutants with a nonfunctional PMT1 gene. Strains bearing a pmt1 pmt2 double disruption show a severe growth defect but retain residual O mannosylation activity indicating the presence of at least one more protein-O mannosyltransferase. PMID- 7852349 TI - Interaction of biglycan with type I collagen. AB - The small proteoglycan decorin is known to interact with type I collagen fibrils, thereby influencing the kinetics of fibril formation and the distance between adjacent collagen fibrils. The structurally related proteoglycan biglycan has been proposed not to bind to fibrillar collagens. However, when osteosarcoma cells were cultured on reconstituted type I collagen fibrils, both decorin and biglycan were retained by the matrix. Immunogold labeling at the electron microscopic level showed that both proteoglycans were distributed along collagen fibrils not only in osteosarcoma cell-populated collagen lattices but also in human skin. Reconstituted type I collagen fibrils were able to bind in vitro native and N-glycan-free biglycan as well as recombinant biglycan core protein. From Scatchard plots dissociation, constants were obtained that were higher for glycanated biglycan (8.7 x 10(-8) mol/liter) than for glycanated decorin (7 x 10( 10) mol/liter and 3 x 10(-9) mol/liter, respectively). A similar number of binding sites for either proteoglycan was calculated. Recombinant biglycan and decorin were characterized by lower dissociation constants compared with the glycanated forms. Glycanated as well as recombinant decorin competed with glycanated biglycan for collagen binding, suggesting that identical or adjacent binding sites on the fibril are used by both proteoglycans. These data suggest that, because of its trivalency, biglycan could have a special organizing function on the assembly of the extracellular matrix. PMID- 7852350 TI - Molecular requirements for the interaction of class II major histocompatibility complex molecules and invariant chain with calnexin. AB - Molecular chaperones are believed to retain misfolded and incompletely assembled oligomeric proteins in the endoplasmic reticulum (ER). Here, we have further analyzed the association of one such chaperone, calnexin, with human major histocompatibility complex class II alpha and beta subunits and the invariant chain. Calnexin associates with transport-competent invariant chain trimers (p33 or p41), as well as ER-retained trimers (p35/33 or p43/41), suggesting that ER retention of the latter is not because of calnexin association. Neither the replacement of the transmembrane segment of the DR beta subunit with a glycosyl phosphatidylinositol anchor nor deglycosylation of any of these proteins with tunicamycin or endoglycosidase H treatment abolished calnexin association. Using a cell-permeabilization system, we were unable to observe association of newly synthesized glycopeptides with calnexin, arguing that calnexin may not act like a simple lectin for association with glycoproteins. The results indicate that neither transmembrane regions nor N-linked glycans are exclusively responsible for calnexin association. Based on our data and the observations of others, we suggest that these features may have varying significance for different glycoproteins in determining their interaction with calnexin. PMID- 7852351 TI - Regulation of Zap-70 by Src family tyrosine protein kinases in an antigen specific T-cell line. AB - To further understand the interactions between Zap-70, Src family kinases, and other T-cell proteins, we have examined the regulation of Zap-70 in the antigen specific T-cell line BI-141. By analyzing derivatives containing an activated version of either p56lck or p59fynT, it was observed that the two Src-related enzymes augmented T-cell receptor (TCR)-mediated tyrosine phosphorylation of Zap 70, as well as its association with components of the antigen receptor complex. Importantly, the accumulation of TCR.Zap-70 complexes quantitatively and temporally correlated with the induction of tyrosine phosphorylation of the CD3 and zeta chains of TCR. Using a CD4-positive variant of BI-141, we also found that the ability of Zap-70 to undergo tyrosine phosphorylation and associate with TCR was enhanced by aggregation of TCR with the CD4 co-receptor. Further studies allowed the identification of two distinct pools of tyrosine-phosphorylated Zap 70 in activated T-cells. While one population was associated with TCR, the other was co-immunoprecipitated with a 120-kDa tyrosine-phosphorylated protein of unknown identity. In addition to supporting the notion that Src-related enzymes regulate the recruitment of Zap-70 in TCR signaling, these data added further complexity to previous models of regulation of Zap-70. Furthermore, they suggested that p120 may be an effector and/or a regulator of Zap-70 in activated T-lymphocytes. PMID- 7852352 TI - Poly(A) tail length control is caused by termination of processive synthesis. AB - Poly(A) polymerase synthesizes poly(A) tails rapidly and processively only when the substrate RNA is bound simultaneously by two stimulatory proteins, the cleavage and polyadenylation specificity factor (CPSF) and poly(A)-binding protein II (PAB II). A burst of synthesis terminates after the addition of about 250 nucleotides, a length corresponding to that of newly synthesized poly(A) tails in vivo. Further elongation is slow. Length control can be reproduced with premade poly(A) tails of different lengths and is insensitive to large changes in the elongation rate. Thus, the control mechanism truly measures the length of the poly(A) tail. The stimulatory action of PAB II is similar on long and short tails. Coating of poly(A) with one PAB II molecule for approximately 30 nucleotides is required, such that the number of PAB II molecules in the polyadenylation complex is a direct measure of poly(A) tail length. CPSF also stimulates poly(A) polymerase on long and short tails. Long tails differ from short ones only in that they do not permit the simultaneous stimulation of poly(A) polymerase by CPSF and PAB II. Consequently, elongation of long tails is distributive. Thus, length control is brought about by an interruption of the interactions responsible for rapid and processive elongation of short tails. The 3'-end of the poly(A) tail is not sequestered in the protein-RNA complex when the correct length has been reached. Neither ATP hydrolysis nor turnover of the polymerized AMP is involved in length control. PMID- 7852354 TI - Assembly of F0 sector of Escherichia coli H+ ATP synthase. Interdependence of subunit insertion into the membrane. AB - The F0 sector of the Escherichia coli H+ transporting ATP synthase is composed of a complex of three subunits, each of which traverses the inner membrane. We have studied the interdependence of subunit insertion into the membrane in a series of chromosomal mutants in which the primary mutation prevented insertion of one of the F0 subunits. Subunit insertion was assessed using Western blots of mutant membrane preparations. Subunit b and subunit c were found to insert into the membrane independently of the other two F0 subunits. On the other hand, subunit a was not inserted into membranes that lacked either subunit b or subunit c. The conclusion that subunit a insertion is dependent upon the co-insertion of subunits b and c differs from the conclusion of several studies, where subunits were expressed from multicopy plasmids. PMID- 7852353 TI - Characterization of human thrombospondin-4. AB - The thrombospondins are a family of extracellular calcium binding proteins that are involved in cell proliferation, adhesion, and migration. We have sequenced full-length human thrombospondin-4 and characterized the recombinant protein. In contrast to Xenopus laevis thrombospondin-4, the human protein contains an RGD cell binding sequence in the third type 3 repeat. Transfection of mouse NIH3T3 fibroblasts or C2C12 myoblasts with a full-length human thrombospondin-4 cDNA results in the expression of a polypeptide with a reduced molecular weight of 140,000. In the absence of reducing agent, the expressed protein has an apparent molecular weight of 550,000. Recombinant thrombospondin-4 has been purified from the culture supernatant by heparin-Sepharose and anti-thrombospondin-4 antibody Affi-gel affinity chromatography. Electron microscopy indicates that thrombospondin-4 is composed of five subunits with globular domains at each end. The observation of a calcium-dependent change in the electron microscopic appearance of thrombospondin-4 is consistent with limited tryptic digestion data that indicate that thrombospondin-4 is resistant to digestion in the presence of calcium. These data indicate that thrombospondin-4 is a pentameric protein that binds to heparin and calcium. PMID- 7852355 TI - The structure of chicken liver xanthine dehydrogenase. cDNA cloning and the domain structure. AB - The amino acid sequence of chicken liver xanthine dehydrogenase (EC 1.1.1.204) was determined by cDNA cloning and partial amino acid sequencing of the purified enzyme. The enzyme consisted of 1358 amino acids with calculated molecular mass of 149,633 Da. In order to compare the structure of the chicken and rat enzymes, limited proteolysis was performed with the purified chicken liver xanthine dehydrogenase. When the enzyme was digested with subtilisin, it was not converted from the NAD-dependent dehydrogenase type to the O2-dependent oxidase type, in contrast with the mammalian enzyme. However, the enzyme was cleaved mainly into three fragments in a manner similar to that for the rat enzyme at pH 8.2 (20, 37, and 84 kDa) and retaining a full complement of redox centers. The cleavage sites were identified by determination of amino-terminal sequences of the produced fragments. It was concluded that the 20-kDa fragment was amino-terminal, the 84 kDa fragment carboxyl-terminal, and the 37-kDa fragment an intermediate portion in the enzyme protein. On the other hand, when the enzyme was digested with the same protease at pH 10.5, the sample contained only the 20- and 84-kDa portions and lacked the 37-kDa portion. The resultant sample possessed xanthine dichlorophenol indophenol reductase activity, indicating that the molybdenum center remained intact. The absorption spectrum showed the sample was very similar to deflavo-enzyme. From these results and sequence analyses, the domain structure of the enzyme is discussed. PMID- 7852356 TI - Cloning, sequencing, and transcriptional analysis of the coenzyme F420-dependent methylene-5,6,7,8-tetrahydromethanopterin dehydrogenase gene from Methanobacterium thermoautotrophicum strain Marburg and functional expression in Escherichia coli. AB - Two methylenetetrahydromethanopterin dehydrogenases have been purified from Methanobacterium thermoautotrophicum strain Marburg: one (MTD) is coenzyme F420 dependent and oxygen-stable (Mukhopadhyay, B., and Daniels, L. (1989) Can. J. Microbiol. 35, 499-507), and the other (MTH) is coenzyme F420-independent (or hydrogenase-type) and oxygen-sensitive (Zirngibl, C., Hedderich, R., and Thauer, R. K. (1990) FEBS Lett. 261, 112-116). Based on the NH2-terminal sequence of MTD, a 36-mer oligonucleotide was designed and used to identify and clone a 6.1 kilobase pair EcoRI fragment of M. thermoautotrophicum DNA. Sequencing of this fragment revealed an 825-base pair (bp) MTD encoding gene (mtd), which was expressed in Escherichia coli yielding an enzyme that, like the native enzyme, was oxygen-stable, strictly dependent on coenzyme F420, thermostable, thermophilic, and exhibited maximum activity at an acidic pH. The amino acid sequence predicts that MTD is a hydrophobic and acidic protein with no identifiable homology to MTH (von Bunau, R., Zirngibl, C., Thauer, R. K., and Klein, A. (1991) Eur. J. Biochem. 202, 1205-1208), but comparisons with coenzyme F420 utilizing enzymes revealed a conserved region at the NH2 terminus of MTD that could correspond to the ability to interact with coenzyme F420. The mtd transcript was approximately 900 nucleotides long and initiated 8 bp upstream of the translation initiation codon and 22 bp downstream from an archaeal promoter sequence. The mtd coding sequence was followed by several poly(dT) sequences and an inverted repeat that could be transcription termination signals. PMID- 7852357 TI - The human type 1 inositol 1,4,5-trisphosphate receptor from T lymphocytes. Structure, localization, and tyrosine phosphorylation. AB - Inositol 1,4,5-trisphosphate receptors (IP3R) are intracellular calcium release channels involved in diverse signaling pathways. An IP3R is thought to play a role in mobilizing calcium required for activation of T lymphocytes. The IP3R is a tetrameric structure comprised of four approximately 300-kDa subunits encoded by a approximately 10-kilobase mRNA. In the present study we determined the structure of the human type 1 IP3R expressed in T lymphocytes (Jurkats). The IP3R in human T cells had a predicted molecular mass of 308 kDa and was most similar to the non-neuronal form of the rodent type 1 IP3R. Two putative tyrosine phosphorylation sites were identified, one near the amino terminus and one near the putative channel pore at the carboxyl terminus. During T cell activation the IP3R was tyrosine phosphorylated. A site-specific anti-IP3R antibody was used to localize the carboxyl terminus of the IP3R to the cytoplasm in T cells. PMID- 7852358 TI - Differential recognition of alpha 1-antitrypsin-elastase and alpha 1 antichymotrypsin-cathepsin G complexes by the low density lipoprotein receptor related protein. AB - Two multifunctional receptors, low density lipoprotein receptor-related protein (LRP) and gp330, have been implicated in the cellular uptake and degradation of a wide spectrum of functionally diverse ligands including plasma lipoproteins, proteases, and proteinase-inhibitor complexes. The two receptors show distinct tissue-specific expression patterns, suggesting different physiological functions. We have examined the cellular degradation of two serine proteinase inhibitor (serpin)-protease complexes, alpha 1-antitrypsin-neutrophil elastase (alpha 1AT.NEL) and alpha 1-antichymotrypsin-cathepsin G (alpha 1ACT.CathG) by normal murine fibroblasts (MEF) expressing LRP, and by a mutant fibroblast cell line (PEA13) which is genetically deficient for LRP. alpha 1AT.NEL complexes bound to LRP on ligand blots and were degraded efficiently by the MEF cells, but not by PEA13 cells. Degradation of the complexes was also significantly reduced by antibodies directed against LRP, further suggesting that fibroblasts require LRP for the cellular uptake and degradation of alpha 1AT.NEL complexes. In contrast to alpha 1AT.NEL, MEF cells did not degrade alpha 1ACT.CathG complexes. However, these complexes were rapidly degraded by the rat embryonal carcinoma cell line L2p58 which abundantly expresses gp330, raising the possibility that the alpha 1ACT.CathG complex might be recognized by gp330. Both complexes were efficiently metabolized by the hepatoma cell line HepG2, presumably involving the serpin-enzyme complex receptor. The differential recognition of serpin-protease complexes by fibroblasts and hepatoma cells, however, indicates that LRP, gp330, and the serpin-enzyme complex receptor are distinct proteins. PMID- 7852359 TI - Ascorbic acid enhances iron-induced ferritin translation in human leukemia and hepatoma cells. AB - Ascorbate is an important cofactor in many cellular metabolic reactions and is intimately linked to iron homeostasis. Continuously cultured cells are ascorbate deficient due to the lability of the vitamin in solution and to the fact that daily supplementation of media with ascorbate is unusual. We found that ascorbate repletion alone did not alter ferritin synthesis. However, ascorbate-replete human hepatoma cells, Hep3B and HepG2, as well as K562 human leukemia cells achieved a substantially higher cellular ferritin content in response to a challenge with iron than did their ascorbate-deficient counterparts grown under standard culture conditions. Most of the elevation in ferritin content was due to an increase in de novo ferritin synthesis of greater than 50-fold, as shown by in vivo labeling with [35S]methionine and immunoprecipitation. RNA-blot analysis showed only minor changes in steady state levels of ferritin mRNA, suggesting that ascorbate enhances iron-induced ferritin synthesis primarily by post transcriptional events. Transient gene expression experiments using chloramphenicol acetyltransferase reporter gene constructs showed that the ascorbate effect on ferritin translation is not mediated through the stem-loop near the translational start site that transduces ferritin synthesis in response to cytokines. The data suggest that ascorbate possibly modifies the action of the iron-responsive element on ferritin translation, although more precise structure function studies are needed to clarify this issue. These data demonstrate a novel role of ascorbate as a signaling molecule in post-transcriptional gene regulation. The mechanism by which ascorbate modulates cellular iron metabolism is complex and requires additional detailed investigation. PMID- 7852360 TI - Activation of the alpha-internexin promoter by the Brn-3a transcription factor is dependent on the N-terminal region of the protein. AB - The Brn-3a, Brn-3b, and Brn-3c proteins are closely related POU (Pit-Oct-Unc) family transcription factors which are expressed predominantly in neuronal cells. We have identified the alpha-internexin gene as the first reported, neuronally expressed, target gene whose promoter activity is modulated by these factors. Both the Brn-3a and Brn-3c factors can activate the alpha-internexin promoter while Brn-3b represses it and can prevent activation by Brn-3a. Using chimeric constructs containing different regions of Brn-3a or Brn-3b, we show that activation of the alpha-internexin promoter requires the N-terminal region of Brn 3a. In contrast the activation by Brn-3a but not Brn-3b of an artificial promoter containing a synthetic Brn-3 binding site can be shown using the same constructs to be dependent on the POU domain of Brn-3a. Moreover, the isolated POU domain of Brn-3a can activate this artificial promoter but not the alpha-internexin promoter. Hence Brn-3a contains two distinct transactivation domains, at the N terminus and within the POU domain, whose effect is dependent upon the target promoter. The relationship of gene transactivation by Brn-3a to its ability to transform primary cells which is also dependent on the N-terminal region of the protein is discussed. PMID- 7852361 TI - Cell cycle arrest induced by an inhibitor of glucosylceramide synthase. Correlation with cyclin-dependent kinases. AB - In an attempt to define the basis for sphingolipid regulation of cell proliferation, we studied the effects of glucosylceramide (GlcCer) synthase inhibition by threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) on NIH 3T3 cells overexpressing insulin-like growth factor-1 (IGF-1) receptor. PDMP treatment resulted in a time-dependent decrease in GlcCer levels and an increase in cellular ceramide levels. PDMP abolished serum and IGF-1-stimulated cell proliferation, as measured by a reduction in [3H]thymidine incorporation, protein, and DNA levels. However it did not affect IGF-1-mediated early signaling events, including receptor tyrosine kinase, MAP kinase, and phosphatidylinositol 3-kinase activities. Two-color flow cytometry with propidium iodide and 5-bromo 2'-deoxyuridine monophosphate labeling revealed an arrest of the cell cycle at G1/S and G2/M transitions in an asynchronous population of cells. These changes were time dependent, with maximal effects seen by 12-24 h. Removal of PDMP from the cell medium resulted in reversal of the cell cycle changes, with cells re entering the S phase. The cell cycle arrest at the G1/S and G2/M transitions was confirmed in cells synchronized by pretreatment with nocodazole, aphidicolin, or hydroxyurea, and released from blockade in the presence of PDMP. A decrease in the activities of two cyclin-dependent kinases, p34cdc2 kinase and cdk2 kinase, was observed with PDMP treatment. When cell ceramide levels were increased by N acetylsphingosine, comparable changes in the cell cycle distribution were seen. However, sphingomyelinase treatment was without effect. Therefore, it appears that ceramide mediates in part the inhibitory effect of GlcCer synthase inhibition on IGF-1-induced cell proliferation in 3T3 cells. The rapid production of decreased cyclin-dependent kinase activities by PDMP suggests that one of the crucial sites of action of the inhibitor lies in this area. PMID- 7852362 TI - Polymorphic sequences encoding the first open reading frame protein from LINE-1 ribonucleoprotein particles. AB - The mouse LINE-1 (L1) retrotransposon contains two open reading frames (ORFs). Three classes of the protein encoded by the first open reading frame (ORF1) are expressed in the mouse embryonal carcinoma cell line, F9; the apparent molecular sizes of these proteins are 41.3, 43, and 43.5 kDa. Two of these three proteins (41.3 and 43 kDa) are translated in vitro from full-length, sense-strand L1 RNA isolated from ribonucleoprotein particles. A reverse transcription-polymerase chain reaction approach was used to clone the ORF1 region from RNA isolated from ribonucleoprotein particles, then the coding capacity of these clones was examined using in vitro transcription and translation. Multiple sequences that encode ORF1 were recovered by this approach, indicating that multiple loci of L1 in the mouse genome are expressed in F9 cells. In addition, L1 sequences with intact ORF1 regions appear to be selectively enriched in the ribonucleoprotein particles. PMID- 7852363 TI - Mapping the domain(s) critical for the binding of human tumor necrosis factor alpha to its two receptors. AB - The extracellular domains of the two human tumor necrosis factor (TNF) receptors critical for binding TNF-alpha were examined by deletion mapping. The ligand binding capability of full-length and truncated recombinant soluble TNF receptors (TNFRs) was assessed by ligand blot analysis and their binding affinity determined by Scatchard analysis. The results showed that deletion of the fourth cysteine-rich domain of the p55 receptor (TNFR-1) did not alter ligand binding affinity significantly. Deletion of domains 3 and 4 of TNFR-1 resulted in no ligand binding, suggesting that domain 3, but not 4, of TNFR-1 binds directly to ligand. Deletion of domain 4 of TNFR-2 resulted in drastically reduced protein yield and 3-fold reduction in ligand binding affinity, while deletion of both domains 4 and 3 yielded no protein. Thus, the domain 4 of TNFR-2, but not that of TNFR-1, appears to be involved directly in binding TNF, although it is also possible that the domain 4 of TNFR-2 is involved in the correct folding of other domains. These results suggest that the modes of interaction between TNF-alpha and its dual receptors are different, providing opportunity to modulate each receptor specifically for research and therapeutic purposes. PMID- 7852364 TI - The sequence of phosphatidylinositol-4-phosphate 5-kinase defines a novel family of lipid kinases. AB - Phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) occupies an essential position in the phosphoinositide signal transduction cascades as the precursor to second messengers and is thought to regulate many cellular proteins directly. The final step in the synthesis of PtdIns(4,5)P2 is the phosphorylation of PtdIns(4)P by PtdIns(4)P 5-kinase (PIP5K). Using peptide sequences from a purified PIP5K, a cDNA for a human placental PIP5K was isolated and sequenced. Expression of this cDNA in Escherichia coli produced an active PIP5K. Surprisingly, the sequence of this PIP5K has no homology to known PtdIns kinases or protein kinases. However, the PIP5K is homologous to the Saccharomyces cerevisiae proteins Fab1p and Mss4p. PMID- 7852365 TI - Concomitant acceleration of the activation and inactivation kinetics of the human delayed rectifier K+ channel (Kv1.1) by Ca(2+)-independent phospholipase A2. AB - The electrophysiologic sequelae of arachidonic acid release mediated by the major phospholipase A2 (PLA2) in electrically active tissues (i.e. the 40-kDa Ca(2+) independent PLA2) were assessed in Sf9 cells expressing the human recombinant delayed rectifier K+ channel Kv1.1. Intracellular administration of Ca(2+) independent PLA2 increased the rate of activation of the macroscopic current (from tau act = 6.25 +/- 0.76 ms to tau act, PLA2 = 2.78 +/- 0.78 ms at 40 mV) and resulted in channel inactivation (from no observed inactivation to tau inact = 103 +/- 6 ms at 40 mV), which were: 1) dependent on the enrichment of Sf9 cell phospholipids in esterified arachidonic acid; 2) ablated by pretreatment of the PLA2 by the mechanism-based inhibitor (E)-6-(bromomethylene)-3-(1-naphthalenyl) 2H-tetrahydropyran-2-one; and 3) manifest prior to development of alterations in cellular permeability. The bidirectional effects of Ca(2+)-independent PLA2 were indistinguishable from the effects of exogenously applied arachidonic acid (AA), which specifically and reversibly increased the rates of channel activation (from tau act = 5.73 +/- 0.88 ms to tau act,AA = 1.91 +/- 0.39 ms at 40 mV) and inactivation (from no observed inactivation to tau inact = 76.6 +/- 1.4 ms at 40 mV). These electrophysiologic alterations resulted from the effects of arachidonic acid per se since Sf9 cells did not produce oxygenated eicosanoid metabolites, and neither exogenous administration nor in situ generation of other fatty acids resulted in these effects. Collectively, these results unambiguously demonstrate the role of arachidonic acid per se on Kv1.1 electrophysiologic function and suggest the importance of Ca(2+)-independent PLAs as an enzymic modulator of ion channel function in electrically active tissues. PMID- 7852367 TI - Quantitative analysis of the complex between p21ras and the Ras-binding domain of the human Raf-1 protein kinase. AB - The Ras-binding domain (RBD) of human Raf-1 was purified from Escherichia coli, and its interaction with Ras was investigated. Its dissociation constant with p21ras.guanyl-5'-yl imidodiphosphate was found to be 18 nM, with a slight preference for H-ras over K- and N-ras. Oncogenic forms bind with slightly lower affinity. The affinity of RBD for effector region mutants or the GDP-bound form of p21ras is in the micromolar range, which means that 100-fold lower affinity is not sufficient for signal transduction. The rate of the GTPase of p21ras is not modified by RBD. Since P(i) release is found not to be rate limiting, the Ras-Raf signal of the cell may be terminated by the intrinsic GTPase of p21ras. PMID- 7852366 TI - The mouse MRF4 promoter is trans-activated directly and indirectly by muscle specific transcription factors. AB - MRF4 is a member of the basic helix-loop-helix (bHLH) family of muscle-specific transcription factors, which also includes MyoD, myogenin, and myf5. The myocyte enhancer binding factor 2 (MEF2) proteins also serve as important muscle-specific transcription factors. In addition to activating the expression of many muscle specific structural genes, various members of these two classes of proteins activate their own expression and the expression of each other in a complex transcriptional network that results in the establishment and maintenance of the muscle phenotype. To begin to determine how the expression of MRF4 is regulated by other muscle-specific transcription factors, we have isolated a region of the MRF4 gene that confers muscle-specific expression and have analyzed this promoter region for cis-acting elements involved in trans-activation by the myogenic bHLH and MEF2 transcription factors. Here, we show that in 10T1/2 fibroblasts the MRF4 promoter is trans-activated by myogenin, MyoD, myf5, and by the MEF2 factors, but that MRF4 does not activate expression of its own promoter. Myogenin activated the MRF4 promoter directly by an E box-dependent mechanism, while MEF2 factors activated the promoter through an indirect pathway. The E box-dependent regulation of the MRF4 promoter is in contrast to the regulation of the myogenin and MyoD promoters and may represent a mechanism for the differential expression of these factors during myogenesis. PMID- 7852368 TI - Oxidation of bromide by the human leukocyte enzymes myeloperoxidase and eosinophil peroxidase. Formation of bromamines. AB - Myeloperoxidase and eosinophil peroxidase catalyzed the oxidation of bromide ion by hydrogen peroxide (H2O2) and produced a brominating agent that reacted with amine compounds to form bromamines, which are long-lived oxidants containing covalent nitrogen-bromine bonds. Results were consistent with oxidation of bromide to an equilibrium mixture of hypobromous acid (HOBr) and hypobromite ion (OBr-). Up to 1 mol of bromamine was produced per mole of H2O2, indicating that bromamine formation prevented the reduction of HOBr/OBr- by H2O2 and the loss of oxidizing and brominating activity. Bromamines differed from HOBr/OBr- in that bromamines reacted slowly with H2O2, were not reduced by dimethyl sulfoxide, and had absorption spectra similar to those of chloramines, but shifted 36 nm toward higher wavelengths. Mono- and di-bromo derivatives (RNHBr and RNHBr2) of the beta amino acid taurine were relatively stable with half-lives of 70 and 16 h at pH 7, 37 degrees C. The mono-bromamine was obtained with a 200-fold excess of amine over the amount of HOBr/OBr- and the di-bromamine at a 2:1 ratio of HOBr/OBr- to the amine. In the presence of physiologic levels of both bromide (0.1 mM) and chloride (0.1 M), myeloperoxidase and eosinophil peroxidase produced mixtures of bromamines and chloramines containing 6 +/- 4% and 88 +/- 4% bromamine. In contrast, only the mono-chloramine derivative (RNHCl) was formed when a mixture of hypochlorous acid (HOCl) and hypochlorite ion (OCl-) was added to solutions containing bromide and excess amine. The rapid formation of the chloramine prevented the oxidation of bromide by HOCl/OCl-, and the chloramine did not react with bromide within 1 h at 37 degrees C. The results indicate that when enzyme catalyzed bromide or chloride oxidation took place in the presence of an amine compound at 10 mM or higher, bromamines were not produced in secondary reactions such as the oxidation of bromide by HOCl/OCl- and the exchange of bromide with chlorine atoms of chloramines. Therefore, the amount of bromamine produced by myeloperoxidase or eosinophil peroxidase was equal to the amount of bromide oxidized by the enzyme. Bromide was preferred over chloride as the substrate for both enzymes. PMID- 7852369 TI - A 25-kDa beta-lactam-induced outer membrane protein of Vibrio cholerae. Purification and characterization. AB - A 25-kDa outer membrane protein, induced following treatment of Vibrio cholerae cells with beta-lactam antibiotics and constituting about 8-10% of the total outer membrane proteins of beta-lactam-resistant mutants, has been purified to homogeneity. It is a basic (pI 8.5) protein rich in beta-sheet structure and is a homodimer, the monomers being held together by hydrophobic interactions. The effective hydrophobicity of the protein is low, and a large part of the protein is exposed on the surface of the outer membrane. The protein does not have beta lactamase or autolytic activity and is not a penicillin-binding protein. The Stoke's radius of the 25-kDa protein (26 A) is comparable to the pore size of the V. cholerae OmpF-like porin. Proteoliposome swelling assay showed that the 25-kDa protein might block the pores of OmpF through which beta-lactam antibiotics normally enter the cells. Twenty-two amino acid residues from the N-terminal end of the 25-kDa protein have been sequenced, and a 32-mer oligonucleotide probe was synthesized using the amino acid residues 2-12. This probe was used to identify the gene encoding the 25-kDa protein. The beta-lactam-resistant cells are insensitive to changes in the osmolarity of the growth medium in contrast to the wild type cells which exhibit osmoregulation of OmpF and OmpC synthesis. All beta lactam-resistant mutants examined are resistant to novobiocin. PMID- 7852370 TI - Expression of de-N-acetyl-gangliosides in human melanoma cells is induced by genistein or nocodazole. AB - Neuraminic acid is the core structure of most known sialic acids. In natural systems, the amino group at the 5 position of neuraminic acid residues is usually assumed to be acylated. Previously, synthetic de-N-acetyl-gangliosides (with free amino groups at the 5 position of neuraminic acids) have been shown to modulate cellular proliferation and tyrosine phosphokinase reactions. While indirect evidence has suggested that traces of these molecules exist naturally in certain tumor cells, further exploration has been hampered by the lack of a system showing consistent expression at an easily detectable level. Using synthetic compounds as antigens, we have developed highly specific monoclonal antibodies against de-N-acetyl-GM3 and de-N-acetyl-GD3 that require both the free amino group and the exocyclic side chain of sialic acids for recognition. Cultured human melanoma cells showed low but variably detectable levels of reactivity with these antibodies. The ability of various biologically active molecules to stimulate this reactivity was explored. Of many compounds tested, only the tyrosine kinase inhibitor genistein induced reactivity in a dose-dependent manner. Antibody reactivity with ganglioside extracts from genistein-treated cells was abolished by chemical re-N-acetylation and/or truncation of sialic acid side chains by mild periodate oxidation. High performance thin layer chromatography immuno-overlay analysis confirmed the presence of the novel compound de-N-acetyl-GD3 in these extracts. Several other tyrosine kinase inhibitors tested did not give the same increase in de-N-acetyl-ganglioside expression. However, the microtubule inhibitor nocodazole caused a similar accumulation of these molecules, particularly in non-adherent cells expected to be arrested at metaphase. Thus, genistein may induce de-N-acetyl-ganglioside expression by virtue of its known ability to arrest cells in the G2M phase, rather than as a general consequence of tyrosine kinase inhibition. These studies also provide a system in which to analyze the enzymatic basis of de-N-acetyl ganglioside expression and their potential roles as growth regulating molecules. PMID- 7852371 TI - Hydrodynamic and electrical characterization of T-vimentin dimers and tetramers by transient electric birefringence measurements. AB - The structure and charge distribution of T-vimentin, which differs from the intact intermediate filament protein vimentin through the absence of the first 70 amino acids, has been studied by transient electric birefringence measurements. It is found that in 0.7 mM phosphate, pH 7.5 buffer, exclusively single dimers (with a hydrodynamic length of 40 to 43 nm) are present, which are considerably bent and/or flexible and which have a relatively large permanent dipole moment. This indicates a parallel alignment of two protein chains. In 0.2 mM phosphate, 0.5 mM MgCl2, pH 7.5, predominantly tetrameric T-vimentin is found with a rigid structure, no permanent dipole moment, and a length of 63 to 68 nm. Tetramer formation is likely to be induced by binding of Mg2+ to the protein. The observed length is in agreement with that of intact vimentin tetramers in which the 1B regions of the rod domains of the dimers overlap (A11 configuration). A minor part of the tetramers may be in a flexible or bent A22 form. The loss of the permanent dipole moment when tetramers are formed is, apart from charge compensation, presumably due to the antiparallel alignment of the constituting dimers in which their dipoles cancel. PMID- 7852372 TI - The Bacillus subtilis histone-like protein Hbsu is required for DNA resolution and DNA inversion mediated by the beta recombinase of plasmid pSM19035. AB - The beta recombinase, encoded by the Gram-positive bacterial plasmid pSM19035, is unable to mediate DNA recombination in vitro unless a host factor is provided. The factor has now been identified as the Bacillus subtilis Hbsu protein. Hbsu is a nonspecific DNA-binding and DNA-bending protein. The beta recombinase, in the presence of highly purified Hbsu protein, is able to catalyze in vitro intramolecular recombination between two specific recombination sites on a supercoiled DNA molecule. DNA resolution was obtained when the two crossing over sites (six sites) were directly oriented, whereas DNA inversion was the product when the six sites were in inverse orientation. The ability of the Escherichia coli chromatin-associated proteins HU, IHF, Fis, and H-NS to substitute for Hbsu was investigated. HU efficiently stimulated beta-mediated recombination, while the effect of IHF was partial and that of Fis and H-NS was undetectable. In addition, the beta protein was able to mediate DNA recombination in both wild type and IHF-deficient E. coli cells, but failed to do so in an HU-deficient strain. The data presented provide direct evidence that a chromatin-associated protein is strictly required for beta-mediated recombination. PMID- 7852373 TI - Specificity of G protein alpha-gamma subunit interactions. N-terminal 15 amino acids of gamma subunit specifies interaction with alpha subunit. AB - The existence of multiple alpha, beta, and gamma subunits raises questions regarding the assembly of particular G proteins. Based on the results of a previous study (Rahmatullah, M., and Robishaw, J. D. (1994) J. Biol. Chem. 269, 3574-3580), we hypothesized that the assembly of G proteins may be determined by the interactions of the more structurally diverse alpha and gamma subunits. This hypothesis was confirmed in the present study by showing striking differences in the abilities of the gamma 1 and gamma 2 subunits to interact with the alpha o subunit. Chimeras of the gamma 1 and gamma 2 subunits were used to delineate which region is responsible. Support for the importance of the N-terminal region of the gamma subunit comes from our observations that 1) the gamma 2 subunit and the gamma 211 chimera bound strongly to the alpha o-agarose matrix, but the gamma 1 subunit and the gamma 112 chimera bound weakly, if at all; 2) an N-terminal peptide made to the gamma 2 subunit blocked the binding of the gamma 211 chimera to the alpha o-agarose matrix; 3) both the gamma 211 chimera and the N-terminal peptide were able to partially protect the alpha o subunit against tryptic cleavage; and 4) the gamma 211 chimera, but not the gamma 112 chimera, supported ADP-ribosylation of the alpha o subunit. PMID- 7852374 TI - Transport of serum transthyretin into chicken oocytes. A receptor-mediated mechanism. AB - Transthyretin (TTR) is involved in the transport of thyroid hormones and, due to its interaction with serum retinol-binding protein, also of vitamin A. The importance of both ligands in vertebrate embryonic development has prompted us to investigate the molecular details of TTR transport function in a powerful germ cell system, the rapidly growing chicken oocytes. Yolk TTR is derived from the circulatory system, since biotinylated TTR was recovered by immunoaffinity chromatography of yolk obtained from a hen previously infused with in vitro biotinylated chicken serum proteins. In concordance with the intraoocytic localization in an endosomal compartment, ligand blotting and chemical cross linking experiments revealed the presence of a approximately 115-kDa TTR-binding oocyte membrane protein. This putative TTR receptor was not detected in chicken ovarian granulosa cells or embryonic fibroblasts and was different from the previously described oocyte-specific receptor for two estrogen-induced chicken serum lipoproteins, vitellogenin and very low density lipoprotein (Barber, D. L., Sanders, E. J., Aebersold, R., and Schneider, W. J. (1991) J. Biol. Chem. 266, 18761-18770). Furthermore, in contrast to the serum levels of the yolk precursor lipoproteins, those of TTR were not significantly changed by estrogen; thus, TTR represents a newly defined, estrogen-independent class of yolk precursor proteins. These data strongly suggest that oocytic TTR is derived from the circulation, where it is a constitutive component, and deposited into yolk as a result of endocytosis mediated by a specific receptor. PMID- 7852375 TI - Characterization of the human spuma retrovirus integrase by site-directed mutagenesis, by complementation analysis, and by swapping the zinc finger domain of HIV-1. AB - The human spuma retrovirus or foamy virus integrase (HFV IN) is an enzymatically active protein consisting of domains similar to other retroviral integrases: an amino-terminal HH-CC finger, a centrally located region with the conserved D, D 35-E protein motif required for catalytic activity and oligomerization, and at least one DNA binding domain implicated in the 3' DNA processing activity and integrase. Recombinant, purified HFV IN protein carrying 10 histidine residues displays a site-specific endonuclease, an integrase, and a disintegrase activity with oligonucleotide substrates that mimic the viral long terminal repeat (LTR) ends. Site-directed mutagenesis of conserved HFV IN residues of the catalytic domain had increased endonuclease and disintegrase activities. Deletion mutants at both ends of the HFV IN protein were generated, purified, and characterized. Unexpectedly, it was found that the HFV integrase and disintegrase activities require an intact NH2-terminal sequence and that COOH-terminal deletions led to an increase in disintegrase activity. The HH-CC finger of HFV IN was exchanged with that of the human immunodeficiency virus-1 (HIV-1) IN protein. The resulting chimeric IN had a 3' processing activity that utilized the HFV LTR instead of the HIV LTR, indicating that the central domain is crucial for substrate recognition. Functional complementation of the amino-terminal deletion mutant of HFV IN was achieved by a carboxyl-terminal deletion mutant of the chimeric IN, resulting in high levels of integrase activity. PMID- 7852376 TI - Effect of nucleotide on the binding of peptides to 70-kDa heat shock protein. AB - In previous work we found that bovine brain hsp70 has a single binding site for nucleotide, and that, with ATP at this site, the rates of association and dissociation of clathrin from hsp70 are fast, whereas with ADP at this site, these rates are unmeasurably slow. In the present study we show, first, that peptide C, cytochrome c peptide, and RNase S peptide bind competitively with clathrin, suggesting that they bind to the same site on hsp70, although RNase S peptide binds an order of magnitude more weakly than peptide C and cytochrome c peptide. Second, we show that, with ADP bound to hsp70, as occurs with clathrin, the rate constant for dissociation of peptide markedly decreases compared to the rate constant observed in ATP. In contrast, ADP only slightly decreases the rate of association of peptide. Based on these data we propose a model in which substrates of hsp70 bind to and dissociate from the ATP form of the enzyme, while, following ATP hydrolysis, they are locked onto the ATP form of the enzyme, unable to dissociate until ADP is released and ATP rebinds. PMID- 7852377 TI - Mild dyslipidemia in mice following targeted inactivation of the hepatic lipase gene. AB - In order to gain better understanding of the function of hepatic lipase (HL) in vivo, we have generated mice that lack HL using gene targeting in embryonic stem cells. No mRNA for HL was detected in the liver of homozygous mutants, and no HL activity was detected in their plasma. Total cholesterol levels in plasma of mutant mice were increased by about 30% compared with wild type animals. Plasma phospholipids and high density lipoprotein (HDL) cholesterol were also increased, but plasma levels of triglycerides were not altered. Analysis of density fractions of plasma lipoproteins revealed that HDL1 (d = 1.02-1.04) was increased in homozygous mutants fed regular chow. In response to a diet containing high fat and high cholesterol, HDL cholesterol was doubled in the mutants, but was slightly decreased in the wild type mice. These results clearly demonstrate the importance of HL in HDL remodeling and metabolism in vivo. Various earlier studies suggested a role of HL in metabolism of triglyceride-rich particles, but the mutant mice appear to have no impairment in clearing them; the mutants clear exogenously introduced chylomicrons from plasma at a normal rate, and they tolerate acute fat loading as well as normal animals unless the loading is extreme. These differences may reflect species differences. However, it is also possible that the consequence of absence of HL as in our mutants is different from the consequence when nonfunctional HL protein is present as in the human HL deficient patients and in rats treated with HL antibodies. We hypothesize that absence of HL in mutant mice allows other lipases to bind to the sites in the liver normally occupied by HL and facilitate the clearance of triglyceride-rich particles in these mice. PMID- 7852378 TI - Isolation of a human cDNA that complements a mutant hamster cell defective in methotrexate uptake. AB - A clone has been isolated from a human lymphoblastic cDNA expression library that complements a mutant Chinese hamster cell defective in the uptake of the folate analogue methotrexate. When transfected with this clone the mutant cells regain the ability to transport the drug and, as a consequence, become sensitive to its cytotoxic action. The clone is 2863 base pairs long and has an open reading frame of 1770 base pairs that codes for a putative protein of 64 kDa. The putative protein has 51 and 50% identity at the amino acid level with the mouse and hamster functions, respectively, involved in the transport of reduced folates. Together these three proteins share 47% identity and have similar predicted structural features. The data are consistent with this human clone encoding either the reduced folate transporter or an auxiliary function that interacts with this transporter. PMID- 7852379 TI - Glutamic acid 327 in the sheep alpha 1 isoform of Na+,K(+)-ATPase stabilizes a K(+)-induced conformational change. AB - By combining the tools of site-directed mutagenesis and [3H]ouabain binding, the functional role of glutamic acid 327 in the fourth transmembrane domain of the sheep alpha 1 isoform of Na+,K(+)-ATPase was examined with respect to its interactions with ouabain, Na+,K+,Mg2+, and inorganic phosphate. Using site directed mutagenesis, this glutamic acid was substituted with alanine, aspartic acid, glutamine, and leucine. The mutant proteins were constructed in a sheep alpha 1 protein background such that [3H]ouabain binding could be utilized as a highly specific probe of the exogenous protein expressed in NIH 3T3 cells. Na+ competition of [3H]ouabain binding to the mutant forms of Na+,K(+)-ATPase revealed only slight alterations in their affinities for Na+ and in their abilities to undergo Na(+)-induced conformational changes which inhibit ouabain binding. In contrast, K+ competition of [3H]ouabain binding to all four mutant forms of Na+,K(+)-ATPase displayed severely altered interactions between these proteins and K+. Interestingly, [3H]ouabain binding to the mutant E327Q was not inhibited by the presence of K+. This mutant was previously reported to be functionally able to support cation transport with a 5-fold reduced K0.5 for K(+) dependent ATPase activity (Jewell-Motz, E. A., and Lingrel, J.B. (1993) Biochemistry 32, 13523-13530; Vilsen, B. (1993) Biochemistry 32, 13340-13349). Thus, it appears that this glutamic acid in the fourth transmembrane domain may be important for stabilizing a K(+)-induced conformation within the catalytic cycle of Na+,K(+)-ATPase that is not rate-limiting in the overall ATPase cycle but that displays a greatly reduced affinity for ouabain. PMID- 7852380 TI - Endogenous retinoic acid receptor (RAR)-retinoid X receptor (RXR) heterodimers are the major functional forms regulating retinoid-responsive elements in adult human keratinocytes. Binding of ligands to RAR only is sufficient for RAR-RXR heterodimers to confer ligand-dependent activation of hRAR beta 2/RARE (DR5). AB - We have examined how retinoic acid receptors (RARs) and retinoid X receptors (RXRs) at physiological concentrations regulate distinct retinoid-responsive elements, hRAR beta 2/beta RARE (DR5) and rCRBPII/RXRE (DR1), in keratinocytes from human skin, a major retinoid target. In vitro, endogenous RAR gamma and RXRs bound to these elements as heterodimers (RAR.RXR) but not homodimers (RAR.RAR or RXR.RXR). In cultured keratinocytes, all-trans retinoic acid, 9-cis retinoic acid, and CD367 activated beta RARE but not RXRE via endogenous RAR.RXR (ED50 = 2.3, 3.8, and 0.3 nM, respectively) whereas SR11237 showed no significant effect. All-trans retinoic acid, 9-cis retinoic acid, and SR11237 activated RXRE via overexpressed RXR.RXR (ED50 = 110, 120, and 11 nM, respectively), indicating interconversion between retinoic acid isomers, whereas co-overexpression of RAR alpha or RAR gamma suppressed this activation. Unlike 9cRA, CD367 neither induced formation of nor activated RXR.RXR. Overexpression of RAR or RXR mutated in transactivation domain AF-2 suppressed endogenous receptor activity over beta RARE. Our data suggest that 1) in keratinocytes, RAR.RXR-mediated pathway dominates over that mediated by RXR.RXR; 2) RAR-selective CD367 and RXR-selective SR11237 can be used to identify these two distinct pathways, respectively; 3) beta RARE is mainly regulated by RAR.RXR, in which RAR alone confers ligand inducibility whereas AF-2 of unliganded RXR is required for transactivation by liganded RAR AF-2; 4) lack of RXRE activity in keratinocytes is due to low endogenous levels of RXR.RXR and inhibition by RAR.RXR; and 5) interaction among RXRs is much lower than that between RAR and RXR. PMID- 7852381 TI - Mapping of an NH2-terminal ligand binding site of the insulin receptor by alanine scanning mutagenesis. AB - Affinity labeling studies and mutational analyses have implicated the involvement of a predicted domain of the insulin receptor (L1, amino acids 1-119) in ligand binding. In order to obtain a higher resolution localization of this ligand binding site, we have performed alanine scanning mutagenesis of this domain. Alanine mutant cDNAs encoding a secreted recombinant insulin receptor extracellular domain were expressed transiently in adenovirus transformed human embryonic kidney cells and the affinity of the expressed receptor for insulin was determined. Mutation of 14 amino acids located in four discontinuous peptide segments to alanine was disruptive of insulin binding: Segment 1, amino acids 12 15; Segment 2, amino acids 34-44; Segment 3, amino acids 64-67; and Segment 4, amino acids 89-91. The quantitative contribution of the four segments to the free energy of insulin binding was 1 > 3 > 2 > 4. Of the 14 amino acids whose mutation compromised insulin binding, 3 are charged, 3 hydrophobic, 5 aromatic, and 3 are amides. PMID- 7852382 TI - Conformational changes in the junctional foot protein/Ca2+ release channel mediate depolarization-induced Ca2+ release from sarcoplasmic reticulum. AB - In an attempt to monitor the kinetic events occurring in the junctional foot protein (JFP) during excitation-contraction coupling, the JFP moiety of isolated triads was covalently labeled in a site-directed manner with methylcoumarin acetate (MCA) using a recently developed technique (Kang, J.J., Tarcsafalvi, A., Carlos, A.D., Fujimoto, E., Shahrokh, Z., Thevenin, B.J.M., Shohet, S.B., and Ikemoto, N. (1992) Biochemistry 31, 3288-3293). Chemical depolarization of the transverse tubular system (T-tubule) moiety of labeled triads after appropriate priming induced first a rapid increase of the fluorescence intensity of the JFP bound MCA probe, and then sarcoplasmic reticulum (SR) Ca2+ release. Upon increasing the magnitude of T-tubule depolarization by increasing the magnitude of T-tubule depolarization by increasing the degree of ionic replacement, both the amplitude of the MCA fluorescence change and the amount of released Ca2+ increased in parallel. Blockers of T-tubule-to-SR communication, such as nimodipine and low concentration of neomycin, inhibited both the MCA fluorescence change and the SR Ca2+ release. In contrast, the release blocking concentration of Mg2+ (2 mM) inhibited only SR Ca2+ release without affecting the fluorescence change. These results suggest that upon T-tubule depolarization the original state of the JFP (R) isomerizes to an activated state with higher MCA fluorescence (*R), which in turn changes into a subsequent state in which the release channel is open (*Ro):R-->*R-->*Ro. PMID- 7852383 TI - Characterization of FP21, a cytosolic glycoprotein from Dictyostelium. AB - FP21 is a glycoprotein which, when tracked by radioactivity in its fucosyl moiety, was previously detected in the cytosol of Dictyostelium cells after cell fractionation. This compartmentalization is confirmed by SDS-polyacrylamide gel electrophoresis/Western blotting of cell fractions using three different antibodies. Although a substantial fraction of FP21 is also detected in the particulate fraction using these new antibodies, particulate FP21 is released by disrupting protein-protein interactions, but not membrane disruption. Since purified FP21 is susceptible to aggregation, and purified nuclei do not contain FP21, particulate FP21 is also part of the cytosol. Additional compositional and structural information provides strong evidence that FP21 does not at any time traverse the rough endoplasmic reticulum. First, cDNAs spanning the entire coding region of the FP21 gene predict no hydrophobic motifs expected to promote membrane insertion, but do predict an NH2-terminal coiled coil domain which could explain aggregation. Second, monosaccharide composition analysis of the predominant glycoform of FP21 yields 2 mol of galactose, 1 mol of xylose, and 1 mol of fucose/mol of polypeptide; FP21 from a fucosylation-defective mutant contains 1 additional mol of xylose in place of fucose. Thus the N-glycosylation sequon present in FP21 is not utilized by oligosaccharyl transferase, which resides in the rough endoplasmic reticulum. These findings indicate that nascent FP21 remains in the cytosol after synthesis and is therefore glycosylated by unusual cytosolic xylosyl-, galactosyl-, and fucosyltransferases. PMID- 7852384 TI - The myxoma virus-soluble interferon-gamma receptor homolog, M-T7, inhibits interferon-gamma in a species-specific manner. AB - The myxoma virus M-T7 protein contains significant sequence similarity to the ligand binding domain of the mammalian interferon-gamma receptors, and functions as a soluble homolog which can bind and inhibit the biological activities of rabbit interferon-gamma (Upton, C., Mossman, K., and McFadden, G. (1992) Science 258:1369-1372). M-T7, the most abundantly secreted protein from myxoma virus infected cells, was shown to be expressed in significant biological amounts as a typical poxvirus early gene product, efficiently secreted at early times of infection to levels that exceed 5 x 10(7) molecules/cell, and function as a stable inhibitory protein in infected cell supernatants until late times of infection. M-T7 was specific in binding and inhibiting rabbit interferon-gamma, and did not bind either human or murine interferon-gamma. Scatchard analysis of rabbit interferon-gamma binding curves yielded a single high affinity binding site on M-T7, with a Kd of 1.2 x 10(-9) M, which is comparable to the affinity between soluble forms of cellular interferon-gamma receptors and their cognate ligands. In comparison, rabbit interferon-gamma was shown to bind its cellular receptor with a Kd of 5.9 x 10(-10) M, again comparable to the affinity of membrane bound forms of other mammalian interferon-gamma receptors for interferon gamma. Thus, the myxoma virus M-T7 protein is a functional soluble interferon gamma receptor homolog which binds and inhibits interferon-gamma with high affinity in a species-specific manner. PMID- 7852385 TI - The upstream promoter element of the glucagon gene, G1, confers pancreatic alpha cell-specific expression. AB - The glucagon gene is expressed in the endocrine pancreas, the intestine, and the brain. In the endocrine pancreas, expression of the glucagon gene is restricted to the alpha cells of the islets of Langerhans. We previously showed that 168 base pairs of the promoter was critical for this restricted expression. To further characterize the mechanisms involved in alpha cell specificity, we analyzed the responsible DNA sequences by transient transfection studies into glucagon- and insulin-producing cell lines. We localized alpha cell-specific sequences between nt 100 and 52, a region that corresponds to the upstream promoter element G1. Four protein complexes, B1, B2, B3, and B6 interact with G1; B6 requires most of G1 to be formed. B1, B2, and B3, by contrast, bind on closely overlapping sequences, display similar methylation interference patterns, and appear to be related complexes. Point mutations of G1 indicate, however, that their binding specificities are different. All four complexes are islet-specific, and impairment of their binding results in decreased transcription. We conclude that G1 interacts with islet cell-specific proteins to restrict glucagon gene expression to the alpha cells. PMID- 7852386 TI - N-acetylsphingosine (C2-ceramide) inhibited neutrophil superoxide formation and calcium influx. AB - Ceramide, a product arising from sphingomyelinase activity, has been shown to act as an intracellular second messenger in effecting growth inhibition, cellular differentiation, and apoptosis. In the present study, the relative effects of cell-permeable ceramides, N-acetylsphingosine (C2-ceramide) and N hexanoylsphingosine (C6-ceramide), on neutrophil responses were measured. When cells were activated with fMet-Leu-Phe, C2-ceramide both potentiated (< 1 microM) and inhibited (> 1 microM) superoxide generation. C2- and C6-ceramide inhibited phorbol ester-induced superoxide release from neutrophils at IC50 values of 5 and 120 microM, respectively. C2-ceramide had no effect on semipurified protein kinase C activity. Neither ceramide affected significantly the general level of phosphorylated proteins in phorbol ester-treated cells. C2-ceramide (1-20 microM) alone did not change cytosolic free Ca2+ levels but inhibited Ca2+ and Mn2+ influx in fMet-Leu-Phe-activated neutrophils. In contrast, sphingosine enhanced Ca2+ entry; thus, ceramide conversion to sphingosine was not significant. Unlike C2-ceramide, C2-dihydroceramide failed to block superoxide generation or Ca2+ influx. Preincubation of cells with 10 nM okadaic acid reversed slightly the effects of C2-ceramide. Calyculin A, tautomycin, and much higher concentrations of okadaic acid inhibited agonist-induced Ca2+ influx. We postulate that C2 ceramide may inhibit neutrophil superoxide release by activation of type 2A protein phosphatases. Results suggest that protein phosphatase type 1 up regulates Ca2+ entry, whereas type 2A (or a ceramide-activated subtype) forestalls Ca2+ entry by inactivating a calcium influx factor. PMID- 7852387 TI - The alpha-helical to beta-strand transition in the amino-terminal fragment of the amyloid beta-peptide modulates amyloid formation. AB - Amyloid-beta peptide (A beta) consists of a hydrophobic C-terminal domain (residues 29-42) that adopts beta-strand conformation and an N-terminal domain (amino acids 10-24) whose sequence permits the existence of a dynamic equilibrium between an alpha-helix and a beta-strand. In this paper we analyzed the effect of the alternate N-terminal conformations on amyloid fibril formation through the study of the analogous A beta peptides containing single amino acidic substitutions. The single mutation of valine 18 to alanine induces a significant increment of the alpha-helical content of A beta, determined by Fourier transform infrared spectroscopy and circular dichroism and dramatically diminishes fibrillogenesis, measured by turbidity, thioflavine T binding, Congo red staining, and electron microscopic examination. In hereditary Dutch cerebral hemorrhage with amyloidosis (a variant of Alzheimer's disease), the substitution of glutamine for glutamic acid at position 22 decreased the propensity of the A beta N-terminal domain to adopt an alpha-helical structure, with a concomitant increase in amyloid formation. We propose that A beta exists in an equilibrium between two species: one "able" and another "unable" to form amyloid, depending on the secondary structure adopted by the N-terminal domain. Thus, manipulation of the A beta secondary structure with therapeutical compounds that promote the alpha-helical conformation may provides a tool to control the amyloid deposition observed in Alzheimer's disease patients. PMID- 7852388 TI - Prevention of apoptotic neuronal death by GM1 ganglioside. Involvement of Trk neurotrophin receptors. AB - We have used serum-deprived cultures of wild type and genetically modified PC12 cells to investigate the molecular mechanisms by which monosialoganglioside (GM1) rescues neuronal cells from apoptotic death elicited by withdrawal of trophic support. Our findings indicate that GM1-promoted survival can be mediated in part by the Trk NGF receptor as well as by TrkB, and potentially by tyrosine kinase receptors for additional neurotrophic growth factors. Experiments employing K 252a, an inhibitor of Trk kinases, and PC12 cells overexpressing a dominant inhibitory form of Trk both indicate that a portion of the survival-promoting activity of GM1 is evoked by receptor dimerization and autophosphorylation. In consonance with this we find that GM1 stimulates Trk tyrosine autophosphorylation and Trk-associated protein kinase activity. These observations may provide a mechanism to account for the reported in vitro and in vivo trophic actions of GM1. PMID- 7852389 TI - Crystal structure and site-directed mutagenesis of Bacillus macerans endo-1,3-1,4 beta-glucanase. AB - In beta-glucans those beta-1,4 glycosidic bonds which are adjacent to beta-1,3 bonds are cleaved by endo-1,3-1,4-beta-glucanases (beta-glucanases). Here, the relationship between structure and activity of the beta-glucanase of Bacillus macerans is studied by x-ray crystallography and site-directed mutagenesis of active site residues. Crystal structure analysis at 2.3-A resolution reveals a jelly-roll protein structure with a deep active site channel harboring the amino acid residues Trp101, Glu103, Asp105, and Glu107 as in the hybrid Bacillus beta glucanase H(A16-M) (Keitel, T., Simon, O., Borriss, R., and Heinemann, U. (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 5287-5291). Different mutant proteins with substitutions in these residues are generated by site-directed mutagenesis, isolated, and characterized. Compared with the wild-type enzyme their activity is reduced to less than 1%. Several mutants with isosteric substitutions in Glu103 and Glu107 are completely inactive, suggesting a direct role of these residues in glycosyl bond hydrolysis. The kinetic properties of mutant beta-glucanases and the crystal structure of the wild-type enzyme are consistent with a mechanism where Glu103 and Glu107 are the catalytic amino acid residues responsible for cleavage of the beta-1,4 glycosidic bond within the substrate molecule. PMID- 7852390 TI - The tryptophan fluorescence change upon conformational transition of the phosphoenzyme intermediate in sarcoplasmic reticulum Ca(2+)-ATPase is revealed in the absence of K+ and the presence of lasalocid. AB - ATP-induced changes in the tryptophan fluorescence of the Ca(2+)-ATPase were determined with sarcoplasmic reticulum vesicles at pH 7.0 and 0 degrees C by steady-state measurements in the presence of Ca2+ and the absence of K+ with and without added lasalocid (a carboxylic ionophore, 50 microM), which was previously shown to cause a predominant accumulation of the ADP-insensitive form of the phosphoenzyme intermediate (EP) (Kawashima, T., Hara, H., and Kanazawa, T. (1990) J. Biol. Chem. 265, 10993-10999). When ATP was added in the absence of lasalocid, the fluorescence decreased by 1.7%. The addition of lasalocid quenched 71% of the fluorescence but did not reduce the ATP-induced fluorescence drop. The fluorescence drop and the EP formation were also determined in the presence of lasalocid by stopped-flow spectrometry and continuous-flow rapid quenching. The observed fluorescence drop was biphasic. The first phase coincided with the formation of EP, which was largely ADP-sensitive in this early stage of the reaction. The second phase was much slower than the first phase and coincided with the accumulation of ADP-insensitive EP. When the transition of EP from the ADP-sensitive form to the ADP-insensitive form was blocked by N-ethylmaleimide treatment, the second phase disappeared, and the fluorescence drop entirely coincided with the formation of ADP-sensitive EP. These findings demonstrate that the first phase of the fluorescence drop is attributed to the formation of ADP sensitive EP, the second phase being attributed to the transition of EP from the ADP-sensitive form to the ADP-insensitive form. The present results reveal the conditions that definitely discriminate these two phases. PMID- 7852391 TI - Synthesis of neoglycoproteins using oligosaccharide-transfer activity with endo beta-N-acetylglucosaminidase. AB - We describe a novel method for the enzymatic synthesis of neoglycoproteins. Endo beta-N-acetylglucosaminidase from Arthrobacter protophormiae (Endo-A) had high levels of transglycosylation activity. The enzyme activity of Endo-A was markedly increased by adding 4-L-aspartyl-glycosylamine (GlcNAc-Asn) to the reaction mixture. Digesting (Man)6(GlcNAc)2 with the enzyme in the presence of GlcNAc-Asn gave a mixture of hydrolytic ((Man)6GlcNAc) and transglycosylic ((Man)6(GlcNAc)2 Asn) products. By means of transglycosylation, (Man)6GlcNAc was transferred en bloc to the partially deglycosylated ovalbumin glycopeptide (EEKYN(GlcNAc)LTSVL) concomitant with the hydrolysis of (Man)6-GlcNAc)2Asn. The structure of the transglycosylation product was designated as (Man)6(GlcNAc)2-peptide by amino acid composition and sequence analysis as well as ion mass spectrometry. The enzyme also transferred oligosaccharide to partially deglycosylated ribonuclease B (GlcNAc-protein) during the hydrolysis of (Man)6-(GlcNAc)2Asn. Native ribonuclease B had (Man)5-9 (GlcNAc)2 as its heterogeneous N-linked sugar chains. High performance liquid chromatography showed that all of the N-linked sugar chains of the synthetic neoribonuclease of the pyridylamino derivatives were modified to (Man)6(GlcNAc)2. PMID- 7852393 TI - Role of the transmembrane domain and flanking amino acids in internalization and down-regulation of the insulin receptor. AB - We have characterized the internalization and down-regulation of the insulin receptor and nine receptors with mutations in the transmembrane (TM) domain and/or flanking charged amino acids to define the role of this domain in receptor cycling. When expressed in Chinese hamster ovary cells, all had normal tetrameric structure and normal insulin-stimulated autophosphorylation/kinase activity. Replacement of the TM domain with that of the platelet-derived growth factor receptor, insertion of 3 amino acids, and substitution of Asp for Val938 or of Ala for either Gly933 or Pro934 had no effect on internalization. Replacement of the TM domain with that of c-neu or conversion of the charged amino acids on the cytoplasmic flank to uncharged amino acids, on the other hand, resulted in a 40 60% decrease in insulin-dependent internalization rate constants. By contrast, substitution of Ala for both Gly933 and Pro934 increases lateral diffusion mobility and accelerates internalization rate. These changes in internalization were due to decreased or increased rates of redistribution of receptors from microvilli to the nonvillous cell surface. In all cases, receptor down-regulation and receptor-mediated insulin degradation paralleled the changes in internalization. Thus, the structure of the transmembrane domain of the insulin receptor and flanking amino acids are major determinants of receptor internalization, insulin degradation, and receptor down-regulation. PMID- 7852392 TI - Similar ligand-induced conformational changes of thyroid hormone receptors regulate homo- and heterodimeric functions. AB - Thyroid hormone receptors (TRs) bind specific thyroid hormone response elements (TREs) as heterodimers with retinoid X receptors (RXRs) and act as transcriptional activators. As homodimers, TRs can bind a distinct set of sequences and function as ligand sensitive repressors. In our study, we compared the natural malic enzyme TRE (ME-TRE) as a model system for the TR/RXR heterodimer pathway to the chicken lysozyme silencer element F2-TRE which is strongly bound and regulated by TR/TR homodimers. Using electrophoretic mobility shift assays, transient transfections with a variety of natural and synthetic triiodothyronine and thyroxine derivatives as well as limited proteolytic analysis, we show that the natural homo- and heterodimeric pathways show similar ligand requirements. Furthermore, we observe that the ligand-induced conformational changes in the receptor proteins that either result in a loss of TR/TR homodimer binding and release of transcriptional repression or in transcriptional activation of TR/RXR heterodimers are indistinguishable. Therefore, we propose that in TR/TR homodimers and TR/RXR heterodimers very similar moieties of the receptors are involved in ligand binding and subsequent conformational changes that lead to loss of gene repression (TR/TR homodimer) and gain of gene activation (TR/RXR heterodimer). PMID- 7852394 TI - Differential transcriptional activation in vitro by NF-kappa B/Rel proteins. AB - Distinct NF-kappa B subunit combinations contribute to the specificity of NF kappa B-mediated transcriptional activation and to the induction of multiple cytokine genes including interferon-beta (IFN-beta). To evaluate the regulatory influence of different homo- and heterodimers, NF-kappa B subunits were analyzed for transcriptional activity in vitro using test templates containing two types of NF-kappa B recognition elements (the human immunodeficiency virus type 1 enhancer and the IFN-beta-positive regulatory domain-II (PRDII) as well as IFN beta PRDIII-PRDI-PRDII linked to the -56 minimal promoter of rabbit beta-globin. Recombinant NF-kappa B subunits (p50, p65, c-Rel, p52, and I kappa B alpha) and interferon regulatory factor 1 were produced from either Escherichia coli or baculovirus expression systems. Transcriptional analysis in vitro demonstrated that 1) various dimeric complexes of NF-kappa B differentially stimulated transcription through the human immunodeficiency virus enhancer or PRDII up to 20 fold; 2) recombinant I kappa B alpha specifically inhibited NF-kappa B-dependent transcription in vitro; and 3) different NF-kappa B complexes and interferon regulatory factor 1 cooperated to stimulate transcription in vitro through the PRDIII-PRDI-PRDII virus-inducible regulatory domains of the IFN-beta promoter. These results demonstrate the role of NF-kappa B protein dimerization in differential transcriptional activation in vitro and emphasize the role of cooperativity between transcription factor families as an additional regulatory level to maintain transcriptional specificity. PMID- 7852395 TI - Trehalose as a possible precursor of the sulfated L-galactan in the ascidian tunic. AB - Among sulfated polysaccharides, those in the tunic of ascidians are unique: their major constituent sugar is galactose, which occurs exclusively in the L enantiomeric form. Incorporation of D-[14C]glucose into tunic slices in vitro revealed that the cells epimerize D-glucose into L-galactose during biosynthesis of the sulfated polysaccharides. The interconversion of these two sugars involves exchange of hydrogen atoms at the epimerization sites with protons of the medium. Tunic cells also synthesize trehalose, although this disaccharide is not a prominent constituent of the tissue. Pulse-chase experiments using D-[14C]glucose reveal that incorporation of label into trehalose precedes the synthesis of the sulfated L-galactan. In addition, the loss of label from trehalose coincides with the appearance of label in the sulfated L-galactan. Based on these results, we speculate that trehalose in the ascidian tunic may be a precursor of the sulfated L-galactan. PMID- 7852396 TI - Structure-function of muscarinic receptor coupling to G proteins. Random saturation mutagenesis identifies a critical determinant of receptor affinity for G proteins. AB - To derive structure-function relationships for receptor-G protein coupling, libraries were created of human m5 muscarinic acetylcholine receptors (m5) randomly mutated in the C-terminal region of the third intracellular loop. Functional receptors were identified based on their ability to amplify NIH 3T3 cells in a ligand-dependent manner. These receptors either had wild-type phenotypes (Group 1) or were functionally impaired (Group 2). No "activated receptors" were identified. Tolerated substitutions in Group 2 receptors were randomly distributed and frequently included prolines and glycines. In contrast, tolerated substitutions in Group 1 receptors exhibited a periodicity proximal to transmembrane domain 6 were proline and glycine substitutions were not observed. These observations are consistent with a short alpha-helical extension of the C terminal region of the third intracellular loop from transmembrane domain 6. Mutations at Ala-441 were most commonly associated with impaired function of Group 2 receptors. Twelve point mutations at Ala-441 were tested, and all caused marked increases in EC50 values with little effect on maximal response or agonist binding affinity. These results indicate that Ala-441 is a key determinant of m5 receptor affinity for G proteins and exists within the structural context of a short alpha-helix. PMID- 7852397 TI - The methionine salvage pathway in Klebsiella pneumoniae and rat liver. Identification and characterization of two novel dioxygenases. AB - The 5-methylthio-D-ribose moiety of 5'-(methylthio)-adenosine is converted to methionine in a wide variety of organisms. 1,2-Dihydroxy-3-keto-5 methylthiopentene anion (an aci-reductone) is an advanced intermediate in the methionine salvage pathway present in the Gram-negative bacterium Klebsiella pneumoniae and rat liver. This metabolite is oxidized spontaneously in air to formate and 2-keto-4-methylthiobutyric acid (the alpha-keto acid precursor of methionine). Previously, we had purified an enzyme (E2) from Klebsiella which catalyzes the oxidative degradation of the aci-reductone to formate, CO, and methylthiopropionic acid. To further characterize the reactions of the aci reductone we used its desthio analog, 1-2-dihydroxy-3-ketohexene anion (III), which was described previously. This molecule undergoes the analogous enzymatic and non-enzymatic reactions of the natural substrate, namely the formation of formate, CO, and butyrate from III. Experiments with 18O2 show that E2 is a dioxygenase which incorporates one molecule of 18O into formate and butyric acid. No cofactor has been identified. We were unable to find an enzyme which catalyzes the conversion of 1,2-dihydroxy-3-keto-5-methylthiopentane to a keto acid precursor of methionine. The keto acid is probably produced non-enzymically in Klebsiella. We have, however, identified and purified an enzyme (E3) from rat liver, which catalyzes the formation of formate and 2-oxopentanoic acid from III. This enzyme has a monomeric molecular mass of 28,000 daltons, and no chromophoric cofactor has been identified. Experiments with 18O2 show that E3 is a dioxygenase which incorporates an 18O molecule into formate and the alpha-keto acid. In rat liver CO formation was not detected. PMID- 7852398 TI - Biochemical and genetic definition of the cellular protease required for HIV-1 gp160 processing. AB - The surface glycoproteins of enveloped viruses bind to target cell receptors and trigger membrane fusion for infection. The human immunodeficiency virus 1 (HIV-1) envelope glycoprotein gp120 (CD4 binding protein) and gp41 (transmembrane fusion protein) are initially synthesized as a gp160 precursor. The intracellular cleavage of gp160 by a host cell protease during transit through the secretory pathway is essential for viral activities such as infectivity, membrane fusion, and T-cell syncytium formation. We report that gp160 biogenesis, protein processing, and cell-surface expression have been successfully reproduced in the yeast Saccharomyces cerevisiae. Genetic and biochemical approaches are used for defining that the unique cellular protease, Kex2p, is directly responsible for HIV-gp160 processing in yeast, in vivo and in vitro. The yeast system described in this report represents a powerful strategy for identifying, characterizing and inhibiting the host T-cell protease essential for HIV infectivity and AIDS. PMID- 7852399 TI - Structure of the nicotinic receptor acetylcholine-binding site. Identification of acidic residues in the delta subunit within 0.9 nm of the 5 alpha subunit binding. AB - In the nicotinic receptor, the quaternary ammonium group of acetylcholine (ACh) binds to a negative subsite at most 1 nm from a readily reducible disulfide formed between alpha-subunit residues Cys192 and Cys193. The cross-linker S-(2 [3H]glycylamidoethyl)dithio-2-pyridine formed a disulfide bond with reduced alpha Cys192/Cys193 and an amide bond with an acidic residue in the delta subunit (Czajkoswski, C., and Karlin, A. (1991) J. Biol. Chem. 266, 22603-22612). The fully extended cross-linking moiety -NHCH2CONHCH2CH2S- is is 0.9 nm long. After the disulfide bond linking -NHCH2CONHCH2CH2S- to the alpha subunit was reduced, NHCH2CONHCH2CH2SH remained linked to the delta subunit by an amide bond. The delta subunit was cleaved at Met residues, and the radioactive fragments were isolated and sequenced by automated Edman degradation. Additionally, the isolated radioactive fragments were further cleaved at Trp residues and sequenced. Peaks of release of radioactivity were obtained in the sequencing cycles corresponding to delta Asp165, delta Asp180, and delta Glu182. The mutation of delta Asp180 to Asn decreased the affinity of the receptor for ACh 100-fold, whereas the mutation of either delta Asp165, delta Glu182, or 8 other acidic residues in the same region of delta decreased the affinity by 3-fold or less (Czajkowski, C., Kaufmann, C., and Karlin, A. (1993) Proc. Natl. Acad. Sci. U.S.A 90, 6285-6289). Because delta Asp180 both contributes to ACh binding and is suitably close to the binding site disulfide, it is likely to be part of the ACh-binding site formed in the interface between the alpha and the delta subunits. PMID- 7852400 TI - Low molecular weight GTP-binding proteins in HL-60 granulocytes. Assessment of the role of ARF and of a 50-kDa cytosolic protein in phospholipase D activation. AB - Phospholipase D (PLD) activation by guanine nucleotides requires protein cofactors in both the plasma membrane and the cytosol. HL-60 cytosol was fractionated by ammonium sulfate and gel-permeation chromatography. Two cytosolic protein fractions were found to reconstitute the GTP gamma S (guanosine 5'-3-O (thio)triphosphate)-stimulated PLD in a reconstitution assay consisting of 3H labeled HL-60 membranes and eluted column fractions. The major peak of reconstituting activity was in the region of 50 kDa, and a second discrete peak of PLD reconstitution activity was observed in the region of 18 kDa. Rho GDP/GTP exchange inhibitor, Rho GDI, comigrated with Rac2 and RhoA, but not Rac1. RhoA and Rac2 were entirely complexed with Rho GDI and eluted with an apparent molecular mass of 43 kDa by gel filtration chromatography. The partial overlap between cytosolic Rac2 and RhoA with the 50-kDa peak of reconstituting activity was not consistent with the participation of cytosolic Rho-related GTPases in the activation of PLD by guanine nucleotides. However, recombinant Rho GDI, which inhibits nucleotide exchange on the Rho family of small GTP-binding proteins, reduced GTP gamma S-stimulated PLD activity in HL-60 homogenates. The stimulatory exchange factor, Smg GDS, which is active on Rho and Rac, could be partially separated from the PLD-stimulating factor(s) by gel-permeation chromatography. Moreover, recombinant Smg GDS failed to stimulate GTP-dependent PLD activity. Cytosolic ADP-ribosylation factor (ARF) was exclusively located in the 18-kDa peak of reconstitution activity. Faint amounts of membrane-bound ARF were also detected using the monoclonal antibody 1D9. The effects of the 50-kDa and 18-kDa PLD-inducing factors on the salt-extracted PLD activity were synergistic. The weak stimulatory effect of ARF alone suggested that the GTP gamma S-stimulated PLD activity is dependent on the presence of another protein(s), presumably ARF regulatory proteins. We propose that a membrane-bound GTP-binding protein, possibly ARF, may be involved in the activation of PLD when combined with the component(s) of the 50-kDa fraction. PMID- 7852402 TI - The major protein of messenger ribonucleoprotein particles in somatic cells is a member of the Y-box binding transcription factor family. AB - A cDNA encoding the major core protein, p50, of cytoplasmic messenger ribonucleoprotein particles (mRNPs) of somatic cells was cloned from a rabbit reticulocyte cDNA library. From the derived 324-amino acid sequence, p50 is identified as a member of the Y-box binding transcription factor family. The protein was earlier described as a repressor of globin mRNA translation. These findings suggest that p50 may affect protein biosynthesis at two levels: mRNA transcription in the nucleus and mRNA translation in the cytoplasm. Together with recently published results showing that masked mRNA in germ cells also is associated with proteins of the Y-box binding protein family, the present finding indicates that these proteins are universal core proteins responsible for the formation of cytoplasmic mRNPs in eukaryotes. Highly purified p50 forms large 18 S homomultimeric complexes with a molecular mass of about 800 kilodaltons and melts RNA secondary structure. This suggests that p50 may affect translation by changing the overall structure of the mRNA. PMID- 7852401 TI - Calcium and membrane binding properties of bovine neurocalcin delta expressed in Escherichia coli. AB - Neurocalcins are brain-specific proteins that belong to a new subclass of the EF hand superfamily of calcium binding proteins, defined by the photoreceptor cell specific protein, recoverin. Recoverin, which regulates the desensitization of photo-excited rhodopsin, is myristoylated and exhibits a calcium-myristoyl switch. Like recoverin, neurocalcins have a signal for N-myristoylation and possess four EF-hands, although the first one lacks some residues critical for calcium binding. In this work, I have examined the calcium and membrane binding properties of recombinant myristoylated and unmyristoylated neurocalcin delta. I show that neurocalcin, like recoverin, binds to biological membranes in a calcium and myristoyl-dependent manner. Both myristoylated and unmyristoylated proteins bind three calcium ions. However, the unmyristoylated form exhibits a higher affinity for calcium than the myristoylated protein but shows a lower cooperativity in binding calcium. These data support the model for the calcium myristoyl switch mechanism proposed for recoverin (Zozulya, S., and Stryer, L. (1992) Proc. Natl. Acad. Sci. U.S.A. 89, 11569-11573; Dizhoor, A. M., Chen, C. K., Olshevskaya, E., Sinelnikova, V. V., and Hurley, J. B. (1993) Science 259, 829-832). Using point mutations, I have investigated the relative importance of each of the three functional EF hands (EF2, EF3, and EF4) in the calcium and membrane binding properties of neurocalcin. Calcium and membrane binding properties of the mutant-myristoylated proteins suggest that binding of calcium to EF2 is critical in triggering the binding of the protein to membranes. PMID- 7852403 TI - Modulation of the heme environment of neutrophil cytochrome b558 to a "cytochrome P450-like" structure by pyridine. AB - The effect of pyridine on the heme environment of cytochrome b558 was studied using ESR and optical absorption spectroscopy in relation to the O2(-)-generating activity in the NADPH oxidase system of stimulated pig neutrophils. As the concentration of pyridine increased, the absorption maxima of the alpha- and gamma-bands of cytochrome b558 shifted which correlated with a concomitant decrease in O2(-)-generating activity. In addition, the g = 3.2 signal of cytochrome b558 decreased with the concomitant appearance of a new ESR spectrum that strikingly resembled that of cytochrome P450. The results suggest that pyridine induces a structural modification in the heme environment of cytochrome b558 by shifting the 5th heme ligand (histidine) to a nearby thiolate group without direct binding of pyridine to the heme. The existence of a reactive thiolate near the heme iron was confirmed by pretreatment of blocked cytochrome b558 with p-chloromercuribenzoate, which completely inhibited the formation of the cytochrome P450-like ESR spectrum. The results provide further evidence that a low-spin heme iron of cytochrome b558 with a g-value of 3.2 is essential to the O2(-)-forming reaction of the NADPH oxidase system. From sequence alignments of cytochrome P450 with those of large and small subunits of cytochrome b558, the heme in cytochrome b558 appears to be specifically associated with the large subunit. PMID- 7852404 TI - Reversibility of the binding of cytochrome c to liposomes. Implications for lipid protein interactions. AB - Studies on the membrane binding of cytochrome c revealed liposome-associated and soluble cytochrome c not to be in rapid equilibrium. In brief, cytochrome c attached to pyrene phospholipid-labeled, fluorescent liposomes containing either 17.6 mol % cardiolipin (CL) or 30 mol % egg phosphatidylglycerol (PG) is practically not at all or very slowly, respectively, detached by a subsequently added excess (up to 20-fold) of nonlabeled liposomes containing these acidic lipids. Cytochrome c was fully dissociated from PG-containing liposomes by increasing the ionic strength by NaCl, whereas dissociation from CL-containing membranes was less complete, presumably because of the scavenging of the protein within inverted intramembrane micelles. Importantly, the apparent irreversibility of the binding of cytochrome c to liposomes is strongly dependent on the structure of the acidic phospholipid. Cytochrome c bound to lyso-PG/PC liposomes could be dissociated with an excess of nonlabeled PG-containing liposomes. Cytochrome c was also efficiently bound to membranes containing the negatively charged dicetylphosphate yet could be readily dissociated by nonlabeled PG containing liposomes. We conclude both proper geometry of the phosphate group and the presence of two acyl chains to be required for the tight binding of cytochrome c to acidic phospholipids. These data provide evidence for the membrane association of cytochrome c by an acidic phospholipid in the extended conformation (Kinnunen, P. K. J., Koiv, A., Lehtonen, J. Y. A., Rytomaa, M., and Mustonen, P. (1994) Chem. Phys. Lipids 73, 181-207) in which one of the acyl chains of the lipid becomes accommodated within a hydrophobic cavity of the protein. Based on the crystal structure of cytochrome c we putatively assign the invariant Asn-52 (horse heart cytochrome c) as the site liganding the protonated phosphate of the lipid, whereas Lys-72 and -73 should bind the deprotonated form. PMID- 7852405 TI - Apoptosis in an interleukin-2-dependent cytotoxic T lymphocyte cell line is associated with intracellular acidification. Role of the Na(+)/H(+)-antiport. AB - Apoptosis is a form of cell death associated with DNA fragmentation and chromatin condensation. We recently established that intracellular acidification occurred during apoptosis following cytotoxic insult. The current studies were designed to determine whether intracellular acidification was more generally associated with apoptosis, specifically in a model of growth factor withdrawal. Upon withdrawal of interleukin-2, CTLL-2 cells accumulated in the G1 phase of the cell cycle and started to fragment their DNA around 12 h concurrent with both decreased pH and increased Ca2. Chelation of Ca2+ did not inhibit DNA digestion, whereas incubation with a calcium ionophore prevented both acidification and DNA digestion. Hence, acidification rather than increased Ca2+ was associated with apoptosis. The acidified cells represented a discrete population up to 0.7 pH units below normal. The extent of acidification depended upon the extracellular pH; above pH 6.3, intracellular pH was significantly below extracellular pH, whereas below pH 6.3, the cells still regulated their pH. Inhibition of the Na+/H(+)-antiport prevented the apoptotic cells from regulating their intracellular pH under these acidic conditions. These intracellular pH under these acidic conditions. These results demonstrate that apoptotic cells retain a functional antiport but that its set-point has changed. Many survival factors are known to phosphorylate and activate the antiport, hence apoptosis is likely to be associated with dephosphorylation. Although acidification always occurred during apoptosis, maintaining intracellular pH above 7.2 did not prevent apoptosis, suggesting that an acid pH is not essential for apoptosis. We hypothesize that other critical regulators of apoptosis must be subject to dephosphorylation. PMID- 7852406 TI - Localization of the disulfide bond involved in post-translational processing of glycosylasparaginase and disrupted by a mutation in the Finnish-type aspartylglycosaminuria. AB - The heavy chain of human glycosylasparaginase (N4-(beta-N-acetylglucosaminyl)-L asparaginase (EC 3.5.1.26)) has five cysteinyl residues (Cys-61, Cys-64, Cys-69, Cys-163, and Cys-179). A Cys-163 to serine substitution due to a point mutation in the glycosylasparaginase gene causes the most common disorder of glycoprotein degradation, the Finnish-type aspartylglycosaminuria. To localize the potential disulfide bonds, the isolated heavy chain of human leukocyte glycosylasparaginase was treated with the enzyme alpha-chymotrypsin, and the resulting peptides were separated by high performance liquid chromatography prior to and after reduction and S-carboxymethylation. The peptide containing the Cys-163 residue and the peptide to which it is connected with a disulfide were structurally characterized by mass spectrometry. The disulfide bond crucial for catalytic activity, subunit processing, and biological transport of glycosylasparaginase was located close to the carboxyl terminus of the heavy chain at positions 163 and 179. PMID- 7852407 TI - Nicotinate adenine dinucleotide phosphate (NAADP) triggers a specific calcium release system in sea urchin eggs. AB - Transient fluxes of intracellular ionized calcium (Ca2+) from intracellular stores are integral components of regulatory signaling pathways operating in numerous biological regulations, including in early stages of egg fertilization. Therefore, we explored whether NADP, which is rapidly generated by phosphorylation of NAD upon fertilization may, directly or indirectly, exert a regulatory role as a trigger of Ca2+ release from intracellular stores in sea urchin eggs. NADP had no effect, but we found that the deamidated derivative of NADP, nicotinate adenine dinucleotide phosphate (beta-NAADP), is a potent and specific stimulus (ED50 16 nM) for Ca2+ release in sea urchin egg homogenates. NAADP triggers the Ca2+ release via a mechanism which is distinct from the well known Ca2+ release systems triggered either by inositol-1,4,5-triphosphate (IP3) or by cyclic adenosine diphospho-ribose (cADPR). The NAADP-induced release of Ca2+ is not blocked by heparin, an antagonist of IP3, or by procaine or ruthenium red, antagonists of cADPR. However, it is selectively blocked by thionicotinamide NADP which does not inhibit the actions of IP3 or cADPR. NAADP produced by heating of NADP in alkaline (pH = 12) medium or synthetized enzymatically by nicotinic acid-NADP reaction catalyzed by NAD glycohydrolase have identical properties. The results presented herein thus describe a novel endocellular Ca(2+)-releasing system controlled by NAADP as a specific stimulus. The NAADP controlled Ca2+ release system may be an integral component of multiple intracellular regulations occurring in fertilized sea urchin eggs, which are mediated by intracellular Ca2+ release, and may also have similar role(s) in other tissues. PMID- 7852408 TI - Characterization of the nicotinic acetylcholine receptor beta 3 gene. Its regulation within the avian nervous system is effected by a promoter 143 base pairs in length. AB - Genomic and cDNA clones encoding the chicken neuronal nicotinic acetylcholine receptor beta 3 subunit were isolated and sequenced. The beta 3 gene consists of six protein-encoding exons and the deduced protein has the structural features found in all other members of the neuronal nicotinic acetylcholine receptor subunit family. Although they are undetectable in most brain compartments, beta 3 mRNAs are relatively abundant in the developing retina and in the trigeminal ganglion. In situ hybridization and immunohistochemical analysis demonstrated that in retina, beta 3 transcripts and protein are confined to subpopulations of cells in the inner nuclear and ganglion cell layers. Beta 3 is expressed in the proximal and distal regions of the developing trigeminal ganglion, i.e. in both placode- and neural crest-derived neurons. Transient transfection assays in cells freshly dissociated from selected regions of the central nervous system at different developmental stages allowed the identification of genetic elements involved in the neuronal-selective expression of the beta 3 gene. A promoter fragment 143 base pairs in length and containing TATA, CAAT, and other consensus sequences is sufficient to restrict reporter gene expression to a subpopulation of retinal neurons. This promoter is totally inactive upon transfection into neuronal and non-neuronal cells from other regions of the central nervous system. PMID- 7852409 TI - Superoxide dismutase 1 subunits with mutations linked to familial amyotrophic lateral sclerosis do not affect wild-type subunit function. AB - Mutations in superoxide dismutase 1 (SOD1) have been linked to familial amyotrophic lateral sclerosis, a dominantly inherited motor neuron disorder of midlife. Because SOD1 is a homodimeric enzyme, dimerization of mutant and wild type SOD1 subunits could dominantly alter the activity, stability, or localization of wild-type SOD1 subunits. To explore these possibilities, we used transient and stable gene transfection to express high levels of either of two mutant human SOD1 subunits in the presence of limited levels of wild-type mouse and/or human SOD1 subunits. Although both mutant subunits displayed diminished half-lives and free radical scavenging activities, their presence caused no change in the half-life or activity of wild-type SOD1 subunits. Our data indicate that mutant subunits do not dominantly affect the function of wild-type SOD1 subunits. These findings, together with observations that many mutant SOD1 subunits retain significant stability and activity, suggest that motor neuron damage in familial amyotrophic lateral sclerosis is caused by the acquisition of injurious properties by mutant SOD1 subunits. PMID- 7852410 TI - Role of glutamic acid 988 of human poly-ADP-ribose polymerase in polymer formation. Evidence for active site similarities to the ADP-ribosylating toxins. AB - Sequence similarities between the enzymatic region of poly-ADP-ribose polymerase and the corresponding region of mono-ADP-ribosylating bacterial toxins suggest similarities in active site structure and catalytic mechanism. Glu988 of the human polymerase aligns with the catalytic glutamic acid of the toxins, and replacement of this residue with Gln, Asp, or Ala caused major reductions in synthesis of enzyme-linked poly-ADP-ribose. Replacement of any of 3 other nearby Glu residues had little effect. The Glu988 mutations produced similar changes in activity in the carboxyl-terminal 40-kDa catalytic fragment fused to maltose binding protein: E988Q and E988A reduced polymer elongation > 2000-fold, and E988D approximately 20-fold. Smaller changes were seen in chain initiation. The mutations had little effect on the Km of NAD, indicating a predominantly catalytic function for Glu988. The results support the concept of similar active sites of the polymerase and the ADP-ribosylating toxins. Glu988 may function in polymer elongation similarly to the toxins' active site glutamate, as a general base to activate the attacking nucleophile (in the case of the polymerase, the 2' OH of the terminal adenosine group of a nascent poly-ADP-ribose chain). PMID- 7852411 TI - The activation of type 1 and type 2 plasminogen by type I and type II tissue plasminogen activator. AB - Tissue plasminogen activator (tPA) was fractionated using lysine-Sepharose affinity chromatography. Type I, type II, and a minor peak with high affinity for lysine (designated type D) tPA were recovered. In an indirect amidolytic assay involving native human Glu-plasminogen and fibrin, type II tPA showed a 2-fold higher activity than type I. To explore the combinatorial effect of the variable glycosylation status of both tPA and plasminogen, kinetic constants for fibrin dependent plasminogen activation were determined for combinations of type I, II, and D tPA with type 1 and 2 plasminogen. Within a 4-fold range, the fastest rate was achieved from the combination of type D (type II + D) tPA and type 2 plasminogen. N-Glycosylation of plasminogen increased the Km value for activation by all tPA variants; N-glycosylation of type I tPA at Asn184 decreased the kcat (turnover) values for the fibrin-dependent activation of plasminogen over type II tPA, while type D tPA showed the highest turnover rate. In the presence of fibrinogen fragments, N-glycosylation of plasminogen at site 289 modulates the kinetics of association of enzyme and substrate, while N-glycosylation at site 184 on tPA modulates the turnover rate of the enzyme. PMID- 7852412 TI - CXC chemokines connective tissue activating peptide-III and neutrophil activating peptide-2 are heparin/heparan sulfate-degrading enzymes. AB - Heparan sulfate proteoglycans at cell surfaces or in extracellular matrices bind diverse molecules, including growth factors and cytokines, and it is believed that the activities of these molecules may be regulated by the metabolism of heparan sulfate. In this study, purification of a heparan sulfate-degrading enzyme from human platelets led to the discovery that the enzymatic activity residues in at least two members of the platelet basic protein (PBP) family known as connective tissue activating peptide-III (CTAP-III) and neutrophil activating peptide-2. PBP and its N-truncated derivatives, CTAP-III and neutrophil activating peptide-2, are CXC chemokines, a group of molecules involved in inflammation and wound healing. SDS-polyacrylamide gel electrophoresis analysis of the purified heparanase resulted in a single broad band at 8-10 kDa, the known molecular weight of PBP and its truncated derivatives. Gel filtration chromatography of heparanase resulted in peaks of activity corresponding to monomers, dimers, and tetramers; these higher order aggregates are known to form among the chemokines. N-terminal sequence analysis of the same preparation indicated that only PBP and truncated derivatives were present, and commercial CTAP-III from three suppliers had heparanase activity. Antisera produced in animals immunized with a C-terminal synthetic peptide of PBP inhibited heparanase activity by 95%, compared with activity of the purified enzyme in the presence of the preimmune sera. The synthetic peptide also inhibited heparanase by 95% at 250 microM, compared to the 33% inhibition of heparanase activity by two other peptides. The enzyme was determined to be an endoglucosaminidase, and it degraded both heparin and heparan sulfate with optimal activity at pH 5.8. Chromatofocusing of the purified heparanase resulted in two protein peaks: an inactive peak at pI7.3, and an active peak at pI 4.8-5.1. Sequence analysis showed that the two peaks contained identical protein, suggesting that a post translational modification activates the enzyme. PMID- 7852413 TI - Altered coding for a strictly conserved di-glycine in the major bilirubin UDP glucuronosyltransferase of a Crigler-Najjar type I patient. AB - The characterization (Ritter, J.K., Chen, F., Sheen, Y. Y., Tran, H.M., Kimura, S., Yeatman, M.T., and Owens, I. S. (1992) J. Biol. Chem. 267, 3257-3261) of the single-copy UGT1 gene complex locus encoding both bilirubin and phenol UDP glucuronosyltransferases (transferase) has been critical to the determination of genetic defects in Crigler-Najjar patients. The complex (UGT1A-UGT1M) codes for at least two bilirubin, three bilirubin-like, and eight phenol transferase isozymes. In the 5' region, a minimum of 13 different exons 1, each with an upstream promoter, are arrayed in series with 4 common exons in the 3' region of the locus. Each exon 1 encodes the amino terminus of a transferase, and the common exons encode the common carboxyl terminus of each isoform. Although a deleterious mutation in a common exon inactivates the entire locus, a deleterious mutation in an exon 1, as we report here for the UGT1A gene in a Crigler-Najjar Type I patient, affects the amino terminus of that single isoform. Recessively inherited mutant alleles for the predominant bilirubin isozyme, the HUG-Br1 protein, substituted Arg for Gly at codon 276 (G276R) in exon 1 of UGT1A abolishing a conserved di-glycine. The mutant HUG-Br1-G276R protein expressed in COS-1 cells had no detectable bilirubin glucuronidating activity at either pH 7.6 or 6.4. Although each of the bilirubin-type isozymes contains a conserved peptide between residues 270 and 288, all UDP-glucuronosyltransferases contain a di glycine at approximately position 276-277, making it strictly conserved. Structure-function relationship was studied by site-directed mutations of the HUG Br1 cDNA; G276A, G276Q, G276E, G276I, and P270G mutants were inactive, and V2751- and P285G-altered transferases expressed normal activity. Conservation of residues between the related baculoviral ecdysone UDP-glucosyltransferase and the UDP-glucuronosyltransferases confirms the critical role of the Gly-276 as well as other residues. PMID- 7852414 TI - A specific sequence of the laminin alpha 2 chain critical for the initiation of heterotrimer assembly. AB - Triple-stranded laminin molecules assemble via an alpha-helical coiled-coil structure spanning approximately 600 amino acid residues of each chain. We reported that the C termini of the beta 1 and gamma 1 chains direct the specific dimer and trimer assembly (Utani, A., Nomizu, M., Timpl, R., Roller, P.P., and Yamada, Y. (1994) J. Biol. Chem. 269, 19167-19175). In this study, we focused on the mechanism of trimer formation of the alpha 2 chain utilizing three different approaches. First, competition assays using mutated recombinant alpha 2 chain defined a 25-amino acid sequence at the C terminus of the long arm as an essential site for assembly with beta 1 and gamma 1 chain. Site-specific mutations and synthetic peptides of this site revealed that both positively charged amino acid residues and the alpha-helical structure within this site were critical. Second, overexpression studies of recombinant alpha 2 chain long arm confirmed that the C-terminal end was critical for the trimer assembly within NIH 3T3 cells. Third, circular dichroism spectroscopic examination of the complexes reconstituted in vitro revealed dynamic conformational changes of the alpha 2 and gamma 1 chains in the process of assembly. These studies also revealed that the proper folding of the extreme C terminus of alpha 2 chain was critical for the stability of trimer. From these data, it is concluded that the C terminus of alpha 2 chain long arm is required for the effective initiation of laminin heterotrimer assembly. PMID- 7852415 TI - A 60-kDa prion protein (PrP) with properties of both the normal and scrapie associated forms of PrP. AB - Scrapie is a transmissible spongiform encephalopathy of sheep and other mammals in which disease appears to be caused by the accumulation of an abnormal form of a host protein, prion protein (PrP), in the brain and other tissues. The process by which the normal protease-sensitive form of PrP is converted into the abnormal protease-resistant form is unknown. Several hypotheses predict that oligomeric forms of either the normal or abnormal PrP may act as intermediates in the conversion process. We have now identified a 60-kDa PrP derived from hamster PrP expressed in murine neuroblastoma cells. Peptide mapping studies provided evidence that the 60-kDa PrP was composed solely of PrP and, based on its molecular mass, appeared to be a PrP dimer. The 60-kDa PrP was not dissociated under several harsh denaturing conditions, which indicated that it was covalently linked. It was similar to the disease-associated form of PrP in that it formed large aggregates. However, it resembled the normal form of PrP in that it was sensitive to proteinase K and had a short metabolic half-life. The 60-kDa PrP, therefore, had characteristics of both the normal and disease-associated forms of PrP. Formation and aggregation of the 60-kDa hamster PrP occurs in uninfected mouse neuroblastoma cells, which suggests that hamster PrP has a predisposition to aggregate even in the absence of scrapie infectivity. Similar 60-kDa PrP bands were identified in scrapie-infected hamster brain but not in uninfected brain. Therefore, a 60-kDa molecule might participate in the scrapie-associated conversion of protease-sensitive PrP to protease-resistant PrP. PMID- 7852416 TI - Functional co-expression of the beta 1 and type IIA alpha subunits of sodium channels in a mammalian cell line. AB - Brain sodium channels are a complex of alpha (260 kDa), beta 1 (36 kDa), and beta 2 (33 kDa) subunits, alpha subunits are functional as voltage-gated sodium channels by themselves. When expressed in Xenopus oocytes, beta 1 subunits accelerate the time course of sodium channel activation and inactivation by shifting them to a fast gating mode, but alpha subunits expressed alone in mammalian cells activate and inactivate rapidly without co-expression of beta 1 subunits. In these experiments, we show that the Chinese hamster cell lines CHO and 1610 do not express endogenous beta 1 subunits as determined by Northern blotting, immunoblotting, and assay for beta 1 subunit function by expression of cellular mRNA in Xenopus oocytes. alpha subunits expressed alone in stable lines of these cells activate and inactivate rapidly. Co-expression of beta 1 subunits increases the level of sodium channels 2- to 4-fold as determined from saxitoxin binding, but does not affect the Kd for saxitoxin. Co-expression of beta 1 subunits also shifts the voltage dependence of sodium channel inactivation to more negative membrane potentials by 10 to 12 mV and shifts the voltage dependence of channel activation to more negative membrane potentials by 2 to 11 mV. These effects of beta 1 subunits on sodium channel function in mammalian cells may be physiologically important determinants of sodium channel function in vivo. PMID- 7852417 TI - Differential effects of simple repeating DNA sequences on gene expression from the SV40 early promoter. AB - The influence of simple repeat sequences, cloned into different positions relative to the SV40 early promoter/enhancer, on the transient expression of the chloramphenicol acetyltransferase (CAT) gene was investigated. Insertion of (G)29.(C)29 in either orientation into the 5'-untranslated region of the CAT gene reduced expression in CV-1 cells 50-100 fold when compared with controls with random sequence inserts. Analysis of CAT-specific mRNA levels demonstrated that the effect was due to a reduction of CAT mRNA production rather than to posttranscriptional events. In contrast, insertion of the same insert in either orientation upstream of the promoter-enhancer or downstream of the gene stimulated gene expression 2-3-fold. These effects could be reversed by cotransfection of a competitor plasmid carrying (G)25.(C)25 sequences. The results suggest that a G.C-binding transcription factor modulates gene expression in this system and that promoter strength can be regulated by providing protein binding sites in trans. Although constructs containing longer tracts of alternating (C-G), (T-G), or (A-T) sequences inhibited CAT expression when inserted in the 5'-untranslated region of the CAT gene, the amount of CAT mRNA was unaffected. Hence, these inhibitions must be due to posttranscriptional events, presumably at the level of translation. These effects of microsatellite sequences on gene expression are discussed with respect to recent data on related simple repeat sequences which cause several human genetic diseases. PMID- 7852418 TI - An essential interaction between distinct domains of HIV-1 integrase mediates assembly of the active multimer. AB - Integrase mediates integration of the retroviral genome into a host cell chromosome, an essential step in the viral life cycle. In vitro, a stable complex containing only purified human immunodeficiency virus (HIV) integrase and a model viral DNA substrate processively executes the 3'-end processing and DNA joining steps in the integration reaction. We examined the relationship of three essential components of the HIV integrase: the HHCC domain, a putative zinc finger near the N terminus; the phylogenetically conserved "DD35E" motif, which defines the catalytic domain; and a feature recognized by its sensitivity to the alkylating agent N-ethylmaleimide (NEM). HIV integrase is a multimer, and these three components can be distributed among at least two subunits of the multimeric enzyme. The components function asymmetrically in the active multimer; the DD35E motif and NEM-sensitive site are required in trans to the HHCC region. A divalent cation-dependent interaction involving the NEM-sensitive site of one integrase subunit and the HHCC region of another subunit points to a role for these two features of integrase in multimer assembly. Deletion of the HHCC domain, or modification of integrase with NEM, impaired the assembly of a stable complex between integrase and viral DNA, suggesting that this initial step in the integration pathway requires assembly of the active integrase multimer. PMID- 7852419 TI - Presence of isl-1-related LIM domain homeobox genes in teleost and their similar patterns of expression in brain and spinal cord. AB - Three novel LIM domain homeobox cDNAs encoding proteins structurally related to the Isl-1 protein were isolated from a chinook salmon pituitary cDNA library. Southern blot analysis of genomic DNA indicate that they are derived from three distinct genes, designated as isl-2a, isl-2b, and isl-3 genes. Nucleotide sequence analysis of reverse transcriptase-polymerase chain reaction amplified products reveal that the isl gene family contains two members (a and b) each of both isl-1 and isl-2 genes, and one member of isl-3 gene in the two tetraploid salmonid species, chinook salmon and rainbow trout, and only one member each of isl-1, isl-2, and isl-3 genes in the diploid zebrafish. The expression of the three isl genes in the rainbow trout were studied by reverse transcriptase polymerase chain reaction analysis of embryonic and adult RNAs, and by in situ hybridization analysis of 8-week-old hatchlings. The transcripts of all three genes could be detected as early as 4 weeks postfertilization (the eye stage) and increased dramatically in 5-week-old embryos. In the adult, the three isl mRNAs appear to be differentially distributed in various tissues. The level of isl-1 mRNA is generally higher than those of isl-2 and isl-3 mRNAs. In situ hybridization analysis indicates that the transcripts of all three genes are localized in subsets of neurons in the brain and spinal cord. In the retina, isl 1 mRNA could be found in both the ganglion and inner nuclear layers while isl-2 and isl-3 mRNAs could only be detected in the ganglion layer. High level of isl-1 mRNA could also be found in mid-gut and interrenal organ where endocrine cells are densely populated. Based on these observations, we speculate that the three structurally related isl genes may play similar roles in cell determination and differentiation in the developing nervous system. PMID- 7852420 TI - Chronic desensitization and down-regulation of the gastrin-releasing peptide receptor are mediated by a protein kinase C-dependent mechanism. AB - The cellular basis of down-regulation and desensitization in phospholipase C linked receptors is unclear. Recent studies with some receptors suggest that elements in the carboxyl terminus of the receptor are important in mediating these processes. Three mutant gastrin-releasing peptide receptors (GRP-R) were studied: one whose last 37 carboxyl-terminal amino acids were eliminated (construct MGT346); one that replaced all of the carboxyl-terminal Ser and Thr eliminated in MGT346 with Ala, Asn, or Gly (construct JF1); and one that selectively replaced the Ser and Thr of the protein kinase C consensus sequence (PKC-CS) located within the same region with alanine (construct TS360AA). Desensitization was assessed by measuring the ability to activate phospholipase C and increase cellular [3H]inositol phosphates, or increase [Ca2+]i, after pre exposure to 3 nM bombesin for 24 h. Wild-type GRP-R was maximally desensitized and down-regulated after a 24-h exposure to 3 nM bombesin, and removal of the PKC CS alone markedly attenuated each process. Elimination of additional serines and threonines by truncation (MGT346) or replacement (JF1) did not decrease down regulation or desensitization further. To confirm the necessity of second messenger activation in mediating down-regulation, we further investigated two additional mutant GRP-R that bound agonist with high affinity but fail to activate phospholipase C (constructs R139G and A263E). Neither construct underwent significant down-regulation. Removal of all GRP-R carboxyl-terminal Ser or Thr, either by MGT346 or JF1, reduced internalization by > 80%, whereas elimination of the PKC-CS in TS360AA only attenuated internalization by 21 +/- 2%. These data suggest that activation of the distal carboxyl-terminal PKC-CS is essential for chronic desensitization and down-regulation of the GRP-R, and provide no evidence for involvement of second messenger-independent processes. In contrast, internalization is equally regulated by both second messenger-dependent and independent processes. PMID- 7852421 TI - Overlapping pathways mediate the opposing actions of tumor necrosis factor-alpha and transforming growth factor-beta on alpha 2(I) collagen gene transcription. AB - Transforming growth factor-beta (TGF-beta) and tumor necrosis factor-alpha (TNF alpha) are multifunctional peptides intimately involved in the process of extracellular matrix remodeling. We recently showed that TGF-beta stimulates the human alpha 2(I) collagen gene by increasing the affinity of an Sp1-containing transcriptional complex bound to an upstream sequence termed the TbRE (Inagaki, Y., Truter, S. and Ramirez, F. (1994) J. Biol. Chem. 269, 14828-14834). Here, we report that the TbRE-bound complex also mediates the inhibitory signal of TNF alpha. Nuclear proteins from cells treated with TNF-alpha bind to the TbRE sequence substantially more strongly than those from untreated cells. Additionally, TNF-alpha increases binding of a second protein complex that recognizes the negatively cis-acting element located immediately next to the TbRE. Thus, we postulate that TNF-alpha counteracts the TGF-beta-elicited stimulation of collagen gene expression through overlapping nuclear signaling pathways. One modifies the TGF-beta-targeted transcriptional complex, probably by reducing its stimulatory effect on collagen transcription. The other acts on the binding of the adjacent factor, presumably by increasing its effectiveness in repressing the activity of the collagen promoter. The convergence of the TGF-beta and TNF-alpha pathways on the same sequence of the alpha 2(I) collagen promoter is yet another example of combinatorial gene regulation achieved through composite response elements. PMID- 7852422 TI - Selectivity of cell cycle regulation of glucocorticoid receptor function. AB - The restricted expression of some genes to distinct stages of the cell cycle is often brought about through alterations in the activity and/or abundance of specific transcription factors. Many cells have been shown to be unresponsive to glucocorticoid hormone action during the G2 phase of the mammalian cell cycle, suggesting that some activities of the glucocorticoid receptor (GR), a ligand activated transcription factor, are subjected to cell cycle control. We show here that GR insensitivity in G2 is selective, affecting receptor-mediated transactivation from a simple glucocorticoid response element, but not repression from a composite glucocorticoid response element. Since glucocorticoid-dependent down-regulation of GR protein levels is also unaffected in G2, distinct activities of the receptor that participate in this homologous down-regulation must be operating as effectively in G2-synchronized cells as in asynchronous cells. Finally, the phosphorylation state of the GR is altered in G2-synchronized cells reflecting, in part, both site-specific phosphorylation and dephosphorylation events. These results suggest that, while GR may be a target for cell cycle regulated kinases and phosphatases, the resulting changes in receptor phosphorylation have an impact only on selected GR functions. PMID- 7852423 TI - The N-terminal portion of growth inhibitory factor is sufficient for biological activity. AB - To determine its active site, growth inhibitory factor (GIF), a central nervous system-specific metallothionein-like protein, was digested with trypsin followed by Staphylococcus aureus protease V8 digestion. Of 5 peptide fragments separated from trypsin-digested GIF by reverse-phase high pressure liquid chromatography and gel filtration, only GIF1-26 or longer peptides showed growth inhibitory activity on cortical neurons in culture. A shorter peptide, GIF5-23, which was obtained by further digestion of GIF1-26 with V8 protease, also showed growth inhibitory activity. However, a synthetic peptide corresponding to GIF5-23 did not show growth inhibitory activity. Metal-free GIF1-26 prepared by acid treatment showed a similar level of growth inhibitory activity to that of metal containing GIF1-26, indicating that metal in the peptide does not affect the activity. Treatment of metal-free GIF1-26 with beta-mercaptoethanol resulted in the loss of activity. The CD spectrum of beta-mercaptoethanol-treated metal-free GIF1-26 was different from that of nontreated metal-free GIF1-26. These results indicate that the N-terminal portion of GIF is required for growth inhibitory activity and that folding of the peptide via S-metal bonding is critical for biological activity. PMID- 7852424 TI - Identification of domains of poly(ADP-ribose) polymerase for protein binding and self-association. AB - Cellular proteins extracted from normal and cancer cells bind polymerizing ADP ribose transferase (pADPRT) on nitrocellulose membrane transblots. Histones at 1 mg/ml concentration completely prevent the binding of pADPRT to cellular proteins, indicating that the binding of histones to pADPRT sites competitively blocks the association of pADPRT to proteins other than histones. The direct binding of pADPRT to histones is shown by cross-linking with glutaraldehyde. The COOH-terminal basic histone H1 tail binds to the basic polypeptide domain of pADPRT. The basic domain present in the NH2-terminal part of core histones is the probable common structural feature of all core histones that accounts for their binding to pADPRT. Two polypeptide domains of pADPRT were identified, by way of CNBr fragments, to bind histones. These two domains are located within the 64-kDa fragment of pADPRT and are contiguous with the polypeptide domains that were shown to participate in self-association of pADPRT, ending at the 606th amino acid residue. The polypeptide domains of pADPRT which participate in DNA binding are thus shown to associate also with other proteins. Intact pADPRT binds to both the zinc-free or zinc-reconstituted basic polypeptide fragments of pADPRT. Histones activate auto-poly(ADP)-ribosylation of pADPRT by increasing the number of short oligomers on pADPRT. This reaction is also dependent in a biphasic manner on the concentration of pADPRT. Histones in solution are only marginally poly(ADP)-ribosylated but are good polymer acceptors when incorporated into artificial nucleosome structures. PMID- 7852426 TI - Naturally occurring antisense transcripts are present in chick embryo chondrocytes simultaneously with the down-regulation of the alpha 1 (I) collagen gene. AB - It has previously been shown that very low steady state levels of alpha 1 (I) collagen mRNA are present in chick embryo sternal chondrocytes (Askew, G. R., Wang, S., and Lukens, L. N. (1991) J. Biol. Chem. 266, 16834-16841), yet nuclear run-on experiments with double-stranded cDNA probes indicated a high transcription rate at this locus. These findings were investigated in this study using single-stranded probes, where nuclear run-on experiments showed that antisense transcription of the alpha 1 (I) collagen gene was occurring in chondrocytes, while sense strand transcription was down-regulated. Treatment of these chondrocytes with 5-bromo-2'-deoxyuridine (BrdU), which causes the cells to resemble their mesenchymal precursors, resulted in an antiparallel situation, where antisense transcription was lost, and instead, sense strand transcription was acquired, suggesting that the reverse switch from sense to antisense transcription occurs during chondrogenesis. Very large (> 10 kilobases) and heterogeneous antisense transcripts of moderate stability were shown to span both ends of the gene in chondrocytes, while their absence was shown in BrdU-treated chondrocytes, chick embryo fibroblasts, and a variety of other tissues. The function of these antisense transcripts is so far unknown, but their unusual chondrocyte-specific appearance, concurrent with little or no sense strand transcription, suggests a possible functional role in the down-regulation of the alpha 1 (I) collagen gene. PMID- 7852425 TI - Agrin is a heparan sulfate proteoglycan. AB - In the present study we have identified the extracellular matrix protein agrin as a major heparan sulfate proteoglycan (HSPG) in embryonic chick brain. Using monoclonal antibodies and a polyclonal antiserum to the core protein of a previously identified HSPG from embryonic chick brain, our expression screened a random-primed E9 chick brain cDNA library. Twelve cDNAs were isolated that were shown to be identical to the chick extracellular matrix protein agrin. Western blot analysis and immunocytochemistry confirmed that agrin is a HSPG that is identical with the HSPG from embryonic chick brain. A polyclonal antiserum to recombinant agrin protein recognized agrin as a diffuse band of over 400 kDa in extracts from brain and vitreous humor. The agrin immunoreactivity on the blot was shifted to a defined band of approximately 250 kDa after treatment of the samples with heparitinase or nitrous acid, and this banding pattern was indistinguishable from immunoreactivity obtained with antibodies to the brain HSPG. We also show that agrin binds tightly to anion exchange beads, indicating that the molecule is highly negatively charged, which is a hallmark of all proteoglycans. Furthermore, the agrin antiserum recognizes the affinity purified HSPG from chick brain and vitreous humor. Immunocytochemistry demonstrated that agrin is expressed in developing brain, and is especially abundant in developing axonal tracts, in a distribution identical to the staining of the brain HSPG with monoclonal antibodies. We also show that the anti-HSPG antibodies stain the synaptic site of the neuromuscular junction, in agreement with agrin expression. Thus, our studies demonstrate that chick agrin is a HSPG that is prominent in the embryonic chick brain. Since previous studies from our laboratories have shown that this proteoglycan interacts with neural cell adhesion molecule, our studies raise the interesting possibility that neural cell adhesion molecule and agrin are interactive partners that may regulate a variety of cell adhesion processes during neural development, including synaptogenesis. PMID- 7852427 TI - Human umbilical vein endothelial cells express high affinity neurotensin receptors coupled to intracellular calcium release. AB - The binding of 125I-neurotensin (NT) to human umbilical vein endothelial cell monolayers was studied. At 20 degrees C, 125I-NT bound to a single class of binding sites with a dissociation constant of 0.23 +/- 0.08 nM and a binding site density of 5500 +/- 1300 sites/cell (n = 3). 125I-NT also bound to human aortic endothelial cells with a dissociation constant of 0.6 +/- 0.26 nM and a binding site density of 32000 +/- 1700 sites/cell. Association and dissociation kinetics were of a pseudo-first order and gave association and dissociation rate constant values of 1.6 x 10(6) M-1 s-1 and 3.5 x 10(-4) s-1, respectively. 125I-NT binding was inhibited by NT analogues with a rank order of potency similar to that characterizing brain high affinity NT binding sites (K0.5, nM): NT8-13 (0.11) > NT (0.35) > acetyl-NT8-13 (1.5) > [Phe11]NT (12) > [D-Tyr11]NT (> 1000). 125I-NT binding was also inhibited by the non-peptide NT antagonist SR 48692 (Ki = 16 nM) but was not affected by levocabastine, an inhibitor of low affinity brain NT binding sites. NT had no effect on cGMP levels in endothelial cells but NT and its analogues increased 45Ca2+ efflux from endothelial cells at nanomolar concentrations with a rank order of potency which was identical to that observed in binding experiments. This effect was inhibited by SR 48692 (IC50 = 8 nM). NT was able to increase phosphoinositide turnover in these cells, and this effect was blocked by SR 48692. The correlation between dissociation constants of NT analogues in binding experiments and IC50 values in 45Ca2+ efflux experiments was very high (r = 0.997) with a slope near unity, indicating that 125I-NT binding sites are functional NT receptors coupled to phosphoinositide hydrolysis and Ca2+ release in human umbilical vein endothelial cells. PMID- 7852428 TI - The carboxyl terminus of the membrane-binding domain of cytochrome b5 spans the bilayer of the endoplasmic reticulum. AB - Preliminary studies (Vergeres, G., and Waskell, L. (1992) J. Biol. Chem. 267, 12583-12591) have suggested that the carboxyl-terminal membrane-binding domain of cytochrome b5 traverses the membrane and that the carboxyl terminus is in the lumen of the endoplasmic reticulum. In order to confirm and extend these studies, additional experiments were conducted. The gene coding for rat cytochrome b5 was transcribed and the resulting mRNA was translated in vitro in a rabbit reticulocyte lysate in the presence of microsomes. The binding and topology of cytochrome b5 were investigated by treating microsomes containing the newly incorporated cytochrome b5 with carboxypeptidase Y and trypsin. Our studies indicate that cytochrome b5 is inserted both co- and post-translationally into microsomes in a topology in which the membrane-binding domain spans the bilayer with its COOH terminus in the lumen. Cytochrome b5 is also incorporated into microsomes pretreated with trypsin in a topology indistinguishable from the one resulting from the insertion of the protein into untreated microsomes, reconfirming that cytochrome b5 does not use the signal recognition particle dependent translocation machinery. Our results do not allow a distinction to be made between a spontaneous insertion mode or some other trypsin-resistant receptor-mediated mechanism. A role for Pro115 in the middle of the membrane binding domain of cytochrome b5 was also examined by mutating it to an alanine and subsequently characterizing the ability of the mutant protein to be incorporated into membranes. The mutant protein inserted more slowly in vitro into microsomes as well as into pure lipid bilayers by a factor of 2 to 3. PMID- 7852429 TI - Myofibroblasts from scleroderma skin synthesize elevated levels of collagen and tissue inhibitor of metalloproteinase (TIMP-1) with two forms of TIMP-1. AB - Cultured fibroblasts derived from skin biopsies from scleroderma patients and normal individuals were examined for the presence of smooth muscle alpha-actin, a marker for myofibroblasts. Six of eight scleroderma cell lines were found to be 50% or more positive for alpha-actin while three of four normal lines and one cell line derived from unaffected skin of a scleroderma patient were less than 10% positive. The cultured fibroblasts from affected scleroderma skin were largely myofibroblasts, a phenotype found in biopsies of scleroderma tissue, as well as other fibrotic lesions, wound healing, and tumor desmoplasia. The data support the hypothesis that a certain activated fibroblast phenotype predominates in scleroderma. The activated fibroblast is the myofibroblast. Both collagen and TIMP (tissue inhibitor of metalloproteinases) were elevated in the alpha-actin positive (myofibroblast enriched) cultures. In addition, the myofibroblast enriched cultures displayed a more prominent TIMP doublet band pattern on SDS polyacrylamide gel electrophoresis. PMID- 7852430 TI - Activation of mitogen-activated protein kinase and phosphatidylinositol 3'-kinase is not sufficient for the hormonal stimulation of glucose uptake, lipogenesis, or glycogen synthesis in 3T3-L1 adipocytes. AB - The precise mechanism by which insulin regulates glucose metabolism is not fully understood. However, it is known that insulin activates two enzymes, phosphatidylinositol 3'-kinase (PI 3'-K) and mitogen-activated protein kinase (MAPK), which may be involved in stimulating the metabolic effects of insulin. The role of these enzymes in glucose metabolism was examined by comparing the effects of insulin, platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) in 3T3-L1 adipocytes. Treatment of the cells with PDGF or EGF for 5 min increased the MAPK activity 3-5-fold, while insulin treatment produced a 2.5 fold increase. The MAPK activity remained elevated for 1 h after either PDGF or insulin treatment. PDGF and insulin, but not EGF, caused a transient increase in the amount PI 3'-K activity coprecipitated with tyrosine phosphorylated proteins. Although PDGF and insulin caused a similar increase in the activities of these two enzymes, only insulin caused substantial increases in glucose utilization. Insulin increased the transport of glucose and the synthesis of lipid 4- and 17 fold, respectively, while PDGF did not affect these processes significantly. Glycogen synthesis was increased 15-fold in response to insulin and only 3-fold in response to PDGF. Thus, the activation of MAPK and PI 3'-K are not sufficient for the complete stimulation of glucose transport, lipid synthesis, or glycogen synthesis by hormones in 3T3-L1 adipocytes, suggesting a requirement for other signaling mechanisms that may be uniquely responsive to insulin. PMID- 7852432 TI - Identification of R-X-(X)-S/T-X3-S/T as consensus sequence motif for autophosphorylation-dependent protein kinase. PMID- 7852431 TI - Galectin-8. A new rat lectin, related to galectin-4. AB - A protein of 35 kDa which has the characteristic properties of galectins (S-type lectins) was cloned from rat liver cDNA expression library. Since names for galectins 1-7 were already assigned, this new protein was named galectin-8. Three lines of evidence demonstrate that galectin-8 is indeed a novel galectin: (i) its deduced amino acid sequence contains two domains with conserved motifs that are implicated in the carbohydrate binding of galectins, (ii) in vitro translation products of galectin-8 cDNA or bacterially expressed recombinant galectin-8 are biologically active and possess sugar binding and hemagglutination activity, and (iii) a protein of the expected size (34 kDa) that binds to lactosyl-Sepharose and reacts with galectin-8-specific antibodies is present in rat liver and comprises approximately 0.025% of the total Triton X-100-soluble hepatic proteins. Overall, galectin-8 is structurally related (34% identity) to galectin 4, a soluble rat galectin with two carbohydrate-binding domains in the same polypeptide chain, joined by a link peptide. Nonetheless, several important features distinguish these two galectins: (i) Northern blot analysis revealed that, unlike galectin-4 that is confined to the intestine and stomach, galectin-8 is expressed in liver, kidney, cardiac muscle, lung, and brain; (ii) unlike galectin-4, but similar to galectins-1 and -2, galectin-8 contains 4 Cys residues; (iii) the link peptide of galectin-8 is unique and bears no similarity to any known protein; (iv) the N-terminal carbohydrate-binding region of galectin 8 contains a unique WG-E-I motif instead of the consensus WG-E-R/K motif implicated as playing an essential role in sugar-binding of all galectins. Together with galectin-4, galectin-8 therefore represents a subfamily of galectins consisting of a tandem repeat of structurally different carbohydrate recognition domains within a single polypeptide chain. PMID- 7852433 TI - Facial injury: a review of biomechanical studies and test procedures for facial injury assessment. AB - A review of biomechanical studies that have attempted to measure fracture tolerances of facial bones has been carried out. The particular bones of interest were the mandible, the zygoma, the maxilla and the nasal bones. Numerical values have been given for the peak force and pressure fracture tolerances for these bones. A study of these values illustrates just how variable the bone strength of various individuals is. A review of various methods that have attempted to measure and quantify the physical effects of a blow to the face has also been carried out. Three major types of test procedure exist, namely frangible elements, peak force and pressure sensing elements and deformable elements. Frangible and deformable elements generally replace the face of a standard test dummy, fracturing and deforming at appropriate impact force levels, respectively. These surrogate face forms are used for two different reasons; either they are used to measure the damage to the human face for some impact scenario or they are simply used to better simulate the response of the whole head to impact by simulating the compliance of the face. Peak force and pressure sensing elements take the form of piezoelectric sensors and pressure-sensitive, colour 'Fuji film'. Both these methods are complicated and really only suitable for research purposes only. Finally, it is recommended that a mathematical model approach be used to establish the principal injury mechanism and support further development of an acceptable face form test. PMID- 7852434 TI - The application of segment axial density profiles to a human body inertia model. AB - The intention of this study was to construct segment density profiles and compare segment inertias calculated when uniform densities and profile densities are used in a mathematical model. Axial densities from computerized tomography (CT) slices for the body segments of a sample of Chinese females (Zheng et al., Proceedings of the Beijing Asian Games Scientific Congress, 1990) were used to form profiles which could be employed in body segment models. Polynomials based on proportion of segment length were fitted to the reported mean slice densities. These profiles were then used with five widely divergent samples (n = 10); young adult females, young adult males, infants, male children and elderly adults. The mathematical model used is based on an assumption that all segments can be represented by stacked elliptic cylinders. The results show that when the profile densities were substituted for average cadaver densities the increase in the estimated total body mass was less than 0.85%. For the individual segments, use of the profile rather than average density increased the average segment mass estimate by up to 2.7%. The centres of mass and the principal moments were affected by the variations in density along the axis as well as the magnitudes, by up to 0.54 and 3.8%, respectively. Although the effects of using the profiles appear to be small the differences for individual samples, segments and parameters ranged up to 22.5%. It is not possible to decide if average or profile densities produce more accurate estimates of inertia, but the profile allows for axial variation in density and is therefore recommended. PMID- 7852435 TI - On the assumption of bilateral lower extremity joint moment symmetry during the sit-to-stand task. AB - This study examined the validity of the assumption of bilateral lower extremity joint moment symmetry during the sit-to-stand motion for a group of young (n = 7) and a group of elderly (n = 7) female subjects. Two force plates and a motion analysis system were used to determine peak joint moments at the ankles, knees, and hips following liftoff from a chair. Statistically, bilateral asymmetries in peak joint moments were found at the knee joint in the young group [a right to left difference of 0.43% BW x BH (body weight x body height)] and at the hip joint in both subject groups (differences of 0.20% BW x BH and 1.09% BW x BH for the young and elderly subjects, respectively). Subsequent data analysis, using an algorithm that assumed bilateral ground reaction force (GRF) symmetry, was performed to determine whether the bilateral differences were a result of kinematic or GRF asymmetry. It was concluded from these results that both the kinematic and GRF data account for the bilateral asymmetry. The results of the subsequent analysis also showed that the method which assumed bilateral GRF symmetry underestimated the peak joint moments at the ankles, knees, and hips, with the greatest difference between methods being 0.10% BW x BH for the ankle joint. The results of this study suggest that the assumption of bilateral symmetry of lower extremity joint moments during the sit-to-stand is not valid. However, the biomechanical significance of the errors associated with assuming symmetry must also be taken into account.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7852436 TI - Transfer function between tibial acceleration and ground reaction force. AB - The purpose of the present study was to capture the relationship between ground reaction force (GRF) and tibial axial acceleration. Tibia acceleration and GRF were simultaneously recorded from five subjects during running. The acceleration of the bone was measured with a transducer mounted onto an intracortical pin. The signals were analyzed in the frequency domain to characterize the relationship between GRF and tibial acceleration. The results confirmed that for each subject this relationship could be represented by a frequency transfer function. The existence of a more general relationship for all five subjects was also confirmed by the results. The transfer functions provided information about transient shock transmissibility for the entire impact phase of running. PMID- 7852437 TI - Two-dimensional rigid-body kinematics using image contour registration. AB - A method for calculating two-dimensional rigid-body kinematic parameters using shape features is presented. Proposed applications include the noninvasive quantification of planar joint motion in vivo. By using digitized images (computed tomographs, radiographs, etc.) of a bone contour at two positions, the contour curvatures can be 'best-fit' to obtain a one-to-one mapping or registration of the bone images. This produces a dense field of displacement vectors from which planar rigid-body kinematic parameters can be estimated. Accuracy was studied using radiographic images of cadaveric femoral bone. The two motions of pure rotation with a fixed center of rotation and of pure translation were simulated. For pure rotation, error in rotation was independent of the rotation magnitude, with an average (n = 10) error of 0.3 +/- 0.8 degrees. The translation error averaged 0.9 +/- 0.5 mm. For pure translation, the error in rotation was -0.01 +/- 0.69 degrees and the error in translation was -0.62 +/- 0.98 mm (n = 10). This novel method has broad applications in the field of planar kinematics, especially in cases for which marker fixation is neither possible nor practical. PMID- 7852438 TI - Flow instabilities induced by coronary artery stents: assessment with an in vitro pulse duplicator. AB - An in vitro pulse duplicator system was used to investigate whether coronary artery stents induce downstream flow instabilities. Hot film or electrochemical probes were used to measure wall shear stress before and after deployment of both single and multiple (overlapping) stents in normal and diseased coronary geometries. Left main coronary diameters ranged from 4 to 5 mm, whereas left anterior descending (LAD) and left circumflex (LCX) diameters ranged from 2 to 4 mm. Under resting conditions, all coronary flow waveforms remained laminar, even after stent placement. However, disturbances were found downstream from a stent placed in the proximal LAD under mild exercise conditions. These disturbances were found 5 mm distal to the stent, in both the LAD and the proximal LCX. Turbulence intensities of order 5% were induced by a single slotted stent in a normal LAD geometry. In cases of distal disease, the turbulence intensity was 9% with one stent and 11% with tandem stents. In cases of proximal disease, these values were 19 and 25%, respectively. The shear stress from these disturbances (20-200 dynes cm-2) is sufficient to delay re-endothelialization and promote restenosis. Therefore, the disturbances could contribute to the increased incidence of restenosis reported with multiple stents, and with stents used in cases of diffuse coronary disease. PMID- 7852439 TI - Stress analysis of bone modeling response to rat molar orthodontics. AB - The purpose of this project was to determine if alveolar bone modeling could be associated with altered mechanical environment. Finite element stress analysis of an orthodontically tipped rat molar periodontium was performed. The distributions of mechanical components within the periodontal ligament and cortical bone were compared to the well-documented bone formation and resorption patterns in the alveolus of the tooth. It was concluded that in orthodontically induced bone modeling activity, locations of osteogenesis uniquely coincided with increased tension within the periodontal ligament, while bone resorption areas could be associated with increases in other components (minimum principal and maximum shear stresses, strain energy density, and von Mises) within the bone itself. PMID- 7852440 TI - High frequency components of bone strain in dogs measured during various activities. AB - Rubin et al. [J. Biomechanics 23, 43-54 (1990)] proposed that high frequency bone strains in the 15-30 Hz range might have significant influence on the morphological adaptation of bone tissue. We sought to further their findings by determining the magnitude of high frequency strains during various activities. We measured strains in the forelimbs of dogs during walking, standing and with their limbs unweighted. As negative controls, we measured strains while the dogs were tranquilized and after sacrifice. Strains in the 15-30 Hz range were not significantly greater than controls for any activity except walking, in which they were less than 4% as large as in the 0-15 Hz range. The high frequency strains observed during walking seemed to occur prior to footfall, suggesting that they were not the result of foot strike. The biological significance of high frequency bone strains has yet to be determined, but may be less than originally proposed because of the relatively small magnitude of these strains. PMID- 7852441 TI - Peristaltic transport of a biofluid in a pipe of elliptic cross section. AB - Peristaltic transport of two fluids occupying the peripheral layer and the core in an elliptic tube is investigated in elliptic cylindrical co-ordinate system, under long wavelength and low Reynolds number approximations. The effect of peripheral-layer viscosity on the flow rate and the frictional force for a slightly elliptic tube is discussed. The limiting results for the one-fluid model are obtained for different eccentricities of the undisturbed tube cross sections with the same area. As a result of non-uniformity of the peristaltic wave, two different amplitude ratios are defined and the time-averaged flux and mechanical efficiency are studied for different eccentricities. It is observed that the time averaged flux is not affected significantly by the pressure drop when the eccentricity is large. For the peristaltic waves with same area variation, the pumping seems to improve with the eccentricity. PMID- 7852442 TI - An analytical model of intervertebral disc mechanics. AB - The intervertebral disc is a complex mechanical structure, and it is important to understand the loading of specific structures which might cause damage leading to failure or mechanical impairment. At present it is only possible to model such internal loadings owing to the extreme technical difficulties involved in experimental measurement. The simple analytical model described in this paper makes exact predictions of the loads carried by fibres and also their path within the annulus fibrosus, without pre-defining the fibre configuration. The disc is modelled as an axially symmetric structure comprising a fluid filled centre, retained by a thin, doubly curved, fibre-reinforced membrane under tensile stress. The annulus is taken to consist of two lamellae reinforced by oppositely oriented collagen fibres that are free to follow paths defined by one of two geometrical rules. The predictive power and possible uses of the model are illustrated using boundary conditions experimentally determined from a typical young disc. The model was used to calculate the shape of the membrane surface, fibre path, volume of disc, area of annulus, length of fibre bundle and tension at a point along length of fibre. Equatorial fibre angle could be approximately predicted (to about 5 degrees), since there was only a small range of valid solutions to the model. The predicted surface profiles, fibre loads and angles were found to be in reasonable agreement with published experimental studies. Two examples of how the static model might be used to calculate changes in disc morphology and loading are included to demonstrate how a wide range of experimental data and theoretical behavior might be incorporated. This analytical model is important since it enables exact solutions to be calculated for the forces acting at any point along a fibre, their paths and also the surface geometry, from a small number of physical measurements without the need to estimate the mechanical properties of individual areas of the disc. It facilitates the prediction of the behaviour of the disc under varying load by providing a framework that can be further developed using a wide range and combination of experimental conditions and theoretical relationships. PMID- 7852443 TI - A new method to determine trabecular bone elastic properties and loading using micromechanical finite-element models. AB - The apparent mechanical behavior of trabecular bone depends on properties at the tissue or trabecular level. Many investigators have attempted to determine trabecular tissue properties and loading. However, accuracy and applicability of all methods reported are limited. The small size of the trabeculae and a possible size effect are complicating factors when using traditional testing methods on single trabeculae. Other methods reported, using models that describe the trabecular structure, are of limited value because they consider bone as a repetitive structure in order to describe a reasonably large region of bone. The present study introduces a new finite-element method strategy that enables analysis of reasonably large regions of trabecular bone in full detail. The method uses three-dimensional serial reconstruction techniques to construct a large-scale FE model, by directly converting voxels to elements. A 5 mm cube of trabecular bone was modeled in this way, resulting in a FE model that consists of 296,679 elements. Special strategies were developed to solve the set of equations that results from the FE approach. Using this model in combination with experimental apparent data taken from the literature, the upper and lower boundaries for the tissue modulus were calculated to be 10.1 and 2.23 GPa, respectively. From the local stress and strain distributions it was concluded that the deformation mode of the trabeculae in the present cube was predominantly in bending. It was concluded that the method developed offers new perspectives for the study of trabecular bone. PMID- 7852444 TI - Mean sarcomere length-force relationship of rat muscle fibre bundles. AB - To study how sarcomere length inhomogeneities and the duration of activation affect sarcomere length-force characteristics of muscle, the mean sarcomere length-force relationship was determined for twitches and at 100 and 300 ms during tetanic activation for rat extensor digitorum longus and gastrocnemius medialis muscle fibre bundles. Mean sarcomere length is the mean length of all sarcomeres within the fibre, calculated by dividing fibre length by the number of sarcomeres in series in the fibre. The twitch mean sarcomere length-force relationship is shifted to larger sarcomere lengths (optimum mean sarcomere length = 2.69 microns) compared to the relationships determined at 100 or 300 ms of tetanic activation (optimum mean sarcomere length = 2.38 microns), which were the same. It is shown that the normalized Gordon et al. rationale results in a large overestimate of force (at most 68% of force at a sarcomere length of 1.60 microns) for mean sarcomere lengths between 1.4 and 2.0 microns, and in an underestimate of force between 2.3 and 3.0 microns. It is concluded that modelling skeletal mammalian muscle length-force relationships can be improved by using mean sarcomere length-force relations of mammalian fibres instead of the normalized rationale of Gordon et al. derived from a selected homogeneous part of frog fibre. PMID- 7852445 TI - Optimal control for an above-knee prosthesis with two degrees of freedom. AB - Our previous research and clinical tests of a self-contained powered above-knee prosthesis (AKP) showed that a knee joint with one degree of freedom (DOF) increases the energy cost of walking with respect to able-bodied subjects. Better symmetry of the gait can improve performance, so we suggest here the integration of a second powered DOF into the knee joint mechanism to control the internal external rotation of the shank-foot complex. The control for the AKP with two DOFs is based on a method of optimal tracking. The data used for analysis were collected in able-bodied subjects braced with an ankle splint to experimentally duplicate a gait like that of amputees using a two-DOF prosthesis. The simulation showed the following: (1) the technique of optimal programming can be used for simulation of the artificial leg during locomotion; (2) the optimal tracking method is an efficient tool for selection of actuators for the above-knee prosthesis, ensuring that the tracking remains within limits. Limitation of joint torque is desirable in order to reduce the size of the motor, but beyond a certain point limiting maximal torques lead to tracking errors that are associated with higher energy costs and hence the need for a larger power source. The errors are also associated with higher forces at the interface between the socket and the prosthesis. The optimal tracking method allows the optimization of tracking with constraints on the size of the motor used and its energy cost. PMID- 7852446 TI - Wave characteristics of butterfly swimming. AB - In this study it was hypothesized that elite butterfly performance is characterized by wave motions with particular frequency, amplitude, and phase characteristics. Particular emphasis was accorded the question of whether 'waves' travel along the body during the butterfly stroke. Selected body landmarks and the center of mass (CM) of eight elite males and eight elite female swimmers were quantified. Fourier analysis was conducted to determine the frequency, amplitude, and phase characteristics of the vertical undulations of the vertex of the head, shoulders, hips, knees, and ankles. The differences in phase between these landmarks for the first (H1) and second (H2) Fourier frequencies were investigated to establish whether waves travelled along the body in a caudal direction. The absolute average velocity of H1 wave travel from vertex to ankle was found to be a mean of 0.34 ms-1 faster than the forward velocity of the CM for the male swimmers and 0.17 m s-1 faster for the female swimmers. There was a very strong relationship (p < 0.01) between velocity of H1 wave travel and CM velocity. There was no evidence to suggest that elite swimmers timed their actions to minimise vertical CM displacement to reduce mechanical work. In fact, the phase relationships among adjacent segments suggested that energy gained by raising the CM was transmitted caudally and contributed to a propulsive 'whip like' action. PMID- 7852447 TI - Factors affecting sensitivity of a transducer for measuring anterior cruciate ligament force. AB - In order to determine the measurements and calibration methods necessary to accurately measure in vivo forces in the anterior cruciate ligament (ACL) of the goat, an in vitro study was conducted to evaluate the effect of several factors that could influence the sensitivity of a transducer implanted within the ligament. Four factors were studied in six specimens: flexion angle [0 degrees, 10 degrees, 30 degrees, 50 degrees, and 70 degrees from full extension (FFE)]; tibial rotation (0 degrees and 10 degrees of internal rotation at 30 degrees, 50 degrees, and 70 degrees flexion FFE); loading rate (cycling frequencies of 0.2, 0.5, 1.0, and 2.0 Hz); and temperature (22 degrees C and 37 degrees C). Anteroposterior tibial displacements were applied to the specimens following tissue resection to isolate the ACL. The resultant ACL force magnitude was measured with a multi-component load cell, and transducer sensitivity was calculated as the slope of the output vs force curve in the linear response region. Transducer sensitivity varied with joint position in each specimen, but there was no consistent trend from specimen to specimen in how the sensitivity changed. As a result, there were no statistically significant mean differences (p > 0.05). There were no significant differences and little variation in sensitivity due to changes in either loading rate or tissue temperature, although the latter produced a voltage offset. The results show that the transducer output with zero force on the ligament must be determined in vivo, after which in vitro calibrations may be conducted at room temperature.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7852448 TI - The 1994 presidential address. Accepting the challenge. PMID- 7852449 TI - The 1994 Lindberg Award. The production of tumor necrosis factor, interleukin-1, interleukin-6, and prostaglandin E2 by isolated enterocytes and gut macrophages: effect of lipopolysaccharide and thermal injury. AB - Increasing evidence shows that cells other than immune cells have the potential for producing cytokines and arachidonate metabolites. It was the purpose of this study to determine whether isolated enterocytes could produce tumor necrosis factor, interleukin-1, interleukin-6, and prostaglandin E2, to compare the production with that of isolated gut macrophages, and to determine whether a difference existed in the production of these mediators after thermal injury. Guinea pigs received a 30% total body surface area burn and were killed 24 hours after injury. Isolated enterocytes and related intestinal macrophages (5 x 10(5) cells/ml) were cultured for 24 hours in the presence and absence of endotoxin, and the supernatants were assayed for the mediators. An increase was seen in production of interleukin-6 by enterocytes and by macrophages after thermal injury. In general enterocytes and gut macrophages produced about the same amounts of the different mediators. In contrast to macrophages from other tissues, enterocytes did not produce more prostaglandin E2 after stimulation with lipopolysaccharide, and with one exception gut macrophages did not produce larger amounts of mediators after stimulation with lipopolysaccharide. Enterocytes may be a significant source of immunomediator production and could contribute to the inflammatory response. PMID- 7852450 TI - The 1994 Moyer Award. Growth and differentiation of normal human keratinocytes in culture: modulation of gelsolin expression. PMID- 7852451 TI - The 1994 Clinical Research Award. A prospective clinical study of the polysomnographic stages of sleep after burn injury. AB - Although subjective evidence suggests that patients with burns are deprived of sleep, previous clinical studies have been limited to observational data and have not to date included electroencephalographic or polysomnographic recordings. The purpose of this study was to characterize the sleep pattern of patients suffering from thermal injury. Biweekly 24-hour polysomnographic measurements (electromyography, electrooculography, and electroencephalography) were performed with 12 leads. This measuring permitted continuous recording of intrinsic electrical activity in skeletal muscles via chin electrodes, eye movement via outer canthal electrodes, and brain wave activity with the other bipolar electrodes. Determinations were obtained on 11 patients with thermal injuries for a total of 43 24-hour periods. The patients had a mean age of 8.31 +/- 1.5 years (range 1.4 to 16 years), a mean total body surface area burn of 55.1% +/- 16.5% (range 17.5% to 90.5%), and a mean full-thickness burn of 48.5% +/- 8.1% (range 10.5% to 90.5%). Although mean total sleep time was seemingly adequate (625.1 +/- 31.6 min/patient/24 hrs), large aberrations in sleep stage distribution were noted. Significant decreases in stage 3 + 4 and in rapid eye movement (deep sleep) and increases in stages 1 and 2 (light sleep) were noted, suggesting a cycling back to stages 1 or 2 after disruption of sleep. Overall, in 43 runs 40% of the subjects were completely lacking stage 3 + 4, and 19% were missing rapid eye movement during an entire 24-hour run.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7852453 TI - The interrelationships between wound management, thermal stress, energy metabolism, and temperature profiles of patients with burns. AB - This prospective randomized study was performed to evaluate the metabolic and thermal responsiveness of patients with burns to thermal stress with three protocols of wound care: group I (n = 7) treated with dressings and variable ambient temperature selected for patients subjective comfort; group II (n = 7) treated without dressings and variable ambient temperature for patient comfort; group III (n = 6) treated without dressings and ambient temperature of 25 degrees C, electromagnetic heaters were set to achieve patient subjective comfort; and group IV (n = 6) healthy volunteers. After baseline partitional calorimetry was performed, individual patients were cold-challenged while subjectively comfortable by sequentially lowering either the ambient temperature or the output from the electromagnetic heaters. Heat balance and temperatures were obtained after each perturbation in external energy support. For patients in groups I and II, subjective perception of thermal comfort (warm, neutral, neutral and fed, cool, or cold) was more strongly correlated (p < 0.02) with the changes in the rate of heat production than the actual ambient temperature. For patients treated with electromagnetic heaters, changes in heat production were most strongly correlated with the energy output from the electromagnetic heaters. Even though the environmental conditions required to achieve a particular level of comfort are quite different between treatment groups, the difference in temperature between the patient's surface and ambient is approximately the same for groups I, II, and IV for each subjective state.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7852452 TI - Burn injury enhances alveolar macrophage endotoxin sensitivity. AB - Systemic activation of inflammatory cascades has been implicated in the pathogenesis of the multiple organ dysfunction syndrome. To begin to determine whether dysregulation of macrophage cytokine expression after burn plays a role in organ failure, we examined tumor necrosis factor alpha bioactivity of liver and lung macrophages under two conditions: (1) at 1, 3, 5, and 7 days after 40% scald burn, and (2) after sequential insult consisting of 40% scald burn followed by in vitro incubation with endotoxin. Burn alone did not significantly alter alveolar macrophage or Kupffer cell tumor necrosis factor alpha bioactivity at any of the timepoints examined. Sequential insult did not result in significant changes in Kupffer cell tumor necrosis factor alpha, but tumor necrosis factor alpha was increased 11.1 times in alveolar macrophages harvested on postburn day 3. Therefore macrophage cytokine responses to thermal injury are apparently both tissue-specific and time-dependent. PMID- 7852454 TI - Dehydroepiandrosterone fails to improve immunoglobulin synthesis and lymphocyte mitogenic response after burn injury. AB - Dehydroepiandrosterone has been proposed as a means of restoring immune function after injury. In this study we examined the effect of dehydroepiandrosterone on the impaired immunoglobulin M synthesis and depressed lymphocyte mitogenic responses observed after burn injury. We divided BALB/c mice (n = 28) into four equal groups that received either a 25% total body surface area dorsal steam burn or a sham procedure. One hour later we injected mice subcutaneously either with 100 micrograms dehydroepiandrosterone or vehicle alone. Five days later we isolated splenocytes for assessment of immune function. We stimulated splenocytes with lipopolysaccharide and 5 days later measured immunoglobulin M synthesis specific for peptidoglycan polysaccharide, a ubiquitous bacterial antigen. We stimulated additional cultures with lipopolysaccharide or concanavalin A to measure B- or T-lymphocyte mitogenic response. Burn injury impaired peptidoglycan polysaccharide-specific immunoglobulin M synthesis compared with sham (p < 0.05), and this impairment was not restored by the administration of dehydroepiandrosterone (p < 0.05). Furthermore dehydroepiandrosterone did not correct the burn-induced impairments of B- and T-cell mitogenic responses (p < 0.05). Our study demonstrates that in this model the administration of dehydroepiandrosterone in vivo does not correct the impairments of humoral or cellular immunity induced by burn injury. PMID- 7852455 TI - Midazolam infusion in pediatric patients with burns who are undergoing mechanical ventilation. AB - Adequate sedation is an integral component of mechanical ventilation. To document the safety and efficacy of midazolam infusion in pediatric patients with burns who were undergoing mechanical ventilation, a retrospective review was done of all patients requiring mechanical ventilation over a 22-month period. Twenty-four acutely burned pediatric patients required mechanical ventilation. The average age was 6.4 years (range 7 months to 12 years), and the average burn size was 50% of the body surface (range 40% to 95%). Midazolam infusion was initiated at an average dose of 0.045 mg/kg/hr (range 0.01 to 0.09 mg/kg/hr). The maximum dose administered averaged 0.11 mg/kg/hr (range 0.04 to 0.35 mg/kg/hr). The duration of infusion averaged 16.5 days (range 4 to 56 days). All patients received simultaneous infusions of morphine sulfate. Midazolam infusion was titrated to achieve a diminished narcotic requirement, decreased anxiety, and better tolerance of dressing changes. No hypotension or problems weaning from mechanical ventilation were seen. Two (8.3%) children experienced reversible neurologic abnormalities attributed to midazolam infusion but made full neurologic recoveries. In conclusion, our experience with midazolam infusion in pediatric patients with burns who were undergoing mechanical ventilation is favorable and supports its continued use. PMID- 7852456 TI - Evaluation of traditional African medicine "Compound R" for the treatment of thermal burn wounds in fuzzy rats. AB - The efficacy of an oil-in-water emulsion of a traditional Kenyan medicine, Compound R, on thermal burn wounds in fuzzy rats is reported. The burn wounds were inflicted on the depilated skin of rats with a 2 cm diameter aluminum template heated at 65 degrees C. Mean +/- SD days to healing (complete closure) were 9.9 +/- 2.2 (range 7 to 14 days) and 13.3 +/- 2.4 (range 10 to 16 days) for the treated and control (untreated) wounds, respectively (paired Student's t test, t value -5.667, p = 0.0003). Preliminary microbiologic results showed no activity of Compound R against some of the commonly encountered pathogens in burn wounds. Compound R appears to decrease the days to burn wound healing in fuzzy rats. This study provides preliminary data for further investigations of Compound R in managing burn wounds. PMID- 7852457 TI - Management of a burn sustained as a result of contact with 2400 degrees F molten metal. AB - A case of burns of the right leg caused by immersion in molten metal at 2400 degrees F is presented. Management by standard excision and grafting yielded a good result. The importance of protective garments is stressed. PMID- 7852458 TI - Spinal cord injury in a boy with normal radiologic findings. PMID- 7852459 TI - Current understanding of autoimmune disease. PMID- 7852460 TI - Recurrent infection in a patient with chronic neutropenia. PMID- 7852461 TI - Nutritional advice and exercise. PMID- 7852462 TI - So what happened to the patient? PMID- 7852463 TI - A simplified approach to urinary tract infection. AB - Recent changes in management have focused on reducing cost by abbreviating both the diagnostic workup and duration of treatment. Patients without a clinically obvious complicated UTI usually receive a short course of empiric therapy. Attention is also given to predisposing behaviors, such as urine retention, use of barrier contraception, inadequate fluid intake, and poor hygiene. PMID- 7852465 TI - Case in point. Trichuriasis. PMID- 7852464 TI - Weakness and dyspnea in a man with hemolytic anemia. PMID- 7852466 TI - Management of the poststroke patient. AB - Most patients survive the acute episode, their subsequent life affected by some degree of functional deficit. The classic neurologic findings are well known. Their implications for decisions on rehabilitation, long-term care, and prevention of complications are perhaps less well appreciated. PMID- 7852467 TI - The computer start-up: mostly a matter of faith. PMID- 7852468 TI - Focus on the somatoform disorders. PMID- 7852469 TI - A ring-enhancing parietal lobe lesion in an HIV-positive man. PMID- 7852470 TI - The diverse spectrum of irritable bowel syndrome. AB - The cardinal symptoms of IBS are abdominal pain and either diarrhea or constipation. Two cases with very different presentations illustrate a simplified diagnostic workup and provide practical suggestions for management. Patients can expect substantial benefits from treatment, provided they are willing to participate in its execution. PMID- 7852471 TI - When is a word a word? AB - Although adult-based words co-occur in the period of transition to speech with a variety of non-word vocalizations, little attention has been given to the formidable problem of identifying these earliest words. This paper specifies explicit, maximally 'inclusive' identification procedures, with criteria based on both phonetic and contextual parameters. A formal system for evaluating phonetic match is suggested, as well as a set of child-derived functional categories reflecting use in context. Analysis of word use across two samples of 10 children each, followed from 0;9 to 1;4, provides evidence to suggest that context-bound words can be 'trained' by focusing on eliciting language, but that the timing of context-flexible word use remains independent of such training. PMID- 7852472 TI - Object transfer, intersubjectivity and third position repair: early developmental observations of one child. AB - Interaction sequences are explored which are initiated by either child requests or adult offers of objects. The focus is on those sequences in which the child does not want an object that is passed to her, and on how the child manages such an interactional contingency. Throughout the age range in question, 1;0 to 1;8, the child uses re-requests where this contingency occurs in request sequences. The analysis traces the development of these re-requests and compares them with other forms of re-request. In addition, differences are uncovered as between request and offer sequences concerning the child's ways of dealing with an unwanted object that is passed to her. Linkages are made between these themes and work on third position repair within conversation analysis. Home based video recordings of one child between the ages of 1;0 and 1;8 constitute the data base for the study. PMID- 7852473 TI - A metrical template account of children's weak syllable omissions from multisyllabic words. AB - Young children learning English as well as many other languages frequently omit weakly stressed syllables from multisyllabic words. In particular, they are more likely to omit weak syllables from word-initial positions than from word-internal or -final positions. For example, the weak syllable of a weak-strong (WS) word like giraffe is much more likely to be omitted than the weak syllable of a SW word like tiger. Three hypotheses for this omission pattern have been offered. In two, children's weak syllable omissions reflect innate perceptual biases either to ignore initial weak syllables or to encode word-final syllables. In contrast, the SW Production Template Hypothesis states that children have a template for producing a strong syllable followed by an optional weak syllable. When they apply a series of SW templates to their intended utterances, weak syllables that do not fit the templates are more likely to be omitted than those that do. To compare the three hypotheses, young two-year-olds were asked to say four-syllable SWWS and WSWS nonsense words. Children's pattern of weak syllable preservations was highly consistent with the SW production template hypothesis, but not with the perception-based hypotheses. Implications of this research for children's function morpheme omissions and for the relation of metrical and segmental production templates are discussed. PMID- 7852474 TI - The development of segmental phonological production in a bilingual child. AB - A longitudinal diary-and-videotape study of the production of phonological segments by a Spanish-English bilingual child, age I; I-3; 9, revealed four stages in consonantal acquisition: presystematic variation, formation of a single system, separation into two systems corresponding to the two languages, and achievement of adult target values with later interference of one language in the other. Vocalic acquisition proceeded with widespread variation, followed by stabilization at target adult values, without any apparent intermediate unitary system stage. Relevance of the data adduced here to the issue of whether bilingual children first function with a single system before acquiring two discrete languages is discussed. The issue of what it may mean to have one or two systems of phonology is addressed. PMID- 7852475 TI - The unintelligibility of speech to children: effects of referent availability. AB - Speech addressed to children is supposed to be helpfully redundant, but redundant or predictable words addressed to adults tend to lose intelligibility. Word tokens extracted from the spontaneous speech of the parents of 12 children aged 1; 10 to 3; 0 and presented in isolation to adult listeners showed loss of intelligibility when the words were redundant because they had occurred in repetitions of an utterance (Experiment 1) or referred to an entity which was physically present when named (Experiment 2). Though children (N = 64; mean age 3; 5, S.D. 6.1 months) recognized fewer excerpted object names than adults (N = 40), less intelligible tokens appeared to induce child listeners to rely on the word's extra-linguistic context during the recognition process (Experiment 3), much as such tokens normally induce adults to rely on discourse context. It is proposed that interpreting parental utterances with reference to non-verbal context furthers linguistic development. PMID- 7852476 TI - Early grammatical and prosodic marking of utterance modality in French: a longitudinal case study. AB - The study investigates how basic communicative functions expressed by utterance modalities (declarative, exclamative, injunctive, interrogative) emerged in the early language of a French child, and examines whether and how morphosyntactic and prosodic devices were used to mark these contrasts. A longitudinal corpus of naturalistic productions was collected between the ages of 1; 2 and 1; 9, and 960 utterances were subjected to functional, prosodic and grammatical analyses. Declarative, exclamative and injunctive utterances were found from 1; 2, and first interrogatives appeared at 1; 6. Intonation contours varied as a function of utterance modality and were largely in accordance with the patterns in French: declaratives and exclamatives were falling, interrogatives rising and injunctives split between falling and rising contours depending on their specific functions. A quarter of the productions involved an elementary grammatical marking of utterance modality such as interjections, imperative or indicative verbal forms, or interrogative morphemes. These findings indicate an early and complementary use of prosodic and grammatical devices in the child's construction of the linguistic system. PMID- 7852477 TI - Addressee co-operation and request reformulation in young children. AB - The purpose of the present study was to show that children under age 3;0 are capable of reformulating requests in different ways depending on how their addressee responds to the request. This adaptive ability is considered to be an indication of the use of both communicative and conversational skills. Children from French-speaking families were observed at two developmental thresholds: the end of the prelinguistic period (1;6) and the start of the linguistic period (2;6). The verbal and nonverbal outputs of the two groups of 12 children (1;6 and 2;6) were compared in three object request situations: the adult immediately complies with the request (satisfaction), the adult asks a clarification question (clarification), and the adult refuses to comply with the request (refusal). The ways in which the children adapted to each situation were found to be similar at the two ages considered. In the clarification situation, vocal productions and their repairs were more numerous, whereas in the refusal situation, non reformulations and gazes to and from the requested object and addressee predominated. The discussion deals with the significance of these results in the development of communicative and conversational skills in children. PMID- 7852478 TI - A developmental study of the acquisition of colour terms in Setswana. AB - We report a study of the acquisition of colour terms by speakers of Setswana, the language of Botswana in Southern Africa. This was carried out as a test of Berlin & Kay's theory of colour term universals, on a language with less than the maximum complement of eleven basic colour terms, and in order to document changes in Setswana under the impact of economic development. Seventy-seven five- to nine year-olds were studied on two colour tasks: elicited lists and colour naming. In general the data were consistent with Berlin & Kay's theory: the rank order of frequency of correct use of colour terms was similar to the order of the Berlin & Kay hierarchy; and primary colour terms were offered more frequently and were more likely to be used correctly than secondary colour terms. The use of English colour terms was prevalent, especially amongst the younger groups, but they functioned as substitutes for Setswana terms, rather than as a means to fill the vacant basic colour term slots. PMID- 7852479 TI - The development of infinitives from three to five. AB - This study investigated the form of infinitival sentences produced by young children and their knowledge of the control properties of this sentence form. Twenty-five children between the ages of 3;7 and 5;4 participated in a story completion task designed to elicit infinitive sentences and in an act-out comprehension task. Although the infinitive form was productive for even the youngest children in this study, development of this form was not complete even for the five-year-olds, nor did any child demonstrate adult knowledge of control. In addition, two competing claims regarding order of acquisition (that of Limber, 1973, and Hyams, 1985) were evaluated. PMID- 7852480 TI - Children's songs to infant siblings: parallels with speech. AB - Children aged 2;11 to 8;3 sang informally, once in the presence of their infant sibling and once when the infant was out of view. Paired excerpts from 22 children were presented to adult listeners, who were required to identify the infant-directed excerpt in each pair. Listeners' accuracy was above chance levels but below what would be expected for mothers' singing in comparable contexts. Children altered their singing style in the infant's presence by singing at a higher pitch level and with a different vocal quality. PMID- 7852481 TI - Factors that influence the determination of residual solvents in pharmaceuticals by automated static headspace sampling coupled to capillary GC-MS. AB - The impact of several experimental parameters on static headspace sampling for volatile impurities is discussed. Figures of merit are provided for some common organic solvents dissolved in dimethylacetamide. The performance is compound specific, but in the best case, detectability is about 0.2 mg/L with the mass spectrometer operating in the scanning mode. Sensitivity improves by about a factor of 50 when single ion monitoring is used. Linearity extends for about 4 orders of magnitude. This system is used to determine acetone as a residual solvent in the sulfonamide antibiotic, sulfamethazine, at levels of 1 to 15 mg/kg with precision of 3 to 5%. PMID- 7852482 TI - P53 protein accumulates in Cushings adenomas and invasive non-functional adenomas. AB - The p53 protein, a negative regulator of cell growth, plays an important role in the pathogenesis of many human tumours following gene mutation and/or deletion. We screened a large number of sporadic pituitary tumours for p53 protein accumulation suggestive of gene mutation. Samples were divided into benign adenomas (n = 95) and invasive tumours with local or distant invasion (n = 26). All main tumour classes were represented. Putative p53 mutations were detected by immunohistochemistry on paraffin-embedded sections using polyclonal CM-1 and monoclonal DO-7 and PAb1801 antibodies. Results were compared to normal post mortem pituitary tissue controls (n = 17). p53 protein accumulation was detected in invasive tumours (16%), but only in corticotrophinomas (2/4) and non functional tumours (4/15). In non-invasive adenomas, protein accumulation was observed only in ACTH-secreting tumours where 50% were positive (16/32). No protein accumulation was identified in any control tissue. These results indicate that p53 protein accumulation may play a role in the development of Cushings adenomas and in the progression of non-functional tumours to the invasive state. PMID- 7852483 TI - Clinical review 66: Thyroxine suppression therapy for benign nodular disease. PMID- 7852484 TI - Extensive personal experience: Paget's disease of bone. PMID- 7852485 TI - Therapeutic controversies. Radioiodine therapy does not aggravate Graves' ophthalmopathy. PMID- 7852486 TI - Therapeutic controversies. Radioiodine may be bad for Graves' ophthalmopathy, but.... PMID- 7852487 TI - Therapeutic controversies. Retrobulbar radiation in Graves' ophthalmopathy. PMID- 7852488 TI - Therapeutic controversies. Summation, commentary, and overview: concerns over aggravation of Graves' ophthalmopathy by radioactive iodine treatment and the use of retrobulbar radiation therapy. PMID- 7852489 TI - Pathogenic role of asialo human chorionic gonadotropin in gestational thyrotoxicosis. AB - We reported that gestational thyrotoxicosis is induced by thyroid-stimulating activity (TSA) of circulating hCG. However, the serum immunological hCG concentration did not correlate to TSA. To elucidate this, we examined the relation of carbohydrate moieties of hCG to bioactivity in 79 early pregnant women, divided into 4 groups: no emesis, mild emesis, hyperemesis, and gestational thyrotoxicosis with hyperemesis. Serum free T4 (FT4) and free T3 (FT3) levels were significantly higher and TSH was lower in the hyperemesis (FT4, 23.42 +/- 5.02 pmol/L; FT3, 6.26 +/- 1.80 pmol/L; TSH, 0.30 +/- 0.44 mU/L) and in gestational thyrotoxicosis (FT4, 48.65 +/- 14.80 pmol/L; FT3, 14.71 +/- 3.47 pmol/L; TSH, < 0.04 mU/L) groups than in the no emesis group (FT4, 16.99 +/- 2.48 pmol/L; FT3, 5.51 +/- 0.75 pmol/L; TSH, 1.37 +/- 1.23 mU/L; P < 0.0005). TSA was also significantly higher in the hyperemesis (566 +/- 187%) and gestational thyrotoxicosis (832 +/- 168%) groups than in the no emesis group (321 +/- 135%). We found no significant difference among serum hCG concentrations measured by immunoassay in the four groups. To characterize the carbohydrate chains, serum hCG was fractionated by Concanavalin-A and ricin lectin affinity chromatography. The fraction firmly bound to Con-canavalin-A, which contains hCG with high mannose and hybrid-type carbohydrate chains, was significantly higher in the hyperemesis group (91.07 +/- 2.06%; n = 15) than in the no emesis group (89.61 +/ 2.38%; n = 24; P < 0.04). The fraction firmly bound to ricin column, which contains hCG with asialo-carbohydrate chains, was significantly increased in the gestational thyrotoxicosis group (3.44 +/- 1.70%; n = 5) compared with that in the no emesis group (1.77 +/- 0.49%; n = 24; P < 0.03). Serum FT4 positively correlated to the hCG fraction firmly bound to ricin column (r = 0.61; P < 0.001). We conclude that thyrotoxicosis with hyperemesis may be caused by circulating asialo-hCG with higher thyrotropic bioactivity. PMID- 7852490 TI - The effects of short and long-term growth hormone replacement therapy in hypopituitary adults on lipid metabolism and carbohydrate tolerance. AB - The effects of replacement with biosynthetic human GH on carbohydrate tolerance and lipid metabolism were studied in 40 hypopituitary adults during a randomized double blind, placebo-controlled trial for 6 months, followed by a 12-month open trial. The daily GH dose was 0.04 +/- 0.01 IU/kg. Fasting plasma glucose, serum fructosamine, plasmid lipids, lipoproteins, and plasma C-peptide concentrations were measured, and an oral glucose tolerance test was performed every 6 months. There was no change in fasting triglyceride levels at any stage of the study. There was no significant change in fasting total or LDL cholesterol, total HDL cholesterol, high density lipoprotein2 (HDL2) cholesterol, HDL3 cholesterol, apoprotein-A1, or apoprotein-B during GH or placebo treatment in the placebo controlled 6-months study. In the open phase of the trial, total and low density lipoprotein cholesterol showed a sustained downward trend during GH therapy. Compared to the pretreatment level, the HDL cholesterol concentration was significantly higher at 18 months. Cholesterol subfractions HDL2 and HDL3 and apoprotein-A1 and -B were not different from the pretreatment levels. The total/HDL cholesterol ratio decreased significantly at 12 and 18 months. During the controlled phase, fasting plasma glucose was similar during GH and placebo administration, but fasting insulin and C-peptide increased during GH therapy, but not during placebo treatment. The mean area under the curve (AUC) for glucose increased by a small, but significant, extent over the 6 months of GH treatment and was higher at 6 months than during placebo treatment. The AUC for insulin also increased during GH treatment. During the open trial, the fasting plasma glucose level increased at 6 and 12 months, and the fasting plasma insulin level increased at 6, 12, and 18 months of GH treatment. The plasma glucose AUC during the oral glucose tolerance test was significantly higher at 6 months, and the plasma insulin AUC was significantly higher at 6, 12, and 18 months of GH therapy. In conclusion, GH therapy has some metabolic effects that are considered beneficial and others that are less desirable. PMID- 7852492 TI - Properties of a progesterone-induced relaxation in human placental arteries and veins. AB - To study the effects of progesterone on placental vascular tone, we used isolated (1-2 mm in diameter) placental arteries and veins from term uncomplicated pregnancies. These vessels, incubated in Krebs buffer (pH 7.4) under 5% O2-5% CO2 (balance N2, PO2 approximately 35 torr) and precontracted with serotonin were exposed to incremental doses of progesterone (0.01-30 mumol/L) in the presence or absence of endothelium, 10 mumol/L indomethacin (inhibits prostaglandin synthesis), 10 mumol/L methylene blue (a soluble guanylate cyclase inhibitor), 100 mumol/L nitro-L-arginine (inhibits L-arginine metabolism), 1 mmol/L isobutylmethylxanthine (a cAMP phosphodiesterase inhibitor), or 30 mumol/L mifepristone (RU 38486, an antiprogestin). Progesterone elicited an acute dose dependent relaxation in both arteries and veins that was not altered by removal of the endothelium or pretreatment with indomethacin, nitro-L-arginine, or methylene blue, excluding a role for prostaglandins, L-arginine products, or cGMP in mediating this relaxation. However, isobutylmethylxanthine significantly enhanced the relaxation in response to progesterone, suggesting a role for cAMP. RU 38486 inhibited the relaxation by 50-100%, depending on the progesterone dose, consistent with a role for progesterone receptors. These results suggest that progesterone causes a dose-dependent endothelium-independent relaxation of human placental arteries and veins. This relaxation seems to be mediated by a receptor activated cAMP mechanism and could be physiologically important in maintaining low resistance and adequate blood flow in the placental circulation. PMID- 7852491 TI - Postgastroplasty recovery of ideal body weight normalizes glucose and insulin metabolism in obese women. AB - To study the metabolic effects of normalizing body weight, a frequently sampled iv glucose tolerance test (0.3 g/kg) was performed before [body mass index (BMI), 37.7 +/- 0.5 kg/m2] and 14 +/- 2 months after successful gastroplasty (BMI, 23.7 +/- 0.6 kg/m2) in eight obese women and, for comparison, in eight age- and weight matched nonobese control women (BMI, 23.6 +/- 0.7 kg/m2). All subjects had normal oral glucose tolerance. The insulin secretion rate (ISR) was derived by deconvolution of plasma C-peptide levels and the insulin MCR (MCRI) by dividing the 0-180 min area under the curve (AUC) of ISR by that of plasma insulin levels (IRI). The insulin sensitivity index (SI) and the glucose effectiveness index (SG) were calculated using Bergman's minimal model. Before gastroplasty, obese subjects showed higher AUC-IRI (P < 0.001) and AUC-ISR (P < 0.02), lower MCRI (P < 0.005) and SI (P < 0.002), but similar SG values, compared to nonobese controls. After gastroplasty, the AUC-IRI dramatically decreased, due to both a reduction of AUC-ISR (from 58,252 +/- 8,437 to 36,675 +/- 4,274 pmol; P < 0.05) and an increase in MCRI (from 658 +/- 117 to 1,299 +/- 127 mL/min.m-2; P < 0.02). SI significantly rose from 4.74 +/- 0.74 to 9.15 +/- 0.96 10(-5) min-1/pmol.L (P < 0.01), whereas SG remained unchanged. All of these parameters became similar to those in nonobese controls (respectively, 32,522 +/- 3,458, 1,180 +/- 101, and 8.48 +/- 1.25; all P = NS). In conclusion, after gastroplasty-induced normalization of body weight, postobese women recover normal insulin secretion, clearance, and action on glucose metabolism. PMID- 7852493 TI - Replacement of growth hormone (GH) in normally growing GH-deficient patients operated for craniopharyngioma. AB - Removal of a craniopharyngioma usually results in panhypopituitarism. Some children, however, grow normally or even excessively after extirpation of the tumor despite a proven lack of GH and have so far not been treated with hGH. We studied the effects of short (2-day) and long term (1-yr) administration of hGH on metabolism and growth in six patients receiving regular hormonal replacement therapy. During short term human (h) GH treatment, 15N retention was not significantly increased (mean +/- SEM, 115.4 +/- 9.6% of basal balance) and was not different from the control value. In contrast, 15N retention was 210.3 +/- 20.7% in children with GH deficiency from other causes. Long term administration of hGH (2 IU/m2.day, sc, for 12 months) did not influence growth velocity, but increased the calf circumference and decreased the body mass index and skinfold thickness in prepubertal patients. Insulin-like growth factor-I (IGF-I), IGF binding protein-3 (IGFBP-3), and the 150-kilodalton IGFBP complex were decreased before and restored to normal during treatment. The reverse was observed for the 50-kilodalton IGFBP complex. Growth (velocity) in these patients did not correlate with any of the usual indicators of the growth status and remains unexplained. Although hGH did not affect growth, it had other beneficial effects and is recommended for these patients. PMID- 7852494 TI - Hyperinsulinemic hypoglycemia of infancy (nesidioblastosis) in clinical remission: high incidence of diabetes mellitus and persistent beta-cell dysfunction at long-term follow-up. AB - In persistent hyperinsulinemic hypoglycemia of infancy (PHHI), the long term outcome of the disease is not well documented. Previous reports suggested that partial pancreatectomy in infants does not endanger future islet function. We evaluated endocrine pancreatic function in 14 PHHI patients 6.5-21 yr after diagnosis. Eight underwent early subtotal pancreatectomy, and 6 were medically treated; all were in clinical remission. Intravenous glucose tolerance and C peptide suppression tests were performed, with multiple determinations of hormone levels. The insulin response to glucose was blunted in all pancreatectomized and in 2 conservatively treated patients. Glucose disposal was reduced in 6 pancreatectomized patients and in 2 medically treated subjects. Six of the pancreatectomized patients, including two with normal glucose disposal at first evaluation, developed overt diabetes during puberty. None in the medically treated group became diabetic; however, only 2 patients have reached puberty. C Peptide suppression in response to hypoglycemia was inadequate in 4 of 5 pancreatectomized and 3 of 5 nonpancreatectomized patients studied. These results show that children with PHHI have impaired insulin responses to glucose and lack of suppressibility of endogenous insulin secretion several years after clinical remission. Thus, the beta-cell defect responsible for the disease in infancy is not corrected with time despite the disappearance of spontaneous hypoglycemia. Insulin secretion seems more disturbed in pancreatectomized patients; the majority develop insulin-requiring diabetes during puberty. An effort should be made to treat PHHI patients medically to avoid pancreatectomy; this may reduce the incidence of diabetes at puberty. PMID- 7852495 TI - Modified glucagon test allowing simultaneous estimation of insulin secretion and insulin sensitivity: application to obesity, insulin-dependent diabetes mellitus, and noninsulin-dependent diabetes mellitus. AB - The aim of this study was to describe an adaptation of the glucagon test allowing the simultaneous characterization of insulin secretion and sensitivity. A glucagon test (1 mg/m2) was performed in healthy subjects (n = 11), obese patients (n = 5), insulin-dependent diabetics (n = 9), nonobese noninsulin dependent diabetics (n = 7), and overweight noninsulin-dependent diabetics (n = 8). Previously, they had been connected to the Biostator, modified for continuous blood collection. Endogenous insulin secretion induced by glucagon was derived from integrated C-peptide concentrations. An index of insulin sensitivity was obtained by dividing the rate of decrease in blood glucose by the total amount of insulin entering the circulation (secreted+infused by the Biostator). The indices of insulin sensitivity obtained in the above groups of subjects were, respectively, 0.064 +/- 0.006, 0.030 +/- 0.006, 0.037 +/- 0.007, 0.021 +/- 0.006, and 0.016 +/- 0.002 mmol/L.U.min (P < 0.001). The estimated insulin secretion values in the 20 min following glucagon injection were, respectively, 0.38 +/- 0.05, 0.65 +/- 0.08, 0.05 +/- 0.01, 0.26 +/- 0.15, and 0.30 +/- 0.07 U (P < 0.001). The insulin sensitivity index obtained from this test correlated with the glucose MCR obtained from a euglycemic glucose clamp (r = 0.816; P < 0.001; n = 12). C-Peptide levels after glucagon administration were also significantly correlated with the estimated endogenous insulin secretion (r = 0.808; P < 0.001; n = 30). This adaptation of the classical glucagon test is an efficient and simple method to simultaneously evaluate insulin secretion and insulin sensitivity. PMID- 7852496 TI - Adrenal androgen excess in women: lack of a role for 17-hydroxylase and 17,20 lyase dysregulation. AB - Some investigators have suggested that "dysregulation" of cytochrome P450c17 alpha may result in the exaggerated secretion of ovarian androgens in hyperandrogenism. Although the majority of hyperandrogenic (HA) patients demonstrate an ovarian source for their androgens, approximately 50% also display adrenocortical hyperactivity and adrenal androgen excess. To determine whether 17 hydroxylase (17-OH) and/or 17,20-lyase dysregulation is responsible for the adrenocortical abnormalities noted in many HA patients, we studied 92 consecutive women with hirsutism and/or HA oligomenorrhea; 26 healthy eumenorrheic nonhirsute women served as controls. The basal levels of total and free testosterone (T), sex hormone-binding globulin, and dehydroepiandrosterone sulfate were measured, and pregnenolone, 17-hydroxypregnenolone, progesterone, 17-hydroxyprogesterone, dehydroepiandrosterone, and androstenedione were measured 0 and 60 min after the acute iv administration of ACTH-(1-24). Controls and HA patients did not differ in mean age or body mass, but HA women had higher basal T, free T, dehydroepiandrosterone sulfate, androstenedione, and LH/FSH and lower sex hormone binding globulin levels. The mean estimated basal 17-OH activity was higher among HA patients than in controls. Although 52 HA patients demonstrated solely an exaggerated basal delta 5-17-OH activity estimate, few HA patients had an exaggerated estimate for either basal delta 4-17-OH or ACTH-stimulated 17-OH activity. No HA patient demonstrated an exaggerated 17,20-lyase basal activity, whereas 14 demonstrated an exaggerated delta 4-17,20-lyase ACTH-stimulated activity only. There was no association between these estimates of 17-OH and 17,20-lyase activities and the circulating adrenal androgen levels in HA women. Importantly, none of the patients demonstrated an increase in the basal activities of both 17-OH and 17,20-lyase, and only 4 patients demonstrated an exaggerated ACTH-stimulated activity of both 17-OH and 17,20-lyase. In conclusion, the steroidogenic profile observed in this population of HA women before and after ACTH-(1-24) stimulation is not consistent with dysregulation of cytochrome P450c17 alpha and probably represents a generalized alteration of adrenocortical control or biosynthesis. PMID- 7852497 TI - An investigation of sources of variation in calcium absorption efficiency. AB - To examine putative sources of interindividual variation in calcium absorption efficiency, we studied 41 healthy premenopausal women (mean age, 36.4 yr). About half were randomized to pretreatment with supplemental 25-hydroxyvitamin D (25OHD; 20 micrograms/day [corrected] for approximately 34 days) before testing. We measured dietary factors, humoral regulators, intestinal motility, mucosal histology, mucosal vitamin D receptor levels, and calcium absorption efficiency. In winter tests, but not in summer tests, calcium absorption fraction was significantly higher in the pretreated group (mean, 0.465 vs. 0.387). Serum 25OHD, intestinal transit, and urinary calcium to creatinine ratio were all significantly and positively correlated to calcium absorption efficiency. However, neither the level of 1,25-dihydroxyvitamin D receptors in duodenal mucosa nor circulating 1,25-dihydroxyvitamin D was related to calcium absorption efficiency. These findings, which are consistent with other published human data, suggest that 25OHD plays a more prominent role in the regulation of calcium absorption than is generally believed. In a multiple regression model, serum 25OHD, mouth to cecum transit time, and fasting urinary calcium/creatinine ratio explained 44% of the observed variation in calcium absorption efficiency. PMID- 7852498 TI - A comparison of the effects of human and ovine corticotropin-releasing hormone on the pituitary-adrenal axis. AB - To compare the clinical efficacy of ovine and human sequence corticotropin releasing hormone (CRH), we examined the effects of both peptides on ACTH and cortisol secretion in normal human volunteers, obese subjects, and patients with pituitary-dependent (Cushing's disease) and adrenal-dependent Cushing's syndrome. All subjects in each group were studied twice in random order. One hundred micrograms of CRH were administered as an iv bolus through an in-dwelling forearm cannula at 0930 h, and thereafter, blood was drawn every 15 min for 2 h for the measurement of ACTH and cortisol. In the normal subjects, the peak ACTH, peak incremental ACTH, and mean area under the curve after CRH treatment were greater with ovine CRH than human CRH, although there was no difference in the cortisol response, however it was analyzed. There was no difference in the ACTH or cortisol response to the two preparations in the obese subjects, and no significant difference was found, for either cortisol or ACTH, between obese subjects and normal volunteers. With both varieties of CRH, Cushing's disease resulted in greater responses for ACTH and cortisol than those seen in the other 2 groups (P < 0.001 for all comparisons), but there was no difference between the sequences. However, a significant cortisol response, defined as an increase of greater than 4 times the coefficient of variation of the assay (24%), was seen in all 10 Cushing's patients with human CRH, but in only 8 with ovine CRH. In 3 patients with adrenal tumors, serum cortisol did not change after the administration of either preparation, whereas plasma ACTH remained undetectable throughout the study. We suggest that although ovine sequence CRH causes more prolonged and greater ACTH, and possibly cortisol, secretion compared to human CRH, the discriminatory value of the CRH test, in terms of either the diagnosis or differential diagnosis of Cushing's syndrome, is comparable for the two peptide sequences. PMID- 7852499 TI - Identification and characterization of opioid-binding sites present in the Ishikawa human endometrial adenocarcinoma cell line. AB - Normal epithelial cells of human endometrium, and Ishikawa human endometrial adenocarcinoma cells (an in vitro model for the study of steroid hormone effects on human endometrium) have been found to express and secrete opioid peptides deriving from proenkephalin, prodynorphin, and proopiomelanocortin. These opioids may act locally, affecting the uterine tissues. In the present study, we identified and characterized opioid-binding sites on the Ishikawa cell line, producing evidence for the mechanism of local opioid action. We used an acid shock before the receptor assay to dissociate any endogenously bound peptide. The acidification improved specific binding by 2- to 4.5-fold. Characterization of opioid binding using different radiolabeled opioids and effectors has shown the existence of a low concentration of delta-sites (Kd, 6.20 nmol/L; 4,890 sites/cell), no mu-sites, low affinity kappa 1-sites (Kd, 10.8 nmol/L; 276,000 sites/cell), kappa 2-sites with high affinity for ethylketocyclazocine (Kd, approximately 1 nmol/L) and low affinity for diprenorphine (Kd, approximately 8 nmol/L) at a concentration of 93,000 sites/cell, and high affinity kappa 3-sites (Kd, 3.6 nmol/L; 77,000 sites/cell). In conclusion, our report characterizes opioid sites in a particular and homogeneous cell type of human endometrium, i.e. in epithelial cells. The coexistence of opioid sites and their endogenous ligands in the Ishikawa cell line makes these cells a good model for the study of autocrine/paracrine interactions of opioids in nonneural tissues. PMID- 7852500 TI - Amino acid substitution R384P in aldosterone synthase causes corticosterone methyloxidase type I deficiency. AB - Corticosterone methyloxidase type I (CMO-I) deficiency is an autosomal recessively inherited disorder causing congenital hypoaldosteronism due to defects in aldosterone synthase (P450aldo), the enzyme that converts 11 deoxycorticosterone to corticosterone, 18-hydroxycorticosterone, and aldosterone. To clarify the molecular basis of CMO-I deficiency and gain further insight into the structure-function relationship of P450aldo, we cloned and sequenced the CYP11B2 gene (encoding P450aldo) of a male Caucasian patient suffering from CMO-I deficiency and identified a single point mutation leading to substitution of the highly conserved arginine-384 by proline (R384P). Differential hybridization of mutation-specific oligonucleotide probes to polymerase chain reaction-amplified CYP11B2 fragments revealed that both parents were heterozygous carriers for R384P, whereas the patient appeared homozygous. The patient's healthy brother and 85 individuals without known aldosterone synthase deficiency did not carry the R384P mutation. Introduction of this mutation into a CYP11B2 complementary DNA expression vector construct and subsequent expression in COS cells revealed that R384P leads to complete loss of 11 beta- and 18-hydroxylase activities of P450aldo. Thus, the R384P mutation provides a molecular explanation for the CMO-I deficiency in this patient and suggests that arginine-384 plays a major role in P450aldo function. PMID- 7852501 TI - Gonadotropin-releasing hormone receptor gene expression in human ovary and granulosa-lutein cells. AB - GnRH regulates gonadotropin biosynthesis and release in the anterior pituitary via specific receptors. Although extrapituitary expression and action of GnRH have been shown in some species, in the human it is not clear whether GnRH has a peripheral action. In this study we sought to determine whether the human ovary expresses GnRH receptor (GnRHR) messenger ribonucleic acid (mRNA). Ovarian tissues from 11 women (32-61 yr old) and granulosa-lutein (GL) cells purified from follicular aspirates of 51 women undergoing oocyte retrieval for in vitro fertilization were analyzed by ribonuclease protection assay and reverse transcriptase-polymerase chain reaction (RT-PCR). Human pituitaries, lymphocytes, and placenta were also studied. Measurable levels of GnRHR mRNA were found by ribonuclease protection assay in 2 of 10 ovaries, in 2 of 4 GL cells preparations from women whose ovarian hyperstimulation involved a GnRH agonist, in GL cells from 3 women whose ovarian hyperstimulation involved a GnRH antagonist, and in human pituitaries. Relative to the total amount of RNA analyzed, the level of GnRHR mRNA was about 200-fold lower in the ovary than in the pituitary. A sequence of 314 basepairs of GnRHR mRNA was amplified by RT-PCR in the pituitary, in 9 of 10 ovaries, and in 4 of 5 GL cell preparations. No message could be amplified in human lymphocytes, and placental specimens showed a weak signal. The relative GnRHR mRNA levels in GL cells from 13 women analyzed by quantitative RT PCR showed a wide range of individual differences. These results suggest that GnRHR mRNA is expressed in GL cells and the human ovary across different functional stages, implying that multiple ovarian compartments may express GnRH receptors. The administration of GnRH analogs may have a further direct action on the human ovary. PMID- 7852502 TI - Effects of aging on epinephrine secretion and regional release of epinephrine from the human heart. AB - In contrast to the sympathetic nervous system, which is activated by aging in at least some sympathetic nervous outflows, epinephrine release from the adrenal medulla appears to be either normal or low in the elderly. Using isotope dilution methodology, we studied the effect of aging on the secretion of epinephrine in 19 men, aged 20-30 yr, and 15 men, aged 60-75 yr. Measurements were made both at rest and during the application of laboratory stressors, as diminished adrenal medullary responsiveness possibly contributes to the impairment of some cardiovascular and metabolic responses to stress described previously in the elderly. Epinephrine secretion at rest was lower in the older men (mean +/- SEM, 0.86 +/- 0.10 nmol/min) than in the younger men (1.45 +/- 0.17 nmol/min; P < 0.05). Due to 20% lower plasma epinephrine clearance in the older men (P < 0.01), the reduction in the plasma concentration of epinephrine (0.37 +/- 0.03 vs. 0.52 +/- 0.06 nmol/L; P = 0.06) was proportionally less than that in epinephrine secretion. In the younger men, epinephrine secretion doubled or tripled during mental stress, isometric exercise, and dynamic exercise. Epinephrine responses to the stressors were reduced in older men, being equivalent to only 44% (P < 0.05), 44% (P = 0.1), and 33% (P = 0.01) of the corresponding responses in the younger men. After uptake from plasma, in some circumstances epinephrine is released from sympathetic nerves as a cotransmitter, where it can augment the release of the major sympathetic transmitter, norepinephrine. We also measured regional extraadrenal release of epinephrine from the heart to test whether the previously described increased release of norepinephrine from the cardiac sympathetic nerves with aging might result from facilitator effects of epinephrine released as a cotransmitter. At rest, epinephrine was released from the heart (9.4 +/- 2.6 pmol/min) in older men only (P < 0.01) despite the fact that adrenal medullary secretion of epinephrine was reduced. Failure of epinephrine and norepinephrine spillover from the heart to increase in parallel in the elderly during the sympathetic excitation accompanying exercise suggested that epinephrine lay outside the sympathetic nerves, perhaps arising from extraneuronal synthesis in the heart. We have not yet tested whether extraneuronal, in contrast to neuronal, epinephrine release in the heart could contribute to the observed higher rates of norepinephrine release in the elderly. PMID- 7852503 TI - Regulation of sex steroid receptor gene expression by progesterone and testosterone in cultured human endometrial stromal cells. AB - Progesterone (P) is known to regulate sex steroid receptors in uterine cells. However, its precise regulation at the messenger ribonucleic acid (mRNA) level is unclear. In this study we examined the effects of P and testosterone (T) on the regulation of sex steroid receptors in cultured human endometrial stromal cells (ESC), using the quantitative reverse transcriptase polymerase chain reaction method. We isolated ESC from human endometrial tissues and cultured them with or without P (10(-6) mol/L) or T (10(-8) mol/L) for 9 days. Incubation with P decreased progesterone receptor (PR), estrogen receptor, and androgen receptor mRNA levels in cultured human ESC to 0.56 +/- 0.04-, 0.53 +/- 0.08-, and 0.84 +/- 0.04-fold (mean +/- SE), respectively. T also decreased PR, estrogen receptor, and androgen receptor mRNA levels in cultured human ESC to 0.48 +/- 0.06-, 0.52 +/- 0.05-, and 0.82 +/- 0.04-fold (mean +/- SE), respectively. These decreases by P and T occurred in a dose-dependent manner. We also examined the sex steroid receptor levels in human ESC cultured for 0, 3, 6, and 9 days. The PR mRNA level in ESC without P was increased in a time-dependent manner. This increase was also inhibited by P, and the mRNA level in the presence of P was almost constant throughout the culture period. Our results demonstrated that P or T is a regulator of sex steroid receptors in ESC and that this regulation may influence the responsiveness to P of decidual change in ESC. PMID- 7852504 TI - The contribution of the sympathoadrenomedullary system to the etiology of essential hypertension: a study using plasma and platelet catecholamine concentrations. AB - Platelets take up and store noradrenaline and adrenaline in proportion to plasma concentrations and may, therefore, provide an integrated index of sympathoadrenomedullary arousal. Plasma and platelet catecholamine concentrations were measured in 290 European and 155 Asian subjects, and were related to blood pressure, insulin levels, and social class. Plasma noradrenaline concentrations correlated with systolic and diastolic blood pressure in both ethnic groups (r = 0.20-0.30), and these levels were significantly elevated in hypertensive subjects (P < 0.003). In Europeans, but not in Asians, these relationships remained significant after adjusting for age and gender, and were independent of the relationship between insulin and blood pressure. There were much weaker relationships between platelet catecholamine concentrations and blood pressure, which were dependent on age and gender as covariates. In neither ethnic group was there any relationship of either plasma or platelet catecholamine concentrations with insulin concentrations, body mass index, or glucose intolerance. European subjects in manual occupations had significantly higher concentrations of plasma noradrenaline than those with nonmanual occupations. The findings suggest a significant role for the sympathetic nervous system in the determination of blood pressure, but do not provide evidence for a connection between hyperinsulinemia and sympathetic nervous system activity. The role of platelet catecholamines as an epidemiological marker of stress has not been supported. PMID- 7852505 TI - Identification of a human serum albumin species associated with familial dysalbuminemic hyperthyroxinemia. AB - Familial dysalbuminemic hyperthyroxinemia (FDH) is a form of euthyroid hyperthyroxinemia that is due to an increased affinity of serum albumin for T4. Unlike the many physiologically neutral alloalbumins that have been identified by serum electrophoresis, FDH variants have not been reproducibly resolved. In the present study, isoelectric focusing in the presence of the denaturants urea and Nonidet P-40, without reduction, produced two bands in the sera of unrelated FDH subjects in place of each of the major albumin bands in the sera of normal subjects. One band of each FDH pair migrated with the normal band; the second migrated at a slightly lower pI. The identity of the new bands as albumin was confirmed by N-terminal sequencing. The two bands of each pair were present in approximately equal amounts, consistent with the autosomal dominant nature of the condition, the expectation that FDH individuals would be heterozygous for normal albumin (Alb-A), and evidence that high and normal affinity T4-binding sites are equimolar or near equimolar. Similar findings in sera from Hispanic and non Hispanic FDH subjects suggest that the same structural change may underlie the FDH phenotype from different populations. The slightly lower pI of the FDH specific bands is consistent with the His for Arg substitution predicted by a G to A base transition recently reported in codon 218 of the gene for the variant albumin (Alb-FDH). PMID- 7852506 TI - Assay of thyroglobulin in serum with thyroglobulin autoantibodies: an unobtainable goal? AB - Measurement of thyroglobulin (Tg) in serum with anti-Tg autoantibodies (TgAb) represents a difficult challenge. Immunoradiometric assays (IRMA) employing monoclonal anti-Tg antibodies not cross-reacting with endogenous TgAb have recently been developed and proposed for Tg assays in TgAb-positive sera. The aim of the present investigation was to assess the clinical reliability of this approach. Assays of serum Tg in patients with and without TgAb using one such monoclonal antibody IRMA (Thyroglobulin IRMA-Pasteur; IRMA-1) were compared with those obtained by a conventional IRMA employing polyclonal anti-Tg antibodies (HTGK-Sorin; IRMA-2). Preliminary studies for assessment of the interference of TgAb showed that the recovery of added Tg was significantly higher (P < 0.01) when determined by IRMA-1 (64.6 +/- 23%) than by IRMA-2 (49.5 +/- 20%). Study groups included 79 patients with differentiated thyroid carcinoma (DTC) treated by total thyroidectomy and radioiodine ablation; 24 had no metastases or residual thyroid tissue, 31 had a thyroid residue, and 24 had metastatic disease. Seventy five patients with autoimmune thyroid disease (47 with Graves' and 28 with Hashimoto's disease) were also included. In TgAb-negative sera from DTC patients, similar Tg concentrations were found by both IRMA, i.e. undetectable in most patients with no residual thyroid or neoplastic tissue, low to moderately elevated in the majority of those with residual thyroid tissue, and markedly elevated in all patients with metastatic disease. Serum Tg was undetectable by both assays in several TgAb-positive sera from DTC patients with residual thyroid tissue or metastatic disease, respectively, in whom a detectable or even high serum Tg concentration was expected. Despite the lower in vitro interference of TgAb in IRMA-1, there was no difference between the two assays. In the group of patients with thyroid autoimmune disease, serum Tg concentrations were found to be high in TgAb-negative sera and much lower in TgAb-positive sera by both IRMAs. In conclusion, the present study demonstrates that the use of a monoclonal antibody IRMA for serum Tg, although less susceptible to in vitro TgAb interference, does not necessarily provide any substantial advantage with respect to a conventional polyclonal IRMA in detecting Tg in TgAb-positive sera. The finding of undetectable or lower than expected serum Tg by either method in TgAb positive serum may well reflect a truly reduced serum Tg concentration. This might be due to an accelerated Tg metabolic clearance in the presence of TgAb.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7852507 TI - Potent thyrotropic activity of human chorionic gonadotropin variants in terms of 125I incorporation and de novo synthesized thyroid hormone release in human thyroid follicles. AB - Using a highly sensitive bioassay for TSH, in which human thyroid follicles incorporate 125I and release de novo synthesized thyroid hormone into the culture medium, the thyrotropic activities of various hCG preparations were studied. Under the culture conditions employed, bovine TSH (bTSH) was approximately 6- to 9-fold more active than human TSH (hTSH). Highly purified hCG prepared from urine of normal pregnant women (CR 127) had only a trivial thyrotropic activity equipotent to 0.00022 microU bTSH/U hCG or 0.0013 microU hTSH/U hCG (19.7 microU hTSH/mg hCG). Hybrid hCG (AB1ER) also elicited low thyrotropic activity (14.0 microU hTSH/mg), whereas crude hCG had moderate thyrotropic activity (0.041 hTSH microU/U hCG or 127 microU/mg protein). Deglycosylated hCG, a very weak LH/hCG receptor agonist, was the most potent agonist in thyroid follicles (588 microU hTSH/mg protein). hCGs purified from urine of patients with trophoblastic tumors had greater TSH-like activity (37-84 microU hTSH/mg protein) than purified hCG. Asialo-hCG purified from a patient with choriocarcinoma had very potent TSH-like activity (468 microU hTSH/mg). Submaximal doses of bTSH and hCG variants produced additive stimulation of thyroid function. Furthermore, the thyrotropic effect of hCG was inhibited by anti-TSH receptor antibody obtained from patients with myxedema. These in vitro findings suggest that although hCG is reported to exert potent cAMP-stimulating activity on rat thyroid-like cells (FRTL-5) and Chinese hamster ovary cells transfected with hTSH receptor complementary DNA (0.092-0.72 microU hTSH/U hCG), the thyrotropic activity induced by authentic hCG in human thyroid follicles is too weak to cause hyperthyroidism in normal pregnancy. However, hCG produced by some trophoblastic tumors, particularly asialo-hCG, has potent thyrotropic activity sufficient to cause clinically overt hyperthyroidism when produced excessively. PMID- 7852508 TI - Evaluation and application of a highly sensitive assay for serum growth hormone (GH) in the study of adult GH deficiency. AB - Previous work from our laboratory addressing the diagnosis of GH deficiency in adults showed that RIA measurement of the 24-h integrated GH concentration (IGHC) was unable to discriminate between hypopituitary and age-, sex-, and body mass index-matched normal subjects because of the occurrence of undetectable levels (< 200 ng/L) within both groups. In contrast, full separation was achieved using stimulation by the insulin tolerance test (ITT). The data showed no significant relationship between IGHC and insulin-like growth factor-I (IGF-I) within either group. To determine whether limited sensitivity obscured diagnostic and physiological information, we assessed and modified a commercially available enzyme-linked immunosorbent assay (Elegance GH ELISA, Bioclone Australia) to achieve a high sensitivity (1 ng/L) and applied it to the study of IGHC and the relationship to IGF-I in a study group of 30 normal and 19 subjects with severe organic hypopituitarism. Using this assay, the IGHCs from all subjects were detectable and correlated significantly with detectable values obtained by RIA (n = 24; r = 0.80; P = 0.0001). Mean IGHC in normal subjects was significantly higher than that in hypopituitary subjects (852 +/- 131 vs. 97 +/- 28 ng/L), but the IGHCs from the two groups were not completely separate. Twenty-six percent of hypopituitary subjects had IGHC values within the normal range (111-3454 ng/L). IGHC decreased with age in normal subjects. Age stratification improved the separation, but an overlap remained in the young (< 50 yr old) and old (> 50 yr old) groups. Measurement of 12-h nocturnal IGHC levels improved the separation between hypopituitary and normal subjects in the young subjects only. IGHC was significantly related to IGF-I in hypopituitary (r = 0.59; P = 0.0084) and normal subjects (r = 0.55; P = 0.0017) and in the combined groups (r = 0.64; P = 0.0001). The data show that a sensitive ELISA reliably quantifies IGHC in normal and hypopituitary subjects. IGHCs in hypopituitary patients are lower, but not clearly separated from values in normal counterparts despite their having unequivocally impaired GH responses to ITT. We conclude that 1) IGHC in normal subjects can be reliably defined by sensitive ELISAs; 2) the diagnostic utility of the IGHC does not match the reliability or simplicity of an ITT, and 3) GH is a significant regulator of IGF-I in both normal and reduced states of GH secretion. PMID- 7852509 TI - Energy metabolism and substrate oxidation in acromegaly. AB - Short term GH administration increases lipid breakdown and oxidation (lipidox) and reduces glucose uptake and carbohydrate oxidation (CHOox). It is not clear whether similar shifts in substrate oxidation occur in acromegaly, and our aim was to investigate this. Using indirect calorimetry, we compared energy expenditure, CHOox, and lipidox in 20 acromegalic patients and 20 normal subjects pair-matched for sex, age, height, and weight. Investigations were performed in the basal state (12-h fast) and during a 75-g oral glucose tolerance test (OGTT). Acromegalic patients had significantly higher fasting glucose levels and greater glucose and insulin responses during an OGTT than normal subjects. Fasting nonesterified free fatty acid and insulin-like growth factor (IGF)-binding protein-1 levels were similar in the two groups, and both were acutely suppressed by oral glucose to the same degree. Basal energy expenditure was significantly greater in the acromegalic patients (1682 +/- 49 vs. 1540 +/- 45 Cal/24 h; P < 0.05), who showed a trend toward higher basal CHOox. Oral glucose resulted in a significantly higher rise in energy expenditure in the normal compared to the acromegalic subjects. During the OGTT, CHOox significantly increased in both groups, but rose to a higher level in the acromegalic patients (177 +/- 10 vs. 138 +/- 9 mg/min; P = 0.004). Oral glucose significantly reduced lipidox in both groups, but lipidox was reduced to a significantly lower level in the acromegalic patients (32 +/- 4 vs. 46 +/- 3 mg/min; P = 0.004). In acromegaly, basal CHOox (r = 0.56; P = 0.01) and postglucose CHOox (r = 0.79; P = 0.0001) were both positively correlated to IGF-I, but not to insulin and/or glucose. In normal subjects, postglucose CHOox was positively correlated to IGF-I. In summary, hyperinsulinemia in acromegaly was associated with higher glucose levels and a blunted thermogenic response to glucose, and displayed no relationship to the pattern of substrate oxidation. CHOox was increased, and lipidox was reduced in acromegaly, and the extent of IGF-I elevation was related to CHOox in the basal and postglucose states. We conclude that 1) the chronic effects of GH excess on substrate oxidation differ from the short term effects of GH administration; 2) impaired insulin action in acromegaly extends to effects on energy expenditure; and 3) IGF-I may be an important regulator of substrate oxidation in acromegaly. PMID- 7852510 TI - Thyroids from siblings with Pendred's syndrome contain thyroglobulin messenger ribonucleic acid variants. AB - We studied thyroid tissue from two siblings with Pendred's syndrome (familial goiter and congenital deafness), both with the Mondini-type inner ear malformation, goiter, and hypothyroidism. Iodine trapping and peroxidase levels were grossly normal. Thyroglobulin (Tg), the only iodoprotein found, had a normal monomer size (330 kilodaltons), but low content of hormone and iodine. Tg's expected N-terminal peptides of 26 and 18 kilodaltons, usually formed in association with iodination and thyroid hormone synthesis, were absent, but appeared after iodination in vitro. Reverse transcription of ribonucleic acid from Pendred thyroid tissue and amplification by polymerase chain reaction of specific regions encoding the most important hormonogenic sites of Tg revealed a normal complementary DNA sequence corresponding to the first 100 amino acid residues in Tg's N-terminus. However, 3 of 35 clones of the 3'-region corresponding to the Tg C-terminus exhibited a deletion of nucleotides 7860-7994; this deletion was not present in any of the 150 clones from 7 other thyroids we examined. Four Pendred clones had a 2-nucleotide deletion at positions 7870-7871, a change that would result in a premature stop codon and was found in thyroids from several other subjects as well. We conclude that the messenger ribonucleic acid encoding the 3'-region of Tg can be abnormal in Pendred's syndrome. Some, but not all, of these changes also occur in other human thyroids. Further work is necessary to show if and how these alterations relate to defective hormone synthesis and goiter. PMID- 7852511 TI - The serotonin-4 receptor agonist cisapride and angiotensin-II exert additive effects on aldosterone secretion in normal man. AB - In animals and man, serotonin (5-HT) exerts a direct stimulatory action on adrenocortical cells through activation of 5-HT4 receptors. In rats, 5-HT also potentiates the stimulatory effect of angiotensin-II (Ang II) on aldosterone secretion. The aim of the present study was to investigate the effect of concomitant administration of the 5-HT4 receptor agonist, cisapride, and Ang II on aldosterone secretion in normal human subjects. Eight healthy male volunteers pretreated with dexamethasone received, at 1-week intervals in random order and simple blind fashion, the following treatments: 1) a single oral dose of 10 mg cisapride, 2) a single oral dose of placebo, 3) a perfusion of graded doses of Ang II (from 1-4 ng/kg.min), 4) a perfusion of placebo, and 5) a single oral dose of 10 mg cisapride associated with a perfusion of Ang II. The oral doses of cisapride and placebo were also administered after a 3-day period of a low sodium diet (10 mmol/day). Plasma aldosterone levels increased significantly within 90 min after the administration of cisapride without any change in renin levels. The comparison between the net increase in aldosterone production induced by cisapride, Ang II, and cisapride plus Ang II showed that the stimulatory effects of cisapride and Ang II on aldosterone secretion were only additive. Similarly, the increase in plasma aldosterone levels induced by a sodium-restricted diet was just additive with the cisapride-evoked stimulation of aldosterone secretion. These results provide further evidence that the action of 5-HT on glomerulosa cells is mediated through activation of 5-HT4 receptors. The data also indicate that in humans, 5-HT does not potentiate the stimulatory effect of Ang II on aldosterone secretion. PMID- 7852512 TI - Abnormal androgen receptor binding affinity in subjects with Kennedy's disease (spinal and bulbar muscular atrophy). AB - We have investigated androgen-binding properties of the androgen receptor (AR) in cultured suprapubic skin fibroblasts from six subjects with Kennedy's disease (X linked spinal and bulbar muscular atrophy). Binding of the synthetic androgen methyltrienolone (R1881) was measured in a monolayer assay, and Scatchard analysis was performed to determine the total number of binding sites and the apparent binding affinity (Kd) of the AR for androgen. Five of the six subjects investigated had an abnormal apparent binding affinity, with Kd values ranging from 0.34-11.7 nmol/L, more than 2 SD from the mean of the normal range (0.19 +/- 0.06 nmol/L). In this group of six patients, there was a significant correlation between the AR Kd and the severity of testicular atrophy and gynecomastia. The number of CAG repeats in the expanded region of exon A of the AR gene was determined in all subjects from whom suprapubic skin fibroblasts were cultured and an additional 12 subjects with Kennedy's disease. In the total group of 18 subjects investigated, there was a trend for an increasing number of CAG repeats associated with decreasing age at onset of different symptoms; however, this correlation was not statistically significant. Thus, we report for the first time a quantitative abnormality of the AR apparent binding affinity in subjects with Kennedy's disease, which appears to be related to the severity of the symptoms of androgen insensitivity. PMID- 7852513 TI - Prostaglandin endoperoxide-H synthase-1 and -2 messenger ribonucleic acid levels in human amnion with spontaneous labor onset. AB - Increased prostaglandin (PG) production within the uterine compartment has a pivotal role in the processes leading to labor onset in women. Two PG endoperoxide-H synthase (PGHS) isoenzymes have been identified in a number of cell types. PGHS-1 is constitutively expressed in most cases, whereas PGHS-2 expression is rapidly induced by several agonists. The aims of this study were to determine the levels of PGHS-1 and PGHS-2 expression before and after spontaneous labor (SL) onset in the amnion and to assess the contribution of PGHS-1 and PGHS 2 to enzyme activity. We established and validated ribonuclease protection assays to quantify PGHS-1 and PGHS-2 messenger ribonucleic acid (mRNA) levels in the amnion. PGHS enzyme activity was measured with an established assay. The antisense RNA probes used in the protection assays were generated using human PGHS-1 and PGHS-2 complementary DNAs. These probes specifically detected the 2.8 kilobase mRNA of PGHS-1 and the 4.8-kilobase mRNA of PGHS-2 in amnion RNA samples on Northern blots. We measured mRNA levels in amnion from patients after SL at term and from patients not in labor undergoing elective cesarean section (CS) at term. PGHS-2 mRNA levels were markedly higher after SL compared to levels in CS amnion [5.18 +/- 1.08 (n = 16) and 2.27 +/- 0.50 (n = 15), densitometric units, respectively; P < 0.02], whereas there was no difference in PGHS-1 mRNA levels after labor compared with CS samples. PGHS-2 mRNA levels were also positively correlated with PGHS enzyme activity in 4 separate assays with a total of 25 patients (r = 0.65-0.88; P < 0.05). There was no correlation between PGHS-1 mRNA levels and enzyme activity. We conclude that PGHS-2 mRNA is present in human amnion; its levels are elevated after SL onset, and they are correlated with enzyme activity. The stimulation of PGHS activity at labor onset probably involves increased expression of PGHS-2. The expression of PGHS-1 does not change in association with labor in human amnion. PMID- 7852515 TI - Endogenous inhibitors of 11 beta-hydroxysteroid dehydrogenase in hypertension. AB - Exogenous inhibitors of 11 beta-hydroxysteroid dehydrogenase (e.g. glycyrrhetinic acid, a constituent of licorice) raise blood pressure by allowing cortisol to activate mineralocorticoid receptors. Endogenous 11 beta-dehydrogenase inhibitors called glycyrrhetinic acid-like factors (GALFs), have been extracted from urine. Increased GALFs could explain the impairment of 11 beta-dehydrogenase in essential hypertension and ectopic ACTH syndrome. We extracted urine on Sep-Paks and quantified GALFs by their inhibition of 11 beta-dehydrogenase bioactivity in microsomes from rat liver. GALFs have no diurnal rhythm and were no different after dexamethasone treatment, in patients with low ACTH, on in 4 patients with ectopic ACTH secretion. In 79 subjects, GALF excretion did not correlate with blood pressure. In 17 subjects, GALF excretion did not correlate with indices of mineralocorticoid receptor activation on 11 beta-dehydrogenase activity. We conclude that GALFs are not ACTH dependent and have no measurable effect on 11 beta-dehydrogenase in vivo. In hypertension associated with impaired 11 beta dehydrogenase activity GALFs are unlikely to play a pathophysiological role. PMID- 7852514 TI - Recovery of serum calcium concentrations following acute hypocalcemia in patients with osteoporosis on long-term oral therapy with the bisphosphonate pamidronate. AB - Bisphosphonates, synthetic compounds that are taken up preferentially by the skeleton and that suppress bone resorption, are currently used in the management of patients with osteoporosis. Long-term uninterrupted administration of low oral doses is the preferred mode of treatment in current clinical trials with newer bisphosphonates. These compounds have, however, a long residence time in the skeleton, and there is no information about their long-term effects on blood calcium homeostasis. We examined the effect of long-term therapy with oral bisphosphonate on blood calcium homeostasis following an acute hypocalcemic stimulus. Twenty patients with vertebral osteoporosis (10 untreated controls and 10 treated with oral pamidronate, 150 mg/day for at least 5 yr) were given intravenous infusions of sodium EDTA, and the concentrations of calcium and PTH in blood were followed for 24 h. Serum calcium concentrations decreased similarly in both groups (maximum decrease 0.21 mmol/L and 0.22 mmol/L, respectively). The recovery of serum calcium concentrations was identical in both groups, and all patients had normal concentrations at 24 h. Plasma PTH increased to a peak of 17.3 +/- 2.5 pmol/L in the control group and to 17.0 +/- 3.1 pmol/L in the pamidronate-treated patients. During the whole study period, there was no difference in either the peak PTH response or in the recovery of plasma PTH values between the two groups. However, when only PTH responses between 60 min and 24 h were examined, there were differences between the two groups. Plasma PTH values, although strictly within the normal range, were significantly higher in the pamidronate-treated patients (P = 0.001). There were no differences in the calcemic responses during this period. Further, there were no detectable changes in immunoreactive PTH-related protein in either group after the EDTA infusions. In conclusion, our study showed that longterm therapy with oral pamidronate does not affect the calcemic response to an acute hypocalcemic stimulus in patients with osteoporosis. PMID- 7852516 TI - Membrane-anchored expression of transforming growth factor-alpha in human pituitary adenoma cells. AB - Growth factors induce cell proliferation and are implicated in the multistep process of tumorigenesis. Transforming growth factor-alpha (TGF alpha), a peptide that binds to the epidermal growth factor receptor, is expressed by carcinomas and normal tissues. To investigate the possible role of TGF alpha in adenohypophysial tumorigenesis, we studied its expression in nontumorous human pituitary and different clinically and morphologically characterized human pituitary adenomas. Ribonucleic acid was reverse transcribed and amplified by polymerase chain reaction; transcript signals were identified with marked variation in 14 of 15 adenomas, and a weak signal was detected in nontumorous pituitary. Immunohistochemical positivity was found with variable intensity in all adenoma types, but not all tumors. Ultrastructural immunogold localized TGF alpha in endoplasmic reticulum, in Golgi apparatus, and on cell membranes; surface localization was confirmed by immunofluorescence. To assess possible secretion, the reverse hemolytic plaque assay was performed; small plaques were identified using an antibody that recognizes the extracellular domain of pro-TGF alpha; however, the plaques did not increase in size with time, suggesting that they detected membrane-anchored TGF alpha. Moreover, TGF alpha was undetectable by enzyme-linked immunosorbent assay in pituitary tumor-conditioned culture media. The marked variable expression of TGF alpha, the absence of secretion in measurable quantities, and the preferential membrane localization suggest a specific juxtacrine mechanism for TGF alpha in pituitary tumorigenesis. PMID- 7852517 TI - Effect of chronic opioid antagonism on the hypothalamic-pituitary-ovarian axis in hyperprolactinemic women. AB - Short term naloxone infusion studies have suggested that enhanced endogenous opioid activity may play a role in inhibiting GnRH and gonadotropin secretion in hyperprolactinemic patients. Because it was not known whether long term opioid antagonism would lead to persistent stimulation of LH with a subsequent ovarian response, we administered the long-acting oral opiate antagonist, naltrexone (NTX), to six hyperprolactinemic amenorrheic women. Blood was drawn from all subjects every 15 min for 10 h on a control day and again on the next day after the administration of 50 mg NTX. Five subjects continued NTX (50 mg daily) for 3 8 weeks. There was a significant increase in the mean concentration of LH (6.7 +/ 1.1 to 12.2 +/- 1.6 IU/L), area under the LH curve (200%), and LH pulse amplitude (3.2 +/- 0.6 to 7.2 +/- 1.0 IU/L) on the first NTX day compared to the control day (P < 0.02). Estradiol levels also increased on the first NTX day (P < 0.01). The mean peak estradiol level increased from 76 +/- 9.9 pmol/L on the control day to 138 +/- 21 pmol/L during NTX treatment (P < 0.02). NTX stimulated LH release in five of six patients, followed by a rise in estradiol in four of these five patients. This initial increase in estradiol was not sustained in most cases, and the mean estradiol level during the entire NTX treatment period was not significantly different from the control level. One patient achieved an estradiol level of 187 pmol/L after 3 weeks of NTX treatment and reported withdrawal bleeding after stopping NTX. No patient ovulated. PRL levels did not change on the first NTX day vs. the control day (166 +/- 79 vs. 167 +/- 67 micrograms/L); however, PRL did increase over time with continued NTX treatment (P < 0.05). The mean PRL level during chronic NTX treatment was 255 +/- 121 micrograms/L. We conclude that treatment of hyperprolactinemic amenorrheic women with NTX results in a prompt partial reactivation of the hypothalamic-pituitary gonadal axis, as indicated by increased gonadotropin and subsequent estradiol release. The effect of opioid antagonism, however, did not lead to a sustained increase in estradiol secretion with chronic treatment. Thus, although endogenous opioids appear to play a key role in mediating PRL-induced gonadal suppression, chronic opioid antagonism with NTX does not appear to be an effective treatment for amenorrhea in these patients. PMID- 7852518 TI - Long-term effect of gonadotropin-releasing hormone agonist therapy on final and near-final height in 26 children with true precocious puberty treated at a median age of less than 5 years. AB - We report a long term study on the effectiveness of chronic GnRH agonist treatment on final or near-final height in 26 patients (20 females and six males) with true precocious puberty (TPP). This study differs from other treatment studies in that the median age at onset of therapy was 4.7 yr for females and 6.2 yr for males, the youngest cohort of treated patients reported to date. We compared patients treated with GnRH agonists who attained final or near-final height with a historical control group of untreated children with TPP (n = 116) matched for mean age of pubertal onset, etiology of TPP (idiopathic or neurogenic), rate of progression, and sex ratio. The current mean height of GnRH agonist-treated females who began therapy at more than 5 yr of age (157.6 +/- 6.6 cm) is already significantly greater than the mean final height of untreated females (152.7 +/- 8.6 cm). The current mean predicted height of the treated females is 164.6 +/- 9.7 cm. The current mean height of females whose treatment was started before 5 yr of age is greater (164.1 +/- 7.7 cm) than that of females whose treatment began after 5 yr of age (157.6 +/- 6.6 cm). The final height of untreated children whose age of sexual precocity was less than 5 yr at diagnosis is significantly less than that of treated patients who were less than 5 yr when they developed TPP (P = 0.0006). The current mean height of GnRH agonist-treated males is 166.3 +/- 12.2 cm, and the current mean predicted height is 170.8 +/- 11.3 cm. This is in sharp contrast to the mean final height of untreated males (155.6 +/- 7.7 cm). The current predicted height correlates negatively with the age at initiation of treatment and the initial bone age and positively with height SD for bone age in the agonist-treated children. The current mean height deviation from target height is significantly less in the 20 treated females (-1 SD) than in 93 untreated females (-2.4 SD; P = 0.006). The mean final height deviation from target height in 23 untreated males (-3.7 SD) is significantly greater than the current height deviation from target height in 6 treated males ( 1.7 SD; P = 0.03). The salutary effects of long term GnRH agonist therapy on stature are more clear-cut in the younger treated children. Young untreated children may have the worst outcome with respect to final height.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7852519 TI - Effect of growth hormone (hGH) replacement therapy on physical work capacity and cardiac and pulmonary function in patients with hGH deficiency acquired in adulthood. AB - The effects of 6 months of replacement therapy with recombinant human GH (hGH) on physical work capacity and cardiac structure and function were investigated in 20 patients with hGH deficiency of adult onset in a double blind, placebo-controlled trial. The GH dose of 12.5 micrograms/kg BW was self-administered daily sc. Oxygen consumption (VO2), CO2 production, and ventilatory volumes were measured during exercise on a bicycle spiroergometer. M-Mode echocardiography was performed using standard techniques. The VO2 max data, expressed per kg BW (mL/min.kg BW) showed a significant increase from 23.2 +/- 2.4 to 30.0 +/- 2.3 (P < 0.01) in the hGH-treated group, whereas the VO2 max data, expressed per lean body mass (milliliters per min/kg lean body mass) did not change significantly in either group. Maximal O2 pulse (milliliters per beat) increased significantly from 15.2 +/- 5.6 to 19.6 +/- 3.3 mL/beat (P < 0.01), but remained constant in the placebo group. The maximal power output (watts +/- SE) increased significantly (P < 0.01) from 192.5 +/- 13.5 to 227.5 +/- 11.5 in the hGH-treated group, but remained constant in the placebo group. Cardiac structure (left ventricular posterior wall, interventricular septum thickness, left ventricular mass, left ventricular end-systolic dimension, and left ventricular end-diastolic dimension) as well as echocardiographically assessed cardiac function did not change significantly after 6 months of treatment in either group. We conclude that hGH replacement in hGH-deficient adults improves oxygen uptake and exercise capacity. These improvements in pulmonary parameters might be due to an increase in respiratory muscle strength and partly to the changes in muscle volume per se observed during hGH replacement therapy. Furthermore, an increased cardiac output might contribute to the improvement in exercise performance during hGH treatment. According to our data, hGH replacement therapy leads to an improvement of exercise capacity and maximal oxygen uptake, but has no significant effect on cardiac structure. PMID- 7852520 TI - Abnormal concentration of maternal serum activin-A in gestational diseases. AB - Serum plasma activin-A is measurable in the maternal circulation of healthy pregnant women, increases in specimens collected during the third trimester of gestation, and is highest at parturition. Hormone abnormalities are known to be associated with preterm labor or diabetes in pregnancy. Therefore, in the present study serum activin-A levels in normal controls were compared to those in pregnant women with preterm labor or gestational diabetes. In some cases, values were obtained before and after insulin therapy. In other controls and patients with preterm labor, the activin-A concentration in cord serum was also studied. A newly developed two-site immunotest was used to determine activin-A levels. Subjects included normal controls (n = 7), who were sampled throughout gestation every 5 weeks; pregnant women at term (38-40 weeks) not in labor (n = 22); pregnant women at term in spontaneous labor (< 3.0 cm dilated; n = 42); women in preterm labor (25-35 weeks; n = 38); and women with gestational diabetes (20-39 weeks; n = 9). In control women, serum activin-A levels increased from 4.8 +/- 5.5 micrograms/L (mean +/- SD) at 20 weeks to 25.4 +/- 27.8 micrograms/L at 40 weeks (P < 0.01), and values correlated with gestational age. Pregnant women in preterm labor had serum activin-A concentrations (89.04 +/- 173.31 micrograms/L) higher than those in normal controls (P < 0.01), and no significant correlation to gestational age was found in this group of pregnant women. Healthy women in labor showed serum activin-A concentrations higher than those in women at term but not in labor (P < 0.01). Diabetic patients had serum activin-A concentrations (52.39 +/- 23.32 micrograms/L) significantly higher than those in normal controls. In these patients, maternal serum activin-A concentrations significantly decreased to the range in healthy controls at the same gestational age after insulin therapy (9.48 +/- 3.82 micrograms/L). The present study shows that preterm labor is associated with increased concentrations of activin-A in the maternal circulation and cord serum. Hypersecretion of activin-A is also shown in same patients with gestation diabetes; this reverts to normal after insulin treatment. PMID- 7852521 TI - Long-term thyroid replacement therapy and levels of lipoprotein(a) and other lipoproteins. AB - There is a general interest to know whether lipoprotein(a) [Lp(a)] is under hormonal control. Hypothyroidism is a well known cause of secondary hyperlipidemia, which mainly affects low density lipoprotein (LDL) cholesterol levels, but the result on the effects of L-T4 replacement therapy on the Lp(a) concentration is controversial. We studied 12 severely hypothyroid, hypercholesterolemic patients under basal conditions and during L-T4 treatment. We found a rapid decrease in both LDL cholesterol (5.71 +/- 0.62 vs. 4.37 +/- 0.44 mmol/L basally and after 1 month of thyroid replacement, respectively) and apolipoprotein-B (Apo-B) levels (1.89 +/- 0.02 vs. 1.52 +/- 0.17 g/L, respectively); these changes persisted for up 1 yr of analytical euthyroidism and paralleled the improvement in the thyroid status of the patients. In contrast, the plasma Lp(a) concentration did not change at any time (496 +/- 123, 464 +/- 128, and 441 +/- 110 mg/L under basal conditions and after 1 and 14-15 months of thyroid replacement, respectively), and the small fluctuations observed in some patients did not correlate with those in LDL cholesterol or Apo-B, and were not associated with any particular Apo(a) phenotype. In relation to HDL fractions, high density lipoprotein3 (HDL3) remained stable, but HDL2 cholesterol and phospholipid levels decreased during treatment, changes that were the inverse of those in postheparin plasma hepatic lipase activity. Patients in the present study were normotriglyceridemic, except one who was hypertriglyceridemic at diagnosis, but even in this patient, triglyceride levels were unaffected by T4 substitution therapy, as was postheparin plasma lipoprotein lipase activity. The changes observed in LDL, HDL2, and hepatic lipase activity delineate the lipoprotein-related response to T4 replacement therapy, whereas potential individual fluctuations in Lp(a) levels are probably more dependent on other factors, such as the production rate, which are not affected by thyroid hormones. PMID- 7852522 TI - Estrogen stimulates oxytocin gene expression in human chorio-decidua. AB - We have recently shown that oxytocin (OT) is synthesized within human amnion, chorion, and decidua during late gestation. The levels of OT messenger ribonucleic acid (mRNA) increased around the time of parturition, suggesting that locally produced OT may play a role in this poorly understood process. In this report, we present results from investigations into the effects of estrogen and progesterone on the synthesis of OT by human chorio-decidua. Using an in vitro incubation system, estradiol at physiological concentrations more than doubled the concentration of OT mRNA. This was reflected by an increase in the amount of OT peptide secreted into the medium. The increase in OT mRNA was antagonized by tamoxifen, suggesting that the effects were estrogen receptor mediated. Progesterone had no effect on OT mRNA synthesis. Using ribonuclease protection assays, mRNAs for estrogen receptor (ER) and progesterone receptor (PR) were detected in all tissues examined. The highest levels were found in decidua, with lower amounts in chorion and very small amounts in amnion and placenta. This is the same relative tissue distribution that we previously demonstrated for OT mRNA. A single transcript was present for ER, and two transcripts were protected for PR. The concentrations of ER mRNA in chorio-decidua were 3-fold higher in tissues obtained after spontaneous labor onset than in tissues obtained from cesarean section at a similar gestational age but before labor onset. Levels of PR did not change significantly. We conclude that synthesis of OT in human chorio decidua may be regulated in part by estrogen, and that regulation of ER levels may be an important factor modulating this effect. These data support the hypothesis of a paracrine network within human fetal membranes and decidua that may participate in regulating the timing of human birth. PMID- 7852523 TI - Alterations in the hypothalamic paraventricular nucleus and its oxytocin neurons (putative satiety cells) in Prader-Willi syndrome: a study of five cases. AB - Animal experiments have shown that the parvocellular oxytocin (OXT) neurons of the hypothalamic paraventricular nucleus (PVN) inhibit food intake. In the present study, the PVN and its OXT neurons have been investigated in an extreme human eating disorder, i.e. the Prader-Willi syndrome (PWS). PWS patients are characterized by gross obesity, insatiable hunger, hypotonia, hypogonadism, and mental retardation. The PVN of 5 PWS patients (2 males and 3 females), varying in age between 22-64 yr, and 27 controls (14 males and 13 females) without any primary neurological or psychiatric diseases was morphometrically investigated after conventional staining with thionine and immunocytochemical staining for OXT and vasopressin (AVP). The thionine-stained volume of the PVN was 28% smaller in PWS patients (P = 0.028), and the total cell number was 38% lower (P = 0.009). The immunoreactivity for OXT and AVP was decreased in PWS patients, although the variability within the groups was high. A strong and highly significant decrease (42%; P = 0.016) was found in the number of OXT-expressing neurons of the PWS patients. The volume of the PVN-containing OXT-expressing neurons decreased by 54% (P = 0.028) in PWS. The number of AVP-expressing neurons in the PVN did not change significantly. The OXT neurons of the PVN seem to be good candidates for playing a physiological role in ingestive behavior as "satiety neurons" in the human hypothalamus. PMID- 7852524 TI - Expression of human gonadotropin-releasing hormone receptor gene in the placenta and its functional relationship to human chorionic gonadotropin secretion. AB - Placental GnRH is one of the potential paracrine regulators of hCG secretion from the trophoblasts during pregnancy. Maternal serum hCG levels exhibit an exponential rise during the first 6 weeks of pregnancy, peak at 9-10 weeks, decline to a nadir at 20 weeks, and remain at low levels during the rest of pregnancy. However, the placental content of GnRH does not parallel the time course of hCG secretion, and GnRH messenger ribonucleic acid (mRNA) levels in the placenta remain unchanged during pregnancy. These data do not conform with a simple paracrine mechanism of GnRH as a regulator of hCG secretion. We, therefore, examined the potential variation in GnRH receptor gene expression in the placenta, which may account for the GnRH-mediated dynamic pattern of hCG secretion during gestation. First, we established a functional relationship of GnRH and hCG secretion. Using a placental explant culture system, a dose-response effect of hCG secretion was observed in the placental explant at 9 weeks when treated with GnRH ranging from 10(-9)-10(-7) mol/L. The effect of GnRH was completely blocked by a GnRH antagonist (Nal-Glu). The relative responsiveness of hCG secretion to GnRH stimulation at 10(-7) mol/L was further evaluated in placental explants at 6, 9, and 40 weeks gestation. Whereas the 9-week placenta showed a maximal response (> 300%) relative to the 6-week placenta, there was no response in term placenta. Again, the effects of GnRH on hCG secretion were blocked by Nal-Glu, supporting a receptor-mediated event. Localization of mRNA encoding human GnRH receptor in human placenta at 6, 9, 12, 20, and 40 weeks gestation was established by in situ hybridization. The mRNA signals were present in both cytotrophoblast and syncytiotrophoblast cell layers. Signal intensities varied with gestational ages and were abundant at 6 weeks, peaked at 9 weeks, declined at 12 and 20 weeks, and were undetectable at term. The present study demonstrates, for the first time, that GnRH receptor mRNA is expressed in both cytotrophoblasts and syncytiotrophoblasts and exhibits changes paralleling the time course of hCG secretion during pregnancy. These data provide a mechanistic understanding that the paracrine/autocrine regulation of hCG secretion by placental GnRH is mediated through an increase followed by a decline in GnRH receptor gene expression from the first trimester to term placenta. PMID- 7852525 TI - Gonadotroph adenoma in a premenopausal woman secreting follicle-stimulating hormone and causing ovarian hyperstimulation. AB - The clinical manifestations of gonadotroph adenomas are almost always neurological, consequences of their large size, and are rarely endocrinological. We report an exception, a 39-yr-old woman whose gonadotroph adenoma caused supranormal serum concentrations of FSH, which resulted in the development of multiple ovarian cysts, persistent elevation of her serum estradiol concentration, and endometrial hyperplasia. She initially presented because of amenorrhea at age 30 yr and was treated for an intrasellar mass by transsphenoidal surgery at age 31 yr and again at age 36 yr. Before and after the second operation she had persistently supranormal plasma estradiol concentrations (> 1840 pmol/L) and endometrial hyperplasia. When she was evaluated at age 39 yr, transvaginal ultrasound showed multiple ovarian cysts and endometrial thickening. Her plasma estradiol level was markedly supranormal (2160 pmol/L), FSH was mildly supranormal (17.8 IU/L), and alpha-subunit was markedly supranormal (23.3 micrograms/L). Characteristic of gonadotroph adenomas, her LH beta level increased by 69% in response to TRH. Neither FSH nor alpha-subunit decreased in response to administration of the GnRH antagonist, Nal-Glu-GnRH (5 mg/12 h for 4 weeks). Excised adenoma tissue exhibited morphological features of a gonadotroph adenoma. This patient appears to be unique, in that her gonadotroph adenoma caused slightly, but persistently, supranormal concentrations of FSH, which caused ovarian stimulation, including supranormal plasma estradiol concentrations, multiple ovarian cysts, and endometrial hyperplasia. We propose that gonadotroph adenomas be considered in the differential diagnosis of patients who have this constellation of abnormalities. PMID- 7852526 TI - A multicenter trial of low dose gallium nitrate in patients with advanced Paget's disease of bone. AB - Gallium nitrate is a potent antiresorptive drug that has been extensively tested in patients with accelerated bone turnover. We have evaluated the effects of this new agent in a pilot multicenter trial of 49 patients with advanced Paget's disease of bone. Patients were randomized to receive 0.05, 0.25, or 0.5 mg/kg.day gallium nitrate administered by sc injection in two 14-day cycles. Serum alkaline phosphatase, fasting 2-h urinary hydroxyproline and N- telopeptide collagen cross links excretion, and quality of life were assessed every 2 weeks for 12 weeks. The group mean alkaline phosphatase activity at baseline was 854 +/- 100 (+/- SEM) IU/L. The mean changes from baseline to week 12 in serum alkaline phosphatase were +0.5%, -24%, and -31%, respectively, for the three doses tested. The differences for each of the higher dose levels (0.25 and 0.5 mg/kg.day) was statistically significant (P < or = 0.05), and nearly half of the patients treated with the 0.5 mg/kg.day dose achieved a 50% or more reduction in enzyme activity. The nadir value in hydroxyproline excretion occurred at 10 weeks, with mean changes of +9%, -10%, and -17% for the 0.05, 0.25, and 0.5 mg/kg.day doses, respectively; the difference was significant only at the 0.5 mg/kg.day level (P < 0.01). Urinary collagen cross-link excretion showed a significant decrease at the 0.25 and 0.5 mg/kg.day doses. We also observed a definite, but nonsignificant, trend for improved quality of life in patients treated at the highest drug dose. Minor discomfort at the injection site was frequently reported, but did not lead to interruption of therapy. Our results in these patients who had received moderate to extensive prior therapies with other drugs show that cyclical, low dose, sc administration of gallium nitrate is safe and effective for treating patients with advanced Paget's disease of bone. PMID- 7852527 TI - The impact of estrogen on adrenal androgen sensitivity and secretion in polycystic ovary syndrome. AB - Adrenal hyperandrogenism is a common feature of patients with polycystic ovary syndrome (PCO). This may be due to enhanced adrenal sensitivity to ACTH. Because enhanced ovarian androgen secretion does not appear to explain this phenomenon, we explored the role of estrogen in inducing enhanced adrenal sensitivity, in that a state of relative hyperestrogenism exists in PCO. Eight patients with PCO and seven matched controls received ovine corticotropin-releasing hormone (oCRH; 0.1 micrograms/kg) iv before and after hypoestrogenism was induced by leuprolide acetate (LA; 1 mg, sc, each day). In patients with PCO, a third oCRH test was repeated after transdermal estradiol (E2; 0.1 mg) had been applied for a week, during which time LA was continued. At baseline, patients with PCO had increased responses of 11 beta-hydroxyandrostenedione and dehydroepiandrosterone (P < 0.03 and P < 0.02) and increased delta maximal ratios of androstenedione (A4)/ACTH and dehydroepiandrosterone/ACTH (P < 0.01) after oCRH treatment. After LA administration to patients with PCO, these ratios were significantly suppressed (P < 0.01) and returned to baseline after E2 was added. There were no changes in controls. Steroid ratio responses to oCRH suggested that 17,20-desmolase activity (delta maximum change in the ratio of A4/17-hydroxyprogesterone) was lowered with estrogen suppression and increased again after transdermal E2 administration. There was a significant positive correlation between changes in E2 levels and delta maximum change in the ratios of A4/17-OHP after oCRH treatment, signifying 17,20-desmolase activity (r = 0.58, P < 0.02). In conclusion, these data provide evidence that estrogen is at least one factor that influences adrenal androgen sensitivity in PCO and may help explain the frequent finding of adrenal hyperandrogenism in this syndrome. PMID- 7852528 TI - Diminished function of the somatotropic axis in older reproductive-aged women. AB - Circulating GH and insulin-like growth factor-I (IGF-I) levels in adults generally fall with age. Studies in aging women have rarely controlled for menstrual cycle stage or status or body mass index. We hypothesized that GH and IGF-I levels in reproductive-aged women fall with age despite the stimulatory effects of endogenous estradiol (E2). Eight older reproductive-aged women (aged 42-46 yr) with regular menses, of normal weight, and in good health were compared to a group of eight young control subjects (aged 19-34 yr). Daytime frequent blood sampling was performed in the early follicular phase of the menstrual cycle to characterize pulsatile GH and LH concentrations. Pooled samples were also analyzed for IGF-I, E2, progesterone, and FSH levels. Older reproductive-aged women had lower 12-h integrated daytime GH concentrations (mean +/- SE, 171 +/- 35 vs. 427 +/- 130 micrograms min/L; P = 0.036) than younger controls and a strong trend for lower IGF-I levels (22.7 +/- 2.1 vs. 31.3 +/- 3.5 nmol/L; P = 0.055) than younger controls despite having higher circulating E2 on the day of sampling (368 +/- 51 vs. 167 +/- 20 pmol/L; P = 0.002). We conclude that older reproductive-aged women have lower daytime GH concentrations than younger controls despite having higher E2 levels on the day of sampling and overall normal gonadal hormone parameters. PMID- 7852529 TI - Decreased insulin sensitivity in prepubertal girls with premature adrenarche and acanthosis nigricans. AB - Benign premature adrenarche (PA) is the term used to refer to girls with the early development of pubic hair before the age of 8 yr and is characterized by mild hyperandrogenism. Hyperandrogenism in adult women is often not as benign and has been associated with insulin resistance, acanthosis nigricans (AN), and the polycystic ovary syndrome. We have seen a group of young girls with PA who have also been found to have AN. The purpose of this study was to determine whether there are any clinical and biochemical differences in those girls with PA with and without AN. Twelve girls with PA were divided into two groups at the time of evaluation: group I, those without AN (n = 5); and group II, those with AN (n = 7). Adrenal androgen levels were determined in all subjects by a 60-min ACTH stimulation test. Insulin sensitivity was measured by the frequently sampled iv glucose tolerance test with tolbutamide and was assessed using the modified minimal model. Mean chronological age, bone age, and weight for length index were similar in the two groups. The baseline and stimulated levels of adrenal androgens were also not significantly different between the two groups. The group I girls (without AN) had an insulin sensitivity index of 6.75 +/- 1.31, which was in the normal prepubertal range. This was significantly different from that in group II (with AN), who had an insulin sensitivity index of 3.69 +/- 1.29. Therefore, many girls with premature adrenarche can have AN and decreased insulin sensitivity. Whether these girls have a truly benign course or are at risk of ovarian dysfunction or carbohydrate intolerance needs to be assessed. PMID- 7852530 TI - Mutations in the RET protooncogene in sporadic pheochromocytomas. AB - Mutations in the RET protooncogene have recently been demonstrated in families with multiple endocrine neoplasia (MEN) types 2A and 2B. We have studied pheochromocytomas from 29 individuals who had no clinical evidence of MEN-2A or 2B to determine the frequency of germline and/or somatic mutations in exons 10, 11, and 16 of the RET protooncogene. Of the 29 tumors examined, 3 (10%) were found to have a mutation in 1 of the 3 exons. These mutations were not found in the DNA from the peripheral blood from these individuals, indicating that the mutations in the tumors were somatic in origin. Although we cannot exclude the possibility of mutations in other regions of the RET protooncogene, our data suggest that 1) individuals presenting with apparently sporadic pheochromocytomas are not likely to have undiagnosed MEN-2A or -2B; and 2) somatic mutations in exons 10, 11, and 16 in the RET protooncogene contribute to the process of tumorigenesis in a small percentage of sporadic pheochromocytomas. PMID- 7852531 TI - The validity of estimating total body fat and fat-free mass from skinfold thickness in adults with growth hormone deficiency. AB - The regression equations of Durnin and Womersley for estimating total body fat (TBF) and fat-free mass (FFM) from skinfold thickness were validated for adult GH deficient (GHD) patients by comparing the values of TBF and FFM from the prediction equations with the directly measured values from dual energy x-ray absorptiometry. Twenty-seven male and 24 female patients (aged 21-61 yr) were studied. GHD was isolated in 5 cases and was part of a spectrum of hypopituitarism due to a variety of causes in 46 cases. The mean period of GHD was 6.9 +/- 4.6 yr. All patients were receiving stable replacement therapy. The validation statistics showed no significant differences (P > 0.05) between measured and predicted values of TBF and FFM in either males (24.5 vs. 24.9 and 65.5 vs. 65.8 kg) or females (24.6 vs. 26.3 and 44.7 vs. 43.9 kg). Mean differences were smaller in males (0.4 and 0.2 kg) than females (1.7 and -0.8 kg); they were less than 1% in males and less than 2% in females. Therefore, the Durnin and Womersley equations are suitable for general use with GHD patients. Using TBF (kilograms) from dual energy x-ray absorptiometry as the dependent variable and the log of the sum of skinfold thickness as the independent variable, linear regression equations were formulated to predict TBF in GHD patients. The lowest SE of estimate was 3.8 kg in males and 4.6 kg in females. To determine their general applicability, these equations will need to be cross validated. PMID- 7852532 TI - Insulin regulates testosterone and sex hormone-binding globulin concentrations in adult normal weight and obese men. AB - There are no studies in vivo on the effects of insulin on androgens and sex hormone-binding globulin (SHBG) in men. We, therefore, investigated the effects of insulin suppression on testosterone and SHBG in two groups of eight nondiabetic adult obese men and six healthy normal weight men who underwent diazoxide treatment (100 mg, three times daily) for 7 days. Blood samples for hormone determination were obtained before the subjects had been selected for the study, immediately before diazoxide administration, and on the last day of treatment. A 24-h oral glucose tolerance test was also performed for glucose, insulin, and C-peptide determinations before and on the last day of treatment. Only one subject experienced significant side-effects, and no significant changes in mean body weight were found during the treatment. Diazoxide administration worsened glucose tolerance in several subjects and reduced fasting and glucose stimulated insulin levels by approximately 50% in both control and obese subjects. No significant difference was present between historical and pretreatment hormone values in either group. Moreover, there were no differences in pretreatment gonadotropin and SHBG concentrations between the two groups, whereas testosterone (free and total) levels were lower in the obese than in the control subjects. After diazoxide administration, testosterone (free and total) decreased slightly, but significantly, whereas LH and SHBG significantly increased in both groups. Diazoxide treatment increased estradiol levels in controls, but not in obese men. In conclusion, these results indicate that in vivo, insulin is capable of stimulating testosterone production and, simultaneously, of inhibiting SHBG concentrations in both normal weight and obese men. PMID- 7852534 TI - Pharmacokinetics of recombinant human luteinizing hormone after intravenous, intramuscular, and subcutaneous administration in monkeys and comparison with intravenous administration of pituitary human luteinizing hormone. AB - To assess the pharmacokinetics of recombinant human LH (rhLH) in monkeys, we measured serum LH levels after single iv injection and after single and repeated doses by the im or sc route. A single iv bolus of 400 IU/kg rhLH or pituitary hLH (phLH) in six cynomolgus monkeys resulted in parallel concentration-time curves. The initial and terminal half-lives of rhLH (0.8 and 11 h) were comparable to those of phLH (0.6 and 10 h). The serum levels of phLH were consistently higher due to the fact that the immunological dose of phLH was higher. Administration of increasing iv doses of rhLH (10, 63, and 400 IU/kg) to six monkeys showed that the pharmacokinetics are linear over this dose range. The total clearance for the two higher doses was 0.03 L/h.kg. Systemic bioavailability was 50% after a single sc injection of 400 IU/kg and 61% after a single im injection of the same dose. The peak concentration (180 IU/L) after im injection was reached after 2.7 h. This was higher and sooner than after sc injection (110 IU/L after 5.3 h). The terminal half-life by both routes was similar to that seen after iv injection (11 h). Daily sc or im administration of 63 IU/kg for 7 days confirmed these findings. There was no accumulation of rhLH. Some monkeys developed antibodies, especially after repeated administration. They were excluded from the analysis. No significant local or systemic adverse events occurred. PMID- 7852533 TI - Cardiac performance and mass in adults with hypopituitarism: effects of one year of growth hormone treatment. AB - We studied the effects of GH administration on myocardial structure and function in 20 patients with hypopituitarism (14 males and 6 females; mean +/- SE age, 47.2 +/- 2.6 yr; range, 31-59 yr) developed in adulthood because of pituitary or parapituitary tumors. All patients had GH deficiency (GHD), as assessed by a GH response of less than 4 micrograms/L to a standard insulin tolerance test (0.05 U kg, iv) and the combined pyridostigmine (120 mg, orally, at -60 min) plus GHRH (1 microgram/kg, iv, at 0 min) test. Patients received either placebo (n = 10) or GH substitution therapy (n = 10; 0.05 U/kg.day GH for 1 yr; 0.03 U/kg.day during the first month). M- and B-mode echocardiography and pulsed Doppler examination of transmitral flow were performed before treatment, 6 months and 1 yr after starting GH or placebo administration, and 15 days and 3 months after GH or placebo withdrawal. Twenty healthy subjects, matched for age, sex, body mass index, and physical activity, served as controls. Left ventricular dimensions, mass, and systolic function were normal in patients with adult-onset GHD; however, diastolic function, specifically E wave deceleration time, was altered. GH administration markedly increased left ventricular performance and reversed diastolic abnormalities at 6 and even more so at 12 months. On the other hand, a clear increase in left ventricular mass was seen after 12, but not after 6, months of GH administration (P < 0.01 vs. pretreatment values). In addition, although all changes induced by GH treatment disappeared within 3 months after GH withdrawal, at that time the increase in left ventricular mass was still detectable (P < 0.05 vs. pretreatment values). These data indicate that augmented left ventricular contractility is not strictly related to cardiac muscle growth, supporting the hypothesis that GH treatment increases the inotropic activity of myocardial fibers. In conclusion, GH treatment enhances cardiac function, increases cardiac mass, and reverses diastolic abnormalities in adults with hypopituitarism and GHD. However, long term studies are required to demonstrate that GH replacement therapy reduces cardiac death rate in these patients. PMID- 7852535 TI - The growth hormone-releasing activity of hexarelin, a new synthetic hexapeptide, in short normal and obese children and in hypopituitary subjects. AB - Hexarelin (Hex) is a new synthetic hexapeptide with potent growth hormone (GH) releasing activity in both animals and men. We evaluated the GH response to a maximal dose of Hex (2 micrograms/kg iv) and GH-releasing hormone (GHRH) (1-29, 1 microgram/kg iv) in 45 short normal children (24 males and 21 females, age 5.9-14 yr, 24 prepubertal and 21 in Tanner stage 2 or 3 of pubertal maturation), in 10 prepubertal obese children (7 males and 3 females, age 7.5-12 yr), and in 5 subjects with organic hypopituitarism (4 males and 1 female, age 8.4-21 yr). In 5 male subjects with constitutional growth delay (age 12.0-13.7 yr), the GH response to Hex was reevaluated 1 week after priming with testosterone enanthate (100 mg im). In all short normal children Hex caused a prompt and clear-cut increase of serum GH concentrations, with peaks occurring between 15-30 min from injection. The GH response to Hex was significantly higher than that observed after GHRH and was not different between males and females or between prepubertal and pubertal subjects. Priming with testosterone resulted in an increased GH response to Hex in all 5 subjects studied. No GH increase was observed in the hypopituitary subjects after either GHRH or Hex administration. In the obese children the GH responses to GHRH and to Hex were significantly lower than in the prepubertal children. Also, in the obese, the GH response to Hex was significantly higher than that observed after GHRH. In all short normal and obese children, but not in the hypopituitary subjects, Hex administration caused a slight but significant increase from baseline of both cortisol and PRL concentrations that returned to the baseline values within 2 h. None of the subjects experienced adverse side effects after Hex administration. This study shows that, in short normal and obese children, Hex is a potent GH-releasing stimulus with potential clinical utility. PMID- 7852536 TI - A "hot spot" in the Pit-1 gene responsible for combined pituitary hormone deficiency: clinical and molecular correlates. AB - Pit-1 is a member of the POU family of transcription factors regulating mammalian development. Pit-1 is thought to be the major cell-specific activator of both the somatotrophs and lactotrophs in the anterior pituitary. When bound to DNA, Pit-1 activates GH and PRL gene expression. Pit-1 is also important for hormonal regulation of the PRL and TSH-beta genes by TRH and cAMP. We studied two unrelated patients with GH, PRL, and TSH deficiencies. Both patients have the same point mutation in the POU homeodomain of the Pit-1 gene (R271W). Patient 1 was studied as an adult and had combined deficiencies of GH, PRL, and TSH. Patient 2, who was studied in infancy, also had GH and PRL deficiencies, but had low thyroid hormone levels with a measurable basal level of TSH and a delayed response of TSH to TRH. Consequently, the current description of Pit-1 gene mutations leading to complete GH, PRL, and TSH deficiencies needs to be expanded to GH and PRL deficiencies associated with a compromise of the thyrotroph's ability to synthesize TSH. PMID- 7852537 TI - Insulin degradation by adipose tissue is increased in human obesity. AB - White adipose tissue samples from obese and lean patients were used for the estimation of insulin protease and insulin:glutathione transhydrogenase using 125I-labeled insulin. There was no activity detected in the absence of reduced glutathione, which indicates that insulin is cleaved in human adipose tissue through reduction of the disulfide bridge between the chains. Obese patients showed higher transhydrogenase activity (per U tissue protein wt, per U tissue wt, and in the total adipose tissue mass) than the lean group. There is a significant correlation between the activity per U tissue wt, and protein and total activity in the whole adipose tissue with respect to body mass index, with a higher activity in obese patients. The potential of insulin cleavage by adipose tissue in obese patients was a mean 5.6-fold higher than that in controls. The coexistence of high insulinemia and high cleavage capability implies that insulin secretion and turnover are increased in the obese. Thus, white adipose tissue may be crucial in the control of energy availability through modulation of insulin cleavage. PMID- 7852538 TI - Serum angiotensin-I-converting enzyme activity in women with cardiological syndrome X: relation to blood pressure and lipid and carbohydrate metabolic risk markers for coronary heart disease. AB - Polymorphism of the angiotensin-I-converting enzyme (ACE) gene is associated with variations in serum ACE activity and the incidence of cardiovascular disease. Whether a similar association exists with cardiological syndrome X (chest pain, positive ECG exercise test, and normal angiography) is unclear. As ACE activity affects vascular tone, it could be involved in the pathogenesis of this syndrome. We measured serum ACE activity in 18 postmenopausal women with syndrome X and in 18 healthy controls matched for age, adiposity, and menopausal status. The relationship of ACE activity to coronary heart disease risk factors was also examined within these groups. Serum ACE activity did not differ significantly between women with syndrome X and controls. Neither blood pressure, serum total cholesterol, triglyceride, nor high density lipoprotein subfraction 2 cholesterol was associated with ACE activity in either patient group. However, serum high density lipoprotein cholesterol, high density lipoprotein subfraction 3 cholesterol, and apolipoprotein-A-I and -A-II were inversely associated with ACE activity in women with syndrome X, but not in controls. Insulin sensitivity, fasting plasma glucose, insulin, and C-peptide as well as their postglucose challenge concentration profiles were not significantly associated with ACE activity in either group. We conclude that serum ACE activity and, consequently, ACE polymorphism are not associated with syndrome X and are largely independent of metabolic risk factors in these women. PMID- 7852539 TI - Effects of insulin reduction with benfluorex on serum dehydroepiandrosterone (DHEA), DHEA sulfate, and blood pressure in hypertensive middle-aged and elderly men. AB - To determine whether a reduction in insulinemia would be associated with a rise in serum dehydroepiandrosterone (DHEA) sulfate in insulin-resistant men, 29 middle-aged (30-59 yr old) and 28 elderly (60-80 yr old) hypertensive men were enrolled into a single blind, placebo-controlled study, in which benfluorex was administered to improve insulin sensitivity and reduce circulating insulin. Men in each age group received either benfluorex (150 mg) or placebo three times daily for 6 weeks, and fasting serum insulin, glucose, DHEA, DHEA sulfate, and cortisol were determined before and after treatment. Glucose tolerance was also assessed by an oral glucose tolerance test. Benfluorex treatment lowered diastolic and systolic blood pressures and improved glucose tolerance in both age groups. In middle-aged men, benfluorex (n = 12) reduced both the area under the curve for glucose (AUCGLUCOSE; from 977 +/- 27 to 814 +/- 27 mmol/L.min; P = 0.0001) and the AUCINSULIN (from 78.1 +/- 7.9 to 44.5 +/- 5.7 nmol/L.min; P < 0.0001) during the oral glucose tolerance test. In elderly men, benfluorex (n = 15) also reduced both the AUCGLUCOSE (from 1100 +/- 60 to 864 +/- 26 mmol/L.min; P < 0.0001) and the AUCINSULIN (from 88.9 +/- 5.6 to 44.8 +/- 5.8 nmol/L.min; P < 0.0001). Concurrent with the reduction in insulinemia, benfluorex treatment was associated with rises in both serum DHEA sulfate and unconjugated DHEA. In middle aged men, serum DHEA sulfate and DHEA rose from 6.80 +/- 0.75 to 10.52 +/- 1.02 mumol/L (P < 0.015) and from 13.69 +/- 1.95 to 22.78 +/- 2.90 nmol/L (P < 0.03), respectively. In elderly men, serum DHEA sulfate and DHEA rose from 5.16 +/- 0.67 to 8.36 +/- 1.21 mumol/L (P < 0.015) and from 8.47 +/- 0.99 to 22.61 +/- 3.24 nmol/L (P < 0.0005), respectively. In neither middle-aged nor elderly men did serum cortisol change with benfluorex treatment. Neither glucose tolerance nor serum DHEA, DHEA sulfate, or cortisol levels changed in either middle-aged (n = 17) or elderly (n = 13) men treated with placebo. We conclude that benfluorex treatment lowers blood pressure, improves glucose tolerance, reduces the glucose stimulated insulin response, and increases serum DHEA and DHEA sulfate in both middle-aged and elderly men.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7852540 TI - The human Leydig insulin-like (hLEY I-L) gene is expressed in the corpus luteum and trophoblast. AB - A novel member of the insulin superfamily has previously been shown to be expressed only in porcine pre and postnatal Leydig cells and its human analogue demonstrated in the human testes but not in other organs and hence has been tentatively termed Leydig insulin-like peptide (Ley I-L). However, we have detected hLey I-L gene expression in the cyclic human corpus luteum and trophoblast by the reverse transcriptase-polymerase chain reaction (RT-PCR), with primers selected from the published human Ley I-L sequence. Normal and neoplastic breast tissue and fetal membranes with adhering decidua did not express the gene. The overall sequence of the trophoblast gene was in agreement with that reported with minor changes only in the putative connecting peptide, confirmed by restricted enzyme digestion. A 290 bp RT-PCR product was cloned and used as a cDNA probe in Northern analyses; hybridization was readily shown with cyclic corpora lutea but not with other tissues. The broader spectrum of the expression of this gene will warrant a new nomenclature when its biological activities are known. The different intensity of expression in the corpus luteum and trophoblast suggest endocrine and autocrine/paracrine roles respectively in these tissues in which H2 relaxin and H1/H2 relaxins coexist respectively and at similar levels of expression. Operationally the amino acid sequence homologies between the processed H1 and H2 relaxins and hLey I-L may qualify the specificity claimed for immunostaining the human relaxins in the corpus luteum and trophoblast. PMID- 7852541 TI - Relationship between basic fibroblast growth factor and transforming growth factor-beta 2 in breast cyst fluid. AB - Women with "apocrine" breast cysts (usually having intracystic Na/K < 3) may have a higher risk of developing breast cancer than women with breast cysts lined by flattened epithelium (usually having intracystic Na/K > 3). In this study the concentrations of basic fibroblast growth factor (bFGF), a potent mitogen, and transforming growth factor-beta 2 (TGF-beta 2), which exerts a growth inhibitory effect on epithelial cell types, were measured in breast cyst fluid and their relationship studied. Both growth factors were measured by "sandwich" enzyme immunometric assays. The concentrations of both bFGF and TGF-beta 2 were significantly higher (P < 0.001) in the Na/K > 3 group (median 444 fmol/L, range: < 56 fmol/L-7,890 fmol/L, n = 23 and median 1,776 pmol/L, range: 20.4 pmol/L 5,000 pmol/L, n = 19 respectively) than in the Na/K < 3 group (median < 56 fmol/L, range: < 56 fmol/L-2,722 fmol/L, n = 21 and median 176 pmol/L, range: 12 pmol/L-1,940 pmol/L, n = 23 respectively). Significantly positive correlations were found between bFGF and TGF-beta 2 (rS = 0.496, n = 37, P = 0.002), bFGF and Na/K (rS = 0.599, n = 44, P < 0.001) and TGF-beta 2 and Na/K (rS = 0.521, n = 42, P < 0.001). The significantly higher concentrations of the growth inhibitory TGF beta 2 in the Na/K > 3 cyst group may provide an explanation for the lower risk of breast cancer which has been observed in this group of women. The role of bFGF in mammary carcinogenesis is unclear as lower levels of this growth factor are present in breast cancer tissue and breast cancer cell lines than in normal breast tissue and cell lines. The positive correlation between bFGF and TGF-beta 2 may indicate regulation by a common factor or that one of these growth factors may regulate the production of the other. This is the subject of further study. PMID- 7852542 TI - Prenatal development of the human osseous temporomandibular region. AB - The purpose of the present study was to describe the sequence in which the lateral cranial base ossifies, particularly in the temporomandibular region. Charting the ossification sequence in the lateral normal cranial base is important for evaluating deviations in pre- and postnatal temporomandibular development. The material consisted of 74 normal human fetuses (crown-rump length = 25-228 mm). The period investigated covers the interval from the early start of ossification at 8 weeks gestational age to the occurrence of a complex ossification pattern at 21 weeks gestational age. Ossification of the cranial base in the sagittal plane is assessed mainly by radiography. The findings are confirmed by marking structures before X-ray, devisceration, and histology. This investigation confirms previous findings concerning regularity in cranial ossification sequences. In addition, the ossification in the temporomandibular region is divided into eight developmental stages according to the pattern of ossification. Thus, a developmental reference material has been established based on the following sequence in ossification of the cranial base (including the mandible and the zygomatic bone): mandible, maxilla, medial pterygoid process of the sphenoid bone, the horizontal part of the frontal bone, the zygomatic bone, the zygomatic arch of the temporal bone, the squamous part of the temporal bone and the occipital squama followed by ossification in the greater wing of the sphenoid bone, the tympanic ring, the occipital condyle, the minor wing of the sphenoid bone (anterior clinoid process), and the lateral part of the postsphenoid bone.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7852543 TI - Craniofacial features in patients with deficient and excessive growth hormone. AB - We studied the role of growth hormone (GH) in craniofacial growth by analyzing the craniofacial structures in patients with either deficient or excessive GH. The cephalogrammes of 21 patients with isolated or combined GH deficiency and of two patients with GH excess were compared with cephalogrammes of age and sex matched controls, and the patients with deficient GH also with height and sex matched controls. In cephalometric measurements, skeletal anatomy was followed as closely as possible. All patients had a Class I or an end-to-end dental occlusion. Head circumference was normal in all patients. Facial widths were significantly smaller in patients with deficient GH but at the level of + 2 SDs in the two with GH excess when compared to Finnish norms. In patients with deficient GH, facial heights were significantly smaller than in age matched controls, but of the same order with height controls for anterior facial height. Posterior facial height was smaller even in this comparison. In patients with GH excess, facial heights were much larger and at the levels of +3 and +6 SD. Clivus was shorter in patients with deficient GH and longer (+ 1.9 and +3 SD) in the two with GH excess. All angulations of the sphenoidal plane deviated from those of the controls in the group with GH deficiency. The cranial base angle (CL-SPhen) was smaller than in controls while it was normal in patients with GH excess. We are inclined to interpret the craniofacial structure of those with deficient GH as being unique to the condition rather than merely negative allometry.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7852544 TI - Cranial size and configuration in the Apert syndrome. AB - The cranial size and configuration of the Apert cranium are unique. True megalencephaly is characteristic, postmortem brain weights being dramatically increased above the 95th centile regardless of age. In addition, all Apert newborn infants have coronal synostosis with a widely patent midline calvarial defect. Thus, the head is unusually heavy and the cranium is disproportionately high. These characteristics, which are present at birth, result in a mean newborn length and weight above the 50th centile. The widely patent midline calvarial defect, allowing the brain to expand anteriorly into the metopic area, and some increase in the head breadth permit the mean head circumference at birth to normalize slightly above the 50th centile. In our series of surgically unoperated patients of different ages from the 1960s and earlier, most head circumference values fall below the mean but within or at -2 SD. Thus, the natural history of the unoperated growing cranium, beginning slightly above the 50th centile at birth, consists of a slowing of head circumference expansion to a greater degree than normal. Studies of intracranial volume show that mean adult male and female volumes far exceed normal adult values. Cranial shape is distinctive with head breadth either being normal or slightly increased, head length being significantly shortened, and head height being dramatically increased. The mean cephalic index is hyperbrachycephalic. Sexual dimorphism is found, with higher values in females than in males; the cause is unknown, although the contributing component appears to be head breadth. The disproportionately high cranium in the Apert syndrome is dramatically shown by the great differences from normal in the head height/head breadth index and in the head height/head length index. Finally, the crania of Apert and Crouzon syndromes are compared in terms of size, shape, and volume. For Crouzon syndrome, the mean adult cephalic index is normocephalic and the mean adult intracranial volume is smaller than normal. PMID- 7852545 TI - Cleidocranial dysplasia: craniofacial morphology in adult patients. AB - The aim of the study was to carry out a detailed quantitative analysis of craniofacial morphology in a relatively large sample (N = 35) of adult patients with cleidocranial dysplasia (CCD) in order to contribute to the understanding of the characteristic craniofacial abnormalities. Roentgencephalometric films in the lateral, frontal, and basal projections were analyzed and mean facial diagrams for the lateral and frontal films were produced based on registration of 216 reference points. In the calvaria an increased width and a relatively more prominent frontal region were found. In the cranial base the most significant findings were reduced width, a cranial displacement of the clivus and sella, and an anteriorly facing foramen magnum. The orbital openings were high and narrow and nearly all patients had hypoplasia or aplasia of the nasal bones. The maxilla and mandible were reduced in height and width and the mandible was anteriorly inclined. It was concluded that all craniofacial regions are affected in CCD. Based on the present and previous studies, it is suggested that the abnormal craniofacial morphology in CCD may be explained by the skeletal dysplasia, combined with early cranial deformation and dysplastic and compensatory skeletal growth. Thus, the findings lead to the comprehension that several primary and secondary causal factors are involved in craniofacial morphogenesis in CCD, and that knowledge of early development is important when etiology and pathogenesis in a syndrome is searched for. PMID- 7852546 TI - Defective development of the craniofacial/digestive complex of Xenopus laevis after treatment with endogenous galactoside-binding lectin or its hapten inhibitor thiodigalactoside. AB - The regions of the developing craniofacial skeleton and gut of Xenopus laevis have been confronted in vivo with purified embryonic galactoside-binding lectin or its hapten inhibitor thiodigalactoside (TDG). Confrontation was carried out at stage 24-26 (cranial neural crest migrating). Further development of the head skeleton and gut has been monitored in living animals and in histological cross sections of selected head regions. Lectin treatment correlates with the development of larger heads than controls. TDG treatment correlates with the development of narrower heads than controls. After both treatments, head cartilages are composed of fewer total chondrocytes. Both neural crest and non neural crest cartilages are affected. The gut forms larger, irregular coils after lectin or TDG confrontation. The results suggest that galactoside-binding lectin/galactoside-bearing receptor adhesive interactions are important in development of the craniofacial/visceral skeleton and gut. PMID- 7852547 TI - Exencephaly and axial skeletal malformations induced by maternal administration of sodium valproate in the MF1 mouse. AB - Clinical and epidemiological studies indicate that maternal use of valproic acid (VPA) during pregnancy causes an increased risk for spina bifida in the fetus. A proportion of infants exposed to VPA in utero exhibit a characteristic pattern of facial malformations. Despite the developmental interdependence of the neural plate and paraxial mesoderm during normal morphogenesis, the possible involvement of the axial skeleton in VPA-induced NTD has not been clearly documented. So the objective of this investigation was to determine the nature and extent of involvement of the axial skeleton in VPA-induced exencephaly in the mouse. A single dose of 600 mg/kg of sodium valproate was administered (IP) to MF1 mouse on day 8 of gestation. This treatment resulted in significant increase in resorption, reduction in mean fetal weight, and exencephaly (25%) of live fetuses. Several craniofacial malformations and subcutaneous haematomas were associated with exencephaly. Alizarin red-stained skeletal preparations revealed maxillary-, mandibular hypoplasia, absence of skull vault, hypoplasia and/or agenesis of basicranial bones, and obtuse angulation of the craniovertebral junction. Hemivertebrae, longitudinal fusion of the vertebral arches and bodies, accessory ribs (cervical and lumbar), fusion of thoracic ribs, and several patterns of sternal variations were observed. Nonexencephalic VPA-treated embryos exhibited mandibular, maxillary hypoplasia, arched and cleft palates, cleft lip, kinky tail, and vertebral and sternal anomalies. Treated embryos at early stages of development revealed delay in elevation and fusion of neural folds, distended IVth ventricle, kinky spinal cord, incomplete separation of somites and growth retardation. When viewed in light of the published work on VPA action on embryonic systems, these observations suggest that abnormalities associated with VPA-induced exencephaly may be due to either a direct action of VPA on the precursors of these organs or secondary to its action on neural tube. A significantly high incidence of NTD and their consistent association with defective development of the axial skeleton suggest that this is an excellent experimental model for investigating the pathogenetic mechanism(s) of VPA induced NTD. PMID- 7852548 TI - Discrimination of epidemic and sporadic isolates of Acinetobacter baumannii by repetitive element PCR-mediated DNA fingerprinting. AB - In 1990, there was a significant increase in the number of lower respiratory tract infections and surgical wound infections in the adult intensive care units of our tertiary care teaching hospital caused by Acinetobacter baumannii compared with the number in 1989. During the 5-month period from April through August 1990, 84 isolates of A. baumannii were recovered from 50 hospitalized patients. Biotyping, comparison of antibiograms, plasmid analysis, and DNA polymorphisms of 20 isolates from 20 different patients, determined by the use of repetitive element PCR with primers aimed at repetitive extragenic palindromic sequences and enterobacterial repetitive intergenic consensus sequences, were used to investigate this apparent outbreak. Biotyping, antibiograms, plasmid analysis, and enterobacterial repetitive intergenic consensus PCR were not useful epidemiologically. Repetitive element PCR-mediated DNA fingerprinting using repetitive extragenic palindromic primers discriminated between epidemic and sporadic strains of A. baumannii and demonstrated four discrete clusters which were unique epidemiologically. PMID- 7852549 TI - Rapid screening for early detection of mother-to-child transmission of human immunodeficiency virus type 1. AB - The testing of dried blood spots (DBSs) for the presence of human immunodeficiency type 1 (HIV-1) proviral DNA by PCR was first described in 1991. The technology has proven to be particularly valuable for resolving the infection status in HIV-1-indeterminate infants born to HIV-1-seropositive mothers. To broaden the applicability of DBS PCR, we adapted it to a standardized, commercially available microwell plate amplification and detection kit, Amplicor HIV-1, produced by Roche Diagnostic Systems. The microwell assay is rapid and easy to perform and uses equipment that is readily available in routine diagnostic laboratories. The high level of performance of the assay was demonstrated in 1,168 duplicate tests performed on 584 DBSs from 178 uninfected and 100 HIV-1-infected individuals, including 56 children with perinatally acquired HIV-1. Of 12 infants who were followed prospectively from birth, 3 (25%) were infected in utero (PCR positive at birth) and 9 (75%) were infected intrapartum (PCR negative, culture negative at birth). Overall, HIV-1 DNA was identified in 3 of 11 (27.3%) DBSs collected from infected infants during the first 4 days of life, 8 of 9 (88.9%) DBSs collected between 10 and 15 days postpartum, and 166 of 167 (99.4%) DBSs collected after 15 days of age. All 320 DBSs from uninfected children were PCR DNA negative. These findings indicate that use of the Roche microwell DBS PCR assay provides a powerful new approach for large-scale perinatal screening programs and population-based studies of vertical transmission. PMID- 7852550 TI - Evolution and replacement of Candida albicans strains during recurrent vaginitis demonstrated by DNA fingerprinting. AB - Southern blot hybridization with the Ca3 probe and the C fragment of the Ca3 probe was used to assess the genetic relatedness of Candida albicans strains from one patient with recurrent C. albicans infection in whom the same strain was maintained, one patient in whom the infecting strain was replaced, and their male sexual partners. In the patient in whom the infecting strain was maintained, the infecting strain exhibited a minor genetic change in each successive episode of Candida vaginitis. These genetic changes occurred in the C-fragment bands of the Ca3 hybridization pattern. In the patient in whom the infecting strain was replaced by another infecting strain, a transition infection involved a genetically mixed infecting population, and the replacement strain appeared to have originated from the oral cavity of the male partner. The results demonstrate that the infecting strains of recurrent Candida vaginitis are not genetically stable, that drug treatment can result in the selection of variants of the previously infecting strain or replacement by a genetically unrelated strain, and that the male partner can be the source of a replacement strain. PMID- 7852551 TI - Diagnosis of cytomegalovirus infections by shell vial assay and conventional cell culture during antiviral prophylaxis. AB - A total of 3,552 specimens for conventional cytomegalovirus (CMV) culture and shell vial assay for CMV immediate-early antigen were obtained during a prospective randomized trial for prophylaxis of CMV disease after liver transplantation. Prophylaxis with ganciclovir for 2 weeks and then high-dose acyclovir for 2.5 months was compared with high-dose acyclovir alone for 3 months. During the first 12 weeks after transplantation, when the patients were on prophylaxis, there were significantly more clinical samples positive by the shell vial assay and negative by standard culture in comparison with the number of samples obtained from weeks 13 to 24, after prophylaxis was discontinued, that were positive by the shell vial assay and negative by standard culture. In contrast, significantly fewer samples were positive by both the shell vial assay and standard culture during the first 12 weeks compared with the number obtained 13 to 24 weeks after transplantation that were positive by both methods. Samples positive by the shell vial assay only were obtained significantly more frequently from patients with asymptomatic than symptomatic CMV infections, while samples positive by both methods were obtained significantly more often from patients with symptomatic CMV infection. It was concluded that antiviral prophylaxis with high-dose acyclovir or ganciclovir and then high-dose acyclovir and asymptomatic CMV infection are associated with a decrease in the level of CMV isolation by standard cell culture in comparison with that by the shell vial assay. PMID- 7852552 TI - Differentiation of Brucella abortus bv. 1, 2, and 4, Brucella melitensis, Brucella ovis, and Brucella suis bv. 1 by PCR. AB - Several PCR assays which identify the genus Brucella but do not discriminate among species have been reported. We describe a PCR assay that comprises five oligonucleotide primers which can identify selected biovars of four species of Brucella. Individual biovars within a species are not differentiated. The assay can identify three biovars (1, 2, and 4) of B. abortus, all three biovars of B. melitensis, biovar 1 of B. suis, and all B. ovis biovars. These biovars include all of the Brucella species typically isolated from cattle in the United States, a goal of the present research. The assay exploits the polymorphism arising from species-specific localization of the genetic element IS711 in the Brucella chromosome. Identity is determined by the size(s) of the product(s) amplified from primers hybridizing at various distances from the element. The performance of the assay with U.S. field isolates was highly effective. When 107 field isolates were screened by the described method, there was 100% agreement with the identifications made by conventional methods. Six closely related bacteria (Agrobacterium radiobacter, Agrobacterium rhizogenes, Ochrobactrum anthropi, Rhizobium leguminosarum, Rhizobium meliloti, and Rhodospirillum rubrum) and two control bacteria (Bordetella bronchiseptica and Escherichia coli) tested negative by the assay. PMID- 7852553 TI - Comparison of PCR assay with bacterial culture for detecting Streptococcus pneumoniae in middle ear fluid of children with acute otitis media. AB - We have studied etiological diagnosis of acute otitis media (AOM) by comparing a newly developed pneumococcal PCR for Streptococcus pneumoniae to bacterial culture with 180 middle ear fluid (MEF) samples of 125 children with 125 episodes of AOM. For pneumococcal PCR assay, DNA from MEF samples was extracted by phenol chloroform. The outer primers used amplified a 348-bp region of the pneumolysin gene, and the inner primers amplified a 208-bp region. S. pneumoniae was cultured in 33 (18%) samples, and pneumolysin PCR was positive for 51 (28%) of 180 MEF samples. Only 2 of 21 PCR-positive, S. pneumoniae culture-negative samples were positive for other otitis pathogens. By combining MEF culture and PCR results, 54 (30%) of 180 MEF samples had evidence of pneumococcal etiology. In conclusion, pneumolysin PCR is a sensitive and specific new method to study pneumococcal involvement in MEF samples of children with AOM. PMID- 7852554 TI - Risk factors for acquiring ampicillin-resistant enterococci and clinical outcomes at a Canadian tertiary-care hospital. AB - The number of ampicillin-resistant enterococci (ARE) was noted to be increased at our teaching hospital. To determine the risk factors for acquiring this organism and to compare clinical outcomes, over a 5-month period 38 patients infected or colonized with ARE were compared with 76 patients, infected or colonized with ampicillin-susceptible enterococci (ASE). Risk factors included nosocomial acquisition, duration of hospitalization, admission to a medical service, prior antimicrobial therapy, and combination therapy for at least 7 days. The mortality rate of patients infected or colonized with ARE was higher than that of patients infected or colonized with ASE (34 versus 14%; P = 0.03), but most deaths did not appear to be related to enterococcal infection. Over a 2-year period, 16 patients with ARE bacteremia were also compared with 23 patients with ASE bacteremia. The risk factors associated with ARE bacteremia also included nosocomial acquisition, duration of hospitalization, and prior antimicrobial therapy. The mortality of patients with ARE bacteremia was also higher than that of patients with ASE bacteremia (81 versus 30%; P = 0.003), with most deaths being due to the underlying disease or a complication of it. Typing of ARE isolates by pulsed field gel electrophoresis showed that two genotypes predominated in our institution. A prolonged hospital stay, exposure to multiple antimicrobial agents, and perhaps nosocomial transmission are important factors in acquiring ARE. The presence of ARE may also be a marker for poor outcome. PMID- 7852555 TI - Characterization of a hospital outbreak of imipenem-resistant Acinetobacter baumannii by phenotypic and genotypic typing methods. AB - During a 13-month period, 31 patients hospitalized primarily in two intensive care units (ICUs) were either colonized or infected by imipenem-resistant Acinetobacter baumannii. Typing of the isolates by three methods (antibiotyping, biotyping, and pulsed-field gel electrophoresis) revealed that two distinct strains were involved in the first 9 cases of the outbreak and that one of these strains, which had acquired a higher level of imipenem resistance as well as resistance to all aminoglycosides, accounted for 21 of 22 cases in the second part of the outbreak. ICU environmental contamination was recognized as an important reservoir of this epidemic strain. The outbreak ceased only after the ICUs were closed for complete cleaning and disinfection. PMID- 7852556 TI - Diagnosis of Chlamydia trachomatis infections in men and women by testing first void urine by ligase chain reaction. AB - From April to September 1993, 305 men and 447 women in Hamilton, Canada, consented to the collection of a urethral or cervical swab, respectively, for culture and 20 ml of first-void urine (FVU) for testing by the enzyme immunoassay Chlamydiazyme and by ligase chain reaction (LCR) in the form of a kit from Abbott Laboratories called LCx Chlamydia trachomatis. Evaluation of test performance with each specimen was calculated on the basis of an expanded "gold standard" of a patient found to be positive by culture or by a confirmed nonculture test. By using this expanded standard, the prevalence of infection was determined to be 6% (27/447) for the women and 18.4% (56/305) for the men. LCR testing of FVU in both studies was the most sensitive approach (96%). The performance of Chlamydiazyme was as follows: cervical swab, 78.3% sensitivity; female FVU, 37% sensitivity; and male FVU, 67.9% sensitivity. Culture was the least sensitive approach to diagnosis: female cervix, 55.6%; and male urethra, 37.5%. LCR testing of FVU from men or women diagnosed the greatest number of genitourinary tract infections with no false positives. PMID- 7852557 TI - Primary identification of Aureobacterium spp. isolated from clinical specimens as "Corynebacterium aquaticum". AB - Over a 6-year period 11 yellow-pigmented gram-positive rods (GPRs) with an oxidative carbohydrate metabolism were isolated from clinical specimens or were received as reference cultures and tentatively identified as "Corynebacterium aquaticum" according to the guide of Hollis and Weaver for the differentiation of GPRs (D. G. Hollis and R. E. Weaver, Gram-Positive Organisms: a Guide to Identification, 1981). Because these isolates seemed to be rather heterogeneous, comparative analyses with the type strain of "C. aquaticum" as well as six type strains of species belonging to the genus Aureobacterium were performed by biochemical and chemotaxonomic methods. Only four clinical strains were found to be "C. aquaticum," whereas seven strains were found to belong to the genus Aureobacterium. Discriminative phenotypic reactions between "C. aquaticum" and Aureobacterium spp. included hydrolysis of gelatin and casein (both reactions negative for "C. aquaticum" strains but positive for most Aureobacterium strains). Moreover, peptidoglycan analysis provided a reliable means of differentiating yellow-pigmented GPRs at the genus level (diaminobutyric acid as the interpeptide bridge in "C. aquaticum" and glycine-ornithine as the interpeptide bridge in Aureobacterium spp.). Antimicrobial susceptibility testing revealed that vancomycin showed an intermediate MIC for three of the four clinical "C. aquaticum" isolates, whereas all Aureobacterium strains were susceptible to vancomycin. To our knowledge, this is the first report outlining the isolation of Aureobacterium spp. from clinical specimens. However, Aureobacterium isolates could not be identified to the species level by the tests used in the study. PMID- 7852558 TI - Epidemiologic investigation by macrorestriction analysis and by using monoclonal antibodies of nosocomial pneumonia caused by Legionella pneumophila serogroup 10. AB - A 67-year-old woman was hospitalized with an acute pneumonia of the left lower lobe. Legionella pneumophila serogroup 10 was cultured from two sputum specimens taken on days 18 and 20 and was also detected by direct immunofluorescence assay by using a commercially available species-specific monoclonal antibody as well as serogroup 10-specific monoclonal antibodies. Antigenuria was detected in enzyme linked immunosorbent assays by using serogroup 10-specific polyclonal and monoclonal antibodies. In the indirect immunofluorescence test rising antibody titers against serogroups 1, 4, 5, 8, 9, 10, 14, and 15 were found in serum, with the highest titers found against serogroups 8, 9, and 10. L. pneumophila serogroups 10 and 6 and a strain that reacted with serogroup 4 and 14 antisera were cultured from both central and peripheral hot water systems of the hospital. Macrorestriction analyses of the genomic DNAs by pulsed-field gel electrophoresis showed that the isolate from the patient was identical to the serogroup 10 strains from the hospital hot water system. In contrast, the genomic DNAs of 16 unrelated L. pneumophila serogroup 10 strains showed 12 different restriction patterns. Monoclonal antibody subtyping revealed only minor differences in L. pneumophila serogroup 10 strains isolated from different sources. In conclusion, macrorestriction analysis is a valuable tool for studying the molecular epidemiology of L. pneumophila serogroup 10. PMID- 7852559 TI - Evaluation of two rapid antigen assays, BioStar Strep A OIA and Pacific Biotech CARDS O.S., and culture for detection of group A streptococci in throat swabs. AB - Two rapid methods, BioStar Strep A OIA (OIA; BioStar, Inc., Boulder, Colo.), an optical immunoassay, and CARDS O.S. (O.S.; Pacific Biotech, Inc., San Diego, Calif.), a color immunochromographic assay, and two culture methods, one with 5% sheep blood agar (SBA) and one with Todd-Hewitt broth (TH; Remel, Lenexa, Kans.), were evaluated for use in the detection of Streptococcus pyogenes from pharnygeal swabs. Seven hundred forty-six double swabs (Culturette II) were processed, with OIA and SBA culture performed on one swab and O.S. and SBA culture performed on the other swab. The pledget from the Culturette II was incubated overnight in TH and was subcultured onto SBA for an additional 48 h in ambient air. All beta hemolytic streptococci from culture were tested by a direct fluorescent-antibody test (Difco Laboratories, Detroit, Mich.). Specimens with discordant fluorescent antibody test and rapid test results were also tested by using the Streptex latex agglutination reagent (Murex Diagnostics Limited, Dartford, England). The results obtained by all testing methods were compared with a combined test result ("gold standard"), which was defined as any positive culture detected by the SBA or TH culture methods and confirmed by Streptex latex agglutination or, in the case of negative results by both culture methods, a concomitant positive result by OIA and O.S. antigen testing. Sensitivity and specificity results for each of the methods were as follows, respectively: OIA, 81.0 and 97.5%; O.S., 74.4 and 99.0%; SBA culture, 92.3 and 98.3%; and TH culture, 86.4 and 100%. Both OIA and O.S. are suitable screening methods for detecting S. pyogenes directly from throat swabs but are of insufficient sensitivity to eliminate the need for backup cultures for specimens with negative OIA and O.S. results. PMID- 7852560 TI - Routine identification of Mycobacterium tuberculosis complex isolates by automated hybridization. AB - Methodologies for biochemical identification of mycobacteria isolated from clinical samples are still cumbersome, taking skilled technicians 3 to 6 weeks. We describe here a 2-h identification system for mycobacterial isolates belonging to the Mycobacterium tuberculosis complex using a DNA probe. After 30 min of hands-off sample preparation, the 1.5-h hybridization test is totally automated in the newly developed VIDAS system (bioMerieux, Marcyl'Etoile, France), which performs solid-phase specific hybridization of 16S rRNA at 37 degrees C. The strain collection of actinomycetes tested was composed of 662 isolates from 27 species: 461 members of the M. tuberculosis complex (443 M. tuberculosis, 10 M. bovis, and 8 M. bovis BCG isolates) and 201 isolates of other species, including 55 M. avium-intracellulare isolates). They were identified by traditional methods: growth rate, colonial morphology, pigmentation, and biochemical profiles. The automated probe assay displayed an excellent correlation with the reference results. The four members of the Nocardia and Rhodococcus genera tested did not cross-hybridize. This flexible random-access and automated technology was shown to suit the routine context of the laboratory by rapidly delivering the results. PMID- 7852561 TI - Surgical wound infection caused by Rahnella aquatilis. AB - Rahnella aquatilis is a water-residing gram-negative rod, a member of the family Enterobacteriaceae, isolated rarely from clinical specimens of immunocompromised patients. A case of a surgical wound infection caused by R. aquatilis in a patient who underwent a prosthetic surgical intervention is reported. The presence of inducible beta-lactamase was suggested by the disk induction test and the conventional agar dilution assay. Literature on R. aquatilis infections in humans is reviewed. PMID- 7852562 TI - Comparative quantitation of human cytomegalovirus DNA in blood leukocytes and plasma of transplant and AIDS patients. AB - A new method for the quantitation of human cytomegalovirus (HCMV) DNA was used to determine the levels of viral DNA in parallel in 120 blood leukocyte (leukoDNAemia) and plasma (plasmaDNAemia) samples from 8 heart or heart-lung transplant patients and 17 AIDS patients with disseminated HCMV infection. PlasmaDNAemia was consistently associated with leukoDNAemia in both groups of patients. However, at least in the transplant patients, plasmaDNAemia was not necessarily associated with clinical symptoms, appearing later and disappearing earlier than leukoDNAemia during the course of infection. Quantitative mean levels of leukoDNAemia were mostly higher than those of plasmaDNAemia in both transplant and AIDS patients. However, in the absence of antiviral treatment, plasmaDNAemia levels were significantly higher in AIDS patients than in transplant recipients, whereas leukoDNAemia levels were not significantly different between the two groups of patients. A significant correlation was found between leukoDNAemia and plasmaDNAemia in AIDS patients, as well as in transplant recipients, although to a lesser degree. However, from a diagnostic standpoint, quantitative determination of plasmaDNAemia appears to represent a much less sensitive parameter than that of leukoDNAemia (or antigenemia) for monitoring HCMV infections and antiviral treatment. PMID- 7852563 TI - Susceptibility of white-tailed deer (Odocoileus virginianus) to infection with Ehrlichia chaffeensis, the etiologic agent of human ehrlichiosis. AB - Although more than 320 cases of human ehrlichiosis have been diagnosed in 27 states since 1986, the reservoir host or hosts remain unknown. Since antibodies reactive to Ehrlichia chaffeensis, the etiologic agent of human ehrlichiosis, have been found in white-tailed deer (Odocoileus virginianus), we experimentally evaluated the susceptibilities of four white-tailed deer to infection with E. chaffeensis and Ehrlichia canis, a closely related species. A fifth deer served as a negative control. Isolation and nested PCR amplification results from peripheral blood indicated that E. chaffeensis circulated for at least 2 weeks. The deer developed antibodies to E. chaffeensis by day 10 after inoculation, but there was no indication of clinical disease. Immunohistochemical staining identified E. chaffeensis within macrophage-type cells in lymph nodes. The deer inoculated with E. canis did not become infected and did not seroconvert. These results indicate that white-tailed deer can support an E. chaffeensis infection with resulting rickettsemia of at least 2 weeks. The resistance to infection and the absence of seroconversion upon exposure to E. canis indicate that antibody responses previously detected among wild deer are not E. canis cross-reactions. The role of deer as competent reservoirs in the life cycle of E. chaffeensis remains to be explored with suspected tick vectors. PMID- 7852564 TI - Development of PCR assays to detect ampicillin resistance genes in cerebrospinal fluid samples containing Haemophilus influenzae. AB - We developed PCR primers specific for the blaTEM and blaROB ampicillin resistance genes. The specificity of the primers was confirmed by testing a series of Escherichia coli isolates containing a variety of ampicillin resistance genes and a series of ampicillin-resistant and ampicillin-susceptible Haemophilus influenzae isolates. There was a perfect correlation between ampicillin MICs, the presence of beta-lactamase (as determined by the nitrocefin test), and the results with the blaTEM and blaROB primers. Isolates of H. influenzae and Streptococcus pneumoniae obtained from 25 frozen cerebrospinal fluid (CSF) specimens were also tested. Four of 14 H. influenzae isolates were positive with the blaTEM primers; none were positive with the blaROB primers. Ampicillin MICs were determined for the H. influenzae isolates, and penicillin MICs were determined for the S. pneumoniae isolates. Only the four PCR-positive H. influenzae isolates had elevated MICs of ampicillin and were beta-lactamase positive. None of the H. influenzae isolates contained the blaROB gene, and none of the S. pneumoniae isolates produced positive reactions with either primer set. We then used universal primers directed to conserved regions of rRNA and a Haemophilus detection probe to identify which of the 25 frozen samples of CSF contained H. influenzae. Fourteen of the 25 CSF specimens were positive for H. influenzae, which correlated with the number of organisms obtained by culture of the CSF samples. Four of the CSF samples were positive with the blaTEM primer set, and these correlated with the four H. influenzae isolates that were positive when tested directly by PCR. The blaTEM assay required the use of native Taq polymerase because Amplitaq preparations were contaminated with vector DNA that contained the blaTEM-1 gene. PMID- 7852566 TI - Ribotyping as an additional molecular marker for studying Neisseria meningitidis serogroup B epidemic strains. AB - The molecular method of ribotyping was used as an additional epidemiological marker to study the epidemic strains of Neisseria meningitidis serogroup B, referred to as the ET-5 complex, responsible for the epidemic which occurred in greater Sao Paulo, Brazil. Ribotyping analysis of these strains showed only a single rRNA gene restriction pattern (Rb1), obtained with ClaI restriction enzyme. This method, as well as multilocus enzyme electrophoresis, provided useful information about the clonal characteristics of the N. meningitidis serogroup B strains isolated during this epidemic. The N. meningitidis serogroup B isolates obtained from epidemics which occurred in Norway, Chile, and Cuba also demonstrated the same pattern (Rb1). Ribotyping was a procedure which could be applied to a large number of isolates and was felt to be appropriate for routine use in laboratories, especially because of the convenience of using nonradioactive probes. PMID- 7852565 TI - Detection of bacterial DNA in cerebrospinal fluid by an assay for simultaneous detection of Neisseria meningitidis, Haemophilus influenzae, and streptococci using a seminested PCR strategy. AB - Primers specific to conserved and variable regions in the 16S rRNA sequence were selected from the partially sequenced 16S rRNA genes of Neisseria meningitidis, Haemophilus influenzae, Streptococcus pneumoniae, S. agalactiae, and Staphylococcus epidermidis. The PCR assay was divided into two DNA amplifications. The first resulted in a general bacterial amplicon, and the second resulted in a species-specific amplicon. The high specificity of the PCR assay was documented after testing bacteria of 28 different species (133 strains). A total of 304 clinical cerebrospinal fluid samples, including 125 samples from patients with bacterial meningitis, were assayed to investigate the diagnostic sensitivity and specificity for bacterial meningitis. The assay showed high sensitivity (0.94) and specificity (0.96) with the clinical samples, although some false results were obtained, the reasons for which are discussed. With agarose gel electrophoresis for detection of the PCR products, the detection limit for meningococci in cerebrospinal fluid was 3 x 10(2) CFU/ml. PMID- 7852567 TI - RTX toxin genotypes and phenotypes in Actinobacillus pleuropneumoniae field strains. AB - Actinobacillus pleuropneumoniae serotype reference strains and 204 A. pleuropneumoniae field strains representing all 12 serotypes and both biovars 1 and 2, obtained from laboratories from various countries worldwide, were analyzed for the presence of the toxin genes apxIC, apxIA, apxIB, apxID, apxIIC, apxIIA, apxIIIC, apxIIIA, apxIIIB, and apxIIID by DNA-DNA hybridization with specific gene probes. Expression of the toxins ApxI, ApxII, and ApxIII was assessed by immunoblot analysis with monoclonal antibodies. The results show that the patterns of apx genes and those of the expressed Apx toxins in biovar 1 field strains are the same as those of the genes and toxins of corresponding serotype reference strain. We found only three strains which had certain apx genes missing compared with the genes in their serotype reference strains. Analysis of the expression of the three toxins showed that nearly all strains expressed their apx genes and produced the same Apx toxins as their serotype reference strain. We found only one strain that did not produce ApxI, although it contained the apxICABD genes, and one strain which did not express ApxII but which contained apxIICA. Several field strains which initially showed that their serotype did not correspond to the apx gene profile of the reference strain and which had an unexpected virulence for the given serotype revealed that their initial serotyping was erroneous. We show that the apx gene profiles are inherent to a given serotype. The method cannot differentiate between all 12 serotypes. However, it allowed us to distinguish five groups of toxin gene patterns which showed pathological, toxicological, and epidemiological significance. None of the biovar 2 strains contained apxIII genes. The apxI and apxII genes in the biovar 2 strains, however, were the same as those found in the serotype reference strains of biovar 1. PMID- 7852568 TI - Cryptosporidium antigen detection in human feces by reverse passive hemagglutination assay. AB - A reverse passive hemagglutination (RPH) assay was developed for Cryptosporidium oocyst antigen with an antioocyst monoclonal antibody (MAb; MAb-C1) coupled to stabilized sheep erythrocytes. RPH was compared with microscopy of auramine phenol-stained smears of 56 oocyst-positive fecal samples, each of which was tested blindly by RPH with two oocyst-negative samples received on the same day (a total of 112 controls). Thirty-nine additional fecal samples from human immunodeficiency virus type 1 antibody-positive patients with diarrhea (10 of which were positive in auramine-phenol-stained smears) were stored at -20 degrees C before testing. Thirty specimens with a variety of other fecal pathogens (all negative for oocysts) were also tested. Of the 237 samples tested, 69 were positive by one or both methods: 65 by RPH and 66 by microscopy. The kappa coefficient of agreement between the methods was very high at 0.926. The sensitivity of RPH was 93.9%, the specificity was 98.2%, the positive predictive value was 95.4%, and the negative predictive value was 97.7%. Visible oocyst numbers and RPH titers were measured after storage of fecal samples and oocyst concentrates for 8 days at 4 degrees C. Oocyst morphology was generally poor in specimens from the human immunodeficiency virus type 1 antibody-positive group, and it degenerated during the 8-day storage experiments. MAb-C1-reactive antigen eluted from oocysts to give progressively higher reciprocal titers during storage, and it was partially removed from the oocysts by concentration. RPH is a promising technique for the detection of Cryptosporidium antigen in human feces and may be useful when specimens are stored before testing. Studies of the sensitivity of Cryptosporidium immunoassays should take into account the possible release of antigen from oocysts. PMID- 7852569 TI - Polyclonal and monoclonal antibody and PCR-amplified small-subunit rRNA identification of a microsporidian, Encephalitozoon hellem, isolated from an AIDS patient with disseminated infection. AB - Microsporidia are primitive, spore-forming, mitochondria-lacking, eukaryotic protozoa that are obligate intracellular parasites. They are known to parasitize almost every group of animals including humans. Recently, microsporidia have increasingly been found to infect patients with AIDS. Five genera (Encephalitozoon, Enterocytozoon, Nosema, Septata, and Pleistophora) of microsporidia are known to infect humans. Enterocytozoon organisms cause gastrointestinal disease in a majority of AIDS patients with microsporidiosis. However, a smaller, but an expanding, number of patients with AIDS are being diagnosed with ocular and disseminated infection with Encephalitozoon hellem. Although microsporidial spores can be identified in clinical samples by a staining technique such as one with Weber's chromotrope stain, identification to the species level is dependent on cumbersome and time-consuming electron microscopy. We have recently isolated and established in continuous culture several strains of E. hellem from urine, bronchoalveolar lavage, and sputum samples from AIDS patients with disseminated microsporidiosis. We developed polyclonal and monoclonal antibodies and PCR primers to a strain of E. hellem that can be used successfully to identify E. hellem from other species of microsporidia either in clinical specimens or in cultures established from clinical specimens. Since patients infected with Encephalitozoon spp. are known to respond favorably to albendazole, identification of the parasite to the species level would be invaluable in the treatment of disseminated microsporidiosis. PMID- 7852570 TI - Comparison of six typing methods for Actinobacillus actinomycetemcomitans. AB - Actinobacillus actinomycetemcomitans is an important pathogen in the etiology of severe periodontitis. For epidemiological studies on the prevalence of certain pathogenic clones and transmission of this bacterium, adequate typing methods are necessary. The purpose of this study was to compare six different typing methods for A. actinomycetemcomitans. Five reference strains and 27 fresh clinical isolates from periodontitis patients were used. Serotyping showed 12 serotype a strains, 13 type b strains, 6 type c strains, and 1 nontypeable strain. Biotyping on the basis of the fermentation of mannose, mannitol, and xylose resulted in six biotypes. Antibiogram typing was evaluated by measuring the inhibition zones of seven antibiotics in agar diffusion tests. With this method eight main types which could be further differentiated into 15 subtypes were found. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis patterns of outer membrane proteins were similar among all isolates tested. Restriction endonuclease analysis (REA) of whole chromosomal DNA resulted in five main types. These five main types were further differentiated into 24 subtypes on the basis of DNA fragment differences in the high-molecular-weight region. Hybridization of DNA fragments with ribosomal DNA (ribotyping) resulted in 22 to 24 different types, depending on the restriction endonuclease used. Ribotype patterns were easy to interpret and provided an univocal distinction between different strains compared with REA results. When applied to epidemiologically related isolates, all methods were able to discriminate two clonal types among five isolates from five children from one family. We conclude that serotyping, biotyping, and outer membrane patterns were reproducible but had a low discriminatory potential. REA and ribotyping were reproducible and gave the highest number of distinct types. When the DNA typing methodis were compared, all strains tested could be distinguished. These findings confirm the heterogeneity found within the species A. actinomycetemcomitans. PMID- 7852571 TI - Characterization of phenotypic, serological, and toxigenic traits of Vibrio cholerae O139 bengal. AB - Biochemical and physiological traits of a collection of strains of Vibrio cholerae O139 Bengal isolated from India, Bangladesh, and Thailand showed that these strains formed a phenotypically homogeneous group with identical characteristics that were essentially similar to those of the O1 serogroup. Resistance to 150 micrograms of the vibriostatic agent O/129 (2,4-diamino-6,7 diisopropylpteridine) and Mukherjee's El Tor phage 5 and classical phage IV and the nonagglutinability of the strains with O1 antiserum were the only discernible differences between the O139 and O1 serogroups. Extensive serological characterization further revealed the O139 serogroup to be distinct from the existing 138 serogroups of V. cholerae. Antiserum raised against the O139 serogroup required absorption with the R reference strain CA385 and with the reference strain representing serogroup O22 to remove cross-reacting agglutinins. All of the 223 representative strains of V. cholerae O139 examined hybridized with DNA probes specific for the cholera toxin (CT) gene, zonula occludens toxin gene, and El Tor hemolysin gene but not with the probe specific for the heat stable enterotoxin gene. The amount of CT present in stool samples of patients infected with the O139 serogroup was higher than that found in stools of patients infected with O1 El Tor, and this echoed findings that the amount of CT produced by O139 strains in vitro was higher than that produced by the O1 El Tor strains. The nucleotide sequences of the genes encoding the A and B subunits of CT of the O139 serogroup were identical to the sequences reported for the CT gene of O1 El Tor. The CT gene of O139 strains could be amplified by using primers developed for detection of the CT gene of the O1 serogroup by a PCR assay, which could also be used to detect the CT gene in stool samples of patients infected with strains of the O139 serogroup. PMID- 7852572 TI - Transmission of Rickettsia tsutsugamushi strains among humans, wild rodents, and trombiculid mites in an area of Japan in which tsutsugamushi disease is newly endemic. AB - Thirty-two newly isolated strains of Rickettsia tsutsugamushi, 14 from patients with tsutsugamushi disease, 12 from wild rodents, and 6 from trombiculid mites parasitizing rodents in Gifu Prefecture, Japan, were examined for reactivities to 12 monoclonal antibodies by an indirect fluorescent-antibody test to classify their antigenicities. All of the isolates could be classified into one of six groups (KN-1, KN-2, KN-3, GJ-1, R158, and R161) according to their reactivities to the monoclonal antibodies. The KN-1 and GJ-1 strains that are prevalent among patients from Gifu Prefecture had the same reactivities as the Kawasaki and Kuroki strains, respectively, which have been isolated and are prevalent in the Miyazaki and Kagoshima prefectures in southwest Japan. The isolates from patients were different in serotype from those from rodents and mites (Leptotrombidium pallidum). The KN-2 and KN-3 strains were most prevalent among patients and among rodents and mites, respectively. No close similarity between KN-2 and other strains tested was observed. KN-3 is only a minor contributor to diseases in patients in Gifu Prefecture; however, it was proven that the same strain was prevalent in Niigata Prefecture in northern Japan. Thus, Gifu Prefecture is an area where southern, northern, and local strains are found. We hypothesize that humans are prone to infection with KN-2, GJ-1 (very similar to Kuroki), and KN-1 (very similar to Kawasaki), probably by infestation with Leptotrombidium scutellare. While both L. scutellare and L. pallidum parasitize wild rodents and may carry any rickettsial strain, the most virulent strain, KN-3, is predominant among wild rodents. Antigenic analysis using monoclonal antibodies to R. tsutsugamushi should be useful for epidemiological studies of infection with this organism. PMID- 7852573 TI - Disk diffusion versus broth microdilution susceptibility testing of Haemophilus species and Moraxella catarrhalis using seven oral antimicrobial agents: application of updated susceptibility guidelines of the National Committee for Clinical Laboratory Standards. AB - Susceptibility testing of Haemophilus species and Moraxella catarrhalis is medium and inoculum dependent. Seven oral agents, ampicillin, amoxicillin-clavulanic acid, cefaclor, loracarbef, cefuroxime-axetil, cefixime, and erythromycin, were tested against 400 beta-lactamase-positive and -negative clinically significant respiratory strains of Haemophilus species and 100 strains of M. catarrhalis. Sources of the strains included teaching and regional hospitals and a private laboratory. All strains were tested by broth microdilution and disk diffusion in haemophilus test medium for Haemophilus species and Mueller-Hinton broth and agar for M. catarrhalis. Appropriate National Committee for Clinical Laboratory Standards (NCCLS) standards were followed. For Haemophilus species, by disk diffusion and broth microdilution, respectively, 27 and 27% of strains were resistant to ampicillin, 37 and 5% were resistant to erythromycin, 3 and 0.5% were resistant to cefaclor, 2 and 0.5% were resistant to loracarbef, and 0% were resistant to cefuroxime-axetil, cefixime, and amoxicillin-clavulanic acid. beta Lactamase-negative ampicillin-resistant strains were not observed. Of M. catarrhalis strains, 56% were resistant to ampicillin by disk diffusion and 95% were resistant by broth microdilution. This species was susceptible to all other agents tested by either method. The disagreements between disk diffusion results and MICs for cefaclor, ampicillin, cefuroxime, and loracarbef that occurred with use of the 1990 NCCLS tables were resolved when the 1992 NCCLS tables were used. PMID- 7852575 TI - The superoxide dismutase gene, a target for detection and identification of mycobacteria by PCR. AB - The superoxide dismutase gene has been identified as a target in screening for the presence of mycobacteria on the genus level and differentiating relevant mycobacterial species from one another by PCR. Consensus primers deduced from known superoxide dismutase gene sequences allowed the amplification of DNAs from a variety of bacteria, fungi, and protozoa. Selected amplicons from Actinomyces viscosus, Corynebacterium diphtheriae, Corynebacterium pseudodiphtheriticum, Mycobacterium avium, M. fortuitum, M. gordonae, M. intracellulare, M. kansasii, M. scrofulaceum, M. simiae, M. tuberculosis, M. xenopi, and Nocardia asteroides were subsequently cloned and sequenced. The alignment of those sequences facilitated the selection of primers targeting conserved regions present in myobacterial species but absent in nonmycobacterial species and thus allowed the genus-specific amplification of all 28 different mycobacterial species tested. A pool of genus-specific allowed the genus-specific amplification of all 28 different mycobacterial species tested. A pool of genus-specific probes recognized 23 of the 28 mycobacterial species and did not cross-react with any of the 96 nonmycobacterial species tested. In addition, probes recognizing species specific variable regions within the superoxide dismutase genes of M. avium, M. fortuitum, M. gordonae, M. intracellulare, M. kansasii, M. scrofulaceum, M. simiae, the M. tuberculosis complex, and M. xenopi were identified. All probes recognized only the species from which they were derived and did not cross-react with any other mycobacterial species or with any of the nonmycobacterial species tested. We conclude that the superoxide dismutase gene is a suitable target for amplifying mycobacteria by PCR on the genus level, confirming correct amplification by genus-specific probes, and differentiating relevant species from one another by a set of species-specific probes. PMID- 7852574 TI - Use of an ATP bioluminescent assay to evaluate viability of Pneumocystis carinii from rats. AB - A bioluminescent assay which employs the luciferin-luciferase ATP-dependent reaction was used to evaluate the viability of populations of Pneumocystis carinii derived from infected rat lungs. Contamination with host cells was reduced by a purification method which involved a combination of low- and high speed centrifugations resulting in a 1,000-fold reduction of the rat cells while enriching for the trophic form of P. carinii. A linear correlation for the number of P. carinii nuclei versus the amount of ATP was observed. The ATP content of the organism populations could be maintained at inoculum levels for one week, although the number of organisms did not increase. Addition of respiratory chain inhibitors dramatically decreased the ATP content of the P. carinii after 24 h of incubation, with the exception of the antibiotic oligomycin B. Low concentrations of trimethoprim-sulfamethoxazole and pentamidine isethionate reduced the organism ATP content by over 50% after 24 h of exposure, while no effect was observed with 100-fold greater concentrations of ampicillin. The bioluminescent assay was found to be a more sensitive indicator of viability than a dual fluorescent staining technique. This assay does not require replication of P. carinii and should be a useful method for in vitro drug screening and viability assessment of P. carinii populations. PMID- 7852576 TI - Value of PCR for evaluating occurrence of parasitemia in immunocompromised patients with cerebral and extracerebral toxoplasmosis. AB - PCR was used to evaluate the occurrence of Toxoplasma gondii parasitemia by detection of the B1 gene in blood samples in two groups of immunosuppressed patients (148 subjects) suspected of having cerebral or extracerebral infection, respectively. Group I consisted of 52 patients with AIDS with suspected cerebral toxoplasmosis. The diagnosis was clinically proven in 15 cases. Parasitemia was detected by PCR in only two of these patients (13.3%), both showing evidence of disseminated infection. Group II consisted of 96 immunocompromised patients, either with AIDS or receiving iatrogenic immunosuppressive therapy. Of these patients, 65 (34 with AIDS and 31 others) showed abnormalities only in chest radiography and were first screened for the presence of Toxoplasma DNA in bronchoalveolar lavage fluid. Blood was then analyzed when the parasite was detected in the bronchoalveolar lavage fluid. The remaining 31 subjects (22 with AIDS and 9 others) were suspected of having extracerebral, pulmonary, or disseminated toxoplasmosis, and blood was studied directly in these cases. Among the nine patients with clinically diagnosed extracerebral infection in group II, the parasite was detected by PCR in the blood of five patients (55.5%), all having pulmonary toxoplasmosis. If all patients with clinical manifestations of extracerebral toxoplasmosis (from both groups) who had not received antitoxoplasma therapy when the samples were collected are considered, PCR detected parasitemia in seven of the nine cases (77.8%). The present study indicates that examination of blood by PCR may be valuable in cases of extracerebral toxoplasmosis because of the disseminated nature of the disease. Since most cases of cerebral toxoplasmosis result from the local reactivation of latent brain cysts, detection of parasitemia by PCR is useful only in cases associated with severe cerebral infection or dissemination of this disease. PMID- 7852577 TI - Comparison of Chlamydia pneumoniae isolates by western blot (immunoblot) analysis and DNA sequencing of the omp 2 gene. AB - The 60-kDa cysteine-rich outer membrane protein gene (omp 2) from nine Chlamydia pneumoniae isolates (TW-183, CM-1, CWL-050, CWL-011, IOL-207, FIL, Kajaani-6, Helsinki-12, and Parjaanonen) was amplified by PCR and sequenced from positions 1 to 580. In contrast to the sequence differences previously observed in this gene in other chlamydial species, all nine C. pneumoniae isolates were 100% identical. However, when sera from C. pneumoniae microimmunofluorescence-positive patients (with clinical signs of persistent cough or asthma) were immunoblotted against five C. pneumoniae isolates, distinct antigenic differences were observed. TW-183 was characterized by major bands at 35 and 43 kDa. In contrast, the other four isolates tested produced similar, though not identical, immunoblot profiles, characterized by strong bands at 18, 25, 29, 40, 46, and 53 kDa. These data support the fact that significant differences do exist between C. pneumoniae isolates, but unlike the case with other chlamydial species, these differences do not reside in either of the commonly studied outer membrane protein genes, omp 1 or omp 2. PMID- 7852578 TI - Osteomyelitis of the sternum caused by Apophysomyces elegans. AB - Apophysomyces elegans, a member of the family Mucoraceae, was found to infect the chest wall and sternum of an immunocompetent man following minor trauma. As in previous cases, amphotericin B therapy alone was inadequate. Extensive surgical debridement was required in order to eradicate the infection. PMID- 7852579 TI - Effects of volume and periodicity on blood cultures. AB - Blood specimens collected for culture by using the high-volume resin-based BACTEC system over an 18-month period at the Seattle Veterans Administration Center were examined in this study. Of 7,783 cultures obtained, 624 were classified as true positives. Patients in this group had between 20 and 60 ml of blood drawn per culture and separated into 10-ml aliquots for incubation. Analysis of the results stratified by cultured volume and time interval between specimen collection accorded yield advantage to culture volume at the maximal amounts tested. No advantage was observed with any particular interval of collection. Increasing cultured volume from 20 to 40 ml increased yield by 19%. Increasing cultured volume from 40 to 60 ml increased yield by an additional 10%. The same effect was seen whether cultures were drawn simultaneously or serially within 24 h. These observations support other reports demonstrating increased yield with increased cultured blood volume. However, they demonstrate increases in yield at volumes much higher than previously considered. In conclusion, this study demonstrates that high-volume blood cultures drawn serially or simultaneously return the best yields. PMID- 7852580 TI - Osteomyelitis caused by Neosartorya pseudofischeri. AB - The first case of osteomyelitis caused by Neosartorya pseudofischeri is reported. The patient, a 77-year-old male with a history of silicosis and tuberculosis, on X-ray examination revealed lytic lesions of L2 and L3 vertebrae suspicious for metastatic lesions. Histologic examination of biopsy specimens from vertebral bodies showed short, distorted, extra- and intracellular, hyaline hyphal fragments. The culture from the biopsy tissue produced numerous, evanescent asci containing eight ellipsoidal ascospores with two distinctive equatorial bands ca. 1 micron wide. When examined by a scanning electron microscope, ascospores exhibited a convex surface ornamented with raised flaps of tissue, in shape resembling triangular projections or long ridge lines. The conidial state (anamorph) was identified as Aspergillus thermomutatus on the basis of conidial columns which were smaller and less tightly packed as well as of a lighter shade of green than those observed in Aspergillus fumigatus. On the basis of the morphologic features of the ascospores, the teleomorph was identified as N. pseudofischeri. PMID- 7852581 TI - Simple test of synergy between ampicillin and vancomycin for resistant strains of Enterococcus faecium. AB - The combination of ampicillin and vancomycin kills some but not all strains of ampicillin- and vancomycin-resistant Enterococcus faecium. We compared a simple test for synergy utilizing a commercially available microdilution susceptibility system with time-kill studies and determined acceptable breakpoints for this test for 20 strains of ampicillin- and vancomycin-resistant E. faecium. The combination of ampicillin and vancomycin was tested for synergy by time-kill, broth macrodilution, and broth microdilution procedures. Repeat testing of isolates by macro- and microdilution synergy methods yielded MICs that were within one twofold dilution of each other for both intra- and intertest comparisons. Synergy was always detected by time-kill studies when the MIC of ampicillin in the combination synergy screen was < or = 8 micrograms/ml in the presence of vancomycin. No synergy was detected when the MIC was > 16 micrograms/ml in the combination microdilution synergy screen. The determination of the synergy by the broth microdilution procedure appears to be simple, convenient, and accurate. PMID- 7852582 TI - Evaluation and characterization of multiresistant Enterococcus faecium from 12 U.S. medical centers. AB - Forty-two Enterococcus faecium isolates resistant to ampicillin, penicillin, gentamicin, streptomycin, vancomycin, and teicoplanin (VanA phenotype) from 12 U.S. medical centers were analyzed by pulsed-field gel electrophoresis of chromosomal DNA. The isolates were tested for susceptibility to 12 alternative drugs. The results indicated both intrahospital and interhospital diversity among multiresistant vanA enterococcal isolates. Furthermore, the finding of isolates with identical pulsed-field gel electrophoresis patterns in different centers strongly suggests some interhospital clonal transmission. PMID- 7852583 TI - Detection of Escherichia coli K95 strains by bacteriophages. AB - A set of three bacteriophages (phi K5, phi K20, and phi K95) was used to discriminate between Escherichia coli K5 and K95 strains isolated from patients with urinary tract infections. All the strains tested were detected primarily by phi K5 and thought to carry the capsular antigen K5. Ten O2, 33 O6, and 32 O18 strains proved to be sensitive to the three phages. Eleven of 44 O75:H- strains, all 8 O75:H5 strains, 1 O17 strain, and 1 OR strain were not lysed by phage phi K20, the only phage without activity toward the K95 test strain. It has been suggested that the phi K20-resistant strains carry K95. These findings were confirmed by countercurrent immunoelectrophoresis with K-antigen extracts and anti-K95 serum. These preliminary data indicate the usefulness of these phages to detect K95 strains among K5 isolates. PMID- 7852584 TI - Interpretive criteria for susceptibilities of Haemophilus influenzae to ampicillin, amoxicillin, and amoxicillin-clavulanic acid. AB - One hundred fifty isolates of Haemophilus influenzae (including 30 beta-lactamase positive strains and 23 beta-lactamase-negative, ampicillin-resistant strains) were tested for susceptibilities to ampicillin, amoxicillin, and amoxicillin clavulanic acid (A/C) by the broth microdilution method in Haemophilus test medium (HTM) and in Mueller-Hinton medium with lysed horse blood and by the disk diffusion method on HTM agar. Our results support the use of HTM for susceptibility testing of H. influenzae but raise a number of questions regarding the interpretive criteria currently in use, particularly with respect to the fourfold difference in MIC susceptibility breakpoints for ampicillin and A/C and a resulting high proportion of A/C-susceptible beta-lactamase-negative, ampicillin-resistant strains. PMID- 7852585 TI - Unexpected isolation of Bordetella pertussis from a blood culture. AB - Bordetella pertussis was isolated from a culture of blood from a 31-year-old man with Wegener's granulomatosis. The organism was detected with the BACTEC 9240 system after 6 days of incubation and was confirmed as B. pertussis by the Centers for Disease Control and Prevention. To our knowledge, this is the first published report of the recovery of B. pertussis from blood. PMID- 7852586 TI - Isolation of Yokenella regensburgei ("Koserella trabulsii") from a patient with transient bacteremia and from a patient with a septic knee. AB - Yokenella regensburgei ("Koserella trabulsii") was isolated from a 74-year-old male with a septic knee and from a 35-year-old immunocompromised female whose transient bacteremia occurred without overt signs of sepsis. Neither strain was correctly identified by laboratories using a variety of techniques. PMID- 7852587 TI - Pneumonia caused by Stenotrophomonas maltophilia with a mucoid phenotype. AB - We describe the first known case of pneumonia caused by a mucoid Stenotrophomonas maltophilia (Xanthomonas maltophilia) strain in a patient with bronchiectasis. The patient was admitted because of mild hemoptysis and productive cough with infiltrative shadow in the right lower lung field on chest X ray. The clinical symptoms were mild, and treatment with minocycline was effective. PMID- 7852588 TI - Detection of human immunodeficiency virus type 1 (HIV-1) in heel prick blood on filter paper from children born to HIV-1-seropositive mothers. AB - The human immunodeficiency virus type 1 (HIV-1) DNA PCR results of 94 dried blood spot (DBS) samples on filter paper and corresponding venous blood in EDTA obtained from infants born to HIV-1-seropositive mothers were compared. In addition, the results of HIV-1 DNA PCR on DBS and the HIV-1 RNA PCR from plasma of 70 paired samples were compared. A 100% specificity and a 95% sensitivity for HIV-1 DNA PCR on DBS compared with results for venous blood were observed for the 94 paired samples. The results of the DBS HIV-1 DNA PCR and HIV-1 RNA PCR of 70 corresponding plasma samples correlated perfectly (100%). The DBS HIV-1 DNA PCR method proved reliable for HIV-1 detection. PMID- 7852589 TI - Validation of respiratory syncytial virus enzyme immunoassay and shell vial assay results. AB - The Pathfinder respiratory syncytial virus (RSV) enzyme immunoassay (EIA) (Kallestad), the shell vial (SV) technique, and conventional cell culture (CC) were compared for detection of RSV in nasopharyngeal aspirates. We found sensitivities, specificities, and positive and negative predictive values of 58.4, 100, 100, and 68.2%; 80.7, 97.2, 97.0, and 81.9%; and 77.6, 97.2, 96.9, and 79.5% for the CC, EIA, and SV methods, respectively. The SV and EIA techniques were both more sensitive than CC (P < 0.001). Finally, 29 respiratory viruses other than RSV were identified by CC. PMID- 7852590 TI - Intestinal colonization of symptomatic and asymptomatic schoolchildren with Blastocystis hominis. AB - A study of single stool specimens was done to determine the prevalence of intestinal parasites among 1,000 primary school children. A questionnaire was completed by each child's parents. Specimens were examined by using wet-mount preparation, formaline-ether concentration, and Sheather's flotation technique. Trichrome and acid-fast stains were done. Blastocystis hominis was observed in 203 (20.3%) of the specimens examined, and 175 specimens contained this organism in the absence of other pathogenic parasites. Older children had fewer B. hominis infections (6 to 7 years old, 50% infection rate; 8 to 9 years, 27.5%; 10 to 12 years, 9.5%). The most common complaints reported by 75 children harboring the parasite were a mild recurrent diarrhea, abdominal pain, nausea, anorexia, and fatigue. Blastocystosis is quite common among schoolchildren. Contaminated drinking water is suspected to be the source of infection. PMID- 7852591 TI - Clostridium bifermentans bacteremia with metastatic osteomyelitis. AB - Osteomyelitis caused solely by an anaerobic organism is uncommon. We report a case of recurrent Clostridium bifermentans bacteremia resulting in metastatic osteomyelitis involving the sacrum, spine, and ribs. The emergence of resistance of this organism to imipenem and metronidazole is noteworthy because of the usual susceptibility of clostridial species to these antibiotics. PMID- 7852592 TI - Increased phenotypic switching in strains of Candida albicans associated with invasive infections. AB - This study reports the rates of phenotypic switching in strains of Candida albicans isolated from superficial and invasive infections. Of 19 invasive strains, 68% showed switching activity, often at very high rates, compared with only 28% of 40 strains isolated from superficial sites (P = 0.004). PMID- 7852593 TI - Comparison of goat and horse blood as culture medium supplements for isolation and identification of Haemophilus influenzae and Streptococcus pneumoniae from upper respiratory tract secretions. AB - The results of this study show that goat blood as a culture medium supplement is as supportive as horse blood for the isolation and identification of Haemophilus influenzae and Streptococcus pneumoniae from clinical material. Care is required in the preparation of goat blood chocolate agar to ensure that a thermolabile growth inhibitor of NAD-dependent Haemophilus species is eliminated. PMID- 7852594 TI - Typing of Mycoplasma pneumoniae by PCR-mediated DNA fingerprinting. AB - PCR fingerprinting was used to characterize clinical isolates of Mycoplasma pneumoniae. Among 24 strains tested, two types were distinguished. Nineteen strains belonged to type 1, whereas only 5 strains belonged to type 2. The majority of strains isolated since 1991 in Belgium belong to type 1. No variations in fingerprinting patterns were observed within each group, confirming the highly conserved nature of the M. pneumoniae genome. PMID- 7852595 TI - Bovine rotavirus V1005 a P5, not a P12, type like all viruses in a German survey. AB - Bovine rotavirus (BRV) V1005, like 34 further cell culture-adapted strains in a 6 year survey in Upper Bavaria, Germany, is not a P12 but a P5 P-type rotavirus. The conclusion is based on dot blot hybridization with P1-, P5-, and P11-specific cDNAs, encompassing the VP8* region of major sequence diversity, and on PCR using P1-, P5-, and P11-specific primer pairs derived from the VP5* region of VP4 (VP5* and VP8*, respectively, are the larger and smaller tryptic cleavage products of VP4). Sequencing of the hyperdivergent region of VP4 confirmed the close relatedness of BRV V1005 to BRV UK, the P5 prototype virus. PMID- 7852596 TI - Serovars of Mycobacterium avium complex isolated from patients in Denmark. AB - Danish isolates of Mycobacterium avium complex were serotyped by the use of seroagglutination. The most prevalent serovars among patients with AIDS (n = 89) were 4 and 6, while among non-AIDS patients the most prevalent serovars were 1, 6, and 4, with no major differences between those in patients with pulmonary disease (n = 65) and those in patients with lymph node infection (n = 58). The results suggest a Scandinavian distribution of serovars with a predominance of serovar 6 and fail to demonstrate any selective protection against different serovars by Mycobacterium bovis BCG vaccination. PMID- 7852598 TI - Transmission of nonfermenting gram-negative bacilli by multiple-dose inhalers. PMID- 7852597 TI - Alpha-mannosidase in Arcanobacterium haemolyticum. PMID- 7852599 TI - A case of conversion from MT-2-positive to MT-2-negative phenotype. PMID- 7852600 TI - Remedying the Achilles heel of behavior research and therapy: prescriptive matching of intervention and psychopathology. AB - Recent calls for eclecticism in clinical practice have been fueled by the putative limitations of behavioral techniques in treating a variety of psychological problems. However, calls for such integration do not appear to be justified for two related reasons. First, the precise conditions under which behavioral interventions are and are not effective have not yet been adequately delineated. Consequently, rejection of behavioral interventions in favor of relatively indiscriminate application of cognitive strategies is premature. Second, behavior therapy has as its hallmark a thorough grounding in inductive empiricism, while cognitive/dynamic theories are wholly based in deductive rationalism. As a result, wholesale acceptance of alternative theories and techniques by behaviorists is both inconsistent and retrogressive. Cognitive interventions have their place, but only when cognitive distortions have been specifically identified. Therefore, refinement of behavioral treatments into prescriptive interventions is warranted. The parameters of prescriptive behavior therapy are described in this paper. PMID- 7852601 TI - Feather picking disorder and trichotillomania: an avian model of human psychopathology. AB - Animal models of psychopathology have been extremely valuable in conceptualizing various human disorders. The human condition known as trichotillomania (compulsive hair pulling) has considerable similarities with an avian disorder called feather picking, with respect to analogous behavior, proposed etiologies, evoking cues, response to behavior therapy, and response to pharmacological treatments based on serotonin re-uptake inhibitors. We suggest that feather picking disorder has the potential to be a useful animal model of trichotillomania, and lends itself to studies on the experimental psychopathology of compulsive hair pulling. PMID- 7852602 TI - Behavioral treatment of phobic avoidance in multiple chemical sensitivity. AB - The clinical ecology model of environmental illness, or multiple chemical sensitivity (MCS), and particularly the theoretical assumptions, diagnostic procedures, and therapeutic recommendations promulgated by clinical ecologists are reviewed. No scientific evidence is found for their claims. MCS is conceptualized, instead, as a phobic disorder explicable in terms of the two factor model of avoidance. Three cases of MCS are discussed in light of this model, and a comprehensive behavioral treatment package that includes biofeedback assisted in vivo desensitization and cognitive restructuring is proposed. PMID- 7852603 TI - Disproportionate dental anxiety in the over 50s. AB - Explanations of dental anxiety in terms of either conditioning or personality predispositions alone are not sufficient to account for all individuals presenting with dental anxiety, since they are not a homogenous group. It was hypothesized that individuals, with wide ranging anxiety problems would be more likely to carry dental anxiety into old age. This prediction was supported by a comparison of older dentally anxious individuals with other older individuals who admitted to dental anxiety previously but were no longer dentally anxious. The results were interpreted in terms of Lang's bioinformation model of anxiety. PMID- 7852604 TI - Eye movement desensitization across subjects: subjective and physiological measures of treatment efficacy. AB - Eye movement desensitization (EMD) was investigated in an experimental multiple baseline across subjects design. Six subjects who met the diagnostic criteria for Posttraumatic Stress Disorder (PTSD) were included in the study. While the EMD technique advanced by Shapiro has been reported to be clinically effective, major methodological issues have been raised which remain to be addressed. One issue raised is whether exposure to the traumatic image is sufficient to account for the reported clinical effects of EMD or whether the addition of saccadic eye movements is central to the treatment. This study attempted to address this concern by comparing two EMD-based procedures: a Non-saccade phase (without the saccadic eye movements) which functioned as a control and a second that included saccadic eye movements. Dependent variables included self-report information (SUDs, behavioral symptoms reports) and physiological data (heart rate and systolic blood pressure). The results showed no significant decreases in SUDs level with the EMD minus the saccadic eye movements procedure. However, five of the six subjects reported clinically significant decreases in their SUDs levels with the inclusion of the saccadic eye movements. This study appears to corroborate previous work employing single-case design as well as pre and postcomparisons. PMID- 7852605 TI - Eye movement desensitization: a partial dismantling study. AB - Twenty-three PTSD subjects were exposed to either: (1) standard eye movement desensitization (EMD), (2) a variant of EMD in which eye movements were engendered through a light tracking task, or (3) a variant of EMD in which fixed visual attention replaced eye movements. All three interventions produced significant positive changes in all dependent measures and these changes were maintained at follow-up. No significant differences between groups were observed. It was concluded that the eye movements peculiar to EMD are not essential to treatment outcome. The implications of the present findings and previous reports are discussed and recommendations for future research provided. PMID- 7852606 TI - The effects of training in nonaversive behavior management on the attitudes and understanding of direct care staff. AB - Recent developments in behavior therapy for persons with developmental disabilities and behavior disorders emphasize positive treatment designs that focus on understanding the causes of behavior, teaching functional alternatives, and enhancing the quality of daily experiences, rather than simple contingency management. There is little information on how well direct care staff can support these nonaversive strategies. This study examined the effects of training in traditional (positive) behavior management versus nonaversive principles on the understanding and attitudes of direct care staff. Overall, nonprofessional level staff receiving the nonaversive training showed increased sophistication in understanding the range of possible causes of behavior and were able to generate treatment suggestions based on skill development and environmental change. The effectiveness of staff in implementing state-of-the-art behavior therapy procedures is likely to be an important component of the continued success of behavior therapy, especially in residential settings, both institutional and community-based. PMID- 7852607 TI - A brief instrument to assess knowledge of behavioral principles. PMID- 7852608 TI - A treatment model for motor tics based on a specific tension-reduction technique. AB - A model is proposed in which motor tics are considered to be tension reducing responses to a specific sensory stimulus. It is hypothesized that the sensory stimulus is of a proprioceptive nature. The first phase of therapy concerns the identification of the stimulus. The patient is then taught a socially acceptable, alternative response, which also reduces the sensory stimulus. Two case reports illustrate this model. The applicability of the model with respect to other movement disorders is discussed. PMID- 7852609 TI - A longitudinal study from prepuberty to puberty of gingivitis. Correlation between the occurrence of Prevotella intermedia and sex hormones. AB - A longitudinal study of 24 subjects progressing normally from prepuberty to puberty was undertaken to evaluate the effects of sex hormone levels on clinical and microbiologic parameters and on serum antibodies. During elementary school, at the beginning of the longitudinal monitoring, 2 groups, 12 subjects with gingivitis and 12 gingivitis-free subjects, were selected and observed through puberty. Bone ages and self-assessment of secondary sex characteristics were used to confirm puberty. A statistically significant increase in the proportions of Prevotella intermedia including Prevotella nigrescens and serum antibody levels against P. intermedia was seen in gingivitis group throughout the longitudinal study. Serum levels of testosterone in boys and estradiol and progesterone in girls was positively correlated with levels of P. intermedia and P. nigrescens. In puberty, a slight but significant increase in GI scores over prepuberty has been shown; however, there was no significant change in PlI from prepuberty to puberty. Our study confirmed that there was a statistically significant increase in gingival inflammation and in the proportion of P. intermedia and P. nigrescens in puberty relative to the baseline value, except in the gingivitis-free male group. Our findings suggest that these increases are correlated with elevation in systemic levels of the sex hormones. PMID- 7852610 TI - The width of radiologically-defined attached gingiva over permanent teeth in children. AB - Several authors have determined clinically the width of attached gingiva (AG) over the deciduous and early permanent dentitions in children. They have noticed that when comparing the width of AG over deciduous teeth to the width of AG over the succeeding newly erupted permanent teeth, a clear diminishing in AG can be seen. The aim of the present cross-sectional study was to assess the width of radiologically-defined AG (RAG) over the permanent teeth of 6-, 10- and 12-year old children. Altogether 123 subjects were recruited. The mucogingival junction (MGJ) was revealed with Schiller's iodine solution and marked over each tooth with a piece of metal wire before taking a panoramic radiograph. The width of RAG over permanent teeth was measured from the radiographs as the midfacial distance from the cementoenamel junction to the mucogingival junction. When comparing the width of RAG over 1st molars and the 1st and 2nd incisors, statistically significant differences were found between 6- and 10-year-olds, between 6- and 12 year-olds and between 10- and 12-year-olds. For the 1st maxillary incisor, the difference in width was not statistically significant between ages 10 and 12 years. The findings seem to justify the conclusion that an inadequate width of AG will correct itself from 6 to 12 years of age without interference by means of periodontal surgery. PMID- 7852611 TI - Clinical characteristics of periodontal sites with probing attachment loss following initial periodontal treatment. AB - Periodontal sites which had undergone probing attachment loss were identified in 16 advanced periodontitis patients subjected to initial periodontal treatment and monitored every 3rd month for 42 months. Many sites with probing attachment loss showed no increase in probing depth and bled on probing at a few of the examinations during maintenance. Others showed increase in depth, frequent bleeding and suppuration. An arbitrary classification of 'questionable periodontitis' sites was used and included sites with the following characteristics: probing depth at 42 months < or = 3.5 mm + bleeding on probing at no more than 5 of the 14 examinations 3-42 months + no suppuration on probing 3-42 months. The % sites in this category ranged from 21-35%, depending upon method used to determine probing attachment loss. Widely varying characteristics of sites identified with probing attachment loss were evident for all surface locations and all subgroups of initial probing depth. From a traditional viewpoint, a significant proportion of the losing sites might not have been afflicted with periodonitis. On the other hand, deterioration does not necessarily have to be coupled with obvious inflammation, particularly following therapy. PMID- 7852612 TI - Antioxidative activities of some chemotherapeutics. A possible mechanism in reducing gingival inflammation. AB - Inflammatory periodontal diseases are related to dental plaque formation. Increase in the perfusion of the inflamed tissue results in increased oxygen supply. Although oxygen has healing effects, it is bound to be a mediator of peroxidation in biological membranes. Chemotherapeutic agents such as chlorhexidine, listerine, sanguinarine, and cetylpridinium chloride and oral antibiotics such as tetracycline HCl and doxycyline were tested for their antioxidative activities. While doxycycline has the highest antioxidant activity in lower volumes (0.1 ml), sanguinarine, listerine and a pace after them, tetracycline HCl, had similar effects in higher volumes (0.3 and 0.4 ml). The results showed that in addition to their antiseptic or antimicrobial effects, these preparations have an antioxidative activity against spontaneous oxidation. PMID- 7852613 TI - Service mix in general dental practices employing and not employing dental hygienists. AB - Service mix studies conducted in Australia have indicated a low provision of periodontal services. The service mix in Australian general dental practices employing dental hygienists has not been studied. This study compares the service mix between 18 practices employing hygienists and 29 practices not employing hygienists in Adelaide. Practices employing hygienists tended to be larger group practices, with younger dentists seeing a younger set of patients. Practices employing dental hygienists provided a mean of 97.9 services to 57.2 patients over 2 days, significantly higher than the mean of 68.8 procedures to 39.1 patients in practices not employing dental hygienists. Comparing the % of procedures provided in treatment categories as a ratio of total procedures, practices employing dental hygienists provided significantly more periodontal procedures and less oral surgery, prosthetic and restorative procedures. Periodontally-related services accounted for an average of 37.7% of procedures in practices employing dental hygienists compared with 18.9% in practices not employing dental hygienists (p < 0.05). Periodontal and preventive treatment of 50.7% of patients in practices employing hygienists was delegated to a hygienist, and the level of delegation of periodontally-related procedures was 77.2%. Over 90% of procedures performed by hygienists were periodontally-related, with the removal of subgingival calculus accounting for 57.7% of all procedures provided by dental hygienists. In conclusion, practices employing hygienists had a more periodontally-orientated service mix, with hygienists acting to complement the services of dentists in the provision of periodontal services, rather than as a substitute for the dentist. PMID- 7852614 TI - Evaluation of the efficacy of a redox agent in the treatment of chronic periodontitis. AB - A redox dye, methylene blue, was compared with subgingival root surface debridement and sterile water in the treatment of adult periodontitis. Plaque and gingival indices, bleeding on probing, and microbiological samples were obtained at baseline, and at 1, 4, 8 and 12 weeks following treatment. All subjects had matched pockets in each of the 4 quadrants, of 5 mm or more. One treatment consisted of 0.1% methylene blue gel irrigated professionally at 0, 1 and 4 weeks, and by subjects at days in between up to 4 weeks, at chosen sites within a randomly selected quadrant (split-mouth design). A 2nd treatment was sterile water irrigation as above. A 3rd quadrant received subgingival debridement, and sites in the 4th received methylene blue incorporated into a slow-release device of a biodegradable collagen alginate vicryl composite. All sites showed improvements in clinical and microbiological parameters. However, no statistically significant differences between treatment types were found for clinical measurements. Although plaque index tended to increase after week 1, gingival index was reduced, as was the papilla bleeding index. Probing depth reductions were approximately 1.2 mm for all treatments. Microbiological variables showed an increase in cocci and a decrease in motile organisms for all groups, the latter reaching statistical significance for subgingival debridement. The reductions in spirochaetes were significant for subgingival debridement and methylene blue by slow-release. Culture demonstrated an increase in the aerobe:anaerobe ratio for all groups, which was statistically significant initially (weeks 1 and 4) for subgingival debridement. Methylene blue was also effective statistically in improving this ratio, both by irrigation and slow release (week 4). Methylene blue also significantly reduced the numbers of black pigmented anaerobes during the trial period, both by irrigation and slow-release, which sterile water and subgingival debridement failed to do. No serious adverse experiences were seen, however, significantly greater morbidity was associated with subgingival debridement. These results clearly demonstrate that in altering the microflora to one that is more compatible with periodontal health, methylene blue treatment is comparable, or even better, than the currently standard treatment of subgingival debridement, and is better tolerated. PMID- 7852616 TI - Variability of sonic scaling tip movement. AB - The sonic scaler operates at frequencies of 2 to 6 kHz and is powered by pressurised air from the dental unit. Variables likely to affect how these instruments perform include the air pressure input and load applied by the operator. Other variables include the brand of scaler used and the clinical technique of the operator. The aim of this study was to investigate differences in instrument performance within a dental teaching hospital. Light microscopy was used to measure the displacement amplitudes in air of 32 Sonic scalers which were in regular clinical use in three departments (Periodontal Unit, Restorative Unit and School of Hygiene). During operation, the air pressure was kept at a constant 2.8 kg cm-2 and measurements were made on each instrument with three scaling tips (universal, sickle and periodontal). The periodontal scaling tip exhibited the greatest vibration although this was not significant (p > 0.1). There was a significant difference in performance between the different clinical environments where the scalers were used (p < 0.01). 4 new sonic scaling instruments made by different manufacturers were selected for displacement amplitude measurements. One brand of sonic scaler demonstrated a significantly greater displacement amplitude in comparative measurements between instruments (p < 0.01). This study demonstrated differences in the oscillation of sonic scalers which should be recognised by clinicians when using these instruments, since they may influence clinical performance. PMID- 7852615 TI - Effect of a new pre-brushing rinse on dental plaque removal. AB - Non-prescription prebrushing rinses to facilitate dental plaque removal have been advertised in recent years. The purpose of the present study was to determine the plaque removal effectiveness of Plax (Colgate) prebrushing rinse by comparing it to a placebo solution. 19 dental students volunteered for this double blind study which consisted of 2 experimental periods. The following procedure was followed: 3 weeks after scaling and polishing, the participants abstained from oral hygiene for 3 days to allow dental plaque to accumulate. After plaque disclosing, the 4 mandibular incisors were photographed using a strictly defined technique, as described by Quirynen et al. Then the volunteers mouthrinsed for 30 s with 15 ml of a solution provided to them. Neither the volunteers nor the examiners knew which solution (test or control) was used. After mouthrinsing, the participants were allowed to brush their teeth and the remaining plaque was photographed again. During the 2nd experimental period, the same procedure was followed, and the 2nd solution was used for mouthrinsing. The effectiveness of the solutions was evaluated by comparing the proportion of dental plaque removed during the 2 experimental periods. The area of dental plaque was measured by an electronic high-precision device (planimeter). The proportion of plaque removed after rinsing with Plax was 0.40 +/- 0.23 and after rising with placebo 0.42 +/- 0.24, of the tooth surface (p = 0.962). Analysis of data by means of paired t-test between the 2 experimental periods revealed no beneficial effect regarding plaque removal when Plax was used. PMID- 7852617 TI - Periodontal manifestation of hypophosphatasia. A family case report. AB - Hypophosphatasia is a rare inherited disease, the 1st clinical sign of which is often a premature loss of deciduous teeth. We describe clinical, histological and SEM findings of 2 cases of hypophosphatasia from a single family and discuss the pathological mechanisms with reference to the literature. PMID- 7852618 TI - Triclosan protects the skin against dermatitis caused by sodium lauryl sulphate exposure. AB - It has recently been suggested that the lipid-soluble, antibacterial agent triclosan possesses an anti-inflammatory effect in the oral cavity. The aim of the present study was to examine whether triclosan can protect the skin from the irritation or inflammation that may be caused by exposure to sodium lauryl sulphate (SLS). Finn Chamber patch tests on the forearms of 10 volunteers showed that a mixture of SLS and triclosan caused no inflammation, whereas SLS alone caused reactions in all the subjects. Pre-treatment with triclosan before SLS exposure had a slight effect whereas treatment after exposure showed a significant effect. It is suspected that the reported anti-gingivitis effect of triclosan may at least in part be explained by an anti-inflammatory effect. PMID- 7852619 TI - Some microbiological, histopathological and immunohistochemical characteristics of progressive periodontal disease. AB - The aim of the present investigation was to study the local nature of human periodontal disease by assessing the microbiota and the composition of the tissue lesions at sites with progressive attachment loss in periodontitis susceptible subjects. 300 subjects with periodontal disease were monitored for 2 years without treatment. 8 subjects lost > 2 mm of attachment at > or = 3 sites during both the first and the second 12 month interval. These 8 subjects (progressive disease group; PD) were recalled for a microbiological and histopathological examination. A group of age- and sex-matched subjects were identified who during the 2 years of monitoring exhibited gingivitis and deep pockets, but no further attachment loss. This group of 11 subjects (non-progressive disease group; NPD) served as controls. From the 8 active disease subjects, > or = 1 interproximal site which had displayed disease activity (progressive disease active; PDA) and > or = 1 contralateral site without disease progression (progressive disease inactive; PDI) were sampled. From the 11 control subjects, 1 site/subject was sampled (NPD). The total number of viable micro-organisms (TVC) in the subgingival microbiota was estimated and a series of bacterial species were identified and enumerated. The gingival tissue of the sampling site was excised and the soft tissue prepared for morphometrical and immunohistochemical analyses. No differences were observed in the subgingival microbiota of the sample sites in the subjects who exhibited disease progression (PD) when compared with the subjects with periodontally diseased but stable conditions (NPD).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7852620 TI - The effect of electronic dental analgesia during sonic scaling. AB - The aim of the present study was to investigate the effects of electronic dental analgesia (EDA) during sonic scaling. The clinical trial included 30 healthy adult subjects and was conducted as a randomised single-blind split-mouth design. The applied procedure consisted of periodontal scaling by means of a sonic scaler, while using the EDA device either in an active or placebo state. Rather similar results were obtained for the subjective pain rating in both the active and the placebo trials. When patients rated their discomfort on a scale 0-4 from no pain to very severe pain, the mean (s.d.) score for both the EDA and the placebo was 1.2 (0.6). The subjective pain estimate was positively correlated to the electrical current intensity provided. This implied that with a stronger pain experience, patients tried to administer more anaesthesia by turning the dial of the control box to an increased intensity of the electrical current. This remained insufficient to eliminate pain sensation. It was concluded that application of electronic dental anaesthesia in periodontal treatment remains questionable. PMID- 7852621 TI - Anatomical connections of the primate pretectal nucleus of the optic tract. AB - The pretectal nucleus of the optic tract (NOT) plays an essential role in optokinetic nystagmus, the reflexive movements of the eyes to motion of the entire visual scene. To determine how the NOT can influence structures that move the eyes, we injected it with lectin-conjugated horseradish peroxidase and characterized its afferent and efferent connections. The NOT sent its heaviest projection to the caudal half of the ipsilateral dorsal cap of Kooy in the inferior olive. The rostral dorsal cap was free of labeling. The NOT sent lighter, but consistent, projections to other visual and oculomotor-related areas including, from rostral to caudal, the ipsilateral pregeniculate nucleus, the contralateral NOT, the lateral and medial terminal nuclei of the accessory optic system bilaterally, the ipsilateral dorsolateral pontine nucleus, the ipsilateral nucleus prepositus hypoglossi, and the ipsilateral medial vestibular nucleus. The NOT received input from the contralateral NOT, the lateral terminal nuclei bilaterally, and the ipsilateral pregeniculate nucleus. Although our injections involved the pretectal olivary nucleus (PON), there was neither orthograde nor retrograde labeling in the contralateral PON. Our results indicate that the NOT can influence brainstem preoculomotor pathways both directly through the medial vestibular nucleus and nucleus prepositus hypoglossi and indirectly through both climbing and mossy fiber pathways to the cerebellar flocculus. In addition, the NOT communicates strongly with other retino-recipient zones, whose neurons are driven by either horizontal (contralateral NOT) or vertical (medial and lateral terminal nuclei) fullfield image motion. PMID- 7852622 TI - Innervation of the larynx, pharynx, and upper esophageal sphincter of the rat. AB - We identified a 'semicircular' compartment of the rat thyropharyngeus muscle at the pharyngoesophageal junction and used the glycogen depletion method to determine how the fibers of this muscle (as well as all others of the pharynx and larynx) are innervated by different cranial nerve branches. The semicircular compartment appears anatomically homologous to the human cricopharyngeus muscle, an important component of the upper esophageal sphincter. While we found very little overlap in the muscle targets of the pharyngeal, superior laryngeal and recurrent laryngeal nerves within the pharynx and larynx, the semicircular muscle receives a dual, interdigitating innervation from two vagal branches: the pharyngeal nerve and a branch of the superior laryngeal nerve we call the dorsal accessory branch. After applying horseradish peroxidase to either of these two nerves, we compared the distribution and number of cells labeled in the brainstem. The dorsal accessory branch conveys a more heterogeneous set of efferent fibers than does the pharyngeal nerve, including the axons of pharyngeal and esophageal motor neurons and parasympathetic preganglionic neurons. The observed distribution of labeled motor neurons in nucleus ambiguus also leads us to suggest that the semicircular compartment is innervated by two subsets of motor neurons, one of which is displaced ventrolateral to the main pharyngeal motor column. This arrangement raises the possibility of functional differences among semicircular compartment motor neurons correlated with the observed differences in brainstem location of cell bodies. PMID- 7852623 TI - Implants of polymer-encapsulated human NGF-secreting cells in the nonhuman primate: rescue and sprouting of degenerating cholinergic basal forebrain neurons. AB - Baby hamster kidney (BHK) cells were genetically modified to secrete high levels of human nerve growth factor (BHK-hNGF). Following polymer encapsulation, these cells were implanted into the lateral ventricle of four cynomolgus monkeys immediately following a unilateral transection/aspiration of the fornix. Three control monkeys received identical implants, with the exception that the BHK cells were not genetically modified to secrete hNGF and thus differed only by the hNGF construct. One monkey received a fornix transection only. All monkeys displayed complete transections of the fornix as revealed by a comprehensive loss of acetylcholinesterase-containing fibers within the hippocampus ipsilateral to the lesion. Control monkeys that were either unimplanted or received BHK-control (non-NGF secreting) cell implants did not differ from each other and displayed extensive losses of choline acetyltransferase and p75 NGF receptor (NGFr) immunoreactive neurons within the medial septum (MS; 53 and 54%, respectively) and vertical limb of the diagonal band (VLDB; 21 and 30%, respectively) ipsilateral to the lesion. In contrast, monkeys receiving implants of BHK-hNGF cells exhibited a only a modest loss of cholinergic neurons within the septum (19 and 20%, respectively) and VLDB (7%). Furthermore, only implants of hNGF secreting cells induced a dense sprouting of cholinergic fibers within the septum, which ramified against the ependymal lining of the ventricle adjacent to the transplant site. Examination of the capsules retreived from monkeys just prior to their death revealed an abundance of cells that produced detectable levels of hNGF in a sufficient concentration to differentiate PC12A cells in culture. These findings support the use of polymer-encapsulated cell therapy as a potential treatment for neurodegenerative diseases such as Alzheimer disease where basal forebrain degeneration is a consistent pathological feature. Moreover, this encapsulated xenogeneic system may provide therapeutically effective levels of a number of neurotrophic factors, alone or in combination, to select populations of neurons within the central nervous system. PMID- 7852624 TI - trk-immunoreactivity in the monkey central nervous system: forebrain. AB - Neurotrophins such as nerve growth factor (NGF) mediate their effects through interactions with high-affinity tropomycin-related kinase (trk) receptors. The present study employed a polyclonal antibody to characterize the distribution of trk-immunoreactive neurons within the nonhuman primate brain. Both young adult and aged cebus and rhesus monkeys displayed trk-immunoreactive neurons within all subdivisions of the basal forebrain. Colocalization studies revealed that between 66% and 76% of trk-immunoreactive basal forebrain neurons also expressed immunoreactivity for the low-affinity p75 NGF receptor, an excellent marker for cholinergic basal forebrain cells. In this experiment, most single-labeled basal forebrain neurons contained only trk immunoreactivity, whereas 4% of basal forebrain neurons expressed only the low-affinity p75 NGF receptor. Scattered trk immunoreactive neurons also were observed within the caudate nucleus and putamen. Although dual-localization studies with choline acetyltransferase (ChAT) were not performed, striatal neurons codistributed with ChAT-immunoreactive cells, and both types of cells were similar in size and morphology. This suggests that trk immunoreactivity is expressed within cholinergic interneurons within the primate striatum. Finally, lightly stained trk-immunoreactive neurons were observed within the stratum oriens of the hippocampal formation and within the hypothalamus. These data indicate that both cholinergic and, possibly, noncholinergic forebrain neurons express the protein for the high-affinity trk receptor, which transduces the signal mediating the trophic effects of neurotrophins. In addition, the pattern of trk immunoreactivity was preserved in two aged (26 and 29 years old) rhesus monkeys, suggesting that the expression of trk, for the most part, is sustained throughout the lifetime of the organism. PMID- 7852625 TI - Directionally specific changes in arterial pressure induce differential patterns of fos expression in discrete areas of the rat brainstem: a double-labeling study for Fos and catecholamines. AB - Although the nucleus tractus solitarii (NTS) has been established as the primary site of synaptic integration for the baroreceptor reflex, the higher-order pathways responsive to, and mediating, changes in vasomotor tone are not well characterized. We used immunohistochemistry to determine the distribution of cells expressing the Fos protein following pharmacologically induced, directionally specific changes in arterial pressure. The goal of this investigation was to determine if this immediate early gene product is differentially expressed in neurons of the rat brainstem following increased (pressor) versus decreased (depressor) arterial blood pressure (AP). Because brainstem catecholaminergic (CA) cell groups have been implicated in cardiovascular regulation, a double-labeling immunohistochemical procedure was used to examine the distribution of Fos in CA cells. Animals received continuous intravenous infusion of either a vasoconstrictor (l-phenylephrine hydrochloride), a vasodilator (sodium nitroprusside), or physiological saline. Extensive Fos-like immunoreactivity (FLI) was induced in both the pressor and depressor conditions in the NTS, caudal ventrolateral medulla (CVLM), rostral ventrolateral medulla (RVLM), A5, locus coeruleus (LC), Kolliker-Fuse, and parabrachial nucleus (PBN). These regions have all been implicated in central cardiovascular regulation. There were differences in the anatomical distribution of Fos-positive cells along the rostrocaudal axis of CVLM in the pressor and depressor conditions. Specifically, increased AP induced significantly more FLI cells within the rostral aspects of CVLM, whereas decreased AP resulted in a significantly greater number of FLI cells within the caudal CVLM. This result suggests that selective vasomotor responses differentially engaged discrete subsets of neurons within this brainstem region. Overall, approximately 50% of CA-immunoreactive cells were also FLI (CA-FLI) in the A1, A5, and A7 regions. Interestingly, increased AP produced significantly more CA-FLI double-labeled cells within the caudal than rostral A1 compared with depressor and control groups. Additionally, increased AP yielded significantly less CA-FLI double-labeled cells within the caudal A2 region. This suggests that CA barosensitive neurons in the CVLM/A1 and NTS/A2 regions are functionally segregated along the rostrocaudal axis of these structures. While twice as many PNMT-FLI double-labeled neurons were found in the C1-C3 regions following vasomotor changes versus saline control, there were no differences in the numbers or anatomical locations of labeled cells between pressor versus depressor groups. The results of this study indicate that (1) tonic changes in AP induce robust Fos expression in brainstem cardiovascular areas and (2) neurons responsive to specific directional changes in arterial pressure are segregated in some brainstem regions. PMID- 7852626 TI - Visual pontocerebellar projections in the macaque. AB - The cerebellum plays an important role in the visual guidance of movement. In order to understand the anatomical basis of visuomotor control, we studied the projection of pontine visual cells onto the cerebellar cortex of monkeys. Wheat germ agglutinin horseradish peroxidase was injected into the dorsolateral pons two monkeys. Retrogradely labelled cells were mapped in the cerebral cortex and superior colliculus, and orthogradely labelled fibers in the cerebellar cortex. The largest number of retrogradely labelled cells in the cerebral cortex was in a group of medial extrastriate visual areas. The major cerebellar target of these dorsolateral pontine cells is the dorsal paraflocculus. There is a weaker projection to the uvula, paramedian lobe, and Crus II, and a sparse but definite projection to the ventral paraflocculus. There are virtually no projections to the flocculus. There are sparse ipsilateral pontocerebellar projections to these same regions of cerebellar cortex. In nine monkeys, we made small injections of the tracer into the cerebellar cortex and studied the location of retrogradely filled cells in the pontine nuclei and inferior olive. Injections into the dorsal paraflocculus or rostral folia of the uvula retrogradely labelled large numbers of cells in the dorsolateral region of the contralateral pontine nuclei. Labelled cells were found ipsilaterally, but in reduced numbers. Injections outside of these areas in ventral paraflocculus or paramedian lobule labelled far fewer cells in this region of the pons. We conclude that the principal source of cerebral cortical visual information arises from a medial group of extrastriate visual areas and is relayed through cells in the dorsolateral pontine nuclei. The principal target of pontine visual cells is the dorsal paraflocculus. PMID- 7852627 TI - Histological and ultrastructural localization of the kainate receptor subunits, KA2 and GluR6/7, in the rat nervous system using selective antipeptide antibodies. AB - Kainate receptors are found throughout many regions of the brain and presumably contribute to responses of neurons to glutamate and other excitatory amino acids. Two affinity-purified polyclonal antibodies that recognize the kainate binding subunits, KA2 and GluR6, were made using C-terminus peptides. A previous study demonstrated that each antibody is specific for its subunit, although antibody to GluR6 recognizes GluR7 to some extent (hence the designation GluR6/7). Vibratome sections immunostained with either antibody showed light to moderate staining in many structures in the brain as well as in cervical spinal cord, dorsal root and vestibular ganglia, and pineal and pituitary glands. Moderate levels were seen in the olfactory bulb, cerebral cortex, caudate/putamen, and hypothalamus, whereas much of the thalamus was stained lightly. In the hippocampus, CA3 pyramidal cells were stained more densely than CA1 pyramidal cells--the difference more evident with antibody to GluR6/7. In addition, neuropilar staining was densest in the stratum lucidum of the CA3 region. In the brainstem, staining was moderate to moderately dense in a number of sensory, motor, and reticular nuclei. The moderately dense staining in the reticulothalamic nucleus and pontine nuclei with antibody to GluR6/7 may represent its recognition of GluR7. In the cerebellum, staining was moderate in granular and molecular layers with antibody to KA2 and in the molecular layer with antibody to GluR6/7, whereas it was moderately dense to dense in the granular layer with the GluR6/7 antibody. Outside of the brain, densest staining was seen with antibody to KA2 in the intermediate lobe of the pituitary gland. Ultrastructural localization of immunostaining was examined in the hippocampus, cerebral cortex, and cerebellar cortex. Typically, major staining was in postsynaptic densities apposed by unstained presynaptic terminals with round or mainly round vesicles and in associated dendrites. The light microscope pattern of staining was fairly similar to that of previous [3H]kainate binding and in situ hybridization studies. In addition, comparison with previous studies on distribution of other types of glutamate receptors indicates that KA2 and GluR6/7 are found with various other subunits in many of the same cell populations throughout the nervous system. PMID- 7852628 TI - Immunocytochemical localization of the alpha 7 subunit of the nicotinic acetylcholine receptor in the rat central nervous system. AB - Previous molecular cloning studies have revealed that alpha-bungarotoxin binding proteins present in the brain are members of the neuronal nicotinic acetylcholine receptor gene family. The alpha 7 subunit is structurally related to the agonist binding subunits present in the central and peripheral nervous systems and, when expressed in Xenopus oocytes, forms functional channels blockable by alpha bungarotoxin. In the present study, three different monoclonal antibodies raised against the alpha 7 subunit were used to map its distribution throughout the central nervous system of the rat. Immunohistochemical localization revealed that the alpha 7 subunit is expressed in most regions of the brain, being, overall, well correlated with previous "in situ" localization of alpha 7 transcripts and alpha-bungarotoxin autoradiographic binding studies. Particularly strong immunoreactivity was observed in several sensory and motor nuclei of the brainstem as well as the red nucleus. At the cellular level, alpha 7 immunostaining was usually found both in somata and dendrites, whereas axonal and terminal labeling was not observed. The widespread distribution of the alpha 7 subunit polypeptide is consistent with immunoprecipitation data demonstrating that it is a component of the predominant subtype of brain alpha-bungarotoxin sensitive nicotinic receptors. PMID- 7852629 TI - Morphology of retinal axons induced to arborize in a novel target, the medial geniculate nucleus. I. Comparison with arbors in normal targets. AB - Ferret retinal axons can be induced to innervate the medial geniculate nucleus (MGN) by a combination of brain lesions early in development. Our previous work suggests that the retinal ganglion cells responsible for this plasticity are W cells. The present study continues this work with a morphological investigation of normal retinal ganglion-cell axons and retinal ganglion-cell axons induced to arborize in the MGN. Retinal axons were bulk filled with horseradish peroxidase placed in the optic tract, and individual axons were serially reconstructed from sagittal sections. The control population consisted of fine-caliber axons arborizing in the superior colliculus (SC) and in the ventral C laminae of the lateral geniculate nucleus (LGN) of normal ferrets. We also compared the axons in the MGN of lesioned ferrets to intracellularly filled X and Y axons from normal ferrets as reported by Roe et al. ([1989] J. Comp. Neurol. 288:208). We have found that the retino-MGN axons in the lesioned ferrets do not resemble X or Y axons in normal ferrets in axon diameter, arbor volume, bouton number, or bouton density. However, they do resemble the fine-caliber, presumed W axons arborizing in the C laminae of the LGN and in the SC of normal ferrets. Thus, this study, in combination with previous studies, suggests strongly that W retinal ganglion cells are responsible for the retinal input to the MGN in lesioned animals. In addition, we find that the retino-MGN axons are of two types, branched and unbranched, which may correspond to different subtypes of retinal W cells. PMID- 7852631 TI - Hearing, vocalization and the external ear of a marsupial, the northern Quoll, Dasyurus hallucatus. AB - As part of a continuing study of the development of the marsupial auditory system, auditory brainstem responses (ABR) were recorded and an ABR audiogram was constructed for five female Northern Quolls (Dasyurus hallucatus), which are nocturnal carnivores. The best frequency for hearing lies between 8 and 10 kHz, and at 50 dB SPL there is a range from about 0.5 to 40 kHz. Vocalizations of adult quolls and pouch-young were recorded with a digital audio tape recorder, and the power spectra of representative calls were compared with the ABR audiogram. The common adult vocalizations have most energy at the lower end of the hearing range, whereas frequencies that are dominant in the isolation calls of the pouch-young lie close to the best frequency of hearing. Samples of nocturnal sounds of the habitat of the quoll were also recorded and analyzed. Power spectra have peak energy at frequencies between 2 and 5 kHz, with a smaller contribution above 10 kHz. The spectrum contains relatively little power at the best frequency of hearing. Measurements of the sound pressure level at the external ear canal as a function of stimulus frequency and location in space suggest that the directional amplifying properties of the pinna will operate most effectively on sound frequencies at the upper end of the quoll's hearing range, a region that may be important in prey detection. Comparisons are made with other mammalian nocturnal carnivores and with other marsupials. We speculate that, for nocturnal carnivores, one role of the low-frequency part of the hearing range concerns the recognition of adult conspecifics, the mid-frequency range is important for the detection of pouch-young, and the upper range may be particularly concerned with prey/predator detection. PMID- 7852630 TI - Morphology of retinal axon arbors induced to arborize in a novel target, the medial geniculate nucleus. II. Comparison with axons from the inferior colliculus. AB - Specific neonatal lesions in ferrets can induce retinal axons to project into the medial geniculate nucleus (MGN). In the accompanying paper (Pallas et al., this issue), we described the morphology of these retinal ganglion cell axons. Those results and others (Roe et al. [1993] J. Comp. Neurol. 334:263) suggest that these axons belong to the W class of retinal axons. In this paper, the retino-MGN axons are compared with the normal inputs to the MGN from the brachium of the inferior colliculus (BIC). We first sought to determine further the extent to which a novel target might influence retinal axon arbor morphology. The second issue concerns retinal topography. Ferrets with retinal projections to the MGN have a two-dimensional retinotopic map in the MGN and the primary auditory cortex rather than the one-dimensional tonotopic map normally present (Roe et al. [1990] Science 250:818). To investigate whether there might be an anatomical substrate for a two-dimensional retinotopic map in the MGN, we compared the space-filling characteristics of the retino-MGN axons with the IC-MGN axons. Our results show that the branched retino-MGN axons resemble normal retinal W axons much more closely than they resemble the normal inputs to MGN. In addition, most of the axon arbors from the BIC are elongated along the rostrocaudal (isofrequency) axis, whereas the branched retino-MGN axons are more spatially restricted, suggesting an anatomical substrate for a retinotopic map in the MGN of the rewired ferrets. PMID- 7852632 TI - Expression of multiple neuregulin transcripts in postnatal rat brains. AB - The distribution of neuregulin transcripts in rat brains was studied by both RNA blotting and in situ hybridization. Our data demonstrate that multiple neuregulin transcripts are expressed in neurons of the basal forebrain, the hippocampus, the diencephalon, the cerebellum, the brainstem, and the spinal cord. Developmental changes in the distribution of neuregulin transcripts were observed only in the cerebellum and the hippocampus. The intense neuregulin hybridization signals in the brainstem motor and sensory nuclei and the spinal motor neurons are suggestive of a functional involvement of neuregulins in motor and sensory systems. The expression of neuregulins in other parts of the brain also indicates that these factors are involved in a variety of central nervous system functions. PMID- 7852633 TI - Cytoarchitecture and responsiveness of the medial ansate region of the cat primary somatosensory cortex. AB - To understand its relationship to somatosensory areas in other species, we studied the rostral bank of the medial ansate sulcus in adult cats. Neurons in the shoulder and upper part of the sulcal wall responded to low-threshold cutaneous stimuli much like neurons on the crown of the gyrus, whereas neurons in some deeper portions of the sulcus required more intense but innocuous somatic stimuli. Because we found much of the body surface re-represented in this area, we suggest that, besides the representation in area 3b, there is another cutaneous representation of the hindlimb and trunk located on the gyral crown near the medial end of the medial ansate sulcus and of the forelimb and trunk within the medial ansate sulcus. Posterior to this second cutaneous representation, many parts of the body were also represented in regions activated by more intense stimuli and having a different cytoarchitecture, suggesting that they were part of another body representation. Area 3b and the shoulder of the gyrus were distinguished by relatively intense acetylcholinesterase staining of layers III and IV. In the wall of the sulcus, all layers except layer I were uniformly stained to a point where electrophysiological recordings showed the cortex to be unresponsive, whereupon the outer two-thirds of layer I became very pale. Neurons activated by afferents from knee joints were found only in a small area; we did not find a mediolateral band serving joint afferents as is reported in primates. These data suggest that cat somatosensory cortex differs in some ways from primates but that it contains multiple representations of the body, as do most other mammals. PMID- 7852634 TI - Projections of individual Purkinje cells of identified zones in the flocculus to the vestibular and cerebellar nuclei in the rabbit. AB - The rabbit flocculus can be divided into five zones (zones 1, 2, 3, 4, and C2) with the use of acetylcholinesterase histochemistry. The projections of individual Purkinje cells in these zones to the vestibular and cerebellar nuclei were studied by using biocytin as an anterograde tracer. The zones were physiologically identified in terms of the Purkinje cell complex spike modulation occurring in response to optokinetic stimulation. In zones 1 and 3 neurons respond best to rotation about a horizontal axis that is close to perpendicular to the ipsilateral anterior semicircular canal, whereas in zones 2 and 4 neurons respond best to rotation about the vertical axis. Complex spike activity in zone C2 is unresponsive to optokinetic stimulation. Collectively, Purkinje cells of zone 1 projected to the ventral dentate nucleus, dorsal group y, and superior vestibular nucleus; Purkinje cells of zones 2 and 4 projected to the magnocellular and parvicellular parts of the medial vestibular nucleus; Purkinje cells of zone 3 projected to dorsal group y, ventral group y, and the superior vestibular nucleus; and Purkinje cells of zone C2 projected to the interposed posterior nucleus and dorsal group y. Some of the labeled Purkinje cell axons branched and innervated two nuclei. Branching axons from zone 1 either innervated both the ventral dentate nucleus and the superior vestibular nucleus or both dorsal group y and the superior vestibular nucleus. Branching axons from zones 2 and 4 innervated both the magnocellular and the parvicellular parts of the medial vestibular nucleus. Branching axons from zone 3 innervated both dorsal group y and the superior vestibular nucleus, or both ventral group y and the superior vestibular nucleus. Branching axons from zone C2 innervated both the interposed posterior nucleus and dorsal group y. Some of the target nuclei of the floccular Purkinje cell axons (e.g., dorsal group y and interposed posterior nucleus) project to the part of the inferior olive that, in turn, projects to the corresponding floccular zone, thus completing a closed pathway consisting of the inferior olive, the cerebellar cortex, and the cerebellar and vestibular nuclei. Other target nuclei (e.g., superior vestibular nucleus and medial vestibular nucleus) do not project back to the olivary subnuclei that innervate the flocculus and are part of an open olivofloccular pathway. An individual Purkinje cell thus can innervate a nucleus in the closed pathway as well as a nucleus in the open pathway.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7852635 TI - Projections of individual Purkinje cells of identified zones in the ventral nodulus to the vestibular and cerebellar nuclei in the rabbit. AB - The projections of Purkinje cells from zones in the ventral nodulus of pigmented rabbits were studied with the use of extracellularly injected biocytin as an anterograde tracer. The zones were physiologically identified according to the complex spike modulation of Purkinje cells in response to optokinetic stimulation. Purkinje cells in the most medial zone do not respond to optokinetic stimulation; they project to the fastigial nucleus, the perifastigial white matter, the periinterposed white matter, and the medial vestibular nucleus. In the adjacent zone, Purkinje cells respond best to optokinetic stimulation about the vertical axis; they project to the periinterposed white matter and the medial vestibular nucleus. Purkinje cells in the next zone respond best to optokinetic stimulation about an axis approximately perpendicular to the ipsilateral anterior canal; they project to the periinterposed white matter, dorsal group y, the superior vestibular nucleus, and the medial vestibular nucleus. In the most lateral zone, Purkinje cells respond best to optokinetic stimulation about the vertical axis; they project to the periinterposed white matter, dorsal group y, and the medial vestibular nucleus. The majority of axons gave off collaterals and innervated more than one nucleus. Often, three or four different areas received terminals from a single Purkinje cell axon. The zonal projection pattern of the ventral nodulus is compared to that of the flocculus, which, with respect to the visual climbing fiber afferents, has similar zones. PMID- 7852636 TI - Overexpression of nerve growth factor in transgenic mice induces novel sympathetic projections to primary sensory neurons. AB - Peripheral nerve crush induces novel projections from noradrenergic sympathetic neurons to sensory ganglia, and it has been suggested that these projections provide an anatomical substrate for chronic pain syndromes that occur after nerve injury. The present study demonstrates that novel sympathetic projections to sensory neurons are also induced in transgenic mice that overexpress nerve growth factor (NGF) in the skin. Specifically, a large proportion of trigeminal neurons in NGF transgenic mice were innervated by tyrosine hydroxylase (TH)-positive pericellular arborizations that were seen only rarely in controls. Electron microscopic analysis of NGF transgenic mice revealed that trigeminal neurons were surrounded by numerous axonal varicosities containing synaptic specializations. Removal of the superior cervical ganglion abolished TH-immunoreactive arborizations in the ipsilateral trigeminal ganglion confirming that these fibers were sympathetic axons. A two-site enzyme-linked immunosorbent assay revealed that transgenic ganglia contained a tenfold increase in NGF peptide compared to controls. However, reverse transcriptase polymerase chain reaction analysis showed no apparent expression of transgene mRNA in sensory ganglia, suggesting that the additional NGF was derived from increased NGF expression in the skin. These results indicate that NGF can induce novel sympathetic projections to sensory neurons in vivo and suggests a model in which increased NGF expression plays a role in the development of sympathetic hyperalgesia after nerve injury. PMID- 7852637 TI - Adjuvant-induced inflammation of rat paw is associated with altered calcitonin gene-related peptide immunoreactivity within cell bodies and peripheral endings of primary afferent neurons. AB - Local inflammation is associated with profound changes in the biochemistry and physiology of primary afferent nerve fibers and the central neurons responding to their signals. In some tissues, the neural changes accompanying inflammation include sprouting and cytochemical changes that are delayed several days after the initial injury. In the present study, we have analyzed the effect of complete Freund's adjuvant (CFA)-induced inflammation in the rat paw on calcitonin gene related peptide (CGRP) immunoreactivity (IR) in dorsal root ganglia and within tissue of the inflamed paw. We quantified the CGRP-IR within the L1, L4, and L6 ganglia, and in ankle, midpaw, joint and toe tissues. Analysis of the processed tissue revealed a significant increase in the percentage of CGRP-positive cells within L4 dorsal root ganglia ipsilateral to an inflamed hindpaw six days after administration of CFA. There was a parallel increase in the number and staining density of detectable CGRP-immunoreactive fibers in periarticular and perivascular tissues of the inflamed digits and inflamed ankle. The other tissues of the paw, including epidermis and the regions surrounding the abcesses, did not have detectable changes in CGRP-immunoreactive fibers, despite tissue swelling and dystrophic changes in the foot that included loss of mast cell staining. These data demonstrate that local inflammation of the rat paw has delayed influences on the peripheral nervous system, in addition to a number of previously characterized acute effects. The alterations of CGRP-IR were focused around specific tissue types, such as joints and subdermal blood vessels, and absent from others, such as epidermis or in the areas surrounding abscesses. This suggests production of local factors within reactive tissues that selectively interact with nerve fibers to induce changes in CGRP-IR within the fibers. PMID- 7852638 TI - Rapid expression and transport of embryonic N-CAM in dentate gyrus following entorhinal cortex lesion: ultrastructural analysis. AB - Neural cell adhesion molecules are known to be important in axon guidance and synapse formation in the developing brain. The embryonic form of neural cell adhesion molecule (eN-CAM) is reexpressed in the outer molecular layer (OML) of the dentate gyrus following entorhinal cortex (ERC) lesion. Ultrastructural analysis revealed localization of eN-CAM to the membrane of granule-cell dendritic membranes and occasionally axons within the denervated zone. Because eN CAM is expressed rapidly (within 2 days) after ERC lesion, we were interested in the temporal sequence of expression. Denervated hippocampi (12, 15, 24, and 48 hours post-ERC lesion) were stained with anti-eN-CAM and processed for immunoelectron microscopy. At 12 hours, there was no evidence of staining for eN CAM. By 15 hours after lesion, membranes of both dendrites and axons throughout the molecular layer exhibited moderate eN-CAM staining, and dendritic cytoplasm was heavily labeled. Twenty-four hours following lesion, plasma membrane staining of eN-CAM on both axons and dendrites had increased in intensity within the OML, whereas membrane eN-CAM staining was diminished in the inner molecular layer (IML), and the intradendritic cytoplasmic staining disappeared. By 48 hours after lesion, eN-CAM staining had disappeared from the IML but remained intense and widely distributed in the OML. These findings suggest a rapid transport of de novo synthesized protein. A generalized reaction appears to occur immediately following denervation, and eN-CAM is up-regulated in the complete expanse of the dendritic membrane, despite the fact that only the OML is denervated.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7852639 TI - The role of adhesion molecules in cutaneous inflammation. PMID- 7852640 TI - Cadherins in cutaneous biology. AB - The role of cadherins in cutaneous biology has focused mainly on the classical cadherins, E- and P-cadherin. In this review, roles for cadherins in skin morphogenesis, keratinocyte differentiation, and cancer metastasis are discussed. E-cadherin is expressed on the surfaces of whole epidermal layer cells, and P cadherin is expressed only on the surfaces of basal cells. Ultrastructural studies have shown that E-cadherin is distributed on the cytoplasmic membranes of keratinocytes with a condensation in the intercellular space of the desmosomes. During human skin development, P-cadherin expression is spatiotemporally controlled and closely related to the segregation of basal layers as well as to the arrangement of epidermal cells into eccrine ducts. In human skin diseases, E cadherin expression is markedly reduced on the acantholytic cells of tissues in pemphigus and also in Darier's disease. Keratinocytes cultured in high calcium produce a much more intense immunofluorescence of intercellular E- and P-cadherin than do cells grown in low calcium. Ultrastructural studies show that E-cadherin on the cytoplasmic membrane of the keratinocytes is shifted to desmosomes under physiological conditions and therein expresses an adhesion function is association with other desmosomal cadherins. Cell adhesion molecules are now considered to play significant roles in the cellular connections of cancers and metastatic cells. Reduced expression of E-cadherin on invasive neoplastic cells has been demonstrated for cancers of the stomach, liver, breast, and several other organs. This reduced expression of E-cadherin is observed in squamous cell carcinoma and Paget's disease. Soluble E-cadherins in sera are elevated in various skin diseases, including bullous pemphigoid, pemphigus vulgaris and psoriasis, but not in patients with burns. Markedly high levels in soluble E cadherin are demonstrated in patients with metastatic cancers. PMID- 7852641 TI - The regulation of cell adhesion molecule gene expression. PMID- 7852642 TI - Role of integrins in cell adhesion and polarity in normal keratinocytes and human skin pathologies. AB - In vitro, normal human keratinocytes reconstitute a differentiated stratified epidermis, maintaining the same gene expression pattern as its in vivo counterpart and are suitable for permanent grafting onto patients. Keratinocyte adhesion to basal lamina and lateral interactions among basal epidermal cells are also mediated by integrin receptors that are sorted to defined plasma membrane domains. The hemidesmosome-associated integrin alpha 6 beta 4 is sharply localized at the basal surface of basal cells and codistributes with laminin and nicein/kalinin; the alpha 2 beta 1 and alpha 3 beta 1 integrins are enriched laterally and play crucial roles in cell-cell interaction and proper colony morphology. During wound healing, proliferating and migrating keratinocytes express on their plasma membrane alpha v beta 5 and alpha 5 beta 1, which allow keratinocyte attachment and migration over the provisional matrix present in the wound. TGF beta, which is an autocrine and paracrine mediator in wound healing, specifically increases the synthesis and expression of alpha v beta 5 and alpha 5 beta 1, induces the de novo expression of alpha v beta 6, and determines the loss of integrin polarization. In hyperproliferative skin diseases, such as skin cancer or psoriasis vulgaris, and in normal keratinocytes forced into more frequent cell cycles, the polarized expression of integrins is lost, and alpha 5 beta 1 becomes costitutively expressed on the plasma membrane. In addition, the alpha 6 beta 4 integrin becomes associated with focal contacts. Nerve growth factor (NGF) is a potent autocrine stimulator of keratinocyte growth and induces melanocyte migration toward the leading edge of a healing wound.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7852643 TI - T cell receptor expression by dendritic epidermal T cells. AB - Dendritic epidermal T cells (DETC) in murine epidermis express the gamma delta T cell receptor (TCR). The major population of DETC utilize V gamma 5 and V delta 1 without any junctional diversity, corresponding to the earliest fetal thymocytes which express TCR gamma delta. Using PCR, we recently found another population of DETC which express V gamma 1-V delta 6 with junctional diversity in addition to V gamma 5-V delta 1, although they exist in small numbers in normal mice. In athymic nude mice, V gamma 1+ cells also exist. Therefore, this subset of gamma delta T cells is the product of an extrathymic pathway. These V gamma 1+ cells may recognize mycobacterium antigen or heat shock protein (HSP), thus playing an important role in the first defense of the skin. In contrast to normal mice, in nude mice, we could not detect any DETC using anti CD3 epsilon antibody (2C11). In order to solve this puzzle, we examined the components of TCR complex utilizing immunoprecipitation and northern blot analysis. TCR is composed of either alpha beta or gamma delta chains associated with CD3 gamma, delta, epsilon and zeta-zeta chains. By immunoprecipitation of 125I labelled DETC cell lines using anti-CD3 epsilon antibody, we detected gamma delta chains and CD3 gamma and CD3 epsilon chains, but not CD3 delta or CD3 zeta chains. Northern blot analysis showed that these cells express CD3 gamma, epsilon, and zeta chains, but not the CD3 delta chain.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7852644 TI - Autoantibodies against cell adhesion molecules in pemphigus. AB - cDNA cloning has demonstrated that pemphigus autoantigens of both pemphigus vulgaris (PV) and pemphigus foliaceus are members of the desmoglein subfamily of the cadherin supergene family. The availability of these cDNAs allowed us to utilize molecular engineering to attempt to understand the pathophysiology of pemphigus. Transfection study with a chimeric molecule containing the extracellular domain of PV antigen (PVA) and the cytoplasmic domain of E-cadherin demonstrated that the extracellular domain of PVA mediates weak homophilic cell adhesion. Bacterial fusion proteins representing different parts of PVA showed that the major immunogenic domains are EC1, EC2, and EC4 and that at least one pathogenic epitope is located on the amino-terminal region of PVA, an area thought to be important for classic cadherin homophilic interaction. Further, a secreted form of PVA recombinant protein, PVIg, was produced by baculovirus expression. Immunoabsorption assay has demonstrated that PVIg is capable of absorbing pathogenic autoantibodies from patients' sera and preventing blister formation in neonatal mice. PMID- 7852645 TI - Antibody-binding to the 180-kD bullous pemphigoid antigens at the lateral cell surface causes their internalization and inhibits their assembly at the basal cell surface in cultured keratinocytes. AB - We demonstrated the effects of monoclonal antibodies to the 180-kD and 230-kD BP antigens (BPA) and of BP sera on Ca(++)-induced formation of hemidesmosomes in cultured human keratinocytes (a cell line, DJM-1) by immunofluorescence microscopy. Under low Ca++ (0.07 mM) conditions, the 180-kD and 230-kD BPAs were distributed homogeneously on the basal plasma membrane, while they formed a peculiar concentric ring or arch (ring/arch) arrangement in high-Ca++ (1.87 mM) medium. On the other hand, the apical-lateral cell membrane was stained homogeneously with antibodies to the 180-kD BPA, but not to the 230-kD BPA, both in low and high Ca++ media. The low-high Ca++ switch at first caused disappearance of the antigen from the basal plasma membrane and then formed the high-Ca++ ring/arch pattern within 3 hrs. In this system, monoclonal antibodies to the 180-kD and 230-kD BPAs and the sera from 5 BP patients, 2 pemphigus vulgaris (PV) patients, and 4 normal volunteers were added into the culture media. The addition of anti-180-kD BPA antibodies or any BP serum caused the internalization of the 180-kD BPA from the apical-lateral cell membrane and inhibited the Ca(++)-induced formation of the ring/arch pattern on the basal membrane, possibly by inhibiting the movement of the antigen from the lateral to the basal membrane to form hemidesmosomes.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7852646 TI - Differential cell surface distribution of adhesion molecules demonstrated by immuno-scanning electron microscopy. AB - Scanning electron microscopy with immuno-gold labeling revealed that epidermal keratinocytes expressed ICAM-1 and HLA-DR molecules on their surfaces in patterns that differed in mycosis fungoides (MF) and lichenoid reaction (LR). ICAM-1 molecules, visualized as deposits of gold particles, were present as clusters adjacent to the junctions interconnecting the keratinocytes of MF lesions. LFA-1 molecules were seen as granules on the surfaces of all infiltrates, most of which also expressed ICAM-1. HLA-DR molecules were seen continuously along the borders of the individual keratinocytes. In LR, ICAM-1 and HLA-DR were expressed only sparsely on the undersurface of the epidermis, whereas the infiltrates expressed LFA-1 molecules on their surfaces. These findings may explain the differing histological features of MF and LR: ICAM-1 molecules present on the intercellular junctions of MF epidermis lead the LFA-1-bearing cells to migrate into the interspaces of the keratinocytes, thus producing "epidermotropism". These cells aggregate by means of co-expressed ICAM-1 to thus produce the appearance of a "microabscess". In LR, on the other hand, the minimal expression of ICAM-1 on the epidermal undersurface leaves most infiltrates within the dermis, thus producing a "band-like infiltrate" beneath the epidermis. PMID- 7852647 TI - Novel experimental approaches to melanoma diagnosis and therapy. AB - We have investigated the potential use of immune therapies on the growth of melanoma metastases in a new animal model that more closely approximates the clinical situation. We have found that significant benefits towards decreased metastatic growth and subsequent animal survival can be achieved by treatment of tumor-bearing mice with melanoma-specific monoclonal antibodies or alternatively, with various types of monovalent or polyvalent vaccines. The beneficial effects of those vaccines can be significantly enhanced by concomitant interleukin-2 therapy. PMID- 7852648 TI - Cytogenetic aspects of melanocytic neoplasia. PMID- 7852649 TI - Criteria for histopathologic diagnosis of melanoma, including melanoma in situ, in historical perspective. PMID- 7852650 TI - Reducing mortality and morbidity of cutaneous melanoma: a six year plan. A). Identifying the population at risk. PMID- 7852651 TI - Reducing mortality and morbidity of cutaneous melanoma: a six year plan. B). Identifying high and low risk pigmented lesions using epiluminescence microscopy. PMID- 7852652 TI - Computerized digital image analysis: an aid for melanoma diagnosis--preliminary investigations and brief review. AB - Both digital imaging and epiluminescence microscopy hold promise for improved early detection of cutaneous melanoma. Several centers have been actively working in these areas during the past decade. These experiences and preliminary work based on the image capture of 83 pigmented lesions at our center using a prototype digital imaging system (SKINVIEW) are described. This system is based, in part, on the analysis of lesional morphologic features, such as shape, border, and radii. Histopathologic correlation was matched against these features to assess the efficacy of diagnosis. At our center, these parameters alone were not sufficient to discriminate between benign and malignant lesions, in part, because the melanomas were, in general, early lesions and many of the nevi were sufficiently clinically atypical to require removal for discrimination from melanoma. In addition, technical improvements in the image capturing and processing mechanism are needed. Rapid progress in this area is anticipated. PMID- 7852653 TI - Diagnosis and differential diagnosis of malignant melanoma by dermatoscope and videomicroscope. PMID- 7852654 TI - Melanogenesis investigation leading to selective melanoma neutron capture therapy and diagnosis. AB - Basic investigation into the nature of melanin monomer and polymer synthesis in pigment cells has revealed many of the new underlying factors involved in its regulation and control by three melanogenesis-related genes, tyrosinase, TRP-1 and TRP-2, and other non-tyrosinase glycoproteins. Pigment cells can undergo clinically and biologically recognizable progressive multi-step carcinogenesis. Generally parallel to this progressive cancerization is accentuated melanogenesis. Using this accentuated melanogenesis to develop a specific diagnosis and cure for melanoma (Mm) has long been a challenge. However, until recently, no success was achieved. As an example, attempting to utilize the fact that dopa accumulates as a melanin substrate within Mm cells, hybrid compounds of dopa and cytotoxic drugs were developed. However, these compounds were found to have severe systemic side effects and were therefore unusable. Another newer Mm treatment involves high energy radiation such as fast neutrons. But this is quite non-selective, killing both the target cancer and the normal surrounding tissue. Since 1972, I have developed the idea of coupling the high energy releasing system of thermal neutron irradiation with the non-toxic 10B-dopa analogue, 10B1 L-p-boronophenylalanine (10B1-L-BPA). Thermal neutrons are essentially harmless, but, after specific absorption by 10B, release high LET alpha-particles and 7Li atoms with an energy of 2.33 MeV up to a distance of 14 mu, the diameter of Mm cells, thus selectively killing them without damaging surrounding normal tissue. After the synthesis of 10B1-L-BPA, exhaustive in vitro and in vivo radiological studies on its enhanced killing effect were done to develop optimal Mm Boron Neutron Capture Therapy (NCT).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7852655 TI - Hyperthermic isolated limb perfusion with intra-arterial administration of carboplatin and/or interferon-beta for the treatment of malignant melanoma of the leg. AB - Our experiences of hyperthermic isolated limb perfusion with administration of carboplatin, interferon-beta or a combination of both are reported. Administration of high doses of these reagents was well tolerated by patients with melanoma without severe complications after the treatment. A total of 8 patients underwent this therapeutic modality. Remarkable clinical improvement was seen in the first patient, who was in Stage III at the time of the perfusion. Histopathological findings indicated severe damage to the melanoma cells after the operation. Prophylactic hyperthermic perfusion was performed in 6 other patients with Stage II-III melanoma of the lower limb. None of them have shown any signs of recurrence 1-10 months later. The activities of natural killer cells or T lymphocytes appeared to be increased when the perfusion was carried out with concomitant administration of both carboplatin and interferon-beta. These results suggest that hyperthermic isolated limb perfusion with carboplatin and/or interferon beta administration is effective in patients with advanced stage melanoma. PMID- 7852656 TI - Immune parameters in euthymic bipolar patients and normal volunteers. AB - Immune system parameters were investigated in euthymic bipolar patients and matched normal volunteers. A review of the existing literature suggested that bipolar patients might be more likely to demonstrate signs of immune activation. Serum-soluble interleukin-2 receptors, circulating phenotypic lymphocyte markers, levels were measured. Euthymic bipolar patients and normal volunteers did not differ or any of these measures. Furthermore, bipolar patients could not be differentiated by medication status or gender. In conclusion, there was no evidence of immune system activation in euthymic bipolar patients. PMID- 7852657 TI - A study of life events in mania. AB - After clinical recovery, 46 manic patients were screened for evidence of life events during a period of 6 months before the first episode of mania (DSMIIIR criteria) and 6 months after the episode. Within-patient group comparisons showed that patients who reported life events had a significantly higher presumptive mean stress score before manic episode as compared with the period after the illness. When life events were considered in relation to age, sex, marital status and family history of affective disorder, on a logistic regression equation, it was found that life events before mania were significantly associated with males and with a younger age of onset. The implications of these findings are discussed. PMID- 7852658 TI - 5-Methyltetrahydrofolate level in the serum of depressed subjects and its relationship to the outcome of ECT. AB - Serum 5-MeTHF levels are reported in 26 subjects, before and after completing a course of ECT, and compared to 21 healthy volunteers. 5-MeTHF levels of depressed subjects were significantly lower than controls before and after ECT. There was no difference in 5-MeTHF levels between ECT responders and non-responders but folate deficiency was related to severity of depression before ECT. Serum 5-MeTHF was not related to treatment response and values remained markedly low even after a good response to treatment. PMID- 7852659 TI - Moclobemide and fluoxetine in atypical depression: a double-blind trial. AB - The effectiveness of moclobemide or fluoxetine in the treatment of atypical (n = 53) and other depressive patients (n = 156) was compared in a 6-week double-blind randomized trial. HDRS, MARDS, GCI and the Atypical Depression Diagnostic Scale were used in clinical assessment. Significant differences were seen in MADRS and GCI scores in favour of moclobemide in the treatment of atypical depression, but not with HDRS. No major differences were seen between the two drugs in the treatment of other depressive patients. A positive response, defined by a > 50% decrease in HDRS score and a GCI Improvement Score of 1 or 2, was seen among 67% of atypical patients treated with moclobemide and among 55% treated with fluoxetine and in 60 and 48% of other depressive patients, respectively. Both drugs gave results with atypical patients at least as good as with other depressive patients. Our results suggest that patients suffering from atypical depression may respond more favourably to moclobemide than to fluoxetine treatment. PMID- 7852660 TI - Treatment of manic episodes in Scandinavia: the use of neuroleptic drugs in a clinical routine setting. AB - To provide longitudinal data on the treatment of acute mania with neuroleptics in a routine setting, 125 consecutively admitted manic patients were examined. Out of the 125 patients, 111 (89%) were primarily treated with neuroleptics during the index episode, and a substantial use of drug combinations was observed. Of the 111 patients, 27% were still hospitalized and in a manic state after 10 weeks. Our results indicate that treatment under routine conditions is an outcome variable which is determined by the severity and persistence of the manic symptoms. If typical neuroleptics are used as first choice antimanic agents, dosages can be minimized by the concomitant use of a benzodiazepine. In non responders, a mere shift from one neuroleptic to another does not seem rational, so to improve outcome, a mood stabilizer should be added. PMID- 7852661 TI - A controlled trial of cyanocobalamin (vitamin B12) in the treatment of winter seasonal affective disorder. AB - To test the hypothesis that cyanocobalamin (vitamin B12) is an effective treatment for winter seasonal affective disorder (SAD). 2 weeks of double-blind placebo washout, followed by random assignment to parallel treatments for 2 weeks with cyanocobalamin vs. placebo. Observations were made during weekly outpatient visits. All subjects met criteria for SAD. 27 patients were studied. After the washout period, 14 were randomly assigned to 1.5 mg cyanocobalamin (3 x/day) and 13 remained on placebo on the same schedule. 29 item SIGH-SAD scores were used to determine antidepressant efficacy. No significant differences were found in the responses between the two groups. Cyanocobalamin does not appear to be an effective short-term treatment for depression in SAD patients. The usefulness as a treatment for SAD of the methylated form of Vitamin B12, which has been used extensively in related studies, remains to be explored. PMID- 7852662 TI - Testing definitions of dysphoric mania and hypomania: prevalence, clinical characteristics and inter-episode stability. AB - 37 outpatients with at least one prospectively observed manic or hypomanic episode comprised a sample for comparison of five definitions of dysphoric (hypo)mania. Dysphoric symptoms were continuously rather than bimodally distributed. Prevalence of dysphoria varied from 5 to 73% depending on the definition used. Female gender was associated with dysphoria under two of the five definitions. Inter-episode stability in patients with at least two prospectively observed episodes (n = 15) was not significantly different from chance. These data do not indicate that (hypo)mania can be dichotomized on the basis of dysphoria. Advantages and disadvantages of dimensional and categorical approaches to specifying mood in mania or hypomania are discussed. PMID- 7852663 TI - Acute vs. chronic EEG effects in maprotiline- and in clomipramine-treated depressive inpatients and the prediction of therapeutic outcome. AB - Patients treated with the norepinephrine uptake inhibitor maprotiline showed an opposite tendency between acute and chronic effect of EEG. Whereas the acute effect indicated a decrease upon EEG vigilance, the chronic effect indicated an increase. Under clomipramine which acts upon different transmitter systems in a complex, up to now not fully understood way, acute and chronic EEG effects could not be differentiated. PMID- 7852664 TI - Natural history of chronic depression: predictors of change in severity over time. AB - In a prospective study of patients with chronic depression, none of a series of variables reported to be predictive of outcome in episodic depression emerged as significant predictors of change in depression scores over time. It is concluded that either greater changes in depression severity than those observed may be required to detect predictors of outcome in chronic depression, or that other variables, perhaps related to the social context of the patient rather than to the depression itself, may determine the course of chronic depression. PMID- 7852665 TI - Anacardium occidentale (cashew) pollen allergy in patients with allergic bronchial asthma. AB - BACKGROUND: The cashew tree grows in abundance in the hills and plains of Goa, India. Because of the financial yield, more and more trees are being planted each year. The cashew tree flowers once a year between January and March, but pollination is mostly entomophilous. OBJECTIVE: For the first time, a study was conducted to establish the possible role of the cashew pollen in triggering allergic asthma. METHODS: A stock solution of pollen extract was prepared with the standard weight/volume method for intradermal skin tests and a bronchial provocation tests (BPTs). The protein content of the antigen, estimated with the use of Folin phenol reagent and a spectrophotometer, was 28.72 mg/ml. Ten healthy volunteers and 65 subjects with allergic asthma, as documented by previous positive skin test reactions to various pollens, were studied. RESULTS: Of the 65 patients, 26 (40%) had positive skin test reactions in various grades. BPTs were performed in 22 of the 26 patients after their baseline peak expiratory flow volume was assessed. Twenty (90.9%) patients had a positive BPT result, and the majority of patients had grade III and grade IV reactions. None of the control subjects (n = 10) had positive responses to either intradermal tests or the BPT. Serum IgE levels, estimated by ELISA, were high in patients with positive skin test responses and showed a linear correlation with cutaneous sensitivity. Control subjects showed normal levels of IgE (39.0 +/- 7.87 IU/ml). CONCLUSIONS: This study provided us with knowledge of an additional pollen, Anacardium occidentale, which could trigger an asthmatic response in allergic individuals. PMID- 7852666 TI - Theophylline attenuation of airway responses to allergen: comparison with cromolyn metered-dose inhaler. AB - BACKGROUND: The purpose of this study was to compare the protection afforded by individualized doses of theophylline and a cromolyn metered-dose inhaler (MDI) during allergen challenge. METHODS: The study design was randomized, double blind, and crossover. Responses to inhaled allergen were measured in 16 subjects with allergic asthma (age range, 18 to 35 years) after 7 days of treatment with either placebo, once daily slow-release theophylline producing a mean +/- SD serum concentration of 16 +/- 5 micrograms/ml during the late phase, or 2 mg of cromolyn administered by MDI four times daily. Forced expiratory volume in 1 second was measured at frequent intervals, and airway responsiveness to histamine was measured before and 3 hours after allergen challenge. RESULTS: The mean +/- SD maximum decrease in forced expiratory volume in 1 second during the late phase was 30% +/- 14% during placebo treatment, 16% +/- 13% during theophylline treatment, and 13% +/- 14% during cromolyn treatment (placebo vs theophylline and cromolyn, p = 0.0001; theophylline vs cromolyn, p = 0.1). The geometric mean fold increase in airway responsiveness was 3.0 +/- 1.7 during placebo treatment, 1.7 +/- 1.7 during theophylline treatment, and 1.5 +/- 1.6 during cromolyn treatment (placebo vs theophylline and cromolyn, p = 0.0001; theophylline vs cromolyn, p = 0.1). CONCLUSIONS: Theophylline, when administered once daily as a slow-release formulation, was as effective as cromolyn, administered four times daily through an MDI, in attenuating airway responses to inhaled allergen. The protection afforded by both treatments, however, was modest when compared with the results of similar studies with inhaled corticosteroids or other cromolyn formulations that deliver more drug to the lungs than the MDI available in the United States. PMID- 7852667 TI - Effect of intranasal azelastine and beclomethasone dipropionate on nasal symptoms, nasal cytology, and bronchial responsiveness to methacholine in allergic rhinitis in response to grass pollens. AB - BACKGROUND: We compared the effect of nasal azelastine (0.56 mg/day), nasal beclomethasone dipropionate (BDP, 200 micrograms/day) and matched placebo on seasonal symptoms, nasal cytology, and the increase in bronchial responsiveness occurring during pollen season in a group of subjects with history of allergic rhinitis to grass pollens only. METHODS: The study was completed by nine subjects in the azelastine group, 13 subjects in the BDP group, and 13 subjects in the placebo group. Treatments were randomly administered for 6 weeks. Each subject recorded daily nasal, eye and chest symptoms and additional treatment requirement for the entire pollen season. Each subject performed nasal lavage 4 weeks into the pollen season. Bronchial responsiveness to methacholine was measured before and 4 weeks into the pollen season. Response was expressed as provocative dose causing a 20% fall in forced expiratory volume in 1 second in micromoles. RESULTS: Azelastine-treated subjects had significantly fewer nasal symptoms during week 4 (p < 0.05), and BDP-treated subjects had fewer nasal symptoms during week 4 (p < 0.05) and week 5 (p < 0.05) compared with subjects given placebo. Both treatments significantly reduced the need for additional medications. BDP, but not azelastine, treatment significantly reduced the percent of eosinophils recovered in nasal lavage (p < 0.05). Neither azelastine nor BDP protected against the increase in bronchial responsiveness to methacholine occurring during the pollen season. CONCLUSION: We demonstrated that both azelastine and BDP are effective treatments for nasal symptoms of seasonal allergic rhinitis after 4 weeks of therapy. However, we were not able to demonstrate an antiinflammatory activity of nasally administered azelastine. Nasal therapy with azelastine and BDP did not block the increase in bronchial responsiveness to methacholine caused by seasonal allergen exposure. PMID- 7852668 TI - Neuropsychiatric effects of medications for allergic diseases. PMID- 7852669 TI - A self-management program for adult asthma. Part I: Development and evaluation. AB - BACKGROUND: We developed and evaluated a self-management program for adult asthma. In developing the program, we considered questions of format and behavior control. The format we selected included components known to be effective in educational settings. We regulated asthma management behavior through the introduction of environmental cues. METHODS: Seventy-six subjects, whose asthma was generally under medical control, were assigned randomly to either a treatment group or a waiting-list control group. Those in the treatment group were exposed to a 7-week program that incorporated proven features of providing effective training and establishing behavioral control. Subsequently, subjects in the control group received the treatment. Short-term evaluation of the treatment was made after the subjects in the experimental group were trained but before the control subjects were trained. Long-term evaluation was conducted after both groups of subjects were trained. RESULTS: Over the short term, self-management training led to fewer asthma symptoms and physician visits and improvement in asthma management skills and cognitive abilities. Over the long term, self management training was related to lower asthma attack frequency, reduced medication use, improvement in cognitive measures, and increased use of self management skills. CONCLUSIONS: The program improved asthma management in patients whose conditions were already under good medical control. The effects of the program were apparent a year after the conclusion of self-management training. PMID- 7852670 TI - Asthma symptoms and airway hyperresponsiveness are lower during treatment with nedocromil sodium than during treatment with regular inhaled albuterol. AB - In a double-blind, double-dummy, multicenter study, 212 patients with asthma whose symptoms were not controlled by as-needed use of inhaled bronchodilators were randomized to receive either 4 mg of nedocromil sodium or 180 micrograms of albuterol four times daily for 12 weeks. Asthma symptom scores (daytime asthma, nighttime asthma, morning chest tightness, and cough) and peak expiratory flow rate were recorded daily on diary cards. Bronchial hyperresponsiveness was assessed by changes in diurnal variation in peak expiratory flow rate and by methacholine inhalation challenge. Statistically significant differences were found between groups favoring nedocromil sodium for relief of day and nighttime asthma and morning chest tightness. Patients treated with nedocromil sodium also had significantly lower diurnal variation in peak expiratory flow rate compared with patients treated with albuterol. Compared with patients treated with albuterol, patients treated with nedocromil sodium showed a greater improvement in cough and a decreased sensitivity to methacholine challenge. Patients in both groups reduced their as-needed albuterol use. Regular treatment with nedocromil sodium therefore led to greater asthma symptom control and reduced bronchial responsiveness compared with regular treatment with albuterol. The study also showed that more frequent use of a beta 2-agonist (for symptom relief or not) did not improve asthma control. Both drugs were well tolerated. PMID- 7852672 TI - Allergy to latex, avocado pear, and banana: evidence for a 30 kd antigen in immunoblotting. AB - Allergens of natural latex, latex gloves, avocado pear, and banana extracts were investigated by an immunoblotting technique in sera of patients experiencing associated latex and fruit allergies. Extracts were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and electroblotted onto nitrocellulose. After incubation with patients' sera, IgE antibodies were revealed by a goat anti-human IgE alkaline-phosphatase conjugate. Seventeen serum samples from patients with well-documented latex allergy were studied. Among these patients, 10 demonstrated an allergy to avocado pear sometimes associated with banana. In sera from patients with latex and fruit allergy, prominent IgE binding was revealed at about 30 kd with latex and fruit extracts. Serum controls remained negative. Cross-inhibition of immunoblotting confirmed that this main allergen is linked to a common epitope present in latex and fruits. This must be related to clinical findings and previous observations of cross-reactivity. PMID- 7852671 TI - Relations of bronchial responsiveness to allergy skin test reactivity, lung function, respiratory symptoms, and diagnoses in thirteen-year-old New Zealand children. AB - BACKGROUND: Many factors have been found to relate univariately to bronchial responsiveness (BR), but their independent relationships are often unclear because many are interrelated. OBJECTIVE: The purpose of this study was to present a multivariate analysis of the closeness of the association of various factors that are related univariately to BR, including allergy skin tests. METHODS: The results of methacholine challenge were transformed into a continuous variable (BRindex), which has a nearly Gaussian distribution. With stepwise multiple regression, the closeness of the association of the independent variables with BRindex was evaluated. RESULTS: Of the 11 skin tests applied, four showed independent relationships to BRindex (mite, cat, dog, and Aspergillus species). The sizes of these skin test reactions were correlated with BRindex, and their sum appeared to maximize the overall correlation of allergy skin tests with BRindex (r = 0.516). The lowness of the ratio of forced expiratory volume in 1 second to vital capacity and of percent predicted forced expiratory volume in 1 second added significantly to the skin tests in correlating with BRindex, (multiple r = 0.621). Adding diagnoses and symptoms increased the multiple r to 0.685. CONCLUSIONS: The size of the reactions to the four skin tests noted above showed much closer correlations with BR than total serum IgE had shown at age 11, and the relationship was present in asthmatic and nonasthmatic subjects. PMID- 7852673 TI - Role of neutrophils in mediating human epithelial cell detachment from native basement membrane. AB - Epithelial cell detachment from underlying basement membrane is a feature of diseases of many organs. In the lungs it is seen in disorders as diverse as bronchiectasis, allograft rejection, and asthma. The potential for different leukocytes to induce this change is not clear. In asthma both eosinophils and neutrophils are found in affected tissues, but the capacity of each of these types of cells to induce detachment of native epithelial cells from basement membrane requires clarification. Although eosinophils damage rather than detach human epithelial cells, the effects of neutrophils on epithelial cells naturally attached to basement membrane have not previously been described. Using the human amnion in vitro model, we tested the hypothesis that neutrophils have the capacity to detach intact human epithelial cells from basement membrane. The data indicate that increasing concentrations of neutrophils are able to detach epithelial cells from their underlying basement membrane. Detachment was increased when the neutrophils were activated in situ with tetradecanoyl phorbol acetate and after longer incubation periods. Platelet activating factor and opsonized zymosan showed similar boosting effects, whereas activated complement and formyl-methyl-leucyl-phenylalanine did not. Physical contact of the neutrophils with the epithelial cells was required to induce detachment. Detachment could be inhibited by glutathione and by soybean trypsin inhibitor, an inhibition pattern similar to cathepsin G and trypsin, but not collagenase, in this system. We conclude that neutrophils are capable of detaching human epithelial cells from basement membrane, which in part involves the release of chymotrypsin-like serine proteases, probably in conjunction with oxidants, and that this detachment can be inhibited. PMID- 7852674 TI - Hypersensitivity pneumonitis caused by soybean antigens. PMID- 7852675 TI - Elevation of IgE in HIV-infected children and its correlation with the progression of disease. AB - BACKGROUND: According to recent data, a switch from a TH1 to a TH2 pattern of cytokines might be a critical step in the progression of human immunodeficiency virus (HIV) infection. Previous studies have demonstrated a disturbance in IgE synthesis in HIV-infected adults. METHODS: Fifty-eight children infected vertically with HIV and 35 children with seroreversion, aged 4 months to 11 years, were evaluated for IgE serum level, CD4+ cell count, skin prick test responses to common airborne and food allergens, individual and family history of atopy, and presence of opportunistic infections. In thirty of the 58 HIV-infected children serum interleukin-4 and interferon-gamma levels were assessed. Thirty three of the 58 HIV-infected children had a follow-up of 1 year for IgE levels, CD4+ cell count, and occurrence of opportunistic infections and recurrent bacterial infections. RESULTS: Both IgE concentration and the percentage of children with IgE elevation were markedly increased (with no correlation to skin prick test responses or opportunistic infections) in the group of 58 HIV-infected children as compared with the 35 children with seroreversion (p < 0.05). The same parameters were higher in children with acquired immunodeficiency syndrome as compared with children with asymptomatic or mildly symptomatic disease (p < 0.05). Serum interleukin-4 and interferon-gamma levels do not account for IgE hyperproduction. There was a significant association between persistent IgE elevation and severe decline ( > or = 30% over 1 year) in CD4+ counts, as well as increased susceptibility to bacterial infections. CONCLUSIONS: Our study demonstrates a spectrum of IgE dysfunction in children, which is similar to that observed in adults. A persistent IgE hyperproduction appears to be associated with a severe decline in CD4+ cell count, suggesting that this clinical test is a useful marker of disease progression. PMID- 7852676 TI - Reduction of house dust mite allergens after dehumidifier use. PMID- 7852677 TI - Underreporting of anaphylaxis in a community emergency room. PMID- 7852678 TI - Aspartame-induced hives. PMID- 7852679 TI - The contribution of the side chain of penicillins in the induction of allergic reactions. PMID- 7852682 TI - Vision vs reality: ADA members as food/food management experts. PMID- 7852681 TI - The skinny on cooking chicken. PMID- 7852680 TI - Formulas with branched-chain amino acids cause controversy. PMID- 7852683 TI - Secular trends in diet and risk factors for cardiovascular disease: the Framingham Study. AB - OBJECTIVE: In this study we examined changes in dietary intake and risk factors for cardiovascular disease that occurred over three decades in a US-population based sample. DESIGN: Secular trends in dietary profiles and risk factors were studied in cross-sectional samples of subjects from the Framingham Study in 1957 1960, 1966-1969, and 1984-1988. RESULTS: Dietary levels of cholesterol appeared to have declined considerably, whereas macronutrient and fatty acid intakes appeared to change only slightly. Men appeared to increase their saturated fat intakes from 16.4% in 1966-1969 to 17.0% in 1984-1988 (P < .01). In spite of relatively stable mean total fat intake levels, 35% to 60% of Framingham Study men and women reported decreased consumption of higher-fat animal products over the 10-year period between 1974-1978 and 1984-1988. Framingham subjects who reported modifying their diets by substituting lower-fat foods for high-fat items between 1974-1978 and 1984-1988 were more likely to achieve the guidelines of the National Cholesterol Education Program and Healthy People 2000 for dietary fat and cholesterol intake and for serum total cholesterol level. Levels of systolic and diastolic blood pressure, total and low-density lipoprotein cholesterol, and cigarette smoking were also lower in 1984-1988 than in earlier times. Compared with 1957-1960, mean body mass index and prevalence rates of overweight and hypertension were higher in 1984-1988, despite higher levels of reported physical activity. CONCLUSIONS: The observed secular trends in diet and risk factor levels for cardiovascular disease in the Framingham population are important to guide the development and implementation of population-based strategies for promoting cardiovascular health, including nutrition interventions. PMID- 7852684 TI - Nutrient intakes and eating behavior scores of vegetarian and nonvegetarian women. AB - OBJECTIVE: To compare nutrient intakes between vegetarians and nonvegetarians with similar health practices, and to assess relationships with eating behavior scores from the Three-Factor Eating Questionnaire. DESIGN: Survey. SETTING: Metropolitan area in western Canada. SUBJECTS: Subjects (n = 45) were participants in a study comparing subclinical menstrual disturbances between vegetarians and nonvegetarians. To be included, women had to be 20 to 40 years old, be weight stable with a body mass index (BMI; kg/m2) of 18 to 25, be a nonsmoker, exercise 7 hours a week or less, consume one alcoholic drink or less a day, and not be using oral contraceptives. Nonvegetarians (n = 22) ate red meat three times a week or more, and vegetarians (n = 23, 8 vegans and 15 lactovegetarians) had excluded all meat, fish, and poultry for 2 years or more. MAIN OUTCOME MEASURES: Nutrient intake assessed by three 3-day diet records; supplement use; body composition; and dietary restraint (conscious limitation of food intake), disinhibition, and hunger assessed by the Three-Factor Eating Questionnaire. STATISTICAL ANALYSES PERFORMED: Anthropometric variables, nutrient intakes, and eating behavior scores were compared between vegetarians and nonvegetarians using unpaired t tests, and among vegans, lactovegetarians, and nonvegetarians using one-way analysis of variance and Duncan's test. Supplement use was compared using chi 2 analysis. The Pearson correlation coefficient was used to evaluate relationships between variables. RESULTS: Diets of all women adhered closely to current nutrition recommendations. Vegetarians had lower protein and cholesterol intakes and higher percentage of energy as carbohydrate, ratio of polyunsaturated fat to saturated fat (P:S ratio), and fiber intake than nonvegetarians. Vegetarians had lower riboflavin, niacin, vitamin B-12, zinc, and sodium intakes and higher folate, vitamin C, and copper intakes. However, many differences were not apparent between the subgroup of lactovegetarians and nonvegetarians (their P:S ratios and carbohydrate, fiber, riboflavin, folate, vitamin C, and copper intakes were similar). In contrast, differences existed between the lactovegetarian and the vegan subgroups. Supplement use was similar between groups, except for greater vitamin C use by vegetarians. Vegetarians were leaner than nonvegetarians, had lower restraint scores, and had significant associations between restraint and BMI (r = .49; P < .05) and energy per kilogram body weight (r = -.60; P < .01). APPLICATIONS/CONCLUSIONS: Current nutrition recommendations can be attained by vegetarians and nonvegetarians alike, but nutrient intakes cannot be inferred from dietary pattern. In this study, the intakes of health-conscious nonvegetarians and lactovegetarians were more similar than the intakes of lactovegetarians and vegans. Vegans' calcium and vitamin B-12 intakes may need attention. Vegetarians' lower restraint scores suggest that they are not at increased risk for eating disorders. PMID- 7852685 TI - Survey of dental nutrition knowledge of WIC nutritionists and public health dental hygienists. AB - OBJECTIVE: To assess two groups' knowledge of the role of diet in the etiology of dental caries: nutritionists in the Special Supplemental Food Program for Women, Infants, and Children (WIC) and public health dental hygienists. DESIGN: A self administered survey contained questions about the cause of dental caries, the importance of caries-preventive measures, dietary factors linked to dental caries, dietary advice for patients with active dental caries, and diet-related topics discussed with clients. SUBJECTS: Surveys were sent to all WIC nutritionists and public health dental hygienists in Washington, Oregon, and Idaho. Of the 235 surveys mailed, 188 completed surveys composed the final sample. STATISTICAL ANALYSES PERFORMED: Descriptive tests, means and frequencies, and the chi 2 test were used to measure differences in nutritionists' and hygienists' responses. RESULTS: One half of the nutritionists and three fourths of the hygienists recognized that dental caries was caused by a bacterial infection. Most dental researchers consider fluoride exposure and dental sealants to be highly effective caries-preventive measures; in contrast, WIC nutritionists and dental hygienists identified oral hygiene as being most important in preventing caries. Frequency of snacking and retentiveness of food in the mouth were accurately rated important dietary factors in the development of dental caries by both groups. However, limiting intake of fermentable carbohydrates between meals was not considered the most important dietary advice for clients. APPLICATIONS: Results suggest that current research about the role of diet in the prevention of dental caries should be included in both nutrition and dental hygiene curriculums and continuing education courses for these professionals. PMID- 7852686 TI - Sources of energy and six nutrients in diets of low-income Hispanic-American women and their children: quantitative data from HHANES, 1982-1984. AB - OBJECTIVE: Identification of important food sources of energy, protein, fat, vitamin A, vitamin C, calcium, and iron for low-income Hispanic women and their children. DESIGN: A subset of 24-hour recalls from the Hispanic Health and Nutrition Examination Survey (HHANES), a sample representing 76% of the Hispanic origin population, provides the most comprehensive examination of Hispanic food habits in the United States. SUBJECTS/SAMPLES: The sample, which approximates the population of the Special Supplemental Food Program for Women, Infants, and Children (WIC), included 1,046 17- to 34-year-old women with household income less than 185% of poverty level and their 1- to 5-year-old children (n = 1,063). MAIN OUTCOME MEASURES: Tables show the percentage that each food contributes to total intake of energy and six nutrients for women and for children and percentage of persons who reported consuming each food during a 24-hour period. RESULTS: Cultural foods contributed less to the energy and nutrient intake of the population than expected, with few exceptions, notably beans, rice, tortillas, and salsa. Major sources of energy and nutrients were similar to those seen for blacks and whites in the second National Health and Nutrition Examination Survey (1976-1980). APPLICATIONS: The data presented should be useful to researchers designing dietary assessment instruments and to nutrition educators designing or adapting educational materials. The data may be of particular interest to WIC staff who work with low-income Hispanic populations. PMID- 7852687 TI - Dietary fiber intake of children and young adults: the Bogalusa Heart Study. AB - OBJECTIVE: To determine dietary fiber intake of children and young adults. DESIGN AND SETTING: Cross-sectional surveys of children and young adults in Bogalusa, La. SUBJECTS: Twenty-four-hour dietary recalls were collected from 1976 to 1988 on five cohorts of 10-year-olds (n = 1,254), two cohorts of 13-year-olds (n = 360), and young adults (n = 504) 19 to 28 years of age. STATISTICS: Dietary fiber intake data were analyzed for age, race, and gender differences and for secular trends. Descriptive and inferential statistics were calculated where appropriate. Dietary composition and food sources were examined for race-specific and gender specific quartiles for dietary fiber intake adjusted per 1,000 kcal. RESULTS: Even after adjusting for energy intake, total dietary fiber intake remained unchanged from 1976 to 1988, averaging 12 g or 5 g/1,000 kcal. Blacks and males had higher total fiber intakes than whites and females at all ages. Consumption of vegetables and soups and breads and grains accounted for 53% (10-year-olds) to 70% (13-year-olds) of the total fiber consumed. When children were stratified into quartiles on the basis of fiber intake per 1,000 kcal, the percentage of energy from total fat and saturated fat was lower, and the percentage of energy from carbohydrate was higher, in children with higher fiber intakes per 1,000 kcal. APPLICATIONS: Dietary fiber intake of children has remained the same in the past 12 years and is comparable with the intake of young adults, which is well below the recommended level. Children with high fiber intakes (upper quartile) consumed less fat, particularly saturated fat, and more carbohydrate than children with low fiber intakes. Increasing consumption of whole-grain products, fruits, vegetables, and legumes (prepared with minimal added fat) will be necessary to reach the goal of optimal fiber intake and could result in an eating pattern that approaches the current recommendations for dietary fat and saturated fat. PMID- 7852688 TI - Current perspective on assessment of human body proportions of relevance to amputees. AB - Weights of segmental components of the human body are important when evaluating the nutritional status of an amputee. Original standards for components were compiled in 1889 using three male cadavers. Since that time, studies of living subjects have shown men and women to be similar in percentage weight of body components. Cadaver data from 1955 and 1969, which were based on 21 male subjects, showed that human bodies carry greater weight in the head and torso and less weight in legs and arms than indicated by the earlier data. Some differences in component weight may be attributable to ethnicity and aging, but further research is needed to define these differences. The 1955 and 1969 data--whether the result of larger sample size, ethnic differences, or actual change in human body proportions over a 60-year period--are different from the standards for body proportions in the 1889 data, which are presently used, and should be incorporated into the assessment of weight status of amputees. PMID- 7852689 TI - Kindergarten students' food preferences are not consistent with their knowledge of the Dietary Guidelines. AB - OBJECTIVES: To evaluate kindergarten students' understanding of the concepts and terminology in the Dietary Guidelines for Americans; to determine whether kindergarteners could name food sources of fat, salt, and sugar; and to find out how well they understood the relationship between diet, exercise, body fat, and health. Additionally, food preference information was collected so that kindergarteners' knowledge about the Dietary Guidelines could be compared with their food choices. DESIGN AND SUBJECTS: Focus-group interviews were conducted in two elementary schools with 12 groups of about five students each (n = 62). Four classrooms were self-selected depending on the teacher's willingness to facilitate student participation; the sample was not random. RESULTS: Students understood the general relationship between food choices, exercise, body fat, and health. They were able to name foods high in salt, fat, and sugar and thought consumption of sugary or fatty foods should be limited. Nevertheless, their food preferences were not consistent with recommendations of the Dietary Guidelines to moderate foods high in these nutrients. APPLICATIONS: Nutrition educators should be aware that young children might not understand terms frequently used such as animal sources of foods or variety. Students know what to eat, but their practices are inconsistent with their knowledge. Providing information about what to do is not enough. To help students transfer factual information to personal dietary practices, nutrition educators need to teach them how to apply the Dietary Guidelines within their food environment while maintaining acceptability in regard to taste. PMID- 7852690 TI - Dual diagnosis: patients with eating and substance-related disorders. PMID- 7852692 TI - Importance of food choice influences for working young adults. PMID- 7852691 TI - Characteristics of effective preceptors: a review of allied health literature. PMID- 7852693 TI - Position of the American Dietetic Association: legal and ethical issues in feeding permanently unconscious patients. AB - Health care team members, including the dietitian, must set patient-centered treatment goals that are handled individually and that respect the unique values and personal decision of the patient. The patient's expressed desire is the primary guide for determining the extent of nutrition and hydration once the patient is diagnosed as being in a PVS. Within the extent of the law, the family should share decision making when the patient's preference is not stated and the family is in agreement about medical care. The health care team will need to discuss with the family as needed the issues of ethics, values, religious guidelines, and pastoral advice. If the patient's choice is feeding, the dietitian will ensure that the composition of the feeding promotes nutritional health. If the patient's choice is cessation of feeding, the dietitian should explain what is known about the duration of time between cessation of feeding and death. Sensitivity to the family's needs and responsiveness to their questions are imperative in both scenarios. Within institutions, the ethics committee should help establish and implement defined written guidelines for care of the permanently unconscious. The dietitian should be required to be a member of or consultant to such a committee and should serve an integral role in development of institutional policy. The dietitian must provide education about nutrition and hydration issues, serve as a patient advocate, and participate in the legal and ethical issues regarding feeding. The dietetics community is involved in the legislative arena at the state and local level to promote the use of advanced directives and to affect legislative and societal changes that result in appropriate care for patients in a PVS. PMID- 7852694 TI - Position paper update for 1995. PMID- 7852695 TI - Opportunities in commercial foodservice--the members' perspective. PMID- 7852696 TI - 1995 JCAHO standards: development and relevance to dietetics practice. PMID- 7852697 TI - JCAHO update: the nuts and bolts of competency standards, including requirements for age-specific competencies. PMID- 7852698 TI - Commitment to mission 100 years at the New England College of Optometry. PMID- 7852699 TI - Providing service and education through community outreach. AB - We have described several of the innovative ways in which the New England College of Optometry has addressed its goal of cultivating compassionate and ethical behavior in its students while providing them with unique educational opportunities. In these four projects the New England College of Optometry has taken its services to where those in need are located. All of these projects have received enthusiastic support from their host institutions and from the many clients and students who have benefited from their services. PMID- 7852700 TI - Diagnosing inclusion conjunctivitis. AB - BACKGROUND: Diagnosing adult inclusion and neonatal conjunctivitis can be challenging. They are sexually transmitted diseases that can easily be managed without any serious ocular or systemic sequelae if recognized and treated early on. METHODS: A proper differential diagnosis and careful examination is essential in the management of chlamydial conjunctivitis. RESULTS: Two case reports of patients with laboratory-confirmed inclusion conjunctivitis will be presented. CONCLUSIONS: A careful history and ophthalmic evaluation, along with laboratory studies, which revealed inclusion bodies, confirmed the diagnosis of adult inclusion conjunctivitis. Therefore, proper treatment and management of each case occurred. PMID- 7852701 TI - Functional vision loss. AB - BACKGROUND: Functional vision loss (FVL) is a condition whereby a patient experiences a visual deficit without an organic or sensory basis. FVL is a diagnosis of exclusion, made only after organic pathology and sensory problems have been ruled out. METHODS: The authors reviewed the literature on FVL, delineated the etiologies and applied their clinical experience to the subject to provide the reader with a clinical appreciation and practical approach to FVL. This includes diagnostic strategies and etiology-based management. RESULTS: There are numerous sociopsychological etiologies of FVL of which the optometrist should be aware. Since FVL is a non-organic condition, the optimal treatment is usually multi-disciplinary, including a range of providers. CONCLUSIONS: The authors present an overview of FVL, classification of etiology, a diagnostic strategy, comanagement recommendations, and case reports. PMID- 7852702 TI - Idiopathic macular hole: a clinical review and current concepts in the diagnosis and management. AB - BACKGROUND: A full-thickness macular hole is a retinal opening involving the fovea causing severe central vision loss among the elderly. METHODS: This paper examines the pathogenesis and mechanistic constructs for the development and formation of idiopathic macular hole, reviews the stages of evolution, and provides guidelines for management by the primary care clinician. An update of the current methods of diagnosis and the criteria for surgical intervention, including vitrectomy and epiretinal membrane removal are presented. A perspective on the emerging trends in the treatment of macular hole using transforming growth factor beta-2 application is also introduced. CONCLUSIONS: Clinical practice guidelines for the management of patients with macular holes can be established based on an improved understanding of the pathogenesis of macular hole formation, a knowledge of the various stages of evolution, and the primary care clinician's familiarity with improved diagnostic techniques. An enhanced understanding of the pathogenesis of macular hole will help to predict the risk for the fellow eye, will promote more effective patient education and counseling, and will result in more timely surgical intervention. RESULTS: More promising results in the surgical closure of macula holes can prevent or minimize significant central vision loss. PMID- 7852703 TI - New England College of Optometry's impact on Boston neighborhoods. AB - BACKGROUND: In the 1960s, the city of Boston developed and implemented an innovative plan creating an urban primary health care system. This bold undertaking was predicated on the maximal utilization of a growing network of multidisciplinary neighborhood health centers. Almost concurrently, the New England College of Optometry (NEWENCO) began a total restructuring of its clinical curriculum. The objectives of this NEWENCO initiative were compatible with those of the city's health care restructuring plan. METHODS: The background, planning, structure, implementation and benefits of this collaborative effort are addressed. RESULTS: The two formed a unique partnership that elevated the quality of care for the residents of Boston's neighborhoods and dramatically improved the training experience for NEWENCO students. CONCLUSIONS: The NEWENCO-City of Boston partnership has improved the quality of health care in the urban neighborhoods and enhanced the clinical training of optometric externs. PMID- 7852704 TI - A forced choice procedure for evaluation of contrast sensitivity function in preschool children. AB - BACKGROUND: The ability to clinically use Contrast Sensitivity Function (CSF) in adults for detection of visual pathway disorders has been demonstrated. The results of CAF testing would be especially meaningful clinically for young children for earlier diagnosis and treatment of visual disorders. In preschool children (ages 3-5 years), CSF assessment has been more laborious and less practical clinically and has met with limited use or success when dealing with preschool children. The purpose of this study was to evaluate the effectiveness of a modified two-alternative forced choice (2AFC) procedure in testing the CSF in preschool children. METHODS: The subjects in this study consisted of 26 children between the ages of 35 and 60 months of age. The children were free of any detectable visual deficits, illness, and neurological or developmental abnormalities. A Vistech Vision Contrast Sensitivity System (CTS 6500) chart was modified and applied in a two-alternative forced choice procedure to determine the contrast sensitivity threshold for five spatial frequencies (1.5, 3.0, 6.0, 12.0, and 18.0 cycles/degree). RESULTS: All 26 children completed the testing at all five spatial frequency levels with both eyes under monocular testing conditions. The average actual testing time required less than 7.0 minutes for the combined right and left eye test time for all subjects. The results suggest that as the age increased, there was a tendency for an overall increase in the child's ability to detect lower contrast levels. The results indicate that this modified procedure yielded values proximal to adult CSF values, especially in the higher spatial frequencies. CONCLUSIONS: We have demonstrated that a modified forced-choice procedure using Vistech CSF gratings could be used in a preschool population. The two alternative forced choice method used in this study was found to be an effective and clinically efficient technique for evaluating the CSF levels in preschool children and makes it possible to screen for a variety of visual and neurological conditions in the preschool child. PMID- 7852705 TI - Developing innovative programs for unique student populations. AB - BACKGROUND: Optometric education has been faced with ever-increasing expectations. These include the ability to educate students and practitioners to care for new patient populations, deal with more diverse and complex clinical problems, to be significant participants in the research community and to fulfill leadership positions within the profession. To fulfill this expectation, schools and colleges need to diversify their program offerings to attract and educate unique student populations who come from diverse backgrounds and bring a range of pre-existing knowledge and skills. RESULTS: This paper provides an overview of The New England College of Optometry's efforts in this area and two programs, the "Advanced Standing International Program" and the "Accelerated Doctor of Optometry Degree Program," are examined in detail. An emphasis is placed on outcomes assessment to ensure the programs are fulfilling their purpose and the results of a retrospective analysis of the two programs is provided. PMID- 7852706 TI - Research and scholarship at the New England College of Optometry. AB - BACKGROUND: The development of the research and scholarly environment of the New England College of Optometry is recounted. We note three distinct phases in this development during the 1970s, 1980s, and 1990s. Unique interests of the faculty are discussed as well as affiliations with other institutions. An emphasis is placed on the current building of a strong research and scholarship program. PMID- 7852707 TI - Answering a need: geropsychiatric nursing course development. AB - 1. A part of the commitment to holistic nursing care is meeting the mental health needs of its clients. 2. There exists a great need to deal with both mental and physical problems in older persons. Moreover, geropsychiatry is greatly lacking in the policy and practice of nursing education. 3. Graduate-level courses must focus on both mental health promotion and disease prevention, particularly for the older persons who are consumers. PMID- 7852708 TI - Reducing restraints. Impact on staff attitudes. AB - 1. Changing the practice of using physical restraints must include nursing staff members as one of the main targets for change. 2. Following education and the implementation of a restraint-reduction program, 58% of the nursing staff participants found restraint use to be less important in caring for the elderly. Changes were more significant, however, immediately after the mandatory inservice program. 3. Nursing staff members whose perceptions changed tended to be registered nurses or licensed practical nurses who had more years of experience and more seniority at work. 4. The provision of ongoing education to nursing staff members is a necessary step to decrease feelings of frustration and stress and to assist the staff in being aware of alternatives to restraints. PMID- 7852709 TI - Guardianship for elders: process and issues. AB - 1. Guardianship for the elderly is a complex legal and social issue that affects all individuals involved in the care of elderly clients. 2. Professionals from the medical, nursing, and legal fields are spear-heading policy changes to address the needs of elderly guardianship. 3. Government continues to enact reforms allowing states to act in the best interests of the ward and the guardian. PMID- 7852710 TI - DSCUs: a study of behavior before and after residence. AB - 1. Environmental design, family involvement, consistent routines and activity programs designed to meet the special needs of persons with dementia are hallmarks of most dementia programs. There is a lack of research to support the usefulness of Dementia Specific Care Units (DSCUs) for residents of long-term care facilities that have irreversible dementia. 2. A specialized 24-bed DSCU was designed for those residents with cognitive impairment who would benefit from enhanced programming, and controlled and balanced environmental stimulation. 3. Assessments of residents' behavior and need for physical and chemical restraints were done one month prior to and two months after the opening of a DSCU. Of the 8 behaviors measured, 7 showed improvement and paired t-tests revealed this to be a statistically significant difference. 4. Even though causal claims cannot be made, the results strongly demonstrate an improvement in behaviors associated with dementia from pre- to post-measurement. There is a need for units to become increasingly able to meet the specialized needs of clients. PMID- 7852711 TI - Educating nurses for a restructured health care world. PMID- 7852712 TI - Herpes zoster and the aging. PMID- 7852713 TI - Where are we headed? Facing the challenge of elderly trauma. AB - 1. The elder population, in comparison with younger populations, not only suffers different types of trauma injury, but also responds differently to their injuries. 2. Nursing care in the resuscitation phase includes careful assessment to evaluate physiologic trends and patterns of response. Ideally, this is done, along with treatment of injuries, within the first hour following trauma. 3. During the first 24 hours post-trauma, a hypermetabolic state occurs approximating twice the normal state. Within 24 to 96 hours postinjury, the body remains acutely catabolic and stressed, but hemodynamic stability is achievable. 4. While strict attention is given to the prevention of infection throughout the resuscitation phase, sepsis remains one of the most serious complications facing the trauma patient. Pain also cannot be dissociated from the acute to the recovery phase of the illness. PMID- 7852714 TI - Availability and utilization of services by Alzheimer's disease caregivers. AB - 1. Studies show that a high percentage of family caregivers of persons with Alzheimer's disease either do not use support services or are unaware of their availability. 2. Family caregivers in rural areas use proportionately more services than caregivers in urban areas. 3. Nursing will be an integral part in improving the quality of care and living for persons with Alzheimer's disease. PMID- 7852715 TI - Nursing in Japan: caregivers of elderly family members with dementia. AB - 1. The difficulties that caregivers of elderly family members suffering from dementia confronted are divided into five categories: incomprehensible situations, strange behavior, deterioration of dementia, trouble or inconvenience caused by demented behavior, and remarks vis-a-vis support network. 2. The considerable differences among caregivers of elderly persons suffering from dementia, in terms of problems faced and methods of coping, existed in beginning and awakening stages. 3. Nurses must assess which stages of the developmental process families are going through to implement effective nursing interventions that vary between the two stages. PMID- 7852716 TI - Unity in diversity: geropsychiatric nursing survey outcomes. AB - 1. Most nurse respondents stated that increased education is of crucial importance in the care of geropsychiatric patients. This need for increased education covers a wide range of areas and includes the problems unique to elderly patients, medications in use, and ensuring that caregiving staff are adequately prepared to deal with geropsychiatric problems. 2. Of the 264 respondents to the survey, their degrees of education and certification and their employment settings represent a diversity of preparation and experience in their fields. This diversity allows them to incorporate a variety of skills in the care of geropsychiatric patients. 3. It is hoped that the survey information can aid in forming sound standards in geropsychiatric education and in the future, gaining certification in geropsychiatric nursing as a subspecialty. PMID- 7852718 TI - A cure for a common myth. PMID- 7852717 TI - Standardized care plan. Managing Alzheimer's patients at home. AB - 1. Family-provided care of members with Alzheimer's disease and related disorders (ADRD) is complicated by the presence of secondary behavioral symptoms, such as agitation, that lead to caregiver depression, burden, and breakdown. 2. Caregiver education to manage secondary symptoms in ADRD can be simplified by using a theoretical framework of person-environment fit, providing a selection of interventions to modify the environment to reduce demand on the dwindling resources of the demented person. 3. The Progressively Lowered Stress Threshold (PLST) model identifies six areas of stress for persons with ADRD fatigue, change of caregiver, environment or routine, demands to achieve beyond capability, multiple and competing stimuli, affective response to perceived losses, and physical stressors. PMID- 7852719 TI - Geriatric mental health interventions in the home. PMID- 7852720 TI - Elderly residents: perceptions of nurses' comforting touch. AB - 1. Elderly nursing home residents often feel unwanted or unloved because of a lack of physical contact with others or their caregivers' inability to communicate love and belonging. 2. In a study of 25 elderly nursing home residents, it was found that those who were subjected to comforting touch by their nurses perceived an increased feeling of affection and immediacy. 3. The conscious and intentional use of comforting touch by nurses and caregivers to elderly nursing home residents should be encouraged because of its beneficial effect of conveying love and belonging. PMID- 7852721 TI - Universal maximal sterile barrier precautions may be unnecessary. PMID- 7852722 TI - Three-dimensional graphs misleading. PMID- 7852723 TI - Toward better antibiotic use in hospitals. PMID- 7852724 TI - Analysis of epidemic and endemic isolates of Xanthomonas maltophilia by contour clamped homogeneous electric field gel electrophoresis. AB - BACKGROUND: Xanthomonas maltophilia is increasingly a cause of nosocomial infections. The mode of transmission of this organism is not well known. OBJECTIVE: To investigate clonality of X maltophilia isolates in epidemic and endemic settings. METHODS: An outbreak of X maltophilia was noted in the Intensive Care Nursery (ICN). Over the ensuing 9 months, hospital wide isolates of X maltophilia were analyzed using contour-clamped homogeneous electric field (CHEF) gel electrophoresis of chromosomal DNA. This method was compared with the antibiogram for detecting differences and similarities among strains. RESULTS: X maltophilia was recovered from 76 sites in 72 patients; 65 isolates from 61 patients and the hands of one nurse were available for analysis. CHEF demonstrated differences between most epidemiologically unrelated strains and similarity between most epidemiologically related strains. Several strains, initially presumed to be related because of temporal and spatial proximity of the patients involved, were determined by CHEF analysis to be independent infections. One pair of isolates whose XbaI CHEF patterns differed by a single band were differentiated clearly by SspI. There was enough variation in the minimum inhibitory concentrations of selected antibiotics to allow typing of some strains. The antibiogram, however, did not group all of the ICN outbreak isolates with others found to be genetically identical by CHEF, and it grouped 39 of 56 isolates with others not genetically the same. CONCLUSIONS: Although it is a convenient and economical tool, the antibiogram has limitations. Analysis by CHEF should help to elucidate the epidemiological spread of X maltophilia in the hospital. PMID- 7852725 TI - Effectiveness of liquid soap vs. chlorhexidine gluconate for the removal of Clostridium difficile from bare hands and gloved hands. AB - OBJECTIVE: To compare liquid soap versus 4% chlorhexidine gluconate in 4% alcohol for the decontamination of bare or gloved hands inoculated with an epidemic strain of Clostridium difficile. DESIGN: C difficile (6.7 log10 colony-forming units [CFU], 47% spores), was seeded onto bare or latex gloved hands of ten volunteers and allowed to dry. Half the volunteers initially washed with soap and half with chlorhexidine, followed by the other agent 1 week later. Cultures were done with Rodac plates at three sites on the hand: finger/thumbtips, the palmar surfaces of the fingers, and the palm. Statistical comparison was by paired Student's t test. RESULTS: On bare hands, soap and chlorhexidine did not differ in residual bacterial counts on the finger/thumbtips (log10 CFU, 2.0 and 2.1, P = NS) and fingers (log10 CFU, 2.4 and 2.5, P = NS). Counts were too high on bare palms to quantitate. On gloved hands, soap was more effective than chlorhexidine on fingers (log10 CFU 1.3 and 1.7, P < .01) and palms (log10 CFU 1.5 and 2.0, P < .01), but not finger/thumbtips (log10 CFU 1.6 with each, P = NS). Residual C difficile counts were lower on gloved hands than bare hands (P < 0.01 to < 0.0001). CONCLUSIONS: The two agents did not differ significantly in residual counts of C difficile on bare hands, but on gloved hands residual counts were lower following soap wash than following chlorhexidine wash. These observations support the use of either soap or chlorhexidine as a handwash for removal of C difficile, but efficacy in the prevention of C difficile transmission must be determined by prospective clinical trials. PMID- 7852726 TI - Colonization and transmission of high-level gentamicin-resistant enterococci in a long-term care facility. AB - OBJECTIVES: To assess the prevalence of high-level gentamicin-resistant enterococcus (HGRE) colonization, transmission patterns, and spectrum of illness among residents of a long-term care facility. DESIGN: Monthly surveillance for HGRE colonization of wounds, rectum, and perineum over a 1-year period. SETTING: A Veterans Affairs long-term care facility attached to an acute-care facility. PATIENTS: All 341 patients in the facility during the observation period. RESULTS: Over the 1-year period, 120 patients (35.2%) were colonized with HGRE at least once, with an overall monthly colonization rate of 20 +/- 1.5%. HGRE were isolated from rectum (12.8%), wounds (11.7%), and perineum (9.3%). Patients with the poorest functional status had the highest rate of colonization (P < 0.0005). HGRE-colonized patients were more likely to be colonized with methicillin resistant Staphylococcus aureus (51% versus 25%; P < 0.0005). Seventy-four patients (21.7%) were colonized at admission or at the start of the study. Another 46 patients (13.5%) acquired HGRE during the study, including 36 who acquired HGRE while in the long-term care facility and 10 who were positive when transferred back from the acute-care hospital. Based on plasmid profiles, only two patients appeared to have isolates similar to those of current or previous roommates. Carriage of HGRE was transient in most cases. Only 20 patients were colonized for 4 or more months, and those patients usually carried different strains intermittently. Infections were infrequent, occurring in only 4.1% of total patients. CONCLUSIONS: In our long-term care facility, HGRE were endemic, and new acquisition of HGRE occurred frequently. However, only two patients had evidence of acquisition from a roommate, suggesting that cross-infection from a roommate was not a major route of spread of HGRE. PMID- 7852727 TI - Drug use evaluation of antibiotics in a pediatric teaching hospital. AB - OBJECTIVE: To determine the incidence and type of antibiotic use variances at our institution. DESIGN: Inpatient bacterial culture and susceptibility results were reviewed for 1 week per month. Medication administration records were evaluated to determine whether antibiotic selection was appropriate, given the susceptibility of the organism. Process indicators included use of the least costly antibiotic, as well as appropriate dose, interval, and route of administration. The complete medical record was reviewed for all patients if management did not appear to meet criteria. SETTING: A 225-bed, tertiary-care children's teaching hospital. RESULTS: Thirty-five (8.2%) of 428 patients reviewed over 12 months had a total of 49 variances: failure to treat (3), treatment of contaminant/colonizer (2), use of more costly agent (10), failure to revise therapy (8), inappropriate route (2), inappropriate empiric antibiotic (4), incorrect dose (3), unnecessary multiple antibiotics (6), inappropriate drug (8), and prolonged prophylaxis (3). CONCLUSIONS: Thirty-five patients with 10 types of variances were identified during the study. Follow-up monitoring will assess the impact of educational efforts on the incidence of variances. Specific problem antibiotics have been identified for further audits. PMID- 7852728 TI - Gowns: selection on a procedure-driven basis. AB - The Occupational Safety and Health Administration requires that the types and characteristics of personal protective equipment used "depend upon the task and degree of exposure anticipated." The level of protection required, therefore, is logically contingent upon the operative site, estimated blood loss, and duration of the procedure. However, more recent studies provide data that specifically identify the personnel and areas of the body that are most likely to become contaminated. This adds a new dimension to the procedure-oriented selection process that is worthy of consideration. PMID- 7852729 TI - Surveillance for surgical site infections: the uses of antibiotic exposure. AB - Conventional methods of surveillance for surgical site infections are resource intensive, thus creating an incentive to develop simpler alternatives. Antibiotic exposure may serve as a satisfactory marker for a physician's belief that infection is present and, therefore, may be a more efficient, and perhaps more accurate, measure than identification of an explicit diagnosis in the medical record. Surveillance strategies that use antibiotic exposure may provide resource efficient adjuncts for surveillance of surgical site infections or be used in selected circumstances as substitutes for conventional surveillance methods. PMID- 7852730 TI - Glutaraldehyde: current status and uses. AB - Glutaraldehyde (pentanedial) is a dialdehyde that displays potent bactericidal, fungicidal, mycobactericidal, sporicidal, and virucidal activity. Pertinent to its activity is its interaction with amino groups in proteins and enzymes, but this simplistic statement masks the manner in which it inactivates various types of microorganisms. Notwithstanding its toxicity for medical staff, glutaraldehyde remains an invaluable compound for high-level disinfection purposes in endoscopy units. PMID- 7852731 TI - Guidelines for good practice in central venous catheterization. Hospital Infection Society and the Research Unit of the Royal College of Physicians. AB - Central venous catheters (CVC) are commonly used in clinical practice and are associated with several complications, including early and late onset infection. In these guidelines, an outline of good practice for the use of CVC and the prevention of associated infections is presented. Definitions of both localized and systemic catheter-related sepsis are given. Subsequent good practice in relation to the insertion of CVC, including patient preparation, planned duration of catheterization, catheter materials and design of the CVC, are presented. Skin fixation and insertion site care, including the use of dressings and administration sets, as well as an approach to flow obstructions, are also reviewed. The clinical and microbiological diagnosis of catheter-related sepsis and its treatment is next presented. Finally, guidelines for CVC removal and replacement are given. The guidelines are designed to facilitate the development of good practice in the use of CVC, allowing appropriate protocols to be formulated and to reduce infection risk. PMID- 7852732 TI - Complications of urinary tract infections associated with devices used for long term bladder management. AB - The long-term indwelling urethral catheter continues to be a major cause of morbidity in patients in hospitals, nursing homes and home care. Many authorities have recommended that wherever possible, alternative techniques should be considered for the management of patients with urinary retention or incontinence. This article considers the complications that develop from the urinary tract infections associated with long-term indwelling catheterization and reviews the evidence that the other options for bladder management pose less serious threats to health. PMID- 7852733 TI - Asymptomatic foodhandlers as the source of nosocomial salmonellosis. AB - A nosocomial outbreak of salmonellosis affected 22 patients and seven staff on 14 wards in two hospitals with shared catering facilities. The outbreak was characterized by a low level intermittent infection with Salmonella enteritidis phage type 4 over a 19-day period. The epidemiology did not suggest a common source for the outbreak and there was little evidence for person-to-person spread. Extensive food and environmental sampling failed to yield salmonella. Control measures within the kitchens and on wards early in the outbreak had no effect on the rate of infection. Faecal screening of asymptomatic people demonstrated a high carriage rate among catering staff (12.3%), compared with ward staff (2.2%) or patients (0.8%). A case-control study failed to reveal any association between illness and particular meals, food types, wards, medical attendants, medical procedures, or medication. However there was an association between illness and eating meals prepared by one carrier (P = 0.02). Transmission was believed to be via intermittent contamination of occasional meals. No further cases occurred after the exclusion of infected food handlers. The identifiable costs of the outbreak amounted to approximately pounds 33,000. These results indicate that asymptomatic food handlers may be the source of nosocomial salmonella outbreaks, and that efforts should be made to identify carriers and treat them. PMID- 7852734 TI - Outbreak of gentamicin, ciprofloxacin-resistant Pseudomonas aeruginosa in an intensive care unit, traced to contaminated quivers. AB - An outbreak of gentamicin, ciprofloxacin-resistant Pseudomonas aeruginosa in an intensive care unit, was investigated. The majority of isolates were from sputum and the organism was not isolated from any other patient in the hospital, except those admitted to the unit. A prospective study was set up, and the organism was found to be associated with contaminated quivers, used to store suction tubing between use on ventilated patients. Once the quivers were disinfected and changed between patients daily, the outbreak stopped. Suction of ventilated patients may be an important source of contamination of the respiratory tract with nosocomial pathogens. It is important that infection control teams regularly review procedures to ensure the correct practices are being followed, so that nosocomial outbreaks of infection may be prevented. PMID- 7852735 TI - Clinical and bacteriological survey after change in aminoglycoside treatment to control an epidemic of Enterobacter cloacae. AB - The effect of a change in the first line antibiotic treatment in a neonatal unit was studied. A total of 238 neonates (G1), admitted between 1 January and 31 July 1989, and treated with gentamicin, were compared with 398 (G2) admitted between 1 August 1989 and 31 July 1990 who received amikacin, in the combination of ampicillin plus an aminoglycoside. This change was implemented in an attempt to prevent the spread of an epidemic strain of Enterobacter cloacae resistant to third generation cephalosporins and all aminoglycosides, except amikacin. The change in treatment had no effect on the incidence of nosocomial infections [19.7% (G1) vs. 16.3% (G2) RR = 1.21 (0.86-1.70)], but the proportion of patients with nosocomial infections caused by the E. cloacae decreased (6.3% vs. 2.0% RR 3.14 CI 1.35-7.28). Certain trends in the bacterial ecology emerged: E. aerogenes and Enterococci increased in G2. The proportion of gentamicin-resistant strains such as E. cloacae or Staphylococci decreased and there was no increase in aminoglycoside-resistant strains, except in Escherichia coli, in which resistance to amikacin rose from 0 to 3%. This study illustrates the influence of antimicrobial therapy on the species and the resistance of strains isolated in nosocomial infections. It also highlights the need for epidemiologic surveillance, and poses the question of how best to modify antibiotic policy. PMID- 7852736 TI - Typing of Clostridium difficile by polymerase chain reaction with an arbitrary primer. AB - We assessed the use of the polymerase chain reactions (PCR) with an arbitrary primer (AP-PCR) to investigate a major hospital outbreak of diarrhoea due to Clostridium difficile. A single pattern consisting of three bands of 240, 580 and 1100 bp was obtained from all isolates studied. AP-PCR is a simple, rapid technique which should find increased application in the rapid investigation of suspected outbreaks of many different bacterial species, particularly new pathogens or those for which no accepted typing scheme exists. PMID- 7852737 TI - Intranasal mupirocin. PMID- 7852738 TI - Prevention of transfusion of Yersinia enterocolitica. PMID- 7852739 TI - The cost of postoperative wound infections. PMID- 7852740 TI - Bibliography of the current world literature in hypertension. PMID- 7852741 TI - Evaluation of the angiotensin II receptor AT1B gene as a candidate gene for blood pressure. AB - OBJECTIVE: To answer two specific questions concerning the possible role played by the angiotensin II receptor AT1B (AT1B) locus in genetic hypertension. First, do alleles at the AT1B locus cosegregate with blood pressure in F2 populations in the rat and, if so, is this due to AT1B or a closely linked quantitative trait locus (QTL)? Secondly, are there any significant nucleotide differences between the coding regions of the AT1B gene of the inbred Dahl salt-sensitive (SS/Jr) strain and various control strains, or between the Lyon hypertensive (LH) strain the Lyon normotensive (LN) strain? DESIGN: The first objective was achieved by studying several F2 rat populations and by analyzing DNA markers around the AT1B locus. The second objective was accomplished by amplifying the AT1B coding regions by polymerase chain reaction from the genomic DNA, and by sequencing the relevant coding regions of the AT1B genes. RESULTS: In two F2 populations involving the SS/Jr rat, AT1B cosegregated only weakly with systolic blood pressure. Also, nucleotide differences resulting in conservative changes in three amino acids were detected between the coding region of the SS/Jr AT1B allele and the AT1B alleles of the several control strains. No nucleotide differences were found in the coding regions of the AT1B alleles between the LH and LN strains. CONCLUSION: There appeared to be a QTL which had a minor effect on blood pressure, located near the AT1B locus on rat chromosome 2. However, the AT1B gene itself is not supported as the candidate gene for causing blood pressure differences, because no nucleotide changes in the coding region that were functionally meaningful or concordant with the cosegregation analysis were detected. PMID- 7852742 TI - Effect of Na,K-ATPase inhibition on cytosolic free calcium ions in vascular smooth muscle cells of spontaneously hypertensive and normotensive rats. AB - OBJECTIVE: To investigate the role of Na(+)-Ca2+ exchange in the regulation of cytosolic free Ca2+ and the pathogenesis of primary hypertension. METHOD: Cytosolic free Ca2+ ([Ca2+]i) in cultured vascular smooth muscle cells from normotensive and spontaneously hypertensive rats of the Munster strain was measured using the fluorescent dye fura-2 after inhibition of Na+,K+ATPase by ouabain and after addition of angiotensin II. RESULTS: [Ca2+]i showed a rapid increase together with a depolarization of membrane potential as measured by merocyanine 540. The ouabain-induced increase in [Ca2+]i was blocked in Ca(2+) free medium and by nifedipine, but incubation with the inhibitor of the Na(+) Ca2+ exchange, NiCl2, did not diminish the effect of ouabain. Likewise, in Na(+) free medium the response to ouabain was not suppressed. The angiotensin II induced changes in [Ca2+]i were diminished in Ca(2+)-free medium and by nifedipine, but enhanced by NiCl2. CONCLUSION: The increase in [Ca2+]i after Na+,K+ ATPase inhibition is not due to a modulation of Na(+)-Ca2+ exchange, but to a Ca2+ influx through Ca2+ channels. Changes in Na(+)-Ca2+ exchange caused by Na+,K+ ATPase inhibition may not play an important role in vascular smooth muscle cells of spontaneously hypertensive rats. PMID- 7852743 TI - Sodium but not chloride ion modulates left ventricular hypertrophy in two-kidney, one clip hypertension. AB - OBJECTIVE: To assess the role of dietary sodium with or without chloride on the development of hypertension and left ventricular hypertrophy. METHODS AND RESULTS: Forty-nine male Sprague-Dawley rats with two-kidney, one clip hypertension were fed three different diets for 4 weeks after clipping: free access to sodium chloride, sodium citrate or sodium-free diet. Sham-operated rats were used as controls. The final conscious systolic arterial pressure was similar in all hypertensive groups, regardless of diet. A similar increase in left ventricular mass was observed in the rats on the sodium chloride and sodium citrate diets, whereas left ventricular hypertrophy was strikingly attenuated in the rats on the sodium-free diet. CONCLUSION: Dietary sodium restriction prevented the development of left ventricular hypertrophy without affecting consistently the final level of hypertension. Also, the anion associated with sodium had no influence on the level of arterial pressure and left ventricular mass when compared with rats maintained on sodium chloride. It is suggested that dietary sodium itself might be an important modulator of the left ventricular response to hypertension. PMID- 7852744 TI - Cardiovascular effects of social stress in borderline hypertensive rats. AB - OBJECTIVE: To test the hypothesis that chronic exposure to psychosocial stress, alone or in combination with elevated levels of dietary salt, leads to hypertension and cardiac pathology in a susceptible strain of rats. DESIGN AND METHODS: In four experiments, borderline hypertensive rats, maintained on normal or high-salt diets, were exposed to 14-16 weeks aggregation in a colony housing or in larger breeder cages. Pulsatile blood pressure was measured once a week in unrestrained male rats by pressure telemetry. Direct carotid pressures of the aggregated rats and of control rats were measured before they were killed; at necropsy cardiac and adrenal weights and ventricular design were determined. RESULTS: Despite continuous fighting, their weekly measured blood pressures remained stable; no differences in final carotid pressures between experimental and control rats were found. Rats from three aggregations showed significant increases in left and right ventricular and adrenal weights. CONCLUSION: No hypertension developed in any aggregation, although most of the rats showed signs of perceived stress (significantly reduced weight gain, enlarged adrenals and a large number of body wounds). Cardiac hypertrophy did ensue, possibly reflecting increased physical activity or intermittent increases in sympathetic activity, or both. PMID- 7852745 TI - Abnormal pressure-natriuresis in transgenic renin gene rats. AB - OBJECTIVE: Pressure-diuresis-natriuresis relationships were compared in rats made transgenic by implantation of the mouse salivary gland renin gene [TGR(mRen-2)27 rats] and Sprague-Dawley/Hannover rats to determine whether resetting of renal function contributes to the development of hypertension in these rats. METHODS: Differences in the neural and hormonal background were minimized by denervating the kidney and holding plasma vasopressin, aldosterone, cortisol and norepinephrine levels constant by intravenous infusion. RESULTS: In Hannover rats (n = 9), urine flow and sodium excretion increased from 26.4 +/- 6.2 to 86.8 +/- 8.6 microliters/min per g kidney weight and from 5.1 +/- 0.8 to 15.3 +/- 1.0 mumol/min per g kidney weight as renal perfusion pressure (RPP) was increased from 107 to 153 mmHg. The renal blood flow (RBF) and glomerular filtration rate (GFR) were well-autoregulated and averaged 6.6 and 1.5 ml/min per g kidney weight throughout the range of pressures studied. In TGR (n = 10), urine flow and sodium excretion increased from 30.0 +/- 6.1 to 59.7 +/- 7.2 microliters/min per g kidney weight and from 3.8 +/- 0.9 to 8.5 +/- 1.3 mumol/min per g kidney weight in response to an elevation in RPP from 170 to 212 mmHg. The RBF and GFR were about 20% lower in TGR than in Hannover rats and averaged 4.1 and 1.0 ml/min per g kidney weight, respectively. CONCLUSION: The results show that the pressure diuresis-natriuresis relationship is shifted to higher pressure levels in TGR and that this is associated with enhanced tubular reabsorption.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7852747 TI - Reduction of blood pressure and plasma triglycerides by omega-3 fatty acids in treated hypertensives. AB - OBJECTIVE: To assess the effects of omega-3 (n-3) fatty acid supplementation on blood pressure and plasma lipids in hypertensives treated with diuretics or beta blockers. DESIGN: Double-blind placebo-controlled cross-over trial consisting of a 4-week run-in phase and two 6-week intervention phases. PATIENTS: A total of 43 patients of either sex taking a beta-blocker only (n = 29), a diuretic only (n = 3) or a beta-blocker plus diuretic (n = 11) for hypertension were recruited from general practice. One patient from the latter group was withdrawn. METHODS: Seated blood pressure was measured every 2 weeks in the clinic with a Dinamap. After the run-in phase, participants were randomly assigned to take a supplement of either Omacor (85% n-3 fatty acid concentrate) or corn oil (four 1-g capsules/day) for 6 weeks, after which they crossed over to the other supplement. Fasted blood samples were taken at the end of each phase for lipid analysis. MAIN OUTCOME MEASURES: The within-individual differences in systolic and diastolic pressure and plasma lipids between Omacor and corn oil treatment. RESULTS: Systolic/diastolic blood pressures measured during the run-in phase were normal (132 +/- 2/76 +/- 1 mmHg, n = 42) but decreased further with n-3 fatty acid supplementation. The mean within-individual difference in blood pressure compared with corn oil supplementation was 3.1 +/- 1.0/1.8 +/- 0.6 mmHg (P < 0.01). This was accompanied by a 21% reduction in plasma triglycerides (P < 0.01) and a 15% increase in high-density lipoprotein-2 cholesterol (P < 0.01) but there were no significant differences in total or low-density lipoprotein cholesterol. CONCLUSION: The antihypertensive and hypotriglyceridaemic effects of n-3 fatty acid supplementation seen in the present study suggest that it may be a useful adjunct to antihypertensive therapy with beta-blockers or diuretics. PMID- 7852746 TI - Ambulatory pressure decreases on long-term placebo treatment in older patients with isolated systolic hypertension. Syst-Eur Investigators. AB - OBJECTIVE: This long-term study investigated the widely accepted hypothesis that ambulatory pressure does not decrease in patients given placebo. METHODS: One hundred and twelve older (> or = 60 years) outpatients with isolated systolic hypertension were recruited. Treatment consisted of a placebo during a 3-month baseline period and long-term follow-up. RESULTS: At baseline, on placebo treatment, clinic systolic/diastolic (SBP/DBP) blood pressure (+/- SD) averaged 176 +/- 12/86 +/- 7 mmHg and 24-h SBP/DBP 151 +/- 15/81 +/- 10 mmHg. These pressures were unaltered in 51 patients in whom the baseline measurements were repeated after a further month on placebo. After the 112 patients had received placebo for 1 year (median), clinic SBP/DBP fell by 6.6 +/- 15.9 (P < 0.001)/1.4 +/- 7.4 (P = 0.06)mmHg and 24-h SBP by 2.4 +/- 10.7 mmHg (P < 0.05), whereas 24-h DBP did not change significantly. The 24-h SBP decreased more with higher baseline level and longer follow-up (5-21 months). CONCLUSIONS: These findings in older patients with isolated systolic hypertension suggest that in long-term studies the ambulatory pressure may slightly but significantly decrease on a placebo. Like those using conventional sphygmomanometry, long-term studies using non-invasive ambulatory monitoring require a placebo-controlled design. PMID- 7852748 TI - The effect of antihypertensive therapy on responsiveness to local intra-arterial NG-monomethyl-L-arginine in patients with essential hypertension. AB - OBJECTIVE: The nitric oxide (NO) system is abnormal in essential hypertension and the response of the forearm vascular bed to local intra-arterial infusions of NG monomethyl-L-arginine (L-NMMA) is diminished in patients with untreated essential hypertension. Animal data suggest that treatment of hypertension may restore normal NO-mediated responses. We have prospectively examined the effect of standard antihypertensive therapy on the responsiveness to local intra-arterial infusions of L-NMMA in 18 newly diagnosed hypertensive patients. DESIGN: This was a double-blind, randomized, parallel-group study. Patients were randomized to treatment with 10 mg enalapril daily, 5 mg amlodipine daily or matched placebo for 6 weeks (with dose titration after 2 weeks if necessary). METHODS: Forearm blood flow during direct infusion into the brachial artery of L-NMMA (1, 2 and 4 mumol/min) was measured using venous occlusion plethysmography at the beginning and end of the 6-week treatment period. RESULTS: Both enalapril and amlodipine reduced blood pressure significantly compared with placebo. After 6 weeks of antihypertensive therapy, forearm blood flow (+/- SEM) in response to the maximum dose of L-NMMA (4 mumol/min) was reduced by 54.8 (6.9)% (P = 0.012), 58.9 (7.0)% (P = 0.016) and 33.1 (3.0)% (P = 0.17) in the enalapril, amlodipine and placebo groups, respectively. There was no significant difference between enalapril and amlodipine treatment groups. CONCLUSIONS: The forearm arterial responsiveness to L-NMMA in newly diagnosed patients with essential hypertension returns to normal with normalization of blood pressure by antihypertensive drugs with different modes of action. It remains to be determined whether this phenomenon is a consequence of the change in pressure per se or a result of the action of either drug by a common or separate mechanism. PMID- 7852749 TI - Within-patient correlation between the antihypertensive effects of atenolol, lisinopril and nifedipine. AB - OBJECTIVE: To investigate whether there are definable subgroups of patients with essential hypertension who respond specifically to particular antihypertensive drugs. DESIGN: Randomized cross-over comparison of the antihypertensive effect of 50 mg atenolol per day, 10 mg lisinopril per day and 20 mg nifedipine retard twice a day. Ambulatory blood pressure monitoring was used to assess the blood pressure level both for recruitment and at the end of each treatment period. The treatment periods lasted 4 weeks and were preceded by 4 weeks of placebo. PATIENTS: Seventy-two untreated hypertensive patients with a mean age of 52 (SD 8.4) years were recruited from six general practices and from the hospital outpatient clinic. Sixty-eight patients completed the trial. MAIN OUTCOME MEASURES: To assess the within-patient correlations among the blood pressure responses to each drug and explore the possible role of simple characteristics, such as the initial blood pressure, plasma renin concentration and age, in identifying the responders to a particular drug. RESULTS: Systolic/diastolic blood pressure fell significantly with each agent (P < 0.001): atenolol reduced it by 16.3 +/- 13.3/9.9 +/- 8.8, lisinopril by 14.8 +/- 15.0/9.4 +/- 9.1 and nifedipine by 11.6 +/- 12.3/6.7 +/- 8.3 mmHg. There was a low degree of correlation between the changes in blood pressure with the three drugs in individual patients. With each drug there was a small percentage (8.9-14.7%) of non-responders. The initial level of systolic blood pressure was weakly correlated with the antihypertensive effect of nifedipine (r = 0.47, P < 0.001) and plasma renin concentration was related to the effect of atenolol (r = 0.32, P < 0.01). Age did not predict the blood pressure response to any agent. CONCLUSIONS: The low level of the correlation between the blood pressure changes with the three drugs suggests that different mechanisms may be involved in the aetiology of essential hypertension. Plasma renin concentration and the initial level of systolic blood pressure contribute only weakly to the identification of responders to the three drugs. PMID- 7852750 TI - Compensatory hyperinsulinemia and the forearm vasodilator response during an oral glucose-tolerance test in obese hypertensives. AB - OBJECTIVE: To determine whether obese hypertensive patients manifest a diminished regional vasodilator response to an oral glucose challenge. METHODS: Nineteen obese hypertensives (body mass index 34.1 +/- 1.3 kg/m2, blood pressure 144 +/- 3/96 +/- 2 mmHg) and 13 lean controls (23.6 +/- 0.3 kg/m2, 127 +/- 4/83 +/- 3 mmHg) were studied. After 1 week on a standard diet, forearm blood flow (plethysmography), systemic hemodynamics (impedance cardiography), glucose and insulin levels were measured at baseline and again at 15, 30, 60, 90 and 120 min during an oral glucose-tolerance test (OGTT). RESULTS: Forearm blood flow increased after the oral glucose ingestion in obese hypertensives and lean controls. The rise in forearm blood flow was greater in obese hypertensives than in lean controls during the 2-h OGTT. Insulin levels also increased more in obese patients after the glucose load. During the second hour of the OGTT the ratio of changes in forearm blood flow and insulin level, an index of vascular insulin resistance, was similar in both groups. In contrast to the regional hemodynamic findings, total systemic vascular resistance decreased in lean controls but did not change in obese hypertensives during the second hour of the OGTT. CONCLUSION: The forearm vasodilator response to oral glucose in overweight, non-diabetic hypertensives is not impaired. If dynamic increases in flow are indeed important to insulin-mediated glucose disposal, then these observations raise the possibility that the greater increase of regional blood flow during an OGTT in obese hypertensives represents a component of the compensatory response for their defect in glucose metabolism. PMID- 7852751 TI - Increased basal concentrations of plasma endothelin in borderline hypertension. AB - BACKGROUND: There is evidence for an altered endothelial function in established hypertension but little is known about endothelial function in borderline hypertension. It has also been suggested that the early stages of hypertension are characterized by an increased sympathetic drive. OBJECTIVE: To investigate whether alterations in endothelin, neuropeptide Y (NPY) and calcitonin gene related peptide (CGRP) are already present in the borderline hypertensive stage. DESIGN: A case-control study of age-matched men recruited from a population screening programme. METHODS: Seventy-five men with stable borderline hypertension [diastolic blood pressure (DBP), 85-94 mmHg] and 75 age- and sex matched normotensive controls (DBP < or = 80 mmHg) were investigated. Plasma samples were drawn in a standardized fashion, and extracted and analysed using competitive radio immunoassays. RESULTS: Basal concentrations of NPY and CGRP were similar in the two groups (28.4 versus 26.7 pmol/l and 24.2 versus 21.7 pmol/l, respectively). Basal concentrations of endothelin were significantly higher in the borderline hypertensive group (2.0 versus 1.5 pmol/l, P < 0.0001). CONCLUSIONS: These results suggest that a disturbed endothelial function, represented by endothelin, could be involved in the early hypertensive processes. They also suggest that these changes could be present before the basal sympathetic/parasympathetic drive alters, warranting further research into this area. PMID- 7852752 TI - The relationships between casual and ambulatory blood pressure measurements and central hemodynamics in essential human hypertension. AB - OBJECTIVE: To determine the association between ambulatory blood pressure (ABP) and central hemodynamics in hypertensive patients and between the area under the 24-h blood pressure curve and the hemodynamic indexes. PATIENT POPULATION: Forty untreated essential hypertensive patients (28 previously untreated, 12 withdrawn from therapy for > 12 weeks). METHODS: Patients underwent casual and 24-h ABP monitoring and invasive measurements of central hemodynamics. Central measures of ABP included 24-h mean, awake, and sleep values guided by activity journals. The ABP data were modeled by Fourier series and the ability of the smoothed and unsmoothed data to predict hemodynamics was compared. Individual blood pressure curves were analyzed by calculating the area under the curve using different threshold awake and sleep values to test the correlations between this form of blood pressure load and hemodynamics. RESULTS: Hemodynamic measures were not predicted by casual blood pressure but were related to ABP. Total peripheral resistance was strongly predicted by the area under the diastolic blood pressure (DBP) curve using an awake threshold of 90 mmHg and a sleep threshold of 80 mmHg (r = 0.56, P < 0.001). Data smoothing using Fourier transformation did not alter any correlations between ABP and hemodynamics. Exercise stroke index, an indicator of cardiac function impaired in early hypertensive heart disease, was also best predicted by area under the DBP curve using the same thresholds as above (r = -0.56, P < 0.001). CONCLUSIONS: These data imply that integrated areas under the ABP curve are related to hemodynamic hypertensive indexes and could be used to assess the extent of hypertensive burden in clinical trials. PMID- 7852753 TI - Effects of age and isolated systolic hypertension on cardiovascular reflexes. AB - OBJECTIVES: Given the reported relationship between systolic hypertension and orthostatic hypotension in the elderly, to test the hypothesis that systolic hypertension causes impairment of the cardiovascular reflex function additional to the effects of age alone. DESIGN: Responses were compared in normotensive healthy young (n = 12) and elderly (n = 15) participants and elderly participants with disproportionate supine systolic hypertension (n = 11) using a baroreceptor mediated stress (head-up tilt) and two non-baroreceptor-mediated stimuli (cold pressor test and isometric exercise). METHODS: Blood pressure and heart rate were measured by oscillometry before and during the three stress tests. Forearm blood flow was measured by venous occlusion plethysmography and pulse wave velocity (PWV) by Doppler ultrasound. RESULTS: Percentage changes in systolic/diastolic (SBP/DBP) blood pressure with head-up tilt were 0/+11, -3/0 and -6/+1 mmHg in the young and elderly normotensives and elderly systolic hypertensives, respectively. Both elderly groups had reduced DBP responses to tilt compared with the young (P < 0.01). All three groups had similar percentage changes in blood pressure responses to non-baroreflex-mediated stresses (cold pressor test: +10/+23, +11/+11, +10/+15; sustained isometric exercise: +18/+33, +22/+24, +13/+17 in the young and elderly normotensives and elderly systolic hypertensives, respectively). Aorto-iliac PWV adjusted for blood pressure was significantly higher in both elderly groups compared with the young (P < 0.01) but there was no difference between elderly normotensives and hypertensives. Unadjusted PWV was higher in elderly hypertensives than in elderly normotensives (P < 0.05). CONCLUSIONS: Compared with healthy young participants, both elderly groups had similarly attenuated blood pressure responses to tilt and reduced arterial compliance. Systolic hypertension is not associated with additional impairment of cardiovascular reflex function over and above the effects of age. The reported association between supine systolic hypertension and orthostatic hypotension does not appear to be a causative one. PMID- 7852754 TI - A comparison of the British Hypertension Society and Association for the Advancement of Medical Instrumentation protocols for validating blood pressure measuring devices: can the two be reconciled? AB - BACKGROUND: Experience with the original protocols of the Association for the Advancement of Medical Instrumentation (AAMI) and the British Hypertension Society (BHS) for validating blood pressure has provided valuable insight into the methodological problems associated with device validation and has influenced both the BHS and the AAMI in revising their protocols. OBJECTIVES: To review the revisions of the original BHS and AAMI protocols; to compare the protocols; and, using the BHS protocol as a framework for validation, to determine how it should be modified to a protocol that will fulfil the criteria of both the AAMI and the BHS. CONCLUSIONS: The revised protocols have many similarities but there are some important differences. These differences merit consideration so as to facilitate manufacturers seeking to validate devices for acceptance in both Europe and the United States. Of the two protocols, the BHS protocol is the more elaborate in that (1) it takes particular care to ensure that observers are trained to a very high standard, (2) it makes provision for special group validation and (3) it recommends in-use validation of all devices. By modifying the BHS protocol, it is possible to validate blood pressure measuring devices (ambulatory devices require special consideration) to satisfy the criteria of both protocols. PMID- 7852755 TI - Patterns and predictors of hypertension incidence among Hispanics and non Hispanic whites: the San Luis Valley Diabetes Study. AB - OBJECTIVES: To determine whether Hispanics are at lower risk for the development of hypertension than non-Hispanic Whites. We also examined selected predictors of hypertension incidence and explored the role of markers of insulin resistance in the development of hypertension. DESIGN: A cohort study of a geographically-based sample of Hispanic and non-Hispanic white southern Colorado residents who were re examined an average of 4 years after their baseline examination. METHODS: These analyses included 664 participants who were normotensive and confirmed nondiabetic by an oral glucose tolerance test at their baseline examination. Hypertension was defined as systolic blood pressure > or = 140 mmHg or diastolic blood pressure > or = 90 mmHg or use of antihypertensive medication. RESULTS: Hispanics and non-Hispanic Whites had similar hypertension incidence rates. The strongest predictors of hypertension incidence were baseline blood pressure and age. Higher baseline heart rates and higher body mass index also predicted hypertension. Increased fasting insulin levels were associated with hypertension incidence among lean participants, though the association disappeared once baseline blood pressure levels were added to the models. Models investigating change in systolic or diastolic blood pressure levels found higher baseline levels of insulin area under the glucose tolerance curve predicted greater increases in systolic blood pressure in non-Hispanic Whites only. CONCLUSIONS: Hypertension incidence rates were similar in Hispanics and non-Hispanic Whites. Higher levels of insulin area were associated with larger increases in systolic blood pressure among non-Hispanic Whites only. PMID- 7852757 TI - Molecular aspects of signal transduction of shear stress in the endothelial cell. PMID- 7852756 TI - A north-south comparison of blood pressure and factors related to blood pressure in the People's Republic of China: a report from the PRC-USA Collaborative Study of Cardiovascular Epidemiology. AB - OBJECTIVES: To compare blood pressures in northern (Beijing) and southern (Guangzhou) Chinese population samples aged 35-54 years, males and females, urban and rural, and to assess the role of blood pressure-related traits in explaining north-south differences. DESIGN: Cross-sectional surveys were conducted in 1983 1984 of northern and southern populations employed in industry (urban) or farming (rural). METHODS: In the north samples were selected from the Capital Iron and Steel Complex (urban) and Shijingshan district (rural); in the south samples from the Guangzhou Shipyard (urban) and Panyu County (rural) were used. RESULTS: The number of subjects surveyed in north and south were 4706 and 4179, respectively: 1500 and 1052 urban males, and 717 and 914 rural males; and 1300 and 1061 urban females, and 1189 and 1152 rural females, respectively. Average systolic (SBP) and diastolic (DBP) blood pressures, were consistently higher in the north than in the south. SBP and DBP were significantly and independently related to age, body mass index, heart rate, use of antihypertensive drugs, serum triglycerides level, alcohol use (males only) and inversely to cigarette smoking. Northerners were older, taller, heavier and had higher body mass index and triglycerides level than southerners. With adjustment of SBP and DBP for blood pressure-related traits, north-south blood pressure differences decreased, but remained significant for urban males, rural males and rural females, with sizeable differences for rural samples in particular. CONCLUSIONS: North-south differences in blood pressure in these samples are accounted for only partly by north-south differences in the cited blood pressure-related traits. The role of other traits requires assessment. PMID- 7852758 TI - Baclofen as an adjuvant analgesic. AB - Baclofen is a gamma-aminobutyric acid (GABA) agonist approved for the treatment of spasticity and commonly used in the management of many types of neuropathic pain. Controlled studies have demonstrated the efficacy of this drug in trigeminal neuralgia. Although its precise mechanism of analgesic action is unknown, it is likely that a drug-induced increase in inhibitory activity is sufficient to interrupt the cascade of neural events that culminates in aberrant activity of wide dynamic range neurons, or more rostral neurons in nociceptive pathways, that is the substrate for some types of neuropathic pain. The optimal use of baclofen as an adjuvant analgesic requires an understanding of its pharmacology, side effect spectrum, and dosing guidelines that have proven useful in clinical practice. Failure of baclofen therapy following a prolonged trial requires dose tapering prior to discontinuation due to the potential for a withdrawal syndrome. PMID- 7852759 TI - Depression in painful chronic disorders: the role of pain and conflict about pain. AB - Chronic pain severity, the responses of the significant other to the patient's pain, and social network relationships were investigated for their contributions to depression among patients with myofascial pain disorders (N = 67) and arthritis (N = 83). Interview data were gathered using the Beck Depression Inventory, McGill Pain Inventory, Multidimensional Pain Inventory, and Interpersonal Relationships Inventory. Patients with myofascial pain disorders reported significantly more severe depression and pain, more conflict about their pain, and more network conflict than those with arthritis. They also reported less network social support. After controlling for the type of painful chronic disorder, multiple linear regression analyses indicated that more severe depression was significantly associated with more severe pain, conflict about pain, and less network social support. Conflict about pain may increase the risk of depression for patients with chronic painful disorders. Patients with myofascial pain disorders, however, may experience more conflict about their pain because of the absence of objective physical findings that corroborate the report of pain. PMID- 7852761 TI - [Structure and function of pancreatic group I phospholipase A2 receptor]. PMID- 7852760 TI - Phototherapy in the treatment of depression in the terminally ill. AB - Research in affective disorders has shown that there is a clear link between mood and light exposure, and that exposure to bright wide-spectrum light (phototherapy) may be an effective antidepressant treatment in some clinical situations. Cancer patients, especially those in the terminal phase of illness, have a high incidence of depression. Furthermore, their mobility is often severely reduced, resulting in little exposure to direct sunlight. We report the use of phototherapy in three terminally ill patients to alleviate symptoms of depression. PMID- 7852762 TI - [Glycosaminoglycan sulfotransferases and the function of proteoglycans]. PMID- 7852763 TI - [Significance of cellular signal transduction system in peroxisome proliferation]. PMID- 7852764 TI - [Prolyl oligopeptidase family: a new serine protease family distributed in endo- and exo-peptidases]. PMID- 7852765 TI - [Extraordinarily thermo-stable hairpin structures: partial structure of single stranded nucleic acids]. PMID- 7852766 TI - [Role of a pituitary adenylate cyclase-activating polypeptide (PACAP) receptor in pancreatic beta-cell function]. PMID- 7852767 TI - [Carbohydrate-deficient glycoprotein syndrome: N-linked oligosaccharide transfer deficiency]. PMID- 7852769 TI - [The effects of aging on renal function test]. AB - To determine the effect of aging on renal functions, I measured the concentration of blood urea nitrogen (BUN), serum uric acid and serum creatinine. Seven hundred and forty-six healthy women who underwent health screening were divided into 4 groups, 28-39 years old (thirties), 40-49 (forties), 50-59 (fifties) and 60-69 (sixties). I found no significant differences between groups of thirties and forties in the BUN and serum uric acid concentrations. The BUN and uric acid concentrations in groups of fifties and sixties were significantly higher than those in groups of thirties and forties (p < 0.01). On the other hand, no significant differences were found among the four groups in the serum creatinine level. In conclusion, women over the age 50 had significantly higher BUN and serum uric acid values. On the other hand, the serum creatinine concentration remained constant in the thirties to sixties groups. Between the age of 45 and 54, the serum uric acid level in postmenopausal women was significantly higher than that in women prior to the menopause. Considering that the mean age of the menopause is 50 years, the results suggested that female sex hormones had some effect on renal function tests. But further examination, for example comparing the levels of renal function tests in men and women is needed to confirm the effects of female sex hormones. PMID- 7852768 TI - [Perinatal outcome of pregnancies following therapy of infertility]. AB - To evaluate the risks involved in post infertility pregnancy, the perinatal outcomes of 571 patients with infertility treatment in 9 institutions were analyzed by questionnaire retrospectively. The rate of multiple pregnancy and premature delivery was 14.5% (83/571) and 13.3% (76/571) respectively. Multiple pregnancies occurred in 33 cases with ovulation induction, 22 cases with artificial insemination by the husband (AIH) and 25 cases with in-vitro fertilization by embryo transfer (IVF). Premature deliveries occurred in 32 cases with ovulation induction. 26 cases with AIH and 14 cases with IVF. Three babies were dead and 4 babies were handicapped. In single post infertility pregnancy, the rate of premature birth was twice as high (9.0%) as in normal controls. The mortality rate was 0.45% (2/449), which was higher than that of controls. This suggests that post infertility pregnancies tend to result in multiple pregnancy and premature birth. In addition, in single post infertility pregnancies there was the possibility of poor perinatal outcome. PMID- 7852770 TI - [Expression of prolactin gene in human decidua]. AB - This study was designed to detect the localization of prolactin gene expressing cells in the human utero-placental unit during pregnancy. METHODS: Human endometrium was obtained at hysterectomy from normally cycling women who underwent surgery for myoma uteri. Decidual and trophoblast tissues from early pregnancy were obtained by curettage from patients undergoing therapeutic abortion at 8-10 weeks of gestation. Term placenta was obtained from patients with uncomplicated deliveries at 38-40 weeks. Total RNAs of these tissues were extracted to perform Northern blot hybridization (NBH) with the radiolabelled human pituitary prolactin cDNA probe. Frozen sections of these tissues were cut and processed for in situ hybridization (ISH) with the radiolabelled RNA probe complementary for human prolactin mRNA. RESULTS: 1. By NBH, approximately a 1.3 kilobase (kb) size band was detected in the total RNA obtained from late secretory endometrium (day 26), decidua of early pregnancy and placenta of term pregnancy, and the decidua had the most significant signal. No hybridization signal was detected in the chorionic villi in early pregnancy. 2. By ISH, a significant hybridization signal was detected in the cytoplasm of the decidual cells in early and term pregnancy. No hybridization signal was detected in the endometrial grandsand trophoblast cells. CONCLUSION: These results indicate that prolactin is synthesized in the decidual cells in the human uterus during pregnancy. PMID- 7852771 TI - [The predictive factor of postpartum impaired glucose tolerance in pregnant women with abnormal glucose tolerance]. AB - To determine factors predictive of impaired glucose tolerance (IGT) in the postpartum period, we examined the maternal and perinatal characteristics of fifty-eight women with abnormal glucose tolerance during pregnancy. A 75g oral glucose tolerance test (OGTT) was performed on the women again around 4 weeks after delivery. Forty women who had a 2-hour plasma glucose level of 140mg/dl or more were defined as IGT in postpartum (group IGT), and the other eighteen women with a 2-hour plasma glucose level lower than 140mg/dl were defined as having normalized glucose tolerance (group N). The women in group IGT weighed more during pregnancy than those in group N (p < 0.05). Insulin secretion during the antepartum OGTT was lower in group IGT than in group N. On the basis of the prepregnant body mass index (BMI) for the obese group (BMI > or = 24), the women in group IGT weighed much more during pregnancy than those in group N (p < 0.03). In the non-obese group, the women in group IGT had higher glucose levels and lower insulin responses than those in group N. We concluded that, in obese women, excessive weight gain during pregnancy is predictive of postpartum IGT, while in non-obese women, the severity of glucose intolerance during pregnancy is related to poor postpartum prognosis. PMID- 7852772 TI - [Rectosigmoidectomy following neoadjuvant chemotherapy for advanced ovarian cancer]. AB - Eleven women underwent rectosigmoidectomy as part of an en bloc removal of the adnexal masses, uterus, and pelvic peritoneum during cytoreductive surgery following neoadjuvant chemotherapy for advanced ovarian cancer. While 7 patients with stage IIIc underwent an exploratory laparotomy, 4 cases with stage IV did not because of their poor performance status (PS). Histologic subtypes were as follows: serous, 10 cases; endometrioid, 1 case. Patients with pleural effusion and ascites received immunotherapy. Thereafter, all patients were treated with 4 6 courses of neoadjuvant chemotherapy with cisplatin containing combinations, which delivered 9 PR, 1 MR and 1 NC. The PS score was improved by neoadjuvant chemotherapy and immunotherapy which may contribute to the low mortality and morbidity. Residual tumor of the largest diameter after debulking surgery were as follows: absent (5 cases), present (< 0.5cm; 2 cases, < 2cm; 3 cases, > or = 2cm; 1 case). The median survival for the entire group was 32.6 months. None of the 7 cases with residual disease < 0.5cm died of the disease within 2 years. Rectosigmoidectomy following neoadjuvant chemotherapy might be a useful procedure for patients who will be left with minimal residual disease after completion debulking surgery. PMID- 7852773 TI - [A clinical and pathological study on paraaortic lymph node metastasis in uterine cervical carcinoma]. AB - Three hundred and three patients with uterine cervical cancer underwent radical hysterectomy including Paraaortic lymph node (PAN) dissection between June, 1982 and March, 1990. We analyzed the relationship between PAN metastasis and the clinical stage, histologic type, parametrial invasion and pelvic lymph node (PLN) metastasis, and obtained the following results. 1) The incidence of PAN metastasis in clinical stages Ib, II and III was 0.9%, 4.5% and 16.7%, respectively. 2) The PAN metastasis rate in case of adenocarcinoma was 8.3% which tended to be higher than that for squamous cell carcinoma (4.9%) and mixed carcinoma (3.2%). 3) Deeply invading carcinoma penetrating to the parametrium (including the parametrial initial zone) was seen in 15 out of 16 cases (93.8%) with PAN metastasis. PAN metastasis was rare in cases without parameterial invasion (1/114). 4) Positive PAN was found in 48.3%, 34.8% and 41.9% of cases with metastasis in more than four lymph node groups, bilateral PLN and common iliac lymph node (CILN), respectively. The present results suggest that a regular careful check up for PAN metastasis is necessary for case with multiple PLN metastasis (bilateral and more than four groups) and CILN metastasis. PMID- 7852774 TI - [A comparative study on fine structure of the glomerular changes of kidney in pure toxemia of pregnancy and superimposed toxemia of pregnancy]. AB - It is known that changes occur in the renal glomerulus in toxemia of pregnancy, but what are extremely rate are the reports on a comparative study of the difference between the pure toxemia of pregnancy (called the pure type) and the superimposed toxemia of pregnancy (called the superimposed type). I have therefore clarified the difference between the morbidities by making observations of the two types mainly by transmission electron microscopy (TEM). The subjects were 19 cases of the pure type and 6 cases of the superimposed type, and light microscopic (LM) and TEM observations were made both after informed consent by performing a needle biopsy in the right kidney at cesarean section. By TEM observation, comparisons were made by giving 0-3 points for the findings in the endothelial cells epithelial cells, mesangium and basement membrane. By LM, the changes in the renal glomeruli in the pure type were classified roughly into the extracapillary type, endocapillary type and capillary type, but what was seen in many cases was a mixture of these changes. Regarding the morbidities in the superimposed type cases, my attention was attracted to adhesion with Bowman's capsule and a sclerotic image. In TEM observations, greater changes in the mesangium and basement membrane were seen in the superimposed type cases than in the pure type cases, compared with the changes in endothelial cells and epithelial cells.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7852775 TI - [Comparison between old and new FIGO staging of endometrial carcinoma--the significance of positive peritoneal cytology]. AB - Three hundred fifty-two patients with endometrial adenocarcinoma who underwent primary surgical therapy between 1984 and 1991 were evaluated. (1) Eighty-three (23.6%) had positive peritoneal cytology (PPC). (2) The cumulative 5-year survival rates (5-y. survival rate) for the former clinical stages were 88.8%, 86.1%, 52.9% and 0% for stages I-IV, respectively, showing a significant difference between stage III and IV (p < 0.05). The new clinical stage 5-5. survival rates were 97.5%, 100%, 69.9% and 25.9% for stages I-IV, respectively. There was no significant difference between stages I and II, but there were significant differences between stages I.II and III (p < 0.001) and between stages III and IV (p < 0.05). (3) In cases of new stage III, 5-y. survival rates for stage IIIA and IIIB.C were 83.7% and 33.6%, respectively (p < 0.01). Those for stage IIIA with PPC were very good in comparison with stage IIIA cases with other factors (90.3% vs 49.2%; p < 0.05). When the patients in stage IIIA with only PPC were separated into 2 groups, i.e., a myometrial invasion less than 1/2 and no cervical involvement group and a myometrial invasion greater than 1/2 or/and cervical involvement group, their 5-y. survival rates were 97.2% and 75.1% respectively (p < 0.05). (4) Recurrence developed in 15.3% of patients in stage IIIA with only PPC, and in 64.7% of patients in stage IIIA with other factors (p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7852776 TI - [Studies on the expression of prolactin receptor gene in human decidua by in situ hybridization]. PMID- 7852777 TI - [Amino acid sequences of fucoidin binding protein in human spermatozoa]. PMID- 7852778 TI - [The clinical feature and the fetal therapy of congenital complete A-V block (CCAVB) associated with maternal anti-SSA (B) antibody]. PMID- 7852779 TI - [Prevention of perinatal bacterial infection with polyvinyl pyrrolidone-iodine cream]. PMID- 7852780 TI - [Management of the infected total knee arthroplasty]. PMID- 7852781 TI - [Lumbar canal stenosis and arteriosclerosis obliterans--differential diagnosis and conservative treatment]. PMID- 7852783 TI - [A role for lipoproteins in the recovery from CPPD crystal-induced arthritis]. AB - Calcium pyrophosphate dihydrate (CPPD) crystal-induced inflammation subsides spontaneously, and there have been few reports on its mechanism. It has recently been proposed that lipoproteins in the inflammatory synovial fluid played a role in the recovery from crystal-induced arthritis. This study investigated the inhibitory effect of lipoprotein on the inflammation-inducing activity of CPPD crystals in vitro and in vivo. Lipoproteins (very low density lipoprotein--VLDL, and low density lipoprotein-LDL) were isolated from human serum (in vitro) and rat serum (in vivo) by the sequential ultracentrifugal technique. In the in vitro studies, saline with lipoproteins was mixed with CPPD crystals, and co-incubated with isolated polymorphonuclear leukocytes (PMN). The production of superoxide anion (O-(2)) was measured as an index of inflammatory activity. In the in vivo studies, suspensions of CPPD crystals and rat lipoprotein solutions, were injected into the rat air pouch. The total number of white blood cells (WBC), crystal-containing WBCs, and concentrations of beta-glucronidase and prostaglandin (PG) E2, were measured. In the in vitro studies, O-(2) production by PMNs was more significantly suppressed after treating the CPPD crystals with VLDL or LDL than when the crystals were not treated with VLDL or LDL. In the in vivo studies, treatment of the CPPD crystals with lipoproteins significantly decreased the number of WBC and crystal-containing WBC, as well as the concentration of beta-glucronidase, and tended to depress the concentration of PGE2. These findings suggested that lipoproteins, especially LDL in inflammatory synovial fluid played an important role in the recovery from CPPD crystal-induced arthritis. PMID- 7852782 TI - [Stress analysis on the acetabular side of bipolar hemiarthroplasty by the two dimensional finite element method incorporating the boundary friction layer]. AB - We compared the biomechanical characteristics of bipolar and unipolar hemiarthroplasty on the proximal migration of the outer head by determining the von Mises stress distribution and acetabular (outer head) displacement with clinical assessment of hemiarthroplasty in 75 patients. This analysis used the two-dimensional finite element method, which incorporated boundary friction layers on both the inner and outer bearings of the prosthesis. Acetabular reaming increased stress within the pelvic bone and migration of the outer head. A combination of the acetabular reaming and bone transplantation increased the stress within the pelvic bone and grafted bone, and caused outer head migration. These findings were supported by clinical results. Although the bipolar endoprosthesis was biomechanically superior to the unipolar endoprosthesis, migration of the outer head still occurred. The bipolar endoprosthesis appeared to be indicated in cases of a femoral neck fracture or of avascular necrosis in the femoral head, but its use in cases of osteoarthritis in the hip required caution. PMID- 7852784 TI - Effects of pancreatic transplantation on osteopenia in streptozotocin-induced non insulin-dependent diabetic rats. AB - The effect of pancreatic transplantation on mineral homeostasis and the histomorphometric changes were studied in streptozotocin (STZ)-induced non insulin-dependent diabetic rat. Although the fasting blood-glucose levels in diabetic rat were similar to those in controls, intravenous glucose tolerance tests (ivGTT) showed diabetic patterns in the diabetic rat. Serum ALP was found to be significantly higher, but bony ALP (calvarium) and circulating 1;25(OH)D were markedly decreased, in diabetic rat. The histomorphometric study showed a decreased relative osteoid volume (ROV), a decreased total osteoid volume (TOV), and an increased inert surface of the osteoid. Tetracycline (TC) labeling failed to be acquired in diabetic rat. These findings indicated that long-term insulin deficiency may be related to a lack in the maturity of the bone matrix and reduced turn-over. Transplanted rat showed a normal response to ivGTT and increased bony ALP. Histologically, ROV and TOV increased together, with acquired TC double labeling lines. These results indicated that diabetic osteopenia can be reversed by pancreatic transplantation. PMID- 7852785 TI - [An experimental study of ischemic damage and repair on the femoral head epiphysis in growing rabbits]. AB - The vascular changes and repair processes in the femoral head epiphysis and growth plate in growing rabbits influenced by an interruption in the blood supply were investigated angiographically and histologically. Forty-one rabbits (six week-old female Japanese White rabbit) were sacrificed for this study. The Interruption in the blood supply to the femoral head epiphysis was achieved by severing the nutrient arteries by electrocauterization in surgery. The revascularization process was examined by microangiography and histopathology of the epiphysis and growth plate at two-week intervals from 2 to 16 weeks after the surgery. The penetration of newly formed vessels into the bony epiphysis began at 4 to 6 weeks after the surgery. At 16 weeks, the vessels had penetrated into the growth plate. Granulation tissue without woven bone formation was seen on the loaded portion of the bony epiphysis, although woven bone was seen on the non loaded portion. The articular cartilage diminished in thickness and cellular counts declined during the 16 weeks after the surgery. The degenerated columnar structure was replaced with mesenchymal tissue which intruded into the growth plate and connected epiphysis to the metaphysis at 8 weeks. The columnar structure of the growth plate was progressively disorganized with time, after 8 weeks. From these results, we concluded that the deformation of the femoral head epiphysis and premature closure of the growth plate were influenced by the vascular interruption of the nutrient arteries. PMID- 7852786 TI - [Experimental study on interpositional arthroplasty using collagen membrane]. AB - The efficacy of collagen membrane was compared with that of fascia for interpositional arthroplasty in 45 knee joints of rabbits. Under general anesthesia, a parapatellar incision was made in the right knee and the articular cartilage of the femur and tibia was removed. Then either atelocollagen membrane derived from bovine tendon or autogenous fascia was placed over the femoral condylar defect. The animals were subsequently sacrificed after 3 to 12 weeks, and the right knee joints were removed for histological and roentogenological examination. At six weeks after interposition of the collagen membrane, the femoral and tibial defects were both covered with fibrocartilage. The joint space was preserved throughout the postoperative period. Radiological examination showed that the articular surfaces of the femur and tibia underwent smoothing and remodelling in a time-dependent manner. In contrast, the knee joints with fascia grafts showed the development of adhesions even at 3 weeks, and the joint cavity was filled with scar tissue at 12 weeks. Thus, the present study indicated that collagen membrane may be clinically efficient for interpositional arthroplasty. PMID- 7852787 TI - [Profile of arthritis]. PMID- 7852788 TI - [Anatomical structure and etiology of arthritis]. PMID- 7852789 TI - [Epidemiology of arthritis]. PMID- 7852790 TI - [Physiopathology of arthritis]. PMID- 7852791 TI - [Etiological mechanism of arthritis]. PMID- 7852792 TI - [Pharmacological study of non-steroidal anti-inflammatory agents for arthritis]. PMID- 7852793 TI - [Diagnosis of arthritis]. PMID- 7852794 TI - [Diagnosis and therapy of acute monoarthritis]. PMID- 7852795 TI - [Diagnosis and therapy of chronic monoarthritis]. PMID- 7852796 TI - [Diagnosis and therapy of acute polyarthritis]. PMID- 7852797 TI - [Diagnosis and therapy of chronic polyarthritis]. PMID- 7852798 TI - [Diagnostic imaging of arthritis]. PMID- 7852799 TI - [Diagnosis and therapy of reactive arthritis]. PMID- 7852800 TI - [Diagnosis and therapy of idiopathic femur head necrosis]. PMID- 7852802 TI - [Arthritis and quality of life]. PMID- 7852801 TI - [Diagnosis and therapy of hypertrophic osteoarthropathy]. PMID- 7852803 TI - [Early diagnosis and therapy of rheumatoid arthritis. Discussion]. PMID- 7852804 TI - [Case of spinal cord neoplasm with raised intracranial pressure and upside-down champagne bottle shaped muscular atrophy]. PMID- 7852805 TI - [Case of elevated intra-tumoral blood coagulation and fibrinolysis system in hepatoma]. PMID- 7852806 TI - [A case of leprous neuritis]. PMID- 7852807 TI - [Case of Guillain-Barre syndrome manifesting cerebral-infarction like symptom in lower left pons]. PMID- 7852808 TI - [A case of essential mixed cryoglobulinemia]. PMID- 7852809 TI - [A case of minocycline-induced hypersensitivity pneumonitis with radiographic finding of multiple nodules]. PMID- 7852810 TI - [A case of variant angina pectoris with repetitive syncope]. PMID- 7852811 TI - [Immunodeficiency caused by retrovirus infections]. PMID- 7852812 TI - [Genetic diagnosis of hereditary spinocerebellar degeneration]. PMID- 7852813 TI - DNA damage produced by exposure of supercoiled plasmid DNA to high- and low-LET ionizing radiation: effects of hydroxyl radical quenchers. AB - Production of DNA damage by exposure to ionizing radiation was measured in two in vitro systems. A supercoiled plasmid of 7.3 kbp was isolated and exposed in an aqueous environment to 60Co gamma rays and JANUS 0.85 MeV fission-spectrum neutrons. Dose responses for the production of single-strand breaks (ssbs) and double-strand breaks (dsbs) were computed from the conversion of the supercoil to its relaxed and linear forms. The relative effectiveness (neutrons:gamma-rays) for destruction of genetic transforming activity of M13 viral DNA was 0.23, close to that for ssb production, in contrast with the situation for biological effects such as lethality, mutagenesis and cellular transformation measured in mammalian cells, where RBEs are > 1. The role of hydroxyl (OH) radicals in DNA damage induction by neutrons was investigated by exposure of plasmid in the presence of known quenchers of this species. Of four quenchers tested, all were able to reduce the yields of both ssbs and dsbs. These findings are consistent with a model for ssb and dsb induction by high linear energy transfer radiation that involves OH radical medication. PMID- 7852814 TI - Flow cytometric analysis of micronucleus induction in mice by internal exposure to 137Cs at very low dose rates. AB - Internal radiation from 137Cs, intraperitoneally injected into mice, induced chromosome damage seen as micronuclei in erythrocytes of peripheral blood harvested 72 h after injection and analysed with flow cytometry. The retention of injected 137Cs activity was determined and the absorbed doses obtained from the beta-radiation of 137Cs were calculated for the whole bodies and bone marrow of the treated mice. The absorbed doses during the most relevant period for micronucleus induction were 2.7-18.3 mGy per day. The dose to the bone marrow during the same period was calculated to be 6-44 mGy per day. A linear dose response relationship was found. PMID- 7852815 TI - Estimating the true frequency of X-ray-induced complex chromosome exchanges using fluorescence in situ hybridization. AB - Fluorescence in situ hybridization (FISH) with a series of composite probes for human chromosomes 1, 4, 5, 7 and 13, applied separately with a total centromere probe, was used to identify X-ray-induced, chromosome-type aberrations in primary untransformed human fibroblasts. Visible complex exchanges, i.e. those involving three or more breaks in two or more chromosomes, were classified with reference to possible complex FISH patterns derived from a set of theoretical interactions. At 4 Gy, approximately 20% of all exchanges we observed were visibly complex. Using an interaction scheme, which allows either loose end of a break to restitute with its partner, or join with any other loose end within the potential complex, we modelled a set of interactions that matched the frequencies of the complex FISH patterns identified. The direct score of visible complex patterns is an under-estimate of the true frequency because some apparently 'simple' two break exchanges (dicentrics and translocations) are actually derived from three or more breaks. Using the model we estimate that these account for 20% of the simples scored. Taking this into account, we estimate the true frequency of complexes at 4 Gy to be 35% of all exchanges scored and we believe that the majority of these involve five breaks in four chromosomes. PMID- 7852816 TI - Radioprotective effects of prostaglandins for chromosomal aberrations and cell killing in V79 Chinese hamster cells grown as spheroids in vitro and for mouse spermatogonial stem cells and bone marrow cells in vivo. AB - The radioprotective effects of prostaglandins (PGE2, PGE1 and its analogue misoprostol (MP) were investigated in cultures of V79 Chinese hamster (CHO) cells grown as spheroids and as monolayers, CHO cells grown as monolayers, and in bone marrow polychromatic erythrocytes and spermatogonial stem cells in mouse. The X ray doses were 0.75 Gy (hamster cells) and 5, 8 and 10 Gy (mouse experiments). Prostaglandin pre-irradiation treatment resulted in a marked reduction in the frequencies of chromosomal aberrations in V79 spheroids and of reciprocal translocations in mouse stem cell spermatogonia. The amount of mouse spermatogonial stem cell killing was likewise significantly reduced. No radioprotective effects of prostaglandins could be demonstrated, however, for chromosomal aberrations in hamster cells grown as monolayers, for survival of V79 cells grown as spheroids, and for the induction of micronuclei in bone marrow polychromatic erythrocytes of mouse. PMID- 7852817 TI - Haematopoietic radioprotection by Cremophor EL: a polyethoxylated castor oil. AB - The polyethoxylated castor oil, Cremophor EL (Cremophor) is approved for human use as a vehicle for oral and intravenous administration of water-insoluble compounds. Cremophor has also previously been shown to reverse the multidrug resistance phenotype at clinically acceptable doses. This study demonstrates that doses of Cremophor in the range of 25-50 microliters/kg intravenously (i.v.) administered 1 day prior to near-lethal irradiation protected the regenerative capacity of the marrow, resulting in haematopoietic radioprotection and long-term survival of near-lethally-irradiated mice. In normal mice, Cremophor administration (1) markedly reduced the level of serum haematopoietic inhibitory activity 4-8 h following injection; (2) resulted in a transient decrease in femoral bone marrow cellularity and upregulated B220 (B cells), and 7/4 (neutrophils and activated macrophages), but not Thy-1 (T-cells) surface antigen expression in bone marrow cells within 24 h of injection; and (3) transiently elevated the incidence of both primitive and committed haematopoietic progenitor cells detected in clonal agar culture within 48 h of injection. Bone marrow progenitor cell content, and peripheral blood white cell, platelet and reticulocyte counts were unaffected. This suggests that the haematopoietic radioprotection and recovery observed in irradiated mice pretreated with Cremophor may be the result of accessory cell activation and/or modulation of accessory factors regulating haematopoietic progenitor cells. Our data suggest a potential clinical use of Cremophor as an adjunct to, or as a substitute for, cytokines to minimize myelosuppression following cytotoxic therapy. PMID- 7852818 TI - Radiosensitivity and cell cycle redistribution of cultured human tumour cells during fractionated daily 2-Gy irradiations. AB - Exponentially growing SQ-5 human lung squamous cell carcinoma cells were irradiated in vitro at 2-Gy per fraction per day continuously for 14 days. The number of total cells continued to increase exponentially till day 5, and reached a plateau level thereafter. The cell cycle distribution changed marginally for the first 5 days, and showed a prominent G2/M accumulation at day 7. Plating efficiencies decreased exponentially with increasing fractionation while the total clonogenic cell number remained constant until day 4. Radiosensitivity at each fraction was stable until day 9, but significantly increased at day 11. A comparison of plating efficiencies between the immediate and 24-h delayed assays revealed that the capacity of cells to spare 2-Gy damage increased with the number of 2-Gy fractions. These results suggest that sublethal damage could accumulate during multifraction daily irradiations, while repair of potentially lethal damage and/or proliferation could rather increase. PMID- 7852819 TI - DNA double-strand break induction and rejoining as determinants of human tumour cell radiosensitivity. A pulsed-field gel electrophoresis study. AB - Measurement of the surviving fraction after 2 Gy (SF2) may predict for local control of the tumour and patients cure, but clonogenic assays are unsuitable for wider clinical application. Promising results have been obtained using DNA damage assays such as pulsed-field gel electrophoresis, PFGE. In the current study, nine human tumour cell lines (SF2, range 0.08-0.62) were studied for DNA double-strand break (dsb) induction and six of these for dsb rejoining using PFGE. Differences in dsb induction, as the slope (+/- SEM) of DNA release per Gy, varied from 1.30 (0.05) to 2.42 (0.17). The dsb induction frequency varied from 3.55 (0.33) to 9.69 (2.18) dsb x 10(-9)/bp/Gy (21-56 dsb/Gy/cell). Variations in the half-time for fast phase (18-60 min) and slow phase (38-445 min) dsb rejoining were observed. Statistically significant correlations were found between SF2 and the slope of the DNA release curve (p = 0.003), DNA release after 10 Gy (p = 0.029) and 20 Gy (p = 0.011) and slow phase dsb rejoining (p = 0.012). While the underlying mechanisms of cell killing remain unclear, PFGF measurement of dsb induction and rejoining shows great potential as a predictive assay for intrinsic cellular radiosensitivity. PMID- 7852820 TI - Effect of chronic irradiation on the humoral immune response of a marine fish, the eelpout (Zoarces viviparus L.). AB - Eelpout (Zoarces viviparus), a marine fish, were exposed to gamma-radiation at a dose-rate of 2.0 mGy h-1. They were injected with the antigen trinitrophenyl keyhole limpet haemocyanin (TNP-KLH) and their specific humoral immune response to the TNP hapten measured. There were no differences in the primary antibody response between unirradiated controls and treated fish. However, the response to a second injection of antigen was significantly increased in irradiated fish. There were no significant radiation effects on total serum protein or serum lysozyme. Radiation effects on testis were also examined and there was a significant radiation-induced reduction in relative weight (gonadosomatic index). These results are discussed with reference to environmental radiation levels in areas of authorized radioactive waste disposal. PMID- 7852821 TI - Role of oxygen in the phototoxicity of phthalocyanines. AB - The presence of molecular oxygen is a determinant in the phototoxicity of phthalocyanines, and photosensitized oxidation is the accepted chemical mechanism for photo-dynamic action. However, it is difficult to establish whether the process is initiated by a type I electron transfer, or by a type II energy transfer reaction to form singlet oxygen. Usually, the involvement of singlet oxygen in photodamage has been indicated by the inhibition of the biological effect by a competitive physical or chemical singlet oxygen quencher, or by a rate increase in D2O, in which singlet oxygen has a longer lifetime than in H2O. Unfortunately, these techniques are not completely specific for singlet oxygen. Moreover, thermodynamic considerations suggest that photoinduced electron abstraction from appropriate biomaterials could compete with singlet oxygen production under in vivo conditions. This likely source of one electron-oxidized primary radicals, which can provide the precursors of the oxidative damage in phthalocyanine photosensitization, suggests the possibility of modulated toxicity by interaction with chemical additives. Examples of such additives recently studied are ascorbate, tocopherol and quercetin, all of which are natural antioxidants. PMID- 7852822 TI - Response of a rodent fibrosarcoma to photodynamic therapy using 5-aminolaevulinic acid or polyhaematoporphyrin. AB - The effects of 5-aminolaevulinic acid (ALA)-based photodynamic therapy (PDT) on the growth of an intradermal rat fibrosarcoma have been determined following topical, intravenous, or intratumour application of ALA. The pattern of tumour growth was identical following each type of therapy and we conclude that the efficacy of ALA-PDT is independent of the route of drug administration, at least in this tumour system. We have also compared the efficacy of interstitial ALA based PDT with similar therapy using a conventional photosensitizer, polyhaematoporphyrin (PHP). ALA-PDT was less effective than PHP-based therapy at inhibiting the growth of a subcutaneous rat fibrosarcoma at light doses over 300 J. It is suggested that protoporphyrin IX photo-bleaching may limit the effectiveness of treatment, whilst the more bleach-resistant PHP may continue to be effective at higher light doses. PMID- 7852823 TI - The delirious ICU patient: often misdiagnosed and undertreated. PMID- 7852824 TI - Extensive mononeuritis multiplex as a solitary presentation of polyarteritis nodosa. PMID- 7852825 TI - Delayed diagnosis of congenital adrenal hyperplasia in a premature female infant. AB - A preterm female infant was diagnosed with congenital adrenal hyperplasia after the first month of life. Electrolyte abnormalities and prominent clitoris were originally attributed to the prematurity of the infant. Congenital adrenal hyperplasia was confirmed when the abnormalities persisted. Delay in diagnosis can be prevented with the installation of newborn screening programs. PMID- 7852826 TI - How to avoid burnout in medical practice. PMID- 7852827 TI - Psychiatric symptoms in "stable" bipolar outpatients. PMID- 7852829 TI - Professional liability in postgraduate medical education. Who is liable for resident negligence? PMID- 7852828 TI - Health care value: cost ratio. PMID- 7852830 TI - Benefits determination under health care reform. Who should decide coverage policy? PMID- 7852831 TI - The use of uncharged misconduct evidence in physician malpractice and hospital liability litigation. PMID- 7852832 TI - Signal transduction by cell adhesion receptors in leukocytes. AB - Leukocytes usually pass through the blood stream as nonadherent cells, but during an immune response and inflammation, they become adherent in order to migrate through tissues. Three families of adhesion molecules, the immunoglobulin family, the selectins, and the integrins, participate in interactions between leukocytes and tissues. Near sites of inflammation, leukocytes initially interact with the endothelium via selectins, causing them to slow down and to roll along the walls of blood vessels. Next, chemoattractans induce the activation of integrins on leukocytes. Finally, activated integrins mediate leukocyte migration through the endothelium into the inflamed site. Interactions of leukocytes with other cells and various extracellular matrix (ECM) proteins lead to different functional cell responses, including changes in growth, behavior, and differentiation. Many of these interactions are mediated by integrins, which "integrate" ECM protein signals with the cytoskeleton and which also act as true receptors that generate biochemical signals within the cell. Changes in pH, cytoplasmic Ca2+ concentration, phosphorylation, and gene induction have all been observed after integrin engagement. Adhesion-mediated gene induction in monocytes is perhaps the best example that integrins initiate signaling cascades in the cell to deliver information from the ECM all the way to the nucleus. PMID- 7852833 TI - Temporal and spatial changes of quinolinic acid immunoreactivity in the immune system of lipopolysaccharide-stimulated mice. AB - Quinolinic acid (Quin), a metabolite of tryptophan, is a neurotoxin that has been implicated in a variety of neuropathologic disorders that have immune components. The goal of this study was to characterize the changes in the cellular localization of Quin immunoreactivity in a paradigm of immune stimulation with lipopolysaccharide (LPS) in vivo to provide a basis for further studies on the physiological role of Quin in the immune system. Intraperitoneal LPS injection significantly increased Quin immunoreactivity (IR) in lymphoid tissues within 24 h. Spatial changes in splenic Quin-IR demonstrated a shift from the periarterial lymphoid sheaths to the follicles before returning to control levels by 72 h post LPS. The strongly Quin-IR cells were tentatively identified as interdigitating dendritic cells and macrophages. Only minimal Quin-IR was detected in liver and lung, even under conditions of LPS stimulation combined with tryptophan loading. These data emphasize the temporally and spatially specific nature of Quin-IR changes in lymphoid tissues under conditions of immune stimulation and raise the possibility that Quin may have an immunomodulatory function. PMID- 7852834 TI - Differential effects of the anti-inflammatory compounds heparin, mannose-6 phosphate, and castanospermine on degradation of the vascular basement membrane by leukocytes, endothelial cells, and platelets. AB - Recent studies suggest that heparin, mannose-6-phosphate (M6P), and castanospermine (CS) may mediate their anti-inflammatory effects by inhibiting the passage of leukocytes through the subendothelial basement membrane (BM). In order to test this hypothesis, heparin, M6P, and CS were examined for their ability to prevent the in vitro degradation of a 35SO4-labeled extracellular matrix (ECM) by neutrophils, lymphocytes, endothelial cells (ECs), and platelets, the labeled ECM degradation products being analyzed by gel filtration chromatography. All three compounds inhibited 35SO4-labeled ECM degradation, but M6P and CS were cell-type specific in their effects. Heparin inhibited the heparanase activity of all cell types examined, confirming the results of previous studies using similar in vitro techniques. M6P selectively inhibited lymphocyte heparanase but not that of platelets, neutrophils, or ECs. CS selectively inhibited phorbol myristate acetate (PMA)-induced EC heparanase and sulfatase activity but did not affect the constitutive expression of degradative enzymes by non-stimulated ECs. These findings provide important clues to the mode of action of these compounds and the characteristic inflammatory pathology associated with the use of each anti-inflammatory agent. In particular, the data support the view that leukocytes markedly differ in the mechanisms they use to degrade BM/ECM to enable extravasation and that some degree of cooperation with EC is required in this process. PMID- 7852835 TI - Functional deficiencies in two distinct interferon alpha-producing cell populations in peripheral blood mononuclear cells from human immunodeficiency virus seropositive patients. AB - Two populations of IFN-alpha producing cells (IPC) were examined to determine whether they are coordinately dysregulated in human immunodeficiency virus (HIV) disease. IFN-alpha produced in response to herpes simplex virus (HSV) and Sendai virus (SV) was measured and the frequencies of the IPC were obtained by ELISpot assay. IPC that respond to HSV (natural IFN-alpha producing cells) and those responding to SV (predominantly monocytes) were present, on average, at 7.6 and 138 per 10(4) PBMC in healthy controls, respectively. More patients had a reduced IFN-alpha response to HSV than to SV, and individual patients did not show a decreased response to SV without a decreased response to HSV. Neither IPC function was correlated with CD4+ cell levels. We conclude that the defects in IFN-alpha production in these two cell populations arise independently, possibly due to differences in susceptibility to HIV infection or molecular regulation. PMID- 7852836 TI - Characterization of eosinophil homotypic aggregation. AB - Guinea pig peritoneal eosinophils stimulated by platelet-activating factor (PAF), leukotriene B4 (LTB4), and human recombinant C5a (C5a) undergo a rapid concentration-dependent and partially reversible homotypic aggregation as assessed by changes in light transmission. The phorbol ester phorbol myristate acetate similarly induces a concentration-dependent aggregation, which is, however, slower in onset, takes longer to reach maximal aggregation, and is irreversible. In addition, we confirmed, using light microscopy, that these agonist-induced changes in light transmission do indeed represent true homotypic aggregation. We further characterized the aggregation response and showed that there is homologous but little heterologous desensitization when PAF and LTB4 are used as stimuli. A requirement for both Ca2+ and Mg2+ for full manifestation of agonist-induced aggregation was observed. LTB4- and PAF-induced superoxide anion generation is enhanced by the diacyglycerol kinase inhibitor R59022, whereas aggregation induced by LTB4, but not PAF, is augmented. Lastly, we show that eosinophil aggregation is partially dependent on the adhesion glycoprotein CD18. In summary, therefore, we believe that eosinophil aggregation provides a useful and reliable measure of eosinophil activation. PMID- 7852837 TI - Retention of phagocytic functions in cryopreserved human monocytes. AB - Phagocytosis and respiratory burst activity were measured by flow cytometry in fresh and cryopreserved human monocytes, after ingestion of Escherichia coli and Staphylococcus aureus. Mononuclear leukocytes, isolated from 15 healthy donors, were divided into two portions, of which one was examined immediately and the other was cryopreserved for 3 weeks. Morphological characteristics and expression of receptors involved in phagocytosis were similar in fresh and cryopreserved monocytes. Furthermore, both internalization of bacteria and respiratory burst activity remained unchanged after cryopreservation. Transmission electron microscopy confirmed actual internalization of bacteria and not merely bacterial attachment to monocytes. Monocytes were demonstrated to retain integral cellular functions during cryopreservation. This may imply that the method has potential for use in basal and clinical trials. PMID- 7852838 TI - In vitro and in vivo effects of pentoxifylline on macrophages and lymphocytes derived from autoimmune MRL-lpr/lpr mice. AB - MRL-lpr/lpr mice develop an autoimmune disease similar to human systemic lupus erythematosus (SLE). The main characteristics of this disease are increasing autoantibody formation, elevated plasma levels of immune complexes, a massive lymphoproliferation, a rising proteinuria, and arthritic symptoms. Finally, the mice die at an age of about 6 months due to a fatal immune complex glomerulonephritis. Macrophages are involved in the development of SLE due to their functions as antigen-presenting as well as cytokine-producing cells. T and B cells are involved in the disease by secreting cytokines and producing antibodies. Pentoxifylline (PTX), a xanthine derivative, is known to exert different effects on functions of leukocytes and erythrocytes and has been used in clinical studies, e.g., in septic shock syndrome. In our studies we first investigated the in vitro effect of PTX on macrophages and lymphocytes derived from MRL-lpr mice. Our investigations concerning production of superoxide anion and TNF-alpha by LPS and/or IFN-gamma activated bone marrow and peritoneal macrophages, MHC class II expression on these cells, and the proliferative capacity and Il-2 production of mitogen activated lymphocytes, revealed that PTX reduces the activation and the inflammatory response of these cells. Based on these results, we further investigated the effect of in vivo treatment with PTX. MRL-lpr mice treated with PTX showed diminished proteinuria, reduced titer of dsDNA-autoantibodies in the plasma and an increased survival rate. Our data clearly demonstrate that PTX is able to diminish the severity of the disease and to prolong the life of MRL-lpr/lpr mice. PMID- 7852839 TI - Effects of oxo and dihydro metabolites of 12-hydroxy-5,8,10,14-eicosatetraenoic acid on chemotaxis and cytosolic calcium levels in human neutrophils. AB - One of the pathways of metabolism of leukotriene B4 (LTB4) and 12-hydroxy 5,8,10,14-eicosatetraenoic acid (12-HETE) in leukocytes is oxidation of the 12 hydroxyl group, followed by reduction of the 10,11-double bond. In the case of 12R-HETE and 12S-HETE, this results in the formation of 12-oxo-ETE, 10,11-dihydro 12-oxo-ETE, and the 12R and 12S isomers of 10,11-dihydro-12-HETE (i.e., 12R-HETrE and 12S-HETrE). We investigated the effects of metabolites of 12-HETE formed by this pathway on cytosolic calcium levels and chemotaxis in human neutrophils. Of the above series of metabolites, 12S-HETrE (which has the same absolute stereochemistry at C-12 as 12R-HETE) was the most potent in stimulating both cytosolic calcium levels and chemotaxis. It was slightly less potent than 12R HETE, consistent with the concept that reduction of the 10,11-double bond results in a loss of biological activity on neutrophils. The effect of 12S-HETrE on calcium levels was blocked by preincubation of these cells with LTB4, suggesting that it acted by stimulating the LTB4 receptor. 12R-HETrE was about 20 times less potent than its 12S isomer in stimulating cytosolic calcium in neutrophils and was also less active as a chemotactic agent. Oxidation of the 12-hydroxyl group to an oxo group resulted in a further loss of biological activity. 12-Oxo-ETE, 8 trans-12-oxo-ETE, and 12-oxo-ETrE had only modest effects on cytosolic calcium levels at concentrations as high as 10 microM and did not display detectable chemotactic activity. However, 12-oxo-ETE and its 8-trans isomer inhibited calcium responses to LTB4 by about 40%. It is concluded that reduction of the 10,11-double bond of 12-HETE results in a slight loss of biological activity on neutrophils, whereas oxidation of the 12-hydroxyl group results in a considerably greater loss of activity. PMID- 7852840 TI - Mycoplasma stimulates the production of oxidative radicals by murine peritoneal macrophages. AB - Mycoplasmas and mycoplasma membranes have been shown to induce the production of inflammatory cytokines, including tumor necrosis factor alpha and interleukin-6, as well as nitric oxide, by mouse macrophages and rat brain astrocytes. Luminol enhanced chemiluminescence was used as a sensitive method to show that Mycoplasma capricolum membranes induce mouse peritoneal macrophages to produce reactive oxygen radicals. Coincubation of the mycoplasma with a secondary stimulus, namely macrophage-activating factor or interferon-gamma, increased the chemiluminescence. The augmentation was abolished by the nitric oxide synthase inhibitor NG-methyl-L-arginine, indicating the involvement of nitric oxide. The coproduction of superoxide and nitric oxide by the same cell allows the formation of the powerful oxidant peroxynitrite, which could be responsible for the increased chemiluminescence. Induction of oxidizing radicals by mycoplasmas may contribute to the clinical pathology seen in mycoplasma infections. PMID- 7852841 TI - Distinct biochemical responses of hepatic macrophages and endothelial cells to platelet-activating factor during endotoxemia. AB - Acute endotoxemia is associated with activation of hepatic macrophages and endothelial cells. These cells release a variety of inflammatory mediators that have been implicated in tissue injury. In the present studies, we analyzed the biochemical responses of these cells to platelet-activating factor (PAF), a lipid autacoid released during hepatic inflammatory responses. To induce acute endotoxemia, rats were injected intravenously with lipopolysaccharide (LPS). Using the calcium sensitive fluorescent indicator dye Indo-1, we found that PAF induced a rapid and transient increase in intracellular calcium in both hepatic macrophages and endothelial cells. Induction of acute endotoxemia resulted in an increase in the amount of calcium mobilized by both cell types. Although endothelial cells from control rats were less responsive to PAF than macrophages, these cells were more sensitive to in vivo endotoxin. PAF was also found to cause a rapid decrease in intracellular pH in hepatic macrophages that was quantified by fluorescence image analysis using the pH sensitive dye SNAFL-calcein. This decrease occurred more rapidly in macrophages from endotoxemic rats. In cells from both control and endotoxemic rats, the effects of PAF on intracellular pH were inhibited by the specific PAF antagonist triazolam. In contrast to hepatic macrophages, PAF had no effect on intracellular pH in endothelial cells from either control or endotoxemic rats. Ligand binding studies demonstrated that both hepatic macrophages and endothelial cells possess high affinity binding sites for PAF. Macrophages expressed 6- to 7-fold more binding sites/cell than endothelial cells and exhibited a higher Kd. Whereas treatment of rats with LPS had no effect on the Kd for PAF binding to macrophages or on the number of binding sites, a significant increase in both of these receptor characteristics was observed in endothelial cells. Taken together, the present data suggest that the biochemical responses of endothelial cells and macrophages to PAF are distinct. Furthermore, cellular activation induced by PAF in endothelial cells appears to be independent of changes in intracellular pH. PMID- 7852842 TI - Effects of bafilomycin A1 on functional capabilities of LPS-activated alveolar macrophages. AB - Resident alveolar macrophages (m phi) possess plasmalemmal vacuolar-type H(+) ATPase (V-ATPase) that plays a crucial role in regulation of intracellular pH (pHi). To assess the importance of this V-ATPase to m phi effector functions, resident alveolar m phi from rabbits were activated with E. coli-derived lipopolysaccharide (LPS) and exposed to bafilomycin A1, a specific inhibitor of V ATPase. Bafilomycin caused a significant cytosolic acidification in both the absence and presence of CO2-HCO3-, and in both unstimulated and activated m phi. Superoxide production and Fc receptor-mediated phagocytosis also were reduced in bafilomycin-treated m phi. Similar effects were elicited by acidifying the cytoplasm in the absence of bafilomycin, by lowering extracellular pH (pHo) from 7.4 to 6.5-6.6. Thus, the effects of bafilomycin on phagocytosis and superoxide production probably were related to cytosolic acidification, secondary to blockade of V-ATPase-mediated H+ extrusion across the plasma membrane. Conversely, bafilomycin significantly increased TNF-alpha release. This effect cannot be explained by a bafilomycin-induced acidosis because acidic pHo significantly reduced TNF-alpha release. The results demonstrate that V-ATPase activity is an important determinant of the effector functions of LPS-activated m phi. PMID- 7852843 TI - An inhibitor of polyamine biosynthesis impairs human polymorphonuclear leukocyte priming by tumor necrosis factor alpha. AB - TNF primes polymorphonuclear leukocytes (PMNs) for enhanced oxidative and secretory activity and directly induces adhesion and IL-1 beta expression. Previous reports suggest that polyamine biosynthesis by ornithine decarboxylase (ODC) has an essential role in macrophage activation by TNF. In the current study, TNF induced rapid increases in the putrescine and spermine content of PMNs. Difluoromethylornithine (DFMO), a selective inhibitor of ODC, inhibited these increases and blunted the enhancement of superoxide generation and secondary granule release associated with priming by TNF. DFMO did not affect the expression of TNF receptors or block receptor-independent activation of the respiratory burst by phorbol esters. Moreover, DFMO did not antagonize induction of adhesion or IL-1 beta mRNA expression by TNF. Thus, polyamine biosynthesis plays an important role in priming by TNF, but is not involved in all PMN responses to this cytokine. This suggests that ODC is a potential target for selective chemotherapeutic modulation of the inflammatory response. PMID- 7852844 TI - Transforming growth factor beta modulates C3 and factor B biosynthesis and complement receptor 3 expression in cultured human monocytes. AB - Complement biosynthesis in monocytes is stimulated by different pathogens and modulated by a variety of cytokines, but little is known about the possible effect of transforming growth factor beta (TGF-beta) on this monocyte function. We therefore studied the effect of TGF-beta 1 and TGF-beta 2 on constitutive, lipopolysaccharide (LPS)- and Candida albicans-induced monocyte biosynthesis of complement components C3 and factor B. Under all three conditions, both forms of TGF-beta (20 ng/ml) induced a two- to fourfold increase in C3 concentration in monocyte supernatants harvested after 2 or 5 days of cell culture, an effect that was abrogated by cycloheximide. In contrast, constitutive and pathogen-induced production of factor B was suppressed by TGF-beta. The effects of TGF-beta on complement production were neutralized by a monoclonal anti-TGF-beta antibody. Moreover, TGF-beta suppressed the pathogen-induced release of granulocyte macrophage colony-stimulating factor and down-regulated the expression of complement receptor 3 (CD11b/CD18), while the expression of CD11a/CD18, a related beta 2 integrin, was unaffected. These novel effects of TGF-beta emphasize the immunomodulatory significance of this cytokine. PMID- 7852845 TI - Cyclic GMP and guanylate cyclase mediate lipopolysaccharide-induced Kupffer cell tumor necrosis factor-alpha synthesis. AB - Tumor necrosis factor-alpha (TNF-alpha) is an important mediator in sepsis and septic shock. Kupffer cells (KCs) are the resident macrophages of the liver and are potent producers of TNF-alpha in response to inflammatory stimuli such as bacterial endotoxin or lipopolysaccharide (LPS). Although the effects of exogenous cytokines such as interferon-gamma on TNF-alpha production by macrophages have been fairly well studied, the intracellular pathways regulating KC TNF-alpha synthesis are largely unknown. We investigated the role of guanylate cyclase and cGMP in LPS-induced KC TNF-alpha synthesis. Exogenous 8-BrcGMP and dbcGMP increased LPS-stimulated TNF-alpha synthesis but had no effect on KC TNF alpha in the absence of LPS. Sodium nitroprusside (SNP), a nitric oxide-releasing substance that stimulates guanylate cyclase, increased TNF-alpha synthesis in response to LPS, whereas methylene blue and LY83583, guanylate cyclase inhibitors, decreased KC TNF-alpha synthesis. The inhibitory effect of methylene blue could be overcome with exogenous dbcGMP or SNP. Our results demonstrate that guanylate cyclase and cGMP mediate LPS-induced KC TNF-alpha synthesis and suggest that agents that alter cyclic nucleotide metabolism in KCs may affect the response of these cells to inflammation and inflammatory stimuli. PMID- 7852846 TI - Differential effects of anti-inflammatory cytokines (IL-4, IL-10 and IL-13) on tumoricidal and chemotactic properties of human monocytes induced by monocyte chemotactic and activating factor. AB - The effect of recombinant human IL-4, IL-10, and IL-13 on the chemotaxis and antitumor activity of human blood monocytes induced by monocyte chemotactic and activating factor (MCAF) was examined. MCAF alone did not induce monocyte mediated cytotoxicity against human melanoma (A375-M) cells whereas it significantly enhanced the cytotoxicity by norMDP-stimulated monocytes. MCAF, unlike IFN-gamma, had no priming effect on monocyte activation by norMDP. MCAF acted with norMDP or LPS to enhance the production of both IL-1 beta and TNF alpha. Enhanced cytotoxicity of monocytes stimulated with MCAF plus norMDP was reduced by IL-1 receptor antagonist and anti-TNF-alpha antibody. IL-4, IL-10, and IL-13 suppressed the generation of antitumor activity and cytokine production (IL 1 beta and TNF-alpha) of monocytes stimulated with MCAF plus norMDP or LPS. Chemotaxis of monocytes induced by MCAF was not affected by norMDP or any of the anti-inflammatory cytokines (IL-4, IL-10, and IL-13). Moreover, the pretreatment of monocytes with anti-inflammatory cytokines did not suppress monocyte chemotaxis. These findings suggest that in vivo recruitment and anti-tumor expression of blood monocytes induced by MCAF may be differently regulated by anti-inflammatory cytokines in vivo. PMID- 7852847 TI - Activation of casein kinase II in ML-1 human myeloblastic leukemia cells requires IGF-1 and transferrin. AB - Casein kinase II (CK II), a key enzyme involved in the regulation of cell growth, has been variously reported to be activated by diverse mitogens, including insulin-like growth factor 1 (IGF-1) and epidermal growth factor (EGF). Activation of the enzyme is generally carried out in the presence of serum, and we examined the question whether serum components participate in the activation process. We demonstrated previously that ML-1 cells require IGF-1 plus transferrin (TF) for growth and transforming growth factor beta or tumor necrosis factor alpha plus TF for differentiation. We now found that CK II is activated only when the cells are exposed to both IGF-1 and TF or when TF is replaced in this combination with relatively high levels of iron salts. Induction of differentiation with TGF-beta and TF did not result in CK II activation. These results show that CK II activation in ML-1 cells requires the application of both components of the growth signal, IGF-1 and TF, demonstrating that the growth factor alone is incapable of enhancing the activity of the enzyme. PMID- 7852848 TI - Modulation of IL-8 receptor expression on purified human T lymphocytes is associated with changed chemotactic responses to IL-8. AB - Interleukin-8 is a member of the chemokine superfamily and is a major mediator of acute inflammation. Although IL-8 has been reported by some laboratories also to be a chemoattractant for T lymphocytes, this has been difficult to confirm and remains a controversial issue. By using freshly purified human T cells (90-95% CD3+), we could demonstrate consistent directional migration of T cells to recombinant human IL-8. IL-8 was as potent as RANTES, MIP1 alpha, and MIP1 beta in inducing T cell chemotaxis. Highly purified T cells, however, incubated at 37 degrees C for more than 12 h or cultured overnight with anti-CD3 antibody cross linked to plastic dishes, showed a markedly reduced capacity to migrate in response to IL-8. This was associated with a decrease in binding of radioiodinated IL-8 to T cells. Northern blot and polymerase chain reaction analyses showed that freshly purified T cells expressed mRNA for both IL-8 receptor type A and type B. Steady-state levels of mRNA for the IL-8RA and IL-8RB genes were also reduced by incubation of the cells with or without anti-CD3 for 12 h at 37 degrees C. These results indicate that T cells are indeed one of the target cell populations for IL-8. The regulation of IL-8 receptor expression on T lymphocytes may contribute to the pathophysiological role of IL-8 in inducing the homing and infiltration of T cells. PMID- 7852849 TI - Evidence for LFA-1/ICAM-1 dependent stimulation of protein tyrosine phosphorylation in human B lymphoid cell lines during homotypic adhesion. AB - JK32.1 and SKW6.4 are Epstein-Barr virus (EBV)-positive human B cell lines that undergo spontaneous, lymphocyte function-associated antigen 1 (LFA-1) dependent homotypic adhesion in culture. This process is associated with induction of tyrosine phosphoproteins of molecular mass 90, 106, and 120 kDa and could be reproduced when these cells were centrifugationally aggregated. Antibodies to the beta 2 (CD18) chain of LFA-1 interfered with induction of p120, p106, and p90 during cellular aggregation. Response induction was abrogated when cells were incubated with protein tyrosine kinase (PTK) inhibitors (erbstatin, genistein, and geldanomycin) or cytochalasin B prior to aggregation. An in vitro kinase assay did not reveal activation of focal adhesion kinase. Although the role of LFA-1-dependent tyrosine phosphorylation in B cells is uncertain, patients with the leukocyte adhesion defect (LAD) exhibit humoral abnormalities. Moreover, aggregation did not induce specific tyrosine phosphoproteins in an EBV transformed B cell line from a LAD patient. These results suggest that an LFA-1 dependent PTK pathway may play an important role in human B cell function. PMID- 7852850 TI - Structure and binding of unconjugated bilirubin: relevance for physiological and pathophysiological function. PMID- 7852851 TI - Role of bile salt hydrophobicity in hepatic microtubule-dependent bile salt secretion. AB - Under basal conditions, bile salt secretion by the liver is not affected by microtubule disruption. However, when a bile salt load is imposed on the liver, a microtubule-dependent secretion mechanism is recruited (J. Lipid Res. 1988. 29: 144-156). We tested the hypothesis that recruitment of this microtubule-dependent mechanism is influenced by the relative hydrophobicity of the bile salts being secreted. Intact male rats were depleted of bile salts by overnight biliary diversion, pretreated with colchicine (a microtubule inhibitor) or its inactive isomer, lumicolchicine (control), and reinfused intravenously with bile salts of increasing hydrophobicity (taurodehydrocholate < tauroursodeoxycholate < taurocholate) at 200 nmol/min.100 g. After 45 min, when steady-state bile salt secretion was achieved, tracer [3H]taurocholate was administered intravenously. The colchicine-insensitive component of bulk bile salt secretion was constant at approximately 130 nmol/min.100 g, and the colchicine-sensitive component increased from approximately 0 to 35 and 60 nmol/min.100 g, respectively, with reinfusion of the more hydrophobic bile salts. Retained bile salts accumulated in the liver and serum and were detectable in urine. Peak biliary secretion of [3H]taurocholate in control animals increased linearly from 15.3 to 18.0% administered dose/min with increasing hydrophobicity of the secreted bile salts (P < 0.002). In colchicine-pretreated animals, peak secretion rates decreased linearly from 13.8 to 9.2%/min (P < 0.001), with maximal inhibition in taurocholate-reinfused animals (P < 0.01). Utilization of a microtubule-dependent secretion mechanism increases with increasing bile salt hydrophobicity. This mechanism permits more efficient hepatic secretion of bile salts, but increases the susceptibility of bile salt secretion to microtubule disruption. We postulate that microtubule-dependent insertion of bile salt transporters into the canalicular membrane underlies the enhanced bile salt secretion observed when a bile salt load is imposed upon the liver. PMID- 7852852 TI - Oxidative modification of human lipoproteins by lipoxygenases of different positional specificities. AB - Cellular lipoxygenases have been implicated in foam cell formation during the early stages of atherogenesis. We studied the interaction of lipoxygenases of different positional specificities with human lipoproteins and found that the arachidonate 15-lipoxygenases of rabbit and humans and the arachidonate 12 lipoxygenase of porcine leukocytes oxygenate lipoproteins as indicated by the formation of oxygenated lipids and changes in electrophoretic mobility of low density lipoprotein. The arachidonate 12-lipoxygenase of human platelets, the recombinant arachidonate 5-lipoxygenase of human leukocyte, and the soybean lipoxygenase I were less effective in oxidizing human LDL. As a major oxygenation product, esterified 13S-hydro(pero)xy-9Z,11E-octadecadienoic acid was identified for both the rabbit reticulocyte 15- and the porcine leukocyte 12-lipoxygenase. In addition, esterified 15S-hydro(pero)xy-5,8,11,13(Z,Z,Z,E)-eicosatetraenoic acid (for the rabbit 15-lipoxygenase) and 12S-hydro(pero)xy-5,8,10,14(Z,Z,E,Z) eicosatetraenoic acid (for the porcine 12-lipoxygenase) as well as small amounts of racemic 9-hydro(pero)xy-10,12-octadecadienoic acid isomers were detected. More than 90% of the oxygenated polyenoic fatty acids were found in the ester lipid fraction, particularly in the cholesteryl esters and in various phospholipid classes (phosphatidylcholine and phosphatidylethanolamine). The possible biological significance of lipoxygenase-induced oxidative modification of lipoproteins in the pathogenesis of atherosclerosis is discussed. PMID- 7852853 TI - Low density lipoprotein receptors in rat adipose cells: subcellular localization and regulation by insulin. AB - The distribution of LDL receptors within subcellular compartments of isolated rat adipose cells and the effects of insulin on their expression have been assessed. By immunoblotting with specific anti-rat LDL receptor antibodies, LDL receptors were 2.3- and 4.5-fold enriched in endoplasmic reticulum-rich high-density microsomes (HDM) and Golgi complex-rich low-density microsomes (LDM), respectively, compared to plasma membranes (PM). This distribution was similar in cultured cells in which total receptors were increased 2.5-fold compared to freshly isolated cells. After correction for enzyme recoveries, LDL receptors were distributed approximately 4% in HDM, approximately 73% in LDM, and approximately 23% in PM. Insulin decreased total LDL receptors in adipose cells approximately 44%, with a 48% and 49% decrease in HDM and LDM, respectively, without any changes in PM. In contrast, insulin caused an increase of glucose transporters in PM while also decreasing glucose transporters in LDM. When adipose cells were depleted of potassium to inhibit receptor-mediated endocytosis, insulin again caused a decrease of LDL receptors in LDM but now increased LDL receptors in PM. Insulin increased the rate of LDL receptor synthesis approximately 24%, but decreased their half life approximately 40%. Thus, in isolated adipose cells the majority of LDL receptors appear to be located in an intracellular compartment that co-sediments with the Golgi complex rather than located in the PM. The LDL receptors localized in intracellular compartments seem to be functionally regulated as insulin acutely diminishes the number of receptors by apparently accelerating their rate of degradation through, as yet, incompletely determined mechanisms. PMID- 7852854 TI - Polyunsaturated fatty acids increase lipid radical formation induced by oxidant stress in endothelial cells. AB - Lipid-derived free radicals were detected by electron paramagnetic resonance (EPR) spectrometry when cultured endothelial cells attached to Cytodex beads were exposed to iron-induced oxidant stress in the presence of the spin trap alpha-(4 pyridyl-1-oxide)-N-tert-butylnitrone (POBN). Radical adduct formation was enhanced greatly when the cells were supplemented during growth with polyunsaturated fatty acids. The largest EPR signal intensity was observed in cells enriched with docosahexaenoic acid (DHA) or eicosapentaenoic acid, but enhanced radical adduct production also occurred after exposure to arachidonic, alpha-linolenic, gamma-linolenic, or linoleic acids. Radical adduct formation increased as the DHA content of the cells increased and approached a maximum after only 6 h of exposure to DHA. Ascorbic acid, acting as a pro-oxidant, enhanced radical adduct formation in cells enriched with DHA. The EPR signal intensity was reduced when the cells were tested 6 h after replacement of the DHA enriched medium with a medium containing 5-20 microM oleic acid, indicating that the increased endothelial responsiveness to oxidant stress is reversible. Likewise, when U937 monocytes enriched with DHA were exposed subsequently to 20 microM oleic acid, a 35-45% decrease in radical adduct formation also occurred. These findings suggest that the endothelium may become more susceptible to oxidative injury when it is exposed to elevated amounts of polyunsaturated fatty acids. However, the effect appears to be temporary. The protective action of oleic acid against oxidant stress is not confined to the endothelium; it applies to monocytes as well. PMID- 7852855 TI - Fatty acids as determinants of triglyceride and cholesteryl ester synthesis by isolated hepatocytes: kinetics as a function of various fatty acids. AB - Triglyceride synthesis by hepatocytes is currently thought to be the rate limiting step for lipoprotein formation. In order to determine whether triglyceride and cholesteryl ester syntheses in hepatocytes are sensitive to physiological fluctuations of serum fatty acids, the fatty acid dependence of these pathways was examined. Uptake of various fatty acids and incorporation into triglyceride and cholesteryl esters were studied in isolated rat hepatocytes. Rates were determined under conditions of linear incorporation and related to the concentrations of total and unbound fatty acid in a mixture of fatty acids and albumin. The findings were: pathways for triglyceride and cholesteryl ester synthesis saturated at unbound fatty acid concentrations (or fatty acid albumin ratios) within the range of serum values and thus would be acutely modulated by fluctuations in serum fatty acids. Addition of cholesterol to the medium increased cellular cholesterol, but did not alter rates of cholesterol esterification, suggesting that endogenous cholesterol synthesis provided the needed substrate. Oleate, palmitate, and linoleate were comparable in their saturation kinetics and ability to support triglyceride and cholesteryl ester synthesis. Consequently, their binding affinity for serum albumin would determine their lipid-incorporation rates. On this basis, in humans, oleate would yield the lowest rates as it has the lowest unbound fatty acid at each fatty acid-albumin ratio. Stearate, in contrast to the other fatty acids, was poorly esterified into neutral lipids by hepatocytes. Poor hepatic metabolism of stearate most likely explains previous findings of a hypocholesteremic effect of diets high in stearate as compared to other saturated fatty acids.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7852856 TI - Bile acid synthesis in HepG2 cells: effect of cyclosporin. AB - The hypothesis that cyclosporin specifically affects the pathway of bile acid synthesis that begins with 27-hydroxylation of cholesterol was evaluated in HepG2 cells, which synthesize chenodeoxycholic acid and cholic acid from endogenous 7 alpha-hydroxycholesterol. At a concentration in the medium of 8.3 microM cyclosporin, the proportion of cholic acid increased from 29 +/- 7% to 44 +/- 6% (P < 0.001) with no major change in total bile acid production. Chenodeoxycholic acid synthesis was enhanced by the addition of either 7 alpha-hydroxycholesterol or 5 beta-cholestane-3 alpha,7 alpha-diol to the medium and cholic acid synthesis was enhanced by the addition of 5 beta-cholestane-3 alpha,7 alpha,12 alpha-triol to the medium. Cyclosporin significantly inhibited only enhanced chenodeoxycholic acid synthesis, indicating a selective interference in mitochondrial side chain oxidation of less polar intermediates in bile acid synthesis derived from either initial 7 alpha- or initial 27-hydroxylation of cholesterol. The increase in the proportion of cholic acid that occurs in the presence of cyclosporin mimics that occurring in genetically determined sterol 27-hydroxylase deficiency (cerebrotendinous xanthomatosis). Cyclosporin is useful for dissecting the subcellular pathways of bile acid synthesis. PMID- 7852857 TI - Lipid balance in HepG2 cells: active synthesis and impaired mobilization. AB - The human hepatoma cell line HepG2 in culture medium synthesized fatty acids de novo (144 +/- 9 nmol fatty acid/mg protein per 24 h) at a rate similar to that observed in freshly prepared rat hepatocytes (192 +/- 8 nmol/mg per 24 h) and in primary cultures of rat hepatocytes (165.4 +/- 29.3 nmol/mg per 24 h). In HepG2 cells, fatty acid synthesis was inhibited by extracellular oleate (0.75 mM), and, to a lesser extent, by glucagon (10(-7) M). Insulin (7.8 x 10(-8) M) had a mild stimulatory effect. Fatty acid synthesis was not influenced by lipogenic precursors (lactate plus pyruvate), substances which, in rat hepatocytes, had pronounced stimulatory effects. Fatty acid synthesis rates were also unchanged in the presence of prostaglandin E2 (PGE2). In general, compared to rat hepatocytes, fatty acid synthesis in HepG2 cells was less sensitive to manipulation of the culture medium in vitro. HepG2 cells had a high capacity for triacylglycerol synthesis from extracellular oleate (469 +/- 43 nmol triacylglycerol/mg protein per 24 h) but phospholipid synthesis was relatively low (15.8 +/- 0.4% of total glycerolipids). Very little of the above newly synthesized triacylglycerol was secreted as lipoprotein (4.62 +/- 0.88 nmol triacylglycerol/mg protein per 24 h) resulting in a large intracellular accumulation of triacylglycerol. This was exacerbated by the absence of any detectable ketogenesis. The secretion of triacylglycerol produced from de novo synthesized fatty acids was also very low in HepG2 compared to that observed in primary cultures of rat hapatocytes.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7852858 TI - In vivo metabolism of apolipoproteins A-I and E in patients with abetalipoproteinemia: implications for the roles of apolipoproteins B and E in HDL metabolism. AB - The metabolism of high density lipoproteins (HDL) is tightly linked to the metabolism of apoB-containing lipoproteins through the exchange and transfer of lipids and apolipoproteins within the plasma compartment. Abetalipoproteinemia (ABL), a genetic disease in which apoB is absent from the plasma and HDL are the sole plasma lipoproteins, is a model for the investigation of HDL metabolism without modification by apoB-containing lipoproteins. Apolipoproteins A-I and E are two of the major apolipoproteins in HDL. Plasma apoA-I levels, but not apoE levels, have been reported to be decreased in patients with ABL. Furthermore, HDL from ABL patients is enriched in apoE compared with normal subjects. The purpose of the present study was: 1) to elucidate the metabolic basis of the low apoA-I levels in ABL; 2) to determine whether in vivo apoE production rates are normal in the absence of apoB-lipoprotein secretion; and 3) to test the hypothesis that apoE influences apoA-I and HDL catabolism in ABL. 131I-labeled apoA-I and 125I labeled apoE were reassociated with autologous lipoproteins and injected into two unrelated ABL patients and control subjects. The mean residence time of apoA-I in ABL (2.4 days) was significantly decreased by nearly 50% compared with control subjects (4.7 +/- 0.6 days). ApoA-I production rates were also significantly decreased by 40% in ABL (7.1 mg/kg-d) compared with control subjects (11.8 +/- 1.7 mg/kg-d). The mean residence time of apoE in ABL (0.50 days) was somewhat shorter than that of control subjects (0.66 +/- 0.15 days), whereas the mean apoE production rate in ABL (2.14 mg/kg-d) was not substantially different from that of control subjects (1.55 +/- 0.62 mg/kg-d). HDL subfractions LpA-I and LpA-I:A II were isolated using immunoaffinity chromatography. In contrast to the normal metabolism, apoA-I in LpA-I:A-II particles was catabolized at a faster rate than apoA-I in LpA-I, accounting for the greater decrease of plasma LpA-I:A-II relative to LpA-I in the ABL patients. HDL subfractions with and without apoE were also isolated using anti-apoE immunoaffinity chromatography. Labeled apoA-I in apoE-containing HDL was catabolized faster than that in HDL without apoE. Among the three different forms of apoE, the apoE monomer was catabolized at the fastest rate, the apoE homodimer at an intermediate rate, and the apoE-A-II heterodimer had the slowest rate of catabolism.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7852859 TI - Mitochondrial 2,4-dienoyl-CoA reductases in the rat: differential responses to clofibrate treatment. AB - The effect of a peroxisome proliferator, clofibrate, on mitochondrial 2,4-dienoyl CoA reductases was studied in rat liver. The specific activity of reductase measured with 2,4-hexadienoyl-CoA as the substrate increased 2.9-fold in the liver homogenate and 2.5-fold in the mitochondrial extract, whereas acyl-CoA oxidase activity increased 13-fold and delta 3, delta 2-enoyl-CoA isomerase activity, 25-fold in the homogenate. Chromatography of the rat liver homogenate on hydroxylapatite, which separates the mitochondrial isoforms (M(r) 120,000 and M(r) 60,000) showed that the M(r) 60,000 isoform increased 3.5-fold and the M(r) 120,000 isoform 6-fold. When the isoforms were assayed with 2,4-hexadienoyl-CoA and trans-2,cis-4,7,10,13,16,19-docosaheptaenoyl-CoA, the activity ratios of C6 to C22 were 1.5-2.1 for the both isoforms isolated from livers of either control or clofibrate-treated rats. A quantitative immunological experiment with the antibody for the 120,000 reductase in the mitochondrial extracts showed a 6.9 fold increase in the signal, confirming the observation that this isoform is induced more than the other. The mRNA levels of reductase, isomerase, and peroxisomal multifunctional enzyme (MFE) were found to rise in a parallel manner when analyzed by in situ or slot hybridizations, which suggests that the increase was mediated by the same mechanism. Peroxisome proliferators have been shown to increase the mRNA levels of MFE by inducing peroxisome proliferator-activated receptor (PPAR)-mediated expression of the corresponding gene. The short-chain delta 3, delta 2-enoyl-CoA isomerase and the M(r) 120,000 reductase are exceptions among the mitochondrial beta-oxidation proteins, which usually show only a minor response to peroxisome proliferators. PMID- 7852860 TI - Pharmacological properties of a novel ACAT inhibitor (CP-113,818) in cholesterol fed rats, hamsters, rabbits, and monkeys. AB - The novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor CP-113,818 has been characterized in vitro against ACAT isolated from liver and intestine from a variety of species including human subjects, and in vivo in cholesterol-fed rats, hamsters, rabbits, and two species of nonhuman primates. CP-113,818 is a potent and specific inhibitor of liver and intestinal ACAT with IC50s ranging from 17 to 75 nM. This ACAT inhibitor also prevented the absorption of exogenous radiolabeled cholesterol in hamsters (ED50 = 6 micrograms/kg), rabbits (ED50 1/2 10 micrograms/kg), and cynomolgus and African green monkeys (40 and 26% inhibition at 10 mg/kg, respectively). CP-113,818 effectively prevented the increase in liver cholesterol levels in cholesterol-fed rats, hamsters, and rabbits. In lipoprotein characterization studies in rabbits, CP-113,818 selectively decreased apoB-containing lipoproteins (beta-VLDL, IDL, and LDL) and shifted the distribution of cholesterol from beta-VLDL, IDL, and LDL (96% before treatment to 81% after treatment) to HDL (4% before treatment to 19% after treatment). Finally, in monkeys, CP-113,818 significantly decreased LDL cholesterol by approximately 30% while either increasing HDL cholesterol (cynomolgus monkeys) or not affecting HDL cholesterol (African green monkeys), thereby improving the total plasma cholesterol/HDL ratios. In summary, CP-113,818 significantly inhibited cholesterol absorption, prevented the increase in liver cholesterol, and improved the lipoprotein profiles by selectively decreasing the cholesterol concentrations of the atherogenic lipoproteins (VLDL, IDL, and LDL) in a variety of cholesterol-fed animals. These data suggest that ACAT inhibition may be a useful therapeutic approach for lowering LDL cholesterol and thereby reducing the risk of developing coronary heart disease. PMID- 7852862 TI - Metabolism of emulsions containing medium- and long-chain triglycerides or interesterified triglycerides. AB - This study compares the clearing and metabolism of three different lipid emulsions. They had the same phospholipid emulsifier and similar particle sizes. In one (LLL) the core component was long-chain triglycerides (TG), the second (MMM/LLL) contained equal molar amounts of medium- and long-chain TG, the third (MLM) contained synthetic TG with medium-chain (M) fatty acids in the 1,3 positions and a long-chain (L) fatty acid in the 2-position. In model experiments with bovine lipoprotein lipase, the MMM component was hydrolyzed preferentially in the MMM/LLL emulsion so that the initial products were M fatty acids and M monoglycerides. The MLM emulsion, in contrast, gave M fatty acids and formation of L-MG (monoglyceride) throughout hydrolysis. For in vivo studies [3H]oleic acid was incorporated into the emulsion TG as marker for the long-chain component. After bolus injection to rats, the MMM/LLL and MLM emulsions were cleared more rapidly than the LLL emulsion. This was true at all TG loads studied (4-64 mg for a 200 g rat). The labeled oleic acid was oxidized somewhat more rapidly when administered in the MLM emulsion compared to the MMM/LLL emulsion. There were only slight differences in tissue distribution of label. Hence, differences in in vivo metabolism of the long-chain fatty acids were small compared to the marked differences in TG structure and in patterns of product release during in vitro lipolysis. PMID- 7852861 TI - A second complementation class of cholesterol transport mutants with a variant Niemann-Pick type C phenotype. AB - We previously isolated Chinese Hamster ovary cell mutants that were defective in the intracellular transport of low density lipoprotein (LDL)-derived cholesterol (Dahl, N.K., K.L. Reed, M.A. Daunais, J.R. Faust, and L. Liscum. 1992 J. Biol. Chem. 267: 4889-4896). Several of the mutants exhibited the same biochemical phenotype as classical Niemann-Pick type C (NPC) fibroblasts. Complementation analysis between these mutants and other cholesterol transport mutants with a variant biochemical phenotype has defined two complementation classes. One class is characterized by expression of the classical NPC phenotype and may represent a true cholesterol transport mutant, while the second is characterized by expression of a variant NPC phenotype and may represent a signaling defect in LDL sensitive homeostatic responses. PMID- 7852864 TI - Antithetic relationship of dietary arachidonic acid and eicosapentaenoic acid on eicosanoid production in vivo. AB - Eicosanoids are oxidative derivatives of arachidonic acid. When produced in excessive amounts, many are proinflammatory and/or prothrombotic agents. N-3 polyunsaturated fatty acids (PUFA) have been used to attenuate tissue arachidonic acid (AA, 20:4 n-6) levels and thus modulate eicosanoid production. However, there is growing evidence that dietary arachidonic acid may also be able to modulate eicosanoid formation by enriching tissue phospholipids with AA. Therefore, the effects of dietary AA and n-3 PUFA are in diametric opposition. This study investigates the antithetic relationship of dietary AA and eicosapentaenoic acid (EPA, 20:5 n-3) on fatty acid composition of hepatic phospholipids and eicosanoid production in vivo. Forty-nine CD-1 male mice were randomly divided into four dietary groups. Identical diets were supplemented with ethyl esters (1.5% w/w) of the following fatty acids: oleic acid (OA, 18:1 n-9), AA, EPA or AA+EPA. After 4 weeks on diet, peritoneal cells were stimulated in vivo with opsonized zymosan and the peritoneal exudates were analyzed for eicosanoid production (PGE2, 6-keto-PGF1 alpha, TXB2, LTB4, LTE4, and LTE5). Hepatic phospholipids were enriched with AA when AA was included in the diet, and EPA was enriched at the expense of AA when EPA was added to the diet. However, when AA was added to the diet containing equivalent amounts of EPA (AA+EPA), any effect EPA had on modulating hepatic phospholipid fatty acid composition was almost completely eliminated. Similar effects were observed with eicosanoid production. The pooled eicosanoid production in the AA group was 41% and 300% higher compared to the OA (control) and EPA groups, respectively.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7852863 TI - Three enzymes involved in oligosaccharide-lipid assembly in Chinese hamster ovary cells differ in lipid substrate preference. AB - Initial steps in N-linked glycosylation involve formation of a large oligosaccharide structure on a lipid carrier, dolichyl phosphate. We have previously characterized Chinese hamster ovary (CHO) glycosylation mutants (Lec9 cells) that utilize the polyisoprenoid lipid polyprenyl phosphate rather than dolichyl phosphate in these glycosylation reactions. Polyprenyl phosphate differs from dolichyl phosphate only in the degree of saturation of its terminal isoprenyl unit. Our goal was to determine whether the glycosylation defect of Lec9 cells could be explained simply by knowing lipid substrate preferences of the enzymes involved in the assembly of oligosaccharide-lipid (OSL) intermediates. In this study, we have used in vitro assay systems to compare the ability of dolichyl phosphate and polyprenyl phosphate to act as substrates for three glycosyl transferase enzymes involved in OSL assembly. In order to insure that we were only examining lipid substrate preferences of the enzymes and not other potential defects present in Lec9 cells, we used membranes prepared from wild-type cells in these in vitro reactions. Our results indicate that one of the enzymes, mannosylphosphoryldolichol (MPD) synthase, exhibited a significant preference for the dolichol substrate. Glucosylphosphoryldolichol (GPD) synthase, on the other hand, showed no binding specificity for the dolichol substrate, although the enzyme used the dolichol substrate at a twofold higher rate. N,N' diacetyl-chitobiosylpyrophosphoryldolichol (CPD) synthase was able to use either lipid substrate with equal efficiency. These results suggest that not all glycosyl transferases in this pathway show a preference for dolichol derivatives.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7852865 TI - Inverse relationship between plasma cholestanol concentrations and bile acid synthesis in sitosterolemia. AB - We investigated the relationship between plasma cholestanol (5 alpha dihydrocholesterol) concentrations and the activity and mRNA levels of cholesterol 7 alpha-hydroxylase, the rate-controlling enzyme for bile acid synthesis, in three female sitosterolemic homozygotes. In this lipid storage disease, large amounts of plant sterols and cholestanol accumulate because of hyperabsorption and endogenous synthesis, respectively. Plasma cholestanol concentrations were 14 times greater in the three sitosterolemic homozygotes than the mean for five control subjects. To investigate the cholestanol biosynthetic pathway, tracer doses of two putative precursors, [1,2-3H]4-cholesten-3-one and [4-14C]7 alpha-hydroxycholesterol were injected intravenously into a homozygote, and radioactivity was sought in cholestanol, bile acids, cholesterol, and sitosterol fractions isolated from plasma and bile. Tritium was concentrated only in cholestanol; neither cholesterol, sitosterol nor bile acids were derived from [1,2-3H]4-cholesten-3-one. In contrast, bile acids were labeled exclusively with 14C from [4-14C]7 alpha-hydroxycholesterol; no 14C radioactivity was detected in cholestanol. Mathematical analysis of specific activity versus time curves for [3H]cholestanol revealed very slow decay, large exchangeable pools, and enhanced synthesis in the sitosterolemic homozygote. Measurements of cholesterol 7 alpha hydroxylase activity were 39% lower in whole liver microsomes from three sitosterolemic homozygotes that contained 19% plant sterols as compared to the mean value for six control microsomal specimens that contained 0.1% plant sterols. Removal of the excess plant sterols from the microsomes, in vitro, normalized microsomal cholesterol 7 alpha-hydroxylase activity in the homozygotes but did not affect enzyme activity in the controls. Equal amounts of cholesterol 7 alpha-hydroxylase mRNA were detected in the livers of both control and sitosterolemic subjects. Bile acid malabsorption after ileal bypass surgery stimulated cholesterol 7 alpha-hydroxylase activity 78% in sitosterolemic whole liver microsomes and reduced plasma cholesterol, sitosterol, and cholestanol levels 61%, 55% and 91%, respectively, producing a pronounced decrease in the cholestanol/cholesterol ratio without changing the sitosterol/cholesterol ratio. These results demonstrate that increased cholestanol is synthesized from 4 cholesten-3-one and not 7 alpha-hydroxycholesterol in sitosterolemia. Enhanced pools and plasma concentrations are related inversely to hepatic cholesterol 7 alpha-hydroxylase activity. Competitive inhibition of cholesterol 7 alpha hydroxylase by the large microsomal plant sterol pool diverts cholesterol into cholestanol. Alternatively, stimulating cholesterol 7 alpha-hydroxylase activity after ileal bypass surgery markedly diminished plasma cholestanol levels.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7852866 TI - Non-sterol regulation of low density lipoprotein receptor gene expression in T cells. AB - Non-sterol regulation of low density lipoprotein (LDL) receptor gene expression was examined in a mitogen-responsive human T cell line. Stimulation of the leukemic T cell line Jurkat with the phorbol ester phorbol 12-myristate 13 acetate (PMA) and the calcium ionophore ionomycin rapidly and transiently increased LDL receptor mRNA levels. Inhibition of protein synthesis with cycloheximide (CHX) or puromycin resulted in superinduction of LDL receptor mRNA levels by mitogenic stimulation. The increase in LDL receptor mRNA levels resulted from increased gene transcription rather than stabilization of mRNA half life. Thus, similar results were obtained when reporter gene expression was assessed in Jurkat cells transfected with LDL receptor promoter constructs and mRNA half-life was not significantly altered by the stimuli. Neither mitogenic induction nor superinduction of LDL receptor mRNA levels in Jurkat cells was prevented by sterol downregulation of LDL receptor gene expression. The protein synthesis inhibitors CHX and anisomycin, but not puromycin, also directly stimulated LDL receptor mRNA levels, suggesting that these compounds could provide a signal required for LDL receptor gene transcription. Taken together, these data indicate that various non-sterol stimuli, including activation of protein kinase C, increases in intracellular calcium, inhibition of protein synthesis, and signals generated by the protein synthesis inhibitors CHX and anisomycin, induce LDL receptor gene expression. Thus, transcription of the LDL receptor gene is not only regulated by ambient sterols but also by a variety of influences that govern the various primary response or immediate early genes. These stimuli may play an important role in normal regulation of LDL receptor gene expression. PMID- 7852867 TI - Apolipoprotein[a] is not associated with apolipoprotein B in human liver. AB - The aim of this research was to determine whether apolipoprotein[a] (apo[a]) is linked to apolipoprotein B (apoB) in human liver. Four ELISAs were developed: 1) a competition assay that measures apoB; 2) a competition assay that measures apo[a]; 3) a capture assay based on capture of apo[a] by a polyclonal antibody and detection of co-immobilized apoB using a monoclonal antibody; and 4) a capture assay based on capture of apo[a] using a polyclonal antibody and detection of immobilized apo[a] using a monoclonal antibody. Assays 2 and 4, therefore, measure apo[a] either free or in complex with other proteins, while assay 3 measures apo[a] associated with apoB. The levels of apo[a] ranged from 25 to 440 micrograms/g liver in nine individual liver samples. There was no significant difference between apo[a] levels in individual human liver samples measured using ELISA 1 or 3; however, it was not possible to detect apo[a]/apoB using assay 3. ApoB was present in human liver homogenates at levels ranging from 90 to 700 micrograms/g measured using assay 1. These results suggest, therefore, that apo[a] is not coupled to apoB in the liver and may be secreted in the free form to bind with low density lipoprotein (LDL) in the extracellular fluid or plasma. PMID- 7852868 TI - Conditions for solid-phase extraction of urinary bile acids with octadecylsilane bonded silica. AB - Fast atom bombardment mass spectrometry was used as a detection method in a study of the extraction of urinary bile acids with octadecylsilane-bonded silica. The procedure commonly used in many laboratories was found to result in significant losses of sulfated taurine-conjugated bile acids. Losses of other double conjugates and of bile acid and bile alcohol glucuronides were also seen. The losses were avoided by addition of an equal volume of 0.5 M triethylamine sulfate to the urine before passing it through the sorbent bed. Quantitative elution was then achieved with methanol. Batch variations were observed with sorbents from two different manufacturers. PMID- 7852869 TI - [Understanding the poor results after surgery for superficial venous insufficiency]. AB - Effectiveness and value of surgical treatment in varicose veins remains difficult to assess for many reasons. They are discussed in details in front of this general review devoted to poor results after varicose vein surgery. An other pathology is often associated with venous insufficiency and is frequently missed and responsible of poor results. Many factors contribute to make uneasy assessment of poor results. The lack of objective criteria to appreciate the natural evolution of varicose disease different from one patient to another. The difficulty to grade clinical disease severity. Results published before the use of modern preoperative investigations make their report obsolete. Precise data of surgical treatment undertaken are often not detailed. The quality of therapists (surgeon or phlebologist) is uneasy to check. The difficulty to assess results after treatment: subjective results (patient) vs objective results (audit). Duration of follow-up. Imprecise vocabulary to qualify results. Clinical assessment remains the cornerstone but supplementary investigations must be undertaken. Duplex-Scan is currently accepted as the gold standard investigation. Phlebography or (and) plethysmography can be helpful in some cases. After detailed assessment patients can be classified in different groups. This classification allows to determinate the most adequate treatment. In some selected patients redosurgery is strongly recommended. Prevention of recurrence after surgical treatment of varicose veins can not be complete. Strict respect of several rules can however reduce it. They can be summarised as follows: Respect of temporary of definitive contraindications to surgical treatment. Thorough investigation before surgery. Preoperative precise aim of what must be treated by the surgical procedure. Correct operative procedure.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7852870 TI - [Deep venous thrombosis and cancer. A one year evaluation of etiologic screening of patients hospitalized in Internal Medicine]. AB - The aim of this study was to evaluate over one year the minimal etiologic screening carried out on each patient hospitalized in Internal Medicine for a deep venous thrombosis (DVT) and to search for clinical features possibly relating thrombosis to neoplasia. 53 patients (27 male and 26 female; mean age 63.6 years, range: 18-19) with DVT of the lower limbs were included in the study. The initial etiologic screening consisted of a complete clinical examination, a biological assessment (blood cell and platelet count, Activated Partial Thromboplastin Time, inflammation and liver investigations), a radiography of the thorax and abdomino-pelvic ultrasonography. This etiologic screening was evaluated one year after the thrombotic event. The initial assessment was positive in 44 cases (83% of the patients), 9 thrombosis remained unexplained. Neoplasia was identified in 8 cases (15% of the patients), the diagnosis being often evoked at the time of interrogation or during the clinical examination; the systematic biological assessment only revealed an etiology in one case: this was a primary thrombocythemia discovered by platelet count. On evaluation one year later, amount the 9 DVT unexplained by the initial screening, 8 remained totally unexplained. On the other hand, a cancer of the colon revealed by proctorrhagia during oral anticoagulant treatment, had been undiscovered. No significant difference was found between the two groups (cancers and noncancerous etiologies) as concerns age, sex, thrombus topography, the side affected or the embolic events. However, the occurrence of subsequent thrombosis under well controlled anticoagulant treatment clearly characterises thrombosis associated with neoplasia.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7852871 TI - [Functional capacity of fibrinogen and erythrocyte aggregation in the diabetic]. AB - The aim of this work is to study the possible influence of a qualitative modification of fibrinogen on its capacity of erythrocyte aggregation. Fibrinogens were isolated and then purified from blood sample of 15 insulin dependent diabetics and of 7 healthy subjects. The erythrocyte aggregative effect of the purified fibrinogens was measured for various concentrations (0 g/1-5 g/l). The erythrocyte aggregation was determined by the ECHO CELL whose functioning principle is based upon ultrasonic interferometry. Results allow one to distinguish three kinds of fibrinogen: the first kind inducing a similar erythrocyte aggregation as that obtained by the fibrinogens from healthy subjects, the second kind inducing an erythrocyte hyperaggregation, the third kind inducing an erythrocyte hypoaggregation. Thus the possibility of a qualitative abnormality of fibrinogen, affecting its erythrocyte aggregative capacity in diabetic patients, could be suggested. This qualitative abnormality of fibrinogen might be due to a modification of its molecular structure because of an abnormal elevated glycation during diabetes. PMID- 7852872 TI - [Computerized medical register of venous thromboembolic disease at the Grenoble University Hospital Center: description and evaluation]. AB - The number of vascular exams for venous thromboembolic disease increases dramatically in the vascular medicine unit at the Grenoble University Hospital (France). In order to improve the efficiency and the homogeneity of all the medical staff involved, a computerized register has been created. It automatically provides a letter for the prescriber of the consultation. This database, working on a computer network, has three main functions: office automation (medical folder, report), education, and clinical research. The office automation evaluation is performed after a 6 month experience, comparing 100 medical reports about venous thrombosis assisted by the computer to 100 medical reports written before the installation of the system. The introduction of digitized register is real, still this evaluation has induced some modification in the system in order to be more efficient. PMID- 7852873 TI - [Venous thromboembolic disease in a geriatric environment. Importance of its detection and treatment]. AB - The elderly population is particularly exposed to risk of venous thromboembolism because the risk of thrombosis increases with age but also because of the side effects of anticoagulant therapy. Clinical signs are neither sensitive nor specific and systematic screen for deep vein thrombosis in elderly patients could be justified using noninvasive techniques such as echo-Doppler or assay of D Dimers. The aim of this study was to determine the prevalence of venous thrombosis diagnosed by echo-Doppler screening in a population of institutionalized elderly subjects. The frequency of risk factors and the cost of screening and subsequent health care were also evaluated. This study included 96 patients who underwent systematic echo-Doppler measurements. Clinical, biological and echographic data were recorded on individual file-cards for analysis. The prevalence of deep vein thrombosis diagnosis was 13.5% (13/96). All the deep vein thromboses discovered were in the popliteal area. No high risk group was found and there was found and there was no significant link with clinical signs or the level of D-Dimers. The cost of diagnosis and treatment in the particular conditions of our study were 5000 and 10,700 FRF respectively for each deep vein thrombosis diagnosed. The cost of diagnostic screening and treatment should be considered in light of the life expectancy and quality of life in this population. Thus in elderly institutionalized subjects, it would appear not to be reasonable to undertake systematic screening for venous thrombosis using echo Doppler or D-Dimer assay. PMID- 7852874 TI - [Idiopathic periaortic fibrosis: a difficult diagnosis in internal medicine]. AB - Peri-aortitis retroperitoneal fibrosis is characterized by a reaction of a variable inflammatory nature while constricting the organs crossing the retroperitoneal space, notably the ureters and the blood vessels. It is difficult to diagnose such a rare disease. We bring about here six cases of periaortic retroperitoneal fibrosis diagnosed from systemic, digestive, urinary or vascular signs. Early diagnosis is often difficult and is shown to be established after an average of three months investigation. The average age of these patients, all of the male sex, is 58 years old (54 to 90). In the six cases this disease appears to be idiopathic even though in two cases it is associated to giant temporal arteritis and polymyalgia rheumatica. TDM remains the best diagnostic tool to point out the existence of this fibrosis, to observe its evolution and to investigate for any extension of the disease. The etiology of this fibrosis remains a mysterious one; however an immunologic origin has been suggested. Medical treatment by corticosteroids is often successful but the long term evolution of the disease is still uncertain. PMID- 7852875 TI - [Echo-Doppler for early diagnosis of deep venous thrombosis in orthopedic surgery and traumatology. A retrospective study of 1,647 patients]. AB - The authors report the results of duplex ultrasound scanning investigation for the detection of deep venous thrombosis after orthopedic surgery and compare asymptomatic and symptomatic populations. PURPOSE OF THE STUDY: To estimate the rate of deep venous thrombosis diagnosed by duplex scanning in those 2 populations and precise their features. MATERIAL: A total of 1,647 in-patients all receiving low-molecular-weight heparin and investigated from 1989 to 1993. either for screening because of high risk of thrombosis (asymptomatic group: 930 patients, mean age +/- SD 63 +/- 17 years) or for clinical suspicion of deep vein thrombosis (symptomatic group; 717 patients, mean age +/- SD: 57 +/- 21 years). Difference between the two groups mean ages were significant (p < 10(-8). METHODS: An Hitachi EUB 450 duplex and an Acuson colour duplex 128 XP, with 3.5 MHz and 7.5 MHz linear probes were used. Veins were tested for compressibility in transverse view from caval site to both ankles. Retrospective analysis of patients database results has been achieved. RESULTS: There was no significant difference in deep vein thrombosis rate between screening asymptomatic group (356/930:38%) and symptomatic group (253/717: 35%). There was a linear relation, in the 2 groups, between age and deep vein thrombosis rate, from 10% before twenty to 45% after eighty years old. For a relative risk to have thrombosis detected before twenty definite at 1, it was 2.1 for 20-29, 4.9 for 40-49, 6.2 for 60-69 and 8.6 later than 80 years old. Proximal deep vein thrombosis was detected in only 5% (87/1,647) of patients. Distal muscular soleal veins were the most usual involved sites of thrombosis. Isolated soleal thrombosis were detected in 16% (270/1,647) of patients. There was non significant difference between the deep vein thrombosis rate after total knee or hip arthroplasty among selected patients for duplex scanning from 1989, and the true prevalence assessed among all the patients who have undergone total hip or knee arthroplaty during the last 6 months. DISCUSSION: Pessimistic results previously reported for duplex screening among asymptomatic patients are not confirmed. Calf vein thrombosis rate assessed by duplex scanning exceeds by 15 a 20% usual rates assessed by contrast venography, among patients receiving low-molecular-weight heparins. That difference could be assigned to the isolated muscular soleal thrombosis usually missed at contrast venography. CONCLUSION: Deep vein thrombosis rate among orthopedic surgical patients, is much higher when detected with Duplex ultrasound scanning than detected with contrast venography, and is related to patient age. Screening for deep venous thrombosis by duplex scanning in orthopedic surgery is as efficient among asymptomatic as among symptomatic patients and could become soon a systematic screening. Soleal vein thrombosis are the most usual. Mechanical calf venous pump stimulation in association with low molecular weight heparin, has to be evaluated in attempting to reduce those muscular soleal veins thrombosis. PMID- 7852876 TI - [Antheor percutaneous endocaval filter. Multicenter evaluation based on 300 cases]. AB - The authors report a follow up from 6 months to 2 1/2 years concerning 300 Antheor caval filters. This multicenter study was brought about so as to assess the effectiveness of the interruption barrier as well as possible complications stemming from features of the filter. The biomechanical parameters and the specifications for the filter are presented: filtration principle, nature of the alloy and biocompatibility, self-centered doubly fixed mechanism and antimigration clipping system. The main indications taken into account are pulmonary embolism (65% of cases), floating femoro-ilio-caval thrombus (33%) and contraindications of anticoagulants. Insertion conditions are analyzed as is the technique employed almost constantly percutaneous, and somewhat more often femoral than jugulo-sub-clavian. The authors then expose the modalities of the surveillance protocol. Controls are made after 1 week, 2 months, 6 months, 12 months, 18 months, and 24 months an half. They consist of a clinical evaluation, an analysis of the nature of the anticoagulant or anti-aggregation treatment, a plain abdominal radiology, a venous duplex scan examination of the lower limbs and the inferior vena cava and, in some case, a phlebographic and scanographic examination. In terms of the effectiveness, the reported results are convincing, with a rate of only 1% of recurrent embolism and 98% of vena cava patency. PMID- 7852877 TI - [Cerebral atrophy of vascular origin in the course of neurofibromatosis]. AB - The authors report the case of a 39-year-old woman with type I neurofibromatosis who presented a right incomplete proportional hemiplegia which progressively worsened over a 6-month period. Left hemispheric atrophy with heterogeneous features, predominant in the temporoparietal region, was revealed by computerized tomography. Atrophy was associated with diffuse vascular lesions in the distal part of the left sylvian and anterior cerebral arteries, leading to major cortical hypoperfusion. Vascular examination showed no hypertension nor any sign of arterial involvement in another region. This case illustrates the nature of vasculopathy associated with neurofibromatosis. Its expression is polymorphous, with lesions inducing stenosis (the most common ones), aneurysmal lesions or veritable angiodysplasias (either hypo- or hyperplastic). The vascular expression of neurofibromatosis is often overlooked. However, in the presence of an inexplicable occlusive or aneurysmal vasculopathy, it is advisable to search for signs of neurofibromatosis since ill-defined forms exist. PMID- 7852878 TI - [Atrophic polychondritis presenting as multiple arterial stenosis. Report of a case]. AB - A case of multiple arterial stenosis is reported in a pattern with atrophic polychondritis. The disease was diagnosed retrospectively nine years after the first vascular signs on the basis of clinical course. Atrophic polychondritis is a rare connective tissue disease with characteristic chondritis. Cardiovascular involvement occurs in one-fourth of the cases during the clinical course leading to poor prognosis. Stenosis of the peripheral arteries has not been reported, to our knowledge, as the inaugural sign in atrophic polychondritis. PMID- 7852879 TI - [Ehlers-Danlos type IV syndrome presenting as renovascular hypertension]. AB - The association of Ehlers-Danlos type IV syndrome and acrogeria with renovascular hypertension is reported. Ultrastructural abnormalities observed in our case were different of those associated with acrogeria. We propose that acrogeria associated with Ehlers-Danlos type IV syndrome be a different disease of acrogeria of Gottron. The occurrence of renovascular hypertension in Ehlers Danlos is unusual. PMID- 7852880 TI - [Opto-electronic volumetry: another method for quantification of edema]. PMID- 7852881 TI - Protein kinase C in the thyroid. PMID- 7852882 TI - Time-course of vertebral and femoral bone loss in rats administered gonadotrophin releasing hormone agonist. AB - This study was carried out (1) to compare the time-course of the change in bone metabolism in rats administered gonadotrophin-releasing hormone agonist (GnRHa) and bilaterally ovariectomized (OVX) rats and (2) to investigate the changes in bone metabolism after discontinuance of GnRHa. Seventy female Sprague-Dawley rats, aged 90 days, were divided into four groups. Group 1 underwent a sham operation, group 2 was surgically ovariectomized and group 3 was given a GnRHa (leuprorelin acetate for depot suspension) s.c. injection every 30 days. Group 3 was further divided into three subgroups: rats were administered GnRHa for 12 months (GnRHa 12M), 6 months (GnRHa 6M) or 3 months (GnRHa 3M). Group 4 served as a basal control. The bone mineral density (BMD) of lumbar vertebrae and femoral bone, measured by dual-energy X-ray absorptiometry, and the serum bone metabolic parameters were determined every 45-90 days. The bone histomorphometry of lumbar vertebra was measured on days 180 and 360 after surgery. GnRHa 12M rats showed significantly lower BMD of vertebrae and femoral bone, lower bone volume and higher bone turnover compared with sham-operated rats and those with secondary hyperparathyroidism on days 180 and 360. Their time-course for changes in bone metabolism was almost the same as that of OVX rats. GnRHa-discontinued rats showed a recovery of bone turnover. The recovery of BMD in GnRHa 6M rats was smaller than that of GnRHa 3M rats after GnRHa discontinuance. The bone volume for GnRHa 6M rats was significantly lower than that for GnRHa 3M on day 360. PMID- 7852883 TI - Insulin-like growth factor-II and transforming growth factor-alpha in developing human fetal pancreatic islets. AB - To understand the development of the human pancreas better, we studied the expression and regulation of insulin, insulin-like growth factor-II (IGF-II) and transforming growth factor-alpha (TGF-alpha) genes in the human fetal pancreas and islet-like cell clusters (ICC) from the second trimester human fetuses. Northern blot analysis revealed an abundant expression of IGF-II, insulin and TGF alpha mRNAs in the intact pancreas and the cultured ICCs. Furthermore, transcripts for insulin receptor, type-1 and -2 IGF receptors, and GH receptor could be amplified by polymerase chain reaction analysis from the pancreas and the ICCs. With in-situ hybridization, IGF-II mRNA was found in abundance in both the exocrine and endocrine pancreas, exceeding the amount of insulin mRNA. In ICCs, insulin mRNA-containing cells were present as small clusters in the periphery and in the centre of the clusters corresponding to the immunolocation of insulin. The ICCs also contained many epidermal growth factor-, insulin- and type-1 IGF receptor- and TGF-alpha-positive cells. When the ICCs were cultured in the presence of various secretagogues, only dibutyryl cyclic AMP was found to up regulate insulin mRNA (39%; P < 0.05). IGF-II mRNA was also under cyclic AMP dependent regulation (threefold increase; P = 0.025). Furthermore, blocking the type-1 IGF receptor with a monoclonal receptor antibody drastically reduced insulin expression (87%; P = 0.005) and additionally down-regulated IGF-II mRNA (49%; P = 0.005). IGF-1, IGF-II, TGF-alpha or epidermal growth factor-receptor antibody had no significant effect on either insulin or IGF-II mRNA. Exogenous TGF-alpha inhibited the release of insulin by the ICCs. It was concluded that IGF II and TGF-alpha may be involved in the regulation of islet growth and differentiation. PMID- 7852884 TI - Endogenous opioid regulation of oxytocin release during parturition is reduced in ovariectomized rats. AB - Pregnant rats were ovariectomized (or sham-ovariectomized) on days 17, 18 or 21 of pregnancy and oestradiol-17 beta and progesterone were replaced. Prepartum oxytocin concentrations were significantly lower in ovariectomized steroid treated rats than in intact controls, and on day 21 of pregnancy injection of relaxin into acutely ovariectomized rats significantly increased plasma oxytocin concentrations. During parturition, injection of the opioid antagonist naloxone induced significant increases in plasma oxytocin concentration compared with saline-injected rats. The naloxone-induced increase was significantly less in ovariectomized steroid-treated rats than in rats with intact ovaries, indicating that endogenous opioid activity is less in ovariectomized rats than in intact rats. The progress of parturition in the ovariectomized steroid-treated rats was severely disrupted compared with sham-ovariectomized rats despite similar plasma oxytocin levels at the birth of pup number 2; this disruption was not overcome by injection of naloxone or by the consequent increase in oxytocin secretion, indicating deficient preparation of the uterus and birth canal in the absence of relaxin. We conclude that the decreased oxytocin concentrations prepartum, the prolongation of parturition and the decrease in opioid tone in ovariectomized steroid-treated rats may be partly due to a lack of relaxin produced by the ovary. PMID- 7852885 TI - pGlutamylglutamylprolineamide modulation of growth hormone secretion in domestic fowl: antagonism of thyrotrophin-releasing hormone action? AB - Pyroglutamyglutamylprolineamide (pGlu-Glu-ProNH2) is a tripeptide with structural and immunological similarities to thyrotrophin-releasing hormone (TRH; pGlu-His ProNH2). Since TRH stimulates GH secretion in domestic fowl, the possibility that pGlu-Glu-ProNH2 may also provoke GH release was investigated. Unlike TRH, pGlu Glu-ProNH2 alone had no effect on GH release from incubated chicken pituitary glands and did not down-regulate pituitary TRH receptors. However, pGlu-Glu ProNH2 suppressed TRH-induced GH release from pituitary glands incubated in vitro and competitively displaced [3H]methyl3-histidine2-TRH from pituitary membranes. Systemic injections of pGlu-Glu-ProNH2 had no significant effect on basal GH concentrations in conscious birds, but promptly lowered circulating GH levels in sodium-pentobarbitone anaesthetized fowl. Submaximal GH responses of conscious and anaesthetized birds to systemic TRH challenge were, however, potentiated by prior or concomitant administration of pGlu-Glu-ProNH2. These results demonstrate, for the first time, that pGlu-Glu-ProNH2 has biological activity, with inhibitory and stimulatory actions within the avian hypothalamo-pituitary axis. These results indicate that pGlu-Glu-ProNH2 may act as a TRH receptor antagonist within this axis. PMID- 7852886 TI - Plasma measurements of corticotrophin-releasing hormone-binding protein in normal and abnormal human pregnancy. AB - Using corticotrophin-releasing hormone-binding protein (CRHBP) purified from human plasma and a 25 amino acid peptide corresponding to the C-terminus of CRHBP we have been able to produce rabbit polyclonal antisera specific for CRHBP. This has allowed the development of a radioimmunoassay which is able to detect CRHBP specifically in human plasma regardless of the presence of endogenous CRH. We have used this assay to estimate the level of CRHBP in non-pregnant human plasma to be approximately 20 nmol/l with a range of 9.1-40.6 nmol/l. We have also examined sequential plasma samples taken from 84 normal pregnant women at fortnightly intervals from 16 weeks gestation through to term. Four women were also sampled during labour and the first week postpartum. The median plasma level of CRHBP at week 16 of normal pregnancy was 21.59 nmol/l, levels rose slightly during the early part of the third trimester (26.76 nmol/l at week 30, (P < 0.01) and fell markedly towards term (19.72 nmol/l, P < 0.01) with only 8.70 nmol/l at labour. CRHBP levels returned to normal non-pregnant levels within 48 h of parturition suggesting a role for the fetoplacental unit in CRHBP production. In eight pregnancies complicated by diabetes, CRHBP levels at each gestational age were similar to those recorded for normal pregnancy. However, in pregnancies complicated by pre-term labour (n = 9) and pre-eclampsia (n = 7), plasma CRHBP levels were significantly reduced (P < 0.01). PMID- 7852887 TI - Glucagon-like peptide-1 (7-36)amide and glucose-dependent insulinotropic polypeptide secretion in response to nutrient ingestion in man: acute post prandial and 24-h secretion patterns. AB - The acute effects of different macronutrients on the secretion of glucagon-like peptide-1(7-36)amide (GLP-1(7-36)amide) and glucose-dependent insulinotropic polypeptide (GIP) were compared in healthy human subjects. Circulating levels of the two hormones were measured over a 24-h period during which subjects consumed a mixed diet. In the first study, eight subjects consumed three equicaloric (375 kcal) test meals of carbohydrate, fat and protein. Small increases in plasma GLP 1(7-36) amide were found after all meals. Levels reached a maximum 30 min after the carbohydrate and 150 min after the fat load. Ingestion of both carbohydrate and fat induced substantial rises in GIP secretion, but the protein meal had no effect. In a second study, eight subjects consumed 75 g glucose or the equivalent portion of complex carbohydrate as boiled brown rice or barley. Plasma GIP, insulin and glucose levels increased after all three meals, the largest increase being observed following glucose and the smallest following the barley meal. Plasma GLP-1(7-36)amide levels rose only following the glucose meal. In the 24-h study, plasma GLP-1(7-36)amide and GIP concentrations were increased following every meal and remained elevated throughout the day, only falling to fasting levels at night. The increases in circulating GLP-1(7-36)amide and GIP levels following carbohydrate or a mixed meal are consistent with their role as incretins. The more sustained rises observed in the daytime during the 24-h study are consistent with an anabolic role in lipid metabolism. PMID- 7852888 TI - Effects of consumption of milk and milk constituents on plasma concentrations of gastric inhibitory polypeptide and metabolites in preruminant goat kids. AB - Plasma concentrations of gastric inhibitory polypeptide (GIP) were measured in preruminant goat kids before and after consumption of milk, skimmed milk or solutions of milk fat, lactose, glucose or casein plus lactose. GIP concentrations increased significantly within 1 h of consumption of milk or milk fat, and were elevated for the remainder of the 5-h sampling period. The integrated mean change in GIP concentration during this period did not differ between these two meals. GIP levels were slightly increased above basal values 5 h after skimmed milk consumption, probably reflecting the absorption of a small amount of fat, but overall there was no significant GIP response to this or to any of the other test meals. The marked increase in GIP concentration after a milk feed indicates a physiological role for the hormone in preruminants but, in contrast to the situation in simple-stomached animals, carbohydrate absorption does not elicit GIP secretion in the preruminant goat. The data strongly suggest that fat is the major nutrient to stimulate GIP secretion in these animals. PMID- 7852889 TI - In-vitro effects of insulin-like growth factor-I on gill Na+,K(+)-ATPase in coho salmon, Oncorhynchus kisutch. AB - The effect of ovine GH (oGH) in vivo and recombinant bovine insulin-like growth factor-I (rbIGF-I) in vitro on gill Na+,K(+)-ATPase activity was investigated in two seasonal experiments conducted during the parr-smolt transformation period of coho salmon. In 1991, when fish were held under a photoperiod of 12 h light : 12 h darkness, the stimulatory effect of oGH (1 microgram/g) on gill Na+,K(+)-ATPase in vivo decreased at the time of expected parr-smolt transformation. Gill Na+,K(+)-ATPase from control fish was insensitive to rbIGF-I in vitro from February to June, whereas GH treatment induced sensitivity to rbIGF-I (100-1000 micrograms/l) in vitro in February and March, but not later in development. In 1992, when fish were held under natural conditions, oGH (4 micrograms/g) stimulated gill Na+,K(+)-ATPase in vivo from February to July. There was, however, of pronounced developmental change in sensitivity of gill Na+,K(+) ATPase to rbIGF-I in vitro. In February, gills from control fish were insensitive, but oGH treatment in vivo induced sensitivity to rbIGF-I in vitro (100-1000 micrograms/l). In April and May, control fish were sensitive to rbIGF-I in vitro. This sensitivity was not further potentiated by oGH treatment in vivo. In June, gills from control or oGH-treated fish were not sensitive to rbIGF-I in vitro, but in July exogenous oGH again induced gill tissue sensitivity to rbIGF-I at 1000 micrograms/l. Both studies showed that rbIGF-I stimulates gill Na(+),K(+) ATPase directly; an ability that may depend on priming by endogenous or exogenous GH. This supports the role of IGF-I as an endocrine mediator for GH action during parr-smolt transformation. PMID- 7852890 TI - 19-Hydroxyandrostenedione amplifies the hypertensive action of mineralocorticoids in rats. AB - We have reported that 19-hydroxyandrostenedione (19-OH-A-dione) amplifies the sodium-retaining action of aldosterone. To evaluate whether it also amplifies the hypertensive action of small doses of aldosterone, mononephrectomized rats were given 0.5 mg aldosterone, 10 mg 19-OH-A-dione or a combination of both once a week for 19 weeks, and changes in blood pressure were evaluated. Rats were given 154 mmol NaCl/l to drink. The blood pressure of controls, rats given aldosterone alone, 19-OH-A-dione alone or a combination of both in week 19 were 137 +/- 4 (S.E.M.), 146 +/- 7, 147 +/- 4 and 191 +/- 8 mmHg respectively. The blood pressure of rats given the combination was significantly higher than any of the other three groups. These results indicate that 19-OH-A-dione amplifies the hypertensive action of aldosterone and may be considered a potent hypertensive agent in the presence of aldosterone. To evaluate whether 19-OH-A-dione amplifies the hypertensive action of small doses of deoxycorticosterone acetate (DOCA), another experiment was carried out in which similar rats were given 5 mg DOCA or a combination of 5 mg DOCA and 10 mg 19-OH-A-dione once a week for 8 weeks. The blood pressure of controls, rats given DOCA alone and a combination of DOCA and 19-OH-A-dione in week 8 were 139 +/- 5, 166 +/- 7 and 208 +/- 12 mmHg respectively. The blood pressure of rats given a combination of DOCA and 19-OH-A dione was significantly higher than that of control rats or the rats given DOCA alone. These results indicate that 19-OH-A-dione can also amplify the hypertensive action of DOCA. It is concluded that 19-OH-A-dione amplifies the hypertensive action of mineralocorticoids as well as the sodium-retaining action of aldosterone. PMID- 7852891 TI - Episodic and seasonal rhythms of cortisol secretion in male Eld's deer (Cervus eldi thamin). AB - Episodic and seasonal rhythms of cortisol secretion were evaluated in six adult Eld's deer (Cervus eldi thamin) stags. Plasma cortisol was measured in serial blood samples collected via remote catheterization every 10 min for 10 h within 2 weeks of the summer solstice (21 June), autumn equinox (22 September), winter solstice (21 December) and spring equinox (20 March), and in weekly blood samples collected from sedated stags. Cortisol was secreted episodically at a rate of approximately 0.6 peaks/h. Based on quantitative peak detection analyses of each 10-h data series, no overall seasonal differences (P > 0.05) were detected in the number of peaks (mean range, 5.7-6.2), maximal peak height (mean range, 30.1-40.8 nmol/l), mean peak height as per cent increase (mean range, 158-168%), mean interval between peaks (mean range, 80.1-88.6 min), mean peak width (mean range, 55.1-65.1 min) and mean peak area under the curve (mean range, 675-816 nmol/l min). Based on weekly blood sampling, spring cortisol concentrations were elevated (P < 0.05) compared with summer and autumn concentrations. However, when mean cortisol concentrations derived from the 10-h quarterly data sets were analysed, no seasonal differences (P > 0.05) were detected. The present study represents the first detailed confirmation of episodic cortisol secretion in any cervid. Results (1) indicate that Eld's deer stags lack a distinct seasonal rhythm of cortisol secretion and (2) clearly illustrate the need for frequent blood sampling in fully conscious individuals to ensure accurate assessment of adrenal status in cervids. PMID- 7852892 TI - [125I]iodomelatonin-binding sites in the bursa of Fabricius of birds: binding characteristics, subcellular distribution, diurnal variations and age studies. AB - The melatonin-binding sites in membrane preparations of the bursa of Fabricius of birds were studied using [125I]iodomelatonin as a radioligand. The binding sites were stable, saturable, reversible and of high affinity. Scatchard analysis of specific binding revealed equilibrium binding constants (Kd) of (means +/- S.E.M.) 43.1 +/- 5.9, 73.3 +/- 7.6 and 35.3 +/- 4.8 pmol/l respectively at the mid-point of the light period (mid-light) in chickens, pigeons and quail, with a total number of binding sites (Bmax) of 1.23 +/- 0.15, 1.33 +/- 0.18 and 0.94 +/- 0.07 fmol/mg protein. The diurnal variation in [125I]iodomelatonin binding showed that the Bmax was 45, 115 and 70% higher at mid-light than at mid-dark in the bursae of chickens, pigeons and quail respectively. The Kd value determined from kinetic analysis was 49.0 +/- 6.4 pmol/l at mid-light in the chicken bursa. The [125I]iodomelatonin-binding sites of chicken bursal membranes had the following order of pharmacological affinities: 2-iodomelatonin > melatonin > 6 chloromelatonin > 6-hydroxymelatonin > N-acetyl-serotonin > 5-hydroxytryptamine, tryptamine, 5-methoxytryptophol, 1-acetylindole-3-carboxaldehyde, 3-acetylindole, L-tryptophan, 5-hydroxyindole-3-acetic acid, 5-hydroxytryptophan suggesting that the [125I]iodomelatonin-binding sites were highly specific for melatonin. The subcellular distribution of binding sites in the chicken bursa was in the following descending order: nuclear > mitochondrial > microsomal > cytosolic fraction. There was an age-related decrease in [125I]iodomelatonin-binding in chicken bursal membranes, with higher densities in the neonate.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7852893 TI - Vitamin D hydroxylases and their regulation in a naturally vitamin D-deficient subterranean mammal, the naked mole rat (Heterocephalus glaber). AB - The vitamin D hormone 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) is generated by a series of hydroxylation steps in the liver and kidneys. We investigated whether naturally vitamin D-deficient subterranean mammals (naked mole rats, Heterocephalus glaber) employ the same enzymatic pathways, and whether these are regulated in a similar manner to that established for other mammals. Vitamin D3 25-hydroxylase in the liver and both 25-hydroxyvitamin D3-1-hydroxylase and 25 hydroxyvitamin D3-24 hydroxylase (1-OHase and 24-OHase) in the kidney were detectable in mole rats. As expected for vitamin D-deficient mammals, the 1-OHase activity predominated over the 24-OHase. After mole rats received a supraphysiological supplement of vitamin D3, 1-OHase activity was suppressed and 24-OHase activity was enhanced. Irrespective of vitamin D status, forskolin (a protein kinase A activator) and dibutyryl cyclic AMP did not alter the activity of either 1-OHase or 24-OHase. These findings suggest that the response of renal hydroxylases to parathyroid hormone was blunted. Phorbol esters, 12-O tetradecanoylphorbol 13-acetate (TPA) and 1-oleoyl-2-acetylglycerol (OAG) (protein kinase C activators), suppressed 1-OHase activity. 24-OHase activity was induced by TPA but not by OAG. These effects were similar to those illicited by vitamin D3 supplementation but were additive in that they increased the responses shown in vitamin D-replete mole rats. These data confirm that naturally vitamin D deficient mole rats can convert vitamin D3 to the hormone, 1,25(OH)2D3.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7852894 TI - Phospholipid methylation decreases in human chorionic gonadotrophin-induced desensitized rat Leydig cells. AB - Phospholipid methylation in Leydig cells from desensitized rats was studied. The incorporation of L-[methyl-3H]methionine into phospholipids in intact Leydig cells decreased when animals were injected with a single high dose of human chorionic gonadotrophin (hCG). This effect was detected on the first day after hCG injection and remained up to 12 days after treatment. The inhibition was not due to a reduced uptake of L-[methyl-3H]methionine. A decreased phospholipid methylation with unaltered phospholipid methyltransferase activity was observed on days 1, 6 and 12 after the hCG. On day 3 after hCG injection, phospholipid methyltransferase activity and phospholipid methylation in intact Leydig cells were both inhibited by 40%. Also, a minimal amount of LH free receptors and the lowest number of total receptors was observed at this time. Thus, a relationship between the reduced enzymatic activity and the maximal decrease in LH surface receptors is suggested. In addition, the decreased incorporation of L-[methyl 3H]methionine into phospholipids on days 1, 6 and 12 after hCG injection, could be associated with other cellular changes related to the desensitization process. PMID- 7852895 TI - Modulation of the prostaglandin responses of conscious rabbits to the pyrogen polyinosinic:polycytidylic acid by corticotrophin-releasing factor-41. AB - The pyrogenic interferon inducer polyinosinic:polycytidylic acid (Poly I:C) was shown to stimulate rises in both prostaglandin E2 (PGE2) and prostaglandin F2 alpha (PGF2 alpha) in conscious rabbits in vivo. Poly I:C (2.5 micrograms/kg) stimulated a fivefold rise in circulating immunoreactive (ir) PGE2, with a lag phase of 60 min, which was sustained during the subsequent 4-h period of observation. Poly I:C also stimulated a 2.5-fold rise in circulating irPGF2 alpha with a lag phase of 90 min, which was followed by a return to basal levels after 5 h. The rises in circulating irPGE2 and irPGF2 alpha stimulated by Poly I:C were prevented by pretreatment with the non-steroidal anti-inflammatory drug ketoprofen. Both the irPGE2 and irPGF2 alpha responses to Poly I:C (2.5 micrograms/kg, i.v.) were antagonized by the corticotrophin-releasing factor-41 (CRF-41) receptor antagonist (alpha-helical CRF (9-41), 25 micrograms/kg, i.v.) administered 5 min prior to the pyrogen. Peripheral immunoneutralization using an anti-CRF-41 monoclonal antibody (KCHMB001, 2.5 mg/kg, i.v.) administered 5 min prior to the pyrogen, also inhibited both the PGE2 and PGF2 alpha responses to Poly I:C (2.5 micrograms/kg, i.v.). However, control mouse IgG also inhibited the PGE2 response. In conclusion, these results suggest a modulatory role for endogenous peripheral CRF-41 in the circulating prostaglandin responses to the pyrogen Poly I:C and this effect may be responsible for the antipyretic actions of peripherally administered CRF-41 antagonists and antibodies. PMID- 7852896 TI - Growth hormone secretion in the horse: unusual pattern at birth and pulsatile secretion through to maturity. AB - A heterologous radioimmunoassay was developed and validated for the measurement of horse GH in plasma. It utilized recombinant-derived bovine GH as the radiolabelled ligand, a guinea-pig anti-porcine GH serum as first antibody and pituitary-derived horse GH as standard. Cross-reactivities were high with all of the pituitary and recombinant-derived GH preparations tested (49-140%) and very low (< 0.3%) with horse FSH, LH and prolactin. A synthetic analogue of GH releasing factor(1-29) stimulated the expected pattern of GH release in foals. Plasma GH concentrations in foals were low at birth (< 20 ng/ml) but rose sharply to a definite and, in most cases, very large peak (18-195 ng/ml) during the first 30-40 min post partum, followed by a steady decline to basal levels again by 60 100 min post partum. GH secretion was clearly pulsatile in all older foals tested (2 weeks, 1 month and 4 months of age) and in six adults (three mares and three stallions), all bled at 15-min intervals for 7-8 h. Basal levels and pulse amplitudes were higher in foals than in adults and pulse frequency was higher in stallions than in mares (3-5 pulses/8 h vs 1-2 pulses/8 h). Pulsatile secretion was further characterized in one mare by simultaneous sampling of jugular vein and pituitary cavernous sinus blood. Peak GH concentrations in cavernous sinus blood draining the pituitary gland were more than tenfold higher than the corresponding peak concentrations in peripheral circulation.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7852897 TI - Presence of growth hormone-binding proteins in cattle plasma and milk. AB - The presence of GH-binding proteins (GHBPs) in the plasma of adult cattle was investigated using Sephadex G-200 filtration, Western ligand blotting and Western blotting. The changes in the concentration of GHBP in the plasma of dairy half sister heifers during the first year of life as well as the presence of GHBP in milk were also investigated. When analytical chromatography (on a 1.6 x 100 cm column) was performed, five peaks of recombinant bovine GH (rbGH)-associated radioactivity were revealed in cattle plasma; the first peak, which appeared near the void volume, was presumed to represent aggregates, the second (M(r) 290 kDa) and the third peaks (M(r) 75 kDa) corresponded to specific rbGH-GHBP complexes; the last two peaks representing free 125I-labelled rbGH and Na[125I]. Western ligand blotting revealed multiple GHBPs. Three major bands were observed at approximately 190, 58 and 31 kDa; an excess of unlabelled hormone blocked the binding of 125I-labelled rbGH. Minor non-specific binding bands were also detected in cattle plasma with molecular weights between 40 and 136 kDa. One monoclonal antibody (8H7) produced against synthetic peptide (amino acids 54-63 of the extracellular domain of the bovine GH receptor) specifically interacted with 190 and 58 kDa bands while the 31 kDa band was not recognized. Finally, Western ligand blots were performed to evaluate the changes in plasma GHBP during the first year of life in 55 dairy half-sister heifers and to identify GHBP in milk. In plasma, the intensity of the 31 kDa band varied greatly between animals while the other specific bands remained stable.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7852898 TI - Radioimmunoassay of mouse vas deferens protein: developmental profile and hormonal regulation. AB - This study investigated the hormonal regulation of the developmental pattern of a major protein of the mouse vas deferens (MVDP) which represents 10% of the vas deferens protein content. Using a specific radioimmunoassay, MVDP was first detected in 10-day-old males and its concentration increased sharply between 10 and 30 days, reaching adult levels at 40 days. In adult males, MVDP disappeared after castration, and testosterone treatment for 15 days was necessary to reverse the effect of castration completely. In 10-day-old mice castrated at birth, MVDP levels were similar to those measured in controls of the same age. Testosterone administration from 1 to 10 days of age did not induce precocious accumulation of MVDP. These results suggested that the neonatal expression of MVDP is independent of androgens. From 10 to 30 days, the increase in MVDP levels was androgen dependent as shown by the castration and injection experiments. In males castrated at birth, the androgen-induced accumulation of MVDP was greatly reduced in adulthood. This suggested that neonatal androgens are necessary to obtain full expression of the MVDP gene in adults. PMID- 7852899 TI - Locomotory energetics and metabolic fuel reserves of the Virginia opossum. AB - Marsupials have lower resting metabolic rates than placental mammals, but it is not clear whether particular species can extend this energetic advantage to locomotion. Some active marsupials have a low cost of locomotion, but other more sedentary species, such as the Virginia opossum, appear to run very inefficiently. Steady-state rates of O2 consumption (VO2) and CO2 production (VCO2) were measured at rest and during horizontal treadmill exercise in wild caught, trained opossums. Average daily VO2 in in undisturbed animals was 7.73 +/ 0.40 ml O2 kg-1 min-1 (5.67 +/- 0.20 ml O2 kg-1 min-1 during light and 9.84 +/- 0.81 ml O2 kg-1 min-1 during dark hours, mean +/- S.E.M., N = 6). Net cost of locomotion ranged between 6.16 and 8.99 J kg-1 s-1 as speed increased and was always higher than for an average mammal of equivalent mass. Net cost of transport decreased as speed increased and was 15-80% higher than for an average mammal. During aerobic locomotion, most of the energy was provided by carbohydrate oxidation, which accounted for 60-95% of VO2 as speed increased. Glycogen and triglyceride reserves were quantified in the major storage depots to estimate potential survival time and travelling distance. Enough metabolic fuel was stored to survive for at least 1 week without eating, and 95% of this energy was in adipose tissue triglycerides. However, maximal travelling distance was less than 2 km because opossum locomotion is mainly supported by carbohydrate reserves, which represented only 4% of the available energy. We conclude that aerobic, ground locomotion of Virginia opossums is associated with two major energetic handicaps because their particularly high cost of transport and the nature of the main oxidative fuel they consume are both incompatible with prolonged locomotion. PMID- 7852900 TI - The effect of ATP-sensitive potassium channel modulation on heart rate in isolated muskrat and guinea pig hearts. AB - Muskrats (Ondontra zibethicus) are common freshwater diving mammals exhibiting a bradycardia with both forced and voluntary diving. This bradycardia is mediated by vagal innervation; however, if hypoxia is present there may be local factors that also decrease heart rate. Some of these local factors may include ATP sensitive potassium channel activation and extracellular accumulation of potassium ions, hydrogen ions and lactate. The purpose of this study was to investigate the role of these factors in the isolated perfused hearts of muskrats and of a non-diving mammal, the guinea pig. Although lactate and proton administration reduced heart rate in isolated muskrat and guinea pig hearts, there was no difference in the response to lactate and proton infusion between the two species. Muskrat hearts were more sensitive to the heart-rate-lowering effects of exogenously applied potassium than were guinea pig hearts. Early increases in extracellular potassium concentration during hypoxia are thought to be mediated by the ATP-sensitive potassium channel. Activation of these channels under normoxic conditions had a mildly negative chronotropic effect in both species; however, activation of these channels with Lemakalim under hypoxic conditions caused the guinea pig heart to respond with an augmented bradycardia similar to that seen in the hypoxic muskrat heart in the absence of drugs. Inhibition of these channels by glibenclamide during hypoxia was partially successful in blocking the bradycardia in guinea pig hearts, but inhibition of the same channels in hypoxic muskrat hearts had a damaging effect as two of five hearts went into contracture during the hypoxia. Thus, although ATP-sensitive potassium channels appear to have a major role in the bradycardia of hypoxia in guinea pigs, the failure to prevent the bradycardia by inhibition of these channels in muskrat hearts suggests that multiple factors are involved in the hypoxia-induced bradycardia in this species. PMID- 7852901 TI - The efficiency of frog ventricular muscle. AB - Mechanical power and oxygen consumption (VO2) were measured simultaneously from isolated segments of trabecular muscle from the frog (Rana pipiens) ventricle. Power was measured using the work-loop technique, in which bundles of trabeculae were subjected to cyclic, sinusoidal length change and phasic stimulation. VO2 was measured using a polarographic O2 electrode. Both mechanical power and VO2 increased with increasing cycle frequency (0.4-0.9 Hz), with increasing muscle length and with increasing strain (= shortening, range 0-25% of resting length). Net efficiency, defined as the ratio of mechanical power output to the energy equivalent of the increase in VO2 above resting level, was independent of cycle frequency and increased from 8.1 to 13.0% with increasing muscle length, and from 0 to 13% with increasing strain, in the ranges examined. Delta efficiency, defined as the slope of the line relating mechanical power output to the energy equivalent of VO2, was 24-43%, similar to that reported from studies using intact hearts. The cost of increasing power output was greater if power was increased by increasing cycle frequency or muscle length than if it was increased by increasing strain. The results suggest that the observation that pressure-loading is more costly than volume-loading is inherent to these muscle fibres and that frog cardiac muscle is, if anything, less efficient than most skeletal muscles studied thus far. PMID- 7852902 TI - Respiratory rhythm in the isolated central nervous system of newborn opossum. AB - 1. Respiratory activity was recorded from spinal ventral roots in the isolated intact central nervous system (CNS) of newborn opossum, Monodelphis domestica. These signals occurred in synchrony with movements of the ribs and the electromyogram (EMG) recorded from the intercostal muscles during inspiration. Rhythmical activity could be recorded for more than 6 h in acute preparations. 2. The rhythm-generating region was shown to be located in the lower brain stem by perfusing different CNS regions with medium containing 20 mmoll-1 Mg2+, which blocks synaptic transmission reversibly in the opossum CNS. The conclusion that respiration was generated by neurones in the lower brain stem was further confirmed by selective ablation of part of the CNS. 3. Recordings were made from 128 neurones in the respiratory region of the lower brain stem with activity related to the respiratory rhythm. They consisted of two inspiratory groups and two expiratory groups. In the groups of inspiratory units, recordings were made from 69 early inspiratory and 38 inspiratory units. In the groups of expiratory units, recordings were made from 17 post-inspiratory and 4 expiratory units. The sites of 22 respiratory neurones were marked in 4-day-old animals by injecting Pontamine Sky Blue. These neurones were distributed from 175 microns anterior to 525 microns posterior to the obex, from 225 to 450 microns lateral to the midline and from 175 to 425 microns deep to the ventral surface of the brain stem. 4. The respiratory rhythm recorded in the isolated CNS was influenced by pH and neurotransmitters. The respiratory rate decreased by about 26% at high pH (7.7) and increased by about 33% at low pH (7.1). Bath application of noradrenaline (30 100 mumol l-1) decreased the respiratory rate and increased the amplitude of the rhythmic bursts significantly. All these effects were reversible. 5. The results presented here indicate that the isolated intact CNS of newborn opossum offers advantages for exploring mechanisms responsible for generating the respiratory rhythm. PMID- 7852903 TI - Regulation of feeding behavior in adult Drosophila melanogaster varies with feeding regime and nutritional state. AB - The regulation of feeding behavior in adult Drosophila melanogaster includes such elements as ingestion responsiveness, volume ingested in a single meal, food storage in the crop and rate of defecation. Our results suggest that feeding behavior varies in a manner dependent on feeding regime (food-deprived or ad libitum-fed) and nutritional state. Fed flies that are subsequently food-deprived become increasingly more responsive to food stimuli over time and, when offered 1% agar diets containing different concentrations of sucrose, ingest greater amounts of diets that have higher sucrose concentrations. When fed ad libitum for 72 h on these same diets, D. melanogaster maintained much smaller crops on average than food-deprived flies fed a single meal. Additionally, ad-libitum-fed flies are grouped into two categories depending on the concentration of sucrose in the diet. Flies fed for 72 h on 1% agar diets having 50 mmoll-1 sucrose or more are not affected by the concentration of sucrose in the diet, while flies fed on diets of 15 or 25 mmoll-1 sucrose increase ingestion responsiveness, crop size and the rate of defecation with decreasing concentrations of sucrose in the diet. Flies fed on even lower sucrose concentrations (5 or 10 mmoll-1 sucrose) for 27-72 h exhibit both a shift over time to larger crop sizes and increased mortality over those of flies fed 15 mmoll-1 sucrose. These data suggest that flies fed ad libitum are capable of modulating their feeding behavior in response to their nutritional state. PMID- 7852904 TI - Substrate structure and amino acid/K+ symport in brush-border membrane vesicles from larval Manduca sexta midgut. AB - The effects of amino acid sidechain length, substituent position and c chirality on amino acid/K+ symport have been examined in rapid filtration experiments on brush-border membrane vesicles prepared from larval Manduca sexta midgut. Cis inhibition and trans-stimulation protocols were used to examine the effects of amino acid analogs on the uptake of alanine, phenylalanine, leucine and lysine, which are cotransported with K+ by a zwitterionic symporter at the high pH characteristic of the midgut in vivo. The symporter was found to translocate both L- and D-stereoisomers of alanine, leucine and lysine, but only the L-form of phenylalanine. Alterations to substrate structure that leave the charge distribution unchanged do not affect symport. Thus, moving the methyl group from C-3 to C-5 in the sequence isoleucine, leucine and norleucine has no effect on their ability to inhibit leucine symport. Increasing sidechain length among alanine homologs has little effect on their ability to inhibit alanine uptake, but increasing the sidechain length of lysine homologs from 1 to 3 methylene groups enhances cis-inhibition and trans-stimulation of lysine symport. The substantial difference in molecular charge distribution among aminobutanoic acid isomers has a large impact on alanine symport with only alpha- (or 2-) aminobutanoic acid functioning as an alanine analog. Only those changes in substrate structure that are coupled to the molecular charge distribution seem to affect symport. The tolerance of the symporter may reflect a balance mandated by the conflicting demands of selectivity and throughput. PMID- 7852905 TI - Dynamic and static stability in hexapedal runners. AB - Stability is fundamental to the performance of terrestrial locomotion. Running cockroaches met the criteria for static stability over a wide range of speeds, yet several locomotor variables changed in a way that revealed an increase in the importance of dynamic stability as speed increased. Duty factors (the fraction of time that a leg spends on the ground relative to the stride period) decreased to 0.5 and below with an increase in speed. The duration of double support (i.e. when both tripods, or all six legs, were on the ground) decreased significantly with an increase in speed. All legs had similar touch-down phases in the tripod, but the shortest leg, the front one, lifted off before the middle and the rear leg, so that only two legs of the tripod were in contact with the ground at the highest speeds. Per cent stability margin (the shortest distance from the center of gravity to the boundaries of support, normalized to the maximum possible stability margin) decreased with increasing speed from 60% at 10 cms-1 to values less than zero at speeds faster than 50 cms-1, indicating instances of static instability at fast speeds. The center of mass moved rearward or posteriorly with respect to the base of support as speed increased. Moments about the center of mass, as shown by the center of pressure (the equivalent of a single 'effective' leg), were variable, but were balanced by opposing moments over a stride. Thus, hexapods can exploit the advantages of both static and dynamic stability. Static or quasi-static assumptions alone were insufficient to explain straight-ahead, constant-speed locomotion and may hinder discovery of behaviors that are dynamic, where kinetic energy and momentum can act as a bridge from one step to the next. PMID- 7852906 TI - The effects of altering extracellular potassium ion concentration on the membrane potential and circadian clock of Paramecium bursaria. AB - In some neural models of circadian rhythmicity, membrane potential and transmembrane flux of potassium and calcium ions appear to play important roles in the entrainment and central mechanisms of the biological clock. We wondered whether these cellular variables might be generally involved in circadian clocks, even non-neural clocks. Therefore, we tested the impact of changing extracellular potassium level on the circadian rhythm of photoaccumulation of Paramecium cells, whose membrane potential responds to changes of extracellular potassium in a manner similar to that of neurones. We found that pulse or step changes of extracellular potassium concentration did not phase-shift the circadian clock of P. bursaria cells in a phase-specific manner. Furthermore, modifying the extracellular concentration of calcium did not affect the magnitude of light induced phase resetting. Therefore, while membrane potential and calcium fluxes may be crucial components of the circadian clock system in some organisms, especially in neural systems that involve intercellular communication, the P. bursaria data indicate that membrane potential changes are not necessarily an intrinsic component of circadian organization at the cellular level. PMID- 7852907 TI - Heterothermy, torpor, respiratory gas exchange, water balance and the effect of feeding in Gould's long-eared bat Nyctophilus gouldi. AB - The effects of temperature and nutritional status on the metabolic rate of Nyctophilus gouldi were examined. Bats fed marked meals first defecated approximately 1.34 h after feeding and were calculated to have a mean retention time of 5.38 +/- 0.57 h but to be truly post-absorptive after 9 h. Over the temperature range 1-35 degrees C, the metabolic rate (Vo2) and body temperature (Tb) of fasted bats were extremely labile. Below 30 degrees C, the bats all entered torpor and between 10 and 15 degrees C showed a mean 84% reduction over the maximal Vo2. Body temperature was also minimal over this range (Tb = 12.5 degrees C, Ta = 10-15 degrees C). Both total and dry thermal conductance increased in a curvilinear manner with temperature, total conductance from 3.38 +/- 0.65 J g-1 h-1 degree C-1 at 1 degree C to 24.25 +/- 1.99 J g-1 h-1 degree C 1 at 35 degrees C (mean +/- S.E.M.), while the rate of evaporative water loss increased with Ta by a maximum of 10-fold from 0.21 mg g-1 h-1 at 5 degrees C to 2.69 mg g-1h-1 at 35 degrees C. Between 10 and 25 degrees C, intermittent respiration characterised by episodic bouts of breathing/gas exchange and periods of apnoea with no measurable Vo2 occurred. Although the duration of apnoea decreased when temperature was increased, the volume of oxygen taken up in each episode did not change. Mean respiratory exchange ratio (RER) was low (0.64-0.77) in post-absorptive bats, typical of fat utilisation, but during torpor ranged from near 0 to near 2, indicating discontinuous and disproportional gas exchange. Feeding produced a condition of relatively sustained homeothermy and high RER in the bats which persisted for 9 h, after which the N. gouldi became torpid. Immediately after feeding, the Vo2 of the bats increased fivefold above the post absorptive level, while the Vco2 increased by more than eightfold. Similarly, body temperature also increased, declining to torpid values after 9. The RER in immediately post-feeding bats was near 1.0 but subsequently declined to near 0.7, indicating a switch from carbohydrate to fat utilisation. Therefore, the N. gouldi were heterothermic, exhibited a highly labile metabolic rate, and rates of heat and water loss, and Tb which were influenced both by ambient temperature and by nutritional status. PMID- 7852908 TI - Embryonic and larval respiration in the arboreal foam nests of the African frog Chiromantis xerampelina. AB - In Zimbabwe, female Chiromantis xerampelina construct spherical foam nests that are suspended above temporary water. The nests average 624 ml in volume and contain 854 eggs. The 1.7 mm ova have exceptionally thin jelly capsules and are dispersed in the foamy core of the nest, which is surrounded by a layer of eggless foam. At 25 degrees C, each embryo requires 3.5 days to reach hatching at developmental stage 22, during which it consumes 30 microliters of oxygen. After hatching, each larva remains in the nest for 2 more days and consumes a further 123 microliters of oxygen. The fresh foam contains 77% air, which is sufficient to supply all of the oxygen requirements of the embryos until well after they hatch. Therefore, the size of the egg mass is not limited by oxygen availability as it is in many other anurans. Oxygen also diffuses into the nest from the atmosphere, but the rate is severely restricted by the wet foam, despite the presence of bubbles. Drying of the outer layer of foam greatly increases its oxygen conductance, but the larvae remain in the inner core of wet foam, where they compete for oxygen at the periphery. With further drying of the nest, the wet foam diminishes in volume and concentrates the larvae at a time when their oxygen demands are approaching the maximum. Oxygen pressures within the wet foam drop below 10 kPa and oxygen uptake by the larvae becomes progressively limited, possibly stimulating their emergence from the nest. The delay between hatching and escape from the nest permits the larvae to grow and mature to a stage at which all of the clutch can emerge simultaneously. PMID- 7852909 TI - Odor plumes and how blue crabs use them in finding prey. AB - Orientation of animals using chemical cues often takes place in flows, where the stimulus properties of odorants are affected by the characteristics of fluid motion. Kinematic analysis of movement patterns by animals responding to odor plumes has been used to provide insight into the behavioral and physiological aspects of olfactory-mediated orientation, particularly in terrestrial insects. We have used this approach in analyzing predatory searching by blue crabs in response to plumes of attractant metabolites released from the siphons of live clams in controlled hydrodynamic environments. Crabs proceed directly upstream towards clams in smooth-turbulent flows and show high locomotory velocities and few periods of motionlessness. Crabs assume more indirect trajectories and display slower locomotion and more stopping in rough-turbulent flows. This degradation of foraging performance is most pronounced as flow shifts from a smooth- to a rough-turbulent regime, where the change in hydraulic properties is associated with contraction of the viscous sublayer region of the boundary layer. Because flow in this region is quasilaminar, the viscous sublayer may be a particularly effective vehicle for chemical stimulus transmission, such that orientation is severely compromised when it is reduced or removed. Our results also suggest that rheotactic and chemical information are both necessary for successful orientation. Perception of chemical cues acts to bias locomotion upcurrent, and feedback from odorant stimulus distributions appears directly to regulate subsequent stopping and turning en route to prey. Although the mechanisms of orientation to odorant plumes displayed by insects and blue crabs are largely similar, blue crabs appear to rely more heavily on spatial and/or temporal aspects of chemical stimulus distributions than has been suggested for insect systems. PMID- 7852910 TI - Modulating a modulator: biogenic amines at subthreshold levels potentiate peptide mediated cardioexcitation of the heart of the tobacco hawkmoth Manduca sexta. AB - The central nervous system of the moth Manduca sexta contains a group of myoregulatory neuropeptides, the CAPs (Cardioacceleratory Peptides), which cause a physiologically important, dose-dependent increase in heart rate during wing inflation and flight in adult moths. We report here that the response of the adult heart to a subset of the CAPs, the CAP2S, is potentiated nearly twofold in the chronic presence of subthreshold levels of the biogenic amine octopamine or near-threshold levels of the biogenic amine serotonin. Subthreshold levels of the CAP2S fail to alter the response of the heart to octopamine. We have begun to investigate the molecular mechanisms underlying this potentiation. Previous work on the adult heart has shown that the CAP2s act through an inositol-1,4,5 trisphosphate second-messenger system. Here, we demonstrate that the cardioexcitatory effects of the two amines, in contrast to those of the CAP2S, are both mediated by cyclic AMP. Application to the heart of either 10(-5) moll-1 octopamine or 10(-6)moll-1 serotonin elicits a threefold increase in intracellular cyclic AMP levels. The CAP2S have no effect on cyclic AMP levels in the heart. These results illustrate a mechanism by which the effectiveness of a neurohormone can be increased with minimal cost to the animal. In Manduca sexta, subthreshold levels of octopamine are found in the haemolymph during wing inflation and flight. Thus, it is possible that octopamine up-regulates the effects of CAP2 via a cyclic-AMP-dependent mechanism during these activities. PMID- 7852911 TI - The dorsal giant interneurons mediate evasive behavior in flying cockroaches. PMID- 7852912 TI - The malpighian tubules of Drosophila melanogaster: a novel phenotype for studies of fluid secretion and its control. PMID- 7852913 TI - The future internist: how do we conceive of him or her as a student? PMID- 7852914 TI - Brain repair. AB - Significant improvements in the treatment of common neurological diseases can be expected over the next few years from the application of advances now occurring in the basic neurosciences. In many disorders of the central nervous system, disability accumulates as a result of the degenerative process and its failure to repair. In part, this is because with differentiation, cells in the adult nervous system lose the ability to proliferate and migrate. A family of growth factors orchestrates proliferation, migration, differentiation and survival of neurones and glia; because certain of these growth factors also protect from injury cells which they support during development, there should soon be opportunities for limiting damage following a variety of insults and for rescuing degenerating neurones and glia. The discovery that axon regeneration is actively inhibited, perhaps in order to maintain stability in the complex systems and circuits that are established during development, suggests new strategies for enhancing axonal regeneration in spinal and head injury. Recruiting cells that are capable of restoring glial-neuronal interactions into areas of damage will be an important part of the brain repair strategy but it may prove possible to restore complex cellular arrangements through cell implantation only. Grafted neurones survive, produce appropriate neurotransmitters, form connections and restore some behaviours, but their relative inability to grow limits the degree of structural and functional repair that can be achieved: nevertheless, nerve cell implantation is now being used in the management of certain neurodegenerative diseases of the human central nervous system. There are also prospects for increasing the remyelination which occurs following acute inflammatory disease of the central nervous system, through the combination of immunological treatments that limit the disease process, growth factors that recruit oligodendrocytes and implantation of glial progenitors into demyelinated areas. PMID- 7852915 TI - Heart failure: a growing public health problem. AB - At a time when deaths from coronary heart disease and stroke are markedly declining, mortality from heart failure is increasing. Heart failure is a costly and devastating disease, and throughout much of the industrialized world, escalating health-care costs constitute a serious burden on both public and private systems of financing health care, and about one-third of all heart failure patients are admitted to hospital each year. Both prevalance and incidence of heart failure increase steeply with increasing age. The prevalence rate is about 1% at the age of 50, whilst at the age of 80 and above, almost one out of 10 persons will suffer from heart failure. Until recently, the goals for heart failure treatment were to relieve symptoms and enhance functional capacity. Recently, some large scale studies have shown that ACE inhibitors can reduce mortality, prevent development of heart failure, avoid the need for hospitalization and improve prognosis. ACE inhibitors may therefore have promising effects both on patients and on society. A challenge for the future must be early recognition and timely and adequate treatment of heart failure. Such a strategy might have great economic benefits as far as public health is concerned. However, the most rewarding efforts for the population will be to prevent the underlying causes of coronary heart failure as well as risk factors for heart failure. This review will study the magnitude of heart failure as a growing public health problem, the underlying causes, risk factors and treatment. PMID- 7852916 TI - The putative role of alpha-1-antitrypsin in the disaggregation of amyloid lambda fibrils. AB - BACKGROUND AND OBJECTIVES: Interactions between hydrophobic compounds like cholesterol and lithocholic acid and alpha-1-antitrypsin (alpha-1-AT) have previously been described. We studied the putative interaction between alpha-1-AT and the insoluble, hydrophobic, beta-pleated sheet, light-chain-derived fibrils that predominate the tissue deposits in primary immunocytic (AL) related amyloidosis. SUBJECTS AND METHODS: Amyloid fibrils were isolated from two cases with lambda and two cases with kappa AL amyloidosis. RESULTS: The lambda fibrils could be completely disaggregated (as shown by light and electron microscopy and Congo red uptake) by alpha-1-AT added in the molar ratio 1:5, whereas fibrils with predominantly kappa chains remained unaffected. The lambda-chain interaction was accompanied by characteristic changes of the physicochemical and biological properties of alpha-1-AT apparent in an increased thermal stability and loss of elastase-inhibitory activity. These findings are compatible with a transition of alpha-1-AT from a native, stressed conformation to a relaxed form. CONCLUSIONS: Disaggregation of lambda AL amyloid fibrils can be achieved by addition of alpha 1-AT. The findings may have therapeutic implications in primary amyloidosis. PMID- 7852917 TI - Diagnostic features of acute myocardial infarction--changes over time from 1983 to 1990: results from the FINMONICA AMI Register Study. AB - OBJECTIVES: To examine, whether the acute myocardial infarctions (AMIs) are becoming smaller. DESIGN: Analysis of electrocardiogram (ECG) and enzyme findings of community-based AMI registers in three geographical areas of Finland during the 8-year period 1983-90. SETTING: In the FINMONICA AMI Register, all suspected coronary events in persons aged 25-64 years have been registered since 1983 according to the protocol of the WHO MONICA project in the provinces of North Karelia and Kuopio in eastern Finland and Turku/Loimaa area in south-western Finland. SUBJECTS: Each consecutive case of suspected AMI originating from the monitored populations. During the study period, 11,487 definite or possible AMIs were registered. MAIN OUTCOME MEASURES: Trends in ECG findings classified as definite or probable, and trends in enzyme findings classified as abnormal or equivocal. RESULTS: Of the registered AMIs, 8439 (73.5%) reached the hospital alive and survived > or = 24 h from the beginning of the symptoms. They were included in the analyses of this report and divided further, to first ever AMIs (n = 5392) and to recurrent AMIs (3047). During the study period, the proportion of ECG findings classified as definite on the basis of the serial Minnesota coding declined in men 3.1% year-1 (P < 0.0001) on average for first AMIs and 1.9% year-1 (P = 0.004) for recurrent AMIs. In women, the corresponding declines were 1.9% year-1 (P = 0.007) and 1.6% year-1 (P = 0.02), respectively. Also, the proportion of enzymes classified as abnormal declined amongst men 2.2% year (P < 0.0001) for first AMIs and 2.8% year-1 (P < 0.0001) for recurrent AMIs. In women, the corresponding declines for abnormal enzymes was 1.3% year-1 (P = 0.13) and 3.0% year-1 (P = 0.02). These findings were consistent in all three areas with different registration teams and different laboratories. The proportion of definite ECG findings amongst patients hospitalized for AMI declined almost by half and the proportion of abnormal enzyme findings declined almost by one-third during the study period. CONCLUSIONS: Our findings are compatible with the clinical observation that the hospitalized AMIs are becoming smaller. The timing and magnitude of the changes suggest that they are mainly caused by decreased risk-factor levels in the population. Improved treatment of coronary heart disease and changed hospital admission policy are likely to be contributing factors. PMID- 7852919 TI - Body fat as a predictor of the antihypertensive effect of nifedipine. AB - OBJECTIVE: The aim of this study was to investigate the relationship between the blood pressure response and body fat in patients treated with the calcium entry blocker nifedipine. SUBJECTS: Forty untreated subjects with moderate hypertension completed the study. INTERVENTIONS: Height, weight, body mass index (BMI) and body fat (measured by near infrared spectrophotometry using Futrex 5000) were measured before the start of the study. Based on blood pressure measurements before and 30 min after one capsule of 10 mg nifedipine, the patients were allocated to treatment with 10 mg nifedipine daily in the responder group (reduction in diastolic blood pressure > or = 10 mmHg) and with 20 mg nifedipine daily in the non-responder group. Finally, the blood pressure was measured after 1 week. RESULTS: Twelve patients were classified as responders and 28 patients as non-responders. The responder/non-responder groups were comparable with respect to the blood pressure readings initially and to age, whereas the non-responders had higher weight (P < 0.01) and BMI (P < 0.01), more body fat (P < 0.01) and were smaller in height (P < 0.01). After 1 week no additional antihypertensive effect was observed in either group. The blood pressure reduction was negatively correlated to the body fat mass in kilogrammes (P < 0.05 for systolic and P < 0.01 for diastolic blood pressure) in the responder group but not in the non responder group, whereas no significant correlations were found to BMI in either group. CONCLUSION: Our data indicate that the body fat can be used to predict the antihypertensive effect of nifedipine. PMID- 7852918 TI - Lowering of body iron stores by blood letting and oxidation resistance of serum lipoproteins: a randomized cross-over trial in male smokers. AB - OBJECTIVES: The purpose of this study was to test the hypothesis that the reduction of body iron stores by venesection (blood letting) would reduce the susceptibility to oxidation of atherogenic serum lipoproteins. DESIGN: This is a randomized, controlled cross-over trial in 14 regularly smoking men with elevated serum ferritin concentration. The study design comprised two 14-week study periods, with a 14-week wash-out period in between, with either blood donations or control. SETTING: The study site was the Research Institute of Public Health, University of Kuopio. Investigators from the Division of Epidemiology, University of Minnesota, Minneapolis, participated in the planning of the study. SUBJECTS: Fourteen volunteers who were heavy smokers and had previous experience in blood letting were recruited for the study. INTERVENTIONS: During the intervention periods, the subjects donated 450 mg (500 mL) of blood three times in 14 weeks. MAIN OUTCOME MEASUREMENTS: Oxidation resistance of very low density lipoprotein (VLDL)/low density lipoprotein (LDL) was measured after inducing oxidation with haemin and H2O2. RESULTS: Serum ferritin concentration was reduced by 44% [95% confidence interval (CI) 8-82%, P = 0.021] during the venesection periods, the maximal oxidation velocity was decreased by 20% (95% CI 3-30%, P = 0.032), and the lag time to start of oxidation was lengthened (oxidation resistance increased) by 33% (95% CI 1-64%, P = 0.036). CONCLUSIONS: These observations indicate that the reduction of body iron stores by venesection can increase the oxidation resistance of serum VLDL/LDL in regularly smoking men. PMID- 7852920 TI - Rapid detection and prevalence of the variants of the angiotensinogen gene in patients with essential hypertension. AB - OBJECTIVES: The angiotensinogen (AGT) gene has been implicated as a candidate gene of high blood pressure. However, because the variants of the AGT gene are point mutations, it is difficult to detect them in large scale population studies. The aims of this study were to develop a rapid screening method for the point mutations and, using this method, to determine the possible role of the AGT gene variant in high blood pressure in the Japanese population. DESIGN AND SUBJECTS: A rapid screening method for the point mutations by means of primer specified restriction map modification is described here. Using this method, the distribution of two variants of the AGT gene, M235T and T174M, was determined in 80 patients with essential hypertension (EHT) and 100 normotensive controls (control). RESULT: The hypertensive group showed a significantly (P < 0.05) higher frequency for the T174M variant but the same frequency for the M235T variant. CONCLUSION: These data provide evidence in favour of an association between hypertension and a genetic variant of AGT in human EHT, and a marked ethnic difference in the AGT gene. PMID- 7852921 TI - Imaging of the sella in the syndrome of inappropriate secretion of antidiuretic hormone. AB - OBJECTIVE: The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) results either from ectopic production or inappropriate release of antidiuretic hormone from the neurohypophysis. Although magnetic resonance imaging (MRI) has provided new insights into the morphological changes of the hypophysis in health and disease, no previous studies have evaluated its use in SIADH: The aim of this study was to evaluate the MRI appearance of the neurohypophysis in patients with SIADH: DESIGN: Retrospective case-control study. SETTING: Tertiary care teaching hospital. SUBJECTS: We studied retrospectively eight patients with SIADH who had been hospitalized in Boston's Beth Israel between 1984 and 1994 and who had MRI scans including the sella turcica. We also evaluated prospectively the MRIs of the heads of 23 consecutive control patients who had no pituitary pathology and no serum osmolality or electrolyte abnormalities. INTERVENTIONS: Clinical evaluation as well as sagittal and axial T1-MR images. MAIN OUTCOME MEASURES: Presence or absence of the high intensity signal of the neurohypophysis. RESULTS: In seven out of eight patients (87.5%) the normal high intensity signal of the neurohypophysis was not present. In one patient (12.5%), two interpreting radiologists disagreed about its presence. The high intensity signal was present in the neurohypophysis of 20 out of 23 controls (87.5%). CONCLUSIONS: Our data indicate an association of SIADH with the absence of the normal hyperintense signal of the neurohypophysis, confirming the usefulness of MRI as a tool to visualize ADH processing. These data also raise the possibility that the absence of the high intensity signal may be useful diagnostic tool in cases of SIADH that are difficult to diagnose clinically. Additional studies to correlate this signal with various forms of SIADH will be needed. PMID- 7852922 TI - Iron deficiency and iron overload in Swedish male adolescents. AB - OBJECTIVES: The present study was undertaken to confirm or reject recent findings indicating a high prevalence of iron deficiency in Swedish male adolescents; a second aim was to study the prevalence of genetic iron overload. DESIGN: The diagnostic criteria were: anaemia: Hb < 130 g L-1 (a): iron deficiency: serum ferritin (SF) < 12 micrograms L-1 + transferrin saturation (TS) < 16% (b): iron deficiency anaemia a + b. Iron overload: SF (90th percentile) + TS (90th percentile) in repeat tests. SETTING: Central Sweden. SUBJECTS: A total 3975 men aged 18 years studied on enrollment into military service. RESULTS: Serum ferritin averaged 36.8 micrograms L-1. Anaemia was present in 0.5%, iron deficiency anaemia in 0.17% and iron deficiency in 0.4%. If iron deficiency is defined as SF < 16 micrograms L-1, as was recently suggested, the prevalence would be 2.8%. Such a cut-off value would include 73% normal people (false positives). Iron overload had the same prevalence as iron deficiency, 0.4%. CONCLUSIONS: Iron stores, as measured by serum ferritin, are small in young men studied at the end of their growth spurt. However, iron deficiency is rare. Therefore, the present study has not been able to confirm the high prevalence of iron deficiency recently reported. A prevalence of genetic haemochromatosis of 0.4%, confirms earlier findings and would mean that 12.6% of the population are heterozygotic carriers of the iron-loading genes. These findings give no support for a proposed, more effective iron-enrichment of food. It is not needed and can be harmful. PMID- 7852923 TI - Microalbuminuria, insulin sensitivity and haemostatic factors in non-diabetic treated hypertensive men. Risk Factor Intervention Study Group. AB - OBJECTIVE: To examine whether microalbuminuria in non-diabetic, treated hypertensive men is associated with insulin resistance and measures of endothelial function, thrombogenesis and fibrinolysis. DESIGN: Cross-sectional study. SETTING: Outpatient clinic in city hospital. PATIENTS: Ninety-two treated hypertensive men, aged 57-77 years, either with a serum cholesterol of > or = 6.5 mmol L-1 or smokers, or both. Patients with diabetes mellitus or overnight urinary albumin excretion of > 100 mg 12 h-1 were excluded. MAIN OUTCOME MEASURES: Overnight urinary albumin excretion, insulin-mediated glucose disposal (hyperinsulinaemic euglycaemic clamp), blood glucose and plasma insulin during oral glucose tolerance test, fibrinogen, von Willebrand factor and plasminogen activator inhibitor activity. RESULTS: Microalbuminuric patients had increased blood glucose concentrations during the oral glucose tolerance test and higher plasma fibrinogen levels compared with the normoalbuminuric patients. In a randomly selected subgroup (n = 36), insulin-mediated glucose disposal was lower in microalbuminuric than in normoalbuminuric patients, and an inverse relationship between insulin sensitivity and albuminuria (r = -0.37; P = 0.028) was found. This relationship was not significant after adjustment for body-mass index (P = 0.098). In the univariate analyses including all patients, albuminuria was associated with blood glucose, serum creatinine, body-mass index, systolic blood pressure, fibrinogen, von Willebrand factor and cholesterol (negatively). In a multiple regression analysis, only the body-mass index was independently related to urinary albumin excretion. CONCLUSIONS: Microalbuminuria was associated with insulin resistance but obesity was a confounding factor. Relationships between microalbuminuria and fibrinogen as well as von Willebrand factor were found, but only in univariate analysis. PMID- 7852924 TI - Leucocyte doubling time is a useful predictor of progression-free survival in chronic lymphocytic leukaemia. AB - OBJECTIVE: To assess leucocyte doubling time (LDT) in relation to progression free survival in patients with chronic lymphocytic leukaemia (CLL). In addition, to define the impact of a second LDT in both untreated and treated patients. DESIGN: Retrospective study of LDT in previously untreated patients with CLL. SUBJECTS AND SETTING: Sixty patients diagnosed over a 13-year period at a county hospital. In forty-five of the 60 patients, an LDT could be defined. These patients were included in the final analysis. MAIN OUTCOME MEASURES: LDT below and above 12 months, progression-free and overall survival. RESULTS: Patients in Binet stages B and C had a median LDT of 4 months as compared to 26 months in stage A patients (P < 0.01). The projected progression-free survival at 3 years was 24% in patients with an LDT of < 12 months. The corresponding figure for the remaining patients was 68% (P < 0.01). The overall 5-year survival did not differ significantly between patients with an LDT below and above 12 months, respectively. In seven untreated patients, a second LDT could be calculated which was shorter than the first recorded LDT. A second LDT was also identified in five patients post treatment that was consistently shorter than their first LDT. CONCLUSIONS: Measurement of LDT is a simple complement in predicting progression free survival in patients with CLL. Thus, monitoring of LDT may add to the clinical evaluation and therapeutic decision making for the many elderly patients with this often indolent disease. PMID- 7852925 TI - Refractory oedema in congestive heart failure: a contributory role of loop diuretics? AB - We report a patient with congestive heart failure (CHF) who presented with massive oedema resistant to therapy with maximal doses of loop diuretics, despite an adequate renal function. After a diuretic pause and dietary salt restriction, a conventional dose of furosemide in combination with distally active diuretics induced a prompt weight loss exceeding 30 kg with stable renal function. We suggest that the 'refractory' oedema in this patient was due to a combination of CHF and inappropriate (loop) diuretic therapy in conjunction with a high dietary sodium intake. We conclude that in the absence of hyponatremia and renal failure, even severe oedema may not represent a negative prognostic indicator. The recognition of diuretic-associated mechanisms complicating cardiac oedema is essential to avoid the vicious circle of worsening oedema whilst escalating therapy with loop diuretics. PMID- 7852926 TI - Neurobiology of sleep and cardiac diseases amongst elderly people. PMID- 7852927 TI - Takayasu's arteritis. PMID- 7852928 TI - Vasectomy technique for Norplant removal. PMID- 7852929 TI - Asthma: palpation and injections. PMID- 7852930 TI - Circumcision devices. PMID- 7852931 TI - Postrejection paronychia. PMID- 7852932 TI - Computerized sampling techniques. PMID- 7852933 TI - The Norplant System: where are we in 1995? PMID- 7852934 TI - Surgery in nonagenarians: morbidity, mortality, and functional outcome. AB - BACKGROUND: There are few studies that document the outcomes experienced by very old patients who undergo major surgery. METHODS: This is a case series and 7-year follow-up of 116 consecutive patients who were aged 90 years or older and underwent major surgery at a large university-affiliated community hospital. We describe the functional status, short- and long-term mortality, and predictors of mortality in this group of frail elders. RESULTS: The 116 nonagenarians in this study underwent 134 major operations. Sixty-three patients were admitted to the hospital from a nursing home. The most common surgical procedures were for hip fracture, lower extremity amputation, and abdominal problems. Nineteen patients died in the hospital following surgery, and 23 patients died within 30 days of operation. Follow-up at 7 years revealed that all but three patients had died. Survival was worse for patients admitted from nursing homes, those who were nonambulatory before surgery, and those with major or complete functional impairment. CONCLUSIONS: Major surgery in nonagenarians is associated with a 20% perioperative mortality. Functional status and ambulatory ability are maintained in most patients. Whether to operate on these frail elders is a complex decision. PMID- 7852935 TI - Communal showers and the risk of plantar warts. AB - BACKGROUND: Plantar warts occur most commonly in adolescents and are more prevalent among users of public locker rooms. Previous studies have not differentiated shower rooms from locker rooms as risk factors. METHODS: The current study examined the prevalence of plantar warts among a group of 146 adolescents who used locker rooms. Subjects ranged in age from 10 to 18 years and were recruited from a public school and a swim club. All subjects used public locker rooms but only those in the swim club used communal showers on a regular basis. All subjects were interviewed by a physician and underwent an examination of the feet. RESULTS: There was a statistically significant difference in the prevalence of plantar warts between the shower room users (27%) and those who used only locker rooms (1.25%). CONCLUSIONS: The present study suggests that public shower users are at greater risk for plantar warts than are locker room users who do not use communal showers. PMID- 7852936 TI - Proteinuria in patients with sleep apnea. AB - BACKGROUND: Proteinuria severe enough to be in the nephrotic range has been noted on occasion in patients with obstructive sleep apnea (OSA), but it is not known what factors are related to the severity of proteinuria in these patients. This study was conducted to determine if the severity of proteinuria is related to the number of apneas. METHODS: The level of proteinuria was determined by the dipstick method in 407 patients in whom OSA had been diagnosed. The apnea hypopnea index (AHI) was calculated in each patient after all-night polysomnography. Sleep apnea was defined as the presence of at least 30 apneas during a 6- to 8-hour monitoring period and an AHI greater than 15. RESULTS: The apnea-hypopnea index in patients without proteinuria was similar to that of patients with 1+ to 3+ proteinuria. However, the AHI was significantly greater in the 9 patients with 4+ proteinuria. CONCLUSIONS: While severe proteinuria in OSA occurs in patients with a higher rate of sleep apneas, the lesser degree of proteinuria cannot be explained by AHI alone. Other factors that determine the severity of the disease, such as hypoxemia, merit further investigation. PMID- 7852937 TI - Effect of distance and travel time on rural women's compliance with screening mammography: an UPRNet study. Upper Peninsula Research Network. AB - BACKGROUND: The purpose of this study was to determine whether the distance and time required for rural women to travel for a mammogram is associated with their compliance with screening mammography recommendations. METHODS: Women who were > or = 40 years old and visiting family physician offices for any reason were given a questionnaire regarding their frequency of mammography during the past 4 years, the distance and travel time from their homes to the nearest mammography unit, their attitudes and knowledge about mammography, and demographics. The study was conducted in the 12 family practices of the Upper Peninsula Research Network (UPRNet), a Michigan rural family practice research network. RESULTS: Eighty eight percent (N = 416) of the women in the study had previously had mammography, but 41% were not compliant with American Cancer Society guidelines regarding mammography screening. After controlling for confounding, none of the measures of travel time or distance were associated with mammography compliance. CONCLUSIONS: In this rural population, mammography compliance is not affected by distance, travel time, or transportation. A population-based study in a more remote area is needed to further explore geographic barriers to mammography compliance among rural women. PMID- 7852938 TI - Physician counseling for smoking cessation: is the glass half empty? AB - BACKGROUND: Professional groups urge physicians to aggressively counsel their patients who smoke, but research evaluating the effectiveness of physician counseling has produced mixed results. METHODS: Four hundred ten smokers identified in a previous study were contacted 1 year later to determine whether they had quit smoking. In both studies, smokers were asked whether their physicians had counseled them in any of six specific ways (eg, advising the patient of personal health risks and the need to stop smoking, or discussing cessation methods). RESULTS: Seventy-nine percent of patients reported that their physician counseled them either at the initial visit or at some time during the following year; 42% reported having tried to quit at least once during the year, but only 5.9% were nonsmokers at 1-year follow-up. Physician counseling had no effect on the rate of successful attempts to quit. Patients with serious health problems were more likely to be counseled and to attempt to quit (P < .02). Non Hispanic white patients were more likely to be counseled but less likely to attempt to quit (P < .01). CONCLUSIONS: Counseling by physicians appears to motivate some patients to attempt to quit, but this study did not show significant improvement in actual quit rates in patients who were counseled by a physician. PMID- 7852939 TI - Maternity care in family medicine: economics and malpractice. AB - BACKGROUND: The number of family physicians delivering babies in Florida in 1991 was at an all-time low. Concerns about malpractice risk and insurance costs have resulted in only 2% of Florida's family practice residency graduates choosing to deliver babies. The purpose of this study was to compare the practices of family physicians in Florida who delivered babies in private practice (termed the "OB group") with those who did not (the "non-OB group"). METHODS: A potential study group of 293 family physicians was mailed an extensive survey that explored 132 variables related to medical practice economics and demographics, lifestyle and satisfactions, and malpractice costs and risks. RESULTS: The obstetrical (OB) group was significantly more likely than the non-OB group to perform a variety of procedures and report more patients under age 6 years (15% vs 5%; P = .003) and fewer patients 65 years or older (19% vs 33%; P < .001). Even though the number of patients seen and the number of hours worked were similar, the 1991 incomes were much higher for those practicing maternity care (mean = $164,000 vs $104,000; P = .04). Compared with the non-OB group, the OB group was more likely to report that their financial and psychological compensation was adequate (P < .001), would be more likely to choose medicine as a profession again (94% vs 60%, P < .05), paid more for malpractice insurance (mean = $22,000 vs $11,000; P = .01), and reported 30% fewer nonobstetrical malpractice claims. CONCLUSIONS: Family physicians in Florida who deliver babies, as compared with those who do not, are more likely to report (1) increased financial and psychological satisfaction for the same hours worked; (2) increased satisfaction with medicine and family practice; (3) more frequent performance of a wider range of procedures; (4) younger practices serving a greater number of complete families and fewer Medicare patients; (5) a more diverse and comprehensive hospital and office practice; and, despite paying significantly higher malpractice insurance premiums, (6) few obstetrical malpractice claims and lawsuits, and (7) fewer nonobstetrical malpractice claims and lawsuits. PMID- 7852940 TI - The 'Modified U' technique: a refined method of Norplant removal. AB - Norplant removal has been much more difficult for many physicians than might have been anticipated. Dr Untung Praptohardjo of Indonesia recently developed the "U" technique, speeding the time required to remove the six Norplant implants to an average of 7 minutes. In his technique, a unique oval-ring-tipped forceps with an internal diameter of 2.2 mm is used to reach through a 4-mm incision to firmly grasp each of the implants. The incision is made parallel to the implants between the lower tips of implants 3 and 4. The "U" technique requires grasping the implant within 4 mm to 5 mm of its tip. This preliminary paper describes the "Modified U" technique, which allows the physician who is removing the implants to grasp them anywhere along their shaft, not just near the tip. The Modified U technique involves the use of an improved ring-tipped forceps with a circular tip rather than the oval tip used in the "U" technique. This instrument, called Norgrasp, is a modification of the vas deferens fixation forceps used in the no scalpel vasectomy (NSV) technique. In another adaptation of NSV instruments, an NSV dissecting forceps (a sharpened, curved hemostat) is used to free the implants from their tissue envelope and quickly deliver them through the skin incision. Using the Modified U technique, the time required to remove Norplant implants in 20 patients in the United States has ranged from 8 to 13 minutes. Improperly placed implants are readily removed with this technique. The Modified U technique requires a minimal incision and offers both the physician and the patient a speedy, positive removal. PMID- 7852941 TI - Norplant removal facilitated by use of ultrasound for localization. AB - Two case reports are presented, describing the use of a 7-MHz ultrasound transducer to locate and visualize Norplant rods that could not easily be removed. The first patient was referred to the radiology department for a sonogram for unrelated reasons; her self-reported history led to the attempt to locate a retained Norplant rod. The second patient was first referred by a physician for the stated purpose of rod localization. After ultrasonic localization of the retained rods, both patients returned to their physicians' offices and underwent successful removal of the rods. Morbidity related to difficult rod retrieval can be reduced by using ultrasound for localization. PMID- 7852942 TI - Norplant neuropathy: peripheral neurologic symptoms associated with subdermal contraceptive implants. AB - Seventy to 80% of women using subdermal contraceptive implants (Norplant) have reported side effects, such as uterine bleeding, headache, mastalgia, and local pain at the site of insertion. This is a report of two patients who presented with peripheral neuropathy associated with the implants. One patient responded to removal of the device. The second patient, whose symptoms were thought to be related to trauma, was successfully treated with nonsteroidal anti-inflammatory agents. PMID- 7852943 TI - Maternity care in family practice. PMID- 7852944 TI - I'm worried about this daughter. PMID- 7852945 TI - Characterization of plasma membrane Na+/H+ exchange in eel (Anguilla anguilla) intestinal epithelial cells. AB - The ability of eel intestinal epithelial cells to recover from an acute acid load was analysed using the fluorescent dye 2',7'-bis-carboxy-ethyl-5,6 carboxyfluorescein (BCECF) and cell suspensions. Under these experimental conditions (bicarbonate-free solutions) the resting pHi in cells prepared from sea-water (7.52 +/- 0.031) and fresh-water (7.50 +/- 0.094) adapted animals proved to be similar. The recovery rate (following an acid load) increases by increasing the Na ion concentration in the extracellular medium. This pHi recovery is competitively inhibited by the specific inhibitor dimethylamiloride (DMA) with a low Ki in sea- (1.2 microM) as well as in fresh-water (1.3 microM) adapted animals, indicating the presence of a specific Na/H exchange activity in these cells. Using basolateral membrane vesicles it could be demonstrated that this activity is located on the basolateral side of the enterocyte membrane. The kinetic parameters (Kapp and Jmax) of this exchanger are similar in fresh-water and sea-water adapted animals suggesting that no salinity adaptation occurs, thus excluding the involvement of the antiporter in the osmoregulatory processes. These results are in agreement with the presence in the plasma membrane of the eel enterocytes of a Na/H-1 (housekeeper) form of the antiporter. PMID- 7852946 TI - Fiber types and myosin heavy chain composition in muscles of common shrew (Sorex araneus). AB - Red-toothed shrews of subfamily Soricinae are small mammals with very high mass specific metabolic rate. Owing to their high aerobic power they are interesting objects for studies concerning the limits and constraints of skeletal muscle adaptation. In order to clarify the correlation between metabolic rate and muscle properties, we have analyzed fiber types, fiber size, and myosin heavy chain composition of the common shrew (Sorex araneus) and compared them to those of rat (Rattus norvegicus). Three distinct differences between shrew and rat muscles were noted. 1) The fibers of shrew muscles are exceptionally small in comparison to rat myofibers. 2) Electrophoretic and histochemical analysis showed that shrew muscles are composed of only fast fibers (fiber types IIB and IID), the slow type I fibers being totally absent. 3) The shrew muscles are much more homogenous than rat muscles in regard to myosin heavy chain and fiber type composition. The shrew diaphragm consists exclusively myosin heavy chain type IId (MHCIId), while masseter and soleus are composed 95% and 87% of MHCIId, respectively. Other four studied muscles contain MHCIIb and MHCIId approximately in equal proportions. The present findings show that shrew muscles are composed of small, highly aerobic, fast type II fibers, which may be sufficiently fatigue-resistant to function both as postural muscles and to power fast and high frequency movements of limbs and diaphragm. PMID- 7852947 TI - External and internal influences on indices of physiological stress. I. Seasonal and population variation in adrenocortical secretion of free-living lizards, Sceloporus occidentalis. AB - The plasma levels of glucocorticoid hormones (e.g., corticosterone and cortisol) are often used as an index of physiological stress. However, under natural conditions, glucocorticoid secretion can respond to both environmental influences (e.g., extreme climatic conditions) and internal influences (populational differences and annual seasonal cycles). To distinguish between these kinds of influences, we examined seasonal variation in basal levels of corticosterone and the adrenocortical response to acute stress in six populations of western fence lizards Sceloporus occidentalis. Three populations (Mojave CA, Lone Pine CA, and Tulalip WA) were near the periphery of the species distribution, and three were in the central part of the range (Ojai CA, Hopland CA, and Bend OR). Basal corticosterone showed no consistent pattern of variation, but the adrenocortical response to acute stress was consistently highest 1) in populations living at the margin of the species range, 2) during the hottest and driest seasons, and 3) in individuals with the largest decrements in physiological condition (length adjusted mass). Thus, basal adrenal secretion and adrenal responsiveness to acute stress were dissociated, and the latter more likely reflected the physiological condition of an individual and the severity of its environment. However, further analysis showed that physiological condition only partially explains the variation in adrenocortical responsiveness and that intrinsic seasonal and population differences may be as important as the external influences of the physical environment. After factoring out seasonal changes in physiological condition, adrenocortical response of two populations under identical controlled laboratory conditions also showed that a peripheral population (Mojave, CA) maintained a higher response than a central population (Bend, OR) that was not attributable to population differences in physiological condition. PMID- 7852948 TI - Model for cooperative control of positional information in Drosophila by bicoid and maternal hunchback. AB - The blastoderm of the fruit fly Drosophila melanogaster is unusually well suited for analysis of fundamental questions in animal development. One such question is how genes specify the positional information which determines the developmental pathways (fate) of cells at appropriate spatial locations. In this paper we propose a dynamical model of gene regulation which explicitly describes how positional information is used in the blastoderm. The model is applied to analyze important experimental findings on the dependence of cell fate on the concentration of the Bicoid morphogen. The model shows that positional information in the presumptive middle body is cooperatively determined by maternal products of the bicoid and hunchback genes. PMID- 7852949 TI - Activation of murine oocytes with Ca2+ ionophore and cycloheximide. AB - A Ca2+ ionophore (A23187, 3 microM) and inhibitor of protein synthesis (cycloheximide, 10 micrograms/ml) were used sequentially as a unique method for activating mouse oocytes in vitro. Brief exposure of oocytes to A23187 followed by 6 hr in cycloheximide resulted in a higher activation rate (93.8%) compared to A23187 or cycloheximide alone (37.7% and 36.5%, respectively) or the two reagents in reverse order (29.8%). The parthenogenones consistently contained a single pronucleus and second polar body, and showed a high degree of developmental potential, as assessed by transfer to recipient females or addition of a male pronucleus followed by transfer to recipients. This method is a useful way of obtaining large numbers of activated haploid mammalian oocytes for further developmental studies. PMID- 7852950 TI - Immunohistochemical evidence that gonads and gonad-associated tissues are sites for enrichment with immunoglobulin-containing cells in adult chickens. AB - Immunohistochemical staining of tissue sections prepared from gonads and gonad associated tissues obtained from adult chickens was performed in order to assess the possibility that these tissues may be sites of enrichment with IgM-containing cells in various B lineages. Evidence is presented which suggests that IgM containing B lineage cells are present in 1) the ovarian stroma and subcapsular areas of the ovary and 2) the interstitium and subcapsular areas of the epididymis of the testes. These represent new sites reported for B lineage cells in adult chickens. Some questions relevant to the physiologic, ontogenetic, and phylogenetic implications of these observations relative to vertebrate hematolymphopoietic processes are included. PMID- 7852951 TI - Hepatitis B vaccination in children: persistence of immunity at 9 years. PMID- 7852952 TI - Homologous and heterologous neutralization antibody responses after immunization with Japanese encephalitis vaccine among Taiwan children. AB - Because 21 immunized children (13%) among the 162 confirmed Japanese encephalitis (JE) cases during 1986-1991 occurred in Taiwan, we collected 320 serum samples from Taiwan children aged 15-31 and 27-44 months immediately before the 1st dose (n = 41) and 1-3 months after the 2nd dose (n = 78, 27 pairs), and immediately before (n = 58) and 1-3 months after the 3rd dose (n = 143, 44 pairs) to determine neutralization antibody (Nt Ab) against the Nakayama (N) and Beijing-1 (B) strains and two Taiwan wild type JE viruses (JEV): CC-27 and CH-1392. Our Nt results showed that (1) B vaccine stimulated a better homologous Ab response than N vaccine for Nt Ab seropositivity rate (NASR), produced a higher level of Nt titer after the primary immunization [2 doses = 100% vs. 91%, geometric mean titer (GMT) = 115 vs. 22], had a greater booster effect (3 doses: 100% vs. 95%; GMT = 320 vs 33), and showed a better capability to neutralize two local Taiwan JEV strains, particularly only after 3 doses (ave. NASR for B vs. N = 90% vs. 10%; and GMT for B vs. N = 154 vs. 1); (2) the two wild type JEV strains had different plaque morphology and antigenic variation and the CC-27 strain was not neutralized as well as the CH-1392 strain after 3 doses of vaccine (BBB or NNN or NNB); and (3) 30% of the children had lost JEV Nt Ab one year after the 2nd dose of N vaccine and natural infection with JE virus did occur among those children after immunization. In conclusion, (1) three doses of mouse-brain vaccine are the minimum requirement to protect children against the local Taiwan JEV-, (2) the best strain for a JE vaccine depends on level of Nt Ab it induced, the molecular epidemiology and antigenic variation of the JEV in each local area; and (3) future vaccine must produce better B- and T-cell memory. PMID- 7852953 TI - Laboratory study of HIV-1 and HTLV-I/II coinfection. AB - A Retroviral Coinfection Clinic was established in 1991 at Charity Hospital Medical Center of Louisiana to study patients dually infected with human immunodeficiency virus (HIV) and human T lymphotropic virus (HTLV-I, HTLV-II). Eight patients were evaluated clinically, and by immunological and virological studies. Multiple neuromuscular diseases were observed, including tropical spastic paraparesis, polymyositis, and polyneuropathies. Only one patient developed AIDS. HIV-1 infected patients with HTLV-I, but not HTLV-II, coinfection have maintained stable CD4 counts, despite the fact that quantitative HIV DNA PCR suggests a relatively high copy number. HTLV-I/II antigens were detected in lymphocyte cultures from four patients, and lymphoblastoid cell lines have been established from two. These results support the contention that upregulated HTLV I/II virus expression and disease manifestations occur during coinfection with HIV, sometimes in association with normal CD4 counts. PMID- 7852954 TI - Review: protective efficacy of hepatitis B vaccines in neonates. AB - A literature search was carried out to investigate the factors that influence the protective efficacy (PE) of hepatitis B vaccines when given to neonates of hepatitis B surface antigen and e antigen positive mothers. Hepatitis B vaccines with either high or low antigen doses are very effective in preventing chronic hepatitis B infection in neonates at risk, but there is evidence that with lower dosages simultaneous use of hepatitis B immune globulin (HBIG) administration is more important than with higher dosages to elicit good protection (PE > or = 90%). There is also a tendency for lower dosages to confer high PE less consistently, with noticeably greater numbers of chronic surface antigen carriers in neonates who received a complete vaccination course. Furthermore vaccination courses with higher vaccine dosages give high PEs, without concomitant HBIG administration at birth, provided that the first vaccine dose is given at birth and that the second dose follows within 2 months. PMID- 7852955 TI - Biological and genetic characterization of a hemagglutinating coronavirus isolated from a diarrhoeic child. AB - The coronavirus strain HECV-4408 was isolated from diarrhea fluid of a 6-year-old child with acute diarrhea and propagated in human rectal tumor (HRT-18) cells. Electron microscopy revealed coronavirus particles in the diarrhea fluid sample and the infected HRT-18 cell cultures. This virus possessed hemagglutinating and acetylesterase activities and caused cytopathic effects in HRT-18 cells but not in MDBK, GBK and FE cells. One of four S-specific monoclonal antibodies reacted in Western blots with HECV-4408, BCV-L9 and BCV-LY138 but not with HCV-OC43, and two reacted with BCV-L9 but not with HECV-4408, BCV-LY138 and HCV-OC43. One S specific and two N-specific monoclonal antibodies reacted with all of these strains. cDNA encompassing the 3' 8.5 kb of the viral RNA genome was isolated by reverse transcription followed by polymerase chain reaction amplification had size and restriction endonuclease patterns similar to those of BCV-L9 and BCV LY138. In contrast, the M gene of HCV-OC43 differed in restriction patterns from HECV-4408 and BCV. A genomic deletion located between the S and M within the non structural genes of HCV-OC43 was not detected in HECV-4408. DNA sequence analyses of the S and HE genes revealed more than 99% nucleotide and deduced amino acid homologies between HECV-4408 and the virulent wild-type BCV. Forty-nine nucleotide and 22 amino acid differences were found between the HE genes of HECV 4408 and HCV-OC43, while only 16 nucleotide and 3 amino acid differences occurred between the HE genes of HECV-4408 and BCV-LY138. We thus conclude that the strain HECV-4408 is a hemagglutinating enteric coronavirus that is biologically, antigenically and genomically more closely related to the virulent BCV-LY138 than to HCV-OC43. PMID- 7852956 TI - Serotyping of human rotaviruses in the Tokyo area (1990-1993) by enzyme immunoassay with monoclonal antibodies and by reverse transcription and polymerase chain reaction amplification. AB - Serotyping of human rotavirus in the Tokyo area was conducted from 1990 to 1993 by enzyme immunoassay with monoclonal antibodies (EIA-MAbs) against VP7 and by reverse transcription and polymerase chain reaction (RT-PCR) amplification of the VP4 and VP7 genes. The results by EIA-MAbs were very similar to those obtained by RT-PCR. Evidence of intraserotypic variations was suggested because strains of undetermined serotypes were detected by either EIA-MAb or RT-PCR. This kind of study is required for vaccine development. PMID- 7852957 TI - Sequence conservation of the major outer capsid glycoprotein of human group C rotaviruses. AB - Several outbreaks of Group C rotavirus infection have occurred in the United Kingdom, in one instance infection was associated with the death of a 4-month-old infant in the Bristol area. The origin of human group C rotavirus is unknown although there has been some speculation that porcine species may be a possible source of human infection. Direct reverse transcription-polymerase chain reaction sequencing of VP7 genes from two UK outbreaks (Bristol and Preston) and sequence analysis from a sporadic case of infection from Brazil (Belem) showed that each of these genes was identical in size (1,063 bp) and has revealed a surprising level (97.8-99.8%) of gene sequence conservation. Sequence comparisons with an isolate from Japan imply that the human group C rotaviruses so far characterised originate from a recent common ancestor with a worldwide distribution. PMID- 7852958 TI - Detection of cytomegalovirus-matrix protein (pp65) in leukocytes of HIV-infected patients with painful peripheral neuropathy. AB - Painful peripheral neuropathy (PPN) in HIV-infected patients has been increasingly associated with cytomegalovirus (CMV) infection at other sites. In the last few years, the detection of CMV lower matrix phosphoprotein (pp65) antigen in leukocytes has become a major tool in the diagnosis of CMV systemic infection in immunocompromised patients. In this study, CMV antigen detection was assessed in 13 HIV-infected patients with PPN and, as controls, in 82 HIV seropositive patients without any evidence of peripheral nerve syndromes (10 with CMV retinitis and 72 without CMV end-organ disease). CMV antigenemia was found in 10 (76.9%) patients with PPN, in 5 (6.9%) without CMV disease, and in all 10 patients (100%) with CMV retinitis. Of the 10 PPN patients with CMV antigenemia, only 3 presented with CMV retinitis, while the remaining 7 had no clinical evidence of overt CMV infection at other sites. CMV pp65-positive cells were also found in three of the four cerebrospinal fluid (CSF) samples collected from PPN patients. Ganciclovir was effective in improving neurological symptoms in two of the four treated patients. The findings suggest that active CMV infection may be associated with PPN in HIV infection even in the absence of CMV disease at other sites. The detection of CMV-matrix pp65 antigen in the blood and CSF leukocytes could represent a simple and rapid tool of selecting PPN patients for antiviral therapy. PMID- 7852959 TI - Genetic diversity of hepatitis B virus strains isolated in Rio de Janeiro, Brazil. AB - Hepatitis B virus (HBV) genomes have been classified into six groups, A-F, group F being the most divergent. South America has provided the smallest number of strains studied at the genome level. The only HBV strain from this region sequenced completely has been classified in group F, and contains the most divergent of the HBV genomes presently known [Naumann et al. (1983): Journal of General Virology 74:1627-1632]. To evaluate genetic relatedness between strains isolated in South America and in the rest of the world, a restriction endonuclease analysis was carried out on 14 HBV strains (4 adw2, 3 adw4, 3 ayw2, and 4 ayw3) isolated in Rio de Janeiro, Brazil. C, pre-S, and X genes along with the 5' part of the P gene from these strains were amplified by the polymerase chain reaction. The DNA fragments were digested by BamHI, BstEII, EcoRI, HhaI, and TaqI endonucleases. The restriction patterns obtained were compared with those deduced from the nucleotide sequence of 26 HBV strains isolated in other continents. The results showed a large genetic variability of Brazilian strains. Taking into account that all the samples examined possessed the w antigenic subdeterminant, the number of different restriction patterns of strains isolated in Rio de Janeiro was at least as large as that of the reference strains isolated in the rest of the world. Some original restriction patterns were found in adw4 and ayw2 HBV strains. PMID- 7852960 TI - Expression and characterization of a soluble rubella virus E1 envelope protein. AB - Individual specific antigenic rubella virus (RV) structural proteins are required for accurate serological diagnosis of acute and congenital rubella infections as well as rubella immune status. The RV envelope glycoprotein E1 is the major target antigen and plays an important role in viral-specific immune responses. The native virion is difficult to produce in large quantities and the protein subunits are also difficult to isolate without loss of antigenicity. The production of a soluble RV E1 (designated E1 delta Tm) using the baculovirus insect cell expression system is described. In contrast to wild-type RV E1, the genetically engineered E1 delta Tm protein lacks a transmembrane anchor. It behaved as a secretory protein and was secreted abundantly from insect cells. Pulse-chase studies were used to examine the synthesis, glycosylation, and secretion of E1 delta Tm by the insect cells. The secreted E1 delta Tm protein was purified from serum-free medium by one-step immunochromatography. The purified E1 delta Tm protein retained full antigenicity and may be a convenient source of E1 protein for use in diagnostic assay and rubella vaccine development. PMID- 7852961 TI - Hepatitis may precede the occurrence of precore region mutation in hepatitis B virus genome during infection in young carriers. AB - To understand when the mutation with a stop codon of precore region in hepatitis B virus genome occurs, the prevalence of the mutation of viral DNA clones propagated from sera of school-age carriers was investigated with respect to hepatitis B e antigen (HBeAg)/anti-HBe and sequential changes of mutants along HBeAg seroconversion were analyzed. Of 32 carriers aged 8-18 years, 14 HBeAg(+) patients had 2.2% mutant clones, whereas 8 patients with low titer anti-HBe had a higher rate of 18.1% (P < 0.01) and the highest rate of 61.3% was found in 10 patients with high anti-HBe titer (P < 0.001). By contrast, the amount of viral DNA decreased significantly in patients with anti-HBe. Sequential analysis in six cases revealed three types of seroconversion with time difference of the emergence and increase of mutant clones. It is concluded that mutation occurs at a relatively young age and increases along time and/or HBeAg seroconversion. Hepatitis might precede or accelerate the emergence and increase of mutant population which might be predictive of sustained resolution of the disease. PMID- 7852962 TI - Analysis of deletion of the integrated human papillomavirus 16 sequence in cervical cancer: a rapid multiplex polymerase chain reaction approach. AB - A protocol for a rapid physical mapping of the integrated type 16 human papillomavirus (HPV16) sequences in biopsied and paraffin-embedded archival cervical cancer samples is described. The procedure involves the use of an anchor primer and a mixture of indicator primers in a multiplex polymerase chain reaction (PCR). A minimal conserved region of viral integration of 2,745 bp in length has been mapped between nucleotide (nt) 6102-941, containing the entire regulatory region and the E6 and E7 open reading frames (ORFs). A general deletion domain of 1,465 bp in the integrated viral genome has been defined between nt 1417-2881, covering most of the E1 ORF at the 3'-half and 60 bp at the 5' terminus of the E2 ORF. This common deleted sequence contains an ATPase active domain speculated to be associated with a DNA helicase function essential for the viral replication, and it also falls within the actively spliced E1-E2 segment of the primary RNA transcripts. Detection of the loss of the 3'-half of the E1 ORF would be an ideal marker for PCR-based rapid determination of HPV integration in cervical cancer cells. PMID- 7852963 TI - Detection of adeno-associated virus DNA in human genital tissue and in material from spontaneous abortion. AB - The human helper virus-dependent parvovirus, adeno-associated virus (AAV) has never been associated with disease in humans [Berns et al. (1987): Advances in Virus Research 32:243-306; Siegl et al. (1985): Intervirology 23:61-73]. However, in pregnant mice, infection with AAV induces early abortion [Botquin et al. (1993): Journal of Cancer Research and Clinical Oncology 119:24]. We investigated whether this common human virus may be found in human genital tissue or in curettage material from spontaneous abortion. Using the polymerase chain reaction (PCR) AAV type 2 DNA was amplified in histological sections of 19 of 30 biopsies of the uterine mucosa. In addition, AAV-2 DNA was detected in abortion material during the first trimester of pregnancy (12/30 cases were positive) but not in material of abortion from the second or third trimester (9 cases). Whereas in tissues from the uterus AAV DNA was found only by PCR, large amounts of viral DNA were detectable by Southern blot analysis in abortion material. In situ hybridization revealed DNA of AAV to be present in the villous moiety (trophoblast) of the placenta but not in the embryo or decidua. in the same cells, AAV proteins (including the replication-associated rep proteins) were detected by immunofluorescence analysis. These results suggest (1) that AAV infects the uterine mucosa (possibly persistently) and (2) that it can replicate in trophoblast cells. This might disturb placenta development and may play a role in early miscarriage.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7852964 TI - Evaluation of commercially available assays for antibodies to HIV-1 in serum obtained from South African patients infected with HIV-1 subtypes B, C, and D. AB - Between 1984 and 1990, virus was routinely isolated and serum collected from patients diagnosed at hospitals in the Western Cape as suffering from AIDS or AIDS-related conditions (ARC). From these, 17 virus strains were selected at random for sequencing and molecular characterisation of the env gene. The strains were previously characterised as belonging to HIV-1 subtypes B, C and D. The purpose of the present study was to evaluate retrospectively the serological diagnosis of HIV-1 in these 17 South African patients. Thirteen anti-HIV screening assays, including 7 rapid/simple test devices (RTDs), 4 enzyme-linked immunosorbent assays (EIAs) and 2 Western immunoblot assays were evaluated. Using commercial EIAs, 16 serum samples were HIV antibody-positive and these results were confirmed by Western immunoblot analysis. Serum from one terminal AIDS patient was found negative with all the serological tests. Some RTDs gave false negative antibody reactions on specimens from patients infected with subtype D strains. To investigate the false negative antibody reactions, the polymerase chain reaction (PCR) was used to amplify, clone and sequence proviral DNA from the immunodominant gp41 region from 7 of the HIV-1 strains. Two patients, both subtype D strains (D214 and D482) with false negative results in the RTDs, showed a significant amino acid substitution, i.e., substitution of a histidine residue for leucine at env position 607. It was concluded that although there were false negative RTD reactions on patients with HIV-1 subtype D strains, the commercial EIAs tested are sensitive and are able to detect patients infected with HIV-1 subtypes B, C and D that are present in South Africa. PMID- 7852965 TI - Presence of infective Epstein-Barr virus in the urine of patients with infectious mononucleosis. AB - The presence of Epstein-Barr virus (EBV) in the blood and urine of 20 patients with infectious mononucleosis (IM) was investigated together with the clinical course of the disease, and in 9 patients up to 2-7 months after recovery. EBV DNA, analyzed by the polymerase chain reaction (PCR), was detected in the blood of all 20 patients from the first sample obtained and detected between 3 to 42 days from the beginning of symptoms and up to 2-3 months after recovery. In the urine, EBV DNA was detected in 15 out of 16 (93%) patients in the first sample obtained and detected between 3 to 50 days during the clinical course of the disease. In four patients EBV DNA was detected in the urine up to 3 months after full recovery. Seventeen out of 26 (65%) urine samples including 3 which were obtained 2-7 months after recovery infected B cells as assessed by PCR. Nine out of 12 (75%) urine samples tested induced Epstein-Barr nuclear antigen (EBNA) in the infected B-cell line. In addition to the persistence of EBV in the blood of IM patients, these studies show for the first time the presence of infective EBV in the urine during the clinical course of the disease and up to 7 months after full clinical recovery. PMID- 7852966 TI - Genotypes of hepatitis C virus in chronic liver disease in Taiwan. AB - The genotypes of hepatitis C virus (HCV) infection in 81 patients with liver cirrhosis (LC) or hepatocellular carcinoma (HCC) were investigated by the polymerase chain reaction using type-specific primers. All the patients were positive for HCV RNA in the serum. Forty-two patients had LC with HCC, while the remaining 39 patients had LC without HCC. Genotype II was detected in 47 samples (58.0%), type III in 6 samples (7.4%), and type IV in 4 (6.2%). No evidence of genotype I was found. Mixed infection was detected in 11 samples (13.6%). The prevalence of genotype II in LC with HCC patients (69.0%) was significantly higher (P < 0.05) than in the LC without HCC patients (46.2%). It is concluded that genotype II is the most predominant type in patients with LC or HCC in Taiwan, and is found more frequently in patients who had LC with HCC than in those who had LC alone. PMID- 7852967 TI - Human rotavirus subgroups and serotypes in children with acute gastroenteritis in Saudi Arabia from 1988 to 1992. AB - Rotavirus infection was detected in 524 (42.2%) of the 1,242 stool specimens collected from infants and young children with acute gastroenteritis admitted to a major pediatric hospital in Jeddah, Saudi Arabia, between March 1988 and December 1992. Enzyme-linked immunosorbent assay (ELISA) and monoclonal antibodies specific for subgroup I and II were used to examine 80 rotavirus positive specimens. Subgroup I was detected in 21 (26.3%) and subgroup II in 49 (61.3%) specimens. Six specimens reacted with both subgroup I and II monoclonal antibodies and four specimens were untypeable. Serotyping of 355 rotavirus positive specimens using monoclonal antibodies specific for the human rotavirus serotypes 1 to 4 revealed a distribution profile of serotype 1, 53.5%; serotype 2, 6.8%; serotype 3, 5.9%; and serotype 4, 22.8%, along with mixed and untypeable specimens (11%). When the correlation between subgroup and serotype specificities was examined in 62 specimens, all subgroup I specimens were found to be serotype 2 or untypeable and all subgroup II specimens belonged predominantly to serotypes 1 (54.7%) and 4 (9.4%). Serotype 1, followed by, to a lesser extent, serotype 4, exhibited a temporal predominance in the 5-year investigation. A significant clustering of the various serotypes during the cooler months was evident almost throughout the study, particularly in 1989 and 1990. PMID- 7852969 TI - Simple procedure for discrimination and typing of enteric adenoviruses after detection by polymerase chain reaction. AB - A procedure was developed for specific discrimination and typing of the enteric human adenoviruses, Ad40 and Ad41, after polymerase chain reaction (PCR) amplification of a sequence in the hexon gene highly conserved among all 47 serotypes recognised. By Taq I restriction of the 300 bp amplimers, subgenus F DNA could be discriminated from DNAs of adenoviruses belonging to all other subgenera. Discrimination between Ad40 and Ad41 was subsequently achieved by cleavage with either Cfo I, HinP I, Mae III, Mvn I, and/or Rsa I. Thus, PCR detection of viral DNA combined with restriction analysis of amplified products provides a valuable tool for use in epidemiological studies of diarrhoea of adenoviral aetiology. PMID- 7852968 TI - Degradation of p53 only is not sufficient for the growth stimulatory effect of human papillomavirus 16 E6 oncoprotein in human embryonic fibroblasts. AB - Certain types of human papillomavirus (HPV), such as types 16 and 18, are thought to be responsible for the development of cervical carcinomas. The E6 and E7 genes of these viruses have transforming activities in various cultured cells and their mRNAs and proteins are expressed in almost all cervical carcinoma cells. Inactivation of the tumor suppressor p53 protein by the E6 gene is believed to be critical for transformation by these oncogenic HPVs. To determine whether degradation of the p53 protein is, in fact, sufficient for cellular transformation by the E6 gene, the E6 gene of HPV16 was introduced into human embryonic fibroblasts (HEF) using recombinant murine retrovirus and examined whether reduction of the p53 protein could substitute for the E6 function. It was found that HEF cells transfected with the E6 gene showed an increased saturation density and degraded the p53 protein. However, when expression of the p53 protein in normal HEF cells was suppressed by the antisense oligonucleotide of the p53 gene, growth stimulation was not observed. These results show that the E6 gene stimulates growth of HEF cells, but that this activity involves some other E6 gene-mediated functions than degradation of the p53 protein. PMID- 7852970 TI - Activation of a varicella-zoster virus-specific IgA response during acute Epstein Barr virus infection. AB - The influence of an acute Epstein-Barr virus (EBV) infection on the serological parameters of persistent varicella-zoster virus (VZV) and herpes simplex virus (HSV) was studied. Sera from 161 patients with infectious mononucleosis caused by EBV and 178 age-matched controls were tested for HSV- and VZV-specific IgA. 98.7 percent of VZV-IgG-positive controls were negative for VZV-IgA, pointing to the stringent control of latent VZV in healthy individuals. During acute EBV infection, 33.8% of VZV-IgG-positive infectious mononucleosis patients produced VZV-specific IgA. This result may be explained either by reactivation of VZV due to transient suppression of cellular immune functions during acute EBV infection or by polyclonal stimulation caused by EBV. Due to the high incidence of HSV-IgA in healthy HSV-IgG-positive individuals, only a marginal effect of acute EBV infection on the appearance of HSV-specific IgA was found. PMID- 7852971 TI - Detection of varicella-zoster virus DNA in blood of children with varicella. AB - The nested polymerase chain reaction was used to detect varicella zoster virus (VZV) DNA in 67 samples of peripheral blood mononuclear cells (PBMC) from 39 otherwise healthy children with varicella. Eleven were during the incubation period and 56 were after appearance of rash. VZV DNA was detected in two of eight (25%) PBMC at the early phase of the incubation period (day -14 to -11). The rate of the detection increased to 67% in -5 to -1 days prior to the onset of the rash and 46% in 0-4 days after the onset. It declined gradually with time and was undetectable in patients after 15 days from the clinical onset. The serum antibody determined with the fluorescent antibody to membrane antigen was first detected in the samples on day 2 and subsequently increased to 100% rapidly. In conclusion, VZV DNA cannot be detected usually in PBMC of healthy children except in varicella. PMID- 7852972 TI - Genomic diversity of small round structured viruses in the United Kingdom. AB - Fifty-two faecal specimens collected in the United Kingdom between 1986 and 1992, which contained small round structured virus (SRSV) particles, were tested by reverse transcriptase polymerase chain reaction assays using two primer pairs derived from sequences of Snow Mountain Agent and Norwalk virus. There was poor correlation between results obtained with each primer pair. Twenty specimens (38%) gave positive bands with SM51/31 primers and 18 (34%) were positive with SM52/32 primers, with a total of 30 specimens (57.7%) giving amplification products of the expected size with one or both primer pairs. Genomic variation was investigated by sequencing a 266 bp region of the RNA polymerase gene from nine strains which had been antigenically typed by solid phase immune electron microscopy (SPIEM). RNA sequence identities ranged from 53 to 99%. Three genomic groups were suggested by phylogenic analysis, the first of which contained Norwalk virus, Southampton virus, and strains typed by SPIEM as SRSV UK2. The second contained Snow Mountain agent and strains typed as either SRSV UK3 or UK4. The third contained strains typed as SRSV UK1 and strains untypeable by SPIEM. Some correlation was demonstrated when antigen typing by SPIEM and phylogenic grouping based on sequence data were compared. PMID- 7852973 TI - Detection of hepatitis B virus DNA in the serum of Canadian hepatitis B surface antigen negative, anti-HBc positive individuals, using the polymerase chain reaction. AB - Continuing hepatitis B virus (HBV) infection is normally associated with the presence of hepatitis B surface antigen (HBsAg) in the serum. In spite of sensitive screening assays for HBsAg, rare cases of post-transfusion HBV infection are still observed. Antibody to hepatitis B core antigen (anti-HBc) often indicates remote HBV infection but DNA hybridisation and more sensitive polymerase chain reaction (PCR) assays have demonstrated that some HBsAg negative individuals, positive for anti-HBc, have continuing HBV replication. To determine the incidence of ongoing HBV infection in a Canadian HBsAg negative, anti-HBc positive population we studied three groups with this combination of HBV markers: Group A, 36 patients referred for investigation of raised serum aminotransferases; Group B, 21 Canadian Red Cross blood donors; Group C, seven vaccinees in an Ottawa Health Care Student hepatitis B vaccination programme. The PCR was carried out using a nested PCR reaction with primers specific for the pre core region of HBV. Seven of 36 (19%) patients in Group A had detectable HBV DNA whereas none of Group B or C were positive. This data indicates that in some HBsAg negative patients with ongoing hepatic inflammation, continuing HBV replication may persist. This was not observed in any healthy blood donors or health care students investigated. Larger studies are required, but this data would suggest that, in Canada, the addition of anti-HBc testing for all blood donors for detection of low level HBV replication would not be indicated. PMID- 7852974 TI - Brain and kidney of progressive multifocal leukoencephalopathy patients contain identical rearrangements of the JC virus promoter/enhancer. AB - The kidneys of six progressive multifocal leukoencephalopathy (PML) patients were examined by PCR amplification for the presence of JC virus. Amplification of three different areas of the viral genome from multiple samples of each kidney revealed three that were positive for the virus. The use of a PCR-based typing assay on all tissue samples, and cloned sequences from the viral coding region from each positive kidney showed that the same viral genome was present in the kidney as in the brain of the patient. Regulatory region clones all had the archetypal promoter/enhancer structure. However, when PCR fragments from the regulatory region were digested with a restriction enzyme which cuts in region D, the region most often deleted in PML-type promoters, a low level of undigested DNA remained. This DNA refractory to digestion had a rearranged sequence identical to that of the unique rearranged promoter in the brain of each patient. PMID- 7852975 TI - Investigation of cytomegalovirus infection as a risk factor for coronary atherosclerosis in the explanted hearts of patients undergoing heart transplantation. AB - Infection with a human herpes virus, particularly cytomegalovirus (CMV), has been hypothesized to be a cofactor in the development of atherosclerosis in humans. We investigated the association of prior CMV infection with the presence of atherosclerosis in the coronary arteries of the native heart of 314 individuals undergoing heart transplantation. Age, male gender, race, tobacco use, and previous general and cardiac surgery were also studied as covariables. Factors associated with the presence of coronary atherosclerosis by univariate analysis were age greater than the median of 48 years (odds ratio [OR] = 5.9, 95% confidence intervals [CI] 3.0-11.6; P < 0.0001), tobacco use (OR = 3.8, 95% CI 2.1-7.0; P < 0.005), CMV seropositivity (OR = 3.1, 95% CI 1.8-5.5; P < 0.001), and male gender (OR = 3.0, 95% CI 1.6-5.4; P < 0.0005). When patients were divided into quartiles based on age, coronary atherosclerosis was shown to be associated with CMV seropositive status only in the youngest quartile of patients (OR = 3.6, 95% CI 1.4-8.9; P < 0.01) but not in the older three quartiles of patients (OR = 0.9, 95% CI = 0.3-2.4; P > 0.5). In multiple logistic regression analyses, CMV seropositivity was not a significant independent variable in the whole group of patients (P = 0.13) but remained a significant variable in the youngest quartile of patients (P = 0.01). However, 43% of these younger patients and 29% of all patients with coronary atherosclerosis were seronegative for CMV.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7852976 TI - Use of the colonic carcinoma cell line CaCo-2 for in vivo amplification and detection of enteric viruses. AB - The use of the continuous cell line CaCo-2 as an in vivo amplification system for the detection of fastidious human enteric viruses is reported. CaCo-2 cells showed an increased sensitivity to laboratory strains of group A rotavirus 3, reovirus 3, astrovirus 1, poliovirus 1, coxsackievirus A 24, enterovirus 70, and adenovirus 5, 40 and 41, when compared to a routine host cell line for each virus. Nucleic acids from wild-type infectious rotavirus, astrovirus, and adenovirus 40 in stool samples of patients with acute gastroenteritis could be amplified after infection of CaCo-2 cells with trypsin-pre-treated virus inocula. Virus diagnosis was carried out subsequently by dot-blot hybridisation with specific cDNA probes. An amplification factor between 10 and 1,000x was obtained by infection of CaCo-2 cells, thus enabling specific detection of low numbers of a wide range of enteric viruses, and the differentiation between infectious and noninfectious particles. PMID- 7852977 TI - Comparison of personality traits of only and sibling school children in Beijing. AB - The number of only children in China has increased rapidly since the late 1970s, when the Chinese government advocated the "one-child-per-family" policy. This increase has caused much public concern about the healthy growth of the young generation. In this study the behavioral traits of Chinese, urban, only children were investigated. The participants were 444 children with siblings and 473 only children from Grades 1, 3, and 5 in Beijing primary schools. An inventory consisting of 27 items covering three behavioral traits was developed. The children were rated on the inventory by the principal teacher of the class. Factor analysis revealed three main factors: achievement motivation, interpersonal skills, and attitude toward manual labor. The only children exceeded the sibling children on achievement motivation. No differences were found between only children and sibling children on interpersonal skills and attitude toward manual labor. Gender differences were evident; girls consistently received higher ratings on achievement motivation and interpersonal skills. The possible underlying reasons for these differences are discussed. PMID- 7852978 TI - Structure of leadership among preschool children. AB - The purpose of the present study was to examine the structure of leadership among preschool children. Leadership behaviors of 18 five-year-old Japanese children were observed during free play and scored on the basis of a 15-item leadership scale. A factor analysis of the items indicated two factors: facilitation of play and consideration-evaluation of playmates. Children who had a central role in group play showed more leadership behaviors on the consideration-evaluation of playmates dimension than those on the periphery. For the dimension of facilitation of play, however, no significant difference was seen between the two groups. PMID- 7852979 TI - Elementary school achievement and absence due to illness. AB - The aim of the present study was to examine whether school performance is influenced by absence because of illness and if there are any differences in the relationship due to grade, sex, and season of birth. Data were taken for 598 pupils born in 1947 whose complete records for the 1st through 6th grades were stored at the city archive of Uppsala. Simple correlational analyses were conducted between spring absence due to illness in the 2nd through 6th grades and teacher-assigned grades during the same spring for verbal and arithmetic performance. Significant negative correlations were found between absence and both arithmetic and verbal performance in Grades 5 and 6. Subgroup analysis revealed significant correlations for the girls in the 5th grade and for boys in the 6th grade. However, only girls and boys born during the first half of the year showed these significant correlations between absence due to illness and performance. PMID- 7852980 TI - Children's use of mnemonic strategies: variability in response to metamemory training. AB - In this study, 8- to 12-year-old children were tested to determine their level of use of a strategy for organizing lists of low-associated words into semantic groups. Then, on the basis of their scores in the strategy tests, the children were placed in either a strategic or nonstrategic group. The groups were divided into a sort-instruction training condition, in which they were told to group words so that they "go together" in some way, and a metamemory training condition, in which these instructions were supplemented by feedback, strategy reminders, and opportunities to self-test. One week later, each child's strategy use was reassessed. Children in the strategic group sorted semantically throughout training and transfer, and they showed high recall, regardless of condition. Children in the nonstrategic group showed high strategy use and recall during training, but they showed significantly more variability in recall than did the children in the strategic group. Children in the nonstrategic-metamemory condition who benefited from training were also more likely to transfer the use of the strategy than were children trained in the sort-instruction condition. PMID- 7852981 TI - Adjectives or nouns to refer to objects: effects on the complementation and inclusion performance of 6- to 9-year-old children. AB - Due to the exclusivity bias (a given object is considered to have only one generic name), inclusion problem solving by children should be adversely affected by the use of nouns rather than adjectives to refer to objects. In contrast, the children's complementation behavior should be facilitated, because naming promotes the organization of objects into additive subclasses under a generic class. Groups of children 6 to 9 years old were asked to solve complementation and inclusion problems about a set of objects designated by nouns or by real or nonsensical adjectives. The results showed that complementation performance was indeed enhanced by the use of nouns, but inclusion behavior was not affected by the type of term used. PMID- 7852982 TI - The assessment of childhood sibling relationships: varying perspectives on cooperation and conflict. AB - The levels of cooperation and conflict in the relationships of 40 sibling pairs, 11 to 14 years old, were explored from several different perspectives. Ratings of levels of cooperation and conflict in the sibling relationship were obtained from the participants, siblings, and mothers. Amounts of cooperation and conflict were also coded from responses to a projective story test that elicited perceptions of the relationship from each child, and from their conjoint performance on three interactive tasks. Either child's perspective on the sibling relationship evidenced more conflict and less cooperation relative to maternal evaluations. Interactive tasks revealed more cooperation, whereas projective stories revealed more conflict for these siblings. In addition, levels of cooperation varied by sex, birth order, and dyad type, whereas conflict levels differed only by dyad type. PMID- 7852983 TI - The Adult Attachment Interview and questionnaires for attachment style, temperament, and memories of parental behavior. AB - Relations between Adult Attachment Interview (AAI) outcomes and data from questionnaires on attachment style, temperament, and memories of parental caregiving behavior were investigated to examine theoretical and methodological specificity of the AAI. The participants were 83 mothers of 1-year-olds. No differences between the three AAI classifications (autonomous, dismissing, or preoccupied) were found. Correlations between scales yielded few significant relations, with the exception of strong relations between some AAI scales for experiences and self-reported memories of parental behavior. The self-report questionnaires for attachment style and memories of parental behavior were therefore found to be not suitable for obtaining information about attachment working models as assessed by the AAI. Furthermore, attachment working models appear independent of temperament. PMID- 7852984 TI - Reliability of the Harter Self-Perception Profile for Children and predictors of global self-worth. AB - Harter's (1985) Self-Perception Profile for Children is one of the measures most widely used by developmental social psychologists. The aim of the present study was to investigate the test-retest reliability of the subscales for 24 children over a 3-year period. The results show that scores on the global self-worth subscale at age 8 correlated highly with scores at age 11 (r = .61) and did not change over time, t(23) = 0.22. These results suggest that perceptions of global self-worth remain highly stable. However, domain-specific measures of competence did not show the same level of stability. Harter (1990) has suggested that global self-worth is a function of domain-specific measures. The relationship between global self-worth and the domain-specific measures was also investigated at each age; although the perception of physical appearance was the single best predictor of global self-worth at both age 8 and age 11, the second best predictor at age 8 was perception of social acceptance, whereas at age 11 it was scholastic competence. PMID- 7852985 TI - A comparison of children's performance on different linear-ordering tasks. AB - The discrepancy between children's performances on Brown and Murphy's (1975) and Piaget and Inhelder's (1956) studies of ordering tasks was investigated. Twenty two 4-year-old children were asked to carry out a linear-ordering task that was based on Piaget and Inhelder's (1956) task in which children copied the arrangement of clothes on a clothesline. The type of instructions and the type of layout were varied. There was an effect for the type of layout (p < .01), but the children performed equally well irrespective of the instructions they were given, and overall they were very successful. The results support Brown and Murphy's findings that ability to reproduce a sequence in linear-ordering tasks is developed earlier than previous research has indicated. PMID- 7852986 TI - Questioning a universal theory of mind: mental-real distinctions made by Indian children. AB - The purposes of this experiment were to investigate the effects of age, item type, and culture on the mental-real distinction made by children. A sample of 42 children (21 affluent and 21 deprived) in three age ranges (3- and 4-year-olds, 5 and 6-year-olds, and 7- and 8-year-olds) participated. Nine items were used. The behavioral-sensory and public-existence criteria (Wellman & Estes, 1986) were used to gauge the children's ability to make the distinction. Contrary to previous research findings, the 3- and 4-year-olds in this study were unable to make the mental-real distinction. An age-related improvement in making this distinction was observed, and item type affected the mental-real distinction. The affluent children consistently outperformed their deprived counterparts. This finding was partly construed as evidence for the influence of culture on the ability to make this distinction in these age groups. PMID- 7852987 TI - The impact of delayed fatherhood on the father-child relationship. AB - There is little empirical research on the impact of delayed fatherhood on the father-child relationship. From a large, nationally representative sample of adults in the United States, a subsample was drawn of 47 men who were both fathers of minor children and had fathered their first child after their 35th birthday. Ordinary least-squares regression analysis was used to test four hypotheses. Late-time fathers were found to (a) spend more time in leisure activities with their children, (b) have higher expectations for their children's behavior, and (c) be more nurturant toward their children, but they (d) showed no difference in controlling behavior toward their children when compared with on time fathers. Empirical support is presented for the establishment of age 35 as the criterion for delayed fatherhood in future studies. Recommendations for future research are offered. PMID- 7852988 TI - Neurotrophic factors: an evolutionary perspective. PMID- 7852989 TI - The role of neurotrophins in the developing nervous system. AB - Neurotrophins were originally identified by their ability to promote the survival of developing neurons. However, recent work on these proteins indicates that they may also influence the proliferation and differentiation of neuron progenitor cells and regulate several differentiated traits of neurons throughout life. Moreover, the effects of neurotrophins on survival have turned out to be more complex than originally thought. Some neurons switch their survival requirements from one set of neurotrophins to another during development, and several neurotrophins may be involved in regulating the survival of a population of neurons at any one time. Much of our understanding of the developmental physiology of neurotrophins has come from studying neurons of the peripheral nervous system. Because these neurons and their progenitors are segregated into anatomically discrete sites, it has been possible to obtain these cells for in vitro experimental studies from the earliest stage of their development. The recent generation of mice having null mutations in the neurotrophin and neurotrophin receptor genes has opened up an unparalleled opportunity to assess the physiological relevance of the wealth of data obtained from these in vitro studies. Here I provide a chronological account of the effects of members of the NGF family of neurotrophins on cells of the neural lineage with special reference to the peripheral nervous system. PMID- 7852990 TI - Structure-function relationships in the neurotrophin family. AB - The study of structure-function relationships in the neurotrophin family has in recent years increased our understanding of several important aspects of neurotrophin function. Site-directed mutagenesis studies have localized amino acid residues important for binding to the low-affinity (p75LNGFR), as well as to the members of the Trk family of tyrosine kinase receptors. A cluster of positively charged residues has been shown to form a surface for binding to p75LNGFR in all four neurotrophins. Differences in the spatial distribution of these charges among the different neurotrophins may explain some of their distinct binding properties. Elimination of these positive charges drastically reduces binding to p75LNGFR but not to the Trk family members, and it does not impair the biological properties of the neurotrophins in vitro, arguing that binding to and activation of Trk receptors is sufficient to mediate the biological responses of neurotrophins. In contrast, the binding sites to Trk receptors appear to be formed by discontinuous stretches of amino acid residues distributed throughout the primary sequence of the molecule. These include the N terminus, some of the variable loop regions and a beta-strand. Despite their apparent distribution, when viewed in the three-dimensional structure of NGF, these residues appear grouped on one side of the neurotrophin dimer, delineating a continuous surface extending approximately parallel to the twofold symmetry axis of the molecule. Two symmetrical surfaces are formed along the axis of the neurotrophin dimer providing a model for ligand-mediated receptor dimerization. In the neurotrophin family, co-evolution of cognate ligands and Trk receptors has developed specific contacts through different residues in the same variable regions of the neurotrophins. Thus, binding specificity is determined by the cooperation of distinct active and inhibitory binding determinants that restrict ligand-receptor interactions. Binding determinants to the Trk receptors can be manipulated independently in a rational fashion to create neurotrophin analogues with novel ligand-binding properties. In this way, second-generation chimeric neurotrophins with multiple specificities (pan-neurotrophins) have been engineered which may have valuable applications in the treatment of neurodegeneration and nerve damage. PMID- 7852991 TI - Activity-dependent and hormonal regulation of neurotrophin mRNA levels in the brain--implications for neuronal plasticity. AB - The neurotrophins exhibit neurotrophic effects on specific, partially overlapping populations of neurons both in the peripheral and the central nervous system (CNS). In the periphery, they are synthesized by a variety of nonneuronal cells, and their synthesis seems to be independent of the neuronal input. In contrast, in the CNS all neurotrophins are expressed under physiological conditions primarily by neurons. The production of NGF and BDNF is controlled by neuronal activity: up-regulation by glutamate and acetylcholine, down-regulation by gamma aminobutyric acid. In contrast, NT-3 regulation is independent of neuronal activity, but it is up-regulated by thyroid hormones and BDNF. The latter observation suggests that NT-3 might be controlled indirectly by neuronal activity via BDNF. In peripheral nonneuronal tissues, glucocorticoid hormones down-regulate NGF mRNA levels both in vitro and in vivo. In contrast, in the CNS, neuronal production of NGF is enhanced by glucocorticoids. The rapid regulation of NGF and BDNF by subtle physiological stimuli together with the recent demonstration that the neurotrophins release neurotransmitters such as acetylcholine opens up interesting perspectives for the function of neurotrophins as mediators of neuronal plasticity. PMID- 7852992 TI - The p75 neurotrophin receptor. AB - The low-affinity p75 molecule and trk tyrosine kinases serve as receptors for target-derived neurotrophins. While the mechanism by which receptor tyrosine kinases impart intracellular signaling has become well understood, the precise roles of the p75 receptor are not fully defined. The p75 neurotrophin receptor belongs to a family of transmembrane molecules which also serve as receptors for the tumor necrosis factor family of cytokines. Each receptor shares a common extracellular structure highlighted by conserved cysteine-rich repeats. Because NGF, BDNF, NT-3, and NT-4/5 bind to p75 with similar affinity, p75 may either act as a common subunit in a neurotrophin receptor complex with trk family members, or act by independent mechanisms to mediate biological actions of each neurotrophin. PMID- 7852993 TI - The Trk family of neurotrophin receptors. AB - Accumulating evidence indicates that the Trk family of tyrosine protein kinase receptors, Trk (also known as TrkA), TrkB, and TrkC, are responsible for mediating the trophic effects of the NGF family of neurotrophins. Nerve growth factor (NGF) specifically recognizes Trk, a receptor identified in all major NGF targets, including sympathetic, trigeminal, and dorsal root ganglia as well as in cholinergic neurons of the basal forebrain and the striatum. Brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT-4) specifically activate the TrkB tyrosine kinase receptor. trkB transcripts encoding this receptor are found throughout multiple structures of the central and peripheral nervous system. Neurotrophin-3 (NT-3) primarily activates the TrkC tyrosine protein kinases, four related isoforms encoded by alternative splicing of trkC, a gene also widely expressed throughout the mammalian nervous system. Unlike the other neurotrophins, NT-3 appears to be somewhat promiscuous since it can activate Trk and TrkB kinase receptors, at least in certain cell systems. The trkB and trkC genes also encode noncatalytic neurotrophin receptor isoforms of an as yet, unknown function. Recently, strains of mice lacking each of these tyrosine kinase receptors have been generated. Preliminary characterization of these mutant mice has provided significant information regarding the role of these receptors in the ontogeny of the mammalian nervous system. For instance, mice deficient for Trk receptors lack most sympathetic neurons and do not display nociceptive and temperature sensations, two defects likely to result from severe neuronal cell loss in their trigeminal and dorsal root ganglia. Mice lacking TrkB tyrosine kinase receptors die postnatally due to their inability to intake food. Neuron cell loss in their trigeminal, nodose and petrosal sensory ganglia as well as in the facial motor nucleus are likely to contribute to this phenotype. Finally, TrkC-deficient mice display strikingly abnormal movements consistent with loss of proprioception, a defect likely to be a consequence of the complete loss of Ia muscle afferents observed in this mutant mice. PMID- 7852994 TI - Neurotrophin signal transduction by the Trk receptor. AB - The initial event in the neuronal differentiation of PC12 cells is the binding of the neurotrophin nerve growth factor (NGF) to the Trk receptor. This interaction stimulates the intrinsic tyrosine kinase activity of Trk, initiating a signalling cascade involving the phosphorylation of intracellular proteins on tyrosine, serine, and threonine residues. These signals are then in turn propagated to other messengers, ultimately leading to differentiation, neurotrophin-dependent survival, and the loss of proliferative capacity. To transmit NGF signals, NGF activated Trk rapidly associates with the cytoplasmic proteins, SHC, PI-3 kinase, and PLC-gamma 1. These proteins are involved in stimulating the formation of various second messenger molecules and activating the Ras signal transduction pathway. Studies with Trk mutants indicate that the activation of the Ras pathway is necessary for complete differentiation of PC12-derived cells and for the maintenance of the differentiated phenotype. Trk also induces the tyrosine phosphorylation of SNT, a specific target of neurotrophic factor activity in neuronal cells. This review will discuss the potential roles of Trk and the proteins of the Trk signalling pathways in NGF function, and summarize our attempts to understand the mechanisms used by Trk to generate the many phenotypic responses of PC12 cells to NGF. PMID- 7852995 TI - Neurotrophic factor therapy for nervous system degenerative diseases. AB - The ability of neurotrophic factors to regulate developmental neuronal survival and adult nervous system plasticity suggests the use of these molecules to treat neurodegeneration associated with human diseases. Solid rationales exist for the use of NGF and neurotrophin-3 in the treatment of neuropathies of the peripheral sensory system, insulin-like growth factor and ciliary neurotrophic factor in motor neuron atrophy, and NGF in Alzheimer's disease. Growth factors have been identified for neurons affected in Parkinson's disease, Huntington's disease, and acute brain and spinal cord injury. Various strategies are actively pursued to deliver neurotrophic factors to the brain, and develop therapeutically useful molecules that mimic neurotrophic factor actions or stimulate their production or receptor mechanisms. PMID- 7852996 TI - Ciliary neurotrophic factor. AB - Ciliary neurotrophic factor (CNTF) was first identified and partially purified from embryonic chick eye tissues. Subsequently, it was shown that CNTF is also present in large amounts in sciatic nerves of adult rats and rabbits, which led to its final purification and cloning. CNTF is not secreted by the classical secretory pathway involving the endoplasmatic reticulum and Golgi complex, but can be detected in high quantities within the cytoplasm of myelinating Schwann cells and astrocytes using immunohistochemistry. CNTF supports survival and/or differentiation of a variety of neuronal cell types including sensory, sympathetic, and motoneurons. Also, nonneuronal cells, such as oligodendrocytes, microglial cells, liver cells, and skeletal muscle cells, respond to exogenously administered CNTF, both in vitro and in vivo. During development, expression of CNTF is very low, if indeed it is expressed at all, and the phenotype of mice lacking endogenous CNTF after inactivation of the CNTF gene by homologous recombination suggests that CNTF does not play a crucial role for responsive cells during embryonic development. However, motoneurons are lost postnatally in mice lacking endogenous CNTF, suggesting that CNTF acts physiologically on the maintenance of these cells. The ability of exogenous CNTF to protect against motoneuron loss following lesion or in other animal models indicates that CNTF might be useful in the treatment of human motoneuron disorders, provided appropriate means of administration can be found. PMID- 7852997 TI - The tripartite CNTF receptor complex: activation and signaling involves components shared with other cytokines. AB - Recent efforts to understand the mechanism of action of CNTF have led to the identification of a three-component receptor complex for CNTF. The distributions of these receptor components explain the known target cell specificity of CNTF, and have also helped identify new and unexpected targets of CNTF action. In addition to including a CNTF-specific component, known as CNTFR alpha, the CNTF receptor complex utilizes two receptor components, gp130 and LIFR beta, that are shared with members of a family of broadly acting cytokines, including leukemia inhibitory factor (LIF) and interleukin-6 (IL6). The finding that the CNTF receptor complex shares components with this family of cytokines has led to the realization that CNTF should also be considered a cytokine--but one that differs from its relatives in that its actions are largely limited to cells of the nervous system due to the restricted expression of one of its receptor components, CNTFR alpha. CNTFR alpha does not play a direct role in signaling, but instead forms a complex with CNTF that promotes its binding to the signal transducing "beta" receptor components, gp130 and LIFR beta. Thus CNTF utilizes identical signal transducing receptor components in neurons that its relatives use on nonneuronal cells to elicit strikingly dissimilar responses, indicating that different cells interpret the same cell surface signal in dramatically different ways. The three CNTF receptor components are initially unassociated on the cell surface, and are brought together in step-wise fashion upon CNTF binding. CNTF first binds to CNTFR alpha, then recruits gp130, and finally complexes with LIFR beta. It is this last step in complex formation, involving heterodimerization between "beta" components, that activates intracellular signaling. Signal initiation is due to activation of members of a family of cytoplasmic tyrosine kinase, known as the Jak/Tyk kinases, which are preassociated with the beta components in an inactive state and then become activated upon beta component dimerization; the Jak/Tyk kinases, in turn, activate a variety of intracellular signaling molecules, such as members of the STAT family of DNA binding transcriptional activators. A detailed understanding of the mechanism of activation of the CNTF receptor complex has led to the realization that all members of the CNTF family of cytokines activate signaling in much the same way, by inducing either homo- or heterodimerization of beta receptor components and thus activation of the preassociated Jak/Tyk kinases; this mode of receptor activation may prove to be more generally applicable to all cytokine receptors.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7852998 TI - Fibroblast growth factors in the nervous system. AB - Fibroblast growth factors (FGFs) exhibit widespread mitogenic and neurotrophic activities. Nine members of the family are currently known, and FGF-1 and FGF-2 are present in relatively high levels in CNS. FGF-1 is expressed by a subset of neuronal populations, while FGF-2 is expressed by astrocytes. FGF-1 and FGF-2 lack signal peptides and appear to be present mainly in intracellular compartments. This suggests that the factors may act as initiators of a repair response after injury. Support for this notion comes from observations that FGF-1 and FGF-2 levels are low during critical phases of development, but high in the adult CNS. A family of transmembrane tyrosine kinase receptors (FGFRs) mediates the effects of FGFs. Four different genes coding for FGF receptors are currently known, three of which are expressed in cell type-specific patterns in the CNS. The main receptor variants present in this tissue, however, can by themselves not distinguish between FGF-1 and FGF-2. Additional selectivity may be established by interaction of the FGFs and their receptors with select heparan proteoglycans (HSPGs). Therefore, the precise physiological role of FGFs is determined by the combination of cell type-specific patterns of expression of FGFs, FGFRs and HSPGs together with the mechanisms that regulate the extracellular availability of FGFs. PMID- 7852999 TI - Cucurbitacins, cell adhesion inhibitors from Conobea scoparioides. AB - In the course of screening natural products for antagonists of CD18-mediated cell adhesion, an extract with inhibitory activity was identified from the stem and leaves of Conobea scoparioides. Bioassay-guided fractionation led to a pure compound, identified by spectroscopy as cucurbitacin E [1]. Although many biological activities have been reported for the cucurbitacins, this is the first report of cell adhesion inhibition. Furthermore, closely related cucurbitacin analogues had different potencies, pointing to substructural features that are important for the activity. PMID- 7853000 TI - Patuletin acetylrhamnosides from Kalanchoe brasiliensis as inhibitors of human lymphocyte proliferative activity. AB - The fractionation of the juice of fresh stems and leaves of Kalanchoe brasiliensis was monitored by an assay measuring lymphocyte proliferative activity and allowed the isolation and identification of seven patuletin rhamnoside derivatives [1-7]. Three of them are novel, namely, patuletin 3-O-(4" O-acetyl-alpha-L-rhamnopyranosyl)-7-O-(2'"-O-acetyl- alpha-L-rhamnopyranoside) [1], patuletin 3-O-alpha-L-rhamnopyranosyl-7-O-(2'"-O-acetyl-alpha-L- rhamnopyranoside) [3], and patuletin 3-O-(4"-O-acetyl-alpha-L-rhamnopyranosyl)-7 O- rhamnopyranoside [4], and four are known [2, 5-7]. Their structures were determined by the analysis of 1H-1H and 1H-13C COSY nmr, ci, and fab mass spectra. PMID- 7853001 TI - Novel naphthoquinones from Conospermum incurvum. AB - During the reisolation of the trimeric naphthoquinone derivative conocurvone [1] from an extract of the Australian shrub Conospermum incurvum, six monomeric naphthoquinones were isolated. These include three novel 1,4-naphthoquinone derivatives: 3-methyl-14,15-dihydro-15-hydroxyteretifolione B [3], 3-methyl-14,15 dihydro-15-hydroxyteretifolione B methyl ether [4], and 2,3-dimethyl-6-hydroxy-7 methoxy-1,4-naphthoquinone [5]. In addition, the previously reported compounds 3 methylteretifolione B [6], 3-methylteretifolione B methyl ether [7], and 8 geranyl-2,7-dihydroxy-3-methyl-1,4-naphthoquinone [8] were isolated and identified. The structures of the novel 1,4-naphthoquinones were elucidated by spectral methods. While conocurvone [1] is a potent inhibitor of HIV-1-induced cell killing, all of the monomeric naphthoquinone derivatives were inactive against HIV-1. PMID- 7853002 TI - Indole alkaloids from Peschiera laeta that enhance vinblastine-mediated cytotoxicity with multidrug-resistant cells. AB - Coronaridine [1], conoduramine [2], and voacamine [3], three indole alkaloids isolated from Peschiera laeta, have been found to enhance the cytotoxic response mediated by vinblastine [4] with multidrug-resistant KB cells. Inhibition of vinblastine binding with membrane vesicles isolated from this cell line was also assessed, and the bisindole alkaloids conoduramine [2] and voacamine [3] were found to be more potent inhibitory agents than the monomeric alkaloid, coronaridine [1]. Thus, these compounds appear to function by binding with P glycoprotein. PMID- 7853003 TI - Protein kinase C inhibitors: novel spirosesquiterpene aldehydes from a marine sponge Aka (= Siphonodictyon) coralliphagum. AB - Two novel spirosesquiterpene aldehydes, corallidictyals A [1] and B [2], were isolated as a mixture from the marine sponge Aka (= Siphonodictyon) coralliphagum, and their structures were determined by detailed spectroscopic methods. These compounds were identified in a screen for inhibitors of protein kinase C. PMID- 7853004 TI - Isolation of the furan fatty acid, (8Z,11Z,14Z,17Z)-3,6-epoxyeicos-3,5,8,11,14,17 hexenoic acid from the New Zealand sponge Hymeniacidon hauraki. PMID- 7853005 TI - Norcucurbitacin gentiobiosides from Fevillea trilobata. AB - The new norcucurbitacin glycosides, andirobicin A gentiobioside [2], and andirobicin C gentiobioside [1], and the known fevicordin F gentiobioside [3], were isolated from the aqueous MeOH fraction of a liquid-liquid partition of the MeOH extract of the seeds of Fevillea trilobata. Their structures were determined by nmr and ms techniques. PMID- 7853006 TI - Yunantaxusin A, a new 11(15-->1)-abeo-taxane from Taxus yunnanensis. AB - Yunantaxusin A [2], an 11(15-->1)abeo-taxane-type diterpene with an opened oxetane ring, has been isolated from the leaves and stems of Taxus yunnanensis. Its structure was established from its spectral data. PMID- 7853008 TI - Vibrindole A, a metabolite of the marine bacterium, Vibrio parahaemolyticus, isolated from the toxic mucus of the boxfish Ostracion cubicus. AB - The EtOAc extract of the whole culture medium of Vibrio parahaemolyticus, which inhabits the toxic mucus of the box fish Ostracion cubicus, afforded a new indole derived natural product, vibrindole A [1], along with some known cyclic dipeptides and indoles. The structure of 1 was determined by analysis of its physicochemical characteristics. PMID- 7853007 TI - Structure and absolute configuration of palmonine F, a new eunicellin-based diterpene from the gorgonian Eunicella verrucosa. AB - In addition to the palmonines reported in a previous communication, a new eunicellin-type diterpene, palmonine F [1], has been isolated from the gorgonian Eunicella verrucosa. Its structure was elucidated by interpretation of spectral data and chemical interconversions and its absolute configuration was established using the Mosher's method. The cytotoxicity assay results for the palmonines are reported. PMID- 7853009 TI - Inhibitors of protein tyrosine kinase pp60v-src: sterol sulfates from the brittle star Ophiarachna incrassata. AB - Bioactivity-guided fractionation of the extracts of the green brittle star Ophiarachna incrassata using a protein tyrosine kinase pp60v-src inhibition assay led to the isolation of a new sterol sulfate [2] together with four known ones (1,3-5). All five compounds were found to inhibit protein tyrosine kinase pp 60v src. PMID- 7853010 TI - A novel cytotoxic macrolide, superstolide B, related to superstolide A, from the New Caledonian marine sponge Neosiphonia superstes. AB - The structure of a new cytotoxic macrolide, superstolide B [1], isolated from the deep water sponge Neosiphonia superstes, collected off New Caledonia, was elucidated mainly on the basis of nmr data. Compound 1 is closely related to superstolide A [2], a major cytotoxic component isolated from that organism, but lacks the 25-hydroxyl group found in 2 and has a C-24 (C-25)-double bond. PMID- 7853011 TI - Konbamidin, a new indole alkaloid from the Okinawan marine sponge Ircinia sp. PMID- 7853012 TI - Antibacterial and antifungal sulfated alkane and alkenes from the hepatopancreas of the ascidian Halocynthia roretzi. AB - Four new antibacterial and antifungal sulfates, 2,6-dimethylheptyl sulfate [1], (4Z,7Z)-4,7-decadienyl sulfate [2], (4Z,7E)-4,7-decadienyl sulfate [3], and (3Z,6Z)-3,6,9-decatrienyl sulfate [4], have been isolated from the hepatopancreas of the ascidian Halocynthia roretzi. The structures were determined by spectral analysis. PMID- 7853013 TI - A neuropathological study of paraparetic rats injected with HTLV-I-producing T cells. AB - In order to clarify the pathogenesis of HTLV-I-associated myelopathy or tropical spastic paraparesis (HAM/TSP), we injected HTLV-I-producing rabbit or human T cells intravenously into WKA and F344 rats. Infection was confirmed from increase in the anti-HTLV-I antibody titer and from the presence of HTLV-I proviral DNA. Only WKA rats developed hindlimb paraparesis 78-124 weeks after the injection. Neuropathological examination of 5 rats showed degeneration of the anterolateral and posterior funiculi as well as the peripheral nerves, and this degeneration was characterized by prominent vacuolation and macrophage infiltration. The myelopathy and neuropathy were grossly similar to those in human HAM/TSP. Although pathological changes of the spinal cord were very mild in 2 paretic rats, and similar lesions were found in the spinal cords and peripheral nerves of 2 control WKA rats, the myelopathy, radiculoneuropathy, or both in the paretic rats showed greater severity than in the controls. The contribution of the aging process to the lesions of the spinal cord and peripheral nerve is discussed. It appears possible that HTLV-I may accelerate the aging process and give rise to paraparesis. The precise role of HTLV-I in the pathogenesis of rat paraparesis remains to be elucidated taking the role of the aging process of the spinal cord and peripheral nerve into account. PMID- 7853014 TI - Protection against cisplatin induced neurotoxicity by ORG 2766: histological and electrophysiological evidence. AB - Prolonged administration of the anti-tumor agent cisplatin may cause a neuropathy in patients. In an animal model, too, neurotoxicity, as evidenced by a decrease in H-related sensory nerve conduction velocity (SNCV), can be induced by repetitive injections of cisplatin. In an attempt to further the insight into the effects of cisplatin on the peripheral nervous system a combined electrophysiological and histomorphological investigation was performed on 2 groups of 6 rats, treated with cisplatin for 7.5 weeks, and a control group (n = 6). Concomitant administration of ORG 2766, an ACTH(4-9) analog, was previously shown to prevent cisplatin neurotoxicity in this model and more recently in patients as well. One group of rats was therefore co-treated with this peptide during the complete treatment period. A marked decrease in SCNV was observed in cisplatin/saline treated rats, but not in cisplatin/ORG 2766 treated rats. Though no statistically significant difference was seen in the total number of myelinated fibers in the sural nerves of cisplatin treated rats, a decrease in the proportion of thick myelinated fibers was present in the cisplatin/saline treated rats. This shift in fiber distribution was absent in ORG 2766 co-treated animals. Mean internodal distances and g-ratios were not affected, and signs of axonal degeneration, or de- or remyelination were not observed. PMID- 7853015 TI - An electrophysiological and histological study of trypsin induced demyelination. AB - Ten-microliters quantities of trypsin or saline were injected into rat tibial nerve and the physiological and histological changes evaluated and compared to the focal demyelinating lesions induced by intraneural injection of rabbit EAN serum and proteinase K. The injection of trypsin produced progressive conduction block that was maximal on day 4, and a slowing of motor nerve conduction. Early retraction of myelin at paranodes, vesicular change, and macrophage stripping of myelin from nerve axons were seen on histological examination. At day 4, the first groups of completely demyelinated axons were seen, typically in a perivascular distribution. These changes were similar to those seen in the positive controls and thus support the postulate that proteolytic enzymes from macrophages--the dominant cellular species within the demyelinating lesion, play a central role in degradation of the myelin sheath in demyelinating diseases. PMID- 7853016 TI - Changing expression of GTPase activating proteins with differentiation in neuroblastoma. AB - p21ras is a membrane-associated guanine nucleotide-binding protein with intrinsic GTPase activity. Like other guanine nucleotide-binding proteins p21ras is active when GTP bound and inactive when GDP bound. Phosphorylation of p21ras is regulated by the GTPase activity of type I GAP120 and NF1-GRD. In this study we have identified type I GAP120 and two NF1-GRD mRNAs in three neuroblastoma cell lines, IMR-32, SK-N-SH and SK-N-MC. NF1-GRD mRNA was expressed in all cell lines at a similar level but type I GAP120 mRNA was more abundant in the IMR-32 cell line. Retinoic acid induced differentiation of all three cell lines, this effect was most marked in the SK-N-SH line. This differentiation was accompanied by an increase in both type I GAP120 and NF1-GRD mRNAs. Retinoic acid induced differentiation had no effect on the ratio of type I to type II NF1-GRD mRNA. In seven patient tumour samples examined type I GAP120 and NF1-GRD were coexpressed, type I GAP120 at a higher level than NF1-GRD in all tumour stages. Type I was the predominant NF1-GRD mRNA. The expression of type I GAP120 was similar in all tumour stages but the total level of NF1-GRD was higher in stage 2 and 3 tumours than in stage 4 tumours. In summary, these results suggest increased type I GAP120 and NF1-GRD mRNA are associated with differentiation in neuroblastoma cells. PMID- 7853017 TI - Prevention of HIV coat protein (gp120) toxicity in cortical cell cultures by riluzole. AB - Neurological complications observed in HIV-infected patients are very frequent. Neocortical lesions include reduced neuronal density due to neuronal degeneration. The HIV envelope protein gp120 has potent neurotoxic properties in cell cultures blocked either by NMDA antagonists or calcium channel antagonists. Moreover, human monocytoid cell lines infected by HIV release endogenous toxic factors with comparable cellular actions. We have analysed the effects of riluzole, a compound reducing the excitatory amino acid release on gp120-induced neurotoxicity in primary neuronal cultures. Riluzole, which blocks the release of glutamate and aspartate from nerve terminals, prevents (10(-7) M) the neuronal degeneration produced by 20 pM of gp120 in cortical cell cultures. This result could suggest that toxic factors produced by activated macrophages might increase glutamate release, and that this may be prevented by riluzole. PMID- 7853018 TI - Lazaroids enhance skeletal myogenesis in primary cultures of dystrophin-deficient mdx mice. AB - Growing evidence suggests a role for free radicals in the degeneration of dystrophin-deficient muscle (as observed in Duchenne muscular dystrophy). We therefore decided to test the action of the lazaroid antioxidant compounds on primary skeletal muscle cell cultures derived from an animal model of Duchenne muscular dystrophy, the mdx mouse. Both vitamin E-derived U-83836E and glucocorticoid-derived U-74389F enhanced myogenesis of dystrophin-deficient cultures as determined by the number of myotubes, the amount of nicotinic acetylcholine receptor, skeletal muscle alpha-actin levels and myosin light chain. U-83836E enhanced myogenesis of control congenic C57BL/10 mouse-derived muscle cultures whereas U-74389F had no detectable effect. This enhanced myogenesis was in most respects similar to the one triggered by alpha methylprednisolone which is the only drug known to be beneficial in Duchenne muscular dystrophy. PMID- 7853019 TI - Mixed connective tissue disease: recurrent episodes of optic neuropathy and transverse myelopathy. Successful treatment with plasmapheresis. AB - Severe neuropsychiatric manifestations in mixed connective tissue disease (MCTD) are thought to be quite rare. We report an unusual case of MCTD with recurrent optic neuropathy and transverse myelopathy suggestive of a relapsing-remitting demyelinating disorder. Symptoms responded dramatically to a treatment with plasmapheresis and immunosuppressive medication. PMID- 7853020 TI - Influence of local tissue temperature on vibration detection threshold. AB - We used the Computer Assisted Sensory Examination (CASE IV) and a new, rapid 4, 2, and 1 stepping algorithm to determine the influence of local temperature on vibratory detection threshold (VDT) in the great toe of 11 healthy adult subjects. We found that over a broad range of temperatures, VDT did not vary much. A large cooling offset resulted in a small increase in VDT, but warming did not change VDT significantly. PMID- 7853021 TI - Benign monomelic amyotrophy of lower limb: a rare entity with a characteristic muscular CT. AB - Six patients presented with amyotrophy confined to a single lower limb and characterized by insidious onset, slow progression and later stabilization. Wasting was out of proportion with disability and there were no sensory, pyramidal tract or bulbar signs. All cases were sporadic, and there was no history of poliomyelitis. CK, anti-ganglioside antibodies, motor and sensory conductions were normal. Quantitative EMG and muscle biopsy revealed neurogenic features also in clinically unaffected limbs. Muscular CT showed selective or predominant, asymmetrical involvement of posterior leg muscles and caput longus of biceps femoris. Monomelic amyotrophy of lower limb is a clinically localized variant of spinal muscular atrophy with a particularly benign course. Although in the early stage there are no clinical or laboratory findings which allow differential diagnosis with other motor neuron diseases, the history of an amyotrophy clinically localized for more than 3 years to a lower single limb and the characteristic muscular CT pattern suggest the diagnosis since the first observation and indicate a favorable prognosis. PMID- 7853022 TI - Subcortical impairment in subclinical hepatic encephalopathy. AB - We have used short latency somatosensory evoked potential (SEP) in 108 patients with liver cirrhosis by viral hepatitis to evaluate hepatic encephalopathy. Short latency SEPs were recorded by the MEM-4104 apparatus (Nihon Kohden Inc., Tokyo) in response to median nerve stimulation. For a precise analysis of the early components, we averaged 1000 responses during a 30-msec period. Early SEP components were prolonged in patients with decompensated, but not in those with compensated, cirrhosis. We also examined the relationship between consciousness level and interpeak latency (IPL) N13-N20 of SEP and between consciousness level and electroencephalograph in 51 patients among 108 patients with liver cirrhosis. The IPL N13-N20 was prolonged in the decompensated stage with normal consciousness, but EEG findings had not deteriorated in this stage. EEG grade became worse in the stage of abnormal consciousness. The prolongation of the IPL N13-N20 was attributed to the central conduction impairment. We postulate that subcortical impairment may occur in patients with subclinical hepatic encephalopathy. when the cortex is little affected. PMID- 7853023 TI - Reliability of reaction time measurements in brain-damaged patients. AB - The higher sensitivity of chronometric analysis leads to an increase of their use in the evaluation of brain-damaged patients. However, patients have usually higher reaction time (RT) variability, suggesting a possible decrease in the reliability of RT measurement. This reliability has never been evaluated in patients. This study assessed the reliability of RT estimates in 2 populations of brain-damaged patients and controls, using the Kendall coefficient of concordance W. Concordance coefficients were computed for simple detection and choice tests. W values were good and significant. This study suggests that RT measured in simple detection and choice tasks represent a reliable measurement and supports the idea that the higher sensitivity associated with the use of chronometric analysis is not obtained at the cost of a lower reliability. Moreover, these results provide information for the elaboration of RT tests. PMID- 7853024 TI - Gamma delta T cell distribution in cerebrospinal fluid and peripheral blood of patients with multiple sclerosis. AB - The distribution of gamma delta T cells was determined in peripheral blood of 50 patients in acute relapse of clinically definite multiple sclerosis (MS), 8 patients with primary progressive MS, 26 patients with inflammatory neurological disease (IND), 33 patients with non-inflammatory neurological disease (NIND) and 31 healthy subjects. Paired cerebrospinal fluid samples were obtained from 37 patients with relapsing-remitting MS, 2 patients with primary progressive MS, 14 with IND and 18 with NIND. The monoclonal antibodies pan-alpha beta TCR, TCR delta 1, delta TCS1 and anti-delta V2(a) which identify alpha beta T cells, gamma delta T cells, V delta 1, and V delta 2 gene products respectively, were used to define the T cell receptor repertoire. gamma delta T cells expressed as a percentage of CD3+ lymphocytes were lower in MS CSF compared to NIND CSF (3.4% +/ 0.5 versus 7.3% +/- 1.4; p < 0.001). This was due to a lower MS CSF. Peripheral blood levels of gamma delta T cells were normal in each study group. CD45RA expression was increased on gamma delta T cells in CSF of each patient group when compared with the paired blood samples. These results suggest that V delta 1 + and V delta 2 + gamma delta T cells with altered CD45 expression are reduced in CSF of patients with established MS. This finding may be related to sequestration or apoptosis of gamma delta T cells within active MS lesions. PMID- 7853025 TI - HLA class II genotypes in Leber's hereditary optic neuropathy. AB - There is an association between Leber's hereditary optic neuropathy (LHON) and a multiple sclerosis-like illness, raising the possibility of autoimmune pathogenetic mechanisms in LHON. We therefore investigated the frequency of HLA DR genotypes in members of 79 families with LHON, defined by the presence of a pathogenic mitochondrial DNA mutation. There was no association between LHON and any HLA-DR genotype. Furthermore, affected relative pairs did not share HLA genotypes more than discordant pairs. We conclude that the HLA-DR locus is not a major genetic determinant for the development of blindness in LHON. PMID- 7853026 TI - Peak time difference of time-density curve in contrast media transit as an indicator of asymmetric cerebral perfusion. AB - Time-density curve study in contrast media transit has a theoretical possibility to evaluate asymmetric cerebral perfusion. We studied the right-to-left hemispheric difference of peak time in regional time-density curve. Twenty-seven chronic stroke patients underwent either dynamic CT or intravenous digital subtraction angiography (IVDSA), and single photon emission CT (SPECT). We placed symmetric regions of interest as appropriate in each study, and obtained a peak time of each regional time-density curve in IVDSA or dynamic CT, and a laterality index of reconstructed counts in SPECT. Right-to-left difference of peak time significantly correlated to the laterality index both in IVDSA and dynamic CT (r = -0.88, p < 0.001, and r = -0.82, p < 0.001, respectively). Thus, time-density curve study well reflected unilateral reduction of cerebral perfusion. Recent progress in acute thrombolytic intervention for ischemic stroke recommends a quick and efficient evaluation of ischemic status, and time-density curve study may satisfy this requirement. PMID- 7853027 TI - A riboflavin-responsive lipid storage myopathy due to multiple acyl-CoA dehydrogenase deficiency: an adult case. AB - A 62-year-old man was admitted to our hospital because of easy fatigability of the lower limbs during walking. The biopsied muscle specimen showed excessive lipid accumulation. The carnitine concentration in the muscle was at the lower level of the normal range. Organic acid urinalysis was consistent with the diagnosis of multiple acyl-CoA dehydrogenase deficiency or glutaric acidemia type II. In cultured lymphoblastoid cells from this patient there was impaired beta oxidation, but the activities of acyl-CoA dehydrogenases were normal. Riboflavin therapy resulted in a dramatic improvement in both clinical and biochemical aspects. In this patient, the defect in coenzyme binding to electron transfer flavoprotein (ETF) or ETF-dehydrogenase was suspected. In the adult case of lipid storage myopathy, multiple acyl-CoA dehydrogenase deficiency should be suspected as one of its pathogenesis and riboflavin therapy should be considered. PMID- 7853028 TI - Calcium homeostasis in fibroblasts from patients with amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative disorder of the motor system in the CNS characterized by motor neuron death in the spinal cord, brain stem and cortex. Readily available tissues such as fibroblasts from ALS patients can serve as simple model systems to study the molecular mechanisms leading to degenerative disorders. We have used Fura-2 fluorescence microscopy and single-cell imaging to study the spatiotemporal dynamics of intracellular free calcium ([Ca2+]i) in primary cultures of fibroblasts from skin biopsies from ALS and normal subjects. Increases in [Ca2+]i were induced by stimulation with bradykinin (100 nM); neurotensin (50 nM); N-formyl-Met-Leu-Phe (chemotactic peptide) (1 microM); [Arg8]-vasopressin (1 microM) and histamine (10 microM). The levels of [Ca2+]i in 80-120 individual cells per agonist were monitored for 15 min. No significant differences were found in the resting levels of [Ca2+]i in control (102 +/- 4 nM) and ALS (98 +/- 6 nM) fibroblasts and in the maximal [Ca2+]i levels after stimulation with N-formyl-Met-Leu-Phe, [Arg8]-vasopressin, and histamine. Significantly lower [Ca2+]i transients were found in fibroblasts from ALS donors compared to controls when stimulated with neurotensin (p < 0.002) and bradykinin (p < 0.005). The percentage of individual cells reacting to a given agonist (40-100%) was similar in both groups. The molecular basis of the impaired calcium homeostasis in fibroblasts from ALS patients is not known, but a generalized membrane defect can be excluded since the [Ca2+]i responses are defective only when bradykinin or neurotensin are used as agonists. PMID- 7853029 TI - Neurobehavioral changes following bilateral infarct in the caudate nuclei: a case report with pathological analysis. AB - A patient presenting with loss of psychic self activation (LPSA) was studied clinically and at autopsy. Clinically, the patient showed changes that can be ascribed to the interruption of frontal-subcortical circuits. Pathological analysis revealed bilateral lesions of the caudate nuclei. This case extends others based on radiological findings and confirms the importance of the caudate nuclei in behavioral functions. PMID- 7853030 TI - A single report of hemiplegic arm stretching related to yawning: further investigation using apomorphine administration. AB - We observed a stroke patient with an infarct of the internal capsule interrupting the pyramidal tract who stretched his hemiplegic arm during spontaneous and apomorphine-induced yawning. The putative mechanism by which yawning can induce the paradoxical motor response of the plegic arm in the patient might be the functional efficiency of a pathway projecting directly from the stimulated basal ganglia to lower motor systems in the brainstem. PMID- 7853031 TI - Magnetic resonance imaging and neuropathological findings in two patients with Creutzfeldt-Jakob disease. AB - We report 2 autopsy-proven patients with Creutzfeldt-Jakob disease (CJD) showing bilateral decreased signal intensity in the thalamus on T2-weighted images. On post-mortem examination, all affected areas showed the characteristic features of CJD, such as neuronal loss, gliosis, and status spongiosus. These findings are another distinctive MRI appearance in CJD. PMID- 7853032 TI - Multifactorial obstructive sleep apnea in a patient with Chiari malformation. AB - We report a patient with severe obstructive sleep apnea (OSA) associated with a unique combination of syringobulbia-myelia, Chiari malformation type I (CM), absent hypoxic ventilatory drive, vocal cord paralysis, post-menopausal status, obesity, and acute respiratory failure necessitating mechanical ventilation. The remote onset of OSA five years after surgery underscores the need for long-term follow-up of patients with syringobulbia-myelia and CM and the importance of addressing multiple interacting neurologic, metabolic, and mechanical predispositions to sleep-disordered breathing. PMID- 7853033 TI - Does iron-catalyzed oxidation of neuronal hemoglobin contribute to motor neuron degeneration? PMID- 7853035 TI - The Potsdam International Consultation on Meta-Analysis. Potsdam, Germany, March 1994. PMID- 7853034 TI - Points of view concerning the diffusion theory for blood-CSF barrier function and dysfunction. PMID- 7853036 TI - The challenge of meta-analysis. PMID- 7853037 TI - Exploratory or analytic meta-analysis: should we distinguish between them? AB - Meta-analysis has been defined as a study and "statistical analysis which combines or integrates the results of several independent studies." Included in this definition are other terms, such as systematic overviews, pooling data, pooling study results, and quantitative literature reviews. Like any study, the questions being asked will influence the design and the method of analysis of the meta-analysis. Since a meta-analysis is a study based on a literature review, it is inherently observational rather than experimental in nature. This idea is supported by the fact that the meta-analyst has limited control over the availability of studies or the information collected and reported in the individual studies. Meta-analysis has been applied to clinical trials and epidemiology. At first glance the potential for bias appears greater in epidemiology than in clinical trials. But this may depend on the question being asked. If randomized clinical trials are limited to improving an estimate of effect or testing a hypothesis in a relatively homogeneous set of effect sizes, the clinical trial will tend to be less prone to bias than a comparable set of epidemiologic studies. In this context, the issue of combinability may dominate the meta-analysis. We refer to this type of meta-analysis as an "analytic" meta analysis. On the other hand when the goal is to resolve controversy, or pose and answer new questions the main concern of the meta-analysis is to explain the variation in the effect sizes. We refer to this application of a meta-analysis as an "exploratory" meta-analysis. In this second type of meta-analysis the characteristics of the different studies become the focus of the analysis. This leads to the idea that protocols for a meta-analysis should reflect its goals and how the results are to be used. Finally, we will consider whether there is a role of meta-analysis in the field of drug development. PMID- 7853038 TI - Meta-analytic methods for diagnostic test accuracy. AB - Meta-analyses of diagnostic test accuracy are uncommon and often based on separate pooling of sensitivity and specificity, which can lead to biased estimates. Recently, several appropriate methods have been developed for meta analysing diagnostic test data from primary studies. Primary studies usually only provide binary test data, for which Moses et al. have developed a method to estimate Summary Receiver Operating Characteristic Curves, thereby taking account of possible test threshold differences between studies. Several methods are also available for analysing multicategory and continuous test data. The usefulness of applying these methods is constrained by publication bias and the generally poor quality of primary studies of diagnostic test accuracy. Meta-analysts need to highlight important defects in quality and how they affect summary estimates to ensure that better primary studies are available for meta-analysis in the future. PMID- 7853039 TI - Statistical and theoretical considerations in meta-analysis. AB - An historical perspective of statistical methods for combining the results of independent studies is provided. The information explosion subsequent to 1950 has been a critical factor in the development of the field. An example of a meta analysis is used to illustrate all alternative analyses that should be considered for conducting a meta-analytic study. PMID- 7853040 TI - The practice of meta-analysis. AB - Meta-analysis seems to have a potentially useful role in carefully selected situations where the primary literature is of good quality, heterogeneity in the response to treatment of the tested population is small and well-understood, interest centers on estimation of a specific, critical parameter of outcome, and the meta-analyst is deeply expert in the subject matter. Other uses can produce, and have produced, results that may be seriously misleading. Five short case studies are presented (diethylstilbestrol and outcome of pregnancy, chlorination of drinking water and cancer, cisplatin and cancer of the ovary, antibiotic therapy for otitis media with effusion, and beta-agonists and asthma). PMID- 7853041 TI - Selecting the language of the publications included in a meta-analysis: is there a Tower of Babel bias? AB - Although they usually claim a very thorough search to retrieve every pertinent work, most meta-analyses published in English restrict their search to papers which were also published in English. We reviewed all the meta-analyses printed from 1 January 1991 to 1 April 1993 in 8 medical journals published in English and selected those who stated linguistic restrictions for inclusion in the analysis. The computerized search methods used in these meta-analyses were then duplicated looking specifically for publications written in the excluded languages. Each meta-analysis was then redone with identical statistical tests to determine if its conclusions would have been different if the paper(s) absent only for linguistic reasons had been included. A total of 36 meta-analyses of which 28 had language restrictions were identified. The computer searches yielded 19 papers scientifically acceptable but excluded for linguistic reasons. Eleven of these articles were retained as having the potential to modify their corresponding 7 meta-analyses. One meta-analysis which concluded that selective decontamination of the digestive tract in intensive care units did not produce a significant change in mortality between treatment and control patients (OR 0.70; 95% CI 0.45-1.09) would have arrived at a different conclusion (OR 0.67; 95% CI 0.47-0.95) if a paper written in German in a Swiss journal had been included in the analysis. Our study demonstrates that, in at least one out of 36 consecutive meta-analyses the exclusion of papers for linguistic reasons produced results different from those which would have been obtained if this exclusion criteria had not been used. PMID- 7853042 TI - "The practice of meta-analysis": discussion. Meta-analysis of observational studies: a case study of work in progress. PMID- 7853043 TI - Methodologic guidelines for systematic reviews of randomized control trials in health care from the Potsdam Consultation on Meta-Analysis. PMID- 7853044 TI - "Best-evidence synthesis: an intelligent alternative to meta-analysis": discussion. A case of "either-or" or "as well". PMID- 7853045 TI - Large-scale randomized evidence: large, simple trials and overviews of trials. PMID- 7853046 TI - "Large-scale randomized evidence: large, simple trials and overviews of trials": discussion. A clinician's perspective on meta-analyses. PMID- 7853047 TI - Cumulative meta-analysis of clinical trials builds evidence for exemplary medical care. AB - Cumulative meta-analysis of clinical trials (a Bayesian interpretation for accumulating evidence) will profoundly affect medical care by summarizing evidence in the assessment of technology innovations. Application of the technique to the randomized control trials (RCTs) of streptokinase treatment of acute myocardial infarction, reduction of peri-operative mortality by antibiotic prophylaxis, and prevention of death from bleeding peptic ulcers has revealed efficacy years before it was suspected by any other means. Arrangement of the trials according to event rate in the controls, effect sizes, quality of the trials or according to covariables of interest has supplied unique information. If carried out prospectively the technique supplies invaluable information regarding indications for another trial, the number of patients necessary to determine the validity of past trends, and the type of patients who might be benefitted. Careful examination in a cumulative manner of the prior trials can reduce the need for future large trials. PMID- 7853048 TI - "The challenge of meta-analysis": discussion. Indications and contra-indications for meta-analysis. PMID- 7853049 TI - Applying overviews and meta-analyses at the bedside. PMID- 7853050 TI - Meta-analysis: statistical alchemy for the 21st century. PMID- 7853051 TI - "Meta-analysis: statistical alchemy for the 21st century": discussion. A plea for a more balanced view of meta-analysis and systematic overviews of the effect of health care interventions. AB - The paper discusses some of the most common criticisms to meta-analysis presented by Professor Feinstein in this Conference. As many of the points raised in his contributions are not new, a critique to them is presented in the context of the type of contribution given by systematic reviews (meta-analysis) to the analysis of the effects of health care interventions. After discussing some terminological issues, the paper challenges Feinsteins' arguments indicating that meta-analysis is inherently faulted on four grounds: (a) reproducibility, (b) precision, (c) suitable extrapolation, (d) fair comparison. Each point is discussed providing examples drawn from the published literature with a view to indicate that- despite their current limitations--systematic reviews are a necessary step to synthesize information, orient clinical research and help produce practice guidelines. PMID- 7853052 TI - A statistician looks at met-analysis. AB - I begin by considering origins and meanings for the term met-analysis/meta analysis. The underlying ideas have a long history, not only in medical but also in the agricultural and social sciences. Met-analysis is a form of critical review of research on a stated topic, distinctive for its emphasis on producing quantitative conclusions. It is not in itself a specific technique, but rather an approach to aggregating information with the aid of critical deployment of standard statistical techniques. I shall discuss types of data on which met analysis may be practised. These may be published papers or reports on past research, or the complete data on which such publications were based, whether from well-designed experiments or from other sources, or even--least satisfactorily--from spontaneously submitted information. Particular dangers are bias arising from the manner in which component studies are chosen, possibly affected by publication bias, and the pernicious influence of the modern tendency to deify the statistical significance test. A further important issue is that of the scale to be used as a measure of the effect of the treatment (or treatments) under study. I end with general comments on the conduct of met-analyses. PMID- 7853053 TI - Best evidence synthesis: an intelligent alternative to meta-analysis. AB - Research review has long been one of the most important scholarly activities in all branches of science. While there is sometimes a single study so well designed, well carried out, and difficult to replicate that its findings are accepted as conclusive, more often there are many studies on a given topic, no one of which clearly supersedes the others. These studies may be done by different investigators using different methods or different populations. They may arrive at different conclusions. When this is the case, there is a need for reviewers to carefully consider the evidence and to put forth conclusions or hypotheses about where the weight of the evidence lies. PMID- 7853054 TI - On clinical teaching. PMID- 7853055 TI - Perceptions of effective clinical teachers in associate degree programs. AB - This study examined students' and faculty's perceptions of important characteristics of associate degree clinical teachers. Differences in perceptions were compared. Perceptions were measured using the Nursing Clinical Teacher Effectiveness Inventory. Associate degree nursing students (N = 199) and faculty (N = 22) from two southwestern community colleges participated in the study. All 48 items were rated highly by both students and faculty, ranging from 3.86 for "Directs students to useful literature in nursing" to 4.85 for "Corrects students' mistakes without belittling them." Students' and faculty's perceptions of important characteristics of effective clinical teachers by subsets were not significantly different. Since few studies on students' and faculty's perceptions have been done at the associate degree level, the results were comparable except for the item "good role modeling," which was not rated as highly in this study as in previous studies of baccalaureate students. PMID- 7853056 TI - The clinical evaluation tool: a measure of the quality of clinical performance of baccalaureate nursing students. AB - This article describes an approach to the evaluation of students' clinical performance. Specifically, the paper describes: (a) the history of the evaluation of clinical performance in nursing education; (b) the development of the Clinical Evaluation Tool (CET), an instrument designed to measure the clinical performance of nursing students across settings; and (c) the relationships between basic baccalaureate nursing students' scores on the CET and the following variables: age, college credits earned prior to entry to the program, grade point average at entry, college aptitude, and moral reasoning. PMID- 7853057 TI - Role model behaviors in the clinical setting. AB - The purpose of this study was to identify the role modeling behaviors of clinical nursing faculty that junior and senior baccalaureate students consider important. Bandura's Social Learning Theory provided the theoretical framework for the three research questions. A questionnaire, composed of 28 role model behaviors, was constructed to correspond to the three research questions. The overall alpha coefficient for the questionnaire was .95. The findings of this study indicate that clinical faculty are considered role models by their students. Students perceived themselves as practicing the role model behaviors, but they also perceived that the clinical faculty were inconsistent in rewarding them for their attempts to emulate those behaviors considered important. Areas for future research are discussed. PMID- 7853058 TI - Education for clinical practice: an alternative approach. AB - Although there have been many advances in technology, nursing science, and the professional role, there has been little planned, substantive change in the approach to clinical education. Documented problems include faculty workload, clinical placements, student anxiety, and concurrent teaching and evaluation. This article reviews the current status of clinical education and offers an alternative approach. The recommendation involves teaching a course on clinical practice, which includes patient care and adaptive competencies, evaluation in the college laboratory, and placing students with preceptors in the clinical laboratory. Ideas for implementation are offered, which include curricular changes and student-centered teaching strategies that encourage activities such as reflection and decision making. Advantages include opportunities for professional development for faculty and preceptors, improved student learning, and elimination of reality shock. The need for faculty development and educational research is emphasized. PMID- 7853059 TI - Clinical education: a caring approach. PMID- 7853060 TI - Issues in the organization and structure of clinical education for undergraduate nursing programs. PMID- 7853061 TI - Clinical teaching associate model: creating effective BSN student/faculty/staff nurse triads. PMID- 7853062 TI - Pediatric clinical experience: preparation for the 21st century. PMID- 7853063 TI - The evaluation of the scientific evidence for a relationship between calcium and hypertension. PMID- 7853064 TI - Nurse practitioners, certified nurse midwives, and nurse anesthetists: changing care in acute care hospitals in New York City. AB - To respond to the shrinking pool of primary care physicians and to demands from managed care programs for cost containment, hospitals in New York City have increased their use of nurse practitioners, certified nurse midwives, and nurse anesthetists, creating an increased demand for these personnel. We report here on a survey of hospitals and schools of nursing in New York City and present findings on (a) current use of, and projected demand for nurse practitioners (NPs), certified nurse midwives (midwives) and nurse anesthetists (anesthetists) in hospitals in New York City; (b) the practice patterns of NPs, midwives, and anesthetists currently employed in hospitals; and (c) current and projected enrollment and curriculum in NP, midwifery, and anesthetist education programs in the New York metropolitan area. PMID- 7853065 TI - Bibliography: nursing research dissemination. PMID- 7853066 TI - Codes of ethics as resources for nurse executives in ethical decision making. PMID- 7853067 TI - Using object relations theory to understand childhood deprivation. AB - In clinical practice, it has been noted that many patients referred for eating disorders, self-abuse, and other self-destructive behavior patterns had a common history of deprivation in childhood. Little research or conceptual literature has been devoted to the study or clarification of the phenomenon of emotional deprivation. Current literature focuses on the more obvious, measurable factors of abuse and neglect. This article defines deprivation from an object relations perspective, demonstrates its overlap with abuse, and suggests that deprivation, alone or in conjunction with other trauma and abuse, places individuals at risk for devastating, life-long problems. Nurses encounter patients who are sufferers of emotional deprivation and need to be well-informed in order to help stop the cycle of violence and abuse. PMID- 7853068 TI - Beta blocker use in the treatment of community hospital patients discharged after myocardial infarction. AB - OBJECTIVE: To explore the reasons for underutilization of beta blocker treatment after acute myocardial infarction. DESIGN: A retrospective chart review. SETTING: Two large community hospitals in Milwaukee, Wisconsin. PATIENTS/PARTICIPANTS: All subjects (n = 694) discharged alive from July 1, 1990, to June 30, 1991, who had a diagnosis of acute myocardial infarction were eligible. Of these, 250 had missing data, resulting in a final sample of 444. RESULTS: Twenty-nine percent of the 444 patients were prescribed beta blocker therapy on discharge. Characteristics of the patients and their treatment associated with receipt of beta blocker therapy were identified with a logistic regression model. The adjusted odds ratios were 0.52 for female gender, 0.34 for no health insurance, 0.21 for chronic obstructive pulmonary disease, 0.46 for congestive heart failure, 0.28 for atrioventricular block, 1.86 for hypertension, 1.93 for chest pain during acute myocardial infarction, and 4.65 for prehospital beta blocker use. Prescription of beta blocker therapy was also influenced by receipt of other treatment modalities. The adjusted odds ratios were 0.23 for receipt of beta blocker therapy associated with myocardial revascularization, 0.18 for prescription on discharge of calcium channel blockers, and 0.22 for receipt of angiotensin-converting enzyme inhibitors. CONCLUSION: A minority of patients discharged after acute myocardial infarction receive beta blocker therapy, and women are only half as likely as men to receive it, after controlling for other factors. Though there are no data relating to whether calcium channel blockers or angiotensin-converting enzyme inhibitors lessen the protective effect of beta blocker therapy post-acute myocardial infarction, it would appear that these agents are frequently being used in lieu of beta blocker therapy for post-acute myocardial infarction patients. PMID- 7853069 TI - Necessary but not sufficient: the effect of screening and feedback on outcomes of primary care patients with untreated anxiety. AB - OBJECTIVE: To consider the impact on primary care patient outcomes of using both a screener to determine elevated anxiety levels among patients with previously undetected anxiety and a physician intervention to inform physicians of their patients' conditions. DESIGN: Participating physicians were randomized to either the demonstration or the control arm, and patients were assigned to a study arm based on the randomization of their physicians. The patients were followed for change in outcome measures during the five-month study period. SETTING: A mixed model health maintenance organization serving approximately 110,000 enrollees in central Colorado. PATIENTS/PARTICIPANTS: 573 patients who had unrecognized and untreated anxiety identified from the approximately 8,000 patients who completed the waiting room screening questionnaire. INTERVENTIONS: A physician intervention served the dual function of 1) providing an educational demonstration of anxiety in the primary care setting and 2) providing a reporting system for summarizing the anxiety symptom levels and functioning status of the patients enrolled in the study. MEASUREMENTS AND MAIN RESULTS: Patient outcomes were measured as changes in global anxiety scores, functioning and well-being, and patients' reports of global improvements. CONCLUSIONS: The findings indicate that this method of reporting symptoms and functioning status to primary care physicians did not significantly change patient outcomes. Improvement in outcomes appeared to be more closely associated with the patient's severity of psychological distress. PMID- 7853070 TI - A randomized crossover trial of Quick Medical Reference (QMR) as a teaching tool for medical interns. AB - OBJECTIVE: To determine whether the addition of Quick Medical Reference (QMR) to usual educational tools improves an intern's performance in managing clinical cases that test diagnostic and investigative skills. DESIGN: Randomized, controlled, single-blinded crossover study. SETTING: Tertiary care teaching hospital. SUBJECTS: Comprehensive medical interns who are proficient in the use of QMR. INTERVENTION: A total of 16 interns trained in the use of QMR were randomized to work up a total of six diagnostically challenging cases, three using medical textbooks plus access to QMR and three using textbooks and no access to QMR. MEASUREMENTS: The interns provided their solutions to the cases, which consisted of the differential diagnosis and investigations. They were scored by comparing their answers with the consensus answers provided by subspecialty consultants. For each intern, the difference in mean total scores with and without QMR was calculated. RESULTS: The mean difference in total scores was 7.2% benefit (p < 0.05, 95% CI = 0.05 to 14.4) using QMR. The beneficial difference was driven mainly by improvement in diagnostic scores, with the mean difference being 11.6% (p = 0.01, 95% CI = 2.4 to 20.8). Regression analysis showed that the more difficult the case, the greater the benefit of QMR. CONCLUSIONS: Quick Medical Reference may be a useful adjunct to interns in formulating diagnostic strategies for difficult clinical cases. However, since optimal conditions were chosen for QMR benefit in this study design, the small benefit in test scores must be weighed against the time required to teach QMR to interns. PMID- 7853071 TI - Long-term effects of ethics education on the quality of care for patients who have do-not-resuscitate orders. AB - OBJECTIVE: To assess the long-term clinical impact of a broad-based ethics education program for medical houseofficers with specific emphasis on appropriate care for patients who have do-not-resuscitate (DNR) orders. DESIGN: Prospective, with an initial randomized phase. SETTING: The medical service of a university teaching hospital. PARTICIPANTS: Medical houseofficers and their inpatients. INTERVENTIONS: A pilot program in 1988, and a full program with a two-year curricular cycle from 1989 to 1991. MEASUREMENTS AND MAIN RESULTS: The authors measured compliance with specific standards of care by reviewing charts of patients who had DNR orders at baseline (n = 39, 1988), after the pilot phase (n = 57, 1989), and at the end of the first curricular cycle (n = 56, 1991), noticing who wrote the DNR order, whether the reasons for the order and appropriate consent were documented, and whether there was documented attention to any of 11 concurrent care concerns (CCCs), such as spiritual needs, the appropriateness of tube feedings or pressors, and adjustment of analgesic dose. The percentage of DNR orders written by houseofficers increased from 26% in 1988 to 67% in 1991 (p < 0.01). The percentage of charts documenting the rationale and consent for the DNR order was consistently high. The percentage of charts documenting attention to any CCC increased from 68% in 1988 to 86% in 1991 (p < 0.01). The mean number of CCCs addressed per DNA order increased from 1.34 in 1988 to 2.14 in 1991. The mean number of CCCs addressed per DNR order for patients who had AIDS increased from 0.89 in 1988 to 2.25 in 1991 (p = 0.03). CONCLUSIONS: The quality of care for patients who had DNR orders, both overall and for those who had AIDS, improved over long-term observation in the setting of an ethics education program for medical houseofficers. The results suggest that ethics education may alter physician practices and improve patient care. PMID- 7853072 TI - The medical applications of the internet: informational resources for research, education, and patient care. PMID- 7853074 TI - Recent weight loss is related to short-term mortality in nursing homes. AB - A two-year review of weight changes and mortality in nursing home residents was completed. Factors examined included age, gender, principal diagnosis, cause of death, and amount and duration of weight loss before death. A 10% loss of body weight over a six-month interval strongly predicted mortality in the ensuing six months, with sensitivity 0.60, specificity 0.91, positive predictive value 0.62 and negative predictive value 0.90. Diagnosis and cause of death did not appear to influence this relationship. Routine weight measurements may be useful as predictors of six-month survival in certain nursing home residents. PMID- 7853073 TI - Anesthesia. PMID- 7853075 TI - Pneumonia in a nursing home. AB - The authors studied nursing home residents serologically to determine whether atypical organisms were causes of radiologic pneumonia. The study was conducted at the Wisconsin Veterans Home, a facility with on-site microbiology and x-ray. Over one year, serologic examinations for Legionella, Mycoplasma, and Chlamydia were conducted for the residents who had pneumonia. Cultures and mortality were reviewed. Fifty-six episodes were studied (mean resident age 78 years). There was no fourfold titer change. Seventeen quality sputum specimens revealed Streptococcus pneumoniae (5), normal flora (4), Hemophilus influenzae (4), Moraxella catarrhalis (3), Staphylococcus aureus (1), and beta-hemolytic Streptococcus, not group A (1). The two-month mortality was 21%. This study did not result in serologic confirmation of atypical organisms' causing pneumonia. Antibiotic choice should be based on coverage of prevalent organisms, including Hemophilus influenzae, Moraxella, and Staphylococcus, as well as clinical features. PMID- 7853076 TI - Are computer diagnostic assistants useful tools for clinicians and educators? PMID- 7853077 TI - Measuring the effectiveness of ethics education. PMID- 7853078 TI - Kill the ump! PMID- 7853079 TI - Family planning. PMID- 7853080 TI - On infertility. AB - Infertility is not one objective life event and is not necessarily the salient event in understanding infertile couples' behaviors. Common behaviors observed in infertile couples may have different meanings. The nursing care of infertile couples is enhanced and more faithful to individual experience when the complexity and variation of infertility is recognized. PMID- 7853081 TI - A nursing model for a community hospital preterm birth prevention program. AB - Newer interventions for the treatment of preterm labor led to the development of a nursing program for preterm birth prevention. The Roy adaptation model was used as a framework for patient and community education. Quality improvement activities provided the impetus for nursing practice changes. Tools were developed to produce a comprehensive, consistent approach for patient care from assessment to discharge. PMID- 7853082 TI - Nursing care of the childbearing Muslim family. AB - It is estimated that 2 to 3 million Muslims live in the United States. This article describes the Islamic beliefs and practices nurses must be aware of to understand the spiritual needs of childbearing Muslim families. Strategies are suggested for developing a plan of care to meet the needs of childbearing Muslim families during the prenatal, intrapartal, and postpartal periods. PMID- 7853083 TI - Adult respiratory distress in pregnancy: critical care issues. AB - Adult respiratory distress syndrome (ARDS) is a complex disease process involving noncardiogenic pulmonary edema, central hypovolemia, widespread atelectasis, and, in the final stages, an inability to perfuse end organs. Uteroplacental perfusion is usually compromised in such situations, which may be catastrophic, depending on the amount of fetal oxygen reserve. ARDS is often preceded by sepsis and frequently ends in maternal death, despite aggressive intervention. Inflammatory responses, complement activation, and prostaglandins have been implicated as probable mediators of both sepsis and ARDS. Invasive hemodynamic monitoring and mechanical ventilation are usually warranted to provide detailed assessment and support. However, when a critical illness affects the family unit, emotional and spiritual issues must receive significant attention to provide holistic care. PMID- 7853084 TI - A national survey of neonatal intensive-care units: criteria used to determine readiness for oral feedings. AB - OBJECTIVE: To describe criteria used to determine readiness for oral feedings in stable, preterm infants. DESIGN: A 25-item survey questionnaire was mailed to hospitals having level II or level III NICUs. SETTING: Nurseries identified in the 1987 National Perinatal Directory (576 in all) as level II or level III NICUs. PARTICIPANTS: Head nurses (HN) and staff nurses (SN) at 420 hospitals comprised 73% of the sample surveyed. PROCEDURES: Survey items were predominantly multiple choice and included an "other" option to encourage comments. MAIN OUTCOME MEASURES: Respondents described clinical practice in their nurseries relative to feeding policies, use of traditional decision criteria, or behavioral cues and related interventions. RESULTS/CONCLUSIONS: Fewer than 50% of nurseries identified a specific feeding policy for the initiation of oral feedings. Seventy five percent used either gestational age or weight criteria in deciding when to start oral feedings. Eighty-six percent considered infant behavior as well when determining feeding readiness. Findings suggest an emerging emphasis on infant behavioral cues in addition to gestational age and weight criteria when making feeding decisions. PMID- 7853085 TI - Adolescent mothers: caregiving, approval, and family functioning. AB - OBJECTIVE: This study tested the Adolescent Family Assessment Model, which describes the relationships between caregiving behaviors, caregiving knowledge, peer and family approval, and family functioning. DESIGN: A descriptive correlational design was used along with causal modeling procedures to test the model. SETTING: Subjects were recruited from teen parent programs and an obstetrician's office. SUBJECTS: A convenience sample of 134 adolescent mothers participated in the study. Each subject had not completed her high school education and was living in the same household as her child. MAIN OUTCOME MEASURES: Subjects completed a demographic questionnaire, the Infant Caregiving Inventory (caregiving knowledge), the Peer and Family Approval Instruments (social approval), and Smilkstein's Family APGAR (family functioning). Instruments were completed twice by each subject, with a 2-week period between administration. RESULTS: Fifteen percent of the variance of caregiving behaviors was explained by ethnicity (beta = -.30) and age of the first child (beta = .26). Ten percent of the variance of family functioning was explained by age of the first child (beta = -.24) and ethnicity (beta = -.20). CONCLUSIONS: It appears that family functioning declines for the first 2 years after the birth of the adolescent's child. PMID- 7853086 TI - Infrared tympanic thermometry for neonatal temperature assessment. AB - OBJECTIVE: To investigate the accuracy and precision of infrared tympanic thermometer use with neonates by comparing with axillary and rectal measurements. DESIGN: Descriptive, comparative study. SETTING: Newborn nursery of a tertiary level perinatal center. SUBJECTS: Thirty-four full-term newborns. INSTRUMENTS: Infrared thermometers were used to collect tympanic temperatures. An electronic thermometer was used to collect axillary and rectal temperatures. RESULTS: There was no significant difference between tympanic and axillary temperatures. The range of variation (95% CI) was +/- 0.7-.9 degrees C. The mean difference between tympanic and rectal measurements was 0.4 degrees C. The range of variation was +/ 0.7-0.75 degrees C. Right ear measurements produced the best approximation of axillary temperature, and protected ear measurements produced the best approximation of rectal temperature. The protected ear was 0.2-0.3 degrees C higher than the exposed ear. CONCLUSIONS: There was more variation between tympanic versus axillary and tympanic versus rectal measurements than between axillary and rectal measurements. Tympanic thermometry may be useful for rapid screening of neonatal temperature, but its usefulness for monitoring unstable neonates remains in question. PMID- 7853087 TI - Pictorial depth cues: a new slant. AB - Pictorial depth cues such as perspective projection, aspect ratio, and texture gradients can specify mathematically the slant of a planar surface. We performed experiments to measure the accuracy of human perception of surface slant from these cues. We calculated the perceived slant from judgments of the relative lengths of a pair of orthogonal lines embedded in the surface. Our results indicate that slant judgments are accurate to within 3 deg. This level of accuracy was achieved whether the cues were luminance differences or equiluminous color differences. We found no evidence of the recession to the frontal plane that has been reported by Gibson [J.J. Gibson, The Perception of the Visual World (Houghton Mifflin, Boston, Mass., 1950]) and others. We did find evidence suggesting that subjects do not make accurate depth estimates of disconnected surfaces. This may be the source of the discrepancy between our measures and those of Gibson and others. This research, combined with previous findings, supports a model of perception that involves at least two and possibly more representations of space: one local veridical representation of surface orientation derived primarily from pictorial cues and another global representation of observer-centered distance derived primarily from binocular disparity and motion parallax. PMID- 7853088 TI - Chromatic-discrimination axes, CRT phosphor spectra, and individual variation in color vision. AB - There is a growing use of color monitor systems in visual research and a parallel growth in the use of cone-excitation space to define stimuli and to report data. Color specification in monitor systems is accomplished by combination of the phosphor chromaticities. The effect of interobserver variation on color specification is highly dependent on the spectroradiometric properties of the primaries. We review potential sources of biologic variability and its effect on the nominal axes in a cone-excitation diagram for a color monitor system. Variation in preretinal pigment (lens and macular pigment), in the effective optical density and the spectral sensitivity of the visual photopigments, and in the cone weighting used to derive the spectral luminosity function are considered. The consequences of such biological variability are rotation and translation of the axes for a given observer relative to the nominal axes that the observer used for color specification. The importance of such rotations can be viewed within the framework of a particular experimental paradigm. PMID- 7853089 TI - Metric for separation discrimination by the human visual system. AB - It is now clear that models of positional coding for elements sufficiently separated to permit individual identification require not only a first stage of linear filtering but also a second stage of representation that is preceded by a rectifying type of nonlinearity. To address the issue of the metric of this second stage we measure separation discrimination for Gabor stimuli of different sizes and of different peak spatial frequencies and separation, with and without different types of lateral distractors. Our results show that there is only a weak dependence of separation discrimination on the spatial frequency of equidetectable, spatially narrow-band stimuli; however, carrier spatial frequency can affect the influence that lateral distractors have on separation judgments. We conclude that (1) the second-stage representation is a space-size one consistent with the fact that there are scaled distributions of energy detectors of different sizes and (2) the influence of distractor elements suggests a spatial-frequency influence either at the second-stage representation or at a site beyond this second stage. PMID- 7853090 TI - Color appearance under chromatic adaptation varied along theoretically significant axes in color space. AB - Changes in color appearance caused by chromatic adaptation were measured with a wide range of adapting fields. Observers viewed a 39'-55' annular test field composed of an admixture of lights from the red phosphor and the green phosphor of a CRT. The annular mixture field was centered and superimposed upon a 4.7 degrees steady, circular background field. After the observer was completely adapted to the background, the luminance of the red phosphor in the test was held fixed while the observer adjusted the luminance of the green phosphor until the test appeared neither reddish nor greenish. Twenty-two equiluminant backgrounds (4.5 cd/m2, approximately 50 Td) were systematically selected along two axes in Judd chromaticity space. One axis was along tritanopic confusion lines, with middle-wavelength-sensitive- (M-) and long-wavelength-sensitive- (L-) cone stimulation held constant. The other axis maintained constant short-wavelength sensitive- (S-) cone stimulation. The results show that adapting backgrounds that were varied along tritanopic confusion lines do not have a differential effect on color appearance at high test levels (well above the adapting level). At lower test levels there is a systematic change in color appearance of the test light, which is quantitatively described by additive redness. Along constant S-cone stimulation lines, adapting backgrounds differentially affect color appearance in a systematic way, reflecting changes in receptoral gain and the additive contribution. The measurements taken with adapting fields throughout color space are described by the two-process model of chromatic adaptation. PMID- 7853091 TI - Comparison of healing of allograft/endoprosthetic composites with three types of gluteus medius attachment. AB - This study compared three methods of gluteus medius tendon attachment to an allograft/endoprosthetic composite of the proximal 25% of the femur in a canine model. The three methods were bone to bone, tendon to bone, and tendon to tendon attachment. In an in vivo study, 24 dogs were assigned to three groups of eight dogs each, and serial radiography and weight-bearing analyses were performed throughout the study. The dogs were killed at 6 months, and the specimens were tested in tension to failure and were analyzed histologically. In an in vitro study, each repair was done on six limbs, with a contralateral limb serving as a control for each. In these specimens, the bone to bone attachments were significantly stronger (99.1% of the controls) than the tendon to bone attachments (71.8% of the controls) and the tendon to tendon attachments (40.0% of the controls); there were no differences in tensile stiffness among the three types of attachment. By 6 months, the tensile strength of the tendon to tendon attachments increased significantly and that of the tendon to bone attachments decreased significantly. There were no significant differences in tensile strength among the three types of attachment. The tensile stiffness of the bone to bone attachments (91.0% of the controls) was significantly greater than that of the tendon to bone attachments (40.8% of the controls) but not significantly different from that of the tendon to tendon attachments (63.2% of the controls). The bone to bone attachment was associated with increased bone resorption, bone remodeling, and bone porosity, accompanied by thinner allograft cortices, when compared with the other types of attachment. In dogs with a bone to bone attachment, weight-bearing increased more slowly than in dogs with either of the other two attachments. These changes associated with the bone to bone attachment may merely be secondary to healing of the bone to bone attachment to the greater trochanter; therefore, they may only be temporary phenomena or they may be the portents for long-term complications. Longer term studies of at least 1-2 years must be performed before these questions can be answered. PMID- 7853092 TI - Patellar tracking measurement in the normal knee. AB - Eleven fresh frozen cadaveric knee specimens were mounted in a knee kinematics test device, and normal patellar movements were evaluated with use of an external device for direct measurement of patellar movements. The effects of four different measurement conditions were assessed through alteration of one condition and determination of its effect on patellar kinematics with the use of six specimens. The four conditions included (a) change of the measuring axis from an axis parallel to the central axis of the femur (femoral axis) to one parallel to the central axis of the tibia (tibial axis), (b) rotation of the femoral axis internally 6 degrees, (c) change of the direction of the quadriceps force from parallel to the mechanical line of the lower extremity to a direction parallel to the femoral shaft, and (d) increase of the magnitude of the quadriceps force from 111 to 500 N. During knee flexion, the patella shifted laterally after a slight initial medial shift, tilted laterally from midflexion to 90 degrees, and gradually rotated medially. The patellar shift relative to the tibial axis appeared to be more medial than the shift measured relative to the femoral axis; the discrepancy was caused by the valgus position of the tibia relative to the femur. Changing the rotational angle of the femoral axis artificially changed the patellar position. Varying the direction of the quadriceps within the narrow range and increasing the quadriceps force did not affect patellar movements.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7853093 TI - Indomethacin inhibition of ossification induced by direct current stimulation. AB - In this study, we sought to clarify the mechanism of ossification induced by direct current stimulation by analyzing changes in local blood flow and vascular permeability and by examining the involvement of chemical mediators. Changes in blood flow were studied with laser Doppler flowmetry, and vascular permeability was determined by microquantification. To examine the involvement of chemical mediators, we determined the effect on vascular permeability of histamine H1 and H2-receptor blockers and indomethacin. In addition, direct current stimulation was performed during administration of indomethacin to determine whether indomethacin inhibits electrically induced callus formation. Local blood flow remained unchanged in the control group and in the group receiving 5 microA of stimulation, but it increased in the groups receiving 10 and 50 microA. Vascular permeability increased in the 5 and 10 microA stimulation groups. This increase was not suppressed by histamine-receptor blockers, but it was suppressed by indomethacin. Two weeks of electrical stimulation without concomitant indomethacin treatment resulted in active callus formation around the needle electrode and in the vicinity of the endosteum; however, direct current stimulation during administration of indomethacin inhibited callus formation. The results suggest that these changes serve as microenvironmental factors that play an important role in the promotion of ossification and that a prostaglandin mediated mechanism is involved in the promotion of ossification by direct current stimulation. PMID- 7853095 TI - Tibial intercalary allograft incorporation: comparison of fixation with locked intramedullary nail and dynamic compression plate. AB - The healing and incorporation of intercalary cortical bone allografts stabilized with locked intramedullary nails was compared with that of allografts fixed with compression plates in a sheep model. Both techniques achieved healing of the allograft to host tibia, and there was no measurable difference in the area of callus or the quality of union histologically. Incorporation of the allograft as measured by fluorescent labeling was not different in the two groups. PMID- 7853094 TI - Lysyl oxidase and Maillard reaction-mediated crosslinks in aging and osteoarthritic rabbit cartilage. AB - Alterations in the integrity of the extracellular matrix play an important role in osteoarthritis. Matrix crosslinks in articular cartilage of the knee were studied in partially meniscectomized rabbits to compare changes due to osteoarthritis with those occurring during aging. Pyridinoline, a lysyl oxidase initiated crosslink, and pentosidine, a crosslink formed by the Maillard/glycation reaction, were assayed separately on reverse-phase high performance liquid chromatography. A significant increase in the percentage of insoluble collagen was observed in normal 12-month-old rabbits compared with the levels in 3-month-old animals, whereas osteoarthritis was associated with a shift toward more soluble fractions. Total pyridinoline content did not change with age or osteoarthritis. Total pentosidine, however, increased significantly with age but remained constant with osteoarthritis. Analysis of the distribution of crosslinks among solubility fractions indicated a significant shift of pyridinoline from the pepsin-released fraction to the insoluble fraction with osteoarthritis, but no changes were observed with age. Pentosidine distribution shifted toward the pepsin-released fraction in osteoarthritis, with a shift toward the insoluble fraction with age. Because of the low levels of pentosidine present, its precise location, whether collagenous or noncollagenous, remains unclear. However, since pentosidine represents a marker for the overall Maillard reaction, the results of our studies support a role for Maillard reaction products in the aging of extracellular matrix. The shift of pentosidine toward more soluble fractions suggests the presence of matrix degradation and repair in osteoarthritis. PMID- 7853096 TI - Growth of severed flexor tendons in chickens. AB - To examine tendon growth in both the distal and proximal portions of severed tendons, we investigated the growth of severed flexor tendons within the fibro osseous tunnel in young chickens. When the tendon was severed at the proximal site in the sole, dynamic tension applied by the muscle was lost. Growth in the distal tendon was retarded considerably, although passive tension initially was maintained through the residual vincula and later by adhesion to the chiasma of adjacent flexors. When the tendon was severed at the insertion, passive tension from the extensors was lost. Proximal tendon growth continued if active tension was maintained through the residual vincula. If not, the tendon was markedly shortened and degenerated. Maintaining normal tension may be the most important factor in longitudinal tendon growth. PMID- 7853098 TI - Hamstrings and gastrocnemius co-contraction protects the anterior cruciate ligament against failure: an in vivo study in the rat. AB - An anesthetized rat model was used to study the effects of muscle contraction on the ultimate tensile load and the energy absorption at failure of the anterior cruciate ligament. In both knees, the joint capsule and ligaments, except for the anterior cruciate ligament, were divided, and the menisci were removed with the aid of a stereomicroscope. The cruciate ligament of the right knee was tested in tension until failure by femorotibial distraction during contraction of the hamstrings and calf muscles induced by electrical stimulation of the ischiatic nerve. The cruciate ligament of the left knee, which was loaded to failure with nonstimulated (relaxed) muscles, served as the control. The mean ultimate tensile load during muscle contraction was 86 N compared with 53 N when tested with relaxed muscles (p < 0.001). The energy absorption at failure was 0.41 and 0.19 J during contraction and relaxation, respectively (p < 0.05). This study suggests that previous investigations evaluating the force and energy necessary to rupture the anterior cruciate ligament (with use of a femur-anterior cruciate ligament tibia complex stripped of all soft tissues and without gastrocnemius-hamstring muscle contractions) are incomplete and probably not representative of the in vivo situation. PMID- 7853097 TI - Cyclic compressive loading results in fatigue cracks in ultra high molecular weight polyethylene. AB - Wear damage to the articulating surfaces of total joint components made of ultra high molecular weight polyethylene is associated with a fatigue fracture mechanism, despite the fact that these surfaces are subjected to primarily compressive and compressive-tensile cyclic stresses. The question arises as to whether fatigue cracks will form under such loading conditions. In this study, we experimentally demonstrated that fatigue cracks could be initiated and propagated in notched ultra high molecular weight polyethylene specimens subjected to fully compressive and compressive-tensile cyclic loading. Under these loading conditions, growth of fatigue cracks was limited: the cracks arrested without catastrophic failure of the test specimens. The final length of the crack was dependent on the load ratio of the fatigue cycle; fatigue cracks propagated to greater lengths as the load ratio was increased. PMID- 7853099 TI - Research involving ultra high molecular weight polyethylene. PMID- 7853100 TI - Effect of static load on matrix synthesis rates in the intervertebral disc measured in vitro by a new perfusion technique. AB - The effect of static loading on matrix synthesis was measured in intact bovine coccygeal discs. The discs were maintained at 37 degrees C in a humid atmosphere and were perfused across their upper and lower surfaces for as long as 8 hours with media containing radioisotopes (3H-proline and 35S-sulphate) via porous filter disks embedded in Perspex (Plexiglas) holders. Static loads were applied to the disc with use of weights. The activity of free, nonincorporated isotope in the centre of the disc was monitored continuously with a microdialysis probe. Incorporated tracer in different regions of the disc was determined at the end of each experiment from the activity of the nondialysable tracer. Free tracer activity rose steeply over the first 3-4 hours of perfusion, as tracer diffused into the disc, and reached a steady value after 5-6 hours, as expected from diffusion theory. The rate of tracer incorporation estimated from the integrated value of free tracer concentration was constant for as long as 8 hours. Incorporation rates varied across the disc: the highest rates were in the inner layer of the annulus fibrosus, and the lowest rates were in the outer layer of the annulus. The rates for both 35S-sulphate and 3H-proline varied with load. The rates were lowest in the nucleus pulposus and the inner layer of the annulus fibrosus with a 0.5 kg load, and they almost doubled as the load was increased to 5-10 kg. Heavier loads (15 kg) led to a decrease in incorporation.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7853101 TI - Femoral abnormalities and vitamin D metabolism in X-linked hypophosphatemic (Hyp and Gy) mice. AB - X-linked hypophosphatemia is a genetic bone disease in humans and mice. Two closely linked mutations in mice, Hyp and Gy, cause low plasma phosphate and a rachitic and osteomalacic bone disease. Because of the controversy as to whether Gy is a good model for X-linked hypophosphatemia, the phenotypic severity of these two mutations was compared in both sexes and on two genetic backgrounds. The depression in plasma levels of phosphate was similar in all 10-week-old mutant mice. Male Hyp mice and heterozygous female Hyp mice were affected with similar severity in terms of reduced tail growth, shortened femora, reduced femoral mineral content, and abnormal mineral composition of the femoral matrix. In contrast, male Gy mice did not survive on the C57BL/6J background and were more severely affected than female Gy mice on the B6C3H background. The hybrid B6C3H background ameliorated the bone disease compared with the inbred C57BL/6J background for both mutant strains. There was no evidence of change in the plasma levels of 1,25-dihydroxyvitamin D, duodenal level of vitamin D-dependent calcium binding protein, or urinary level of calcium in these adult mutant mice. In summary, Gy mice have a sexual dimorphism not present in Hyp mice. These two genes may indicate the presence of multiple gene loci in the human disease, with multiple proteins involved in the pathophysiology of the bone disease. PMID- 7853102 TI - Expression of type-X collagen in osteoarthritis. AB - The present study was undertaken to examine how osteoarthritis affects the expression of type-X collagen, a hypertrophic chondrocyte-specific collagen in articular cartilage. A well characterized sheep polyclonal antiserum, as well as three mouse monoclonal antibodies against canine type-X collagen, was used to immunolocalize type-X collagen in human and canine joints. Its expression in osteoarthritic cartilage was altered in several locations. In the canine osteoarthritic joints, type-X collagen increased in and just above the zone of calcified cartilage and was present diffusely throughout the calcified matrix. In both the human and canine cartilage, type-X collagen was localized around cell clones in the transitional zone of cartilage. This is surprising, since that region of the cartilage does not calcify and one of the proposed roles of type-X collagen is in mineralization. Thus, the osteoarthritic process may damage the matrix in the superficial layer and induce changes leading to the expression of the hypertrophic chondrocyte phenotype. PMID- 7853103 TI - Diminished material properties and altered bone structure in rat femora during pregnancy. AB - Pregnancy and lactation are known to cause structural and mechanical changes in bone, but the effects of pregnancy alone have not been evaluated thoroughly. This study used radiographic measurements, torsion testing, mineral analyses, and histological evaluation to determine whether there are changes in bone material and geometric properties during pregnancy in the growing rat, as implied by earlier biochemical and histological studies. The bones of pregnant 9 to 12-week old rats and controls that were not pregnant and were matched by age (but not weight) were evaluated at times corresponding to 5, 10, 15, and 20 days of the 23 day gestation period to address the following questions: (a) How is the growth of whole bone affected by pregnancy in the growing rat (as determined by radiographic analyses)? (b) How are the mechanical properties (structural and material) of whole bone affected by pregnancy (as assessed by torsion testing)? (c) Are there changes in the characteristics of bone mineral during pregnancy (as determined by measurement of mineral content and x-ray diffraction analyses)? and (d) Are there detectable morphological or ultrastructural differences between the bones of pregnant and control rats (as assessed by analyses based on histology and back-scattered electron imaging)? The presence of statistically significant differences in this study was determined initially on the basis of a two-factor analysis of variance. In general, significant differences were noted only at late gestation (day 20), when the bones were longer and had a greater outer radius and cortical thickness; this indicates that more growth occurred during pregnancy.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7853104 TI - Changes of cytoskeletal architecture and incorporation of 3H-proline in contracted anterior cruciate ligament. AB - Changes of cytoskeletal architecture and incorporation of 3H-proline were investigated in contracted anterior cruciate ligaments with use of a model of contracture. In control ligaments, fibroblasts were shown by immunofluorescence microscopy to contain actin, vimentin, and myosin in their cytoplasm. Cytoskeletons were visualized by electron microscopy as a mesh network of microfilaments among cell organelles. In contracted anterior cruciate ligaments, fibroblasts were spindle-shaped and their cytoplasm could not be observed clearly in sections stained with hematoxylin and eosin. Actin staining was distributed irregularly and extensively, whereas vimentin and myosin staining was not scattered so extensively. When compared electromyographically, the actin staining appeared in cytoplasmic pseudopods of the fibroblasts. It was thought that these cytoplasmic pseudopods contained mainly actin and little or no other cytoskeletal elements such as vimentin and myosin. In autoradiographs, contracted anterior cruciate ligaments were shown, with use of 3H-proline, to experience a decrease in the number of labeled cells. On the basis of these findings of cytoskeletal rearrangement and of decreased incorporation of 3H-proline, we hypothesized that fibroblasts of the anterior cruciate ligament had the capacity to change their character during knee immobilization and to play a role in ligament contracture. PMID- 7853105 TI - Autogenous flexor tendon grafts: fibroblast activity and matrix remodeling in dogs. AB - To investigate rates of cellular proliferation and matrix turnover in autogenous flexor tendon grafts, hindlimb intrasynovial (flexor digitorum profundus) and extrasynovial (peroneus longus) tendons were placed within the synovial sheaths of the medial and lateral forepaw digits of 18 dogs and treated with controlled early passive motion. After the dogs had been killed, short-term culture and labeling in vitro were utilized to determine rates of DNA, proteoglycan, collagen, and noncollagen protein synthesis. Schiff base covalent collagen crosslink concentrations and total collagen and protein content also were evaluated at intervals through 6 weeks. Tendon grafts of extrasynovial origin showed greater rates of DNA synthesis and significantly elevated levels of proteoglycan, collagen, and noncollagen protein synthesis and Schiff base covalent collagen crosslink concentrations (dihydroxylysinonorleucine) compared with intrasynovial tendon grafts. It was not clear to what extent the increased activity in the extrasynovial graft was due to actual differences between the intrasynovial and extrasynovial tendons or to the responses of the connective tissue surrounding the extrasynovial tendon graft. Since both types of grafts demonstrated similar unaltered levels of collagen and protein content over time, these data suggest greater rates of matrix turnover in tendon grafts of extrasynovial origin than in those of intrasynovial origin. Coupled with previous findings showing increased cellular proliferation in extrasynovial tendon grafts, these data indicate that the process of translation to an intrasynovial environment necessitates a more active process of soft-tissue repair and remodeling when extrasynovial donor tendons are used. PMID- 7853106 TI - Platelet-derived growth factor in fibrous musculoskeletal disorders: a study of pathologic tissue sections and in vitro primary cell cultures. AB - Despite the great variability in the clinical behavior of fibrous lesions of the musculoskeletal system, they are composed of cytologically similar fibrocytes. Receptors for estrogen or progesterone, or both, are present in some of these lesions and some increase their rate of growth during periods of high levels of sex steroid hormones. The platelet-derived growth factor-B (PDGF-B) proto oncogene encodes the B chain of PDGF, a mitogen for fibrocytes. Tissue from aggressive fibromatosis, fibrous dysplasia, plantar fibromatosis, and recurrent plantar fibromatosis was analyzed with use of the polymerase chain reaction and in situ hybridization for the expression of PDGF-B and PDGF beta receptor. Cell culture was used to determine if estrogen and progesterone stimulation modulated the expression of PDGF-B. Aggressive fibromatosis, fibrous dysplasia, and recurrent plantar fibromatosis expressed PDGF-B; plantar fibromatosis, normal plantar fascia, normal fascia lata, and mature scar did not. All of the tissues expressed PDGF beta receptor. The level of expression in aggressive fibromatosis and fibrous dysplasia was four times that in the recurrent plantar fibromatosis. Estrogen and progesterone stimulation in aggressive fibromatosis resulted in an increase in the level of expression. Therefore, the detection of PDGF-B may be an adjunct in the pathologic identification of locally invasive lesions. Its production may be a common mechanism leading to a fibroproliferative response through deregulation of the control of growth by both paracrine and autocrine mechanisms. PMID- 7853107 TI - Histomorphometric analysis of innervation of the anterior cruciate ligament in osteoarthritis. AB - The aim of this study was to determine whether there are quantitative changes in the innervation of the anterior cruciate ligament in osteoarthritis. Eleven whole anterior cruciate ligaments were obtained at autopsy from cadavera of individuals with advanced osteoarthritis: five healthy ligaments were used as controls. The ligaments were transected and stained with hematoxylin and eosin, oil red O for fat, and a modification of Gairn's gold chloride method. The latter stain permits visualization of axons, mechanoreceptors, and free nerve endings that are not apparent on routine stains. The ratio of nerve tissue to periligamentous synovial tissue was determined histomorphometrically by the point-counting method. The nerve tissue was located almost exclusively in the periligamentous synovial tissue. There was a statistically significantly greater area of nerve tissue (as a percentage of the total area) around the anterior cruciate ligaments in the osteoarthritic group than around the ligaments in the control group (p < 0.02). The nerve tissue was distributed evenly throughout the periligamentous synovial tissue in the specimens in both groups. A neurological role has been proposed for the anterior cruciate ligament in osteoarthritis. This study provides morphological evidence for neural pathology of the anterior cruciate ligament in subjects with osteoarthritis. PMID- 7853108 TI - Method for the measurement of friction between tendon and pulley. AB - An experimental system was developed that allows direct measurement of friction at the tendon-pulley interface, and the results were interpreted by use of a theoretical model for friction of a cable around a fixed pulley. Validation experiments were conducted with a nylon cable around a nylon rod. One end of the cable was connected to an actuator via a load cell, and the other end was connected to a 4.9 N load via a similar load cell. The cable was passed around the nylon rod and then pulled toward the actuator. Tests were performed at five different arcs of contact. The friction forces, as measured by the difference between two load transducers, were compared with those determined for a theoretical model and were used for calculation of the friction coefficient. The measurement system then was used to study the friction force between the flexor digitorum profundus tendon and the A2 pulley on nine fresh frozen index digits. The method allows us to measure the direct interaction between the tendon and pulley and could be used to evaluate and compare procedures for tendon-pulley and pulley repair and reconstruction, as well as for the study of tendon-pulley friction in various pathological conditions. PMID- 7853109 TI - Effects of freeze/thaw conditioning on the tensile properties and failure mode of bone-muscle-bone units: a biomechanical and histological study in dogs. AB - Eight pairs of canine supraspinatus bone-muscle-bone units were mechanically tested to failure in tension. One side was tested immediately post mortem, and the other side was tested after exposure to a standard freeze/thaw process (-60 degrees C). The failure site was analyzed histologically. Fresh specimens had greater values for ultimate strength (p < 0.001), stiffness (p < 0.001), and energy to failure (p < 0.001). All specimens failed in the muscle close to the musculotendinous junction. The length of muscles subjected to the freezing process was reduced (9.3%). In addition, the load-displacement curves for the fresh and frozen specimens showed marked differences in shape. The loss of tensile strength in muscle tissue is due to damage of the intracellular contractile elements caused by postmortem autolysis; this type of damage is increased as a result of the freeze/thaw process. The freeze/thaw process significantly altered the tensile properties of normal muscle tissue, no matter how carefully it was done. One cannot expect to receive representative data if muscle is frozen and thawed. PMID- 7853110 TI - Preserving plantar flexion strength after surgical treatment for contracture of the triceps surae: a computer simulation study. AB - Contractures of the triceps surae commonly are treated by surgical lengthening of the gastrocnemius aponeurosis or the Achilles tendon. Although these procedures generally relieve contractures, patients sometimes are left with dramatically decreased plantar flexion strength (i.e., decreased capacity to generate plantar flexion moment). The purpose of this study was to examine the trade-off between restoring range of motion and maintaining plantar flexion strength after surgical treatment for contracture of the triceps surae. A computer model representing the normal moment-generating characteristics of the triceps surae was altered to represent two conditions: isolated contracture of the gastrocnemius and contracture of both the gastrocnemius and the soleus. The effects of lengthening the gastrocnemius aponeurosis and the Achilles tendon were simulated for each condition. The simulations showed that nearly normal moment-generating characteristics could be restored when isolated gastrocnemius contracture was treated with lengthening of the gastrocnemius aponeurosis. However, when isolated gastrocnemius contracture was treated with lengthening of the Achilles tendon, the moment-generating capacity of the plantar flexors decreased greatly. This suggests that lengthening of the Achilles tendon should be avoided in persons with isolated gastrocnemius contracture. Our simulations also suggest that neither lengthening of the gastrocnemius aponeurosis nor lengthening of the Achilles tendon by itself is an effective treatment for combined contracture of the gastrocnemius and soleus. Lengthening the gastrocnemius aponeurosis did not decrease the excessive passive moment developed by the contracted soleus. Lengthening the Achilles tendon restored the normal passive range of motion but substantially decreased the active force-generating capacity of the muscles.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7853111 TI - Venous access device study: identification of number of patients with venous access device lines. AB - As part of the Quality Assurance and Improvement Process, the need to determine the number and location of patients having venous access devices in a 600-bed tertiary care facility was identified. In the overall study, 167 patients on 18 wards had venous access device lines in place for a total of 455 weeks. As a direct result of the study, policies/procedures and other practice changes regarding patients with venous access devices have been reviewed and revised. Furthermore, the data helped to provide an in-depth look at the central-line issues for patient care. PMID- 7853112 TI - Three-hour paclitaxel infusion in the outpatient setting. AB - Paclitaxel (Taxol, Bristol-Myers Squibb Company, Princeton, NJ), a naturally occurring antineoplastic agent discovered in the 1960s, is now considered to be one of the most promising drugs of the decade. Administration of paclitaxel requires a thorough patient assessment, extensive patient monitoring during infusion, as well as special patient education. When the 3-hour infusion of paclitaxel is compared with the 20-hour infusion, a decrease in the severity of neutropenia has been demonstrated. In this article, specific patient side effects, required monitoring, and specific patient education are described. PMID- 7853114 TI - Home infusion of intravenous immunoglobulin. AB - Intravenous immunoglobulin (IGIV) is being used extensively in the home-care setting to treat patients with a wide variety of disorders. This therapy can be managed more effectively when the patient and/or caregiver have been educated regarding the therapy. In this article, a therapy education plan, policies, and procedures that address the key components of providing IGIV treatments in the home-care setting will be presented. Instructional information is presented in "patient-friendly terms" that can be readily applied to the nursing care plan. This plan will be applicable for patients who will become independent with the administration of their IGIV as well as for those who will have their IGIV administered by the home-care nurse. PMID- 7853113 TI - Market your expertise for the changing future of intravenous therapy. AB - Redirecting an i.v. team is a progressive approach to interdepartmental and community i.v. needs for the future viability of i.v. therapy. Cut backs and cost justification can be redirected to increase revenue. First the i.v. team should present a proposal to hospital management that includes statistics of i.v. team duties, cost justification by phlebitis and infection, and ways that revenue can be increased. Areas of expertise and needs in the department, hospital or agency, and community must be determined. The possibilities and feasibility of implementation should be researched and prioritized. These possibilities should then be planned, developed, and implemented according to the prioritized list. PMID- 7853115 TI - Antiretroviral activity of furocoumarins plus UVA light detected by a replication defective retrovirus. AB - The replication defective retrovirus, pXM5(N2), was used for an easy, safe and reproducible test for the screening of furocoumarins with antiretroviral activity. High titer viral supernatants have been photomodified by UVA light (20 kJ m-2) in the presence of different concentrations of two psolarens (8 methoxypsoralen, 8-MOP and 4,5',8-trimethylpsoralen, TMP) and one angelicin (4,6,4'-trimethylangelicin, TMA). At low concentrations (100-250 ng ml-1) 8-MOP and TMA did not show any significant antiviral activity, while TMP demonstrated a reduction of virus infectivity by one log at 250 ng ml-1. At the highest concentration (5 micrograms ml-1), TMA and TMP reduced the virus titer by one and more than two logs, respectively, being, therefore, two and four times more active than 8-MOP. The most active compound, TMP, was further tested on HIV-1 viral supernatants. Total inactivation of the HIV-1 (200 SFU) was obtained in the presence of 1 microgram ml-1 of TMP and 20 kJ m-2 of UVA light. Our results support the validity of the N2 system to detect the antiretroviral activity of furocoumarins and suggest the potential of TMP in combination with UVA light against HIV-1. PMID- 7853116 TI - Singlet oxygen generation by Photofrin in homogeneous and light-scattering media. AB - The singlet oxygen quantum yield (phi delta) for Photofrin solubilized by Triton X-100 was measured in homogeneous and light-scattering media using the photosensitized inactivation of lysozyme as an internal actinometer. Higher values of phi delta at 630 nm than at 514 nm are attributed to the formation of a far-red-absorbing photosensitizing photoproduct. PMID- 7853117 TI - Effects of low-power 632 nm radiation (HeNe laser) on a human cell line: influence on adenylnucleotides and cytoskeletal structures. AB - HeNe (632 nm) irradiation (5, 15 and 30 min) of an embryonal human cell line (EUE) was used to study the short-term effects on energy charge and the rapid, energy-dependent, remodelling processes of cytoskeletal and adhesion structures. The adenosine triphosphate (ATP) concentration, tested by luminometric and high performance liquid chromatography (HPLC) procedures, is constant after 15 and 30 min of HeNe treatment; the lower phosphorylated nucleotides, i.e. adenosine diphosphate (ADP) and adenosine monophosphate (AMP), change after 30 min in opposite directions: the ADP concentration decreases by 39% whilst that of AMP increases about sixfold. The adenylate energy charge (AEC) decreases by 21.7% in treated EUE cells (AEC = 0.65) in comparison with untreated EUE cells (AEC = 0.83). In HeNe-treated cells, the remodelling of cytoskeletal and adhesion molecules becomes evident after 15 min of treatment. The following events are important: (1) modification of stress fibre assembly and increase in vinculin containing adhesion plaques; (2) assembly and bundling of intermediate filaments; (3) increase in laminin and L-cell adhesion molecules (L-CAM) expression. The lowered energy charge in irradiated cells is related to the increase in AMP production at the expense of ADP. ATP is dynamically constant despite its requirement in short-time remodelling processes of the cytoskeletal network which are enhanced in irradiated cells. PMID- 7853118 TI - Both UVA and UVB induce cytoskeleton-dependent surface blebbing in epidermoid cells. AB - Data on the morphological changes induced by UVA or UVB irradiation of A431 epidermoid cells in culture are presented. After irradiation with different doses of UVB (120-2400 J m-2) or UVA (10(4)-10(5) J m-2), the membrane and cytoskeleton of these cells were analysed by immunofluorescence and scanning electron microscopy at different times after exposure (0-48 h). Both UVA and UVB alter microtubules and microfilaments and surface blebs are formed after UV irradiation. In particular, UVB induces multiple small blebs on the cells, while UVA induces one single large bleb on each cell. Since cytoskeletal damage and surface blebbing of this type are also induced by oxidative stress, these results add to the body of evidence indicating that UV radiation is capable of pro oxidant behaviour. Specifically, the morphological changes described in this paper are reminiscent of the modifications which accompany epidermal keratinocytes during their transformation to sunburn cells after UV irradiation. The physiological implications of these findings are discussed. PMID- 7853119 TI - The effect of N-acetylcysteine on the UVB-induced inhibition of epidermal DNA synthesis in rat skin. AB - The effect of N-acetylcysteine (NAC), on the UVB-induced inhibition of epidermal DNA synthesis in rat skin was investigated. Topical application of NAC, 30 min prior to UVB irradiation (20 kJ m-2), significantly reduced the UVB-induced inhibition of the epidermal (methyl-1',2'-3H)-thymidine uptake. These results indicate that NAC affords protection against at least some of the damaging effects of UVB radiation on epidermal DNA, probably by neutralization of UVB induced reactive species. PMID- 7853120 TI - Dietary carotenoids protect human cells from damage. AB - A physical chemistry technique based on singlet oxygen luminescence at about 1270 nm and a biological cell membrane technique were used to study the quenching of singlet oxygen by four carotenoids bound to the surface of lymphoid cells. All the carotenoids studied showed a beneficial effect in cell protection, but there were subtle differences between them. PMID- 7853121 TI - Trapping magnetically oriented chloroplast thylakoid membranes in gels for electric measurements. AB - Electrochromic absorbance change and light gradient photovoltage measurements were carried out in chloroplast thylakoid membranes embedded in different compositions of gels. The goal was to find a system suitable for determining the dependence of the amplitude of the anomalous light gradient photovoltage signal, with opposite sign with respect to the ordinary signal, on the alignment of membranes. We found that polyacrylamide gel drastically increased the permeability of membranes which rendered electric measurements impossible in this gel. Agarose gel was successfully used in electric measurements. We will show that the light gradient photovoltage induced by a 580 nm laser flash depends strongly on the alignment of membranes with respect to the direction of the excitation beam. With face-aligned membranes the amplitude of the anomalous (negative) signal was drastically diminished, and the ordinary (positive) signal became clearly discernible. The observed differences in the decay of the two signals are tentatively explained by differences in the rates of ionic equilibration between different subcompartments of the inner aqueous phase of the thylakoid membrane system. PMID- 7853123 TI - Phenotypic characterization of mononuclear cells following anorganic bovine bone implantation in rats. AB - The purpose of this study was to measure inflammatory changes associated with implantation of anorganic bovine bone and bovine bone/collagen composite grafts, and to compare the response to that obtained following grafting with hydroxyapatite. Anorganic bovine bone, either with or without bovine collagen, as well as granular and block forms of synthetic hydroxyapatite, were implanted subcutaneously in Wistar rats. Saline and turpentine oil were used as controls. Biopsies were obtained after 3 days and at 1, 2, 4, 6, and 8 weeks. A panel of 6 monoclonal antibodies was used to detect monocytes, several distinct macrophage subsets, Ia-antigen expression, and T- and B-lymphocytes. Cells identified by each antibody were counted after immunocytochemical staining, and sera obtained 6 weeks after grafting were used in immunoblotting assays to detect antibodies to bovine serum proteins and collagen. Anorganic bovine bone, bovine bone/collagen, and hydroxyapatite all produced a transient macrophage infiltrate that was maximum 3 days after implantation, but resolved to normal levels within 6 to 8 weeks. Lymphocyte infiltration was not elicited by any bovine graft material, and antibodies to bovine serum proteins or type I collagen were not detected in any of the animals examined. These data indicate that a systemic or local immune response does not develop following implantation with anorganic bovine bone or with anorganic bovine bone/collagen materials. It appears appropriate to explore further the merits of these materials for periodontal regenerative procedures. PMID- 7853122 TI - Cytokine-dependent synergistic regulation of interleukin-8 production from human gingival fibroblasts. AB - Human Gingival Fibroblasts (HGF) may have an important role in the orchestration of immuno-participant cells infiltrating the gingiva in response to continuously recurring bacterial infection. To examine the cytokine network regulating HGF derived interleukin (IL)-8, a potent neutrophil chemotactic cytokine, we analyzed the effects of inflammatory cytokines alone and in combination on IL-8 production by HGF. IL-1 beta, tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN gamma), IL-6, and IL-8 were used as stimulants. HGF secreted IL-8 in a dose dependent manner after stimulation with either IL-1 beta or TNF-alpha, but not with IFN-gamma or IL-6. Furthermore, IL-8 itself did not affect IL-8 mRNA accumulation in HGF in an autocrine manner. The combination of IL-1 beta and TNF alpha synergistically enhanced the secretion of IL-8, whereas IFN-gamma suppressed IL-8 secretion by IL-1 beta- or TNF-alpha-stimulated HGF. These effects were also observed at each level of IL-8 mRNA expression in HGF. IL-8 secretion by cytokine-stimulated HGF was not influenced by the inhibition of PGE2 synthesis with indomethacin, indicating that endogenous PGE2 was not involved in IL-8 production by HGF. These results indicate that IL-8 production by HGF is synergistically stimulated by specific cytokines, IL-1 beta and TNF-alpha, and suggest that these stimulatory effects are down-regulated by IFN-gamma at the transcriptional level through PGE2-independent pathways. Thus, neutrophil mediated processes in periodontal disease may be regulated in part by HGF in the cytokine network of immuno-participant cells. PMID- 7853124 TI - Mechanism of irrigation effects on gingivitis. AB - Although gingivitis is initiated by plaque and plaque removal controls gingivitis, gingival irrigation with water has been shown to reduce gingivitis without reducing plaque. This study attempted to explore possible mechanisms involved in the treatment of gingivitis by water irrigation. Patients (n = 125) with more than 20 teeth, less than 4 sites with probing depth (PD) deeper than 6 mm, bleeding on probing (BOP) frequency of 30% or higher, and no systemic disease were randomized to one of four treatment groups: toothbrushing alone (brush), toothbrushing plus chlorhexidine 0.12% rinse 2x/day (CHX), toothbrushing plus water irrigation 1x/day (irr+H2O), or toothbrushing plus chlorhexidine 0.04% irrigation 1x/day (irr+CHX). Six sites/tooth were examined at baseline, and at 3 and 6 months for BOP and PD using an automated probe, and for gingival index (GI) and plaque index (PI) by standard means. A prophylaxis and oral hygiene instructions were provided after baseline and 6 month measurements. Subgingival microbial samples and crevicular fluid (GCF) were collected from 2 teeth/subject at each time point. Microbial samples were processed for anaerobic culture and the predominant cultivable flora was determined. CHX and irr+CHX had a 30 to 35% decrease in mean PI, while brush and irr+H2O had only a 12 to 16% decrease. BOP was reduced by 14% in the brush group and 23 to 24% in the other groups. GI was significantly correlated with PI in the brush, CHX, and irr+CHX groups, but not in the irr+H2O group. Prevotella intermedia was significantly reduced in both irrigation groups, but not CHX or brush groups.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7853125 TI - Effect of treatment on some periodontopathogens and their antibody levels in periodontal abscesses. AB - Twenty patients suffering from abscess of periodontal origin were treated and followed clinically and microbiologically for 6 months. Microbiological examination was performed by culture technique. One deep and one shallow periodontal pocket in the same patient were examined concomitantly. Serum was collected and analyzed for specific antibody level using ELISA methodology. Treatment included supragingival scaling, drainage, and irrigation of the periodontal pocket with 0.85% sodium chloride and systemic tetracycline administration, 1 g per day for 2 weeks. At baseline, 90% of the abscesses harbored Porphyromonas gingivalis and/or Prevotella intermedia. After 6 months, abscess sites demonstrated a reduced probing depth, less bleeding on probing, and gain of attachment. Abscess sites showed no P. gingivalis and the proportion of P. intermedia was significantly reduced 6 months after treatment. In deep periodontal pockets a similar pattern was seen. Shallow pockets demonstrated few clinical signs of inflammation and the number of bacteria was generally low. Campylobacter rectus, Capnocytophaga spp, and Fusobacterium nucleatum were frequently seen in low numbers in most sites during the study period, while Actinobacillus actinomycetemcomitans was detected only in a few sites. The IgG levels in patient sera against antigens of homologous bacterial strains remained fairly constant for 6 months. The result of the present study indicates that P. gingivalis and P. intermedia are involved in periodontal abscess formation. Also, treatment where drainage is combined with tetracycline administration promotes healing and reattachment. PMID- 7853126 TI - Evaluation of an absorbable collagen membrane in treating Class II furcation defects. AB - Recent research has focused upon the utilization of an absorbable collagen membrane in guided tissue regeneration (GTR). Concern exists as to whether this type of membrane is beneficial in the treatment of periodontal defects. The purpose of this study was to evaluate the effect of a type I bovine collagen membrane on treatment of Class II furcation defects. Twelve systemically healthy patients (six male and six female, ages 32 to 68) were treated. Each had bilateral mandibular furcation defects with attachment loss > or = 6 mm. Prior to surgery all patients completed initial therapy including scaling and root planing. At the time of the surgery, teeth were randomly assigned to either a control (flap debridement alone) or test (flap debridement plus collagen membrane) group. Data were collected on the day of surgery, and 2, 4, and 6 months post-surgery and at the 12 month re-entry surgery. Clinical measurements included probing depth (PD), clinical attachment level (CAL), gingival recession (GR), stent to base of defect (SB), crestal bone to base of defect (CB), width of defect, and mobility. Statistical analysis was performed utilizing the paired t test. Both control and test groups demonstrated significant (P < 0.05) improvement at 12 months re-entry in PD, CAL, SB, and CB when compared to the presurgery status. While there is no significant difference in PD, CAL, GR, width of defect, and mobility between control and test groups, sites treated with the collagen membrane had significantly higher bone fill (SB and CB) at re entry.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7853127 TI - Synthetic bioabsorbable barrier for regeneration in human periodontal defects. AB - Guided tissue regeneration (GTR) may result in the formation of new bone, cementum, and periodontal ligament. The purpose of this study was to assess the efficacy of a resorbable synthetic material, which has been used extensively in general surgery for wound support, to promote GTR. Forty healthy patients with adult periodontitis, each having a Class II furcation defect, participated in the study. After initial therapy, mucoperiosteal flaps were elevated and furcations debrided with hand and rotary instruments. In 20 patients the molar Class II furcation defects were treated with a GTR procedure using the resorbable synthetic material (experimental), and 20 patients received a mucoperiosteal flap debridement procedure without barrier placement (control). Probing depth and attachment level measurements were taken immediately before surgery, at 6 weeks, and 2, 3, 4, 5, and 6 months after surgery. All areas healed uneventfully. Comparison of clinical attachment level measurements indicated significantly greater gain of attachment at sites receiving barriers. Fifteen of 20 Class II furcations in the synthetic barrier group, but only one of 20 in the control group, were converted to Class I defects. Barriers were still clinically detectable at 4 weeks, but were absent at 6 weeks. The synthetic barriers enhanced gain of clinical attachment in human Class II furcation defects. PMID- 7853128 TI - Comparative detection frequency of 6 putative periodontal pathogens in Sudanese and Norwegian adult periodontitis patients. AB - Twenty-five sudanese and 18 norwegian adult periodontitis patients were selected to participate in this study. The purpose was to compare cultivation results of Porphyromonas gingivalis, Prevotella intermedia, Actinobacillus actinomycetemcomitans, Fusobacterium nucleatum, and Capnocytophaga species as well as various enteric rods in both populations. In addition, DNA probe analysis was used to identify P. gingivalis, P. intermedia, A. actinomycetemcomitans, F. nucleatum, and Bacteroides forsythus in the Sudanese patients and results were compared with those obtained by cultivation. The paper point technique was used to sample 99 sites in the Sudanese group (4 paper points/site) and 119 sites in the Norwegian patients (3 paper points/site). In the Sudanese subjects, the fourth paper point was used for the DNA probe analysis. The chi-square test and the Wilcoxon signed rank test were used to test for statistically significant differences between Sudanese and Norwegian cultivation results as well as between cultivation and DNA results in the Sudanese group. Cultivation results indicated that the Sudanese subjects had significantly lower prevalence of P. gingivalis, P. intermedia, and F. nucleatum (P < 0.01), significantly higher prevalence of Capnocytophaga species (P < 0.05), and similar prevalence of A. actinomycetemcomitans. Almost all Sudanese subjects tested positive for various enteric rods, while none of the Norwegians did so. The extent to which unrestricted use of antibiotics and transport media influenced the levels of enteric species is not known, however.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7853129 TI - Microbial associations of 4 putative periodontal pathogens in Sudanese adult periodontitis patients determined by DNA probe analysis. AB - The few previous cultivation studies on the in vivo associations between various periodontal microbial species have shown several positive and negative associations. The present investigation utilized DNA probe analysis to examine possible in vivo associations between the periodontal pathogens Porphyromonas gingivalis, Prevotella intermedia, Fusobacterium nucleatum, and Bacteroides forsythus in subgingival plaque samples obtained from 25 Sudanese untreated adult periodontitis patients. The standard paper point technique was used to sample 99 sites with a mean probing depth of 6.8 mm (range 6.0 to 10.0). Microbial associations were determined by detecting the effect of the presence or absence of one species (effector) on the occurrence of the other 3 species (target). The Wilcoxon signed rank test was used to examine variations in occurrence of each target bacteria in the presence or absence of the effector. In addition, the Spearman's rank correlation test was used to assess the relationship between the level of each bacteria to that of the other 3. Results showed bacterial associations with the following effector-on-target effects: F. nucleatum (P < 0.01 Wilcoxon; P < 0.001 Spearman) >> P. gingivalis (P < 0.01 Wilcoxon; P < 0.001 Spearman), and B. forsythus (P < 0.05 Wilcoxon; P < 0.001 Spearman) > P. intermedia (P < 0.01 Spearman). The study demonstrated positive associations between the 4 species investigated, while no neutral or negative associations were revealed. The most striking finding was the effect exerted by F. nucleatum on the colonization of P. intermedia; P. intermedia was never detected in a site unless F. nucleatum was also present. PMID- 7853130 TI - Clinical and microbiological effects of controlled-release locally delivered minocycline in periodontitis. AB - The clinical efficacy of minocycline in a subgingival local delivery system was evaluated alone (M) or as an adjunct to scaling and root planing (M + SRP), in comparison to scaling and root planing (SRP) or to no subgingival treatment (NoTx) in adult periodontitis. Fifty-one adult patients with > or = 7 mm periodontal pockets demonstrating the presence by culture of Porphyromonas gingivalis (Pg), Prevotella intermedia (P(i)), or Actinobacillus actinomycetemcomitans (Aa) were randomized into one of the above 4 treatment groups. All sites > or = 5 mm in the most diseased quadrant in each patient received the therapy. Other quadrants were not treated. All patients received standardized oral hygiene instructions at the beginning of the study. At 0, 1, 3 and 6 months following therapy the 7 mm experimental sites were evaluated for selected periodontal pathogens by DNA probe analysis. At these same time points, the plaque index, gingival index, and bleeding on probing were evaluated as well as probing depth and relative clinical attachment level which were assessed by means of an automated probe. Probing depth reduction with M + SRP was significantly greater than all other groups at one month and significantly greater than NoTx and SRP at 3 months. There were no differences in probing depth reduction among groups at 6 months. At 6 months the gain in clinical attachment level was significantly greater for SRP than for either the NoTx or M groups. The prevalence of Pg decreased significantly in the M and M + SRP groups at one month.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7853131 TI - Association of the severity of periodontal disease with organ complications in type 1 diabetic patients. AB - This study examined the relationship between the severity of periodontal disease and organ complications in long-term Type 1 or insulin-dependent diabetes mellitus patients, taking account of the severity and concomitant existence of these complications. The population studied consisted of 26 Type 1 diabetics 26 to 34 years old, who had had diabetes for at least 10 years. Severity of periodontal disease was shown to increase with severity of organ complications. Patients with advanced complications had significantly more bleeding on probing, pockets > or = 4 mm deep, and more attachment loss than patients with incipient complications or no complications. Stepwise multiple regression analysis showed that the existence of advanced complications was the only diabetes-related factor predicting pockets > or = 4 mm deep. Subgingival calculus, sex, and smoking were other significant variables. Retinopathy was the organ complication most suited to comparison, since it is usually the first to appear and can easily be classified from non-existent to severe. Differences in severity of periodontal disease were less obvious if metabolic balance alone was considered than between subgroups formed on the basis of the existence of advanced complications. Severity of periodontal disease and the existence of complications were more closely related to long-term glucose balance than single, most recent HbA1 values. Prevalence of pockets at sites with subgingival calculus increased with severity of complications.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7853132 TI - Microbiota of rapidly progressive periodontitis lesions in association with clinical parameters. AB - The microbial population in 73 rapidly progressive periodontitis (RPP) lesions in 10 young adults aged 25 to 35 years (5 males, 5 females) was studied in relation to the clinical parameters probing depth, bleeding on probing, and suppuration, which were recorded at the sampled sites. Porphyromonas gingivalis was found to predominate (26.7%) in 73 periodontal lesions with clinical probing depth > 6 mm, followed by Bacteroides forsythus (23.6%), and Prevotella intermedia (15.7%). The prevalence of P. gingivalis was 91.7%, Fusobacterium nucleatum, 90.4%; Streptococcus intermedius, 87.7%; and B. forsythus, 53.4%. Significant differences between bleeding index 0, 1, and 2 (P < 0.05) in frequency of detection were found for P. intermedia, Campylobacter concisus, Selenomonas sputigena, and Peptostreptococcus micros at bleeding sites and for Streptococcus sanguis, Actinobacillus actinomycetemcomitans, and B. forsythus (P < 0.001) at non-bleeding sites. Between suppurating and non-suppurating sites, significant differences (P < 0.05) in frequency of isolation were found for P. intermedia, Capnocytophaga ochracea, and A. actinomycetemcomitans at suppurating sites and for F. nucleatum at non-suppurating sites. PMID- 7853133 TI - The vasculature of the periodontal ligament: a scanning electron microscopic study using corrosion casts in the rat. AB - The purpose of this study was to examine the 3-dimensional architecture of the microvascular system of the rat periodontal ligament (PDL). Vascular corrosion casts were prepared and examined by scanning electron microscopy. Cervically, arterioles and venules communicated with the profuse capillary network of the gingiva. The mid-root segment of the PDL contained arterioles and venules that mainly coursed occluso-apically near the alveolar wall, as well as capillary loops located closer to the root surface. Arterioles entered the PDL through vascular canals from the bone marrow, then coursed coronally and branched into an interconnected network of capillaries. The capillaries formed hairpin loops pointing coronally. At the tip, the capillary loops were enlarged in diameter and had an irregular luminar surface. The capillaries then coursed apically, anastomosing freely, until entering a venule. Large venules mainly followed a coronal-apical path, giving the PDL vasculature a palisade-like appearance. These vessels either left the PDL through vascular canals in the alveolar wall or connected in an apical, venous cap with venules exiting through the apical foramen. The results show that the microvasculature forms a highly organized system presumably related to the specialized functions of the periodontium. Cervically, a dense capillary system may be required for antimicrobial defense and rapid tissue turnover. The vasculature in the middle segment supports the suspensory structures, while the venous cap in the apical region may be designed to cushion masticatory forces.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7853134 TI - Expanded polytetrafluoroethylene titanium-reinforced membranes for regeneration of mucogingival recession defects. A 12-case report. AB - The regeneration of tissue to treat mucogingival recession defects is well established but these defects pose additional challenges for the clinician in the creation and maintenance of a space under the guiding membrane. We used titanium reinforced membranes of expanded polytetrafluoroethylene (ePTFE) to facilitate the creation and maintenance of such spaces in 12 patients with mucogingival recession defects. The membranes were judged according to their ease of handling and placement and the regenerative results; the patients were evaluated for gingival recession and the quantity of attached gingiva before and for as long as 15 months after treatment. At 15 months, the average gingival recession was 1.4 mm (pretreatment = 5.3 mm), and the attached gingiva measured 3.3 mm (pretreatment = 1.4 mm). Titanium-reinforced ePTFE membranes result in a simpler, faster, and more predictable surgical procedure. Comparison of titanium reinforced ePTFE membranes to other available procedures awaits assessment in clinical trials. PMID- 7853135 TI - Periodontal disease in non-insulin dependent diabetes mellitus (NIDDM). The effect of age and time since diagnosis. AB - The association of periodontal disease with diabetes was studied in non-insulin dependent diabetes mellitus (NIDDM) patients. In a cross-sectional design, 100 patients (46 males and 54 females) were selected in 4 groups according to age and years since diagnosis of diabetes. The groups were: group 1, > 55 years old, diabetes diagnosed > or = 5 years; group 2, < or = 55 years old, diabetes diagnosed > or = 5 years; group 3, > 55 years, diabetes diagnosed < 5 years; and group 4, < or = 55 years, diabetes diagnosed < 5 years. Buccal and lingual pockets were deeper and lingual and buccal recessions greater for groups diagnosed 5 or more years ago, (P < 0.0001). In groups diagnosed less than 5 years, higher recession indices were found for patients older than 55. The loss of buccal insertion was also greater for groups diagnosed 5 or more years ago (P < 0.0001). For groups diagnosed less than 5 years ago, the loss was greater in the group older than 55 (P = 0.01). There was a marginal difference in gingival bleeding among the 4 groups (P = 0.047). Post-hoc analysis showed differences between the 2 groups who had been diagnosed less than 5 years, with lower indices for patients < or = 55. All groups were statistically different regarding bone loss (P < 0.0001), with higher indices for the groups with older age, and for groups with 5 or more years since diagnosis. There was no difference in dental mobility among the 4 groups (P = 0.0981). It was concluded that years since diagnosis of diabetes is more significant than age for severity of periodontal disease in NIDDM. PMID- 7853136 TI - Smoking as an additional risk for tooth loss. AB - Epidemiological studies have shown that loss of teeth is associated with increasing age. This was explained as the result of the action of microorganisms which, as components of dental plaque, destroyed the tooth by causing caries or periodontitis. Routine prevention programs therefore concentrated on removal of plaque, resulting in good oral hygiene. Despite good oral hygiene some individuals developed periodontitis. Studies have indicated that smoking may be a risk factor for this disease. This study was undertaken to determine whether or not smoking is also a risk factor for tooth loss. A total of 273 individuals were followed for 10 years, during which 93 individuals lost a total of 260 teeth. Younger individuals and especially males smoking more than 15 cigarettes a day were found to have the highest relative risk of losing teeth (4.55 and 3.18 respectively). In the younger age groups the proportional attributable risk was also highest; 78% for smokers smoking more than 15 cigarettes a day. The combination of a high plaque score and smoking was, together with age, the strongest predictor of tooth loss. The findings of this study suggest that smokers, especially those in the age group < 50 years, are a high risk group for tooth loss. PMID- 7853138 TI - Pharmacological effects of melatonin treatment on both locomotor activity and brain serotonin release in rats. AB - The effects of intraperitoneal administration of pharmacological doses of melatonin (60 mg/kg) on both locomotor activity and brain monoamine release were assessed in rats. The spontaneous levels of either horizontal motion, vertical motion, or total distance traveled were decreased following melatonin injection. On the other hand, the spontaneous levels of postural freezing increased after treatment. External heat exposure (36 degrees C) produced increases in locomotion (including horizontal motion, vertical motion, and total distance traveled) as well as decreases of postural freezing in rats. The heat-induced increases of horizontal motion and total distance traveled as well as decreases of postural freezing were attenuated by melatonin treatment. In addition, cold exposure (4 degrees C) produced increases of vertical motion as well as decreases of postural freezing. Again, the cold-induced behavioral responses were attenuated by melatonin treatment. Biochemical data revealed that the serum levels of melatonin were decreased by both heat and cold exposure in rats. Furthermore, voltammetric data revealed that intraperitoneal administration of melatonin (60 mg/kg) decreased serotonin, but not the dopamine, release in the hypothalamus, the corpus striatum or nucleus accumbens of rat brain. Neither the locomotor activity responses to thermal stress nor brain monoamine release was affected by a smaller dose of melatonin (30 mg/kg, i.p.). The results suggest that systemic administration of melatonin, at pharmacological doses, inhibits brain serotonin release and results in a reduction in both the spontaneous locomotion and the thermal stress-induced locomotor activity responses in rats. PMID- 7853137 TI - Detection and quantification of melatonin in a dinoflagellate, Gonyaulax polyedra: solutions to the problem of methoxyindole destruction in non-vertebrate material. AB - Preservative procedures are described for the extraction and quantification of melatonin in cell material from the dinoflagellate Gonyaulax polyedra, an organism in which this indoleamine is rapidly degraded due to interaction with free oxygen radicals and photooxidation. Cells were shock-frozen in liquid nitrogen and pulverized. Various extraction methods were applied to the powder, and rates of recovery were compared. For the determination of melatonin by high performance liquid chromatography (HPLC), extractions with acetone or perchloric acid were more suitable than the use of other solvents. For purposes of radioimmunoassay (RIA), extraction with acetone gave the best results. Several other inorganic solvents, which are often applied in melatonin research, such as chloroform, dichloromethane, and diethyl ether, led to considerable losses of the indoleamine. The procedures developed for HPLC with either electrochemical or fluorescence detection also allow the quantification of other indolic compounds, in particular, tryptophan and 5-methoxytryptamine. The methods described may be of value in the further search for melatonin and related indoleamines in non vertebrate material, especially, from unicells, multicellular plants, and invertebrates. PMID- 7853139 TI - Melatonin concentrations in pineal organ culture are suppressed by sera from tumor-bearing mice. AB - The melatonin rhythm is significantly attenuated in a wide range of human and animal tumor types. Since surgical removal of the tumor has been shown to restore this rhythm, we hypothesized that a plasma borne tumor-associated factor (TAMF) could be responsible. A population of mice were injected with tumor cells and sequentially killed and bled over the following 9 days, i.e., to the maximal state of tumor growth. Pooled serum from the different collection days was added to an established pineal organ culture system, and melatonin concentrations measured. A highly significant correlation between melatonin concentrations and the stage of tumor growth was seen with maximal inhibition occurring at day 9 (P < 0.01). These findings support our hypothesis and may help to explain the mechanism whereby melatonin rhythmicity is suppressed in cancer patients. PMID- 7853140 TI - Immunohistochemical studies on the coexistence of catecholamine-synthesizing enzymes and neuropeptide Y in nerve fibers of the porcine pineal gland. AB - The distribution of nerve fibers immunoreactive (IR) to catecholamine synthesizing enzymes, tyrosine hydroxylase (TH), dopamine-beta-hydroxylase (D beta H), and phenylethanolamine-N-methyltransferase (PNMT) as well as neuropeptide Y (NPY), in the pineal gland of adult sows was investigated by the use of double-labeling immunohistochemistry. The porcine pineal gland was found to be supplied by TH-IR nerve fibers, the vast majority of which were also D beta H-positive. TH- and TH/D beta H-IR nerves were located mostly in the capsula and connective septa of the pineal gland, and their fine varicose branches terminated in the adherent parenchyma. NPY-IR fibers formed a loose network overlapping that was observed in the case of TH- and D beta H-IR fibers. Most of NPY-IR fibers were also positive for TH. The density of the fiber networks depended on the region of the gland. No PNMT-IR structures were observed. PMID- 7853141 TI - Melatonin modulates growth factor activity in MCF-7 human breast cancer cells. AB - Melatonin has been shown to have direct oncostatic actions on estrogen responsive, MCF-7 human breast cancer cells in culture. In the present study, we examined whether these inhibitory actions on cell growth may be mediated through actions on bioassayable growth factor activity. In order to test this hypothesis, we estimated the growth factor activity of conditioned medium (CM) from estradiol (E2), or melatonin-treated cells, in the presence or absence of melatonin on MCF 7 cell growth. We also determined whether melatonin inhibits the action of epidermal growth factor (EGF) action in the absence of E2. The addition of melatonin (10(-9) M) to the cultures of MCF-7 cells with CM from E2 (10(-8) M) treated cells significantly inhibited the growth stimulatory activity of CM, suggesting that melatonin inhibited cell proliferation by blocking the action of E2-induced autocrine growth stimulatory factors. Conditioned medium from melatonin-treated cells significantly inhibited cell proliferation, while an additional supply of melatonin to these cultures had an even greater inhibitory effect. Melatonin was also active in the complete absence of serum as long as cell growth was stimulated by EGF, an E2-inducible growth factor. The inhibitory effect of melatonin increased as the dose of EGF increased. This non antiestrogenic inhibitory effect of melatonin was reversed by E2, but not by EGF itself, suggesting that melatonin requires accessible estrogen receptor sites for its inhibitory activity on the growth stimulating action of EGF. Taken together, these findings suggest that melatonin may inhibit the action and/or release of growth stimulatory factors as well as stimulate the release of growth inhibitory factors in culture.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7853142 TI - Pharmacologic characterization of melatonin-mediated phosphoinositide hydrolysis in pigeon brain. AB - High densities of [125I]-iodomelatonin binding sites have been demonstrated in pigeon brain. Melatonin binding sites have been shown to be linked to signal transduction mechanisms in other species. The present study investigated the melatonin-mediated second messenger response of phosphoinositide hydrolysis in slices of telencephalon, optic tectum, cerebellum, hypothalamus, and pons medulla of pigeon brain. The highest rates of melatonin-mediated phosphoinositide hydrolysis were observed in telencephalon and pons/medulla. Relative potencies of melatonin agonists to induce phosphoinositide hydrolysis were as follows: 2 iodomelatonin > 6-chloromelatonin > N-acetylserotonin > melatonin > > serotonin (5-HT). Agonist-induced phosphoinositide hydrolysis was blocked by N acetyltryptamine (NAT), a melatonin antagonist, but not by ketanserin, a 5HT2A/2C receptor antagonist, demonstrating that phosphoinositide hydrolysis did not result from 5HT2A or 5HT2C receptor stimulation. In addition, the effects of melatonin agonists were sensitive to prazosin, an alpha-adrenergic antagonist reported to exhibit nanomolar affinity for melatonin binding sites in hamster brain, but not to phentolamine, an alpha-adrenergic antagonist that shows no affinity for melatonin binding sites. These data provide evidence that signal transduction associated with melatonin in pigeon brain involves the induction of phosphoinositide hydrolysis as a second messenger. PMID- 7853143 TI - Localization and characterization of [125I]iodomelatonin binding sites in duck gonads. AB - The characterization and localization of [125I]iodomelatonin binding sites in the gonads advances the understanding of possible regulatory sites of melatonin action. With the availability of [125I]iodomelatonin as a biologically active radioligand, our study utilized a combined approach of autoradiography for anatomical resolution together with an established radioligand binding assay to assess mid-light [125I]iodomelatonin binding in the testes and ovaries of ducks. In the autoradiography study, specific [125I]iodomelatonin binding was shown to be homogeneous throughout the testes, while in the ovaries, specific [125I]iodomelatonin binding appeared to be concentrated around the follicle. Radioligand binding assay results indicated a single class of binding sites with the maximum number of [125I]iodomelatonin binding sites measured at 1.91 +/- 0.70 fmol/mg protein in testicular membrane and 4.54 +/- 0.64 fmol/mg protein in ovarian membrane. [125I]Iodomelatonin binding affinity, characterized by equilibrium dissociation constants of 29 +/- 6 pmol/L in testicular membrane and 53 +/- 9 pmol/L in ovarian membrane, was in accordance with circulating melatonin levels, suggesting an appropriate concentration for eliciting a physiological response. [125I]Iodomelatonin binding in duck gonads satisfied all the criteria for a binding site, being rapid, stable, saturable, reversible, specific, and of high affinity, and may indicate a direct pineal-gonadal connection. PMID- 7853145 TI - [Molecular biology of L-histidine decarboxylase]. AB - L-Histidine decarboxylase (HDC) catalyzes the formation of histamine from L histidine. This biogenic amine is known to exert various effects in physiological and pathological reactions. In contrast to the well-known mechanism of histamine action through its interaction with specific receptors, the mechanisms regulating HDC gene expression are not elucidated. We have purified HDC from mouse mastocytoma cells, and isolated mouse HDC cDNA, and found that the primary translated product is posttranslationally processed to yield a mature active enzyme. In mastocytoma cells, we demonstrated that the induction of HDC activity and HDC mRNA synergistically occurred on treatment with dexamethasone+TPA, and also cAMP+Ca2+. To clarify the mechanism of up-regulation by these stimuli of the transcription of the HDC gene, we have isolated a genomic DNA clone encoding 5' flanking region sequence and the first two exons. The transcription start site and the nucleotide sequences of the promoter regions including TATA- and GC-boxes were determined. With mastocytoma cells transiently transfected with 5' deletion constructs of HDC-CAT fusion gene, it was found that the sequences from -132 to 53 and -267 to -53 are essential for the regulatory elements involved in the increased transcription of the HDC gene with dexamethasone+TPA and cAMP+Ca2+, respectively. Furthermore, we have isolated a genomic DNA from human basophilic cells, and analysed its structure to elucidate the mechanisms regulating the tissue specificity of HDC gene expression. PMID- 7853144 TI - Photoperiod and the pineal gland regulate the male phenotype of the Harderian glands of male Syrian hamsters after androgen withdrawal. AB - The Harderian glands of Syrian hamsters exhibit a marked sexual dimorphism in cell types and porphyrin production. The glands of male hamsters have two secretory cell types (Type I and II) while the glands of females consist of a single secretory cell type (female Type I) and large intraluminal deposits of porphyrins. Besides androgens, there is evidence that the pineal gland, through the secretion of melatonin, contributes to the maintenance of the "male" and "female" phenotypes. In this study, we investigated the effects of castration, short photoperiods, and pinealectomy on the distribution of secretory cells and porphyrin deposits in the Harderian glands of male Syrian hamsters. Two groups of animals were maintained in long days (14 hr light/day). Hamsters in one group were left intact and those in the other were castrated. Another three groups were maintained in short days (8 hr light/day); these animals were either left intact, castrated, or both castrated and pinealectomized. The duration of the experiment was 5 weeks. Castration of long photoperiod-exposed animals resulted in a significant drop in the number of Type II cells and a large increase in the porphyrin deposits (P < 0.01). However, castrated animals exposed to short photoperiod showed a significant smaller change in both parameters compared with those exposed to long days (P < 0.05). Pinealectomy prevented the effects of short days in castrated animals. No significant changes were observed in the relative number of mitotic figures or in the number of cell nuclei, indicating that the changes observed were due in part to a transformation of Type II into Type I cells. In a second experiment, male hamsters were injected daily either with 25 micrograms of melatonin late in the afternoon or with the saline for 8 weeks. The administration of melatonin resulted in a significant (P < 0.05) increase in the percentage of Type II cells. We conclude that when circulating androgens are very low or absent, pineal melatonin maintains the male phenotype in the Syrian hamster Harderian gland. PMID- 7853146 TI - [Development of L-threo-DOPS, a norepinephrine precursor amino acid]. AB - threo-Dihydroxyphenylserine (DOPS) is a synthetic amino acid which can be decarboxylated by L-aromatic amino acid decarboxylase to yield natural form of norepinephrine (l-NE), a principal neurotransmitter in both central and peripheral (sympathetic) nervous systems. Like L-Dopa as an agent for dopamine precursor therapy, DOPS was expected to have a potential as an agent for NE precursor therapy. Previous studies carried out by several groups in early 1970s, however, reached a negative conclusion that threo-DOPS was not an effective precursor of NE in the brain because of its low NE-increasing activity and weak pharmacological action. Since the latter half of 1970s, on the contrary, three Japanese research groups have successfully shown the possibility of DOPS as a useful NE-precursor. That is, Tanaka (Kobe Univ.) showed that L-threo-DOPS is the real l-NE precursor among four DOPS-enantiomers, and that it has several pharmacological activities such as a slow-onset and long-lasting pressor effect, an inhibitory effect on harmaline-induced tremor and so on. Hayashi and Suzuki (Osaka Univ.) found through the mobility study on familial amyloid polyneuropatchy (FAP) that the progress of the disease develops NE-deficiency (NE D), that severe orthostatic hypotention in FAP might be due to NE-D, and that L DOPS has favorable effects on this symptom. Narabayashi (Juntendo Univ.) found that NE-D develops in patients with advanced Parkinson's disease (PD), that a freezing phenomenon in these patients might be associated with NE-D, and that L DOPS improves the phenomenon. Based on these findings, the development of L-DOPS for registration had been undertaken by Sumitomo Pharmaceuticals Co., and an approval was given to it in 1989 as an agent for the treatment orthostatic hypotention in FAP or Shy-Drager syndrome and freezing phenomenon in PD. Preclinical and clinical studies done in the R&D confirmed that L-DOPS markedly restored NE-D and improved related-syndrome in the NE-deficient animals/patients, and that its actions were slow-onset, long-lasting and gentle. The R & D of L DOPS described in this paper includes studies on industrial production, efficacy pharmacology (mode of action), metabolism and clinical trial of this agent. PMID- 7853147 TI - [Novel synthetic retinoid agonists and antagonists]. AB - Retinoic acid acts as a specific modulator of cellular differentiation and proliferation. Its natural and synthetic analogs, classified as retinoids, can be applied to the chemotherapy in the field of dermatology and oncology. Various benzoic acid derivatives exhibited the specific biological responses of retinoic acid and were named retinobenzoic acids. Especially, the aromatic amides such as Am80 and Am580 have better therapeutic effects than retinoic acid. N-Methylation of these highly active aromatic secondary amides caused the disappearance of the activity due to the change of the amide conformation from trans into cis. From such observations, the conformation of the linking group between alkyl substituted benzene ring and benzoic acid moiety is an important factor for the activity. Some retinobenzoic acids do not bind to the cellular-retinoic acid binding protein, but bind to nuclear retinoic acid receptors (RARs) with the binding affinity corresponding to the potency of their biological activities. Among them, Am80 can bind to two of the three RAR subtypes (RAR alpha and beta). The selectivity is favorable for the clinical application of retinoid since it has possibility to elicit a part of a number of the biological activities of retinoic acid. PMID- 7853148 TI - [Genetical and biochemical studies on the metabolisms and biological roles of membrane phospholipids in mammalian cells]. AB - The genetical and biochemical approach is used as a powerful tool for the elucidation of the metabolic regulation as well as the biological significance of various constituents in living cells. This technique has been successfully applied to the membrane phospholipids in mammalian cells, actually to phosphatidylserine, sphingomyelin, and cardiolipin, all of which are rather minor constituents in membrane phospholipids. Isolation and characterization of the mutant cells defective in biosyntheses and biosynthetic regulations of these phospholipids led to the new findings of the in vivo biosynthetic pathways and also of the biological significance of these phospholipids. By analyzing the five different kinds of mutant cells unusual in metabolisms of phosphatidylserine in CHO-K1 cells, we found a series of the following evidence. Phosphatidylserine is synthesized by the two kinds of base-exchange enzymes, namely serine-exchange enzyme I and II, through the chain reactions in participation of phosphatidylserine decarboxylase; phosphatidylcholine-->phosphatidylserine- >phosphatidylethanolamine--> phosphatidylserine. The substrates of serine exchange enzyme I are phosphatidylcholine, and either choline, serine, or ethanolamine, while those of serine-exchange enzyme II are phosphatidylethanolamine, and serine or ethanolamine but not choline. The last phosphatidylserine produced in consequence of the chain reaction again becomes a substrate of phosphatidylserine decarboxylase, and so this metabolic flow of the biosynthesis of phosphatidylserine is finally connected to a cyclic reaction between phosphatidylethanolamine and phosphatidylserine catalyzed by serine exchange enzyme II and phosphatidylserine decarboxylase. Localization of serine exchange enzyme I is on the cytoplasmic side of endoplasmic reticulum, while that of enzyme II is on its lumen side. There is a lot of evidence including our immunological observation that phosphatidylserine decarboxylase is exclusively located in the inner membrane of mitochondria. Thus, during the process of the above-mentioned reactions, phosphatidylserine have to move from endoplasmic reticulum to mitochondria, and phosphatidylethanolamine does from mitochondria to endoplasmic reticulum. The biological significance of these movements is now under investigation. Enveloped virus infection and its maturation are closely associated with the membrane functions of host mammalian cells. In order to get further information concerning the biological functions of phosphatidylserine and/or phosphatidylethanolamine in mammalian cell membranes, Sindbis virus infection system was examined. Deficiency of phosphatidylserine and/or phosphatidylethanolamine was found to give a profound effect on the maturation of the virus, mainly due to low efficiency of membrane fusion between the viral envelope and endosomal membranes of the host cells. All these results indicate that phosphatidylserine and/or phosphatidylethanolamine are essential to membrane fusion at least in enveloped viral infection.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7853149 TI - [New development of ammonium ylide chemistry]. AB - Benzylammonium N-alkylides were generated by reaction of N-[1 (trimethylsilyl)alkyl]benzylammonium salts with cesium fluoride in DMF or HMPA, and their rearrangement products were investigated. [2,3]Sigmatropic rearrangement of the ylides initially occurred to give isotoluene derivatives and then they were transformed into Sommelet-Hauser rearrangement products and/or Stevens products. The isotoluenes having bicyclic structures were stable at room temperature and aromatized with the aid of a base. The relationship between the configuration of cyclic ammonium ylides and the rearrangement paths is described. PMID- 7853150 TI - [Application of the Limulus test for practical quality control on endotoxin content in commercial human serum albumin (HSA) products. In comparison with the rabbit pyrogen test]. AB - The bacterial endotoxin content in human serum albumin (HSA) products measured by two different Limulus amebocyte lysate (LAL) test methods, colorimetric and kinetic turbidimetric methods, were compared. So far as endotoxin-specific LAL reagents which do not show a false-positive reaction with (1-->3)-beta-D-glucan are used, a definite correlation was found between the results with the two LAL test methods. Endotoxin added to HSA products was recovered in a quantitative manner showing neither inhibition nor enhancement by HSA to the both LAL test methods. Results of the LAL tests showed a significant correlation with that of the rabbit pyrogen test. The correlation was much improved with endotoxin-added HSA. The present results indicate the practical applicability of the LAL test as an alternative method for the rabbit pyrogen test. PMID- 7853151 TI - [Enhancement of rectal absorption of rifampicin by sodium para-aminosalicylate dihydrate in human subjects]. AB - The suppositories of rifampicin (RFP) containing sodium para-aminosalicylate dihydrate (PAS-Na) were prepared in order to enhance the rectal absorption of RFP. By the addition of PAS-Na, the in vitro release of RFP from the suppositories was enhanced and the hardness of the suppositories decreased. The rectal absorption of RFP from the suppositories containing no PAS-Na (control suppositories) was significantly lower compared to oral administration of it (26%) in human subjects. When PAS-Na was added to the suppository (300 mg), both the area under the plasma concentration-time curve (AUC) and the maximum plasma concentration (Cmax) increased significantly compared to those of the control suppositories. The rectal absorption of PAS-Na itself from the suppositories seemed to be fast. PAS-Na might increase the absorption of RFP dissolved in the rectal fluid from the suppositories, but not affect the undissolved RFP. PMID- 7853152 TI - [Protective effects of sesamol and its related compounds on carbon tetrachloride induced liver injury in rats]. AB - Sesamol is a kind of antioxidant and exists in sesame oil. This paper describes the protective effect of sesamol against carbon tetrachloride (CCl4)-induced liver injury in rats. Sesamol had a significant effect in case of intraperitoneal, subcutaneous and oral administration. In order to examine the relationship between the chemical constitution of sesamol and its protective effect, the protective effects of 20 kinds of sesamol related compounds against liver injury induced by CCl4 were investigated in rats. Consequently, significant protective effects were found in methylenedioxybenzene, isosafrole, safrole, methylenedioxyaniline and methylenedioxyacetophenone. These five compounds had a methylenedioxy group had protective effects, it was considered that the protective effects of the methylenedioxy group were influenced by substituent groups on 4 position of methylenedioxy phenyl compounds. In addition, sesamol, methylenedioxybenzene and isosafrole showed significant protective effects against cholestasis induced by CCl4. PMID- 7853153 TI - Acute dysvascular limb in a young adult. A case study. AB - Acute dysvascular limb in young adults is a rare entity. Diagnosis is often difficult because symptoms are not recognized as ischemic. The most common causes of this condition are premature atherosclerosis, thromboangiitis obliterans, microemboli, popliteal entrapment syndrome, collagen vascular disease, Takaysu's arteritis, and coagulopathy. A case study is presented to illustrate the disease process. A systematic approach to diagnosis, consisting of history and physical examination, palpation and auscultation of peripheral pulses at rest and following exercise, and noninvasive vascular examination at rest and following exercise, is recommended. Suggestion of an ischemic condition following noninvasive studies should be followed up with an arteriogram. The prognosis is dependent on the underlying etiology of the ischemia, early detection, and appropriate treatment. PMID- 7853154 TI - Electrodynographic evaluation of the foot during treadmill versus overground locomotion. AB - Biomechanical foot function as expressed by the duration of successive ground contact phases and by dynamic variables, such as the peak pressure on different parts of the foot, their respective loading rate, and duration, is compared for two walking and running conditions: overground on a 20-m walkway and on a treadmill. Statistical analysis revealed foot pressure characteristics as measured with a Electrodynogram during walking and running to alter significantly when using a treadmill. The differences were more pronounced for walking than for running. During walking, loading of the forefoot tends to last longer (longer propulsion phase) on a treadmill. Loading rate is decreased for the whole foot during either walking or running. Maximum heel pressure is diminished for walking but increased during running on a treadmill. Moderate variations of treadmill velocity were shown to have no significant influence on the measurements. PMID- 7853155 TI - Plantar fascial release. AB - The author reviews the literature for the possible etiology and the conservative and surgical treatment alternatives for mechanically induced plantar heel pain. A long-term retrospective study on a plantar fascial release surgery performed on patients with recalcitrant plantar heel pain, all of whom were unresponsive to conservative therapy, is presented. PMID- 7853156 TI - Aloe vera, hydrocortisone, and sterol influence on wound tensile strength and anti-inflammation. AB - Aloe vera at doses of 100 and 300 mg/kg daily for 4 days blocked the wound healing suppression of hydrocortisone acetate up to 100% using the wound tensile strength assay. This response was because of the growth factors present in A. vera masking the wound healing inhibitors such as sterols and certain amino acids. The sterols showed good anti-inflammatory activity (-36%) in reducing the croton oil-induced ear swelling. This activity displayed a dose-response relationship. PMID- 7853157 TI - Rare case of lichen sclerosus et atrophicus associated with morphea. AB - A rare case of lichen sclerosus et atrophicus coexisting with morphea in the foot was presented. Orthotic therapy was required to alleviate an antalgic gait. PMID- 7853158 TI - Acrometastases. Initial presentation as diffuse ankle pain. AB - Acrometastases are rare and often misdiagnosed or overlooked. When it involves the feet, it generally attacks the larger bones containing the higher amounts of red marrow. The patient may or may not have a known history of cancer, which makes diagnosis much more difficult. The symptomatology is generally vague and can mimic other conditions, such as osteomyelitis, gouty rheumatoid arthritis, Reiter's syndrome, Paget's disease, osteochondral lesions, and ligamentous sprains. Therefore, the physician must consider metastatic disease in the differential diagnosis. Once the diagnosis is made, the prognosis is poor and treatment is limited to pain relief and maintaining function. PMID- 7853159 TI - Mechanisms whereby macrophage-derived nitric oxide is involved in morphine induced suppression of splenic lymphocyte proliferation. AB - Previous research by our laboratory demonstrated that in vivo administration of morphine to rats suppresses concanavalin-A (Con-A)-stimulated proliferation of splenic lymphocytes in a dose-dependent, naltrexone-reversible manner. More recently, we showed that morphine-induced suppression of Con A-stimulated proliferation of lymphocytes depends on an increase in macrophage production of nitric oxide (NO) in splenocyte cultures. The present study investigated effector mechanisms through which morphine-induced increases in macrophage-derived NO decrease lymphocyte proliferation in Con A-stimulated splenocyte cultures. The results show that the addition of hemoglobin, a scavenger of extracellular NO, to Con A-stimulated splenocyte cultures dose-dependently attenuates the suppressive effect of morphine on proliferation. The addition of superoxide dismutase, a scavenger of superoxide anions, to splenocyte cultures does not antagonize the suppressive effect of morphine on Con A-stimulated proliferation. The addition of either methylene blue or 6-anilino-5, 8-quinolinedione (LY 83583), two inhibitors of soluble guanylate cyclase, to splenocyte cultures dose-dependently antagonizes the suppressive effect of morphine on Con A-stimulated proliferation. Taken together with our previous results, the present results suggest that in vivo administration of morphine increases the synthesis and extracellular release of NO from macrophages in Con A-stimulated splenocyte cultures. The results further suggest that the formation of the oxidant peroxynitrite through a reaction between NO and superoxide anion does not contribute significantly to the suppression of lymphocyte proliferation; instead, the activation of soluble guanylate cyclase by NO in target cells, most likely the lymphocytes, accounts more completely for the morphine-induced suppression of lymphocyte proliferation. PMID- 7853160 TI - Disposition of glutathione monoethyl ester in the rat: glutathione ester is a slow release form of extracellular glutathione. AB - Glutathione monethyl ester (GSHE) is though to deliver glutathione (GSH) directly and intact into cell cytosol and therefore might have therapeutic potential in states of GSH deficiency. To better understand the disposition of GSHE, the pharmacokinetics of GSHE and GSH were compared in rats. Fifteen min after an i.v. dose of 5 mmol/kg GSHE, the plasma concentration of GSHE was 7.2 +/- 1.2 mmol/l and the plasma concentration of GSH had increased from 0.009 +/- 0.002 to 2.5 +/- 0.3 mmol/l. The areas under the plasma concentration time curves of GSH were identical after either the administration of GSHE or GSH, but the mean residence time of GSH in plasma was significantly longer after GSHE. The concentration of GSHE in liver reached a peak of 0.66 +/- 0.09 mumol/g. Intrahepatic concentrations of cysteine and GSH increased from 53 +/- 15 to 319 +/- 41 nmol/g and from 5.5 +/- 0.4 to 7.8 +/- 1.5 mumol/g, respectively, and remained elevated for 2 hr. Similar increases occurred after administration of GSH. However, the concentrations of cysteine and GSH peaked earlier and had returned to baseline by 2 hr. Qualitatively similar results were obtained in rats pretreated with L buthionine-[S, R]-sulfoximine that partially inhibits GSH synthesis. GSHE added to rat plasma at a concentration of 10 mM was hydrolyzed to GSH at a rate of 0.1 mumol/min. Our data indicate that GSHE is not readily taken up by the liver, but is hydrolyzed by esterases in plasma and thereby gradually releases GSH in the extracellular space.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7853161 TI - Inhibition of dihydropyridine-sensitive Ca++ channels by ethanol in undifferentiated and nerve growth factor-treated PC12 cells: interaction with the inactivated state. AB - The effects of acute exposure to ethanol on high-voltage activated calcium (Ca++) channels in undifferentiated (UND) pheochromocytoma (PC12) cells and in PC12 cells treated with nerve growth factor (NGF) were compared using the nystatin perforated-patch voltage-clamp technique. Both UND and NGF-treated cells expressed noninactivating, dihydropyridine-sensitive Ca++ current. Ethanol (10, 25 and 50 mM) reversibly inhibited noninactivating current in both UND and NGF treated cells. However, the reduction of current was significantly greater in UND cells. NGF-treated cells expressed, in addition to dihydropyridine-sensitive current, omega-conotoxin GVIA-sensitive Ca++ current. The reduced ethanol inhibition in NGF-treated cells was not due to the contribution of these channels to the overall current since conotoxin did not alter the level of ethanol inhibition. In both cell types, ethanol had no significant effect after exposure of the cells to nifedipine, suggesting that these drugs act on the same dihydropyridine-sensitive Ca++ channel type. In both cell types, inhibition was greatest when voltage steps were made from depolarized holding potentials, suggesting that ethanol has a greater effect on the inactivated state than on the resting or activated state. Steady-state inactivation measurements indicated that ethanol caused a significant hyperpolarizing shift in the half-maximal inactivation potential for both cell types, supporting this proposition. The magnitude of this shift was correlated with the magnitude of ethanol inhibition of currents elicited from a holding potential of -40 mV. Thus, one mechanism by which ethanol inhibits Ca++ currents in PC12 cells is via a shift in steady-state inactivation An additional mechanism in UND cells must underlie the difference in ethanol sensitivity of Ca++ channels in the two cell types. PMID- 7853162 TI - Effects of morphine on the pathogenesis of murine Friend retrovirus infection. AB - The immunomodulatory effects of opiates can modify host defenses against infection. We investigated the mechanisms involved in these effects by studying the influence of morphine on the pathogenesis of murine Friend retrovirus infection. The response to this opiate varied greatly according to the treatment schedule. Daily intraperitoneal administration of morphine (50 mg/kg) for 16 to 27 days attenuated pathological manifestations in infected animals without modifying the mortality rate. The protective effect increased proportionately with the duration of treatment and depended on the time of treatment initiation relative to inoculation. Naloxone (100 mg/kg/day i.p.) inhibited the morphine induced decrease in both splenomegaly and viral titer. Mifepristone--a glucocorticoid receptor inhibitor--had no significant effect on the morphine induced attenuation of splenomegaly. The influence of the infection on acute morphine toxicity was also analyzed using a nonlethal dose in noninfected mice (200 mg/kg). Susceptibility to morphine increased in parallel to the development of the infection, with mortality rates ranging from 20% on day 14 to 90% on day 21. Simultaneous administration of naloxone (20-100 mg/kg) reduced the mortality rate and postponed death. Administration of mifepristone, terfenadin, phentolamine or propranolol did not modify mortality at the doses used. These findings show that the influence of morphine on the development of Friend virus infection in mice depends on the conditions of administration. The transient protective effect seen in certain conditions of administration appears to be due essentially to the direct effects of morphine on its specific receptors. PMID- 7853163 TI - Comparative analysis of buprenorphine- and norbuprenorphine-induced analgesic effects based on pharmacokinetic-pharmacodynamic modeling. AB - The relationships between plasma or brain concentrations and analgesic effects of both buprenorphine (BN) and an active metabolite, norbuprenorphine (NBN), were investigated in rats. Maximal analgesic effects measured by a tail flick test were obtained at 10 and 30 min after intravenous (i.v.) administration of BN (8 micrograms/kg dose) and NBN (100 micrograms/kg dose), respectively. No correlation was observed between analgesic effect and the early plasma BN or NBN concentrations. However, at latency times, the concentration of BN in the plasma, cerebellum and the rest of the brain (including the brainstem, midbrain and cerebrum) was related in a counterclockwise hysteresis fashion to analgesia. There was no relationship between the estimated specific binding concentration of BN in the brain and the analgesic effects. After i.v. administration of BN or NBN, the analgesic effect of NBN was approximately one-fiftieth that of BN. The n octanol/water partition coefficient of NBN was one-tenth that of BN. Further, the results of intraventricular administration of each drug suggested that the intrinsic analgesic activity of NBN was one-fourth that of BN. From these findings, we conclude that the remarkably weak pharmacological effect of NBN after i.v. administration may be due not only to the low permeability of NBN into the brain but also to its small intrinsic pharmacological effect. PMID- 7853164 TI - Comparison of A4 and A2a binding sites in striatum and COS cells transfected with adenosine A2a receptors. AB - A putative A4 adenosine receptor is characterized by a distinct structure activity profile of compounds in competition for [3H]2-phenylaminoadenosine ([3H]CV 1808) binding sites on rat brain membranes assayed at 4 degrees C. We now confirm that A4 binding sites can be demonstrated on ice-cold membranes of rat striatum and demonstrate a similar binding site on COS cells transfected with rat A2a adenosine receptors (COS/A2a). The characteristic A4 potency order is: CV 1808 > [1R-(1 alpha, 2 alpha, 3 beta, 5 beta)]-3-(2,6-diamino-N2-(3 carbethoxyphenyl)-9 H-purin-9-yl)-5'-(N-ethylcarbamoyl)-1,2-cyclopentanediol (CGS 22988) >> 5'-N-ethylcarboxamidoadenosine (NECA) > or = 2-[4-(2- carboxyethyl)phenylethylamino]-5'-N-ethylcarboxamidoadenosine (CGS 21680); 9 chloro-2-(2-furyl)[1,2,4]-triaolo[1,5-c]-quinazolin-5-a min e (CGS 15943) only partially inhibits binding at 1 microM. If [3H]CGS 21680 is used for ice-cold assays, or if either [3H]CV 1808 or [3H]CGS 21680 are used for assays at 21 degrees C, the potency order of competing compounds changes markedly and becomes characteristic of A2a adenosine receptor binding sites; CGS 15943 > or = CGS 21680 congruent to NECA > CGS 22988 > or = CV 1808. Binding of [3H]CGS 21680, but not [3H]CV 1808, is significantly enhanced by the pore-forming antibiotic, alamethicin. Guanosine 5'-O-(3-thiotriphosphate) decreases the binding of both radioligands to striatal membranes at 21 degrees C significantly more than to membranes on ice.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7853165 TI - Role of prejunctional beta adrenoceptors in rat cardiac sympathetic neurotransmission. AB - This study examines the role of prejunctional beta adrenoceptors in the modulation of sympathetic neurotransmission in the rat heart. Under anesthesia, the heart with right cardiac sympathetic nerves attached was isolated and perfused with Krebs' bicarbonate buffer containing cocaine (10 microM), corticosterone (40 microM) and atropine (6 microM). Stimulation of sympathetic nerves at frequencies of 0.05 to 3 Hz (15 pulses, supramaximal voltage, 2-msec pulse duration) produced a pronounced frequency-dependent increase in heart rate. A maximal increase of 89 +/- 10 bpm was obtained at 3 Hz. Propranolol (0.1 microM) had no significant effect on the stimulus-induced NE overflow in the absence and presence of alpha adrenoceptor blockade alone or combined with adenosine receptor blockade. The beta-2 adrenoceptor agonist salbutamol increased stimulus-induced NE overflow (15 pulses) at 0.1 Hz but not at 0.5 Hz. Alpha adrenoceptor blockade did not alter the salbutamol-evoked facilitation at 0.1 Hz but revealed salbutamol-evoked facilitation at 0.5 Hz. Salbutamol did not alter NE overflow at 1 Hz even in the presence of alpha adrenoceptor blockade. In conclusion, prejunctional beta adrenoceptor facilitation of NE overflow is frequency and alpha adrenoceptor modulated. At low frequency (0.1 Hz), beta adrenoceptor-mediated facilitation is maximal and alpha adrenoceptor independent; at intermediate frequency (0.5 Hz) it is alpha adrenoceptor restrained and it is absent at 1 Hz. Finally, NE does not modulate its own release via the prejunctional beta adrenoceptors. PMID- 7853166 TI - Pharmacological characterization of nerve growth factor and/or monosialoganglioside GM1 effects on cholinergic markers in the adult lesioned brain. AB - The regulation of cholinergic markers by exogenous nerve growth factor (NGF) and/or monosialoganglioside GM1 (GM1) treatment was examined in various brain areas of unilaterally decorticated rats, with particular emphasis on the basal forebrain system. Treatment of decorticated rats, i.c.v. via a minipump, with various doses of NGF or GM1 for a period of 7 days prevented the lesion-induced decline in nucleus basalis magnocellularis choline acetyltransferase (ChAT) activity in a dose-dependent manner. These treatments also stimulated cortical ChAT activity as well as high-affinity choline uptake. Cholinergic markers in other brain areas studied were unaffected by the lesion or these treatments, except in the striatum in which exogenous NGF but not GM1 caused dose-dependent increases in ChAT activity and high-affinity choline uptake. Glutamic acid decarboxylase activity was unaffected by the lesion or treatments in all brain areas studied. Cotreatment of lesioned rats with GM1 did not affect NGF potency but did increase its maximal efficacy in the nucleus basalis magnocellularis and cortex, but not in the striatum. Treatment of cortically lesioned rats with maximal doses of GM1 and/or NGF did not differentially alter "soluble" or "membrane bound" forms of ChAT. In addition, choline uptake kinetic parameters also were affected similarly by these agents as evidenced by augmented Vmax and unaltered Km values. Distinct effects of NGF and GM1 were observed, however, in regard to the delay possible in treatment time onset. No significant alteration in NGF receptor density or affinity were noted in the remaining cortex of GM1 treated decorticated rats, suggesting that GM1 interacts with an alternative facet of NGF signal transduction to potentiate NGF effects on cholinergic markers. PMID- 7853167 TI - Aquaretic effect of a potent, orally active, nonpeptide V2 antagonist in men. AB - Solute-free water diuretics (aquaretics) that antagonize hydrosmotic vasopressin 2 (V2) receptors may be useful in treating diseases in which water is retained. An orally active, nonpeptide, selective V2 antagonist (OPC-31260) was administered in six dose steps (3, 15, 30, 60, 100 and 200 mg) to six healthy, normally hydrated men to investigate the aquaretic effects in comparison with 12 placebo-treated control subjects (two at each dose). All subjects tolerated all six doses without serious clinical side effects. OPC-31260 increased the first 6 hr hypotonic urine volume dose-dependently. Administration at 30 mg raised the 6 hr urine volume to 2 times, 100 mg to 3 times and 200 mg to 4 times (1828.0 +/- 130.2 ml/6 hr) that of the placebo group (470.4 +/- 52.1 ml/6 hr). The drug increased urine flow maximally between 1 and 1.5 hr at all doses (e.g., 10.0 +/- 0.7-10.8 +/- 0.4 ml/min at 60-200 mg). The drug rapidly lowered urine osmolality for 4 hr, particularly between 60 and 90 min (e.g., 72.3 +/- 2.3 and 62.3 +/- 5.1 mOsm/kg at 100 and 200 mg, respectively). In marked hypotonic diuresis, mean free water clearance of the 6-hr urine increased dose-proportionally into the positive range, reaching 2.82 +/- 0.21 ml/min at 200 mg.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7853168 TI - Repeated acquisition of behavioral chains in squirrel monkeys: comparisons of a mu, kappa and delta opioid agonist. AB - Responding by squirrel monkeys was maintained by food presentation under a repeated acquisition of behavioral chains procedure. Monkeys acquired a different three-response chain each session. Sequence completions were reinforced under a fixed-ratio 5 schedule, whereas errors produced a brief time out. Morphine (0.1 3.2 mg/kg) produced dose-related decreases in response rate at doses that had little or no effect on errors. U50488H ([trans]3,4-dichloro-N-methyl-N-[2-(1 pyrrolidinyl)- cyclohexyl]benzeneacetamide methane sulfonate hydrate) (0.018-0.56 mg/kg) yielded a steep dose-effect curve, decreasing response rate only at high doses that also had little or no effect on errors. The delta opioid agonist BW373U86 (+/-)-4-((alpha-R*)-alpha-((2S*,5R*)-4-allyl-2,5-dimethyl-1- piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide dihydrochloride (0.0056-0.32 mg/kg) produced dose-related decreases in response rate and increased errors. The delta opioid receptor antagonist naltrindole (0.056-18 mg/kg) alone had no effect on either the rate of responding or percent errors. The rate-decreasing and error increasing effects produced by BW373U86 were antagonized by naltrindole. BW373U86 alone at doses of > or = 0.56 mg/kg produced brief tonic-clonic convulsions in all monkeys. Naltrindole (1 mg/kg) also antagonized the convulsant effects of BW373U86. At doses at which naltrindole was an effective antagonist of BW373U86, it failed to antagonize either morphine or U50488H. These results demonstrate that the delta opioid agonist BW373U86 produces effects on acquisition that differ dramatically from prototypical mu and kappa opioid agonists.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7853169 TI - Marijuana smoking: effects of varying puff volume and breathhold duration. AB - Two studies were conducted to quantify biological and behavioral effects resulting from exposure to controlled doses of marijuana smoke. In one study, puff volume (30, 60 and 90 ml) and in a second study, breathhold duration (0, 10 and 20 sec) were systematically varied while holding constant other smoking topography parameters (number of puffs = 10, interpuff interval = 60 sec and inhalation volume = 25% of vital capacity). Each study also varied levels of delta 9-tetrahydro-cannabinol marijuana cigarette content (1.75% and 3.55%). Regular marijuana users served as subjects (n = 7 in each experiment). Subjects smoked 10 puffs in each of six sessions; a seventh, nonsmoking session (all measures recorded at the same times as in active smoking sessions) served as a control. Variations in puff volume produced significant dose-related changes in postsmoking plasma delta 9-tetrahydro-cannabinol levels, carbon monoxide boost and subjective effects (e.g., "high"). In contrast, breathholding for 10 or 20 sec versus 0 sec increased plasma delta 9-tetrahydro-cannabinol levels but not CO boost or subjective effects. Task performance measures were not reliably influenced by marijuana smoke exposure within the dosing ranges examined. These findings confirm the utility of the controlled smoking technology, support the notion that cumulative puff volume systematically influences biological exposure and subjective effects, but cast doubt on the common belief that prolonged breathholding of marijuana smoke enhances classical subjective effects associated with its reinforcing value in humans. PMID- 7853170 TI - Abecarnil and alprazolam in humans: behavioral, subjective and reinforcing effects. AB - Abecarnil, a novel beta-carboline, is under development for the treatment of Generalized Anxiety Disorder. This study compared the behavioral, subjective and reinforcing effects of abecarnil to those of the benzodiazepine alprazolam in 14 healthy males with histories of sedative drug abuse. Placebo, abecarnil (10, 20, 40 mg) and alprazolam (1.0, 2.0, 4.0 mg) were administered p.o. in a double blind, cross-over design. Abecarnil and alprazolam produced comparable dose dependent decreases in behavioral performance on balance, circular lights, digit recall and digit-symbol-substitution tasks that peaked 2-4 hr after drug administration. Both drugs produced a profile of sedative effects and were categorized by subjects as predominantly barbiturate- or benzodiazepine-like. However, the high dose of alprazolam increased subject-ratings of sleepy, fatigued and tired; these ratings were significantly different from both placebo and all doses of abecarnil. Abecarnil and alprazolam produced comparable dose dependent increases in ratings of drug strength. The highest dose of alprazolam produced increases in Next Day ratings of drug liking, good effects, monetary value of the drug, and desire to take the drug again that were significantly greater than placebo and the highest dose of abecarnil. Abecarnil, but not alprazolam, produced increases in Next Day ratings of "bad effects" that were significantly greater than placebo. The highest dose of alprazolam produced increases in a direct measure of drug reinforcement (drug vs. money Multiple Choice Procedure) that were significantly greater than placebo and all doses of abecarnil. Collectively, these data suggest that abecarnil may have less potential for abuse than alprazolam in a sedative-abusing population. PMID- 7853171 TI - Comparison of the properties of agmatine and endogenous clonidine-displacing substance at imidazoline and alpha-2 adrenergic receptors. AB - Nonadrenergic imidazoline receptors (I receptors) mediate the central antihypertensive effects of clonidine. Agmatine, an arginine metabolite that is synthesized within bovine brain and exhibits clonidine-displacing substance (CDS) activity, might be the endogenous I receptor neurotransmitter. The authors compared the affinity of agmatine versus the potency of endogenous bovine hypothalamic CDS, at bovine adrenomedullary I1 receptors and at human clonidine binding sites: human alpha-2A, alpha-2B and alpha-2C expressed on transfected cell lines, I1 sites on human platelet plasma membranes and I2b (amiloride insensitive) sites on human platelet intracellular membranes. The alpha-2 and I1 sites were labeled with [125I]p-iodoclonidine and the I2b sites were labeled with [3H]-idazoxan. Agmatine displayed preferential affinity for I1 receptors, with both high (H) and low (L) affinity components; the rank order was I1(human)(H) > I1(bovine)(H) > I2b = I1(human)(L) = I1(bovine) (L) = alpha-2A = alpha-2B = alpha 2C. By comparison, hypothalamic CDS competition curves modeled to a single site for all receptors, i.e., I1(bovine) > I2b = alpha-2C > I1(human) = alpha-2A = alpha-2B. Thus, agmatine alone cannot explain the rank order of potency of hypothalamic CDS. Moreover, I1 sites on human platelets differ from I1 sites on bovine adrenomedullary cells with respect to CDS potency but not agmatine affinity. These results do not rule out agmatine as an I1 transmitter but suggest that other I-receptor ligands might exist within endogenous CDS. PMID- 7853172 TI - Metabolism of allylbenzene 2',3'-oxide and estragole 2',3'-oxide in the isolated perfused rat liver. AB - The metabolism of allylbenzene 2',3'-oxide, estragole 2',3'-oxide, allylbenzene and estragole was studied in the isolated perfused rat liver. Formation of dihydrodiol and glutathione conjugate metabolites was detected for both epoxides and the presence of dihydrodiol metabolites after perfusion of allylbenzene or estragole indicated the formation of allylic epoxide intermediates in the intact liver. A comparison of elimination kinetics for parent compounds and epoxides indicated that epoxides were relatively rapidly detoxified and probably do not accumulate on formation in vivo. Acute toxicity of epoxides, measured as the release of alanine aminotransferase activity into the perfusate, or genetic toxicity, determined as covalent binding of radiolabeled epoxide to DNA, were not observed. It was concluded that both epoxide hydrolases and glutathione S transferases can effectively detoxify the allylic epoxides derived from either allylbenzene or estragole and effectively prevent cellular or genetic toxicity of these reactive intermediates. Epoxide hydrolases appear to play the major role in the detoxication of these epoxides in vivo. PMID- 7853173 TI - Therapeutic trial of reconstituted human high-density lipoprotein in a canine model of gram-negative septic shock. AB - In a controlled, randomized trial, the authors investigated the effects of reconstituted human high-density lipoprotein (R-HDL) on survival, endotoxemia, cytokine production and pathophysiologic and metabolic events in an animal model of gram-negative septic shock. At 0.5, 8 and 16 hr after implantation of a clot infected with Escherichia coli, canines received intravenous R-HDL (n = 13), control lipid (n = 7) or human serum albumin (HSA, n = 7) divided into three doses (0.3, 0.1 and 0.1 g/kg, respectively) at an hourly rate of 0.1 g/kg. All animals were treated with antibiotics and fluids. Animals treated with R-HDL had lower levels of circulating endotoxin and tumor necrosis factor and a smaller decrease in white blood cell counts than did animals treated with lipids and HSA (all P < .05). The survival times of lipid- and HSA-treated animals were similar (P = .3) and were significantly greater than those of R-HDL-treated animals (P = .02). During the first 6 hr after clot implantation, R-HDL-treated animals had significantly greater abnormalities in liver function test findings compared with lipid- and HSA-treated animals (all P < .05). For the first 24 hr, R-HDL-treated animals had significant increases in HDL levels; however, there were no significant relationships between these levels and the constituents of HDL (apolipoprotein AI and phosphatidylcholine) or liver function abnormalities and survival times (all r < .2, P > .3). In normal animals, administration of R-HDL (in similar doses) caused transient elevation of liver enzymes; in animals given sterile clot i.p., R-HDL caused seizures.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7853174 TI - In vivo receptor occupancy of the angiotensin II receptor by nonpeptide antagonists: relationship to in vitro affinities and in vivo pharmacologic potency. AB - The affinities of 13 angiotensin II antagonists for the AT1 subtype determined in vitro with tissue homogenates were shown not to correlate well with in vivo pharmacologic potency. The addition of human serum albumin to the in vitro assay to mimic in vivo plasma protein interactions reduced the measured affinity by reducing the effective free concentrations of antagonists, but the resulting affinities were not predictive of the in vivo effects. Using an in vivo radioligand competition assay, in which receptor occupancy is demonstrated via competitive blockade of the in vivo binding of [125I][Sar1,Ile8]angiotensin II to AT1 receptors in rat kidney cortex, we demonstrated that the in vivo pharmacologic potencies reflect receptor occupancy. By comparing the effects of rat plasma and bovine serum albumin on the in vitro affinity of two antagonists, we suggest that the use of plasma would alter free plasma concentrations in a manner more consistent with in vivo measures of potencies. PMID- 7853175 TI - Repression of angiotensin II and potentiation of bradykinin contribute to the synergistic effects of dual metalloprotease inhibition in heart failure. AB - Neutral endopeptidase inhibition (NEP-I) and angiotensin converting enzyme inhibition (ACE-I) act synergistically to produce acute beneficial hemodynamic effects in models of heart failure. Blockade of the formation of angiotensin II (Ang II) acting together with potentiation of the natriuretic peptides, bradykinin and other vasoactive peptides may mediate the interaction of dual enzyme inhibition. In this study, the potential roles of Ang II repression and bradykinin potentiation were evaluated in conscious cardiomyopathic hamsters with compensated heart failure. The Ang II AT1 receptor antagonist, SR 47436 (BMS 186295), was administered at 30 mumol/kg, i.v. followed by i.v. infusion at 1 mumol/kg/min in combination with NEP-I (SQ-28603 at 30 mumol/kg i.v.). Cardiac preload (left ventricular end diastolic pressure) and afterload (left ventricular systolic pressure) decreased significantly more after the combination of Ang II blockade and NEP-I than after either treatment alone. This indicated that repression of Ang II contributes importantly to the NEP-I/ACE-I interaction. Bradykinin B2 receptor antagonism by Hoe 140 at 100 micrograms/kg, i.v. significantly blunted the decrease in left ventricular end diastolic pressure but not the decrease in left ventricular systolic pressure after dual NEP-I/ACE-I (SQ 28603 and enalaprilat each at 30 mumol/kg, i.v.). This suggests that bradykinin potentiation contributes to the preload-reducing, but not the afterload-reducing, acute effects of NEP-I/ACE-I. Hence, both Ang II repression and bradykinin potentiation are factors contributing to the synergistic hemodynamic effects of combined NEP-I and ACE-I in hamsters with heart failure.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7853176 TI - Buprenorphine effects in methadone-maintained volunteers: effects at two hours after methadone. AB - Buprenorphine is an opioid partial agonist being developed for possible use in the treatment of opioid dependence. In a previous study up to 8 mg of buprenorphine administered 20 hr after a daily dose of methadone in methadone maintained volunteers produced neither agonist-like nor antagonist-like effects. The purpose of this study was to examine the effects of buprenorphine challenges given 2 hr after a daily methadone dose in maintained volunteers. Seven male volunteers maintained on 30 mg of methadone daily underwent pharmacologic challenges two to three times per week. Medication challenges consisted of double blind i.m. injections of buprenorphine (0.5-8.0 mg), the opioid antagonist naloxone (0.1 and 0.2 mg), the prototypic opioid mu agonist hydromorphone (5 and 10 mg) or saline. Assessments of physiologic measures, volunteers' self-reports and observer ratings of drug effects were collected in a laboratory session for 2 hr after drug administration, and then for 8 additional hr postsession. Results from the laboratory session showed that on subject and observer ratings naloxone produced typical antagonist-like effects, hydromorphone produced mild agonist like effects and buprenorphine produced antagonist-like effects. Interestingly, buprenorphine's antagonist activity was not directly dose-related; its most prominent antagonist effects occurred at the 1- and 2-mg doses. These results are consistent with buprenorphine's action as a partial mu opioid agonist and demonstrate that antagonist-like effects can occur under some conditions suggesting buprenorphine should have a low abuse liability in methadone maintained patients. PMID- 7853177 TI - Identification of a reversible component in the in vitro inhibition of rat hepatic cytochrome P450 2B1 by parathion. AB - Cytochrome P450 (P450) enzymes are inactivated in suicidal fashion during microsomal parathion oxidation. In the present study, two distinct components of the inhibition of the phenobarbital (PB)-inducible P450 2B1 by parathion were characterized. Here we report for the first time that low concentrations of parathion potently and reversibly inhibited, but did not inactivate, 2B1. In contrast, the previously described inactivation process occurred only at considerably higher parathion concentrations, at which concentrations enzyme activity was already extensively inhibited. At low concentration, parathion was a competitive inhibitor of 2B1-mediated androstenedione 16 beta-hydroxylation (Ki = 0.44 +/- 0.07 microM) and of 7-pentylresorufin O-depentylation (Ki = 0.40 +/- 0.03 microM) in microsomes from PB-pretreated rats and was similarly effective against androstenedione 16 alpha- and 16 beta-hydroxylation catalyzed by purified 2B1. Although preincubation of higher concentrations of parathion (> 5 microM) with NADPH-supplemented microsomes from PB-pretreated rat liver decreased holo P450, heme loss was not observed near the Ki values. Instead, half-maximal loss of P450 occurred at 6 microM and at 9 microM parathion in PB-pretreated microsomes and in the reconstituted system, respectively. Parathion metabolism was efficient in PB-microsomes (Km values for 4-nitrophenol and paraoxon formation were 13 microM and 10 microM, respectively) and in the reconstituted system (corresponding Km values were 19 microM and 14 microM). Thus the constants for P450 inactivation and for parathion metabolism were similar and were at least 15-fold greater than the Ki values for the reversible process.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7853178 TI - Chronic administration of a cocaine "binge" alters basal extracellular levels in male rats: an in vivo microdialysis study. AB - The purpose of this study was to determine the effects of chronic "binge" administration of cocaine (hourly x 3 i.p.). Male Fisher rats were treated for 13 days with cocaine (3 x 10 or 15 mg/kg) or saline (3 x 1 ml/kg). On day 14, microdialysis was performed on the rats and all received cocaine (3 x 10 or 15 mg/kg). Dialysate samples were collected from the ventromedial (nucleus accumbens and immediate surrounding striatum) and dorsolateral striata. After 13 days of daily cocaine "binges," estimated basal dopamine levels were lowered in the ventromedial striatum: 10 mg/kg x 3: 3.32 +/- 0.52 nM (n = 9) vs. 5.50 +/- 1.28 nM (n = 7) (t test, P < .1), and 15 mg/kg x 3: 3.50 +/- 0.37 nM (n = 6) vs. 5.66 +/- 0.58 nM (n = 7) (P < .01); and in the dorsolateral striatum 10 mg/kg x 3: 7.17 +/- 0.55 nM (n = 9) vs. 9.54 +/- 1.08 nM (n = 7) (t test, P < .05), and 15 mg/kg x 3: 6.88 +/- 0.22 nM (n = 5) vs. 10.00 +/- 1.04 nM (n = 7) (t test, P < .03). In cocaine-pretreated animals the cocaine "binge" on day 14 resulted in a lower elevation in extracellular DA levels than their corresponding values in saline-pretreated animals (pretreatment effect, P < .04 in the ventromedial striatum; P < .05 in the dorsolateral striatum), although the percent increases over baseline were of similar magnitude. In addition, the acute tolerance phenomenon observed during an initial cocaine binge was abolished after chronic exposure.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7853179 TI - Cross-tolerance between kappa and mu opioid agonists in the guinea pig ileum myenteric plexus. AB - The aim of the present investigation was to determine whether chronic activation of kappa opioid receptor induces development of tolerance of kappa (specific tolerance) and to mu (cross-tolerance) agonists in the guinea pig ileum myenteric plexus-longitudinal muscle strip. trans(+/-)-3,4-dichloro-N-methyl-N-[2-(1- pyrrolidynyl)ciclohexyl]-benzeneacetamide (U-50,488H) a selective kappa agonist, morphine (prototype of a mu agonist) and DAMGO (a selective mu agonist) were chosen. Tolerance to the kappa agonist was induced by chronic administration of the kappa agonist (15 mg/kg i.p. twice a day for 4 days). The guinea pigs were killed on day 5. Tolerance to U-50,488H was observed after its chronic administration and was revealed as a rightward shift of the concentration response curve. In addition, we observed a decrease in the maximum response and in the slope. Preparations from chronically U-50,488H-treated guinea pigs were also tolerant to the inhibitory effects of both the mu-selective agonist DAMGO and morphine. That is, there was cross-tolerance to the mu agonists. The development of tolerance to DAMGO and morphine was characterized by a rightward shift of the concentration-response curve, a decrease in maximum response and a decrease in the slope, although the degree of tolerance appeared to be less than that observed to U-50,488H. These data suggest that tolerance at the myenteric plexus level may be associated with a functional change in the myenteric neurons that is unrelated to the individual receptor system. PMID- 7853180 TI - Kinetics of interactions of para-aminohippurate, probenecid, cysteine conjugates and N-acetyl cysteine conjugates with basolateral organic anion transporter in isolated rabbit proximal renal tubules. AB - Kinetics of the first 15 s of para-aminohippurate (PAH) uptake across the basolateral membrane of single isolated S2 segments of rabbit proximal renal tubules and the effects of probenecid and cysteine conjugates on them were determined. For PAH uptake in control tubules, Kt (the concentration of PAH at 1/2 Jmax) was about 110 microM and Jmax (maximal rate of PAH transport) was about 6.5 pmol min-1 nl-1. In tubules preloaded with alpha-ketoglutarate (alpha-KG), thereby stimulating PAH/alpha-KG countertransport, Jmax doubled with little change in Kt. Probenecid cis-inhibited PAH uptake with an apparent Ki of about 13 to 15 microM whether or not the tubules were preloaded with alpha-KG. High probenecid concentrations cis-inhibited PAH uptake by > 98%, indicating that essentially all movement of PAH across the basolateral membrane is carrier mediated. Zwitterionic nephrotoxic cysteine conjugate, S-(1,2-dichlorovinyl)-L cysteine (DCVC), and nontoxic cysteine conjugate, S-(2-benzothiazole)-L-cysteine (BTC) cis-inhibited PAH uptake (apparent Ki: approximately 86 microM for DCVC; approximately 37 microM for BTC) at least as effectively as their negatively charged N-acetyl derivatives (NAC-DCVC and NAC-BTC) (apparent Ki: approximately 310 microM for NAC-DCVC; approximately 35 microM for NAC-BTC). The inhibition by both DCVC and NAC-DCVC was competitive in nature. NAC-DCVC also cis-inhibited net transepithelial secretion of PAH by isolated, perfused S2 segments. The presence of DCVC and NAC-DCVC, as well as PAH itself, in the bathing medium trans stimulated the 15 s efflux of PAH across the basolateral membrane of single S2 segments with oil-filled lumens. These data indicate that these cysteine conjugates and their N-acetyl derivatives, not only interact competitively with the PAH transporter, but are transported by it. PMID- 7853181 TI - Characterization of neuropeptide Y binding sites in rat brain membrane preparations using [125I][Leu31,Pro34]peptide YY and [125I]peptide YY3-36 as selective Y1 and Y2 radioligands. AB - The peptide YY (PYY)-derivatives [Leu31,Pro34]PYY and PYY3-36 were respectively developed as selective Y1 and Y2 radioligands devoid of affinity for the Y3 receptor subtype. Each analog was iodinated by the chloramine T method after a purification by reverse-phase high-performance liquid chromatography. Both radioligands bind with high affinity, low capacity and in a time-dependent and saturable manner to specific sites present in rat frontoparietal cortical or hippocampal membrane preparations. [125I][Leu31,Pro34]PYY demonstrated apparent affinities (Kd) of 0.42 +/- 0.07 and 0.22 +/- 0.08 nM and maximal capacities (Bmax) of 185 +/- 14 and 33 +/- 4 fmol/mg of protein to a single class of sites in cortical and hippocampal membrane homogenates, respectively. Conversely, [125I]PYY3-36 apparently bound to a greater amount of sites in hippocampal (Bmax of 109 +/- 13 fmol/mg of protein; Kd of 0.13 +/- 0.03 mM) compared with cortical (Bmax of 33 +/- 5 fmol/mg of protein; Kd of 0.37 +/- 0.06 nM) membrane preparations, which suggests the differential enrichment of these two brain regions with a given neuropeptide Y (NPY) receptor subtype. The comparative ligand selectivity profile of these two radiolabeled PYY derivatives confirmed this hypothesis and revealed that, although the rat frontoparietal cortex is enriched with Y1 sites, Y2, receptor binding sites are most abundant in the hippocampus.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7853182 TI - Inhibition of amine oxidase activity by derivatives that recognize imidazoline I2 sites. AB - Nonadrenergic imidazoline binding sites (imidazoline I2 sites) have been described to be colocated with monoamine oxidase (MAO) in the mitochondrial fraction of various cell types. In the present work, the authors considered whether this colocation could be associated with a functional interplay. In rat liver membranes, [3H]-idazoxan binding to I2 receptors was competed for by naphazoline and idazoxan, which also shared a high affinity for alpha-2 adrenoceptors (alpha-2 ARs). The chemicals 2-n-heptylimidazoline (S 15430), 1 methyl-5-n-heptylimidazole (S 15674), 2-benzofuran-2-yl-imidazoline (RX 801077) and 2-(1,3-benzodioxanyl)-2-imidazoline (RX 821029) exhibited higher affinity for I2 receptors than for alpha-2 ARs. The most selective agent was S 15430 with a 150-fold higher affinity for liver I2 receptors than for adipocyte alpha-2 ARs. Moreover, [3H]-idazoxan binding was also competed for by several MAO inhibitors (MAOI) that are not imidazoline or guanidinium derivatives such as tranylcypromine, harmaline, clorgiline and pargyline. Rat liver MAO activity was not only inhibited by MAOIs but also by some imidazoline derivatives: cirazoline, naphazoline, S 15674, RX 801077 and RX 821029. Idazoxan had no effect on MAO activity; it neither inhibited MAO nor prevented the inhibition induced by other imidazolines or MAOIs. This suggested that the ligand recognition site of I2 receptors was distinct from the MAOI target site. Furthermore, some imidazolines inhibited the activity of bovine plasma amine oxidase, an enzyme that does not possess the same cofactor as MAO and is insensitive to harmaline or pargyline.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7853183 TI - Separation of immunomodulatory and cholesterol-lowering activities of heterocyclic azaspiranes. AB - Azaspiranes are novel immunomodulators which are effective in a variety of autoimmune diseases. One azaspirane analog, SK&F 105685 (N,N-dimethyl-8,8 dipropyl-2-azaspiro [4.5] decane-2-propanamine dihydrochloride), caused a decrease in total serum cholesterol in dogs after oral administration. To determine whether an effect on cholesterol was common to this class of compounds, the immunomodulatory activity was compared with the cholesterol-lowering activity of six azaspirane analogs. The compounds were given to beagles at a dose of 1 mg/kg p.o. for 28 days, and the effect on serum cholesterol was determined. The results from this study showed a clear dissociation between the immunomodulatory and hypocholesterolemic activities of these compounds. Studies performed to determine the mechanism of the decrease in serum cholesterol caused by SK&F 105685 indicated that it was not due to inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase or acyl-CoA:cholesterol acyltransferase activities, or to a potentiation of cholesterol-7 alpha-hydroxylase activity. In addition, analysis by gas chromatography of the nonsaponifiable sterol fraction in dog plasma after treatment with SK&F 105685 or SK&F 106333 showed a decrease in cholesterol and an accumulation of lathosterol and an unknown sterol, indicating that the conversion of these sterols is inhibited and cholesterol synthesis is blocked at these steps. SK&F 105685 affected the sterol profile in human hepatoblastoma cells (Hep G2) in a similar way. Characterization of the unknown sterol by gas chromatography and mass spectrometry indicated that the unknown sterol is very similar to cholesterol and lathosterol, but its identity has yet to be established. These results show that the hypocholesterolemic effects of azaspiranes are related to inhibition of one or more of the final steps in the biosynthetic pathway of cholesterol. PMID- 7853184 TI - Low doses of anandamides inhibit pharmacological effects of delta 9 tetrahydrocannabinol. AB - It has been shown previously that the endogenous cannabinoid receptor ligand arachidonylethanolamide (anandamide 20:4, n-6) induces in vivo and in vivo effects typical of a cannabinoid partial agonist. We now report that the synthetic docosahexaenylethanolamide (anandamide 22:6, n-3) shows similar activities. In addition we show that these two anandamides, under certain experimental conditions, antagonize the effects of delta 9-THC both in vivo and in vitro. Thus a significant decrease in the potency of delta 9-THC-induced inhibition of adenylate cyclase was observed in N18TG2 neuroblastoma cells that were pretreated with low concentrations of anandamides. At these low concentrations of anandamides had no effect when applied alone. In vivo, Sabra or ICR mice were subjected to a tetrad of tests, designed to detect cannabinoid induced effects. Mice pretreated (i.p.) with 10 mg/kg of delta 9-THC received injections with anandamides. Only low doses (0.0001-0.1 mg/kg) of the anandamides, which had no effects when administered alone, partially or fully inhibited the THC-induced effects. These findings suggest that the inhibition of delta 9-THC-induced effects by low doses of anandamides may be due to partial agonistic effects of these materials. It is possible that low doses of the anandamides are capable of activating a Gs protein mediated signaling pathway, or may cause an allosteric modulation of the cannabinoid receptor. PMID- 7853185 TI - Voltage-dependent inhibition of the ATP-sensitive K+ current by the class Ia agent disopyramide in cat ventricular myocytes. AB - The inhibition of the adenosine triphosphate-sensitive K+ (KATP) current by disopyramide, a class Ia antiarrhythmic drug, was studied using whole cell voltage clamp in cat ventricular myocytes at 37 degrees C and was compared to that seen with quinidine, a prototypical class Ia drug. The inhibition of the levcromakalim-induced KATP current was concentration dependent, with Ki, at -20 mV, of 4.9 +/- 0.6 and 1.5 +/- 0.1 microM for disopyramide and quinidine, respectively. Disopyramide also inhibited the KATP current elicited during the metabolic inhibition induced by the uncoupler CCCP. Disopyramide (9 microM) produced a 75% inhibition in comparison to the 82% inhibition of the levcromakalim-elicited current. The degree of inhibition increased with depolarization. This effect was quantified using the fractional electrical distance (delta) as an index of the voltage dependence, yielding equivalent voltage dependency values of 0.48 +/- 0.02 and 0.51 +/- 0.08 for disopyramide and quinidine, respectively. Depolarizing and repolarizing voltage steps in presence of tetrodotoxin (5-30 microM), nitrendipine (1 microM), and 4-aminopyridine (1.5 microM) failed to reveal clear kinetics of block and unblock, suggesting either a very fast block (< 3 ms) or a tonic (i.e., time-independent) inhibition. The preferential inhibition of KATP channels at depolarized potentials during metabolic inhibition may contribute to preserve the ability of class Ia agents to prolong action potential duration without compromising resting potential. PMID- 7853186 TI - Optimization of the potency and duration of action of N-hydroxyurea 5 lipoxygenase inhibitors. AB - As in vitro glucuronidation assay and several biochemical assays were utilized to discover potent new N-hydroxyurea-containing 5-lipoxygenase inhibitors with long durations of action. The best of these, A-78773, is a racemic mixture of two enantiomers. These enantiomers were purified and the R(+)-enantiomer A-79175 was found to be superior to the S(-)-enantiomer with respect to in vitro metabolism and duration of action in the monkey. A-79175 was a potent selective inhibitor of 5-hydroxyeicosatetraenoic acid formation in rat basophilic leukemic homogenates (IC50 = 54 nM) and of calcium ionophore-induced leukotriene B4 (LTB4) formation in purified human polymorphonuclear leukocytes (IC50 = 25 nM) and human whole blood (IC50 = 80 nM). The compound inhibited LT formation in the rat with oral ED50s of 1 to 2 mg/kg. It also was a potent inhibitor of edema and inflammatory cell influx in rats and mice. A-79175 was resistant to glucuronidation and had an elimination half-life of nearly 9 hr in cynomolgus monkeys. A-79175 inhibited ex vivo LTB4 formation by monkeys for extended periods. A single 0.5-mg/kg oral dose gave > 50% inhibition of calcium ionophore-induced LTB4 formation ex vivo for 12 hr. A good correlation was found between the elimination half-life for A-78773 and its enantiomers in cynomolgus monkeys and humans. These data indicate that A 79175 is a promising long-acting agent that should be useful to delineate the importance of LTs in animal and human studies. PMID- 7853187 TI - Interaction between noradrenergic and histamine-containing neurons in the rat vas deferens. AB - A decussation of histamine (HA)-containing nervous pathways, at the level of the sympathetic ganglionic clusters of the rat vas deferens, was formerly described in this laboratory. This type of neuronal distribution is confirmed in the present study by using surgical interruptions of nervous pathways and determining changes in L-histidine decarboxylase (HD) activity, as an HA-containing neuron marker, after nerve degeneration. Decreases of HD activity follow previously found decreases of HA levels in the vas deferens submitted to the same type of surgical interruptions. An interaction between noradrenergic neurons and HA containing neurons is suggested, because electrical stimulation of the preganglionic sympathetic nerve causes a rapid increase in HD activity in the ipsilateral vas deferens, possibly as a signal of the activation of HA-containing neurons, whose pathways come from the opposite ganglion. This activation appears to be indirect, presumably through a sensory interneuron, which upon being excited by the enhanced sympathetic discharge crosses over to stimulate the contralateral ganglionic HA-containing neuron. The sympathetic discharge-induced peripheral loop reflex resulting in an increase in HD activity depends upon the integrity of the noradrenergic neuron. An, as yet unknown, interaction seems to occur between the noradrenergic neurons and the HA-containing neurons in the rat vas deferens, when the sympathetic activity of the latter is enhanced. PMID- 7853188 TI - Absorption-enhancing mechanism of sodium caprate and decanoylcarnitine in Caco-2 cells. AB - The mechanism of action of the absorption enhancers such as sodium caprate (C10) and decanoylcarnitine (DC) was examined. Both C10 and DC increased the epithelial permeability of fluorescein isothiocyanate dextran 4000 and decreased the transepithelial electrical resistance in Caco-2 cell monolayer. Irrespective of the presence or absence of mucosal calcium, C10 rapidly increased intracellular calcium levels dose-dependently. Compound 48/80, a phospholipase C inhibitor, prevented the increases of the intracellular calcium level and permeability of fluorescein isothiocyanate dextran 4000 by C10. Furthermore, N-(6-aminohexyl)-5 chloro-1-naphthalenesulfonamide hydrochloride, a strong calmodulin inhibitor, also significantly decreased the enhancing effect of C10. These results suggest that C10 releases calcium from intracellular stores via activation of phospholipase C in plasma membrane. The increase of the calcium levels was considered to induce the contraction of calmodulin-dependent actin microfilament, followed by dilatation of the paracellular route. Although DC also increased intracellular calcium levels, neither compound 48/80 nor N-(6-aminohexyl)-5 chloro-1-naphthalenesulfonamide hydrochloride decreased the enhancing effect of DC. The enhancing mechanisms were different for C10 and DC. PMID- 7853189 TI - Selective inhibition by zatebradine and discrete parasympathetic stimulation of the positive chronotropic response to sympathetic stimulation in anesthetized dogs. AB - To investigate how to reduce the positive chronotropic response to sympathetic nerve activation selectively without affecting other cardiac actions, we studied the effects of zatebradine, an inhibitor of the hyperpolarization-activated current (I(f)), verapamil and parasympathetic nerve stimulation on the positive chronotropic, dromotropic and inotropic responses to sympathetic nerve stimulation in the autonomically decentralized heart of the open-chest anesthetized dog. Parasympathetic input was activated by stimulation of the cervical vagus (CV) or parasympathetic nerves to the sinoatrial (SA) nodal region (SAP). Zatebradine (0.1-3 mumol/kg i.v.) decreased the heart rate but not other cardiac responses to sympathetic nerve stimulation, i.e., a wave component of the right atrial pressure (RAP), the first derivative of the RAP (dRAP/dt), atrioventricular (AV) conduction time (AVCT), right ventricular pressure (RVP) and its first derivative (dRVP/dt). Zatebradine (1 mumol/kg) inhibited basal heart rate by 28% but inhibited the chronotropic response to sympathetic stimulation by 85%. Verapamil (0.06-0.6 mumol/kg i.v.) attenuated the increases in heart rate, RVP and dRVP/dt elicited by sympathetic stimulation but potentiated shortening of the AVCT from the prolonged basal AVCT. The SAP stimulation attenuated the heart rate and dRAP/dt responses to sympathetic stimulation without affecting other cardiac responses, whereas CV stimulation decreased the positive chronotropic and atrial and ventricular inotropic responses. Cervical vagus stimulation did not change the positive dromotropic response. These results demonstrate that in contrast to CV nerve activation or verapamil, zatebradine and SAP stimulation cause bradycardia but preserve the myocardial contractile force and AVCT in response to sympathetic nerve activation or sympathomimetic drugs in the heart in situ. PMID- 7853190 TI - Pharmacological effects of GR138950, a novel angiotensin AT1 receptor antagonist. AB - The antagonist activity of GR138950 (1-[[3-bromo-2-[2 [[(trifluoromethyl)sulphonyl]amino]phenyl]-5- benzofuranyl]methyl]-4-cyclopropyl 2-ethyl-1H-imidazole-5-carboxamide) was investigated at angiotensin AT1 receptors and AT2 receptors in vitro and on blood pressure in conscious rats. GR138950 suppressed and displaced angiotensin II (AII) concentration-effect curves in the rabbit isolated aorta (pKb approximately 9.0-9.7) but had no effect against phenylephrine or serotonin induced-contractions. GR138950 competed with [3H]-AII for angiotensin AT1 receptors in rat liver membranes (pKi = 9.09). GR138950 had no apparent affinity for angiotensin AT2 receptors (bovine cerebellum; pKi < 6.0). GR138950 (1 mg/kg i.a. and p.o.) inhibited pressor responses to AII, but not phenylephrine, in conscious normotensive rats. Parallel displacements in AII dose-response curves occurred without any reduction in the maximum response to AII. The antagonist activity of GR138950 lasted for up to 24 h. GR138950 (> 0.03 mg/kg i.a., > 0.3 mg/kg p.o.) significantly reduced diastolic blood pressure (DBP) in renal artery ligated hypertensive rats. DBP was reduced maximally, 5 to 7 h after administration and the antihypertensive effect of GR138950 lasted for up to 48 h. Daily administration (5 days) of GR138950 to renal artery ligated hypertensive rats produced a sustained reduction in DBP. Acute administration of GR138950 (1 mg/kg i.a.) also significantly reduced DBP in spontaneously hypertensive rats but not in normotensive rats. Heart rate was little changed in renal artery ligated hypertensive rats, normotensive rats and spontaneously hypertensive rats. These experiments demonstrate that GR138950 is a potent, selective and specific angiotensin AT1 receptor antagonist that is orally active and reduces DBP in conscious hypertensive rats.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7853191 TI - Characterization of a behavioral model for peripherally evoked itch suggests platelet-activating factor as a potent pruritogen. AB - The studies described herein characterize animal behavioral models for conjunctival and cutaneous itch. Histamine was used as the reference stimulus for model development because it is firmly established as a pruritogen in both conjunctiva and skin. Itching evokes the desire to scratch in human subjects, so hind limb scratching at the afflicted area was used to identify pruritogenic stimuli. Under optimized environmental conditions, hind limb scratching behavior yielded substantial and highly reproducible responses. The conjunctival itch scratch response was delineated from pain and foreign body sensations by using appropriate stimuli. Examination of a large and diverse variety of autocoids revealed that only histamine, platelet-activating factor (PAF) and arachidonic acid and its cyclooxygenase metabolite prostaglandin E2 possessed meaningful pruritogenic activity. PAF-induced ocular pruritus did not involve histamine release, according to studies with appropriate antagonists. Thus PAF-induced ocular pruritus was unaffected by the histamine H1-receptor antagonist pyrilamine but was substantially attenuated by the PAF antagonists WEB 2086 and CV-6209 and was virtually abolished by E-6123. Similar itch-scratch behaviors were quantified in hairless guinea pig skin following the application of cowhage or the iontophoretic administration of histamine and PAF. Findings from these newly developed itching models suggest that PAF could be an important mediator of the pruritic sensation by activating a population of nerve endings responsible for encoding the itch sensation. PMID- 7853192 TI - Tissue distribution of zinc-mesoporphyrin in rats: relationship to inhibition of heme oxygenase. AB - Metalloporphyrins, including heme and others that inhibit heme oxygenase, are agents with expanding therapeutic potential. Recent results from our laboratory showed that a combination of heme and zinc-mesoporphyrin was remarkably effective in ameliorating biochemical features of acute porphyria. The aim of this study was to assess plasma clearance, tissue distribution and persistence, stability, toxicology and metabolic effects of zinc-mesoporphyrin, after its i.v. administration to rats. After administration of 15 mumol/kg b.wt. of zinc mesoporphyrin (bound to serum albumin in a 1:1 molar ratio) the metalloporphyrin was rapidly cleared from plasma (half-life 3.6 h) with uptake primarily into liver and spleen, considerably less into the kidney and none detectable into the heart or brain. Hepatic heme oxygenase activity was undetectable for 4 days and less than 50% of control 1 week later. Inhibition of splenic heme oxygenase activity was also substantial but less marked than in the liver. No mortality was observed in any of the treated animals, and there was no detectable effect on gross or microscopic appearance of the liver, spleen, kidneys, heart, lungs or brain. Blood counts and chemistries remained within normal limits. We conclude that single doses of ZnMP-serum albumin are nontoxic, rapidly cleared from the plasma and persist primarily in the liver and spleen where heme oxygenase is inhibited for prolonged periods. PMID- 7853193 TI - Characterization of diethyldithiocarbamate methyl ester sulfine as an intermediate in the bioactivation of disulfiram. AB - Disulfiram is bioactivated through a series of intermediates, ultimately forming S-methyl-N,N-diethylthiolcarbamate sulfoxide (DETC-Me sulfoxide), the metabolite proposed to be responsible for the in vivo inhibition of rat liver mitochondrial low Km aldehyde dehydrogenase (ALDH2). Diethyldithiocarbamate methyl ester sulfine (DDTC-Me sulfine) also has been recently identified as a possible metabolite of disulfiram (Madan and Faiman, 1994). In the present studies, DDTC Me sulfine was characterized and was found to inhibit ALDH2 in vivo (ID50 = 57 mumol/kg) but not in vitro. Maximum inhibition of ALDH2 in rats was observed 1 hr after the i.p. administration of DDTC-Me sulfine. Pretreatment of rats with 1 benzylimidazole, a cytochrome P450 inhibitor, blocked the DDTC-Me sulfine mediated inhibition of ALDH2. This suggested that DDTC-Me sulfine was further bioactivated by a cytochrome P450-dependent mechanism. DDTC-Me sulfine could not be detected in rat plasma after the i.p. administration of disulfiram (75 mg/kg), DDTC-Me (122 mg/kg) or DDTC-Me sulfine (22.6 mg/kg). However, S-methyl N,N diethylthiolcarbamate (DETC-Me), the desulfurated form of DDTC-Me, was detected as a major metabolite of DDTC-Me sulfine in rat plasma after DDTC-Me sulfine administration. Also, a disulfiram-like-ethanol reaction was observed in rats treated with DDTC-Me sulfine and challenged with ethanol. These data provided additional support for the idea that DDTC-Me sulfine is an intermediate formed after DDTC-Me metabolism and is probably a precursor to DETC-Me in the overall bioactivation of disulfiram to DETC-Me sulfoxide. PMID- 7853194 TI - Profound decrease of mesolimbic dopaminergic neuronal activity in morphine withdrawn rats. AB - The spontaneous neuronal activity of meso-accumbens dopaminergic neurons was recorded in unanesthetized rats withdrawn from chronic morphine administration (15 days) by means of single cell extracellular recording techniques coupled with antidromic identification from the nucleus accumbens. Twenty-four h after last morphine administration, firing rate and burst firing were found to be drastically reduced and the relative refractory periods of the same neurons were prolonged in morphine-dependent rats as compared with chronic saline-treated controls. The number of spontaneously active dopaminergic neurons, however, did not differ between the two groups. Administration of morphine restored electrophysiological parameters. When rats were tested 2 h after last morphine administration, i.v. challenge with the opiate antagonist naloxone caused an abrupt and virtually complete reduction of dopaminergic firing rate, burst rate and a prolongation of the relative refractory period. These effects were not observed in control rats. The results indicate that the mesolimbic dopaminergic system is tonically reduced in its activity during morphine withdrawal syndrome and considering its role in the reinforcing properties of opioids, its depressed activity during the morphine withdrawal syndrome may bear relevance for the dysphoric state associated to morphine withdrawal in humans. PMID- 7853195 TI - Pertussis toxin attenuates presynaptic inhibition of cholinergic but not nonadrenergic noncholinergic contraction in guinea pig airways. AB - Several alpha-2- and opioid receptors exert their intracellular effects via a pertussis toxin-sensitive G protein. Both cholinergic and nonadrenergic noncholinergic nerve-mediated contractions of airways can be reduced by stimulation of presynaptic alpha-2- and opioid receptors. Using guinea pig trachea and bronchi, pretreated with pertussis toxin 100 micrograms/kg or 0.9% NaCl, we investigated whether these inhibitory effects on airway contractions, evoked by electrical field stimulation, are mediated via a pertussis toxin sensitive G protein. The results indicate a difference between cholinergic and excitatory nonadrenergic non-cholinergic neurotransmission. Inhibition of cholinergic contraction via presynaptic alpha-2- and opioid receptors seems to be mediated via a pertussis toxin-sensitive G protein, whereas inhibition of nonadrenergic noncholinergic contraction is not affected by pertussis toxin. PMID- 7853196 TI - Calcium channel blockers antagonize some of cocaine's cardiovascular effects, but fail to alter cocaine's behavioral effects. AB - The effects of cocaine alone and in combination with the calcium channel blockers nimodipine, verapamil and diltiazem were determined for different groups of squirrel monkeys on cardiovascular function, schedule-controlled behavior and drug self-administration. Cocaine alone (0.3 mg/kg) produced increases in both blood pressure and heart rate. All three calcium channel blockers antagonized the pressor effect, but were ineffective against the tachycardiac effect of cocaine. Nimodipine was the most potent agent in antagonizing the pressor effect of cocaine. Response rates for monkeys responding on a second-order schedule of food presentation were increased by intermediate doses of cocaine (0.1-1.0 mg/kg) and were primarily decreased at a higher dose (3.0 mg/kg). Quarter-life values, an index of response patterning, were only decreased by cocaine. None of the calcium channel blockers altered cocaine's effects on either response rate or response patterning. In the self-administration experiments, the training dose of 56 micrograms/kg cocaine maintained high rates of responding on a simple fixed-ratio schedule. As with schedule-controlled behavior, none of the calcium channel blockers altered cocaine self-administration even when administered before self administration sessions during 5 consecutive days. These results suggest that the calcium channel blockers may be useful in treating cardiovascular-related complications after cocaine use, but they would not be effective as long-term treatment agents for cocaine abuse. PMID- 7853197 TI - In vivo effects of a novel thromboxane A2/prostaglandin H2 (TXA2/PGH2) partial agonist, (+)5(Z)-7-[3-endo-phenylsulfonylamino[2.2.1]- bicyclohept-2-exo-yl] heptenoic acid [(+)-S-145], on vascular, platelet and cardiac function. AB - A novel thromboxane A2/prostaglandin H2 (TXA2/PGH2) receptor ligand, (+)5(Z)-7-[3 endo-phenylsulfonylamino[2.2.1]-bicyclohept-2-e xo- yl]-heptenoic acid [(+)-S 145], was evaluated in guinea pigs to assess the in vivo pharmacodynamic profile of this compound at vascular, cardiac and platelet TXA2/PGH2 receptors. Comparison was made to the TXA2/PGH2 receptor antagonist SQ29548. Upon i.v. injection, (+)-S-145, but not SQ29548, elicited transient (approximately 1 min) increases in mean arterial blood pressure (ED50 +/- 95% confidence limit = 6.1 + 4.0, -2.2 micrograms/kg). The potency of i.v. (+)-S-145 (ID50 = 6.3 + 2.3, -2.3 micrograms/kg) against the pressor response to subsequent i.v. TXA2/PGH2 mimetic, U44069, was 9.5-fold greater than that of SQ29548 (ID50 = 59.1 + 52.9, - 52.9 micrograms/kg). Intravenous (+)-S-145 inhibited U44069-induced decreases in circulating platelet count (ID50 = 4.2 + 4.1, - 2.0 micrograms/kg). In thoracotomized guinea pigs, i.v. (+)-S-145 (31.6 micrograms/kg) and increasing i.v. doses of U44069 increased mean arterial blood pressure, total peripheral resistance, left ventricular end-diastolic pressure and left ventricular peak positive dP/dt (LV + dP/dt) and depressed cardiac output (P < .05). Pretreatment with i.v. (+)-S-145 (31.6 micrograms/kg) abolished these U44069-induced effects. In thoracotomized guinea pigs in which left ventricular end-diastolic pressure and HR were held constant, U44069 again increased LV + dP/dt (P < .05), but (+)-S 145 decreased LV + dP/dt (P < .05), which indicates the lack of an (+)-S-145 direct inotropic effect.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7853198 TI - Suppression of interleukin-1 alpha production by protein kinase C activators in human vascular endothelial cells. AB - In human umbilical endothelial cells, treatment with tumor necrosis factor (TNF) alpha stimulated the production of cell-associated interleukin (IL)-1 alpha. Combined treatment of human umbilical endothelial cells with TNF-alpha and the protein kinase C (PKC) activator 12-O-tetradecanoylphorbol 13-acetate (TPA) suppressed the TNF-alpha-induced production of IL-1 alpha. However, concentrations of 6-keto-prostaglandin F1 alpha in the conditioned medium were increased to a greater extent by combined treatment with TNF-alpha and TPA than by single treatment with TNF-alpha or TPA. Pretreatment with TPA for 15 min was enough to suppress the TNF-alpha-induced IL-1 alpha production. Pretreatment for 15 min with other PKC activators such as aplysiatoxin or teleocidin, also inhibited the TNF-alpha-induced IL-1 alpha production. Stimulation of cell associated IL-1 alpha production by IL-1 beta or lipopolysaccharide was also inhibited by pretreatment with the PKC activator TPA, aplysiatoxin or teleocidin. However, treatment with the protein kinase inhibitor 1-(5-isoquinoline-sulphonyl) 2- methylpiperazine dihydrochloride (H-7) did not block the inhibitory effect of TPA, aplysiatoxin or teleocidin on the cell-associated IL-1 alpha production stimulated by TNF-alpha, IL-1 beta or lipopolysaccharide, although the PKC activator-induced stimulation of 6-keto-prostaglandin F1 alpha production was counteracted by H-7 treatment. The present work indicates that the production of cell-associated IL-1 alpha stimulated by TNF-alpha, IL-1 beta or lipopolysaccharide is inhibited by treatment with TPA, aplysiatoxin or teleocidin.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7853199 TI - Interleukin-2 (IL-2) induces corticotropin-releasing factor (CRF) release from the amygdala and involves a nitric oxide-mediated signaling; comparison with the hypothalamic response. AB - Interleukin-2 (IL-2)-like immunoreactivity and IL-2 receptor immunoreactivity have been reported in different brain regions, under normal and pathophysiological conditions. IL-2 stimulates hypothalamic corticotropin releasing factor (CRF) and arginine vasopressin (AVP) release and that of pituitary adrenocorticotropin. The amygdala, known to contain high levels of CRF, is involved in stress-related reactions, including regulation of the hypothalamo pituitary-adrenal axis. IL-2 will release AVP from both the hypothalamus and the amygdala, which further supports a role for cytokine effects in the amygdala in neuroimmune interactions. In the present study, we compared the effects of IL-2, acetylcholine and norepinephrine on the in vitro release of CRF from the amygdala or hypothalamus. In addition, we used these release systems to evaluate the possible involvement of nitric oxide (NO)-mediated signaling in CRF release. IL-2 stimulates CRF release in both regions, in a calcium- and dose-dependent manner. Nitroprusside, an NO generator, also induces CRF release. This IL-2-induced CRF release is antagonized by Ng-methyl-L-arginine and hemoglobin, known NO antagonists. Finally, norepinephrine and acetylcholine induce CRF release. The norepinephrine-induced CRF release is antagonized by phentolamine and propanolol and the acetylcholine-induced release by atropine and mecamylamine, which suggests the involvement of both alpha and beta adrenergic receptors and both muscarinic and nicotinic receptors. The acetylcholine-induced CRF release is antagonized by Ng-methyl-L-arginine, but the norepinephrine-induced response is not. These data support the suggestion that the amygdala may participate in communications between the neuroendocrine and immune systems. PMID- 7853200 TI - A selective type V phosphodiesterase inhibitor, E4021, dilates porcine large coronary artery. AB - We investigated the inhibitory effects of a newly synthesized compound, sodium 1 [6-chloro-4-(3,4-methylenedioxybenzyl)-aminoquinazolin-2-y l]piperidine-4- carboxylate sesquihydrate (E4021), on five phosphodiesterase (PDE) isozymes isolated from porcine aortic smooth muscle. E4021 specifically inhibited type V phosphodiesterase (cyclic guanosine monophosphate [cGMP]-specific PDE) in a competitive manner. A comparison of the inhibitory profiles of zaprinast and E4021 indicated that E4021 is 100 times more potent and selective as a type V PDE inhibitor. E4021 caused a significant and sustained increase in the cGMP level in endothelium-denuded porcine coronary artery, but it had no effect on the cAMP level. This compound had a relaxant effect in porcine coronary artery precontracted by prostaglandin F2 alpha in the absence of endothelial cells and relaxed it more markedly in the presence of endothelial cells. E4021 had a synergistic effect with nitroglycerin in both the increase in cGMP level and the relaxant effect in isolated porcine coronary artery. E4021 caused a dose dependent dilation of the large epicardial coronary artery, with a reduction in mean pulmonary arterial pressure, in conscious pigs instrumented chronically with a pair of piezoelectric crystals. These results suggest that the highly selective and potent inhibitor of type V phosphodiesterase E4021 causes relaxation of the large coronary artery via an increase in the cGMP level. PMID- 7853201 TI - Some novel 5-hydroxytryptamine1A (5-HT1A) receptor agonists reduce gastric acid and pepsin secretion, reduce experimental gastric mucosal injury and enhance gastric mucus in rats. AB - The present studies examined the actions of a series of novel arylpiperazine 5 hydroxytryptamine1A (5-HT1A) agonists, developed originally for anxiolytic efficacy, in several models of gastric secretion and experimental gastric mucosal injury. These models included conscious gastric acid secretion, pylorus ligation (gastric acid and pepsin secretion), stress-induced gastric mucosal injury, ethanol-induced gastric mucosal damage and gastric adherent mucus levels. 2-(4-[4 (4-Nitropyrazol-1- yl)butyl]-1-piperazinyl)pyrimidine (E4414) and 2-(4-[4-(4 chloropyrazol-1-yl)butyl]-1-piperazinyl)pyrimidine dihydrochloride (E4424) significantly inhibited gastric acid secretion in conscious as well as in pylorus ligated rats. Both compounds also significantly reduced pepsin secretion in pylorus-ligated animals. E4414 and E4424 significantly reduced both stress induced and ethanol-induced gastric mucosal injury, and both compounds significantly maintained gastric adherent mucus levels in rats subjected to stress. The antisecretory and gastroprotective actions of E4414 and E4424 were of significantly greater magnitude than those of the reference 5-HT1A agonists, buspirone and 8-hydroxy-2-(di-n- propylamino)tetralin. These results suggest that some novel 5-HT1A agonists exert gastroprotection not only through reduction of aggressive elements in the gut (acid and pepsin secretion) but also through enhancement of defensive gastrointestinal factors such as adherent mucus. PMID- 7853202 TI - Are negative chronotropic and inotropic responses to adenosine differentiated at the receptor or postreceptor levels in isolated dog hearts? AB - Inhibition by zatebradine, a specific bradycardic agent, of the negative inotropic but not chronotropic responses to adenosine has been briefly reported in the isolated, perfused dog heart. We therefore investigated whether subtypes of adenosine receptors or postreceptor transduction mechanisms differentiated the negative chronotropic and inotropic responses to adenosine in the isolated, blood perfused atrial and ventricular preparations of the dog. Adenosine (1-3000 nmol), adenosine A1 receptor agonists, 2-chloroadenosine (CAD, 0.1-300 nmol) and N6 cyclohexyladenosine (CHA, 1-300 nmol) and a nonselective adenosine receptor agonist, 5'-N-ethyl-carboxamidoadenosine (NECA, 0.1-100 nmol), induced the negative chronotropic and inotropic responses. The potency order was NECA > CAD > adenosine > or = CHA. An adenosine A1 receptor antagonist, 1,3-dipropyl-8 cyclopentylxanthine (DPCPX, 10-300 nmol), dose-dependently inhibited the negative chronotropic and inotropic responses to adenosine, CAD and NECA in the isolated, perfused right atrium. DPCPX also blocked the negative inotropic responses to adenosine, CAD and NECA in the isolated left ventricle. However, an adenosine A2 receptor antagonist, 3,7-dimethyl-1-propargylxanthine (DMPX, 300 nmol), did not affect the negative cardiac responses to adenosine and NECA. Although the negative inotropic but not chronotropic responses to CAD and adenosine were dose dependently inhibited by zatebradine, K+ channel inhibitors 4-aminopyridine and E 4031 did not modify the cardiac responses to adenosine and CAD. These results suggest that the negative cardiac responses to adenosine are mediated by adenosine A1 receptors and the negative chronotropic and inotropic responses to adenosine are differentiated at the postreceptor transduction level(s) in the dog heart. PMID- 7853203 TI - Butorphanol: characterization of agonist and antagonist effects in rhesus monkeys. AB - The effects of butorphanol were studied in assays of antinociception, respiratory depression, sedation, diuresis and reinforcing effects in rhesus monkeys, and opioid binding in monkey brain. Butorphanol (0.003-0.1 mg/kg s.c.) was effective in the warm-water tail withdrawal assay in 50 degrees C water but not in 55 degrees C. Over a similar dose range, butorphanol caused substantial respiratory depression, without an obvious plateau. Constrained quadazocine apparent pA2 analysis on the respiratory depressant and antinociceptive effects of butorphanol yielded different values between the two assays (respiratory depression pA2 = 6.61; antinociception pA2 = 8.26). Butorphanol (0.1 mg/kg) antagonized the antinociceptive effects of etonitazene in 55 degrees C water, but caused a nonparallel leftward shift in the U50,488 dose-effect curve; both effects were probably due to butorphanol's intermediate efficacy at mu receptors. Butorphanol (0.0001-0.003 mg/kg per injection i.v.) was self-administered; unlike other mu opioid agonists, its maximum effect was depressed after pretreatment with quadazocine (0.01-1.0 mg/kg). Butorphanol (0.003-0.32 mg/kg) was devoid of substantial sedative or muscle relaxant effects, as measured by observational rating scales. Butorphanol (0.01-0.1 mg/kg s.c.), unlike U50,488 (0.01-0.32 mg/kg) did not cause diuresis. Kappa agonist or antagonist effects of butorphanol were not detected in the present studies. This profile is consistent with butorphanol's binding characteristics in rhesus monkey brain which indicated 12 fold mu:kappa selectively and 34-fold mu:delta selectivity. PMID- 7853204 TI - Continuous administration decreases and pulsatile administration increases behavioral sensitivity to a novel dopamine D2 agonist (U-91356A) in MPTP-exposed monkeys. AB - We compared the behavioral effects of a novel and highly selective dopamine D2 receptor agonist, U-91356A, administered to 6 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-exposed parkinsonian monkeys for 27 days following an intermittent (n = 3) or continuous (n = 3) schedule, using subcutaneous osmotic minipumps for the latter group. Each group received equivalent amount of drug daily. Dopamine D1 and D2 receptor binding assays were performed on striatal tissue homogenates with tritiated selective antagonists and were compared with those of 3 healthy control animals and 3 MPTP-exposed monkeys treated in parallel with daily doses of levodopa and 2 additional MPTP-exposed monkeys otherwise untreated. U-91356A quickly relieved all parkinsonian features and greatly stimulated locomotion in all animals. The pulsatile administration group showed progressive sensitization to the drug, and all 3 animals developed chorea during the first week of treatment that subsequently increased in intensity. The same pattern was seen in the levodopa-treated animals. In contrast, an apparent, incomplete tachyphylaxis were observed in 2 of 3 animals in the continuous infusion group during the first 10 days of treatment. Only 1 of these animals developed minimal and transient choreic dyskinesia. An apparent decrease of D2 receptor binding was observed. No upregulation of dopamine receptors occurred in the dyskinetic monkeys of the pulsatile group, but a tendency toward upregulation of putaminal D1 receptors was observed in the levodopa-treated, dyskinetic animals. These results confirm that the mode of administration of dopaminergic agents may result in a markedly different clinical outcome.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7853205 TI - Role of hypothermia in the mechanism of protection against serotonergic toxicity. II. Experiments with methamphetamine, p-chloroamphetamine, fenfluramine, dizocilpine and dextromethorphan. AB - Several amphetamine analogs, when administered in high-dose regimens, have been shown to cause long-lasting depletions of central serotonin (5-HT), which are indicative of neuronal toxicity. These depletions and the resulting toxicity can be attenuated pharmacologically or by lowering ambient temperature. The noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (DZ) blocks depletion of 5-HT induced by methamphetamine (METH) and p chloroamphetamine (PCA), but not fenfluramine (FEN). This study investigated whether the effects of DZ and another calcium channel antagonist, dextromethorphan (DEX), are due to induction of hypothermia. Male Sprague-Dawley rats were injected with either saline (SAL), DZ (1 or 2 injections of 2.5 mg/kg), or DEX (75.0 mg/kg) followed by either SAL, METH (4 injections of 10.0 mg/kg), PCA (1 injection of 10.0 mg/kg) or FEN (2 or 4 injections of 12.5 mg/kg). Core body temperature (TEMP) was monitored for 4 h or longer with radiotelemetry. Base line TEMP was between 37.0 and 37.6 degrees C. SAL/METH caused a significant increase in TEMP which peaked at 40.8 +/- 0.50 degrees C after the last injection. Coadministration of DZ with METH caused TEMP to decrease to 33.8 +/- 0.30 degrees C within 2 h of the first injection and lasting more than 3 h, and protected against depletion of 5-HT. SAL/PCA caused a small increase in TEMP to 37.7 +/- 0.36 degrees C, whereas coadministration of DZ with PCA decreased TEMP to 35.2 +/- 0.50 degrees C, lasting 2 h, in a dose regimen which has been shown to be neuroprotective.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7853206 TI - Identification of distinct components, with different time courses, of the changes in response to convulsive stimuli during ethanol withdrawal. AB - The time courses of changes in sensitivity to handling-induced hyperexcitability, audiogenic seizures and a variety of chemical convulsants were compared in mice during a 24-hr period after withdrawal from chronic ethanol treatment. The peak increase in handling-induced hyperexcitability was seen between 3 and 5 hr after the withdrawal, disappearing by 12 hr, whereas the peak sensitivity to an audiogenic stimulus was found 8 hr into the withdrawal period. No changes were seen in thresholds to bicuculline during the 24-hr study. The thresholds to N methyl-D-aspartate were decreased during the withdrawal period, with a maximum change at the 16-hr interval. In contrast, the thresholds to aminophylline were increased at 4 hr into withdrawal. The thresholds to 4-aminopyridine were also increased, with maximum changes at the 8-hr and 12-hr intervals. The only alterations in sensitivity to methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3 carboxylate and kainate were increases in the thresholds immediately on withdrawal, which were likely to have been due to residual ethanol. The results indicate that a complex pattern of neuronal changes occurs during ethanol withdrawal with a series of alterations in responses to convulsive stimuli which differ both in direction and in time course, suggesting different underlying mechanisms. PMID- 7853207 TI - Effects of acute and delayed effects of prior chronic cocaine administration on regional rates of cerebral protein synthesis in rats. AB - Single or repeated treatments with cocaine (15 mg/kg, i.p.) in rats modify rates of local cerebral protein synthesis (ICPSleu) measured with the [1-14C]leucine method. A single dose of cocaine to naive rats reduced ICPSleu by about 10% throughout the brain; the most statistically significant reduction was in the nucleus accumbens, shell portion (P = .0003). A comparable dose of cocaine administered acutely after 1 wk of daily cocaine injections had no effects on ICPSleu. Delayed effects of prior chronic cocaine treatment were studied in experiments in which one rat of each pair received injections with saline for 8 days and the other cocaine, and on the 15th day ICPSleu was measured. In these experiments delayed effects of the chronic cocaine treatment were observed; in the cocaine-treated rats ICPSleu was significantly increased in selective brain regions, i.e., prefrontal and primary olfactory cortex (P < .006). These results suggest that acute effects of a single dose of cocaine and residual effects of chronic cocaine treatment on ICPSleu are distinctly different and occur in different regions of the brain. PMID- 7853208 TI - Behavioral and local cerebral metabolic effects of the novel tropane analog, 2 beta-propanoyl-3 beta-(4-tolyl)-tropane. AB - A novel cocaine analog, 2 beta-propanoyl-3 beta-(4-tolyl)-tropane (PTT), in which both esters have been removed, has been shown to be more potent at and more selective for dopamine transporters than cocaine. The i.v. administration of PTT (0.1-2.0 mg/kg) to rats produced dose-dependent increases in forward locomotor activity and stereotypies at high doses. The 2-[14C]deoxyglucose method was used to measure the effects of PTT (0.1-1.0 mg/kg) on rates of local cerebral glucose utilization. The administration of high doses of PTT (0.5 and 1.0 mg/kg i.v.) resulted in widespread elevations in glucose utilization in portions of the mesocorticolimbic and nigrostriatal systems. Alterations were also noted in hippocampus, locus coeruleus and dorsal raphe. In contrast, a low dose of PTT (0.1 mg/kg) decreased cerebral metabolic activity in the nucleus accumbens and olfactory tubercle, with few effects in other regions. Decreased metabolic rates at low doses have not been observed with other stimulants and, therefore, represent a unique effect of this analog. The administration of the active enantiomer of PTT (0.075 mg/kg), approximately comparable to the 0.1 mg/kg of the racemic mixture, produced patterns of behavior and cerebral metabolic activity similar to the 0.1 mg/kg dose. The effects of PTT, then, are specific to its active enantiomer rather than the inactive form. The present data demonstrate that PTT acts as a stimulant in vivo, paralleling its effects in vitro, but its behavioral and cerebral metabolic effects are qualitatively different from those of cocaine. This is consistent with the selectivity and pharmacokinetic differences between PTT and cocaine. PMID- 7853209 TI - Protective effects of AE0047, a novel calcium antagonist, on incidence of stroke and hemodynamic disturbances in stroke-prone spontaneously hypertensive rats. AB - To test for evidence of stroke-preventive action, we initially examined the effect on salt-loaded stroke-prone spontaneously hypertensive rats of chronic treatment with 4-(4-benzhy-drylpiperazino)phenethyl methyl 1,4-dihydro-2,6 dimethyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylate dihydrochloride (AE0047), a novel calcium antagonist with slow onset and long-lasting hypotensive effect, and compared its efficacy with that of the calcium antagonist nicardipine and the vasodilator hydralazine. We then used radioactive microspheres to study the effects of these three agents on hemodynamic impairment to clarify the mechanism of the test drug's putative preventive action. In a 12-week repeated administration study using animals of initial age 9 weeks; all vehicle-treated subjects died within 37 days as a result of severe hypertension and stroke, whereas those treated with AE0047, at doses of 1 or 3 mg/kg/day, remained free of stroke and showed no signs of hemorrhage, brain softening or the cerebrovascular lesions typical in this animal model. Significant suppression of the development of hypertension was not noted at the lower of these doses nor at a nicardipine dose of 10 mg/kg/day, which failed to prevent stroke in most cases. A 10 mg/kg/day dose of hydralazine did suppress the development of hypertension but failed to prevent death in half of all cases. In the hemodynamic study, 4-week treatment with AE0047 averted the marked decreases in cardiac output and blood flow in the brain, heart, kidneys and adrenal glands observed in the control group, as well as the accompanying rise in total peripheral resistance before and after stroke.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7853210 TI - Are postsynaptic 5-HT1A receptors involved in the anxiolytic effects of 5-HT1A receptor agonists and in their inhibitory effects on the firing of serotonergic neurons in the rat? AB - Previous studies have shown that injection of 5-hydroxytryptamine (serotonin) receptor agonists in the dorsal raphe nucleus (DRN) to stimulate somatodendritic 5-HT1A autoreceptors or in the hippocampus to stimulate postsynaptic 5-HT1A receptors, induces anxiolytic-like effects in the rat. The mechanisms triggered by the latter treatment were investigated by measuring both the electrical activity of serotonergic DRN neurons and the anxiolytic response in rats receiving injections with 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) or ipsapirone into the dorsal hippocampus. Anxiety-related behavior was estimated by recording the time of ultrasonic vocalization (USV) due to electric foot shocks under standardized conditions. Intrahippocampal application of 8-OH-DPAT or ipsapirone produced a dose-dependent inhibition of the firing of serotonergic DRN neurons and of the shock-induced USV response. However, the range of efficient doses of 8-OH-DPAT via the intrahippocampal route (1-10 micrograms/rat) was larger than that using the i.v. route of injection (0.15-2.5 micrograms/rat). Furthermore, maximal inhibition of the firing of DRN serotonergic neurons occurred earlier when 8-OH-DPAT was injected i.v. (within 1-2 min) than when it was injected into the dorsal hippocampus (within 5 min). Interestingly, the injection of 8-OH-DPAT into the striatum, where 5-HT1A receptors are hardly detectable, or a lateral ventricle, also yielded dose-dependent reduction in both the firing rate of serotonergic DRN neurons and the USV response. Finally, local lesion with ibotenic acid to eliminate postsynaptic 5-HT1A receptors did not alter the inhibitory effects of intrahippocampal application of 8-OH-DPAT on the firing of serotonergic DRN neurons and the USV response. These data indicated that postsynaptic 5-HT1A receptors were not responsible for the inhibitory effects of 8-OH-DPAT and ipsapirone injected in forebrain areas on the electrical activity of serotonergic neurons and the USV response in rats. As shown by the autoradiographic labeling by [3H]8-OH-DPAT at distance from its injection site in the dorsal hippocampus, the diffusion of 5-HT1A receptor agonists (from injected areas in the forebrain to the DRN where they directly inhibit the electrical activity of serotonergic neurons) more likely accounted for their anxiolytic-like effects. PMID- 7853211 TI - Ursodeoxycholate (UDCA) inhibits the mitochondrial membrane permeability transition induced by glycochenodeoxycholate: a mechanism of UDCA cytoprotection. AB - Ursodeoxycholate (UDCA), a hydrophilic bile salt, ameliorates hepatocellular injury by toxic bile salts and is used to treat cholestatic liver disease. However, the mechanisms of bile salt-mediated hepatocyte necrosis and UDCA cytoprotection remain unclear. Hepatocyte necrosis is thought to be caused by the mitochondrial membrane permeability transition (MMPT). Thus, the aims of our study were to determine if a toxic bile salt, glycochenodeoxycholate (GCDC) induces the MMPT and if so, whether UDCA prevents the bile salt-induced MMPT. The MMPT was assessed in isolated rat liver mitochondria. Cell viability was measured in isolated rat hepatocytes. GCDC induced the MMPT in a dose-dependent manner. The GCDC-induced MMPT was partially blocked by cyclosporin A plus trifluoperazine, known inhibitors of the MMPT. UDCA also inhibited the GCDC induced MMPT, and partially blocked the MMPT by phenylarsene oxide, an established mediator of the MMPT. UDCA or cyclosporin A plus trifluoperazine protected against loss of hepatocyte viability during treatment with GCDC. In conclusion, GCDC induces a MMPT; a finding providing a physicochemical explanation for the bioenergetic form of cell necrosis caused by toxic bile salts. UDCA cytoprotection may, in part, be due to inhibition of the bile salt induced MMPT. PMID- 7853212 TI - Mepyramine, a histamine H1 receptor antagonist, inhibits the metabolic activity of rat and human P450 2D forms. AB - The interaction of antihistaminics, including mepyramine, with rat hepatic cytochrome P450s (P450s) was investigated. We first investigated mepyramine binding to eight forms of rat hepatic P450s. Mepyramine bound specifically to P450 2D1, which suggests that it inhibits P450 2D activity. Histamine H1 receptor antagonists (mepyramine, diphenhydramine, chlorpheniramine and triprolidine) inhibited the lidocaine 3-hydroxylation activity catalyzed by P450 2D1 but did not inhibit the testosterone hydroxylation activities catalyzed by P450s other than P450 2D forms. The Ki values of these antagonists for the catalytic activity of P450 2D1 were low and were similar to those of quinine and quinidine, which are specific inhibitors of P450 2D forms. The Ki value of mepyramine was especially low, at 34 nM. Furthermore, the effects of mepyramine on human P450 2D6 were investigated. Among the ten forms of human P450 expressed in yeast, mepyramine bound specifically to P450 2D6 in a binding assay. In human hepatic microsomes, mepyramine inhibited the debrisoquine 4-hydroxylation activity catalyzed by P450 2D6. These results indicate that histamine H1 receptor antagonists such as mepyramine are potent inhibitors of P450 2D forms because of their high affinity for these enzymes. PMID- 7853213 TI - A novel quantitative method for determining the biodistribution of radiolabeled xenobiotics using whole-body cryosectioning and autoradioluminography. AB - A novel method is described for quantitative whole-body autoradioluminography using [14C]-radioactive standards prepared from rat red blood cells. MicroComputer Imaging Device model 2 (MCID) and ImageQuant (IQ) imaging systems were evaluated for imaging performance and autoradioluminography quantitation. Weighted linear regression analysis resulted in linearity over five orders of magnitude with a lower limit of quantitation of 2.7 nCi/g. Using IQ, 16 days were necessary for image analysis and data processing of 30 whole-body cryosections and 1080 standards. MCID reduced the image and data processing of the same cryosections and standards to only 4 days. Embedding a series of radioactive standards with each specimen in the same carboxymethyl cellulose block provided an effective method of assessing intrasection and intersection variations in thickness of whole-body cryosections. These results demonstrated that autoradioluminography provided a sensitive, accurate, precise and reproducible method for the quantitative measurement of the tissue distribution of [14C] radiolabeled xenobiotics in whole-body cryosections. Evaluating the biodistribution of [14C]-xenobiotics by autoradioluminography, not only provides pharmacokinetic data required for predicting the potential tissue deposition of an absorbed dose of radioactivity in man, but also allows for visual and quantitative evaluation of radioactivity in small anatomical structures that otherwise could not be detected or measured by conventional tissue combustion technology. PMID- 7853214 TI - Role of cell volume and protein kinase C in regulation of a Cl- conductance in single proximal tubule cells of Rana temporaria. AB - 1. The whole-cell patch clamp technique was used to investigate Cl- currents in single proximal tubule cells isolated from kidneys of Rana temporaria. 2. Immediately following establishment of the whole-cell clamp, the Cl- conductance (gCl) of the cells was low. However, with 2 mM ATP in the pipette there was a time-dependent activation of gCl. Such activation was inhibited when the bath contained a hypertonic Ringer solution. 3. The Cl- conductance was not directly dependent on cell volume; gCl increased with hypotonic shock and decreased with hypertonic shock, but only in the presence of ATP. 4. Activation of gCl by ATP was dependent on extracellular Ca2+; however, the conductance was not directly Ca2+ sensitive. Activation was inhibited by Gd3+, which also had a direct inhibitory action on gCl. 5. Inhibition of protein kinase C (PKC), by 10 microM PKC pseudo-substrate (PKC-ps), completely abolished the ATP-dependent activation of gCl, while stimulation of PKC, by the PKC activator 4 beta-phorbol 12 myristate, 13-acetate (PMA), increased the degree of activation typically observed with ATP. 6. We propose that gCl is activated by PKC-mediated phosphorylation and plays a role in volume regulation of the cells. PMID- 7853215 TI - 5-Hydoxytryptamine evokes depolarizations and membrane potential oscillations in rat sympathetic preganglionic neurones. AB - 1. Whole-cell recordings were made from seventy-seven identified rat sympathetic preganglionic neurones (SPN) in spinal cord slices. Perfusion of 5-HT (0.5-30 microM) strongly depolarized 90% of neurones. The response was slow in onset, could last over 10 min and was associated with an increase in input resistance. 5 HT could also evoke rhythmical membrane potential oscillations in a population of previously quiescent neurones. 2. The 5-HT response persisted in TTX and also in low-Ca(2+)-high-Mg2+ artificial cerebrospinal fluid (ACSF), suggesting that the receptors are on SPN. The 5-HT uptake inhibitor 6-nitroquipazine potentiated the 5-HT-induced depolarization. 3. The 5-HT-induced depolarization was reduced and then abolished by membrane hyperpolarization to potentials of about -100 mV, but was not reversed in sign by further hyperpolarization. In voltage clamp, 5-HT evoked inward currents associated with the reduction of an outwardly rectifying potassium conductance. 4. The 5-HT2 receptor agonist alpha-methyl-5-HT mimicked the 5-HT response on all neurones, as did the 5-HT1 receptor agonist 5 carboxamidotryptamine (5-CT) on 71% of SPN. The responses to 5-HT, alpha-methyl-5 HT and 5-CT were inhibited by the 5-HT2 antagonists ketanserin and ritanserin. 5. Pressure ejection of 5-HT over the central canal region could evoke a biphasic inhibitory-excitatory response. This response persisted in TTX, suggesting that an inhibitory 5-HT receptor may be located on the medial dendrites. 6. SPN are powerfully depolarized by 5-HT acting at 5-HT2 receptors, via the closure of an outwardly rectifying potassium conductance. The long duration of the response and the ability of 5-HT to induce rhythmical oscillations suggest that 5-HT may have an important role in regulating SPN excitability. PMID- 7853216 TI - Voltage clamp analysis of excitatory synaptic transmission in the avian nucleus magnocellularis. AB - 1. The properties of evoked excitatory postsynaptic currents (EPSCs) and spontaneous miniature excitatory postsynaptic currents (mEPSCs) have been studied in neurons of the nucleus magnocellularis (nMAG), one of the avian cochlear nuclei which receive somatic, calyceal innervation from auditory nerve fibres. Whole-cell patch clamp techniques were used to voltage clamp visually identified neurons in brain slices. 2. EPSCs resulting from activation of single axonal inputs were on average -5.3 nA at a driving force of -25 mV. Current-voltage relationships for the peak of the EPSC were linear with a peak conductance of 211 nS. The rate of EPSC decay showed a linear increase with temperature, with a temperature coefficient (Q10) of 2.2 between 25 and 35 degrees C; in vivo (41 degrees C) the EPSC would decay in 0.2 ms. 3. The EPSC was composed of two pharmacologically and kinetically distinct components: an early phase due to non NMDA (N-methyl-D-aspartate) receptors and a late phase resulting from NMDA receptors. Both components reversed near 0 mV. While both subtypes of glutamate receptor were activated by transmitter, NMDA receptors had a peak conductance at positive potentials which was only 11% of the peak non-NMDA receptor component. 4. EPSCs during trains of stimuli exhibited a progressive decrease in amplitude. The extent of depression increased with the frequency of stimulation and was reduced by drugs which prevent receptor desensitization, indicating that, in part, postsynaptic factors limit synaptic strength during repetitive synaptic activity. Additionally, the coefficient of variation of the EPSC amplitude increased during trains, consistent with presynaptic depression. 5. mEPSCs occurred randomly in the presence of tetrodotoxin and presumably correspond to transmitter quanta. These synaptic events rose (10-90%) within 100 microseconds and decayed with an exponential of 180 microseconds at 29-32 degrees C. Despite the somatic location of the synapse, mEPSCs varied widely in amplitude, suggesting differences in the quantal synaptic current at each synaptic site. The ratio of the average peak conductance of the EPSC and mEPSC gave an estimated quantal content of 103. PMID- 7853218 TI - Topography of saccadic eye movements evoked by microstimulation in rabbit cerebellar vermis. AB - 1. We investigated saccadic eye movements elicited by microstimulation in the vermis of the rabbit. Scleral search coils were implanted under the conjunctiva of both eyes and a recording chamber was placed over the cerebellar vermis. 2. Conjugate saccadic eye movements were evoked in lobules VIa, b and c and VII of the vermis by currents ranging from 4 to 60 microA. All movements were horizontal with no apparent vertical component. 3. The cortex on both sides of the vermal mid-line could be divided in two zones, dependent on the direction of elicited saccades. In the medial zone saccades were directed ipsilaterally, in the lateral zone contralaterally. 4. We conclude that the topography of saccadic eye movements in the rabbit cerebellar vermis is, unlike in monkey and cat, organized in parasagittal zones. PMID- 7853217 TI - Development of spinal reflex pathways from muscle afferents to motoneurones in chick embryos devoid of descending inputs. AB - 1. The synaptic connections of reflex pathways between hindlimb muscle afferents and motoneurones were investigated in chicken embryos. Descending inputs to the lumbar spinal cord were eliminated by removing two to four segments of the thoracic spinal cord at embryonic day 2 (E2; gap operation). Intracellular recordings from motoneurones innervating the lateral gastrocnemius (LG) muscle were performed in isolated spinal cord preparations of normal and gap-operated embryos at E14-E15. 2. In both normal and gap-operated embryos, homonymous and synergistic muscle nerve stimulation evoked EPSPs in LG motoneurones at a short and fixed latency, suggesting that they were evoked monosynaptically. EPSPs from synergistic muscle afferents were much smaller than those from homonymous muscle afferents. The volleys from the antagonistic muscle nerve evoked IPSPs at a longer central latency than found for EPSPs in both embryos. 3. The maximal amplitudes of homonymous and synergistic EPSPs in gap-operated embryos were 1.3 and 1.7 times, respectively, larger than in normal embryos. Homonymous EPSPs were observed in all LG motoneurones examined, but synergistic EPSPs were more common in gap-operated than in normal embryos. 4. Antagonistic IPSPs were more common in motoneurones of gap-operated embryos than in those of normal embryos. Homonymous and synergistic muscle nerve stimulation also elicited IPSPs in LG motoneurones in both normal and gap-operated embryos. IPSPs evoked both by homonymous and by synergistic muscle nerve stimulation were more common in gap-operated than in normal embryos. 5. The spatial pattern of reflex pathways from hindlimb muscle afferents to motoneurones in chick embryos devoid of both supraspinal and long propriospinal inputs to the lumbar spinal cord is similar to that in normal embryos. However, both mono- and polysynaptic connections in these pathways are enhanced by the blockade of descending projections. PMID- 7853219 TI - Oxytocin receptors on oxytocin neurones: histoautoradiographic detection in the lactating rat. AB - 1. The purpose of the present study was the detection at the cellular scale of the oxytocin (OT) receptors involved in the facilitatory effect of this neuropeptide on its own release during the milk ejection reflex. 2. OT binding sites were demonstrated in brain sections by using a highly selective 125I labelled OT antagonist detected by film- and histoautoradiography. 3. Film autoradiographs revealed the presence of OT binding sites in the hypothalamic magnocellular (supraoptic, paraventricular and anterior commissural) nuclei in lactating rats, suckled or not. This detection was only possible after acute i.c.v. injection of OT antagonist which probably induced an upregulation of the OT binding sites to autoradiographically detectable levels. 4. Combined application of histoautoradiographic and immunohistochemical techniques showed that the OT binding sites were concentrated on OT magnocellular neurones. Labelling concerned cell bodies and dendrites but not the axons and endings in the pituitary neural lobe. 5. The presently detected somatodendritic autoreceptors on OT neurones probably mediate the facilitatory effect of OT on its own release during the milk ejection reflex. PMID- 7853220 TI - Effect of pulmonary lymphatic obstruction on respiratory rate and airway rapidly adapting receptor activity in rabbits. AB - 1. The effects on respiratory rate of obstruction of pulmonary lymph flow, reduction of plasma protein concentration and a combination of the two procedures were examined in anaesthetized rabbits. The former was achieved by raising the pressure in a pouch created from the right external jugular vein and the latter by batch plasmapheresis. 2. In spontaneously breathing rabbits, neither pulmonary lymphatic obstruction (n = 6) nor plasmapheresis (n = 5) produced a significant change in respiratory rate. However, their combination (n = 8) produced a significant increase in respiratory rate (P < 0.05). 3. Cooling of the cervical vagi to 8-9 degrees C (n = 4) and vagotomy (n = 7) abolished this response. 4. There was a significant increase in the activity of the airway rapidly adapting receptors (RARs; n = 9) during pulmonary lymphatic obstruction, plasmapheresis and their combination (P < 0.05). 5. It is concluded that in the rabbit, obstruction of lymphatic drainage from the lung after plasmapheresis causes a reflex increase in respiratory rate. The afferent pathway for this reflex response lies in the vagus nerve and the RARs are likely to be the receptors involved in this response. PMID- 7853221 TI - The importance of hand use to discharge of interpositus neurones of the monkey. AB - 1. Monkey interpositus neurones show large discharge modulations during reaching to grasp, however, the same neurones show little or no modulation during operation of devices that exercise individual forelimb joints. We tested the hypothesis that grasping during the reach-to-grasp is necessary for eliciting high discharge modulation. 2. Three monkeys (Macaca mulatta) moved an articulated lever between low and high target zones. While in the lower zone the monkey's hand was at its waist, in the upper zone its hand was in a position that required forelimb extension at right-angles to the body axis. Small drawers adjacent to the target zones contained raisins, and the drawers could be remotely opened. Thus, we could elicit two types of reaches having similar trajectories: one reach involved limb transport while holding the lever handle, and the other involved limb transport while forming the hand to grasp a raisin. 3. Eighty-one neurones from two monkeys, mostly from interpositus with some from adjacent regions of dentate, were tested during device use and reaching to grasp: 93% of the neurones discharged at high rates during at least one of the tasks. Of these, about half increased discharge rate solely during reaching to grasp; the other half showed some increase during device use but only discharged strongly during reaching to grasp. Overall, discharge modulations during the reach-to-grasp averaged twice as high as during the corresponding device movement (112 versus 56 impulses s-1). 4. Individual neurones consistently discharged with characteristic patterns during the reach-to-grasp with rates often exceeding 300 impulses s-1. Discharge during the reach-to-grasp was independent of reach trajectory: discharge patterns and amplitudes were similar when reaching from either the lower or upper target zone to the upper raisin drawer as when reaching from the upper target zone to the upper raisin drawer. Reach direction also made little difference: reaches from the upper target zone to the lower drawer typically elicited similar discharge modulation as those from the lower target zone to the upper drawer. 5. High discharge rates associated with grasping were independent of the item being grasped: typically, grasping the device handle elicited as high discharge rates as grasping a raisin. 6. The hypothesis was confirmed that grasping is critical for eliciting high discharge modulation in interpositus during reaching to grasp. Discharge pattern and modulation do not vary with reach direction or amplitude of the reach and, therefore, it is unlikely that intermediate cerebellum controls these features of the reach-to-grasp.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7853222 TI - Non-monosynaptic transmission of the cortical command for voluntary movement in man. AB - 1. The possibility was investigated that, in man, some of the descending command for tonic voluntary wrist extension is transmitted to extensor motoneurones over a non-monosynaptic pathway. 2. Stimulation of the cutaneous superficial radial nerve at 3 times perceptual threshold depressed the electromyogram (EMG) of extensor carpi radialis (ECR) and the discharge of single ECR motor units, both with a mean central delay of 4.2 ms. Such stimuli depressed the response to transcranial magnetic stimulation of the motor cortex, but had little effect on the H reflex. 3. The possibility that the relative sparing of the H reflex was due to an alteration in transmission of the afferent volley for the H reflex was excluded. 4. The central latency of the cutaneous-induced depression of the discharge of single motor units in biceps brachii (C5-C6) was shorter by about 1 ms than that of the more caudal wrist and finger extensor motor units. This suggests that the locus for the cutaneous-induced effects was spinal but above the cervical enlargement. 5. The pattern of EMG depression (evoked by superficial radial but not palmar stimuli, in wrist extensors but not wrist flexors) is that previously described for the presumed propriospinal system of human subjects. 6. It is concluded that a significant component of the voluntary command for tonic wrist extension reaches the relevant motoneurone pool via a non-monosynaptic pathway. It is suggested that the interposed neurones could be C3-C4 propriospinal neurones. PMID- 7853223 TI - Local, stochastic release of Ca2+ in voltage-clamped rat heart cells: visualization with confocal microscopy. AB - 1. Confocal microscopy and the fluorescent Ca2+ indicator fluo-3 (K+ salt) were used to measure cytosolic free calcium ion concentration ([Ca2+]) during excitation-contraction (E-C) coupling in single, voltage-clamped, rat cardiac ventricular cells. 2. Local [Ca2+]i transients were measured nearly simultaneously in different, separate, subcellular volumes of approximately 2.0 microns 3. During depolarization, local [Ca2+]i transients were distinctly different from each other and from whole-cell [Ca2+]i transients. These differences were particularly apparent during small depolarizations, and were substantially reduced by ryanodine. 3. Components of the local [Ca2+]i transients, particularly those evoked by small depolarizations, were closely similar, in time course and amplitude, to spontaneous local [Ca2+]i transients, or 'sparks' (which have been shown previously to be Ca2+ released from sarcoplasmic reticulum). 4. Analysis of local [Ca2+]i transients in the spatial frequency domain (power spectrum) revealed that high power at spatial frequencies of 0.05-0.2 microns-1 was always associated with spontaneous calcium 'sparks' and with local [Ca2+]i transients evoked by small depolarizing pulses (e.g. to -31 mV). Evoked local [Ca2+]o transients in the presence of ryanodine, and those evoked by depolarization to very positive clamp-pulse potentials (+45 mV), were associated with considerably lower power at this frequency. 5. The results suggest that whole-cell [Ca2+]i transients evoked by voltage-clamp depolarization, and thus by L-type Ca2+ current, are comprised of local [Ca2+]i transients that are similar to the spontaneous calcium 'sparks'. At very positive clamp-pulse potentials, however, the electrically evoked local [Ca2+]i transients may be smaller, perhaps as a result of smaller unitary L-type Ca2+ current. PMID- 7853224 TI - Relaxation, [Ca2+]i and [Mg2+]i during prolonged tetanic stimulation of intact, single fibres from mouse skeletal muscle. AB - 1. In skeletal muscle there is generally a slowing of relaxation with increasing tetanus duration and it has been suggested that this is due to Ca2+ loading of parvalbumin (PA). To study this we have produced prolonged tetani in intact, single fibres from a mouse foot muscle which contain a high concentration of PA. We measured the rate of tension relaxation and also various aspects of Ca2+ handling. 2. During 'interrupted' tetani (15 repeated cycles of 100 ms with stimulation and 50 ms without) we observed a marked slowing of the relaxation both under control conditions and in acidosis (obtained by increasing the bath CO2 content). This slowing was not accompanied by any reduction of the initial rate of decline of the free myoplasmic Ca2+ concentration ([Ca2+]i), which was measured with indo-1. 3. The functioning of the sarcoplasmic reticulum (SR) pump after tetani of various durations was analysed by plotting d[Ca2+]i/dt vs. [Ca2+]i during the final slow decline of [Ca2+]i after tetani. This analysis showed that the rate of SR Ca2+ pumping after a 1 s tetanus is less than half of that after a 100 ms tetanus. 4. The amplitude of the tail of [Ca2+]i 250 ms into relaxation was measured after tetani of various durations. This amplitude increased with tetanus duration and could be fitted to the sum of one exponential and one linear function. The exponential component increased with a time constant of 0.17 s and probably reflects Ca2+ loading of PA. 5. Ca2+ binding to PA will displace Mg2+ and hence the free myoplasmic concentration of Mg2+ ([Mg2+]i) will increase. To study this we used the fluorescent Mg2+ indicator furaptra. The results showed an increase of [Mg2+]i during prolonged tetani which, after removing the Ca2+ component of the fluorescent signal, amounted to about 0.5 mM. 6. A model of Ca2+ movements and tension production in skeletal muscle was used. The model showed that the increase of the amplitude of [Ca2+]i tails after tetani of various durations can be explained by the combined effect of Ca2+ loading of PA and slowed SR Ca2+ pumping. In contrast to the experimental data, the model predicted a slight reduction of the initial rate of [Ca2+]i decline with increased tetanus duration. 7. In conclusion, we observed a marked slowing of relaxation during prolonged tetanic stimulation. Altered Ca2+ handling, including Ca2+ loading of PA, seems not to be important for this slowing. Thus, the slowing appears to be due to altered cross-bridge kinetics. PMID- 7853225 TI - The role of troponin C in modulating the Ca2+ sensitivity of mammalian skinned cardiac and skeletal muscle fibres. AB - 1. We investigated the effects of acidosis, inorganic phosphate (Pi) and caffeine on the Ca2+ affinity of isolated fast-twitch skeletal and cardiac troponin C (TnC), labelled with fluorescent probes to report Ca2+ binding to the regulatory sites. We also measured the effects of these interventions on the maximum force development and the Ca2+ sensitivity of skinned fibres from fast-twitch skeletal muscle and cardiac muscle, as has been done previously. The two types of experiment were carried out under similar solution conditions, so that we could assess the contribution of any direct actions on TnC to the modulation of Ca2+ sensitivity in the skinned muscle fibres. 2. In skinned fibres, acidosis (decreasing pH from 7.0 to 6.2) and Pi (20 mM) suppressed maximum force to the same extent within a given muscle type, but had greater effects on cardiac fibres compared with skeletal fibres. Caffeine (20 mM) depressed maximum force equally in cardiac and skeletal muscle. Thus, the fall of force induced by acidosis or Pi may involve a different mechanism from that induced by caffeine. 3. Skinned skeletal fibres were more Ca2+ sensitive than cardiac fibres by 0.29 pCa units (pCa = -log10[Ca2+]). Isolated skeletal TnC also had a greater Ca2+ affinity than cardiac TnC, by 0.20 pCa units. These results suggest that the Ca2+ sensitivity of skinned fibres is at least partly determined by the type of TnC present. 4. Acidosis reduced the Ca2+ sensitivity of force in skinned fibres profoundly and had a 2-fold greater effect in cardiac muscle than skeletal muscle (falls in pCa for 50% activation, pCa50, were 1.09 and 0.55, respectively). Acidosis also reduced the Ca2+ affinity of TnC, again having double the effect on the pCa50 for cardiac TnC (0.58) as on that for skeletal TnC (0.28). The greater effect of acidosis on cardiac skinned fibres, compared with skeletal, may be partly explained, therefore, by the type of TnC present, and one-half of the effect on fibres may be attributed to the direct effect of H+ on TnC. 5. Pi reduced the Ca2+ sensitivity of force in skeletal and cardiac skinned fibres by 0.30 and 0.19 pCa units, respectively. However, the Ca2+ affinity of isolated cardiac and skeletal TnC was unaffected by Pi, indicating that the decrease in muscle Ca2+ sensitivity is not mediated by a direct action of Pi on TnC. 6. Caffeine increased the Ca2+ sensitivity of cardiac skinned fibres by 0.31 pCa units, which was 3 times greater than for the skeletal fibres (0.09 pCa units).(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7853226 TI - Calcium dependence of quantal secretion from visualized sympathetic nerve varicosities on the mouse vas deferens. AB - 1. The effects of calcium on the secretion of quanta recorded from single varicosities on the surface of the mouse vas deferens has been determined. 2. If recordings were made from two adjacent varicosities and the [Ca2+]o increased from a low value (1 mM), then the increase in the mean quantal content of the endplate potential (m(e)) was almost entirely due to an increase in the binomial probability for secretion (pe). At higher [Ca2+]o there was an increasing tendency for the binomial parameter (ne) to increase from 1 to 2. When ne increased there was very little change in pe, indicating that the new release site recruited from the other varicosity has a relatively low probability for secretion. 3. If recordings were restricted to single varicosities and the [Ca2+]o increased in the range from 1 to 4 mM then the increases in m(e) were almost always due to an increase in pe. The gradient relating the log of m(e) to the log of [Ca2+]o for [Ca2+]o of 1.0-1.5 mM was in the range 3.2-5.4 (mean 4.2). 4. Test impulses gave a similar proportional increase in m(e) following a conditioning impulse at all varicosities from which recordings were made. 5. Facilitation of m(e) declined exponentially with an increase in the test conditioning interval from 0.5 to 4 s. The time constant for this decline was about 6 s. 6. The results indicate that single release sites show a similar fourth power dependency on [Ca2+]o and facilitate to about the same degree following a conditioning impulse. PMID- 7853227 TI - The actions of extracellular H+ on the electrophysiological properties of isolated human detrusor smooth muscle cells. AB - 1. The influence of extracellular pH changes on intracellular pH and [Ca2+], as well as on L-type Ca2+ currents, has been investigated in isolated human detrusor smooth muscle cells. 2. Alteration of extracellular pH by changing superfusate PCO2 also changed intracellular pH. A change of superfusate pH made by altering the [NaHCO3] at constant PCO2 was not reflected in a change in intracellular pH. 3. Extracellular acidosis attenuated the magnitude and rate of change of intracellular [Ca2+] evoked by raising the extracellular [KCl]. 4. Extracellular acidosis attenuated the rate of rise and amplitude of the action potential, as well as the magnitude of the L-type Ca2+ current. In the pH range 6.78-7.62 no alteration to the voltage dependence of Ca2+ current activation or inactivation was recorded. 5. A close proportional relationship between tension generated by multicellular strips and the magnitude of peak inward Ca2+ current in isolated cells was noted over a wide range of the two variables using a number of interventions, including alteration to extracellular pH, [Ca2+] and [Mg2+]. 6. Extracellular acidosis attenuated the magnitude of caffeine-dependent intracellular Ca2+ transients and the resting [Ca2+]i between transients. Acidosis was without effect on the rise of [Ca2+]i induced by carbachol. 7. The results suggest that the negative inotropic effect of extracellular acidosis can be accounted for by attenuation of the L-type Ca2+ current. The results also imply that intracellular stores are influenced by transmembrane Ca2+ fluxes at rest and that such fluxes are also attenuated by extracellular H+. PMID- 7853228 TI - M1 muscarinic receptor-mediated facilitation of acetylcholine release in the rat urinary bladder. AB - 1. Release of [3H]ACh in response to electrical field stimulation (10 Hz) was measured in strips of rat urinary bladder and cardiac atrial tissues previously incubated with [3H]choline. 2. The volley output of [3H]ACh release was positively correlated with frequency of stimulation in the urinary bladder but negatively correlated in the atrium. 3. The quantity of [3H]ACh release was influenced by the pattern and duration of stimulation. Continuous stimulation (CS) with trains of 100 shocks released 10 times larger amounts of ACh than the same number of shocks presented as short trains of intermittent stimulation (IS): ten shocks per train with 5 s inter-train intervals. 4. The facilitation of transmitter release was antagonized completely by the administration of atropine (1 microM) or pirenzepine (0.05 microM), a selective M1 antagonist. Eserine, an anticholinesterase agent, markedly facilitated ACh release induced by CS and IS. This effect was blocked by atropine. 5. Release of ACh from atrial strips did not exhibit CS-induced facilitation. Eserine decreased IS- and CS-evoked ACh release in the atrium. 6. It is concluded that continuous stimulation of postganglionic cholinergic nerves in the rat urinary bladder leads to the activation of M1 muscarinic, facilitatory presynaptic receptors which enhance the release of ACh. Presynaptic facilitation may be an important mechanism for modulating neural input to the bladder during micturition. PMID- 7853229 TI - The action of Na+ as a cofactor in the inhibition by cytoplasmic protons of the cardiac Na(+)-Ca2+ exchanger in the guinea-pig. AB - 1. Na(+)-Ca2+ exchange current was activated in giant excised patches of guinea pig cardiac sarcolemma by raising the intracellular sodium concentration ([Na+]i). When the pHi was simultaneously acidified to 6.4, the current was transient, dropping by 80% in 30 s. 2. Pre-exposure to a pHi of 6.4 for 15 s reduced the peak Na(+)-Ca2+ exchange current without altering the decay rate or steady-state current. Recovery from proton inhibition was seen when [Na+]i was removed for 9 s. 3. A mathematical model of Na(+)-Ca2+ exchange function reproduced the experimental results. In addition, two model-dependent predictions were seen experimentally. (i) [Na+]i-dependent 'inactivation' of Na(+)-Ca2+ exchange may arise from pHi effects. We observed experimentally that pre-exposure to acidic pHi can remove the transient current component attributed to [Na+]i dependent 'inactivation'. (ii) self-exchange should be inhibited by acidification. This has been observed by other investigators. 4. We have hypothesized that there are two components to inhibition of the Na(+)-Ca2+ exchanger by intracellular protons, and that one is enhanced by increased [Na+]i (Doering & Lederer, 1993b). This hypothesis is supported by the data presented here and by a model of Na(+)-Ca2+ exchange behaviour in which binding of intracellular sodium to the exchanger enhances the affinity of the exchanger for inhibitory intracellular protons. PMID- 7853230 TI - Mutation of the proto-oncogene c-kit blocks development of interstitial cells and electrical rhythmicity in murine intestine. AB - 1. Interstitial cells of Cajal (ICs) have been proposed as pacemakers in the gastrointestinal tract. We studied the characteristics and distribution of ICs and electrical activity of small intestinal muscles from mice with mutations at the dominant-white spotting/c-kit (W) locus because the tyrosine kinase function of c-kit may be important in the development of the IC network. 2. W/WV mutants (days 3-30 postpartum) had few ICs in the myenteric plexus region compared with wild type (+/+) siblings. The few ICs present were associated with neural elements and lay between myenteric ganglia and the longitudinal muscle layer. 3. Electrical recordings from intestinal muscle strips showed that electrical slow waves were always present in muscles of +/+ siblings, but were absent in W/WV mice. 4. Muscles from W/WV mice responded to stimulation of intrinsic nerves. Neural responses, attributed to the release of acetylcholine, nitric oxide and other unidentified transmitters, were recorded. 5. These findings are consistent with the hypothesis that ICs are a critical element in the generation of electrical rhythmicity in intestinal muscles. The data also show that neural regulation of gastrointestinal muscles can develop independently of the IC network. 6. W locus mutants provide a powerful new model for studies of the physiological role of ICs and the significance of electrical rhythmicity to normal gastrointestinal motility. PMID- 7853231 TI - Phenylalanine transport in rabbit small intestine. AB - 1. The proposal that rabbit small intestine possesses a separate, sodium dependent carrier of phenylalanine has been examined by measurements of the unidirectional influx of amino acids across the brush-border membrane of the intact epithelium of the rabbit small intestine. 2. We demonstrate that, like alanine, glycine and leucine, phenylalanine shares sodium-dependent as well as sodium-independent transport with lysine. 3. Using the distal ileum we applied the A (phenylalanine)-B (leucine)-C (alanine) test on the sodium-dependent, lysine-resistant transport of phenylalanine. For phenylalanine, K1/2 (concentration required for half-maximal transport) was 3.1 +/- 0.2 mM (n = 7) and Ki (inhibitor constant) against leucine transport was 3.1 +/- 0.2 mM (n = 4). For leucine, K1/2 was 1.1 +/- 0.1 mM (n = 4) and Ki against transport of phenylalanine was 1.1 +/- 0.1 mM (n = 4). For alanine, K1/2 was 12.6 +/- 1.1 mM (n = 3), Ki against phenylalanine was 13.1 +/- 1.8 mM (n = 4) and Ki against leucine was 11.0 +/- 0.4 mM (n = 4). 4. Using the jejunum we applied the A (phenylalanine)-B (alanine)-C (methionine) test on the lysine-resistant, sodium dependent transport of phenylalanine. For phenylalanine, K1/2 was 4.7 +/- 0.2 mM (n = 7) and Ki against alanine was 4.8 +/- 0.2 mM (n = 4). For alanine, K1/2 was 15.6 +/- 0.8 mM (n = 7) and Ki against phenylalanine was 18.1 +/- 0.9 mM (n = 5).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7853232 TI - Evidence that glial cells modulate extracellular pH transients induced by neuronal activity in the leech central nervous system. AB - 1. The role of the giant neuropile glial cells in the buffering of activity related extracellular pH changes was studied in segmental ganglia of the leech Hirudo medicinalis L. using pH-sensitive microelectrodes and a slow, two electrode voltage-clamp system. Neuronal activity was induced by electrical stimulation of a ganglionic side nerve (20 Hz, 1 min). 2. In CO2-HCO3(-)-buffered saline the glial cells were depolarized by 6.5 +/- 2.3 mV and alkalinized by 0.024 +/- 0.006 pH units (mean +/- SD) during the stimulation. The stimulation induced an acidification of 0.032 +/- 0.006 pH units in the extracellular spaces (ECS). 3. Voltage clamping the glial cells suppressed the stimulus-induced glial depolarization and turned the intraglial alkalinization into an acidification of 0.045 +/- 0.021 pH units (n = 6) that closely resembled the acidification observed in the presence of the anion transport blocker DIDS (4,4' diisothiocyanatostilbene-2,2'-disulphonic acid, 0.5 mM), and in CO2-HCO(3-)-free saline. 4. Voltage clamping the glial cell resulted in the appearance of a distinct stimulus-induced extracellular alkalinization of 0.024 +/- 0.013 pH units at the onset of the stimulation, as also observed during DIDS application and in the absence of CO2-HCO3-. 5. The results suggest that glial uptake of bicarbonate is mediated by depolarization-induced activation of the electrogenic Na(+)-HCO3- cotransport, which suppresses the profound alkalinization of the ECS during neuronal activity. This is the first direct evidence the glial cells actively modulate extracellular pH changes in a voltage-dependent manner. PMID- 7853233 TI - Dependence of ATP consumption on cross-bridge phosphorylation in swine carotid smooth muscle. AB - 1. Ca(2+)-dependent phosphorylation of the myosin regulatory light chain (MRLC) initiates cross-bridge cycling and contraction in smooth muscle. A four-state cross-bridge model, in which Ca(2+)-dependent phosphorylation is the only proposed regulatory mechanism, can predict the mechanical output of the swine carotid media. Our aims were to determine whether ATP consumption rates and the economy of force maintenance are regulated functions of MRLC phosphorylation as predicted by the model. 2. Steady-state force and oxygen consumption were measured in medial rings of swine carotid arteries activated with depolarizing solutions and agents capable of maintaining a wide range of steady-state myoplasmic Ca2+ and MRLC phosphorylation levels. 3. Suprabasal ATP consumption increased almost linearly with MRLC phosphorylation and exhibited a hyperbolic increase with active stress, as predicted. 4. The economy of stress maintenance fell with increases in suprabasal phosphorylation. 5. In absolute terms the energetic cost of covalent regulation by cross-bridge phosphorylation was small, although it may be a significant fraction of the ATP consumption associated with contraction. PMID- 7853234 TI - Fluo-3 signals associated with potassium contractures in single amphibian muscle fibres. AB - 1. The calcium-sensitive dye fluo-3 AM was used to obtain fluorescence signals and calcium transients associated with K+ contractures, twitches and tetani, in intact single muscle fibres of the tropical toad Leptodactylus insularis. 2. The changes in free calcium concentration in the myoplasm ([Ca2+]i) were calculated using the values of the 'off' (k- = 33.5 s-1) and 'on' (k+ = 13.1 microM-1 s-1) rate constants for the binding of calcium to the dye (dissociation constant, Kd = k-/k+). The mean (+/- S.E.M., n = 7) peak [Ca2+]i value during twitches or tetani was 3.9 +/- 0.3 or 4.1 +/- 0.3 microM, respectively, while during maximal K+ contractures, it was 10.3 +/- 0.8 microM. The threshold [Ca2+]i for tension development was about 1 microM. 3. For responses elicited with high [K+]o (80-190 mM), the calcium transients decayed faster than tension. At lower [K+]o (30-70 mM), the decay was slower, and relaxation was complete when [Ca2+]i was still above contractile threshold values. 4. Following a K+ contracture, recovery of the calcium transients associated with twitches occurred before recovery of tension, indicating an apparent dissociation between [Ca2+]i and tension output. This apparent dissociation between calcium and tension output could be attributed to the desensitization of the contractile proteins to calcium, or, more probably, to the non-uniform behaviour of calcium release and/or uptake sites, leading to an unhomogeneous distribution of active sarcomeres along the fibre length and localized sarcomere relaxation. PMID- 7853235 TI - Aminophylline enhances resting Ca2+ concentrations and twitch tension by adenosine receptor blockade in Rana pipiens. AB - 1. We hypothesized that the xanthine aminophylline acts to block adenosine receptors on the surface of skeletal muscle fibres, thereby inhibiting a depressant action of endogenous adenosine. We further hypothesized that this action results in increased concentrations of intracellular resting Ca2+ and enhanced twitch tension upon muscle stimulation. 2. Peak twitch tension (Pt) of the semitendinosus muscle in normal frog Ringer solution (NFR) ranged from 6.8 to 9.4 g. Intracellular Ca2+ concentrations in control resting fibres ranged from 67 to 70 nM. Aminophylline at 100 microM produced increases of 26 and 22% in Pt and Ca2+ concentrations, respectively. 3. The adenosine receptor antagonists 8 phenyltheophylline (8-PT) and 1,3-dipropyl-7-methylxanthine (1,3-d-7-M) both increased Pt by 32% over values in NFR. In addition, 1,3-d-7-M increased resting Ca2+ concentrations by 29% over control levels. 4. Adenosine deaminase increased twitch tension and resting intracellular Ca2+ concentrations by 22 and 26% over controls, respectively. 5. N6-(2-phenylisopropyl)adenosine (R-PIA, 1 microM), a potent adenosine analogue, partially blocked both the increase in Pt and intracellular Ca2+ concentrations induced by the xanthines, possibly by competing for the adenosine receptor. 6. The data herein provide support for the existence of adenosine receptors on the membranes of skeletal muscle fibres and suggest a possible role for adenosine receptors in the regulation of twitch tension. PMID- 7853237 TI - Effects of thyroid hormone on fast- and slow-twitch skeletal muscles in young and old rats. AB - 1. The effects of 4 weeks of thyroid hormone treatment on contractile, enzyme histochemical and morphometric properties and on the myosin isoform composition were compared in the slow-twitch soleus and the fast-twitch extensor digitorum longus (EDL) muscle in young (3-6 months) and old (20-24 months) male rats. 2. In the soleus of untreated controls, contraction and half-relaxation times of the isometric twitch increased by 19-32% with age. The change in contractile properties was paralleled by an age-related increase in the proportions of type I fibres and type I myosin heavy chain (MHC) and slow myosin light chain (MLC) isoforms. 3. In the EDL of controls, contraction and half-relaxation times were significantly prolonged (21-38%) in the post-tetanus twitch in the old animals. No significant age-related changes were observed in enzyme-histochemical fibre type proportions, although the number of fibres expressing both type IIA and IIB MHCs and of fibres expressing slow MLC isoforms was increased in the old animals. 4. Serum 3,5,3',5'-tetraiodothyronine (T4) levels were lower (34%) in the old animals, but the primary byproduct of T4, 3,5,3'-triiodothyronine (T3), did not differ between young and old animals. 5. The effects of 4 weeks of thyroid hormone treatment were highly muscle specific, and were more pronounced in soleus than in EDL, irrespective of animal age. In the soleus, this treatment shortened the contraction and half-relaxation times by 35-57% and decreased the number of type I fibres by 66-77% in both young and old animals. In EDL, thyroid hormone treatment significantly shortened the contraction time by 24%, but the change was restricted to the old animals. 6. In conclusion, the ability of skeletal muscle to respond to thyroid hormone treatment was not impaired in old age and the age related changes in speed of contraction and enzyme-histochemical properties and myosin isoform compositions were diminished after thyroid hormone treatment in both the soleus and EDL. PMID- 7853236 TI - Lactate efflux from fatigued fast-twitch muscle fibres of Xenopus laevis under various extracellular conditions. AB - 1. Isolated, fast-twitch, low-oxidative muscle fibres from the iliofibularis muscle of Xenopus laevis were fatigued by intermittent tetanic stimulation at 20 degrees C in different Ringer solutions and the amount of lactate released was determined. 2. The rate of lactate efflux was constant during 10 min of intermittent stimulation while lactate in the fibres accumulated, and lactate efflux was not hampered by an unstirred layer surrounding the isolated muscle fibre. 3. The rate of lactate efflux at extracellular pH 7.2 was the same as that at pH 7.8, but depended on the type of buffer used; the highest efflux rate (mean +/- S.E.M., 7.4 +/- 2.2 mumol min-1 (g dry weight)-1, n = 8) was observed in bicarbonate-buffered Ringer solution. This rate was about 2.5 times higher than the rate in phosphate-buffered Ringer solution (2.9 +/- 1.3 mumol min-1 (g dry weight)-1, n = 8), indicating that lactate-bicarbonate exchange is the most important route for lactate extrusion in vivo. 4. The highest rate of lactate efflux corresponds to a rate of glycolytic ATP production which is only about 30% of the oxidative rate of ATP production (calculated from the maximum rate of oxygen consumption determined previously). 5. In the presence of 5 mM alpha-cyano 4-hydroxycinnamate (CHC) the lowest lactate efflux rate (1.5 +/- 0.6 mumol min-1 (g dry weight)-1, n = 16) was found. This rate was independent of the composition of the Ringer solution. Assuming that 5 mM CHC completely inhibits lactate transporters in the sarcolemma, the rate of lactate efflux in the presence of 5 mM CHC can be explained by passive diffusion, but only if most lactate is extruded via the T-tubules. PMID- 7853239 TI - Effects of increased and decreased tissue pressure on haemodynamic and capillary events in cat skeletal muscle. AB - 1. The controversial problem concerning the unusual haemodynamics of the deranged circulation during increased hydrostatic tissue pressure (PT) was elucidated by detailed studies of arterial, capillary and venous functions in cat skeletal muscle exposed to graded experimental changes of PT over a wide range. 2. The results indicated that the impaired circulatory state in skeletal muscle during raised tissue pressure is characterized by the following train of events: (a) a primary partial passive compression of the most distal part of the venous system due to negative vascular transmural pressure selectively at this site, in turn leading to the prompt development of a distinct 'venous outflow orifice resistance' graded in relation to the PT rise; (b) a consequent reduction of blood flow graded in relation to this resistance increase; (c) a rise in intramuscular venous pressure proximal of the 'venous outflow orifice' by the same extent as the PT increase; (d) transmission of the raised venous pressure to more proximal vessels in relation to the prevailing segmental resistance ratios; (e) a consequent maintenance of clearly positive transmural pressures in all vascular sections proximal to the 'venous outflow orifice', preventing collapse of these vessels; (f) maintenance of a largely normal capillary filtration coefficient and functional capillary surface area; and (g) an increase in capillary pressure by approximately 85% of the PT rise which reduces the rate of net transcapillary fluid absorption to about one-seventh of that expected from the PT rise per se. 3. Previous concepts of a 'vascular waterfall phenomenon', a capillary collapse, or an arteriolar 'critical closure phenomenon' did not seem to be valid for the skeletal muscle circulation during increased PT. 4. The rate of net transcapillary fluid flux per unit PT change was much smaller during positive than negative PT, since capillary pressure rose considerably when PT was increased above control, but was largely unchanged when PT was decreased below control. 5. Possible ways to improve the circulatory state in conditions with an oedema-induced tissue pressure rise are discussed. PMID- 7853238 TI - Oxygen deprivation inhibits a K+ channel independently of cytosolic factors in rat central neurons. AB - 1. K+ channel modulation has been shown to be an integral and important cellular response to O2 deprivation. Although part of this modulation occurs as a result of changes in concentrations of several cytosolic factors such as ATP and Ca2+, it is unknown whether there are mechanisms other than those originating from the cytosol. To test the hypothesis that membrane-delimited mechanisms participate in the O2-sensing process and are involved in the modulation of K+ channel activity in central neurons, we performed experiments using patch-clamp techniques and dissociated cells from the rat neocortex and substantia nigra. 2. Whole-cell outward currents were studied in voltage-clamp mode using Na(+)-free or low-Na+ (5 mM, with 1 microM tetrodotoxin) extracellular medium plus 0.5 mM Co2+. O2 deprivation produced a biphasic response in current amplitude, i.e. an initial transient increase followed by a pronounced decrease in outward currents. The reduction in outward currents was a reversible process since perfusion with a medium of PO2 > 100 mmHg (1 mmHg = 133 Pa) led to a complete recovery. 3. In cell free excised membrane patches, we found that a specific K+ current (large conductance, inhibited by micromolar concentrations of ATP and activated by Ca2+) was reversibly inhibited by lack of O2. This was characterized by a marked decrease in channel open-state probability and a slight reduction in unitary conductance. The magnitude of channel inhibition by O2 deprivation was closely dependent on O2 tension. The PO2 level for 50% channel inhibition was about 10 mmHg with little or no inhibition at PO2 > or = 20 mmHg. 4. Single-channel kinetic analysis showed that channel open times consisted of two components and closed times were composed of three. The hypoxia-induced inhibition of K+ channel activity was mediated by selective suppression of the longer time constant channel openings without significantly affecting closed time constants. This led to an increase in frequency of opening and closing and rapid channel flickerings. 5. Our data showed that O2 deprivation had no effect on another K+ current characterized by a much smaller conductance and Ca2+ independence. This provides evidence for the selective nature of the hypoxia-induced inhibition of some species of K+ channels. 6. These results therefore provide the first evidence for regulation of K+ channel activity by O2 deprivation in cell-free excised patches from central neurons. PMID- 7853240 TI - Static sensitivity of tendon organs to tetanic contraction of in-series motor units in feline peroneus tertius muscle. AB - 1. The results of several studies have indicated an absence of any consistent relationship between the discharge of Ib Golgi tendon organ afferents and the steady-state tetanic tension generated by activating motor units. This question has been re-examined by recording the responses of individual tendon organs to tetanic, isometric contractions of one or more motor units from the peroneus tertius muscle of anaesthetized cats. 2. In three experiments, seventy-three individual tendon organ-motor unit interactions were recorded. The motor units were stimulated at 30-150 s-1 and for each tendon organ-motor unit pair a linear relationship was found between steady-state tetanic tension and Ib afferent discharge. The slopes of these relationships (the static sensitivities) were steepest for the weakest units. 3. When motor units were stimulated in combination, the relationship between discharge frequency and plateau tension was again linear but the static sensitivities were generally much lower than for single units and approached 1 impulse s-1 g-1. 4. Expression of these relationships in terms of the relative tensions generated revealed that the tendon organs were activated most strongly by the IIb muscle fibres, the static sensitivities being reduced by unloading effects. 5. The linear relationships observed during stimulation of single, and groups of, motor units suggest that the patterns of discharge from the tendon organs can mirror the steady-state contractile tensions within the muscle. PMID- 7853242 TI - Mediation of baroreceptor inhibition of sympathetic nerve activity via both a brainstem and spinal site in rats. AB - 1. The possible involvement of a spinal site of sympatho-inhibitory action in the baroreceptor reflex pathways was investigated by determining the effect of phenylephrine-induced, baroreceptor-mediated inhibition on a spinally evoked excitatory response of renal nerve activity before, during and after removal of tonic descending excitatory drive from the rostral ventrolateral medulla (RVLM). 2. Stimulation of descending excitatory axons at the C4 vertebral level evoked a highly reproducible excitatory response (mean variance, 2.2 +/- 0.6%) in a renal sympathetic nerve with a latency of 72 +/- 5.7 ms and duration of 211 +/- 32 ms. 3. Following baroreceptor activation, the magnitude of this spinally evoked response was reduced by 33.5 +/- 4.2% compared with control spinal response. 4. To remove tonic descending excitatory drive, glycine was microinjected bilaterally into the RVLM (RVLM block); this briefly and reversibly abolished spontaneous sympathetic nerve activity. 5. Following RVLM block, the spinally evoked response in a renal sympathetic nerve was inhibited by 16.9 +/- 4.4% during baroreceptor activation. 6. Intrathecal administration of the glycine antagonist strychnine to the lower thoracic segments of the spinal cord virtually abolished this inhibition. 7. It was concluded that baroreceptor inhibition of sympathetic activity occurs at a spinal site as well as a supraspinal one. Glycine is a likely mediator of the inhibition at the spinal site. PMID- 7853241 TI - Effect of inhibitors of nitric oxide release and action on vascular tone in isolated lungs of pig, sheep, dog and man. AB - 1. The actions of inhibitors of the release or action of nitric oxide (NO) on pulmonary vascular resistance (PVR) were investigated in lungs isolated from pig, sheep, dog and man. 2. In pig, sheep and human lungs perfused with Krebs-dextran solution, both N omega-nitro-L-arginine methyl ester (L-NAME; 10(-5) M) and Methylene Blue (10(-4) M) increased basal PVR. This increase was reversed by sodium nitroprusside (10(-5) M). In pig lungs N omega-monomethyl-L-arginine (10( 4) M) increased PVR by 154%. This increase was partially reversed by L-arginine (10(-3) M). L-NAME had no effect in dog lungs. 3. Pulmonary artery pressure-flow (PPA/Q) relationships were studied over a wide range of flows. In pigs, sheep and human lungs perfused with Krebs-dextran solution, L-NAME increased the PPA/Q slope. This increase was reversed by sodium nitroprusside. In dog lungs L-NAME had no effect. 4. In blood-perfused lungs, the respective responses to L-NAME were similar to those observed with saline. Acute hypoxia in pig and dog lungs increased intercept pressure. Addition of L-NAME during hypoxia increased the PPA/Q slope in both species. 5. In the human, there was no difference in the absolute increase of PVR or PPA/Q slope elicited by L-NAME between hypertensive and control lungs. 6. We conclude that NO is continuously released in the pulmonary vascular bed of pig, sheep and humans under normoxic conditions. In dog lungs inhibition of NO synthesis increases PVR only under hypoxic conditions. In human lungs with pulmonary hypertension, NO is still released under basal conditions. PMID- 7853243 TI - Regional alternans in relaxation and the onset of pulsus alternans in the heart of the anaesthetized pig. AB - 1. The factors leading to the alternation in myocardial contractility believed primarily responsible for pulsus alternans are not known. We examine regional and global contraction patterns in the in situ heart at stimulation rates just below the threshold for pulsus alternans to determine if events occurring in the transition to alternans can give clues to cellular mechanisms. 2. Twelve pigs were anaesthetized, the chest wall removed and regional contraction measured in three areas of the left ventricle using tripodal strain gauges. We analysed regional and global dynamics during right atrial pacing at cycle lengths 50-150 ms greater than the threshold for pulsus alternans. 3. At pacing cycle lengths 50 ms greater than that required to produce pulsus alternans seven of twelve pigs showed alternans in the maximum rate of ventricular pressure decay but none showed alternans in the maximum rate of pressure rise. Pigs showing alternans in global relaxation were more likely to show alternans in regional contracility (P < 0.05). 4. Twenty-six of the thirty-six areas sampled showed alternans in end diastolic length at pacing rates below the threshold for pulsus alternans. In fifteen of these areas alternation in end-diastolic length occurred in the absence of alternans in measures of contractility. 5. Alternans in global measures of relaxation may simply be a manifestation of regional alternans in contractility. It is therefore not appropriate, from global haemodynamic data, to suppose that alternans in relaxation is the primary abnormality in the generation of pulsus alternans.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7853244 TI - Proximal tubular cell electrolytes during volume expansion in the rat. AB - 1. Proximal tubular intracellular elements were measured by electron microprobe X ray analysis (a) in rats volume-expanded with albumin-saline in which peritubular oncotic pressure remained normal and (b) in rats in which the renal artery was snared before volume expansion (the early snare model). Glomerular filtration rate and urine Na+ excretion were measured in addition to intracellular Rb+ following a 30 s infusion of RbCl as a marker for K+ transport. 2. In albumin saline volume-expanded rats, intracellular levels of Na+ ([Na+]i) at 21.5 +/- 0.6 mmol (kg wet wt)-1, Cl- ([Cl-]i) at 18.0 +/- 0.4 mmol (kg wet wt)-1 and Rb+ ([Rb+]i) at 9.4 +/- 0.4 mmol (kg wet wt)-1 were significantly higher (P < 0.0001) than the levels in non-expanded rats ([Na+]i, [Cl-]i and [Rb+]i at 17.7 +/- 0.4, 14.6 +/- 0.3 and 4.7 +/- 0.4 mmol (kg wet wt)-1, respectively; means +/- S.E.M.). The data are consistent with Na+ pump inhibition in the proximal tubule, although this cannot be directly derived from intracellular element measurements. 3. In an early snare model of volume expansion, [Na+]i, intracellular K+ ([K+]i) and [Rb+]i remained unchanged (16.1 +/- 0.4, 131.0 +/- 2.0 and 5.2 +/- 0.3 mmol (kg wet wt)-1, respectively) compared to non-expanded snared kidneys (15.9 +/- 0.6, 131.3 +/- 1.8 and 4.8 +/- 0.3 mmol (kg wet wt)-1, respectively). [Cl-]i at 18.3 +/- 0.5 mmol (kg wet wt)-1 increased (P < 0.0008) compared to controls at 15.8 +/ 0.5 mmol (kg wet wt)-1. Thus, in these rats, evidence for an inhibition of the Na+ pump was no longer observed. This points to a major intrinsic mechanism within the kidney for mediating natriuresis, since circulating factors were identical to those in the unsnared kidney, where significant natriuresis occurred. PMID- 7853245 TI - The role of ascending excitatory and descending inhibitory pathways in peristalsis in the isolated guinea-pig small intestine. AB - 1. The effects of experimental manipulations to alter the activation of ascending excitatory and descending inhibitory reflexes on peristalsis were studied in isolated segments of guinea-pig small intestine. 2. The normal site of initiation of the peristaltic contraction, the oral end, was always shifted to a point just anal to a crush which interrupted enteric neuronal pathways. 3. Shortening the functional length of the intestine by a series of crushes, thus effectively reducing the length of enteric neuronal reflex pathways, led to a progressive increase in the threshold distension for triggering the peristaltic contraction. 4. A sleeve placed around the intestine to prevent it from being distended by fluid led to a shift in the site of initiation of the peristaltic contraction to a point just anal to the sleeve. Furthermore, sleeves placed in the anal half of the intestine were able to stop propagation of the contraction. 5. The effect of these manipulations on peristalsis suggests that ascending excitatory and descending inhibitory enteric pathways, activated by distension, determine the pattern of peristaltic activity. The peristaltic contraction is initiated at the oral end as a result of the summation of ascending excitatory inputs and the relative absence of inputs from descending inhibitory pathways at this point. The magnitude of the distension for triggering this contraction is determined by a balance between ascending excitatory and descending inhibitory inputs to the circular muscle. Propagation of the circular muscle contraction requires the activation of ascending excitatory pathways at each point along the intestine and the sequential inactivation of the descending inhibitory reflex pathways anal to the contraction. The propagation of the circular muscle contraction stops when there is no longer a sufficient distension stimulus ahead. PMID- 7853246 TI - Increase of sympathetic discharge to skeletal muscle but not to skin during mild lower body negative pressure in humans. AB - 1. Haemodynamic studies in humans have concluded that the cutaneous circulation is regulated by cardiopulmonary baroreceptors. In contrast, neurophysiological studies have indicated that skin sympathetic outflow, unlike muscle sympathetic outflow, is unaffected by perturbations in baroreceptor activity. 2. Thus, in an attempt to resolve this discrepancy, both muscle and skin sympathetic nerve activity was recorded during unloading of mainly cardiopulmonary afferents with non-hypotensive lower body negative pressure (LBNP) performed in both normothermic and hyperthermic conditions. The function of the sympathetic activity was studied by estimations of skin blood flow (laser Doppler velocimetry), of calf blood flow (plethysmography) and of sudomotor activity (electrodermal responses). 3. A level of LBNP that caused robust increases in sympathetic outflow and vascular resistance in the skeletal muscle of the lower leg had no effect on sympathetic activity and vascular resistance in the skin of the same region in the same subjects. Both at normothermia and during hyperthermia LBNP decreased electrodermal activity. Experiments performed during sham LBNP and with skin temperature kept constant suggest that the electrodermal response was due to a decrease in skin temperature produced by the LBNP. 4. In conclusion, these findings challenge the concept that the cutaneous circulation participates importantly in the peripheral circulatory adjustments to unloading of cardiopulmonary afferents during orthostatic stress in humans. During non hypotensive LBNP, the skeletal muscle bed accounts for all of the reflex vasoconstriction in the calf. PMID- 7853247 TI - Transcranial electrical stimulation of the motor cortex in man: further evidence for the site of activation. AB - 1. The motor cortex was stimulated electrically (vertex anode; cathode 6 cm lateral) in neurologically normal subjects undergoing surgery for scoliosis, and the evoked corticospinal volleys were recorded from the spinal cord using epidural electrodes. 2. Stimuli > 330 V produced a complex D-wave volley containing three separate peaks, with high-threshold components, 0.8 ms (D2) and 1.6 ms (D3), in advance of the lowest-threshold component (D1). As stimuli increased up to 1500 V, D3 replaced the later components completely, but there was no further latency 'jump'. 3. Brainstem stimulation using electrodes over each mastoid process produced a descending volley that had the same latencies as D3. At threshold, stimulation of the brainstem or spinal cord attenuated the D wave evoked by simultaneous cortical stimulation. 4. It is concluded that transcranial electrical stimulation of the motor cortex at high intensities can access corticospinal neurones at the pyramidal decussation, and that stimulation of the brainstem (and the spinal cord) preferentially accesses corticospinal axons. At threshold, motor cortex stimulation probably activates corticospinal neurones at or near the cerebral cortex. PMID- 7853248 TI - Comparison of neuronal nicotinic receptors in rat sympathetic neurones with subunit pairs expressed in Xenopus oocytes. AB - 1. The agonist sensitivity of nicotinic acetylcholine receptors in rat superior cervical ganglion (SCG) neurones was compared with that of cloned receptors expressed in Xenopus oocytes by pairwise injections of alpha 3-beta 2 or alpha 3 beta 4 neuronal nicotinic subunit combinations. 2. Agonist responses in rat SCG neurones indicated that cytisine was the most potent agonist and lobeline the least potent (rank order of potency: cytisine > dimethylphenylpiperazinium iodide (DMPP) > nicotine > ACh > carbachol > lobeline). 3. Receptors expressed in oocytes by injection of alpha 3 and beta 2 subunits had a relatively high sensitivity to DMPP and low sensitivity to cytisine (rank order of potency: DMPP > ACh > lobeline > carbachol > nicotine > cytisine), whereas receptors composed of alpha 3 and beta 4 subunits had a high sensitivity to cytisine and low sensitivity to DMPP (rank-order of potency: cytisine > nicotine approximately ACh > DMPP > carbachol > lobeline). 4. With the exception of responses to DMPP, agonist sensitivity measurements suggest that nicotinic receptors in the rat SCG are composed of alpha 3 and beta 4 subunits. The results are discussed in terms of the receptor subunit mRNAs known to be expressed in the rat SCG and previous evidence of functional heterogeneity of rat SCG nicotinic acetylcholine receptors. PMID- 7853249 TI - Concentration dependence of neurotransmitter effects on calcium current kinetics in frog sympathetic neurones. AB - 1. Noradrenaline (NA) slows the activation kinetics of N-type calcium channels, via G proteins. It has been suggested that the G proteins act by binding directly to the calcium channels. If the slow kinetics reflect binding and unbinding of G proteins, the rates should depend on the concentration of activated G protein. 2. We used different concentrations of NA, and increasing durations of intracellular dialysis with GTP-gamma-S, to vary the concentration of activated G protein. 3. At depolarized potentials (-20 or -10 mV), the slow activation kinetics showed no detectable concentration dependence. This analysis required correction for effects of inactivation on the measured time constants. 4. At -80 mV, reinhibition of calcium channel current was more rapid for larger responses. Thus, the effect appears to be concentration dependent at -80 mV, but not at more depolarized voltages. 5. This voltage dependence is actually expected from kinetic principles: the binding step is rate limiting when the position of equilibrium is toward the bound state (at -80 mV), but not when equilibrium favours unbinding (when the channel is open). 6. During inhibition, the channel appears to 'sense' directly the concentration of the modulator, possibly active G proteins. PMID- 7853250 TI - Reversal of rectification and alteration of selectivity and pharmacology in a mammalian Kv1.1 potassium channel by deletion of domains S1 to S4. AB - 1. A possible relation between the family of inwardly rectifying K+ channels and the Shaker superfamily of K+ channels was investigated using a deletion mutant (DelS1-S4) of a delayed rectifier Kv1.1 (RCK1) K+ channel. 2. The mutant DelS1-S4 was made by eliminating the sequence coding for transmembrane domains S1 to S4 of the Kv1.1 K+ channel, and re-ligating the sequence coding for the cytoplasmic amino terminus to transmembrane domain S5. Microelectrode voltage-clamp and patch clamp experiments were performed on Xenopus laevis oocytes after injection of in vitro transcribed mRNA coding for mutant and wild-type channels. 3. The lack of transmembrane domains S1 to S4 converts a depolarization-activated wild-type Kv1.1 K+ channel with outward rectification into a hyperpolarization-activated channel with inward rectification. Although the pore region of the deletion mutant is identical to the wild-type channel, the mutant channel is a non selective cation channel and is characterized by an altered pharmacology profile. PMID- 7853252 TI - Effect of parapulpal pins on conservative restoration of pulpless premolars. AB - Conservative restoration of pulpless premolars with composite resins is indicated in specific instances. The effect of parapulpal pins on marginal leakage and fracture resistance was evaluated in this in vitro study for composite resin restorations in 80 extracted, pulpless premolars. Conservatively prepared pulpless premolars restored with composite resin were resistant to occlusal forces and parapulpal pins were effective in reducing gingival marginal microleakage. Parapulpal pins significantly improved the marginal seal of composite resin restorations in pulpless teeth when the gingival margins of the restoration were placed in dentin. PMID- 7853251 TI - A branching dendritic model of a rodent CA3 pyramidal neurone. AB - 1. We constructed a branching dendritic compartmental model of a CA3 pyramidal neurone, using experimental data from guinea-pig and rat cells obtained in vitro. The goal was to understand interactions between synaptic events impinging on dendritic branches and voltage- and calcium-dependent currents. The model contained sixty-four soma-dendrite (SD) compartments, an axon initial segment (IS), and four axonal compartments. There were six active conductances in the SD membrane, including a sodium conductance (gNa) and a high-threshold calcium conductance (gCa), with kinetic properties similar to those reported in a previous study. 2. The distribution of conductance densities across the IS and SD was adjusted by testing the model response to antidromic stimulation and current pulses or sustained currents injected into the soma or apical dendrites. As before, gNa was concentrated on and near the soma with lower density in the dendrites, while gCa had a higher density in apical dendrites than at the soma. 3. The model predicts that CA3 pyramidal neurones in media blocking synaptic transmission should fire a burst of action potentials following antidromic stimulation. This was confirmed experimentally in hippocampal slices. 4. Both in the model and in guinea-pig neurones, dendritic IPSCs can delay the onset of bursting. If an IPSC begins soon enough after the first fast action potential, the later burst envelope is attenuated. This effect results from suppression of dendritic Ca2+ electrogenesis. 5. The model predicts that an appropriately timed dendritic IPSC (after the first somatic spike but before the dendritic Ca2+ spike) may suppress the transient local [Ca2+] signal, while having a negligible effect on the electrical output of the neurone. This phenomenon has been reported in guinea-pig Purkinje cells. 6. We conclude that active dendritic currents are critical for regulation of the electrical output of CA3 pyramidal neurones. We suggest also that dendritic [Ca2+] signals might be controlled in individual dendrites independently of action potential outputs, an effect of possible importance for synaptic plasticity. PMID- 7853253 TI - Bond strength of adhesive resin to three nickel-chromium alloys with varying chromium content. AB - This in vitro study evaluated the influence of chromium content on bond strength and durability between nickel-chromium alloys and an adhesive resin that contained 4-methacryloxyethyl trimellitate anhydride. Three nickel-chromium alloys with different chromium content, as well as pure chromium and pure nickel metals, were bonded and tested for shear strength. After repeated thermocycling, shear bond strength decrease was lower in alloys containing high chromium content. Pure chromium metal demonstrated a 15.2% decrease, whereas pure nickel metal demonstrated the greatest (53.7%) decrease. The results suggest that nickel chromium alloys with higher chromium content are desirable for 4-methacryloxy ethyl trimellitate anhydride resin-bonded restorations. PMID- 7853254 TI - In vitro marginal adaptation of alumina porcelain ceramic crowns. AB - This study evaluated the dimensional stability during firing of In-Ceram alumina porcelain ceramic and examined the marginal fit for three different configurations of tooth preparation. A stereomicroscope was used to measure the space between the margin of restorations and tooth preparations. The three methods of tooth preparation were statistically compared and revealed suitable dimensional stability during the firing and glazing process. A better marginal fit was recorded for artificial crowns fabricated on a chamfer or 50-degree shoulder tooth preparation. PMID- 7853255 TI - Retention of posts cemented with various dentinal bonding cements. AB - This investigation evaluated the retention of preformed posts with four different cements: C & B Metabond, Panavia, All-Bond 2, and Ketac-Cem. Sixty intact maxillary canines were selected for the study. The clinical crowns were removed and endodontic therapy done on each root, which was then prepared to receive prefabricated posts. The 60 samples were divided into four groups of 15, and the posts in each group were cemented with one of the four cements. The roots were mounted in acrylic resin blocks and the posts were separated from the canals with an Instron testing machine. Analysis of the forces needed to dislodge the posts with analysis of variance and Student-Newman-Keuls test disclosed that C & B Metabond cement was the most retentive (p < 0.05). No difference in retention was recorded between Ketac-Cem and Panavia cements. All-Bond 2 cement was the least retentive of cements. PMID- 7853256 TI - Technique for fabrication of centric relation-based occlusal splint with central bearing device. AB - This study presents a technique for constructing an occlusal appliance. The central relation position must be located with Gothic arch registration. A central bearing post is fixed to the upper vacuum-adapted sheet and a registration plate is made for the lower cast. For the eccentric guidance construction, a prefabricated guiding ramp is secured just behind the most anterior point of the Gothic arch. The eccentric guidances, which harmonize with condylar movements, are printed by the mandibular canines on the surface of the self-curing resin as the post slides on the inclined surface of the ramp. PMID- 7853257 TI - Shock-absorbing behavior of four processed soft denture liners. AB - The cushioning effect of soft denture liners was evaluated with the use of a free drop test with an accelerometer. The materials tested included SuperSoft, Kurepeet-Dough, Molteno Soft, and Molloplast-B brands. All materials were found to reduce the impact force when compared with denture base resin. A 2.4 mm layer of soft denture material demonstrated good shock absorption. The Molloplast-B and Molteno Soft materials showed excellent shock absorption. When the soft denture liner was stored in distilled water for 180 days, the damping effect recorded for all materials tested was increased. The aging of all materials also affected the cushioning effect. PMID- 7853258 TI - Changes caused by processing complete mandibular dentures. AB - Qualitative and quantitative comparisons were made before and after complete mandibular dentures were processed. Linear measurements indicated shrinkage in all dimensions, and the greatest shrinkage occurred in an anteroposterior direction along the lingual flanges. Differences in shrinkage across the various points measured suggest that the denture material twists during curing, and the final qualitative changes appear as pressure areas in the distolingual and anterolabial regions. PMID- 7853260 TI - Proceedings of the 4th International Symposium on Implant Dentistry: Focus on Esthetics. San Diego, California, January 27-29, 1994. Abstracts. PMID- 7853259 TI - Stress analysis of different osseointegrated implants supporting a distal extension prosthesis. AB - Controversy exists when implants are used to restore distal extension in edentulous patients. Some have advocated the use of a rigidly connected implant to the natural abutment teeth and others have recommended the inclusion of a stress-breaking element. In this study, a comparison between these two approaches was done. With the technology of strain gauges, it was possible to record stresses under a rigid and a resilient implant system connected to a natural abutment with the same prosthesis under the same loading conditions. The results of this study showed that a resilient implant system was better for the abutment and the implant. This study provides a test method that will help dentists in choosing implants for their patients with predictable results. PMID- 7853261 TI - Effect of polyethylene fiber reinforcement on the strength of denture base resins polymerized by microwave energy. AB - This study investigated the effect of addition of polyethylene fibers on the transverse strength, deflection, and elastic modulus of two denture base acrylic resins polymerized by microwave irradiation. Specimens of each resin, Lucitone 199 and Acron MC, were fabricated with 0.0%, 0.5%, 1.5%, and 3.0% fiber loading. Specimens were tested with use of a three-point flexure apparatus with an Instron universal testing machine after storage in water for 10 days at 37 degrees C. The results showed that polyethylene fibers significantly decreased the transverse strength of Acron MC resin and slightly increased the transverse strength of Lucitone 199 resin at a loading of 0.5% by weight. Fiber loading did not significantly affect the deflection and the elastic modulus of either material. PMID- 7853262 TI - Wetting the repair surface with methyl methacrylate affects the transverse strength of repaired heat-polymerized resin. AB - This study investigated the transverse strength of repaired test specimens of heat-cured acrylic resin. The repair surfaces of the specimens were wetted with methyl methacrylate for various amounts of time before the autopolymerizing acrylic resin was applied to the joint space. A three-point loading test was used to determine the transverse strength of the test specimens, and the morphologic changes in the methyl methacrylate-wetted repair surface was analyzed by scanning electron microscopy. Visual inspection was used to determine whether the failures were adhesive or cohesive. The results revealed that repaired test specimens were weaker than those unrepaired (p < 0.001). The strength of the test specimens increased as the duration of methyl methacrylate wetting of the repair surfaces increased (p < 0.001). Furthermore, the number of adhesive failures was small if the repair surfaces were adequately wetted with methyl methacrylate. Scanning electron micrographs revealed that after 60- and 180-second wetting periods, the poly(methyl methacrylate) was noted to be dissolved with a smooth surface texture. This study suggests that proper wetting of the repair surface makes an important contribution to the strength of repaired acrylic resin. PMID- 7853263 TI - Cytotoxicity of eluates from light-polymerized denture base resins. AB - This study examined the metabolic effects of eluates from four light-polymerized denture base resins and one heat-polymerized denture base resin on oral epithelial cells in vitro. The eluate was cell culture medium that contained either or both of apparently nonpolymerized components and reaction products that diffused out of the resin samples. Eluates were prepared by daily transfer of sample disks in a cell culture medium over 10 days. Toxicity of eluates was tested immediately after transfer (fresh) and after storage for 30 days (aged) by use of radioisotope incorporation and cell viability studies. The fresh eluates inhibited cell metabolism, whereas the aged eluates stimulated then inhibited the responses. Results suggest that the components that leach out of the tested materials do so at different rates and have prolonged toxic effects on cells. Thus soaking prosthesis in water before insertion may be beneficial. PMID- 7853264 TI - Effect of disinfection of custom tray materials on adhesive properties of several impression material systems. AB - The effects of impression tray disinfection procedures on the bond strength of impression-material adhesives to two types of resin trays were evaluated with a tensile test. Autopolymerizing acrylic resin and a visible light-curing resin were formed into one-half inch cubes. A screw eye was attached to each cube before polymerization. Perforated trays were fabricated with stops to maintain an even one-eighth inch of impression material over the resin block. Hooks on the opposite side permitted attachment of the metal plate to a mechanical testing machine. Before adhesive was applied, one third of the resin specimens were immersed in a 1:213 iodophor solution; one third in a 10% sodium hypochlorite solution, and one third were kept in the "as fabricated" condition. Polysulfide, polyether, and polyvinyl siloxane impression material-adhesive systems were evaluated. The resin-impression material-metal plate couples were attached to a mechanical testing machine and tensile forces were applied at a separation rate of 5 inches per minute. Mean values for adhesive strength ranged from 3.49 kg/cm2 for the autopolymerizing acrylic resin/iodophor/polyether combination to 10.55 kg/cm2 for the autopolymerizing acrylic resin/untreated/polyvinyl siloxane combination. Differences were detected among materials and disinfecting procedure. Clinically, disinfection of resin trays may adversely affect retention of the impression material to the tray. PMID- 7853265 TI - Effects of denture cleansers on direct soft denture lining materials. AB - The deterioration of six commercial resilient denture lining materials immersed in seven groups of denture cleansers was investigated. Although the grades of deterioration of these soft liners were not related to the amount of peroxide content or the pH of denture cleansers, the effects of peroxide cleansers were, with few exceptions, more severe than those of the other types. For example, an enzyme cleanser caused severe changes of one soft liner. The grades of surface porosity were correlated well with the log of the gelation time of the tissue conditioners (except for one soft liner), in four kinds of peroxide cleansers. These results suggest that various components of denture cleansers and soft lining materials, particularly peroxides, in cleansers and gel formation components of soft liners play important roles in the deterioration of soft liners caused by cleansers. PMID- 7853266 TI - A cast orientation index. AB - This article describes a technique that allows multiple master casts to be precisely oriented to the same path of insertion and withdrawal. This technique is useful in situations where multiple fixed prosthodontic preparations require surveyed restorations and a single master cast is not available. PMID- 7853267 TI - A new procedure for separating the edentulous distal extension portion from the master cast when an altered cast is made. AB - Making an altered cast requires separating the edentulous portion from the rest of the master cast. A plaster saw, which is commonly used for this purpose, requires considerable time and effort. A simplified and efficient procedure is presented for separating the edentulous portion from the rest of the master cast without the use of a plaster saw. PMID- 7853268 TI - Temporization of Class II gold restorations. PMID- 7853269 TI - A protective guard for an osseointegrated implant superstructure. PMID- 7853270 TI - Evaluation of two dentin adhesives in cervical lesions. PMID- 7853271 TI - Adenomyosis. AB - The clinical diagnosis of adenomyosis is elusive but should be suspected in women who complain of abnormal uterine bleeding or dysmenorrhea and have a regular but enlarged uterus. The use of newer diagnostic imaging modalities and recent research on myometrial biopsies should enable the clinician to arrive at a definite preoperative diagnosis and offer the patient treatment tailored to her needs. PMID- 7853272 TI - Laparoscopic treatment of ectopic pregnancy. Residents' learning experience. AB - Although operative laparoscopy is a safe and effective method of treating ectopic pregnancy, its widespread acceptance requires appropriate operator training and experience. This retrospective study correlated operative results with experience of the resident performing surgery. Thirteen postgraduate year 3 and 4 gynecology residents treated 60 ectopic pregnancies by laparoscopy. There were four complications: two cases of atelectasis and two of persistent human chorionic gonadotropin titers. There were no blood transfusions. We found that the duration of surgery decreased as operator experience increased, and residents who had experience with five or more cases required a mean operative time of 74 minutes. We conclude from our results that the minimal amount of supervised training necessary for gynecology residents to safety and expeditiously treat ectopic pregnancy laparoscopically is five cases. Furthermore, the minimal morbidity in this study supports our continued recommendation that each resident have prior training experience of at least 10 laparoscopic sterilizations before attempting his or her first case of ectopic pregnancy. PMID- 7853273 TI - Hormonal factors in vulvar cancer. A case-control study. AB - As part of a case-control study of vulvar cancer, we examined the role of reproductive history, menstrual history, exogenous estrogen use and body mass in the etiology of this disease. A total of 330 women with vulvar squamous cell cancer (259 in situ, 81 invasive), aged 18-79 years, who were diagnosed with this tumor during 1980-1990 were interviewed. Their responses were compared to those of 1,010 women who were selected from the general population by means of random digit dialing. Cases and controls did not differ regarding age at menopause, parity, number of prior pregnancies or number of prior births, history of miscarriage or use of noncontraceptive estrogens. Women diagnosed with vulvar cancer were slightly more likely to have experienced menarche at < 12 years (odds ratio [OR] = 1.8, 95% confidence interval [CI] = 1.2-2.7, in situ cancer; OR = 1.6, 95% CI = 0.8-3.1, invasive cancer), to have excess weight (invasive cancer only, OR = 2.9, 95% CI = 1.5-5.8 for highest tertile of Quetelet's index) and, among gravid women, to have had their first pregnancy after age 24 (in situ cancer only, OR = 1.5, 95% CI = 0.9-2.5). These data, together with similar results from previous studies and quantitative studies of hormone receptors in vulvar tissue, suggest that in situ and invasive vulvar cancer are not strongly hormone dependent tumors. PMID- 7853274 TI - Laparoscopic Pomeroy tubal ligation as a teaching model for residents. AB - We reviewed our preliminary experience with laparoscopically directed bilateral midtubal resection for tubal ligation (endoscopic Pomeroy) as a potential teaching tool for the acquisition of endoscopic skills during residency training. Thirty-five laparoscopic Pomeroy and 206 banding procedures were reviewed. Age, parity and weight were similar in the two groups. The operative time for banding was reduced slightly after experience with > 10 procedures. In contrast, the operative time for laparoscopic Pomeroy procedures decreased dramatically after individual experience with only a few (< or = 5) procedures. The mean operative time for the Pomeroy group approached that of the more traditional banding technique at five procedures. Our data indicate that laparoscopic Pomeroy sterilization can be an effective teaching tool for operative laparoscopy, allowing residents to repeatedly perform an easy and safe procedure that incorporates basic techniques. Advanced operative endoscopic procedures could then be taught more efficiently after the acquisition of basic skills. PMID- 7853275 TI - The hypoosmotic swelling test. AB - In the present study, the effect of the concentration of the hypoosmotic solution, incubation time and duration from sperm collection to incubation on the hypoosmotic swelling (HOS) test were evaluated. Sperm were obtained from 20 fertile donors. The most stable sperm tail swelling was obtained at 150 mOsm. Incubation for 30 minutes was sufficient for the evaluation of overall swelling but not for the evaluation of b- and g-type sperm swelling. This suggests that incubation for one hour is necessary to obtain stable results. Incubation for more than one hour did not affect the percentage or type of sperm swelling. The time from sperm collection to incubation did not affect the HOS test. The HOS test is practical and not affected by the duration of incubation or time from sperm collection to incubation. PMID- 7853276 TI - Comparison of three types of ultrasound transducers in evaluating the amniotic fluid index. AB - The purpose of this study was to determine whether there was good correlation between amniotic fluid index measurements obtained with different types of ultrasound transducer. Women undergoing obstetric ultrasonography for multiple indications between 26 and 40 weeks' gestation had the four-quadrant amniotic fluid index measured with three ultrasound transducers: 3.5-MHz linear, 3.5-MHz sector and 3.5-MHz convex. Pearson product-moment correlation and linear regression analysis were utilized to compare the amniotic fluid index values. Sixty-five women participated in the study. A statistically significant correlation was noted between the three ultrasound transducers evaluated (P < .001). Placental location did not appear to affect the results. Amniotic fluid index values obtained with the sector or convex transducers were as reliable as those obtained with the "gold standard" linear transducer and may be interpreted in the same manner. PMID- 7853277 TI - Removal rates of subdermal levonorgestrel implants. AB - This study attempted to quantify an achievable removal rate of subdermal levonorgestrel implants (SLIs) in an unselected population and develop strategies for increasing continuation. Over 16 months, 1,076 SLIs were inserted in eligible patients from a lower socioeconomic group at high risk for unintended pregnancy. Extensive preinsertion and postinsertion counseling and follow-up care were given. Patients developing problems were counseled and managed conservatively. If a patient requested removal of the Norplant after this process, removal was done. Twenty-two removals occurred due to SLI-related problems, for a rate of 2.04%; no trends based on age or parity were found. The most common reasons for removal were bleeding/irregular menses (31.8%), headaches (18.1%) and hair loss (13.6%). An episode of thrombophlebitis, not thought to be caused by the SLI, led to one removal. Seventy-seven percent of removals occurred in the first six months, with peak rates in the fourth and fifth. Five patients became pregnant inadvertently within six months of removal. An extremely low removal rate and high continuation rate are possible in an inner city clinic population at risk for unintended pregnancy. Acceptance will increase if the SLI can be maintained at least past six months. Extensive counseling, patient support and conservative medical management constitute a successful approach. PMID- 7853278 TI - Postthaw viability of frozen human ovarian cancer tumor specimens. AB - Thirty-five human ovarian cancer tumor specimens were frozen by both rapid freeze and slow freeze with dimethyl sulfoxide (DMSO) to determine which method results in optimal postthaw viability. Median viability following a rapid freeze was 8% as compared to 90% with slow freeze with DMSO (P = .0001). Eighty-seven percent of tumors had a viability of > 80% following slow freeze with DMSO. When experimentation on human ovarian cancer tumor cells requires postthaw viability, we recommend slow freeze with DMSO. PMID- 7853279 TI - Once a cerclage, not always a cerclage. AB - A study was performed to evaluate the outcome of pregnancies in which the decision was not to repeat cerclage in women with a doubtful indication for the previous one. Thirty-five women with a history of at least one previous McDonald cerclage were followed prospectively. Pregnancy complications and outcome were compared to those in the previous pregnancy with a cerclage. These patients had 58 pregnancies with a cerclage and 52 pregnancies without. The pregnancies without a cerclage had fewer complications, were longer and resulted in the delivery of significantly larger infants (P < .05). Whereas all 52 cumulative pregnancies without a cerclage had a favorable outcome, there were nine perinatal losses in the 58 pregnancies with a cerclage (P < .05). The decision not to repeat a cervical cerclage, when the grounds for the previous procedure are doubtful, is a safe one. PMID- 7853280 TI - Clinical implementation of a rapid, automated assay for assessing fetal lung maturity. AB - We retrospectively determined cutoff levels and implemented the use of the TDxFLx assay in assessing the likelihood or absence of respiratory distress syndrome or fetal lung maturity (FLM) in a high-risk obstetric setting when compared to the lecithin/sphingomyelin (L/S) ratio and disaturated lecithin (DSL) measurements. Using a mature TDxFLx cutoff value of > or = 50 mg/g and an immature cutoff value of < 20 mg/g, 88% of L/S ratio and DSL measurements could be eliminated without compromise to the patient. The > or = 50 mg/g TDxFLx cutoff value resulted in a sensitivity of 100% and specificity of 88%. We also recommend the use of the TDxFLx assay as a screening test in diabetic pregnancies. More timely patient care occurred when the rapid TDxFLx assay was implemented by the laboratory and used by clinicians. PMID- 7853281 TI - Meconium-stained amniotic fluid. Current controversies. AB - Meconium-stained amniotic fluid is commonly found in obstetrics: it occurs in 9 20% of deliveries. Meconium passage into the amniotic fluid may be an antepartum or intrapartum event. Meconium aspiration may occur antepartum or intrapartum or at the infant's first breath. The prognosis in neonates with meconium aspiration syndrome appears to be related to antepartum hypoxemic damage to the lungs. This paper covers the pathophysiology of meconium aspiration and meconium aspiration syndrome, treatment options to prevent meconium aspiration and practical information on assessing fetal heart rate tracings. The necessity of tracheal suctioning in all neonates with meconium-stained amniotic fluid is controversial. PMID- 7853282 TI - The Cell-Sweep. A new cervical cytology sampling device. AB - The Cell-Sweep, a new cervical cytology sampling device, was prospectively evaluated. From September 1, 1992, to October 31, 1992, 548 cervical cytology smears were prepared using the Cell-Sweep. They were compared to 524 cervical smears performed between January 1, 1993, and February 28, 1993, using the Cytobrush and Ayre spatula. One smear in the Cell-Sweep group and nine in the Cytobrush/Ayre spatula group were unsatisfactory for evaluation secondary to drying artifact (P < .01). Seven (1.2%) of the Cell-Sweep smears and 13 (2.4%) of the Cytobrush/Ayre spatula smears were inadequate due to obscuring of the epithelial cells by blood (P = .11). Of the smears obtained with the Cell-Sweep, 66 (12%) contained no endocervical component versus 42 (8%) of the smears obtained with the Cytobrush/Ayre spatula (P = .03). In the Cell-Sweep group there were 130 (23.7%) abnormal smears versus 110 (20.9%) in the Cytobrush/Ayre spatula group (P = .3). However, high grade squamous intraepithelial lesions (SILs) were identified in 10 (1.8%) smears obtained with the Cell-Sweep and in 2 (0.4%) obtained with the Cytobrush/Ayre spatula (P = .02). The Cell-Sweep produced a small proportion of unsatisfactory smears due to drying artifact or blood. Even though the proportion of smears lacking endocervical cells was statistically greater with the Cell-Sweep than with the Cytobrush/Ayre spatula, there was no difference in the rate of detection of atypical squamous cells and low grade SIL. The Cell-Sweep appears to detect an increased number of high grade SILs. This device deserves further study with histopathologic correlation. PMID- 7853283 TI - Vaginal cuff closure with abdominal hysterectomy. A new approach. AB - A 2.5-year study was conducted to compare side-to-side closure of the vaginal cuff with the traditional front-to-back closure. Candidates for abdominal hysterectomy were selected from among those in the author's private practice, and 100 patients were chosen to participate in the study. All surgery was performed by the author. Comparisons were made of blood loss, enterocele formation and postoperative results, consisting of vaginal depth, vaginal support, and discomfort from and stress on the vaginal cuff scar as they related to the patients' complaints of dyspareunia with deep penetration. PMID- 7853284 TI - Advanced ovarian cancer in a woman with a family history of ovarian cancer, discovered at referral for prophylactic oophorectomy. A case report. AB - Despite an initial complete response to therapy, she died of the disease 60 months after the diagnosis. Although only a small percentage of ovarian cancer patients report a family history positive for ovarian cancer, such a history remains the most recognizable risk factor in this elusive disease. Accurate prediction of the risk of ovarian cancer in subjects with multiple affected family members and the efficacy of prophylactic oophorectomy need to be determined. PMID- 7853285 TI - Sonographic appearance of suspected iatrogenic uterine perforation. A case report. AB - A case of iatrogenic uterine perforation occurred during dilation and curettage for treatment of a missed abortion at 14 weeks' gestation. Real-time transabdominal sonography was used to detect the fundal perforation and to follow serially the amount of fluid in the cul-de-sac. It is recommended that this noninvasive and direct diagnostic tool be used in the management of uterine perforation. PMID- 7853286 TI - Laser ablation of squamous cell carcinoma in situ of the anal canal. A case report. AB - A case of squamous cell carcinoma in situ of the anal canal was discovered incidentally during a hemorrhoidectomy in a man. The anal canal was evaluated by colposcopy prior to ablation of the lesion with a CO2 laser. To our knowledge, this technique has not been reported previously. PMID- 7853287 TI - Percutaneous angiographic arterial embolization for gynecologic and obstetric pelvic hemorrhage. A report of three cases. AB - Percutaneous angiographic arterial embolization for control of intractable hemorrhage is being utilized increasingly in general surgery and trauma patients. Recently there have been several reports on the application of this technique in patients experiencing bleeding from the pelvic vasculature. We describe our management of three patients by percutaneous iliac arterial angiographic embolization. One patient, following repeat cesarean section for a twin gestation, developed intraabdominal bleeding that failed to respond to classic maneuvers, including cesarean hysterectomy. A second patient suffered a deep vaginal sulcus tear during spontaneous vaginal delivery. The third patient developed a hemorrhage from the vaginal cuff 31 days after vaginal hysterectomy. In each case, angiography demonstrated extravasation of dye from a branch of the hypogastric artery. Selective embolization was uniformly successful in quickly achieving hemostasis. There were no major complications associated with the procedure. PMID- 7853288 TI - Labial edema in pregnancy. A case report. AB - Edema is a frequently encountered medical sign in pregnancy. Edema confined strictly to the labia, however, is not as common. This report describes severe labial edema in a patient with a twin gestation while on intravenous magnesium sulfate tocolysis. The tocolysis could have initiated the process of labial swelling in the presence of other, predisposing factors. PMID- 7853289 TI - Use of a menstrual calendar in patients with Rokitansky syndrome. A report of two cases. AB - In two cases the menstrual calendar was used to determine the cyclic nature of abdominal pain in women with the Rokitansky syndrome who could not otherwise find a regular pattern in their symptoms. Surgical intervention to remove the rudimentary bicornuate uterus was needed in both, and complete resolution of pain was attained. The menstrual calendar is a valuable diagnostic tool in confirming the cyclic nature of pain and can be used in guiding treatment decisions. PMID- 7853290 TI - Endometrial cancer in a double uterus. A report of two cases. AB - Two cases of double uteri associated with endometrial adenocarcinoma are presented. A correct diagnosis in this situation may be difficult to make due to anatomic difficulties or the unrecognized presence of a second uterine cavity. Ultrasound imaging should be considered to look for a second uterine cavity after a negative endometrial biopsy when clinically suspecting endometrial cancer. PMID- 7853291 TI - Failed prostaglandin abortion associated with placenta accreta. A case report. AB - Prostaglandin E2 vaginal suppositories are a highly effective method of second trimester pregnancy termination. Management of a failed prostaglandin abortion must include a search for the cause of the failure. This case report is the first description of a failed prostaglandin abortion associated with placenta accreta. PMID- 7853292 TI - Privational rickets: a modern perspective. PMID- 7853293 TI - Alcoholic brain damage. PMID- 7853294 TI - Leonard Colebrook: the chemotherapy and control of streptococcal infections. PMID- 7853295 TI - Current trends in the management of tuberculosis. PMID- 7853296 TI - Convulsion of the lung: an historical analysis of the cause of Dr Johnson's fatal emphysema. AB - Of Johnson's fatal emphysema, it appears probable, on available historical and anatomic evidence, that it resulted from bronchiectasis, a diagnosis favoured by the pattern of illness: a protracted and severe respiratory infection succeeded by annual episodes of severe winter bronchitis, remitting in summer, and culminating in respiratory insufficiency; and by the findings of pleural adhesion and cor pulmonale at necropsy. That is resulted from chronic bronchitis is a proposition both plausible and irrefutable without the specimen. PMID- 7853297 TI - Down's syndrome. PMID- 7853298 TI - Erosive pustular dermatosis of the scalp secondary synthetic fibre implantation. PMID- 7853299 TI - Keats: a tragedy in three Acts 1815-1821 with coda. PMID- 7853300 TI - The "makyng" and re-making of man: 1. Mary Shelley's Frankenstein, and transplant surgery. PMID- 7853301 TI - The makyng and re-making of man: 2. Mary Shelley, or, the modern Pandora, and gene therapy. PMID- 7853302 TI - The myth of Prometheus and the liver. PMID- 7853303 TI - The plague of Athens. PMID- 7853304 TI - John Knight and the King's healing. PMID- 7853305 TI - William Osler and Aequanimitas: an appraisal of his reactions to adversity. PMID- 7853306 TI - Music and melancholia. AB - This is a brief look at the psychiatric ailments of some of the great composers: two of whom committed suicide; four suffered from severe depression; three had other assorted ailments; and three were suffering from manic depressive illnesses. Their mood swings are compared with their periods of intense composition. For some composers it seems that they are most productive immediately after a phase of depression. PMID- 7853307 TI - Freud and Wagner's Meistersinger. PMID- 7853308 TI - Chopin's illnesses. PMID- 7853309 TI - Beethoven's nephropathy and death. PMID- 7853310 TI - Surgeon James Ramsay, 1733-1789: the Navy and the slave trade. AB - The end of the American War of Independence in 1783 coincided with two very different, but closely related initiatives: the settlement of New South Wales and the fight against the slave trade. In both, James Ramsay, a naval surgeon, played a decisive role. James Ramsay was born on 25 July 1733 at Fraserburgh on the Aberdeenshire coast. After a grammar school education, he was apprenticed to a Dr Findlay, surgeon and physician in Fraserburgh. Through his proficiency in Latin, he obtained a small bursary which enabled him to enter King's College in the University of Aberdeen and brought Ramsay under the influence of Dr Thomas Reid, the professor of moral philosophy, who exercised a profound influence on Ramsay's thinking (Vol 17, pp 632-3). PMID- 7853311 TI - Turbulence in the Lock. PMID- 7853312 TI - Daniel Turner and the Art of Surgery in early eighteenth-century London. PMID- 7853313 TI - John Hunter and pain referred. PMID- 7853314 TI - Where there is no psychiatrist: the development of a psychiatric service on St Helena. PMID- 7853315 TI - Tachycardias in the elderly. PMID- 7853316 TI - Medical ethics and evolution. PMID- 7853318 TI - The molecular basis of autoantibody pathogenicity. PMID- 7853317 TI - Risks of manipulation. PMID- 7853319 TI - Carotid sinus syndrome in the elderly. PMID- 7853320 TI - Swallowing in motor neurone disease. AB - Ninety-two patients with motor neurone disease have been assessed clinically and radiologically for evidence of swallowing problems. At the time of examination, moderate or severe swallowing difficulty was present in 89% of those whose disease had presented as bulbar palsy, in 45% of those in whom the disease began many months before as progressive muscular atrophy and in 29% of those with amyotrophic lateral sclerosis. Patients with more severe swallowing symptoms appeared more likely to have abnormal findings on videofluoroscopy overall. However, not all patients with an abnormal radiological picture had swallowing difficulties. It is suggested that radiological signs should only be used within the context of clinical symptoms and signs in the selection of patients for palliative surgery. Thirteen patients with pseudobulbar symptoms and signs had a cricopharyngeal myotomy performed: two suffered major post-operative complications. However, the satisfaction rate was 89% and we recommend cricopharyngeal myotomy for such patients. Pharyngostomy was performed for seven patients unable to initiate swallowing, six had post-operative complications. PMID- 7853321 TI - 3-D reconstruction of an ancient Egyptian mummy using X-ray computer tomography. AB - Computer tomography has been used to image and reconstruct in 3-D an Egyptian mummy from the collection of the British Museum. This study of Tjentmutengebtiu, a priestess from the 22nd dynasty (945-715 BC) revealed invaluable information of a scientific, Egyptological and palaeopathological nature without mutilation and destruction of the painted cartonnage case or linen wrappings. Precise details on the removal of the brain through the nasal cavity and the viscera from the abdominal cavity were obtained. The nature and composition of the false eyes were investigated. The detailed analysis of the teeth provided a much closer approximation of age at death. The identification of materials used for the various amulets including that of the figures placed in the viscera was graphically demonstrated using this technique. PMID- 7853322 TI - Spectrum of hypertensive target organ damage in Africa: a review of published studies. AB - This paper reviews the evidence of hypertensive target organ damage (HTOD) in Africa, and the difficulties of its assessment, with a focus on implications for further research and prevention. Specific examples of HTOD reviewed include left ventricular hypertrophy, heart failure, ischaemic heart disease, arrhythmias and sudden death, kidney failure, cerebrovascular accidents, retinopathy and central as well as peripheral vascular disease. There is evidence that the prevalence of hypertension is increasing in some parts of Africa, thus increasing the number of people who suffer from fatal and nonfatal complications. Analysis of the type, frequency and distribution of HTOD is critical to the design of interventions to prevent and manage hypertension, and in the design of future clinical research. As would be expected, the frequency of atherosclerotic complications, particularly involving the heart, is lower in Africa than in developed countries. Stroke, renal failure and heart failure appear to be the principal adverse outcomes and are likely to be associated with a high case fatality rate. Community-based data on these issues are limited, however, and hospital series cannot estimate the population burden and may be unreliable in describing the case mix. Improved data on HTOD will more accurately reflect the health impact of hypertension, provide the basis for aggressive efforts at prevention, detection and control of high BP and establish their relevance in the overall scheme of resource allocation during fiscal austerity and limited healthcare spending. Additionally, knowledge of the prevalence and relative frequencies of HTOD has direct and important implications for clinical outcomes research in hypertension. PMID- 7853323 TI - Microalbuminuria and progressive renal disease. AB - Microalbuminuria is a predictor of excess cardiovascular morbidity and mortality in both hypertensive and diabetic subjects. The reasons for this are multifactorial and relate to metabolic and haemodynamic problems seen in this population. In diabetic patients, microalbuminuria correlates more with glycosylated haemoglobin than with the duration of diabetes. The pathogensis of microalbuminuria includes alterations in glomerular shunting of albumin, increased intraglomerular pressure and increased amounts of certain growth factors that alter cell permeability. The urine Micral test is an easy way to screen for the presence of microalbuminuria. The increase in microalbuminuria over time can be documented by annual quantitation using a radioimmunoassay technology. Aggressive control of BP is vitally important in order to preserve renal function. Antihypertensive agents that lower both intraglomerular pressure and volume are preferable, since they consistently attenuate both the increase in microalbuminuria and structural changes within the glomerulus. In addition to BP control, other measures known to reduce the rise in microalbuminuria include a reduced dietary protein intake and good long-term blood glucose control. Unfortunately, there is no definitive study, in humans, that conclusively demonstrates a preservation of renal function directly relates to an attenuated rise in microalbuminuria. Thus, while microalbuminuria is clearly a risk factor for development of diabetic nephropathy and an indicator of hypertensive renal disease, its reduction has not demonstrated functional or structural benefit in humans. This is in large part due to the inpracticality of such a trial because of the duration needed to see an effect. Interestingly, a beneficial effect on renal survival has been shown with albuminuria reduction independent of BP reduction. PMID- 7853324 TI - Which cuff size is preferable for blood pressure monitoring in most hypertensive patients? AB - The accuracy of blood pressure (BP) measurements in obese hypertensives is still controversial. We investigated whether a large sized cuff could be appropriate for BP measurements in patients with different arm circumferences. Fifty hypertensive patients (23 males and 27 females, mean age 54 +/- 12 years, mean weight 75 +/- 12 kg) underwent BP measurements under standardised conditions using both a standard cuff (23 x 12 cm) and a large cuff (34 x 15 cm). Ambulatory blood pressure monitoring (ABPM) was subsequently performed in each subject using a large cuff. The average of two measurements performed in the clinic was compared with the mean daytime measurements. Thirty-one subjects had an arm circumference of < 30 cm (group 1) and weighted 68 +/- 10 kg, while 19 (group 2) had a larger arm circumference (> or = 30 cm) and were overweight (86 +/- 8 kg). BP in group 1 was 149 +/- 23/91 +/- 12 mmHg with the standard cuff and 143 +/- 24/88 +/- 13 mmHg with the large cuff (P < 0.003). In group 2, the respective readings were 153 +/- 22/100 +/- 16 mmHg (standard cuff) and 144 +/- 19/93 +/- 16 mmHg (large cuff; P < 0.0004). These findings suggest that in overweight hypertensives, the use of the standard cuff results in overestimation of BP and that large cuffs should be used exclusively in this population. The use of a large cuff in lean patients has yet to be clarified. PMID- 7853325 TI - Prevalence of hypertension and subtypes in an Indian rural population: clinical and electrocardiographic correlates. AB - The aims of this study were to determine the prevalence of hypertension (systolic > or = 140 and/or diastolic > or = 90 mmHg) and its subtypes such as borderline isolated systolic hypertension (systolic > or = 140, diastolic < 90 mmHg), definite isolated systolic hypertension (systolic > or = 160, diastolic < 90 mmHg), isolated diastolic hypertension (systolic < 160, diastolic > or = 90 mmHg) and definite hypertension (systolic > or = 160 and diastolic > or = 90 mmHg or hypertensives on treatment) in a rural population of a developing country. We have conducted a total community cross-sectional survey in a rural population of western India. 3148 persons (1982 males and 1166 females), aged > or = 20 years were examined in a cluster of three villages in Rajasthan. These were grouped into various subtypes of hypertension according to the US Fifth Joint National Committee and Framingham Study guidelines. The overall prevalence of hypertension and its subtypes was 24% in males and 17% in females. There was an age related increase in the prevalence of hypertension in both males and females. Only 7% males and 8% females were aware of their high BP. On subclassification of hypertensives it was seen that in males 12% had borderline isolated systolic hypertension, 2% had definite isolated systolic hypertension, 70% had isolated diastolic hypertension and 16% had definite hypertension. In females 18% had borderline isolated systolic hypertension, 2% had definite isolated systolic hypertension, 53% had isolated diastolic hypertension and 17% had definite hypertension.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7853326 TI - Dyslipidaemias in white and black treated essential hypertensive patients. AB - Serum lipid profiles were evaluated in 143 white (31 men, 112 women, aged 58.4 +/ 0.9 years) and in 75 black-individuals (16 men, 59 women, aged 52.6 +/- 1.0 years) with treated essential hypertension. Hypertension onset was earlier in the blacks than the whites (39.7 +/- 1.0 vs. 46.6 +/- 1.1 years). Duration of hypertension was similar in both races (11.8 +/- 1.0 and 12.9 +/- 1.0 years) and did not correlate with serum lipid values. Mean serum lipids, excluding HDL-C, were significantly higher in white than in black hypertensives (LDL-C 4.19 +/- 0.08 vs. 3.82 +/- 0.13; TG 1.80 +/- 0.10 vs. 1.40 +/- 0.09 mmol/l; LDL-C/HDL-C 4.0 +/- 0.1 vs. 3.6 +/- 0.2). The prevalence of dyslipidaemia was significantly higher in white than in black patients (64% vs. 52%). Types IIa, IIb and IV were more prevalent in whites and isolated low HDL-C in blacks. Obesity was found in 27% of the whites and 31% of the blacks. Hypertriglyceridaemia was more frequent in obese hypertensives of both races, but mostly among the white obese patients. Among lipid values within the normal range, the mean levels of serum lipids were similar in both races, with the exception of triglyceridaemia, which was significantly lower in black than in white hypertensives. These findings may be attributed to racial differences rather than to nutritional trends. PMID- 7853327 TI - Relationship between change in erythrocyte sodium and antihypertensive response to enalapril. AB - To investigate the effects of enalapril and hydrochlorothiazide on erythrocyte sodium and potassium in relation to their effects on BP, 28 men (mean age 46 years, range 22-64 years) with previously untreated essential hypertension (casual DBP > or = 95 mmHg) were randomised to enalapril (n = 14) or hydrochlorothiazide (n = 14) treatment. BP was also measured intraarterially (brachial artery) and the mean arterial pressure (MAP) recorded. Intraerythrocyte sodium and potassium were measured by flame photometry at baseline and after 26 weeks of active treatment in the hypertensive patients and also in 28 age- and sex-matched normotensive control subjects. There was a significant positive relationship between intra-arterial BP and intraerythrocyte sodium in untreated hypertensives, but there was no significant difference in mean intraerythrocyte sodium or potassium content between hypertensive and normotensive subjects at baseline. The distribution of values of intraerythrocyte sodium, however, differed between hypertensive and normotensive subjects. Supine MAP was lowered from 113 +/- 4 to 97 +/- 3 mmHg and from 110 +/- 3 to 102 +/- 2 mmHg on enalapril and hydrochlorothiazide treatment, respectively. BP reduction with enalapril was associated with a significant decrease in intraerythrocyte sodium (P = 0.02), while hydrochlorothiazide had no effect. There was no significant correlation between delta MAP and delta intraerythrocyte sodium after 26 weeks in any of the groups. Intraerythrocyte potassium did not change on treatment with either drug. In conclusion, there wa a significant relationship between intra-arterial BP and intraerythrocyte sodium in untreated hypertensives. Both enalapril and hydrochlorothiazide reduced BP effectively while enalapril only reduced intraerythrocyte sodium.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7853328 TI - Antioxidant status in controlled and uncontrolled hypertension and its relationship to endothelial damage. AB - Hypertension is associated with an increased risk of atherosclerosis. Free radical oxidative damage has been implicated in the atherogenic process. We measured levels of the antioxidants uric acid, thiols, vitamins C, A and E as well as the total antioxidant capacity in 21 normotensive controls, 22 patients whose hypertension was controlled on drugs and 30 patients with uncontrolled hypertension. Mean BPs in the groups were 125/76, 132/80 and 181/98 mmHg, respectively. When compared with controls, both hypertensive groups had significantly lower serum ascorbic acid (54 +/- 5 vs. 37 +/- 6 vs. 38 +/- 5 mumol/l, P < 0.05) and albumin-corrected thiol levels (9.91 +/- 0.18 vs. 8.69 +/- 0.20 vs. 8.92 +/- 0.19 mumol/g, P < 0.05). The levels of the other antioxidants did not differ significantly between the groups. Levels of von Willebrand factor, a marker of endothelial damage, were correlated with SBP but not with antioxidant status. We conclude that hypertensive subjects have lower levels of the antioxidants vitamin C and thiols and this may reflect greater oxidative consumption. The implications for atherogenesis and endothelial function and integrity in hypertension are discussed. PMID- 7853329 TI - Influence of daily-life activation on pulse rate and blood pressure changes during the menstrual cycle. AB - The aim of the present study was to evaluate the influence of endogenous cyclic changes in female sex hormones during the complete normal menstrual cycle on the daily-life activation of blood pressure and pulse rate. Sixteen normotensive women were investigated daily in the morning during strict bed rest and in the evening after normal daily activities throughout two complete menstrual cycles. Analysis of variance revealed a significant change in morning temperature during the menstrual cycle (P < 0.001), with a raise after midcycle. There was no significant variation in body weight during the cycle. Resting pulse rate increased by 1.7 beats/min from follicular (days 2-8) to luteal (days 20-26) phase in morning recordings (P < 0.01) and by 2.9 beats/min in evening recordings (P < 0.001). Pulse pressure was 2.7 mmHg and systolic blood pressure 3.9 mmHg higher in the evening compared with the morning readings (P < 0.05 for both) in the luteal phase, but were similar in the follicular phase. The influence of daily-life activation on pulse rate and systolic blood pressure, defined as the difference between morning and evening levels, was significantly greater in the luteal phase compared with the follicular phase (delta 1.3 beats/min, P < 0.05 and delta 3.0 mmHg, P < 0.05, respectively). In the present study we find evidence of an altered response in haemodynamic recordings to environmental stress during the menstrual cycle. This interpretation is supported by previous findings of increased responses to experimental stress and extends these observations to naturally occurring stress in daily-life. PMID- 7853330 TI - Possibilities for antihypertensive drug therapy withdrawal in the elderly. AB - The aims of this study were to determine: (1) the proportion of elderly hypertensive subjects currently attending a hospital hypertension clinic suitable for a trial of antihypertensive drug withdrawal, (2) the proportion of suitable patients who can be successfully withdrawn from drug therapy while receiving nonpharmacological advice, and (3) the factors associated with successful withdrawal. One hundred and five consecutive hypertensive subjects, 53% female, mean age 76 years (range 65-84 years) on pharmacological antihypertensive therapy for > 1 year were studied, of whom 78 (74%) had a clinic SBP < 175 mmHg and DBP < 100 mmHg. Subjects with recent myocardial infarction or stroke or with symptoms of ischaemic heart disease were excluded. Antihypertensive drug therapy was withdrawn in this group and nonpharmacological advice to lower BP was instituted. Clinic BP and weight were subsequently recorded monthly for 12 months in all subjects and at every three months in those who had a possible follow-up period of 24 months. The 24h ambulatory BP was measured at baseline and repeated one month off therapy; 24h urine electrolytes were also assessed at baseline and at 12 months or before restarting drug therapy. Seventy-four (70%) subjects had a potential follow-up of 12 months (four were withdrawn from the study) and 64 were available for two years of follow-up. Antihypertensive treatment was restarted if SBP > or = 160 mmHg and/or DBP > or = 90 mmHg on two consecutive visits. After 12 months, 20 (25%) of those withdrawn remained normotensive, the majority restarting therapy did so in the first three months.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7853331 TI - Synthesis and antitumor activity of novel water soluble derivatives of camptothecin as specific inhibitors of topoisomerase I. AB - The synthesis and antitumor activities of the novel water soluble camptothecin derivatives 7-[(4-methylpiperazino)methyl]-10,11-(methylenedioxy)-(20S)-campto thecin trifluoroacetate (6) and 7-[(4-methylpiperazino)methyl]-10,11 (ethylenedioxy)-(20S)-camptot hecin trifluoroacetate (7) are described. The solubilities of compounds 6 and 7 were measured to be 4.5 and 5.8 mg/mL, respectively, in pH 5 acetate buffer in contrast to < 0.003 mg/mL for camptothecin in the same buffer. In the purified topoisomerase I cleavable complex enzyme assay, compounds 6 and 7 demonstrated potent inhibition of topoisomerase I with IC50's of 300 and 416 nM, respectively, in comparison to 679 nM for camptothecin and 1028 nM for topotecan. In human tumor cell cytotoxicity assays, compounds 6 and 7 demonstrated potent antitumor activity against ovarian (SKOV3), ovarian with upregulated MDRp-glycoprotein (SKVLB), melanoma (LOX), breast (T47D), and colon (HT29) with IC50's ranging from 0.5 to 102 nM. Compounds 6 and 7 induced tumor regressions in the HT29 human colon tumor xenograft model and demonstrated similar rank order of potency compared to in vitro assay results. PMID- 7853332 TI - 7'-Substituted amino acid conjugates of naltrindole. Hydrophilic groups as determinants of selective antagonism of delta 1 opioid receptor-mediated antinociception in mice. AB - A series of amino acid conjugates (2-6) of naltrindole (1) were synthesized from 7'-carboxynaltrindole (7) in order to obtain delta antagonists that would have minimal access to the central nervous system (CNS) upon peripheral administration. All of the ligands (2-7) were tested in smooth muscle preparations and found to be potent and selective delta opioid antagonists. Receptor binding showed 2-7 to be highly delta-selective, with Ki ratios (mu/delta, kappa/delta) ranging from 127 to 38,000. Two of the more selective conjugates, the glycinate 2 and aspartate 3, were evaluated by the iv and icv routes in mice, and they afforded very high iv/icv dose ratios (112,766 and 46,667, respectively) consistent with poor CNS penetration. The in vivo testing revealed that 2 and 3 are delta 1-selective antagonists, in contrast to naltriben and related ligands which are delta 2-selective. The fact that the binding data are not consistent with the in vivo data suggests that the origin of the selectivity of naltrindole congeners may be related to selective access to tissue compartments in the CNS rather than to binding affinity differences between delta opioid receptor subtypes. PMID- 7853333 TI - Self-assembly of a quinobenzoxazine-Mg2+ complex on DNA: a new paradigm for the structure of a drug-DNA complex and implications for the structure of the quinolone bacterial gyrase-DNA complex. AB - The quinobenzoxazine compounds A-62176 and A-85226 belong to a novel class of antineoplastic agents that are catalytic inhibitors of topoisomerase II and also structural analogs of the antibacterial DNA gyrase inhibitor Norfloxacin. In vitro studies have shown that their antineoplastic activity is dependent upon the presence of divalent metal ions such as Mg2+ and Mn2+, although the precise role of these ions in the mechanism of action is unknown. In this study we have investigated the structures of the binary complex between the quinobenzoxazines and Mg2+ and the ternary complex between quinobenzoxazine-Mg2+ and DNA. The stoichiometry of the binary and ternary complexes and the biophysical studies suggest that a 2:2 drug:Mg2+ complex forms a "heterodimer complex" with respect to DNA in which one drug molecule is intercalated into DNA and the second drug molecule is externally bound, held to the first molecule by two Mg2+ bridges, which themselves are chelated to phosphates on DNA. There is a cooperativity in binding of the quinobenzoxazines to DNA, and a 4:4 drug:Mg2+ complex is proposed in which the two externally bound molecules from two different 2:2 dimers interact via pi-pi interactions. The externally bound quinobenzoxazine molecules can be replaced by the quinolone antibacterial compound Norfloxacin to form mixed structure dimers on DNA. Based upon the proposed model for the 2:2 quinobenzoxazine:Mg2+ complex on DNA, a parallel model for the antibacterial quinolone-Mg2(+)-DNA gyrase complex is proposed that relies upon the ATP-fueled unwinding of DNA by gyrase downstream of the cleavable complex site. These models, which have analogies to leucine zippers, represent a new paradigm for the structure of drug-DNA complexes. In addition, these models have important implications for the design of new gyrase and topoisomerase II inhibitors, in that optimization for structure-activity relationships should be carried out on two different quinolone molecules rather than a single molecule. PMID- 7853334 TI - Impact of polyamine analogues on the NMDA receptor. AB - Several N,N'-terminal dialkylated homologs of the tetraamine spermine exhibit a pronounced biphasic activity at the N-methyl-D-aspartate (NMDA) receptor-channel complex in rat cerebral cortex membranes in the presence of 100 microM L glutamate and 100 microM glycine. At low micromolar polyamine concentrations, these analogs enhance binding of [3H]-(+)-5-methyl-10,11-dihydro-5H dibenzo[a,d]cyclohepten-5,10-im ine ([3H]MK-801) similar to spermine (SPM). At higher concentrations (e.g., > or = 10 microM), the analogs are antagonists of [3H]MK-801 binding. The most potent analog, N1,N14-bis(1-adamantyl)homospermine, is almost totally devoid of agonist activity and is a potent antagonist at concentrations > or = 5 microM. Three structural features of the tetraamines studied appear to correlate with potency of inhibition: (1) N-terminally alkylated polyamines > terminal primary amines (e.g., SPM); (2) length of the polyamine backbone, e.g., DMHSPM > DMNSPM; and (3) size of the terminal alkyl groups, i.e., adamantyl > tert-butyl > ethyl > methyl. These findings emphasize the potential of the tetraamine backbone as a pharmacophore to modulate NMDA receptor-channel function. PMID- 7853335 TI - 11 beta-Substituted estradiol derivatives, potential high-affinity carbon-11 labeled probes for the estrogen receptor: a structure-affinity relationship study. AB - In view of their possible development as carbon-11-labeled receptor-based radiotracers for imaging estrogen-responsive breast tumors, we have synthesized a series of estradiols (1), estriols (2), 11 beta-ethylestradiols (3), 11 beta ethylestriols (4), 11 beta-methoxyestradiols (5), and 11 beta-methoxyestriols (6), differing in the type of substituent R present at the 17 alpha-position (a, H; b, -CH3; c, -C identical to CH; d, -C identical to CCH3; e, -Ph; f, -CH = CHMe cis), and measured their binding affinity for the estrogen receptor relative to estradiol (RBA). As expected, all the derivatives having an 11 beta-ethyl substituent have good binding properties (3a-d, 4a-d, RBA (25 degrees C): 109 3000%), and among them there are several promising candidates for carbon-11 labeling. Moxestrol (RBA (25 degrees C) = 185%) and its corresponding estriol derivative (4c, RBA (25 degrees C) = 20%) were the analogs having the highest affinity in the 11 beta-methoxyestradiol (5a-f) and 11 beta-methoxyestriol (6a-e) series, respectively; other analogs (R = Me, C identical to CMe, Ph, or cis-CH = CHMe) had uniformly lower RBA values. PMID- 7853336 TI - Phosphinyl acid-based bisubstrate analog inhibitors of Ras farnesyl protein transferase. AB - The rational design, synthesis, and biological activity of phosphonyl- and phosphinyl-linked bisubstrate analog inhibitors of the enzyme Ras farnesyl protein transferase (FPT) are described. The design strategy for these bisubstrate inhibitors involved connection of the critical binding components of the two substrates of FPT (ras protein and farnesyl pyrophosphate, FPP) through a phosphonyl- or phosphinyl-bearing linker. Compound 14, the first example in this series, was found to be a potent FPT inhibitor (I50 = 60 nM). A further 15-fold enhancement in activity was observed upon replacement of the VLS tripeptide sequence in 14 with VVM (15, I50 = 6 nM). The phosphinic acid analog 16 (I50 = 6 nM) was equiactive to phosphonic acid 15. Compounds 14-16 afforded 1000-fold selectivity for FPT against the closely related enzyme geranylgeranyl protein transferase type I, GGT-I [14, I50(GGT-I) = 59 microM; 15 I50(GGT-I) = 10 microM; 16 I50(GGT-I) = 21 microM]. Methyl and POM ester prodrugs 17-19 were prepared and evaluated in whole cell assays and appear to block ras-induced cell transformation, as well as colony formation in soft agar. A distinctive feature of this novel class of potent and selective bisubstrate FPT inhibitors is that they are non-sulfhydryl in nature. PMID- 7853337 TI - Cosalane analogues with enhanced potencies as inhibitors of HIV-1 protease and integrase. AB - Several new analogues of the novel anti-HIV agent cosalane have been synthesized and evaluated as inhibitors of HIV-1 integrase and protease, HIV-1 replication, HIV-1 and HIV-2 cytopathicity, HIV-1- and HIV-2-mediated syncytium formation, and cytopathicity of a variety of human pathogenic viruses. The congeners displayed enhanced potencies relative to cosalane itself as inhibitors of HIV-1 integrase and protease. The two most potent analogues against HIV-1 integrase displayed IC50 values of 2.2 microM, while the three most potent compounds against HIV-1 protease had IC50 values in the 0.35-0.39 microM range. In addition to its activity against HIV-1 and HIV-2 cytopathicity, cosalane inhibited the cytopathic effects of herpes simplex virus-1, herpes simplex virus-2, and human cytomegalovirus at concentrations that were well below the cytotoxic concentrations. Potentially useful antiviral activities were also revealed for some of the new cosalane congeners against influenza virus, Junin virus, and Tacaribe virus. PMID- 7853338 TI - 2,3-Dihydro-1-benzofuran-5-ols as analogues of alpha-tocopherol that inhibit in vitro and ex vivo lipid autoxidation and protect mice against central nervous system trauma. AB - A series of alpha-tocopherol analogues was synthesized with potential therapeutic value for such pathological conditions as stroke and trauma. A set of criteria such as the inhibition of in vitro lipid peroxidation, superoxyl radical scavenging, and brain penetration, as measured by ex vivo inhibition of lipid peroxidation, was applied to select the most effective compound. 2,3-Dihydro 2,2,4,6,7-pentamethyl-3-[(4-methylpiperazino)methyl]-1 - benzofuran-5-ol dihydrochloride (22) was selected because of its superior antioxidant properties and better brain penetration. This compound also protected mice against the effects of head injury. The criteria thus turned out to be useful for the characterization of a neuroprotective analogue of alpha-tocopherol. PMID- 7853339 TI - Pimelautide or trimexautide as built-in adjuvants associated with an HIV-1 derived peptide: synthesis and in vivo induction of antibody and virus-specific cytotoxic T-lymphocyte-mediated response. AB - Covalent association of lipopeptidic immunostimulants is known to improve the immunogenicity of short peptides. In this paper, we describe the synthesis of four analytically pure immunogens, prepared by two different strategies, in which a hexadecameric peptide (V3) derived from the principal neutralizing domain of HIV-1 envelope glycoprotein was associated with two different murein-derived lauroyl-peptides, Pimelautide (RP 44102), or Trimexautide (RP 56142). The in vivo immunogenicity of these compounds was evaluated according to two different criteria: the ability to elicit a cellular-T cytotoxic (CTL response) and the ability to stimulate antibody response. Our studies show that one of our compounds (TrxSucV3) was able to efficiently induce a relevant virus-specific CTL response, while another one (PimSucV3) was able to stimulate a strong antibody response to the linked peptide, or to a co-injected protein. These results suggest that both activities rely on different structure-activity relationships and that such a chemically defined model of peptide vaccines may be used to selectively stimulate subpopulations of immunocompetent cells. PMID- 7853340 TI - De novo design of enzyme inhibitors by Monte Carlo ligand generation. AB - A new computational method for the in situ generation of small molecules within the binding site of a protein is described. The method has been evaluated using two well-studied systems, dihydrofolate reductase and thymidylate synthase. The method has also been used to guide improvements to inhibitors of HIV-1 protease. One such improvement resulted in a compound selected for preclinical studies as an antiviral agent against AIDS. PMID- 7853341 TI - 3-Heteroaryl-substituted quinuclidin-3-ol and quinuclidin-2-ene derivatives as muscarinic antagonists. Synthesis and structure-activity relationships. AB - A number of 3-heteroaryl-substituted quinuclidin-3-ol and quinuclidin-2-ene derivatives have been prepared and evaluated for muscarinic and antimuscarinic properties. The affinities of the new compounds (13, 14, 16-32, and 36-52a,b) were tested in homogenates of cerebral cortex, heart, parotid gland, and urinary bladder from guinea pigs using (-)-[3H]-3-quinuclidinyl benzilate [(-)-[3H]QNB] as the radioligand and in a functional assay using isolated guinea pig urinary bladder. The present compounds behaved as competitive muscarinic antagonists in the urinary bladder. The highest receptor binding affinity, Ki (cortex) = 9.6 nM, was observed for 3-(2-benzofuranyl)quinuclidin-2-ene (31). The corresponding 3 benzofuranyl (36) and 3-benzothienyl (37) homologues had about 3.5-fold lower affinity for cortical muscarinic receptors. All quinuclidin-3-ol derivatives (14 and 16-25) had lower binding affinities for the different muscarinic receptor subtypes than the corresponding quinuclidin-2-ene analogues when examined in the various tissue homogenates. In general, the new compounds showed low subtype selectivity. The structure-affinity relationships are discussed in terms of differences in proton basicity of the azabicyclic nitrogen and differences in geometric, conformational, and/or electronic properties of the compounds. The cortical antimuscarinic potency is also related to the complementarity of the compounds to the putative binding site of the muscarinic m1 receptor. PMID- 7853342 TI - 5'-[4-(Pivaloyloxy)-1,3,2-dioxaphosphorinan-2-yl]-2'-deoxy-5-fluorouridine: a membrane-permeating prodrug of 5-fluoro-2'-deoxyuridylic acid (FdUMP). AB - 5'-[4-(Pivaloyloxy)-1,3,2-dioxaphosphorinan-2-yl]-2'-deoxy-5 -fluorouridine (1c) was designed as a potential membrane-permeable prodrug of 2'-deoxy-5 fluorouridine 5'-monophosphate (FdUMP), a putative active metabolite of the antitumor drug 5-fluorouracil (FU). It was anticipated that 1c would be hydrolyzed in vivo by carboxylate esterase (E.C. 3.1.1.1) to the labile 4-hydroxy analogue 2a, which should penetrate cells by passive diffusion and ring open to the aldehyde 3a. Spontaneous elimination of acrolein from 3a would then generate the free nucleotide, FdUMP. 1c might also penetrate cells directly and undergo the same degradation sequence after hydrolysis by cellular esterases. 1c was prepared by condensing 2-hydroxy-2-oxo-4-(pivaloyloxy)-1,3,2-dioxaphosphorinane with 2'-deoxy-5-fluorouridine (FUdR) in the presence of triphenylphosphine and diethyl azodicarboxylate. 1c was moderately stable in aqueous buffers over the pH range 1-7.4 (T1/2 > 30 h). In the presence of carboxylate esterase, however, it was degraded, in a concentration-dependent manner, to FdUMP. No intermediates were detected in the incubation mixture. In mouse plasma, 1c was degraded first to FdUMP and then to FUdR. The latter is presumably formed by dephosphorylation of FdUMP by plasma 5'-nucleotidases or phosphatases. 1c and FU inhibited the growth of Chinese hamster ovary (CHO) cells in culture at a concentration of 5 x 10(-6) M. 1c was equally potent against a CHO variant that was 20-fold resistant to FU. Administered intraperitoneally for 5 consecutive days, 1c was as effective as FU at prolonging the life span of mice bearing P-388 leukemia. In the presence of 2-mercaptoehtanesulfonic acid, an acrolein scavenger, 1c was equally effective against a P-388 mutant cell line that was resistant to FU. Collectively, these data suggest that 1c acts as a membrane-permeable prodrug of FdUMP. This prodrug strategy may be generally useful for introducing dianionic phosphates and phosphonates into cells. PMID- 7853343 TI - Amphoteric drugs. 3. Synthesis and antiallergic activity of 3-[(5,11 dihydro[1]benzoxepino[4,3-b]pyridin-11- ylidene)piperidino]propionic acid derivatives and related compounds. AB - An important approach to the design of antiallergic agents with reduced penetration into the central nervous system (CNS) is described. A series of 3 [(5,11- dihydro[1]benzoxepino[4,3-b]-pyridin-11-ylidene)piperidino]propion ic acid derivatives (31-47) and related compounds (48-54) were synthesized and evaluated for antiallergic activity and penetration of a compound into the CNS in comparison with the corresponding 6H-dibenz[b,e]oxepin derivative (3). Combination of zwitterionization and introduction of a pyridine component resulted in an increase in antiallergic activity and a great reduction of penetration into the CNS, which was evaluated by the selectivity (B/A) of antihistaminic activities in the central system [ID50 value (B) for ex vivo H1 binding to mouse brain membranes] and in the peripheral system [ED50 value (A) for inhibitory effect on histamine-induced increase in vascular permeability in mice]. This surprising reduction of penetration into the CNS could be considered on the basis of an increase in hydrophilicity caused by both of the zwitterionization and the introduction of a pyridine component. 3-[4-(8-Fluoro 5,11-dihydro[1]benzoxepino[4,3- b]pyridin-11-ylidene)piperidino]propionic acid (33) exhibited a strong antiallergic effect in various experimental models and very low penetration into the CNS. Compound 33 (HSR-609) is now under clinical trial as a promising antiallergic agent with greatly reduced penetration into the CNS. PMID- 7853345 TI - Chromophore-modified antitumor anthracenediones: synthesis, DNA binding, and cytotoxic activity of 1,4-bis[(aminoalkyl)amino]benzo[g]-phthalazine-5,10-diones. AB - As part of a program aimed at exploring the effect of the introduction of heteroatoms into the anthracene-9,10-dione chromophore, we have synthesized novel 1,4-bis[(aminoalkyl)amino]-benzo[g]phthalazine-5,10-diones (BPDs) 1 which are related to the antitumor agents ametantrone and mitoxantrone. Derivatives 1 were prepared by chromic acid oxidation of acylated benzo[g]phthalazines 5 followed by acid hydrolysis or by silylation-amination of 5,10-dihydroxybenzo[g]phthalazine 1,4-dione (8). The 1-[(aminoalkyl)amino]-4-amino congeners 2 were isolated in low yields as byproducts from the oxidation of 5. Against a panel of human tumor cell lines, the benzo[g]phthalazine-5,10-diones 1 and 2 exhibited cytotoxic activity comparable or even superior to that of mitoxantrone. In compounds 1, structure activity relationships different than those operative in the carbocyclic series appeared to emerge. DNA-binding studies with the ametantrone-like compound 1c and its single-armed congener 2c indicated that the introduction of a 2,3-diaza subunit into the anthracene-9,10-dione chromophore reduces the affinity of the drug for DNA in comparison with ametantrone. On the other hand, the number of side-chain groups does not affect binding to a great extent. These findings seem to suggest mechanisms of cell death other than those induced by simple interaction of the 1,4-BPDs 1 and 2 with DNA. PMID- 7853344 TI - N-acyl-2-substituted-1,3-thiazolidines, a new class of non-narcotic antitussive agents: studies leading to the discovery of ethyl 2-[(2-methoxyphenoxy)methyl] beta-oxothiazolidine-3-propanoate. AB - The synthesis of a novel class of antitussive agents is described. The compounds were examined for antitussive activity in guinea pig after cough induction by electrical or chemical stimulation. Ethyl 2-[(2-methoxyphenoxy)methyl]-beta oxothiazolidine-3-propanoate (BBR 2173, moguisteine, 7) and other structurally related compounds showed a significant level of activity, comparable to that of codeine and dextromethorphan. The compounds presented in this paper are characterized by the N-acyl-2-substituted-1,3-thiazolidine moiety, which is a novel entry in the field of antitussive agents. The serendipitous discovery of the role played by the thiazolidine moiety in determining the antitussive effect promoted extensive investigations on these structures. This optimization process on N-acyl-2-substituted-1,3-thiazolidines led to the initial identification of 2 [(2-methoxypheoxy)methyl]-3-[2-(acetylthio)acetyl]- 1,3-thiazolidine (18a) as an interesting lead compound. The careful study of the rapid and very complicated metabolism of 18a provided further insights for the design of newer related derivatives. The observation that the metabolic oxidation on the lateral chain's sulfur of 18a to sulfoxide maintained the antitussive properties suggested the introduction of isosteric functional groups with respect to the sulfoxide moiety. Subsequent structural modifications showed that hydrolyzable malonic residues in the 3-position of the thiazolidine ring were able to assure high antitussive activity. This optimization ultimately led to the selection of moguisteine (7) as the most effective and safest representative of the series. Moguisteine is completely devoid of unwanted side effects (such as sedation and addiction), and its activity was demonstrated also in clinical studies. PMID- 7853346 TI - Synthesis of novel thiol-containing citric acid analogues. Kinetic evaluation of these and other potential active-site-directed and mechanism-based inhibitors of ATP citrate lyase. AB - ATP citrate lyase is an enzyme involved in mammalian lipogenesis and cholesterogenesis. Inhibitors of the enzyme represent a potentially novel class of hypolipidemic agents. Citric acid analogues 5-16 bearing electrophilic and latent electrophilic substituents were synthesized and evaluated as irreversible inhibitors of the enzyme. The design of these agents was based on the classical enzymatic mechanism where an active-site nucleophile (thiol) was believed to be critically involved in catalysis. Reversible inhibition (Ki's ranging from ca. 20 to 500 microM) was observed for compounds 5, 10, and 12-16. Compounds 6-9 and 11 had no appreciable affinity for enzyme (Ki > 1 mM). Time-dependent inactivation of the enzyme by 5-16 was not detected following long incubation times (> 1 h, 37 degrees C) at 2 mM inhibitor concentrations. PMID- 7853347 TI - Mechanism-based isocoumarin inhibitors for human leukocyte elastase. Effect of the 7-amino substituent and 3-alkoxy group in 3-alkoxy-7-amino-4 chloroisocoumarins on inhibitory potency. AB - A series of 3-alkoxy-7-amino-4-chloroisocoumarins with various 3-alkoxy substituents have been prepared and evaluated as inhibitors of human leukocyte elastase (HLE). In addition, a new series of acyl, urea, and carbamate derivatives of 7-amino-4-chloro-3-methoxyisocoumarin (1), 7-amino-4-chloro-3 propoxyisocoumarin (3), and 7-amino-4-chloro-3-(2-bromoethoxy)isocoumarin (6) have been synthesized. Most of the synthesized compounds are very potent inhibitors of HLE with kobs/[I] values between 10(4) and 10(6) M-1 s-1. Hydrophobic substituents on the 7-amino position of the isocoumarin ring afford the best selectivity and inhibitory potency for HLE. In the 2-bromoethoxy series, compound 24 with a PhNHCONH 7-substituent had a kobs/[I] value of 1.2 x 10(6) M-1 s-1, was very selective for HLE, and was the most potent inhibitor of HLE tested. Of the extended chain L-phenylalanyl derivatives, the Bz-L-Phe compound 66 with a kobs/[I] value of 1.8 x 10(5) M-1 s-1 was the most potent inhibitor of HLE in the 3-methoxyisocoumarin series and was also very selective for HLE. Our results indicate that a high degree of selectivity, along with potency, can be introduced into mechanism-based isocoumarin inhibitors. PMID- 7853348 TI - Three-dimensional structure of cyclohexapeptides containing a phosphinic bond in aqueous solution: a template for zinc metalloprotease inhibitors. A NMR and restrained molecular dynamics study. AB - The 3D structures of two phosphinic cyclic hexapeptide inhibitors of bacterial collagenase, cyclo-(Gly1-Pro2-Phe3 psi[PO2-CH2]Gly4-Pro5-Nle6) (compound I) and cyclo(Gly1-Pro2-D-Phe3 psi[PO2-CH2]-Gly4-Pro5-Nle6) (compound II), in aqueous solution, as derived from NMR spectroscopy and molecular dynamics simulations, are described. The general structures of these cyclic hexapeptides closely resemble the "canonic" two-reverse-turn structure, with the proline occupying the (i + 1) position of the turns and the glycine the connecting positions. The phosphinic bond is located between the (i + 2) and (i + 3) positions of one of these turns. However, a striking feature of the backbone structure of these peptides is the presence of double type VIII-turns in compound I, and in compound II of type VIII- and tentatively named type IX-turns. The comparison of the 3D structures of these two cyclic hexapeptides shows that the stereochemistry of the phenylalanylphosphinyl residue influences not only the local conformation but also the global topology of the peptide macrocycle. The differences in the 3D structure of these compounds are discussed in relation to their inhibitory potencies and with the view of using these constrained cyclic peptides as a scaffold for the development of rigid metalloproteases inhibitors. PMID- 7853349 TI - (+)-cis-N-(para-, meta-, and ortho-substituted benzyl)-N-normetazocines: synthesis and binding affinity at the [3H]-(+)-pentazocine-labeled (sigma 1) site and quantitative structure-affinity relationship studies. AB - sigma 1 receptor ligands have potential pharmacological significance as antipsychotic drugs, as tools in the study of drug-induced motor function disorders, and as radiopharmaceutical imaging agents for the noninvasive imaging of malignant tumors in human subjects. A series of substituted N-benzyl-N normetazocines were synthesized and their binding affinity at the sigma 1 receptor evaluated in order to examine the details of the structure--affinity relationships (SAR) of a previously determined high-affinity lead compound, (+) cis-N-benzyl-N-normetazocine (Ki = 0.67 nM). Variation in the benzyl substituents of these compounds produced a 1590-fold range in affinity at the sigma 1 receptor from the unsubstituted benzyl analog to the lowest affinity p-tert-butylbenzyl analog (Ki = 1066 nM). The nanomolar binding affinity for the sigma 1 receptor of (+)-cis-N-(4-fluorobenzyl)-N-normetzocine suggests that this analog may be a useful PET imaging agent. PMID- 7853350 TI - Isothiocyanate-substituted benzyl ether opioid receptor ligands derived from 6 beta-naltrexol. AB - A series of regioisomeric substituted 6-O-benzyl ethers of 6 beta-naltrexol (12) in which isothiocyanate groups were attached directly to or one carbon removed from the aromatic ring of the benzyl group were prepared. These agents were prepared to obtain electrophilic opioid ligands potentially useful in the characterization of opioid receptors and drug-receptor interactions. Preparation of these ligands was accomplished from 3-O-trityl-6 beta-naltrexol (13) via phase transfer-catalyzed alkylation of the regioisomeric o-, m-, and p-nitrobenzyl halides and the o-, m-, and p-cyanobenzyl halides. The intermediates were deprotected and reduced, and formation of the isothiocyanates from the corresponding amines completed the synthesis. The ligands (6-11) were tested in radioligand displacement assays in guinea pig brain homogenate for opioid receptor binding affinity and irreversibility. All six of the isothiocyanates demonstrated significant affinity in the displacement assays for all three opioid receptors. They also appeared to be irreversibly bound at each of the receptor types. Compound 6, the o-isothiocyanatobenzyl ether analog, had the highest affinity, and it demonstrated significant irreversibility at very low concentration. It appears to be suitable for further investigation. PMID- 7853351 TI - Dioxygenase and co-oxidase activities of rat hepatic cytosolic lipoxygenase. AB - The role of rat liver cytosolic lipoxygenase in the metabolism of benzidine was studied using linoleic acid as a cosubstrate. Under optimum assay conditions, cytosolic dioxygenase activity in the presence of 3.5 mM linoleic acid at pH 7.2 was 74.07 +/- 1.43 nmoles/min/mg protein. Benzidine was oxidized at the rate of 3.18 +/- 0.13 nmoles/min/mg cytosolic protein to benzidine diimine at pH 7.2 in the presence of 3.65 mM linoleic acid. Both dioxygenase and co-oxidase reactions were inhibited by nordihydroguaiaretic acid in a concentration-dependent manner. Partially purified preparations of rat liver lipoxygenase, free of hemoglobin, exhibited a dioxygenase activity of 223.1 +/- 65.9 nmoles/min/mg protein and co oxidase activity of 6.1 +/- 0.5 nmoles/min/mg protein toward benzidine. These results suggest that hepatic lipoxygenase may play an important role in the metabolism of this hepatocarcinogen. PMID- 7853352 TI - Phospholipase A2 activation in cultured mouse hepatocytes exposed to tumor necrosis factor-alpha. AB - High concentrations of tumor necrosis factor alpha (TNF alpha) are cytotoxic to cultured hepatocytes. Impairment of energy metabolism and generation of an intracellular oxidant stress are important events in the pathogenesis of this toxicity (6). In the present study, we have examined the role of phospholipase A2 activation in TNF alpha-induced toxicity in mouse hepatocytes, since it has been reported to play a key role in TNF alpha cytolytic activity in other cell types. Recombinant murine TNF alpha (0.1 microgram/mL) caused a dose-dependent increase in PLA2 activity in cultured mouse hepatocytes. The increase in PLA2 activity was observed after only 0.5 hour of exposure (152 +/- 10% of control), and continued to increased over the first 4 hours of exposure (292 +/- 32%). However, TNF alpha induced GSSG efflux and ATP depletion did not occur until after 2 hours of exposure. Furthermore, a small level of cytotoxicity was observed after a 24 hour incubation period. Putative PLA2 inhibitors, chlorpromazine (CPZ) and 4 bromophenacyl bromide (BPB), both prevented the TNF alpha-induced increase in PLA2 activity. They also reduced ATP depletion, GSSG efflux, and cytotoxicity. The PLA2 inhibitor, manoalide (a natural marine product), completely prevented PLA2 activation and cytotoxicity induced by TNF alpha. Pretreatment of hepatocytes with cycloheximide, to inhibit protein synthesis, increased TNF alpha induced cytotoxicity. Cycloheximide pretreatment also potentiated PLA2 activation, ATP depletion, and GSSG efflux. CPZ and BPB both reduced the extent of PLA2 activation, ATP depletion, GSSG formation, and cytotoxicity in the cycloheximide pretreated cells exposed to TNF alpha. Taken together, these results demonstrate that TNF alpha activates PLA2, which occurs prior to other deleterious events in hepatocytes, and that inhibition of PLA2 activity reduces cell injury by TNF alpha. This suggests that PLA2 activation may lead to impairment of energy metabolism, an oxidant stress, and cytotoxicity in cells exposed to TNF alpha. Additionally, protein synthesis inhibition potentiates TNF alpha induction of PLA2 and toxicity, suggesting that there is a protein synthesis-dependent protective mechanism in hepatocytes which ameliorates the effects induced by PLA2. These findings provide strong evidence that PLA2 activation plays an important role in the pathogenesis of toxicity induced by TNF alpha in cultured mouse hepatocytes. PMID- 7853353 TI - Molecular interaction of [2,3-14C] acrylonitrile with DNA in gastric tissue of rat. AB - Acrylonitrile (VCN) is used extensively in polymer industries, and is known to induce gastric cancer following oral administration. A paucity of information exists regarding the mechanism(s) by which acrylonitrile induces gastric neoplasia. The time course for uptake of radioactivity by gastric tissue and covalent binding of [2,3-14C] VCN or its metabolites to gastric DNA were determined following a single oral dose of 46.5 mg/kg. The rates of DNA synthesis and repair, as measured by unscheduled DNA synthesis in the gastric tissue of VCN treated rats, were also studied. Maximum tissue uptake and covalent binding of radioactivity to gastric DNA were observed at 15 minutes following [2,3-14C] VCN administration. At 6 hours following VCN administration, significant inhibition (37% of control) in gastric replicative DNA synthesis was observed. A rebound followed by an increase (211% of control) in replicative DNA synthesis was observed at 24 hours. A three-fold elevation in unscheduled DNA synthesis was observed at 24 hours following treatment with VCN. These results indicate that VCN or its metabolites irreversibly interact with gastric DNA, causing DNA damage. The results also indicate that the delayed VCN-induced DNA repair, determined as unscheduled DNA synthesis, is inefficient for the removal of the resulting DNA lesions. PMID- 7853354 TI - Comparative kinetic study of the binding between 2,3,7,8-tetrachlorodibenzo-p dioxin and related ligands with the hepatic Ah receptors from several rodent species. AB - Kinetic analysis of the time course of association of [3H]-2,3,7,8 tetrachlorodibenzo-p-dioxin with hepatic cytosol from five rodent species gave additional evidence for differences in the properties of the Ah receptor ligand binding subunit between species. A parallel study of the association of six tritiated polychlorinated dibenzo-p-dioxins and dibenzofurans with hepatic Ah receptor from Wistar rat and C57BL/6 mouse showed that their rank order for kinetic affinity did not correlate with the rank ordering of their toxic potency and may vary according to the source of the Ah receptor. PMID- 7853355 TI - Arachidonic acid release in renal proximal tubule cell injuries and death. AB - Arachidonic acid release and the effect of phospholipase inhibitors on various types of cell injuries and death to rabbit renal proximal tubule suspensions were determined. Proximal tubules were exposed to the mitochondrial inhibitor antimycin A (0.1 microM), the protonophore carbonyl cyanide p trifluoromethoxyphenylhydrazone (1 microM FCCP), the oxidant tert-butyl hydroperoxide (0.5 mM TBHP), or the calcium ionophore ionomycin (5 microM) in the absence or presence of the putative phospholipase inhibitors dibucaine, mepacrine, chlorpromazine, or U-26384. The phospholipase inhibitors had no effect on the proximal tubule lactate dehydrogenase (LDH) release (a marker of cell death) produced by FCCP, antimycin A, or ionomycin after 1,2, or 2 hours of exposure, respectively. Only dibucaine and mepacrine decreased LDH release in TBHP-treated proximal tubules without decreasing TBHP-induced lipid peroxidation. Antimycin A and ionomycin did not release arachidonic acid from proximal tubules prelabeled with [1-14C] arachidonic acid. In contrast, TBHP released arachidonic acid from proximal tubules prior to the onset of cell death, and dibucaine and mepacrine decreased the TBHP-induced release. Thus, phospholipase inhibitors were cytoprotective in those injuries that produced arachidonic acid release. These results suggest that arachidonic acid release and phospholipase A2 activation play a contributing role in oxidant-induced renal proximal tubule cell injury and death but not in mitochondrial inhibitor- or calcium ionophore-induced proximal tubule cell injury and death. PMID- 7853356 TI - The effects of ricin on the sympathetic vascular neuroeffector system of the rabbit. AB - Ricin is a toxic lectin that inhibits protein synthesis. Because ricin decreases arterial pressure and causes cardiovascular collapse, its effects on the vascular neuroeffector system were investigated. Rabbits were given either of two doses of ricin, and then norepinephrine (NE) release from aorta to transmural stimulation, NE uptake into aorta, NE content of aorta, monoamine oxidase activity, and catechol-O-methyl transferase activity in aorta were determined 18 hours, 4 days or 7 days later. Norepinephrine uptake and enzyme activities in the aorta were not altered by ricin administration. Norepinephrine release and content of aorta were increased at most time periods following ricin administration, significantly so for NE content at 4 days and for release at 18 hours following the lower dose of ricin. We conclude that the mechanisms involved in the release of NE from sympathetic nerves in the vasculature are not impaired by ricin administration, but rather show changes that indicate increased compensatory activity. PMID- 7853358 TI - Cyanide induces protein kinase C translocation: blockade by NMDA antagonists. AB - Activation and translocation of protein kinase C (PKC) during KCN-induced histotoxic hypoxia was studied in rat brain slices prepared from cerebellum, hippocampus, and cortex. Treatment with 1-10 mM KCN produced a significant increase in PKC translocation and enzyme activity in the particulate fraction of cerebellar and hippocampal slices. In cortical slices, PKC activity was not affected by cyanide treatment. The membrane-associated PKC activity reached a maximum 30 minutes after incubation with KCN and remained elevated up to 60 minutes in both the hippocampus and cerebellum. Pretreatment with MK-801 and APV, specific NMDA receptor antagonists, blocked the cyanide-stimulated translocation in the hippocampus and cerebellum, whereas CNQX, an AMPA/kainate receptor antagonist, did not alter the response. These results demonstrate that cyanide stimulates PKC activation and translocation from the cytosol to membranes in select brain areas and NMDA receptor activation mediates this process. PMID- 7853357 TI - Characterization of heterologously expressed recombinant retinoic acid receptors with natural or synthetic retinoids. AB - The first step in retinoid action is binding to their nuclear receptors. Therefore, characterization of binding characteristics of retinoids is of major importance. Human retinoic acid receptors alpha (hRAR alpha), hRAR beta, and mouse RAR gamma (mRAR gamma) were expressed heterologously in Escherichia coli as a recombinant glutathione S-transferase (GST) fusion protein. The expressed fusion proteins were functional and bound specifically to the all-trans-retinoic acid (RA). The dissociation constants (Kd) for RA were 1.4 nM for GST-hRAR alpha, 1.4 nM for GST-hRAR beta, and 3.3 nM for GST-mRAR gamma, respectively. The fusion proteins were further used for competitive displacement assays to determine the displacement constant (DC50) for other selected retinoids. All-trans-RA and 4-oxo all-trans-RA have high affinity with all three receptors (DC50 = 0.8-55 nM). The 13-cis RA binds to hRAR alpha with low affinity, but not to other RARs evaluated here. All-trans-N-ethylretinamide, all-trans-retinylacetate, and an ethyl ester of tetrahydronaphthalene derivative had no affinity to any RARs. The hRAR alpha and mRAR gamma receptors did not bind a naphthalene carboxylic acid derivative of RA, but hRAR beta binds this chemical with high affinity. Results indicated that the three recombinant proteins were functional in binding various RA congeners. The affinity and binding data of these retinoids were compared to their observed teratogenic activity. PMID- 7853359 TI - Differential modulation of hepatic cytochrome P-450 enzymes in rat and Syrian hamster by 4'-trifluoromethyl-2,3,4,5-tetrachlorobiphenyl. AB - The effects of a single injection (40 mg/kg) of 4'-trifluoromethyl-2,3,4,5 tetrachlorobiphenyl (CF3) on hepatic cytochrome P-450 monooxygenases were assessed in rat and syrian hamster. The CF3 treatment significantly increased the total amount of cytochrome P-450 in both species. In rats, CF3 treatment caused marked increases in ethoxyresorufin O-deethylase (EROD), arylhydrocarbon hydroxylase (AHH), and testosterone 7 alpha-hydroxylase activities but significantly reduced the activities of benzphetamine N-demethylase (BzND), erythromycin N-demethylase (ErND), testosterone 6 beta, 16 alpha, and 16 beta hydroxylase, and formation of androstenedione. Administration of CF3 to hamsters strongly induced the activities of EROD, AHH, BzND, testosterone 15 alpha, and 16 alpha-hydroxylases, and androstenedione production, whereas ErND, testosterone 6 beta, and 7 alpha-hydroxylases were decreased. Administration of CF3 to rats induced the CYP1A family proteins and CYP2A1, while CF3 reduced the level of CYP2B1, and, to a lesser extent, of CYP6 beta 2. In hamsters, CF3 treatment significantly induced the CYP1A2, CYP2A1, CYP2A8, and CYP2B1 isozymes, whereas the CYP6 beta 2 level was decreased. The ability of hepatic microsomes to activate aflatoxin B1 and benzo(a)pyrene was elevated by CF3 treatment in hamsters, while activation of aflatoxin B1 was decreased in microsomes from CF3 treated rats. These results showed differences in the CF3-induced pattern of rat and hamster cytochrome P-450 monooxygenases. PMID- 7853360 TI - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-induced reduction of adenosine deaminase activity in vivo and in vitro. AB - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent immunosuppressant in several animal species. The purpose of this study was to determine if TCDD affected the activity of adenosine deaminase (ADA), a purine metabolizing enzyme that is vital to the proper functioning of the immune system. The effect of TCDD on ADA activity was studied in various tissues of male Balb/c mice (a TCDD responsive strain) and DBA/2 mice (a less-responsive strain). Of the tissues examined after administration of TCDD in vivo (115 micrograms/kg, i.p.), ADA activity was found to be significantly reduced in thymic and splenic tissues of Balb/c mice at 24 hours postadministration. The enzyme activity in these affected tissues remained consistently low through 10 days postadministration. Such an effect of TCDD was both dose and time related in the thymic tissue of Balb/c mice. In contrast, no appreciable alterations in ADA activity were evident in any of the tissues of DBA/2 mice at any of the sampling intervals, indicating that such an effect of TCDD is likely to be mediated through the Ah receptor. This in vivo effect of TCDD on thymic ADA activity was also reproducible in situ where isolated whole thymuses were directly incubated with 10 nM TCDD. In this model, TCDD's effects on ADA activity were antagonized by known protein kinase or phosphorylation inhibitors such as quercetin, genistein, tyrphostin, and neomycin. These results indicate that the effect of TCDD on ADA activity in the thymus may be related to its property to elevate protein kinase activities in this tissue. ADA activity was also reduced in 3T3 cells that were treated with 10 nM TCDD in a low (1%) serum media. In contrast, 25 ng/mL epidermal growth factor (EGF) under such conditions consistently stimulated ADA activity. Interestingly, EGF at a similar concentration failed to elicit a stimulatory effect on ADA activity when cells were pretreated with TCDD. The property of TCDD to lower ADA activity under in vivo, in situ, as well as in vitro conditions appears to be largely related to its action to modulate protein phosphorylation activities. PMID- 7853361 TI - Choline derivatives and sodium fluoride protect acetylcholinesterase against irreversible inhibition and aging by DFP and paraoxon. AB - A light addressable potentiometric sensor was used to measure acetylcholinesterase (AChE) activity in order to evaluate the protective effects of quaternary compounds and NaF against enzyme phosphorylation and aging by two organophosphates. The use of the immobilized AChE made possible the quick removal of reagents (i.e., organophosphate, 2-pralidoxime, and protectant), thereby permitting accurate determination of AChE activity before and after phosphorylation and aging. Paraoxon was 15-fold more potent in inhibiting AChE than DFP, while the percent aging following phosphorylation by diisopropylfluorophosphate (DFP) was much higher. Sodium fluoride (NaF), the most effective protectant against phosphorylation and aging, and the quaternary ammonium compounds reduced significantly AChE inhibition by DFP and paraoxon, to similar degrees. Even though the percent AChE activity that was lost to aging was reduced by these agents, aging as a percent of phosphorylated AChE was not reduced. Thus, their major effect was in reducing the percent AChE phosphorylation, which consequently resulted in reduction of total aged AChE. The finding that quaternary ammonium compounds protect against phosphorylation is consonant with the proposed presence of the active site of AChE in an aromatic gorge. PMID- 7853362 TI - Hepatic cytochrome P450 2B induction by ethyl/phenyl-substituted congeners of phenobarbital in the B6C3F1 mouse. AB - The abilities of structural congeners of phenobarbital to induce immunoreactive hepatic cytochrome P450 2B (CYP2B) protein and associated catalytic activity (benzyloxyresorufin O-dealkylation) in the male B6C3F1 mouse were examined. Interspecies differences in inducing ability were examined through comparison of the results with induction data obtained previously with the male F344/NCr rat. The congeners were administered in the diet for 2 weeks at concentrations equimolar to 500 ppm of the prototype CYP2B inducer, phenobarbital. Of the series of compounds tested, phenobarbital was the most effective inducer of benzyloxyresorufin O-dealkylation and immunoreactive CYP2B protein, with 2-ethyl 2-phenylsuccinimide, 5-ethyl-5-phenylhydantoin, primidone, and glutethimide being only 19-42% as effective. 5-Ethyl-5-phenyloxazolidinedione and the ring-opened and decarboxylated congeners, N-(2-ethyl-2-phenylacetyl)urea and 2-ethyl-2 phenylmalonamide, displayed minimal induction of these catalytic activities. Dose response experiments performed with 5-ethyl-5-phenylhydantoin indicated that the intrinsic CYP2B-inducing activity of this congener was as great as that of phenobarbital in the mouse, although a fourfold greater dietary concentration of this hydantoin (2000 ppm) was required to elicit a response equivalent to that caused by 500 ppm phenobarbital. When extent of induction was related to serum total xenobiotic concentration rather than to administered dietary concentration, the potencies of the two congeners were determined to be more similar (58 vs. > or = 78 microM for phenobarbital and 5-ethyl-5-phenylhydantoin, respectively). PMID- 7853363 TI - Diagnostic distinction between anencephaly and amnion rupture sequence based on skeletal analysis. AB - The axial skeletal development of eight second trimester aborted fetuses, clinically diagnosed as amnion rupture sequence with cranial involvement, was examined radiographically and histologically. Three of the eight fetuses showed axial skeletal malformation in the spine and the craniofacial skeleton corresponding to the malformations seen in anencephaly. These are vertebral body malformations, consisting of double corpora and of osseous malformations in the components of the cranial base, the corpus of the occipital bone, and the postsphenoid bone. These types of malformation, which have previously been described, are located along the original course of the notochord. The findings show that it is possible by means of radiography of the axial skeleton to distinguish between anencephalic fetuses which become secondarily involved in amnion rupture and fetuses which were initially normally developed. The method supplements detailed fetal examination and provides important information for genetic counselling. PMID- 7853364 TI - Pulmonary atresia associated with maternal 22q11.2 deletion: possible parent of origin effect in the conotruncal anomaly face syndrome. AB - A blind study was designed to test the hypothesis that some persons with a relatively rare cardiac malformation, pulmonary atresia with ventriculoseptal defect (PA/VSD), have a recognisable phenotype. Fourteen patients with cyanotic congenital heart lesions were examined by dysmorphologists blinded to the type of cardiac malformation. Six children were judged to have a similar craniofacial appearance; all had PA/VSD. These children were not originally considered to fall within the classic phenotypes of the DiGeorge sequence or the velocardiofacial syndrome, both of which have been shown to be associated with deletions of 22q11. More recently, 22q11 deletions have been documented in the conotruncal anomaly face syndrome and apparently isolated conotruncal heart defects. A new acronym, CATCH 22 syndrome (Cardiac defects, Abnormal facies, Thymic hypoplasia, Cleft palate, and Hypocalcaemia) has been suggested to encompass this very broad phenotypic spectrum. A preliminary molecular study was conducted using the dinucleotide repeat D22S264 located on chromosome 22q11.2. All cases tested with the subtle but recognisable phenotype had deletions, all lacking the maternal contribution at this locus, suggesting there may be a parent of origin effect. PMID- 7853365 TI - Parental origin of Gs alpha gene mutations in Albright's hereditary osteodystrophy. AB - Heterozygous mutations of the Gs alpha gene leading to reduced Gs alpha activity have been identified in patients with Albright's hereditary osteodystrophy (AHO). However, AHO may be associated with hormone resistance (pseudohypoparathyroidism type Ia, PHPIa) or a normal response (pseudo-pseudohypoparathyroidism, PPHP). As both disorders may occur within the same family, the relationship between Gs alpha genotype and phenotype remains unresolved. The AHO phenotype may be dependent upon the sex of the parent transmitting the Gs alpha mutation, perhaps through a gene imprinting mechanism. We have used an intragenic Gs alpha FokI polymorphism to determine the parental origin of Gs alpha gene mutations in sporadic and familial AHO. We now show that a de novo G-->A substitution at the exon 5 donor splice junction in a child with PPHP was paternally derived. Furthermore, in a female with PPHP, the Gs alpha abnormality was shown to be of paternal origin, while subsequent maternal processing and transmission resulted in PHPIa in two offspring. As transmission of PPHP has rarely been reported, determining parental origin of the disease allele in sporadic cases may provide insight into the mechanism of hormone resistance in AHO. PMID- 7853366 TI - Possible role of imprinting in the Turner phenotype. AB - We have attempted to investigate the role of imprinting in the phenotype of Turner's syndrome. Sixty-three patients were investigated for parental origin of the retained normal X chromosome; 43 were found to retain the maternal X (XM) and 20 the paternal (XP). The relationship between a child's pretreatment height centile and parental height centiles was examined in 36 patients. No significant correlation was found between child and parental height centiles for XP or child and paternal height centiles for XM (p > 0.05) but a strong correlation was found between child's height centile and maternal height centile (p < 0.01) for XM. Using pooled data from this and other studies there was no significant correlation with renal anomalies but a strong correlation between cardiovascular abnormalities and XM (0.01 > p > 0.001) and neck webbing and XM (p < 0.05). We conclude that imprinting may play a part in the Turner's syndrome phenotype, especially with respect to pretreatment height, cardiovascular anomalies, and neck webbing. PMID- 7853367 TI - Deletions in the 5' region of dystrophin and resulting phenotypes. AB - Deletions in the dystrophin gene give rise to both Duchenne and Becker muscular dystrophies. Good correlation is generally found between the severity of the phenotype and the effect of the deletion on the reading frame: deletions that disrupt the reading frame result in a severe phenotype, while in frame deletions are associated with a milder disease course. Rare exceptions to this rule, mainly owing to frameshift mutations in the 5' region of the gene (in particular deletions involving exons 3 to 7) which are associated with a milder than expected phenotype, have been reported previously. In order to characterise better the relationship between genotype and phenotype as a result of mutations arising in the 5' region of the gene, we have studied a large cohort of patients with small in frame and out of frame deletions in the first 13 exons of the dystrophin gene. Fifty-five patients with a deletion in this area were identified; approximately one third of them had a phenotype different from that theoretically expected. Patients were divided into two groups: (1) patients with a severe clinical phenotype despite the presence of a small, in frame deletion and (2) patients with a mild phenotype and an out of frame deletion. Noticeable examples observed in the first group were Duchenne boys with a deletion of exon 5, of exon 3, and of exons 3-13. In the second group we observed several patients with an intermediate or Becker phenotype and out of frame deletions involving not only the usual exons 3-7 but also 5-7 and 3-6. These data indicate that a high proportion of patients with a deletion in the 5' end of the gene have a phenotype that is not predictable on the basis of the effect of the deletion on the reading frame. The N-terminus of dystrophin has at least one actin binding domain that might be affected by the small, in frame deletions in this area. The effect of the in frame deletions of exon 3, 5, and 3-13 on this domain might account for the severe phenotype observed in these patients. Other mechanisms, such as unexpected effect of the deletion on splicing behaviour, might, however, also be implicated in determining the phenotype outcome. PMID- 7853368 TI - Retinitis pigmentosa families showing apparent X linked inheritance but unlinked to the RP2 or RP3 loci. AB - Three families with retinitis pigmentosa (RP) are described in which the disorder shows apparent X linked inheritance but does not show linkage to the RP2 and RP3 regions of the short arm of the X chromosome. The families are also inconsistent with a localisation of the disease gene between DXS164 and DXS28. In one case, reassessment of the family in the light of these results suggested that the family may have an autosomal dominant form of RP. The remaining two families are consistent with X linkage and suggest the possibility of a new X linked RP (XLRP) locus. These families highlight the difficulties in determining the mode of inheritance on the basis of pedigree structure and clinical data alone. Molecular genetics plays an important role in confirming the mode of inheritance and in detecting potential misclassifications, particularly in a group of disorders as heterogeneous as RP. They emphasise that caution is required in genetic counselling of RP families, particularly in the absence of any molecular genetic analysis. PMID- 7853369 TI - Neurofibromatosis type 1 in Israel: survey of young adults. AB - Neurofibromatosis type 1 (NF1) (von Recklinghausen's disease) is one of the most common human autosomal dominant disorders. In a survey of 374440 17 year old Jewish recruits for military service, 390 cases of NF1 were discovered, with a prevalence of 1.04/1000 (0.94/1000 for males and 1.19/1000 for females), or two to five times the reported prevalence of this disease. NF1 was more common in youngsters whose parents were of North African and Asian origin (1.81/1000 and 0.95/1000, respectively) and less common in those of European and North American origin (0.64/1000). All these differences were statistically significant and may be partially explained by the more advanced parental age of the NF group (as suggested by the larger number of children in the North African and Asian families) or by founder effect or both. The height and weight of the NF1 subjects was significantly lower than those of the controls. The intelligence score of persons with NF1 was similar to that of the control group when corrected for gender and ethnic origin. No significant increase in epilepsy or mental illnesses was found. This study provides evidence of the high overall prevalence of NF1 among Jews in Israel, with significantly increased prevalence in certain ethnic groups. PMID- 7853370 TI - Genetic study of congenital heart defects in Northern Ireland (1974-1978). AB - Congenital heart defects are a major congenital abnormality and are assuming increasing importance. A study was undertaken to estimate the incidence of congenital heart defects in Northern Ireland over a five year period (1974-1978), to determine the age at diagnosis and to assess the risk of recurrence in sibs. An incidence rate of 7.3 per 1000 total births was found. This reduced to 3.1 per 1000 total births if only invasive methods of diagnosis (catheter studies, surgery, or necropsy) were considered. The overall risk of recurrence for sibs (excluding index patients with chromosomal abnormalities and syndromes) was 3.1%. In addition, excluding families with an affected parent and child gave a recurrence risk of 2.6%. By 6 weeks of age 63% of index patients had been diagnosed and this figure had risen to 88% by 1 year. This has important implications for studies which include only congenital heart defects diagnosed in the first year of life. Of 388 patients with a congenital heart defect confirmed by invasive criteria, 96 (24.7%) were found to have an extracardiac abnormality (ECA). Excluding those with epilepsy or mental handicap as the sole ECA left 91 (23.5%) with an ECA. This highlights the importance of looking for other abnormalities in a child with a congenital heart defect. The 388 index patients had 952 sibs of whom 72 (7.6%) had an ECA. Excluding those with minor abnormalities (inguinal hernias, undescended testes) as the sole ECA left 62 (6.5%) with a major ECA. In addition, excluding those with epilepsy or mental handicap as the sole ECA left 51 (5.4%) with a major ECA. Since parents are often reassured after the birth of a child with a congenital heart defect that their risk of having a child with a noncardiac abnormality is no greater than the general population this finding has important implications for genetic counselling. PMID- 7853371 TI - Counselling following diagnosis of a fetal abnormality: the differing approaches of obstetricians, clinical geneticists, and genetic nurses. AB - Women receiving a positive diagnosis of an abnormality during pregnancy may be counselled about a termination by one of several types of health professionals including obstetricians, geneticists, and genetic nurses. There is anecdotal evidence to suggest that these groups differ in both their approaches to counselling and their attitudes towards abnormality. The aim of the current study is to document how genetic nurses, geneticists, and obstetricians describe their own counselling of women following the diagnosis of specific fetal abnormalities. Obstetricians reported counselling in a significantly more directive fashion than did geneticists, who in turn reported counselling in a more directive way than did genetic nurses. The extent to which the groups differed in their reported approaches varied across conditions. The most marked difference was evident for Down's syndrome: 94% of genetic nurses, 57% of geneticists, and 32% of obstetricians reported counselling non-directively. Future research needs to focus on what these different groups see as the objectives of counselling in this situation, how they actually counsel, and with what effects. PMID- 7853372 TI - Genetic mapping of the FACC gene and linkage analysis in Fanconi anaemia families. AB - Fanconi anaemia is an autosomal recessive disorder associated with increased chromosome breakage and progressive bone marrow failure. The gene for complementation group C (FACC) has been cloned and mapped to chromosome 9q22.3, but neither its genetic location nor the proportion of patients belonging to group C is known. We have used a polymorphism within the FACC gene to localise it within a 5 cM interval on chromosome 9q, bounded by D9S196/D9S197 and D9S176. The genes for Gorlin's syndrome and multiple self-healing squamous epitheliomata have also been mapped to this interval. Linkage analysis with the three highly informative microsatellite polymorphisms flanking FACC in 36 Fanconi anaemia families showed that only 8% of families were linked to this locus. This indicates that the genes for the other Fanconi anaemia complementation groups must map to one or more different chromosomal locations. The markers also allowed rapid exclusion of 56% of the families in our panel from complementation group C, thus substantially reducing the number of patients who need to be screened for FACC mutations. PMID- 7853373 TI - Trinucleotide repeat length and progression of illness in Huntington's disease. AB - The genetic defect causing Huntington's disease (HD) has been identified as an unstable expansion of a trinucleotide (CAG) repeat sequence within the coding region of the IT15 gene on chromosome 4. In 50 patients with manifest HD who were evaluated prospectively and uniformly, we examined the relationship between the extent of the DNA expansion and the rate of illness progression. Although the length of CAG repeats showed a strong inverse correlation with the age at onset of HD, there was no such relationship between the number of CAG repeats and the rate of clinical decline. These findings suggest that the CAG repeat length may influence or trigger the onset of HD, but other genetic, neurobiological, or environmental factors contribute to the progression of illness and the underlying pace of neuronal degeneration. PMID- 7853374 TI - Pyruvate dehydrogenase deficiency. PMID- 7853375 TI - Non-radioactive detection of 17p11.2 duplication in CMT1A: a study of 78 patients. AB - Charcot-Marie-Tooth disease type 1 (CMT1) is a peripheral neuropathy characterised by progressive distal muscular atrophy and sensory loss with markedly decreased nerve conduction velocity, mostly inherited as an autosomal dominant trait. The most common form, type 1A, is associated with a 1.5Mb DNA duplication in region p11.2-p12 of chromosome 17 in many patients. In this study a non-radioactive test for detection of the CMT1A duplication based on an RM11-GT microsatellite polymorphism is presented. Although different methods have been devised for this purpose, the present method has the advantage of being rapid, informative, economical, easily interpretable, and, therefore, it represents a very useful tool for diagnosis of CMT1A, especially before clear manifestation of clinical symptoms. Seventy-eight patients diagnosed clinically as having CMT and evaluated by electrophysiological methods were tested with an RM11-GT microsatellite and with probe pVAW409R3. The CMT1A duplication was found in 76% of the 56 unrelated patients. RM11-GT was the most informative marker with a heterozygosity of 89%. PMID- 7853376 TI - Duplication of 16q22-->qter confirmed by fluorescence in situ hybridisation and molecular analysis. AB - We report a female infant with congenital dislocation of the knee and dysmorphic features including a prominent forehead, midface hypoplasia, and micrognathia. Fluorescence in situ hybridisation and PCR amplification of microsatellite repeats were used to show that she had a de novo unbalanced translocation resulting in partial trisomy for 16q and partial monosomy for 15q (46,XX, -15, tder(15)t(15;16)(q26.1;q22). The consequences of partial aneuploidy of 16q are discussed. PMID- 7853377 TI - APC mutation associated with late onset of familial adenomatous polyposis. AB - Familial adenomatous polyposis is an autosomal dominantly inherited disorder. Mutation studies in the corresponding gene (APC) may provide information for predictive tests for persons at risk in affected families. We report here a new mutation in exon 6 (codon 233) of the APC gene and clinical data in a large family with late onset of the disease in most affected persons. PMID- 7853378 TI - High CTG repeat number in nodular thyroid tissue from a myotonic dystrophy patient. AB - CTG triplet expansion was studied in lymphocytes and thyroid tissue in a patient with myotonic dystrophy (DM) and associated thyroid nodular disease. An approximately 7 fold larger amplification was found in abnormal thyroid tissue compared to lymphocytes, suggesting that anomalies in the putative DM kinase gene might contribute to thyroid dysfunction. PMID- 7853379 TI - Forensic medicine, PCR, and Bayesian approach. PMID- 7853380 TI - The possible Middle East origin of the mutation for the limb/pelvis hypoplasia/aplasia syndrome. PMID- 7853381 TI - No association between dopamine D4 receptor polymorphism and manic depressive illness. PMID- 7853382 TI - 3-M syndrome and intracerebral aneurysms. PMID- 7853383 TI - Magnetic susceptibility mapping of the human thorax using a SQUID biomagnetometer. AB - Biomagnetism is essentially the study of the weak magnetic fields generated by biological organisms, in particular the human body. The human thorax is composed of a variety of tissues and organs of slightly different magnetic susceptibility. In an applied magnetic field (of the order of milliTeslas) these small differences in susceptibility lead to measurable field variations (of the order of nanoTeslas) at the body surface which may be of diagnostic value. Physiological processes such as cardiac activity, cardiac output, blood flow and respiratory related lung volume changes also contribute to the observed signal. In this study susceptibility 'maps' were obtained by measuring the magnetic field at several hundred points over the thorax. Results indicate that magnetic susceptibility mapping produces low-resolution images of internal body structures from which is should be possible to detect pathologies that cause alterations in tissue susceptibility. PMID- 7853384 TI - A scientific basis for the National Health Service. PMID- 7853385 TI - The influence of charitable foundations on medical research policy. PMID- 7853386 TI - Clinical considerations and comparative measures of assessing curvature of the spine. AB - Two instruments, an inclinometer and a flexicurve for surface measurement of spine curvature were compared. No significant correlations were found between sets of measurements using these devices to measure a known curve whose angles of curvature at marked points have been calculated mathematically. However, differences were found between actual values and those measured by each instrument with respect to total discrepancies, and those were in favour of the flexicure. Several advantages were noted in using the flexicure as a measuring device not only for assessing range of motion in limbs. Additional advantages over use of the inclinometer included cheapness, ease of use, better accuracy and better reliability. PMID- 7853387 TI - Unstained and in vivo fluorescently stained bacterial nucleoids and plasmolysis observed by a new specimen preparation method for high-power light microscopy of metabolically active cells. AB - Microscope slides were coated with a layer of gelatin, the thickness of the gelatin increasing linearly along the long axis. The bacterial suspension is applied to the dried gelatin and covered by a coverslip. The medium is absorbed by the gelatin and thus the cells applied against the coverslip. By this method, cultures of concentrations below 10(8) cells/ml provide statistically relevant numbers for observation without prior concentration steps. It is easier to apply than the existing methods for the observation of bacterial nucleoids by phase contrast imaging. Because the cells are maintained in growing conditions the method is useful for the vital fluorescence DAPI-staining of various bacterial species and for observations of plasmolysis and its reversal at different physiological conditions and extracellular osmolalities. The previously generally assumed view that the plasmolytic changes of the cell morphology are immediate upon the hyperosmotic shock and are rapidly repaired when the cell is able to metabolize actively was confirmed; this is in contrast to some recent claims. PMID- 7853388 TI - Fibre optic scrambling in light microscopy: a computer simulation and analysis. AB - Optical fibres bent in two mutually perpendicular planes have proven useful for randomizing illumination in light microscopes. These optical scramblers can increase the resolution and/or contrast obtained with several modes of light microscopy. Here, computer simulations are used to investigate several parameters affecting light randomization in curved optical fibres in order to further the theoretical basis for scrambler design. Light passing through 90 degrees bends of optical fibre of varying radii of curvature was modelled by ray tracing in two dimensions, and scrambling mechanisms were observed. The effects of varying the position and angle of entry of light on the phase and direction of propagation of the emergent light were determined. It was found that (a) thorough scrambling does not necessarily require high numerical aperture (NA) entry of light into the fibre, (b) considerable order persists after a single 90 degrees bend of an idealized fibre and (c) a higher degree of scrambling (at the cost of transmission efficiency) is achieved in more tightly curved fibres. The pathlength variations introduced by scrambling proved smaller than typical laser coherence lengths, requiring temporal scrambling (vibrating the fibre). PMID- 7853389 TI - Nuclear diffuseness as a measure of texture: definition and application to the computer-assisted diagnosis of parathyroid adenoma and carcinoma. AB - A measure of texture, the nuclear diffuseness, was formulated for use in biological classification, and specifically to characterize quantitatively chromatin texture. Nuclear diffuseness corresponds to the amount of local intensity variation in the digitized image of a nuclear profile. As a setting in which to test the efficacy of nuclear diffuseness as a diagnostic tool, the identification of parathyroid adenoma and carcinoma was considered. Digitized images of sections of parathyroid chief cell nuclei were obtained from 16 biopsies, and the nuclear diffuseness, as well as other morphometric descriptors, were computed. With just the average nuclear diffuseness and average nuclear profile area, jackknife (leave-one-out) classification using an artificial neural network was able to diagnose correctly and unambiguously the condition (normal, parathyroid adenoma, or parathyroid carcinoma) in 15 of 16 cases. In one case, the neural network assigned a higher weight to the correct diagnosis, but was unable to distinguish between normal and adenoma conclusively. PMID- 7853390 TI - Transmembrane alpha-helix interactions are required for the functional assembly of the Escherichia coli Tol complex. AB - TolQ, TolR and TolA are membrane proteins involved in maintaining the structure of Escherichia coli cell envelope. TolQ and TolR span the inner membrane with three and with one alpha-helical segments, respectively. The tolQ925 mutation (A177V), located in the third putative transmembrane helix of TolQ (TolQ-III), induces cell sensitivity to bile salts and tolerance towards colicin A but not colicin E1, unlike a null tolQ mutation, which induces tolerance to all group A colicins. Since TolQ is required for colicin A and E1 uptake, in contrast to TolR, which is necessary only for colicin A, we hypothesized that the tolQ925 mutation might affect an interaction between TolQ and TolR. We therefore searched for suppressor mutations in TolR that would restore cell envelope integrity and colicin A sensitivity to the tolQ925 mutant. Five different tolR alleles were isolated and characterized. Four of these suppressor mutations were found to be clustered in the single putative transmembrane helix of TolR (TolR-I) and one was located at the extreme C terminus of the protein. In addition, we isolated a spontaneous intragenic suppressor localized in the first transmembrane helix of TolQ (TolQ-I). These observations strongly suggest that TolR and TolQ interact via their transmembrane segments. Sequence analysis indicates that Ala177 lies on the alpha-helix face of TolQ-III that, according to its composition and evolutionary conservation, is the most likely to be involved in protein/protein interaction. Energy minimization of atomic models of the wild-type and mutated forms of TolQ-III and TolR-I suggests that the deleterious effect of the A177V substitution arises from a direct steric hindrance of this residue with neighboring transmembrane segments, and that suppressor mutations may alleviate this effect either directly or indirectly, e.g. by affecting the stability of conformational equilibrium of the transmembrane region of the complex. PMID- 7853391 TI - An atomic model of the unregulated thin filament obtained by X-ray fiber diffraction on oriented actin-tropomyosin gels. AB - We present a model of the actin-tropomyosin complex in which the radial and azimuthal position of tropomyosin was adjusted to fit the X-ray fiber diffraction patterns from oriented actin-tropomyosin gels at a resolution of 1/8 A-1. We used the recently published atomic F-actin model for the calculations. The atomic model of tropomyosin was obtained by model-building a coiled coiled-coil structure from the tropomyosin sequence. The resulting atomic model is strongly preferred and shows strong electrostatic interactions between charged side-chains of tropomyosin residues and actin residues in subdomain 3 and subdomain 4. Furthermore, calculations of enthalpies based upon electrostatic interactions indicate that there is a favored rotational position of the tropomyosin core at the calculated azimuthal and radial position given by the X-ray refinement. Rotations of the tropomyosin strand out of this position turn strongly attractive electrostatic interactions into repulsive forces. The resulting binding radius of 39 A and the determined azimuthal position of tropomyosin are in good agreement with electron microscopy reconstructions and neutron diffraction experiments. Furthermore, the calculated position of tropomyosin would still partly block the rigor interaction of myosin cross-bridges with actin, whereas it very likely allows undisturbed binding of the cross-bridges in a weak binding state. PMID- 7853392 TI - Many combinations of amino acid sequences in a conserved region of the D1 protein satisfy photosystem II function. AB - The putative de helix of the D1 protein is located at the acceptor side of photosystem II (PS II) and serves as an indispensable part of a niche that binds the secondary plastoquinone QB. Combinatorial mutagenesis was applied to a stretch of four residues in a highly conserved region of this putative helix in order to reveal amino acid combinations that are able to support PS II function. An obligate photoheterotrophic mutant of the cyanobacterium Synechocystis sp. PCC 6803, missing four residues (delta YFGR254-7) in the de helix, was transformed with a D1-coding sequence carrying fully degenerate combinations of codons at the site of the deletion. Upon selection for photoautotrophy, 25 mutants with functional PS II were isolated. All mutants showed different codon combinations at positions 254 to 257; none was identical to the wild-type sequence, and none of the conserved residues was found to be mandatory for PS II function. However, 24 of the mutants contained Tyr of Phe at position 254 while at the other three positions many different amino acid combinations could be functionally accommodated. Most sequences maintained an amphiphilic arrangement of the helix that may align Tyr254 facing the QB binding pocket. This residue is proposed to be functionally analogous to Phe216 of the L subunit in purple bacteria which contributes to binding of QB. Most of the PS II properties were similar in the mutants compared to wild-type. Noticeable modifications in the mutants concerned the semiquinone equilibrium of electron transfer between QA and QB, and the affinity of PS II inhibitors. Differential effects on the semiquinone equilibrium were observed between two distinct quinones occupying the QB site (plastoquinone versus 2,5-dichloro-p-benzo- quinone), implying that residues in this domain are involved, directly or indirectly, with different binding determinants of the quinones. Even though many different combinations of amino acids in positions 254 to 257 of the D1 protein may satisfy the primary function of PS II, complex requirements need to be combined for optimized performance of the QB binding niche. PMID- 7853393 TI - Intramolecular transmission of the ATP regulatory signal in Escherichia coli aspartate transcarbamylase: specific involvement of a clustered set of amino acid interactions at an interface between regulatory and catalytic subunits. AB - Aspartate transcarbamylase from Escherichia coli is stimulated by ATP and feedback-inhibited by CTP and UTP. Previous work allowed the identification of the hydrophobic interface between the two domains of the regulatory chain as a structural element specifically involved in the transmission of the ATP regulatory signal toward the catalytic sites. The present work describes the identification of a cluster of amino acid interactions at an interface between the regulatory chains and the catalytic chains of the enzyme as another structural feature involved in the transmission of the ATP regulatory signal but not in those of CTP and UTP. These interactions involve residues 146 to 149 of the regulatory chain and residues 242 to 245 of the catalytic chain. Perturbations of these interactions also alter to various extents the co operativity between the catalytic sites for aspartate binding. These findings are in agreement with the idea that the primary effect of ATP might consist, in part, of a modulation of the stability of the interfaces between regulatory and catalytic subunits, thereby facilitating the T to R transition induced by aspartate binding, as was put forward in two recently proposed models, the "effector modulated transition" model and the "nucleotide perturbation" model. This does not exclude that this cluster of interactions could also act as a relay to transmit the ATP regulatory signal to the catalytic sites according to the previously proposed "primary-secondary effects" model. PMID- 7853394 TI - Structure of a retro-binding peptide inhibitor complexed with human alpha thrombin. AB - The crystallographic structure of the ternary complex between human alpha thrombin, hirugen and the peptidyl inhibitor Phe-alloThr-Phe-O-CH3, which is acylated at its N terminus with 4-guanidino butanoic acid (BMS-183507), has been determined at 2.6 A resolution. The structure reveals a unique "retro-binding" mode for this tripeptide active site inhibitor. The inhibitor binds with its alkyl-guanidine moiety in the primary specificity pocket and its two phenyl rings occupying the hydrophobic proximal and distal pockets of the thrombin active site. In this arrangement the backbone of the tripeptide forms a parallel beta strand to the thrombin main-chain at the binding site. This is opposite to the orientation of the natural substrate, fibrinogen, and all the small active site directed thrombin inhibitors whose bound structures have been previously reported. BMS-183507 is the first synthetic inhibitor proved to bind in a retro binding fashion to thrombin, in a fashion similar to that of the N-terminal residues of the natural inhibitor hirudin. Furthermore, this new potent thrombin inhibitor (Ki = 17.2 nM) is selective for thrombin over other serine proteases tested and may be a template to be considered in designing hirudin-based thrombin inhibitors with interactions at the specificity pocket. PMID- 7853395 TI - Solution structure of a quinomycin bisintercalator-DNA complex. AB - The quinomycin antibiotic UK-63052 (designated QN) exhibits a chemical structure related to the antibiotic echinomycin which is known to bisintercalate into DNA. Common features among these antibiotics include two heterocyclic aromatic ring systems propagating from a cross-bridged cyclic octadepsipeptide scaffold. We report on the solution structure of the QN-d(A1-C2-A3-C4-G5-T6-G7-T8) complex (one QN molecule per duplex) based on a combined NMR-molecular dynamics study including intensity-based refinement. The 3-hydroxy quinaldic acid rings bisintercalate into the duplex at (A3-C4).(G5-T6) steps and stack with flanking Watson-Crick A3.T6 and C4.G5 base-pairs. The intercalation sites at (A3-C4).(G5 T6) steps are wedge-shaped and unwound, with significant unwinding also observed at the (C4-C5).(C4-G5) step bracketed between the intercalation sites. The cross bridged cyclic octadepsipeptide is positioned in the minor groove with the methyl groups on its Ala and NMe-MCp residues directed towards and making van der Waals contacts with the minor groove edge of the duplex. A pair of adjacent intermolecular hydrogen bonds between the Ala backbone atoms and the G5 minor groove edge (Ala-NH to G5-N(3) and G5-NH2e to Ala-CO) account for the sequence specificity associated with complex formation. The solution structure of the QN DNA oligomer complex, which contains only Watson-Crick base-pairs flanking the bisintercalation site, is compared with the crystal structure of the related echinomycin-DNA oligomer complex, which contains Hoogsteen base-pairs on either side of the bisintercalation site. PMID- 7853396 TI - High-resolution structure of the phosphorylated form of the histidine-containing phosphocarrier protein HPr from Escherichia coli determined by restrained molecular dynamics from NMR-NOE data. AB - The solution structure of the phosphorylated form of the histidine-containing phosphocarrier protein, HPr, from Escherichia coli has been determined by NMR in combination with restrained molecular dynamics simulations. The structure of phospho-HPr (P-HPr) results from a molecular dynamics simulation in water, using time-dependent distance restraints to attain agreement with the measured NOEs. Experimental restraints were identified from both three-dimensional 1H-1H-15N HSQC-NOESY and two-dimensional 1H-1HNOESY spectra, and compared with those of the unphosphorylated form. Structural changes upon phosphorylation of HPr are limited to the active site, as evidenced by changes in chemical shifts, in 3JNHH alpha coupling constants and NOE patterns. Chemical shift changes were obtained mainly for protons that were positioned close to the phosphoryl group attached to the His15 imidazole ring. Differences could be detected in the intensity of the NOEs involving the side-chain protons of His15 and Pro18, resulting from a change in the relative position of the two rings. In addition, a small change could be detected in the three-bond J-coupling between the amide proton and the H alpha proton of Thr16 and Arg17 upon phosphorylation, in agreement with the changes of the phi torsion angle of these two residues obtained from time-averaged restrained molecular dynamics simulations in water. The proposed role of the torsion-angle strain at residue 16 in the mechanism of Streptococcus faecalis HPr is not supported by these results. In contrast, phosphorylation seems to introduce torsion angle strain at residue His15. This strain could facilitate the transfer of the phosphoryl group to the A-domain at enzyme II. The phospho histidine is not stabilised by hydrogen bonds to the side-chain group of Arg17; instead stable hydrogen bonds are formed between the phosphate group and the backbone amide protons of Thr16 and Arg17, which show the largest changes in chemical shift upon phosphorylation, and a hydrogen bond involving the side-chain O gamma proton of Thr16. HPr accepts the phosphoryl group from enzyme I and donates it subsequently to the A domain of various enzyme II species. The binding site for EI on HPr resembles that of the A domain of the mannitol-specific enzyme II, as can be concluded from the changes on the amide proton and nitrogen chemical shifts observed via heteromolecular single-quantum coherence spectroscopy. PMID- 7853397 TI - Solution structure of an oncogenic DNA duplex, the K-ras gene and the sequence containing a central C.A or A.G mismatch as a function of pH: nuclear magnetic resonance and molecular dynamics studies. AB - The DNA duplex 5' d(GCCACCAGCTC)-d(GAGCTGGTGGC) corresponds to the sequence 29 to 39 of the K-ras gene, which contains a hot spot for mutations. This has been studied by one and two-dimensional nuclear magnetic resonance, energy minimization and molecular dynamics. The results show that it adopts a globally B DNA type structure. We have introduced, at the central base-pair, the mismatches C.A and A.G. The mismatch position is that of the first base of the Gly12 codon, the hot spot. For the C.A mismatch we observe a structural change as a function of pH with an apparent pKa of 7.2. At low pH, the mismatch pair adopts a structure close to a classic wobble conformation with the cytidine residue displaced into the major groove. It is stabilised by two hydrogen bonds in which the adenosine residue is protonated and the cytidine residue has a significant C3'-endo population. At high pH, the mispair structure is in equilibrium between wobble and reverse wobble conformations. Similar studies are reported on the A.G mismatch, which also undergoes a transition as a function of pH. 31P spectra have been recorded on all systems and as a function of pH. No evidence for BII phosphodiester backbone conformations was found. The NMR results are well corroborated by molecular dynamics calculations performed with or without distance constraints. The dynamics at the mismatch sites have been examined. Although the overall structures are close to B-DNA, helical parameters fluctuate differently at these sites. Different hydrogen bonding alternatives in dynamic equilibrium that can involve three-centred hydrogen bonds are observed. PMID- 7853398 TI - Helical parameters, fluctuations, alternative hydrogen bonding, and bending in oligonucleotides containing a mistmatched base-pair by NOESY distance restrained and distance free molecular dynamics. AB - We have analysed and compared the molecular structures and dynamics of the DNA duplex, that corresponds to the sequence 29 to 39 of the K-ras gene, where the central base-pair is the normal C.G base or a mismatch base-pair C.A, C.A+, A.G and A+.G. Molecular dynamics runs of 100 picoseconds without or with distance restraints derived from NOE measurements are analysed and compared in all cases. (1) The EMBO convention of helical parameters for nucleic acids is extended to account for the construction and the description of any DNA mismatched base-pair. (2) Both types of MD runs reproduce very well all NMR data, except the H8 H2 inter-residue distances where agreement is not as good. (3) Average parameter values and fluctuations are in good agreement with results derived from persistence length and torsion modulus measurements. (4) Our molecular dynamics suggest the presence, in certain cases, of three-centred hydrogen bonds, which should be viewed as an equilibrium between hydrogen-bonding alternatives. In the case of the C.A mismatch, we observe the correlation between transient DNA bending and possible hydrogen bonding between a base and its 5' neighbour on the opposite strand in the sequence CCA. (5) These molecular dynamics analyses and observations provide a coherent view for the results obtained from recent DNA crystal structures and for results derived from other techniques such as gel electrophoresis at C.A steps. PMID- 7853399 TI - Crystal structures of a schistosomal drug and vaccine target: glutathione S transferase from Schistosoma japonica and its complex with the leading antischistosomal drug praziquantel. AB - Glutathione S-transferase (GST), an essential detoxification enzyme in parasitic helminths, is a major vaccine target and an attractive drug target against schistosomiasis and other helminthic diseases. Crystal structures of the 26 kDa GST from the helminth Schistosoma japonica (SjGST) have been determined for the unligated enzyme (resolution = 2.4 A, R-factor = 19.7%) and for the enzyme bound to the leading antischistosomal drug praziquantel (resolution = 2.6 A, R-factor = 21.2%). The protein, recombinantly expressed using the Pharamacia PGEX-3X vector for production of GST fusion proteins, contains all 218 residues of SjGST and an additional 13 residues at the C terminus. The structure of unligated SjGST shows that the glutathione binding site pre-exists unchanged in the ligand-free enzyme and is conserved between parasitic and the mammalian class mu enzymes. At therapeutic concentrations the leading antischistosomal drug praziquantel (PZQ) binds one drug per enzyme homodimer in the dimer interface groove adjoining the two catalytic sites. This establishes a protein target for PZQ, identifies the GST non-substrate ligand transport site, and implicates PZQ in steric inhibition of SjGST catalytic and transport for large ligands. Thus, increased expression or mutagenesis of SjGST by the parasite may confer resistance to PZQ. Differences in the xenobiotic binding region between parasitic and mammalian GSTs reveal a distinct substrate repertoire for SjGST and, together with the newly identified PZQ binding site, provide the basis for design of novel antischistosomal drugs. Due to the widespread use expression systems based on SjGST fusions, the atomic structure of SjGST should also provide an important tool for phasing fusion protein structures by molecular replacement. PMID- 7853400 TI - The crystal structure of dihydrodipicolinate synthase from Escherichia coli at 2.5 A resolution. AB - The crystal structure of dihydrodipicolinate synthase from E. coli was determined by multiple isomorphous replacement methods. The structure was refined at a resolution of 2.5 A and the final R-factor is 19.6% for 32,190 reflections between 10.0 A and 2.5 A and F > 2 sigma (F). The crystallographic asymmetric unit contains two monomers related by approximate 2-fold symmetry. A tetramer with approximate 222 symmetry is built up by crystallographic symmetry. The tetramer is almost planar with no contacts between the subunits related by the non-crystallographic dyad. The active sites are accessible from a wide water filled channel in the center of the tetramer. The dihydrodipicolinate synthase monomer is composed of two domains. Each polypeptide chain is folded into an 8 fold alpha/beta barrel and a C-terminal alpha-helical domain comprising residues 224 to 292. The fold is similar to that of N-acetylneuraminate lyase. The active site lysine 161 is located in the alpha/beta barrel and has access via two entrances from the C-terminal side of the barrel. PMID- 7853401 TI - Tetravalent miniantibodies with high avidity assembling in Escherichia coli. AB - We have designed tetravelent miniantibodies assembling in the periplasm of Escherichia coli. They are based on single-chain Fv fragments, connected via a flexible hinge to an amphipathic helix which tetramerizes the molecule. The amphipathic helix is derived from the coiled coil helix of the transcription factor GCN4, in which all hydrophobic a positions of every heptad repeat have been exchanged to leucine and all d positions to isoleucine. Gel filtration shows tetramer assembly of the miniantibody even at low concentrations. As expected, the functional affinity (avidity) of the tetravalent miniantibody is higher in ELISA and BIAcore measurements than that of the bivalent construct and the gain is dependent on surface epitope density. PMID- 7853402 TI - A sequence-induced superhelical DNA segment serves as transcriptional enhancer. AB - The initiation of transcription at the sigma 54-dependent promoter glnAp2 of Escherichia coli is activated by the protein NR1(NTRC)-phosphate, which binds to two sites located upstream of the promoter that together constitute an enhancer. The cooperative binding facilitates the oligomerization of NR1-phosphate endowing it with the ATPase activity required for its ability to serve as transcriptional activator. We show here that these sites can be replaced by sequence-dependent superhelical inserts, lacking any homology to the nucleotide sequence of the enhancers. These superhelical inserts, irrespective of their chirality, are as effective as the paired sites in binding NR1-phosphate and in stimulating its oligomerization. We conclude that a specific sequence of nucleotides and the three-dimensional structure of DNA can determine its affinity for the NR1 activator protein capable of binding to DNA. PMID- 7853403 TI - Developmental regulation of a silkworm gene encoding multiple GATA-type transcription factors by alternative splicing. AB - Gene BmGATA beta of the silkworm Bombyx mori was previously shown to encode factor BCFI, which regulates the expression of a class of chorion genes expressed during the late stages of choriogenesis. We now show that the expression of the BmGATA beta gene is spatially and temporally regulated by alternative splicing that generates two major (BmGATA beta 1 and BmGATA beta 2) and one minor (BmGATA beta 3) mRNA isoforms of non-identical tissue distribution. The three isoforms differ in the organization of the DNA-binding domains of the corresponding polypeptides. While all three isoforms are expressed in ovarian follicular cells and in testes, only one of them, BmGATA beta 1, is gonad-specific. BmGATA beta 2 is expressed in a variety of other larval and pupal tissues, while BmGATA beta 3 is detected in some pupal but none of the larval tissues. Analysis of RNA isolated from follicular cells of developing ovarian follicles has shown that the onset of ovarian transcription for all three mRNA isoforms occurs during late vitellogenesis, and that the level of accumulated mRNA declines significantly at the onset of choriogenesis. Coincident with the onset of late chorion gene expression, we have observed a significant change in the preference of splice site selection in favour of the one that results in the generation of BmGATA beta 1 mRNA. The transcriptional activation of the BmGATA beta gene in follicular cells during late vitellogenesis correlates with the previously demonstrated initial accumulation of factor BCFI in the cytoplasm of follicular cells and its appearance in follicular cell nuclei only during the late stages of choriogenesis. The relationship between factor BCFI and the different polypeptides encoded by the three BmGATA beta mRNA isoforms is discussed. PMID- 7853404 TI - Nicking activity of TrwC directed against the origin of transfer of the IncW plasmid R388. AB - TrwC is required for conjugal DNA transfer of the broad host range plasmid R388. The purified protein shows in vitro DNA helicase activity. Here we report that it also has in vitro oriT-endonuclease activity. TrwC specifically nicks oriT containing supercoiled plasmid DNA in the presence of Mg2+, and the nicked DNA can be visualized after treatment with SDS. Sequencing of the nicked DNA showed a specific interruption of the lower DNA strand on the R388 oriT sequence. Both the 5' and the 3' ends of the nick were mapped. The 5' end was not accesible to phosphorylation by T4 polynucleotyde kinase, suggesting a covalent association with TrwC. Analysis of a collection of deletions in oriT indicated that the nucleotide sequences immediately surrounding the nic site are important, but not the only essential feature, for the nicking reaction. Comparison of the R388 nic site with previously published nic DNA sequences suggests that IncF, IncN and IncW plasmids form a family of related nic sites. During the course of this work we have also demonstrated a terminal transferase activity of Sequenase Version 2.0 DNA polymerase, as yet undocumented, which could account for some discrepancies in previously mapped nic sites in other systems. PMID- 7853406 TI - Structural repertoire in VH pseudogenes of immunoglobulins: comparison with human germline genes and human amino acid sequences. AB - In the pool of human immunoglobulin VH gene segments, pseudogenes amount to roughly 30% of the total number of genes. Some of them are highly conserved among unrelated individuals. These facts suggest a possible functional role for pseudogenes in the human immune response diversity. This paper intends to provide additional information about the structure of VH pseudogene sequences to evaluate the possible role of pseudogenes in the immune response. Mutations capable of altering framework stability in human VH pseudogenes were analyzed. Results indicate that VH pseudogenes are about 14 times as divergent as human VH functional germline genes on the one hand, and four times as divergent in the case of human VH amino acid sequences on the other. The high number of disruptive mutations in pseudogenes is an expected result because of the lack of functionality of these genes. In the second part of the work we analyze whether or not the same takes place in the positions that determine the existence of canonical structures in the hypervariable loops in VH pseudogenes. An extension of such analysis is applied to all species with reported VH pseudogenes. In contrast with results concerning framework positions, 69% of known human VH pseudogenes have canonical structures in the first hypervariable loop, while 48% do so in the second one. Comparison of these results with those found in human VH functional germline genes and human VH amino acid sequences shows that in the former as many as 100% and in the latter 96% have canonical structures. In VH amino acid sequences the result is similar to pseudogenes for H1. For H2, such value lies between the percentage of germline genes (96%) and the percentage of pseudogenes (48%). The possible significance of the existence of canonical structures in the hypervariable loops of VH pseudogenes is discussed. PMID- 7853405 TI - Repetitive Alu elements form a cruciform structure that regulates the function of the human CD8 alpha T cell-specific enhancer. AB - We previously identified a T cell-specific enhancer in the last intron of the human CD8 alpha gene that is adjacent to a sequence element that significantly represses enhancer function. This negative regulatory region consists of a half Alu sequence that has potential to base-pair with a downstream Alu element, which is part of the fully active enhancer, to form a cruciform structure. The activity of this half-Alu silencer sequence is position and orientation-dependent, suggesting that DNA structure plays an important role in its function. Using site directed mutational analysis and P1 nuclease mapping, we directly demonstrate that formation of a cruciform structure is required for repression of enhancer function in transient transfection assays. Finally, a P1 nuclease-sensitive site is present in the endogenous CD8 alpha gene in T cell lines providing indirect evidence that the stem-loop may form in vivo. Taken together, these results suggest that Alu elements may contribute to the regulation of the CD8 alpha gene enhancer through the formation of secondary structure that disrupts enhancer function. PMID- 7853407 TI - Refined structures of two insertion/deletion mutants probe function of the maltodextrin binding protein. AB - The X-ray structures of the maltose bound forms of two insertion/deletion mutants of the Escherichia coli maltodextrin binding protein, MalE322 and MalE178, have been determined and refined. MalE322 involves a one residue deletion, two residue insertion in a hinge segment connecting the two (N and C) domains of the protein, an area already identified as being critical for the correct functioning of the protein. MalE178 involves a nine residue deletion and two residue insertion in a helix at the periphery of the C-domain. The function of both mutant proteins is similar to the wild-type, although MalE322 increases the ability to transport maltose and maltodextrin whilst inhibiting the ability of the cell to grow on dextrins. Both proteins exhibit very localized and conservative conformational changes due to their mutations. The structure of MalE322 shows some deformation of the third hinge strand, indicating the likely cause of change in its biochemistry. MalE178 is stable and its activity virtually unchanged from the wild-type. This is most likely due to the long distance of the mutation from the binding site and conservation of the number of interactions between the area around the deletion site and the main body of the protein. PMID- 7853408 TI - Informational suppression to investigate structural functional and evolutionary aspects of the Erwinia chrysanthemi cellulase EGZ. AB - The cellulase EGZ produced by the plant pathogen Erwinia chrysanthemi belongs to family 5 of the beta-glycohydrolases (also referred to as cellulase family A), which contains over 40 members from Gram-negative and Gram-positive bacteria and fungi. Amber mutations were introduced into 16 codons of the celZ gene encoding EGZ. Targeted residues included: (1) two Glu, two His and one Arg residue, strictly conserved throughout family 5; (2) one Arg and one His residue conserved in sub-family 5-2; and (3) one His and six Arg residues not conserved at all. Each amber allele was introduced into 13 Escherichia coli strains each carrying a different suppressor tRNA that inserts an amino acid at the mutated position. In vivo stability of the mutated forms of EGZ and their cellulase activity were analysed as well as suppression efficiency. For some positions of particular interest, missense mutations were introduced into the celZ gene either to confirm the effect of the suppressor-mediated amino acid substitution or to broaden the spectrum of mutations available. The substitution patterns of the two Glu positions were interpretable in the light of the stereospecificity of the reaction catalysed by EGZ: Glu133 and Glu220 are proposed to act as a proton donor and as a nucleophile, respectively, forming the glycosyl-enzyme intermediate. Substitution at His-occupied positions, including two non-conserved positions, yielded proteins affected in their catalytic activity but not their in vivo stability. In particular, evidence was obtained for His at position 98 to be involved in interactions with the substrate. The view that Arg residues are important in stabilizing proteins was supported by the identification of three Arg residues, whose substitution yielded thermosensitive forms of EGZ. In addition, Pro substitutions of any of the six Arg residues altered protein stability in vivo but the substitutions scored almost neutral for activity. Five positions, predicted to be within alpha-helices, were found to be susceptible to Pro substitutions (but not to Ala) with respect to stability in vivo. Overall, the systematic alteration of all His and Arg residues coupled with the simultaneous analysis of activity and in vivo stability allowed us to demonstrate that substitution matrices vary at each position and for each biological property considered. Ideally, therefore, substitution matrices used in sequence alignment procedures should be reconsidered as position-specific and as property specific.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7853409 TI - Binding of the junction-resolving enzyme bacteriophage T7 endonuclease I to DNA: separation of binding and catalysis by mutation. AB - Bacteriophage T7 endonuclease I is a resolving enzyme that selectively cleaves four-way DNA junctions, and related branched species. We have isolated mutants of this protein that retain full structural selectivity of binding to four-way junctions, but which are completely inactive as nucleases. This is consistent with a divisibility of structure-selective binding and catalysis. The mutations that inactivate endonuclease I as a nuclease are clustered into the second quarter of the primary sequence, a region that displays some sequence similarity with the related junction-resolving enzyme endonuclease VII from bacteriophage T4. This suggests that these residues may form the active site of these enzymes. The configuration of the helical arms of the junction bound by mutant endonuclease I has been investigated by gel electrophoretic methods. We find that the junction is bound in the presence or absence of magnesium ions, and that the global structure of the bound form is apparently identical with or without cations. The patterns of mobilities suggest that the structure of the junction becomes perturbed by the binding of the protein. PMID- 7853410 TI - Inhibition of prostate cancer metastasis: a critical challenge ahead. PMID- 7853411 TI - Should anticancer drug doses be adjusted in the obese patient? PMID- 7853412 TI - Secondary leukemias receive increased attention. PMID- 7853413 TI - British trial aims to settle mammography questions. PMID- 7853414 TI - Immune system may benefit from the ability to laugh. PMID- 7853415 TI - COMMIT anti-smoking program shows modest success. PMID- 7853416 TI - Inhibition of spontaneous metastasis in a rat prostate cancer model by oral administration of modified citrus pectin. AB - BACKGROUND: Prostate cancer is the most common cancer diagnosed in U.S. men and remains incurable once it has metastasized. Many stages of the metastatic cascade involve cellular interactions mediated by cell surface components, such as carbohydrate-binding proteins, including galactoside-binding lectins (galectins). Modified citrus pectin (pH-modified), a soluble component of plant fiber derived from citrus fruit, has been shown to interfere with cell-cell interactions mediated by cell surface carbohydrate-binding galectin-3 molecules. PURPOSE: The aim of this study was to determine whether modified citrus pectin, a complex polysaccharide rich in galactosyl residues, could inhibit spontaneous metastasis of prostate adenocarcinoma cells in the rat. METHODS: The ability of modified citrus pectin to inhibit the adhesion of Dunning rat prostate cancer MAT-LyLu cells to rat endothelial cells was measured by 51Cr-labeling. Modified citrus pectin inhibition of MAT-LyLu cell anchorage-independent growth was measured by colony formation in agarose. The presence of galectin-3 in rat MAT-LyLu cells and human prostate carcinoma was demonstrated by immunoblotting and immunohistochemistry. One million MAT-LyLu cells were injected subcutaneously into the hind limb of male Copenhagen rats on day 0. Rats were given 0.0%, 0.01%, 0.1%, or 1.0% (wt/vol) modified citrus pectin continuously in their drinking water (from day 4 until necropsy on day 30). The number of MAT-LyLu tumor colonies in the lungs were counted. RESULTS: Compared with 15 or 16 control rats that had lung metastases on day 30, seven of 14 rats in the 0.1% and nine of 16 rats in the 1.0% modified citrus-pectin group had statistically significant (two sided; P < .03 and P < .001, respectively) reductions in lung metastases. The lungs of the 1.0% modified citrus pectin-treated rats had significantly (two sided; P < .05) fewer metastatic colonies than control groups (9 colonies +/- 4 [mean +/- SE] in the control group compared with 1 colony +/- 1 in the treated group). Modified citrus pectin had no effect on the growth of the primary tumors. In vitro, modified citrus pectin inhibited MAT-LyLu cell adhesion to rat endothelial cells in a time- and dose-dependent manner as well as their colony formation in semisolid medium. CONCLUSIONS: We present a novel therapy in which oral intake of modified citrus pectin acts as a potent inhibitor of spontaneous prostate carcinoma metastasis in the Copenhagen rat. IMPLICATIONS: Further investigations are warranted to determine the following: 1) the role of galectin 3 in normal and cancerous prostate tissues and 2) the ability of modified citrus pectin to inhibit human prostate metastasis in nude mice. PMID- 7853417 TI - Obesity and therapy-related toxicity in patients treated for small-cell lung cancer. AB - BACKGROUND: Obese individuals have altered pharmacokinetics for many medications when compared with the non-obese. For the oncologist treating an obese cancer patient, these changes in drug disposition may potentially cause increased therapy-related toxicity. As a consequence, oncologists frequently treat obese patients with dose reductions in an effort to decrease chemotherapy toxicity. However, little clinical data exist to either support or refute this policy. PURPOSE: The clinical course of a cohort of patients treated for small-cell lung cancer (SCLC) was evaluated to determine if the obese patients had an increase in therapy-related toxicity. METHODS: The study sample included 262 patients with histologically confirmed SCLC treated in clinical trials from 1977 through 1993. Before 1986, patients with limited stage SCLC were treated with a cyclophosphamide-based regimen with (n = 47) or without (n = 46) chest radiotherapy. Subsequent patients with limited stage disease (n = 54) received etoposide and cisplatin plus twice-daily chest radiotherapy. Patients with extensive stage SCLC were randomly treated with standard-dose (n = 46) or high dose etoposide plus cisplatin (n = 44); poor-risk patients with extensive stage disease (n = 25) were assigned to standard dose etoposide plus cisplatin. For all patients, actual body weight was used when determining initial doses of chemotherapy. The measure of relative weight was the body mass index (BMI), which was calculated from the pretreatment height and weight data. The BMI was evaluated both on a continuum and with patients grouped into BMI levels (normal, obese, and severely obese). Toxicity parameters were collected during induction chemotherapy and were compared with the BMI. In addition, the overall survival of the entire cohort was evaluated, with patients divided into different groups based on their BMI level. RESULTS: We performed 170 comparisons between the BMI as a continuum or the BMI level and the 15 toxicity parameters. There were no consistent associations of significance found between increasing BMI or BMI levels and increasing toxicity from therapy. When survival was evaluated, no statistically significant differences were found between the survival of patients within the different BMI levels. CONCLUSIONS: In this group of 262 patients with SCLC, obesity at the start of treatment was not associated with increased toxicity from treatment or a shortened survival. No support for empiric chemotherapy dose reductions based on ideal body weight was evident from this study. PMID- 7853418 TI - Expression of scatter factor in human bladder carcinoma. AB - BACKGROUND: Scatter factor (SF) is a protein secreted by stromal (supporting) cells that induces disruption of intercellular junctions and stimulates motility and invasiveness of carcinoma cells. SF is also a potent inducer of angiogenesis (new blood vessel formation), a process required for tumor growth and dissemination. Invasion and angiogenesis are characteristics of biologically aggressive tumors, suggesting that the accumulation of SF within tumors might promote progression to a more malignant phenotype. PURPOSE: This study was designed to determine if SF is overexpressed in carcinoma of the bladder and to evaluate the potential mechanisms that might account for such overproduction. METHODS: We measured the SF content in urine from 20 patients with carcinoma of the bladder and various control groups. We also measured expression of SF in bladder tumor extracts, histologic sections of tumors, and cell culture models, using a variety of techniques, including enzyme-linked immunosorbent assays, immunohistochemistry, and Western and Northern blot analyses. Statistical comparisons were performed using two-tailed t tests. RESULTS: Urinary SF content was found to be significantly elevated in patients with bladder carcinoma as compared with normal control subjects (P < .001), patients with benign prostatic hypertrophy (P = .0055), and patients with prostate carcinoma, another genitourinary malignancy (P = .002). Extracts of bladder cancers, especially those from high-grade, invasive tumors, contained very high levels of SF. Both SF and its proto-oncogene (c-met)-encoded receptor were detected in bladder carcinoma tissue sections by immunostaining. Three different bladder carcinoma cell lines produced no detectable SF but produced very high titers of a high molecular-weight (> 30 kd), heat-sensitive protein that stimulates SF production by stromal cell types. High titers of a similar SF-inducing activity were detected in vivo, in bladder carcinoma extracts, and in the urine of patients with bladder carcinoma. CONCLUSIONS: Our results suggest that SF is overproduced in bladder carcinomas and accumulates within the tumor and in the urine. Overproduction of SF may result from an abnormal urothelial-stromal interaction in which dysplastic or carcinomatous urothelium secretes factors that stimulate SF expression by bladder wall stromal cells. IMPLICATION: Quantitation of SF in the urine and tumor deserves further study as a possible marker of urothelial malignancy. PMID- 7853419 TI - Radon and cancers other than lung cancer in underground miners: a collaborative analysis of 11 studies. AB - BACKGROUND: Exposure to the radioactive gas radon and its progeny (222Rn and its radioactive decay products) has recently been linked to a variety of cancers other than lung cancer in geographic correlation studies of domestic radon exposure and in individual cohorts of occupationally exposed miners. PURPOSE: This study was designed to characterize further the risks for cancers other than lung cancer (i.e., non-lung cancers) from atmospheric radon. METHODS: Mortality from non-lung cancer was examined in a collaborative analysis of data from 11 cohorts of underground miners in which radon-related excesses of lung cancer had been established. The study included 64,209 men who were employed in the mines for 6.4 years on average, received average cumulative exposures of 155 working level months (WLM), and were followed for 16.9 years on average. RESULTS: For all non-lung cancers combined, mortality was close to that expected from mortality rates in the areas surrounding the mines (ratio of observed to expected deaths [O/E] = 1.01; 95% confidence interval [CI] = 0.95-1.07, based on 1179 deaths), and mortality did not increase with increasing cumulative exposure. Among 28 individual cancer categories, statistically significant increases in mortality for cancers of the stomach (O/E = 1.33; 95% CI = 1.16-1.52) and liver (O/E = 1.73; 95% CI = 1.29-2.28) and statistically significant decreases for cancers of the tongue and mouth (O/E = 0.52; 95% CI = 0.26-0.93), pharynx (O/E = 0.35; 95% CI = 0.16-0.66), and colon (O/E = 0.77; 95% CI = 0.63-0.95) were observed. For leukemia, mortality was increased in the period less than 10 years since starting work (O/E = 1.93; 95% CI = 1.19-2.95) but not subsequently. For none of these diseases was mortality significantly related to cumulative exposure. Among the remaining individual categories of non-lung cancer, mortality was related to cumulative exposure only for cancer of the pancreas (excess relative risk per WLM = 0.07%; 95% CI = 0.01-0.12) and, in the period less than 10 years since the start of employment, for other and unspecified cancers (excess relative risk per WLM = 0.22%; 95% CI = 0.08-0.37). CONCLUSIONS: The increases in mortality from stomach and liver cancers and leukemia are unlikely to have been caused by radon, since they are unrelated to cumulative exposure. The association between cumulative exposure and pancreatic cancer seems likely to be a chance finding, while the association between cumulative exposure and other and unspecified cancers was caused by deaths certified as due to carcinomatosis (widespread disseminated cancer throughout the body) that were likely to have been due to lung cancers. This study, therefore, provides considerable evidence that high concentrations of radon in air do not cause a material risk of mortality from cancers other than lung cancer. IMPLICATIONS: Protection standards for radon should continue to be based on consideration of the lung cancer risk alone. PMID- 7853420 TI - Detection of (11;22)(q24;q12) translocation-bearing cells in peripheral blood progenitor cells of patients with Ewing's sarcoma family of tumors. PMID- 7853421 TI - Effect of cyclic phenyl saligenin phosphate and paraoxon treatment on vascular response to adrenergic and cholinergic agents in hens. AB - The response of peripheral blood vessels to adrenergic and cholinergic agonists was examined 1, 3, 7, and 21 d after hens were treated with a single intramuscular injection of 2.5 mg/kg cyclic phenyl saligenin phosphate (PSP) or 0.10 mg/kg paraoxon (PXN). These two organophosphates (OPs) cause different clinical effects in exposed animals, as PSP causes organophosphate-induced delayed neuropathy (OPIDN) and PXN causes acute poisoning through inhibition of acetylcholinesterase. For these studies, the ischiadic artery was cannulated both prograde and retrograde and the blood was shunted through a pump to maintain a constant flow. Alterations in pressure measured at the pump outflow were used to indicate changes in limb vascular resistance. Dose-response curves were generated for the response to intravenous administration of acetylcholine (ACh), phenylephrine (PE), or salbutamol (SAL) (10(-8) to 10(-4) mol/kg). Acetylcholine at 10(-8) to 10(-7) mol/kg caused an increase in vascular resistance, whereas concentrations of 10(-5) to 10(-4) mol/kg caused a decrease in vascular resistance in hens given PSP 1 and 3 d previously. The response of PXN-treated hens to ACh was not significantly altered from that of vehicle-treated hens. The resistance generated in response to PE, an alpha 1-adrenergic agonist, in PSP treated hens was greater than levels in vehicle-treated hens on d 1 and 3 and greater than the response seen in hens treated with PXN. Salbutamol, a beta 2 adrenergic agonist, at concentrations of 10(-7) to 10(-4) mol/kg caused an increase in resistance 1 and 3 d after PSP and a decrease on d 7. The responses to SAL were different in PXN-treated hens, as these hens demonstrated a lesser increase in resistance at concentrations of 10(-8) to 10(-7) mol/kg and a decrease in resistance at 10(-5) to 10(-4) mol/kg 1 d after administration of PXN. These observations indicate that response to vasoactive agents is altered in OP-treated hens and that responses differ between a compound capable of causing OPIDN (PSP) and a compound that only causes acute effects (PXN). PMID- 7853423 TI - Dose-, route-, and sex-dependent urinary excretion of phenol metabolites in B6C3F1 mice. AB - Phenol is the major oxidized metabolite of benzene, a known human leukemogen and ubiquitous environmental pollutant. Unlike benzene, phenol does not induce tumors in mice following oral exposure; benzene also exhibits sex-related differences in genotoxicity to bone marrow cells that are not observed following phenol administration. We studied the urinary excretion of phenol metabolites in mice as a means to further investigate the metabolic basis for differences in benzene- and phenol-induced toxicity. Male and female B6C3F1 mice (n = 3/group) were exposed to 15, 40, 100, or 225 mumol [14C]phenol/kg by i.v. tail vein injection (6 microCi/mouse). First-pass intestinal metabolism of phenol was evaluated by comparison of urinary excretion of phenol metabolites following i.v. administration with additional groups of male mice that received the same dose levels by oral gavage. Mice were placed in glass metabolism cages, and urine was collected over dry ice for 48 h. Urinary metabolites were separated by high pressure liquid chromatography (HPLC) and quantified by liquid scintillation spectrometry. Urinary excretion of conjugated metabolites of phenol was dose dependent in both male and female mice administered phenol by i.v. injection or gavage. The major urinary metabolites of phenol were phenol sulfate (PS), phenol glucuronide (PG), and hydroquinone glucuronide (HQG). Sulfation was the dominant pathway at all dose levels, but decreased as a percent of the excreted dose with a concomitant increase in glucuronidation as the dose level increased. Male mice consistently excreted a higher proportion of phenol as the oxidized conjugated metabolite, HQG, compared to female mice, suggesting that male mice oxidize phenol to hydroquinone more rapidly than female mice. Increased oxidation of phenol to hydroquinone by male mice compared to female mice is consistent with both the greater sensitivity of male mice to the genotoxic effects of benzene and the greater potency of hydroquinone compared to phenol as a genotoxicant. Intestinal conjugation of phenol prior to absorption was significant only at low doses and thus alone does not provide an explanation for the lack of carcinogenicity of phenol in bioassays conducted at much higher dose levels. PMID- 7853422 TI - Comparative disposition of 2,3-epoxy-1-propanol (glycidol) in rats following oral and intravenous administration. AB - Glycidol (2,3-epoxy-1-propanol), an industrial chemical, has been shown to be a reproductive toxicant in short-term studies and a carcinogen in rats and mice in oncogenicity studies. The reproductive toxicity of glycidol was believed to result from its conversion to alpha-chlorohydrin by the action of HCl in the stomach. The comparative disposition of glycidol was investigated in rats following oral (po) or intravenous (iv) administration at doses of 37.5 and 75 mg/kg. These were the doses used in the National Toxicology Program (NTP) oncogenicity study with glycidol. Approximately 87-92% of the dose was absorbed from the gastrointestinal tract of the rat. [14C]Glycidol equivalents were eliminated in urine (40-48% of dose in 72 h), feces (5-12%), and exhaled as CO2 (26-32%). At both doses, 9-12% and 7-8% (estimated) of the dose remained in tissues at 24 and 72 h following dosing, respectively. In general, the concentrations of glycidol equivalents in tissues were proportional to the dose. The highest concentrations of radioactivity were observed in blood cells, thyroid, liver, kidney, and spleen, and the lowest in adipose tissue, skeletal muscle, and plasma. The pattern of distribution of radioactivity in tissues was similar for both the iv and po routes. The total recovery of radioactivity ranged from 87 to 91% of dose. Urinary radioactivity was resolved by high-performance liquid chromatography (HPLC) analysis into 15 metabolites. There were one major (14-21% of the dose) and four lesser metabolites (each representing 2-8%); the others were minor, each representing 1% or less of the dose. In general, the urinary metabolic profile was similar following either iv or po administration at the two doses studied. Previous studies by other investigators suggested that alpha-chlorohydrin, which was presumably formed from glycidol by the HCl in the stomach, was metabolized and excreted in urine as beta-chlorolactic acid. The results of the present study show that very little, if any, urinary radioactivity coeluted with authentic beta-chlorolactic acid following either iv or po administration. Therefore, it is concluded that the conversion of glycidol to alpha-chlorohydrin is quantitatively insignificant. However, it may be significant with regard to glycidol reproductive toxicity. Also, the NTP oncogenicity study with glycidol was carried out within the dose range in which its disposition characteristics were linear. PMID- 7853424 TI - Physico-chemical fate of chromium compounds in the sheep lung model. AB - Transmission electron microscopy (TEM) equipped with energy-dispersive x-ray analysis (EDX), electron spectroscopy for chemical analysis (ESCA), secondary ion mass spectrometry (SIMS), and laser microprobe for mass analysis (LAMMA) were used to follow the fate of chromium compounds deposited in the sheep tracheal lobe. Four chromium compounds were used: two chromium(VI) compounds (lead chromate and chromium trioxide) and two chromium(III) compounds (chronic oxide and chromium sulfate). Chromium trioxide is very soluble and the other three are slightly soluble. The compositions, concentrations, and sizes of particles were determined in the bronchoalveolar lavages (BAL) at d 2, 3, 5, and 30 after instillation and on the lung samples collected at d 31. The concentrations of particles in the BAL samples separated the chromium compounds in two groups where Cr2O3 and PbCrO4 (as Pb) were higher than Cr2(SO4)3, PbCrO4 (as Cr), and CrO3. The half-life for alveolar clearance of Cr2O3 and Cr2(SO4)3 has been calculated respectively at 11 and 80 d. Prismatic PbCrO4 particles break up in the lung and sustain a high concentration of isometric particles of lead chromate and another lead-containing compound in the BAL. The CrO3 instilled particles react with endogenous compounds or are transformed to insoluble hydroxyl complexes instead of diffusing very rapidly through the alveolar-capillary barrier. The alveolar clearance as measured in the BAL is not different from the control. PMID- 7853425 TI - Alterations of nucleolar organizer regions of smooth muscle cells in bile duct following biliary ligation in rat. AB - Clinical experience indicates that bile duct dilatation is often associated with patients presenting with cholestasis. The purpose of this study is to propose a hypothesis that such a biliary dilatation, resulting from extra-hepatic obstruction, partially contributes to the rapidly occurring hypertrophy and hyperplasia of the smooth muscle cells in the bile duct; and that such an alteration could possibly lead to the development of neoplastic tissue. Twenty seven male Wistar rats were divided into 4 groups: Control Group (n = 7) with sham operation, Day 4 Group (n = 6) with common bile duct ligated for 4 days, Day 7 Group (n = 7) with common bile duct ligated for 7 days, and Day 14 Group (n = 7) with common bile duct ligated for 14 days. Complete extrahepatic biliary obstruction was induced in Wistar rats by distal ligation of the common bile duct (CBD). The CBD specimens were stained by H & E and argyrophilic techniques (AgNOR method), and the smooth muscle cells were identified and studied with light microscopy and an image analyzer. To determine maximum width of cell size, the widths of smooth muscle cells were found to be 2.82 +/- 0.07 microns, 3.05 +/- 0.06 microns, 4.53 +/- 0.10 microns, and 4.89 +/- 0.12 microns (Mean +/- S.E.) for the Control Group, Day 4 Group, Day 7 Group and Day 14 Group, respectively.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7853426 TI - Influence of meal energy on gastric emptying in healthy Chinese. AB - Radionuclide gastric emptying studies of liquid phases were used to evaluate the gastric motility of healthy Chinese. A total of 53 normal volunteers were included in this study and divided into two groups. Group 1, included 20 males and 8 females (ages: 17-73) who received a meal which consisted of 500ml normal saline containing 500 uCi of Tc-99m phytate. Group 2, included 19 males and 6 females (ages: 27-73) who received a meal which consisted of 500ml 5% glucose solution (25g glucose, 100Kcal) labeled with 500 uCi Tc-99m phytate. Studies were performed with the subjects in the supine position and a gamma camera in a left anterior oblique (LAO) position, while data were collected for 30 minutes after injection of the liquid meal. The gastric emptying time was presented as the half time (T1/2) for the food to empty from the stomach. The study results showed that the T1/2 was 20.5 +/- 7.2 min in Group 1 and 35.3 +/- 11.7 min in Group 2. We conclude that gastric emptying is slower for a liquid meal with a higher caloric content. PMID- 7853427 TI - Effects of fluoride on dental pulp of young rabbits. AB - Fluoride has been adopting as an anticariogenic agent for many years. Many histologic experiments with the effect of fluoride were made on dental hard tissue, but little is known about its effect on dental pulp. We made histopathological tests on dental pulp of rabbits during administration of fluoride. In this study, 24 young New Zealand rabbits aged 7 days were used. The experimental group (N = 20) was given two intraperitoneal injections of sodium fluoride that contained approximately 7 mg F/kg body mass. The control group (N = 4) was injected with an equivalent volume of normal saline. At the thirteenth day after the final injection, the mandibles were collected and processed according to routine histologic methods. Selected sections were stained with hematoxylin and eosin stain. The mandibular incisor pulp was microscopically examined. The following results were obtained. In the experimental group, histopathologic alterations were observed in the pulp, with loss of palisading of the odontoblastic layer. Slightly elongated swollen odontoblasts were found which showed hydropic alterations. Dilatation and hyperemia of blood vessels were also noted. This dose affected deciduous root resorption and changes in secretory ameloblasts; and also appeared to disturb the dental pulp. The present observations of initial reactions in the pulp following intraperitoneal injection of fluoride are considered suitable as a basis for detailed discussion of histopathologic implications. PMID- 7853428 TI - [A preliminary study of the determinants of hospital length of stay among the aged]. AB - The current study reviewed the medical records of those inpatients who were 55 years old at admission and were admitted to Kaohsiung Medical College Hospital between 1983 and 1992. The purpose was to investigate the influences of patient characteristics and disease factor on the length of hospital stay. The long-term goals of these results are to provide a better understanding of the medical needs of aged people, especially the need of hospital beds, and to aid in an effective planning of medical resources for them to maintain their health. 57,009 records were collected. The average length of stay was 14.28 days with a standard deviation of 21.06. Gender, age, condition at discharge, number of diseases diagnosed, year admitted, and whether insured showed significant difference when they were tested by univariate statistical procedures. Multiple regression (MR) analysis was used to test the relative importance of these variables. It showed that whether or not cataracts were diagnosed had the most influence on the length of stay for the pooled samples. Condition at discharge, numbers of admissions, number of diseases diagnosed, and insurance had moderate predictive power. MR on the ten leading diseases separately showed that numbers of admissions, conditions at discharge, and insurance status were the three most important predictors at most models. Number of diseases diagnosed and admission year were also in several of the 10 models. However, gender did not enter any model. PMID- 7853429 TI - [Epidemiological study of anemia in the elderly aged over 65 years in Taiwan]. AB - We investigated the prevalence rate of anemia in a study of the health of the elderly population in four Taiwan urban communities. A total of 2,518 noninstitutionalized persons aged 65-93 were evaluated in 1989-1991. The age adjusted prevalence rates of anemia (hemoglobin < 12.5 g/dl in men and < 11.5 g/dl in women) were 6.5% in men and 8.3% in women. Prevalence rates increased significantly with age in women, while they were not so prominent in men. The men with anemia had higher creatinine and thyroid stimulating hormone levels, but had lower bilirubin and albumin level than men without anemia. Compared with the non anemic female group, the anemic women had higher creatinine and lower bilirubin and albumin levels. Regardless of sex, anemic elderly had significantly higher rates of high serum creatinine. Hence, high serum creatinine may be one of the important factors of anemia in the elderly. PMID- 7853430 TI - [Ender nailing of humeral shaft fractures]. AB - From March 1991 to June 1992, thirteen patients with humeral shaft fracture were managed at our hospital with closed reduction and internal fixation with Ender nails. These patients were mainly victims of traffic accidents and falls and had fractures, head injuries, and chest trauma. The follow-up period was more than 1 year. Operations were performed under C-arm guide and, according to the method of Hall and Pankovich, divided into antegrade and retrograde methods. The average operation time was 104 minutes, ranging from 70 to 160 minutes, and blood loss was less than 100 ml. Twelve patients were available for follow-up with 11 unions (91.6%), and the functional results were satisfactory. Complications included 2 nails backing out and one iatrogenic fracture. There was no infection and no radial nerve injury. We concluded that for those humeral shaft fractures with surgical indication, Ender nailing was a good choice. The advantages include a simple procedure, lower infection rate and less nonunions. PMID- 7853431 TI - [Rhinocerebral mucormycosis in a case of malignant lymphoma]. AB - Mucormycosis, an uncommon opportunistic fungal infection, usually occurs in immunocompromised patients. It is rapidly progressive and almost always fatal. Patients with lymphoma are susceptible to pulmonary or disseminated mucormycosis, whereas rhinocerebral mucormycosis in such patients, as far as we know, is rarely reported. We present a patient with malignant lymphoma who exhibited such an acute rhinocerebral infection after chemotherapy which manifested initially as a stuffy nose and intractable headache. Then ptosis, proptosis, chemosis and multiple cranial nerve palsies appeared. Eschar was found in the nasal cavity. Direct KOH smear and tissue biopsy revealed mucormycotic infection. He survived because of early diagnosis and prompt treatment. PMID- 7853432 TI - An unusual intracranial metastasis of osteosarcoma. AB - Intracranial metastasis is unusual in osteosarcoma. A case of osteosarcoma was presented with a large intracranial "stone" which was a subdural convexity metastasis. Smaller epidural metastases over other areas were noted also in brain CT scan. Using the radiographs and bone scans, many other lesions at bones, the mediastinum, pleura, perirenal space, and adrenal gland were detected simultaneously. This condition might result from either early metastases or multifocal osteosarcomas. Because many of the above lesion sites were not frequent locations of primary osteosarcoma and had been reported as metastatic targets of osteosarcoma. So the explanation of a very malignant osteosarcoma with early metastases may be more appropriate for this case. The baseball-like tumor in the subdural space with marked compression of the brain surface was grossly totally excised. Histopathologic examination confirmed the diagnosis of osteosarcoma. Postoperatively, the man's condition improved dramatically, though only for two months. He died 5 months later. Reports of such metastatic osteosarcomas are reviewed. PMID- 7853433 TI - Child health beyond year 2000. PMID- 7853434 TI - Double-blind comparison of oral gentamicin and nalidixic acid in the treatment of acute shigellosis in children. AB - To compare the efficacy of oral gentamicin with nalidixic acid in the treatment of acute shigellosis, we studied, in a double blind-trial, 79 comparable children with bloody diarrhoea of less than 72 h duration. Of them Shigella spp. were isolated in 71 patients. Patients were randomly assigned to receive either gentamicin 30 mg/kg/day or nalidixic acid 60 mg/kg/day, both given orally in four equal doses for 5 days. Stool frequency differed significantly between the groups from day two until completion of the study. Treatment failure was observed in 14 (42 per cent) patients receiving oral gentamicin compared to none of those with nalidixic acid-sensitive strains of Shigella spp. (P = 0.0002). Although all the shigella isolates were sensitive to gentamicin in vitro, 19 (58 per cent) patients on gentamicin therapy failed to eliminate shigella organisms from stool, compared to none in the nalidixic acid treated group infected with nalidixic acid sensitive Shigella spp. (P < 0.001). One patient in each group had a bacteriological relapse. We conclude that gentamicin given orally was therapeutically ineffective in the treatment of acute shigellosis. PMID- 7853435 TI - Subacute sclerosing panencephalitis in Delhi. AB - Between 1989 and 1992 (to October), 65 patients of subacute sclerosing panencephalitis were referred to the Virology Laboratory of the National Institute of Communicable Diseases, Delhi, from the major hospitals of Delhi. The cases were mainly residents of Delhi, but a few were from states bordering Delhi. The age group of affected cases ranged from 2 to 24 years. The disease (SSPE) was six times more common in males than in females. All but four patients below 3 years of age gave a past history of measles. No patient had history of measles vaccination. The titres of haemagglutination inhibition antibodies (HAI) to measles virus in serum of SSPE patients ranged from 1:8 to 1:2048 and in CSF it ranged from 1:4 to 1:64, while in the control group it ranged from 1:2 to 1:256 in serum and nil in CSF. The geometric mean titres in serum was 10-fold higher in serum and four-fold higher in CSF from SSPE cases as compared to control. PMID- 7853436 TI - An increase in Giardia duodenalis infection among children receiving periodic Anthelmintic treatment in Bangladesh. AB - During a deworming study in northern Bangladesh, the prevalence of Giardia duodenalis increased significantly among three groups of children receiving periodic treatment with mebendazole. This was first observed in the treatment group (Group A) of a 12-month study. Giardia increased from 5 to 31 per cent in Group A (n = 49 chi 2 = 10.42, P < 0.005), but did not increase significantly in the placebo group (Group B) (11 to 18 per cent; chi 2 = 0.4, P = NS). The prevalence of Giardia in the treatment and placebo groups was not significantly different at the beginning of the study (n = 89, chi 2 = 0.8, P = NS). During a 6 month follow-up study, children in Groups A and B received 2-monthly treatment with mebendazole. Within 6 months the prevalence of Giardia increased significantly in Group B from 18 to 44 per cent (chi 2(1) = 6.14, P < 0.05). The prevalence of Giardia was also examined in 265 children at the end of an 18-month deworming study in the same area and found to be significantly higher among the treatment group (Group C) compared with the placebo group (Group D) (38 v. 21 per cent, chi 2 = 8.87, P < 0.005). Finally, the prevalence of Giardia was significantly higher in Group B after being treated than in Group D which had not been treated (44 and 21 per cent, respectively, chi 2 = 9.08, P < 0.005). These children were from the same villages and measured during the same month of the monsoon season.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7853437 TI - Acute respiratory infection in Malaysian children. AB - A cross-sectional community-based survey was conducted to determine the prevalence of acute respiratory infection (ARI) in children below 7 years of age and to obtain baseline information for an intervention programme. A total of 6190 households comprising 38,632 persons with 12,273 children (32 per cent) below 7 years of age were surveyed. Information on socio-demographic variables, environmental sanitation, occurrence of ARI and diarrhoea, treatment seeking behaviour during episodes of those illnesses and immunizations among children were obtained. Thirty per cent of children had experienced ARI in the 2-week period prior to the interview, and 94 per cent had mild ARI, 1 per cent had moderate and 5 per cent had severe ARI. There was lack of concurrence between mother's perception of severity and that of the investigators' (Kappa coefficient = 0.083 (95 per cent CI = 0.017-0.149). Twenty-four and 39 per cent of severe and moderate ARI, respectively, were reported by mothers to be mild. There is cause for concern as these children may not receive timely and appropriate treatment. The findings from this study contribute to identification of target populations and priority areas for health education of the population. The survey has provided useful baseline data for the implementation of an intervention programme for the control of ARI in children. PMID- 7853438 TI - Nasal continuous positive airway pressure in the treatment of respiratory distress syndrome: an experience from a developing country. AB - Forty-four premature infants with respiratory distress syndrome (RDS) were admitted and initially treated with binasal continuous positive airway pressure (CPAP) using Beneveniste's valve and silastic nasal prongs. Twenty-seven cases (61 per cent) were successfully treated compared to 17 cases (39 per cent) who failed to respond to CPAP. Neither gestational age nor birth weight had a detremental effect on the success of nasal CPAP. There was significant improvement of RDS with a mild to moderate degree of severity on CPAP. No pneumothorax was reported in any of our cases. The success group had a significantly lower incidence of infection, apnea, intraventricular haemorrhage and retinopathy of prematurity. PMID- 7853439 TI - Evaluation of immune response in infants with different nutritional status: vaccinated against tuberculosis, measles and poliomyelitis. AB - Immune response of infants vaccinated under Expanded Programme on Immunization (EPI) was evaluated for measles, poliomyelitis, and tuberculosis in Ifo/Otta area of Ogun State and Badagry area of Lagos State, Nigeria. In the prevaccination evaluation of measles antibody, 59 per cent were protected and 41 per cent were at risk in Ifo/Otta area, while 49 per cent were protected and 51 per cent were at risk in the Badagry area. After measles vaccination, 89 per cent of those evaluated seroconverted and 11 per cent did not in Ifo/Otta area, while in Badagry area, 86 per cent of those evaluated seroconverted and 14 per cent did not. For polio neutralizing antibody evaluated at post-immunization, 91 per cent seroconverted, while 9 per cent did not in Ifo/Otta area, while in Badagry area 66 per cent seroconverted and 34 per cent did not. Tuberculin test was used to evaluate the cellular response to BCG vaccination against tuberculosis. 64 per cent were found protected, while 18 per cent were at risk in both areas examined and 18 per cent dropped out. Using Gomez method to evaluate the nutritional status of the infants, 34 per cent were malnourished in Ifo/Otta area and are mostly immigrants. In Badagry area, 53 per cent were normal while 47 per cent were malnourished and most of the malnourished infants were plagued with diarrhoea, severe cough, high fever or malaria infection. Most of the malnourished in the two areas screened were between 9 and 18 months of age, which is the crucial period in the growing stage of the children.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7853440 TI - Infectious agents causing acute watery diarrhoea in infants and young children in Bangladesh and their public health implications. AB - We studied the age specific distribution of enteropathogens in young children presenting at a large diarrhoeal diseases hospital in urban Bangladesh. A 5 per cent systematic sample was used to examine 1207 rectal swab specimens of children aged 1-35 months with acute watery diarrhoea. Variation in isolation rates of enteropathogens was observed in different age groups. Overall rotavirus (26 per cent) and Campylobacter (26 per cent) were the most common pathogens followed by enterotoxigenic Escherichia coli (15 per cent), Vibrio cholerae 01 (7 per cent), other Vibrios (9 per cent), Shigella (4 per cent), and Salmonella (< 1 per cent). In early infancy (1-5 months) more rectal swab specimens did not yield any enteropathogen compared to older children of 24-35 months old (44 v. 30 per cent). Rotavirus was most frequently detected (35 per cent) in children between 6 and 11 months old. Attendance of cholera cases at the hospital was alarmingly high in the third year of life (29 per cent). The study provided useful information that, in general, children under 2 years are predominantly infected with agents [rotavirus, Campylobacter, and enterotoxigenic Escherichia coli (ETEC)] for which antibiotic therapy is not usually indicated. These patients can be managed effectively with oral rehydration therapy and proper feeding. Knowledge of pathogens associated with more severe forms of diarrhoea may help in optimizing strategies for vaccination when suitable vaccines are available against enteric infections. PMID- 7853441 TI - Shigellosis in Jordanian children: a clinico-epidemiologic prospective study and susceptibility to antibiotics. AB - During a 2-year prospective study of children hospitalized with gastroenteritis, shigellosis was detected in 66 cases (9 per cent of 726 admissions). The age group for peak shigella incidence was 1-4 years. The incidence increased from 8 per cent in 1991, to 11 per cent in 1992. Shigella flexneri was the most common isolate (65 per cent), followed by Shigella sonnei (17 per cent), Shigella boydi (11 per cent), and Shigella dysenteriae (7 per cent). At presentation, 44 per cent had watery diarrhoea, followed by dysentery during hospitalization in the majority of cases. Seizures occurred in 27 per cent of cases and preceded diarrhoea in 15 per cent. Most Shigella flexneri and dysenteriae strains were resistant to co-trimoxazole, ampicillin, tetracyclin, and chloramphenicol. Nalidixic acid, gentamicin and cefotaxime were the most effective antibacterial agents. Case fatality was 3 per cent associated with strains resistant to the antibiotics used initially in the treatment. PMID- 7853442 TI - Studies on the effectiveness, safety and acceptability of fluids from local foodstuffs in the prevention and management of dehydration caused by diarrhoea in children. AB - Two fluids derived from local staple food, Manioc Salt Solution (MSS) and Pap Salt Solution (PSS) were assessed and compared with the World Health Organization/Oral Rehydration Solution (WHO/ORS) in 333 children aged between 6 and 60 months in a clinical trial. All the children had some dehydration after episodes of acute watery diarrhoea using WHO criteria. All the children who were placed on MSS and PSS, as well as ORS were satisfactorily rehydrated. There was no significant difference in pre- and postserum electrolytes of the children on the three types of fluids. The fluids were found to be acceptable, readily available, easy to prepare and cheaper than the ORS fluid. There was no taboo against the fluid. It is noteworthy that there was no significant difference in the sugar and electrolyte contents of the different varieties of the manioc and pap available in this environment, thus making the MSS and PSS effective and readily available substitutes to ORS. The two fluids are therefore recommended as rehydrating fluids for children with some dehydration in the absence of WHO/ORS fluid. PMID- 7853443 TI - Predictive perinatal score in the diagnosis of neonatal sepsis. AB - A scoring system for prediction of neonatal sepsis was evolved after determining the interdependence of perinatal risk factors for infection. Records of 100 babies with a history of one or more perinatal risk factors were analysed for incidence of infection within 4 hours of birth and followed for 1 week thereafter for appearance of any clinical or laboratory signs of infection. The incidence of sepsis was compared amongst various risk factors. Since majority of perinatal risk factors occur in combinations interdependence of factors was determined using actuarial analysis and score assignment was done whether the factor was dependent or independent. No definite infection was seen in the control group of 100 babies having no history of high risk factors. The scoring system thus elucidated is recommended as a screening procedure for selecting of neonates for laboratory evaluation. PMID- 7853444 TI - Clinical evaluation and bacterial survey in infants and young children with diarrhoea in the Santa Cruz district, Bolivia. AB - Clinical and laboratory studies on a total of 211 of infants and young children admitted to the National Santa Cruz General Hospital for various types of diarrhoea during 1991-1992 are described. A peak cluster was observed in children aged 1 year of which 80 per cent were acute diarrhoea and the remaining 20 per cent were prolonged or chronic diarrhoea. The major bacterial pathogen was enteropathogenic Escherichia coli. Other bacterial pathogens such as Klebsiella, Shigella, Cholera, etc., were detected. Ascaris, E. histolytica, Giardia and Ankylostoma were also detected. Many of the patients infected with enteropathogenic E. coli showed elevated serum titre to these bacterial antigens. Most of the detected E. coli and Shigella revealed that they were resistant to ampicillin, trimethoprim/sulfamethoxazole, and erythromycin, and some were resistant to gentamycin and chloramphenicol in vitro tests. It was difficult to make a diagnosis by clinical diagnosis alone for cholera of the el Tor Ogawa type. The detection of faecal leukocytes seems to be an useful predictor for diagnosis of invasive diarrhoea with mucobloody stools. Faecal pH and erythrocytes did not seem to be reliable diagnostic predictors. Fourteen cases (7 per cent) died of diarrhoeal disease. Many of them had complications with marked dehydration, hypoelectrolytaemia, malnutrition and infections, and rapid deterioration within 10 days despite rehydration therapy. Timely rapid rehydration and restoration of electrolytes followed by suitable management of complications are necessary. PMID- 7853445 TI - Serum vitamin A and beta-carotene levels in pre-school age children. PMID- 7853446 TI - Child growth monitoring: errors of measurement with the TALC direct recording scale. AB - Young children in the Seychelles were weighed and charted using both a beam balance with the standard growth chart and using the TALC direct recording scale with integral chart. The oscillating pointer and unwanted horizontal movement of the chart in the scale resulted in unacceptable misclassification of nutritional status equivalent to a weighing error in infants of +/- 2 kg. The electronic walk on scale may provide the most important next step forward in low cost scale technology in primary health care. PMID- 7853447 TI - Socio-anthropological determinants and home management in childhood diarrhoea in a squatter settlement of Karachi, Pakistan. PMID- 7853448 TI - The natural physical alternative to cognitive theories of motor behaviour: an invitation for interdisciplinary research in sports science? AB - This review examines the viability of the natural physical alternative to traditional cognitive modelling of the sport performer. It is concluded that the natural physical perspective offers an attractive framework for the study of movement control and co-ordination in sport, but, at present, does not seem capable of superseding cognitive explanations. As a consequence of the nature of the questions they are asking, natural physical theorists offer a significant avenue for interdisciplinary research in sports science. Significant differences in the philosophy underpinning both theoretical views are acknowledged, but growing support for an integrated approach to motor control is highlighted. A major task for sports scientists may be to verify empirically the nature of an integrated model of the sport performer. PMID- 7853449 TI - Information recall of younger and older skilled athletes: the role of display complexity, attentional resources and visual exposure duration. AB - This study was concerned with the interactive role of experience of athletic skill with other relevant environmental variables (display complexity, attentional resources, exposure time of stimuli) on perception (recall) of structured handball game situations. Nineteen experienced (older) and 19 less experienced (younger) handball players were assigned randomly either to ball bouncing (diverted attention) or to calm seated (focused attention) conditions. In each of the two conditions, the subjects were exposed to a total of 36 slides containing 2-3, 5-6 and 8-10 players. Eighteen slides were exposed for 0.5 s and 18 for 1.0 s. All the slides contained structured defence and offence situations. Recall scores were subjected to repeated-measures ANOVA using attention condition and age as between-subject factors and task complexity and exposure duration as within-subject factors. The results showed that the recall of less experienced players deteriorated more than the recall of more experienced players following exposure to complex displays (> or = 8 players) while engaging in a secondary task (bouncing). The findings suggest that research paradigms should be applied in the field of sport which share both ecological validity and a potential to discover the cognitive substrates underlying experience and age in skilled motor performance. PMID- 7853450 TI - Effect of aerobic and strength training on pain tolerance, pain appraisal and mood of unfit males as a function of pain location. AB - The purpose of this study was to examine the effect of aerobic and strength conditioning on pain tolerance, pain appraisal and mood as a function of upper and lower limb pain location. Unfit males (n = 48) were randomly assigned to one of four groups: aerobic training, strength training, combined aerobic and strength training, and a 'no training' (control) group. The fitness regimens consisted of exercising at least three times per week for 12 weeks. Pain tolerance and appraisal and mood were ascertained before the treatment (baseline), and after 6 and 12 weeks. Statistical analyses using MANOVA indicated that the presence of aerobic training increased upper limb pain tolerance but was also linked to a more severe pain appraisal compared with the absence of aerobic training. Aerobic work also improved vigour while decreasing fatigue, tension and depression. Strength training had no influence on pain tolerance and positive mood states, but increased depression. Lower limb pain tolerance was unaffected by the treatments. PMID- 7853451 TI - Exercise-induced analgesia and the role of reactivity in pain sensitivity. AB - The present study was designed to evaluate whether pain perception and pain tolerance are altered by submaximal aerobic exercise. Sixty male volunteers were randomly assigned to one of two control or experimental groups in the first of two sessions. In session 1, baseline measures of pain tolerance and pain perception were obtained for half of the subjects in each of the experimental and control groups, respectively. In addition, all subjects completed the Reactivity Scale, followed by estimation of their maximum aerobic power (VO2 max) using the Canadian Home Fitness Test. In session 2, the subjects in the two experimental groups exercised for 12 min by climbing a double step to pre-recorded musical cadences, working on average at 63% VO2 max, whereas the subjects in the two control groups spent approximately 12 min completing two short unrelated questionnaires. Measures of pain tolerance and pain perception were obtained from all subjects after exercising or completing questionnaires. Pain tolerance was assessed by the amount of time (up to 10 min) that subjects could voluntarily endure a 2300 g pressure to the index finger of their dominant hand. Pain perception was defined by participants' intensity ratings on an 11-point scale, made at 30 and 60 s. The results showed that reactivity and exercise were significant predictors of pain tolerance, together accounting for approximately 22% of the variance. The finding that submaximal workloads produce analgesia supports the potential usefulness of exercise in therapeutic intervention. PMID- 7853452 TI - Effect of vibratory stimulation training on maximal force and flexibility. AB - In this study, we investigated a new method of training for maximal strength and flexibility, which included exertion with superimposed vibration (vibratory stimulation, VS) on target muscles. Twenty-eight male athletes were divided into three groups, and trained three times a week for 3 weeks in one of the following conditions: (A) conventional exercises for strength of the arms and VS stretching exercises for the legs; (B) VS strength exercises for the arms and conventional stretching exercises for the legs; (C) irrelevant training (control group). The vibration was applied at 44 Hz while its amplitude was 3 mm. The effect of training was evaluated by means of isotonic maximal force, heel-to-heel length in the two-leg split across, and flex-and-reach test for body flexion. The VS strength training yielded an average increase in isotonic maximal strength of 49.8%, compared with an average gain of 16% with conventional training, while no gain was observed for the control group. The VS flexibility training resulted in an average gain in the legs split of 14.5 cm compared with 4.1 cm for the conventional training and 2 cm for the control groups, respectively. The ANOVA revealed significant pre-post training effects and an interaction between pre post training and 'treatment' effects (P < 0.001) for the isotonic maximal force and both flexibility tests. It was concluded that superimposed vibrations applied for short periods allow for increased gains in maximal strength and flexibility. PMID- 7853454 TI - A stochastic approach to predicting competition squash match-play. AB - Modelling sport competition is an informative analytic technique for the investigation of athletic behaviour because it focuses attention on the critical aspects of data which characterize sporting success. A stochastic (Markov) model of championship squash match-play is reported which infers prospective behaviour from previous sport performance through forecasting shot response and associated outcome from the preceding shot. The results presently restrict the model to the competing players already analysed because, while a consistent athletic response was established when competing against the same opponent (P > 0.25), an inconsistent response was found when competing against different opponents (P < 0.25). These results may impact the information value traditionally drawn from previous sport analysis. The hypothesis that future squash match-play can be successfully predicted from previous sport performance requires further investigation, since it remains unclear whether the present analysis failed to identify the preceding condition(s) which elicit a reasonably stable behavioural response, or indeed whether athletic behaviour in championship squash is more variant than initially believed. Alternative modelling considerations are discussed and a refinement to the present model is proposed in an effort to improve future model utility and application. PMID- 7853453 TI - Maximal isometric force and muscle cross-sectional area of the forearm in fencers. AB - The maximal isometric force (MIF) of a muscle is directly related to its cross sectional area (CSA). Strength training produces an increase in muscular force while muscular hypertrophy becomes appreciable at a later time; in asymmetric sports, training causes significant increases in force and muscular mass of the dominant limb of the athlete. The aim of this study was to analyse the differences in muscular force and trophism between the dominant and non-dominant forearms in fencers and in controls. The data of 17 male distance runners (age 21.4 +/- 2.4 years, body mass 74.0 +/- 5.0 kg, height 180 +/- 6 cm) were compared with those of 58 male fencers (age 23.0 +/- 6.7 years, body mass 71.9 +/- 9.3 kg, height 178 +/- 7 cm) drawn from the ranking lists of the National Fencing Committee. They trained for a mean of 11.4 +/- 6.0 (range 2-36) years, commencing at 10.7 +/- 4.5 years of age. Cross-sectional area (muscle plus bone) was estimated in the dominant and non-dominant forearm using a simplified anthropometric method. Maximal isometric force was determined using a mechanical handgrip dynamometer. The differences in CSA and isometric force between the two limbs and between fencers and controls were tested using paired and unpaired Student's t-tests, respectively. Significant differences in CSA and maximal force were observed between the dominant and non-dominant forearm in fencers (both P < 0.001) and in controls (P < 0.005 and P < 0.001, respectively). The fencers showed a greater CSA (P < 0.001) and force (P < 0.001) in the dominant forearm compared with the control group. Furthermore, the differences between the dominant and non-dominant limb of the fencers were significantly greater than the differences between the dominant and non-dominant limb of the controls (P < 0.001 for CSA and P < 0.05 for force). No significant differences in stress ratio (force/CSA) were obtained in either group.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7853455 TI - Pharmacokinetics of sulphamethoxazole and trimethoprim administered intravenously and orally to Japanese quails. AB - The pharmacokinetic behaviour of sulphamethoxazole and trimethoprim was studied after combined intravenous (i.v.) administration at doses of 20 mg/kg and 4 mg/kg, respectively, and after oral administration at doses of 50 mg/kg and 10 mg/kg. The serum concentration versus time data after i.v. administration were best described by the biexponential equations C = 34.77.e-2.655.t + 39.03.e 0.241.t for sulphamethoxazole and C = 3.29.e-3.878.t + 0.83.e-0.306.t for trimethoprim. Mean biological half-lives of the drugs were 2.89 +/- 0.11 and 2.38 +/- 0.33 h, respectively. The distribution volumes (V area) were 0.475 +/- 0.026 l/kg (sulphamethoxazole) and 3.89 +/- 0.61 l/kg (trimethoprim). Orally administered sulphamethoxazole and trimethoprim were rapidly absorbed. The maximum serum concentrations were reached 0.5-1 h after administration. The bioavailability was 81% for sulphamethoxazole and 41% for trimethoprim. PMID- 7853456 TI - Pharmacokinetics of thiopentone in the horse. AB - The pharmacokinetics of thiopentone sodium administered intravenously as a single dose (11 mg/kg) were studied in acepromazine pre-medicated horses and ponies in which anaesthesia was maintained with either halothane (Group 1) or isoflurane (Group 2). The results showed that the disposition kinetics of thiopentone in horses and ponies were best described by a three-compartment open model. In plasma, a very short initial distribution phase in both horses and ponies, half life 1.4 +/- 1.2 min (mean +/- SD) and 1.3 +/- 0.7 min, respectively, was obtained, which was followed by a second comparatively slower redistribution phase, half-life 16 +/- 12 min and 11 +/- 5 min, respectively. The volume of distribution for the drug was large, especially in the ponies which received isoflurane (1127 +/- 86 ml/kg), compared to the horses which received halothane (742 +/- 89 ml/kg). The drug had a somewhat shorter elimination half-life in the horses (147 +/- 21 min) than in than ponies (222 +/- 44 min), but no obvious difference in clearance of the drug was observed between the horses (3.5 +/- 0.5 ml/min/kg) and ponies (3.6 +/- 0.8 ml/min/kg). PMID- 7853457 TI - Fate of etiproston, a synthetic analogue of PGF2 alpha, in cows. AB - The pharmacokinetics and metabolic fate of labelled compounds were investigated after intramuscular administration of 3H-radiolabelled etiproston to nine cows. Elimination was rapid (t 1/2 beta = 2.8 h). Forty-eight h after administration 92.6% of the radioactivity had been eliminated, mainly via the urinary (66% at 48 h) and faecal routes (26% at 48 h). In comparison, little elimination in milk occurred (less than 0.034% dose/l by 24 h). Radioactivity at the injection site 48 h after administration was seen in one cow (< 4.68 x 10(-5%) dose/g). No radioactivity was detected in the tissues. Urinary metabolites were purified and isolated using XAD-2 extraction and preparative HPLC in reverse and normal phases. The main urinary metabolite, identified by mass spectrometry, was the tetranor acid derivative in equilibrium with its lactone form. PMID- 7853458 TI - Types of serotonergic receptors involved in the control of reticulo-ruminal myoelectric activity in sheep. AB - The effects of peripheral (intravenous, i.v.) and central (intracerebroventricular, ICV) administration of agonists of 5-HT1A, 5-HT2, 5-HT3 and 5-HT4 receptors were investigated in conscious sheep chronically fitted with intraparietal electrodes on the reticulum and the dorsal, ventral and caudo ventral rumen. The 5-HT1A agonist 8-hydroxydipropylaminotetralin increased reticular and decreased ruminal spike burst frequency when given i.v. (80 micrograms/kg) and ICV (8 micrograms/kg). The 5-HT2 and 5-HT3 agonists, alpha methylserotonin and 2-methylserotonin, induced a moderate inhibition of rumino reticular contractions when given i.v. at 100 and 150 micrograms/kg, respectively, while marked inhibition was observed after ICV administration at doses of 10 and 5 micrograms/kg, respectively. The 5-HT4 agonist 5 methoxytryptamine strongly stimulated rumino-reticular motility by the ICV (10 micrograms/kg) route, whereas it induced a moderate inhibition when administered i.v. (200 micrograms/kg). The selective antagonist of 5-HT1A, 5-HT2, 5-HT3 and 5 HT4 receptors, spiroxatrine, ritanserin, granisetron and DAU 6285, respectively, blocked the responses of the respective agonists given by the same route. Moreover, the antagonists given ICV blocked the effects of the agonists given i.v. except for DAU 6285 ICV, which did not antagonize the inhibition induced by 5-methoxytryptamine i.v. It is concluded that the four types of serotonergic receptors investigated control rumino-reticular motility at the central level. However, according to the receptor type and the forestomach area (reticulum or rumen) this control may be stimulatory or inhibitory, demonstrating a pleiotropic role of serotonin in the control of rumino-reticular motility in sheep. PMID- 7853460 TI - Comparative pharmacokinetics of ampicillin-sulbactam combination in calves and sheep. AB - The pharmacokinetics of ampicillin and sulbactam administered in combination were studied in calves and sheep. The animals were administered an aqueous solution of ampicillin/sulbactam (2:1, w/w) intravenously and intramuscularly at doses of 13.2 and 6.6 mg.kg-1, respectively. A microbiological method was used to detect ampicillin, and HPLC was used to detect sulbactam in serum. Following intravenous (i.v.) administration, the distribution phases were rapid and similar (about 15 min) for both drugs in both species, whereas sulbactam in calves and ampicillin in sheep showed a faster elimination rate. After intramuscular (i.m.) administration both drugs showed peak concentrations higher in calves than in sheep; the peak time of sulbactam was shorter in calves than in sheep. No other significant differences in the pharmacokinetics of the combination were observed between the species after i.m. injection. The mean residence and absorption times, calculated by non-compartmental analysis, for both calves and sheep suggested that the differences in ampicillin and sulbactam pharmacokinetics could be attributable to the different molecular structures. PMID- 7853459 TI - Disposition of human drug preparations in the horse. III. Orally administered alclofenac. AB - Concentrations of the non-steroidal anti-inflammatory drug (NSAID) alclofenac were determined by a sensitive high performance liquid chromatographic procedure in plasma and urine of horses following oral administration of a dose of 3 g. In plasma, alclofenac was present in detectable concentrations for 72 h. The plasma disposition in individual horses was best described by a bi-compartmental model with two successive rate constants ka1 = 0.05 +/- 0.06 h-1 and ka2 = 0.06 +/- 0.01 h-1. Alclofenac half-lives t1/2 alpha and t1/2 beta were 1.0 +/- 0.8 h and 6.9 +/- 1.5 h, respectively. Maximal concentrations (38.9 +/- 16.2 micrograms/ml) were obtained after 8.5 +/- 2.4 h. Alclofenac was detected in urine for at least 48 h after dosing. The percentage of the dose excreted as unchanged alclofenac in 12 h was very low (0.68 +/- 0.19%), total (free+conjugated) alclofenac accounted for 2.16 +/- 0.55% of the dose. PMID- 7853461 TI - Thiamphenicol pharmacokinetics in beef and dairy cattle. AB - The pharmacokinetics of thiamphenicol were investigated in 10 calves and six lactating cows. It was found that this drug is rapidly absorbed (15 min) following intramuscular injection with an absorption rate constant and a bioavailability of 8.7 h-1 and 84%, respectively. The drug appears to be widely distributed into various body fluids, yielding a volume of distribution (Vd(area) of approximately 0.9 l/kg. The micro-rate constants indicated that the antibiotic rapidly diffuses into the peripheral compartment (k12 > k21). Elimination from plasma is relatively rapid, with a biological half-life of about 1.75 h. Thiamphenicol appears shortly in milk (15 min) after its intravenous administration, and gives milk to plasma concentration ratios greater than one between 4 and 12 h. PMID- 7853462 TI - Pharmacokinetics of gentamicin following single dose intravenous administration in normal and febrile goats. AB - A pharmacokinetic study of gentamicin (5 mg/kg intravenous (i.v.)) was conducted first in clinically healthy female goats and then in the same goats after induction of fever by Escherichia coli endotoxin (0.2 microgram/kg i.v.). Rectal temperature increased 1 degrees to 1.5 degrees C in febrile goats. Differences in the blood serum concentrations of gentamicin were not observed at any time between febrile and normal goats. The disposition kinetics of gentamicin were described by a biexponential expression CP = Ae-alpha t + Be-beta t. Median values for the half-lives of gentamicin were 103.6 min in normal and 136.0 min in febrile goats. The apparent volume of distribution (Vd) was 263.3 ml/kg in the febrile goats which was not different from that in the normal goats (240.6 ml/kg). The volume of the central compartment (Vc) was almost identical in normal and febrile goats. The body clearance (Cl beta) was observed to be 1.7 and 1.6 ml/min.kg in normal and febrile goats, respectively. Dosage regimens for gentamicin were calculated on the basis of median kinetic data. PMID- 7853463 TI - The effects of aspirin and paracetamol on the aggregation of equine blood platelets. AB - The responses of equine blood platelets in citrated platelet-rich plasma to arachidonic acid, U44069 (prostaglandin endoperoxide analogue), adenosine 5' diphosphate, platelet-activating factor or collagen were investigated by turbidimetric aggregometry. Pre-treatment of the platelets with aspirin (1 mmol/l) or paracetamol (1.3 mmol/l) abolished shape change and aggregation in response to arachidonic acid; decreased the rate of aggregation in response to collagen, with no separate effect on shape change; had no marked effect on aggregation caused by the other agonists; but in no case transformed irreversible aggregation to reversible aggregation. We conclude that thromboxane A2 generation is of minor importance in the aggregation of equine platelets, and in particular that thromboxane A2 is not a significant mediator of irreversible aggregation. PMID- 7853464 TI - Disposition of ciprofloxacin following intravenous administration in dogs. AB - The pharmacokinetics of ciprofloxacin (CIP) following intravenous administration in dogs have been investigated. The drug was administered at three doses (2.5, 5 and 10 mg/kg body weight) and was assayed in biological fluid samples (plasma and urine) by an HPLC method. The plasma concentration-time curves were best described by a two-compartment open pharmacokinetic model. The drug was widely distributed (Vd(area) almost 3 l/kg), being distributed in the dog more rapidly than in other species (t1/2(lambda 1) 3 min approximately). The elimination half life (t1/2 lambda 2) was 129-180 min which is similar to values obtained in other species. The unchanged drug eliminated in urine was less than 37% of the administered dose, which is less than the values obtained in humans, calves and pigs. The glomerular filtration rate and the renal clearance of CIP in the dog suggest that renal elimination probably occurs mainly by glomerular filtration. The results showed that the pharmacokinetics of CIP, as in other species, was linear in dogs in the dose range studied. PMID- 7853465 TI - Effects of phenylbutazone on thiamylal disposition and anaesthesia in ponies. AB - Phenylbutazone given during the perisurgical period has been reported to increase the intensity and duration of thiamylal anaesthesia in horses. A possible mechanism of competitive plasma protein binding has been suggested. The purpose of the present study was to experimentally reproduce the phenomenon of increased intensity and/or duration of thiamylal anaesthesia and to determine if there is competitive displacement of plasma protein bound thiamylal by phenylbutazone. Six ponies each received one of three treatments, 11 mg/kg intravenous (i.v.) thiamylal; 8.8 mg/kg i.v. phenylbutazone; and 11 mg/kg i.v. thiamylal with 8.8 mg/kg i.v. phenylbutazone given 9 min later. Thirteen blood samples were collected from 0 time through 600 min following drug administration and plasma drug concentrations quantified by high performance liquid chromatography. The pharmacokinetics of thiamylal and phenylbutazone were best described by three- and two-compartment models, respectively. There were no significant differences in pharmacokinetic parameters for thiamylal in the presence of phenylbutazone. However, there were differences in phenylbutazone pharmacokinetics when preceded by thiamylal administration. Unbound phenylbutazone concentrations were increased at 171, 231 and 351 min when given with thiamylal, accompanied by decreases in per cent bound phenylbutazone (P < 0.05). There were also significant (P < 0.05) changes in per cent plasma protein binding of thiamylal and phenylbutazone between 120 and 360 min, when in combination. No changes in intensity or duration of anaesthesia were observed. PMID- 7853466 TI - Pharmacokinetics of apramycin in Japanese quails. PMID- 7853467 TI - Influence of tolmetin on the zinc, copper and magnesium content of guinea pig tissues. PMID- 7853468 TI - Evaluation of a microstrain gauge algesimeter for quantitative measurement of nociception in the dog. PMID- 7853469 TI - Pharmacokinetics of gentamicin in Mammoth asses. PMID- 7853470 TI - Cloning and characterization of herpes simplex virus type 1 oriL: comparison of replication and protein-DNA complex formation by oriL and oriS. AB - The herpes simplex virus type 1 genome contains three origins of DNA replication: two copies of oriS and one copy of oriL. Although oriS has been characterized extensively, characterization of oriL has been severely limited by the inability to amplify oriL sequences in an undeleted form in Escherichia coli. We report the successful cloning of intact oriL sequences in an E. coli strain, SURE, which contains mutations in a series of genes involved in independent DNA repair pathways shown to be important in the rearrangement and deletion of DNA containing irregular structures such as palindromes. The oriL-containing clones propagated in SURE cells contained no deletions, as determined by Southern blot hybridization and DNA sequence analysis, and were replication competent in transient DNA replication assays. Deletion of 400 bp of flanking sequences decreased the replication efficiency of oriL twofold in transient assays, demonstrating a role for flanking sequences in enhancing replication efficiency. Comparison of the replication efficiencies of an 822-bp oriS-containing plasmid and an 833-bp oriL-containing plasmid demonstrated that the kinetics of replication of the two plasmids were similar but that the oriL-containing plasmid replicated 60 to 70% as efficiently as the oriS-containing plasmid at both early and late times after infection with herpes simplex virus type 1. The virus specified origin-binding protein (OBP) and a cellular factor(s) (OF-1) have been shown in gel mobility shift experiments to bind specific sequences in oriS (C.E. Dabrowski, P. Carmillo, and P.A. Schaffer, Mol. Cell. Biol. 14:2545-2555, 1994; C.E. Dabrowski and P.A. Schaffer, J. Virol. 65:3140-3150, 1991). Although the nucleotides required for the binding of OBP to OBP binding site I in oriL and oriS are the same, a single nucleotide difference distinguishes OBP binding site III in the two origins. The nucleotides adjacent to oriS sites I and III have been shown to be important for the binding of OF-1 to oriS site I. Several nucleotide differences exist in these sequences in oriL and oriS. Despite these minor nucleotide differences, the protein-DNA complexes that formed with oriL and oriS sites I and III were indistinguishable when extracts of infected and uninfected cells were used as the source of protein. Furthermore, the results of competition analysis suggest that the proteins involved in protein-DNA complex formation with sites I and III of the two origins are likely the same. PMID- 7853472 TI - Initial lentivirus-host interactions within lymph nodes: a study of maedi-visna virus infection in sheep. AB - Reactive changes occurring within lymph nodes draining the subcutaneous site of acute infection with maedi-visna virus (MVV) were studied, and the appearance of infected cells correlated with the immune response. Cells infected with virus were detected in the node by cocultivation from day 4 postinfection (p.i.), with maximum numbers being seen between days 7 and 14, but even then infected cells were rare, with a maximum frequency of 23 50% tissue culture infective doses (TCID50) in 10(6) lymph node cells. At later times, infected cells were still detected, but their numbers fell to 1 to 2 TCID50 per 10(6) cells. Virus-specific CD8+ cytotoxic T-cell precursors (CTLp) were isolated from infected nodes from day 10 p.i. onwards, and T-cell proliferative responses to MVV were first detected on day 7 and consistently detected after day 18. Histological analysis showed a vigorous immune response in the node. There was a marked blast reaction in the T-cell-rich zones, which was greatest at the time when the number of virally infected cells was at its height. At this stage, large numbers of plasma cells were seen in the medullary cords, indicating that extensive T-cell dependent B-cell activation was occurring in the T-cell-rich zones. Germinal centers were prominent shortly after the onset of the T-zone response and were still present at 40 days p.i. Phenotype studies of isolated lymph node cells failed to detect major changes in the proportion or phenotype of macrophages, CD1+ interdigitating cells, and CD4+ or CD8+ T cells despite the fact that CD8+ lymphoblasts form a major population leaving the node in efferent lymph. This suggests that there is a balanced increase in the number of all cell types in response to the virus within the node and selective migration of CD8+ lymphoblasts containing virus-specific CTLp from the node. Virus-specific immune responses are therefore present within the node when infectious virus isolation is maximal, but cellular immunity may act to control the level of infection from day 18 onwards. PMID- 7853471 TI - Quantification of transcripts from the ICP4 and thymidine kinase genes in mouse ganglia latently infected with herpes simplex virus. AB - Herpes simplex virus establishes latency in nervous tissue in which it is maintained for the life of the mammalian host, with occasional reactivation leading to subsequent spread. Latency-associated transcripts are abundant during latency, but viral proteins and productive cycle RNAs have not been detected. Using sensitive, quantitative PCR assays, we have quantified certain viral RNAs specific to productive-cycle genes in mouse ganglia latently infected with herpes simplex virus type 1. Sense-strand RNA specific to the essential immediate-early gene, ICP4, was present in most ganglia in variable amounts relative to the amount of viral DNA, with one to seven molecules of RNA per viral genome in about 20% of ganglia. In contrast, the amount of latency-associated transcripts was much less variable, at an average of 4 x 10(4) molecules per viral genome. The amounts of ICP4-specific RNA were similar at 30 and 60 days postinfection, and at least some of these transcripts initiated within a region consistent with utilization of the ICP4 promoter. RNA specific to the thymidine kinase gene, whose transcription in productive infection is dependent on ICP4, was present in latently infected ganglia at a maximum level of 3.2 x 10(6) molecules per ganglion (500 molecules per viral genome). ICP4-specific and tk-specific RNAs measured from the same samples showed a positive correlation extending over 2 orders of magnitude. We conclude that ICP4-specific RNA is expressed in the absence of detectable reactivation and discuss possible implications of our findings for latent gene expression. PMID- 7853473 TI - Induction of focal spongiform neurodegeneration in developmentally resistant mice by implantation of murine retrovirus-infected microglia. AB - FrCasE is a highly neurovirulent murine leukemia virus which causes a noninflammatory spongiform neurodegenerative disease after neonatal inoculation. The central nervous system (CNS) infection is wide-spread, involving several different cell types, whereas the lesions are localized to motor areas of the brain and spinal cord. Inoculation of FrCasE at 10 days of age (P10) results in viremia, but infection of the CNS is restricted and neurological disease is not observed (M. Czub, S. Czub, F. McAtee, and J. Portis, J. Virol. 65:2539-2544, 1991). In this study, we used this developmental resistance to restrict the extent and the distribution of FrCasE in the brain to examine whether the spongiform degeneration is a consequence of infection of cells in proximity to the lesions. Two approaches were used to infect the brain on or after P10. First, mice were inoculated with FrCasE at P10 to induce viremia and then at P17 were subjected to focal CNS injury within brain regions known to be susceptible to virus-induced spongiform degeneration. The injury resulted in local inflammation, glial activation, migration of inflammatory cells into the wound site, and high level parenchymal infection about the wound site. However, no evidence of spongiform neurodegeneration was observed over a period of 3 months. The second approach involved the implantation of FrCasE-infected microglia into the CNS at > or = P10. This resulted in microglial engraftment and focal CNS infection unilaterally at the implantation sites and bilaterally along white matter tracts of the corpus callosum and pons and in cells of the subventricular layers of the lateral cerebral ventricles. Strikingly, focal spongiform degeneration colocalized with the sites of infection. In contrast to the wounding experiments, the implantation model was not associated with an inflammatory response or significant glial activation. Results of these studies suggest that (i) the developmental resistance of the CNS to infection lies at the blood-brain barrier and can be bypassed by direct introduction into the brain of virus-infected cells, (ii) the neuropathology induced by this virus is a consequence of local effects of the infection and does not appear to require endothelial or neuronal infection, and (iii) elements of the inflammatory response and/or glial activation may modulate the expression of neuropathology induced by neurovirulent retroviruses. PMID- 7853474 TI - Host response to Sendai virus in mice lacking class II major histocompatibility complex glycoproteins. AB - The development of Sendai virus-specific cytotoxic T-lymphocyte (CTL) effectors and precursors (CTLp) has been compared for mice that are homozygous (-/-) for a disruption of the H-2I-Ab class II major histocompatibility complex glycoprotein and for normal (+/+) controls. The generation of CD8+ CTLp was not diminished in the -/- mice, though they failed to make virus-specific immunoglobulin G class antibodies. While the cellularity of the regional lymph nodes was decreased, the inflammatory process assayed by bronchoalveolar lavage (BAL) of the pneumonic lung was not modified, and potent CTL effectors were present in BAL populations recovered from both groups at day 10 after infection. There was little effect on virus clearance. Production of interleukin-2 by both freshly isolated BAL inflammatory cells and cultured lymph node cells was greatly diminished, though the -/- mice still made substantial levels of gamma interferon. However, treating the mice with a single dose of a monoclonal antibody to this cytokine, at least some of which is made by CD8+ T cells, did not decrease CTLp frequencies. As found previously with CD4-depleted H-2b mice, the development of Sendai virus specific CD8+ T-cell-mediated immunity is not compromised by the absence of a concurrent class II major histocompatibility complex-restricted response. PMID- 7853475 TI - Vesicular stomatitis virus glycoprotein mutations that affect membrane fusion activity and abolish virus infectivity. AB - We have introduced amino acid substitutions into two regions of the extracellular domain of the vesicular stomatitis virus (VSV) glycoprotein (G protein) and examined the effect of these mutations on protein transport, low-pH-induced stability of G protein oligomers, and membrane fusion activity. We suggested previously that the region between amino acids 118 and 139 may be important for the membrane fusion activity of G protein, on the basis of the characterization of a fusion-defective G protein mutant (M. A. Whitt, P. Zagouras, B. Crise, and J. K. Rose, J. Virol. 64:4907-4913, 1990). It has also been postulated by others that this region as well as the region between amino acids 181 and 212 may constitute putative internal fusion domains of VSV G protein. In this report, we show that three different amino acids substitutions between residues 118 and 139 (G-124-->E, P-127-->D, and A-133-->K) either altered or abolished low-pH dependent membrane fusion activity. In contrast, substitutions between residues 192 and 212 resulted either in G proteins that had wild-type fusion activity or in mutant proteins in which the mutation prevented transport of G protein to the cell surface. Two of the substitutions between residues 118 and 139 (G-124-->E and P-127-->D) resulted in G proteins that were fusion defective at pH 5.7, although syncytia were observed after cells were treated with fusion buffer at pH 5.5, albeit at levels significantly less than that induced by wild-type G protein. Interestingly, when either G-124-->E or P-127-->D was incorporated into tsO45 virions, the resulting particles were not infectious, presumably because the viral envelope was not able to fuse with the proper intracellular membrane. These results support the hypothesis that the region between amino acids 118 and 139 is important for the membrane fusion activity of VSV G protein and may constitute an internal fusion domain. PMID- 7853476 TI - Mokola virus glycoprotein and chimeric proteins can replace rabies virus glycoprotein in the rescue of infectious defective rabies virus particles. AB - A reverse genetics approach which allows the generation of infectious defective rabies virus (RV) particles entirely from plasmid-encoded genomes and proteins (K.-K. Conzelmann and M. Schnell, J. Virol. 68:713-719, 1994) was used to investigate the ability of a heterologous lyssavirus glycoprotein (G) and chimeric G constructs to function in the formation of infectious RV-like particles. Virions containing a chloramphenicol acetyltransferase (CAT) reporter gene (SDI-CAT) were generated in cells simultaneously expressing the genomic RNA analog, the RV N, P, M, and L proteins, and engineered G constructs from transfected plasmids. The infectivity of particles was determined by a CAT assay after passage to helper virus-infected cells. The heterologous G protein from Eth 16 virus (Mokola virus, lyssavirus serotype 3) as well as a construct in which the ectodomain of RV G was fused to the cytoplasmic and transmembrane domains of the Eth-16 virus G rescued infectious SDI-CAT particles. In contrast, a chimeric protein composed of the amino-terminal half of the Eth-16 virus G and the carboxy terminal half of RV G failed to produce infectious particles. Site-directed mutagenesis was used to convert the antigenic site III of RV G to the corresponding sequence of Eth-16 G. This chimeric protein rescued infectious SDI CAT particles as efficiently as RV G. Virions containing the chimeric protein were specifically neutralized by an anti-Eth-16 virus serum and escaped neutralization by a monoclonal antibody directed against RV antigenic site III. The results show that entire structural domains as well as short surface epitopes of lyssavirus G proteins may be exchanged without affecting the structure required to mediate infection of cells. PMID- 7853477 TI - Overlapping TATA-dependent and TATA-independent early promoter activities in the baculovirus gp64 envelope fusion protein gene. AB - In previous studies to characterize basal and activated transcription from the early promoter of the gp64 envelope fusion protein (efp) gene of the Orgyia pseudotsugata multicapsid nuclear polyhedrosis virus, the TATA box was identified as a functional element, essential for basal transcription from a minimal promoter construct. In the current study, we used discrete deletions and multiple point mutations that removed the functional TATA box from larger promoter constructs of the gp64 efp gene to reveal an overlapping TATA-independent transcriptional activity. TATA-independent transcriptional activity was inhibited in vitro by alpha-amanitin but not by tagetitoxin, demonstrating that like the TATA-dependent activity, the TATA-independent activity is mediated by RNA polymerase II. Using constructs in which the TATA box (TATATAA) was destroyed by substitution mutations, we identified four elements that are required for the TATA-independent activity. Two of the required elements, GATA (at -114) and CACGTG (at -104), were previously shown to specifically bind host transcription factors and activate transcription from the TATA-dependent wild-type gp64 efp promoter. The role of the early start site consensus CAGT sequence in TATA independent transcription was also examined. Single-nucleotide substitution mutations in the CAGT sequence indicated that certain nucleotides within the CAGT start site were essential. In addition to the start site sequence and two upstream elements, a fourth essential element was identified in the 5' untranslated leader region (5'UTR). While the 5'UTR was not necessary for TATA dependent transcription, deletion of a 10-bp 5'UTR sequence resulted in the loss of TATA-independent transcriptional activity. Although necessary, neither the GATA, CACGTG, start site region, nor 5'UTR element was alone sufficient for accurately initiated TATA-independent transcription from the consensus CAGT start site. Thus, the gp64 efp early promoter contains overlapping TATA-dependent and TATA-independent transcriptional activities. A number of common sequence elements (GATA, CACGTG, and start site CAGT) are involved in both of these activities, while one element (in the 5'UTR) is required only in the TATA-independent context. PMID- 7853479 TI - Adeno-associated virus vectors transduce primary cells much less efficiently than immortalized cells. AB - Immortalized cell lines have been used to study infection and replication of adeno-associated virus (AAV) in culture, but primary cells presumably provide a better model for AAV behavior in animals. Here, we have evaluated the ability of AAV vectors to transduce primary and immortalized strains of human epithelial cells and fibroblasts. Two AAV vectors were used, one that transduced an alkaline phosphatase gene (AAV-LAPSN), and one that transduced a beta galactosidase/neomycin phosphotransferase fusion gene (AAV-L beta geo). The transduction efficiency of the AAV-LAPSN vector, quantitated by measurement of alkaline phosphatase-positive cell foci following infection, was 10 to 60 times greater in immortalized human cells than in primary cells, and total alkaline phosphatase activity in cell lysates was 40 to 50 times greater in immortalized cells. The AAV-L beta geo vector gave similar results. In contrast, the transduction efficiency of a retrovirus vector encoding alkaline phosphatase was equivalent in primary and immortalized cells. Analysis of the quantity and state of the AAV vector genomes in cells showed that primary and immortalized cells contained comparable numbers of vector copies per cell and that the vast majority of vector DNA was not integrated into the cell genome. Additionally, the level of AAV vector-derived message paralleled the transduction efficiency. These results indicate that the block to functional transduction in primary cells occurred after virus entry and limited the abundance of vector-derived message. Data from AAV transduction in cultures of human cells containing immortalizing genes suggest that cellular changes secondary to the introduction of immortalizing genes increased permissiveness for transduction by AAV vectors. In summary, our data demonstrate that AAV vectors transduce primary human cells much less efficiently than immortalized cells and indicate the importance of using primary cells to evaluate AAV vectors for gene therapy applications. PMID- 7853478 TI - Temperature dependence of cell-cell fusion induced by the envelope glycoprotein of human immunodeficiency virus type 1. AB - We investigated cell-cell fusion induced by the envelope glycoprotein of human immunodeficiency virus type 1 strain IIIB expressed on the surface of CHO cells. These cells formed syncytia when incubated together with CD4-positive human lymphoblastoid SupT1 cells or HeLa-CD4 cells but not when incubated with CD4 negative cell lines. A new assay for binding and fusion was developed by using fluorescent phospholipid analogs that were produced in SupT1 cells by metabolic incorporation of BODIPY-labeled fatty acids. Fusion occurred as early as 10 min after mixing of labeled SupT1 cells with unlabeled CHO-gp160 cells at 37 degrees C. When both the fluorescence assay and formation of syncytia were used, fusion of SupT1 and HeLa-CD4 cells with CHO-gp160 cells was observed only at temperatures above 25 degrees C, confirming recent observations (Y.-K. Fu, T.K. Hart, Z.L. Jonak, and P.J. Bugelski, J. Virol. 67:3818-3825, 1993). This temperature dependence was not observed with influenza virus-induced cell-cell fusion, which was quantitatively similar at both 20 and 37 degrees C, indicating that cell-cell fusion in general is not temperature dependent in this range. gp120-CD4-specific cell-cell binding was found over the entire 0 to 37 degrees C range but increased markedly above 25 degrees C. The enhanced binding and fusion were reduced by cytochalasins B and D. Binding of soluble gp120 to CD4-expressing cells was equivalent at 37 and 16 degrees C. Together, these data indicate that during gp120-gp41-induced syncytium formation, initial cell-cell binding is followed by a cytoskeleton-dependent increase in the number of gp120-CD4 complexes, leading to an increase in the avidity of cell-cell binding. The increased number of gp120-CD4 complexes is required for fusion, which suggests that the formation of a fusion complex consisting of multiple CD4 and gp120-gp41 molecules is a step in the fusion mechanism. PMID- 7853480 TI - Expression of influenza virus hemagglutinin activates transcription factor NF kappa B. AB - Influenza virus infection initiates transcription of a variety of genes for cytokines such as tumor necrosis factor alpha (TNF-alpha), TNF-beta, interleukin 1 alpha, (IL-1 alpha), IL-1 beta, IL-2, IL-4, IL-6, IL-10, granulocyte macrophage colony-stimulating factor, and gamma interferon. However, the mechanism by which virus infection elicits cytokine expression remains unknown. Six influenza virus induced cytokine genes are targets for the inducible transcription factor NF kappa B, a central regulator of the human immune response. Here, we show that expression of a single influenza virus protein, the virion surface hemagglutinin, strongly activates NF-kappa B DNA binding and transactivation. Activation is inhibited in the presence of the antioxidant dithiothreitol, suggesting that, similar to the findings for previously described inducers of NF-kappa B, hemagglutinin expression generates radical oxygen intermediates which activate the transcription factor. Hemagglutinin is the first secretory and structural viral protein reported to activate NF-kappa B and thus represents a new class of inducers for this transcription factor. We discuss these results in the context of clinical complications of influenza virus infection. PMID- 7853481 TI - Host-specific alterations in viral RNA accumulation and infection spread in a brome mosaic virus isolate with an expanded host range. AB - To facilitate studies of virus-host interaction and the determinants of viral host range, we constructed full-length cDNA clones to all three genomic RNAs of an unusual brome mosaic virus (BMV) isolate with an expanded host range. While other BMV strains, including the previously cloned M1 strain, systemically infect barley and other grasses but not legumes, the expanded-host-range isolate and the set of transcripts from its cDNA clones, designated the M2 strain of BMV, systemically infect both barley and cowpea line TVu-612, a legume. All reassorted combinations of M1 and M2 genomic RNAs were equally competent for replication in barley protoplasts and systemic infection of barley plants but showed widely varying levels of viral RNA accumulation in cowpea protoplasts and systemic infection in TVu-612 cowpea plants. Systemic infection levels were influenced by all three genomic RNAs. M2 RNA2 and M2 RNA3 made independent and additive contributions to the frequency with which reassortants infected TVu-612 systemically. The greater individual effect segregated with M2 RNA3, which encodes functions required for infection spread (the 3a movement protein and coat protein). M2 RNA3 also directed accelerated expansion of BMV lesions in inoculated TVu-612 leaves. If the inoculum contained M2 RNA3, the frequency with which reassortants infected TVu-612 systemically could be further enhanced by the presence of M2 RNA1 rather than M1 RNA1. RNA1 encodes the 1a RNA replication protein, and despite similar accumulation in barley protoplasts, in cowpea protoplasts all reassortants bearing M2 RNA1 accumulated positive- and negative strand RNAs to levels at least six- to eightfold higher than reassortants bearing M1 RNA1. Overall, the results indicate that changes in several distinct virus functions contribute to adapting BMV-M2 to systemically infect TVu-612 cowpea. PMID- 7853482 TI - Enhanced sensitivity to neutralizing antibodies in a variant of equine infectious anemia virus is linked to amino acid substitutions in the surface unit envelope glycoprotein. AB - Serial passage of the prototype (PR) cell-adapted Wyoming strain of equine infectious anemia virus (EIAV) in fetal donkey dermal (FDD) rather than fetal horse (designated fetal equine kidney [FEK]) cell cultures resulted in the generation of a variant virus strain which produced accelerated cytopathic effects in FDD cells and was 100- to 1,000-fold more sensitive to neutralizing antibodies than its parent. This neutralization-sensitive variant was designated the FDD strain. Although there were differences in glycosylation between the PR and FDD strains, passage of the FDD virus in FEK cells did not reduce its sensitivity to neutralizing antibody. Nucleotide sequencing of the region encoding the surface unit (SU) protein from the FDD strain revealed nine amino acid substitutions compared with the PR strain. Two of these substitutions resulted in changes in the polarity of charge, four caused the introduction of a charged residue, and three had no net change in charge. Nucleotide sequence analysis was extended to the region of the FDD virus genome encoding the extracellular domain of the transmembrane envelope glycoprotein (TM). Unlike the situation with the FDD virus coding region, there were minor variations in nucleotide sequence between individual molecular clones containing this region of the TM gene. Although each clone contained three nucleotide substitutions compared with the PR strain, only one of these was common to all, and this did not affect the amino acid content. Of the remaining two nucleotide substitutions, only one resulted in an amino acid change, and in each case, this change appeared to be conservative. To determine if amino acid substitutions in the SU protein of FDD cell-grown viruses were responsible for the enhanced sensitivity to neutralizing antibodies, chimeric viruses were constructed by using an infectious molecular clone of EIAV. These chimeric viruses contained all of the amino acid substitutions found in the FDD virus strain and were significantly more sensitive to neutralizing antibodies than viruses from the parental (PR) molecular clone. These results demonstrated that sensitivity to neutralizing antibodies in EIAV can be conferred by amino acid residues in the SU protein. However, such amino acid substitutions were not sufficient to enhance cytopathogenicity, as the chimeric viruses did not cause excessive degenererative effects in FDD cells, as was observed with the parental FDD virus strain. PMID- 7853484 TI - The human immunodeficiency virus type 1 Vpu protein specifically binds to the cytoplasmic domain of CD4: implications for the mechanism of degradation. AB - We have recently demonstrated that coexpression of Vpu and CD4 in HeLa cells results in the degradation of CD4 in the endoplasmic reticulum. The sensitivity of CD4 to Vpu-mediated degradation is conferred by the presence of specific sequences located between amino acids 402 and 420 in the CD4 cytoplasmic domain. Using an in vitro translation system, we also showed that degradation of CD4 by Vpu requires the two proteins to be present in the same membrane compartment. Although these results suggest that spatial proximity between CD4 and Vpu may be critical in triggering degradation, it remains unknown whether the two molecules have the ability to interact with each other. In order to better define the mechanisms involved in CD4 degradation, we investigated the existence and functional relevance of direct interactions between CD4 and Vpu. Coimmunoprecipitation experiments showed that Vpu specifically binds to the cytoplasmic tail of CD4. This phenomenon is relevant to the mechanism of CD4 degradation since the ability of CD8/CD4 chimeric molecules and various CD4 mutants to form complexes with Vpu correlates with their sensitivity to degradation. Accordingly, we found that amino acid residues in the CD4 cytoplasmic tail previously shown to be important for degradation are necessary for Vpu binding. We further demonstrate that a deletion mutant of Vpu as well as a phosphorylation mutant, both biologically inactive with regard to CD4 degradation, retained the capacity to interact with the CD4 cytoplasmic domain. Taken together, these results indicate that Vpu binding is necessary to trigger CD4 degradation. However, the binding to target molecules is not sufficient per se to cause degradation. Interaction between CD4 and Vpu is thus likely to be an early event critical in triggering a multistep process leading to CD4 degradation. PMID- 7853483 TI - Regulation of I kappa B alpha and p105 in monocytes and macrophages persistently infected with human immunodeficiency virus. AB - The mechanisms regulating human immunodeficiency virus (HIV) persistence in human monocytes/macrophages are partially understood. Persistent HIV infection of U937 monocytic cells results in NF-kappa B activation. Whether virus-induced NF-kappa B activation is a mechanism that favors continuous viral replication in macrophages remains unknown. To further delineate the molecular mechanisms involved in the activation of NF-kappa B in HIV-infected monocytes and macrophages, we have focused on the regulation of the I kappa B molecules. First, we show that persistent HIV infection results in the activation of NF-kappa B not only in monocytic cells but also in macrophages. In HIV-infected cells, I kappa B alpha protein levels are decreased secondary to enhanced protein degradation. This parallels the increased I kappa B alpha synthesis secondary to increased I kappa B alpha gene transcription, i.e., increased RNA and transcriptional activity of its promoter-enhancer. Another protein with I kappa B function, p105, is also modified in HIV-infected cells: p105 and p50 steady-state protein levels are increased as a result of increased synthesis and proteolytic processing of p105. Transcriptional activity of p105 is also increased in infected cells and is also mediated by NF-kappa B through a specific kappa B motif. These results demonstrate the existence of a triple autoregulatory loop in monocytes and macrophages involving HIV, p105 and p50, and MAD3, with the end result of persistent NF-kappa B activation and viral persistence. Furthermore, persistent HIV infection of monocytes and macrophages provides a useful model with which to study concomitant modifications of different I kappa B molecules. PMID- 7853485 TI - Analysis and mapping of a family of 3'-coterminal transcripts containing coding sequences for human cytomegalovirus open reading frames UL93 through UL99. AB - Human cytomegalovirus (HCMV) open reading frames (ORFs) UL93 through UL99 are contained within a region of viral genome that is well conserved in all herpesviruses. Previous reports detailing the expression of ORF UL99 (also referred to as the 28-kDa virion phosphoprotein or pp28) indicated that the pattern of transcription proximal to pp28 is extremely complex and involves a number of large overlapping transcripts, none of which have been characterized. We have used an RNA-mapping approach consisting of Northern (RNA) hybridization, RNase protection, and primer extensions to determine the coding capacity of several large-molecular-weight transcripts which overlap the 1.3- and 1.6-kb UL99 specific transcripts. Our results suggest that six differentially regulated transcripts with sizes of 2.6, 4.7, 5.6, 7.3, 9.1, and 10.5 kb, and derived from the same strand of the viral genome overlap, are 3'-coterminal with the smaller UL99-specific transcripts. On the basis of 5'-end mapping via primer extension and RNase protection, we have determined that the 2.6- to 10.5-kb messages initiate upstream of each of the potential ORFs in this region, UL98, UL97, UL96, UL95, UL94, and UL93. By using cycloheximide and ganciclovir [9-(1,3-dihydroxy-2 propoxymethyl)guanine] to block de novo viral protein synthesis and viral DNA replication, respectively, we have determined that the 2.6-, 4.7-, 5.6-, and 7.3 kb messages have characteristics of early or early-late transcripts, whereas the 9.1- and 10.5-kb messages appear to be true late transcripts. The evolutionary conservation of ORFs UL93 through UL99 and their transcriptional regulation in other herpesviruses are discussed. PMID- 7853486 TI - Mutation of the aspartic acid residues of the GDD sequence motif of poliovirus RNA-dependent RNA polymerase results in enzymes with altered metal ion requirements for activity. AB - The poliovirus RNA-dependent RNA polymerase, 3Dpol, is known to share a region of sequence homology with all RNA polymerases centered at the GDD amino acid motif. The two aspartic acids have been postulated to be involved in the catalytic activity and metal ion coordination of the enzyme. To test this hypothesis, we have utilized oligonucleotide site-directed mutagenesis to generate defined mutations in the aspartic acids of the GDD motif of the 3Dpol gene. The codon for the first aspartate (3D-D-328 [D refers to the single amino acid change, and the number refers to its position in the polymerase]) was changed to that for glutamic acid, histidine, asparagine, or glutamine; the codons for both aspartic acids were simultaneously changed to those for glutamic acids; and the codon for the second aspartic acid (3D-D-329) was changed to that for glutamic acid or asparagine. The mutant enzymes were expressed in Escherichia coli, and the in vitro poly(U) polymerase activity was characterized. All of the mutant 3Dpol enzymes were enzymatically inactive in vitro when tested over a range of Mg2+ concentrations. However, when Mn2+ was substituted for Mg2+ in the in vitro assays, the mutant that substituted the second aspartic acid for asparagine (3D-N 329) was active. To further substantiate this finding, a series of different transition metal ions were substituted for Mg2+ in the poly(U) polymerase assay. The wild-type enzyme was active with all metals except Ca2+, while the 3D-N-329 mutant was active only when FeC6H7O5 was used in the reaction. To determine the effects of the mutations on poliovirus replication, the mutant 3Dpol genes were subcloned into an infectious cDNA of poliovirus. The cDNAs containing the mutant 3Dpol genes did not produce infectious virus when transfected into tissue culture cells under standard conditions. Because of the activity of the 3D-N-329 mutant in the presence of Fe2+ and Mn2+, transfections were also performed in the presence of the different metal ions. Surprisingly, the transfection of the cDNA containing the 3D-N-329 mutation resulted in the production of virus at a low frequency in the presence of FeSO4 or CoCl2. The virus derived from transfection in the presence of FeSO4 grew slowly, while the viruses recovered from transfection in CoCl2 grew at a rate which was similar to that of the wild-type poliovirus.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7853487 TI - Amino acid substitutions in the poliovirus maturation cleavage site affect assembly and result in accumulation of provirions. AB - The assembly of infectious poliovirus virions requires a proteolytic cleavage between an asparagine-serine amino acid pair (the maturation cleavage site) in VP0 after encapsidation of the genomic RNA. In this study, we have investigated the effects that mutations in the maturation cleavage site have on P1 polyprotein processing, assembly of subviral intermediates, and encapsidation of the viral genomic RNA. We have made mutations in the maturation cleavage site which change the asparagine-serine amino acid pair to either glutamine-glycine or threonine serine. The mutations were created by site-directed mutagenesis of P1 cDNAs which were recombined into wild-type vaccinia virus to generate recombinant vaccinia viruses. The P1 polyproteins expressed from the recombinant vaccinia viruses were analyzed for proteolytic processing and assembly defects in cells coinfected with a recombinant vaccinia virus (VV-P3) that expresses the poliovirus 3CD protease. A trans complementation system using a defective poliovirus genome was utilized to assess the capacity of the mutant P1 proteins to encapsidate genomic RNA (D. C. Ansardi, D. C. Porter, and C. D. Morrow, J. Virol. 67:3684-3690, 1993). The mutant P1 proteins containing the glutamine-glycine amino acid pair (VP4-QG) and the threonine-serine pair (VP4-TS) were processed by 3CD provided in trans from VV-P3. The processed capsid proteins VP0, VP3, and VP1 derived from the mutant precursor VP4-QG were unstable and failed to assemble into subviral structures in cells coinfected with VV-P3. However, the capsid proteins derived from VP4-QG did assemble into empty-capsid-like structures in the presence of the defective poliovirus genome. In contrast, the capsid proteins derived from processing of the VP4-TS mutant assembled into subviral intermediates both in the presence and in the absence of the defective genome RNA. By a sedimentation analysis, we determined that the capsid proteins derived from the VP4-TS precursor encapsidated the defective genome RNA. However, the cleavage of VP0 to VP4 and VP2 was delayed, resulting in the accumulation of provirions. The maturation cleavage of the VP0 protein containing the VP4-TS mutation was accelerated by incubation of the provirions at 37 degrees C. The results of these studies demonstrate that mutations in the maturation cleavage site have profound effects on the subsequent capability of the capsid proteins to assemble and provide evidence for the existence of the provirion as an assembly intermediate. PMID- 7853488 TI - Encapsidation of poliovirus replicons encoding the complete human immunodeficiency virus type 1 gag gene by using a complementation system which provides the P1 capsid protein in trans. AB - Poliovirus genomes which contain small regions of the human immunodeficiency virus type 1 (HIV-1) gag, pol, and env genes substituted in frame for the P1 capsid region replicate and express HIV-1 proteins as fusion proteins with the P1 capsid precursor protein upon transfection into cells (W. S. Choi, R. Pal-Ghosh, and C. D. Morrow, J. Virol. 65:2875-2883, 1991). Since these genomes, referred to as replicons, do not express capsid proteins, a complementation system was developed to encapsidate the genomes by providing P1 capsid proteins in trans from a recombinant vaccinia virus, VV-P1. Virus stocks of encapsidated replicons were generated after serial passage of the replicon genomes into cells previously infected with VV-P1 (D. C. Porter, D. C. Ansardi, W. S. Choi, and C. D. Morrow, J. Virol. 67:3712-3719, 1993). Using this system, we have further defined the role of the P1 region in viral protein expression and RNA encapsidation. In the present study, we constructed poliovirus replicons which contain the complete 1,492-bp gag gene of HIV-1 substituted for the entire P1 region of poliovirus. To investigate whether the VP4 coding region was required for the replication and encapsidation of poliovirus RNA, a second replicon in which the complete gag gene was substituted for the VP2, VP3, and VP1 capsid sequences was constructed. Transfection of replicon RNA with and without the VP4 coding region into cells resulted in similar levels of expression of the HIV-1 Gag protein and poliovirus 3CD protein, as indicated by immunoprecipitation using specific antibodies. Northern (RNA) blot analysis of RNA from transfected cells demonstrated comparable levels of RNA replication for each replicon. Transfection of the replicon genomes into cells infected with VV-P1 resulted in the encapsidation of the genomes; serial passage in the presence of VV-P1 resulted in the generation of virus stocks of encapsidated replicons. Analysis of the levels of protein expression and encapsidated replicon RNA from virus stocks after 21 serial passages of the replicon genomes with VV-P1 indicated that the replicon which contained the VP4 coding region was present at a higher level than the replicon which contained a complete substitution of the P1 capsid sequences. These differences in encapsidation, though, were not detected after only two serial passages of the replicons with VV-P1 or upon coinfection and serial passage with type 1 Sabin poliovirus.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7853489 TI - Structure-function relation of the NH2-terminal domain of the Semliki Forest virus capsid protein. AB - The capsid (C) protein of alphaviruses consists of two protein domains: a serine protease at the COOH terminus and an NH2-terminal domain which is thought to interact with RNA in the virus nucleocapsid (NC). The latter domain is very rich in positively charged amino acid residues. In this work, we have introduced large deletions into the corresponding region of a full-length cDNA clone of Semliki Forest virus, expressed the transcribed RNA in BHK-21 cells, and monitored the autoprotease activity of C, the formation of intracellular NCs, and the release of infectious virus. Our results show that if the gene region encoding the whole NH2-terminal domain is removed, the expressed C protein fragment cannot assemble into NCs and virus particles but it is still able to function as an autoprotease. Thus, these results underline the general importance of the NH2-terminal domain in the virus assembly process and furthermore show that the serine protease domain can function independently of the NH2 terminus. Surprisingly, analysis of additional C protein deletion variants showed that not all of the NH2-terminal domain is required for virus assembly, but large deletions involving up to one third of its positively charged residues are still compatible with NC and virus formation. The fact that so much flexibility is allowed in the structure of the NH2-terminal domain of C suggests that most of this region is involved in nonspecific interactions with the encapsidated RNA, probably through its positively charged amino acid residues. PMID- 7853490 TI - Reactivation of human immunodeficiency virus type 2 in macaques after simian immunodeficiency virus SIVmac superinfection. AB - By superinfection of human immunodeficiency virus type 2 (HIV-2) strain HIV-2ben infected macaques with simian immunodeficiency virus (SIV) strain SIVmac, we investigated the mutual influences of an apathogenic and a pathogenic virus in vivo. Four rhesus and two cynomolgus monkeys were infected with HIV-2ben in 1988 and 1989, respectively. Virus could be reisolated from five of six animals 6 weeks after infection. The monkeys remained healthy over the next 2 to 3 years. PCR for viral RNA became negative, and virus could no longer be reisolated by coculture. All six macaques were superinfected with the pathogenic SIVmac251/32H. Subsequently, five monkeys became persistently viremic, while one animal was protected against the SIVmac infection. In the peripheral blood mononuclear cells and cocultures of the five viremic animals, DNA from both HIV-2 and SIVmac was present. The plasma contained RNA from both viruses. Thus, superinfection with SIVmac activated HIV-2. A proliferative T-cell response against both HIV-2 and SIVmac was measured in all animals after superinfection. Such a response was regularly seen after infection with the apathogenic HIV-2 but never when the pathogenic SIVmac alone was administered. While naive control monkeys inoculated with SIVmac251/32H regularly develop AIDS-like symptoms soon after infection and have to be killed, none of the preinfected animals has developed AIDS-like symptoms, but two of six animals developed tumors. After the SIVmac challenge, however, apoptotic lymphocytes were detected in the peripheral blood mononuclear cells of all animals. Thus, the presence of an apathogenic viral variant seems to retard the disease occurring after infection with a pathogenic virus rather than to confirm total protection. This partial protection appears to depend on a specific proliferative T-cell response early after infection. PMID- 7853491 TI - Hepatitis C virus-encoded nonstructural protein NS4A has versatile functions in viral protein processing. AB - A transient protein expression system in COS-1 cells was used to study the role of hepatitis C virus (HCV)-encoded NS4A protein on HCV nonstructural polyprotein processing. By analyzing the protein expression and processing of a deletion mutant polypeptide, NS delta 4A, which encodes the entire putative HCV nonstructural polyprotein except the region encoding NS4A, the versatile functions of NS4A were revealed. Most of the NS3 processed from NS delta 4A was localized in the cytosol fraction and was degraded promptly. Coproduction of NS4A stabilizes NS3 and assists in its localization in the membrane. NS4A was found to be indispensable for cleavage at the 4B/5A site but not essential for cleavage at the 5A/5B site in NS delta 4A. The functioning of NS4A as a cofactor for cleavage at the 4B/5A site was also observed when 30 amino acids around this site was used as a substrate and a serine proteinase domain of 167 amino acids, from Gly-1049 to Ser-1215, was used as an enzyme protein, suggesting that possible domains for the interaction of NS4A were in those regions of the enzyme protein (NS3) and/or the substrate protein. Two proteins, p58 and p56, were produced from NS5A. For the production of p58, equal or excess molar amounts of NS4A relative to NS delta 4A were required. Deletion analysis of NS4A revealed a minimum functional domain of NS4A of 10 amino acids, from Gly-1678 to Ile-1687. PMID- 7853492 TI - Debilitation of plant potyvirus infectivity by P1 proteinase-inactivating mutations and restoration by second-site modifications. AB - Tobacco etch virus (TEV) encodes three proteinases that catalyze processing of the genome-encoded polyprotein. The P1 proteinase originates from the N terminus of the polyprotein and catalyzes proteolysis between itself and the helper component proteinase (HC-Pro). Mutations resulting in substitution of a single amino acid, small insertions, or deletions were introduced into the P1 coding sequence of the TEV genome. Deletion of the N-terminal, nonproteolytic domain of P1 had only minor effects on virus infection in protoplasts and whole plants. Insertion mutations that did not impair proteolytic activity had no measurable effects regardless of whether the modification affected the N-terminal nonproteolytic or C-terminal proteolytic domain. In contrast, three mutations (termed S256A, F, and delta 304) that debilitated P1 proteolytic activity rendered the virus nonviable, whereas a fourth proteinase-debilitating mutation (termed C) resulted in a slow-infection phenotype. A strategy was devised to determine whether the defect in the P1 mutants was due to an inactive proteinase domain or due simply to a lack of proteolytic maturation between P1 and HC-Pro. Sequences coding for a surrogate cleavage site recognized by the TEV NIa proteinase were inserted into the genome of each processing-debilitated mutant at positions that resulted in NIa-mediated proteolysis between P1 and HC-Pro. The infectivity of each mutant was restored by these second-site modifications. These data indicate that P1 proteinase activity is not essential for viral infectivity but that separation of P1 and HC-Pro is required. The data also provide evidence that the proteinase domain is involved in additional, nonproteolytic functions. PMID- 7853494 TI - Mutagenesis of the yellow fever virus NS2B/3 cleavage site: determinants of cleavage site specificity and effects on polyprotein processing and viral replication. AB - The determinants of cleavage site specificity of the yellow fever virus (YF) NS3 proteinase for its 2B/3 cleavage site have been studied by using site-directed mutagenesis. Mutations at residues within the GARR decreases S sequence were tested for effects on cis cleavage of an NS2B-3(181) polyprotein during cell-free translation. At the P1 position, only the conservative substitution R-->K exhibited significant levels of cleavage. Conservative and nonconservative substitutions were tolerated at the P1' and P2 positions, resulting in intermediate levels of cleavage. Substitutions at the P3 and P4 positions had no effects on cleavage efficiency in the cell-free assay. Processing at other dibasic sites was studied by using transient expression of a sig2A-5(356) polyprotein. Cleavage at the 2B/3 site was not required for processing at downstream sites. However, increased accumulation of high-molecular-weight viral polyproteins was generally observed for mutations which reduced cleavage efficiency at the 2B/3 site. Several mutations were also tested for their effects on viral replication. Virus was not recovered from substitutions which blocked or substantially reduced cleavage in the cell-free assay, suggesting that efficient cleavage at the 2B/3 site is required for flavivirus replication. PMID- 7853493 TI - Use of a human immunodeficiency virus type 1 Rev mutant without nucleolar dysfunction as a candidate for potential AIDS therapy. AB - Applications of transdominant mutants of human immunodeficiency virus type 1 (HIV 1) regulatory proteins, especially Rev mutant, have been attempted for gene therapy against AIDS, because the Rev protein is essential for viral replication. We have previously reported that a mutant Rev protein (dRev) lacking its nucleolar targeting signal remained out of nuclei in expressed cells and strongly inhibited the function of Rev. To investigate the effects of dRev on HIV-1 replication, we established several dRev-expressing human cell lines with two different vector systems and examined virus production in these cells. An HIV-1 derived vector containing drev cDNA was constructed and introduced into CD4 positive HeLa cells and cells of the human T-cell line CCRF-CEM (CEM). In dRev expressing HeLa cells, virus replication, syncytium formation, and cell death caused by HIV-1 infection were remarkably suppressed, and the same vector also conferred a resistant phenotype on CEM cells. The production was also suppressed in CEM cells containing the drev gene driven by a cytomegalovirus promoter. In addition, we found that dRev did not cause nucleolar dysfunction in a transient assay, in contrast to other transdominant mutants and wild-type Rev. Since dRev cannot migrate into the nuclei, it is expected not to interfere with nuclear/nucleolar functions of the host cell. We conclude that dRev is one promising candidate as an antiviral molecule for gene therapy against AIDS. PMID- 7853495 TI - Sanctuary growth of human immunodeficiency virus in the presence of 3'-azido-3' deoxythymidine. AB - Human immunodeficiency virus (HIV) resistance to the nonnucleoside reverse transcriptase inhibitors emerges very rapidly under selection in culture and in patients. In contrast, zidovudine (3'-azido-3'-deoxythymidine [AZT])-resistant HIV generally emerges in patients only after more-prolonged therapy. Although HIV can be cultured from many patients shortly after the initiation of AZT treatment, characterization of the virus that is cultured generally indicates that it is sensitive to AZT. To initiate an evaluation of the mechanisms contributing to early HIV breakthrough in the presence of AZT and other nucleoside analogs, we have utilized replication-defective HIV encoding reporter genes. These recombinant HIV allow a quantitative analysis of a single cycle of infection. Results with these defective HIV indicate that early infection in the presence of AZT often results from the infection of a cell which is refractory to the antiretroviral effects of AZT. Characterization of a cell line derived from one such cell has demonstrated decreased accumulation of AZT triphosphate, increased phosphorylation of thymidine to thymidine triphosphate, and increased levels of thymidine kinase activity. In addition, AZT inhibition of replication-competent HIV infection is also significantly impaired in this cell line. Attempts to detect and characterize the mechanisms responsible for early viral infection after initiation of AZT therapy may result in the development of new strategies for prolonged suppression of viral infection prior to the emergence of drug resistant virus. PMID- 7853496 TI - Lentivirus Tat proteins specifically associate with a cellular protein kinase, TAK, that hyperphosphorylates the carboxyl-terminal domain of the large subunit of RNA polymerase II: candidate for a Tat cofactor. AB - Efficient replication of human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2) requires the virus transactivator proteins known as Tat. In order to understand the molecular mechanisms involved in Tat transactivation, it is essential to identify the cellular target(s) of the Tat activation domain. Using an in vitro kinase assay, we previously identified a cellular protein kinase activity, Tat-associated kinase (TAK), that specifically binds to the activation domains of Tat proteins. Here it is demonstrated that TAK fulfills the genetic criteria established for a Tat cofactor. TAK binds in vitro to the activation domains of the Tat proteins of HIV-1 and HIV-2 and the distantly related lentivirus equine infectious anemia virus but not to mutant Tat proteins that contain nonfunctional activation domains. In addition, it is shown that TAK is sensitive to dichloro-1-beta-D-ribofuranosylbenzimidazole, a nucleoside analog that inhibits a limited number of kinases and is known to inhibit Tat transactivation in vivo and in vitro. We have further identified an in vitro substrate of TAK, the carboxyl-terminal domain of the large subunit of RNA polymerase II. Phosphorylation of the carboxyl-terminal domain has been proposed to trigger the transition from initiation to active elongation and also to influence later stages during elongation. Taken together, these results imply that TAK is a very promising candidate for a cellular factor that mediates Tat transactivation. PMID- 7853497 TI - Involvement of the molecular chaperone BiP in maturation of Sindbis virus envelope glycoproteins. AB - Sindbis virus codes for two membrane glycoproteins, E1 and PE2, which assemble into heterodimers within the endoplasmic reticulum. We have examined the role of the molecular chaperone BiP (grp78) in the maturation of these two proteins. E1, which folds into its mature conformation via at least three intermediates differing in the configurations of their disulfide bonds, was found to interact strongly and transiently with BiP after synthesis. ATP depletion mediated by carbonyl cyanide m-chlorophenylhydrazone treatment results in the stabilization of complexes between BiP and E1. The depletion of intracellular ATP levels also greatly inhibits conversions between the E1 folding intermediates and results in the slow incorporation of E1 into disulfide-stabilized aggregates. These results suggest that the ATP-regulated binding and release of BiP have a role in modulating disulfide bond formation during E1 folding. In comparison with E1, very little PE2 is normally recovered in association with BiP. However, under conditions in which E1 folding is aberrant, increased amounts of PE2 become directly associated with BiP. The formation of these BiP-PE2 interactions occurs after E1 begins to misfold or fails to fold efficiently. We propose that nascent PE2 is stable prior to pairing with E1 for only a limited period of time, after which unpaired PE2 becomes recognized by BiP. This implies that the productive association of PE2 and E1 must occur within a restricted time frame and only after E1 has accomplished certain folding steps mediated by BiP binding and release. Kinetic studies which show that the pairing of E1 with PE2 is delayed after translocation support this conclusion. PMID- 7853498 TI - Adenovirus E1A proteins interact with the cellular YY1 transcription factor. AB - The adenovirus 12S and 13S E1A proteins have been shown to relieve repression mediated by the cellular transcription factor YY1. The 13S E1A protein not only relieves repression but also activates transcription through YY1 binding sites. In this study, using a variety of in vivo and in vitro assays, we demonstrate that both E1A proteins can bind to YY1, although the 13S E1A protein binds more efficiently than the 12S E1A protein. Two domains on the E1A proteins interact with YY1: an amino-terminal sequence (residues 15 to 35) that is present in both E1A proteins and a domain that includes at least a portion of conserved region 3 (residues 140 to 188) that is present in the 13S but not the 12S E1A protein. Two domains on YY1 interact with E1A proteins: one is contained within residues 54 to 260, and the other is contained within the carboxy-terminal domain of YY1 (residues 332 to 414). Cotransfection of a plasmid expressing carboxy-terminal amino acids 332 to 414 of YY1 fused to the GAL4 DNA-binding domain can inhibit expression from a reporter construct with GAL4 DNA binding sites in its promoter, and inclusion of a third plasmid expressing E1A proteins can relieve the repression. Thus, we find a correlation between the ability of E1A to interact with the carboxy-terminal domain of YY1 and its ability to relieve repression caused by the carboxy-terminal domain of YY1. We propose that E1A proteins normally relieve YY1-mediated transcriptional repression by binding directly to the cellular transcription factor. PMID- 7853499 TI - Interactions between the cytoplasmic proteins and the intergenic (promoter) sequence of mouse hepatitis virus RNA: correlation with the amounts of subgenomic mRNA transcribed. AB - Previous studies suggested that coronavirus RNA transcription involves interaction between leader RNA and the intergenic (IG) sequences, probably via protein-RNA interactions (X. M. Zhang, C.-L. Liao, and M. M. C. Lai, J. Virol., 68:4738-4746, 1994; X. M. Zhang and M. M. C. Lai, J. Virol., 68:6626-6633, 1994). To determine whether cellular proteins are involved in this process, we performed UV cross-linking experiments using cytoplasmic extracts of uninfected cells and the IG (promoter) sequence between genes 6 and 7 (IG7) and the 5' untranslational region of mouse hepatitis virus genomic RNA. We demonstrated that three different cellular proteins (p70, p48, and p35/38) bound to the promoter sequence of the template RNA. Deletion analyses of the template RNA mapped the binding site of p35/38 at the consensus transcription initiation signal. In contrast, the binding of p70 and p48 was less specific. p35/38 is the same protein as the one previously identified to bind to the complementary strand of the leader RNA; its binding affinity to the leader was approximately 15 times stronger than that to IG7. Site-directed mutagenesis of the IG sequence revealed that mutations in the consensus sequence of IG7 (UCUAAUCUAAAC to UCGAAAC and GCUAAAG), which resulted in reduced subgenomic mRNA transcription, also caused correspondingly reduced levels of p35/38 binding. These results demonstrated that the extent of protein binding to the IG sequences correlated with the amounts of subgenomic mRNAs transcribed from the IG site. These studies suggest that these RNA-binding proteins are involved in coronavirus RNA transcription and may represent transcription factors. PMID- 7853500 TI - Differential effects of human cytomegalovirus on integrated and unintegrated human immunodeficiency virus sequences. AB - Human cytomegalovirus (HCMV) has been implicated as a potential cofactor in human immunodeficiency virus type 1 (HIV-1)-related disease. Previously, we reported that HCMV inhibits HIV-1 RNA and protein synthesis in cells productively infected with both viruses but, in transient assays, activates an HIV-1 long terminal repeat-chloramphenicol acetyltransferase (LTR-CAT) construct introduced into the cell by transfection (V. Koval, C. Clark, M. Vaishnav, S. A. Spector, and D. H. Spector, J. Virol. 65:6969-6978, 1991). We show here that HCMV can also activate an infectious proviral HIV-1 genome transiently transfected into a cell. To ascertain whether integration of the HIV-1 provirus plays a role in these differential effects, we generated monoclonal and polyclonal cell lines that each contain a single integrated copy of an HIV-1 LTR-CAT construct and compared the regulatory effects of HCMV and HIV-1 infection in these cells with those occurring in the same type of cell transiently transfected with the HIV-1 LTR-CAT construct. We find that HCMV activates the transfected HIV-1 promoter 230-fold but activates the integrated promoter only 2.8- to 54-fold. In contrast, HIV-1 stimulates the integrated HIV-1 promoter 2,700- to 6,000-fold but stimulates the transfected promoter only 80-fold. Thus, the relative response of the HIV-1 promoter to HCMV and HIV-1 regulatory proteins depends upon whether it is integrated. To determine if HIV-1 gene products are necessary for the HCMV mediated repression, we constructed cell lines containing two different stably integrated HIV-1 proviruses: one is tat- and nef-minus and transcriptionally inactive, while the other is env- and nef-minus but actively expresses the other HIV-1 gene products. Upon infection with HCMV, HIV-1 antigen production was stimulated from the inactive HIV-1 genome but inhibited from the active genome. We propose that HCMV has two separate effects on HIV-1 replication during a coinfection. One is a slight stimulatory effect which would be undetectable during an active HIV-1 infection, while the other is a net inhibitory effect that is mediated by an interaction between HCMV and HIV-1 gene products. PMID- 7853501 TI - The NS1 polypeptide of the murine parvovirus minute virus of mice binds to DNA sequences containing the motif [ACCA]2-3. AB - A DNA fragment containing the minute virus of mice 3' replication origin was specifically coprecipitated in immune complexes containing the virally coded NS1, but not the NS2, polypeptide. Antibodies directed against the amino- or carboxy terminal regions of NS1 precipitated the NS1-origin complexes, but antibodies directed against NS1 amino acids 284 to 459 blocked complex formation. Using affinity-purified histidine-tagged NS1 preparations, we have shown that the specific protein-DNA interaction is of moderate affinity, being stable in 0.1 M salt but rapidly lost at higher salt concentrations. In contrast, generalized (or nonspecific) DNA binding by NS1 could be demonstrated only in low salt. Addition of ATP or gamma S-ATP enhanced specific DNA binding by wild-type NS1 severalfold, but binding was lost under conditions which favored ATP hydrolysis. NS1 molecules with mutations in a critical lysine residue (amino acid 405) in the consensus ATP binding site bound to the origin, but this binding could not be enhanced by ATP addition. DNase I protection assays carried out with wild-type NS1 in the presence of gamma S-ATP gave footprints which extended over 43 nucleotides on both DNA strands, from the middle of the origin bubble sequence to a position some 14 bp beyond the nick site. The DNA-binding site for NS1 was mapped to a 22 bp fragment from the middle of the 3' replication origin which contains the sequence ACCAACCA. This conforms to a reiterated motif (ACCA)2-3, which occurs, in more or less degenerate form, at many sites throughout the minute virus of mice genome (J. W. Bodner, Virus Genes 2:167-182, 1989). Insertion of a single copy of the sequence (ACCA)3 was shown to be sufficient to confer NS1 binding on an otherwise unrecognized plasmid fragment. The functions of NS1 in the viral life cycle are reevaluated in the light of this result. PMID- 7853502 TI - The hemagglutinin envelope protein of canine distemper virus (CDV) confers cell tropism as illustrated by CDV and measles virus complementation analysis. AB - Measles virus (MV) and canine distemper virus (CDV) are morbilliviruses that cause acute illnesses and several persistent central nervous system infections in humans and in dogs, respectively. Characteristically, the cytopathic effect of these viruses is the formation of syncytia in permissive cells. In this study, a vaccinia virus expression system was used to express MV and CDV hemagglutinin (HA) and fusion (F) envelope proteins. We found that cotransfecting F and HA genes of MV or F and HA genes of CDV resulted in extensive syncytium formation in permissive cells while transfecting either F or HA alone did not. Similar experiments with heterologous pairs of proteins, CDV-F with MV-HA or MV-F with CDV-HA, caused significant cell fusion in both cases. These results indicate that in this expression system, cell fusion requires both F and HA; however, the functions of these proteins are interchangeable between the two types of morbilliviruses. Human-mouse somatic hybrids were used to determine the human chromosome conferring susceptibility to either MV and CDV. Of the 12 hybrids screened, none were sensitive to MV. Two of the hybrids containing human chromosome 19 formed syncytia following CDV infection. In addition, these two hybrids underwent cell fusion when cotransfected with CDV-F and CDV-HA (but not MV-F and MV-HA) glycoproteins by using the vaccinia virus expression system. To discover the viral component responsible for cell specificity, complementation experiments coexpressing CDV-HA with MV-F or CDV-F with MV-HA in the CDV sensitive hybrids were performed. We found that syncytia were formed only in the presence of CDV-HA. These results support the idea that the HA protein is responsible for cell tropism. Furthermore, while the F protein is necessary for the fusion process, it is interchangeable with the F protein from other morbilliviruses. PMID- 7853503 TI - Bipartite DNA-binding region of the Epstein-Barr virus BMRF1 product essential for DNA polymerase accessory function. AB - The Epstein-Barr virus (EBV) BMRF1 gene product is necessary for DNA polymerase catalytic subunit (BALF5) activity in 100 mM ammonium sulfate. To map regions of BMRF1 necessary for polymerase accessory function, linker insertion and deletion mutant BMRF1 polypeptides were expressed by in vitro transcription-translation and assayed for DNA polymerase elongation activity and binding to double-stranded DNA (dsDNA)-cellulose. Amino-terminal deletions up to residue 303 were defective for stimulation of elongation. Deletions between residues 44 and 194 and residues 238 and 303 abolished binding to dsDNA-cellulose. The region from residues 194 to 238, therefore, is necessary for stimulation of BALF5 elongation but dispensable for dsDNA-cellulose binding. Deletion analysis also localized reactive epitopes of two neutralizing monoclonal antibodies to BMRF1 to a carboxy-terminal region which is dispensable for activity. These data suggest that a bipartite DNA binding region is an essential component of the DNA polymerase accessory function and that the two noncontiguous regions are separated by a region (residues 194 to 217) which is essential for stimulation; therefore, it may interact with the BALF5 catalytic subunit of EBV DNA polymerase. Both EBV BMRF1 and herpes simplex virus UL42 gene products are DNA polymerase accessory proteins which bind dsDNA and increase the processivity of their corresponding catalytic components. Outstanding similarities between their primary amino acid sequences are not evident. However, it appears that their structural organizations are similar. PMID- 7853504 TI - Canine distemper virus persistence in the nervous system is associated with noncytolytic selective virus spread. AB - Canine distemper virus (CDV), a negative-strand RNA morbillivirus, causes a progressive demyelinating disease in which virus persistence plays an essential role. The antiviral immune response leads to virus clearance in the inflammatory lesions. However, CDV can replicate and persist outside these inflammatory lesions within the brain. How CDV is capable of persisting in the presence of an effective antiviral immune response is poorly understood. In the present investigation, we studied several aspects of virus replication in primary dog brain cell cultures (DBCC), comparing an attenuated CDV strain and a virulent CDV strain. Confluent DBCC were infected with either virulent A75/17-CDV or attenuated Onderstepoort-CDV and monitored for 60 days. Persistence was not associated with defective virus production, because all mRNAs and corresponding proteins were continuously expressed in the noncytolytic infection. Quantitative measurements did not detect a difference between the two types of infection in the rate of virus transcription and protein synthesis at the level of the single cell. However, electron microscopy and virus titration experiments showed that in the persistent CDV infection virus budding is strongly limited compared with that of the attenuated virus. Morphometry and immunocytochemistry showed profound differences in the way the two viruses spread in the culture. The attenuated CDV spread randomly to immediately adjacent cells, whereas persistent CDV spread selectively to more-distant cells by way of cell processes. In conclusion, the present study supports a mechanism of CDV persistence through selective spread by way of cell processes, enabling virulent CDV to invade the central nervous system without the need of releasing much virus into the extracellular space. PMID- 7853505 TI - Nucleotide sequence stability of the genome of hepatitis delta virus. AB - Cultured cells were cotransfected with a fully sequenced 1,679-base cDNA clone of human hepatitis delta virus (HDV) RNA genome and a cDNA for the genome of woodchuck hepatitis virus (WHV). The HDV particles released were able to infect a woodchuck that was chronically infected with WHV. The HDV so produced was passaged a total of six times in woodchucks in order to determine the stability of the HDV nucleotide sequence. During a final chronic infection with such virus, liver RNA was extracted, and the HDV nucleotide sequence for the 352-base region, positions 905 to 1256, was obtained. By means of PCR, we obtained double-stranded cDNA both for direct sequencing and also for molecular cloning followed by sequencing. By direct sequencing, we found that a consensus sequence existed and was identical to the original sequence. From the sequences of 31 clones, we found 32% (10 of 31) to be identical to the original single nucleotide sequence. For the remainder, there were neither insertions nor deletions but there was a small number of single-nucleotide changes. These changes were predominantly transitions rather than transversions. Furthermore, the transitions were largely of just two types, uridine to cytidine and adenosine to guanosine. Of the 40 changes detected on HDV, 35% (14 of 40) occurred within an eight-nucleotide region that included position 1012, previously shown to be a site of RNA editing. These findings may have significant implications regarding both the stability of the HDV RNA genome and the mechanism of RNA editing. PMID- 7853506 TI - Specific proteolytic cleavage of recombinant Norwalk virus capsid protein. AB - Norwalk virus (NV) causes epidemic outbreaks of acute nonbacterial gastroenteritis in humans. The NV capsid is made up of a single protein, and expression of the capsid protein in baculovirus recombinants results in spontaneous assembly of the protein into virus-like particles (X. Jiang, M. Wang, D. Y. Graham, and M. K. Estes, J. Virol. 66:6527-6532, 1992). We have investigated whether the NV capsid protein undergoes a specific proteolytic cleavage. Recombinant NV (rNV) particles were digested with trypsin to determine if a specific cleavage occurred. A predominant band with a molecular weight of approximately 32,000 (32K protein) was observed when trypsin-treated rNV was electrophoresed on sodium dodecyl sulfate-polyacrylamide gels. Determination of the N-terminal sequence of this band showed that a trypsin-specific cleavage occurred at amino acid residue 227. Early studies identified two proteins with molecular weights of 59,000 and 30,000 (59K and 30K proteins) in the stool of NV infected volunteers that were reactive with postinfection antiserum. (H. B. Greenberg, J. R. Valdesuso, A. R. Kalica, R. G. Wyatt, V. J. McAuliffe, A. Z. Kapikian, and R. M. Chanock, J. Virol. 37:994-999, 1981). We hypothesized that the 32K rNV cleavage product might be analogous to the 30K soluble protein detected in stools of NV-infected volunteers. Immunoprecipitation of soluble protein from these stool extracts with a rabbit polyclonal antiserum made against rNV, and Western blot detection with a mouse polyclonal antiserum made against rNV, revealed a single band with an apparent molecular weight of 30,000 that migrated similarly to the trypsin cleavage product observed in vitro. The N terminus of this band was identical to that of the 32K cleavage product of rNV capsid protein. These data show that the 30K protein in stool is produced by specific cleavage of the NV capsid protein in vivo. Trypsin cleavage of isolated soluble rNV 58K capsid protein and of assembled particles showed that only soluble 58K capsid protein is susceptible to cleavage. The presence of a large amount of soluble capsid protein may influence the immune response to or pathogenicity of NV infections. PMID- 7853507 TI - Highly specific antibody to Rous sarcoma virus src gene product recognizes nuclear and nucleolar antigens in human cells. AB - An antiserum to the Rous sarcoma virus-transforming protein pp60v-src, raised in rabbits immunized with the bacterially produced protein alpha p60 serum (M. D. Resh and R. L. Erikson, J. Cell Biol. 100:409-417, 1985) previously reported to detect very specifically a novel population of pp60v-src and pp60c-src molecules associated with juxtareticular nuclear membranes in normal and Rous sarcoma virus infected cells of avian and mammalian origin, was used here to investigate by immunofluorescence microscopy localization patterns of Src molecules in human cell lines, either normal or derived from spontaneous tumors. We found that the alpha p60 serum reveals nuclear and nucleolar concentrations of antigens in all the human cell lines tested and in two rat and mouse hepatoma cell lines derived from adult tumorous tissues but not in any established rat and mouse cell lines either untransformed or transformed by the src and ras oncogenes. Both the nuclear and nucleolar stainings can be totally extinguished by preincubation of the serum with highly purified chicken c-Src. We show also that the partitioning of the alpha p60-reactive proteins among the whole nucleus and the nucleolus depends mostly on two different parameters: the position in the cell cycle and the degree of cell confluency. Our observations raise the attractive possibility that, in differentiated cells, pp60c-src and related proteins might be involved not only in mediating the transduction of mitogenic signals at the plasma membrane level but also in controlling progression through the cell cycle and entry in mitosis by interacting with cell division cycle regulatory components at the nuclear level. PMID- 7853508 TI - Cell surface activation of the erythropoietin receptor by Friend spleen focus forming virus gp55. AB - The leukemogenic membrane glycoprotein gp55, encoded by Friend spleen focus forming virus (SFFV), induces erythroid cell proliferation through its interaction with the erythropoietin receptor (EPO-R). There are two forms of gp55 in SFFV-infected cells: an intracellular form (more than 95% of the total protein), which is localized within the endoplasmic reticulum (ER) membranes, and a cell surface form (about 3 to 5%). Because both forms of the viral proteins bind to EPO-R, it is not clear whether the viral protein induces mitogenesis intracellularly or at the cell surface. To address this question, we constructed an EPO-R mutant that contained a 6-amino-acid (DEKKMP) C-terminus ER retention signal. Biochemical and functional analyses with this mutant indicated that it was completely retained in the ER and not expressed at the cell surface. Further analysis showed that the mutant, like the wild-type EPO-R, interacted with SFFV gp55. However, this apparent intracellular interaction between the two proteins failed to induce growth factor-independent proliferation of Ba/F3 cells. Furthermore, spontaneous variants of the ER-retained EPO-R selected on the basis of their ability to induce cell proliferation when coexpressed with gp55 were exclusively expressed at the cell surface. Thus, our results support the hypothesis that the mitogenic activation of the EPO-R by gp55 requires the interaction of the two proteins at the cell surface. PMID- 7853509 TI - Pestivirus NS3 (p80) protein possesses RNA helicase activity. AB - The pestivirus bovine viral diarrhea virus (BVDV) p80 protein (referred to here as the NS3 protein) contains amino acid sequence motifs predictive of three enzymatic activities: serine proteinase, nucleoside triphosphatase, and RNA helicase. We have previously demonstrated that the former two enzymatic activities are associated with this protein. Here, we show that a purified recombinant BVDV NS3 protein derived from baculovirus-infected insect cells possesses RNA helicase activity. BVDV NS3 RNA helicase activity was specifically inhibited by monoclonal antibodies to the p80 protein. The activity was dependent on the presence of nucleoside triphosphate and divalent cation, with a preference for ATP and Mn2+. Hydrolysis of the nucleoside triphosphate was necessary for strand displacement. The helicase activity required substrates with an un-base paired region on the template strand 3' of the duplex region. As few as three un base-paired nucleotides were sufficient for efficient oligonucleotide displacement. However, the enzyme did not act on substrates having a single stranded region only to the 5' end of the duplex or on substrates lacking single stranded regions altogether (blunt-ended duplex substrates), suggesting that the directionality of the BVDV RNA helicase was 3' to 5' with respect to the template strand. The BVDV helicase activity was able to displace both RNA and DNA oligonucleotides from RNA template strands but was unable to release oligonucleotides from DNA templates. The possible role of this activity in pestivirus replication is discussed. PMID- 7853510 TI - Cleavage specificity of purified recombinant hepatitis A virus 3C proteinase on natural substrates. AB - Hepatitis A virus (HAV) 3C proteinase expressed in Escherichia coli was purified to homogeneity, and its cleavage specificity towards various parts of the viral polyprotein was analyzed. Intermolecular cleavage of the P2-P3 domain of the HAV polyprotein gave rise to proteins 2A, 2B, 2C, 3ABC, and 3D, suggesting that in addition to the primary cleavage site, all secondary sites within P2 as well as the 3C/3D junction are cleaved by 3C. 3C-mediated processing of the P1-P2 precursor liberated 2A and 2BC, in addition to the structural proteins VP0, VP3, and VP1-2A and the respective intermediate products. A clear dependence on proteinase concentration was found for most cleavage sites, possibly reflecting the cleavage site preference of 3C. The most efficient cleavage occurred at the 2A/2B and 2C/3A junctions. The electrophoretic mobility of processing product 2B, as well as cleavage of the synthetic peptide KGLFSQ*AKISLFYT, suggests that the 2A/2B junction is located at amino acid position 836/837 of the HAV polyprotein. Furthermore, using suitable substrates we obtained evidence that sites VP3/VP1 and VP1/2A are alternatively processed by 3C, leading to either VP1-2A or to P1 and 2A. The results with regard to intermolecular cleavage by purified 3C were confirmed by the product pattern derived from cell-free expression and intramolecular processing of the entire polyprotein. We therefore propose that polyprotein processing of HAV relies on 3C as the single proteinase, possibly assisted by as-yet-undetermined viral or host cell factors and presumably controlled in a concentration-dependent fashion. PMID- 7853511 TI - Human cytomegalovirus UL102 gene. AB - We have identified and characterized the transcript for the human cytomegalovirus (HCMV) UL102 gene. The UL102 gene product is proposed to encode the primase associated factor. The primase-associated factor is one of the three components of the helicase-primase complex, along with UL105 (helicase) and UL70 (primase). In order to characterize the UL102 transcription unit we used single-stranded antisense RNA probes to identify an abundant 2.7-kb transcript originating from the UL102 region. This transcript can be initially detected at 24 h postinfection and in the presence of phosphonoformic acid but not in the presence of cycloheximide. A 2.7-kb cDNA clone containing this transcript was isolated from a 72-h HCMV (strain Towne) cDNA library. Sequence analysis of this clone revealed a continuous unspliced transcript between the region of UL101X and UL102; the only in-frame translational stop codon is 2,619 bp downstream from the first ATG in the message. Genome sequencing of the UL102 region from strains AD169 and Towne revealed that the UL101X stop codon TAA was actually TAC and that the cDNA and genomic sequences were in agreement. The cDNA clone starts 5 nucleotides (nt) upstream of the UL101X ATG, continues through the putative ATG of UL102, and ends 97 nt downstream of the putative termination codon of the UL102 open reading frame. Primer extension analysis indicated a transcriptional start site 23 nt upstream of the UL101X open reading frame. PMID- 7853512 TI - Aura alphavirus subgenomic RNA is packaged into virions of two sizes. AB - The alphavirus genome is 11.8 kb in size. During infection, a 4.2-kb subgenomic RNA is also produced. Most alphaviruses package only the genomic RNA into virions, which are enveloped particles with icosahedral symmetry, having a triangulation number (T) = 4. Aura virus, however, packages both the genomic RNA and the subgenomic RNA into virions. The genomic RNA is primarily packaged into a virion that has a diameter of 72 nm and which appears to be identical to the virions produced by other alphaviruses. The subgenomic RNA is packaged into two major, regular particles with diameters of 72 and 62 nm. The 72-nm-diameter particle appears to be identical in construction to virions containing genomic RNA. The 62-nm-diameter particle probably has T = 3. The large and small Aura virions can be partially separated in sucrose gradients. In addition to these two major classes of particles, there are other particles produced that appear to arise from abortive assembly. From these results and from previous studies of alphavirus assembly, we suggest that during assembly of alphavirus nucleocapsids in the infected cell there is a specific initiation event followed by recruitment of additional capsid subunits into the complex, that the triangulation number of the complex is not predetermined but depends upon the size of the RNA and interactions that occur during assembly, and that budding of assembled nucleocapsids results in the acquisition of an envelope containing glycoproteins arranged in a manner determined by the nucleocapsid. PMID- 7853513 TI - Expression of the rotavirus SA11 protein VP7 in the simple eukaryote Dictyostelium discoideum. AB - The outer capsid protein of rotavirus, VP7, is a major neutralization antigen and is considered a necessary component of any subunit vaccine developed against rotavirus infection. For this reason, significant effort has been directed towards producing recombinant VP7 that maintains the antigenic characteristics of the native molecule. Using a relatively new expression system, the simple eukaryote Dictyostelium discoideum, we have cloned the portion of simian rotavirus SA11 genome segment 9, encoding the mature VP7 protein, downstream of a native D. discoideum secretion signal sequence in a high-copy-number extrachromosomal vector. The majority of the recombinant VP7 expressed by transformants was intracellular and was detected by Western immunoblot following gel electrophoresis as two or three bands with an apparent molecular mass of 35.5 to 37.5 kDa. A small amount of VP7 having an apparent molecular mass of 37.5 kDa was secreted. Both the intracellular VP7 and the secreted VP7 were N glycosylated and sensitive to endoglycosidase H digestion. Under nonreducing electrophoresis conditions, over half the intracellular VP7 migrated as a monomer while the remainder migrated with an apparent molecular mass approximately twice that of the monomeric form. In an enzyme-linked immunosorbent assay, intracellular VP7 reacted with both nonneutralizing and neutralizing antibodies. The monoclonal antibody recognition pattern paralleled that found with VP7 expressed in either vaccinia virus or herpes simplex virus type 1 and confirms that D. discoideum expressed VP7 is able to form the major neutralization domains present on viral VP7. Because D. discoideum cells are easy and cheap to grow, this expression system provides a valuable alternative for the large-scale production of recombinant VP7 protein. PMID- 7853514 TI - V3-independent determinants of macrophage tropism in a primary human immunodeficiency virus type 1 isolate. AB - Human immunodeficiency virus type 1 isolates differ in their ability to productively infect macrophages, and several groups have mapped the genetic basis for macrophage tropism to regions of env that include the third hypervariable region (V3 loop). We recently described a primary isolate (89.6) which is highly macrophage tropic and yet differs from other macrophage-tropic strains studied in that it is cytopathic in T cells. Genetic mapping of macrophage tropism determinants in this virus was done by using chimeras generated with the prototypic non-macrophage-tropic strain HXB2. Replacement of a 2.7-kb env containing region of HXB with corresponding sequences from 89.6 conferred the macrophage-tropic phenotype, but insertion of the 89.6 V3 loop along with V4/V5 sequences did not. Conversely, placement of HXB sequences that included V3 into 89.6 did not impair this strain's ability to replicate in macrophages. Sequence analysis of V3 shows that 89.6 differs markedly from previously described macrophage-tropic consensus sequences and that it is more similar to highly charged non-macrophage-tropic strains. This suggests either that macrophage tropism is defined by structural determinants resulting from complex interactions among multiple env regions rather than V3 sequence-specific requirements or that there are multiple mechanisms by which different strains may establish productive macrophage infection. In addition, because the HXB V3 loop supports productive macrophage infection in the background of 89.6, phenotypic characterization of V3 sequences should be considered specific to the viral context in which they are placed. PMID- 7853515 TI - Latency, without persistence, of murine cytomegalovirus in the spleen and kidney. AB - It is not known if murine cytomegalovirus (MCMV) establishes a state of molecular latency independent of low-level persistent infection. The presence of low levels of infectious MCMV distinguishes persistence from molecular latency. Thus, the distinction between persistence and latency has depended on the sensitivity of plaque assays for detecting low levels of infectious virus in tissue of previously infected mice. To determine whether MCMV establishes molecular latency or remains persistent, we developed two assays for detecting low levels of MCMV in tissue. Using prolonged in vitro culture of virus with either mouse embryonic fibroblasts or the murine 3T12 fibroblast cell line, we reproducibly detected a single PFU of MCMV. Inclusion of undiluted sonicated tissue in this assay decreased sensitivity by up to 100-fold. However, sensitivity was improved to 1 PFU of MCMV when sonicated tissue was appropriately diluted. Severe combined immunodeficient (SCID) mice were also used to detect MCMV in sonicated tissue. Infection of SCID mice with a single PFU of MCMV killed two of eight SCID mice, and the 50% lethal dose of MCMV in SCID mice was 2 to 3 PFU. Applying these two methods, we detected infectious virus in 0 of 34 spleens, 1 of 34 kidneys, and 0 of 37 salivary glands from latently infected mice. Spleens and kidneys assessed for persistent virus contained MCMV DNA by PCR and reactivated after 10 to 50 days in explant cultures. Latently infected kidney cells reactivated after adoptive transfer to SCID mice. Quantitation of the MCMV genome by PCR showed that latently infected spleens without detectable infectious MCMV contained about 3,000,000 copies of the MCMV genome. These results demonstrate that MCMV latency in spleen and kidney exists in the absence of low-level persistent infection. Use of assays with defined sensitivity for detection of MCMV in tissue provides a basis for evaluation of cytomegalovirus gene expression in the spleen and kidney during molecular latency. PMID- 7853516 TI - An amino-terminal domain of the hepatitis C virus NS3 protease is essential for interaction with NS4A. AB - Hepatitis C virus (HCV) genomic RNA is translated into a large polyprotein that is processed into structural and nonstructural proteins. Processing at the N termini of several nonstructural proteins requires sequences contained in both NS3 and NS4A. NS3 contains a serine protease, whereas the function of NS4A in proteolysis is yet to be determined. By using the vaccinia virus-T7 hybrid expression system to transiently express HCV polypeptides in HeLa cells, we studied the effect of several N-terminal and C-terminal deletions of HCV NS3 on the processing activity at all the downstream cleavage sites. In this way, we have delineated the minimal domain of NS3 required for the serine protease activity associated with this protein. In addition, we demonstrate the formation of a stable complex between NS3 and NS4A: analysis of the deletion mutants reveals a region at the N terminus of NS3 that is necessary for both complex formation and modulation of the proteolytic activity by NS4A but not for the NS4A independent serine protease activity of NS3. PMID- 7853517 TI - The central globular domain of the nucleocapsid protein of human immunodeficiency virus type 1 is critical for virion structure and infectivity. AB - The nucleocapsid protein NCp7 of human immunodeficiency virus type 1 (HIV-1) is a 72-amino-acid peptide containing two CCHC-type zinc fingers linked by a short basic sequence, 29RAPRKKG35, which is conserved in HIV-1 and simian immunodeficiency virus. The complete three-dimensional structure of NCp7 has been determined by 1H-nuclear magnetic resonance spectroscopy (N. Morellet, H. de Rocquigny, Y. Mely, N. Jullian, H. Demene, M. Ottmann, D. Gerard, J. L. Darlix, M. C. Fournie-Zaluski, and B. P. Roques, J. Mol. Biol. 235:287-301, 1994) and revealed a central globular domain where the two zinc fingers are brought in close proximity by the RAPRKKG linker. To examine the role of this globular structure and more precisely of the RAPRKKG linker in virion structure and infectivity, we generated HIV-1 DNA mutants in the RAPRKK sequence of NCp7 and analyzed the mutant virions produced by transfected cells. Mutations that probably alter the structure of NCp7 structure led to the formation of very poorly infectious virus (A30P) or noninfectious virus (P31L and R32G). In addition, the P31L mutant did not contain detectable amounts of reverse transcriptase and had an immature core morphology, as determined by electron microscopy. On the other hand, mutations changing the basic nature of NCp7 had poor effect. R29S had a wild-type phenotype, and the replacement of 32RKK34 by SSS (S3 mutant) resulted in a decrease by no more than 100-fold of the virus titer. These results clearly show that the RAPRKKG linker contains residues that are critical for virion structure and infectivity. PMID- 7853518 TI - Characterization of a ubiquitinated protein which is externally located in African swine fever virions. AB - An antiserum was raised against the African swine fever virus (ASFV)-encoded ubiquitin-conjugating enzyme (UBCv1) and used to demonstrate by Western blotting (immunoblotting) and immunofluorescence that the enzyme is present in purified extracellular virions, is expressed both early and late after infection of cells with ASFV, and is cytoplasmically located. Antiubiquitin serum was used to identify novel ubiquitin conjugates present during ASFV infections. This antiserum stained virus factories late after infection, suggesting that virion proteins may be ubiquitinated. This possibility was confirmed by Western blotting, which identified three major antiubiquitin-immunoreactive proteins with molecular masses of 5, 18, and 58 kDa in purified extracellular virions. The 18 kDa protein was solubilized from virions at relatively low concentrations of the detergent n-octyl-beta-D-glucopyranoside, indicating that it is externally located and is possibly in the virus capsid. The 18-kDa protein was purified, and N-terminal amino acid sequencing confirmed that the protein was ubiquitinated and was ASFV encoded. The ASFV gene encoding this protein (PIG1) was sequenced, and the encoded protein expressed in an Escherichia coli expression vector. Recombinant PIG1 was ubiquitinated in the presence of E. coli expressed UBCv1 in vitro. These results suggest that PIG1 may be a substrate for UBCv1. The predicted molecular masses of the PIG1 protein and recombinant ubiquitinated protein were larger than the 18-kDa molecular mass of the ubiquitinated protein present in virions. Therefore, during viral replication, a precursor protein may undergo limited proteolysis to generate the ubiquitinated 18-kDa protein. PMID- 7853519 TI - Sequence-specific inhibition of gene expression by a novel antisense oligodeoxynucleotide phosphorothioate directed against a nonregulatory region of the human immunodeficiency virus type 1 genome. AB - Previous studies have demonstrated that oligodeoxynucleotide phosphorothioates complementary to human immunodeficiency virus type 1 (HIV-1) RNA are more nuclease resistant and are effective inhibitors of HIV-1 replication than their unmodified counterpart. In this study, antisense oligodeoxynucleotide sequences were evaluated for therapeutic potential in the treatment of HIV infections. The use of HIV-infected lymphocytes to test the efficacy of a drug is very complex, and therefore it is difficult to draw conclusions about the mechanism. We used a COS-like Monkey kidney cell line (CMT3) stably transfected with plasmids pCMVgagpol-rre-r (containing gag and pol genes) and pCMVrev (containing the rev gene of HIV-1), derived from cDNA clone BH10, as a model. A biologically active provirus that transcribes and translates their nucleotide sequences into viral proteins p24, p39/41, p55, and p160 was generated. Sequence-specific and dose dependent inhibition of HIV-1 viral protein synthesis and significant inhibition at the mRNA level were demonstrated by antisense construct GPI2A, directed against a nonregulatory region of the HIV-1 genome. Also, our studies demonstrated enhancement of the antisense effect through encapsulation in a cationic lipid preparation. The observed attenuation of HIV-1 mRNA levels suggests that, at least in part, the mechanism of action of GPI2A was at the transcript level. Further studies have also shown antiviral activity of this construct as determined by the reverse transcriptase assay using acutely and chronically infected cells of lymphoid origin (H9 cells). Toxicological studies involving cell growth characteristics, colony-forming ability, effects on cellular proteins, specific activities of labeled proteins, and DNA synthesis in cell culture showed no cytotoxic effects of GPI2A. PMID- 7853520 TI - Purification and characterization of the major nonstructural protein (NS-1) of Aleutian mink disease parvovirus. AB - We have previously described the expression of the major nonstructural protein (NS-1) of Aleutian mink disease parvovirus (ADV) in insect cells by using a baculovirus vector (J. Christensen, T. Storgaard, B. Bloch, S. Alexandersen, and B. Aasted, J. Virol. 67:229-238, 1993). To study its biochemical properties, ADV NS-1 was expressed in Sf9 insect cells and purified to apparent homogeneity with a combination of nuclear extraction, Zn2+ ion chromatography, and immunoaffinity chromatography on monoclonal antibodies. The purified protein showed ATP binding and ATPase- and ATP- or dATP-dependent helicase activity requiring either Mg2+ or Mn2+ as a cofactor. The ATPase activity of NS-1 was efficiently stimulated by single-stranded DNA and, to a lesser extent, double-stranded DNA. We also describe the expression, purification, and characterization of a mutant NS-1 protein, in which a lysine in the putative nucleotide binding consensus sequence of the molecule was replaced with serine. The mutated NS-1 was expressed at 10 fold higher levels than wild-type NS-1, but it exhibited no ATP binding. ATPase, or helicase activity. The availability of large amounts of purified functional NS 1 protein will facilitate studies of the biochemistry of ADV replication and gene regulation leading to disease in mink. PMID- 7853522 TI - Vaccinia virus gene H5R encodes a protein that is phosphorylated by the multisubstrate vaccinia virus B1R protein kinase. AB - Vaccinia virus gene B1R encodes a protein kinase, the previously identified substrates of which include the proteins S2 and Sa of 40S ribosomal subunits. This work characterizes another substrate of the B1R kinase: a 36-kDa protein induced at the early stage of infection. Partially purified 36-kDa protein, eluted from a single-stranded DNA-cellulose column by 0.5 M NaCl, was separated by two-dimensional gel electrophoresis. Phosphorylation in vitro yielded multiple forms of the 36-kDa protein with approximate isoelectric points (pI) of 5.5, 5.7, 5.9, and 6.3, in addition to the apparently unphosphorylated form with a pI of approximately 6.8. The tryptic peptides derived from 36-kDa proteins with pI values of 5.7, 5.9, and 6.3 yielded almost identical high-pressure liquid chromatography profiles, strongly suggesting that the 36-kDa protein was modified by the phosphorylation of at least four sites, which were characterized as threonine residues. The amino acid sequence of several tryptic peptides derived from the 36-kDa protein showed that the 36-kDa protein was encoded by gene H5R of vaccinia virus. Consistent with this, the B1R kinase--either expressed in Escherichia coli or highly purified from HeLa cells--phosphorylated a recombinant trpE-H5R fusion protein in vitro. Fingerprints of the trpE-H5R and 36-kDa proteins phosphorylated by recombinant B1R kinase revealed common sites of phosphorylation, although some tryptic peptides were specific to either protein. Comparison was made of fingerprints of tryptic phosphopeptides derived from 36 kDa single-stranded DNA-binding protein labelled in vivo or in vitro. A common subset of peptides was observed, suggesting that some sites on H5R protein are phosphorylated by the B1R kinase in infected cells. These results suggest that some of the multiple threonine sites in the H5R protein are phosphorylated in vivo by the B1R protein kinase. PMID- 7853523 TI - Definition of a minimal activation domain in human T-cell leukemia virus type I Tax. AB - Fourteen mutants were used to delineate a minimal activation domain in the Tax protein of human T-cell leukemia virus type I. In an assay using a Gal4-Tax (GalTx) fusion protein and a responsive promoter containing Gal4 consensus binding sites, we found that activation was "squelched" by coexpression of wild type Tax protein in trans. When Tax mutants were tested for squelching, many competed effectively against GalTx. However, those containing changes in amino acids 289 to 322 failed to inhibit activity. In particular, three mutants that were expressed stably, with changes at amino acids 289, 296, and 320 respectively, did not squelch GalTx activity. On the other hand, mutants with individual changes at amino acid 3, 9, 29, 41, 273, and 337 efficiently inhibited GalTx function. Three other mutants failed to be stably expressed. In separate experiments, when fused alone to the DNA-binding domain of Gal4, amino acids 289 to 322 of Tax conferred trans activation ability. This fusion protein was able to activate a core promoter. These findings suggest that amino acids 289 to 322 define a region that contacts an essential transcription factor and that this region is a modular activation domain. PMID- 7853521 TI - Syncytium-inducing (SI) phenotype suppression at seroconversion after intramuscular inoculation of a non-syncytium-inducing/SI phenotypically mixed human immunodeficiency virus population. AB - Two distinct biological phenotypes of human immunodeficiency virus (HIV) have been described: the non-syncytium-inducing (NSI) phenotype, best characterized by the inability to infect MT-2 cells, and the syncytium-inducing (SI) phenotype, with the ability to infect MT-2 cells. The earliest virus population observed following HIV transmission is generally of the NSI phenotype, even after exposure to inocula of mixed NSI/SI phenotype. In this study, the issue of intrapatient selection of virus phenotype following transmission was addressed by studying two cases of accidental transmission. A comparison of the sequences of the V1-V2 and the V3 coding regions of the envelope gene and the p17 region of the gag gene showed that the donor-recipient pairs were tightly clustered in all gene segments, but away from local and published transmission controls. The intrasample variation of the p17 sequence was greater in the recipients and smaller in the donors than that of the V3 region sequence, indicating selection of V3 at transmission. In these transmission cases, the effects of an intravenous inoculation of a small quantity of blood containing predominantly SI V3 sequences (6 of 8 clonal sequences) were compared with those of an intramuscular inoculation of a large quantity of blood containing predominantly NSI viruses (14 of 16 clonal sequences). Both SI and NSI V3 regions were demonstrated to be phenotypic expressions of genetically related viral strains. The inoculation of the predominantly SI virus population resulted in the persistence of an SI virus population in the recipient and a rapid CD4+ T-cell decline. The inoculation of the predominantly NSI population resulted in a selective amplification of SI viruses before seroconversion, followed by a suppression of SI viruses at seroconversion and a rapid decline of CD4+ T-cell numbers. These data suggest that the suppression of SI viruses can be accomplished following the development of HIV-specific immunity and that the ability to suppress SI viruses does not prevent the development of immunodeficiency. PMID- 7853524 TI - Distinct regions in human T-cell lymphotropic virus type I tax mediate interactions with activator protein CREB and basal transcription factors. AB - Human T-cell lymphotropic virus type I (HTLV-I) transactivator Tax augments transcription from three (cyclic AMP response element (CRE)-containing 21-bp repeats in the viral long terminal repeat and several other cis regulatory elements, including the NF-kappa B binding sites and the serum response element. Tax does not bind DNA directly; rather, it acts via cellular sequence-specific DNA binding proteins to stimulate transcription. We have shown recently that Tax forms multiprotein complexes with the heterodimeric and homodimeric forms of a ubiquitous cellular transcription factor, CREB (CRE binding protein). In vitro selection for preferred Tax-CREB binding sites indicates that the Tax-CREB complex exhibits greatly increased DNA recognition specificity and assembles preferentially on CRE motifs, TGACGT/C, flanked by long runs of G (5') and/or C (3') residues, as found in the HTLV-I 21-bp repeats. The indirect tethering of Tax to the 21-bp repeats via CREB is crucial for Tax transactivation. We now report the domain organization of Tax by characterizing its mutants. Tax mutants with alterations in the NH2 terminus, including three deletion mutants, Tax(6 353), Tax(21-353), and Tax(89-353), and two amino acid substitution mutants, M1 (H3S) and M7 (C29A, P30S), all failed to interact with CREB in vitro. In contrast, a short COOH-terminal deletion, Tax(1-319), and a Tax mutant with amino acid substitutions near the COOH end, M47 (L319R, L320S), were able to interact with CREB and the 21-bp repeats to assemble ternary Tax-CREB-DNA complexes. As demonstrated earlier, M1, M7, and M47 all failed to transactivate the HTLV-I long terminal repeat. Our data indicate that the defects in M1 and M7 result from an inability to interact with CREB. In contrast, the COOH-terminal mutations in M47 most likely inactivated the transactivation domain of Tax. As anticipated, a Tax mutant, M22 (G137A, L138S) which activated transcription from the 21-bp repeats with reduced capacity and was defective in trans activating the NF-kappa B binding sites, continued to interact with CREB in vitro, albeit with a lower level of efficiency. Finally, a glutathione S-transferase (GST)-Tax fusion protein with the GST moiety fused to the NH2 terminus of Tax failed to interact with CREB. Removal of the GST domain from GST-Tax by thrombin restores Tax's ability to assemble a ternary Tax-CREB-21-bp-repeat complex.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7853525 TI - Human immunodeficiency virus type 1 Nef protein inhibits activation pathways in peripheral blood mononuclear cells and T-cell lines. AB - Human immunodeficiency virus type 1 (HIV-1) Nef protein causes the loss of cell surface CD4 and interleukin-2 (IL-2) receptor (Tac) from peripheral blood mononuclear cells (PBMC) and CD4+ T-cell lines. As both CD4 and the IL-2 receptor play crucial roles in antigen-driven helper T-cell signalling and T-cell proliferation, respectively, the role of Nef in the viral life cycle may be to perturb signalling pathways emanating from these receptors. However, the intracellular targets for Nef that result in receptor down-regulation are unknown. Using a recombinant glutathione S-transferase-full-length 27 kDa Nef (Nef27) fusion protein, produced in Escherichia coli by translation from the first start codon of HIV-1 nef clone pNL4-3, as an affinity reagent to probe cytoplasmic extracts of MT-2 cells and PBMC, we have shown interaction with at least seven host cell protein species ranging from 24 to 75 kDa. Immunoblotting identified four of these proteins as p56lck, CD4, p53, and p44mapk/erk1, all of which are intimately involved in intracellular signalling. To assess the relevance of these interactions and further define the biochemical activity of Nef in signal transduction pathways, highly purified Nef27 protein was introduced directly into PBMC by electroporation. Nef27-treated PBMC showed reduced proliferative responsiveness to exogenous recombinant IL-2. Normally, stimulation of T-cells by IL-2 or phorbol 12-myristate 13-acetate provokes both augmentation of p56lck activity and corresponding posttranslational modification of p56lck. These changes were also inhibited by treatment of PBMC with Nef, suggesting that Nef interferes with activation of p56lck and as a consequence of signalling via the IL-2 receptor. Further evidence for Nef interfering with cell proliferation was the decreased production of the proto-oncogene c-myb, which is required for cell cycle progression, in Nef-treated MT-2 cells. In contrast to the binding characteristics and biological effects of Nef27, the alternate 25-kDa isoform of Nef (Nef25) produced by translation from the second start codon of HIV nef pNL4-3 (57 nucleotide residues downstream) was shown to interact with only three cellular proteins of approximately 26, 28, and 56 kDa from PBMC and MT-2 cells, one of which was identified as p56lck. Also, proliferation and posttranslational modification of p56lck in response to IL-2 stimulation were not profoundly affected by treatment of PBMC with Nef25 compared with Nef27.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7853526 TI - Direct interaction of the hepatitis B virus HBx protein with p53 leads to inhibition by HBx of p53 response element-directed transactivation. AB - Hepatitis B virus is a major risk factor in human hepatocellular carcinomas. We have used protein affinity chromatography to show that the 17-kDa hepatitis B virus gene product, HBx, binds directly to the human tumor suppressor gene product, p53. Interaction of HBx with p53 did not prevent p53 from specifically binding DNA. Instead, HBx enhanced p53's oligomerization state on a DNA oligonucleotide containing a p53 response element. Optimal binding of HBx to p53 required intact p53, but weaker binding to both the N-terminal activation domain of p53 and a protein fragment containing the C-terminal DNA-binding and oligomerization domains of p53 was observed. In transient transfection experiments with human Calu-6 cells, HBx inhibited transactivation by p53 of a reporter gene containing a p53 response element. Also, HBx inhibited p53 stimulated transcription in vitro even when added to the reaction mixture after the formation of the preinitiation complex. Interaction of HBx with p53 did not prevent the activation domain of p53 from binding two general initiation factors, the TATA-box binding protein subunit of TFIID and the p62 subunit of TFIIH. To explain these results, we propose that localization of HBx to a promoter by interaction with DNA-bound p53 enables a repression domain in HBx to directly contact the basal transcription machinery and thereby repress transcription. PMID- 7853527 TI - Spontaneous reversion of human immunodeficiency virus type 1 neutralization resistant variant HXB2thr582: in vitro selection against cytopathicity highlights gp120-gp41 interactive regions. AB - Spontaneous revertants of the immune-selected variant HXB2thr582, which resists neutralization by certain conformationally dependent antibodies specific for the CD4-binding site on gp120 (such as F105), appeared after long-term culture in the absence of immune-selecting serum. Molecular analysis showed some of the viruses in the revertant stock contained a simple back mutation, whereas others retained the Thr-582 codon but contained a substitution of serine for phenylalanine in gp41 at position 673. Neutralization sensitivity to the selecting serum and to F105 of infectious clones containing either the back mutation or the compensatory mutation, HXB2thr582ser673, was confirmed. HXB2thr582-infected cells have a greater propensity for syncytium formation and single cell killing than do either the parental HXB2 or the revertant HXB2thr582ser673. This suggests that the revertant arose by selection in vitro for a less cytopathic virus. Our results link three envelope regions shown to influence virus-cell fusion as well as neutralization by antibody: the CD4-binding region, the leucine zipper domain, and a region hidden to antipeptide antibodies upon envelope oligomerization. Taken together they illustrate the functional importance of the gp120-gp41 interaction and emphasize the impact of the interplay between envelope regions on overall conformation and function and on recognition by neutralizing antibodies. PMID- 7853528 TI - Human immunodeficiency virus type 1 cellular RNA load and splicing patterns predict disease progression in a longitudinally studied cohort. AB - We report the results of a longitudinal study of RNA splicing patterns in 31 early-stage human immunodeficiency virus disease patients with an average follow up time of 3 years. Eighteen patients showed no evidence for disease progression, whereas 13 patients either showed a > or = 50% reduction in baseline CD4 count or developed opportunistic infections. Levels of unspliced, tat, rev, and nef mRNAs in peripheral blood mononuclear cells were measured by a reverse transcriptase quantitative, competitive PCR assay. Viral RNA was detected in all patients at all time points. All 13 rapid progressors had viral RNA loads that were > or = 1 log unit greater than those of the slow progressors. In addition, seven of the rapid progressors showed a reduction of more than threefold in the ratio of spliced to unspliced RNA over the 3 years of follow-up. Conversely, two slow progressors with intermediate levels of viral RNA showed no splicing shift. These results confirm earlier observations that viral RNA is uniformly expressed in early-stage patients. We further show that cellular RNA viral load is predictive of disease progression. Importantly, the shift from a predominately spliced or regulatory viral mRNA pattern to a predominately unspliced pattern both is associated with disease progression and adds predictive utility to measurement of either RNA class alone. PMID- 7853529 TI - Cellular proteins bind to the downstream component of the lytic origin of DNA replication of Epstein-Barr virus. AB - The lytic origin of DNA replication of Epstein-Barr virus, oriLyt, is a complex eukaryotic origin which is activated during the lytic phase of the viral life cycle. It consists of at least two independent cis-acting components, one of which plays a dual role in transcription and DNA replication. The binding of the viral factor BZLF1, a member of the AP1 family of transcription factors, to this upstream component is crucial for oriLyt function (A. Schepers, D. Pich, and W. Hammerschmidt, EMBO J. 12:3921-3929, 1993). The second cis-acting element, the downstream component of oriLyt, is equally indispensable; however, its function is unknown. In this study, the downstream component was found to be the binding target of several cellular proteins. One could be identified as Sp1 or as a related protein which binds twice to the downstream component of oriLyt. Mutational analysis indicated that Sp1 alone is not directly involved in mediating DNA replication; however, other factors which share the same binding sequence or bind closely to one of the Sp1 binding sites are likely candidates to contribute to a replication protein complex at the downstream component of oriLyt. The sequence requirements for the downstream component are remarkably stringent, indicating that at least one of the putative factors is a sequence specific DNA-binding protein which is required for the activation of oriLyt. PMID- 7853530 TI - Infection by retroviral vectors outside of their host range in the presence of replication-defective adenovirus. AB - Retrovirus infection is normally limited to cells within a specific host range which express a cognate receptor that is recognized by the product of the env gene. We describe retrovirus infection of cells outside of their normal host range when the infection is performed in the presence of a replication-defective adenovirus (dl312). In the presence of adenovirus, several different ecotropic vectors are shown to infect human cell lines (HeLa and PLC/PRF), and a xenotropic vector is shown to infect murine cells (NIH 3T3). Infectivity is demonstrated by 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside (X-Gal) staining, selection with G418 for neomycin resistance, and PCR identification of the provirus in infected cells. Infectivity is quantitatively dependent upon both the concentration of adenovirus (10(6) to 10(8) PFU/ml) and the concentration of retrovirus. Infection requires the simultaneous presence of adenovirus in the retrovirus infection medium and is not stimulated by preincubation and removal of adenovirus from the cells before retrovirus infection. The presence of adenovirus is shown to enhance the uptake of fluorescently labeled retrovirus particles into cells outside of their normal host range, demonstrating that the adenovirus enhances viral entry into cells in the absence of the recognized cognate receptor. This observation suggests new opportunities for developing safe retroviral vectors for gene therapy and new mechanisms for the pathogenesis of retroviral disease. PMID- 7853531 TI - Bone marrow is a major site of long-term antibody production after acute viral infection. AB - Antiviral antibody production is often sustained for long periods after resolution of an acute viral infection. Despite extensive documentation of this phenomenon, the mechanisms involved in maintaining long-term antibody production remain poorly defined. As a first step towards understanding the nature of long term humoral immunity, we examined the anatomical location of antibody-producing cells during acute viral infection. Using the lymphocytic choriomeningitis virus (LCMV) model, we found that after resolution of the acute infection, when antiviral plasma cells in the spleen decline, a population of virus-specific plasma cells appears in the bone marrow and constitutes the major source of long term antibody production. Following infection of adult mice, LCMV-specific antibody-secreting cells (ASC) peaked in the spleen at 8 days postinfection but were undetectable in the bone marrow at that time. The infection was essentially cleared by 15 days, and the ASC numbers in the spleen rapidly declined while an increasing population of LCMV-specific ASC began to appear in the bone marrow. Compared with the peak response at 8 days postinfection, time points from 30 days to more than 1 year later demonstrated greater-than-10-fold reductions in splenic ASC. In contrast, LCMV-specific plasma cell numbers in the bone marrow remained high and correlated with the high levels of antiviral serum antibody. The presence of LCMV-specific plasma cells in the bone marrow was not due to persistent infection at this site, since the virus was cleared from both the spleen and bone marrow with similar kinetics as determined by infectivity and PCR assays. The immunoglobulin G subclass profile of antibody-secreting cells derived from bone marrow and the spleen correlated with the immunoglobulin G subclass distribution of LCMV-specific antibody in the serum. Upon rechallenge with LCMV, the spleen exhibited a substantial increase in virus-specific plasma cell numbers during the early phase of the secondary response, followed by an equally sharp decline. Bone marrow ASC populations and LCMV-specific antibody levels in the serum did not change during the early phase of the reinfection, but both increased about two-fold by 15 days postchallenge. After both primary and secondary viral infections, LCMV-specific plasma cells were maintained in the bone marrow, showing that the bone marrow is a major site of long-term antibody production after acute viral infection. These results documenting long-term persistence of plasma cells in the bone marrow suggest a reexamination of our current notions regarding the half-life of plasma cells. PMID- 7853532 TI - Virions released from cells transfected with a molecular clone of human T-cell leukemia virus type I give rise to primary and secondary infections of T cells. AB - The ability of molecular clones of human T-cell leukemia virus type I (HTLV-I) to direct the synthesis of infectious virions has not previously been demonstrated. An HTLV-I provirus originating from an adult T-cell leukemia patient was cloned into a plasmid vector and is designated pCS-HTLV. This molecular clone was shown to direct the synthesis of viral mRNA and proteins in transiently transfected cells; in addition, virus structural proteins were released into the culture medium. Viral proteins were assembled into virions that sedimented at a buoyant density characteristic of retrovirus particles and whose morphology was verified by electron microscopy. Virions concentrated from transiently transfected cell supernatants were incubated with primary cord blood lymphocytes or with transformed T-cell lines to establish that these particles were infectious. Expression of spliced, viral mRNAs in the T-cell cultures after both primary and secondary infections with cell-free virus revealed that pCS-HTLV encodes an infectious provirus. PMID- 7853533 TI - Localization of monoclonal antibody epitopes and functional domains in the hemagglutinin protein of measles virus. AB - The expression of chimeric proteins was performed for the localization of monoclonal antibody (MAb) epitopes and functional domains in the hemagglutinin (H) protein of measles virus. The fusion helper function of the H protein was ablated by a single amino acid substitution at residue 98. Loss of reactivity to MAb 79-XV-V17 and to MAbs 16-CD-11 and 80-II-B2 was attributed to substitutions between residues 211 and 291 and between 451 and 505, respectively. The 80-II-B2 MAb epitope also seemed to be within a domain required for hemadsorption and hemagglutination activities. PMID- 7853534 TI - Packaging in a yeast double-stranded RNA virus. AB - The yeast virus ScV-L1 has only two genes, cap and pol, which encode the capsid polypeptide and the viral polymerase, respectively. The second gene is translated only as a cap-pol fusion protein. This fusion protein is responsible for recognition of a specific small stem and loop region of the viral plus strands, of 19 to 31 bases in length, ensuring packaging specificity. We have used a related virus, ScV-La, which has about 29% codon identity with ScV-L1 in the most conserved region of the pol gene, to map the region in pol that is responsible for packaging L1. Characterization of a number of chimeric viral proteins that recognize L1 but have the La capsid region delimits the region necessary for recognition of L1 to a 76- to 82-codon portion of pol. In addition, we show that overproduction of the La capsid polypeptide results in curing of the ScV-La virus, analogous to the production of plants resistant to RNA viruses by virtue of systemic production of viral coat protein. PMID- 7853535 TI - Genetically simpler bovine leukemia virus derivatives can replicate independently of Tax and Rex. AB - Retrovirus genomes have a conserved modular organization that consists of trans acting gag, pol, and env genes that function through cis-acting sequences to replicate the RNA genome to the DNA provirus. Genetically more complex retroviruses also encode regulatory genes and cis-acting sequences that are essential for their replication. We sought to convert a more complex retrovirus into a simpler retrovirus derivative that can replicate. We constructed novel, hybrid retrovirus vectors to replicate the gag, pol, and env genes of the more complex bovine leukemia virus (BLV) in the absence of regulatory genes and cis acting response sequences. Most of the cis-acting sequences involved in the replication and regulation of BLV were replaced by the cis-acting transcriptional control sequences of a simpler retrovirus, spleen necrosis virus. We found that the resulting hybrid BLV derivatives can replicate independently of BLV Tax and Rex and the Tax and Rex cis-acting response sequences, as measured by successive passages of virus on target cells, detection of provirus sequences, and analyses of provirus and encapsidated RNAs. PMID- 7853536 TI - Expression of human cytomegalovirus UL36 and UL37 genes is required for viral DNA replication. AB - It was previously reported that the region encoding human cytomegalovirus (HCMV) genes UL36 to UL38 was required for origin-dependent DNA replication. These genes encode transactivators that upregulate viral and cellular transcription. However, their requirement for viral DNA replication has not been demonstrated. We have now used an antisense phosphorothioate oligonucleotide complementary to the intron-exon boundary of the UL36 and UL37 unspliced RNA to show that these gene products are required for HCMV DNA replication. Southern analysis showed that this oligonucleotide almost completely inhibits HCMV DNA replication when used at concentrations as low as 0.08 microM. The ability of this oligonucleotide to inhibit DNA replication was not the result of an inhibition of virus adsorption. Southern blots showed no impairment of viral adsorption or internalization in the presence of either specific or nonspecific phosphorothioate oligonucleotides. In addition, Northern (RNA) blots confirm that this antisense compound specifically reduced UL36 mRNA in treated cells to undetectable levels while the steady-state levels of immediate-early transcripts IE1 and IE2 were unaffected. These results demonstrate that the UL36 and UL37 gene products provide an essential function in initiation of HCMV DNA replication. PMID- 7853537 TI - Int-6, a highly conserved, widely expressed gene, is mutated by mouse mammary tumor virus in mammary preneoplasia. AB - With a unique mouse mammary tumor model system in which mouse mammary tumor virus (MMTV) insertional mutations can be detected during progression from preneoplasia to frank malignancy, including metastasis, we have discovered a new common integration site (designated Int-6) for MMTV in mouse mammary tumors. MMTV was integrated into Int-6 in a mammary hyperplastic outgrowth line, its tumors and metastases, and two independent mammary tumors arising in unrelated mice. The Int 6 gene is ubiquitously expressed as a 1.4-kb RNA species in adult tissues and is detected beginning at day 8 of embryonic development. The nucleotide sequence of Int-6 is unrelated to any of the known genes in the GenBank database. MMTV integrates within introns of the gene in the opposite transcriptional orientation. In each tumor tested, this results in the expression of a truncated Int-6/long terminal repeat (LTR) chimeric RNA species which is terminated at a cryptic termination signal in the MMTV LTR. Since the nonrearranged Int-6 alleles in these tumors contain no mutations, we favor the conclusion that truncation of the Int-6 gene product either biologically activates its function or represents a dominant-negative mutation. PMID- 7853538 TI - Antibody responses to Four Corners hantavirus infections in the deer mouse (Peromyscus maniculatus): identification of an immunodominant region of the viral nucleocapsid protein. AB - Antibody responses to Four Corners hantavirus (FCV) infections in the deer mouse (Peromyscus maniculatus) were characterized by using FCV nucleocapsid protein (N), glycoprotein 1 (G1), and glycoprotein 2 (G2) recombinant polypeptides in Western immunoblot assays. Strong immunoglobulin G reactivities to FCV N were observed among FCV-infected wild P. maniculatus mice (n = 34) and in laboratory infected P. maniculatus mice (n = 11). No immunoglobulin G antibody reactivities to FCV G1 or G2 linear determinants were detected. The strongest N responses were mapped to an amino-proximal segment between amino acids 17 and 59 (QLVTARQKLKDAERAVELDPDDVNKSTLQSRRAAVSALETKLG). FCV N antibodies cross-reacted with recombinant N proteins encoded by Puumala, Seoul, and Hantaan viruses. PMID- 7853539 TI - Contribution of conserved amino acids in mediating the interaction between EBNA2 and CBF1/RBPJk. AB - The Epstein-Barr virus EBNA2 protein is a transcriptional activator that achieves promoter specificity through interaction with the cellular DNA-binding protein CBF1/RBPJk. Within the amino acid 252-to-425 EBNA2 domain that targets CBF1/RBPJk lie three amino acid clusters, conserved regions (CR) 5, 6, and 7, that are retained in the Epstein-Barr virus type A and type B and herpesvirus papio proteins. To further define the important features of the targeting domain, we constructed EBNA2 polypeptides containing deletions in the targeting domain and double or triple point mutations in the conserved motifs. The ability of these polypeptides and the type B and herpesvirus papio domains to interact with CBF1/RBPJk was examined by performing electrophoretic mobility shift assays and correlated with the effect of the mutations on EBNA2 transactivation. Both human type B EBNA2 and herpesvirus papio EBNA2 bound CBF1/RBPJk efficiently. Mutation of hydrophobic residues in CR6 severely impaired CBF1/RBPJk interaction and transactivation, while mutation of CR5 led to a moderate decrease in both activities. Mutation of CR7 had only a minor effect. Synthetic peptides corresponding to each of the conserved motifs were also used as competitors in an electrophoretic mobility shift assay. Only the peptide representing CR6 (amino acids 318 to 327), and not a version of this peptide mutated at the tryptophan residues at positions 323 and 324 (WW323,324), could compete for EBNA2 complex formation with CBF1/RBPJk. Overall, the data indicated that CR5 contributes to an optimal interaction, perhaps through stabilizing contacts, while CR6 forms a crucial interface with CBF1/RBPJk. The peptide competition data are consistent with direct contacts between WW323,324 and CBF1/RBPJk. PMID- 7853540 TI - Capped nonviral sequences at the 5' end of the mRNAs of rice hoja blanca virus RNA4. AB - Subgenomic RNAs of both polarities corresponding to rice hoja blanca virus (RHBV) ambisense RNA4 were detected in RHBV-infected rice tissues. Total RNA extracted from RHBV-infected and noninfected rice tissues and RNA4 purified from RHBV ribonucleoprotein particles were used as templates for primer extension studies. The RNAs extracted from RHBV-infected tissues contain a population of RNA molecules with 10 to 17 nonviral nucleotides at their 5' end. The RNA-cDNA hybrids resulting from primer extension of such RNA molecules were specifically immunoselected with anti-cap antibodies, indicating that the subgenomic RNAs are capped and probably serve as mRNAs and that the additional nucleotides at their 5' end possibly derive from host mRNAs via a cap-snatching mechanism. PMID- 7853541 TI - Interleukin-12 gene expression after viral infection in the mouse. AB - Interleukin-12 is a lymphokine that triggers gamma interferon secretion by various cells and differentiation of T-helper lymphocytes towards the Th1 subtype. Since viruses are potent inducers of gamma interferon production and elicit immune responses most probably mediated by Th1 cells, like B-cell immunoglobulin G2a secretion, we analyzed interleukin-12 message expression after infection of mice with lactate dehydrogenase-elevating virus, mouse hepatitis virus, and mouse adenovirus. Our results indicated that the message for the p40 component of interleukin-12 was transiently increased shortly after infection. Interleukin-12 was expressed mainly by macrophages. Therefore, production of interleukin-12 might constitute the initial event that would determine the subsequent characteristics of the immune response elicited by viral infections. PMID- 7853542 TI - Characterization of a live, attenuated human parainfluenza type 3 virus candidate vaccine strain. AB - Characterization of a temperature-sensitive and live, attenuated human parainfluenza type 3 virus strain (cp45) grown at a permissive temperature (32 degrees C) suggested that the virus efficiently multiplies in cell lines and retains antigenic and functional properties of the envelope glycoproteins. When grown at a nonpermissive temperature (39.5 degrees C), the cp45 virus exhibited poor replication; however, shifting to a permissive temperature allowed virus growth. Although at a nonpermissive temperature virus polypeptide synthesis was significantly reduced, the hemagglutinin-neuraminidase and fusion glycoproteins were transported to cell surfaces and retained their characteristic biologic activities. Studies on mRNA synthesis from the P protein gene suggested a poor transcriptional activity of the cp45 virus at a nonpermissive temperature. Results from this study indicate that the temperature sensitivity of cp45 virus is related to altered transcriptional activity and a marked reduction in virus polypeptide synthesis. PMID- 7853543 TI - Nucleus-targeting domain of the matrix protein (M1) of influenza virus. AB - The matrix protein M1 of influenza virus A/WSN/33 was shown by immunofluorescent staining to be transported into the nuclei of transfected cells without requiring other viral proteins. We postulated the existence of a potential signal sequence at amino acids 101 to 105 (RKLKR) that is required for nuclear localization of the M1 protein. When CV1 cells were transfected with recombinant vectors expressing the entire M1 protein (amino acids 1 to 252) or just the first 112 N terminal amino acids, both the complete M1 protein and the truncated M1 protein were transported to the nucleus. In contrast, expression in CV1 cells of vectors coding for M1 proteins with deletions from amino acids 77 to 202 or amino acids 1 to 134 resulted only in cytoplasmic immunofluorescent staining of these truncated M1 proteins without protein being transported to the nucleus. Moreover, no nuclear membrane translocation occurred when CV1 cells were transfected with recombinant vectors expressing M1 proteins with deletions of amino acids 101 to 105 or with substitution at amino acids 101 to 105 of SNLNS for RKLKR. Furthermore, a synthetic oligopeptide corresponding to M1 protein amino acids 90 to 108 was also transported into isolated nuclei derived from CV1 cells, whereas oligopeptides corresponding to amino acid sequences 25 to 40, 67 to 81, and 135 to 164 were not transported into the isolated cell nuclei. These data suggest that the amino acid sequence 101RKLKR105 is the nuclear localization signal of the M1 protein. PMID- 7853544 TI - Constitutive and inducible kappa B binding activities in the cytosol of v-Rel transformed lymphoid cells. AB - Constitutive and inducible kapp B binding activities associated with v-Rel and c Rel in the cytosol of v-Rel-transformed cells have been identified. These activities were resolved by electrophoretic mobility shift assay and chromatographic techniques into a high-molecular-weight protein-DNA complex designated complex I containing v- and c-Rel and lower-molecular-weight complexes II, III and IV which contained only v-Rel and which were stimulated by nucleotides, low pH, and detergent. These experiments suggest that interaction of v-Rel and c-Rel decreases the DNA-binding activity of each. PMID- 7853545 TI - A newly recognized virus associated with a fatal case of hantavirus pulmonary syndrome in Louisiana. AB - Genetic analysis of virus detected in autopsy tissues of a fatal hantavirus pulmonary syndrome-like case in Louisiana revealed the presence of a previously unrecognized hantavirus. Nucleotide sequence analysis of PCR fragments of the complete S and M segments of the virus amplified from RNA extracted from the tissues showed the virus to be novel, differing from the closest related hantavirus, Sin Nombre virus, by approximately 30%. Both genome segments were unique, and there was no evidence of genetic reassortment with previously characterized hantaviruses. The primary rodent reservoir of Sin Nombre virus, the deer mouse Peromyscus maniculatus, is absent from Louisiana. Thus, the virus detected in Louisiana, referred to here as Bayou virus, must possess a different rodent reservoir. PMID- 7853546 TI - Virion incorporation of envelope glycoproteins with long but not short cytoplasmic tails is blocked by specific, single amino acid substitutions in the human immunodeficiency virus type 1 matrix. AB - Incorporation of envelope glycoproteins into a budding retrovirus is an essential step in the formation of an infectious virus particle. By using site-directed mutagenesis, we identified specific amino acid residues in the matrix domain of the human immunodeficiency virus type 1 (HIV-1) Gag protein that are critical to the incorporation of HIV-1 envelope glycoproteins into virus particles. Pseudotyping analyses were used to demonstrate that two heterologous envelope glycoproteins with short cytoplasmic tails (the envelope of the amphotropic murine leukemia virus and a naturally truncated HIV-2 envelope) are efficiently incorporated into HIV-1 particles bearing the matrix mutations. Furthermore, deletion of the cytoplasmic tail of HIV-1 transmembrane envelope glycoprotein gp41 from 150 to 7 or 47 residues reversed the incorporation block imposed by the matrix mutations. These results suggest the existence of a specific functional interaction between the HIV-1 matrix and the gp41 cytoplasmic tail. PMID- 7853548 TI - Indications for ultrasound guided transition zone biopsies in the detection of prostate cancer. AB - Transrectal prostate ultrasound and systematic sextant biopsies have improved peripheral zone cancer diagnosis but they may miss many cancers arising in the transition zone. Biopsies directed into the transition zone have been used to detect residual prostate cancer in patients diagnosed by transurethral resection and they have been suggested as potentially useful additions to systematic sextant biopsies. To define the indications for transition zone biopsies 187 men underwent evaluation including systematic sextant biopsies and transition zone biopsies. These patients were classified into 4 categories based on clinical presentation. Category 1 included 26 men with palpable nodularity and an elevated prostate specific antigen (PSA), of whom 16 (61.5%) had positive biopsies but none was positive only in the transition zone biopsies. Category 2 consisted of 49 men with sonographic abnormalities in the transition zone, of whom 15 (30.6%) had positive biopsies, including 2 (13.3%) with only positive transition zone biopsies. Category 3 consisted of 65 men with normal rectal examination and elevated PSA level, of whom 24 (36.9%) had biopsies positive for cancer, including 8 (33.3%) with only positive transition zone biopsies. Category 4 consisted of 47 men with a clinical presentation highly suspicious of prostatic malignancy but no cancer on prior systematic sextant biopsies, of whom 17 (37.7%) had positive biopsies, including 9 (53.0%) with only positive transition zone biopsies. We conclude that transition zone biopsies are useful in patients with a high suspicion of prostate cancer and negative prior systematic sextant biopsies. Cancer can also be demonstrated in many men with a normal digital rectal examination and an elevated PSA level. Patients with transition zone abnormalities on ultrasound images or palpable nodularity do not have substantially increased cancer detection with the addition of transition zone biopsies. PMID- 7853547 TI - Roles of immunoglobulin valency and the heavy-chain constant domain in antibody mediated downregulation of Sindbis virus replication in persistently infected neurons. AB - Clearance of infectious Sindbis virus from neurons is mediated by antibody to the E2 glycoprotein. Properties of the antibody important for downregulation of Sindbis virus replication are unknown. Immunoglobulin isotypes and valency determine many biological properties of antibodies. An immunoglobulin G1 (IgG1) isotype switch mutant and F(ab')2 and Fab fragments of IgG3 monoclonal antibody 209 were prepared and tested for clearance of infectious virus from persistently infected rat dorsal root ganglion neurons in vitro. IgG1, IgG3, and IgG3-derived F(ab')2 fragments were similarly efficacious, while IgG3-derived Fab fragments had no effect on virus replication. Cross-linking of Fab with secondary antibodies restored antiviral activity. Therefore, we found no evidence that IgG subclass plays a role in control of intracellular Sindbis virus replication. However, bivalency appears to be crucial for the ability of E2-specific IgG molecules to mediate clearance of infectious virus from neuron cells, suggesting that cross-linking of E2 molecules is essential. PMID- 7853549 TI - Deoxyribonucleic acid ploidy analysis as a predictor of recurrence following radical prostatectomy for stage T2 disease. AB - Deoxyribonucleic acid (DNA) ploidy image analysis was used postoperatively to predict recurrence of 112 clinically localized adenocarcinomas of the prostate. All men underwent radical retropubic prostatectomy between 1978 and 1991. Patients with positive lymph nodes or positive seminal vesicles were excluded because progression is nearly inevitable in these men. The minimum followup for men without progression was 5 years (range 5 to 15). Patients were considered to have clinically evident disease progression based on local recurrence (8%), distant metastases (4%) and/or an isolated elevation of serum prostate specific antigen (87%). Of the tumors 43% were diploid and 57% were nondiploid. In a multivariate analysis comparing grade, ploidy, capsular penetration and surgical margins, Gleason sum was the best predictor of progression (p < 0.0001). Nevertheless, a subset of patients remained with well to moderately differentiated Gleason grade tumors (Gleason sum 6 or less) who failed. DNA ploidy was able to predict recurrence in this particular group (p = 0.034). In addition, we compared different methods of tissue preparation to determine which best predicted progression. We found that ploidy analysis on tissue sections was more predictive than ploidy performed on disaggregated tissue. In summary, our study revealed that DNA ploidy analysis can offer additional prognostic information following radical prostatectomy for men with low grade prostatic adenocarcinoma. PMID- 7853550 TI - Experience with radical prostatectomy and radiation therapy for localized prostate cancer at a Veterans Affairs Medical Center. AB - We assessed the actuarial survival of 357 patients with localized prostate cancer who were treated with radical prostatectomy or radiation therapy at a Veterans Affairs Medical Center between 1980 and 1991 and who were followed for a median of 59 months. During this period patients with clinical stages A2 and B tumors who had an anticipated life expectancy of 10 years or greater were generally treated with surgery. Patients with stages A2 and B tumors who were not candidates for surgery and those with stage C tumors were generally treated with radiation therapy. There were no significant differences among the cause specific, clinical disease-free and prostate specific antigen disease-free survival curves of patients with stages A2 and B tumors who were treated with radical prostatectomy (138) or radiation therapy (138) but the all cause and metastases-free survival curves favored the surgery group (p < 0.000001 and 0.046, respectively). There was no significant difference between the all cause survival curves of the patients with stages A2 and B tumors and of 81 patients with stage C tumors who were treated with radiation therapy. However, the cause specific survival curves favored the patients with stages A2 and B tumors (p = 0.000007). This study demonstrates that there is a high risk of death from co morbidities in a hospital based population of American veterans with localized prostate cancer who are not candidates for radical prostatectomy. PMID- 7853551 TI - Prostate cancer: some issues of treatment and tumor behavior. PMID- 7853552 TI - Urodynamics and the etiology of post-prostatectomy urinary incontinence: the initial Columbia experience. AB - Post-prostatectomy incontinence is a disabling disorder. Urodynamic studies in 56 patients with post-prostatectomy incontinence were reviewed to determine its etiology. Of the patients 31 had undergone transurethral prostatectomy and 25 radical retropubic prostatectomy. After careful history and neurourological examination, uroflowmetry, post-void residual determination and synchronous multichannel video pressure/flow studies were done. The most common etiology for incontinence was detrusor instability alone, which was present in 34 patients (61%), including 24 (77%) after transurethral resection of the prostate and 10 (40%) after radical retropubic prostatectomy. Stress incontinence alone was present in only 3 patients (5%), including 1 (3%) after transurethral resection of the prostate and 2 (8%) after radical retropubic prostatectomy. Detrusor instability with stress incontinence was present in 19 patients (34%), including 6 (19%) after transurethral resection of the prostate and 13 (52%) after radical retropubic prostatectomy. Of these 19 patients 4 (21%) had poorly compliant bladders. This study demonstrates that stress incontinence alone is a relatively rare cause of post-prostatectomy incontinence, with detrusor instability present in more than 90% of the patients. Accurate diagnosis of post-prostatectomy incontinence etiology could ensure proper treatment for this disorder. PMID- 7853553 TI - Post-prostatectomy incontinence: the importance of bladder dysfunction. PMID- 7853554 TI - Aromatase activity in an estrogen-producing adrenocortical carcinoma in a young man. AB - We report on a 19-year-old man with adrenocortical adenoma producing an excessive amount of estrogen. Determination of aromatase activity of the carcinoma tissue revealed its marked enhancement compared with that of 3 normal adrenal glands and the adipose tissue. The enhanced activity of aromatase was mainly responsible for the overproduction of estrogen in the adrenocortical carcinoma of our case. PMID- 7853555 TI - Nephrostomy tract tumor seeding following percutaneous manipulation of a ureteral carcinoma. AB - We report a case of nephrostomy tract tumor seeding following percutaneous nephrostomy tube placement and endoscopic manipulation of ureteral carcinoma. While never previously reported to our knowledge, tumor seeding is a potential risk of percutaneous endoscopic management of upper tract urothelial carcinomas. PMID- 7853557 TI - Implantation metastasis after laparoscopic biopsy of bladder cancer. AB - We report a case of tumor implantation in the abdominal wall following laparoscopic biopsy of a transitional cell tumor. Tumor seeding is a known risk in patients with transitional cell carcinoma and we recommend that laparoscopic biopsy of urothelial tumors be avoided. PMID- 7853556 TI - Functional replacement of bladder and urethra after cystectomy for bladder cancer in a female patient. AB - We describe a new concept for female bladder replacement introducing an ileocecal pouch with the intact appendix vermiformis used as an orthotopic neourethra. Based upon the results of preceding experimental studies this procedure was performed on a woman with the diagnosis of focal invasive bladder cancer. Eight months after the operation the patient is completely continent and back to work. This new type of urinary diversion with improved body image can be offered to female patients undergoing cystectomy for bladder cancer. PMID- 7853558 TI - Ossified cystic metastasis of bladder tumor to abdominal wound after partial cystectomy. PMID- 7853559 TI - Primary penile lymphoma presenting as a penile ulcer. AB - Primary penile lymphoma is rare. The clinical manifestations can be quite subtle, which may lead to misdiagnosis. Treatments have included radical surgery, chemotherapy and radiation. We report on an 18-year-old man with primary penile lymphoma whose lesion caused prolonged diagnostic uncertainty. He was treated with chemotherapy alone, and he has had no tumor recurrence for 27 months. PMID- 7853560 TI - Malignant mesothelioma of the tunica vaginalis. AB - Malignant mesothelioma is a rare, often aggressive tumor of the tunica vaginalis. We report 2 cases and review the literature concerning current management strategies. It appears that, although adjuvant chemotherapy and radiotherapy have little value, local and nodal recurrence may be successfully treated by local excision. PMID- 7853561 TI - Angiosarcoma following treatment of testicular seminoma: case report and literature review. AB - We report a case of paravertebral angiosarcoma 10 years after treatment for testicular seminoma. The patient underwent irradiation treatment to areas including the mediastinum. Tumor induction by therapeutic irradiation remains the most likely etiology. Other possibilities include a natural association between seminoma and angiosarcoma, and perhaps the use of chemotherapy. PMID- 7853562 TI - Late seminomatous relapse of a mixed germ cell tumor of the testis on intensive surveillance. AB - We report a case of a pure seminomatous relapse in the retroperitoneum 6 years after orchiectomy for an apparent stage I mixed germ cell tumor of the testis. The 4 cm. metastatic mass was not imaged on computerized tomography, tumor markers were negative and confounding symptoms made diagnosis difficult. The propensity for seminomatous tumors to relapse later than nonseminomatous tumors has profound implications for intensive surveillance programs for apparent stage I disease in mixed germ cell tumors. These programs often involve routine computerized tomography only for the first 2 years and rely on physical examination, simple radiology and serum tumor markers thereafter. Such programs may fail to detect pure seminomatous relapse and delay the onset of curative treatment. PMID- 7853563 TI - Recurrence of a nonseminomatous germ cell tumor 9 years postoperatively: is surveillance alone acceptable? AB - We report on a patient who underwent left radical orchiectomy for a nonseminomatous germ cell tumor and was placed into a surveillance program only to experience recurrence 9 years later. The deficiencies with surveillance protocols, including inadequate followup, imaging study difficulties, possible higher mortality with relapse of carcinoma during the surveillance period, and increased cost and labor for longer surveillance protocols are discussed. Methods of distinguishing patients at low and high risk of relapse are still evolving and further studies are required. PMID- 7853564 TI - Leiomyoma of the epididymis. PMID- 7853565 TI - Primary yolk sac tumor of the prostate in a patient with Klinefelter's syndrome. AB - Primary yolk sac (endodermal sinus) tumor of the prostate is extremely rare with only 2 cases reported in the literature. We describe a case of primary yolk sac tumor of the prostate in a man with Klinefelter's syndrome. Treatment included 4 courses of combination chemotherapy followed by retroperitoneal lymph node dissection, cystoprostatectomy and ileal conduit urinary diversion. We review the association of Klinefelter's syndrome with extragonadal germ cell tumor along with the management of this rare disease. PMID- 7853566 TI - Needle tract seeding after percutaneous biopsy of Wilms tumor. AB - We report a case of tumor implantation along the needle tract after percutaneous biopsy of Wilms tumor. This is a rare but important complication in the management of Wilms tumor. PMID- 7853567 TI - Bilateral testis tumors in an infant: synchronous teratoma and epidermoid cyst. AB - Teratoma ranks second in frequency to yolk sac carcinoma among testicular germ cell tumors in infants, accounting for 25% of cases. Testicular teratomas are uniformly benign in children younger than 24 months old. Epidermoid cysts are tumor-like lesions of unknown etiology, probably monodermal teratomas, comprising 3% of all pediatric testis tumors. Bilaterality is rare for both tumors. We report a case of a synchronous left testis teratoma and a right testis epidermoid cyst. Appropriate therapy is discussed. PMID- 7853568 TI - Primary carcinoid of the prostate in conjunction with multiple endocrine neoplasia IIb in a child. AB - Prostatic neoplasms are rare in childhood. We report a case of primary prostatic carcinoid in a 7-year-old boy who was subsequently diagnosed with multiple endocrine neoplasia IIb. To our knowledge this is the first report of either pediatric carcinoid of the prostate or of prostatic carcinoid in conjunction with neuronal intestinal dysplasia and medullary thyroid carcinoma suggestive of multiple endocrine neoplasia IIb. Management and histogenesis regarding this prostatic tumor are discussed as is a possible association with other neuroendocrine tumors. PMID- 7853569 TI - Advanced bladder cancer: the need to identify new agents in the post-M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) world. PMID- 7853570 TI - Renal cell carcinoma: tumor size, stage and survival. Members of the Cancer Incidence and End Results Committee. AB - In an attempt to define the relationship among tumor size, stage and survival, the Cancer Incidence and End Results Committee of the American Cancer Society, Illinois Division, Inc. reviewed the records of 2,473 patients with a histological diagnosis of renal cell carcinoma. Tumor size was related to stage and survival. Larger tumors were generally associated with an increased stage (p < or = 0.0005) as well as poorer survival (p < or = 0.005). For Robson stages II, III and IV, tumor size may contribute additional prognostic information for patient survival. PMID- 7853571 TI - Prospective analysis of multifocality in renal cell carcinoma: influence of histological pattern, grade, number, size, volume and deoxyribonucleic acid ploidy. AB - In an effort to characterize more fully multifocal renal cell carcinoma, 100 radical nephrectomy specimens with localized renal cell carcinoma were analyzed in a prospective fashion. Analysis of each specimen consisted of preoperative computerized tomography or magnetic resonance imaging, standard pathological examination with frozen section and 3 mm. step sectioning under magnification. Multifocal renal cell carcinoma was found in 16 specimens. Multifocal disease was suspected by preoperative imaging in 7 specimens (44%) and confirmed after standard pathological investigation in 10 (63%). Papillary and mixed histological patterns occurred at a significantly increased rate in specimens with multifocal disease (p = 0.011). Other parameters, such as stage, tumor size and volume, histological grade and deoxyribonucleic acid ploidy were evaluated and did not correlate with the presence or extent of multifocality. The number of secondary tumors per specimen varied from 1 to 50 (median 2) and were of higher grade in 3 (19%) and of lower grade in 2 (12%) when compared with the predominant tumor. In conclusion, information from preoperative and to some degree intraoperative tests (except histological pattern) cannot reliably predict multifocality. The true risk for unknown multifocality in a surgical setting seems to be 6%, which roughly corresponds to the incidence of locally recurrent disease in published large institutional series. PMID- 7853572 TI - Hereditary papillary renal cell carcinoma: clinical studies in 10 families. AB - We recently described a 3-generation family with members affected with papillary renal cell carcinoma, an uncommon histological type of renal cell carcinoma. Possibly family 150 is an isolated occurrence, a reflection of some as yet unknown environmental factor. Alternatively, family 150 may represent a distinct class of inherited cancer. To distinguish between these 2 possibilities we sought additional families with papillary renal cell carcinoma and we identified 9 with members affected with papillary renal cell carcinoma. There were 29 affected male and 12 affected female subjects (ratio 2.41:1), including affected members of family 150. Papillary renal cell carcinomas were often detected incidentally in asymptomatic individuals or during screening of asymptomatic members of renal cell carcinoma families. The penetrance, the proportion of obligate gene carriers that showed clinical evidence of the disease, was reduced. The median survival of affected individuals was 52 years. The results support the concept that the predisposition to develop papillary renal cell carcinomas may be inherited and that hereditary papillary renal cell carcinoma constitutes a distinct class of inherited cancer. PMID- 7853573 TI - Parenchymal sparing surgery in patients with hereditary renal cell carcinoma. AB - The von Hippel-Lindau syndrome is the most well known cause of familial renal cancer. Because affected individuals with renal lesions can have complex, multisystem manifestations of von Hippel-Lindau disease, our renal management strategy has included parenchymal sparing surgery whenever possible. From May 1988 to January 1993, 20 patients with hereditary renal cell carcinoma (19 with von Hippel-Lindau disease and 1 with hereditary papillary renal cancer) underwent renal exploration with the intent of performing parenchymal sparing surgery. A total of 7 nephrectomies and 27 parenchymal sparing procedures was performed. Additional procedures performed included 2 bilateral adrenalectomies for pheochromocytomas, 1 resection of a renal vein thrombus and 1 resection of a pancreatic islet cell tumor. Renal atrophy occurred in 3 of 27 kidneys (11%) treated by parenchymal sparing surgery. In 8 kidneys of 7 patients new solid lesions developed and in 14 kidneys of 12 patients no new solid lesions developed during a mean followup of 26 months (range 6 to 60 months). The use of parenchymal sparing surgery in patients with familial forms of kidney cancer is based on a desire to maintain renal function as long as possible while reducing the risk of metastases. The potential advantages and disadvantages of more ablative surgical treatment requiring subsequent dialysis or transplantation in patients with existing or potential central nervous system, eye, pancreas and/or adrenal tumors must be weighed against the possibility of renal cancer metastases or recurrence when deciding on the use of parenchymal sparing surgery. PMID- 7853574 TI - Biological and therapeutic challenges of renal carcinoma. PMID- 7853575 TI - Long-term outcome related to epidermal growth factor receptor status in bladder cancer. AB - For bladder cancer we currently lack accurate methods of predicting outcome, although clinical stage and histological grade are broad determinants of prognosis. Preliminary data have indicated that assessment of epidermal growth factor receptor status is a method of further subclassifying bladder cancer. We assessed prospectively the clinical significance of determining epidermal growth factor receptor status in 212 patients with newly diagnosed bladder cancer who were followed for 1 to 96 months (mean 26.5). In multivariate analyses epidermal growth factor receptor was confirmed to be an independent predictor of survival (p = 0.004) and stage progression (p = 0.0004). Most importantly, epidermal growth factor receptor status was found to be 80% sensitive and 93% specific in predicting stage progression in T1, grade 3 bladder cancer. We conclude that epidermal growth factor receptor status is a useful molecular marker in patients with bladder cancer, especially those without infiltration of the detrusor muscle at presentation. PMID- 7853576 TI - Keyhole-limpet hemocyanin immunotherapy in the bilharzial bladder: a new treatment modality? Phase II trial: superficial bladder cancer. AB - The efficacy of immunotherapy with keyhole-limpet hemocyanin or bacillus Calmette Guerin for superficial bladder cancer is well known. A strong similarity has been noted between keyhole-limpet hemocyanin antigen and schistosomal antigen. In regard to this finding, we investigated the mechanisms of specific immunotherapy with keyhole-limpet hemocyanin in schistosomal associated transitional cell carcinoma. Keyhole-limpet hemocyanin was used for its ability to prevent tumor recurrence and because of its similarity to schistosomal antigen for intravesical specific immunotherapy in 13 patients with superficial transitional cell bladder tumors (Ta, Tis, T1) associated with urinary schistosomiasis. Keyhole-limpet hemocyanin immunotherapy reduced the recurrence rate of superficial bladder tumors to 15.4% compared to 76.9% before therapy. PMID- 7853577 TI - A randomized study of intravesical mitomycin C, bacillus Calmette-Guerin Tice and bacillus Calmette-Guerin RIVM treatment in pTa-pT1 papillary carcinoma and carcinoma in situ of the bladder. AB - Results of a randomized prospective study are reported in which mitomycin C, Tice bacillus Calmette-Guerin (BCG) and RIVM-BCG were compared in 437 patients with primary or recurrent pTa and pT1 bladder tumors, including carcinoma in situ. The followup (or time in study) varied from 2 to 81 months (mean 36 months). After complete transurethral resection of all visible tumors the patients were treated with 30 mg. mitomycin C once a week for 4 consecutive weeks and thereafter every month for a total of 6 months, and 5 x 10(8) colony-forming units Tice BCG or RIVM-BCG once a week for 6 consecutive weeks. For papillary tumors mitomycin C and RIVM-BCG treatments were equally effective (p = 0.53), and mitomycin C was more effective than Tice BCG therapy (p = 0.01). PMID- 7853578 TI - Intravesical adjuvant chemotherapy for superficial transitional cell bladder carcinoma: results of 2 European Organization for Research and Treatment of Cancer randomized trials with mitomycin C and doxorubicin comparing early versus delayed instillations and short-term versus long-term treatment. European Organization for Research and Treatment of Cancer Genitourinary Group. AB - The European Organization for Research and Treatment of Cancer genitourinary group has completed 2 parallel prospective randomized studies, one with 30 mg. mitomycin C and the other with 50 mg. doxorubicin as adjuvant intravesical treatment after transurethral resection of superficial transitional cell bladder carcinoma. These studies were designed to compare early (the day of resection) versus delayed (between 7 and 15 days after resection) instillations and short term (6 months) versus long-term (12 months) treatment. The results indicate that in regard to recurrence rate patients having a delayed and short-term treatment do worse than those having early instillations (for 6 or 12 months) or those having prolonged treatment (either immediate or delayed). With an average followup of 4 years survival, progression beyond T1 disease, development of distant metastases and appearance of a second primary were not influenced by the therapeutic regimen. A multivariate analysis of prognostic factors is presented, which indicates that after adjustment for these factors, patients in the delay, no maintenance arm have a significantly higher recurrence rate than the other patients. PMID- 7853579 TI - Bladder cancer: improving patient selection and treatment. PMID- 7853580 TI - Management of transitional cell carcinoma involving von Brunn's nests. AB - We reviewed data collected from 371 patients with superficial transitional cell carcinoma of the bladder to determine whether carcinoma within von Brunn's nests is a risk factor for cancer progression and an indication for radical cystectomy. Cystectomy was done in 20 of 73 patients (27%) with transitional cell carcinoma in von Brunn's nests and in 42 of 298 patients (14%) without von Brunn's nest involvement. There was no significant difference in the Kaplan-Meier crude and disease-specific survival between patients with and without transitional cell carcinoma in von Brunn's nests, irrespective of whether radical cystectomy was performed initially. Of those patients with von Brunn's nest involvement none who underwent cystectomy died of bladder carcinoma, while 3 (6%) managed conservatively died of bladder cancer. Of those patients without von Brunn's nest involvement 1 (5%) managed with cystectomy and 9 (4%) managed conservatively died of bladder carcinoma. Furthermore, only 8 patients (15%) with and 29 (11%) without transitional cell carcinoma in von Brunn's nests showed disease progression after initial conservative management. Based on this analysis, our conclusion is that transitional cell carcinoma within von Brunn's nests is not a risk factor for disease progression or an absolute indication for radical cystectomy. PMID- 7853581 TI - The risk of urethral tumors in female bladder cancer: can the urethra be used for orthotopic reconstruction of the lower urinary tract? AB - We studied the risk of synchronous or secondary urethral tumors after long-term followup in women with bladder cancer. The charts of women treated for various stages of bladder cancer between 1973 and 1992 were reviewed. Of 356 evaluable patients 268 presented initially with primary and 78 with multilocular tumor involvement. There were 498 episodes of recurrent tumors in 127 patients, and a total 1,210 tumor locations in 854 primary and recurrent episodes of bladder cancer. Mean followup for these patients was 5.5 years (range 0.05 to 33.1). Overall 7 of 356 patients (2%) had urethral tumor involvement, all at initial presentation. Statistical comparison of various defined tumor localizations in the bladder revealed that the bladder neck (p < 0.000) and trigone (p < 0.035) were significantly more often the region of primary tumor occurrence in the urethral tumor group. All patients with secondary urethral tumors had tumor involvement of the bladder neck at the same time. A 1% urethral tumor involvement was seen among 104 patients with clinical stage T2 to 3b, N0, M0 transitional cell carcinoma, who could have been considered for curative radical cystectomy. No patient presenting with tumor recurrence regardless of its location was found to have urethral tumors. Subtotal urethrectomy is an option in select female patients after cystectomy for localized bladder cancer to allow orthotopic reconstruction of the lower urinary tract provided the bladder neck is free of tumor. PMID- 7853582 TI - Orthotopic ileal neobladder in female patients after radical cystectomy: 2-year experience. AB - We describe a surgical technique to conserve urinary continence in 7 women who underwent radical cystectomy with construction of an orthotopic ileal neobladder for infiltrating bladder carcinoma. The selection of the patients and the surgical procedure to preserve the anatomical and functional integrity of the female urethra are described. Followup ranged from 7 to 28 months. There were no postoperative deaths or serious clinical complications. The urinary continence rate was 100% during the day and 71% at night with micturition at regular 3-hour intervals. The vesical capacity varied from 250 to 400 cc and pressure at maximum capacity from 10 to 25 cm. water. Urinary flow was satisfactory and the urethral pressure profile showed a normal sphincteric mechanism at rest. Two patients died of metastases at 14 and 8 months postoperatively, and 5 are alive and disease free. We believe that these results confirm the possibility of obtaining micturition in women via the urethra following radical cystectomy. PMID- 7853583 TI - A new approach using local combined microwave hyperthermia and chemotherapy in superficial transitional bladder carcinoma treatment. AB - For some time hyperthermia, alone or in combination with radiotherapy or chemotherapy, has proved to be a promising method for treating several kinds of solid tumors. After intensive laboratory investigations a new device, based on a microwave source delivering local bladder hyperthermia together with intravesical mitomycin C chemotherapy has been clinically tested as a neoadjuvant approach in 44 patients suffering from superficial cancer of the bladder. The combined approach was administered on an outpatient basis without major complications and with acceptable local toxicity. Endoscopic and histological evaluations proved that combined local hyperthermia and chemotherapy can induce necrosis of transitional tumors. The overall response rate was 90.8%, with 70.4% complete and 20.4% partial, leaving 4 patients (9.2%) nonrespondent. Clinical and histological evaluations have confirmed the feasibility and safety of this combined treatment. Further multicentric studies have been initiated. PMID- 7853584 TI - Neoadjuvant cisplatin chemotherapy before radical cystectomy in invasive transitional cell carcinoma of the bladder: a prospective randomized phase III study. AB - From November 1984 to April 1989, 122 patients with clinical T2-4a Nx-2 M0 transitional cell carcinoma of the bladder were entered in a prospective randomized trial to compare survival between a control group of 60 patients treated only with radical cystectomy (arm A) and a group of 62 patients treated with 3 cycles of 100 mg./m.2 neoadjuvant cisplatin before radical cystectomy (arm B). Secondary objectives of the trial were comparison of the disease-free interval and time to death, significance of response of the primary tumor to cisplatin, pattern of relapse and toxicity. As of April 1993 after a median followup of 78.2 months (range 48 to 101) no difference in survival between the control patients and those who received neoadjuvant cisplatin has been observed. The overall direct survival is 37.3% for arm A and 35.5% for arm B. The survival rate of the 109 patients who complied with the protocol is 38.2% for 55 patients of the control group and 40.7% for 54 patients of the cisplatin group. Survival rates of patients theoretically rendered free of disease by radical cystectomy (complete response pT0-4a, pN0-2, M0) is 43.7% for 40 control patients and 47.8% for 41 cisplatin treated patients. The time to relapse in complete response patients was significantly longer (p = 0.0298) for those who received cisplatin (arm A 13.1 months versus arm B 30.3 months). The time to death (cause specific) did not differ significantly between both groups overall (p = 0.1349) but it was significantly different between controls and responders (p = 0.0501). Preoperative cisplatin downstaged the primary tumor in 19 patients (33.9%), of whom 11 (19.6%) had no tumor in the cystectomy specimen (pT0) and 8 (14.3%) had superficial tumor (pTis pTa pT1). In 6 patients (9.7%) disease progressed during chemotherapy. The survival of the responders was significantly better than that of nonresponders (p = 0.0142), with specific death rate of 26.3% and 62.5%, respectively, and a median time to death of 43 months for responders and 30.5 months for nonresponders. Patients without nodal involvement (pN0) or with only 1 micrometastasis (pN1) fared significantly better (p = 0.0001) than those with major node invasion (pN2-4), irrespective of the treatment received. The survival rate is 48.6% for patients with pN0 disease, 37.5% for pN1 and 5% for pN2-4. Toxicity of cisplatin was minimal and there were no differences in perioperative morbidity between the arms.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7853585 TI - Bladder cancer: the power of study design, interpretation of data and clinical application. PMID- 7853586 TI - Complications of post-chemotherapy retroperitoneal lymph node dissection. AB - The surgical morbidity rate of 603 patients who underwent lymphadenectomy after primary chemotherapy for clinical stages II and III testis cancer from 1982 to 1992 was reviewed. There were 144 complications in 125 patients (20.7%). The majority of patients (93%) had a tumor volume of greater than 5 cm. Five patients died 3 to 47 days postoperatively, for an operative mortality rate of 0.8%. Pulmonary complications were the most frequent cause of severe morbidity: 6 patients had the adult respiratory distress syndrome and 5 needed prolonged ventilation. The underlying cause was a combination of bleomycin induced pulmonary toxicity, and large volume retroperitoneal and pulmonary disease resected in these patients. Limiting inspired oxygen concentration and perioperative volume replacement are imperative to minimize bleomycin related pulmonary morbidity. Additional procedures, such as nephrectomy and colectomy, did not add to the morbidity rate. Among patients undergoing concomitant venacavectomy there was a higher occurrence of postoperative chylous ascites. Most of the other complications (gastrointestinal, lymphatic, neurological and renal) were temporary and treated conservatively. Perioperative management of the post-chemotherapy testis cancer patient is different from that of the patient undergoing primary retroperitoneal lymphadenectomy. The latter operation is usually performed in physically fit patients and the surgical template of dissection is of a smaller scale. Thus, the complications in this group are minor and without mortality. Specific technical considerations and difficulties are common to post-chemotherapy patients. Factors, such as large volume of disease, post-chemotherapy desmoplastic reaction and extensive retroperitoneal dissection, make these patients more prone to have complications. Decreased pulmonary, renal and nutritional reserves add to the surgical morbidity. Knowledge of possible pitfalls and their causes can avoid unnecessary operative complications. PMID- 7853587 TI - A review of scrotal violation in testicular cancer: is adjuvant local therapy necessary? AB - High inguinal orchiectomy is the standard initial treatment for suspected testicular carcinoma. Nonstandard surgical approaches (scrotal violations), including scrotal orchiectomy, open testicular biopsy and fine needle aspiration, have historically been condemned as significantly compromising patient prognosis. Patients with scrotal violation are often subjected to potentially morbid or disfiguring local therapies. In addition, patients with scrotal violations are usually disqualified from surveillance protocols. A review was conducted of all published series of testicular cancer patients in whom scrotal violation occurred. A meta-analysis was then performed to choose a subset for critical analysis on the effect of scrotal violation on patient prognosis. Of 1,182 cases included in the final analysis scrotal violation occurred in 206. The rates for local recurrence, distant recurrence and survival were analyzed separately for all patients, patients with stage I disease and patients with pure seminoma or nonseminomatous germ cell tumor. Additionally, the effect of local treatment for scrotal violation on prognosis was examined. Although statistically significant differences were found in the local recurrence rate among the scrotal violation and inguinal group studies, the overall local recurrence rates were small (2.9% versus 0.4%, respectively). There were no statistical differences in distant recurrence or survival rates in all groups analyzed. Patients with scrotal violation who did not receive any local therapy fared as well as those who did receive local therapy. Although the standard treatment of primary testicular cancer remains high inguinal orchiectomy, these data suggest that scrotal violation does not impart a significantly worse overall prognosis. These data would also indicate that patients with stage I disease and scrotal violation should not necessarily be disqualified from surveillance protocols or subjected to adjuvant local therapy. PMID- 7853588 TI - Testis cancer: the cost of progress. PMID- 7853589 TI - Pathological features of hereditary prostate cancer. AB - The aim of this study was to characterize the pathological features of hereditary prostate cancer, a recently recognized variant of prostate cancer with an autosomal dominant inheritance of a rare highly penetrant gene associated with early onset of disease. We compared the histology at radical prostatectomy of clinical stage T2 prostate cancer, including its relationship to prostatic intraepithelial neoplasia, in men with a family history of prostate cancer to those without a family history of prostate cancer. Three cohorts (hereditary, familial and sporadic) were identified based on pedigree analysis. A hereditary subgroup (28 patients) met 1 of the following 3 criteria: 1) cluster of greater than 3 affected relatives within the nuclear family, 2) occurrence of prostate cancer in each of 3 generations in either the proband paternal or maternal lineage, or 3) a cluster of 2 relatives affected at an early age of less than 55 years. This subgroup was compared to an age-matched subgroup with family history of prostate cancer (26 patients) yet the aforementioned conditions for inclusion within the hereditary subgroup were not met and to a sporadic subgroup without a family history of prostate cancer (27 patients). All parameters were statistically similar among the groups except that hereditary and familial group multifocal tumors were of lower grade (p = 0.0001), sporadic cases had a greater proportion of small multifocal cancers associated with prostatic intraepithelial neoplasia (p = 0.02) and the familial group had a weaker correlation between total tumor volume and grade. In conclusion, our analysis failed to demonstrate substantial pathological differences among hereditary, familial and sporadic forms of prostate cancer. Rather, our data are remarkable for the wide range of all parameters studied in each group. Even the sporadic cases had features, such as increased numbers of precursor lesions and tumor multifocality, which in other organs are commonly associated with either hereditary cancer or cancer arising in a field effect due to diffuse exposure to a carcinogen. PMID- 7853590 TI - The use and accuracy of cross-sectional imaging and fine needle aspiration cytology for detection of pelvic lymph node metastases before radical prostatectomy. AB - The role of cross-sectional pelvic imaging with computerized tomography or magnetic resonance imaging and fine needle aspiration in the assessment of pelvic lymph nodes in patients with prostate cancer is undefined. To address this issue we used formal decision analysis, comparing an imaging arm to a no imaging arm. Patient utility values were calculated, and test parameters and complication rates were extracted from the literature. Imaging was superior to no imaging only when the pretest probability of pelvic lymph node metastases was high. The most important parameter was the sensitivity of cross-sectional imaging for lymphadenopathy. When the sensitivity was 36%, which was the baseline figure derived from the literature, the probability of lymph node metastases required for imaging to be beneficial overall was 32%. We also performed a retrospective review of magnetic resonance imaging examinations at our institution in 174 patients with newly diagnosed prostate cancer and pathological confirmation of nodal status. The sensitivity for detecting nodal metastases was 25%. With this figure, the estimated probability of nodal metastases required to make imaging beneficial would be 45%, which is possible to achieve with highly selective clinical criteria. With a policy of imaging only in select patients the marginal cost is $794 per patient benefited (aborted radical prostatectomy because of nodal metastases detected with fine needle aspiration) compared to $50,661 per patient benefited if all patients are imaged. Thus, cross-sectional pelvic imaging before radical prostatectomy, solely for the purpose of detecting pelvic lymph node metastases, is not justified routinely. However, it is worthwhile on the basis of patient use values and cost-effectiveness in a select group of patients at high risk for nodal metastases. PMID- 7853591 TI - Knowledge, know-how, and vascular surgeons. AB - Vascular surgeons know vascular disease and its treatment, yet uncertainties about the future of their specialty require an examination of its two basic components: knowledge and know-how. Knowledge, or understanding, flows from research efforts, and expands the scientific basis of our medical knowledge. It is imperative that new knowledge through funded research continues so that vascular surgical science progresses. Know-how, or skill, is a crucial component of the vascular surgeon's armamentarium and has been recognized through our history as a criterion of a surgeon's proficiency. The vascular fellowship program provides the vascular surgical trainee with the knowledge and know-how necessary to become accomplished and qualified for certification in this specialty. Future progress in vascular surgery depends on new knowledge and know how and their innovative application to human vascular disease. This may involve a formal cooperative relationship between the two national vascular societies and our colleagues in interventional radiology to develop a comprehensive vascular health care program. The societies together must continually evaluate the forces for change that are prevalent in the health care environment to expand this program. This will ensure a healthy forecast for our dynamic specialty in the twenty-first century. PMID- 7853592 TI - Transabdominal versus retroperitoneal incision for abdominal aortic surgery: report of a prospective randomized trial. AB - PURPOSE: The purpose of this study was to perform a randomized, prospective trial that compares the transabdominal with the retroperitoneal approach to the aorta for routine infrarenal aortic reconstruction. METHODS: From August 1990 through November 1993, patients undergoing surgery for abdominal aortic aneurysm (AAA) disease or aortoiliac occlusive disease (AIOD) were asked to participate in a randomized trial comparing the transabdominal incision (TAI) to the retroperitoneal incision (RPI) for aortic surgery. One hundred forty-five patients were randomized, with 75 (41 with AAA and 34 with AIOD) in the TAI group and 70 (40 with AAA and 30 with AIOD) in the RPI group. There were no significant differences between the groups in terms of age, sex, postoperative pain control (epidural vs patient-controlled analgesia), or comorbid conditions, except for a higher incidence of chronic obstructive pulmonary disease in the TAI group (21 vs 8 patients). RESULTS: The incidence of intraoperative complications was similar for both groups. After surgery, the incidence of prolonged ileus (p = 0.013) and small bowel obstruction (p = 0.05) was higher in the TAI group. Overall, the RPI group had significantly fewer complications (p < 0.0001). The overall postoperative mortality rate (two deaths) was 1.4%, with both occurring in the TAI group (p = 0.507). The RPI group also had significantly shorter stays in the intensive care unit (p = 0.006), a trend toward shorter hospitalization (p = 0.10), lower total hospital charges (p = 0.019), and lower total hospital costs (p = 0.017). There was no difference in pulmonary complications (p = 0.71). In long-term follow-up (mean 23 months), the RPI group reported more incisional pain (p = 0.056), but no difference was found in incisional hernias or bulges (p = 0.297). CONCLUSIONS: We conclude that the RPI approach for abdominal aortic surgery is associated with fewer postoperative complications, shorter stays in the hospital and intensive care unit, and lower cost. There is, however, an increase in long-term incisional pain. Current methods of postoperative pain control seem to decrease the incidence of pulmonary complications. PMID- 7853593 TI - Secondary aortoenteric fistula: contemporary outcome with use of extraanatomic bypass and infected graft excision. AB - PURPOSE: The standard treatment for secondary aortoenteric fistula (SAEF) has been infected graft removal (IGR) and extraanatomic bypass (EAB), an approach criticized for its high rate of death, amputation, and disruption of aortic closure. Recently, graft excision and in situ graft replacement has been proposed as a safer treatment alternative. Because the current outcome that can be achieved by use of the standard treatment of SAEF has really not been established, we reviewed the records of 33 patients treated for SAEF at our institution during a contemporary time interval (1980 to 1992). METHODS: Thirteen patients (39.4%) were admitted with evidence of gastrointestinal bleeding and infection, whereas nine (27.3%) only had bleeding, 10 (30.3%) only had signs of infection, and one SAEF was entirely occult (graft thrombosis). Four patients required emergency operation. The fistula type was anastomotic in 13 (39.4%) patients, paraprosthetic in 15 (45.5%), and not specified in 4 cases. Thirty-two patients underwent EAB followed immediately by IGR (n = 16, 48.5%) or followed by IGR after a short interval, averaging 3.9 days (n = 16, 48.5%). The final patient underwent IGR, followed by EAB. RESULTS: Follow-up on 31 patients (93.9%) averaged 4.4 +/- 3.7 years. There were nine deaths (27.3%) resulting from the SAEF, six perioperative and three late. Three patients (9.1%) had disrupted aortic closure. There were four amputations in three patients (9.1%), two perioperative and two late. Late EAB infection occurred in five patients (15.2%), leading to one death and one amputation. EAB failure occurred in six patients, two during operation and four late, leading to one amputation. The cumulative cure rate for this SAEF group was 70% at 3 years and thereafter. Compared with our earlier SAEF experience, this is a decline of 21% in the mortality rate, 19% in aortic disruption, and 27% in limb loss. CONCLUSIONS: We conclude that outcome reports based on SAEF series extending over long time intervals do not accurately represent the results that are currently achieved with standard SAEF treatment with use of EAB plus IGR. This improved outcome is attributed to wide debridement of infected tissue beds, reduced intervals of lower body ischemia, and advances in perioperative management. To determine whether any new treatment approach actually offers improved outcome in the management of SAEF, comparison with EAB plus IGR should be limited to patients treated within the last decade at most. PMID- 7853594 TI - Surgical management of dialysis-dependent ischemic nephropathy. AB - PURPOSE: This retrospective review describes surgical management of dialysis dependent ischemic nephropathy. METHODS: From February 1987 through September 1993, 340 patients underwent operative renal artery (RA) reconstruction at our center. A subgroup of 20 patients (6 women; 14 men; mean age 66 years) dependent on hemodialysis immediately before RA repair form the basis of this report. Glomerular filtration rates (EGFR) were estimated from at least three serum creatinine measurements obtained 26 weeks before and after operation. A linear regression model was used to estimate the mean rate of change of EGFR before and after RA repair. Comparative analysis of kidney status and change in EGFR were performed. The influence of function response on follow-up survival was determined by the product-limit method. RESULTS: Hemodialysis was discontinued in 16 of 20 patients (80%). For these 16 patients, postoperative EGFR ranged from 9.0 to 56.1 ml/min/1.73 m2 (mean 32.4 ml/min/1.73 m2). Two of 16 patients resumed hemodialysis 4 and 6 months after surgery. Discontinuation of dialysis was more likely after bilateral or complete RA repair (15 of 16 patients) versus unilateral repair (one of four patients; p = 0.01). Permanent discontinuation of dialysis was associated with a rapid preoperative rate of decline in EGFR (mean slope log(e) EGFR: -0.1393 +/- 0.0340 without dialysis; -0.0188 +/- 0.0464 with dialysis; p = 0.04, but NS after controlling for multiple comparisons). Immediate increase in EGFR after operation was inversely correlated with the severity of nephrosclerosis (rank correlation: -0.57; 95% confidence interval [-0.83, 0.10]). Follow-up death was associated with dialysis dependence; two deaths occurred among 14 patients not receiving dialysis, whereas five of six patients dependent on dialysis died (p < 0.01). CONCLUSION: Surgical correction of ischemic nephropathy can retrieve renal function in selected patients dependent on dialysis characterized by a rapid decline in preoperative EGFR in combination with global renal ischemia treated by complete or bilateral renal revascularization. After RA repair, discontinuation of dialysis may be associated with improved survival rates when compared with continued dialysis dependence. PMID- 7853595 TI - Pediatric renovascular hypertension: a thirty-year experience of operative treatment. AB - PURPOSE: This study was undertaken to characterize the changing operative treatment of pediatric renovascular hypertension and subsequent outcomes in a 30 year experience at a single institution. METHODS: Clinical data were analyzed on 57 pediatric patients, 24 girls and 33 boys, ranging in age from 10 months to 17 years, who underwent operations for renovascular hypertension from 1963 to 1993 at the University of Michigan. Renal artery disease included atypical medial perimedial dysplasia, often with secondary intimal fibroplasia (88%), and inflammatory mural fibrosis (12%). Abdominal aortic narrowings affected 15 patients. Data were categorized into three chronologic eras (I:1963-1972, II:1973 1980, and III:1981-1993) to allow identification of therapeutic trends. RESULTS: Primary surgical procedures were undertaken 74 times. Ex vivo reconstruction was necessary once. Primary operations included aortorenal bypass with autogenous vein grafts (n = 26) or internal iliac artery grafts (n = 7); iliorenal bypass with vein grafts (n = 2); renal artery resection beyond the stenosis and reimplantation into the aorta (n = 10), the main renal artery (n = 2), an adjacent segmental renal artery (n = 3), or the superior mesenteric artery (n = 3); renal artery resection and reanastomosis (n = 3); focal renal arterioplasty (n = 2); operative dilation (n = 7); splenorenal bypass (n = 2); and primary nephrectomy (n = 7). Among 23 primary operations performed in era I, 56.5% were aortorenal bypasses with vein grafts, but in era III this form of revascularization represented only 3% of 33 primary operations. No reimplantations were performed in era I, whereas reimplantations accounted for 51.5% of era III procedures. Thirteen patients underwent staged or concomitant aortic reconstructions with thoracoabdominal aortoaortic bypass grafts (n = 5) or patch aortoplasty (n = 8). Fourteen patients underwent a total of 20 secondary operations, including seven secondary nephrectomies. Operative therapy benefited 98% of these children: hypertension was cured in 45 (79%), improved in 11 (19%), and unchanged in one (2%). There were no operative deaths. CONCLUSIONS: Contemporary surgical management emphasizes direct reimplantation of main renal arteries into the aorta, reimplantation of segmental arteries into adjacent renal arteries, patch aortoplasty for associated abdominal aortic coarctations, and single-stage revascularizations. Pediatric patients with renovascular hypertension clearly benefit from carefully executed operative therapy. PMID- 7853596 TI - Isolation of genes differentially expressed at the downstream anastomosis of prosthetic arterial grafts with use of mRNA differential display. AB - PURPOSE: Downstream anastomotic intimal hyperplasia in prosthetic arterial grafts remains a major cause of delayed graft failure. The new method of messenger RNA (mRNA) differential display was used to screen numerous genes to gain insight into the molecular mechanisms of intimal hyperplasia. METHODS: Fifty-centimeter long 8 mm expanded polytetrafluoroethylene grafts were placed in four mongrel dogs from the carotid artery to the distal abdominal aorta. At 3 months the distal anastomoses and adjacent normal aortas were harvested; a portion was taken for histologic examination, and total RNA was isolated from the remainder. Differential mRNA display was used to identify candidate cDNA clones whose expression differed in anastomotic intimal hyperplasia as compared with adjacent unaffected aorta. The clones were sequenced, and national gene databases were searched. Northern blot analysis confirmed alteration of gene expression. RESULTS: Approximately 5000 mRNA species were screened, and 11 candidate clones were obtained. DNA sequence revealed homology of five clones to known gene sequences. Homologous genes included an interferon-gamma-induced human gene, (IGUP I-5111), alpha-1 protease inhibitor gene, human retinoblastoma susceptibility gene, and human creatine kinase gene (two clones). Northern blot analysis revealed altered gene expression in 4 of 11, nonregulation in 1 of 11, and undetectable signals in 6 of 11. Expression of the clone representing IGUP I 5111 in the segment of intimal hyperplasia was found to be decreased over threefold to only 31% +/- 16.4% SE of the level seen in normal aorta. CONCLUSIONS: The technique of mRNA differential display has identified differences in gene expression in an in vivo model of anastomotic intimal hyperplasia. Expression of RNA with homology to an interferon-gamma-induced human gene was consistently decreased within the hyperplastic region at the downstream polytetrafluoroethylene arterial anastomosis. PMID- 7853597 TI - Comparative efficacy and complications of vena caval filters. AB - PURPOSE: A variety of vena caval filters (VCFs) are available for usage. The choice of filter type depends on physician preference and certain patient variables. An evaluation of the different VCFs used in our institution was done to compare their efficacy and complication rates. METHODS: The medical records of all patients who underwent insertion of a VCF from January 1987 to June 1993 at the University of Iowa Hospitals & Clinics and the affiliated Veterans Administration Medical Center were reviewed. One hundred ninety-nine VCFs were placed in 196 patients (123 males, 73 females), with a mean age of 61 years (range 13 to 87 years). Thirty-five (18%) VCFs (30 stainless steel Greenfield filters [SGFs] and five titanium Greenfield filters with modified hook [TGF-MHs]) were inserted in the operating room via an open technique. The remaining 164 VCFs (82%) were inserted in the radiology suite by a percutaneous technique (38 SGF, 23 TGF-MH, 51 Vena Tech filters [VTFs], 48 Bird's nest filters [BNFs] and 4 Simon Nitinol filters). Thromboembolic risk factors in these 196 patients included malignancy (99), trauma (21), recent surgery (27), cerebrovascular accident with paralysis (6), and miscellaneous conditions (43). Indications for VCF placement included a contraindication to anticoagulation (92), complication of anticoagulation (44), failure of anticoagulation (26), prophylaxis (31), adjunct to pulmonary embolectomy (1), noncompliance (1), hemodynamically unstable patient (1), and prior VCF complication (3). Mean follow-up of the patients was 12 months (range 0 to 87 months). Because there were only four Simon Nitinol filters inserted during the study period, they were excluded from further analysis. RESULTS: A comparative analysis revealed that there was a significantly higher incidence of symptomatic IVC thrombosis with the use of the BNF (n = 7) (14.6%) versus the SGF (n = 0) (0%), TGF-MH (n = 1) (3.6%), or VTF (n = 2) (4%) (p < 0.05 by chi-squared testing). The VCF-related mortality rate was also higher with the BNF (n = 5) (10.9%) versus the SGF (n = 1) (1.5%), TGF-MH (n = 1) (3.6%), or VTF (n = 0) (0%) (p < 0.05 by chi-squared testing). However there was no significant difference in the occurrence of clinically apparent recurrent pulmonary embolism during follow-up between the four different filter types (2 [4.2%] BNF, 3 [4.4%] SGF, 1 [3.6%] TGF-MH, and 1 [2%] VTF). CONCLUSION: These data indicate that the use of the BNF was associated with increased morbidity and mortality rates compared with the use of the SGF, TGF-MH, and VTF filters. PMID- 7853598 TI - Do patients with the heparin-induced thrombocytopenia syndrome have heparin specific antibodies? AB - PURPOSE: Patients with the heparin-induced thrombocytopenia syndrome (HIT) have heparin-associated antibodies (HAb+), which, in the presence of heparin, are responsible for platelet activation and aggregation. This study addressed the questions: (1) are the antibodies specific for heparin; and (2) how do the antibodies cause platelet aggregation? METHODS: Plasmas from 79 patients with HIT were divided into seven plasma samples: HAb+ plasma sample 1 (24 pooled plasmas); HAb+ plasma sample 2 (50 pooled plasmas); and HAb+ plasma samples 3 through 7 (individual plasmas). Normal patient plasmas were used as controls (HAb-). RESULTS: All seven HAb+ plasma samples caused platelet aggregation (PLA) in the presence of heparin and formed a precipitation line with heparin in gel immunodiffusion plates (HAb- plasmas did neither). The HAb+ plasma samples reacted with heparin, as determined by immunoprecipitation in sodium dodecylsulfate-polyacrylamide gel, with the production of a band at 50 kd (no band with HAb- plasmas). The plasma samples 1 and 2 were passed over heparin sepharose beads three times; the unabsorbed plasmas produced 3+ PLA, the first effluent produced 2+ PLA, and the second and third effluents produced no PLA. The heparin sepharose beads stained 3+, 2+, and 1+, after the respective passages, with fluorescein-labeled goat sera containing anti-human immunoglobulin G antibody. HAb+ plasma samples were digested with pepsin to separate the F(ab')2 fragments from the Fc fragments. The F(ab')2 fragments reacted with heparin as determined by immunoprecipitation in sodium dodecylsulfate-polyacrylamide gel with the production of a band at 25 kd, but did not cause PLA in the presence of heparin. CONCLUSION: Patients with HIT have heparin-specific antibodies that react with heparin in a classic F(ab')2 reaction and require the Fc fragment for platelet aggregation. PMID- 7853599 TI - Directional atherectomy versus balloon angioplasty in segmental femoropopliteal artery disease: two-year follow-up with color-flow duplex scanning. AB - PURPOSE: Directional atherectomy is an endovascular interventional technique for excision and removal of obstructive arterial lesions. To evaluate whether atherectomy would provide better results than conventional balloon angioplasty (BA) in symptomatic femoropopliteal disease, a prospective randomized study comparing the early and late outcomes of these techniques was conducted. The rate of restenosis or occlusion was assessed by use of color-flow duplex scanning during the follow-up period. METHODS: Seventy-three patients were randomized between atherectomy (38 patients) and BA (35 patients). All patients had segmental lesions of the femoropopliteal arteries amenable to either technique. The median follow-up duration was 13 months (range 1 to 39). Follow-up comprised regular clinical and hemodynamic assessment and color-flow duplex examinations. Restenosis was defined on the basis of a peak systolic velocity ratio of 2.5 or greater, and occlusion of the treated segment was diagnosed if flow signals were absent, that is, loss of patency. RESULTS: Residual stenoses (> or = 30% diameter reduction) resulted in five patients (13%) undergoing atherectomy and three patients (9%) undergoing BA. At 1 month clinical and hemodynamic improvement by Society for Vascular Surgery/International Society for Cardiovascular Surgery criteria for lower limb ischemia was observed in 34 patients (89%) treated with atherectomy and in 34 (97%) treated with BA. By life-table analysis the cumulative rate of clinical and hemodynamic success at 2 years was 52% in patients treated with atherectomy and 87% in patients treated with BA (p = 0.06). The patency rate at 2 years of treated segments was 34% in the atherectomy group and 56% in patients treated with BA (p = 0.07). In patients with lesions greater than 2 cm, the 1-year patency rate of AT was significantly lower than BA (p = 0.03). CONCLUSIONS: Atherectomy does not result in an improved clinical and hemodynamic outcome. Furthermore atherectomy of segmental atherosclerotic femoropopliteal disease does not result in a better patency rate than BA, and, in lesions with greater length than 2 cm, the atherectomy results are significantly worse. PMID- 7853600 TI - Early outcome and intermediate follow-up of vascular stents in the femoral and popliteal arteries without long-term anticoagulation. AB - PURPOSE: The role of arterial stenting in the treatment of femoral and popliteal arterial disease is controversial and has been hampered by recommendations for patients to be given anticoagulants (oral warfarin) for several months or more. This study was undertaken to evaluate the immediate and midterm outcomes of vascular stents implanted percutaneously in the femoral and popliteal arteries, without long-term anticoagulation. METHODS: Over a 3-year period, 32 patients admitted to a vascular surgery service had arterial stents implanted in the femoral (n = 22) or popliteal (n = 10) artery for the following indications: recurrent stenosis after angioplasty (n = 13), suboptimal result after angioplasty of occluded (n = 12) or calcified stenotic arteries (n = 2), percutaneous transluminal angioplasty-induced thrombosis or dissection (n = 5). Access to the artery was gained by percutaneous insertion of a hemostatic sheath into the ipsilateral common femoral artery. Systemic heparin was given at the time of stent insertion, and patients were prescribed daily low-dose aspirin. RESULTS: Successful stent implantation was achieved in 31 of the 32 patients. Acute thrombosis (< 30 days) occurred in two patients. There was no incidence of false aneurysm formation, acute leg ischemia, or vessel perforation. All patients were monitored by Doppler scanning index and duplex scanning within 24 hours, and thereafter at 3- to 6-month intervals. The mean ankle-brachial systolic pressure index improved from 0.60 (before treatment) to 0.88 (3 to 6 months after stenting). Stent occlusion has occurred in six patients; two stents were successfully salvaged with urokinase infusion. In follow-up to date (range 3 to 33 months) the primary patency rate by life-table analysis was 75% at 18 months, whereas the secondary patency rate was 89% at the same interval. Restenosis (> 50% lumen diameter) was detected by duplex ultrasonography in seven of 25 patent stents (28%) at a mean interval of 9.5 months (range 4 to 15 months); of these, four patients remained clinically symptom-free despite the ultrasound findings. CONCLUSIONS: We conclude that vascular stents can be implanted into the femoropopliteal arteries with few complications and with acceptable early and intermediate patency rates, without the need for long-term anticoagulation. Restenosis is not prevented by stents, and the main value of stenting at this site appears to be in salvaging acute complications of percutaneous transluminal angioplasty, or to correct suboptimal results after recanalization of occluded arteries. PMID- 7853601 TI - Preferred strategies for secondary infrainguinal bypass: lessons learned from 300 consecutive reoperations. AB - PURPOSE: To determine the optimal surgical strategies in reoperative infrainguinal bypass, we reviewed our results in 300 consecutive secondary bypasses in 251 patients operated on between Jan. 1, 1975, and Nov. 1, 1993. METHODS: There were 168 men (67%) and 83 women (33%), with a mean age of 64.8 years and a typical distribution of risk factors including smoking (76.4%), diabetes (33.7%), and coronary artery disease (47.1%). The indications for surgery were limb-threatening ischemia in 83.5% and severe claudication in 16.5% of patients. The majority of conduits (n = 213) were autogenous vein and were composed of a single segment of greater saphenous vein in 121 bypasses (57%) and various alternative veins including composite, arm, and lesser saphenous vein in 92 bypasses (43%). Prosthetic conduits included 69 polytetrafluoroethylene, 16 umbilical vein, and two Dacron grafts. RESULTS: There was one perioperative death (0.3%) and a 25% total morbidity rate including a 1.7% myocardial infarction rate. There was a 28.6% early (< 30 days) graft failure and 10.7% early amputation rate for prosthetic bypass grafts compared with 13.6% early graft failure and 5.6% early amputation rates for vein grafts. Autogenous vein bypasses had higher 5-year secondary patency rates than had prosthetic grafts (51.5% +/- 4.6% vs 27.4% +/- 6.1%, p < 0.001). Results with autogenous vein bypass improved significantly from the 1975 to 1984 to the 1985 to 1993 interval with 5-year secondary patency rates increasing from 38.3% +/- 6.9% to 59.1% +/- 5.8% (p = 0.017) and 5-year limb-salvage rates increasing from 40.4% +/- 7.6% to 72.4% +/- 6.6% (p < 0.001). Vein grafts to the popliteal and tibial outflow levels had equivalent long-term results. Vein grafts completed for claudication demonstrated results superior to those for limb salvage, with a 5-year secondary patency rate of 75.8% +/- 8.1% versus 52.3% +/- 7.9% (p = 0.048). Secondary autogenous vein bypass grafting performed after early primary graft failure (< 3 months) did particularly poorly, with only a 27.2% +/- 7.7% 4-year secondary patency rate. Greater saphenous veins tended to perform better than alternative vein bypasses, with a 5-year secondary patency rate of 68.5% +/- 6.0% compared with 48.3% +/- 10.5% (p = 0.09) and a 5-year limb-salvage rate of 77.8% +/- 7.4% versus 54.2% +/ 11.8% (p = 0.046). CONCLUSIONS: When patients suffer a recurrence of limb threatening ischemia at the time of infrainguinal graft failure, aggressive attempts at secondary revascularization with autogenous vein are warranted based on the low surgical morbidity and mortality rates and the improved patency and limb salvage rates that are currently attainable. PMID- 7853602 TI - The influence of sex and aortic size on late patency after aortofemoral revascularization in young adults. AB - PURPOSE: The purpose of this study was to determine whether aortic size influences late patency of aortofemoral reconstructions in men and women with premature atherosclerosis. METHODS: We studied 37 consecutive young women (mean age +/- SEM, 44 +/- .7 years) and 36 young men (mean age 44 +/- .8 years) who underwent elective operations for aortoiliac occlusive disease during the past 15 years. Clinical data from patients with occluded versus patent grafts were studied, and angiographic findings in patients with occluded versus patent grafts and in young adult patients in a control group (n = 50) who had nonatherosclerotic conditions were compared. RESULTS: Twenty (54%) women and 17 (47%) men had limb occlusions within a mean of 31 +/- 6 months. These occlusions resulted in major amputations in 17 (23%) patients. When patients with occluded versus patent grafts were compared no differences were found in age, sex, symptoms, type or number of atherosclerotic risk factors, or operative details. As a whole, patients in the study group had smaller infrarenal aortas than did patients in the control group (p = 0.009). Women with limb occlusions had smaller infrarenal aortas than did women with patent grafts (p = 0.03) or healthy female patients in the control group (p = 0.002). Men with limb occlusions had smaller infrarenal aortas than did men with patent grafts (p = 0.017) or male patients in the control group (p < 0.001). Angiographic outflow scores were not different in men or women with occluded versus patent grafts. Among all variables studied proportional hazards regression analysis indicated that only mean infrarenal aortic diameter was predictive of graft patency. CONCLUSIONS: These data suggest that late graft failure after aortofemoral reconstruction is common in young adults. Patients with premature atherosclerosis have smaller infrarenal aortas compared with young adults in a control group, making them more vulnerable to symptoms from atherosclerotic lesions. Size of the infrarenal aortic segment is a critical determinant of late graft patency regardless of sex. PMID- 7853603 TI - Relationship between changes in the deep venous system and the development of the postthrombotic syndrome after an acute episode of lower limb deep vein thrombosis: a one- to six-year follow-up. AB - PURPOSE: This study investigated changes in the deep venous system and the development of the postthrombotic syndrome (PTS) after an episode of acute deep vein thrombosis (DVT). METHODS: Seventy-eight patients (41 male patients, 37 female patients) with acute DVT in 83 legs (31 right, 42 left, five bilateral) underwent annual follow-up examinations for 1 to 6 years (median, 3 years) for symptoms and signs of the PTS. A venous duplex scan was performed at each visit to detect obstruction and reflux in the veins, both of which may contribute to the development of the PTS. DVT was primary in 69 limbs and recurrent in 14 limbs. RESULTS: When last examined 49 limbs were free of symptoms, and 34 had the PTS (23 edema only, 11 hyperpigmentation). Only two patients had ulcers during the follow-up period; both patients had the ulcers in areas of hyperpigmentation in limbs with recurrent DVT. The extent of disease was similar in limbs with the PTS (79% multisegment, 18% single segment) and those without the PTS (69% multisegment, 12% single segment). In limbs with the PTS the deep veins were normal in only one (3%), six (18%) showed reflux only, five (15%) obstruction only, and 22 had features of both obstruction and reflux (65%). In limbs without the PTS the deep veins showed no abnormality in nine (18%), reflux only in 17 (35%), obstruction only in six (12%), and reflux with obstruction in 17 (35%). In the 11 limbs with hyperpigmentation nine had obstruction and reflux noted, one had obstruction only, and one had reflux alone. CONCLUSIONS: After an episode of acute DVT 12% of the limbs returned to normal by duplex criteria. Although only 13% developed skin complications, 41% had features of the PTS. Limbs with the PTS had more than three times the odds of having combined reflux and obstruction than did limbs without the PTS (odds ratio = 3.5, 0.95 confidence intervals = 1.4, 8.6). Continued study of these patients will determine the course of those limbs with venous abnormalities that have not yet developed symptoms and signs of the PTS. PMID- 7853604 TI - Atherosclerotic innominate artery occlusive disease: early and long-term results of surgical reconstruction. AB - PURPOSE: Few articles have dealt specifically with surgical management of innominate artery (IA) atherosclerotic occlusive disease. We herein present our early and long-term results in a large series of patients. METHODS: During a 20 year period (1974 to 1993) we operated on 148 patients with IA atherosclerotic occlusive disease. The mean age was 55.8 +/- 9.4 years. Approach was through a median sternotomy in 135 (91%) patients. Endarterectomy was performed in 32 (22%) patients, whereas 116 (78%) patients underwent bypass. RESULTS: Eight (5.4%) patients died in the perioperative period (four of heart-related causes, two of hemorrhage, one each of pulmonary infection and multiorgan failure). There were five (3.4%) perioperative strokes (three ipsilateral, two contralateral) and three (2.0%) ipsilateral perioperative transient ischemic attacks. Ten (7%) patients were lost to follow-up. Mean follow-up was 77 (2 to 193) months. Thirty three (24%) patients were monitored 10 or more years. There were 45 (35%) late deaths (19 from cardiovascular-related causes, 15 from cancer, 7 from other known causes, and 4 from unknown causes). Although 11 (8.5%) patients had late neurologic events, only one late stroke occurred in the contralateral hemisphere and no ipsilateral late strokes occurred. Sixteen (11%) patients had late myocardial infarctions, nine of which were lethal. Life-table analysis and perioperative events were used to calculate the probability of survival, which was 77.5% +/- 9.5% and 51.9% +/- 20.8% at 5 and 10 years, respectively, with a 4.4% annual mortality rate. The overall probability of freedom from any neurologic/ocular event was 88.8% +/- 6.2% and 80.4% +/- 11.9% at 5 and 10 years, respectively, with a 1.6% annual occurrence rate. The probability of freedom from ipsilateral neurologic/ocular event was 92.7% +/- 4.8% and 84.0% +/- 11.2% at 5 and 10 years, respectively, with a 1.4% annual occurrence rate. The probability of freedom from ipsilateral stroke was 98.6% +/- 1.9% at 5 and 10 years. The primary patency rate was 98.4% +/- 2.1% and 96.3% +/- 4.7% at 5 and 10 years, respectively. The probability of freedom from reoperation was 95.6% +/- 3.9% and 93.5% +/- 5.9% at 5 and 10 years, respectively. CONCLUSIONS: Surgical reconstruction of IA atherosclerotic occlusive disease yields acceptable rates of perioperative complications and late mortality and excellent long-term patency and freedom from neurologic events and reoperation. PMID- 7853606 TI - The natural history of moderate (50% to 79%) internal carotid artery stenosis in symptomatic, nonhemispheric, and asymptomatic patients. AB - PURPOSE: This study was undertaken to determine the incidence of disease progression of moderate (50% to 79%) internal carotid artery stenosis in patients with symptoms, patients with nonhemispheric symptoms, and symptom-free patients and to define the risk of development of new neurologic events in each group. METHODS: Over a 6-year period, 272 patients with moderate internal carotid artery stenoses were monitored for a mean of 44 months with color-flow duplex scanning (CFS). At the time of the initial scan, 142 patients were symptom free, 87 had experienced transient ischemic attacks, amaurosis fugax, or mild strokes, and 43 had ill-defined nonhemispheric symptoms. The average number of follow-up scans was 2.4 per patient (range 1 to 11). RESULTS: During follow-up, 23 (26%) of the patients with symptoms, 17 (40%) of the patients with nonhemispheric symptoms, and 30 (21%) of the symptom-free patients had development of additional neurologic symptoms. Life-table comparison of ipsilateral ischemic events showed a significantly (p = 0.03) higher cumulative rate in the symptomatic group (20%) than in the asymptomatic group (7%) at 2 years. Mean annual stroke rates were 6% and 2% in patients in the symptomatic and asymptomatic groups, respectively. None of the patients in the nonhemispheric group had a stroke within 4 years of the initial study. Disease progression occurred in 16% of the patients. In the asymptomatic group, ipsilateral stroke occurred more frequently (p = 0.0001) in patients with disease progression (25%) than in patients with stable lesions (1%). CFS detected disease progression in 19 (79%) of 24 patients before the artery occluded or stroke occurred. In patients with symptoms, stroke was more frequent (p = 0.02) in patients with six or more risk factors (29%) than in those with five or fewer risk factors (7%). CONCLUSION: Although the risk of stroke is less in patients with moderate stenosis than it is in patients with severely stenotic lesions, symptom-free patients with advancing disease and patients with symptoms and multiple risk factors are at increased risk for development of neurologic events. These findings support the use of CFS to monitor patients with carotid artery disease and suggest that a more aggressive surgical approach may be indicated in selected patients with moderate carotid artery stenosis. PMID- 7853605 TI - Compromised cerebral blood flow reactivity is a predictor of stroke in patients with symptomatic carotid artery occlusive disease. AB - PURPOSE: The purpose of this study was to determine whether the hemodynamic consequences of extracranial carotid disease correlate with the risk of subsequent cerebral infarction. METHODS: In 95 patients with symptoms who had greater than or equal to 70% stenosis (31 patients) or who had occlusion (64 patients) of the ipsilateral carotid artery, cerebral blood flow was measured by the stable xenon/computed tomography technique both at baseline and after vasodilatory challenge with intravenous acetazolamide. Patients were stratified into group 1, 43 patients with no more than a 5% decrease in flow in any vascular territory, and group 2, 52 patients with greater than a 5% decrease in one or more vascular territories after an acetazolamide challenge. RESULTS: In group 2, 15 (28.9%) of 52 patients had a new stroke, but only one (2.3%) of 43 patients in group 1 did (p = 0.0005). Of patients with total carotid occlusion 10 (26%) of 38 in group 2 and none (0%) of 26 in group 1 had a new stroke (p = 0.003). Of patients with greater than or equal to 70% stenosis, five (36%) of 14 in group 2 and only one (6%) of 17 in group 1 had a stroke (p = 0.067). CONCLUSION: The loss of cerebral reactivity in patients with symptoms who had greater than or equal to 70% carotid stenosis or occlusion is an important predictor of impending cerebral infarction. PMID- 7853608 TI - A piece of my mind. Cristina. PMID- 7853609 TI - Research in emergency circumstances. PMID- 7853607 TI - Risk factors for stroke after cardiac surgery: Buffalo Cardiac-Cerebral Study Group. AB - PURPOSE: The purpose of this study was to identify risk factors for stroke in patients undergoing heart surgery. METHODS: A retrospective chart review of patients who underwent cardiac surgery in three hospitals of the State University of New York at Buffalo system over a 36-month period was completed. Demographics and risk factors were recorded, and stroke and death were determined by chart review. Carotid artery stenosis was determined by duplex examination. Data were analyzed by chi-squared and multiple logistic regression. RESULTS: One thousand one hundred seventy-nine cases were analyzed, with a mortality rate of 2.3%, stroke rate of 1.6%, and combined stroke/death rate of 3.1%. Four variables were found to be associated with an increased risk of stroke: carotid artery stenosis greater than 50%, redo heart surgery, valve surgery, and prior stroke. Five variables were associated with increased mortality rates:; carotid artery stenosis greater than 50%, redo surgery, peripheral vascular disease, longer pump time, and hypercholesterolemia. Carotid artery stenosis greater than 50% was present in 14.7% of cases. Carotid artery stenosis greater than 75% was not itself associated with increased stroke risk. Most strokes occurred more than 24 hours after surgery. Stroke distribution did not correlate with site of carotid artery stenosis greater than 50%. CONCLUSIONS: Most neurologic events after heart surgery occur in a subset of patients who can be defined before operation. Whereas carotid artery stenosis greater than 50% is a strong risk factor, the role of prophylactic endarterectomy is unclear. Future studies should focus on this high-risk subgroup. A prospective study of prophylactic carotid endarterectomy in patients undergoing coronary artery bypass grafting is needed. PMID- 7853610 TI - First annual medical alliance month starts today. PMID- 7853611 TI - Why has 'historic' public disclosure of hospital performance data attracted so little attention? PMID- 7853612 TI - From the Joint Commission on Accreditation of Healthcare Organizations. PMID- 7853613 TI - From the Centers for Disease Control and Prevention. Update: acquired immunodeficiency syndrome--United States, 1994. PMID- 7853614 TI - From the Centers for Disease Control and Prevention. Recommended childhood immunization schedule--United States, January 1995. Advisory committee on Immunization Practices, American Academy of Pediatrics, and American Academy of Family Physicians. PMID- 7853615 TI - From the Centers for Disease Control and Prevention. Occupational silicosis- Ohio, 1989-1994. PMID- 7853616 TI - The appropriateness of tympanostomy tubes for children. PMID- 7853618 TI - The appropriateness of tympanostomy tubes for children. PMID- 7853617 TI - The appropriateness of tympanostomy tubes for children. PMID- 7853619 TI - The appropriateness of tympanostomy tubes for children. PMID- 7853620 TI - The appropriateness of tympanostomy tubes for children. PMID- 7853621 TI - The appropriateness of tympanostomy tubes for children. PMID- 7853622 TI - The appropriateness of tympanostomy tubes for children. PMID- 7853623 TI - The appropriateness of tympanostomy tubes for children. PMID- 7853624 TI - The appropriateness of tympanostomy tubes for children. PMID- 7853625 TI - Mammographic screening in women younger than 50 years. PMID- 7853626 TI - Ethnicity, sex, and the NBME Part I examination. PMID- 7853627 TI - Determinants in Canadian health care workers of the decision to withdraw life support from the critically ill. Canadian Critical Care Trials Group. AB - OBJECTIVE: To examine the attitudes of health care workers regarding the withdrawal of life support. DESIGN: Cross-sectional survey. PARTICIPANTS: Attending staff, house staff, and intensive care unit (ICU) nurses in 37 Canadian university-affiliated hospitals. MAIN OUTCOME MEASURES: Health care workers' ratings of the importance of 17 factors considered in the decision to withdraw life support, and their ratings of five levels of care ranging from comfort measures to intensive care in two of 12 different clinical scenarios. RESULTS: We surveyed 1361 respondents (149 of 167 potentially eligible ICU attending staff, 142 of 173 ICU house staff, and 1070 of 1455 ICU nurses, with response rates of 89%, 82% and 74%, respectively). The most important factors were likelihood of surviving the current episode, likelihood of long-term survival, premorbid cognitive function, and age of the patient. In choosing the level of care for the patient scenarios, the same option was chosen by more than 50% of respondents in only one of 12 scenarios; opposite extremes of care were chosen by more than 10% of the respondents in eight of 12 scenarios. Respondent characteristics affecting choices included the number of years since graduation, the city and province in which they worked, the number of beds in their ICU, and their assessment of the likelihood that they would withdraw life support in comparison with their colleagues (P < .001 for all comparisons). CONCLUSIONS: While ICU health care workers consistently identify a number of patient factors as important in decisions to withdraw care, there is extreme variability, which may be explained in part by the values of individual health care providers. PMID- 7853628 TI - Birth weight and perinatal mortality. A comparison of the United States and Norway. AB - OBJECTIVE: To compare perinatal mortality in the United States and Norway, using a new analytic approach based on relative birth weight. DESIGN: Comparison of linked birth and perinatal death records for US and Norwegian births from 1986 through 1987, the most recently available 2-year period. SETTING: Norway and the United States. PARTICIPANTS: A total of 7,445,914 US births and 105,084 Norwegian births. INTERVENTIONS: None. MAIN OUTCOME MEASURE: Perinatal weight-specific mortality after adjustment for each country's own mean birth weight. RESULTS: The higher rate of perinatal death in the United States compared with Norway is due to an excess of preterm deliveries in the United States. Low-weight, preterm births comprise 2.9% of US births compared with 2.1% of Norwegian births. If the United States could eliminate this slight excess of preterm delivery, perinatal mortality in the United States would decrease to the level in Norway. Unexpectedly, the survival of newborns at any given birth weight is virtually the same in the United States and Norway when newborns' birth weights are considered relative to their own nation's mean weight. CONCLUSIONS: Low rates of perinatal mortality in the Scandinavian countries have usually been attributed to the heavier weights of their newborns. Higher mortality among US infants is in fact due entirely to a small excess of preterm deliveries. The lighter weights of US newborns at term appear not to affect perinatal survival. Furthermore, the apparent survival advantage of low-weight US newborns (used by policymakers as evidence of superior US intensive neonatal care) may be at least partly an artifact. When weight-specific mortality rates are adjusted to relative birth weight, low-weight newborns have the same survival in Norway as in the United States. The prevention of excess mortality among US infants depends on the prevention of preterm births, not on changes in mean birth weight. PMID- 7853629 TI - Foot infections in diabetic patients. Decision and cost-effectiveness analyses. AB - OBJECTIVE: To examine the cost-effectiveness of approaches to the diagnosis and treatment of patients with type II (non-insulin-dependent) diabetes mellitus (NIDDM) who have foot infections and suspected osteomyelitis. DESIGN: Decision and cost-effectiveness analyses were performed using a Markov model. We examined the prevalence of osteomyelitis, the major complications and efficacies of long term antibiotic therapy and surgery, and the performance characteristics of four diagnostic tests (roentgenography, technetium Tc 99m bone scanning, indium in 111 labeled white blood cell scanning, and magnetic resonance imaging). Data were drawn from the English-language literature using MEDLINE searches and bibliographies from selected articles. SETTING: Primary care. PATIENTS: Patients with NIDDM who had foot infections and suspected osteomyelitis but no signs of systemic toxicity. INTERVENTIONS: Following hospitalization for surgical debridement and intravenous antibiotic therapy: (1) treatment for presumed soft tissue infection, (2) culture-guided empiric treatment for presumed osteomyelitis, (3) 71 combinations of diagnostic tests preceding antibiotic therapy for osteomyelitis, (4) 71 combinations of tests preceding amputation, and (5) immediate amputation. MAIN OUTCOME MEASURES: Quality-adjusted life expectancy, average costs. RESULTS: Culture-guided empiric treatment for osteomyelitis with 10 weeks of oral antibiotic therapy has similar effectiveness to testing followed by a long course of antibiotic therapy if any test result is positive. However, empiric treatment is the least expensive strategy. CONCLUSIONS: Noninvasive testing adds significant expense to the treatment of patients with NIDDM in whom pedal osteomyelitis is suspected, and such testing may result in little improvement in health outcomes. In patients without systemic toxicity, a 10-week course of culture-guided oral antibiotic therapy following surgical debridement may be as effective as and less costly than other approaches. PMID- 7853630 TI - Probing to bone in infected pedal ulcers. A clinical sign of underlying osteomyelitis in diabetic patients. AB - OBJECTIVE: To assess a bedside technique for diagnosing osteomyelitis. DESIGN: We prospectively assessed infected pedal ulcers for detectable bone by probing with a sterile, blunt, stainless steel probe. We then examined the relationship between detection of bone and the presence or absence of osteomyelitis that was defined histopathologically and/or clinically. SETTING: A tertiary care center. PATIENTS: Seventy-five hospitalized diabetic patients with a total of 76 infected foot ulcers were studied. RESULTS: Osteomyelitis was diagnosed in 50 instances (66%) and was excluded in 26 instances. Bone was detected by probing in 33 of 50 ulcers with contiguous osteomyelitis; in contrast, bone was probed in only four of 26 ulcers without contiguous osteomyelitis (P < .001). Bone detected on probing was visible in only three instances. Palpating bone on probing the pedal ulcer had a sensitivity of 66% for osteomyelitis, a specificity of 85%, a positive predictive value of 89%, and a negative predictive value of 56%. CONCLUSIONS: Palpation of bone in the depths of infected pedal ulcers in patients with diabetes is strongly correlated with the presence of underlying osteomyelitis. If bone is palpated on probing, specialized roentgenographic and radionuclide tests to diagnose osteomyelitis are unnecessary. Probing for bone should be included in the initial assessment of all diabetic patients with infected pedal ulcers. PMID- 7853631 TI - Language barriers in medicine in the United States. PMID- 7853632 TI - Helicobacter pylori, gastroduodenal disease, and recurrent abdominal pain in children. AB - OBJECTIVE: To assess the evidence for a cause-and-effect relationship between Helicobacter pylori infection and antral gastritis, peptic ulcer disease, and recurrent abdominal pain in children. DATA SOURCES: A MEDLINE search from January 1983 through July 1994 was used to identify pertinent English-language publications. Current Contents and selected specialty journals were searched manually. Editorials, reviews, case reports, abstracts, and letters to the editor were excluded. STUDY SELECTION: All studies in children (ie, 0 to 18 years) were included. DATA EXTRACTION: Hill's criteria for causal inference were used to determine the strength of the evidence for a causal relationship. DATA SYNTHESIS: In total, 45 studies (case series, cross-sectional surveys, and treatment trials) were retrieved. The rate ratio of antral gastritis in children with H pylori infection (compared with uninfected children) ranged from 1.9 to 71.0 (median, 4.6). The prevalence of H pylori infection in children with duodenal ulcer was high (range, 33% to 100%; median, 92%) compared with children with gastric ulcer (range, 11% to 75%; median, 25%). Prevalence rates of infection in children with recurrent abdominal pain were inconsistent (range, 0% to 81%; median, 22%), with lower rates in children meeting Apley's criteria (range, 0% to 9%; median, 6%). CONCLUSIONS: There is strong evidence for an association between H pylori infection and antral gastritis and duodenal ulcer disease in children; however, data from randomized, double-blind, placebo-controlled treatment trials are required. There is weak evidence for an association with gastric ulcer and weak or no evidence for an association with recurrent abdominal pain. PMID- 7853633 TI - Human T-cell lymphotropic virus type I-associated adult T-cell leukemia. The Joseph Goldberger Clinical Investigator Lecture. PMID- 7853634 TI - Withdrawing life support. How is the decision made? PMID- 7853635 TI - The continuing challenge of preterm delivery. PMID- 7853636 TI - A historical review of Pneumocystis carinii. PMID- 7853637 TI - [Premedications and NPO status in anesthesia of pediatric patients]. PMID- 7853639 TI - [Cardiopulmonary resuscitation]. PMID- 7853638 TI - [Anesthetic management for fetuses and premature infants]. PMID- 7853640 TI - [Advances in brain protection]. PMID- 7853641 TI - [Sleep regulation and sleep substances]. PMID- 7853642 TI - [The new tendency on clinical anesthesia]. PMID- 7853643 TI - [Preoperative care, but not premedication]. PMID- 7853644 TI - [Induction of anesthesia with the combination of midazolam and barbiturate]. PMID- 7853645 TI - [Total intravenous anesthesia]. PMID- 7853646 TI - [Low-flow, closed-circuit anesthesia]. PMID- 7853647 TI - [Laryngeal mask for general anesthesia]. PMID- 7853648 TI - [Spinal-continuous epidural anesthesia]. PMID- 7853649 TI - [Anesthesia for laparoscopic surgery]. PMID- 7853650 TI - [Quality assurance in anesthesia]. PMID- 7853651 TI - [Anesthesia and nitric oxide]. PMID- 7853653 TI - [Vascular endothelium and anesthesia]. PMID- 7853652 TI - [Roles of nitric oxide in the body]. PMID- 7853655 TI - [Role of nitric oxide in the nociceptive information transmission in the spinal cord]. PMID- 7853654 TI - [New concepts in anesthetic management of coronary artery bypass graft surgery]. PMID- 7853656 TI - [Nitric oxide and volatile anesthetics]. PMID- 7853657 TI - [Inhalational nitric oxide therapy for pulmonary hypertension]. PMID- 7853658 TI - [Anesthesia and nitric oxide]. PMID- 7853659 TI - [Recent advances in continuous noninvasive monitoring for the perioperative patients]. PMID- 7853660 TI - [Continuous intra-arterial blood gas monitoring]. PMID- 7853661 TI - [Evaluation of cerebral circulation with transcranial Doppler]. PMID- 7853662 TI - [Continuous respiratory monitoring for lung mechanics determination at bedside: instrumentation and clinical evaluation]. PMID- 7853663 TI - [Near-infrared spectrophotometry for perioperative patients monitoring]. PMID- 7853664 TI - [The effects of inhalation anesthetics on cardiac function]. PMID- 7853665 TI - [Pathophysiologic rationales for clinical management of heart failure]. PMID- 7853666 TI - [Reappraisal of airway management for anesthetists]. PMID- 7853667 TI - [Reconsideration of mechanical ventilation on the basis of pulmonary pathophysiology]. PMID- 7853668 TI - [Analgesia by spiral cord stimulation]. PMID- 7853669 TI - [Anesthesia for patients with increased intracranial pressure]. PMID- 7853670 TI - [Malignant hyperthermia--clinical update]. PMID- 7853671 TI - [The evaluation of preoperative pulmonary function]. PMID- 7853672 TI - [Current role of penicillin antibiotics: focused on sulbactam sodium/ampicillin sodium. Discussion]. PMID- 7853673 TI - [Re-evaluation of current antimicrobials. Series 19: ceftriaxone. Discussion]. PMID- 7853674 TI - [Re-evaluation of current antimicrobials. Series 20: netilmicin sulfate. Discussion]. PMID- 7853675 TI - [Re-evaluation of current antimicrobials. Series 21: cefixime. Discussion]. PMID- 7853676 TI - [Pharmacokinetic, bacteriological and clinical studies on cefozopran in children]. AB - Pharmacokinetic, bacteriological and clinical studies on cefozopran (CZOP) were performed in children. The results were as followed: 1. A total of 13 patients were treated with CZOP. The tested dose was 20 mg/kg (50 mg/kg in maxillary sinusitis), and the drug administered via intravenous bolus injection or 30 minute intravenous drip infusion 3 times daily, for 3-11 days. Clinical efficacies of CZOP in 13 patients with bacterial infections (11 with pneumonia, 1 with otitis media and 1 with maxillary sinusitis) were evaluated as excellent in 13 with an efficacy rate of 100%. Any adverse reactions or abnormal laboratory test results were not observed in any patients. Fourteen causative strains were found in 10 patients. Streptococcus pneumoniae in 4 cases out of 4, Streptococcus pyogenes in 1/1, Moraxella (Branhamella) catarrhalis in 3/3, Haemophilus influenzae in 4/6 were eradicated. 2. Pharmacokinetic studies. The mean serum concentration immediately after intravenous drip infusion over 30-minute of 20 mg/kg was 39.1 micrograms/ml (range: 25.6-52.5 micrograms/ml). The mean urinary recovery rate over 8 hours after administration was 49.0% (range: 45.2-51.8%). Based on the above results and the broad spectrum and great antibacterial activity of CZOP, it is considered that CZOP is a promising antibiotic usable as a single agent for the primary therapy of acute bacterial infections ranging from mild to severe in children. PMID- 7853677 TI - [Clinical evaluation of cefozopran in the pediatric field]. AB - A new parenteral cephem, cefozopran (CZOP), was evaluated for its safety and efficacy in 21 children with acute infections. A mild side effect or an abnormality in laboratory tests was observed in one case each, but the safety of CZOP was otherwise observed. CZOP was effective in all of the 18 bacterial infections tested including pneumonia, cellulitis and urinary tract infections, and all the causative organisms were eradicated. Serum half-lives of CZOP were 1.5-1.8 hours and the urinary excretion rates were 63-96% in the first 5-8 hours after administration. These data suggest that CZOP is safe and effective in children with susceptible bacterial infections. PMID- 7853678 TI - [Studies on cefozopran in the pediatric field]. AB - Pharmacokinetic and clinical evaluations of cefozopran (CZOP) were carried out in pediatric patients. The following results were obtained: 1. Upon 30-minute intravenous drip infusion at a dose of 20mg/kg, plasma concentrations of CZOP reached their peaks at the end of drip infusion with an average value of 77.1 micrograms/ml, and the average plasma half-life was 1.78 hours in the beta-phase. Upon 30-minute intravenous drip infusion at a dose of 10 mg/kg, peak plasma concentration was 40.5 micrograms/ml and plasma half-life was 1.62 hours. 2. The urinary excretion rates of CZOP after 30-minute intravenous infusion at doses of 20 and 10 mg/kg were 53.2% and 56.2%, respectively. 3. CZOP was administered to 17 cases (upper and lower respiratory tract infections, pneumonia, lymphadenitis and urinary tract infections) at daily doses of 60-90 mg/kg divided into 3 dosages using 30-minute intravenous drip infusion. Clinical responses were "excellent" in 13 patients, "good" in 3, and "poor" in 1, hence the efficacy rate of 94.1% was obtained. 4. Bacteria identified from various disease cases included 19 strains of 8 species, and the eradication rate was 94.7%. 5. Soft stool occurred in 1 case as an adverse reaction. Laboratory test results showed abnormalities in 2 cases with elevation of GOT and GPT. PMID- 7853679 TI - [Pharmacokinetic and clinical studies on cefozopran in pediatrics]. AB - Cefozopran (CZOP, SCE-2787), a new parenteral cephalosporin antibiotic, was studied for its pharmacokinetics, bacteriological and clinical effects in the field of pediatrics. The serum and cerebrospinal fluid concentrations 1 hour after a bolus intravenous injection of 50 mg/kg were, respectively, 92.1, 10.5 micrograms/ml, and penetration rate to cerebrospinal fluid of CZOP in patients with purulent meningitis was 11.4%. 25 patients, including those with purulent meningitis, pneumonia, urinary tract infections, staphylococcal scalded skin syndrome (SSSS) etc., were treated with CZOP at dose levels of 16.0 to 50.0 mg/kg 3-4 times daily, via intravenous injection and intravenous drip infusion. CZOP gave "excellent" or "good" responses in all the 25 patients. In bacteriological examinations, 25 strains were identified and were eradicated except 1 strain of Staphylococcus aureus and 2 strains of Salmonella sp. As a side effect, diarrhea was observed in 1 patient among the 27 patients treated with the drug. As for abnormal laboratory findings, eosinophilia was observed in 1 patient, increases of thrombocytes in 3 and GPT in 2. Influences on blood coagulation parameters were studied. No changes in PIVKA II, HPT or APTT were observed during the treatment. Based on the above results, it has been concluded that CZOP is a safe and effective drug to use in the treatment of pediatric infections. The normal recommended dosage and administration should be 20 to 50 mg/kg of CZOP at a time, using intravenous injection or intravenous drip infusion 3 to 4 times a day. PMID- 7853680 TI - [Pharmacokinetic and clinical evaluation of cefozopran in the pediatric field]. AB - We conducted pharmacokinetic and clinical studies on cefozopran (CZOP, SCE-2787), an aminothiadiazolmethoxyiminoacetamido cephalosporin, and obtained the following results. 1. Concentrations in serum/excretion in urine We studied pharmacokinetic in children upon intravenous bolus injection and 30-minute intravenous drip infusion in single doses of 10 and 20 mg/kg. Upon intravenous bolus injection, mean serum concentrations 30 minutes after administration of 10 and 20 mg/kg were 27.8 and 52.3 micrograms/ml, respectively, and half-lives were 2.01 and 2.02 hours, respectively. Upon 30-minute intravenous drip infusion, mean serum concentrations on completion of the drip infusions of 10 and 20 mg/kg were 36.8 and 70.3 micrograms/ml, respectively, and half-lives were 1.74 and 4.11 hours, respectively. Their urinary recovery rates in the first 8 hours after administration were higher than 67.0% in the former regimen and between 23.2 to 98.0% in the latter. 2. Clinical results 54 patients were treated with CZOP for 32 cases of pneumonia, 11 cases of bronchitis, 3 cases of cervical lymphadenitis, 1 case of purulent tonsillitis, 2 cases of phlegmon, 2 cases of enterogastritis and 3 cases of urinary tract infections. CZOP gave "excellent" or "good" responses in 53 cases. 1 case of urinary tract infection showed fair response. Diarrhea was observed in 1 case. Abnormal laboratory test results were noted in 9 patients including elevations of eosinophils, GOT and GPT. In no cases the treatment had to be discontinued. PMID- 7853681 TI - [Pharmacokinetic and clinical studies of cefozopran in the field of pediatrics]. AB - Pharmacokinetic and clinical studies on cefozopran (CZOP, SCE-2787), a new cephalosporin antibiotic, were carried out in the field of pediatrics. The results obtained are summarized below. 1. Serum concentrations and urinary excretion rates were determined after intravenous bolus injection of CZOP at a dose of 20 mg/kg for 5 minutes in 3 cases. The mean serum concentration of CZOP was 45.9 micrograms/ml at 30 minutes with the serum half-life of 1.77 hours. The mean cumulative urinary excretion rate in the first 8 hours after administration was 71.4%. 2. Fourteen patients with bacterial infections (pneumonia 9 cases, urinary tract infection 4 cases and lymphadenitis 1 case) were treated with CZOP at a daily dose of 55.8-65.7 mg/kg. The overall clinical efficacy and bacteriological eradication rates were both 100%. 3. No adverse reactions were observed. Abnormal laboratory test results were mild, slight elevation of GOT and GOT, GPT & LDH in 1 each and eosinophilia and thrombocytosis in 2 cases each. PMID- 7853682 TI - [Pharmacokinetic and clinical evaluation of cefozopran in the pediatric field]. AB - We conducted a pharmacokinetic and clinical studies on cefozopran (CZOP), a new cephem antibiotic for injection. 1. Changes in serum levels of the agent after intravenous bolus injection at a dose of 20 mg/kg to 4 pediatric patients (age: 5 10 years) were observed. The levels at 30 minutes after injection were 32.9-73.4 micrograms/ml average: 55.4 +/- 18.1 micrograms/ml), then the levels gradually decreased with half-lives of 1.67-2.24 hours (average: 1.85 +/- 0.27 hours) to 0.8-1.8 micrograms/ml (average: 1.2 +/- 0.4 micrograms/ml) at 8 hours after injections. Urinary levels reached at the maximum as, 1,773-3,450 micrograms/ml (average: 2,693 +/- 698 micrograms/ml) within 0-2 hours or 2-4 hours after injection, and recovery rates from urine in the first 8 hours after injection were 55.4-91.1% (average: 71.6 +/- 16.8%). 2. Transition to cerebrospinal fluid was examined in cases with purulent meningitis and aseptic meningoencephalitis. In the meningitis case, the level in cerebrospinal fluid 1 hour after administration was 8.8 micrograms/ml in the second day after the start of 4 times a day intravenous bolus injections with 42.5 mg/kg at each dose; The ratio of the drug level in cerebrospinal fluid to that in serum was 24.0%. In the meningoencephalitis, the levels in cerebrospinal fluid 1 hour after administrations were 1.1 micrograms/ml and 1.5 micrograms/ml in the second and the sixth days respectively, after the start of 4 times a day intravenous bolus injections with 50 mg/kg at each dose; the ratio of the levels in cerebrospinal fluid to those in sera were 0.93% and 2.41% respectively, at the second and the sixth day. 3. CZOP was clinically evaluated in 29 cases (ages: 2 months to 15 years) of pediatric infectious diseases. The agent was administered 3-4 times daily with 17-50 mg/kg at each dose, continued for 5-13 days. Total doses were 1.95-24.05 g. Clinical efficacy was evaluated in a total of 28 cases (1 case of purulent meningitis, 2 cases of acute purulent tonsillitis, 20 cases of acute pneumonia, 3 cases of urinary tract infections, 1 case of purulent lymphadenitis in cervical part and 1 case of cellulitis in face); The efficacies were "excellent" in 22 cases and "good" in 6 cases.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7853683 TI - [Pharmacokinetic and clinical studies of cefozopran in the field of pediatrics]. AB - Cefozopran (CZOP) was administered intravenously to 22 infants (aged 3 months to 15 years) with infections excluding suppurative meningitis in doses of 10 to 40 mg/kg 3 to 4 times daily for periods of 3 to 16 days and its efficacy and safety in infantile infections as well as pharmacokinetic parameters were determined. The half-lives of CZOP after intravenous administration at doses of 10, 20 and 40 mg/kg were 2.84, 2.36 +/- 0.67, and 2.48 hours, respectively. The rates of recovery in the urine within 6 hours of administration were 83.6%, 62.9 +/- 23.1%, and 77.3%, respectively. The subjects for whom drug responses were evaluable consisted of 1 case of suppurative meningitis, 8 cases of respiratory tract infection, 2 cases of urinary tract infection, 2 cases of oral infection, 2 cases of pharyngotonsillitis, 1 case of skin soft tissue infection, and 1 case of external otitis, totaling 17 cases. The efficacy rate was 88.2%. The drug proved so effective on suppurative meningitis in particular that the patient was healed without leaving any sequela behind. Seven strains were identified as causative pathogens (5 strains of Haemophilus influenzae, 1 strain of Staphylococcus aureus, 1 strain of group B Streptococcus) isolated from 6 patients. All but 1 strain were eradicated (the rate of eradication 83.3%). In the patients with suppurative meningitis the bacterial count of spinal fluid was markedly decreased 6 hours after drug administration and the organism was eradicated in 45 hours. Eruption was noted in 1 patient as a side effect of CZOP, but disappeared soon after discontinuation.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7853684 TI - [Bacteriological and clinical studies on cefozopran in pediatric field]. AB - We carried out clinical studies on cefozopran (CZOP, SCE-2787). The results are summarized as follows. Treatment with CZOP was made in 17 cases of pediatric bacterial infections including 2 cases of purulent tonsillitis, 11 cases of acute pneumonia and 2 cases each of urinary tract infections and enteritis. Results obtained were excellent in 12 cases, good in 2 cases, fair in 2 cases and poor in 1 case. All of 9 isolated bacteria were eradicated by the treatment. As side effects and laboratory test results, rash was observed in one case and transient increase of platelets in one case, slight increase of eosinophil in 2 cases and transient elevation of GPT and GOT.GPT in one case. PMID- 7853685 TI - [Clinical evaluation of a new parenteral cephem, cefozopran, in children]. AB - Cefozopran (CZOP, SCE-2787), a new parenteral cephem, was evaluated for its antibacterial activity and clinical efficacy. CZOP, 24.0-78.0 mg/kg/day, was given to 11 pediatric patients in 3 dose a day via 30-minute drip infusion. Clinically evaluated were nine patients including 4 with acute pneumonia, 2 with urinary tract infections, 2 with lymphadenitis and 1 with sepsis. Two patients were excluded because of possible non-bacterial infections. Clinical efficacies were excellent in 5, good in 3 and fair in 1. Bacteriological responses were confirmed for 5 strains in 5 patients. Four strains were eradicated, but one strain was not. MICs of CZOP were equal to those of ceftazidime. Side effects or abnormal laboratory test results were observed in 3 patients; diarrhea in 1, elevated GPT in 1 and thrombocytosis in 1, but none of them was significant. PMID- 7853686 TI - [Clinical studies on cefozopran in pediatrics]. AB - Cefozopran (CZOP) was administered via intravenous injection to 9 patients (ages ranging from 1 month to 13 years) with pediatric bacterial infections, at daily dose levels between 56.7 and 200 mg/kg, divided into 3 or 4 doses. The following results were obtained. 1. Eight patients, including 1 with purulent meningitis, 1 with sepsis, 3 with acute pneumonia and 3 with lymphadenitis, were treated and subjected to clinical evaluation. Clinical effects were excellent in 6 cases and good in 2, with an overall efficacy rate of 100%. One case with pyoderma was not evaluated because of a combined use of an external antibiotic. 2. Organisms suspected as pathogens included 5 strains: 3 strains of Haemophilus influenzae, 1 strain of Staphylococcus aureus and 1 of Escherichia coli. Bacteriologically, all the strains were eradicated. 3. Side effects or abnormal laboratory test results were observed in 4 cases; wheal in 1 case, elevated GOT and GPT in 2 cases and eosinophilia in 1 case. 4. From the results described above, we considered that CZOP would be an effective drug for use in pediatric bacterial infections. PMID- 7853687 TI - [Pharmacokinetic and clinical studies on cefozopran in the field of pediatrics]. AB - Blood and urine levels of cefozopran (CZOP) were determined, and its efficacy and safety profile was evaluated in the field of pediatrics. The results of this study are summarized as follows. 1. Blood levels of CZOP peaked in 30 minutes to 1 hour (initial blood collection) after intravenous administration at a dose of 20 or 40 mg/kg. Its blood levels at 6 hours after intravenous administration were 1.6 micrograms/ml (HPLC) or 1.9 micrograms/ml (bioassay) at a dose of 20 mg/kg and 2.9 to 9.1 micrograms/ml (HPLC) or 2.9 to 8.4 micrograms/ml (bioassay) at a dose of 40 mg/kg. The half-lives were 1.58 to 2.27 hours (HPLC) and 1.53 to 1.85 hours (bioassay), respectively. The rate of recovery of CZOP in the urine in the first 8 hours after intravenous administration at a dose of 20 mg/kg was 61.5% (HPLC) or 54.6% (bioassay), and urine levels of CZOP at 6 to 8 hours after administration were 157.3 micrograms/ml (HPLC) and 129.7 micrograms/ml (bioassay). 2. When CZOP was administered to 16 patients with respiratory tract infections, 2 patients with urinary tract infections, 2 patients with acute enteritis, 1 patient with skin soft tissue infection, and 1 patient with purulent lymphadenitis, the responses were excellent in 68% of patients and good in 32% with an overall efficacy rate of 100%. 3. Bacteriological effect of CZOP was excellent and the rate of bacterial eradication was 100% (9/9). 4. MICs of CZOP against clinical isolates (Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), Streptococcus pneumoniae, Escherichia coli, Moraxella (Branhamella) catarrhalis) were compared to those of other injectable cephems ceftazidime (CAZ), cefuzonam (CZON), flomoxef (FMOX), cefmetazole (CMZ). The MICs of cefozopran (CZOP) against Gram-positive organisms, S. aureus, MRSA, and S. pneumoniae, were nearly as low as those of CZON and were clearly lower than those of CAZ. MICs of CZOP against Gram-negative organisms were examined and the MIC against E. coli was as low as those of other antibiotics but the MIC of CZOP against M. (B.) catarrhalis was higher, at 1.56 micrograms/ml, than those of CAZ, FMOX, and CMZ. 5. Diarrhea was experienced by 1 of 22 patients as a side effect from CZOP, and abnormal laboratory tests including increases of eosinophil counts in 2 patients (9.1%), a decrease of neutrophil counts in 1 patient (4.5%), thrombocytosis in 1 patient (4.5%), and an elevation of GPT in 3 patients (13.6%).(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7853688 TI - [Clinical studies on cefozopran in pediatrics]. AB - We conducted clinical studies on cefozopran (CZOP), a newly developed parenteral cephalosporin, for its clinical application in the field of pediatrics. 1. A clinical study was performed on 16 children with infections, including 9 with pneumonia, 1 each with acute bronchitis, enterocolitis, purulent lymphadenitis, 4 with skin and soft tissue infections. CZOP was administered by 30 minutes intravenous drip infusion. Doses varying from 20 to 35 mg/kg body weight were given t.i.d. Lengths of treatment ranged from 4 to 14 days. 2. Clinical efficacies were excellent in 10 and good in 6 cases, with an efficacy rate of 100%. The overall bacterial eradication rate for the pathogenic bacteria was also 100%. 3. Side effect was noted in 1 case with skin rash. Abnormal laboratory test data were found in 5 cases including slight elevations of GPT in 4 cases and GOT in 2 cases. PMID- 7853689 TI - [Clinical studies on cefozopran in pediatrics]. AB - Cefozopran (CZOP, SCE-2787) was given intravenously to 12 children with acute bacterial infections including 9 with acute pneumonia, 1 each with acute pyothorax, impetigo and staphylococcal scalded skin syndrome. Good or excellent clinical responses were obtained in all of the 12 patients and bacterial eradications were achieved for all 10 strains identified in these cases. No side effects were noted. Eosinophilia was observed in one case, however. From the above clinical results, it appears that CZOP is a useful antibiotic for treatment of pediatric patients with various bacterial infections. PMID- 7853690 TI - [Pharmacokinetic, bacteriological and clinical studies on cefozopran in the pediatric field]. AB - Cefozopran (CZOP, SCE-2787), a newly developed parenteral cephem antibiotic, was administered to children with bacterial infections. We determined its antibacterial activity, pharmacokinetics, efficacy and safety in these patients. 1. Antibacterial activity MICs of cefmetazole, ceftazidime, cefuzonam, flomoxef and CZOP were determined against a total of 19 strains. For Gram-positive cocci, MICs of CZOP ranged from 0.39 to 0.78 microgram/ml against Staphylococcus aureus (3 strains), from 0.05 to 6.25 micrograms/ml against Streptococcus pneumoniae (5 strains), and 12.5 micrograms/ml against Enterococcus faecalis (1 strain). These MICs were generally similar to those of other cephems, but the MIC of CZOP against E. faecalis was lower than those of the other cephems examined. For Gram negative bacilli, MICs of CZOP were 25 micrograms/ml against Citrobacter freundii (1 strain), and 6.25 micrograms/ml against Pseudomonas aeruginosa (1 strain). These values were similar to or lower than those of other cephems, MICs of CZOP against Haemophilus influenzae (7 strains) ranged from 0.1 to 0.39 microgram/ml. However, the MIC of CZOP against Serratia marcescens (1 strain) was higher than 100 micrograms/ml, and CZOP was as ineffective as the other cephems against this organism. 2. Pharmacokinetics CZOP was administered to children at 20 or 40 mg/kg via intravenous injection, and determinations were made for its serum concentrations, urinary concentrations and concentrations in cerebrospinal fluid (CSF) using the bioassay. Serum concentrations at 30 minutes after administration were 60.4 micrograms/ml with a dose of 20 mg/kg to one patient and 93.9 and 99.0 micrograms/ml with 40 mg/kg to two patients. The corresponding half-lives were 1.55 hours for 20 mg/kg administration, and 1.10 and 3.41 hours for 40 mg/kg, while the AUCs were 136.5 micrograms.hr/ml for 20 mg/kg, and 194.4 and 264.5 micrograms.hr/ml for 40 mg/kg. The rates of urinary recovery in the first 8 hours after administration were 45.0% in the patient receiving 20 mg/kg, and 84.6 and 97.6% in the two patients receiving 40 mg/kg. The concentrations in the CSF determined in 3 patients with purulent meningitis ranged from 2.6 to 16.0 micrograms/ml 1 hour after administration, and the CSF/serum concentration ratio ranged from 6.5 to 39.0%. These values for pharmacokinetic parameters obtained in the bioassay were similar to those obtained using HPLC. 3. Clinical evaluation Forty-eight patients were clinically evaluated. Of these patients, 75% were less than 3 years of age and there were slightly more male children than female children.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7853691 TI - [Recent trends in research on lipoprotein metabolism]. AB - New trends in the research works on lipoprotein metabolism are focused on four aspects, namely metabolism of remnant particles, VLDL's, LDL's and HDL's. Metabolic behaviors of remnants, VLDL's and HDL's are closely related to the concentration or percentage of small dense LDL particles which are more susceptible to oxidation. Hyperinsulinism and increased hepatic triglyceride lipase could be involved in these disorders. PMID- 7853692 TI - [Lipoprotein (a)]. AB - Lipoprotein (a) [Lp (a)] is a low density lipoprotein (LDL) disulfide-linked to apolipoprotein (a) [apo (a)] and considered to be an independent risk factor for atherosclerotic cardiovascular disease. Apo (a) has a high homology with plasminogen, which has stimulated a lot of interest in the mechanism of atherogenicity and thrombogenicity of this lipoprotein. Recent advances in this mechanism were reviewed. We are still unclear about the physiological role of Lp (a). This research aspect must receive attention in the future. Furthermore, the most pressing need is for drugs that will lower serum Lp (a) concentrations. PMID- 7853693 TI - [Lipoprotein Z]. AB - The term lipoprotein Z (remnant-like particles) refers to lipoproteins that do not have an immunoaffinity to gel mixture of anti-apo A-I and apo B100 monoclonal antibodies (JI-H antibody). Lp Z is enriched in apo E and cholesterol esters. Quantification of this lipoprotein provides a useful index of atherogenic chyromicron and VLDL remnant particles. Serum concentration of this lipoprotein is well correlated to serum triglycerides in normal subjects and patients with hypertriglyceridemia, and to serum LDL-cholesterol in normal subjects. The normal range of this lipoprotein is below 5 mg/dl and the increased serum concentration is often observed in ischemic heart disease, diabetes mellitus, hypertriglyceridemia and fatty liver. PMID- 7853694 TI - [Modified low-density lipoprotein]. AB - Oxidative modification of low-density lipoprotein (LDL) has been implicated in the pathogenesis of coronary artery disease (CAD). Macrophages take up oxidized LDL via scavenger receptors, which is not regulated by cellular cholesterol contents, and oxidized LDL stimulates cholesterol esterification and this results in cellular cholesterol accumulation and foam cell formation. Several papers have reported a positive correlation between the severity of coronary atherosclerosis and the oxidative susceptibility of LDL. Small, dense LDL, LDL rich in polyunsaturated fatty acids (PUFA) or LDL poor in antioxidants (vitamin E, beta carotene, CoQ10) should be more susceptible to lipid peroxidation and possibly more atherogenic. Therefore, to prevent CAD, it is important not only to reduce LDL cholesterol levels but also to suppress the oxidative modification of LDL. PMID- 7853695 TI - [Glycosylated lipoprotein]. AB - Diabetes is frequently associated with cardiovascular diseases (coronary heart disease, cerebrovascular disease, peripheral vascular disease), and several risk factors have been proposed. Recent studies have strengthened the importance of chronic hyperglycemia because this modifies a variety of circulating substances including lipoproteins, and the glycosylated ones can be involved in the process of accelerating atherosclerosis. In this review, previous studies indicating the significance of glycosylated lipoproteins in the progression of atherosclerosis were overviewed. We also discussed AGE (advanced glycation end products) which may play an important role of atherogenesis in diabetes. PMID- 7853696 TI - [Structure and function of apolipoproteins]. AB - Plasma lipoproteins are macromolecular complexes that transport hydrophobic lipids, cholesteryl ester, and triglycerides, in their cores. Regulation of the plasma levels of the major lipoproteins, very low density lipoprotein (VLDL), low density lipoprotein (LDL), and high density lipoprotein (HDL) is complex, but the rate of secretion of these lipoproteins, and their accompanying apolipoproteins, are clearly key factors in this process. Apo B is the major apolipoprotein of VLDL and LDL, and plays a key role in assembling VLDL as well as in LDL receptor mediated catabolism of LDL. Apo E is the major apolipoprotein of chylomicron remnant and mediates the recognition by remnant receptor, VLDL receptor as well as LDL receptor. Apo A-I and apo C II are well known as activators of LCAT and LPL, respectively. The purpose of this article is to summarize the current information available concerning the relationship between the structure and function of apolipoproteins. PMID- 7853697 TI - [Apolipoproteins A]. AB - Apolipoproteins A include apoA-I, apoA-II and apoA-IV. These apolipoproteins are involved in the metabolism of HDL and reverse cholesterol transport. The genes encoding apoA-I, apoA-II and apoA-IV have arisen from a common ancestor. This review describes the structures of the genes encoding apoA-I, apoA-II and apoA IV, and the structures and functions of the gene products with special reference to the metabolism of HDL and reverse cholesterol transport. Further studies are required to elucidate the full role of apolipoproteins A, especially apoA-II and apoA-IV in HDL metabolism. Analysis of human genetic deficiency and transgenic animal model will be useful for the elucidation of the functions of apolipoproteins A. PMID- 7853698 TI - [Apolipoprotein B]. AB - The gene encoding human apo B has been mapped to the short arm of chromosome 2 in the p23-p24 region. The apo B gene extends over 43 kb and is composed of 29 exons and 28 introns. Both apo B 100 and apo B 48 were encoded by the same gene. All intestinal cDNA clones contained a single C to T base substitution in the codon CAA encoding Gln2153 in apo B 100 cDNA, resulting in a translational stop. In human intestinal cells, apo B mRNA is recognized by a specific enzyme that modifies cytosine 6666 to a uracil, introducing a stop codon. Recently, a human apo B mRNA editing protein was cloned. The cDNA sequence predicts a translation product of 236-aa residues. The human apo B mRNA editing protein is a cytidine deaminase and exists as a homodimer. Familial hypobetalipoproteinemia can be caused by mutations in the apoB gene that interfere with the translation of a full-length apo B molecule. Frequently, a truncated apo B molecule can be detected in the plasma lipoproteins of familial hypobetalipoproteinemia. Abetalipoproteinemia is caused by defect of the gene encoding the large subunit of a microsomal triglyceride transfer protein. PMID- 7853699 TI - [Apolipoprotein C gene and molecular biology]. AB - The biological structure and function of genes encoding the polypeptide components of apolipoprotein C are of importance because of the central role they play in the regulation of triglycerides rich lipoprotein metabolism. On this paper, we summarized the current knowledge of apolipoprotein C-I, C-II and C-III gene and the molecular structure. An improved understanding of the structural relationship of apolipoprotein C will help elucidating the mechanism of triglycerides metabolism. PMID- 7853700 TI - [Apolipoprotein E]. AB - Apolipoprotein E (apo E) is one of the apolipoprotein components in very low density lipoproteins (VLDL) and high density lipoproteins (HDL). Apo E binds to low density lipoprotein (LDL) receptors and apo E-specific remnant receptors, and regulates remnant lipoprotein metabolism through these receptors in the liver. In the general population, apo E shows genetic heterogeneity, with three alleles (epsilon 4, epsilon 3, and epsilon 4) which produce apo E isoproteins, apo E4, apo E3, and apo E2, respectively. Apo E2 is defective in its binding to lipoprotein receptors, resulting in the accumulation of lipoprotein remnants in the plasma. Type III hyperlipoproteinemia appears in a few percent of the individuals who are homozygous for apo E2 and the development of hyperlipoproteinemia requires the presence of other genetic or environmental factors. Even heterozygous individuals with apo E2 or apo E4 differ from those with only apo E3 in plasma lipoprotein metabolism. Subjects with an E3/2 phenotype had reduced LDL and increased VLDL levels, and those with an E4/3 phenotype had increased LDL levels in serum. In addition to these common apo E isoproteins, there are several unique mutants of apo E, which are associated with hyperlipoproteinemia and atherosclerosis. PMID- 7853701 TI - [Apolipoprotein (a)]. AB - Apo (a) consists of multiple tandem repeat of kringle 4, which resembles a counterpart of plasminogen. Plasma Lp (a) levels are genetically determined primarily by alleles at the apo (a) gene. Apo (a) shows size heterogeneity on the analysis of the protein and the mRNA. Pulse field gel electrophoresis revealed that size heterogeneity is largely due to different numbers of kringle 4-encoding sequences in the apo (a) gene. The cloning of apo (a) gene and identification of the 5'-flanking promoter region provide tools to study the regulation of apo (a) gene. The development of transgenic mice expressing human apo (a) offered a good model for understanding of atherosclerosis associated with elevated plasma levels of Lp (a). PMID- 7853702 TI - [Recent advances in apolipoprotein measurement]. AB - Owing to the development of protein measurement methods, apolipoprotein can be measured more rapidly and precisely. It has been only in recent years that apolipoprotein measurement widely prevails in the clinical field. Various apolipoprotein measurement systems are available for the clinical laboratory in Japan. Formerly, apolipoprotein was manually measured mainly by a single radial immunodiffusion system, but recently more sophisticated automated systems for apolipoprotein measurement have been developed and applied. The more the need to detect apolipoprotein in the clinical laboratory and the larger the scale for apolipoprotein measurement, the more progress to be made in rapidity and cost performance. That is, the advances in apolipoprotein measurement depend on the requirement of its test by the clinicians. In the global trend, standardization for apolipoprotein measurement is being discussed and is in progress. The effort of standardization is fulfilled in some results of external standardization surveys on apolipoprotein measurement. In this report, we introduced the advances in apolipoprotein measurement which supported the standardization process in Japan. PMID- 7853703 TI - [Lipoprotein lipase]. AB - We describe molecular and physiological properties of human lipoprotein lipase (LPL) based on recent advanced knowledges. Human LPL is a lipolytic glycoprotein enzyme synthesized by extrahepatic tissues, mainly adipocytes, and its gene is located on chromosome 8p22 with 10 exons that encode mRNAs of 3.4 kb and 3.8 kb. Clinical and biochemical studies indicate that LPL plays a key role in hydrolyzing the triglycerides of chylomicrons and very low density lipoproteins (VLDL) at the first step in their metabolism. LPL is believed to be taken on a functionally active form at the site of capillary endothelial cell surface following a series of three major processes: (1) the synthesis and secretion of LPL by adipocytes, (2) the transport of LPL from adipocytes to the capillary endothelium, and (3) the binding of LPL to heparan sulfate proteoglycan chains which are localized in the plasma membrane of the endothelium. LPL is released into the circulation after intravenous injection of heparin, and LPL is recovered in postheparin plasma (PHP). LPL purified from human PHP is catalytically active in a monomeric form, and its molecular size is 61 k dalton in good agreement with mature LPL size estimated by cDNA of LPL. PMID- 7853704 TI - [Hepatic triglyceride lipase]. AB - Human hepatic triglyceride lipase (HTGL) is a 476 residue glycoprotein that hydrolyzes triglyceride rich lipoproteins and high density lipoproteins. Comparison of the HTGL, LPL and PL gene structures established them as members of a lipase gene family. Familial HTGL deficiency is a rare disorder that is characterized by premature atherosclerosis and abnormal circulating lipoproteins. In HTGL transgenic mice, plasma HDL cholesterol and total cholesterol levels were found to be low and were correlated with decrease in the accumulation of aortic cholesterol. These results suggest that HTGL may have a protective effect against formation of atherosclerosis. PMID- 7853705 TI - [Lecithin: cholesterol acyltransferase]. AB - Lecithin:cholesterol acyltransferase (LCAT) is a plasma enzyme that catalyzes esterification of plasma lipoprotein unesterified cholesterol, and plays a central role in maintaining reverse cholesterol transport through action with high density lipoprotein (HDL) and Cholesterol ester transfer protein (CETP). Cloned cDNA sequence of LCAT, consisted of about 1400 base pair which codes 416 amino acids, revealed high content of alpha-helix and beta-sheet, identity of amino acid sequence with various lipases, and putative structure of catalytic sites and mechanism of enzymatic action is proposed. Close relationship between location of gene mutation and severity of clinical and biochemical characteristics revealed by gene analysis in patients of LCAT deficiency and Fish eye disease is summarized. PMID- 7853706 TI - [Cholesterol ester transfer protein (CETP)]. AB - Plasma CETP plays an important role in the reverse cholesterol transport system in conjunction with lecithin:cholesterol acyltransferase (LCAT). CETP mediates transfer of cholesteryl ester from HDL to apo B containing lipoproteins and also mediates transfer of triglyceride from VLDL and IDL to HDL. In this review, molecular characteristics, mechanism of lipid transfer, site of synthesis, factors regulating production and activity of CETP and lipoprotein abnormalities in CETP deficiency were described. High activity of CETP is considered to promote atherosclerosis, because the lipoprotein changes resulting from CETP activity are completely atherogenic and animals who have low CETP activity are resistant to atherosclerosis. PMID- 7853707 TI - [Molecular analysis of the LDL receptor]. AB - The LDL receptor is a cell surface glycoprotein that regulates plasma cholesterol by mediating endocytosis of LDL, the major cholesterol transport protein in human plasma. Mutations in the LDL receptor gene cause familial hypercholesterolemia (FH). The LDL receptor was purified in 1982, its cDNA was cloned in 1984 by Yamamoto et al, and its gene was isolated in 1985 by Sudhof et al. This review attempts to focus on the molecular basis of the LDL receptor pathway and its regulatory roles in cholesterol homeostasis in the body. PMID- 7853708 TI - [VLDL receptor]. AB - The LDL receptor was discovered by Goldstein and Brown in 1974. This discovery has led to dramatic progress toward understanding the mechanisms of cholesterol homeostasis. Recently we have found a second lipoprotein receptor that specifically binds apoE-containing lipoproteins. This new lipoprotein receptor designated VLDL receptor is composed of five functional domains that resemble the LDL receptor. The VLDL mRNA is abundant in heart, muscle and adipose tissue, suggesting that the receptor mediates the uptake of triglyceriderich lipoproteins thereby providing muscle and fat cells with fatty acid. PMID- 7853709 TI - [Regulation of gene expression by cholesterol and macrophage scavenger receptor]. AB - Cellular cholesterol level is strictly regulated by the synthesis and the incorporation of cholesterol. Cholesterol synthetic enzymes and lipoprotein receptors are regulated mainly at the transcriptional level. Recently, sterol regulatory element binding proteins (SREBPs) which induce LDL receptor expression, were cloned and the mechanism of sterol-mediated gene regulation was proposed. Cholesterol synthesizing enzymes such as HMG-CoA reductase, farnesyl pyrophosphate synthase and squalene synthase are also regulated by the cellular cholesterol level, but it is suggested that SREBPs are not play critical role in their regulation. Scavenger receptors also uptake cholesterol into macrophage, but the receptors are not regulated by the cellular cholesterol level and this leads to the abnormal accumulation of cholesterol in macrophages. PMID- 7853710 TI - [HDL receptor]. AB - Epidemiological studies have demonstrated that high density lipoprotein cholesterol (HDL-C) is inversely related to the incidence of coronary heart disease morbidity and mortality. In the present paper, we summarized the recently published data on HDL receptor, reverse cholesterol transport, and antiatherogenic effect of HDL particle. Several investigators have reported the apparent molecular weight of HDL binding protein using ligand blotting by radiolabeled HDL and immunoblotting by antibody against the purified binding protein. These results, however, were not consistent among the data reported from several laboratories. In 1992 a cDNA of HDL binding protein (HBP) was isolated from a human fibroblast and a human erythroleukemia cell cDNA library but it does not contain a classical hydrophobic membranes spanning domain. At present, it is reasonable to assume that HBP is different structurally and functionally from a classical plasma membrane receptor. We hope putative HDL receptor will be isolated, characterized and its cDNA will be cloned in the near future. It has been postulated that there are four functional steps in the pathway of reverse cholesterol transport. The main step is CETP-mediated transfer of cholesteryl esters from HDL to the VLDL/LDL fraction. Recent development of molecular biological techniques enable us to make a animal model over expressing apolipoprotein A-I or A-II, namely a transgenic mouse. These models indicated that apolipoprotein A-I has an antiatherogenic effect in vivo but apolipoprotein A-II does not. PMID- 7853711 TI - [Genotyping of hyperlipoproteinemia]. AB - In lipoprotein metabolism are involved many proteins among which are apolipoproteins, lipoprotein receptors, lipases and lipid transfer proteins. Recent years the DNAs have been cloned for almost all of these proteins and their construction has been characterized. Through the analysis of the cases with inherited lipid disorders, the molecular basis of hyperlipoproteinemia has been elucidated and the functional domains of the proteins have been clarified, which enabled us the genotyping of hyperlipoproteinemia. So far, many mutations and polymorphisms have been identified to explain the genesis of hyperlipoproteinemias. However, for the majority of the cases, genetic causes are still ambiguous, and some of them are supposed to be rather polygenic. This review deal with the characteristics of the genes involved in lipoprotein metabolism and the genetic mechanisms including gene-gene interaction which are considered to give a rise to hyperlipoproteinemias. PMID- 7853712 TI - [Familial LCAT deficiency]. AB - Familial plasma lecithine: cholesterol acyltransferase (LCAT) deficiency is a disease that is inherited as an autosomal recessing trait. The main clinical abnormalities are corneal opacities, anemia and frequently, though not invariably, proteinuria. These abnormalities result from a failure of LCAT to esterify cholesterol in plasma. Renal failure can be a life-threatening complication. In plasma, all lipoprotein classes show abnormalities including lipid composition, shape, distribution and concentration. Fish eye disease, which is characterized by corneal opacities and plasma lipoprotein abnormalities, is also a result from deficiency of LCAT activity. As LCAT gene has been cloned, molecular defects of both familial LCAT deficiency and fish eye disease have been reported recently. PMID- 7853713 TI - [CETP deficiency]. AB - Four different CETP gene mutations have been reported to be causes of increased levels of HDL cholesterol by us and other investigators; two splice donor site mutations involving intron 14, one missense mutation of D442G in exon 15, and one nonsense mutation of Q309X in exon10. Two splice donor site mutations are G (+1) to-A transition (Int14A) and T insertion at the +3 position (Int14T), and both mutations result in null phenotype as well as a nonsense mutation. In contrast, D442G mutation is partially defective in CETP activity. Two mutations of Int14A and D442G are common mutations in the general Japanese population with a high frequency of the heterozygotes of 2% and 7%, respectively. Heterozygous CETP deficiency is sufficiently common to explain a significant fraction of the variation in HDL-C level in the general Japanese population. PMID- 7853714 TI - [Primary lipoprotein lipase deficiency: clinical and genetic aspects]. AB - Primary deficiency of the enzyme lipoprotein lipase (LPL) is an autosomal recessive disorder characterized by chylomicronemia, recurrent pancreatitis and xanthomas. In recent years, a growing number of mutations have been identified in patients with this inherited disorder and molecular defects include insertions and deletions, splicing defects, and nonsense and missense mutations. Most of these mutations are clustered in the region encoded by exon 4, 5 and 6 which forms the catalytic domain of LPL. The study of these mutations also contributes to our understanding of the structure, function relationships of the enzyme. PMID- 7853715 TI - [LDL receptor gene analysis and phenotypic variation of familial hypercholesterolemia]. AB - Familial hypercholesterolemia, one of the most common single-gene disease in which defective catabolism of LDL is responsible for the increased plasma cholesterol and leads to the deposition of cholesterol in the arterial wall and premature coronary artery disease, is caused by inherited defects in the gene for the low density lipoprotein receptor. Clinical variation is known to exist in familial hypercholesterolemia. Since cloning of the human LDL receptor gene, it has been revealed that the nature of the LDL receptor gene mutation contributes to these clinical variability of familial hypercholesterolemia. Other mutations not linked to LDL receptor gene, such as apo E, apo B and several growth factor genes, and environmental factors may also be related to the severity of symptom or response to the treatment in familial hypercholesterolemia. Further study in the molecular biological field using knock-out and transgenic expression techniques is needed to elucidate the key factors which influence the clinical varieties of expression in familial hypercholesterolemia and to develop the new methods for treatment. PMID- 7853716 TI - [Tangier disease]. AB - Tangier disease, a familial HDL-deficiency syndrome, was first reported by Fredrickson et al. in 1961. Since then, a great deal research on the mechanism of HDL-deficiency in this disease has been done from the prospective of lipoprotein compositions, in vivo HDL kinetics, cell and receptor interactions and genomic DNA analysis. These studies have found a relatively increased fractional catabolic rate of apo HDL with essentially no change in the synthesis of apo HDL. As yet, no structural defect has been found in the apo A-I gene. However, there have been reports of irregular lipid metabolism and of disorders in the Golgi apparatus and lysosome processing. Interestingly, the frequency of coronary heart disease is low in patients with Tangier disease. In this report, we describe the clinical and biochemical characteristics of Tangier disease and suggest some possible mechanisms for preventing coronary heart disease. PMID- 7853717 TI - [Apolipoprotein C-II deficiency]. AB - Apo C-II has a central role in triglyceride metabolism as a cofactor for lipoprotein lipase (LPL), the enzyme that catalyzes the hydrolysis of triglycerides on plasma lipoproteins. Apo C-II deficiency is a rare genetic disorder that is inherited as an autosomal recessive trait. Patients with this syndrome have marked alterations of triglyceride metabolism which include elevated fasting triglycerides, chylomicrons, and VLDL. Clinical features also include lipemia retinalis, eruptive xanthomas, and an increased incidence of pancreatitis. The initial description of the first patient with apo C-II deficiency by Breckenridge et al. established the important role of apo C-II as a cofactor for LPL. Since then, many kindreds with apo C-II deficiency have been described and the underlying molecular defect characterized. PMID- 7853718 TI - [Molecular and clinical abnormalities of apolipoprotein A-I]. AB - Several epidemiological and clinical studies have shown an inverse correlation between low plasma concentration of high density lipoprotein (HDL) cholesterol as well as its major protein component, apolipoprotein A-I (apo A-I), and the risk of coronary artery disease. Apo A-I plays an important role in a reverse cholesterol transport. In this model, HDL mediates the cholesterol flux from peripheral cells to the liver. The structure and function of HDL-deficiency syndromes and apo A-I variants provides genetic markers of whether the presence of these molecular defects accounts for low HDL cholesterol levels and the coronary risk. PMID- 7853720 TI - [Apolipoprotein E4 and late-onset Alzheimer's disease]. AB - Apolipoprotein E [APOE for protein; APOE for gene] is a 34 kDa plasma protein involved in cholesterol transport. In addition to hepatic cells, glial cells in the nervous system also produce APOE, which is postulated to be involved in the growth and repair of the nervous system during development or after injury. The APOE immunoreactivity was associated with amyloid both in senile plaques and cerebral blood vessels and neurofibrillary tangles (NFTs) in Alzheimer's disease (AD). The immunoreactivity was also found in amyloid of kuru plaques in Creutzfeldt-Jakob disease and other types of cerebral and systemic amyloid. Three common genetic variants of APOE result from different alleles coding for proteins with single amino acid substitutions. The APOE alleles are designated epsilon 4 (Cys 112-->Arg), epsilon 3 (Cys at amino acid 112) and epsilon 4 (Arg 158-->Cys) [E4, E3 and E2 for proteins, respectively]. The APOE-epsilon 4 allele was genetically associated with late-onset familial and sporadic forms of AD as well as with early-onset AD. Protective effect of APOE-epsilon 2 allele for late-onset AD was also reported. APOE was found to be able to bind synthetic amyloid beta peptide (A beta), the primary constituent of senile plaque and cerebrovascular amyloid, forming a complex that resisted dissociation by boiling in SDS. The binding of A beta to APOE-E4 was much more rapid than to APOE-E3. APOE-E3 was also shown to bind to tau, the major component of NFTs, presumably protecting tau from abnormal phosphorylation and slowing the formation of NFTs.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7853719 TI - [Apolipoprotein A I-C III-A IV deficiency]. AB - The genes coding for apolipoprotein A-I, apo C-III, A-IV are located on the long arm of chromosome 11. The three genes are tandemly organized. Familial apolipoprotein A-I, C-III, A-IV deficiency was reported. The homozygous proband had extremely low HDL-cholesterol and premature coronary atherosclerosis. Analysis of the abnormal allele revealed the complete deletion of the apo A-I, C III, A-IV genes. The deletion occurred in areas of repetitive DNA sequence. Familial apolipoprotein A-I, C-III deficiency has been shown to be due to the DNA inversion between the exon 4 of apo A-I and the first intron of apo C-III. The homozygous proband has HDL, deficiency and severe atherosclerosis. RFLP in this gene lesion has been reported and is closely related with the decrease of HDL, hypertriglyceridemia and coronary atherosclerosis. The elucidation of the relation between one particular allele in the lesion of apo A-I, C-III, A-IV gene cluster with lipoprotein metabolism and coronary atherosclerosis will require further determination of the precise nucleotide sequence variation. PMID- 7853721 TI - [Drug treatment of hyperlipoproteinemia: bile acid-binding resins]. AB - Bile acid-binding resins, one of which is cholestyramine that has long been used in Japan, are extremely safe and effective hypocholesterolemic agents. The agents block an enterohepatic circulation of bile acids leading to an enhancement of bile acid synthesis, which may lead to decrease in hepatic levels of cholesterol. This will induce the liver to upregulate the LDL receptor activity causing a reduction of serum LDL cholesterol levels. One of the major problems of cholestyramine is a poor drug compliance. MCI-196, a newly developed bile acid resin, is more potent than cholestyramine and will be expected to improve this problem. PMID- 7853722 TI - [HMG-CoA reductase inhibitor for therapy of patients with hyperlipoproteinemia ]. AB - The discovery and production of HMGCoA reductase inhibitor and the fundamental research work of the LDL receptor unraveled a receptor-mediated cholesterol homeostasis. HMGCoA reductase inhibitors are the most commonly prescribed class of lipid-lowering drugs in many countries. The decrease of the intracellular cholesterol caused by the inhibitor induces the compensatory increase of LDL receptor protein at liver plasma membrane. The increased receptor promotes LDL catabolism and results in decrease of plasma LDL. Serious side effects involving the liver or muscle are rare. But the risk of myopathy is increased when the drug is used with other hypolipidemic agents. A principle of the treatment of hyperlipidemia, including secondary one associated with diabetes mellitus and renal disease, by HMGCoA reductase is discussed in this review. PMID- 7853723 TI - [Probucol treatment of hyperlipidemia]. AB - Probucol lowers total and LDL cholesterol levels, and also lowers HDL cholesterol levels. Probucol is able to lower cholesterol levels in homozygous patients with familial hypercholesterolemia as well as in heterozygous patients. In heterozygous familial hypercholesterolemia, probucol lowered total cholesterol levels by 22%, LDL-cholesterol levels by 17%, and HDL-cholesterol levels by 40%, respectively. The lowering HDL cholesterol levels by probucol may reflect increased reverse cholesterol transport. Probucol increases cholesteryl ester transfer protein concentration, and diminishes HDL particle size. Probucol has been reported to retard and even regress atherosclerosis in animal models and to diminish tendinous xanthomas in man. Its lowering LDL-cholesterol levels, activation of reverse cholesterol transport process, and antioxidant effects may cause an antiatherogenic action. PMID- 7853724 TI - [Clofibrate treatment of hyperlipoproteinemia]. AB - Clofibrate has cholesterol- and triglyceride-lowering effect. They affect on the various points in the metabolic pathway of lipoproteins. They improve VLDL synthesis in liver and increase the activity of LPL and hepatic TG lipase. As the results, HDL-cholesterol increases and LDL decreases. Therefore Clofibrate decreases not only plasma triglyceride but cholesterol levels. It has been reported that Clofibrate have a preventive effect on cardiovascular disease. So these agents are useful in the treatment for hyperlipidemic patients with or without atherosclerosis. PMID- 7853725 TI - [Nicotinic acid and derivatives for therapy of hyperlipoproteinemia]. AB - Nicotinic acid and derivatives are effective in numerous forms of hyperlipoproteinemia. Its primary mode of action is to inhibit lipolysis in adipose tissue and to prevent the utilization of free fatty acids for TG-rich lipoprotein synthesis in the liver. Consequently, it decreases the plasma lipoproteins which are considered to be atherogenic--VLDL, LDL and Lp(a), while it increases the antiatherogenic lipoprotein--HDL. A gradual administration of nicotinic acid or derivatives is useful to reduce the side effects such as flushing and itching. In the secondary prevention trials, nicotinic acid therapy with other hypolipidemic drugs asserted protective effects on the development/progression of cardiovascular disease. PMID- 7853726 TI - [LDL apheresis in the treatment of hyperlipoproteinemia]. AB - In order to the reduce the LDL level of Familial hypercholesterolemia (FH), direct LDL removal techniques have been used in several laboratories. In Japan, selective LDL-apheresis by dextran sulfate cellulose column have been developed and is used in treatment of homo- and heterozygous FH patients. In this paper, I reviewed the effectiveness of LDL-apheresis treatment in FH patients with many evidences of regression of atherosclerosis and discussed the potential role of this technique in the future treatment for coronary heart disease. No significant side effect for long term treatment is not experienced. PMID- 7853727 TI - [Perspective of gene therapy in hyperlipoproteinemia]. AB - Several experimental trials are under way to correct the deficiency of LDL receptor function known as Familial Hypercholesterolemia (FH) that develops devastating atherosclerosis leading to premature fatal coronary occlusion. Recently, a 28-year-old FH homozygous woman has received ex vivo autologous liver transplantation after transduction with retroviral vector expressing functional LDL receptors. The outcome is partially successful but is still controversial because of an argument that the apparent small decrease in the total plasma cholesterol level is not necessarily caused by the correction of the LDL receptor expression. In addition to retrovirus, adenovirus vector and non-viral methods are being employed as potential tools for FH gene therapy. PMID- 7853728 TI - [Toxic shock like syndrome due to S. pyogenes (TSLS)]. AB - Resurgence of severe infection, caused by Streptococcus pyogenes was observed in the USA from the middle of the 1980s. Toxic Shock like Syndrome due to Streptococcus pyogenes (TSLS) has been one of the most life-threatening diseases with soft tissue infections, such as necrotizing fasciitis, myositis, bacteremia and shock. Patients with TSLS has been reported in Europe, USA, Canada, etc. The first report of TSLS in Japan was described by Y. Shimizu and his colleague, Asahi General Hospital, Chiba, 1992. Since then more cases of TSLS, diagnosed by CDC's Criteria, have been found in various parts of Japan, including Chiba prefecture. They are characterised by rapid development of shock and death. Some of the isolated strains from blood or tissues have been identified as S. pyogenes, M3, M1 with SPEA (Streptococcal pyrogenic exotoxin A). PMID- 7853729 TI - [Tumor suppressor genes]. AB - Cell fusion experiments performed by Harris et al. informed that tumor suppressor genes are inactivated in malignant cells. Inactivation of tumor suppressor genes induced by genetic alteration such as point mutation and deletion leads to disturbance in the control of cell proliferation resulting in deregulated growth of normal cells. Recently, many challenges of scientists including clinicians trying to direct the studies of tumor suppressors toward cancer therapy have been stimulated. For that purpose, it is important to understand the molecular mechanism in which change of normal phenotypes into tumor take place. In this review, recent topics on tumor suppressors such as Rb, p53, Wt1, APC, NF1, s-Myc and H19 are included to discuss their significance and function. PMID- 7853730 TI - Repetitive low-dose tissue plasminogen activator for the clearance of experimental vitreous hemorrhage. AB - Our previous experimental work with tissue plasminogen activator (TPA) suggested the possibility of the clearance of vitreous hemorrhage by repetitive injections of low-dose TPA. We therefore investigated in rabbits the effect of both repeated injections of TPA and the change of the integrity of the vitreous body on the clearance of vitreous hemorrhage. Vitreous hemorrhage was produced by intravitreal injection of 0.05 ml of autologous whole blood in the pigmented rabbit eyes with intact vitreous or gas-compressed vitreous. Three intravitreal injections of 3-g TPA (total dose of 9 micrograms), separated by 7-day intervals, were performed. The endpoint for vitreous hemorrhage clearance was defined as clear visualization of the posterior central retina of the rabbits. Regardless of whether gas compression vitrectomy was performed, repeated injections of low-dose TPA resulted in rapid clearance of fresh vitreous hemorrhage in approximately two to three weeks after the last TPA injection. No evidence of retinal toxicity was seen in all experimental groups. Repetitive injections of low-dose TPA may be effective in the treatment of fresh vitreous hemorrhage. PMID- 7853731 TI - Vitrectomy for severe proliferative diabetic retinopathy. AB - To analyse the results of diabetic vitrectomy according to the severity of proliferation [severe (SPG) vs. less-severe proliferation group (LSPG)], and methods of the operation, which was complete removal of anteroposterior vitreous traction with or without complete removal of preretinal memebrane, we compared both groups by using anatomic success rate and postoperative visual acuities (VA). The results were as follows: The anatomic success rate and postoperative VA were significantly better in LSPG than in SPG. In SPG, anatomic success rate and postoperative VA tended to be better when complete removal of anteroposterior traction was possible than when impossible. In SPG, postoperative VA tended to be better when complete removal of preretinal membrane was possible, but the anatomic success rate was the same for each group. So, when severe proliferation (including table-top elevation of posterior retina), complete removal of anteroposterior traction only can improve the anatomic success rate of the surgery. PMID- 7853732 TI - Quantitative analysis of changes of automated perimetric thresholds after pupillary dilation and induced myopia in normal subjects. AB - We quantitatively analyzed the changes of the (retinal) threshold sensitivities between normal status and dilated emmetropic status, and between dilated emmetropic status and -1.0D induced myopic status. Three consecutive visual field examinations by Humphrey Field Analyzer C-30-2 threshold test and STATPAC program were performed in 36 eyes of 21 normal subjects who ranged in age from 23 to 40 years. The results were as follows: 1) There was a statistically significant decrease (0.87 +/- 0.91dB)in the mean threshold sensitivity within the central 30 degrees at the dilated emmetropic status (27.90dB) as compared with the normal status (28.77dB)(p = 0.0001). 2) There was a statistically significant decrease(0.99 +/- 0.61dB) at -1.0D induced myopic status(26.91dB) as compared with the dilated emmetropic status(27.90dB)(p = 0.0001). 3) After dilation, the mean threshold sensitivity between 20 and 30 degrees of field showed statistically significant decrease as compared with those within the central 20 degrees of visual field(p < 0.05). In case of -1.0D induced myopia, there were uniform decreases in the mean threshold sensitivities within the central 30 degrees of visual field (p > 0.05). Therefore, we emphasize the importance of consistent pupillary size and correct refractive state in performing the serial automated visual field tests. PMID- 7853733 TI - Effects of intracameral carbachol and acetylcholine on early postoperative intraocular pressure after cataract extraction. AB - We performed a randomized, prospective study to evaluate the effect of intraoperative, intracameral carbachol or acetylcholine on early postoperative intraocular pressure(IOP) after extracapsular cataract extraction(ECCE) and posterior chamber lens(PCL) implantation. Fifty-six eyes of 56 patients scheduled for routine ECCE and PCL implantation were randomly assigned into three groups: (1)carbachol infusion (19 eyes) (2) acetylcholine infusion (15 eyes) (3)balanced salt solution (BSS) infusion (control, 22 eyes). We compared the preoperative IOP, early postoperative IOP, postoperative 24 hours IOP and postoperative 1 week IOP. In the measurement of early postoperative IOP, IOP was measured at least twice at 3, 6 or 9 hours postoperatively. There was no significant difference in IOP between the three groups preoperatively, at postoperative 3 hours, and 1 week. At postoperative 6 hours, both the carbachol infusion group and acetylcholine infusion group were significantly different from the BSS infusion group. At postoperative 9 and 24 hours, only carbachol infusion group had a significant difference from BSS infusion group in suppression of postoperative IOP increase. Our results suggest that intraoperative, intracameral administration of carbachol or acetylcholine prevents early postoperative IOP increase, and that carbachol has a more lasting effect. PMID- 7853734 TI - Expression of major histocompatibility complex antigen in Lewis rat cornea. AB - Fresh rat corneas as well as corneas preserved in several different corneal preservation media were stained with Avidin-Biotin-peroxidase Complex method in order to evaluate major histocompatibility complex (MHC) antigen expression. In fresh corneas, class I antigen was identified in corneal epithelium, stroma and endothelium. Class II antigen was identified only in stroma. In corneas preserved in the media which contained chondroitin and dextran for 7 days, class I antigen was somewhat decreased but class II antigen was increased. In corneas preserved in the medium which contained insulin or epidermal growth factor for 7 days, class II antigens seemed to be increased compaired to the fresh cornea. Expression of MHC antigens of corneas in the medium with fetal bovine serum were similar to those of fresh corneas. PMID- 7853735 TI - The change of visual acuity and visual field by diminished illumination in eyes with multifocal intraocular lens. AB - To investigate the effect of illumination on visual acuity and visual field in eyes with multifocal intraocular lens (IOL), the near and far visual acuity of the eyes with multifocal implants were compared to those of the eyes with monofocal implants in the diminished illumination, and the visual fields of two groups were also compared by the different target size and intensity. The near and far visual acuity of the eyes with multifocal implants were significantly decreased as compared to those of the eyes with monofocal implants under diminished illumination, and the visual field of the multifocal implanted eyes also significantly decreased as compared to that of the monofocal implanted eyes by the reduction of spot size and intensity. From the above results, it is assumed that the bifocal separation of incident light to two simultaneous focal points in the multifocal implants causes more decreased visual acuity and narrower visual field in the diminished illumination as compared to that of the eyes with monofocal implants. PMID- 7853736 TI - Aconite induced myelo-optic neuropathy in a rabbit model. AB - Aconite is a common remedy of herb doctors and is widely used in the Far East. Clinical aspects of the visual disturbance produced by this drug have been described, but little is known about its pathology. Tinctura aconiti (0.6 mg of total alkaloid/kg 2x) was administered intraperitoneally in rabbits to evaluate its toxic effects on the visual system. The alteration in the visual evoked potential following aconite injection consisted of a delay in the onset and peak latency. Histopathologically, there were damages to the myelin sheath of the visual pathway, spinal cord and peripheral nerves. These findings suggest that aconite may cause primarily myelo-optic neuropathy. PMID- 7853737 TI - Combined study on the causes of strabismus after the retinal surgery. AB - Extraocular muscle imbalance and diplopia after retina surgery have been previously reported, but the etiology is still controversial. In order to better understand the cause of strabismus after retinal surgery, the authors retrospectively studied 30 patients with persistent strabismus following retinal surgery and combined the result about seven patients of strabismus after retinal surgery in the previous report. Results showed multiple etiologies for the strabismus. Causes of strabismus included fat adherence syndrome (14 patients), non-specific restrictive adhesion (11), displacement of superior oblique tendon (2), scleral explant interfering with ocular motility (1), lost or slipped muscle with adhesion (2), sensory strabismus (2), macular pucker causing ectopic fovea (2), and previous strabismus before the retinal surgery (3). Knowledge of the varieties of abnormalities that can cause strabismus and diplopia will help both the retina and strabismus surgeon prevent and treat strabismus after retinal surgery. PMID- 7853738 TI - [Disseminated intravascular coagulation (DIC) and pre-DIC due to severe infection in the elderly]. AB - Because of pre-thrombotic state frequently present in the elderly, sepsis easily progresses to pre-DIC and DIC, sometimes with a fatal outcome. We assessed 31 elderly patients who developed pre-DIC and DIC due to severe infection. They were divided into two groups, early death group: 14 elderly patients with poor prognosis died within 14 days, and long survival group: 17 patients with good prognosis lived 15 days or more. Controls consisted of 31 elderly thrombotic disease cases and 25 healthy elderly cases. The DIC score was significantly higher in the early death group than in the long survival group, and there was a correlation between DIC score and survival. Moreover, many of the early death group were long-termed bed-ridden patients, serum BUN and Cre levels were significantly increased in the early death group compared to the long survival group. While plasma TAT, PIC and D-dimer levels were increased in thrombotic disease group compared to the healthy control group, TAT and D-dimer were also increased in the pre-DIC and DIC state than in the thrombotic state. In the early death group, D-dimer was higher than in the long survival group. We suggest that early diagnosis by molecular marker is important in the DIC stage, and a high D dimer level may be a poor prognostic factor. PMID- 7853739 TI - [Longitudinal change in independence in the elderly--Kahoku Longitudinal Aging Study (KLAS)]. AB - A community based study named Kahoku Longitudinal Aging Study (KLAS) was conducted since 1990 for the purpose of evaluating the comprehensive geriatric functional assessment (CGA) and preventing a decline in CGA in the community dwelling elderly population. It was carried out in a Japanese rural town, in which 32% of the population was over 65 years of age. This study included a questionnaire about activity of daily living (ADL), information-related physical function, mental (cognitive and affective) and social functional domains. In addition to subjective informative instruments, various types of objective assessment such as quantitative neuro-behavioral function tests and medical examinations were performed. Subjects were all the eligible elderly aged over 65 years in the community. Although the ratio of subjects who were independent in ADL decreased with advancing age in both 1991 and 1993, the ratio of the independent elderly in ADL became significant higher (74%) in 1993 than in 1991 (71%). Scores on 2 kinds of neurobehavioral function tests in the 159 subjects aged over 75 years who attended the examination every year showed a significant and slight decrease during two years. However, some test indices significantly improved during the 2 years. These results suggested that age-related dependency in ADL and some kind of neurobehavioral functions might be prevented, in part, by health promoting education and improvement of life style. PMID- 7853740 TI - [Comparative study of activity of daily living in the elderly between in Kahoku and in Yaku]. AB - A comparative community-based study of physical activity in the elderly was carried out between two Japanese rural towns, Kahoku and Yaku. This study included a questionnaire about activity of daily living (ADL) and information related functions in relation to lifestyle. Subjects were all the eligible elderly aged over 65 years of each community (1618 and 704 subjects in Kahoku and Yaku respectively). The ratio of the eligible elderly aged over 65 years were 32% in Kahoku and 2% in Yaku. The response rates were 91% in Kahoku and 51% in Yaku. Common findings in both towns were as below; 1) scores in ADL decreased with advancing age, 2) information-related functions were similar in each town, and between genders, 3) marital condition among males was similar in both towns, 4) ADL scores were higher in the financially rich group than in the poor one, 5) ADL scores were higher in female subjects whose husbands were alive than in widows, 6) ADL scores were higher in subjects who walked every day than those who did not, 7) ADL scores were lower in subjects who took medicine every day than those who did not, however, this finding did not apply to antihypertensive drugs, 8) ADL scores were higher in subjects who drank in beverages than in those who never imbibed. The different results between Kahoku and Yaku were supposed to be due to differences in lifestyle.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7853741 TI - [Comparative study of blood pressure variability in the elderly in Kahoku and in Yaku]. AB - A comparative community-based study of blood pressure (BP) variability in the elderly was carried out in the Japanese rural towns of Kahoku and Yaku. The prevalence of hypertension, orthostatic hypotension and use of antihypertensive drugs, effects of postute on BP and the "white coat" effect in BP were examined in each town. There was no difference in the prevalence of hypertension between in the two towns. Orthostatic increase in BP and pulse rate was more common in elderly females than in elderly males in both towns, indicating that standing itself was a load for subjects and activated sympathetic nervous tone in the female elderly. The prevalence of orthostatic hypotension was 8.5% and 12% in Kahoku and Yaku respectively, and the "white coat" effect on BP was demonstrated in the elderly in each town. In conclusion, we should take orthostatic change and the "white coat" effect into consideration in the evaluation of BP among the elderly. PMID- 7853742 TI - [Comparative study of serum lipids and other blood chemistry factors in the elderly in Kahoku and Yaku]. AB - A comparative community-based study of serum lipids and other blood chemistry data in the elderly was carried out in two Japanese rural towns, Kahoku and Yaku. We studied the following blood chemistry factors; total proteins (TP), albumin (Alb), blood glucose (glucose), urea nitrogen (BUN), uric acid (UA), total cholesterol (T-Cho), high density lipoprotein (HDL-C) and lipoprotein (a) (Lp(a)). Subjects were the 312 eligible elderly aged over 75 years in Kahoku, and 172 similar elderly in Yaku. There were no significant differences in TP, Alb, glucose, BUN and UA of the elderly in the two areas. Mean HDL-C level was significantly lower and mean Lp(a) concentration was significantly higher in the elderly in Kahoku than in Yaku, Mean value of T-Cho did not differ significantly between the elderly in the two areas, however, the ratio of subjects whose T-Cho concentrations were over 220 mg/dl was significantly higher in Kahoku than in Yaku. These data suggested that the risk of atherosclerosis from the standpoint of view of serum lipids was higher in the elderly in Kahoku than in those in Yaku. Epidemiological data of Kochi and Kagoshima prefecture indicated that the mortality ratio from ischemic heart disease was higher in Kahoku than in Yaku, although that from cerebral infarction was lower in Kahoku than in Yaku. Comparative study of laboratory data in various districts is useful to investigate the relationship between lifestyle and diseases. PMID- 7853743 TI - [Comparative study of neurobehavioral function in the elderly between in Kahoku and Yaku]. AB - A comparative study of neurobehavioral functions in the elderly was carried out between two Japanese rural towns, Kahoku and in Yaku. To evaluate of neurobehavioral functions, we used 1) Mini Mental State Examination (MMS), 2) Hasegawa Dementia Scale Revised (HDSR), 3) Kohs block design test, 4) Visuospatial cognitive performance score (VCPS), 5) Button Score (Button-S), 6) Up & Go test, and 7) Functional reach (FR). A questionnaire about ADL, information-related function and lifestyle was also done. Subjects consisted of all the eligible 332 elderly aged over 75 in Kahoku and 194 elderly aged over 75 in Yaku. In Kahoku, each function test had a significant correlation with age. However, in Yaku, the Up & Go, FR, MMS and HDSR results showed no significant correlation with age. Scores in cognitive function tests such as MMS, VCPS, and the Kohs test were better in kahoku than in Yaku, although scores in behavioral function tests such as FR were better in Yaku than in Kahoku. MMS, HDSR and Kohs tests significantly correlated with information-related function while Button-S, Up Go and FR tests had significant correlation one with ADL in both areas. Scores on function tests were better in the living-alone group and the group who had a daily work than in other groups in Kahoku. However, differences in scores in function tests between these two types of groups failed to reach a level of significance in Yaku. These data suggested that the difference in life-style influenced neurobehavioral functions in the elderly. PMID- 7853744 TI - [Comparative study of quality of life in the elderly between in Kahoku and in Yaku]. AB - A comparative community-based study of quality of life (QOL) in the elderly was carried out between two Japanese rural towns, Kahoku and Yaku.QOL, which included the subjective sense of health, appetite, sleep at night, mood, memory, family relationships, friendship, economic condition, life satisfaction and happiness was assessed using a visual analogue scale (VAS) as well a Geriatric depression Scale (GDS), a variety of neurobehavioral function tests, and a questionnaire about activity of daily living (ADL). Subjects were all the eligible elderly aged over 75 years in both communities. Inter-rater reproducibility in VSA was more reliable than that in GDS. Life satisfaction and a subjective sense of happiness highly correlated with mood, family relationships, friendship and economic condition. GDS and VAS significantly correlated with family relationships, active participation in a group and economic condition, however, they did not correlated with age. The subjective sense of happiness correlated with ADL and steadiness of walk as assessed by neurobehavioral function tests. Living style correlated with VAS in the male elderly, but not female. Each score in VAS for family relationships, friendship, economic condition, life satisfaction and subjective sense of happiness was significantly higher in the elderly in Yaku than in Kohoku. The diseases which elderly people wanted to avoid were dimentia cancer, stroke, and cardiovascular disease in that order. In conclusion, QOL in the elderly population was influenced by disease, neurobehavioral functions, especially walking function, gender difference, lifestyle as well as cultural environment. PMID- 7853745 TI - [Age-related changes of urinary collagen crosslinks and serum osteocalcin in postmenopausal women]. AB - Urinary collagen crosslinks, lysyl pyridinoline (LP) and hydroxy lysyl pyridinoline (HL), have been shown to be specific parameters of bone degradation, while serum osteocalcin, referred to as bone Gla-protein (BGP), has been used as a sensitive marker of bone formation. The current cross-sectional study was designed to compare between pyridinoline contents in initial fasting urine and serum BGP in postmenopausal women aged 50-90 years. Both LP and HL increased by around 20% and BGP increased by nearly 30% in a later stage of menopause, indicating the possibility that bone turnover did not decline with age as far as could be assessed by these chemical markers. It was of interest that significant correlations of pyridinoline to BGP in the 50s and 60s (r = 0.52 - 0.60, p < 0.05) became insignificant after age 70. Although there is a limitation to these biochemical markers, the present data indicate that the coupling mechanism between bone resorption and formation may become inefficient with aging in postmenopausal women. PMID- 7853746 TI - [A case of hypophosphatemia induced by intravenous administration of saccharated iron oxide]. AB - An 81-year-old woman was hospitalised because of pneumonia in December 1989. In February 1991, an iliac bone biopsy was performed on the suspicion of disturbed bone metabolism due to chronic renal failure. Since she developed anemia due to continuous bleeding from the surgical wounds, saccharated iron oxide was administered beginning in March. Hypophosphatemia was noted 23 days after the beginning of administration. Due to the possibility of osteomalacia, active vitamin D was given but the hypophosphatemia persisted. Following an EDTA-2 Na load test performed to evaluate the reabsorption of phosphorus in the renal tubules, it was considered that the patient had a functional disorder of the parathyroid glands and that reabsorption of phosphorus was interrupted in the renal tubules. Furthermore, abnormal distributions of phosphorus seemed to occur in the same areas where sucrose was metabolized and iron was stored. Therefore, it was considered that these abnormalities induced hypophosphatemia following the intravenous administration of saccharated iron oxide. In addition to these actions, the possibility remained that phosphate absorption was inhibited in the small intestine by calcium lactate. PMID- 7853747 TI - [A case of successful antisyphilitic treatment for a patient with general paresis]. AB - A 59-year-old male patient with general paresis was hospitalized because of personality changes and memory disturbances without any neurological deficits. His Mini Mental State score was 11, and his total IQ on the WAIS-R was 56. TPHA titers in serum and the CSF were over 40960x and 640x respectively. Both the white blood cell count as well as total protein were found to be increased in the CSF and FTA-ABS in the CSF was positive. The patient was treated with penicillin, one million units per day intramuscularly for 14 days, and four million units per day intravenously for 10 days. The abnormal findings in the CSF, his unstable mood and agitation improved, as well as his scores on the Mini Mental State (17) and total IQ (74), and the patient was able to once again function socially. This case emphasizes the importance of early diagnosis and treatment of general paresis. PMID- 7853748 TI - Genetic study of Japanese encephalitis viruses isolated in Malaysia. AB - Two hundred and forty nucleotides from the pre-M gene region of 10 Japanese encephalitis (JE) virus strains isolated in Malaysia in 1992 were sequenced and compared with the other JE virus strains from different geographic areas in Asia. Our JE virus strains belong to the largest genotypic group that includes strains isolated in temperate regions such as Japan, China, and Taiwan. Our Malaysian JE virus strains differed in 32 nucleotides (13.3%) from WTP/70/22 strain isolated from Malaysia in 1970, which belonged to another distinct genotypic group. PMID- 7853749 TI - Inhibition with lactoferrin of in vitro infection with human herpes virus. AB - Human lactoferrin (hLF) as well as bovine lactoferrin (bLF) inhibited infection of tissue culture cells with human cytomegalovirus (HCMV) and human herpes simplex virus-1 (HSV-1). The addition of lactoferrin (LF) inhibited both in vitro infection and replication of HCMV and HSV-1 in human embryo lung host cells. The maximum inhibition by more than six exponentials of TCID50 for HCMV and four exponentials for HSV-1 was obtained at a concentration in a range from 0.5 to 1 mg of LF per ml of medium. The antiviral activity of LF was associated with its protein moiety, but not with its iron molecule or sialic acid. None of other transferrin gene family members bound to ferrous ions or sialic acid possessed significant antiviral activity. Additionally, we found that LF prevented virus adsorption and/or penetration into host cells, indicating an effect on the early events of virus infection. Preincubation of host cells with LF for 5 to 10 min was sufficient to prevent HCMV infection, even when LF was removed after addition of virus. These results suggest that LF possesses a potent antiviral activity and may be useful in preventing HCMV and HSV-1 infection in humans. PMID- 7853750 TI - The immune function and measles virus infection in three different socioeconomic child populations in Karachi, Pakistan. AB - The immune function as well as anti-measles virus antibody level were investigated with 111 children in Karachi who were classified into high-, middle- and low-income groups. No difference in the blood cell counts or the biochemical data among three groups indicates no marked difference in the general health conditions among them. In the low-income group, levels of IgG, IgA and anti measles virus antibody were significantly higher than those in the other two groups. Although 30% of children of the low-income group kept extremely high levels of immunoglobulin, no significant correlation was observed between IgG levels and anti-measles virus antibody levels. In the high-income group, the level of IgM was significantly lower and the incidence of anti-measles virus antibody-negative children was high (7/38; 18.4%). These antibody-negative children kept lower immunoglobulin levels although they were over four years old. These results suggest that the living environmental conditions of these different socioeconomic groups vary greatly and hygienic conditions must influence the chance of encountering infectious pathogens including measles virus. The relation between living environment and risk of subacute sclerosing panencephalitis (SSPE) in child population of Krachi is discussed. PMID- 7853751 TI - Measurement of the extracellular matrix in glomeruli from patients with diabetic nephropathy using an automatic image analyzer. AB - To elucidate the characteristics of glycoproteins in the mesangial matrix in glomeruli from patients with diabetic nephropathy (DN) in non-insulin-dependent diabetes mellitus (NIDDM), we examined periodic acid-Shiff (PAS) and immunofluorescence staining of types III (III-C), IV (IV-C), V (V-C) and VI (VI C) collagen, fibronectin (FN), fibrinogen (FBG) and laminin (LN) in the glomeruli of 16 patients with DN and 12 patients with diffuse proliferative glomerulonephritis (DPGN). The percentage of positively staining areas in the glomeruli were calculated using an automatic image analyzer. The percentages of areas positive for PAS, III-C, IV-C, V-C, VI-C or FN in DN were significantly greater than those in DPGN. Moreover, the percentages of PAS-positive areas were significantly correlated with not only IV-C-positive areas, but also FN-positive areas in patients with DN. The percentages of PAS-positive areas were also significantly correlated with the levels of serum creatinine and the degree of proteinuria in these patients. It was concluded that mesangial expansion in this disease might be associated mainly with an increase in IV-C and FN. These changes appear to affect the deterioration of renal function and the appearance of proteinuria, and vice versa. PMID- 7853752 TI - Reduction of albuminuria by a calcium antagonist, manidipine, in rats with passive Heymann nephritis. AB - We evaluated the effects of a novel calcium antagonist, manidipine, on albuminuria in rats with passive Heymann nephritis (PHN). Treatment with 0.05% manidipine significantly reduced urinary albumin excretion (62.1 +/- 7.5 vs. 46.9 +/- 8.5 mg/urinary creatinine excretion mg, P < 0.05) and attenuated lipid peroxidation of the renal cortices (0.97 +/- 0.08 vs 0.84 +/- 0.11 nM MDA/mg protein, P < 0.05) on day 14 in PHN. Manidipine affected neither the light microscopic, immunofluorescent nor electron microscopic findings. These results indicate that manidipine reduced proteinuria in rats with PHN, and that its antiproteinuric effect was associated with the reduction of lipid peroxidation. PMID- 7853753 TI - Immunocytochemical detection of active DNA synthesis by in vivo labelling with anti-bromodeoxyuridine antibodies in glomeruli of rats with nephrotoxic serum nephritis. AB - We studied DNA synthesis in rats with nephrotoxic serum nephritis (NTSN), a model of a glomerular disease, using in vivo labelling with 5-bromo-2'-deoxyuridine (BrdUrd). NTSN was induced by intravenous injection of subnephritogenic doses of rabbit anti-rat GBM antiserum into male Sprague-Dawley rats. Each rat received a single injection of the DNA precursor, 3H-thymidine analog (BrdUrd), ten min before the tissues were removed. For immunocytochemical detection of DNA synthesis, semithin sections were prepared at various intervals (4 h up to 84 days) after pulse labelling. Using a monoclonal anti-BrdUrd antibody, BrdUrd incorporated DNA-synthesizing cells were noted in the proliferative zone of the gastric mucosa at all times. In NTSN, BrdUd incorporated DNA-synthesizing cells were detected in the glomeruli from 4h through 28 days after inoculation, with the peak occurring at days 2 to 4. On those days, up to half of the glomeruli showed BrdUrd-incorporated cells, with 8 cells per glomerulus as a maximum. From days 7 to 28, few glomerular cells incorporated BrdUrd, and none did so after day 28. The majority of the BrdUrd-incorporated cells were endothelial. These results suggest that active DNA synthesis by glomerular endothelial cells occurs during a short period of the heterologous phase in this model, and that the lack of mesangial cell proliferation might explain the self-limiting nature of this model. By using in vivo labelling with BrdUrd, we were also able to easily and accurately detect active DNA synthesis without consideration of the normal cell renewal.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7853754 TI - Contribution of ED-1- and CD-8-positive cells to the development of crescentic type anti-GBM nephritis in rats. AB - The current studies were designed to identify which mononuclear leukocytes have an important role in the development of glomerular injury using rats with original-type (mild injury) and crescentic-type (severe injury) anti-glomerular basement membrane (GBM) nephritis. 1) Proteinuria was persistent in crescentic type anti-GBM nephritis compared with original-type anti-GBM nephritis. Macrophages/monocytes (ED-1), cytotoxic/suppressor T cells (CD-8), interleukin-2 receptor (CD-25)-positive cells and Ia-positive cells accumulated remarkably and persisted for longer in crescentic-type nephritic glomeruli. 2) We then performed investigations using immunosuppressants. Cyclosporin A abrogated proteinuria more effectively than azathioprine in crescentic-type nephritis. However, plasma antibody titer and glomerular rat IgG deposition were equally reduced by both azathioprine and cyclosporin A. The increase in the numbers of ED-1-, CD-8- and CD-25-positive cells in nephritic glomeruli was completely inhibited by cyclosporin A, but inhibited only slightly by azathioprine. 3) There was a correlation between the degree of proteinuria and the number of ED-1- and CD-8 positive cells. It is likely that these cells are leukocytes that lead to glomerular injury in nephritis. 4) In additional experiments using monoclonal antibodies against macrophages/monocytes and cytotoxic/suppressor T cells, urinary protein excretion and accumulation of these cells were blunted in nephritic rats treated with these antibodies. These results suggest that ED-1- and CD-8-positive cells are involved in the development of crescentic-type anti GBM nephritis. PMID- 7853755 TI - Effects of D-glucose on oxygen consumption of renal cortex suffering from ischemic injury. AB - Alterations of Na(+)-dependent D-glucose transport in the proximal tubules resulting from ischemic injury were investigated. We measured the cortical oxygen (O2) consumption at various concentrations of exogenous D-glucose 1 day after ischemic injury in a kidney in which ischemia was induced by complete unilateral renal artery occlusion for 60 minutes and in a contralateral non-ischemic (control) kidney. Both kidneys exhibited a D-glucose concentration-dependent increase in O2 consumption. The increases in O2 consumption in both kidneys exhibited Michaelis-Menten-type saturation kinetics. However, increased Km and decreased Vmax were observed in the ischemic kidney. Phlorizin significantly inhibited O2 consumption in both kidneys at 5 mM, but the effect was not significantly at 0 mM of D-glucose. In contrast, ouabain significantly inhibited O2 consumption in both kidneys at 0 and 5 mM of D-glucose. The level of O2 consumption inhibition by phlorizin and ouabain in the ischemic kidney was markedly less than in the control kidney. The present study demonstrated that the decreased Na(+)-dependent D-glucose transport capacity can be attributed to a reduction in both phlorizin-sensitive transport capacity for D-glucose and ouabain-sensitive Na+, K(+)-ATPase activity 1 day after 60 minutes of ischemia. PMID- 7853756 TI - Renal gluconeogenesis in man: comparison with rats and rabbits. AB - To provide evidence on renal gluconeogenesis in humans and to compare with rats and rabbits, glucose production from several substrates was determined using cortical slices of the three species. In humans, the normal parts of kidney tissue were obtained from six cases of transitional cell carcinoma of the renal pelvis and four cases of renal cell carcinoma. Renal cortical slices were incubated aerobically with or without substrates, and the glucose contents were assayed photometrically. The specificity of human kidneys was evaluated by comparison with the results obtained from rats and rabbits. The rank order of renal gluconeogenesis from various substrates was as follows: Humans: pyruvate > oxaloacetic acid > lactic acid > fructose-1,6-diphosphate > L-glutamine. Rats: pyruvate > fructose-1,6-diphosphate > oxaloacetic acid > lactic acid > L glutamine. Rabbits: fructose-1,6-diphosphate > pyruvate > oxaloacetic acid > lactic acid >> L-glutamine = 0. In general, the human kidney can produce glucose at the lowest rate among the three species. The substrate specificity of humans was more or less similar to that of rats. These results suggest the existence of a species difference in renal gluconeogenesis both in substrate specificities and quantitative activities. PMID- 7853757 TI - Effects of glycated protein on the expression of very late antigen 5 (VLA5), a fibronectin receptor, of cultured rat mesangial cells. AB - Advanced glycosylation end products are believed to play a role in the increase in extracellular matrix in diabetic glomerulosclerosis via a pathway involving a mesangial cell fibronectin receptor. In the present study, I assessed cultured rat mesangial cells for the presence of mRNA for VLA5, one of the fibronectin receptors. Using these cells, I also evaluated the effects of glycated proteins on the expression of VLA5 and fibronectin. Mesangial cells of Wistar rats were cultured in RPMI 1640 containing 20% FCS. The cells were incubated for 72 hr in a medium containing 50 mg/ml of nonglycated BSA or in a medium containing 50 mg/ml glycated BSA (AGE-BSA). Immunostaining and Northern blot analyses showed that the cells incubated with AGE-BSA exhibited a decrease in VLA5 protein and related mRNA, but showed an increase in the synthesis of fibronectin and related mRNA. On the other hand, non-glycated BSA did not induce these changes in the expression of VLA5 or fibronectin in the mesanginal cells. Northern blot analysis for VLA5 mRNA was also conducted using mesangial cells cultured in a medium with a high glucose concentration (30 mM). However, the high glucose condition did not have any effect on the expression of VLA5 protein or related mRNA. These results suggest that glycated proteins may regulate fibronectin synthesis in mesangial cells by modifying the expression of fibronectin receptors, such as the inhibition of VLA5 synthesis that acts as negative feedback of fibronectin synthesis. PMID- 7853758 TI - Ultrastructural changes in cultured glomerular epithelial cells induced by puromycin aminonucleoside: a quick-freezing and deep-etching study. AB - The effects of puromycin aminonucleoside (PAN) on rat glomerular epithelial cells (GECs) in primary culture were studied using a quick-freezing and deep-etching method. On the 5th day after seeding, GECs were treated with PAN for 24 hours. The three-dimensional structure of the cell organelles, microtubules, and intermediate filaments were observed, primarily in the perinuclear areas of untreated GECs. Microfilaments were observed in marginal and basal areas. The GECs treated with PAN became rounded and partially detached from the substratum. Intermediate filaments formed bundled structures. A slight decrease in the number of microfilaments and a significant widening of their networks were observed in the basal areas of the GECs treated with PAN. These results suggest that PAN may affect the cytoskeletal components of GECs, such as the intermediate filaments and microfilaments, and may induce detachment of the cells from the substratum. PMID- 7853759 TI - Pharmacologic evaluation of the renal handling of uric acid and oxypurines. AB - The effect of drugs that alter the renal tubular transport of urate in the renal excretion of the oxypurines, hypoxanthine (Hx) and xanthine (X), was used to analyze the tubular mechanisms involved in oxypurine excretion in normal subjects and in patients with idiopathic renal hypouricemia. In healthy subjects, administration of the drugs, benzbromarone (Bb) and probenecid (Pb), brought a marked uricosuric effect, but did not alter oxypurine excretion. One of 2 hypouricemic patients exhibited no uricosuric effects with Bb and the other showed a slight uricosuric effect with the drug. Bb administration, however, produced no increase in oxypurine excretion in either patient. In healthy subjects, administration of pyrazinamide (PZA) suppressed the excretion of urate and oxypurines to varying degrees: relative to the baseline values, the fraction excretion of urate was reduced by 95% or more, that of Hx by about 24%, and that of X by about 64%. In patients with hypouricemia, the effects of PZA on urate and oxypurine excretion were impaired. According to these findings, we can speculate that the oxypurines have the same renal secretory mechanism as uric acid. However, the reabsorptive mechanisms of oxypurines at the postsecretory site are likely to differ from that of uric acid. PMID- 7853760 TI - Light chain nephropathy with remarkable accumulation of multinucleated giant cells in the kidney. AB - A case of light chain deposition disease with multinucleated giant cell accumulation in the kidney is described. A 54-year-old man was admitted to out hospital due to moderate renal failure. Complicated with eosinophilic pneumonia two months after admission, his renal function abruptly deteriorated and hemodialysis was started. Three-day methylprednisolone pulse therapy, however, partially recovered his renal function and hemodialysis was discontinued. His renal biopsy specimen revealed kappa light chain deposition disease with nodular mesangial expansion and subendothelial electron dense deposits. The most characteristic finding in this patient was accumulation of foreign body type multinucleated giant cells around atrophic tubules, small arteries and obsolescent glomeruli, probably associated with light chain deposition. No increase in kappa light chain was detected in his serum or concentrated urine. Such disseminated giant cell reaction, other than intra-luminal infiltration in the tubules, has not been reported in the literature and might be related to the physicochemical or structural properties of the deposited protein. PMID- 7853761 TI - Charge distribution of plasma IgG and IgG immune complexes in IgA nephropathy. AB - IgA nephropathy is characterized by a predominant deposition of IgA in the glomerular mesangium. However, in many cases, deposition of IgG also occurs and the concentration of circulating IgG immune complexes is higher than that in controls. To examine further the possible role of the charge of immunoglobulins in the pathogenesis of IgA nephropathy, we used isoelectric focusing (IEF) and densitometry to investigate the charge distribution of plasma IgG and IgG immune complexes in patients with this disease. Blood samples were taken from patients and healthy adults, and plasma and samples treated with 7.0% polyethylene glycol (PEG) were used. All samples were focused with a Multiphor II flatbet electrofocusing unit apparatus on an agarose gel, then immunofixed with polyclonal goat anti-human IgG, and stained with Coomassie blue R 250. The stained gels were analyzed by densitometry. 1. In plasma, the areas of PI 10-8.9 and PI 10-8.6 in IgA nephropathy were higher in the patients than in the controls. 2. In the 7.0% PEG precipitation, the area PI 8.1-6.1 was higher in the patients than in the controls. These findings suggest that a change in charge distribution of IgG and IgG immune complexes may contribute to the pathogenesis of IgA nephropathy. PMID- 7853762 TI - Effects of recombinant human erythropoietin (rHuEPO) on nutritional status of hemodialysis patients: investigation of direct anabolic effects of rHuEPO. AB - To investigate whether the nutritional improvement achieved by recombinant human erythropoietin (rHuEPO) treatment is the result of anemia correction with rHuEPO or the direct anabolic effects of rHuEPO per se, nutritional assessment was performed in 2 studies (study I and II) on hemodialysis (HD) patients. Nutritional assessment included blood biochemistry determinations, anthropometric measurements, daily protein intake (DPI) and dialysis efficiency. In study I, 5 HD patients who had not been given rHuEPO and had a hematocrit (Hct) of < or = 25%, were administered rHuEPO at the initial dose of 96.2 U/kgBW. Nutritional assessment of these patients was performed before rHuEPO treatment and every 4 weeks until the 24th week after rHuEPO treatment. In study II, the same nutritional assessment as in study I except for DPI, was performed in 2 groups with the same Hct level and dialysis regimen; an EPO group (n = 8) previously given rHuEPO (88.2 +/- 13.7 U/kgBW, 25.8 +/- 2.5 mos) and a non-EPO group (n = 8) not given rHuEPO. In study I, the mean Hct level was significantly increased 4 weeks after rHuEPO treatment (23.3 +/- 0.6 to 26.9 +/- 0.9%). However, the nutritional parameters and dialysis efficiency were nearly constant over 24 weeks, suggesting either the absence of a short-term direct anabolic effect of rHuEPO or masking of such an effect due to general condition improvement by anemia correction with rHuEPO. In study II, no significant differences in nutritional assessment were confirmed between the groups, suggesting that a long term direct anabolic effect of rHuEPO may not exist and nutritional improvement may result from correction of anemia with rHuEPO.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7853763 TI - Effect of tonsillectomy on peripheral blood T cell surface markers and cytokine production in patients with IgA nephropathy accompanied by chronic tonsillitis. AB - The present study investigated changes in peripheral blood T cell surface markers and cytokines (interleukin-2, IL-2; tumor necrosis factor-alpha, TNF-alpha; and interferon-gamma, IFN-gamma) following tonsillectomy in patients with IgA nephropathy accompanied by chronic tonsillitis. Peripheral blood CD8+ cells, CD45RA+CD4+ cells and CD8+CD11b- cells increased significantly after tonsillectomy, compared with their preoperative values. In some cases, the preoperative serum TNF-alpha and IFN-gamma levels were higher than normal before surgery, but decreased after surgery. These results suggest that tonsillectomy suppresses a decrease in suppressor T cells in patients with IgA nephropathy and corrects abnormal cell-mediated immune responses in these patients. PMID- 7853764 TI - Fabry-like laminated myelin body associated with IgA nephropathy. AB - We present the first female patient to exhibit Fabry-like myelin bodies in the glomerular epithelial cell in association with IgA nephropathy. This previously healthy 36-year-old woman presented with proteinuria and hematuria without skin lesions. Renal biopsy showed typical IgA nephropathy, with paramesangial deposits, mesangial proliferation and scattered myelin bodies. The leukocytic alpha-galactosidase A activity was abnormally low. She had no family history of Fabry's disease nor the characteristic features, such as skin lesion, neuralgia, or hypohidrosis. Fabry's disease is diagnosed from the renal biopsy findings and the activity of alpha-galactosidase A in leukocytes and/or fibroblasts. We diagnosed the present case with Fabry' disease and IgA nephropathy from these results. PMID- 7853765 TI - An autopsy case of licorice-induced hypokalemic rhabdomyolysis associated with acute renal failure: special reference to profound calcium deposition in skeletal and cardiac muscle. AB - A 78-year-old man was hospitalized because of muscular weakness and acute renal failure. He had been taking glycyrrhizin (280 mg/day) for the last 7 years. Hypertension was noted in his history. Serum potassium was 1.9 mEq/l with metabolic alkalosis. There was hyporeninemic hypoaldosteronism. Serum enzymes, including GOT, LDH and CPK were markedly elevated. In addition, serum myoglobin was as high as 46 micrograms/ml with massive myoglobinuria. Oliguria occurred and blood urea nitrogen and serum creatinine rapidly elevated from 20.9 to 87 mg/dl and from 1.3 to 6.7 mg/dl, respectively. Profound calcium deposition was found in the damaged skeletal muscles, including the quadriceps femoris, axillar, neck, and cardiac muscles. These results indicate that licorice-induced pseudoaldosteronism produces hypokalemic rhabdomyolysis, resulting in acute renal failure and profound deposition of calcium into the damaged skeletal and cardiac muscles. PMID- 7853766 TI - A case of primary glomerular fibrosis associated with the accumulation of type I and type III collagen. AB - A 49-year-old woman suffering from nephrotic syndrome (NS) was admitted for renal biopsy and treatment of NS. Light microscopy demonstrated that the glomerular capillary wall was markedly thickened with diffuse accumulation of periodic acid Schiff- and periodic acid methenamine-positive materials, leading to lobular accentuation of glomerular tufts. By electron microscopy, numerous collagenous fibers were observed in the mesangium and subenodothelial area. The fibers were peculiarly curved and frayed, as reported in nail-patella syndrome. These materials were thought to be type I and type III collagen as a result of immunohistochemical studies. No laboratory data or pathological findings were found to be compatible with previously described glomerulonephritis. The primary glomerular fibrosis in the present patient seemed to be a case of collagenofibrotic glomerulonephropathy. PMID- 7853767 TI - Renal complications during pregnancy in a patient with diabetes mellitus. AB - We present a 23-year-old woman with a 7-year history of insulin-dependent diabetes mellitus (IDDM) who became pregnant. At the 23rd week of pregnancy she exhibited the signs and symptoms (hypertension, edema, proteinuria) of both diabetic nephropathy and preeclampsia. A cesarean section was successfully performed. The proteinuria persisted for more than 3 months after delivery. Renal biopsy confirmed the diagnosis of diabetic glomerulosclerosis together with the renal findings attributable to preeclampsia. The rapid acceleration of diabetic nephropathy in this patient was attributed to preeclampsia. We therefore recommend that patients with DM be followed closely during pregnancy in an attempt to prevent the acceleration of renal damage by preeclampsia. PMID- 7853768 TI - [Clinical study of patients with idiopathic interstitial pneumonia accompanied by diabetes mellitus]. AB - We retrospectively analyzed the clinical presentation of non-insulin-dependent diabetes mellitus (NIDDM) in patients with idiopathic interstitial pneumonia (IIP). Between 1977 to 1993, 75 patients with IIP were admitted to our hospital. None had previously received corticosteroids. To compare the incidence of NIDDM with other pulmonary diseases and the degree of obesity, we randomly selected 200 patients without IIP who were admitted to our hospital in 1992 and 160 healthy subjects. We analyzed weight indices using two methods, body mass index and weight as a percentage of ideal body weight. Eighteen patients (24.0%) with IIP and 9 patients (4.5%) in the disease control group had NIDDM (p < 0.001). As the incidence of NIDDM is approximately 10% in Japan, it was suggested that these IIP patients showed a high prevalence of accompanying NIDDM. Among females, patients with IIP showed a strong tendency toward obesity compared with the healthy control subjects (p < 0.001), but this was not noted among males. Female patients with NIDDM showed a strong tendency toward obesity compared to those without NIDDM, but this was not noted among males. Although the correlation between IIP and NIDDM is unclear, we noted recent reports that advanced glycation and products can stimulate macrophages to secrete tumor necrosis factor and interleukin-1 in vitro, and can stimulate free radical generation by early glycation products in vitro. These cytokines and oxygen radicals may play a role in the pathogenesis or induction of IIP. PMID- 7853769 TI - [Immunoregulatory role of gamma delta T cell receptor in atopic asthma- association with the IgE response to molds antigen]. AB - To evaluate the role of gamma delta T cells in atopic asthma, we examined the relationship among atopy bronchial asthma, and genetic polymorphism of the gamma chain of T cell receptors (TCR) in families through atopic asthmatic probands. We recruited 5 families (69 subjects). Total serum IgE levels were estimated by a radioimmunosorbent test (IgE RIST). Skin prick tests were done with inhaled allergens consisting of house dust, grass and tree pollens, common molds, and animal danders. Antigen-specific IgE levels in response to these allergens were also measured by multiple antigen simultaneous test (IgE MAST). The atopic phenotype was determined by the presence of a positive skin test, an elevated antigen specific IgE value, an elevated total IgE level, or some combination of these. Although linkage of atopy or bronchial asthma to the gene encoding the gamma chain of TCR was excluded, the lod score between this gene and molds specific IgE responses was 0.42 at the recombination fraction of 0.1. In an association study, a 19 kb allele of the gamma chain of the TCR gene was found more frequently in asthmatic subjects than in non-asthmatic subjects (p = 0.068). Also, molds-specific IgE responses were significantly associated with this allele (p = 0.018). These findings suggest that molds-specific IgE responses underlying atopic asthma are partly regulated by the gene encoding the gamma chain of the TCR. PMID- 7853770 TI - [Relationship between power spectra of breath sounds and inspiratory flows at different frequencies]. AB - Regional ventilation and changes in airway caliber have been studied by analysis of breath sounds. The aim of this study was to find which frequency band is most suitable for such purposes. The subjects were 19 healthy men. Breath sounds at 6 sites on the chest wall, airflow rate at the mouth, and ECG were digitized and recorded for 30 seconds. Power spectra of breath sounds at various frequency bands (10-50 Hz, 50-100 Hz, 100-150 Hz, ...., 950-1000 Hz) were calculated with a fast-Fourier transform (FFT) for every block of 512 points (102.4 msec), and mean airflow rates for the blocks were calculated. Data recorded during inspiration when airflow ranged between 0.5 L/s and 3 L/s were analyzed. For frequency bands from 150 Hz to 850 Hz the logarithms of the power spectra were linearly correlated with the logarithms of the airflow rates, and the correlation coefficients exceeded 0.8, but for lower frequency bands the correlations were poor. When the data contaminated by heart sounds and those recorded late in inspiration were excluded the correlations at frequency bands below 150 Hz improved. The slope of log (power)/log (flow) was about 4 for the bands from 100 to 300 Hz, but it became steeper (4 to 6) for higher frequency bands. This means that the power spectra were proportional to the fourth power of the airflow rate for bands below 300 Hz, but the relation was from the fourth to the sixth power for higher frequency bands.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7853771 TI - [Lung pathology of cryptococcosis]. AB - To elucidate the relationship between the clinical manifestations and pathologic findings of the lung in patients with cryptococcosis, we reviewed 14 autopsied cases of cryptococcosis. Five patients had pulmonary cryptococcosis and 9 had disseminated cryptococcosis. Patients with pulmonary cryptococcosis showed granulomatous reactions of the lung, such as fibrocaseous cryptococcoma (n = 2), discrete granuloma (n = 2), and granulomatous pneumonia (n = 1). Patients with disseminated cryptococcosis showed intracapillary/interstitial involvement (n = 2), mucoid pneumonia (n = 3), histiocytic pneumonia (n = 1), and granulomatous pneumonia (n = 3). There was a distinct difference between pulmonary cryptococcosis and disseminated cryptococcosis in lung pathology. Intracapillary/interstitial involvement and mucoid pneumonia were fatal because of extensive hematogeneous dissemination to other organs. Hilar lymph node involvement of cryptococcosis was found in all of the nine patients with disseminated cryptococcosis and in one of the five patients with pulmonary cryptococcosis. Pleural involvement of cryptococcosis was found in six of the nine patients with disseminated cryptococcosis. We conclude that the clinical manifestations of cryptococcosis are closely associated with the variety of lung pathology of cryptococcosis. Clinicians should understand the morphologic features to cope with patients with cryptococcosis. PMID- 7853772 TI - [Nuclear magnetic resonance relaxation times for human lung cancer and lung tissues]. AB - We investigated the nuclear magnetic resonance (NMR) relaxation times, T1 and T2, for lung cancer tissue, and other samples of lung tissue obtained from surgical specimens. The samples were nine squamous cell carcinoma, five necrotic squamous cell carcinoma, 15 adenocarcinoma, two benign mesothelioma, and 13 fibrotic lungs. The relaxation times were measured with a 90 MHz NMR spectrometer and the results were correlated with histological changes. The values of T1 and T2 for squamous cell carcinoma and mesothelioma were significantly longer than those of adenocarcinoma and fibrotic lung tissue. There were no significant differences in values of T1 and T2 between adenocarcinoma and lung tissue. The values of T1 and T2 for benign mesothelioma were similar to those of squamous cell carcinoma, which suggested that increases in T1 and T2 are not specific to malignant tissues. PMID- 7853773 TI - [Continuous monitoring of nitric oxide release from airway mucosa]. AB - There is increasing evidence that nitric oxide (NO) plays a role in the regulation of airway and vascular smooth muscle tone, pulmonary microvascular permeability, and host defense. However, it remains uncertain whether NO is actually released from airway mucosa. We therefore directly measured NO concentrations in the perfusate of rabbit tracheal mucosal surface, with an NO selective electrode. The electrode was made of Pt/Ir alloy coated with a three layered membrane that consisted of KCl, No-selective silicone resin, and a normal silicone membrane. Termination of tracheal perfusion with Krebs-Henseleit solution increased the electrical current derived from oxidation of NO at the electrode, and reperfusion rapidly decreased the current to the baseline value. Addition of L-NG-arginine methylester (L-NAME, 10(-3) M) to the perfusate decreased NO release, but D-NAME had no effect. Subsequent addition of L-arginine (10(-3) M) reversed the inhibition by L-NAME and greatly increased NO release above the baseline value. Histochemical staining to reveal NADPH diaphorase activity in the tracheal tissue showed a strong blue reaction mainly in the epithelial cells. These results suggest that NO is continuously released in the airway mucosal surface, probably from the epithelial cells rich in NO synthase. PMID- 7853774 TI - [Mycobacterium kansasii lung infection associated with myelofibrosis--a case refractory to treatment with antitubercular agents]. AB - A case of Mycobacterium kanasasii lung infection associated with myelofibrosis is reported. A 32-year-old woman was admitted to Keio University Hospital because of fever. One year before admission, a diagnosis of myelofibrosis was made at another hospital. The initial chest X-ray film showed bilateral diffuse infiltrative shadows and right hilar enlargement. Sputum cultures yielded Mycobacterium kansasii on 3 occasions. A fever of 38 degrees C or higher persisted for about 4 months despite the use of antitubercular agents, including INH, RFP, SM, and PZA. During the course of treatment, the hilar and mediastinal lymph node enlargement became more severe, and this was followed by calcification of the nodes. The fever and chest X-ray findings improved in response to the addition of treatment with EB, Ofloxacin, TH, and an increase in the doses of INH (from 300 to 500 mg/day) and RFP (from 450 to 600 mg/day). The patient was discharged 14 months after admission. It is rare especially in Japan for a Mycobacterium kansasii lung infection (not disseminated) to persist in spite of treatment with antitubercular drugs, including RFP or TH. The response to treatment may have been impaired by an immunological disorder associated with the myelofibrosis. PMID- 7853775 TI - [A case of Castleman's disease that recurred nine years after initial surgical removal]. AB - Castleman's disease (CD) is a lymphoproliferative disorder with resemblance in histopathology of thymoma. Here we describe a 48-year-old man with bloody sputum and a mass lesion of the right hilum on chest roentgenogram. He had undergone an incomplete surgical removal of a mediastinal tumor nine years earlier, which proved to be CD with characteristics of hyaline-vascular type pathology. The regrown mass lesion as well as the right upper and middle lobes were removed surgically. Histological examination of the tumor specimen revealed characteristics of hyaline-vascular type CD which were nearly identical to those of the tumor removed nine years earlier. Recurrence of CD as observed in the present report is very uncommon, since only 5 cases, including this one, have been reported. We suggest that in CD the primary tumor as well as regional lymph nodes should be completely removed, and the patients should be kept under long term postoperative observation to check for recurrence. PMID- 7853776 TI - [A case of miliary tuberculosis with high-grade fever that remitted without antituberculosis therapy]. AB - A 23-year-old man was admitted with a persistent high-grade fever of 20 days duration. Chest roentgenogram showed diffuse miliary shadows in both lung fields, highly suggestive of miliary tuberculosis. Sputum, gastric juice, and bronchoalveolar lavage fluid did not, however, reveal acid-fast bacilli on smears. A bone marrow aspirate and a transbronchial lung biopsy were also negative for caseating granulomas and tubercule bacilli. After admission, the high-grade fever remitted in several days without continuous antibiotic, antituberculosis or antipyretic therapy. Levels of inflammatory markers (CRP, ESR, alpha 2-globulin dropped simultaneously. Despite the atypical clinical course, miliary tuberculosis was suspected. We therefore carried out an open lung biopsy. The presence of caseating granulomas and acid-fast bacilli confirmed the diagnosis of miliary tuberculosis. The remission of miliary tuberculosis without treatment is very rare and the details of this case are presented herein with a discussion of the pertinent literature. PMID- 7853777 TI - [A case of adult respiratory distress syndrome treated with 5 ppm nitric oxide inhalation]. AB - A cases of adult respiratory distress syndrome, ARDS, was treated with nitric oxide (NO) inhalation for 10 days. The optimal dose of inhaled NO was determined by the dose-response relationship with NO concentration ranging from 5 to 160 ppm. 5 ppm of NO inhalation considerably increased PaO2 and decreased mean pulmonary arterial pressure (mPAP). Further increase in concentration of inhaled NO did not result in remarkable change in PaO2, but decreased mPAP. NO inhalation therapy was begun with 20 ppm of NO and 0.95 of FIO2, and on the 6th day NO concentration was decreased to 5 ppm with 0.7 of FIO2. In this case of ARDS, FIO2 could be sufficiently decreased and PaO2 maintained at more than 60 Torr with 5 ppm NO inhalation. PMID- 7853778 TI - [A case of eosinophilic pneumonia with elevated levels of carcino-embryonic antigen (CEA)]. AB - A 70-year-old woman was admitted for productive cough and infiltrative shadows in the right lower lung field on chest X-ray film. Eosinophilia (17%) in blood, an abnormally high percentage of eosinophiles (7%) in bronchoalveolar lavage fluid and eosinophilic infiltration with proliferated goblet cells in transbronchial lung biopsy specimens led to the diagnosis of eosinophilic pneumonia. Laboratory data on admission also revealed a high level of CEA (17.1 ng/ml) in serum. After administration of prednisolone (30 mg/day), the symptoms ameliorated and the CEA levels were normalized. The proliferated goblet cells were immunohistochemically positive for CEA, which suggests that the high levels of CEA were caused by excessive CEA secretion from the goblet cells associated with eosinophilic pneumonia. These studies showed that serum CEA also may be a marker for disease activity in eosinophilic pneumonia. PMID- 7853779 TI - [A case of idiopathic pulmonary hemosiderosis of adult onset]. AB - A 69-year-old woman suddenly suffered massive hemoptysis and was admitted to the hospital. The test of anti-glomerular basement membrane antibodies was negative. Chest radiograph showed diffuse infiltrative shadows similar to those of lung edema in the both lung fields. The patient's condition worsened gradually during the next 3 weeks, with repeated massive hemoptysis. Steroid pulse therapy had limited effects on the progressive respiratory failure, and the patient died. Autopsy showed alveolar hemorrhage and macrophages containing haemosiderin. Immunofluoresence microscopy showed no deposits of immunoglobulin in the kidney. Idiopathic pulmonary hemosiderosis of adult onset with acute respiratory failure is rare in Japan. PMID- 7853780 TI - [An autopsy case of lung cancer metastasizing to renal cell cancer and rectal villous adenoma]. AB - A 67-year-old woman with bloody stool was admitted to our hospital. Chest radiograph on admission showed a tumor shadow in the right lower lung field. Lung adenocarcinoma of right S6 and villous adenoma of the rectum were detected. Although she was treated with chemotherapy and radiotherapy, she died of respiratory failure. At autopsy, moderately differentiated adenocarcinoma of the right lung, renal cell carcinoma, and villous adenoma of the rectum were confirmed. Lung adenocarcinomas were detected in the focus of the renal cell carcinoma and in the villous adenoma. Metastasis of a cancer into another coexisting tumor in the same individual is extremely rare, and a satisfactory explanation for this phenomenon has not yet been offered. PMID- 7853781 TI - [A case of pneumonitis induced by PL granules]. AB - We report a case of pneumonitis induced by PL granules. A 45-year-old man took PL granules and other drugs for fever and headache. Because he subsequently developed high grade fever, cough and diarrhea, he was admitted to our hospital. His chest X-ray film revealed multiple patchy shadows in both lung fields. Analysis of bronchoalveolar lavage fluid (BALF) disclosed a high number of cells (total), lymphocytes, and a high CD4/CD8 ratio. Microscopic examination of transbronchial lung biopsy (TBLB) specimens showed infiltration of mononuclear cells and thickening of the alveolar wall. After discontinuation of drugs, his condition (symptoms, laboratory data, and chest X-ray findings) promptly improved. Lymphocyte stimulation tests (LST) for PL granules and acetaminophen were positive and an oral challenge test with PL granules was also positive. Based on these findings, we diagnosed this as a case of pneumonitis and enteritis due to PL granules. To our knowledge, this is the first reported case of pneumonitis due to PL granules. PMID- 7853782 TI - [A case of acute idiopathic mediastinitis that responded rapidly to treatment]. AB - A 50-year-old man had a feeling of a foreign substance such as fish bone in his throat at breakfast. The feeling gradually changed to retrosternal pain and pain on swallowing, so he went to hospital, but the results of all examinations were normal. The next day he was referred to our emergency center because of the increasing pain and disturbance in swallowing. On admission he had a fever of 37.9 degrees C, a WBC of 35,000 cells/mm3, and a CRP level of 18.3 mg/dl. There was no widening of the mediastinum visible on the chest radiograph, but on the chest CT a tumorous shadow was seen around the esophagus from the cervical to the gastric portion, and was suspected to be an abscess. Some antibiotics were given, based on the diagnosis of acute mediastinitis. The pain gradually subsided, and the tumorous shadow was obscured, without mediastinal drainage. Prompt therapy resulted in rapid improvement, and the patient was discharged on hospital day 23. PMID- 7853783 TI - [Two cases of thymic cyst]. AB - Thymic cysts were diagnosed by thoracotomy in two women with leprosy, both 64 years old, within 12 months. Both were asymptomatic and an abnormal mediastinal shadow on an annual screening chest radiograph was a clue to the diagnosis in both cases. According to retrospective studies it took at least six or seven years for the thymic cysts to become large enough to be detected. Real-time echography was effective in the diagnosis of a cystic lesion in one case. Thymic cysts are important cystic lesions rarely found in the anterior mediastinum. A resective operation is thought to be indispensable to differentiate them from thymomas accompanied by large cystic degeneration and from thymic cysts accompanied by malignancies. PMID- 7853784 TI - Renal manifestations of hepatitis C virus infection. PMID- 7853785 TI - Genetics of Wilms' tumor: a blend of aberrant development and genomic imprinting. PMID- 7853786 TI - Distribution and functional role of renal ET receptor subtypes in normotensive and hypertensive rats. AB - Experiments were designed to compare the distribution and physiological roles of endothelin (ET) receptor subtypes, ETA and ETB, in the kidneys of normotensive Sprague-Dawley (SD) and spontaneously hypertensive (SH) rats. Using [125I] ET-1 and subtype-selective ligands sarafotoxin 6c (S6c, ETB-selective agonist) and BQ123 (ETA-selective antagonist), the distribution of ETA and ETB receptors in SD rat kidney cortex, outer medulla and papilla was calculated to be 50:50, 30:70 and 10:90, respectively. The ET receptor subtypes in outer medulla and papilla of age-matched SH rats were similar to those of SD. However, in the cortex of SH rats, the ratio of ETA to ETB was 25:75 compared to 50:50 in SD rats. In addition, the affinity of the ET receptors was also higher in SH rats (117 pM vs. 235 pM). In the conscious SD rats, bolus i.v. injections of ET-1 and S6c elicited similar dose-dependent decrease in renal blood flow (RBF), which were unaffected by the infusion of the selective ETA receptor antagonist, BQ123. The SH rats were more sensitive to the renal vasoconstrictor effect of S6c and ET-1. Also, the dose-response curve to S6c was shifted to the left when compared to ET-1; however, BQ123 infusion abolished this difference. In renal clearance studies, BQ123 infusions decreased RBF and glomerular filtration rate (GFR) only in SH rats, and the fractional excretion of sodium only in SD rats. The combined data indicate that the distribution and functional roles of ETA and ETB receptor subtypes are altered in the kidneys of SH rats. PMID- 7853787 TI - Immunoregulation and TGF-beta 1. Suppression of a nephritogenic murine T cell clone. AB - Transforming growth factor beta (TGF-beta) has been clearly linked in several model systems to the development of pathologic extracellular matrix deposition in the glomerulus and interstitium. TGF-beta additionally exerts multiple immunomodulatory effects on T and B lymphocytes, including growth inhibition. Such pleiotropic effects make it difficult to predict how TGF-beta might directionally affect the expression of T cell mediated kidney disease. We have examined the effects of TGF-beta 1 on the activity of effector T cells in a model of autoimmune interstitial nephritis. M52.26 is an antigen-specific, nephritogenic, cytotoxic T cell clone. TGF-beta 1 mediates a concentration dependent inhibition of M52.26-directed cytotoxicity of tubular epithelial cells in culture, and also of M52.26-mediated transfer of interstitial nephritis to syngeneic recipients. The loss of these functional activities is associated with distinct changes in cytokine gene expression in M52.26. These cytokine alterations consist of a loss of IFN-gamma and perforin expression, and an up regulation of TGF-beta expression, which is likely relevant to the observed effector T cell inactivation. PMID- 7853788 TI - Mutations in the COL4A5 gene in Alport syndrome: a possible mutation in primordial germ cells. AB - Using a combination of gene amplification with single strand conformation polymorphisms analysis and sequencing, we examined the COL4A5 gene in 37 patients with Alport syndrome. In patient A8, a single base insertion was noted at codon 1,597 tyrosine in exon 49. The premature terminal signal appeared and 89 amino acids (approximately one-third) of the non-collagenous domain were lost. The mutation was present in the mother, hence she is heterozygous. In patient A12, the nucleotide changed from C to T at codon 1,679 glutamine in exon 51, which created a termination codon, and 7 amino acids at the carboxyl terminus were lost. Gene tracking using peripheral leukocytes revealed that the parents did not carry the mutant allele, while the sister was heterozygous. DNA samples from hair roots and skin fibroblasts of the mother were normal and immunological examination of the epidermis of the mother indicated that the alpha 5(IV) chain was normally expressed. As these results suggest that somatic cells of the mother do not carry the mutant allele, the primordial germ cells possibly carry a fresh mutation in the mother of patient A12. PMID- 7853789 TI - Human high density lipoproteins stimulate endothelin-1 release by cultured human renal proximal tubular cells. AB - The vasoconstrictive and mitogenic actions of endothelins have been implicated in the pathogenesis of progressive renal disease. In the present study, we have assessed whether plasma high density lipoproteins (HDL), the major filtered urinary lipoprotein in nephrotic states, can influence endothelin-1 (ET-1) production by cultured human renal proximal tubular cells. Human HDL was found to stimulate ET-1 secretion up to fourfold in a dose- and time-dependent manner; the effect was greater in subconfluent cultures than in confluent ones. There was little difference between the stimulatory effect of HDL2 and the major HDL subclass, HDL3. Preincubation of the cells with albumin did not abolish the HDL effect, while partially- or fully-delipidated HDL3 largely reproduced the effect of whole HDL3. These findings suggest that stimulation of ET-1 secretion was not simply due to protein or lipid repletion of the cells. Rather, the effect was mediated by HDL apolipoproteins, although binding to the HDL receptors involved in cellular cholesterol homeostasis was not required as tetranitromethane modified HDL3 was an equally effective agonist of ET-1 release. Apolipoprotein (apo) A-I was indirectly implicated in the process since modified HDL3 in which apoA-II largely replaced apoA-I was less potent than HDL3. A one hour exposure of the cells to HDL3 was sufficient to activate ET-1 production for the following 12 hours, although maximum activation required six hours.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7853790 TI - Elevated cysteinyl leukotriene excretion in experimental glomerulonephritis. AB - The involvement of cysteinyl leukotrienes (LT) in the etiology of glomerulonephritis (GN) was investigated in a rat model of nephrotoxic serum nephritis in which renal function, morphology, LTC4 synthase activity and urinary cysteinyl LT excretion were monitored over seven days. Significant alterations in renal function and morphology were evident on day 1 in nephritic rats, with a 12% decline in creatinine clearance, a greater than three-fold increase in urinary protein excretion and histologic evidence of basement membrane thickening. Urinary LTC4 excretion in the nephritic rats was elevated at this time to 140 +/- 38 pg/hr (P < 0.01) compared to undetectable levels in control animals. On days 3 and 7, while proteinuria intensified and glomerular filtration remained depressed, LTC4 excretion declined 14% (NS) and 79% (P < 0.05), respectively. The temporal changes in urinary LTC4 excretion were paralleled by concomitant alterations in LTC4 synthase activity in renal cortical microsomes, where an 84% (P < 0.01) drop in enzyme activity occurred from day 1 to day 7 in the nephritic group. This data provides the first measurement of urinary cysteinyl LT excretion and altered LTC4 synthase activity in a model of experimental GN and supports an early role for LT's in the development of subsequent functional changes. PMID- 7853791 TI - Renal autacoids are involved in the stimulation of renin gene expression by low perfusion pressure. AB - This study aimed to examine the role of local autacoids for the regulation of renin secretion and renin gene expression by the renal perfusion pressure. To this end the effects of unilateral reduction of renal perfusion by 0.2 mm clips on plasma renin activity and on renal renin mRNA levels were examined in rats treated with the cyclooxygenase inhibitor meclofenamate (8 mg/kg body wt, twice a day), with the NO-synthase inhibitor nitro-L-arginine-methylester (L-NAME, 40 mg/kg body wt, twice a day) or with a combination of both. L-NAME alone decreased basal PRA values from 9.9 to 5.4 ng Ang I/hr x ml, while meclofenamate alone and the combination meclofenamate/L-NAME had no consistent effect on basal PRA. Unilateral renal artery clipping increased PRA values from 9.9 ng Ang I/hr x ml to 34, 27, and 16 ng Ang I/hr x ml in vehicle, meclofenamate, and L-NAME treated animals, respectively, but did not increase PRA in meclofenamate/L-NAME treated rats (9.5 ng Ang I/hr x ml). Renal renin mRNA levels in the clipped kidneys increased 4.8-, 2.6-, 2.5- and 1.8-fold in the clipped kidneys in vehicle, meclofenamate, L-NAME and meclofenamate/L-NAME injected animals, respectively. These findings indicate that both the inhibition of prostaglandin synthesis and of the formation of endothelium-derived relaxing factor (EDRF) attenuate the increase of renin gene expression and of renin secretion in response to acute unilateral renal hypoperfusion and that the effects of both maneuvers are additive.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7853792 TI - The transgenic SAD mouse: a model of human sickle cell glomerulopathy. AB - The transgenic SAD mouse which expresses a modified sickle hemoglobin, Hb SAD, displays in vivo hemoglobin polymerization and erythrocyte sickling. In the presence study functional and morphological renal analyses were performed in SAD mice in order to compare the renal pathology of SAD mice with the human disease. The SAD mice display renal hemosiderosis, microvascular occlusions, vascular thrombosis, cortical infarcts and papillary necrosis. In the medulla, hemoglobin polymers could be observed with infrequent erythrocyte sickling, which may explain the absence of significant renal concentration defect, whereas in humans, the difference in the vascularization network leads to more extensive sickling. Most animals develop glomerular hypertrophy and mesangial sclerosis which increases in frequency and severity with age. The glomerular damage is associated with functional defects, including increased blood urea nitrogen levels and non selective proteinuria. The glomerular lesions of SAD mice strikingly mimic sickle cell glomerulosclerosis, the most severe renal complication of sickle cell disease in humans. In summary, the SAD mouse is a valuable model of the thrombotic and glomerulosclerotic complications of human sickle cell glomerulopathy and can serve for pathophysiologic studies, and, eventually, for prevention and therapy investigation. PMID- 7853793 TI - Contribution of renal angiotensin II type I receptor to gene expressions in hypertension-induced renal injury. AB - Recent evidence indicates that transforming growth factor-beta 1 (TGF-beta 1) plays an important role in renal fibrosis via stimulation of extracellular matrix synthesis. The present study was undertaken to investigate the role of angiotensin II type I receptor (AT1 receptor) in hypertension-induced renal injury. Twenty-two-week-old stroke-prone spontaneously hypertensive rats (SHRSP), which had established hypertension and moderate renal damage, were orally given TCV-116, a selective non-peptide AT1 receptor antagonist (0.1, 1 or 10 mg/kg/day), enalapril (10 mg/kg/day) or vehicle once a day for 10 weeks. At the end point of the treatment, we examined renal function, the gene expressions of TGF-beta 1 and extracellular matrix components in the interstitium [collagen types I (COI) and III (COIII), fibronectin (FN)] and the basement membrane (COIV and laminin), and renal microscopic morphology in rats aged 32 weeks. In vehicle treated 32 week-old SHRSP with renal dysfunction and nephrosclerosis, renal mRNA levels for TGF-beta 1, COI, COIII, FN, COIV were all several-fold higher than in WKY. Thus, renal TGF-beta 1 gene expression was enhanced in SHRSP, which may contribute to the increased renal expressions of COI, COIII, FN, COIV in SHRSP. Treatment with TCV-116 (0.1 mg/kg/day) in SHRSP, in spite of no reduction of blood pressure, decreased renal mRNA levels for TGF-beta 1, COI, COIII, FN, COIV, being accompanied by the significant decrease in urinary protein and albumin excretion, blood urea nitrogen and plasma creatinine. Treatment with TCV-116 (10 mg/kg/day) in SHRSP decreased mRNAs for TGF-beta 1, COI, COIII, FN and COIV to almost the same levels as WKY, being associated with normalization of urinary protein and albumin excretion and the prevention of nephrosclerosis, as judged by microscopic histological observations. On the other hand, the effects of enalapril (10 mg/kg/day) on the above mentioned mRNA levels, renal function and renal morphology were weaker than those of TCV-116 (10 mg/kg/day) and were as much as TCV-116 (1 mg/kg/day). These results suggest that independently of hypotensive action, AT1 receptor antagonist has a potent renal protective effect by inhibiting the gene expression of renal TGF-beta 1 and extracellular matrix components. PMID- 7853794 TI - Effects of matrix glycation on mesangial cell adhesion, spreading and proliferation. AB - We examined the effects of in vitro nonenzymatic glycosylation (NEG) of the extracellular matrix (ECM) on various aspects of the adhesive interaction between the ECM and human kidney mesangial (HKM) cells, and also on the ability of HKM cells to spread and proliferate. Isolated type IV collagen (tIV) or intact complexes of glomerular basement membrane and mesangial matrix (GBM/MM) were used as substrates following control incubation or modest glycation. We observed that HKM cells adhered less effectively to glycated tIV at early time intervals and were delayed in attaining maximal levels of adhesion compared to cells interacting with control tIV. The nature of the adhesive interaction was also different since antibodies which blocked the function of beta 1-containing integrins more effectively inhibited adhesion between HKM cells and glycated tIV than cells and control tIV. HKM cells interacting with glycated tIV also demonstrated less cell surface microspike and ruffle formation at five minutes after plating, less extensive spreading throughout the examined time intervals (> or = 90 min after plating), and slightly increased cell numbers 5 to 10 days after plating when compared to cells interacting with control tIV. However, increased cell numbers were not observed when HKM cells were grown on glycated GBM/MM. Similar changes in response to glycated substrate were observed when HKM cells were grown in either 5 or 25 mM glucose. In conclusion, relatively modest glycation of the ECM alone was sufficient to result in specific changes in HKM cell behavior in vitro.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7853795 TI - Tubular basement membrane changes during induction and regression of drug-induced polycystic kidney disease. AB - Defective cell-extracellular matrix (ECM) biophysiology is considered a factor in the development of polycystic kidney disease (PKD). Altered biosynthesis of various ECM components may result in tubular dysmorphogenesis and uncontrolled tubular cystic expansion. In this study, expression of certain ECM components was investigated in a diphenylthiazole (DPT)-induced rat model of PKD. DPT induces cystic change in all the collecting tubules, most severe in the outer medulla and inner cortex, and following withdrawal of DPT, cystic tubules return to normal with persistence of focal interstitial fibrosis. SDS-PAGE analyses of isolated tubular basement membranes (TBMs) of control and PKD kidneys revealed overall similar electrophoretic migratory bands. However, in PKD, there were relative increases in components with M(r) approximately 380,000, 250,000 and 145,000, and a decrease in the component with M(r) approximately 55,000. Immunoblot analyses revealed that the major components of TBM (type-IV collagen, laminin beta 1 and beta 2 chains and entactin) were present in the same relative concentrations in control and PKD. The expression of tubulointerstitial (TIN) antigen was decreased. Also, the relative concentrations of type-I collagen and fibronectin were increased in the PKD group. Following recovery, the expressions of TIN and fibronectin returned to normal, whereas type-I collagen remained elevated. ELISA determinations revealed increased expression of interstitial collagens type-I, -V and -VI in PKD vs control and they remained elevated following recovery, while that of type-III was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7853796 TI - Improved treatment of thrombosed hemodialysis access sites with thrombolysis and angioplasty. AB - We treated percutaneously 135 expanded polytetrafluoroethylene (PTFE) prosthetic grafts which had thrombosed using thrombolysis with urokinase followed by balloon angioplasty. Functional patency was re-established in 38 of 62 (61%) using single catheter technique, and in 62 of 73 (85%) using crossed catheter technique (P < 0.01). Hemorrhagic complications were reduced from 12.9% in the single catheter technique to 1.4% in the crossed catheter technique (P < 0.01). Median "primary patency after treatment" of the PTFE accesses after successful restoration of function was 98 days. Cumulative "primary patency after treatment" from the time of successful recanalization of the thrombosis for the PTFE grafts was 70.5% at one month, 45.8% at 6 months, and 16.2% at 12 months. Among a smaller group of 26 PTFE patients who were treated with only interventional radiologic procedures (repeat thrombolysis and/or angioplasty), without surgical revision, "secondary patency after treatment" from the time of thrombosis was 92.3% at 1 month, 80.2% at 6 months, 69.4% at 12 months, and 36.5% at 24 months. We conclude that lysis/angioplasty is a valuable means of treating thrombosed hemodialysis access sites. The crossed catheter technique produces superior initial technical success compared with single catheter infusion of the lytic agent. "Primary patency after treatment" after successful recanalization is relatively short, but long-term patency is improved substantially with retreatment of recurrent failure of the access with repeat thrombolysis and/or angioplasty. PMID- 7853797 TI - Phosphorus and protein restriction and parathyroid function in chronic renal failure. AB - Phosphorus retention as a result of chronic renal failure (CRF) induces secondary hyperparathyroidism (HPT II) while supplemented low-phosphorus low-protein diets (LPD) prevent it. The aim of this study was to assess in seven patients with advanced CRF and biological HPT II the effects of a LPD providing daily 5 to 7 mg/kg phosphorus, 0.4 g/kg protein, 300 mg calcium (Ca) and supplemented with amino acids, ketoacids, CaCO3 and vitamin D2, on the relationship between ionized Ca (iCa) and PTH concentrations. Hyper- and hypocalcemia were induced by CaCl2 and Na2-EDTA infusion. After three months of LPD, serum phosphorus decreased from 1.59 +/- 0.15 to 1.26 +/- 0.24 mmol/liter (mean +/- SEM, P < 0.02), basal PTH levels from 251 +/- 25 to 127 +/- 16 pg/ml (P < 0.03), while basal iCa and GFR did not vary. The sigmoidal PTH-calcium curve shifted downward with maximal PTH decreased from 482 +/- 86 to 319 +/- 60 pg/ml (P < 0.02) and minimal PTH from 35 +/- 4 to 21 +/- 4 pg/ml (P < 0.05). On the other hand, the slope of the % maximal PTH-iCa curve, which is an indicator of the sensitivity of the parathyroid cell to changes in iCa concentrations, did not vary significantly. The set point of Ca and calcitriol levels were not modified. These results demonstrate a direct inhibition of PTH secretion over a wide range of iCa concentration by LPD in patients with advanced CRF and mild HPT II over a three months period. This effect is independent of changes in plasma calcitriol levels. PMID- 7853798 TI - Influence of erythropoietin on paradoxical responses of growth hormone to thyrotropin-releasing hormone in uremic patients. AB - Several alterations in growth hormone (GH) secretion have been reported in patients with chronic renal failure. The aim of the present report has been to assess the effect of acutely administered recombinant human erythropoietin (rHuEPO) infusion on GH responses to thyrotropin-releasing hormone (TRH) in uremic patients. Twelve male patients (mean age 46.2 years, range 24 to 69) were studied. Seven of them were on continuous ambulatory peritoneal dialysis (CAPD), two on chronic hemodialysis (HD) and two in pre-dialysis (PreD). None had been treated before with rHuEPO. Each patient was tested with TRH (400 micrograms i.v. in bolus), and with TRH plus rHuEPO (40 U/kg in constant infusion for 30 min) on different days. TRH administration provoked a paradoxical response of GH (peak > 5 micrograms/liter) in nine (5 CAPD, 2 HD, 2 PreD) out of 12 patients. In this group of patients with anomalous GH responses, rHuEPO infusion produced an abolishment of the paradoxical responses (GH peak < 5 micrograms/liter) in eight patients and a marked decrease in a further one. On the contrary, in patients with no paradoxical GH response, stimulation with TRH plus rHuEPO did not induce any change in GH release compared with that observed after TRH alone. rHuEPO had no effect on TRH-induced thyrotropin release. These results suggest that the paradoxical GH response to TRH in patients with chronic renal failure is blocked by rHuEPO administration. This rHuEPO action might be mediated by an increased release of somatostatin or an inhibited GH-releasing hormone secretion. PMID- 7853799 TI - Race and the risk of peritonitis: an analysis of factors associated with the initial episode. AB - To study how clinical characteristics influence the risk of peritonitis in African American patients with end-stage renal disease treated with continuous ambulatory peritoneal dialysis (CAPD), we examined the risk of developing a first episode of peritonitis among 1,595 new dialysis patients initially treated by CAPD over a two year period in North Carolina, South Carolina, and Georgia (Network 6). Characteristics examined were demographic and socioeconomic factors, functional status, serum albumin and comorbid conditions. There were 538 initial episodes of peritonitis during an average of 8.8 patient months of follow-up; the time to peritonitis for the entire cohort was 26 months. Factors found to be independently associated with a risk for peritonitis were student status (Odds Ratio and 95% Confidence Interval = 2.4; 1.4 to 4.3), rental housing (1.2; 1.0 to 1.5), and substance abuse (1.9; 1.1 to 3.2). African Americans were 60% more likely to have an initial episode of peritonitis during follow-up than whites (1.6; 1.3 to 1.8). The time to the initial episode was 21 months for African Americans versus 32 months for whites (P < 0.001). Even after adjusting for other factors, African Americans were significantly more likely to develop peritonitis (1.5; 1.2 to 1.8). Thus, the increased risk of peritonitis of African American patients treated by CAPD is independent of other demographic, socioeconomic and comorbid characteristics. PMID- 7853800 TI - Erythropoiesis after withdrawal of enalapril in post-transplant erythrocytosis. AB - Enalapril effectively decreases hematocrits in patients with postrenal transplant erythrocytosis (PTE). We studied the effect of enalapril withdrawal on erythropoiesis in 18 patients with PTE who had been treated for 13 +/- 8 months. Hematocrit, reticulocyte count, plasma erythropoietin, and plasma insulin-like growth factor I were measured biweekly for six weeks. Red cell mass, plasma volume, transferrin saturation, and plasma angiotensin II were measured at withdrawal and six weeks later. Hematocrit increased by at least 0.04 in 13 patients ('responders') but changed by -0.08 to 0.01 in five patients ('nonresponders'). In the responder subgroup, hematocrit increased from 0.43 +/- 0.05 to 0.51 +/- 0.05 (P < 0.001), red cell mass increased from 25.4 +/- 5.9 to 28.9 +/- 5.9 ml/kg body weight (P < 0.001), and transferrin saturation decreased from 41 +/- 16 to 27 +/- 9 percent (P < 0.01). Reticulocyte count increased two weeks after withdrawal of enalapril. Plasma volume did not change significantly. No measurement changed in the nonresponder subgroup. Plasma levels of erythropoietin, total erythroid stimulating activity, insulin-like growth factor I, and angiotensin II did not change significantly in either subgroup. Enalaprilat did not inhibit erythropoiesis in cell culture. Thus, erythropoiesis increased in 13 of 18 patients after stopping enalapril and was independent of changes in circulating concentrations of several erythropoietic factors, including erythropoietin. The pathogenesis of PTE and mechanism underlying the beneficial effect of angiotensin converting enzyme inhibition remain undetermined. PMID- 7853801 TI - Characterization of platelet-activating factor synthesis in glomerular endothelial cell lines. AB - Platelet-activating factor synthesis in two transformed lines of glomerular endothelial cells was characterized and contrasted with platelet-activating factor production in macrovascular-derived endothelial cells as well as with glomerular cells of mesenchymal origin. Platelet-activating factor synthesis was assessed in intact cells and in cell-free preparations. Glomerular endothelial cells constitutively synthesize bio-active alkyl-PAF, and this basal activity can be chronically augmented by various inflammatory and thrombotic agents. In contrast, thrombin-mediated platelet-activating factor formation in bovine pulmonary aortic endothelial cells as well as in glomerular mesangial cells is acute and transient. The potential role of anti-inflammatory prostanoids to function as negative feedback modulators of thrombin- or endothelin-mediated platelet-activating factor synthesis was also investigated, as the synthesis of platelet-activating factor is often associated with the formation of these prostanoids. Indomethacin augmented receptor-mediated platelet-activating factor synthesis while prostanoids of the E and I series reduced agonist-stimulated PAF synthesis. In summary, the unique capacity of glomerular endothelial cells to respond to inflammatory stimuli with sustained platelet-activating factor synthesis is a clear indication of this cell's pivotal role in augmenting the inflammatory response in the limited environment of the glomerulus. PMID- 7853802 TI - Immunohistochemical study of alpha 1-5 chains of type IV collagen in hereditary nephritis. AB - The distribution of alpha 1-5 chains of type IV collagen [alpha 1-5(IV)] in the glomerular basement membrane (GBM) and epidermal basement membrane (EBM) of 23 families with hereditary nephritis was examined by indirect immunofluorescence. These families were divided into three clinicopathological groups. Group I (10 families) patients showed a widespread "basket weave" pattern of the GBM and a family history of nephritis was present. Group II (6 families) patients showed a widespread "basket weave" change without a family history of nephritis. Group III (7 families) patients showed a widespread attenuation of the GBM but no "basket weave" change, and had a family history of nephritis and chronic renal failure. alpha 1(IV) and alpha 2(IV) were present in all affected and unaffected family members and controls. All normal family members and controls expressed alpha 3(IV), alpha 4(IV) and alpha 5(IV) in the GBM and alpha 5(IV) in the EBM in a diffuse pattern. All group I families and three of the group II families exhibited complete loss of the alpha 5(IV) antigen from the GBM and EBM in male patients, and segmental loss of the alpha 5(IV) antigen in female patients. In these families the alpha 3(IV) and alpha 4(IV) antigens were completely lost from the GBM in male patients with severe nephritis, whereas alpha 3(IV) alpha 4(IV) were present but diminished in male patients with mild nephritis. Three group II and all group III families expressed the alpha 3-5(IV) antigens in an identical manner to that of normal controls. These findings indicate that the heterogeneity of hereditary nephritis reflects a variety of aberrant expression patterns of alpha 3-5(IV) and that immunohistochemical examination of alpha 5(IV) in the EBM is a useful method for the diagnosis of X-linked Alport syndrome. PMID- 7853803 TI - Appearance of tumor necrosis factor-alpha and soluble TNF-receptors I and II in peritoneal effluent of CAPD. AB - Dialysate and serum concentrations of tumor necrosis factor-alpha (TNF-alpha), soluble TNF-receptor I (sTNFRI) and soluble TNF-receptor II (sTNFRII) were measured during stable and infectious CAPD to determine whether these mediators are released intraperitoneally or derived from the circulation. Dialysate/serum ratios were compared to those of various marker proteins for peritoneal transport and to interleukin-6 (IL-6), which is locally produced. Peritoneal immunoreactive TNF-alpha could be detected in 19 of 20 stable CAPD patients after a night dwell, but only occasionally and in lower concentrations during and after a standard four-hour peritoneal permeability test. Both sTNFRs highly exceeded TNF-alpha dialysate concentrations. In case of peritonitis a median 16-fold increase in dialysate TNF-alpha occurred on the first day, which declined towards control values during a longitudinal follow-up of eight consecutive days. sTNFRI and sTNFRII in dialysate increased three- to fourfold. Their peaks, however, appeared on the second peritonitis day. Bioactive TNF-alpha was only detected when immunoreactive levels exceeded 1000 pg/ml. Serum values of all variables were not altered during infection; sTNFRs exceeded TNF-alpha 300- to 400-fold. During stable CAPD indirect evidence was obtained for transperitoneal transport from plasma to dialysate of TNF-alpha (molecular wt 17 kD), sTNFRI (55 kD) and sTNFRII (75 kD). Dialysate/serum (D/S) ratios were higher, the lower the molecular weight; they were related to D/S ratios of those marker proteins with the nearest molecular weight; D/S ratios were unrelated to the intraperitoneally produced IL 6. Furthermore, the observed D/S ratios were as expected theoretically for their molecular weights.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7853804 TI - An ELISA for the detection of type IV collagen in human urine--application to patients with glomerulonephritis. PMID- 7853805 TI - Bioimpedance analysis of total body water in hemodialysis patients. PMID- 7853806 TI - Acute renal failure in the setting of bone marrow transplantation. PMID- 7853807 TI - [Prospects of the use of cyclosporin A in rheumatic diseases]. PMID- 7853808 TI - [Concept of fever]. PMID- 7853809 TI - [Characteristics of external respiration function and pulmonary circulation in patients with ischemic heart disease complicated by disorders of intraventricular conduction]. AB - The authors provide evidence on the condition of external respiration and hemodynamic shifts in the lesser and greater circulation in coronary patients with bundle-branch block; establish early objective quantitative criteria of the diagnosis of hemodynamic impairment arising in formation of the above blocks basing on ECG, phonocardiography, echocardiography findings; compare hemodynamic effects of single-dose nitrosorbide and corinfar in the above patients. Nitrosorbide and corinfar correct hemodynamics and external respiration, the former being more effective in normalizing the greater, while corinfar the lesser circulation. PMID- 7853810 TI - [A new approach to the evaluation of the effectiveness of antihypertensive therapy in patients with mild and moderate arterial hypertension based on the example of isoptin retard]. AB - Isoptin-retard (Knoll, BASF) in a single dose 240 mg/day provides a significant hypotensive effect in patients with mild and moderate essential hypertension noticeable as early as treatment day 2. Sensitivity to the drug does not tend to decrease with time. The treatment should be conducted under ECG monitoring. PMID- 7853811 TI - [Changes in clinical-instrumental parameters in patients with mitral stenosis after balloon catheterization valvuloplasty of the mitral valve]. AB - The results of mitral valvuloplasty using a balloon catheter were presented for 104 patients with mitral stenosis. Instrumental measurements and clinical symptoms were evaluated before the operation, 6 and 12 months after it (62 and 42 patients, respectively). The balloon dilatation has increased mitral orifice from 120.5 +/- 5.8 to 333.88 +/- 7.45 mm2, transmitral diastolic pressure gradient decreased from 22 +/- 1 to 7.91 +/- 0.6 mm Hg. All the patients benefited clinically: cough, blood spitting, lower limb edemas, protodiastolic murmur disappeared, dyspnea noticeably reduced. NYHA functional class I-II was established in 85% of the patients. The highest effect was achieved in patients with isolated mitral stenosis. PMID- 7853812 TI - [Role of lipoproteins and triglycerides in cholesterol lithogenesis]. AB - Serum lipoprotein spectrum was evaluated in 63 patients with cholelithiasis at various stages versus 10 healthy subjects as control. The patients were found to develop lipoprotein shifts as early as a physicochemical stage of the disease. Abnormal proportions of lipoproteins and triglycerides, changes in the formation of free radical products justify correction of dyslipoproteinemia early in cholelithiasis course. PMID- 7853813 TI - [Jejunoileal bypass in the prevention and treatment of clinical manifestations of atherosclerosis in patients with morbid obesity]. AB - Jejunoileostomy effects on blood lipids and cardiovascular system were investigated in obese patients. They were found to lose 30% of their body mass within 6 postoperative months with parallel reduction in concentrations of total cholesterol, triglycerides, LDL and VLDL cholesterol and apoprotein B. These changes persisted for 4.5 years of the follow-up. The surgery in males has a more pronounced effect on blood lipids than in females. Significant changes were not registered in post- and preoperative levels of HDL cholesterol and apolipoprotein A-1. Jejunoileostomy promoted a fall in blood pressure, a rise in exercise tolerance, alleviation of atherosclerosis symptoms. PMID- 7853814 TI - [Effects of pregnancy on the course of systemic lupus erythematosus]. AB - A SLE course has been analyzed retrospectively in pregnancy and after delivery for 34 patients (44 pregnancies). Aggravation of the disease was registered in 6 cases (13.5%). Only two of them received prophylactic corticosteroid maintenance. Two SLE patients with unaffected kidneys had no pregnancy-related SLE exacerbations though they developed nephropathy of the pregnant. After delivery the disease aggravated in 12 patients (27.3%). Five patients had moderate exacerbations within half a year after the delivery, seven patients developed severe exacerbations within 3-11 postnatal months. Five out of seven women presented nephrotic syndrome. One of the patients died of rapidly progressive glomerulonephritis. Three women had renal damage after the delivery as initial condition. SLE exacerbations were reported more frequently in young patients (under 30, in 15 of 31 pregnancies) than in older ones (over 30, in 3 of 13 pregnancies). Postnatal SLE aggravations can be prevented by large doses of prednisolone (20-30 mg/day) administered for 2-3 weeks. PMID- 7853815 TI - [Complement system in patients with rheumatoid arthritis related to administered drug therapy]. PMID- 7853816 TI - [Role of magnesium and calcium ions in the pathogenesis of bronchial asthma]. AB - Nuclear absorption spectrophotometry (ACC-508, Hitachi, Japan) and selective ionometry (Microlyte, Kone, Finland) were used to measure Mg and Ca concentrations in the serum, red cells, lymphocytes and 24-h urine of 26 patients with atopic and 23 patients with bacterial bronchial asthma (BA) aged 15-65. Irrespective of BA variant, phase, severity and bronchial obstruction, the blood of the examinees contained insufficient quantities of Mg and excessive ones of Ca. 24-h urinary excretion of Mg was subnormal. BA-specific changes in cell electrolyte composition impair cAMP metabolism and activate lipid peroxidation. This results in emergence of bronchial hyperreactivity. It is suggested that abnormal intracellular homeostasis of bivalent cations in BA patients may be due to hyperactivation of free-radical oxidation of cell membrane lipids. PMID- 7853817 TI - [Comparative study of the effectiveness of equivalent doses of the preparation ditek, disodium cromoglycate and fenoterol in atopic bronchial asthma]. AB - 18-45-year-old patients with atopic bronchial asthma free of associated inflammatory diseases received ditek, lomudal and berotek (28, 10 and 10 patients, respectively). Biochemical assessment of allergic inflammation activity demonstrated that ditek is most effective of the above three drugs both in relation to induction of clinical remission and to inhibition of allergic inflammation. PMID- 7853818 TI - [Levels of gastrin and somatostatin in blood and gastroduodenal gastrin and somatostatin cells in the differentiation of treatment of patients with duodenal ulcer]. AB - Radioimmunoassay and immunomorphological methods were used in the study of pepsinogen 1, basal and food-stimulated gastrin and somatostatin blood levels, the number of gastroduodenal G- and D-cells as well as gastric secretion during routine-dose treatment with gastrozepin and ranisan of 45 gastroduodenal ulcer patients versus 15 controls. The patients were divided into 2 types according to blood gastrin levels and the number of pyloric G-cells: with hypergastrinemia and/or hyperplasia of the G-cells, with normogastrinemia and normal number of G cells. A course treatment with gastrozepin of type 1 patients brought about normalization of serum gastrin and the number of the G-cells with elevation of blood somatostatin levels. In patients of type 2 the above parameters did not change. The same picture in them remained after ranisan treatment, though they developed hypergastrinemia. In patients of type 1 after ranisan treatment the above parameters did not change. The data obtained demonstrate once more heterogeneity of duodenal ulcer. PMID- 7853819 TI - [Results of treatment of patients with chronic glomerulonephritis at different health resorts]. AB - The results of sanatorium treatment were compared for different health resorts (in the Middle Asia, Yalta, Sestroretsk) where 374 patients underwent 455 courses for chronic glomerulonephritis. The results of the treatment were similar except for the Middle Asia and Yalta sanatoria where the condition of the patients aggravated. This suggests a conclusion of an unfavorable effect of hot climate on the course of chronic glomerulonephritis. PMID- 7853820 TI - [Case of plasma cell hemoblastosis with clinical manifestations as hypercalcemic crisis]. PMID- 7853821 TI - [Case of food poisoning in a female patient in coma]. PMID- 7853822 TI - [Acute viral encephalitis]. PMID- 7853823 TI - [Principles and methods of current pathogenetic therapy of acute pneumonia]. PMID- 7853824 TI - [Debatable issues in the diagnosis and therapy of advanced hepatobiliary and pancreatic diseases]. PMID- 7853825 TI - [Problems of integration of medical education, medical science and practice]. PMID- 7853826 TI - Genotype-phenotype agreement of aldehyde dehydrogenase 2 in 120 healthy Japanese. AB - An individual genotype of aldehyde dehydrogenase 2 was observed using nail clippings by an improved method consisting of DNA extraction with guanidium thiocyanate, genomic DNA amplification by non-isotopic polymerase chain reaction, and gel electrophoresis of the DNA fragment. The results were consistent with those obtained using the corresponding peripheral blood samples. The individual phenotype was also determined by the Tokyo-University ALDH2-Phenotype Screening Test. Both types of ALDH2 were observed in 120 healthy Japanese and 48% were the typical or normal homozygote, 43% were the heterozygote, and 9% were the atypical or mutant homozygote of ALDH2. Among 57 individuals of both sexes with the typical homozygote, 88% were the phenotype of a non-flusher. Similarly 76% of the 63 heterozygote/atypical homozygotes had the phenotype of a flusher. PMID- 7853827 TI - Effects of K-7259 on neuronal activity and synaptic transmission in the rat dorsolateral septal nucleus. AB - K-7259 is a dilazep dihydrochloride derivative that minimizes the damaged area from middle cerebral artery hemiocclusion in the rat (Yamauchi et al. 1992a, b). The effects of K-7259 on the electrophysiological properties of neurons in the rat dorsolateral septal nuclei (DLSN) were examined. K-7259 (100 microM-3 mM) depolarized the membrane with a decrease in input resistance in 36% of the DLSN cells. K-7259 (100 microM) depressed the inhibitory postsynaptic potential (IPSP) and the late hyperpolarizing potential (LHP). The magnitudes of the depressions of the IPSP and LHP with 100 microM K-7259 were 50 +/- 25% (n = 5) and 52 +/- 15% (n = 4), respectively. The amplitudes of the excitatory postsynaptic potentials (EPSPs) were augmented during the inhibition of the IPSP and LHP. However, a voltage-clamp analysis showed that K-7259 did not affect the isolated excitatory postsynaptic current (EPSC). The outward current produced by pressure application of gamma-aminobutyric acid (GABA) to the recording cell was not inhibited by K 7259. These results indicate that K-7259 presynaptically inhibits the IPSP and LHP through a GABAergic pathway. PMID- 7853829 TI - Function of asialoglycoprotein receptor of hepatocytes in patients with Wilson's disease. AB - The function of hepatocyte asialoglycoprotein receptors was analyzed in normal subjects, in patients with Wilson's disease and in patients with chronic hepatitis C. A new radionuclide liver imaging, using Technetium-99m diethylenetriamine-pentaacetic acid-galactosyl human serum albumin, was applied to evaluate the function of the receptor, and a Receptor Index, LHL 15, which was calculated by dividing the radioactivity of the liver region-of-interest (ROI) by that of the liver plus heart ROI at 15 min after the radiolabeled ligand injection, was evaluated. The values were similar between the patients with Wilson's disease and patients with chronic hepatitis C. Hepatocyte receptors for asialoglycoproteins were not affected specifically in patients with Wilson's disease, suggesting that the defect in patients with Wilson's disease involves steps other than receptor-mediated endocytosis of asialoceruloplasmin via asialoglycoprotein receptor. PMID- 7853828 TI - Asialoglycoprotein receptor function of hepatocytes in patients with autoimmune hepatitis. AB - To assess whether the hepatocyte asialoglycoprotein receptors are affected in patients with autoimmune hepatitis, the function of the hepatocyte asialoglycoprotein receptor was investigated in patients with autoimmune hepatitis or chronic hepatitis C. A new radionuclide liver imaging technique, Technetium-99m diethylenetriamine-pentaacetic acid-galactosyl human serum albumin, was applied to evaluate the function of the receptor. A Receptor Index (LHL 15) was calculated by dividing the radioactivity of the liver region-of interest (ROI) by that of the liver plus heart ROI 15 min after radiolabeled ligand injection. Serum albumin, prothrombin time, hepaplastin test and plasma retention rate of indocyanine green at 15 min were not significantly different between patients in the autoimmune hepatitis group and chronic hepatitis C group. In addition, the Receptor Index of patients with autoimmune hepatitis, in whom the asialoglycoprotein receptor is a candidate target antigen for autoimmune response, was similar to that of patients with chronic hepatitis C. These results indicate that the hepatocyte receptor for asialoglycoproteins is not affected in patients with autoimmune hepatitis. PMID- 7853830 TI - The effect of orally-administered retinoid on lectin binding in guinea pig keratinocytes. AB - Retinoids influence proliferation and differentiation of epithelial cells. The present paper was designed to examine the change of lectin binding in isolated keratinocytes from retinoid-treated guinea pigs. Aromatic retinoid, etretinate, in peanut oil (5 mg/kg/day) was given orally for a period of 14 days. Skin samples were obtained from animals on days 1, 3, 7, and 14 after beginning the administration. Free keratinocytes were obtained by treatment with EDTA and trypsin. They were separated into 3 fractions by centrifugation on a continuous colloidal silica (Percoll) density gradient. The cells in each fraction were stained by biotinyl lectins and avidin-FITC, and the fluorescence intensity was measured by cytofluorometry. The lectins used were Concanavalin A (Con A), soybean agglutinin (SBA), peanut agglutinin (PNA), Dolichos biflorus agglutinin (DBA), and Ricinus communis agglutinin (RCA). The PNA-binding was diminished in both the intermediate and lower density fractions at 7 and 14 days. The binding of SBA was reduced in all fractions from 1 to 7 days. With Con A, RCA and DBA, no changes in intensity were found. PMID- 7853831 TI - Phagocytic ability of polymorphonuclear cells and macrophage is not decreased in aged bed ridden patients. AB - The phagocytic ability of polymorphonuclear cells and macrophages from aged, bed ridden patients was investigated. Phagocytosis of carbon in aged bed ridden patients did not differ from that of young controls, and extent of upregulation of granulocytes phagocytosis in response to elevation of incubation temperature was also similar between the two groups. Morphological changes of macrophages in response to ingestion of colloidal carbon was more prominent in young controls. These data suggest that a depressed phagocytosis is not an important factor in the increased susceptibility to infections of aged bed ridden patients, although the reactivity of macrophages may be more closely related to the infection defence. PMID- 7853832 TI - A 15-year-old girl with pubertal masculinization due to bilateral gonadoblastoma and 45,X/46,X,+mar karyotype. AB - We report the case of a 15-year-old girl with bilateral gonadoblastoma and 45,X/46,X,+mar karyotype. She was short but had no other stigmata of Turner syndrome. Her genitalia were completely of the female type until she began to show signs of masculinization at age 13 years. She had breasts of Tanner stage 4, primary amenorrhea, clitoromegaly, hirsutism and low voice. Plasma testosterone level was elevated and returned to normal after the successful removal of the bilateral gonadoblastoma. Her karyotype was 45,X/46,X,+mar and it was proved that the marker chromosome was derived from the short arm of the Y chromosome by Southern blot analysis with a Y chromosome specific probe, pDP1007. Even when there are no stigmata of Turner syndrome or signs of intrauterine virilization, the possibility of gonadoblastoma should not be ruled out in girls who show postnatal virilization. PMID- 7853833 TI - Adenosine 5'-triphosphate induces membrane depolarization through P2Y receptors in rabbit parasympathetic neurons. PMID- 7853834 TI - [Explosive themes--creative models]. PMID- 7853835 TI - [Experiences with aid to Romania. The difficulty of helping effectively]. PMID- 7853836 TI - [Recognizing different living environments]. PMID- 7853837 TI - [Without my family I could not stand it]. PMID- 7853839 TI - [Drawing an arch...]. PMID- 7853838 TI - [Working less after pregnancy--how to proceed?]. PMID- 7853840 TI - [Transcultural nursing]. PMID- 7853841 TI - [How nurses can help parents and their dying children. Planning the farewell]. PMID- 7853842 TI - [Madeleine Leininger in Switzerland at last]. PMID- 7853843 TI - [Response to an identity problem]. PMID- 7853845 TI - [Contested licensing]. PMID- 7853844 TI - [Writing: a pleasure to discover. Interview by Brigitte Kocher]. PMID- 7853846 TI - [Welcoming new residents]. PMID- 7853847 TI - Animal models for Lyme disease. PMID- 7853848 TI - The biology of cancer gene therapy. PMID- 7853849 TI - Chronic lyme disease in the rhesus monkey. AB - BACKGROUND: We have previously reported the clinical, pathologic, and immunologic features of "early" Borrelia burgdorferi infection in rhesus monkeys (3). We have now evaluated these features during the chronic phase of Lyme disease in this animal model. EXPERIMENTAL DESIGN: Clinical signs, and pathologic changes at the gross and microscopic levels, were investigated 6 months post-infection in several organ systems of five rhesus macaques (Macaca mulatta), which were infected with Borrelia burgdorferi by allowing infected Ixodes scapularis nymphal ticks to feed on them. A sixth animal was used as an uninfected control. Borrelia antigens recognized by serum antibody were identified longitudinally by Western blot analysis, and C1q-binding immune complexes were quantified. Localization of the spirochete in the tissues was achieved by immunohistochemistry and in vitro culture. The species of spirocheta cultured was confirmed by the polymerase chain reaction. RESULTS: Chronic arthritis was observed in five out of five animals. The knee and elbow joints were the most consistently affected. Articular cartilage necrosis and/or degenerative arthropathy were the most severe joint structural changes. Synovial cell hyperplasia and a mononuclear/lymphocyte infiltrate were commonly seen. Nerve lesions were also observed, including nerve sheath fibrosis and focal demyelinization of the spinal cord. Peripheral neuropathy was observed in five out of five animals and could be correlated in the most severely affected monkey with the presence of higher levels of circulating immune complexes. Differences in disease severity did not correlate with differences in the antigens recognized on Western blot analysis. CONCLUSIONS: B. burgdorferi infection in rhesus macaques mirrors several aspects of both the early and chronic phases of the disease in humans. This animal model will facilitate the study of the pathogenesis of Lyme arthritis and neuroborreliosis. PMID- 7853850 TI - Induction and intracellular localization of 90-kilodalton heat-shock protein in rat kidneys with acute gentamicin nephropathy. AB - BACKGROUND: We previously reported the induction of 73-kilodalton heat-shock protein (HSP73) in injured tubular epithelial cells in rat kidneys with gentamicin-induced acute renal failure. In the present study, we examined serial expression of 90-kilodalton heat-shock protein (HSP90), another major HSP, in this animal model. EXPERIMENTAL DESIGN: Sprague-Dawley rats received gentamicin (80 mg/kg/day) for 14 days and developed acute proximal tubular injury. Serial immunohistochemical localization of HSP90 was observed at both light microscopic and electron microscopic levels, using a specific antibody against HSP90. In addition, serial renal extracts were analyzed by immunoblot. RESULTS: On light microscopy, HSP90 was induced in injured proximal tubular epithelial cells and accumulated in fine granules 36 hours after the gentamicin exposure. The size and number of these granules gradually increased to Day 12 and decreased from Day 18, and the granules disappeared on Day 27. Electron microscopy showed the accumulation of HSP90 in the swollen lysosomes and the nucleoli of the injured proximal tubular epithelial cells. On serial immunoblot analysis of renal extracts, increased amounts of HSP90 were found in association with the induction of HSP90 in injured cells. Furthermore, on immunoblot of nuclear fractions from kidneys at Days 0 and 6, HSP90 was detected in the fraction at Day 6. CONCLUSIONS: These results demonstrate that HSP90 is induced in the lysosomes and the nucleoli of damaged cells during the course of gentamicin-induced acute tubular injury. HSP90 may have roles in the disposition of degenerated proteins and in the new protein synthesis for the protection and repair of target cells from gentamicin nephrotoxicity. PMID- 7853851 TI - Detailed examination of vascular lesions triggered by an inhibitor of endothelium derived relaxing factor. AB - BACKGROUND: Inhibition of an endothelium-derived relaxing factor (EDRF) may contribute to the pathogenesis of thrombotic arterial occlusions. EXPERIMENTAL DESIGN: We measured the blood pressure and urinary excretion of protein, sodium, and potassium and histologically examined the brains, hearts, and kidneys in normotensive Wistar Kyoto rats (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP) fed on a diet containing: (a) EDRF inhibitor (L-N-nitroarginine:L NNA); (b) L-arginine, which reverses the effect of L-NNA; or (c) both L-NNA and L arginine for 1 to 8 weeks. In addition, we examined L-NNA-treated SHRSP, the blood pressures of which were lowered using hydralazine. Furthermore, we produced and examined Goldblatt's renal hypertensive rats, which are of a different type from those resulting from the L-NNA treatment. RESULTS: Both WKY and SHRSP rats fed on a diet containing L-NNA suffered from hypertension and cerebral infarctions in a dose-dependent manner. Cerebral infarctions occurred whether or not SHRSP rats were treated with an antihypertensive agent when they were fed a high dosage of L-NNA. In contrast, SHRSP rats, treated simultaneously with both L NNA and L-arginine, suffered few cerebral infarctions, although they were severely hypertensive. In addition, there were no cerebral infarctions in Goldblatt's renal hypertensive rats, although they suffered from advanced hypertension. CONCLUSIONS: The data indicate that the inhibition of EDRF injures the vessel walls and encourages platelet adhesion to the damaged areas. The adhering platelets narrow the lumen with resultant thrombotic arterial occlusions. Pathophysiologic conditions that decrease EDRF synthesis appear to play an important role in cerebral, renal, and myocardial infarctions. PMID- 7853852 TI - Cyclosporin A exacerbates mercuric chloride-induced vasculitis in the brown Norway rat. AB - BACKGROUND: Administration of mercuric chloride (HgCl2) to the Brown Norway (BN) rat induces a necrotizing leukocytoclastic vasculitis (most marked in the gut) and anti-myeloperoxidase (anti-MPO) antibodies. The development of autoimmunity in the BN rat is a T cell-dependent phenomenon, and there is evidence that the induction of autoantibodies and tissue injury is a Th2-driven process. Cyclosporin A (CyA) is an anti-T cell agent with a dose-dependent differential effect on Th cell subsets that can ameliorate or enhance autoimmune responses. In the BN it can suppress HgCl2-induced autoantibody production, but the effect on tissue injury has not been previously examined. EXPERIMENTAL DESIGN: We have studied the effect of CyA given "early" (Days 1-10, concurrently with the HgCl2) or "late" (Days 11-14) on tissue injury and autoantibody response. Serial blood samples were taken for anti-glomerular basement membrane, anti-MPO, and IgE antibody levels. Necropsies were performed on animals killed on Day 15. The presence and extent of vasculitis was scored macroscopically and histologically. Controls were incorporated to assess the effect of vehicle and of CyA alone. RESULTS: CyA given early delayed the rise in anti-MPO and anti-glomerular basement membrane levels and ameliorated tissue injury, whereas CyA given late, although suppressing the rise in anti-MPO and anti-glomerular basement membrane antibodies, caused a marked exacerbation of vasculitis. CONCLUSIONS: The effect of CyA depends on the timing of treatment with respect to HgCl2. Anti-MPO antibodies are not of primary importance in the pathogenesis of tissue injury. The late effect may be due to a direct toxic effect on the endothelium or to loss of a protective T cell subset. These observations have implications for the use of CyA in the treatment of systemic vasculitis in humans. PMID- 7853853 TI - Expression of group II phospholipase A2 in the human gastrointestinal tract. AB - BACKGROUND: It has been suggested that group II phospholipase A2 (PLA2-II) plays an essential role in inflammation, but the cellular source(s) of the enzyme is (are) largely unknown. EXPERIMENTAL DESIGN: Expression of PLA2-II was analyzed in human gastrointestinal tract at both protein and mRNA levels. Both normal tissues and specimen from patients with a few different common gastrointestinal disorders were analyzed. RESULTS: Expression of PLA2-II mRNA was seen in the Paneth cells but not in any other cell type of the intestinal tract. Blood vessel walls showed PLA2-II immunoreactivity but were negative in in situ hybridization for PLA2-II mRNA. CONCLUSIONS: It was concluded that nonpancreatic group II PLA2 is synthesized and stored by Paneth cells, whereas other cell types of the gastrointestinal tract seem incapable of synthesis of this enzyme. The positive immunoreaction in vascular structures may reflect the entry of circulating PLA2 II into vessel walls rather than local production of the enzyme. PMID- 7853854 TI - Detection of 17p loss in gastric carcinoma using polymerase chain reaction. AB - BACKGROUND: The loss of heterozygosity (LOH) of 17p has been previously studied with conventional Southern blot-restriction fragment length polymorphism analysis, but the relatively low informativity was an obstacle to extensive analysis. To overcome this problem and to investigate the significance of 17p LOH in gastric carcinoma, we employed polymerase chain reaction and subsequent silver staining of DNA. EXPERIMENTAL DESIGN: LOH of p53 gene and D17S5 locus on 17p was analyzed using polymerase reaction; the relationships between 17p LOH and conventional clinicopathologic parameters were evaluated. RESULTS: The LOH of p53 gene and D17S5 was found in 36.5% (23 out of 63) and 63.3% (38 out of 60) informative cases, respectively. There was no significant correlation between LOH of these two loci, whereas the frequency of the D17S5 locus was significantly higher (p < 0.01), which suggested that there may be another putative tumor suppressor gene between the two loci or distal to D17S5. The LOH of p53 gene and D17S5 locus was not significantly associated with abnormal p53 expression, depth of invasion, histologic type of the tumor (Lauren's classification), or the status of lymph node metastasis. CONCLUSIONS: The polymerase chain reaction and silver staining of DNA seemed to be a simple and excellent method for the evaluation of chromosomal allelic loss. The 17p LOH was frequently found in gastric carcinoma, but specific association with conventional clinicopathologic parameters was not found. PMID- 7853855 TI - The establishment and characterization of a peripheral neuroepithelioma cell line in soft tissue of extremity. AB - BACKGROUND: The histogenetic and biologic features of peripheral neuroepithelioma (PN) are still a matter of controversy. More detailed analyses might be facilitated by permanent PN cell lines. However, there have been only a few reports on the establishment of a PN cell line. EXPERIMENTAL DESIGN: We established and characterized a PN cell line and further carried out experiments for potentiality of drug-induced neural differentiation. RESULTS: The cultured cells were spindle shaped with slender cytoplasmic processes. The histologic features of transplanted tumors in nude mice were essentially the same as those of the original tumor. Immunohistochemically, the neuroectodermal characteristics of the cell line were demonstrated by positive stain for neuron specific enolase, glial fibrillary acidic protein, S-100 protein, neurofilament, and beta 2 microglobulin. Ultrastructurally, microtubules and dense core granules were observed in the cultured cells. Northern blot analyses revealed that c-myc was overexpressed in the cell line, whereas N-myc was not. The cell line showed neural differentiation after treatment with cAMP elevating reagents and nerve growth factor (NGF). The synergistic effects of cAMP analog and NGF on the neurite outgrowth were also observed. Furthermore, a cAMP-dependent protein kinase (PKA) inhibitor strongly blocked the action of cAMP analog, although it was not able to inhibit the same action of NGF. These findings suggested that the neurite outgrowth induced by the cAMP analog requires activation of PKA, whereas the same actions of NGF do not mediate such a pathway involving PKA activation. CONCLUSIONS: This is, to our knowledge, the first NGF responsive cell line derived from PN. This cell line might be valuable for further investigations of signal transduction pathways induced by cAMP analogs and NGF, for more precise analyses of the biological characteristics of PN, and finally, for the identification of differences between PN and several related tumors. PMID- 7853856 TI - Alzheimer's disease and the eye. AB - AD patients may have substantial defects in the visual system despite a normal routine eye exam. Specific methods should be utilized to assess the ability of these patients to understand what they see and read. Subtle defects of eye movements may be present. Problems with contrast sensitivity, color vision, and stereo vision may be also be present, as well as early signs of optic atrophy. An awareness of the specific problems that AD patients present will lead the clinician to accurate diagnosis. PMID- 7853857 TI - Multi-infarct dementia (MID). PMID- 7853858 TI - Treatment strategies for the cognitive deficits of Alzheimer's disease. PMID- 7853859 TI - New approaches in the treatment of Alzheimer's disease. PMID- 7853860 TI - Aluminum neurotoxicity and Alzheimer's disease. PMID- 7853861 TI - Endothelium-dependent and independent effects of garlic on rat aorta. AB - Effects of garlic on isolated rat aorta were investigated by comparing with those of acetylcholine and L-arginine in the presence and absence of endothelium. For this purpose, certain linear and non-linear regression models were applied for concentration-response curves obtained by acetylcholine, L-arginine and garlic in the rat aorta. Garlic caused dose-dependent relaxations in isolated rat aorta which were attenuated by the removal of endothelium as in the case of acetylcholine. However, the relaxant responses to acetylcholine, L-arginine and garlic were not completely abolished by the endothelial denudation. Application of a number of regression models for the vasorelaxant effects of acetylcholine and garlic revealed that mechanism(s) of the effect of garlic may be different from that of acetylcholine. Furthermore, it was noted that L-arginine-induced relaxations, but not those induced by acetylcholine and garlic, are enhanced by a 2 or 4 h incubation period in the bathing medium. The findings obtained strongly suggested that the vasorelaxant effect of garlic is important in its hypotensive activity and mediated by the production of endothelium-and/or muscle-derived relaxing factors. PMID- 7853862 TI - Hypoglycaemic effect of Momordica charantia extracts in normoglycaemic or cyproheptadine-induced hyperglycaemic mice. AB - The hypoglycaemic effect of orally administered extracts of Momordica charantia L. fruits was examined in normoglycaemic or cyproheptadine-induced hyperglycaemic mice. The aqueous extract reduced the fasting glucose levels of hyperglycaemic or normoglycaemic mice. However, the ethanol extract did not affect the fasting or nonfasting glucose levels significantly in both groups of mice. There was no significant difference between the glucose-loaded and glucose-loaded plus aqueous extract given group. On the other hand, oral glucose-loading of the cyproheptadine-induced hyperglycaemic animals reduced the fasting glucose levels significantly. These results showed that aqueous extract of M. charantia fruits has a hypoglycaemic activity without improving the tolerance to glucose in cyproheptadine-induced diabetic mice. PMID- 7853863 TI - Anti-inflammatory activity of the latex of Calotropis procera. AB - The anti-inflammatory property of the latex of Calotropis procera was studied on carrageenin- and formalin-induced rat paw oedema model. A single dose of the aqueous suspension of the dried latex was effective to a significant level against the acute inflammatory response. PMID- 7853864 TI - In vitro antibacterial screening of Cryptolepis sanguinolenta alkaloids. AB - The ethanol and aqueous crude extracts and five alkaloids isolated from the roots of Crytolepis sanguinolenta (Lindl.) Schlechter were screened for antibacterial activity against 7 reference strains by the twofold serial broth microdilution assay. The ethanol extract and the alkaloids cryptolepine and cryptoheptine inhibited the growth of all strains tested except that of Pseudomonas aeruginosa. PMID- 7853865 TI - Effect of Tribulus terrestris on oxalate metabolism in rats. AB - This study concerns the effect of an aqueous extract of Tribulus terrestris on the metabolism of oxalate in male rats fed sodium glycolate. Glycolate feeding resulted in hyperoxaluria as well as increased activities of oxalate synthesizing enzymes of the liver i.e. glycolate oxidase (GAO), glycolate dehydrogenase (GAD) and lactate dehydrogenase (LDH), and decreased kidney LDH activity. T. terrestris administration to sodium glycolate fed rats produced a significant decrease in urinary oxalate excretion, and a significant increase in urinary glyoxylate excretion, as compared to sodium glycolate fed animals. The supplementation of T. terrestris with sodium glycolate also caused a reduction in liver GAO and GAD activities, whereas liver LDH activity remained unaltered. The isoenzyme pattern of kidney LDH revealed that normalization of kidney LDH by T. terrestris feeding was mainly due to an increase in the LDH 5 fraction. The LDH 1 isoenzyme remained unchanged in all the groups. PMID- 7853866 TI - Reinforcement effects of Boschniakia rossica on discrimination learning in cholinergic lesions of rats. AB - The dried herb or stem of Boschniakia rossica (Boschniakiae Herba) has been used as an antisenile agent in the Jilin Province of China. To elucidate the effects of Boschniakiae Herba on decreased learning ability and memory weakness, a 50% ethanol extract of Boschniakiae Herba was administered to rats whose nucleus basalis of Meynert had been destroyed by the injection of ibotenic acid. This administration showed a significant improvement in the decrease of the ratio of correct responses caused by destruction of the nucleus basalis of Meynert. These results suggest that B. rossica would be therapeutic in senility. PMID- 7853868 TI - Effects on anti-lipid peroxidation of Cudrania cochinchinensis var. gerontogea. AB - From the root bark of Cudrania cochinchinensis (Lour.) Kudo et Masamune var. gerontogea (Sieb. et Zucc.) Kudo et Masamune, 3 xanthones, cudraxanthone I, 1,3,7 trihydroxy-2-(3-methylbut-2- enyl)-xanthone, and lancerin, were further isolated and characterized. It was found that pretreatment with 600 mg/kg oral dose of the EtOH root extract of Cudrania cochinchinensis var. gerontogea in mice inhibited the lipid peroxidation stimulated by FeCl2-ascorbic acid-adenosine 5'-diphosphate (ADP) mixture. For searching bioactive constituents, the isolated xanthones from this folk medicine were investigated in anti-lipid peroxidative activities in the rat liver homogenate. The results showed that most of the tested xanthones effectively exhibited anti-lipid peroxidation stimulated by (a) FeCl2-ascorbic acid mixture or (b) CCl4-nicotinamide adenine dinucleotide phosphate (NADPH) mixture. As shown by the result, gerontoxanthone C and I were more active than vitamin E. PMID- 7853867 TI - Cryptolepis sanguinolenta activity against diarrhoeal bacteria. AB - Cryptolepine is the main alkaloid of Cryptolepis sanguinolenta (Lindl.) Schlechter, a plant used in traditional medicine in West Africa. The minimal inhibitory concentrations (MICs) of cryptolepine, ethanol and aqueous extracts of Cryptolepis sanguinolenta root were determined for 65 strains of Campylobacter jejuni, 41 strains of Campylobacter coli isolated from sporadic cases of gastroenteritis in Portugal and 86 strains of Vibrio cholerae isolated from patients with enteric infections in Angola, Brazil and Portugal. The ethanol extract activity against Campylobacter strains (MIC90% = 25 micrograms/ml) is higher than that of co-trimoxazole and sulfamethoxazole and Campylobacter strains susceptibility for cryptolepine (MIC90% = 12.5 micrograms/ml) is equal for ampicillin. The ethanol extract and cryptolepine show some activity against the Vibrio cholerae strains, although their activities are lower than that of tetracycline. The results suggest that these roots could be a therapeutic alternative for bacterial etiologic diarrhoea in West Africa. PMID- 7853869 TI - Comparison of extraction procedures on the immunocontraceptive activity of neem seed extracts. AB - Azadirachta indica (Neem) seed extracts are known to activate the local cell mediated immune reactions after a single intrauterine administration, leading to a long term reversible block of fertility. In order to identify and characterize the active fraction responsible for this activity, neem seeds were extracted by both mechanical expression and solvent extraction using a range of polar to non polar solvents which yielded 3 broad fractions. The mechanically expressed oil was fractionated using different approaches and studied for antifertility activity. The hexane extract and a corresponding column fraction showed potent and reproducible antifertility activity. Other fractions were less stable with regard to reproducibility of effects and composition. It is our conclusion that for subsequent fractionation to reach the last active fraction, the hexane extract is the most useful starting material. PMID- 7853870 TI - Effect of Momordica charantia on key hepatic enzymes. AB - The effect of Momordica charantia on certain key hepatic enzymes was investigated using male Sprague-Dawley rats as the animal model. Fruit juice and seed extract of Momordica charantia were administered orally at a daily dose of 1 ml/100 g body weight for 30 days under light ether anaesthesia while the control group received equivalent amounts of distilled water under identical conditions (n = 10 in each case). Serum gamma-glutamyl transferase (P < 0.001) and alkaline phosphatase (P < 0.01-0.001) concentrations were found to be significantly elevated following oral administration of both the fruit juice and the seed extract. Consistent significant histopathological changes in the liver were not observed in either treatment group although the prevalence of dilatation and/or congestion of the central vein sinusoidal system appeared to be twice as high following fruit juice treatment than in the other 2 groups. Thus, Momordica charantia may either contain hepatotoxins capable of causing cellular damage at the molecular level without causing significant histopathological changes or the plant may have an enzyme inducing effect. PMID- 7853871 TI - The effect on blood clotting of some west African plants used against snakebite. AB - Aqueous extracts of the bark of Schumanniophyton magnificum and the leaves of Mucuna pruriens var. utilis, Strophanthus gratus and Strophanthus hispidus show a dose related ability to prolong the time taken to clot for blood treated with a standardised dose of the venom of Echis carinatus. Strophanthus hispidus was shown to be the most potent of the plants tested. The dose-response profiles obtained showed that the increased clotting time was due to different processes for the different plant extracts. PMID- 7853872 TI - Is there a renaissance in thoracic surgery? PMID- 7853873 TI - Nitroglycerin maintains graft vascular homeostasis and enhances preservation in an orthotopic rat lung transplant model. AB - Transplanted lungs often fail during the peritransplantation period for poorly understood reasons. Because the nitric oxide pathway regulates pulmonary vascular tone, helps to maintain the integrity of the endothelial barrier, and modulates neutrophil adhesivity and activation, we hypothesized that perturbation of this pathway during the preservation and reperfusion of transplanted lungs might play a critical role in mediating early graft failure. To evaluate whether supplementing the preservation solution with the nitric oxide donor nitroglycerin enhances lung preservation for transplantation, we obtained hemodynamic measurements in a model of orthotopic left lung transplantation in the rat after ligation of the native right pulmonary artery. In these experiments, recipient survival and hemodynamics depended solely on the transplanted lung. The left lung was harvested from 22 rats, flushed with either lactated Ringer's solution alone (control, n = 11) or Ringer's solution supplemented with nitroglycerin (0.1 mg/ml, n = 11), preserved for 4 hours at 4 degrees C, and then transplanted using a rapid cuff technique for bronchial and vascular anastomoses. Nitroglycerin significantly improved arterial blood oxygenation (339 +/- 66 versus 130 +/- 12 mm Hg, p < 0.05), increased pulmonary arterial flow (7.6 +/- 1.9 versus 0.9 +/- 0.2 ml/min, p < 0.005), decreased pulmonary vascular resistance (1.7 +/- 0.4 versus 6.6 +/- 1.9 x 10(3) Wood units, p < 0.05), and enhanced recipient survival (64% versus 0%, p < 0.05). Control grafts had significantly greater neutrophil accumulation (50% greater as quantified by myeloperoxidase activity, p < 0.05) than grafts preserved in the presence of nitroglycerin. These studies show that supplementation of the preservation solution with the nitric oxide donor nitroglycerin maintains graft vascular homeostasis and significantly improves pulmonary function and recipient survival after transplantation. PMID- 7853874 TI - Lung transplantation with cardiopulmonary bypass exaggerates pulmonary vasomotor dysfunction in the transplanted lung. AB - Pulmonary vascular resistance is significantly increased in the transplanted lung. If cardiopulmonary bypass is required, the transplanted lung is reperfused with activated blood elements, which might exacerbate the reperfusion injury. The purpose of this study was to examine the influence of cardiopulmonary bypass on the following mechanisms of pulmonary vasomotor control in a dog model of autologous lung transplantation: (1) endothelium-dependent cyclic guanosine monophosphate-mediated relaxation (response to acetylcholine), (2) endothelium independent cyclic guanosine monophosphate-mediated relaxation (response to nitroprusside), and (3) beta-adrenergic cyclic adenosine monophosphate-mediated relaxation (response to isoproterenol). Autologous right lung transplants were performed with (n = 4 dogs) and without (n = 5 dogs) bypass. Lungs were stored in cold saline solution (4 degrees C, 3 hours) before reimplantation. Pulmonary vasomotor control mechanisms were studied in isolated pulmonary arterial rings immediately after harvest and 1 hour after reimplantation. Ten rings were studied in each group at each time. Statistical analysis was by analysis of variance. Without bypass, endothelium-dependent cyclic guanosine monophosphate-mediated relaxation and beta-adrenergic cyclic adenosine monophosphate-mediated relaxation were significantly impaired, although endothelium-independent cyclic guanosine monophosphate-mediated relaxation was not. Use of bypass produced significantly greater impairment of both endothelium-dependent cyclic guanosine monophosphate mediated relaxation and beta-adrenergic cyclic adenosine monophosphate-mediated relaxation. In addition, use of bypass produced significant dysfunction of endothelium-independent cyclic guanosine monophosphate-mediated relaxation as well. We conclude that using cardiopulmonary bypass to perform lung transplantation greatly exaggerates pulmonary vasomotor dysfunction in the transplanted lung. This dysfunction may contribute to significantly higher pulmonary vascular resistance in the transplanted lung if cardiopulmonary bypass is used. PMID- 7853875 TI - The allograft valve in heart transplantation and valve replacement. Genetic assessment of the origin of the cells by means of deoxyribonucleic acid profiles. AB - Assessment of the cellular origin of allograft valves is essential in comprehending their biologic behavior and in improving preparation methods. In this study we retrospectively analyzed 10 allografts obtained from patients who underwent valve replacement or heart transplantation. Histologic evaluation and deoxyribonucleic acid amplification by polymerase chain reaction technology with fluorescence labeled primers was performed on different parts of the valve leaflets. Automated analyses of the obtained amplimers showed in the heart transplantation group the presence of receptor cells interspersed with native donor cells in three cases. Preliminary results for the valve replacement group are inconclusive as yet. PMID- 7853876 TI - Marked enhancement in myocardial function resulting from overexpression of a human beta-adrenergic receptor gene. AB - Transgenic mice with intense cardiac expression of a human beta-adrenergic receptor gene were engineered and shown to display marked improvements in baseline myocardial and left ventricular function. Heart/body weight ratios and histologic appearance were not found to be significantly altered, suggesting that receptor gene expression did not induce pathologic changes. Given the substantial reduction in beta-adrenergic receptor density and resultant reduction in inotropic responsiveness observed in chronic heart failure, these findings represent a novel approach for increasing myocardial function with important clinical implications. PMID- 7853877 TI - Resuscitative retrograde blood cardioplegia. Are amino acids or continuous warm techniques necessary? AB - This experiment was designed to determine the relative degree of cardiac functional recovery provided by various forms of resuscitative retrograde blood cardioplegia after global ischemic injury. Twenty-four dogs were subjected to 20 minutes of normothermic global myocardial ischemia followed by 60 minutes of cardioplegic arrest by one of three methods: group 1, standard cold blood cardioplegia with a cold terminal dose (n = 8); group 2, aspartate-glutamate enhanced blood cardioplegia with warm induction and terminal enhancement (n = 8); and group 3, continuous warm blood cardioplegia (n = 8). Sonomicrometry was used to analyze left ventricular function for maximal elastance and preload recruitable stroke work area. Data were recorded at baseline and after 30 and 60 minutes of unloaded reperfusion. The results showed improved early recovery of preload recruitable stroke work area, but not of maximal elastance, after reperfusion of ischemic hearts with warm resuscitative blood cardioplegic solution enhanced with amino acids. The functional improvement provided by this technique was transient, however, and no significant differences were detectable among the groups after 60 minutes of unloaded reperfusion. Neither amino acid enhancement nor continuous warm cardioplegia offered a significant advantage in functional recovery over the standard method of cold blood cardioplegia reperfusion. PMID- 7853878 TI - Microemboli during coronary artery bypass grafting. Genesis and effect on outcome. AB - Cerebral dysfunction after coronary artery bypass operations represents some of the most serious and costly complications of cardiac surgery. We used transcranial Doppler ultrasonography to detect and quantify the number of microemboli in the right middle cerebral artery of patients undergoing elective first coronary bypass operations (n = 117) and second coronary bypass operations (n = 10). We hypothesized that total microemboli were related to clinical outcome. A 2 MHz transducer was positioned in front of the ear above the zygomatic arch and depth gated to 50 mm. Microemboli were recorded as perturbations of the blood flow velocity in the middle cerebral artery and aurally monitored. Each episode of microembolism was specified both by clock time and as a perfusion or surgical event. Forty-one patients (32%) completed neuropsychologic evaluation with a battery of tests for cognitive function. Anxiety states and traits were also assessed. The distribution of microembolism showed that there were three groups of patients: < 30 microemboli (n = 83); 30 to 59 (n = 24); and > 60 (n = 20). Seven of 10 patients with cerebral complications (stroke, coma, delirium, aberrant behavior) were in the > 60 microemboli group. Those with cerebral complications had 20.7 +/- 4.5 microemboli from perfusion and 57.4 +/- 15.6 from surgical events. The 13 patients in the > 60 microemboli group without central nervous system symptoms had 95.5 +/- 19.5 microemboli from perfusion and 36.0 +/- 6.9 from surgical events. Neuropsychologic scores were most often depressed for memory (73%), comprehension (49%), attention (46%), and constructional ability (44%). The greatest change was in total score in the > 60 microemboli group (-3.3 +/- 0.6) compared with -1.1 +/- 0.2 and -1.9 +/- 0.2 for the 30 to 59 and < 30 groups, respectively. The incidences of cardiac and pulmonary complications and mortality were different between those patients with < 60 microemboli versus those with > 60 microemboli. Cardiac and pulmonary complications and mortality percentages were 4.7%, 3.7%, and 0.9%, respectively, for the < 60 microemboli group and 20%, 20%, and 15%, respectively, for the > 60 microemboli group. We concluded that transcranial Doppler ultrasonography is a useful technique to quantify and detect the source of microemboli during coronary artery bypass operations and may be useful in assessing new operative strategies, the quality of the perfusion, and potentially as an indicator for pharmacologic therapy in the operating room in patients with high microemboli counts. PMID- 7853879 TI - Retrograde cerebral perfusion during hypothermic circulatory arrest reduces neurologic morbidity. AB - Hypothermic circulatory arrest has become an accepted technique for a variety of cardiac and complex aortic operations. However, prolonged periods (> 45 min) of hypothermic circulatory arrest in older patients is associated with marginal cerebral protection and an increased incidence of adverse neurologic events. In an effort to minimize such morbidity, we used a technique of retrograde cerebral perfusion with continuous monitoring of cerebral hemoglobin oxygen saturation during hypothermic circulatory arrest in 35 patients who underwent thoracic aortic operations or resection of intracardiac tumor. There were 27 men and 8 women (mean age 60 years, range 21 to 83 years). Sixteen patients had acute dissection, 6 had contained rupture of a thoracic aortic aneurysm, 10 had either a chronic dissection or aneurysm, and 3 had hypernephromas extending into the heart. Six patients underwent root replacement by means of an open technique for their distal anastomosis, 7 underwent root and partial arch replacement, 12 had root and total arch replacement, 7 had total arch replacement, and 3 had resection of tumor in the heart and retrohepatic vena cava. Seven patients had simultaneous coronary artery bypass grafting, 3 had replacement of one of the arch vessels, and 2 patients had a cesarean section. Sixteen cases were emergency, 6 urgent, and 13 elective. Nine (26%) were reoperations. Thirty-four patients underwent the procedure via a median sternotomy and one patient through a posterolateral thoracotomy. The mean retrograde cerebral perfusion time was 63 minutes (range 35 to 128 minutes), with 30 (86%) patients having more than 45 minutes, 12 (34%) having more than 65 minutes, and 4 (11%) having more than 90 minutes. There was 1 operative death caused by a preoperative myocardial infarction from an aortic dissection, and there were 2 late deaths (multiple organ failure and ruptured total aortic aneurysm). One patient had a stroke with a residual right hemiplegia and a pronounced aphasia. There were no other significant neurologic events or reoperations for bleeding. The average length of stay for patients having elective operations was 11 days and for those having emergency operations, 27 days. At a mean follow-up of 6 months all surviving patients (91%) are well. Hypothermic circulatory arrest is a relatively simple technique that provides a bloodless field and good visualization without the need for aortic crossclamps. Moreover, retrograde cerebral perfusion with continuous monitoring of cerebral oxygen saturation extends the "safe" time for hypothermic circulatory arrest, allowing ample opportunity to perform complicated cardiac and aortic operations with reduced risk of adverse neurologic events. PMID- 7853880 TI - Blood cardioplegia in the senescent heart. AB - As an increasingly aged population undergoes cardiac surgery, myocardial protective strategies must address the fundamental differences between adult and senescent myocardium. In a test of the hypothesis that senescent myocardium is less tolerant of cardioplegic arrest, adult (0.5 to 1.0 years) and senescent (6 to 9 years) sheep underwent 55 minutes of hypothermic blood cardioplegic arrest. A 5-minute dose of terminal warm blood cardioplegic solution was administered followed by 30 minutes of vented reperfusion. Left ventricular volume was monitored by means of sonomicrometric crystals in three orthogonal planes. Myocardial function was assessed with the preload recruitable stroke work relationship. Diastolic function was assessed with two techniques: the "stiffness" coefficient (beta), derived from the exponential end-diastolic pressure-volume relationship, and the time constant of isovolumic left ventricular pressure decay (tau). Data were acquired before arrest and after the reperfusion period. Contractility in the adult hearts was well preserved (preload recruitable stroke work: 63.7 +/- 6.1 versus 56.8 +/- 4.1 mJ/beat per milliliter per 100 gm, prearrest versus postarrest, p = not significant). In contrast, senescent heart contractility was poorly preserved (56.8 +/- 4.1 versus 35.4 +/- 4.2 mJ/beat per milliliter per 100 gm, p < 0.025). Early diastolic relaxation (tau) was prolonged in the adult hearts (42.5 +/- 3.3 versus 48.8 +/- 3.5 msec prearrest versus postarrest, p < 0.05), whereas the senescent hearts were essentially unchanged (49.3 +/- 3.1 versus 52.3 +/- 4.5 msec. p = 0.35). Myocardial stiffness (beta) was unchanged in both groups. When compared with adult hearts, contractility in senescent hearts is poorly preserved after cold blood cardioplegic arrest. Active diastolic relaxation, however, is more prolonged in adult hearts. Passive diastolic properties are unchanged in both groups. Because there are specific age-related differences in tolerance to cardioplegic arrest, extrapolation of myocardial protective strategies from studies in adult hearts to elderly patients may not be appropriate. PMID- 7853881 TI - Optimizing selection of patients for major lung resection. AB - OBJECTIVES: It is not known whether a normal diffusing capacity for carbon monoxide permits safe lung resection in patients with marginal spirometric values, or whether normal spirometric values negate the adverse effects of a low diffusing capacity. The purposes of this study were (1) to determine the best predictors of morbidity and mortality and (2) to assess whether interactions exist between diffusing capacity and spirometry that help estimate outcome after major lung resection. DESIGN: A retrospective analysis of 376 patients who underwent lung resection was performed. Three hundred three had lung cancer and 73 had other disease. Two hundred eighty-four underwent lobectomy/bilobectomy and 92 had pneumonectomy. We assessed the relationship of 23 preoperative variables to 18 postoperative events classified into categories as pulmonary or cardiac complications, overall morbidity, and operative mortality. RESULTS: The best single predictor of complications was the percent predicted postoperative diffusing capacity. The incidences of pulmonary and cardiac complications, morbidity, and mortality were inversely related to predicted postoperative diffusing capacity percent (p < 0.004 for each). Multivariate logistic regression analyses identified only predicted postoperative diffusing capacity percent and age as significant independent predictors of pulmonary complications, morbidity, and death, and these with prior myocardial infarction predicted cardiac complications. There were no interactions between percent predicted postoperative forced expiratory volume in 1 second and predicted postoperative diffusing capacity percent in estimating risks of complications. CONCLUSION: Predicted postoperative diffusing capacity percent is the strongest single predictor of risk of complications and mortality after lung resection. There is little interrelationship of predicted postoperative diffusing capacity percent and predicted postoperative forced expiratory volume in 1 second, indicating that these values should be assessed independently in estimating operative risk. PMID- 7853882 TI - Factors influencing early and late outcome of the arterial switch operation for transposition of the great arteries. AB - Between January 1983 and January 1992, 470 patients underwent an arterial switch operation at our institution. An intact (or virtually intact) ventricular septum was present in 278 of 470 (59%); a ventricular septal defect was closed in the remaining 192. Survivals at 1 month and 1, 5, and 8 years among the 470 patients were 93%, 92%, 91%, and 91%, respectively. The hazard function for death (at any time) had a rapidly declining single phase that approached zero by one year after the operation. Risk factors for death included coronary artery patterns with a retropulmonary course of the left coronary artery (two types) and a pattern in which the right coronary artery and left anterior descending arose from the anterior sinus with a posterior course of the circumflex coronary. The only procedural risk factor identified was augmentation of the aortic arch; longer duration of circulatory arrest was also a risk factor for death. Earlier date of operation was a risk factor for death, but only in the case of the senior surgeon. Reinterventions were performed to relieve right ventricular and/or pulmonary artery stenoses alone in 28 patients. The hazard function for reintervention for pulmonary artery or valve stenosis revealed an early phase that peaked at 9 months after the operation and a constant phase for the duration of follow-up. Incremental risk factors for the early phase included multiple ventricular septal defects, the rapid two-stage arterial switch, and a coronary pattern with a single ostium supplying the right coronary and left anterior descending, with a retropulmonary course of the circumflex. The need for reintervention has decreased with time. The arterial switch operation can currently be performed early in life with a low mortality risk (< 5%) and a low incidence of reintervention (< 10%) for supravalvular pulmonary stenosis. The analyses indicate that both the mortality and reintervention risks are lower in patients with less complex anatomy. PMID- 7853883 TI - Arrhythmias and intracardiac conduction after the arterial switch operation. AB - Intraatrial baffling procedures such as the Mustard or Senning repair of transposition of the great arteries have been associated with a high incidence of cardiac arrhythmias. These abnormalities are thought to arise from trauma to the sinus node and atrial muscle during the procedure. In the arterial switch operation, there is little intraatrial manipulation other than the repair of the atrial septal defect. In theory, rhythm disturbances after the arterial switch operation should be less prevalent. From January 1, 1983, to December 31, 1990, 390 patients (230 with intact ventricular septum and 160 with a coexisting ventricular septal defect) underwent an arterial switch operation. Electrocardiograms and 24-hour Holter monitor studies were obtained in the 364 survivors at hospital discharge and during follow-up. Limited intracardiac electrophysiologic studies were performed 6 to 12 months after the operation. RESULTS: Atrioventricular node function was preserved in most patients; seven patients (2%) had first-degree, two (0.7%) second-degree, and five (1.7%) had complete atrioventricular block (all with coexisting ventricular septal defect). All five patients with complete heart block received a permanent pacemaker. In those patients not having a permanent pacemaker, sinus rhythm was present in 96% on the surface electrocardiogram and 99% during 24-hour Holter monitor studies (1 month to 8.5 years, mean 2.1 years after the operation). Intracardiac electrophysiologic studies (n = 158) demonstrated normal corrected sinus node recovery times and AH intervals in 97% of patients. Atrial ectopy was present in 152 of 172 (81%) patients, with the majority (64%) of patients having only occasional premature beats without repetitive forms. Ventricular ectopy was a frequent finding during 24-hour monitoring. At hospital discharge 70% had ventricular ectopy; these values fell to 57% (in patients with intact ventricular septum) and 30% (in patients with a coexisting ventricular septal defect) at follow-up. In the early postoperative period, there were 25 episodes of supraventricular tachycardia (14 of which required therapy), 6 episodes of junctional ectopic tachycardia, and 9 episodes of ventricular tachycardia. The incidence of supraventricular tachycardia had fallen to 5% at follow-up, with no atrial flutter or fibrillation noted. Three patients had ventricular tachycardia on follow-up Holter studies. In summary, our results confirm the theoretical advantages of anatomic correction over atrial level correction of transposition of the great arteries with respect to preservation of sinus node function and low incidence of clinically significant tachyarrhythmias. PMID- 7853884 TI - Status of the left ventricle after arterial switch operation for transposition of the great arteries. Hemodynamic and echocardiographic evaluation. AB - BACKGROUND: The potential for improved preservation of systemic ventricular function represents an important reason for the increasing popularity of the arterial switch operation. In support of this expectation, prior studies in patients early after arterial switch operation have found normal ventricular contractility and function. This study was conducted to extend those observations to up to 10 years of follow-up and to directly examine the effects of a coexisting ventricular septal defect or short-term preparatory banding of the pulmonary artery before the arterial switch operation. METHODS: Patients operated on from 1983 through 1991 were included. Echocardiographic and catheterization data were collected as part of a prospective evaluation of outcome in all patients who undergo the arterial switch operation at Boston Children's Hospital, with inclusion of data from the most recent catheterization only. Echocardiograms performed at least 6 months after the operation were included, with assessment of both the most recent status as well as serial trends. Whenever possible, echocardiographic evaluation included data necessary to perform analysis of ventricular mechanics including indices of afterload, preload, and contractility. Comparison was made to normal values and between subgroups defined on the basis of an arterial switch operation with or without ventricular septal defect and those who had a rapid two-stage arterial switch operation. RESULTS: Invasive measures of left and right ventricular filling pressures, cardiac index, and pulmonary vascular resistance did not differ among the three groups. Overall, echocardiographic left ventricular end-diastolic dimension, wall thickness, mass, afterload (end-systolic wall stress), function (fractional shortening and rate corrected velocity of fiber shortening), contractility (stress-velocity and stress-shortening relations), and preload were normal, and none of these variables was different between the groups with and without a ventricular septal defect. Serial evaluation indicated a slight but significant trend toward ventricular dilatation, perhaps related to a relatively high incidence of at least mild aortic regurgitation (30%). In contrast, in the rapid two-stage group the echocardiographic indices of left ventricular function (fractional shortening and velocity of fiber shortening) and contractility (stress-velocity and stress shortening relations) were found to be mildly but significantly reduced compared with normal subjects and with the other arterial switch operation groups. Over the duration of follow-up encompassed by this study, no tendency toward progressive depression of function was seen. CONCLUSIONS: As the length of observation after the arterial switch operation continues to increase, left ventricular size, mass, functional status, and contractility continues to be normal, with no evidence of time-related deterioration of function. As previously reported, the rapid two-stage arterial switch operation does represent a higher risk for mild impairment of myocardial mechanics. PMID- 7853885 TI - Renal replacement therapy after repair of congenital heart disease in children. A comparison of hemofiltration and peritoneal dialysis. AB - The development of renal failure necessitating peritoneal dialysis after cardiac operations is associated with a reported mortality greater than 50%. Improved fluid removal and nutritional support have been reported with the use of continuous arteriovenous hemofiltration and continuous venovenous hemofiltration techniques. We have compared our experience with all three techniques in managing children who required renal replacement therapy after cardiac operations in terms of efficacy (fluid removal, calorie intake, and clearance of urea and creatinine), complications, and outcome. Over a 5-year period renal replacement therapy was initiated in 42 children, and in 34 of them it was successfully established for more than a 24-hour period: 17 were managed with peritoneal dialysis, 8 with continuous arteriovenous hemofiltration, and 9 with continuous venovenous hemofiltration. A net negative fluid balance was achieved in only 6 (35%) patients treated with peritoneal dialysis compared with 50% of those treated with continuous venovenous hemofiltration and 89% of those treated with continuous venovenous hemofiltration. In terms of nutritional support, calorie intake increased by 43% after peritoneal dialysis was started compared with 515% and 409% in the arteriovenous and venovenous hemofiltration groups, respectively, (p < 0.005). The serum urea levels fell by 36% (p = 0.02) and 39% (p = 0.005) compared with pre-therapy levels with arteriovenous and venovenous hemofiltration, respectively, and the creatinine content was reduced by 19% and 33% (p = 0.003). Neither parameter was reduced in the peritoneal dialysis group. We conclude that the use of hemofiltration as a renal replacement therapy after surgical correction of congenital heart disease offers significant advantages over the more traditional approach of peritoneal dialysis. In addition, we suggest that a more aggressive approach to the management of fluid overload and nutritional depletion with hemofiltration may result in a decrease in the very high mortality seen in renal failure after cardiac operations. PMID- 7853886 TI - Repair of the aortic valve in patients with aortic insufficiency and aortic root aneurysm. AB - Patients with aneurysms of the ascending aorta or aortic root frequently have aortic insufficiency despite normal aortic leaflets. The aortic valve dysfunction is caused by dilatation of the sinotubular junction, distortion or dilatation of the sinuses of Valsalva, annuloaortic ectasia, or a combination of these problems. In the case of annuloaortic ectasia, reconstruction of the aortic root is performed by reimplanting the aortic valve in a tubular Dacron graft (reimplantation). In the case of mild or no annuloaortic ectasia, reconstruction of the aortic root is performed by correcting the dilated sinotubular junction and replacement of the aortic sinuses if they are also dilated with an appropriately tailored Dacron graft (remodeling). From July 1989 to March 1994, 45 patients have had either reimplantation of the aortic valve (19 patients) or remodeling of the aortic root (26 patients). Fourteen patients had Marfan's syndrome, 11 had acute and five had chronic type A aortic dissection, and nine also had transverse arch aneurysm. There were two operative deaths, both in the remodeling group. One patient who had reimplantation needed composite replacement of the aortic valve and ascending aorta because of persistent aortic insufficiency after the repair. A young patient with Marfan's syndrome had progressive aortic valve dysfunction during a growth spurt and had aortic valve replacement 2 years after the initial operation. No other valve-related complication has occurred. The remaining 41 patients have only mild or no aortic insufficiency, and the repair remains stable from 1 to 58 months, mean 18 months. These two types of aortic valve reconstruction have provided excellent clinical results in carefully selected adult patients. PMID- 7853887 TI - Clinical and left ventricular function outcomes up to five years after dynamic cardiomyoplasty. AB - Improvement in congestive heart failure and left ventricular function after dynamic cardiomyoplasty has been reported in patients with severe cardiomyopathies, but the long-term effects of this procedure remain unclear. In this investigation 31 patients undergoing cardiomyoplasty for treatment of idiopathic dilated cardiomyopathy were annually investigated with radionuclide scintigraphy, Doppler echocardiography, and right-sided heart catheterization. They were in New York Heart Association functional class III or IV before the operation. No hospital deaths occurred, but one patient with progressive heart failure required urgent heart transplantation 42 days after cardiomyoplasty. The other patients were followed up from 6 to 70 months (mean 25.6 months) and 12 patients died at late follow-up. Actuarial survivals were 86% at 1 year, 61.4% at 2 years, and 42.5% at 3 to 5 years of follow-up. Multivariate analysis of factors influencing outcome showed that long-term survival was significantly affected by preoperative functional class and pulmonary vascular resistance. Functional class improved from 3.2 +/- 0.4 to 1.7 +/- 0.7 in the surviving patients (p < 0.01). Furthermore, left ventricular ejection fraction improved from 19.8% +/- 3% to 23.9% +/- 7.2% (p < 0.01), and significant changes in stroke index, arterial pressure, pulmonary wedge pressure, and left ventricular stroke work index were also found at 6 months of follow-up. In the late postoperative period, the left ventricular ejection fraction tended to decrease and returned to preoperative levels at 5 years, whereas hemodynamic variables did not change significantly. Thus, despite the tendency of the left ventricular ejection fraction to decrease at late follow-up, the long-term course of these patients seems to be characterized by the maintenance of hemodynamic improvement. However, long-term survival after cardiomyoplasty is limited by the severity of the patient's condition before the operation. PMID- 7853888 TI - Coronary artery bypass grafting in familial hypercholesterolemia. AB - Familial hypercholesterolemia is an autosomal dominant disorder caused by a mutation of the gene for the low-density lipoprotein receptor and is characterized by rapidly progressing coronary atherosclerosis. We assessed the long-term results of coronary artery bypass grafting performed during the past 13 years in 62 patients with heterozygous familial hypercholesterolemia, whose mean plasma total and low-density lipoprotein cholesterol level was 327 mg/dl, respectively. The patients had severe coronary atherosclerosis, with coronary stenosis index of 19.7, and the prevalence of extracoronary atherosclerotic lesions was 27%. Sixty-one patients underwent successful coronary artery bypass operation, with an average of 2.5 grafts, and the coronary stenosis index decreased to 7.1. After operation, all patients consumed a cholesterol-lowering diet and received drug therapy with pravastatin, probucol, or cholestyramine. Seven patients who were resistant to drug therapy were treated with plasma low density lipoprotein apheresis. The cholesterol-lowering therapy reduced plasma total cholesterol level by 37%, low-density lipoprotein cholesterol level by 42%, and low-density lipoprotein/high-density lipoprotein cholesterol ratio by 37% (p < 0.001). During the follow-up period (mean, 52 months; range, 10 to 157 months), there was no cardiac death, but three patients died of malignant disease. The actuarial survival rate was 95% at 5 years and 89% at 12 years after operation. The actuarial freedom from recurrent angina was 90% at 5 years and 53% at 11 years after operation. Four patients underwent reoperation, an average of 8 years postoperatively, because of vein graft atherosclerosis. In spite of severe coronary atherosclerosis, these patients with familial hypercholesterolemia showed good long-term outcome after coronary artery bypass operation. The present findings suggest that aggressive use of arterial grafts, intensive cholesterol lowering drug therapy, and low-density lipoprotein apheresis may be useful in patients with familial hypercholesterolemia. PMID- 7853889 TI - Heat shock protein (HSP 72) expression in patients undergoing cardiac operations. AB - The major mammalian stress-inducible protein, heat shock protein 72, protects cells from certain stresses and rapidly accumulates in cells after ischemia. Heat shock protein 72 is rapidly synthesized in the myocardium of various species in response to ischemia, but it has not been investigated in human heart. To determine if heat shock protein 72 accumulated in the ischemic myocardium of patients undergoing cardiac operations, we obtained sequential right atrial biopsy specimens from 12 patients undergoing repair at three intervals: before bypass, after reperfusion, and after bypass. Immunoblot analysis for heat shock protein 72 demonstrated a high expression in the human heart compared with other mammalian hearts, p (Binomial) = 0.01. Compared with before bypass, heat shock protein 72 contents after reperfusion and after bypass were 98.2% +/- 8.9%, p (signed-rank) = 0.65, and 87.6% +/- 17.1%, p (signed-rank) = 0.28, respectively. Although heat shock protein 72 concentration was unchanged in hearts after reperfusion and after bypass, the initial prebypass level of heat shock protein 72 was high. The high heat shock protein 72 level detected in human hearts may reflect preoperative disease and drug therapy, or inherently high levels may be usual in the human myocardium. These findings indicate that the myocardium of patients undergoing cardiac operations contains relatively high concentrations of heat shock protein 72, which are not increased during the surgical procedure. PMID- 7853890 TI - Regional distribution of atrial electrical changes induced by stimulation of extracardiac and intracardiac neural elements. AB - Autonomic nerves and intrinsic cardiac neural elements are known to influence the electrophysiologic and dynamic properties of the heart. This study describes the regional distribution in the canine atria of electrophysiologic effects induced by stimulation of the right and left cervical vagosympathetic complexes, the right atrial ganglionated plexus, and the right and left stellate ganglia. Local atrial effects were determined from changes in QRST area of unipolar electrograms recorded from multiple sites with plaque electrodes sewn onto the atria in 16 anesthetized dogs. RESULTS: (1) Although being very consistent in any given preparation, atrial changes varied between animals when similar neural structures were stimulated. (2) Among the common features identified between preparations, consistent effects were induced by neural stimulation in the region of the sinus node, indicating that this atrial region is the most richly innervated. (3) All other regions of the atria could be affected by stimulation of either right-sided or left-sided efferent nerves. (4) Responses to right atrial ganglionated plexus stimulation after atropine administration indicated that the corresponding fat pad contains both sympathetic and parasympathetic neural elements. CONCLUSION: This study demonstrates that there is considerable overlapping of atrial innervation affecting all regions of the atria, as well as the sinus node region. PMID- 7853891 TI - Adjustable suture of the vertical pulmonary vein for repair of infracardiac total anomalous pulmonary venous connection. PMID- 7853892 TI - Innominate artery pseudoaneurysm presenting as a widened mediastinum. PMID- 7853894 TI - Anomalous left main coronary artery arising from the pulmonary artery in an adult: treatment by internal mammary artery grafting. PMID- 7853895 TI - Intraoperative visualization of the aortic valve from the left ventricle. PMID- 7853893 TI - A simplified technique for selective jugular vein cannulation. PMID- 7853896 TI - The periprosthetic sac-innominate vein shunt: an effective way to control bleeding after aortic root operations. PMID- 7853897 TI - Invited letter concerning: clinical and left ventricular function outcomes up to five years after dynamic cardiomyoplasty. PMID- 7853898 TI - Anomalous origin of the left coronary artery from the pulmonary artery: new technique or modification of "old" technique. PMID- 7853899 TI - The location of station 11 pulmonary lymph nodes. PMID- 7853900 TI - [A Swedish clinic in Hanoi--security for Westerners]. PMID- 7853901 TI - [Physicians in the new occupational health services: winners or losers?]. PMID- 7853902 TI - [Interns in the emergency service need good support]. PMID- 7853903 TI - [The intensive pediatric care is a part of care for all children]. PMID- 7853904 TI - [Ovarian neoplasms. Protective or hazardous effects of sterilization, hysterectomy and hormonal infertility therapy?]. PMID- 7853905 TI - [Of 1000 youngsters who smoke 500 will die because of smoking. Is further documentation necessary?]. PMID- 7853907 TI - [What is a myocardial infarction? Technical diagnosis is varying between different hospitals. Quality comparisons require uniformity]. PMID- 7853906 TI - [Immunomediated polyneuropathies. New discoveries on pathogenesis and treatment]. PMID- 7853908 TI - [Corticosteroids and acute optic nerve neuritis. A therapeutic method requiring further studies]. PMID- 7853909 TI - [Penetrating trauma. Wood splinters mimicking fat and air in CT examinations]. PMID- 7853910 TI - [A case report. Nosebleed as the first symptom of choanal polyps]. PMID- 7853911 TI - [The role of home visits in family practice. Waste of time or well-utilized quality work?]. PMID- 7853912 TI - [Support to relatives of patients with stroke]. PMID- 7853913 TI - [Developing empathy in medical students. Clinical courses may enhance empathic ability]. PMID- 7853914 TI - [Advancing medical gastroenterology. Continuing education is spreading in the country]. PMID- 7853915 TI - [Intravenous immunoglobulin in gestational pemphigoid. The itching disappeared and skin changes healed]. PMID- 7853916 TI - [The employer and the abusing physician. Efficient leadership and empathy are needed]. PMID- 7853917 TI - [Abusing physicians are a distinct risk for the patients. Misdirected loyalty prevents reporting]. PMID- 7853918 TI - [Alzheimer disease. Great progress in the understanding of causes in spite of lack of adequate treatment and knowledge about markers]. PMID- 7853919 TI - [Separation and attempted suicide. Risk of aggression against the woman/rival!]. PMID- 7853920 TI - [Increased risk of thrombosis in FXII deficiency?]. PMID- 7853922 TI - [Do women receive worse treatment than men?]. PMID- 7853921 TI - [Gene amplification in viral CNS infections. Rapid diagnostic identification of herpesviruses]. AB - DNA amplification with the polymerase chain reaction (PCR) technique was used as a diagnostic test on cerebrospinal fluid samples in cases where herpesvirus infection of the central nervous system (CNS) was suspected. During the period, 1992-93, 47 (8.9%) of 528 patients tested were positive for one or another of the following herpesviruses: herpes simplex virus type 1 (n = 16) or type 2 (n = 9), cytomegalovirus (n = 16), varicella-zoster virus (n = 4), or Epstein-Barr virus (n = 2). The study showed PCR to be a rapid and useful diagnostic method in clinical routine, enabling early antiviral intervention in several cases with an atypical clinical picture. Moreover, cytomegalovirus was found to be an important CNS pathogen in addition to herpes simplex virus, especially during childhood. PMID- 7853923 TI - [Healthy tomorrow--or in the future? Caution against one-sided research directions]. PMID- 7853924 TI - [How the EEC membership influences drug supply in Sweden]. PMID- 7853925 TI - [Reflections on "Is amalgam hazardous to health?"]. PMID- 7853926 TI - [Folic acid should be administered to all pregnant women. Good assurance against neural tube defects in children]. PMID- 7853927 TI - [Should gynecologists discontinue curettage? Ultrasound is better in the diagnosis of endometrial cancer]. PMID- 7853928 TI - [Increase the quality of Swedish hernia surgery! Improvement of long-term results is a challenge to occupational ethics]. PMID- 7853929 TI - [Folic acid prevents neural tube defects. All women of fertile age should increase their intake of folic acid]. PMID- 7853930 TI - [Hematometra. Complication after transcervical resection of the endometrium]. PMID- 7853931 TI - [Older immigrants' health compared with that of native Swedes. Greatest differences are subjective in nature]. AB - Within the framework of the gerontological and geriatric population studies in Gothenburg, Sweden, the health of immigrants of non-Nordic origin was compared with that of native Swedes in a cohort of 70-year-olds born in 1922. Of the sample examined, 11.4 per cent were of non-Nordic origin, among whom the non response rate was relatively high (48%). Although there were few differences in "objective" health criteria between the Swedish and immigrant subgroups, there were manifest differences in "subjective" criteria and quality of life. In view of the increasing proportion of elderly immigrants in the Swedish community, these findings need to be borne in mind. PMID- 7853932 TI - [Intensive care of the 90's. Is the increased need overlooked?]. PMID- 7853933 TI - [Economic analysis of self treatment with desmopressin. Nasal spray in bleeding. Cost saving]. PMID- 7853934 TI - [Microbiological purity during medical intervention]. PMID- 7853935 TI - [Report from a world congress on social psychiatry. A breakthrough for the "Trialog"]. PMID- 7853936 TI - [Neuropeptide antagonists. Drugs for the year 2000]. PMID- 7853937 TI - [Gastrin-/CCK-B antagonists are neuropharmacological tools]. PMID- 7853938 TI - [Effects of tachykinin antagonists on inflammation]. PMID- 7853939 TI - [Medical work at a new center for refugees. "We never felt so important"]. PMID- 7853940 TI - [The first evaluation of the British health care reform. Lessons to be learnt in relation to Swedish development]. PMID- 7853941 TI - [Normal pressure hydrocephalus. A condition of dementia, improved by shunt surgery]. PMID- 7853942 TI - [600,000 women are examined by mammography per year. Every fifth of them refuses screening]. PMID- 7853943 TI - Care-management: a disastrous mistake. PMID- 7853944 TI - Westernised Asians and cardiovascular disease: nature or nurture? PMID- 7853945 TI - Nitrogen dioxide and allergic asthma: starting to clarify an obscure association. PMID- 7853946 TI - Worms, spirals, flukes as carcinogens. PMID- 7853947 TI - The downside of isoniazid chemoprophylaxis. PMID- 7853948 TI - Coronary risk factors in people from the Indian subcontinent living in west London and their siblings in India. AB - Several reports have shown that migrants from southeast Asia tend to have an increased risk of coronary heart disease when settled in their new country. We compared coronary risk factors in a randomly selected group of 247 migrants from the Indian subcontinent of Punjabi origin living in West London and 117 of their siblings living in the Punjab in India. The West London cohort had a greater body mass index (p < 0.001), systolic blood pressure (p = 0.0087), serum cholesterol (p < 0.001), apolipoprotein B (p < 0.001), lower high-density lipoprotein cholesterol (p < 0.05) and higher fasting blood glucose (p < 0.05) than their siblings in the Punjab. Insulin sensitivity, derived from the homoeostatic assessment mathematical model, was lower in men in West London than in their counterparts in India (p < 0.05). Indians in West London had lower beta cell function than those in the Punjab (p < 0.001). Serum lipoprotein (a) concentrations were similar in both the West London and Punjab population, but were significantly higher (p = 0.01) than those of white European populations in the UK. Increases in serum cholesterol after migration from India lead to increased coronary risk conferred by high serum lipoprotein (a) concentrations and greater insulin resistance. Such between-country comparisons are an important means of establishing the importance of coronary risk factors. PMID- 7853949 TI - Social services case-management for long-term mental disorders: a randomised controlled trial. AB - Case management arose in the USA as a solution to the difficulties of providing community care to people with severe mental disorders. The basic principle of the approach is that a case manager takes responsibility for a client; arranges an assessment of need, a comprehensive service plan, delivery of suitable services, and monitoring and assessment of services delivered. The case-management approach has been widely accepted, to the extent that recent legislation has made case management the cornerstone of community care in the UK. We did a randomised controlled trial to evaluate a social services case-management team for people with long-term mental disorders. Subjects were referred from hostels for the homeless, night shelters, a general-practitioner clinic for the homeless, the Oxford City Council homelessness unit, and local voluntary-sector group homes. Of 103 subjects referred, 80 consented to be randomised to treatment or control groups. At 14-month follow-up, as assessed by standardised interviews, there were no significant differences between groups in number of needs, quality of life, employment status, quality of accommodation, social behaviour, or severity of psychiatric symptoms. In the case-management group there was a significant reduction in deviant behaviour on a standardised behaviour rating scale (REHAB) (mean = 0.79; 95% CI 0.26-1.32). It is unfortunate, in view of the limited effectiveness we have shown, that social services case-management was not evaluated in randomised controlled trials before its implementation in the UK. PMID- 7853950 TI - Community infection ratio as an indicator for tuberculosis control. AB - The epidemiology of tuberculosis remains poorly understood. We investigated the relative importance of within-household and community transmission of infection among children aged 6 months to 14 years living in a Peruvian shanty-town. The prevalence of Mycobacterium tuberculosis exposure among 175 contact children (sharing a household with a person who had confirmed pulmonary tuberculosis) and 382 control children (living in nearby households free of active tuberculosis) was defined as the proportion of children with a positive purified protein derivative (PPD) skin-test. 97 (55%) contact children and 129 (34%) controls were PPD positive. Living in a contact household (odds ratio 1.74, 95% CI 1.11-2.73) and age (1.11, 1.06-1.18) were significant risk factors for PPD positivity. We calculated the community infection ratio (CIR) as the odds ratio of PPD-positive controls to PPD-positive contacts: CIR = [formula: see text] A low CIR therefore suggests mainly household spread of infection, whereas a high value suggests frequent transmission outside the household. The adjusted odds ratio (for age, sex, within-household correlation, and household size) was 0.40 (95% CI 0.26 0.64), compared with values of 0.18-0.37 in studies elsewhere. Currently recommended tuberculosis control strategies are suitable for areas with low CIRs. Different strategies may be needed for areas, such as that we studied, with high values. PMID- 7853951 TI - Posture, blood velocity in common femoral vein, and prophylaxis of venous thromboembolism. AB - Might leg elevation and avoidance of poor postures provide better prophylaxis against venous thromboembolism than heparin or mechanical methods? 12 supine subjects tilted in 3 degrees increments from 6 degrees leg-down to 12 degrees leg up showed linear increase in mean peak blood velocity and reduction in calibre in the common femoral vein (colour-duplex ultrasound). Between horizontal and 6 degrees leg-up, velocity was increased by 17% and diameter reduced by 14%. A ranking of mean peak velocities in six postures (sitting; standing; trunk raised 35 degrees to legs which were first horizontal and then tilted up 6 degrees; supine, first horizontal then 6 degrees leg-up) showed significant increases in velocity between consecutive positions. PMID- 7853952 TI - Effect of low-dose heparin on urinary albumin excretion in insulin-dependent diabetes mellitus. AB - We investigated the effect of heparin on urinary albumin excretion in patients with insulin-dependent diabetes mellitus. 39 patients with persistent urinary albumin excretion of 30-300 mg/24 h were randomly treated for 3 months with subcutaneous injections twice daily of isotonic saline, 5000 IU unfractionated heparin, or 2000 anti-Xa IU low-molecular-weight heparin. Unfractionated and low molecular-weight heparin induced a significant reduction in urinary albumin excretion (p = 0.04 and p = 0.004). The mechanism and clinical relevance is unknown but deserve further attention. PMID- 7853954 TI - Myoplasmic Ca2+ concentration during exertional rhabdomyolysis. AB - Exertional rhabdomyolysis can destroy muscle but the pathophysiology is unknown. Using intracellular selective microelectrodes, we found that intracellular Ca2+ concentration ([Ca2+]i) was 1.27 (0.17) mumol/L (median and interquartile range) in skeletal-muscle biopsy specimens from patients with exertional rhabdomyolysis compared with 0.12 (0.01) mumol/L in controls. 3 days treatment with dantrolene, a drug that inhibits Ca2+ release from the sarcoplasmic reticulum, decreased [Ca2+]i to 0.22 (0.05) mumol/L and accelerated patients' recovery. This study demonstrated that exertional rhabdomyolysis is associated with elevated [Ca2+]i, and that dantrolene has a beneficial effect in this syndrome. PMID- 7853953 TI - Vitamin-D-receptor-gene polymorphisms and change in lumbar-spine bone mineral density. AB - Common vitamin-D-receptor (VDR) gene allelic variants predict bone mineral density. We analysed VDR alleles and rate of change of lumbar-spine bone mineral density over 18 months in 72 elderly subjects. 9 BB homozygotes lost bone mineral density but 26 homozygotes for the alternative genotype (bb) did not (mean change -2.3 [SE 1.0] vs 0.9 [0.7]% per year, p < 0.05), irrespective of calcium intake. Among 37 heterozygotes (Bb), however, change in bone mineral density correlated with calcium intake (r = 0.35, p < 0.03). This association between a genetic marker and rate of bone loss in the elderly suggests that the effect of calcium intake on maintenance of bone mass could relate to VDR gene polymorphisms. PMID- 7853956 TI - Gene therapy and immune restoration for HIV disease. PMID- 7853955 TI - Reduced experimental contact sensitivity in squamous cell but not basal cell carcinomas of skin. AB - Basal cell carcinomas (BCC) and squamous cell carcinomas (SCC) show clinical and epidemiological differences not accounted for by different ultraviolet radiation exposure. We have studied experimentally induced contact sensitivity to dinitrochlorobenzene by measuring increases in skin-fold thickness. Patients (n = 37) with squamous tumours had impaired responses compared with controls (33) and patients with BCCs (31) (mean increase 4.5 vs 7.8 and 8.6 mm, respectively; p = 0.002). This diminished immunological response may be causally related to the development of SCC. Because glutathione S-transferase (GST) metabolises dinitrochlorobenzene and polymorphisms of GST are associated with multiple skin tumours, variations in GST may underlie these differences. PMID- 7853957 TI - The Lao national drug policy: lessons along the journey. PMID- 7853958 TI - Bronchoprotective role for endogenous prostaglandin E2. AB - The possibility that impaired production of bronchoprotective factors contributes to the pathogenesis of asthma cannot be excluded. Prostaglandin E2 (PGE2) could be such a factor. It is a dominant cyclo-oxygenase product of airway epithelium and smooth muscle; it has inhibitory effects on inflammatory cells and pathways involved in bronchoconstriction at concentrations known to occur in the airway; inhalation of PGE2 has considerable bronchoprotective effects in patients with asthma; and manoeuvres that increase or decrease endogenous production of PGE2 have beneficial and deleterious effects on airway function. PMID- 7853959 TI - UK's complacence on record inequality gap. PMID- 7853960 TI - Warning about natural reversal of vasectomy. PMID- 7853961 TI - Hyperimmunoglobulinaemia D syndrome. PMID- 7853962 TI - Hypotension induced by interleukin-3 in patients on angiotensin-converting enzyme inhibitors. PMID- 7853963 TI - Nitric oxide in ulcerative colitis. PMID- 7853964 TI - Nitric oxide in ulcerative colitis. PMID- 7853965 TI - Factor XIII substitution in ulcerative colitis. PMID- 7853966 TI - Return of trench fever. PMID- 7853967 TI - Water intoxication after nebulised tribavirin. PMID- 7853968 TI - Enzyme replacement therapy in type 1 and type 3 Gaucher's disease. PMID- 7853969 TI - Mitochondrial mutation in diabetic patient with gastrointestinal symptoms. PMID- 7853970 TI - Hepatocellular carcinoma after treatment with cyproterone acetate combined with ethinyloestradiol. PMID- 7853971 TI - The politics of masturbation. PMID- 7853972 TI - The politics of masturbation. PMID- 7853973 TI - The politics of masturbation. PMID- 7853974 TI - Electronic clinical data systems: can they decrease the administrative burden of physicians? PMID- 7853975 TI - Collaboration between Japan and China towards poliomyelitis eradication. PMID- 7853976 TI - Increased length of hospital stay due to Clostridium difficile associated diarrhoea. PMID- 7853977 TI - Role for traditional healers in eye care. PMID- 7853979 TI - Penicillin-resistant pneumococci. PMID- 7853978 TI - Caudate nuclei volumes in schizophrenic patients treated with typical antipsychotics or clozapine. PMID- 7853980 TI - Pituitary apoplexy after goserelin. PMID- 7853981 TI - Benign intracranial hypertension induced by growth hormone treatment. PMID- 7853982 TI - Systemic lupus erythematosus presenting as fulminating cerebral lupus. PMID- 7853983 TI - Sore throat, antibiotics, and progression to meningococcal disease. PMID- 7853984 TI - Exacerbation of peripheral neuropathy by lamivudine. PMID- 7853985 TI - Hyperekplexia as cause of abnormal intrauterine movements. PMID- 7853986 TI - Acute gout associated with omeprazole. PMID- 7853987 TI - Fascioliasis due to imported khat. PMID- 7853988 TI - Salmonella in alfalfa sprouts. PMID- 7853989 TI - Tick-borne encephalitis in southern Germany. PMID- 7853990 TI - Immunological and bacteriological distinction between parapertussis and pertussis. PMID- 7853991 TI - Endoscopic cross-infection with Helicobacter pylori. PMID- 7853992 TI - [Cholera threatens again]. AB - The etiology, epidemiology, pathogenesis, clinical manifestations and treatment procedures of cholera with the point to new experience are presented. This work was motivated by the intensifying interest for this old disease which has reappeared in Europe in epidemic form. PMID- 7853993 TI - [Cardiovascular disease mortality trends in Croatia from 1968 to 1985]. AB - In the period from 1968 to 1985, the mortality from cardiovascular diseases in Croatia was increasing. In age specific rates (0-44, 45-64 and 65+), mortality in males was remarkably higher than that for women. Considering the deaths from ischemic heart disease (ICD code 410-414) as one and deaths from all other cardiovascular diseases as another group, the analysis of the mortality by age shows greater sex differences for ischemic heart diseases. The presented data reveal a particularly interesting fact: in 1980, in the age group 65+ (70% of men and 90% of women suffering from cardiovascular diseases are in that age group), there was a steep decrease in the ischemic heart disease mortality, and, at the same time, a sudden increase in the mortality of all other heart diseases. It suggests that there were no real changes in the mortality pattern, the changes being the consequence of the difference in causes of death registration on the basis of the IX ICD revision. PMID- 7853994 TI - [Relation between P-fimbriae and resistance to amoxicillin, carbenicillin and tetracycline in uropathogenic strains of Escherichia coli]. AB - Escherichia coli is the most common cause of uncomplicated urinary tract infections. The ability of adherence enables E. coli colonization of mucosal surfaces of the urinary tract, and strains which express P-fimbriae significantly more often cause unobstructive pyelonephritis. The relationship between adhesin type and susceptibility to 13 antimicrobial agents of 160 E. coli strains isolated from urine from individuals with acute pyelonephritis, chronic pyelonephritis, acute cystitis and asymptomatic bacteriuria was investigated. The adhesins of investigated strains of E. coli were determined by hemagglutination, and susceptibility to antimicrobial agents by Kirby-Bauer disk diffusion method. P-fimbriated strains were more frequently resistant to tetracycline and carbenicillin than strains in which P-fimbriae were not detected, and they all were resistant to amoxicillin, in contrast with non P-fimbriated strains (p < 0.01). The observed relationship between P-fimbriae and antimicrobial resistance among strains in which different serogroups were detected suggest the possibility of horizontal gene transfer of these properties. It can be concluded that in patients with symptoms of acute upper urinary tract infection amoxicillin should not be used empirically because there is a great possibility that infection is caused by P-fimbriated and amoxicillin resistant strain of E. coli. PMID- 7853995 TI - [Modern diagnosis and treatment of pheochromocytoma in children]. AB - Pheochromocytoma is a rare tumor of chromaffin tissue of the adrenal gland that synthesizes, stores and releases cathecolamines. In 10% of the patients it arises outside the adrenal gland, and has been called paraganglioma. The following study describes our experience in the diagnostic process and treatment of pheochromocytoma in two children, a 8-year-old boy with the right ureteral paraganglioma, and a 8-year-old girl with pheo-chromocytoma of the leftsuprarenal gland. Characteristic clinical features with predominant signs of hypertension, as well as the diagnostic flow diagram, have been presented. We have analysed recent diagnostic possibilities, sensitivity of diagnostic methods (ultrasonography, CT, selective angiography and J131 MIBG scintigraphy), indications for their use, and the importance of appropriate preoperative management. The major role of the J131-metaiodobenzilguanidine scintigraphy in diagnostic assessment, especially in precise preoperative localization and postoperative verification of tumour removal, has been stressed. PMID- 7853996 TI - [Homocystinuria: case reports with a note on hyperhomocysteinemia as a risk factor for the early onset of vascular disease]. AB - Two brothers and a sister suffering from homocystinuria caused by cystathionine beta-synthase deficiency and the possibilities of treatment are presented. Possible clinical variability, the necessity for early diagnosis and the importance of hyperhomocysteinemia as a risk factor for early-onset vascular disease are discussed. PMID- 7853997 TI - [Bilateral glomus caroticum tumors]. AB - Paragangliomas of the head and neck are tumors which are believed to function as chemosensory reflex receptors that respond to changes in their chemical environment. They may occur in the carotid body, on the vagus nerve, along the jugular vein, in the middle ear, in the orbit, in the larynx and nasopharynx. The incidence of multiple paragangliomas is about 3% of all the patients with this tumor and 26% of the patients with positive family history. PMID- 7853998 TI - [Mediastinal and pulmonary hemangiopericytoma]. AB - Two cases of hemangiopericytomas, localized in the mediastinum and lung were described. In the former case the tumour was operated 19 years ago and later three relapses of the disease occurred. Today the patient is well without signs of the tumour. In the second case there was no relapse 6 years after the operation. The biological behaviour of hemangiopericytomas cannot be predicted on the basis of the clinical and morphological signs. PMID- 7853999 TI - [The role of color doppler sonography in the diagnosis of atherosclerotic changes in arteries of the lower extremities]. AB - In this study doppler ultrasound methods were evaluated from the point diagnostical values, and were compared with the standard X-ray methods (angiography). One of the basic question was, whether noninvasive doppler ultrasonic methods could replace the invasive contrast angiography i. e. in what relations and volume. The investigations were done by CW Doppler and angiodynography, and the results obtained, were compared with the ones of angiography that was taken as the referent method. The 264 segments of blood vessels of lower extremities arterial three were analyzed, and then ranged into the advance defined categories, on the basis of the degree of obstruction. The evaluation of the data obtained was statistically accomplished by the means of "decision matrix" test, and results were displayed by positive predictive values. Positive predictive value for the CW Doppler was 94.07 (in groups varied from 93.10-100) and for angiodynography was 97.35 (in groups varied from 93.15 to 100). From the data obtained, it could be concluded that Doppler's methods are very accurate in a way of diagnostical interpretation (96.03%). The advantages of the Doppler's methods against the conventional standard radiological researches reflect in the following facts: they enable dynamic indicators in real time, they are noninvasive, very exact, and the possibility of verification of stenosis is enabling us to apply the adequate diagnosic (angiography) and therapeutic methods in time. PMID- 7854000 TI - [Free choice of a physician in general medicine]. AB - The purpose of this paper was to study the implementation of a free choice of a physician in general practice (GP) in 1992, as well as to study how it was influenced by the characteristics of GPs, population that made this choice, and health system. The study group of 71 GPs consisted of 37 (52.1%) specialists of general practice, 50 (70.4%) female GPs, 42 (59.2%) who worked in town and 52 (73.3%) who had their practices situated close to the place of residence of the majority of their patients. There were significant differences in the number (range, 450-5000 patients) and structure of patients on the lists of the studied GPs. The proportion of partial and whole families on the lists of the examined GPs was somewhat over 50%, and the same proportion of 50% had preschool children in care. No statistically significant differences were found in the size and structure of population on the lists between the studied GPs according to their age, sex or level of professional education. However, the site of outpatient clinic in a village and suburban area of a town or a town had a significant influence on the size and structure of the population in care of GPs. GPs who worked in the rural or outlying residential district of a town had a statistically significantly higher portion of families and preschool children on their lists than GPs who worked in towns. For the implementation of a free choice of a physician, it is mandatory to anticipate the period for adjustment and reconstruction of the primary health care (PHC) system.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7854001 TI - [Bacterial adherence and its importance in the pathogenesis of infections]. AB - Bacteria usually attack the susceptible animal or human organisms at mucosal surfaces of the respiratory, gastrointestinal or genitourinary tract. To colonize these surfaces they must penetrate a number of nonspecific defense barriers including cleansing mechanisms such as sneezing, coughing, peristalsis and fluid flow. Successful microorganisms escape recognition by soluble immune or nonimmune molecules, and bind to the mucosal surfaces via specialised molecules exposed on their surface (adhesions) which recognize and interact with complementary molecules (receptors) on the surface of specific host cells. This key step in the pathogenesis of infectious diseases is currently the subject of intensive investigation. In this review the mechanism and the role of adherence in different bacterial infections are considered. PMID- 7854002 TI - [Global developmental disorders--etiology and classification dilemmas]. AB - We report in this paper pervasive developmental disorders. They represent a rather numerous group of severe psychic diseases of early childhood, of unknown etiology. All psychic functions are disturbed: thinking, emotions and mental functioning. Different classifications of these disorders include various terms for similar clinical conditions. So, there is a dilemma whether it is a case of special nosologic entities or different clinical conditions of the same disorder. Infantile autism, Asperger syndrome, Rett syndrome and atypical psychosis are described. Although prognosis is commonly unfavourable, therapy may be very helpful. PMID- 7854003 TI - [If blood is accepted only from volunteer donors then why payment for blood preparations?]. PMID- 7854004 TI - Effects of site-directed mutagenesis on the serine residues of human lecithin:cholesterol acyltransferase. AB - Lecithin:cholesterol acyltransferase (LCAT) is a serine protease-type enzyme that esterifies cholesterol in human plasma and is activated by apolipoprotein A-I in high-density lipoproteins. LCAT contains 22 serine residues, including Ser181, which is thought to be part of the catalytic site. In order to determine the importance of these serine residues in LCAT, we prepared six LCAT mutants: LCAT (Ser19-->Ala), LCAT (Ser181-->Gly), LCAT (Ser208-->Ala), LCAT (SEr216-->Ala), LCAT (Ser225-->Ala) and LCAT (Ser383-->Ala). We also replaced the adjacent asparagine residues in two additional mutants, LCAT (Ser19-->Ala, Asn20-->Thr) and LCAT (Ser383-->Ala, Asn384-->Thr), in order to ascertain the effect of the serines on N-glycosylation. The mutant complementary DNA (cDNA) were subcloned into a eukaryotic expression vector (pSG5) and expressed in COS-6 cells. By polymerase chain reaction analysis, LCAT-specific messenger RNA (mRNA) was found in all mutant and wild-type transfectants. Western blot analysis revealed LCAT specific bands in media and lysates of the transfected cells. With two exceptions, the amounts of LCAT mass secreted by the transfectants were similar to that of the wild type (mean, 90% mass of wild type; range, 34-138%). Except for LCAT (Ser181-->Gly), which was inactive, the specific activities of the remainder of the mutant enzymes were also similar (mean 95% activity of wild type; range, 65-169%). These results indicate that Ser181 is part of the catalytic site and that stereoconservative substitutions for serines have minor effects on the synthesis, secretion and specific activities of human LCAT. PMID- 7854005 TI - Cholesteryl ester transfer protein inhibition by PD 140195. AB - The presence of plasma cholesteryl ester transfer protein (CETP) activity may be atherogenic, and, therefore, strategies to inhibit its activity or production may result in a beneficial effect on lipoprotein profiles and the disease process. The current report describes 4-phenyl-5-tridecyl-4H-1,2,4- triazole-3-thiol (PD 140195), a novel CETP inhibitor. The concentration-dependent inhibition of CETP by PD 140195 and the inhibitory monoclonal antibody (Mab) TP2 is demonstrated in a variety of in vitro assay systems. Molecular models of PD 140195 suggest a spatial mimicry of the cholesteryl ester structure. Despite the structural similarity, kinetic studies with a fluorescent cholesteryl ester analog suggest that the inhibition of transfer is not competitive. PD 140195 also selectively inhibited cholesteryl ester but not triglyceride transfer, while the Mab TP2 blocked CETP transfer of both. Studies were carried out to determine whether CETP inhibition observed in vitro could also be demonstrated in vivo. When PD 140195 was intravenously infused to anesthetized rabbits (up to 20 mg/kg), only transient CETP inhibition was observed. In vitro reconstitution studies in the presence of bovine serum albumin resulted in marked reduction of PD 140195 inhibitory activity. Thus, the low activity of PD 140195 in whole plasma probably results from binding to other plasma proteins. PMID- 7854006 TI - Interactions of MDL 29,311 and probucol metabolites with cholesteryl esters. AB - The hypothesis that the efficacy of hydrophobic antioxidants in animal models of atherogenesis may, in part, be related to physical effects on cholesteryl esters in cells was probed with analogs and metabolites of probucol. The interactions of an effective bis-thiomethane analog (MDL 29,311) and selected metabolites of probucol with cholesteryl oleate were examined by differential scanning calorimetry and polarized light microscopy. Like probucol, MDL 29,311 and the bisphenol metabolite decrease the liquid-crystalline phase transition enthalpy of cholesteryl oleate with increasing concentrations. At 20 mol%, no transition is detectable. By contrast, the spiroquinone metabolite of probucol and the diphenoquinone metabolite common to both molecules have minimal effects on the liquid-crystalline transitions of cholesteryl oleate. At 20 mol%, neither compound has as great an effect as 1 mol% MDL 29,311. Consistent with their effects on dry cholesteryl oleate, MDL 29,311 and the bisphenol metabolite convert lipid inclusions in cells supplemented with cholesterol to an isotropic physical state similar to that observed with probucol. The number of anisotropic inclusions in the cells decreases with increasing concentration in the medium in the range of 50 to 250 micrograms/mL. In cells fed with the spiroquinone or diphenoquinone metabolites, the lipid inclusions are liquid-crystalline and resemble those observed with cholesterol-fed controls. These data are interpreted in terms of a model in which hydrophobic antioxidants closely related to probucol disrupt the packing of cellular cholesteryl esters. PMID- 7854007 TI - Differential effects of eicosapentaenoic acid and docosahexaenoic acid on human skin fibroblasts. AB - To better understand the mode of action of omega 3 fatty acids in cell membranes, human foreskin fibroblasts were grown in serum-free medium supplemented with 50 microM oleic acid linoleic acid, eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), and the effects on membrane composition, fluorescence polarization and enzyme activities were followed. The cells were enriched with EPA and DHA up to 7 and 13% of total lipids, respectively, of which > 95% was associated with phospholipids. In addition, the concentration of 22:5n-3 increased with both EPA and DHA to 7.5, and 2.1% of the total fatty acids, respectively. When compared to controls (oleic acid), cells treated with DHA showed a decrease in cholesterol, phospholipids, arachidonic acid (AA) and free cholesterol/phospholipid ratio (P < 0.05). In the presence of EPA, only decreases in AA and cholesterol were significant (P < 0.05). Membrane fluidity, assessed by fluorescence anisotropy, was increased 16% in cells enriched with DHA (P < 0.05), but showed no change with EPA or linoleic acid. There was an increase in membrane-associated 5' nucleotidase (+27%) and adenylate cyclase (+19%) activities (P < 0.05), in DHA enriched, but not in EPA-enriched cells, when compared with oleate controls. The studies show that incorporation of DHA, but not EPA, into cell membranes of fibroblasts alters membrane biophysical characteristics and function. We suggest that these two major n-3 fatty acids of fish oils have differential effects on cell membranes, and this may be related to the known differences in their physiological effects. PMID- 7854008 TI - Comparison of linoleic acid and eicosapentaenoic acid incorporation into human breast cancer cells. AB - To gain some insight into the mechanisms involved in the opposing effects of linoleic acid (LA) and eicosapentaenoic acid (EPA) on the growth and invasiveness of MDA-MB-435 human breast cancer cells, the dynamics of the uptake by cells and the incorporation of [14C]LA and [14C]EPA into major lipid and phospholipid pools, as well as the effects of unlabeled EPA or LA on the uptake and distribution of [14C]LA or [14C]EPA, respectively, were examined. Cells were exposed to [14C]LA (1.28 micrograms/mL) or [14C]EPA (1.0 micrograms/mL) and unlabeled EPA or LA, respectively, at 0, 1, 4 and 16 micrograms/mL for 24 h in serum-free media. The uptake of each fatty acid (FA) was linear over time and was not affected by the presence of the opposing FA. For both FA, 80-90% was incorporated into the phospholipid fraction with the remaining 10-20% in neutral lipids. The relative distribution profile of [14C]LA among the phospholipid classes indicated a preferential incorporation into phosphatidylcholine (65%), whereas [14C]EPA was mostly found in phosphatidylethanolamine (58%). In the presence of unlabeled EPA or LA at various concentrations, corresponding dose dependent shifts of [14C]LA or [14C]EPA from the phospholipid to the neutral lipid pool were noted, which did not alter the relative distribution of the FA among the phospholipid classes. Exogenous exposure to EPA or LA increased its content in membrane phospholipids while concurrently decreasing LA or EPA content, respectively, in a dose-dependent manner. Arachidonic acid content of membrane phospholipids remained constant.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7854009 TI - Levels of polyunsaturated fatty acids in tissues from zinc-deficient rats fed a linseed oil diet. AB - The effect of zinc deficiency on the levels of n-6 and n-3 polyunsaturated fatty acids (PUFA) in lipids from tissues of rats fed a diet containing linseed oil was investigated. Rats were fed either a control diet (25 mg Zn/kg) or a zinc deficient diet (0.8 mg Zn/kg) for 10 d. To avoid energy and nutrient deficiency, 11.6 g of diet per day was administered by gastric tube. At the end of the experiment, rats fed the zinc-deficient diet had drastically reduced plasma zinc concentration and alkaline phosphatase activity consistent with severe zinc deficiency in these rats. Zinc-deficient rats had higher levels of n-3 PUFA, in particular eicosapentaenoic acid (EPA), and lower levels of n-6 PUFA, in particular linoleic acid, in liver and plasma phosphatidylcholine (PC) and in erythrocyte membrane total lipids than did control rats. By contrast, the levels of n-3 PUFA in PC from testes and heart, and in phosphatidylethanolamine (PE) from liver, testes and heart, were only slightly different between zinc-deficient and control rats. The study suggests that desaturation of alpha-linolenic acid is not inhibited by zinc deficiency, and that in zinc-deficient rats, n-3 PUFA preferentially incorporated into phospholipids at the expense of n-6 PUFA, especially EPA into PC. The study also shows that the effect of zinc deficiency on PUFA levels is different for PC and PE in rat tissues. PMID- 7854010 TI - The n-3 polyunsaturated fatty acid levels in rat tissue lipids increase in response to dietary olive oil relative to sunflower oil. AB - In the present study, changes in phospholipid compositions of liver microsomes, erythrocyte membranes, platelets, aorta, cardiac muscle and brain of rats fed olive oil were compared with those of rats fed sunflower oil. Four groups of rats starting at weaning were fed for four weeks a basal diet containing 5 or 25% olive oil or sunflower oil. We found that oleic acid was higher and linoleic acid was lower in membrane phospholipids of olive oil fed rats compared to sunflower oil fed rats. Polyunsaturated fatty acids of the n-3 series were markedly elevated in all tissues of rats on the olive oil diets relative to those on the sunflower oil diets. The results are consistent with a lower linoleic/linolenic acid ratio induced by the olive oil diets, suggesting a positive correlation between olive oil ingestion and n-3 polyunsaturated fatty acid levels in cell and tissue lipids. The study suggests that an adequate intake of olive oil may enhance the conversion of n-3 fatty acids. PMID- 7854011 TI - Dietary omega 3 fatty acids and cholesterol modify enterocyte microsomal membrane phospholipids, cholesterol content and phospholipid enzyme activities in diabetic rats. AB - Diabetes-associated changes in intestinal uptake of nutrients are modified by isocaloric variations in the type of dietary lipids, and are associated with alterations in the phospholipid and fatty acyl content of the intestinal brush border membrane. The present study was designed to test the hypothesis that diet- and diabetes-associated changes in enterocyte microsomal membrane phospholipids are due to variations in the activity of two phospholipid metabolizing enzymes, 1,2-diacylglycerol:CDPcholine cholinephosphotransferase (CPT) and phosphatidylethanolamine methyltransferase (PEMT). Adult female Wistar rats were fed one of four semisynthetic diets--beef tallow low in cholesterol (BT), beef tallow high in cholesterol (BTC), fish oil low in cholesterol (FO) or fish oil high in cholesterol. In half of the animals, diabetes mellitus was produced by injection of streptozotocin. Jejunal and ileal enterocyte microsomes (EMM) were isolated and analyzed for cholesterol and phospholipids, as well as for CPT and PEMT activities. In control animals, feeding FO reduced EMM total phospholipids including phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylinositol. Feeding FO resulted in a greater than 95% reduction in the activity of CPT. Diabetes was associated with increased jejunal EMM total phospholipids including sphingomyelin (SM) and PE, without associated changes in CPT or PEMT. Dietary cholesterol supplementation did not affect EMM total cholesterol or phosphlipid composition in control rats fed BT or FO, but was associated with an increase in EMM cholesterol in diabetic rats fed BT or FO. A decrease in total phospholipids due to a decline in SM, PC and PE in diabetic rats fed FO was not associated with changes in the activities of CPT or PEMT in EMM.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7854013 TI - The lipids of slugs and snails: evolution, diet and biosynthesis. AB - There is a considerable gap in current knowledge of the lipid composition of snails and slugs, both of which belong to the phylum Mollusca. We have therefore analyzed the sterol and fatty acid compositions of three species of slugs and three species of snails. The sterols of slugs included eight different sterols: cholesterol contributed 76-85% of the total sterols, brassicasterol accounted for 4-13%; other sterols we identified were lathosterol, 24-methylene cholesterol, campesterol, stigmasterol, sitosterol and sitostanol. In contrast, snails contained two additional sterols, desmosterol and cholestanol. Of the polyunsaturated fatty acids in slugs, linoleic (18:2n-6) and arachidonic acids (20:4n-6) were the major n-6 fatty acids, while linoleic (18:3n-3) and eicosapentaenoic acids (20:5n-3) were the predominant n-3 fatty acids. Docosahexaenoic acid (22:6n-3), the end product in the n-3 fatty acid synthetic pathway and an important membrane fatty acid of mammals, fish and birds, was absent in both slugs and snails. However, the analogous product of n-6 fatty acid synthesis, 22:5n-6, was found in both snails and slugs. This raises speculation about preference for n-6 fatty acid synthesis in these species. Our data show the unique sterol and fatty acid compositions of slugs and snails, as well as similarities and differences in sterol composition between the two. The results between the two land mollusks are contrasted with those of marine mollusks, such as oysters, clams and scallops. PMID- 7854012 TI - Hematological and lipid changes in newborn piglets fed milk replacer diets containing vegetable oils with different levels of n-3 fatty acids. AB - To test if linolenic acid (18:3n-3) from vegetable oils would affect bleeding times and platelet counts in newborns, piglets were used as a model fed milk replacer diets containing 25% (by wt) vegetable oils or oil mixtures for 28 d and compared to sow-reared piglets. The oils tested included soybean, canola, olive, high oleic sunflower (HOAS), a canola/coconut mixture and a mixture of oils mimicking canola in fatty acid composition. All piglets fed the milk replacer diets showed normal growth. Bleeding times increased after birth from 4-6 min to 7-10 min by week 4 (P < 0.001), and were higher in pigs fed diets containing 18:3n-3, as well as in sow-reared piglets receiving n-3 polyunsaturated fatty acids (PUFA) in the milk, as compared to diets low in 18:3n-3. Platelet numbers increased within the first week in newborn piglets from 300 to 550 x 10(9)/L, and remained high thereafter. Milk replacer diets, containing vegetable oils, generally showed a transient delay in the rise of platelet numbers, which was partially associated with an increased platelet volume. The oils showed differences in the length of delay, but by the third week of age, all platelet counts were > 500 x 10(9)/L. The delay in rise in platelet counts appeared to be related to the fatty acid composition of the oil, as the effect was reproduced by a mixture of oils with a certain fatty acid profile, and disappeared upon the addition of saturated fatty acids to the vegetable oil. There were no alterations in the coagulation factors due to the dietary oils. Blood plasma, platelets and red blood cell membranes showed increased levels of 18:3n-3 and long-chain n-3 PUFA in response to dietary 18:3n-3. The level of saturated fatty acids in blood lipids was generally lower in canola and HOAS oil-fed piglets as compared to piglets fed soybean oil or reared with the sow. The results suggest that consumption of milk replacer diets containing vegetable oils rich in 18:3n-3 does not represent a bleeding risk, and that the transient lower platelet count can be counterbalanced by the addition of saturated fatty acids to the vegetable oils. PMID- 7854014 TI - Peroxidation reactions in plant membranes: effects of free fatty acids. AB - Free fatty acids accumulate in plant membranes after exposure of plants to environmental stress, such as freezing and desiccation. Fatty acid accumulation has been linked to various biophysical changes and to the occurrence of lipid peroxidation, but the relationships appear complex and inconsistent. The interactions between oxygen free radicals, free fatty acids and lipid peroxidation in plant membranes were examined further by studying peroxidation reactions in a model membrane system composed of a complex mixture of plant phospholipids, including various free fatty acids. Multilamellar liposomes were treated with oxygen free radicals generated from iron ascorbate. Increased concentrations of free palmitic acid up to 10 mol% (fatty acid/phospholipid) reduced the production of aldehydes detected by the thiobarbituric acid assay, but enhanced the production of fluorescent products. By contrast, increased concentrations of free linolenic acid increased aldehyde production and reduced the formation of fluorescent products. The two free fatty acids both enhanced the susceptibility of phospholipids to degradation as shown by the reduced recovery of esterified polyunsaturated fatty acids (linoleic and linolenic). The free radical reactions with or without free fatty acid additions catalyzed the selective degradation of phospholipids in the order phosphatidylethanolamine > phosphatidylcholine > phosphatidylinositol > phosphatidylglycerol. Selective degradation of phospholipids is often observed after periods of environmental stress or during senescence of plants, and has been cited as evidence for the involvement of phospholipases in these degenerative processes. The results indicate that selectivity is not a criterion for eliminating the involvement of oxygen free radicals in these degenerative processes. Furthermore, the results suggest that modifications of lipid composition during a plant's acclimation to adverse environments may determine the types of free radical reactions that occur due to stress. PMID- 7854015 TI - Reactions of diazomethane with glycerolipids in the presence of serum or inorganic salts. AB - Diazomethane is widely used for the selective methylation of nonesterified fatty acids in the presence of other lipids. However, when the reaction is carried out directly with plasma or serum, substantial methanolysis of phospholipid acyl groups occurs. Because of the importance of rigorous selectivity in the assay of unesterified fatty acids which are present only in trace amounts in cells and body fluids, we have investigated the diazomethane procedure in detail and reached the following conclusions: (i) When diazomethane reacts with lipid extracts in organic solvent, no ester hydrolysis occurs. (ii) In the presence of serum or plasma, diazomethane reacts with water and inorganic salts, causing the solution to become basic (CH2N2 + NaCl + HOH-->Ch3Cl + Na+ + OH- + N2); methoxide ions are formed from methanol (CH3OH + OH(-)-->CH3O- + HOH) causing extensive methanolysis (CH3O- + RO-CO-R'-->CH3O-CO-R' + RO-). An analogous reaction takes place with ethanol. All esters of glycerol are transesterified in aqueous salt solution by this mechanism. It is therefore essential to prepare a lipid extract prior to the assay of unesterified fatty acids when using the diazomethane procedure. PMID- 7854016 TI - Ultrasound in fatty acid chemistry: synthesis of a 1-pyrroline fatty acid ester isomer from methyl ricinoleate. AB - A novel 1-pyrroline fatty acid ester isomer (viz. 8-5-hexyl-1-pyrrolin-2-yl) octanoate) has been synthesized from methyl ricinoleate by two routes with an overall yield of 42 and 30%, respectively. Most of the reactions are carried out under concomitant ultrasonic irradiation (20 KHz, ca. 53 watts/cm2). Under such a reaction condition, the reaction time is considerably shortened, and product yields are high. Dehydrobromination under concomitant ultrasonic irradiation of methyl 9, 10-dibromo-12-hydroxyoctadecanoate with KOH in EtOH furnishes methyl 12 hydroxy-9-octadecynoate (66%) within 15 min. Hydration of the latter under ultrasound with mercury(II)acetate in aqueous tetrahydrofuran yields exclusively methyl 12-hydroxy-9-oxo-octadecanoate (95%) in 30 min. The hydroxy group in the latter compound is transformed to the azido function via the mesylate, and treatment of the azido-oxo intermediate (methyl 12-azido-9-oxooctadecanoate) with Ph3P under ultrasonic irradiation furnishes the requisite 1-pyrroline fatty acid ester (77%). The same azido-oxo intermediate has also been obtained by the oxidation of methyl 12-azido-9-cis-octadecenoate using benzoquinone and a catalytic amount of Pd(II)chloride in aqueous tetrahydrofuran under concomitant ultrasonic irradiation (90 min) to give the product in 45% yield. The latter reaction does not take place even under prolonged silent stirring of the reaction mixture. PMID- 7854017 TI - Rapid determination of double bond configuration and position along the hydrocarbon chain in cyclic fatty acid monomers. AB - This study reports the structural elucidation of diunsaturated 5- or 6-membered ring cyclic fatty acid monomers (CFAM) isolated from heated flaxseed oil by complementary gas chromatography (GC)-mass spectrometry (MS) and GC-matrix isolation-Fourier transform infrared spectroscopy (MI-FTIR). Infrared measurements of CFAM were carried out on methyl ester derivatives as well resolved chromatograms were obtained on a polar 100% cyanopropyl polysiloxane capillary GC column. By contrast, electron ionization MS of methyl ester derivatives was of limited value because of double bond migration during the ionization process in the mass spectrometer. This communication reports definitive MS fragmentation patterns that can confirm ring position and double bond position along the fatty acid chain in 1,2-disubstituted CFAM determined as 2-alkenyl-4,4-dimethyl-oxazoline derivatives. Double bond configuration (cis, trans, or conjugated cis,cis) in CFAM was confirmed by GC-MI-FTIR. The presence of CFAM, degradation products found in used frying oils, is a potential source of dietary toxicity. PMID- 7854018 TI - Inhalation MR lymphography: a new method for selective enhancement of the lung hilar and mediastinal lymph nodes. AB - On MR lymphography, a new approach to the lung hilar and mediastinal nodes was developed in an animal model. Five rabbits were made to inhale iron colloid (cideferron) that was nebulized to aerosol. Two days after inhalation of the agent, the mediastinal lymph nodes decreased in signal on SE 2000/30 and SE 2000/60 images and proved to have iron on histological evaluation, whereas the popliteal nodes did not have any iron. Experimental results indicate that inhalational administration can deliver the agent to the pulmonary lymphatic system and has the potential of lung hilar and mediastinal MR lymphography. PMID- 7854019 TI - Magnetic resonance imaging of the uterus in vivo and in vitro at an ultra low magnetic field (0.02 T): assessment of its normal structure and of leiomyomas. AB - The purpose of this investigation was to analyze the normal anatomy and leiomyomas of the uterus with an ultra low field (0.02 T) magnetic resonance imaging (MRI) device. MR imaging was performed on 18 uteri, 11 of which were imaged both preoperatively (in vivo) and as an operative specimen (in vitro), 6 only as an operative specimen, and 1 only preoperatively. All uteri were examined histologically after imaging. The junctional zone was much better delineated in vivo than in vitro, indicating that its appearance on MR is partly due to blood flow. No structures contributing to its visibility in vitro could be demonstrated histologically. Twenty leiomyomas (size range 7-79 mm) in 12 uteri were found with MRI. They were slightly better discerned in vivo than in vitro. The leiomyomas, having no degenerative changes, had a signal intensity which was the same or lower than that of the myometrium. On images obtained in vitro the signal intensity of these leiomyomas relative to that of myometrium correlated directly with their muscular content (R = 0.74, p = .002). The authors conclude that the junctional zone is a sum of physiological and structural factors, the latter being responsible for its in vitro delineation. MR imaging of the uterus in vitro did not give more information than MR imaging in vivo. All leiomyomas larger than 10 mm could be detected, indicating that MR imaging at 0.02 T is an accurate method for the imaging of the uterine leiomyomas. PMID- 7854020 TI - MR imaging findings in recurrent primary osseous Ewing sarcoma. AB - The objective of this study was to determine the value of magnetic resonance (MR) imaging in diagnosing local recurrence of Ewing sarcoma. We retrospectively reviewed radiographs, Tc99m-methylene diphosphonate (MDP) skeletal scintigraphy, computed tomography scans, and MR studies of 11 patients who had local recurrences of osseous Ewing sarcoma following initial responses to chemotherapy and local radiation. The MR images were compared to those of a control group of nine patients who had no evidence of relapse. T1- and T2-weighted MR images identified 9 of the 11 recurrences. Computed tomography was diagnostic in 4 of 6 cases evaluated, Tc99m-MDP bone scintigraphy in 4 of 11 cases, and plain radiographs in 2 of 10. MR findings at relapse included changes in signal intensity, increased extent of abnormal marrow signal on T1- and T2-weighted images, and identification of a new soft tissue mass. These findings suggest that MR imaging is valuable in the routine follow-up of primary osseous Ewing sarcoma. PMID- 7854021 TI - Diagnostic performance of low field MRI in acute knee injuries. AB - The diagnostic performance of low field (0.1 T) magnetic resonance imaging (MRI) was studied prospectively and double-blindly among 33 patients with acute knee injuries. The subsequent arthroscopy was the golden standard. For lesions of the medial meniscus low field MR had a sensitivity of 88% and a specificity of 80%; for lesions of the lateral meniscus the sensitivity was 25% and the specificity 97%. For anterior cruciate ligament tears, low field MRI had a sensitivity of 83% and a specificity of 85%. The specificity for posterior cruciate ligament tears was 97%. The performance of low field MRI equalled that reported earlier for high field MRI, the only exception being the sensitivity for lateral meniscus lesions. PMID- 7854022 TI - Visualization of superior mesenteric lymph nodes by the combined oral and intravenous administration of the ultrasmall superparamagnetic iron oxide, AMI 227. AB - Superior mesentric lymph nodes which lie as a chain near the small intestine are difficult to visualize in the rat with MRI either with or without the use of contrast agents. We previously demonstrated that the oral administration of an ultrasmall superparamagnetic iron oxide (AMI-227) produces a brightening of the lumen of the GI tract with a T1-weighted spin-echo pulse sequence. We have also shown that AMI-227 darkens abdominal lymph nodes. In the present study we show that the combined oral and intravenous administration of AMI-227 produces a brightening of the lumen of the GI tract and a darkening of the superior mesenteric lymph node chain. As a result of these combined and opposing effects on image signal intensity, a necessary contrast is established to reliably locate the superior mesenteric lymph nodes in vivo, which, to our knowledge, have been elusive by other techniques. PMID- 7854023 TI - Measurement of diffusion coefficients using a quick echo split NMR imaging technique. AB - A new method for the ultrafast generation of diffusion-weighted images is reported. The technique combines a quick echo split NMR imaging sequence with the principle of Stejskal and Tanner. It allows to determine the diffusion constant with nearly the same accuracy as the conventional spin-echo technique, requiring only a fraction of the time. The determined values for water doped with 1 g Cu(NO3)2 per liter of H2O and pure acetone were Dwater = (1.95 +/- 0.02) x 10(-9) m2/s and Dacetone = (4.05 +/- 0.02) x 10(-9) m2/s at 18.5 degrees C. They are in good agreement both with literature and our own reference measurements using a diffusion-weighted spin-echo sequence. In addition, the temperature dependence of Dwater was measured in the range of 18.5-45.9 degrees C and a good correspondence with reported data was found. PMID- 7854024 TI - Incidence of apparent restricted diffusion in three different models of cerebral infarction. AB - High speed magnetic resonance imaging (MRI) and short diffusion times are used to investigate the appearance of restricted diffusion in three different models of cerebral infarction. The models are: the middle cerebral artery occlusion (MCAO) model in the rat, the carotid occlusion model in the gerbil, and the Rose Bengal microvascular occlusion model in the rat. All three were investigated for 16 b values equally spaced between 10 and 1510 s/mm2 using two distinct experiments. In the ct (constant time) experiment, the diffusion time was held constant at 11.7 ms while the b-value was varied with the gradient strength. In the cg (constant gradient) experiment, the gradient strength was held constant and the b value increased by varying the diffusion time from 4.4 to 11.7 ms. A monoexponential decay of the signal intensity with b-value in the ct experiment accompanied by nonmonoexponential (NME) decay in the cg experiment is indicative of restricted diffusion. As this phenomenon is detectable only at short diffusion times, it cannot be due to restriction by impermeable membranes, and we have thus termed this apparent restriction. For the MCAO model and the carotid occlusion model, apparent restriction was found both inside the infarct territory and in some regions outside it. No definite evidence for restriction was found for the Rose Bengal model, which was, however, only studied from 24 h post-insult. PMID- 7854025 TI - High resolution high field rodent cardiac imaging with flow enhancement suppression. AB - A method that incorporates cardiorespiratory-gated 2DFT spin-echo imaging with blood flow enhancement suppression is described which enables high resolution microimaging of the rodent heart. This methodology was applied to obtain in vivo cardiac mouse and rat images with in-plane resolutions of 100-200 microns using high field vertical bore magnet systems. Suppression of intraventricular blood flow enhancement was achieved using a combined spin-echo/gradient-refocussed sequence to dephase magnetization from flowing spins prior to imaging. PMID- 7854026 TI - Improvements to the quality of MRI cluster analysis. AB - Cluster analysis techniques are gaining widespread use for segmentation of MRI data, especially for volume measurement and 3-D display purposes. This paper describes four improvements to such techniques: (1) The use of intensity simulations to model cluster plots; (2) Correction of image nonuniformity; (3) Anisotropic smoothing of data; and (4) Automatic isolation of tissues of interest. Simulation of cluster plots allows an informed choice of pulse sequence(s) and acquisition parameters to be made. Correction of image nonuniformity and anisotropic smoothing reduce the spread of signal intensity from a single tissue thus producing significantly more compact clusters, whilst the isolation of tissues of interest prevents overlap of clusters from the tissues of interest with those not under consideration. These techniques may be used to improve the results of cluster analysis or traded off, for example to allow lower signal-to-noise images, shorter repetition time images, or fewer images to be used for segmentation. PMID- 7854027 TI - An integrated program for amplitude-modulated RF pulse generation and re-mapping with shaped gradients. AB - Efficient generation of amplitude modulated, frequency selective RF pulses has been demonstrated by the Shinnar-Le Roux (SLR) algorithm. In the present article, we provide an overview of a relatively comprehensive computer program that includes a version of the SLR algorithm and also incorporates an algorithm for re mapping a selective RF pulse onto a new dwell time with modulated gradients. The re-mapping may be used to reduce SAR, or to shorten the RF pulse time by increasing the gradient and RF strength in regions where the original RF pulse amplitude was low. The program includes additional useful features including a Bloch equations algorithm, and pulse scaling, to enable examination of pulse profiles under a variety of conditions such as RF inhomogeneity and even nuclear relaxation. The program, MATPULSE, was developed with the MATLAB for Windows programming language and makes extensive use of the MATLAB graphical user interface (GUI) features to generate a user-friendly interface. A number of examples are provided to illustrate the capabilities of the MATPULSE program. PMID- 7854028 TI - Proton spectroscopy of human stroke: assessment of transverse relaxation times and partial volume effects in single volume steam MRS. AB - Proton T2 relaxation times were measured in 13 stroke patients and 13 aged matched normal subjects at 2.1 T. Spectra were acquired from an 8-cc volume using the STEAM sequence with echo times (TE) of 30.4 ms and 270.0 ms and repetition time of 2.8 s. Transverse relaxation times were estimated using two-point calculations. Percentage volume of infarct in the STEAM voxel was measured on spin-echo MRI encompassing the infarct and correlated with the peak amplitude of N-acetylated compounds (NA). T2 values of NA, creatine, and choline resonances showed no significant difference between patients and controls. T2 for lactate in patients was 780 +/- 257 ms, respectively (mean +/- SE, n = 7). In stroke patients, high inverse correlation was found between the absolute NA signal and partial volume of normal brain contributing to each spectrum (p < .001, r = 0.97). Together with unchanged T2, this suggests that NAA largely disappears from infarcted tissue within 24 hr postinfarct. PMID- 7854029 TI - MR-visible water content in human brain: a proton MRS study. AB - In vivo measurement of metabolite concentrations in the human brain by means of proton-MRS contributes significantly to the clinical evaluation of patients with diseases of the brain. The fully relaxed water signal has been proposed as an internal standard for calibration of the MRS measurements. The major drawbacks are the necessity to make the assumptions that the water concentrations in the brain and that all tissue water is MR-visible. A number of in vivo measurements were carried out to estimate the concentration of MR-visible water in the brain of healthy volunteers divided into four age groups: newborn (0-23 days), adolescents (10-15 yr), adults (22-28 yr), and elderly people (60-74 yr). The examinations were carried out using a Siemens Helicon SP 63/84 MR-scanner operating at 1.5 T. Except for the newborn, four regions were studied in each subject using stimulated echo (STEAM) sequences without water suppression. In vitro measurements on a standard phantom were used for calibration. The calculated water concentrations ranged between 35.8 and 39.6 (mean 36.9) mol.[kg wet weight]-1 in the three groups, whereas it was 51.5 mol.[kg wet weight]-1 in the newborn, p < .01. The observed water concentration of neither the four regions nor of the three oldest age groups were significantly different. Comparisons between the water concentrations measured and those expected based on estimation of the content of grey and white matter in the region of interest from T1-weighted images and biochemical data published, suggest that only a small fraction (< 5%) of the tissue water may be MR-invisible.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7854030 TI - In vivo proton magnetic resonance spectroscopy of alcohol in rhesus monkey brain. AB - Brain alcohol was measured in rhesus monkeys (Macaca mulatta) by proton magnetic resonance spectroscopy (MRS) following acute nasogastric alcohol administration (0.8 g/kg). Monkeys were anesthetized with ketamine and xylazine. A 1.5 T whole body imager and a 3-inch surface coil were used to acquire TE 30 and 270 ms spectra from a 7.5 cc voxel localized with a stimulated echo (STEAM) sequence. Venous blood samples were collected during spectral acquisitions for gas chromatographic determination of temporally concordant blood alcohol levels (BALs). Acute alcohol administration did not alter the resonance areas of N acetylaspartate/N-acetyl containing compounds (NAA), choline containing compounds, or total creatine. The NAA resonance was used as an internal standard to calculate approximate brain alcohol concentrations, which averaged 27 +/- 3% and 27 +/- 8% of temporally concordant BALs (T2-corrected TE 30 and TE 270 ms spectra, respectively). In addition to reconfirming results from prior studies finding incomplete detection of brain alcohol with MRS, these results demonstrate the feasibility of measuring brain alcohol in anesthetized nonhuman primates to examine relationships between alcohol exposure history and MRS-visibility of brain alcohol. PMID- 7854031 TI - Pulse sequence design for MR velocity mapping of complex flow: notes on the necessity of low echo times. AB - Lowering of the echo time (TE) has been proposed as a way to reduce effects of phase dispersion in MR velocity mapping, because a low TE reduces sensitivity to higher-order motion terms while first-order velocity sensitivity is maintained. Methods of lowering TE involves the use of extreme gradient ramp times and gradient strengths as well as reduction of the duration of transmit/receive windows, the latter method causing decrements in image resolution. When reducing higher-order sensitivity, however, it is not the overall TE that is the critical parameter, but rather the time pattern of the gradients used in the experiment. Hence, changes in TE without subsequent variations in gradient pattern would, according to theory, not affect quantitative measurements of complex flow and vice versa. In this study, we experimentally demonstrate this relation and utilize the experience to create a sequence robust towards complex flow without sacrifices in image resolution. Our experimental observations show that variations in TE alone while maintaining the time course of the velocity-encoding gradient does not significantly affect measurements of through-plane average complex flow in the studied velocity range. A parameter that cannot be measured as accurately if TE is increased is the peak flow. A phase mapping sequence with prolonged TE from 3 ms to 5 ms but with short duration of the velocity-encoding (section-selective) gradient and improved in-plane resolution was demonstrated in vivo. PMID- 7854032 TI - Cavernous hemangioma of the adrenal gland: MR findings. AB - Adrenal hemangioma is considered a rare tumor and is pathologically similar to hemangiomas found elsewhere in the body. Magnetic resonance imaging (MRI) findings thought to be highly suggestive of this neoplasm are presented. Correlation with pathologic findings in this case, as well as imaging and pathologic findings in other reported cases, is provided. PMID- 7854033 TI - Brain abscess observed by localized proton magnetic resonance spectroscopy. AB - We encountered a case of brain abscess that was difficult to differentiate from glioblastoma. Localized 1H-MRS was found to be useful for obtaining information on the biochemical status of brain abscess. The peak of lipid and high residual peak of NAA (N-acetyl-aspartate) were observed in the cystic lesion of the brain abscess by 1H-MRS. The NAA/Cho (Choline-containing compounds) ratio in brain parenchyma showing an edematous lesion before therapy gradually increased with the relief of inflammation. PMID- 7854034 TI - Detection of viable myocardium in segments with fixed defects on thaillium-201 scintigraphy: usefulness of magnetic resonance imaging early after acute myocardial infarction. PMID- 7854035 TI - Modifications of glial metabolism of glutamate after serotonergic neuron degeneration in the hippocampus of the rat. AB - We have investigated the role of serotonergic neurons on the astrocytes catabolism of glutamate by analyzing glutamine synthetase (GS) and glutamate dehydrogenase (GDH) expression in the hippocampus after the degeneration of serotonergic neurons by a specific neurotoxin (5,7-DHT). 5,7-DHT caused reactive gliosis with hypertrophy (increase in glial fibrillary acidic protein (GFAP) expression) but not proliferation of astrocytes. Glutamate metabolism appeared preferentially regulated by a control of GDH expression rather than GS since the expression of GDH was specifically and significantly induced in the hippocampus whereas the level of GS remained unchanged. The inhibition of serotonin synthesis (by para-chlorophenylalanine (p-CPA) administration) produced no significant increase of GDH level. This suggests that serotonin is not the principal factor involved in this control of GDH expression. PMID- 7854036 TI - Persistent reduction of immediate early gene mRNA in rat forebrain following single or multiple doses of cocaine. AB - Stimulus-induced expression of immediate early genes (IEGs) is believed to be involved in the transduction of extracellular stimuli into prolonged modifications of cellular function. Previous studies have demonstrated that the IEGs NGFI-A (zif268) and c-fos are each rapidly induced in the caudate putamen (CP) by treatment with the indirect dopamine agonist cocaine. The short-term course of this induction has been well studied. However, the consequences of cocaine use are not limited to immediate pharmacological effects. Withdrawal, especially from prolonged or repeated use, can produce extended physiological and behavioral changes. At the cellular level, these longer-term effects may be mediated by or reflected in changes in the expression of IEGs. For this reason, we have investigated long-term perturbations in IEG expression during withdrawal from intravenously (IV) or intraperitoneally (IP) administered cocaine. Levels of NGFI-A and c-fos were measured in the CP of rats by Northern blot analysis, which confirmed that cocaine-induced increases of NGFI-A and c-fos mRNA lasts for several hours after drug administration. Immediately following this induction, however, there is a prolonged period during which a marked reduction in the relative amount of mRNA for both NGFI-A and c-fos is observed in cocaine-treated animals when compared to matched, vehicle-treated controls. This repression persisted for several hours after a single injection and as long as several days following multiple injections, strongly suggesting a cumulative effect for repeated exposures.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7854037 TI - Microtubule-associated protein MAP1B showing a fetal phosphorylation pattern is present in sites of neurofibrillary degeneration in brains of Alzheimer's disease patients. AB - Alzheimer's disease results in the appearance of cytoskeletal disorders yielding pathological structures such a neurofibrillary tangles or dystrophic neurites. It has been previously described that the microtubule-associated protein, tau, modified by phosphorylation in serines adjacent to prolines, is a major component of these structures. Here, we show that another microtubule associated protein, MAP1B, aberrantly phosphorylated by a proline-dependent protein kinase, is a component of these previously mentioned structures. Thus, a possible common phosphorylation of axonal MAPs such as tau or MAP1B may correlate with their association with those aberrant cytoskeletal structures present in AD. PMID- 7854038 TI - Effects of modafinil-induced wakefulness on glutamine synthetase regulation in the rat brain. AB - Changes in the level of glutamine synthetase (GS), an enzyme chiefly found in glial cells, were investigated in the brains of rats treated with modafinil, an awakening drug interfering with central catecholamine function. Two hours (waking period) and 7 h (recovery period) after intra-peritoneal injection of 128 mg/kg modafinil, a significant increase in the level of GS protein was observed by immunotitration in both the locus coeruleus (+30%) and in the frontoparietal cortex (+50%). No changes were observed with 64 mg/kg of modafinil. GS mRNA was quantified in the entire cortex by Northern blot hybridization using an oligonucleotidic GS cDNA probe. A significant increase in the GS-mRNA level (+70%) was observed in the CX of rats 2 h after injection of 128 mg/kg modafinil; the level tended to return to control values 7 h later during the recovery period. The level of glial acid fibrillary protein (GFAP), an astroglial marker, was unchanged after modafinil treatment. These changes in GS levels after modafinil treatment are discussed in terms of neuron-glia interactions in the regulation of brain metabolism during pharmacologically induced wakefulness, excluding possible stress effects. PMID- 7854039 TI - Effects of adrenalectomy and type I or type II glucocorticoid receptor activation on AVP and CRH mRNA in the rat hypothalamus. AB - The brain contains two types of adrenal steroid receptors, which play a role in mediating adrenal steroid effects on neuropeptide and other types of gene expression in discrete brain regions. Because the paraventricular nuclei of the hypothalamus (PVN) have adrenal steroid-sensitive neuropeptide systems, they provide a bench-mark to assess the doses of receptor agonists that may act selectively via Type I and Type II receptors. In the present study, in situ hybridization histochemistry was used to examine the effects of adrenalectomy (ADX) and Type I and Type II receptor agonists on arginine vasopressin (AVP) mRNA and corticotropin-releasing hormone (CRH) mRNA in rat brain. In agreement with previous reports, adrenal steroid regulation of AVP and CRH mRNA was found to be mediated primarily through the Type II receptor. Furthermore, adrenalectomy significantly increased AVP mRNA in the parvocellular region of the hypothalamic paraventricular nucleus (PVN), and systemic administration of the specific Type II agonist, RU28362 (10 micrograms/microliters/h), as well as corticosterone (CORT) pellets of 50 and 300 mg, prevented this increase. CRH mRNA was not significantly increased after ADX, but was markedly decreased in the PVN of rats receiving either RU28362 or a 300 mg pellet of CORT. Aldosterone, a specific Type I agonist, did not significantly affect either AVP or CRH mRNA levels when administered at 10 micrograms/h. Moreover, in the magnocellular regions of the PVN and SON AVP mRNA did not vary as a function of steroid manipulation.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7854040 TI - An in situ hybridization study on interleukin-1 beta mRNA induced by transient forebrain ischemia in the rat brain. AB - Expression of interleukin-1 beta (IL-1 beta) mRNA in the rat brain after transient forebrain ischemia was investigated by in situ hybridization histochemistry. Thirty min after the start of recirculation, IL-1 beta mRNA was induced in the several brain regions, including the olfactory bulb, cerebral cortex, hippocampus, striatum and thalamus where neuronal degeneration was reported to be observed after transient forebrain ischemia. The hybridization signals were observed both on the glial cells and around the vascular walls. PMID- 7854041 TI - Cloning and characterization of a pharmacologically distinct A1 adenosine receptor from guinea pig brain. AB - Three full-length cDNA clones encoding the guinea pig A1 adenosine receptor have been isolated by polymerase chain reaction (PCR) and low-stringency hybridization screening of a guinea pig brain cDNA library. These three cDNAs, though differing in their 5' untranslated regions, contain the same open reading frame encoding a 326 amino acid residue protein with seven hydrophobic alpha-helices long enough to form the transmembrane domains, suggesting that it belongs to the G protein coupled receptor superfamily. This protein is highly homologous to the A1 adenosine receptors previously cloned from other species. Pharmacological characterization of this receptor transiently expressed in mammalian cells demonstrates that, despite its high homology to A1 adenosine receptors of other species, the guinea pig A1 adenosine receptor displays a unique pharmacological profile: high affinity for the A1-selective antagonist CPX, yet very low affinity for some A1-selective agonists such as CCPA, CHA and R-PIA. Northern blotting for different guinea pig tissues and in situ hybridization for guinea pig brain sections reveal an abundant and broad distribution of mRNA of this A1 subtype receptor in the brain. PMID- 7854042 TI - Linear dimeric interleukin-2 obtained by the use of a defective herpes simplex viral vector: conformation-activity relationship. AB - An interleukin-2 dimer, produced enzymatically by a nerve-derived transglutaminase in vitro, is cytotoxic to oligodendrocytes, unlike the immune derived monomeric interleukin-2. The object of this study was to establish a way to produce a dimer of interleukin-2 in quantities, by means of genetic engineering, and to confirm that the structure of the resulting molecule is critical for its function. A defective herpes simplex virus vector was utilized for overproduction of a dimeric interleukin-2. The resulting linear dimer, which is a translational product, differs from the enzymatically produced dimer, which is a posttranslational modification of interleukin-2. The linear dimer, while retaining the known interleukin-2 activity of monomeric interleukin-2 with respect to mitogenicity on T cells, was not cytotoxic to oligodendrocytes. This finding suggests that the lack of cytotoxicity of the linear dimeric interleukin 2 is not caused by a loss of activity during its preparation but is related to its conformational structure, which evidently does not meet the requirements for cytotoxicity. This study opens the way to the design at the transcriptional level of modified proteins and their efficient production, provided that the new transcript encodes for the desired modification in the protein at the appropriate sites. PMID- 7854043 TI - Effects of an acute immobilization stress upon proopiomelanocortin (POMC) mRNA levels in the mediobasal hypothalamus: a quantitative in situ hybridization study. AB - The aim of this study was to examine by quantitative in situ hybridization the effects of an acute stress on the expression of the POMC gene in the mediobasal hypothalamus (MBH) of the rat. In control animals, the highest levels of POMC mRNA were observed in the posterior periventricular region of the MBH. Lower levels were found in the anterior and posterior arcuate nucleus. At the end of a one hour immobilization, a small decrease (-8%) was observed in the periventricular region only. Four hours after the end of immobilization, increases in POMC mRNA levels were detected in the anterior part (7%), in the posterior part (25%) and in the periventricular region (13%) of the MBH. These results suggest that MBH POMC-derived peptides might be an important component in the central response to stress. PMID- 7854044 TI - Expression of GAD mRNA in spinal cord neurons of normal and monoarthritic rats. AB - This study was carried out to investigate whether the increase of GABA levels in spinal cord dorsal horn in response to chronic inflammatory lesions results from an enhanced expression of the gene that governs the production of glutamate decarboxylase (GAD), the enzyme responsible for GABA synthesis. In situ hybridization was used to visualize neurons expressing GAD mRNA within the spinal cord, in both intact rats and in animals bearing chronic monoarthritis induced by intraarticular injection of complete Freund's adjuvant. In control normal animals, neuronal labeling by an antisense oligonucleotide probe occurred throughout the spinal gray matter, except in the motoneuronal pool of Rexed's lamina IX. In treated animals 4 days after the induction of monoarthritis, a significant increase in the number of labeled cells occurred in the superficial laminae (25.3%) and the neck (17.2%) of the ipsilateral dorsal horn at segments L4-L5 which contain the projection domain of the ankle joint. At 2 weeks, values were, respectively, 20.2% and 13.9% over contralateral values, and an increase of 12.4% was found in the ventral horn. At 3 weeks, the ipsilateral increase of labeled cells was restricted to the superficial dorsal horn (15.2%). These findings emphasize the role played by the spinal GABAergic system in the modulation of chronic nociceptive input. It is suggested that the response of the spinal GABAergic system depends on the activation of GAD gene transcription in spinal neurons. PMID- 7854045 TI - Enhancer trapping by a human mid-sized neurofilament transgene reveals unexpected patterns of neuronal enhancer activity. AB - In ten transgenic lines, expression of a human mid-sized (M) neurofilament (NF) transgene was restricted to neurons in the central and peripheral nervous systems. However, no two lines gave identical expression patterns and none exactly matched the expression of mouse NF(M). These varied expression patterns within the neural compartment likely result from interactions of the transgene with enhancer elements located in the regions flanking the insertion site. Unexpected patterns of enhancer activity included an enhancer active in subsets of cerebellar basket cells as well as others preferentially active in subsets of motor or sensory neurons. PMID- 7854046 TI - Agonist administration in ovo down-regulates cerebellar GABAA receptors in the chick embryo. AB - Chick embryos with an undeveloped blood-brain barrier were used to examine the down-regulation of GABAA receptors in vivo. The GABAA receptor agonist isoguvacine (5 mumol) was applied to the vascularized chorioallantoic membrane of 8 day embryos. This treatment was repeated on embryonic days 11, 14, and 17, and the embryos were sacrificed on day 18 (stage 42). Isoguvacine administration reduced the clonazepam-displaceable binding of [3H]flunitrazepam to washed cerebellar membranes by 34.0 +/- 3.0% compared to vehicle-treated controls. Binding reductions of lower magnitude were found in membranes from the cerebrum and optic lobes. Administration of isoguvacine had no significant effect on the wet weights of whole embryos or cerebella, the yield of cerebellar membranes, or the binding of [3H]N-methylscopolamine. The reduction of [3H]flunitrazepam binding to cerebellar membranes was dose-dependent, allowing a half saturation value of 8 microM isoguvacine to be estimated. Scatchard analysis showed that the Bmax for [3H]flunitrazepam binding was reduced by 28.3 +/- 6.7% compared to controls, without a change in the Kd. Embryonic exposure to isoguvacine also caused a reduction of 43.6 +/- 6.0% in the binding of the GABAA receptor channel ligand [35S]t-butylbicyclophosphorothionate to washed cerebellar membranes. Taken together, these results indicate that isoguvacine induces a down-regulation of the receptor subunits in vivo. However, measurements of cerebellar GABAA receptor mRNAs for the alpha 1, beta 2L, beta 2S, beta 4, gamma 1, gamma 2L, and gamma 2S subunits by reverse transcriptase-polymerase chain reaction (RT-PCR) revealed no significant alterations by isoguvacine administration. The data suggest that translational or post-translational mechanisms, rather than those modulating the synthesis or stability of subunit mRNAs, take precedence in establishing GABAA receptor down-regulation. PMID- 7854047 TI - Differential expression of sgk mRNA, a member of the Ser/Thr protein kinase gene family, in rat brain after CNS injury. AB - We cloned genes the expression of which were induced 3 days after cortical injury of rat brain by a differential display technique, and four novel and known sequences were isolated. Among these sequences, the sgk gene which was recently identified as a novel member of the serine/threonine protein kinase gene family, was selected for analysis of its expression patterns in rat brain by northern blotting and in situ hybridization, because hybridization signals were strong at the lesion sites. Expression of sgk mRNA was induced within 3 days after injury, and was maintained at a high level for at least 14 days. The cells which strongly expressed the sgk gene were in the deep layers of the cortex and in the corpus callosum. In situ hybridization analysis for sgk and myelin proteolipid protein mRNA using serial sections showed that the distribution of both signals was very similar at the damaged regions. Therefore, it is likely that the sgk transcript is expressed by oligodendrocytes after brain injury. Investigation of the developmental expression of the sgk gene showed that neurons in layers I and II of the cortex, lateroposterior and laterodorsal thalamic nucleus, and ventral posterolateral and posteromedial thalamic nucleus strongly expressed sgk mRNA at postnatal day 1 and day 7, but these neurons showed no expression in fetal or adult brain. These results suggest that the induction of sgk gene may be associated with a series of axonal regenerations after brain injury, and in addition, the sgk gene may also play important roles in the development of particular groups of neurons in the postnatal brain. PMID- 7854048 TI - Molecular cloning of a gene under control of the circadian clock and light in the rodent SCN. AB - We recently found a mouse unusual per repeat genomic gene showing circadian expression in the suprachiasmatic nucleus (SCN) of rat brain. As an initial step to the better understanding of biological functions of mammalian per repeat family, we isolated a new cDNA clone that encodes for the putative open reading frame of 133 amino acids, designating as mp41, having a per repeat sequence of (ACAGC)32 which lacks one base pair from a mouse unusual per repeat sequence (ACAGGC)n. In situ hybridization showed that the mRNA of mp41 gene expression is detected in the rat pancreas, uterus, ovary, liver, adrenal glands, kidney, intestine, spleen and brain. In brain, daily fluctuations of mp41 mRNA levels were found in the SCN under light and dark cycles--high during the day time and lower during the night time, even in constant darkness for 15 days. After exposing rats to light, mp41 mRNA increased only during the subjective night of the circadian cycle when light also induced the c-fos mRNA expression in the SCN. These results suggest that the transcriptional control of mp41 gene is regulated by light and a circadian clock and indicate that mp41 is a new marker gene for a cycling transcript in the SCN. PMID- 7854049 TI - Cytotoxicity mediated by conditional expression of a carboxyl-terminal derivative of the beta-amyloid precursor protein. AB - The beta amyloid peptide which accumulates within the brains of patients with Alzheimer's disease (AD) is proteolytically derived from a precursor protein (beta PP). We established and characterized four stably transformed human neuroblastoma cell lines which conditionally expressed a partial beta PP fusion protein (amino-17 residues+carboxyl-99 residues; S beta C). Conditional expression of S beta C was achieved using a tetracycline-responsive promoter system. Expression of this fusion protein in one of the cell lines resulted in pronounced cytotoxicity. Addition of n6,O2'-dibutyryl adenosine 3',5'-cyclic monophosphate and/or fetal bovine serum to the culture medium of this cell line further elevated the level of S beta C expression and enhanced the associated cytotoxicity. Conditioned medium, acquired from cells expressing S beta C, was not cytotoxic. These findings suggest that modulation of beta PP expression and/or metabolism can have cytotoxic consequences. This is the first report of cytotoxic effects mediated by conditional expression of a beta PP derivative. This immortal cell line provides a unique opportunity to screen for complementary DNAs which suppress this toxicity. Such cDNAs could help elucidate the processes underlying S beta C mediated cytotoxicity which in turn could further our understanding of the pathogenesis of AD and could also provide additional candidate genes for various forms of familial AD. PMID- 7854050 TI - Four repeat MAP2 isoforms in human and rat brain. AB - In mammalian brain, variations in the primary structure of the characterized microtubule-associated protein 2 (MAP2) isoforms have only been observed in their projection domains whose length determines the spacing between neighboring microtubules. We now report that, as with MAP4 and tau, MAP2 isoforms containing four (4R) instead of three (3R) tandem repeats in their microtubule binding domains do exist in human and rat brain. The additional sequence, inserted between the first and second repeat of the 3R-MAP2 messages, appears on mRNAs encoding both high and low molecular weight (Hwt and Lwt) rat MAP2 variants. In contrast to the corresponding 3R-messages, 4R-Hwt MAP2 concentrations decrease during early postnatal rat brain development, while the amount of 4R-Lwt MAP2 messages remains constant. In general, 4R-/3R-MAP2 mRNA ratios appear to be low with the highest levels of 4R-messages found in the cerebellum. PMID- 7854051 TI - Alternate 5' exons in the rat brain-derived neurotrophic factor gene: differential patterns of expression across brain regions. AB - Brain-derived neurotrophic factor (BDNF) enhances the survival of dopaminergic neurons and protects them from neurotoxins in vitro. This trophic factor might thus be of therapeutic value for the treatment of Parkinsonian syndromes. The rat BDNF gene consists of several upstream noncoding exons that are alternatively spliced to a common coding exon. To investigate BDNF 5' exons expressed in the adult rat brain, we subjected RNA from cerebellum to 5'-RACE analysis and compared the resulting clones to previously reported 5' exon sequences from rat brain and hippocampus. In addition to known 5' exons, we isolated a BDNF transcript with a novel 5' sequence representing yet another alternate upstream exon in this gene. Quantitative PCR analysis of BDNF mRNAs containing each of the five upstream exons indicated that each of the alternate transcripts is most abundant in the hippocampus, intermediate in the substantia nigra and cerebellum and least abundant in the striatum. However, the magnitude of these differences in expression varied considerably suggesting that BDNF gene transcription in the mature brain is regulated by alternate promoters that are differentially active across regions. PMID- 7854052 TI - Organization of the mouse 5-HT3 receptor gene and functional expression of two splice variants. AB - The structure of the mouse 5-HT3 receptor gene, 5-HT3R-A, is most similar to nicotinic acetylcholine receptor (nAChR) genes, in particular to the gene encoding the neuronal nAChR subunit alpha 7. These genes share among other things the location of three adjacent introns, suggesting that 5-HT3R-A and nAChR genes arose from a common precursor gene. The alternative use of two adjacent splice acceptor sites in intron 8 creates, in addition to the original 5-HT3R-A cDNA (5 HT3R-AL), a shorter isoform (5-HT3R-AS) which lacks six codons in the segment that translates into the major intracellular domain. This splice consensus sequence is not found in human genomic DNA. In mouse, we demonstrate by RNAse protection assay that 5-HT3R-AS mRNA is approximately 5 times more abundant than 5-HT3R-AL mRNA in both neuroblastoma cell lines and neuronal tissues. We used the Semliki Forest virus expression system for electrophysiological characterization of 5-HT3R-AS and 5-HT3R-AL in mammalian cells. No differences in electrophysiological characteristics, such as voltage dependence, desensitization kinetics, or unitary conductance were found between homomeric 5-HT3R-AS and 5 HT3R-AL receptors. Their properties are very similar to those of 5-HT3 receptors in mouse neuroblastoma cell lines. PMID- 7854053 TI - Postnatal handling alters glucocorticoid, but not mineralocorticoid messenger RNA expression in the hippocampus of adult rats. AB - Postnatal handling alters hypothalamic-pituitary-adrenal (HPA) responses to stress in the rat. Handling also increases hippocampal glucocorticoid receptor density, and this effect appears to form, in part at least, the basis for the effect of handling on HPA responsiveness to stress. In the present study we have used in situ hybridization techniques to examine the effect of postnatal handling on the expression of glucocorticoid and mineralocorticoid receptor mRNAs in various cell fields of the dorsal hippocampus in adult rats. Grain counting analysis over individual cells showed that postnatal handling significantly increased (40-50%) glucocorticoid receptor mRNA in all hippocampal cell fields. In contrast, handling had no effect on mineralocorticoid receptor mRNA expression. These findings are consistent with the results of receptor binding studies showing that handling increases hippocampal glucocorticoid receptor, but not mineralocorticoid receptor density. Thus, the increase in glucocorticoid receptor binding in handled animals is likely associated with altered rates of receptor biosynthesis. Moreover, the handling effect is quite specific, altering glucocorticoid receptor, but not mineralocorticoid receptor mRNA expression. The mechanism(s) whereby glucocorticoid receptor gene expression is permanently increased by postnatal handling remains to be determined. PMID- 7854054 TI - Coexpression of c-fos and hsp70 mRNAs in gerbil brain after ischemia: induction threshold, distribution and time course evaluated by in situ hybridization. AB - Levels of mRNAs encoding the proto-oncogene, c-fos, and the 70 kDa stress protein, hsp70, were evaluated in gerbil brain following transient cerebral ischemia of varied duration by in situ and blot hybridization techniques. Blots of total hippocampal RNA obtained after 5 min ischemic insults confirmed a characteristic, transient time course of c-fos expression with a striking elevation within 1 h and a return to control levels by 3 h recirculation. Hsp70 hybridization was significant at 1 h and continued to increase until 3-6 h after the insult. Striking accumulation of c-fos mRNA was detected within 15 min recirculation in dentate granule cells, persisting through 1 h, and a weaker signal was evident in CA1 and CA3 pyramidal neurons of hippocampus, as well as in prepiriform/entorhinal cortex and neocortical regions, during the same interval. Hsp70 hybridization showed an identical distribution at 1 h recirculation. Ischemic insults of 1 min duration resulted in no detectable increase of either mRNA, while 2 min ischemia resulted in changes comparable to those seen after 5 min insults. This common threshold corresponds to the ischemic interval required for energy depletion and resultant failure of intracellular ion homeostasis. In contrast, expression of hsp70 mRNA was not observed under conditions of brief depolarization accompanying cortical or hippocampal spreading depression that were shown to induce c-fos. A delayed component of c-fos mRNA expression was not detected in this model, while persistent hsp70 hybridization, restricted to hippocampal CA1 neurons, was evident at 48 h after either 2 min or 5 min ischemic insults. The parallels in c-fos and hsp70 mRNA expression during early recirculation suggest that overlapping mechanisms triggered following postischemic depolarization contribute to their induction after transient ischemia. PMID- 7854055 TI - The transcription factor CREB is not phosphorylated at serine 133 in axotomized neurons: implications for the expression of AP-1 proteins. AB - The present study has investigated whether nerve fiber transection alters the phosphorylation of serine at position 133 (Ser133) of the transcription factor CREB (phosphoCREB). Activation of CREB by phosphorylation has a major function in the control of gene transcription. PhosphoCREB was visualized by antisera that specifically react with an epitope comprising the phosphorylated Ser133 of CREB as well as of CREM and ATF1 proteins. In untreated rats, nuclear immunoreactivity (IR) of phosphoCREB was consistently visible, e.g. in the cortex, thalamic and hypothalamic compartments and central termination areas of primary somatosensory afferents. Transection of peripheral (sciatic nerve), cranial (hypoglossal and facial nerve) and central (medial forebrain bundle and mammillo-thalamic tract) nerve fibers did not increase phosphoCREB-IR in the axotomized neurons between 5 min and 30 days post-axotomy. In contrast, phosphoCREB-IR appeared after 24 h in glial cells adjacent to the axotomized motoneurons and persisted up to 4 weeks. This increase in glial phosphoCREB-IR was paralleled by enhanced expression of the CREB protein itself. Between 20 min and 24 h following sciatic nerve transection, the number of phosphoCREB labeled nuclei also increased in neurons of the ipsilateral superficial dorsal horn of lumbar L3-L5 spinal cord segments. These data suggest that phosphorylation of Ser133 in CREB/CREM/ATF1 proteins is not involved in the transcriptional control of early-response genes such as c-jun in axotomized neurons following nerve transection. This is in contrast to the reported phosphorylation of CREB and its trans-acting effects on immediate-early genes such as c-fos after transynaptic neuronal excitation. PMID- 7854056 TI - Expression of the growth-associated protein B-50/GAP43 via a defective herpes simplex virus vector results in profound morphological changes in non-neuronal cells. AB - This study describes the creation and application of a defective herpes simplex viral (HSV) vector for B-50/GAP-43, a neural growth-associated phosphoprotein. We demonstrate abundant expression of B-50/GAP-43 in cultured non-neuronal cells (African green monkey kidney cells [vero cells] and Rabbit skin cells) via this HSV vector. When B-50/GAP-43 was expressed in non-neuronal cells major morphological changes occurred that included extensive membrane ruffling, the formation of filopodia and long thin extensions reminiscent of neurites. These extensions often terminated in growth cone-like structures. Quantitation of these morphological changes at different times following infection demonstrates that the surface area of the B-50/GAP-43-expressing cells started to increase between 6 and 10 h post-infection. At 72 h, B-50/GAP-43-positive cells were 3.0 times larger in size and one third of the cells expressed long processes with a mean length of 165 +/- 14.5 microns. Ultrastructural studies of cells 48 h after infection revealed that B-50/GAP-43 is predominantly localized at the plasma membrane of the elaborated processes. Some immunoreactivity was associated with vesicular structures that appear to be in-transit in the processes. These observations suggest that B-50/GAP-43 acts at the plasmamembrane to induce a neuron-like morphology in non-neuronal cells persisting for several days in culture. In the future the defective viral vector will enable gene transfer to express B-50/GAP-43 in neurons in vivo in order to study its involvement in regenerative sprouting and neuroplasticity. PMID- 7854057 TI - Glucocorticoids and the expression of mRNAs for neurotrophins, their receptors and GAP-43 in the rat hippocampus. AB - The genes encoding brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT 3), and basic fibroblast growth factor (bFGF) are all expressed in the adult rat hippocampus. The colocalization of the these factors with the receptors to which they bind, namely trkB, trkC and the bFGF receptor, respectively, suggests that in the hippocampus they may exert their putative protective and trophic effects through an autocrine mechanism. The morphology and survival of hippocampal neurons are also affected by glucocorticoids, which can act as transcriptional activators of gene expression. In this study we have used in situ hybridization to investigate the adrenal steroid regulation of the mRNAs encoding the neurotrophic factors BDNF, NT-3, and bFGF, their respective receptors, and the growth-associated protein GAP-43. After 7 days of adrenalectomy (ADX), there was an increase in the level of GAP-43 mRNA expression in the CA1 and CA3 pyramidal cell layers of the hippocampus, that was prevented by corticosterone replacement to the ADX animals. In the CA2 subregion, adrenalectomy resulted in a decrease in bFGF mRNA expression, that was reversed by steroid treatment. There was evidence for glucocorticoid modulation of the BDNF and NT-3 mRNAs in pyramidal cell layers and in the dentate gyrus, but not of the mRNAs encoding the trkB, trk C or bFGF receptors. PMID- 7854058 TI - Vasopressin mRNA changes during kindling: the effects of kindling site and stage. AB - Because of the many anatomical and functional links to the limbic system, the neuroendocrine system is often affected by limbic disturbances. Limbic seizures in humans and animals alter neuroendocrine function and hormone levels. We have shown that in an animal model for partial seizures, the amygdala kindled rat, plasma vasopressin levels are elevated and a sustained increase in vasopressin (VP) mRNA follows stage 5 kindled seizures. In the present experiments we sought to determine when during the course of amygdala kindling the VP mRNA increase occurs and whether specific anatomical pathways mediate this increase. Animals kindled to early seizure stages (stages 1, 2 or 3) had no consistent increase in VP mRNA in the supraoptic nucleus (SON) while animals kindled to generalized seizures, stages 4 or 5, invariably had increased VP mRNA relative to controls. Electrical kindling to stage 5 seizures from two other brain sites, the dorsal hippocampus and the anterior olfactory nucleus, consistently resulted in a significant increase in VP mRNA one week after completing kindling. In all experiments the increase in VP mRNA in the SON showed no differences related to the side or proximity of the electrodes used for kindling. Measures of water balance did not change following kindling. These results indicate that kindled seizure generalization is a prerequisite for the long-term increase in VP mRNA. Furthermore, the VP mRNA increase appears to involve polysynaptic pathways accessible from different limbic kindling sites. These studies support the hypothesis that changes in mRNA regulation may contribute to the neuroendocrine pathophysiology accompanying limbic seizures. PMID- 7854059 TI - Forskolin stabilizes epsilon subunit-containing acetylcholine receptors. AB - Fetal muscle-like acetylcholine receptors (AChRs) are composed of alpha, beta, gamma, delta subunits (gamma-AChRs) and have a rapid half life (t1/2), whereas adult muscle-like AChRs are composed of alpha, beta, epsilon, delta subunits (epsilon-AChRs) and have a slow t1/2. Two populations of AChRs, a slowly degrading population and a rapidly degrading population, have been shown to coexist in the postsynaptic membrane after denervation [In: Penn et al. (Eds.), Myasthenia Gravis and Related Disorders, Vol. 681, NY Acad. Sci., 1993, pp. 155 164]. Treatment of rat myotubes or mouse diaphragm muscle in organ culture with forskolin or cAMP analogues causes and increase in the t1/2 of the slowly degrading population of AChRs with no apparent effect on the rapidly degrading population of AChRs19. In this study, we have investigated the effect of forskolin on the cell surface half-lives of mouse gamma-AChRs, epsilon-AChRs and alpha beta delta complexes stably expressed in mouse fibroblasts. Forskolin had no significant effect on the t1/2 of gamma-AChRs or alpha beta delta complexes. The effect of forskolin on surface AChRs (alpha beta gamma delta) expressed in the C2 muscle cell line was similar to its effect on gamma-AChRs expressed in fibroblasts. In contrast, forskolin stabilized the epsilon-AChRs by approximately 2 fold. We show that the epsilon-subunit is phosphorylated in vivo, phosphorylation of epsilon increases with forskolin treatment, and the forskolin effect is reversible. Although the precise role of epsilon-subunit phosphorylation is yet to be determined, our results support the hypothesis that the slowly degrading population of AChRs consists of epsilon-AChRs and the rapidly degrading population of AChRs consists of gamma-AChRs. PMID- 7854060 TI - Analysis of the secretory glycoproteins of the subcommissural organ of the dogfish (Scyliorhinus canicula). AB - The subcomissural organ (SCO) is an ancient and conserved brain gland secreting glycoproteins into the cerebrospinal fluid which condense to form Reissner's fiber (RF). The SCO of an elasmobranch species, the dogfish Scyliorhinus canicula, was investigated applying morphological and biochemical methods. The SCO of 34 dogfishes were processed for the following techniques: (1) conventional transmission electron microscopy; (2) light and electron microscopy lectin histochemistry (Concanavalin A, Con A; wheat germ agglutinin, WGA; Limax flavus agglutinin, LFA); (3) light and electron microscopy immunocytochemistry using antisera raised against the glycoproteins of the bovine RF (anti-bovine RF), and the secretory material of the dogfish SCO (anti-dogfish SCO). The former reacts with the SCO of virtually all vertebrate species [19] (conserved epitopes); the latter reacts only with the SCO of elasmobranchs [Cell Tissue Res., 276 (1994) 515-522] (class-specific epitopes). At the light microscopic level both antisera immunoreacted selectively with the SCO and RF; no other structure of the central nervous system was reactive. Within the SCO the binding sites for WGA (affinity = glucosamine, sialic acid) and LFA (affinity = sialic acid) displayed the same density and intracellular distribution. At the ultrastructural level two types of granules were distinguished. Type I granules (200-400 nm) were numerous, reacted with both antisera, bound WGA but not Con A. Type II granules (0.8-1.8 microns) reacted with the anti-bovine RF serum but not with the anti-dogfish SCO serum, bound Con A and WGA. The content of dilated cisternae of the rough endoplasmic reticulum reacted with both antisera and bound Con A; it did not bind WGA. The SCOs of 4500 dogfishes were extracted in ammonium bicarbonate. This extract was used for SDS-PAGE and blotting. Blots were processed for immunolabeling using anti-bovine RF and anti-dogfish SCO sera, and for lectin binding (Con A, WGA and LFA). The anti-bovine RF revealed four compounds with apparent molecular weights of 750, 380, 145 and 35 kDa. The two former also reacted with the anti-dogfish SCO serum and bound Con A. Only the 380 kDa compound bound WGA and LFA. The findings indicate that both the conserved and the class-specific epitopes are part of the same compounds (780, 380 kDa), which would be stored in type I granules. The lectin binding properties of these compounds point to the 780 kDa compound as a precursor form and the 380 kDa polypeptide as a processed form. PMID- 7854062 TI - Peptide YY derivatives as selective neuropeptide Y/peptide YY Y1 and Y2 agonists devoided of activity for the Y3 receptor sub-type. AB - Peptide YY derivatives were evaluated for their respective ability to bind and activate the NPY/PYY receptor sub-types (Y1, Y2 and Y3) present in various preparations. The analogue [Leu31,Pro34]PYY demonstrated high (nM) affinity in rat frontoparietal cortical membrane preparations (Y1-enriched tissue) and the rabbit saphenous vein (Y1 in vitro bioassay) but only low affinity in a Y2 enriched preparation (rat hippocampus). In contrast, PYY C-terminal fragments such as PYY3-36 and PYY13-36 were more potent in Y2 than Y1 assays. Interestingly, and in contrast to [Leu31,Pro34]NPY and NPY13-36, the PYY derivatives [Leu31,Pro34]PYY and PYY3-36 were inactive in a purported Y3 bioassay (rat colon). These results suggest that [Leu31,Pro34]PYY and PYY3-36 respectively represent the first selective and potent Y1 and Y2 agonists, devoided of significant affinity/activity for the Y3 receptor class. PMID- 7854061 TI - Analysis of the hippocampal GABAA receptor system in kindled rats by autoradiographic and in situ hybridization techniques: contingent tolerance to carbamazepine. AB - Tolerance to the anticonvulsant effects of carbamazepine (CBZ) in the amygdala kindling paradigm is a contingent process, since it only develops in rats treated with CBZ before the kindling stimulation and not in those animals treated after the stimulation. The present study was designed to investigate the GABAA receptor system in CBZ contingent tolerance. Receptor autoradiography utilizing various radioligands that bind to different components of the GABAA receptor system and in situ hybridization with oligonucleotides that recognize different subunits of the GABAA receptor were performed. Kindling increased binding to benzodiazepine, picrotoxin, and GABA recognition sites selectively in the dentate gyrus of the hippocampus. Kindling also increased levels of mRNA for the alpha 4, beta 1, and beta 3 subunits but did not change alpha 1, alpha 2, or gamma 2 subunit levels. Rats tolerant to CBZ showed decreased [3H]muscimol binding, diazepam-insensitive [3H]Ro 15-4513 binding, and decreased alpha 4 subunit mRNA content compared to non-tolerant rats, whereas [3H]flunitrazepam binding, [35S]TBPS binding, and the levels of beta 1, and beta 3 subunit mRNAs remained elevated. The data suggest an indirect interaction of CBZ with the GABAA receptor system, since CBZ reportedly does not bind to this receptor system. PMID- 7854063 TI - Glial cell-line derived neurotrophic factor (GDNF) mRNA upregulation in striatum and cortical areas after pilocarpine-induced status epilepticus in rats. AB - Glial cell-line derived neurotrophic factor (GDNF) has recently been cloned and shown to have trophic effects on dopaminergic nigral neurons. However, GDNF mRNA has not been detected in striatum or other forebrain areas of adult rat. Using limbic motor status epilepticus induced by pilocarpine to activate neurons in motor and limbic areas, we now demonstrate GDNF mRNA signals in the striatum, hippocampus and cortex using in situ hybridisation. The finding of GDNF mRNA in the stimulated striatum opens the possibility that GDNF may be a target-derived, trophic factor in the nigro-striatal system. This expression of GDNF mRNA may be linked to excitatory cortical input. Increases in GDNF mRNA after status epilepticus in hippocampus and neocortex indicate additional roles for GDNF. PMID- 7854065 TI - Production of specific antibodies against GABA transporter subtypes (GAT1, GAT2, GAT3) and their application to immunocytochemistry. AB - Polyclonal subtype-specific antibodies were developed against three subtypes of GABA transporters (GAT1, GAT2 and GAT3). By immunoblot analysis, each antibody detected a single band that could be blocked by absorption of the antibody with the respective antigen. GAT2 was found in various tissues, while GAT1 and GAT3 were detected only in the brain. GAT1 was distributed throughout the brain with the highest amount in the olfactory bulb, CA3 region of the hippocampus, layer I of the cerebral cortex, piriform cortex, superior colliculus, interpeduncular nucleus and nucleus spinal tract of the trigeminal nerve, while the GAT3 was densely found in the olfactory bulb, thalamus, hypothalamus, pons and medulla, globus pallidus, central gray, substantia nigra, deep cerebellar nuclei and nucleus spinal tract of the trigeminal nerve but not in the hippocampus, cerebral cortex, caudate-putamen and cerebellar cortex. GAT2 immunoreactivity was faint throughout the brain but was concentrated in the arachnoid and ependymal cells. Both GAT1 and GAT3 were found in the neuropil but not in the cell bodies nor in the white matter. These results suggest that GAT1, GAT2 and GAT3 are expressed in different cells and that GAT1 and GAT3 are involved in distinct GABAergic transmission while GAT2 may be related to non-neuronal function. PMID- 7854064 TI - Localization of 63-kDa calmodulin-stimulated phosphodiesterase mRNA in the rat brain by in situ hybridization histochemistry. AB - We studied the localization of 63-kDa Ca2+/calmodulin stimulated phosphodiesterase mRNA in the rat brain by in situ hybridization histochemistry using an oligonucleotides probe specific to this enzyme. The signals were especially concentrated in several brain regions such as the olfactory tubercle, accumbens nucleus, caudate putamen, fundus striati, dentate gyrus of the hippocampus, pontine nuclei and dorsal tegmental nucleus. These results suggest that in the neuronal groups containing the strong signals this enzyme is involved in calcium-dependent signal transduction system coupled to cyclic nucleotides messenger systems. PMID- 7854066 TI - Cholinergic stimulation of skeletal muscle cells induces rapid immediate early gene expression: role of intracellular calcium. AB - Many properties of skeletal muscle are closely regulated by motor nerves. We have shown that nerve stimulation in vivo induced a rapid rise in mRNA for the immediate early gene (IEG) zif268 in stimulated muscle. However, the mechanisms leading to neural regulation of zif268 gene expression in muscle are not yet known. In this study, we used a mammalian skeletal muscle cell line (C2C12) to analyze the role of cholinergic transmission, and calcium flux, in the neural regulation of zif268. Treatment of the C2C12 muscle cells with carbachol, a cholinergic agonist, induced zif268 gene expression rapidly and transiently. This effect was blocked by alpha-bungarotoxin (alpha-BuTx), which specifically blocks nicotinic acetylcholine receptors. Treatment with ryanodine or dantrolene, which block the calcium release channel of the sarcoplasmic reticulum, inhibited the carbachol-induced zif268 response essentially completely. Calcium influx produced by A23187, a calcium ionophore, induced an increase of zif268 gene expression equivalent to the effect of carbachol stimulation. These results suggest that the effect of neural stimulation on zif268 may be attributable to cholinergic transmission, and the subsequent release of calcium from the sarcoplasmic reticulum. PMID- 7854067 TI - Upregulation of intercellular adhesion molecule 1 (ICAM-1) on brain microvascular endothelial cells in rat ischemic cortex. AB - The expression of intercellular adhesion molecule 1 (ICAM-1) was studied in rat focal ischemic cortex. A significant increase in ICAM-1 mRNA expression in the ischemic cortex over levels in contralateral (nonischemic) site was observed by means of Northern blot analysis following either permanent or temporary occlusion with reperfusion of the middle cerebral artery (PMCAO or MCAO with reperfusion) in spontaneously hypertensive rats. In the ischemic cortex, levels of ICAM-1 mRNA increased significantly at 3 h (2.6-fold, n = 3, P < 0.05), peaked at 6 to 12 h (6.0-fold, P < 0.01) and remained elevated up to 5 days (2.5-fold, P < 0.05) after PMCAO. The profile of ICAM-1 mRNA expression in the ischemic cortex following MCAO with reperfusion was similar to that following PMCAO, except that ICAM-1 mRNA was significantly increased as early as 1 h (6.3-fold, n = 3, P < 0.05) and then gradually reached a peak at 12 h (12-fold, P < 0.01) after reperfusion. ICAM-1 mRNA expression in ischemic cortex following PMCAO was significantly greater in hypertensive rats than in two normotensive rat strains. Immunostaining using anti-ICAM-1 antibodies indicated that upregulated ICAM-1 expression was localized to endothelial cells of intraparenchymal blood vessels in the ischemic but not contralateral cortex. The data suggest that an upregulation of ICAM-1 mRNA and protein on brain capillary endothelium may play an important role in leukocyte migration into ischemic brain tissue. PMID- 7854068 TI - Role of neuropeptide Y in the regulation of gonadotropin-releasing hormone gene expression in the rat preoptic area. AB - It is well documented that neuropeptide Y (NPY) is involved in the regulation of the hypothalamo-pituitary gonadal axis. In order to determine the influence of NPY on the biosynthesis of GnRH, we have studied the effects of NPY and some NPY analogs on GnRH gene expression in neurons in the male rat preoptic area (POA). The following peptides NPY, peptide YY (PYY), [Leu31,Pro34]NPY (a Y1 receptor agonist) and NPY13-36 (a Y2 receptor agonist) were injected into the left lateral ventricle of adult castrated male rats. In another series of experiments, the same peptides were administered intravenously (IV). All the animals were perfused with 4% paraformaldehyde 4 hours after injection. Cryostat sections through the POA were processed for quantitative in situ hybridization. The intracerebroventricular injection of PYY, NPY and [Leu31,Pro34]NPY induced a marked increase in the number of grains overlying the labelled neurons (20 to 45% over control). On the other hand, the Y2 receptor agonist NPY13-36 did not influence mRNA levels. Similar results were obtained following the i.v. administration although the magnitude of the stimulating effect was less important (12 to 20% over control). These data then strongly suggest that NPY positively regulates the genetic expression of GnRH in neurons via the Y1 NPY receptor subtype. PMID- 7854069 TI - Prenatal haloperidol induces a selective reduction in the expression of plasticity-related genes in neonate rat forebrain. AB - Haloperidol, a dopamine receptor antagonist clinically used as an antipsychotic drug, induces long-term deleterious effects in offspring development when administered prenatally. However, the basis for this overall response to the drug remains unknown. Here we describe that prenatal administration of haloperidol in rats induces a drastic and selective reduction in the expression of plasticity related genes in neonate forebrain, but not in mesencephalon. GABAergic and enkephalinergic markers such as glutamic acid decarboxylase activity and mRNA, and preproenkephalin mRNA were also diminished in forebrain. However, the expression of other genes such as epidermal growth factor-receptor, glial fibrillary acidic protein, and several proto-oncogenes (src, fos and myc), and a cholinergic marker such as choline acetyltransferase activity were unaltered. In addition, haloperidol promoted a significant decrease in mitotic cell number and cellular density in the striatum, one of the forebrain regions with the highest dopamine receptor density. These findings suggest that prenatal dopamine receptor occupancy may be a critical factor in controlling the development of forebrain target cells through mechanisms involving changes in the expression of plasticity related genes. PMID- 7854070 TI - An improved method detects differential NGF and BDNF gene expression in response to depolarization in cultured hippocampal neurons. AB - Differential regulation of individual neurotrophins by impulse activity potentially allows transformation of instantaneous signalling into diverse, long lasting neural alterations. To define the temporal profiles of trophin gene expression we examined nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) mRNAs in dissociated cell cultures of rat hippocampus using an improved solution hybridization technique. Traditional methods lack the precision and sensitivity to detect small changes during brief intervals and the facility to process large sample numbers simultaneously. This improved method has now allowed us to better define the dynamics of depolarization-induced changes in expression of individual trophin genes. Using elevated K+ as a depolarizing stimulus, NGF mRNA increased 40% after 48 h. In contrast, BDNF message rose almost 4-fold within 3 h and attained a maximal 6-fold increase within 6 h. Similar increases in BDNF mRNA levels were exhibited following treatment of cultures with glutamate, an excitatory neurotransmitter. To document the sensitivity of BDNF mRNA to depolarizing conditions, we examined expression after K+ withdrawal. BDNF message began decreasing within one hour post-depolarization, and returned to basal levels after 6 h. Observations indicate that BDNF and NGF mRNAs are induced differentially in response to impulse activity; BDNF message is acutely responsive to ongoing changes, whereas NGF mRNA responds more slowly and sluggishly. The physiological implications of this differential regulation are discussed. PMID- 7854071 TI - Differential regulation of the expression of nerve growth factor, brain-derived neurotrophic factor and neurotrophin-3 mRNAs in adult rat brain after intrahippocampal injection of quinolinic acid. AB - Intrahippocampal injection of the endogenous excitotoxin quinolinic acid (QUIN) induces seizures together with local, delayed neurodegeneration in specific cell layers. In situ hybridization histochemistry was used to study the spatio temporal pattern of expression of neurotrophins (NTFs) after this treatment. As in other excitatory paradigms, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) mRNA levels increased dramatically and transiently in dentate gyrus after the administration of 120 nmol of QUIN to the left hippocampus. BDNF, but not NGF, mRNA also increased in the hippocampal pyramidal cell layer, mainly in the CA1 field. Neurotrophin-3 (NT3) mRNA levels decreased in dentate gyrus, practically disappeared around 12 h after the insult and returned to basal levels four days later. A very different pattern of expression of NTFs was found locally: (a) upregulation of NGF and BDNF mRNAs expression was prevented in a spherical region of 1-2 mm diameter around the injection site, (b) a delayed increase in NT3 mRNA levels, beginning at 12 h and lasting for at least 4 days after the administration of QUIN, was found in the same region, in cell layers showing neurodegeneration. Pretreatment with the non-competitive NMDA antagonist MK-801 (2 mg/kg, 30 min before the insult), partially blocked the increase in both BDNF and NGF mRNAs, as well as the decrease in NT3, in the contralateral hippocampus. However, this treatment did not prevent the QUIN induced local downregulation of NGF and BDNF. Treatment with the AMPA/kainate antagonist NBQX (30 mg/kg, 15 and 5 min before, and 10 min after the insult) did not influence the effect of QUIN upon NGF or BDNF mRNA levels, although it partially prevented the hippocampal contralateral decrease in NT3 mRNA. In conclusion, the present study strongly supports previous work concerning different regulation of BDNF/NGF respect to NT3 in seizure inducing paradigms. Moreover, the different and to some extent opposite regulation of NTFs in the hippocampal region contiguous to the injection site, respect to the remaining hippocampus, suggests a differential regulation of NTFs in QUIN-induced neurodegenerative and seizural processes. Finally, our pharmacological data, (i) show that the upregulation of NGF and BDNF mRNAs, indirectly induced by QUIN, is not mediated by AMPA receptors, and (ii) suggest other effects for QUIN, apart from the stimulation of NMDA receptors. PMID- 7854072 TI - Developmental up-regulation and agonist-dependent down-regulation of GABAA receptor subunit mRNAs in chick cortical neurons. AB - We have used quantitative reverse transcriptase-polymerase chain reaction (RT PCR) to analyze the expression of GABAA receptor subunit genes in cultured neurons from the chick embryo cerebral cortex. During maturation of the neurons between day 2 and day 8 in culture, levels of the alpha 1 subunit transcript (per ng total RNA) increased 3.8 +/- 0.3 fold, while those for the beta 2S and beta 4S subunits increased 2.4 +/- 0.4 and 1.8 +/- 0.2 fold, respectively. The accumulation of the beta 4 S subunit mRNA was more rapid than those encoding either the alpha 1 or beta 2S polypeptides. After 4 days in culture the beta 4S subunit transcript level reached 105 +/- 7.7% of that found after 8 days, while the corresponding amounts for the alpha 1 and beta 2S subunit mRNAs were 50 +/- 7.1% and 44 +/- 10.7%, respectively. On the other hand, no significant differences were observed in the level of either the gamma 1 or the gamma 2S subunit mRNA during development in vitro. Likewise, the ratios of the large/small splice variants (beta 2 = 0.16 +/- 0.02; beta 4 = 0.57 +/- 0.02; gamma 2 = 0.30 +/- 0.06) did not show detectable changes during this period. To study the down regulation of the mRNAs, a single dose of 100 microM GABA was added to the culture medium. After 7 days of exposure to GABA, the levels of transcripts for the alpha 1, beta 2, beta 4, gamma 1, and gamma 2 subunits and their splice variants (where present) were all reduced by 47-65% compared to untreated controls.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7854073 TI - Copy-dependent and correct developmental expression of the human neurofilament heavy gene in transgenic mice. AB - We recently produced four lines of transgenic mice bearing a 34 kb DNA fragment that includes the human gene coding for the neurofilament heavy (NF-H) chain. Analysis of the NF-H transgenics revealed an increase in human NF-H mRNA and protein that parallels the increase in gene copy number, providing the first example of a transgene with copy-dependent expression in neurons. In addition, expression of the human NF-H transgene is induced post-natally following a developmental pattern similar to the endogenous mouse NF-H gene. PMID- 7854074 TI - Personal physician: an expert system designed for patients. PMID- 7854075 TI - A computer-administered health screening interview for hospital personnel. AB - We developed a computer-administered health screening interview for the employees of an urban teaching hospital. The interview is part of the integrated Center for Clinical Computing (CCC) clinical information system used throughout the hospital, and is available on any of 2000 terminals. Conducted in private and with protection of confidentiality, the interview seeks information on medical problems and patterns of living for which behavioral change is considered desirable. In a four-year period ending in May 1994, 1937 employees completed the interview. The results showed that stress and unhappiness were common: 57% of the employees reported high levels of stress, and 42% reported feeling sad, discouraged, or hopeless in the previous month; 6% indicated that life sometimes did not seem worth living. Eighty-six percent of the employees expressed an interest in the health-related programs offered by the hospital: 72% were interested in the fitness center, and 37% in the stress-reduction program. We conclude that if interactive health-promotion programs are easily available, they will be used and appreciated in the work place. The programs can be written to reveal the employees' health concerns and stimulate their interest in promoting their own health. PMID- 7854076 TI - Use of a standardized personal medical record by patients with hypertension: a randomized controlled prospective trial. AB - It is widely believed that patients' compliance can be increased by persuading them to participate in their own care. We tested whether patients with hypertension could manage their own clinical records and whether their doing so would affect the quality of their care. Two hundred patients were randomly assigned to an intervention or a control group. Those in the intervention group were asked to complete a 10-page booklet containing a personal standardized medical record. All patients were scheduled for a follow-up appointment at the end of one year and were referred to their general practitioners for interim care. At the end of the follow-up period, the proportion of patients seen was comparable in the two groups. More of the patients in the intervention group than in the control group filled out a questionnaire as requested, and more added comments. Within the intervention group, the proportion of patients seen and the fall in systolic blood pressure were significantly higher among the 44 patients who had completed the personal record as requested than among the 57 who had not. Patients who completed the personal record also had fewer compliance problems. PMID- 7854077 TI - Allocation of subjects in medical experiments. 1974. PMID- 7854078 TI - Implementation of a province-wide computerized network in Quebec: the FAMUS Project. AB - General practitioners have busy schedules and are accustomed to working autonomously. But they will take an interest in research issues that could increase their efficiency or improve patient care. The use of medical informatics tools to facilitate collaborative research networks requires that participants accept the tools. This article describes the implementation of a province-wide computing network and discusses the opportunities afforded by the creation of a large central database documenting the process of care. PMID- 7854079 TI - The science and ethics of the randomized clinical trial. PMID- 7854080 TI - International data standards for hospital-based drug surveillance. AB - A conference of leading pharmacoepidemiologists and experts in clinical computing has highlighted the need to support drug surveillance as an important component of automated patient care data. Citing shortcomings in existing systems, the participants made suggestions for improving the collection, storage, and compatibility of the data in hospital-based drug surveillance systems. This article describes the history and current status of this effort and may serve as a guide for others interested in international drug therapy standards. PMID- 7854082 TI - Another reason to go to Paris. PMID- 7854081 TI - An interactive computer system for formulary management using cost-effectiveness analysis. PMID- 7854083 TI - [Infective endocarditis and drug addiction]. AB - A total of 103 patients (P) with infectious endocarditis (IE) were treated during the period 1982-1993; 72% of them were male. Mean age was 46.4 (SD 19.7). Eighteen patients were intravenous drug addicts (D) (17.5%). The first case of drug addiction in the IE group was seen in 1986; since then, there was a steady increase of this condition, reaching 50% of all cases. The average age of D patients was 28.17 +/- 8.15 years significantly lower than that corresponding to non-drug addicts (ND), 48.64 +/- 19.5 (p < 0.00001). The infection was located mainly in the left heart of the ND (93%), and in the right heart of the D (78%), the difference being statistically significant. All the cases of left IE occurred on previously damaged valves. Right location in ND was found in all cases in immunosuppressed individuals being treated for systemic diseases, except in one patient having an endocavitary pacemaker. No differences were found between ND and D with regard to the presence of fever, cutaneous manifestations, splenomegaly or cerebrovascular accident. Differences were noted, however, in the case of respiratory involvement, which showed a significantly higher frequency in D (38.9% versus 12.9%; p < 0.014). Blood cultures were positive in 81.6% of the total number of patients, no difference being found between the two groups. Staphylococcal infections were predominant in D (44%) and streptococcal infections in ND (48%), the difference being statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7854085 TI - [Smoking habit questionnaire for outpatients]. AB - During September 1992, outpatients of a general hospital received questionnaire on medical smoking cessation advice and smoking habit assessment by a physician. The staff of the Internal Medicine Service were asked about the frequency of outpatient smoking habit assessment. Of 185 patients interviewed, 37% were smokers, 38.5% were ex-smokers and 24.5% had never smoked; 46% of smokers reported that they had been told to quit smoking by a physician. Those who smoked more cigarettes per day were more likely to have been advised to stop. Of ex smokers, 16% said that they had received medical aid for quitting. The frequency of smoking habit assessment was; in every physician-patient contact 20%, sometimes 36%, hardly ever 12% and 32% said that they were never questioned about smoking habits (Table 2). Those who reported to have been counseled to quit, were more likely to report smoking habit assessment (Table 3). Of physicians, 81% reported assessing routinely all ambulatory patients' smoking habit. Smoking prevalence among physicians was 43.3%, and 23.3% of them smoked in the office. These findings on the frequency of physicians' smoking advice are similar to those of Anda et al and Frank et al (Table 4). CONCLUSIONS: 1) physician's smoking cessation advice and smoking habits assessment reported by patients were low, 2) physicians report higher frequency of smoking habit assessment than patients, 3) physicians' smoking prevalence was higher than patients' prevalence. As a first approach to increase medical interventions against smoking, quitting programs directed to health personnel must be implemented. PMID- 7854084 TI - [Relative risk of hepatitis C virus transmission in polytransfused patients]. AB - Hepatitis C virus (HCV) has been shown to be responsible for a significant proportion of hepatitis cases among patients undergoing frequent blood transfusions. The prevalence in blood serum of anti-HCV antibodies was studied in 48 patients who had undergone dialysis and multiple blood transfusions. In 42 of these patients the average number of transfusions during their treatment was 11.2. The patients were stratified into four groups according to the number of transfusions received (I: < 5, II:6-9, III:10-15 and IV > 15). Odds ratios were used in order to estimate the probability of finding anti-HCV antibodies in groups II, III and IV in relation to the least exposed group I. Anti-HCV antibodies were found in 59% of patients receiving transfusions. As grouped by increasing number of transfusions, each set showed 16, 66, 62.5 and 100% presence of anti-HCV antibodies, respectively. This shows a direct correspondence between the number of transfusions and the serum-born incidence of anti-HCV antibodies. These results closely coincide with those of a similar study, done in the city of Cordoba, Argentina, in 1992. The two studies confirm the necessity to check blood units in order to discard those with anti-HCV antibodies. PMID- 7854086 TI - [Analysis of antihypertensive effectiveness by means of ambulatory blood pressure monitoring. Usefulness of the Discrete Fourier Transform Model]. AB - In order to assess the usefulness of the Discrete Fourier Transform Model (DFT) to evaluate time-course drug effects on hypertensive patients studied with Ambulatory Blood Pressure Monitoring (ABPM) a number of experiments were carried out. A total of 10 mild to moderate hypertensive patients were evaluated under placebo and after 8 weeks of active treatment with Enalapril 20 mg per day using ABPM. Systolic and Diastolic blood pressure (SBP and DBP) were registered every 15 minutes during daytime and every 30 minutes at night. Pressure profiles of each patient were initially smoothed by hourly means. DFT was then applied to these profiles. The minimum number of harmonics necessary to generate a statistically significant fitting of the blood pressure profile, were obtained by residuals analysis (run test and analysis of variance of the mean sum of residual squares with each new harmonic incorporated to the model). A profile of the blood pressure differences (treatment-placebo) with the rough data of each patient was smoothed by hourly means. DFT was applied again on these substraction profiles. To estimate peak and trough drug effects for the blood pressure decrease function, maximum, minimum and inflexion points were calculated defining the following parameters: T peak: time from drug administration to maximum pressure decrease; T late response: time from drug administration to the inflexion point following the last minimum previous to the next dose; BP peak: the maximum blood pressure decrease amplitude; and the slope BP peak/T peak. The stability of the individual circadian rhythm was confirmed for both ABPM controls comparing times of maximum and minimum on the DFT smoothed profiles.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7854087 TI - [Expression of p53 in gastric carcinoma. Prognostic value]. AB - P53 gene mutation has been described with variable frequency in gastric cancer and its biological significance remains unclear. We studied 101 gastric carcinomas to evaluate the association between this genetic alteration and the evolution of gastric cancer. Of these, 67 patients were men and 34 were women. The median age at diagnosis was 68 years. The tumors were obtained from gastrectomies. The p53 gene mutation was determined with the monoclonal antibody DO7 (Novocastra). The neoplasms were classified as tumors with high or low level p53 expression according to the intensity and distribution of the nuclear staining. Forty eight tumors showed high level of p53 immunoreactivity. The association of p53 expression with age, sex, tumor size, histologic type, histologic grade, depth of invasion, localization, lymph node metastases, type of surgery and 5 year survival rate was investigated. The results did not demonstrate any significant association between p53 expression and the factors mentioned above. PMID- 7854088 TI - [Hypothermic preservation of the liver. Evaluation of Eurocollins solution using rats liver slices]. AB - In the present work, we analyze the effects produced by cold ischemia on the liver using Eurocollins solution (EC). This evaluates the function of slices obtained from preserved livers in EC (livers from adult female Wistar rats were used), which were perfused with Krebs-Henseleit solution (KH) for 10 min. and then with cold EC. These livers were stored at 4 degrees C in EC for 7, 24 and 48 hours. At the end of each period of preservation, the livers were sliced and they were incubated 1 hour at 37 degrees C in KH. The following parameters were determined: tissular water distribution and electrolytes content (K+ and Na+), LDH release at the incubation medium, thiobarbituric acid reactive substances (TBARS) and urea synthesis. The slices obtained from preserved livers (7 hours), showed an increase of tissular water, expressed by the expansion of the extracellular space, a progressive diminution of tissular K+ content and an increase in TBARS and the LDH release with the increment of the preservation time. No changes in ureogenesis rate were observed. These results suggest that the cold ischemia in EC, in periods that exceed 5 hours, cause, changes in the membrane permeability and severely affects the mechanism of regulation of the tissular volume and may compromise the functional viability of the organ to be transplanted. PMID- 7854089 TI - [Effect of complement type 1 receptor pre-binding on the phagocytosis mediated by Fc receptor]. AB - As a result of IgG-Fc interaction, sheep erythrocytes sensitized with IgG (E-IgG) are constitutively phagocytosed by resting PMN, although in low numbers. The low efficiency of the system can be improved by opsonization with C3b, since the combination of C3b and IgG makes a powerful opsonic signal. It is accepted that the mechanism of C3b enhancement of IgG mediated phagocytosis is achieved by increasing the adherence of the targets to the phagocyte. Recently, a non-opsonic role for C3b enhancement of IgG mediated phagocytosis has been proposed, in cultured human monocytes. These cells, when adhered on glass surfaces precoated with C3b, showed a marked increase in E-IgG internalization. The effect was dose dependent and it was reproduced utilizing a monoclonal antibody against CR1 (C3b receptor). In the present work we studied the existence of this phenomenon in resting neutrophils and in neutrophils stimulated with two kinds of agents: a phorbol ester (PDBu), which activates the CR1 and fMLP, which increases the expression of this receptor. In previous experiments we determined that the adherence of resting neutrophils on different concentrations of iC3 (which binds CR1 and exerts the same effect that C3b), did not increase the phagocytosis of the E-IgG, using as a control neutrophils adhered on the same concentrations of human serum albumin (HSA) (data not shown).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7854090 TI - [Immune complex glomerulonephritis associated with pulmonary tuberculosis]. AB - A 32 year old man was admitted for dyspnea, hemoptysis, macroscopic hematuria, hypertension (140/100), peripheral edema and hemodynamic decompensation. Lung Xrays revealed pulmonary edema and a cavity in the left apex. Laboratory determinations revealed an altered renal function with increased creatinine and urea levels and nephrotic syndrome. There was leucocyturia, hematuria and cylindruria. The sputum showed a large number of acid-fast bacilli. The patient began anti-tuberculosis treatment with three drugs (isoniacid, rifampicin, pirazinamide). On ultrasonography, both kidneys revealed ecogenic lesions with size, shape and cortico-medular relationship preserved. The patient persisted with altered renal function, steady levels of urea nitrogen, creatinine and potassium, preserved diuresis and hypertension. Bidimensional echocardiogram: LVDD 55 mm, hypoquinetic septum, pericardic effusion, thickened pericardium, pleural effusion, shortening fraction decreased. He received treatment for this congestive cardiac failure and hypertension with enalapril, nifedipine and fursemide. A percutaneous renal biopsy was performed with anatomopathologic diagnosis of diffuse encocapillar proliferative glomerulonephritis with crescents (15%) and total glomerular sclerosis (33%). Immunofluorescence: positive, immune complexes with IgM and C3. The patient gradually recovered his normal renal function, improved his pleural effusions and normalized his cardiac function. He was discharged in good clinical condition on the 69th day of anti-tuberculosis treatment. An association between pulmonary tuberculosis and glomerulonephritis is discussed. It is proposed that renal lesions might be the consequence of the tuberculosis due to the sedimentation of circulating immune-complexes. PMID- 7854091 TI - [Treatment of respiratory insufficiency secondary to vocal cord bilateral paralysis with continuous positive pressure]. AB - Vocal cord paralysis can produce extrathoracic airway obstruction with severe respiratory failure, post-surgical traumatism being the most frequent. Definitive treatment can require aritenoidectomy. For emergency treatment tracheal intubation of tracheotomy are frequently needed. We report a patient with acute post-surgical upper airway obstruction successfully treated with CPAP application through nasal mask. A 29 year-old female showed stridor and retraction of the supraclavicular, intercostal and epigastric region following an uncomplicated tracheal extubation immediately after surgery (radical thyroidectomy with nodal dissection). Pulsosaturometry showed O2 desaturation despite high flow O2 administration. She received intravenous steroids and O2 through intermittent positive pressure by nasal mask (manual resuscitator) increasing SpO2 to 90%. Laringoscopy showed both vocal cords fixed at medium line. CPAP through a nasal mask was initiated with a 5 cm H2O pressure and high FIO2. Immediately afterwards, dyspnea, stridor, supraclavicular retraction and respiratory accessory muscles use disappeared. Heart rate decreased (120 to 92 x min.) and SpO2 increased to 99%. Arterial blood gases did not show hypercapnia. Dyspnea and physical signs of upper airway obstruction appeared immediately after interrupting CPAP application, with a marked decrease in SpO2. So the mask was reinstalled keeping the same pressure level during 18 hs. The procedure was well tolerated. There were no local or hemodynamic complications. CPAP was progressively discontinued.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7854092 TI - [Multiple cerebral hydatid disease]. AB - A case of hydatid cerebral disease with multiple cysts is reported with the purpose of presenting this unusual form of hydatid neurological involvement and to discuss some aspects of the pathogenesis and treatment. In this patient, the liver hydatid cyst surgery two years prior to the development of multiple pulmonary and cerebral cysts suggests a vascular invasion of oncoesphere during the hepatic surgery with hematological dissemination to the lungs and brain. The multiplicity and deep localization of the cerebral cysts prevented the performance of a definitive surgical resection. The multiple percutaneous drainage of the cysts was useful in this case to reduce the endocraneal hypertension and to achieve a neurological improvement. Albendazole has proved of benefit as a chemo-therapeutic agent in these cases and Magnetic Resonance Imaging has proven useful for surgical planning. PMID- 7854093 TI - [Hypopituitarism caused by colonic carcinoma metastasis associated with hypophysial aspergillosis]. AB - Pituitary metastases constitute 1% to 8.3% of all metastatic brain tumors. The most frequent localization is in the posterior lobe and diabetes insipidus may be the only symptom of dysfunction. Cerebral aspergillosis is an unusual disease and it has been described complicating an underlying malignancy or following intracraneal surgery. We describe a case of hypopituitarism and hyperprolactinemia in a patient with pituitary metastases of a colon carcinoma and aspergillosis. Two years before a colon adenocarcinoma (Class C1 of Duke) had been resected. There were no clinical signs of hypopituitarism or galactorrea. The laboratory findings showed deficiency of cortocotropin (ACTH), luteinizing hormone (LH), follicle stimulating hormone (FSH) and slight hyperprolactinemia (PRL). Cerebral magnetic resonance image (MRI) revealed an intra and suprasellar mass which extended to the hypothalamus. Chest X-ray film and computed tomographic scanning (TC) confirmed a macronodular mass at the apical segment of the inferior left lung lobule with mediastinal hypertrophic lymph nodes. A non functional pituitary tumor was diagnosed and transphenoidal surgery was carried out. At microscopic examination a malignant proliferation was found suggesting colonic differentiation. Fragments of tumoral pituitary tissue showed hyphae of aspergillus in the form of abscess. Aspergillosis complicating neoplastic disease is more often present in leukemia and lymphoma than in solid tumors.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7854094 TI - [Diabetes, kidney failure, hyperkalemia, parahilar pulmonary image]. PMID- 7854095 TI - [Interferon gamma as an immunological strategy for the treatment of human leishmaniasis]. AB - T lymphocytes from patients with visceral leishmaniasis treated in vitro with leishmania antigens are unable to proliferate and to produce gamma interferon. These patients have negative specific skin tests. Opposite results are obtained in patients with another clinical form of the disease named mucocutaneous leishmaniasis, in which both tests are positive. Nevertheless, patients with visceral leishmaniasis or mucocutaneous leishmaniasis, refractory to chemotherapy (antimonium complex), were cured when treated with antimonium in combination with gamma interferon, in spite of different immunological profiles. Different interpretative hypotheses of the reversion of chemoresistance induced by gamma interferon are discussed. PMID- 7854096 TI - [Information for smokers]. PMID- 7854097 TI - [Information and consent procedures medical practice]. PMID- 7854098 TI - [Tolerance or resistance to bronchodilators]. PMID- 7854099 TI - [Current status of governmental drug control in the country]. PMID- 7854100 TI - [Neurological atheroembolism]. PMID- 7854101 TI - [Absence of hepatitis B virus DNA in serum of patients not responding to the recombinant vaccine]. PMID- 7854102 TI - [Porphyria cutanea tarda and kidney transplantation]. PMID- 7854103 TI - [Analysis of the basic bioelectric action of the brain in workers chronically exposed to certain organic solvents]. AB - The bioelectric action of the brain was analysed by means of EEC examination with an exclusive or almost exclusive alpha rythm in workers chronically exposed to tetrachloroethylene and in workers exposed to the mixture of solvents which contain aliphatic derivatives of benzene with nine or ten carbon atoms. The study covered 30 male workers of the similar age group, period of employment and work shifts. No symptoms of the nervous system damage were observed. There were either no significant differences in the frequency of alpha rythm according to EEC examination in workers exposed to organic solvents when compared with controls. PMID- 7854104 TI - [Exposure to ceramic fibers in the occupational environment. I. Production, kinds of ceramic fibers, changes in structure of these fibers, preliminary studies in the working environment]. AB - The production of fireproof SiO2/Al2O3 ceramic fibres started in the late forties. Primarily, the production was designed entirely for the aircraft industry. In the sixties the application of ceramic fibres became more wider. The first ceramic fibrous materials were characterised by thermal resistance reaching 1200 degrees C. Certain kinds of materials produced currently can be used in the temperature accounting for 1600 degrees C. Aluminosiliceous ceramic fibres recrystallise at high temperature (above 1000 degrees C) and produce mullite and crostobalite. Ceramic fibrous material may become hazardous to workers as a source of respirable fibres. Studies, carried out in plants which manufacture products from aluminosiliceous ceramic fibres, indicated that mean concentrations of respirable fibres ranged from 0.14 to 1.13 f/cm3 while the levels of mean concentrations of total dust accounted for 0.4-13.6 mg/m3. At working posts of plants producing china, where heat-insulating materials were changed mean level of respirable fibre concentration was 0.28-1.65 f/cm3 and concentration of total dust ranged from 7.0 to 17.7 mg/m3. PMID- 7854105 TI - [Evaluation of exposure to metallic mercury following the measurement of mercury vapor concentration in air of the working zone where acetic aldehyde and chlorine are produced]. AB - The analysis of mercury vapour concentrations in the working zone indicated considerable variations in full shift measurements--from 1/10 MAC to over 3 MAC at the acetic aldehyde production and 40 MAC at the chlorine electrolysis. Individual dosimeters were used in the sample collection and an absorptive ASA atomic spectometry with cool vapour attachment was applied for qualitative determination. The results obtained correspond, to greater extent, with observed high level of mercury excreted with urine than with data of stationary measurements taken in the period of even higher production. PMID- 7854106 TI - [Contamination of archives by filamentous fungi and their evaluation for potential pathogenicity]. AB - The results of microbiological examinations of dust samples collected from mortgage registers in the court archives are presented. In the samples examined filamentous fungi of Penicillium genus were observed as well as Cladosporium herbarum, Geotrichum candidum, Cephalosporium glutineum, Mucor racemosus, Trichoderma viride and Aspergillus niger. Filamentous fungi of Penicillium genus occurred in the highest concentration accounting for 350,000 CFU/g. The levels of the remaining fungi were lower--they ranged from 500 CFU/g to 100,000 CFU/g. The concentration of filamentous fungi observed in archives can create health risk for workers. PMID- 7854107 TI - [Occupational noise at washer and pouring stations in dairy plants]. AB - The level of noise at washer and pouring system stations was estimated in 12 dairy plants in 7 regions of the country (voivodships). dB(A) and dB(Lin) were measured and the octave analysis performed within the range of 31.5-8000 Hz. The examined premises were found to be a source of hazard to hearing in workers. Mean value of the sound level expressed in dB(A) accounted for 90.61 dB at the washer station and 90.22 dB at the pouring system station. PMID- 7854108 TI - [Treatment and prevention of injuries in meat industry workers]. AB - The hand woundings among the meat industry workers are the main cause of high rates of work accident-related sick absenteeism. That can be proved by comparing sick absenteeism rates in other production plants. An increased work accident related sick absenteeism results from the fact that a knife is the main tool used by workers employed in such kind of production. Protective gloves used in the past did not decrease the number of hand woundings because of their poor quality. The change in salaries of the sick because of hand wounding decreased considerably the number of accidents. However, that can contribute to harmful dissimulation from the hygienic and epidemiological points of view. PMID- 7854109 TI - [C14-aminopyrine breath test and enzymatic liver tests in workers employed by the coke tar distillation department]. AB - A group of 400 subjects divided into three sub-groups was examined. Group I consisted of 130 persons employed at the coke tar distillation department. Group II (controls) consisted of 70 persons also employed at the coke plant but free from occupational exposure. Group III was composed of 200 workers employed at the Building Factory. C14-aminopyrine breath test (ABT) was performed in 30 subjects randomly assigned from each group. A standard enzymatic liver test was assessed in all subjects examined. The range of tests performed did not permit to indicate the toxic effect of occupational environment on the liver tissue. Abnormal enzymatic liver test found in all groups could results, among others, from alcohol abuse among those tested. However, it was revealed that aromatic hydrocarbons to which workers of the coke tar distillation department were exposed to, stimulated the activity of the liver microsomal oxygenase assessed by ABT. PMID- 7854110 TI - [Evaluation of the nervous system in workers as needed for preventive examinations. Methodology. I. Subjective examinations]. AB - A model for taking a case history useful in the preliminary evaluation of the nervous system is proposed. The evaluation is to be made by physicians/working in the occupational health services who are not neurologists. Guidelines how to take a case history are given and some questions are thoroughly discussed. The most important questions apply to the loss of consciousness and past diseases of the nervous system. PMID- 7854111 TI - [Safer radiologic examinations]. AB - The paper presents a short survey of reasons why high doses are used in diagnostic X-ray examinations and methods for their reduction. Special attention is paid to the use of cassettes with rare-earth intensifying screens. The results of dose measurements made for several combinations of cassette-film are also presented. Patients can receive the lowest doses if it would be possible to use DuPont cassettes with FOTON films. PMID- 7854113 TI - [Contribution and role of polymorphonuclear leucocytes in inflammatory reactions of asbestosis]. AB - The mechanism of lung fibrosis after asbestos exposure is unknown. Observations suggest that neutrophils may play a role in the development of the lung injury in asbestosis. They are attracted to the lungs by macrophages mediators and there they phagocyte asbestos fibres. A cytotoxic effect of asbestos exerted on polymorphonuclear leucocytes releases proteolytic enzymes such as collagenase and elastase. Besides, asbestos produces highly reactive oxidants in neutrophils responsible for an additional damage of tissues. However, the role of polymorphonuclear leucocytes in pathogenesis of asbestosis still remains controversial. PMID- 7854112 TI - [Nephrotoxicity of metallic mercury in conditions of occupational exposure]. AB - The authors discuss the nephrotoxic effect of metallic mercury vapour in conditions of occupational exposure on the basis of literature available. They present the current knowledge on the ways of absorption, distribution and effect of mercury on the human body. Then they focus on biochemical enzymatic and immunological indices used in the assessment of early stage of kidney damage. They also present results of epidemiological survey in workers occupationally exposed to vapour of metallic mercury. PMID- 7854114 TI - [The French occupational health system. I. Organization of the French occupational health system]. AB - In the first part the author discusses the fundamental principles of occupational health in France, organisational structure of company and inter-company occupational health services as well as the role and responsibilities of occupational physicians. Part II will deal with the evolution of the system. Occupational health in France deserves attention, at least, because of two reasons. Firstly, a great role of an occupational physician distinguishes it from occupational health in other European countries. Secondly, the French experience can be very useful in restructuring of the Polish occupational health system. PMID- 7854115 TI - Mutants of Escherichia coli Trp repressor with changes of conserved, helix-turn helix residue threonine 81 have altered DNA-binding specificities. AB - Threonine is found at the third position of the second alpha-helix in the helix turn-helix motifs of most bacterial DNA-binding proteins. To investigate the role of this conserved residue in Escherichia coli Trp repressor function, plasmids encoding mutant Trp repressors with each of the 19 amino acid changes of Thr-81 were made by site-directed mutagenesis. All 19 changes decrease the activity of Trp holorepressor, indicating that the Thr-81 side-chain is critical for TrpR function. Three mutant repressors, Ser-81, Lys-81 and Arg-81, retain partial DNA binding activity and inhibit transcription from the wild-type trp promoter/operator complex; challenge-phage assays show that Ser-81 and Lys-81 holorepressors have altered DNA-binding specificities. The side-chain of Thr-81 may make direct contacts with base pairs 4 and 3 of the trp operator, consistent with the nuclear magnetic resonance solution structures of the holorepressor operator complex. PMID- 7854116 TI - TcpA pilin sequences and colonization requirements for O1 and O139 vibrio cholerae. AB - The distribution, characterization and function of the tcpA gene was investigated in Vibrio cholerae O1 strains of the El Tor biotype and in a newly emergent non O1 strain classified as serogroup O139. The V. cholerae tcpA gene from the classical biotype strain O395 was used as a probe to identify a clone carrying the tcpA gene from the El Tor biotype strain E7946. The sequence of the E7946 tcpA gene revealed that the mature El Tor TcpA pilin has the same number of residues as, and is 82% identical to, TcpA of classical biotype strain O395. The majority of differences in primary structure are either conservative or clustered in a manner such that compensatory changes retain regional amino acid size, polarity and charge. In a functional analysis, the cloned gene was used to construct an El Tor mutant strain containing an insertion in tcpA. This strain exhibited a colonization defect in the infant mouse cholera model similar in magnitude to that previously described for classical biotype tcpA mutants, thus establishing an equivalent role for TCP in intestinal colonization by El Tor biotype strains. The tcpA analysis was further extended to both a prototype El Tor strain from the Peru epidemic and to the first non-O1 strain known to cause epidemic cholera, an O139 V. cholerae isolate from the current widespread Asian epidemic. These strains were shown to carry tcpA with a sequence identical to E7946. These results provide further evidence that the newly emergent non-O1 serogroup O139 strain represents a derivative of an El Tor biotype strain and, despite its different LPS structure, shares common TCP-associated antigens.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7854117 TI - Sigma S-dependent growth-phase induction of the csgBA promoter in Escherichia coli can be achieved in vivo by sigma 70 in the absence of the nucleoid associated protein H-NS. AB - The stationary-phase-specific sigma factor sigma S (RpoS/KatF) is required for Escherichia coli to induce expression of fibronectin-binding curli organelles upon reaching stationary phase. We show that the csgA gene which encodes the curlin subunit protein belongs to a dicistronic operon, csgBA. The transcriptional start site of csgBA was determined and an AT-rich up-stream activating sequence (UAS) required for transcriptional activation was identified. The pcsgBA promoter is not specific for sigma S since the same promoter sequence can be used by E sigma 70 in vivo in a strain lacking nucleoid-associated protein H-NS and sigma S. Transcription remained growth-phase induced and dependent upon the UAS in such a double mutant. Furthermore, we demonstrate that an additional operon, hdeAB, which is also dependent upon sigma S for transcription, can be transcribed by E sigma 70 in vivo in the absence of H-NS by utilizing the phdeAB promoter. Two other genes known to be under the control of sigma S for expression, bolA and katE, remained transcriptionally silent in the absence of H NS. It is suggested that a subset of E. coli promoters can be recognized by both E sigma S and E sigma 70 in vivo but H-NS interacting with these sequences prevents formation of successful transcription-initiation complexes with E sigma 70. PMID- 7854119 TI - Nitrite and nitrate regulation at the promoters of two Escherichia coli operons encoding nitrite reductase: identification of common target heptamers for both NarP- and NarL-dependent regulation. AB - Expression from both the Escherichia coli nir and nrf promoters is dependent on anaerobic induction by FNR but is further regulated by NarL and NarP in response to the presence of nitrite and nitrate in the growth medium. The nir promoter is activated by NarL in response to nitrate and nitrite and activated by NarP in response to nitrate but not nitrite. The effects of point mutations suggest that NarL and NarP both bind to the same target, which is a pair of heptamer sequences organized as an inverted repeat, centred 69 1/2 bp upstream of the transcript startpoint. The nrf promoter can be activated by either NarP or NarL in response to nitrite but is repressed by NarL in response to nitrate. Mutational analysis of the nrf promoter has been exploited to corroborate the location of the -10 hexamer and the FNR-binding site, and to find the sites essential for nitrite dependent activation and nitrate-dependent repression. Optimal activation by NarP or NarL in response to nitrite requires an inverted pair of heptamer sequences, similar to that found at the nir promoter, but centred 74 1/2 bp upstream from the transcript start. NarL-dependent repression by nitrate is due to two heptamer sequences that flank the FNR-binding sequence. We conclude that NarL and NarP bind to the same heptamer sequences, but that the affinities for the two factors vary from site to site. PMID- 7854118 TI - Molecular characterization and transcription of the histone H2B gene from the protozoan parasite Trypanosoma cruzi. AB - The structure, genomic organization and transcription of the gene encoding histone H2B in the protozoan parasite Trypanosoma cruzi have been studied. This gene consists of a 746-nucleotide unit, tandemly repeated at least 18 times in each of two clusters. DNA probes corresponding to histones H2B and H3 hybridized to different chromosomes revealing that the genes coding for these two histones are not physically linked in the genome of T. cruzi. The primary transcription product of the H2B gene is processed by trans-splicing and polyadenylation. Inhibition of DNA synthesis with aphidicolin resulted in the reduction of histone H2B mRNA to undetectable levels in about two hours, suggesting that its abundance is regulated throughout the cell cycle as it occurs in other eukaryotes. In addition, a concomitant inhibition of translation by cycloheximide reverted this effect indicating that de novo protein synthesis is required for RNA instability. Histone mRNA abundance was dependent on the life-cycle stage of T. cruzi: abundant in amastigotes and epimastigotes, the dividing forms in the host cell and the insect vector, respectively, while undetected in trypomastigotes, the parasite's non-dividing life stage. PMID- 7854120 TI - Gene expression in mycobacteria: transcriptional fusions based on xylE and analysis of the promoter region of the response regulator mtrA from Mycobacterium tuberculosis. AB - Understanding promoter regulation and signal-transduction systems in pathogenic mycobacteria is critical for uncovering the processes that govern interactions of these bacteria with the human host. In order to develop additional genetic tools for analysis of mycobacterial promoters, the xyIE gene from Pseudomonas was tested as a transcriptional fusion reporter in fast- and slow-growing mycobacteria. Initially, its utility was demonstrated by expression behind the hsp60 promoter in Mycobacterium smegmatis and Mycobacterium bovis BCG. The presence of an active promoter in front of the promoterless xyIE cassette on a plasmid was scored by development of a bright yellow colour upon spraying of mycobacterial colonies on plates with a solution of catechol. The gene product of xyIE, catechol 2,3 dioxygenase, was measurable in sonic extracts and whole cells, permitting quantitative determination of promoter activity in both fast- and slow growing mycobacteria. The xyIE-based mycobacterial transcriptional fusion plasmid pRCX3 was constructed and used to assess promoter activity within the sequences located upstream of the newly characterized Mycobacterium tuberculosis H37Rv response regulator mtrA, a member of the superfamily of bacterial signal transduction systems. PMID- 7854121 TI - Glycopeptide resistance mediated by enterococcal transposon Tn1546 requires production of VanX for hydrolysis of D-alanyl-D-alanine. AB - Cloning and nucleotide sequencing indicated that transposon Tn1546 from Enterococcus faecium BM4147 encodes a 23,365 Da protein, VanX, required for glycopeptide resistance. The vanX gene was located downstream from genes encoding the VanA ligase and the VanH dehydrogenase which synthesize the depsipeptide D alanyl-D-lactate (D-Ala-D-Lac). In the presence of ramoplanin, an Enterococcus faecalis JH2-2 derivative producing VanH, VanA and VanX accumulated mainly UDP MurNAc-L-Ala-gamma-D-Glu-L-Lys-D-Ala-D-Lac (pentadepsipeptide) and small amounts of UDP-MurNAc-L-Ala-gamma-D-Glu-L-Lys-D-Ala-D-Ala (pentapeptide) in the ratio 49:1. Insertional inactivation of vanX led to increased synthesis of pentapeptide with a resulting change in the ratio of pentadepsipeptide: pentapeptide to less than 1:1. Expression of vanX in E. faecalis and Escherichia coli resulted in production of a D,D-dipeptidase that hydrolysed D-Ala-D-Ala. Pentadepsipeptide, pentapeptide and D-Ala-D-Lac were not substrates for the enzyme. These results establish that VanX is required for production of a D,D-dipeptidase that hydrolyses D-Ala-D-Ala, thereby preventing pentapeptide synthesis and subsequent binding of glycopeptides to D-Ala-D-Ala-containing peptidoglycan precursors at the cell surface. PMID- 7854122 TI - Characterization of a gene, pilU, required for twitching motility but not phage sensitivity in Pseudomonas aeruginosa. AB - Type 4 fimbriae (or pilli) are associated with a form of bacterial surface translocation known as twitching motility. Fimbriae are also associated with sensitivity to certain bacteriophages such as PO4. Transposon mutagenesis was used to generate a library of Pseudomonas aeruginosa mutants which lack the spreading-colony morphology characteristic of twitching motility. In four of these mutants the transposon was found to be located in the vicinity of the previously described pilT locus, but in only one case was it found to have inserted within the pilT coding sequence. Two twitching-motility mutants originally isolated by Bradley, K2.2, and PAO2001.2, which have been widely used in studies of P. aeruginosa fimbrial structure and expression, were also shown to affect pilT and to comprise a small deletion and a frameshift mutation, respectively. The other three transposon mutations were found to have occurred within a new gene located directly downstream of pilT. This gene, termed pilU, encodes a 382-amino-acid protein closely related to PilT and to other members of a family of putative nucleotide-binding proteins which are involved in the assembly of cell surface-associated complexes. Furthermore, the pilT and pilU genes appear to be independently expressed. Like pilT mutants, the pilU mutants were hyperfimbriate, but in neither case was this associated with an increase in transcription of the fimbrial subunit gene pilA. However, in contrast to pilT mutants, the pilU mutants had not also acquired resistance to infection by bacteriophage PO4. A broader survey showed differential patterns of sensitivity to various fimbrial-specific phages among the pilU mutants and other twitching motility mutants in the transposon library. The fact that twitching motility is not obligatorily associated with phage sensitivity suggests that the latter may not be directly dependent upon fimbrial function but rather may be a consequence of some common factor(s) involved in their assembly or export pathways. PMID- 7854123 TI - Anthrax toxin lethal factor contains a zinc metalloprotease consensus sequence which is required for lethal toxin activity. AB - Comparison of the anthrax toxin lethal factor (LF) amino acid sequence with sequences in the Swiss protein database revealed short regions of similarity with the consensus zinc-binding site, HEXXH, that is characteristic of metalloproteases. Several protease inhibitors, including bestatin and captopril, prevented intoxication of macrophages by lethal toxin. LF was fully inactivated by site-directed mutagenesis that substituted Ala for either of the residues (H 686 and H-690) implicated in zinc binding. Similarly, LF was inactivated by substitution of Cys for E-687, which is thought to be an essential part of the catalytic site. In contrast, replacement of E-720 and E-721 with Ala had no effect on LF activity. LF bound 65Zn both in solution and on protein blots. The 65Zn binding was reduced for several of the LF mutants. These data suggest that anthrax toxin LF is a zinc metallopeptidase, the catalytic function of which is responsible for the lethal activity observed in cultured cells and in animals. PMID- 7854124 TI - Positive selection for resistance to 2-deoxyglucose gives rise, in Streptococcus salivarius, to seven classes of pleiotropic mutants, including ptsH and ptsI missense mutants. AB - We have used the toxic non-metabolizable glucose/mannose analogue 2-deoxyglucose to isolate a comprehensive collection of mutants of the phosphoenolpyruvate:sugar phosphotransferase system from Streptococcus salivarius. To increase the range of possible mutations, we isolated spontaneous mutants on different media containing 2-deoxyglucose and various metabolizable sugars, either lactose, melibiose, galactose or fructose. We found that the frequency at which 2-deoxyglucose resistant mutants were isolated varied according to the growth substrate. The highest frequency was obtained with the combination galactose and 2-deoxyglucose and was 15-fold higher than the rate observed with the mixture melibiose and 2 deoxyglucose, the combination that gave the lowest frequency. By combining results from: (i) Western blot analysis of IIIMan, a specific component of the phosphoenolpyruvate:mannose phosphotransferase system in S. salivarius; (ii) rocket immunoelectrophoresis of HPr and EI, the two general energy-coupling proteins of the phosphotransferase system; and (iii) from gene sequencing, mutants could be assigned to seven classes.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7854125 TI - Immunity proteins to pore-forming colicins: structure-function relationships. AB - Colicin A and B immunity proteins (Cai and Cbi, respectively) are homologous integral membrane proteins that interact within the core of the lipid bilayer with hydrophobic transmembrane helices of the corresponding colicin channel. By using various approaches (exchange of hydrophilic loops between Cai and Cbi, construction of Cbi/Cai hybrids, production of Cai as two fragments), we studied the structure-function relationships of Cai and Cbi. The results revealed unexpectedly high structural constraints for the function of these proteins. The periplasmic loops of Cai and Cbi did not carry the determinants for colicin recognition although most of these loops were required for Cai function; the cytoplasmic loop of Cai was found to be involved in topology and function of Cai. The immunity function did not seem to be confined to a particular region of the immunity proteins. PMID- 7854126 TI - The colicin A pore-forming domain fused to mitochondrial intermembrane space sorting signals can be functionally inserted into the Escherichia coli plasma membrane by a mechanism that bypasses the Tol proteins. AB - Colicin A is a pore-forming bacteriocin that depends upon the Tol proteins in order to be transported from its receptor at the outer membrane surface to its target, the inner membrane. The presequence of yeast mitochondria cytochrome c1 (pc1) as well as the first 167 amino acids of cytochrome b2 (pb2) were fused to the pore-forming domain of colicin A (pfColA). Both hybrid proteins (pc1-pfCoIA and pb2-pfColA) were cytotoxic for Escherichia coli strains devoid of colicin A immunity protein whereas the pore-forming domain without presequence had no lethal effect. The entire precursors and their processed forms were found entirely associated with the bacterial inner membrane and their cytotoxicities were related to their pore-forming activities. The proteins were also shown to kill the tol bacterial strains, which are unable to transport colicins. In addition, we showed that both the cytochrome c1 presequence fused to the dihydrofolate reductase (pc1-DHFR) and the cytochrome c1 presequence moiety of pc1-pfCoIA were translocated across inverted membrane vesicles. Our results indicated that: (i) pc1-pfCoIA produced in the cell cytoplasm was able to assemble in the inner membrane by a mechanism independent of the tol genes; (ii) the inserted pore-forming domain had a channel activity; and (iii) this channel activity was inhibited within the membrane by the immunity protein. PMID- 7854127 TI - The role of the pilus in recipient cell recognition during bacterial conjugation mediated by F-like plasmids. AB - The effects of defined mutations in the lipopolysaccharide (LPS) and the outer membrane protein OmpA of the recipient cell on mating-pair formation in liquid media by the transfer systems of the F-like plasmids pOX38 (F), ColB2 and R100-1 were investigated. Transfer of all three plasmids was affected differently by mutations in the rfa (LPS) locus of the recipient cell, the F plasmid being most sensitive to mutations that affected rfaP gene expression which is responsible for the addition of pyrophosphorylethanolamine (PPEA) to heptose I of the inner core of the LPS. ColB2 transfer was more strongly affected by mutations in the heptose II-heptose III region of the LPS (rfaF) whereas R100-1 was not strongly affected by any of the rfa mutations tested. ompA but not rfa mutations further decreased the mating efficiency of an F plasmid carrying a mutation in the mating pair stabilization protein TraN. An F derivative with a chloramphenicol acetyltransferase (CAT) cassette interrupting the traA pilin gene was constructed and pilin genes from F-like plasmids (F, ColB2, R100-1) were used to complement this mutation. Unexpectedly, the results suggested that the differences in the pilin sequences were not responsible for recognizing specific groups in the LPS, OmpA or the TraT surface exclusion protein. Other corroborating evidence is presented suggesting the presence of an adhesin at the F pilus tip. PMID- 7854128 TI - Transfer of the plJ101 plasmid in Streptomyces lividans requires a cis-acting function dispensable for chromosomal gene transfer. AB - The tra gene of Streptomyces lividans plasmid plJ101 is required for both plasmid DNA transfer and plJ101-induced mobilization of chromosomal genes during mating. We show that a chromosomally inserted copy of tra mediates transfer of chromosomal DNA at high frequency but promotes efficient transfer of plasmids only when they contain a previously unknown locus, here named clt. Insertional mutation or deletion of clt from plJ101 reduced plasmid transfer mediated by either plasmid-borne or chromosomally located tra by at least three orders of magnitude, abolished the transfer-associated pocking phenomenon, and interfered with the ability of tra+ plasmids to promote transfer of chromosomal DNA. Our results indicate that plasmid transfer in S. lividans involves a cis-acting function dispensable for chromosomal gene transfer and imply that either the S. lividans chromosome encodes its own clt-like function or, alternatively, that transfer of plasmid and chromosomal DNA occurs by different mechanisms. PMID- 7854129 TI - Synergism of mosquitocidal toxicity between CytA and CryIVD proteins using inclusions produced from cloned genes of Bacillus thuringiensis. AB - The toxicity to mosquito larvae of the parasporal body produced by Bacillus thuringiensis subsp. israelensis and the PG-14 isolate of B. thuringiensis subsp. morrisoni is at least 20-fold greater than any of the four mosquitocidal proteins of which it is composed (CytA, CryIVA, B, and D). This high toxicity is postulated to be due to synergistic interactions among parasporal proteins. However, this remains controversial because values reported for the specific toxicity of individual proteins, especially the CytA protein, vary widely owing to the methods used to purify and assay toxins against larvae. In an attempt to resolve questions of purity, specific toxicity, and synergism, individual genes encoding the CytA and CryIVD toxins were cloned and expressed in acrystalliferous B. thuringiensis subsp. israelensis cells using the shuttle vector pHT3101. CytA and CryIVD inclusions were purified and their toxicity was determined alone and when combined at different ratios using bioassays against first instars of Aedes aegypti. The LC50 for the CytA inclusion was 60 ng ml-1, whereas the LC50 for the CryIVD was 85 ng ml-1. In comparison, the LC50s for different combinations of CytA and CryIVD inclusions ranged from 12-15 ng ml-1, 4-5 times higher than the toxicity of either protein alone, demonstrating marked synergism between these two proteins. These results suggest that the high toxicity of the wild-type parasporal bodies of B. thuringiensis subspp. israelensis and morrisoni is due to synergism among three or four of their major proteins. PMID- 7854130 TI - The pilE gene product of Pseudomonas aeruginosa, required for pilus biogenesis, shares amino acid sequence identity with the N-termini of type 4 prepilin proteins. AB - A new locus required for type 4 pilus biogenesis by Pseudomonas aeruginosa has been identified. A pilE mutant, designated MJ-6, was broadly resistant to pili specific phages and unable to translocate across solid surfaces by the pilus dependent mechanism of twitching motility (Twt-). Immunoblot analysis demonstrated that MJ-6 was devoid of pili (Pil-) but was unaffected in the production of unassembled pilin pools. Genetic studies aimed at localizing the pilE mutation on the P. aeruginosa PAO chromosome demonstrated a strong co linkage between MJ-6 phage resistance and the proB marker located at 71 min. Cloning of the pilE gene was facilitated by the isolation and identification of a pro(B+)-containing plasmid from a PAO1 cosmid library. Upon introduction of the PAO1 proB+ cosmid clone into MJ-6, sensitivity to pili-specific phage, twitching motility and pilus production were restored. The nucleotide sequence of a 1 kb EcoRV-ClaI fragment containing the pilE region revealed a single complete open reading frame with characteristic P. aeruginosa codon bias. PilE, a protein with a molecular weight of 15,278, showed significant sequence identity to the pilin precursors of P. aeruginosa and to other type 4 prepilin proteins. The region of highest homology was localized to the N-terminal 40 amino acid residues. The putative PilE N-terminus contained a seven-residue basic leader sequence followed by a consensus cleavage site for prepilin peptidase and a largely hydrophobic region which contained tyrosine residues (Tyr-24 and Tyr-27) previously implicated in maintaining pilin subunit-subunit interactions. The requirement of PilE in pilus biogenesis was confirmed by demonstrating that chromosomal pilE insertion mutants were pilus- and twitching-motility deficient. PMID- 7854131 TI - Regulation of R100 conjugation requires traM in cis to traJ. AB - Deletion mutants of R100-1 were constructed by classical methods to remove various segments of the traM open reading frame, pTraM-binding sites and the traM promoters. Complementation tests showed that traM was efficiently complemented only when the trans-acting fragment contained both the complete traM gene and the adjacent traJ promoter and leader sequences. The conclusion is that traM and traJ constitute a complex operon. A deletion mutant lacking all of the traJ gene, and one containing a frameshifting traM deletion, retained the ability to transfer at a low level, thereby showing that neither pTraM nor pTraJ is absolutely essential for transfer. PMID- 7854132 TI - A conceptual model for improving the social life of individuals with mental retardation. AB - Fostering and improving the social relationships of individuals with disabilities have become recognized as legitimate roles for service providers. This is, in part, a logical outgrowth of a shift from services that emphasized health, safety, and skill development to services whose mission is seen as also including "lifestyle support." In this paper we reviewed ways in which social life has been conceptualized and measured and suggested how such concepts might be integrated into a comprehensive model to spur research and development benefitting individuals with mental retardation. PMID- 7854133 TI - Educational/support group for Latino families of children with Down syndrome. AB - Experiences and observations based on an ongoing parent education-support group for Mexican-origin Latino parents of children with Down syndrome were described. Culturally mediated concepts were discussed in terms of their relevance to specific aspects of group functioning, including group structure, membership, and leadership. Problems of particular concern to this population that might adversely affect maintenance and growth of the group were also examined. Finally, the potential value of such support groups for this parent population were considered as were guidelines for enhancing the group experience. PMID- 7854134 TI - Cash subsidy program: family satisfaction and need. AB - Families of children with severe developmental disabilities who were participating in a cash subsidy program were surveyed about their satisfaction with the program. They were also asked about their need for a variety of other services. Families were satisfied with the operation of the program and with the amount of the subsidy they received. Families indicated a need for more respite care or sitters more often than any other service. Respondents were found to use their subsidy for the types of services they said they needed. PMID- 7854135 TI - Partners in policymaking: the first five years. AB - Many individuals with disabilities and their families are becoming empowered by learning effective self-advocacy strategies. In this article one enpowerment and self-advocacy training program, Partners in Policymaking, for parents of young children and adults with disabilities was described. Initially developed in Minnesota, the Partners program has completed its fifth year, has 163 graduates, and is being replicated in several other states. Follow-up data, qualitative and quantitative, were collected from program graduates. Results indicated both satisfaction with the program and the presence of many active citizen-advocates in the community. PMID- 7854136 TI - Position paper on social work values: practice with individuals who have developmental disabilities. AB - This position paper was developed in response to a discussion led by Iris Gordon, president of the Social Work Division of the American Association on Mental Retardation (AAMR) at the 1991 annual meeting on the importance of social work values and the need for clarification in other divisions of the AAMR. The role of social workers and the importance of social work values in the field of developmental disabilities were discussed. PMID- 7854137 TI - 1994: new frontiers in mental retardation. PMID- 7854138 TI - Reflections on "self-advocacy: voices for choices". PMID- 7854139 TI - On the need for confirmation of negative genotoxicity results in vitro and on the usefulness of mammalian cell mutation tests in a core battery: experiences of a contract research laboratory. AB - There are currently unresolved discussions on two important topics in regulatory genetic toxicology, namely whether or not it is necessary to confirm clearly negative results from in vitro assays in independent experiments, and whether or not the mammalian cell gene mutation test should be part of a core battery of tests. Analysis of in-house data, using full regulatory protocols, suggests that for bacterial mutation tests (144 compounds reviewed) it is impractical to design a single experiment to incorporate all relevant variables and, therefore, confirmation of negative results using modified methodology is desirable. On the other hand, data from TK mutation assays (65 compounds reviewed) and chromosomal aberration tests (94 compounds reviewed) suggest that confirmation of negative results in well-designed mammalian cell studies is not necessary. Analysis of 32 chemicals, each tested in Ames, TK mutation and chromosomal aberration tests, revealed two positives unique to the TK assay and one unique to the chromosomal aberration test. As the TK assay did not show increased susceptibility to false positives (frequency of positives is similar to other in vitro assays) and these two unique positives were clearly observed (> 2-fold increase in mutation frequency at 60-70% relative survival in both cases), they do appear to be 'real' results. Both compounds induced small colony mutants (one also induced 'large'), and yet in vitro chromosomal aberration and in vivo micronucleus tests were negative. The single unique chromosomal aberration positive may be an artefact of high cytotoxicity, and certainly the substance was negative for micronuclei and UDS in vivo, so it might be argued that the chromosomal aberration test is surplus to requirements. Overall, however, it would seem premature to reject either assay at this time, and experience suggests the extra information provided by two mammalian cell tests instead of one is extremely valuable in assessing risk and deciding upon appropriate follow-up tests in vivo. PMID- 7854140 TI - Thresholds for aneuploidy-inducing chemicals. Advisory Committee on Mutagenicity of Chemicals in Food, Consumer Products and the Environment of the UK Department of Health. PMID- 7854141 TI - Micronucleus test and metaphase analyses in mice exposed to known and suspected spindle poisons. AB - Micronucleus (Mn) and metaphase chromosome analyses were performed in mouse bone marrow cells with two known and eight suspected mitotic spindle poisons. Polychromatic (PCEs) and normochromatic (NCEs) erythrocytes were scored for presence of Mn, while structural (CAs) and numerical chromosome aberrations (NCAs), i.e. hyperploid cells, were evaluated by metaphase analysis. CAs were scored in first, and NCAs in the second metaphases, identified by BrdUrd differential staining. Hydroquinone induced Mn, NCAs and CAs; colchicine, vinblastine and, to a lesser extent, chloral hydrate, diazepam and econazole induced both Mn and NCAs; cadmium chloride and thimerosal induced Mn and CAs, while pyrimethamine and thiabendazole induced Mn only. The proposed stepwise protocol allowed satisfactory statistical evaluation of the effects induced with a reduction in the number of animals killed. An acceptable agreement was found between induction of Mn and NCAs, suggesting a possible use of the Mn test for revealing compounds with aneugenic properties. PMID- 7854142 TI - Evaluation of the genotoxicity of 4-diethylamino-4'-nitroazobenzene and seven analogues. AB - A series of eight nitroaromatic azo compounds based on 4-diethylamino-4' nitroazobenzene has been examined for genotoxic activity in a collaborative study conducted under the auspices of the Ecological and Toxicological Association of Dyes and Organic Pigments Manufacturers (ETAD). The evaluation has been conducted in two parts, firstly an examination in vitro to assess any intrinsic genotoxic activity of the compound. The chemicals were examined in the Salmonella assay in a standard plate incorporation protocol in both the presence and absence of S9 and in a minimum of the four tester strains recommended in the OECD guideline for this assay, i.e. TA1535, TA1537, TA98 and TA100. All of the compounds were mutagenic in one or more of the Salmonella tester strains, and all were positive in TA98 with S9. A considerable range of potency was seen in this assay. The chemicals were further examined in vitro for mammalian cell gene mutation at either the HGPRT or TK locus in a standard (CHO, V79 or L5178Y) cell system. Only one of the chemicals was mutagenic and only with S9. This chemical also showed the most potent response in the Salmonella assay. The second part of the study was an examination in vivo to see whether any genotoxic activity was expressed in the whole animal. The in vivo rat liver DNA repair (unscheduled DNA synthesis; UDS) assay was chosen as being the most likely to be sensitive to aromatic nitroazo compounds. All of the materials were negative when tested alongside a structurally related positive control. The chemicals were also examined in the mouse bone marrow micronucleus assay in order to provide a second in vivo assessment.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7854143 TI - Moderate inhibition of mutagenicity and carcinogenicity of benzo[a]pyrene, 1,6 dinitropyrene and 3,9-dinitrofluoranthene by Chinese medicinal herbs. AB - The activity of six Chinese medicinal herbs against the environmental mutagens and carcinogens benzo[a]pyrene (B[a]P), 1,6-dinitropyrene (1,6-diNP) and 3,9 dinitrofluoranthene (3,9-diNF) was determined. Samples of Prunella spica, Rheum palmatum, Polygonum multiflorum, Agrimonia pilosa, Ephedra sinica and Teitoutou were tested in an in vitro system. Antimutagenic activity against B[a]P was marked in the presence of extracts (boiled for 2 h in a water bath) whereas that against 1,6-diNP and 3,9-diNF varied from 20 to 86%. The differences in inhibition might be due to inactivation of metabolic enzymes. An extract of P. multiflorum was divided into ether, ethyl acetate and water soluble fractions, which were tested for antimutagenic activity against B[a]P. The antimutagenic action of the ethyl acetate soluble fraction was substantial and dose-dependent. Tannins and related compounds were the major components of the extract, of which epigallocatechin, epigallocatechin gallate, epicatechin gallate and tannic acid strongly inhibited the mutagenicity of B[a]P (2.5 micrograms/plate) in Salmonella typhimurium TA98 with S9 mix. To confirm the results of the in vitro test system, F344/DuCrj male rats were given a subcutaneous injection of B[a]P. Thereafter, they received water extracts of the six Chinese medicinal herbs for 50 weeks and were examined for tumors. The P. multiflorum extract significantly reduced the tumor incidence. PMID- 7854144 TI - Resolution and conservation of mismatches in DNA end joining. AB - DNA end joining is a major pathway for the elimination of double-strand breaks from chromosomal DNA of higher eucaryotic cells. Extracts of Xenopus laevis eggs rejoin such breaks even when their short single-stranded termini are expected to form imperfectly matched overlaps. However, end-joined products cloned in Escherichia coli, necessarily give rise to perfectly matched products. Therefore it has not been possible to determine whether the end joining process creates mismatched products, perfectly matched (resolved) products or both. To investigate whether mismatch resolution was the result of the X. laevis end joining process or of activities of the bacterial host we used denaturing gradient gel electrophoresis to analyse joined products. We found that the end joining process does include mismatch resolution, the degree of which varies with regard to the nature of the original overlap structure. Mismatches 3' to a gap are completely resolved, mismatches 3' to a nick and 5' to a nick or gap are resolved to some extent but are generally conserved. Mismatches between base matches are always conserved. These findings suggest competing processes of ligation, DNA fill-in synthesis or exonucleolytic excision of mismatched bases next to a gap or nick. At mismatches 3' to a nick the probability of ligation is greater than that of excision while at mismatches 3' to a gap the probability of excision is greater than elongation of a given mismatch. At mismatches 5' to nicks or gaps it appears that ligation or elongation and ligation, respectively, are the most probable pathways but products resulting from mismatch excision, elongation and ligation are also detected. PMID- 7854145 TI - Multiplex polymerase chain reaction-based deletion analysis of spontaneous, gamma ray- and alpha-induced hprt mutants of CHO-K1 cells. AB - Independent Chinese hamster ovary (CHO)-K1 cell mutants at the hypoxanthine guanine phosphoribosyltransferase (hprt) locus were isolated from untreated, 60Co gamma ray- and 212Bi alpha-exposed cells and the genetic changes underlying the mutation determined by multiplex polymerase chain reaction (PCR)-based exon deletion analysis. In the 71 spontaneous mutants analyzed, 77.5% of the clones showed no change in exon number or size, 15.5% showed a loss of a single exon, 4.2% showed a loss of 2-8 exons, and 2.8% showed loss of all nine hprt exons (total gene deletion). Exposure to 6 Gy of gamma rays, which reduced survival levels to 10%, produced a significantly different deletion spectrum that was shifted toward deletions with 45% of the 20 mutants analyzed showing a loss of a single exon and 30% showing a loss of all nine exons. Exposure to 2 Gy alpha radiation from 212Bi, a 220Rn daughter, a dose which also reduced survival levels to about 10%, resulted in a deletion spectrum similar to the gamma-ray spectrum in that more than 75% of the 49 mutants analyzed were deletions. The alpha spectrum, however, was significantly different from both the spontaneous and gamma spectra with 55.1% of the alpha mutants showing a loss of all nine exons, 10.2% showing loss of a single exon, and 14.3% showing loss of 2-8 exons. Thus, alpha-radiation appears to produce larger intragenic deletions than gamma radiation. The results suggest that intragenic deletion size should be considered when low- and high linear energy transfer (LET) mutation spectra are compared. PMID- 7854146 TI - The influence of postovulatory ageing on the retardation of mouse oocyte maturation and chromosome segregation induced by vinblastine. AB - Certain compounds can induce ovulated metaphase I (MI) oocytes. To study if these MI oocytes can overcome this blockage, ICR mice were given human chorionic gonadotrophin and 0.6 mg/kg vinblastine sulfate (VBS). Their ovulated oocytes were collected at 17, 19, 21, 23 and 25 h later. The results showed that the frequencies of MI oocytes decreased, the proportions of diploid metaphase II (MII) oocytes increased and the frequencies of hyperploid MII oocytes did not significantly differ (P > 0.05) among the five harvest or postovulatory times. We also found that the proportions of MII oocytes exhibiting premature anaphase II and premature centromere separation increased with postovulatory ageing, and that these frequencies were consistently higher in controls than in the VBS groups. These findings indicate that some of the oocytes blocked in MI can overcome this inhibition and produce primarily diploid MII oocytes. The ultimate fate of ovulated MI and diploid oocytes on aneuploid production hinges upon the formation of a functioning meiotic spindle, which is affected by both dosage and the specific chemical. PMID- 7854147 TI - 9-Methoxytariacuripyrone, a naturally occurring nitro-aromatic compound with strong mutagenicity in Salmonella typhimurium. AB - 9-Methoxytariacuripyrone, a nitro-aromatic compound isolated from Aristolochia brevipes showed strong mutagenic activity in strain TA98, TA100 and some YG strains of Salmonella typhimurium with and without S9 mix. Incubation with cytosol resulted in a heavy increase in mutagenicity. When incubated with microsomes the activity was dramatically decreased. The results are discussed in view of the enzymes possibly involved in activation and detoxification of the compound. The role of the basic structure on the mutagenicity mediated through the nitro group was also considered. PMID- 7854148 TI - Activation of benzylic alcohols to mutagens by human hepatic sulphotransferases. AB - Four primary and five secondary benzylic alcohols derived from polycyclic aromatic hydrocarbons were tested for mutagenicity in Salmonella typhimurium TA98 in the presence of 3'-phosphoadenosine-5'-phosphosulphate, the cofactor for sulphotransferases, and varying amounts of hepatic cytosol from three or four different human subjects, a 3-year-old child, an adult female, an adult male and one unknown. All compounds except one, 4H-cyclopenta[def]phenanthren-4-ol, were activated to mutagens. The interindividual variation in the activities was at most 3-fold and the individual activities towards the different substrates were correlated with each other. The same compounds had previously been tested in the presence of hepatic cytosol from rats and all compounds activated in one species were also activated in the other species. However, there were marked quantitative differences, which were further complicated by the observation of a substantial sex difference in the rat. Male and female rat liver cytosol showed higher sulphotransferase activities towards 1-hydroxymethylpyrene, 9 hydroxymethylanthracene, 7-hydroxymethyl-12-methylbenz[a]anthracene and 4H cyclopenta[def]chrysen-4-ol than human liver cytosol. The largest difference in activity was seen with 7-hydroxymethyl-12-methylbenz[a]anthracene, reaching a factor of approximately 100 between human and female rat. However, with other benzylic alcohols, the activity in human liver cytosol was in the range of that found in the less active sex of rat (3-hydroxy-3,4-dihydrocyclopenta[cd]pyrene, 2 hydroxymethylpyrene) or the more active sex of rat [1-(1 pyrenyl)ethanol].(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7854149 TI - Preservation of cytoplasm in the human lymphocyte micronucleus assay. AB - A major limitation in the quantitative accuracy of the human lymphocyte micronucleus (MN) assay is preservation of the cytoplasm during the cell harvesting. In this short communication, an improved method for cytoplasm preservation in a cytokinesis-blocked, whole-blood microculture (0.3 ml) technique is described. We believe that the timing of the hypotonic treatment, speed of centrifugation, handling of the cell suspension and proper Giemsa staining are important variables in the human peripheral lymphocyte MN assay. PMID- 7854150 TI - Industrial Genotoxicology Group: automation of genotoxicity assays and structure activity relationships, Unicorn House, the Wellcome Foundation, London, UK, December 1993. PMID- 7854151 TI - Painting of Macaca fascicularis chromosomes using a DNA probe for human chromosome 2. PMID- 7854152 TI - Determination of doubly labeled water by gas-phase Fourier transform infrared spectroscopy. AB - Both 2H (deuterium) and 18O (oxygen 18) in isotopically enriched water have been detected by gas-phase Fourier transform infrared (FTIR) spectroscopy at 2,720 and 3,661.8 cm-1, respectively. A linear relationship between varying concentrations of each of these isotopes and their absorbance at the above frequencies indicates that gas-phase FTIR may provide a rapid and potentially less expensive approach to measure doubly labeled water in biological fluids for the estimation of energy expenditure and total body water. PMID- 7854153 TI - Stimulation of cyclic adenosine monophosphate formation by the novel vasorelaxant peptide adrenomedullin in cultured rat mesangial cells. AB - The present study was designed to examine the effect of synthetic adrenomedullin (AM), a novel vasorelaxant peptide originally isolated from human pheochromocytoma, on intracellular cyclic adenosine monophosphate (cAMP) formation in cultured rat mesangial cells. The effect of AM on cAMP formation in rat mesangial cells was compared with its effect in cultured rat vascular smooth muscle cells. cAMP levels were determined by radioimmunoassay after stimulation for 30 minutes with different concentrations (10(-10) to 10(-7) mol/L) of rat and human AM. Rat and human AM concentration-dependently (10(-9) to 10(-7) mol/L) stimulated cAMP formation in cultured mesangial cells. This stimulatory effect of rat AM was significantly greater than human AM. The stimulatory effect of rat AM in mesangial cells was significantly weaker than its potency in vascular smooth muscle cells. These preliminary data suggest that mesangial cells, as well as vascular smooth muscle cells, possess AM receptors functionally coupled to adenylate cyclase. PMID- 7854155 TI - Effects of angiotensin II and phenylephrine on urinary endothelin in normal female volunteers. AB - Endothelin (ET) is a 21-amino acid peptide produced and secreted mainly by endothelial cells. Small amounts of ET are found in plasma, whereas large amounts are present in the urine. Despite the abundance of ET in the kidneys and urine, little is known about its regulation and clinical significance. The present study was designed to examine the effects of angiotensin II (Ang II) and phenylephrine (Phe) on the excretion of ET in normal female volunteers. Ang II and Phe were infused for 1 hour each and titrated to increase the mean arterial pressure by 20 mm Hg. There was a 60-minute recovery period before the second drug, and the order of the drugs was randomized. Infusion of Phe induced mild diuresis and natriuresis, which were associated with a significant increase in the excretion of ET. In addition, Phe significantly increased plasma atrial natriuretic factor (ANF). In contrast, infusion of equipressor doses of Ang II decreased urinary sodium excretion and did not significantly alter the excretion of ET. Moreover, Ang II induced only a small and nonsignificant increase in plasma ANF. These results demonstrate that (1) physiological doses of Ang II do not affect excretion of either ET or ANF; (2) Phe markedly increased the excretion of ET and ANF, independently of its effect on blood pressure; and (3) neither agent changed plasma ET, but Phe increased plasma ANF. PMID- 7854154 TI - The associations of high-density lipoprotein subclasses with insulin and glucose levels, physical activity, resting heart rate, and regional adiposity in men with coronary artery disease: the Stanford Coronary Risk Intervention Project baseline survey. AB - We used nondenaturing polyacrylamide gradient gel electrophoresis to examine the associations of high-density lipoprotein (HDL) subclasses with adiposity, physical activity, resting heart rate (an indicator of sympathetic drive), and plasma insulin and glucose levels in 97 men with angiographically documented coronary artery disease. These men neither smoked nor used medications known to affect lipoproteins. The absorbency of protein stain was used as an index of mass concentrations at intervals of 0.01 nm within five HDL subclasses: HDL3c (7.2 to 7.8 nm), HDL3b (7.8 to 8.2 nm), HDL3a (8.2 to 8.8 nm), HDL2a (8.8 to 9.7 nm), and HDL2b (9.7 to 12 nm). HDL peak diameter was determined from the predominant peak of the HDL particle distribution when plotted against particle diameter. Four men who were non-insulin-dependent diabetics as defined by a fasting glucose exceeding 140 mg/dL had significantly higher plasma HDL3b levels and significantly smaller HDL peak diameters than nondiabetic men, and were therefore excluded from further analyses. In the remaining 93 nondiabetic men, plasma HDL3b levels correlated positively with indices of truncal obesity (waist to hip ratio and subscapular skinfold), whereas plasma HDL2b levels correlated negatively with indices of total adiposity (body mass index [BMI]) and truncal obesity (subscapular and abdominal skinfold). Fasting plasma insulin levels correlated negatively with HDL3a, HDL2a, and HDL2b. Obesity significantly affected the relationships of resting heart rate with insulin and HDL subclasses.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7854156 TI - Effects of clenbuterol and salbutamol on tissue rubidium uptake in vivo. AB - In anesthetized rats, injection of the beta 2-adrenoceptor (beta 2-AR) agonist clenbuterol (0.45 mumol/kg) caused a marked stimulation of 86RbCl (Rb) uptake by skeletal muscle, but had no effect on other tissues; soleus muscle showed the largest (144% increase) response. Injection of another beta 2-AR agonist (salbutamol 0.45 mumol/kg) had no effect on Rb uptake by any tissue except soleus muscle (83%). Both agonists increased body (colonic) temperature to the same extent. A 3-day treatment with salbutamol as a dietary admixture had no effect on body weight, muscle mass, or tissue Rb uptake, whereas the same treatment using clenbuterol produced significant increases in body weight and muscle mass and significant decreases in Rb uptake in three of the four muscle groups studied; Rb uptake in soleus was not affected. In another experiment, the short-term effect of clenbuterol injection on muscle Rb uptake was found to be resistant to a high dose (20 mg/kg) of the selective beta 2-AR antagonist ICI 118551. It was concluded that the selective effects of short-term administration of clenbuterol on muscle Rb uptake, coupled with its effects over 3 days on Rb uptake and muscle hypertrophy, implicate beta-AR modulation of cation transport (possibly via Na,K adenosine triphosphatase [ATPase] activity) in the anabolic effects of clenbuterol on muscle protein deposition. Since the stimulation of Rb uptake by clenbuterol was resistant to high doses of a selective beta 2-AR antagonist and since salbutamol had little or no effect on muscle hypertrophy or Rb uptake, it is suggested that clenbuterol may exert its effects via an atypical beta-AR. PMID- 7854157 TI - Effects of zinc deficiency on protein synthesis and expression of specific mRNAs in rat liver. AB - The effects of zinc deficiency on protein synthesis and expression of specific mRNAs were assessed in rat liver. Zinc deficiency had no apparent effect on liver weight, protein content, or RNA content when these properties were compared with values obtained using pair-fed rats. However, zinc deficiency resulted in a lower rate of hepatic protein synthesis. The decreased rate of protein synthesis was due to a decrease in the rate of synthesis of proteins retained in the liver, with no apparent change in the synthesis of secreted proteins. Analysis of expression of specific gene products, as assessed by in vitro translation of total RNA followed by two-dimensional gel analysis, showed that the expression of only a few mRNAs was altered by zinc deficiency. The patterns of change in gene expression resulting from zinc deficiency varied from almost complete repression to full expression. In additional studies, cDNA clones to serum retinol-binding protein and transthyretin were used to examine the effect of zinc deficiency on the relative abundance of mRNA for these two proteins. The relative abundance of mRNA for transthyretin was specifically elevated as a result of zinc deficiency. In contrast, the relative abundance of mRNA for hepatic serum retinol-binding protein was increased in both zinc-deficient and pair-fed rats. Therefore, the observed change in mRNA for serum retinol-binding protein was apparently at least in part due to the inanition that accompanies zinc deficiency. Overall, the results suggest that zinc can regulate the synthesis of specific proteins in rat liver through changes in the relative abundance of specific mRNAs. PMID- 7854158 TI - Tolbutamide causes a modest increase in insulin secretion in cystic fibrosis patients with impaired glucose tolerance. AB - We examined the effect of intravenous (i.v.) tolbutamide administration on glucose and hormone levels in cystic fibrosis (CF) patients with impaired first phase insulin secretion and oral glucose tolerance (oral glucose tolerance test [OGTT]) and compared them with CF patients with only an impaired first-phase insulin secretion and healthy control subjects. Five CF patients with an impaired OGTT, ie, a serum glucose value of 7.8 mmol/L or greater 120 minutes after an oral glucose load (group I), five CF patients with a normal OGTT, ie, a serum glucose not exceeding 7.8 mmol/L 120 minutes after oral glucose (group II), and five healthy control (CON) subjects underwent IV glucose tolerance tests with glucose alone (IVGTT) and glucose administered in conjunction with tolbutamide ([IVTTT] 25 mg/kg; maximum dose, 1 g). Serum glucose levels were measured using the glucose oxidase method; insulin, C-peptide, and glucagon levels were measured by the double-antibody radioimmunoassay (RIA) technique. Serum immunoreactive trypsin (IRT) and hemoglobin A1 (HbA1) levels and height and weight were measured for each subject, and in addition, pulmonary function was assessed in those with CF. There were no significant differences in the area under the curve (AUC) for glucose or glucose or glucagon levels or the serum glucose disappearance rate (k value) between group I, group II, or CON subjects during the IVGTT. First-phase insulin and C-peptide secretion was abnormal during IVGTT and IVTTT in the CF groups: in group I it was severely impaired, whereas in group II it was between group I and CON values. During the IVTTT serum glucose levels and glucose k values were not significantly altered in any of the three groups as compared with the IVGTT.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7854159 TI - Metabolic modulation of the growth hormone-releasing activity of hexarelin in man. AB - Hexarelin (His-D-2-methyl-Trp-Ala-Trp-D-Phe-Lys-NH2) is a new potent synthetic growth hormone (GH)-releasing hexapeptide. The mechanism of action of hexarelin in man has never been evaluated. Hexarelin may act directly on specific pituitary receptors and indirectly on the hypothalamus. To elucidate its mechanism of action in man, we studied the interaction of hexarelin with glucose and free fatty acids (FFA), two metabolic factors known to inhibit both basal and GH releasing hormone (GHRH) stimulated GH secretion. Glucose is thought to inhibit GH secretion via stimulation of endogenous somatostatin release, whereas FFA could also act directly on somatotrope cells. Therefore, we investigated the effect of oral glucose (100 g) and lipid-heparin infusion (250 mL of a 10% lipid solution + 2,500 U heparin) on the GH response to a maximal dose (2 micrograms/kg intravenously [IV]) of hexarelin or GHRH in six normal men. Hexarelin elicited a clear-cut GH response (mean +/- SEM; peak, 62.6 +/- 8.0 micrograms/L) that was higher (P < .01) than that observed after GHRH (peak, 19.8 +/- 2.4 micrograms/L). Although similar increases in plasma glucose were observed with the two peptides, oral glucose almost abolished the GH response to GHRH (peak, 5.6 +/- 0.9 micrograms/L, P < .01) while only blunting the somatotrope response to hexarelin (peak, 38.4 +/- 7.9 micrograms/L, P < .05). Similarly, lipid-heparin infusion nearly abolished the GH response to GHRH (peak, 4.9 +/- 1.0 micrograms/L, P < .01) while only blunting the somatotrope response to hexarelin (peak, 34.2 +/- 4.5 micrograms/L, P < .05).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7854160 TI - Inhibition of hepatic very-low-density lipoprotein secretion in obese Zucker rats adapted to a high-protein diet. AB - The effect of a high-protein (HP) diet on hepatic very-low-density lipoprotein (VLDL) secretion was studied in obese and lean Zucker rats. With the control (C) diet, isolated hepatocytes from obese as compared with lean rats displayed higher uptake of [1-14C]oleate 0.7 mmol/L, 95% of which was esterified to glycerolipids; greater oleate incorporation into VLDL-triacylglycerol (TG); 2.6 times higher total VLDL-TG secretion; and 11-fold higher de novo fatty acid synthesis. Adaptation to HP feeding decreased weight gains in both phenotypes and hepatocyte TG content in obese rats. Oleate uptake by hepatocytes was appreciably reduced in the obese phenotype only. Despite esterification rates similar to those for the C diet, oleate incorporation into VLDL-TG decreased by 34% and 55% in obese and lean rats, respectively. Total (mass) VLDL-TG secretion was drastically decreased by 65% and 48% in obese and lean rat hepatocytes, respectively. HP feeding combined with overnight fasting accentuated the above decreases. Fatty acid synthesis was 50% lower in cells from HP-fed obese rats, but increased 1.7-fold in lean ones. Plasma glucagon increased in both phenotypes under HP feeding, whereas plasma insulin either increased (obese) or decreased (lean), with the insulin to glucagon ratio slightly decreasing. Thus, HP feeding drastically inhibited hepatic VLDL secretion in obese and lean Zucker rats by an undefined mechanism that was apparently related neither to de novo fatty acid synthesis nor to changes in oleate partitioning between esterification and oxidation. PMID- 7854161 TI - Age-related changes in musculoskeletal mass between black and white women. AB - Earlier studies from our laboratory indicated that matched black and white women differ significantly in total body potassium (TBK), total body bone density (TBD), and total body bone mineral (TBBM). The aim of this investigation was to examine absolute levels and the kinetics of age-related changes in TBK, TBD, TBBM, and percent body fat in a cross-sectional cohort of 34 matched pairs (age +/- 4 years, weight +/- 2 kg, and height +/- 4 cm) of black and white healthy non obese women. Black and white women had a similar percentage of body weight as fat, although adipose tissue distribution (ie, waist to hip circumference ratio [WHR]) differed significantly (P < .0007) between the two groups (WHR, mean +/- SD: black, 0.837 +/- 0.062; white, 0.788 +/- 0.043). TBBM and TBD were significantly (P < .0001) higher in young black women, and ethnic differences in total bone mineral mass persisted at all ages. TBK (P = 0.0482) and appendicular skeletal muscle mass (P < .0001) were higher in young black women; however, by ages 60 to 70 years, the two groups had similar TBK. Both groups of women lost musculoskeletal mass (ie, TBK and TBBM) and gained fat mass at similar rates. The results of this study suggest that black women have a greater appendicular muscle and skeletal mass, as well as upper-body fat distribution, than white women. These differences are independent of body weight, height, or percent fat, and the ethnic skeletal differences persist throughout the adult life span. The higher appendicular muscle mass, skeletal mass, and upper-body fat distribution suggest that black women may have greater androgenic activity than white women. PMID- 7854163 TI - Serum lipoprotein(a) levels before and after subtotal thyroidectomy in subjects with hyperthyroidism. AB - Lipoprotein(a) [Lp(a)], a lipoprotein that structurally resembles low-density lipoprotein (LDL), contains apolipoprotein(a) [apo(a)] and apolipoprotein B-100 (apo B). There exists a close inverse correlation between serum concentrations of LDL or apo B and concentrations of thyroid hormone in patients with thyroid disease, probably due to a change in LDL receptor activity. To clarify the relations between thyroid hormone and Lp(a), we measured serum Lp(a) levels in 13 hyperthyroid subjects before treatment (stage H), during the euthyroid stage induced immediately before performing a subtotal thyroidectomy (stage E), and during the hypothyroid stage observed transiently after the operation (stage L). The mean serum concentration of Lp(a) increased significantly (P = .01) from 9.4 mg/dL in stage H to 26.8 in stage L through the level of 15.5 mg/dL in stage E. There was no significant difference between the mean serum concentration of Lp(a) in these patients in stage E and healthy controls (14.2 mg/dL). There was a low but statistically significant negative correlation between the Lp(a) level and the serum free thyroxine (fT4) concentration (r = .31, P < .05). The results suggest that thyroid hormone is a potent modulator of Lp(a) metabolism. PMID- 7854162 TI - Fasting serum insulin in relation to components of the metabolic syndrome in European healthy men: the European Fat Distribution Study. AB - To investigate the "metabolic" syndrome in different European populations, samples of 38-year-old healthy men were randomly selected from six centers: Gothenburg (Sweden), Warsaw (Poland), Deinze (Belgium), Verona (Italy), Lumiar (Portugal), and Ede (The Netherlands). In total, 515 men were studied. Anthropometric measurements and blood pressure levels were taken by one or two operators in each center after a common operator's training course. Each blood parameter was analyzed in one laboratory. There were significant intercenter differences in mean values for anthropometric parameters, blood pressure, serum lipids (except for low-density lipoprotein [LDL] cholesterol), and fasting insulin. In particular, fasting serum insulin showed the highest values in Sweden and The Netherlands and the lowest values in Italy and Portugal. In pooled men, fasting insulin was strongly related (P < .001) to body mass index (BMI), waist to hip (WHR) and waist to thigh (WTR) circumference ratios, serum lipids (except for LDL cholesterol), and blood pressure. On the contrary, there were relevant differences in the correlation of insulin with serum lipids and blood pressure when the data were evaluated for each center. However, generally both in each center and in all centers together all these correlations disappeared after adjustment for BMI, with the exception of the correlation with serum triglycerides. In pooled men, multiple regression analysis showed an independent association of fasting insulin, BMI, and WHR with serum triglyceride (P < .001). On the contrary, total, LDL, and high-density lipoprotein (HDL) cholesterol and blood pressure values showed independent associations with BMI and/or WHR but not with fasting insulin in multivariate models.2+ off PMID- 7854164 TI - Role of basal insulin in maintenance of intracellular glucose metabolic pathways in non-insulin-dependent diabetes mellitus. AB - Impairments of both basal and insulin-stimulated oxidative (Gox) and nonoxidative (Nox) glucose metabolism are documented to exist in non-insulin-dependent diabetes mellitus (NIDDM). Although these defects have been well characterized during insulin stimulation, little is known about the effects of basal insulin or its deficiency on intracellular glucose metabolism in NIDDM. To determine the physiological significance of basal insulin in the maintenance of glucose metabolism in NIDDM, we studied nine subjects with NIDDM in the basal and insulin deficient state produced by 3 hours of somatostatin (SRIF) infusion (0.08 pmol/kg/min). Glucose turnover rates were quantified by [3-3H]glucose turnover, and substrate oxidation was assessed by a combination of indirect calorimetry and urinary nitrogen measurements. Skeletal muscle glycogen synthase (GS) and pyruvate dehydrogenase (PDH) activities were also measured in the basal state and during SRIF infusion. Basal glucose levels were maintained during SRIF infusion by exogenous glucose infusion (12.5 +/- 0.9 mmol/L in the basal state v 12.8 +/- 0.8 during SRIF infusion, P = NS). During the last hour of SRIF infusion, plasma C-peptide levels declined by 88% from 0.73 +/- 0.11 to 0.09 +/- 0.02 nmol/L (P < .001), and serum insulin concentrations were undetectable (< 14 pmol/L). During insulinopenic conditions, rates of glucose uptake (GU) were decreased by 12% from basal level of 2.26 +/- 0.13 to 1.99 +/- 0.12 mg/kg/min (P < .05), and were entirely accounted for by reduced rates of Gox (1.01 +/- 0.10 to 0.65 +/- 0.14 mg/kg/min, P < .01).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7854165 TI - Insulinotropic action of human glicentin in dogs. AB - Glicentin has been demonstrated to be released in response to the intraluminal administration of nutrients, but its biological action remains unknown. To clarify the effect of glicentin on the endocrine function of the pancreas, the present study was performed using an in vivo local circulation system of the canine pancreas. During infusion of 0.5% solution of glucose or arginine, 100 and 400 pmol glicentin and 400 pmol glucagon were administered into the pancreaticoduodenal artery (PA) within 10 minutes at 40-minute intervals successively. During glucose infusion, blood glucose in the femoral artery did not change following administration of 100 pmol glicentin, but slightly increased following 400 pmol glicentin. Plasma insulin (immunoreactive insulin [IRI]) in the pancreaticoduodenal vein (PV) increased significantly only following infusion of 400 pmol glicentin. Plasma glucagon (immunoreactive glucagon [IRG]), measured with a specific antiserum to the C-terminal portion of glucagon, did not change following administration of 100 pmol glicentin, but was slightly elevated following 400 pmol glicentin. Plasma total IRG, measured with a nonspecific antiserum, increased promptly after administration of 100 and 400 pmol glicentin. During arginine infusion, the response of plasma IRI to glicentin was markedly exaggerated both in dosages of 100 and 400 pmol. From the present study it was concluded that human glicentin clearly increases insulin release from the canine pancreas. PMID- 7854166 TI - Influence of the sympathetic nervous system on insulin sensitivity and adipose tissue metabolism: a study in spinal cord-injured subjects. AB - To evaluate insulin sensitivity and adipose tissue metabolism, seven spinal cord injured (SCI) subjects (age, 43 +/- 6 years; body mass index, 22.8 +/- 1.4; mean +/- SE) and their seven siblings (age, 45 +/- 6 years; body mass index, 24.8 +/- 0.8) were studied using oral glucose (100-g) tolerance tests (OGTTs), euglycemic insulin clamps (insulin infusion, 1 mU/kg.min), and microdialysis of the subcutaneous tissue. Blood glucose and insulin after oral glucose were significantly increased in SCI subjects as compared with their siblings. During insulin clamping, plasma adrenaline increased significantly in controls, but not in SCI subjects. However, the rates of glucose production (2.02 +/- 0.36 v 1.59 +/- 0.09 mg/kg.min) and utilization (5.13 +/- 0.71 v 5.78 +/- 0.34) were similar in the two groups. Furthermore, interstitial subcutaneous glycerol and lactate concentrations before and after oral glucose were similar in the two groups, even in neurally decentralized tissue with broken connection between the central nervous system and peripheral sympathetic nerves. The data suggest that (1) well mobilized SCI subjects show minor insulin resistance, and (2) sympathetic nervous activity has a minor influence on adipose tissue metabolism in the postabsorptive state, but may affect insulin sensitivity during euglycemic clamping. PMID- 7854167 TI - Protein and energy balance following femoral neck fracture in geriatric patients. AB - To elucidate the effect of total peripheral parenteral nutrition (TPPN) on protein kinetics following injury, we compared the whole-body leucine kinetic response using a primed-constant infusion of L-[1-14C]leucine in 33 elderly patients (aged 82 +/- 1.0 years) following hip fracture and 33 healthy elderly control subjects (aged 75 +/- 0.7 years). Following a 36-hour fast, leucine release from protein breakdown was 1.2 +/- 0.10 mumol.kg-1.min-1 and leucine incorporation into protein was 0.94 +/- 0.095 mumol.kg-1.min-1 in control subjects, and in injured subjects leucine release from protein breakdown was 1.3 +/- 0.14 mumol.kg-1.min-1 and leucine incorporation into protein was 0.97 +/- 0.092 mumol.kg-1.min-1. Control and injured subjects were then administered TPPN (protein, 1.5 g amino acids.kg-1; carbohydrate, 10.0 kcal.kg-1; lipid, 15.0 kcal.kg-1) for 24 hours, and leucine kinetics were redetermined. Compared with protein kinetics in the fasting state, leucine release from protein decreased to 1.0 +/- 0.14 mumol.kg-1.min-1 and leucine incorporation into protein increased to 1.16 +/- 0.097 mumol.kg-1.min-1 in control subjects. Injured patients also responded to TPPN with a decrease in leucine release from protein breakdown (1.12 +/- 0.156 mumol.kg-1.min-1) and an increase in leucine incorporation into protein (1.29 +/- 0.164 mumol.kg-1.min-1). These results indicate that in a geriatric population, whole-body leucine kinetics following hip fracture and the anabolic response to TPPN are not significantly altered from those of uninjured subjects.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7854168 TI - Effects of recombinant human growth hormone on basal metabolic rate in adults with pituitary deficiency. AB - The effect of recombinant human growth hormone (rhGH) on basal metabolic rate (BMR) was studied in a placebo-controlled, double-blind, crossover trial. Ten patients with a history of complete pituitary insufficiency were randomized for 26 weeks in each period. Three patients were excluded due to withdrawal, fever, and claustrophobia, respectively. All patients had received adrenal, thyroid, and gonadal substitution therapy for at least 1 year before the study. The dose of rhGH was 0.25 to 0.5 U/kg/wk, administered subcutaneously once a day in the evening. BMR was determined by indirect calorimetry in a computerized ventilated open-hood system. Body composition was examined using four different methods- computed tomography (CT), tritium dilution, 40K determinations, and total body nitrogen (TBN) measured with neutron activation. The body composition data have previously been reported. Fat-free mass (FFM) increased and body fat (BF) decreased during the first 6 weeks of rhGH treatment, but no further changes in body composition occurred between 6 and 26 weeks. Baseline BMRs in GH-deficient (GHD) patients were in the lower part of the reference range, but BMR and the ratio between BMR and FFM (BMR/FFM) were not significantly lower than in a carefully selected control group. BMR increased between 0 and 6 weeks (mean +/- SD: from 6.68 +/- 1.55 to 7.75 +/- 1.35 MJ/24 h, P < .001) and then remained unchanged between 6 and 26 weeks. The increase in BMR was closely related to the increase in FFM (r = .91, P < .01).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7854169 TI - Insulin resistance in rats harboring growth hormone-secreting tumors: decreased receptor number but increased kinase activity in liver. AB - Growth hormone (GH) is a potent antagonist of insulin action, and this resistance occurs primarily at a post-binding step(s). To elucidate the underlying mechanisms, the effects of chronic GH excess on the structure and function of insulin receptors partially purified from the liver were examined in rats harboring GH-secreting tumors. Insulin resistance was established in this animal model of GH hypersecretion by a hyperinsulinemic euglycemic clamp. Specific binding of 125I-insulin and receptor number were reduced in tumor animals by 40% and 62%, respectively, reflecting downregulation of the insulin receptor by hyperinsulinemia in these animals. Receptors from tumor animals showed a 50% increase in beta-subunit phosphorylation and in the kinase activity toward the synthetic polypeptide Glu4:Tyr1 when measured in vitro in the absence of insulin; however, the incremental stimulation by insulin (170 nmol/L) of the phosphorylation of either the beta-subunit or Glu4:Tyr1 was not different between control and experimental animals. There was no difference between the two groups in Glu4:Tyr1 phosphorylation measured after immunodepletion of receptors by antibodies to the insulin receptor, indicating that the observed alteration in the kinase activity of tumor animals was intrinsic to the insulin receptor. Exposure to chronic GH excess did not alter insulin receptor structure, as evidenced by electrophoretic mobility under reducing and nonreducing conditions. The enhanced basal kinase activity of the receptor from tumor animals may reflect a more highly phosphorylated state of the receptor (and hence elevated enzyme activity) in these animals due to elevated serum insulin levels. These results demonstrate that the hepatic insulin resistance in rats chronically exposed to GH excess is not due to impaired insulin receptor kinase activity. PMID- 7854170 TI - Modification of the responses of endothelin-1 to exhaustive physical exercise under simulated high-altitude conditions with acute hypoxia. AB - To assess whether acute alveolar hypoxia leads to the release of endothelin-1 (ET) in vivo, ET, cortisol (CORT), and lactate (LA) levels were determined in 15 healthy subjects at rest and during exhaustive incremental cycle ergometry on two separate test days. The subjects were to breathe a gas mixture with reduced O2 content ([H] fraction of inspired O2, 0.14) on one day and normal air on the other (N). Modified responses of LA and CORT to exhaustive incremental cycle ergometry on the H day indicated elevated anaerobic tissue metabolism and increased physical stress. With acute alveolar hypoxia, the response of ET to exhaustive physical labor was found to be augmented. PMID- 7854171 TI - Antihypertensive therapy with enalapril improves glucose storage and insulin sensitivity in hypertensive patients with non-insulin-dependent diabetes mellitus. AB - A double-blind, placebo-controlled, 4-week trial was performed to determine the antihypertensive and metabolic effects of enalapril (20 to 40 mg/d) in 16 hypertensive patients with non-insulin-dependent diabetes mellitus (NIDDM) aged 55 +/- 2 years and with a body mass index of 29 +/- 1 kg/m2. Glucose utilization was determined after an overnight fast and during insulin stimulation at 0 and 4 weeks (methods: euglycemic clamp, [3-3H]glucose infusion, indirect calorimetry). Enalapril decreased systolic (166 +/- 4 v 152 +/- 5 mm Hg, P < .05) and diastolic (102 +/- 2 v 95 +/- 2 mm Hg, P < .05) blood pressure. Peripheral insulin sensitivity, ie, insulin stimulation of glucose utilization, increased approximately 30%, or by 4.3 +/- 1.7 mumol/kg.min (13.1 +/- 2.0 v 17.4 +/- 3.5 mumol/kg.min, P < .05, 0 v 4 weeks) during enalapril treatment, but remained unchanged during placebo treatment (15.4 +/- 2.8 v 15.3 +/- 2.7 mumol/kg.min, respectively). The increase in glucose utilization during enalapril treatment was fully explained by an increase of 4.1 +/- 1.7 mumol/kg.min in glucose storage (4.1 +/- 1.2 v 8.1 +/- 2.9 mumol/kg.min, P < .05) while glucose oxidation remained unchanged. High-density lipoprotein (HDL) cholesterol increased by 8% (P < .05) and hemoglobin A1c (HbA1c) improved slightly (7.7% +/- 0.7% v 7.3% +/- 0.7%, P < .05) in the enalapril group, but not in the placebo group. We conclude that enalapril improves insulin sensitivity by increasing glucose storage in hypertensive patients with NIDDM.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7854172 TI - Relationship of smoking cessation and nicotine gum use to salivary androstenedione and testosterone in middle-aged men. AB - Cross-sectional studies have associated cigarette smoking in men with elevated androstenedione and little net effect on other sex steroids. However, it is not clear if such findings reflect the impact of nicotine exposure or if sex hormone levels change following smoking cessation. The relationship of the reported number of cigarettes smoked per day and salivary cotinine to salivary testosterone and androstenedione was examined in 221 men aged 35 to 59 years at baseline and 1 year following randomization into a clinical trial including a smoking-cessation intervention. At baseline, salivary cotinine was related to increased salivary androstenedione and testosterone following control for age, body mass, alcohol intake, and time of day of specimen collection (partial r = +.14 and +.30 P < .05 and .01, respectively). The reported number of cigarettes smoked per day was unrelated to either hormone. At the first annual visit, there was a significant decrease in the salivary androstenedione of men who had quite smoking and were currently using nicotine gum (94 v 60 pg/mL, P < .05, n = 34) and of men who had quit smoking and were not exposed to nicotine (86 v 56 pg/mL, P < .05, n = 48), whereas the salivary androstenedione of men who remained smokers at the first annual visit was unchanged (83 v 85 pg/mL, n = 139). Salivary testosterone levels were not significantly affected by a change in smoking status.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7854173 TI - Plasma glucose, insulin, and glucagon before and after long-term overfeeding in identical twins. AB - Plasma glucose, insulin, and glucagon levels were measured before and after long term overfeeding (4.2 MJ/d during a 100-day period) in 24 lean adults (12 pairs of monozygotic twins). Fasting plasma glucose, insulin, and glucagon were significantly increased by overfeeding. During a 75-g oral glucose tolerance test (OGTT), no major alteration in glucose tolerance was observed and insulin area under the curve was increased. During a meal test, insulin and glucagon areas under the curve were increased. The pre-overfeeding values for glucose, insulin, and glucagon (fasting and areas) were not correlated with the gains in body weight and in fat mass. However, fasting glucagon before overfeeding was positively correlated with the gains in abdominal visceral fat and in femoral fat. The changes with overfeeding in insulin area during the OGTT were positively correlated with the changes in total subcutaneous fat, even after adjustment for total body fat gain. Significant twin intrapair similarity was observed for fasting plasma glucagon before overfeeding and for the changes in fasting insulin and glucagon with overfeeding. These results indicate that (1) in response to long-term overfeeding, both fasting insulin and glucagon are increased; (2) initial levels of glucose, insulin, and glucagon do not predict the gains in body weight and total body fat during overfeeding, but are related to changes in indicators of fat topography; (3) the changes in total subcutaneous fat represent an important correlate of insulin changes with overfeeding; and (4) the genotype could be an important determinant of insulin and glucagon responses to a prolonged positive-energy-balance period. PMID- 7854174 TI - Stability of dimeric retroviral proteases. AB - The determination of dimer stabilities for the retroviral proteases has proved more challenging than anticipated, but it is a tractable problem when careful attention is made to potential interferences. For investigations of retroviral proteases not yet characterized, the fundamentally rigorous sedimentation equilibrium and other biophysical techniques may yet provide useful Kd values. They are preferable to the indirect methods emphasized in this chapter but nevertheless should be coupled with basic considerations such as recovery of activity at the end of an experiment and the relevance of values obtained to other situations. In the likely event that nanomolar Kd values are encountered in new investigations, the assay techniques provide the most readily available methods for many laboratories. Because these methods are sensitive to anything that affects enzyme activity, the use of complementary methods to verify dimerization constants is imperative. Inactivating reactions not due to monomer formation should be explored, and the potential impact of those reactions on the constants being measured should be estimated. Most of the Kd and dimerization rate data available for retroviral proteases are obtained with the HIV-1 protease, with each investigator choosing methods and solvent conditions different from the others. The confusing diversity of results should be the impetus for a direct comparison of methods for the identification of the sources of differences. If more comprehensive and rigorous measures of the kinetics and thermodynamics of subunit aggregation are obtained, they might be coupled with the large volume of detailed structural data accumulating for this class of protein to provide insights into more general problems of protein-folding chemistry. PMID- 7854175 TI - Use of steady state kinetic methods to elucidate the kinetic and chemical mechanisms of retroviral proteases. AB - Despite the current plethora of structural data of HIV-1 protease and the availability of potent inhibitors, whose structures are based in part on the presumed mechanism of action of this enzyme, our actual understanding of its chemical mechanism has been until now based largely on the precedents of the mammalian and fungal aspartic proteases and static three-dimensional data. The available steady state kinetic data of the protease, as reviewed here, constitute a first step in a detailed description of the mechanism of the enzyme to complement the structural data. PMID- 7854176 TI - X-ray structures of retroviral proteases and their inhibitor-bound complexes. PMID- 7854177 TI - Genetic approaches designed to minimize cytotoxicity of retroviral protease. PMID- 7854178 TI - Probing structure-function relationships in human immunodeficiency virus type 1 protease via molecular dynamics simulation. AB - This chapter has focused on the application of molecular dynamics computer simulations and related molecular modeling techniques to the study of HIV protease structure and structure-function relationships. The abundance of crystallographic data provides ample experimental quantities (average structures, temperature factors, and hydrogen bond topography) to validate the computational techniques employed. Furthermore, these studies provide insight into the structure and functional energetics of HIV-1 protease that would be difficult or impossible to study experimentally. This chapter covers studies that investigate correlated motion between and within subunits of the protease, mutants of the protease that disrupt the tertiary structure and dimer formation, and studies of HIV-1 protease-inhibitor complexes that rationalize both the protonation state of the active site and the observed binding strength of these complexes. These studies demonstrate that MD is capable of contributing to our understanding of structure-function relationships and may aid in the design of potential therapeutics. PMID- 7854179 TI - Relationships of human immunodeficiency virus protease with eukaryotic aspartic proteases. PMID- 7854180 TI - Processing of retroviral Gag polyproteins: an in vitro approach. PMID- 7854181 TI - Subsite preferences of retroviral proteinases. PMID- 7854183 TI - Host strain selection for bacterial expression of toxic proteins. PMID- 7854182 TI - Specificity of retroviral proteases: an analysis of viral and nonviral protein substrates. PMID- 7854184 TI - Expression systems for retroviral proteases. PMID- 7854185 TI - Rapid determination of endoprotease specificity using peptide mixtures and Edman degradation analysis. PMID- 7854186 TI - Design of tight-binding human immunodeficiency virus type 1 protease inhibitors. PMID- 7854187 TI - Design of symmetry-based, peptidomimetic inhibitors of human immunodeficiency virus protease. PMID- 7854188 TI - Advances in automated docking applied to human immunodeficiency virus type 1 protease. PMID- 7854189 TI - Use of molecular dynamics and free energy perturbation calculations in anti-human immunodeficiency virus drug design. PMID- 7854191 TI - Assay methods for retroviral proteases. AB - A variety of assay methods for retroviral proteases have been developed in response to different experimental requirements, such as initial identification of a protease, subsequent enzymatic characterization, and high-capacity automated screening of potential inhibitors. This chapter has reviewed a number of these methods above; most have been closely tailored to match specific experimental requirements, and some of them are described in greater detail in other chapters in this volume. They include analysis of polyprotein cleavage using SDS-PAGE, analysis of the determinants of substrate cleavage using either chromogenic peptides or reversed-phase HPLC for product separation after cleavage of unmodified peptides, and the design and utilization of quenched fluoregenic peptides for use in continuous assay. PMID- 7854190 TI - Qualitative study of drug resistance in retroviral protease using structural modeling and site-directed mutagenesis. PMID- 7854193 TI - Synthetic approaches to continuous assays of retroviral proteases. AB - This chapter has described a number of approaches for continuous assay of retroviral proteases using either chromogenic or fluorogenic synthetic substrates. The significant progress in this area has been catalyzed by the intense interest in HIV protease as a therapeutic target, but these versatile methods will be used widely in future for studies of many other proteases. PMID- 7854192 TI - Analysis of human immunodeficiency virus type 1 protease activity in eukaryotic and bacterial cells. PMID- 7854194 TI - Identification, purification, and cell culture assays of retroviral proteases. PMID- 7854196 TI - Failure of Saccharomyces boulardii to hydrolyse bile acids in vitro. AB - The bile acid deconjugating capacity of Saccharomyces boulardii was tested in isolated culture and in co-culture upon the bile acid metabolizing capacity of Bacteroides fragilis. S. boulardii was grown over 60 h in plain brain heart infusion (BHI) broth and in the presence of either 2 mM glycocholic or glycochenodeoxycholic acid under both aerobic and anaerobic conditions. S. boulardii did not metabolize either glycocholic acid or glycochenodeoxycholic acid. S. boulardii and B. fragilis were grown anaerobically together in BHI broth supplemented with either 0.1 mM glycholic acid or 0.1 mM glycochenodeoxycholic acid. When S. boulardii and B. fragilis were anaerobically co-cultured, S. boulardii did not alter the bile acid metabolism of B. fragilis. Specifically primary and conjugated bile acids decreased over time, while keto bile acids and free bile acids increased. S. boulardii not only fails to metabolize primary conjugated bile acids but it does not enhance or inhibit the bile acid metabolism of B. fragilis when the organisms are co-cultured in anaerobic medium. PMID- 7854195 TI - Influence of ammonium and 2,4-dichlorophenoxy acetic acid on nitrogenase activity in Azospirillum species from rice rhizosphere. AB - The influence of 2,4-dichlorophenoxy acetic acid (2,4-D) and ammonium on the nitrogenase activity of Azospirillum sp. under normal fixing and low-fixing conditions was evaluated. Nitrogenase activity was substantially stimulated following exposure to 2,4-D at various concentrations up to 5 ppm under normal fixing conditions. A pronounced enhancement in activity occurred with incubation. Significant reduction of the nitrogenase activity occurred in the presence of NH(4+)-N at almost all concentrations of 2,4-D. With incubation the toxic effects of combined nitrogen were alleviated in the presence of higher levels of 2,4-D. Results indicated that the toxic effects of a combination of agrochemicals on nitrogenase in Azospirillum sp. could be mitigated following a long exposure. PMID- 7854197 TI - Effects of temperature on the bactericidal activities of ciprofloxacin and levofloxacin against Escherichia coli and Pseudomonas aeruginosa. AB - The bactericidal activities of the 4-quinolones ciprofloxacin and levofloxacin against Escherichia coli and Pseudomonas aeruginosa in nutrient broth were drastically reduced as the temperature of incubation was decreased from 37 to 30 to 25 to 20 degrees C. With E. coli a biphasic response was observed with either 4-quinolone at any one of the four temperatures tested. At the optimum bactericidal concentrations (OBCs) of ciprofloxacin or levofloxacin against E. coli the activity at 20 degrees C was 68- and 56-fold less than at 37 degrees C, respectively. As expected, with P. aeruginosa biphasic responses were not observed so OBC values could not be estimated. At the peak serum concentrations of ciprofloxacin or levofloxacin the bactericidal activity against P. aeruginosa was reduced by 61- or 50-fold, respectively, as temperature was decreased from 37 to 20 degrees C. This was similar in scale to the reductions in bactericidal activity observed with E. coli at its OBC values. PMID- 7854198 TI - Simian virus 40 large tumour antigen is produced but not expressed in revertant cell lines RD2005 and RXHO24. AB - Revertant cell lines RD2005 and RXHO24 obtained from the reversion of the transformed cell lines TD2005 and TXHO24 produced Simian virus 40 large tumour antigen. Transformed cells resulted in the transfection of the FR3T3 cell line with the mutant plasmids of Simian virus (SV40) called D2005 and XHO24. The first plasmid D2005 encoded the large tumour (LT) antigen in its entire size. The second plasmid XHO24 encoded only a small portion: 19% of the LT-antigen. The analysis of the viral protein by immunoprecipitation showed the production of the LT protein in revertant cells. The LT oncogenes produced in revertant cells could not be expressed, because some cellular factors or some epigenetic and genetic events controlled their expression. The modulation of the expression of a viral oncogene could also be associated with alterations in the chromatin structures. This may explain the loss or the reacquisition of its activity, providing a useful dynamic heterogeneity model of tumoral progression in cancer cells. PMID- 7854199 TI - Stimulation of the autophagic activity in blastospores of Candida albicans exposed in vitro to fluconazole. AB - Blastospores of Candida albicans were exposed in vitro to fluconazole, a bis triazole which inhibits ergosterol biosynthesis in fungi by interfering with the cytochrome P-450 dependent 14 alpha-demethylase. Electron microscope examination revealed that a low dose (3 micrograms/ml), short treatment (1-3 h) with this compound greatly stimulated autophagic activity not accompanied by alterations of the cell organelles. Only rarely, wall thickenings and some damage to the membrane system, except for the plasma membrane, was noted. This unusual phenomenon suggests that in the presence of fluconazole, due to the depletion of ergosterol and the consequent accumulation of 14 alpha-methylsterols, changes are induced in the properties of the tonoplast. It seems that in the presence of the molecule the membrane is not able to distinguish what is to be degraded from what is still useful for intracellular metabolism with the consequent disintegration of cell compartmentation. Fluconazole may be useful for indicating the mechanism for controlling lytic activity and the homeostatic role of the vacuole in yeasts. PMID- 7854200 TI - Colony-like communities of bacteria. AB - The morphology and some other biological properties of colony-like communities are described. Colony-like communities are formed after the growth of large numbers of bacteria simultaneously plated onto the limited area of agar. The morphology of colony-like communities of bacteria of different genera and species is similar and differs from that of colonies of these microbes. The number of colony-forming units reaches a maximal value at 24 h and does not depend on the number of bacteria in inocula. PMID- 7854201 TI - Purification and characterization of the glucoamylase produced by a strain of Aspergillus flavus. AB - A strain of Aspergillus flavus isolated from an agricultural soil in Egypt produced a gluycoamylase which when purified had a molecular weight of 51,300 +/- 800 Daltons. The optimum pH for activity was 4 and the optimum temperature was 60 degrees C. The enzyme was stable at 70 degrees C for 15 min but denatured at 90 degrees C over 30 min. The Km value with soluble starch was 2.85 mg ml-1, and 10 mM HgCl2 inhibited the enzyme. It was possible to store the enzyme for at least 1 year at -20 degrees C without significant loss in activity. PMID- 7854202 TI - The endothelial vesicular system in cardiac capillaries subjected to hypoxia. AB - The precise role of the numerous plasmalemmal vesicles in capillary endothelia is unclear. They undoubtedly play a part in macromolecular transport across the endothelium but, as serial section studies have shown the vast majority of vesicles to be attached to either the luminal or abluminal membrane, it is possible that transport is not their primary role. The suggestion that vesicles form a membrane reserve was explored in capillaries of isolated perfused rat hearts subjected to hypoxia, which has been reported to cause endothelial cell swelling. Luminal, "cytoplasmic," and abluminal vesicles were counted and their diameters measured in well-oxygenated and hypoxic hearts and a number of other endothelial cell parameters were measured. Total capillary and luminal cross sectional area and luminal and abluminal membrane length decreased in hypoxia. There was no change in endothelial cell cross-sectional area despite an appearance of swelling. The numbers of abluminal and "cytoplasmic" vesicles did not change as a result of hypoxia. Luminal vesicles were, however, reduced in number but increased in size and density. The results are consistent both with the theory that the vesicles are a membrane reserve and that they may be present in order to expose membrane enzymes and receptors on the cell surface or internalise them in response to a variety of external stimuli. PMID- 7854203 TI - Increases in oxygen tension evoke arteriolar constriction by inhibiting endothelial prostaglandin synthesis. AB - In vivo and in vitro studies concerned with the role of oxygen in the regulation of blood flow have primarily investigated the response of blood vessels to decreases in oxygen tension. In this study, we examined the response of isolated rat cremaster skeletal muscle arterioles to increases in oxygen tensions. First order arterioles with an average diameter of 90 microns were cannulated and pressurized to 65 mm Hg and studied under constant pressure in a no-flow state. Arterioles were equilibrated in a Krebs bicarbonate-buffered solution (ph 7.4) gassed with 21% O2, 5% CO2, 74% N2. Changes in arteriolar diameters were continuously measured and recorded in response to increases in bath PO2 (20 to 660 mm Hg). Arterioles were studied before and after either the removal of the endothelium or the administration of indomethacin (IND, 10(-5) M), to inhibit prostaglandin synthesis. When the bath PO2 was increased from 20 to 150 mm Hg, arteriolar diameters decreased by 37%; they then decreased an additional 14% when bath PO2 was increased from 150 to 660 mm Hg. Removal of the endothelium or administration of IND completely eliminated the arteriolar constrictions in response to increases in PO2 from 20 to 150 mm Hg, and from 150 to 660 mm Hg. These observations suggest that rat cremaster arterioles constrict to increases in oxygen tension by reduction in the synthesis of endothelium-derived dilator prostaglandins. PMID- 7854204 TI - Cell-associated proteoglycans of retinal pericytes and endothelial cells: modulation by glucose and ascorbic acid. AB - Abnormalities of retinal pericytes and endothelial cells are prominent features of diabetic retinopathy. In this study, we used cultures of bovine retinal cells to examine the regulation of cell-associated proteoglycans, a class of highly sulfated macromolecules important in the regulation of cell growth. Bovine retinal pericytes and endothelial cells were radiolabeled with 35SO4 and cell associated proteoglycans were removed from the cell surface, quantified, and characterized. The effects of high glucose concentration (25 mM), phorbol 12,13 dibutyrate (PDBu, 0.1 microM), and ascorbic acid (0.1 mM) on cell-associated proteoglycans and growth of these cells were studied. Our results showed that both the ionically bound and the membrane-intercalated forms of cell-associated proteoglycans are present on retinal cells. The predominant cell-associated proteoglycan of pericytes is chondroitin sulfate and for endothelial cells it is heparan sulfate. High glucose concentration and ascorbic acid increased the cell associated proteoglycans on pericytes but reduced them on endothelial cells. In contrast to this divergent trend, high glucose concentration and ascorbic acid inhibited the growth of both pericytes and endothelial cells. The effects of high glucose on retinal cell-associated proteoglycans were mimicked by PDBu added in a manner to stimulate protein kinase C activity. We conclude that cell-associated proteoglycans are present on retinal pericytes and endothelial cells. High glucose concentration and ascorbic acid affect cell-associated proteoglycans of these two cell types in opposite directions, whereas both suppress the growth of the two cell types. Therefore, it is not likely that high glucose concentration and ascorbic acid change the rate of retinal cell growth directly by affecting cell-associated proteoglycan levels. PMID- 7854205 TI - Slightly altered permeability-surface area products imply some cerebral capillary recruitment during hypercapnia. AB - To test the capillary recruitment hypothesis in brain, cerebral blood flow was raised markedly in rats by exposure to 8% CO2 (hypercapnia), and capillary permeability-surface area (PS) products were measured. Local cerebral blood flow (LCBF), volume of radiolabeled blood in parenchymal microvessels (also referred to as the blood space or Vb), plus the local capillary influx rate constants (K1) and PS products of [14C]antipyrine and 3-O-[14C]methyl-D-glucose (3OMG) were estimated in 44 brain areas. Hypercapnia raised PaO2 to 140 mm Hg, elevated LCBF by two- to threefold through out the brain, and increased Vb from 5 to 33% (mean = 22%) in 42 of 44 brain areas; hypercapnia did not, however, alter microvessel hematocrit. With hypercapnia, the influx of antipyrine was increased by 40-65% in all brain areas, and the PS products of antipyrine were elevated from 0-35% (mean = 17%). The PS products of antipyrine plus the parenchymal blood spaces suggest modest (< 30%) capillary recruitment in most brain areas as well as some microvessel dilation, mainly in forebrain gray matter and white matter areas. In contrast, hypercapnia did not appreciably alter K1 nor PS of 3OMG; it slightly but not significantly raised the blood levels of glucose. In view of the blood space and antipyrine evidence for modest capillary recruitment and vasodilation, the lack of change in PS of 3OMG implies that glucose transporter activity was lowered by hypercapnia, an effect similar to that reported for high-dose pentobarbital. Finally, the microvessel hematocrit and 3OMG data suggest that cerebral capillary permeability (P) was not increased by hypercapnia. Overall, hypercapnia seems to increase LCBF mainly by raising the velocity of blood flow; capillary recruitment and dilation appear to play relatively minor roles in this flow increase. PMID- 7854206 TI - Mechanisms of cholera toxin prevention of thrombin- and PMA-induced endothelial cell barrier dysfunction. AB - Thrombin-induced endothelial cell (EC) activation leads to compromise of monolayer barrier function due to cellular retraction/contraction and intercellular gap formation. Cyclic AMP induces relaxation in other contractile cells and promotes barrier function in EC. To investigate mechanisms involved in cAMP protection in thrombin-induced permeability, we pretreated bovine pulmonary arterial EC monolayers with 1 microgram/ml cholera holotoxin which catalyzed ADP ribosylation of Gs and increased synthesis of cAMP. The holotoxin, but not the binding subunit, reduced basal permeability and prevented gap formation and permeability following challenge with 1 microM thrombin, 100 microM thrombin receptor-activating peptide, or 1 microM phorbol myristate acetate (PMA). Furthermore, thrombin-induced gap formation and permeability were reversed by cholera toxin post-treatment. Pretreatment with 5 microM forskolin or 1 mM dibutyryl cAMP, with or without 1 mM isobutyl methylxanthine, but not cGMP analogs, protected against thrombin-induced EC permeability, mimicking the cholera toxin effect. Although downregulation of protein kinase C attenuated both thrombin- and PMA-induced permeability, cholera toxin did not alter either PMA induced protein kinase C activation or thrombin-induced Ca2+ mobilization. In contrast, cholera toxin attenuated thrombin-induced myosin light chain phosphorylation and largely prevented actin redistribution. These studies suggest that cholera toxin: (1) protects endothelial barrier function and reverses established dysfunction via increased cAMP (2) does not alter thrombin receptor interaction or early signal events such as Ca2+ mobilization and PKC activation, (3) attenuates myosin light chain kinase activation and actomyosin contractile interaction subsequent to thrombin activation, and (4) abrogates contractile processes subsequent to PKC activation, which is also an important mechanism in thrombin-induced permeability but is independent of myosin light chain kinase activation. PMID- 7854207 TI - Transperineurial capillary abnormalities in the sural nerve of patients with diabetic neuropathy. AB - Morphometric techniques were employed to assess perineurial capillary abnormalities in the sural nerve of 20 diabetic patients with neuropathy and 10 normal control subjects. Structural abnormalities were related to quantitative neurophysiological and neuropathological measures of neuropathy. Perineurial capillary endothelial cell area (P < 0.001) and endothelial cell profile number (P < 0.01) were increased and luminal area (P < 0.001) was reduced in diabetic patients when compared with control subjects. A significant relationship was observed between endothelial cell hyperplasia and measures of neuropathic severity. These findings provide evidence for perineurial capillary luminal occlusion due primarily to both endothelial cell hypertrophy and hyperplasia. Such a reduction in luminal size is expected to reduce transperineurial and hence endoneurial blood flow, resulting in endoneurial hypoxia and hence human diabetic neuropathy. PMID- 7854208 TI - Changes in vessel pressure and interstitial fluid pressure of normal subcutis and subcutaneous tumor in rats due to angiotensin II. AB - To elucidate the mechanism of enhancement of transport of anticancer drugs into tumor tissue due to angiotensin II (AII), changes in microvascular pressure (MVP) and interstitial fluid pressure (IFP) due to AII were measured in normal subcutis and subcutaneous tumor in rats. Two different tumor cell lines AH109A and AH272 were used. MVP and IFP were measured using a microocclusion method and a diffusion chamber method, respectively. Insignificant changes in the pressure of normal venous vessels and the IFP of normal subcutis were brought about by AII induced hypertension. In both AH109A and AH272, the IFP of the same region within the tumor increased with enlargement of tumor volume. The IFP of AH109A tumor (tumor volume = 1.8-2.2 cm3) increased slightly due to AII, but the tumor MVP of AH109A and AH272 increased markedly. Though both tumor IFP and MVP increased significantly due to AII, the increases the hydrostatic pressure difference between tumor vascular and interstitial spaces and leads to enhancement of the efficiency of filtration from tumor vessels to tumor tissue, which is one of the mechanisms of enhancement of drug delivery to tumor tissue due to AII. PMID- 7854209 TI - Siderophore-mediated utilization of iron bound to transferrin by Vibrio parahaemolyticus. AB - Vibrio parahaemolyticus produces a structurally novel type of siderophore, termed vibrioferrin, in response to iron-limitation. This study was performed to examine whether vibrioferrin can assimilate iron from human iron-binding proteins for growth. Comparison of the growth rates between V. parahaemolyticus AQ 3354 and its spontaneously arising, vibrioferrin-deficient mutant revealed that vibrioferrin was able to sequester iron from 30% iron-saturated human transferrin for growth, but not from human lactoferrin even if fully saturated with iron. In both strains, iron limitation induced two high-molecular-weight outer membrane proteins with apparent molecular masses of approximately 78 and 83 kDa. Since only the outer membrane fraction including these proteins showed a binding capacity to ferric vibrioferrin complex, either of them may function as its cell surface receptor. These results suggested that the organism might utilize such a source of host iron through the action of vibrioferrin during in vivo survival and proliferation, although its importance in pathogenesis is unknown. PMID- 7854210 TI - Prevalence of colonization factor antigens (CFAs) and adherence to HeLa cells in enterotoxigenic Escherichia coli isolated from feces of children in Sao Paulo. AB - Fifty-eight enterotoxigenic Escherichia coli (ETEC) strains, isolated from children with and without diarrhea in Sao Paulo, were examined for the presence of colonization factor antigens (CFAs) and their ability to adhere to HeLa cells. Antisera to CFA/I, the coli surface (CS) antigens CS1CS3, CS2CS3, and CS2 of CFA/II, CFA/III, and CS5CS6 and CS6 of CFA/IV were used. CFAs were identified in 43% of the ETEC strains: 40% of the CFAs strains with CFAs harbored CFA/I, 24% carried CFA/II (CS1CS3), 24% carried CFA/IV (CS6), and 12% carried CFA/IV (CS5CS6). CFAs occurred mainly among ETEC strains producing only heat-stable (ST I) enterotoxin and in strains also producing heat-labile toxin (LT-I). No ETEC strains tested expressed CFA/III. A marked change in serotypes of ST-I-producing strains was found in Sao Paulo between 1979 and 1990. Adherence to HeLa cells was detected in 14% of the ETEC strains. All of them had a diffuse adherence pattern and produced only ST-I, and 88% carried CS6 antigen. PMID- 7854211 TI - The role of tumor necrosis factor in host defense against scrub typhus rickettsiae. I. Inhibition of growth of Rickettsia tsutsugamushi, Karp strain, in cultured murine embryonic cells and macrophages by recombinant tumor necrosis factor-alpha. AB - Recombinant murine tumor necrosis factor-alpha (TNF-alpha) inhibited intracellular growth of Rickettsia tsutsugamushi, Karp strain, in the mouse embryo cell line C3H/10T1/2 clone 8 at doses of 100 to 10 U/ml. The growth inhibitory effect of TNF-alpha was also evident when peritoneal exudate macrophages or bone marrow-derived macrophages were used as the host cell for rickettsial growth. Interferon-gamma (IFN-gamma), at doses up to 1,000 U/ml, did not affect the growth of this strain of rickettsiae in the mouse embryo cell line but, as expected, profoundly inhibited rickettsial growth in peritoneal exudate macrophages and bone marrow-derived macrophages. The effect of TNF-alpha on rickettsial growth in the mouse embryo cell line was not reproducibly enhanced by IFN-gamma. Treatment of the cell line with TNF-alpha delayed rickettsial cytopathic effects, but the rickettsiae ultimately grew to high numbers in the cells and caused cell death. These findings show that, at least in our system, R. tsutsugamushi is resistant to IFN-gamma-mediated antirickettsial effects in cells other than macrophages. The results of this study support the suggestion that TNF alpha may inhibit rickettsial growth in cells other than macrophages. PMID- 7854212 TI - The role of tumor necrosis factor in host defense against scrub typhus rickettsiae. II. Differential induction of tumor necrosis factor-alpha production by Rickettsia tsutsugamushi and Rickettsia conorii. AB - The present study was undertaken to investigate the ability of members of two different groups of Rickettsia to stimulate macrophages or immune lymphocytes to produce TNF. It was found that R. conorii, a spotted fever group rickettsia, readily induced murine peritoneal macrophages or the macrophage-like cell line P388D1 to produce relatively high levels of TNF. The interaction of macrophages with viable organisms or heat-killed organisms resulted in TNF production. In contrast, viable or killed R. tsutsugamushi did not stimulate the production of detectable TNF even though viable organisms grew to high numbers in both cell types. It was found that the appropriate immune spleen cells stimulated with heat killed R. tsutsugamushi or R. conorii produced TNF, and TNF activity was found in the sera of immune mice after injection with rickettsial antigen. Infection of naive mice with viable R. tsutsugamushi resulted in high TNF levels in ascites, but TNF was not found in ascites obtained from infected athymic (nu/nu) mice. These data support the suggestion that spotted fever group rickettsiae, such as R. conorii, possess components perhaps on the surface that interact with macrophages to induce TNF production and this component is lacking in R. tsutsugamushi. Antigens of R. tsutsugamushi and R. conorii will stimulate immune cells to produce TNF activity. These data are compatible with the suggestion that the TH-1 subset of T cells is predominant in immunity to R. tsutsugamushi. PMID- 7854213 TI - Target cells of cytotoxic T lymphocytes directed to the individual structural proteins of rabies virus. AB - Target cells of cytotoxic T lymphocytes (CTL) directed to the individual structural proteins (except for the large polymerase (L) protein) of rabies virus were established by expressing only the respective protein in murine neuroblastoma (NA) and murine macrophage (J774-1) cell lines. Mice infected with the ERA strain of rabies virus developed CTL responses to all of these rabies virus proteins. The cytotoxic activity was abrogated by pretreatment of the effector cells with anti-CD8 monoclonal antibody (MAb) and complement but not with anti-CD4 MAb. Cell lysis by CTL was blocked in the presence of anti-major histocompatibility complex (MHC) class 1 antibodies in J774-1 cell lines. Rabies virus-infected cells express these proteins at the surface, which can be recognized and lysed by the respective CTL. Mice immunized with beta propiolactone-inactivated virus induced a CTL response against glycoprotein but not against internal viral components. This assay system might be useful for further analysis of the possible contribution of these proteins in the cell mediated immune protection against rabies. PMID- 7854214 TI - Characterization of immunological activity of a low toxicity antitumor lipopolysaccharide from Bordetella pertussis. AB - Immunological properties of a low toxicity lipopolysaccharide (BP-LPS) extracted from Bordetella pertussis (Tohama strain) which was reported to have high antitumor activity against murine tumors were examined and compared with those of LPS extracted from other enterobacteria. The activation or stimulation of murine macrophages and lymphocytes by these LPS, including TNF induction, was found to be similar. However, BP-LPS was clearly less active in its stimulation of murine and human neutrophils as estimated by neutrophil-adherence assay and by their TNF production than E. coli LPS. Furthermore, BP-LPS also suppressed the activation of human neutrophils by Escherichia coli LPS. A comparative study with 7 LPS preparations indicated that their toxicity in terms of animal body weight loss correlated with their ability to induce human neutrophil adherence. The inability of BP-LPS to activate neutrophils may thus have some bearing on its low toxicity. PMID- 7854215 TI - Augmentation of host resistance against bacterial infection by treatment with leustroducsin B, a new CSF inducer. AB - We tested the in vivo activity of leustroducsin B (LSN B), a new colony stimulating factor (CSF) inducer isolated from the culture broth of Streptomyces platensis, with mice infected with Escherichia coli. Treatment with LSN B augmented the host resistance to lethal infection of E. coli at doses between 0.1 mg/kg and 1 mg/kg. Serum interleukin-6 (IL-6) levels were found to increase after this treatment, and superoxide anion generation of neutrophils was enhanced in vivo, suggesting that LSN B augmented the host resistance at least in part by inducing IL-6, which subsequently enhanced the bactericidal activity of the neutrophils. PMID- 7854216 TI - Complement-mediated killing of Borrelia garinii--bactericidal activity of wild deer serum. AB - The susceptibility of Borrelia garinii to fresh wild deer sera was determined by incubating strain SIKA2 at 10% serum concentration for 1 hr at 37 C in an in vitro bactericidal assay. Each serum showed bactericidal effects at various levels. The effect was dependent on the concentration of antibody to the spirochetes. Complement was essential in the bactericidal assay because the inactivated deer serum showed greatly decreased activity. Our results suggest that B. garinii is sensitive to deer serum, in the presence of antibody and the bactericidal effect is important for preventing Lyme disease in wild sika deer. PMID- 7854217 TI - Isolation and classification of temperature-sensitive mutants of influenza B virus. AB - We isolated 25 temperature-sensitive mutants of B/Kanagawa/73 strain generated by mutagenesis with 5-fluorouracil and classified them into seven recombination groups by pair-wise crosses. All mutants showed a ratio of plaquing efficiency at the nonpermissive temperature (37.5 C) to the permissive temperature (32 C) of 10(-4) or less. At 37.5 C most of group I, II, and III mutants did not produce appreciable amounts of protein, but all other group mutants were protein synthesis-positive. A group VII mutant produced active hemagglutinin (HA) and neuraminidase (NA) at the nonpermissive temperature, but Group V mutants produced only active NA and were defective in the HA molecule. The other group mutants, including group IV mutants with mutation only in the NA gene (8, 10), lacked both activities at the nonpermissive temperature. One of nine influenza B virus isolates in 1989 had EOP 37.5/32 of 1/3 x 10(-2) and belonged to recombination group VII. PMID- 7854218 TI - Comparison of cytokine induction by lipopolysaccharide of Bacteroides fragilis with Salmonella typhimurium in mice. AB - Comparison of cytokine stimulation by lipopolysaccharide (LPS) of Bacteroides fragilis and Salmonella typhimurium was done to study the early events occurring in vivo. Mice injected intraperitoneally with either LPS demonstrated endogenous production of all the cytokines studied (tumor necrosis factor-alpha, interferon gamma and interleukin-6) within 6 hr in the bloodstream. However induction of all the cytokines by B. fragilis LPS (50 micrograms/mouse) was much weaker compared with S. typhimurium LPS (50 micrograms/mouse). Even a dose of S. typhimurium LPS 40 times smaller (1.2 micrograms/mouse) induced cytokines more strongly compared with B. fragilis LPS. Thus, a weak biological response to B. fragilis LPS as evidenced by chick embryo lethality, limulus lysate gelation, LD50 for mice and rabbit pyrogenicity could be due to weak induction of bioactive mediators by LPS. PMID- 7854219 TI - Is drinking water a hazard to our health? PMID- 7854220 TI - New antiepileptic medications. PMID- 7854221 TI - Murray River water, raised cyanobacterial cell counts, and gastrointestinal and dermatological symptoms. AB - OBJECTIVE: To investigate whether exposure to Murray River and allied water sources during a period of raised cyanobacterial cell counts was associated with gastrointestinal and dermatological symptoms. DESIGN: A case-control study selecting gastrointestinal and dermatological cases and controls from subjects attending 21 general practitioners in eight Murray River towns. The association between the proportion of consultations for such symptoms and mean log cyanobacterial count was also examined. SUBJECTS: 102 gastrointestinal cases, 86 dermatological cases and 132 controls. MAIN OUTCOME MEASURE: The relative odds of gastrointestinal and dermatological symptoms, respectively, as opposed to no such symptoms, according to water-contact history during the week preceding the medical consultation. RESULTS: After adjusting for concurrent risk factors, subjects drinking chlorinated river water rather than rain water had a raised risk of gastrointestinal symptoms (P = 0.008), and those using untreated river water for domestic purposes rather than rain water had a raised risk of gastrointestinal (P = 0.034) and of dermatological (P = 0.048) symptoms. The proportion of consultations for gastrointestinal and dermatological symptoms correlated on a weekly basis with the mean log cyanobacterial cell count, although statistical significance was not achieved for the correlation with dermatological consultations or for separate reaches of the river. CONCLUSIONS: The raised risks of gastrointestinal and dermatological symptoms in those using Murray River water for drinking and other domestic purposes are consistent with causal relationships. However, the evidence for adverse health effects is, at best, only suggestive. Further research is indicated. PMID- 7854222 TI - The criminal justice system and the sexually abused child. Help or hindrance? AB - OBJECTIVE: To assess the progress of 59 sexually abused children in the criminal justice system to see whether they testified, whether there were any effects on their self-esteem or behaviour, whether it resulted in depression and what their parents' perceptions of the process were. DESIGN: A prospective study of sexually abused children, with data from interviews with the parents and psychological testing of the children. RESULTS: Thirty-three cases were committed for trial or sentencing, resulting in 20 convictions. Twenty-two children testified at the committal hearing and eight at trials. Although 55% of parents expressed dissatisfaction with the legal system, thinking it was stressful to their children, a comparison of children who did not testify with those who did showed no significant differences on indices of depression, self-esteem or behaviour. As most children were involved in court-preparation programs and most mothers were supportive of their children, these may have been ameliorating factors. CONCLUSIONS: Even though the initial stressful effects of children appearing in court appear to be transient, there should be increased use of screens, closed circuit television and preparation-for-court programs to make court appearances less intimidating. PMID- 7854223 TI - Laparoscopic surgery in women with a clinical diagnosis of acute appendicitis. AB - OBJECTIVES: To assess the routine use of diagnostic laparoscopy and laparoscopic appendicectomy in women with a clinical diagnosis of acute appendicitis. METHODS: Women who presented with a clinical diagnosis of acute appendicitis between 1 January 1992 and 31 August 1993 were prospectively assessed and 107 underwent diagnostic laparoscopy. RESULTS: Appendicitis was confirmed in 63 women (59%) and no diagnosis could be made in seven (6%). An alternative diagnosis, most commonly a gynaecological disorder, was made in 37 women (35%). Twenty-eight women with an alternative diagnosis (76%) did not require a laparotomy. Seventy-three patients had a laparoscopic appendicectomy, with an 8% conversion rate to an open operation. The morbidity rate for laparoscopic procedures was 3%, the median inpatient stay was two days and the median time to return to normal activities was eight days. CONCLUSIONS: Diagnostic laparoscopy should be performed in women who present with a clinical diagnosis of acute appendicitis to confirm the diagnosis, reduce the rate of unnecessary appendicectomy and avoid an unnecessary laparotomy. When acute appendicitis is confirmed, appendicectomy may be performed laparoscopically. PMID- 7854224 TI - Juvenile myoclonic epilepsy: diagnosis, management and outcome. AB - OBJECTIVES: To study delay in diagnosis, seizure control, seizure-provoking factors, suitable medications and drug side effects in patients with juvenile myoclonic epilepsy. DESIGN: Telephone and personal interview of patients and review of their clinical notes. PARTICIPANTS AND SETTING: Thirty-six patients attending an epilepsy clinic at a tertiary referral hospital. RESULTS: There was a substantial delay in the diagnosis of juvenile myoclonic epilepsy because the symptom of early-morning myoclonus was not specifically sought. Sodium valproate is the drug of choice, producing absolute seizure control in 63% of cases (19/30). Most patients with poor seizure control had provoked seizures only, emphasising the importance of lifestyle in management. Half of the patients taking sodium valproate experienced side effects, such as weight gain. Lamotrigine is the most suitable alternative. CONCLUSIONS: Juvenile myoclonic epilepsy is a common, under-recognised form of epilepsy which is best treated with sodium valproate. If side effects occur, lamotrigine should be used. PMID- 7854225 TI - Emergency contraception. General practitioner knowledge, attitudes and practices in New South Wales. AB - OBJECTIVES: To assess the knowledge, attitudes and practices of general practitioners in New South Wales regarding the provision of emergency contraception. DESIGN: Randomised group comparison of 100 rural and 100 urban general practitioners (GPs) by questionnaire. RESULTS: Eighty-four rural and 76 urban GPs responded. More rural GPs were knowledgeable about emergency contraception than urban GPs (95% v. 78%), and more women knew about it than men. More urban GPs frequently prescribed emergency contraception than rural GPs (26% v. 6%) and female GPs prescribed it more readily than male GPs (22% v. 12%). There was great variation in the regimens prescribed, especially among rural GPs. Twenty-five per cent of urban GPs and 31% of rural GPs did not offer women information about emergency contraception, while 16% of both groups included such information in any discussion about contraceptive options, and 18% gave information only if requested by the woman. More than 60% of the GPs would provide information about emergency contraception as a back-up to use of barrier methods. CONCLUSIONS: The sex, attitude and knowledge of the GPs influence the likelihood of women being made aware of or being given emergency contraception in NSW. There is a need to further educate both the public and practitioners about emergency contraception. PMID- 7854226 TI - Mental health care practices and educational needs of general practitioners. AB - OBJECTIVES: To describe current mental health care practices of general practitioners and to identify their educational priorities and training preferences. METHOD: Self-administered questionnaire to a stratified random sample of New South Wales general practitioners. SUBJECTS: 721 full-time general practitioners, of whom 534 (74%) responded. RESULTS: Mental health problems recognised by general practitioners at least once per week were psychosomatic (93%), emotional (89%), addiction (79%), social/economic (71%) and family (69%). At least two-thirds recognised sexual problems, sexual abuse and major psychiatric problems less frequently than once per week. Sixty-four per cent of general practitioners reported that patients felt uncomfortable about being referred to psychiatrists; 53% that referral service waiting lists were too long; 51% that there were insufficient local mental health services; and 25% that communication difficulties between referring general practitioners and mental health specialists obstructed optimal care. Educational priorities were diagnostic and counselling skills, with particular emphasis on crisis, family, individual and marital counselling and strategies to prevent general practitioner burn-out. CONCLUSIONS: General practitioners are interested in improving their mental health counselling and diagnostic skills but barriers remain. Both structural and educational initiatives are essential to enhance the quality of mental health care in general practice. PMID- 7854227 TI - Lessons from a training program for methadone prescribers. PMID- 7854228 TI - The clinical use of ondansetron. New South Wales Therapeutic Assessment Group. AB - OBJECTIVE: To establish guidelines for use of ondansetron. DATA SOURCES: MEDLINE computer search (to July 1993) and information from the manufacturer. DATA EXTRACTION: We circulated a position paper based on our literature review for comment by clinicians and directors of pharmacy in major teaching hospitals in New South Wales who had an interest in ondansetron. DATA SYNTHESIS: Ondansetron is effective in the control of nausea and vomiting occurring 24-48 hours after highly emetogenic chemotherapy and after radiotherapy. There are no data to support its use in delayed emesis. Combination with dexamethasone may improve emetic control. The most commonly reported adverse effects are headache and constipation. Optimal dose, frequency of dosing and route of administration have not been established. The cost for each inpatient treated successfully is about 3% more than conventional antiemetic therapy. CONCLUSIONS: Ondansetron shows clinical benefit in the management of acute nausea and vomiting in patients receiving highly emetogenic chemotherapy, those who have responded poorly to other antiemetics after moderately emetogenic chemotherapy, those who have intolerable side effects with conventional antiemetic agents and those receiving radiotherapy to the upper abdomen. It is also marketed for the prevention and treatment of postoperative nausea and vomiting. PMID- 7854229 TI - The changing epidemiology of human hookworm infection in Australia. AB - OBJECTIVE: To document the distribution of human hookworm infection in Australia. DESIGN: A retrospective study of published data and accessible archival records. METHODS: The core data were derived from the report of the Australian Hookworm Campaign, annual reports of various State health departments and the Queensland Institute of Medical Research, and unpublished files of the former Queensland Aboriginal Health Programme. FINDINGS: Today, hookworm infection is endemic only among Aboriginal communities of northern Western Australia and the Northern Territory, where Ancylostoma duodenale may be the sole species. Early this century, infection was also established in Queensland and northern New South Wales, in both Aboriginal and white communities, and Necator americanus predominated. The origin of these parasites is obscure. Sustained control programs seem to have eradicated hookworms from Queensland. CONCLUSIONS: Improved sanitation, hygiene and chemotherapy have eliminated hookworms from white populations of Australia. Continued anthelminthic campaigns will also clear the parasites from Aboriginal communities, but unless living conditions improve significantly infection will recur. PMID- 7854230 TI - Lower gastrointestinal tract. 1. Constipation. AB - An accurate diagnosis is of primary importance in lower gastrointestinal problems in the elderly. Reversible causes should be treated specifically whenever possible, but symptomatic treatment can be a useful adjunct or a mainstay if no cause can be found. For constipation symptomatic treatment should proceed stepwise, commencing with increase in dietary fibre content. Only if this approach fails should laxatives (osmotic) be used. Stimulant laxatives and paraffin are best used intermittently, if at all, because of their side effects. PMID- 7854231 TI - Ipratropium, sodium cromoglycate and antihistamines. PMID- 7854232 TI - Who bears the costs of antidepressants in Australia? PMID- 7854233 TI - Who bears the costs of antidepressants in Australia? PMID- 7854234 TI - Who bears the costs of antidepressants in Australia? PMID- 7854235 TI - Who bears the costs of antidepressants in Australia? PMID- 7854236 TI - Who bears the costs of antidepressants in Australia? PMID- 7854237 TI - Abnormal vaginal bleeding is common, malignancy rare. PMID- 7854238 TI - Hepatitis C on the north coast of NSW. PMID- 7854240 TI - Occupation and the carpal tunnel syndrome. PMID- 7854241 TI - Angiosarcoma of the liver in Australia. PMID- 7854239 TI - Tarsal tunnel syndrome. PMID- 7854242 TI - Is cerebral concussion a transient phenomenon? PMID- 7854243 TI - The Royal Flying Doctor Service of Australia: its foundation and early development. PMID- 7854244 TI - Generic prescribing. PMID- 7854245 TI - Political unrest in Europe: a medical student perspective. PMID- 7854246 TI - Post-Q fever syndrome. PMID- 7854247 TI - The Royal Flying Doctor Service of Australia: its foundation and early development. PMID- 7854248 TI - Use of fluorochromes for direct enumeration of total bacteria in environmental samples: past and present. AB - Understanding the role of bacteria in microbial food webs is intimately connected to the methods applied in the direct enumeration of bacteria. We have examined over 220 papers describing studies in which fluorochrome staining followed by epifluorescent microscopic direct counts was used to estimate total bacterial abundances. In this review, we summarize patterns in the use of 3,6 bis[dimethylamino]acridinium chloride (acridine orange) and 4',6-diamidino-2 phenylindole (DAPI), the two stains most frequently used in bacterial enumeration. The staining of samples with these fluorochromes, followed by filtration and direct counting of bacterial cells on filter surfaces, has become routine over the past 10 years. We examine trends in features of the standard direct count methods, such as sample preservation and preparation techniques, membrane filter types used, applied stain concentrations, duration of staining, and counting strategies, in relation to the types of samples being examined. The high variability in bacterial counts observed within similar sample types may be partially accounted for by differences in methods. Synthesizing review findings, we include a recommended method for the direct enumeration of bacteria in environmental samples. PMID- 7854249 TI - Chemostat cultivation as a tool for studies on sugar transport in yeasts. AB - Chemostat cultivation enables investigations into the effects of individual environmental parameters on sugar transport in yeasts. Various means are available to manipulate the specific rate of sugar uptake (qs) in sugar-limited chemostat cultures. A straightforward way to manipulate qs is variation of the dilution rate, which, in substrate-limited chemostat cultures, is equal to the specific growth rate. Alternatively, qs can be varied independently of the growth rate by mixed-substrate cultivation or by variation of the biomass yield on sugar. The latter can be achieved, for example, by addition of nonmetabolizable weak acids to the growth medium or by variation of the oxygen supply. Such controlled manipulation of metabolic fluxes cannot be achieved in batch cultures, in which various parameters that are essential for the kinetics of sugar transport cannot be controlled. In sugar-limited chemostat cultures, yeasts adapt their sugar transport systems to cope with the low residual sugar concentrations, which are often in the micromolar range. Under the conditions, yeasts with high affinity proton symport carriers have a competitive advantage over yeasts that transport sugars via facilitated-diffusion carriers. Chemostat cultivation offers unique possibilities to study the energetic consequences of sugar transport in growing cells. For example, anaerobic, sugar-limited chemostat cultivation has been used to quantify the energy requirement for maltose-proton symport in Saccharomyces cerevisiae. Controlled variation of growth conditions in chemostat cultures can be used to study the differential expression of genes involved in sugar transport and as such can make an important contribution to the ongoing studies on the molecular biology of sugar transport in yeasts. PMID- 7854250 TI - The arginine repressor of Escherichia coli. AB - This review tells the story of the arginine repressor of Escherichia coli from the time of its discovery in the 1950s until the present. It describes how the research progressed through physiological, genetic, and biochemical phases and how the nature of the repressor and its interaction with its target sites were unraveled. The studies of the repression of arginine biosynthesis revealed unique features at every level of the investigations. In the early phase of the work they showed that the genes controlled by the arginine repressor were scattered over the linkage map and were not united, as in other cases, in a single operon. This led to the concept of the regulon as a physiological unit of regulation. It was also shown that different alleles of the arginine repressor could result in either inhibition of enzyme formation, as in E. coli K-12, or in stimulation of enzyme formation, as in E. coli B. Later it was shown that the arginine repressor is a hexamer, whereas other repressors of biosynthetic pathways are dimers. As a consequence the arginine repressor binds to two palindromic sites rather than to one. It was found that the arginine repressor not only acts in the repression of enzyme synthesis but also is required for the resolution of plasmid multimers to monomers, a completely unrelated function. Finally, the arginine repressor does not possess characteristic structural features seen in other prokaryotic repressors, such as a helix-turn-helix motif or an antiparallel beta-sheet motif. The unique features have sustained continuous interest in the arginine repressor and have made it a challenging subject of investigation. PMID- 7854252 TI - Persistent chlamydiae: from cell culture to a paradigm for chlamydial pathogenesis. AB - Chlamydiae are medically important bacteria responsible for a wide range of human infections and diseases. Repeated episodes of infection promote chronic inflammation associated with detrimental immune system-mediated pathologic changes. However, the true nature of chlamydial pathogenesis may encompass repeated infection superimposed upon persistent infection, which would allow for heightened immune reactivity. During the course of chlamydial infection, numerous host elaborated factors with inhibitory or modifying effects may cause alterations in the chlamydia-host cell relationship such that the organism is maintained in a nonproductive stage of growth. Abnormal or persistent chlamydiae have been recognized under a variety of cell culture systems. The numerous factors associated with altered growth suggest an innate flexibility in the developmental cycle of chlamydiae. This review evaluates in vitro studies of chlamydial persistence and correlates these model systems to features of natural chlamydial disease. PMID- 7854255 TI - [Depressive pseudodementia. Diagnostic importance of quantified EEG]. AB - The accuracy of computerized EEG to discriminate depressive pseudodementia from dementia was evaluated in 12 inpatients with recent cognitive impairments (all with DSM III R diagnosis of dementia). EEG were performed during wash-out period, then all subjects underwent an ECT and/or antidepressant trial. After this trial, clinical improvement was significant for six patients, while the six others remained unimproved. According to these two groups, electrophysiological data were retrospectively compared. Discriminant stepwise analysis exhibited that the combination of two parameters: symmetry of occipital alpha power and frontal alpha/theta ratio, was able to discriminate future responders from non responders patients with a greater accuracy than clinical and classical EEG parameters. PMID- 7854251 TI - Bacterial dehalogenases: biochemistry, genetics, and biotechnological applications. AB - This review is a survey of bacterial dehalogenases that catalyze the cleavage of halogen substituents from haloaromatics, haloalkanes, haloalcohols, and haloalkanoic acids. Concerning the enzymatic cleavage of the carbon-halogen bond, seven mechanisms of dehalogenation are known, namely, reductive, oxygenolytic, hydrolytic, and thiolytic dehalogenation; intramolecular nucleophilic displacement; dehydrohalogenation; and hydration. Spontaneous dehalogenation reactions may occur as a result of chemical decomposition of unstable primary products of an unassociated enzyme reaction, and fortuitous dehalogenation can result from the action of broad-specificity enzymes converting halogenated analogs of their natural substrate. Reductive dehalogenation either is catalyzed by a specific dehalogenase or may be mediated by free or enzyme-bound transition metal cofactors (porphyrins, corrins). Desulfomonile tiedjei DCB-1 couples energy conservation to a reductive dechlorination reaction. The biochemistry and genetics of oxygenolytic and hydrolytic haloaromatic dehalogenases are discussed. Concerning the haloalkanes, oxygenases, glutathione S-transferases, halidohydrolases, and dehydrohalogenases are involved in the dehalogenation of different haloalkane compounds. The epoxide-forming halohydrin hydrogen halide lyases form a distinct class of dehalogenases. The dehalogenation of alpha halosubstituted alkanoic acids is catalyzed by halidohydrolases, which, according to their substrate and inhibitor specificity and mode of product formation, are placed into distinct mechanistic groups. beta-Halosubstituted alkanoic acids are dehalogenated by halidohydrolases acting on the coenzyme A ester of the beta haloalkanoic acid. Microbial systems offer a versatile potential for biotechnological applications. Because of their enantiomer selectivity, some dehalogenases are used as industrial biocatalysts for the synthesis of chiral compounds. The application of dehalogenases or bacterial strains in environmental protection technologies is discussed in detail. PMID- 7854256 TI - Bit-mapped somatosensory evoked potentials in Down's syndrome individuals. AB - Middle-latency somatosensory evoked potentials (MLSEPs) were recorded from 19 scalp electrodes in 19 patients with Down's syndrome (DS), in 13 age-matched normal controls and in 11 aged normal individuals. DS patients showed an increase in amplitude of P22, N30, P45, and N60. P100 latency was significantly shortened. After this potential, DS subjects showed the occurrence of a high voltage negative potential at around 100-110 msec followed by another high-voltage positive deflection; both these components showed a frontal-central distribution and were not observed in the two control groups. MLSEPs of DS subjects show peculiar alterations which could be supported by particular neurometabolic and/or neuropathologic changes. PMID- 7854257 TI - EEG diagnostic and predictive value on HIV infection in childhood. AB - This prospective study evaluated the electroencephalographic (EEG) diagnostic and prognostic value in childhood HIV infection. It was carried out on 125 subjects and included all Piemonte's seropositive children. The EEG was repeated every three months during the first 15 months of life, and then, at least, annually in the P1 and P2 group. Data of group P2 was compared blindly to that of the seroconverted control group of the same age and risk. EEG results were normal in P0, P1 and control patients. In group P2, EEG was abnormal in 35.5% of subjects, of these 54.6% developed an encephalopathy with a delay of 2.5 months to 2 years 11 months. EEG is therefore useful to evaluate early CNS damage and to identify onset features and evolution of encephalopathy in P2 patients. PMID- 7854258 TI - [Sympathetic skin potentials and neuroperineal disorders. Sixty-eight cases]. AB - Sympathetic pathways can be assessed by using different electrophysiological tests. Sympathetic skin responses (SSR) are elicited with peripheral electrical stimulation of the median nerve. SSR are recorded from the skin of the hand and foot and from the genital skin. SSR were always obtained from normal volunteers with a latency of 1,685 ms. Absence of SSP recorded on the perineum is often the first sign observed in neurogenic perineal disorders. PMID- 7854254 TI - Desiccation tolerance of prokaryotes. AB - The removal of cell-bound water through air drying and the addition of water to air-dried cells are forces that have played a pivotal role in the evolution of the prokaryotes. In bacterial cells that have been subjected to air drying, the evaporation of free cytoplasmic water (Vf) can be instantaneous, and an equilibrium between cell-bound water (Vb) and the environmental water (vapor) potential (psi wv) may be achieved rapidly. In the air-dried state some bacteria survive only for seconds whereas others can tolerate desiccation for thousands, perhaps millions, of years. The desiccated (anhydrobiotic) cell is characterized by its singular lack of water--with contents as low as 0.02 g of H2O g (dry weight)-1. At these levels the monolayer coverage by water of macromolecules, including DNA and proteins, is disturbed. As a consequence the mechanisms that confer desiccation tolerance upon air-dried bacteria are markedly different from those, such as the mechanism of preferential exclusion of compatible solutes, that preserve the integrity of salt-, osmotically, and freeze-thaw-stressed cells. Desiccation tolerance reflects a complex array of interactions at the structural, physiological, and molecular levels. Many of the mechanisms remain cryptic, but it is clear that they involve interactions, such as those between proteins and co-solvents, that derive from the unique properties of the water molecule. A water replacement hypothesis accounts for how the nonreducing disaccharides trehalose and sucrose preserve the integrity of membranes and proteins. Nevertheless, we have virtually no insight into the state of the cytoplasm of an air-dried cell. There is no evidence for any obvious adaptations of proteins that can counter the effects of air drying or for the occurrence of any proteins that provide a direct and a tangible contribution to cell stability. Among the prokaryotes that can exist as anhydrobiotic cells, the cyanobacteria have a marked capacity to do so. One form, Nostoc commune, encompasses a number of the features that appear to be critical to the withstanding of a long-term water deficit, including the elaboration of a conspicuous extracellular glycan, synthesis of abundant UV-absorbing pigments, and maintenance of protein stability and structural integrity. There are indications of a growing technology for air dried cells and enzymes. Paradoxically, desiccation tolerance of bacteria has virtually been ignored for the past quarter century. The present review considers what is known, and what is not known, about desiccation, a phenomenon that impinges upon every facet of the distributions and activities of prokaryotic cells. PMID- 7854259 TI - The newborn with ambiguous genitalia. AB - This article reviews the normal embryological process of sex determination and differentiation, along with classifications of abnormalities of sex differentiation. It also outlines an approach to the diagnostic evaluation and gender assignment in infants with ambiguous genitalia and discusses implications for nursing care of these infants and their families. PMID- 7854260 TI - High-frequency oscillatory ventilation: a nursing approach to bedside care. AB - The introduction of high-frequency oscillatory ventilation (HFOV) to the intensive care nursery has stimulated us to develop infant care protocols for babies so treated. We identified specific areas unique to the SensorMedics HFOV and initiated nursing techniques to address each of the following areas: assessment, airway care, feedings, positioning, and safety. In summary, while on HFOV, an infant's assessment and care need not be minimized. PMID- 7854261 TI - Mothers of chronically ill neonates and primary nurses in the NICU: transfer of care. AB - The purpose of this study was to explore the relationship between nurse and mother during the ill neonate's hospitalization and examine how this relationship influenced the mother's parenting of her infant during the hospitalization. Using qualitative methods, we separately interviewed ten mothers and nine primary nurses about their relationships, their views on each other, and the mothers' infant care. The tape-recorded interviews were transcribed verbatim, themes were extracted, and categories were developed for coding the data. As issues emerged, they were further explored in follow-up interviews. We identified four stages in the process of transferring the care of the infant from nurse to mother. The mother-nurse relationships were influenced by both the nurses' and the mothers' typical interactional patterns. Nurses had definite ideas about who was an "ideal" mother. To the mothers, the nurses' competence and caring attitude toward their infants were most important. The process by which the nurse and mother interact to provide care for the infant and alter their roles during the course of the hospitalization is linked to various factors and aspects of the nurse mother relationship. PMID- 7854263 TI - Health care reform: it ain't about health care. PMID- 7854262 TI - The art of writing successful research abstracts. AB - Successful dissemination of your research requires planning. Your abstract is a succinct presentation of a portion of your research specifically designed to capture the attention of the audience you have chosen. The art of writing a successful abstract involves planning, like any other work of art, and is accomplished in stages. This article provides pointers for dissemination of research, describes the stages involved in writing competitive abstracts, and suggests alternative approaches to writing abstracts. PMID- 7854265 TI - Neonatal care in the Ukraine. PMID- 7854264 TI - Development of a neonatal intensive care nursery resuscitation and triage team: impact on nursing care and infant outcome. AB - The admission and initial stabilization of an infant in the neonatal intensive care unit pose a time of increased stress for the neonate as well as the caregivers. Constant observation by nursing personnel is critical so that major physiologic and anatomic changes that naturally occur do not compromise the neonate during this time of extrauterine adjustment. Continuous reassessment of temperature, respiration, heart rate, blood pressure, color, tone, and behavior during the initial four-hour postnatal period is crucial for the infant's survival and the preservation of an intact central nervous system and cardiopulmonary function. The complexity of the admission process should not jeopardize the nursing care of other infants in a busy neonatal intensive care unit. We developed a framework that separates bedside nursing activities from the resuscitation and admission process that ensures the infant's transition to the nursery is met with urgency and consistency without subjecting the remaining infants to a decreased level of care. PMID- 7854266 TI - Health care reform. PMID- 7854267 TI - NNP certification: different states, different rules. PMID- 7854268 TI - What do families need and what can we do to meet their needs? PMID- 7854269 TI - Discharge teaching: sending babies home safely. PMID- 7854270 TI - Drawing blood from arterial lines in neonates. PMID- 7854271 TI - Physiologic and methodologic issues: neonatal insensible water loss. PMID- 7854272 TI - Comparison of two NICU patterns of caregiving over 24 hours for preterm infants. PMID- 7854253 TI - Chloroplast ribosomes and protein synthesis. AB - Consistent with their postulated origin from endosymbiotic cyanobacteria, chloroplasts of plants and algae have ribosomes whose component RNAs and proteins are strikingly similar to those of eubacteria. Comparison of the secondary structures of 16S rRNAs of chloroplasts and bacteria has been particularly useful in identifying highly conserved regions likely to have essential functions. Comparative analysis of ribosomal protein sequences may likewise prove valuable in determining their roles in protein synthesis. This review is concerned primarily with the RNAs and proteins that constitute the chloroplast ribosome, the genes that encode these components, and their expression. It begins with an overview of chloroplast genome structure in land plants and algae and then presents a brief comparison of chloroplast and prokaryotic protein-synthesizing systems and a more detailed analysis of chloroplast rRNAs and ribosomal proteins. A description of the synthesis and assembly of chloroplast ribosomes follows. The review concludes with discussion of whether chloroplast protein synthesis is essential for cell survival. PMID- 7854273 TI - Severe sequelae from umbilical arterial catheter administration of dopamine. PMID- 7854274 TI - Therapeutic handling techniques for the infant affected by cocaine. AB - The effects of maternal cocaine abuse can be manifested in infants as physiologic, psychologic, cognitive, and developmental deficits. The effects of cocaine disrupt the sleep and wake cycles, which may cause the infant to be difficult to handle or unresponsive to parents or caregivers. Assessments of sleep/wake states and interventions to aid these infants are described. Cocaine affected infants can also present with hypertonic or hypotonic muscle tone disorders. Interventions to improve muscle tone are included in the discussion. PMID- 7854275 TI - Hats used to maintain body temperature. PMID- 7854276 TI - Changes in care of the newborn: personal reflections over forty years. PMID- 7854277 TI - Neonatal transformation: thirty years. PMID- 7854278 TI - The evolution of neonatal developmental care: a personal journey. PMID- 7854279 TI - The evolution of parental roles in the NICU. PMID- 7854280 TI - Newborn country USA: positioning for the fourth decade. PMID- 7854281 TI - Memories of a transport nurse. PMID- 7854282 TI - Significant events in neonatal care. PMID- 7854283 TI - Perinatal outreach education: the beginning. PMID- 7854284 TI - Teamwork: the key to quality neonatal care. PMID- 7854285 TI - Twenty years of special caring: perspective of a neonatal nurse. PMID- 7854286 TI - We've come a long way baby! Mechanical ventilation of the newborn. PMID- 7854287 TI - We chose babies. Interview by Jeanette Zaichkin. PMID- 7854288 TI - Changes in practice/services in neonatal care. PMID- 7854289 TI - Discharge planning and the role of the visiting nurse in the special care nursery. PMID- 7854290 TI - Virginia Apgar, MD, MPhH. PMID- 7854291 TI - A decade with NANN. PMID- 7854292 TI - NANN's tenth anniversary: getting experience together. PMID- 7854293 TI - Historical notes: the feeding of infants and children. 1922. PMID- 7854295 TI - Supporting parental bonding in the NICU: a care plan for nurses. AB - New and improved technology in the NICU has assisted in supporting critically ill neonates, especially those born at very low birth weights. These small patients require the dedicated hand of the NICU staff, but also the love and support of their parents. Family bonding in the NICU is often a very difficult process, which is interrupted by separation of parent and child at birth and continued by the physical constraints of this highly complex critical care environment. Neonatal nurses are most often the front line managers and coordinators of family care in the NICU. They are charged with the challenge of understanding and providing "state of the art" technological care in an environment that must also adapt to the ever changing needs of parents and families who cannot be considered visitors, but an integral part of their infants' care and survival. Each infant and family in the NICU requires individualized assessment and nursing care. This article reviews the process of parental bonding as it relates to the premature or ill infant and provides for nurses a plan of care written to foster and support family bonding in the NICU. Stages of bonding with a sick or premature infant are explored in the context of a theoretical framework of adaptation provided by Sister Callista Roy. PMID- 7854294 TI - Nonnutritive sucking and necrotizing enterocolitis. AB - The purpose of this study was to explore the possible protective effect of nonnutritive sucking (NNS) against the development of necrotizing enterocolitis (NEC). A retrospective chart review was conducted to examine the histories of 12 preterm infants who were enrolled in a longitudinal study of the effects of NNS on energy expenditure, weight gain, and feeding readiness. Six infants were enrolled in the control group; they did not receive NNS but did develop NEC. Six infants were in the experimental group and did not develop NEC. The groups were compared on the basis of clinical correlates associated with NEC. These included race, gender, birth weight, five-minute Apgar, maternal bleeding, maternal age, and length of ruptured membranes. For infants who developed NEC, the number of clinical correlates ranged from one to four. For infants who received NNS, the range of clinical correlates was from one to five. It is not possible to conclude from this study that NNS protects preterm infants from NEC. Prospective studies of larger sample sizes that involve examination of the effect of NNS on gastric motility and enzyme and hormone secretion are needed. PMID- 7854296 TI - An educational program for neonatal intensive care unit developmental care. AB - An innovative educational program on developmental care of the neonate was successfully implemented within the high-tech environment of a Level III NICU. Devised by a multidisciplinary team, the program provided appropriate levels of education to all personnel--from neonatologists to housekeeping staff--involved on a day-to-day basis with the infants. To assist those wishing to implement a similar program in their institution, details of program development, content, implementation, evaluation, and future goals are discussed. PMID- 7854297 TI - Accuracy of electronic axillary temperature measurement in term and preterm neonates. AB - The accuracy of axillary temperature measurement using an electronic thermometer in the predictive mode was investigated in term and preterm infants. Predictive mode measurements were compared to axillary monitoring mode measurements and to rectal temperature recordings. Fifty temperature recordings were obtained in each of four groups of neonates (full-term/radiant warmer, full-term/open crib, preterm/radiant warmer, preterm/incubator). Correlation of axillary predictive and monitoring mode temperatures ranged from r = 0.83 to 0.90. Correlations between axillary monitoring mode and rectal measurements were r = 0.69 to 0.80, and between predictive mode and rectal measurements were r = 0.59 to 0.80. Small, statistically significant differences were found between predictive and monitoring mode axillary temperatures in preterm neonates (0.1 to 0.2 degrees F). Rectal temperatures were higher than axillary predictive temperatures by 0.5 degrees F and higher than axillary monitoring mode temperatures by 0.7 degrees F. Ranges of variation of +/- 0.8 to 1.1 degrees F were similar in comparisons of rectal with axillary predictive and monitoring mode measurements. The results of this study support the use of axillary measurement in the predictive mode for clinical measurement of temperature in neonates. Clinicians should be aware of the expected differences between measurements at axillary and rectal sites and the potential for variation in measurements across measurement modes and sites. PMID- 7854298 TI - Case management and critical pathways: friend or foe? PMID- 7854299 TI - Stability. PMID- 7854301 TI - Preventing infant abductions from health care facilities. PMID- 7854300 TI - More survey results: economic issues and advanced practice. PMID- 7854302 TI - Methadone maintenance and breast feeding: do they mix? PMID- 7854303 TI - A urinary collection device for very low birth weight infants. PMID- 7854304 TI - Intraosseous infusions. PMID- 7854305 TI - Nursing case management in the neonatal intensive care unit. Part 1: Pioneering new territory. AB - Nursing case management is a model of care delivery that focuses on achieving optimal patient outcomes in expected time frames while containing costs. This is accomplished through a multidisciplinary team approach, guided by a multidisciplinary care plan, called a critical pathway. This model of care meets the standards of regulatory agencies and is in line with health care reform activities at the federal level. It should be considered as an effective, new way to provide care in the NICU. PMID- 7854306 TI - A brave new world? PMID- 7854307 TI - New documentation guidelines for evaluation and management services. PMID- 7854308 TI - Ophthalmology quiz #11. Arteritic ischemic optic neuritis. PMID- 7854309 TI - Ophthalmology quiz #11. Retinal detachment. PMID- 7854310 TI - E. coli O157:H7 is an emerging pathogen in Missouri. AB - Dramatic media reports of recent outbreaks of illness caused by Escherichia coli O157:H7 have drawn national attention to this emerging pathogen. In 1993, a widely publicized outbreak of over 500 culture-confirmed cases was traced to fast food hamburgers in Washington, Idaho, Nevada and California. Closer to home, the first (and still the largest) reported waterborne outbreak of this disease occurred in Cabool, Missouri in 1989. That outbreak affected 243 people, of whom 32 were hospitalized, 2 had hemolytic uremic syndrome, and 4 died. E. coli O157:H7 was added to the list of reportable diseases in Missouri in mid-1992, but its importance is still not widely recognized. This article reviews the results of state and national surveillance for the disease, and suggests methods for improving diagnosis and reporting. PMID- 7854311 TI - The use of a somatostatin analog in the treatment of an external pancreatic fistula. AB - A search of the scientific literature reveals several reports of the successful use of somatostatin and its analog octreotide for treatment of external pancreatic fistulas. Both somatostatin and octreotide have been reported to promote closure of external pancreatic fistulas at relatively shorter intervals than spontaneous closure. However, the benefits of somatostatin and somatostatin analog therapy appear to be limited to cases without other pathologic or anatomic complications. A case is presented of an external pancreatic fistula in which there was no such apparent complication and in which octreotide failed to shorten the time of fistula closure. PMID- 7854312 TI - The CLS2 gene encodes a protein with multiple membrane-spanning domains that is important Ca2+ tolerance in yeast. AB - Genetic screening of Saccharomyces cerevisiae mutants defective in Ca2+ homeostasis identified cls2, which exhibits a specific Ca(2+)-sensitive growth phenotype. We describe here the CLS2 gene and a multicopy suppressor (named BCL21, for bypass of CLS2) of the cls2 mutation. The CLS2 gene encodes a polypeptide of 410 amino acid residues, and its hydropathy profile indicates that the predicted Cls2 protein (Cls2p) contains ten putative membrane spanning regions. Immunofluorescent staining of the yeast cells expressing epitope-tagged Cls2p suggests that Cls2p is localized to endoplasmatic reticulum (ER) membrane. A cls2 disruption strain is viable, but shows a Ca(2+)-sensitive phenotype like the original cls2 mutants. BCL21 suppresses the cls2 disruption mutation, indicating that the multicopy suppression does not require the Cls2p. Suppression of cls2 was observed even after introduction of a single-copy plasmid harboring BCL21. The BCL21 gene encodes a protein of 382 amino acid residues and is identical to the SUR1 gene. sur1 was originally isolated as a suppressor of rvs161, which has reduced viability in nutrient starvation conditions. Possible mechanisms of the multicopy suppression are discussed. PMID- 7854313 TI - Characterization of a region of the X chromosome of Drosophila including multi sex combs (mxc), a Polycomb group gene which also functions as a tumour suppressor. AB - Genetic analysis of the 8D3;8D8-9 segment of the Drosophila melanogaster X chromosome has assigned seven complementation groups to this region, three of which are new. A Polycomb group (Pc-G) gene, multi sex combs (mxc), is characterized and mutant alleles are described. Besides common homeotic transformations characteristic of Pc-G mutants that mimic the ectopic gain of function of BX-C and ANT-C genes, mxc mutants show other phenotypes: they zygotically mimic, in males and females, the characteristic lack of germ line seen in progeny of some maternal effect mutants of the so-called posterior group (the grandchildless phenotype). Loss of normal mxc function can promote uncontrolled malignant growth which indicates a possible relationship between Pc G genes and tumour suppressor genes. We propose that gain-of-function of genes normally repressed by the wild-type mxc product could, in mxc mutants, give rise to an incoherent signal which would be devoid of meaning in normal development. Such a signal could divert somatic and germ line development pathways, provoke the loss of cell affinities, but allow or promote growth. PMID- 7854314 TI - Genetic interactions and dosage effects of Polycomb group genes of Drosophila. AB - The Polycomb (Pc) group of genes are required for maintenance of cell determination in Drosophila melanogaster. At least 11 Pc group genes have been described and there may be up to 40; all are required for normal regulation of homeotic genes, but as a group, their phenotypes are rather diverse. It has been suggested that the products of Pc group genes might be members of a heteromeric complex that acts to regulate the chromatin structure of target loci. We examined the phenotypes of adult flies heterozygous for every pairwise combination of Pc group genes in an attempt to subdivide the Pc group functionally. The results support the idea that Additional sex combs (Asx), Pc, Polycomblike (Pcl), Posterior sex combs (Psc), Sex combs on midleg (Scm), and Sex combs extra (Sce) have similar functions in some imaginal tissues. We show genetic interactions among extra sex combs (esc) and Asx, Enhancer of Pc, Pcl, Enhancer of zeste E(z), and super sex combs and reassess the idea that most Pc group genes function independently of esc. Most duplications of Pc group genes neither exhibit anterior transformations nor suppress the extra sex comb phenotype of Pc group mutations, suggesting that not all Pc group genes behave as predicted by the mass action model. Surprisingly, duplications of E(z) enhance homeotic phenotypes of esc mutants. Flies with increasing doses of esc+ exhibit anterior transformations, but these are not enhanced by mutations in trithorax group genes. The results are discussed with respect to current models of Pc group function. PMID- 7854315 TI - Replication of the broad-host-range plasmid RK2: isolation and characterization of a spontaneous deletion mutant that can replicate in Agrobacterium tumefaciens but not in Escherichia coli. AB - Two spontaneous deletions of a derivative of the broad-host-range plasmid RK2 were isolated from Agrobacterium tumefaciens. The two deletions have lost 56 and 505 bp, respectively, near the origin of replication (oriV). Of the eight 17-bp repeats present in the RK2 oriV, the smaller deletion has lost the first two while the larger one has lost the first three. The deletions led to a significant increase (3- to 7-fold) in plasmid copy number in A. tumefaciens, indicating their importance in copy number control. While the smaller deletion could replicate in Escherichia coli, the larger one could not. The role of the oriV sequences in the replication of pRK2 in A. tumefaciens and in E. coli is discussed. PMID- 7854316 TI - The RCK1 and RCK2 protein kinase genes from Saccharomyces cerevisiae suppress cell cycle checkpoint mutations in Schizosaccharomyces pombe. AB - The protein kinase-encoding genes RCK1 and RCK2 from Saccharomyces cerevisiae have been identified as suppressors of Schizosaccharomyces pombe cell cycle checkpoint mutations. Upon expression of these genes, radiation resistance is partially restored in S. pombe mutants with checkpoint deficiencies, but not in mutants with DNA repair defects. Some checkpoint mutants are sensitive to the DNA synthesis inhibitor hydroxyurea, and this sensitivity is also suppressed by RCK1 and RCK2. The degree of suppression can be modulated by varying expression levels. Expression of RCK1 or RCK2 in S. pombe causes cell elongation and decelerated growth. Cells expressing these genes have a single nucleus and a 2n DNA content. We conclude that these genes act in S. pombe to prolong the G2 phase of the cell cycle. PMID- 7854317 TI - Abundance, variability and chromosomal location of microsatellites in wheat. AB - The potential of microsatellite sequences as genetic markers in hexaploid wheat (Triticum aestivum) was investigated with respect to their abundance, variability, chromosomal location and usefulness in related species. By screening a lambda phage library, the total number of (GA)n blocks was estimated to be 3.6 x 10(4) and the number of (GT)n blocks to be 2.3 x 10(4) per haploid wheat genome. This results in an average distance of approximately 270 kb between these two microsatellite types combined. Based on sequence analysis data from 70 isolated microsatellites, it was found that wheat microsatellites are relatively long containing up to 40 dinucleotide repeats. Of the tested primer pairs, 36% resulted in fragments with a size corresponding to the expected length of the sequenced microsatellite clone. The variability of 15 microsatellite markers was investigated on 18 wheat accessions. Significantly, more variation was detected with the microsatellite markers than with RFLP markers with, on average, 4.6 different alleles per microsatellite. The 15 PCR-amplified microsatellites were further localized on chromosome arms using cytogenetic stocks of Chinese Spring. Finally, the primers for the 15 wheat microsatellites were used for PCR amplification with rye (Secale cereale) and barley accessions (Hordeum vulgare, H. spontaneum). Amplified fragments were observed for ten primer pairs with barley DNA and for nine primer pairs with rye DNA as template. A microsatellite was found by dot blot analysis in the PCR products of barley and rye DNA for only one primer pair. PMID- 7854318 TI - Expression of the dihydroorotate dehydrogenase gene, dhod, during spermatogenesis in Drosophila melanogaster. AB - The dhod gene encodes dihydroorotate dehydrogenase (DHOdehase), which catalyzes the fourth step of de novo pyrimidine biosynthesis. In addition to the common 1.5 kb dhod RNA expressed by embryos and females, adult males produce a group of slightly longer RNAs. Evidence is presented that the latter RNAs arise through transcription initiation at sites upstream from that of the common RNA and expression of these male-specific RNAs is limited to spermatogenesis. In situ hybridization analysis shows that these RNAs accumulate during spermatocyte growth and persist through meiosis and early spermatid differentiation. In contrast, DHOdehase activity is virtually absent in spermatocytes, meiotic cells, and in early spermatid cysts, then it becomes highly abundant in elongated spermatid cysts and disappears in late spermatogenesis. Thus, testis-limited expression of dhod conforms to a model proposed for other genes that function during spermiogenesis: transcription in spermatocytes, storage of translationally inactive RNA through meiosis, translation of the RNA during spermiogenesis. Very similar expression of a testis promoter-lacZ fusion transgene indicates that sequences required for the spermatogenesis transcription and translation patterns are confined to the 5' end of the dhod gene. Deletion analysis of that 5' region delimits all sequences necessary for spermatid expression of the transgene to a 89 bp fragment. These results are discussed in the contexts of known mechanisms of gene regulation during spermatogenesis and potential roles of DHOdehase during spermiogenesis. PMID- 7854319 TI - The frequency of integrative transformation at phase-specific genes of Candida albicans correlates with their transcriptional state. AB - The phase transition between the white and opaque phenotypes in the switching system of Candida albicans strain WO-1 is accompanied by the differential expression of the white-specific gene WH11 and the opaque-specific gene PEP1. The frequency of integrative transformation at the white-specific gene locus WH11 is between 4.5 and 7.0 times more frequent in white than in opaque spheroplasts, and the frequency of disruptive transformation at the opaque-specific gene locus PEP1 is 30.5 times more frequent in opaque spheroplasts than in white spheroplasts. In contrast, the frequencies of integrative transformation at the constitutively expressed loci ADE2 and EF1 alpha 2 are similar in the white and opaque phases. Therefore, the frequency of integration of linear plasmid DNA containing sequences of phase-specific genes correlates with the transcriptional state of the targeted locus. PMID- 7854320 TI - A multigene family related to chitin synthase genes of yeast in the opportunistic pathogen Aspergillus fumigatus. AB - Two approaches were used to isolate fragments of chitin synthase genes from the opportunistic human pathogen Aspergillus fumigatus. Firstly, regions of amino acid conservation in chitin synthases of Saccharomyces cerevisiae were used to design degenerate primers for amplification of portions of related genes, and secondly, a segment of the S. cerevisiae CSD2 gene was used to screen an A. fumigatus lambda genomic DNA library. the polymerase chain reaction (PCR)-based approach led to the identification of five different genes, designated chsA, chsB, chsC, chsD and chsE. chsA, chsB, and chsC fall into Classes I, II and III of the 'zymogen type' chitin synthases, respectively. The chsD fragment has approximately 35% amino acid sequence identity to both the zymogen type genes and the non-zymogen type CSD2 gene. chsF appears to be a homologue of CSD2, being 80% identical to CSD2 over 100 amino acids. An unexpected finding was the isolation by heterologous hybridization of another gene (chsE), which also has strong sequence similarity (54% identity at the amino acid level over the same region as chsF) to CSD2. Reverse transcriptase-PCR was used to show that each gene is expressed during hyphal growth in submerged cultures. PMID- 7854321 TI - Overexpression of the yeast MCK1 protein kinase suppresses conditional mutations in centromere-binding protein genes CBF2 and CBF5. AB - We find that overexpression in yeast of the yeast MCK1 gene, which encodes a meiosis and centromere regulatory kinase, suppresses the temperature-sensitive phenotype of certain mutations in essential centromere binding protein genes CBF2 and CBF5. Since Mck1p is a known serine/threonine protein kinase, this suppression is postulated to be due to Mck1p-catalyzed in vivo phosphorylation of centromere binding proteins. Evidence in support of this model was provided by the finding that purified Mck1p phosphorylates in vitro the 110 kDa subunit (Cbf2p) of the multimeric centromere binding factor CBF3. This phosphorylation occurs on both serine and threonine residues in Cbf2p. PMID- 7854322 TI - Identification and characterization of regulatory elements in the phosphoenolpyruvate carboxykinase gene PCK1 of Saccharomyces cerevisiae. AB - Phosphoenolpyruvate carboxykinase is a key enzyme in gluconeogenesis. The expression of the PCK1 gene in Saccharomyces cerevisiae is strictly regulated and dependent on the carbon source provided. Two upstream activation sites (UAS1PCK1 and UAS2PCK1) and one upstream repression site (URSPCK1) were localized by detailed deletion analysis. The efficacy of these three promoter elements when separated from each other was confirmed by investigations using heterologous promoter test plasmids. Activation mediated by UAS1PCK1 or UAS2PCK1 did not occur in the presence of glucose, indicating that these elements are essential for glucose derepression. The repressing effect caused by URSPCK1 was much stronger in glucose-grown cells than in ethanol-grown cells. PMID- 7854323 TI - Male recombination with single and homologous P elements in Drosophila melanogaster. AB - It has previously been shown that, in the presence of a source of P element transposase, male recombination in Drosophila melanogaster is induced at a rate of about 1% in the region of a single P[CaSpeR] element. This paper shows that recombinant chromosomes retain unaltered P[CaSpeR] elements at the original site in a high proportion of cases. This result is incompatible with a simple model in which recombination occurs by resolution of a Holliday junction following P element excision and repair. It has also previously been shown that homozygous regions containing a P element produce male recombination levels of 10-20%, an order of magnitude higher than that given by a single element. This paper shows that reciprocal recombinant chromosomes retaining P[CaSpeR] elements can be combined to produce similarly high levels of recombination. This result potentially allows for recombinant chromosomes from homologous recombination to be analysed at the molecular level in the region of the inserted element. PMID- 7854325 TI - An unusual mutation in RepA increases the copy number of a stringently controlled plasmid (Rts1 derivative) by over one hundred fold. AB - A copy number mutant of the Rts1 replicon (copy number 1-2 copies/cell) was obtained. A one-base substitution in the repA region results in a single amino acid change from histidine to asparagine at position 159. This mutation increased the plasmid copy number by up to 120-fold depending upon the growth conditions. At 42.5 degrees C the plasmid with the wild type replicon was unstable while the mutated replicon was relatively stable. PMID- 7854324 TI - Cloning and expression of a Xenopus gene that prevents mitotic catastrophe in fission yeast. AB - In fission yeast the Wee1 kinase and the functionally redundant Mik1 kinase provide a regulatory mechanism to ensure that mitosis is initiated only after the completion of DNA synthesis. Yeast in which both Wee1 and Mik1 kinases are defective exhibit a mitotic catastrophe phenotype, presumably due to premature entry into mitosis. Because of the functional conservation of cell cycle control elements, the expression of a vertebrate wee1 or mik1 homolog would be expected to rescue such lethal mutations in yeast. A Xenopus total ovary cDNA library was constructed in a fission yeast expression vector and used to transform a yeast temperature-dependent mitotic catastrophe mutant defective in both wee1 and mik1. Here we report the identification of a Xenopus cDNA clone that can rescue several different yeast mitotic catastrophe mutants defective in Wee1 kinase function. The expression of this clone in a wee1/mik1-deficient mutant causes an elongated cell phenotype under non-permissive growth conditions. The 2.0 kb cDNA clone contains an open reading frame of 1263 nucleotides, encoding a predicted 47 kDa protein. Bacterially expressed recombinant protein was used to raise a polyclonal antibody, which specifically recognizes a 47 kDa protein from Xenopus oocyte nuclei, suggesting the gene encodes a nuclear protein in Xenopus. The ability of this cDNA to complement mitotic catastrophe mutations is independent of Wee1 kinase activity. PMID- 7854326 TI - Oxidative stress-induced perturbations of calcium homeostasis and cell death in cultured myocytes: role of extracellular calcium. AB - The role of extracellular calcium in the process of oxidative stress-induced calcium overload and cell death was investigated in cultured neonatal rat myocytes. Oxidative stress was induced by addition of cumene hydroperoxide (CHPO), a toxic organic hydroperoxide, in combination with varying extracellular calcium concentrations (1. normal calcium buffer: 2.5 mM Ca2+, 2. low calcium buffer: 5 microM Ca2+, 3. zero calcium buffer: 2.5 mM EGTA, no CaC12). Intracellular free calcium ion concentration ([Ca2+]i) was measured with fura-2 using a spectrofluorometer. To study the toxicant-induced changes in [Ca2+]i in more detail, single cell imaging was performed using digital imaging fluorescence microscopy (DIFM). In control experiments (in the absence of CHPO, but under different extracellular Ca2+ conditions) the [Ca2+]i remained at the basal level and cell viability was preserved. Administration of CHPO (50 microM) to the myocyte cultures generated a sustained increase in [Ca2+]i followed by loss of cell viability. A low extracellular calcium concentration (5 microM), in the absence or presence of diltiazem (10 microM), induced a delay in the rise in [Ca2+]i but was not able to prevent the CHPO-induced calcium overload and cell necrosis. Addition of EGTA (2.5 mM) to the low calcium buffer resulted also in CHPO-induced cell death, although no increase in [Ca2+]i was observed. In normal and low calcium buffers, DIFM revealed that CHPO produced a temporally and spatially heterogeneous distribution of [Ca2+]i in a group of myocytes. So, in the presence of normal or low extracellular Ca2+, CHPO intoxication of cultured myocytes leads to an increase of [Ca2+]i prior to the onset of cell death. If extracellular Ca2+ is chelated by EGTA, CHPO also induces cell death which is not preceded by cellular calcium overload. Apparently a disturbance in the calcium homeostasis is not causally related with oxidative stress-induced myocardial cell death. PMID- 7854327 TI - Determination of cytosolic Mg2+ activity and buffering in BC3H-1 cells with mag fura-2. AB - The magnesium buffer coefficient (BMg) was calculated for BC3H-1 cells from the rise in cytosolic Mg2+ activity observed when magnesium was released from ATP after iodoacetate (IAA) and NaCN treatment. The basal cytosolic Mg2+ activity (0.54 +/- 0.1 mM) measured with mag-fura-2 doubled when 4.54 mM magnesium was liberated from ATP: BMg was 12.9 indicating that a 1 mM increase in Mg2+ activity requires an addition of about 13 mM magnesium. The accuracy of this value depends on these assumptions: (a) all of the magnesium released from ATP stayed in the cells; (b) the rise in Mg2+ was not secondary to pH-induced changes in BMg; (c) mag-fura-2 measured Mg2+ and not Ca2+; and (d) the accuracy of the mag-fura-2 calibration. Total magnesium did not change in response to IAA/CN treatment, thus the change in Mg2+ activity reflected a redistribution of cell magnesium. pH changes induced by NH4Cl pulse and removal had little effect on Mg2+ activity and the changes were slower than and opposite to pH-induced changes in Ca2+ activity measured by fura-2. Ca2+ responses were temporally uncoupled from Mg2+ responses when the cells were treated with IAA only and in no cases did Ca2+ levels rise above 1 microM, showing that the mag-fura-2 is responding to Mg2+. Additional studies demonstrated that approximately 90% of the mag-fura-2 signal was cytosolic in origin. The remaining non-diffusible mag-fura-2 either was bound to cytosolic membranes or sequestered in organelles with the fluorescence characteristics of the Mg2(+)-complexed form, even when cytosolic free Mg2+ activity was approximately 0.5 mM. This bound mag-fura-2 would appear to increase the Kd and thus clearly limits the accuracy of our estimmate for BMg. Despite this limitation, we demonstrate that Mg2+ is tightly regulated in face of large changes in extracellular Mg2+, and that interplay observed between pH, Ca2+ and Mg2+ activities strongly supports the hypothesis that these factors interact through a shared buffer capacity of the cell. PMID- 7854328 TI - Insulin stimulates turnover of phosphatidylcholine in rat adipocytes. AB - The present study investigated the effect of insulin on phosphatidylcholine turnover in rat adipocytes labelled to equilibrium with [14C]-choline. Insulin induced a rapid turnover of this major phospholipid that was maximal by 1 min and transient in nature. Following a 1 min stimulation of the cells with insulin at a maximally effective concentration (7 nM), a 4-6% decrease in the percentage of total cellular choline associated with this phospholipid was observed. This reflected a significant transient increase in the percentage of total cellular choline associated with phosphorylcholine, which together with diacylglycerol are the phospholipase C cleavage products of phosphatidylcholine. These effects were observed over a physiological range of insulin concentrations. No effect of insulin on any other choline phospholipid or metabolite (sphingomyelin, lysophophatidylcholine, glycerophosphocholine or choline) was seen. These results suggest that insulin stimulates a phospholipase C-mediated turnover of phosphatidylcholine in rat adipocytes. The rapid nature of this turnover suggests a potential role in signal transduction. PMID- 7854329 TI - Transformation of adult ventricular myocytes with the temperature sensitive A58 (tsA58) mutant of the SV40 large T antigen. AB - Freshly isolated ventricular myocytes have been used extensively as an adult cardiac model system. Due to their inability to undergo cytokinesis in vitro and their dedifferentiated properties in long-term culture, they can not be used for extended studies. Recent reports tell of the establishment of fetal and neonatal cardiac cell lines and the development of adult cardiomyocytes from transgenic animals. A recent report by Kirshenbaum [1], is the first to demonstrate insertion of genes in to adult ventricular myocytes using viral infection. This paper discusses the infection of primary adult differentiated cardiomyocytes with the SV40 large T antigen and subsequent proliferation under temperature sensitive control. Upon further characterization, the cells could be used as a model to study muscle differentiation and repair as well as adult cardiac cell physiology. PMID- 7854330 TI - Expression of calcium-binding protein regucalcin mRNA in rat liver is stimulated by calcitonin: the hormonal effect is mediated through calcium. AB - The involvement of a hypocalcemic hormone calcitonin (CT) in the expression of hepatic Ca(2+)-binding protein regucalcin mRNA was investigated. The change of regucalcin mRNA levels was analyzed by Northern blotting using liver regucalcin complementary DNA (0.9 kb). A single oral administration of calcium chloride (100 mg Ca/100 g body weight) to rats induced a remarkable increase in the serum calcium concentration and a corresponding elevation of the liver calcium content during 120 min after the administration. Thyroparathyroidectomy (TPTX) did not cause a significant increase in the liver calcium content after calcium administration. Hepatic regucalcin mRNA level was markedly elevated by calcium administration; the level was about 180% of controls at 60 min after the administration. This increase was completely abolished by TPTX. A single subcutaneous administration of CT (synthetic eel CT; 25-100 MRC mU/100 g) to TPTX rats received oral administration of calcium (100 mg/100 g) produced a remarkable increase in hepatic regucalcin mRNA levels; the level was about 280% of controls with the dose of 25 MRC mU CT/100 g. The present finding suggests that the expression of hepatic mRNA is stimulated by CT, and that the hormonal effect is mediated through Ca2+ in rat liver. PMID- 7854331 TI - The human BAT3 ortholog in rodents is predominantly and developmentally expressed in testis. AB - A partial cDNA clone, RLC34, was isolated from a rat brain cDNA library. Its sequence exhibits high identity with BAT3 (88.4% and 94.9% for DNA and the deduced amino acid sequence, respectively), a gene located within the region of human major histocompatibility complex III (MCHIII region). RLC34 detected a transcript the same size in human and rat, similar to that reported for BAT3. Southern blot analysis of RLC34 showed similar restriction patterns as those of the human BAT3 gene. A panel of rodent tissue samples were examined and the RLC34 was found to be predominantly expressed in the germ cells of rodent testes. The expression is developmentally regulated with increased transcripts seen at 17-20 days after birth. Its testicular expression, its association with spermatogenesis, and its location in MCHIII suggest a correlation of RLC34 with the growth-reproduction complex (grc). This finding may also provide a clue to study the function of other genes localized in this area of the MCHIII region. PMID- 7854332 TI - 4-Deoxypyridoxine inhibits chronic granuloma formation induced by potassium permanganate in vivo. AB - 4-Deoxypyridoxine (4-DPD) is a potent antagonist of Vitamin B6 coenzyme which inhibits IL-1, lymphocyte proliferation and has demonstrated that tolerance to skin grafts can be induced by administering splenic cells to pyridoxine-deficient mice. Chronic inflammation induced by dorsal injections of 200 microliters of a 1:40 saturated crystal solution of potassium permanganate (KMnO4) in mice treated or untreated with 4-DPD (400 micrograms/dose), has been investigated. After 7 days all mice developed a subcutaneous granulomatous tissue indicative of a chronic inflammatory response, at the site of injection. KMnO4-treated mice injected intraperitoneally with 4-DPD (400 micrograms/dose) on 5 consecutive days (the first at the same time of induction of the granuloma) show a significant decrease in size and weight of granuloma when compared to mice not treated with 4 DPD (Controls). In addition, in all mice treated with 4-DPD there was a strong inhibition of TNF alpha in serum (P < 0.01) and in supernatant fluids (P < 0.05) from minced granuloma, while IL-6 was inhibited in the supernatant fluids (P < 0.05) of minced granulomas but was not detected in the serum of treated and untreated mice. In this study we show for the first time the antiinflammatory effect of 4-DPD on chronic inflammation and the inhibitory effect of TNF and IL-6 generation in supernatant fluids from minced granulomas. PMID- 7854333 TI - O-acetylated sialic acid as a distinct marker for differentiation between several leukemia erythrocytes. AB - AchatininH (ATNH) is a lectin, isolated from the hemolymph of Achatina fulica snail, which has been shown to have narrow specificity towards 9-O-acetyl sialic acid. Usually ATNH does not agglutinate normal human erythrocytes, however, it is capable of agglutinating erythrocytes of patients suffering from acute lymphocytic and acute myelogenous leukemia. Determination of binding constants, numbers of binding sites and lectin overlay experiments using patients' erythrocytes ghost, have suggested that some alterations in erythrocyte cell surface sialoglycoproteins or more precisely appearance of some O-acetylated sialoglycoprotein as a result of pathological transformations has caused this change in the binding of ATNH. PMID- 7854334 TI - Activating effect of regucalcin on (Ca(2+)-Mg2+)-ATPase in rat liver plasma membranes: relation to sulfhydryl group. AB - The activating mechanism of regucalcin, a calcium-binding protein isolated from rat liver cytosol, on (Ca(2+)-Mg2+)-ATPase in the plasma membranes of rat liver was investigated. (Ca(2+)-Mg2+)-ATPase activity was markedly increased by a sulfhydryl (SH) group protecting reagent dithiothreitol (DTT; 2.5 and 5 mM as a final concentration), while the enzyme activity was significantly decreased by a SH group modifying reagent N-ethylmaleimide (NEM; 0.5-5 mM). The effect of DTT (5 mM) to increase the enzyme activity was clearly blocked by NEM (5 mM). Regucalcin (0.25-1.0 microM) significantly increased (Ca(2+)-Mg2+)-ATPase activity. This increase was completely blocked by NEM (5 mM). Meanwhile, digitonin (0.04%), which can solubilize the membranous lipids, significantly decreased (Ca(2+)-Mg2+) ATPase activity. Digitonin did not have an effect on the DTT (5 mM)-increased enzyme activity. However, the effect of regucalcin (0.25 microM) increasing (Ca(2+)-Mg2+)-ATPase activity was entirely blocked by the presence of digitonin. The present results suggest that regucalcin activates (Ca(2+)-Mg2+)-ATPase by the binding to liver plasma membrane lipids, and that the activation is involved in the SH groups which are an active site of the enzyme. PMID- 7854335 TI - Serum release of hepatic calcium-binding protein regucalcin by liver injury with galactosamine administration in rats. AB - Whether calcium-binding protein regucalcin, which mainly localizes in liver, is released into the serum by liver injury was investigated in rats administered galactosamine. Galactosamine (25 mg/100 g body weight) was intraperitoneally administered 3 times at 2 h intervals in rats, and the animals were sacrificed at 10, 24 and 48 h after the first administration of galactosamine. Liver regucalcin mRNA levels were clearly reduced at 24 and 48 h after galactosamine administration with estimating for Northern blotting assay. When hepatic regucalcin concentration was estimated by enzyme-linked immunoadsorbent assay (ELISA) with rabbit-anti-regucalcin IgG, liver regucalcin concentration was not significantly altered by galactosamine administration. Serum regucalcin concentration was markedly elevated at 10 and 24 h after the first administration of galactosamine. Serum transaminases (GOT and GPT) activities were significantly increased by galactosamine administration, indicating that liver injury was induced. The present study demonstrates that liver regucalcin is released into the serum by liver injury with galactosamine administration in rats. PMID- 7854336 TI - A transformed murine Leydig cell line expresses the ETA receptor subtype. AB - We recently demonstrated that transformed murine Leydig cells (MA-10) responded to endothelin-1 (ET-1) via increased steroidogenesis. This study addresses the endothelin receptor subtype present on this cell line and whether or not the cells produce ET-1. The expression of the preproendothelin-1 (PPET-1) gene was investigated by Northern blot analysis, and PPET-1 mRNA was found to be < 0.2% of that present in pulmonary endothelial cells. The medium from MA-10 cells, maintained under serum-free conditions, was analyzed by radio-immunoassay to determine immunoreactive-ET-1 production and ET-1 levels were found to be below the sensitivity of the assay (< 10 pg/ml). The data from competitive binding experiments with [125I]ET-1 and unlabeled ET-1, ET-3 and receptor subtype selective ligands yielded a single class of high affinity binding sites with ETA receptor subtype characteristics. The results of this study demonstrate that MA 10 cells possess the ETA receptor subtype but do not produce significant quantities of ET-1 under basal conditions. PMID- 7854337 TI - Stabilizing and destabilizing effects on plasma membrane Ca(2+)-ATPase activity. AB - We have examined the temperature-dependent effects of several organic compounds on the activity of the purified Ca(2+)-ATPase of erythrocytes. The monomeric enzyme was activated either by interaction with calmodulin or by oligomerization in the absence of calmodulin. Of the four homologous solute series studied including polyols, alkanols, aprotic solvents, and N-methyl derivatives of formamide and acetamide only polyols stabilized the enzyme over a broad range of concentration and temperature. Similarity of Ca(2+)-ATPase activity patterns at 25 and 37 degrees C and in the presence of glycerol is in agreement with indirect, stabilizing interactions. Glycerol also protected the Ca(2+)-ATPase from thermal denaturation at 45 degrees C. Within each homologous series, inhibitory effects increased with increasing solute concentration and with increasing structural similarity to detergents, indicating that direct destabilizing interactions are responsible for the observed inhibition. These were comparable to the destabilizing effect of urea. Oligomers were more resistant to all inhibitory solutes as compared to calmodulin-activated monomers suggesting that the nonpolar patches of the oligomerized enzyme are less accessible to solutes. PMID- 7854338 TI - Splanchnic amino acid pattern in genetic and dietary obesity in the rat. AB - The study of intestinal and hepatic uptake of amino acids by obese rats has been the main objective of this work. The obese animals used were either from genetic or from nutritional basis. In fed state, the intestinal release of amino acids was higher in obese animals than in lean ones (around the double values), but nutritionally and genetically obese rat showed a related pattern, specially for the case of alanine (increased release in relation to controls by a factor of 10). The higher alanine release by intestine is not reversed by 12-h food deprivation. The hepatic availability was also higher in obesity models than in lean animals (increases over 30%). However, the hepatic uptake was increased in genetically obese animals (more than 35%) and decreased in nutritionally obese animals (more than 40%), especially due to alanine uptake (2419, 1100 and 3794 nmols/min/g protein in lean, Diet-ob and fa/fa animals respectively). In obese animals the food deprivation tended to normalize the hepatic uptake of alanine. The differences in alanine uptake between both types of obesity may reflect the differences of urea synthesis. PMID- 7854339 TI - Induction of ethanol dependence increases signal peptidase mRNA levels in rat brain. AB - Differential Northern blot hybridization was used as a screening tool to identify mRNAs that respond quantitatively to the induction of ethanol dependence. Adult male rats were treated with repeated, high doses of ethanol for 4 consecutive days. This regimen resulted in the development of tolerance and dependence upon ethanol. RNA isolated from the ethanol-dependent rat brains was used to construct a cDNA library. One cDNA was identified that hybridized to a mRNA which increased in rat brain during the ethanol treatment. Sequence analysis of the cDNA indicated that it recognized a mRNA in rat brain which was very similar to that which encodes the 18 kDa subunit of canine signal peptidase. The rat signal peptidase mRNA was observed to increase in brain nearly 2-fold within 48 h after the initiation of ethanol treatment. Ethanol did not significantly alter beta actin mRNA levels during the treatment period. These results support the existence of an ethanol-responsive signal peptidase mRNA in rat brain. PMID- 7854340 TI - Purpurogallin, a scavenger of polymorphonuclear leukocyte-derived oxyradicals. AB - Purpurogallin (PPG) is a phenolic compound extracted from nutgalls formed on oak trees. It has been used as an additive to edible or nonedible oils or fats, and to hydrocarbon fuels or lubricants to retard their oxidation. We investigated by luminol-dependent chemiluminescence (PMNL-CL), the ability of PPG to scavenge oxygen free radicals (OFRs) generated by zymosan-activated polympophonuclear leukocytes (PMNLs). Its OFR-scavenging ability was also investigated by the use of nitro blue tetrazolium (NBT). We also investigated by the dye-exclusion method, if PPG affects the viability of PMNLs. PPG in the concentrations of 0.005 0.4 mM was used in this study. PPG scavenged OFRs produced by zymosan-activated PMNLs in a concentration-dependent manner. Almost complete scavenging was observed at a concentration of 0.2 mM. The NBT test indicated that PPG (0.2 mM) did not completely prevent the activation of PMNLs by zymosan. Viability of PMNLs in the absence or presence of PPG (0.4 mM) were 95.77 +/- 0.56% and 96.78 +/- 0.60% respectively. The results suggest that PPG scavenges OFRs produced from activated PMNLs in a concentration-dependent manner and that the cell viability is not affected by PPG. PPG is a potent scavenger of OFRs and should be of value in the prevention and treatment of diseases in the pathophysiology of which OFRs are invovled. PMID- 7854341 TI - Technical considerations for assessing alterations in skeletal muscle sarcoplasmic reticulum Ca(++)-sequestration function in vitro. AB - A multiple measurement system for assessing sarcoplasmic reticulum (SR) Ca(++) ATPase activity and Ca(++)-uptake was used to examine the effects of SR fractionation and quick freezing on rat white (WG) and red (RG) gastrocnemius muscle. In vitro measurements were performed on whole muscle homogenates (HOM) and crude microsomal fractions (CM) enriched in SR vesicles before and after quick freezing in liquid nitrogen. Isolation of the CM fraction resulted in protein yields of 0.96 +/- 0.1 and 0.99 +/- 0.1 mg/g in WG and RG, respectively. The percent Ca(++)-ATPase recovery for CM compared to HOM was 14.5% (WG) and 10.1% (RG). SR Ca(++)-activated Ca(++)-ATPase activity was not affected by quick freezing of HOM or CM, but basal ATPase was reduced (P < 0.05) in frozen HOM (5.12 +/- 0.18-3.98 +/- 0.20 mole/g tissue/min in WG and from 5.39 +/- 0.20-4.48 +/- 0.24 mumole/g tissue/min in RG). Ca(++)-uptake was measured at a range of physiological free [Ca++] using the Ca++ fluorescent dye Indo-1. Maximum Ca(++) uptake rates when corrected for initial [Ca++]f were not altered in HOM or CM by quick freezing but uptake between 300 and 400nM free Ca++ was reduced (P < 0.05) in quick frozen HOM (1.30 +/- 0.1-0.66 +/- 0.1 mumole/g tissue/min in WG and 1.04 +/- 0.2-0.60 +/- 0.1 mumole/g tissue/min in RG). Linear correlations between Ca(++)-uptake and Ca(++)-ATPase activity measured in the presence of the Ca++ ionophore A23187 were r = +0.25, (P < 0.05) and r = +0.74 (P < 0.05) in HOM and CM preparations, respectively, and were not altered by freezing. The linear relationships between HOM and CM maximum Ca(++)-uptake (r = +0.44, P < 0.05) and between HOM and CM Ca(++)-ATPase activity (r = +0.34, P < 0.05) were also not altered by tissue freezing. These data suggest that alterations in maximal SR Ca(++)-uptake function and maximal Ca(++)-ATPase activity may be measured in both HOM and CM fractions following freezing and short term storage. PMID- 7854342 TI - Direct measurement of increased myocardial cellular 23Na NMR signals in perfused guinea-pig heart induced by dihydroouabain and grayanotoxin-I. AB - The effects of the cardiac glycoside dihydroouabain (DHO), and the ericaceous toxin grayanotoxin-I (GTX-I) on myocardial cellular sodium (Nai) concentrations were investigated using sodium-23 nuclear magnetic resonance (23Na NMR) spectroscopy at 30 degrees C in isolated perfused guinea-pig hearts. The Nai NMR signals from perfused Langendorff heart preparations were obtained by the modified inversion recovery (IR) method based on the previous observation that the spin-lattice relaxation time (T1) of the Nai (25 or 34 msec at 8.46 Tesla (T)) is much faster than that of extracellular sodium (64 msec at 9.4 T). Nai was estimated from the calibration curve of the frequency area of the 23Na NMR FT spectra plotted against the standard Na concentration. The Nai concentration of the heart increased concomitantly with the positive inotropic effects (PIE) of DHO, GTX-I and monensin (MON). The cumulative sequential addition of DHO (5 x 10( 6) M), GTX-I (7 x 10(-8) M) and MON (5 x 10(-6) M), each of which alone induced no appreciable PIE, produced a 22% elevation in Nai concentration relative to that of the control (100%) accompanying a PIE of 44%. The mechanism of this Nai elevation induced by combinational addition of DHO, GTX-I and MON may be mediated as follows: GTX-I increases the net Na-influx via Na+ channels; DHO inhibits the pumping out of Na+ from the cell; and MON transports external Na+ into the cell, acting as a sodium ionophore. Consequently, these drugs act synergistically to increase the Nai, thereby increasing the intracellular Ca2+ concentration via Na(+)-Ca2+. exchange. PMID- 7854343 TI - Metabolism of n-6 fatty acids by NIH-3T3 cells transfected with the ras oncogene. AB - N-6 fatty acid metabolism was compared in NIH-3T3 cells and DT cells, which differ only in the presence of the v-Ki-ras oncogene. Non-dividing cells were incubated with [1-14C]-labelled fatty acids (18:2n-6, 18:3n-6, 20:3n-6 and 20:4n 6) at different time intervals (2-24 h) and concentration (0-120 microM). In both cells lines, the uptake of different fatty acids from the medium was similar and reached a maximum at 6-8 h. All fatty acids reached the same maximum level in DT cells, whereas, the relative uptake of added fatty acids by NIH-3T3 cells was different: 20:4n-6 > 20:3n-6 > 18:2n-6 = 18:3n-6. Throughout the incubation (2-24 h), desaturation and elongation of n-6 fatty acids was more active in DT cells than in NIH-3T3 cells. However, in both cell lines, incubated with different n-6 fatty acid precursors, the levels of radiolabelled 20:4n-6 were relatively constant. In DT cells, phosphatidylcholine was found to be the major fraction labelled with n-6 fatty acids precursors and those of endogenous synthesis, whereas, in NIH-3T3 cells the neutral lipid fraction, particularly triglycerides, was also strongly labelled. In concentration dependent studies, phospholipid labelling by fatty acids was saturable. At lower concentrations, especially in DT cells, phospholipids were labelled predominantly. As the concentration increased there was an overflow into the triglyceride fraction. Since the differences in fatty acid metabolism between the two cell lines cannot be related to the growth rate, it is suggested that they were a consequence of the expression of the v-Ki ras oncogene. PMID- 7854344 TI - Interaction of newly synthesized antiprogesterone ZK98299 with progesterone receptor from human myometrium. AB - We have undertaken characterization of binding of the newly synthesized progesterone receptor (PR) antagonist ZK98299 in the cellular fractions of human myometrium. Specific [3H]progesterone and [3H]ZK98299 binding was observed in the cytosol and the nuclear fractions, and could be competitively replaced by either of the steroids in their radioinert form. Although PR occupied by both steroids exhibited nuclear uptake, the extent of nuclear binding was lower with [3H]ZK98299-receptor complexes. The binding of both ligands to PR was a function of the duration of incubation and the protein concentration: it was saturable at 3-6 nM steroids with a dissociation constant of approximately 2 nM. However, the number of ZK98299 binding sites (72 fmoles/mg protein) was lower compared to that of progesterone (322 fmoles/mg protein). The relative binding affinity (RBA) of ZK98299 for the nuclear PR was about 33% that of progesterone. The results of our study suggest that ZK98299 binds to PR in the cytosol and the nuclear fractions. The antiprogestin effects of ZK98299 reported in the literature are PR-mediated and may result from suboptimal nuclear binding/retention of antiprogestin receptor complexes. Since this study did not involve isolation and study of individual PR isoforms, PR-A and PR-B, the present data should be viewed as representing an average of contributions by the two receptor forms. PMID- 7854346 TI - The somatostatin receptor SSTR1 is coupled to phosphotyrosine phosphatase activity in CHO-K1 cells. AB - Somatostatin receptors are abundantly expressed on a variety of human endocrine and epithelial tumors. The ability of these receptors to couple to effector pathways that inhibit the growth of these tumor cells has prompted the use of somatostatin agonists in the treatment of human neoplasms. It has been demonstrated that somatostatin stimulates a phosphotyrosine phosphatase in human tumor cells through a receptor-mediated process. This stimulation may counteract the growth-promoting properties of growth factors and the receptor tyrosine kinases that they activate. The recent cloning and characterization of distinct somatostatin receptor subtypes raise the possibility that different receptor subtypes mediate distinct effector pathways. To determine whether cloned somatostatin receptors could mediate coupling to phosphotyrosine phosphotyrosine phosphatase activity, we examined phosphatase activity after somatotostatin activation of the rat somatostatin receptors SSTR1 and SSTR2 after their stable expression in heterologous Chinese Hamster Ovary (CHO-K1) cells. We found that stimulation of SSTR1 cells was capable of increasing phosphotyrosine phosphatase activity, despite the coupling of both receptors to the inhibition of adenylyl cyclase in these cells. This activation was characterized by an EC50 of 70 nM and was sensitive to pertussis toxin. In addition, we demonstrate that activation of phosphotyrosine phosphatase activity in pituitary cell lines correlates with the endogenous expression of the SSTR1 gene within these cells. PMID- 7854347 TI - Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain. AB - POMC, the precursor of ACTH, MSH, and beta-endorphin peptides, is expressed in the pituitary and in two sites in the brain, in the arcuate nucleus of the hypothalamus and the commissural nucleus of the solitary tract of the brain stem. Little is known regarding the functions of melanocortin (ACTH and MSH) peptides in the brain. We report here the detailed neuroanatomical distribution of the MC4 R mRNA in the adult rat brain. The melanocortin 3 receptor (MC3-R), characterized previously, was found to be expressed in arcuate nucleus neurons and in a subset of their presumptive terminal fields but in few regions of the brainstem. The highly conserved MC4-R is much more widely expressed than MC3-R and is pharmacologically distinct. MC4-R mRNA was found in multiple sites in virtually every brain region, including the cortex, thalamus, hypothalamus, brainstem, and spinal cord. Unlike the MC3-R, MC4-R mRNA is found in both parvicellular and magnocellular neurons of the paraventricular nucleus of the hypothalamus, suggesting a role in the central control of pituitary function. MC4-R is also unique in its expression in numerous cortical and brainstem nuclei. Together, MC3 R and/or MC-4R mRNA are found in every nucleus reported to bind MSH in the adult rat brain and define neuronal circuitry known to be involved in the control of diverse neuroendocrine and autonomic functions. The high degree of conservation, distinct pharmacology, and unique neuronal distribution of the MC4 receptor suggest specific and complex roles for the melanocortin peptides in neuroendocrine and autonomic control. PMID- 7854348 TI - Identification of a cyclic adenosine 3',5'-monophosphate-response element in the rat aromatase promoter that is required for transcriptional activation in rat granulosa cells and R2C leydig cells. AB - Cytochrome P450 aromatase, which converts testosterone to estradiol, is transcriptionally induced by FSH and cAMP during ovarian follicular development. At least one promoter element [-82/-31 base pairs (bp)] required for stimulation of the rat gene in granulosa cells binds steroidogenic factor-1, an orphan steroid receptor. In this paper, we demonstrate that an additional region, -161/ 138 bp is required for cAMP regulation. This region shares homology with promoter sequences in the bovine 21-hydroxylase and mouse 11 beta-hydroxylase genes that are also induced by cAMP, yet each binds different proteins in granulosa cell nuclear extracts. The aromatase -161/-138 bp region contains a cAMP-response element (CRE)-like sequence, TGCACGTCA. Deletion or mutation of this sequence reduces promoter activity of chimeric chloramphenicol acetyl transferase (CAT) reporter constructs that are transiently transfected into granulosa cells and R2C Leydig cells. Granulosa cell nuclear proteins and R2C cell nuclear proteins specifically bind the -161/-138 bp region and form three protein/DNA complexes. Recombinant CRE-binding protein (CREB) binds the CRE-like sequence and forms a single band, and a CREB antibody retards the migration of CREB and one granulosa cell protein-aromatase DNA binding complex. Using Western blot analysis, CREB was demonstrated in granulosa cell nuclear extracts from all stages of follicular development. Thus, aromatase is transcriptionally regulated by a hexameric sequence binding SF-1 and a CRE sequence binding CREB and other factors present in granulosa cells and in R2C Leydig cells. The presence of identical SF-1 and CRE-like sequences in the human ovarian aromatase promoter II suggests that the human promoter may also be regulated in a similar manner. PMID- 7854345 TI - Oxygen free radicals and calcium homeostasis in the heart. AB - Many experiments have been done to clarify the effects of oxygen free radicals on Ca2+ homeostasis in the hearts. A burst of oxygen free radicals occurs immediately after reperfusion, but we have to be reminded that the exact levels of oxygen free radicals in the hearts are yet unknown in both physiological and pathophysiological conditions. Therefore, we should give careful consideration to this point when we perform the experiments and analyze the results. It is, however, evident that Ca2+ overload occurs when the hearts are exposed to an excess amount of oxygen free radicals. Through ATP-independent Ca2+ binding is increased, Ca2+ influx through Ca2+ channel does not increase in the presence of oxygen free radicals. Another possible pathway through which Ca2+ can enter the myocytes is Na(+)-Ca2+ exchanger. Although, the activities of Na(+)-K+ ATPase and Na(+)-H(+) exchange are inhibited by oxygen free radicals, it is not known whether intracellular Na(+) level increases under oxidative stress or not. The question has to be solved for the understanding of the importance of Na(+)-Ca2+ exchange in Ca2+ influx process from extracellular space. Another question is 'which way does Na(+)-Ca2+ exchange work under oxidative stress? Net influx or efflux of Ca2+?' Membrane permeability for Ca2+ may be maintained in a relatively early phase of free radical injury. Since sarcolemmal Ca(2+)-pump ATPase activity is depressed by oxygen free radicals, Ca2+ extrusion from cytosol to extracellular space is considered to be reduced. It has also been shown that oxygen free radicals promote Ca2+ release from sarcoplasmic reticulum and inhibit Ca2+ sequestration to sarcoplasmic reticulum. Thus, these changes in Ca2+ handling systems could cause the Ca2+ overload due to oxygen free radicals. PMID- 7854350 TI - Glucocorticoid regulation of rat whey acidic protein gene expression involves hormone-induced alterations of chromatin structure in the distal promoter region. AB - Milk protein gene expression is regulated by the synergistic interactions of several lactogenic hormones, including insulin, PRL, and glucocorticoids. Whey acidic protein (WAP) gene expression is highly dependent on glucocorticoids, and to a lesser extent than casein gene expression, on the presence of PRL. Previous studies have demonstrated that a distal DNase I hypersensitive site in the rat WAP gene 5'-flanking region containing several binding sites for nuclear factor I is required for high level WAP gene expression in transgenic mice. In this study several specific glucocorticoid receptor (GR) binding sites were identified flanking these nuclear factor I sites using an in vitro DNase I footprinting assay with baculovirus-expressed GR. These sites were able to confer dexamethasone inducibility to a heterologous thymidine kinase-chloramphenicol acetyltransferase reporter gene construct in transient cotransfection experiments with GR in CV1 cells. Administration of dexamethasone to adrenal-ectomized mice carrying the +2020 rat WAP transgene during lactation demonstrated that glucocorticoids are required to maintain transgene expression in the mammary gland. Furthermore, glucocorticoid-induced changes in transgene expression were correlated with the appearance of DNase I hypersensitive sites. These results indicate that at least part of glucocorticoid regulation of WAP gene expression is mediated through the direct interaction of GR with glucocorticoid response elements in the distal promoter region resulting in steroid hormone-dependent alterations in chromatin structure. PMID- 7854349 TI - A sequence in the rat Pit-1 gene promoter confers synergistic activation by glucocorticoids and protein kinase-C. AB - The 5'-flanking region of the gene for Pit-1, a pituitary-specific transcription factor, was isolated from a rat liver genomic library and sequenced. Expression of a reporter construct containing Pit-1 promoter sequences linked to the bacterial chloramphenicol acetyltransferase (CAT) gene was assessed by transient transfection in rat pituitary GH4C1 cells. Treatment of transfected cells with either dexamethasone (DEX) for 48 h or the phorbol ester 12-O tetradecanoylphorbol 13-acetate (TPA) for the final 20 h of the 48-h posttransfection period had minimal effects on CAT expression. However, CAT activity was elevated about 20-fold when transfected cells were treated with both DEX and TPA. This apparent synergistic activation was lost when DEX treatment was also limited to the final 20 h of the 48-h posttransfection period, suggesting that a time-dependent accumulation of a DEX-induced gene product might be involved. This putative DEX-induced product appeared to be relatively stable, because synergistic activation was observed in cells treated with DEX alone for 36 h, followed by a 10-h incubation without DEX before the addition of TPA. The Pit-1 gene promoter region between -210 and -142 from the transcription start site conferred synergistic regulation by DEX and TPA when placed upstream of position -105 in the herpes viral thymidine kinase promoter.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7854351 TI - Coordinate regulation of glucocorticoid receptor and c-jun mRNA levels: evidence for cross-talk between two signaling pathways' at the transcriptional level. AB - Autologous regulation of steroid receptors by their cognate ligands has been demonstrated for a number of nuclear receptor family members. To determine the molecular mechanism for glucocorticoid receptor (GR) autoregulation, the expression of glucocorticoid receptor mRNA and protein levels were examined in the mouse AtT-20 pituitary tumor cell line. The expression of c-jun and c-fos mRNA and protein was also examined in the same cell extracts. A rapid down regulation of the GR protein was observed after treatment with the glucocorticoid analog, triamcinolone acetonide (TA). An oscillatory, parallel regulation of both GR and c-jun mRNA levels occurred. In contrast, POMC mRNA levels remained at a stable, low level during chronic TA treatment. Dose-response analyses also revealed a coordinate down-regulation of GR and c-jun (but not POMC or c-fos) mRNA levels. FOS protein levels were unaffected by TA treatment. Surprisingly, JUN protein levels were increased by TA, even when the c-jun mRNA levels were decreasing. Perhaps a derepression of c-jun mRNA translation occurs after TA treatment, and this may be due to GR/JUN heteromer formation interfering with JUN repression of c-jun mRNA translation. The effect of TA on GR and c-jun gene expression was a primary effect, as it occurred rapidly and was not inhibited by cycloheximide (CHX). Nuclear run-on transcription assays revealed a rapid (15 min) down-regulation in both GR and c-jun gene transcription rates, while POMC gene transcription was unaffected at this early time. Treatment of AtT-20 cells with all-trans retinoic acid gave different kinetics for GR and c-jun mRNA regulation than obtained with TA; however, the GR and c-jun mRNA levels were still coordinately regulated after retinoic acid treatment. Based upon these data, the promoter structures of the GR and c-jun genes, and previously published results, a novel mechanism for the coupled regulation of GR and c-jun transcription, via a direct transcriptional interference with AP-1 (FOS/JUN) activity, is proposed. PMID- 7854352 TI - A third transactivation function (AF3) of human progesterone receptors located in the unique N-terminal segment of the B-isoform. AB - Human progesterone target tissues contain two progesterone receptors: B-receptors (hPRB), which are 933 amino acids in length, and A-receptors (hPRA), which lack the N-terminal 164 amino acids. The two isoforms differ functionally when they are occupied by agonists or antagonists. We postulated that the unique 164-amino acid, B-upstream segment (BUS) is in part responsible for the functional differences between the two isoforms and have constructed a series of hPR expression vectors encoding BUS fused to isolated down-stream functional domains of the receptors. These include the two transactivation domains: activation function-1 (AF1), located in a 90-amino acid segment just up-stream of the DNA binding domain (DBD) and nuclear localization signal (NLS), and AF2, located in the hormone-binding domain. BUS is a highly phosphorylated domain, and contains the serine residues responsible for the hPRB triplet protein structure. The construct containing BUS-DBD-NLS binds tightly to DNA when aided by accessory nuclear factors. In HeLa cells, BUS-DBD-NLS strongly and autonomously activates transcription of chloramphenicol acetyltransferase (CAT) from a promoter containing two progesterone response elements (PRE2-TATAtk-CAT). Transcription levels with BUS-DBD-NLS are equivalent to those seen with full-length hPRB, and are higher than those seen with hPRA. BUS specifically requires an intact hPR DBD to be transcriptionally active. DBD mutants that cannot bind DNA or whose DNA binding specificity has been switched to an estrogen response element cannot cooperate in BUS transcriptional activity. The function of BUS-DBD-NLS is promoter and cell specific. It does not transactivate a CAT reporter driven by the mouse mammary tumor virus promoter in HeLa cells and poorly transactivates PRE2-TATAtk-CAT in PR-negative T47D breast cancer cells. However, in the breast cancer cells, BUS-DBD-NLS transactivation of PRE2-TATAtk-CAT can be reconstituted by either elevating cellular levels of cAMP or linking BUS and DBD to AF1 or AF2 of hPR, each of which alone is also inactive in these cells. We conclude that hPRB contains a unique third activation function (AF3) located within BUS and requiring the functional DBD of hPR. Depending on the promoter or cell tested, AF3 can activate transcription autonomously, or it can functionally synergize with AF1 or AF2. Autonomous AF3 function may explain the unexpected transactivating actions of antiprogestin-occupied hPRB, an issue of importance in hormone-resistant breast cancers and in tissue-specific agonist-like effects of hormone antagonists. PMID- 7854353 TI - Insulin regulation of malic enzyme gene expression in rat liver: evidence for nuclear proteins that bind to two putative insulin response elements. AB - Diabetes in rats is characterized by insulin deficiency accompanied by a decrease in lipogenic enzymes. The malic enzyme (ME) gene, which encodes an important lipogenic enzyme, was used to investigate insulin regulation of gene expression. ME mRNA levels were reduced by more than 90% in the liver of diabetic rats. The administration of insulin (3 U/15 days) to either control or diabetic rats increased ME mRNA by 2- to 10-fold, respectively. Since diabetes reduces circulating T3 and the levels of nuclear T3-receptors, the potential role of thyroid hormone on insulin regulation of ME gene expression was also evaluated in thyroidectomized-diabetic rats. In these animals the levels of ME mRNA were undetectable but were increased by insulin even in the absence of thyroid hormones. These in vivo effects of insulin and T3 were not additive. The transcription rate of the gene was also reduced in the diabetic liver and recovered after insulin therapy. By computer analyses we have identified two different putative insulin response elements (IREs) in the ME gene promoter, hereafter referred to as IRE-I (-683 to -692), which is similar to the phosphoenol pyruvate carboxy kinase promoter IRE and IRE-II (-161 to -170), which is similar to the glyceraldehyde phosphate dehydrogenase gene promoter IRE-A. Results from gel retardation assays suggest that a single nuclear protein binds to IRE-I whereas two different nuclear proteins bind to IRE-II. The protein/IRE-I complex increased in liver nuclear extracts from diabetic rats and decreased after insulin administration.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7854354 TI - T cell activation and increases in protein kinase C activity enhance retinoic acid-induced gene transcription. AB - Retinoic acid (RA) has profound effects on cell growth and differentiation. Its receptors are members of the steroid/thyroid hormone receptor superfamily, which regulates nuclear transcription and gene expression by binding specific response elements. Protein kinase C (PKC) is activated during signal transduction initiated by a variety of membrane receptors. Using a RA-responsive element and reporter gene construct transfected into a T cell, we found: 1) T cell activation and PKC activators enhance transactivation by RA, 2) down-regulation of PKC protein has little effect on RA transactivation but abolishes superinduction by phorbol ester, which is restored by cotransfection of a PKC alpha-expression vector, and 3) cotransfection of dominant-negative c-jun does not prevent superinduction by phorbol ester. Together, these data demonstrate that PKC can modulate RA signal transduction, apparently without involvement of AP-1, and provide a new example of cross-talk between signal transduction pathways. PMID- 7854355 TI - Characterization of a corticotropin-releasing hormone-responsive element in the rat proopiomelanocortin gene promoter and molecular cloning of its binding protein. AB - A corticotropin-releasing hormone (CRH) and cAMP-responsive region (-236/-133) in the rat POMC gene promoter previously reported to confer CRH/cAMP responsiveness to heterologous reporter constructs has been characterized. DNAse footprint analysis revealed that multiple elements in this region were bound by nuclear proteins from the POMC expressing AtT20 cells. When these individual DNA elements were separately tested in heterologous reporter constructs for CRH induction, only one element, designated PCRH-RE (POMC CRH responsive element, -171/-160) was found to give strong CRH stimulation (5- to 7-fold). This element appears novel as to the possible binding factors, although it has homology to the mouse metallothionein metal regulatory element. Gel shift analyses of the PCRH-RE with AtT20 cell nuclear extracts showed marked stimulation of retarded nucleoproteins following CRH stimulation, suggesting that the possible binding factor(s) may mediate transcriptional regulation at this site. The activity of PCRH-RE binding protein was inhibited by divalent cations, with Cu2+ and Cd2+ being most effective; Zn2+ had no effect, indicating that this binding factor(s) is functionally distinct from the metallothionein metal regulatory element binding protein. A 2.6 kilobase cDNA clone encoding a protein (PCRH-REB-1) binding to this element was isolated by Southwestern screening of an AtT20 expression library with radiolabeled PCRH-RE oligonucleotides. This clone was used to isolate several other cDNA clones to determine the sequence corresponding to the entire coding region of the protein (PCRH-REB), which proved to be identical to a recently described DNA binding protein of the replication factor C complex, mRFC140/Mouse Southwestern. Primer extension and Northern blot analysis revealed that the size of the full length mRNA is about 4.9 kilobases. PCRH-REB mRNA expression is not restricted to corticotrophs but is present in a broad tissue distribution as evaluated by reverse transcription polymerase chain reaction analysis. A bacterially expressed beta-galactosidase-PCRH-REB-1 fusion protein was shown to bind PCRH-RE efficiently. Furthermore, binding of the PCRH-REB-1 fusion protein to the POMC CRH-responsive element was inhibited by divalent cations with similar sensitivities to those observed using AtT20 nuclear extracts. The predicted PCHR-REB protein sequence presents several interesting motifs: one p-Loop motif (ATP binding site), nine protein kinase A phosphorylation sites (implying a possible role in responding to the CRH-induced cAMP signal), and regions of homology to proteins involved in DNA replication and repair. PCRH-REB is, therefore, a potential transacting factor binding to a major CRH-responsive element in the POMC promoter. PMID- 7854356 TI - Antiestrogens increase protein tyrosine phosphatase activity in human breast cancer cells. AB - Growth of human breast cancer cells is controlled by multiple interacting factors that trigger different intracellular signaling pathways. The nonsteroidal antagonist 4-hydroxytamoxifen (OH-Tam), which acts as an antiestrogen, is also able to inhibit the mitogenic activity of epidermal growth factor (EGF) on hormone-responsive MCF7 cells. To further characterize the mechanism of this antigrowth factor activity, which is accompanied by an increase of high-affinity EGF binding and a drastic decrease in EGF receptor autophosphorylation, we studied the effect of OH-Tam on protein tyrosine phosphatase (PTPase) activity with specific in vitro assays using two different substrates. OH-Tam increased membrane PTPase activity in a time- and dose-dependent fashion whereas cytoplasmic enzyme activity remained unchanged. The increase in PTPase activity was mediated by the estrogen receptor (ER) since it was restricted to ER-positive cells, and the optimal OH-Tam concentration (ED50 = 1 nM) was correlated with the ligand affinity for ER. The increase in enzyme activity was selectively obtained with nuclear receptor ligands (OH-Tam, ICI 164,384) that inhibited growth factor induced proliferation, whereas other inhibitors of estrogenic responses such as synthetic progestins and antiprogestins had no effect. The time course of stimulation (maximal stimulation at day 4) was concomitant to the loss of EGF mitogenic response. Moreover, addition of a specific PTPase inhibitor (5 microM sodium orthovanadate) to intact cells in culture prevented OH-Tam inhibition of cell proliferation, suggesting that these two events are closely associated.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7854357 TI - The interaction of human estrogen receptor with DNA is modulated by receptor associated proteins. AB - To better define the role of accessory protein as mediators of estrogen receptor (ER) function, we have used immuno-, steroid-, and site-specific DNA-affinity chromatography to identify and characterize proteins that associate with ER in extracts from ER-expressing Chinese hamster ovary (CHO-ER) cells. Two associated proteins [70 and 55 kilodaltons (kDa)] were observed by sodium dodecyl sulfate polyacrylamide gel electrophoresis silver stain analysis of all three column eluates. Two additional proteins (45 and 48 kDa) were preferentially retained by the ER-specific DNA affinity column. The 70-kDa protein was subsequently identified by Western blot analysis as a heat shock protein (hsp70). The 55-kDa protein was identified by N-terminal microsequencing as a member of the protein disulfide isomerase family. The 48- and 45-kDa proteins remain unidentified. To determine the possible differential effects of estrogen agonists and antagonists on human (h) ER interaction with these proteins, CHO-ER cells were labeled with [35S]methionine in the presence of estradiol, 4-hydroxytamoxifen (OH-Tam; partial agonist/antagonist), or ICI 182,780 (complete antagonist). None of these ligands altered the pattern of associated proteins when hER complexes were isolated by adsorption to the vitellogenin A2 estrogen response element (ERE). However, when hER was isolated by immunoadsorption, a reduction in the level of associated hsp70 was observed following treatment with estradiol or OH-Tam, compared to no treatment or treatment with ICI 182,780. By gel retardation analysis, maximal interaction of affinity-purified hER with ERE occurred in the presence of all four associated proteins. Removal of the 48- and 45-kDa proteins and/or hsp70 resulted in a decrease in hER/ERE association, which could be restored by the addition of purified hsp70 and/or a mixture of the 48- and 45-kDa proteins. The increased stability of the restored complex was due primarily to an increase in the association rate of hER with ERE. These results suggest that accessory proteins may be required for maximal ER interaction with EREs and that estrogens and estrogen antagonists may promote differential retention of hsp70 in the presence or absence of a specific ERE. PMID- 7854358 TI - Cloning of a novel orphan receptor (GCNF) expressed during germ cell development. AB - We have cloned a novel member of the nuclear receptor superfamily that has been identified from complementary DNA libraries derived from mouse tissues using a low stringency cross hybridization strategy. The deduced protein sequence contains 495 amino acids and consists of the characteristic DNA-binding and ligand-binding domains of the nuclear receptor superfamily. The primary sequence of this new orphan is distinct from those of previously cloned members and subgroups. Analysis of the DNA-binding properties of the in vitro synthesized protein revealed that this new orphan receptor binds to the sequence TCAAGGTCA that includes the steroidogenic factor-1 half-site and direct repeat with 0 bp spacing elements. Northern blot and ribonuclease protection assays showed that the receptor was predominantly expressed in the testis. Results from in situ hybridization experiments confirmed this observation and showed it to be located in the spermatogenic cells. High level expression was also detected in developing oocytes in the ovary. Thus, high level expression of this gene is restricted to developing germ cells, the oocytes and spermatogenic cells. We speculate that this orphan receptor may be a molecule involved in regulating some aspect of meiosis, and that the major function of this factor is likely to be involved in the regulation of gene expression in germ cell development during gametogenesis. It has been designated germ cell nuclear factor. PMID- 7854359 TI - [27th Scientific Meeting of the German-Speaking Language Mycology Association. Greifswald, 30 September-3 October 1993]. PMID- 7854360 TI - [Treatment of superficial mycoses in the tropics. Results of a double-blind study in the Karonga District, Malawi]. AB - A double-blind trial was undertaken in Karonga District, Northern Malawi comparing Whitfield's cream (3% salicylic acid and 6% benzoylic acid) and clotrimazole cream in the treatment of dermatophyte infections of the skin. To date, 138 patients have been reviewed; 65 of these patients received Whitfield's cream and 73 received clotrimazole cream. Within 4 weeks to 4 months after the beginning of treatment, there were six definite treatment failures in each group. In view of the considerable difference in price between the two preparations, Whitfield's cream should be considered as the treatment of choice in tropical primary health care. PMID- 7854361 TI - [Indication for and effectiveness of fluconazole in oral candidiasis]. AB - From 1991 until 1993 we used fluconazole in 56 cases of oral candidosis which could not be managed by local therapy only. In seven cases there was no clinical improvement. A mycological cure was seen in 44 cases. In cases of oral candidosis which do not respond to local therapy fluconazole has proven a success especially in the follow up of patients with oral cancer and in cases of oral precancerous lesions with mycotic colonization. PMID- 7854362 TI - [Festival lecture. The position of microorganisms in the global phylogenetic system of three domains]. AB - New insights into genealogic relations among organisms due to similarities of 16S rRNA sequences of more than 1000 representatives of the various groups led to a classification of the presently known living beings into three domains: Bacteria, Archaea (Archaebacteria) and Eucarya. All medical relevant prokaryotes belong to the domain Bacteria. The systematics of the eukaryote microorganisms (protista and fungi) and their numerous medically relevant representatives will be widely changed in the near future due to latest scientific findings on phylogenetic relations. The retrospective analysis of the 16S rRNA phylogenetic tree led to assuming a chemolithoautotrophic origin of life and an early splitting into three domains in an early precellular phase of evolution. PMID- 7854363 TI - [One hundred years of cryptococcosis. Medical mycology in the 19th century in Greifswald]. AB - Not later than 1842 medico-mycological investigations began at Greifswald in Germany following the appointment of Wilhelm Baum (1799-1883) to the chair of surgery at the university. This is indicated by some theses as well as by the discovery of the contagious characteristics of pityriasis versicolor by Carl Ferdinand Eichstedt (1816-1892) who found a fungus as the cause (1846), which was named Microsporon furfur later (C. Robin 1853). In 1868 the physician (Karl) Friedrich Mosler (1831-1911) published clinical-mycological studies and investigations on animal feeding with yeasts. Some time later (1870) Friedrich Grohe (1830-1886) and his assistants Alwin R. A. Block (1843-?) and M. R. Roth of the Pathological Institute described results of transmission-studies with "Aspergillus glaucus, Penicillium glaucum and yeast". The successor to the chair, Paul Grawitz (1850-1932), also published results of his own mycological investigations. Finally, on 7 July, 1894, during the evening lecture of the Greifswald Medical Society Abraham Buschke (1868-1943) from the Hospital of Surgery gave a talk "on a peculiar disease caused by coccidia" followed by the talk of pathologist Otto Busse (1867-1922) on a "demonstration of a pathogenic coccidia species". Busse's subsequent publications are the first proper descriptions of cryptococcosis (1894 f). Nevertheless, Cryptococcus neoformans has been named in connection with F. Sanfelice, whose results were published later (1895). PMID- 7854364 TI - [Pathogenesis, immunobiology and epidemiology of cryptococcosis]. AB - Cryptococcus neoformans is taken up by the human host via the respiratory tract. The polysaccharide capsule is regarded as the pathogenetic principle inhibiting phagocytosis of the fungus by cells of the unspecific host defense. Unspecific opsonization of Cr. n. by early phase proteins causes a rapid and successful elimination in the non-compromised host. In case of non-elimination the presence of Cr. n. capsule antigen in excess results in a downregulation of antibody formation thereby inhibiting specific opsonization. Furthermore the blockade of specific T cells and cytotoxic cells by means of free antigen and/or immunocomplexes causes a downregulation of the cellular immunity: Cr. n. antigens of different character induce T suppressor cells inhibiting cellular immunity via a cascade of effector cells and soluble factors. The AIDS patient enters cryptococcosis in a state comparable to a Cr. n.-infected non-AIDS patient whose cellular immunity is already downregulated by this mycosis itself. Both phenomena -the mycosis-induced downregulation of cellular immunity as well as the AIDS specific lack of CD4 helper cells and its consequences--act, therefore, synergistically in the same pathogenetic direction. This explains the fulminant development and sequel of cryptococcosis typical with AIDS patients. Most probably each exposition of an AIDS patient to Cr. n. results in clinically manifest cryptococcosis. The frequence of cryptococcosis in AIDS is, therefore, reflecting the general exposure of humans to Cr. n. in a given region. Cryptococcosis in AIDS is at least about 1000x more frequent than cryptococcosis in non-AIDS individuals.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7854365 TI - [Health risks of mycotoxins for humans]. AB - Fungi cause diseases in humans in different ways. Due to production of secondary metabolites by molds, dematiaceous hyphomycetes, and primary plant pathogenic fungus species intoxications are included in their pathogenic potency. Mycotoxins mostly enter the body by ingestion of food because they are contaminants of plant products and in case of carry over also of animal products. Recent investigations have shown that mycotoxins detected in feed and food during microbial deterioration can also be produced inside warm-blooded organism, e. g. with aspergillosis in animals (mammals and birds). This means an enhanced risk for humans to suffer from mycotoxicosis, in which the toxic agent has an exogenic or endogenic source. Therefore, attention should be paid to the fact that mycotoxins are not only damaging cells; they very often possess a genotoxic potential. PMID- 7854366 TI - [Dimorphism of Candida albicans in the model of continuous flow culture]. AB - We investigated the opportunistic pathogen Candida albicans in a continuous flow culture with regard to particular growth conditions. Germ counts of only 10(7) cfu/ml were obtained in a steady state of an anaerobic culture. In a parallel experiment with aerobic conditions excessive growth occurred and the invasive forms of Candida, i.e. germ tubes and pseudomycelium, also developed. Neither by different carbohydrates and concentration of nutrients in the culture medium nor by changing the flow rate the growth of Candida could be influenced. Excessive overgrowth was triggered by a sufficient oxygen supply. PMID- 7854367 TI - [Pulsed-field gel electrophoresis for the epidemiological analysis of yeast isolates]. AB - Up to now, pulsed field gel electrophoresis (PFGE) has been used successfully for the analysis of the chains of infection of multiresistant staphylococci, enterococci and other germs involved in hospitalism. The purpose of this study was to find out whether yeast isolates from mothers and those from their newborns differed in genotypes. In this investigation, 103 parturient mothers and their children were examined for colonization by yeasts in sampling the vaginal secret at delivery and by taking swabs from the oral mucosa and the anus of the children on the third day after parturition. The samples were cultured on Sabouraud glucose agar and incubated for 48 hrs at 37 degrees C. The differentiation of the isolates was done biochemically by means of the VITEK-AMS system and morphologically on rice-extract agar. Subsequently DNA-fingerprinting analysis was carried out. In 6 cases we could prove the presence of Candida spp. in the mothers as well as in their children. In all cases the strains from mother and child showed the same banding pattern. Likewise, the strains isolated out of the vaginal secretion and the vaginal epithelium of individual women were identical. The differences observed between strains isolated from various women were of low or medium degree. This shows the PFGE to be an efficient procedure to demonstrate the relation of strains derived from mothers and their newborns. PMID- 7854368 TI - [Correlation between resistance testing and typing of Candida albicans--isolates from AIDS patients and chronic recurrent oral candidiasis]. AB - In patients with AIDS and recurrent oropharyngeal candidosis results of biotyping and serotyping were compared with antifungal susceptibility testing. Biotype B1 was found predominantly with 44.3% from 169 C. albicans isolates. Serotype A was seen in 150/169 C. albicans isolates. No close correlation between high MIC values (> or = 25 micrograms/ml) for C. albicans isolates against fluconazole nor a change to a particular biotype or serotype has been observed in recurrences of oral candidosis. PMID- 7854369 TI - [Fluconazole sensitivity of Candida strains in vitro in the microdilution test and agar diffusion test]. AB - The comparison of the in vitro-susceptibility of Candida isolates collected from the oral cavity of different groups of patients to fluconazole ist reported. The isolates of HIV-patients treated with fluconazole, HIV-patients and dermatological patients without fluconazole exposure were investigated. The in vitro-susceptibility of these isolates was determined by microdilution test and agar diffusion test. 88.7% of the 194 Candida isolates were susceptible in vitro, 6.7% less sensitive and 4.6% resistant to fluconazole. Comparing the susceptibility within the groups there was a higher number of isolates less sensitive (14.7%) and resistant (11.8%) to fluconazole in the group of HIV patients treated with fluconazole than in the other 2 groups without treatment. The less sensitive isolates were 4 C. albicans and 6 C. glabrata. The resistant isolates were 2 C. albicans, 2 C. glabrata and 4 C. krusei. In the group of HIV patients without fluconazole exposure there were only 2.7% of the isolates less sensitive (2 C. glabrata) and 1.4% resistant to fluconazole (1 C. glabrata). In dermatological patients there were 2% of the isolates less sensitive (2 C. glabrata) and no resistant isolate. Resistance both in vivo and in vitro was found in 2 patients. PMID- 7854370 TI - [Detection of anti-Candida antibodies of the classes IgM, IgG and IgA using enzyme immunoassay in sequential serum samples of hospitalized patients]. AB - Anti-Candida antibodies were determined in 2053 sera with an indirect hemagglutination test (HAT; Labor Diagnostika, Heiden, Germany) and with an enzyme immunoassay (ELISA) which detects IgG antibodies (Institut Virion, Wurzburg, Germany). Antigen diagnostics was performed with the Cand-Tec-test (Ramco, Houston, USA). Eighty-eight sera from sixteen patients which were positive for IgG antibodies were screened for IgA and IgM antibodies by ELISA. A humoral immune response during the hospital stay of the sixteen patients was detected first by the HAT. The HAT was also reactive when the IgG and/or IgA antibodies rose above the upper reference value and the IgM antibody level remained unchanged. Synchronous changes of IgG, IgM and IgA antibody concentrations even within the normal range are detected by the HAT several days before one or more of these antibodies rose above the upper reference value. In most patients the IgM immune response preceded an increase in IgG and/or IgA antibody concentration by several days. In patients in whom the serum HAT titer remains constant as a consequence of a decreasing IgM antibody level and an increasing IgG antibody concentration, the selective determination of IgM antibodies by ELISA may yield additional information, e.g. a drop in IgM antibodies may be due to a successful therapy. In several patients antigen detection and antibody screening by HAT should be complemented by an immunoglobulin specific measurement of anti-Candida antibodies. PMID- 7854371 TI - [Comparison of immunodiffusion and counterimmunoelectrophoresis for the detection of precipitating antibodies against Candida and Aspergillus antigens]. AB - Early diagnosis of disseminated fungal infections is a major problem in patients at risk, e.g. patients with malignancies or other severe illnesses. A number of serological tests for the detection of fungal antigens or antibodies can be performed in addition to culture methods. Valuable serological tests exist for the detection of precipitating antibodies to Candida sp. or Aspergillus sp. Precipitating antibodies against intracellular fungal antibodies can be detected by the immunodiffusion test (ID) or by counterimmunoelectrophoresis (CIE). In our study 103 patients' sera were examined in parallel with these two methods for antibodies against Candida sp. and 100 sera for antibodies against Aspergillus sp. The results indicate that counterimmunoelectrophoresis is more sensitive than immunodiffusion, and that the results of CIE also correlate better with elevated titers in other serological tests, e.g. the hemagglutination test or the immunofluorescence test. One of the limitations is that precipitating antibodies cannot be detected until relatively late in the course of infection. This disadvantage is further intensified by the long duration of performance of the immunodiffusion test in the laboratory. In comparison with the ID test, the detection of precipitating antibodies by counterimmunoelectrophoresis shortened the duration of performance in our laboratory by up to 5 days. PMID- 7854372 TI - [Amphotericin B level in feces and serum during oral administration in newborns at risk]. AB - The aim of this study was to determine the efficacy of orally administered amphotericin B (Ampho B) on the elimination and suppression of yeasts in the orointestinal tract and on the clinical success regarding the Ampho B concentrations in faeces and serum. A total of 23 newborns at risk suffering from oral and/or cutaneous candidosis and massive colonization of yeasts in the orointestinal tract received Ampho-Moronal suspension (Squibb-Heyden, Munchen) for 10 days: newborns < 1500 g 4 x 20 mg Ampho B/d and newborns > 1500 g 4 x 40 mg/d. Ampho B was detected in concentrations between 0.6 and 20 micrograms/g in the faeces of all patients 24 hours after beginning and 2-6 days after the end of the application. During this time Ampho B concentrations between 0.06 and 0.58 microgram/ml were also detected in the serum of the newborns. During the administration of Ampho-Moronal suspension for 10 days the initial available yeasts were eliminated in 18 patients (78%) out of the faeces. In 7 out of 17 patients (41%) the oral and cutaneous candidosis was cured. After finishing the administration of Ampho-Moronal Candida albicans was isolated again from the faeces during the following 5 days in half of the newborns who had reached negative mycological findings during the prophylaxis. For that reason Ampho Moronal should be prophylactically administered for a longer time during the period of increased risk for systemic mycosis. PMID- 7854373 TI - [Detection of Exophiala dermatitidis (Kano) De Hoog 1977 in septicemia of a child with acute lymphatic leukemia and in patients with cystic fibrosis]. AB - In 1992 black yeasts of the species Exophiala dermatitidis were isolated for the first time from patients at the University Clinics in Dresden. Since that time this relatively rarely detected fungus has been frequently cultivated from clinical specimens. Our observations were: Patient with acute lymphatic leukaemia: In a 3 1/2 years old boy E. dermatitidis was isolated from 8 blood cultures during a septicaemic phase. Elimination of the fungus and decreasing of the fever were reached after removing a central venous catheter and treatment with amphotericin B and 5-fluorocytosine for 3 weeks. In this patient E. dermatitidis was assessed to be the cause of the septicaemia setting in via catheter. Patients with cystic fibrosis: In 8 of 51 mycologically surveyed patients E. dermatitidis was frequently - in 2 cases for a long time up to 7 months - isolated from sputum specimens. The occurrence of this fungus was considered to be a colonization with subclinical development. In these patients no fungal invasion or systemic mycosis were seen. The administration of itraconazole for 4 respectively 7 months did not succeed in eliminating E. dermatitidis out of the respiratory tract. It is recommended to include mycological longtime cultures in the surveillance of cystic fibrosis patients for detection of E. dermatitidis. PMID- 7854374 TI - [Therapy with ciclopirox lacquer of onychomycoses caused by molds]. AB - 60 patients, suffering from an onychomycosis produced by molds were treated for a maximum of 6 months with ciclopirox nail lacquer (8%). These molds determined by culture were Scopulariopsis brevicaulis (51 x), Aspergillus niger (6 x), Aspergillus fumigatus (2 x) and Hendersonula toruloidea. Anamnesis gave no hints, why molds were the causing fungi of onychomycosis. The achieved mycological cure rate was determined with 90% (culture) respectively 85% (KOH preparation). The local treatment with ciclopirox nail lacquer was well tolerated by all patients during the entire treatment period of max. 6 months. No side effects occurred. The local therapy with ciclopirox nail lacquer proved to be as effective in the treatment of onychomycosis caused by molds as in the treatment of onychomycosis due to dermatophytes and yeasts. PMID- 7854375 TI - A randomized trial of three antipneumocystis agents in patients with advanced human immunodeficiency virus infection. NIAID AIDS Clinical Trials Group. AB - BACKGROUND: We evaluated the effectiveness of three treatment strategies for the prevention of a first episode of Pneumocystis carinii pneumonia in patients infected with the human immunodeficiency virus (HIV). METHODS: In an open-label trial, 843 patients with HIV infection and fewer than 200 CD4+ cells per cubic millimeter received zidovudine plus one of three randomly assigned prophylactic agents, beginning with trimethoprim-sulfamethoxazole, dapsone, or aerosolized pentamidine and followed by a defined sequence of other drugs to be used in cases of intolerance. RESULTS: The estimated 36-month cumulative risks of P. carinii pneumonia were 18 percent, 17 percent, and 21 percent in the trimethoprim sulfamethoxazole, dapsone, and aerosolized-pentamidine groups, respectively (P = 0.22). The difference in risk among treatment strategies was negligible in patients entering the study with 100 or more CD4+ lymphocytes per cubic millimeter. In those entering with fewer than 100 CD4+ cells per cubic millimeter, the risk was 33 percent with aerosolized pentamidine, as compared with 19 percent with trimethoprim-sulfamethoxazole and 22 percent with dapsone (P = 0.04). The lowest failure rates occurred in patients receiving trimethoprim sulfamethoxazole, and failures were more common with 50 mg of dapsone than with 100 mg. Toxoplasmosis developed in less than 3 percent of patients. Of the patients assigned to the two systemic therapies, only 23 percent were receiving their assigned drug and dose when they completed the study. The median survival was approximately 39 months in all three groups, and the mortality attributable to P. carinii pneumonia was only 1 percent. CONCLUSIONS: In patients with advanced HIV infection, the three treatment strategies we examined have similar effectiveness in preventing P. carinii pneumonia. Strategies that start with trimethoprim-sulfamethoxazole or with high-dose dapsone, rather than aerosolized pentamidine, are superior in patients with fewer than 100 CD4+ lymphocytes per cubic millimeter. PMID- 7854376 TI - A randomized trial comparing fluconazole with clotrimazole troches for the prevention of fungal infections in patients with advanced human immunodeficiency virus infection. NIAID AIDS Clinical Trials Group. AB - BACKGROUND: Cryptococcal meningitis and other serious fungal infections are common complications in patients infected with the human immunodeficiency virus (HIV). Fluconazole is effective for long-term suppression of many fungal infections, but its effectiveness as primary prophylaxis had not been adequately evaluated. METHODS: We conducted a prospective, randomized trial that compared fluconazole (200 mg per day) with clotrimazole troches (10 mg taken five times daily) in patients who were also participating in a randomized trial of primary prophylaxis for Pneumocystis carinii pneumonia. RESULTS: After a median follow-up of 35 months, invasive fungal infections had developed in 4.1 percent of the patients in the fluconazole group (9 of 217) and in 10.9 percent of those in the clotrimazole group (23 of 211; relative hazard, as adjusted for the CD4+ count, 3.3; 95 percent confidence interval, 1.5 to 7.6). Of the 32 invasive fungal infections, 17 were cryptococcosis (2 in the fluconazole group and 15 in the clotrimazole group; adjusted relative hazard, 8.5; 95 percent confidence interval, 1.9 to 37.6). The benefit of fluconazole was greater for the patients with 50 or fewer CD4+ cells per cubic millimeter than for the patients with higher counts. Fluconazole was also effective in preventing esophageal candidiasis (adjusted relative hazard, 5.8; 95 percent confidence interval, 1.7 to 20.0; P = 0.004) and confirmed and presumed oropharyngeal candidiasis (5.7 and 38.1 cases per 100 years of follow-up in the fluconazole and clotrimazole groups, respectively; P < 0.001). Survival was similar in the two groups. CONCLUSIONS: Fluconazole taken prophylactically reduces the frequency of cryptococcosis, esophageal candidiasis, and superficial fungal infections in HIV-infected patients, especially those with 50 or fewer CD4+ lymphocytes per cubic millimeter, but the drug does not reduce overall mortality. PMID- 7854377 TI - A prospective evaluation of an angiotensin-converting-enzyme gene polymorphism and the risk of ischemic heart disease. AB - BACKGROUND: In a previous study, men with a history of myocardial infarction were found to have an increased prevalence of homozygosity for the deletional allele (D) of the angiotensin-converting-enzyme (ACE) gene. The D allele is associated with higher levels of ACE, which may predispose a person to ischemic heart disease. We investigated the association between the ACE genotype and the incidence of myocardial infarction, as well as other manifestations of ischemic heart disease, in a large, prospective cohort of U.S. male physicians. METHODS: In the Physicians' Health Study, ischemic heart disease as defined by angina, coronary revascularization, or myocardial infarction developed in 1250 men by 1992. They were matched with 2340 controls according to age and smoking history. Zygosity for the deletion-insertion (D-I) polymorphism of the ACE gene was determined by an assay based on the polymerase chain reaction. Data were analyzed for both matched pairs and unmatched samples, with adjustment for the effects of known or suspected risk factors by conditional and nonconditional logistic regression, respectively. RESULTS: The ACE genotype was not associated with the occurrence of either ischemic heart disease or myocardial infarction. The adjusted relative risk associated with the D allele was 1.07 (95 percent confidence interval, 0.96 to 1.19; P = 0.24) for ischemic heart disease and 1.05 (95 percent confidence interval, 0.89 to 1.25; P = 0.56) for myocardial infarction, if an additive mode of inheritance is assumed. Additional analyses assuming dominant and recessive effects of the D allele also failed to show any association, as did the examination of low-risk subgroups. CONCLUSIONS: In a large, prospectively followed population of U.S. male physicians, the presence of the D allele of the ACE gene conferred no appreciable increase in the risk of ischemic heart disease or myocardial infarction. PMID- 7854378 TI - Association between cigarette smoking and mutation of the p53 gene in squamous cell carcinoma of the head and neck. AB - BACKGROUND: Although epidemiologic studies have long associated tobacco and alcohol use with the development of squamous-cell carcinoma of the head and neck, the molecular targets of these carcinogens have yet to be identified. We performed a molecular analysis to determine the pattern of mutations in the p53 gene in neoplasms from patients with squamous-cell carcinoma of the head and neck and a history of tobacco or alcohol use. METHODS: Sequence analysis of the conserved regions of the p53 gene was performed in tumor samples from 129 patients with primary squamous-cell carcinoma of the head and neck. We then used statistical analysis to identify any patient characteristics associated with mutation of the p53 gene. RESULTS: We found p53 mutations in 42 percent of the patients (54 of 129). Fifty-eight percent of the patients who smoked cigarettes and used alcohol (37 of 64; 95 percent confidence interval, 45 to 70 percent), 33 percent of the patients who smoked but abstained from alcohol (13 of 39; 95 percent confidence interval, 19 to 50 percent), and 17 percent of the patients who neither smoked nor drank alcohol (4 of 24, 95 percent confidence interval, 5 to 37 percent) had p53 mutations (P = 0.001). (Two patients used alcohol but did not smoke, and neither had a p53 mutation.) Furthermore, 100 percent of the mutations in the patients who neither drank nor smoked occurred at sites containing cytidine phosphate guanosine dinucleotides (potentially representing endogenous mutations) within the p53 gene (5 of 5 mutations; 95 percent confidence interval, 48 to 100 percent), whereas only 23 percent of those in cigarette smokers consisted of such changes (12 of 53 mutations; 95 percent confidence interval, 12 to 36 percent; P = 0.001). CONCLUSIONS: In our study, a history of tobacco and alcohol use was associated with a high frequency of p53 mutations in patients with squamous-cell carcinoma of the head and neck. Preliminary evidence linked cigarette smoking to p53 mutations at nonendogenous mutation sites. Our findings suggest a role for tobacco in the molecular progression of squamous-cell carcinoma of the head and neck and support the epidemiologic evidence that abstinence from smoking is important to prevent head and neck cancer. PMID- 7854379 TI - Images in clinical medicine. Tripolar mitotic figure. PMID- 7854380 TI - The cost effectiveness of preoperative autologous blood donations. AB - BACKGROUND: Since the recognition that human immunodeficiency virus is transmissible by blood transfusion there has been increasing public and professional support for autologous blood donations before elective surgery. Autologous blood donation is, however, a more expensive process than the donation of allogeneic blood by community volunteers. Furthermore, there have been recent improvements in the safety of the volunteer blood supply. METHODS: We used a decision-analysis model to assess the cost effectiveness of donating autologous blood for four surgical procedures. Cost data were collected from the observation of transfusion practice at the University of California, Los Angeles, in 1992. Estimates of the risks of transfusion-associated diseases and the costs of treating them came from the medical literature. Cost effectiveness was expressed in dollars per quality-adjusted year of life saved. We performed sensitivity analyses of the variables in our model and examined the effect of strategies suggested to reduce costs. RESULTS: Substituting autologous for allogeneic blood resulted in little expected health benefit (0.0002 to 0.00044 quality-adjusted year of life saved) at considerable additional cost ($68 to $4,783 per unit of blood). The additional cost of autologous blood was primarily a function of the discarding of units that were donated but not transfused and of a more labor intensive donation process. The cost-effectiveness ratios ranged from $235,000 to over $23 million per quality-adjusted year of life saved. CONCLUSIONS: Given the improved safety of allogeneic transfusions today, the increased protection afforded by donating autologous blood is limited and may not justify the increased cost. PMID- 7854381 TI - Evaluation of patients with chronic diarrhea. PMID- 7854382 TI - Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 8-1995. A 75-year-old man with multiple cranial-nerve defects and weakness and pain in the extremities. PMID- 7854384 TI - Autologous blood donation--can we bank on it? PMID- 7854383 TI - Primary prophylaxis against opportunistic infections in patients with AIDS. PMID- 7854385 TI - The relation between universal health insurance and cost control. PMID- 7854386 TI - Reframing the debate on health care reform by replacing our metaphors. PMID- 7854387 TI - Treatment of mitral stenosis. PMID- 7854388 TI - Treatment of mitral stenosis. PMID- 7854389 TI - Treatment of mitral stenosis. PMID- 7854390 TI - Treatment of mitral stenosis. PMID- 7854391 TI - Prophylactic immune globulin in children with HIV disease. PMID- 7854392 TI - Improvement in cyclosporine-associated gingival hyperplasia with azithromycin therapy. PMID- 7854393 TI - Skin cancer occurring 10 years after the extravasation of doxorubicin. PMID- 7854394 TI - More on drug-name confusion. PMID- 7854395 TI - More on drug-name confusion. PMID- 7854396 TI - Clinton's dark horse. PMID- 7854397 TI - France's blood scandal. PMID- 7854398 TI - Merck releases first 'gene index' sequences. PMID- 7854399 TI - Blood transfusion chief is refused parole. PMID- 7854400 TI - British MPs 'likely to oppose gene patents'. PMID- 7854401 TI - CNRS plays down 'embryo freezing' results. PMID- 7854402 TI - Darwinist Lysenko? PMID- 7854403 TI - Polite row about models in biology. PMID- 7854404 TI - Redox enzymes. Splitting molecular hydrogen. PMID- 7854405 TI - Evolution. The molecular explosion. PMID- 7854406 TI - Cell cycle. Tense spindles can relax. PMID- 7854407 TI - Neurobiology. La difference vive. PMID- 7854408 TI - Visual neuroscience. Reflections on transparent motion. PMID- 7854409 TI - Neuronal networks. Vibrations in the memory. PMID- 7854410 TI - Hydrophobicity and phylogeny. PMID- 7854411 TI - Complex bacterial patterns. PMID- 7854412 TI - Biological levels. PMID- 7854413 TI - Crystal structure of the nickel-iron hydrogenase from Desulfovibrio gigas. AB - The X-ray structure of the heterodimeric Ni-Fe hydrogenase from Desulfovibrio gigas, the enzyme responsible for the metabolism of molecular hydrogen, has been solved at 2.85 A resolution. The active site, which appears to contain, besides nickel, a second metal ion, is buried in the 60K subunit. The 28K subunit, which coordinates one [3Fe-4S] and two [4Fe-4S] clusters, contains an amino-terminal domain with similarities to the redox protein flavodoxin. The structure suggests plausible electron and proton transfer pathways. PMID- 7854414 TI - Chemical and thermal response of Jupiter's atmosphere following the impact of comet Shoemaker-Levy 9. AB - In July 1994, the collisions of the fragments of comet Shoemaker-Levy 9 with Jupiter resulted in dramatic changes in the planet's atmosphere. Observations of the events suggest that the composition and thermal properties of the atmosphere were considerably modified at the impact sites, with the changes persisting for times lasting from minutes to weeks (see, for example, refs 1-4). Here we report observations of the impact sites at millimetre wave-lengths, which reveal strong emission lines associated with carbon monoxide, carbonyl sulphide and carbon monosulphide. The abundance of carbon monoxide in the jovian atmosphere is normally very low; carbonyl sulphide and carbon monosulphide, on the other hand, have not hitherto been detected. We find that the largest fragments (G and K) each produced approximately 10(14) g of carbon monoxide, 3 x 10(12) g of carbonyl sulphide and 3 x 10(11) g of carbon monosulphide, most probably by shock-induced chemical reactions. Our observations also place firm constraints on the thermal response of Jupiter's stratosphere to the impacts. PMID- 7854415 TI - An Early Miocene anthropoid skull from the Chilean Andes. AB - Partly because of their poor fossil record, the relationships of neotropical platyrrhine monkeys to other groups of primates and to each other remain perhaps the most poorly known for any major primate clade. Here we report the discovery of a complete platyrrhine skull from the Andes of central Chile, by far the best preserved Tertiary primate cranium from South America. This find, coupled with recent phylogenetic analyses of higher groups of anthropoid primates, has the potential to revise substantially our understanding of platyrrhine interrelationships, indicating, among other points, significant modification to reconstruction of the ancestral platyrrhine morphotype and a likely African origin for New World monkeys. A 40Ar/39Ar radioisotopic date directly associated with the skull indicates an Early Miocene age, marking the first report of South American mammals of this age from outside Argentine Patagonia. Finally, this discovery demonstrates the enormous potential of vastly distributed, but virtually untapped, Andean volcaniclastic deposits to yield further insights into the origin and diversification of South American primates. PMID- 7854416 TI - Sex differences in the functional organization of the brain for language. AB - A much debated question is whether sex differences exist in the functional organization of the brain for language. A long-held hypothesis posits that language functions are more likely to be highly lateralized in males and to be represented in both cerebral hemispheres in females, but attempts to demonstrate this have been inconclusive. Here we use echo-planar functional magnetic resonance imaging to study 38 right-handed subjects (19 males and 19 females) during orthographic (letter recognition), phonological (rhyme) and semantic (semantic category) tasks. During phonological tasks, brain activation in males is lateralized to the left inferior frontal gyrus regions; in females the pattern of activation is very different, engaging more diffuse neural systems that involve both the left and right inferior frontal gyrus. Our data provide clear evidence for a sex difference in the functional organization of the brain for language and indicate that these variations exist at the level of phonological processing. PMID- 7854417 TI - Integration of motion and stereopsis in middle temporal cortical area of macaques. AB - The primate visual system incorporates a highly specialized subsystem for the analysis of motion in the visual field. A key element of this subsystem is the middle temporal (MT) cortical area, which contains a majority of direction selective neurons. MT neurons are also selective for binocular disparity (depth), which is perplexing given that they are not sensitive to motion through depth. What is the role of disparity in MT? Our data suggest an important link between disparity and transparent motion detection. Motion signals in different directions tend to inhibit each other within a given MT receptive field. This inhibition has an averaging effect which minimizes MT responses to random motion signals created by light intensity changes and other non-motion stimuli (motion noise). But, in the absence of disparity cues, inhibition may also occur between surfaces moving in different directions through the same part of the visual field (transparent motion), thus impairing the detection of either surface. Here we show that inhibition in MT occurs mainly between motion signals with similar disparities. Transparent surface movements at different depths are thus represented independently in MT (that is, without inhibiting each other) whereas spurious motion signals from a given surface tend to cancel out. To our knowledge, these results provide the first evidence for a functional integration of motion and disparity in MT. PMID- 7854418 TI - Synchronized oscillations in interneuron networks driven by metabotropic glutamate receptor activation. AB - Partially synchronous 40-Hz oscillations of cortical neurons have been implicated in cognitive function. Specifically, coherence of these oscillations between different parts of the cortex may provide conjunctive properties to solve the 'binding problem': associating features detected by the cortex into unified perceived objects. Here we report an emergent 40-Hz oscillation in networks of inhibitory neurons connected by synapses using GABAA (gamma-aminobutyric acid) receptors in slices of rat hippocampus and neocortex. These network inhibitory postsynaptic potential oscillations occur in response to the activation of metabotropic glutamate receptors. The oscillations can entrain pyramidal cell discharges. The oscillation frequency is determined both by the net excitation of interneurons and by the kinetics of the inhibitory postsynaptic potentials between them. We propose that interneuron network oscillations, in conjunction with intrinsic membrane resonances and long-loop (such as thalamocortical) interactions, contribute to 40-Hz rhythms in vivo. PMID- 7854419 TI - Selective requirement for MAP kinase activation in thymocyte differentiation. AB - ENGAGEMENT of the T-cell receptor (TCR) with cognate ligands provokes different outcomes depending on the developmental stage of the T cell and on the properties of the ligand. In immature thymocytes TCR stimulation may result in maturation (positive selection) or death (negative selection), whereas in mature T cells it may induce proliferation, death or unresponsiveness. To investigate the different signals involved in these processes, we have analysed the role of the MAP kinase (MAPK) cascade, which is required for growth-factor-stimulated replication and for differentiation in other cell types, by expressing a catalytically inactive form of MAPK kinase (MEK-1) in thymocytes, thereby blocking MAPK activation. We find that positive selection of these cells is inhibited but that negative selection and TCR-induced proliferation are unaffected. Our results indicate that the intracellular signals regulating lineage commitment in T cells parallel those in photoreceptor cell specification in Drosophila and vulval cell differentiation in Caenorhabditis elegans, suggesting that general rules for cell-type specification could apply among all metazoans. PMID- 7854420 TI - Axl receptor tyrosine kinase stimulated by the vitamin K-dependent protein encoded by growth-arrest-specific gene 6. AB - The Axl receptor tyrosine kinase was identified as a protein encoded by a transforming gene from primary human myeloid leukaemia cells by DNA-mediated transformation of NIH 3T3 cells. Axl is the founding member of a family of related receptors that includes Eyk, encoded by a chicken proto-oncogene originally described as a retroviral transforming gene, and c-Mer, encoded by a human proto-oncogene expressed in neoplastic B- and T-cell lines. The transforming activity of Axl demonstrates that the receptor can drive cellular proliferation. The function of Axl in non-transformed cells and tissues is unknown, but may involve the stimulation of cell proliferation in response to an appropriate signal, namely a ligand that activates the receptor. We report here the purification of an Axl stimulatory factor, and its identification as the product of growth-arrest-specific gene 6 (ref. 6). This is, to our knowledge, the first description of a ligand for the Axl family of receptors. PMID- 7854421 TI - SNAP-mediated protein-protein interactions essential for neurotransmitter release. AB - The constitutive fusion of transport vesicles with intracellular membranes requires soluble proteins called SNAPs. Certain presynaptic proteins implicated in synaptic vesicle exocytosis also bind SNAPs, suggesting that SNAPs participate in the calcium-regulated membrane fusion events mediating neurotransmitter release. Here we show that injection of recombinant SNAPs into the giant synapse of squid enhances transmitter release. Conversely, injection of peptides designed to mimic the sites at which SNAP interacts with its binding partners inhibits transmitter release downstream of synaptic vesicle docking. A SNAP-dependent protein complex must therefore mediate transmitter release, showing that transmitter release shares a common molecular mechanism with constitutive membrane fusion. PMID- 7854422 TI - Mitotic forces control a cell-cycle checkpoint. AB - Every time a cell divides, the chromosomes must be distributed accurately to the daughter cells. Errors in distribution arise if chromosomes are improperly attached to the mitotic spindle. Improper attachment is detected by a cell-cycle checkpoint in many cells and the completion of cell division is delayed, allowing time for error correction. How is an improperly attached chromosome detected? An absence of tension from mitotic forces is one possibility. Here we test this possibility directly by applying tension to an improperly attached chromosome with a micromanipulation needle. In the absence of tension, the entry into anaphase and the completion of mitosis was delayed by 5-6 hours. When the misattached chromosome was placed under tension, however, the cell entered anaphase in 56 minutes, on average. Tension from mitotic forces or from a micromanipulator's needle evidently signals to the checkpoint that all is in order and that cell division can proceed. PMID- 7854423 TI - Interaction with RAP74 subunit of TFIIF is required for transcriptional activation by serum response factor. AB - A few general transcription factors, in particular TFIID and TFIIB, have been found to bind transcriptional activators. Here we show that the general transcription factor TFIIF is also a target for a transcriptional activator, namely serum response factor (SRF), which binds to the c-fos promoter. Using a yeast interaction assay, we find that SRF binds the RAP74 subunit of TFIIF and that SRF's transcriptional activation domain is the region involved in this binding. Further, RAP74's central charged cluster domain is required for binding to SRF's activation domain. Deletion of this domain impairs RAP74's ability to support SRF-activated transcription in vitro but has little effect on the protein's basal transcription activity or its ability to support SP1-activated transcription. The correlation of SRF-RAP74 binding with transcriptional activation suggests that RAP74 is a critical target for SRF-activated transcription. PMID- 7854424 TI - Crystal structure of the GreA transcript cleavage factor from Escherichia coli. AB - Transcription elongation factors stimulate the activity of DNA-dependent RNA polymerases by increasing the overall elongation rate and the completion of RNA chains. One group of such factors, which includes Escherichia coli GreA, GreB and eukaryotic SII (TFIIS), acts by inducing hydrolytic cleavage of the transcript within the RNA polymerase, followed by release of the 3'-terminal fragment. Here we report the crystal structure of GreA at 2.2 A resolution. The structure contains an amino-terminal domain consisting of an antiparallel alpha-helical coiled-coil dimer which extends into solution, reminiscent of the coiled coil in seryl-tRNA synthetases. A site near the tip of the coiled-coil 'finger' plays a direct role in the transcript cleavage reaction by contacting the 3'-end of the transcript. The structure exhibits an unusual asymmetric charge distribution which indicates the manner in which GreA interacts with the RNA polymerase elongation complex. PMID- 7854425 TI - Genetic expectations. PMID- 7854426 TI - Institute Pasteur to adopt 'automatic' misconduct process. PMID- 7854428 TI - More focus urged for Japan's drug research. PMID- 7854427 TI - Medical schools fight their corner. PMID- 7854429 TI - NIH resolves dispute on cancer gene patent. PMID- 7854430 TI - France takes control of genome programme. PMID- 7854431 TI - Indian confirms identity of plague. PMID- 7854432 TI - Australian researchers hold government to its promises. PMID- 7854433 TI - Misinterpreting Aquinas. PMID- 7854434 TI - Misinterpreting Aquinas. PMID- 7854435 TI - Solar system. Europa's oxygen atmosphere. PMID- 7854436 TI - Molecular motors. Two heads are better than one. PMID- 7854437 TI - Developmental biology. Hedgehog digs up an old friend. PMID- 7854438 TI - Fast-focus telephoto eye. PMID- 7854439 TI - Life at the margins. PMID- 7854440 TI - Adolf Butenandt (1903-1995). PMID- 7854441 TI - Transcriptional activators. Enter a polypeptide messenger. PMID- 7854442 TI - Anticipated stimuli across skin. PMID- 7854443 TI - Improved green fluorescence. PMID- 7854444 TI - Kinetics of protein folding. PMID- 7854445 TI - Do long branches attract flies? PMID- 7854446 TI - Pathway of processive ATP hydrolysis by kinesin. AB - Direct measurement of the kinetics of kinesin dissociation from microtubules, the release of phosphate and ADP from kinesin, and rebinding of kinesin to the microtubule have defined the mechanism for the kinesin ATPase cycle. The processivity of ATP hydrolysis is ten molecules per site at low salt concentration but is reduced to one ATP per site at higher salt concentration. Kinesin dissociates from the microtubule after ATP hydrolysis. This step is rate limiting. The subsequent rebinding of kinesin-ADP to the microtubule is fast, so kinesin spends only a small fraction of its duty cycle in the dissociated state. These results provide an explanation for the motility differences between skeletal myosin and kinesin. PMID- 7854447 TI - Detection of an oxygen atmosphere on Jupiter's moon Europa. AB - Europa, the second large satellite out from Jupiter, is roughly the size of Earth's Moon, but unlike the Moon, it has water ice on its surface. There have been suggestions that an oxygen atmosphere should accumulate around such a body, through reactions which break up the water molecules and form molecular hydrogen and oxygen. The lighter H2 molecules would escape from Europa relatively easily, leaving behind an atmosphere rich in oxygen. Here we report the detection of atomic oxygen emission from Europa, which we interpret as being produced by the simultaneous dissociation and excitation of atmospheric O2 by electrons from Jupiter's magnetosphere. Europa's molecular oxygen atmosphere is very tenuous, with a surface pressure about 10(-11) that of the Earth's atmosphere at sea level. PMID- 7854448 TI - Differences in the chemical reactivity of individual molecules of an enzyme. AB - Much attention has been focused recently on the detection and physical characterization of individual molecules. Using such methods to study the chemical properties, such as reactivity, of single molecules offers the potential to investigate how these might vary from molecule to molecule, and for individual molecules as a function of time. The complex structures of biomolecules such as enzymes make them particularly attractive targets for studying how subtle changes or differences at the molecular level might influence chemical reactivity. We have shown previously that very small (zeptomole) amounts of enzymes can be studied using a fluorescence microassay; single enzyme molecules have also been detected in oil-dispersed droplets by fluorescence microscopy. Here we report the observation of reactions of individual molecules of lactate dehydrogenase (LDH 1), which produces NADH from lactate and nicotinamide adenine dinucleotide (NAD+). When they are present at very low concentrations in a narrow capillary, each enzyme molecule produces a discrete zone of NADH; these can be manipulated electrophoretically and monitored by fluorescence spectroscopy. We find that the activity of individual electrophoretically pure enzyme molecules can vary by up to a factor of four, and that these activities remain unchanged over a two-hour period. We suggest that the origin of the activity differences may lie in the presence of several stable forms of the enzyme. PMID- 7854449 TI - A possible prebiotic synthesis of pantetheine, a precursor to coenzyme A. AB - The involvement of coenzyme A in many enzyme reactions suggests that it acted in this capacity very early in the development of life on Earth. Particularly relevant in this regard is its role in the activation of amino acids and hydroxy acids in the biosynthesis of some peptide antibiotics--a mechanism of peptide synthesis that forms the basis for the proposal that a thioester world could have preceded the RNA world. The components of coenzyme A have been shown to be probable prebiotic compounds: beta-alanine, pantoyl lactone and cysteamine and possibly adenosine. We show here that the pantetheine moiety of coenzyme A (which also occurs in a number of enzymes) can be synthesized in yields of several per cent by heating pantoyl lactone, beta-alanine and cysteamine at temperatures as low as 40 degrees C. These components are extremely soluble and so would have been preferentially concentrated in evaporating bodies of water, for example on beaches and at lagoon margins. Our results show that amide bonds can be formed at temperatures as low as 40 degrees C, and provide circumstantial support for the suggestion that pantetheine and coenzyme A were important in the earliest metabolic systems. PMID- 7854450 TI - A negatively powered lens in the chameleon. AB - Chameleons are arboral lizards that spot their prey visually and catch it by highly precise shots with their long sticky tongue. They scan their environment by large-amplitude independent saccadic eye movements; once an insect is detected, the head axis is aligned towards the target ('head tracking', both eyes come forward to fixate the insect and, in a phase called 'initial protrusion', the sticky tongue is loaded with tension by a special hyoid apparatus and subsequently shot out of the mouth with great precision. Lenses placed in front of the eyes produce predictable errors in distance estimation, suggesting that chameleons rely on accommodation cues when measuring the distance to their prey, but focusing has never been measured directly. Using a new technique to measure accommodation, we now show that accommodation is precise enough to serve as the major distance cue. Because accurate focusing requires large retinal images, we have tested image magnification and find that it is higher than in any other vertebrate eye scaled to the same size. This is a result of a unique optical design: unlike other vertebrate eyes, the crystalline lens of the chameleon has negative refractive power. Although there is a trend among vertebrates to increase corneal power and to decrease lens power with higher visual acuity, only in the chameleon eye has this tendency led to a reversal of the sign of the power of the lens. PMID- 7854451 TI - Colour constancy influenced by contrast adaptation. AB - Visual sensitivity is controlled by at least two distinct types of adaptation: light adaptation adjusts sensitivity to the mean luminance and colour in the stimulus, and contrast adaptation adjusts sensitivity to the variations in luminance and colour. Light adaptation is thought to be important in maintaining the perceived colour of objects despite changes in illumination ('colour constancy'), compensating for the mean changes in the light reflected from scenes under different illuminants. But for naturalistic colour signals, we show here that changes in an illuminant can also alter colour contrasts in images (how colours are distributed around the mean) enough to alter the state of contrast adaptation. Thus perceived colour under different illuminants may also be noticeably influenced by contrast adaptation. PMID- 7854452 TI - Scatter factor/hepatocyte growth factor is essential for liver development. AB - Polypeptide growth factors are important effectors of cell growth and differentiation in vitro and are thought to be critical for processes such as specification of cell fate, tissue growth and organogenesis in vivo. Scatter factor/hepatocyte growth factor (SF/HGF) is the prototype of an emerging family of growth factors that resemble in their domain structure and mechanism of activation the blood proteinase plasminogen. The cellular responses of SF/HGF are mediated by the c-Met tyrosine kinase receptor. Here we report that mice lacking SF/HGF fail to complete development and die in utero. The mutation affects the embryonic liver, which is reduced in size and shows extensive loss of parenchymal cells. In addition, development of the placenta, particularly of trophoblast cells, is impaired. Thus, SF/HGF is essential for the development of several epithelial organs. PMID- 7854453 TI - Placental defect and embryonic lethality in mice lacking hepatocyte growth factor/scatter factor. AB - Hepatocyte growth factor/scatter factor (HGF/SF) functions as a mitogen, motogen and morphogen for a variety of cultured cells. The genes for HGF/SF and its receptor (the c-met proto-oncogene product) are expressed in many tissues during the embryonic periods and in the adult. HGF/SF is thought to mediate a signal exchange between the mesenchyme and epithelia during mouse development. To examine the physiological role of HGF/SF, we generated mutant mice with a targeted disruption of the HGF/SF gene. Here we report that homozygous mutant embryos have severely impaired placentas with markedly reduced numbers of labyrinthine trophoblast cells, and die before birth. The growth of trophoblast cells was stimulated by HGF/SF in vitro, and the HGF/SF activity was released by allantois in primary culture of normal but not mutant embryos. These findings suggest that HGF/SF is an essential mediator of allantoic mesenchyme trophoblastic epithelia interaction required for placental organogenesis. PMID- 7854454 TI - Regulation of furrow progression in the Drosophila eye by cAMP-dependent protein kinase A. AB - The earliest physical sign of differentiation in the Drosophila retina is the passage of the morphogenetic furrow across the epithelium of the eye disc. Secreted factors encoded by hedgehog (hh) and decapentaplegic (dpp) have been implicated in propagation of the furrow and the subsequent initiation of photoreceptor differentiation. The morphogenetic furrow initiates at the posterior edge of the third larval instar eye imaginal disc. Its continued progression towards the anterior is believed to depend upon secretion of Hh protein by the differentiating clusters of photoreceptors that emerge posterior to the moving furrow. This progression is marked by the initiation of expression of the transforming growth factor-beta homologue Dpp in cells entering the furrow anteriorly, and loss of dpp expression in cells emerging posteriorly. Although the transmembrane protein encoded by the patched gene has been genetically implicated as the Hh receptor, the intercellular signalling pathways involved in these inductive processes remain uncharacterized. Here we show that the catalytic subunit of cyclic AMP-dependent protein kinase A (Pka-C1) is required for the correct spatial regulation of dpp expression during eye development. Loss of Pka C1 function is sufficient to produce an ectopic morphogenetic wave marked by premature ectopic photoreceptor differentiation and non-autonomous propagation of dpp expression. Our results indicate that Pka-C1 lies in a signalling pathway that controls the orderly temporal progression of differentiation across the eye imaginal disc. PMID- 7854455 TI - Growth and differentiation in the Drosophila eye coordinated by hedgehog. AB - Differentiation of the Drosophila retina is asynchronous: it starts at the posterior margin of the eye imaginal disc and progresses anteriorly over two days. During this time the disc continues to grow, increasing in size by approximately eightfold. An indentation in the epithelium, the morphogenetic furrow, marks the front edge of the differentiation wave. Anterior progression of the furrow is thought to be driven by signals emanating from differentiating photoreceptor cells in the posterior eye disc. A good candidate for such a signal is the product of the hedgehog (hh) gene; it is expressed, and presumably secreted, by differentiating photoreceptors and its function is required for continued furrow movement. Here we show that ectopic expression of hedgehog sets in motion ectopic furrows in the anterior eye disc. In addition to changes in cell shape, these ectopic furrows are associated with a tightly orchestrated series of events, including proliferation, cell cycle synchronization and pattern formation, that parallel normal furrow progression. We propose that the morphogenetic furrow coincides with a transient boundary that coordinates growth and differentiation of the eye disc, and that hedgehog is necessary and sufficient to propagate this boundary across the epithelium. PMID- 7854456 TI - Signal transduction by cAMP-dependent protein kinase A in Drosophila limb patterning. AB - Interaction between distinctly specified cells in adjacent compartments establishes organizing centres that control growth and specify cell fate in the developing limbs of Drosophila. Localized expression of the secreted Hedgehog protein (Hh) by cells in the posterior compartment induces expression of the secreted signalling molecules decapentaplegic (dpp) or wingless (wg) in nearby anterior cells. wg and dpp in turn organize spatial pattern in the wing and leg imaginal discs. The Hh signal is thought to act by antagonizing the ability of the patched (ptc) gene product to repress wg and dpp expression. Here we present evidence that removing activity of the gene encoding cyclic AMP-dependent protein kinase A (pka) is functionally equivalent to removing ptc activity or to providing cells with the Hh signal. These findings suggest that cyclic AMP dependent protein kinase A is a component of the signal transduction pathway through which Hh and Ptc direct localized expression of dpp (or wg) and establish the compartment boundary organizer. PMID- 7854457 TI - Molecular characterization of eukaryotic polysialyltransferase-1. AB - Polysialic acid (PSA) is a dynamically regulated product of post-translational modification of the neural cell adhesion molecule, NCAM. Presence of the large anionic carbohydrate modulates NCAM binding properties and, by increasing the intercellular space, influences interactions between other cell surface molecules. PSA expression underlies cell type- and developmental-specific alterations and correlates with stages of cellular motility. In the adult, PSA becomes restricted to regions of permanent neural plasticity and regenerating neural and muscle tissues. Recent data implicate its important function in spatial learning and memory, and in tumour biology. Here we describe the molecular characterization of polysialyltransferase-1, the key enzyme of eukaryotic PSA synthesis. In reconstitution experiments, the newly cloned enzyme induces PSA synthesis in all NCAM-expressing cell lines. Our data therefore represent convincing evidence that the polycondensation of alpha-2,8-linked sialic acids in mammals is the result of a single enzymatic activity and provide a new basis for studying the functional role of PSA in neuro- and tumour biology. PMID- 7854458 TI - Failure of a single-headed kinesin to track parallel to microtubule protofilaments. AB - Kinesin, a two-headed motor enzyme molecule, hydrolyses ATP to direct organelle transport along microtubules. As it moves along a microtubule, kinesin remains associated with, or 'tracks', microtubule protofilaments. We have prepared truncated kinesin derivatives that contain either two mechanochemical head domains or only a single head. Unlike intact kinesin and the two-headed derivatives, the one-headed enzyme frequently fails to track protofilaments, suggesting that it detaches from microtubules during movement. In this way, the one-headed kinesin derivative is similar to the motor enzyme myosin, which frequently detaches from the actin filament during movement. For myosin (which has two heads), the consequence of this detachment is that single molecules do not appear to drive continuous movement along the filament. Our observations suggest that the ability of single two-headed kinesin molecules to drive continuous movement results from a 'hand-over-hand' mechanism in which one head remains bound to the microtubule while the other detaches and moves forwards. PMID- 7854459 TI - Sequence specificity and transcriptional activation in the binding of lactoferrin to DNA. AB - Lactoferrin, an iron-binding glycoprotein found in high concentrations in human milk and other epithelial secretions and in the secondary (specific) granules of neutrophils, is thought to be responsible for primary defence against microbial infection, mainly as a result of lactoferrin sequestration of iron required for microbial growth. Many other functions have been attributed to lactoferrin, including immunomodulation and cell growth regulation (reviewed in ref. 4). Some of these functions appear to be at least in part independent of the iron-binding activity of lactoferrin. It also has been consistently observed that lactoferrin interacts avidly with nucleic acids. Lactoferrin enhancement of the activity of natural killer and lymphokine-activated killer cells in vitro is inhibited by RNA and DNA. Lactoferrin taken up by K562 human myelogenous leukaemia cells appears in the nucleus where it is bound to DNA. We report here that binding of lactoferrin to DNA occurs under stringent conditions with distinct sequence specificity, and that interaction between lactoferrin and these sequences intracellularly leads to transcriptional activation. PMID- 7854460 TI - Pre-bending of a promoter sequence enhances affinity for the TATA-binding factor. AB - TATA-binding protein (TBP) binds the minor groove of the TATA element with the DNA bent 80 degrees towards the major groove. A constrained minicircle strategy has been used to test the effect of DNA topology on the affinity of TBP for the TATA element. We report here that TBP bound to DNA which was slightly pre-bent towards the major groove with 100-fold higher affinity than unbent (linear) DNA of identical sequence and 300-fold higher affinity than DNA pre-bent towards the minor groove. Similar discrimination was observed with the holo-TFIID transcription complex. DNA topology, particularly bending, is determined by many factors including chromatin in cells and may, through changes in the affinity of the TATA factor, be important in the control of transcription. PMID- 7854461 TI - Meeting the challenge of HIV. PMID- 7854462 TI - Changes in the house of medicine. PMID- 7854463 TI - Is this medicine? Physician participation in capital punishment in North Carolina. PMID- 7854464 TI - Treatment of isolated laryngeal blastomycosis with ketoconazole. Photographic documentation of a successful case. PMID- 7854465 TI - Intermittent ureteropelvic junction obstruction in the adult. PMID- 7854466 TI - Silent night, blurry night. PMID- 7854467 TI - Alzheimer's disease. New hope in the '90s. PMID- 7854468 TI - The numbers are important. Taking care of my diabetes. PMID- 7854469 TI - Ocular hypertension. A convenience sample survey of blood pressure and intraocular pressure determinations in blacks. PMID- 7854471 TI - Ageism distorts how medical students (and doctors?) see and assess patients. PMID- 7854470 TI - Medical needs of the homeless. A profile of residents at the Chapel Hill Homeless Shelter. PMID- 7854472 TI - Special management of diabetics, pregnant women, blacks, and children may enhance long-term organ transplant success. PMID- 7854473 TI - Maintaining wellness in preparation for a transplant. PMID- 7854474 TI - Dialysis trials: assessing the value of renal therapy in the compromised patient. PMID- 7854475 TI - International health care models: a comparative analysis. PMID- 7854476 TI - At what cost should nephrologists preserve life? PMID- 7854477 TI - Renal rehabilitation: lessons learned and challenges for change. PMID- 7854478 TI - Treating chronic renal failure in Lithuania. PMID- 7854479 TI - [Nutrition problems in nursing home patients caused by restrictions in functions]. PMID- 7854480 TI - [Clinical effectiveness of zidovudine]. PMID- 7854481 TI - [Long-term follow-up study of persons with a solitary kidney]. PMID- 7854482 TI - [Dietary fiber in tube feeding: promises and facts]. PMID- 7854483 TI - [Patient education; also in psychiatry]. PMID- 7854484 TI - [Nutrition and nutritional status of female somatic nursing home patients]. AB - OBJECTIVE: To determine if the intake of energy and particular nutrients is adequate among elderly non-demented nursing home patients, and to identify possible causes of a marginal status. SETTING: A nursing home, neighbouring service flat and a group of independently living elderly in Zeist, the Netherlands. DESIGN: Descriptive cross-sectional study. METHOD: Data were collected about habitual food consumption, anthropometry and indicators of nutritional status from 51 female nursing home patients (response 65%), 29 elderly women living in service flats (response 56%) and 52 independently living elderly women. Comparisons were made among the groups, with the recommended dietary allowance and with cut off values. RESULTS: The mean daily energy intake of 5.9 MJ (SD: 1.4) by the group of nursing home patients was lower than the recommended allowance (7.8 MJ). Mean values for the anthropometric measurements hardly varied among the groups. This suggested that the low energy intake was in accordance with the actual energy requirement. Especially among the nursing home women low blood levels were frequently seen of folic acid, pyridoxine, 25-hydroxy vitamin D, vitamin C and selenium. A lower food consumption and unfavourable food choices were considered to be mainly responsible. Low mobility and pathological processes may also play a part. CONCLUSION: Low blood levels among non-demented nursing home patients were caused by low food consumption, unfavourable food choices and probably by health status. Prevention may include: more physical activity (whenever possible), giving information to patient and nurse, supplying food with higher nutrient density, presenting more menu choices, reporting to physician or dietician when food offered is not eaten. PMID- 7854485 TI - [Less headache following lumbar puncture with the use of an atraumatic needle; double-blind randomized study]. AB - OBJECTIVE: To investigate the difference in frequency of headache after lumbar puncture with a standard needle or an atraumatic needle. DESIGN: Prospective, randomised double blind study. SETTING: Department of Neurology, Merwedeziekenhuis, Dordrecht. METHOD: One hundred sequential patients were randomised to lumbar puncture with a 'standard needle' (20 gauge) or an 'atraumatic needle' (pencil point, 22 gauge). The patients were interviewed one week later. Patient and interviewer were unaware of the needle used. RESULTS: After puncture with the standard needle 32% of the patients suffered from postlumbar puncture headache, after use of the atraumatic needle 6% (p < 0.001; 95% confidence interval of the difference: 0.11-0.40). Postpuncture complaints appeared to be less severe after puncture with the atraumatic needle. CONCLUSION: In comparison with a standard needle, there is significantly less postpuncture headache after lumbar puncture with an atraumatic needle. PMID- 7854486 TI - [Subfertility in South Limburg: calculation of incidence and appeal for specialist care]. AB - OBJECTIVE: To estimate the prevalence of subfertility in a region of the Netherlands clearly defined as to medical care. DESIGN: Descriptive. SETTING: Six regional hospitals and one university medical centre. METHODS: Prospective registration of all 1060 new patients attending one of the seven hospitals and complaining of subfertility, in 1992. RESULTS: After exclusion of patients living outside the health care region, and/or having pursued pregnancy for less than 12 months, and/or having visited one of the other hospitals (with the same complaint) before, 536 patients remained. For this region, with a population of 641,876 at the time of the study, we estimated the cumulative incidence of subfertility in 1992 to be 10.4% (95% confidence interval: 9.6-11.2%). Between 14 and 16.5% of couples sought specialist medical care for their fertility problem. CONCLUSION: Between 14 and 16.5% of couples sought specialist medical care for fertility problems during their reproductive life. More than 10 percent fulfilled the criteria for subfertility. PMID- 7854487 TI - [Colitis cystica profunda]. AB - In two patients, women of 65 and 76 years old, colitis cystica profunda was diagnosed, a rare, benign disease of colon and rectum. In the first patient, radio-enteritis, in the second patient mucinous adenocarcinoma was diagnosed as well. PMID- 7854488 TI - [Sexual contact between physician and patient--report of a work conference]. PMID- 7854489 TI - [Information and consent in health care; current developments]. PMID- 7854490 TI - [Information and consent in health care; current developments]. PMID- 7854491 TI - [Pain in an arthritic hip; not always 'old news']. PMID- 7854492 TI - Circulating epidermal growth factor (EGF) and insulin-like growth factor-I (IGF I) in patients with epithelial ovarian carcinoma. AB - Circulating epidermal growth factor (EGF) and insulin-like growth factor-I (IGF I) were estimated in 58 patients with epithelial ovarian cancer and were correlated with clinically and biochemically important prognosticators. IGF-I levels were significantly low in patients as compared to controls. The relation of growth factors with clinically important prognosticators was non-significant. Moreover, the levels of EGF and IGF-I in the ER+/PR+ and ER-/PR- groups and in the low and high EGFR+ tumors did not differ significantly. Patients with EGF < 1.0 ng/ml had significantly better survival than those with EGF > 1.0 ng/ml. PMID- 7854493 TI - Biochemical analysis of breast cyst fluid as a possible predictor of breast carcinoma development. AB - The occurrence of breast cancer in patients with gross cystic disease is 2-5 times higher as compared to control group of women. During 3 years, 183 cyst fluid samples were analyzed in 129 females, in 30 patients of them the samples were analysed repeatedly. The distribution of the Na+/K+ ratio, considered as the measure of cancer risk, was found to be bimodal. In repeated analyses the type I cyst fluid markedly predominated (Na+/K+ < or = 4.0). A direct dependence on this ratio was found in the concentration of glucose, albumin, carcinoembryonic antigen (CEA), tissue polypeptide antigen (TPA) and its specific form, TPS; an indirect dependence was found for the level of uric acid, phosphates, alkaline phosphatase (ALP) and alpha-amylase (AMS). The predominance of apocrine metaplasia cells released into the cyst fluid is characteristic of type I cysts. A definitive assessment of significance of these parameters will be enabled by a long-term follow-up of the disease in the respective patients. PMID- 7854494 TI - Antitumor, nephrotoxic and clastogenic effect of cis-DDP with DDTC or NAC. AB - Diethyldithiocarbamate (DDTC) and N-acetylcysteine (NAC) are nucleophile sulfur containing compounds which can protect the platinum-induced nephrotoxicity. Combinations of cis-diamminedichloroplatinum(II) (cis-DDP) and DDTC or NAC were tested on the leukemia L1210 and melanoma B 16 tumor models. Nephrotoxicity of cis-DDP alone and in combination with DDTC or NAC was evaluated. On both of the investigated tumor models clastogenic effects in bone marrow cells were detected. DNA synthetic and mitotic activity of L1210 cells in vivo were evaluated by 3H thymidine incorporation and cytogenetic analysis. Amelioration of the platinum induced nephrotoxicity and preservation of the antitumor activity of cis-DDP through combined application with DDTC or NAC were obtained at the L1210 model. Maximal inhibition of the DNA synthesis in L1210 cells was detected with the cis DDP treatment. The sulfurcontaining nucleophiles DDTC or NAC could modulate the inhibitory effect of cis-DDP on the incorporation of 3H-thymidine into the nuclei of L1210 cells. Enhanced mitotic activity was detected during cytotoxic therapy with cis-DDP. Cis-DDP alone and in combination with DDTC or NAC caused a significant growth inhibition on the s.c. tumor of the melanoma B16 bearing mice. Two times better therapeutic results at this model were obtained with cis-DDP alone (T/C = 234.09%, T/C = 136.36% for cis-DDP+DDTC and T/C = 151.14% for cis DDP+NAC). The usefulness of DDTC or NAC as adjuvants in the platinum based chemotherapy of human cancers have been discussed. Clastogenic effect and antitumor activity are probably connected and it is supposed that the reduction of the genotoxicity could lead to a decreased antitumor activity of the platinum complex. PMID- 7854495 TI - Drug-resistance associated alterations of cell surface antigen expression in a human anthracycline-resistant ovarian carcinoma cell line. AB - The anthracycline uptake and cell surface expression of plasma membrane antigens (HLA class I, c-erbB-2, protectin-CD59, integrin beta 1-chain-CD29, etc.) were compared on a parental anthracycline sensitive and an anthracycline-resistant subline of the human ovarian carcinoma cell line A2780. The anthracycline resistant (A2780/ADR) subline incubated for 30 min in the presence of daunomycin displayed two subpopulations with different anthracycline cell content as determined by flow cytometry. The subpopulation with lower daunomycin cell content was absent in the parental anthracycline sensitive cell line. The most predominant antigenic changes on the resistant subline as compared with the sensitive one were as follow: Loss of HLA class I and a twofold increase in the expression of CD59 antigen and a slight decrease of integrin beta 1-chain on the cell surface of the resistant subline. PMID- 7854497 TI - Hyperthermia in cancer treatment (I). AB - In recent years there have been numerous randomized and nonrandomized studies conducted to assess the efficacy of hyperthermia combined with either radiation therapy or chemotherapy especially in the treatment of superficially seated malignant tumors. The major impact of hyperthermia is currently on loco-regional control of tumor. Heat may be directly cytotoxic to tumor cells or inhibit repair of both sublethal and potentially lethal damage after radiation. These effects are augmented by the physiological conditions in tumor which lead to states of acidosis and hypoxia. Blood flow is often impaired in tumor relative to normal tissue, and hyperthermia may lead to a further decrease in blood flow and augment heat-sensitivity. Three major areas of clinical investigation have borne the greatest fruit for hyperthermia as adjunctive therapy to radiation therapy. These include recurrent and primary breast lesions, melanoma, and head and neck neoplasms. Thermal enhancement ratio was increased in all cases and is estimated to be 1.4 for neck nodes, 1.5 for breast and 2 for malignant melanoma. In general, the most important prognostic factors for complete response are radiation dose, tumor size and minimal thermal parameters (minimal thermal dose (t43min), mean minimal temperature (Tmin) or T90, i.e., temperature exceeded by 90% of thermal sensors). The number of heat fractions administered per week appears to have no bearing on the overall response, which may be indicative of the effects of thermotolerance. The total number of heat fractions delivered also appears irrelevant provided adequate heat is delivered in one or two sessions. The major prognostic factors for the duration of local control are tumor histology, concurrent radiation therapy, dose, tumor depth and Tmin. PMID- 7854496 TI - Systemic chemotherapy for muscle invasive bladder cancer. AB - A total of 60 patients with muscle invasive transitional cell carcinoma of the bladder were entered into the nonrandomized study. The 1st group consisted of 30 patients treated by M-VAC neo-adjuvant chemotherapy followed by radical cystectomy when a residual tumor had been detected by biopsy made after the treatment. The overall clinical response was 70%. Fifteen (50%) out of 30 patients achieved clinical complete response (cCR). Objective pathologic response was attained in 6 (66.7%) of 9 evaluable patients who underwent radical cystectomy, pathologic complete response (pCR) was observed in two (22.2%) patients. Ten (33.3%) patients are still alive at a median follow-up of 22+ months. There were three (10%) drug-related deaths. The 2nd group consisted of 30 patients treated by CMV (with carboplatin) neo-adjuvant chemotherapy followed by radical pathologic response was attained in 9 (47.4%) of 19 evaluable patients, with pCR in 6 (31.6%) patients. Twenty four (80%) patients are still alive at a median follow-up of 13+ months. There was one (3.3%) drug-related death. The authors recommend immediate radical cystectomy following neo-adjuvant chemotherapy in all patients if their total status it allows. PMID- 7854498 TI - Biological rationale for hyperthermia in cancer treatment (II). AB - Hyperthermia (HT) has gained a great interest in the past two decades. The nature of hyperthermia-induced cell lethality is quite different from that of radiation induced killing. The G1-phase of the cell cycle is the most resistant to HT while S-phase cells are quite sensitive. In addition to heat-induced cytotoxicity, HT sensitizes cells to low LET ionizing radiation. The mechanism of heat cytotoxicity is distinct from that of ionizing radiation. Unlike the response to ionizing radiation, heat cytotoxicity is influenced by thermotolerance, low pH and nutritional deprivation, but is independent of acute hypoxia. Also, blood flow influences the heating characteristics of a tumor relative to normal tissue, and vascular collapse may occur after heating. Thermotolerance is a nonheritable resistance to HT induced by exposure to heat and other cytotoxic agents. Thermotolerance develops within 2-3 h during exposure to temperatures less than 43 degrees C. Cells exposed for a brief period to temperatures higher than 43 degrees C are sensitized to exposure to temperatures below 43 degrees C. This is called "stepdown heating, SDH". SDH results from the inhibition of thermotolerance development by exposure to the high temperature. Cells are sensitized to HT damage by acutely lowering pH, and thermotolerance development is reduced at low pH. Reduced pH also enhances thermoradiosensitization. Since much of a tumor population is at low pH, and these tumor cells are very likely to be hypoxic and radioresistant, this offers one of the strongest reasons for combining HT with radiation therapy in the treatment of human tumors. The neovasculature in tumors does not respond to increased temperatures as do blood vessels in normal tissues, and these differences in blood flow may lead to selective tumor heating. HT dramatically enhances the cytotoxicity of the electron affinic radiosensitizers in hypoxic cells. HT sensitizes the cell to many cytotoxic agents and even converts some drugs that are innocuous to highly toxic. HT chemosensitization may occur by an increased reaction rate, increased permeability, or decreased repair. The most promising chemosensitization by HT would seem to be with alkylating agents and cis-platinum since they are enhanced at all elevated temperatures. PMID- 7854499 TI - Enhanced erythropoietin and suppression of gamma-glutamyl transpeptidase (GGT) activity in murine lymphoma following administration of vanadium. AB - Administration of vanadium as ammonium monovanadate (0.005 microgram/0.1 ml/mouse/day) was found to reduce the tumor cell proliferation in the host mice bearing Dalton's lymphoma. The high activity of gamma-glutamyl transpeptidase (GGT), a neoplastic marker, was seen in the host cells bearing lymphoma. Vanadium effectively prevented an increase in activity of gamma-glutamyl transpeptidase and maintained a sustained low activity of this enzyme. In addition, an improvement of the hematological aspects of the mice and almost fourfold elevation of erythropoietin (Epo) was obtained following vanadium treatment. This increase in Epo activity may play a vital role in regulating the growth of cellular neoplasia. The present study further confirms the antitumorigenic potential of vanadium in the control of tumor progression in lymphoma via modulating several factors involving erythropoiesis and may emerge as a new chemopreventive agent for the future. PMID- 7854500 TI - Effect of pentoxifylline on P-glycoprotein mediated vincristine resistance of L1210 mouse leukemic cell line. AB - Effect of pentoxifylline (PTX) on vincristine (VCR) resistance of multidrug resistant L1210/VCR mouse leukemic cell line was studied. Reversal effect of PTX (in concentration 50-150 mg/l) on vincristine resistance, i.e. potentiation of vincristine cytotoxicity on L1210/VCR cells by PTX was found. PTX alone in the above concentration did not exert any significant cytotoxic effect on sensitive or resistant cell lines in the absence of vincristine. Resistance of L1210/VCR cell line was found previously to be accompanied with overexpression of drug transporting P-glycoprotein. Indeed, lower level of 3H-vincristine accumulation by resistant L1210/VCR cell line in comparison with sensitive L1210 cell line was observed. Accumulation of 3H-vincristine by L1210/VCR cell line was significantly increased in the presence of PTX. PTX in the same condition did not exert any considerable effect on accumulation of 3H-vincristine by nonresistant L1210 cells. Observable morphological damage was observed in L1210/VCR cells cultivated in medium containing vincristine (0.2 mg/l) and pentoxifylline (100 mg/l) in comparison with the non-damaged cells in the presence of vincristine or pentoxifylline alone. The results obtained indicate that pentoxifylline may be considered as a reversal agent in multidrug resistance. PMID- 7854501 TI - [Therapy of acute polyradiculoneuritis (Guillain-Barre syndrome)]. AB - The Guillain-Barre syndrome (GBS) is the most common cause of acute paralysis. It requires early institution of therapy to avoid life-threatening complications, to speed up recovery and minimize residual handicap. Advances in supportive care (treatment of infections, anticoagulation) and the introduction of intensive care (assisted ventilation, treatment of autonomic disturbances) have greatly improved the management of this disease and consequently its prognosis. A better understanding of the underlying immune mechanisms prompted pathogenetically oriented therapy. Plasma exchange and high dose intravenous immunoglobulin have been demonstrated in large controlled trials to hasten recovery in GBS. Problems of these studies are discussed and the presumed mode of action of these therapies is reviewed. Corticosteroids have shown no benefit. Ongoing trials are listed and future strategies for immunointervention are outlined. PMID- 7854502 TI - [Nitric oxide and mechanisms of vascular and tissue damage. New hope for research and therapy of multiple sclerosis]. AB - Nitric oxide (NO) was recently recognized as a--from a biological point of view rather unusual--signalling molecule and ubiquitous mediator. Soon after the discovery of the significance of NO for intercellular communication and intracellular regulations, it became apparent that the NO-dependent processes play a part also in the immune and inflammatory mechanisms of vascular and tissue damage, including affections of the CNS. In higher concentrations, NO acts directly as a toxic factor and co-factor, and in lower concentrations it has rather more regulatory and even protective properties. In the present article the role played by NO in some mechanisms that, according to present knowledge, participate in the pathogenesis of multiple sclerosis is reviewed. These are as follows: The production and action of cytokines, especially interferon-gamma, tumour necrosis factor and interleukins; Interactions between leukocytes, thrombocytes and endothelial cells; The arachidonic acid cascade, metabolism and effects of reactive oxygen species and actions of corticosteroids; Glia-dependent cytotoxic and immunopathological events; Virus-host interactions. It has become increasingly clear that the research focused on NO and related problems brings significant progress in our understanding of the pathogenesis of many neurological diseases and, moreover, may provide new stimuli in the search for novel therapeutic approaches in multiple sclerosis. PMID- 7854503 TI - [Therapeutic hypothermia after cerebral ischemia. Theoretical principles and possible clinical applications]. AB - In animal models of cerebral ischemia hypothermia has been shown to have a beneficial effect. Reduction of infarct size, fewer potentially neurotoxic metabolites, and a better neurological outcome were observed compared to sham operated animals. In clinical practice hypothermia has been widely used in cardiovascular surgery and occasionally in neurosurgery. The first trials with hypothermia in patients with severe head injury have also shown beneficial results. However, studies on therapeutic hypothermia in the clinical management of acute stroke are not yet available. PMID- 7854504 TI - [Validating rehabilitation after stroke]. AB - Evaluation of therapeutic efficacy in neurologic rehabilitation is methodologically limited by the well established polypragmasia and the lack of untreated controls. Controversial discussion is generated by the following topics: superiority of specific therapy versus spontaneous recovery, higher efficacy of in-patient-setting versus out-patient-setting and the value of neurorehabilitation treatment in latency of more than 1 year after the event. To develop a practicable method for the evaluation of efficacy, we surveyed retrospectively 30 patients after stroke in a sequential study design on 4 scheduled visits: first admission to in-patient rehabilitation, discharge to out patient treatment, admission and discharge of second in-patient rehabilitation. Impairment, disability and handicap were documented by NIH-Stroke Scale, Barthel Index, CGI, WWK-Pflegeskala N and Risk-Profile. A descriptive data-analysis implies a therapeutic gain of stroke rehabilitation in-patient setting which is apparently superior to out-patient treatment. A measurable therapeutic effect was evident even more than one year after the stroke. PMID- 7854505 TI - [Magnetic resonance tomography and skeletal scintigraphy in spondylodiscitis]. AB - 12 patients were diagnosed as suffering from spondylodiscitis by means of clinical and laboratory investigations. Magnetic resonance tomography (MRT) and bone scintigraphy (with Tc 99m-diphosphonate) were performed and 6 patients had further MRT follow up investigations. In the initial state of disease the comparison of MRT and bone scan both revealed a sensitivity of 92%. The specificity was 83% for MRT and 50% for bone scintigraphy, respectively. Therefore we conclude MRT is a more specific diagnostic tool in patients with spondylodiscitis. 6 patients were followed up with additional 13 MRT scans. During the first two months of treatment period in most of the patients more distinct pathological findings were seen in MRT in comparison with MRT at the start. No signs of any improvement despite effective treatment were found in the first three months of therapy. PMID- 7854506 TI - [Simple decompression of the ulnar nerve in cubital tunnel syndrome with and without morphologic changes. Report of experiences based on 523 cases]. AB - The transposition of the ulnar nerve has proved to be an effective therapy in ulnar neuritis at the elbow but has also many risks and technical problems. In contrast the simple decompression or release of the nerve within the cubital tunnel which was first described by Osborne and Feindel and Stratford is an operation which is free of complications and postoperative morbidity and can be performed in local anesthesia. According to the results of a former study of 139 cases and this follow-up study of further 523 cases the simple decompression proved to be an efficacious and almost entirely substitute for the more complicated and extensive procedure of volar transposition-not only for the "idiopathic" cubital tunnel syndrome but also for the "symptomatic" forms as tardy ulnar palsy, luxation of the ulnar nerve or other abnormalities i.e. epitrochleoanconeus muscle, ganglia, lipomas, bursitis. Depending on the severity of nerve damage and duration of symptoms but widely independent from etiology the electroneurographic follow-up study indicated a significant improvement of conduction velocity in about 90% of cases and was therefore a good indicator for successful decompression. It is suggested to give up the concept of different etiologies especially the widely used "sulcus-ulnaris-syndrome" and to replace it by the term "cubital tunnel syndrome" (with or without morphological alterations). Most important for the outcome of surgery is an early operation. Once muscle atrophy has developed the prognosis will be poor. This is also true for cases with concomitant polyneuropathy. Anterior transposition may be restricted to very few cases of extreme cubitus valgus. PMID- 7854507 TI - [Intracerebral hematoma as an acute manifestation of intracranial tumors]. AB - Sixteen patients with spontaneous intracerebral haematoma due to intracranial tumours are discussed. The total number of patients with intracranial tumour treated in the period concerned was 594, so the incidence of tumour haemorrhage was 2.7%. In most of the patients we found metastatic neoplasm (n = 6) and glioblastoma (n = 3). All patients were acute admissions. Seven were comatose, seven were somnolent, and two patients were alert. In ten patients the haemorrhage represented the first reliable clinical sign. In six patients a tumour disease was known. Fourteen patients were operated on. Six patients died. Extensive neuro-radiological examination is very important, particularly since 30% of these acute intracerebral haemorrhages occur in patients with benign intracranial tumours. PMID- 7854508 TI - [Cerebral lateralization in constitutional dyslexia. Electrophysiologic findings]. AB - Event-related brain potentials were recorded from a group of developmental dyslexics using a simple visual discrimination task and compared to the results of a control group. A large P3 component was elicited which did not differ in overall amplitude between groups. While the distribution was virtually symmetrical in the dyslexic group, there was a left hemispheric preponderance in the control group. The latencies of the P3 were longer in the dyslexic group than in the control group. The results are compared to findings of neuroanatomical and neuroimaging studies which revealed less hemispheric asymmetries in dyslexics compared to control subjects. PMID- 7854509 TI - [Creutzfeldt-Jakob disease. Report of a case with an unusually long course and immunohistochemical localization of the prion protein and overview of current information]. AB - The human spongiform encephalopathies are a group of neurodegenerative disorders of unknown origin. They comprise a group of horizontally transmissible and genetically determined diseases. We present here a case of Creutzfeldt-Jakob disease with an unusually long clinical course, in which the prion protein was localized immunohistochemically. The generally accepted hypothesis on the pathogenesis of these diseases is the so-called 'prion-hypothesis'. The implications of this hypothesis are discussed and a short review of the literature is given. PMID- 7854510 TI - [Spinal claudication and malum perforans pedis. Late sequela of ankylosing spondylitis (Bechterew disease) with cystic lumbosacral arachnopathy]. AB - Enlargement of the caudal sac with bony erosions of the spinal vertebrae may be a late sequel of ankylosing spondylitis. CT scans demonstrate typical changes. We report a case with spinal claudication and a neuropathic ulcer. PMID- 7854511 TI - [Immune augmenting therapy as treatment of multiple sclerosis. Warning regarding a potentially toxic alternative treatment method]. PMID- 7854512 TI - [Therapy of acute Guillain-Barre syndrome. A national multicenter study]. AB - Current treatment concepts in Guillain-Barre syndrome (GBS) are discussed, followed by a call for participation in a randomized multicenter trial in GBS. This study compares intravenous immune globulin, plasma exchange, and selective adsorption. The study is currently underway. PMID- 7854513 TI - An algorithm for the management of Parkinson's disease. PMID- 7854514 TI - Diagnosis and evaluation of dementia. PMID- 7854515 TI - Serotonin syndrome. AB - We describe a patient treated with trazodone, isocarboxazid, and methylphenidate hydrochloride who developed confusion, agitation, poor concentration, rigidity, myoclonus, involuntary movements, orthostatic hypotension, and hyperreflexia. CK was normal, and the syndrome resolved spontaneously over 12 hours. The serotonin syndrome occurs following the use of serotomimetic agents (serotonin reuptake inhibitors, tricyclic and tetracyclic antidepressants, tryptophan, 3,4 methylenedioxy-methamphetamine, dextromethorphan, meperidine, S adenosylmethionine) alone or in combination with monoamine oxidase inhibitors. It is characterized by various combinations of myoclonus, rigidity, hyperreflexia, shivering, confusion, agitation, restlessness, coma, autonomic instability, low grade fever, nausea, diarrhea, diaphoresis, flushing, and rarely, rhabdomyolysis and death. PMID- 7854516 TI - A randomized controlled trial of chronic vagus nerve stimulation for treatment of medically intractable seizures. The Vagus Nerve Stimulation Study Group. AB - Preliminary reports have suggested that chronic, intermittent stimulation of the vagus nerve (VNS) is an alternative treatment for patients with medically refractory seizures. We performed a multicenter, randomized, controlled trial to evaluate the efficacy and safety of adjunctive VNS in patients with poorly controlled partial seizures. An implanted, programmable pacemaker-like device was connected to two stimulating electrodes wrapped around the left vagus nerve. One hundred fourteen patients were randomized to receive 14 weeks of high-level stimulation (presumed therapeutic dose) or low-level stimulation (presumed subtherapeutic dose) using a blinded, parallel study design. Seizure frequency was compared with a 12-week baseline. Mean reduction in seizure frequency was 24.5% for the "high" stimulation group versus 6.1% for the "low" stimulation group (p = 0.01). Thirty-one percent of patients receiving high stimulation had a seizure frequency reduction of > or = 50%, versus 13% of patients in the low group (p = 0.02). Treatment emergent side effects were largely limited to a transient hoarseness occurring during the stimulation train. One patient with no previous history of cardiac disease experienced a myocardial infarction during the third month of vagal stimulation. VNS may be an effective alternative treatment for patients who have failed antiepileptic drug therapy and are not optimal candidates for epilepsy surgery. PMID- 7854517 TI - Amnesia of the epileptic aura. AB - In a prospective study lasting 6 months, we recorded on video 108 seizures with aura of 23 patients in an attempt to evaluate the mechanisms involved in the encoding of memories. In 88 of those seizures, we also recorded an EEG. The percentage of auras remembered decreased significantly with increasing severity of the seizures. The recollection of auras was also significantly dependent on the ictal EEG changes during the aura. Ninety-seven percent of the auras without EEG changes, 94% of the auras with unilateral EEG changes, and 73% of the auras with bilateral EEG changes during the aura were remembered. The spread of the ictal EEG pattern during the aura also showed a significant correlation with the severity of the ensuing seizure. Three patients with bitemporal epilepsy made up a considerable proportion of those who never remembered their aura before secondary generalized tonic-clonic seizures (2 of 3) and of those who had a transient postictal amnesia of their aura (2 of 3). The only patient who failed to remember a previously documented isolated aura also suffered from bitemporal epilepsy. During the second part of the study, we questioned whether information provided during the history could be helpful in defining the type of epilepsy syndrome or localizing the EEG seizure pattern of the 80 patients who had been admitted for presurgical epilepsy diagnosis. Localized (regional, unilateral, and independent left and right lateral) EEG seizure patterns occurred in 82% of the 51 patients with auras in their history as compared with 24% of the 17 patients who did not have auras in their history (p < 0.01). PMID- 7854518 TI - The effect of seizures on memory for recently learned material. AB - We gave 58 patients with refractory partial seizures who were undergoing video EEG telemetry a variety of memory tests shortly after the telemetry commenced, and we reassessed memory for this material 48 hours later. Thirty patients had one or more seizures during this period; 22 of these had complex partial seizures, secondary generalized seizures, or both. Eighteen patients did not have any seizures during the study period. Patients who had seizures forgot no more than patients who did not have seizures. There was no correlation between memory performance and the timing of seizures or the number of seizures. These findings indicate that isolated seizures do not generally cause patients to forget material they have recently learned. PMID- 7854519 TI - Anosognosia during intracarotid barbiturate anesthesia: unawareness or amnesia for weakness. AB - Previous studies have demonstrated asymmetric hemispheric contributions to deficit awareness during hemisphere inactivation with intracarotid barbiturate infusion (Wada studies). These observations provide insight into the neuropsychological basis of anosognosia for hemiparesis (AHP), arguing against earlier explanations based upon psychological denial, global cognitive disturbance, or emotional indifference. Although prior Wada studies equated AHP after the procedure with AHP during the period of deficit, a selective memory failure could also account for these findings. We, therefore, assessed the occurrence of AHP during and after right-hemisphere inactivation in a group of epilepsy patients undergoing preoperative Wada testing. Because aphasia obscures assessment of deficit awareness during left carotid studies, we compared the frequency of AHP between right- and left-hemisphere inactivation only after recovery. As noted in earlier reports, AHP was present significantly more often after right- than left-hemisphere inactivation. The proportions of subjects with AHP during right-hemisphere anesthesia compared with the proportion of subjects with AHP after the procedure were statistically equivalent, suggesting that the AHP observed after right-hemisphere anesthesia results from true failure of deficit awareness rather than inability to recall the deficit. PMID- 7854520 TI - Optic neuritis: a population-based study in Olmsted County, Minnesota. AB - We reviewed the records of all patients with optic neuritis (ON) in Olmsted County, Minnesota, identified through the comprehensive records-linkage system at the Mayo Clinic, and identified 156 ON patients from 1935 to 1991 who had onset of the disease while residing in Olmsted County (incidence cases). Poisson regression analysis revealed that age, gender, and calendar year were associated with incidence. The annual age- and sex-adjusted incidence rate was 5.1 per 100,000 person-years from 1985 to 1991. On December 1, 1991, 128 patients with a documented history of ON resided in Olmsted County (prevalence cohort). The age- and sex-adjusted prevalence rate per 100,000 was 115. The average length of follow-up for the incidence cohort was 13.2 years. Life table analysis showed that 39% of the 95 patients with isolated ON in the incidence cohort had progressed to clinically definite multiple sclerosis (MS) by 10 years of follow up, that 49% had by 20 years, 54% by 30 years, and 60% by 40 years. There was no difference in the risk of developing MS between men and women. The presence of venous sheathing (p = 0.044) and evidence for recurrent ON (p < 0.0001) were associated with an increased likelihood of developing MS. The estimated 25-year survival rate was 88.3% +/- 5.8% for the incidence cohort with isolated ON, compared with 83.9% for the general US population of similar age and sex. PMID- 7854521 TI - Disease steps in multiple sclerosis: a simple approach to evaluate disease progression. AB - Current clinical scales in multiple sclerosis (MS) are often complicated to administer, suffer from interrater variability and lack of uniform representation across grades, and are insensitive to progression at certain stages. Furthermore, they are not easily applied by neurologists and do not clearly differentiate among functional stages of MS. For these reasons, we developed Disease Steps to assess disability in MS. A total of 1,323 patients were classified using both Disease Steps and the Expanded Disability Status Scale (EDSS) for a total of 2,755 assessments. The Disease Steps scale consists of 0 = Normal; 1 = Mild disability, mild symptoms or signs; 2 = Moderate disability, visible abnormality of gait; 3 = Early cane, intermittent use of cane; 4 = Late cane, cane-dependent; 5 = Bilateral support; 6 = Confined to wheelchair; and U = Unclassifiable. Results demonstrate that raters could simply and quickly categorize patients using Disease Steps. Patients were uniformly distributed with Disease Steps, whereas a bimodal distribution occurred with the EDSS. On the EDSS, 40.3% of patients scored between 1.0 and 3.5 and 36.0% scored from 6.0 to 6.5, with only 6.9% of patients scoring between 4.0 and 5.5. For 60 patients seen by two neurologists, concordance between raters was excellent for Disease Steps (kappa = 0.8) but only moderate for the EDSS (kappa = 0.54). As a simple and reproducible measure of different functional steps of MS, Disease Steps can be used as a guide in therapeutic decision-making, following response to therapy, and in assessing disease progression. PMID- 7854522 TI - Correlations between changes in disability and T2-weighted brain MRI activity in multiple sclerosis: a follow-up study. AB - We obtained two conventional unenhanced T2-weighted brain MRI scans, separated by an interval of 24 to 36 months, in 281 patients with multiple sclerosis (MS). At the time of each scan, clinical disability was rated using the Kurtzke Expanded Disability Status Scale (EDSS). Changes in disability between the two examinations correlated weakly but significantly with the number of new (Spearman's rank correlation coefficient = 0.13; p = 0.02) and enlarging (Spearman's rank correlation coefficient = 0.18; p = 0.002) MRI lesions. This result suggests that brain T2-weighted MRI is a useful supplementary marker of disease activity in definitive (phase III) clinical treatment trials in MS. PMID- 7854523 TI - Neurologic signs and symptoms in a cohort of homosexual men followed for 4.5 years. AB - We traced the development of neurologic impairment in 207 homosexual men (123 human immunodeficiency virus [HIV]-positive and 84 HIV-negative controls) over 4.5 years of follow-up. We applied generalized estimating equations to logistic regression analyses with repeated measures to examine the differences between HIV positive and HIV-negative subjects with respect to the likelihood of developing six neurologic outcomes derived from a factor analysis, significant neurologic impairment (modified Kurtzke disability score of > or = 3), or significant neuropsychological impairment. We found that, over time, HIV-positive subjects were more likely to develop clinically significant extrapyramidal signs and frontal release signs than HIV-negative subjects. Controlling for age or education, as CD4 count declined, the odds of developing significant extrapyramidal signs, abnormalities in alternating movements, frontal release signs, and a Kurtzke score > or = 3 increased. HIV-positive subjects were almost five times as likely (odds ratio [OR], 4.6; 95% CI, 1.6 to 13.4) as HIV-negative subjects to stay the same or worsen neurologically on the next visit, and those with CD4 < or = 200 were 4.8 times as likely (OR, 4.8; 95% CI, 2.2 to 10.7) to maintain or worsen neurologically relative to those with higher CD4 counts. We conclude that neurologic impairment becomes increasingly apparent over time in HIV-infected men, especially in those with low CD4 counts. PMID- 7854524 TI - Cognitive performance after progression to AIDS: a longitudinal study from the Multicenter AIDS Cohort Study. AB - OBJECTIVE: To describe changes in cognitive functioning before and after development of an acquired immune deficiency syndrome (AIDS)-defining illness or CD4+ lymphocyte count < 200/mm3 in participants in the Multicenter AIDS Cohort Study. METHODS: The study population included participants who either were diagnosed with an AIDS-defining illness (n = 52) or had at least one measurement of CD4+ count < 200/mm3 (n = 57) and who had at least four neuropsychological (NP) evaluations, two or more before and two or more after the AIDS diagnosis. A group of subjects with clinical diagnosis of dementia (n = 29) was also included for comparison. The NP test battery included measures of attention, memory, constructional abilities, and psychomotor speed. Longitudinal data analysis, using the generalized estimating equation, was performed separately for each NP measure. Time was measured in months from the date of clinical AIDS or CD4+ < 200/mm3. RESULTS: Before AIDS< the dementia group showed significant decline (slope different from zero) only on measures of psychomotor speed. For all other measures, there was no evidence of decline in performance before AIDS for the other groups. After development of AIDS, the group with clinical AIDS showed significant decline on psychomotor speed but none on the other cognitive measures. The group with CD4+ < 200/mm3 did not show significant decline on any of the cognitive measures after AIDS. As expected, the dementia group showed significant decline on all measures. Sensory neuropathy was associated with a significant decline in performance on measures of psychomotor speed after AIDS. Antiretroviral therapy was not associated with any measurable changes in NP performance. CONCLUSION: These results are consistent with previous findings showing no significant decline in cognitive functions before AIDS, unless overt dementia is present, and no decline in immunosuppressed subjects who have had no AIDS-defining illness. By contrast, in subjects who have developed clinical AIDS, there is mild decline in fine motor skills but no significant change in other cognitive domains. PMID- 7854525 TI - Repetitive paroxysmal nystagmus and vertigo. AB - A 55-year-old woman had paroxysms of vertigo and visual blurring associated with complex combined torsional, horizontal, and vertical nystagmus. These episodes occurred regularly at 2-minute intervals, each attack lasting for 15 seconds. Between attacks, there was a much finer asymptomatic nystagmus whose components were in the opposite direction to those associated with the paroxysmal attacks. A brain MRI revealed an arteriovenous malformation in close proximity to the left vestibular nucleus, with evidence of previous bleeding. Caloric testing demonstrated a left-sided vestibular paresis. We suggest that neurons in this patient's damaged left vestibular nucleus are usually underactive but regularly produce pathologic brief bursts of hyperactivity causing episodic reversal and gross exacerbation of her resting nystagmus. Treatment with low-dose carbamazepine was successful in abolishing both the paroxysms of nystagmus and the symptoms of vertigo and visual disturbance. PMID- 7854526 TI - Dopa-responsive dystonia and normalization of soleus H-reflex test results with treatment. AB - We studied the ratio of the maximal H-reflex to maximal direct muscle potential (H/M ratio), late facilitation and late inhibition in the recovery curve, and vibratory inhibition of the soleus H-reflex in three consecutive patients with hereditary dopa-responsive dystonia, before and during treatment with levodopa. In one patient, we repeated the H-reflex tests twice after withdrawal of levodopa. The results were compared with those in a group of 48 healthy subjects. In the patients before treatment, the soleus H-reflex recovery curve showed increased late facilitation and depressed late inhibition, reflecting alterations in postsynaptic interneuronal activity. Vibratory inhibition, predominantly reflecting presynaptic inhibitory action, was depressed. Normalization of these test results occurred during levodopa treatment, concurrent with a clear clinical response. The H/M ratio, reflecting the excitability state of the motoneuron pool, was similar during and without levodopa treatment. In the one patient tested after levodopa withdrawal, enhancement of late facilitation and decrease of vibratory inhibition paralleled the reoccurrence of dystonia most clearly. Since soleus H-reflex tests mainly reflect mechanisms operating at the spinal level, spinal aminergic or dopaminergic systems are probably involved in dopa responsive dystonia. PMID- 7854527 TI - Mitochondrial encephalomyopathy associated with a single nucleotide pair deletion in the mitochondrial tRNALeu(UUR) gene. AB - The investigation of pathogenic mitochondrial DNA (mtDNA) mutations has revealed a complex relation between patient genotype and phenotype. For unknown reasons, some mtDNA mutations produce specific clinical manifestations such as chronic progressive external ophthalmoplegia; myoclonic epilepsy and ragged-red fiber disease (MERRF); and mitochondrial encephalomyopathy, lactic acidosis, and stroke like episodes (MELAS). To enhance our understanding of the association between genotype and phenotype, we investigated a patient with mitochondrial encephalomyopathy and severe cerebral calcifications for a mtDNA mutation. There was a deletion of one of three T:A nucleotide pairs in the tRNALeu(UUR) gene of the mtDNA involving positions 3271 to 3273. Pedigree analysis suggested that this mutation may have occurred spontaneously in the proband. This analysis represents the smallest mtDNA deletion observed to date and is the first deletion identified within a mitochondrial tRNA. This observation emphasizes the importance of delineating the precise mutation responsible for an oxidative phosphorylation disease for patient diagnosis as well as for genetic counseling of maternal lineage relatives. PMID- 7854528 TI - Analysis of lesions by MRI in stroke patients with acoustic-phonetic processing deficits. AB - We tested 10 aphasic stroke patients for the ability to discriminate and identify English phonemes. All patients underwent MRI and had their scans analyzed morphometrically. Patients with impairments in acoustic-phonetic processing tended to have lesions involving the left posterior supramarginal gyrus and the bordering parietal operculum, an observation further supported by regression and correlation analyses. These results are interpreted as evidence that the region including the left posterior supramarginal gyrus and parietal operculum plays a significant role in acoustic-phonetic processing. PMID- 7854529 TI - Gender differences in language of AD patients: a longitudinal study. AB - We examined gender differences in probable Alzheimer's disease (AD) patients on language measures at four data collections (entry, 6, 12, and 18 months) and a normal elderly (NE) comparison group at entry and 18 months. Comparison of gender differences in language abilities of 60 (29 men, 31 women) early (Clinical Dementia Ratings I and II) AD subjects at entry revealed significant effects for gender on the Boston Naming Test (BNT) and Peabody Picture Vocabulary Test Revised (PPVT-R) but not on the Word Fluency Test, shortened Token Test, or modified Reporter's Test. The 37 subjects (18 men, 19 women) who completed less than four data collection sessions compared with the 23 subjects (11 men, 12 women) who completed all four sessions differed on education and Reporter's Test scores. Longitudinal analysis of measures showed that gender differences persisted for the BNT and PPVT-R and that time differences were found on all measures. Gender differences remained after correcting for age, education, duration of illness, and mental status. We found no differences for the NE comparison group for gender or time. All AD subject trends were downward, suggesting that (1) language is affected over time in AD, (2) both men and women decline at similar rates, and (3) language abilities of women are more severely impaired at all time points. PMID- 7854530 TI - Magnetic cortical stimulation in acute spinal cord injury. AB - We studied 25 patients within 6 hours of acute spinal cord injury using magnetically evoked cortical motor evoked potentials (MEPs). The subjects included 16 quadriplegics with cervical spine injuries and eight paraplegics. MEPs were recorded from abductor digiti minimi (ADM), biceps, flexor hallucis brevis, and tibialis anterior muscles on each side using appropriate directions of coil current. MEPs were not obtained, either at rest or during attempted voluntary contraction, in patients without preceding clinical evidence of voluntary activation. This was the case even for muscles that later had motor recovery after an initial paralysis. In comparison with normal controls, MEP thresholds at rest in ADM and biceps were elevated even for muscles innervated above the level of injury (p < 0.001). On repeat testing, 6 weeks postinjury, there was a return toward normal, but a significant threshold elevation remained for ADM (p < 0.05). We conclude that in acutely injured spinal cord patients, magnetically evoked MEPs do not provide useful information regarding the likelihood of motor recovery. PMID- 7854531 TI - Muscular fatigue in Duchenne muscular dystrophy. AB - We used a 4-minute sustained maximum voluntary contraction to investigate fatigability of the anterior tibial muscle in eight healthy boys and 11 boys with Duchenne muscular dystrophy (DMD) (ages 5 to 10 years). Before exercise, the force generation of dystrophic muscle and the compound muscle action potential amplitude were lower and half-relaxation time of the tetanus was longer in patients than in controls. During exercise, the decline in tetanic force and potentiation in twitch tension were similar in both groups. However, during exercise, there was less decline in maximum voluntary contraction and less added force in DMD patients, suggesting that there was less central fatigue in patients than in controls. Thus, patients with DMD and controls have similar intramuscular fatigability and excitation-contraction coupling, and central activation in patients is functioning as well as or better than in healthy controls. PMID- 7854532 TI - The syndrome of autosomal recessive pontocerebellar hypoplasia, microcephaly, and extrapyramidal dyskinesia (pontocerebellar hypoplasia type 2): compiled data from 10 pedigrees. AB - The syndrome of autosomal recessive pontocerebellar hypoplasia, microcephaly, severely impaired mental and motor development, and extrapyramidal dyskinesia is a distinct system degeneration, previously designated pontocerebellar hypoplasia type 2 (PCH-2). To further characterize its clinical and neuroimaging features, we compiled data from 10 nonrelated pedigrees. Six pedigrees were Dutch, two Swedish, and two German. All 16 patients showed an identical profile of virtually absent developmental milestones, early-onset severe chorea, and microcephaly together with pontocerebellar hypoplasia. Family distribution supports autosomal recessive transmission. The present data support the PCH-2 phenotype as a distinct neurogenetic entity. PMID- 7854534 TI - Autosomal dominant, familial spastic paraplegia, type I: clinical and genetic analysis of a large North American family. AB - "Familial spastic paraplegia" (FSP) refers to clinically and genetically diverse syndromes characterized by insidiously progressive lower extremity spasticity. We evaluated 126 members of a large kindred, including 31 affected subjects, in which FSP was transmitted as a stereotyped, autosomal dominant disorder that showed complete genetic penetrance. Affected subjects developed insidiously progressive gait disturbance between ages 12 and thirty-five. Neurologic examination revealed hyperreflexia and spasticity in the lower extremities, weakness of hip flexion and ankle dorsiflexion, extensor plantar response, diminished vibratory sense in the feet, and pes cavus. Using genetic linkage analysis, we excluded the FSP1 locus on chromosome 14q11.2 as the disease locus in this family. We present the clinical and genetic features of FSP type I, including the age-adjusted risk of developing the disorder in this family. PMID- 7854533 TI - Cross-sectional area of the posterior hippocampus in autistic patients with cerebellar and corpus callosum abnormalities. AB - Using MRI methods previously shown to optimize visualization of cytoarchitectonic details in the body of the hippocampal formation caudal to the pes hippocampi, we imaged and quantified the hippocampus proper including the subiculum and the dentate gyrus in 33 autistic patients between the ages of 6 and 42 years and in 23 age-matched normal healthy volunteers. Measures of these structures in autistic patients and normal healthy volunteers differed nonsignificantly, by less than 1.4%, regardless of whether or not the autistic patients were retarded or had a history of seizure episodes. By contrast, measures of vermian lobules VI and VII and the posterior portion of the corpus callosum in these same autistic and normal volunteers differed significantly, by more than 9.9%. The lack of a significant difference in the cross-sectional size of the posterior hippocampal formation between autistic and normal 6- to 42-year-olds is discrepant with predictions based on some, but not all, autopsy studies. This suggests that there is a need for additional quantitative autopsy study of the hippocampal formation and quantitative MRI study of rostral hippocampal regions that we did not explore in the present report. Also, quantitative autopsy and MRI studies have yet to examine hippocampal development in autistic patients younger than 6 years of age; whether early stages of growth are normal or not is unknown. PMID- 7854535 TI - Hereditary leukoencephalopathy and palmoplantar keratoderma: a new disorder with increased skin collagen content. AB - We report a new neurocutaneous syndrome of apparent autosomal recessive inheritance consisting of early-childhood-onset palmoplantar keratoderma followed in adulthood by progressive tetrapyramidal syndrome and cognitive impairment. Of the four affected siblings, two were available for evaluation. Investigation disclosed cerebral white-matter involvement on MRI and arylsulfatase A pseudodeficiency carrier state, which was also identified in clinically unaffected family members. Since skin biopsies showed dermal connective tissue abnormalities, we studied collagens I, III, and VI biosynthesis. Northern blotting of RNA extracted from cultured skin fibroblasts revealed an increased steady-state messenger RNA (mRNA) level of alpha 1(VI) collagen, whereas no differences were detected for pro alpha 1(I), pro alpha 1(III), and tropoelastin mRNAs. The skin content of collagen and total protein was higher in the patients than in controls. We suggest that an extracellular matrix abnormality may be involved in the pathogenesis of this disorder. PMID- 7854536 TI - Treatment of myasthenia gravis by immunoadsorption of plasma. AB - We treated 16 patients with moderately severe to severe generalized myasthenia gravis (MG) by immunoadsorption (perfusion through a resin that adsorbs proteins) of 2,500 ml plasma on each of four alternate days. Fourteen patients who completed treatment all had significant improvement in strength (6 excellent, 6 good, and 2 fair), which began a mean of 42 hours after the first immunoadsorption, reached a maximum 4 days after the fourth immunoadsorption (mean, 250% of baseline strength), and returned to baseline over a mean of 2 months. Thirty-seven grams of plasma proteins were removed during each immunoadsorption, which required no replacement, compared with 175 grams during plasma exchange, which requires replacement with albumin. Serum or plasma concentration of all proteins fell, more so for most of the larger proteins than for the smaller ones: acetylcholine receptor antibody (AChR Ab) fell to a mean of 23% of original level, fibrinogen to 26%, C4 to 29%, IgM to 33%, IgG to 35%, CH50 to 41%, C3 to 42%, IgA to 54%, and albumin to 76%. All proteins, including AChR Ab, returned to their original levels within 1 to 3 weeks after the last immunoadsorption, while improvement in strength lasted a mean of 6 weeks longer. One seronegative patient had excellent improvement lasting more than a month. Activated complement C5a and white blood cell count rose during each immunoadsorption, while activated complement C3a fell, and each returned to its original level within hours. Eight patients had transient symptomatic hypotension attributable to withdrawal of blood more rapidly than it was returned; this hypotension was prevented or ameliorated by intravenous saline.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7854538 TI - Language dominance in patients with early childhood tumors near left hemisphere language areas. AB - RATIONALE: Language function often develops in the right hemisphere following an acute left hemispheric insult in early childhood. Little is known, however, about lateralization of language function in patients with early childhood tumors near potential left hemisphere language areas. Issues of language dominance are important in the strategy for resection of left temporal and frontal tumors. METHODS: We studied 12 patients who had determination of hemispheric language dominance by the intracarotid amobarbital procedure prior to resection of a left inferolateral frontal or left mid or posterior temporal tumor that (1) was near a classic language area and (2) first manifested with partial seizures by age 6 years (mean, 3.7). RESULTS: Hemispheric language dominance was left in 10 patients (83%), right in one patient, and bilateral in one patient. Six patients with left temporal tumors had localization of Wernicke's area with cortical stimulation, and in five the language area was posterior to the tumor. In one patient, the tumor infiltrated Wernicke's area. Eleven of the 12 patients had complete tumor resection (mean age at operation, 11.8 years) and were seizure free at follow-up (mean, 3.1 years). Neuropsychological testing showed a tendency for improved language function after operation, and no patient had new overt language deficits. CONCLUSIONS: Early low-grade left frontal and temporal tumors usually did not result in transfer of language dominance to the contralateral hemisphere. Tumors may grow slowly along with the developing brain in young children, with continued left hemisphere language development in regions separate from the neoplasm. Successful tumor resection can be accomplished, but it may require cortical stimulation for localization and sparing of nearby language areas. PMID- 7854537 TI - Carbidopa/levodopa and selegiline do not affect platelet mitochondrial function in early parkinsonism. AB - Previous studies have demonstrated impaired complex I activity in platelets from Parkinson's disease (PD) patients who were receiving levodopa and other medications for their disease. Eleven patients with early PD underwent three sequential plateletphereses: while on no medication, after receiving carbidopa/levodopa for 1 month, and after receiving carbidopa/levodopa plus selegiline for 1 additional month. As expected, carbidopa/levodopa and selegiline significantly improved motor function in these patients. Treatment with carbidopa/levodopa alone and carbidopa/levodopa plus selegiline did not affect the activities of complexes I, II/III, and IV and citrate synthetase. These observations support the hypothesis that impaired complex I activity in PD patients is a characteristic of the disease and not due to medications. PMID- 7854539 TI - Selective neuroanatomic abnormalities in Down's syndrome and their cognitive correlates: evidence from MRI morphometry. AB - We examined the pattern of neuroanatomic abnormalities in adults with Down's syndrome (DS) and the cognitive correlates of these abnormalities. Specifically, we compared this pattern with what would be predicted by the hypotheses attributing DS pathology to either premature aging or Alzheimer's disease. We measured a number of brain regions on MRIs of 25 subjects: 13 persons with the DS phenotype and 12 age- and sex-matched healthy volunteers. Study participants had no history of cardiovascular disease, diabetes, thyroid dysfunction, or seizure disorder. After statistical adjustment for differences in body size, we found that, in comparison with controls, DS subjects had substantially smaller cerebral and cerebellar hemispheres, ventral pons, mammillary bodies, and hippocampal formations. In the cerebellar vermis of DS subjects, we observed smaller lobules VI to VIII without appreciable differences in other regions. In addition, we noted trends for shrinkage of the dorsolateral prefrontal cortex, anterior cingulate gyrus, inferior temporal and parietal cortices, parietal white matter, and pericalcarine cortex in DS subjects compared with normal controls. The parahippocampal gyrus was larger in DS subjects. We found no significant group differences in the volumes of the prefrontal white matter, the orbitofrontal cortex, the pre- and postcentral gyri, or the basal ganglia. We conclude that the pattern of selective cerebral damage in DS does not clearly fit the predictions of the premature aging or Alzheimer's disease hypotheses. To examine the relationship between brain abnormalities and cognitive deficits observed in DS, we correlated the size of brain regions that were significantly reduced in DS with performance on tests of intelligence and language. The correlation analysis suggested age-related decline in the DS subjects in general intelligence and basic linguistic skills. General intelligence and mastery of linguistic concepts correlated negatively with the volume of the parahippocampal gyrus. There was no relationship between total brain size and the cognitive variables. PMID- 7854540 TI - Differential effects of beta and gamma interferons on expression of major histocompatibility complex antigens and intercellular adhesion molecule-1 in cultured fetal human astrocytes. AB - We investigated the modulatory effects of human interferon beta (IFN-beta) and gamma (IFN-gamma) on expression of class I and II major histocompatibility complex (MHC) antigens and intercellular adhesion molecule-1 (ICAM-1) in fetal human astrocytes in culture using flow cytometry and immunocytochemistry. Under the baseline condition, class I MHC antigen and ICAM-1 were expressed in a moderate number (23 to 76%) of astrocytes, whereas class II MHC antigen was expressed in only a small number (0.3 to 8%) of astrocytes. Following a 72-hour treatment with IFN-gamma (10 to 100 U/ml), expression of all three antigens increased greatly. Expression of class I MHC antigen was also elevated by exposure to IFN-beta (10 and 100 IU/ml). However, IFN-beta did not significantly induce expression of class II MHC antigen or ICAM-1. Furthermore, IFN-beta significantly reduced IFN-gamma-induced expression of class II MHC antigen but not of class I MHC antigen or of ICAM-1. The differential effects of IFN-beta and IFN-gamma on expression of class I and II MHC antigens and ICAM-1 in fetal human astrocytes suggest that interferons serve as modulators of astrocyte function at sites of inflammation in the human CNS. PMID- 7854541 TI - Multifocal inflammatory leukoencephalopathy associated with levamisole therapy. AB - Cerebral demyelinating disease developed in a patient during adjuvant therapy with levamisole for malignant melanoma. This patient had no evidence of previous neurologic disease. Levamisole was administered for 5 weeks (total dose, 1,500 mg). Over a period of 3 weeks, the patient became progressively confused and ataxic. MRI with gadolinium enhancement demonstrated prominent multifocal enhancing white matter lesions. CSF examination revealed an inflammatory profile. After discontinuation of treatment with levamisole and a short course of corticosteroid therapy, the patient's condition dramatically improved. MRI also indicated improvement. Observations in our patient suggest that the leukoencephalopathy that developed in previously reported patients who received 5 fluorouracil and levamisole may have been caused at least partly by levamisole. PMID- 7854542 TI - Attention and anosognosia: the case of a jargonaphasic patient with unawareness of language deficit. AB - Some patients with aphasia lack awareness of the language errors they make. We describe a man with undifferentiated jargonaphasia and preserved auditory comprehension who was unaware of his speech production errors when he had to both speak and listen simultaneously. However, when listening to a recording of his speech, he could detect the speech errors he had made. We attribute this patient's unawareness of his speech production errors to a reduced attentional capacity for simultaneous linguistic tasks. PMID- 7854544 TI - Frequency of anti-nuclear antibodies in multiple sclerosis. AB - We found anti-nuclear antibodies (ANA) in 26.7% of 150 relapsing-remitting and in 30.4% of 23 chronic progressive definite multiple sclerosis (MS) patients by retrospective chart review. These patients did not have systemic lupus erythematosus. Since ANA are not pathogenically relevant in MS, they are false positive, and likely reflect systemic immune dysregulation in MS. PMID- 7854543 TI - Myasthenia gravis during interferon alfa therapy. AB - Patients treated with interferon alfa can develop autoantibodies and autoimmune diseases. We describe two patients who developed myasthenia gravis with abnormal levels of serum anti-acetylcholine receptor antibodies during interferon alfa-2b treatment for malignancies. One of these patients had myopathic findings on EMG and focal deficiency of cytochrome c oxidase on muscle biopsy. PMID- 7854545 TI - Distorted color discrimination in 'de novo' parkinsonian patients. AB - We performed the Farnsworth-Munsell 100-hue test in 16 "de novo" patients with Parkinson's disease and 16 age-matched controls to determine their color discrimination ability. The mean total error score in patients was significantly elevated as compared with controls (64.6 in patients versus 16.0 in controls). We conclude that the impairment of color discrimination may be an early sign in Parkinson's disease. PMID- 7854546 TI - What can preservation of autobiographic memory after muscarinic blockade tell us about the scopolamine model of dementia? AB - Autobiographic memory is reported to be impaired in patients with Alzheimer's disease (AD). To determine if cholinergic blockade fully reproduces the amnestic disorder found in dementia, we evaluated aspects of autobiographic and episodic memory in six healthy elderly controls after both scopolamine and placebo administration compared with untreated age- and education-matched patients with AD. The performance of patients with AD was significantly worse than that of controls after both treatment conditions. Scopolamine impaired episodic but not autobiographic memory. Thus, even though the cholinergic system is severely affected in patients with AD, muscarinic blockade alone does not seem to be a good model of this disorder. PMID- 7854547 TI - Acute bacterial myositis due to Staphylococcus aureus septicemia. PMID- 7854549 TI - Dopamine denervation, age of onset, and Parkinson's disease. PMID- 7854548 TI - Decreased hippocampal volume asymmetry on MRIs in nondemented elderly subjects carrying the apolipoprotein E epsilon 4 allele. PMID- 7854550 TI - Cataplexy associated with midbrain lesion. PMID- 7854551 TI - Wada testing. PMID- 7854552 TI - Dihydroergotamine nasal spray. PMID- 7854553 TI - The cerebellum and autism. PMID- 7854554 TI - [Nonmetastatic osteosarcoma of the limbs treated with neoadjuvant chemotherapy: correlation of tumor volume evaluated by CT and prognosis]. AB - A relationship between tumor volume and prognosis has been demonstrated in extraosseaous solid tumors, soft tissue tumors and Ewing's sarcoma. Fifty-five osteosarcoma patients, treated according to IOR-OS/NEO 3 protocol, have been studied in an attempt to verify if tumor volume is also a significant prognostic factor for the osteosarcoma of the extremities. Tumor volume was measured by CT Scan. A trend towards a better prognosis for smaller tumors was observed, but no statistically significant differences were demonstrated according to the tumor size in the population studied. The authors conclude that for patients with osteosarcoma of the extremities, tumor volume can not be considered an adequate prognostic factor on the basis of which to tailor the chemotherapy treatment, as been recently proposed by other authors. PMID- 7854555 TI - [Lp(a) and lipid order in a group of secondary school students selected according to their family anamnesis]. AB - In this study we evaluated the several risk-factors, Lp(a) and lipids order, related to the family history for ischaemic cardiovascular disease (CHD) atherosclerotic cerebrovasculopathy and arterious hypertension, in a healthy adolescent group, to stress possible early and significant alteration of the lipids order and Lp(a); we also considered which of these parameters may be considered the risk factor most closely related to family history. We studies 130 healty high school students, mean age 16.5 +/- 5.5 years, selected in four groups related to the family history: the first one composed of 34 subjects with positive family history for CHD; the second one of 32 subjects with positive family history for cerebral infarction (CI); the third by 32 subjects with family history for arterial hypertension and the last group by 30 control subjects. Mean value of all variables considered was in the normality range. Lp(a) resulted in the normality range with the exception of the group with positive family history for CHD. Also the traditional risk factors (Total-Col., LDL/Col. and Triglycerides) were increased in this group. Besides the differences between the mean of Lp(a) and Total/Col. in the group with positive family history for CHD and in the control group were statistically significant. The results showed that Lp(a), even if it cannot replace the family history in the screening of coronary atherosclerotic disease, might be considered a risk marker of early atherosclerotic disease. PMID- 7854556 TI - [FDDF (fast dissolving dosage form) piroxicam for sublingual administration in the treatment of rheumatoid arthritis]. AB - Open non-comparative study for the evaluation of the efficacy and tolerance of piroxicam FDDF for sublingual administration in the treatment of rheumatoid arthritis. Thirty patients (6 males and 24 females) suffering from rheumatoid arthritis in the active phase have been treated. All the patients had to fulfil the criteria for the rheumatoid arthritis classification proposed by the American Rheumatism Association (ARA). The efficacy of therapy has been evaluated, after 2, 4 and 6 week of treatment, through the changes in: the number of painful or tender joints on motion, the number of swollen joints, grip strength, ESR. Also day pain, night pain, duration of morning stiffness and functional index have been evaluated. As regards the functional index, activities as dressing, arising, eating, walking, taking care of hygiene, bending, standing and sitting have been considered. The study sample was composed by 30 patients, with a mean age of 59.73 years, suffering from rheumatoid arthritis from 4.76 years. As regards efficacy parameters, day pain, which is recorded on a 21 compartment visual analogue scale, was initially of 8.13 (+/- 3.73), and after 2 weeks of therapy decreased of about 1 point and after 4 weeks was of 6.57 (+/- 3.73). This improvement was already statistically significant at the first control (p = 0.01). At the first control also morning stiffness resulted improved in a statistically significant way (p < 0.0001). As regards functional index a statistically significant improvement was observed in the disability of walking and of picking up objects after 2 weeks; after 4 weeks a significant improvement was observed in the disability of arising and of bending. These changes in functional ability probably depend upon the kind of joint involved and the duration of these lesions. Also the grip strength resulted statistically improved at the 2 control. As regards objective values, there was a statistically significant improvement in tender and swollen joints after only 2 weeks. As regards ESR, which is an index of disease activity, was initially of 40.73 (+/- 16.75) in mean; at the end of the 6th week it was of 34.72 (+/- 15.13): this reduction was statistically significant. No improvement was observed in night pain, normally the pain form which is more difficult to cure. As regards toleration, only 2 patients reported side-effects: the first reported epigastralgia and the second oral burning Both side-effects lasted 1 day and, according to the physician, their relation with the study drug is not sure.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7854557 TI - [Intrahepatic cholestasis due to biochemical errors of bile acids. II. Clinical and therapeutic aspects]. AB - Within the "primary" cholestasis we can discriminate "essential" forms due to an endogenous biochemical error of bile acid metabolism and/or secretion and "conditioned" forms, in which a known precipitating factor is required to elicit the functional disorder responsible for cholestasis. Among the essential forms of cholestasis must be included benign recurrent intrahepatic cholestasis or Summerskill-Walshe disease, Aagenaes disease, progressive familial intrahepatic cholestasis or Byler's disease, and forms due to disorders of the peroxisomes. Benign recurrent intrahepatic cholestasis, the best known form, is characterized by recurrent episodes of itching and jaundice with an acute onset separated by symptom-free intervals, which shows no tendency to progress to liver failure. The conditioned cholestasis group comprises cholestasis of pregnancy and drug-induced cholestasis. Benign recurrent cholestasis of pregnancy is a form induced "by" pregnancy and not a form occurring "in" pregnancy, such as cholestasis due to hepatitis, to primary biliary cirrhosis, to cholelithiasis. Drug-induced cholestasis is a chapter of great clinical relevance: forms due to steroid hormones and due to phenothiazines are discussed. PMID- 7854558 TI - [Zinc and atherosclerosis]. AB - The relationship between zinc and atherosclerosis is reviewed. Administration of strong doses of the mineral can turn out atherogenic through three mechanisms: 1. Through the alterations of the lipidic arrangement: decrease of HDL, increase of total cholesterol and LDL cholesterol (action promoted by the induced hypocupremia). 2. Through the alterations of the vasal wall, in consequence of the biochemical modifications of the basic substance (again, through secondary hypocupremia). 3. Through the increased platelet aggregation which seems to be produced by strong doses of zinc. In addition to these harmful actions, the antioxidative action, typical of zinc, must be stressed, which prevents oxidation of LDL and consequently stops the main mechanism of atherogenesis. Besides, the mineral restricts and nullifies the loss of metallothionein in zinc, produced by free radicals and subsequent functional alterations. Moreover, the calcium antagonist action of zinc must be considered: it blocks calcium and its several favorable actions on atherogenesis. In consideration of these last aspects, the rule of zinc, in suitable doses, could be considered as basic in the context of a strategy of prophylaxis and therapy of the atherosclerosis process. PMID- 7854559 TI - [Eosinophilic gastroenteritis. A case with predominant involvement of mucosal and muscular layers]. AB - Eosinophilic gastroenteritis is an uncommon disease of unknown aetiology, whose distinctive features are eosinophilia in peripheral blood and eosinophilic infiltration of the bowel wall. Its clinical course shows recurrent crises, even after a period of years, of symptoms that underline the predominant involvement of mucosal, muscular or subserosal layers of the bowel wall. The prognosis of the disease is essentially benign and pharmacologic therapy is not always necessary. A case with predominant involvement of both muscular and mucosal layers is described. PMID- 7854560 TI - [Lymphoblastic lymphoma of the renal cavity associated with hemorrhagic pericarditis. Description of a case]. AB - The authors describe a case of lymphoblastic lymphoma of the renal lodge complicated by hemorrhagic pericarditis, cardiac tamponade and quickly evolved in an unfavourable way. Lymphoblastic lymphoma is classified into lymphocytic lymphomas (or non-Hodgkin) with a higher grade of malignancy. These lymphomas have, in 40% of cases, an initially extra-lymph node localization: among these, the renal or perirenal localization is not very frequent. The concomitant presence of a pericarditis of hemorrhagic type is also less frequent. Unlike Hodgkin's lymphomas, lymphocytic lymphomas are frequently in an advanced stage at the moment of diagnosis, and their evolution is of acute-subacute, often fatal type. The case report is about a 70 year old male, who arrived at the clinical investigation for the subjective presence of asthenia, dyspnea, tachycardia and the objective evidence of jugular turgor, hepatomegaly and distal edemas, hypophonesis of right lung basis, according to a clinical picture of systemic venous congestion which instrumental examinations confirm to be of pericardial origin. The abdominal echographic examination showed an occupation of the perirenal space, so the CAT characterized as a 25 cm long formation (from the renal cavity to pelvis), with a dislocation of close structures. Unfortunately, the clinical picture had a quick evolution towards the exitus for cardiac tamponade, only permitting us a bioptic examination for the diagnosis of the case. PMID- 7854562 TI - [Increase of paraovarian cysts. Differential diagnosis, macroscopic and microscopic aspects and role of laparoscopy]. AB - The authors, by means of a literature review, report the essential findings on the increase of paraovarian cysts. They report the study on 15 women with paraovarian cystic lymphangioma. At the end the authors underline the macro and microscopic aspects of considered cases for a differential diagnosis with the most common cystic increase of the area. PMID- 7854561 TI - [Transvaginal ultrasonography and nuclear magnetic resonance. Comparison of techniques in the evaluation of ovarian lesions]. AB - A total of 53 patients were included in this study, aged between 21 and 72 years old and hospitalised with the diagnosis of ovarian tumour. All patients underwent a clinical examination, ultrasonography and NMR prior to surgery. The findings of ultrasonography and NMR were correlated with histological results in order to evaluate the value of these methods in the differential diagnosis of benign and malignant ovarian tumours. Histological tests revealed 46 benign tumours, 3 borderline cases and 4 malignant growths. Transvaginal ultrasonography revealed precisely 47 out of 53 ovarian tumours, and NMR 49 out of 53. The main limitation of both techniques was the tendency to overestimate ovarian lesions (specificity: ultrasonography 89%, NMR 93%). As far as concerns the identification of malignant lesions NMR does not appear to offer significant advantages in comparison to ultrasonography (sensitivity 85% ultrasonography = NMR). PMID- 7854563 TI - [Invasive neoplasms of the female genital system. Clinical-epidemiological considerations]. AB - Invasive neoplasia of female genital tract diagnosed within 1980 and 1990 are considered. Among 235 cases, 49% are endometrial cancer diagnosed prevalently (83.4%) in patients older than 55 years and in the first stage (58%). Cervical cancer represents 24% of total cases and is prevalently distributed in post menopausal patients. Ib, IIa, IIb stage are diagnosed in 65.9% of cases. Ovarian cancer represents 21% of total cases. It is diagnosed prevalently in the 5th, 6th and 7th case decade. Vulvar carcinoma is prevalently diagnosed in the 7th and 8th decade, even if it has also been recorded in several younger women. PMID- 7854564 TI - [Chlamydia trachomatis and sterility]. AB - The infection caused by Chlamydia is one of the sexually transmitted diseases and the correlation between Chlamydia infection and sterility has long been known. In this work, the authors discuss how frequent the isolation of Chlamydia is in women with organic tubal damage, a datum supporting the hypothesis which sees tubal damage as secondary to the rooting of Chlamydia in the tube itself. PMID- 7854565 TI - [Beta-interferon treatment of HPV infections of the lower genital tract in women]. AB - In the period 9-1989/12-1991, 47 fertile women affected by genital HPV infection have been treated with i.m. systemic beta-interferon (3 x 10 x 6 UI every other day for 4 weeks). We have noticed 1 case of drop-out (2, 1%). At the short-medium follow-up (> or = 6 months), the therapy has proved to be probably and/or certainly efficacious in 74.4% of cases (35/47). In patients with condylomas in the cervical region, the less respondent part, we have noticed a reaction in 64.3% of cases; in those who have an extra-cervical or diffused HPV infection, in 89.4%. In the patients with complete follow-up, treated with supplementary DTC if necessary, the recovery ratio reached 92.5%. The i.m. systemic therapy with beta IFN is efficacious in the treatment of genital HPV infections: it is well tolerated and offers the possibility of obtaining a useful "therapeutic integration" with the traditional destructive physical techniques of therapy. PMID- 7854566 TI - [New pharmacological approach to therapy of perimenopausal meno-metrorrhagia. Vaginal use of progesterone]. AB - The authors evaluate the effectiveness of a therapy based on natural progesterone to be employed as a vaginal cream in the treatment of meno-metrorrhagia in peri menopause in 40 patients who were not prepared to consider surgery as a solution for their problems. In the polycentric out-patient study this new preparation has proved to be efficacious and to induce a regression of the endometrial hyperplasia in more than 90% of patients subject to five months' treatment. PMID- 7854567 TI - [Echographic markers of chromosome abnormalities]. AB - Many recent studies have identified biometric parameters which can be used as screening factors in the diagnosis of chromosomic anomalies. This derives from the assertion that karyotype testing in over-35-year-old women alone only allows 20-30% of fetuses suffering from chromosomic anomalies to be diagnosed. The majority of these fetuses remain undiagnosed during the prenatal period given that a high percentage of younger women are excluded from screening. For a long time researchers have hoped to introduce the assay of clinical and instrumental parameters thus allowing anomalous fetuses to be diagnosed in under-35-year-old women. It is now possible to define a biochemical parameter in maternal sera which can identify women at risk and refer them for cytogenetic tests: AFP assay and still more recently the contemporary assay of AFP, estriol and beta-HCG allows greater diagnostic accuracy. However, even using this method only part of those fetuses with chromosomic alterations are identified. Since it is unlikely that screening could be performed without indications in the under 35-year-old age group, it is important to identify routine echographic parameters which can then serve as the indication for subsequent cytogenetic tests and a definitive diagnosis. In this way, by integrating ultrasonographic examination, using biometric and morphological tests, with a biochemical evaluation it will be possible to achieve a higher percentage of diagnosis. This paper examines the most common malformations including trisomy 13, trisomy 18 and trisomy 21 syndromes, Turner's syndrome and triploidy, together with the main echographic findings which accompany them. PMID- 7854568 TI - [Diagnostic evaluation of breast nodules]. AB - Nowadays many women see a gynaecologist because of breast problems; in fact in the last years the frequency and the women's capacities to perform a breast self examination are increased. The prognosis efficacy and the improvement to detect breast nodules thanks to the mammary self palpation nowadays are still difficult to evaluate. Therefore it is important that the family doctor begin with anamnestic data, goes on with an accurate medical examination and, if necessary, sends the patients to perform assessments, clinical and instrumental ones. At the first ambulatory examination we can accurately diagnose the 90% of breast masses thanks to a diagnostic triad, consisting of: bilateral clinical evaluation; bilateral mammography (performed in antero-posterior and in latero-lateral scanning); fine needle aspiration cytology. In fact a careful mammography certainly has reduced mortality due to breast cancer. An useful approach to diagnose breast cancer in all women, especially under thirty years old, is fine needle aspiration cytology, that allows us to avoid surgical treatment in case of benign pathology. If by these approaches a mammary nodule is not definitely diagnosed (impalpable lesion but suspicious by mammography) it needs surgical excision biopsy, in any case, at any age. Another diagnostic possibility is surely ultrasound examination, that is useful to diagnose inflammatory disease and to differentiate cystic or solid lesions. Other diagnostic procedures are thermography, diaphanoscopy and galactography. Because of the multiple and increasing frequency of benign or malignant breast disease, the role of the family doctor is very important.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7854569 TI - Paterson COMMIT: a smoke-free community initiative. AB - Paterson COMMIT is an effort to combat cigarette smoking. The theme for 1994 was "The Smoke-Free Household," and programs were aimed at altering community norms and helping smokers quit. Paterson COMMIT is a successful demonstration of what a community can accomplish. PMID- 7854570 TI - Medical staff: privileging and credentialing. AB - There is a need to understand the purpose and process of credentialing, privileging, and staff membership. This understanding promotes accurate language, proper usage, and meaningful dialogue. Physicians can benefit by reviewing these terms and their meanings. PMID- 7854571 TI - Hemolytic uremic syndrome in New Jersey. AB - In an 18-month study period, the authors identified 23 cases of hemolytic uremic syndrome (HUS) in New Jersey children. Increased identification and reporting of Escherichia coli O157:H7 are needed to prevent additional morbidity and mortality. PMID- 7854572 TI - Adrenal pseudocyst: report of two cases. AB - Adrenal cysts are uncommon lesions. The authors discuss two cases of adrenal pseudocyst, and its classification and possible pathogenesis and complications. The role of radiologic findings in preoperative evaluation of renal/suprarenal masses also is detailed. PMID- 7854573 TI - Case report: Pasturella multocida empyema. AB - Pasturella multocida is a species of small, bipolar staining coccobacillus residing, saprophytically, in the oropharynx of many domestic and wild animals. Infection or cellulitis caused by Pasturella multocida most often occurs after a dog bite or cat bite. PMID- 7854574 TI - A new understanding of dreams. PMID- 7854575 TI - Memory and hippocampal function as targets for neurotoxic substances. AB - The functional consequences of neurotoxins can be assessed only by behavioral testing. Impairments of recent memory are often produced by any damage to the hippocampus or related neuroanatomical structures. The ways of assessing recent memory in animal models are reviewed, with specific examples of test procedures. The effects of different types of neurotoxins on hippocampal function as assessed by performance in these tasks indicates the ways in which sensitive behavioral testing procedures can be designed to describe the functional consequences of neurotoxins that impair recent memory and produce neuropathology in the septohippocampal system. PMID- 7854576 TI - Proceedings of the 4th meeting of the International Neurotoxicology Association. Elsinore, Denmark, June 6-11, 1993. PMID- 7854577 TI - Neuropathology of the hippocampus and its susceptibility to neurotoxic insult. AB - The hippocampal formation and its cholinergic input are an important neurobiological substrate for learning and memory processes. Since alterations in learning and memory are a common consequence of toxicant exposure it is possible that the hippocampus is an important target site for neurotoxicity. In fact, the hippocampus has been shown to be preferentially susceptible to a wide variety of toxic insults. For example, the hippocampus is damaged by environmental toxicants such as heavy metals, drugs of abuse such as alcohol and by cerebrovascular insufficiency finally resulting in hypoxia. The NMDA subtype of glutamatergic receptor plays a major role in learning and memory and in excitoxicity secondary to ischemia, hypoglycemia and trauma. The nature of the adverse effects of neurotoxins at this receptor site may be linked to the neurobiological characteristics that make this structure uniquely susceptible to toxic insult. PMID- 7854578 TI - Neurophysiological aspects of hippocampal neurotoxicity. AB - Identification and analysis of chemical neurotoxicity in the central nervous system deals with synaptic transmission and plasticity. The hippocampus slice technique rendered a powerful tool for electrophysiological analysis of these events as modulated by neurotoxic chemicals. It does not only allow the detection of potentially harmful compounds, but also the elucidation of their mechanism of action. This might render it possible to analyze the risk of neurotoxic chemicals on the basis of quantitative data. PMID- 7854579 TI - Neurochemical aspects of hippocampal and cortical Pb2+ neurotoxicity. AB - The amino acid glutamate is the neurotransmitter used by most excitatory synapses in the mammalian brain. Glutamatergic synapses in the hippocampus and cerebral cortex play an important role in synaptic plasticity. In the developing brain, the interaction of neurotoxins with presynaptic and/or postsynaptic sites on glutamatergic neurons could alter synaptic plasticity. Recent studies have shown that chronic lead (Pb2+) exposure may impair neuronal process underlying synaptic plasticity via a direct interaction with the N-Methyl-D-Aspartate (NMDA) glutamate receptor subtype. The NMDA receptor-ion channel complex regulates calcium influx and is involved in the initiation of changes in synaptic plasticity. In vitro and in vivo neurochemical studies have found that Pb2+ has a marked inhibitory effect on the activation of the NMDA receptor-ion channel complex. Evidence indicates that the inhibitory effect of Pb2+ on the NMDA receptor complex may be mediated by its interaction with a zinc regulatory site on the receptor complex. The ability of Pb2+ to inhibit NMDA receptor-ion channel function was shown to be age-dependent and brain region-specific. The age dependent effects of Pb2+ on the NMDA receptor complex may help explain the selective toxicity of this heavy metal in the developing brain. PMID- 7854580 TI - Strategies to limit brain injury and promote recovery of function. AB - Neurotoxicology integrates the best aspects of pharmacology, neuroscience, and toxicology and has established unique approaches, questions, and model systems. It has contributed to (i) isolating the multitude of environmental factors that damage the nervous system, (ii) characterizing the nature of the insult in both developing and mature organisms, and (iii) identifying the populations at risk. These efforts have symbolized the scope of modern neurotoxicology but there is now a growing appreciation that neurotoxicology, neurology, and biological psychiatry share common interests that are based upon a set of unified conceptual questions. The unifying goals for all of these disciplines are to discern the biology of neural insult, its functional consequences, and the extent and underlying mechanisms of recovery of function. While research is beginning to unravel the biology of neurological disorders there is a widening gap between our understanding of the substrates of these diseases and our ability to prevent or treat them. A concerted effort must be mounted to develop new and appropriate treatments for neurodegenerative disorders. The vulnerability of the hippocampus to a broad spectrum of insults (cerebrovascular insufficiency, excitotoxins, age related neurodegenerative disorders, drugs of abuse) and its involvement in cognitive function makes it a logical focal point for the study of the behavioral and neurobiological correlates of recovery of function. This article discusses models of neurodegeneration and different therapeutic strategies that might limit injury or promote recovery of function. PMID- 7854581 TI - Neurotoxicity and excitatory amino acid antagonists. AB - The cytotoxic action of excitatory amino acids (glutamate, aspartate, NMDA, AMPA, and kainate) was studied in cultured neocortical neurons. It was demonstrated that all amino acids triggered an increase in the intracellular Ca2+ concentration which appeared to be prerequisite for their cytotoxic action. However, while glutamate and NMDA affected both Ca2+ influx and release from intracellular stores, AMPA and kainate preferentially stimulated influx with little (kainate) or no (AMPA) effect on the intracellular store. Using NMDA and non-NMDA receptor selective antagonists it was shown that glutamate cytotoxicity in these neurons is mediated by both receptor subtypes. using the AMPA/kainate selective antagonists AMOA and AMNH it was demonstrated that excitation and neurotoxicity may not be correlated in a simple manner. antagonist and an agonist at AMPA receptors depending on the AMPA concentration. PMID- 7854582 TI - Central administration of the excitotoxin N-methyl-D-aspartate increases nerve growth factor mRNA in vivo. AB - N-methyl-D-aspartate (NMDA) receptor activation in the hippocampal formation is thought to play an important role in learning and memory. This limbic structure contains one of the highest concentrations of NMDA binding sites in the brain. The hippocampal formation also contains high levels of nerve growth factor (NGF) mRNA and protein in the central nervous system. The expression of this neurotrophic factor may be regulated by events involving glutamatergic neurotransmission. In the present study, in situ hybridization histochemistry was used to determine the effects of NMDA receptor activation on NGF mRNA expression in the hippocampal formation. The gene encoding this neurotrophic factor was increased exclusively in the granule cells of the dentate gyrus, a hippocampal structure that receives extensive glutamatergic innervation from the entorhinal cortex. It is suggested that one consequence of glutamatergic neurotransmission in the dentate gyrus is the activation of NGF mRNA. The increased expression of this neurotrophic factor may ultimately influence the function of NGF-responsive cells innervating the hippocampal formation. PMID- 7854583 TI - Phosphoinositide second messengers in cholinergic excitotoxicity. AB - Acetylcholine (ACh) is a powerful excitotoxic neurotransmitter in the brain. By stimulating Ca(2+)-mobilizing receptors, ACh, through G-protein(s), stimulates phospholipase C and causes the hydrolysis of a membrane phospholipid, phosphatidylinositol-4,5-bisphosphate to two second messengers, inositol-1,4,5 trisphosphate (ins-(1,4,5)-P3), and diacylglycerol. Ins-(1,4,5)-P3 is important in cholinergic neuronal stimulation, and injury. Cholinergic agonists cause tonic clonic convulsions which may be either transient or persistent. Even short-term cholinergic convulsions may be associated with neuronal injury, especially in the basal forebrain and the hippocampus. Cholinergic-induced convulsions also elevate levels of brain Ca2+ which precede neuronal injury. Female sex and senescence increase the sensitivity of rats to cholinergic excitotoxicity. Even if cholinergic-induced brain phosphoinositide signalling is likely to trigger cholinergic excitotoxicity, several other processes may be involved in the ensuing neuronal injury. Once initiated, cholinergic convulsions cannot be stopped with cholinergic antagonists such as atropine even though they are effective when given prior to a cholinergic agonist. However, glutaminergic antagonists, and GABAergic agonists, are effective in the attenuation of ongoing cholinergic status epilepticus. Cholinergic brain stimulation may be, in fact, under a partial control of brain GABAergic tonus, but also cause the release of glutamate. Glutamate stimulates inositol lipid signalling in several neuronal cells and, therefore, underlines the significance of inositol lipid signalling in cholinergic-induced excitotoxicity. Moreover, the anatomical distribution of cholinergic brain damage correlates well with that of glutaminergic neurons. Furthermore, glutamate increases neuronal oxidative stress, i.e. it increases the levels of free intracellular calcium, the production of reactive oxygen species, and causes the depletion of neuronal glutathione. The role of excitatory amino acids as common mediators of cholinergic excitotoxicity may offer new insights into the neurotoxic consequences of cholinergic neuronal stimulation. PMID- 7854584 TI - Lead-induced alterations in rod-mediated visual functions and cGMP metabolism: new insights. AB - Long-term scotopic (rod-mediated) visual deficits following developmental lead exposure occur in monkeys and hooded rats. This report describes and summarizes previous ERG and biochemical findings, presents new biochemical data aimed at determining the mechanism of inhibition of lead on rod cGMP-PDE, presents an integratory framework for understanding the ERG and cGMP results and speculates on the implications of the present data. A- and b-wave voltage-log intensity and latency-log intensity functions, generated from single-flash ERGs in fully dark adapted rats, revealed that low and moderate level lead exposure caused decreases in absolute sensitivity and amplitude, and increases in latency. Rod- and cone mediated flicker fusion frequency measures revealed selective rod deficits in temporal resolution. In addition, the slope of the increment threshold function was decreased, but only at scotopic adapting backgrounds, and dark adaptation was delayed. Prior exposure to lead produced a dose-response inhibition of retinal cGMP-phosphodiesterase (PDE) resulting in an increase in cGMP in dark-adapted and light-adapted states and an increase in the calcium content of rods. In vitro experiments with adult rat retinas incubated with 10(-9) to 10(-4) M Pb2+ revealed a concentration-dependent inhibition of cGMP-PDE which suggested that Pb2+ directly inhibited the rod cGMP-PDE. This was confirmed in experiments conducted with isolated, purified, trypsin-activated bovine rod cGMP-specific PDE exposed to 5 x 10(-8) to 10(-4) M Pb2+. The cGMP data are entirely consistent with the observed ERG changes. The ERG data is relevant to low level pediatric lead poisoning since rat rods are similar to human rods. Finally, since a lesion in the gene that codes for a cAMP-PDE leads to defective learning and memory in the Drosophila dunce flies, it is possible that lead-induced alterations in cyclic nucleotide phosphodiesterases contribute to the long-term CNS deficits produced by developmental lead exposure. PMID- 7854585 TI - Compensatory changes in the hippocampus following intradentate infusion of colchicine. AB - Direct infusion of colchicine into the dentate gyrus of the hippocampus kills granule cells and elicits behavioral, neurochemical and neuroanatomical changes. Colchicine-treated rats are less sensitive to the behavioral effects of cholinergic muscarinic receptor antagonists and more sensitive to cholinergic agonists. These behavioral changes are associated with time- and dose-dependent alterations in the cholinergic signal transduction mechanism. Carbachol stimulated turnover of phosphoinositides is increased in the hippocampus of colchicine-treated rats; similar changes are not observed in the cortex or striatum of colchicine-treated animals. Intradentate colchicine produces a significant increase in choline- acetyltransferase activity and staining for acetylcholinesterase activity in the hippocampus, suggesting reactive synaptogenesis of cholinergic fibers. Other studies have shown that the integrity of the septohippocampal pathway is necessary for these colchicine-induced compensatory changes to occur. It is suggested that the mechanism for these neurochemical changes in colchicine-treated animals may be occurring via alterations in negative feedback control of receptor-G-protein-mediated phosphoinositide hydrolysis. PMID- 7854586 TI - Synaptic protein phosphorylation changes in animals exposed to neurotoxicants during development. AB - Protein phosphorylation represents a key process by which neuronal function is regulated by first messengers interacting with extracellular membrane receptors. Protein kinases transfer the phosphate group from ATP to neuron specific proteins and phosphatases, catalyzing the removal of the phosphate group, shut off the signal by restoring the reactive form of the protein. These phosphorylation processes seem to be particularly important in long-term changes which follow sustained activation of neurons. Particular importance has been given to the Calcium/phospholipid-dependent protein kinase (PKC) as the molecular mechanism in synaptic plasticity associated with learning and memory. We have studied the changes of PKC activity in an animal model of impaired cognitive functions as a consequence of an exposure during embryonic life to an antimitotic agent, methylazoxy-methanol acetate (MAM). Treatment at gestational day (GD) 15 results in offspring showing a dose-dependent reduction in the size of cortex and hippocampus. When adult, these animals show impairments in several tests for learning and memory. In hippocampal slice preparations from MAM-treated rats, Long-Term Potentiation could not be induced in the CA1 region, the area affected by the treatment. However, in the hippocampal dentate gyrus, an area not affected by the treatment, LTP could be induced. Moreover, these animals show area specific changes in the phosphorylation state of the protein B-50/GAP-43, a well characterized neuron specific substrate for PKC. By changing the time of MAM exposure, i.e. at GD19, a different pattern of brain damage occurs and this results both in a different pattern in behavior and B-50 phosphorylation.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7854587 TI - Excitotoxins in foods. AB - Evidence is reviewed pertaining to excitatory neurotoxins (excitotoxins) encountered in human food supply. The most frequently encountered food excitotoxin is glutamate (Glu) which is commercially added to many foods despite evidence that it can freely penetrate certain brain regions and rapidly destroy neurons by hyperactivating the NMDA subtype of Glu receptor. Hypersensitivity of NMDA receptors during development makes the immature nervous system especially sensitive to Glu excitotoxicity. On the other hand, elderly consumers are particularly sensitive to domoic acid, a powerful excitotoxic Glu analog that activates both NMDA and non-NMDA receptors. A high content of domoic acid in shell fish caused a recent food poisoning incident that killed some elderly victims and caused brain damage and memory impairment in others. Neurolathyrism is a crippling neurodegenerative condition associated with ingestion of a legume that naturally contains BOAA, an excitotoxic Glu analog that hyperactivates non NMDA receptors. Thus, the human food supply is a source of excitotoxins that can damage the brain by one type of mechanism to which immature consumers are hypervulnerable, or by other mechanisms to which adult and elderly consumers are peculiarly sensitive. PMID- 7854588 TI - Recent advances in the study of mechanism of action of marine neurotoxins. AB - A variety of marine neurotoxins exert potent and specific actions on neuronal sodium channels. Tetrodotoxin and saxitoxin block the sodium channel selectively without any effect on other types of voltage-activated and transmitter-activated ion channels. They bind to a site near the external orifice of the sodium channel on a one-to-one stoichiometric basis. The block is influenced by the membrane potential in a complex manner, and binding and penetration of calcium ions to the sodium channel appear to be responsible for the voltage-dependent block. Owing to the potent and specific sodium channel blocking action, tetrodotoxin and saxitoxin have been used extensively in various studies of ion channels. The dorsal root ganglion neurons of the rat are endowed with tetrodotoxin-sensitive and tetrodotoxin-resistant sodium channels. The latter is also resistant to saxitoxin. These two types of sodium channels exhibit different physiological and pharmacological profiles. Tetrodotoxin-resistant sodium channels are slower in time course and open and inactivate at less negative membrane potentials than tetrodotoxin-sensitive sodium channels. Lidocaine blocks tetrodotoxin-sensitive sodium channels more potently than tetrodotoxin-resistant sodium channels. However, Pb2+ and Cd2+ block tetrodotoxin-resistant channels more strongly. The pyrethroid insecticide allethrin modifies tetrodotoxin-resistant sodium channels while affecting tetrodotoxin-sensitive sodium channels to a much lesser extent. The differences in pharmacological and toxicological profiles between the two types of sodium channels are deemed critically important in understanding the mechanisms of action of various chemicals in animals. PMID- 7854589 TI - Nutrition and alcohol neurotoxicity. AB - Neurological complications of alcoholism such as Wernicke-Korsakoff syndrome and polyneuropathy often originate from interactive factors involving direct nervous system toxicity of ethanol and nutrient deficiencies associated to heavy drinking. Not all patients are equally susceptible to these disorders and a genetic predisposition to thiamine deficiency has been described in subjects with Wernicke's encephalopathy. At moderate alcohol dosages, nutrient abnormalities may be marginal, inducing no obvious manifestations until other neurotoxic agents are absorbed. Examples are presented illustrating the interaction of ethanol and styrene on brain glutathione metabolism in rats, and cases of methanol poisoning in alcoholics. In these patients, ethanol-induced folate deficiency can potentiate visual toxicity of methanol due to impairment of the folate-dependent pathway involved in formate detoxication. The notion that nutritional deficiencies and ethanol toxicity may act synergistically in the nervous system outlines the importance of adequate nutritional strategies in the treatment of alcoholism and also indicates that methodological flaws may result during experimental studies from failure to control for nutritional variables. PMID- 7854590 TI - Rat and human sensory evoked potentials and the predictability of human neurotoxicity from rat data. AB - The development of comprehensive quantitative models as alternatives to risk assessment based on uncertainty factors will require many steps, among them consideration of the relationships between the health endpoints which are measured in laboratory animals and humans. Sensory evoked potentials are measures of sensory function which can be recorded from many species, including humans, and as such provide an opportunity for examining the extrapolation of neurotoxicity data from laboratory animals to humans. Our research strategy for investigating how well laboratory rat data predict human neurotoxic risk involves comparing parametric stimulus manipulations and drug treatments in both species. Finally, we are comparing results in humans with neurodegenerative conditions, including those induced by neurotoxicant exposure, with animal models. To date, we have focused on pattern-elicited visual evoked potentials (VEPs) recorded from pigmented rats and humans. Parametric manipulations of spatial frequency, temporal frequency and stimulus contrast revealed parallel functions, displaced for differences in absolute sensitivity. Additionally, diazepam produced similar effects in rats and human volunteers. A quantitative cross-species map was developed to illustrate the prediction of human effects from rat data. Exposure to carbon disulfide produced changes in rat VEP-derived contrast sensitivity functions, which resembled psychophysically-measured loss of visual contrast sensitivity in human workers exposed to organic solvents. The results of these continuing efforts should help indicate how well animal electrophysiological measures predict human neurotoxicity. PMID- 7854591 TI - Nuclear magnetic resonance spectroscopy: biochemical evaluation of brain function in vivo and in vitro. AB - Nuclear magnetic resonance spectroscopy (MRS) offers a unique opportunity to monitor mmolar concentrations of high energy phosphates, glucose, lactate and amino acids. The possibility of obtaining information about chemical constituents noninvasively is of great importance. MRS and chemical shift imaging (CSI) are emerging as tools for tumor grading, monitoring of treatment, ischemia research, in pediatric research for follow-up of children with borderline mental retardation, for defining brain death and to define epileptic foci. It is important to know which cell type (neuronal or glial) shows changes as a result of external manipulations (e.g. excitotoxins) or internal changes (brain pathology). Metabolic studies have been carried out on brain cell cultures. By using 13C labeled glucose and acetate in combination with 13C MRS it was shown that astrocytes release lactate, glutamine, citrate and alanine and that cerebral cortical neurons use glutamine released from astrocytes as a precursor for GABA synthesis. An important feature in MRS is the localization of N-acetyl aspartate in neurons, since this enables monitoring of neuronal reactions, such as survival after neurotoxic insults. Recent advances have yielded high speed functional echo planar imaging (EPI) techniques that are sensitive to changes in cerebral blood volume, blood flow and blood oxygenation (Functional MRI). During cognitive task performance, local alterations in neuronal activity induce local changes in cerebral metabolism and cerebral perfusion, which can now be detected with MRI. PMID- 7854592 TI - PCBs have a predominantly neurotoxic effect on dissociated cultures of the nervous system. AB - Although their manufacture and use have been restricted or banned in Europe and the United States since the 1970s, polychlorinated biphenyls (PCBs) are still an ubiquitous environmental contaminant whose low-term effects are as yet not completely clear. Clinical case studies of patients with occupational exposure report cognitive impairment and peripheral neuropathy. In our defined nerve cell culture models in which we use pure neurons, pure glia and mixed cultures prepared from dorsal root ganglia of chick embryos we observed a neurotoxic effect after the application of a PCB compound (Clophen). It was only at higher concentrations that an additional gliatoxic effect could be observed. PMID- 7854593 TI - Acute exposure to acetone in a factory and ratings of well-being. AB - Eight workers occupationally exposed to acetone and eight nonexposed controls were investigated on nine shift days both during work and leisure. The mean exposure to acetone was near 1000 ppm (2400 mg/m3). Acetone in urine was moderately correlated to acetone in the air. Ratings on scales of well-being and acute symptoms (SPES) correlated significantly with concentrations of acetone in urine but not with concentrations of acetone in the air. PMID- 7854594 TI - Heterogeneity of effects of ethanol ingestion on postural stability as measured by two devices. AB - Measurement of postural stability has been used to assess effects of exposure to selected neurotoxicants. Its widespread application has been limited by several factors, including the use of cumbersome, expensive measurement systems and limited demonstration of sensitivity for detecting neurotoxicity. Recently, a less expensive, portable device for assessing postural stability via measurement of head position has been developed and used in some field studies. Although this head position monitor (HPM) is commercially available, no validation information for it has been published. To evaluate the HPM's utility, it was compared to a force platform (FP) system in an ethanol experiment. Ten adult male subjects were given 0.5 ml/kg ethanol and placebo using a counterbalanced, cross-over design. Stability measurements were made immediately prior to administration of alcohol or placebo and at fifteen minute intervals for two hours following administration. At each time interval, stability was monitored during two eyes open trials alternated with two eyes-closed trials, each of 60-second duration. On a group basis, marginally significant effects of alcohol consumption consistent with results of other published studies were observed with both devices. The maximum increase in speed of sway occurred at 15 minutes post ethanol ingestion for the eyes-closed condition. Specifically, sway speed increased from 1.11 cm/sec pre-ingestion to 1.50 cm/sec 15 minutes post-ingestion for the HPM, and from 1.81 m/sec to 2.13 cm/sec for the FP. No significant increase in sway speed was observed for the eyes-open condition. These groups differences obscured substantial heterogeneity of response to ethanol among the ten subjects, i.e., only two of the 10 subjects showed an observable increase in sway speed following ethanol ingestion.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7854595 TI - Astrocytes as targets for CNS effects of organic solvents in vitro. AB - The aim of the study was to evaluate astrocytes in vitro as a model for studies of solvent neurotoxicity. Primary astrocyte cultures were established from newborn rat cerebella. The cells were cultured in the modified Minimum Essential Medium (MEM), and the neural membranes isolated from cultures were exposed to solvents in incubation mixtures containing different solvent concentrations (3, 6, and 9 mM) for one hour. The activity of membrane-bound total ATPase was determined after exposure to aromatic hydrocarbons (benzene, toluene, xylene, styrene and ethylbenzene), and to n-hexane and cyclohexane. The enzyme activities were decreased by aromatic hydrocarbons linearly according to the log dose and in order to the log lipid/water partition coefficients, benzene having the smallest and ethylbenzene the greatest effect in all concentrations studied. Cyclohexane caused much smaller enzyme inhibition (18% of control activity in 9 mM concentration) than ethylbenzene (67% in 9 mM), in spite of very similar partition coefficients. N-hexane had clearly slighter enzyme inhibiting effect than aromatic hydrocarbons, in spite of its markedly greater lipophilicity. In addition to lipophilicity, the structure of solvent molecule seems to be important when considering the CNS toxicity. These results suggest that organic solvents exert their toxic effects on CNS, at least in part, by disturbing ATPase dependent astrocytic regulatory functions. PMID- 7854596 TI - Neurobehavioral effects of long-term exposure to xylene and mixed organic solvents in shipyard spray painters. AB - A cross-sectional study was performed in shipyard painters exposed to organic solvents and age-matched referents. The work duties of the painters mainly involved spray painting with solvent-based paints containing > 50% xylene. Testing methods consisted of a symptoms questionnaire, measurement of peripheral sensory and motor nerve parameters and computerized performance tests. Results indicate that complaints regarding mood changes, equilibrium and fatigue were more severe in painters than in referents, but were not related to the estimated life-time exposure index. Decreased nerve function was observed in the lower extremities and to some extent in the upper extremities. The refractory period appeared to be a sensitive parameter in motor nerves. Most neurophysiological parameters investigated were significantly related to the exposure index. Behavioral testing revealed impairment of simple visuo-motor performance and complex perceptual coding. A relationship between effects on perceptual coding and the exposure index was also demonstrated. PMID- 7854597 TI - Persistent effects of 80 ppm toluene on dopamine-regulated locomotor activity and prolactin secretion in the male rat. AB - Neurotoxicology 15(3): 621-624, 1994. In the present study we have investigated the effects of toluene exposure (80 ppm, 4 weeks, 5 day/week, 6 h/day) on the serum levels of prolactin, and elaborated our earlier findings about persistent effects of toluene exposure on apomorphine-induced (1 mg/kg, s.c.) locomotor activity. We found that the serum levels of prolactin were increased by 67% in the toluene-exposed rats, as analyzed 17 days after the last exposure. The locomotor activity counts of the control rats were not normally distributed before log-transformation, since most rats showed a low level of activity and only a few showed a very high activity level. The toluene-exposed rats showed a higher level of apomorphine-induced locomotion and motility but not rearing, as analyzed 17 days after the last exposure, whereas spontaneous locomotor activity was unaffected. These results indicate that subacute exposure to 80 ppm of toluene causes persistent impairments in dopamine-mediated neurotransmission. PMID- 7854598 TI - Electroretinal responses are modified by chronic exposure to trichloroethylene. AB - Using an inhalation chamber, New Zealand albino rabbits were exposed to 350 ppm (n = 6) and 700 ppm (n = 8) of trichloroethylene (TRI) 4 hrs/day, 4 days/week for 12 weeks. Electroretinograms (ERG) and oscillatory potentials (OPs) were recorded weekly under mesopic conditions. Blood samples were also collected weekly to determine the concentration of TRI and its main metabolites. Recordings from the 350 and 700 ppm exposed groups showed a significant (p < 0.01) increase in the amplitude of the a- and b-waves (ERG), while the amplitude of the OPs was significantly (p < 0.01) decreased at 350 ppm and increased at 700 ppm. These electroretinal changes were reversed to the baseline value within six weeks after the inhalation stopped. The observed variations in a-wave and OP amplitudes were related to plasmatic level of trichloroethanol, while the effects on the b-wave were related to the blood level of TRI. These results confirm the neuro ophthalmotoxicity of TRI and support the hypothesis that trichloroethanol is the major neurotoxic metabolite of TRI. PMID- 7854599 TI - Neurotoxic lesion of oculomotor neruons: evidence for rearrangement of axon terminals of surviving afferent neurons. AB - The fate of abducens internuclear neurons was studied after the loss of their target medical rectus motoneurons of the oculomotor nucleus in adult cats. Target motoneurons were killed by injecting ricin, a toxin lectin, into the medial rectus muscle of the eye. The entire population of abducens internuclear neurons survived the loss of target for a long time (1 year), although they exhibited an initial critical period after target loss characterized by a marked reduction of afferent synaptic transmission. One month later, the normal parameters of synaptic transmission resumed. In contrast, the density of axonal terminals of abducens internuclear neurons in the oculomotor nucleus progressively decreased during the year following target loss. Evidence is presented for the reinnervation of a new neuronal target within the oculomotor nucleus that might support both the long-term survival and the recovery of physiological characteristics in the abducens internuclear neurons. PMID- 7854600 TI - Olfactory adaptation, threshold shift and recovery at low levels of exposure to methyl isobutyl ketone (MIBK). AB - The anatomic position of olfactory receptors renders them vulnerable to airborne pollutants. Chamber inhalation studies have shown dose-dependent olfactory adaptation and temporary olfactory threshold perception shift for particular inhaled substances. The present study was undertaken to examine olfactory perception threshold (OPT) and adaptation of healthy subjects exposed for 7h to MIBK. Volunteers (n = 4) were exposed in an inhalation chamber to MIBK at concentrations of 20 ppm and 40 ppm. For each of 6 exposure days, OPT for MIBK and PM-Carbinol were determined once before exposure and at 3 successive intervals following exit. Exhaled air samples were taken at regular intervals during and after exposure. Perceived odor intensity and symptoms were ascertained through a questionnaire filled out hourly. On all days, post-exposure OPT-MIBK at chamber exit was significantly higher than pre-exposure, representing a ninefold increase in concentration; recovery was dose-dependent and not complete 95 min. after exit. No threshold shift was observed for OPT-PM-Carbinol. Perceived odor intensity was high when entering the chamber, but diminished with time, stabilizing after approximately 2 hours. Symptoms of nose, eye or throat irritation and headache were present in some subjects. The findings of this study suggest that at these levels of MIBK, there is olfactory adaptation during exposure and a transient OPT shift for the inhaled substance. Persons exposed professionally or environmentally to certain organic solvents may suffer temporary smell loss which hinders odor detection. PMID- 7854601 TI - The toxicity of IDPN on the vestibular system of the rat: new insights on its effects on behavior and neurofilament transport. AB - 3,3'-Iminodipropionitrile (IDPN) causes a permanent syndrome of abnormalities in spontaneous behavior and a deficit in the axonal transport of neurofilaments (NF). Male Long-Evans rats were given IDPN (0, 200, 400, 600, or 1000 mg/kg, ip, in saline) and assessed for behaviors indicative of vestibular function at 1 week post-dosing. The morphology of the peripheral vestibular system in animals dosed with 0, 200, 400, 600, 800, or 1000 mg/kg of IDPN was assessed at 4 days post dosing by light microscopy on semithin sections. Animals receiving 1000, 1500, or 2000 mg/kg of IDPN were assessed for morphological alterations in the vestibular ganglion at 8 days post-dosing. Behavioral data indicated a dose-dependent loss of vestibular function after IDPN, the vestibular deficits first appearing at the 400 mg/kg dose level. IDPN exposure was also observed to result in degeneration of the vestibular sensory hair cells. Degenerative changes were already found at the 400 mg/kg dose level, and were extensive after 1000 mg/kg. In the ganglion neurons, no effects were observed after 1000 mg/kg of IDPN, but perikaryal accumulations of NF were found after 1500 or 2000 mg/kg. In conclusion, the data showed that low doses of IDPN are toxic to the vestibular hair cells, and suggest a link between this action and the effects of the chemical on spontaneous behavior. In addition, doses of IDPN larger than those required for toxicity to the vestibular sensory cells, induced accumulations of NF in the myelinated cell bodies of the vestibular ganglion neurons.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7854602 TI - Induction of trimethyltin neurotoxicity by dietary administration. AB - Groups of 12 male and 12 female rats were fed diets containing 0 or 8ppm trimethyltin chloride for up to 25 days. All the animals were observed prior to the study start and daily throughout the study for any changes in clinical condition. In addition, detailed clinical observations, including quantitative assessments of landing foot splay, sensory perception, muscle weakness and locomotor activity were monitored during the study. At the end of the study, the rats were killed and subjected to a full Post-mortem. Selected nervous system tissues were removed, processed and examined microscopically. Clinical signs typical of trimethyltin neurotoxicity (e.g. aggression, shaking and convulsions) were seen in rats receiving diets containing 8ppm trimethyltin chloride for as little as 22 days. Neuropathological lesions consisting of extensive neuronal cell necrosis in the limbic region of the brain, vacuolar degeneration of ventral horn cells of the spinal cord and a marginal increase in Wallerian-type degeneration were seen. The study demonstrates that trimethyltin neurotoxicity can be induced by dietary administration and that both male and female rats are equally sensitive. PMID- 7854603 TI - Diadochokinesimetry: a study of patients with Parkinson's disease and manganese exposed workers. AB - Diadochokinesia, the ability to perform rapid alternating movements is often impaired in patients with extrapyramidal disease. It is a common sign among patients with Parkinsonism or manganism. In the present study we compare patients with Parkinson's disease (n = 11), workers formerly exposed to manganese (n = 10) and control subjects (n = 11) performing rapid alternating hand movements for 5 s under four conditions repeated twice (natural cadence and maximal speed with one or two hands). Data recorded using a diadochokinesimeter built in our laboratory and connected to a 486/33 microcomputer were digitized in real time while subjects rotated back and forth hand held foam spheres connected to flexible rods articulated with optical encoders. Significant differences were found between control subjects and patients with Parkinson's disease, but not with manganese exposed workers, in most variables examined. However, trajectory length (a combination of movement amplitude and velocity) indicated that manganese exposed workers and patients with Parkinson's disease were significantly different from the controls in functional asymmetries between right and left hand. In addition, workers and patients tend to have marked differences between the performance of right and left hands. Improved quantitative measurement of rapid alternating movements may prove to be an important tool in early and differential diagnosis of Parkinson's disease and manganese exposure. PMID- 7854604 TI - Developmental delay of astrocytes in hippocampus of rhesus monkeys reflects the effect of pre- and postnatal chronic low level lead exposure. AB - Rhesus monkeys were pre- and postnatally exposed to lead-acetate at 0, 350, or 600 ppm in diet for nine years, followed by a period of lead-free diet for 32 months. During this time blood lead levels declined to normal, but still showed dose-related differences. In behavioral and neurophysiological studies the rhesus monkeys exhibited dose-related cognitive and functional deficits. After sacrifice hippocampal sections were processed for immunohistological staining. GFAP, introduced as a marker of neurotoxicity and Vimentin, which is expressed by immature or reactive astrocytes were investigated. A dose-dependent increase of GFAP due to prenatal and chronic low level lead exposure was not observed. We found a dose-related increase of GFAP-positive radial glia and star-shaped Vimentin-positive astrocytes in the high lead group. We consider these findings as indication of immature astrocytes, which are not able to react with gliosis in respond to pre- and postnatal low level lead exposure. The lack of pronounced glial response due to low level lead exposure may result in a delay of astrocytic differentiation, shown by persistence of radial glia. PMID- 7854605 TI - Using psychological tests for the early detection of neurotoxic effects of low level manganese exposure. AB - The neurotoxic effects from chronic exposure to high concentrations of manganese dust are well known from studies of highly exposed miners, as well as from numerous clinical reports. The very first of these reports dates back to the early 19th century (Couper, 1837). A thorough review of the toxicity of manganese was provided by the WHO in 1981 (WHO, 1981). It is evident from these early reports that the critical effect from manganese exposure, i.e. the effect used in the establishment of environmental exposure criteria, is the effect on the central nervous system (CNS). Furthermore, impaired motor functions are clearly central to the manganese syndrome (WHO, 1981). It is also obvious from the clinical knowledge gathered over the years, that once the neurotoxic effects from manganese exposure are openly manifested at the clinical level, the damage to the CNS is essentially irreversible, and may, in some cases, be progressive. For this reason, detection of early signs of Mn exposure is fundamental to the prevention of chronic neurotoxic illness in manganese exposed populations. Very few investigations have been studying early signs of manganese toxicity by the use of behavioural methods in groups of active workers before the onset of clinically observable problems. To our knowledge, there are only four studies reported using behavioural measures to explore possible CNS effects from current industrial levels of manganese exposure in asymptomatic populations (Siegl and Bergert, 1982; Roels et al., 1987; Iregren, 1990; Roels et al., 1992).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7854606 TI - Effects of occupational lead exposure on motor and somatosensory evoked potentials. AB - In order to objectivate the effects of inorganic lead compounds on the nervous system, 17 men occupationally exposed have been recorded for Motor Electric Potentials (MEPs) of the abductor policis brevis muscles with transcranial, cervical root and peripheral electrical stimulations, for Somatosensory Evoked Potentials (SEPs) of median and tibial posterior nerves, and for Electromyography (EMG). Considering each subject, 16 out of the 17 lead exposed ones exhibited electrophysiological abnormalities, occurring at both peripheral and central levels for the somatosensory as well as for the motor systems. As compared to a normal control group, the lead exposed one showed decreased sensory and motor peripheral conduction velocities, increased motor central conduction time, and delayed cortical P22 SEPs component that could be interpreted as a sensory-motor cortical dysfunction. The respective contributions of MEPs and SEPs are compared to clinical, biological and EMG examinations in the evaluation of the neurotoxic effects of inorganic lead compounds. PMID- 7854607 TI - Effects of chronic low level lead exposure on the expression of GFAP and vimentin mRNA in the rat brain hippocampus analysed by in situ hybridization. AB - In this study we used in situ hybridization to examine the effects of chronic low level lead toxicity during different periods of brain development. Low level lead is known to affect astroglia. GFAP and Vimentin were chosen as glialtypic markers for neurotoxicity. The effects of lead were investigated on male Wistar rats. Animals were divided into four groups: a control group, a permanent group exposed during gestation, lactation and post-weaning (E0-P100), a perinatal group exposed during gestation and postnatally until weaning (E0-P16), and a post-weaning exposed group (P16-P100). All experimental animals were fed a diet containing 750 ppm lead acetate. With respect to Vimentin mRNA no major differences could be detected among the treatment groups. Significant differences in GFAP mRNA levels were detected in the post-weaning group relative to controls. In this group we observed a strong increase of GFAP mRNA in the polymorphic zone of the dentate gyrus and in the CA1 region of the hippocampus. Permanent and perinatal groups showed no overt changes compared to controls. Our findings suggest that an irritation of the mature astrocyte results in a change from the quiescent to the reactive state. The majority of astrocytes that have been exposed during their development and differentiation fail to react even if the exposure is continued to adulthood. This suggests an irreversible insult by low level lead exposure during this period of time. PMID- 7854608 TI - Prenatal and perinatal low level lead exposure alters brainstem auditory evoked responses in infants. AB - Wave III latency and the III-V interpeak interval of brainstem auditory evoked responses in infants in the first weeks of life decreased and increased, respectively, in association with mid-pregnancy maternal blood lead levels (2.5 35 micrograms/dl) in a group of 30 prospectively followed healthy pregnancies and deliveries. The rapid myelination of brainstem auditory pathways occurring around mid-pregnancy and the lengthening of the III-V interpeak interval with increased mid-pregnancy maternal lead suggest that brain structures involved in spatial localization of sound may be compromised by prenatal lead exposure. The data also indicate that maternal blood lead measurements during pregnancy provide an adequate surrogate index of fetal exposure. PMID- 7854609 TI - Low-dose glutathione administration in the prevention of cisplatin-induced peripheral neuropathy in rats. AB - So far various drugs have been used in an attempt to prevent or reduce cisplatin (CDDP)-induced peripheral neuropathy. Of those tried reduced glutathione (GSH) is one of the most promising. Its effectiveness has already been demonstrated by means of morphological methods in CDDP-treated rats in which high doses of GSH (up to 1200 mg/kg) were given. In the current study neurophysiological and morphological methods were used to evaluate the effect of low doses (150-300 mg/kg) of GSH i.p. on the peripheral nervous system of the rat. Four groups of 8 female Wistar rats were treated as follows: (A) CDDP 2 mg/kg i.p. weekly for 9 courses; (B) same as (A) plus GSH 150 mg/kg i.p. weekly; (C) same as (A) plus GSH 300 mg/kg i.p. weekly; (D) same as (A) plus GSH 150 mg/kg i.p. on the day of DDP injection followed by 150 mg/kg/day over the next 2 days. Eleven age-matched untreated rats were used as controls. Sensory conduction velocity was recorded in the tail nerve and morphologic and morphometric examinations were performed on the dorsal root ganglia neurons (L4-L6) in each animal. The results demonstrated that the neurophysiological and pathological changes induced by CDDP administration were less severe in rats co-treated with GSH. No significant differences could be related to the 3 different regimens of GSH co-treatments. This experiment confirms that GSH is able to reduce the neurotoxicity of CDDP and that it is effective even at doses as low as those used in the present study. PMID- 7854610 TI - Neurobehavioral and neurophysiological observations in six year old children with low lead levels in East and West Germany. AB - Within a larger comparative environmental health screening program in East and West Germany neurobehavioral and neurophysiological measures were taken in 367 six year old children in Leipzig (N = 179), Gardelegen (N = 68), and Duisburg (N = 120). Lead concentrations from venous blood samples (PbB) and from deciduous teeth (PbT) were measured as markers of environmental lead exposure by electrothermal AAS. Dependent variables included four subtests from NES1 (tapping, reaction time, pattern comparison, and Benton visual retention), as well as VEP-latencies (N2, P100, N3) evoked by checkerboard patterns of different size and contrast. The overall median blood lead-concentration was 5 micrograms/dl (range: 1.3-19.0 micrograms/dl), and the corresponding tooth lead concentration was 2 micrograms/g (0.2-14 micrograms/g). The 95-percentile of the overall frequency distribution for PbB was below 10 micrograms/dl. Associations between markers of lead-exposure and neurobehavioral or neurophysiological outcome were assessed by means of multiple linear or logistic regression analyses. After adjusting for relevant confounders/covariates significant (p < 0.05) Pb-related deficit was found for tapping and pattern recognition with respect to PbB but not PbT. No such associations could be established for VEP latencies. These results are compatible with the hypothesis that subtle neurobehavioral dysfunction in children may be associated with very low PbB. PMID- 7854611 TI - Long-term treatment of aggregating brain cell cultures with low concentrations of lead acetate. AB - Aggregating brain cell cultures were used as a model to study the effect of chronic exposure to low levels of lead acetate. Long-term maintenance of cultures could be improved by supplementation of the medium with albumin-bound lipids. Exposure for 9 days to 10(-6)-10(-4) M lead acetate caused a decrease of GABAergic (glutamic acid decarboxylase) and astrocytic (glutamine synthetase) markers which was also found after prolonged treatment (50 days) with 10(-7) M lead acetate. Total protein content and choline acetyltransferase were not changed. The results show that prolonged exposure of aggregating brain cell cultures to a low concentration of lead acetate causes distinct changes of cell type-specific parameters. PMID- 7854612 TI - Aftermath of a chemical spill: psychological and physiological sequelae. AB - Psychological, and psychophysiological sequelae were studied in a community which had experienced a railroad chemical spill of 19,000 gallons of the toxic pesticide metam sodium. Information was collected on 350 persons living in the area of the spill (spill residents) and 114 nonexposed controls, recruited using a randomized sampling strategy, from a nearby similar, but unexposed control town. Psychological measures used were the MMPI-2, POMS, IES Scale, Environmental Worry, Perceived Social Support and Perceived Control Scale. Physiological measurements were two measurements of blood pressure, pulse, and salivary cortisol level, taken both at the beginning and the conclusion of the study. Demographic and medical information was asked in a Questionnaire. Results indicate greater levels of depression, anxiety, and somatic symptoms in the spill residents in addition to greater environmental worry and lower perceived social support. Spill odor perception was related to increased psychological and physiological sequelae. The spill residents had higher blood pressure and less fluctuation of cortisol levels than the controls. Comparison of spill residents who were litigants and those who were not, indicates no differences for blood pressure, pulse, and cortisol, MMPI-2, Environmental Worry and the Control Scale. Litigants scored slightly higher on the IES, Intrusion and the POMS scales. No dose/response relationship between distance to the river and evacuation status was obtained. The chemical spills was associated with a wide variety of psychological and physiological reactions. PMID- 7854613 TI - EEG changes caused by dimethoate treatment in three generations of rats. AB - Wistar rats were continuously treated with 7.0, 10.5, 14.0, 28.0 mg/kg (1/100, 1/75, 1/50 and 1/25 LD50) of dimethoate per os including the pregnancy of dams and the lactation period of pups as well as in adulthood for three subsequent generations. The EEG of male rats of each generation was recorded at the age of 12-13 weeks. The mean frequency, mean amplitude, EEG index and the power spectrum were analysed. The data showed that the overall EEG activity of the treated rats was greater than of the controls. The mean frequency was higher, the mean amplitude and the EEG index were lower, the activity of the lower frequency wave bands decreased, that of the higher frequency wave bands increased. The changes of the mentioned EEG parameters were most pronounced in the third generation. PMID- 7854614 TI - Altered modulation by excitatory amino acids of cortical phosphatidylinositol system stimulated by carbachol in rats poisoned by an anti-cholinesterase compound, diisopropyl fluorophosphate. AB - The effects of glutamate and N-methyl aspartate (NMDA) on carbachol-induced inositol phosphate (IP) accumulation were evaluated in slices of the cerebral cortex of rats treated with diisopropyl fluorophosphate (DFP) for 2 weeks. This induced an about 75% inhibition of cholinesterases. The IP accumulation induced by carbachol (expressed as ratio stimulated/basal IP content) was lower in DFP rats than in controls when incorporation of [3H]-myoinositol into membrane phospholipids and their hydrolysis were measured (no washing step between labeling and hydrolytic incubation). There were no differences in carbachol induced IP accumulation between control and DFP rats when only phosphoinositide hydrolysis was determined (hydrolytic incubation of prelabeled washed slices). When both incorporation of [3H]-myoinositol and the hydrolysis were measured, 0.5 mM glutamate and 0.1 mM NMDA caused a significant, about 40%, decrease of carbachol-induced IP accumulation in control rats; the inhibitory effects of glutamate and NMDA were not significant in DFP rats. When only hydrolytic IP accumulation by carbachol was studied, the inhibitory effects of glutamate and NMDA were very similar in control and DFP rats. Additional experiments on inositol phospholipid synthesis showed a significantly lesser [3H]-myoinositol incorporation (by about 30%) in DFP rats. This may explain the differences between the results obtained by the two methods. The overall data suggest that the attenuation of glutamate and NMDA effects in DFP-rats depends on a decrease of carbachol-induced IP accumulation or phosphoinositide synthesis rather than on the EAA specific action. PMID- 7854615 TI - Changes of brain evoked potentials caused by dimethoate treatment in three generations of rats. AB - Wistar rats were continuously treated with 7.0, 10.5, 14.0, and 28.0 mg/kg (1/100, 1/70, 1/50 and 1/25 LD50) of dimethoate per os including the pregnancy and lactation periods for three subsequent generations. The somatosensory, visual and auditory evoked brain potentials of male rats of each generation were registered at the age of 12-13 weeks with silver electrodes placed on the primary somatosensory, visual and auditory cortex. The measured parameters were the latency and duration of the evoked potentials. There were differences in the changes among the various evoked potentials in all of the generations. The strongest effect caused by dimethoate was seen in the case of the somatosensory evoked potentials compared to the control. The changes of the visual and auditory evoked potentials were milder. Comparing the changes of the evoked potentials of the three generations it was found that there were no significant changes between the data of the three populations. PMID- 7854616 TI - On the neurotoxicity of systemically administered putrescine: influence of kinetic factors. AB - Putrescine (PUT) given ip to male rats produced a dose-dependent behavioural response. The observed signs were mainly shaking behaviour and motor disorders. The severity of the motor signs closely correlated with cortical PUT levels. After [14C]-PUT, the levels of related radioactivity ([14C]-PUTrr) in frontal cortex paralleled the levels of tracer in blood. Furthermore, the levels of tracer in blood and in frontal cortex were higher in the animals with toxicity signs than in non-affected ones. The frontal cortex levels of polyamines determined by HPLC revealed that only PUT paralleled the severity of the clinical status of the rats. No modifications of spermidine (SD) or spermine (SM) content were detected. Two hours after [14C]-PUT administration, only about 30% of the cortical [14C]-PUTrr was analyzed as PUT itself and no radioactivity was detected as SD and SM. Our results suggest that the radioactivity not associated to PUT could be related to more polar metabolites than SD or SM as acetylated derivatives. PMID- 7854617 TI - Multiple interferences on catecholamine metabolism by tetrahydroisoquinolines (TIQs). AB - TIQs are thought to be formed by condensation between dopamine and certain metabolites of ethanol, organic solvents and anesthetic gases. Described here are experiments aimed at evaluating TIQs interference with catecholamine synthesis. Rat adrenal pheochromocytoma (PC12) cell lysates were exposed to benzyl-TIQ and phenyl-TIQ. The activities of tyrosine hydroxylase (TH) and dopamine beta hydroxylase (DBH) were measured by HPLC-based methods following exposure to variable concentrations of TIQs. The effects of TIQs on DBH activity were also assessed in human serum. Dixon plot analyses revealed that TIQs act on TH as competitive inhibitors with different affinity. Ki for benzyl- and phenyl-TIQ were 5 and 3 microM respectively. DBH activity in serum exposed to benzyl- and phenyl-TIQ ranging from 0.2 to 20 microM rose respectively by 12.5% to 58% for benzyl- and by 7.8% to 26% for phenyl-TIQ. Such TIQs interferences with catecholamine metabolism seem to account for dopamine (DA) depletion observed in parallel in vitro experiments on PC12 cells. The dose-dependent inhibition of TH and the increased activity of DBH together with the relatively low effective doses of TIQs suggest this mechanism as a possible explanation of the selective toxicity of styrene and other solvents to dopaminergic systems observed in rabbits following experimental exposure and suspected to occur in occupationally exposed workers. PMID- 7854618 TI - Upregulation of the POMC gene in rats by a neurotoxicant which targets motoneurones. AB - Immunocytochemistry and histochemical in situ hybridisation were used to detect POMC-derived peptides (beta-endorphin and alpha-MSH) and POMC mRNA respectively, in the lumbar spinal cord of adult rats. In normal rats the incidence of ventral horn cells which expressed the peptides or mRNA was negligible. However after treatment with IDPN a neurotoxicant which targets the motoneurones the peptides and POMC mRNA were detectable in over 65% of ventral horn motoneurones. After treatment with 1,3 DNB a neurotoxicant which does not target motoneurones immunostaining for the peptides and mRNA was negligible. Thus chemical intoxication of the motoneurones causes upregulation of the POMC gene. PMID- 7854619 TI - Lipid peroxidation potential and antioxidant status of circumventricular organs of rat brain following neonatal monosodium glutamate. AB - Glutamate (glu), an excitatory aminoacid neurotransmitter is abundantly present in the brain of mammals, as well as in dietary protein. Earlier studies with glu mostly involved histopathological and neuroendocrine changes in the blood-brain barrier deficient areas of brain following its systemic administration. The present study examined lipid peroxidation potential and anti-oxidant parameters of immature rat mid-brain region which include arcuate nucleus, hypothalamus, and other circumventricular organs (CVO) following their exposure to monosodium glutamate (MSG) neonatally. This compound was administered at a dose of 4 mg/g bwt, sc, for the first ten days of postnatal period. Animals were sacrificed on postnatal day 25, and the lipid peroxidation potential was evaluated. The treatment of MSG significantly increased lipid peroxidation (P < 0.01) as well as the activity of anti-oxidant enzyme catalase (P < 0.025) and significantly depleted total and free sulfhydryl groups (P < 0.05) in the CVO. These results indicate that neonatal MSG treatment produces neuronal damage in the CVO by increasing lipid peroxidation and is in agreement with the hypothesis that excitotoxins may generate free radicals in causing neurotoxicity. PMID- 7854620 TI - Distance learning through computer conferences. AB - Computer conferencing offers a new delivery mode for distance education for nurses. This qualitative study examined the experiences of post-RN students taking a nursing course by computer conference. Initially, the students found the technology frustrating, but once they established contact, they appreciated participating in discussions and scheduling their own learning time. They formed a cohesive, friendly group through the computer system. Comparisons are made among computer conferencing and other distance delivery modes for nurses. PMID- 7854621 TI - Indicators of critical thinking, communication, and therapeutic intervention among first-line nursing supervisors. AB - With the focus of the National League for Nursing on therapeutic intervention, critical thinking, and communication skills, nursing programs are challenged to measure these outcomes for their BSN graduates. The authors report the use of the Critical Incident Technique to identify behavioral indicators of communication, critical thinking, and therapeutic intervention skills from first-line nursing supervisors' descriptions of exemplary nursing practice. PMID- 7854622 TI - May I tape this class? Issues and solutions. AB - Student requests to audiotape classes are increasing as technology advances. Faculty members are faced with making decisions spontaneously without time to consider the ramifications of their responses. The authors identify educational, ethical, and procedural problems encountered in student audiotaping and provide approaches to manage student tape recording in the classroom in a sensitive and ethical way. PMID- 7854623 TI - Health behaviors and academic success. AB - Many educators are interested in ways to help students achieve academic success. The authors determined the relationship between health behaviors and academic success and found that establishing an at-risk profile of health behaviors can assist faculty members in addressing problems that directly influence student performance. PMID- 7854624 TI - Finding voices through writing. AB - Assisting students to find their writing "voices" is another way to emphasize writing as a professional tool for nursing. The author discusses a teaching strategy that required students to write using a variety of styles. Students wrote fables, poetry, and letters, and used other creative writing styles to illustrate their views and feelings on professional nursing issues. Creation of a class book empowered students to see versatility with writing styles can be a powerful communication tool to use with peers, clients, and society. PMID- 7854625 TI - The Americans with Disabilities Act and essential functions in nursing programs. AB - With the recent passage of the Americans with Disabilities Act, the author conducted a study to determine what percentage of BSN nursing programs had a list of essential functions that students must be capable of performing while enrolled. Results showed that the majority of programs have not developed lists and currently do not request information, during the admissions process, related to the applicant's ability to complete the essential functions of the programs, with or without reasonable accomodation. Almost half of the programs surveyed plan to request this information during the admissions process in the future. PMID- 7854626 TI - Guidelines for reducing bias in nursing examinations. AB - As our nation becomes more diversified, many schools of nursing strive to improve the recruitment and retention of English as a Second Language (ESL) and minority nursing students. An important aspect of this commitment to diversity is the reduction of biased items in nursing examinations, with the goal of making the evaluation process fair for all students. The author defines test and item bias, provides examples of biased items, and presents specific guidelines for decreasing item bias in teacher-made nursing examinations. A discussion of the related topic of whether ESL students should be given extended testing time is included. PMID- 7854627 TI - Teaching venipuncture in an outpatient surgery unit. AB - In the spring of 1992, the skill of venipuncture, inserting an intravenous (IV) needle, was added to the last quarter in an associate degree nursing curriculum. After theory and demonstration, 71 graduating students were rotated through an 8 hour venipuncture practice laboratory in an outpatient surgery unit. The instructor worked with a single student to start an IV line on a client. The personalized instructional method and sequencing of events resulted in a positive learning experience. PMID- 7854628 TI - Realistic venipuncture simulation. AB - Both educators and nursing administrators are eager to find instruction methods that prepare practitioners for skillful venipuncture. A second concern, shared by everyone, is providing such instruction in the most cost-effective manner possible. The authors present a plan that enhances the teaching of venipuncture, through stimulation, using inexpensive, easily obtained equipment. PMID- 7854629 TI - Bafa' Bafa': a cultural awareness game. PMID- 7854630 TI - Nursing education on child sexual abuse: a three-tiered strategy. PMID- 7854631 TI - Yes, an Easter egg hunt! PMID- 7854632 TI - IGRO: a unique re-entry program for inactive registered nurses. AB - A unique re-entry program for inactive registered nurses is the Individualized Guided Remediated Opportunity (IGRO) program. This program uses modern technology and strong faculty support to update and prepare inactive registered nurses returning to nursing practice. This type of program can be adapted by other schools of nursing that want to use their learning resources in a creative manner while providing a service for the nursing profession. PMID- 7854633 TI - Perspectives of faculty practice and clinical competence: a trilogy of paradox. AB - The authors present three different views of nursing faculty competence and mandated faculty practice. The first author supports faculty practice as a requirement for educators. The second author believes that too much is expected of nurse educators and asks, "What about life?" The third author, who has devoted more than 30 years to nursing education, attempted to go back to being a staff nurse and failed to "come up to speed." The authors offer the rationale for their positions and suggestions for our readers' consideration. PMID- 7854634 TI - The effect of a mock trial on nursing students' ability to make clinically sound legal judgments. AB - In an attempt to enhance nursing students' abilities to make legally sound clinical judgments, a mock trial experience was developed and evaluated. Using a quasi-experimental design, students' learning was assessed using scenarios derived from actual cases involving nurses. Satisfaction with a traditional learning approach was compared to learning through attendance at a mock trial. A significant difference was found in learning before and after the trial (t = 2.26, P < 0.05), and students preferred the mock trial experience to traditional classroom presentations. PMID- 7854635 TI - An innovative model for clinical teaching. AB - Using traditional approaches, nursing faculty members may find clinical teaching stressful in today's fast-paced hospital settings. The Clinical Teaching Associate Model, pilot tested by an associate and a baccalaureate degree program in three hospitals, enabled staff nurses to assist faculty members in the direct clinical supervision of students. The benefits for students and faculty members and the potential use of the model to design varied clinical experiences for students are discussed. PMID- 7854636 TI - Teaching nursing theory: a walk around the golf course. AB - What do golf courses, shopping malls, and neighborhoods have to do with teaching a graduate level nursing theory course? Walks around familiar places can help students see how the concrete becomes abstract in the process of theory development. Walks also can help students begin to see which elements or concepts are essential to the particular theory being discussed. PMID- 7854637 TI - Essential factors for a healthy RN educational mobility program. AB - There is little research concerning which factors registered nurse (RN) students perceive as constituting a healthy educational mobility program. Because of this, a study was undertaken to identify the factors that RN students perceive as contributing to a healthy educational mobility RN/BSN/MSN program. Findings indicated that the RN students value flexibility, ease in planning, and convenience of course offerings as most important to their program selection. Registered nurse students emphasized the critical factors of faculty sensitivity to students' diverse opinions, faculty respect for students, and faculty expertise as important. These findings highlight the importance of sensitizing faculty members and nurse administrators to the needs of RN students. PMID- 7854638 TI - Implementation of writing-to-learn in a program of nursing. AB - Writing-to-learn (WTL) is a paradigm for coordinating the learning of content with the development of cognitive skills needed to contextualize knowledge. The authors describe the place of writing assignments in existing courses, give examples of how assignments were revised to satisfy the intent of WTL as an instructional strategy, and describe the resources and support needed to facilitate its implementation in the curriculum. PMID- 7854639 TI - Humor as a teaching strategy. AB - Nurse educators often look for alternate teaching strategies to increase students' attention, comprehension, motivation, and retention of content. Frequently, the use of humor has been shown qualitatively to be such a strategy. The author gives some of the theoretical basis for the use of humor in education and some examples of how humor has been used in her own teaching. PMID- 7854640 TI - Using humor to enhance learning in the skills laboratory. AB - No matter how eager students may be to learn, anxiety can prevent them from easily learning a skill. Nursing faculty members also face a dilemma--losing interest and enthusiasm if they repeatedly teach the same material. By adding humor and a little creativity, the skills laboratory can be a stimulating learning environment for both the teacher and the students. PMID- 7854641 TI - Outcomes among graduates from Washington State Community College associate degree nursing programs. PMID- 7854642 TI - Collegiality: the key to the future. PMID- 7854643 TI - Attitude toward menopause in baccalaureate nursing students. PMID- 7854644 TI - A modified preceptorship experience. PMID- 7854645 TI - Test banks: understanding memorization. PMID- 7854646 TI - Teaching on compressed video: helpful hints. PMID- 7854647 TI - Journal club for nursing students. PMID- 7854648 TI - Ethics in the professional curriculum. PMID- 7854649 TI - Micronutrient effects on blood pressure regulation. AB - Five micronutrients have been shown to directly influence blood pressure: sodium, calcium, potassium, magnesium, and chloride. The data presented here are based on accumulated findings from epidemiologic, laboratory, and clinical investigations, many of which focused primarily on a single nutrient. However, as also discussed here, nutrients are not consumed in isolation, and their physiologic interactions and combined effects on blood pressure are the subjects of much of the current research in the area of diet and hypertension. PMID- 7854650 TI - 1 alpha,25(OH)2 vitamin D3-regulated expression of the eukaryotic genome. AB - 1 alpha,25(OH)2vitamin-D3, [1 alpha,25(OH)2D3] is a potent steroid hormone that produces a wide array of biologic effects in a variety of target tissues within the body through its ability to modulate gene transcription of specific target genes. Evidence for transcription regulation of a specific gene typically includes 1 alpha,25(OH)2D3-induced modulation in mRNA levels. Additionally, evidence may include measurements of transcription and/or the presence of a vitamin D response element within the promoter region of the gene. To date, over 50 genes have been reported to be transcriptionally regulated by 1 alpha,25(OH)2D3. We present a current list of these genes and the evidence supporting their inclusion on the list. PMID- 7854651 TI - Vitamin nutrition status and homocysteine: an atherogenic risk factor. AB - In an epidemiologic survey, a marginal status of folic acid, vitamin B12, and vitamin B6 was shown to be associated with hyperhomocysteinemia. In a case control study, a low plasma folate concentration was associated with increased coronary heart disease risk. This phenomenon appears to be mediated by folate's effect on homocysteine metabolism. Both studies offer further perspectives on homocysteine as an atherogenic risk factor. PMID- 7854652 TI - An integrin-mobilferrin iron transport pathway in intestine and hematopoietic cells. AB - A pathway of iron transport not involving transferrin or transferrin receptors has been described as functioning in iron uptake into intestinal cells and in a hematopoietic cell line. Evidence was presented to show that it is mediated by a transmembrane protein (integrin) and a cytosolic protein (mobilferrin). PMID- 7854653 TI - The Maternal Phenylketonuria Collaborative Study: a status report. PMID- 7854654 TI - Revising the Dietary Guidelines for Americans: history and rationale. PMID- 7854655 TI - Maximal genetic potential for adult stature: is this aim desirable? (Nutr Rev 1994;52:208-10) PMID- 7854656 TI - Avoiding burnout. PMID- 7854658 TI - Describing signs and symptoms correctly. PMID- 7854657 TI - The power of touch. PMID- 7854659 TI - Performing pulse oximetry. PMID- 7854660 TI - Failure to inform. PMID- 7854661 TI - Preparing your patient for home infusion. PMID- 7854662 TI - Chemotherapy and radiation: reducing your risks. PMID- 7854663 TI - Creating a written report system. PMID- 7854664 TI - Treating convulsive status epilepticus. PMID- 7854665 TI - Pulmonary edema. PMID- 7854666 TI - Catching deep vein thrombosis in time. PMID- 7854667 TI - Close-up on monoclonal antibodies. PMID- 7854669 TI - Confronting sexual harassment. PMID- 7854668 TI - Friends until the end. PMID- 7854670 TI - Stumping Dr. O'Connell. PMID- 7854671 TI - Dealing with complications of epidural analgesia. PMID- 7854672 TI - Working on the right moves. Part 1. PMID- 7854673 TI - Nuclear cardiology stress testing: from start to finish. PMID- 7854674 TI - Queen Sharon. PMID- 7854675 TI - Dealing with an anticholinergic overdose. PMID- 7854676 TI - How to start a morphine drip effectively. PMID- 7854677 TI - Self-test: managing congestive heart failure. PMID- 7854678 TI - Myths & facts ... about irritable bowel syndrome. PMID- 7854679 TI - Assessing upper abdominal pain. PMID- 7854680 TI - Taking C.A.R.E. to tell it like it is. PMID- 7854681 TI - Developing your professional identity. PMID- 7854682 TI - Room full of love. PMID- 7854683 TI - Myths & facts....about subacute care units. PMID- 7854684 TI - How to stop the spread of M.R.S.A. PMID- 7854685 TI - Managing nausea. PMID- 7854686 TI - How to apply a self-adhesive condom catheter. PMID- 7854687 TI - Antibiotic therapy: a guide to adverse effects. PMID- 7854688 TI - What you need to know about sickle-cell disease. PMID- 7854689 TI - Managing the adverse effects of opioids. PMID- 7854690 TI - Patient-teaching aid. How to use a volume incentive spirometer. PMID- 7854691 TI - Medicating the geriatric patient. PMID- 7854692 TI - Occluded airway. PMID- 7854693 TI - Taking blood pressure correctly--it's no off-the-cuff matter. PMID- 7854694 TI - Staying on top of transdermal drug patches. PMID- 7854695 TI - Healing touch. PMID- 7854696 TI - Sinus bradycardia: elevating a slow heart rate. PMID- 7854698 TI - Working on the right moves. PMID- 7854697 TI - Close-up on antioxidants. PMID- 7854699 TI - Christmas without Wynn. PMID- 7854700 TI - Atropine and Down's syndrome: dangerous mix? PMID- 7854701 TI - Dealing with H.I.V.-related pulmonary infections. PMID- 7854702 TI - Cold comfort: treating prostate cancer with cryosurgery. PMID- 7854703 TI - Self-test: providing effective cancer care. PMID- 7854704 TI - An issue of floating. PMID- 7854706 TI - Improving your self-esteem. PMID- 7854705 TI - How to respond to adverse drug reactions. PMID- 7854707 TI - Saving time using C.I.N.A.H.L. on C.D.-R.O.M. PMID- 7854708 TI - A simple thank you. PMID- 7854709 TI - Administering prophylactic antibiotics before surgery. PMID- 7854710 TI - Inserting an oropharyngeal airway properly. PMID- 7854711 TI - Falling short of the standard of care. PMID- 7854712 TI - Overcoming sedation. PMID- 7854714 TI - Understanding the dangers of neuromuscular blockers. PMID- 7854713 TI - Fulfilling Tammy's dream. PMID- 7854716 TI - How to conduct better interviews. PMID- 7854715 TI - Making the best of inadequate analgesics. PMID- 7854717 TI - Solving managers' dilemmas. PMID- 7854718 TI - Organ donation: what families need to know. PMID- 7854719 TI - Developing successful preceptor programs. PMID- 7854720 TI - Identifying infarctions: how you can use the E.C.G. PMID- 7854721 TI - Auto-P.E.E.P. A complication you can't afford to overlook. PMID- 7854722 TI - 9 tips for better charting. PMID- 7854723 TI - A.C.L.S. in review: you can't always trust the monitor. PMID- 7854724 TI - Anticoagulation-induced epistaxis. PMID- 7854725 TI - A.R.D.S. revisited. New ways to fight an old enemy. PMID- 7854726 TI - The first one. PMID- 7854727 TI - A working Christmas turns into one to remember. PMID- 7854728 TI - Documenting wounds through the camera's eye. PMID- 7854729 TI - Close-up on atrial natriuretic factor. PMID- 7854730 TI - Sinus tachycardia: lowering a high heart rate. PMID- 7854731 TI - How to avoid getting a no from a nursing assistant. PMID- 7854732 TI - Myths & facts ... about alcoholism. PMID- 7854733 TI - Self-test: reviewing nursing pharmacology. PMID- 7854734 TI - Changing your specialty with confidence. PMID- 7854735 TI - Reconfirmed. PMID- 7854737 TI - Logrolling a patient safely. PMID- 7854736 TI - Getting even with the past. PMID- 7854738 TI - How to choose and use gloves. PMID- 7854739 TI - Seeing Iris's reverse potential. PMID- 7854740 TI - Myths & facts ... about testicular cancer. PMID- 7854741 TI - Setting up a P.C.A. pump. PMID- 7854742 TI - Avoiding abbreviation errors. PMID- 7854743 TI - A case of rough removal. PMID- 7854744 TI - Febrile seizure. PMID- 7854746 TI - Giving report: how to sidestep common pitfalls. PMID- 7854745 TI - Terminal weaning: it's not simply "pulling the plug". PMID- 7854747 TI - Caring for patients with cirrhosis. PMID- 7854748 TI - Hospital restructuring: how to cope with the changes. PMID- 7854750 TI - Healing with humor. PMID- 7854749 TI - Using the no-touch technique to change a dressing. PMID- 7854751 TI - Interpreting B.U.N./creatinine levels: it's not as simple as you think. PMID- 7854752 TI - Faltering heart. PMID- 7854754 TI - Indwelling urinary catheters: reducing infection risks. PMID- 7854753 TI - Banishing phantom pain. PMID- 7854755 TI - Voice of a stranger. PMID- 7854756 TI - Taking the gloves off: caring for confused patients without using restraints. PMID- 7854757 TI - Understanding infectious diseases. PMID- 7854758 TI - Workers' compensation. Coverage for H.I.V. PMID- 7854759 TI - Ensuring pain relief. PMID- 7854760 TI - Evaluating syncopal episodes. PMID- 7854761 TI - Handling change effectively. PMID- 7854762 TI - Dentists benefit from new professional practice options. PMID- 7854763 TI - Simplified approach to use of electrical pulp tester. AB - The routine use of gloves as a barrier technique is recommended by the American Dental Association and the Centers for Disease Control. The use of the electrical pulp tester necessitates that the dentist contact the patient's skin or mucosa to complete the circuit. A technique is presented that simplifies the operation of the electrical pulp tester by the dentist wearing gloves. Advantages of this method include a sound barrier technique, an enhanced psychological benefit to the dentist, and an abatement in discomfort for the patient. PMID- 7854764 TI - Impacted teeth: prophylactic extractions or not? AB - Pathologic changes related to impacted teeth are infrequent. However, considerable damage to bone and adjacent teeth may result if they do occur. Four patients are described in whom different circumstances existed with impacted teeth. Extractions are indicated when the anatomic location of the impacted teeth is most favorable and when the patient's systemic and hematologic condition is least compromising, even if the teeth are asymptomatic at that time. PMID- 7854765 TI - Electrical permeability of vinyl gloves. AB - Electrical (ionic) conductivity through operating gloves is a test of glove integrity. In 1958 Penikett and Gorrill used electrical conductivity as a test for glove leaks. In 1959 similar work was done by Beck to verify electrical conductivity as an indicator of leaky gloves. Further research was done by Russell, Roque and Miller in 1956 to verify the relationship between leaky gloves and electrical conductivity. In 1994 Ozata, Septcioglu, Turkin and Eltem found that the one brand of vinyl gloves they tested all passed electricity. Our research was undertaken to test and expand the findings of Ozata and his group on several brands of vinyl gloves widely distributed in the U.S. PMID- 7854766 TI - Electrical permeability of latex gloves. PMID- 7854767 TI - A not so golden age. PMID- 7854768 TI - Immunohistochemical fibronectin staining pattern and prognosis in invasive breast carcinoma. AB - Fibronectin (FN) in 99 female patients with invasive breast carcinomas (IBCs) was studied by immunohistochemistry using a monoclonal antibody to human plasma FN. Sixty-five (65.7%) of 99 IBCs were FN-positive and 34 (34.3%) were FN-negative. The FN staining pattern was not correlated with patient characteristics, such as age, tumor size, nodal involvement and estrogen receptor status. Relapse-free survival (RFS) of patients with FN-positive tumors was significantly better than that of patients with FN-negative tumors. A multivariate analysis using the Cox proportional hazards model showed that the FN staining pattern was independently correlated with RFS as well as nodal status. The results show that FN staining pattern may be an independent prognostic factor in IBCs. It is suggested that patients with FN-negative tumors should be carefully followed up, even if axillary nodal invasion is absent. PMID- 7854769 TI - Intracellular glutathione content in leukemias. AB - The intracellular glutathione (GSH) content was measured in 73 patients with leukemia and compared with controls. GSH content was between 1.16 and 5.55 mumol/g protein (mean 2.96 +/- 0.86) in the study group and between 0.5 and 1.48 mumol/g protein (mean 1.31 +/- 0.27) in the control group, statistically significant difference (p = 0.0000). There was no significant difference between acute and chronic leukemias, lymphoid and myeloid leukemias and, more importantly, newly diagnosed and relapsed patients. GSH content did not change significantly with clinical and hematologic parameters such as age, sex, and initial hematologic findings. In addition, variable changes were detected over 24 h in 9 patients. It can be concluded that GSH content in leukemic cells was higher than in controls and showed a wide range. The absence of a relationship between GSH content and clinical and laboratory parameters suggested that GSH is not the sole determinant of response to cytotoxic drugs. GSH variation over a 24 hour period may be important in the timing and success of chemotherapy for leukemias. PMID- 7854770 TI - Flow cytometric analysis of the DNA content of tumor cells in cases of gastric cancer in the upper third of the stomach and in the remnant stomach. AB - Thirteen samples of gastric tumors that had developed in the remnant stomach (remnant gastric cancer) were compared with 63 samples of primary gastric tumors located in the upper third of the stomach (primary gastric cancer) by both clinicopathologic and flow cytometric analysis. The depths of invasion of all these tumors corresponded to the mucosa, submucosa, or muscularis propria layers and the histological stages were stages I, II, or III. There was no significant difference between the two groups of samples either histopathologically or clinically (the 5-year survival rates were 74.6% for patients with remnant gastric cancer and 90.4% for patients with primary gastric cancer). DNA aneuploidy was encountered in 23.1% of the cases of remnant gastric cancer and in 33.3% of the cases of primary gastric cancer. Little difference was found in the S-phase fractions between tumors and normal gastric mucosa of the upper third of the stomach and the remnant stomach. Thus, while the environments in the upper third of the stomach and in the remnant stomach are very different, histopathological and biological characteristics of adenocarcinomas that developed in the remnant stomach are very similar to those of adenocarcinomas in the upper third of the stomach. PMID- 7854771 TI - Flow cytometric analysis of p53 expression during the cell cycle. AB - Mutant p53 expressed in many types of carcinoma lacks an inhibitory function on cell growth, but its role has been unclear. We performed two-parameter flow cytometry (FCM) to elucidate the relationship between the expression of p53 and the cell cycle in A431 cells. Fluorescence in situ hybridization proved that an A431 cell had two p53 genes whereas chromosome 17 was tetraploid. FCM showed that A431 cells expressed constantly high levels of p53 during the cell cycle. Under conditions of both serum deprivation and presence of hydroxyurea, p53 expression was decreased throughout the cell cycle, and the bivariate DNA/p53 distribution pattern during the cell cycle did not change. The expression of p53 was reduced to 60% for the first 4 h after the addition of cycloheximide, and showed no significant changes at least for 20 h. Treatment with Triton X-100 increased p53 immunoreactivity throughout the cell cycle. These results indicate that mutant p53 differs from proliferative markers such as PCNA, Ki-67 and DNA polymerase alpha, and that there are no links between the expression of p53 and the cell cycle in A431 cells. PMID- 7854772 TI - Serum level of macrophage colony-stimulating factor as a marker for gynecologic malignancies. AB - We determined the serum levels of macrophage colony-stimulating factor (M-CSF) in 441 women with gynecologic diseases to evaluate its role as a marker for gynecologic malignancy. Serum M-CSF levels were above the normal baseline level of 1,056 U/ml in 64% (56/88) of patients with ovarian cancer, 27% (16/60) of those with cervical cancer, and 25% (15/61) of those with endometrial cancer. M CSF was significantly elevated in the serum of patients with advanced as compared with early stage cancer (stage I) of the ovary (p < 0.01), cervix (p < 0.05), and endometrium (p < 0.05). Only 5.6% of the patients with benign ovarian tumors and 7.0% of those with endometrial cysts had serum levels of M-CSF that exceeded 1,056 U/ml. M-CSF was localized in the glandular epithelial cells as well as in the stromal macrophages and the endothelial cells of the ovarian cancers. M-CSF thus appeared to be a marker with high specificity for ovarian cancer. PMID- 7854773 TI - Proliferating cell nuclear antigen expression correlates with the metastatic potential of submucosal invasive colorectal carcinoma. AB - To examine the malignant potential of submucosal invasive colorectal carcinoma, the relationship between proliferating cell nuclear antigen (PCNA) expression and clinicopathologic risk factors for lymph node metastasis was studied in 149 patients with submucosal invasive colorectal carcinoma. The depth of submucosal invasion was classified as scanty or massive. Histologic subclassification at the submucosal deepest invasive portion was done as follows: well differentiated (W), moderately well differentiated (Mw), moderately poorly differentiated (Mp) or poorly differentiated (Por). Tumor growth was divided into polypoid growth and nonpolypoid growth. The PCNA expression (labeling index, LI) was examined at the submucosal deepest invasive portion. The PCNA-LI of tumors showing lymph node metastasis (mean, 56.5 +/- 19.0%) was significantly higher than that of tumors without lymph node metastasis (mean, 41.5 +/- 19.3%; p < 0.01). The PCNA-LI of Mp tumors (mean, 57.7 +/- 16.5%) was significantly higher than that of W (mean, 38.5 +/- 19.0%; p < 0.05) and Mw (mean, 43.7 +/- 19.1%; p < 0.05) tumors. The PCNA-LI of tumors without adenomatous features (mean, 47.9 +/- 20.5%) was significantly higher than that of tumors with such features (mean, 37.1 +/- 17.1%; p < 0.05). The PCNA-LI was not correlated with other risk factors for lymph node metastasis, such as lymphatic invasion, depth of submucosal invasion, macroscopic type, and growth pattern. These results indicate that the PCNA-LI may be useful marker for predicting the potential metastases to lymph nodes in submucosal invasive colorectal carcinoma, while the proliferative activity of cancer cells correlates with the degree of the differentiation in the area of deepest invasion. PMID- 7854774 TI - New mucin-like cancer-associated antigens (CA M 26, CA M 29 and CA 549) and a new proliferation marker (TPS) in patients with primary or advanced breast cancer. AB - In patients with breast cancer no tumor markers giving satisfactory results have been found yet. The aim of our investigation was to compare the usefulness of newly developed tumor markers with the most common used carcinoembryonic antigen and cancer antigen (CA) 15-3. We evaluated the concentrations of carcinoma associated antigen (CA) 549, carcinoma-associated mucin antigen (CA M) 26 and CA M 29, and the proliferation markers tissue polypeptide antigen (TPA) and tissue polypeptide-specific antigen (TPS) in 84 breast cancer patients with disease progression and in 69 patients with no evidence of disease after surgery for breast cancer. Using receiver-operating characteristic curves (ROC curves) we were able to demonstrate increased sensitivity and specificity of all tested tumor markers in patients with metastatic disease compared with local disease. In our investigation TPA is superior to TPS in all disease states. In local disease, none of the tested markers shows satisfying results. In metastatic disease, the new mucin markers CA M 26 and CA M 29 show slightly better results than CA 15-3 although their ROC curves are nearly congruent. CA 549 is exceeded by the other mucin markers. The best results in this investigation were obtained with CA M 29. The overall results concerning the detection of small tumor masses (i.e. local disease) were unsatisfactory. PMID- 7854775 TI - Immunocytochemical determination of EGFR, OV 632 and OC 125 in primary ovarian cancer patients. AB - An immunocytochemistry study was performed to compare the immunoreactivity of the monoclonal antibodies OC 125, EGFR and OV 632 with smear imprints from 60 ovarian tumours (21 serous cystadenocarcinomas, 12 mucinous cystadenocarcinomas, 9 endometrioid carcinomas, 5 clear cell carcinomas and 5 mixed tumours). Twenty-six patients were premenopausal and 34 postmenopausal. The results showed that 75% of mucinous cystadenocarcinomas were negative for all 3 antigens as were 2 of the 5 (40%) clear cell carcinomas. All other tumours were positive for at least one of the three antigens. OV 632 had an overall sensitivity of 73.3%, EGFR 55% and OC 125 46.6%. Four tumours were OC 125-positive and OV 632-negative. There was no significant difference in positivity of OV 632, OC 125 and EGFR, between pre- and post-menopausal patients (chi 2 = 0.03) or between tumours of stage I and stage III [chi 2 = 0.075 (EGFR) 0.95 (OV 632) and 10.49 (OC 125)]. OV 632 was conducted to be the most sensitive antibody in all types of tumours but OC 125, while less sensitive by itself, increased the overall sensitivity in combination with OV 632 from 73.3 to 80% (not statistically significant). PMID- 7854777 TI - Humulon, a bitter in the hop, inhibits tumor promotion by 12-O tetradecanoylphorbol-13-acetate in two-stage carcinogenesis in mouse skin. AB - Humulon, one of the bitters in the hop, was isolated from the female flowers of Humulus lupulus. This component has inhibitory activity against 12-O tetradecanoylphorbol-13-acetate (TPA)-induced inflammation. At 1 mg/mouse, humulon inhibited markedly the tumor-promoting effect of TPA (1 microgram/mouse) on skin tumor formation following initiation with 7,12-dimethylbenz[a]anthracene (50 micrograms/mouse). Furthermore, humulon inhibited arachidonic acid-induced inflammatory ear edema in mice. PMID- 7854776 TI - Effects of eicosanoid synthesis inhibitors on the in vitro growth and prostaglandin E and leukotriene B secretion of a human breast cancer cell line. AB - We investigated the effects of cyclooxygenase and lipoxygenase inhibitors on a human breast cancer cell line (MDA-MB-231) in culture. Indomethacin (INDO), piroxicam, esculetin, and nordihydroguaiaretic acid (NDGA) significantly suppressed cell growth, although piroxicam caused significant suppression only at high concentrations. Esculetin and NDGA caused significantly reduced secretion of leukotriene B (LTB), while INDO and piroxicam caused significantly reduced secretion of prostaglandin E (PGE). Consequently, cell growth was significantly correlated with the LTB concentration when the cells were treated with esculetin or NDGA, whereas it was significantly correlated with the PGE concentration when they were treated with INDO or piroxicam. Therefore, MDA-MB-231 cell growth in vitro was independently associated with both the PG and LTB concentrations. PMID- 7854778 TI - Immunoendocrine therapy with low-dose subcutaneous interleukin-2 plus melatonin of locally advanced or metastatic endocrine tumors. AB - Recent evidence has shown that endocrine tumors are under an endocrine and an immune regulation, and that biotherapies with interferon or the long-acting somatostatin analog octreotide may be effective in the control of tumor growth and clinical symptomatology. Within the biotherapies of tumors, interleukin-2(IL 2) has appeared to play an essential role in the antitumor immune response. Despite its important antitumor role, very few studies have been carried out to investigate the possible use of IL-2 in the treatment of advanced endocrine tumors. Its potential toxicity would represent the main limiting factor for the clinical experiments with IL-2. Our previous studies have shown that the pineal hormone melatonin (MLT) may amplify the antitumor activity of IL-2, either through immunomodulating mechanisms or through a direct cytostatic activity by inhibiting tumor growth factor production. On this basis, we have performed a phase II pilot study with low-dose IL-2 plus MLT in 14 patients with untreatable endocrine tumors because of disseminated disease, lack of response to previous standard biotherapies or chemotherapies, or tumors for whom no effective therapy is available. Thyroid cancers, carcinoid and endodrine pancreatic tumors were the most frequent neoplasms. IL-2 was given at 3 million IU/day s.c. at 8 p.m. for 6 days/week for 4 weeks, corresponding to one cycle. MLT was given orally at 40 mg/day at 8 p.m. every day. In nonprogressed patients, a second cycle was given after a 21-day rest period. Patients were considered as evaluable when they received at least one complete cycle, and 12 patients were fully evaluable. According to WHO criteria, a partial response was achieved in 3/12 (25%) patients (carcinoid tumor: 1; neuroendocrine lung tumor: 1; pancreatic islet cell tumor: 1). Another patient with gastrinoma had a more than 50% reduction of tumor markers. Toxicity was low in all patients. This preliminary study suggests that low-dose IL-2 immunotherapy in association with the pineal hormone MLT may constitute a new well-tolerated and potentially active therapy of untreatable advanced endocrine tumors. PMID- 7854779 TI - Clinical experience with tegafur and low dose oral leucovorin: a dose-finding study. AB - Tegafur is an effective oral fluoropyrimidine that shows the same activity as 5 fluorouracil for a similar spectrum of cancers. Their biochemical modulation with oral Leucovorin (LV) attempts to simulate treatment with a continuous infusion of 5-fluorouracil and LV with the added advantage of outpatient administration. Thirty-three patients with advanced adenocarcinoma were included in the study. The treatment consisted of tegafur, 0.75 g/m2/day, for 21 days, with oral LV at different dose levels, 15, 30, 45, 60 and 90 mg/day, in a 28-day cycle. A correlation between the LV dose and an increase in grade III/IV toxicity (especially diarrhea, oral mucositis and fatigue) was established in the nonlinear regression model, reaching a plateau at 60 mg of LV. For the tegafur dose used, the recommended dose of LV is in the range of 45-60 mg/day. This schedule could be considered to evaluate the possible therapeutic effect in phase II trials. PMID- 7854780 TI - Perioperative blood transfusions and prognosis in patients with curatively resected locally advanced gastric cancer. AB - Several reports have demonstrated an adverse effect of perioperative blood transfusions on the survival of patients with various solid tumors treated surgically. We retrospectively investigated the relationship between perioperative blood transfusions and the survival of 501 patients who underwent radical subtotal gastrectomy for locally advanced gastric cancer (stage II-IIIB) from January 1984 to December 1989. Three hundred and fifty-two patients (70.3%) received blood transfusions within the perioperative period. The transfused group included patients with tumors of larger size (5.1 vs. 4.4 cm, p = 0.001) and more advanced stage (stage IIIB: 27.6 vs. 10.7%, p = 0.0001) than the nontransfused group. Although the 5-year overall survival rate was significantly lower (52.9 vs. 66.7%, p = 0.026) in the transfused patients than the nontransfused, subgroup analysis according to the pathologic stage showed no statistically significant difference in survival in each stage between the two groups. In conclusion, we could not find any causal relationships between transfusion and prognosis in patients with curatively resected locally advanced gastric cancer. Circumstances such as advanced stage necessitating transfusions may be more important prognostic factors. PMID- 7854781 TI - Neurologic complications in pediatric solid tumors. AB - The cases of 61 children, consecutively diagnosed during 1986-1990 as having malignant solid tumors (but excluding those with brain tumors and lymphoproliferative diseases), were reviewed. Neurologic complications occurred in 19 (31%), most often in association with neuroblastomas and sarcomas. Complications observed in order of frequency were: brain metastases in 6 children, spinal cord compression in 5, peripheral or cranial neuropathies in 4, and seizures in the remaining 4. Early recognition of neurologic compromise and rapid initiation of treatment are mandatory in order to prevent permanent disability. PMID- 7854782 TI - Mortality from Hodgkin's disease and other lymphomas in Europe, 1960-1990. AB - Trends in mortality from Hodgkin's disease (HD) and non-Hodgkin's lymphomas (NHL) in the whole of Europe and in two broad European geographic areas (Western and Eastern Europe) were reviewed over the period of 1960-1990, on the basis of official death certifications derived from the World Health Organization database. Between the early 1960s and 1990, HD mortality in the whole of Europe declined from 2.1 to 0.9/100,000 males (-58%), and from 1.1 to 0.5/100,000 (-56%) females. The decline was larger in Western Europe (around 65%), but appreciably smaller in Eastern Europe (around 30%). In contrast, mortality from NHL increased in males from 2.2 to 4.2/100,000 (+93%), and in females from 1.2 to 2.6/100,000 (+112%). These upward trends were larger in Western (over 100%) than in Eastern Europe (around 80%). The declines in HD were larger and the increases in NHL were smaller in populations below age 65. When all lymphomas were considered together, an increase was observed in both sexes (from 4.3 to 5.1/100,000 males; from 2.4 to 3.1/100,000 females) that was comparable in various areas of the continent. These data confirm a major impact of newer integrated diagnostic and therapeutic approaches in reducing HD mortality, while indicating that this impact has been delayed and limited in Eastern Europe. The upward trends in mortality from NHL probably reflect both real increases in incidence and better case ascertainment and certification, but are inconsistent with a noticeable impact of newer therapies on mortality from NHL. It is also conceivable that the introduction of immunophenotypic and immunogenotypic characterization of lymphomas has selectively eliminated from HD a worse-prognosis subset previously classified on the basis of Sternbergoid cells, which has been subsequently classified as NHL. This would have increased survival and decreased mortality from HD, while increasing incidence and mortality from NHL to an extent which is unknown but worth considering. PMID- 7854783 TI - [Federico Harden: "The federation endeavors to be heard by the nursing personnel". Interview by Harald Verworner]. PMID- 7854784 TI - [Abandoned without rights or treatment with respect and dignity?]. PMID- 7854785 TI - [Effects of placement legislation on psychiatric care]. PMID- 7854786 TI - [Extramural psychiatric care]. PMID- 7854787 TI - [Quality assurance by means of practice guidance]. PMID- 7854788 TI - [What is what?--Understanding concepts. Terminology from Bohm's nursing model]. PMID- 7854789 TI - John J. Bonica 1917-1994. Emma B. Bonica 1915-1994. PMID- 7854790 TI - Factors that influence the behavioral pain responses of premature infants. AB - The responses of preterm neonates to acute tissue-damaging stimuli have been described. However, factors which influence these responses have received little attention. In this study, we observed 124 premature infants before, during and after a routine heel lance and determined how two contextual variables (severity of illness and behavioral state) influenced their behavioral responses. Significant changes in facial actions occurred between baseline and the most invasive phase of the heel lance procedure, stick. The fundamental frequency, harmonic structure and peak spectral energy of the infant's cry were also significantly increased during the stick phase. Behavioral state was found to influence the facial action variables and severity of illness modified the acoustic cry variables. Accurate identification of pain in premature infants requires consideration of factors that influence their response. PMID- 7854791 TI - Functional reorganization in the rat dorsal horn during an experimental myositis. AB - In anaesthetized rats, the influence of an acute inflammation (2-8 h duration) of the gastrocnemius-soleus (GS) muscle on the excitability of dorsal horn neurones was studied using a mapping procedure. One of the main effects of the myositis was that the neurone population responding to GS A-fibre input increased in size. The increase was most marked in the lateral segments L6-L3 which received little input from the GS muscle in control animals. Excitability testing showed a myositis-induced lowering in threshold, combined with an increase in latency, jitter and input convergence. This suggests that new oligo- or polysynaptic connections become functional under the influence of a myositis. Neuronal effects induced by C fibres in the GS nerves were not significantly altered by a myositis, but C fibre-induced activations from the peroneal and sural nerves increased in the lateral dorsal horn. The results show that an acute myositis leads to marked changes in the functional connectivity of the dorsal horn within a few hours. The main increase in excitability took place in the lateral dorsal horn, where many neurones acquired a new input from the GS muscle. This mechanism may be involved in the spread or referral of muscle pain. PMID- 7854792 TI - The sensation of angina can be evoked by stimulation of the human thalamus. AB - We have performed single-neuron recording and microstimulation in the region of the thalamic principal sensory nucleus (ventrocaudal nucleus, Vc) prior to implantation of a deep brain-stimulating electrode in a patient with pain secondary to arachnoiditis and with a past history of unstable angina. Cells located in the 16 mm lateral plane had cutaneous receptive fields on the chest wall. At and posterior to the location of these cells stimulation coincided precisely with the sensation of angina (stimulation-associated angina). The description of stimulation-associated angina was measured using a questionnaire and was identical to the patient's usual angina except that it began and terminated suddenly. Stimulation-associated angina was coincident with a tingling sensation in the leg. Clinical, hemodynamic, electrophysiologic and biochemical measures of cardiac function showed no evidence of myocardial strain or injury related to stimulation-associated angina. Since cells in the region of the principle sensory nucleus of thalamus respond to cardiac injury in animals, the present results suggest that this region mediates the sensation of angina. PMID- 7854793 TI - Dextromethorphan for the treatment of neuropathic pain: a double-blind randomised controlled crossover trial with integral n-of-1 design. AB - The aim was to compare the analgesic effectiveness and adverse effect incidence of oral dextromethorphan (DM) with placebo in patients with neuropathic pain. The first 10-day treatment period was a multiple-dose double-blind randomised controlled cross-over comparison of 13.5 mg of DM 3 times a day (t.d.s.) with placebo t.d.s.: 5 treatment pairs, each pair 1 day DM and 1 day placebo. The second 10-day treatment period used 27 mg of DM t.d.s. vs. placebo, with the same design. The study incorporated a 5 pair n-of-1 design for each of the 2 doses of DM. Patients took the study medication in addition to any pre-existing analgesic regime. Patients who reported benefit could continue with DM after the study. Nineteen patients with chronic neuropathic pain were studied over two 10-day treatment periods. Outcome measures were pain intensity, pain relief, adverse effects, mood, sleep and global rating of treatment. These were recorded by daily patient diaries and by clinic assessments before and after each treatment period. There were no significant differences between DM and placebo on any of the clinic assessment outcome measures. Two patients had significantly better analgesia on more than one outcome measure on within-patient testing. One had better analgesia with DM. The other had better analgesia with placebo. Ten patients had no adverse effects on either dose of DM. Two patients withdrew during the first treatment period because of adverse effects (which included increased pain intensity), and 5 during the second period. Five patients continued with DM after the study for 1 3 months. No long-term clinical benefit was apparent in those who continued with open DM. Dextromethorphan at either 40.5 or 81 mg daily did not relieve neuropathic pain. PMID- 7854794 TI - Epidural somatostatin as an analgesic in upper abdominal surgery: a double-blind study. AB - Somatostatin 1-14, a natural occurring neuropeptide (Somiaton), has been reported to have analgesic effects in humans in different painful conditions. The aim of the present study was to investigate if epidural somatostatin produced clinical analgesia to postoperative pain after upper abdominal surgery. In a randomized double-blind controlled study, 40 patients received either 125 micrograms of epidural somatostatin infusions every hour (using a continuous infusion pump: CADD-PCA model 5200 PCX, Pharmacia) or placebo: mannitol (somatostatin inactif ingredient) 2.5 mg during the first 3 postoperative days (plus additional pulses of either substance, 250 micrograms or 5 mg, respectively, according to the level of analgesia needed by the patient). Additional subcutaneous analgesic treatment with 1 mg/kg pethidine chlorhydrate was administered at the patient's request. The degree of pain was quantified with visual analogue scale at baseline, 1 h after the operation and at every 4 h for the next 3 days. Arterial blood gases and spirometry values were determined at different intervals throughout the study period. Somatostatin was significantly better than placebo for pain relief (P < 0.01) and respiratory function preservation (P < 0.05). The total consumption (and ranges) of somatostatin at 24, 48 and 72 h were: 5.2 +/- 1.4 mg (4.0-6.25 mg), 4.2 +/- 0.8 mg (2.2-5.0 mg) and 3.7 +/- 0.4 mg (2.2-4.7 mg) respectively. During the whole study the need for complementary analgesia (pethidine chlorhydrate) was significantly higher in the placebo group: 5.4 +/- 3.5 vs. 2.7 +/- 1.9 (mean +/- SD) P < 0.01, dose/72 h. Side effects were irrelevant and scarce in both groups. The sustained pain relief combined with the respiratory function preservation in the somatostatin group suggests an important role of this drug in postoperative analgesia. PMID- 7854795 TI - Intrathecal morphine and clonidine in the management of spinal cord injury pain: a case report. AB - Neuropathic pain following spinal cord injury (SCI) can be difficult to manage using currently available pain management techniques. We describe a case of chronic pain following SCI which failed to respond to a variety of approaches including intrathecal administration of morphine. Use of clonidine in addition to the morphine resulted in a marked decrease in pain. The use of intrathecal clonidine with or without opioids may present an effective alternative in the management of intractable SCI pain and other forms of neuropathic pain. PMID- 7854796 TI - Sciatic entrapment neuropathy associated with an anomalous piriformis muscle. AB - Piriformis syndrome is an often overlooked cause of sciatica that typically responds to intramuscular local anesthetic and steroid injection. In this report, our patient presented with sciatica that responded poorly to epidural steroid injection and only transiently to piriformis injection. Surgical exploration of the sciatic nerve revealed a fascial constricting band around the nerve as well as a piriformis muscle lying anterior to the nerve. This unusual anatomical relationship between the piriformis and the sciatic nerve has not been previously described in the literature. Subsequent sectioning of the anomalous muscle and the constricting band yielded complete resolution of our patient's symptoms. PMID- 7854797 TI - Comments on coeliac plexus block and paraplegia. PMID- 7854798 TI - Deafferentation pain after local treatment in non-metastatic breast carcinoma. PMID- 7854799 TI - Comments on low cost acute pain services. PMID- 7854800 TI - Comments on Goucke et al., PAIN, 56 (1994) 145-149. PMID- 7854802 TI - A call for national initiatives on pain. PMID- 7854801 TI - Multi-method assessment of experimental and clinical pain in patients with fibromyalgia. AB - Experimental measures of responsiveness to painful and non-painful stimuli as well as measures of typical and present clinical pain were assessed in 26 female patients with fibromyalgia and in an equal number of age-matched healthy women. Pressure pain thresholds, determined by means of a dolorimeter, were lower in the patients compared to the control subjects both at a tender point (trapezius) and at a non-tender control point (inner forearm). The same was true for the heat pain thresholds, measured using a contact thermode. In contrast, the pain thresholds for electrocutaneous stimuli were decreased only at the tender point. The detection thresholds for non-painful stimuli (warmth, cold and electrical stimuli) seemed to be less affected in the fibromyalgia patients, with only the detection threshold for cold being lower at both sites. Tender points were more sensitive than control points for mechanical pressure. The reverse was found for the other modalities which were tested. Although the 3 experimental pain thresholds showed patterns of either generalized or site-specific pain hyperresponsiveness, the between-methods correlations were not very high. While the correlations between the experimental pain thresholds and the various measures of clinical pain (Localized Pain Rating, McGill Pain Questionnaire) in the patients were generally low, there were significant negative correlations between pressure pain thresholds at the two sites and the level of present pain assessed by the Localized Pain Rating. We conclude that a pattern of pain hyperresponsiveness, generalized across the site of noxious stimulation and across the physical nature of the stressor, is associated with fibromyalgia.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7854803 TI - Perception threshold and electrode position for spinal cord stimulation. AB - The perception threshold for epidural spinal cord stimulation in chronic pain management was analyzed on 3,923 testing data obtained from 136 implanted patients. The initial areas of paresthesiae due to stimulation were recorded and reported as the stimulation map according to the location of electrodes. Measurement of dorsal thickness of the cerebrospinal fluid (CSF) layer was obtained from 26 subjects using magnetic resonance imaging (MRI). The results indicate that the perception threshold is a function of the spinal level of the implanted electrodes, of the mediolateral position in the spinal canal and the contact separation of electrode. Differences in perception threshold at various vertebral levels are mainly due to varying depths of the dorsal CSF layer. The medially placed electrodes caudal to the mid-cervical levels have a higher perception threshold than more laterally placed ones. The electrodes at high and mid-cervical levels, however, have a smaller perception threshold if placed medially. The information obtained from this investigation has important implications for the design of a new-generation stimulation system and clinical application to maximize the longevity of the power source. PMID- 7854804 TI - Botulinum toxin in the treatment of myofascial pain syndrome. AB - Six patients with chronic myofascial pain syndrome involving cervical paraspinal and shoulder girdle muscles received trigger point injections of botulinum toxin type A (Botox) or saline in a randomized, double-blind, placebo-controlled study. Four patients experienced reduction in pain of at least 30% following Botox, but not saline, injections, as measured by visual analog scales, verbal descriptors for pain intensity and unpleasantness, palpable muscle firmness, and pressure pain thresholds. Results were statistically significant. Botox, which inhibits muscle contraction by blocking the release of acetylcholine from peripheral nerves, appears to be an effective treatment for focal myofascial pain disorders. PMID- 7854805 TI - Pain beliefs: assessment and utility. AB - When pain becomes persistent, patients may abandon previously held cultural or personal beliefs about pain to form new pain beliefs that are more consistent with their persistent pain experience. The Pain Beliefs and Perceptions Inventory (PBPI) is an instrument to assess these new beliefs. This paper presents 4 studies examining the utility of the PBPI. Two studies are factor analytic and support recent literature identifying 4 belief factors associated with this instrument. The third and fourth studies used a new scoring method for the PBPI creating 4 scales: Mystery, Self-blame, Pain Permanence, and Pain Constancy. These scales were then correlated with important pain indices such as measures of pain quality, psychological states (i.e., depression and anxiety), personality traits, physical functioning, and coping strategies. Each belief appears to have a unique association with the pain indices thus supporting the rescoring of this instrument with 4 scales. Belief in pain constancy is associated with greater pain self-report, permanence is associated with anxiety, mystery is associated with greatest overall distress, and self-blame is associated with depressive symptoms. An appendix is included that provides clinical norms for the use of the PBPI and a revised scoring key. PMID- 7854806 TI - Catastrophizing, depression and the sensory, affective and evaluative aspects of chronic pain. AB - Research has shown that catastrophizing is related to increased depression and chronic pain. However, some researchers have questioned the utility of catastrophizing as a separate construct, suggesting that it may just be a symptom of depression. The present investigation used path analysis to determine if catastrophizing was related to McGill Pain Questionnaire scores when controlling for depression as assessed by the Beck Depression Inventory in a group of 85 chronic pain patients. According to Fields' model of the relationship between pain and depression, we predicted that catastrophizing would mediate the the relationship between depression and the evaluative and affective aspects of pain, but not the sensory aspect. The resulting path coefficients appear to support these predictions. The results suggest that catastrophizing is a separate construct which may impact on pain perception and treatment. The data also provide some support for Field's neurobiological model of the relationship between depression and pain. PMID- 7854807 TI - Characterization of the foot withdrawal response to noxious radiant heat in the rat. AB - The rat foot withdrawal response to noxious radiant heat has been used as a model of nociception that is particularly useful for measurements of unilateral changes in nociceptive responses. The purpose of these studies was to characterize the foot withdrawal response to graded rates of noxious skin heating. Response latencies and both surface and subsurface temperatures produced by 6 different intensities of radiant heat were measured to determine whether response latency is an appropriate measure of nociceptive threshold. With constant intensity heating, the temperature of the skin surface increased as logarithmic function of time, while subsurface temperature increased linearly with time. In contrast, a heating function that linearly increased the temperature at the skin surface increased the subsurface temperature as an exponential function of time. These results and published reports of nociceptive afferent recordings which used similar skin heating parameters, indicate that nociceptive foot withdrawal responses occur at about the same skin temperature as the activation of nociceptors. These results also indicate that since constant intensity heating produces linear increases in the subsurface temperature, then response latency can be used as an accurate measure of changes in nociceptive threshold produced by drug treatments. These observations lead to the conclusion that the foot withdrawal response latency is a valid and useful measure of nociceptive threshold in rodents. PMID- 7854808 TI - Non-steroidal anti-inflammatory drugs and spinal nociceptive processing. AB - Non-steroidal anti-inflammatory drugs have a direct action on spinal nociceptive processing in vivo with a relative order of potency which correlates with their capacity as inhibitors of cyclooxygenase activity. However, recent clinical surveys and new in vivo evidence strongly suggest that for some of these agents, centrally mediated analgesia may also be achieved by additional mechanisms, which are independent of prostaglandin synthesis inhibition. In this review we explore the likelihood for such mechanisms following an extensive survey of existing data. The implications of these mechanisms are discussed in the light of our current understanding of spinal nociceptive processing. PMID- 7854810 TI - The four A's of restraint reduction: attitude, assessment, anticipation, avoidance. AB - The use of physical restraints in the nursing care of older persons is a controversial intervention. Consumer groups and regulatory bodies have issued statements and guidelines that call into question the use of restraints in all but the most extreme situations. This article reviews the changing perspectives on restraint use, including the growing body of research that documents the untoward effects of physical restraints. Alternatives to restraint use are discussed in relation to three broad areas: changing entrenched attitudes and beliefs, conducting thorough and frequent patients assessments, and planning interventions that anticipate events and behaviors and avoid problems that may lead to restraint use. PMID- 7854809 TI - Reduction in joint swelling and hyperalgesia following post-treatment with a non NMDA glutamate receptor antagonist. AB - The experimental arthritis of the knee joint used in the present study leads to joint swelling, increased joint temperature, limping, guarding, and a decrease in paw withdrawal latency (PWL) to radiant heat (hyperalgesia) within hours in rats. Unexpectedly, administration of the non-NMDA receptor antagonist, CNQX, in the spinal cord 4 h after initiation of the arthritis significantly reduced the degree of joint inflammation and returned PWL times to baseline. Therefore, the present results indicate that established joint swelling and hyperalgesia can be reduced significantly by CNQX. PMID- 7854811 TI - Acute confusion: nursing intervention in older patients. AB - Older patients are at high risk for developing acute confusion while hospitalized with an associated increased risk of morbidity and mortality. Causes for acute confusion include physiologic, psychosocial, and environmental alterations. Often not recognized by nurses, acute confusion needs to be differentiated from depression and dementia. Nursing assessment of acute confusion should include baseline data on cognition, behavior, and functional status. Standard, routine, and systematic assessments of cognition, behavior, and functional status need to be ongoing during hospitalization if nurses are to identify and manage acute confusion in hospitalized older patients. PMID- 7854812 TI - Orthopaedic nursing research priorities: a Delphi study. AB - Research has been an integral component of the mission of the National Association of Orthopaedic Nurses. Operationalization of this component of the mission has included a national research committee, funding of research grants, offering of educational sessions that highlight research methodology as well as research findings, and the formalization of a research editor position within Orthopaedic Nursing. The National Center for Nursing Research has recognized that the individual specialty nursing organizations have a role to play in determining priorities for that specialty. Consequently, NAON has been queried as to its research emphasis. This article presents the study conducted by NAON's Research Committee to determine research priorities within orthopaedic nursing. PMID- 7854813 TI - Transcultural nursing: a view of the Russian health care system. AB - In October 1991, I visited Russia, Hungary, and Czechoslovakia as a member of a delegation of orthopaedic nurses. The 30 delegates were assembled under the Citizen Ambassador Program of People to People International. Our focus was a sharing of information about orthopaedic nursing practice and the cultural influences related to health care practice. This article reflects my experiences and observations in St. Petersburg and Moscow as far as the facilities visited, patient population, nursing management, treatment modalities, equipment, ancillary departments, nurses' educational preparation, and the nurses' roles within the health care system. PMID- 7854815 TI - Authorship. PMID- 7854814 TI - Perceived body space and self-esteem in adult females with chronic low back pain. AB - This comparative descriptive study, an extension of previous research on adult males with chronic low back pain, investigated perceived body space (PBS) and self-esteem in adult females with chronic low back pain (CLBP). Findings were compared to adult males with CLBP and adult female populations without acute or chronic health conditions. Results indicated that no significant difference existed between adult females and males with CLBP regarding PBS and self-esteem. Additional analyses indicated that PBS in adult females with CLBP was significantly different from several groups of "healthy" adult females. Ancillary findings indicated that adult females with CLBP were significantly more depressed than adult males with CLBP. PMID- 7854816 TI - Models of nursing care in a changing environment: current challenges and future directions. AB - The last decade of health care in America has been characterized by elements that converged to mandate the need for restructuring health care delivery, which included rising costs, the prospective payment system, consumer expectations, patient care monitoring, the quality movement, and the nursing shortage. This changing environment has resulted in an array of nursing care delivery models to restructure care to assure quality of care, patient satisfaction, and cost containment. Some of the models include paired practice, case management, patient focused care, cross-training, and product line management. To meet the challenges of future health care delivery, nurses need to be aware of predicted future trends: decreasing specialization of health care personnel, flexibility of the traditional nursing role, increased community-based care, and expanded roles for nurses. PMID- 7854817 TI - Fraudulent publication. PMID- 7854818 TI - Traction basics: Part I. AB - Traction is a treatment modality used for the reduction or immobilization of fractures or dislocations. It is used to maintain alignment, decrease muscle spasms, relieve pain, correct, lessen or prevent deformities, expand joint spaces prior to surgery, promote rest to diseased or injured body parts and to promote exercise. Nurses need a working knowledge of the various types of traction along with its rationale, correct setup, and maintenance. They must become familiar with potential complications and use nursing diagnoses to work with patients to strive to achieve expected patient outcomes. PMID- 7854819 TI - Informed consent: the information component. AB - Patients are asked to give informed consent for both treatment and research protocols. Yet, is their consent really informed? This article focuses on the information component of informed consent. The author discusses informed consent as it relates to the ethical principle of respect for autonomy, presents nurses' perceptions of informed consent, and makes several recommendations that nurses can use to ensure that consent is informed. PMID- 7854820 TI - Vitamins: nutrients, food additives, or medications--vitamin C. PMID- 7854821 TI - A brief summary of the health care reform proposals and a look at the people behind them. PMID- 7854822 TI - Colles fracture. Smith fracture. PMID- 7854823 TI - Bursitis and tendinitis. AB - "Joint pain" may be a chief complaint reported by patients who are suffering from bursitis or tendinitis. Both disorders can develop in various joints throughout the body, but this article emphasizes the heel area since it is a common site for both disorders. Also addressed are the essential diagnostic features, general medical management, and nursing issues relevant to these disorders. PMID- 7854824 TI - Acute spondylolysis in an adolescent. AB - Back pain in the adolescent, though less frequent than in adults, is more likely to indicate pathology. Thus, persistent low back pain in an adolescent should not be overlooked. This article presents a case study of a 15-year-old female gymnast who experienced low back pain during practice sessions. Differential diagnosis and treatment options are discussed. PMID- 7854825 TI - Use of cryotherapy for orthopaedic patients. AB - Effective pain management and prevention of edema are goals for orthopaedic patients after injury and after surgery. Cryotherapy is the use of cold to decrease swelling and pain when tissue is damaged secondary to trauma or surgery. Although cryotherapy has been used for years by some practitioners to achieve these goals, it is gaining wider acceptance in sports medicine for acute and postoperative care. Newer techniques of application have broadened its use for postoperative care. This article reviews the physiology of cold, basic principles of cryotherapy, various techniques of cold application, nursing assessment and care, and patient teaching for a patient with cryotherapy. PMID- 7854826 TI - Competitive athletes and injuries: a rehabilitation performance perspective. Interview by Charles A Maher and Mary Faut Rodts. AB - The injured competitive athlete can be considered from a perspective that we term a rehabilitation performance perspective. Through consideration of the injured competitive athlete in this way, the health care provider can be guided in discovering and deciding how to formulate assessment protocols and plan for effective interventions. Aspects of our rehabilitation performance perspective and its seven psychologic states are illustrated with selected comments from an interview with Haley Scott. Scott, a competitive swimmer and student athlete from the University of Notre Dame, who had been paralyzed from a bus accident, has now returned to competition, school, and a full life. PMID- 7854827 TI - Electrolytes and their relationship to normal and abnormal muscle function. AB - Electrolytes are essential to normal skeletal muscle contraction and are thought to play a role in muscle fatigue. Excess accumulation of ammonia and hydrogen ions after strenuous bouts of physical activity are thought to slow muscle contractions and decrease muscle tension development. Certain disease states cause abnormal levels of such electrolytes as calcium, magnesium, potassium, or sodium. Excessively high or low levels of these ions in the serum are associated with symptoms such as muscle weakness or cramping. Nurses should know the effects of abnormal electrolyte levels on muscle function in the assessment and treatment of their patients. PMID- 7854828 TI - Patients with long-term vascular access devices: care and complications. AB - Orthopaedic nurses will be dealing with more long-term vascular access devices, such as tunneled catheters, implanted ports, and peripherally inserted central catheters as antibiotic and other supportive intravenous therapy is administered over longer periods. Caring for patients with these devices requires an understanding of the purpose and design of the device, use and maintenance of the catheter or port, and actions to take if complications arise. Knowing the cause and response to the most common clinical problems, such as infection, occlusion, and thrombosis, will help in problem solving and support a variety of teaching strategies for patients. Nurses who are familiar with these central venous devices will be able to provide safe and effective care for patients in the hospital and at home. PMID- 7854829 TI - Osteoporosis medications: what's your source of information? AB - New drugs for osteoporosis continue to be developed as the drug industry recognizes the increasing elderly population. Methods of treatment for osteoporosis differ according to the cause of the osteoporosis in each individual. To carry out appropriate treatment, nurses need to know the types of osteoporosis and their predisposing factors. PMID- 7854830 TI - Traction basics: Part IV. Traction for lower extremities. AB - Traction is a treatment modality used for the reduction or immobilization of fractures or dislocations. It is used to maintain alignment; decrease muscle spasms, relieve pain; correct, lessen, or prevent deformities, expand joint spaces before surgery; promote rest to diseased or injured body parts; and promote exercise. Nurses need a working knowledge of the various types of traction along with its rationale, correct setup, and maintenance. They must become familiar with potential complications and use nursing diagnoses to work with patients to strive to achieve expected patient outcomes. PMID- 7854831 TI - Gosselin fracture. Maisonneuve fracture. PMID- 7854832 TI - Aerobic dance injuries. AB - Aerobic dance has taken the spotlight as one of the most popular forms of exercise in America. The benefits of a well developed, comprehensive program include an increase in strength, flexibility, and endurance while promoting a healthy cardiovascular system. Orthopaedic nurse clinicians frequently come in contact with aerobic dance participants before and after injury occurs. This article discusses the occurrence of aerobic dance injuries, treatment, and prevention. PMID- 7854833 TI - Penetrating wounds of the extremities. Methods of identifying arterial injury. AB - Controversy surrounds the optimal management of a wound in proximity to a major vascular structure without clinical evidence of arterial injury. Current data suggest that physical examination alone can detect significant arterial injuries. If an arterial lesion is clinically silent on initial presentation, the natural history is most likely benign. In the rare case in which the arterial lesion degenerates into a more significant lesion, then it will do so slowly and can be repaired electively. In certain instances, there may be a penetrating wound that presents with a pulse deficit that resolves completely with observation. At this time, this is considered a hard sign of vascular injury and warrants aggressive preoperative evaluation. PMID- 7854834 TI - Cervical spine fusions for trauma. A long-term radiographic and clinical evaluation. AB - Ninety-six successful cervical spine fusions performed for trauma, with a minimum of 5 years' follow-up, were retrospectively reviewed. Radiographic degenerative changes adjacent to fusion masses were assessed and correlated with clinical symptoms. The type of fusion, fusion extension, and final kyphosis of the involved segments were also analyzed. Twenty-eight patients had fusion masses aligned in 20 degrees or more of kyphosis. There was a significant increase in complaints of cervical pain in patients with neck fusions equal to or exceeding 20 degrees of kyphosis (P < 0.01). Evidence of mild degenerative changes adjacent to fusion masses was common, but did not correlate with symptoms. PMID- 7854836 TI - Minifragmentation plating for comminuted distal patella fractures. A report of three cases. AB - A new technique using a minifragmentation plate to assist in the open reduction and internal fixation of displaced, comminuted distal-pole patella fractures was used in three patients with good results. This technique adds to the choices of treatment available to the orthopaedic surgeon who manages these difficult fractures. PMID- 7854837 TI - Professor Emile Letournel. PMID- 7854835 TI - Bilateral femoral head fracture with posterior hip dislocation. AB - Bilateral posterior hip dislocations with femoral head fractures are rare. We report the case of a 71-year-old woman who was an unrestrained driver involved in a head-on motor vehicle collision. The right hip was stable after reduction, while the left hip was felt to be unstable. Bilateral bipolar endoprostheses were inserted via standard posterior approaches. Fracture fragments composed approximately 35% of the femoral head in both hips. We believe an elderly polytrauma patient with a significant femoral head fracture may benefit from primary arthroplasty as a treatment option, especially in cases of bilateral injury. PMID- 7854838 TI - A new oral examination. PMID- 7854839 TI - Scaphoid fractures and scaphoid nonunion. Diagnosis and treatment. AB - Scaphoid nonunion can cause pain, loss of wrist motion, and loss of grip strength. Because initial roentgenograms are not always definitive, patients suspected of having a scaphoid fracture despite negative initial radiographs should undergo bone scan. Treatment of acute nondisplaced fracture of the scaphoid generally nonoperative, involving immobilization in a cast. Treatment of scaphoid nonunion is generally operative, and many procedures and their associated risks are reviewed. There is no consensus about the clinical implications of scaphoid malunion. PMID- 7854840 TI - The medial tibial syndrome. The role of surgery. AB - Among authors over the past 35 years, medial tibial syndrome, or "shin splints," has been interpreted to mean many different things. We present a review of the literature to attempt to ascribe one definition to this clinical entity, and to clearly define its symptoms, signs, pathophysiology, biomechanics, and treatment. In addition, we describe our results with five patients whose seven affected limbs eventually required surgery for this condition, and we compare them to the results in the literature. PMID- 7854841 TI - Irreducible volar rotatory dislocation of the proximal interphalangeal joint. AB - Volar rotatory dislocation of the proximal interphalangeal (PIP) joint often cannot be reduced by closed manipulation because of interposition of soft tissues. In this case, the condyle of the proximal phalanx was trapped between the central slip and the lateral band. This case is reported to reemphasize the importance of recognizing serious injuries involving the soft tissues around the PIP joint. Deprival of its normal dorsal stabilizing forces can cause a loss of both static and dynamic joint support. Secondary scarring and contractures affect all damaged structures of the joint. PMID- 7854842 TI - Bilateral spontaneous patellar tendon rupture in the absence of concomitant systemic disease or steroid use. AB - A case of bilateral patellar tendon rupture in an otherwise healthy 41-year-old man is presented. This is the 15th case reported in the literature. The mechanism of injury is attributed to a flexion moment coupled with a contraction of the quadriceps muscle in nearly all reported cases. Surgical repair produces excellent results. PMID- 7854843 TI - A 16-year-old boy with a swollen knee after a skateboarding accident. AB - The following case is presented to illustrate the roentgenographic and clinical findings of a condition of interest to the orthopaedic surgeon. The final clinical and differential diagnoses can be found on the following pages. PMID- 7854844 TI - Localization of the acromioclavicular joint. AB - Localizing the acromioclavicular joint can be difficult. Using bony landmarks- the clavicle and the spine of the scapula--the acromioclavicular joint can be consistently localized for physical examination, injections, and surgery. PMID- 7854845 TI - The evolution of parasite manipulation of host behaviour: a theoretical analysis. AB - Parasite-induced modifications of host behaviour are known from a wide range of host-parasite associations. In many cases, these behavioural changes are thought to be adaptive and benefit the parasite by increasing its probability of successful transmission. However, in many cases, energy spent on host manipulation will not be available for other functions, such as growth. These trade-offs suggest that in the absence of other constraints, natural selection will optimize, and not maximize, the influence of parasites on host behaviour. This argument is developed and expanded into theoretical considerations of the evolution of host behaviour manipulation by parasites. Among populations of the same parasite species or among closely-related species, the optimal investment into manipulation, or optimal manipulative effort (ME*), of individual parasites is predicted to increase as (1) typical infrapopulation size decreases, (2) prevalence increases, (3) the longevity of the infected host, or of the parasite in its host, decreases, (4) passive transmission rates decrease, and (5) parasite fecundity decreases. This evolutionary analysis indicates that ecological and life history variables may have played an important role in the evolution of manipulation of host behaviour by parasites. PMID- 7854846 TI - Physiological bases for parasite-induced alterations of host behaviour. AB - Parasitism is defined in various ways as an intimate relationship in which one partner, the parasite, lives on or in another, the host, generally at the expense of the latter. Parasitism commonly results in a unique array of host physiological responses and adaptations. Most studies of the physiological effects of parasitism have focused on the pathological consequence of infection and disease. While many physiological changes contribute to pathogenesis, it is now recognized that parasitic infections at sub-clinical levels also produce physiological effects that either ameliorate or may not contribute to the disease process. Moreover, these physiological changes are often manifested by altered host behaviour. Behavioural studies have enabled an ecological- and evolutionary oriented evaluation of host responses. In this fashion, physiological effects may be assessed as to whether they affect fitness and confer benefit or harm to one or both of the symbionts involved. We briefly examine how these physiological responses, specifically neural, endocrine, neuromodulatory, and immunomodulatory components, may interact to modify host behaviors. We consider the adaptiveness of these responses and how the behavioural patterns elicited may simultaneously appear adaptive for the parasite as well as the host. In addition, we address how parasite-host physiological and behavioural interactions may be altered during the course of parasitism. PMID- 7854847 TI - Behavioural defense against parasites: interaction with parasite invasiveness. AB - Behavioural patterns involved in avoiding, repelling, or removing parasites allow mammalian hosts to defend themselves from an array of parasites that threaten the host's fitness in the natural world. Some examples of behavioural defenses and the presumed target parasites are: grooming to remove ticks, grouping to reduce attack rate of biting flies, fly repelling movements to reduce parasitic flies, and selective grazing to reduce intake of faecal-borne parasites. These behavioural defenses are discussed with regard to effectiveness in controlling the target parasites. Parasites have sometimes evolved behavioural strategies of evading, penetrating or disabling these behavioural defenses. These parasite behavioural strategies, though less studied, are discussed. Also discussed is the possibility that host behavioural patterns that may defend against one parasite may be exploited by a different type of parasite to facilitate its own transmission. The interplay between host defensive strategies, the cost versus the effectiveness of such strategies, and a parasite's evasion or exploitation of such strategies, may be useful in understanding some aspects of host-parasite dynamics in nature. PMID- 7854848 TI - Physiological analyses of host-finding behaviour in trematode cercariae: adaptations for transmission success. AB - Physiological analyses of the behaviour of several cercarial species which actively find and invade their hosts have revealed very complex sequences of behaviour patterns and responses to very different stimuli from the environment and the host. A result of these physiological studies is that the behaviour patterns of each of the species investigated are surprisingly individual. The behavioural patterns of host-finding of those species analysed in some detail reveal profound adaptations to maximize transmission success. This can be demonstrated for movement patterns during swimming, for responses to environmental conditions such as gravity, light and temperature, for responses to stimuli emanating from the host such as shadows, water turbulence and chemical compounds and especially for the responses after contact with the host. The behaviour patterns can be interpreted as adaptations to: (1) dispersal by leaving the habitat of the snail intermediate host and distribution within the area; (2) long survival by energy saving swimming behaviour, by avoiding responses to inappropriate stimuli, by selecting favourable microhabitats and probably by avoiding predation; (3) finding and invading particular host types by selecting microhabitats frequented by the hosts and responding to sequences of specific stimuli emanating from the hosts. PMID- 7854849 TI - Behaviours in trematode cercariae that enhance parasite transmission: patterns and processes. PMID- 7854850 TI - The ecology of host-finding behaviour and parasite transmission: past and future perspectives. AB - Host location by parasites can be achieved by either active or passive mechanisms. In spite of their significance, the efficacy of these methods has been little researched. High fecundity in parasites is discussed in terms of the role it plays in dispersal and transmission. Some concepts developed by mainstream behavioural ecologists are outlined and their relevance to parasitology is indicated. 'Reproductive value' is recommended as an appropriate measure of the costs and benefits of behavioural cts. Although costs of reproduction have been rarely studied in parasites, they are likely to occur in cosexual insects, nematodes and crustaceans. Experiments using captive hosts and/or in vitro cultivation could help in the construction of realistic optimality models. We suggest that r- and K-selection theory could assist in the study of the evolution of parasite behaviour. We discuss how parasite populations are dispersed and controlled and consider the implications of overdispersion. We outline three sources of signals to which parasites may respond and suggest that understanding evolutionary mechanisms and community organisation of parasites and hosts requires evaluation of fundamental behavioural responses to environmental signals. The study of closely related groups of parasites and their hosts may advance our knowledge of the evolution of parasite life cycles and the evolutionary costs and benefits of behavioural acts. PMID- 7854851 TI - Optimal habitat selection by helminths within the host environment. AB - Helminth parasites of vertebrates usually select very specific regions or habitats in their hosts, and this is often preceded by a tortuous migration through various host organs. However, the proximate mechanisms of migration and habitat selection have remained enigmatic despite considerable effort by parasitologists. In this paper a new approach to studying helminth behaviour in the host is proposed. The core idea is that behaviour strategies must be considered from the perspective of the parasites and their perceptions of their environment. A guiding principle is that the environmental features to which an animal responds, and the actions which are required for responding to the environment, form a fundamental unit of behaviour. Thus, we can deduce an animal's behavioural strategy from the details of its response to environmental signals and from its sensory capabilities. The evidence presented suggests that helminth behaviours in the host often occur as fixed (or modal) action patterns which are usually seen in response to constant, or predictable environmental features. Thus, a working hypothesis is that the mechanisms of physiological and biochemical homeostasis within the host provide an extremely predictable environment for the parasite. Under these conditions, a parasite needs to perceive only small subsets of the total information available from the environment to respond appropriately. Studies on sensory and nervous systems of these organisms are critical to understanding parasite perception, but there are formidable technical obstacles that prevent easy access to parasite nervous systems. Therefore, a multidisciplinary approach, using ideas from parasitology, ecology, evolutionary biology and neuroethology, is considered requisite for reconstructing the parasites' behaviour strategies. It is suggested that future directions should pursue integration of studies on sensory physiology with the behavioural ecology of these organisms. PMID- 7854852 TI - Doubt and certainty about the pathways of invasive juvenile parasites inside hosts. AB - It is generally believed that the patterns of in-host migration of the infective stages of most invasive macroparasites of man and domestic animals are matters of established fact. In reality, the textbook treatment of this topic, and much of the experimental approach to it, are a legacy of an uncritical past. With few exceptions the true picture concerning particular host/parasite systems is confused by the acceptance of inadequate criteria of proof. In important instances these bogus 'proofs' have been generalized within a suspect inductive framework which employs the basic assumption that all migratory parasites that enter the same portal and travel to the same destination do so by the same route. The discussion of such issues serves as a background to the presentation in detail of a more rigorous conceptual and experimental framework. PMID- 7854853 TI - Niche restriction in parasites: proximate and ultimate causes. AB - Hutchinson's (1957) definition of an ecological niche as a multidimensional hypervolume determined by a number of physical and biotic variables is adopted. The number of niche dimensions is very great, but as a working hypothesis it is assumed that a few are sufficient to characterize the niche of a parasite species to a high degree of accuracy. They are host species, microhabitat(s), macrohabitat(s), geographical range, sex and age of host, season, food and hyperparasites. Methods to measure niche width, in particular specificity indices, are discussed, and some examples of niche restriction are described. Proximate and ultimate causes of niche restriction are discussed, mainly using marine parasites as examples. Among proximate causes of one niche dimension, host specificity, are ecological factors restricting exposure to infection to certain host species; host-specific chemical factors that induce hatching, direct infective stages to a host and bring about settlement of a parasite; factors that lead to mortality in or on the wrong host; morphological adaptations that guarantee survival in or on the 'correct' host; and availability of suitable hosts. Many factors are likely to be responsible for microhabitat specificity, but have been little studied, except for some physiological and morphological adaptations to particular microhabitats. Macrohabitats and geographical range may be determined by the distribution of intermediate hosts and certain food items, and by a variety of chemical and physical factors. Hosts of different sexes may differ in feeding habits and the composition of the skin, and thus acquire parasites differentially. Hosts of different age may be differentially infected due to accumulation of parasites with age, loss of parasites due to developing resistance (or immunity), and different size and feeding habits. Among ultimate causes of niche restriction and segregation are avoidance of competition, predation and hyperparasites; facilitation of mating; reinforcement of reproductive barriers; and adaptations to environmental complexity. Few studies permit a decision on which factor or factors are responsible in particular cases. Interspecific competition may play a greater role in helminth communities of some host groups than of others, but it seems that, overall, its role has been exaggerated at least for marine parasites. Some 'classical' examples of microhabitat segregation explained by interspecific competition can also be explained by reinforcement of reproductive barriers. There is evidence for the importance of facilitation of mating in microhabitat restriction, and the availability of many vacant niches indicates that competition, overall, is not of great importance. PMID- 7854854 TI - Evolutionary factors influencing the nature of parasite specificity. AB - This article considers how specificity patterns are shaped during the course of parasite evolution. Parasites are first and foremost specific to site, or microhabitat; host ranges are far more subject to change than is microhabitat. Specificity results from a number of convergent phenomena starting with habits (microhabitat and feeding styles) of free-living progenitors and the way in which the parasitic association arises (e.g., passive oral contamination as opposed to intrusive entry). These bias the types of interaction parasites have with the host, and, through this, the way specificity develops. Host ecology acts as an external factor affecting specificity and predominates in parasites that interact minimally with the hosts physiological and immune systems. Coevolutionary factors are more important in parasites that feed on host tissues or occur in extraintestinal sites. Here, parasites must present the right cues, and respond appropriately to the host defense system. The ability to generalize these cues and responses across host boundaries may act as a constraint on host range. The functional role of the host in the parasite life history also affects the degree of specificity; thus, parasites may act as host generalists in hosts that act as trophic channels to the final host. The role of competition in determining specificity is difficult to assess. However, competition has been reported to influence microhabitat and host distribution through interactive site selection and/or competitive seclusion. PMID- 7854855 TI - The population dynamics of parasitic helminth communities. AB - This paper describes a mathematical model which allows us to compare the data collected from short-term cross-sectional surveys with the population dynamics of host and parasite populations over longer periods of time. The model extends an earlier framework for two parasite species in one host, to one for an arbitrary number of parasite species. We show that the conditions necessary for the coexistence of two parasite species extend to expressions for the coexistence of three or more parasite species. Furthermore, the model suggests that those species which form the 'core' of the parasite community are those whose high fecundity and transmission efficiency permit them to colonize hosts readily. In contrast, those species which are classified as 'satellite' species of the community are either species with low fecundity, or low transmission efficiencies. This work confirms earlier studies that suggest that increasing degrees of aggregation are crucial in allowing several species of parasites to coexist in the same species of hosts. The properties of the model are compared with patterns observed in data collected for helminth parasites of Anolis lizards, wood mice and eels. This combined theoretical and empirical approach confirms the importance of the life history strategies of the parasite in determining the abundance of each species in the community. It suggests that studies of parasite community structure have to pay more attention to the strategies pursued by each individual species before interactions between species are considered. PMID- 7854856 TI - [Adherence of isolated Candida albicans strains from HIV+ infected patients to buccal epithelial cells: correlation with serotype, sensitivity to fluconazole and virulence]. AB - During infection by human immunodeficiency virus (HIV), oral pseudomembranous candidiasis frequency is high. Adherence of Candida albicans to epithelial cells constitutes one of the first step in the setting up of candidiasis. Adherence ability of Candida albicans to buccal epithelial cells (BEC) is estimated for 83 isolates. The yeasts are isolated from buccal swabs from HIV+ patients with clinical oropharyngeal candidiasis. Results show that Candida albicans ability to adhere to BEC is variable within isolates; it appears that most of the isolates are weakly adherent. In addition, adherence is not correlated with the serotype A or B of yeasts. We do not either observe any correlation between adherence capacity and sensibility of yeasts to fluconazole. Moreover, no correlation is observed between a group of 13 genetically identical isolates (analysed on 21 loci with isoenzymes method) and their adherence to BEC. Finally, Candida albicans virulence, which is studied in vivo on intravenously infected mouse model, does not seem to be correlated with capacity of each yeast to adhere on BEC in vitro. PMID- 7854857 TI - [Detection of anti-neutrophil cytoplasmic antibodies with proteinase 3 specificity by immunoblotting]. AB - Antineutrophil cytoplasmic antibodies (ANCA) are autoantibodies mainly directed against alpha granules' components (especially proteinase 3 (PR 3) and myeloperoxidase (MPO). They are usually detected by indirect immunofluorescence (IIF) giving essentially two staining patterns, cytoplasmic and perinuclear. Nevertheless the IIF method does not allow to precise the true specificity of ANCA. From now on a better classification of systemic vasculitis requires such a determination. This can be done only by solid phase tests that require to be reliable, highly purified antigen, and, from a practical point of view, only a MPO-ELISA is currently available. We report on our experience with Western blot analysis of 67 IIF-ANCA positive sera. Using Western blot analysis to characterize ANCA specificity is not so easy as in the case of antibodies directed against extractable nuclear antigens: only PR 3 ANCA detection could be done reproducibly. PR 3 ANCA are mainly detected in the c-ACPN positive sera of patients with Wegener's granylomatosis. Nevertheless using both MPO-ELISA and PR 3 blot seems to increase the frequency of serum containing the two types of ANCA (anti PR 3 and anti MPO). PMID- 7854859 TI - [Antibacterial activity of ciprofloxacin in the urine during four days after a single 500 mg and 750 mg oral dose]. AB - Antibacterial activity of ciprofloxacin was studied in the urine after a single 500 mg and 750 mg oral dose in ten healthy female volunteers. Urine was collected, after each single oral dose, during seven time periods: 0-3 h, 3-6 h, 6-12 h, 12-24 h, 24-48 h, 48-72 h, 72-96 h. Ciprofloxacin concentrations were assayed by microbiological method. Urine antibacterial activity was determined for five bacterial strains isolated in urine: 2 E. coli strains, one sensitive and the other resistant to nalidixic acid (Nal-A), 1 Klebsiella pneumoniae resistant to nalidixic acid (Nal-B), 1 Staphylococcus saprophyticus and 1 Enterococcus faecalis. MICs of ciprofloxacin against these strains were respectively 0.003, 0.06, 0.25, 0.06 and 0.5 micrograms/ml. Ciprofloxacin mean concentrations in the seven urine samples were 292.5 +/- 55.8, 81.1 +/- 16.9, 43.7 +/- 11.6, 11.5 +/- 1.9, 1.3 +/- 0.2, 0.3 +/- 0.05 et 0.1 +/- 0.05 micrograms/ml after a single 500 mg oral dose and 215.1 +/- 68.1, 56.1 +/- 17.8, 43 +/- 8.8, 14.4 +/- 5.5, 1.4 +/- 0.2, 0.4 +/- 0.1 and 0.2 +/- 0.05 micrograms/ml after a single 750 mg oral dose. Urine bacteriostatic activity was not very different after a 500 mg dose and a 750 mg dose. Against enterobacteriacae, after a 500 mg dose it was > or = 16 the first day; it was > or = 512 for the Nal-S E. coli. It was > or = 64 the first day, and remained between 2 and 32 the second day for the Nal-R strains (E. coli and Klebsiella).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7854858 TI - Thyroid stimulating antibodies in sarcoidosis. AB - OBJECTIVES: Thyroid disorders, particularly euthyroid goiters and hyperthyroidism, can be observed in sarcoidosis. The aim of this study was to analyze the presence of thyroid stimulating antibodies (TSAb) in 21 patients with sarcoidosis. 12 patients out of 21 had simultaneous euthyroid goiter. The others were euthyroid and free of goiter. METHODS: The TSAb testing was carried out using the rat thyroid fragment perifusion technique. Thyroid response to IgG was determined by the mean rate of T4 release (R) during a 30-min perifusion and the secretion peak (Imax). Antibodies inhibiting TSH binding to its receptors were also looked for. RESULTS: Ten patients were TSAb+ and eleven were TSAb-. There was no difference between the TSAb+ and TSAb- groups in the clinical parameters for sarcoidosis, nor in the number of goiters found (n = 6 for both groups). In 5 out of the 6 cases where goiter was present in the TSAb+ group it was homogeneous and diagnosed at the same time as or after the first signs of sarcoidosis, whereas in 5 out of the 6 cases of goiter in TSAb- patients, it was nodular, diagnosed before sarcoidosis in 3 of them, endemic in one of them, and familial in another. The search for antibodies inhibiting TSH binding to its receptors was negative in 10 out of 21 patients tested. CONCLUSION: Although the presence of thyroid-stimulating antibodies in the serum of patients with sarcoidosis, found here for the first time, remains to be explained, it pleads in favor of the immunologic nature of the association of sarcoidosis with thyroid disorders. PMID- 7854860 TI - [Transmission of hepatitis C virus from mother to infant]. AB - The transmission of hepatitis C virus (VHC) by percutaneous exposure to blood contamination is well documented but account for only 50 to 60% of hepatitis C cases. The transmission route for sporadic cases remains controversial and transmission by sexual contact and vertical transmission have been implicated. Antibodies to HCV are detected in 0 to 4.3% of pregnant women varying across geographic regions or origins. Passively transmitted maternal anti-HCV are detected in most of the new-born babies and persist during 6 to 18 months. The estimated risk of vertical transmission varies widely in the literature probably because of methodological considerations. But the detection of HCV-RNA in the blood of children has confirmed vertical transmission of HCV from mother to infant in mothers coinfected or not with human immunodeficiency virus type 1. In case of vertical transmission, some children develop an acute hepatitis or a chronic carrier state with or without chronic liver disease. In this case, the course of HCV RNA and transaminases might reflect the fluctuating viral replication. Some other children, infected at birth, seem to clear the HCV virus. The babies' HCV-antibodies are detected in some infected children but not in all. The follow up of HCV-seropositive pregnant women and their offsprings with more reliable methods should clarify the clinical importance, the rate of transmission and the factors which influence it. PMID- 7854861 TI - [The desmosome: structure, function and acquired pathology]. AB - The essential function of the skin is that of a barriere against the outside. The epidermis is the tissue which assures the solidity and the resistance of the skin against forces of traction. The desmosomes, allowing the adhesion of epidermal cells, the keratinocytes, between them, are the structures of resistance of the epidermis. This adhesion function is possible thanks to the interactions between the desmosomial molecules and cytosqueletal filaments. Currently fifteen desmosomal proteins implicated in this process have been characterized. The role of desmosome in integrity of epidermis is demonstrated by the existence of the auto immune dermatosis, the pemphigus, in which the inflammatory reaction against desmosomal proteins results in the loss of the cohesion of keratinocytes. PMID- 7854862 TI - [The extracellular matrix: from supporting tissue to regulation of cytokines]. AB - Extracellular matrix is a polymorphic structure composed of at least thirty molecules (collagens, glycoproteins, elastin, and proteoglycans) associated in a complex network. This insoluble structured framework ensures tissue cohesiveness, and allows cells to adhere, migrate and interact. Together with cytokines extracellular matrix is also involved in the control of various aspects of cell activities. Cytokines mediate cell to cell communication. Their broad effect result from their pleiotropic and overlapping activities. Once secreted, these molecules diffuse between cells--i.e. across extracellular matrix--to reach their target cells. An increasing number of cytokines are now known to bind to the extracellular matrix. These interactions change the availability of cytokines on effector cells, activate some growth factors, localize and/or increase the duration of the expected effect. Matrix-cytokines interactions are a new field of investigation which has changed our view on extracellular matrix. First considered as a supporting tissue, extracellular matrix appears now to be critically involved in the regulation of cytokine activities. PMID- 7854863 TI - [Normal values of growth hormone assay in urine in adults, established with a commercial kit]. AB - Normal range values of urinary growth hormone excretion (GH-u) were established in 30 healthy adults with a commercial kit (h GH u Coatria, bioMerieux). Six complete GH-deficient patients, three acromegalic patients, and five diabetic patients with nephropathy were also studied. The authors conclude that GH-u measurement in adults in useful to evaluate GH production in subjects with normal renal function. PMID- 7854864 TI - Working with families. Opportunities for early intervention. AB - The birth or arrival of a baby is a defining event for families. Most infants progress through predictable, yet individual, patterns of development. All families want the opportunity to optimize their children's futures, yet each spurt of development is a transition that can stress the child and the entire family system. These biobehavioral shifts, or "touchpoints," provide opportunities for the pediatrician to help the family understand, adapt, enhance, and promote the child's outcome. This family level approach serves as a form of anticipatory guidance that helps both parent and child successfully manage the challenging phases of development: motor, cognitive, social, and emotional. The "touchpoints" concept can be adapted for the pediatrician to help older children and their families. PMID- 7854865 TI - The referral role of pediatricians. AB - Pediatricians have a vital role in making effective mental health referrals for many children and their families. After selecting families who are appropriate for referral, for which type of resource, and the severity of their problems, the clinician should carry out a careful process to ensure the success of the referral. Special attention should be paid to finding the pain in individual family members, locating appropriate resources, and following up once a referral has been made. PMID- 7854866 TI - Family-oriented pediatric care. Taking the next step. AB - Pediatricians often have more information at their disposal than they use. They are frequently aware of some of the family issues that can contribute to their patient's health. This article has presented a framework for moving beyond a solely biomedical model to one that uses this information to create a more comprehensive picture of the family--one that offers the potential to unlock impasses and increase both physician and family satisfaction. PMID- 7854867 TI - The first interview with a family. AB - The family interview is the essence of family-focused pediatric care. The first interview is especially critical because it provides the creation of a therapeutic alliance, an assessment of the family and its concerns, and the formation of goals and solutions. Knowing interviewing techniques will ensure a successful outcome for the family and the pediatrician. PMID- 7854868 TI - Brief solution-focused strategies for behavioral pediatrics. AB - In an era of shrinking resources and managed care, brief models of psychotherapy are receiving increasing attention. One of the newest and innovative of those, brief, solution-focused therapy, is particularly efficient, because it concentrates on the present and the future; builds on strengths; focuses on clear, realistic goals; uses tasks; and develops client cooperation and efficacy. Parents have long turned to pediatricians for help in addressing a variety of child-rearing and other family concerns. Behavioral pediatricians who are looking for time-effective ways to counsel families should consider the six solution focused techniques described in this article and pursue training in this approach to family therapy, yet another example of family-focused pediatrics. PMID- 7854869 TI - Family violence. A child-centered, family-focused approach. AB - Child maltreatment and spousal abuse are complex problems without simple solutions. Pediatricians can play a critical role in the early detection of abuse, carry out an initial assessment, and make appropriate referrals. By taking a family-focused perspective, and considering the social-emotional and economic context in which all family members live, the pediatrician will be more sensitive and alert to both the stressors and strengths within each family. Child maltreatment and spousal abuse affect children directly and indirectly in a variety of domains, including social-interactional, emotional status, self-image, behavior, and learning. A better understanding of these issues will enhance the comprehensiveness of the pediatrician's efforts and provide a better outcome for children and their families. PMID- 7854870 TI - Recognizing the impact of marital discord and parental depression on children. A family-centered approach. AB - The American family is changing. Pediatricians are increasingly aware of treating children within a family systems context. Patients present with a variety of biopsychosocial problems, and pediatrics must continue to adjust to fit the changing needs of children and their families. Pediatricians must view themselves as members of a community of caretakers for families and children. The pediatrician faces increasing responsibility in responding to the increased stress experienced by children and their families. Family-focused pediatrics is becoming an increasingly accepted part of pediatric practice. The authors have sought to provide strategies for assessing and intervening with families in which depression and marital discord are impairing children's well-being and development. The pediatrician's role as a trusted family consultant creates a unique situation in which problems that often go unnoticed and unattended can be recognized and addressed early. In this way, children can be spared the consequences of exposure to parental conflict and the decreased functioning of a depressed parent. PMID- 7854871 TI - Best interests of the child in the family and community. Social, legal, and medical implications for pediatricians. AB - Pediatricians play a large role in social-legal efforts to assure children of appropriate priorities in a democratic society. Pediatricians must be aware of the social, legal, and medical ramifications of divorce, physical or sexual abuse, and medical/pediatric problems and how to serve the best interests of the child. PMID- 7854872 TI - Training for family-oriented pediatric care. Issues and options. AB - Pediatrics is by its nature a family-oriented medical specialty, and pediatricians gain a great deal of knowledge regarding the strengths and vulnerabilities of families in the course of traditional training and practice. The biomedical focus of pediatric training has resulted, however, in relatively little directed teaching about the contextual aspects of pediatrics. This lack is most notable with respect to training for effective work with families. Over the past 2 to 3 decades, the family systems model has developed. The perspective and applications gained through this model have provided important potential skills and knowledge for medical and psychological professionals. Pediatricians who wish to enhance their skills with families need to take an active role in designing, selecting, and integrating the training that best fits their practice and their interests. This requires a process of realistically assessing the level of work with families that they wish to implement and finding the training and supervision experiences that will support such goals. This training often brings with it particular challenges to traditional practice methods. The effectiveness of continuing education programs in family-oriented care may be gauged, in part, by their ability to assist pediatricians in meeting these challenges. A variety of training options and resources are described in the appendix of this article. PMID- 7854873 TI - When community resources fail. Assisting the frightened or angry parent. AB - The failure to receive expected community services or specialized in-home medical care can be upsetting for some parents. This article is designed to help pediatricians interpret inappropriate family behaviors and to therapeutically defuse verbal anger, unrealistic expectations, and unfounded fears. PMID- 7854874 TI - Toward multiculturality. Implications for the pediatrician. AB - Pediatricians must become more aware of America's growing ethnic, racial, and immigrant populations. A pediatrician who is not a member of an ethnic group can certainly become a minority family's doctor. It is the position of this article that the pediatrician must understand the importance of cultural issues and allow the family to become his or her guide. The suggested interview is provided as an outline for readers to both use with immigrants and to discover personal areas of cultural awareness and either knowledge or sensitivity gaps. Some individuals may want to only think about the questions and mentally relate them to certain families. Considering questions of this nature can help each pediatrician to become better spontaneous interviewers and to keep cultural concepts within working memory. PMID- 7854875 TI - Alcoholism in adolescents and their families. Family-focused assessment and management. AB - A family-focused approach is the most effective clinical method in the assessment and management of substance abuse in adolescents and their parents. The impact of alcoholism and substance abuse on parents and children, psychosocial risk factors, and indicators of alcoholism are important considerations when using this approach. Education regarding the family-focused approach to the treatment of substance abuse deserves a high priority in the training of pediatricians and other primary care physicians. As Doherty and Baird suggest," . . . the key to this training will not be . . . the development of a more sensitive liver function test, . . . but (rather) will be to help primary care physicians view individual patients as a part of a social context. The challenge will be to train the physicians to evaluate the patient in his or her social and family system for significant disturbances that commonly occur with chemical dependency. By evaluating the presenting patient in a family context, the primary care physician has the means to discover chemical dependency in early stages, when treatment options are less disruptive; when outcome is improved; and when the emotional and economic losses to patient, family and community are reduced." PMID- 7854876 TI - Beyond the nuclear family. Resources and implications for pediatricians. AB - In the United States, the shift from traditional nuclear families to diverse family forms has been dramatic. As a result, it is estimated that only 50% of children will live with their biologic parents until their 18th birthday. Consequently, many of the children seen by pediatricians live in non-nuclear family homes. Despite society's difficulty in accepting family diversity, research indicates it is not the form of the family that leads to problems for children, but it is conflict in the family that can produce lasting emotional difficulties. The family's task is to create emotionally supportive interactions within the family, regardless of family type. The pediatrician is a major societal contact for many families. As such, pediatricians are in a position to make a meaningful difference in the health of children and families. This can bring rewards to the family and to the pediatrician. By being more knowledgeable about the child's form of family, its intrinsic strengths and potential problems, and more specifically about the nature of relationships within the family, a pediatrician can play a major role in the anticipation, early detection, and intervention of problems. The knowledge and techniques suggested in this article, when used appropriately, will assure a better outcome for children and their families. PMID- 7854877 TI - Promoting resilience in families experiencing stress. AB - All families experience many different life events, strains, and hassles over their life spans. Stress emerges in the family when demands exceed capabilities. When this imbalance persists and becomes larger, children and other family members often show signs and symptoms of distress, including health-related problems. Pediatricians are increasingly called on to evaluate this situation and to be helpful to stressed families and their children. A family assessment model is presented to aid pediatricians in helping families to identify the sources and degree of stress they are experiencing, and even more importantly, to facilitate their ability to discover and use their own strengths and resources. The goal for the pediatrician is to promote balance and resilience in families, which, in turn, will contribute to better health and functioning in children. PMID- 7854878 TI - Beyond anticipatory guidance. Parenting and the family life cycle. AB - To review life cycle issues as well as the individual development of children and parents can be extremely constructive for long-term health care. An increased awareness of developmental patterns helps parents to take, provide, and pass on leadership. Conversations about the individual and family life cycles in primary care settings enrich primary health care and provides a forum for dealing with a variety of pediatric and health care issues. PMID- 7854879 TI - No child is an island. Contextual pediatrics and the "new" health supervision. AB - This article emphasizes the necessity for the pediatrician to view the child, the family, and the community as a part of a seamless continuum. For their maximal effectiveness, the disease prevention and health promotion goals of child health supervision require such a contextual pediatric approach. PMID- 7854880 TI - The influence of families on child health. Family behaviors and child outcomes. AB - The family is the most central and enduring influence on children. Families, regardless of their composition, are themselves subject to a variety of social forces that influence how well they are able to meet children's needs. Pediatricians who understand the functions families serve and the factors that constrain them will be better able to assist parents in promoting their children's health and well-being. PMID- 7854881 TI - Congenital syphilis: evaluation and management of neonates born to mothers with reactive serologic tests for syphilis. PMID- 7854882 TI - Surveillance of pharyngeal colonization: detection and control of serious bacterial illness in low birth weight infants. AB - Routine surveillance for bacterial colonization has been used for the past three decades as a tool for the prediction of nosocomial infection in low birth weight infants; however, its usefulness has never been proven. A prospective cohort study was conducted to examine the utility of surveillance for pharyngeal colonization in detection and control of serious bacterial illness in low birth weight infants. One hundred fifty-four infants who weighed less than 1750 g and who were admitted to the Neonatal Intensive Care Unit were enrolled and followed for a total of 5620 infant-days. Pharyngeal cultures were collected at the time of enrollment and then weekly. All infants had bacterial pharyngeal colonization by the third day of life. Coagulase-negative staphylococci were the most common organisms cultured from the pharynx, followed by viridans streptococci and Staphylococcus aureus. More than 90% of the pharyngeal cultures grew multiple isolates. Gram-positive organisms, particularly coagulase-negative staphylococci, were the most prevalent organism recovered from blood and cerebrospinal fluid cultures. Fifty-two episodes of bacteremia and 6 episodes of cerebrospinal fluid infection occurred in 42 infants. Among infants with viridans streptococci in pharyngeal cultures, the subsequent risk of serious bacterial illness was significantly reduced (odds ratio = 0.16). However, pharyngeal cultures were poor predictors of the causative organism in an episode of serious bacterial illness. Pharyngeal and blood/cerebrospinal fluid cultures were concordant in only 11% of invasive infections. We conclude that pharyngeal surveillance cultures provide little clinically meaningful information and have no apparent utility in the Neonatal Intensive Care Unit setting. PMID- 7854883 TI - Early discontinuation of antibiotic treatment in newborns admitted to rule out sepsis: a decision rule. AB - We developed a decision rule to define a group of newborns eligible for discontinuation of antibiotic treatment 24 hours after initiation. The decision rule is based on two clinical assessments, three demographic variables, four maternal risk factors and six laboratory studies. The rule was created by retrospective analysis of all admissions to rule out sepsis at 10 Kaiser Permanente Northern California Region nurseries during a 2-month period in 1990. Of the 214 study subjects, 11 (5%) had a positive bacterial or viral culture result. No deaths occurred, but three babies who had negative culture results experienced late deterioration (after 24 hours in the special care nursery). After 24 hours of antibiotic treatment, 133 (67%) of the 199 babies who had negative culture results were asymptomatic, 36 (18%) had clear signs of illness and 30 (15%) had questionable signs of illness. The rule correctly identified all babies with positive culture results as well as all persistently symptomatic babies with negative culture results. The rule also identified 57 low-risk babies eligible for only 24 hours of antibiotic treatment. We tested the rule on a second data set. The rule identified 19 of 20 newborns with positive culture results in this independent group. The 20th baby was not identified because a required test (complete blood count at 12 to 24 hours of age) was not done. Under controlled clinical conditions, this baby could have returned to the nursery to complete antibiotic treatment. We concluded that early discontinuation of antibiotic treatment in selected newborns is safe and could lead to a 1 to 2% decrease in special care nursery days in our 10 hospitals. PMID- 7854884 TI - The role of heparin in the prevention of extremity and digit necrosis in meningococcal purpura fulminans. AB - In order to gather data regarding the utility of heparin therapy in limiting digit and extremity necrosis resulting from meningococcal purpura fulminans in children, we reviewed the charts of 24 pediatric patients with PF associated with meningococcal disease. Our study population was comprised of the 13 patients who survived more than 2 days. Clinical and outcome data were compared between the group of patients who received therapeutic heparin treatment in the initial 72 hours (> or = 50 units/kg bolus followed by an infusion, three patients) and the group who did not (10 patients). Demographic and initial clinical and laboratory findings were similar between groups (P > 0.15). When the two groups were compared for dermatologic and orthopedic sequelae, the mean number of digits (6.3 vs. 11.1; P = 0.35) and extremities (1.7 vs. 3.0; P = 0.17) with necrosis was less in those patients who received therapeutic doses of heparin, although the differences were not statistically significant. When only those patients on whom diffuse purpura were noted on admission were compared, these differences were greater. This small, retrospective series suggests that heparin therapy may limit digit and extremity necrosis when used early and in therapeutic doses in meningococcal purpura fulminans. Therefore, a larger, prospective controlled trial is warranted. PMID- 7854885 TI - Invasive pneumococcal disease in a pediatric population, Auckland, New Zealand. AB - Streptococcus pneumoniae is one of the major invasive pathogens in childhood. The increasing worldwide prevalence of penicillin-resistant strains makes management of invasive infections difficult and underscores the need for effective vaccines. Currently available vaccines are of limited value in the pediatric age group. Trials are taking place to evaluate conjugated pneumococcal vaccines and in view of this it is important to establish local epidemiology of pneumococcal disease. The aims of this population-based study were to review all of the cases of invasive pneumococcal disease occurring during a 9-year period (1984 to 1992) in Auckland, New Zealand. Through the use of laboratory records and hospital discharge codes, 413 isolates from 407 patients were found. Age-specific incidence for all invasive disease was 22.0/100,000 for children less than 15 years old but 56.0/100,000 for children less than 5 years old (chi 2 Yates corrected 18.20; P = 0.001). Two-thirds were less than 2 years old. The rates were higher in Maori and Pacific Island children than in Caucasian children. A total of 70 isolates from 68 patients with meningitis occurred. The majority were less than 5 years old (incidence of meningitis was 10.0/100,000) and 84% were less than 2 years old. The overall mortality from meningitis was 4.3%. Of the 129 isolates serogrouped or serotyped, 14, 6 and 19 accounted for 23%, 16% and 16%, respectively, of cases. Although 98% of serotypes identified would be covered by the currently available 23-valent vaccine, two-thirds of the children affected by these isolates would be unprotected because of poor immunogenicity of polysaccharide vaccines in children less than 2 years old. PMID- 7854886 TI - Antimicrobial therapy for children with chronic suppurative otitis media without cholesteatoma. AB - This study was designed to determine the middle ear bacterial pathogens, the frequency of serum immunoglobulin deficiency and the efficacy of medical management in patients with chronic suppurative otitis media without cholesteatoma. This was an open noncomparative clinical trial performed at the National Children's Hospital, San Jose, Costa Rica, and included 186 patients older than 2 months of age with a confirmed diagnosis of chronic suppurative otitis media without cholesteatoma. Middle ear cultures and serum for immunoglobulin determinations were obtained on admission. The first 40 patients were treated only with ceftazidime and from patient 41 and up, if a Gram-positive organism was cultured, oxacillin was added to (for combined infection) or replaced ceftazidime. Parenteral antibiotics and suction twice daily were continued until three days after the middle ear became dry. Trimethropimsulfamethoxazole prophylaxis was administered during the follow-up period. Middle ear bacterial cultures were positive in 166 patients. Pseudomonas sp. (35.6%), enteric Gram-negative organisms (28.7%) and Gram-positive cocci (26%) were the most common organisms. Immunoglobulin determinations were below normal in 3 of 69 (4.3%) evaluable patients. Dryness of the ear was achieved in 174 patients (93.5%) including 130 of 139 patients treated with ceftazidime, 28 of 28 patients treated with oxacillin and 14 of 14 patients treated with ceftazidime and oxacillin. Recurrent otorrhea developed in 39 (23.4%) patients. Twice-daily canal aspiration and parenteral ceftazidime for Gram-negative organisms and/or oxacillin for Gram-positive bacteria for 3 days after dryness of the middle ear followed by prophylactic oral antimicrobials are effective for treatment of most chronic suppurative otitis media without cholesteatoma patients. PMID- 7854887 TI - Nosocomial calicivirus gastroenteritis in a pediatric hospital. AB - At St. Goran's Children's Hospital (a tertiary center), we perform electron microscopy of feces in most cases of nosocomial gastroenteritis. From September 1987 through April 1992 we identified 32 episodes of calicivirus infection, 25 of which were nosocomial and, except for one outbreak, sporadic. Systematic study of the nosocomial outbreak of calicivirus gastroenteritis from November 1991 to January 1992, revealed calicivirus in the stools of 8 of 23 children with diarrhea and 0 of 10 without diarrhea. In 3 of 7 sampled after cessation of diarrhea, calicivirus excretion continued for 3 to 6 days. We found no calicivirus in 42 staff members or 9 members of infected patients' families. Nosocomial transmission of calicivirus can occur among infants. PMID- 7854888 TI - Lack of intrafamilial transmission of hepatitis C virus in family members of children with chronic hepatitis c infection. AB - Intrafamilial transmission of hepatitis C virus (HCV) was studied in family members of 44 children with chronic hepatitis C infection (index cases). There were 22 males and the mean age of all patients was 9.5 years (range, 1.5 to 16 years). Eleven index patients were multitransfused because of thalassemia major. Aminotransferase serum concentrations and anti-HCV antibodies were evaluated in 77 parents (38 fathers) and 56 siblings (28 males; mean age, 11.2 years; range, 2.5 to 18 years). No sibling showed evidence of liver disease or HCV infection. Eight parents (14%) were found to be anti-HCV positive, but only one of them acquired HCV infection from an index case through an accidental needle stick injury. A nonsexual person-to-person transmission of HCV was conceivable only in a girl (index case) who had no risk factor other than the contact with anti-HCV positive father. Vertical transmission played a role in five children (index cases) (three males) from five different mothers. Among the eight children belonging to these mothers, three did not show evidence of HCV infection although born after their HCV-infected siblings. Furthermore, we have not identified factors related to activity of disease or to duration of contact with index cases or to peculiar features of family members capable of favoring the spreading of HCV infection. Different from hepatitis b, pediatric age does not seem to represent a reservoir for HCV infection since the majority of children acquired HCV infection through parenteral routes and no HCV-infected child transmitted HCV infection horizontally. PMID- 7854889 TI - Acquisition of serum isotype-specific and G type-specific antirotavirus antibodies among children in day care centers. AB - The acquisition of serum antirotavirus antibodies among children in day care centers was monitored through two rotavirus seasons. Twenty-six children were monitored daily for diarrhea and weekly for stool rotavirus excretion through a rotavirus season of infections with serotype G1 and a successive season of infections with both G1 and G3. Sera were collected before and after each rotavirus season and tested for antirotavirus IgA and IgG and for G type-specific blocking antibody. The prevalence of protective serum IgA and IgG titers increased from 36% and 45% before Season 1 to 77% and 96% after Season 2, respectively (P < 0.02 and 0.001). G type-specific antibodies also increased (G1, P < 0.001; G2, P = 0.005; G3, P = 0.003; G4, P = 0.006), including for noncirculating types. Homotypic and heterotypic antibodies increased as the number of rotavirus infections experienced by a child increased. The group of children with two proven infections developed protective isotype-specific and G type-specific antibodies. These results indicate that in first exposures to rotavirus G types, children develop predominantly homotypic antibody. However, as the number of rotavirus infections increase, children develop heterotypic antibody to G types at levels that correlate with broad protection against rotavirus infection and illness, despite exposure to a restricted number of G types. PMID- 7854890 TI - Increased soluble CD8 (sCD8) in human immunodeficiency virus 1-infected children in the first month and year of life. AB - The purpose of this study was to determine whether soluble CD8 (sCD8) in serum of perinatally human immunodeficiency virus 1 (HIV-1)-infected children during the first year of life differs from that of HIV-1-uninfected control children. Soluble CD8 concentrations in stored plasma and serum samples of children of HIV 1-infected and uninfected mothers were determined using a sandwich immune assay. In the first month of life significantly greater concentrations of sCD8 occurred in 12 HIV-1-infected infants than in 9 uninfected infants born to infected mothers (mean = 1054, SD 540 vs. 589, SD 370 units/ml, P < 0.05), although the CD8+ T cell proportions were not different (21.7 vs. 21.1, P > 0.5). The difference in sCD8 concentrations was most pronounced in 8 infants who were HIV-1 culture positive on initial testing in the first week of life compared with the remaining 4 patients when virus was first detected on subsequent analysis (mean = 1315, SD 446 vs. 529, SD 231 units/ml, P < 0.01). The concentration of sCD8 was also greater in 26 HIV-1-infected children than in either 26 uninfected children born to infected mothers or 25 seronegative children during the first year of life (mean = 1268, SD 529 vs. 630, SD 290 vs. 553, SD 315 units/ml, P < 0.05). Early and persistent elevation in sCD8 probably reflects immune activation resulting from HIV-1 infection. The occurrence of this increase in the neonatal period may reflect prenatal viral transmission, a higher viral inoculum or coinfection with other agents stimulating immune activation. PMID- 7854891 TI - Use of DNA fingerprinting and biotyping methods to study a Candida albicans outbreak in a neonatal intensive care unit. AB - During a 15-day period, 7 premature infants hospitalized in a neonatal intensive care unit presented with sepsis caused by Candida albicans. The local environment and hands of all 54 persons involved in the intensive care unit were examined for the presence of this organism. Five techniques were used in the analysis of the isolates recovered from blood cultures of the children, the hands of personnel and 10 control isolates. The methods used were serotype determination, genetic fingerprinting, morphotyping, resistotyping and killer yeast typing. Morphotyping and genetic fingerprinting proved to be the most discriminatory techniques, and only combined analysis of the results obtained with these various methods allowed the source of the outbreak to be identified. An isolate from the hands of a healthy staff member and isolates from infected children all belonged to the same strain. PMID- 7854892 TI - Assessment of neutrophil function disorders: practical and preventive interventions. PMID- 7854893 TI - A blueprint for care, treatment, and prevention of HIV/AIDS in children. PMID- 7854894 TI - Hydrops of the gallbladder associated with Epstein-Barr virus infection: a report of two cases and review of the literature. PMID- 7854895 TI - Preliminary results treating persistent central venous catheter infections with the antibiotic lock technique in pediatric patients. PMID- 7854896 TI - Transient surface antigenemia in newborn infants vaccinated with Engerix B: occurrence and duration. PMID- 7854897 TI - Impaired immunity to pneumococcal polysaccharide antigens in children with human immunodeficiency virus infection immunized with pneumococcal vaccine. PMID- 7854898 TI - Human cryptosporidiosis acquired from a pet lamb. PMID- 7854899 TI - Compliance of hepatitis B vaccination in patients presenting to a teenage clinic. PMID- 7854900 TI - Environmental contamination leading to false-positive polymerase chain reaction for pertussis. PMID- 7854901 TI - Furuncular myiasis. PMID- 7854902 TI - Influenza complicated by Moraxella catarrhalis bacteremia. PMID- 7854903 TI - Management of a football player with infectious mononucleosis. PMID- 7854904 TI - Recommendations for infection control in outpatient care for the prevention of tuberculosis. PMID- 7854905 TI - Nursing datasource 1994. Volume II--Graduate education in nursing advanced practice nursing. PMID- 7854906 TI - [Eastern Europe and scandinavia--a new epidemiological situation?]. PMID- 7854907 TI - [Panorama of infections among refugees--the risk of epidemics from the East]. AB - The article consists in an account of the numbers of reported cases of infectious diseases among approximately 10,000 refugees who came to the Stockholm area, primarily from the former Yugoslavia, Africa, Asia and Irak during the period 1992-1993. High prevalences were noted of hepatitis B and tuberculosis, and in certain groups high prevalences of HIV. Hitherto there has been no increase in the spread of infections to the general population. In the event of a wave of refugees from Russia and the Baltic countries, it is primarily diphtheria and tuberculosis that will entail vigilance. PMID- 7854908 TI - [Multiresistant bacteria in a Scandinavian perspective]. AB - The global increase in multiresistant bacteria may herald the end of the antibiotic era. Recently, the most ominous sign has been the increasing resistance in pneumococci, enterococci and Staphylococcus aureus, as this has not been met with new effective antimicrobials. Resistant Haemophilus influenzae and meningococci are potential future problems. Except for the occurrence of multiresistant pneumococci in Iceland, hitherto the Nordic countries have largely escaped these problems, though multiresistant enterococci are being isolated with increasing frequency and penicillin-resistant pneumococci have become endemic in southern Sweden. Concerted action is needed in an attempt to halt the increasing resistance among important bacterial pathogens. PMID- 7854909 TI - [Tuberculosis control in Scandinavia]. AB - Compared with the rest of the world, the situation regarding tuberculosis is favourable in the Nordic countries. In 1993, the incidence for persons born in respective country (per 100,000 of the population) was 4.1 in Denmark, 3.2 in Iceland and Sweden, 3.8 in Norway and 10.0 in Finland. The respective average figures for foreign-born residents were 6-14 times higher. Programmes for contending with tuberculosis have been uniform in the Nordic countries, with the exception of BCG (bacillus Calmette-Guerin) vaccination policy, though childhood tuberculosis is rare in the area. However, tuberculosis represents a manifest problem among the foreign-born population, first and foremost among the increasing number of refugees. PMID- 7854910 TI - [Diphtheria prevention among children in Denmark]. AB - Immunisation against diphtheria has been practised in Denmark since 1943, and has been integrated in the childhood immunisation programme since 1950. Three doses of DT-IPV, given at the ages of 5, 6 and 15 months provide an immunisation coverage of 95-99 percent. Although prevalent, with recurrent epidemics during the pre-vaccine era, with the introduction of immunisation, diphtheria has been practically eliminated for the past 40 years. However, the present epidemic in Russia and Eastern Europe emphasises that, even today, the absence of diphtheria can only be maintained through an effective immunisation programme. It is intended to reinforce the Danish immunisation programme with a fourth vaccination (with deoxythymidine) at school entry. PMID- 7854911 TI - [Infection with group A Streptococcus]. AB - In the last 8-10 years, the prevalence of severe group A streptococcus (GAS) infections such as bacteremia, erysipelas, necrotizing fasciitis and puerperal fever has increased significantly in industrialized countries. Shock, acute respiratory distress syndrome and multiorgan failure have been common features, and the attributable mortality has been as high as 30 per cent. The majority of infections have occurred in otherwise healthy adolescents and adults, and the GAS strains have been predominantly M types 1 and 3, which produce pyrogenic exotoxins, indicating an increased virulence of these strains. The article reports on the prevalence, pathogenesis, clinical features and treatment of severe GAS infections. PMID- 7854912 TI - [Hepatitis C in Scandinavia]. AB - The Nordic countries constitute a low hepatitis C prevalence area, only 0.05-0.30 percent of new blood donors are being found to be seropositive. However, hepatitis C is very common among such risk groups as intravenous drug abusers and patients with bleeding disorders. Though normally mild in the acute phase, hepatitis C usually results in a permanent carrier state and often in chronic asymptomatic liver inflammation, even liver cirrhosis in some cases. Therapeutic guidelines are still in the process of development, and intensive studies of alpha-interferon and oral tribavirin are in progress also in the Nordic countries. PMID- 7854913 TI - [Anders Jahre Prize for young researchers 1994. Chronic intestinal inflammation studies with multi-colored immunohistochemistry]. AB - Multi-colour immunofluorescence can be a potent tool in investigating the cause of chronic inflammation of unknown etiology. The immune system uses two main mechanisms for target destruction; antibody-induced, complement-mediated or cell mediated lysis. Immunohistochemical tracing of complement activation and immunoglobulin deposition in intestinal lesions from patients with ulcerative colitis and Crohn's disease show that ulcerative colitis may be an autoimmune disease characterized by an autoantibody of the IgG1 subclass to an apically located colonic autoantigen, which induce in situ complement activation and cellular lysis. The apical immune complex deposits co-localized with a previous identified putative autoantigen of 40kD, with peptide sequence homology with tropomyosin. Coeliac disease is a mucosal hypersensitivity to the wheat protein gluten. The intestinal lesion shows a peculiar disease specific increased percentage of T cell receptor (TCR)gamma/delta cells in the epithelium; differential use of CD45-isoforms and proliferative activation of intraepithelial T cells. T-helper(CD4) cells in the lamina propria show a non proliferative activation (CD25) which can be induced after gluten challenge in vitro. Immunomagnetic isolation of such in vitro activated T cells renders it possible to establish gluten reactive T cell clones that respond to gluten presented in the context of the disease associated human leucocyte antigen HLA-DQ2. PMID- 7854914 TI - [Stomach physiology--an elucidation]. PMID- 7854915 TI - [Emergency psychiatric treatment of survivors of the Estonia disaster]. AB - The sinking of the car ferry, Estonia, was one of the world's most devastating marine disasters of all time. Mass casualty situations tend to give rise to more mental than physical injuries among the survivors. Psychiatric crisis intervention is in the process of becoming established as one arm in the management of disaster victims. In the article is described the emergency psychiatric care which University Hospital, Abo, was able to offer survivors of the Estonia catastrophe. On the basis of the experience gained, the authors suggest that emergency psychiatric plans should be drawn up at all larger hospitals, as there is no time for careful planning in the event of a major incident. PMID- 7854916 TI - [Study on physicians' conditions in Norway]. AB - In 1992, the Norwegian Medical Association started a comprehensive research program on physician health and welfare. More than 30 studies are planned to be performed in a three year period, based on a variety of data-sets and methodologies. The core of the program is the 1993 questionnaire survey to 9,266 active Norwegian physicians. One questionnaire was common, the three others were randomly distributed among all the recipients. The purpose of this design was to increase the potential of multivariate models in the analysis. The first findings are now being published. PMID- 7854917 TI - [Development of cooperation in a surgical department. A group dynamics approach]. AB - Knowledge of group dynamics is considered as an essential precondition in establishing good functioning teams. In order to develop cooperation within an administrative council at a surgical ward, a training programme primarily based on the participants own experiences in unstructured groups, was established. We present the theoretical background and the practical amplification of the programme and describe the process and the evaluation of it. In a time when the health services are exposed to great demands concerning quality and effectivity, we will recommend long lasting programmes for the development of communication and cooperation. PMID- 7854918 TI - [Prophylaxis of radiation-induced thyroid cancers in children after the reactor catastrophy of Chernobyl]. AB - The incidence of thyroid cancer in children living in heavily contaminated regions some 100 km away from the Chernobyl nuclear power plant has increased significantly between 1989 and 1993. On the basis of this observation, preparations for iodine blockage of the thyroid in cases of reactor accidents should be made not only near but also far from nuclear power plants. The WHO recommendations on age-related dosage should be followed; the total iodide dose ranging between 15 and 150 mg daily may be split into several portions. In addition, prophylaxis of iodine-deficient goiters with 50-200 micrograms of iodide daily leads to a significant reduction of the risk of radiation-induced cancers. Consequent elimination of alimentary iodine deficiency should therefore be considered as the basis of precautions against health affects of reactor accidents. Thyroid hormones are indicated only in cases of thyroid enlargement, provided that lesions suspicious for malignancy have been definitely excluded. In the case of thyroid nodules in childhood, the indication for surgery and histological verification of the lesion has to be taken generously. PMID- 7854919 TI - [Thyroid volume and iodine supply of 6 to 17 year old students. Results 3 years after the introduction of increased iodized salt]. AB - In Austria, a law stipulating that table salt should be iodized with 10 mg Kl/kg was introduced in 1963. Nevertheless, investigations carried out between 1982 and 1984 on iodine supply and goitre frequency revealed that there was a general iodine deficiency of first to second degree according to WHO criteria. These results led to an increase in salt iodization to 20 mg Kl/kg in 1990. The aim of the study was to determine iodine supply and thyroid volumes of schoolchildren 3 years thereafter. 734 children at primary and secondary schools were examined. The mean value of iodine excretion was 121 micrograms/g Cr, corresponding to an improvement in iodine intake. Compared to previous data, the corresponding age groups showed lower mean thyroid volumes. PMID- 7854920 TI - Evaluation of cerebral vasoreactivity by SPECT and transcranial Doppler sonography using the acetazolamide test. AB - rCBF SPECT with 99mTc-HMPAO was performed prospectively in 29 patients (3 controls and 26 stroke patients) as well as TCD studies in 20 patients (3 controls and 17 stroke patients) before and after 1 g i.v. acetazolamide. The sensitivity of rCBF SPECT increased from 62% to 77% after acetazolamide provocation in stroke patients. In patients with a reversible neurological deficit, the sensitivity under resting conditions was 50% which increased to 71%, while in cases with a permanent deficit it increased from 75% to 83%. In the evaluation of the cerebrovascular reserve capacity the results of rCBF SPECT and TCD coincided in 91% of the hemispheres. The correlation was statistically significant. PMID- 7854921 TI - Evaluation of obstructed kidneys by discriminant analysis of 99mTc-MAG3 renograms. AB - This study sought to develop a method of improving the differential diagnostic between healthy and obstructed kidneys using only parameters derived from the 99mTc-MAG3 renogram. The analysis included data from 46 healthy and 36 obstructed kidney units. The parameters calculated were: mean transit time (MTT), time at 20% of the initial height of the renal retention function (T20) and time to peak of the renogram (TP). A discriminant analysis was carried out to obtain a discriminant function in order to differentiate between the two groups. The best results were obtained using the function: (2.5629 InT20) + (2.1280 In TP) 27.1224 which correctly classified 97.56% of the cases, giving a sensitivity of 94.44% and a specificity of 99.99%. PMID- 7854922 TI - [Quantitative radionuclide leakage control during isolated limb perfusion]. AB - In order to reduce side effects of high-dose chemotherapy the penetration of the cytostatic substances into the main circulation should be prevented or limited. An efficient procedure for checking the leakage is generally based on the addition of a radionuclide to the perfusate. By scintillation probes the distribution of this radionuclide in the body of the patient is checked. A method is presented which continuously calculates the actual volume of the fluid which is penetrating into the main circulation during the perfusion. The values of momentary and cumulative volume crossover enables the surgical oncologist to detect a leakage readily and reliably and may be the basis for measures of confining it. PMID- 7854923 TI - [Radiation exposure from diagnostic nuclear medicine in Germany 1992 (the former Federal Republic)]. AB - Up to now, exact data on the frequency and collective effective dose of nuclear medicine examinations were missing for Germany. On the basis of official reimbursement statistics for outpatients, compiled by the Kassenarztliche Bundesvereinigung, the total frequency of nuclear medicine examinations is estimated. 2.3 million examinations have been performed in 1992 in the western part of Germany, corresponding to 35 examinations per 1000 inhabitants. 77% of the patients examined were older than 40 years. Thyroid scintigraphy leads the frequency statistics with 51%, followed by bone scintigraphy (28%) and myocardial perfusion scans (7%). The mean effective dose per examination according to ICRP 53, amounts to 3.5 mSv which corresponds to 0.12 mSv per caput. The major contributions to the collective effective dose derive from bone scintigraphy (39%) and myocardial perfusion scintigraphy (35%); the contribution of thyroid scintigraphy to the collective effective dose is only 10%. If the data are corrected for sex and age, the collective effective dose is reduced to 1.4 mSv per examination and to 0.05 mSv per caput, respectively. PMID- 7854924 TI - [Functional autonomy of goiter]. AB - The article summarizes the status of knowledge on functional autonomy of the thyroid gland from the standpoint of definition, pathogenesis, pathophysiology, epidemiology, diagnostics and treatment. PMID- 7854925 TI - [Lymphatic outflow scintigraphy in a case of artificial edema of the lower limb]. AB - The case of a young woman is reported who after injury to the left leg was three times hospitalized for diagnosing the cause of her lower limb edema. It took two months to verify its artificial origin. Scintigraphy showed an intensive acceleration of the lymphatic outflow from the left leg. PMID- 7854926 TI - Highlights of the 1st Croatian International Congress of Nuclear Medicine. Zagreb, October 13-15, 1994. Abstracts. PMID- 7854927 TI - Quality of life through the eyes of survivors of breast cancer. PMID- 7854928 TI - Smoking interventions for patients with cancer: guidelines for nursing practice. AB - PURPOSE/OBJECTIVES: To identify strategies for oncology nurses to assist patients with cancer in modifying their smoking behaviors. DATA SOURCES: Published research articles, conference proceedings, Surgeon General Reports, and book chapters. DATA SYNTHESIS: Cigarette smoking is associated with a variety of cancers, and persistent smoking following a cancer diagnosis contributes to increased morbidity and mortality. Smoking cessation affords numerous health benefits to patients with cancer, including improved respiratory functioning, increased activity tolerance, and a personal sense of accomplishment. To date, few smoking interventions have targeted patients with cancer. CONCLUSIONS: Oncology nurses can become more actively involved in effective smoking interventions by incorporating current research findings and theoretical models of behavior change into daily practice. NURSING IMPLICATIONS: Oncology nurses can more effectively help their patients who smoke by assessing smoking status and patients' readiness to quit; providing brief, supportive messages consistently over time; offering or referring patients to appropriate resources; and providing continued follow-up. PMID- 7854929 TI - The effects of infusion methods on platelet count, morphology, and corrected count increment in children with cancer: in vitro and in vivo studies. AB - PURPOSE/OBJECTIVES: To determine whether infusion method influences the quality of platelets transfused. DESIGN: Linked in vitro and in vivo study. Quasi experimental design for in vitro and cross-over design with balanced randomization for in vivo. SETTING: Pediatric cancer center in the midsouthern United States. SAMPLE: Pheresed/pooled platelet units in vitro (n = 12). In vivo convenience sample of 26 children, ages 2-19 years, with cancer and thrombocytopenia who required platelet transfusion. METHODS: Two infusion pumps (IMED 980 and Gemini, IMED Corp., San Diego, CA) versus gravity flow for in vitro platelet infusion. Gemini infusion pump versus gravity flow for in vivo platelet transfusion. MAIN OUTCOME MEASURES: Platelet count, morphology score, and corrected count increment. FINDINGS: No significant differences noted in platelet count or morphology score among or across the three infusion methods in vitro. No significant differences noted between the two infusion methods in platelet count or corrected count increment in vivo. CONCLUSIONS: Although limited to a specific patient population, setting, and infusion device, findings revealed that the pump was clinically acceptable because it did not negatively affect platelet recovery. Replication of this study with other infusion devices is recommended. IMPLICATIONS FOR NURSING PRACTICE: Study findings validate the current nursing procedure for the administration of platelets at the study setting. Use of infusion pumps for platelet transfusions is time-efficient and energy-efficient for nurses because the pumps offer a well-controlled infusion rate, accurate volume measurement, and an alarm system for monitoring the infusion. PMID- 7854930 TI - An oncology unit's initiation of a bereavement support program. AB - PURPOSE/OBJECTIVES: To describe how a multidisciplinary task force on an oncology unit developed and implemented a program offering educational and emotional support for recently bereaved families. DATA SOURCES: Published books and articles and bereavement support models. DATA SYNTHESIS: Program components included bereavement cards and a biannual survivor support program. One program held during the holidays offered formal presentations on grief and stressors and coping strategies. A second program held in the spring explored ways for survivors to experience personal growth. In addition to this program, a staff education component was developed. CONCLUSIONS: Sending bereavement cards served as a nonthreatening way for staff members to begin establishing closure after a patient's death. Staff participation in planning a support program is crucial, and initial staff resistance can be overcome by educating them and including them in program planning. The support program was highly rated by participants, and their evaluations showed that they felt a bond with the nursing staff who had cared for their loved ones. IMPLICATIONS FOR NURSING PRACTICE: These types of programs bring survivors and staff members together. Interaction in the program can enhance survivors' coping skills, acknowledge the bond between caregivers and survivors, and ease staff members' stress caused by caring for dying patients. PMID- 7854931 TI - A national survey of infection prevention practices on bone marrow transplant units. AB - PURPOSE/OBJECTIVES: To identify and describe bone marrow transplant (BMT) specific infection prevention measures in the United States. DESIGN: Survey design using a mailed questionnaire. SETTING: BMT programs across the United States. SAMPLE: 91 BMT programs (80.5% response rate). METHODS: A questionnaire containing both closed- and open-ended items was mailed to identified nurse contacts following introductory phone calls. Descriptive statistics were computed on responses to closed-ended questions; content analysis was performed on responses to open-ended questions. FINDINGS: Although all programs used some type of protected environment, practices varied considerably. Wide variation existed in cover-garment and hand-washing practices, regardless of the type of protected environment in use. Other protective measures included skin decontamination (69%), gut decontamination with oral nonabsorbable antibiotics (30%), antifungal therapy (73%), acyclovir therapy (82%), immunotherapy (73%), granulocyte macrophage colony stimulating factor therapy (58%), and modified microbial diets (66%). Numerous mouth care regimens, visitor and patient precautions, and environmental maintenance routines were described. CONCLUSION: Little standardization of infection-prevention practices exists nationwide. IMPLICATIONS FOR NURSING PRACTICE: Efforts should be made to test the cost effectiveness and benefits of the various measures in use prior to the development of national standards. PMID- 7854932 TI - Quality of life and coping in patients with gynecologic cancer and their spouses. AB - PURPOSE/OBJECTIVES: To examine differences in and relationships between quality of life (QOL) and coping of patients with gynecologic (GYN) cancer and their spouses. SETTING: An oncology ambulatory care center in the midwestern United States. DESIGN: Cross-sectional. SAMPLE: 40 patients with GYN cancer and their spouses. METHODS: Patients and spouses completed the Quality of Life-Cancer Version scale and the Coping Scale. FINDINGS: Patients with GYN cancer and their spouses recorded similar responses. They were fairly satisfied with their QOL especially regarding family. Similarities and differences existed in the use of coping strategies between the two groups. Patients were more inclined to do something about their situation, whereas spouses tended to hope that problems would go away. For spouses, finding positive aspects of the illness experience correlated with three QOL indicators; correlations also were found between health/functioning and three coping strategies. CONCLUSIONS: In this study, no significant differences were found between patients with GYN cancer and their spouses in overall QOL or QOL domains. Family was the highest QOL domain for both groups. Patients reported significantly more use of cognitive restructuring and threat minimization than spouses. For both groups, especially patients, different strategies correlated with different QOL areas. IMPLICATIONS FOR NURSING PRACTICE: Nurses working in GYN oncology ambulatory care centers are in a key position to assess areas of QOL with which patients and spouses are most and least satisfied and the types of coping strategies they are using. Differences in coping strategies used suggest that patients and spouses might benefit by being assessed separately. PMID- 7854933 TI - Validity and reliability of medical and surgical oncology patient acuity tools. AB - PURPOSE/OBJECTIVES: To develop valid and reliable medical and surgical acuity tools as part of an overall classification system for patients with cancer. SETTING: An acute care, tertiary, research, academic oncology hospital in the southeastern United States. SAMPLE: Clinical nursing experts in medical and surgical oncology; 125 patient observations for the surgical oncology acuity tool, and 75 patient observations for the medical oncology acuity tool. METHOD: The nursing division developed a medical oncology acuity tool and a surgical oncology acuity tool using the Johns Hopkins Oncology Patient Classification System as a model. They then studied the validity of developed tools using content validity indexes (CVIs). Two independent raters studied the interrater reliability of each tool. FINDINGS: CVIs for items on the surgical tool ranged from 0.57-1.0; the overall CVI for this tool was 0.86. CVIs for items on the medical tool ranged from 0.25-1.0. The overall CVI for this tool was 0.88. Pearson correlation coefficients were r = 0.95 (p < 0.001) for the surgical oncology acuity tool and r = 0.92 (p < 0.001) for the medical tool. Interrater reliability, tested continually for four years, was greater than 95%. CONCLUSIONS: The tools are reliable and valid. IMPLICATIONS FOR NURSING PRACTICE: Medical and surgical oncology acuity tools that are nursing diagnosis based, interface with nursing standards of care, are easy to use, and require no calculation provide reliable quantification of nursing work loads based on the care needs of patients with cancer. Supervisors use data from these tools to determine variable nursing hours per patient per day, establish productivity for units, make staffing and scheduling decisions, assign patients, work on budgets, and, ultimately, establish charges for nursing services. As the needs of medical and surgical oncology patients evolve, continued refinement of indicators and acuity levels will be needed. As other medical and surgical oncology tools are developed, further comparison will be warranted. Additional study would determine if the tools could be modified for these nursing uses in other cancer centers as well as in designated medical and surgical oncology units of other types of hospitals. Oncology acuity systems also could be established in the future as the basis for third-party reimbursement. PMID- 7854934 TI - Recalled anxiety: from discovery to diagnosis of a benign breast mass. AB - PURPOSE/OBJECTIVES: To determine the amount of anxiety recalled by women who have had benign breast biopsies and to describe coping strategies used by these women during the time from discovery of the mass to definitive diagnosis. DESIGN: Descriptive, retrospective. SETTING: Surgical oncology practices, private and academic, treating patients living in five southern states. SAMPLE: 238 women who had excisional biopsies with benign results within the previous two years. Mean age of 52 years, 80% Caucasian, and 20% African American. METHODS: Subjects rated their anxiety from discovery to diagnosis on a 16-point visual analogue scale and answered a short-answer question about the coping strategies used to deal with the anxiety. MAIN RESEARCH VARIABLES: Anxiety and coping strategies. FINDINGS: The mean length of time from discovery to diagnosis was 35 days. No statistically significant relationship was found between the length of time from discovery to diagnosis and the amount of anxiety experienced. However, 58% of the women recalled severe amounts of anxiety during this time. Qualitative analysis grouped coping strategies into five patterns (themes): diversionary, spiritual, interpersonal, hopeful, and avoidance. CONCLUSIONS: The time between discovery of a breast mass and definitive diagnosis is a time of considerable anxiety for many women. Substantial time elapses between discovery and diagnosis, contributing to the possible morbidity associated with severe anxiety. IMPLICATIONS FOR NURSING PRACTICE: Nurses can work to decrease the time occupied by the diagnostic process, counsel women regarding the anxiety being experienced, and present coping strategies that may help. PMID- 7854935 TI - Chemotherapy toxicity assessment using a self-report tool. AB - PURPOSE/OBJECTIVES: To improve the data collection process for patients participating in clinical trials and to ensure patient safety. DATA SOURCES: Clinical trial toxicity assessment forms and clinical experience. DATA SYNTHESIS: A comprehensive self-report form was developed to collect information regarding the toxicity experienced. The form was designed to be easy for patients to complete and nurses/physicians to interpret. CONCLUSIONS: Preliminary evaluation indicates that a self-administered form provides accurate and more complete information regarding chemotherapy toxicity than a simple patient interview. It is not limited by the setting. IMPLICATIONS FOR NURSING PRACTICE: The self-report form allows the nurse to assess chemotherapy toxicity and to make dose modifications as necessary, regardless of the patient's clinical trial status. PMID- 7854936 TI - Blending cultural beliefs with conventional treatments enhances patient care. PMID- 7854937 TI - Multicultural Patient Care Team ensures quality care for all cultures. PMID- 7854938 TI - Language and culture provide challenges to nursing care. PMID- 7854939 TI - Translation service helps nurses to overcome language barriers for patients in the home. PMID- 7854940 TI - Oncology Nursing Society. Chapter directory. Special Interest Group Directory. PMID- 7854941 TI - Dan Quayle was right. PMID- 7854942 TI - Solitary supernumerary primary canine. PMID- 7854943 TI - More on bite-mark analysis. PMID- 7854944 TI - The case of good luck. PMID- 7854945 TI - Pulpotomy therapy in primary teeth: new modalities for old rationales. AB - Pulpotomy therapy for the primary dentition has developed along three lines: devitalization, preservation, and regeneration. Devitalization, where the intent is to destroy vital tissue, is typified by formocresol and electrocautery. Preservation, the retention of maximum vital tissue with no induction of reparative dentin, is exemplified by glutaraldehyde and ferric sulfate treatment. Regeneration, the stimulation of a dentin bridge, has long been associated with calcium hydroxide. Of the three categories, regeneration is expected to develop the most rapidly in the coming years. Advances in the field of bone morphogenetic protein (BMP) have opened new vistas in pulp therapy. Human BMPs with dentinogenic properties are becoming available through recombinant technology. We are now entering an era of pulpotomy therapy with healing as the guiding principle. PMID- 7854947 TI - A biopsychosocial model to predict caries in preschool children. AB - The purpose of the study is to assess a multidisciplinary caries-prediction model. Enrolled in the study were 184 low-income children ages 3-5 years old in two Head Start programs in Connecticut. Children were examined by a dentist at baseline and at 1 year for dental caries. Each child also provided a saliva sample to obtain a measure of S. mutans. The children's caregivers completed an interview that assessed oral health behaviors, and cognitive and socioeconomic factors. The prevalence of decay (1 dmfs) increased from 40 to 58% and the number of dmfs increased significantly from 2.5 (7.1) dmfs to 4.5 (8.8) dmfs (P < 0.001) in 1 year. S. mutans did not change significantly. Discriminant function analysis predicting change in caries in the second year from data obtained in the first year showed that S. mutans, dmfs, and toothbrushing significantly predicted caries risk (canonical correlation = 0.5571; x2 = 51; df = 3; P < 0.001). Children with higher dmfs, higher S. mutans, and whose parents reported more frequent brushing had more decay in the second year. None of the other behavioral, cognitive, or demographic factors was significant. The results emphasize the importance of early intervention in preventing dental caries in an underserved population. PMID- 7854946 TI - In vitro effect of human saliva on the output of fluoride from controlled-release devices. AB - This study was designed to determine the in vitro fluoride output from controlled release devices in stimulated, whole human saliva, and to assess changes in the salivary calcium concentration following immersion of the devices. Twenty fluoride (F) controlled-release devices of the hydroxyethyl methacrylate (HEMA)/methyl methacrylate (MMA)-type were employed. Each was designed to release 1-2 mg F per day. All devices were placed individually in 10.0 ml of deionized water for 3 days to assess baseline F output. Seven devices with markedly high or low output were discarded. During days 4-13, three of the remaining 13 devices were placed individually in 10.0 ml of stimulated, whole saliva donated by three volunteers. All devices were returned to deionized water during days 14-17. All solutions were replaced daily with fresh solutions, and each test tube was inverted once every 24 hr. The study was conducted at 19-21 degrees C. Fluoride concentration of the deionized water and human saliva was assessed by ion specific electrode; calcium concentration of the saliva was assessed pre- and postimmersion by flame atomic absorption spectrometry. The fluoride output of the devices placed in saliva decreased to 36% of their baseline rates (P < 0.001). The calcium concentration of the human saliva decreased from a mean preimmersion value of 3.58 mg/100 ml (+/- 0.63 SD) to a postimmersion value of 2.64 (+/- 1.12 SD; P < 0.001). These results suggest an interaction between the fluoride released by the devices and calcium in the saliva.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7854948 TI - Epidemiology of dental emergency visits to an urban children's hospital. AB - All 1482 emergency room dental visits to Seattle's Children's Hospital and Medical Center from 1982 to 1991 were studied to evaluate trends in patients seeking care: 60% of visits were for trauma, the remainder for infection or other reasons. The number of visits was 2.1 times greater in 1991 than in 1982. Comparing the periods of 1982-1987 and 1988-1991, there was an increase in the proportion of infection-related visits from 30.5 to 43.5% of all visits. Spring/summer and weekends had the highest volume. More males (61.2%) than females received care. The largest number of visits (47.9%) occurred between 6:00 PM and midnight. Nearly two-thirds (62%) of children did not have a usual source of medical care; 30.2% of children had no medical insurance, and 21.5% received Medicaid benefits. Medicaid patients were twice as likely to be seen for infection as for trauma. Among the uninsured, there was no difference in the rates of trauma or infection. Non-Caucasian patients were twice as likely to be seen for infection as Caucasians. Infection visits were for pulpitis (32.1%), and periapical and gingival abscess (53.5%). Trauma patients were younger (66 months) than infection patients (89 months). Trauma was primarily to the maxillary anterior teeth (70.1%) and upper lip and gingiva (12.1%). Common agents for trauma were furniture, bicycles, and sports. PMID- 7854949 TI - Six percent citric acid better than hydrogen peroxide in removing smear layer: an in vitro pilot study. PMID- 7854950 TI - Dental caries risk in hereditary epidermolysis bullosa. AB - Epidermolysis bullosa (EB) is a clinically diverse group of conditions characterized by skin fragility and, in certain types, marked dental involvement. The purpose of this study was to determine the prevalence of dental caries in EB and control populations. Healthy individuals and participants from the Southern Clinical Center of the National EB Registry were examined with artificial light and a #23 dental explorer. Caries levels were evaluated by chi-square analysis, regression analyses, and ANOVA (P < 0.05 being significant). The study included 252 individuals with EB, aged 2.3-71 years, and 57 similarly aged controls. The prevalence of dental caries, scored as DMFS (decayed, missing, filled surfaces), was significantly higher in the junctional (mean = 58.6) and recessive dystrophic (mean = 37.6) EB types than controls (mean = 23.2). The simplex (mean = 25.6) and dominant dystrophic (mean = 21.6) EB groups had DMFS levels similar to the control group. Individuals with recessive dystrophic EB had the most severe oral blistering and scarring and did not have generalized enamel hypoplasia. In contrast, junctional EB always was associated with generalized enamel hypoplasia yet the intraoral blistering rarely involved scarring. This study shows that dental caries is increased in dystrophic and junctional EB compared with unaffected individuals or other EB types. While rampant caries appears related to the soft tissue and enamel involvement in these two EB types, other as yet unclear cofactors also must be involved. PMID- 7854951 TI - Enamel pretreatment with sodium hypochlorite to enhance bonding in hypocalcified amelogenesis imperfecta: case report and SEM analysis. AB - Bonding composite resin to enamel of teeth affected by amelogenesis imperfecta (AI) is often problematic, especially in cases with poorly mineralized, friable enamel. Difficulty in bonding hypomineralized enamel can significantly limit the restorative and orthodontic treatment options for AI patients. In this report, we document a novel approach to bonding AI enamel by pretreating the tooth surface with 5% sodium hypochlorite (NaOCl), resulting in improved bonding of an orthodontic bracket to a previously impacted maxillary canine. PMID- 7854952 TI - Spectrum of dentin dysplasia in a family: case report and literature review. AB - The dentin dysplasias (DD), which may be classified as type 1 (DD1) or type 2 (DD2), form a group of rare, inherited dentin abnormalities that are clinically distinct from dentinogenesis imperfecta. Studies of affected families may help to distinguish different types of DD and provide further insight into their etiology and clinical management. This report describes a family that showed characteristic dental features of DD1, including clinically normal crowns in both primary and permanent dentitions, and mobile teeth that may be associated with premature exfoliation. Radiographic features included calcification of the pulp with crescent-shaped, radiolucent pulp remnants, short, tapering, taurodontic roots, and many periapical pathoses that may be cysts or granulomas. A spectrum of dentin dysplasia was noted within the family. Strategies to prevent pulp and periapical infections and early exfoliation of the teeth include meticulous oral hygiene and effective caries-preventive measures. PMID- 7854953 TI - Compulsive brushing in an adolescent patient: case report. PMID- 7854954 TI - Nonrational communication. PMID- 7854955 TI - [Advances in the field of electrocardiography]. PMID- 7854956 TI - [Estimation of 24-h excretion of some promotors and inhibitors of crystallization and degree of urine saturation with calcium oxalate in calcium urinary calculi]. AB - The aim of the study was to estimate the renal citrate excretion in basal condition and to find out the relationship between their excretion and excretion of calcium, oxalate, magnesium and phosphate in patients with calcium stone disease and in control group. In 93 patients with urolithiasis and 46 healthy subjects 24-h excretion of calcium, magnesium, oxalate, phosphate and citrate as well as the degree of urine saturation with calcium oxalate was evaluated. 24-h renal excretion of calcium was significantly higher in patients with urolithiasis than in control group (p < 0001). Excretion of magnesium, phosphate and oxalate were'nt significantly different between patients with urolithiasis and healthy subjects. Daily excretion of citrate was significantly lower in patients with calcium stone disease (p < 0.01) and the degree of urine saturation with calcium oxalate was significantly higher in this group (p < 0.001). Hypocitraturia was observed in 61.3% stone-formers. A significant positive correlation was observed between excretion of citrate and calcium (r = 0.2760 p < 0.01) as well as citrate and oxalate (r = 0.5310 p < 0.001) in patients with urolithiasis. CONCLUSIONS: 1. In 61.3% of patients with urolithiasis the daily citrate excretion was reduced. In 50% of patients with urolithiasis and reduced citrate excretion "idiopathic" hypocitraturia was recognized. The daily citrate excretion was reduced in 70.2% of stone-formers with infected urine. 2. The positive correlation between 24-h excretion of calcium and citrate suggests that high excretion of lithogenic factor is accompanied by high excretion of this inhibitor of crystallization. PMID- 7854957 TI - [Effect of salbutamol on left ventricular function and selected biochemical parameters in patients with bronchial asthma]. AB - Many authors link increased mortality in course of bronchial asthma (BA) with the administration of excessive doses of beta-2 agonists, one of the causes considered being their cardiotoxic effect. The aim of the present study was to evaluate the effect of 0.5 mg intravenous bolus of salbutamol (S) on left ventricular (LV) function assessed by echocardiography and on the selected biochemical parameters: the activity of creatinine kinase (CK) and its cardiac specific isoenzyme (CK-MB), potassium (K+) and free fatty acids (FFA) serum concentration as well as partial arterial oxygen pressure (PaO2). The studied group consisted of 16 patients (pts)--12 males and 4 females, aged 36-60 yrs, mean 49.0 +/- 7 yrs with BA and moderate airway obstruction (FEV1%VC--60 +/- 7%). Pts with cardiac disorders were excluded from the study. Echocardiographic examination was performed before and 30 min after S injection. Biochemical determinations were carried out at 5 min., 30 min, 2 h, and 4 h following S administration. We found mean HR increase by 20 beats per min (p < 0.001) and mean systolic blood pressure elevation by 19 mmHg at 30 min (p < 0.001) after S. It was accompanied by significant increase of cardiac output (CO) from 5.7 +/- 1.5 to 8.4 +/- 1.8 l/min (p < 0.001) and mean rate of circumferential shortening (mVcf) from 1.48 +/- 0.27 to 1.88 +/- 0.43 (circ/sec), p < 0.01. Stroke volume (SV), ejection fraction (EF%), fractional shortening of LV (FS%) increased nonsignificantly.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7854958 TI - [Left ventricular systolic function after PTCA--recent and late assessment by exercise echocardiography]. AB - The purpose of this study was to determine whether global and segmental left ventricle (LV) systolic function, assessed by exercise echocardiography (EE), improves after PTCA in patients without previous myocardial infarction (MI) and after infarction and angioplasty of infarct related coronary artery. 32 patients without MI and 35 patients with previous (4 +/- 3 months) MI were examined before PTCA (percutaneous transluminal coronary angioplasty), 3-5 days after successful elective PTCA and 6 months later with EE (modified Bruce protocol). LV ejection fraction (EF) and wall motion score index (WMSI) at the baseline and immediately after exercise were assessed. Following angioplasty (after 3-5 days and 6 months later), exercise duration was significantly (p < 0.001) increased in both groups of patients. Resting EF and WMSI did not change after angioplasty of infarct related artery, but in patients without prior MI resting EF increased (p < 0.001) after PTCA in comparison with pre-PTCA values. Significant improvement of exercise EF and WMSI were observed in both groups of patients. In 25 of 35 patients with old MI wall motion improvement in the infarcted region after PTCA was observed. Twenty of these 25 patients developed exercise-induced akinesia in this area during pre-PTCA EE. Among 10 patients without improvement of the regional contractility were 9 after type Q-wave infarction and only 2 developed angina during EE. These data demonstrate improvement in global and regional systolic LV function and better exercise tolerance following successful PTCA both in patients without prior MI and with old MI after angioplasty of a stenosis in an infarct-related coronary artery.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7854959 TI - [Lipid peroxidation, antioxidant enzyme activity and trace element concentration in II and III trimester of pregnancy in pregnant women with diabetes]. AB - The aim of the study was to evaluate the concentration of malondialdehyde (MDA)- end product of lipid peroxidation, activity of antioxidant enzymes: superoxide dismutase (CuZn-SOD), glutathione peroxidase (GSH-Px), and catalase (Cat) as well as selenium (Se), zinc (Zn) and copper (Cu) concentration in erythrocytes in 63 patients divided into the three groups: I--control group, II--normal pregnancy, III--pregnant type I diabetics. All parameters were investigated in hemolysate of erythrocytes. MDA concentration increased significantly in pregnant women when compared with control group, as well as in pregnant diabetics when compared with healthy pregnant women. The activity of GSH-Px decreased significantly in pregnant diabetics in comparison with groups I and II. The activity of CuZn-SOD and Cat was significantly lower in III group than in control group. The concentration of Se and Zn decreased, and the concentration of Cu increased significantly in pregnant diabetics in comparison with the other groups. No differences in concentration of MDA, Se, Zn, Cu and activity of GSH-Px were found between particular trimesters in studied patients. The activity of CuZn-SOD and Cat were significantly higher in III trimester than in II one in pregnant diabetics while the activity of GSH-Px remained unchanged during pregnancy. CONCLUSIONS: Increased lipid peroxidation and the lack of compensatory mechanisms -an increase in antioxidant enzymes activity as well as disorder of trace elements concentration are found in pregnant type I diabetics. PMID- 7854960 TI - [Effect of epirubicin on left ventricular function in patients with malignant lymphoma]. AB - The effect of epidoxorubicin (epiDX) on contractility of left ventricle was followed up in patients treated according to protocols containing the drug. The examined group comprised 30 pts with Hodgkin's disease. 16 women and 14 men, aged 17-70 years, and 9 pts with high grade malignant lymphoma, 3 females and 6 males in the age of 21-64 years. Using Hewlett-Packard echocardiograph diastolic and systolic diameter of left ventricle in typical place was evaluated, 24 hrs before and after 40 mg of epiDX application as well as after completing therapy (total dose epiDX 80-480m mg). The percentages of fractional shortening of the left ventricle dimension (FS%) and ejection fraction (EF%) were calculated from the above parameters. There were no changes in measurements of cardiac function after the first dose of the drug. The fractional shortening of left ventricle dimension and EF in patients who have completed therapy were statistically significantly lower in comparison with those before therapy and control group. Heart failure was not observed. Decreased indices of heart muscle contractility and ejection fraction found in our patients may be connected with the epiDX therapy, though in dosis lower than 50% of the cumulative one, and may express the late toxicity of the drug. PMID- 7854961 TI - [Effect of elevated blood pressure and proteinuria on progression of mesangioproliferative glomerulonephritis]. AB - Mesangioproliferative glomerulonephritis (GNpm) is one of the most frequent histopathological forms in patients with proteinuria and erythrocyturia. The aim of this study was to assess the rate of deterioration of renal function in 39 patients with mesangioproliferative glomerulonephritis. All patients (25 M and 14 F, age from 19 do 55 year) were diagnosed in the Department of Nephrology Silesian University School of Medicine in Katowice two times: before and at least 12 month after renal biopsy respectively. 21 patients with mesangioproliferative glomerulonephritis was oligosymptomatic. In 6 patients the leading sign of GNpm was moderate arterial hypertension while in the other 22 nephrotic syndrome. 17 patients with mesangioproliferative glomerulonephritis received immunosuppressive medication while in the other 22 patients these drugs were not used. Deterioration of renal function was assessed using a progression index (PI) which is calculated by dividing delta of serum creatinine (mumol/l) by the observation period (months). Deterioration of renal function was faster in nephrotic patients (PI = 0.27 +/- 0.11 mumol creat./month) and in patients with the hypertensive form of mesangioproliferative glomerulonephritis (PI = 0.69 +/- 0.29 umol creat./month) than in patients with oligosymptomatic mesangioproliferative glomerulonephritis (PI = 0.06 +/- 0.04 mumol creat./month). Significantly slower deterioration of renal function was noticed in patients treated with immunosuppressive drugs than medicated only symptomatically (PI = 0.05 +/- 0.007 mumol creat./month vs 0.70 +/- 0.06 mumol creat./month). CONCLUSIONS: 1) Presence of hypertension and of a nephrotic syndrome does influence adversely the progression of mesangioproliferative glomerulonephritis.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7854962 TI - [Prognostic factors in myelodysplastic syndromes]. PMID- 7854963 TI - [Screening for colorectal neoplasms--today and tomorrow]. PMID- 7854964 TI - [Does hyperthyroidism promote drug hepatotoxicity]. AB - Mechanisms and circumstances in which drugs injure hepatocytes are not clear. It is known that thyroid gland hormones sensitize the liver to hepatic toxins, but not to commonly used drugs. We report two cases of liver injury mediated by acetaminophen and oestrogens which occurred during hepatic exposure to increased plasma level of thyroid hormones. We suggest that hyperthyroidism might promote drug hepatotoxicity. PMID- 7854965 TI - [Spurious macrocytosis associated with cold agglutinins: report of two cases]. AB - Two rare cases of spurious macrocytosis are reported: in a patient with lymphocytic lymphoma and in another patient with pneumonia caused by Klebsiella pneumoniae. High blood titer of cold agglutinins resulted in appearing of microagglutination in vitro and false erythrocyte indices as measured by automatic blood cell counting. PMID- 7854966 TI - Vasoactive intestinal peptide modulation of adherence and mobility in rat peritoneal lymphocytes and macrophages. AB - In this work, the effects of vasoactive intestinal peptide (VIP) in a concentration range from 10(-13) to 10(-7) M were studied in vitro on two common activities of peritoneal rat lymphocytes and macrophages: adherence and mobility (spontaneous and chemotaxis). The results show that VIP stimulated the adherence of the two cells studied, and increased the macrophage mobility but decreased this activity in lymphocytes. Moreover, a specific protein kinase C (PKC) activator such as phorbol myristate acetate (PMA, 50 ng/ml) also stimulated significantly the adherence and chemotaxis of both macrophages and lymphocytes. By contrast, a PKC inhibitor, retinal (2 x 10(-5) M), decreased significantly these capacities. Macrophages incubated with both VIP and PMA in relation to those incubated with VIP or PMA showed an increase in adherence and chemotaxis, whereas in lymphocytes adherence was also increased but chemotaxis decreased. The incubation with forskolin (10(-5) M), an enhancer of intracellular cAMP levels, produced an inhibitory effect of the chemotaxis activity in both types of cells. VIP prevented this inhibitory effect of forskolin in macrophages but not in lymphocytes. In addition, VIP was chemoattractant for macrophages but not for lymphocytes. The present study proves that VIP proves that VIP has a coronary effect on the two principal and representative types of immune cells in the rat peritoneum: lymphocytes and macrophages, stimulating macrophage chemotaxis through PKC activation and inhibiting lymphocyte chemotaxis through adenylate cyclase activation. PMID- 7854967 TI - Structure-activity studies of allatostatin 4 on the inhibition of juvenile hormone biosynthesis by corpora allata: the importance of individual side chains and stereochemistry. AB - The production of juvenile hormone III (JH III) by the corpora allata of the cockroach Diploptera punctata is regulated in part by peptides originating from the brain. One group of these peptides, termed allatostatins, reversibly inhibits the biosynthesis of JH in vitro. Allatostatin 4 (AST4: Asp-Arg-Leu-Tyr-Ser-Phe Gly-Leu-amide) is the smallest member of the AST family yet defined and was used as the benchmark peptide for these initial structure-activity studies. Two initial analog series of AST4 were examined for the ability of each analog to inhibit JH biosynthesis by corpora allata in vitro. Each analog series consisted of analogs that contained a single amino acid change from the native AST4 sequence. The first series contained Ala replacement analogs and the second contained analogs with D-amino acid replacements. The first analog series used Ala replacements to help indicate which amino acid side chains were most important for inhibition of JH biosynthesis. The most important side chain appeared to be Leu8 followed by Phe6 and Tyr4. Additionally, the D-amino acid series suggested that a secondary structural element(s) at the C-terminus of AST4 could be important to the biological activity. PMID- 7854968 TI - The core and complementary sequence responsible for biological activity of the diapause hormone of the silkworm, Bombyx mori. AB - To evaluate the structure-function relationship of the diapause hormone of the silkworm, Bombyx mori, the entire molecule and selected fragment and deleted analogues were chemically synthesized to compare their biological activity. The C terminal pentapeptide amide was the shortest fragment that elicited 11% diapause eggs at maximum, indicating that this sequence is the core-active structure required for a biological response. The full biological response of about 70% diapause eggs was expressed by the C-terminal hexapeptide amide. However, an ED50 value of this peptide amide was 1000-fold higher than that of the parent molecule. The serial elongation of peptide chain lengths toward the N-terminus brought about the sudden decrease in ED50 values at two positions between Arg9 Gly10 and Thr1-Asp2. The deletion of duplicated sequence(s) located in the middle part of the molecule or the truncation of N-terminal region of the parent molecule increased ED50 values but had no effects on response. Thus, N-terminal region and duplicated sequences act as the complementary structures for full potency of diapause hormone. PMID- 7854969 TI - An in situ hybridization and immunohistochemical study of vasotocin neurons in the hypothalamus of water-deprived chickens. AB - The distribution of immunoreactive vasotocin (IR-AVT) and AVT mRNA in the hypothalamus of White Leghorn cocks was determined by immunohistochemistry and in situ hybridization, respectively. In control birds that were provided with water ad lib, AVT mRNA was distributed in the periventricular and lateral regions of the hypothalamus in clusters of neurons that correspond structurally with the mammalian paraventricular (PVN) and supraoptic (SON) nuclei. Although the distribution of AVT, identified by immunohistochemistry of adjacent serial sections within the hypothalamus, was similar to the distribution of AVT mRNA, the possibility that some positive staining was due to mesotocin neurons was not excluded. Water deprivation for 2 and 4 days resulted in both an increase in levels of AVT mRNA per neuron and the number of AVT mRNA-containing cells. Additionally, water deprivation resulted in a decrease in the amount of IR-AVT per neuron. The results indicate that osmotic stimulation increases AVT gene expression not only in individual neurons but also by activating subpopulation of neurons that are not observed in normally hydrated birds. PMID- 7854970 TI - Purification and characterization of enkephalin-related peptides released by in vitro peptic digestion of bovine plasma proteins. AB - In vitro pepsin treatment of plasma proteins generates biologically active peptides such as enkephalin-related peptides. These peptides were characterized using chromatographic techniques along with a radioimmunoassay procedure involving the use of Leu-enkephalin and Met-enkephalin antisera. Serum albumin is the only existing source of Met-enkephalin-immunoreactive peptides. One of these peptides consists of nine residues with the sequence NH2-Glu-Lys-Leu-Gly-Glu-Tyr Gly-Phe-Gln; a second immunoreactive peptide might be the hexapeptide NH2-Gly-Glu Tyr-Gly-Phe-Gln, which has been already identified in a rat serum albumin hydrolysate. Our results indicate that immunoglobulins constitute the main source of Leu-enkephalin-immunoreactive peptides. Immunoreactive NH2-Tyr-Phe-Leu was isolated from pepsin-treated bovine immunoglobulins. Binding experiments and cyclic nucleotide measurements suggested that this peptide was an enkephalin related peptide. Similar experiments could be carried out to identify the proteins that contain enkephalin-like peptide sequences with the view to investigating the various biological processes occurring in enzymatically treated proteins. PMID- 7854971 TI - Heterogeneous expression of angiotensin II AT1 receptors in neointima of rat carotid artery and aorta after balloon catheter injury. AB - We examined the expression of angiotensin II receptor subtypes and angiotensin converting enzyme in the rat aorta and carotid artery at 1, 2, 4, 8, 15, and 30 days after balloon catheter injury or sham surgery. The AT1 receptor expression was enhanced in the neointima at 8 days in the aorta and carotid artery compared to that in intact media. Maintenance of the high expression of AT1 receptors in the neonintimal tissue at 15 and 30 days was localized to a subpopulation of neointimal cell close to the lumen of the vessel and was correlated to the distribution of smooth muscle cells immunoreactive to proliferating cell nuclear antigen. During the initial stages after injury, binding of [125I]351A to angiotensin-converting enzyme was significantly decreased in both the intima/media layers as well as adventitia in carotid artery and aorta. Binding of [125I] 351A to angiotensin-converting enzyme was significantly lower in the neointima compared to that in the intima/media of intact vessels. Our results reveal that the expression of AT1 receptors is heterogeneous in the neointima, and suggest that enhanced expression of AT1 receptors in the balloon catheter injured carotid artery and aorta may be limited to proliferating intimal smooth muscle cells. PMID- 7854972 TI - Effect of differentiation on hydrolysis and association of Leu-enkephalin to K562(S) cells. AB - Hydrolysis of Leu-enkephalin and association to cells of the peptide-radioactive label have been studied on the K562(S) erythroleukemic cell subline. Data obtained indicate that in the presence of these cells, Leu-enkephalin is hydrolyzed, that the peptide's radioactive label is partially associated to cells, and that these phenomena are related. Hydrolysis and association are inversely modified by the cells' differentiation: hydrolysis is increased and association is decreased in differentiated compared with nondifferentiated cells. Moreover, the ratio of hydrolysis by-products is dissimilar between differentiated and nondifferentiated cells as a result of a significant modification of the soluble enzymes' release. The alterations induced by differentiation on all parameters investigated seem to indicate significant changes in the membrane structures responsible for the mechanisms controlling these phenomena. PMID- 7854973 TI - [13C]NMR studies of the effect of the somatostatin analogue octreotide on hepatic glycogenesis and glycogenolysis. AB - NMR spectroscopy is a useful tool for monitoring multiple intermediate metabolic pathways in different organs in intact animals and humans. We report the effect of the somatostatin analogue octreotide on the fate of 13C-labeled glucose administered to fasted and well-fed rats as determined by NMR spectroscopy. The production of 13C-labeled glycogen and its subsequent breakdown after the end of infusion was identified with a time resolution of 7 min. Hepatic glycogen synthesis was not different between control and octreotide-treated animals but persisted for 15 min after the end of the infusion only in control animals. Glycogenolysis, however, was initiated immediately after the end of infusion in octreotide-treated animals where the half-life of glycogen was 40 min compared with 68 min in control animals. However, once initiated, the rate of glycogenolysis was not significantly altered by octreotide. Although octreotide had no effect on glucose signal intensities in fasted animals, 13C glucose signals were more intense in octreotide compared with control well-fed animals. In conclusion, octreotide alters rat hepatic metabolism by accelerating the onset of glycogenolysis and stimulating glucose accumulation without significantly interfering with glycogen synthesis. PMID- 7854974 TI - Detection of somatostatin receptor subtype 2 (SSTR2) in established tumors and tumor cell lines: evidence for SSTR2 heterogeneity. AB - The somatostatin receptor subtype 2 (SSTR2) was detected in a wide range of human and rat tumors using in vitro receptor binding ([125I]MK-678), receptor gene expression analysis, and immunoblotting techniques. The highest receptor concentrations were observed in the rat AR42J pancreatic and human small cell lung cancer (SCLC) cell lines, NCI-H69 and NCI-H345, with much lower levels detected in breast, prostate, melanoma, and hepatic tumors. Several human pancreas tumors were devoid of SSTR2. For all tumors showing detectable [125I]MK 678 binding, SSTR2 receptor mRNA was expressed. Furthermore, a mRNA transcript corresponding to a truncated isoform of SSTR2 was detected at low levels in the human SCLC NCI-H69 cell line, and likely represents a human homologue of rodent SSTR2B. Immunoblotting analysis using the SSTR2-specific antibody, 2e3, detected multiple immunoreactive protein species, including a predominant 150-kDa molecule, which could be blocked by the SSTR2-derived 2e3 peptide. Somatostatin (SRIF) peptides with high SSTR2 affinity and antiproliferative properties were potent inhibitors of [125I]MK-678 binding to several tumor types, suggesting that they may exert antitumor effects via the SSTR2 receptor. PMID- 7854975 TI - The effects of PACAP and VIP on guinea pig tracheal smooth muscle in vitro. AB - Neither pituitary adenylate cyclase activating polypeptide-38 (PACAP) nor its homologue, vasoactive intestinal polypeptide (VIP), contracted guinea pig isolated trachea (GPT), but on preparations contracted with KCl (40 mM), both caused concentration-related relaxation (3 nM-3 microM, VIP IC50 = 72 nM, PACAP IC50 = 224 nM). Relaxant curves to PACAP were slower in reaching a maximum than those to VIP (approximately 150 and 50 min, respectively). The protease inhibitors, phosphoramidon (1 microM), leupeptin (50 microM), bestatin (100 microM), soya bean trypsin inhibitor (1 microM), and aprotinin (5 microM), together caused a small enhancement of relaxations to VIP, but not to PACAP. The VIP antagonist, [4-Cl-D-Phe6, Leu17]VIP (1-10 microM), did not inhibit the relaxation to either peptide, but did cause large contractions, which were enhanced by protease inhibition. These findings demonstrate that PACAP relaxes GPT in a similar manner to VIP. PMID- 7854977 TI - C-type natriuretic peptide (CNP) increases [125I]ANF binding to FRTL-5 rat thyroid cells by increasing ANF receptor affinity. AB - To examine a possible role for C-type natriuretic peptide (CNP) in the thyroid, we studied the ability of this peptide to compete with atrial natriuretic factor (ANF) binding to FRTL-5 rat thyroid cells. Rather than competing for ANF binding, CNP significantly elevated [125I]ANF binding above control at both 23 degrees and 2 degrees C. The increase in ANF binding was due largely to a threefold increase in receptor affinity in the presence of CNP (control, Kd = 8.7 nM; 1 microM CNP, Kd = 3.1 nM). Despite the failure to compete for ANF binding, CNP was almost as effective as ANF at inducing cGMP production in FRTL-5 cells. Competition binding studies using [125I]CNP indicated the presence of a relatively low-affinity site for CNP (Kd = 77 nM) that bound ANF with equal affinity. These results show for the first time that ANF receptor binding can be positively regulated by the related natriuretic peptide, CNP. PMID- 7854976 TI - The effects of IAPP and CGRP on guinea pig tracheal smooth muscle in vitro. AB - Neither the novel peptide, islet amyloid polypeptide (IAPP), nor its homologue, calcitonin gene-related peptide (CGRP), contracted guinea pig isolated trachea (GPT), but on preparations contracted with KCl (40 mM), both caused concentration related relaxation (1 nM-3 microM). Relaxant curves to both were shallow and slow in development, with clear maxima not being obtained. The protease inhibitors, phosphoramidon (1 microM), leupeptin (50 microM), bestatin (100 microM), soya bean trypsin inhibitor (1 microM), and aprotinin (5 microM), together had no effect on relaxations to CGRP, but depressed those to IAPP. Aprotinin appeared to be responsible for this depression. The specific CGRP antagonist, CGRP(8-37), 1 10 microM, had no effect on relaxations to either peptide. These findings demonstrate that IAPP relaxes GPT in a similar manner to CGRP. PMID- 7854978 TI - Measurement of angiotensin II: use of two injectors to minimize HPLC shadowing. AB - We investigated the use of two HPLC injectors, one reserved for standards and the other for blanks or biological samples, to minimize shadowing in the measurement of angiotensin II (ANGII). HPLC carryover of standard ANGII to blank with a one injector and a two-injector system were 47.0 +/- 5.0 and 2.4 +/- 0.5 fmol/ml, respectively, a 19.6-fold reduction. Measured normal canine left ventricular myocardium ANGII level by the two-injector HPLC-RIA system was 22.3 +/- 2.4 fmol/g, with a signal-to-noise ratio of 11.7, an improved signal-to-noise ratio of 29.3 fold vs. the one injector. This innovation reduced the incidence of false positive ANGII results, and thus can be applied to other compounds that exhibit HPLC-derived shadowing. PMID- 7854980 TI - Characterization of binding sites of a memory-enhancing peptide AVP(4-8) in rat cortical synaptosomal membranes. AB - The pentapeptide pGlu-Asn-Cyt-Pro-Arg [AVP(4-8), termed ZNC(C)PR in this article] has been found as a metabolite of arginine-vasopressin (AVP) in rat brain and has been shown to have potent memory-enhancing activity and to yield a series of biochemical events in brain tissues. [35S]ZNC(C)PR was chemically synthesized with high specific activity (232 Ci/mmol), and specific binding sites for ZNC(C)PR were located in synaptosomal membrane preparations of rat brain. We identified a specific binding site for ZNC(C)PR with a Kd of 3.12 nM and Bmax of 31 fmol/mg protein in anterior cortical synaptosomal membranes in the presence of 5 mM Ni2+. A comparison of synthetic analogues of ZNC(C)PR competing with [35S]ZNC(C)PR for binding to anterior cortical receptor are presented. ZDC(C)PR, a 2-aspartyl substitute of the 2-asparaginyl residue in ZNC(C)PR, had the most potent competition, but AVP did not show significant ability to compete for the receptor with ZNC(C)PR. PMID- 7854981 TI - Identification of the human seminal TRH-like peptide pGlu-Phe-Pro-NH2 in normal human prostate. AB - Human and rat prostate contain thyrotropin-releasing hormone immunoreactivity (iTRH) including TRH and an uncharged TRH-like peptide. Recently the uncharged TRH-like peptide pGlu-Phe-Pro-NH2 was purified from human semen. To determine whether this peptide was of prostatic origin, human and rat prostate extracts were analyzed by ion-exchange chromatography and reversed-phase HPLC. The predominant uncharged iTRH comigrated exactly with synthetic pGlu-Phe-Pro-NH2 on HPLC and had identical affinity to pGlu-Phe-Pro-NH2 in a TRH radioimmunoassay. We conclude that prostate is a source of this peptide in humans and rats. This amidated TRH-like peptide may play a role in human reproductive physiology. PMID- 7854979 TI - Differences in binding affinities of human PTH(1-84) do not alter biological potency: a comparison between chemically synthesized hormone, natural and mutant forms. AB - The purpose of this study was to evaluate receptor binding affinities and biological properties in vitro and in vivo of various recombinant hPTH(1-84) forms representing the natural hormone and a mutagenized hPTH form, [Gln26]hPTH(1 84) (QPTH), after expression in E. coli and Saccharomyces cerevisiae. In LLC-PK1 cells stably transformed with the rat PTH/PTHrP receptor, chemically synthesized hPTH(1-84) and QPTH showed a reduced binding affinity (apparent Kd 18 and 23 nM, respectively) than the recombinant, hPTH(1-84) (apparent Kd 9.5 nM). All recombinant hPTH forms showed a similar potency to stimulate cellular cAMP production (EC50 1.5 nM) and significantly better than chemically synthesized hPTH (EC50 5.7 nM). All hormone forms showed an about equipotent activity in causing elevation in serum calcium, increased excretion of urine phosphate, and cAMP. Thus, the natural recombinant PTH forms showed higher binding affinities and adenylate cyclase activation potencies in LLC-PK1 cells, but the reduced receptor binding affinity exerted by QPTH did not transcend differences in cAMP generation and in vivo biological activities. PMID- 7854982 TI - Effects of the peptide BCH-325 upon the efficacy of common antiepileptic drugs. AB - It was shown that BCH-325 (Pro-D-Phe-Pro-Gly), a des-tyrosine derivative of beta casomorphin, exhibits anticonvulsive effects. In the present study, we combined the peptide with clinically used antiepileptic drugs (phenytoine, carbamazepine, diazepam, phenobarbital, and dipropyl acetate) to investigate possible interactions and, moreover, to draw conclusions concerning the mode of action of BCH-325. There were no interactions with phenytoine and carbamazepine, which might be interpreted to mean that BCH-325 exerted no action on sodium channels. The efficacy of the combinations with the other drugs (diazepam, phenobarbital, dipropyl acetate) was increased. The data suggest that the anticonvulsant effect of BCH-325 might occur by interference with elements of GABA/benzodiazepinergic neurotransmission. PMID- 7854983 TI - Autoradiographic demonstration of 125I-Tyr4-bombesin binding sites on rat anterior pituitary cells. AB - Because several direct effects of bombesin related peptides on pituitary hormone release have been demonstrated, we chose to study the presence of bombesin binding sites in the adult male rat anterior pituitary in aggregate cell culture by autoradiographic localization of 125I-tyrosine4-bombesin (125I-Tyr4-BBN) binding and immunocytochemical localization of the anterior pituitary hormones. When aggregates were cultured in medium without hormonal supplements, the number of cells with detectable 125I-Tyr4-BBN binding was below 1%. In cell aggregates cultured in the presence of 1 nM estradiol (E2) 125I-Tyr4-BBN binding was detected on 5.4 +/- 0.8% of the cells after redispersion and on 5.8 +/- 1.1% of the cells in sections of paraffin embedded aggregates. The binding cell types were mainly lactotrophs and somatotrophs. The binding of 125I-Tyr4-BBN (3 or 5 nM) was specific because it was inhibited by the addition of an excess of unlabelled Tyr4-BBN or the bombesin receptor antagonist L686,095. In aggregates cultured in the presence of 1 nM E2 and 4 nM dex, the percentage of cells with detectable 125I-Tyr4-BBN binding was significantly lower than that in aggregates cultured in the presence of 1 nM E2 alone. Binding on somatotrophes almost completely disappeared. The present data show that specific 125I-Tyr4-BBN binding sites are present on anterior pituitary cells, are detectable mainly on a small subpopulation of lactotrophs and somatotrophs, and are affected by hormonal conditions.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7854984 TI - Synthesis and biological evaluation of alpha-MSH analogues substituted with alanine. AB - The influence of single amino acid replacements by alanine on the binding affinity and biological activity of alpha-MSH in B16 murine melanoma cells has been studied systematically. alpha-MSH analogues were synthesized by solid-phase peptide synthesis and their binding affinities to the melanocortin receptor expressed by B16 mouse melanoma cells were determined using a radioreceptor assay. Biological activity of the analogues was determined by measuring tyrosinase stimulation. Relative activity and affinity data were generally in agreement with earlier results using terminal deletion fragments of alpha-MSH, but the alanine scan revealed important new insights into the role of individual residues. The three terminal amino acids at either end were not necessary for binding or activity, with amino acids 4-9 forming a core sequence required for receptor binding and triggering of the biological response. It was observed that replacement of the glutamic acid residue in position 5 was possible without loss of affinity or activity, whereas replacement of Met4 resulted in a 100-fold loss of binding affinity and biological activity. Each residue within the conserved melanocortin sequence His-Phe-Arg-Trp was shown to be essential with Phe7, Arg8, and Trp9 being the most sensitive to replacement by alanine. Generally, there was a rank correlation between binding affinity and tyrosinase stimulation within the group of analogues studied. Tyrosinase activity was less affected by alanine substitution than binding affinity, which suggests that full receptor binding is not required for maximum biological response. PMID- 7854985 TI - The opiate system in invertebrates. AB - The presence in diverse species of a similar mode of communication, that of a soluble messenger binding to a receptor, raises the question as to whether the specific components of this system are equally widespread. Do invertebrates use the same hormones and receptors as vertebrates do? Invertebrates ranging from unicellular organisms to insects have been shown to contain opiate-like peptides and binding sites, and they exhibit biological responses to opiates. However, critical genetic data are lacking. It is not known how signal systems arise phylogenetically, but it is conceivable that signal molecules that are already present cause the formation of their own receptors from membrane proteins. PMID- 7854987 TI - [Antihistaminic agents in the treatment of allergic diseases]. PMID- 7854986 TI - GRP-preferring bombesin receptor subtype mediates contractile activity in cat terminal ileum. AB - Mammalian bombesin-like peptides, such as gastrin-releasing peptide and neuromedin B, are known to increase motility of different segments in the gut. The present study was carried out to identify the receptor subtype mediating these contractions of ileal longitudinal muscles in cats, in vitro. Both gastrin releasing peptide (GRP) and neuromedin B (NMB) evoked concentration-dependent contractions of the strips. [D-Phe6]Bombesin(6-13)-methyl-ester, a highly selective GRP-preferring receptor antagonist, competitively inhibited contractions induced by either agonist. On the other hand, D-Nal-Cys-Tyr-D-Trp Lys-Val-Cys-Nal-NH2, a selective NMB receptor antagonist, did not affect the actions of either gastrin-releasing peptide or neuromedin B. Our results suggest that bombesin-like peptides contract cat terminal ileum via activating GRP receptors. PMID- 7854988 TI - [Incidence of chronic diseases in families of allergic children with recurrent infections]. AB - An incidence of the chronic ailments has been determined in families of allergic children with recurrent infections. Typical allergic disorders and syndromes, including infantile eczema in the first year of life (48.0% of children), and positive skin prick tests (52.0%), have been characteristic for this group of children. Moreover, cell-mediated immunological deficit has been seen in 37.0% of these children, humoral immunological disorders--in 23.0%, and phagocytosis disturbances--in 30.0% of children. Sixty five percent of the examined children has been hospitalized from 1 to 10 times and more. A percentage of children being sick at home for 1 month and longer has been similar. The following diseases have been detected in the population of 1,049 parents and the I line relatives of these children: allergic diseases--mainly bronchial asthma in 16.0%; neoplasms in 9.8%; arterial blood hypertension in 5.1%; tuberculosis in 2.6%; duodenal or peptic ulcers in 2.6%; rheumatoid disorders in 2.5%; diabetes mellitus in 1.9%, and psoriasis in 1.1%. Statistically significant differences (0.01 > p > 0.001) between an incidence of the allergic disorders, mainly bronchial asthma, and neoplastic diseases has been found in the examined population of parents and relatives of allergic children with recurrent infections and general population. Such a result suggest similarity of the probable immunological dysfunction in both groups. PMID- 7854989 TI - [Coexistence of various types of urticaria and non-infectious rhinitis]. AB - The studied material comprised 179 patients with three types of non-infectious rhinitis and 8 types of urticaria. Out of 24 possible combinations of coexistence of the types of these disease entities in and overwhelming majority of patients (95.6%) only 6 combinations were found, while the remaining 18 combinations were very rare, and were noted in only 4.4% of patients. PMID- 7854990 TI - [Oto-respiratory reflex in patients with pollinosis]. AB - The examinations of the external auditory canals among the group of 53 asymptomatic (before the season) grass pollen sensitive patients have been performed by means of fiberoptic otoscope. The mechanical irritation of the walls of the auditory canals resulted in the cough reflex in 11 patients. The analysis of the lack or presence of any bronchial symptoms (during or out of the season) among the whole group has been made. The conclusion was, that oto-respiratory (or oto-cough) reflex may be the predictive measure of any bronchial symptoms among pollinosis patients. In the aspect, the sensitivity of the was 50%, but its specificity--92%. PMID- 7854991 TI - [Positive immediate skin reactions to environmental allergens in patients with schizophrenia and affective diseases]. PMID- 7854992 TI - [Specific IgE antibodies for nuts in infants]. AB - An introduction of several foodstuffs containing nuts into the diet in Poland increased the incidence of allergy. Therefore, an incidence of nuts-specific IgE antibodies in infants have been determined. The study involved 163 infants aged between 1 and 12 months with the symptoms of food allergy and matched control group. Specific IgE antibodies against food allergens such as cow milk, eggs, wheat flour, corn, soya, cod-fish, hazel- and peanuts have been assayed. Specific IgE antibodies against cow milk have been found in 105 (64.4%) infants, soya in 85 (52.1%), eggs in 64 (39.2%), wheat flour in 45 (27.6%), hazelnuts in 68 (41.7%), and peanuts in 47 (28.8%) infants. According to the parents, these infants have never been given any foodstuff containing nuts but such foodstuffs have been eaten by their mothers during pregnancy and breast-feeding. Therefore, pregnant and breast-feeding women should be warned against eating nuts and introducing them to infant diet too early. PMID- 7854993 TI - [Natural history of allergic reactions to Hymenoptera insect bites]. AB - In 30 patients suffering from systemic allergic reactions following Hymenoptera insect bites risk factors have been evaluated. Life-style, place of living, patients' age, sex and the presence of atopy have been considered. Moreover, the clinical course and value of the intracutaneous quantitative tests have been analysed and their value in both the diagnosis and prognosis of the said reactions have been assessed. Significant correlation between the results of quantitative diagnostic tests and severity of the hypersensitivity to insect poison has been found. A phenomena of the spontaneous diminished skin reactions has been noted. It has been found that only an individual analysis of the natural history might be a base for the choice of appropriate therapy. PMID- 7854994 TI - [Results of treatment with loratadine in patients with chronic urticaria]. AB - This study aimed at evaluating loratadine efficiency versus placebo in the treatment of patients with chronic urticaria. The single blind trial involved 31 patients divided into the group treated with active drug (21 patients), and placebo (10 patients). Loratadine in a daily dose of 10 mg (1 tablet in the evening) was administered for 28 days whereas placebo was given for 14 days. Patients filled so-called self-observation charts in which a severity of disease symptoms and/or adverse reactions were noted every day. Skin test with histamine was performed in the hospital before the trial, after 2 weeks, and in the last day of the treatment. The obtained results showed a marked decrease in erythema, wheals, and prurigo in patients treated with loratadine. No such an improvement was seen in placebo group. Skin reaction to histamine was also markedly reduced in loratadine group. Loratadine proved an efficient agent in the treatment of the chronic urticaria in 71% of patients. PMID- 7854995 TI - [Effect of cetirizine therapy on the rate of adverse reactions to specific desensitization]. AB - An effect of cetirizine--one of antihistaminic agents--on the rate of adverse reactions to the specific desensitization has been evaluated in patients with atopic respiratory diseases. The study included 270 patients desensitized in 1988 1993 for the atopic diseases due to hypersensitivity to grass pollens and Dermatophagoides pteronyssinus. Standard Alvac-P. Pollinex, and Alvac-S HDM vaccines have been used. Occurrence and severity of the adverse reactions noted during 3,368 injections of vaccines have been analysed. Frequency and adverse reactions severity have been compared for two periods--1988-1990 when patients have not been given antihistaminic agent, and 1991-1993--when ceterizine has been administered during the whole period of desensitization. It has been found that simultaneous cetirizine administration decreases frequency and severity of adverse reaction to the used vaccines. Such a procedure may be recommended to patients with advance hypersensitivity given vaccines in out-patient clinics. PMID- 7854996 TI - [Bronchial asthma and complications after corticosteroids]. PMID- 7854997 TI - [Bronchial asthma caused by exposure to ash wood dust]. AB - A 42-year-old man reported attacks of dyspnoea on non-professional exposure to ash wood dust. The skin prick tests with common allergens and ash pollen were positive. Inhalation of ash wood dust (challenge test) elicited a very strong, immediate bronchospastic reaction, associated with profuse watery rhinorrhea, conjunctival congestion and lacrimation. The symptoms did not occurred after inhalation of pine wood dust. A positive skin (prick test) reaction to ash wood extract was documented. When the patient remained unexposed to ash wood dust the dyspnoea subsided and 4-fold decrease in bronchial reactivity to histamine-PC20 increase from 0.53 mg/ml to 2.1 mg/ml (according to Cockroft) was observed. The authors conclude that the immediate bronchial reaction to inhaled ash wood dust and the immediate skin positive response to ash wood extract were due to IgE allergen reaction. This is the second case of hypersensitivity to ash wood dust reported in the literature. PMID- 7854999 TI - [Allergic reaction to products made of natural rubber]. AB - In the previous few years, there has been a startling escalation in intraoperative and radiologic anaphylactic episodes, some of them lethal, that have been assigned to rubber exposure. Immediate hypersensitivity reactions to natural rubber pose a significant risk to patient with spina bifida and urogenital abnormalities, health care workers, and rubber industry workers. It has been estimated that 2% to 10% of physicians and nursing personnel are latex allergic. The clinical syndromes associated with reactions to latex may be divided into three broad categories a) contact dermatitis--limited to skin directly in contact with latex, b) contact urticaria syndrome a broad spectrum of contact reactions including not only immediate wheal and flare reactions, but also dyshidrotic vesiculation, and accelerated contact reactions including erythema, burning or pruritus occurring within 10-30 minutes after contact, c) systemic allergic reactions-including generalized urticaria or pruritus, rhinoconjunctivitis or asthma, as well as the multiple presentations of anaphylaxis. Contact dermatitis reactions are thought to be a T-cell mediated type IV reaction, systemic reactions to latex appear to be an IgE-mediated phenomenon. Contact urticaria syndrome seems to be a heterogeneous group of reactions. Diagnosis of latex allergy is made on clinical grounds, however, history alone is insufficient to recognize all patients at risk, and conscientious testing materials are not yet available. Prick tests utilizing extracts from latex gloves or from raw latex preparation can be used but the specificity of this test remains unknown. Skin prick testing must be considered experimental and should be only done by experienced physician. Serologic testing for latex allergy remains a safe alternative, although the sensitivity and specificity of this procedure is still undefined. Prophylactic regimes to avoid rubber exposure and decrease the antigen content of natural rubber products by the rubber industry should be implemented to decrease the rate of sensitization in the future and prevent allergic reactions. PMID- 7854998 TI - [Churg-Strauss syndrome: two cases histories]. AB - Two cases of Churg-Strauss syndrome with severe polyneuropathy have been diagnosed according to clinical and histopathologic criteria. Perforation of small intestine, successfully treated with surgery, was observed in one of two cases. The resected part of gut presented specific histologic picture of Churg Strauss syndrome. PMID- 7855000 TI - [Significance of skin dryness in atopic dermatitis]. PMID- 7855001 TI - Mitotic activity and prognosis in prostatic adenocarcinoma. AB - Mitotic figures were quantitated by two different methods (number of mitotic figures in 10 high power fields, MI; number of mitotic figures/mm2 of neoplastic epithelium, M/V) in a series of 303 prostatic adenocarcinomas, and the results were related to clinical and histological features as well as to prognosis. Gleason score and mitotic indices were significantly interrelated. Invasive T3-4 tumors showed higher mitosis counts than did the local ones, and metastasis at the time of diagnosis was related to mitotic indices as well. Progression and progression-free survival were related significantly to Gleason score and mitotic indices. In univariate survival analysis, T-category, M-category, Gleason score, MI, and M/V were significant prognostic factors. In multivariate analysis, independent predictors of survival were M-category, T-category, Gleason score, patient age, and the M/V index. If the Gleason score was not included, M/V included all the available prognostic information in T1-2M0 carcinomas. The results show that, in addition to the conventional Gleason grading system, mitotic indices are useful prognostic parameters while evaluating the long-term prognosis in prostatic adenocarcinoma. PMID- 7855002 TI - Cellular proliferation in prostatic adenocarcinoma as assessed by bromodeoxyuridine uptake and Ki-67 and PCNA expression. AB - Prostatic carcinomas vary in their biological potential, even when stratified by grade and stage. Measurement of cellular proliferation by various methods has been shown to correlate with outcome for several human cancers, including prostatic carcinoma. Uptake of bromodeoxyuridine (BrdUrd), a thymidine analogue, has been accepted as a measure of cellular proliferative rate. However, the technique is somewhat complex, requiring incubation with fresh tissue. We compared cellular proliferation as measured by BrdUrd uptake with two more simple immunohistochemical methods in 44 prostatic adenocarcinoma specimens and correlated the results with standard clinical parameters. The tissue was obtained via needle biopsy, channel transurethral resection, and radical prostatectomy. Specimens were incubated in vitro with BrdUrd and then fixed and paraffin embedded. Sections were immunohistochemically stained with antibodies to BrdUrd, proliferating cell nuclear antigen (PCNA), and Ki-67. At least 1,000 cells were scored, and a labeling index (LI) was calculated (number of positive cells/total number of cells). The mean LI determined by all three indices was low (BrdUrd = 3.0, PCNA = 7.0, Ki-67 = 3.4), consistent with the knowledge that prostatic tumors grow slowly. In 36 patients who had not been treated at the time of analysis, the LI as determined by all three methods correlated well with clinical stage and pathological grade. Furthermore, the LIs discriminated between those with tumor confined to the prostate and those with extension to the seminal vesicles, lymph nodes, or bone (P = 0.003, 0.004, 0.008 for BrdUrd, PCNA, and Ki 67, respectively). The LIs for PCNA and Ki-67 correlated well with that for BrdUrd (r = 0.84; r = 0.85), while the LIs for Ki-67 and PCNA correlated slightly less well with each other (r = 0.78). PCNA and Ki-67 expression appear to reflect essentially the same biological process as BrdUrd uptake. Either can substitute for BrdUrd as a measure of cellular proliferation, and Ki-67 seems to offer the fewest technical problems. PMID- 7855003 TI - Gastrointestinal autonomic nerve tumor: a case report with electron microscopic and immunohistochemical analysis and review of the literature. AB - A case of an adolescent girl with metastatic gastric stromal tumor is described. There were three metastatic nodules in the liver at the time of the admission. A subtotal gastrectomy was performed. The tumor had distinctly nodular appearance and was composed of a variety of cells suggestive of smooth muscle differentiation. Electron microscopy revealed cytoplasmic neural processes and densecore neurosecretory granules. Immunohistochemistry showed positive neuron specific enolase, synaptophysin, and chromogranin A in some of the tumor cells. Similar findings in the primary tumor and its liver metastases indicated a primitive neural differentiation and enabled us to classify the lesion as a gastric autonomic nerve tumor. No other tumors that would suggest that the gastric lesion is a part of Carney's triad were detected. The child was treated with chemotherapy but the liver metastases did not change significantly. She is alive with unresectable liver metastases 10 months after the gastrectomy. PMID- 7855004 TI - Role of asphyxia and feeding in a neonatal rat model of necrotizing enterocolitis. AB - Necrotizing enterocolitis (NEC) is a common gastrointestinal disorder affecting premature infants. To investigate critically the importance of the purported risk factors of NEC (formula feeding, asphyxia, bacteria, and prematurity), we developed a neonatal rat model that closely mimics the human disease. Full-term and premature newborn rats were stressed with formula feeding, asphyxia, and/or exogenous bacterial colonization and subsequently evaluated grossly and histologically for the development of intestinal injury. We found that most animals treated with asphyxia, formula feeding, and bacteria developed NEC (77%) and died (86%) by 96 h. All maternally fed animals treated with asphyxia and bacterial colonization survived and had normal intestinal histology. Furthermore, asphyxia was a critical instigating factor, because formula and bacterial exposure without asphyxia resulted in normal intestine and minimal mortality (12%). Enteral bacterial colonization was not a significant determinant of NEC in this model. We conclude that the neonatal rat model is an excellent test system for the study of NEC. As in the human disease, asphyxia and formula feeding play an important role in the pathophysiology of experimental NEC. PMID- 7855005 TI - Nevus cells and special nevomelanocytic lesions in children. AB - Nevomelanocytic lesions in children represent a wide spectrum of proliferative neurocristopathies, ranging from the common small and benign congenital nevi to the garment-type congenital lesions. Included in this spectrum are some rare entities like neurocutaneous melanocytosis, malignant melanoma simulants, and special variants of congenital pigmented nevi. Here, we analyze some tissue culture characteristics of nevomelanocytic cells from giant and small congenital nevi, neurocutaneous melanocytosis, and a rare variant of nevus named "bulky nevocytoma." Correlations with their histological, immunohistochemical, and ultrastructural features are addressed. PMID- 7855006 TI - Glandular inclusions in inguinal hernia sacs: a clinicopathological study of six cases. AB - Glandular inclusions in inguinal hernia sacs are not frequent. We present six cases of inguinal hernia with this finding, which represents an incidence of 2.6% in males and shows a predominance in the prepubertal stage. Five patients showed cryptorchidism and two cases were related to congenital malformations of the single umbilical artery type and 47,XY chromosome disorder with chromosomal marker. The most important differential diagnosis must be made with normal histological structures such as the vas deferens or epididymis. The mean diameter of the inclusions was 0.1988 mm and there was a significant difference in size between the inclusions and the vas deferens, but not the epididymis. Differentiation from the latter is based on the absence of a well-developed muscular coat in the wall of the inclusions. It is important to recognize that these inclusions can occur in hernia sacs because of the clinical and medicolegal implications that arise if they are confused with true epididymis or vas deferens. They may arise from paratesticular embryonal remnants. PMID- 7855007 TI - Intranuclear Birbeck granules in Langerhans cell histiocytosis. PMID- 7855008 TI - Chromosomal instability in hereditary tyrosinemia type I. PMID- 7855009 TI - Phrenic nerve involvement in Dejerine-Sottas disease: a clinicopathological case study. AB - We present the clinical and pathological data on a 12-year-old girl with Dejerine Sottas disease who died suddenly in her sleep following the onset of mild flulike symptoms. The autopsy revealed diffuse and severe axonal loss with prominent onion bulbs in all nerves including the phrenic nerve. Early changes of pneumonia and bronchiolitis were evident in the lungs. To our knowledge, this is the first clinicopathological description of phrenic nerve involvement in Dejerine-Sottas disease. PMID- 7855010 TI - Intracardiac teratoma in a child simulating an atrioventricular nodal tumor. AB - Intracardiac teratoma is an extremely rare pediatric neoplasm. We studied the case of a 6-year-old girl with a right intraventricular cardiac mass. The tumor consisted of clusters of monotonous round epithelial cells scattered in a dense fibrotic stroma and was thought to represent an atrioventricular nodal tumor. Three years later the tumor recurred, with multiple mature elements derived from all three germ layers, and was diagnosed as mature cystic teratoma. Still present, however, were multiple areas that were histologically similar to the earlier lesion. Immunostaining revealed strong positivity for insulin, glucagon, somatostatin, and chromogranin consistent with overgrown pancreatic islets of Langerhans within a mature teratoma. PMID- 7855011 TI - Thrombotic thrombocytopenic purpura as the cause of death in an HIV-positive child. AB - A case of fatal thrombotic thrombocytopenic purpura (TTP) in a pediatric patients with HIV infection is reported. The diagnosis was made at autopsy based on the presence of platelet microthrombi in multiple organs, including the cardiac conduction system. The disease presented atypically with hemorrhagic manifestations, thrombocytopenia, and hemolytic anemia, without significant accompanying neurologic and renal abnormalities. Autoimmune-based thrombocytopenia has been well documented in the presence of HIV infection in both the adult and the pediatric population. We believe this to be the first reported case of TTP in an HIV-positive child. PMID- 7855012 TI - Necrotizing funisitis associated with Actinomyces meyeri infection: a case report. AB - Necrotizing funisitis is associated with an increased rate of stillbirth, perinatal infection, and preterm delivery. No one organism has been associated with necrotizing funisitis, although this condition has been linked with congenital syphilis in some studies. We report a case of necrotizing funisitis in a 24-year-old G2P0A2 woman who experienced preterm labor at 31 weeks of gestation. Examination of the placenta revealed severe chorioamnionitis and necrotizing funisitis; large numbers of gram-positive filamentous branching organisms could be seen on the surface of the cord and within Wharton jelly. Initial cultures of the placenta, which had not been maintained under anaerobic conditions after delivery, were negative. A fragment of the cord was then homogenized; anaerobic culture on brain-heart infusion agar yielded Actinomyces meyeri. This organism usually resides in the periodontal sulcus and has not been previously reported in the female genital tract. The mother gave a history of a dental abscess that flared up and drained with each of her three pregnancies; the pain was particularly severe during the last 2 months of this pregnancy, so she had the tooth removed after delivery. The infant was treated for prematurity and presumed sepsis and did well. PMID- 7855013 TI - Deficient metanephric blastema--a cause of oligomeganephronia? AB - The histopathology and morphometric findings in two cases of oligomeganephronia occurring in a fetus and a preterm infant are reported. Metanephric blastema was decreased in the kidney from an 18-week fetus and was absent in the kidney from a liveborn preterm infant of 33 weeks gestation. These findings support the hypothesis that a primary deficiency of metanephric blastema may be a pathogenetic mechanism of oligomeganephronia. PMID- 7855014 TI - Surfactant replacement therapy in preterm neonates: a comparison of postmortem pulmonary histology in treated and untreated infants. AB - New histological lesions have been reported in the lungs of preterm neonates treated with surfactant for respiratory distress syndrome (RDS). Globular deposits of hyaline maternal in parenchymal air spaces, absence of hyaline membranes, and increased interstitial cellularity and edema without associated fibrosis have been described. Fifteen histological findings were assessed in the lung pathology of 76 infants with RDS from three study groups. Group I (24 infants) died in the presurfactant era (before 1982), group II (26 infants) died despite having surfactant treatment, and group III (26 infants) were either untreated controls or did not receive surfactant for other reasons. The three groups were comparable in respect of sex and survival time. All infants were 34 weeks of gestation or less. Infants with a significant congenital abnormality or pulmonary hypoplasia were excluded. The 76 cases were assessed independently and "blindly" by two pathologists. The histological findings assessed were alveolar collapse; epithelial necrosis, proliferation, and metaplasia; hyaline membranes; dilated lymphatics; pulmonary interstitial emphysema; interstitial edema, inflammation, and fibrosis; arteriolar muscular hyperplasia; interstitial and intra alveolar hemorrhage; massive pulmonary hemorrhage; and pneumonia. No significant differences were found in any of the histological findings between the three groups. The hyaline membranes seen in the surfactant-treated infants were identical to those in the untreated lungs and were of the characteristic linear type. Interstitial fibrosis, inflammation, and edema were present in all three groups. It has also been suggested that surfactant therapy protects preterm infants from interstitial hemorrhage but predisposes them to intra-alveolar hemorrhage. No significant difference in the incidence of intra-alveolar and interstitial hemorrhage in the three groups was identified. PMID- 7855015 TI - Giant cell and lymphocytic interstitial pneumonia associated with fetal pneumonia. AB - In a review of 96 consecutive perinatal autopsies (42 nonautolyzed stillborn and 54 liveborn infants 12 h or less of age) with histologic sections of placental tissues and an undistended lung, we were impressed by the frequent occurrence of lymphocytic infiltrates in the interstitium of the lung. To study this phenomenon further we analyzed the cases for 56 clinicopathologic variables. Lymphocytic interstitial infiltrates were present in 22 of the cases, 5 stillborn and 17 liveborn. The severity of the infiltrates was highly significantly correlated with the severity of chorioamnionitis, funisitis, and fetal pneumonia (P < .001). A positive association was found with livebirth and a negative association with hyaline membrane disease (both P < .05). No significant association was found with gestational age, body size, or other complications of pregnancy, labor, delivery, or the immediate perinatal period. Twenty-seven cases had fetal pneumonia without lymphocytic interstitial infiltrates. Two cases had interstitial lymphocytic infiltrates in the absence of fetal pneumonia, but both had chorioamnionitis. Two other cases had numerous giant cells, shown to be of macrophage origin by immunoperoxidase stains, in the airways in addition to severe fetal pneumonia and lymphocytic interstitial pneumonia. The observations show that lymphocytic interstitial infiltrates and giant cells may be a feature of fetal pneumonia. PMID- 7855016 TI - 46,XX gonadal agenesis in a neonate with multiple congenital anomalies: case report and review of the literature. AB - We report a neonate with 46,XX gonadal agenesis, a rare disorder, confirmed by autopsy, karyotype determination, and fluorescent in situ hybridization examination of intact cells. Multiple other anomalies, including diaphragmatic hernia, a doomed bicuspid aortic valve, and mullerian derivative defects, were present. There was no sexual ambiguity. The age of this patient and the presence of anatomically dispersed congenital anomalies are unique among reported examples of 46,XX gonadal agenesis. Review of the literature reveals that all five previously reported cytogenetically confirmed patients with 46,XX gonadal agenesis were 17 to 25 years of age, none were diagnosed before their teens, all had female phenotype with sexual infantilism, three had mullerian derivative anomalies, and none had nongenitourinary anomalies. The abnormalities in this case may represent a polytopic field defect due to unknown insults occurring at approximately 6 weeks of developmental age. PMID- 7855017 TI - Organ weights in sudden infant death syndrome. AB - This comprehensive study of organ weights in sudden infant death syndrome (SIDS) should be of use to those studying postmortem data in SIDS and may have application to issues of growth and development. Analysis of data from 500 autopsies, performed over 15 years by one individual, revealed mean body weights generally below the 50th percentile for living infants. The weights of the thymus, lungs, liver, and brain were significantly greater than published norms. Thymic weights in SIDS probably represent the normal state more closely than those reported in several other series; elevated lung weights are presumably due to the intense pulmonary congestion and edema commonly encountered in SIDS; the liver edge routinely extends below the costal margins at SIDS autopsies, but the reason for increased weight is unknown, although a hemodynamic alteration seems likely; elevated brain weight has been described previously in SIDS. Other organs showed trends differing from "normal"--heart weights showed a marginally significant increase above published norms; for the adrenal glands, a uniform decrease was apparent, but slopes of linear regressions were low, hampering statistical analysis. Organ weights correlated more closely with body weight than with age. When victims were classified as "possible SIDS," "probable SIDS," or "classic SIDS," differences in organ weights were rarely significant. Analysis of organ weights using Z scores and their standard deviations (sigma-Z, or "pattern variability index") revealed increased variability in SIDS victims. Explanations for these findings include the possibility that some weights previously published as normal are low due to confounding variables. Changes could also be genuine, resulting from disturbances in growth or physiology, or artifactual, possibly the result of agonal or postmortem changes. A database on carefully selected, previously healthy infants who died suddenly and unexpectedly of known causes (i.e., trauma) is much needed. PMID- 7855018 TI - Sudden death in childhood due to right ventricular dysplasia: report of two cases. AB - Two cases of sudden death due to arrhythmogenic right ventricular dysplasia (ARVD) occurring in the pediatric age group are described. One of the subjects, at the age of 7 years, is believed to be the youngest child in whom ARVD has been diagnosed at autopsy. The clinical and pathological characteristics of ARVD are discussed. PMID- 7855020 TI - Juvenile delinquency: considerations for pediatricians. PMID- 7855019 TI - Investigation of the fetal pulmonary inflammatory reaction in chorioamnionitis, using an in situ Y chromosome marker. AB - Chorioamnionitis is a frequent finding in the placenta in second-trimester premature labor. Seventy-six archival perinatal and fetal autopsies between 15 and 28 weeks of gestation with a morphologic diagnosis of chorioamnionitis were reviewed. Of the 76 cases, 52 (68%) had inflammatory cells in the lungs, which is higher than the reported incidence of clinical infection in neonates with chorioamnionitis. In 23 cases there were peribronchial lymphocytic hyperplasia and neutrophils in the airspaces, in 8 there was a lesser degree of interstitial inflammation as well as luminal neutrophils, and in 21 (40%) there were neutrophils in the airspaces only. To determine whether the neutrophils in the airspaces in the latter were maternal or fetal in origin, the lung sections of seven male fetuses in the group were examined by in situ hybridization for the Y repeat probe pHY 2.1, together with appropriate controls. Two of the tests were technical failures. The remaining five, and the positive controls, showed positivity for pHY 2.1 in 70-86% of luminal neutrophils. We conclude that luminal neutrophils in fetal lungs in this situation are fetal in origin. PMID- 7855021 TI - Tonsils and adenoids: an update. PMID- 7855022 TI - Vesicoureteral reflux. PMID- 7855023 TI - Conversion and somatization in pediatrics. PMID- 7855024 TI - Ingestion of coins and batteries. PMID- 7855025 TI - Index of suspicion. Case 1. Diagnosis: Mallet finger. PMID- 7855026 TI - Index of suspicion. Case 2. Diagnosis: recurrent respiratory papillomatosis. PMID- 7855027 TI - Index of suspicion. Case 3. Diagnosis: pertussis. PMID- 7855028 TI - Hirschsprung disease. PMID- 7855029 TI - Liver transplantation. When is it indicated and what can be expected afterwards? AB - Orthotopic liver transplantation is an established form of therapy for selected patients who have chronic parenchymal liver disease with cirrhosis, a chronic cholestatic syndrome, fulminant hepatic failure, or unresectable hepatic malignant disease. In most centers with experienced staff, 5-year survival rates exceed 70%. For a good outcome, it is essential that the patient be referred to a transplant center early, before overt clinical deterioration occurs. Following transplantation, lifelong immunosuppression is required to prevent allograft rejection, and extensive follow-up is necessary for early reversal of complications. The primary care physician plays a critical role in identifying organ donors. PMID- 7855030 TI - Kawasaki syndrome. An important consideration in the febrile child. AB - Many aspects of Kawasaki syndrome remain a mystery. The cause of the disease has eluded researchers, and its pathophysiology is a subject of much debate. However, the diagnostic features have been identified: A significant fever for at least 5 days, bilateral nonexudative conjunctivitis, erythema of the palms and soles, a polymorphic diffuse rash, cervical lymphadenopathy, and injection of the mouth and oropharynx. The recently instituted treatment protocol of high-dose aspirin with gamma globulin (Gamastan, Gammar) helps patients recover more quickly and with fewer potentially life-threatening sequelae than does aspirin alone. PMID- 7855031 TI - Diagnosis of chest pain. Pluses and minuses of stress tests. AB - The differential diagnosis of chest pain often can be made by careful history taking. However, an adequate physical examination is also important and is considered mandatory by patients. If a definite diagnosis of nonanginal chest pain is made, no further studies are necessary. Electrocardiographic stress tests give important prognostic information in patients with definite angina and also give diagnostic information in patients with atypical angina. They are poor screening procedures for detecting persons at risk for sudden death. Radionuclide and echocardiographic stress tests are expensive and usually not necessary. PMID- 7855032 TI - Bronchiectasis. How to identify, treat, and prevent. AB - Bronchiectasis is not as common as it once was. In developed countries, the causes include congenital disorders, cystic fibrosis, allergic bronchopulmonary aspergillosis, and immune deficiency states. Bronchiectasis can usually be diagnosed with little difficulty by supplementing complete physical examination with chest radiography, biochemical and serologic studies, and computed tomography of the lungs. Once the diagnosis is established, therapy is aimed at eradicating the underlying disease. Surgery is indicated for local lesions and for patients with massive hemoptysis or recurrent infection that is unresponsive to medical therapy. PMID- 7855033 TI - Equal time for the AMA. PMID- 7855034 TI - Acute inflammation after injury. Quick control speeds rehabilitation. AB - Acute inflammation is an important part of the healing process after musculoskeletal injury, but unless it is controlled early, it can significantly hamper rehabilitation. Simple physical methods, such as immediate application of ice and adequate rest for the injured site, may be all that is required in mild injury. For more severe cases, ultrasound and electrical stimulation methods may be needed. Medical therapy also helps control inflammation and relieve pain. Nonsteroidal antiinflammatory drugs reduce swelling, but effects may not be seen for several days in severe cases, and gastrointestinal side effects are not uncommon. Therefore, analgesics alone should be used if pain is the only symptom. Adjunctive corticosteroid injections are often beneficial but require precautions and the cooperation of the patient. When inflammation is controlled and the repair process is under way, therapeutic exercises should be prescribed to restore range of motion, strength, and endurance. The injured site should be protected (eg, taped) during exercise until rehabilitation is complete. PMID- 7855035 TI - Management of concussion in collision sports. Guidelines for the sidelines. AB - During high-risk sports events, it is important for team physicians to be alert to the possibility of concussion in athletes who may not realize they have been injured or may want to conceal their injury. If concussion is suspected and the player is conscious, history taking should include inquiries about loss of consciousness, loss of memory of events before and after the impact, headache, visual abnormalities, motor and sensory changes, and back, neck, and extremity pain. In an unconscious player, the airway, breathing, circulation, and cervical spine should be checked. The cervical spine must be stabilized before the player is moved if injury to it is suspected. Athletes with such an injury and those who have lost consciousness require hospital evaluation. If there is no cervical spine injury, a complete neurologic evaluation should be carried out on the sidelines and the player checked for signs of skull fracture. The Colorado Medical Society guidelines for grading concussions and deciding when athletes may return to competition are an excellent aid to clinical judgment. PMID- 7855036 TI - Shoulder problems in athletes. Hastening the return to full function. AB - Shoulder disorders in athletes initially may appear perplexing, but most can be resolved successfully with a systematic approach to clinical evaluation. Newer imaging techniques can be extremely helpful in diagnosing difficult cases or in planning surgery. Arthroscopy also can be helpful in confirming diagnoses and in treating problems resistant to nonoperative regimens. PMID- 7855037 TI - Insulin therapy and the reluctant patient. Overcoming obstacles to success. AB - When diabetic patients learn that insulin therapy is necessary, they may feel overwhelmed by anticipated changes in lifestyle. The key to success is to realize that every person with diabetes has individual needs and that these must be assessed, addressed, and accommodated. Better diabetes control will be the result. PMID- 7855038 TI - Probing the mechanisms of drug release from hydroxypropylmethyl cellulose matrices. AB - The transient dynamic swelling and dissolution behavior during drug release from hydroxypropylmethyl cellulose (HPMC) matrices was investigated using fluorescein as a model drug. A new flow-through cell capable of providing a well-defined hydrodynamic condition and a non-destructive mode of operation was designed for this purpose to assess the associated moving front kinetics. The results obtained show a continuous increase in transient gel layer thickness irrespective of the polymer viscosity grade or drug loading. This is attributed to the faster rate of swelling solvent penetration than that of polymer dissolution under the present experimental condition. On the other hand, the observed shrinkage of sample diameter over a longer time period demonstrates that polymer dissolution does indeed occur in HPMC matrices. Further, both the rates of polymer swelling and dissolution as well as the corresponding rate of drug release increase with either higher levels of drug loading or lower viscosity grades of HPMC. For water soluble drugs, the present results suggest that the effect of HPMC dissolution on drug release is insignificant and the release kinetics are mostly regulated by a swelling-controlled diffusional process, particularly for higher viscosity grades of HPMC. PMID- 7855039 TI - Formulation and intestinal absorption enhancement evaluation of water-in-oil microemulsions incorporating medium-chain glycerides. AB - We developed self-emulsifying water-in-oil (w/o) microemulsions incorporating medium-chain glycerides and measured their conductance, viscosity, refractive index and particle size. Formulation of Calcein (a water-soluble marker molecule, MW = 623), or SK&F 106760 (a water-soluble RGD peptide, MW = 634) in a w/o microemulsion having a composition of Captex 355/Capmul MCM/Tween 80/Aqueous (65/22/10/3, % w/w), resulted in significant bioavailability enhancement in rats relative to their aqueous formulations. Upon intraduodenal administration the bioavailability was enhanced from 2% for Calcein in isotonic Tris, pH 7.4 to 45% in the microemulsion and from 0.5% for SK&F 106760 in physiological saline to 27% in the microemulsion formulation. The microemulsion did not induce gross changes in GI mucosa at a dosing volume of 3.3 ml/kg. These results suggest that water-in oil microemulsion systems may be utilized for enhancement of intestinal drug absorption. PMID- 7855040 TI - Dependence of dissolution rate on surface area: is a simple linear relationship valid for co-compressed drug mixtures? AB - A quantitative analysis of the dependence of dissolution rate on the relative surface area occupied by two non-interacting drug mixtures from co-compressed slabs is described. The results from the experimental dissolution rates of each component from naproxen/phenytoin co-compressed slabs under laminar flow conditions, when corrected for the area occupied by that component in the slab, contradict the stagnant layer model predictions, where dissolution rates are assumed to be directly proportional to the occupied surface area. Simulations from non-mixed co-compressates of naproxen and phenytoin indicated that dissolution rates are proportional to bL2/3, as reported for pure compounds in the laminar dissolution apparatus by Shah and Nelson. However, for a well mixed co-compressate, which differs with the non-mixed case only in the distribution of particles, this proportionality did not hold. The deviation was explained by 'carryover' of material from one section of the component to the next due to fluid flow, resulting in an increase in apparent effective length of the component in the slab (Leff). PMID- 7855041 TI - Vehicle effects on in vitro percutaneous absorption through rat and human skin. AB - We studied the effects of three vehicles (propylene glycol, octanol and ethyl decanoate) with differing polarity on the in vitro percutaneous absorption of three chemicals (fluazifop-butyl, dimethyl phthalate and fomesafen sodium salt) with a range of physico-chemical properties. Absorption rate measurements were made from high vehicle volume (200 microliters/cm2) and low vehicle volume (< 10 microliters/cm2) applications. For the lipophilic fluazifop-butyl absorption rate was highest from the more polar vehicle propylene glycol, but this effect was only significant under high-volume conditions. There was a variable vehicle effect on absorption of the intermediate chemical dimethyl phthalate. The largest vehicle effect was seen for the more hydrophilic fomesafen sodium salt where absorption was fastest from the least polar vehicle ethyl decanoate. These results support the hypothesis that the absorption process can in part be predicted from a knowledge of solute solubility. Vehicle effects were greater from high volume applications than from those more comparable to occupational exposure conditions. PMID- 7855042 TI - Decanoic acid induced enhancement of rectal absorption of hydrophilic compounds in rats. AB - The enhancing effect of decanoic acid (C10) on the rectal absorption of phenolsulfonphtalein (PSP) was analyzed with a pharmacokinetic model. The transfer index of PSP from the rectal lumen to the epithelial layer in the presence of C10 was proportional to the product of the C10 disappearance rate from the rectal lumen and its calcium ion sequestration capacity. The enhancement of rectal PSP absorption by different doses of C10 was also predictable by using a permeability index, Pa, of PSP, which was defined as a proportionality constant relating transfer index and the product value described above. The Pa values of various hydrophilic compounds with different molecular weights were also estimated from their rectal bioavailability in the presence of C10. A linear relationship was observed between Pa values and reciprocal values of the square root of individual molecular weight. These findings suggest that the Pa index is related to the permeant's diffusion coefficient through paracellular aqueous openings formed by C10. PMID- 7855043 TI - Mechanism and kinetics of transcellular transport of a new beta-lactam antibiotic loracarbef across an intestinal epithelial membrane model system (Caco-2). AB - Various processes involved in the transcellular transport (TT) of loracarbef (LOR) were studied in the Caco-2 cell monolayer, a cell culture model of the small intestinal epithelium. The results provide support for presence of two AP to BL peptide TT pathways in the intestinal epithelial cell monolayer (Caco-2). The H+ gradient-dependent pathway (Km = 0.789 mM, and Jmax = 163 pmol/min per cm2) is relatively "high affinity" and "low capacity" compared to H+ gradient independent pathway (Km = 8.28 mM, and Jmax = 316 pmol/min per cm2). In addition, TT of LOR in the presence of a H+ gradient was inhibited 77% to 88% (p < 0.05) by 10 mM of cephalexin, enalapril, Gly-Pro and Phe-Pro, while TT of LOR in the absence of a H+ gradient was only inhibited 42% to 48% (p < 0.05) by 10 mM of Gly Pro and Phe-Pro. Since AP uptake is H+ gradient-dependent and saturable while the BL efflux is mostly nonsaturable and not driven by a H+ gradient, these two transmembrane transport processes must be different, which could be the result of two different peptide carriers. In vivo, these two transport processes must have worked in concert to produce transcellular flux of loracarbef. To explain the differences between kinetic characteristics of AP uptake and TT transport, a cellular pharmacokinetic (PK) model was developed and the results indicate that the PK model appropriately described the kinetics of LOR TT. The use of this PK model may provide an additional advantage to the use of the cell culture model because kinetic parameters at both sides of the intestinal epithelial membrane may be obtained using the same preparation. Taken together, the Caco-2 model system represents an excellent model system for the study of carrier-mediated processes involved in the TT of peptides and peptide-like drugs. PMID- 7855044 TI - Organization of stratum corneum lipids in relation to permeability: influence of sodium lauryl sulfate and preheating. AB - The role of the structural organization of intercorneocyte lipids in the barrier function of human stratum corneum was evaluated by treatment with heat and sodium lauryl sulfate. Measurement of transepidermal water loss in treated samples was used to quantify variations in stratum corneum permeability. Thermodynamic transition of lamellar lipids and their degree of organization were evaluated by differential scanning calorimetry and small-angle X-ray diffraction, respectively. Progressively preheating stratum corneum samples from 75 degrees C to 90 degrees C increased stratum corneum permeability to water vapor, while the fusion temperature of lamellar lipids and the intensity of the X-ray diffraction peaks of the polar lipids decreased. Sodium lauryl sulfate induced similar variations of these three parameters. These results support the hypothesis that, in addition to the chemical nature of intercorneocyte lipids, their structural arrangement and thermodynamic properties play an important role in the barrier function of the stratum corneum to water vapor. PMID- 7855045 TI - Follicular (pilosebaceous unit) deposition and pharmacological behavior of cimetidine as a function of formulation. AB - The effect of formulation on cimetidine delivery to the pilosebaceous unit and other skin phases was studied. In vitro and in vivo deposition determinations as well as a pharmacodynamic antiandrogenic sebaceous gland bioassays were made. A complex variety of factors influence how the formulation affects both the degree of drug deposition and its pharmacological activity in the pilosebaceous unit. When cimetidine was applied in formulations at pH values where it was predominately unionized, the thermodynamic driving force proved the dominant factor in influencing the extent of drug deposition into the pilosebaceous unit. Although more cimetidine was deposited into the pilosebaceous unit in vivo from the phospholipid-based liposomal formulation when cimetidine was ionized, this formulation was also the only one devoid of significant antiandrogenic action. Of great importance, it is clear from the studies that deposition from complex formulations, such as liposomes, where bilayer/drug interactions can persist in the skin, may give a false impression of the activity of a drug within a tissue. Moreover, data for cimetidine in 50% alcohol solution show that one can maintain local effects while reducing systemic activity by simply manipulating drug concentration in the application. PMID- 7855046 TI - Relationship between enoxacin and ciprofloxacin plasma concentrations and theophylline disposition. AB - Certain fluoroquinolone antibiotics affect theophylline (THEO) disposition by inhibition of its metabolism, yet no studies to date have investigated the relationship between fluoroquinolone plasma concentration and THEO pharmacokinetics. The effects of two fluoroquinolones, enoxacin (ENOX) and ciprofloxacin (CIPRO), have been studied in male Sprague-Dawley rats (n = 33-46) at steady state plasma concentrations of 0-33 mg.l-1, achieved by supplementing an intravenous bolus dose with a constant rate infusion. The effects of steady state ENOX and CIPRO plasma concentrations on the clearance of THEO determined after an intravenous bolus dose of 6 mg.kg-1 were described using a competitive inhibition model. The model consisted of two components, one describing a residual component of THEO clearance, which was unaffected by fluoroquinolone, the other describing the non-linear reduction of THEO clearance by fluoroquinolone. The residual clearance estimated from the model was comparable to renal clearance for THEO in the rat. The potency of each fluoroquinolone was characterised by a Ki value, the concentration reducing THEO clearance by 50% of the maximum change. These values were 4.7 microM and 16.3 microM for ENOX and CIPRO, respectively. Thus, in this study, ENOX was found to be a more potent inhibitor of THEO clearance than CIPRO. The method allowed direct in vivo comparison of potency between different fluoroquinolones, as pharmacokinetic differences, such as clearance, volume of distribution and bioavailability, were 'designed out.' PMID- 7855047 TI - Comparative pharmacokinetic and pharmacodynamic analysis of phthaloyl glycine derivatives with potential antiepileptic activity. AB - Glycine, in addition to GABA, is one of the most important neurotransmitter amino acids. The described structure pharmacokinetic pharmacodynamic relationships (SPPR) study explored the possibility of utilizing phthaloyl derivatives of glycine as new antiepileptics. This was carried out by investigating the pharmacokinetics and pharmacodynamics (anticonvulsant activity and neurotoxicity) of the following four phthalimide derivatives: phthaloyl glycine, phthaloyl glycinamide, N,N-diethyl phthaloyl glycinamide and N,N-diisopropyl phthaloyl glycinamide. Phthaloyl glycine did not demonstrate anticonvulsant activity, possibly because of its poor pharmacokinetics, high clearance, low volume of distribution and short half life. The three glycinamide derivatives showed anticonvulsant activity and had better pharmacokinetic profiles, longer half life and mean residence time, than phthaloyl glycine. Phthaloyl glycinamide was more potent than one of the major antiepileptic agents--valproic acid and showed a better margin between activity and neurotoxicity. The four investigated phthaloyl glycine derivatives did not operate as chemical drug delivery systems (CDDS) of glycine, but acted rather as drugs on their own. Phthaloyl glycine was excreted unchanged in the urine while the urinary metabolites of the glycinamide derivatives were phthaloyl glycine and phthaloyl glycinamide. In this analogous series of phthalimide derivatives, minor chemical changes affected dramatically the compounds' pharmacokinetics. The current study demonstrates the benefit of the SPPR approach in developing and selecting a potent antiepileptic compound in intact animals based not only on its intrinsic pharmacodynamic activity, but also on its better pharmacokinetic profile.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7855048 TI - Pharmacokinetic and pharmacodynamic aspects of an ophthalmic pilocarpine nanoparticle-delivery-system. AB - The regional pharmacokinetics as well as the pharmacodynamics of pilocarpine loaded nanoparticles for the treatment of glaucoma were investigated and compared to a solution of this drug. Polybutylcyanoacrylate nanoparticles were prepared by an emulsion polymerization process. Formulations with different drug concentrations (2-6%) as well as different particle concentrations were investigated and analyzed for size and drug loading. Drug binding to the particles was achieved at a level of 10-18% of the total drug content. The colloidal nanoparticles were sufficiently small (diameter: 100-300 nm) for a non irritating application to the eye. All preparations were applied to the eyes of New Zealand white rabbits which were treated with betamethasone before to create an elevated intraocular pressure (IOP). Pilocarpine concentrations, assayed from aqueous humor using gaschromatography, increased by 23% (AUC) for nanoparticle suspensions compared to aqueous reference solutions. Additionally, t1/2 was prolonged and the elimination coefficient was significantly decreased. Pharmacodynamic effects such as miosis and IOP reduction were investigated. tmax values of aqueous humor concentration were observed to be in a similar time range as miosis tmax readings. It was found that at lower drug contents a more pronounced prolongation of miosis was achieved with nanoparticles versus a standard solution. The IOP-reduction was significantly prolonged with nanoparticles preparations; whereas maximum reduction was obtained with a reference solution after 1-2 hours, it was reached with nanoparticles at about 2 3 hours. Differences between nanoparticles and aqueous solutions were most pronounced at lower drug concentrations. PMID- 7855050 TI - Renin inhibitor: transport mechanism in rat small intestinal brush-border membrane vesicles. AB - The transport characteristics of the renin inhibitor ((3S,4S)-4-[N morpholinoacetyl-(1-naphthyl)-L-alanyl-N-methyl-(4-t hiazolyl)-L- alanyl]amino-3 hydroxy-5-cyclohexyl-1-(4-pyridyl)-1-pentanone; CH3-18) in rat small intestinal brush-border membrane vesicles (BBMV) were examined by a rapid filtration technique. The uptake of CH3-18 was markedly stimulated by an inwardly directed H+ gradient (pH 7.5 inside, pH 5.5 outside) and showed an uphill transport. It was competitively inhibited by tripeptides and tetrapeptides, but not by amino acids or dipeptides. A countertransport effect on the uptake of CH3-18 was observed in the vesicle preloaded with a tripeptide. Effects of the fragments of several renin inhibitors were evaluated by their inhibitory and countertransport effects on the uptake of CH3-18. The morpholino group at the N-terminal was found to be important for the uptake of CH3-18. PMID- 7855049 TI - Renin inhibitor: relationship between molecular structure and oral absorption. AB - Common problems in developing renin inhibitors are low solubility, insufficient oral absorption, and fast hepatic clearance. We focused on the molecular structure of renin inhibitors to overcome these problems. Cyclodextrins (CD) improved the low solubility of renin inhibitors, with beta-CD showing the best ability to dissolve renin inhibitors. The intestinal absorption of renin inhibitors varied with both their solubility and molecular structure. Coadministration of beta-CD improved the intestinal absorption of some renin inhibitors with low solubility as measured by transport into the mesenteric vein in the absorption experiment using the rat intestinal loop. Substitutions at both the N and C terminals was essential for absorption from the small intestine. A naphthyl group at the N-terminal further improved intestinal absorption. A carrier system appeared to be involved in the intestinal absorption of some renin inhibitors. N-methylation at the amide bond of thiazolylalanine suppressed the high hepatic clearance of one of the test compounds 18 which was well absorbed from the small intestine and it improved its oral bioavailability. PMID- 7855051 TI - Interaction of benzothiadiazides with human serum albumin studied by dialysis and spectroscopic methods. AB - The interaction of a series of benzothiadiazides with human serum albumin (HSA) was investigated by equilibrium dialysis (ED) and spectroscopic methods including circular dichroism (CD). The primary binding site of benzothiadiazides was designated site II, the diazepam site on the HSA molecule, as indicated by displacement experiments using different site-selective probes. Tyrosine and lysine amino acid residues were probably involved in the binding site of these compounds to HSA. Both electrostatic and hydrophobic interactions were found to play a role in the binding of these compounds to HSA. Among the compounds tested, chlorothiazide had the highest affinity (K1 = 5.5 x 10(4) M-1, K2 = 5.8 x 10(3) M 1). The primary binding affinity of the compounds for HSA was of the order: chlorothiazide > cyclopenthiazide > polythiazide > ethiazide > trichlormethiazide = methyclothiazde > hydrochlorothiazide. Binding was insensitive to the N-B transition of HSA. The binding site is proposed to consist of a cationic site on the surface of the HSA molecular with a hydrophobic crevice to accommodate the aromatic ring of the compounds. Positions 3 and 7 of the benzothiadiazide molecule is thought to affect the binding affinity to HSA. PMID- 7855053 TI - A bayesian approach to Arrhenius prediction of shelf-life. AB - The use of a bayesian method for estimating the shelf-life of pharmaceutical formulations is evaluated and compared with classical linear regression. Using three real data sets, the greater flexibility provided by the bayesian approach is demonstrated. In particular, the bayesian approach enabled the consideration of cases when the error distribution is non-normal. However much more computation is required with the bayesian method. PMID- 7855052 TI - Cyclosporin absorption is impaired by the fat substitutes, sucrose polyester and tricarballylate triester, in the rat. AB - The effect of non-absorbable fat substitutes (sucrose polyester (SPE) and tricarballylate triester (TCTE)) on cyclosporin A (CsA) intestinal absorption was studied in the rat using in situ perfusion and gastric intubation techniques. A first experiment using the recirculating intestinal perfusion model showed that emulsions of either 5% SPE or TCTE significantly reduced (p < 0.0008) CsA absorption, whereas no difference was found between results for saline and 5% olive oil emulsion. In single-pass intestinal perfusion experiments SPE dose dependently inhibited CsA absorption at SPE concentrations of 0.31% (p < 0.0004) and higher. Using gastric intubation, whole blood CsA concentrations significantly decreased when administered with SPE and TCTE in comparison with olive oil (p < 0.04). These results confirm that the CsA fraction dissolved in the undigested oil phase, constituted by the undigested and nonabsorbed fat substitute, is unavailable for intestinal absorption. PMID- 7855054 TI - The effect of bulking agent on the solid-state stability of freeze-dried methylprednisolone sodium succinate. AB - The rate of hydrolysis of methylprednisolone sodium succinate in the freeze dried solid state at 40 degrees C was determined in the presence of two common bulking agents--mannitol and lactose--at two different ratios of drug to excipient. Residual moisture levels were less than 1% in all samples tested, with no significant difference in residual moisture among different formulations. Rate of hydrolysis was significantly higher in mannitol-containing formulations versus lactose-containing formulations, and the rate of hydrolysis increases with increasing ratio of mannitol to drug. Thermal analysis and x-ray diffraction data are consistent with a composition-dependent rate of crystallization of mannitol in the formulation and its subsequent effect on distribution of water in the freeze-dried matrix. Increased water in the microenvironment of the drug decreases the glass transition temperature of the amorphous phase, resulting in an increased rate of reaction. The physical state of lactose remained constant throughout the duration of the study, and the rate of hydrolysis was not significantly different from the control formulation containing no excipient. Thermal analysis and x-ray diffraction data are consistent with formation of a liquid crystal phase in freeze-concentrated solutions of methylprednisolone sodium succinate containing no excipient. PMID- 7855055 TI - Processing considerations for an EC latex coating system: influence of curing time and temperature. AB - The influence of curing time and curing temperature for a commercially available ethylcellulose latex coating dispersion (Aquacoat) were evaluated using response surface methodology. Levels for the factor curing time ranged from 30 to 300 minutes while levels for curing temperature ranged from 45 degrees to 75 degrees C. Responses, A, kappa, and gamma, were derived from regression analysis of the dissolution profiles and correspond to the maximum amount of drug released over the 12 hour sampling period, the rate of release, and the inflection point of the dissolution profile, respectively. The nature of the response surface was dramatically influenced by the plasticizer incorporated into the coating formula. When dibutyl sebacate was employed as the plasticizer, faster release resulted (higher A and kappa values, lower gamma values) when samples were exposed to higher curing temperatures or were stored for longer periods of time. Paradoxically, when tributyl citrate was used as the plasticizer, slower release resulted when samples were exposed to more rigorous conditions. Overall, curing temperature had a more dramatic effect than curing time. PMID- 7855056 TI - Polylactide microparticles prepared by double emulsion/evaporation technique. I. Effect of primary emulsion stability. AB - The process of microencapsulation of proteins by double emulsion/evaporation in a matrix of polylactide (PLA) can be divided into three successive steps: first, an aqueous solution of the active compound is emulsified into an organic solution of the hydrophobic coating polymer; second, this primary water-in-oil emulsion (w/o) is dispersed in water with formation of a double water-oil-water emulsion (w/o/w); third, the organic solvent is removed with formation of solid microparticles. This paper focuses on the effect of primary emulsion stability on the morphology and properties of polylactide microparticles loaded with bovine serum albumin (BSA) used as model drug. Depending on the stability of the primary emulsion, the internal structure of microparticles can be changed from a multivesicular to a matrix-like structure. Similarly, the average porosity can be controlled in a range from a few tenths of a micron to ca. 20 to 30 microns. This morphology control could find potential applications not only for the controlled drug delivery but also for the production of microporous particles intended for some specific applications, such as cell culture supports and chromatographic matrices. Although, the interplay of several processing parameters (polymer precipitation rate, polymer coprecipitation with interfacial compounds such as protein or surfactant, stirring rate...) may not be disregarded, this study also indicated that a high loading of a hydrophilic drug can only be expected from a stable primary emulsion. When the stability of the primary emulsion is such as to prevent formation of macropores (> 10 microns), the total pore volume is close to that of the originally dispersed aqueous drug solution. PMID- 7855057 TI - Gamma sterilization of a semi-solid poly(ortho ester) designed for controlled drug delivery--validation and radiation effects. AB - Radiation sterilization is becoming increasingly popular for the sterilization of many pharmaceutical products. Although this technique is not limited to the sterilization of polymers, it is probably the most suitable method for such materials. This method however suffers several drawbacks. The sterilization of a product must lead to a safety level of 10(-6), i.e. one chance in a million to find a contaminated sample. In many cases, this assurance of sterility can be achieved by using a uniform treatment dose of 2.5 Mrad, recommended by the pharmacopeia. We investigated the possibility of using doses of radiation inferior to 2.5 Mrad to sterilize a semi-solid poly(ortho ester) (POE) developed for use as carrier in controlled drug delivery. After determination of the initial bioburden, the polymer was intentionally contaminated with the bioindicator Bacillus pumilus E 601. Following exposure to gamma irradiation, the D10 value of the radio resistant bioindicator was determined. Using the initial contamination value, the reduction factor D10 and the safety level, it is possible to calculate an optimal sterilizing dose for POE. All polymers are affected by ionizing radiation and the amount of radiation which produces a significant change in properties may vary from one polymer to the other. A molecular weight and dynamic viscosity decrease resulting from backbone cleavage was observed for this POE at a dose lower than 2.0 Mrad. Evaluation of the structure using 1H-NMR, 13C-NMR and IR analysis shows that for doses higher than 2.0 Mrad, another degredation process takes place.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7855058 TI - Selective precipitation of interleukin-4 using hydrophobic ion pairing: a method for improved analysis of proteins formulated with large excesses of human serum albumin. AB - In order to ensure the stability of protein pharmaceuticals, human serum albumin (HSA) is often added as an excipient, frequently in large excess. This makes chromatographic analysis of the stability of the active protein difficult. In the case of interleukin-4 (IL-4), separation from HSA can be achieved to some degree by size exclusion chromatography, but some HSA co-elutes with the IL-4. Hydrophobic ion pairing provides a method for selective precipitation of IL-4 from HSA. Hydrophobic ion pairing involves the electrostatic interaction of ionic detergents with oppositely charged polypeptides. Even when HSA is present in fifty-fold excess (w/w), the resulting precipitate contains greater than 70% of the IL-4. Selective precipitation with SDS produces enhancements in IL-4 over HSA of more than 2000-fold. This approach permits subsequent facile analysis of IL-4 by conventional reverse phase HPLC. PMID- 7855059 TI - Effects of various protease inhibitors on the intestinal absorption and degradation of insulin in rats. AB - The effects of protease inhibitors on the intestinal absorption of insulin were investigated in situ in closed small and large intestinal loops in rats, and the stability of insulin was examined in homogenates of the small and large intestine. The intestinal absorption of insulin was evaluated by its hypoglycemic effect. When insulin alone was administered into small or large intestinal loops, no marked hypoglycemic response was observed in either region. Of the coadministered protease inhibitors, soybean trypsin inhibitor (1.5, 10 mg/ml) marginally promoted insulin absorption from the large intestine, whereas aprotinin (10 mg/ml) did to a moderate degree. However, a significant hypoglycemic effect was obtained following large intestinal administration of insulin with 20 mM of Na-glycocholate, camostat mesilate and bacitracin, when compared with the controls. In contrast, we found little hypoglycemic effect following small intestinal coadministration of insulin with these protease inhibitors. In the stability experiment, bacitracin, camostat mesilate and Na glycocholate were effective in reducing insulin degradation in both small and large intestinal homogenates. It was found that the reduction in the proteolytic rate of insulin was related to the decrease in plasma glucose concentration by these protease inhibitors in the large intestine. These findings suggest that coadministration of protease inhibitors would be useful for improving the large intestinal absorption of insulin. PMID- 7855060 TI - Intestinal permeability enhancement: structure-activity and structure-toxicity relationships for nonylphenoxypolyoxyethylene surfactant permeability enhancers. PMID- 7855061 TI - A simple method of correlating pharmacodynamic equivalence with absolute bioavailability following noninvasive delivery of insulin. PMID- 7855062 TI - Melanocyte destruction and repopulation in vitiligo. PMID- 7855063 TI - Papers from the XVth International Pigment Cell Conference. London, September 26 30, 1993. Part II. PMID- 7855064 TI - The presence of tyrosinase and related proteins in human epidermis and their relationship to melanin type. AB - The present study was carried out to investigate the abundance of tyrosinase and related proteins (TRP-1 and TRP-2) in human epidermis and their relationship to melanin type. Positive immunocytochemical staining was seen for all three proteins in epidermal melanocytes. For each protein the numbers of positively stained melanocytes were similar in all subjects studied irrespective of skin type. Following 5 daily suberythemal doses of UVB the melanocytes were larger, more dendritic, and increased in number. With TRP-1 and TRP-2 the increase in number in response to UVB was unrelated to skin type and, hence, with melanin type but with tyrosinase there was a much greater increase in skin types III and IV than in skin type I and II. The enhanced numbers of tyrosinase-positive melanocytes were accompanied by increased staining intensity, suggesting a greater expression of tyrosinase in the melanocytes from skin types III and IV compared with skin types I and II. This increase in tyrosinase could be related to the greater levels of eumelanin found in skin types III and IV, and this is in keeping with the view that higher levels of tyrosinase are associated with the production of eumelanin than phaeomelanin. PMID- 7855065 TI - Growth of neural crest cells in vitro is enhanced by extracts from Silky Fowl embryonic tissues. AB - In the Silky Fowl (SF) breed of chicken, most of the internal organs are infiltrated with melanocytes. Previous studies have shown that this generalized mesodermal pigmentation is not due to a cell autonomous abnormality of the melanocytes but to environmental factors able to promote both the homing of pigment cell precursors in abnormal embryonic sites and their proliferation and differentiation. To analyse the mode of these environmental cues, we tested the effect of SF embryo extract (SFEE) on cultured quail neural crest cells as compared with that of EE from normal chickens of the JA57 strain (JA57EE). We found that SFEE enhances crest cell proliferation as judged by 3H-TdR incorporation and cell counting. In contrast, no effect of SFEE was observed either on the proportion of cultured cells that are engaged into the melanocytic differentiation pathway or on the amount of melanin produced by each differentiated pigment cell. The simple observation, however, reveals that SFEE has a significant effect on pigmentation of the cultured quail neural crest cells. This effect has therefore to be accounted for by the general increase in cell number induced by SFEE. The question is raised as to whether the in vivo SF phenotype is generated exclusively by this mechanism. PMID- 7855067 TI - Tamoxifen inhibition of ocular melanoma cell attachment to matrix proteins. AB - Tamoxifen plays a major role in the management of breast cancer in women and is currently used to a lesser extent in other neoplasias. Many of the pharmacological properties of tamoxifen are consistent with anti-estrogen activity, but it also has significant, although lesser, benefit in patients whose tumours are estrogen-receptor negative. We recently reported that murine B16 melanoma cell attachment to extracellular matrix proteins can be inhibited by calmodulin antagonists. In seeking a calmodulin antagonist that could be used clinically, we investigated tamoxifen, which is known to have calmodulin antagonist activity in vitro, and confirmed that it will inhibit murine melanoma cell attachment in vitro. In the current study, we examined the effect of tamoxifen on the attachment of human ocular melanoma cell lines to a range of extracellular matrix substrates to evaluate the potential relevance of calmodulin antagonists, including tamoxifen, to reducing metastatic spread of these tumours. We report that six ocular melanoma cell lines established from choroidal melanoma tumours showed rapid attachment to a range of substrates and that this attachment can be significantly reduced by an experimental calmodulin antagonist (J8) and by tamoxifen. In summary, we conclude that the ability of calmodulin antagonists, including tamoxifen, to inhibit ocular melanoma cell attachment to matrix proteins in vitro merits further investigation as it may offer another approach to reducing metastatic spread of these tumours. PMID- 7855068 TI - DHICA oxidase activity of TRP1 and interactions with other melanogenic enzymes. AB - Tyrosinase-related protein 1 (TRP1) maps to the brown locus in mice. Although the specific function of TRP1 has been in dispute, mutations in its structural gene result in the formation of brown rather than black melanin. We have investigated the melanogenic function of TRP1 by using immune-affinity purification of the protein and also by using transfection of its gene into fibroblasts to study its characteristics. We show that TRP1 has the ability to oxidize DHICA, a melanogenic intermediate derived from DOPAchrome. In addition, TRP1 has the ability to interact with tyrosinase and significantly stabilize the latter's catalytic function. PMID- 7855066 TI - Cultured human melanocytes respond to MSH peptides and ACTH. AB - Although the administration of melanocyte-stimulating hormone (MSH) peptides results in skin darkening in man, cultured human melanocytes have been reported to be unresponsive to these peptides. This may be a consequence of the conditions under which the cells were maintained in vitro, particularly the use of phorbol esters and cholera toxin as melanocyte mitogens. By culturing the cells in the absence of these additives, we demonstrate that alpha-MSH and its synthetic analogue Nle4DPhe7 alpha-MSH (NDP-MSH) induce dose-related increases in melanin content and tyrosinase activity and affect cell morphology in the majority of human melanocyte cultures. In addition, NDP-MSH induces increases in tyrosinase mRNA and tyrosinase-related protein-1 (TRP-1) mRNA. The dose-response curves for the MSH peptides are sigmoidal and the two peptides are equipotent in their effects on human melanocytes. Adrenocorticotropic hormone (ACTH) also affects morphology and stimulates melanogenesis and tyrosinase activity in human melanocytes. However, the dose-response curves for ACTH are biphasic, and the melanocytes respond to lower concentrations of ACTH than MSH peptides, similar to those normally present in human plasma. These findings may be important in understanding the role of these pro-opiomelanocortin peptides in human skin pigmentation. PMID- 7855069 TI - Expression studies of pigmentation and POU-domain genes in human melanoma cells. AB - Human melanoma cell lines have been used to examine the regulation of the tyrosinase (TYR) and tyrosinase-related protein genes TRP-1 and TRP-2 in response to differentiating chemicals and UV irradiation. TRP-1 mRNA levels can be repressed by treatment with the differentiating chemicals DMSO and HMBA. There is little effect of UV irradiation on pigment synthesis by human melanoma cell lines or tyrosinase activity, with variable effects on the levels of the TYR, TRP-1, and TRP-2 gene transcripts. The human TRP-1 gene promoter has been isolated and its activity tested by transient cell transfection to begin an examination of signal transduction mechanisms operating in response to pigmenting and differentiating agents. To identify transcription factors that may be involved in melanocytic gene expression, we studied the N-Oct-3 and N-Oct-5 octamer-binding activities normally expressed in the neuroectodermal cell lineage and which are expressed at high levels in melanoma cells. POU-domain-containing cDNA have been isolated from the A2058 human melanoma cell line that are homologous to the brn-2 gene that encodes N-Oct-3 and N-Oct-5. PMID- 7855071 TI - Melanoma treatment. PMID- 7855070 TI - Evolution and expression of tyrosinase-related proteins. PMID- 7855072 TI - Biophysics of melanin and informal group on the characterization of neuromelanin. PMID- 7855073 TI - Regulation of melanogenesis induced by 5-methoxypsoralen without ultraviolet light in murine melanoma cells. AB - Melanogenesis in melanoma cells can be enhanced by psoralens in the absence of UV light. Melanin biosynthesis is regulated by a number of melanocyte-specific proteins, including tyrosinase, DOPAchrome tautomerase (DCT), and tyrosinase related protein-1 (TRP-1, gp75). To get more insight on the molecular mechanisms involved in psoralens-induced melanogenesis, we determined tyrosinase and DCT activities as well as mRNA and protein levels of tyrosinase, DCT, and TRP-1 in S91 mouse melanoma cells treated by 5-MOP. High concentration of 5-MOP (5 x 10( 5) M) induced a time-dependent increase of tyrosinase activity and melanin content, which was correlated to an increase of both mRNA and protein levels of tyrosinase. These results demonstrate that the 5-MOP stimulation of melanogenesis is related to increased tyrosinase synthesis. In addition, 5-MOP stimulated TRP-1 synthesis and induced a dose-dependent decrease of DCT activity without any modification in the expression of the protein. We explored then the signalling pathways involved in 5-MOP-induced melanogenesis and, particularly, the role of cyclic AMP and protein kinase C (PKC). A small stimulation of cyclic AMP production was observed in presence of 5-MOP. Furthermore, 1-oleoyl-2 acetylglycerol (OAG), a PKC activator, potentiated the 5-MOP stimulation of tyrosinase activity, while calphostin, a specific PKC inhibitor, inhibited the 5 MOP induction of tyrosinase activity. Phorbol-myristate acetate (PMA), described as a strong activator of PKC, inhibited also the effect of 5-MOP when used at long term. Taken together, these results demonstrate that in murine melanoma cells 5-MOP stimulates melanogenesis by increasing activity and synthesis of tyrosinase. Tyrosinase and TRP-1 expression are coordinately regulated by 5-MOP. Furthermore, a negative correlation between melanogenesis and DCT activity was observed under 5-MOP stimulation. At least, PKA and PKC systems appear to play an important role in the melanogenic effect of 5-MOP. PMID- 7855074 TI - X-ray characterization of melanins--I. AB - The intrinsic local structure characterization of natural sepia melanin and L dopa and tyrosine synthetic melanin powder has been carried out by X-ray diffraction using synchrotron radiation. The derived structure factor, S(q), shows six significant diffuse peaks within the q-range from 0.3 A-1 to 16 A-1 in the reciprocal space (q = (4 pi sin theta)/lambda, 2 theta is the scattering angle). The Fourier transform of S(q), which yields the radial distribution function (RDF), gives us information in real space of a 1.42 A distance averaged over the C-C, C-O and C-N bond lengths as well as peaks at 2.40-2.41 A, 3.67-3.71 A and 4.67-4.70 A discrete neighbor distances. There is a great similarity in the scattering intensity profiles of the natural and synthetic melanins indicating that the synthetically prepared material may be essentially similar to "real" melanin in its local atomic arrangements. An evidence of a prepeak at q congruent to 0.45 A-1 has been confirmed which indicates a preferred length scale of approximately 13-20 A that corresponds to the initial particle size in colloidal melanin solutions. PMID- 7855075 TI - X-ray characterization of melanins--II. AB - Structural modeling of amorphous eumelanin has been carried out by comparing calculated data, S(q) and RDF(r), in reciprocal and real space, respectively, for limited random network models with the experimental X-ray scattering data of tyrosine melanin (Cheng et al., 1994). A basic picture of the atomic arrangements in amorphous eumelanin, which accounts for the short and intermediate range order, has been formulated. This reveals domains of a fundamental "particle" dimension of R approximately 15 A, consisting of a paracrystalline array of disordered planar networks polymerized by 4-8 DHI monomers with a graphite-like stacking spacing of approximately 3.45 A, 4-5 layers thick. PMID- 7855076 TI - Effect of heat treatments on trypsin/chyomotrypsin inhibitor activity of red gram (Cajanus cajan L.). AB - The application of dry heat to the seeds and meal was not effective in inactivating the trypsin inhibitory activity (TIA) and chymotrypsin inhibitory activity (CIA). Soaking for 24 hours followed by cooking for 20 min was effective in destroying the TIA and CIA. PMID- 7855077 TI - Traditional production and chemical composition of Ndaleyi, a Nigerian fermented pearl millet food. AB - Ndaleyi, a fermented, sun dried agglomerated powder produced from pearl millet or sorghum is one of the most popular foods consumed in Nigeria, mostly by the Kanuri people of Borno State. Its traditional production is described. The mean yields of ndaleyi (mainly starch), chir ('millet gluten') and 'bran' (overtail or bina) were 30.6, 22.5 and 21.5%, respectively. A mean yield loss of 20% was observed. Chemical analysis revealed that chir and 'bran' have higher protein, fat and ash contents than ndaleyi. The titratable acidities (as percent lactic acid) of ndaleyi and chir were 0.9 and 0.3, while their pH values were 3.3 and 3.5, respectively. PMID- 7855078 TI - Effect of roasting and fermentation on viscosity of cereal-legume based food formulas. AB - With the view of preparing semi-liquid weaning foods of high energy content, the influence of roasting (stationary hot air treatment) and fermentation (with natural and pure culture inocula) on the viscosity of maize-sorghum-soya porridges was investigated. Roasting resulted in porridges of significantly higher viscosity (cooked porridge cooled to 40 degrees C). Porridges made from the individual ingredients (maize, sorghum, soya) did not show this behaviour. Natural fermentation of mixed ingredients resulted in lower porridge viscosities (cooked porridge cooled to 40 degrees C, as well as hot-paste peak viscosity) when pH was 5.0-5.5. At lower pH the viscosity of the final porridges increased. Fermentation experiments of individual ingredients inoculated with pure cultures of Lactobacillus plantarum and Candida famata lead to the conclusion that various factors contribute to the effect of fermentation on porridge viscosity. Porridges of minimum viscosity are obtained at pH 5.0-5.5 corresponding with a moderate extent of fermentation. From a consumer safety point of view, it would be preferable to acidify to lower pH values (pH < 4.5). If necessary, viscosity adjustments could be made using malted cereals. PMID- 7855079 TI - Studies on jicama juice processing. AB - Juice was extracted from jicama (Pachyrrizus erosus Urban) and clarified using a 10,000 daltons molecular weight cut-off membrane to improve its stability. Ultrafiltered juice was tested for general composition and Hunter color. Ultrafiltration (UF) retentate and UF permeate showed some changes, compared to fresh juice, in total and soluble solids, total sugars, and nitrogen, whereas ash and pH remained constant. Hunter color of juice samples exhibited some variation by UF. Results suggest that UF has potential to produce jicama juice with desirable and stable aroma and flavor. PMID- 7855080 TI - Effect of heat treatment and germination on alpha amylase inhibitor activity in chick peas (Cicer arietinum L.). AB - Chick pea seeds of twenty eight varieties were analysed for alpha amylase inhibitor activity (AIA) using salivary amylase. The effects of heat treatment and germination on the activity of the antinutritional factor was investigated. Heat treatment and germination decreased the activity of amylase inhibitor. Chick pea meal was also subjected to UV irradiation and pressure cooking. These treatments decreased alpha amylase inhibitor activity. The amylase inhibitor activity decreased as the days of germination increased and negligible inhibitor activity was observed on the 6th day of germination. PMID- 7855081 TI - Changes in dietary fiber content and its composition as affected by processing of black beans (Phaseolus vulgaris, Tamazulapa variety). AB - This paper presents the effect that the traditional cooking process of black beans (Phaseolus vulgaris, Tamazulapa variety) has on the quantity and composition of soluble (SDF) and insoluble (IDF) dietary fiber of beans, as well as on its protein digestibility and protein quality. There was an increase of IDF from 18.1% in cooked beans to 22.4% in fried beans, and a decrease in SDF from 8.4% to 6.6%, respectively. Starch content decreased from 34.5% to 31.3%. No change was found in lignin. The xylose content was higher in IDF than in SDF and decreased to some extent from cooked to fried beans. Arabinose content was similar in IDF and SDF with no change caused by processing. The fraction containing glucose, mannose and galactose in IDF was higher than in SDF, the content increasing in IDF and decreasing in SDF, with processing. Protein content in IDF was higher than in SDF, with no major change when processing. About 29.5% of the total protein of beans was bound in DF. Protein digestibility and protein quality decreased from cooked to fried beans and was positively related to IDF. PMID- 7855082 TI - Chemical composition and functional properties of blends of maize and bambara groundnut flours for cookie production. AB - Chemical composition and functional properties of flour blends containing various levels of maize (100-0%) and bambara groundnut (0-100%) were studied. The resultant blends were high in protein, carbohydrate and caloric value. The blends contained fair amounts of Ca, P and K but were low in Na and Fe. The oil and water absorption capacities of the blends were fairly high ranging from 3.65 to 3.81 g oil/g sample and 3.40 to 3.80 g water/g sample, respectively. The gelation concentration of the blends tended to increase with increase in amount of maize flour in the blend. On the other hand, increasing the level of maize flour in the blends considerably reduced the foaming capacities of the blends. The flour blends had good emulsifying properties. Cookies prepared from the blends contained proteins ranging from 10.9 to 21.65% The cookies had good spread and were significantly lighter than the wheat control cookies. Sensory evaluation scores for cookies showed that the best level of combination was 75% maize flour and 25% bambara groundnut flour. PMID- 7855083 TI - Nutritive value of baobab milk (gubdi) and mixtures of baobab (Adansonia digitata L.) and hungry rice, acha (Digitaria exilis) flours. AB - The baobab milk and fermented baobab/acha flour mixtures were analyzed chemically for their proximate, ascorbate, mineral and antinutrient composition. The dry pulp scraped from baobab fruits was kneaded, made into solution, extracted through cheese-cloth and stored frozen until analyzed. The acha and baobab grains were cleaned, fermented for 24 to 120 hours, dried and hammermilled into fine flours. The unfermented flours served as controls. The standard assay methods of AOAC were selected for use for the analysis of the nutrients and the antinutrients. The mixtures were composed of 70% acha and 30% baobab flours (70:30 protein basis). The baobab milk contained more protein (1.5%) and minerals (Fe, 17.8 mg; Ca 134.2 mg) than those of human milk (protein, 1.3%, Fe, 0.2 mg, Ca 30 mg) and cow milk (Fe, 0.1 mg; Ca 1.20 mg) and most leading national commercial infant formulas e.g. cerelac (Fe, 10.0 mg). The composite flours contained more nutrients than the baobab or the acha flour alone. The BF96 had greater advantage over other BF flours as a supplement to acha. The mixtures are within the reach of lower income group and can be incorporated into their diets. PMID- 7855084 TI - Production and storage stability of non-alcoholic pawpaw beverage powder. AB - Powder for instant non-alcoholic pawpaw beverage formulation was manufactured by traditional sundrying and controlled ovendrying. The reconstituted beverage was organoleptically acceptable. The effect of sundrying on mats and ovendrying on product quality was investigated. Sundrying resulted into losses of vitamins A and C, and total sugar by 97, 98 and 87 percent; while, oven drying losses were 92, 98 and 87 percent, respectively. Nutrient losses during storage in transparent polythene bags at ambient conditions reached 98, 98 and 82 percent in sundried samples and; 87, 99 and 67 percent in ovendried samples respectively. The moisture content of sundried and oven dried samples increased by 14 percent during storage. The increase in microbial load during storage was higher in sundried samples. PMID- 7855085 TI - Acceptability and keeping quality of soymilk in Tanzania. AB - Acceptability and keeping quality of two soymilk samples produced by hot water grinding and by presoaking in NaHCO3 was determined in Morogoro town. In terms of flavour and taste the two samples were significantly different from cow's milk (p < 0.05) but when vanilla was added (0.5 ml/l) the two samples were not significantly different from cow's milk. As estimated by using pH, titratable acidity and standard Plate Count, the milk samples could be kept at room temperature (25 +/- 2 degrees C) for up to 12 hours. The destroy 99% of the trypsin inhibitors in the soymilk samples, 45 minutes at 98 degrees C were needed for the alkaline presoaked milk while 75 minutes were needed for the plain water presoaked soymilk. PMID- 7855086 TI - Effect of thermal treatments on the chemical and biological value of irradiated and non-irradiated cowpea bean (Vigna unguiculata L. Walp) flour. AB - Chemical and nutritional characteristics of irradiated and nonirradiated cowpea bean at 0.2 kGy submitted to several thermal treatments were studied. The cowpea bean flours irradiated at 0.2 kGy were superior to those non-irradiated concerning digestibility and the flours submitted to microwave oven were superior to those cooked under low pressure, autoclaved or even raw from the nutritional point of view. As to the presence of anti-nutritional factors, the results showed that the variety of cowpea bean under research presented neither trypsin inhibitor nor haemagglutinin activity, however, regarding tannin, a 0.006% content was found and considered negligible. PMID- 7855087 TI - Lipid components of mustard seeds (Brassica juncea L.) as influenced by cadmium levels. AB - In a pot experiment the soil application of different levels of Cd2+ (0, 10, 20, 30, 40 and 60 micrograms g-1 soil) affected the lipid components of mustard seeds (Brassica juncea L. Cv. RH-30) markedly. Total lipids declined with the Cd2+ levels regularly while phospho and glycolipids increased only at higher levels. Fatty acids profile of total, neutral and polar lipid fractions were affected considerably. Erucic acid in total and neutral lipids was observed to increase while it decreased in polar lipids with Cd2+ as compared to control. On the other hand palmitic, oleic and linoleic acids had reverse trend. Cadmium concentration increased consistently with increasing levels of Cd2+. Plant dry weight was also decreased significantly with Cd2+ levels. PMID- 7855089 TI - Tannic acid content in sorghum (Sorghum bicolour M.): effects of processing. AB - Some simple treatments were employed to reduce the tannin content in locally consumed sorghum grain. The treatments included overnight soaking of sorghum in 2% NaHCO3, soaking in different alkalis, ammoniation and autoclaving. Of the above treatments, ammoniation was best for complete removal of tannins. Soaking the seeds in alkalis was also effective. Soaking the sorghum seeds for 18 hours in mixed salt solution (containing 1.5% NaHCO3 + 0.5% Na2CO3 and 0.75% citric acid in w/v ratio) was also found to be effective. PMID- 7855088 TI - Influence of spices on protein utilisation of winged bean (Psophocarpus tetragonolobus) and horsegram (Dolichos biflorus). AB - The influence of a mixture of eleven spices commonly consumed in India on the utilisation of protein from boiled winged bean (Psophocarpus tetragonolobus) and horsegram (Dolichos biflorus) was studied at 10 and 20 percent level of protein intake in experimental rats. Spices used in the mixture include red chillies (Capsicum annum), black pepper (Piper nigrum), coriander (Coriandrum sativum), cumin (Cuminum cyminum), garlic (Allium sativum), ajowan (Carum copticum), turmeric (Curcuma longa), caraway seeds (Carum carui) and fennel seeds (Foeniculum vulgare). Addition of this spice mixture at 1.5% level of the diet decreased the TD of both legumes, significantly only in the case of horsegram. A significant increase was observed in the BV of both the legumes at both levels of protein tested. PMID- 7855090 TI - Nutritional improvement of lentils, chick pea, rice and wheat by natural fermentation. AB - Effect of natural fermentation process (4 days) on the non-protein nitrogen, crude and true protein, amino acids content and in vitro digestibility of two kinds of legumes (lentils and chick pea) and two kinds of cereals (rice and wheat) was investigated. Non-protein nitrogen increased significantly (p < 0.001) in the fermented products. Little increase has occurred in the crude protein while no significant change was observed in the fermented true protein samples. It was observed that methionine and cystine which are considered the limiting amino acids in legume seeds were close to those of FAO/WHO patterns. Also, lysine content (the first limiting amino acid in cereals was higher in fermented rice than that of FAO/WHO pattern. Moreover, fermentation process improved significantly, the in vitro digestibility of both legume and cereal products. PMID- 7855091 TI - Immunological analysis of serum for buckwheat fed celiac patients. AB - Buckwheat (Fagopyrum esculentum, Moench), a herbaceous plant of the Polygonaceae family, does not have any affinity for the Gramineae family. It is commercially rated as a cereal, which has led to some misunderstanding concerning its use in gluten induced enteropathy or celiac disease. The effect of buckwheat flour ingestion by celiac patients was evaluated through the indirect immunofluorescence technique. Samples of serum were collected 30 days after the flour ingestion. Cryostat performed cuts of wheat and buckwheat grains were accomplished in order to compare the reactivity of their proteins and serum of celiac and normal patients. The assay revealed that the buckwheat flour presents no toxicity for the celiac patient and no anti-protein antibodies formation in the grain was observed for serum dilutions of 1:2 up to 1:32 with 0.15 M NaCl solution in 0.01 M phosphate buffer, pH 7.2 throughout the 30 day assay period. The results of the immunological assays showed that the buckwheat flour does not present toxic prolamines to celiac disease patients. PMID- 7855092 TI - Supplementation of irradiated and non-irradiated cowpea bean (Vigna unguiculata L. Walp) protein with cereal proteins. Supplementation of soup with a protein blend of appropriate nutritional value. AB - The quality of the cowpea bean protein was improved through supplementations with flours from beans exposed to microwave oven treated with cereal proteins such as wheat, rice, corn, and sorghum. Biological assays results with these blends showed that the casein exceeded the other diets concerning digestibility only; however, in parameters such as biological value, net protein utilization (NPU), protein efficiency ratio (PER) and nutritional efficiency ratio (NER), no significant differences occurred. Among all elaborated blends, the one with irradiated beans submitted to microwave oven for 30 minutes (65%) + rice (35%) presented the best results. The soup elaborated with the best supplemented blend was satisfactory concerning color, odor, flavor and texture. PMID- 7855093 TI - Green and black tea consumption by humans: impact on polyphenol concentrations in feces, blood and urine. AB - The objective of the study was to determine the effects of green tea, black tea and decaffeinated black tea consumption on urinary and fecal excretions and whole blood and blood serum concentrations of polyphenols. The 56 day study was divided into four randomly arranged experimental periods of 14 days each during which the 10 healthy adult subjects consumed a laboratory controlled, constant, measured diet based on ordinary foods. During separate periods, subjects received no tea, green tea, regular black tea or decaffeinated black tea beverages at the three daily meals. Subjects made complete collections of urine and stools throughout the study and fasting blood samples were drawn at the beginning of the study and at the end of each experimental period. Polyphenols contained in urine, feces, whole blood, blood serums, food and tea were analyzed by the spectrophotometry method of Wah Lau et al. (1989). Green tea consumption resulted in highest intakes in greatest fecal and urinary excretions, highest retentions, and high whole blood concentrations of polyphenols followed by effects of regular black tea, decaffeinated black tea and no tea treatments. These results indicate that polyphenols from tea are at least partly absorbable. Hence, both positive and negative effects of dietary polyphenol may occur internal to the body proper and not only as effects within the intestines. PMID- 7855094 TI - Effects of infrared radiation, solar cooking and microwave cooking on alpha amylase inhibitor in sorghum (Sorghum bicolor L.). AB - Three domestic cooking methods were studied in alpha-amylase inhibitory activity in sorghum grains. In all the treatments, overnight soaked seeds lost amylase inhibitory activity much faster. All the three treatments reduced the inhibitory activity. Use of solar cooker for reducing amylase inhibitory activity works out very economically and efficiently. Microwave cooking eliminates amylase inhibitory activity within 5 minutes. PMID- 7855095 TI - Vitamin contents of cereal grains as affected by storage and insect infestation. AB - There were substantial losses in thiamine, riboflavin and niacin contents of wheat, maize and sorghum grains at three infestation levels (25, 50 and 75%) caused by releasing two insect species viz., Trogoderma granarium and Rhizopertha dominica separately and mixed population. Losses were to the extent of 65 to 69% (thiamine), 50 to 67% (riboflavin) and 10 to 32% (niacin) due to T. granarium and 23 to 29% (thiamine), 13 to 18% (riboflavin) and 4 to 14% (niacin) due to R. dominica at 75% level of infestation in three cereal grains. Storage of grains (1 4 months) in insect free conditions did not show appreciable changes in the vitamin contents. PMID- 7855096 TI - Protein quality of weaning foods based on locally available cereal and pulse combination. AB - Locally available cereals and pulses such as rice (Oryza sativa), kangini (Setaria italica), sanwak (Echinochloa frumentacea), green gram (Vigna radiata) and jaggery were used to formulate three weaning foods. Cereal, pulse and jaggery were mixed in the ratio of 70:30:25. Roasting was the main processing technique used in the formulation of these weaning foods. The developed weaning foods had 5.06 to 5.68 g moisture, 10.28 to 13.71 g protein, 2.91 to 3.77 g ash, 1.08 to 1.87 g fat, 14.42 to 14.98 mg iron, 1.03 to 1.27 g crude fibre, and 357 to 374 Kcal. The weaning foods had a nutrient composition within the range prescribed by the Indian Standard Institute for processed weaning foods. The study indicated that the weaning foods obtained from locally available food stuffs have the potential of being produced locally, adaptable for household consumption and can be good substitute for commercial formulae. PMID- 7855097 TI - Influence of growth conditions on the value of crisphead lettuce. 3. Protein quality and energy density as determined in balance experiments with rats. AB - Crisphead lettuce was cultivated under different growth conditions. Sixteen batches differed in time of planting (early and late), total nitrogen supply (200 kg N/ha, 150 kg N/ha, 100 kg N/ha, 50 kg N/ha) and time of harvest (early and late). Based on chemical analysis and balance studies on rats the nutritive value of each 16 batches was determined. The protein content increased progressively from 16.00 to 19.88% with fertilization level. This increase in protein caused a significant drop in essential amino acids (g/16 g N) demonstrating a lower biological value of this protein. Early planting or early harvest resulted in a higher protein content than in lettuce of late planting or late harvest. Total dietary fibre content was approximately 25% of DM-and this value was not much influenced by the different growth conditions. Soluble dietary fibre was approximately 20-25% of total dietary fibre. Due to the high fibre content, energy digestibility was relatively low. The contents of Cd and Pb were below what is considered as 'acceptable' levels. PMID- 7855099 TI - [Mutations of the mitochondria genome. Diagnosis and pathogenetic significance]. AB - The mitochondrial respiratory chain, which consists of five enzyme complexes, plays a central part in cellular energy metabolism. Thirteen of the protein sub units are encoded by the mitochondrial genome, a circular DNA molecule of about 16,500 base pairs. Knowledge of the mitochondrial genome and alterations to it is essential to reveal functional defects of the respiratory chain. Point mutations, deletions and duplications of this DNA are associated with a growing number of diseases, whose clinical presentations vary quite widely. PMID- 7855098 TI - Zinc bioavailability and tea consumption. Studies in healthy humans consuming self-selected and laboratory-controlled diets. AB - One self-selected study (study A) and one laboratory-controlled study (study B) were conducted to investigate the effect of tea consumption on zinc bioavailability in healthy humans. The 14-day study A consisted of two 7-day experimental periods, while the 28-day study B consisted of two 14-day experimental periods. In study A eight subjects and in study B ten subjects were participated. Subjects of study A consumed self-selected diets and kept a record of foods eaten. In study B, subjects ate a constant and weighted laboratory controlled diet. In both studies, subjects consumed 8 g of instant tea during tea supplementation periods. Complete urine and fecal collections were made by subjects of both studies. Zinc contents of urine, fecal and food samples were determined by using Atomic Absorption Spectrophotometer. Mean zinc intakes of humans consuming self-selected diets were below the RDA. Mean urinary zinc excretion, fecal zinc excretion and zinc balance were unaffected by the tea consumption. Negative zinc balances in study A and positive zinc balances in study B were observed in both tea and no tea dietary treatments. Tea consumption showed a small but not statistically significant adverse affect on zinc bioavailability in humans. PMID- 7855100 TI - [Oncogenes and tumor suppressor genes in the pathogenesis of lung tumors]. AB - The recent results obtained from investigations based on molecular biological techniques have led to a better understanding of recurrent genetic causes important for the pathogenesis of tumors. Several genes have been identified as being involved in the development of cancer. In many cases, the activation of oncogenes or the inactivation of tumor-suppressor genes is the predominant reason for cancerogenic cell transformation. Functional dysregulation is frequently the consequence of mutations, resulting in an alteration of the primary structure of the DNA. As our understanding of the nature, function, and interaction of these genes evolves, new opportunities for early diagnosis, classification, prevention, and treatment of malignant tumors will arise. The present report summarizes the current molecular biological aspects of several oncogenes (erbB, ras, myc, raf, fos, jun, bcl, mdm2, myb, kit CSF1R, met) and tumor suppressor genes (p53, rb, mts) involved in lung-cancer development with respect to the pathology of lung tumors, including the importance of these genes as far as the clinical course of the disease is concerned. PMID- 7855101 TI - [Apoptosis: bcl-2 as a key protein for programmed cell death]. AB - The realization that malignant tumors may grow not only due to proliferation but also because cells don't die when they should provides absolute new directions in basic and clinical tumor research. Thus, apoptosis, the programmed cell death is very hot now in the scientific community. In the center of interest are the regulation mechanisms of apoptosis and its significance in different tumor entities. Recently, numerous studies on apoptosis during embryogenesis, different stages of tissue development and in epithelial and hormone dependent tumors have been published. The data suggested an important role of bcl-2 in regulation of apoptosis. In this view the demonstration of bcl-2 oncogene expression in osteosarcoma, a mesenchymal tumor, is of potential great interest. PMID- 7855102 TI - [Osteosarcoma--apoptosis and proliferation. Study of bcl-2 expression]. AB - The relationship between the growth of tumors and the expression of the protooncogene Bcl-2 could be shown in epithelial tumors. A bcl-2 expression leads to a prolonged cell survival due to an inhibition of apoptosis. The potential meaning of bcl-2 expression in mesenchymal tumors remains still unknown. The fact, that the heterogenous group of osteosarcoma is not sufficiently characterized at present, suggested to investigate the bcl-2 expression in osteosarcoma. Thus, immunohistochemistry was used to analyze 47 specimens of different osteosarcomas of 36 patients. Sixteen cases (46%) showed a strong expression of bcl-2 and 13 cases (35%) were moderately positive for bcl-2. Seven cases (19%) were negative for bcl-2. The heterogenous, negative up to strong expression of bcl-2 yield clues, that the Bcl-2 controlled regulation of programmed cell death could be an important factor of cellular kinetics. Additionally the cellular proliferation rate was determined with the monoclonal antibody MIB 1, directed against the Ki-67 epitope. The data of bcl-2 expression and cellular proliferation rate lead to a classification correlating with the histological classification. To verify the importance of apoptosis in the genesis of mesenchymal tumors and whether Bcl-2 may play an important role as a predictive factor for the prognosis of osteosarcoma, further investigations will be needed. PMID- 7855103 TI - [Moist autoclaving. A simplified method for antigen unmasking]. AB - Wet autoclaving is a simple, reliable and time-effective method for antigen retrieval in routinely processed archival material. Both routine diagnostic (e.g., oestrogen and progesterone receptors, cytoskeletal proteins) and research antibodies (e.g. various p53 antibodies, mdm-2, bcl-2, MIB-1) are reported to demonstrate its application. We autoclaving may allow successful application of antibodies in paraffin-embedded tissues designed for use on frozen sections. The technique has the potential to reliably handle up to 200 sections at a time, without evidence of any significant damage to the sections or nuclear morphology. PMID- 7855104 TI - [Amelanotic polypoid malignant melanoma of the balloon cell type]. AB - We describe a 59-year-old woman with amelanotic polypoid balloon cell melanoma. Physical examination showed exophytic erythematous tumour simulating a basal cell carcinoma or an adnexal tumour. Histopathology revealed a polypoid tumour that was composed mainly of balloon cells in sheets and nests. Examination 37 months after excision of the tumour with 3 cm safety margins disclosed no evidence of enlarged lymph nodes or cutaneous metastases. Metastases to internal organs could not be assessed because the patient repeatedly refused further examination for staging. To our knowledge our patient is the first case of amelanotic polypoid balloon cell melanoma to be reported in the German literature. PMID- 7855105 TI - [Pulmonary lymphangioleiomyomatosis in tuberous sclerosis]. AB - Pulmonary lymphangioleiomyomatosis was diagnosed in a 26-year-old woman with recurrent pneumothorax by histological evaluation of a lung biopsy obtained during video-thoracoscopy. A tumour of the right kidney had been removed 2 years previously; the histological picture was that of an angiomyolipoma. Immunohistochemical staining for anti-smooth muscle actin gave a strongly positive reaction in the tissue of the renal angiomyolipoma and in the pathologic lung tissue. Additional investigations showed an asymptomatic intracerebral tumour 5 cm in diameter in the left frontal lobe (brain scan). This multilocal renal, pulmonary and cerebral manifestation of benign mesenchymal proliferating tumours supports the classification of this case in the tuberous sclerosis complex. PMID- 7855106 TI - [Ectopic meningioma of the tonsil]. AB - To our knowledge this is the first reported case of a primary extracranial meningioma located in the palatine tonsil. Immunohistochemical investigation of the tumour showed coexpression of vimentin and neuron-specific enolase (NSE). No staining was found with antibodies against cytokeratins KL1, 13/10, 8 and 18, epithelial membrane antigen EMA and melanoma protein (HMB-45). It seems justifiable to classify this tumour as an atypical meningioma because of the local increased mitotic activity. PMID- 7855107 TI - [Lymphoepithelial carcinoma of the thyroid gland. A thyroid gland carcinoma with thymus-like differentiation]. AB - An example of lymphoepithelial carcinoma of the thyroid is reported, which was first described 10 years ago and has not as yet been documented in the German literature. This tumour is morphologically identical to the lymphoepithelioma of the nasopharynx. In contrast to neoplasms of such morphology occurring in a variety of other organs, the acronym CASTLE--for carcinoma showing thymus-like differentiation--has been proposed by Chan and Rosai for lymphoepithelioma-like carcinomas of the thyroid gland. In this paper, the aforenamed authors' concept of the histogenesis of thyroid tumours with thymic differentiation is presented. PMID- 7855108 TI - [Fatal generalized AA amyloidosis in mutilating psoriatic arthropathy]. AB - Autopsy findings are reported of a 51-year-old female patient with a 40-year history of mutilating psoriatic arthritis. As a result of this disease the patient developed reactive amyloidosis (AA-type) with generalized vascular involvement, amyloid kidneys and unusual amyloid goitre. The cause of death was ischaemic left ventricular failure due to massive amyloid deposits in the coronary arteries and left ventricular hypertrophy, the latter resulting from renal hypertension. Thus, amyloidosis and ischaemic heart disease were late complications of the underlying inflammatory disease. PMID- 7855109 TI - Dietary intake patterns and sociodemographic factors in the atherosclerosis risk in communities study. ARIC Study Investigators. AB - BACKGROUND: Comprehensive and up-to-date data on differences in dietary intake according to various sociodemographic factors are needed to understand the potential impact of dietary factors on disease risks in the United States. METHODS: Usual dietary intake assessed by a food frequency questionnaire was examined in relation to race, sex, and educational attainment using baseline data obtained from randomly selected samples of 15,800 middle-aged black and white men and women who participated in the Atherosclerosis Risk in Communities Study. RESULTS: In almost all comparisons, higher educational attainment was associated with recommended dietary intake patterns--lower per energy intakes of meats, eggs, chicken with skin, and whole milk and higher intakes of fruits, vegetables, fish, chicken without skin, and low-fat milk. As expected from these food intake patterns, higher educational attainment was associated with lower intakes of saturated fatty acid and cholesterol and with higher intakes of dietary fiber and various micronutrients. Compared with women's diets, men's diets were slightly more atherogenic (in whites only) based upon Keys score and had lower micronutrient levels. Although there were large differences in the food intakes between blacks and whites, the differences in nutrient intakes were generally smaller. However, intakes of cholesterol and vitamin A were somewhat higher and intakes of saturated fatty acid, calcium, and potassium were lower among blacks than in whites. CONCLUSIONS: This community-based study clearly demonstrated that regardless of race and sex, high educational attainment is associated with recommended dietary intake patterns. Continuing efforts to improve general educational level and to promote healthy dietary habits among those with low socioeconomic status are warranted. PMID- 7855110 TI - Correlates of healthy eating habits in low-income black women and Latinas. AB - BACKGROUND: Few factors related to healthy or unhealthy eating habits in low income, ethnic minority groups have been identified. In this study, factors associated with healthy and unhealthy eating habits and intent to change eating habits were examined in a sample of low-income Black and Latino women. METHODS: Survey questionnaires designed to identify correlates of healthy eating habits were administered to 243 Black and Latino women whose children were enrolled in Head Start programs in South Central Los Angeles. RESULTS: Having health insurance, lower perceived susceptibility to cancer, and higher levels of social support were significantly related to healthy eating habits. Exposure to domestic violence, lower income and knowledge of risk factors, and lower perceived efficacy in changing health outcome were associated with lower levels of intent to change eating habits. CONCLUSIONS: Economic factors such as insurance coverage and level of social support should be considered in evaluating and addressing eating habits in low-income, ethnic minority women. Exposure to domestic violence and self-efficacy may also be related to intent to change eating habits in these groups. PMID- 7855111 TI - An environmental intervention to increase fruit and salad purchases in a cafeteria. AB - BACKGROUND: This study explored the hypothesis that consumption of fruit and salad in a cafeteria setting would increase if the variety of offerings was increased and their price reduced. METHOD: Food purchases in a cafeteria setting were observed during 3 weeks of baseline observation, 3 weeks of intervention, and 3 weeks of return to baseline conditions. Intervention consisted of doubling the number of fruit choices, increasing salad ingredient selections by three, and reducing the price of both fruit and salad by 50%. The primary outcome measures in the study were daily sales of fruit and salad as assessed by cash register receipts. RESULTS: Fruit and salad purchases increased threefold in the intervention period compared to those in the nonintervention periods. Women and those trying to control their weight were most likely to make these nutritious food choices. CONCLUSION: Results of this study support the argument that increasing the number of nutritious food choices and making them more attractive economically may be important to changing food choice behavior. Further exploration of the practical application of the concept is recommended. PMID- 7855112 TI - Etiology of low-birthweight birth: a population-based study. AB - BACKGROUND: Preterm and low-birthweight births remain the major correlates of infant mortality in the United States. The recognition that these births result from varying proximal etiologies is essential to the development of preventive strategies specific to each etiologic group. METHODS: Using vital statistics data tapes provided by the North Carolina Center for Health and Environmental Statistics, mothers in 20 counties who delivered infants with birthweights between 1 pound and 5 pounds, 8 ounces were identified. Maternal hospital records of 4,754 women were reviewed for data about prenatal and intrapartal events. Two perinatologists classified births into four proximal etiology groups: term lowbirthweight, medically indicated preterm birth, preterm premature rupture of membranes, and idiopathic preterm birth. Information from birth certificate and hospital records was merged to provide an expanded data set. RESULTS: Race, age, education, and marital status are associated with different patterns of proximal etiology. Rates were higher for all etiologies in black women and in young women; however, the absolute number of LBW births was highest among white women. Idiopathic preterm birth was highest in black women and decreased as age increased; medical indications for preterm birth increased with increasing age. CONCLUSIONS: Classification of LBW births by etiologic group provides insights of value to both clinicians and researchers. Studies in which LBW and/or preterm birth are the outcome variables will be enhanced by identifying etiology. Multiple preventive strategies should address varying etiologic groups. PMID- 7855113 TI - Comparisons of the smoking cessation counseling activities of six types of health professionals. AB - BACKGROUND: This study was designed to assess and compare the smoking cessation counseling activities of primary care physicians, dentists, dental hygienists, family planning counselors, WIC counselors, and community mental health counselors in four counties in the northeastern United States for planning appropriate education programs. METHODS: Lists of the health professionals in each of these groups in the four study counties were obtained from state licensing boards, clinic directors, and telephone directories. Surveys were conducted by mail, using a 19-item instrument which could be completed in 2-4 min. RESULTS: Comparisons among these professional groups showed that physicians, family planning counselors, and WIC counselors felt better prepared to provide cessation advice than did mental health counselors, dentists, and dental hygienists. Physicians, family planning counselors, and WIC counselors also were more active in providing smoking cessation advice to women smokers than were the other three groups. Levels of use of specific counseling activities were generally low. Setting a quit date, arranging for follow-up visits, and referral for further assistance were used for only a minority of women smokers. CONCLUSIONS: Opportunities for educational interventions that could increase these health professionals' effectiveness were apparent for each of the groups. PMID- 7855114 TI - Cardiovascular risk factors in adolescence: prevalence and familial aggregation. AB - BACKGROUND: In the field of primary prevention there is an increasing interest in screening pediatric populations for cardiovascular risk factors. The aim of this study was to determine the overall prevalence of high blood pressure (HBP), obesity, and sedentariness in a population of adolescents. The presence of familial aggregation for these factors was also evaluated. METHODS: The prevalence of HBP, obesity, and low physical activity was determined in 1413 adolescents ages 12-15 years (705 males, 698 females) randomly selected from Turin school children. The prevalence of HBP and obesity in parents was determined. RESULTS: One risk factor was found in 40.9% of females (2.4% HBP, 8.6% obesity, and 29.9% sedentariness) and 39.6% of males (2.8% HBP, 16.4% obesity, and 20.4% sedentariness); the concomitance of two or three risk factors were present, respectively, in 9.9 and 2.7% of females and 10.9 and 1.1% of males with a strong association of obesity and HBP. A significant familial aggregation for obesity was found and no particular relationship was found for BP. CONCLUSION: The ability to identify children developing a single or multiple risk factors is an important contribution to the prevention of serious cardiovascular diseases in adulthood. PMID- 7855115 TI - Predictors of cancer prevention attitudes and participation in cancer screening examinations. AB - BACKGROUND: Few current data are available regarding factors associated with participation in cancer screening examinations in the general population. METHODS: To identify factors associated with participation in cancer screening examinations, random population samples of 25- to 74-year-old men and women in six various-sized communities in three upper-Midwestern states (n = 4,915) were surveyed in 1987-1989. Multivariate-adjusted means were calculated and compared using analysis of covariance. RESULTS: Statistically significant (P < 0.05) strong predictors (other than age and sex) of ever having had a specific cancer screening test were as follows (the numbers in parentheses following each listed association are the absolute maximum differences in mean proportions among the levels of the predictors): (1) rectal examination: higher education (14%); (2) fecal occult blood testing: higher education (6%) and never smoker (5%); (3) sigmoidoscopy: higher income (7%) and higher education (6%); and (5) mammography: higher income (25%), higher education (8%), and a positive family history of breast cancer (7%). There were no strong predictors (out of nine) of ever having had a Papanicolaou smear or a breast self-examination. CONCLUSIONS: The largest differences among the population for participation in cancer screening examinations involves income and the two most expensive cancer screening tests: higher income is a strong predictor of having a mammogram and, to a lesser extent, of having a sigmoidoscopy. The most consistent predictor of participation in cancer screening examinations across all cancer screening tests is education: higher education is a predictor of having each kind of cancer screening test. PMID- 7855116 TI - Alcohol sales to minors: a surrogate study. AB - BACKGROUND: Legislation is a potentially important health promotion strategy to control the consumption of tobacco and alcohol by minors. Effectiveness of such laws may depend on the extent of which laws are adequately drafted, implemented, and enforced. However, studies of adherence with laws banning the sale of cigarettes to minors indicate low levels of enforcement. As a comparison, this study investigated adherence of alcohol retailers to legislation banning the sale of alcohol to minors in New South Wales, Australia. The aim was to determine the proportion and characteristics of alcohol retail outlets which sell alcohol to apparently underage youth. METHOD: Eight 18-year-olds who were judged by independent raters to look younger than the legal age attempted to purchase alcohol from 168 alcohol retail outlets (hotels, registered clubs, and bottle shops), in a nonmetropolitan region of New South Wales. RESULTS: No challenge about age was made for 68% of purchases. Youth were asked their age on 8% of occasions and proof of age was required on only 24% of occasions. Display of a warning sign was not associated with being required to show proof of age, nor was gender or dress of the buyer (casual clothes vs school uniform). Bottle shops were more likely to require proof of age than hotels or clubs. CONCLUSIONS: The results suggest that the implementation of legislation banning the sale of alcohol to minors is currently inadequate and that new efforts are needed to discourage the sale of alcohol to minors. PMID- 7855117 TI - Toombak: a major risk factor for cancer of the oral cavity in Sudan. AB - BACKGROUND: Snuff dipping as practiced in North America and Western Europe is causally associated with cancer of the oral cavity and pharynx. In the Sudan, natives use local Nicotiana rustica, a tobacco species with high levels of nicotine and nornicotine, to prepare their own snuff which they call toombak. The finely ground tobacco leaves are mixed with sodium bicarbonate, water is added, and a paste is made. The resulting "saffa" is placed in the oral vestibule where it remains up to several hours. In general, a saffa is replaced 10-30 times per day. METHODS: A cross-sectional survey was initiated for establishing the extent of toombak dipping in the Northern Sudan. Using earlier published methods, toombak and the saliva of toombak dippers were analyzed for the major carcinogens, the nicotine- and nornicotine-derived tobacco-specific N nitrosamines. RESULTS: Survey data on the use of toombak in the Nile Province in the Northern Sudan encompass 2,000 households with 5,500 adults. About 40% of the males dip toombak, including 9% who are also cigarette smokers. The toombak habit is especially prevalent (> 45%) among males ages 40 years or older. Among women, toombak use is popular only in the older age groups, where up to 10% engage in the habit, whereas cigarette smoking is uncommon (< 1.5%). So far, only one descriptive study has dealt with toombak dipping and oral cancer. Among 62 patients with oral cancer 50 were toombak users; the majority of these had tumors at the site of contact with the tobacco, or in adjacent areas. Chemical analytical studies revealed that toombak contains at least 100-fold higher concentrations of the tobacco-specific N-nitrosamines (TSNA) than US and Swedish commercial snuff brands. The TSNA are by far the most powerful and most abundant carcinogens in snuff. Their concentrations in the saliva of toombak dippers are about the same as those in a solution that had been assayed in rats by twice daily swabbing of the oral cavity and had induced tumors of the cheek and palate. CONCLUSION: The need for in-depth epidemiological studies and further laboratory research to prove that toombak chewing causes cancer is discussed. The data at hand point to the urgent need for educational programs and preventive measures against the use of toombak. PMID- 7855118 TI - New findings in the development of Babesia (Theileria) equi (Laveran, 1901) in the salivary glands of the vector ticks, Hyalomma species. AB - The development of the piroplasm Babesia equi was studied by light microscopy in the salivary glands of three different Hyalomma species during and after the engorgement of nymphs on experimentally infected horses and after adults had fed on a vertebrate host following ecdysis. The stock of B. equi used was isolated from a horse imported from Turkmenistan (CIS) in 1991. The findings, being identical in all three Hyalomma species, differ with regard to the chronological order of the development stages in several respects from the results of previous studies based upon light or electron microscopy. A first sporogony phase of B. equi was found to develop in the salivary glands of the engorged nymphs before the ticks moulted to adults. Beginning at day 6 postinfestation (p. infest.) of the nymphs, spindle-shaped sporozoites appeared to be formed by both rapid sequential fission of a multinucleated complex and a process of radial budding from multiple fission bodies. Sporozoites isolated from the salivary glands of the engorged nymphs proved to be infectious when they were injected into a susceptible horse. After the nymphs had moulted, a second sporogony phase similar to the first one observed in the salivary glands of engorged nymphs could also be initiated in the salivary glands of adults when they were attached to a vertebrate host. Sporozoites produced in the salivary glands of adults were equally infectious for horses. Thus, two completely separate sporogony phases in B. equi seem to develop successively in the salivary glands of Hyalomma species during a transstadial transmission. PMID- 7855119 TI - Acanthamoeba-specific human T-cell clones isolated from healthy individuals. AB - T-cell responses to pathogenic free-living amoebae, Acanthamoeba sp., were analyzed in healthy Japanese individuals. Of 20 healthy subjects, 10 (50%) showed significant proliferative responses of peripheral blood mononuclear cells to the soluble amoebic antigens in vitro. The antigens used were not mitogenic, and no evidence of amoebic superantigens was available. We established human T-cell clones reactive to Acanthamoeba, all of which were CD3- and CD4-positive, CD8 negative, and TCR-alpha beta-positive. We isolated two strains of Acanthamoeba from two patients, one from a patient with meningoencephalitis (CSF strain) and the other from a patient with keratitis (K strain). Of 13 clones, 11 were reactive to the K-strain as well as to the CSF-strain antigen under human leukocyte antigen (HLA)-DR restriction, whereas the other two were specific for the K-strain antigen. All but one clone tested showed TH1-equivalent functions because these cells produced interferon (IFN)-gamma in response to the amoebic antigen but produced no detectable level of interleukin 4 (IL-4). These results suggest that immunocompetent hosts might have acquired protective immunity mediated by Acanthamoeba-specific T-cells during natural sensitization. PMID- 7855120 TI - The development of Hepatozoon sipedon sp. nov. (Apicomplexa: Adeleina: Hepatozoidae) in its natural host, the Northern water snake (Nerodia sipedon sipedon), in the culicine vectors Culex pipiens and C. territans, and in an intermediate host, the Northern leopard frog (Rana pipiens). AB - The life cycle of Hepatozoon sipedon sp. nov. was studied in two snake species, the Northern water snake and the Eastern garter snake, in its mosquito hosts Culex pipiens and C. territans, and in the Northern leopard frog. Gametogenesis, fertilization and sporogony occurred within fat body cells in the haemocoel of mosquitoes that had fed on infected water snakes. Mature oocysts averaging 263 microns in diameter and containing more than 500 sporocysts were observed in mosquitoes 28 days post-feeding. Each sporocyst enclosed eight sporozoites. Dizoic cysts were found in the liver of frogs that had been fed infected mosquitoes seven days previously. Two rounds of merogony in various internal organs and intraerythrocytic gamonts were observed in snakes that had been fed frogs which had been orally inoculated with infected mosquitoes. Developmental stages were not seen in snakes that were fed infected mosquitoes directly. A comparison of this life cycle with those described for other Hepatozoon species infecting snakes is presented with reference to the different modes of transmission featured by these parasites. PMID- 7855122 TI - Effects of gabergic anthelmintics at higher concentrations on the guanidine induced twitch responses in isolated frog rectus preparations. AB - Effects of various gabergic anthelmintics on the guanidine-induced twitch responses in isolated frog rectus preparations were examined. All gabergic anthelmintics such as milbemycin oxime, milbemycin D, avermectin B1a, ivermectin, and diethylcarbamazine (DEC) showed stimulatory effects on the guanidine-induced twitch responses at their higher concentrations. Only piperazine caused inhibitory effects on the twitch responses, even at higher concentrations. The stimulation of the twitch responses by the gabergic anthelmintics was antagonized with tetrodotoxin, hemicholinium-3, d-tubocurarine, and strychnine. These results suggest that all gabergic anthelmintics except piperazine stimulate the release of acetylcholine from the nerve endings and that all of them, including piperazine, have different effects on the gabergic mechanism at lower concentrations and on the cholinergic mechanism at higher concentrations. PMID- 7855121 TI - Leishmania resistant to sodium stibogluconate: drug-associated macrophage dependent killing. AB - A total of 17 Leishmania isolates, 6 of them isolated from antimony-resistant patients, were collected in the Sudan and tested for their sensitivity to sodium stibogluconate (Pentostam) as promastigotes. Six of those isolates were tested as amastigotes infecting a murine macrophage cell line. The results indicated that the conventional promastigote screening assay did not correlate with the clinical picture, whereas the amastigote/macrophage system produced results that pertained to the in vivo responses to the drug. A laboratory-generated resistant strain of L. major was adapted to grow at a high concentration of Pentostam (1000 micrograms/ml) as promastigotes but was quite sensitive to the drug at much lower concentrations in the amastigote/(macrophage system (20 micrograms/ml), thus suggesting that Pentostam's inhibitory action is mediated through the macrophage rather than through a direct toxic effect exerted on the parasite. PMID- 7855123 TI - The expulsion of Echinostoma trivolvis (Trematoda) from ICR mice: extension/retraction mechanisms and ultrastructure of the collar spines. AB - Ultrastructural observations of collar spines and surrounding tissues associated with extension/retraction mechanisms of the spines were made on Echinostoma trivolvis recovered from ICR mice or golden hamsters. The spine consisted mainly of a homogeneous, crystalline structure of moderate to heavy electron density. The spine was surrounded by an outer layer of tegument-like material. Interstitial material was located between this outer layer and the surrounding tegument. Muscle bundles associated with spine movements were anchored by hemidesmosomes to interstitial material. Contraction of these muscles caused an invagination of the tegument surrounding a spine, resulting in spinal protrusion. Relaxation of these muscles resulted in spinal retraction. An immunocytochemistry technique using colloidal gold confirmed the presence of actin in the collar spines. Most of the collar spines of excysted metacercariae and juveniles maintained in a defined medium supplemented with fresh hamster serum were extended, whereas worms maintained in mouse serum mainly showed retracted spines. Apparently, factors in mouse serum are involved in spinal retraction. PMID- 7855124 TI - Ultrastructural observations of development of Eimeria tenella in a novel established avian-derived cell line. AB - Transmission electron microscopy was used to study the in vitro development of Eimeria tenella in a novel established avian-derived cell line (designated CEV 1/F7) used for antigen production in chicken immunization studies. Sporozoites of E. tenella were inoculated onto cell monolayers and the cells were fixed at 24-h intervals. Large numbers of intracellular sporozoites were seen at 24 h postinoculation (p.i.), and trophozoites were identified at 24-48 h p.i. Immature schizonts, some with budding merozoites, were seen by 48 h p.i. At 72-96 h p.i., immature and mature schizonts and extracellular merozoites were observed. No merozoite invasion occurred, but immature second-generation schizogony was seen in parasitophorous vacuoles of first-generation schizonts. No further development occurred and degeneration of most schizonts was seen by 120-144 h p.i. The results confirmed synchronous development of E. tenella until 48 h p.i., followed by asynchronous development and ultrastructural degeneration with increased incubation time. PMID- 7855125 TI - In vitro and in vivo immunolabeling of sporozoites, schizonts, and sexual stages of Eimeria acervulina and E. tenella by a species- and stage-cross-reactive monoclonal antibody. AB - A cross-reactive monoclonal antibody (mAb), designated 1205, was used to study redistribution, parasitophorous vacuole (PV) incorporation, and in situ antigen production during the intracellular parasite development of Eimeria acervulina and E. tenella. Western-blot analysis of sporozoite preparations showed that the mAb recognized antigenic bands at 55 and 80 kDa. Indirect immunofluorescent antibody (IFA) labeling of sporozoites produced an internal dot pattern. Immunogold electron microscopy (IM) showed labeling of dense granules within sporozoites. The IFA pattern changed to a general-internal label in immature schizonts followed by a surface-tip pattern in mature merozoites both in vitro and in vivo. IM of the asexual stages revealed the same labeling pattern for the in vivo development of both species, and labeling of rhoptries was seen. In vitro, the PV membrane together with amorphous material within the PV was labeled by IFA during schizont development for E. tenella. No IM labeling of either the PV membrane or material within the PV was observed. Sexual stages seen in vivo for both species had the general-internal IFA pattern. PMID- 7855126 TI - Studies on compounds promoting the in vitro transformation of Trypanosoma brucei from bloodstream to procyclic forms. AB - In vitro differentiation of pleomorphic blood-stream forms of Trypanosoma brucei to procyclic culture forms occurred rapidly and at high rates at 27 degrees C in a culture medium containing 1 mM cis-aconitate as the transformation-inducing agent. Citrate was required at a much higher concentration (10 mM) to produce a similar transformation rate. The highest percentage of transformed cells was obtained when bloodstream-form trypanosomes were treated with pronase in the absence of a feeder-cell layer. However, under these conditions, the amount of procyclic forms obtained after 72 h was lower than that obtained in the presence of cis-aconitate. Trypsin was also capable of inducing transformation in the absence of a feeder-cell layer, but this treatment again resulted in low numbers of transformed cells. Blood-stream-form trypanosomes were incapable of taking up citrate to any significant extent and the citrate content of these stages was negligible. After 72 h of exposure to citrate (3 mM), intracellular levels of this compound remained very low (< 1 nmol (10(9) cells)-1), increasing in established procyclic stages to approximately 1.7 nmol (10(9) cells)-1. These observations suggest that the tricarboxylic acid (TCA)-cycle metabolite-dependent transformation may be initiated externally to the trypanosome cell membrane. The ability of both citrate and cis-aconitate to bind calcium and, thus, to reduce the concentration of this cation in the culture medium was found not to be responsible for the triggering effect on trypanosome transformation.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7855127 TI - Purification and immunologic characterization of a 30-kDa cysteine proteinase of Entamoeba histolytica. AB - A 30-kDa cysteine proteinase was purified from extracts of axenically grown trophozoites of Entamoeba histolytica strain HM1:IMSS. The purification procedure involved two consecutive chromatographic steps. Sequence analysis revealed high similarity with histolysin and with other 27-kDa cysteine proteinase. Western blot analysis using F(ab')2 fragments of a polyclonal antibody raised against the purified enzyme revealed that when the amebic extract was prepared in the absence of proteinase inhibitors there were many positive bands ranging in relative molecular weight from 115 to 12.5 kDa, but when the extract was prepared in the presence of proteinase inhibitors there was only a single 30-kDa positive band. Similar results were obtained with immunoprecipitates. This phenomenon would suggest the formation of multimer aggregates of the 30-kDa cysteine proteinase after partial proteolysis. PMID- 7855129 TI - A study of the karyotypic patterns of Blastocystis hominis by pulsed-field gradient electrophoresis. PMID- 7855128 TI - Predominance of infected reticulocytes in the peripheral blood of CD4+ T-cell depleted mice chronically infected with Plasmodium chabaudi chabaudi. AB - The distribution of Plasmodium chabaudi chabaudi AS among normocytes and reticulocytes in the peripheral blood of NIH mice undergoing a primary infection was determined from brilliant cresyl blue/Giemsa's stained thin blood films. During the early stages of infection in normal mice, parasites were found exclusively in normocytes. The presence of parasites in reticulocytes was limited to a period of severe immune pressure on the parasites, peak parasitaemia and the ensuing "crisis" phase, at which time the rapid production of new erythrocytes in response to the anaemia in these mice resulted in a high reticulocyte count. Later, during the recrudescence, parasites inhabited normocytes only. Thus, in immunologically competent animals, P. c. chabaudi AS showed no absolute preference for either mature or immature erythrocytes. In marked contrast, in chronically infected CD4+ T-cell-depleted mice, this malaria parasite apparently displayed a pronounced predilection for reticulocytes. During an unremitting parasitaemia of 2.8%-3.9% during days 13-60 post infection, all parasites were found in reticulocytes, even though these comprised only 25% of the total erythrocyte count. The possible reasons for this reversal in preference for the type of erythrocyte inhabited by asexual malaria parasites are discussed. PMID- 7855130 TI - Quantification of praziquantel-induced damage on the surface of adult Schistosoma mansoni worms: estimation of esterase and alkaline phosphatase activity. PMID- 7855132 TI - Similarities between protein 3-D structures. AB - A simple, new, systematic method has been developed to evaluate the structural similarity of proteins. Firstly, similar protein fragments of a definable length are detected, combined in pairs and superimposed. The fits are improved until a maximum number of C alpha atoms show a distance below a given threshold value. The final number of matching C alpha atoms can be used to quantify the similarity of protein folds and to identify the best superposition of two proteins. using this procedure a systematic search for structural similarities of proteins in the Brookhaven Protein Data Bank was performed. The results of these investigations allow us to divide the proteins into 182 structural families and to estimate the relationships between single members of the classes found. PMID- 7855131 TI - Molecular cloning of a Trypanosoma cruzi cDNA encoding a protein homologous with mammalian elongation factor 1 beta. PMID- 7855133 TI - Non-polar nuclei in fungal microbial RNases. AB - An application of a previously proposed method for the analysis of the non-polar structure of proteins is presented. A detailed analysis of the composition and properties of non-polar nuclei and microclusters of fungal microbial ribonucleases has been performed on the basis of the 3-D structures of RNase T1 and related proteins. Three hydrophobic nuclei were found in these structures. It has been shown that all residues in non-polar nuclei have high homology (approximately 89%). Residues in the nuclei are practically fully buried in the interior of a molecule. Detailed analysis of non-polar nuclei properties shows that these nuclei determine the hydrophobic core of a protein and the location and role of each residue in the non-polar interior of proteins. In addition it was found that there are variable residues not only on the surface of a protein but on the surface of the nuclei inside the protein and between the nuclei and that there is a consistent region in all proteins, the hydrophobic gamma-nuclei. An evaluation of the stability of non-polar nuclei, the conservation of their compositions and their positions in the protein globule, allows one to assume that these three nuclei play an important functional role in the stability and folding of molecules of RNases and possibly can be considered as independent structural elements of 3-D structures of these proteins. PMID- 7855134 TI - When awaiting 'Bio' Champollion: dynamic programming regularization of the protein secondary structure predictions. AB - Predictions of protein secondary structure using current methods are often unrealistic, i.e. the predicted alpha-helices or beta-strands are too short. To improve the realism, various heuristic 'filtering' or 'smoothing' methods are used. They are more or less intuitive and are based on ad hoc corrections. We present a regularization method to obtain a realistic secondary structure from predicted propensities. It is based on the known dynamic programming algorithm and is quite objective. It can be used with any prediction method which yields propensities. The regularized predictions conserve well the overall prediction accuracy and improve the 'protein-likeness' of the prediction. PMID- 7855135 TI - Predicting local structural changes that result from point mutations. AB - Point mutations are frequently used to explore the structure and/or function of proteins. The ability to predict the structural effects of point mutations would make the planning of such experiments more reliable. We have now derived a set of detailed predictive rules based on the comparison of crystal structures of point mutants and wild types in 83 cases. Despite the surprising simplicity of these rules, they describe well the conformational changes in 85% of all point mutant structures available at present. PMID- 7855136 TI - Protein stability for single substitution mutants and the extent of local compactness in the denatured state. AB - The stability changes caused by single amino acid substitutions are studied by a simple, empirical method which takes account of the free energy change in the compact denatured state as well as in the native state. The conformational free energy is estimated from effective inter-residue contact energies, as evaluated in our previous study. When this method is applied, with a simple assumption about the compactness of the denatured state, for single amino acid replacements at Glu49 of the tryptophan synthase alpha subunit and at Ile3 of bacteriophage T4 lysozyme, the estimates of the unfolding Gibbs free energy changes correlate well with observed values, especially for hydrophobic amino acids, and it also yields the same magnitudes of energy as the observed values for both proteins. When it is also applied for amino acid replacements at various positions to estimate the average number of contacts at each position in the denatured state from the observed value of unfolding free energy change, those values for replacements with Gly and Ala at the same residue position in staphylococcal nuclease correlate well with each other. The estimated numbers of contacts indicate that the protein is not fully expanded in the denatured state and also that the compact denatured state may have a substantially native-like topology, like the molten globule state, in that there is a weak correlation between the estimated average number of contacts at each residue position in the denatured state and the number of contacts in the native structure. These results provide some further evidence that the inter-residue contact energies as applied here (i) properly reflect actual inter-residue interactions and (ii) can be considered to be a pairwise hydrophobicity scale. Also, the results indicate that characterization of the denatured state is critical to understanding the folding process. PMID- 7855137 TI - Sequence divergence analysis for the prediction of seven-helix membrane protein structures: I. Comparison with bacteriorhodopsin. AB - A method using protein sequence divergence to predict the three-dimensional structure of the transmembrane domain of seven-helix membrane proteins is described. The key component in the multistep procedure is the calculation of a hydrophilic and lipophilic variability index for each amino acid in an alignment of a family of homologous proteins. The variability profile, a plot of the calculated variability index versus alignment position, can be used to predict a tertiary model of the backbone conformation of the transmembrane domain. This method was applied to bacteriorhodopsin (BR) and the model obtained was compared with the known structure of this protein. Using an alignment of the amino acid sequences of BR and closely related (> or = 20% identity) proteins, the boundaries of the transmembrane regions, their secondary structures and orientations inside the membrane bilayer were predicted based on the variability profile. Additional information about the shape of the helix bundle was also obtained from the average variability of each transmembrane helix with the assumption that the helices are packed sequentially and form a closed helix bundle. Correct features of the known structure of BR were found in the model structure, suggesting that a similar strategy can be used to predict transmembrane helices and the packing shape of other membrane proteins with seven transmembrane helices, such as the opsins and other G-protein coupled receptors. PMID- 7855138 TI - Sequence divergence analysis for the prediction of seven-helix membrane protein structures: II. A 3-D model of human rhodopsin. AB - A three-dimensional (3-D) model of the transmembrane domain of human rhodopsin was predicted from the sequence divergence analysis of 42 sequences of rhodopsins and visual pigments without a template. The prediction steps include multiple sequence alignment, calculation of a variability profile of the aligned sequences, use of the variability profile to identify the boundaries of transmembrane regions, their secondary structure and packing shape in a helix bundle, prediction of side-chain conformations and structure refinement. The identification of the retinal binding site was assisted by its known covalent linkage with K296. The structural features of the predicted 3-D model are in good agreement with a low resolution electron density map of bovine rhodopsin and with residues in contact with retinal as determined experimentally. PMID- 7855139 TI - Glycine 85 of the trp-repressor of E. coli is important in forming the hydrophobic tryptophan binding pocket: experimental and computational approaches. AB - Experimental and computational analyses were performed on the corepressor (L tryptophan) binding site of the trp-repressor of Escherichia coli to investigate the ligand-protein interactions. Gly85, one of the residues forming the hydrophobic pocket of the binding site, was systematically replaced with Ala, Val, Leu and Trp by cassette mutagenesis. Biochemical characterization showed that all these mutations caused significant decreases in tryptophan binding activity. Free energy perturbation calculations were performed for the mutants and were consistent with the experimental results. The lack of a side chain at position 85 was concluded to be essential for binding the corepressor; the structure of the binding pocket was suggested to be tight in the vicinity of Gly85. PMID- 7855140 TI - The role of net charge on the renaturation of reduced lysozyme by the sulfhydryl disulfide interchange reaction. AB - Reduced and acetylated lysozymes are basic proteins. When their amino groups were variously acetylated and then renatured by sulfhydryl-disulfide (SH-SS) interchange reaction at pH 8.0, the final folding yield decreased as the number of positive charges decreased. The final folding yield of native and Ac1 lysozyme, with one positive charge eliminated, was less sensitive to increasing protein concentration than that of Ac2 lysozyme, where two positive charges had been eliminated. The final folding yield of reduced Ac2 lysozyme increased in the presence of 1 M urea, which reduced the aggregation of unfolded lysozyme. Thus, the aggregation of unfolded lysozymes, which leads to a decrease in the final folding yield, was found to be heavily dependent on their net charges. Moreover, the final folding yield of reduced lysozyme was shown to be increased by use of cystamine as an oxidizing reagent in comparison with 2-hydroxyethyl disulfide or dithiodiglycolic acid. This may support the idea that the final folding yield is influenced by electrostatic interaction between unfolded lysozymes in the early stage of renaturation. In contrast, the concentration dependency of the final folding yield of Ac1 lysozyme was different from those of carboxymethylated His15 and Asp106 lysozymes whose positive net charges were similar to that of Ac1 lysozyme. On the basis of the observations, it is suggested that the formation of the aggregates in the renaturation process might also be affected by the structure of the unfolded state of lysozyme in solution. PMID- 7855141 TI - C-terminal truncations of a thermostable Bacillus stearothermophilus alpha amylase. AB - A series of truncated proteins from a thermostable Bacillus stearothermophilus alpha-amylase was prepared to study the importance of the extension in the C terminus compared with other liquefying Bacillus alpha-amylases. The mutations introducing new translation termination sites shortened the 515 amino acid residue-long wild type enzyme by 17, 32, 47, 73 or 93 residues. The longer the truncation, the lower the specific activity of the enzyme. Only the two longest mutant proteins were active: the specific activity of the 498 residue variant was 97% and protein 483 was 36% that of the parental enzyme. The Km values of starch hydrolysis changed from 1.09 for wild type enzyme to 0.35 and 0.21 for mutants 498 and 483, respectively, indicating altered substrate binding. The mutant enzymes had almost identical pH and temperature optima with the wild type amylase, but enhanced thermal stability and altered end product profile. The consequences of the truncation to the structure and function of the enzymes were explored with molecular modeling. The liquefying amylases seem to require approximately 480 residues to be active, whereas the C-terminal end of B.stearothermophilus amylase is required for increased activity. PMID- 7855142 TI - Mutational and structural analysis of the lectin activity in binding domain 2 of ricin B chain. AB - The study of the lectin binding sites of ricin B chain and of other homologous members of the small gene family that make up ricin-like molecules has revealed a number of key contact residues involved in sugar binding. In particular, on the basis of data generated by the X-ray crystallographic structure of ricin, comparisons of sequence homologies to other ricin-like molecules and substrate binding studies with these molecules, it has been proposed that His248 of Ricinus communis agglutinin (RCA) B chain may interfere with galactose binding in the second binding domain of that lectin. To test that hypothesis, single binding domain 2 (SBD2) of ricin B chain was expressed as a gene 3 fusion protein on the surface of fd phage to measure directly the effect of mutational changes on this binding site. Replacement of tyrosine with histidine at amino acid position 248 of SBD2 of ricin B chain was shown to reduce lectin activity. The sequences of RCA and ricin B chains were aligned and compared with the tertiary structure of ricin B chain to select various mutations that were introduced as controls in the study. One of these controls, Leu247 to Val247, displayed increased affinity for galactosides. The role of sequence changes is discussed in relation to the structural and functional divergence in these molecules. PMID- 7855144 TI - Introduction of a histidine tail at the N-terminus of a secretory protein expressed in Escherichia coli. PMID- 7855145 TI - Hand-in-hand to the same goal. Quality assurance and research in nursing. AB - 1. The provision of good quality care is a right for all patients and the responsibility of all who deliver it. 2. Care based on knowledge that is validated by research can lead to improved practice and the further development of the service. 3. Patients now question the care they receive and expect an assurance of the quality of care they will receive when in hospital. 4. Quality assurance and the utilisation of research findings can enhance and improve patient care. PMID- 7855143 TI - An unequivocal example of cysteine proteinase activity affected by multiple electrostatic interactions. AB - The role of electrostatic interactions between the ionizable Asp158 and the active site thiolate-imidazolium ion pair of some cysteine proteinases has been the subject of controversy for some time. This study reports the expression of wild type procaricain and Asp158Glu, Asp158Asn and Asp158Ala mutants from Escherichia coli. Purification of autocatalytically matured enzymes yielded sufficient fully active material for pH (kcat/Km) profiles to be obtained. Use of both uncharged and charged substrates allowed the effects of different reactive enzyme species to be separated from the complications of electrostatic effects between enzyme and substrate. At least three ionizations are detectable in the acid limb of wild type caricain and the Glu and Asn mutants. Only two pKa values, however, are detectable in the acid limb using the Ala mutant. Comparison of pH activity profiles shows that whilst an ionizable residue at position 158 is not essential for the formation of the thiolate-imidazolium ion pair, it does form a substantial part of the electrostatic field responsible for increased catalytic competence. Changing the position of this ionizable group in any way reduces activity. Complete removal of the charged group reduces catalytic competence even further. This work indicates that hydronations distant to the active site are contributing to the electrostatic effects leading to multiple active ionization states of the enzyme. PMID- 7855146 TI - Gear future training to practitioners' needs. Attitudes towards intravenous drug users. AB - 1. There is no clear-cut relationship between staff knowledge and their attitudes to HIV and Aids. 2. Perceptions of service delivery to drug users are likely to be affected by respondents' occupational backgrounds. 3. The effectiveness of service delivery is likely to be affected by situational constraints. 4. There is a need for improved training and support, particularly for non-specialist staff. PMID- 7855147 TI - Urinary problems after formation of a Mitrofanoff stoma. AB - 1. Bladder irrigation reduces occlusion of drains with clots and debris, thus protecting anastomoses. 2. Leakage from anastomoses is an acknowledged problem postoperatively but resolves spontaneously in the majority of cases. 3. To establish urinary continence a good fluid intake is essential, bladder capacity must be developed, intermittent catheterisation taught and excessive mucus production eliminated. 4. The risk of urinary tract infections can be minimised by drinking cranberry juice, prophylactic antibiotic therapy and a good intermittent catheterisation technique. A degree of bacteria is inevitable and not always significant. PMID- 7855148 TI - Taking theory into practice: using Peplau's model in the care of a patient. AB - 1. The strength of Peplau's work is in giving the practitioner a structure on which to base his or her interactions with the patient. 2. There is no ideal way in which to document the care given when using Peplau's work as a model. Peplau's theory has a holistic perspective that does not adjust easily to a record-keeping system. 3. Staff will need to be trained, supported and supervised by a consultant nurse if the true philosophy of Peplau is followed. 4. The strength of Peplau's model lies in the fact that it encourages the nurse to develop an attitude of mind that gives a framework to practice. PMID- 7855149 TI - Management and prevention of osteoporosis. AB - 1. Osteoporosis is an increasing healthcare problems in terms of pain, morbidity and mortality. 2. A decrease in bone density can lead to fractures of the spine, hip and wrists (sites particularly high in trabecular bone). 3. Certain risk factors can predispose to osteoporosis. PMID- 7855150 TI - Preventive measures against rabies. AB - 1. Rabies occurs worldwide, and is increasing in many developing countries as well as in Western Europe. 2. Corneal transplants from patients dying from undiagnosed CNSD have resulted in rabies. 3. Trials of an oral vaccine immunisation concealed in baits for wildlife are currently being tried in France. 4. Human diploid cell rabies (HDCV) is used for prophylactic and postexposure treatment. PMID- 7855151 TI - Nursing or chiropody? Nurses' attitudes to toe nail trimming. AB - 1. Trimmed toe nails make an important contribution to the rehabilitation of patients recovering from orthopaedic treatment by eliminating a source of discomfort. 2. Twenty-two nurses in orthopaedic care completed questionnaires about their attitudes toward this aspect of patient hygiene. 3. The majority felt it was part of the work of podiatrists but could be done by nurses in special circumstances. 4. The main deterrents to nurses undertaking toe nail trimming were fear of causing damage to patients' feet and lack of confidence about technique. PMID- 7855152 TI - A creative form of skill development. Elective courses in nurse education. AB - 1. Nurse education needs to continue to strive to enhance teaching and learning in nurse education by the use of creative and innovative activities. 2. The philosophy underpinning electives is that often learners know what they want to learn and how they wish to go about this. 3. The use of nursing electives allows learners to cultivate their abilities in relation to self-directed study. 4. Evaluation of the elective experience undertaken enhances peer group activity and promotes self-confidence. PMID- 7855153 TI - Spread the word and reach a wider audience. Writing for publication. AB - 1. The advancement of nursing depends on sharing ideas through submitting articles for publication. 2. Nurses are often reluctant to write up their ideas for publication. 3. A review of the literature is essential in understanding the principles of writing for publication. 4. A system of peer review should be developed in the workplace to encourage and support nurses in the publication process. PMID- 7855154 TI - Bringing epilepsy care into the 1990s. The epilepsy liaison service. AB - 1. Dissemination of accurate information to all healthcare professionals and clients is vital if standards of care in epilepsy management are to improve. 2. Epilepsy audit is a vital step in raising the profile of epilepsy in general practice and in improving care. 3. People with epilepsy in primary and secondary care need realistic treatment plans and goals. 4. Practice nurses have an essential role to play in devising treatment plans and goals. 5. With a greater effort many people with epilepsy who are still having seizures can become seizure free. PMID- 7855155 TI - Counselling, or being a counsellor? Advice on how to become a qualified nurse counsellor. AB - 1. Using counselling skills and being a counsellor are not the same thing. 2. Various training options are open to nurses who want to work as counsellors. 3. Counsellors in training should receive supervision. PMID- 7855156 TI - Assessing normal and abnormal patterns of growth. AB - The problem of identifying abnormal patterns of growth in the pediatric population has been approached based on a schema that is dictated by the normal physiologic events that occur at each of the phases of infancy, childhood, and pubertal growth. These phases of growth have specific and quantifiable normal patterns, which provide a reference means for defining truly abnormal patterns of growth. The clinical evaluation, therefore, is dependent on and somewhat unique to the particular age group of the child whose growth is in question. By approaching the work-up in this age-specific manner, the clinician can direct his or her attention to the parameters of growth that are most critical to that particular phase, look for explanations that are the most likely, and, it is hoped, avoid unnecessary testing and referral. PMID- 7855157 TI - Childhood nutrition: from breastmilk to burgers. AB - Well-child care provides opportunities for nutrition education and the prevention of nutritional diseases. It is important to look at not only the food that is eaten but the relationships in which the food is offered. Significant impacts on the prevalence of iron deficiency and poverty-related malnutrition are possible. More research is needed on cholesterol reduction and on the prevention and treatment of obesity. PMID- 7855158 TI - Childhood immunization guidelines: current and future. AB - Recent additions to the immunization schedule include acellular pertussis vaccine, and hepatitis B vaccine for all infants and selected adolescents. The third dose of OPV is recommended at 6 months of age and the first dose of MMR vaccine at 12 to 15 months. A new vaccine against Haemophilus influenzae type b has been licensed. Children aged 6 months and older with asthma, diabetes, or heart disease should receive influenza vaccine. Children aged 2 years and older with asplenia, immunosuppression, and nephrotic syndrome may be candidates for pneumococcal immunization. PMID- 7855159 TI - Appropriate screening tests in infants, children, and adolescents. AB - Specific recommendations and the rationale for targeted screening procedures in infants, children, and adolescents have been reviewed. The utility of many tests is uncertain, often because of poor characterization of the disease or problem targeted. For example, the optimum time for treatment and whether treatment results in long-term benefits frequently are unknown. The development of recommendations based on evidence-based approaches promises to rationalize the delivery of preventive health care services in the pediatric population. PMID- 7855160 TI - Injury prevention in children. AB - Injuries are the leading cause of death in children. Approximately 23,000 children are killed each year in the United States, and many more suffer from nonlethal injuries. This article discusses general principles of effective intervention strategies, the most serious injury categories, and practical injury prevention advice for primary care physicians. PMID- 7855161 TI - Children and the influence of the media. AB - Violence, increased sexual activity, and antisocial behaviors involving children and adolescents are being blamed on the media. American children and adolescents spend 21 to 23 hours per week viewing television. Children will see 200,000 violent acts on television by age 18 and view over 14,000 sexual situations and innuendoes per year. The primary care physician can play a crucial role in reducing the potential negative influence of the media on children. PMID- 7855162 TI - Preventive health care for adolescents. AB - Physicians, parents or guardians, and the community all have an important role in preventive care for adolescents. Adolescents desire more interaction with their primary care providers. Physicians can influence the health care of adolescents by developing a collaboration with them that augments protective factors and allows a reduction in risk behaviors. PMID- 7855163 TI - Caring for the school-aged athlete. AB - Younger athletes are participating in more activities today than ever before. The primary care physician needs to fulfill the role of guiding these athletes into their activities safely with recommendations to help prevent injuries and other health conditions that may occur during their training and participation. Knowledge covering preparticipation examinations, cardiovascular concerns, nutrition, maturation, and general rehabilitation of injuries will be necessary for the care of these younger athletes. This article provides a general overview of these areas. PMID- 7855164 TI - [Ethics in psychiatric research]. PMID- 7855165 TI - The validity of the Scandinavian concept of reactive psychoses. AB - The historical background of the Scandinavian concept of reactive psychoses is presented. The reactivity concept consists of several elements. There has to be a traumatic life event of psychological or somatic nature but its duration can be discussed. What is the time lag between the life event and the psychotic reaction? Some say one week, others up to one year. Is a personal disposition (vulnerability) a necessary condition for the psychotic reaction? Are emotional turmoil or non-organic confusion specific symptoms of the reactive psychotic reaction? Does the psychotic reaction have a meaning as an escape or a defense? What is the duration of the psychosis in relation to the duration of the life event? Does reactive psychoses always imply full recovery (good outcome)? The various editions of the ICD- and the DSM-classification include some of these features in their definition of reactive psychoses. Scandinavian experts also emphasize various aspects in their descriptions of these psychoses. Studies have shown that reactive psychoses can be diagnosed reliably. Work on the operatinalization of "reactivity" is under way. In the Scandinavian tradition there is a diagnostic shift from reactive psychoses to schizophrenia in later admissions. Generally, the reactive psychoses have a good outcome, and the outcome is significantly better than for schizophrenia and as good as for manic depressive psychoses. Most cases of reactive psychoses are treated with neuroleptic drugs for some months. Electroconvulsive treatment is rarely given for reactive psychoses. Scandinavian psychiatrists think that DSM-IV and ICD-10 have not taken the concept of reactive psychoses seriously, and that research work has to be done to convince international psychiatry of the value of the concept. PMID- 7855166 TI - [Treatment of patients with borderline personality disorder with dynamic psychotherapy]. PMID- 7855167 TI - [Therapeutic aspects of adolescent psychiatry]. PMID- 7855168 TI - [Classification of psychiatric disorders by ICD-10]. PMID- 7855169 TI - [Psychiatric aspects of patients with epilepsy]. PMID- 7855170 TI - [Concept of mental disorders: financial support from the government]. PMID- 7855171 TI - [Clinical significance of group therapy]. PMID- 7855172 TI - [Recent progress on behavior therapy]. PMID- 7855173 TI - [The function of neologism in relation to the precipitating process of psychosis]. AB - Based on clinical observations, the author presented his reflections on the function of neologism appearing during the initial phase of psychosis. When the patient feels he is being interrogated as to his membership in certain groups significant to him, the neologism becomes manifest; neologism keeps him in touch with the group in that its content reflects how the patient feels he is viewed by the group; the patient, however, is not able to question his membership on a conscious level, but receives all at once, through auditory hallucinations, an affirmative answer in neologism. Why does neologism assume those idiosyncratic forms of language? There seem to be logical necessities. When a subject belongs to a group, he needs to speak a metalanguage that is richer than the language proper to it, in order to convey "It is true that I belong to this group." This is required because he must avoid the Russel type paradox of self-reference. For example, in order for a Japanese to say, "It is true that I am Japanese", he ought to express it in a metalanguage that is richer than his mother tongue. Scientific languages, such as those of anthropology or linguistics, may seem appropriate. However, as Wittgenstein and Lacan have pointed out, such a metalanguage does not really exist. Notwithstanding, it remains the goal of psychotic neologism and is the reason that psychotic neologism is destined to impossibility or dissolution of actual sense. On the other hand, it is conjectured that in normal subjects, group membership is not effectuated by such a metalanguage, but by fragmental and insignificant phonetic element that he incorporates at the earliest phase of development. PMID- 7855174 TI - [Age-delusion: (age-misidentification of chronic schizophrenic patients)]. AB - I noted that some of the schizophrenic patients chronically institutionalized at our hospital mistook their age (age-delusion), and studied the primary symptoms and the psychodynamics of this schizophrenic phenomenon. The subjects were divided into a core group of 24 patients who had schizophrenia without any overt organic brain diseases and a peripheral group of 8 patients who had schizophrenia associated with organic brain diseases. I divided the core group patients into 3 categories. I. Underestimators: These patients insisted that they were much younger than their real age, and they could be divided into a dynamic subgroup (subjective age increased in parallel with time) and a static subgroup (subjective aging did not occur). II. Overestimators: these patients believed that they were much older than their real age. III. Vacillators: These patients sometimes underestimated and sometimes overestimated their age. They could be divided into a subgroup in which the age was decided on the basis of their systematic delusions and a subgroup in which one of two fixed and different ages was always given (one being over and the other under the real age). I compared these schizophrenic age-delusional patients to other organic brain disease patients without schizophrenia who also mistook their age. Organic brain disease patients had a temporal recognition disorder as their primary symptom, while the schizophrenic patients had abnormal time experience as the primary symptom. This abnormality of time experience, mixed with the patient's psychodynamics that they want to objectify and manipulate their age as a number, appeared as a discrepancy between the subjective length of hospitalization and the actual duration, which means the age-delusion. These schizophrenic age-delusional patients had lost the essential 'Zeitlichkeit' and shut themselves up in the unessential 'Zeitlichkeit' according to the concept of Heidegger. Believing in their subjective age seems to allow them to reunify or rewrite their own past history and gain some hope for the future. PMID- 7855175 TI - PET examination of [11C]NNC 687 and [11C]NNC 756 as new radioligands for the D1 dopamine receptor. AB - The benzazepines NNC 687 and NNC 756 have in animal studies been described as selective D1-dopamine receptor antagonists. Both compounds have been labeled with 11C for examination by positron emission tomography (PET). In the present study central receptor binding was studied in monkeys and healthy men. After IV injection of both radioligands in Cynomolgus monkeys radioactivity accumulated markedly in the striatum, a region with a high density of D1-dopamine receptors. This striatal uptake was displaced by high doses of the selective D1-antagonist SCH 23390 (2 mg/kg) but not by the 5HT2-antagonist ketanserin (1.5 mg/kg) or the selective D2-antagonist raclopride (3 mg/kg). The cortical uptake after injection of [11C]NNC 687 was not reduced in displacement experiments with ketanserin. The cortical uptake of [11C]NNC 756 was reduced in displacement and protection experiments with ketanserin by 24-28% (1.5 mg/kg), whereas no reduction could be demonstrated on striatal uptake. In healthy males both compounds accumulated markedly in the striatum. For [11C]NNC 687 the ratio of radioactivity in the putamen to cerebellum was about 1.5. For [11C]NNC 756 the ratio was about 5. This ratio of 5 for [11C]NNC 756 is the highest obtained so far for PET radioligands for the D1-dopamine receptor. PMID- 7855176 TI - Persistent vacuous chewing in rats following neuroleptic treatment: relationship to dopaminergic and cholinergic function. AB - In order to relate the effects of pharmacological intervention to neuroleptic induced increases in oral activity rats were treated continuously (7 mg/kg per week) or discontinuously (7 mg/kg per week or 2 mg/kg per week) with haloperidol for 6 months. Only the two intermittently treated groups developed persisting increases in vacuous chewing movements (VCM) following drug withdrawal. Opposed to control animals and continuously treated rats, the discontinuously treated groups demonstrated significant elevation in mouth movements following stimulation with the dopamine (DA) D1 receptor agonist SK&F 38393 (23 mg/kg), whereas they did not response to an acute challenge with the selective DA D1 receptor antagonist NNC-756 (0.1 mg/kg). The DA D2 receptor antagonist raclopride (1 mg/kg) provoked a general fall in VCM; however, this was only significant in rats treated intermittently with haloperidol 7 mg/kg per week and in control rats. Intermittent neuroleptic treatment also increased apomorphine-induced stereotypy. The effect of challenge with the anticholinergic drug scopolamine (0.25 mg/kg) was not related to oral activity; furthermore, the finding of severe agitation in rats tested with the latter drug points to caution in the interpretation of rating of rats treated with anticholinergics. These results support that intermittent ingestion of neuroleptic drugs lead to long-lasting increases in VCM. They also suggest a relation of persisting elevated oral activity to supersensitivity to DA receptor agonists, as opposed to subsensitivity to D1 receptor antagonists. PMID- 7855177 TI - The effect of chronic treatment with naltrindole, a selective delta-opioid antagonist, on mu-opioid receptor-mediated antinociception in diabetic mice. AB - The effects of chronic treatment with naltrindole (NTI), a selective delta-opioid receptor antagonist, on the antinociceptive effects of mu-opioid agonists, such as morphine and [D-Ala2, N-MePhe4, Gly-ol(5)]enkephalin (DAMGO) were examined in diabetic mice. Antinociception induced by morphine (10 micrograms, ICV) and DAMGO (0.5 microgram, ICV) was significantly lower in diabetic mice than in non diabetic mice. The low sensitivities to the antinociceptive potencies of ICV morphine (10 micrograms) and DAMGO (0.5 micrograms) in diabetic mice were reversed compared with those in saline-treated non-diabetic mice when diabetic mice had been pretreated with NTI (2 mg/kg per day, SC) for 14 days. Naive mice which had been injected with spleen mononuclear cells from saline-treated diabetic mice were less sensitive to DAMGO-induced antinociception. However, adoptive transfer of spleen mononuclear cells from NTI-treated diabetic mice to naive mice had no effect on the recipients' antinociceptive sensitivity to DAMGO. These results suggest that the effect of NTI on the sensitivity to mu-opioid agonists in diabetic mice may be due to the immunosuppressive effects of NTI. PMID- 7855178 TI - Behavioural evidence that different neurochemical mechanisms underly stretching yawning and penile erection induced in male rats by SND 919, a new selective D2 dopamine receptor agonist. AB - The behavioural effects induced in male Wistar rats by SND 919, a new drug reputed to have selective agonistic activity at D2 dopamine (DA) receptors, were studied. The following aspects of behaviour were considered: motor activity, stretching-yawning (SY), penile erection (PE) and stereotyped behaviour (SB). Intraperitoneal injection (IP) of the drug (0.01-20 mg/kg) induced an SY syndrome in the form of a bell-shaped dose-response curve, the effect being maximal at the dose of 0.1 mg/kg and disappearing completely at 10 mg/kg. SND 919 also potently elicited PE; this latter effect, however, was not coincident with SY induction, being maximal at 1 mg/kg and persisting at 10 and 20 mg/kg. SND 919-induced SY was potently antagonized by pretreatment not only with the D2 antagonist, L sulpiride (20 mg/kg), but also with the alpha 2 antagonist, yohimbine (1, 3 mg/kg), and the more selective alpha 2 antagonist, idazoxan (1, 2 and 5 mg/kg). While sulpiride also decreased SND 919-induced PE, idazoxan at all doses and yohimbine at 1 mg/kg did not affect this behaviour. Inhibition of motor activity was induced by the D2 agonist at low doses (0.05, 0.1 mg/kg), while at high doses (1, 10 and 20 mg/kg), it was actually replaced by a form of SB characterized by downward sniffing and licking. When, for comparison, the D2 agonist, RU 24213 (0.1-20 mg/kg IP), was tested for PE, SY, motor activity and SB, it displayed a behavioural pattern very similar to that obtained with SND 919. Idazoxan (2 mg/kg), administered before RU 24213 (10 mg/kg), significantly antagonized the drug-induced SY, but not PE.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7855179 TI - Quantitative assessment of the microstructure of rat behavior: I, f(d), the extension of the scaling hypothesis. AB - Previous studies demonstrated that drug effects on the movement sequences of rats in unconditioned motor activity paradigms can be quantified by scaling measures that describe the average relationship between a variable of interest and an experimental parameter. However, rats engage in a wide variety of geometrically distinct movements that can be influenced differentially by drugs. In this investigation, the extended scaling approach is presented to capture quantitatively the relative contributions of geometrically distinct movement sequences to the overall path structure. The calculation of the spectrum of local spatial scaling exponents, f(d), is based on ensemble methods used in statistical physics. Results of the f(d) analysis confirm that the amount of motor activity is not correlated with the geometrical structure of movement sequences. Changes in the average spatial scaling exponent, d, correspond to shifting the entire f(d) function, and indicate overall changes in path structure. With the extended scaling approach, straight movement sequences are assessed independently from highly circumscribed movements. Thus, the f(d) function identifies drug effects on particular ranges of movement sequences as defined by the geometrical structure of movements. More generally, the f(d) function quantifies the relationship between microscopically recorded variables, in this paradigm consecutive (x,y) locations, and the macroscopic behavioral patterns that constitute the animal's response topography. PMID- 7855181 TI - Determination of plasma and brain concentrations of SCH 39166 and their correlation to conditioned avoidance behavior in rats. AB - Plasma and brain concentrations of the dopamine D1 receptor antagonist, SCH 39166, were measured and compared to behavioral activity in the conditioned avoidance response paradigm (CAR). SCH 39166 was administered at two behaviorally active doses (1 mg/kg, SC and 10 mg/kg, PO) and the time course for CAR activity was compared with the plasma and brain concentrations of unconjugated SCH 39166. Conjugation and N-demethylation of SCH 39166 after oral administration were also determined and first pass metabolism examined. Results from these studies demonstrated a similar time-dependent disappearance of unconjugated SCH 39166 from both the plasma and brain, independent of route of administration. Brain concentrations of SCH 39166 were approximately 5-fold higher than corresponding plasma concentrations, regardless of route. However, plasma and brain concentrations of unconjugated SCH 39166 were higher after SC administration of 1.0 mg/kg, than after PO administration of 10 mg/kg, suggesting a substantial first pass metabolism of SCH 39166. In addition, total (conjugated and unconjugated) plasma concentrations of SCH 39166 were at least 10-fold higher than unconjugated concentrations of SCH 39166 after PO administration of 10 mg/kg, demonstrating that a high proportion of drug was conjugated. Metabolism to the N-desmethyl analog, SCH 40853, was observed after PO administration of 10 mg/kg SCH 39166 and a high proportion of conjugation of the desmethyl analog was also seen. Finally, plasma concentrations of unconjugated SCH 39166 exhibited a high positive correlation (r = 0.934, P < 0.001) with brain concentrations of unconjugated SCH 39166.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7855182 TI - Nicotine withdrawal: a behavioral assessment using schedule controlled responding, locomotor activity, and sensorimotor reactivity. AB - Three different behavioral measures were used to assess the effects of abrupt cessation of chronic nicotine treatment. Nicotine (0, 3, or 6 mg/kg per day) was continuously administered for 12 days in rats by surgically implanting Alzet osmotic mini-pumps subcutaneously. Experiment 1 employed a light/dark discrimination task. There were no significant effects on number of responses or percent correct responding either during nicotine administration, or following cessation of nicotine. Experiment 2 examined ambulatory (locomotor) and nonambulatory activity. Chronic nicotine administration produced significant dose dependent increases in both ambulatory and nonambulatory activity during the first 3 days of exposure. However, no significant alterations were seen in activity levels following nicotine cessation. Experiment 3 examined sensorimotor reactivity using the auditory startle response. During nicotine withdrawal, significant increases were seen in startle amplitude in both nicotine groups for 4 days. Nicotine (0.4 mg/kg, IP) administered before startle testing during the withdrawal phase attenuated the increased reactivity seen during nicotine cessation. These studies indicate that 1) rats display increased sensorimotor reactivity after cessation of chronic nicotine exposure, and 2) the expression of nicotine dependence and withdrawal is dependent on the behavioral task employed. PMID- 7855180 TI - Quantitative assessment of the microstructure of rat behavior: II. Distinctive effects of dopamine releasers and uptake inhibitors. AB - The effects of four indirect dopamine agonists, d-amphetamine (0.25-4.0 mg/kg), cocaine (2.5-40.0 mg/kg), GBR 12909 (10.0-30.0 mg/kg), and nomifensine (5.0-20.0 mg/kg), on the behavioral organization of movements in an unconditioned motor paradigm were investigated in rats. The extended scaling hypothesis using the fluctuation spectrum of local spatial scaling exponents was used to quantify the geometrical characteristics of movements. The results reveal a qualitatively similar disruption of behavioral organization by lower doses of these drugs. Specifically, rats treated with d-amphetamine (< 2.0 mg/kg), cocaine (< 20.0 mg/kg), GBR 12909 (< 20.0 mg/kg), or nomifensine (< 10.0 mg/kg) exhibited a reduced range in the fluctuation spectrum, reflecting a predominance of meandering movements with local spatial scaling exponents between 1.3 and 1.7. This reduction was accompanied dynamically by a reduced predictability of movement sequences as measured by the dynamical entropy, h. By contrast, higher doses of these drugs produced distinctly different changes in behavioral organization. In particular, 4.0 mg/kg d-amphetamine and 40.0 mg/kg cocaine increased the fluctuation range, reflecting relative increases in both straight and circumscribed movements that are interpreted as a combination of spatially extended and local perseveration. In contrast, high doses of 30.0 mg/kg GBR 12909 and 20.0 mg/kg nomifensine induced only local perseveration. High doses of d amphetamine, cocaine, GBR 12909 and nomifensine reduced the dynamical entropy, h, indicating an increased predictability of the movement sequences. These results suggest that the generic behavioral change induced by low doses of dopamine agonists is characterized by a reduced variety of path patterns coupled with an increased variability in sequential movement sequences. The differential effects of higher doses of these drugs may be due to their influences on other neurotransmitter systems or differential affinities for different dopamine subsystems. PMID- 7855183 TI - Nitrous oxide induces an anxiolytic-like effect in the conditioned defensive burying paradigm, which can be reversed with a benzodiazepine receptor blocker. AB - To investigate the anxiolytic effects of nitrous oxide (N2O), male hooded rats were tested in the conditioned defensive burying (CDB) test, a paradigm that exploits a propensity of rats to bury objects associated with aversive stimulation. A single, brief electrical shock was delivered to rats upon contact with an electrified prod, before exposure to one of four mixtures of N2O and oxygen (O2) (10-40% N2O) or room air (RA). Compared to RA-exposed animals, rats exposed to N2O exhibited a concentration-related reduction in duration and height of prod-directed "defensive" burying with floor bedding material; these measures reached statistical significance at 30% N2O. Pretreatment with 20 mg/kg of the benzodiazepine receptor blocker flumazenil, which alone had no effect, effectively antagonized a 30% N2O-induced decrease in burying. Horizontal locomotion and rearing were not significantly affected at concentrations of N2O that attenuated prod-directed burying. Treatment with the benzodiazepine anxiolytic standard, chlordiazepoxide (2.5-10.0 mg/kg) also resulted in dose related attenuation of burying behavior. These findings show that N2O can induce effects similar to those of known anxiolytics in this paradigm and suggest a benzodiazepine mechanism in its mediation. PMID- 7855184 TI - Facilitation of shuttle-box avoidance behaviour in mice treated with nifedipine in combination with amphetamine. AB - The dihydropyridine calcium channel antagonist nifedipine, tested in mice of CD 1, C57BL/6 and DBA/2 strains, at doses of 2.5, 5 and 10 mg/kg IP, had no significant effect on shuttle-box avoidance acquisition. Nifedipine also failed to affect performance retention in CD-1 mice subjected to a one-trial passive avoidance task (step-through). While ineffective alone, nifedipine strongly enhanced the shuttle-box avoidance facilitating action of amphetamine (1 and 2 mg/kg IP) in low performing CD-1 mice. The results indicate that although calcium channel blockers do not affect learning in avoidance paradigms in normal animals, they can interfere with the effects of other centrally acting drugs. Calcium antagonists might interfere with neuronal changes induced by amphetamine, but at present it is difficult to explain the strong avoidance facilitation produced by combinations of nifedipine and amphetamine. A possibility that the action of nifedipine on cerebral circulation is involved in the amphetamine-nifedipine interaction cannot be excluded. PMID- 7855185 TI - CSF/plasma ratio of 10-hydroxynortriptyline is influenced by sex and body height. AB - The CSF/plasma ratios of nortriptyline (NT) and its major metabolite 10-hydroxy NT (10-OH-NT) were investigated retrospectively in 25 depressed patients. For 10 OH-NT (but not NT), a significant influence of sex and body height was found, most conspicuously in males, in whom the ratio related to body height curvilinearly (N = 8; R = 0.93; P < 0.01). In males, the NT/10-OH-NT ratio in plasma correlated with body height (N = 8; r = 0.80; P < 0.05). Hypothetically, CSF circulation is partly influenced by body height, which accounts for a steeper gradient of 10-OH-NT across the blood-brain barrier in taller persons. From the lumbar site, the more polar 10-OH-NT is assumed to be eliminated by bulk flow via the villi, while the less polar NT exits by diffusion in the choroid plexus. Prospective studies are urgently needed to further evaluate the distribution of antidepressants in the CSF. PMID- 7855186 TI - Changes in sleep polygraphic variables and clinical state in depressed patients during treatment with citalopram. AB - Drug-induced improvement of depression may be mediated by changes in sleep physiology. The aim of this study was to relate changes in sleep polygraphic variables to clinical state during treatment with citalopram, a highly specific serotonin uptake inhibitor. Sixteen patients took part. The study was single blind and uncontrolled. A 1-week wash-out period was followed by 1 week of placebo administration, a medication period of 5 weeks, and a 1-week placebo period. For the entire group a significant decrease of rapid eye movement sleep (REMS) and a significant lengthening of REMS latency were observed initially as well as at the end of treatment. No changes in sleep continuity were found, but non-REMS stage 2 (percentage) was significantly increased. On the basis of clinical change, as expressed by the scores of the Hamilton Rating Scale for Depression, at the end of the citalopram treatment the patient group was split in two halves: eight less and eight more improved patients. The groups did not differ with respect to any sleep polygraphic variable. PMID- 7855187 TI - Ethanol-maintained behavior in a foraging context: effects of search and procurement cost. AB - In a simulated foraging procedure, the effects of manipulating search and procurement costs of access to ethanol, food, and water on ethanol self administration were determined in rats. Completion of a response ratio on one lever (search) resulted in the opportunity to complete a high- or low-cost response ratio on one of three other levers (procurement). Each procurement lever was exclusively associated with access to ethanol, food, or water, and the six procurement opportunities occurred in random order. Any procurement opportunity could be rejected, and a new search subsequently initiated. Percent acceptance of high-cost opportunities varied directly with increases in search cost and inversely with increases in high procurement cost. When search cost was increased, daily water and food consumption decreased, whereas daily ethanol consumption was unaffected. Regardless of these manipulations, rats consumed 1.0 2.0 g/kg ethanol daily. Ethanol consumption also was unaffected by increases in low or high food procurement cost values. These results indicate that ethanol self-administration can be analyzed within a foraging environment in which the animal initiates and determines the length and size of all drinking bouts and meals. Within this environment, patterns of ethanol self-administration were orderly and distinguishable from patterns of food- and water-maintained behavior. PMID- 7855188 TI - Influence of prior maze experience on behaviour and response to diazepam in the elevated plus-maze and light/dark tests of anxiety in mice. AB - A single prior undrugged exposure to the elevated plus-maze has been reported to reduce open arm activity on retest and to attenuate/abolish the anxiolytic response to benzodiazepines at retest intervals ranging from 48 h to 14 days. The present study was designed to examine the generality of these findings by comparing the effects of prior maze experience on baseline behaviour and response to diazepam in two murine models of anxiety. Parallel experiments were conducted in which DBA/2 mice were exposed/not exposed to the plus-maze, treated daily with saline or diazepam (2-4 mg/kg daily for 8 days) and then tested on either the elevated plus-maze or in the light/dark test of exploration. Results show that, in both tests, diazepam reduced behavioural indices of anxiety in maze-naive mice only. However, interpretation of this apparent loss of diazepam efficacy is at least partially confounded by the observation that maze experience per se altered baseline behaviour in both procedures, reducing open arm activity in the plus maze and increasing light compartment activity in the light/dark test. The apparent elimination of an anxiolytic response to diazepam in two animal models of anxiety by prior plus-maze experience is discussed in relation to experience related baseline shifts in behaviour. PMID- 7855189 TI - Differential sensitivity to the effects of albuterol on locomotor activity and operant behavior. AB - The purpose of the present study was to determine the effects of the beta-2 selective adrenergic agonist albuterol on three behaviors, locomotor activity, behavior maintained under a differential-reinforcement-of-low-rate (DRL) schedule, and behavior maintained under a multiple fixed-interval, fixed-ratio (FI-FR) schedule of reinforcement. Albuterol reduced response rate under the DRL schedule in a manner that resulted in an increase in reinforcement rate. Similarly, albuterol reduced response rate under both components of the multiple FI-FR schedule in a dose-dependent manner. The ED50 values for the effects of albuterol on these two operant behaviors were calculated to be approximately 1 mg/kg and the minimal effective doses were 0.3-1 mg/kg. In addition to affecting operant behavior, albuterol also reduced locomotor activity; the ED50 values and minimal effective doses were 0.05 and 0.03 mg/kg, respectively. The effects of albuterol on DRL behavior, FI-FR behavior and locomotor activity were antagonized by the beta adrenergic antagonist propranolol; this suggests that the behavioral effects of this agonist were mediated, at least in part, by beta adrenergic receptors. The differential sensitivity of locomotor activity and operant behavior to albuterol suggests that the actions of this drug on locomotor activity may be mediated predominantly by peripheral beta adrenergic receptors and that its effects on operant behavior may be mediated by beta adrenergic receptors in the central nervous system. PMID- 7855190 TI - Effect of clozapine upon schedule-induced polydipsia (SIP) resembles neither the actions of dopamine D1 nor D2 blockade. AB - The effects of clozapine (CLOZ) upon acquired schedule-induced polydipsia in rats were compared to the effects of the dopamine (DA) D1 antagonist SCH 23390 (SCH) and the DA D2 antagonist raclopride (RAC). All three compounds suppressed water consumption, but only SCH and RAC decreased drinking efficiency. SCH was the only compound with an effect on panel pressing (PP), causing suppression even at a dose without effect upon water intake. SCH also affected the temporal pattern of licking (TPL) at all doses, while clozapine, 10 mg/kg, only affected the pattern acutely, and raclopride was without effect. In conclusion, PP and the TPL are more sensitive to D1 than D2 blockade. While PP and the TPL are more sensitive than water intake to D1 blockade, the opposite is true for D2 blockade. It is possible to differentiate between DA D1/D2 antagonists and CLOZ in this model, focusing upon reduction in water consumption, with and without reduction in drinking efficiency. Furthermore, it is possible to differentiate between D1 and D2 blockade by analyzing water consumption, PP and the TPL. PMID- 7855191 TI - Influences of different adenosine receptor subtypes on catalepsy in mice. AB - The effects of adenosine A1 and A2 receptors on catalepsy were studied in mice. The adenosine agonists 5-N'-ethylcarboxamide-adenosine (NECA), N6 phenylisopropyladenosine (PIA) and N6-cyclohexyladenosine (CHA) induced dose dependent catalepsy. The A1 adenosine antagonist 8-phenyltheophylline (8-PT) potentiated catalepsy induced by NECA, R-PIA and CHA. However, theophylline did not potentiate but inhibited the responses induced by NECA, R-PIA and CHA. Neither 8-PT nor theophylline alone has any effect on catalepsy in mice. It is concluded that catalepsy induced by the adenosine agonists may be due to A2 receptor stimulation and that the A1 antagonism may potentiate the response. PMID- 7855192 TI - Effects of housing, restraint and chronic treatments with mCPP and sertraline on behavioural responses to mCPP. AB - The effects of pretreatments on behavioural responses to activation of 5-HT1C receptors by m-chlorophenylpiperazine (mCPP) were investigated. The hypo locomotor and anxiogenic effects of mCPP (social interaction test) were influenced neither by previous housing (single versus grouped) nor by restraint (2 h, 24 h previously). In the absence of mCPP, 24 h group housing led to decreased social interaction and the restraint procedure led to significant decreases of feeding and locomotion. The hypophagic effect of mCPP was unaffected by previous restraint. However, chronic pretreatment with mCPP (2.5 mg/kg per day IP x 14) or with the antidepressant 5-HT reuptake inhibitor sertraline (5 mg/kg per day SC x 14) attenuated all three behaviours. The above findings are discussed with respect to published data on effects of pretreatments on responses to the activation of 5-HT1C receptors. PMID- 7855193 TI - Response outcomes affect the retention of behavioral tolerance to alcohol: information and incentive. AB - Twenty-four male undergraduates acquired tolerance during three sessions where they received moderate doses of alcohol (0.62 g/kg) and repeatedly performed a motor skill task with immediate knowledge of results (KR) on each trial. Subjects were assigned to one of four groups (n = 6) before a retention test session where two groups received alcohol and two expected alcohol but received a placebo. The effect on tolerance retention of withholding KR was tested in alcohol group A. The effect of an incentive in the absence of KR was examined in the other alcohol group (AM) that was offered a delayed monetary reward for nonimpaired performance. Both alcohol groups failed to retain tolerance and their impairment did not differ. The effect of substituting the incentive for KR on a drug compensatory response to placebo was examined in group PM by comparing its performance to group PC where KR was continued. A compensatory response (i.e., performance superior to drug-free baseline) was displayed by the PC group but not by group PM. Thus, despite a monetary incentive to perform well, tolerance to alcohol and a compensatory response to placebo were both disrupted by withholding KR. The results were interpreted in terms of the information about performance conveyed by KR. PMID- 7855194 TI - Smoking is a drug dependence: a reply to Robinson and Pritchard. PMID- 7855195 TI - Behavioral characterization of alpha-ethyltryptamine, a tryptamine derivative with MDMA-like properties in rats. AB - Several reports have speculated that the tryptamine-derived drug alpha ethyltryptamine (AET) may have effects similar to those of the amphetamine derived drug 3,4-methylenedioxymethamphetamine (MDMA). Indeed, the US Drug Enforcement Administration has recently placed AET on the Schedule I list because of its putative similarity to MDMA. The Behavioral Pattern Monitor, which quantifies locomotor and investigatory responses of rats, was used to characterize the effects of AET in a paradigm that distinguishes between the effects of traditional hallucinogens, amphetamine-like stimulants, and MDMA-like drugs. First, a dose-response study revealed that all doses of AET tested (5, 10, 20 mg/kg) significantly increased locomotor activity. Locomotor hyperactivity is produced by MDMA or amphetamine-like stimulants, but not by classical hallucinogens, such as LSD or mescaline. Additionally, AET significantly decreased measures of investigatory behavior. Similar decreases occur with MDMA or hallucinogen administration. Second, as with MDMA, the locomotor hyperactivity induced by AET was attenuated by pretreatment (10 mg/kg) with the serotonin reuptake inhibitor fluoxetine. Thus, AET, a tryptamine-derived drug, appears to produce an MDMA-like profile of behavioral changes by virtue of releasing presynaptic serotonin. PMID- 7855196 TI - Effects of typical and atypical antipsychotic drugs on two-way active avoidance. Relationship to DA receptor blocking profile. AB - The dose-dependent and time-dependent effects of the novel antipsychotic compound remoxipride, as well as the reference compounds chlorpromazine, clozapine, haloperidol, pimozide and sulpiride upon the retention of two-way active avoidance (conditioned avoidance responses, CARs) were studied in male rats. The dose-dependent effects of remoxipride as well as haloperidol and chlorpromazine on the acquisition of CARs were also studied. The acquisition and retention of CARs were tested in shuttleboxes using a 1.0-mA shock intensity and a 10-stone signal (1000 Hz). All the compounds studied, including remoxipride, caused a dose dependent impairment of acquisition and retention of CARs. The effect of remoxipride on CAR acquisition correlated with remoxipride's effectiveness to block the hyperactivity induced by the dopamine (DA) agonist apomorphine. Unlike chlorpromazine and haloperidol, the potency of remoxipride and clozapine for antagonising CAR retention was found at dose levels much lower than those producing cataleptic effects or blocking apomorphine-induced stereotypies. Based on the DA receptor blocking profile and the relative effectiveness to block CAR it is concluded that the mechanism(s) by which clozapine and remoxipride affect CAR differ from typical neuroleptic drugs. This difference may reflect an action upon different subtypes of functionally coupled DA D2 receptors. PMID- 7855197 TI - Methamphetamine exposure during early postnatal development in rats: I. Acoustic startle augmentation and spatial learning deficits. AB - Methamphetamine (MA) induces neurotransmitter reductions and neurotoxicity at high doses in adult animals, but its effects on early brain development and behavior have received less attention. In this experiment the effects of MA exposure during a period equivalent to the human third trimester were examined. Rats (Sprague-Dawley CD) were injected subcutaneously with d-MA (30 mg/kg b.i.d.) early in postnatal development (days 1-10), later (postnatal days 11-20), or with water during both of these periods. Both early and later MA-exposed offspring exhibited augmented acoustic startle and impaired performance in a complex multiple-T water maze. Only the early MA exposure group showed a persistent deficit in weight while only the later MA exposure group showed impaired learning in the Morris hidden platform maze. Effects on locomoter activity are reported in the accompanying article. It was concluded that the effects of MA are both long lasting and stage dependent and involve cognitive as well as arousal functions. PMID- 7855198 TI - Methamphetamine exposure during early postnatal development in rats: II. Hypoactivity and altered responses to pharmacological challenge. AB - Methamphetamine induces neurotransmitter reductions and neurotoxicity at high doses in adult animals, but its effects on early brain development and behavior have received little attention. In this experiment the effects of methamphetamine exposure during a period equivalent to the human third trimester were examined. Rats (Sprague-Dawley CD) were injected subcutaneously with d-methamphetamine (d MA) (30 mg/kg b.i.d.) early in postnatal development (days 1-10), later (postnatal days 11-20), or with water during both of these periods. Both early and later MA-exposed offspring exhibited reduced locomotor activity. The effect was most evident at 30 days of age and was smaller at 45 and 60 days and only present at these latter ages in males. Only the early MA exposure group showed prolonged suppression of activity in response to a challenge dose of fluoxetine and a persistent deficit in weight while only the later MA exposure group showed attenuated suppression of activity in response to a challenge dose of fluoxetine. Based both on the present data and those in the preceding article, it was concluded that the effects of MA are both long lasting and stage dependent and involve arousal as well as cognitive functions. PMID- 7855199 TI - The subjective, behavioral and cognitive effects of subanesthetic concentrations of isoflurane and nitrous oxide in healthy volunteers. AB - A prospective, crossover, double-blind trial was conducted in nine healthy volunteers in which the subjective, psychomotor and memory effects of isoflurane (0.0, 0.3 and 0.6%) and nitrous oxide (N2O) (0, 20 and 40%) were examined. Dependent measures included visual analog scales and a standardized drug effects inventory (subjective effects), reaction time and eye-hand coordination (e.g., psychomotor performance), and immediate and delayed free recall (memory). There were some similarities in subjective effects between the two inhaled drugs (e.g., increased ratings of "drunk" and "spaced out"), but isoflurane had effects which N2O did not have. Isoflurane but not N2O increased visual analog scale ratings of "confused," "sedated," and "carefree," and decreased ratings of "in control of thoughts" and "in control of body." An odor was detected with isoflurane and it was disliked. Psychomotor performance was more grossly impaired during isoflurane inhalation than during N2O inhalation. Psychomotor recovery from both agents was rapid and complete so that 5 min after the inhalation period had ceased, performance had returned to baseline levels. Both isoflurane and nitrous oxide impaired immediate and delayed free recall. The feasibility of using isoflurane in conscious sedation procedures is discussed. PMID- 7855200 TI - Enhancing caffeine reinforcement by behavioral requirements following drug ingestion. AB - Each morning eight adults with caffeine versus placebo discrimination histories ingested letter-coded capsules containing 100 mg caffeine or placebo and then engaged in a relaxation or vigilance activity. Subjects were first exposed to caffeine and placebo once each with each activity. Then each day for 10 days subjects made two choices; they chose which compound they would prefer if vigilance were scheduled and which they would prefer if relaxation were scheduled, with the restriction that they could not choose the same compound with both activities; only one choice (randomly selected) was reinforced. Eight of eight subjects always chose caffeine with vigilance. The next choice condition was identical, except that subjects were free to take either compound with both activities. Six of six subjects reliably chose caffeine with vigilance. Four reliably chose placebo with relaxation. In the final condition, each day for 10 days subjects chose between each drug and each of 52 monetary values; those choices were made separately for vigilance and relaxation; only one choice (randomly selected) was reinforced. For six of seven subjects, the maximum dollar value at which subjects chose drug over money was higher for caffeine in vigilance than for placebo in either activity. For five subjects, the maximum value at which subjects chose caffeine over money was higher in vigilance than in relaxation. Overall, this study demonstrates enhanced caffeine reinforcement when a vigilance activity followed drug ingestion. PMID- 7855201 TI - Chronic variable stress or chronic morphine facilitates immobility in a forced swim test: reversal by naloxone. AB - The behaviors displayed in a forced swim test were investigated in rats previously exposed to a chronic variable stress treatment or chronic administration of morphine. In addition, to further explore the participation of an endogenous opiate mechanism in these behavioral effects, naloxone was either administered during the chronic treatment (prior to each stress or morphine exposure) or immediately prior to the forced swim test. Animals were submitted daily to a different stressor for 1 week or injected with morphine (10 mg/kg, IP) for 6 days, whereas controls were unmanipulated except for the injection process. On the day following the last stressor, control and stressed animals were administered saline or naloxone (2 mg/kg, IP) 15 min prior to the forced swim test. Morphine treated animals were similarly tested on the third day following the last morphine injection. In a separate group of rats, naloxone (2 mg/kg, IP) was administered daily 10 min prior to each stressor of the chronic stress regime or each daily morphine injection. A significant increase in the time spent in immobility was observed in stressed animals as well as in rats chronically treated with morphine. In both groups, this potentiated immobility was attenuated by naloxone pretreatment prior to the forced swim test or when given before each daily stressor or morphine injection. In addition, the concurrent exposure to stress or morphine along with naloxone administration enhanced struggling in the first 5 min of the forced swim test.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7855202 TI - Ultrasounds emitted by female rats during agonistic interactions: effects of morphine and naltrexone. AB - Ultrasonic vocalizations may be an expression of the affective pain response in laboratory rodents. The present experiment compared morphine's effects on high (33-60 kHz) and low (20-32 kHz) frequency ultrasonic vocalizations to its effects on a range of unconditioned behavioral responses to aversive stimuli; the influence of estrous cyclicity on morphine sensitivity was also investigated. In experiment 1, naive female Long-Evans rats, selected during estrus or diestrus, received cumulative morphine (1, 3, 6, 10 mg/kg SC) or saline, and in experiment 2, rats were pretreated with naltrexone (0.1 mg/kg IP) 5 min before morphine (17, 30, 60, 100 mg/kg SC). The following endopoints were measured 20-25 min post injection: (1) tail flick latency; (2) ultrasonic and audible vocalizations; (3) the behavioral response to aggressive attack; and (4) locomotor activity. Following a brief exposure to an attack, rats were threatened by an aggressor but protected from further attack by a wire mesh cage (30 x 21.5 x 20 cm), thereby allowing for continued behavioral and vocal measurement without the risk of physical injury; video and audio recordings were made of the attack encounter and a subset of the protected encounter (1 min). The endpoint most potently and specifically modulated by morphine was high frequency ultrasounds. The rate of high frequency calling varied as a function of the estrous cycle, supporting gonadal hormone modulation of ultrasonic vocalizations. Low frequency ultrasounds, by contrast, were relatively insensitive to opiate manipulation and were less influenced by estrous cyclicity. High frequency vocalizations may be a more sensitive indication of the affective response to an attacking conspecific that low frequency calls.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7855203 TI - Pentagastrin induced panic attacks: enhanced sensitivity in panic disorder patients. AB - The effects of pentagastrin, a synthetic analogue of the cholecystokinin tetrapeptide (CCK4), were studied in 15 patients with panic disorder and 15 healthy controls. Three different intravenous dosages of pentagastrin (0.1, 0.3 and 0.6 microgram/kg) and saline were investigated. Subjects were randomly allocated to two of the four treatment groups and tested on two separate occasions, 1 week apart, using an unbalanced double-blind incomplete block design. The mean panic rate with pentagastrin was 55% (12/22) for patients and 5% (1/22) for controls. None of the subjects panicked with saline. The frequency of panic attacks between the three pentagastrin doses in patients was not different. One control subject had a panic-like attack at the highest dose of pentagastrin. These findings concur with previous studies on the panicogenic effect of CCK4 and pentagastrin and suggest a greater sensitivity for CCK receptor agonists in patients suffering from panic disorder than in healthy controls. PMID- 7855204 TI - Evidence that nicotine can acutely desensitize central nicotinic acetylcholinergic receptors. AB - Current concepts concerning nicotine's CNS mechanism(s) of action suggest that this drug produces its effects via an interaction at nicotinic-cholinergic receptors (nAChRs) sensitive to acetylcholine. In vitro research further suggests that, following its initial agonist effect, this cholinergic drug may also induce a rapid desensitization of the nAChR similar to that of acetylcholine, resulting in termination of its pharmacological effect. Research described in this paper provides evidence of this secondary desensitization process in vivo by demonstrating nicotine's ability to induce acute tolerance in a Discriminative Stimulus (DS) paradigm. The ability of nicotine (400 micrograms/kg, SC) to elicit DS control of behavior in a two-lever operant procedure was significantly reduced via a challenge dose (800 micrograms/kg, SC) of nicotine administered 15-180 min before the training dose. Twenty-three of 52 rats demonstrated this phenomenon. The time to develop acute tolerance varied, providing additional evidence that these effects may be contingent upon individual rat variability. In addition, physostigmine was also observed to induce a similar desensitization in a random population of desensitizing rats. Lastly, there were no differences between desensitizers and non-desensitizers in relation to the ability of mecamylamine (1000 micrograms/kg, SC) to antagonize the DS, while in both populations of rats scopolamine (100 micrograms/kg, SC) failed to antagonize the DS. PMID- 7855205 TI - Comparison of the effects of NMDA and AMPA antagonists on the locomotor activity induced by selective D1 and D2 dopamine agonists in reserpine-treated mice. AB - This study examined the interaction between various glutamate antagonists and selective D1 (SKF 38393) and D2 (RU 24213) dopamine agonists in the production of locomotion in the reserpine-treated mouse. Firstly, in normal mice, the NMDA channel blocker MK 801 (0.1-1.6 mg/kg) caused a biphasic stimulation/depression of locomotor activity, whereas the competitive NMDA antagonists CGP 40116 (0.25-8 mg/kg) and CPP (0.2-20 mg/kg), and the NMDA glycine site antagonist HA 966 (0.4 10 mg/kg) inhibited locomotion monophasically. These compounds caused varying degrees of muscle weakness and impairment of posture and gait, whilst the AMPA receptor blocker NBQX (0.2-25 mg/kg) had no significant effect on unconditioned mouse motor behaviour. None of the antagonists reversed reserpine-induced akinesia by themselves, but they all potentiated the locomotor movements induced by 30 mg/kg SKF 38393. Movements remained fluent with low doses of CPP, HA 966 and NBQX, but became ataxic with MK 801 and CGP 40116, with sedation prevailing at high doses of all the antagonists, as in normal mice. CPP and NBQX also combined synergistically with SKF 38393 to promote tonic convulsions. By contrast, RU 24213-induced locomotion was dose-dependently depressed by MK 801, CGP 40116 and HA 966, but was unaffected by CPP or NBQX. These differential effects of NMDA and AMPA antagonists on D1 and D2 motor responding in the monoamine-depleted mouse are discussed in terms of possible mechanisms and sites of action within the brain, and the implications for their putative use as adjuvants to L-dopa in antiparkinson therapy. PMID- 7855206 TI - Bilateral intra-accumbens self-administration of d-amphetamine: antagonism with intra-accumbens SCH-23390 and sulpiride. AB - The efficacy of d-amphetamine to support a selective bilateral intra-accumbens self-administration response was examined. Bilateral intra-accumbens infusions of d-amphetamine were made contingent upon the acquisition of a lever-pressing response. Two identical levers were available within the operant chamber. Depression of the drug lever resulted in the intra-accumbens delivery of 1 microgram d-amphetamine; responses upon the second, control lever were recorded but had no programmed consequences. Animals were not 'primed' with non-contingent infusions of d-amphetamine at any time during these experiments. Nonetheless, animals readily acquired a selective response upon the drug lever. Removal of the d-amphetamine moiety from the infusate resulted in a large decline in responding, and the abolition of the selectivity of the response for the drug lever. Adulteration of the infusate with either the D1 dopamine receptor antagonist SCH 23390 or the D2 dopamine receptor antagonist sulpiride enhanced the rate of response selectively upon the drug lever. Reductions in the dose of d-amphetamine also increased the rate of response. The effect of co-adulteration of the infusate with both SCH-23390 and sulpiride together was purely additive. The implications of these data for the methodology of intracranial drug self administration, and the relationship between D1 and D2 dopamine receptors within the nucleus accumbens are discussed. PMID- 7855207 TI - Lack of evidence for an involvement of nucleus accumbens dopamine D1 receptors in the initiation of heroin self-administration in the rat. AB - The involvement of dopamine D1 receptor systems in the reinforcing properties of opiate reward was studied by examining the effect of the dopamine D1 antagonist SCH23390 on the initiation of heroin self-administration in rats. The D1 antagonist was administered daily systemically or locally in the nucleus accumbens (NAC), after which the animals were allowed to self-administer heroin (IV) in a 3-h session for 5 consecutive days. Systemic treatment with SCH23390 (0.17 and 0.5 mg.kg-1) significantly decreased heroin intake during initiation of heroin self-administration, while a dose of 0.06 mg.kg-1 was not effective. Local administration of SCH23390 (0.5 and 2.5 micrograms/site) in the NAC did not affect heroin intake. Both systemic and intra-accumbal administration of SCH23390 dose dependently decreased motor behavior measured in a small open field. The attenuation of heroin intake during initiation of heroin self-administration by blockade of dopamine D1 receptor systems may be due to a decrease in the reinforcing effects of heroin or more likely to a reduction in non-reinforcement related behavior. The dopamine D1 receptors present in the NAC are probably not involved in opiate reward. PMID- 7855208 TI - Long-term treatment with low doses of the D1 antagonist NNC 756 and the D2 antagonist raclopride in monkeys previously exposed to dopamine antagonists. AB - Eight Cebus apella monkeys previously exposed to D1 and D2 antagonists were treated subcutaneously for 8 weeks with the D1 antagonist NNC 756 (0.01 mg/kg), followed by a wash-out period of 4 weeks and treatment with the D2 antagonist raclopride for 8 weeks (end doses 0.01 mg/kg). NNC 756 induced no dystonia, while marked dystonia was induced by raclopride. Mild tolerance to the dystonia inducing effect of raclopride slowly developed. Both drugs induced significant sedation and mild bradykinesia. Sedation induced by NNC 756 was stronger than that of raclopride, while no differences were found regarding bradykinesia. The sedative effect of both NNC 756 and raclopride increased over time during chronic treatment. No changes in bradykinesia developed. No significant dyskinesia was induced by NNC 756, while raclopride significantly induced both acute and tardive oral dyskinesia. Furthermore, raclopride-induced acute dyskinesia worsened during chronic treatment. Concomitant treatment with NNC 756 tended to reduce the D1 agonist SKF 81297-induced dyskinesia and grooming, while concomitant treatment with raclopride increased SKF 81297-induced dyskinesia and tended to decrease SKF 81297-induced grooming. Chronic treatment with raclopride induced supersensitivity to both the D2/D3 agonist LY 171555 and SKF 81297, while chronic NNC 756 treatment only induced supersensitivity to SKF 81297. The findings indicate that D1 antagonists may induce less dystonia and oral dyskinesia as compared with D2 antagonists and support the hypothesis of both a permissive and an inhibitory interaction between D1 and D2 receptor systems. PMID- 7855209 TI - Effect of ambient temperature on hyperthermia and hyperkinesis induced by 3,4 methylenedioxymethamphetamine (MDMA or "ecstasy") in rats. AB - A stress-free, biotelemetric monitoring technique was used to investigate the effects of ambient temperature (Ta) on the hyperthermic and hyperkinetic effects of 3,4-methylenedioxymethamphetamine. In the first experiment a single injection of 5.0 or 7.5 mg/kg MDMA produced hyperthermia in rats maintained at a Ta of 24 degrees C but hypothermia in rats maintained at a Ta of 11 degrees C for 24 h prior to the injection. In contrast, hyperkinesis was induced at both Tas. In the second experiment, the effects of acute MDMA administration was compared in rats maintained at a standard Ta of 24 degrees C and in rats which were placed in a cool (11 degrees C) room for a brief (90-min) period commencing 30 min after the injection. The brief exposure to the cool environment produced significant attenuation of MDMA-induced hyperthermia but did not affect the magnitude of hyperkinesis. The implications of the results for the understanding of the thermotoxic effects of MDMA in human drug users are discussed. PMID- 7855210 TI - Platelet adenylate cyclase activity in Israeli victims of Iraqi Scud missile attacks with post-traumatic stress disorder. AB - Platelet adenylate cyclase activity was measured in 16 control subjects and 16 patients who developed post-traumatic stress disorder (PTSD) as a result of damage inflicted on their homes during the Iraqi Scud missile attacks on Israel which occurred during the 1991 Gulf War. There were no differences in basal, NaF stimulated, PGE1-stimulated or forskolin-stimulated activity between controls and PTSD subjects. Epinephrine inhibition of forskolin-stimulated activity, an effect mediated by alpha 2 adrenergic receptors, was slightly but not significantly increased in the PTSD patients compared to the controls, while 5-HT induced inhibition, an effect mediated by putative 5-HT1a-like receptors, was unchanged. The relationship of these activities to measures of anxiety and depression in these patients is discussed. PMID- 7855211 TI - Effects of chronic phenylpropanolamine infusion and termination on body weight, food consumption and water consumption in rats. AB - The present study determined the effect of chronic PPA infusion and withdrawal on weight regulation. Male Sprague-Dawley rats received PPA (0, 90 or 180 mg/kg) via miniosmotic pumps for 2 weeks. Body weight and food and water consumption were measured daily before, during, and for 2 weeks after PPA infusion. Additionally, body weight was measured once 6 weeks after the last day of drug administration. PPA infusion produced dose-dependent reductions in body weight and food consumption throughout drug administration. During the first week of PPA termination, food consumption returned to control levels; however, body weights of drug-treated animals remained below those of controls throughout the 6-week post-drug period. PPA depressed water intake during the first week of drug administration, but tolerance to this effect developed by the second week of administration. These results suggest chronic PPA infusion produces persistent appetite suppression and weight loss and that discontinuation of PPA does not result in hyperphagia or rapid weight gain. These findings may have clinical significance for the many individuals who wish to lose weight but have difficulty reducing intake without pharmacologic assistance. PMID- 7855212 TI - Low dose of 1,3-di(2-tolyl)guanidine (DTG) attenuates MK-801-induced spatial working memory impairment in mice. AB - MK-801 (30-100 micrograms/kg, SC) impaired spontaneous alternation behavior of mice, a behavior related to the spatial working memory. 1,3-Di-(2-tolyl)guanidine (DTG), (+)-pentazocine and (+)-SKF 10,047 (100 micrograms/kg, SC), putative sigma agonists, administered 10 min before MK-801, partially but significantly reversed the impairment, without affecting the concomitant hyperlocomotion. The antagonizing effects by DTG were prevented by BMY-14802 (5 mg/kg, IP), a purported sigma antagonist. These findings suggest that, at low doses, sigma ligands may modulate the N-methyl-D-aspartate dependent memory processes. PMID- 7855213 TI - Exposure to mild stress enhances the reinforcing efficacy of intravenous heroin self-administration in rats. AB - The effect of a mild footshock on intravenous heroin self-administration was examined in male rats. Animals in the stress condition were exposed to 10 min of intermittent footshock (0.5 mA; 0.5 s on, with a mean off period of 40 s) before each of four daily self-administration sessions. Animals in the control group were not exposed to footshock. Following acquisition of heroin-reinforced behavior (100 micrograms/kg per infusion), during which no group differences emerged, animals were placed on a progressive ratio schedule of reinforcement and were subsequently tested under a decreasing series of doses. Animals exposed to footshock before each drug session had higher rates of lever pressing for heroin and achieved higher final ratios on the progressive ratio schedule than animals in the control group at the higher doses of heroin. Thus, under the conditions of this experiment, exposure to mild intermittent stress appeared to enhance the reinforcing efficacy of heroin. The parameters of footshock used in the present study, and its relation to drug availability may characterize conditions under which stress leads to increased opioid abuse. PMID- 7855214 TI - Pharmacologic treatment of schizoaffective disorder. AB - In contrast to the considerable systematic study of the pharmacologic treatment of schizophrenia and mood disorders, the pharmacologic treatment of schizoaffective disorder has been relatively ignored. The authors reviewed the available literature regarding the pharmacologic treatment of schizoaffective disorder. The total number of controlled studies of the acute and prophylactic treatment of schizoaffective disorder was small and few used modern criteria to define the disorder. In studies of schizoaffective disorder, bipolar type (manic), lithium and antipsychotics produced comparable albeit incomplete responses, except in highly agitated patients when antipsychotics exerted superior efficacy. The combination of lithium and antipsychotics appeared to be superior to antipsychotics alone for schizoaffective, bipolar type patients. In the only controlled study of schizoaffective disorder, depressed type, the presumed superiority of combined antidepressant and antipsychotic treatment to antipsychotic alone was not found. Although combined antipsychotic and thymoleptic treatment represents common prophylactic management of schizoaffective disorder in clinical practice, the efficacy of this strategy has not been studied in controlled trials. Advances in the nosology of schizoaffective disorder, emerging epidemiologic data demonstrating large numbers of patients with this disorder in clinical populations, and preliminary evidence that clozapine may have combined antipsychotic and thymoleptic properties as well as efficacy in both the psychotic and affective components of schizoaffective disorder, suggest that renewed interest in the diagnosis and treatment of this disorder may lead to improved delivery of care for this understudied but seriously ill group of patients. PMID- 7855216 TI - Effects of flunitrazepam on responses to lateralized visual stimuli: evidence for cerebral asymmetry of execution of manual movements to targets in contralateral and ipsilateral visual space. AB - In order to examine the effects of benzodiazepines on response execution by the left and right hemisphere, flunitrazepam (1 mg) or placebo was administered to healthy, right handed volunteers in two separate experiments. In experiment 1, drug was administered daily during a treatment period of 8 days, and subjects were instructed to fixate vision centrally and to execute laterally directed manual responses corresponding to the position of visual stimuli presented in either the right or left hemifield. Experiment 2 was performed with a single dose and cross-over design, and subjects responded to the laterally presented visual stimuli by key press of a centrally positioned response device, i. e. neither detection of position of the stimulus in space nor response selection was required before initiation of the response. In experiment 1, intake of flunitrazepam generally increased reaction time more during response execution by the left as compared to the right hemisphere, and the most pronounced effect was observed on responses with the right hand, directed across the body axis, to visual stimuli presented in the left visual field. In contrast to these observations, in experiment 2, flunitrazepam impaired responses with the right and left hand practically to the same extent. Together, the results indicate that benzodiazepines may affect manual responses executed by left and right hemisphere differently, and that this asymmetry may be related to a stimulus-response compatibility effect in tasks that require response selection. PMID- 7855215 TI - Neuronal mechanisms of the attentional dysfunctions in senile dementia and schizophrenia: two sides of the same coin? AB - Deficits in early stages of information processing, specifically the inability to "disattend" irrelevant stimuli and to selectively allocate processing resources (i.e., hyperattention), have been associated with the development of psychotic symptoms. Opposite deficits, i.e., the failure to attend and select stimuli, and to divide attention (i.e., hypoattention), represent a major variable in the development of dementia. The hypothesis that hyperattention and hypoattention are mediated via cortical cholinergic hyperactivity and hypoactivity, respectively, is discussed. Several lines of evidence support the role of cholinergic hyperactivity in the development of psychotic symptoms, including the therapeutic effects of anticholinergic drugs in schizophrenic patients, the psychotic effects of chronic exposure to irreversible cholinesterase inhibitors, and the worsening of psychotic symptoms as a result of the treatment with cholinomimetic compounds. The potent impairments of attentional abilities as a result of the administration of muscarinic antagonists in intact subjects, and the attentional effects of cholinomimetic compounds in demented patients are two examples of the evidence that supports the role of cholinergic hypofunction in the cognitive impairments of dementia. A neuronal model of dopamine-GABAergic modulation of cortical acetylcholine is proposed on the basis of evidence indicating that nucleus accumbens dopamine, via a GABAergic pathway to the substantia innominata of the basal forebrain, modulates cortical acetylcholine release. The available evidence confirms several predictions derived from this model, including the dopaminergic regulation of cortical acetylcholine (ACh) release, the bidirectional modulation of this release by benzodiazepine receptor (BZR) agonists and inverse agonists, and the antipsychotic effects of BZR agonists. Bidirectional deviations in the activity of cortical cholinergic inputs are hypothesized to represent a major neuronal substrate of the attentional dysfunctions associated with, or even underlying, the development of psychotic symptoms and dementia. PMID- 7855217 TI - Binding of antidepressants to human brain receptors: focus on newer generation compounds. AB - Using radioligand binding assays and post-mortem normal human brain tissue, we obtained equilibrium dissociation constants (Kds) for 17 antidepressants and two of their metabolites at histamine H1, muscarinic, alpha 1-adrenergic, alpha 2 adrenergic, dopamine D2, serotonin 5-HT1A, and serotonin 5-HT2 receptors. Several newer antidepressants were compared with older drugs. In addition, we studied some antimuscarinic, antiparkinson, antihistamine, and neuroleptic compounds at some of these receptors. For the antidepressants, classical tricyclic antidepressants were the most potent drugs at five of the seven receptors (all but alpha 2-adrenergic and 5-HT1A receptors). The chlorophenylpiperazine derivative antidepressants (etoperidone, nefazodone, trazodone) were the most potent antidepressants at alpha 2-adrenergic and 5-HT1A receptors. Of ten antihistamines tested, none was more potent than doxepin at histamine H1 receptors. At muscarinic receptors antidepressants and antihistamines had a range of potencies, which were mostly weaker than those for antimuscarinics. From the in vitro data, we expect adinazolam, bupropion, fluoxetine, sertraline, tomoxetine, and venlafaxine not to block any of these five receptors in vivo. An antidepressant's potency for blocking a specific receptor is predictive of certain side effects and drug-drug interactions. These studies can provide guidelines for the clinician in the choice of antidepressant. PMID- 7855218 TI - Sensitive and rapid behavioral differentiation of N-methyl-D-aspartate receptor antagonists. AB - Behavioral effects of PCP-type noncompetitive antagonists of N-methyl-D-aspartate (NMDA) receptors overlap with those of a host of other centrally acting compounds. In the present experiment, locomotor activity and performance on an inverted screen test in untrained mice were used to differentiate PCP-type non competitive NMDA antagonists from other drug classes. These uncompetitive NMDA antagonists [PCP, dizocilpine, (-)-MK-801, TCP, (+)-SKF 10,047, dextrorphan, ketamine] produced dose-related increases in locomotor activity and the percentage of mice falling off an inverted, elevated wire mesh screen. Both effects demonstrated stereoselectivity, occurred at comparable dose levels, and were within the range of doses producing other biological effects (e.g., anticonvulsant). The potencies of these drugs for producing behavioral effects were positively correlated with affinities for PCP ([3H]MK-801) but not sigma([3H]SKF 10,047) receptors. Although muscarinic antagonists (benactyzine, atropine) produced effects in the same direction, locomotor stimulation was small and occurred at lower doses than those inducing screen failures. Competitive NMDA antagonists (LY 274614, LY 233536, CPP, NPC 12626), sigma receptor ligands (DTG, dextromethorphan), postsynaptic dopamine agonists (quinpirole, SKF 38393) and antagonists (haloperidol, SCH 39166), and some depressant compounds (morphine, diazepam) increased failures on the screen test but decreased locomotor activity. Ligands of the polyamine regulatory site of the NMDA receptor (ifenprodil, SL 82.0715-10) and the AMPA receptor antagonist NBQX decreased locomotor activity without increasing screen failures. An antagonist of the strychnine-insensitive glycine receptor (7-chlorokynurenic acid) did not affect performance on either test. Psychomotor stimulants (cocaine and methamphetamine) stimulated locomotor activity without affecting screen performance. The only false positives occurred with barbiturates (pentobarbital, phenobarbital). Nonetheless, the present procedure demonstrates excellent sensitivity and power for rapid discrimination of uncompetitive NMDA antagonists. PMID- 7855220 TI - Differential effects of the serotonin1A agonist, 8-OH-DPAT, on masculine and feminine sexual behavior of the ferret. AB - Administration of the serotonin (5-HT)1A receptor agonist 8-hydroxy-2-(di-n propylamino)tetralin (8-OH-DPAT) facilitates the expression of masculine sexual behavior in male and female rats as well as in male rhesus monkeys and inhibits lordosis behavior in female rats. In the present study the effects of 8-OH-DPAT on masculine coital and feminine proceptive and receptive behaviors were evaluated in the ferret, a carnivore. Doses of 8-OH-DPAT (0.1 or 0.2 mg/kg) that facilitate masculine sexual behavior in rats inhibited masculine sexual behavior in castrated, estradiol benzoate (EB)-treated male ferrets. Lower doses of 8-OH DPAT (5 or 10 micrograms/kg) had no effect on the expression of masculine sexual behavior in either males or females. In contrast to the female rat, administration of 8-OH-DPAT significantly facilitated receptive behaviors in ovariectomized, EB-treated female ferrets. None of the doses of 8-OH-DPAT tested modified proceptive behaviors of gonadectomized, EB-treated male or female ferrets, as assessed in a T-maze in which the subjects could choose to approach either a castrated, sexually inactive male or a castrated, testosterone-primed stud male. Thus whereas the 5-HT1A receptor agonist 8-OH-DPAT facilitates masculine sexual behavior and inhibits lordosis in the rat, it inhibits masculine sexual behavior and facilitates receptivity in the ferret. The different effects of 8-OH-DPAT observed in these two species may reflect differences in the neural control of their masculine coital and feminine receptive responses, respectively. PMID- 7855219 TI - Effects of naloxone on diurnal rhythms in mood and endocrine function: a dose response study in man. AB - This study investigated diurnal variations in the affective and endocrine response to opioid blockade in man and whether there were effects related either to the dose of naloxone or the time of day at which it was given. Normal male subjects were given an intravenous bolus of either 0.2 mg/kg (study 1) or 1 mg/kg naloxone (study 2) or control infusions at two time points (0900 or 1800 hours) in a single-blind crossover design. Before and following each infusion, mood was measured by the Profile of Mood States (POMS) and a visual analogue scale (VAS), and blood samples taken at 15-min intervals. Cortisol, LH ACTH and vasopressin (study 2 only) were measured. Blood pressure and heart rate were also monitored. The lower dose of naloxone had no effect on overall mood (POMS), though tension and confusion were increased in the afternoon. The VAS showed increased depression in the afternoon, and heightened tension, sleepiness and reduced ability to concentrate at both times of day. The higher dose increased overall dysphoria at both time points, though the tension and depression subscales were not altered. VAS depression and tension were increased, and there were changes in sleepiness. Subjective reports showed that 45% of the subjects correctly identified the drug treatment at the lower dose compared with 89% at the higher one. ACTH increased after both doses of naloxone irrespective of time of day. Cortisol was also raised by naloxone; the effect was greater in the afternoon for the lower dose, but not the higher.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7855221 TI - The stimulant effect of modafinil on wakefulness is not associated with an increase in anxiety in mice. A comparison with dexamphetamine. AB - Modafinil is a new drug used in the treatment of narcolepsy. Its administration in mice induced a dose-dependent increase in locomotor activity. The effects of modafinil were compared with those of dexamphetamine on three tests that assessed the anxiety level (drugs were used at doses which induced a roughly similar stimulation of locomotor activity). Dexamphetamine increased the latency of exploration of a white compartment, increased thigmotaxis in an open-field and decreased the time spent in the open arms of an elevated plus-maze. None of these responses was significantly modified by modafinil. We conclude that modafinil does not share the anxiogenic effects of dexamphetamine. PMID- 7855222 TI - Sensitization and tolerance to the discriminative stimulus effects of mu-opioid agonists. AB - The discriminative stimulus effects of several mu-opioid agonists were examined under conditions of opioid sensitization or tolerance, i.e., before and after 1 week SC infusions of naloxone or mu-opioid agonists. Rats were trained to discriminate 3.0 mg/kg morphine from saline using a two-lever, discrete trial, shock-avoidance/escape procedure. The rats generalized completely to morphine, fentanyl, meperidine, buprenorphine, and etorphine, and partially to pentazocine. A 7-day infusion of naloxone (0.3 mg/kg per h) potentiated the discriminative stimulus effects of all of these drugs. The magnitude of the increased potency varied indirectly with the efficacy of the mu-opioid agonists; potency ratios (pre-infusion ED50/post-infusion ED50) ranged from 1.58 (etorphine) to 3.58 (pentazocine). Stimulus generalization to morphine, fentanyl, and meperidine also was examined following infusions of equieffective doses of each of these three drugs. Differences among drugs were generally small, and failed to reach statistical significance. Nonetheless, the induction of mu-opioid tolerance did seem to vary with the efficacy of the three mu-opioid agonists. Thus, meperidine (6.25 mg/kg per h), which has the lowest efficacy of the drugs infused, produced the greatest shift to the right of the stimulus-generalization curves of these three drugs; the post-meperidine PR ranged between 0.40 and 0.61. Fentanyl (0.1 mg/kg per h), a drug with a higher efficacy at mu-opioid receptors, did not produce tolerance to the discriminative stimulus effects of morphine, fentanyl, or meperidine; potency ratios ranged from 0.50 to 0.75. Potency ratios for buprenorphine, etorphine, fentanyl, meperidine, and morphine after 7-day morphine infusions (0.75 mg/kg per h) ranged from 0.38 (buprenorphine) to 0.80 (etorphine). Morphine induced significant tolerance only to the discriminative stimulus effects of fentanyl. Our results suggest that different cellular mechanisms underlie the development of tolerance and sensitization to the discriminative stimulus effects of mu-opioid agonists. PMID- 7855223 TI - Influence of 5-HT3 receptor antagonists and the indirect 5-HT agonist, dexfenfluramine, on heroin self-administration in rats. AB - The purpose of the present study was to examine the effects of the 5-HT3 antagonists ondansetron and MDL72222, and the 5-HT releaser and reuptake inhibitor dexfenfluramine, on intravenous heroin self-administration by Wistar rats. Using separate squads of animals, two separate schedules of heroin reinforcement were used; a relatively low dose (0.03 mg/kg per infusion) made available under a FR5 schedule for 1 h each day, and a moderate heroin dose (0.1 mg/kg per infusion) available under a FR1 schedule for 2 h each day. Following the acquisition of stable levels of responding across days, both naloxone pretreatment (0.25 mg/kg SC) and halving the heroin infusion dose produced increases in operant responding for heroin at each concentration. Neither ondansetron (0.01-1 mg/kg SC) nor MDL72222 (0.1-3 mg/kg SC) pretreatment influenced heroin self-administration. Chronic treatment (5 day) of ondansetron (0.01-0.1 mg/kg) was similarly ineffective. However, dexfenfluramine (0.5-2.5 mg/kg IP) consistently reduced heroin self-administration at doses producing only modest decreases in food responding. These findings are in contrast to place conditioning studies, which show that 5-HT3 antagonists but not indirect 5-HT agonists block a morphine-induced place preference. Reasons for such discrepancies remain to be determined. PMID- 7855224 TI - Drug effects on response duration differentiation. I: Differential effects of drugs of abuse. AB - Rats were trained to respond under a response duration differentiation schedule in which responses on a lever were reinforced if lever press durations were greater than or equal to 1.00 s but were also less than 1.30 s. Dose-effect curves were generated for cocaine, methamphetamine, pentobarbital, phencyclidine, delta-9-tetrahydrocanninabol (delta 9-THC), and morphine. All drugs produced dose dependent decreases in accuracy (the percentage of total response durations that were reinforced); however, the degree to which changes in accuracy were accompanied by changes in response rates varied among drugs. Pentobarbital and morphine affected primarily longer (> 1.3 s) response durations, phencyclidine and delta 9-THC affected primarily shorter response durations, whereas cocaine and methamphetamine affected both shorter and longer response durations. High doses of methamphetamine and cocaine increased the dispersion of response duration distributions with increasing dose, whereas higher doses of pentobarbital, delta 9-THC and morphine did not increase dispersion of response duration distributions as much. These data show that behavior under this novel schedule is differentially sensitive to a number of pharmacologic manipulations, and that the schedule can provide a useful addition to the analysis of drug effects upon behavior. PMID- 7855225 TI - A low dose of subcutaneous nicotine improves information processing in non smokers. AB - Many studies have found that cigarette smoking or nicotine improves mental functioning in abstinent smokers. An unresolved issue is whether this improvement is due primarily to a direct facilitation of performance or to relief of the impairment caused by nicotine withdrawal. We evaluated the performance of 12 non smokers before and twice (15 and 45 min) after a subcutaneous injection of 0.8 mg nicotine, 0.8 ml saline, and a control no treatment, on a choice reaction time (RT) task. Each treatment was given on a separate day; the control day was given on the first session. The order of nicotine and saline was balanced between subjects, and injections were given double-blind. The RT task manipulated stimulus and response processing. These manipulations consisted of two levels of stimulus complexity and two levels of response complexity, resulting in four task conditions. These manipulations along with latency measures of the event-related potential were used to identify the components of processing that mediated nicotine's effects on performance. During each active drug session blood nicotine levels, cardiovascular, and subjective responses were measured before and after each of the three tests (pre-drug, 15 min and 45 min post-drug). For the information processing measures only the comparisons of the pre- and 15-min post test showed significant drug effects. Nicotine compared to saline significantly increased the number of responses at the fast end of the RT distribution. However, there were no changes in accuracy. Nicotine also speeded mean RT compared with saline or the control day, but the effects were only significant for the control-nicotine comparison.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7855227 TI - Ethological study of the effects of tetrahydroaminoacridine (THA) on social recognition in rats. AB - Two major difficulties confront ethopharmacological investigations on cognitive abilities such as social recognition in drug-treated animals involved in free social interactions. The first concerns the choice of the most relevant behaviours, those reflecting the cognitive abilities attributed to the animals and assessing the specificity of the drug activity, and those reflecting non specific drug effects. The second refers to the experimenter's awareness that in contrast to physical objects, social stimuli respond to drug-treated subjects and that their own level of responsiveness may influence the changes of drug-treated subjects' social interest. In addition, their contribution may vary according to the different treatments the drug-treated subjects receive. In examining the effects of tetrahydroaminoacridine (THA) at doses of 0.3, 1 and 3 mg/kg on the ability of adult male rats to recognize previously encountered conspecifics, we attempted to take into consideration such difficulties. A detailed behavioural profile of drug-treated rats was reported to separate specific from non-specific effects of THA. In addition, rats were assigned an index of responsibility for contact which takes into account the interactive dimension of each dyad and allows relevant comparisons between different treatments. The doses of THA which were found to decrease the duration of exploration of a familiar juvenile were also found to decrease the number of contacts initiated by the drug-treated subjects. THA induced a relative increase in body care by comparison to saline treatment. However, it had no effect of locomotor activity and rearing of the subjects. These findings enable dissociation of the effects of THA on cognitive versus non-cognitive processes. PMID- 7855226 TI - Effect of pindolol on the L-5-HTP-induced increase in plasma prolactin and cortisol concentrations in man. AB - Previous studies with direct-acting serotonin (5-HT) agonists and antagonists have demonstrated that stimulation of 5-HT1A, 5-HT1C and 5-HT2 receptors may promote cortisol and prolactin (PRL) secretion in man. There is also evidence that 5-HT1C/2 receptor stimulation contributes to the cortisol and PRL responses following administration of the 5-HT precursor, L-5-hydroxytryptophan (L-5-HTP), in man. To clarify the possible contribution of 5-HT1A receptor stimulation to the ability of L-5-HTP to stimulate cortisol and PRL secretion in man, the effect of pindolol, a beta adrenoceptor antagonist that is also a 5-HT1A partial agonist, on the L-5-HTP-induced increases in cortisol and PRL secretion, was examined in 12 normal male volunteers. Pretreatment with pindolol, 30 mg orally, significantly inhibited the PRL but not the cortisol response to L-5-HTP, 200 mg PO. Pindolol alone decreased basal plasma PRL levels and increased basal plasma cortisol levels, possibly due to 5-HT1A antagonist and agonists effects, respectively. These data, coupled with observations from other studies, suggest that the L-5-HTP-induced increase in PRL but not cortisol secretion requires 5 HT1A receptor activation. PRL secretion due to 5-HT formed from exogenous L-5-HTP may require the availability of both intact 5-HT1A and 5-HT2/5-HT1C receptors, since blockade of either receptor type inhibited the PRL response to L-5-HTP. The implication of this synergistic effect for interpretation of neuroendocrine studies involving the serotonergic system in man is discussed. PMID- 7855228 TI - Effects of (R)-alpha-methylhistamine and scopolamine on spatial learning in the rat assessed using a water maze. AB - The effects of (R)-alpha-methylhistamine ((R)-alpha-MeHA, a selective H3-receptor agonist) and scopolamine (SCOP, a muscarinic antagonist) were investigated on spatial learning and memory in the rat (Hooded Lister) using a water maze (WM). (R)-alpha-MeHA treatment (6.3 and 10 mg/kg IP) had no apparent effect on spatial learning but did result in enhanced spatial recall at the higher dose, assessed by a transfer (probe) test after training. In contrast, SCOP (0.5 mg/kg IP) induced a learning and memory deficit measured both during and after training. In animals treated with (R)-alpha-MeHA and SCOP, (R)-alpha-MeHA partially (6.3 mg/kg) and completely (10 mg/kg) reversed the SCOP-induced deficit during the training phase, while in the post-training transfer test, (R)-alpha-MeHA (10 mg/kg) significantly reduced the SCOP-induced memory deficit. None of the treatments described resulted in impaired visual acuity as demonstrated by a raised platform test. These results are consistent with a role for histamine in cognitive processes and suggest a possible interaction between central histamine and cholinergic mechanisms associated with rodent spatial learning and memory. PMID- 7855229 TI - Antagonism of amphetamine-induced disruption of latent inhibition in rats by haloperidol and ondansetron: implications for a possible antipsychotic action of ondansetron. AB - Latent inhibition (LI) is a behavioural phenomenon whereby preexposure to a stimulus without reinforcement interferes with the formation of subsequent associations to that stimulus. Using preexposure to a tone stimulus which subsequently serves as a conditioned stimulus for suppression of licking, we have confirmed that LI is disrupted by a low dose of amphetamine. Haloperidol was able to prevent this effect of amphetamine. Ondansetron, a selective and potent 5HT3 receptor antagonist, was also shown to be effective at blocking the amphetamine induced disruption of LI at a dose of 0.01 mg/kg, but not at 0.1 mg/kg. In addition, it was demonstrated that ondansetron could enhance LI; using only ten preexposures, no LI was obtained in the saline group, but was apparent in animals given ondansetron, an effect which has been previously shown with haloperidol. Haloperidol, at the higher dose used, reduced suppression of licking, however, ondansetron at the effective dose had no such effect. It is concluded that ondansetron is able to attenuate increases in dopamine activity, produced pharmacologically with amphetamine without affecting baseline dopamine activity. The implications of these findings for a possible antipsychotic action of ondansetron are discussed. PMID- 7855232 TI - The island syndrome in rodent populations. AB - Populations of rodents isolated on islands often show systematic differences in demography, reproduction, behavior, and morphology when compared to mainland populations. These differences, termed the island syndrome, include higher and more stable densities, better survival, increased body mass, and reduced aggressiveness, reproductive output, and dispersal. We synthesize information in the literature on island rodent populations and construct a conceptual model to explain the island syndrome. Population density and other manifestations of the island syndrome are predicted to increase with island isolation and to decrease with island area. The effect of isolation is direct by limiting dispersal, while the effect of area is less direct. As area increases, predators, competitors, and habitat structure increase in diversity. We suggest that the intensity or absence of density-depressing factors (primarily predation in communities comprised of only a few morphologically and trophically divergent species) is primarily responsible for the area effect and serves as a principal factor differentiating island from mainland populations of rodents. Other characteristics associated with the island syndrome may be the result of both short-term and long-term processes or responses. Short-term responses include reproductive, body size, and behavioral changes that may be phenotypic reaction norms in response to higher island densities. Thus, higher densities lead to reduced reproductive output, which then leads to greater body size. Initial behavioral differences may be owing to better survival and reduced dispersal, which result in less population turnover, greater neighbor familiarity, and less aggression. Long-term changes may be due to directional selection for reduced dispersal, increased body size in response to increased intraspecific competition, reduced reproductive output (smaller litters and delayed maturation) in response to reduced mortality schedules, and reduced aggressiveness. While the model is specific to rodent populations, the conclusions may be applicable to other systems if characteristics such as body size, vagility, and community composition are considered. PMID- 7855231 TI - Seroquel (ICI 204,636) restores prepulse inhibition of acoustic startle in apomorphine-treated rats: Similarities to clozapine. AB - Seroquel (ICI 204,636) is a mixed D2/5HT2 antagonist with a preclinical profile suggestive of potential antipsychotic efficacy. We compared seroquel to clozapine in an animal model of sensorimotor gating deficits in shizophrenic patients. Like schizophrenic patients, rats treated with apomophrine (APO) exhibit deficits in prepulse inhibition (PPI) of acoustic startle. The ability of antipsychotics to restore PPI in APO-treated rats correlates (Rs = 0.991) with their clinical potency. Seroquel and clozapine both restore PPI in APO-treated rats. Seroquel's restoration of PPI in apomorphine-treated rats follows simple monotonic ascending dose-response properties, and is not accompanied by consistent changes in startle reflex amplitude. Seroquel's profile in this PPI model mimics that of other antipsychotics. PMID- 7855230 TI - Effects of accumbens DALA microinjections on brain stimulation reward and behavioral activation in intact and 6-OHDA treated rats. AB - The effects of bilateral nucleus accumbens microinjections of d-ala-met enkephalinamide (DALA) were assessed in behavioral activation and lateral hypothalamic self-stimulation (LHSS) rate-frequency curve-shift paradigms in normal and accumbens 6-OHDA (4.0 micrograms) treated rats. Microinjections of DALA (2.5 micrograms/microliters) in the behavioral activation paradigm had little effect on normal activity; however, DALA administered to 6-OHDA treated rats produced a significant overall increase in locomotion. The 6-OHDA DALA induced locomotion effect peaked at 2 weeks after 6-OHDA treatment and then returned to baseline levels by week 5 post-treatment. Using LHSS, DALA tested over a range of doses (2.5, 5, 10, 20 micrograms/microliters) displayed a weak biphasic reward effect only at the highest dose, which was characterized by an initial suppression followed by an elevation. DALA significantly depressed initial operant motor/performance in LHSS in a dose dependent fashion. Microinjections of the normally ineffective low dose of DALA (2.5 micrograms/microliters) following accumbens 6-OHDA treatment produced a significant LHSS reward decrease 2 weeks post-treatment, while LHSS motor/performance was relatively unaffected. Results are discussed in terms of opiate-dopamine and limbic-motor interactions. PMID- 7855233 TI - MR imaging of pineoblastomas. AB - Pineoblastomas, which originate from the pineal gland, are extremely malignant tumors that grow quickly and aggressively. Because they spread so fast and the probability of longterm survival is poor, it is important to diagnose these tumors early. This article discusses magnetic resonance's role in imaging pineoblastomas. MR is particularly effective for this task due to its ability to visualize the pineoblastoma in three different planes, both before and after the administration of gadolinium. PMID- 7855234 TI - Developing curriculum for independent learning. AB - This article describes the evolution of a baccalaureate degree program in radiography designed to develop students' critical thinking and analytical abilities. The curriculum for the program was developed after a review of the literature on student centered learning and encouraging results from a study that showed students responded positively to a problem-solving learning approach. The author describes how the baccalaureate program was implemented and how its student-centered approach gives students the freedom to learn. The author also describes how the new program has affected the attitudes and actions of the students and faculty at the institution. PMID- 7855236 TI - Making the most of clinical education. PMID- 7855235 TI - Early fluoroscopic imaging. PMID- 7855237 TI - In search of an elusive stomach. PMID- 7855238 TI - My cup runneth ... over? Under? Inside? PMID- 7855239 TI - MRI's role in evaluating knee anatomy and injuries. AB - Because its function is related to its bony anatomy, ligamentous structures and integrated muscle groups, the knee is one of the most complex joints in the human body. Not surprisingly, knee injuries rank as one of the major causes of physical disability. Prior to the introduction of magnetic resonance imaging, prompt and accurate diagnosis of knee injuries was a challenge. Now, using MRI, a highly accurate diagnosis can be made in 30 minutes or less without patient discomfort. This article reviews knee anatomy, discusses common injuries and describes magnetic resonance techniques for imaging the knee. PMID- 7855240 TI - [Pathophysiology of fracture healing]. AB - This article briefly summarizes our present knowledge on regulation of proliferation, differentiation and function of bone cells (osteoblasts, osteoclasts) by hormones (1,25-dihydroxyvitamin D3, parathyroid hormone, thyroid hormone, sex steroids, glucocorticoids and calcitonin), cytokines (IL-1, IL-4, IL 6, IL-11 und IFN-gamma) and growth factors (IGF-I, TGF-beta). Interaction of these factors in "basic multicellular units" acting locally on bone surfaces is thought to result in tight coupling of bone formation and resorption in bone remodelling processes. The significance of the latter in different phases of fracture healing, which proceeds from mesenchymal cell proliferation through callus formation to calcification and bone modelling, is emphasized. PMID- 7855241 TI - [Traumatic lesions of the occipitocervical transition]. AB - The availability of better and quicker resuscitation means that more patients with occipitocervical injuries survive. In view of the complex anatomy and functional capabilities of the upper part of the spine it makes sense to discuss injuries to this part separately from any to the lower cervical and thoracolumbar vertebral column. Computerized tomography with additional multiplanar reconstructions, digital radiography and magnetic resonance imaging early in the diagnostic workup improves the likelihood of a quick and satisfactory diagnosis. Our classification of injuries should enable the radiologist to provide the traumatologist with enough information on the damage to bones and soft tissue to allow an accurate assessment of stability, which is mandatory for the selection of appropriate treatment. PMID- 7855242 TI - [Fractures of the cervical spine. Diagnosis in multiple trauma patients]. AB - The purpose of our study was to analyze diagnostic procedures of the cervical spine in severely traumatized patients. Findings in plain radiographs and computed radiography of 234 patients were evaluated. The image quality of the plain radiographs was examined. Casualty reports were evaluated retrospectively. Frequency, distribution and morphology of cervical spine fractures were analyzed: 44 fractures in 35 patients were diagnosed, most of the fractures were located in C2 (20/44). Twenty of the fractures diagnosed in CT were not diagnosed in plain radiography and 7 fractures were uncertain findings; 5 fractures were not detected at the casualty site. A new screening procedure in patients with severe head injury is introduced. PMID- 7855243 TI - [Injuries of the spinal cord]. AB - Every spinal cord injury includes the possibility that neurological symptoms will remain that threaten to reduce the quality of life considerably. Prompt and well planned therapy-often surgical-is required in order to prevent these symptoms. Prompt and relevant diagnostic measures are indicated. MR imaging is the diagnostic modality of choice, since traumatic intramedullary lesions can only be visualized with MRI. Moreover, in the acute stage, MRI findings provide important prognostic information. If MRI is available, it should be carried out in all cases when spinal cord injury is suspected despite the problems involved when examining acutely traumatized patients. PMID- 7855244 TI - [Traumatic lesions of the spine below the axis]. AB - Sports activities and traffic accidents are leading to an increasing incidence of spinal injuries. To assist in correct and quick diagnosis of spinal fractures the radiologist such modern diagnostic tools as computerized tomography, magnetic resonance imaging and digital radiography. Nevertheless. The plain film is of major importance for recognition of the type of fracture from its biomechanical pattern. Apart from this, the radiologist should decide individually what other examination(s) are needed for visualization of the full amount of damage. We found the model of Magerl and co-workers for fracture types and the model of Denis for stability the best, covering almost the entire spine from C3 and L5. The different types of fractures and discoligamentous injuries are discussed with reference to the risks attached of neurological complications and stability. PMID- 7855245 TI - [The traumatized and surgically treated spine. Current diagnostic imaging]. AB - In trauma patients X-ray and CT are the important imaging modalities for detecting instability of the spine and determining the cause of a spinal cord lesion. MRI should be done to demonstrate the spinal cord lesion itself. Operations on spinal injuries are based on X-ray films and CT. Polydirectional tomography is valuable in the assessment of bone healing, determining osteomyelitis with fistulae, pseudarthrosis and imaging of bone graft fusion in the presence of metallic fixation devices. MRI is indicated for diagnosis and ascertaing the prognosis of spinal cord lesions. In the long-term follow-up syrinx, myelomalacia and atrophy can be differentiated. MRI can also be done for osteomyelitis and complications of bone graft fusion. PMID- 7855247 TI - [Sagittal burst fracture of the talus]. AB - Fractures of the talus have a relatively low incidence, accounting for 0.3% of all bone fractures and 3.4% of fractures of bones in the foot. These injuries affect the neck of the talus more frequently than its head or body. Because of the combined traumatic mechanism, sagittal fracture of the talar body is extremely rare; the literature contains only a few case reports, all with severe dislocation of the fragments. Plain film radiographs and CT pictures recorded in a rare case of nondisplaced fracture of the talar body are presented. PMID- 7855246 TI - [Radiology of late damage after spinal cord injuries]. AB - Most patients who have suffered spinal cord injuries now expect a normal life span, so the late complications of these injuries are becoming increasingly frequent. Regular surveillance of the state of the urinary tract and the treatment of impending, even if clinically silent, complications is a well established aspect of follow-up. With an increasing ability to diagnose and treat the neurological complications, surveillance of the state of the spinal cord has now assumed great importance. Magnetic resonance imaging (MRI), or computerized tomography (CT) with myelography if MRI is contra-indicated is the method of choice and can demonstrate the pathology with great clarity. In most patients, midline sagittal T1W images are sufficient for screening purposes and for monitoring the success of treatment. Operative, imaging and postmortem studies have shown that the two main changes that occur are: (a) atrophic and (b) cystic the microcystic and myxoid gel changes of myelomalacia, focal cysts and the larger, more expansive, syringomyelia. As yet, there is no standardization of terminology to describe the various pathological and radiological states. This is critical as only one condition, syringomyelia, is currently amenable to definitive surgery and without conformity, comparisons of incidence in different populations and assessment of the results of surgery are impossible. The published small studies of predominantly symptomatic patients at varying stages of chronicity give differing incidences of changes. Preliminary results of a surveillance MRI study of the spinal cord changes in 153 patients who had had a spinal cord injury over 20 years previously are presented. Atrophy was present in 62%, myelomalacia in 54%, syringomyelia in 22%, focal cysts in 9% and disruption in 7%. PMID- 7855249 TI - [Unusual calcinosis of tibial muscles. Myonecrosis calcificans of the tibial muscles]. PMID- 7855248 TI - [Rheumatoid arthritis of the craniocervical transition. Detection of inflammatory changes in contrast CT and MRI]. AB - A total of 136 patients with rheumatoid arthritis underwent MRI with sagittal T1 weighted spin echo sequences before and after i.v. administration of Gd-DTPA and with a 15-min delay. In addition, T2-weighted gradient echo sequences were performed. Conventional radiographs, including tomography in sagittal and a.p. planes, were also taken of all patients; 51 were also examined by CT before and after i.v. administration of contrast medium and in addition with a 15-min delayed series. The signal intensities of MRI and the changes in density caused by contrast uptake on CT were examined visually and measured quantitatively. The inflammatory changes were classified in four phases by the MRI and CT findings and histological results. A correlation (p < 0.05) was found with the erythrocyte sedimentation rate. MRI was superior to CT in 10% of cases. A discrete effusion in the anterior junction was missed in 4 cases and a hypervascular pannus formation in 1 case by CT. The CT was superior to the other methods in detecting bony lesions and calcifications in the atlantodental region. The local activity of the inflammatory changes can be graded by classifying them with contrast enhanced MRI and CT, which yield an exact result for better monitoring during therapy. PMID- 7855250 TI - Biologically active quinazolones. PMID- 7855251 TI - In search of ideal antihypertensive drugs: progress in five decades. PMID- 7855252 TI - The natural polyamines and the immune system. PMID- 7855253 TI - Drugs for treatment of patients with high cholesterol blood levels and other dyslipidemias. PMID- 7855254 TI - [From the window of the "Calcium and Muscle Contraction" Laboratory]. PMID- 7855255 TI - [The ground of biological research]. PMID- 7855256 TI - [Evolution of the brain and genesis of the mind]. PMID- 7855258 TI - [Two birds with one stone: a proposal of new institution for evolutional taxonomy of molecular biology]. PMID- 7855257 TI - [Genetic factors potentially responsible for human evolution]. PMID- 7855259 TI - [Missing genes]. PMID- 7855260 TI - [SHINKA--unhappy translated word of evolution]. PMID- 7855261 TI - [The reason for Haeckel's dictum is the immortality of genes]. PMID- 7855262 TI - [Evolution of genes and natural selection]. PMID- 7855263 TI - [Hyperthermophiles and early evolution of life]. PMID- 7855265 TI - [Radial symmetry-->bilateral symmetry-->radial symmetry?]. PMID- 7855264 TI - [Genome evolution looked at by a wheat geneticist]. PMID- 7855266 TI - [Evolution and the brain--the problem of scientific objectivity]. PMID- 7855268 TI - [Historical constraints on life]. PMID- 7855267 TI - [Evolution and biodiversity]. PMID- 7855269 TI - [Evolution based upon genetic information]. PMID- 7855270 TI - [Evolution of plant viruses]. PMID- 7855271 TI - [Evolution of virus and host organism]. PMID- 7855272 TI - [Chromosome evolution in higher organisms (the minimum interaction theory)]. PMID- 7855273 TI - [Evolution at levels of DNA and chromosomal bands]. PMID- 7855274 TI - [Molecular biological basis of karyomorphology]. PMID- 7855275 TI - [Evolution of sex determination and sex chromosomes]. PMID- 7855276 TI - [Evolutionary influences on cell-cell communication--from aspects of morphogenesis]. PMID- 7855277 TI - [Evolution of tissue specific genes: an evolutionary link between phenotypic and molecular levels]. PMID- 7855278 TI - [Evolution of developmental mechanisms]. PMID- 7855279 TI - [Ontogeny and phylogeny: the role of egg cleavage modes in phylogenetic branching]. PMID- 7855280 TI - [Evolution of chordates inferred from pattern of embryonic development]. PMID- 7855281 TI - [Regulatory genes of flower development: members of the MADS box gene family]. PMID- 7855282 TI - [Genetics of shoot morphogenesis]. PMID- 7855283 TI - [Diversity and evolution of cytokine receptors]. PMID- 7855284 TI - [The major histocompatibility complex (MHC) and population genetics]. PMID- 7855285 TI - [Origin and evolution of MHC genes]. PMID- 7855286 TI - [Evolution of immunoglobulin and B-cell tolerance]. PMID- 7855287 TI - [The function and evolution of nonclassical class I genes of the major histocompatibility complex]. PMID- 7855288 TI - [Evolution of self-incompatibility in angiosperms]. PMID- 7855289 TI - [Transposon, meiotic drive, and speciation]. PMID- 7855290 TI - [Hybrid inviability and hybrid rescue genes]. PMID- 7855291 TI - [The symbiosis theory and evolution of eukaryotic cells]. PMID- 7855292 TI - [Speciation in plant-insect interactions]. PMID- 7855293 TI - [Plant speciation in oceanic islands]. PMID- 7855294 TI - [Leaf morphogenesis and speciation of rheophytes]. PMID- 7855295 TI - [Evolution of insertions and deletions of nucleotide sequences and their mutation mechanisms]. PMID- 7855296 TI - [Molecular phylogeny of an ancient gene]. PMID- 7855298 TI - [Biodiversity of marine invertebrates and global environment]. PMID- 7855297 TI - [Molecular data and evolution of apogamy in ferns]. PMID- 7855300 TI - [Polymer gels and biological sciences--physics point of view]. PMID- 7855299 TI - [Phylogenetic evolution of eutheria as viewed from molecules]. PMID- 7855302 TI - [Molecular genetic studies on circadian clock of cyanobacteria by bioluminscence reporter]. PMID- 7855303 TI - [Omega-3 fatty acid desaturase genes and genetically engineered enhancement of cold tolerance in higher plants]. PMID- 7855301 TI - [Mitochondrial nuclear division and mitochondriokinesis]. PMID- 7855304 TI - [Remembrance of things past: a career in a chiroptical work]. PMID- 7855305 TI - [Disruption of protein structure in the current CD measurement]. PMID- 7855306 TI - [Cell cycle]. PMID- 7855307 TI - [In memory of Linus Pauling]. PMID- 7855308 TI - TEI-3356, a highly selective agonist for the prostaglandin EP3 receptor. AB - Recently, we cloned cDNAs for the three mouse PGE receptor subtypes, EP1, EP2 and EP3, and the prostacyclin receptor, and established cells that stably express each receptor. We examined the selectivity of TEI-3356, an isocarbacyclin analogue, compared with other EP agonists, sulprostone and misoprostol, using Chinese hamster ovary cells expressing each cloned receptor. TEI-3356 selectively displaced the [3H]PGE2 binding to EP3-expressing cell membranes, but showed very low affinity for both EP1 and EP2. Although TEI-3356 is an isocarbacyclin analogue, it showed low affinity for the prostacyclin receptor. On the other hand, sulprostone strongly displaced the [3H]PGE2 binding to EP1 and EP3, but not to EP2. Misoprostol weakly bound to the three subtypes without selectivity. TEI 3356 decreased the forskolin-induced cAMP formation in a concentration-dependent manner in the EP3-expressing cells, the half-maximal concentration for the inhibition being similar to that of sulprostone but lower than that of PGE2. These results demonstrate that TEI-3356 is a potent and highly selective agonist for the EP3 receptor. PMID- 7855309 TI - Identification and changes in concentrations of prostaglandin H synthase (PGHS) isoforms in rat myometrium at parturition. AB - The isoform(s) of prostaglandin H synthase (PGHS) present in pregnant rat myometrium have been identified and the ontogeny of their expression studied during late gestation and parturition. Concentrations of PGHS have been related to changes in concentration of nuclear and cytosolic estrogen (ER) and progesterone receptors (PR) occurring at this time. Nuclear PR concentrations were maximal on days 16-18 of pregnancy, decreased from days 18 to 22 (delivery) and fell 24 hours postpartum. Nuclear ER concentrations increased significantly from days 20 to 22 of pregnancy and fell postpartum. Whereas the ratio of nuclear ER/PR was firmly in favour of progesterone action on days 16-20 it increased on day 22 corresponding to increased estrogen action. Western immunoblotting with specific antibodies revealed a single 72 kDa PGHS-1 isoform in myometrium at each timepoint. There was no evidence for the inducible PGHS-2 isoform in myometrium. Densitometric analysis showed the concentration of PGHS-1 increased significantly from day 16 to a maximum at the time of delivery on day 22 and decreased immediately afterwards. Expression of the constitutive PGHS-1 isoform is associated with the changing ratio of nuclear ER/PR and may therefore be hormonally regulated. PMID- 7855310 TI - Reduced 5-lipoxygenase metabolism of arachidonic acid in macrophages rrom 1,25 dihydroxyvitamin D3-deficient rats. AB - The peripheral blood monocyte (PBM) migrates into tissues and differentiates into mature tissue macrophages. Previous investigations from our laboratory have demonstrated that PBM have reduced 5-lipoxygenase (5-LO) metabolism of arachidonic acid (AA) and 5-LO activating protein (FLAP) expression as compared to differentiated alveolar macrophages (AM). Moreover, PBM differentiated with 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) displayed increased leukotriene synthesis and a parallel increase in FLAP expression. In the present study, we sought to examine the physiological role of 1,25-(OH)2D3 in the regulation of eicosanoid metabolism in terminally differentiated alveolar and peritoneal macrophages (PM), utilizing a well characterized rat model of vitamin D3-deficiency. AM from vitamin D3-deficient rats demonstrated reduced 5-LO metabolism of AA and a parallel reduction in FLAP expression compared to control rats. Similarly, PM from vitamin D3-deficient rats demonstrated reduced 5-LO metabolism of AA. The effect of vitamin D3 was specific for the 5-LO pathway, not affecting total release of AA or its metabolism via 12-lipoxygenase or cyclooxoygenase (COX) pathways in macrophages. Furthermore, it did not affect COX protein expression in macrophages or type II alveolar epithelial cells. In control animals, 1,25 (OH)2D3 concentrations were greater in bronchoalveolar lavage fluid (2.6-fold) and peritoneal lavage fluid (1.6-fold) than in serum, which may account for the greater FLAP expression in AM and PM than in PBM. These observations suggest that 1,25-(OH)2D3 plays a physiological role in upregulating the 5-LO pathway in tissue macrophages in vivo. PMID- 7855311 TI - Fish oil feeding modulates leukotriene production in murine lupus nephritis. AB - Diets enriched with fish oil (FO) ameliorate kidney disease in the MRL-lpr/lpr murine model of lupus nephritis. Although the mechanisms of this effect are not known, FO is rich in the polyunsaturated fatty acid eicosapentaenoic acid (EPA) which may have profound effects on eicosanoid metabolism. In MRL-lpr/lpr mice, FO feeding reduces renal production of cyclooxygenase metabolites. However, EPA may also affect the metabolism of arachidonate by the 5-lipoxygenase (5-LO) pathway and enhanced production of 5-LO metabolites has been implicated in the pathogenesis of kidney disease in MRL-lpr/lpr mice. We therefore investigated the effects of FO feeding on production of 5-LO metabolites in 20 week old MRL lpr/lpr mice. After 8 weeks of dietary supplementation with FO, both renal hemodynamic function and glomerular histology were improved compared to safflower oil (SO) controls. Amelioration of kidney disease was associated with alterations in the pattern of leukotriene production by macrophages and kidneys from FO fed mice. There was a significant decrease in the production of leukotriene B4 (LTB4) and tetraene peptidoleukotrienes by peritoneal macrophages isolated from mice given FO compared to control animals. Similarly, dietary supplementation with FO decreased renal production of LTB4. Reduced production of tetraene leukotrienes was accompanied by a modest increase in the production of pentaene leukotrienes by macrophages from FO fed mice. We speculate that this modulation of leukotriene production by FO feeding may have beneficial effects on renal disease in autoimmune nephritis. PMID- 7855312 TI - Cellular biology of glomerulosclerosis. AB - The burgeoning literature on glomerulosclerosis makes frequent review of the literature necessary. At this stage, the key processes involved have surely been defined. It is now appropriate to make deductions about possible therapies and to plan experiments and trials. PMID- 7855313 TI - Hemodialysis in the diabetic patient with end-stage renal disease. AB - Diabetes mellitus is now the most common cause of end-stage renal disease (ESRD) in the U.S., and the percentage of ESRD patients with diabetes is increasing yearly. One-year survival in such patients is poorer than in those with other etiologies of ESRD but has improved from 64% to 74% over the past decade. However, overall 5-year survival on dialysis is still less than 20% in this population. It is controversial whether hemodialysis or peritoneal dialysis (CAPD, CCPD) is the best choice. Advantages of hemodialysis include its ready availability and convenience for patients, who are frequently incapacitated by blindness, cerebrovascular disease, and/or amputations. However, patients may tolerate dialytic ultrafiltration poorly due to autonomic neuropathy. Maintenance of vascular access is difficult, which may contribute to inadequate dialysis in some patients. Cardiovascular disease remains the most common cause of death. Management of coronary artery disease is difficult because of the high prevalence of silent ischemia. Control of blood pressure is of paramount importance in preventing cardiovascular complications. Improved survival in diabetics who were dialyzed in a more intensive than usual fashion has been reported recently. In addition, much of the difference in survival rates between diabetics and nondiabetics can be accounted for by the poorer nutritional status in the former group. Thus attention to the dose of dialysis administered and assurance of adequate nutrition should result in improved survival of the diabetic patient on hemodialysis. PMID- 7855314 TI - A paired tracer microinjection technique designed for assessment of single nephron glucose-calcium interactions in the anesthetized rat. AB - The first part of this study evaluates a new paired microinjection technique for studying single-nephron permeability (in this case to calcium) following injection of 5-10 nL of a Ringer solution into a superficial proximal tubule. The mean difference in fractional 45Ca recovery from two identical microinjections into the same nephron site was 2.2 +/- 0.2% for 89 paired microinjections. Individual nephrons therefore normally show differences in calcium permeability with time. However, moment-to-moment variations in ion transport in any one nephron are in a random direction; differences cancel one another out if enough experiments are performed. The technique thus appears well suited to studies where comparisons are made between the acute nephron responses to two test solutions. It specifically overcomes problems of nephron heterogeneity seen in some other micropuncture techniques. The second part of this study uses the new technique to investigate the effects of a raised intratubular D-glucose concentration on single-nephron calcium transport. Urinary 45Ca recoveries from late proximal microinjections were significantly higher when D- (as opposed to L ) glucose was included in the injectate (6.87 +/- 0.88 vs. 5.24 +/- 0.50%; p < .02). The ability of D-glucose to depress tubular calcium reabsorption at distal nephron sites may contribute to the observed hypercalciuria following systemic D glucose loading. It may also be relevant to the acute renal failure accompanying renal stone disease, where a relationship between hypercalciuria, urolithiasis, and the consumption of refined carbohydrates has been proposed. PMID- 7855315 TI - Modification of immunoreactive EGF and EGF receptor after acute tubular necrosis induced by tobramycin or cisplatin. AB - Acute tubular necrosis induced by aminoglycoside antibiotics and various other nephrotoxins is followed by a regenerative process which leads to the restoration of damaged tubules. Several lines of evidence indicate that tubular regeneration is mediated by polypeptide growth factors such as epidermal growth factor (EGF). Previous studies devoted to cisplatin nephrotoxicity have shown that this agent causes tubular cystic degeneration possibly related to an impairment of renal tissue repair. Thus, we examined on a comparative basis the time course of the regenerative response subsequent to tubular damage induced by tobramycin or cisplatin, particular attention being paid to renal EGF and its receptor. Female Sprague-Dawley rats (160-180 g body weight) were treated during 4 consecutive days with daily doses of 200 mg/kg tobramycin i.p. (BID) or 2 mg/kg cisplatin (once a day). Sham-treated rats were given 0.9% NaCl i.p. following the same protocol. Groups of experimental animals (n = 5-10) were terminated at increasing time intervals (1, 4, 7, 14, 21, 60 days) after cessation of treatment. One hour prior to sacrifice, each individual received i.p. 200 mg/kg 5-bromo-2' deoxyuridine (BrdU) for the immunohistochemical demonstration of cell proliferation. Blood was collected at the time of sacrifice in order to assess glomerular filtration rate by measuring serum creatinine and BUN levels. Kidneys were analyzed with respect to total EGF determined by RIA in renal tissue homogenates, and soluble EGF was assayed in extracts prepared by centrifugation. Renal tissue was processed for the immunohistochemical detection of S-phase cells, of EGF, of EGF receptors, and of the intermediate filament vimentin, the latter being used as a marker of epithelium dedifferentiation. In absence of nephrotoxic alterations, EGF was immunolocalized in distal tubules, whereas EGF receptor immunostaining was seen in proximal tubules cells. Vimentin immunostaining was confined to glomeruli and blood vessels. Tobramycin and cisplatin caused acute tubular necrosis in proximal convoluted tubules and proximal straight tubules, respectively. Tissue damage was accompanied by renal dysfunction reflected by an elevation of serum creatinine and BUN levels. Tubular necrosis was followed by a proliferative response indicative of tubular regeneration. Regenerative hyperplasia was associated with a reduction of total immunoreactive EGF due to a decrease of tissue-bound proEGF. Tubules undergoing regenerative repair were characterized by a disappearance of EGF receptors and the presence of immunoreactive vimentin. In tobramycin-treated rats, renal dysfunction lasted for 4-7 days and was fully reversible, as indicated by the return of serum markers to normal values. PMID- 7855316 TI - Postheparin lipolytic activity in acute and chronic renal failure. AB - Lipid profile and postheparin lipolytic activity (PHLA) were investigated in 21 patients with acute renal failure (ARF), 24 with chronic renal failure (CRF), and 23 healthy volunteers. Plasma triglycerides were significantly elevated in ARF (155.19 +/- 72.39 mg/dL) as well as CRF (166.79 +/- 72.36 mg/dL), as compared to controls (89.91 +/- 23.41 mg/dL, p < .001). PHLA was determined at 5, 10, 30, and 60 min after intravenous heparin (100 U/kg) and was observed to be reduced in ARF (7.82 +/- 1.41 mumol FFA/mL/h) as well as CRF (8.44 +/- 1.68 mumol FFA/mL/h) at 10 min, as compared to the values in the control subjects (12.03 +/- 2.43 mumol FFA/mL/h, p < .01). No correlation was found between PHLA and plasma triglycerides in ARF or CRF. In 15 patients in each group, PHLA subfractions, hepatic triglyceride lipase (HTGL), and lipoprotein lipase (LPL) were determined at similar time intervals after heparin. Both fractions were found to be reduced significantly (p < .01) in ARF as well as in CRF versus controls. These findings indicate that the lipid alterations in acute and chronic renal failure share common features including hypertriglyceridemia and reduced PHLA and its subfractions HTGL and LPL. PMID- 7855317 TI - Renal functional reserve in patients with IgA glomerulopathy. AB - Seven patients with histologically proven IgA nephropathy and modest impairment of renal function, and 2 patients with IgA nephropathy and nephrotic syndrome were investigated, compared to a control group of 9 healthy individuals, to study the effects of amino acids on glomerular and tubular function, and to evaluate renal functional reserve in IgA nephropathy with different clinical course. Inulin and PAH clearances were used to evaluate glomerular filtration rate (GFR) and effective renal plasma flow (ERPF); proximal and distal tubular fluid delivery and reabsorption were measured by lithium clearance, before and after submission of a standardized amino acid solution. GFR and ERPF increased significantly during amino acid load in healthy individuals and patients without nephrotic syndrome, while filtration fraction (GFR/ERPF) remained constant. Lithium clearance (CLi) and fractional lithium excretion (CLi/GFR) rose significantly in both groups, whereas the reabsorbed volume of fluid in the proximal tubule did not change. In the distal tubule, fractional volume excretion decreased significantly during amino acid load whereas the reabsorbed volume significantly increased. Baseline values of the two groups did not differ significantly. Two patients with nephrotic course of IgA nephropathy showed a distinct decrease in glomerular and tubular function, and a loss of renal functional reserve after amino acid load. CONCLUSIONS: Despite distinct alterations in renal biopsy, IgA nephropathy without nephrotic course presents with a still adequately preserved kidney function and renal functional reserve. A single determination of renal function with noninvasive functional tests does not give valid prognostic information concerning glomerular and tubular function. Therefore, a repeated measurement of renal function at defined intervals might reveal clinical progression of renal disease. The results of the lithium clearance might indicate an increase in tubular function after amino acid load, indicating a tubular adaptation in state of hyperfiltration. PMID- 7855318 TI - Clinical features and prognosis in childhood IgA nephropathy. AB - Clinical variables and laboratory and histologic findings were evaluated in 53 children with IgA nephropathy, of whom 44 were followed for a mean period of 6.2 years (range 1.2-14). At the end of the follow-up 8 patients (18.2%) had had no urinary anomalies for at least 1 year (stage A disease), 28 (63.6%) had microscopic hematuria with proteinuria < 1 g/m2/day (stage B), 5 (11.4%) had proteinuria > 1 g/m2/day (stage C), and 3 (6.8%) had chronic renal insufficiency (stage D). None of the patients in apparent remission presented with elevated serum IgA levels at disease onset. Gross or microscopic hematuria at onset correlated with stage A/B disease at the end of follow-up (p < .05) whereas the presence of proteinuria or nephritic syndrome at onset correlated with stage C/D disease after follow-up (p > .05). Presenting features of gross or microscopic hematuria without or with proteinuria (< 0.5 g/m2/day) correlated (p < .001) with minimal glomerular abnormalities at biopsy, whereas patients with nephritic syndrome had more severe histologic pictures. The presence of proliferative glomerulonephritis with crescents correlated (p < .0001) with poor outcome. The results demonstrate that the prognosis of IgA nephropathy in childhood must be viewed with caution and that outcome correlates with mode of onset and severity of the renal pathology. PMID- 7855319 TI - Nifedipine does not affect free radical induced lipid peroxidation following renal allograft reperfusion. AB - We prospectively measured lipid peroxidation following reperfusion during 44 renal allograft transplant operations. Twenty-four (55%) recipients were taking nifedipine pre- and then postoperatively, and 20 (45%) were not. There were no differences between the groups in terms of recipient or donor status. Plasma malondialdehyde (MDA), mean 2.2 (0.2) mumol/L (SEM) vs. 1.73 (0.1) was greater in the group not prescribed nifedipine, p < .05, as were cholesterol; 5.89 (0.3) mmol/L vs. 5.58 (0.3) and triglycerides; 2.19 (0.2) mmol/L vs. 1.82 (0.2). Following allograft reperfusion there was a significant increase in the ratio of MDA/cholesterol (x 10(3)) (MDA corrected for changes in plasma volume) from 0.33 (0.03) in the nifedipine group to 0.38 (0.02) at 30 min after reperfusion and 0.38 (0.03) at 60 min, p < .01, and similarly from 0.4 (0.04) to 0.48 (0.03) at 30 min and 0.47 (0.05) after 60 min in the other group, p < .01. There was no difference in the percentage change in MDA/cholesterol ratio between the groups; 27 (5)% vs. 19 (6) at 30 min and 20 (8) vs. 15 (8) at 60 min for the nifedipine and no-nifedipine groups, respectively. There was no difference in postoperative renal function between the groups. This study suggests that the oral administration of nifedipine may not prevent the production of lipid peroxides, as measured by changes in plasma malondialdehyde, following renal allograft reperfusion and that it does not affect renal function in the early postoperative period. PMID- 7855320 TI - Erythropoietin production in patients with chronic renal failure. AB - Studies were performed to reexamine the response of erythropoietin (Epo) production to acute hypoxic stimuli in patients with end-stage renal disease (ESRD). In the absence of acute bleeding or hypoxia, the serum Epo level in ESRD was similar to that of normal subjects despite severe anemia. In 11 dialysis patients with acute bleeding, the decrease in the Hb level from 8.9 to 5.8 g/dL provoked a significant increase in serum Epo up to 52.2 times the normal value. The increase in serum Epo was associated with a significant increase in corrected reticulocyte. Systemic hypoxemia (PaO2 < 65 mm Hg) in 8 dialysis patients provoked a significant elevation in the serum Epo level up to 24.6 times the normal level. There was an inverse relationship between serum Epo and arterial PaO2 (r = -0.715). The serum Epo level in these patients declined to or near the normal value after recovery from acute hypoxic stress. These data suggest that the ability of the Epo production is well preserved in ESRD, indicating that acute hypoxic stimuli provoke a significant increase in serum Epo. PMID- 7855321 TI - Acute renal failure in a case of fatal chromic acid poisoning. AB - Despite its frequent use in industry, acute poisoning by chromic acid has very rarely been reported. We report a patient who developed massive gastrointestinal hemorrhage, acute renal failure, and hepatic injury following chromic acid ingestion, and subsequently died. Postmortem liver and kidney biopsies revealed centrilobular necrosis and severe acute tubular necrosis, respectively. PMID- 7855322 TI - Drug-related myopathies. AB - Myopathies produced by drugs are of vital concern and often confused with other more frequently diagnosed causes, such as the inflammatory myopathies of polymyositis/dermatomyositis and myositis secondary to toxic agents, metabolic and endocrine abnormalities, genetic predisposition, malignancies, and infections, particularly viruses. The drug-induced causes of myopathy warrant special emphasis because they are often overlooked, resulting in misdiagnosis and improper care. PMID- 7855323 TI - Classification and prognosis of inflammatory muscle disease. AB - Although our understanding of the inflammatory myopathies is still evolving, it is becoming increasingly clear that these syndromes are composed of many separate and distinct disorders with widely divergent clinical signs, symptoms, laboratory abnormalities, and prognoses. Their classification remains controversial, but three approaches of dividing the myositis syndromes appear useful in helping to group disorders with similar features together. The three approaches divide these syndromes on the basis of clinical and histopathologic findings, by serology, and by exposures to known environmental agents. Studies of the prognosis of these disorders are limited by the rarity and heterogeneity of the myositis syndromes. Taken together, however, they suggest that a variety of demographic, clinical, and serologic features are associated with a poor outcome. These include older age at myositis onset, severe myositis, delay to diagnosis and therapy, significant cardiac, pulmonary or gastrointestinal involvement, and the presence of cancer, inclusion body myositis, or antisynthetase or anti-SRP auto antibodies. It is hoped that our understanding of the classification and prognosis of the inflammatory myopathies will become more complete as we perceive more fully the interrelationships between the genetic and environmental risk factors necessary for the induction of myositis and develop more rational ways of dividing and treating these increasingly recognized syndromes. PMID- 7855325 TI - Evaluation of laboratory tests as a guide to diagnosis and therapy of myositis. AB - Plasma CK concentrations have been widely used as the primary muscle enzyme marker for diagnosis and progression of myositis. Recently, total CK and CK-MB serum concentrations have been compared to, and used in conjunction with, serum concentrations of aspartate aminotransferase in diagnosis of myositis. The algorithmic use of CK, AST, and aldolase plasma concentrations to diagnose and categorize patients with myopathy may be a useful method of diagnosing specific muscle disease without invasive procedures. CAIII, as a specific marker for skeletal muscle damage, may replace CK as the enzyme of choice in diagnosis and progression of myositis and other muscle disease. Additional studies are required to determine the usefulness of carbonic anhydrase for the diagnosis and assessment of myositis. PMID- 7855324 TI - Evaluation of neuromuscular function in inflammatory myopathy. AB - The assessment of neuromuscular function during the course of treatment in patients with inflammatory myopathy requires a combination of tests tailored to the clinical status of the patient. The use of timed functional tests, pulmonary function, functional grading, and manual muscle strength testing (coordinated with a physical therapist) provides the clinician and patient with reliable, easily performed measurements that are flexible enough for virtually all outpatient settings. Some patients may require assessment with only timed functional tests, such as the time to run 30 feet, climb four steps, and arise from supine to standing; other patients may need an assessment that uses function tests, functional grade scoring, and manual muscle strength testing. The 24-hour urinary excretion of creatinine is a simple method to measure changes in muscle mass, and determinations at 3- to 6-month intervals may provide a useful means to document the effects of treatment. Occasionally, more elaborate methods, such as MR imaging of muscle may be necessary to identify persistent inflammation in certain muscles or aid in the selection of a specific area of muscle to biopsy. The use of myometry, especially fixed myometry with QMT, is most suitable for clinical research. In the future, hand-held myometric equipment and, perhaps, even QMT, may become more adaptable to office practice, and their use will be more feasible for the routine care of patients with inflammatory myopathy. PMID- 7855326 TI - Immune manifestations of inflammatory muscle disease. AB - Evidence of autoimmune muscle injury and of systemic autoimmunity is seen in PM and DM. In typical PM, a cell-mediated attack on muscle fibers by CD8+ cytotoxic T cells predominates, directed at an unknown antigen. In DM, vascular injury is prominent, with loss of muscle capillaries and ischemic muscle damage, apparently mediated by local complement activation in small muscle vessels. Although humoral immunity seems more important in the pathogenesis of DM, serum autoantibodies are commonly found in both forms. About one third of patients have MSAs, whereas others have less specific antibodies such as anti-U1RNP, often associated with overlap syndromes involving myositis. MSAs are mutually exclusive and define characteristic clinical subgroups. Antibodies to five of the aminoacyl-tRNA synthetases are each associated with an "antisynthetase syndrome" marked by myositis, ILD, arthritis, and other features, but individual patients have only a single antisynthetase. Rare autoantibodies to certain translation factors may be associated with a similar syndrome. Anti-SRP is commonly associated with severe, acute, resistant myositis, whereas anti-Mi-2, the only MSA directed at a nuclear protein, is specifically associated with DM. Patients with anti-PM-Scl commonly have an overlap syndrome of PM/DM and SSc. Recent studies have recognized other antibodies in PM and DM, including antibody to endothelial cells, heat shock proteins, and, in a high proportion of patients, a 56-kd component of a ribonucleoprotein particle. The MSAs and their antigens are being characterized in detail. To date, data suggest similarity of predominant epitopes between different patients and a tendency toward conformational epitopes. It is not known if the recognized autoantibodies participate in tissue injury or pathogenetic processes, but production of the MSAs appears to be linked to etiologic factors and can be a clue to understanding the disease. Although these autoimmune responses are becoming better defined, the inciting events leading to generation of these responses and development of PM and DM remain unknown. PMID- 7855327 TI - Mechanisms of inflammation and histopathology in inflammatory myopathy. AB - The term inflammatory myopathy describes a group of disorders characterized by mononuclear cell infiltration of muscle tissue. Abnormalities of cell-mediated immunity have been implicated repeatedly in the pathogenesis of these disorders. In recent years, considerable evidence supporting this view has been obtained, strongly suggesting a central role to T cells in the pathogenetic process. This article reviews the immunopathology and the cellular mechanisms involved in the pathogenesis of inflammatory myopathy. PMID- 7855328 TI - Therapy of inflammatory myopathy. AB - The management of the muscular and extramuscular manifestations of the inflammatory myopathies remains a challenge for the practicing rheumatologist. Although corticosteroids remain the first line of therapy, their side effects often limit their usefulness. Paradoxically, one of the side effects of steroids, muscle weakness, is the very symptom at which therapy is aimed. Other immunosuppressive agents are of proven benefit alone or in combination with corticosteroids. The identification of characteristic autoantibodies that identify poor prognostic outcomes and the availability of newer immunosuppressive regimens should contribute to a more aggressive but perhaps safer therapeutic approach to the patient with myositis. PMID- 7855329 TI - Inflammatory myopathy in children. AB - The symptoms of inflammatory muscle disease in children can be characterized as either acute or chronic in nature; acute muscle complaints are usually associated with viral or bacterial infectious agents. Throughout the world, most of the acute inflammatory myopathies may be a consequence of bacterial or parasitic infection, but in North America, acute myositis is more often a viral cause. A child with chronic inflammatory myositis may have some symptoms that are similar to those seen in adults who develop one of the idiopathic inflammatory myopathies. These myopathies comprise a very diverse group of syndromes that have in common chronic muscle inflammation of unknown pathophysiology resulting in damage and affecting muscle function. PMID- 7855330 TI - Relationship of cancer to inflammatory muscle diseases. Dermatomyositis, polymyositis, and inclusion body myositis. AB - Dermatomyositis (DM) is probably associated with a greater frequency of malignancy than expected in the general population. For polymyositis (PM), there does not appear to be greatly increased risks. Ovarian cancer may be over represented in women with DM. A paraneoplastic course occurs in some patients with DM, but is unusual. Even young patients with DM should be evaluated. The malignancy evaluation should be directed by symptoms, findings on physical examination or laboratory testing, or be age-appropriate. PMID- 7855332 TI - The evolving spectrum of eosinophilia myalgia syndrome. AB - Eosinophilia myalgia syndrome (EMS) is a toxin-induced illness that provides a model for the understanding of idiopathic immune-mediated diseases that have overlapping features. The clinical development and chronic sequelae of EMS, its relationship to related disorders, and the accumulating data suggesting an important role for immune mechanisms in the pathogenesis of this disease are reviewed in this article. PMID- 7855331 TI - Inclusion body myositis. AB - IBM remains a poorly understood form of idiopathic inflammatory myopathy, although great progress in the areas of clinical recognition and pathophysiology have been made recently. The question of whether therapy can favorably influence short- and/or long-term outcome is still unanswered. Several recent reports suggest some possibility of at least slowing progression with immunosuppressive therapy. Long-term therapeutic trials with goals that include stabilization, rather than improvements in strength, are urgently needed. PMID- 7855334 TI - FutuRAD 2: work in progress. PMID- 7855333 TI - The relationship of infectious agents to inflammatory myositis. AB - Several infectious agents have been linked to chronic inflammatory myositis. The mechanisms proposed usually involve presumed persistent infection or induction of an autoimmune response following infection. Agents most often implicated are the enteroviruses (especially coxsackieviruses), echoviruses in patients with agammaglobulinemia, retroviruses including HIV-type 1 and human T-cell lymphotropic virus type 1, and the protozoan Toxoplasma gondii. In the majority of cases, however, no specific infectious agent can be identified. PMID- 7855335 TI - Easily missed injuries around the knee. AB - Most fractures around the knee are easily detected on high-quality radiographs. However, some fractures and musculotendinous and ligamentous injuries have subtle findings and may be difficult to detect even with optimal images; these injuries include tibial plateau fractures, Segond fractures, stress fractures, fibular head fractures and dislocations, injuries to the patella and extensor mechanism, and Salter type fractures. Clinically suspected tibial plateau fractures unseen on standard views may be seen on tangential or tunnel projections. Segond fractures usually have a characteristic appearance on anteroposterior radiographs but occasionally are seen only on tunnel views. Stress fractures of the proximal tibia may be accompanied by a vague band of increased sclerosis or endosteal callus on either side of the epiphyseal scar. Correct diagnosis of fibular head dislocations requires clinical suspicion, since these injuries often are not recognized on initial radiographs. Careful evaluation of the congruity of the tibiofibular joint on the lateral projection is the key to diagnosis. Vertical patellar fractures are often nondisplaced and are best evaluated with sunrise or Merchant views; avulsion fractures from the proximal or distal poles, with lateral views; and osteochondral fractures, with sunrise or internal oblique views. Salter I injuries can be visualized on oblique and anteroposterior views obtained with stress applied to the knee. Some occult Salter I fractures are diagnosed on follow-up radiographs, which show periosteal reaction. Imaging modalities other than radiography are rarely needed to diagnose fractures but are useful for evaluating the extent of displacement or confirming soft-tissue injuries. PMID- 7855336 TI - Labrocapsular ligamentous complex of the shoulder: normal anatomy, anatomic variation, and pitfalls of MR imaging and MR arthrography. AB - Magnetic resonance (MR) imaging is a useful modality for evaluating the labrocapsular ligamentous complex (LCLC) of the shoulder. MR arthrography is an important and occasionally indispensable supplementary modality for accurate differentiation between normal and deranged glenohumeral joints. Because of the joint distention that occurs during MR arthrography, it is especially helpful in detecting subtle capsular derangement, as occurs in patients with atraumatic instability. Also, some of the pitfalls associated with MR imaging of the LCLC are less likely to occur with MR arthrography. Radiologists should look for several key abnormalities when evaluating MR images of the shoulder: an anterior or posterior Bankart lesion; a Hill-Sachs defect; a tear of the rotator cuff, glenoid labrum, or superior labrum-biceps tendon attachment; and loose bodies. Knowledge of normal anatomy, normal variations, and pitfalls in image interpretation related to evaluation of the LCLC will help the radiologist accurately detect debilitating derangements associated with glenohumeral instability. PMID- 7855337 TI - Health care bureaucrats and global budgets: will it work? PMID- 7855338 TI - Musculoskeletal causes of spinal axis compromise: beyond the usual suspects. AB - The majority of cases of spinal canal compromise are caused by common pathologic conditions, including degenerative spondylosis, infection, trauma, and metastatic disease. However, there are other causes of spinal canal compromise that, though unusual, may be seen in everyday practice. Congenital abnormalities of the spine that may produce spinal canal compromise include the os odontoideum, hemivertebra, diastematomyelia, and achondroplasia. Arthritides and enthesopathies such as rheumatoid arthritis, ankylosing spondylitis, synovial cysts of the facet joint, calcium pyrophosphate dihydrate deposition or hydroxyapatite deposition, and ossification of the posterior longitudinal ligament or ligamentum flavum may lead to narrowing of the spinal canal. Primary spinal tumors and tumorlike lesions such as hemangioma, aneurysmal bone cysts, osteochondroma, and osteoblastoma may also cause spinal canal stenosis. Finally, Paget disease of bone may compromise the spinal cord. Radiologists should be aware of these unusual musculoskeletal causes of spinal canal compromise and their radiologic and clinical features. PMID- 7855339 TI - Intrathoracic calcifications: radiographic features and differential diagnoses. AB - Intrathoracic calcifications occur in a wide variety of disorders. Although they are usually harmless sequelae of remote processes, calcifications provide important information for establishing the diagnosis or for evaluating the progression of known disease. They may arise in the pulmonary parenchyma, mediastinum, hilar and mediastinal lymph nodes, pleura, chest wall, or any combination of these structures. The cause of the calcification may be determined by means of the location and pattern of the calcifications within the lung parenchyma and knowledge of the associated clinical features. Calcifications in the thorax are frequently manifestations of previous infectious processes. Less often, they may be due to neoplasms, metabolic disorders, occupational exposure, or previous medical therapy. Large intrathoracid calcifications are usually identified on conventional chest radiographs; detection of smaller calcifications may require use of other imaging modalities, such as dual-energy digital radiography, fluoroscopy, radionuclide scanning, computed tomography (CT), and high-resolution CT. PMID- 7855340 TI - Acute aortic dissection: typical and atypical imaging features. AB - Acute aortic dissection (AAD) is the most common emergency affecting the aorta. Noninvasive imaging allows prompt and reliable diagnosis of AAD and has largely supplanted aortography. However, atypical imaging features and diagnostic pitfalls can delay lifesaving therapy. An intimal flap is the characteristic feature of AAD. If there is flow within both lumina, typical imaging features are probably present. If the false lumen is thrombosed or there is no intimal tear to permit flow through the false lumen, a distinct intimal flap may not be present. Secondary signs of AAD include an intramural or periaortic acute thrombus, which manifests as a high-attenuation cuff or crescent on unenhanced computed tomographic scans. Other conditions that can reduce the conspicuity of the intimal flap include atypical configurations of the flap, such as seen with short dissections or with multiple false channels, in which case the flaps are complex. Finally, aortic anomalies may cause confusion. PMID- 7855341 TI - The implantable pace-maker-cardioverter-defibrillator: radiographic aspects. AB - Safer and easier placement, recent approval by the U.S. Food and Drug Administration of several models, and increasing availability have expanded the use of implantable cardioverter-defibrillators (ICDs) for treatment of life threatening ventricular tachyarrhythmia. Modern ICDs generally use a combination of two transvenously placed electrodes and one subcutaneous electrode; therefore, they do not require a thoracotomy for placement. The authors evaluated the radiographic aspects of one particular ICD--the pacemaker-cardioverter defibrillator (PCD)--including the normal appearance and variations, confusing findings, and such complications as deformity of the subcutaneous patch electrode, lead fracture, and electrode malposition and migration. The PCD can also be combined with a preexisting, surgically placed automatic ICD or with a pacemaker. Familiarity with the PCD and other ICDs is essential, since the radiologist may be the first to recognize a complication that can render the device inoperative and leave the patient vulnerable to sudden death. PMID- 7855342 TI - Diffuse disease of the liver: radiologic-pathologic correlation. AB - Cross-sectional imaging is playing an increasing role in diagnosis of diffuse liver diseases because it clarifies, in many cases, the overlap in clinical and laboratory manifestations often present in diffuse hepatic processes and thus may eliminate the need for a biopsy. Advances in cross-sectional imaging, particularly in magnetic resonance (MR) imaging, enable further characterization of hepatic parenchymal and architectural changes, allowing closer correlation with underlying pathologic changes. Advanced imaging techniques can be used to characterize a variety of metabolic, vascular, toxic, infectious, and neoplastic diffuse liver diseases. These include more common entities such as cirrhosis, Budd-Chiari syndrome, hemochromatosis, Wilson disease, fatty change, and diffuse neoplastic disease (hepatocellular carcinoma, metastasis, and lymphoma) and uncommon entities such as schistosomiasis, sarcoidosis, and amyloidosis. Correlation of computed tomographic and MR imaging findings with underlying pathologic features is helpful in understanding the gamut of diffuse diseases of the liver. PMID- 7855343 TI - Pathways of nodal metastasis from pelvic tumors: CT demonstration. AB - Although the normal pathways of lymphatic drainage from the pelvic organs have been well described in the anatomy literature, the pathways of nodal metastasis from individual pelvic neoplasms are not well illustrated in the imaging literature. The authors retrospectively reviewed computed tomographic scans of the abdomen and pelvis in patients with various pelvic neoplasms, including those of the ovary, testis, prostate, cervix, bladder, anorectum, and other sites, to define the pathways of nodal metastasis. In most patients, pathways of nodal metastasis correlated well with the normal lymphatic pathways described in the anatomy literature, including the superficial inguinal pathway; the anterior, lateral, hypogastric, and presacral routes of the pelvic pathway; and the paraaortic pathway. However, there also were various uncommon pathways of nodal metastasis, such as metastasis along the gonadal vessels, mesenteric and mesocolic nodes, posterior iliac crest nodes, and inferior phrenic nodes. Understanding these common and uncommon lymphatic pathways of metastasis will help radiologists detect disease spread from pelvic tumors. PMID- 7855344 TI - Imaging of the adrenal gland in children. AB - Ultrasonography (US), computed tomography (CT), and magnetic resonance (MR) imaging have replaced intravenous urography and angiography in evaluation of children with suspected disease of the adrenal glands. Although the spatial resolution of MR imaging is still somewhat inferior to that of CT, it allows tissue characterization and better evaluation of tumor extension owing to its multiplanar imaging capability. Initial diagnosis of an adrenal mass in a child is made with US, which is also used to document regression of uncomplicated neonatal adrenal hemorrhage. MR imaging is used for evaluation of tumor extension when surgery is to be performed. Imaging findings such as size, shape, and signal intensity are often not specific for a pathologic condition and must be interpreted in conjunction with the patient's age, the clinical history (eg, trauma), results of physical examination (eg, palpable mass or presence of an endocrine syndrome), and hormone levels in blood and urine. PMID- 7855345 TI - CT of complications in pediatric lung transplantation. AB - The authors review the computed tomographic (CT) findings following single and double lung transplantation in children to show the spectrum of complications. The most common parenchymal complications following transplantation include acute rejection; chronic rejection or bronchiolitis obliterans; bacterial, viral, and fungal infections; and lymphoproliferative disorders. In acute and chronic rejection, CT shows ground-glass attenuation and interlobar septal thickening. The same CT findings are seen in bacterial and viral infections, with occasional pulmonary abscess seen in the former. Fungal infections are characterized by cavitary lesions, air-space disease, and mediastinal adenopathy on CT scans. In lymphoproliferative disorders, CT demonstrates pulmonary nodules or soft-tissue masses. The most frequent posttransplantation airway complications include stenosis, stent migration, and dehiscence. Dehiscence, which usually results from ischemia at the anastomosis site, is evident on CT scans as a disrupted airway and extraluminal air collections. CT is particularly important in the evaluation of airway complications because the CT results can significantly affect patient management. In parenchymal disease, CT often cannot aid in establishing a specific diagnosis, but it can be used to determine a site for biopsy, document extent of disease, and follow up results of treatment. PMID- 7855346 TI - From the archives of the AFIP. Ovarian epithelial neoplasms: radiologic pathologic correlation. AB - Ovarian carcinoma is the most common cause of death from a gynecologic malignant neoplasm. The typically advanced stage at presentation and aggressive nature of these neoplasms result in an overall 5-year survival rate of less than 40%. Most malignant ovarian neoplasms are of the surface epithelial cell type, which includes serous, mucinous, clear cell, endometrioid, and Brenner tumors. However, among the epithelial neoplasms, benign lesions are more common than malignant neoplasms, and other entities (including nonneoplastic masses) are far more common causes of a pelvic mass. Imaging studies (ultra-sound, computed tomography, and magnetic resonance imaging) can depict the tumor morphology: solid or cystic, unilocular or multilocular cystic, with or without thickening of the walls or septa, with or without papillary excrescences or other soft-tissue elements, and with or without calcifications. Evaluation of these morphologic characteristics allows attempted differentiation among malignant, benign neoplastic, and nonneoplastic lesions. Lesion characterization assists in surgical planning. Malignant neoplasms nearly always require laparotomy, whereas benign neoplasms may be managed laparoscopically. In the case of ovarian carcinoma, treatment is primarily surgical, and most patients also receive chemotherapy. Unfortunately, recurrence is common. PMID- 7855347 TI - Steps in the evolution of extracranial time-of-flight MR angiography. AB - Magnetic resonance (MR) angiography is not a set technique but is constantly evolving. This article illustrates changes in image quality in extracranial MR angiography that have been achieved over the past few years by the introduction of several technical developments. Images from patients examined at intervals of 12 months or more demonstrate the improvements in image quality that have resulted from these technical changes. These include bandwidth optimization for operation at 1.0 T and changes in flip angle section thickness, repetition time, and echo time. Improved image quality was assessed with objective measures of contrast-to-noise and signal-to-noise ratios. The cases illustrated show the use of MR angiography to evaluate the portal or systemic veins in patients being evaluated for liver transplantation, venous occlusion, and other venous disease. Improvements in image quality are subjectively apparent and emphasize the importance of keeping pace with technical improvements in MR angiography. PMID- 7855348 TI - The AAPM/RSNA physics tutorial for residents. Contrast mechanisms in spin-echo MR imaging. AB - The majority of sequences used in routine clinical magnetic resonance imaging rely on the concepts involving the spin echo. Spin-echo sequences require long acquisition times (1-10 minutes), but compared with faster gradient-recalled echo methods, spin-echo methods are relatively immune to signal loss and distortions from field inhomogeneity and tissue-induced susceptibility variations. Through modifications of intersequence repetition time (TR), echo formation interval (echo time [TE]), and various gradient moments, image contrast can be altered to emphasize tissue relaxation times T1, T2, or proton density. The TR and TE values control the amount of T1 weighting and T2 weighting, respectively. At long TR intervals (approximately 10 x tissue T1 values) and minimum TE values, the difference in signal intensity arising from relaxation vanishes, and contrast arises solely from the differences in proton density between the two tissues. Images formed with short TR intervals and long TE values exhibit very low signal to-noise ratio and negligible contrast and should be avoided. Recently, fast spin echo sequences have partially overcome the limitation of long acquisition times, with up to 16-fold reduction, by acquiring multiple lines in k space with multiecho sequences. PMID- 7855350 TI - US tissue characterization workstation: applications and design. AB - This article discusses the purpose, design, and uses of an ultrasonographic tissue characterization workstation. The distinguishing characteristic of a tissue characterization workstation is its ability to analyze and classify image textures. Texture is defined as regularly or randomly repeating patterns. Small texture differences in an image are difficult to observe in the presence of noise. Therefore, it is necessary to analyze the image quantitatively. Quantitative measurements include run-length statistics, fractal dimension, and correlation statistics. The workstation is designed so that a radiologist can analyze the patient's images through an easy-to-use graphical user interface. The workstation software is based on standards, so that it can be run on a variety of different hardware platforms. The workstation can be used in a research environment to distinguish between images of malignant and benign breast lesions, which are difficult to diagnose visually. Further work is being done to make the workstation software into a useful clinical tool. PMID- 7855349 TI - Interactive multimedia program for imaging the spleen: concept, design, and development. AB - The authors present some of the decision making and design goals that guided the development of computer-based educational programs, specifically a module to teach the role of computed tomography in detection and evaluation of splenic disease. One goal was that the program would take advantage of the computer yet allow users to recognize or learn quickly the techniques used to navigate through the program. A game interface was chosen as a means to aid retention of the material being taught, as well as to make use of the module enjoyable. The structure used to present the program content was based on the common means by which radiology has traditionally been taught. The four sections of the module consist of the slide lecture, traditional text, a quiz, and teaching files. Each question in the quiz section is linked to the relevant text section for review, and the teaching file section can be used as a self-test by hiding the text and diagnosis fields. Computer-based educational programs are an important resource for residents and practicing professionals, and they will continue to evolve with developments in technology. However, it should be the goal of all new projects to find a balance of form, in which the value of traditional teaching methods can be preserved with the maximum opportunity for innovation. PMID- 7855351 TI - US case of the day. Fournier gangrene. PMID- 7855352 TI - General case of the day. Malignant melanotic schwannoma of the eighth cranial nerve. PMID- 7855353 TI - Pediatric case of the day. Congenital, undifferentiated retroperitoneal fibrosarcoma. PMID- 7855354 TI - [Guide for certification of Triatoma infestans elimination in the South Cone]. PMID- 7855355 TI - [Control of Triatoma infestans in the State of Sao Paulo]. PMID- 7855356 TI - [Plan for the eradication of Triatoma infestans in Brazil]. PMID- 7855357 TI - [Methods and strategy for the surveillance in the final phases of control of T. infestans for Uruguay]. PMID- 7855358 TI - [PAHO/WHO --Task force on the initiative of the South Cone for the elimination of vector transmission and interruption of transfusion transmission of Trypanosoma cruzi. Epidemiologic surveillance of Triatoma infestans]. PMID- 7855359 TI - [Operative indicators for a program for the elimination of Triatoma infestans]. PMID- 7855360 TI - [The importance of the peridomicile in a program for the elimination of Triatoma infestans]. PMID- 7855361 TI - [Research priorities]. PMID- 7855362 TI - Biochemical behavior of Trypanosoma cruzi strains isolated from mice submitted to specific chemotherapy. AB - To investigate the influence of chemotherapy on the biochemical behavior of Trypanosoma cruzi strains, three groups of mice were infected with one of three strains of T. cruzi of different biological and isoenzymic patterns (Peruvian, 21SF and Colombian strains). Each group was subdivided into subgroups: 1-treated with nifurtimox; 2-treated with benznidazole and 3-untreated infected controls. At the end of treatment, that lasted for 90 days, xenodiagnosis, subinocculation of blood into new born mice and hemoculture were performed as tests of cure. From the positive tests, 22 samples of T. cruzi were isolated from all subgroups. Electrophoretic analysis of the isoenzymes PGM, GP1, ALAT and ASAT failed to show any difference between parasite strains isolated from treated and untreated mice, which indicates that no detectable clonal selection or parasite genetic markers alterations concerning the isoenzymes analysed have been determined by treatment with drugs of recognized antiparasitic effect, suggesting stability of the phenotypic characteristics of the three biological types of T. cruzi strains. PMID- 7855363 TI - [Prevalence of schistosomiasis mansoni and parasitic intestinal diseases among students of the rural area of the Municipality of Jaboticatubas, MG, 1992-1993]. AB - Students from a Rural Boarding house of UFMG School of Medicine performed a survey of prevalence of schistosomiasis mansoni and other intestinal parasites in 20 rural schools in Jaboticatubas, MG. An evaluation of house and sanitation conditions was made and stool parasitological examinations were realised in all school children. It was noticed that 15.43% of the children presented S. mansoni's ova in stool--that was the most prevalent parasite. From the examinations we verify 13.76% positive cases for G. lamblia; 12.89% for S. stercoralis; 11.13% for A. lumbricoides; 9.96% for hookworms; 9.57% for E. histolytica. The other parasites appeared with lower prevalence. All the children that presented parasite's ova in stool received treatment. The result that was found shows that schistosomiasis mansoni is a very serious problem of public health and basic sanitation actions are necessary to the endemic control. PMID- 7855364 TI - Aspects of the granulomatous reaction in the liver of mice infected and reinfected with two different geographical strains of Schistosoma mansoni. AB - In this study, which was undertaken in relation to the histopathologic behavior of two different strains (LE-Belo Horizonte, MG and SJ-Sao Jose dos Campos, SP) in infections and reinfections (homologous or heterologous) with Schistosoma mansoni, the authors confirmed a more accentuated pathogenicity of the SJ strain. All the reinfections showed the presence of typical granulomas of the acute phase, when performed either with the same strain (homologous) or with a different strain (heterologous) of the parasite of the primo infection. The possible mechanisms responsible for reactivation of the immunopathologic response in reinfections are discussed. PMID- 7855365 TI - [Longitudinal radiologic study of the esophagus, in an endemic area of Chagas disease, in a period of 13 years]. AB - A radiological study of the oesophagus of a cohort of patients was carried during a 13 year period in the municipality of Mambai Goias. Barium swallow findings were recorded on 70mm film using a portable machine. Of 731 patients examined 382 (52.3%) were seropositive for T. cruzi. The sexes were equally divided. The incidence of detectable megaoesophagus was 7.9% among the cohort and 14.2% in the seropositive individuals. Progression of the disease was noted during this longitudinal study in 21.7% of males and 16.6% of females. PMID- 7855366 TI - [Susceptibility of Triatoma infestans to various strains of Trypanosoma cruzi isolated from chagasic patients from the Triangulo Mineiro]. AB - This data evaluated the susceptibility of T. infestans to seven different strains of T. cruzi from chagasic patients of the Triangulo Mineiro, isolated and adapted in Swiss mice. A total of 200 bugs were fed in mice in acute phase injected with the different strains of T. cruzi and at each 30 days, during 5 months, their feces were obtained by abdominal compression or spontaneous dejection. The overall positivity of T. infestans infection with these different strains of T. cruzi was 62.08%. There was a high mortality rate (60%) during the examination period. We conclude that T. infestans has a low susceptibility to these strains. This could explain the low rate of positivity in the xenodiagnosis in chagasic chronic patients of the Triangulo Minerio. PMID- 7855367 TI - [Chromoblastomycosis associated with leprosy: report of 2 cases]. AB - Thirty cases of chromoblastomycosis were diagnosed at Hospital dos Servidores do Estado do Maranhao, from November, 1988 to March, 1993. The authors report 2 (6.6%) cases, that presented an association with leprosy. The first patient developed both diseases together, showing palpable bilateral cubital nerves, perforanting ulcer of the right foot, infiltration and lesions in verrucoid plaques in left leg, with positive biopsy for dimorphic leprosy. The second case, a patient with history of lepromatous leprosy for 30 years without treatment, with vegetant lesions with a warty aspect in right elbow for 12 months, histopathologic and positive culture for chromoblastomycosis. The possible factors for development of this disease in these patients are discussed. PMID- 7855368 TI - [Fatal visceral leishmaniasis associated with acquired immunodeficiency syndrome: report of a case with necropsy findings and immunohistochemical study]. AB - A case of fatal visceral leishmaniasis associated with immunodeficiency syndrome in a 32 year-old male patient is reported. The protozoonosis was responsible for the patient's death. Visceral leishmaniasis showed itself in an atypical form, at necropsy, with an intense parasitation of the mononuclear phagocitic system and damaging organs not usually affected by the disease, such as the adrenals, the kidneys, the lungs and the brain. Parasitised cells were observed within small vessels in several tissues. An immunohistochemical study was done on samples from the spleen, lymph nodes and brain, showing strong reactivity with antibody directed against leishmania. PMID- 7855369 TI - [Human populations attacked by wild Triatominae in the Amazonas: a new form of transmission of Chagas disease?]. AB - An "attack" of wild triatomines (Rhodnius brethesi) to piacaca workers (Leopoldinia piacaba) is confirmed in the locality of Acuquaia, at Padauari river, affluent of Rio Negro in the municipality of Barcelos, State of Amazonas, Brazil. A serological prevalence of 12.5% for T. cruzi antibodies in human population, in the city of Barcelos, has already been described in a previous paper. A strong association between the serological positivity and the population contact with wild triatomines, known in the area as "piacava's lice", was verified. PMID- 7855370 TI - [American tegumentary leishmaniasis in an endemic region as factor of community mobilization]. PMID- 7855371 TI - Resistance of unfed first instar Dipetalogaster maximus to different environmental conditions. PMID- 7855372 TI - [Registry of activities of the Hemodynamics and Interventional Cardiology Section in 1993]. AB - Results of the Spanish Registry for Interventional Cardiology 1993 are presented, as previous years, by the Section of Haemodinamics and Interventional Cardiology of Sociedad Espanola de Cardiologia. There are 72 participating cardiac catheterization laboratories. That represents 100% of those laboratories who had activity in 1993, Public medicine (51 centers) and Private practice (21 centers). From those, 8 laboratories exclusively performed pediatric cases. There have been performed 47353 diagnostic procedures and 2647 endomiocardial biopsies. In diagnostic cases greater proportion corresponds to coronariography (37591, 75.2%). Therapeutic interventionalism is also accomplished in 61 laboratories, on which 7807 balloon PTCA, 535 coronary atherectomies, 825 mitral valvotomies were performed, and 503 endocoronary prostheses were implanted. Mean rate of coronary interventionalism was 222 procedures by a million of inhabitants. This activity represents approximately a 17% increase from 1992, in diagnostic as well interventional procedures. Results of therapeutic cases did not show any significant changes, balloon PTCA primary success rate is 91.5%, with an incidence of 4.2% of complications that includes 0.7% mortality rate. PMID- 7855373 TI - [National registry of heart transplantation. Fifth report (1984-1993)]. PMID- 7855374 TI - [Perfusion tomographic scintigraphy and coronary angiography as complementary studies for the therapy decision for patients with ischemic cardiopathy]. AB - BACKGROUND: The aim of the present study was to assess the value of tomographic perfusion scintigraphy as a complement to coronary arteriography in the therapeutic management of patients admitted to the hospital for treatment of unstable ischaemic heart disease. METHODS: A review was carried out of the discharge report of 100 consecutive patients (mean age 58 years, 19 females) in which there was a mention of having taken a therapeutic decision on the basis of coronary angiography and tomographic perfusion scintigraphy with 99m-technetium isonitriles under exercise and/or dipyridamole. In 90% of instances the study was performed during drug therapy after the patient had remained stable for at least 3 days. The indication of the studies and the type of therapy was made by the attending physician. Concordance between both studies was said to exist when both pointed to the same type of therapeutic approach, either medical treatment (nonsevere stenosis on coronary arteriography with mild ischaemia on scintigraphy) or revascularization (severe stenosis with moderate or severe ischaemia in tomographic scintigraphy). Discordance was said to be present when ischaemia was mild with severe stenosis on coronary angiography. RESULTS: In 80 patients there was concordance between both studies regarding the subsequent therapeutic approach (medical treatment in 32 and revascularization in 48 [25 coronary angioplasty and 23 bypass surgery]). In the patients with discordance (n:20) medical treatment was decided in 14 patients on the basis of mild ischaemia with significant angiographic stenosis, and in only 6 patients revascularization (angioplasty in 5 and bypass surgery in 1) was indicated, based on the severity of coronary stenosis even if the ischaemia apparent on the scintigraphy was mild. CONCLUSIONS: Therefore, in 80% of patients admitted for unstable coronary artery disease there was a concordance between the results of tomographic scintigraphy and coronary angiography, when both studies were indicated to select the most appropriate therapeutic modality. In the 20% of discordant cases the attending physician decided on a conservative strategy in most cases, as no significant enough perfusion defect was shown on scintigraphy in spite of severe coronary artery stenosis. PMID- 7855375 TI - [Radiofrequency catheter ablation of ventricular tachycardia in patients without apparent structural cardiopathy]. AB - BACKGROUND AND PURPOSE: It has been suggested that the efficacy of radiofrequency ablation of idiopathic ventricular tachycardia (VT) is dependent on the site of VT origin, with the efficacy being greater for VTs originating from right ventricle. The electrophysiologic characteristic and the results of radiofrequency catheter ablation of ventricular tachycardia in patients without structural heart disease are reported. Special emphasis was focused to the differences observed in the pace and activating mapping between VTs originating in the right ventricle and those originating from the left ventricle and its possible implications for radiofrequency efficacy. METHODS AND RESULTS: 14 consecutive patients with idiopathic VT (7 women and 7 men, mean age 35 +/- 16 years), 8 originating in the right ventricle (RV) and 6 in the left ventricle (LTV), underwent catheter ablation using radiofrequency energy. The observation of entrainment with fusion in all LV VT suggested that the electrophysiologic mechanism was a reentry, meanwhile the RV VT were due to focal non-reentrant mechanisms. Sites for radiofrequency energy delivery were selected on the basis of pace and activation mapping in all patients less in two patients with incessant VT in whom only activation mapping was performed. 14 VT were mapped. The activation mapping demonstrated isolated presystolic electrograms in the point of origin in all VT arising from the LV. However in RV tachycardias there was continuous activity between presystolic and systolic electrograms, although the prematurity of these electrograms was similar (31 +/- 16 ms vs 33 +/- 9 ms; p = 0.77). Radiofrequency was successful in eliminating 93% of TV (100% RV TV vs 83% LV TV; p = 0.23). No complications were observed. CONCLUSIONS: The results of this study suggest that radiofrequency ablation is highly successful either in right and left ventricles idiopathic tachycardias when pace and activation mapping are used complementary. PMID- 7855376 TI - [Influence of prolonged inflation on coronary restenosis after balloon angioplasty]. AB - BACKGROUND AND OBJECTIVES: Previous noncontrolled studies yield conflicting data about the influence of long inflation times on restenosis rate after PTCA. To clear these differences, we designed an open, prospective and randomized study to assess the effect of long versus standard balloon inflations in the incidence of restenosis. METHODS: 153 consecutive patients selected for one-vessel PTCA (62 LAD, 43 LCx, 48 RCA), were randomized to prolonged inflation (13.5 +/- 3.3 min) at 6 atmospheres using an autoperfusion catheter (72 patients) or to standard inflations (3.1 +/- 1.6 min) using conventional catheters (81 patients). Vessel diameter < 2.5 mm, lesions located at distal segments, complete occlusions, tortuous, long, bifurcated or thrombotic lesions were excluded. RESULTS: No significant differences in age, gender, coronary risk factors, ejection fraction, incidence of unstable angina or previous myocardial infarction existed between the two groups. There were no differences either between the dilated vessel, type of lesion (A, B, C) or the segment (proximal, mid) attempted. Successful dilation was obtained in 77/81 (95.0%) cases with standard inflation and in 58/72 (80.5%) with prolonged inflations (p = 0.01), leading to a decrease in the percentage of stenosis from 79.1 +/- 10.6% to 20.2 +/- 15.8% and from 81.4% +/- 9.9% to 21.0 +/ 13.0%, respectively (p = NS). A follow-up coronary arteriogram was obtained in 72/77 patients (93.5%) with standard inflation (mean: 18 +/- 6 weeks) and in 54/58 patients (93.1%) with prolonged inflation (mean: 17 +/- 3 weeks). Restenosis (arterial diameter reduction > 50%) was present in 23/72 (31.9%) of the standard inflation and in 22/54 (40.7%) of the prolonged inflation group (p = 0.4). CONCLUSIONS: These results suggest that longer balloon inflation periods do not reduce the restenosis rate after balloon coronary angioplasty. PMID- 7855378 TI - [Clinical pharmacology of calcium antagonists]. PMID- 7855377 TI - [Angioplasty of the stenotic Blalock-Taussig]. AB - BACKGROUND: Balloon angioplasty is a useful therapeutic method in some congenital heart diseases. We show our experience of stenotic Blalock-Taussig angioplasty, which was effective in six cases. PATIENTS AND METHODS: Six symptomatic patients with different congenital heart diseases, reduced pulmonary blood flow and a previous Blalock-Taussig shunt (it was classic in three patients and modified in another three) underwent the procedure. Conventional angioplasty was performed in four cases and coronary angioplasty technique, under monorail system, was applied in the other two. RESULTS: After angioplasty, we observed an increase in the minimum luminal diameter from 1 +/- 0.7 to 4 +/- 0.5 mm (p < 0.01), a reduction in the percentage of the stenosis from 77 +/- 15 to 13 +/- 13 (p < 0.01) and an increase in oxygen saturation from 63 +/- 10% to 82 +/- 5% (p < 0.05). The effectiveness of the technique in an extreme case of a thrombosed Blalock Taussig, hours later the surgery, is reported. In the follow-up, we observed a symptomatic improvement, stable oxygenation levels, and a tendency in the hematocrit reduction. CONCLUSION: We consider that angioplasty of Blalock-Taussig shunt is indicated in those symptomatic patients, in whom a complete surgical correction is contraindicated. We demonstrate the effectiveness of the procedure, the coronary angioplasty, under monorail system is very useful for the stenotic modified Blalock-Taussig. It can be an effective technique when there is a postoperative thrombosis of the fistula. PMID- 7855379 TI - [Intracranial hemorrhage following second thrombolytic treatment of myocardial reinfarction]. AB - Intracranial hemorrhage was observed in a man, aged 66, after a second thrombolytic treatment due to myocardial reinfarction. The patient presented no potential risk factors which have often been associated to intracranial hemorrhage whereas no complications had occurred when thrombolytic therapy was given some months before because of the first infarction. This report emphasizes that a previous thrombolytic treatment with no secondary effects involves no lack of intracranial hemorrhage risk for a second thrombolysis. More research is needed in order to elucidate intracranial hemorrhage mechanisms associated to thrombolytic therapy. PMID- 7855380 TI - [Right ventricular arrhythmogenic dysplasia. The role of heart transplantation in its management]. AB - Arrhythmogenic right ventricular dysplasia is a rare disease that usually presents with ventricular arrhythmias and sometimes with heart failure. Rarely symptoms become severe and refractory to conventional therapy. We present the case of a 36-year-old man with this disease who had sustained ventricular arrhythmias and severe right heart failure. Because these symptoms were poorly controlled with medical therapy, cardiac transplantation was finally chosen as definitive treatment. The patient had a favorable course and now leads near normal life. PMID- 7855381 TI - [Sustained monomorphic ventricular tachycardia in myotonic dystrophy]. AB - Myotonic dystrophy is an hereditary multisystemic disease, characterized by slowly progressive myotonic atrophy of skeletic muscles. The heart is frequently affected with occurrence of arrhythmias and His-Purkinje system dysfunction and, less frequently, myocardial dysfunction. The surface ECG is the most sensible indicator of heart disease, and the most common electrophysiological finding is the prolongation of the H-V interval. Patients usually have few cardiovascular symptoms, but when present, the most frequent are: syncope, arrhythmias, atrioventricular block, congestive heart failure and sudden death. We present two patients with sustained monomorphic ventricular tachycardia as initial presentation of cardiac disease. PMID- 7855382 TI - [Prevalence of Paget's disease in the province of Parma]. PMID- 7855383 TI - Residual B cell activity and insulin requirements in insulin-dependent diabetic patients treated from the beginning with high doses of nicotinamide. A two-year follow-up. AB - Nicotinamide was shown to prevent damage and to stimulate B cell regeneration in experimental diabetes but in humans results are still controversial. To ascertain if long term nicotinamide treatment can induce and/or prolong remission of the disease, 21 type 1 (insulin-dependent) recently diagnosed subjects entered a controlled study and randomly divided in two groups comparable for age, genetic and immunologic patterns: group 1 (11 subjects) received insulin and nicotinamide (3 g/day for 1 year) and group 2 (10 subjects) insulin alone. Bimonthly insulin requirement and HbA1c, and every 6 months C-peptide response to glucagon were registered for 2 years. No significant difference was observed between the two groups in the monitored parameters, including rates of clinical remission, along this time period. In conclusion nicotinamide, when employed after the clinical onset of the disease, has no additional effect on natural history of newly diagnosed type 1 diabetes mellitus, besides results obtained by insulin alone. PMID- 7855384 TI - [Roxatidine in the treatment of gastroduodenal mucosal lesions in hepatic cirrhosis]. AB - In about 50% of patients with liver cirrhosis, upper digestive bleeding is not due to oesaphageal varices rupture, but to a group of peculiar mucosal lesions usually referred as "congestive gastropathy" and "hepatogenic ulcer". The pathogenesis of such mucosal damage is still unclear: an important causative role is commonly thought to be played by portal hypertension, but the role of peptical pathway and of the mucosal barrier impairment must not be underscored as well. Aim of this study was to evaluate the effect of roxatidine in the long-term treatment of mucosal damage in 19 patients with liver cirrhosis. Patients showed a good tolerance and no side effects. The improvement of endoscopic pattern after a three months period of roxatidine therapy was statistically significant; moreover there was no occurrence of digestive bleeding. In conclusion, H2 antagonist may be considered as the drug of choice for the treatment of mucosal damage in patients with liver cirrhosis, for both its safety and effectiveness. PMID- 7855385 TI - [Anti-microsomal, anti-thyroglobulin antibodies and thyroid stimulants in hyperthyroid subjects. Analysis of 315 patients followed-up for 3 years at a single medical center]. AB - The objective of the study was to evaluate the significance of the determination of antithyroid antibodies in hyperthyroid patients. Two-hundred-fifteen untreated Graves' hyperthyroid patients (active toxic diffuse goiter-TDG), 54 Plummer's hyperthyroid patients (focal hyperthyroidism) and 46 subjects with other forms of hyperthyroidism were studied. Serum levels of T4, T3, TSH, TSH receptor antibody (TRAb), microsomal antibody (TMAb), and thyroglobulin antibody (TGAb) were evaluated before starting treatment, at regular intervals during therapy, and during the follow-up period after therapy was withdrawn. The antibodies were positive in all patients with active and non-active TGD but positive in only two patients (3.7%) with focal hyperthyroidism. During the treatment interval, TRAb, TMAb and TGAb serum levels fell with a nadir in the 7th month of therapy. In particular, TRAb fell to normal levels in all patients who had basal levels less than 500 U/l (97.7% of the cases) while TMAb and TGAb remained positive. Relapses, following the completion of therapy, occurred in 20.4% after one year and in 33% after two years. Relapses were always linked to a new increase in TRAb. In conclusion, TRAb can be useful in the determination of early disease and in diagnosing remission. It did not appear useful as a prognostic indicator for relapse in individual patients. PMID- 7855386 TI - [Intestinal mycobacterial infections in AIDS. Clinical course and treatment of infections caused by Mycobacterium avium, Mycobacterium kansasii, Mycobacterium genavense]. AB - Digestive apparatus is a common target of atypical mycobacteriosis in AIDS patients (at least 50% of patients with CD4+ lymphocytes < 50/mm3). We describe the clinical-histological features of two cases of Whipple-like syndrome likely caused by Mycobacterium avium (MAI) (study performed by light and electron microscopy), of one case of infection caused by two morphological variants of a MAI strain with a different sensitivity to antibiotics, of one case of M. kansasii infection and of two cases of M. genavense infection accompanied by sensitivity tests to antibiotics (as far as we know, these are the first described quantitative sensitivity tests of M. genavense to antibiotics). In conclusion, we discuss the present therapeutical outlines for M. kansasii and avium, together with the teramporary pharmacological options for M. genavense as suggested by antibiotic sensitivity tests performed on the strains isolated from the studied patients. PMID- 7855387 TI - [Acute alcoholic myopathy]. AB - A case of acute alcoholic myopathy in a subject with a 20 year history of alcohol abuse is described. The condition emerged during an episode of delirium tremens and had a quickly deadly outcome. The rapid evolution of the clinical situation accompanied by variation in the biohumoral indices (CPK, LDH, myoglobin) is stressed and although this prevented from obtaining anatomopathological samples of the rhabdomyolisis, the specific diagnosis was made with reasonable certainty. The onset of the condition was not foreseeable because of the absence of an accurate history of the subject's alcohol abuse on his admission and of significant biohumoral data indicating the existence of an alcohol correlated pathology. PMID- 7855388 TI - [Early indicators of diabetic nephropathy. Changes in selective proteinuria]. AB - Increased morbidity and mortality occur in diabetics with kidney disease. The decrease in fixed anionic charges is considered an early abnormality occurring well before any clinical sign of disease. It has been attached importance to the study of protein charge-selectivity decreased in diabetes in order to find the parameters which highlight the initial preclinical stage of diabetic nephropathy. To investigate the role of protein charge in early diabetic proteinuria, the clearance of protein differing in charge and/or size (anionic and cationic IgG, albumin) was evaluated in type 1 diabetic patients: 18% of them showed increased values of albuminuria. Anionic and total IgG clearances significantly increased in 30% and 12% of the patients and were correlated with the duration of the disease. The anionic/cationic IgG clearance ratio tended to increase in parallel with albumin clearance, but once above macroalbumonuric levels, it tended to fall again, indicating the concomitant presence of size-selectivity loss. In addition to albumin excretion, the anionic IgG clearance and the anionic/cationic IgG ratio, may be valuable in assessing early kidney protein charge-selectivity impairment and in better characterizing normoalbuminuric patients and those in the preclinical stage of diabetic nephropathy. PMID- 7855389 TI - [Interferon-alpha in the treatment of myeloproliferative syndromes]. AB - In these last years the use of alpha-interferon (alpha-IFN) has received increasing attention especially in the onco-haematological field. alpha-IFN is particularly useful in the treatment of hairy cell leukemia, cryoglobulinemia, multiple myeloma and myeloproliferative syndromes (SMP). Among these latter conditions alpha-IFN must be considered as the treatment of choice of the early chronic phase of chronic myelogenous leukemia (LMC) in patients not eligible for allogenic bone marrow transplantation because its ability to induce a greater number of clinical remission and cytogenetic responses when compared to the classical chemotherapeutic agents. A myelosuppressive, non-leukemogenic effect and a more selective activity on the neoplastic hemopoiesis appear to be the most important advantages of alpha-IFN therapy. Based on the results obtained in LMC the use of alpha-IFN has been extended to the other SMP, essential thrombocytemia (TE), polycythemia vera (PV), idiopathic myelofibrosis with myeloid metaplasia (MMM). alpha-IFN is able to control thrombocytosis which often characterize the SMP so it appears to be particularly effective in TE. Actually a relatively limited literature is available about the alpha-IFN treatment of PV and MMM and so it is difficult to draw a final conclusion about the effectiveness of the treatment in these disorders. However, especially in PV, the use of this cytokine appears to be promising. The latest reports of the literature are here summarized and discussed. PMID- 7855390 TI - Developing a strength training program for older adults: planning, programming, and potential outcomes. AB - Muscle strength is important to older adults in maintaining an independent lifestyle and completing activities of daily living. In this article, the authors discuss changes in muscular functioning that commonly accompany the disuse associated with aging, as well as the impact that strength training can have on the older adult's muscle functioning. The article presents the essential components of developing a strength training program: pretesting, setting individualized goals, designing a strength training program, and establishing methods to evaluate the participants' progress. It also lists the benefits of strengthening particular muscle groups. Strength training programs for older adults should be developed on the basis of individualized expectations and goals, with the ultimate goal of facilitating the older individual's lifestyle and independence. Older adults who have participated in a strength training program have reported the following benefits of participation: improved body image, greater flexibility, increased strength, and increased self-confidence. PMID- 7855391 TI - Reducing falls in a rehabilitation setting: a safer environment through team effort. AB - A 2-year falls prevention project has included a concurrent analysis of all falls and a program to prevent falls in a 160-bed rehabilitation hospital. The program has been designed on the basis of the data collected. A consistent follow-up program involves patients and staff in the continuous monitoring of patient safety. PMID- 7855392 TI - The nurse's role in preventing abuse of elderly patients. AB - Abuse of elderly people came to public awareness in the 1970s. Since that time, programs have been initiated to help combat the problem. Each state has legislation for reporting abuse. However, abuse of the elderly often goes unreported due to ignorance, fear, or lack of concern. Public education and intervention strategies appear to be the answer to abuse of the elderly. Nurses, who spend more time with patients than do any other healthcare professionals, are in an ideal position to identify, intervene in, report, and generally lead the way in preventing abuse of the elderly. PMID- 7855393 TI - Managing physical assault in a healthcare setting. AB - Violence is escalating in society, and it is increasingly recognized that caregivers in the healthcare setting are at risk. Workers who have had appropriate self-defense training are attacked less often, and they incur less serious injuries when they are attacked. Healthcare workers may exert reasonable force in self-defense, although the standard response to possible violence should be to prevent it or to talk one's way out of it, if possible. In this article, the author describes some basic self-defense techniques that healthcare workers can use if necessary. PMID- 7855395 TI - Initial assessment of patient cognition in a rehabilitation hospital. AB - A descriptive study was undertaken to ascertain that the cognitive assessment done by nursing staff on patients' admission to a rehabilitation hospital specifically relates to the rehabilitation population. The study took place on a 40-bed general rehabilitation unit. Eighteen patients were evaluated consecutively using a modified mental status examination. Findings demonstrated that the initial cognitive assessment of the rehabilitation patient should include level of consciousness, orientation, insight, recall, attention, visual spatial skills, affect, and speech. In this article, the authors describe the study results and illustrate the implications for rehabilitation nursing in a case study. PMID- 7855394 TI - Telephone follow-up program evaluation: application of Orem's self-care model. AB - The traditional model of nursing, in which patients are discharged with a follow up medical appointment, is no longer sufficient in the current healthcare environment. Primary nurses working in a 58-bed rehabilitation unit located in a 1,700-bed tertiary care medical center implemented a follow-up telephone call program to support the patient's transition from acute rehabilitation nursing care to community living. Patients discharged to home within a five-state area were called 2 weeks and 6 weeks after discharge. Notes on the telephone conversations were entered on a data collection form and later analyzed using Orem's self-care deficit theory (Orem, 1991). A total of 144 follow-up calls were made. During the first call (n = 105), 157 problems (1.5 per call) were noted, whereas 79 (2.0 per call) were identified during the second call (n = 39). Medication, safety, and bladder problems were most often cited as concerns by patients and caregivers after discharge. The most frequently used helping interventions during both the first and the second telephone calls were guiding and supporting. PMID- 7855396 TI - The rehabilitation nurse's role in spiritual care. AB - For the ill or disabled patient, spiritual distress can prove to be a major nursing care problem that interferes with positive patient outcomes. This article explores major factors involved in spiritual distress and illustrates them through case studies and selected interventions. Nurses should be aware of the possibility that unidentified spiritual distress often is the culprit in an unsuccessful plan of care. PMID- 7855397 TI - The flowered tennis shoes. PMID- 7855398 TI - Distinct probabilities. PMID- 7855399 TI - The current nursing procedure for intermittent urinary catheterization in rehabilitation facilities. AB - The purpose of the research study described in this article was to identify the range of catheterization techniques currently practiced in inpatient care settings and to determine current methods of patient-caregiver education about catheterization in a home setting. A questionnaire was mailed to a random sample of 175 rehabilitation facilities accredited by the Commission on Accreditation of Rehabilitation Facilities (CARF); the return rate was 81%. Data were analyzed on the basis of region of the country, type of practice setting, and number of rehabilitation beds. There were few statistically significant correlations, based on this analysis. These results provide a baseline for current practice and suggest the need for development of a standard for practice based on research. A multicenter study that compares clean with sterile methods needs to be conducted to determine which technique is preferable for inpatient practice and which for patient-caregiver education. PMID- 7855400 TI - Self-management of urinary incontinence among women 31 to 50 years of age. AB - In this exploratory and descriptive study, the self-management of urinary incontinence among women 31 to 50 years old is described. Eight self-selected women participated in unstructured tape-recorded interviews that were guided by an interest in understanding women's perceptions about their incontinence. Self management comprised five specific methods: (a) modifying or avoiding the activities that cause involuntary leaking of urine, (b) keeping the bladder empty, (c) avoiding or limiting beverages that stimulate voiding, (d) wearing protective pads, and (e) doing exercises to strengthen the pelvic floor muscles. Successful self-management was characterized by perceptions of control and normality; unsuccessful self-management by perceptions of noncontrol and abnormality and a consideration of medical management. Three types of medical encounters experienced by participants are described. The study indicates that participants responded differently to two temporal stages in their development of incontinence, and this difference affected how incontinence was managed at the time. The implications of this finding for nursing practice and nursing research are discussed. PMID- 7855401 TI - Developing a patient self-medication program for the rehabilitation setting. AB - Self-medication, the ability of the patient to administer his or her own medication, can be useful in the rehabilitation setting in reducing the incidence of polypharmacy, medication abuse, and inappropriate medication usage. However, a patient self-medication program also introduces a variety of issues, such as defining each team member's responsibilities and outlining the steps of the program. These issues may impede the development and implementation of the program. A review of the rehabilitation literature yields little information about program development in the rehabilitation setting or about dealing with such issues. The purpose of this article is to describe the need for a self medication program in the rehabilitation setting, the development of one such program, and ways to overcome some of the problems that cause such programs to falter. PMID- 7855402 TI - Developing and implementing a stroke education series for patients and families. AB - Stroke is the third leading cause of death and the major reason for disability in American adults (Sullivan, 1992). Stroke can be a recurrent disease, but most strokes are preventable. Patient and family education about stroke is a vital link in eliminating the knowledge deficit that can help lead to stroke. This article describes the process of developing and implementing a stroke education program that involves both patients and their significant others. In 1990, rehabilitation nurses at St. Margaret Mercy Healthcare Centers in Hammond, IN, identified 11 essential areas for education and grouped them into six 1-hour teaching sessions. A program was developed and held weekly for a trial period of 3 months. It was so well received that it continues to be a permanent part of the rehabilitation program. Such structured teaching in a relaxed atmosphere better prepares patients for discharge and eases the transition to the home environment. PMID- 7855403 TI - The benefits of triad communication in home health care. AB - Triad communication can be used by the nurse to facilitate communication with a patient and a caregiver in home health care. The family members may be involved as listeners or in discussion with the patient, the nurse, or both. The caregiver is selected based on specific communication objectives and the third person's ability to assist in meeting these objectives. Triad communication can (a) support the family and patient, (b) increase the caregiver's understanding, (c) increase compliance, (d) increase the nurse's understanding, (e) reinforce instruction, (f) decrease manipulation, (g) promote communication between family members, and (h) facilitate positive patient-family relationships. PMID- 7855404 TI - Development of a patient education program for new amputees. AB - In this article, the authors describe how the needs of the patient with a new amputation were assessed and how behavioral objectives were developed for an educational program that would address the knowledge, motor skills, and attitudes necessary for self-care. Two teaching techniques are described. An evaluation process that identifies the patient's or family's achievement of the objectives is discussed. PMID- 7855405 TI - Case study of a patient with chronic pain. PMID- 7855406 TI - Grandmother's quilt. PMID- 7855407 TI - Cross-cultural views of disability. PMID- 7855408 TI - Applying the Roy Adaptation Model to the care of clients with quadriplegia. AB - The Roy Adaptation Model has provided a framework for nursing practice, education, and research for more than 20 years. This article focuses on the model's contribution to nursing practice. Adaptation, the goal of the model, serves as an effective guide for planning care for the client with quadriplegia. A case study is used to show the effectiveness of using the nursing process within the guidelines of the Roy Adaptation Model to promote adaptation in a client with quadriplegia who is coping with living in a long-term care facility. PMID- 7855409 TI - The social isolation of young men with quadriplegia. AB - This article describes the results of a study undertaken to identify perceptions of possible social isolation among individuals who become quadriplegic as young adults. Two focus group sessions were held with 4 male participants in each group. All the young men were between the ages of 19 years and 35 years, and all had been disabled for more than 3 years. The results showed that the participants felt challenged by the environment and their resources but did not experience the feelings associated with social isolation as defined by Goffman (1963). The participants, however, identified important socially isolating stressors based on the human needs described by Maslow (1970) as existing in a hierarchy. The results of the study suggest that people with disabilities need interpersonal techniques that enable them to feel a sense of security and control of their time; rehabilitation nurses are ideally suited to assist clients in developing such techniques. PMID- 7855410 TI - A model for professional rehabilitation nursing practice. AB - As partners in health care, clinical and administrative nurses must share in the work, risks, and rewards inherent in nursing practice while promoting high quality results in a cost-conscious and cost-effective environment. One way to achieve these results is by developing a nontraditional rehabilitation structure and nursing practice model. This article discusses practical strategies for constructing and implementing such a model; it also identifies tangible outcomes of using the model. The healthcare environment in the 1990s demands a high level of involvement on the part of staff; the rehabilitation nursing model presented in this article meets this challenge. PMID- 7855411 TI - The impact of spinal cord injury on older adults' growth and development: a case study. AB - In this case study, the author discusses how a spinal cord injury affected the achievement of developmental goals by a 73-year-old man for whom the usual coping mechanisms were not effective. Nurses on a neurosurgical unit, under the guidance of a rehabilitation nurse, learned how to incorporate considerations of the psychological aspects of the injury into the patient's plan of care. Strategies to intervene with growth and developmental issues had a positive impact on the patient's rate of progress in the rehabilitation setting. PMID- 7855412 TI - The rehabilitation nursing team in the home healthcare setting. AB - This article discusses the initiation and development of a home care rehabilitation nursing team at a large home care agency in northern Virginia. The team had its origins in the concept of the therapy nurse, which evolved into the current rehabilitation nursing role. A team of rehabilitation nurses at the agency provides in-service programs and consultation and case management services for clients with a variety of medical diagnoses. The idea of the rehabilitation nursing team in the home care setting is a fairly new one and warrants the attention of all rehabilitation nurses who are concerned with patients' posthospital care as well as those nurses who are ready to consider moving into the home care field. PMID- 7855413 TI - Pulmonary rehabilitation with respiratory complications of postpolio syndrome. AB - Pulmonary rehabilitation strives to relieve symptoms, improve functional status, and enhance quality of life for patients with pulmonary disease. This article describes the condition called postpolio syndrome and its associated pulmonary complications. Forty-two percent of the respondents to a national survey on the late effects of polio were experiencing new problems related to breathing. Pulmonary rehabilitation, originally developed to address functional impairment and disability related to chronic obstructive pulmonary disease, can benefit patients with postpolio syndrome. A case study is presented. PMID- 7855414 TI - What's in a name? PMID- 7855415 TI - The Americans with Disabilities Act of 1990: implementation and education in rehabilitation nursing. PMID- 7855416 TI - Ethics in rehabilitation nursing. PMID- 7855417 TI - Directory of product manufacturers. PMID- 7855418 TI - An educational program's effects on students' attitudes toward people with disabilities: a 1-year follow-up. AB - The purpose of the study described here was to examine the attitudes of nursing students toward people with disabilities 1 year after the students had participated in an educational program on caring for such people. The program provided (a) information about this care, (b) simulated experiences related to different aspects of care, and (c) contact with disabled people as well as with rehabilitation health professionals. The study also examined how students' attitudes were influenced by the students' age, the number of years they had spent in the nursing program, their degree of experience in caring for people with disabilities, and their amount of personal interaction with disabled people. The Attitudes Towards Disabled Persons (ATDP) scale was administered to 67 nursing students before they completed the workshop. The participants were tested again 1 year later, thereby providing a matched group for examining attitude changes over time. The participants' attitudes were significantly more positive at the follow-up. At the 1-year follow-up, the ATDP scores of the intervention group were also compared with those of a second group of nursing students (n = 170) who had not participated in the educational program. The findings suggested that completion of the educational program was an important influence on students' development of positive attitudes toward people with disabilities. PMID- 7855419 TI - Bacterial sensor kinase/response regulator systems: an introduction. PMID- 7855420 TI - Response regulators: structure, function and evolution. PMID- 7855421 TI - Signal transduction by the EnvZ-OmpR phosphotransfer system in bacteria. PMID- 7855422 TI - The sensor kinase KdpD and the response regulator KdpE control expression of the kdpFABC operon in Escherichia coli. PMID- 7855423 TI - A transmembrane signalling complex controls transcription of the Uhp sugar phosphate transport system. PMID- 7855424 TI - Regulation of capsule synthesis includes interactions of the RcsC/RcsB regulatory pair. PMID- 7855425 TI - The DegS/DegU and ComP/ComA two-component systems are part of a network controlling degradative enzyme synthesis and competence in Bacillus subtilis. PMID- 7855426 TI - Two-component regulators and genetic competence in Bacillus subtilis. PMID- 7855427 TI - Novel aspects of chemotactic sensory transduction in Bacillus subtilis. PMID- 7855428 TI - The role of FlbD in regulation of flagellar gene transcription in Caulobacter crescentus. AB - The flagellar (fla) genes in Caulobacter crescentus are organized into a regulatory hierarchy of four levels (I-IV) in which transcription of the class III and class IV genes late in the cell cycle from sigma 54-dependent promoters depends on expression of the class II genes above them. The periodicity of fla gene expression has been attributed to sequential activation and repression by specific transcription factors. We have been particularly interested in understanding the function and regulation of one such transcription factor, FlbD. FlbD belongs to the NtrC family of bacterial response regulators that catalyse the initiation of transcription by sigma 54 RNA polymerase (E sigma 54) and its function is required for transcription of the class III and IV fla genes. Here we show that purified FlbD binds to ftr elements that are required for transcription from the sigma 54-dependent class III flbG promoter (ftr1) and repression of transcription from the class II fliF promoter (ftr4). Dimethylsulphate footprinting assays demonstrated that FlbD makes base-specific contacts at highly conserved guanine nucleotides in each half site of the ftr sequences. In a reconstituted in vitro transcription system using E. coli E sigma 54, we found that FlbD was clearly capable of driving transcriptional initiation from the flbG promoter and that this activity relied on the ftr1 binding site. Several observations suggest that phosphorylation plays a role in the regulation of FlbD activity. First, we found that a mutant form of FlbD (FlbDS140F) corresponding to the substitution found in a constitutively active NtrC protein (NtrCS160F), displayed a greater potential for activating E sigma 54-dependent transcription that the wildtype protein. We also observed that high energy-phosphate-containing molecules stimulate transcription activation by the wild type FlbD. Together, these results suggest that FlbD is responsible for mediating fla gene transcription initiation by E sigma 54 and that covalent modification is likely to play a role in governing FlbD activity during the cell cycle. PMID- 7855429 TI - Sensor/response in Myxococcus xanthus to attractants and repellents requires the frz signal transduction system. PMID- 7855430 TI - Aerobic-anaerobic gene regulation in Escherichia coli: control by the ArcAB and Fnr regulons. AB - A variety of pathways for carbon and electron flow in the bacterium Escherichia coli and in other enteric bacteria are differentially expressed depending on whether molecular oxygen is present in the cell environment. This review briefly summarizes the metabolic pathways operative during aerobic versus anaerobic cell growth, and provides a regulatory overview for how the cell controls expression of the many genes involved in these processes. The cell has two distinctly different transcriptional regulators, consisting of the Fnr and the ArcA/ArcB regulatory proteins to accomplish this task. Together, they coordinate gene expression to adjust carbon flow with electron flow and energy generation so that cells can balance growth in an efficiently coupled manner. PMID- 7855431 TI - Dual interacting two-component regulatory systems mediate nitrate- and nitrite regulated gene expression in Escherichia coli. PMID- 7855432 TI - Oxygen regulation of expression of nitrogen fixation genes in Rhizobium meliloti. AB - The sensor kinase FixL and the response regulator FixJ induce the expression of the nitrogen fixation genes of Rhizobium meliloti in response to microaerobiosis, which is a characteristic feature of the plant root nodule interior where the bacteria fix nitrogen. The kinase activity of a purified, soluble derivative of the membrane-bound hemoprotein FixL, designated FixL*, is stimulated under low oxygen conditions, thus increasing FixJ-phosphate levels. FixJ-phosphate is a potent transcriptional activator of the nifA and fixK genes, the products of which, in turn, induce the expression of most if not all of the remaining nitrogen fixation genes. FixL* and FixL*-phosphate also dephosphorylate FixJ phosphate, and this activity is depressed by low oxygen concentrations. In the current model, gene expression is reciprocally coordinated by the kinase and phosphatase activities of FixL according to changes in oxygen tension. PMID- 7855434 TI - The role of the PhoP/PhoQ regulon in Salmonella virulence. AB - Salmonella typhimurium is a facultative intracellular pathogen that is able to survive in a wide variety of inhibitory and nutritionally deprived host environments. The ability to survive under such hostile conditions, which are often encountered during the course of infection, contributes to its pathogenic properties. Some of the virulence determinants of S. typhimurium are under the transcriptional control of the PhoPQ two-component regulatory system. Several virulence phenotypes have been associated with mutations in the phoPQ operon including the inability to survive within macrophages and increased susceptibility to antimicrobial peptides and acid pH. Only 25% of PhoP-modulated genes are involved in virulence and the phoPQ operon is present in both pathogenic and non-pathogenic microbes. These data suggest that PhoP is not exclusively involved in virulence and that it is required for the physiological control of activities common to other bacteria. PMID- 7855433 TI - Host recognition by the VirA, VirG two-component regulatory proteins of agrobacterium tumefaciens. AB - Agrobacterium tumefaciens contains about 25 vir genes localized on a 200-kb tumour-inducing (Ti) plasmid that direct a conjugation-like transfer of tumorigenic DNA from the bacterium to the nuclei of infected plant cells. These genes are strongly and coordinately induced during infection in response to three different classes of stimuli which are thought to be key chemical features of a typical wound site. These stimuli are (i) guaiacol and syringol derivatives such as acetosyringone, (ii) sugars such as glucose and glucuronic acid, and (iii) acidic pH. The sensing of these compounds is carried out by the VirA, VirG and ChvE proteins. VirA is a four-domain histidine protein kinase, while VirG is a transcriptional activator which is activated by VirA-mediated phosphorylation. ChvE is a chromosomally encoded periplasmic sugar binding protein which is required for sensing sugars but dispensable for sensing the other two stimuli. Here we will review the nature of these chemical stimuli, the structure and function of the three regulatory proteins, their similarity to sensors found in human and animal pathogens, the factors influencing their pool size, and their role in the host range of different strains of A. tumefaciens. PMID- 7855435 TI - Eukaryotes have "two-component" signal transducers. AB - The eukaryotic proteins discussed above share a number of amino acid sequence features with prokaryotic members of the two-component signal transducer family. ETR1 and Sln1 each contain putative HPK and receivers, while Skn7 has similarity to receivers only. The other proteins--phytochromes, BCKDH kinase and the dr6 gene product--appear to be distant relatives of the two-component family because they have less-conserved motifs, although even biochemically defined prokaryotic family members can lack conserved motifs (Parkinson and Kofoid, 1992). The eukaryotic and prokaryotic proteins also show similar diversity with respect to the arrangements of the components; transmitters and receivers can lie within the same protein (for example, ETR1 and Sln1 in eukaryotes and BarA and LemA in prokaryotes) or receivers can lie on a separate protein (for example, Skn7 in yeast and CheY in bacteria (Stock et al., 1985)). The new eukaryotic members of the two-component family raise a number of questions, especially since their functions are not yet clearly defined. The identities of the signals transduced are unknown, except for the red light signal for phytochrome. Ethylene is presumably the signal for ETR1, but this has not been demonstrated directly. It also remains to be seen whether eukaryotic two-component modules are functionally homologous to the prokaryotic two-component systems; eukaryotic modules could be utilized in uncharacterized ways, possibly in combination with different signalling components. Among the eukaryotic proteins discussed here, BCKDH kinase has the best-understood function, yet its substrate is not an orthodox response regulator, and moreover, the substrate is phosphorylated at serine residues. PMID- 7855436 TI - Circadian rhythms in microorganisms. PMID- 7855438 TI - In vitro identification of a protein of Saccharomyces cerevisiae that interacts specifically with the G-rich DNA strand of the telomere. AB - The telomeres of Saccharomyces cerevisiae consist of a repeated G2-3T(GT)1-6 DNA sequence that forms a complex with proteins. To date only the RAP1 protein has been shown to bind to the simple sequences in yeast telomeric DNA, as well as to non-telomeric regulatory sites. We have used synthetic oligodeoxyribonucleotides, both double- and single-stranded, to identify specific yeast telomeric proteins in a partially purified yeast extract. Using the gel shift assay, we detected a binding activity that is stable at high ionic strength and that recognizes specifically the G-rich protrusion of a double-stranded synthetic yeast telomere, as well as the G-rich single strand. This is the first evidence of a purely telomeric protein in that it binds to the single-stranded telomeric protrusion of the yeast chromosome. PMID- 7855437 TI - Analysis of a cis-active sequence mediating catabolite repression in gram positive bacteria. AB - One form of catabolite repression (CR) in the Gram-positive genus, Bacillus, is mediated by a cis-acting element (CRE). We use here a consensus sequence to identify such elements in sequenced genes of Gram-positive bacteria. These are analysed with respect to position and type of gene in which they occur. CRE sequences near the promoter region are mainly identified in genes encoding carbon catabolic enzymes, which are thus likely to be subject to CR by a global mechanism. Functional aspects of CREs are evaluated. PMID- 7855439 TI - Molecular phylogeny of Eubacteria: a new multiple tree analysis method applied to 15 sequence data sets questions the monophyly of gram-positive bacteria. AB - Phylogenetic relationships between the major eubacterial phyla were studied using the sequences of 15 homologous bacterial genes. Neither the classical concatenation strategy nor a new multiple tree analysis method involving statistical tests of the inferred phylogenetic relationships provided any (solid) conclusions about eubacterial phylogeny; no pairs of eubacterial phyla proved to be closer to each other in the 15 reconstructed trees than would be expected for trees with random topologies. The phylogeny of Eubacteria therefore appears to be tightly bush-like. Moreover, results from both concatenation and multiple tree analysis raise doubts concerning the monophyly of the so-called Gram-positive bacteria phylum, since the monophyly hypothesis is no more strongly supported by data than its alternatives. It is noteworthy that the structural bases for the Gram-positive phenotype are not incompatible with the hypothesis of independent emergence of this character at two different times. PMID- 7855440 TI - Preferential interaction of Salmonella typhimurium with mouse Peyer's patch M cells. AB - We have used a mouse Peyer's patch gut loop model to investigate the role of the intestinal membranous epithelial (M) cells in the pathogenesis of Salmonella typhimurium. These specialized antigen sampling cells are located in the follicle associated epithelium (FAE) overlying the isolated and aggregated lymphoid follicles in the small and large intestines. Our studies have demonstrated that S. typhimurium adheres more frequently to the Peyer's patch FAE cells than to the villous enterocytes and that, within the FAE, this bacterium preferentially interacts with the M cells. Quantitative light microscopic studies, using the lectin Ulex europaeus 1 (UEA1) to identify M cells, revealed that 34-fold more bacteria bound per unit area of M cells than per unit area of enterocyte. Within a 30-min incubation period, some M cells had clearly been invaded by the Salmonella. We therefore propose that M cells are a major route by which S. typhimurium penetrates the intestinal epithelial barrier. Bacterial adhesion to M cells occurred in a non-uniform pattern, suggesting the existence of M-cell subtypes. The interaction of S. typhimurium with mouse Peyer's patch M cells was accompanied by membrane ruffle formation and polymerized actin redistribution similar to that observed in cultured cell lines infected by this bacterium. This study emphasizes the suitability of Salmonella as an oral vaccine delivery system since, by preferentially interacting with the M cells, these bacteria are targeted to sites where cells of the immune system are concentrated. PMID- 7855441 TI - Analysis of the immune response to Yersinia enterocolitica serotype-O:9-released proteins by immunoblot and ELISA. AB - The immune response towards the released Yersinia enterocolitica outer membrane proteins (Yop) was analysed by immunoblotting and ELISA using a rabbit experimental model. Rabbits orogastrically or intravenously infected with the virulent (plasmid-bearing) Y. enterocolitica O:9 W836 strain developed a significant response by (IgG) antibodies to the released proteins having molecular weights of 51 (YopH) and 41 (LcrV) kDa, respectively. However, only in animals infected via the orogastric route were specific antibodies of the IgG class found against plasmid-encoded polypeptides of 35 (YopN) and 20 (YopQ) kDa. These results suggest that the expression of Yop in vivo may be conditioned by the route of infection used. Using ELISA, a significant response by IgG-class antibodies to YopH protein was evident in the sera from rabbits both orogastrically and intravenously infected with the virulent (pYV+) Y. enterocolitica O:9 W836 strain. By contrast, no specific antibodies to this antigen were detected in sera of rabbit infected with an avirulent (plasmid cured) derivative (pYV-) strain. Accordingly, this protein could be very useful as an antigen in ELISA for serological diagnosis of infections caused by enteropathogenic strains of Yersinia spp. PMID- 7855442 TI - Screening of synthetic trehalose 6,6'-diesters and trehalose 6-monoesters as potential immunoreactants for the serodiagnosis of tuberculosis. AB - The absence of serological cross-reactivity between trehalose 2,3-diester (DAT, formerly SL-IV) and synthetic trehalose 6,6'-diesters and trehalose 6-monoesters was established by ELISA testing using polyclonal immune sera raised in rabbits sensitized with "DAT". From the screening of fifteen synthetic trehalose 6,6'- and 6-esters, "mirror" pseudo cord factor no. 1, "mirror" amides no. 5 and 6, cord factor analogues 7 and 8 and trehalose 6-monoesters 10 and 11 were selected for future, more extensive serological analysis. Paired comparisons of analogues among these fifteen substances showed that serodiagnostic discrimination power was more a function of the carbon chain length of their substituent groups--as well as of their position--than of the "mirror" constitution of the molecules. More exhaustive testing of these seven compounds is needed to select the synthetic product most efficient in the ELISA serodiagnosis of tuberculosis. PMID- 7855443 TI - The therapeutic value of naloxone and mannitol in experimental focal cerebral ischemia. Neurological outcome, histopathological findings, and tissue concentrations of Na+, K+ and water. AB - In this study, the effect of naloxone and mannitol was investigated on focal cerebral ischemia induced by middle cerebral artery occlusion with the transorbital approach in the rabbit model. Rabbits were randomly and blindly assigned to one of three groups (six animals in each): (1) a control group that received equal volumes of physiological saline solution; (2) a naloxone group that received a 5 mg/kg bolus of naloxone i.v. 1 h after occlusion, followed by 2 mg/kg per hour i.v. infusion for 5 h; (3) a mannitol group that received 0.2 g/kg twice with an interval of 10 min at 5 h. The neurological outcome was better in rabbits treated with naloxone than in the others. The ratio of ischemic to total neurons in the cortex was smaller in the naloxone group than in the control and mannitol groups (P < 0.05). In addition, there was a statistically significance reduction in infarct size in the naloxone group compared with the other groups (P < 0.05). Edema was severe in the control and mannitol groups, but moderate in the naloxone group. There was no statistically significant difference in Na+, K+, and water content between groups. Our data provide evidence for the beneficial effects of naloxone on promoting neurological recovery and preserving the ischemic area. PMID- 7855444 TI - Effects of two different inhibitors of the arachidonic acid metabolism on platelet sequestration in endotoxic shock. AB - Metabolites of arachidonic acid are known to play an important part in the pathogenesis of organ injury in endotoxic shock. We compared the effects of the classical cyclooxygenase inhibitor aspirin with that of the dual cyclooxygenase and lipoxygenase inhibitor ketoprofen on the behavior of platelets tagged with 111In-labeled oxine in multiple organs during endotoxin shock. Three groups of sheep (n = 7 in each) were anesthetized before being subjected to endotoxin shock. Group E had no drug treatment (shock controls), group KET received ketoprofen and group ASP received aspirin treatment. In the lungs and in the liver of group E there was a marked sequestration of platelets, which started in both organs immediately after administration of endotoxin and continued throughout the study. In the treated groups, however, the response to endotoxin was both delayed and reduced compared with the untreated shock controls. The first changes in platelet activity were noted after more than 1 h in the treated groups. Four hours after administration of endotoxin, platelet activity (sequestration) had increased in the lungs by 102 +/- 14% in group E, 53 +/- 11% in group ASP and 20 +/- 13% in group KET (P < 0.01, P < 0.01 and P < 0.05 respectively compared to baseline). Corresponding values for the liver were 52 +/ 16% in group E, 22 +/- 19% in group ASP and -2 +/- 12% in group KET (P < 0.01, P < 0.01 and P > 0.05 respectively compared with baseline).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7855445 TI - Serotonin, serotoninergic agents and their antagonists suppress humoral immune reaction in vitro. AB - Serotonin (5-HT), its derivative 5-methoxy-tryptamine (MeOT) and ergot-alkaloid dihydroergosine (DHESN) suppressed the immune reaction of mouse spleen cells against sheep erythrocytes in vitro (PFC assay). Ketanserin and propranolol, antagonists of 5-HT, also caused suppression. However, cells incubated with propranolol 20 min before 5-HT or MeOT produced as many plaques as the non treated cells. Preincubation with ketanserin resulted in similar interference, but the reversal was not complete. It is concluded that serotonin and related agents probably affect several types of immunocompetent cells participating in successive stages of the PFC reaction. The antagonists probably interfered via 5 HT receptors, adrenergic receptors or both. Immunosuppression observed with serotoninergic agents and their antagonists draws attention to possible side effects of such drugs. PMID- 7855446 TI - Simultaneous preparation of rabbit intestinal brush border and basolateral membrane vesicles. AB - A highly reproducible method is described for simultaneous preparation of the rabbit intestinal BBMV and BLMV. When BLMV were purified on continuous sorbitol gradient the final enrichment was over ten-fold for both Na+, K(+)-ATPase and K(+)-activated phosphatase. BBMV were separated using repeated precipitation with magnesium and EGTA. Marker enzymes of the brush border membrane also showed over ten-fold enrichment. There was no contamination with other cellular organelles. The characteristics of the preparations were checked by SDS gel electrophoresis, which showed distinct protein patterns for both membranes; monoclonal antibodies for villin reacted with the BBMV but not with BLMV, showing the absence of contamination of the BLMV fraction. The quality of the membranes, assessed by D glucose transport, showed good functional properties for both BBMV and BLMV. Orientation of the vesicles was checked by permeabilizing with SDS buffered with BSA and showed that BLMV are oriented inside out and BBMV right side out. The model simulates normal transepithelial intestinal transport at the level of membrane vesicles and could be applied in transport studies in physiology and pharmacology. PMID- 7855447 TI - Biochemical and biophysical alterations of lipoprotein after liver transplantation from a living related donor. A biochemical and proton NMR study. AB - Changes in lipoprotein metabolism after liver transplantation from living related donors were investigated in nine pediatric patients by means of biochemical and proton nuclear magnetic resonance (NMR) analyses of lipoprotein. NMR offers rapid and nondestructive measurement of lipoprotein. The ratio of esterified cholesterol to total cholesterol, expected to be a prognostic indicator after liver transplantation, was low before the operation (0.44) and recovered to over 0.6 at 3 weeks. The half line width of the methylene peak of lipoprotein, as measured by proton NMR, was correlated with the ratio of esterified cholesterol to total cholesterol. It is suggested that proton NMR analysis can provide information about the biophysical changes in lipoprotein associated with liver transplantation. PMID- 7855448 TI - Allopurinol dose is important for attenuation of liver dysfunction after normothermic ischemia: correlation between bile flow and liver enzymes in circulation. AB - We have investigated the effect of two doses of allopurinol (ALL) (100 and 50 mg/kg) administered i.v. on liver function after 1 h of normothermic ischemia. ALL given in a concentration of 100 mg/kg significantly improved bile output after 1 and 24 h of reperfusion. Hepatocyte injury reflected by alanine aminotransferase (ALT) and lactic dehydrogenase (LDH) in plasma was also significantly reduced at 24 h, but not at 1 h of reperfusion compared with controls. ALL administered at a concentration of 50 mg/kg had some protective effect. Significant correlation between circulating liver enzymes and bile output at 24 h after reperfusion indicates an important pathophysiologic link between hepatocyte function and injury in this time window. PMID- 7855449 TI - The inhibitory effects of amrinone on isolated rat uterus. AB - Amrinone, a new cardiotonic drug, has received attention as a better therapeutic agent than the cardiac glycosides in the treatment of congestive heart failure. In this study, the effects of amrinone on isolated rat uterus and its probable mechanism of action were investigated. At two different concentrations (0.1 and 0.5 mM), the inhibitory effects of amrinone on the spontaneous contractions of rat uterus were noted. In addition, amrinone (0.5 mM) was found to inhibit the tonic contractions induced by potassium sulphate (K2SO4)-Ringer solution (91.74%) and calcium chloride (CaCl2) (93.04%). These inhibitory effects were compared with regulators of the phosphodiesterase enzyme (PDE). It was concluded that amrinone could behave as a calcium antagonist and PDE inhibitor. PMID- 7855450 TI - Outpatient oncology settings: a variety of services. AB - Where and how can we best care for oncology patients, and what are the models of care that will provide safe patient and family-centered care while containing costs? Because the majority of all cancer care is delivered in the outpatient setting, the types of outpatient oncology settings, the services provided, and the advantages and disadvantages of different types of clinics are important considerations. PMID- 7855451 TI - Nursing care delivery models in ambulatory oncology. AB - Oncology nurse leaders are challenged to design ambulatory nursing care delivery models that are cost-effective, efficient, and facilitate positive patient outcomes. Many of the models used in the inpatient setting can be adapted to the ambulatory setting. Whatever model is implemented, it is important to delineate practice expectations. PMID- 7855452 TI - The ambulatory oncology nurse's role. AB - The increasing complexity of cancer care in the ambulatory setting results in the role of the ambulatory oncology nurse being pivotal to ensuring quality health care. Nurses have created a variety of multifaceted roles that include the staff nurse, advanced practice nurse, clinical trials nurse, office nurse, and the head nurse or nurse manager. Common issues encountered by the ambulatory oncology nurse are telephone triage, limitation of time, and transition of care. PMID- 7855453 TI - Continuity of care: a challenge for ambulatory oncology nursing. AB - Continuity of care has many facets and challenges both as a philosophy and in practice. In an abstract sense, it represents an ideal to which health care professionals strive. It is becoming a professional and consumer expectation that each health care professional contribute to continuity of care. Although a variety of organizational models for providing continuity of care have been established in which nursing plays a prominent role, recent research suggests that some frontline nursing personnel may not fully understand their responsibility to continuity of care. There is a need for nursing curricula in both basic and continuing education programs to address continuity of care concepts, models, and methodologies to strengthen awareness of patient care needs across the disease continuum and across care settings. Performance expectations that include professional accountability for continuity of care also encourage greater attention to this issue. PMID- 7855454 TI - Documentation in the ambulatory setting. AB - Mastering the skill of adequate, succinct, and confidential record keeping is a major challenge in today's health care environment. A variety of documentation tools and styles has been developed to meet the expanding and comprehensive needs of the ambulatory oncology arena. Ethical issues, legal ramifications, financial and reimbursement issues, and quality assurance are important aspects of documenting ambulatory oncology care. PMID- 7855455 TI - Impact of reimbursement and health care reform on the ambulatory oncology setting. AB - Changes in reimbursement and health care reform permeate all practice settings of oncology care today. Chemotherapy and biologic regimens used in cancer therapy are easy targets for reimbursement denials because of regulations against their investigational status, "off-label" usage, methods of administration, and high cost. The clinician requires a knowledge of health care trends, different types of reimbursement, reimbursement issues unique to ambulatory oncology care, and strategies useful in resolving billing issues. PMID- 7855456 TI - Productivity and workload measurement in ambulatory oncology. AB - The future of ambulatory patient classification and workload analysis will depend on the development of an accurate model of data collection, analysis, and reporting. The roles of ambulatory nurses and the delivery of ambulatory services is a foundation for tool development. The development of a consistent productivity system will make it easier to manage resource allocations and to determine appropriate staffing and space allocation. PMID- 7855458 TI - Intervention for stone disease in the era of new technology. PMID- 7855457 TI - Administrative issues in ambulatory oncology care. AB - The major priority of the ambulatory care nurse administrator is to negotiate the role changes that have occurred in ambulatory care and allow nurses to practice developed skills and collaborate with other health care professionals. Defining the scope of practice, developing standards of care, staffing requirements, budgeting, and developing a quality assurance program are major responsibilities of the ambulatory nurse administrator. PMID- 7855459 TI - Management of the incidentally detected solid renal mass. AB - Solid renal masses are being increasingly detected incidentally in individuals with no urologic symptoms. Contemporary imaging modalities allow the diagnosis of RCC to be established with 85% to 90% accuracy. Some solid renal masses with radiographic characteristics of RCC will ultimately prove to be a benign adenoma or oncocytoma. Recent data suggest that radical nephrectomy and nephron-sparing surgery each provide effective curative treatment for patients with a single, small, unilateral, localized RCC. The long-term renal functional advantage of nephron-sparing surgery with a normal opposite kidney remains unproven. Radical nephrectomy remains the treatment of choice for patients with larger (> 4 cm) or multiple localized renal cell carcinomas. PMID- 7855460 TI - The evaluation and management of vesicoureteral reflux. PMID- 7855461 TI - The evaluation and nonsurgical management of impotence. AB - The evaluation of patients with erectile dysfunction and the increasing number of nonsurgical options for its treatment have been reviewed. If nonsurgical options are unsuccessful or unsatisfactory to the patient, then a number of surgical alternatives are available including penile prostheses, and in a selected small number of patients, vascular reconstructive surgical procedures. Hopefully, in the future, a better understanding of erectile dysfunction will result in additional therapeutic options, both nonsurgical and surgical. PMID- 7855462 TI - Antimicrobial therapy for urinary tract infections. PMID- 7855464 TI - A direct, general approach based on isobolograms for assessing the joint action of drugs in pre-clinical experiments. AB - Pharmacologists and other biologists frequently use methods based on the interpretation of isobolograms to quantify the extent of synergy or antagonism between drugs used in combination in pre-clinical studies. Most methods have been unsatisfactory from a statistical viewpoint, many because they have relied solely on visual evaluation, others because the methods have not taken into account the variability of the measurements. We describe a direct approach for quantifying the joint potency of two drugs, a central feature being the use of simple isobole models that lead directly to response surface models for the expected experimental outcomes. The approach is general in the sense that one can use it for discrete or continuous responses, different underlying probability distributions, linear or non-linear dose-response functions of the drugs used singly, and a variety of experimental designs. Our approach extends the suggestions made by Hewlett for measuring the joint potency of drugs, and is similar in spirit to the approaches proposed by Greco et al. and Weinstein et al. We describe the analysis of data from an in vitro experiment conducted to evaluate the efficacy of the antiviral drugs AZT and ddI used in combination. PMID- 7855463 TI - Surgical adrenal disorders. PMID- 7855465 TI - Monitoring of a pilot toxicity study with two adverse outcomes. AB - We consider monitoring a pilot toxicity study in which the adverse outcome is bivariate and the goal is to terminate the trial if evidence of excessive toxicity is encountered. We develop a Bayesian monitoring rule, based on the posterior probability that the frequency of either adverse outcome exceeds that observed under standard therapy. This rule is intuitive and ethical, and extends in a straightforward fashion from the univariate to the multivariate case. Since p-values and confidence intervals are standard methods for reporting the results of clinical trials, we also suggest how frequentist inferences may be drawn at the conclusion of a study monitored in this fashion. This work thus represents an integration of Bayesian and frequentist methodology for sequential clinical trials. PMID- 7855466 TI - On a model-based approach to estimating efficacy in clinical trials. AB - Treatment efficacy is of primary importance in phase III clinical trials. Determining the true size of the treatment effect is often complicated by patient non-compliance with the regimen. This paper examines a model-based approach in the spirit of Efron and Feldman utilizing drug and placebo compliance information. One of the assumptions of this analysis is 'comparability' of drug and placebo compliance. Robustness in estimation of subgroup and population treatment effects when this assumption is violated is investigated in a simulation study. We find that even moderate non-comparability (for example, normalized compliance correlations of 0.4) may produce severely biased estimates. The basis is modulated by the strength of the relationship between compliance and the response on placebo. PMID- 7855467 TI - The use of a square array scheme in blood testing. AB - When testing blood samples for the presence of disease, considerable efficiencies may be achieved by pooling samples and testing them as a batch. It is shown that placing the samples in a square array and pooling rows and columns has substantial advantages, particularly in the reduction of false negatives. The commonly used 8 x 12 array is also considered. PMID- 7855468 TI - Attributable fraction estimates and case definitions for malaria in endemic areas. AB - Asymptomatic carriage of malaria parasites occurs frequently in endemic areas and the detection of parasites in a blood film from a febrile individual does not necessarily indicate clinical malaria. In areas of low and moderate endemicity the parasite prevalence in fever cases can be compared with that in community controls to estimate the fraction of cases which are attributable to malaria. In areas of very high transmission such estimates of the attributable fraction may be imprecise because very few individuals are without parasites. Furthermore, non malarial fevers appear to suppress low levels of parasitaemia resulting in biased estimates of the attributable fraction. Alternative estimation techniques were therefore explored using data collected during 1989-1991 from a highly endemic area of Tanzania, where over 80 per cent of young children are parasitaemic. Logistic regression methods which model fever risk as a continuous function of parasite density give more precise estimates than simple analyses of parasite prevalence and overcome problems of bias caused by the effects of non-malarial fevers. Such models can be used to estimate the probability that any individual episode is malaria-attributable and can be extended to allow for covariates. A case definition for symptomatic malaria that is used widely in endemic areas requires fever together with a parasite density above a specific cutoff. The choice of a cutoff value can be assisted by using the probabilities derived from the logistic model to estimate the sensitivity and specificity of the case definition. PMID- 7855469 TI - Age-related reference ranges: significance tests for models and confidence intervals for centiles. AB - A method of fitting age-related reference ranges using maximized likelihood is presented. The method is illustrated using CD4 counts of uninfected children born to HIV-1 infected women. The likelihood incorporates exponential functions to describe the Box-Cox transformation parameter that induces Normality and the mean and standard deviation of the transformed data, at all ages in the range. This guarantees that the centiles are asymptotic to notional adult values and avoids edge effects. Likelihood ratio tests were used to assess the significance of the model parameters, and profile likelihood confidence intervals were constructed around the fitted centiles. The asymptotes of the resulting CD4 reference range for the childhood dataset were compared with CD4 counts available from a group of uninfected adults. The proposed approach limits the need for arbitrary decisions about grouping of the data, degree of smoothing or choice of model. PMID- 7855470 TI - Determining the size of a cross-sectional sample to estimate the age-specific incidence of an irreversible disease. AB - The design of a cross-sectional survey to estimate the age-specific incidence of an irreversible disease is considered, where the incidence rate is not changing over time and the risk of mortality is not affected by the onset of disease. The sample is assumed to give information on the current age and disease status of individuals, but not on age at onset of the disease. We consider the problem of determining overall sample size in this context, as well as how best to choose the distribution of sampling across various age groups. These issues are considered with the aim of obtaining incidence estimates achieving acceptable levels of precision. The proposed methods are illustrated by measles incidence estimation. PMID- 7855471 TI - On the analysis of life tables for dependent observations. PMID- 7855472 TI - Laparoscopic approaches to abdominal malignancy. AB - The use of laparoscopy for diagnosis and staging of intra-abdominal malignancies is not an exclusive procedure. It is another modality in the armamentarium of caring for the patient. The selection of the appropriate patients is discussed in detail and must include a determination of the long-range plans for intervention. The technical issues include problems of previous abdominal surgery, adhesions, ability to tolerate general endotracheal anesthesia, and ability to properly position the patient for an adequate examination. The endoscopic surgeon must be able to differentiate between the benign and malignant process during endoscopic examination and must be skilled in obtaining appropriate biopsies. In the staging of lymphoma, laparoscopy has virtually replaced the open celiotomy technique. Laparoscopic removal of appropriate lymph nodes is essential. The role of laparoscopy in a second-look operation is discussed as well as contraindications and complications of the procedure. PMID- 7855473 TI - Apneumic laparoscopy in surgical oncology. AB - Minimally invasive techniques now play an important role in virtually every aspect of general surgery. While it is unlikely that celiotomy for malignant disease will fall into obscurity as rapidly as open cholecystectomy, greater use of videoscopic techniques in surgical oncology are inevitable and will undoubtably improve patient care. Techniques of isopneumic laparoscopy have already proven useful in trauma, cholecystectomy, bowel resection, herniorrhaphy, and a variety of other procedures. Further advances in this technique are dependent on the development of "user friendly" abdominal wall retraction systems. PMID- 7855474 TI - Laparoscopy for construction of feeding enteral tubes and diverting stomas. AB - Laparoscopy has now assumed a new and important role in the treatment of malignant diseases. An important part of this role is the establishment of feeding enterostomies and stomas. This function is vital in both those patients who may not be candidates for curative therapy and those being staged for definitive therapy. PMID- 7855475 TI - Laparoscopic surgery for colorectal neoplasms. AB - Laparoscopy is being used to assist in an increasing number and variety of bowel procedures. However, when being used for neoplastic disease concerns of margins and adequacy of mesenteric dissection must be addressed. We've performed 110 laparoscopic-assisted bowel procedures, with 45 of these performed for neoplastic disease. Ninety-two bowel resections were performed including 24 subtotal, total, or proctocolectomies. In this chapter we review the results of our series, as well as other reported series, and discuss some of the controversies involved with laparoscopy for neoplastic disease. PMID- 7855477 TI - Minimally invasive surgery for pulmonary and esophageal tumors. AB - The development of endoscopic video capabilities has opened a new era in thoracic operations. This paper discusses video-assisted thoracic surgery (VATS) as part of the armamentarium of the thoracic surgeon. VATS is the procedure of choice for a solitary pulmonary nodule. It is also a useful staging procedure in selected patients with pulmonary and esophageal tumors. The role of VATS in the definitive resection of certain lung cancers is discussed and there is a call for randomized controlled studies to determine if there is an advantage for the utilization of VATS. The use of VATS for resection of esophageal tumors is discussed. It is currently under development and investigation. PMID- 7855476 TI - The role of laparoscopy in diagnosis and treatment of primary or metastatic liver cancer. AB - Laparoscopy is considered a modality complimentary to the current staging techniques. Radiology offers sophisticated evaluations such as CT, MRI, ultrasound, and invasive vascular radiologic procedures. Laparoscopy when applied appropriately can provide a diagnosis with increased accuracy and eliminate unnecessary delays in formulating a treatment plan. If a patient appears to have a resectable lesion or lesions and is deemed an acceptable surgical candidate, it is appropriate for laparoscopy to be performed just prior to opening the abdomen for purposes of hepatic resection. The techniques of biopsy, laparoscopic intra abdominal ultrasound, and the limitations of laparoscopy are discussed in detail. Lastly, the role of laparoscopic hepatic resection and its application, particularly in superficial or peripheral lesions, is presented. The role of laparoscopy in hepatic lesions is evolving where it is obvious that it offers benefits not available through other means in evaluating the liver tumor. PMID- 7855479 TI - Laparoscopic staging of prostatic carcinoma. AB - Current treatment of prostate cancer is highly controversial, however accurate assessment of pelvic lymph node status is important to determine early in the course of therapy if adjuvant hormonal ablation is necessary. Indications for laparoscopic assessment of pelvic lymph nodes are now better defined and the technique requires a high degree of technical skill and expertise. A series of 50 patients who underwent laparoscopic pelvic lymphadenectomy is presented. A greater than 40% chance of node positivity was found in a group of patients who had either a clinical stage B2, C, DO, or a prostate-specific antigen level greater than 40 ng/dl, or a total Gleason score of 7, 8, 9, or 10. Laparoscopic pelvic lymphadenectomy remains the current method to accurately stage lymph node involvement in prostate carcinoma. PMID- 7855478 TI - Laparoscopic nephrectomy and adrenalectomy. AB - Laparoscopic surgery is a rapidly evolving technique in minimally invasive surgery. In the 1970s and 1980s, the greatest advances in laparoscopy were achieved by the gynecologists. Urologist, however, have used the laparoscope for many diagnostic as well as therapeutic procedures. The initial urological procedures performed included the localization of undescended testicles. Following this, procedures such as pelvic lymphadenectomy and varix ligation became common. This paper will review the current applications of laparoscopic nephrectomy and adrenalectomy. PMID- 7855480 TI - The role of laparoscopy in the management of gynecologic malignancy. AB - With the advent of minimally invasive laparoscopic techniques, most gynecologic procedures for benign conditions can be performed in an outpatient setting. However, the role of such techniques in gynecologic oncology is not well defined. By reviewing the literature and presenting some new data, we attempt to elucidate the applications of operative videolaparoscopy in gynecologic oncology. Advanced laparoscopic techniques are utilized for the management of cervical cancer as well as the staging and treatment of endometrial and ovarian cancers. Such techniques are used in performing radical hysterectomy for early stage cervical cancer, pelvic and paraaortic lymphadenectomy, and second look laparoscopy following chemotherapy for ovarian cancer. Even though preliminary data are encouraging, large prospective controlled studies with long-term follow-up are necessary to better define the role and limitations of laparoscopy in the treatment of gynecologic malignancies. PMID- 7855481 TI - Evaluation of the resistance to Schistosoma mansoni infection in Nectomys squamipes (Rodentia: Cricetidae), a natural host of infection in Brazil. AB - The development of resistance in three stages throughout an active infection (pre ovular, acute and initial chronic stages) was studied, comparing the total number of adult worms recovered from the reinfected group and the control groups. It was shown that Nectomys squamipes was unable to develop resistance in the tested conditions and, on the other hand, reinfection in the pre-ovular period of the parasite led the rodent to present the phenomenonacilitation, with reduction of natural resistance and an increase in the parasite load. These results suggest the existence of other forms of immunity diverse from the concomitant immunity in the host-parasite relationship, according to the employed model. PMID- 7855482 TI - Schistosoma mansoni: identification of a 46KDa antigen of the schistosomular surface by monoclonal antibody. AB - An IgG2a subclass monoclonal antibody, C6G9, was obtained by immunization of BALB/c mice with Schistosoma mansoni egg antigens. With this monoclonal antibody, it was possible to identify a schistosomular antigen with a molecular weight of 46 kilodaltons (KDa), and its expression being evaluated by means of indirect immunofluorescence. The antigen persisted in the integument of the developing schistosomulum, for at least 96 hours post-transformation. The monoclonal antibody also reacted with the cercaria surface, but not with that of adult worm. The C6G9 was also able to mediate significant levels of cytotoxicity in the presence of complement for newly transformed schistosomula. PMID- 7855483 TI - Evaluation of the double diffusion, enzyme immunoassay and immunoblotting techniques, for the diagnosis of human hydatid disease in tropical areas. AB - Hydatid disease in tropical areas poses a serious diagnostic problem due to the high frequence of cross-reactivity with other endemic helminthic infections. The enzyme-linked-immunosorbent assay (ELISA) and the double diffusion arc 5 showed respectively a sensitivity of 73% and 57% and a specificity of 84-95% and 100%. However, the specificity of ELISA was greatly increased by using ovine serum and phosphorylcholine in the diluent buffer. The hydatic antigen obtained from ovine cyst fluid showed three main protein bands of 64, 58 and 30 KDa using SDS PAGE and immunoblotting. Sera from patients with onchocerciasis, cysticercosis, toxocariasis and Strongyloides infection cross-reacted with the 64 and 58 KDa bands by immunoblotting. However, none of the analyzed sera recognized the 30 KDa band, that seems to be specific in this assay. The immunoblotting showed a sensitivity of 80% and a specificity of 100% when used to recognize the 30 KDa band. PMID- 7855484 TI - [An evaluation of the direct agglutination test for the diagnosis of "mal de caderas" in horses]. AB - The usefulness of the direct agglutination test (DA) to diagnose Mal de Caderas disease was evaluated. Forty four sera samples from two lots of horses with natural T. evansi infection (Lot 1 and Lot 2) were used. Thirteen (81.2%) of sixteen horses in which parasites were isolated gave positive agglutination titres (> or = 1:512) in the DA test. Treatment of these positive sera with 2 mercaptoethanol drops three to eight dilutions the agglutination titres in twelve samples (92%), showing the IgM nature of these antibodies. The DA test was also positive in seventeen of twenty eight horses in which parasites could not be detected. Five T. evansi infected horses, Lot three, which had high antibodies levels in the DA test, were treated with Naganol (Bayer-Germany). In four animals these antibodies were mainly IgM. In agreement with negative control for parasites, two months after treatment, IgM could not be detected while IgG antibodies remained detectable in low titres 12 months in three of the five horses. Fifty control horses sera from a T. evansi free area were AD negative. The DA and DA+2-ME are recommended as a routine method to diagnose Mal de Caderas disease in combination with parasitological diagnostic methods. PMID- 7855485 TI - Experimental paracoccidioidomycosis in hamster: transmission electron microscopy of inoculation site lesion. AB - Interaction between Paracoccidioides brasiliensis (Pb) and inflammatory cells in hamster testis was studied sequentially by transmission electron microscopy. In early lesions (six hours after inoculation), polymorphonuclear neutrophils (PMNs) were the major and mononuclear cells and eosinophils were the minor constituents of the inflammatory cells. PMNs were later replaced by mononuclear cells. Viable Pb cells were phagocytosed or surrounded by inflammatory cells. Preserved Pb cells usually had broad host-parasite interphases, whereas dying ones had narrow interphases. The outer layer of the fungus wall was sometimes broken by PMN in some focal points, broken pieces being peeled off and phagocytosed. Small Pb cells were uninuclear, and were often related to broad interphase. Large Pb cells were multinucleated with irregularly shaped wall, and sometimes had lomasome and/or myelin like structures. Different interaction patterns of Pb with inflammatory cells may be due to functionally different host cell flow to the inoculation site or due to the age of Pb cells or both. PMID- 7855486 TI - [Comparison between CSF samples from AIDS and non AIDS patients with neurocryptococcosis]. AB - Neurocryptococcosis was a rare nervous system infection. With the rising number of patients with AIDS it became a very frequent disease. This infection is supposed to infect patients with some kind of immunodeficiency and the CSF alterations often simulate tuberculous meningitis. The purpose of this research was to compare the CSF changes in AIDS and non-AIDS patients with meningoencephalitis caused by Cr. neoformans. There were analysed 41 CSF samples from non-AIDS patients with neurocryptococcosis and 23 CSF samples from AIDS patients with neurocryptococcosis. The results of this research allowed to conclude that the inflammatory changes in the CSF from AIDS patients showed a lower intensity compared to those non-AIDS patients. These results showed as well, that the CSF samples from non-AIDS patients always revealed some changes besides the yeast cells. In some samples of AIDS patients, however the unique change was the presence of the yeast. It was demonstrated also, that the presence of Cr. neoformans in CSF, not accompanied by any other change, may suggest that is a patient with AIDS. In non-AIDS patients CSF alterations often simulates tuberculous meningitis. However these alterations were rare in AIDS patients. The yeast cells were more numerous in CSF samples from AIDS patients than in those from non-AIDS patients. PMID- 7855487 TI - Legionnaires' disease in the renal transplant unit of "Hospital das Clinicas, FMUSP". During a five year period (1988-1993). AB - Several reports have related Legionella pneumophila with pneumonia in renal transplant patients, however this association has not been systematically documented in Brazil. Therefore this paper reports the incidence, by serological assays, of Legionella pneumophila serogroup 1 in these patients during a five year period. For this purpose sera from blood samples of 70 hospitalized patients with pneumonia from the Renal Transplant Unit of Hospital das Clinicas, FMUSP collected at the acute and convalescent phase of infection were submitted to indirect immunofluorescence assay (IFA) to demonstrate anti-Legionella pneumophila serogroup 1 antibodies. Of these 70 patients studied during the period of 1988 to 1993, 18 (25.71%) had significant rises in specific antibody titers for Legionella pneumophila serogroup 1. Incidence was interrupted following Hospital water decontamination procedures, with recurrence of infections after treatment interruption. In this study, the high susceptibility (25.71%) of immunodepressed renal transplant patients to Legionella pneumophila serogroup 1 nosocomial infections is documented. The importance of the implementation and maintenance of water decontamination measures for prophylaxis of the infection is also clearly evident. PMID- 7855488 TI - Seasonal variation of anti-RESA/Pf155 Plasmodium falciparum antibodies in three localities from the state of Amapa, Brazil. AB - Anti-RESA/Pf155 antibodies were assayed in sera of individuals from three localities (Laranjal do Jari, Vila Padaria and Vila Paraiso) in the State of Amapa, Brazil, during the long-rains and short-rains seasons. All of these had negative blood smears for malaria. Most of the sera collected were positive in Indirect Fluorescent Antibody (IFA) with P. falciparum parasites, with no seasonal variation. A high percentage of these sera (62% to 100%) was RESA positive by Modified Indirect Fluorescent Antibody (MIFA), with a significant (p < 0.05) increase of geometric mean titers during the short-rains season, when the transmission of the disease is highest. ELISA with three repetitive RESA peptides (EENV)3 (4 x 3), (EENVEHDA)2 (8 x 2) and (DDEHVEEPTVA)2 (11 x 2) did not reveal statistically significant seasonal variations, although a small enhancement of positivity was observed in V. Padaria (15.3 to 38.8%) in the short-rains season with the 8 x 2 peptides, and with 4 x 3 and 8 x 2 peptides in V. Paraiso, with a decrease in 11 x 2. MIFA titers appeared to be correlated mainly to the peptide 4 x 3 and it was the immunodominant in the three localities. PMID- 7855489 TI - Identification of factors and groups at risk of infection with Schistosoma mansoni: a strategy for the implementation of control measures? AB - A fourteen year schistosomiasis control program in Peri-Peri (Capim Branco, MG) reduced prevalence from 43.5 to 4.4%; incidence from 19.0 to 2.9%, the geometric mean of the number of eggs from 281 to 87 and the level of the hepatoesplenic form cases from 5.9 to 0.0%. In 1991, three years after the interruption of the program, the prevalence had risen to 19.6%. The district consists of Barbosa (a rural area) and Peri-Peri itself (an urban area). In 1991, the prevalence in the two areas was 28.4% and 16.0% respectively. A multivariate analysis of risk factors for schistosomiasis indicated the domestic agricultural activity with population attributive risk (PAR) of 29.82%, the distance (< 10m) from home to water source (PAR = 25.93%) and weekly fishing (PAR = 17.21%) as being responsible for infections in the rural area. The recommended control measures for this area are non-manual irrigation and removal of homes to more than ten meters from irrigation ditches. In the urban area, it was observed that swimming at weekly intervals (PAR = 20.71%), daily domestic agricultural activity (PAR = 4.07%) and the absence of drinking water in the home (PAR = 4.29%) were responsible for infections. Thus, in the urban area the recommended control measures are the substitution of manual irrigation with an irrigation method that avoids contact with water, the creation of leisure options of the population and the provision of a domestic water supply.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7855491 TI - Surveillance of arbovirus infections in the Atlantic Forest Region, State of Sao Paulo, Brazil. I. Detection of hemagglutination-inhibiting antibodies in wild birds between 1978 and 1990. AB - We report data related to arbovirus antibodies detected in wild birds periodically captured from January 1978 to December 1990 in the counties of Salesopolis (Casa Grande Station), Itapetininga and Ribeira Valley, considering the different capture environments. Plasmas were examined using hemagglutination inhibition (HI) tests. Only monotypic reactions were considered, except for two heterotypic reactions in which a significant difference in titer was observed for a determined virus of the same antigenic group. Among a total of 39,911 birds, 269 birds (0.7%) belonging to 66 species and 22 families were found to have a monotypic reaction for Eastern equine encephalitis (EEE), Venezuelan equine encephalitis (VEE), Western equine encephalitis (WEE), Ilheus (ILH), Rocio (ROC), St. Louis encephalitis (SLE), SP An 71686, or Caraparu (CAR) viruses. Analysis of the data provided information of epidemiologic interest with respect to these agents. Birds with positive serology were distributed among different habitats, with a predominance of unforested habitats. The greatest diversity of positive reactions was observed among species which concentrate in culture fields. PMID- 7855492 TI - [Assessment of the efficacy of antivenom injection at the site of the intramuscular inoculation of Bothrops jararaca venom: experimental study in mice]. AB - The 50% effective intraperitoneal (ip) dose of Bothrops jararaca antivenom (ED50) was assessed in mice immediately (ED50 Oh) and thirty minutes (ED50 30') after the intramuscular (im) injection of two 50% lethal dose (LD50) of Bothrops jararaca venom. The efficacy of the antivenom injected at the venom inoculation site was assessed by the inoculation of two LD50 of the venom by im route, followed immediately (ED50 Oh) and 30 minutes later (ED50 30') by administration of the ED50 of the antivenom either entirely by the ip route or 50 percent ip plus 50 percent im, at the same inoculation site. It was shown that the ED50 30' was 3 times greater, than the ED50 Oh and that the antivenom was more protective to mice (lower death rate in 48 hours) when given entirely ip. It was concluded that, in this experimental model, a higher dose of bothropic antivenom is needed when the treatment is started lately, and that there is no benefit in its administration at the venom inoculation site. PMID- 7855490 TI - Etiology and severity of community acquired pneumonia in children from Uruguay: a 4-year study. AB - The 4-year study (1987-1990) covered the major clinical-epidemiological characteristics of pneumonia in children as diagnosed at the emergency service of the Children's Hospital, as well as etiologies, and factors involved in the most severe cases. Etiology was determined in 47.7% of the 541 pneumonia cases, involving 283 pathogens of which 38.6% were viruses and 12.6% bacteria. Viral and mixed etiologies were more frequent in children under 12 months of age. Bacteria predominated in ages between 6 and 23 months. Among the viruses, respiratory syncytial virus predominated (66%). The bacterial pneumonias accounted for 12.2% of the recognized etiologies. The most important bacterial agents were S. pneumoniae (64%) and H. influenzae (19%). H. influenzae and mixed infections had a relevant participation during the 1988 season, pointing to annual variations in the relative participation of pathogens and its possible implication in severity of diseases. Correlation of severity and increased percentage of etiological diagnosis was assessed: patients with respiratory rates over 70 rpm, or pleural effusion and/or extensive pulmonary parenchyma compromise yielded higher positive laboratory results. Various individual and family risk factors were recognized when comparing pneumonia children with healthy controls. PMID- 7855493 TI - Philodryas patagoniensis bite and local envenoming. AB - A 5-year-old boy bitten by a specimen of Philodryas patagoniensis, a colubrid snake currently classified as nonvenomous, developed signs of local envenoming characterized by swelling and warmth on the bitten limb. This is the first time that local envenoming following Philodryas patagoniensis bite is recognized. Based on the clinical findings and misidentification of the snake, the patient was treated as a victim of Bothrops bite, having received unnecessarily the specific antivenom. Educational efforts to make doctors and health workers capable to identify correctly venomous snakes are necessary, to avoid inappropriate indication of antivenom and decrease the risk of its potentially harmful untoward effects. Examination of the bite site can be useful to the differential diagnosis between pit viper and colubrid bites. PMID- 7855494 TI - "In vivo" leukocyte chemotaxis in experimental mice Schistosoma mansoni infection. AB - The "in vivo" chemotaxis was studied in C57Bl/10 mice 10, 30, 50 and 60 days after a Schistosoma mansoni infection in comparison to a control group (uninfected mice). Staphylococcal protein A was injected into a connective tissue air pouch of control and experimental mice and the leukocyte chemotaxis was counted. A decrease in polymorphonuclear (PMN) leukocyte response was found in infected mice in comparison to the control group (p < 0.05). The 10 day infected mice showed a decreased PMN leukocyte response respecting the control group (p < 0.05) and this finding became more evident 30 and 50 days post-infection. Although the PMN leukocyte response of 60 day infected mice increased in comparison to 50 day infected animals, it was still significantly lower the control response. The mononuclear leukocyte response was not significantly different between infected or uninfected mice. PMID- 7855495 TI - [Difficulties in diagnosing atypical primary HIV-1 infection: report of a case]. AB - Several cases of primary HIV-1 infection are not identified, either because the diagnosis is not suspected or because they test negative for HIV-1 antibody. This work presents an uncommon case of primary HIV-1 infection in an young parenteral drug abuser man, who presented symptoms of acute hepatitis. During the initial acute phase the serum sample of the patient tested negative for the presence of antibodies against several viruses, including HIV-1. Nevertheless, the diagnosis of primary HIV-1 infection was suspected by using an alternative method for "in vitro" induced antibody production (IVIAP), and confirmed by p24 antigen serum positivity and seroconversion in serial plasma samples of the patient. The authors suggest the use of the IVIAP and others complementary assays to help the diagnosis of acute HIV-1 infection in persons at high risk conditions. PMID- 7855496 TI - [Are meta-analyses reliable?]. PMID- 7855498 TI - [Detection of deafness in newborn infants]. PMID- 7855497 TI - [Treatment of certain immune deficient peripheral neuropathies with intravenous immunoglobulins]. PMID- 7855500 TI - [Cutaneous repairs of the hand]. AB - Immediate post traumatic skin defects can complicate osteo-articular, tendinous or neurovascular lesions of the hand. Aesthetic and functional repairs permit early rehabilitation. Having to choose between spontaneous heal and microvascular tissue transfer, many pediculated flaps are possible; the size of the wound and an exposure of bone or tendon are the determining factors. Spontaneous healing or skin grafting can be adequate in cases of a superficial wound. Deep wounds with a large exposure shall be covered with flap. A large range of flaps exists: the optimal flap permits adequate coverage with minimal sequellae. PMID- 7855499 TI - [From sclerosis to vascular risk. The unknown contribution of life insurance]. PMID- 7855501 TI - [Injuries of the flexor tendons of the hand]. AB - Diagnosis of clear-cut severing of the two flexor tendons is simple and obvious. This is not true for isolated injury to a single tendon and for partial severing. In this case, careful clinical examination and routine surgical exploration of any wound with regard to the course of the flexor tendon is required. Surgery should aim at the least traumatic repair possible, followed by specialised rehabilitation directed by the surgeon. In the distal region, reinsertion into the bone is required. In other regions, suture consists of a the main suture with a continuous suture of the epitendineum. The region of the digital canal requires rigourous care due to its specific anatomy. The corollary to good surgical repair is rehabilitation, understood and complied with by the patient. Early mobilisation procedures are used predominantly in order to avoid the formation of postsurgical adherences. PMID- 7855502 TI - [Injuries to the extensor tendons of the fingers]. AB - The main risks in case of extensor tendon laceration are firstly, the possibility of misdiagnosis, and secondly the occurrence of adhesions which can compromise the excursion of the extensor apparatus. Extensor tendon lesions at the dorsum of the wrist and hand have a better prognosis regarding the postoperative results than lesions at the finger level. Protected early mobilisation methods represent a real advance in the postoperative management of extensor tendon lesions. PMID- 7855503 TI - [Fractures and luxations of the fingers]. AB - Fracture and luxation of the long fingers are particularly frequent in hand trauma. Untreated or poorly treated, they may leave highly disabling sequelae. The aim of treatment is two-fold: to repair the anatomical lesion and to obtain movement as rapidly as possible, the only means of avoiding joint stiffening. It is important to underline that the metacarpo-phalangeal joints usually stiffen in extension and that the proximal interphalangeal joints on the contrary stiffen in flexion. Thus, in case of immobilisation of the hand, an attempt should be made to obtain an "intrinsec plus" immobilisation, that is, with the metacarpo phalangeal joints in flexion and the interphalangeal joints in extension. PMID- 7855504 TI - [Fractures and luxations of the thumb]. AB - The integrity of the first carpometacarpal column determines the mobility of the thumb in space and thus opposition, a fundamental function of the human hand. Fractures and dislocations of this architecture can jeopardize its function. Joint lesions lead to instability or incongruity and subsequent post-traumatic stiffening arthrosis. Diaphyseal fractures can put out of axis or lead to abnormal rotation which impair the flexion and overall function of the thumb. Great attention should therefore be given to the anatomical reconstruction of these lesions. Open, unstable joint or periosteal fractures should be surgically reduced and a rigid fixation should be used. Dislocations require emergency treatment and in case of postreduction instability should be immobilized. PMID- 7855505 TI - [Dislocations of the carpal bones]. AB - Thirty per cent of the carpal dislocations are missed although a significant injury was sustained by the wrist. The extent of the ligamentous tears is relative to the magnitude of the forces applied and the anterior lunate dislocation corresponds to the more severe lesions. When a scaphoid fracture is associated, its treatment is predominant. Conservative treatment of a perilunate dislocation results very frequently in carpal instability and subsequently in wrist osteoarthritis after a variable period of time. Surgical treatment is now indicated in a great majority of cases, for reduction and fixation of a displaced scaphoid, or for ligament repairs. PMID- 7855506 TI - [Recent injuries of the nerves of the wrist and hand]. AB - The advent of microsurgery has in the last few decades considerably improved the results of treatment of lesions of nerves in the wrist and the hand, both with regard to functional restoration of sensation and movement and to reduction of local irritant factors or those linked to cold injury. Peripheral nerves are frequently injured at the wrist and the hand by contusion, compression, straining or total or partial section. In the case of wrist, hand or finger wound, only well-directed, precise and systematic clinical examination can determine the neurological deficit. Surgery is always indicated. There are often associated complex lesions, and all injured elements must be completely repaired. The order of this repair is always the same: tendons, nerves, then vessels. Concerning nerves, therapy depends on the severity of the contusion and (or) the loss of substance. If the section is distinct, direct suture with physiological tension can be made. On the other hand, if there is contusion or loss of substance, direct suture cannot be performed since nonphysiological tension leads to endoneural ischaemia and fibrosis. Rather, the extremities should be brought closer together in order to avoid retraction and subsequent secondary sutures or short grafts should be made. PMID- 7855507 TI - [Replantation of the hand and fingers]. AB - Using microsurgical techniques to replant an amputated hand or digit is one of the most important progress in the field of hand surgery during the last three decades. The result of a replantation depends on: the mechanism and the level of amputation, the length and the type of ischaemia of the amputated segment, the surgical techniques, the postoperative care, the rehabilitation and so on. Although the success of a replantation is first judged on the survival of the replanted segment, it nevertheless should be assessed on the function achieved. Thanks to the 30-year clinical experience, the final functional result of a replantation can now be anticipated at initial examination; thus indications can be better established by patient selection criteria. The replantation of the hand and the digits is henceforth reasonable only if there is a possibility of a useful functional result. PMID- 7855508 TI - [Replantation of the ring finger]. AB - Tearing of a finger caught by a ring or by another similar mechanism is a rare but spectacular accident. The lesions vary from simple cutaneous erosion to complete separation of the extremity, which is the most spectacular and most difficult to treat. Reimplantation techniques are now well developed and involve very long vascular by pass to perform sutures in healthy zones. The operation is thus technically difficult, it can have a favourable course in some cases whereas in others, despite the use of meticulous technique, it can lead to thrombosis and failure of reimplantation. Alternatives to reimplantation can nevertheless obtain an esthetic hand, by regularisation or by intracarpal osteotomy. However, it appears of interest in young, motivated patients to propose reimplantation using microsurgery. PMID- 7855509 TI - [High pressure injection accident of the hand]. AB - High pressure injection injuries of the hand are rare, but very severe. The material injected acts in two ways: chemical irritation as a result of its toxicity, and physical distension of tissues of the finger, which are not normally distensible, as a result of the pressure of injection of the liquid which may reach 700 kg/cm2. The main complications were necrosis and infection ending in amputation in thirty percent of the cases. Often the conserved fingers suffered cold intolerance. Therefore, the gravity of this accident has led us to believe that it is the "most urgent of hand emergencies". PMID- 7855510 TI - [Phlegmon of the digital and digital-carpal synovial sheaths]. AB - The development of infection within the digital synovial sheaths of the middle fingers, or digital-carpal sheaths of the thumb and the little finger, represents a surgical emergency. Due more often to direct infection than to its spread, such phlegmons risk damage to the finger flexor apparatus, within hours in the first case and within days in the second. Diagnosis is made clinically. It is based on pain at the upper cul-de-sac of the sheath, distinct from that of the causal point. Progression consists of three stages according to presence and quantity of pus in the sheath, the appearance of the synovial membrane and tendon involvement. This diagnosis can be made only at surgery. Each stage requires specific treatment. PMID- 7855511 TI - [Complex injuries of the hand]. AB - For many years, the rule "Emergency Treatment, Deferred Surgery", advocated by Marc Iselin, led to saving severely injured hands by postponing surgery and leaving it to highly specialised surgeons. With the appearance of microsurgery, which can be used for arterial and venous repair, the notion of actual emergency has returned and has led to the philosophy of "One-Stage Repair with Early Mobilisation". This consists in emergency repair of all the lesions and selection of techniques compatible with active mobilisation in the first postsurgical days. It is thus possible to avoid the major complication represented by stiffness of the hand in the fundamental role of grasping which requires mobility and sensitivity. Thus, Units for Emergency Hand Treatment must be created. In 1972 Raymond Vilain had the foresight to open the first such unit, "SOS MAIN". In 1975 a unit was opened in Strasbourg and five years later the European Federation of Units for Emergency Hand Treatment was born; today it comprises approximately 40 units within Europe. PMID- 7855512 TI - [Painful hip. Diagnostic orientation]. PMID- 7855513 TI - [Vaccinations. Immunological and microbiological bases, indications, contra indications, complications, efficacy (excluding mandatory dates and characteristic of vaccinations)]. PMID- 7855514 TI - [Acute edema of the face. Diagnostic orientation]. PMID- 7855515 TI - [Immunity to infection. Mechanisms, specific and non-specific factors]. PMID- 7855516 TI - [Radiologic image of diffuse pulmonary infiltration. Diagnostic orientation]. PMID- 7855517 TI - [Alcoholism: acute and chronic psychiatric complications. Epidemiology, diagnosis, treatment (including prevention)]. PMID- 7855518 TI - [Neuro-imaging of epilepsies]. PMID- 7855519 TI - [Linear IgA dermatosis]. PMID- 7855520 TI - [Strolling through the history of colors]. PMID- 7855521 TI - [Diagnosis of peripheral joint involvement in children]. AB - The diagnosis is assessed by a meticulous anamnesis, the research of associated clinical signs and the duration of the follow-up. If the clinical onset is recent (< 15 days), bacterial osteo-arthritis is to be treated in emergency; traumatic causes are easily advocated; reactive arthritis is infrequent. If the articular disease has been persistent or recurrent for 15 days to 3 months, and because of the urgency of the treatment, it should be unacceptable not to recognize a leukaemia or a metastatic neuroblastoma; the same is true for bacterial origins and some of the vascular alterations of growth cartilage. Reactive arthritis, frequently due to a digestive infection, has also to be considered. The localised articular lesions of traumatic or malformative origin, may be diagnosed by magnetic resonance imaging and arthroscopy. When the duration of the articular disease exceeds 3 months, the diagnosis of juvenile chronic arthritis, spondylarthropathy and connectivitis (disseminated lupus, panarteritis, dermatomyositis) or of some rare systemic diseases (Behcet, sarcoidosis, periodic disease) has to be considered. The non somatic and/or psychogenic causes must be accepted only if any organic disease has been excluded. The diagnosis of the so called "growth pains" remains too often a medical error. PMID- 7855522 TI - [Chronic juvenile arthritis]. AB - Juvenile chronic arthritis encompasses a heterogeneous spectrum of diseases that all include at least one persistent inflammatory arthritis. Its definition is based upon clinical criteria after exclusion of a long list of differential diagnoses. Three main types of onset are generally considered according to the clinical features during the first 3 months of evolution: systemic (20%), oligoarticular (50%), polyarticular (30%). Systemic forms present with acute general symptoms and a wide variety of articular features, from polyarthritis to isolated arthralgias. Oligoarticular forms involve 4 or fewer joints and are often complicated with iridocyclitis especially in case of positive antinuclear antibodies in the serum. Polyarticular forms involve at least 5 joints and include the presence of rheumatoid factor in the serum in 10% of cases. The clinical course of juvenile chronic arthritis is unpredictable and the reliability of the current classification is limited by taking into account only the first 3 months of evolution. PMID- 7855523 TI - [Spondylarthropathies in children]. AB - The term juvenile spondylarthropathy is used for all the inflammatory articular diseases beginning before the age of 16 years and associating peripheral arthritis, enthesiopathy and sometimes spinal involvement, cutaneous or enteric manifestations. The disease occurs more often in boys (85% of cases) between the age of 10 and 12 years. A family history is found in a third of the cases and there is a close linkage to HLA B27 (85% of cases). Asymmetrical arthritis is mainly located on the lower limbs; spinal involvement (lumbar, dorsal spine or sacro-iliac joint) is rare at onset and may occur later. Enthesiopathies involve the calcaneus and the anterior tibial tuberosity. The diagnosis is easy with the usual set of criteria. Functional prognosis is usually good, except in severe cases with destructive hip involvement. Treatment is based on non steroidal anti inflammatory drugs and/or local injections; long-term treatments (such as salazosulfapy-ridine) are sometimes useful in uncontrolled cases. PMID- 7855524 TI - [Ocular involvements in chronic inflammatory diseases in children]. AB - Children uveitis represents 2-6% of all cases of uveitis in an ophthalmology clinic. Uveitis can be due to a specific ophthalmic disease or to a systemic disease: juvenile chronic arthritis. Sarcoidosis, Behcet's disease, and connective tissue diseases. Visual function, in these young patients, may be compromised by severe complications such as band keratopathy, posterior synechiae, cataract, glaucoma, and retinal oedema. In some cases, delayed diagnosis and severity of the uveitis are due to its insidious onset, and to the absence of any complaint from the child. Therapeutic approach based on local and general corticoids in complicated cases, must balance the necessity of controlling ocular inflammation and the secondary effects of this treatment in a growing child. PMID- 7855525 TI - [What is happening to acute rheumatic fever?]. AB - Rheumatic fever is an inflammatory disease of the heart, joints, central nervous system and subcutaneous tissues that develops after a nasopharyngeal infection by one of the group A beta-haemolytic streptococci. The pathogenesis remains an enigma. As the disease has been less florid and some of the more characteristic manifestations less common in developed countries, it has become more difficult to establish the diagnosis on clinical grounds. Rheumatic fever and its sequellae are still active in developing countries. Carditis is a dominant feature of this social disease. Renewed educational efforts concerning this preventable disorder are needed among both physicians and the public. PMID- 7855526 TI - [Septic arthritis in children]. AB - Septic arthritis is a synovial infection of bacterial origin. Such a diagnosis, suggested by pain and diminished resistance to infection, should be confirmed by puncture of the joint effusion. The condition calls for emergency hospitalisation and treatment in a surgical unit. Treatment should include draining and cleaning of the joint, immobilization at least in the early stages, and double parenteral antibiotic administration. Clinical, radiological and laboratory follow-up (CRP and ESR) should be pursued. Detection of the responsible germ is often difficult and requires great care in sampling and analysis. The frequency of Haemophilus in children under 4 years of age requires adaptation of antibiotic therapy. In newborns, diagnosis is often difficult and delayed, explaining the frequency of sequelae in this age group. The only important prognostic factor is the interval before beginning treatment. PMID- 7855527 TI - [Imaging of joints in children]. AB - Magnetic resonance imaging (MRI) has became the technique of choice for noninvasive imaging of the joint in the child, owing to its high tissular contrast. Through injection of paramagnetic contrast media, MRI allows a precise analysis of the synovial inflammation, of the cartilage and of the joint effusion. It offers a precise evaluation of the local activity of the disease. It guides and provides monitoring of local treatment in juvenile chronic arthritis and haemophilic arthropathy. The technique is very sensitive but lacks specificity. Its use is complementary to clinical examination and standard radiography techniques, which remain the initial investigations. PMID- 7855528 TI - [Drug therapy of inflammatory arthritis in children]. AB - The treatment of juvenile chronic arthritis relies on drugs, but not exclusively. Drug efficacy and tolerance vary according to the disease subtype and the patient's age. Aspirin is the commonest nonsteroid antiinflammatory drug (NSAID) available in pediatrics because of the wide variety of presentations allowing an accurate dosage in low-weight children. Most other NSAIDs are not allowed in France in young age despite their good tolerance. Slow acting antirheumatic drugs are mostly used in the polyarticular subtype. Severe side effects have been described in the systemic subtype, particularly with gold and sulphasalazine. Oligoarticular subtype, the long term prognosis of which is fair, is a good indication to local therapy. Eye localisation should be treated by eyedrops, sometimes by oral steroids. Joint pain, frequent in the undifferentiated spondylarthropathies, responds well to NSAIDs. Oral corticosteroids should be used when NSAIDs are totally ineffective or when they induce side effects. Methotrexate represents a good therapeutic choice in juvenile chronic arthritis but its efficacy may vary according to the subtype. The efficacy of other immunosuppressive drugs deserves to be more accurately assessed in prospective multicentre controlled studies. PMID- 7855529 TI - [Role of surgery in the treatment of juvenile chronic arthritis]. AB - The orthopaedic surgeon intervenes in the diagnosis by performing open surgical or arthroscopic biopsies, which entail the main risk of joint stiffening; to treat the disease locally at the inflammatory stage either by synoviorthesis or by tenosynovectomy or open or arthroscopic synovectomy; in case of sequela, when the orthopaedic surgeon may propose surgery aiming to recuperate function of the limbs or the spine. Such surgery includes soft tissue (tenocapsulotomy), osteotomy, arthrodesis, and prosthetic arthroplasty. At the spine, we are faced with three problems: cervical instability, spinal fractures and scolioses. Only teams experienced in heavy paediatric orthopaedic surgery of this type should attempt surgery in chronic inflammatory rheumatism. PMID- 7855530 TI - [Rehabilitation of children with chronic inflammatory arthritis]. AB - All children with chronic arthritis require rehabilitation. Indications of the various techniques are mainly dependent upon the stage of the disease. The choice of the most appropriate technique (preservation of articular mobility, preservation of the muscular strength, orthoses) are based on an accurate assessment of each joint and on imaging. Specific measures are indicated for each localisation. The handicaps resulting from the disease and from its treatments (corticosteroids) should be reduced by adequate information of the family, adaptation of the living environment, and technical helps. PMID- 7855531 TI - [Bacterial cutaneous infections: furuncle. Etiology, diagnosis, course, treatment]. PMID- 7855532 TI - [Alcoholism: acute and chronic neurologic complications induced by alcohol. Epidemiology, diagnosis, treatment (including prevention)]. PMID- 7855533 TI - [Single-factor heredity. Construction and interpretation of a genealogical tree. Principles of genetic counseling]. PMID- 7855534 TI - [Measles. Epidemiology, diagnosis, course, prevention]. PMID- 7855535 TI - [Transfusion of blood and blood derivatives. Immunological bases and indications]. PMID- 7855536 TI - [Pregnancy and diabetes. Diagnosis, complications, treatment]. PMID- 7855537 TI - [Diffuse goiter and thyroid nodule. Diagnostic orientation]. PMID- 7855538 TI - [Surgical anatomy of the parotid region. Current concepts]. AB - Three zones of the parotid region situated in the cervicofacial area were studied. The bilobular architecture of the parotid gland, the relations between the facial nerve and the parotid gland and the cover plans are described. On the posterior border of the parotid there is a cleavage interlobular point where the facial nerve penetrates and can be dissected. Thus the facial nerve has four parts designated as retro, inter, intra and preglandular. The parotid gland and is surrounding capsula is covered by a superficial musculoaponeurosis and the skin. The musculoaponeurosis is used in cervicofacial lifting procedures and palliative treatment of facial palsy. It can also be used in certain situations (primary tumours of moderate size without capsula involvement) to fill retromandibular depressions after total parotidectomy. PMID- 7855539 TI - [Bone distraction using an external fixator: a new mandibular lengthening technic. A preliminary study apropos of 2 cases of children with mandibular hypoplasia]. AB - The authors expose a technical innovation concerning mandibular lengthening without any bone graft, by applying to the mandibular Ilizarov's principles about limb lengthening by osseous distraction. This surgical technique concerns children with mandibular hypoplasia, like the Hanhart's syndrome (aglossia adactylia, first observation), or Hemifacial Microsomia (second observation). The purpose of this new technique is mandibular lengthening with functional and aesthetic correction of the mandibular growth deficiency, and minimal morbidity. A specialist staff is essential to realize a distraction device with his minimal and appropriate shape for children, as well as a protection device conception. This external distraction device is placed with transmandibular pins. After mandibular corticotomy by endobuccal incision, the distraction is accomplished, at home by the parents, at the rythm of 1 mm p. two days. The distraction goes on about 2 months, depending on the lack of mandibular growth, and a retention device, much more light, is necessary during 8 weeks more to stabilize the osteogenesis. At the term of an eight weeks gradual distraction, the mandibular lengthening is 17.5 mm for the horizontal ramus (first observation), and 13 mm for the vertical ramus (second observation). The functional and aesthetic results, the swift and secure surgical procedure, lead to put forward this mandibular distraction technique in any mandibular or facial defects. PMID- 7855540 TI - [A comparative study of rhabdomyosarcoma with cervicofacial involvement in children and adults. A therapeutic protocol]. AB - Rhabdomyosarcoma is a malignant tumour of striated muscles. It is usually encountered in children and rarely in adults. In this study we compared sex ratios, aetiologic factors, different localizations, development stages, modes of extension and treatment as well as prognosis in children and adults with cervicofacial localizations. The differences observed led to the conclusion that cervicofacial rhabdomyosarcomas in children and adults are two very different pathological entities. PMID- 7855541 TI - [Treatment of primary soft tissue sarcoma of the head and neck]. AB - Soft tissue sarcomas of the head and neck account for less than 1% of all malignant neoplasms in this region. A significantly increased risk of treatment failure is associated with high histologic grade, leading to an aggressive treatment. The medical records of 17 patients with soft tissue sarcomas of the head and neck were reviewed. They were divided into two groups according to age: 13 adults and 4 children. The former underwent wide surgical excision with postoperative radiotherapy in some cases and possibly chemotherapy. The 2 and 5 years survivals were 54% and 46% respectively. The latter, with rhabdomyosarcoma, underwent multimodality treatment (chemotherapy, surgery, radiotherapy). The 2 years survival was 50%. The mainstay of treatment of soft tissue sarcomas of the head and neck in adults remains surgery. Patients with incomplete resection or high grade tumour should receive more aggressive treatment (surgery and postoperative radiotherapy). The use of systemic chemotherapy has showed no statistically significant improvement in local control or survival. However, for rhabdomyosarcoma in children, chemotherapy is an essential part of treatment. PMID- 7855542 TI - [Aggressive recurrence of a mixed tumor of the accessory salivary glands with a predominant myoepithelial composition]. AB - A giant pleomorphic adenoma of the palate was observed. Local relapse was highly invasive. There was no cytological evidence of malignancy and the predominant myoepithelial nature of the structure suggested a possible myoepithelioma. Large exeresis of such a tumour is required. PMID- 7855543 TI - [Mandibular metastasis of hepatocellular carcinoma. Apropos of 3 cases]. AB - Three cases of mandibular metastasis of hepatocellular cancer are reported. The specific characteristics are described: rarity, discovery, localization, haemorrhagic biopsies and histological criteria. Prognosis is poor. PMID- 7855544 TI - [Dry socket. Prevention and treatment]. AB - Although dry socket is a frequent and painful affection, its pathogenesis is still unknown. We present here a review of the literature to propose a logical preventive and therapeutic attitude. The clinical and histological aspects are also tackled. PMID- 7855545 TI - [Darier-Ferrand dermatofibrosarcoma. Apropos of a case with frontal involvement]. AB - One case of dermato-fibro-sarcoma protuberans is reported on a 36 years old man. It was an extensive forehead tumor which needed a radically surgical treatment. These excision called a reconstruction with cutaneous graft and scalp flaps. Three years after treatment, there was no evidence of recurrence or lymphadenopathy. The aesthetic results is good. The authors recalled with this observation the important points of this disease particularly characterized by slow invasive growth and local recurrence. PMID- 7855546 TI - [Surgery of the infratemporal fossa. An improved cutaneous access technic]. AB - Surgery in the infra-temporal area, formerly known as the pterygo-maxillary area, is not often performed and raises several problems including the route of access and indications and contraindications. Many procedures have been proposed by ENT or maxillo-facial surgeons dealing with cancer. ANATOMY: The infratemporal area is a basically pyramidal shaped, very deep region of the face. The base of the pyramid formed by the medial aspect of the ramus is triangular and the upper surface of the pyramid is the floor of the skull. The anteromedial aspect corresponds to the posterior aspect of the maxillary bone and the posteroinferior aspect to the pterygomaxillary fascia. INDICATIONS: This type of surgery is generally indicated for locoregional cancers and exceptionally for benign tumors originating in this area, e.g. angiomas, neurinomas of the dental or lingual nerve, either as single tumours or as part of a Recklinhausen disease. Most often, the surgeon is faced with the problem of infra-temporal invasion of a tumour originating outside the area: malignant tumour of the sinus (epidermoid epithelioma), salivary glands, bone tumours, etc. The main problem is naturally to determine the route of access, via the ramus, the parotid, the maxillary sinus or the submandibular region. In the author's opinion, the upper route via a coronal incision combined with a lifting incision on the same side is a particularly interesting approach. Different situations may arise: parotidectomy is required with preservation of the VIIth nerve, resection of the ramus or anterior section, making it possible to fold back the lateral part involved and thus provide sufficient access. PMID- 7855547 TI - Peptostreptococcal infection in children. AB - 680 Peptostreptococcus sp. (Ps) were recovered from 598 (34%) of 1,750 specimens obtained from 554 patients. They included 103 Ps asaccharolyticus, 74 Ps magnus, 56 Ps prevotii, 51 Ps micros, 46 Ps anaerobius, 11 Ps morbilorum, and 10 Ps saccharolyticus. Most infections were polymicrobial (in 553 instances or 92%) but in 45 (8%), Ps were recovered in pure culture. Most Ps were isolated from abscesses (237), ears (104), peritoneal fluid (95), lung infections (66), bone (30) and sinuses (24). Predisposing conditions were present in 224 (40%) children. These were previous surgery (54), immunodeficiency (43), malignancy (35), trauma (34), diabetes (23), prematurity (22), steroid therapy (19), foreign body (10) and sickle-cell anemia (7). The organisms most commonly isolated with Ps were Bacteroides sp. (276, including 190 B. fragilis group), Prevotella sp. (159), Fusobacterium sp. (122), Escherichia coli (114), and Staphylococcus aureus (97). Antimicrobial therapy was administered to all but 14 patients. Surgical drainage or correction of pathology was performed in 307 (56%) patients. 10 patients (2%) died of their infection. These data illustrate the importance of Ps and suggests their enhancing potentials in infection in children. PMID- 7855548 TI - HIV-seropositive rate and HIV test activity among STD clinic attendees in Bergen, Norway. AB - We wanted to determine the HIV seropositive rate and to study the connection between previous HIV testing, acceptance of HIV testing and sexual behaviour among STD clinic patients in Bergen, Norway. Patients attending the STD clinic in 1986-93 requesting HIV testing were registered, and all patients visiting the clinic in April-June 1989 received a questionnaire and were asked if they wanted to be HIV tested. The overall HIV seropositive rate was 0.4% (14/3805); in homo /bisexual men: 2.9% (8/278); IVDUs: 0.4% (1/236) and in heterosexual non-IVDUs: 0.2% (5/3291). Among the 599 individuals offered anonymous HIV testing, 42.2% were HIV tested and 69.2% did not object to HIV-testing. IVDUs/prostitutes (p < 0.001), customers of prostitutes (p < 0.001), homo-/bisexuals (p < 0.01), and patients receiving blood transfusion (p < 0.005) had all been HIV tested more frequently than 'other heterosexuals'. Respondents reporting casual sex, casual sex abroad, infection with STDs, and a greater number of partners were more frequently HIV tested and also accepted HIV testing more frequently than respondents without such behaviour, indicating that there is some rationale behind the decision to be tested. PMID- 7855549 TI - Danish AIDS patients 1988-1993: a recent decline in Pneumocystis carinii pneumonia as AIDS-defining disease related to the period of known HIV positivity. AB - The frequency of PCP among adult Danish AIDS patients notified in 1988-93 was higher among patients tested HIV-positive less than 4 months prior to AIDS than among those known to be positive for > 1 year. Among the latter, the proportion with PCP decreased significantly over the period, from 45.3% in 1988 to 22.0% in 1993, while no such trend was found among patients tested positive for HIV less than 4 months before AIDS was diagnosed. The incidence of PCP as an AIDS-defining disease has decreased, most likely due to the use of PCP prophylaxis. PMID- 7855550 TI - Markers of immune stimulation in the cerebrospinal fluid during HIV infection: a longitudinal study. AB - Markers of immune stimulation were studied in 76 sequential cerebrospinal fluid (CSF) samples from 19 patients infected with HIV-1 without antiretroviral treatment during observation periods ranging from 22 months to 6 years. Eight of these patients were further followed with 14 CSF samples for 3-24 months of zidovudine treatment. During the course of HIV-1 infection, the mean CSF neopterin and beta 2-microglobulin (beta 2M) concentrations increased from 12.7 to 20.4 nmol/l (p < 0.01) and from 1.93 to 2.17 mg/l (p < 0.05), respectively, while the mean peripheral CD4 + T cell count decreased from 624 to 320 cells x 10(6)/l (p < 0.001). The IgG index, reflecting intrathecal immunoglobulin production, increased from 0.72 to 0.92 (p = 0.08). The number of patients with CSF pleocytosis did not change significantly during follow-up (8/19 at baseline, 7/19 at endpoint). In the 8 patients followed up during antiretroviral treatment, a significant reduction in mean CSF levels of neopterin and beta 2M (-48% and 32%, respectively, p < 0.01) was seen after 3-12 months on zidovudine. We suggest that gradual increase in immune stimulation reflected by the rising CSF concentrations of neopterin and beta 2M indicates that HIV-1 infection in the central nervous system is progressive even in neurologically asymptomatic stages. PMID- 7855551 TI - Clindamycin in persisting streptococcal pharyngotonsillitis after penicillin treatment. AB - 239 patients with streptococcal pharyngotonsillitis completed treatment with phenoxymethyl penicillin 12.5 mg per kg body weight b.i.d. for 10 days. At examination after completing therapy, throat specimens from 53 patients (22%) yielded growth of group A streptococci of the same. T-type as the initial culture (bacterial treatment failure). 20 of these 53 (38%) had symptoms and signs of tonsillitis (clinical and bacterial treatment failure). 48 of the patients with bacterial failure were randomly allocated to phenoxymethyl penicillin or clindamycin in an open design; 22 of them received a second course of phenoxymethyl penicillin for 10 days and 26 were given clindamycin, 6.5 mg per kg body weight b.i.d. (children) or 300 mg t.i.d. (adults) for 10 days. After completing their treatment, 14 of 22 patients (64%) given phenoxymethyl penicillin harboured the same T-type as in the previous two cultures, while group A streptococci were not recovered from any of the 26 patients receiving clindamycin. In patients with clinical failure after phenoxymethyl penicillin treatment, a new course with this drug is not motivated. In that situation clindamycin seems to be an efficient choice. PMID- 7855552 TI - Significance of isolation of Moraxella catarrhalis in routine cultures from the respiratory tract in adults: antibody response studied in a whole cell EIA. AB - The significance of the isolation of Moraxella catarrhalis from sputum or nasopharynx was studied in patients treated at an infectious disease clinic. A whole-cell enzyme immunoassay was used to detect a specific antibody response to M. catarrhalis during infection. In all, 27 patients with respiratory tract infections and 4 with other infections were studied. Titre rises were recorded in 11/23 patients with lower respiratory tract infections, whereas patients with common cold or infections elsewhere all had negative serology. In patients with acute bronchitis, 7/10 patients responded with a significant titre rise. Patients with a low titre in their acute serum sample were those who responded with a titre increase during infection. The findings indicate that isolation of M. catarrhalis from sputa and nasopharyngeal samples in adults is of value for the etiological diagnosis of acute bronchitis and other lower respiratory tract infections, and is therefore important for the choice of drug for treatment, as many isolates are resistant to beta-lactam antibiotics. PMID- 7855553 TI - Long-term findings in patients with facial palsy and antibodies against Borrelia burgdorferi. AB - Little is known about the long-term effects of Borrelia burgdorferi (Bb) infection in untreated patients with peripheral facial palsy. We investigated 12 patients with elevated serum Bb antibody levels, with a median follow-up time of 11 years, during which 3 of the 12 still exhibited intrathecal antibody production of antibodies against Bb flagellar antigen, and 2 of the 3 had normal serum Bb antibodies. Four of the 12 had elevated serum antibody titres at the late follow-up examination. Arthralgia, reported by 7 patients, was the single most common complaint. Four patients showed extensive oculomotor disturbances, which were not correlated to antibody titres or intrathecal antibody synthesis. In 1 of the patients with intrathecal Bb antibody production, most symptoms were eradicated by antibiotic treatment 6 years after the initial infection. We conclude that even several years after a Bb infection, intrathecal Bb antibody production can still occur in serum Bb IgG antibody negative patients with a history of facial palsy. PMID- 7855554 TI - The role of Mycobacteria Other Than Tuberculosis (MOTT) in patients with cystic fibrosis. AB - The purpose of this study was to estimate the frequency of and evaluate the clinical impact of pulmonary mycobacterial infections among cystic fibrosis (CF) patients. 185 CF patients aged 2.2-38.5 years were screened by sputum samples and by intracutaneous skin tests against tuberculin and sensitins produced from Mycobacterium chelonae subsp. abscessus, M. avium, M. intracellulare and M. scrofulaceum (the MAIS complex). The skin tests towards the sensitins in BCG vaccinated patients (n = 60) were significantly influenced by the vaccination. 26 of the remaining 125 non-vaccinated patients had > or = 1 positive skin test (95% confidence limits 15-29%). The majority reacted against the MAIS complex. However, the reactions were similar to those of healthy siblings and an age matched control group. Moreover, the lung function, growth and HbA1c were similar among skin test positive and negative patients. Three patients had repeated positive sputum cultures, the point prevalence being 1.6% (M. intracellulare, n = 2 and M. chelonae subsp. abscessus, n = 1). During the subsequent 4 years, 4 additional patients with M. chelonae subsp. abscessus were identified. Based on clinical observations, 5 of the infected patients were considered asymptomatic, while 2 might have been symptomatic. In 1 patient, M. chelonae subsp. abscessus disappeared spontaneously. Despite intensive treatment with new antibiotics against Mycobacteria Other Than Tuberculosis (MOTT) in 4 patients, the mycobacteria were not eradicated. In conclusion, MOTT infection was rare and the clinical impact difficult to prove. Treatment should focus on clinical improvement in the individual patient suspected of suffering from significant symptomatic infection. Eradication of the bacteria should not be expected. PMID- 7855556 TI - Comparison of imipenem versus cefuroxime plus tobramycin as empirical therapy for febrile granulocytopenic patients and efficacy of vancomycin and aztreonam in case of failure. AB - 143 aplastic episodes with fever in 91 haematological patients with granulocytopenia were treated empirically in a randomized prospective study using either imipenem (Imi) or a combination of tobramycin and cefuroxime (T/C). Response after 72 h was significantly better in patients receiving Imi (44/75 vs 27/68, p < 0.05). This was seen especially in patients with bacteriologically proven infections where the isolated staphylococci and streptococci were more susceptible to Imi. In both groups, patients who failed to respond to the initial antibiotic therapy were given vancomycin and aztreonam (V/A). The response rate after another 72 h, measured using the same criteria as after the first 72 h, did not differ statistically between the groups. One patient in each study group died from the bacterial infection, both from Gram-positive bacteraemia. Duration of fever was significantly shorter in the Imi group (4 days vs 7 days, p < 0.04). Serum peak and trough concentrations of the antibiotics were comparable. Both regimens were well tolerated. Our results show that monotherapy with imipenem is superior to the combination of tobramycin and cefuroxime during the first 72 h of therapy and can be safely administered to neutropenic patients with predominantly Gram-positive infections. A combination of vancomycin and aztreonam, given when initial imipenem treatment has failed, was effective in only a few patients. Adjuvant glycopeptide therapy from the outset in the treatment of febrile granulocytopenic patients did not seem worthwhile. PMID- 7855557 TI - Epidemiology of toxic shock syndrome toxin-1 production in Staphylococcus aureus strains isolated in Denmark between 1959 and 1990. AB - A total of 436 Staphylococcus aureus bacteremia strains isolated between 1959 and 1990 were tested for the production of toxic shock syndrome toxin-1 (TSST-1) by a semiquantitative reversed passive latex agglutination test. TSST-1 production was found in 147/260 (57%) of phage group I strains, excluding the "80" complex, and in 17/176 (10%) of non-group I strains. Strains of the 52, 52A, 80, 81 complex ("80" complex), constituting a subgroup of group I, did not have the same high frequency of TSST-1 production as the rest of group I strains (4% versus 57%). The "80" complex has almost disappeared in Denmark. TSST-1 production was found with the same high frequency among group I strains from the beginning (1959) and throughout the observation period. The TSST-1 production was associated with the phages 29 and/or 52, which in turn lysed 95% of group I strains. The TSST-1 production was quantitatively greater in the phage group I strains than in the non-group I strains. TSST-1 production of the bacteremia strains was not correlated to the clinical parameters: mortality, age, gender, bacterial focus, underlying diseases, or whether the infection was hospital or community acquired. PMID- 7855555 TI - Twice daily cefpodoxime proxetil compared with thrice daily amoxicillin/clavulanic acid for treatment of acute otitis media in children. AB - A total of 260 children, 3 months to 11 years old (median age 24 months), with acute otitis media (AOM) received either cefpodoxime proxetil (CP) 8 mg/kg/d b.i.d. or amoxicillin/clavulanic acid (ACA) 40/10 mg/kg/d t.i.d. for 8 days. A significant difference in clinical cure rates was observed between the CP group 71/118 (60%) and the ACA group 42/105 (40%), p = 0.003. At the follow-up visit (20-30 days after the start of treatment), significant advantages were recorded with the CP vs. ACA therapy, in terms of satisfactory clinical response [90/111 (81%) vs 60/94 (63.8%), p = 0.005] residual middle ear effusion (14.4% vs 28.7%, p = 0.01) and normal tympanometry (78% vs 61.4%, p = 0.017). Compliance and adverse event frequency were the same in both treatment groups. The higher clinical cure rate and equivalent safety profile of CP indicates that it is an acceptable alternative to ACA for the treatment of AOM in children. PMID- 7855558 TI - Bacteremia in patients without known underlying disorders. AB - Of 2030 consecutive patients with bacteremia, only 102 were free from underlying disorders. 43 were males, and the median age was 66 years. The sources of infection were the urinary tract (in 48%), lower respiratory tract (13%), endocarditis (7%), biliary tract (6%) and the meninges (5%). The most common pathogens were Escherichia coli (in 45% of patients), Streptococcus pneumoniae (21%), Staphylococcus aureus (9%) and hemolytic streptococci (9%). Overall mortality rate was 13%, 4% in patients with urinary tract infection and 19% in patients with other sources. Half of the deaths occurred within 2 days of hospitalization, and 75% of them within 4 days. All patients with septic shock and all patients with meningitis died. Other factors related to mortality were residence in a nursing home, low functional capacity, advanced age, high blood urea nitrogen and creatinine and low albumin, and infections caused by Staphylococcus aureus, Neisseria meningitidis and polymicrobial infections. A protective effect of appropriate antimicrobial antibiotic therapy could not be demonstrated. In conclusion, bacteremic patients with no known underlying disorder and source of their infection other than the urinary tract should be given maximum supportive treatment and should be closely watched. PMID- 7855559 TI - Cost-benefit analysis of general vaccination against Haemophilus influenzae type b in Sweden. AB - A cost-benefit analysis of general vaccination of infants with a conjugated Haemophilus influenzae type b (HIB) vaccine was performed. Information on incidence and prognosis of HIB meningitis and acute epiglottitis in children was obtained from nation-wide retrospective studies covering the years 1981-83, when the birth rate was approximately 93,000 per year. The annual cost for hospitalization, neurologic and auditory sequelae and parents' absence from work amounted to 54 million Swedish crowns (SEK). A mean of 6 children died every year. Inclusion of value of lives lost added SEK 72 million to the cost of disease. With vaccine prices (approximately SEK 125/dose) and birth rate (approximately 120,000 per year) prevailing in 1993, vaccine costs would be SEK 45 million, provided that 3 doses are sufficient to offer protection close to 100%. Other costs for vaccination, e.g. physicians' and nurses' time, needles and syringes, are negligible, since the vaccine can be given at the same time as other infant vaccinations at already existing Child Health Centres. In conclusion, general vaccination of infants against HIB is cost-effective, saves lives and reduces human suffering. PMID- 7855560 TI - Pneumococcal septicaemia and meningitis in vaccinated splenectomized adult patients. AB - A retrospective survey of the occurrence of pneumococcal septicaemia and meningitis in splenectomized adults was performed at a regional haematological centre after the introduction of pneumococcal vaccination in 1978. During this period 4 episodes of pneumococcal septicaemia were observed in 3 vaccinated, splenectomized patients. In all episodes the pathogenic strain was of an unusual serotype not included in the vaccine lending indirect evidence for the clinical efficacy of the pneumococcal vaccine, even in immunocompromised patients. PMID- 7855561 TI - Myonecrosis in the leg caused by Salmonella enteritidis. AB - Five weeks after an episode of gastroenteritis, a 65-year-old diabetic male developed an extensive myonecrosis, with gas production in the left leg caused by Salmonella enteritidis. The patient was treated with surgical revision and antibiotics. To our knowledge, this is the first case of myonecrosis with gas production in a leg caused by Salmonella enteritidis, in which the patient survived, and the limb was saved. PMID- 7855562 TI - Cellulitis as first clinical presentation of disseminated cryptococcosis in renal transplant recipients. AB - Two renal transplant recipients with cellulitis due to Cryptococcus neoformans are described. The patients were treated empirically for a presumed bacterial erysipelas, but without response. Examination of skin biopsies revealed C. neoformans as the causative organism. In both patients the cellulitis was the presenting clinical manifestation of disseminated cryptococcosis. Therapy with antifungal agents was successful. Disseminated cryptococcal disease occurs mainly in immunocompromised patients. When left untreated, it nearly always has a fatal course. Early diagnosis and appropriate therapy are therefore essential. PMID- 7855563 TI - Mediterranean visceral leishmaniasis in pregnancy. AB - Visceral leishmaniasis (VL) in pregnancy is rare in Mediterranean countries. We report here 2 cases of VL in pregnant women who acquired the infection in Italy. In the first case, the disease was diagnosed and treated with liposomal amphotericin B during the pregnancy. In the second case, diagnosis was established and treatment with meglumine antimoniate both undertaken shortly after delivery. The 2 infants were followed clinically and serologically for 8-9 months after birth, but no evidence of congenital VL was observed. PMID- 7855565 TI - [A lecture on the topic of stress]. PMID- 7855564 TI - Meningeal irritation: possible manifestation of cerebral Echinococcus infestation. AB - A patient with meningeal irritation and a small occipital cystic lesion is presented. Based on serological tests, the condition was diagnosed as presumably echinococcosis. To our knowledge, meningeal irritation has previously not been reported as an early symptom of cerebral Echinococcus infestation. Cysticercosis is discussed as a possible differential diagnosis. PMID- 7855566 TI - [Esthetics, dental materials, medical and legal risks in dentistry. A report on the 118th Annual Meeting of the German Society for Dentistry, Oral Medicine and Orthodontics with the Study Group for Forensic Dentistry in the Society from 6 to 9 October 1994 in Travemunde]. PMID- 7855567 TI - [Digital imaging. A report on the 3rd Symposium on Digital Imaging in Dental Radiology of 13-15 October 1994 in Noordwijkerhout, the Netherlands]. PMID- 7855568 TI - [Endodontics and restoration of the severely disordered pediatric dentition. A report on the joint annual meeting of the German Society for Pediatric Dentistry and Primary Prophylaxis in the German Society for Dentistry, Oral Medicine and Orthodontics and the German Society for Pediatric Dentistry, Inc. of 14-15 October 1944 in Gottingen, Germany]. PMID- 7855569 TI - [Deciduous tooth intrusions and the odontogenesis of the permanent teeth. Developmental disorders of the permanent teeth following intrusion injuries to the deciduous teeth]. AB - Traumata to primary teeth occur very often in small children. The highest prevalence of developmental disturbances of permanent teeth after trauma to their predecessors has been recorded after intrusive injuries of primary teeth. In the present survey 47% of the recalled children had such developmental disturbances. The majority of developmental disturbances consisted of enamel hypoplasia (59%) which included discoloration, defects or a combination of both. In some cases the clinical feature of enamel defects could be diagnosed radiographically before tooth eruption. However, the total number of all enamel discolorations was to be detected after complete tooth eruption only. The so-called pre-eruptive calciotraumatic lines on radiographs corresponded clinically to circular enamel defects or crown dilacerations. Generally, a high correlation was found between the degree of intrusion (of the primary tooth) and the frequency and severity of developmental disturbance (of the permanent tooth). No correlation was found, however, concerning the treatment of intruded primary teeth and the occurrence of developmental disturbances. Whether intruded primary teeth were removed immediately or left to spontaneous re-eruption did not affect the incidence and type of developmental disturbances. PMID- 7855570 TI - [The maxillary implant. A report on the 3rd Conference of the Association for Oral Surgery and Implantology of the Austrian Society for Dentistry, Oral Medicine and Orthodontics in Hof near Salzburg from 5 to 8 October 1994]. PMID- 7855571 TI - [The bear Urs must not endure pain nor settle a bill later]. PMID- 7855572 TI - [Esthetic orthodontics. A report on the annual meeting of the Societe Suisse d'Orthopedie dento-faciale of 10 and 11 November 199 in Basel]. PMID- 7855573 TI - [EuroPerio 1. A report on the EuroPerio Congress in Paris from 12 to 14 May 1994]. PMID- 7855574 TI - [EuroPerio 1, the first congress of the European Federation of periodontology. Interview by Catherine Strahm and Kurt Venner]. PMID- 7855575 TI - [Artists facing AIDS]. PMID- 7855577 TI - [The electromyographic activity of the masticatory muscles during temporomandibular joint clicking]. AB - 16 patients with painless temporomandibular joint clicking were investigated electromyographically. EMGs were recorded during open-close movement from the superior and inferior heads of the lateral pterygoid muscle, the anterior belly of the digastric muscle and the temporal muscle. TMJ clicking was recorded with a microphone located over the TMJ simultaneously with EMG and incisal movement and velocity. 13 of 16 patients showed various changes in EMG patterns. 3 patients showed no changes in EMG patterns. Evidence that a hyperactive muscle induces TMJ clicking, was not observed. These results indicate that there may be many types of adaptation for TMJ clicking from the viewpoint of the various EMG findings of masticatory muscles. It is suggested that most of the electromyographic changes are not the cause of painless TMJ clicking but their result. PMID- 7855576 TI - [The intraoral determination of the sagittal condyle path inclination during face bow recording]. AB - In a clinical trial involving 40 fully dentate persons, three different intraoral procedures to determine the sagittal condyle path inclination were checked for accuracy. In each test person the condyle path inclination was determined three times, i.e. by the central bearing point method, the protrusive check-bite method and by a protrusive bite record integrated in the bite fork. At 5 mm of protrusion the reproducibility of the results obtained with the central bearing point method (mean value 2.1 +/- 2.0 degrees) were far better than that with either of the two other methods; the difference was statistically significant. The protrusive check-bite records and the protrusive bite fork records did not differ from each other as far as their accuracy was concerned (mean values 3.6 +/ 2.1 degrees and 3.4 +/- 1.6 degrees, respectively). The mean value of the condyle path inclination to the hinge axis infra-orbital plane in the sample was about 50 +/- 8 degrees regardless of the method used. Thus, protrusion records can be integrated in the face bow transfer. PMID- 7855578 TI - [Prophylaxis pastes--the new abrasive Perlit compared to conventional polishing substances]. AB - Perlit is a new dental abrasive, based on volcanic silica. It has a flat, irregular disc-shaped structure which fractures readily in use. Individual discs tend to become oriented parallel to the tooth surface during use while the rough edges also become rounded. A Perlit-based prophylactic paste thus produces polished surfaces although it also has excellent cleaning properties on both enamel and dentin when used with either rubber polishing cups or bristle brushes. The Perlit-based prophy paste, Cleanic, yielded the best results when compared to other prophy pastes during laboratory test scored with the Prophylaxis Paste Index (PPI: Cleaning efficacy: [Abrasivity x Surface roughness]). Consequently, Perlit-based prophy pastes can be used initially as cleaning pastes and the same portion will subsequently polish the dental surfaces as well. Thus Perlit nullifies the rule that an efficient cleaning paste will be abrasive and must produce a roughened dental surface. PMID- 7855579 TI - [Necrotizing vasculitis of the tongue. A contribution to the differential diagnosis of ulcerative mucosal changes in HIV-infected patients]. PMID- 7855580 TI - [Solitary bone cysts. The pathogenesis, clinical picture and therapy of solitary bone cysts]. PMID- 7855581 TI - [Work, stress and health]. PMID- 7855582 TI - Radiation studies. PMID- 7855583 TI - AIDS-associated Kaposi's sarcoma. PMID- 7855584 TI - Fungicide regulation and food safety. PMID- 7855585 TI - Filtering a river of cancer data. PMID- 7855586 TI - NIH gets a share of BRCA1 patent. PMID- 7855587 TI - Risk assessment. Agencies decry fuzzy science in bill. PMID- 7855588 TI - Plant genetics. Shedding light on the ticking of internal timekeepers. PMID- 7855589 TI - Keeping PERfect time. PMID- 7855590 TI - Head-on collision between a DNA replication apparatus and RNA polymerase transcription complex. AB - An in vitro system reconstituted from purified proteins has been used to examine what happens when the DNA replication apparatus of bacteriophage T4 collides with an Escherichia coli RNA polymerase ternary transcription complex that is poised to move in the direction opposite to that of the moving replication fork. In the absence of a DNA helicase, the replication fork stalls for many minutes after its encounter with the RNA polymerase. However, when the T4 gene 41 DNA helicase is present, the replication fork passes the RNA polymerase after a pause of a few seconds. This brief pause is longer than the pause observed for a codirectional collision between the same two polymerases, suggesting that there is an inherent disadvantage to having replication and transcription directions oriented head to head. As for a codirectional collision, the RNA polymerase remains competent to resume faithful RNA chain elongation after the DNA replication fork passes; most strikingly, the RNA polymerase has switched from its original template strand to use the newly synthesized daughter DNA strand as the template. PMID- 7855591 TI - Cooperative organization of inorganic-surfactant and biomimetic assemblies. AB - A model that makes use of the cooperative organization of inorganic and organic molecular species into three dimensionally structured arrays is generalized for the synthesis of nanocomposite materials. In this model, the properties and structure of a system are determined by dynamic interplay among ion-pair inorganic and organic species, so that different phases can be readily obtained through small variations of controllable synthesis parameters, including mixture composition and temperature. Nucleation, growth, and phase transitions may be directed by the charge density, coordination, and steric requirements of the inorganic and organic species at the interface and not necessarily by a preformed structure. A specific example is presented in which organic molecules in the presence of multiply charged silicate oligomers self-assemble into silicatropic liquid crystals. The organization of these silicate-surfactant mesophases is investigated with and without interfacial silicate condensation to separate the effects of self-assembly from the kinetics of silicate polymerization. PMID- 7855592 TI - Visual appearance of matte surfaces. AB - All visual sensors, biological and artificial, are finite in resolution by necessity. As a result, the effective reflectance of surfaces in a scene varies with magnification. A reflectance model for matte surfaces is described that incorporates the effect of macroscopic surface undulations on image brightness. The model takes into account complex physical phenomena such as masking, shadowing, and interreflections between points on the surface, and it predicts the appearance of a wide range of natural surfaces. The implications of these results for human vision, machine vision, and computer graphics are demonstrated with both real and rendered images of three-dimensional objects. In particular, objects with extremely rough surfaces produce silhouette images devoid of shading, precluding visual perception of the object's shape. PMID- 7855593 TI - Requirement of carbon dioxide for in vitro assembly of the urease nickel metallocenter. AB - Assembly of protein metallocenters is not well understood. Urease offers a tractable system for examination of this process. Formation of the urease metallocenter in vivo is known to require four accessory proteins: UreD, postulated to be a urease-specific molecular chaperone; UreE, a nickel(II) binding protein; and UreF and UreG, of unknown function. Activation of purified Klebsiella aerogenes urease apoprotein was accomplished in vitro by providing carbon dioxide (half-maximal activation at approximately 0.2 percent carbon dioxide) in addition to nickel ion. Activation coincided with carbon dioxide incorporation into urease in a pH-dependent reaction (pKa > or = 9, where Ka is the acid constant). The concentration of carbon dioxide also affected the amount of activation of UreD-urease apoprotein complexes. These results suggest that carbon dioxide binding to urease apoprotein generates a ligand that facilitates productive nickel binding. PMID- 7855594 TI - A functionally diverse enzyme superfamily that abstracts the alpha protons of carboxylic acids. AB - Mandelate racemase and muconate lactonizing enzyme are structurally homologous but catalyze different reactions, each initiated by proton abstraction from carbon. The structural similarity to mandelate racemase of a previously unidentified gene product was used to deduce its function as a galactonate dehydratase. In this enzyme superfamily that has evolved to catalyze proton abstraction from carbon, three variations of homologous active site architectures are now represented: lysine and histidine bases in the active site of mandelate racemase, only a lysine base in the active site of muconate lactonizing enzyme, and only a histidine base in the active site of galactonate dehydratase. This discovery supports the hypothesis that new enzymatic activities evolve by recruitment of a protein catalyzing the same type of chemical reaction. PMID- 7855595 TI - Circadian clock mutants in Arabidopsis identified by luciferase imaging. AB - The cycling bioluminescence of Arabidopsis plants carrying a firefly luciferase fusion construct was used to identify mutant individuals with aberrant cycling patterns. Both long- and short-period mutants were recovered. A semidominant short-period mutation, timing of CAB expression (toc1), was mapped to chromosome 5. The toc1 mutation shortens the period of two distinct circadian rhythms, the expression of chlorophyll a/b-binding protein (CAB) genes and the movements of primary leaves, although toc1 mutants do not show extensive pleiotropy for other phenotypes. PMID- 7855596 TI - The regulation of circadian period by phototransduction pathways in Arabidopsis. AB - Transgenic Arabidopsis plants expressing a luciferase gene fused to a circadian regulated promoter exhibited robust rhythms in bioluminescence. The cyclic luminescence has a 24.7-hour period in white light but 30- to 36-hour periods under constant darkness. Either red or blue light shortened the period of the wild type to 25 hours. A phytochrome-deficient mutation lengthened the period in continuous red light but had little effect in continuous blue light, whereas seedlings carrying mutations that activate light-dependent pathways in darkness maintained shorter periods in constant darkness. These results suggest that both phytochrome- and blue light-responsive photoreceptor pathways control the period of the circadian clock. PMID- 7855597 TI - A role for exonuclease I from S. pombe in mutation avoidance and mismatch correction. AB - Exonuclease I (Exo I) from Schizosaccharomyces pombe, a 5'-->3' double-stranded DNA exonuclease, is induced during meiotic prophase I. The exo1 gene is a member of a family of related DNA repair genes, including RAD2/rad13/xpgc and YKL510/rad2, conserved from yeast to humans. An exo1 mutant displays a mutator phenotype and alters activity of the ade6-M387 marker effect. These results suggest that Exo I acts in a pathway that corrects mismatched base pairs. PMID- 7855598 TI - PER protein interactions and temperature compensation of a circadian clock in Drosophila. AB - The periods of circadian clocks are relatively temperature-insensitive. Indeed, the perL mutation in the Drosophila melanogaster period gene, a central component of the clock, affects temperature compensation as well as period length. The per protein (PER) contains a dimerization domain (PAS) within which the perL mutation is located. Amino acid substitutions at the perL position rendered PER dimerization temperature-sensitive. In addition, another region of PER interacted with PAS, and the perL mutation enhanced this putative intramolecular interaction, which may compete with PAS-PAS intermolecular interactions. Therefore, temperature compensation of circadian period in Drosophila may be due in part to temperature-independent PER activity, which is based on competition between inter- and intramolecular interactions with similar temperature coefficients. PMID- 7855599 TI - Binding strength between cell adhesion proteoglycans measured by atomic force microscopy. AB - Measurement of binding forces intrinsic to adhesion molecules is necessary to assess their contribution to the maintenance of the anatomical integrity of multicellular organisms. Atomic force microscopy was used to measure the binding strength between cell adhesion proteoglycans from a marine sponge. Under physiological conditions, the adhesive force between two cell adhesion molecules was found to be up to 400 piconewtons. Thus a single pair of molecules could hold the weight of 1600 cells. High intermolecular binding forces are likely to form the basis for the integrity of the multicellular sponge organism. PMID- 7855600 TI - A regulatory role for ARF6 in receptor-mediated endocytosis. AB - Adenosine diphosphate-ribosylation factor 6 (ARF6), ARF6 mutants, and ARF1 were transiently expressed in Chinese hamster ovary cells, and the effects on receptor mediated endocytosis were assessed. Overexpressed ARF6 localized to the cell periphery and led to a redistribution of transferrin receptors to the cell surface and a decrease in the rate of uptake of transferrin. Similar results were obtained when a mutant defective in guanosine triphosphate hydrolysis was expressed. Expression of a dominant negative mutant, ARF6(T27N), resulted in an intracellular distribution of transferrin receptors and an inhibition of transferrin recycling to the cell surface. In contrast, overexpression of ARF1 had little or no effect on these parameters of endocytosis. PMID- 7855601 TI - DNA-dependent kinase (p350) as a candidate gene for the murine SCID defect. AB - Severe combined immunodeficient (SCID) mice are deficient in a recombination process utilized in both DNA double-strand break repair and in V(D)J recombination. The phenotype of these mice involves both cellular hypersensitivity to ionizing radiation and a lack of B and T cell immunity. The catalytic subunit of DNA-dependent protein kinase, p350, was identified as a strong candidate for the murine gene SCID. Both p350 and a gene complementing the SCID defect colocalize to human chromosome 8q11. Chromosomal fragments expressing p350 complement the SCID phenotype, and p350 protein levels are greatly reduced in cells derived from SCID mice compared to cells from wild-type mice. PMID- 7855602 TI - Absence of p350 subunit of DNA-activated protein kinase from a radiosensitive human cell line. AB - The radiosensitive rodent mutant cell line xrs-5 is defective in DNA double strand break repair and lacks the Ku component of the DNA-activated protein kinase, DNA-PK. Here radiosensitive human cell lines were analyzed for DNA-PK activity and for the presence of related proteins. The radiosensitive human malignant glioma M059J cell line was found to be defective in DNA double-strand break repair, but fails to express the p350 subunit of DNA-PK. These results suggest that DNA-PK kinase activity is involved in DNA double-strand break repair. PMID- 7855603 TI - Alternatives to 35S as a label for the differential display of eukaryotic messenger RNA. PMID- 7855604 TI - [The contribution of the general and trauma surgeon in neurotraumatology: experiences and results of 10 years]. AB - In acute medical service, general and traumatic surgeons are faced with the problem of treating severe head and brain injuries. In the department of surgery of the University Hospital in Munich, we have been performing neurotraumatological treatment since 1982. Within 10 years we saw 138 patients with severe head and brain injury. We had 48 cases of epidural hematoma. 81 of acute subdural hematoma. 84 of intracerebral contusional bleeding, 5 of depression fractures and 3 of hygromas. All these patients underwent surgical treatment. Osteoplastic trepanation was performed in 49 patients and osteoclastic trepanation in 60. Further interventions were elevation of the 5 depression fractures and evacuation of the 3 hygromas. Comparison with other investigations in departments of neurological surgery in the United States suggest that our results reflect a similar outcome (according to Jennet and Bond's outcome scale: 1, cured; 2, slightly handicapped; 3 severely handicapped; 4, vegetative state; 5, expired). The Traumatic Coma Data Bank (1991) recorded outcome of severe head and brain injuries as follows: 1, 27%; 2, 16%; 3, 16%; 4, 5%; 5, 36%; and our own results were: 1, 24%; 2, 17%; 3, 15%; 4, 5%; 5, 39%. Organization procedures and treatment strategies are suggested. PMID- 7855605 TI - [Follow-up of fracture healing--indications and clinical relevance of direct radiographic magnification in comparison with conventional roentgen imaging]. AB - Comparison of 83 magnification radiographs with corresponding conventional X-rays showed that direct radiographic magnification (DIMA) yielded additional information in 39 cases (47%), which had implications for the treatment in 19 cases (22.9%). In 11 cases callus was first visualized in magnification radiography; the earliest evidence of callus was found 14 days after surgery. Since magnification radiography means the region that can be examined is smaller, conventional radiographs were necessary in 32.5% of cases to find the position of the fracture in long bones. For statistical evaluation interobserver analysis was performed, anatomical and pathological structures being graded according to four levels. Magnification radiography proved superior in all structures examined. Magnification radiography can be recommended as an additional method to monitor fracture healing. Computed radiography was used together with magnification radiography to reduce the radiation dose and to perform image processing including simulation of conventional technique and edge enhancement. DIMA is a valuable tool in the evaluation of fracture stability and in the adjustment of distraction rates in limb-lengthening procedures. PMID- 7855606 TI - [Cost effectiveness of preventive antibiotic administration for lowering risk of infection by 0.25%]. AB - Antibiotic prophylaxis in closed fractures is cost-effective if the risk of a deep infection is reduced by 0.25%. This control study was undertaken to assess the cost-effectiveness of prophylaxis of postoperative infections after surgical treatment of closed fractures. The costs for 16 patients with infections (8 with deep infections, 8 with superficial infections) were investigated and compared with the costs for 16 similar but non-infected patients with special reference to length of hospital stay, antibiotics and surgery. The data were collected from the trauma department of the University Hospital of the Free University in Amsterdam. Costs in the group of 8 patients with superficial wound infection were not substantially higher than those for their non-infected controls. The occurrence of a deep infection meant costs an average of DFL 35,224 higher than an uneventful postoperative course. On the basis of these results, antibiotic prophylaxis of postoperative wound infections is cost-effective if it reduces the risk of deep wound infections by about 0.25%. PMID- 7855607 TI - [Possibility for detecting HIV-1 in bone transplant by PCR using the HIV-1 microtiter plate assay]. AB - It is known that HIV can be transmitted by allogenous bone transplantation. Hitherto neither chemical nor physical methods have existed to allow reliable disinfection and sterilization of bone specimens without reducing osteogenetic potency. Only demonstration or exclusion of the presence of HIV-1 in a bone specimen guarantees that infection will not occur. The method now presented for HIV detection is based on a polymerase chain reaction (PCR). This HIV microtiter plate assay combines amplification of DNA molecules with a staining reaction. In cultures containing HIV-infected cells definite detection of viruses was possible when 50-100 cells per specimen were infected. Examination of 137 HIV-negative and 25 HIV-positive bone specimens showed sensitivity of 96% and specificity of 97.8% for the test. In subsequent studies, after drying on filter paper viral DNA was again demonstrable by the PCR. This means safe handling and uncomplicated transportation of non-infectious specimens to a central analysis laboratory are possible. This HIV test offers the possibility of quick and safe demonstration that specimens are free of HIV and is therefore likely to enhance the safety of bone transplantation considerably. PMID- 7855608 TI - [Differential treatment of diaphyseal humerus fractures]. AB - The evaluation of 174 humeral shaft fractures treated operatively in our institution and a literature review are used to illustrate the indications for operative treatment. For some indications, the authors prefer Hackethal's bundle nails. A simple operative technique and a small approach incision far distant from the fracture site, which prevents the fracture hematoma, and the very low complication rate are the advantages of this method, making it an alternative to plating and even to bracing. Operative treatment is clearly indicated for compound fractures grades II and III. As the humerus--unlike the tibia--has a good soft tissue envelope, plating can be carried out without the danger of insufficient soft tissue coverage. Complete radial palsy is also an indication for primary operative nerve revision, followed by stable osteosynthesis, preferably with plate. In our series primary radial palsies were observed in 47 (27%) of cases; on revision we found 5 cases of nerve division and 2 of impingement between fragments. Further absolute indications are the rare injuries to the brachial artery, bilateral fractures, and combination with a forearm fracture ("floating elbow"). Closed fractures without concomitant injuries can generally be managed conservatively. We have treated 84 of these fractures with Hackethal's nails. The only serious complications were one non-union (1.2%) and one deep infection (1.2%). PMID- 7855609 TI - [Surgical therapy of radial head fracture--results of osteosynthesis and resection treatment]. AB - Between 1982 and 1993 we performed internal fixation or resection in 95 adult patients for radial head fracture. It was possible to follow up 68 patients for an average of 2.1 years. In 53 cases the initial injury was an isolated radial head fracture, which was treated by internal fixation in 41 and resection in 12 cases. Good results were obtained in 80% of patients. A satisfactory outcome was associated with young age, little initial fragment dislocation, internal fixation with screw + K-wire, and early postoperative physiotherapy. Primary resection for crush fractures of the radial head did not have negative long-term effects. In a comparison group with complex elbow injuries (elbow luxation in 9 and a Monteggia type injury in 6 cases) in addition, results were considerably poorer and did not depend on the above-mentioned factors. PMID- 7855610 TI - [Retrospective analysis of consecutively treated distal radius fractures with the external fixator]. AB - The purpose of this study was to determine retrospectively some subjective and objective parameters following the operative treatment of 32 patients with "complex" (intraarticular and/or comminuted) fractures of the distal radius using the small AO external fixation device. The mean follow-up period was 20 months (minimum 4, maximum 48) and the mean age of the subjects was 62 years (minimum 27, maximum 91). Subjective results such as "general feeling", mobility, strength and pain, expressed with a scoring system (% of maximum obtainable points), showed an overall good result and ranged between 71% (pain), 81% (strength) and 91% (mobility and "general feeling"). Regarding the objective results, no major skin or soft tissue distress (Sudeck dystrophy) was noted. However, there was a general tendency towards a mobility deficit of the wrist operated on, which was statistically significant (P < 0.01) for flexion, extension, supination and abduction (respectively, -17.7%, -12.4%, -7.1% and -12.5%). The late standard radiological and lateral controls showed a mean radial angle of +2.13 degrees (B or lateral radial angle) and +23.13 degrees (A or AP angle), respectively. The analysis of data, as expressed by time after operation (< or > than 10 months), showed no relevant difference between the two groups (age of both similar), as expressed by age (< or > than 60 years); the data only showed differences in strength and pain (scores by 92% vs 82% for force and 92% vs 76% for pain) and in flexion and extension (-22.8% and -14%, P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7855611 TI - [Pediatric pelvic fractures]. AB - From 1977 through 1992 a total of 25 children (age 4 months to 14 years) were hospitalized for pelvic fractures. Clinical outcome and X-ray evaluation had been recorded and were retrieved for 21 children. In 3 patients pelvic fractures required surgery. All pelvic fractures healed uneventfully whether treated by surgery or conservatively. Concomitant injuries, treatment, and types of pelvic fracture are discussed. PMID- 7855613 TI - [Change in subchondral mineralization after reconstruction of the anterior cruciate ligament of the sheep]. AB - The cruciate ligaments are generally regarded as regulators of the joint kinematics, but also increasingly as a "Sensory organ" regulating the periarticular musculature, which influences the position of the contact surfaces and the direction and magnitude of the resultant forces. Indirectly, therefore, they influence the long-term stress distribution, which is itself reflected in the distribution of the subchondral mineralisation. An experimental investigation was therefore undertaken to see whether, in terms of this distribution, the distribution of the stress alters postoperatively, since this could be regarded as an early cause of degenerative change. We examined the distribution of the subchondral mineralisation of six tibiae from six adult Merino sheep 1 year after anterior cruciate ligament reconstruction with patellar tendon. The contralateral tibia we used as controls. Maximum subchondral mineralisation of both the medial and the lateral joint surfaces in all the control joints was found to be central. In the treated knees, however, the medial joint surface maxima were found to have been displaced towards the dorsomedial edge of the surface in every case. If the density pattern on the control side is accepted as the expression of a normal stress distribution, the distribution patterns on the treated side must indicate a pathologic distribution of stress. Reconstruction of the anterior cruciate ligament is therefore--at least in the animal model--not able to prevent the development of a pathologic stress distribution.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7855614 TI - [Equestrian accidents in children and adolescents]. AB - The rate of pediatric equestrian injuries is relatively low, but the severity of injuries is greater than in many other pediatric sport activities. In a 4-year period the charts of 109 patients up through the age of 15 years, who were admitted for equestrian-related injuries were reviewed. Falls from horses are the most frequent cause of injuries and responsible for their anatomic localization and type of injury. In our study the upper extremity was the most common (38%) area injured and head injuries comprised the second largest group with 36%. Forty percent of all injuries were fractures, 72% of which were fractures of long bones. The circumstances surrounding the accident and mechanisms of these injuries were analyzed. Effective safety measures such as improved equestrian helmets and adequate training in dealing with horses could reduce the risk of injuries. PMID- 7855612 TI - [Shortening osteotomy of the femur after knee joint exarticulation]. AB - Our experience with two patients is used as a basis to describe a method of creating a weight-bearing amputation stump after exarticulation of the knee joint in trauma patients who have insufficient soft tissue. Osteotomy is performed to shorten the length of the femur, and in this way sufficient soft tissue becomes available to cover the femoral condyles so that a weight-bearing amputation stump can be created and femoral amputation is prevented. A major advantage of this method is that the joint of the prosthesis can be positioned at exactly the same level as the contralateral healthy joint. PMID- 7855615 TI - Multiple drug resistance: biologic basis and clinical significance in renal-cell carcinoma. PMID- 7855616 TI - Current surgical approaches, nephron-sparing surgery, and the role of surgery in the integrated immunologic approach to renal-cell carcinoma. PMID- 7855617 TI - Genetics of renal-cell carcinoma and evidence for a critical role for von Hippel Lindau in renal tumorigenesis. AB - Using a genetic linkage-based positional cloning approach the VHL gene was identified at chromosome 3p25.5. VHL is mutated in the germlines of affected individuals, and in VHL-associated tumors the mutation is almost always exposed by virtue of chromosomal deletion of the inherited wild-type allele. VHL is also frequently mutated in sporadic, nonpapillary RCC and in familial RCC. This was predicted because such tumors are histologically similar to VHL-associated renal tumors. Knowledge that VHL plays a critical role in sporadic RCC should aid in the future diagnosis and treatment of this malignancy. Detailed analyses of the biology of individual mutations will be required to determine whether the inherited VHL mutations or acquired sporadic mutations cause loss of protein function or have dominant-negative affects. However, the nature of the VHL protein is at present unclear and a complete understanding its function will only be expected after the cloning of the full-length gene. PMID- 7855618 TI - The use of monoclonal antibody G250 in the therapy of renal-cell carcinoma. PMID- 7855619 TI - Chemotherapy for advanced renal-cell carcinoma: 1983-1993. PMID- 7855620 TI - High-dose interleukin-2 in the therapy of metastatic renal-cell carcinoma. PMID- 7855621 TI - Low-dose interleukin-2 in the treatment of metastatic renal-cell carcinoma. PMID- 7855622 TI - Cellular therapy: scientific rationale and clinical results in the treatment of metastatic renal-cell carcinoma. PMID- 7855623 TI - Gene therapy: its potential applications in the treatment of renal-cell carcinoma. PMID- 7855624 TI - Cellular and molecular studies in the treatment of murine renal cancer. AB - Antigen-nonspecific approaches to the use of BRMs for cancer treatment have resulted in only limited success to date. In particular, the use of large numbers of adoptively transferred, broadly cytotoxic LAK cells in combination with IL-2 has been effective for only small subsets of cancer patients. Recent demonstrations of T-lymphocyte-mediated antigen-specific responses against some human tumors, and the more potent effects of these cells in preclinical models, have refocused much of the dialogue for biological therapy to potentiation of T lymphocyte-mediated antitumor effects. Our studies are using the well characterized Renca murine renal cancer model to study the induction of antitumor T-lymphocyte-mediated responses, the mechanisms by which positive effects are achieved, and the reasons why T lymphocytes in tumor-bearing mice may not respond as predicted. One possible reason why T-lymphocyte responses may not be triggered easily by tumors could be an impairment of critical nuclear transcription factors. We also are studying two approaches for stimulating T-cells in tumor conditioned hosts. (1) We have shown that IL-7 has potent costimulatory effects on T cells as well as some antitumor effects. (2) We are developing a comprehensive vaccine-type gene therapy approach whereby T cells and antigen presenting dendritic cells are recruited through the use of antigen, chemokines and GM-CSF. Studies are in progress to determine whether the activity of these recruited cells can then be potentiated by Renca or fibroblast transfectants that express T-cell costimulatory cytokines (IL-2, IL-4, IL-7, or IL-12). This approach should optimize both MHC class I- and class II-dependent pathways for induction of T-lymphocyte-mediated responses to cancer, and perhaps overcome tumor-induced impairments in the T lymphocyte function. PMID- 7855625 TI - Bilirubin metabolism and the hereditary hyperbilirubinemias. PMID- 7855626 TI - Structure, formation, and sources of bilirubin and its transport in plasma. PMID- 7855628 TI - Bile pigments in the gastrointestinal tract and urine. PMID- 7855627 TI - Hepatic uptake, binding, conjugation, and excretion of bilirubin. PMID- 7855630 TI - Hyperbilirubinemia: general considerations. PMID- 7855629 TI - Clinical chemistry and physiology of bilirubin. PMID- 7855631 TI - The familial unconjugated hyperbilirubinemias. PMID- 7855632 TI - The familial conjugated hyperbilirubinemias. PMID- 7855633 TI - Population growth and public health. PMID- 7855634 TI - Strain complex of Schistosoma japonicum in the mainland of China. AB - The present paper deals with studies on the characteristics of Schistosoma japonicum isolated from five localities in the mainland of China. The following items were observed and compared including morphometric data, susceptibility of six mammalian hosts, prepatent period, compatibility between larvae and snail hosts, size of hepatic granuloma produced by eggs, immunoreactions in experimental animals, sensitivity to praziquantel, SDS-PAGE protein pattern and its antigenicity analysis, DNA hybridization and genetic variation and differentiation by analysis with multilocus enzyme electrophoresis. By means of these multidisciplinary methods, from morphological to molecular level, the following conclusions may be drawn from our results. The evidence indicates firstly that S. japonicum in the mainland of China comprises a strain complex with several components of geographically distributed strains. At least four distinct strains exist, ie Yunnan, Guangxi, Sichuan and Anhui-Hubei. Characteristics of each strain are distinct and the results of these studies lead to discussion on the problem of the intraspecific and interstrain differentiation of S. japonicum in the mainland of China. PMID- 7855635 TI - Comparative nucleotide and deduced amino acid sequence of the envelope glycoprotein gene among three dengue virus type 2 strains isolated from patients with different disease severities in Maha Sarakham, northeast Thailand. AB - The nucleotide (nt) sequence of the envelope glycoprotein (E) gene of dengue virus type 2 was determined by the primer-extension dideoxy chain-termination method for 3 dengue virus type 2 (D2) strains which had been isolated from patients with dengue fever (DF), dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS), in Maha Sarakham, Northeast Thailand, in 1986-1987. Their nt sequences were essentially the same except for a single silent nt replacement in each DHF and DSS strain compared with DF strain. Therefore, these 3 strains possessed identical deduced amino acid (AA) sequences in their E protein. The result indicated that the primary structure of the E protein of D2 virus is not related to the clinical severity of the infected patients. Eleven nt replacements which resulted in 4 amino acid replacements were found to be unique to these 3 Northeast Thai strains. Sequence similarity showed that the 3 Northeast Thai strains were closest to the DSS isolate (H) followed by the DHF isolate (D) identified in Bangkok in 1980. PMID- 7855636 TI - Effects of human alpha, beta and gamma interferons on varicella zoster virus in vitro. AB - The antiviral effects of interferon (IFN) on varicella zoster virus (VZV) and herpes simplex virus (HSV) in vitro were examined. The values for the 50% inhibitory dose (ID50) of IFN-alpha, beta and gamma determined by plaque reduction assay, were 0.813, 0.650 and 13.750 IU/ml, respectively, against VZV and 18.00, 10.38 and 115.0 IU/ml, respectively, against HSV. Thus IFN-alpha and beta were more effective than IFN-gamma against both VZV and HSV and VZV was more sensitive than HSV to the IFNs. Five mutants of VZV which were resistant to acyclovir (ACV), phosphonoacetic acid (PAA) or bromodeoxyuridine (BUDR) were also sensitive to IFN beta, their average ID50 being 1.31 IU/ml. Analysis of virus specific proteins by the immunofluorescent technique with various antisera showed that IFN had a significant effect before early protein synthesis. PMID- 7855637 TI - Detection and serotyping of dengue viruses by PCR: a simple, rapid method for the isolation of viral RNA from infected mosquito larvae. AB - Dengue viruses pose a considerable global public health problem with an estimated 100 million cases of illness every year. This illustrates the need for rapid and reliable diagnostic methods for proper patient management and disease control. Currently, laboratory diagnosis depends on serology or virus isolation, with both methods having certain drawbacks. Alternatively, reverse transcription and polymerase chain reaction (RT-PCR) offers the potential for the rapid, highly sensitive and specific detection of dengue viruses. Since we occasionally encounter the problem of insufficient amounts of patient serum for the direct detection of dengue viruses, a method was developed for the extraction of viral RNA after biological amplification in mosquito larvae. Using this method, 15 of 19 clinical samples tested were correctly identified using RT-PCR. PMID- 7855638 TI - Comparative sensitivity of laboratory methods to diagnose dengue virus infections at Husada Hospital, Jakarta. AB - Several methods are available for diagnosis of dengue virus infections including a new commercially available dengue blot IgG assay. We conducted a study to compare the sensitivity of the dengue blot with the conventional diagnostic methods. Serum samples from suspected dengue patients were collected for virus isolation and the following serological assays: the hemagglutination-inhibition assay, an IgM/IgG enzyme-linked immunosorbent assay, and the dengue blot. When suspected dengue samples were tested by all methods, viral isolation detected the fewest dengue infections (10.5%), while the IgM/IgG ELISA was the most successful (46.3%) in diagnosing dengue infections. In a specific comparison between the IgM/IgG ELISA and the dengue blot, the dengue blot had an overall sensitivity of 48.8%, with a specificity of 88.7%. When patients were classified by their serological response, the dengue blot had a sensitivity of only 1.7% in those patients with a primary or recent dengue infection, however in secondary infections, the sensitivity of the dengue blot improved to 93.5%. Testing convalescent samples from patients with primary infections, only slightly changed the sensitivity of the dengue blot. The diagnosis of dengue is needed rapidly by clinicians to insure prompt treatment of patients. The dengue blot provides a rapid and easily performed assay, especially sensitive in secondary dengue infections which are most common in hospitalized cases in Asia. PMID- 7855639 TI - A simplified and highly sensitive detection of Trypanosoma evansi by DNA amplification. AB - In Southeast Asia Trypanosoma evansi infection is a disease of economic importance since it affects the health of buffalo, cattle and swine. The acute stage symptoms include abortion, central nervous system disorder and even death, and in the chronic condition working capacity and productivity of the animals are affected. A polymerase chain reaction (PCR)-based detection technique has been developed with a sensitivity of 0.5 pg of parasite DNA or one single parasite in 10 microliters of blood samples which were allowed to clot and then boiled before DNA amplification. This permitted storage of blood collection at ambient temperature for at least one month. Phosphate-saline-glucose solution, normally used as trypanosome maintenance buffer, inhibited PCR. Although DNA primers used were derived from T. evansi specific sequence, amplification of the genome of T. brucei and T. equiperdum generated the same 227 bp fragment. This method should now make it possible to detect infections in livestock in the very early stages where microscope examination is equivocal and to monitor groups of animals after trypanocidal treatment. PMID- 7855640 TI - In vitro cultivation of third stage larvae of Wuchereria bancrofti to fourth stage: influence of some physico-chemical factors. AB - It has been reported that third stage larvae (L3) of Wuchereria bancrofti strain from Jakarta, molted to the fourth stage (L4) in vitro, in a simple culture medium supplemented with 10% human serum. In the present study, this culture medium has been used to examine the effects of some physico-chemical parameters on larval growth, development and molting of Wuchereria bancrofti from India. Lymph at 10% concentration enhanced the in vitro survival time of larvae. Molting of larvae from L3 to L4 stage has been obtained using human fetal lung cells in cellular co-culture and as a source of conditioned medium. Given these improvements in the medium supplementation, it has been observed that the age of L3s (duration of L3s maintenance within the mosquitos) is one of the most important parameters for the development of L3s in vitro. No molting was observed when one day L3s were used whereas, molting occurred with one or two weeks old L3s. On the contrary, when more than 3 weeks old L3s were used molting failed to occur even though duration of survival of L3s was improved and in this case, most of the larvae were degenerated. PMID- 7855641 TI - The natural first intermediate host of Paragonimus siamensis (Miyazaki and Wykoff, 1965) in Thailand. AB - The first intermediate host of six-known the Paragonimus species in Thailand had not been found until the Filopaludina (Siamopaludina) martensi martensi snail was discovered to maintain the cercariae of a Paragonimus species. An extensive study examined cercarial development through to adult worms by infecting 3 genera of 7 crab species with penetration of cercariae and feeding of snails containing such cercariae. These crabs provided many metacercariae which were fed to cats and bandicoots. The animals gave many Paragonimus adult worms which were characterized as Paragonimus siamensis by the following criteria: 6-lobed ovary and cuticular spines in groups. It is concluded that the Filopaludina martensi martensi snail is a susceptable natural first intermediate host of P. siamensis. Second intermediate hosts Somanniathelphusa brandti, S. sexpunctatum and S. bangkokensis were experimentally infected; prior to this study only S. germaini and S. dugasti had ever been naturally infected with metacercariae of this species. PMID- 7855642 TI - Epidemiologic characteristics of Clonorchiasis sinensis in Guandong Province, China. AB - Extensive survey of the distribution of the liver fluke Clonorchis sinensis in Guandong Province, China, has revealed high frequencies in human populations in some areas and absence in others. The distribution relates in part to the demography of first and second intermediate hosts and animal reservoir hosts, but it relates more clearly to the differing food habits of various populations in particular geographic areas. Thus clonorchiasis is concentrated in the Zhu Jiang (Pearl River) delta and along the Han Jiang (Han River) but is absent in the Leizhou Peninsula and in the western region of the province. Males tend to have higher infection rates than females. Age distribution is not uniform: in some communities infection rates increase with age where adults eat raw or undercooked fish, while in other infections reaches its peak in early teenage children and declines thereafter where children eat small raw fish but the habit does not persist into adult life. While there is some evidence that high C. sinensis rates correlate with high liver cancer rates and vice versa, this issue requires in depth investigation at community level to differentiate hepatocellular carcinoma and early cholangiocarcinoma, since it is possible that C. sinensis infection promotes higher risk of the latter form of liver cancer. PMID- 7855643 TI - The prevalence and intensity of soil-transmitted helminths in some rural villages in northern peninsular Malaysia. AB - The prevalence and intensity of soil-transmitted helminths in five rural villages in northern peninsular were investigated. Generally the prevalence and intensity of infection were low in the 0-10- and above 50-year-old age groups when compared with other age groups. The prevalence and intensity of infection in the five villages were quite similar, because of similar socio-economic status. The highest intensity was observed for Ascaris lumbricoides, followed by hookworms and Trichuris trichiura. PMID- 7855644 TI - Statistical analysis of clinical, immunological and nutritional factors in pediatric cryptosporidiosis in the Philippines. AB - A statistical analysis of clinical, nutritional, and immunological data gathered in a previous study suggest that nutritional factors, and in particular, iron status, appeared to be of significance in mounting an effective immune response to Cryptosporidium infection in young children. The primary protective mechanism seemed to be cell-mediated; humoral immunity was intact in all the study subjects, however, CMI was initially impaired but improved over six weeks. PMID- 7855645 TI - A clinical study on trichinosis in Changwat Phayao, Thailand. AB - An epidemic of trichinosis occurred in Northern Thailand. The source meat was a 150 kg hilltribe pig. A clinical investigation was conducted using indirect IgG ELISA as a criteria for diagnosis. 52 suspected cases who had eaten the trichinous pork and developed relevant symptoms were hospitalized. 49 of them gave positive ELISA within 64 days after infection. The most common clinical features were myalgia (100%), fever (93.88%) and facial edema (87.71%). Diarrhea was found in approximately one half of the patients (55.10%). Skin rashes of various types were unexpectedly high (40.82%). PMID- 7855646 TI - Spontaneous granulomatous amebic encephalitis: report of four cases from Thailand. AB - Granulomatous amebic encephalitis (GAE), or meningoencephalitis caused by Acanthamoeba sp and leptomyxid amebae are uncommon CNS infections that usually occur in an immunocompromised host. From 1990 to 1992, 4 patients with GAE were treated at Siriraj Hospital, Bangkok. One case was diagnosed antemortem, from a brain biopsy. The other three cases were diagnosed as GAE postmortem. Pathological findings included acute and subacute granulomatous inflammation with extensive cerebral necrosis, angiitis, fibrinoid necrosis and fibrin thrombi. One patient had a chronic skin ulcer in which free-living amebic trophozoites were found. No visceral involvement was observed. All patients developed "spontaneous" GAE, but we suspect an undiagnosed abnormality in cell mediated immunity or a deficient humoral immune response. PMID- 7855648 TI - Reliability of two commercial serological kits for serodiagnosing Helicobacter pylori infection. AB - Two commercial serological kits, Pylori-set (Orion Diagnostica, Finland) and Helico-G (Cambridge Biomedical Ltd, UK), and an in-house ELISA were evaluated with sera from 24 Helicobacter pylori-positive and 146 H. pylori-negative dyspeptic patients. Sensitivity, specificity, positive and negative predictive values of Pylori-set were lower than that of Helico-G and in-house ELISA. Helico G was more sensitive (91.7%) than in-house ELISA (83.3%) and both had comparable negative predictive values of 98.3% and 97.3%, respectively. However, specificity (97.9%) and positive predictive value (86.9%) of an in-house ELISA were much higher than specificity (80.1%) and positive predictive value (43.1%) of Helico G. Kappa index of agreement between the three serological tests (Pylori-set, Helico-G or in-house ELISA) and the presence of H. pylori in antral biopsies was very low (k = 0.13; z = 1.9; p > 0.05), moderate (k = 0.49; z = 7.1; p < 0.0001), or substantial (k = 0.82; z = 10.8; p < 0.0001), respectively. Overall, statistical evaluations demonstrated that both commercial kits were not as reliable as the in-house ELISA for serodiagnosing H. pylori infection. PMID- 7855647 TI - An outbreak of gastroenteritis due to Vibrio cholerae 0139 in Pondicherry, South India. PMID- 7855649 TI - Reactivity of the CD D-1 latex test with Clostridium difficile and other bacteria. AB - The reactivity of a commercial latex test with thirty-three species of bacteria was tested. Toxigenic and nontoxigenic strains of Clostridium difficile gave a positive result in the CD D-1 latex test. Cross-reactions were also given by C. putrificum, C. sporogenes and proteolytic C. botulinum. PMID- 7855650 TI - Detection of salmonellae in hen eggs in Thailand. AB - Two thousand four hundred and ninety eggs were collected from retail markets in 6 provinces and from laying hen farms in 3 provinces. Eggs were pooled in groups of 3 to obtain 830 samples for testing. Isolation of salmonellae was made from both egg shell and egg contents. Eggs from retail markets were contaminated with salmonellae on egg shells (13.2%) and in egg contents (3.9%). Three (0.4%) samples yield positive both on egg shells and in egg contents. Of the 86 samples from laying hen farms, salmonellae were found on egg shells and in egg contents, 3.5% and 1.2%, respectively. From the 134 strains tested, twenty-four serotypes were confirmed. Salmonella cerro, S. amsterdam and S. typhimurium were predominantly encountered, 4.8%, 4.3% and 1.4%, respectively. Only two samples were contaminated with S. enteritidis, one each from open market and laying hen farm, one on egg shells and the other in egg content respectively. PMID- 7855651 TI - Incidence of salmonellae in duck eggs in Thailand. AB - Detection of salmonellae was performed on egg shells and egg contents of duck eggs. Five hundred and sixty-four tested samples were came from 1,128 eggs, 2 eggs in each sample. Eggs were collected from retail markets in Bangkok, Chon Buri, Chachoengsao, Lop Buri, Ang Thong and Nakhon Ratchasima provinces during January through June 1992. The percentage of salmonellae contamination on the egg shells only, egg contents only and both shells and contents were 12.4%, 11% and 0.2%, respectively. Twenty three serotypes were identified from the 133 salmonellae isolates. The common serotypes found from duck eggs were Salmonella typhimurium, S. cerro, S. tennessee, S. amsterdam, S. agona and S. infantis accounting for 5.5%, 4.1%, 2.8%, 2.1%, 1.4% and 1.1%, respectively. PMID- 7855652 TI - Nosocomial pneumonias in Thailand. AB - In order to compare the etiology, clinical manifestations, and prognosis of patients acquiring nosocomial pneumonia, we studied and compared sixty normal hosts who acquired nosocomial pneumonia during Jan 1, 1989-Dec 31, 1991 (group I) with seventy-two immunocompromised patients with nosocomial pneumonia who were admitted during 1984-1992 (group II). Both groups were similar in some patterns, eg gram-negative bacilli were common (80%, 50%), the chest roentgenogram showed initial localized lesions (74%, 72%), and there was a high mortality rate (46.7%, 54.2%). The differing findings were that the first group acquired pneumonia more often during the first 7 days after admission, transbronchial aspiration was believed to be the route of entry and most of the patients had productive coughs. Blood cultures rarely yielded the organisms (7%). The second group had pneumonia at a mean of 32 days after admission, hematogenous spread to the lungs was common and blood cultures more often yielded the etiologic organisms (41.7%). PMID- 7855653 TI - Nocturnal physiological and biochemical changes in sudden unexplained death syndrome: a preliminary report of a case control study. AB - Sudden nocturnal deaths among "healthy" workers in Southeast Asia have been termed "sudden unexplained nocturnal death syndrome (SUNDS)" or "sudden unexplained death syndrome (SUDS)". The pathogenesis is still unknown. The paucity of publications on nocturnal monitoring and scientific data stimulated us to perform this study, which included biochemical tests and physiological monitoring during the night in 11 males north-eastern Thai workers. Group 1 (G1) consisted of 5 subjects with neither a previous history of near-SUDS (NSUDS) nor a familial history of SUDS (FHSUDS). Group 2 (G2) consisted of 6 subjects with a family history of either SUDS or NSUDS. Two subjects in G2 presented with NSUDS. Two-day nocturnal monitoring included blood sugar, electrolytes, and respiratory parameters. 24-hour Holter ECGs were monitored for 2 days. The subjects underwent exercise stress tests on the 2nd day of this study. Significant nocturnal hypoxia was more common in G2 than G1 and this abnormality was aggravated by exercise. There were no significant findings in sleep apnea (apnea indices) or in nocturnal biochemical changes, eg blood sugar, electrolytes, thiamine. The recordings of the Holter-ECGs were within normal limits in both groups. We conclude that nocturnal hypoxia might be the primary abnormality in SUDS, and this abnormality was aggravated by the day-time exercise. The cause of nocturnal hypoxia requires further studies. PMID- 7855654 TI - Spirometric volumes in Malaysian males. AB - Spirometry was performed on 1,485 male subjects ranging in age from 13 years to 78 years and comprising of all the main ethnic groups in Malaysia. They were divided into six age categories. Mean forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) were 3.45 +/- 0.02 and 3.10 +/- 0.02, respectively. Both FVC and FEV1 correlated negatively with age. Regression analysis revealed an age-related decline in FVC of 295 ml per decade of life. Multiple stepwise regression of the data for the prediction of an individual's FVC above the age of 20 years gave the equation FVC (1) = 0.0404 (height in cm) 0.0295 (age in years)-2.2892. Predicted FVC values derived from equations based on other populations were considerably higher than the observed mean in this study. This study therefore, reemphasises the need to be cautions when applying formulae derived from one population to another. Grossly erroneous conclusions may be reached unless predicted equations for lung-function tests for a given population group are derived from studies based upon the same population group. PMID- 7855655 TI - The efficacy of compression immobilization technique in retarding spread of radio labeled Russell's viper venom in rhesus monkeys and 'mock venom' NaI131 in human volunteers. AB - The efficacy of the modified compression immobilization technique in retarding spread of radio-labeled Russell's viper venom in 3 rhesus monkeys (Macaca mulata) and "mock venom" NaI131 in 14 human volunteers was studied. 0.1 microgram of Russell's viper venom having 10 microCi radioactivity in 0.2 ml normal saline containing 0.5% bovine serum albumin was injected subcutaneously at the lateral aspect of the right hind limb of a rhesus monkey. A hand-tight bandaging of a rubber pad measuring 55 x 28 x 16 mm over the injection site and splinting effectively retard spread of radio-labeled venom for the entire length of time applied, although complete immobilization was not achieved. In human volunteers, application of a pad measuring 60 x 50 x 17 mm over the subcutaneous injection site of 20 microCi or 12 microCi/0.2 ml NaI131 with a hand-tight bandaging (60 +/ 10 mmHg) and immobilization of limb was found to be effective in retarding the movement of radioactive NaI131. These results suggested that the compression pads tried in this study effectively retard the spread of radio-labeled Russell's viper venom (MW ranging from 20,000-90,000) and radioactive NaI131 (MW 150) from the site of injection. Thus, it is highly likely that the present compression pad will be useful as a first-aid measure in Russell's viper bite victims. PMID- 7855656 TI - Physical fitness of obese school children in Hat Yai, southern Thailand. AB - 259 primary school children (average age 9.2 years) were randomly selected from three groups of children whose weights-for-height were 90-110% (normal 111), > 110-120% (over weight 25), and > 120% (obesity 123) of reference values for Bangkok children. They underwent physical fitness tests which included measurement of speed (50 meters run), flexibility (sit-reach), abdominal strength and endurance (30 seconds sit-up), vital capacity (spirometer), and indirect maximum oxygen uptake (VO2 max-submaximal bicycle ergometer). The results showed that all physical fitness tests were statistically significantly different (p < 0.05) between groups, except for flexibility in boys. But for the girls, only 50 meters run, sit-up and VO2 max showed statistically significant differences (p < 0.05). In the comparison of physical fitness tests between sexes, normal weight boys did better than girls (p < 0.05) for all tests except flexibility. There were no statistically significant differences between sexes in overweight and obese children. This study demonstrated that physical fitness of obese children was worse than that of normal children in both sexes, especially as measured by 50 meters run, sit-up and VO2 max tests. Thus, promotion of exercise in obese children should be stimulated to develop better physical fitness and weight reduction. In comparison of physical fitness between the sexes, boys had better physical fitness than girls, significant in the normal weight group only. There is no definite explanation as to why increase in weight results in no difference of physical fitness between sexes. Lifestyle, physical skills, and genetic determinants should be considered for interpretation of physical fitness. PMID- 7855657 TI - Factors affecting utilization of health centers in a rural area of Chon Buri Province, Thailand. AB - A descriptive study was carried out in two subdistricts of Nong Heng and Nong Kakha, Phan Thong District, Chon Buri Province eastern Thailand with the aim to determine factors affecting health center utilization. A cross-sectional survey was conducted on 206 randomly selected households in which household head or senior person in each household was interviewed using a structured questionnaire. The study household was classified as either high or low health center utilization group on the basis of using health services more than 50% of total health services needed in each household. The results revealed that age group, sex, education, family size, and distance from household to health center were not associated with the utilization of health center, whereas occupation, economic status, knowledge and attitude towards health center and quality as well as convenience of health services were found to be associated with health center utilization. It was seemed that underutilization of health centers was multifactorial, in which some factors were related with the personality of individual whereas others were concerned with the health center itself. PMID- 7855658 TI - Trial of transdermal nicotine patch in smoking cessation. AB - In order to evaluate the efficacy of the transdermal nicotine patch, 37 persons who wore the patches (group 2) were compared with 40 persons who attended an organized smoking cessation program (group 1). At 1 month, 8 persons of group 2 (21.62%) and 22 persons of group 1 (55%) were able to stop smoking. At 3 months, 8 persons of group 2 (21.62%) and 17 persons of group 1 (42.5%) were still abstinent. At 6 months, 7 persons of group 2 (18.9%) and 14 persons of group 1 (35%) were able to quit smoking. Counselling and follow-up support are needed to maintain abstinence. PMID- 7855659 TI - Monitoring resistance gene frequencies in Malaysian Culex quinquefasciatus Say adults using rapid non-specific esterase enzyme microassays. AB - The ability to identify the occurrence of different resistance genotypes in field populations of mosquito is considered important for the purpose of optimising chemical control operations. The recent development of rapid microassays of enzymes responsible for resistance has provided a means for rapidly assessing the genetic background of target mosquito populations. This concept is the topic of investigation in this study. Non-specific esterase activity, which is responsible for the resistance to organophosphates in Malaysian Culex quinquefasciatus Say adults, was determined in 3 field populations from Kuala Lumpur City using rapid enzyme assay. The optical density results were used to estimate the genotypic frequencies of the populations. Subsequently, time-dependent changes in the various frequencies were determined. Such techniques allowed rapid assessment of resistance genotypes for decision-making and its possible use in insect control merits further investigation. PMID- 7855660 TI - Use of hexaflumuron, an insect growth regulator in the control of Aedes albopictus (Skuse). AB - An attempt was made to assess the control potency of an insect growth regulator (IGR), hexaflumuron, against Aedes albopictus, a potent dengue vector, both in the laboratory and under field conditions. Emergence inhibition activity of this IGR against laboratory reared and field collected larvae of Ae. albopictus showed EI50 values of 1.9 x 10(-4) and 1.80 x 10(-4) mg(ai)/l respectively. Under field conditions, no appreciable reduction in immature density occurred at the lowest application rate of 0.001 mg(ai)/l whereas at the rate of 0.01 mg(ai)/l 100% reduction could be seen in earthern pots placed in a garden for 9 days. A reduction of 100% in pupal density was observed for 21 and 18 days at an application rate of 0.1 mg(ai)/l in pots and tyres respectively. Considering that this IGR was effective for about three weeks, it can be used successfully at the rate of 0.1 mg(ai)/l for controlling Ae. albopictus breeding in container habitats. PMID- 7855661 TI - Studies on the mosquito vectors of Japanese encephalitis virus in Mandya District, Karnataka, India. AB - Entomological investigations were carried out in areas affected by Japanese encephalitis (JE) in Mandya District, Karnataka, India, from 1983 to 1988, to determine species composition and the density of mosquito vectors, in relation to the incidence of JE cases. JE cases occurred in two spells in a year, one during April-June (summer epidemic) and another during October-December (winter epidemic). There was very high incidence of JE cases in extensively irrigated areas and a low incidence in some of the taluks with less or no irrigation systems. Among culicines, Culex tritaeniorhynchus was the most predominant species (20.54%), followed by Cx. fuscocephala (16.94), Cx. vishnui (16.48%), Cx. gelidus (10.70%) and other species. The overall mosquito population showed two peaks in a year, one during the March-April, and another during September, usually preceding the human epidemics. Relative abundance of certain species varied in different years. PMID- 7855662 TI - Studies on adult mosquito vectors of Japanese encephalitis in a pig farm in Selangor, Malaysia. AB - Mosquito collections were carried out for a period of one year from January to December 1992 in a pig farm in Sungai Pelek, Selangor, Malaysia. A total of 41,022 mosquitos belonging to 52 species and 20 genera were collected. Culex tritaeniorhynchus and Cx. gelidus, the important vectors, comprised 63% of all mosquitos collected. Both these species were collected in large numbers during the wet months of May and December. The other predominant species in that area were Cx. fuscocephala, Cx. quinquefasciatus, Cx. sitiens, Aedes butleri, and Armigeres subalbatus. PMID- 7855663 TI - Sex ratio and susceptibility of the golden apple snail, Pomacea canaliculata. AB - Golden apple snails, Pomacea canaliculata, were collected at two localities having different ecological environments. In both canal and pond, P. canaliculata males were found more than females during the dry season (summer and winter). In the canal, the male snails were highest in number (86.67%) in May. When rain started, they began decreasing and were lowest at 33.33% in August. Of 575 snails collected, 30.6% were infected by one or more of the three groups of amphistome, distome and echinostome metacercariae. There were two high peaks of infection in April and October, as 60.7% and 68.4%, respectively, during which there were more males than females. The average number of parasites per snail which was highest at 54 was found in the medium-sized males (25 out of 35 males) in October. The number of parasites per snail was significantly correlated with the collected males (p < 0.01), but such relationship was not occurred with the females. Of the females, only the large-sized individuals were infected. In the pond, the female snails were present in much greater numbers than the males during the reproductive time (June-September). The females were highest (94.23%) in August. Only 24 (4.0%) of 605 snails were infected; most of the infected snails were large. PMID- 7855664 TI - Hepatitis A virus antibody in mentally retarded children. PMID- 7855665 TI - Absence of plasmid in mosquitocidal Clostridium bifermentans serovar malaysia. PMID- 7855666 TI - Quinine toxicity when given with doxycycline and mefloquine. AB - The pharmacokinetic and dynamic interactions among 3 antimalarials, ie quinine, doxycycline and mefloquine was observed in a 26-year-old Thai male patient with falciparum malaria. During the acute episode of the infection, the patient was treated with an intravenous dose of quinine hydrochloride at 600 mg qid, together with an oral dose of doxycycline 100 mg bid. Due to nausea, tinnitus and the persistence of parasitemia in peripheral blood smears, the dose of quinine was reduced 2 days after the first treatment to 300 mg; concurrently oral mefloquine 750 mg was given as 2 divided doses at 24 hours apart. During the course of treatment, the patient developed hearing loss; deafness of the right ear lasted for one week after stopping quinine administration. Higher plasma quinine and lower whole blood mefloquine concentrations than would be expected from the simulation profiles were detected 4 days after the first treatment. However, the concentration of mefloquine was increased upon the cessation of quinine treatment. PMID- 7855667 TI - Gastric ascariasis associated with upper gastrointestinal hemorrhage. PMID- 7855668 TI - Fatal diphtheria in a Thai adult. PMID- 7855669 TI - Diabetes mellitus, salmonellosis, fatty liver, and lipid embolism. PMID- 7855670 TI - Concentration time course of praziquantel in Filipinos with mild Schistosoma japonicum infection. AB - Despite extensive use of praziquantel, the current drug of choice for the treatment of schistosomiasis and other helminthic infections, little information is available about its pharmacokinetics in individuals living in geographic areas where such infections are endemic. We investigated the pharmacokinetics of praziquantel by determining its serum concentration-time course in four selected Filipino volunteers with mild Schistosoma japonicum infection who lived in an endemic area in the Southern Philippines. At specified intervals during a 24-hour time period after a single oral dose of praziquantel (25 mg/kg BW), intravenous samples of blood were drawn, processed and analyzed for praziquantel using reverse phase high pressure liquid chromatography. The same study was repeated one week later to assess pharmacokinetic reproducibility. A third study, simulating current field practice, consisted of dosing the patient four hours apart and analyzing for praziquantel in serial blood samples drawn at specified time intervals after the first and second dose. The following results were obtained: 1) Serum concentration-time course of praziquantel was reproducible for each patient but varied from patient to patient. 2) Praziquantel was rapidly absorbed in the gastrointestinal tract as measurable amounts appeared in the blood as early as 15 minutes after dosing. Time to peak serum concentration ranged from 1.50 to 6.00 hours with almost complete elimination from blood by 24 hours whether it was administered as a single dose (1 x 25 mg/kg BW) or as a twice a day dose (2 x 25 mg/kg BW) 4 hours apart. Half-life values ranged from 1.00 to 2.50 hours.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7855671 TI - The quantitative anatomy of the atlas. AB - STUDY DESIGN: This study is based on direct quantitative caliper measurements of 88 isolated anatomic specimens of the C1 vertebra. OBJECTIVES: The study was undertaken to establish the range and variability of the external dimensions of the atlas and to describe the cortical thicknesses and trabecular distribution of this unique vertebra. SUMMARY OF BACKGROUND DATA: Before this study, Francis in 1952 reported the total anterior and posterior diameter of 285 atlas vertebrae. Liu et al reported detailed external dimensions and facet joint surface morphologies on a total of three C1 vertebrae. METHODS: Measurements were made of overall dimensions, canal diameters, and the dimensions of the anterior and posterior arches of 88 dried human C1 vertebrae. Eight specimens were sectioned in the frontal plane, eight in the sagittal plane, and four in the coronal plane. The anatomy of these sections was documented by radiographic imaging. Cortical thicknesses on the sections were then obtained by direct measurement. RESULTS: The canal diameter ranged from 32 mm (SD 2 mm) in the sagittal plane, and 29 mm (SD 2 mm) in the lateral dimension. The mean thickness of the anterior ring was 6 mm (SD 1 mm) and posteriorly was 8 mm (SD 2 mm). Cortical bone was thinnest posteriorly. CONCLUSIONS: These measurements indicated remarkably constant dimensions for the ring itself, suggesting there may be significant functional restraints on the canal size of this unique vertebra. In contrast, a significant variability was noted in objective measurements of lateral mass height and sagittal plane widths of the entire bone. PMID- 7855672 TI - Morphology of C5 ventral nerve rootlets as part of dissociated motor loss of deltoid muscle. AB - STUDY DESIGN: This study analyzed anatomic characteristics of cervical ventral rootlets. After total vertebrectomy, detailed morphology of the ventral rootlets was studied from the anterior. SUMMARY OF BACKGROUND DATA: The clinical study showed the predominance of ventral root lesion. There are few studies concerning the morphologic pathogenesis of cervical amyotrophy and detailed cervical ventral rootlet anatomy. METHODS: Thirty-six embalmed adult human cadavers were studied. The measurements for the ventral rootlets of C5 to C8 were made as follows: 1) angle between the rootlet and spinal cord, 2) longitudinal width of the ventral rootlet origin, and 3) length of the ventral rootlets. RESULTS: The C5 ventral rootlets were shorter and issued more obtusely from the cervical spinal cord than lower rootlets. The spinal cord segment of the deltoid muscle, indicated by the longitudinal widths of the C5 and C6 ventral rootlet exits from the spinal cord, were wider than the C7 and C8 segments. Preforaminal anterior compression at the C4-C5 disc level might affect the lower part of the C5 ventral rootlets and upper part of the C6 ventral rootlets. CONCLUSION: Short C5 ventral rootlets appeared to become taut and easily injured by hemilateral anterior compression. Spinal cord lesion resulting from localized anterior compression at the single disc level might not play as important a role in the pathogenesis of dissociated motor loss of the deltoid muscle because of the wider spinal segments of C5 and C6. PMID- 7855673 TI - The range and nature of flexion-extension motion in the cervical spine. AB - OBJECTIVE: The full flexion to full extension angular ranges of motion (ROM) from C2 to C7 were measured for 78 normal subjects and 50 cervical myelopathic cases to examine the cervical motions for these two groups in a Chinese population. METHODS: Measurements were all taken from standard lateral radiographs. RESULTS: The normal group showed an average total ROM slightly less than in Western subjects, but a similar distribution of motion throughout C2 to C7. The proportion of motion at levels C4:C5 and C5:C6 were functions of the total ROM, the greatest proportion of motion being at C4:C5 for low (< 50 degrees) total ROM and moving to C5:C6 for high (> 90 degrees) total ROM. The myelopathic group showed a similar but less clearly established pattern of motion to this. A significantly lower average total ROM than in the normal group was also found. CONCLUSIONS: This work suggests that the reduction in total angular ROM concomitant with aging results in the emphasis of cervical flexion-extension motion moving from C5:C6 to C4:C5, both in normal cases and those suffering from cervical myelopathy. PMID- 7855674 TI - Ratings of perceived thigh and back exertion in forest workers during repetitive lifting using squat and stoop techniques. AB - STUDY DESIGN: Local thigh and low back perceived exertion (RPE), sagittal peak load moments, and leg and trunk muscular activity during repetitive submaximal lifting, with squat and stoop technique, were investigated. OBJECTIVES: This study analyzed changes in kinetic variables caused by changes in body movements during the lifting bouts, and the contribution of the biomechanical and physiologic variables to the variability in the local RPE responses. SUMMARY OF BACKGROUND DATA: Despite instructions that emphasize the "correct" lifting technique as the squat technique, the stoop technique is reported as more commonly used in practice. Few studies have investigated the effect of lifting technique on differentiated perceptual responses in repetitive lifting. METHODS: Ten experienced forest workers performed submaximal repetitive lifting bouts until steady-state VO2 was reached, using five different weight and frequency combinations with both squat and stoop techniques. Borg's scale was used for RPE measurements. Muscular activity in lumbar, hip, knee extensors, and knee flexors was recorded with surface electrodes. Kinematic data was obtained from electronic liquid-level sensors, and vertical ground reaction forces from a two-dimensional force plate. RESULTS: Low back RPE was higher for stoop than for squat, whereas the opposite was true for thigh RPE. The total accountable variance (R2) for the biomechanical and physiologic variables to the RPE responses ranged from 0.25 (low back RPE in squat lifting) to 0.61-0.76 for the other assessments. During the time course in squat lifting at the highest frequency, the knee load moment decreased and the vertical ground reaction forces increased. CONCLUSIONS: The study indicates that "movement strategies" to reduce the demand on the knee extensor muscles were used during the squat lifting bouts at the highest frequencies, which combined with the relatively high assessed thigh exertions, leads to the hypothesis that quadriceps muscle exertion is the "weak link" for the squat technique. The study also indicates a discrepancy between the measured and perceived low back stress in squat repetitive lifting. PMID- 7855675 TI - Morphology and kinematics of the baboon upper cervical spine. A model of the atlantoaxial complex. AB - STUDY DESIGN: Quantitative and qualitative analyses were performed to compare the anatomy and biomechanics of baboon and human upper cervical spines. OBJECTIVES: This study examined the baboon as a potential model for in vivo and in vitro atlantoaxial research. SUMMARY OF BACKGROUND DATA: A variety of animal models have been used for spine research; however, no species have been used for C1-C2 research. Most species have remarkably different C1-C2 morphology compared with that of humans. METHODS: Twenty baboon and seven human normal adult cadaveric upper cervical spines were studied morphologically. C1-C2 motion segments were analyzed biomechanically using a flexibility method of testing with physiologic range, nondestructive loading. Motion and load-deformation relationships were studied during flexion, extension, bilateral lateral bending, and bilateral axial rotation. RESULTS: The bones and ligaments of the baboon and human upper cervical vertebrae have similarly proportioned structures, identical individual components, and similar geometric configurations. The average size of the baboon vertebrae was 50% to 60% of the human specimens. There were several minor anatomical differences. Baboons had more horizontal C2-C3 facet joints and more vertical C1-C2 articular surfaces; the vertebral arteries were encased in a continuous bony canal in C1. Biomechanical testing demonstrated that baboons and humans had similarly proportioned neutral zones and elastic zones. Compared with humans, baboons had a 2 degrees to 9 degrees wider range of motion in all directions. CONCLUSIONS: The baboon and human upper cervical anatomy and biomechanics are similar. The baboon may be useful to study atlantoaxial biomechanics and pathology. PMID- 7855676 TI - Fusion rate and biomechanical stiffness of hydroxylapatite versus autogenous bone grafts for anterior discectomy. An in vivo animal study. AB - STUDY DESIGN: The fusion rate and biomechanical stiffness were evaluated for 56 goat spinal units from 14 animals that had anterior discectomies and grafting procedures completed using hydroxylapatite and autogenous bone and survived for 6, 12, and 24 week healing times. OBJECTIVES: Harvested spinal units underwent radiographic imaging to assess fusion, biomechanical testing in axial compression, flexion, extension, lateral bending, and axial rotation to assess strength, and histological analysis. The above results were compared for the two procedures and the different healing times. SUMMARY OF BACKGROUND DATA: Because of some of the complications associated with the use of autogenous iliac crest bone graft in spine fusions, there has been considerable interest in the use of calcium phosphate ceramics as a possible substitute for a grafting material. One of the attractive features of calcium phosphate ceramics is the resulting strong bond that is formed with the host bone unlike other inert compounds. METHODS: Surgeries were done at four sites on each animal with two in the cervical spine and two in the lumbar spine. Radiography was done during the survival time and postsacrifice. Biomechanical testing was done on the day of sacrifice under physiological loads. Both hard tissue sections and decalcified sections were histologically evaluated. RESULTS: A 55% fusion rate for bone preparations and a 50% fusion rate for the hydroxylapatite (HA) units was found for the 12 and 24 week preparations. The HA preparations were better at maintaining disc space height. The biomechanical analysis revealed significantly higher stiffness values for fused preparations than for nonfused samples under extension, lateral bending, and axial rotation. Fused units demonstrated no statistical difference in biomechanical stiffness between HA versus autogenous bone units for any mode of loading. CONCLUSIONS: Our results indicate that these dense, nonresorbable hydroxylapatite blocks perform as well as autogenous bone for anterior spinal fusions in this animal model. The use of this hydroxylapatite material in anterior spine fusions may have some clinical validity. PMID- 7855677 TI - Biomechanical analysis of cervical stabilization systems. An assessment of transpedicular screw fixation in the cervical spine. AB - STUDY DESIGN: The biomechanical stability of seven cervical reconstruction methods including the transpedicular screw fixation was evaluated under four instability patterns. These four modalities, based on the range and grade of instability, allowed a reproducible biomechanical assessment to establish the in vitro role of internal fixation in the cervical spine. OBJECTIVES: This study biomechanically investigated the stability of seven reconstruction methods in the cervical spine as influenced by four instability patterns and assessed whether three-column fixation for the cervical spine using transpedicular screw fixation would provide increased stability over that of conventional cervical fixation systems. METHODS: A total of 24 calf cervical spine specimens were divided into four experimental groups. The spinal constructs including seven reconstruction techniques--the posterior AO titanium reconstruction plate, Bohlman's posterior triple-wiring, transpedicular screw fixation, anterior iliac bone graft, anterior AcroMed plate, anterior AO titanium locking plate, and combined fixation with the AO anterior plate and posterior triple-wiring--were tested under four loading modes. RESULTS: Anterior plating methods provided less stability than that of posterior constructs under axial, torsional, and flexural loading conditions. Exclusive posterior procedures provided increased stability compared with the intact spine in one level fixation, however, did not sustain the torsional stability when the anterior and middle column was eliminated in two-level fixation. The stabilizing capabilities of both the combined fixation and transpedicular screw fixation were clearly demonstrated in all loading modes, however, those of the latter were superior in multilevel fixation. CONCLUSION: Front and back approaches, employing the anterior plate and posterior triple wiring, and transpedicular screw fixation demonstrated clear biomechanical advantages when the extent of instability increased to three-column or multilevel. Three-column fixation for the cervical spine using transpedicular screw fixation offers increased stability over that of conventional cervical fixation systems, particularly in multiple level constructs. PMID- 7855678 TI - Biomechanical analysis of facet and graft loading in a Smith-Robinson type cervical spine model. AB - OBJECTIVE: This study determined the effect of change in graft height on the forces across a Smith-Robinson graft as well as across the posterior elements of the same motion segment. STUDY DESIGN: The study utilizes a strain gauge technique for the measurement of facet joint loading and a subminiature load cell for the measurement of graft loads. SUMMARY OF BACKGROUND DATA: A number of cases of Smith-Robinson procedures have had some form of collapse of the interspace and graft material after surgery. Some patients with collapse of the graft go on to have prolonged sclerotomal-type pain or pseudarthrosis. The appropriate amount of distraction is not well defined in the literature and may affect the outcome. METHODS: Cervical spines (C5-C6) were instrumented by placing strain gauges bilaterally on the pedicles of C6 (to measure the forces across the posterior elements). A miniature load cell with matching metallic shims was used to measure the force across the graft site and to distract the segment. Forces across the posterior elements and the graft site were measured, during flexion loading, and compared as the disc space was distracted. RESULTS: The ratio of posterior element load to graft load with increasing disc space distraction significantly decreased from 1.06 +/- 0.65 (1.4 mm distraction) to 0.30 +/- .13 (4.6 mm distraction) (P < .03). The posterior element load decreased significantly after the same distraction, from 46.1 +/- 22.0 to 18.7 +/- 9.7 N/Nm (P < .05). CONCLUSIONS: In spondylotic specimens (4-5 mm disc heights) disc space distraction in excess of 3.0 mm from preoperative height caused a significant decrease in both the ratio of posterior element to graft loading and posterior element loads. These findings may help explain recent clinical reports of a limit of effective disc space distraction. PMID- 7855679 TI - The role of plate and screw fixation in occipitocervical fusion in rheumatoid arthritis. AB - STUDY DESIGN: In a clinical retrospective study, the results of occipitocervical fusion in patients with rheumatoid arthritis were studied and analyzed. OBJECTIVES: The results of two different operative techniques were compared. The advantages of screw fixation compared with wiring techniques in this population of patients were investigated. SUMMARY OF BACKGROUND DATA: Numerous different implants have been presented in the literature for occipitocervical fusion in patients with rheumatoid arthritis. The use of wires being the standard fixation technique. METHODS: Occipitocervical fusion was performed in patients with rheumatoid arthritis: 26 patients with the wiring technique and 33 patients with a new Y-plate fixation. The results were compared at a follow-up period of 24 months and 50 months, respectively. Clinical and radiologic results were investigated. RESULTS: The atlantodental distance could be significantly better reduced in the group with the Y-plate fixation and the neurologic improvement in the wiring group was 40%, whereas in the Y-plate fixation 86% of neurologic improvement was observed. Pseudarthrosis was seen in 27% of the wiring technique and in 6% in the plate and screw fixation technique. CONCLUSIONS: In occipitocervical fusion for patients with rheumatoid arthritis, the screw and plate fixation technique provides superior results than other techniques using wire fixations. PMID- 7855680 TI - Repair of vertebral artery injury during anterior cervical decompression. AB - METHODS: Vertebral artery injury is a rarely described complication of anterior cervical decompression. The authors performed a retrospective review of their operative database for the purposes of defining the optimal management of this complication and its avoidance. RESULTS: Four of 1,215 (0.3%) patients undergoing anterior cervical operation sustained arterial injuries. In three cases, primary repair of the artery was successful; in one case, the artery was exposed and ligated. There were no postoperative ischemic complications. Artery laceration occurred during decompression (n = 2), screw tapping (n = 1), and during soft tissue retraction (n = 1). CONCLUSIONS: Injury to the vertebral artery during anterior approaches can be avoided by preoperative identification of anomalous arteries and by intraoperative attention to the midline. When the artery is injured, primary repair may be the optimal management strategy. PMID- 7855681 TI - Spinal disorders at the cervicothoracic junction. AB - STUDY DESIGN: This study reviewed 36 retrospective patients who underwent surgeries for rare cervico-thoracic junctional problems. OBJECTIVES: The authors review cervico-thoracic junctional disorders and study diagnostic methods, surgical approaches, surgical outcomes, and associated complications. SUMMARY OF BACKGROUND DATA: The literature is sparse on cervico-thoracic junctional problems. This paper is the largest series to date on this subject. METHODS: Thirty-six patients who underwent surgeries for spinal problems at the cervico thoracic region (C7-T3) were reviewed. These included 18 patients with trauma, 15 patients with tumors, 2 patients with herniated discs, and one patient with postlaminectomy instability. There were 20 males and 16 females. The age ranged from 17 to 83 years with a mean of 43.5 years. Surgically, 21 patients had only posterior procedures, that included 12 wiring, 5 Luque rodding, 1 plate-screw fixation for postlaminectomy instability, 1 transpedicular biopsy, 1 foraminotomy for herniated C7-T1 disc, and 1 costotransversectomy for T2-T3 herniated disc. Neurologically, the majority of traumatic patients presented with neurologic deficits (10 complete and 4 incomplete, and 1 root injuries), and nontraumatic disorders were associated with 10 incomplete cord syndromes and 5 root dysfunctions. RESULTS: Follow-up average was 38 months based on 33 of 36 patients. There were three postoperative deaths (two sternotomies, one anterior C7 corpectomy). Neurologically, patients with complete cord injuries remained complete, whereas patients with incomplete or root deficits improved significantly. Complications included C6-C7 subluxation after C7-T2 fusion, pseudomeningocele, vocal cord paralysis, dysphagia, and Horner's syndrome. Other complications included wound infections, urinary tract infections, decubiti, deep vein thrombosis, pneumonia, and tumor recurrence. CONCLUSIONS: In treating patients with cervico-thoracic problems, one should do careful clinical and radiologic survey to avoid missed or delayed diagnoses, and the surgeon must be thoroughly familiar with anterior and posterior landmarks and associated vital structures and remember that the cervico-thoracic junction is an area of potential instability particularly after trauma or laminectomy. Complications of surgery at the cervico-thoracic junction are frequent, and meticulous surgical techniques and postoperative care are important in the prevention of these complications. PMID- 7855682 TI - Realignment of postoperative cervical kyphosis in children by vertebral remodeling. AB - STUDY DESIGN: This study analyzed radiographically change in the sagittal curvature of the cervical spine after atlantoaxial (C1-C2) posterior fusion in children. OBJECTIVES: This study clarified the process of spinal remodeling after postoperative cervical deformation in children. SUMMARY OF BACKGROUND DATA: Postoperative spinal deformations in children are observed frequently. However, there have been only a few reports on postoperative changes in the sagittal curvature of the cervical spine and spinal remodeling after those changes. METHODS: Between 1979 and 1991, there was a total of 12 children who underwent C1 C2 posterior fusions. The average age at the time of surgery was 9.8 years. The alignment of the cervical spine was classified into four groups (lordosis, straight, kyphosis, and swan-neck deformity). Radiographic findings suggestive of the remodeling were as follows: 1) new bone formation on the anterior vertebral cortex, and 2) increase in body/canal ratio (BCR). The follow-up period averaged 6.2 years. RESULTS: Postoperative cervical malalignment (kyphosis or swan-neck deformity) occurred in four patients. In all four patients, new bone formation and increase in BCR at the apex of kyphosis were observed. Therefore, there was gradual improvement of the malalignment by vertebral remodeling. This phenomenon was not observed in eight patients with normal alignment. CONCLUSION: Realignment of postoperative cervical kyphosis by vertebral remodeling was observed in children. The results of this study suggested that remodeling occurred even in the spine, which was similar to the remodeling in long bones. PMID- 7855684 TI - Efficacy of chymopapain in chemonucleolysis. A review. AB - STUDY DESIGN: This study was designed to determine the current experience in the use of chymopapain injection in the treatment of herniated intervertebral discs by analyzing reports appearing between 1985 and 1993. Forty-five clinical studies included 7,335 patients treated worldwide, some including comparisons to open laminectomy/discectomy and others to percutaneous discectomy. OBJECTIVES: Because controversy persists after 30 years of clinical use of chymopapain, the results of current experience should establish the efficacy for those who want to consider chemonucleolysis as a treatment for a herniated nucleus pulposus. SUMMARY OF BACKGROUND DATA: There is the suggestion that use of other than conservative treatment is made only to achieve a better result in the short term. The selection of type of treatment will depend on contraindications, with failures of chemonucleolysis found largely in those having spinal stenosis or sequestrated discs. Worker compensation patients respond less successfully than those with better motivation. METHODS: The 45 studies were analyzed for determination of successful outcome and divided into 16 with more than 100 patients, 13 with less than 100 patients and 16 with comparison to other treatments. RESULTS: Individual success rates exceeded 60% whereas cohort total averaged 76%. In studies comparing chemonucleolysis with open discectomy, success rate averaged 76.2% as compared with 88% for open surgery. In two other studies, percutaneous discectomy was less successful than chemonucleolysis. Where included, duration of hospitalization showed less time and thus less costs for chemonucleolysis. Return to work complications showed time off slightly less for chemonucleolysis than for laminectomy. CONCLUSIONS: Chemonucleolysis, though somewhat less effective than open discectomy, can be successfully and safely used in about four of five carefully selected patients without the trauma, risks, and subsequent fibrosis associated with lumbar disc surgery. PMID- 7855683 TI - A prospective randomized three-week trial of spinal manipulation, transcutaneous muscle stimulation, massage and corset in the treatment of subacute low back pain. AB - STUDY DESIGN: A randomized prospective trial of manipulation, massage, corset and transcutaneous muscle stimulation (TMS) was conducted in patients with subacute low back pain. OBJECTIVES: The authors determined the relative efficacy of chiropractic treatment to massage, corset, and TMS. SUMMARY OF BACKGROUND DATA: Although all of these treatments are used for subacute low back pain treatment, there have been few comparative trials using objective outcome criteria. Patients were enrolled for a period of 3 weeks. They were evaluated once a week by questionnaires, visual analog scale, range of motion, maximum voluntary extension effort, straight leg raising and Biering-Sorensen fatigue test. The dropout rate was highest in the muscle stimulation and corset groups and lowest in the manipulation group. Rates of full compliance did not differ significantly across treatments. A measure of patient confidence was greatest in the manipulation group. RESULTS: After 3 weeks, the manipulation group scored the greatest improvements in flexion and pain while the massage group had the best extension effort and fatigue time, and the muscle stimulation group the best extension. CONCLUSION: None of the changes in physical outcome measures (range of motion, fatigue, strength or pain) were significantly different between any of the groups. PMID- 7855685 TI - Indications for pedicle fixation. Results of NASS/SRS faculty questionnaire. North American Spine Society and Scoliosis Research Society. AB - STUDY DESIGN: The faculty of the North American Spine Society and Scoliosis Research Society pedicle fixation workshop were questioned about their use of pedicle screw implants for fixation of the spine. OBJECTIVES: This study ascertained which faculty members used pedicle implants given specific clinical scenarios and analyzed the data for trends and consensus. SUMMARY OF BACKGROUND DATA: For the past 4 years, the North American Spine Society in conjunction with the Scoliosis Research Society has sponsored a course on pedicle fixation of the spine. During these courses, techniques of pedicle fixation have been discussed. The indications, however, for pedicle fixation have remained controversial, even among the course faculty. METHODS: A questionnaire was developed with 20 clinical scenarios, and the faculty were asked whether they would use pedicle implants as part of their surgical treatment. RESULTS: Thirty-eight of 45 (84%) questionnaires have been received and analyzed. For most scenarios, there was statistically significant consensus among the faculty that they would use a pedicle implant. There was statistically significant consensus that the faculty would not use pedicle implants for thoracic fractures or adolescent idiopathic scoliosis. DISCUSSION: This study is useful in assessing pedicle implant usage in our community but should not be used as a guide for their indications and contraindications. PMID- 7855687 TI - Back muscle injury after posterior lumbar spine surgery. Part 2: Histologic and histochemical analyses in humans. AB - STUDY DESIGN: The histologic and histochemical changes in back muscle were studied in virgin surgery patients with lumbar spine disorders and in patients who underwent repeat posterior lumbar surgery. OBJECTIVES: The results were correlated to provide the evidences of histologic changes of back muscle after posterior lumbar surgery. SUMMARY OF BACKGROUND DATA: Back muscles were examined histologically and histochemically after posterior lumbar surgery. No previous study has assessed these changes. METHODS: Back muscles were obtained before and after retraction from 18 virgin surgery cases with lumbar spine disorders. In four patients, the retraction pressure was monitored and the retraction pressure time products ([P][T]) were calculated. In 21 repeat lumbar surgery cases, muscle samples were obtained before muscle retraction. Samples were evaluated by histologic and histochemical methods. RESULTS: Abnormal findings were slight in virgin surgery cases. Early back muscle injury tended to depend on operation time and [P][T] products. Late back muscle injury in reoperated patients was marked. Various types of neurogenic changes were observed more than 10 months after the first operation. CONCLUSIONS: Histologic damages of back muscle due to previous surgical intervention were long-lasting. To avoid permanent muscle injury, the retraction time and pressure should be shortened or the pressure on the back muscle should be monitored during posterior surgery. PMID- 7855686 TI - Back muscle injury after posterior lumbar spine surgery. Part 1: Histologic and histochemical analyses in rats. AB - STUDY DESIGN: Back muscle injury caused by retractor application during posterior spine surgery in rats was examined histologically and histochemically according to the postoperative time with reference to the retraction time-pressure relationship. OBJECTIVES: The results were correlated to provide the risk factors for back muscle injury during posterior spine surgery. SUMMARY OF BACKGROUND DATA: Back muscles were examined histologically and histochemically after application of quantitative pressure and retraction time. No previous study has assessed this relationship. METHODS: Five groups were studied: Group 1, 1-hour low-pressure load group; Group 2, 1-hour high-pressure load group; Group 3, 3 hour low-pressure load group; Group 4, 3-hour high-pressure load group; and sham group. In each group, the multifidus muscle was evaluated 3 hours, 48 hours, 1 week, 3 weeks, and 6 weeks after surgery. RESULTS: In all groups except the sham group, degeneration of the muscle and neuromuscular junction was found at a very early postoperative time, but regeneration began at 1 week, and recovery was attained by 6 weeks. The extent of muscle fiber necrosis and the severity of degeneration of the neuromuscular junctions showed a parallelism with the magnitude of the pressure load and retraction time. As the duration and pressure load increased, the time required for regeneration also increased. The fiber type grouping in group 3 and 4 was consistent with the severity of degeneration of neuromuscular junctions. CONCLUSIONS: The muscular degeneration and the regeneration was largely dependent on the retraction pressure-time product. These results suggest that denervation muscle injuries are likely secondary responses to muscle retraction injury in any case of posterior spine surgery. PMID- 7855688 TI - Syringomyelia as a complication of spinal arachnoiditis. AB - SUMMARY OF BACKGROUND DATA: The authors report a 46-year-old female patient who was referred to this unit for assessment of chronic postsurgical back pain. She reported severe burning pain in the lumbar region accompanied by burning pain and loss of sensation in the lower limbs. She had previously undergone lumbar spinal surgery on three occasions preceded by myelography. METHODS: Examination revealed generalized weakness and hypertonicity of both lower limbs with loss of all sensory modalities below D7. RESULTS: The MRI scanning of the thoracic spine showed an extensive complex syrinx within the thoracic cord. CONCLUSIONS: She underwent syringopleural shunting, and her condition has remained stable. PMID- 7855689 TI - [Must there be a Spanish transplant group for bone marrow or hematopoietic precursors of peripheral blood?]. PMID- 7855690 TI - [The national hemotherapy plan: an incomplete reform]. PMID- 7855691 TI - [Treatment with oral anticoagulants (acenocoumarol): influence of the initial doses in the incidence of hemorrhagic and thromboembolic episodes]. AB - PURPOSE: To compare two initial doses of oral anticoagulant (acenocoumarin) studying the haemorrhagic and thromboembolic episodes occurred during the first month of treatment, the mean time and necessary controls until achievement of the desired level of anticoagulation. PATIENTS AND METHODS: From january 1992 to december 1993; a comparative study of two groups of patients was performed: group 1, compiling 129 patients chosen at random and retrospectively, who begun oral anticoagulant treatment with 4 daily mg of acenocoumarin; and group 2, compiling 129 patients chosen prospectively, who begun with 2 mg daily. In both groups the mean time and the number of controls performed until achieving the desired level of anticoagulation were analyzed, as well as the haemorrhagic episodes occurred during the first month of treatment, their severity (classified into major and minor ones), the level of anticoagulation when they occurred and their possible causes. In the same way the thromboembolic processes occurred during that period in both groups were studied. RESULTS: The mean time necessary to achieve the desired level of anticoagulation was 3.8 days in group 1 and 6.3 in group 2; the mean number of controls performed in group 1 was 1.2 and in group 2 it was 1.8. We have observed 19 haemorrhagic episodes, 15 in group 1 (4 minor and 11 major); and 4 in group 2 (2 minor and 2 major). We have found significant differences with respect to the mean time (p < 0.01), number of controls (p < 0.01) and incidence of hemorrhages (p = 0.017) between groups 1 and 2. One thromboembolic episode was registered in each group: in group 1 a deep venous thrombosis and in group 2 a stroke. CONCLUSION: The initial daily doses of acenocoumarin of 2 mg is as effective as the 4 mg one in the prevention of thromboembolic episodes, with a significant reduction in the number of haemorrhages observed during the first month of treatment. However this produces a prolongation in the necessary mean time and more number of controls performed until the achievement of the desired level of anticoagulation. PMID- 7855692 TI - [Alloimmunization in polytransfused patients. Usefulness of selecting erythrocytes compatible with antigens different from ABO and D]. AB - PURPOSE: Antibody formation against red blood cells' antigen is a very important complication due to transfusions, and it can make the following transfusions difficult. To avoid this, it has been proposed giving identical red blood cells for the antigens more frequently involved in sensitizations. To evaluate this fact, we have accomplished a study with the transfused patients in our Hospital since 1990. MATERIAL AND METHODS: 10,308 transfused patients in the Hospital Nitra. Sra. de Covadonga (Oviedo), between January 1990 and March 1994, were studied. The patients have been included in two groups: The first one was constituted by 4,226 patients from the Haematology and the Nephrology Departments, who received red blood cells units compatible with ABO and CcDEe antigens. The second group was formed by the remainding patients transfused with red blood cells compatible only with ABO and D antigens. RESULTS: All 165 antibodies were detected in 132 patients, which means an incidence of 1.3 percent. In 63 cases, antibodies were present before the first transfusion. In the remaining patients, an allosentitization of 0.2 percent in group 1 and 1 percent in group 2 (p < 0.0001) was shown. This difference cannot be explained only for transfusing red blood cells with the same Rh phenotype in the group 1, because a lower immune response had persisted when we analyzed the other antibodies. More than 70 percent of antibodies appeared before the 10th transfusion. DISCUSSION: A lower sensitization exist in the patients of group 1. This seems to be caused by a state of immunosuppression for their disease or their treatments. However, in some patients, the risk of allosensitization persists, so we think it is a good practice to transfuse red blood cells without the most immunogenic antigens in haematological and nephrological patients who already have one antibody. PMID- 7855693 TI - [Diagnostic and prognostic value of flow cytometry study of the DNA content and cellular kinetics of paraffin embedded samples of lymphoma]. AB - PURPOSE: The purpose of this study is to demonstrate that flow cytometric measurement of DNA content and cell proliferation is useful and provides significant information about the diagnosis and prognosis of non Hodgkin lymphoma. PATIENTS AND METHODS: Clinical and histologic information of 66 lymphoma patients was registered at diagnosis. Fifty thick sections of lymphoma samples and 67 control samples were deparaffined, rehydrated, dissected and DNA stained using a modification of the method described by Hedley. We have studied the relationship between flow cytometric results and clinical, histologic, treatment outcome and prognosis of lymphoma. RESULTS AND CONCLUSIONS: No DNA aneuploid histograms were obtained from the control non neoplastic, lymphoid samples. Side scatter light values were significantly larger in high grade lymphomas. DNA content didn't show any correlation with clinical presentation and evolution of lymphoma, however, DNA aneuploidy was more frequent in high grade lymphomas (p = 0.0172), and in these patients, aneuploidy was related to with a lower percentage of complete remission achievement (p = 0.0248). A high S phase was associated with shorter survival in patients without remission post-treatment (p < 0.0001) and in low grade lymphomas (p = 0.0174). In conclusion, our data suggest that DNA flow cytometric study provides useful information for the diagnosis of lymphoma and identifies different prognostic groups of patients. PMID- 7855695 TI - [Human recombinant erythropoietin in the treatment of myelodysplastic syndromes anemia. Meta-analytic study]. AB - PURPOSE: To study the usefulness of different published epidemiological and analytic parameters to decide the treatment with human recombinant erythropoietin (rHuEPO) of anaemic patients with myelodysplastic syndromes (MDS). PATIENTS AND METHODS: We have revised 10 published series compiling 115 patients, studying age, sex, initial diagnosis, route of administration and posology, criteria of response, duration of the study, dosis with the response was obtained, response according to initial diagnosis, duration of responses, and effect of the treatment on other hematopoietic series. We have made a comparison between responders and non-responders based on epidemiological and analytical parameters. RESULTS: We have compiled 115 patients with a rate of global response of 23.5%. We have not found significative differences between the route (s.c. or i.v.) or frequency of administration, however the number of responses was higher when rHuEPO was administered three times weekly. A great variability in the criteria of response was observed among the different studies. Most of studies have a duration of three months but we have observed significative differences in the number of responses when the study is longer. We have not found significative differences between responders and non-responders with respect to age, sex, used dosis, transfusional dependency and degree of transfusional dependency, basal serum erythropoietin, time since diagnosis, transfusional period, haemoglobin level among non-transfusion dependent patients and haemoglobin level among transfusion dependent patients. We have found significative differences with respect to initial diagnosis, a higher rate of responses was observed in the refractory anaemia with excess of blasts (RAEB) group. We have not found a higher rate of transformations into acute myeloid leukaemia (AML) among these patients. The effects of the treatment on other haematopoietic series can be considered as anecdotical. CONCLUSION: The different epidemiological and analytic parameters published up to now are not useful in the decision of including an anaemic patient with MDS in the treatment with rHuEPO. Those patients with RAEB can be benefited with the treatment with rHuEPO. The concomitant use of other cytokines could improve these results. PMID- 7855694 TI - [Non-Hodgkin's lymphomas in patients with human immunodeficiency virus infections. Clinicopathologic characteristics, treatment response and prognosis in 40 patients]. AB - BASIS: Non-Hodgkin lymphoma (NHL) is one of the commonest neoplasms appearing in subjects infected by the human immunodeficiency virus (HIV). The purpose of this work was to analyse the clinical and laboratory characteristics, along with the clinical course, response to therapy and prognosis in a series of 40 patients with NHL and HIV infection treated in a single institution between 1985 and 1993. METHODS: The following variables at onset were analysed: age, sex, risky behaviour, NHL location, presence of "B" symptoms, haemoglobin value, platelet count, total number of lymphocytes and CD4-positive lymphocyte count, erythrocyte sedimentation rate, LDH levels, serum albumin, beta 2-microglobulin, NHL type and staging. The following variables during follow-up were also examined: treatment administered, achievement of remission and remission duration, date of relapse and death or date of the last control, relapse-free survival (RFS) and overall survival (OS). A multivariate study of the prognostic factors associated to the achievement of remission, RFS and OS were carried out as well. RESULTS: The frequency of NHL amongst the HIV-positive subjects was 4.4%. Thirty cases had high-grade lymphoma, 20 were stage IV and 33 had extranodal locations. Anaemia was the commonest blood impairment and CD4-positive lymphocyte count was below 0.2 x 10(9)/L in 72% of the cases. Twenty-eight patients with systemic NHL received chemotherapy (CHOP in 25 instances, MACOP-B in 3), and of them 6 were alive, 5 in maintained remission, as for this paper's writing. The median RFS was 7 months and the median OS was 11 months. Increased serum LDH was associated with lesser probability of attaining both remission (p = 0.03) and RFS (p = 0.03). Response to therapy was the main factor in determining survival (p = 0.002); after excluding such factor, increased serum LDH and low serum albumin rates correlated negatively with OS (p = 0.004 and p = 0.007, respectively). CONCLUSIONS: HIV-positive patients, when affected by NHL, usually have high-grade lymphoma, frequently in advanced stages and with extra-nodal involvement. They show poor response to therapy. Increased serum LDH level is the main prognostic factor. PMID- 7855697 TI - [Antonio Raichs Lecture. 35-year history of hematologic cytology]. PMID- 7855696 TI - [Evolutive epidemiologic profile of myelodysplastic syndromes (1959-1993). Comparative study with acute myeloid leukemia and aplastic pancytopenias]. AB - PURPOSE: To compare the maximum epidemiologic data attained from myelodysplastic syndromes (MDS) with those of two main panmyelopathies, namely acute myeloblastic leukaemia (AML) and aplastic pancytopenia (AP). PATIENTS AND METHODS: A retrospective analysis was carried out on 21,135 patients included in the Bone Marrow Study Registry of the Jimenez Diaz Foundation along 35 years (1959-1993). The data were grouped into seven five-year periods. Of these, in the first three the study was performed on bone-marrow aspirates; after 1976 the histopathological study of bone-marrow biopsies was introduced, and since 1979 the karyotype has been regularly examined. The MDS were classified in accordance with the FAB system. With these premises borne in mind, the following aspects were considered: diagnostic interpretation of MDS along the years; diagnostic incidence of MDS, AML and AP in each of the five-year periods; relative frequency of those diagnosis with respect to the total number of cases; evolutive profile of sex and age at diagnosis; quantitative significance of secondary MDS-AL and toxic AP along the years; MDS subtypes and their epidemiologic characteristics. RESULTS: A total of 510 MDS, 610 AML and 223 AP cases were identified. With respect to the sex of the MDS patients, some changes have been seen along the years, from an M/F ratio of 1.9 to 1.0; and the mean age at diagnosis raised from 53.3 years (with only 1.7% of the cases over 65 years of age) to 71.4 years (with 76.9% of the cases over 65 years of age), all this within the 1959-1989 period. The incidence of AML and AP has remained stable for the last 20 years; on the contrary, MDS have been increasing continuously along the 35 years of the study, which poses for a higher number of new cases in every period (from 35 to 119) and also for a higher relative frequency in the registry (from 1.37% to 4.40%) within the period 1959-1989. Valuable toxic history was progressively increasing in secondary MDS-AML and progressively decreasing in AP. With respect to the FAB subtypes of MDS, and taking into account the last of the five-year periods, the most frequently diagnosed were RA and RSA followed by RAEB, CMML and RAEB-T. CONCLUSIONS: The increment of the incidence of MDS cases correlates significantly with the increment of the patients aged over 65 years. This incidence appears to be scarcely influenced by previous mutagenic agents (radiotherapy, chemotherapy) and might be due to a better understanding of MDS. PMID- 7855698 TI - [Interphasic in situ fluorescent hybridization (FISH) in 4 cases of myeloid neoplasias with chromosome 7 changes]. AB - The use of FISH as a complement to the conventional cytogenetic studies is of great help in attaining a better characterisation of the chromosome anomalies present in haematological malignancies, such as chromosome 7 monosomy. A study was carried out in three cases of acute non-lymphoblastic leukaemia and a myelodysplastic syndrome with chromosome 7 involvement, as shown by conventional cytogenetic studies. The Cocktail probe for chromosome 7 (DZ1, DZ2) was used (Oncor) in performing in situ hybridation. A monosomic cell line for chromosome 7, undetected by conventional techniques, was disclosed with this procedure in two of the cases. In the remaining two patients the monosomy of chromosome 7 was confirmed, although at percentages different from those attained with the conventional methods. PMID- 7855699 TI - [Low grade non-Hodgkin's lymphoma after combined therapy for Hodgkin's disease]. AB - The most serious complication of curative therapy for Hodgkin's disease is the development of a second malignancy. A patient who developed a low grade non Hodgkin's lymphoma three years and a half after combined-modality therapy for Hodgkin's disease, is described. It is exceptional this type of non-Hodgkin's lymphoma as a second neoplasm after cytotoxic treatment for Hodgkin's disease. Pathogenic relationships between both processes are discussed. PMID- 7855700 TI - [Deletion (7)(p11p15): an infrequent abnormality in blast crisis in chronic myeloid leukemia]. AB - We report a patient with chronic myelocytic leukaemia (CML) in blastic crisis with a del (7) (p11 p15) in addition to the Philadelphia chromosome. A potential relationship between the presence of this deletion and the therapy in chronic phase is suggested. PMID- 7855701 TI - [Control of oral anticoagulation. Hematology working group at the district hospitals in Catalunia]. PMID- 7855702 TI - [Inappropriate use of emergency coagulation tests in a regional hospital]. PMID- 7855703 TI - [Treatment response and long term survival of a patient seropositive for the human immunodeficiency virus with non-Hodgkin's lymphoma]. PMID- 7855704 TI - [Frequency of sickle cell trait in El Salvador]. PMID- 7855705 TI - The New York City health system: a paradigm under siege. PMID- 7855706 TI - Community based care: the new health social work paradigm. PMID- 7855707 TI - Managed care and social work: constructing a context and a response. AB - Managed care is described as a strategy developed by the health care industry as a means to control profitability in the dispersement of health care resources. Control of utilization, cost and information are the essential elements of this strategy. The potential impact of each strategy on social work practice is explored. A number of suggestions are made to insure that managed care balances the needs of its corporate sponsors with those of the consumer public and providers of health care. PMID- 7855709 TI - Social work, the family and the community. PMID- 7855708 TI - Impact of social work on recidivism and non-medical complaints in the emergency department. AB - Recidivism among patients treated in the hospital Emergency Department (ED) is a significant factor in resource depletion. This study substantiates the efficacy of social work intervention in the ED using recidivism as an outcome measure. Data was collected on all patients seen by social work during the first 12 months of social work services to the ED between the hours of 3:00 p.m. and 11:30 p.m. The greatest decline in recidivism occurred where social work used a proactive intervention strategy as opposed to a more support oriented intervention. PMID- 7855711 TI - Ovarian cancer in pregnancy. AB - A pelvic mass in pregnancy is a relatively common entity, especially considering the increased use of ultrasound or early fetal evaluation. These masses can derive from multiple gynecologic and nongynecologic origin, and fortunately the majority will resolve with observation into the second trimester. Masses persisting into the second trimester should be surgically evaluated given the decreased risk to both mother and fetus at this time. For masses persisting into the third trimester, a 2% to 5% risk of malignancy is to be expected. Documentation of disease (FIGO stage) is critically important in defining need for adjuvant cytotoxic chemotherapy. Above all, potentially lifesaving therapy should not be withheld from patients because they are pregnant, especially considering that chemotherapy is apparently safe in the second and third trimesters. PMID- 7855710 TI - Negative experiences in support groups. AB - Although the benefits of support groups are well documented in the literature, little attention has been given to possible negative effects. A review of the literature related to support groups, negative experiences in groups, and social support, as well as personal accounts of members and practitioners, affirm the importance of considering the negative experiences in support groups. In addition, this material provides a base for the specification of potential problematic group conditions and negative outcomes and points to issues in obtaining information from respondents about negative factors. Findings from mailed questionnaires given to practitioners leading cancer support groups indicate the nature of the negative experiences in groups that these practitioners had led or heard about. Implications of these findings for prevention and intervention are discussed. PMID- 7855712 TI - Bowel obstruction in pregnancy. AB - Intestinal obstruction during pregnancy and in the puerperium is an uncommon complication, although cases are probably underreported. Fortunately, the mortality rate has improved over the decades. Overall, it was greater than 60% in 1900. By the 1930s, maternal mortality had dropped to 21% and fetal mortality decreased to 50%. Modern rates of maternal mortality have shown continued improvement, with Goldthorp reporting an incidence of 12% in 1966. Over the last 30 years the maternal mortality rate has decreased to approximately 6%, as noted in various series published in the English literature. Fetal mortality rates, however, have remained significantly high. They have remained constant at between 20% and 26%. Furthermore, only one third of patients with prenatal bowel obstruction complete term pregnancies after operative resolution of their obstruction. These findings emphasize the importance of remembering that two patients are at risk when intestinal obstruction complicates pregnancy. The delay from presentation to admission and from admission to definitive management continues to be a significant cause of morbidity and mortality. A high index of suspicion is mandated in this patient population, especially in those women presenting with a history of previous abdominal or pelvic surgery. The high incidence of necrotic bowel found in this subset of patients demonstrates the need for aggressive surgical intervention. Only through diligent and urgent intervention can the morbidity and mortality be decreased. The diagnosis and treatment of a pregnant patient suspected of having a bowel obstruction should be no different from those given to a nonpregnant one. PMID- 7855713 TI - Berry aneurysm. AB - Aneurysmal subarachnoid hemorrhage in a pregnant woman is a rare catastrophic situation that places both the mother and the fetus at high risk. When this situation arises, numerous relevant issues must be individualized in the effort to reduce hazards threatening both the mother and the fetus. These issues have been addressed in terms of the published experience and in terms of modern obstetric, anesthetic, and neurologic surgery technology. PMID- 7855714 TI - Urinary tract stones in pregnancy. AB - The presence of stones during an otherwise uneventful pregnancy is a dramatic and potentially serious issue for the mother, the fetus, and the treating physicians alike. The incidence and predisposing factors are generally the same as in nonpregnant, sexually active, childbearing women. Unique metabolic effects in pregnancy such as hyperuricuria and hypercalciuria, changes in inhibitors of lithiasis formation, stasis, relative dehydration, and the presence of infection all have an impact on stone formation. The anatomic changes and physiologic hydronephrosis of pregnancy make the diagnosis and treatment more challenging. Presenting signs and symptoms include colic, flank pain, hematuria, urinary tract infection, irritative voiding, fever, premature onset or cessation of labor, and pre-eclampsia. The initial evaluation and treatment are again similar to those used for the nonpregnant population. The most appropriate first-line test is renal ultrasonography, which may, by itself, allow the diagnosis to be made and provide enough information for treatment. Radiographic studies, including an appropriately performed excretory urogram, give specific information as to size and location of the stones, location of the kidneys, and differential renal function and can be used safely, but the ionizing radiation risks should be considered. All forms of treatment with the exception of extracorporeal shock wave lithotripsy and some medical procedures are appropriate in the pregnant patient. Close coordination by the urologist, the obstetrician, the pediatrician, the anesthesiologist, and the radiologist is required for the appropriate care of these patients. PMID- 7855715 TI - The surgical management of intra-abdominal inflammatory conditions during pregnancy. AB - The timely diagnosis and treatment of intra-abdominal conditions during pregnancy can challenge the surgical consultant. Familiarity with the anatomic and physiologic changes present in normal pregnancy is essential, as is the knowledge of relative risk by trimester. The general surgeon will be called upon to diagnose and treat appendicitis, biliary tract disease (including pancreatitis), and liver disease. Knowledge of how these conditions become manifest is essential. The surgical consultant should be aware that virtually all complications that occur in the management of these conditions are caused by delay in the detection of the disease process. PMID- 7855716 TI - Establishing the criteria for anesthesia and other precautions for surgery during pregnancy. AB - Surgical procedures may be undertaken in the gravida with relatively little risk to the fetus or the continuation of pregnancy. The managing physician requires a thorough knowledge of the maternal physiologic adaptations to pregnancy to minimize maternal iatrogenic risks. The potential fetal effects of the planned procedure, diagnostic tests, therapeutic drugs, and anesthesia must be considered preoperative. Any potential fetal risks must be discussed with the patient and, in some cases, maternal need may obviate undertaking some procedures that place the fetus at some jeopardy. The outcome in most situations of surgery on the gravida is good for both the mother and the fetus. PMID- 7855717 TI - Cancer of the breast in pregnancy. AB - Contrary to common belief, pregnancy does not stimulate the growth of breast cancer. Thus, no justification exists for therapeutic abortion. Generally, treatment should not be altered or delayed because of pregnancy. If the patient so desires, she should be allowed to become pregnant but should be delayed for at least 2 years. The management of breast cancer in pregnancy should involve a team approach, including a breast surgeon, obstetrician, breast counselor, medical oncologist, and radiotherapist. PMID- 7855718 TI - Nodular disease during pregnancy. AB - The incidence of autoimmune disease of the thyroid approaches 10% in women. This autoimmune state, which predisposes to the development of thyroid neoplasia, especially in patients with subclinical hypothyroidism, combined with tumor growth and immunologic factors that occur in the pregnant state, account for the significant incidence of nodular thyroid disease in pregnancy. Thyroid carcinoma of follicular cell origin in a young woman can generally be expected to pursue a slow course with ample time for preoperative preparation and operative treatment. However, the pregnant state should be considered an exception and thyroid nodular disease with suspicious aspiration cytologic features should be managed with a certain degree of urgency. In an excellent article on the subject of pregnancy as a predisposing factor in thyroid neoplasia, Rosen and Walfish present a series of 30 patients with thyroid neoplasia arising during pregnancy. The incidence of thyroid carcinoma was 43% and the incidence of adenoma 37%, for an 80% overall incidence of neoplasia. Furthermore, during the course of the pregnancy, 20% of the patients showed marked increase in nodular growth, including a 26-year-old primiparous woman who developed a small nodule in the first trimester which proved to be cellular on needle aspiration biopsy. In spite of thyroid hormone treatment, the nodule grew markedly in the last trimester. At postpartum operation, the patient was found to have a papillary carcinoma with extensive unilateral neck and mediastinal node disease, which was clinically occult. These authors stress the importance of the operative treatment of thyroid neoplasia of pregnancy, either in the second trimester or immediately after delivery. We agree. PMID- 7855719 TI - Valvular heart surgery during pregnancy. AB - The pathophysiology of mitral and valvular heart disease is presented with an emphasis on the relationship of these conditions to pregnancy. Management options are discussed. Special attention is directed to patients who have prosthetic valves in place and who become pregnant. The care of this group of patients may be difficult, and treatment strategies are presented. PMID- 7855720 TI - Hemorrhoids, anal fissure, and carcinoma of the colon, rectum, and anus during pregnancy. AB - The pregnant patient afflicted with a variety of colorectal conditions merits special consideration for reasons related to the safety and timeliness of operation while preserving fetal viability and fertility. The literature is scanty with respect to hemorrhoids, fissures, and colorectal and anal carcinoma. Therefore, the patient has to have a forthright discussion with her physician(s) about the pros and cons of operative and nonoperative approaches, which can result in either therapeutic abortion and timely surgery versus preserving the fetus and taking on the unknown factor of whether delay in treatment will cause an adverse outcome. This underscores the need for a frank discussion with the patient with regard to anticipated outcomes. In benign conditions, there is more latitude to adopt a conservative approach, as the patient's ability to tolerate the symptoms of her condition would dictate the need for definitive operative therapy. In the patient with malignancy, delaying surgical or radiation therapy carries an unknown risk to the patient. Here, the patient's personal views regarding abortion and future fertility dictate the timing of definitive treatment. PMID- 7855721 TI - Surgical issues in the management of carcinoma of the cervix in pregnancy. AB - Incorporating effective screening into preventive health care for women would theoretically eliminate the diagnosis of cervical cancer in pregnancy. Until this goal is reached, our management decisions are limited by the relatively small and retrospective studies that form the basis for our pertinent knowledge and the ethical issues that would complicate randomized trials of treatment in pregnancy. Limited data suggest that radical hysterectomy with pelvic lymphadenectomy might carry a more favorable therapeutic index than radiation therapy in early-stage disease. In general, improvements in neonatal management may allow earlier intervention, shortening the time between diagnosis and treatment in hope of improving maternal outcome. The actual survival impact of this information remains to be demonstrated. An algorithm has been provided in Figure 3 which summarizes the salient features of the clinical management of significantly abnormal cervical cytology in pregnancy. At many institutions the rate of "atypical" or other nonspecified cytologic abnormalities exceeds 10%, and low grade dysplastic changes are common and less threatening. These conditions place the responsibility for cervical cancer detection firmly upon the clinician and his or her index of suspicion that a significant abnormality exists. Those directing prenatal care must remain compulsive in the proper use of cytologic screening and careful clinical examination. A diagnosis should be rapidly and vigorously pursued when a diagnosis of cancer is suspected, with timely referral when needed. These practices may have the most immediate impact upon both maternal and fetal outcome when facing cervical cancer in pregnancy. PMID- 7855722 TI - The impact of MRI on our understanding of the pathology of sports injuries. AB - NMR imaging has become an important diagnostic tool in the evaluation of musculoskeletal disease. However, its ability to evaluate pathogenic mechanisms of disease may eventually have even a greater impact on patient care. NMR imaging has significantly affected our understanding of the clinical significance of meniscal tears and appropriate patient management. It has also extended our understanding of the prevalence and importance of x-ray and arthroscopically occult bone, tendon and ligament injuries. By knowing the pathogenic mechanisms of disease, we can more reliably diagnose and treat pathology. In particular, many horizontal degenerative tears in older patients may be asymptomatic and are best left in place. Many acute tears may be best treated with immediate meniscal repair. MR imaging can reliably different these tear types with non-invasive imaging. MR's ability to detect bone injuries may lead to aggressive early non weightbearing on injured bone, thereby preserving the subchondral bone from collapse and the joint from secondary osteoarthrosis. MRI's ability to detect and stage degenerative tendonosis of tendons and ligaments, such as the rotator cuff, may lead to arthroscopic decompression or debridement which provides symptomatic relief and may preserve and protect the intact cuff. PMID- 7855723 TI - [Chronic shoulder pain in the volleyball attack player]. AB - 30 competitive volleyball attackers of the German third league, 15 with shoulder pain (group I) and 15 without shoulder pain (group II) were examined clinically and sonographically. Anamnesis was also carried out. The results were compared with those of a control of 15 non-volleyball players not subject to stress caused by overhead use of their arms. On the visual analog scale the average pain was 5.1 (SD 1.4). The average history of pain was 2.7 (SD 2.7) years. Cause for the pain was "spiking without warming up" (n = 7) or "unknown" (n = 8). Spiking respectively serving caused new pain sensation in 14 (11) attackers. Players of group I stretched shorter than those of group II. Pain was located laterally to the greater tuberculum (n = 8), at the origin of the deltoid muscle (n = 3), at the bicipital groove (n = 2) or in the area of the ventral glenoid (n = 2). Pain was caused by active anteversion above 160 degrees (n = 3), active abduction above 140 degrees (n = 2) or both (n = 10). The playing shoulder was depressed in all 30 volleyball attackers. By measuring the distance from the epicondylus radii to the acromion of the other side by maximal forced horizontal adduction, the distance from the margo medialis scapula to the spine, the distance from the tip of middle finger to the lumbar spine by maximal internal rotation of the shoulder up the back showed significant differences between both sides and between the groups. The spiking arm scapula is significantly lateralised compared to the opposite side and compared to sportsmen.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7855724 TI - [Stress-related clinical and ultrasound changes in shoulder joints of handball players]. AB - This prospective clinical and ultrasound study was performed to show specific overuse injuries or changes in the periarticular structures of shoulder joints. Therefore, 11 male handball players with an average age of 23 years and 6 months were evaluated via a standardised shoulder exam sheet and an ultrasound examination before, one hour after, 10-12 hours after, 16-20 hours after and 22 24 hours after specific handball training. Characteristic changes were found in respect of bursitis subacromialis and tendinitis of biceps tendon up to 16-20 hours after training, which were fully reversible 22-24 hours after the stress. The effusion was visible for more than 24 hours after the training but was reversible 60 hours after stress. This study shows characteristic pariarticular changes in the shoulder joint of handball players without any clinical finding in physical examination, so that the ultrasound changes seem to be a physiological reaction to the specific stress. These changes should therefore not be misinterpreted especially if there are no clinical symptoms. PMID- 7855725 TI - [MRI-controlled rehabilitation of femur head dislocation fracture]. AB - As exemplified by the case of a 58-year old patient with a femoral head fracture dislocation, which could not be reduced for 15 hours, the early stage of femoral head revitalisation is well documented by computed tomography before and after reduction, as well as MR imaging after 6 weeks, 6 months and one year. PMID- 7855726 TI - [Results of surgical treatment of peroneal tendon dislocations]. AB - Dislocation of the peroneal tendons is a very uncommon injury and therefore the diagnosis will often be missed and the patient will not be treated sufficiently. This results in a chronic situation which handicaps the patients in their everyday life and in their sports activities. The diagnosis of the acute injury is often "sprain of the ankle" or "rupture of the fibular ligaments". The first one is often treated insufficiently by a tape for a short time, and the second one is treated surgically and the dislocation recognized only during the operation for the first time. Considering the results of the follow-up examination (clinically, X-ray and ultrasonic), surgical treatment of the dislocation of the peroneal tendons is mandatory. The risks during and after the operation are negligible. Surgical treatment enables the patients to return to their everyday life and sports activities without any complaints. PMID- 7855728 TI - [Effect of the injury process on prognosis of surgically treated Achilles tendon rupture. A score for evaluating late results]. AB - 372 Achilles tendon ruptures are reported that were surgically treated at the Staatliche Orthopadische Klinik Munich from 1978 to 1988. 122 Patients were examined on average 5.9 years postoperative. Further 50 patients participated at a questionnaire interview. In this follow-up, special importance was attached to the connection between the mechanism of the trauma that lead to the rupture, the clinical result and the result subjectively assessed by the patient. The following results were obtained: 1. Specific trauma mechanisms like external force on the tendon, supination and pronation trauma and in general all traumas that are able to rupture even a healthy tendon, have a worse prognosis regarding the late results. 2. In case of these mechanisms leading to the trauma, the Achilles tendon rupture is on average diagnosed noticeably later. 3. An early diagnosis and hence quick treatment is of decisive importance for the further prognosis. PMID- 7855727 TI - [Does intravenous gadolinium-DTPA administration have advantages in magnetic resonance imaging of acute injuries or chronic damage to the knee joint?]. AB - 79 patients with acute or chronic lesions of the knee were evaluated by MRI prior to and after application of Gd-DTPA. The MRI examination was performed by a 1.0 tesla imager with SE as well as FEDIF sequences. These MR studies were compared prior to and after intravenous Gd-DTPA application, focusing on the visibility and the definition of a possible lesion, and scored with a 3-point score. Statistic analysis and case analysis revealed that in patients with meniscus degeneration without a tear, Gd application yields no additional diagnostic information. However, in patients with meniscus tears Gd-DTPA significantly facilitates the definition of the lesion. Furthermore, Gd-DTPA makes differentiation possible between the synovial fluid and the synovial membrane. Whereas in cases with capsule or collateral ligament tears Gd-DTPA facilitates the documentation of the lesion, we found no advantage in using Gd-DPTA in patients with ACL tears. In patients with chondropathia patellae Gd-DTPA application supports the visualization of the secondary synovial reaction. PMID- 7855729 TI - [Etiopathogenetic aspects of osteochondrosis dissecans of the femoral condyles]. AB - In an analysis of results from a biostatic examination on the pressure distribution at the weight-bearing femoral condyles under different conditions compared with results from a follow-up examination of patients with osteochondritis dissecans of the knee, we discuss the most likely etiology of this disease, namely mechanical induction. From this comparison it is deduced that the biomechanical impact is the most important factor for the initiation of osteochondritis dissecans at the femoral condyles. PMID- 7855730 TI - Differences in the Cs block of baclofen and 4-aminopyridine induced potassium currents of guinea pig CA3 neurons in vitro. AB - Single-electrode current- and voltage-clamp techniques were employed to study responses elicited by (-)baclofen or gamma-aminobutyric acid (GABA) and 4 aminopyridine (4-AP) induced inhibitory postsynaptic potentials in CA3 pyramidal neurons in guinea pig hippocampal slices. All drugs were applied by the bath to submerged slices in which fast synaptic transmission was blocked by 6-cyano-7 nitroquinoxaline-2,3-dione (10 microM), bicuculline (50 microM), and picrotoxin (50 microM). (-)Baclofen (0.5 microM) and GABA (1 mM) induced equivalent-sized hyperpolarizations and input resistance decreases. The agonist induced hyperpolarization or current and 4-AP induced hyperpolarizations or currents (4 AP induced K-IPSPs or IPSCs) reversed in sign near the K-equilibrium potential (EK). The GABAB receptor antagonists, OH-saclofen (500 microM) and CGP 35348 (100 microM), reduced (-)baclofen responses, and 4-AP induced K-IPSPs, suggesting that they were mediated by GABAB receptors. Intracellular tetraethylammonium-, and extracellular barium-ions (1 mM) diminished the (-)baclofen induced current and 4 AP induced K-IPSCs. Intracellular Cs-ions blocked the (-)baclofen induced outward current at resting membrane potential but did not grossly affect the inward current recorded at membrane potentials negative to EK. 4-AP induced inwardly or outwardly directed K-IPSCs were not blocked by intracellular Cs-ions. Extracellular Cs-ions (5 mM) blocked the (-)baclofen induced inward K-current, but did not block 4-AP induced inwardly directed K-IPSCs. In conclusion, we found differences in the Cs block of activated by (-)baclofen or the endogenous transmitter GABA.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7855731 TI - Three-dimensional quantification of mossy-fiber presynaptic boutons in living hippocampal slices using confocal microscopy. AB - Confocal laser scanning microscopy (CLSM) was used to visualize presynaptic elements of mossy-fiber synapses in living rat hippocampal slices. Mossy fiber (mf) axons and their boutons were labeled in transverse hippocampal slices by injecting one of three fluorescent dyes (diI, diA, or fast diI) into stratum granulosum of the dentate gyrus and/or stratum lucidum of CA3. Three-dimensional (3D) images of the mf boutons were obtained from serial optical sections in stratum lucidum. The 3D data were used to quantify and characterize the size and shape of the boutons based on their volumes (V) and surface areas (A), and the latter were compared with conventional 2D analyses. Various geometric models were fitted to the V-A relationship, one of which provided a reasonable approximation to the data. The results demonstrate that this approach is useful for quantifying and characterizing the size and shape of mf expansions and raise the possibility of detecting and analyzing in real time activity-dependent modifications in presynaptic structure. PMID- 7855732 TI - Release of [3H]5-hydroxytryptamine from the intermediate area of rat thoracic spinal cord is modulated by presynaptic autoreceptors. AB - Serotonin (5-HT) nerve terminals innervate sympathetic preganglionic neurons of the intermediolateral cell column (IML); however, neither the depolarization induced release of 5-HT nor the presence of presynaptic modulatory autoreceptors have been directly studied in this system. We used in vitro superfusion of the microdissected intermediate area (including the intermediolateral cell column, intercalated nucleus, and central autonomic nucleus) of the rat thoracic spinal cord to measure basal and stimulated release of preloaded [3H]5-HT. Elevated K+ evoked a concentration- and Ca(2+)-dependent release of [3H]5-HT. Exogenous 5-HT and the 5-HT1B agonist, CGS-12066B, both decreased the K(+)-stimulated release of [3H]5-HT. A 5-HT1B antagonist (methiothepin) blocked the 5-HT- and the CGS-12066B induced inhibition of K(+)-evoked release of [3H]5-HT. A 5-HT1A antagonist (NAN 190) did not alter the inhibitory actions of exogenous 5-HT. Moreover, a 5-HT1A agonist (8-OH-DPAT), a 5-HT2A/2C agonist [(+/-)-DOI hydrochloride), and a 5-HT3 agonist (2-methyl-5-HT) did not alter the K(+)-evoked release of [3H]5-HT. These data demonstrate that 5-HT is released from the intermediate area of the rat thoracic spinal cord. The 5-HT receptor subtype involved in the inhibition of the evoked release of [3H]5-HT is of the 5-HT1B subtype. These findings may help clarify the complex role of 5-HT in spinal regulation of the sympathetic nervous system. PMID- 7855733 TI - Haloperidol-induced morphological alterations are associated with changes in calcium/calmodulin kinase II activity and glutamate immunoreactivity. AB - Administration of haloperidol for 2 weeks causes an increase within the caudate nucleus of asymmetrical synapses associated with a discontinuous or perforated, postsynaptic density (PSD) [Meshul et al. (1992), Psychopharmacology, 106:45-52; Meshul et al. (1992), Neuropsychopharmacology, 7:285-293]. Coadministration of the N-methyl-D-aspartate noncompetitive antagonist, MK-801, with haloperidol blocked the increase in striatal synapses containing a perforated PSD [Meshul et al. (1994), Brain Res., 648:181-195]. Examination of the caudate using immuno gold electron microscopy revealed the vast majority (90%) of asymmetrical synapses were labelled with a glutamate antibody [Meshul et al. (1994), Brain Res., 648:181-195]. The purpose of this study was to determine if there were any changes in the density of glutamate immunoreactivity within presynaptic terminals of asymmetric synapses within the striatum following treatment with haloperidol for 1 month that would correlate with the previously observed increase in synapses with perforated PSDs. We also determined the activity of striatal calcium/calmodulin kinase II (CaMK II), an enzyme known to be localized within the synaptic region, after administration of haloperidol. We report here that haloperidol causes an increase in the activity of CaMK II and a decrease in the density of immuno-gold labelling for glutamate within the nerve terminals of asymmetrical synapses containing a perforated or nonperforated PSD. These results are consistent with the hypothesis that the haloperidol-induced increase in activity of CaMK II and the increase in glutamate release, as suggested by the decrease in presynaptic glutamate immunoreactivity, may ultimately lead to an increase in the number of synapses displaying a perforated PSD. These results support the speculation that the haloperidol-induced increase in synapses containing a perforated PSD may be associated with enhanced activity at excitatory synapses. PMID- 7855734 TI - 5-HT1a agonist +/-8-OH-DPAT modulates basal and stress-induced changes in medial prefrontal cortical dopamine. AB - Serotonergic 5-HT1a agonists have recently been suggested to be effective in the treatment of human anxiety disorders. The neural mechanisms responsible for their clinical efficacy are unknown. In this study, we investigated the effects of +/-8 hydroxy-2(di-n-propylamino)tetralin [+/-8-OH-DPAT], a serotonergic 5-HT1a agonist, on basal and stress-induced changes in dopamine utilization and release in selected forebrain dopamine terminal fields in the rat. Dopamine utilization and release were respectively assessed by neurochemical analysis of ex vivo brain tissue and by microdialysis in the freely moving animal. Systemic +/-8-OH-DPAT at doses below 225 micrograms/kg had not effect in any region except to slightly decrease dopamine utilization in the nucleus accumbens. However, at a dose of 225 micrograms/kg, +/-8-OH-DPAT significantly increased basal dopamine utilization and release in the medial prefrontal cortex, while simultaneously decreasing serotonin release in this area. By contrast, the same dose of +/-8-OH-DPAT decreased extracellular dopamine in the striatum. The effect of +/-8-OH-DPAT on the response of the dopamine system to mild footshock stress was also assessed. This 5-HT1a agonist diminished the magnitude of footshock-induced increases in prefrontal cortical dopamine utilization. These data suggest that 5-HT1a agonists may dose-dependently modulate both basal and stress-induced changes in dopamine utilization in the medial prefrontal cortex. The possible relevance of these findings to the observed clinical efficacy of 5-HT1a agonists in anxiety disorders is discussed. PMID- 7855735 TI - Binding of 125I-iodovinyltetrabenazine to CNS vesicular monoamine transport sites. AB - Binding characteristics of a novel radioiodinated tetrabenazine (TBZ) analog (iodovinyltetrabenazine; 125I-TBZ-Fraction I) were evaluated. In rat striatal homogenates, 125I-TBZ-I displayed a pharmacological profile consistent with specific binding to vesicular monoamine transport (VMAT) sites. In vitro autoradiographic studies using rat brain sections further demonstrated that 125I TBZ-I labeled the regions rich in VMAT sites, and it may be a useful marker for these sites. This novel radioiodinated ligand, with high specific activity and high binding affinity, may provide a powerful tool for the in vitro assessment of neuronal loss in various neurodegenerative diseases. PMID- 7855736 TI - Amphetamine- and cocaine-induced fos in the rat striatum depends on D2 dopamine receptor activation. AB - Amphetamine or cocaine injection causes expression of the immediate-early gene c fos in the striatum. Previous studies have shown that dopamine D1 receptor activation is necessary for this effect, but have not established a consistent role for D2 receptors. We have investigated the involvement of D2 receptors in indirect dopamine agonist-induced striatal Fos-like immunoreactivity using the selective D2 antagonist eticlopride. Eticlopride treatment (0.5 mg/kg) caused Fos expression by itself, but also decreased Fos expression in the central striatum due to amphetamine (5.0 mg/kg) or cocaine (40 mg/kg) by 90% and 85%, respectively. In striatonigral neurons, identified by labeling with the retrograde tracer Fluorogold iontophoresed into the substantia nigra pars reticulata, the blockade of stimulant-induced Fos-like immunofluorescence by eticlopride was nearly complete, with decreases of 98% for amphetamine and 94% for cocaine. In striatonigral neurons, the D2 antagonist alone had minimal effect. We conclude that activation of both D1 and D2 receptor classes by dopamine agonists is necessary for induction of Fos in the striatonigral cells of normal rats. These results provide an important parallel to behavioral and electrophysiological work that also demonstrates D1/D2 interdependence in the control of normal basal ganglia functions. PMID- 7855737 TI - Molecular biology of serotonin (5-HT) receptors. AB - The hypothesis that multiple serotonin (5-hydroxytryptamine; 5-HT) receptors exist was first developed in the 1950s. However, unequivocal proof of 5-HT receptor multiplicity required the availability of molecular biological technologies. Indeed, the multiplicity of 5-HT receptor subtypes, both within and between species, has far exceeded most of the predictions that might have been made on the basis of pharmacological data. Over the past few years, and especially in 1992 and 1993, numerous "new" 5-HT receptors were reported. In this review, the extensive data generated in the past few years are summarized in an evolutionary context. PMID- 7855738 TI - Cocaine accumulates in dopamine-rich regions of primate brain after i.v. administration: comparison with mazindol distribution. AB - Pharmacological and neurochemical evidence suggest that brain dopamine systems, and the dopamine transporter in particular, contribute significantly to the behavioral effects and reinforcing properties of cocaine. The first objective of this study was to determine whether the brain distribution of cocaine supports these conclusions. A high resolution neuroanatomical map of cocaine disposition in brain after i.v. administration was developed. [3H]Cocaine ([3H](-)-cocaine) was administered to squirrel monkeys (Saimiri sciureus) at a trace dose (0.001 mg/kg) and at doses at or above the threshold for producing behavioral effects (0.1 mg/kg, 0.3 mg/kg). After 15 min, ex vivo autoradiography revealed the highest accumulation of [3H]cocaine in dopamine-rich brain regions, including the caudate nucleus, putamen, and nucleus accumbens/olfactory tubercle. The norepinephrine-rich locus coeruleus, the hippocampus, and amygdala also accumulated large quantities of [3H]cocaine. Moderately high levels were found in the stria terminalis, medial septum, substantia nigra, and other regions. Lowest levels were found in the cerebellum. A high and positive correlation was established for the brain distribution of [3H]cocaine administered at trace or at behaviorally relevant doses (r: 0.94; P < 0.001). To determine whether radioactivity represented [3H]cocaine or its metabolic products, tissue extracts from brain regions with high levels of cocaine were subjected to thin layer chromatography using two solvent systems. In caudate-putamen, nucleus accumbens, cortex, and hippocampus, radioactivity comigrated with standard [3H]cocaine. In substantia nigra, less than 70% of the radioactivity comigrated with [3H]cocaine, suggesting that cocaine metabolites are generated more rapidly in the substantia nigra than in other brain regions. The second objective was to determine the brain distribution of mazindol, a potent norepinephrine and dopamine transport inhibitor with low abuse liability in humans. The disposition of intravenously administered [3H]mazindol in brain (0.001 mg/kg, 0.007 mg/kg) was surveyed by ex vivo autoradiography. In sharp contrast to [3H]cocaine distribution, the highest accumulation of [3H]mazindol was localized in the norepinephrine-rich pineal gland, discrete regions of the hypothalamus (paraventricular nucleus, supraoptic nucleus), and the locus coeruleus. Moderately high levels were detected in the caudate-putamen, nucleus accumbens, and other regions. The following conclusions were drawn: (1) Although dopamine-rich brain regions are principal targets of cocaine after i.v. administration to the nonhuman primate, other prominent targets of cocaine (locus coeruleus, hippocampus, and amygdala) may contribute to the acute and chronic effects of cocaine.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7855739 TI - Localization of serotonin 5-HT1A receptor mRNA in neurons of the human brainstem. PMID- 7855740 TI - In utero exposure to caffeine causes delayed neural tube closure in rat embryos. AB - We have investigated the effect of caffeine on embryo growth and development. Caffeine (25 mg/kg) was administered on gestation day (g.d.) 8-9 and the embryos examined histologically 24 h after the final dose. The crown-rump length of caffeine treated embryos (1.92 +/- 0.08 mm) was significantly smaller (P < 0.001) than the controls (2.91 +/- 0.26 mm) as was the circumferential length (caffeine vs. controls, 3.79 +/- 0.16 mm vs. 6.03 +/- 0.61 mm; P < 0.001). Additional measures, such as development of the heart, eye, and limb buds, were also reduced in the caffeine treated embryos. The most striking difference between the control and caffeine treated embryos was the larger proportion of treated embryos with regions of open neural tube. This was most marked in the caudal region of the embryos where 91% of treated embryos had regions of open neural tube compared with 14% of controls. The amount of open neural tube in any individual caffeine treated embryo did not relate to the crown-rump or circumferential length of that embryo nor was the effect restricted to particular litters. These results indicate that caffeine had a significant effects on embryonic growth and development. PMID- 7855741 TI - Electromagnetic fields and brain tumours: a commentary. AB - Brain tumours are of different cell types, the commonest being tumours of glia called gliomas. Many etiological factors of gliomas have been suggested and certain industries have been implicated. Several epidemiological studies have linked electromagnetic fields (EMFs) to gliomas. Health effects of EMFs have been studied, both in humans and in experimental animals, mainly with negative findings. Positive experimental evidence linking EMFs to tumours is the effect of EMFs on melatonin production by the pineal gland. Removal of the pineal gland in rats increases the incidence of tumours. Further epidemiological and experimental evidence is required to elucidate this possible link between EMFs and brain tumours. PMID- 7855742 TI - Structural basis for the induction of preneoplastic glutathione S-transferase positive foci by hepatocarcinogens. AB - A data base consisting of 100 chemicals tested for the ability to enhance the formation of glutathione-S-transferase (GST) positive preneoplastic lesions were analyzed by the CASE structure-activity relational system. A number of structural determinants associated with the induction of GST-positive foci were recognized. The majority of these describe non-electrophilic moieties. It is concluded that there is a structural basis for the induction of these neoplastic lesions; interestingly, it was found that this activity is associated with structures that are non-electrophilic. Reconstruction experiments have indicated that the identified structures are meaningful and that their significance could be better understood with the availability of test results on additional chemicals. PMID- 7855743 TI - Carcinogenicity of policosanol in Sprague Dawley rats: a 24 month study. AB - The effects of policosanol (50-500 mg/kg) administered orally for 24 months to Sprague Dawley rats of both sexes were investigated. No differences related to daily clinical observations, weight gain, food consumption, or mortality (survival analysis) between groups were found. Histopathological study showed that the frequency of the occurrence of non-neoplastic and neoplastic (benign and malignant) lesions was similar in the control and policosanol-treated groups. The lesions observed in this study were similar to the spontaneous lesions reported in this species in previous studies. Since no drug-related increase in the occurrence of malignant or benign neoplasms was found, nor acceleration in tumors growth in any specific group was observed, this study shows no evidence of policosanol induced carcinogenicity in this strain of rats. PMID- 7855744 TI - [Fractures of the hand skeleton]. AB - The complex anatomical conditions of the hand pose special problems for fracture treatment. On the one hand length and axes as well as rotation of the fractured bones have to be reestablished in order to prevent functional impairment. On the other hand operative possibilities are limited by the overlying vessels, nerves and tendons. Certain types of fractures are successfully treated by conservative means. Disadvantages are the long time of immobilisation and sometimes clumsy bandages. Other types of fractures require operative treatment in order to accomplish correct reduction. In addition stable internal fixation may reduce the time of immobilisation, but the surgical trauma and bulky implants may deteriorate functional results. PMID- 7855745 TI - [Distorsion of the wrist joint]. AB - Wrist hyperextension is a common injury. However, obvious ligamentous ruptures are apparently seldom. The intracarpal locking phenomenon, allowing for correct load transmission, or overlooked pathology might explain this remarkable discrepancy. If the muscle tension fails, i.e., no locking phenomenon happens, and the ligaments are put under abnormal constraints with a high risk of secondary rupture. Such constraints might also appear secondary to bony alteration or previous ligamentous weakening. Patient history allows to define the pathophysiology of the accident, examination will locate the points of maximal tenderness whereas radiology allows to detect malalignment, step-off or bony anomaly. To be valid, radiology must be standardized. Accordingly we describe the radiological techniques. Scintigraphy will show if the lesion is focal (mainly osseous) or not (dystrophy). Arthrography helps to find out which group of ligaments are torn, whereas arthroscopy will quantify the tears and find out additional chondromalacia or synovitis. Magnetic resonance imaging remains limited to vascular trouble shooting. We propose a diagnostic and therapeutical scheme that will help the physician in advising the patient. PMID- 7855746 TI - [Distorsions and dislocations of the finger joints]. AB - Injuries of the finger joints with damage to the capsule and ligaments are quite common. Nevertheless early diagnosis may be missed since patients look for relief only after a period of longstanding pain. A careful clinical and X-ray diagnosis is the prerequisite for appropriate treatment. Surgery is still indicated for most of the injuries of the ulnar ligament of the MP-joint of the thumb. Sprains or dislocations of the middle joint of fingers are quite usual. In most instances they may be treated by immobilisation or functional treatment. Persistent subluxation after reduction of the joint or large avulsion-fractures have to be treated by open surgery. Injuries of the MP-ligaments are frequently misinterpreted. Their treatment should be based on a very careful evaluation of the case. PMID- 7855747 TI - [Idiopathic arthritis of the finger joints]. AB - Degenerative arthritis of the finger joints is a very common disease in middle aged and elderly patients, in females more frequently than in males. Concerning differential diagnosis rheumatoid arthritis and related conditions, gout, calcinosis, tumors and tumor-like lesions must be considered. Therapy is not necessary in every case. Usually treatment is required if the disease causes pains, joint instability or disabling deformity. Conservative treatment such as diet, physiotherapy, orthotics, local physical and antiphlogistic drug treatment or systemic application of non-steroid antiphlogistics should be preferred. Operative procedures such as removal of osteophytes, arthrodesis or arthroplasty are indicated if conservative treatment fails. PMID- 7855748 TI - [Closed extensor tendon injuries of the finger]. AB - The extensor apparatus of the fingers is a complex structure. The diagram of the extensor apparatus as seen in figure 1 is in reality not so clearly structured. Closed lesions are the mallet finger, where either an avulsion of the bony insertion of the tendon occurs or where a fracture of the base of the distal phalanx with dislocation of a bone-fragment together with the tendon insertion has happened. Other closed lesions are the closed Boutonniere deformity and the avulsion of a lumbrical muscle. The mallet finger is mostly treated conservatively with a prefabricated splint holding the DIP-joint in extension or with a temporary arthrodesis with a Kirschner-wire blocking the DIP-joint in extended position. If bigger pieces of bone are extruded from the base of the terminal phalanx this fragment must be fixed operatively. Today, very fine screws are often used. Also in these cases, a temporary arthrodesis may be helpful. This treatment lasts for 7 weeks. Afterwards for another two weeks the DIP-joint should be immobilised with a Stack-splint during the night. In the Boutonniere deformity the PIP-joint is in flexion and the DIP-joint in hyperextension. The reason is a lesion of the central extensor tendon over the PIP-joint with anterior dislocation of the lateral bands of the interosseus tendon. In early cases by stretching the finger passively the lateral band will be repositioned. In these cases, a conservative treatment with a splint holding the PIP-joint in extension may be successful. This can be combined with revision and suturing of the ruptured part.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7855749 TI - [Chronic entrapment syndromes of the tendons]. AB - The chronic entrapment syndromes of the tendons of the hand are: stenosing tendovaginitis of the flexor and extensor tendons, the trigger wrist, and the intersection-syndrome. Pathogenesis, symptoms, diagnosis and differential diagnosis are presented. The focus is on the localization of the individual disease and its particularities. Therapy and possible complications are discussed subsequently. PMID- 7855751 TI - [Nerve compression syndromes of the extremities]. AB - Peripheral entrapment neuropathies occur in high frequency and present clinically with a wide range of variations. They need to be recognized early enough in order to initiate correct therapy and so to obviate serious nerve lesions and possible neurological sequelae. This paper overviews the essentials of the compression neuropathies as they are encountered in both upper and lower extremities. Pathomechanisms , pathogenesis, evaluation considerations as well as differential diagnosis and basic treatment algorithms are emphasized. PMID- 7855750 TI - [Dupuytren contracture--current status in research and clinical practice]. AB - Dupuytren's contracture is a disease of the connective tissue, especially of the palmar side of the hand. Today, by means of electron microscopy and histochemistry, several alternations specific of pathology of the disease can be shown, providing a better understanding. However, a revolutionary change of treatment is far out of reach. Dupuytren's diathesis can be influenced by none of today's known methods, and therapy is still empirical. Operative therapy is only indicated in functional impairment. Treatment should be done by well-trained surgeons and in case of extensive diathesis by carefully planning and longtime follow-up to avoid complications and eruption of the disease. PMID- 7855752 TI - [Tumors of the hand]. AB - Most of the numerous tumors of the hand, arising from the skin, soft-tissues and bones show a benign course. The vast majority of those tumors is classified as a tumor-like lesion, of which the ganglia are the most frequent. Malignant tumors of the hand are extremely rare. The diagnosis of those usually visible and obvious tumors is regularly made on clinical findings. Only tumors of the deep structures and unclear masses of soft-tissues and bone need further diagnostic procedures. In case of potentially malignant tumors of the hand a systematic and thorough approach should be started to receive a full and complete staging of the tumor. Modern treatment regimens include for malignant tumors of the hand an interdisciplinary approach with a combination of chemotherapy, surgery and radiation-therapy. PMID- 7855753 TI - [Infections of the hand]. AB - The possibilities of hand injuries lead to the higher incidence of hand infections. The clinical signs of inflammation (pain, swelling, heat, loss of function and red colour) are found in near all cases. The start of pain and its localisation help to find quickly the layer of the inflammatory process. Bites, foreign bodies, puncture wounds and open wounds especially those acquired in slaughterhouse or agriculture are in most cases the predisposing conditions. Treatment of hand infections demands a consequent protocol consisting in: exact diagnostics including clinical picture, laboratory investigation, bacteriology and in some cases X-ray-examination; operative treatment including incision, irrigation, drainage, excision of necrosis and foreign bodies under the rules of hand surgery (i.g. blood--[without exsanguination] and painfree operation field, magnifying lenses, correct incision avoiding scar contractures); immobilisation (dressing or splinting) in intrinsic-plus-position while acute inflammation is going on, early movement combined with ergotherapy and physiotherapy after this. Use of antibiotics is indicated in septic cases or in cases of complications (sepsis, lymphangitis, osteomyelitis) in concordance with bacteriology but it cannot compensate mistakes in treatment. The most common infections are placed around and under nail (paronychia) and in the subcutaneous space of the distal phalanx (felon). They are treated by incision and spontaneous drainage. More severe are infections of tendon sheath, joint, web space and deep palmar space. If pus is present in such cases there is no place for conservative treatment but operative treatment under clinical conditions is imperative. PMID- 7855754 TI - [History of hand surgery]. AB - Long before the term 'handsurgery' was coined, surgery in the hand was performed. The development towards a surgical speciality, however, is closely bound to the name Sterling Bunnell. By the end of World War II he instituted hand centers, in which tissue specific surgery was replaced by region specific surgery. Introduction of microvascular surgery made an immediate and global repair of all injured structures possible and desirable. PMID- 7855755 TI - [XVth French Pharmacovigilance Conference. Saint-Etienne, 25-26 november 1993]. PMID- 7855756 TI - [Amiodarone-induced pleuropneumopathies: experience 1983-1993 in a drug vigilance Regional Center]. AB - The authors present the results of a ten year retrospective analysis about amiodarone-induced pulmonary toxicity. Only cases without any etiology (after complete explorations made in hospital), and judged probably imputable to amiodarone treatment were kept. This work finds all characteristics usually described with amiodarone pulmonary toxicity: dyspnea, cough, weight loss, restrictive lung disease and interstitial infiltration in the chest roentgenogram. It shows three another points: pulmonary disease is more frequent during first and fourth years of amiodarone treatment, pneumopathy occurs more rapidly in patients with a previous history of pulmonary disease, and patients with amiodarone lung toxicity may have elevation in lactate dehydrogenase activity. PMID- 7855758 TI - [Bepridil and torsades de pointes: are the precautions of use respected?]. AB - The torsades de pointes with bepridil are serious side-effects, known right from 1982, and for which definite therapeutic recommendations were decreed in 1984 then in 1991. The observations of 7 new cases drove us to discuss about the respect for these recommendations. From the study of these 7 middle-aged patients (+/- esm) 76.9 +/- 2.4, we have noticed that they all combined 3 risk-factors at least with an average (+/- esm) 3.71 +/- 0.29 (range 3-5). The non-respect for the methods of prescription of bepridil leads to serious trouble in the rate of heartbeat and can threaten vital prognosis. So, it is advisable for the practicians to be warmly and precisely informed and prescribe another anti-angina pectoris treatment in high risk-patients. PMID- 7855757 TI - [Evaluation of the gastrotoxicity of anti-inflammatory drugs: contribution of general registries of digestive endoscopy]. AB - The evaluation of the rate of gastroduodenal toxicity of anti inflammatory drugs is a difficult problem. We tried to analyse that question by studying the general endoscopic registers of the Gastro-Enterologic department of the hospital. This retrospective study concerns 2,945 endoscopies performed during the year 1988 and 1992 randomly chosen among the last 5 years. 992 results show injuries suggestive of non steroidal anti inflammatory drugs (NSAID) toxicity, however only in 65 cases the potential role of an anti inflammatory drug is mentioned: 36 men and 29 women, mean age: 50.6 +/- 19.6 years. Concerning the drugs, only the pharmacological classes they belong to are mentioned except for Aspirin. Acetyl salicylate acid 7 cases, NSAIDS 36 and Steroids 22. In the drug group 63% of injuries are located to the stomach (ulcers 13%, gastritis 50%), 37% to the duodenum (19% ulcers, 18% duodenitis). Compared to the groups with the same kind of injuries, but without any mention of drugs, there are no statistical difference in the proportion of ulcers. Aging and sex are not influent in our results on the genesis of drug induced ulcers. These results must be discussed because a lot of datas are missing in the registers and so the number of patients taking drugs is probably underestimated. This means that unless a prospective study is held with someone enquiring for all the risk factors, the study of the general endoscopic registers is not a good way to estimate gastrointestinal damages due to drugs. PMID- 7855759 TI - [Convulsions associated with the administration of excessive dose of ceftazidime in patients with renal failure]. AB - Central neurological diseases caused by beta-lactamins are usually associated with excessive dosages in patients with renal failure. Two case reports of convulsive encephalopathy in patients treated with ceftazidime, show the absolute necessity of adapted posology, in case of renal dysfunction. In one case, we could follow plasma levels of ceftazidime during hemodialysis, and calculated the pharmacokinetic parameters. We conclude that extra renal epuration is an efficient technique in case of acute ceftazidime intoxication. PMID- 7855760 TI - [During the treatment or after... drug-induced convulsive accidents. Apropos of 70 cases]. AB - During a five year period (1988-1992) 70 cases of seizures were collected by the Adverse Drug Reaction Monitoring Center of Clermont-Ferrand (3.58% of total collected cases). 31 cases (22 M and 9 F) occurred after a drug withdrawal. Benzodiazepines--either alone or in association--were the most often involved. Mean age was 48.8 +/- 2.6 years in this group and additional factors (alcohol abuse and/or association of drugs that lower the seizure threshold) were associated in 26 cases. 39 cases (14 M and 25 F) occurred on the course of various treatments. The most frequently involved drugs were neuropsychiatric, antiinfectious (especially beta-lactam antibiotics, fluorquinolones and isoniazid) and theophylline. Mean age was 56.5 +/- 3.8 years and additional different factors (high dosages, antecedents of epilepsy, underlying diseases) were present in 22 observations. PMID- 7855761 TI - [Pentasa (mesalazine) and pregnancy]. AB - We analysed the outcome of 11 pregnancies in women treated for inflammatory bowel disease with mesalazine (Pentasa) during part of or throughout pregnancy. There were 9 healthy babies, one spontaneous abortion (the woman had an uterine malformation) and one infant with multiple malformations (but the mother was not treated with mesalazine during organogenesis). Because of the relatively small number of pregnancies exposed to mesalazine (Pentasa) in this study, these data need to be confirmed by other studies. PMID- 7855762 TI - [Tolerance of influenza vaccination in the aged and the nursing staff in a geriatric hospital]. AB - The tolerance of influenza vaccination (Vaxigrip, Pasteur-Merieux) was evaluated during four consecutive years (1989-1992) in the geriatric hospital of Saint Etienne from questionnaires concerning 327 vaccinations in the aged (group 1) and 88 vaccinations in members of the nursing staff (group 2). Minor local symptoms were the more common incidents, respectively for each group: blotch (9.8 and 21.6%), pain (9.2 and 47.7%), nodule (2.4 and 13.6%). Fatigue (4.0 vs 12.5%) and fever (6.1 vs 4.5%) were the more frequent among general symptoms, respectively in each group. No major vaccinal accident was recorded. These results underline that influenza vaccination is well tolerated, much more in aged people than in members of the nursing staff. PMID- 7855763 TI - [Drug vigilance: opinion survey among residents of a university hospital]. AB - To approach perception of drug safety by young practitioners, a nine item questionnaire has been mailed to the 263 residents from Toulouse Hospital. The analysis of the 116 returned questionnaires shows that pharmacovigilance centres are still badly known in France. The level of under-reporting of adverse drug reactions is 44%. However, it decreases when the Regional Pharmacovigilance Centre sends informations to the prescribers. In the University Hospital, the regional pharmacovigilance centre is the more used source of drug information by residents. However, 66% of the residents do not know that spontaneous reporting is compulsory in France and 75% are unable to find the address of the Regional Pharmacovigilance Centre. PMID- 7855764 TI - [The Theriaque database and information on side effects of drugs]. AB - The new module of Theriaque data base deals with side effects of drugs. It is composed of 3,300 monographs. One or more nature of side effect appears on each monograph, to correspond to a defined entity; organ or apparatus, syndrome or special type of pharmacological effect. Side effects are attached to either a whole pharmacological or chemical class, either one or several drugs. Side effects of drugs are described at usual dose, or/and in case of overdose. Data are collected from specialized books and publications. Some difficulties were encountered with this work, particularly side effects frequency. Side effects module content is validated with experts in pharmacology or clinicians, their opinion being a determining factor in case of any doubt, especially on causality assessment or frequency. PMID- 7855766 TI - [Erythema multiforme associated with vitamin E]. PMID- 7855765 TI - [Drug-induced Parkinson syndrome: 10 years of drug vigilance]. PMID- 7855767 TI - [Hypercalcemia and lithium]. PMID- 7855768 TI - [Pseudomembranous colitis associated with josamycin]. PMID- 7855769 TI - [Enteropathy induced by clofazimine (Lamprene) in AIDS]. PMID- 7855770 TI - [Desensitization in HIV seropositive patients with cotrimoxazole hypersensitivity. A series of 18 cases]. PMID- 7855771 TI - [Drug-induced cataracts]. PMID- 7855773 TI - [Paroxysmal nocturnal hemoglobinuria and hemolysis induced by isotretinoin]. PMID- 7855772 TI - Phenylephrine eyedrops, systemic atropine and cardiovascular adverse events. PMID- 7855774 TI - [Adrenal hemorrhage during the treatment with ACTH. Apropos of 2 cases]. PMID- 7855775 TI - [Arterial thrombosis during heparine therapy. Evaluation of the drug vigilance survey]. PMID- 7855776 TI - [Severe hematologic involvement in parvovirus B19 infection. Are antithrombin III injections the origin of the contamination?]. PMID- 7855777 TI - [Pulmonary diseases induced by metformin?]. PMID- 7855779 TI - [Injectable trimebutine dependence: apropos of a case]. PMID- 7855778 TI - [Adverse drug effect in pregnancy: evaluation at the Midi-Pyrenees center]. PMID- 7855780 TI - Low molecular weight heparin therapy: is monitoring needed? AB - Recent meta-analyses indicate that low molecular weight heparins (LMWH) are more effective than unfractionated heparin (UH) in preventing and treating deep vein thrombosis. This article presents the arguments for and against the need for laboratory monitoring. At the present time, the only tests currently available for monitoring LMWH therapy are those which measure the anti Xa activity in the plasma. Due to lower binding to plasma proteins and to cell surfaces, the plasma anti Xa activity generated by a given dose of LMWH is more predictable than for UH. Some clinical trials suggest that LMWH delivered at the recommended dose expose the patient to less bleeding risk than UH. Several meta-analyses indicate comparable risk while any overdose unacceptably increases the haemorrhagic risk. The lowest dose of LMWH still effective in treating established DVT is presently unknown; some reports indicate that inadequate doses of LMWH are associated with a lack of efficacy for prevention. An overview of the published clinical trials indicates that the LMWH dose has never been monitored for prevention of DVT. In the treatment of established DVT, several trials have been performed without any monitoring, while in others the dose was adapted to target a given anti Xa activity. These considerations suggest that in prevention of DVT, monitoring the dose is not required.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7855781 TI - Hypercoagulability state in patients with chronic obstructive pulmonary disease. Chronic Obstructive Bronchitis and Haemostasis Group. AB - Since there is some clinical evidence that the clinical course of patients with chronic obstructive pulmonary disease (COPD) may be complicated by thrombosis in the pulmonary vessels, we studied whether a hypercoagulability state (HS) does occur in COPD. Plasma levels of prothrombin F1 + 2 fragment, a marker of thrombin generation, D-dimer, a marker of in vivo thrombin and plasmin activation, and fibrinogen were measured in 37 COPD patients and in 30 controls matched for sex and age. COPD patients had significantly higher values of F1 + 2 (p = 0.0001) and fibrinogen (p = 0.0005) than healthy subjects. The difference persisted after excluding smoking patients. F1 + 2 was not correlated with PaO2 (r = 0.02, p > 0.05) and PaCO2 (p = 0.12, p > 0.05). In six patients with stable COPD and F1 + 2 greater than 1.65 nM (mean + 2 SD of controls) subcutaneous calcium-heparin therapy (5000 IU t.i.d. for 15 days) significantly reduced F1 + 2 (p = 0.03) and PaCO2 (p = 0.01). This study shows that COPD patients have an ongoing prothrombotic state which could potentially account for thrombosis occurring in pulmonary vessels. The effect of calcium-heparin treatment on clotting system activation and blood gas may suggest this treatment as potential candidate for prospective study in COPD patients. PMID- 7855782 TI - Assessment of therapeutic quality control in a long-term anticoagulant trial in post-myocardial infarction patients. AB - Various methods have been described to evaluate efficacy of anticoagulant therapy using the international normalized ratio (INR). We compared the following approaches: (1) total INR's or the most recent measurement; (2) percent time within therapeutic range, with INR changing directly or halfway between visits; and (3) total observation time assuming INR changing linearly. The study population comprised 1700 post myocardial infarction patients. Treatment comprised 3725 patient-years. There were 61,471 INR assessments with target therapeutic level of 2.8-4.8. Acenocoumarol as well as phenprocoumon were employed. Therapeutic achievement in the first months of treatment was low: less than 60% of INR's were in range. Treatment stabilized after 6 months. Patients on acenocoumarol were within range 70% of the time compared to 80% for phenprocoumon. Method 3 is preferred because it incorporates time and is capable of calculating incidence rates at different INR levels. Our findings call for an urgent improvement of standard of anticoagulant control in the first months following commencement of treatment. PMID- 7855784 TI - High versus ultra-high purity factor VIII concentrate therapy: prospective evaluation of immunological and clinical parameters in HIV seronegative and seropositive hemophiliacs. AB - This study aimed at evaluation of the immunological status and the clinical course of both HIV seronegative and seropositive hemophiliacs treated with either an ultra-pure factor VIII product (UP-F VIII), or a high-purity F VIII (HP-F VIII) concentrate. Eighteen HIV seronegative patients were divided into two groups of therapy and their immune status was followed for 2 years. During the second year of the study 8 patients of the HP-F VIII and 6 from the UP-F VIII therapy groups were switched to the alternative F VIII concentrates. Eighteen asymptomatic HIV seropositive patients were also divided into therapy groups and their immune status and any development of HIV-related symptoms were followed for 4 years. Evaluation of the HIV seronegative patients during the first year did not reveal any differences between the groups in the CD4 or CD8 cell counts, in natural killer cell (NK) activity, or in the mitogenic responses of T lymphocytes to Phytohemagglutinin (PHA), and of B lymphocytes to Pokeweed mitogen (PWM). The switch of 8 patients from the HP-F VIII and 6 from the UP-F VIII groups to the alternative concentrate did not yield any changes in their immune profile during the second year of the study. The HIV seropositive groups differed in the initial CD4 count, with a lower CD4 count (193 +/- 126 vs 437 +/- 142) and a higher F VIII consumption (63,000 +/- 17,000 vs 26,000 +/- 10,000) in the UP-F VIII group.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7855783 TI - Clinical manifestations and management of inherited thrombophilia: retrospective analysis and follow-up after diagnosis of 238 patients with congenital deficiency of antithrombin III, protein C, protein S. AB - The clinical history of 238 patients with inherited thrombophilia (AT III = 94, PC = 103, PS = 41) was analyzed retrospectively at diagnosis and in the follow-up period after diagnosis. At diagnosis 129 patients (54%) had suffered from thrombosis, with a recurrence rate of 48%. The most frequent onset manifestation was deep vein thrombosis of lower limbs (58%). Thrombotic history started before 40 in 80% of the cases. Forty-nine percent of the venous thromboses were preceded by a triggering event, in most cases pregnancy (17%) and surgery (12%). After diagnosis, follow-up lasted a total of 1,113 pt-years. A policy of short-term prophylaxis during risk situations for all patients and long-term prophylaxis in symptomatic patients failed to prevent venous thrombotic episodes (diagnosed by objective methods) in 4 previously asymptomatic subjects and recurrence in 7 previously symptomatic subjects. After knowledge of the patients' diagnosis the incidence of venous thrombosis/100 pt-years was reduced as compared before diagnosis as total episodes (onset+recurrencies) (1.0 vs 1.9), onset episodes (0.7 vs 1.3) and recurrent episodes (1.3 vs 4.8), even though the differences were not statistically significant. However most of the venous thromboses occurred at a more advanced age (67% after 40 years) and without any apparent cause (83%), at significant variance with the period preceding the diagnosis; in particular the incidence of venous thrombotic onset in patients younger than 40 passed from 1.3/100 pt-years to 0.2/100 pt-years. In 6 recurrences after diagnosis a poor compliance for antithrombotic treatment was recognized.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7855785 TI - Antibody-induced acute factor X deficiency: clinical manifestations and properties of the antibody. AB - A patient is described with serious bleeding due to a transient selective deficiency of factor X. Crossed immunoelectrophoresis of patient's plasma with anti-factor X antibody revealed an abnormal factor X arc suggestive of the presence of plasma factor X/anti-factor X immune complexes. A similar abnormal arc was obtained on adding the patient's IgG to normal plasma. Immunoblotting of factor X after reduced SDS-PAGE revealed that the patient's IgG bound to the light chain of intact factor X but not Gla-domainless factor X. The patient's IgG inhibited activation of factor X by VIIa/tissue factor (TF), by IXa/VIIIa/phospholipid complex, and by Russell's viper venom. The IgG failed to inhibit the proteolytic activity of factor Xa towards a chromogenic substrate. However, under reaction conditions of limited factor Xa availability, the IgG could be shown to impair hemostatic functions of factor Xa that require the participation of its light chain: activation of prothrombin by prothrombinase; activation of factor VII bound to TF; and inhibition of VIIa/TF activity by factor Xa/tissue factor pathway inhibitor complexes. A few earlier patients have been described with transient, selective factor X deficiency and serious bleeding, but in only one was evidence obtained of an antibody against factor X. It will be of interest to learn whether use of the techniques described in this report will permit the identification of immunoglobulin with similar binding and functional properties in future patients with this rare syndrome. PMID- 7855786 TI - Venous diameter and compliance after deep venous thrombosis. AB - Duplex sonography was used to measure diameters of the common femoral, superficial femoral, and popliteal veins in 56 patients followed for more than 6 months after DVT and in 17 normal subjects. Diameter changes with Valsalva's maneuver were also measured as an index of venous compliance. Among patients with unilateral thrombosis, segments with residual disease were 0.07 to 0.28 cm smaller than the contralateral disease-free side (p < 0.05 for CFV and SFV) with a diameter index (ipsilateral/contralateral diameter) significantly less than that of normal subjects. In contrast, completely recanalized segments were not significantly different from the contralateral side and had diameter indices indistinguishable from normal subjects. Distensibility with Valsalva's maneuver was not significantly different from normal in DVT patients with either resolved or residual disease. Venous diameter does decrease following DVT, but returns to normal following complete recanalization and is not associated with chronic venous compliance changes. PMID- 7855788 TI - Effects of the synthetic thrombin inhibitor argatroban on fibrin- or clot incorporated thrombin: comparison with heparin and recombinant Hirudin. AB - The inhibitory effects of argatroban on clot- or fibrin-bound human thrombin were studied using the thrombin-specific chromogenic substrate S2238 (200 microM). These effects were compared to those of recombinant hirudin (rHV2 Lys 47) and the heparin/antithrombin III complex. Argatroban concentration-dependently inhibited the cleavage of S2238 by a thrombin solution, which had been titrated to give the same change in OD405 nm as fibrin-bound thrombin, with an IC50 of 1.1 microM with 90% inhibition at 8 microM. rHV2 Lys 47 and heparin had IC50 values of 1.2 nM and 0.003 U/ml respectively under these conditions. However, when the compounds were tested against fibrin-bound thrombin, argatroban had an IC50 of 2.8 microM with 65% inhibition at 8 microM, whereas rHV2 Lys 47 had an IC50 of 23 nM (with only 56% inhibition at 200 nM), and heparin had an IC50 of 0.5 +/- 0.38 U/ml (with only 58% inhibition at 5 U/ml); i. e. the two compounds were 19 and 168 times less active against fibrin-bound thrombin than against thrombin in solution. The differences between the inhibitory effects of the compounds against thrombin bound to a plasma clot were even more striking in that the IC50 of argatroban was increased from 1.1 (vs. thrombin in solution) to 2.7 microM, while, although rHV2 Lys 47 and heparin had IC50 values of 2.8 nM and 0.004 U/ml against thrombin in solution, they had little (32% inhibition by 4 microM rHV2 Lys 47) or no effect (even at 5.0 U/ml heparin) against the amidolytic activity of a plasma clot.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7855787 TI - Additive effect of the combined administration of low molecular weight heparin and recombinant hirudin on thrombus growth in a rabbit jugular vein thrombosis model. AB - Recombinant hirudin (r-hirudin) is a new anticoagulant with specific antithrombin activity independently of antithrombin III. Low molecular weight heparins (LMWH) exert predominantly anti-Xa activity. Therefore, we hypothesized that combined administration of r-hirudin and LMWH would induce a stronger antithrombotic effect as compared to r-hirudin administered alone or combined with unfractionated heparin. To assess the effect on thrombus growth, we determined the accretion of 125I-labeled fibrinogen onto autologous non-radioactive thrombi preformed in the jugular veins of rabbits. The rabbits received unfractionated heparin (80 anti-factor Xa U), LMWH (80 anti-factor Xa U) or r-hirudin (0.3, 5.0 and 10.0 mg/kg) either separately or by combined infusion for a 3 h period. R Hirudin reduced the thrombus growth in a dose dependent fashion. The combined administration of 80 anti-Xa U LMWH and r-hirudin at a dose of 0.3 mg/kg resulted in a stronger antithrombotic effect as compared to the combined infusion of unfractionated heparin and r-Hirudin (thrombus growth: 14.3% +/- 6.0 vs 28.9% +/- 6.5; p = 0.001). This difference in additive antithrombotic effect of 80 anti-Xa U LMWH versus unfractionated heparin on r-hirudin was also observed when LMWH was combined with 5.0 mg/kg and 10.0 mg/kg r-hirudin versus unfractionated heparin combined with r-hirudin (thrombus growth: 16.4% +/- 1.6 vs 29.1% +/- 3.9; p = 0.01 and 10.1% +/- 1.8 vs 20.4% +/- 4.5; p = 0.001, respectively). In conclusion, this study showed an additive antithrombotic effect of LMWH on the thrombus growth reducing effect of r-hirudin.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7855789 TI - Thrombin-Hirudin complex formation, thrombin-antithrombin III complex formation, and thrombin generation after intrinsic activation of plasma. AB - To investigate the relative importance of direct inhibition of thrombin by complex formation and of inhibition of thrombin generation to the mechanisms by that unfractionated heparin (UH) and recombinant hirudin (rH) exert their anticoagulant effects, thrombin-antithrombin III complex (TAT) and thrombin hirudin complex (THC) formation was compared with the generation of thrombin and prothrombin fragments 1 + 2 (F 1 + 2). Clotting was initiated by activation of citrated plasma in the absence or presence of UH or rH using partial thromboplastin, ellagic acid and calcium chloride. THC was determined by means of ELISA using specific antibodies to thrombin and rH. Activation of citrated plasma resulted in a sudden onset of thrombin generation after a lag phase of 2 min. Addition of 50 ng rH/ml plasma or 0.1 UH/ml plasma prolonged the clotting time to 3 min. While the peak of thrombin was only slightly decreased in hirudinized plasma, in heparinized plasma thrombin generation was significantly lower than in not anticoagulated plasma. This difference was more pronounced when the lag phase was prolonged to 5 min using 400 ng rH/ml plasma or 0.35 U UH/ml plasma. Using 1200 ng rH/ml or 0.65 U UH/ml to obtain a clotting time of 9 min only a small amount of thrombin could be detected in heparinized plasma, but hirudinized plasma still showed a high peak of thrombin. F 1 + 2 showed essentially the same pattern as thrombin. Prior to the onset of visible clot formation in all experiments using different concentrations of UH about the same values of TAT were observed.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7855791 TI - Surface independent factor XI activation by thrombin in the presence of high molecular weight kininogen. AB - A deficiency of one of the proteins of the contact system of blood coagulation does not result in a bleeding disorder. For this reason activation of blood coagulation via this system is believed to be an in vitro artefact. However, patients deficient in factor XI do suffer from variable bleeding abnormalities. Recently, an alternative pathway for factor XI activation has been described. Factor XI was found to be activated by thrombin in the presence of dextran sulfate as a surface. However, high molecular weight kininogen (HK), to which factor XI is bound in plasma, and fibrinogen were shown to block this activation suggesting it to be an in vitro phenomenon. We investigated the thrombin-mediated factor XI activation using an amplified detection system consisting of factors IX, VIII and X, which was shown to be very sensitive for factor XIa activity. This assay is approximately 4 to 5 orders of magnitude more sensitive than the normal factor XIa activity assay using a chromogenic substrate. With this assay we found that factor XI activation by thrombin could take place in the absence of dextran sulfate. The initial activation rate was approximately 0.3 pM/min (using 25 nM factor XI and 10 nM thrombin). The presence of dextran sulfate enhanced this rate about 8500-fold. A very rapid and complete factor X activation was observed in the presence of dextran sulfate. Although only minute amounts of factor XIa were formed in the absence of dextran sulfate, significant activation of factor X was detected in the amplification assay within a few minutes.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7855790 TI - Effects of DX-9065a, an orally active, newly synthesized and specific inhibitor of factor Xa, against experimental disseminated intravascular coagulation in rats. AB - We investigated the protective effects of DX-9065a, an orally active, newly synthesized and specific inhibitor of factor Xa, against two kinds of experimental disseminated intravascular coagulation (DIC) in rats. Endotoxin induced experimental DIC was induced by a 4-h sustained infusion of endotoxin at a dose of 100 mg/kg. Thromboplastin-induced experimental DIC was induced by a bolus injection of thromboplastin at a dose of 150 mg/kg. The rats were orally administered DX-9065a at 10, 30 or 100 mg/kg 30 min before endotoxin or thromboplastin injection. In both DIC models, DX-9065a showed a protective effect against DIC, at all doses and in all parameters, including fibrin/fibrinogen degradation products (FDP), fibrinogen level, prothrombin time, activated partial thromboplastin time, platelet count and the number of renal glomeruli with fibrin thrombi. When DX-9065a was orally administrated at 100 mg/kg without endotoxin or thromboplastin, no significant changes were seen in hemostatic parameters except PT and APTT, and no fibrin thrombi or abnormal bleeding were seen in renal specimens. These findings suggest that the new oral anti-Xa drug, DX-9065a, has an effect in reducing the severity of DIC. However, further dose-finding and safety studies of this drug have still to be assessed. PMID- 7855792 TI - Monoclonal purified F VIII for continuous infusion: stability, microbiological safety and clinical experience. AB - Replacement therapy for patients with hemophilia A postoperatively or for major hemorrhage, administered as a continuous infusion, is efficient and reduces the requirement for factor VIII (F VIII). The convenience of the method is increased by using a minipump and not diluting the concentrate further after reconstitution. A monoclonally purified F VIII concentrate (Monoclate-P), was evaluated for its stability after reconstitution in different infusion systems, for its microbiological safety as well as clinical safety and efficacy in continuous infusion. The F VIII activity was unaffected by 2 of the 3 infusion systems at room temperature during 15 days, whereas in the third (CADD-1) it decreased below 80% of initial value after 3-7 days. Addition of heparin (1 U/ml) or low molecular weight heparin (1 anti-Xa U/ml), which are used to prevent thrombophlebitis at the site of infusion, did not affect the stability. Nine out of 9 samples taken from the infusion systems after 3 days and again after 7 days were sterile. After inoculation with Staphylococcus aureus or Escherichia coli the bacterial growth in samples of the reconstituted concentrate was not different from that in lidocaine in saline or heparin in saline. F VIII was given in continuous infusion with a minipump (Infu-Med) to 12 patients undergoing major surgery and 8 patients with major hemorrhage for a total of 157 days. A progressive decrease of the clearance was seen during the first 5 days of infusion from 3.0 to 1.7 ml/kg/h. Hemostasis was effectively achieved, and no infectious complications were registered.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7855793 TI - Inhibition of microarterial thrombosis by activated protein C in a rabbit model. AB - Protein C is the key component in a natural anticoagulant pathway. After its activation by the thrombin-thrombomodulin complex, it degrades the activated forms of coagulation cofactors VIII and V, which leads to downregulation of the coagulation process. Due to its specific anticoagulant activity, activated protein C (APC) is potentially interesting as an antithrombotic agent. The effect of bovine activated protein C on thrombus formation and haemostasis was investigated in a rabbit model of microarterial thrombosis. Segments of both central ear arteries were prepared and blood-flow interrupted with double vascular clamps. Longitudinal arteriotomies (7 mm) and deep vessel wall trauma (5 mm) were performed, whereafter the arteriotomies were closed with running sutures. Five minutes prior to opening of the clamps (reperfusion), boluses of APC (0.8 mg/kg bodyweight) or vehicle alone were administered to two groups, each of 10 rabbits, in a blind random fashion. Vessel patency-rates were drastically improved by the administration of APC compared to vehicle. Correspondingly, thrombus weights were significantly lower in the APC group than in the control group. The activated partial thromboplastin time was prolonged to approximately twice the baseline throughout the 2 h observation interval in the APC group. Levels of circulating platelets were unaffected by the APC infusion, but the arteriotomy bleeding times were significantly longer in the APC group. In summary, activated protein C exerted powerful and long-acting antithrombotic effects in a microarterial model of thrombosis in rabbits. PMID- 7855794 TI - Antithrombotic effects of recombinant human soluble thrombomodulin in a rat model of vascular shunt thrombosis. AB - Thrombomodulin on endothelial cells is a cofactor for thrombin-catalyzed activation of protein C. We have investigated the anticoagulant function of recombinant human soluble thombomodulin (rsTM) in a rat model of arterio-venous (AV)-shunt thrombosis. A bolus injection of rsTM 30 s before the induction of AV shunt thrombosis inhibited the thrombus formation in a dose-dependent manner. The dose of anticoagulant that inhibited thrombus formation by 50% was 0.4 mg/kg rsTM alpha, 0.15 mg/kg rsTM beta, and 13 U/kg heparin. Recently, we characterized three monoclonal antibodies (moAbs) against human TM whose epitopes are located in the TM epidermal growth factor-like domain (Nawa et al., 1994). moAb 2A2 inhibited thrombin binding to rsTM, and abolished both TM functions as a cofactor in thrombin-catalyzed activation of protein C and as an anticoagulant by modifying thrombin-induced fibrinogen clotting and platelet aggregation. moAb 1F2 preserved the latter activities as an anticoagulant, but inhibited cofactor activity. moAb 10A3 had no inhibitory effect on either activity. Analysis of the in vivo anticoagulant mechanism of rsTM was facilitated by the availability of these moAbs. After incubation at rsTM/moAb molar ratios of 1:1.25, the effect of the mixtures were examined in the AV-shunt thrombosis model. An injection of 0.8 mg/kg rsTM alpha or 0.4 mg/kg rsTM beta resulted in a significant reduction on thrombus formation, as expected. moAb 10A3 had no effect on rsTM activity. However, co-injection of rsTM with moAb 1F2 resulted in a significant decrease of the inhibitory activity on thrombus formation. moAb 2A2 essentially abolished the inhibitory effect of rsTM.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7855795 TI - Thromboplastin related differences in the determination of international normalised ratio: a cause for concern? Steering Committee of the UK National External Quality Assessment Scheme in Blood Coagulation. AB - When the International Normalised Ratio (INR) is used for control of oral anticoagulant therapy the same result should be obtained irrespective of the laboratory reagent used. However, in the UK National External Quality Assessment Scheme (NEQAS) for Blood Coagulation INRs determined using different reagents have been significantly different. For 18 NEQAS samples Manchester Reagent (MR) was associated with significantly lower INRs than those obtained using Diagen Activated (DA, p = 0.0004) or Instrumentation Laboratory PT-Fib HS (IL, p = 0.0001). Mean INRs for this group were 3.15, 3.61, and 3.65 for MR, DA, and IL respectively. For 61 fresh samples from warfarinised patients with INRs of greater than 3.0 the relationship between thromboplastins in respect of INR was similar to that observed for NEQAS data. Thus INRs obtained with MR were significantly lower than with DA or IL (p < 0.0001). Mean INRs for this group were 4.01, 4.40, and 4.59 for MR, DA, and IL respectively. We conclude that the differences between INRs measured with the thromboplastins studied here are sufficiently great to influence patient management through warfarin dosage schedules, particularly in the upper therapeutic range of INR. There is clearly a need to address the issues responsible for the observed discrepancies. PMID- 7855796 TI - Relation between plasminogen activator inhibitor-1 and hepatic enzyme concentrations in hyperlipidemic patients. AB - Plasminogen activator inhibitor type-1 (PAI-1) is a key determinant of the fibrinolytic capacity. Its activity correlates with most of the characteristic features of insulin resistance syndrome, i.e. obesity, high blood pressure and hyperlipidemia. We measured plasma PAI-1 antigen levels in 131 asymptomatic men (aged 44.2 +/- 11 years) who had been referred for hyperlipidemia. Those taking medication and those with a secondary hyperlipidemia were excluded. We confirmed the correlation between PAI-1 levels and the following variables: body mass index, blood pressure, triglyceride concentration, and blood glucose and insulin levels before and after an oral glucose tolerance test. We also found a significant and independent correlation between PAI-1 and the concentration of the hepatic enzymes glutamyl transferase, alanine aminotransferase and aspartate aminotransferase. Mild liver abnormalities (presumably steatosis) may thus be one of the factors accounting for high plasma PAI-1 levels in hyperlipidemic patients. PMID- 7855797 TI - Identification of a homozygous single base pair deletion in the gene coding for the human platelet glycoprotein Ib alpha causing Bernard-Soulier syndrome. AB - Bernard-Soulier Syndrome (BSS) is a hereditary bleeding disorder which is caused by the absence or the dysfunction of the platelet glycoprotein Ib/IX/V (GP Ib/IX/V) complex, the major receptor for von Willebrand factor (vWf). BSS is characterized by the presence of giant platelets that show a reduced binding of vWf. Although BSS is a well-characterized disease, and many cases have been described in the literature, the molecular genetic basis of this disorder has been studied in only a few patients. We have studied the genetic basis of the defect in a BSS patient. Flow cytometric analysis of the platelet membrane glycoproteins revealed a significant decrease or absence of GP Ib alpha on the platelet surface, and low levels of GP V and GP IX. In subsequent immunoprecipitation experiments, we confirmed the presence of GP V (although in significantly decreased amounts) on the platelet surface. These results indicated a defect in the GP Ib alpha chain. Genomic DNA coding for GP Ib alpha was amplified, using the polymerase chain reaction (PCR). Subsequent direct sequence analysis demonstrated a homozygous deletion of T317 resulting in a frameshift deletion and predicting a substitution of Arg for Leu76. This deletion causes a shift in the reading frame, predicting a premature stop codon after 19 altered amino-acids, leading to a severily truncated molecule. The molecular genetic defect found in this patient differed from the mutations observed in three other BSS patients described in the literature. This points to a marked hetereogeneity of this disease.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7855798 TI - Elevated thrombomodulin plasma levels as a result of endothelial involvement in plasmodium falciparum malaria. AB - We used thrombomodulin (TM) to assess the participation of the vascular endothelium in human Plasmodium falciparum (P.F.) malaria. Before therapy TM plasma levels were elevated in P.F. malaria and fell to normal values during therapy. Parasitemia, TNF alpha, elastase and TAT levels correlated directly with TM. Elevated TM levels can not be explained by increased synthesis, since incubating HUVEC with pretherapy serum of patients with P.F. malaria, but not reconvalescence serum, suppressed TM transcription. This was partially prevented by adding a TNF alpha neutralizing antibody to patient serum before incubation with HUVEC. However, TNF alpha does not release TM from cultured HUVEC in vitro. Coincubation of HUVEC with pretherapy serum together with neutrophils resulted in endothelial cell destruction, which could be partly prevented by a TNF alpha neutralizing antibody. Hence the increase of TM during P.F. malaria might reflect the concerted action of cytokines and neutrophils on HUVEC. PMID- 7855800 TI - A standard nomenclature for factor VIII and factor IX gene mutations and associated amino acid alterations. On behalf of the ISTH SSC Subcommittee on Factor VIII and Factor IX. PMID- 7855799 TI - High affinity binding sites for activated protein C and protein C on cultured human umbilical vein endothelial cells. Independent of protein S and distinct from known ligands. AB - Activated protein C (APC) is an antithrombotic serine proteinase having anticoagulant, profibrinolytic and anti-inflammatory activities. Despite its potential clinical utility, relatively little is known about its clearance mechanisms. In the present study we have characterized the interaction of APC and its active site blocked forms with human umbilical vein endothelial cells (HUVEC). At 4 degrees C 125I-APC bound to HUVEC in a specific, time dependent, saturable and reversible manner. Scatchard analysis of the binding isotherm demonstrated a Kd value of 6.8 nM and total number of binding sites per cell of 359,000. Similar binding isotherms were obtained using radiolabeled protein C (PC) zymogen as well as D-phe-pro-arg-chloromethylketone (PPACK) inhibited APC indicating that a functional active site was not required. Competition studies showed that the binding of APC, PPACK-APC and PC were mutually exclusive suggesting that they bound to the same site(s). Proteolytic removal of the N terminal gamma-carboxyglutamic acid (gla) domain of PC abolished its ability to compete indicating that the gla-domain was essential for cell binding. Surprisingly, APC binding to these cells appeared to be independent of protein S, a cofactor of APC generally thought to be required for its high affinity binding to cell surfaces. The identity of the cell binding site(s), for the most part, appeared to be distinct from other known APC ligands which are associated with cell membranes or extracellular matrix including phospholipid, thrombomodulin, factor V, plasminogen activator inhibitor type 1 (PAI-1) and heparin. Pretreatment of HUVEC with antifactor VIII antibody caused partial inhibition of 125I-APC binding indicating that factor VIII or a homolog accounted for approximately 30% of APC binding. Studies of the properties of surface bound 125I APC or 125I-PC and their fate at 4 degrees C compared to 37 degrees C were consistent with association of approximately 25% of the initially bound radioligand with an endocytic receptor. However, most of the radioligand appeared not to be bound to an endocytic receptor and dissociated rapidly at 37 degrees C in an intact and functional state. These data indicate the presence of specific, high affinity binding sites for APC and PC on the surface of HUVEC. While a minor proportion of binding sites may be involved in endocytosis, the identity and function of the major proportion is presently unknown. It is speculated that this putative receptor may be a further mechanisms of localizing the PC antithrombitic system to the vascular endothelium. PMID- 7855801 TI - Inventory of coagulation inhibitors from animals feeding on blood. A report prepared on behalf of the Scientific and Standardization Committee's Registry of Exogenous Hemostatic Factors. PMID- 7855802 TI - Patients with AT III, protein C or protein S defects show no associated hereditary APC-resistance. PMID- 7855803 TI - Factor VIII concentrate: what is "high purity"? PMID- 7855804 TI - Questions concerning the new recommended mean normal prothrombin time (MNPT) to calculate the international normalized ratio (INR) PMID- 7855806 TI - [Reduction of the number of fatal traffic accidents. Preventive measures against injuries yield results]. PMID- 7855805 TI - Rebuttal of the article of Bounameaux et al. PMID- 7855807 TI - [Emergency treatment of cerebral infarction]. PMID- 7855808 TI - [Pill-taking drivers]. PMID- 7855809 TI - [Driving under the influence of benzodiazepines. Sale differences in the counties are reflected among drivers suspected of driving under the influence of a drug]. AB - This study was based on all blood samples taken from drivers suspected of being influenced by alcohol and or drugs and sent to the National Institute of Forensic Toxicology in 1992. Benzodiazepines were among the most frequently detected drugs. The ratio between samples containing benzodiazepines and the total number of samples was compared with the sales of benzodiazepines in the different Norwegian provinces. In 95% of the benzodiazepine positive samples, either a combination with other drugs or a concentration significantly higher than usually found after ordinary therapeutic use was observed. These results indicated that the fraction of samples positive on benzodiazepines probably representing drug abuse or misuse correlated with the total prescription of benzodiazepines in the different Norwegian provinces. PMID- 7855810 TI - [Elevated intracranial pressure following brain infarction--a retrospective study]. AB - Brain infarction is a frequent cause of emergency admission to hospital. We have made a retrospective study in order to describe patients who develop fatally elevated intracranial pressure. From 1991 to 1993, seven patients (3.3%) died within the first 96 hours after the symptoms appeared. All these patients died from elevated intracranial pressure caused by oedema in and around an infarction in the territory of the middle cerebral artery. These patients were significantly younger than the general population of patients with infarction (p < 0.01), and also younger than the patients who died from other causes during the observation period (p < 0.01). We think that these cases underline the importance of establishing effective acute treatment for ischemic cerebrovascular diseases, since this is probably the only effective way to protect against formation of oedema. PMID- 7855811 TI - [Elevated intracranial pressure following brain infarction--therapeutical possibilities]. AB - Elevated intracranial pressure is a serious complication in the early phase after brain infarction. The most frequent cause of the elevated pressure is oedema following an infarction in the territory of the middle cerebral artery. Non surgical treatment is inadequate in many of the patients. Although anecdotal, several reports concerning neurosurgical treatment seem to be optimistic. We think that such treatment could be given to selected young patients with large hemispheric infarctions and cerebral oedema. PMID- 7855812 TI - [Regaining of function following severe head injury. From primary rehabilitation to 2 years after the injury]. AB - 72 patients with sequelae after severe traumatic brain injury were studied during primary rehabilitation and two years post-injury. The patients were grouped into two main categories, one dependent as regards activities of daily living (ADL) and one mainly independent group. Most of the dependent patients, except seven low level patients close to a vegetative state, showed marked functional recovery. Among the independent patients, those who were admitted to primary rehabilitation relatively early (< 60 days post-injury) and those who were allowed a longer stay upon first admission to hospital showed better progress in functional level scores than those who were admitted later and were allowed a shorter stay during primary inpatient rehabilitation. PMID- 7855813 TI - [Horner syndrome following insertion of a chest tube]. AB - We describe a case of Horner syndrome following insertion of a chest tube in a 27 year old male. The syndrome was discovered the day after insertion of the tube and persisted for at least three months. By the time of a control examination six months after insertion the symptoms had disappeared. Caution must be taken when inserting a chest tube. Pressure of the tip of the tube against the thoracic aperture should be avoided. PMID- 7855815 TI - [The medical responsibility for health and environment of future generations. The ecological dilemma in the meeting between medicine, environmental health services and protection]. AB - Medical doctors are challenged to consider their responsibility for the health and environment of future generations. The fields of health, medicine, development and the environment overlap in various ways. This article describes ecosystem health and biohistory as new models of medical interest. The ecological dilemma, the biomedical model and postbiomedical thinking are also discussed. The municipal medical officer should regard the whole municipality, with its ecosystems, communities and organizations, as areas of medical concern. He or she should find a credible working style which opens up for interdisciplinary discussions and actions. PMID- 7855816 TI - [Central venous catheter. Better routine for placing of catheters]. AB - Malposition of a central venous catheter is a major cause of serious complications such as perforation and cardiac tamponade. To prevent such complications it is necessary to confirm that the catheter tip is in the correct position. Intravascular electrocardiography is a reliable way of ensuring that the catheter tip is placed above the right atrium. With a minimum of extra equipment and training, we have tested the electrocardiography technique applied to our standard central venous catheter equipment (Secalon Seldy and Hydrocath). Our experience is that this technique makes catheter tip placement distal to the right atrium more easy to achieve. PMID- 7855814 TI - [Hepatitis A in Oslo]. AB - During the last six years we have registered 237 persons with acute hepatitis A in Oslo, 96 of them with non-Scandinavian names. The number with non-Scandinavian names is increasing. Almost all the hepatitis A patients with non-Scandinavian names are children, and two of three had been infected in Pakistan. Adult immigrants from countries where hepatitis A is endemic do not need any prophylaxis against hepatitis A. 29,800 travellers were given human normal immunoglobulin at our department during the last five years and none of them acquired hepatitis A. To prevent import of hepatitis A it is of particular importance to give human normal immunoglobulin or hepatitis A vaccine to all children of immigrants before they visit their parents' country. PMID- 7855817 TI - [The Social Security Court and verdicts on appeals from fibromyalgia patients. Central problems and dilemmas]. AB - The article contains a discussion of conditions which may influence valuations of appeals to the Social Security Court from persons with the diagnosis fibromyalgia. An important question is to what extent economic depression and growing requirements for rights regarding grants from the Social Security System are of importance for the decisions. Of vital significance is the definition of disease in relation to Acts and regulations, especially the distinction between objective and subjective documentation of disease. The court's decisions function as guiding directives for the Social Insurance System in general. This implies that the Social Security Court can function as a social-political corrective. PMID- 7855818 TI - [Antioxidants and cardiovascular disorders--epidemiologic aspects. Should high risk patients receive supplementation?]. AB - Dietary antioxidants such as vitamin E, vitamin C, beta carotene and flavonoids may retard atherosclerosis by preventing low density lipoprotein oxidation. Observational epidemiological studies, including ecological correlations, case control and prospective studies, indicate that high vitamin E levels may be associated with decreased cardiovascular disease. Beta carotene may be protective among smokers and the elderly. Few studies have been able to show that vitamin C has a protective effect. A handful of intervention studies have examined the effects of vitamin E and beta carotene with mixed results. While few side effects of antioxidant supplementation are known, the results of current, large-scale studies in primary intervention must be awaited before recommendations can be made. Increased intake of fruits and vegetables that are rich in antioxidants is recommended. PMID- 7855821 TI - [Evaluation of medical students during basic training]. PMID- 7855819 TI - [A user evaluation of software programs in family practice]. AB - Software for electronic patient journals was evaluated. A questionnaire was sent to a total of 551 general practitioners working on contract, salaried general practitioners and specialist practitioners. Among the 345 respondents, 63% used electronic journals. Three programs dominated. Legeservice (n = 94) was exclusively used by salaried general practitioners, Profdoc (n = 88) and Infodoc (n = 34) were preferred by general practitioners working on contract and by specialists. In the latter group only 40% used electronic journals. In general, the users of Profdoc and Infodoc were satisfied with the central functions of the software and the service provided by the suppliers. The users of Legeservice were significantly less satisfied. In conclusion, some of the existing software for patient journals in Norway can safely be recommended. PMID- 7855820 TI - [A non-traditional occupational health unit. Evaluation after a year's activity]. AB - An Occupational Health Care Unit has been established for 23 car repair workshops. The unit consists of a central unit connected to an Institute of Occupational Medicine, consisting of a coordinating occupational physician, a physiotherapist and an occupational hygienist. This unit cooperates with 11 general practitioners in the district. The unit was evaluated by the employer and one employee in each car repair shop after one year. In general, they were satisfied with their occupational health care, and several improvements to the working environment had been carried out. PMID- 7855822 TI - [What controls our attitudes? Views upon discussion about fibromyalgia and social security services]. PMID- 7855823 TI - [Welfare in the EEC--a differentiated look at the future]. PMID- 7855824 TI - [Data hygiene. Data security, prevention of wrong or useless information and high quality of communication]. PMID- 7855825 TI - [Cardiovascular examination of 40-year-old subjects in Hordaland]. PMID- 7855826 TI - [Norway is an underdeveloping country when it comes to autopsy rate]. PMID- 7855827 TI - [Chances to survive an avalanche--new data]. PMID- 7855828 TI - [Rikshospitalet and Ulleval hospital--joint blood bank]. PMID- 7855829 TI - [Nearsightedness--heredity or environment?]. PMID- 7855830 TI - [(Adeno)tonsillectomy? Many indications, difficult patients selection]. PMID- 7855832 TI - [Psychotherapeutic counselling via telecommunication networks]. AB - The article discusses the effects that video conferencing in psychotherapy (distant therapy) may have upon the interaction between client and therapist. Experiences from distant therapy in North Norway, as well as earlier studies, are discussed in relation to factors such as client power and control, regulation of intimacy, and verbalization. The experiences indicate that physical presence- which is intuitively perceived as the ideal in relation to which the distant therapy settings are assessed--should be treated instead as a variable which can have positive and/or negative effects on a given therapeutic process. PMID- 7855831 TI - [Telepsychiatry--closeness by distance?]. PMID- 7855833 TI - [(Adeno)tonsillectomy in children. A follow-up study]. AB - A retrospective study was performed where parents of 246 children who had undergone (adeno)-tonsillectomy received a questionnaire regarding the symptomatology (14 symptoms) before and after surgery. 92% of the parents were satisfied with the surgical outcome. 98% felt that their children were in a better condition after surgery. There was a significant improvement of all symptoms. The expectations of the parents were fulfilled. The major complaint was the waiting time for operation. In order to reduce the cost of health care an increasing number of operations are performed as day-care surgery. Less than 1% of the parents in our study would like to have the tonsillectomy performed on a day case basis. Anyhow, the majority of the patients would have failed to meet the criteria for outpatient surgery because of obstructive sleep apnoea, recent history of upper airway infection or because they were living too far from the hospital. PMID- 7855834 TI - [Granular corneal dystrophy or Groenouw's disease type 1. A challenge to Norwegian biochemists, geneticists and ophthalmologists]. AB - A Norwegian family with granular corneal dystrophy was described by Saebo (2) as early as 1939. One of the branches in this family is further described in the present work. The sickness, which is autosomal dominant, occurred with high penetrance, especially in generation IV and V, with as many as 12 of 16 affected in generation V. In the youngest generation described only 10 of 23 are affected. The reason for this cannot be predicted from the present work. The results in this generation are more uncertain than in the others because of the age of the patients. If we include the work done by Saebo, a total of 45 of 73 children are affected (62%). Further work is needed. Ophthalmologists, biochemists and persons working on genetics should make a joint effort to study the reason for the formation and the composition of the granulae on the corneas of these patients. PMID- 7855835 TI - [Hypercholesterolemia--a clinical problem in heart transplantation. A therapeutic trial with low-dose lovastatin]. AB - One year after heart transplantation, serum total cholesterol had increased by 24% in 103 recipients on prednisolon, cyclosporin A, and azathioprin immuno suppression, and was above 5.2 mmol/l in 84 of them. Incremental small dose lovastatin treatment up to 20 mg per day safely reduced total cholesterol by 19% and LDL-cholesterol by 24% in 14 patients with serum cholesterol above 7.5 mmol/l. Serum concentration of lovastatin did not increase further after three weeks treatment with 20 mg. It is concluded that hypercholesterolaemia in heart recipients treated with cyclosporin A can be treated safely with small dose lovastatin. Drug therapy should be individualized and conducted by physicians experienced in transplantation medicine. PMID- 7855836 TI - [Chronic left heart ventricle failure and inotropic stimulation]. AB - Congestive left heart failure can be treated using three main strategies: change preload to optimize the Frank-Starling relationship, decrease after-load to reduce external work and increase cardiac contractility by inotropic stimulation. The third option is reviewed in this article, which discusses the pharmacological and clinical effects of different inotropic drugs as known in 1994. It is concluded that digitalis should be considered apart from other inotropic drugs. Even when in sinus rhythm, digitalis seems reasonable as an adjuvans to after load reduction and diuretics. Chronic use of other inotropic drugs for congestive left heart failure is not recommended. PMID- 7855837 TI - [Tampons--an aid in stress incontinence?]. AB - 22 patients with stress incontinence who were waiting for operative treatment tested specially designed vaginal tampons. The tampons, ten per patient, were tested in situations where the patients normally would experience urinary leakage. 20 of the patients afterwards answered a questionnaire: 11 patients had experienced complete continence, and in seven patients the use of the tampon had reduced leakage. Nine patients wanted to continue using tampons until the operation. We believe that vaginal tampons, by eliminating odour and a feeling of wetness, may be a better aid than pads for certain women with stress incontinence. PMID- 7855838 TI - [Hookworm disease. A differential diagnosis in iron deficiency anemia]. AB - Hookworms are among the most widespread of human parasites and occur all over the tropics and subtropics. They are bloodsucking roundworms that inhabit the duodenum and jejunum. Usually the infection is mild (hookworm carrier state), but sometimes the infection is heavy and results in anaemia and/or hypoproteinemia (hookworm disease). Hookworms are occasionally imported to Norway by immigrants. This paper describes two cases of severe and life-threatening hookworm disease treated in our hospital. The first patient was a Pakistani woman born in 1929 who on admission was hypovolemic with severe hypochromic anaemia (haemoglobin 3.6 g/100 ml). The second patient was a Bolivian refugee born in 1946 with a similar clinical picture (haemoglobin 3.3 g/100 ml). Both patients were treated with blood transfusions followed by mebendazol and iron substitution. The article also reviews the current literature on the epidemiology, pathogenesis and therapy of hookworm infection. PMID- 7855840 TI - [The psychiatric semester and recruitment of future psychiatrists]. AB - Before and after the psychiatric course, students from three successive year classes received a questionnaire. Of 102 subjects, 75% responded before and 82% after the course to the question: "Would you like to be a psychiatrist? (1 = definitely not--8 = very much). 11% chose one of the alternatives 6-8 before the course, and 24% after. No differences were noted between the three classes prior to the course. After the course, the students were asked to rate the total profit of the course on a 8-point scale from 1 (no gain) to 8 (very much gain). The class with the highest mean for total profit also had the highest mean for motivation for becoming a psychiatrist. The class with the lowest mean for profit had the lowest mean for psychiatry. Among the former, 38% selected one of the alternatives 6-8 regarding preference for psychiatry. Among the latter the corresponding frequency was 16%. Every class consisted of two groups. In the group with most gain from the course (6-8 on the scale), 48% would like to become a psychiatrist (6-8 on the scale). In the group with the lowest profit, the frequency was 6%. PMID- 7855839 TI - [Diagnosis and treatment of high blood pressure. How to invest?]. AB - High blood pressure is a major risk factor for development of cardiovascular diseases. During 1992 and 1993, several national consensus reports about treatment of arterial hypertension have been published. There are discrepancies between the recommendations contained in the reports, which has caused uncertainty among physicians. We discuss the basic problems connected to evaluation and recommendation, and the demand for standardization and organization of the health service programme for patients with high blood pressure. It is possible to learn from, and thereby achieve better quality of medical practice, through a continuous registration of our routines and results. The Trondheim model is designed to depict specific information from the primary health services in a follow-up programme. This information is sampled in a data base from which primary physicians can obtain feedback on statistical evaluations twice a year. This is defined as a quality assurance programme to secure and improve the quality of the medical service to patients with high blood pressure. PMID- 7855841 TI - [Medical technical equipment--not so dangerous after all?]. AB - More than a decade has passed since the Ofstad committee presented its report on "Control of medical devices". The committee assumed that the use of medical devices constituted a major safety problem in the Norwegian health care system. The frequency of device-related injuries to patients was expected to be high, especially since the amount of non-recorded injuries was expected to be large. During the period since the publication of the report, several medical device reporting systems have been established, and special injury committees have been formed in some hospitals. Several "ombudsmen" for patients now exist, and both a patients' association and an insurance system for compensation to injured patients have been established. Despite this, we still do not know the total number of medical device-related injuries to patients in Norway. However, the existing records do show that device-related injuries to patients are not as abundant as the Ofstad committee feared. PMID- 7855842 TI - [No one is disgraced by the name. About the drug manufacturers' choice of name of their products]. AB - Choosing the "right" trade name for a drug is important for the manufacturer, both because the name identifies the product and because it can create an image which helps the marketing and thus increases the sale of the drug. A name registered as a trade mark is the company's property and cannot be used by others. Choosing a good name from scratch is not easy, but several ground rules exist: Get as close as possible to the non-proprietary (generic) name, the name of the company, the properties of the drug, or a combination of these. Try to have the first letter of the name near the beginning (or the end) of the alphabet. Keep the name short and avoid names that could be difficult to pronounce or may have a bizarre meaning in other languages. In this article, examples of "good" and "bad" drug names are presented. Various aspects of the non proprietary and chemical names of drugs are also discussed, as well as the risk of confusing different drugs that have names that look alike or sound alike. PMID- 7855843 TI - [Philosophy--a valuable tool for psychiatrists]. PMID- 7855844 TI - [The Other--the patient]. PMID- 7855846 TI - [The clinical case. Suspicion of rectal carcinoma in a male basset hound]. PMID- 7855847 TI - [Reactions of heifers in early pregnancy and their offspring delivered at term by cesarean section and in the first postpartum days in a cow-calf operation]. AB - In 11 heifers originating from one mother cow herd and in their offspring delivered by cesarean section heart rate recordings were taken during their staying in the calving box and later on in group housing. Heart rate showed a rhythmicity in accordance with behavioural physiological reactions. The mean heart rate of a 24 hour period in an animal was different between and within the newborn and elder animals. The mean heart rate was increasing in the calves during the first days of their postnatal life and decreasing in the mother cows within some days after parturition. Blood samples taken repeatedly in 9 heifers via an indwelling catheter and in their offspring short after birth and at 24 and 48 hours by venipuncture as well were analysed for acid-base status, cortisol, noradrenaline, adrenaline, hemoglobin and lactate. Comparing the results with other investigations can be used for evaluating the strain of delivery by cesarean section for the young and the mother as well as revealing main influences on the reactions of the animals and their individual specificity. PMID- 7855845 TI - [Simplified identification and differentiation of feline, canine and phocine herpesvirus isolates using monoclonal antibodies]. AB - Infections by alpha-herpesviruses of dogs (canid herpesvirus, CHV) and cats (felid herpesvirus, FHV) are widespread in these species and are of significant clinical relevance. Immunologically closely related herpesviruses have been isolated from harbour seals (Phoca vitulina) showing respiratory disease, hepatitis and/or encephalitis. These isolates are currently referred to as phocid herpesviruses (PhHV). The host spectrum of CHV and FHV, respectively, appears to be restricted to members of the Canidae and Felidae families. Seal herpesviruses, in contrast, cross species barriers, at least in vitro where they productively replicate also in cells of felid origin. Whether cats are susceptible to natural PhHV-infections remains to be elucidated. A reliable etiological diagnosis of acute herpesvirus-associated infections should be desirable especially in breeding kennels and zoos where hosts susceptible for FHV, CHV oder PhHV are reared. For a rapid and unambiguous identification and differentiation of herpesvirus isolates derived from felids, canids and pinnipedia a simple enzyme immunoassay employing monoclonal antibodies is presented. PMID- 7855848 TI - [Laminitis in cattle: a literature review]. AB - Worldwide afflictions of the claws belong to the economically important diseases in dairy cattle. The significance of laminitis has gained importance in the last years since the condition is regarded as the most important predisposing factor for the development of lesions such as sole ulcer, white line disease and heel horn erosion. Apart from the clinical stages (acute, subacute, chronic, chronic recurrent) there is also a subclinical form of laminitis which does not cause lameness. It is characterized by soft yellowish sole and heel horn with haemorrhages in the sole and along the white line. Laminitis is a multifactorial event in which nutrition, genetic disposition and the perinatal period, combined with the associated diseases of high-yielding cows, have a particular significance. Currently, two principally different hypotheses on the pathogenesis are discussed. The generally accepted theory bases on a disturbance in the microcirculation of the corium. According to the other theory the circulatory disturbances are secondary to changes which occur in the horn producing cells of the stratum basale of the epidermis. The predisposing factors and the pathogenesis of laminitis are discussed in the light of possible therapeutic and prophylactic measures. PMID- 7855849 TI - [Hereditary defects in artificially-inseminated breeds]. AB - Since it is possible to analyse genes directly and thus decipher the genome, animal hereditary diseases are in the centre of attention again. This publication presents some selected genetically determined illnesses and points out to the significance of monogene disorders with recessive genetic pathway particularly. By using genetic engineering, e.g. PCR, significant progress can be made in the diagnosis of genetic defects. But it is necessary to find ways of dealing with them. PMID- 7855850 TI - [Somatic cells in goat milk]. AB - In goats the somatic cell content (SCC) of raw milk is in general considerably higher (often several millions/ml milk) than in cow milk. This refers to milk from healthy and from mastitic mammary glands, to samples from infected and from non-infected udder halves and to single gland and to bulk milk samples as well. On the other hand, there is in every herd of dairy goats a considerable proportion of milk samples with low SCC, which fulfill in this respect all exigencies of a good milk quality. Part of this discrepancy is caused by the method that is used to determine the SCC (presence of nonleukocytic cell-like fragments in goat milk). Further research in order to explain the physiological and pathogenetic causes of the differences between SCC of goat and cow milk is needed before SCC standards and regulations for goat milk quality can be introduced finally. PMID- 7855852 TI - [The feeding of "organic swine"--a field study]. AB - In a field study, the feeding practice in fattening pigs practised on 22 organic farms (associations Demeter and Bioland) in the North of Germany was investigated. Diets were calculated and compared with the respective performance requirements and the hygienic status of the feedstuff was evaluated. There were considerable differences between individual farms however, the following tendencies were obvious: Crude protein and essential amino acid supply was below requirements, especially during the initial fattening period. There were also serious imbalances in mineral supply, mostly because some farmers did not add mineral supplements for ideological reasons. Clinically apparent deficiencies, however, were not observed. The hygienic quality of the feedstuff was often objectionable. Considering the daily energy intake the fattening performance of the pigs were lower than expected. Apart from the imbalanced nutrient supply and the bad feed hygiene, the pigs' sometimes poor health conditions has to be considered as a further cause for the low performance. The tendencies described were more prominent with Demeter than Bioland farms. PMID- 7855853 TI - [Tripodia in a pigeon]. AB - In a pigeon of the breed "Thuringian White Bib" a stunted third leg was found, which was attached to the left of the ventral cloacal aspect. A disturbance of the embryonic development at the third to fourth day of incubation was thought to be the cause of this anomaly. PMID- 7855851 TI - [Methods for the determination of pH value and redox potential in the rumen fluid of adult cattle]. AB - pH sticks and pH meters were tested to determine ruminal pH and mV meters in order to measure the redox potential in rumen contents. Rumen pH can be determined by reading pH sticks left in rumen liquor or immediately after removal. Differences between pH sticks and a reference method accounted for 0.01 0.48 pH units, depending on the pH stick used and the pH range of the ruminal contents (pH < 6, 6-7, > 7). Ruminal pH is accurately measured by the pH meters pHep and GPHR (y = -0.22 + 1.03x, or y = 0.15 + 0.97 x). By using a mV meter the redox potential in rumen liquor can be determined 10 min after start of measurement. Results determined with the mV meter GPHR showed a mean difference of 10-23 mV, those determined with ORP a mean difference of 131-202 mV in comparison with a reference method. There is no linear correlation between the data of the mV measurements and the data of the methylene blue reduction test in ruminal contents (y = -328.5 - 0.003 x; p = 0.652). Therefore these data may not be in used in the same manner for rumen liquor diagnosis. PMID- 7855855 TI - [Tapeworms, a problem in equine practice?]. AB - This paper gives a survey on biology and ecology of equine tapeworms as well as on pathogenesis, clinics, diagnosis, therapy, and prophylaxis of tapeworm infections. PMID- 7855854 TI - [Two congenital anomalies of the urinary tract in warmblood horses: ectopia ureteris and diverticulum vesicae]. AB - Two cases of congenital anomalies of the urinary tract of horses are described. In case 1 there was an ectopia ureteris sinistri in an one-year-old mare. The animal showed urinary incontinence without affects of the general condition. The diagnosis was made by rectal, ultrasonic and vaginoscopic examination. Therapeutically a nephrectomy of the left kidney was carried out. In case 2 a six year-old gelding had a congenital diverticulum at the neck of the urinary bladder. It showed colic during urination, dropping of urine and haematuria. The diagnosis was made by rectal exploration, ultrasonic examination and a diagnostic laparotomy. A surgical treatment was not possible. PMID- 7855856 TI - [Total thyroxine (T4) and free thyroxine (FT4) in hypothyroidism and nonthyroid diseases of dogs]. AB - In 1548 dogs total and free thyroxine were determined. 559 of these dogs had been divided into 13 groups: 130 were healthy dogs, 22 suffered from hypothyroidism, two from hyperthyroidism, 405 from various other internal diseases. The other 989 dogs did not belong to one of the groups of interest or could not be attached to a certain group. In all hypothyroid dogs FT4-values were hypothyroid, whereas T4 was hypothyroid just in 16 cases; the other six values were located in the "gray area", which is supposed to be 1.2 to 1.8 micrograms/dl (15 to 23 nmol/l). Many dogs with other diseases expressed low T4- and/or FT4-values, too. Low hormone values could be measured especially in case of severe diseases. If the clinical symptoms corresponded to hypothyroidism and both T4 and FT4 were situated in the hypothyroid area, hypothyroidism is generally assumed. In all the other cases further diagnostic procedures must be performed. PMID- 7855857 TI - [Meningiosis--an additional cause of paraparesis in old dogs]. AB - Based on a case report, occasionally observed, degenerative changes of the spinal meninx in a sense of meningiosis are presented that are not yet described. The patient was a thirteen-year-old dog, showing paraparesis and spinal pain. Findings of X-Ray examination, surgery and histology are described. PMID- 7855858 TI - [Diagnosis of retinal diseases in dogs and cats]. AB - The article presents an overview on the different examination techniques that can be used to make up a diagnosis of retinal disease in the dog and cat. Patient history, examination for visual impairment, direct and indirect ophthalmoscopy, fluorescence angiography, electroretinography and ophthalmic ultrasonography are mentioned. The most important elements of the normal fundus of dogs and cats as well as the ophthalmoscopical features of the most common retinal diseases in these species are given, illustrated by coloured photographs. PMID- 7855859 TI - [Lens-induced uveitis in a rabbit]. AB - The lens-induced uveitis is a diagnostic as well as a therapeutic challenge for the veterinarian. In most cases the ocular structures have already been irreversibly damaged, so that the therapy can only bring relief, but does not lead to full recovery. This is a review of the pathophysiology and the resulting diagnostic consequences of the lens-induced uveitis. One case is discussed and recommendation for medical treatment is given. PMID- 7855860 TI - [The detection of viruses in food of animal origin using the polymerase chain reaction--a review]. AB - Conventional methods for the detection of viruses in food are very time consuming and usually not sensitive enough to detect very low amounts of virus. Modern methods, like nucleic acid hybridization and polymerase chain reaction (PCR), may accelerate the diagnostic procedure considerably. The PCR allows the amplification of a specific DNA-segment by the factor 10(6) or more within a few hours and has already been described for the detection of various food-borne viruses. We summarize the use of PCR in the diagnosis of viral food contaminations and also include some results of our work with the detection of pseudorabies virus (PRV) in artificially contaminated sausages. We found that PCR is in some respect advantageous to the classical tissue culture isolation. The detection level of the PCR in samples of different pH values was compared to virus isolation in tissue culture, and it could be shown that the PCR was less affected by extreme pH values than tissue culture. PMID- 7855861 TI - Agency for Toxic Substances and Disease Registry's toxicological profiles: contribution to public health. PMID- 7855862 TI - Cancer in the vicinity of a Department of Defense superfund site in Massachusetts. PMID- 7855863 TI - Nephrotoxic effects of thermal decomposition mixtures of type C hydraulic fluids. AB - A survey was conducted to check the toxicological impact of ethylene glycol present in a thermal decomposition mixture of type C hydraulic fluid on laboratory animals submitted to an inhalation test. The target organs, i.e. kidneys, of exposed rats were evaluated histologically and oxalic acid--the ethylene glycol metabolite thought to cause renal failure--was quantified in urine samples. The results show that the low ethylene glycol concentrations present in the inhalation chamber produce only a temporarily increased oxalic acid excretion, at levels that are not significant. These findings are supported by the histological evaluation of the kidneys showing no calcium oxalate deposits or other abnormalities. PMID- 7855864 TI - Suppressed natural killer cell activity in patients with silicone breast implants: reversal upon explantation. AB - We have previously shown that natural killer (NK) cell activity is significantly suppressed in patients with silicone breast implants. These patients were symptomatic and the suppression of natural killer cell activity was associated with additional significant immunological abnormalities (Vojdani et al., 1992a). Our studies have recently been confirmed by Smith et al. (1994), who described natural killer cell activity suppression following exposure to silicone gel, and reversal upon removal of the gel. This study has been designed to evaluate natural killer cell activities in symptomatic women with silicone breast implants and again after explantation of the implants. Each patient served as her own control. Our findings show a marked significant increase in previously suppressed natural killer cell activity in 50% of the patients. In the other 50%, no change or suppressed NK activity was observed. These findings are compatible with recent studies in experimental animals, which show that administration of silicone reduces natural killer cell activity, and that this is reversible upon removal of the silicone. Since NK cells are important in the control of tumor cell growth, we propose here that patients with reduced NK cell activity are at a higher risk of developing cancer, a concept recently described in experimental animals (Potter et al., 1994; Salhon et al., 1994). PMID- 7855866 TI - Structure-activity relationships of chemicals causing endocrine, reproductive, neurotoxic, and oncogenic effects--a public health problem. PMID- 7855865 TI - Effect of subacute toluene administration on the enkephalinergic neuromodulatory system in rats and protective action of ganglioside treatments. AB - Gangliosides perform protective functions in the central nervous system. This paper describes a study of the effect of ganglioside administration on toluene neurotoxicity. Rat brain met-enkephalin immunostaining in the central amygdaloid nuclei showed changes in rats treated simultaneously with gangliosides and toluene with respect to rats treated with toluene alone. It is suggested that gangliosides prevent toluene neurotoxicity at this level, leading to hypothetical neurobehavioral changes. PMID- 7855868 TI - Heavy metals and the mammalian thymus: in vivo and in vitro investigations. AB - This experiment was performed to investigate changes in the thymus of Wistar strain male rats administered cadmium chloride (CdCl2), mercuric chloride (HgCl2), and lead chloride (PbCl2) salts. The study involved measurement of: 1) deoxyribonucleic acid (DNA) content; 2) ascorbic acid (vitamin C) content; 3) incorporation of 3h-thymidine during in-vitro investigation; and 4) histological and morphological changes. It was shown in investigations on DNA content that administration of heavy metal salts caused an average 76% decrease in DNA content compared to the control. Moreover, in the thymus of experimental animals, an average 69% decrease in vitamin C content was recorded. In in vitro cultures, heavy metal salts decreased the incorporation of 3H-thymidine in thymic cells. PMID- 7855867 TI - Modulative effects of metabolic effectors on benzo(a)pyrene-induced cytotoxicity and mutagenicity in mammalian cells. AB - Conjugation and detoxification of mixed function oxidase (MFO)-mediated benzo(a)pyrene [B(a)P] metabolites with glucuronic acid and glutathione (GSH) are major pathways of B(a)P elimination and ultimately excretion in vivo. We have studied the effects of uridine diphosphate alpha-D-glucuronic acid (UDPGA) and GSH, a cofactor for the synthesis of glucuronide and GSH conjugates, respectively, on B(a)P-induced cytotoxicity and mutagenicity in mammalian cells. The S9-mix used in the Chinese hamster ovary cell/hypoxanthine-guanine phosphoribosyltransferase (CHO/HPRT) mutational assay was supplemented with either UDPGA, GSH, or GSH plus purified GSH-S-transferases (GSHTs), to study modulation of glucuronide and GSH detoxification mechanisms on B(a)P-induced cytotoxic and mutagenic effects. We found that the addition of UDPGA to S9-mix reduces cytotoxicity induced by either B(a)P or B(a)P 6-OH but not by B(a)P 7,8 diol [B(a)P-diol]. The reduction of B(a)P and B(a)P 6-OH-induced cytotoxicity by glucuronide conjugation is likely due to elimination of cytotoxic phenols and quinones. The addition of GSH to the S9-mix resulted in a reduction of B(a)P- and B(a)P-diol-induced cytotoxicity. GSH plus GSHT reduced B(a)P-induced cytotoxicity and mutagenicity. GSH inhibited the mutagenicity at low concentrations of B(a)P diol. GSH plus GSHTs inhibited the cytotoxicity and mutagenicity of B(a)P-diol at concentrations not affected by GSH alone. These studies demonstrate that mechanisms of detoxification can affect the biological activity of B(a)P and B(a)P-diol as profoundly as bioactivation by the MFO system. Future research should address studies of mutagenicity modulation by metabolic effectors at both the molecular (DNA sequence) and cellular (quantitative mutagenesis) level. PMID- 7855869 TI - A review of the carcinogenicity of chemicals most frequently found at National Priorities List sites. AB - Several studies have shown that numerous National Priorities List (NPL) sites have been contaminated with arsenic (747), cadmium (791), chloroform (596), or nickel (664). The National Toxicology Program (NTP, 1991) has classified these substances as known human carcinogens (arsenic and certain arsenic compounds) or as substances that may reasonably be anticipated to be carcinogens (cadmium and certain cadmium compounds, chloroform, and nickel and certain nickel compounds). The general population is probably exposed to low levels of these hazardous substances through drinking water, eating food, or inhaling contaminated air. People working or living near industries and facilities that manufacture and use chloroform, nickel, arsenic, or cadmium may be exposed to higher than background levels of these hazardous substances. Multiple pathways of exposure may exist for populations near hazardous waste sites. For example, high levels of chloroform (1,890 ppb) were found in well water near a waste site; high levels of cadmium exposure may exist for individuals living near cadmium-contaminated waste sites. PMID- 7855870 TI - Inhalation toxicity study of methanol, toluene, and methanol/toluene mixtures in rats: effects of 28-day exposure. AB - The inhalation toxicity of methanol and toluene was investigated in rats. Young Sprague Dawley rats of both sexes were exposed to vapors of methanol (300 ppm, 3000 ppm), toluene (30 ppm, 300 ppm) or methanol/toluene (300/30 ppm, 300/300 ppm, 3000/30 ppm, and 3000/300 ppm) six hrs per day, five days/week for four weeks. Control animals inhaled air only. Increased serum alkaline phosphatase activity was observed in males exposed to high-dose toluene, and decreased creatinine was noted in the group exposed to high-dose methanol/toluene. The thyroid gland in females appeared to be a target organ for inhaled methanol, toluene, and methanol/toluene, although the changes were confined to a mild, and occasionally moderate, reduction in follicle size. Histopathological changes of the nasal passages, consisting of subepithelial nonsuppurative inflammation, occurred in higher incidences in rats exposed to methanol/toluene than in those exposed to the individual vapors. Inhalation of methanol, toluene, or methanol/toluene produced no changes in liver weights, hepatic mixed-function oxidases, or serum aspartate transaminase activities, and onlly minimal changes in liver histopathology. The only liver changes were decreased liver weight and increased cytoplasmic density of the periportal areas in females exposed to high dose methanol/toluene. These data indicated that exposure to methanol, toluene, or a mixture of both produced mild biochemical effects and histological changes in the thyroid and nasal passage. No apparent interactive effects were observed. PMID- 7855871 TI - Intracellular lipid distribution, transport, and sorting. A cell biologist's need for physicochemical information. PMID- 7855872 TI - Differential scanning and dynamic calorimetric studies of cooperative phase transitions in phospholipid bilayer membranes. PMID- 7855873 TI - Ektacytometry of red cells. PMID- 7855874 TI - Spin-label ESR study of molecular dynamics of lipid/protein association in membranes. PMID- 7855875 TI - NMR methods for measuring membrane transport. PMID- 7855876 TI - Biophysical characterization of membrane and cytoskeletal proteins by sedimentation analysis. PMID- 7855877 TI - Determination of soluble and membrane protein structure by Fourier transform infrared spectroscopy. I. Assignments and model compounds. PMID- 7855878 TI - Determination of soluble and membrane protein structure by Fourier transform infrared spectroscopy. II. Experimental aspects, side chain structure, and H/D exchange. PMID- 7855879 TI - Determination of soluble and membrane protein structure by Fourier transform infrared spectroscopy. III. Secondary structures. PMID- 7855881 TI - Monomolecular layers in the study of biomembranes. PMID- 7855882 TI - The growth of research on protein phosphorylation. PMID- 7855880 TI - X-ray diffraction on biomembranes with emphasis on lipid moiety. PMID- 7855883 TI - Substrate and pseudosubstrate interactions with protein kinases: determinants of specificity. AB - Protein crystallography has revealed that protein kinases have extended protein substrate-binding grooves associated with their active sites. Some protein kinases are autoinhibited by a mechanism in which part of their structure, termed a pseudosubstrate, occupies the active site. Substrates and pseudosubstrates occupy overlapping regions within the extended substrate-binding groove, making multiple specific electrostatic and non-polar contacts. With masterly economy, Nature has exploited the active site in many protein kinases to both recognize substrates with great specificity and autoregulate by remaining inactive until the appropriate activation signal is received. PMID- 7855884 TI - Inhibitors of protein kinases and phosphatases. AB - Inhibitors of eukaryotic protein kinases and phosphatases are a chemically diverse array of natural and synthetic compounds, including medicines, potions and poisons. These substances are valuable pharmacological probes and affinity ligands for the kinases and phosphatases of signalling pathways, enhancing our knowledge of the cellular effects of the pathway in question. More broadly, this basic research is also leading to the development of drugs to control specific cellular responses, and enzyme-based assays to detect toxins in food and water. PMID- 7855886 TI - SH2 and SH3 domains as molecular adhesives: the interactions of Crk and Abl. AB - The Src homology domains SH2 and SH3 are modular components present in many signal transduction proteins. They allow rapid formation of stable protein complexes and may also regulate protein function through intramolecular binding events. SH2 domains recognize phosphotyrosyl residues in a specific sequence context, while SH3 domains recognize a PxxP motif and additional residues that mediate binding specificity. PMID- 7855885 TI - Spatiotemporal distribution of protein kinase and phosphatase activities. AB - Reversible protein phosphorylation plays an essential role in controlling cellular functions. Accumulating evidence indicates that the subcellular distribution of protein kinase and phosphatase activities is organized dynamically. The spatiotemporal dynamics of kinase and phosphatase activities appears to account for the elaborate coordination of the cellular functions achieved by protein phosphorylation and dephosphorylation. PMID- 7855887 TI - Regulation of signal transduction and signal diversity by receptor oligomerization. AB - Receptor oligomerization was initially proposed as a mechanism by which epidermal growth factor activates the protein tyrosine kinase activity of its receptor. It is now well established that ligand-induced receptor oligomerization plays an important role in transmembrane signaling by a large number of receptors for hormones, cytokines and growth factors. Heterodimerization of the extracellular domains of two members of the same receptor family, or interaction with an accessory molecule, can increase the diversity of ligands recognized by individual receptors. Heterodimerization of cytoplasmic domains permits the recruitment of different complements of SH2-domain-containing signaling molecules, increasing the repertoire of signaling pathways that can be activated by a given receptor. PMID- 7855888 TI - Regulation of protein tyrosine kinases in platelets. AB - Platelet activation is accompanied by a dramatic increase in tyrosine phosphorylation of many cellular proteins. Phosphorylation of these proteins occurs in successive waves during the activation process, suggesting that several distinct mechanisms, occurring in a temporal order, regulate protein tyrosine kinases and/or phosphatases in activated platelets. Several tyrosine kinases, including Src family kinases, Syk and FAK, have been implicated in these phosphorylation events. These kinases are regulated by distinct receptor-mediated events involving activation of their catalytic activity and alterations in their cellular localization. PMID- 7855889 TI - MAPKs: new JNK expands the group. AB - Mitogen-activated protein kinases (MAPKs) are activated by dual phosphorylation on threonine and tyrosine in response to a wide array of extracellular stimuli. In the yeast Saccharomyces cerevisiae, a series of extracellular stimuli. In the yeast Saccharomyces cerevisiae, a series of MAPK signal transduction pathways have been demonstrated to control many cellular functions. By contrast, mammalian MAPKs are more poorly understood. However, recent studies have established important roles for three separate groups of mammalian MAPKs, which are characterized by distinct dual phosphorylation motifs. Together, these protein kinases mediate signal transduction in mammalian tissues and control many aspects of cellular physiology. PMID- 7855892 TI - Histidine and aspartate phosphorylation: two-component systems and the limits of homology. AB - Autophosphorylating histidine kinase and response-regulator domains constitute the building blocks of two-component signaling systems. These systems use a unique phosphotransfer chemistry to regulate many aspects of bacterial physiology. Homologous systems are now being found in eukaryotes. Despite their common mechanism of phosphotransfer, the two-component systems display an extensive diversity in the arrangement of their domains, and flexibility in their roles in different signal transduction circuits. PMID- 7855890 TI - The ins and outs of Raf kinases. AB - Raf kinases are signal-integrating enzymes that have the ability to switch tyrosine kinase signalling to serine/threonine phosphorylation and connect growth factor receptors with transcription factors. The connection involves a cascade of protein kinases that is essential for cellular proliferation and differentiation of species ranging from worms to humans. This cascade also mediates transformation by most oncogenes. PMID- 7855891 TI - The coordinated action of protein tyrosine phosphatases and kinases in cell signaling. AB - The levels of tyrosine phosphorylation required for cell growth and differentiation are achieved through the coordinated action of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Depending upon the cellular context, these two types of enzymes may either antagonize or cooperate with each other during the signal transmission process. An imbalance between these enzymes may impair normal cell growth, leading to cellular transformation. Both PTKs and PTPs have evolved to a level of structural diversity that allows them to regulate many cellular processes. This review will focus on several specific examples that highlight the interplay between PTPs and PTKs in cell signaling. PMID- 7855894 TI - The function(s) of CAK, the p34cdc2-activating kinase. AB - The protein kinase p34cdc2 plays a central role in controlling the G2 to mitosis transition in all eukaryotic cells. It is regulated by protein-protein association and by multiple phosphorylations; one of these phosphorylations is absolutely required for activity. Until recently, the molecular identity of the protein kinase that phosphorylates this site was unknown. The subunits of this enzyme have been identified recently as p40MO15, the catalytic subunit, and cyclin H, a regulatory subunit. Similarities between this kinase and the p34cdc2 family of protein kinases suggest how p40MO15 itself may be regulated. PMID- 7855893 TI - eIF-2 kinases: regulators of general and gene-specific translation initiation. AB - Phosphorylation of eukaryotic initiation factor-2 (eIF-2) is an important mechanism regulating general translation initiation. Two mammalian eIF-2 kinases, the double-stranded-RNA-dependent kinase (PKR) and heme-regulated inhibitor kinase (HRI), have been characterized by sequencing, revealing shared sequence and structural features distinct from other eukaryotic protein kinases. Recent work in yeast has shown that a third related kinase, GCN2, also phosphorylates the regulated site in eIF-2. However, unlike the mammalian kinases, this kinase regulates gene-specific translation. Current models are presented for the regulation of each eIF-2 kinase, and the molecular basis for how this general form of regulation is adapted to control expression of a single species of messenger RNA is discussed. PMID- 7855895 TI - Protein kinases and DNA damage. AB - Failure to remove DNA damage is potentially lethal. Eukaryotic cells have therefore devised highly effective ways of detecting and repairing DNA lesions. Recent evidence indicates that protein kinases play essential roles in recognizing DNA damage and in transducing DNA damage signals to bring about changes in cellular metabolism that facilitate DNA repair. PMID- 7855897 TI - Signal transduction in the early Drosophila embryo: when genetics meets biochemistry. AB - An elegant combination of genetic and biochemical approaches has been used to investigate a variety of signal transduction pathways in developmental processes. Here, we describe the 'terminal' signaling system in the Drosophila embryo, which is responsible for pattern formation in the polar regions of the embryo. This pathway involves a membrane-bound receptor tyrosine kinase (RTK) that is similar to other Drosophila RTKs, such as sevenless, and the mammalian RTKs, such as the epidermal growth factor or platelet-derived growth factor receptors. PMID- 7855896 TI - The multifunctional TFIIH complex and transcriptional control. AB - RNA polymerase II (Pol II) requires seven general transcription factors (GTFs) and ATP for transcription initiation. Transcription factor IIH (TFIIH) has emerged as the sole GTF with enzymatic activity. In addition to its essential role in transcription initiation, recent studies have demonstrated a direct involvement of TFIIH in DNA excision repair processes. The enzymatic properties and functional duality of TFIIH make it a prime target for regulation by viral and cellular factors. PMID- 7855898 TI - New directions in adrenoceptor pharmacology. PMID- 7855899 TI - The teaching of pharmacology: needs, challenges and responses for the future. PMID- 7855900 TI - Anilide tertiary carbinols: a novel series of K+ channel openers. PMID- 7855901 TI - The development of gastrointestinal-sparing nonsteroidal anti-inflammatory drugs. PMID- 7855902 TI - Muscarinic acetylcholine receptors and control of smooth muscle tone. PMID- 7855903 TI - On the definition of efficacy. PMID- 7855904 TI - Comments from chairs of institutes of clinical pharmacology in Germany. PMID- 7855905 TI - Comments from the Association of German Clinical Pharmacologists. PMID- 7855906 TI - Calpain inhibition: an overview of its therapeutic potential. AB - Increasing evidence now suggests that excessive activation of the Ca(2+) dependent protease calpain could play a key or contributory role in the pathology of a variety of disorders, including cerebral ischaemia, cataract, myocardial ischaemia, muscular dystrophy and platelet aggregation. In this review, Kevin Wang and Po-Wai Yuen discuss the evidence linking these disorders to calpain overactivation. At present, it is difficult to confirm the exact role of calpain in these disorders because of the lack of potent, selective and cell-permeable calpain inhibitors. However, given the multiple therapeutic indications for calpain, it appears that achievement of selective calpain inhibition is an important pharmacological goal. PMID- 7855907 TI - Non-opioid effects of dynorphins: possible role of the NMDA receptor. AB - Dynorphin A (dynA) and related opioid peptides produce moderate analgesic effects with restricted types of pain stimuli that are often accompanied by a large variety of naloxone-insensitive biochemical and behavioural effects. In binding assays in vitro, dynA possesses a high affinity for mu-, delta- and kappa- opioid receptors with some selectivity for kappa sites, but it also binds to specific non-opioid sites. The involvement of the NMDA receptor has been suggested to explain some of the non-opioid effects of dynA and related peptides. In this article, Vijay Shukla and Simon Lemaire review the experimental evidence that suggests a role for the NMDA receptor in some of the pharmacological effects of dynA and related peptides. PMID- 7855908 TI - Toxins from mamba venoms: small proteins with selectivities for different subtypes of muscarinic acetylcholine receptors. AB - Muscarinic acetylcholine receptors exist as five subtypes that are widely distributed throughout the body. Conventional pharmacological agents are not highly selective for particular subtypes, making investigations on the functional significance of the subtypes difficult. Recent findings indicate that mamba snake venoms contain several small proteins ('muscarinic toxins') that are highly specific for muscarinic receptors, and are discussed in this review by Diana Jerusalinsky and Alan Harvey. Some of these toxins act selectively and irreversibly on individual subtypes of receptor, and some are antagonists, while others activate muscarinic receptors. The toxins should be useful tools in studies of the functions of individual receptor subtypes, and comparisons of their three-dimensional structures should give clues about how selective binding to muscarinic receptor subtypes can be obtained. PMID- 7855909 TI - New developments and old problems. PMID- 7855910 TI - Tuberculosis in Africa--any news? AB - The tuberculosis situation in Africa in the AIDS era has become bleak. The tuberculosis incidence has increased in most sub-Saharan African countries, diagnosis has become more difficult, response to treatment, though initially good, is eventually less effective, and patient compliance, which has been a major problem in tuberculosis control before the HIV epidemic, has now become even more difficult. BCG vaccination, already ineffective before the AIDS era in preventing tuberculosis transmission, is now even less an appropriate tool in tuberculosis control. During a four year stay in Agogo Hospital, Ashanti, Ghana, the author has conducted some studies on tuberculosis and Buruli ulcer, which were combined in an academic thesis, and which are briefly summarized in this review. Immunotherapy using a heat-killed strain of Mycobacterium vaccae may bring about a change in future management of tuberculosis and other mycobacterial infections, but further studies are warranted to confirm a promising impression. PMID- 7855911 TI - Development of a serological test for tuberculosis. Problems and potential. AB - The secreted antigens of 24K and 38K and the hsp of 12K and 16K are valuable as reagents in a serodiagnostic assay for tuberculosis. A combination of the TB72 assay with either the 16K or 24K antigen gives the best sensitivity and specificity. Antigens isolated from mycobacterial cultures are valuable in a serological test. Peptides cannot be used as antigens. The value of antigens obtained with recombinant DNA techniques remains to be determined. In HIV seronegative patients with TB serodiagnosis is a valuable test both in pulmonary and extrapulmonary TB. Unfortunately, the results in HIV-seropositive patients are rather disappointing. The use of likelihood ratios seems to increase the potential of serodiagnostic assays. The value of serodiagnosis should be judged in context with other diagnostic methods such as direct microscopy, bacteriological culture or skin tests. A serological test is especially valuable in cases where direct microscopy, polymerase chain reaction or skin testing is negative and allows antituberculous therapy to be started before results of culture are known. PMID- 7855912 TI - Abnormal calcium and vitamin D metabolism in tuberculosis. AB - A variety of abnormalities in calcium and vitamin D metabolism have been reported in patients with active tuberculosis (TB), including hypercalcaemia, hypercalciuria and increased sensitivity to vitamin D. In this article, the frequency and nature of these abnormalities and the importance of extrarenal 1,25(OH)2D production are discussed. PMID- 7855913 TI - Chest radiography and beta-2-microglobulin levels in HIV-seronegative and HIV seropositive African patients with pulmonary tuberculosis. AB - To examine the relationship between radiographic features, serum beta-2 microglobulin (beta-2-M) levels, results of sputum-smear microscopy and outcome, we performed a retrospective study of 99 HIV-seropositive and 162 HIV seronegative patients with pulmonary tuberculosis (TB) in Dar es Salaam, Tanzania. Radiographic features of primary TB were more common and features of postprimary TB less common in HIV-seropositive compared to seronegative patients (50% vs 31%, p < 0.002; and 40% vs 63%, p < 0.001), respectively). HIV infection had a strong independent effect on the beta-2-M levels. Among HIV-infected patients radiographic findings of primary TB were significantly more often associated with beta-2-M levels of > 4 mg/l than features of postprimary TB (71.1% vs 44.4%, p < 0.02). In patients with features of postprimary TB, acid fast bacilli were more often detected in sputum smears than in patients with primary TB (65% vs 47%, p > 0.05, in HIV-seropositive patients; and 63% vs 31%, p < 0.001) in seronegative patients). The observed mortality was too low to identify radiographic predictors of survival. We conclude that HIV-infected patients with features of primary pulmonary TB are likely in an advanced stage of HIV infection and deserve close supervision during anti-tuberculous therapy. PMID- 7855914 TI - Diagnosis of tuberculous lymphadenitis in an area of HIV infection and limited diagnostic facilities. AB - In order to evaluate procedures leading to the diagnosis of tuberculous lymphadenitis, a prospective clinical study was carried out of patients with lymphadenopathy admitted to the medical wards of a referral hospital in Tanzania. The yield of diagnostic procedures (direct auramine/Ziehl-Neelsen (ZN) stained smears, Lowenstein-Jensen (LJ) cultures, cytology and histological examinations of fine needle aspirations (FNA) and biopsy material of lymph nodes, respectively, was compared. We also tried to identify clinical diagnostic markers. One hundred and twenty-eight (99 HIV-seropositive) patients were included. In 89 (67 HIV-positive) patients TB lymphadenitis could be proven. Histology and LJ culture of a lymph node biopsy had the highest diagnostic yield, 85% and 88% respectively, followed by detection of acid-fast bacilli (AFB) in biopsy smear (53%) and in fine-needle aspirations (35%). The diagnostic yield of the several procedures was not affected by associated HIV infection. Macroscopic caseation was 100% predictive for TB with a sensitivity of 69%. Firm and matted lymph nodes, ESR > 100 mm/hr, a positive PPD skin test and pleural opacity on a chest x-ray proved to be independent predictors for TB. Retrospective testing of a stepwise diagnostic approach based on direct smears of FNA, macroscopic visible caseation and direct smear of biopsy tissue, suggests that in 93% of the patients a definite diagnosis of TB lymphadenitis could have been made. Our data suggest that in HIV/TB epidemic areas most of the cases of TB lymphadenitis can be diagnosed correctly by simple and cheap methods which are generally available at district hospitals. Our findings need further prospective validation, however. PMID- 7855916 TI - Tuberculous pleural effusion in the eastern province of Saudi Arabia. AB - The incidence and clinical pattern of tuberculous pleural effusion (TPE) and the contribution of individual laboratory procedures in the diagnosis of TPE were assessed in a five year prospective study. Two hundred and fifty-three patients presenting in three participating hospitals with pleural effusion (PE) were assessed clinically and had various laboratory investigations. Eighty-nine (35.2%) of them, including 73 (82%) men and 31 (34.8%) Saudis had TPE. Their mean age +/- SD was 33.4 +/- 11.2 years. Main symptoms in rank order were cough (80%), fever (75%), shortness of breath (64%), chest pain (61%), anorexia and weight loss (47%). PPD was positive in 82 (92%) patients. Positive culture or histological evidence of tuberculosis (TB) was observed in pleural biopsy (68.5%), pleural fluid (10%) and sputum (2%). Pleural fluid microscopy was positive in only one patient, chest radiological features of TB in 3 (3.4%). Six months anti-TB therapy resulted in complete recovery in 86 patients. It is concluded that in this community TPE constitutes over a third of all the causes of PE. The relatively young age of patients reflects the age structure of the indigenous population as well as immigrant workers. PPD, histology and culture of pleural biopsy were the most useful diagnostic tools while pleural fluid and sputum microscopy were unhelpful. The 6-months anti-TB therapy was excellent. PMID- 7855915 TI - Diagnosis of tuberculosis in patients with pleural effusion in an area of HIV infection and limited diagnostic facilities. AB - In a prospective study of 118 patients with pleural effusion, tuberculosis (TB) was diagnosed in 112. In 84 patients the diagnosis of TB was made by detection of acid-fast bacilli by stain (auramine, Ziehl-Neelsen) or by culture of mycobacteria (Lowenstein-Jensen medium) in pleural fluid or pleural tissue (obtained by closed biopsy) or by the presence of caseating granulomas in histological sections. In 28 patients the diagnosis of TB was considered probable, based on good response to anti-tuberculous therapy. The highest diagnostic yield was obtained by histology (85%), followed by culture of pleural biopsy (37%) and pleural fluid culture (36%). Pulmonary tuberculosis was found in 8 patients and dissemination of TB to other sites in 25 patients of whom 20 were HIV positive. By logistic regression analysis we identified 2 independent diagnostic markers for TB pleuritis: pleural fluid protein > 50 g/l (Odds ratio 12.1, 95% confidence interval (CI): 1.1-128.3) and adenosine deaminase of > 10 U/l (Odds ratio 11.08, 95% CI: 1.3-96.4). We conclude that conventional facilities of a referral hospital are sufficient to diagnose tuberculous pleuritis as well as disseminated tuberculosis irrespective of HIV infection. However, for regions with overstretched health services and high prevalences of tuberculous pleurisy in patients with pleural effusion we suggest a simplified diagnostic approach based on exclusion of other causes of pleural effusion by simple means and use of these diagnostic markers. PMID- 7855917 TI - Maternal mortality in southern India. AB - In a 4 year prospective community survey of 20,000 women randomly selected in North Arcot District of Tamil Nadu State in South India, the maternal mortality rates per 1,000 liveborn were estimated to be 17.4 and 16.6 for rural and semi urban areas, respectively. The rates based only on direct causes were 11.9 in rural and 14.4 in semi-urban areas. As expected, these figures are considerably higher than those based on official or hospital statistics. Factors associated with such high mortality and the implications for programme planning and implementation are discussed. PMID- 7855918 TI - Community-based surveillance of paediatric deaths in Cross River State, Nigeria. AB - A house-to-house survey of paediatric deaths which occurred from January to December 1991 in the village of Nko, Cross River State, Nigeria, was carried out. Among the 471 total deaths recorded, the leading causes were malaria (29%), protein-energy malnutrition, pneumonia and diarrhoeal disease (11% each). Neonatal deaths were largely due to septicaemia, tetanus and birth asphyxia. Poor domestic and human waste disposal, lack of portable water and basic health facilities appear to be the important related factors to child health problems in this community. The provision of public toilets, safe water, primary health care centres and health education can definitely improve the health status of this rural community. Events in other rural communities in Nigeria are most likely to be similar to that in Nko. Such populations need to be identified and their problems urgently addressed. PMID- 7855919 TI - Infant-feeding practices in urban and rural communities of the Sudan. AB - Infant-feeding and weaning practices were investigated in a multistage randomly selected sample of 1,039 Sudanese mothers who represented six of the nine States of the Sudan. The majority (77.9%) believed that breast milk was best for their babies, emphasizing the previously reported high breast-feeding rate in Sudanese mothers. Food supplementation started by 6 months in 82.5% mainly in urban middle and high classes (UMC and UHC) compared to urban poor class (UPC) and the rural group (RG; p < 0.001). A mixture of food items was used for supplementation by 62.1% of the study group, whereas giving one food item was significantly more practised in RG (54.9%) compared to others (p < 0.001). Household food was introduced by 6 months in 35.4%. Weaning started between 6 and 12 months in 27.1% and thereafter in 64.9%. A greater proportion of rural mothers (36.5%) weaned their babies after the age of 18 months (p < 0.001). About half the children (52.8%) were weaned abruptly, mainly among UPC and RG. The first food item of choice for weaning was fresh goat's or cow's milk (77.6%), followed by powdered or formula milk (16.1%). The commonest second preferred food was a starch gruel (39.1%) made either of rice (24.5%) or fermented sorghum. PMID- 7855920 TI - Survival chances of low birth weight infants in a rural hospital in Ghana. AB - The birthweight and mortality in hospital was recorded of 567 low birth weight (LBW, < or = 2000 g) infants born/admitted during a 7 years period in Agogo Hospital situated in the rainforest area of Ghana. One hundred and fifty-two (26.8%) of these children died in hospital; 87 (57%) of them in the first 48 hours. The average length of stay in hospital of the surviving children was 11.6 days. The death rate varied from 8.4% in the 1,751 to 2,000 g group to 83.3% in infants with a birth weight < or = 1000 g. The proportion LBW children to the total newborn population was 5.5%; the proportion of extreme LBW (< or = 1000 g) to the total number LBW infants was 7.3%. The results are compared with figures from other countries, many of them with a more westernized infrastructure. In our setting, no sophisticated equipment and expensive intensive care provisions were available. This descriptive study was carried out to establish the survival rate in the neonatal period during the primary stay in hospital with low-cost conservative care. Dedicated staff members, who underwent only a simple training programme, and mothers participating in the care for their children contributed to the relatively favourable outcome. PMID- 7855922 TI - Detrimental effects of onchocerciasis on marriage age and breast-feeding. AB - This paper examines the extent to which onchocercal skin lesions affect the age at marriage and the duration of lactation among infected women in forest areas of Nigeria. In a retrospective study, 145 multiparous women were asked about their breast-feeding behaviour. Ninety-seven per cent routinely breast-fed after delivery, although the duration of lactation for 75 infected and 70 non-infected women was different. Of the 75 women with Onchocerca volvulus infection, 73% experienced itching during breast-feeding; 26% breast-fed for not more than 3 months compared to 2.1% of non-infected women who breast-fed for the same period (p < 0.005). A multiple regression model showed severity of onchocercal lesions as an independent predictor of shorter duration of lactation for women with O. volvulus infection. Duration of breast-feeding was reduced by more than 9 months for 6 (25%) out of 24 infected women who breast-fed infants before and after the onset of itching from lesions. Also, while the minimum age at marriage was 9 years for non-infected women, it was 17 years for women whose lesions appeared before marriage. This preliminary study suggest that incessant itching and severe onchocerciasis lesions may be important predictors of failure of women to breast feed for longer periods in rain-forest areas of Nigeria. PMID- 7855921 TI - Newborn's arm circumference as a screening tool of low birth weight in Temeke District, Dar es Salaam, Tanzania. AB - To determine the extent to which newborn's mid-upper-arm circumference (MUAC) could be used as a screening tool for low birth weight (LBW), we examined a total of 601 full-term singleton babies delivered at Temeke District Hospital in Dar es Salaam, Tanzania, between January and April 1992. The mean birth weight and standard deviation (SD) was 2826 (+/- 436) g and the MUAC (SD) 9.9 (+/- 0.8) cm with a correlation coefficient of 0.88 between MUAC and birth weight (p = 0.0001). The percentage of LBW (< 2500 g) and an arm circumference below 9.5 cm were 18.8% and 11.8%, respectively. Use of 9.5 cm measurement as a cut-off point in MUAC was found to be a significant predictor of low birth weight. The sensitivity, specificity and positive predictive value were 57.5%, 98.8% and 91.6%, respectively. Newborns with a mid-upper-arm circumference < 9.5 cm were 10 times more likely to have a LBW compared with an arm circumference > or = 9.5 cm (p = 0.0001). In places where the conventional scales are not readily available MUAC of 9.5 cm could be used as a method to screen LBW babies in Tanzania. Significant maternal factors associated with LBW at the first antenatal clinic (ANC) booking included: weight < 43.5 kg, height < 150 cm, age of 14 to 19 years, positive malaria parasitemia and previous history of LBW. It is recommended that subjects with the above risk factors at ANC booking should be advised to deliver in hospital. PMID- 7855923 TI - Serodifferentiation of human fascioliasis from schistosomiasis. AB - A dot enzyme-linked immunosorbent assay (dot-ELISA) was developed using excretory secretory (ES) antigens of Fasciola gigantica adult worms and freeze-thaw antigen (AFT) of adult Schistosoma mansoni worms. Specific IgG and IgM antibodies were simultaneously investigated in sera from 17 febrile eosinophilic hospitalized patients and 20 healthy controls. Dot-ELISA was shown useful and could differentiate fascioliasis from schistosomiasis prior to parasite egg detection in patient's stool. This assay is field and laboratory applicable. PMID- 7855924 TI - Comparisons of monkeypox viruses from animal and human infections in Zaire. PMID- 7855925 TI - Serological tests for Lyme disease in patients with tropical spastic paraparesis and healthy Jamaicans. AB - The significance of reactive serological tests for Lyme disease in patients with tropical spastic paraparesis (TSP) was assessed by examining serum samples from 128 of these patients and 200 healthy Jamaicans by Lyme indirect immunofluorescent antibody (IFA), enzyme immuno-assay (EIA) and Western blot analyses. Sera were also examined in serological tests for syphilis (STS), an unabsorbed fluorescent treponemal antibody test and leptospira microagglutination test. The prevalence of positive Lyme IFA and EIA results did not differ significantly between sera from TSP patients (12.5%) and healthy controls (10.0%). Western blot analyses showed that the positive Lyme IFA and EIA results observed in this study were due to false positive reactions. Seventy-five per cent of Lyme IFA/EIS positive sera from TSP patients had treponemal antibodies. Eighty per cent of those from healthy controls were negative in standard STS but 85% were positive when tested in an unabsorbed fluorescent treponemal antibody (FTA). These data indicate that reactive serological tests for Lyme disease in Jamaican TSP patients and healthy Jamaicans are false positive reactions due to cross-reactivity with other spirochaetes, notably Treponema pallidum and non pathogenic treponemes. PMID- 7855926 TI - The absence of schistosomiasis mansoni and of the intermediate hosts in Guyana was noted. PMID- 7855927 TI - Intertubular capillary changes in the cortex and medulla of transplanted kidneys and their relationship with transplant glomerulopathy: an ultrastructural study of 12 transplantectomies. AB - Twelve kidney allografts removed 3 to 98 months (mean, 44.8 months) after transplantation were investigated. The presence and severity of intertubular capillary changes, which were characterized by splitting and multilayering of the basement membrane, were carefully noted. These changes were graded as mild, moderate, and severe according to the number of basement membrane layers. They were found in both cortical and medullary capillaries in all but one kidney and were always associated with transplant glomerulopathy. Ultrastructural changes observed in the glomeruli and capillaries were similar, suggesting that they share the same pathogenetic mechanisms, probably connected to immune-mediated endothelial cell damage. Although glomeruli can be absent in small biopsy specimens, intertubular capillaries are easily detectable. Because capillary changes can be considered a marker of transplant glomerulopathy, which is known to have ominous prognostic significance, the identification of such changes acquires clinical relevance. Electron microscopic investigation is therefore strongly advisable whenever a renal biopsy is performed to identify transplant glomerulopathy. PMID- 7855928 TI - Adenovirus infection of the duodenum in an AIDS patient: an ultrastructural study. AB - Intractable diarrhea in a 40-year-old woman with terminal acquired immunodeficiency syndrome resulted from adenovirus infection of the duodenal mucosa. Electron microscopic examination of a duodenal biopsy specimen performed because of clinical suspicion of cryptosporidiosis or microsporidiosis showed pathognomonic viral particles in the nuclei of mucosal epithelium. Extensive sloughing of damaged mucosal cells may have contributed to the diarrhea, for which no other cause was found during either pathologic or microbiologic analysis. PMID- 7855929 TI - Ultrastructural and immunohistochemical study of salivary duct carcinoma of the parotid gland. AB - A case of salivary duct carcinoma of the parotid gland found in an 81-year-old man was studied by light microscopy, immunohistochemistry, and electron microscopy. Histologically, the tumor was composed of elongated cords of cells and ductal structure with desmoplastic stromal reaction. Tumor cell nests sometimes showed central comedonecrosis. Immunohistochemically, the tumor cells were positive for cytokeratin and epithelial membrane antigen, and they were negative for S-100 protein and muscle-specific actin. Electromicroscopically, two cell types were identified. The first cell type showed electron-lucent cytoplasm with scant organelles. The second type cell contained numerous mitochondria. Neither acinar nor myoepithelial cell differentiation was observed. These findings suggest that salivary duct carcinoma originates from the interlobular or excretory ducts. PMID- 7855930 TI - Giant mitochondria with paracrystalline inclusions in paraganglioma of the urinary bladder: correlation with mitochondrial abnormalities in paragangliomas of other sites. AB - Mitochondrial abnormalities have received relatively little attention in the ultrastructural evaluation of paragangliomas. Review of the few literature references dealing with this issue, however, reveals that quantitative and qualitative changes of these organelles occur in that context. A bladder paraganglioma is described that was characterized by numerous mitochondria, which in addition displayed giant forms along with matrical paracrystalline inclusions. Upon retrospective review of 12 archival cases of paragangliomas, enlarged and structurally abnormal mitochondria were found in all of them. Although various speculations can be made, the mechanism of formation and the pathophysiologic significance of these abnormal mitochondria remain unknown. From a morphologic diagnostic point of view, however, these abnormalities, which in this case of bladder paraganglioma were also light microscopically evident, can be of significant help in establishing the correct diagnosis. PMID- 7855931 TI - Pituitary adenoma with neuronal choristoma (PANCH): composite lesion or lineage infidelity? AB - Fifteen cases of the rare association of pituitary adenoma and neuronal choristoma (PANCH) were investigated by histology, immunohistochemistry, and electron microscopy. Acromegaly was apparent clinically in 11 patients and was equivocal in 1, and 3 lesions appeared to be nonfunctioning. Histology revealed various proportions of chromophobic PA and nervous tissue consisting of neuronlike cells and neuropil. Immunohistochemistry documented growth hormone (GH) in every PA, including those unassociated with clinical acromegaly. In contrast, the NCH component showed no consistent immunohistochemical profile. Most frequent reactivities were for the pituitary hormone alpha subunit, thyroid stimulating hormone, and GH, whereas only a few cases displayed scattered positivity for GH-releasing hormone. Low-molecular weight keratin tested positive in PAs and in a few cells and processes of an NCH. A few fibrous bodies were immunoreactive for neurofilament protein. Electron microscopy revealed sparsely granulated GH cell adenoma, neurons, and neuropil. Cells intermediate between PA and neurons were numerous in 1 lesion. The present morphologic findings as well as lack of GH cell hyperplasia and the consistent association of NCH with but one type of PA do not support the causative role of NCH in the initiation of PA, as proposed previously. It appears that NCH is the result of neuronal differentiation within sparsely granulated GH cell adenomas. PMID- 7855932 TI - Myofilament localization and immunoelectron microscopic detection of muscle specific actin in neoplastic myoepithelial cells in pleomorphic adenomas and myoepitheliomas. AB - Elucidating the cellular characteristics of the nonluminal or myoepithelial cells of pleomorphic adenomas is one approach to establishing the diagnostic criteria for myoepitheliomas. Ultrastructural features of nonluminal tumor cells in 22 pleomorphic adenomas and of tumor cells in 9 myoepitheliomas were assessed from micrographs of routinely fixed and epoxy resin-embedded samples. Recognizable myofilaments were only moderately prominent in 1 myoepithelioma. In the rest of the cases, irrespective of whether nonluminal cells of pleomorphic adenomas or tumor cells of myoepitheliomas were spindle, angular, round, or plasmacytoid in form, myofilaments were noted only in one third of the cases and were present even in these in a small proportion of the tumor cells. Intermediate filament accumulations and basal lamina were more frequent findings associated with nonluminal tumor cells. Six pleomorphic adenomas and 2 myoepitheliomas had been fixed in half-strength glutaraldehyde and embedded in LR White resin for immunoelectron microscopic detection of muscle-specific actin. In 3 (2 pleomorphic adenomas and myoepitheliomas) of these 8 cases, readily visualized bands of filaments in many tumor cells were strongly labeled by the colloidal gold probe detecting muscle-specific actin even when myofilaments were minimal and infrequent in 2 cases and undetectable in the third by routine transmission electron microscopy. Lack of myofilament detection by immunocytochemistry or routine electron microscopy does not exclude a diagnosis of pleomorphic adenoma or myoepithelioma when growth patterns and cytology indicate such diagnoses. Immunoelectron microscopy, in fact, shows that muscle-specific actin can be detected even when myofilaments or muscle actin are apparently absent or minimal by routine electron microscopy or immunohistochemistry, respectively. Because examples of pleomorphic adenoma and myoepithelioma each with similar histologic and cytologic features of the myoepitheliomatous cells can have variable degrees or complete absence of expression of myofilaments or muscle-specific actin, the time-honored term myoepithelial for the nonluminal cells of pleomorphic adenomas and the term myoepithelioma are legitimate even in the absence of those markers that are specific for normal myoepithelial cells. PMID- 7855933 TI - Ossifying fibromyxoid tumor of soft parts with stromal cyst formation and ribosome-lamella complexes. AB - Ossifying fibromyxoid tumor of soft parts (OFMT) is a recently named soft tissue tumor of uncertain nature. A case is described that presented in a 13-year-old boy as a discrete mass in the muscles of the lower abdominal wall. Light microscopy showed, in addition to the typical features of this entity, microcysts formed by accumulations of the myxoid stroma. Bone formation was lacking. Tumor cells were strongly immunoreactive for vimentin and glial fibrillary acidic protein and weakly so for S-100 protein. A few cells stained for desmin and alpha smooth muscle actin. Ultrastructurally, there were abundant, patternless cytoplasmic intermediate filaments; short, poorly interdigitating processes; and discontinuous segments of thick external lamina. In addition, several cells contained typical ribosome-lamella complexes in small groups. Ribosome-lamella complexes occur in neoplastic hematopoietic cells but are uncommon in solid tumors, particularly those affecting the soft tissues. These findings extend the range of appearances described for OFMT, which is added to the list of tumors in which ribosome-lamella complexes have been demonstrated. The balance of evidence suggests that OFMT may represent a peripheral nerve sheath tumor of low-grade malignancy, although the picture is incomplete. PMID- 7855934 TI - Intraductal papilloma of the male breast: an ultrastructural and immunohistochemical study. AB - A case of intraductal papilloma of the male breast was studied by electron microscopy and immunohistochemistry. The major components of this lesion were the epithelial and myoepithelial cells. Intermediate cells showing ultrastructural features of both cell types were also observed. Squamous metaplasia was noted in many areas. Numerous intranuclear helioid inclusions were seen in the tumor cells. The features of this lesion are similar to those of papillomas of the female breast. PMID- 7855935 TI - Strange myelinoid particles in cells near the site of esophageal carcinoma. PMID- 7855936 TI - DNA content and the proliferation marker Ki-67 as prognostic indicators in renal cell carcinoma. AB - Patients suffering from renal cell carcinoma have a generally poor prognosis. Even cases that are clinically in comparable stages can, however, take quite different courses. The basic prognostic factors, histological grade and TNM stage do not do justice to the heterogeneous biological behavior of this tumor entity. In this study, the possible prognostic indicators, DNA content and proliferation rate, assessed with Ki-67, were compared with the histological grade and the TNM stage. Though there was no correlation between the proliferation rate (Ki-67) and the two, there was a significant correlation between DNA content and both histological grade and TNM stage. PMID- 7855937 TI - Staging accuracy of magnetic resonance imaging versus transrectal ultrasound in stages A and B prostatic cancer. AB - The present study was undertaken to compare the ability of magnetic resonance imaging (MRI) and transrectal ultrasound (TRUS) to identify the presence or absence of extracapsular tumor extension and seminal vesicle involvement in patients with clinically localized (stages A and B, T1-T2) prostatic cancer. Sixty-four patients (ages 44-77 years) underwent radical retropubic prostatectomy and pelvic lymphadenectomy after staging with both MRI and TRUS. Surgical specimens were step-sectioned and examined at multiple levels. Radiographic staging was correlated with pathological staging. Both MRI and TRUS demonstrated better staging accuracy than conventional digital rectal examination [42% for digital rectal examination (DRE), 63% by TRUS, and 67% by MRI], although they suffered from understaging (31% by TRUS and 22% by MRI). The positive predictive value (PPV) for stage B disease was disappointingly low (42% for DRE, 53% for TRUS and 59% for MRI). However, the PPV for stage C disease was higher (81% for TRUS and 77% for MRI). In the evaluation of extracapsular invasion, the PPV of TRUS (81%) was higher than that of MRI (77%). The negative predictive value (NPV), however, for both TRUS and MRI was low (58 and 56%, respectively). In the evaluation of seminal vesicle invasion, both TRUS and MRI demonstrated poor PPV (50 and 40%, respectively), but the NPV was excellent (90% for TRUS and 96% for MRI). MRI failed to detect metastatic lymph nodes in 4 of 6 patients while falsely predicting their presence in 4 patients.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7855938 TI - Transurethral 137Cs medium dose rate radiotherapy as a boost for small-sized localized prostatic carcinomas. AB - The aim of this study is to present preliminary experience with 137Cs medium dose rate (MDR) afterloading transurethral radiotherapy for small-sized (< 2.5 cm) prostatic carcinomas. The phase II protocol comprises 46 Gy of external beam radiotherapy, followed by two insertions (1 week apart) of 137Cs MDR transurethral brachytherapy, each one delivering 8 Gy to a point 0.5 cm from the urethral walls. The treatment is completed with a 14-Gy boost to the prostatic area through lateral external beam fields. Up to now, 9 patients have been treated. The transurethral insertion is a simple procedure, requires no anesthesia and the ultrasonographic observation precisely and easily guided the positioning of the applicator. All 9 patients are alive and disease-free 12-36 months after the end of radiotherapy. One of them presented a mild degree of urethral stricture and none developed chronic proctitis or cystitis. Seven patients were sexually potent before radiotherapy and all of them maintained their potency. Transurethral radiotherapy for prostatic carcinoma requires further investigation. The radiation dose that the procedure delivers to the prostate is higher than the one prescribed for external beam irradiation regimens. Rectal and bladder dose is substantially reduced. Although the prostatic urethra receives a higher dose, the incidence of urethral stricture is low probably because of the small tissue volume (8 cm3) in the high radiation dose area. PMID- 7855939 TI - Prostaglandin E1 versus linsidomine chlorhydrate in erectile dysfunction. AB - Recent experimental work has demonstrated that nitric oxide (NO) is the neurotransmitter responsible for cavernous smooth muscle relaxation. Different studies on the performance of the direct NO donor linsidomine chlorhydrate (SIN 1) in patients with erectile dysfunction have had conflicting results. We performed a single-blind cross-over trial in 20 patients with erectile dysfunction of mixed etiology comparing prostaglandin E1 (PGE1) to SIN-1 at two different dosages (1 and 2 mg, respectively) in order to determine the effectiveness of SIN-1. PGE1 always achieved the best response, SIN-1 performed statistically significantly poorer irrespective of the dosage used. There were only a few side effects with no significant difference. SIN-1 is not a useful alternative to PGE1 in the treatment of erectile dysfunction. PMID- 7855940 TI - Chlamydia trachomatis infection in the semen of asymptomatic infertile men: detection of the antigen by in situ hybridization. AB - The prevalence of Chlamydia trachomatis and other microbes was studied in 94 semen samples from asymptomatic infertile males. Simultaneously, we sought evidence for inflammation of the genital tract by determining the polymorphonuclear granulocyte (PMN)-elastase concentration in the seminal plasma. The C. trachomatis genome was detected in 8 cases using in situ hybridization. The antigen, however, was undetectable by enzyme-linked assay (Chlamydiazyme) in the same samples. Ureaplasma urealyticum was isolated from 16 cases. The PMN elastase concentration in the semen positive for the C. trachomatis genome was significantly higher than in C. trachomatis-negative and U. urealyticum-positive cases, but no significant difference was observed between C. trachomatis-negative and U. urealyticum-positive cases. C. trachomatis trachomatis in situ hybridization-positive cases correlated well with C. trachomatis-specific IgA antibody positivity and a PMN-elastase concentration over 250 ng/ml. These findings suggest that in situ hybridization is a reliable method for the detection of C. trachomatis infection and that the presence of C. trachomatis, but not U. urealyticum, in the male genital tract correlated well with evidence of inflammation. PMID- 7855941 TI - Papillary cystadenoma of the epididymis as a cause of obstructive azoospermia. AB - We report a case of infertility due to obstructive azoospermia determined by papillary cystadenoma of the epididymis. The 28-year-old patient had other signs of von Hippel-Lindau syndrome and died from neurological complications. The possibility of finding an epididymal neoplasm should be kept in mind in any case of azoospermia with epididymal enlargement. PMID- 7855942 TI - Lymphocytic infiltration of the prostate presenting as retention. AB - A patient with previously undiagnosed asymptomatic chronic lymphocytic leukaemia presenting with acute on chronic retention is reported. The relevant literature is discussed. PMID- 7855943 TI - Nephrogenic adenoma of the bladder. AB - A nephrogenic adenoma of the bladder in a 4-year-old girl with a past history of urologic surgery for vesicorenal reflux is described. The multifocal tumor was treated by transurethral resection. Relapse occurred 15 months later and was again treated by transurethral resection. Pathological aspects, clinical features and therapeutic considerations of this proliferative lesion are reviewed and discussed. PMID- 7855944 TI - Incidentally detected renal cell carcinoma in patients with other cancers. AB - Widespread imaging of the kidneys as part of an abdominal or abdominopelvic evaluation of other diseases has led to a marked increase in the incidence of serendipitous renal cell carcinoma. These tumors are generally small, of low pathological stage, and carry a better prognosis than symptomatic cancers. This may merely be due to their earlier detection than the usual renal cell carcinoma. The malignant potential of these tumors, however, might still be high. We report 2 cases of incidentally detected renal tumors in patients with other cancers. PMID- 7855945 TI - Imaging of common problems in pediatric urology. AB - Many imaging modalities are available to study children with urologic disorders. Ultrasonography, renal scintigraphy, and voiding cystourethrography are best for study of patients with infection and antenatal hydronephrosis; intravenous urography, for hematuria and wetting; ultrasonography and CT, for tumor; and CT, for trauma. PMID- 7855946 TI - Acute scrotal swelling. AB - Acute scrotal swelling is a potential emergency. The differential diagnosis includes torsion of the testis or one of the testicular appendages, hydrocele, varicocele, trauma, tumor, idiopathic scrotal edema, and Henoch-Schonlein purpura. Imaging studies, such as radionuclide scanning and color Doppler ultrasonography, are helpful in equivocal cases. PMID- 7855947 TI - The undescended testis. Theory and management. AB - Surgical techniques and research efforts to define the pathophysiology of cryptorchid testes have progressed rapidly in recent decades. Medical and surgical treatment modalities have focused on the young patient with an undescended testis. The potential adult complications of cryptorchidism, infertility, and malignancy should not be forgotten or dismissed. PMID- 7855948 TI - Pediatric hernias and hydroceles. The urologist's perspective. AB - Pediatric inguinal hernias and hydroceles are due to incomplete or abnormal obliteration of the processus vaginalis. Surgical correction of these conditions is the most common surgical procedure performed on young children. The embryology, anatomy, evaluation, and management of pediatric inguinal hernias and hydroceles are reviewed. A thorough understanding of these topics will aid with the sometimes difficult decisions encountered in the care of these patients. PMID- 7855949 TI - Distal hypospadias. AB - Distal hypospadias, where the urethral meatus is located subcoronal or more distal, is one of the most common congenital anomalies in males. The embryology and etiology of hypospadias, timing of repair, surgical techniques, anesthesia for and complications of hypospadias repair are reviewed. PMID- 7855950 TI - A perspective on vesicoureteral reflux. AB - Prevention of UTI appears to be the most important way to avoid the serious complications of vesicoureteral reflux, which then requires early recognition, ideally prior to bacterial invasion. With early evaluation of children noted to have dilated collecting systems in utero and the screening of siblings and offspring of those with reflux, this prevention becomes possible. This screening should be performed in the first weeks to months after birth, before the first UTI. The choice of management appears to be less important than control of infection, because the results of both medical and surgical management are equal; however, because mild-to-moderate (grades I-III) reflux is likely to resolve, it seems appropriate to pursue an aggressive nonsurgical course in these patients, at least until some minimally invasive, safe interventional treatment becomes available. If reflux remains severe (grades IV and V) beyond 24 to 48 months of age, surgical intervention appears appropriate because resolution is unlikely, assuming, of course, that an experienced surgeon performs the procedure. As was evident from the European branch of the IRS, renal scarring occurred most frequently in the few patients who had ureteral obstruction after failed surgical correction. In those who continued to have mild reflux beyond 5 to 7 years of age, a trial of medication is justifiable. If infection occurs during that time and reflux persists, correction should be considered for those with clinical or scan-documented pyelonephritis. Patients who have reflux plus bacteriuria present a special problem because it is unclear whether their risks are increased. Finally, we must forewarn all our female patients with UTI in childhood that they are at risk for bacilluria during pregnancy and may require prophylaxis regardless of the state of their reflux at that time. PMID- 7855951 TI - Adolescent varicocele. AB - Currently, we recommend varicocele repair in adolescents when (1) the results of semen analysis are abnormal, (2) the volume of the left testis is at least 3 mL less than that of the right, (3) the response of either luteinizing hormone or FSH to Gn-RH stimulation is supranormal, (4) bilaterally palpable varicoceles are detected, or (5) a large symptomatic varicocele is present. When surgery is necessary, the Palomo approach significantly decreases the risk of operative failure and has facilitated "catch-up" growth of the left testis that is comparable to that after artery-sparing procedures. It is important to note that there is potential for impaired fertility whenever a palpable varicocele is present. Unfortunately, no test or group of tests can predict with absolute certainty whether an adolescent with a varicocele will be fertile or infertile. Therefore, it is important to observe untreated patients until they complete their families. Patients who are unwilling or unable to adhere to the follow-up protocol may be candidates for surgical intervention. PMID- 7855952 TI - Common problems in pediatric gynecology. AB - A knowledge of the special concerns and physiology in pediatric female patients allows the physician to obtain pertinent histories and appropriate examinations. This information permits diagnosis and treatment of sequelae of sexual abuse, common gynecologic infections, and trauma. More complex problems, such as determination of sources of vaginal bleeding and endocrinopathies, also can be evaluated. Finally, benign and malignant conditions affecting the internal and external genitalia may be diagnosed and treated or referred to a subspecialist as needed. PMID- 7855953 TI - Pediatric genitourinary trauma. AB - Trauma is the leading cause of death in children in the United States, and blunt trauma is responsible in most cases. The kidney is the urogenital organ most frequently injured. Renal injuries are classified on a scale of I to V. Only grades IV and V injuries need operative intervention. CT is the preferred diagnostic imaging modality in most instances. Cystography and urethrography are necessary to diagnose bladder and ureteral injuries. Genital injuries sometimes are produced by sexual abuse, and the clinician must be alert to this possibility. PMID- 7855954 TI - Postoperative pain management for pediatric urologic surgery. AB - The issues relating to postoperative pain management for pediatric urologic surgery have been discussed. Child development and the behavioral responses to pain have been reviewed, with emphasis on their relation to pain assessment in the pediatric patient. The benefits and limitations of various modalities for the treatment of postoperative pain have been reviewed, and their appropriate use for different urologic surgical procedures has been presented. PMID- 7855955 TI - Pediatric urology facts and figures. Data useful in the management of pediatric urologic patients. AB - This article includes facts and figures useful in the management of pediatric urologic patients. A formulary of commonly used drugs as well as modified doses for use in renal insufficiency is provided. In addition, data on bowel preparations, vital signs, hypertension, creatinine clearance, Tanner stages, and stretched penile length are provided. PMID- 7855956 TI - Prenatal detection of congenital renal disease. AB - Prenatal ultrasonography can identify not only the structural aspects of many abnormalities of the urinary tract but also associated anomalies, some of which may be missed even after birth. Prenatal imaging alerts physicians to some infants with urinary tract lesions that ordinarily show no physical findings at birth, leading to earlier diagnosis. An early diagnosis may prevent the first urinary tract infection in an infant at risk. In addition, there are fewer hospitalizations for infection or electrolyte abnormalities in infants with urinary tract disease. Elective surgery may be planned instead of performed on an urgent basis and thus can be performed with lower morbidity. Although the early diagnosis and treatment of pediatric renal disease have certainly been facilitated by prenatal ultrasonography, longer follow-up is required to determine whether prenatal detection prevents the onset of chronic renal failure as children with congenital renal disease approach adolescence and adult life. PMID- 7855957 TI - Percutaneous management of upper-tract transitional cell carcinoma. AB - Standard management of upper tract transitional cell carcinoma is a nephroureterectomy; however, there is a distinct subgroup of patients who would be rendered dialysis dependent, or at high risk for functionally significant renal insufficiency, and for whom a nephron-sparing approach is warranted. Historically, the options for such "conservative" management have been limited to variations of open pyelotomy or partial nephrectomy. More recently, endourologic techniques have been applied to the treatment of these difficult patients. Though a ureteroscopic approach can occasionally be therapeutic, it may be precluded by the size or location of the tumor, or by a urinary diversion that makes ureteroscopic access difficult or impossible. Many of these patients can, however, be managed with a well planned percutaneous approach that provides excellent access to virtually the entire upper tract. The subsequent addition of topical BCG as an adjunct to percutaneous upper tract tumor resection may then be beneficial in decreasing the incidence of local recurrence. PMID- 7855958 TI - Hydronephrosis. When is obstruction not obstruction? AB - It once was relatively simple for most urologists to diagnose ureteropelvic junction obstruction, and it was previously axiomatic that obstruction required repair to preserve and maximize renal function. Modern imaging studies have cast doubt on previously held concepts, leaving the clinician with an enigma. Prolonged follow-up of some non-operated cases has demonstrated late deterioration of function, further compounding the diagnostic uncertainty. PMID- 7855959 TI - Hematuria in children. A practical approach. AB - The investigation of hematuria in children should never be allowed to pose a greater risk to the child's health than does the problem itself. For this reason, angiography and cystoscopy are rarely employed in the evaluation. The evaluation of the child should proceed methodically and rest firmly on a well-taken history and results of physical examination. The microscopic examination of the urinary sediment is the cornerstone of the evaluation process and can itself suggest the origin of the hematuria. Red cell casts, if present, indicate glomerulonephritis and obviate further urologic evaluation. Genitourinary imaging should be tailored to each clinical situation. PMID- 7855960 TI - Neonatal circumcision. AB - Circumcision remains the most common operation performed in males in the United States. When performed by an experienced operator, circumcision is usually a safe and simple operation. The medical benefits of circumcision appear to exceed the risks of the procedure. The history, embryology, indications, techniques, and complications of neonatal circumcision are discussed. PMID- 7855961 TI - The management of urinary tract infections in children without urinary tract abnormalities. AB - Although most urinary tract infections in children with normal urinary tract anatomy pose little threat to renal function, pyelonephritis, particularly in infants, may cause renal scarring when not diagnosed and treated promptly. For most children, however, the problems of urinary tract infection may be related to a biologic predisposition to recurrent infections and the bothersome clinical symptoms associated with them. In these children, infections should be diagnosed carefully and then treated for 3 days with appropriate antimicrobial agents. In children with frequently recurrent infections (more than two in 6 months), a prophylactic antimicrobial agent in the proper low dosage may be useful. Children bothered by infection-associated symptoms of bladder dysfunction with persistent incontinence may improve with treatment with anticholinergic drugs and/or bladder rehabilitation. There may also be a decrease in the rate of urinary tract infections with this treatment. When covert bacteriuria is found and bothersome symptoms are associated with it, symptoms should be treated. If recurrent covert bacteriuria is truly asymptomatic, however, not treating the infection may be the best option. PMID- 7855962 TI - Wetting and functional voiding disorders. AB - Wetting and voiding dysfunction in children represent a wide spectrum of disorders ranging from uncomplicated nocturnal enuresis, which is not associated with significant uropathology, to more complicated functional voiding dysfunction, which, in the worst of cases, can result in severe deterioration of both bladder and renal function. A complete understanding and thorough evaluation of these clinical entities allow a classification that lends itself to rational and tailored therapy. Optimal response rates can be achieved only with a disciplined and well-defined approach to the evaluation and management of these children. PMID- 7855963 TI - Metabolic evaluation of pediatric patients with stones. AB - Metabolic evaluation of children with urinary stones begins with analysis of calculi or gravel if at all possible. If no stone is available, radiographic appearances may predict types. Once stone composition is known or suspected, a targeted testing program is performed. Serum and urinary tests define the causative abnormality. Therapy is then directed toward correcting this problem. PMID- 7855964 TI - The ileal orthotopic bladder. PMID- 7855965 TI - The colonic orthotopic bladder. PMID- 7855966 TI - Recovery of erectile function by the oral administration of apomorphine. AB - OBJECTIVES: Apomorphine has been reported to be effective in causing erections in animals and man when administered parenterally. The side effects, notably nausea, have seriously limited its clinical usefulness. We formulated apomorphine for controlled sublingual absorption and herein report on four preliminary studies evaluating efficacy and side effects in men with no documentable organic cause of erectile dysfunction. METHODS: Patients complaining of erectile dysfunction underwent a careful evaluation. Those with measurable organic dysfunction or known organic factors were excluded. Men with primarily psychogenic impotence were tested with one of four protocols of an apomorphine preparation (preliminary sublingual liquid, preliminary 5 mg tablet, aqueous nasal spray, and new 3 and 4 mg controlled absorption tablets). The erectile response of these men to the drug with visual erotic or sexually neutral stimulation was studied with the Rigiscan. RESULTS: Seven of 10 evaluable patients responded to the sublingual liquid preparation but the majority experienced significant nausea. The preliminary 5 mg tablet and aqueous forms did not produce useful responses free of side effects. The newly formulated controlled absorption 3 and 4 mg tablets were tested in 12 men. Eight of 12 (67%) developed erections in response to apomorphine. Erectile activity was seen during sexually neutral visual stimulation to a significantly greater extent than with placebo. Home trial use was found to be successful and sustained by 7 of 11 (64%) patients. CONCLUSIONS: We have shown that apomorphine will act as an erectogenic agent when absorbed through the oral mucosa. In a carefully selected group of impotent patients with no documentable organic causes of erectile dysfunction, but with proven erectile potential, 67% will experience significantly durable erections with a dose of 3 or 4 mg of apomorphine when formulated for controlled absorption. The results in these small groups appear to justify larger clinical studies of this proprietary formulation. PMID- 7855967 TI - Living donor nephrectomy: a 20-year experience. AB - OBJECTIVES: To review the selection criteria and perioperative morbidity in patients undergoing living-related donor nephrectomy. METHODS: Retrospective chart review. RESULTS: Six hundred eighty-one patients underwent living donor nephrectomy during a 20-year period without any mortality. The postoperative morbidity included pneumothorax requiring a chest tube in 7%, urinary tract infection in 5%, wound infection in 4%, and need for blood replacement in 0.3% of patients. Two patients had clinically apparent pulmonary emboli. CONCLUSIONS: Living donor nephrectomy remains a valuable source of kidneys for transplantation but is not without risk. By using care in donor selection and surgical management, operative complications can be kept low. PMID- 7855968 TI - Serum ferritin as a clinical marker for renal cell carcinoma: influence of tumor volume. AB - OBJECTIVES: At present, 35% to 50% of patients with clinically localized renal cell carcinoma (RCC) unpredictably have a recurrence after surgical therapy. Presently, no clinical serum marker exists to detect occult metastases and to allow measurement of response to therapy in RCC. Serum ferritin was previously reported to correlate with pathologic stage. We postulated that this increase in serum ferritin with increasing stage might reflect tumor volume, since higher stage tumors are often larger. METHODS: Serum ferritin levels were measured preoperatively in 30 patients with radiologic evidence of RCC. Tumor volume and the largest tumor dimension were calculated from either the pathologic specimen (n = 24) or from the computed tomography or magnetic resonance imaging (n = 30). Pathologic stage was determined for all patients undergoing surgery (T1 = 3, T2 = 12, and T3 = 9). RESULTS: Preoperative serum ferritin levels did not correlate with age, blood urea nitrogen levels, creatinine levels, hematocrit, race, or gender. Although mean serum ferritin levels increased with increasing stage (T1 = 113 +/- 75, T2 = 254 +/- 270, and T3 = 425 +/- 257 ng/mL), these differences did not reach statistical significance (P > 0.05). Serum ferritin did, however, correlate with tumor volume (R = 0.75; P < 0.0001) and the largest tumor dimension measured from radiographic studies (R = 0.8; P < 0.0001). Serum ferritin measured intraoperatively from the renal vein (666 ng/mL) and the inferior vena cava (564 ng/mL) from a patient with a 500 cc tumor (preoperative serum ferritin, 552 ng/mL) suggested that the tumor was the source of the elevated ferritin levels. Histologic sections from tumors taken from patients with high serum ferritin levels were more necrotic and stained intensely positively for iron and immunohistochemically for ferritin, whereas adjacent histologically normal tissue did not. CONCLUSIONS: These data suggest that ferritin may be a useful serum marker for monitoring patients with RCC, but the actual source of the ferritin remains unclear and dictates further investigation. PMID- 7855969 TI - Current indications for open stone surgery in an endourology center. AB - OBJECTIVES: To evaluate the current indications and outcome of open stone surgery in a tertiary endourology unit. METHODS: A 3-year retrospective review (1990 to 1993) of all endoscopic and open stone surgery was undertaken. RESULTS: Twenty five open procedures were performed on 20 patients of a total of 799 stone treatment procedures (3.13%). The most common indications for open stone surgery included large stone burdens in association with abnormal anatomy limiting endoscopic access (31%), concurrent open surgical procedures (24%), or previous failed endourologic procedures (17%). Anatomic factors contributing to the need for open surgery included renal transplantation, morbid obesity, and severe limb contractures. CONCLUSIONS: Open stone surgery has become more complex. Patients undergoing open surgery, who failed endourologic techniques, or for anatomic or medical reasons, currently are the cohorts who may still benefit from treatment for calculus disease using open surgical techniques. PMID- 7855970 TI - A prospective study of microorganisms in urine and bladder biopsies from interstitial cystitis patients and controls. AB - OBJECTIVES: Interstitial cystitis (IC) is a chronic inflammatory condition of the bladder of unknown etiology. We tested the hypothesis that a microorganism would be found at higher prevalence in urine or bladder tissue from women with IC than from control women. METHODS: Urine and bladder tissue were obtained at cystoscopy from 11 IC patients and 7 control subjects. These specimens were cultured for a variety of fastidious and nonfastidious bacteria, mycobacteria, fungi, and viruses. In addition, special staining techniques were used to examine biopsy specimens and cytospun urine, and tissue sections and outgrowths of explanted bladder cells were examined by electron microscopy. RESULTS: Cultures of urine from 6 of 11 IC patients grew five different bacteria (Corynebacterium sp. Klebsiella pneumoniae, Lactobacillus sp, Streptococcus constellatus, and Streptococcus morbillorum), human cytomegalovirus, or Torulopsis glabrata; one of these organisms (Lactobacillus sp) was found in urine from 2 patients. Although contamination by urethral organisms is possible, the prevalence of microorganisms in urine of IC patients (6 of 11) was significantly greater than in urine of control subjects (0 of 7) (P < 0.05). Acridine orange staining revealed rods with appropriate morphology in urine from 4 of the 5 IC patients who had positive bacterial cultures and yeastlike organisms in urine and bladder tissue specimens that grew Torulopsis. Additionally, rodlike organisms were seen in urine from 2 IC patients with negative bacterial cultures and cocci were seen in the urine of 1 control patient. Biopsy specimens from 2 IC patients grew Torulopsis sp or Lactobacillus sp, in agreement with the results of acridine orange staining and culture of urine from these patients; in contrast, specimens from 3 control subjects grew small numbers of Pseudomonas sp or Staphylococcus epidermidis, but no organisms were cultured from urine or seen in acridine orange-stained tissue smears. All other cultures and stains were negative. CONCLUSIONS: These data do not provide evidence that IC is associated with infection or colonization by a single microorganism. However, they do generate the hypothesis that the prevalence of microorganisms, especially bacteria at low concentrations, is greater in the urine of IC patients than of control subjects. If these results are confirmed by other controlled studies, the question of whether the presence of these organisms is a cause or a result of IC should be addressed. PMID- 7855971 TI - Combined laparoscopic and transurethral neodymium: yttrium-aluminum-garnet laser treatment of invasive bladder cancer. AB - OBJECTIVES: The feasibility and efficacy of combined cystoscopic and laparoscopic neodymium: yttrium-aluminum-garnet (Nd:YAG) laser coagulation of invasive bladder cancer were investigated. METHODS: Five patients with extensive Stage T2-T3a bladder cancer who were not candidates for radical cystectomy were treated by Nd:YAG laser irradiation. All patients also underwent transperitoneal laparoscopic mobilization of the intestine away from the bladder with continuous monitoring of the laser treatment. In 2 cases, laser therapy of the serosal surface of the bladder at the site of tumor was also administered. RESULTS: The procedure was completed without complications in all 5 patients. A mean of 58,607 joules (J) of energy was delivered transurethrally with an additional 8000 to 10,000 J utilized via laparoscopy in 2 cases. Local disease recurrence was noted within 1 to 4 months in 4 of the 5 patients. Distant metastases were detected within 1 to 9 months postoperatively in 3 of 5 patients. No perioperative bowel or bladder perforation occurred. CONCLUSIONS: The use of laparoscopy allows for the safe delivery of large amounts of laser energy to the bladder. However, in this small group of patients with extensive bladder tumors, effective palliation of local disease could not be reliably achieved. Further study is necessary to determine whether treatment modifications or selection of patients with less extensive tumors will lead to better results with combined laparoscopic and cystoscopic laser therapy. PMID- 7855972 TI - Long-term experience utilizing a new balloon expandable prostatic endoprosthesis: the Titan stent. North American Titan Stent Study Group. AB - OBJECTIVES: To determine the long-term safety and efficacy of the Titan endoprosthesis as a therapeutic alternative in the management of men with bladder outlet obstruction. METHODS: One hundred forty-four patients (mean age, 73.5 years +/- 4.2) had placement of the Titan stent. The stents were inserted under direct vision and expanded to 33 F using a balloon catheter. Of the 144 patients, 59 (41%) were in urinary retention and 85 (59%) presented with moderate to severe symptoms of prostatism. Patients were assessed at baseline and in follow-up at 1, 3, 6, 12, 18, and 24 months. Parameters of evaluation included the Madsen-Iversen symptom questionnaire, peak flow rate (Qmax), postvoid residual urine volume (PVR), and incidence of adverse events. RESULTS: At 24 months, for the retention cohort, symptoms, Qmax, and PVR were 5.21 +/- 0.81, 11.34 +/- 1.12 mL/s, and 31.00 +/- 12.8 mL, respectively (P < 0.002). For patients with symptoms of bladder outlet obstruction, the results were as follows at 24 months: (1) symptoms decreased from 15.89 +/- 0.47 to 9.33 +/- 0.86 (P < 0.001); (2) Qmax increased from 8.59 +/- 0.41 mL/s to 11.43 +/- 1.12 mL/s (P < 0.001); and (3) PVR decreased from 116.94 +/- 19.95 mL to 74.4 +/- 36.2 mL (P < 0.03). There were minimal complications; stents were removed from 28 patients (19%) because of migration, 10 of which were placed by one investigator. CONCLUSIONS: When properly placed, the Titan stent was an effective therapeutic alternative to prostatectomy or long-term catheterization in high-risk obstructed patients or those in urinary retention. PMID- 7855973 TI - Neodymium: yttrium-aluminum-garnet laser dosimetry for the prolase II side-firing delivery system in the human prostate. AB - OBJECTIVES: The objective of this study was to define optimal treatment parameters and quantitative dosimetry for neodymium:yttrium-aluminum-garnet (Nd:YAG) laser coagulation prostatectomy utilizing the ProLase II side-firing laser delivery system. METHODS: Transurethral Nd:YAG laser application was performed with the ProLase II side-firing laser fiber in adult human prostates prior to planned radical prostatectomy. Depth and volume of prostatic tissue coagulation for single, continuous laser applications were measured at variable power settings from 40 to 80 W, while holding total energy delivery constant. Holding the power setting constant, the extent of tissue coagulation was similarly measured for variable treatment times from 45 to 90 seconds. RESULTS: Peak tissue coagulation for the ProLase II was observed at 60 W--up to a maximum of 13 mm tissue penetration and 3.92 cc volume coagulation following a single spot laser application. The mean depth of tissue coagulation at 60 W power setting was 12.7 mm, with a mean volume of tissue coagulation of 3.07 cc. Holding the power setting constant at 60 W, and increasing treatment time from 45 to 60 seconds, the extent to tissue coagulation increased significantly. However, beyond 60 seconds continuous laser application at 60 W, a plateau in tissue effects was observed, with minimal increase in tissue coagulation between 60 and 90 seconds. CONCLUSIONS: Using the ProLase II side-firing laser fiber, 60-second Nd:YAG spot laser applications at 60 W power setting represent optimal treatment parameters. The quantitative dosimetry curves produced for the ProLase II fiber are compared with prior dosimetry studies with the Urolase delivery system. PMID- 7855974 TI - Laser tissue welding in genitourinary reconstructive surgery: assessment of optimal suture materials. AB - OBJECTIVES: Laser tissue welding in genitourinary reconstructive surgery has been shown in animal models to decrease operative time, improve healing, and decrease postoperative fistula formation when compared with conventional suture controls. Although the absence of suture material is the ultimate goal, this has not been shown to be practical with current technology for larger repairs. Therefore, suture-assisted laser tissue welding will likely be performed. This study sought to determine the optimal suture to be used during laser welding. METHODS: The integrity of various organic and synthetic sutures exposed to laser irradiation were analyzed. Sutures studied included gut, clear Vicryl, clear polydioxanone suture (PDS), and violet PDS. Sutures were irradiated with a potassium titanyl phosphate (KTP)-532 laser or an 808-nm diode laser with and without the addition of a light-absorbing chromophore (fluorescein or indocyanine green, respectively). A remote temperature-sensing device obtained real-time surface temperatures during lasing. The average temperature, time, and total energy at break point were recorded. RESULTS: Overall, gut suture achieved significantly higher temperatures and withstood higher average energy delivery at break point with both the KTP-532 and the 808-nm diode lasers compared with all other groups (P < 0.05). Both chromophore-treated groups had higher average temperatures at break point combined with lower average energy. The break-point temperature for all groups other than gut occurred at 91 degrees C or less. The optimal temperature range for tissue welding appears to be between 60 degrees and 80 degrees C. CONCLUSIONS: Gut suture offers the greatest margin of error for KTP and 808-nm diode laser welding with or without the use of a chromophore. PMID- 7855975 TI - Rectal injuries during radical perineal prostatectomy. AB - OBJECTIVES: To review a contemporary series of rectal injuries occurring during radical perineal prostatectomy. METHODS: Of 81 patients who underwent radical perineal prostatectomy, 9 (11%) sustained a full-thickness laceration of the anterior rectal wall. All 9 patients had a preoperative bowel preparation, although only 1 received a complete oral lavage regimen. All received prophylactic perioperative intravenous antibiotics. None had undergone prior surgery to the rectum or perineum or received prior pelvic radiation therapy. RESULTS: In most cases injury occurred during division of the rectourethralis muscle, but in at least two instances the injury appeared to be the result of undue posterior retraction along the rectal wall. All injuries were recognized at the time of surgery and repaired primarily. No patient had associated postoperative complications. CONCLUSIONS: Rectal injury occurs with significantly greater frequency with radical perineal prostatectomy than with the retropubic approach. However, if the rectum is adequately prepared, the injury promptly recognized and repaired, and postoperative care appropriate, the great majority of cases will not lead to attendant morbidity. PMID- 7855976 TI - Finasteride dose-dependently reduces the proliferation rate of the LnCap human prostatic cancer cell line in vitro. AB - OBJECTIVES: To assess the effects of finasteride, a 5-alpha-reductase inhibitor, and of classic antiandrogens on the growth rate of the LnCap human prostate carcinoma cell line, derived from a primary and well-differentiated neoplasm. METHODS: Cell proliferation experiments in vitro with and without the antiandrogens cyproterone acetate, hydroxyflutamide, and finasteride in the 0.0001 to 10.0 microM range. RESULTS: The growth rate of the LnCap cell line can be dose-dependently inhibited by 5-alpha-reductase inhibition (finasteride) and by antiandrogens (cyproterone acetate and hydroxyflutamide) in vitro, in defined conditions. CONCLUSIONS: Besides other human prostate cell lines derived from metastatic sites (PC3, DU145), also in the LnCap cell line an autonomous androgen dependent mechanism of growth stimulation can be hypothesized, since testosterone and dihydrotestosterone are unable to stimulate the cell proliferation rate at the same molar concentrations. The clinical implications of these results in prostate cancer therapy and the possible future use of these molecules in the prevention of cancer incidence are discussed. PMID- 7855977 TI - Autoaugmentation gastrocystoplasty and demucosalized gastrocystoplasty in a sheep model. AB - OBJECTIVES: To compare the normal sheep bladder at 6 and 12 months with bladders subjected to either an autoaugmentation gastrocystoplasty or a clam demucosalized gastrocystoplasty. METHODS: Twenty male lambs aged between 8 and 10 weeks had an autoaugmentation gastrocystoplasty in which de-epithelialized stomach muscle was added to an intact urothelium. The functional, radiologic, and histologic outcomes were compared with 11 animals who underwent a clam demucosalized gastrocystoplasty and 14 control animals. A total of 18 operated animals had a urodynamic study at 6 months and 9 at 12 months. RESULTS: The average bladder volume for the autoaugmentation gastrocystoplasty group at 12 months was greater than that of the control group (401 +/- 120 mL versus 205 +/- 77 mL). The demucosalized clam bladders had been less effectively enlarged (286 +/- 77 mL). The compliance values for autoaugmentation gastrocystoplasty animals were 14.7 +/ 11.3 mL/cm water (H2O) compared with 9.0 +/- 4.8 mL/cm H2O in the demucosalized gastrocystoplasty group, and 9.1 +/- 3.7 mL/cm H2O for the control animals. CONCLUSIONS: The addition of the autoaugmentation procedure improves the prospect of enlarging the normal sheep bladder when using demucosalized gastric muscle. PMID- 7855978 TI - Reed Nesbit and pediatric urology. AB - OBJECTIVES: To ascertain the pediatric urology experience and contributions of Reed Nesbit, a urologist known primarily as an educator, transurethral resectionist, and prostate expert. METHODS: The writings of Nesbit and appropriate background references were analyzed. RESULTS: Nesbit's contributions to pediatric urology, particularly the Cabot-Nesbit orchidopexy, the buttonhole preputial transposition, the dorsal tunical tuck for chordee, and the elliptical anastomosis were significant. CONCLUSIONS: Nesbit's contributions to pediatric urology were innovative and enduring. PMID- 7855979 TI - Ketoconazole for prevention of postoperative penile erection. AB - OBJECTIVES: To determine if ketoconazole, an inhibitor of testosterone synthesis, can prevent postoperative spontaneous erections in patients undergoing penile surgery. METHODS: Ketoconazole was administered to 8 patients, aged 14 to 42 years, who underwent penile surgery. All patients received ketoconazole 400 mg orally three times daily starting on the day of surgery. Liver function tests were obtained preoperatively and after the completion of treatment. RESULTS: Ketoconazole successfully prevented erections in all patients. None of the patients demonstrated liver function abnormalities. CONCLUSIONS: Ketoconazole is a reliable method to prevent postoperative penile erection. With the proper monitoring of liver function tests and the avoidance of drug interactions, ketoconazole therapy also appears to be safe. PMID- 7855980 TI - Closure of laparoscopic trocar sites using a spring-loaded needle. AB - Closure of laparoscopic trocar sites can be difficult, particularly in the obese patient. We have begun using a spring-loaded needle to facilitate closure of these sites. We have found that the device allows for accurate suture placement, the potential of decreased closure time, reduced risk for trocar site dehiscence, and can be used in obtaining hemostasis of abdominal wall vessels. PMID- 7855981 TI - Urologic causes of gynecomastia: approach to diagnosis and management. AB - A 27-year-old man presented with bilateral painful breast enlargement and recent onset right testicular swelling. After appropriate evaluation, a radical orchiectomy was performed, and a Leydig cell tumor was found. The various urologic etiologies for gynecomastia are presented, as are the potential interventions. A rational approach to the patient with new onset breast swelling is presented. PMID- 7855982 TI - Malignant pericardial effusion as initial solitary site of metastasis from transitional cell carcinoma of the bladder. AB - A patient is presented whose first and sole evidence of metastatic transitional cell carcinoma of the bladder was pericardial metastasis with life-threatening cardiac tamponade. Definitive diagnosis and management was achieved with fluid cytology and video-assisted thoracic surgical pericardial biopsy and pericardial window. PMID- 7855983 TI - Nephrogenic adenoma arising from a urethral diverticulum: magnetic resonance features. AB - Nephrogenic adenoma is a rare benign tumor of the urinary tract. Although its most commonly arises within the urinary bladder, this tumor may also occur within a urethral diverticulum. We report the magnetic resonance imaging (MRI) findings of a nephrogenic adenoma arising within a urethral diverticulum in a 43-year-old woman. MRI appears to be helpful in showing the anatomic extent of the lesion as well as differentiating it from other anterior vaginal wall masses. PMID- 7855984 TI - Laparoscopic enterolysis and placement of an intestinal sling before radiation therapy for the treatment of prostate cancer. AB - We present an interesting application of laparoscopy in a man who was otherwise not a candidate for radiotherapy because of an adherent loop of small bowel in the proposed treatment field. Laparoscopic enterolysis was performed and the involved segment was displaced out of the pelvis; a synthetic mesh was placed to serve as a sling to prevent caudal migration back into the pelvis. The patient had a rapid recovery and subsequently completed a full course of radiotherapy. The experienced laparoscopist may find this a good alternative to open surgery in patients with a fixed loop of small bowel who require radiation therapy for pelvic malignancies. PMID- 7855985 TI - Squamous cell carcinoma of the prostate: a transformation from adenocarcinoma after the use of a luteinizing hormone-releasing hormone agonist and flutamide. AB - We report a primary squamous cell carcinoma of the prostate that developed in a 57-year-old man, 3 years after treatment with leuprolide and flutamide for Stage D1 adenocarcinoma of the prostate. This is the first case that describes this transformation from adenocarcinoma to squamous cell carcinoma following the use of luteinizing hormone agonists. PMID- 7855986 TI - Granular cell tumor of penis and scrotum. AB - Two cases of granular cell tumor of the external male genitalia are reported: one on the scrotum and one on the shaft of the penis. No previous reports of granular cell tumor of the scrotum appear in the literature. Each tumor was treated by simple excision and there was no recurrence. Each tumor showed cytoplasmic S-100 positivity. Tumor was seen in close proximity to small nerve fibers, sweat glands, and erectile smooth muscle. These findings are considered encroachments rather than evidence of origin from any of these structures. An immunohistochemical signature for granular cell tumor has developed in recent years, but, from a practical viewpoint, only the S-100 stain should be used for confirmation of the diagnosis. PMID- 7855987 TI - The imprinted H19 gene as a tumor marker in bladder carcinoma. AB - OBJECTIVES: Genomic imprinting is a newly discovered mechanism in genetics that is involved in tumorigenesis. H19 is an imprinted gene in the human, expressed from the maternal allele. It is extensively transcribed in fetal life but is not translated and functions as an RNA molecule. It has been suggested as a candidate tumor suppressor gene. We studied the expression of H19 in human cancer arising from tissues expressing H19 in fetal life, one of which is bladder mucosa. METHODS: In situ hybridization for H19 mRNA on paraffin sections of bladder carcinoma in different histologic grades. RESULTS: Low-grade (grade 1 of 3), noninvasive (Ta) papillary transitional cell bladder carcinoma did not express H19, but prominent expression was disclosed in higher grades, invasive transitional cell carcinomas (T1-T3/4). Expression was also evident in in situ bladder carcinoma (Tis), which tends to progress rapidly to invasive cancer. CONCLUSIONS: We suggest that H19 can be used as a tumor marker in human bladder carcinoma, where its expression indicates a more malignant potential. PMID- 7855988 TI - A novel technique of ureteroneocystostomy (extravesical seromuscular tunnel): an experimental study in dogs. I. Preliminary results. AB - OBJECTIVES: To present the preliminary results of a novel technique of ureteroneocystostomy with a new principle (extravesical seromuscular tunnel). METHODS: The new technique was applied in the left ureter of 12 mongrel dogs. The dogs were stratified into three groups (4 dogs each) according to the length of the extravesical seromuscular tunnel. Tunnel lengths of 3, 2, and 1 cm were used for groups I, II, and III, respectively. All the dogs were evaluated by excretory urography, radioisotope renography, and ascending cystography before and at 2 weeks and 3 months after ureteroneocystostomy. Urodynamic evaluation by the Whitaker test and ureteral pressure profile were carried out at 3 months. RESULTS: None of the 12 dogs showed vesicoureteral reflux. All but 1 dog of group I and 2 dogs of group II showed evidence of ureteric obstruction. All 4 dogs of group III showed perfect configuration and function of the corresponding renal units at 2 weeks and 3 months after ureteroneocystostomy. Moreover, the intrapelvic pressure and the superimposed ureteral pressure of this group were approximately similar to pressures of the normal contralateral side. CONCLUSIONS: Preliminary results of this new technique of ureteroneocystostomy revealed that an extravesical seromuscular tunnel of 1 cm provides reflux prevention without obstruction. PMID- 7855989 TI - Etiology and management of cystine lithiasis. PMID- 7855990 TI - [The functional characteristics of ototopia during the monaural localization of a mobile sound object in space]. AB - Ototopical function was studied in subjects with normal hearing by their mono- and binaural perception of the sound from a mobile source differently located in space. There was a relationship between ototopicometric parameters and acoustic system function. The discussion covers opportunities of ototopicometry in audiological evaluation of space hearing. PMID- 7855991 TI - [The noise-suppression capacity of the auditory analyzer for interfering speech in one's native and in an unknown language]. AB - Anti-noise potential of the acoustic analyzer in Russian and Armenian speech interference was studied in twenty otologically normal 17-23-year-old subject who speak only Armenian. Intelligibility parameters were measured in a free sound field with the use of two audiometers furnished with recorders and adjusted loud speakers. One of them delivered valuable speech information, the other one was disturbing. Intelligibility of valuable speech information was found higher in masking by foreign speech than by native one. PMID- 7855992 TI - [Immunotherapy with leakadin in the combined therapy of acoustic neurinomas]. AB - The paper reports the data obtained on the efficacy of a new anti-cancer immunomodulator leacadin in neurinoma of the acoustic nerve. Leacadin participates in formation of a close regulatory relation between the brain and immune system, promotes centralization of immunity regulation in conditions of surgical trauma. The drug can also increase the level of natural killers and helpers, reduce neurosensitization and the amount of suppressors. PMID- 7855993 TI - [Cerebral arachnoiditis in patients with chronic rhinosinusitis]. AB - The examination and treatment of 66 patients with rhinosinusogenic cerebral arachnoiditis (RCA) were performed using otorhinolaryngological and neurological tests with special emphasis on pneumoencephalography to provide objective assessment of the brain layers and ventricles. It is shown that RCA occurs most frequently in subjects suffering from chronic purulent axillary sinusitis or recurrent polysinusitis. RCA manifestations depend on the duration of rhinosinusitis and its recurrence rate. RCA onset is usually not acute and takes place at the time of rhinosinusitis exacerbation. There are also mild frontal headaches, pathological changes in the coats of the anterior cranial fossa. The above abnormalities were most pronounced at the side of rhinosinusitis or most affected sinus. The treatment should be first of all oriented on elimination of maxillary infection in line with pathogenetic treatment of RCA. An individual approach to treatment policy is advocated. PMID- 7855994 TI - [The role of microorganisms in the genus Staphylococcus in the origin and development of nasal furuncles]. AB - It is shown that Staphylococcus aureus carriage in the nasal mucosa and nasal furuncle risk are related. The severity of nasal furunculosis depends much on the spectrum of biological and virulent characteristics of the microorganism. It is recommended to determine pathogenetic potential of the causing agent by comprehensive examination of its virulence. PMID- 7855995 TI - [Variants of vasomotor rhinitis in children]. PMID- 7855996 TI - [The clinico-immunological assessment of the efficacy of magnetic-laser therapy in patients with chronic maxillary sinusitis]. AB - Magneto-laser therapy (80 Hz, 0.01 mW/cm2, 12 min) consisting of 10 sessions was performed in patients with maxillary sinusitis (MS). Therapeutic action on the sinus mucosa was conducted through the sinus anterior wall. The magneto-optic attachment coupled with semiconductor laser in the Uzor apparatus was tightly pressed to the facial skin in the sinus projection area. Positive clinical responses associated with stimulation of neutrophil phagocytic activity and with a rise in the portion of rosette-forming neutrophils and Ig A were achieved in 90% of the patients with catarrhal MS and in 83% of those with purulent MS. A 1.5 2-year follow-up registered the effect persistence in 80% and 69% of them, respectively. Compared to standard methods (microwave therapy), magneto-laser treatment was superior both in short-term and long-term effects obtained in purulent MS. The method can be applied in mono- and polytherapy. PMID- 7855997 TI - [The effect of medicinal herbs on lymphocyte rosette-forming function]. AB - The blood samples from ENT patients with immunodeficiency were used in an in vitro trial of some herbs effect on T-lymphocyte rosette formation. Out of 10% infusions made of Hypericum L., Matricaria chamomilla L., Chelidonium L., Salvia officinalis L., Mentha L., stimulation of rosette formation was recorded only after introduction of Matricaria chamomilla L. and Chelidonium L. infusions. PMID- 7855998 TI - [An analysis of reoperations on the middle ear in childhood]. AB - According to the data provided by the Moscow ENT hospitals, the number of resurgery on the middle ear in children rose 3-fold. This is due to frequent failure of antrodrain surgery, higher prevalence of mycotic infection and recurrent inflammation in the middle ear. When planning otic surgery in children it is necessary to take into consideration both the involvement of the middle ear and medical personnel ability to provide proper postoperative care. Resurgery is justified in complicated disease course after primary intervention. PMID- 7855999 TI - [Laryngeal reconstruction after extensive frontolateral resections in locally disseminated laryngeal cancer]. AB - In the department of upper respiratory and gastrointestinal tract tumors of the Russian Cancer Research Center one-stage laryngeal reconstruction after extensive frontal-lateral resection for cancer stage III (T3N0M0) was performed in 11 patients. Two variants of the reconstruction were used: plastic reconstruction of the laryngeal defect with a dermal-muscle graft involving m. sternohyoideus and with down retraction of the epiglottis. The procedures yields good functional results: all the cannulas were removed, respiratory and protective function of the larynx recovered, voices sounded satisfactorily. The above laryngeal plastic surgery allowed avoiding laryngostoma formation and subsequent complicated plastic interventions. This proved beneficial for rehabilitation and the patients' quality of life. PMID- 7856000 TI - [The role of paracentesis in treating acute otitis media in young children]. AB - The study was made of paracentesis efficacy in functional recovery of the acoustic tubes and tympanic membrane in infants with catarrhal and purulent otitis media acuta. Although the procedure had an insignificant effect on the rate of the tubal functional recovery, formation of big scars on the tympanic membrane was registered at dynamic otoscopy and impedancemetry in one case only. Paracentesis is recommended in diagnosis of perforation-free inflammations of the middle ear in infants. PMID- 7856001 TI - [The use of trypsin and lysozyme immobilized on a cellulose carrier in treating otitis externa]. AB - The authors present a theoretical and practical validation of lysozyme+trypsin therapy for diffuse external otitis. A total of 32 patients were treated by a powder of trypsin immobilized on cellulose carrier as well as lysozyme and trypsin immobilized on gauze turundae. The treatment proved effective against bacterial and fungal external otitis. PMID- 7856002 TI - [Complications and the measures for their prevention in stapedioplasty for otosclerosis]. PMID- 7856003 TI - [The role of phytopharmacotherapeutic agents in rehabilitating those who work with chemical substances]. PMID- 7856004 TI - [The development of suppurative pansinusitis and subcutaneous abscess after prolonged nasal tamponade because of gushing nasal hemorrhages]. PMID- 7856005 TI - [A massive nasal hemorrhage occurring from injury to an anomalously located blood vessel]. PMID- 7856006 TI - [Laryngotracheoplasty with a bone-muscle transplant in children]. AB - Laryngotracheoplasty using an osteomuscular graft in modification of the authors was performed in 35 patients aged 5-15. The children suffered from severe cicatricial laryngostenoses and laryngeal-tracheal atresias. Postoperative results are available for 22 children. Decannulation was performed in all the children. They have closed tracheostoma and free breathing. 13 children need phonopedic aid, 5 patients need repeat change of the protector, 2 children underwent resurgery, 2 patients are to undergo reoperation. Further studies should be directed to search for new modalities to prevent granulations growth, to speed up postoperative epithelialization. PMID- 7856007 TI - [The choice of the method for treating patients with Meniere's disease and similar diseases]. AB - The experience gained by the authors in the treatment of Meniere's disease and similar affections which are supposed to have 3 stages provided the following approach to their treatment: after examination of the cochleovestibular analyzer involvement good results may be expected of conservative treatment in stage I-II, chordoplexectomy is justified in stage I, drainage or decompression of the endolymphatic sac and vestibulotomy are indicated in stage II and III, respectively. PMID- 7856008 TI - [Traumatic dislocation of the eyeball into the maxillary sinus]. PMID- 7856009 TI - [2 cases of a rare complication during adenotomy]. PMID- 7856010 TI - [2 rare cases of developmental defects of the ear with a good functional effect after surgical treatment]. PMID- 7856011 TI - [The potentials for diagnosing labyrinth pathology by using objective methods]. AB - Based either on spontaneous or experimental vestibular reactions, diagnostic methods proposed by the authors seem most informative for differential diagnosis of internal ear diseases with simulating conditions. The main thing in the above diagnosis is the vestibular testing unit which provides objective synchronous registration of vestibular-somatic and vascular reactions. The necessity of comparing rotatory nystagmus to postnystagmus, the significance of latent spontaneous nystagmus interpretation are emphasized. PMID- 7856012 TI - [The significance of genetic markers in otosclerotic hearing loss]. AB - Phenotypes HLA-A, HLA-B and HLA-C were determined in 85 patients with otosclerosis verified at surgery and in 113 clinically healthy subjects. The patients were divided into 2 groups: with family predisposition to otosclerosis (13 subjects) and without such (72 subjects). A tendency was established to more frequent occurrence of antigens A2, B12 versus less frequent of antigens B27, B40, Cw1 in patients compared to controls. It is concluded that at least one of the genes determining the resistance to otosclerosis exists in the HLA region, in binding groups B27, B40 and Cw1. It is suggested that genes predisposing to the disease (A2, B12) may be located at the same place. PMID- 7856013 TI - [An optimized variant of plastic repair in a total-cavity rehabilitative hearing preserving operation on the middle ear]. AB - Therapeutic policy proposed by the authors in chronic otitis media purulenta (COMP) provides stable hearing-improving results. The procedure implies fixation of low T-shaped graft without catgut suture. Special tamponade of the postoperative cavity prevents damage to sound conduction system while dressing and improves the conditions of the trepanation cavity healing. Thus, COMP patients undergo shorter aftertreatment because of quicker epidermization of the postoperative cavity. The number of patients with surgical ear disease decreased. PMID- 7856014 TI - [The use of computed tomography of the temporal bone for the early diagnosis and prognosis of otogenic intracranial complications]. AB - The authors propose three-projection procedure of computed tomography (CT) of the temporal bone aimed at early diagnosis and prognosis of intracranial otogenic complications. CT was conducted in 62 patients with chronic purulent epitympanitis. Destruction of the tympanic bone walls and the antrum, inflammatory involvement of the meninges were seen on CT in 15 patients. Carious changes with the wall thinning occurring at the same sites, but without intracranial invasion were noted in 25 patients. The picture was confirmed at surgery. The proposed CT technique provides not only the image of early intracranial inflammation, but also helps predict intracranial complications. PMID- 7856015 TI - [The characteristics of vestibular-visual interaction in patients with cochleovestibular disorders under galvanic stimulation]. AB - The paper deals with the problem of vestibular-visual interactions in pathogenesis of cochleovestibular diseases. The investigations were made on the original unit for registration of visual illusions in response to galvanic stimulation of vestibular structures. The examination covered patients with Meniere's disease, peripheral and central cochleovestibular syndrome, otogenic arachnoiditis. Emergence of visual illusions was related to the degree of vestibular abnormality and threshold stimulation. The greatest compensation of the equilibrium function at the expense of vision was reported in patients with central vestibular disorders. Further studies into the vestibular reactions seem important for elucidation of cochleovestibulopathy pathogenesis. PMID- 7856016 TI - [The function of the oxidant-antioxidant system in patients with laryngeal cancer]. AB - Lipid peroxidation and antioxidant system were studied at hospital admission, on postoperative day 1, 3 weeks and half a year after surgery in 86 patients with different stages of laryngeal cancer. A correlation is stated between lipid peroxidation disturbances and the defects in the protective antioxidant system. Low-frequency laser irradiation of autoblood produced a clinically beneficial effect and stabilized biochemically the relations between lipid peroxidation and antioxidant systems. PMID- 7856017 TI - [The treatment of atopic rhinitis in children with an accelerated variant of specific immunotherapy]. AB - An intensified course of specific immunotherapy (36 days) has been tried in 72 children with atopic vasomotor rhinitis. The age of the patients ranged from 5 to 15 years. The effectiveness of the treatment was assessed by nasal mucosa function, cellular and humoral immunity measured throughout the treatment and 6 moths after it. Good results were obtained in 71.1% of the patients, satisfactory in 24.4%, unresponsive children made up 4.2%. No complications occurred. During the treatment adverse reactions were noted in 11 children. Short-term discontinuation of the allergen administration corrected the situation. Clinical, functional and immunological findings permitted the authors to conclude on the expediency of a short-term specific immunotherapy in atopic rhinitis management in children. PMID- 7856018 TI - [Possible medical errors as a cause of death in ENT patients]. AB - The analysis of 116 case histories of the patients who had died in the Moscow Regional Research Clinical Institute throughout the last 12 years has revealed diagnostic, therapeutic and technical errors in 44% of the cases. The death was due to misdiagnosis, inappropriate therapeutic policy, mediastinitis consequent to esophageal perforation made in the search of a foreign body, unqualified surgery in 4, 3, 3 and 2 patients, respectively. PMID- 7856019 TI - [The theses of the "conservative" surgery of cholesteatoma]. PMID- 7856020 TI - [The potentials for using paracetamol in otorhinolaryngology]. AB - The authors recommend to use paracetamol in otorhinolaryngological practice for anesthesia and lowering of body temperature. The drug effects are specified for 51 patients treated for acute otitis media. Follow-up data are outlined on conventional treatment of acute otitis media. PMID- 7856021 TI - [A method for draining the maxillary sinus]. PMID- 7856022 TI - [The surgical treatment of a mucocele of the sphenoid sinus]. PMID- 7856023 TI - [Acute and sudden sensorineural hearing loss]. AB - Current views on neurosensory hypoacusis necessitate clear definitions and distinctions between acute and sudden hypoacusis as independent nosological entities of hearing defects. Sufficient data available make it possible to characterize the above forms clinically, etiologically and pathogenetically. Common views of many Russian ENT specialists on sudden and acute hypoacusis as the same entity complicate solving the problem of neurosensory hearing disorders. Orderly classification of acute and sudden hypoacusis variants and subgroups will encourage differentiated and sound approach to treatment of neurosensory hearing loss. PMID- 7856024 TI - [A rare tumor of the sphenoid sinus]. PMID- 7856025 TI - [A fibrous choanal polyp with 2 pedicles in a 5-year-old child]. PMID- 7856026 TI - [Retention polycystosis of a supernumerary palatine tonsil simulating a pharyngeal tumor]. PMID- 7856027 TI - [The ecological education and training of medical students and physicians]. PMID- 7856028 TI - [Nobel laureates in the field of otorhinolaryngology]. PMID- 7856029 TI - Norbrook Lecture. Research and higher education: the concept of autonomy. PMID- 7856030 TI - Frequencies of PrP gene variants in healthy cattle and cattle with BSE in Scotland. AB - Bovine spongiform encephalopathy (BSE) is one of a family of scrapie-like diseases which affect various mammals. Polymorphisms and mutations of the PrP gene have been associated with the incidence of experimental and natural scrapie in other animals and this study of the bovine PrP gene was undertaken to discover whether there was a similar association with PrP genotype in cattle with BSE. There are two known polymorphisms of the coding region of the bovine PrP gene, a silent HindII restriction site polymorphism and a difference in the number of an octapeptide repeated sequence (either five or six copies). An analysis of 370 cattle in Scotland revealed no difference between the frequencies of these PrP genotypes in healthy cattle and cattle with BSE. PMID- 7856031 TI - Use of repeated biopsies to monitor endometrial oxytocin receptors in the cow. AB - A transcervical biopsy technique was used for the repeated collection of samples of bovine endometrium from individual cows to monitor the development of oxytocin receptors. The collection of biopsies from three cyclic cows at two-day intervals between days 13 and 17 after oestrus did not result in any shortening of the length of the cycle (mean +/- sem 22.0 +/- 0.5 days). Furthermore, the assay of serial blood samples from three cows around the time of biopsy on days 15 and 17 demonstrated that the technique did not induce any release of prostaglandin F2 alpha (PGF2 alpha). Oxytocin receptors were undetectable (< 20 fmol/mg protein) on days 13 and 15 of the cycle, increased to a mean of 121 +/- 16 fmol/mg protein on day 17 (before luteolysis), and were highest in samples collected at oestrus (498 +/- 84 fmol/mg protein). To determine whether a single biopsy of endometrium would give a representative measure of the concentration of uterine oxytocin receptors, the concentrations were determined in samples of caruncular and intercaruncular endometrium collected from the upper, middle and lower proportions of uteri from three oestrous animals at slaughter. The concentrations were similar in both types of tissue (caruncular 730 +/- 15 fmol/mg protein, intercaruncular 727 +/- 48 fmol/mg protein) and there were no differences between the three regions of the uterus. PMID- 7856032 TI - Polyarthritis in kids associated with Mycoplasma putrefaciens. AB - Fifteen two- to three-week-old kids, fed artificially with goats' milk from a dairy, were found to have polyarthritis. The most affected joints were the carpals, either unilaterally or bilaterally, and in some cases the tarsal joints. Mycoplasma putrefaciens was isolated from the joints which showed an acute fibrinopurulent arthritis. No clinical mastitis was detected in the dairy. PMID- 7856033 TI - A field case of granulocytopenic disease of calves. PMID- 7856034 TI - Salmonella arizonae infection and colonisation of the upper respiratory tract of sheep. PMID- 7856035 TI - Distribution and identification of gyrodactylid species in fish farms and rivers of Northern Ireland. PMID- 7856036 TI - Transmission of bovine viral diarrhoea virus by rectal examination. PMID- 7856037 TI - Neospora-associated abortions in cattle. PMID- 7856038 TI - Spinal fractures in deer. PMID- 7856039 TI - Equine motor neuron disease. PMID- 7856040 TI - Swelling disease of dromedary camels. PMID- 7856041 TI - Immunobiology of pseudorabies virus infection in swine. PMID- 7856042 TI - Bacterial immunogens and protective immunity in swine. AB - This review provides a limited discussion of antibody-mediated immune responses to bacterial pathogens which cause disease in swine. Serum antibody titers or responses have been used to correlate immunization or convalescence with protection from a given disease or infectious agent. Though much effort has been devoted to the elucidation of the host's antibody response to bacterial antigens, there are limited examples where an antibody response to a singular antigen has induced protection from disease. Antibody responses have been shown to be very effective in neutralizing bacterial exotoxins, e.g. Escherichia, Pasteurella, Actinobacillus, and inhibiting the ability of bacterial pathogens to colonize mucosal surfaces, e.g. Escherichia, Salmonella. The protective role of monospecific antibody responses to other bacterial components are less clear; however, antibody responses are generally polyclonal in nature and are an important component of the host immune response following the onset of disease. Anticapsular antibodies have been shown to enhance phagocytosis of numerous pathogens, e.g. Actinobacillus, Streptococcus, Pasteurella. Humoral immune responses directed against the lipopolysaccharide (LPS) of many Gram-negative organisms have been shown to enhance phagocytosis and the activation of complement, e.g. Salmonella. Anti-LPS antibodies have also aided in the identification of the serotypic diversity of Gram-negative organisms, e.g. Serpulina, Salmonella, Pasteurella. Antibody responses to the outer membrane proteins of Gram-negative organisms enhance phagocytosis, activation of complement, or inhibit bacterial adhesion to host cell. Adhesion of Gram-positive microorganisms, e.g. Staphylococcus, Streptococcus, Clostridium, to eukaryotic cells can be inhibited by antibody against the peptidoglycan and these peptidoglycan-specific antibodies may also facilitate opsonization of these organisms. Mycoplasma species have been shown to be metabolically inhibited by antibody directed against membrane proteins. In addition to the protective aspects of humoral immunity, the host's antibody response has been used as a diagnostic and epidemiological tool to identify or determine the prevalence of infectious agents. PMID- 7856043 TI - Swine immunity to selected parasites. AB - Swine parasitism exerts a significant economic impact worldwide. In the United States, the greatest losses are due directly or indirectly to the costs of zoonotic parasitisms. Three of the six most common foodborne parasitic diseases of humans in the United States are associated with pork consumption. These include toxoplasmosis, taeniasis or cysticercosis (caused by the pork tapeworm Taenia solium), and trichinellosis. Toxoplasmosis is of particular concern because of the fulminating disease that occurs in immunocompromised people. Generalizations and extrapolations of information derived from rodent and human studies, to swine parasitisms, are complicated by immunological differences between the hosts, and by the diverse biological characteristics of internal and external parasites studied. Swine studies thus far reported have demonstrated that protective immunity to helminth infection involves both cellular and humoral mechanisms, with antibodies and antibody-mediated responses playing important roles in preventing establishment of newly acquired larvae. Protection against protozoan parasites is primarily by cell-mediated strategies, whereas protective immunity to arthropod infestation is primarily through humoral mechanisms, principally those associated with type 1 hypersensitivity. PMID- 7856044 TI - Porcine T-cell receptors: molecular and biochemical characterization. AB - Two subclasses of CD3 associated T-cell receptors (TcR) have been described so far, consisting of either an alpha and beta chain (TcR alpha beta) or a gamma and delta chain (TcR gamma delta). Of the two subclasses, the TcR alpha beta is the one predominantly expressed on peripheral T lymphocytes of humans and rodents. TcR gamma delta T lymphocytes represent only a minor subset in these species. Among all mammalian species studied so far, swine showed the most diversified composition of the T-lymphocyte population characterized by the expression of CD4 and CD8 differentiation antigens. Besides CD4+CD8- and CD4-CD8+ T lymphocytes, CD4+CD8+ and CD4-CD8- T lymphocytes are prominent in the extrathymic T-lymphocyte compartment. Because of the lack of specific monoclonal antibodies (mAb), to date the porcine TcR can only be characterized with biochemical and molecular biological methods. TcR on porcine peripheral blood T lymphocytes with the phenotype CD4+ and/or CD8+ are characterized as 46-48 kDaR heterodimers which were supposed to represent the porcine TcR alpha beta. Biochemical analyses of the CD4-CD8- T lymphocytes revealed three distinct TcR gamma delta; all are characterized by a 40 kDa delta chain but differed in their gamma chains. One gamma chain with a molecular mass of 38 kDaR is preferentially expressed on CD4 CD8- T lymphocytes derived from peripheral blood; another chain with molecular mass of 37 kDaR is evenly distributed between CD4-CD8- T lymphocytes from blood and lymphoid tissues.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7856045 TI - Development of immune responses in early pig ontogeny. AB - Low amounts of immunoglobulins, produced without any known cause of stimulation, can be detected in sera and cells of fetal and colostrum deprived newborn pigs. These immunoglobulins are believed to represent the preimmune antibody repertoire on the basis of their polyspecificity and reactivity against self antigens. In vitro activation of liver and spleen cells with various polyclonal B cell activators (PBA) results in pronounced immunoglobulins synthesis as measured in the culture media by enzyme-linked immunosorbent assay. Intrauterine injection of fetal and germfree pigs with PBA led to increased IgM, IgG and IgA levels in sera. Specific responses during fetal development were studied after intrauterine immunization. Antibodies to the heapten and its carrier flagellin, could be detected 7 days after the immunization of 55-day-old fetuses. Fetal and colostrum germfree pigs may be useful experimental models in which developmental immunity can be studied in the absence of maternal antibodies and environmental antigens. PMID- 7856046 TI - Immunology of the porcine gastrointestinal tract. AB - The gastrointestinal immune system is presented with a contrasting array of antigens, ranging from harmless dietary components to highly pathogenic microorganisms. The mucosal immune system has the ability to recognise different groups of antigens and has evolved a battery of responses from which an appropriate response may be orchestrated. The question as to how the mucosal immune system categories antigens and selects a particular response is central to this process but it remains largely unanswered. The solution to this question is likely to hold the key to the development of safe and effective mucosal vaccines as well as suggesting methods for the prevention and control of allergic responses. Enteric diseases resulting from antigens (microbial and dietary) presented via the gastrointestinal tract are a major cause of morbidity and mortality. In addition to being of substantial economic importance, growing public awareness on animal welfare and food quality confirms the urgent need for new methods of disease control. PMID- 7856047 TI - The immune system of the respiratory tract in pigs. AB - Although the lung is not a lymphoid organ it contains large numbers of lymphocytes. These can be found in different compartments: (1) the pulmonary intravascular pool, which is organ-specific and shows a unique migration pattern; (2) the interstitial lymphocyte pool, which is equivalent in size to the whole blood pool; (3) the bronchus-associated lymphoid tissue (BALT) which develops as a result of microbial stimulation; (4) the intraepithelial and lamina propria lymphocytes of the bronchi, with their typical subset composition; (5) the lymphocytes in the bronchoalveolar space, which can be sampled by bronchoalveolar lavage. The size and kinetics of the lymphocyte pools have been studied in the pig in more detail than in most other species. Despite this organotypic compartmentalisation of the pulmonary lymphoid cells in the pig, the lung is part of the integrated mucosal immune system, as shown by protective oral immunisation against the lung-pathogenic bacteria Actinobacillus pleuropneumoniae. The lung immune system in the pig is not only of veterinary interest, but also a relevant model for the human respiratory tract. PMID- 7856048 TI - Immunology discovers physiology. AB - Not so long ago, it was believed that the brain is totally devoid of immunologic reactions, that cytokines derived from activated leukocytes serve only as communication molecules between leukocytes and that the immune system is regulated solely by intrinsic mechanisms. One by one, these old-time, traditional views have fallen by the wayside as neuroscientists, endocrinologists and pharmacologists have begun to explore immunology. The old view was that the immune system is autonomous because it neither affects nor is it affected by other physiologic systems. The new view is that cells of the immune system are inextricably linked with other physiological systems, including the neuroendocrine, cardiovascular, reproductive and central nervous systems (CNS). Changes in one system evoke changes in the other, and it is likely that communication loops have evolved between cells of the immune system and those of other tissues to coordinate and regulate functional activities aimed at preserving homeostasis during inflammation. The integrated view of immunophysiologists that cells of the immune system interact with the entire body, rather than existing as a separate physiologic system that operates autonomously, should help to unravel a number of mysteries in immunoregulation, such as the well-recognized redundant and pleiotropic properties of cytokines. Unfortunately, very few of these ideas have been incorporated into studying immunity of domestic animals. A complete understanding of immunobiology will be achieved only after this new field of immunophysiology is integrated into current immunological thinking.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7856049 TI - Sinclair miniature swine: an animal model of human melanoma. AB - Sinclair swine display cutaneous melanoma lesions and develop a generalized depigmentation subsequent to tumor regression. Sinclair swine represent a valuable animal model to study the factors influencing the development of melanoma and also the factors which lead to the development of vitiligo. Therefore, information obtained in studies of Sinclair swine should facilitate our understanding of the mechanisms by which melanoma and vitiligo develop and provide us with possible therapeutic treatments for these human diseases. PMID- 7856050 TI - Swine as an allotransplantation model. AB - Because of their anatomical and physiological similarities to humans, pigs are well suited for solving technical problems associated with clinical transplantation. The availability of genetically defined strains of miniature swine is unique with this species, and has permitted the investigation, in a large animal model, of immunological and genetic aspects of allograft rejection, clinical manifestations associated with bone marrow transplantation, and the feasibility of various approaches for induction of transplantation tolerance. Immunological assays and various reagents are also available in order to pursue these studies. PMID- 7856051 TI - The pig as a potential xenograft donor. AB - Miniature swine have several advantages over other potential donor species as a xenograft donor for clinical use. Among these advantages are: (1) unlimited availability; (2) size (similar to human beings); (3) breeding characteristics; (4) physiologic and immunologic similarities to humans. Because of the genetic disparity between these two species, routine immunosuppression will probably not suffice for the long-term survival of pig to primate xenografts. Studies are therefore underway to induce tolerance across this species barrier, utilizing a mixed chimerism approach which has previously been successful for allogeneic and concordant xenogeneic combinations. Hyperacute rejection has been eliminated by an absorption technique and pig kidney xenograft survivals up to 13 days have been achieved. PMID- 7856052 TI - Current status of the swine leukocyte antigen complex. AB - As immunologists expand their knowledge of the complex factors that regulate immune responses it has become increasingly apparent that genes within the major histocompatibility complex (MHC) play a central role in the processing and presentation of foreign and self antigens. This review is intended to update the reader on the current knowledge of the swine leukocyte antigen (SLA) complex: its genomic structure, the molecular biologic and monoclonal antibody (mAb) probes available for analysis of SLA gene expression, and the role of SLA genes in regulating disease and immune responses. Because of length restrictions, only highlights can be presented. PMID- 7856054 TI - Analyses of anti-human CD monoclonal antibodies for cross reactions with swine cell antigens. AB - For the First International Swine CD Workshop an effort was made to include commercially available anti-human CD monoclonal antibodies (mAb) that had been prescreened to determine whether they were cross-reactive with swine cell CD antigens. Thus before the actual workshop began, ten companies were contacted to determine whether they would participate in this effort. Four companies (Dako Corporation, Carpenteria, CA; T Cell Sciences, Cambridge, MA; Bioproducts for Science, Indianapolis, IN; PharMingen, San Diego, CA) provided a total of 38 mAb for tests of cross-reactions with swine cell antigens. Two companies (Coulter, Hialeah, FL and Becton Dickinson, San Jose, CA) declined to participate because of the low likelihood of positive cross-reactions. Several other companies (Behringewerke, Marburg, Germany; Boehringer Mannheim, Indianapolis, IN; Biosource International, Camarillo, CA; Applied Immune Sciences, Menlo Park, CA) were interested but either had problems in preparing the mAb in time for US importation or in providing the quantities necessary free to the workshop. The studies described below verify that few anti-human CD mAb exhibit consistent, predictable cross-reactions on pig cells; of the seven mAb that showed reactivity on swine cells only one mAb, Dako's anti-CD18, showed consistent reactivity with every pig tested and at the expected intensity level. PMID- 7856053 TI - Overview of the First International Workshop to Define Swine Leukocyte Cluster of Differentiation (CD) Antigens. PMID- 7856055 TI - Summary of first round cluster analysis: complete antibody panel. AB - The reactivities of 141 monoclonal antibodies (mAbs) with 60 target cell types or lines were analysed by flow cytometry and the data subjected to statistical clustering. mAbs were assigned to 23 clusters by statistical similarity and information on specificity supplied by the contributor. Clustered mAbs were examined in more detail in the second round of workshop analyses. PMID- 7856056 TI - Summary of workshop findings for porcine T-lymphocyte antigens. AB - Fifty-four mAb preselected in the first round of the first porcine CD workshop for their possible reactivity with T-lymphocyte specific antigens and/or activation antigens were further analysed in a second round. PBMC, thymocytes and nylon-wool purified T lymphocytes derived from peripheral blood, mesenteric lymph nodes and spleen served as target cells for flow cytometric analyses. For the classification of activation antigens several experiments were performed with activated, mitogen-stimulated T lymphocytes and long-term T-lymphocyte cultures. Out of the 54 mAb, 35 mAb could be distributed to six different CD clusters and two swine workshop clusters (SWC). Five mAb could be distributed to the porcine CD2, four mAb to the CD4. Six mAb seemed to recognize the porcine CD5 and two mAb the porcine CD6 analogue. Six mAb were directed against the porcine CD8, whereas two different epitopes could be defined. One mAb was directed against the porcine CD25 analogue. Nine mAb could be clustered to the SWC1, defining an antigen on T lymphocytes and cells of the myeloic linage. Two mAb with high T-cell specificity were clustered to the SWC2. PMID- 7856057 TI - Monoclonal antibodies recognising differentiation antigens on porcine B cells. AB - Nineteen monoclonal antibodies (mAbs) submitted to the porcine CD Workshop were analysed on porcine B cells from different lymphoid tissues by flow cytometry and immunohistochemistry. Six mAbs only bound to pig B cells and three of these were assigned cluster numbers, 76-7-4 (No. 001):CD1, K231-3B2 (No. 027):CD25 and CC51 (No. 100):CD21. Of the three remaining B cell positive mAbs, one was assigned to a swine cluster, CC55 (No. 101):SWC7, a second, LIG4 (No. 123), recognised cell surface IgM and the third, MUC106A (No. 072), remained unassigned. PMID- 7856058 TI - Workshop studies on monoclonal antibodies reactive against porcine myeloid cells. AB - Investigators from eight laboratories analyzed the reactivity of 22 monoclonal antibodies (mAb) against porcine myeloid cells. Based on binding data, clustering analysis and inhibition studies, workshop mAb 74-22-15 (003) and 6F3 (007) were assigned a swine workshop cluster number 3 (SWC3). These mAb recognized macrophages and neutrophils; neutrophils; a monocyte/macrophage-specific mAb was not identified by this workshop. PMID- 7856059 TI - Report on the behaviour of monoclonal antibodies in the First International Pig CD Workshop identifying the Null cell families. AB - Clustering analyses were carried out on data from five independent laboratories testing 22 monoclonal antibodies (mAbs) reacting with CD2-sIg-lymphocytes on 14 pig blood and/or tissue lymphoid target cells using cytofluorometry. This was coupled with extensive further studies on blood lymphocytes from normal and thymectomised SLAb/b inbred pigs. These mAbs formed two groups: those mainly identifying the large blood-borne thymus-dependent Null T cells (N) and those reacting with tissue and a small number of blood-borne thymus-independent lymphocytes (N'). Based on their tissue cell reaction patterns, the 10 N' mAbs formed three main groups: N'1A and B; N'2A and B; and N'3. The 12N mAbs fell into four groups N4-N7; N6 was divided into subgroups A-D. One N' (032) and two N mAbs (010 and 063) were unclustered. Based on these data, swine workshop cluster numbers were designated to groups N5 (021, 022 and 059) as SWC4, N6 (061 and 117) as SWC5 and N7 (020 and 141) as SWC6, the latter exceptionally as a single antibody, MAC320, since it is the 'type' mAb identifying effectively all blood Null T lymphocytes. Future research and workshops will have to define with a wider range of techniques the relationships, molecular properties and functional roles of the several new, perhaps novel, antigens identified by this family of fascinating, as yet still poorly defined, mAbs. PMID- 7856060 TI - Interferon response in pigs: molecular and biological aspects. AB - This paper reviews the current state of knowledge on porcine interferons (IFN). Three type I IFN subfamilies (IFN alpha, beta and omega) and one type II IFN (IFN gamma) have been identified in the porcine species. A list of the known porcine IFN genes and already produced recombinant proteins, as compiled from the literature, was included. Two major aspects of porcine IFN were discussed: (1) IFNs as host responses to infections, and (2) IFNs in pregnancy. The first part mainly focusses on the IFN production by virus-infected pigs and the nature of IFN alpha secreting leukocytes. The second part reviews recent data showing the secretion of two different IFNs by the pig embryo at the time of implantation. One striking finding was that a non-lymphoid tissue, namely the porcine trophoblast, was able to secrete high levels of IFN gamma. In addition, the expression of another, newly described, IFN gene was also shown in pig trophectoderm. This novel trophoblastic type I IFN differs from the others in size and sequence. Several hypotheses are discussed on the possible role(s) of porcine embryonic IFNs at the initial stages of gestation. PMID- 7856061 TI - Porcine cytokines. AB - Cytokines play a central role in modulation of immunological and physiological processes in animals under both homeostatic and abnormal conditions. Currently available information from a variety of species indicates that interleukins, interferons and tumor necrosis factor mobilize immune responses, activate inflammatory reactions and communicate with organ systems; colony stimulating factors regulate hematopoiesis and hematopoietic cell function; transforming growth factor beta affects wound healing, bone remodeling and cellular differentiation. Our understanding of cytokine biology in pigs is selective and based largely on effects of human proteins in porcine models of human diseases. However, knowledge of the nature and role of cytokines in swine immunology and physiology is increasing rapidly due to the application of molecular cloning techniques to porcine cytokines. This review summarizes the current state of knowledge of porcine cytokines and focuses on biological processes in which the porcine proteins have been investigated in swine. PMID- 7856062 TI - Characteristics of porcine T lymphocytes and T-cell lines. AB - Monoclonal antibodies (mAb) against leucocyte differentiation antigens have altered the way in which immunologists examine the immune system. These mAb allow us to identify distinct surface molecules on leucocyte populations, by which these cells can be classified, isolated and studied for their functional properties. This review summarizes the knowledge about differentiation antigens useful in the characterization of porcine T lymphocytes. Furthermore, it focuses on several properties of porcine T lymphocytes, T-lymphocyte subpopulations and the generation of porcine antigen-specific T-cell lines. PMID- 7856063 TI - The immunoglobulins and immunoglobulin genes of swine. AB - The historical works describing the characterization of swine immunoglobulins are reviewed. The three major isotypes, IgM, IgA and IgG, have been recognized for 25 years and their concentrations in various body fluids, the location of the plasma cells throughout the body which synthesize them and their transport into lacteal secretions and absorption by the gut of the newborn piglet, have been studied by many investigators. Swine like humans, have both kappa and lambda light chains and their frequency of expression is similar to that of humans. Various investigators have provided immunochemical evidence for IgG subclass and allotype diversity, although until the recent advent of molecular biology, the complete sequence of any swine immunoglobulin was unknown. Molecular genetic studies reveal single copies of C alpha and C epsilon but as many as eight copies of C gamma. The sequences of five IgG subclasses, IgG1, IgG2a, IgG2b, IgG3 and IgG4, are now available as well as the sequence and genomic organization of C alpha and the sequence of C mu. Swine CH genes all appear to belong to a single small family very similar to human VHIII. Especially interesting is the high degree of similarity among human and swine Ig genes despite the distinct phylogenetic relationship of these species. The rapid expansion of knowledge and technology in the field of molecular biology, together with the attractiveness of the swine as a model for immunoontogeny, in which the influences of both maternal regulatory factors and intestinal gut flora can be experimentally controlled, promises the beginning of an exciting area in swine immunology. PMID- 7856064 TI - Porcine peripheral blood CD4+/CD8+ dual expressing T-cells. AB - The porcine T-cell population is unique in that there is a large percentage of CD+CD8+ dual expressing peripheral T-cells. This paper reviews the data available on these porcine T-cells and compares them to the much rarer dual expressing T cells in humans. The percent of dual expressing cells increases with activation in in vitro culture with various antigens including pseudorabies virus. The percent of resting dual expressing cells also increases with the age of the pig. Flow-cytometric-sorted dual expressing cells responded in culture to the super antigen staphylococcal enterotoxin B. Selected CD4+CD8- cells cultured in vitro developed expression of CD8 and maintained the dual expressing phenotype for the 12 weeks of culture. Dual expressing cells freshly prepared from porcine blood did not express the IL-2 receptor as demonstrated by their failure to bind FITC IL-2 and an anti-porcine IL-2 receptor monoclonal antibody. In response to activation with phorbol myristic acetate, CD4, but not CD8, was down regulated on the dual expressing T-cells. In summary, porcine dual expressing T-cells constitute a substantial percentage of the porcine peripheral T-cell pool. These cells appear to contain the majority of the memory T-cell with their frequency increasing with blood donor age and in vitro culture. Although the receptor specificity is not known, they have a functional receptor. Finally, the function of the two accessory molecules CD4 and CD8 in these cells is not known, but their regulation is distinct, thereby suggesting no equivalent roles in immune function. PMID- 7856065 TI - Antigen presenting cells and B-cells in the pig. AB - The central position of antigen presenting cells (APC) in the immune system and the heterogeneity of the APC family are discussed; both aspects are illustrated with data from species other than the pig. Thereafter the limited work on porcine APC is reviewed. The section on B-cells, the effector cells of the humoral immune system, exclusively focuses on 'porcine data'. PMID- 7856066 TI - The Null/gamma delta TCR+ T cell family in the pig. AB - The very large population of highly thymus-dependent, non-adherent 'Null' blood lymphocytes in young pigs, which lack most surface markers characteristic of classical T-cell subsets, have recently been shown to bear several novel population- and subset-specific antigens and gamma delta T-cell receptors. These T-lymphocytes differ radically from conventional CD2-positive T-cells in their origins, biological lifespan, tissue distribution, migration behaviour, cell surface phenotype, immunological responsiveness and mechanisms of trafficking through constitutive lymphoid tissues and inflammatory lesions. Elucidation of the roles of these enigmatic cells and their characteristic surface macromolecules in the initiation and regulation of immune functions promises to reveal much of fascination. PMID- 7856067 TI - Lymphoid tissue structure and lymphocyte trafficking in the pig. AB - The organised lymphoid tissues of the pig, though conventionally mammalian in most respects, show several distinctive properties in their structure and physiology. Specialised antigen-presenting lymphoid organs function at three compartmental levels: the body surfaces, their draining lymph nodes and the spleen in the bloodstream. Other organs act as lymphocytic depots and sites of phagocytosis of debris. Pig lymphocytes recirculate continuously through these organs and through different forms of inflammatory change, experimentally induced by mitogens and cytokines, using a spectrum of distinctively different physiological mechanisms. These tissues in the young pig differ both in the resting and activated cell subsets and the molecules involved, many of which remain to be completely defined. Intriguing insights are evident in the subtlety of regulation of the specificity, level and foetal ontogeny of trafficking mechanisms in these different tissues, though they are as yet poorly explained. This subtle molecular physiology is only now emerging because appropriate monoclonal antibody reagents are being developed and rigorous attention is being paid to the use of gentle physiological methods in experiments in vivo. PMID- 7856068 TI - Immunity to transmissible gastroenteritis virus and porcine respiratory coronavirus infections in swine. AB - Despite the pioneering efforts to identify correlates of passive immunity to transmissible gastroenteritis virus (TGEV), effective vaccines for the control of TGE in suckling pigs have remained elusive. The initial concept of an enteromammary immunologic axis in monogastrics originated from studies of lactogenic immunity to TGEV in swine. These studies revealed that infection of pregnant swine with virulent TGEV stimulated high titers of SIgA antibodies in milk which correlated with protection of suckling pigs against TGE; parenteral or oral inoculation with live attenuated or killed TGEV vaccines induced mainly IgG antibodies in milk which generally provided poor protection to suckling pigs. The recent appearance of PRCV infections in swine and continuing studies of TGEV infections, present a unique model for further studies of mucosal immunity. Research using these viruses has increased our understanding of the various components of the common mucosal immune system and their interactions. Although the most important consideration in designing an effective vaccine for TGEV is the stimulation of GALT through intestinal virus replication, studies addressing the contribution of BALT to immunity to TGEV and PRCV may provide insights for alternative vaccine approaches. The mechanism by which exposure to PRCV elicits a variable-degree of immunity to TGEV challenge is unknown. Virus replication in the gut or respiratory tract is a major factor affecting the magnitude of the immune response at the respective site and may be necessary for the recruitment of specific immune cells from other mucosal inductive sites, i.e., GALT to BALT and BALT to GALT migration.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7856069 TI - Porcine immune responses to African swine fever virus (ASFV) infection. AB - Immune responses mediating protection against ASFV are poorly understood. Anti ASFV antibodies may influence the course of the clinical disease but they have never been found to neutralize the virus. Recent developments on cellular defense mechanisms, using swine protection models, and on the induction and role of some cytokines warrant further investigation on these areas. PMID- 7856070 TI - An experimental study of primary feline immunodeficiency virus infection in cats and a historical comparison to acute simian and human immunodeficiency virus diseases. AB - Sixteen adolescent specific pathogen free cats were inoculated with the Petaluma strain of feline immunodeficiency virus (FIV) and two cats were then necropsied at each of 5, 10, 21, 28, 42, 56, 70, and 84 day time points following infection. Lymphadenopathy gradually increased starting at Day 10 and persisted for the duration. Gross clinical signs of fever, mild to severe malaise, anorexia, diarrhea, dehydration, and generalized soreness appeared around Day 42, peaked at Day 56, and disappeared by Days 70-84 post-infection. Leukopenia, associated initially with a mild lymphopenia and later by both a mild lymphopenia and a severe neutropenia, appeared 14-28 days following infection, troughed at Day 56, and persisted thereafter. The CD4+:CD8+ T cell ratio started to decrease around Day 28, reaching a nadir at Days 56-70. This decrease was due to a decline in the absolute numbers and percentage of CD4+ T cells and an increase in the percentage of CD8+ T cells. Significant histopathologic lesions included myeloid hyperplasia between Days 56-70 post-infection; thymitis with cortical involution and follicular hyperplasia starting at Day 42; lymphoid hyperplasia of peripheral and mesenteric nodes, spleen and tonsils beginning around Day 42; typhlitis most evident from Day 56 onward, and an interstitial nephritis and pneumonitis that was most intense after Day 42. Virus was isolated from peripheral blood mononuclear cells (PBMC) beginning 2 weeks post-infection, and plasma viremia appeared 1 week later. Plasma and PBMC-associated viremia peaked at 42-56 days following infection and decreased abruptly thereafter. Proviral DNA was detectable as early as 5 days after infection in blood leukocytes and after 10 days in other organs. The central nervous system, lungs, thymus, tonsils and mesenteric lymph nodes were the earliest sites of virus localization. Antibodies to the FIV capsid protein appeared 14 days following infection and reached peak levels by Days 42-56. Abnormalities occurring during the primary stage of FIV infection were consistent with those described for acute simian and human immunodeficiency virus-induced disease. PMID- 7856071 TI - Production, preliminary characterisation and applications of monoclonal antibodies to porcine circovirus. AB - The preparation of monoclonal antibodies (mAbs) to porcine circovirus is described. Preliminary characterisation was carried out on nine mAbs obtained from two fusions and included isotyping, virus neutralisation assays and indirect immunofluorescence staining patterns obtained following immunostaining of both a porcine circovirus (PCV)-persistently infected pig kidney (PK/15/W) and Vero (Vero-PCV) cell line. Significant differences in the staining patterns were observed in both cell lines which appeared to be dependent on the subculture status of the Vero-PCV cultures. The development of a mAb-based antigen capture enzyme linked immunosorbent assay (ELISA) as an aid to virus purification is also described. The use of mAbs for the detection of PCV antigen in cryostat sections from a pig experimentally infected with the virus leading to identification of the sites of replication of PCV is also reported. PMID- 7856072 TI - Social rank and disease susceptibility in pigs. AB - Two experiments were carried out to investigate the inter-individual variation in immune reactivity and disease susceptibility of group housed pigs of different social status. The social status of the individual pig was determined by the outcome of social ranking fights and food competition tests. On Day 75 after the start of both experiments, all pigs were challenged with 0.5 ml of an Aujeszky disease virus (ADV) in each nostril. Data combined from both experiments showed that mortality and/or morbidity after the ADV challenge was highest among subordinates. In both experiments, a lymphocyte proliferation assay, using purified ADV as an antigenic stimulus, showed that dominant pigs had significantly higher counts per minute than subdominant and subordinate pigs. Kendall's partial correlations showed that morbidity had been associated with high values in haematological and clinicochemical blood parameters and not with social status of the individual pig. In each experiment, maternal derived antibodies against the ADV and the antibody level after the ADV challenge hardly differed between pigs of different social status. Major histocompatibility complex typing of class I and II by iso-electro focusing of all pigs in Experiment 2 showed that not all haplotypes were distributed equally among dominant, subdominant and subordinate pigs. The present work shows that there are large individual differences in immune reactivity and disease susceptibility which appear to be related to the social status of the individual pig in a stable social structure. PMID- 7856073 TI - Distribution of Border disease virus antigen in lymphocyte subpopulations in the peripheral blood of experimentally infected lambs. AB - Ten lambs were experimentally infected with Border disease virus and the distribution of viral antigen in lymphocyte subpopulations studied by flow cytometry. The virus was isolated in culture from the peripheral blood mononuclear cells (MNC) of all experimentally infected lambs for a mean period of 9.8 +/- 1.03 days. The peak virus titre of 3.26 log10 TCID50 per 10(6) MNC was attained Day 9 post-inoculation (pi). Viral antigen was present in peripheral blood lymphocytes of experimentally infected lambs as early as 24 h pi and continued to be detected up to Day 10 pi. The number of lymphocytes expressing viral antigen rose from 12.38 +/- 1.22% in samples taken Day 3 pi to 23.21 +/- 2.82% on those collected Day 7 pi, dropping gradually thereafter. During the peak period of infection, 12.46 +/- 2.09% of B cells, 37.71 +/- 10.96% of T cells and 52.33 +/- 8.27% of lymphocytes which were neither B nor T lymphocytes expressed viral antigen. Most of the infected lymphocytes expressed the OvCD5 (T cell) molecule. The virus affected all T cell subsets but the suppressor/cytotoxic (OvCD8+) cells appeared to be the main targets. During the peak period of infection, 54.20 +/- 6.16% of the infected T cells expressed the OvCD8 molecule, 31.58 +/- 7.12% were OvCD4+, and 12.67 +/- 6.50% were OvWC1+ (T-19+, gamma/delta). PMID- 7856074 TI - Caprine arthritis encephalitis virus infection changes caprine blood monocyte responsiveness to lipopolysaccharide stimulation in vitro. AB - The effects of caprine arthritis encephalitis virus (CAEV) infection on cytokine activity of caprine monocytes stimulated with Escherichia coli lipopolysaccharide (LPS) were examined. Compared with supernatants from LPS-stimulated monocytes of CAEV-negative goats, supernatants from CAEV-positive goats stimulated less proliferation of murine thymocytes in the MTT (3-(4,5-dimethylthiazol-2-yl)2,5 diphenyl tetrazolium bromide) assay, showed about 50% less IL-1 activity on the IL-1-dependent cell line LBRM-33 1 A-5, and showed about 200% more tumor necrosis factor (TNF) activity on the TNF-sensitive murine fibroblast cell line L-929. These results indicate that CAEV infection changes caprine monocyte cytokine responsivity. PMID- 7856076 TI - Endogenous enzymatic activities of the avian reovirus S1133: identification of the viral capping enzyme. AB - Avian reovirus S1133 was shown to contain all the enzymatic activities required for the synthesis of mature viral transcripts, including a dsRNA-dependent RNA polymerase, a nucleoside triphosphate phosphohydrolase, an mRNA guanylyltransferase, and two mRNA methyltransferases. The virus used these enzymes both in vitro and in vivo to catalyze the synthesis of viral mRNAs containing a type-1 cap at their 5' ends. Incubation of reovirions with GTP led to the formation of an intermediate structure consisting of GMP bound to the viral core protein lambda 3 through a phosphoamide linkage. The reaction was specific for GTP and required the presence of both Mg2+ and inorganic pyrophosphatase. The GMP moiety can be transferred from the lambda 3-GMP complex to acceptors such as GDP and GTP, yielding GpppG and GppppG, respectively. Our results demonstrate that lambda 3 is the avian reovirus guanylyltransferase. PMID- 7856075 TI - Capsid protein determinants involved in cell-to-cell and long distance movement of tobacco etch potyvirus. AB - The tobacco etch potyvirus (TEV) capsid protein (CP) is necessary for cell-to cell and long distance transport of the virus in plants. In this study, the transport phenotypes of TEV mutants containing CPs with a substitution of the highly conserved Ser122 (termed S122W) within the core domain, or with a deletion of sequences encoding 17 amino acid residues comprising most of the variable C terminal domain (delta C), were analyzed. The S122W and delta C mutant genomes were amplified to levels comparable to parental virus in protoplasts. The S122W mutant was encapsidation-defective, although in transgenic plants expressing wild type CP a small number of virions were observed after prolonged incubation. Cells infected by the delta C mutant produced virions, indicating that the C-terminal domain is not necessary for encapsidation. The mutants exhibited unique defects in cell-to-cell and long distance movement in plants. The S122W mutant was confined to single, primarily inoculated epidermal cells in nontransgenic plants, but the cell-to-cell movement defect was rescued efficiently by transgenic CP. Long distance movement of this mutant was also rescued in transgenic plants, but accumulation in systemically infected tissue was low compared to parental virus. The delta C mutant exhibited a slow cell-to-cell movement phenotype in inoculated leaves and a complete inability to move systemically in nontransgenic plants. Transgenic CP was able to rescue partially the slow cell-to-cell movement defect of the delta C mutant, but not the long distance transport defect. Taken together with previous results, these data suggest that the core domain of TEV CP provides a function essential during cell-to-cell movement and that the variable N- and C terminal regions exposed on the virion surface are necessary for long distance transport. In addition, trans-inhibition models are presented to account for the widely differing transgenic complementation efficiencies of the various movement defective mutants. PMID- 7856077 TI - A pseudo-revertant of a Sindbis virus 6K protein mutant, which corrects for aberrant particle formation, contains two new mutations that map to the ectodomain of the E2 glycoprotein. AB - Most site-directed mutations in the gene encoding the small, membrane-associated 6K protein of Sindbis virus interfere selectively with virus assembly and budding. Particles are released that are aberrant in structure, with a single membrane enclosing multiple nucleocapsids. A revertant for the mutation that inserted a serine for a cysteine at position 39 in the 6K protein was isolated and found to correct for the defective budding so that normal particles were formed. Genetic analysis of this revertant showed that two additional mutations, which were mapped to the ectodomain of the E2 virus glycoprotein, were present in addition to the original 6K substitution. The phenotype of the revertant differed from the wild-type strain and the original mutation with regard to plaque size, thermostability, and growth in neuronal cells. Five new virus genetic constructs were prepared by insertion of these mutations into the wild-type virus. Phenotypes of these constructs confirmed that the mutations in the E2 ectodomain were responsible for both correcting the original defect in budding as well as imparting changes in cell tropism, plaque size, and thermolability on the virus. These results indicate that 6K may play an indirect role in the packing of the virus spike glycoproteins, which allows for membrane deformation and bending during the budding process. PMID- 7856078 TI - Identification of structural proteins of channel catfish virus by mass spectrometry. AB - Emerging methods that couple mass spectrometry of fragments generated from isolated proteins with database searching offer a powerful means of identifying proteins and the genes that encode them. We have applied this technology to a herpesvirus, channel catfish virus, and have identified 12 genes, 11 viral and 1 cellular, that encode 16 principal structural proteins. These proteins include three components of the mature capsid and a potential scaffolding protein present in immature capsids, three protein kinases, a C3HC4 zinc-binding protein and cellular actin located in the tegument, and a multiply hydrophobic protein associated with the envelope. PMID- 7856079 TI - Genetic analysis of beet curly top virus: examination of the roles of L2 and L3 genes in viral pathogenesis. AB - The monopartite DNA genome of beet curly top geminivirus (BCTV, strain Logan) contains four leftward (complementary sense) open reading frames (ORFs) designated L1, L2, L3, and L4. We investigated the functions of the L2 and L3 ORFs by mutational analysis. We found that in Nicotiana benthamiana and sugarbeet plants, neither a functional L2 nor a functional L3 gene is required for infectivity. Double mutants were also infectious, and no evidence for a synergistic effect of these genes was evident. However, while sugarbeet plants inoculated with L2 or L3 mutants showed symptoms that were indistinguishable from those elicited by wild type virus, mutant-inoculated N. benthamiana plants displayed a novel phenotype in which recovery of the plant from initially severe disease symptoms was greatly enhanced. Enhanced recovery was associated with a large reduction in viral DNA levels. Our studies did not provide evidence for functional homology between the BCTV L2 gene and its presumed homologue (AL2) in the bipartite geminiviruses. In contrast, mutants with lesions in the L3 ORF accumulated three- to five-fold less DNA than wild type virus in a protoplast replication assay, consistent with the interpretation that the BCTV L3 gene is a homologue of the bipartite geminivirus AL3 gene which is known to function as a replication enhancer. Functional homology was directly confirmed in experiments which demonstrated that the BCTV L3 gene can complement a tomato golden mosaic virus AL3 mutant, and vice versa. PMID- 7856080 TI - The UL37 protein of herpes simplex virus type 1 is associated with the tegument of purified virions. AB - The herpes simplex virus type 1 (HSV-1) UL37 open reading frame encodes a 120-kDa late (gamma 1) phosphoprotein in infected cells. Analysis of isolated mature HSV virions and light particles revealed that the UL37 protein is a component of the virion. Detergent solubilization and protease digestion experiments suggest that the UL37 protein is part of the tegument structure. Indirect immunofluorescence experiments using HSV-1-infected cells and cells infected with a vaccinia recombinant virus that expresses the UL37 gene demonstrated that the UL37 protein is present in both the nucleus and cytoplasm of infected cells and that localization to the nucleus does not require additional HSV proteins. PMID- 7856081 TI - HTLV-1 Tax enhances NF-kappa B2 expression and binds to the products p52 and p100, but does not suppress the inhibitory function of p100. AB - Tax protein of HTLV-1 triggers transcriptional activation through enhancers, NF kappa B binding site, 21-bp enhancer, and serum response element. Previously, we demonstrated binding of Tax to transcription factors NF-kappa B1 p105 and p50. Here, we report that Tax enhances expression of NF-kappa B2 at the mRNA level and proteins; the effect was more apparent on the p52 expression than on its precursor p100, suggesting post-translational regulation. Consistent with these observations, HTLV-1-infected T-cell lines expressed higher levels of p52. Tax binds to the protein products p52 and p100 which inhibits NF-kappa B proteins forming cytoplasmic complexes; the binding to p100 was preferential over NF-kappa B1 p105. However, Tax did not induce efficient dissociation of the cytoplasmic complexes p100/c-Rel or p100/p65, and thus did not induce nuclear translocation of c-Rel or p65. This was in sharp contrast to the previous observation that Tax dissociated the p105/c-Rel and I kappa B-gamma/p65 complexes. These results indicate that HTLV-1 Tax interacts with NF-kappa B2 p100 and p52 and upregulate the NF-kappa B function, but their contribution to Tax-mediated transcriptional regulation differs from those of NF-kappa B1. PMID- 7856082 TI - Neurovirulence test for oral live poliovaccines using poliovirus-sensitive transgenic mice. AB - The transgenic mice, ICR-PVRTg21, carrying the human poliovirus receptor gene, were intraspinally inoculated with oral poliovirus vaccine viruses and the viruses that had been derived from a vaccine preparation by passagings at 38 degrees. Dose-dependent incidence of paralysis was observed in the transgenic mice inoculated with any of the viruses used. All transgenic mice showing histopathological lesions in the central nervous system appeared to display clinical signs that resembled those observed in human poliomyelitis. These suggest that relative neurovirulence levels of individual virus preparations can be estimated by values of 50% paralysis dose. Indeed, the parameter correlated well with monkey lesion scores of viruses used. Histopathological changes such as degeneration of neurons resemble those displayed by monkeys and were observed in the spinal cord, medulla oblongata, and pons. Thus, the transgenic mice, ICR PVRTg21, may become a new animal model in place of monkeys for safety testing of oral poliovirus vaccine preparations. PMID- 7856083 TI - HIV-1 envelope glycoprotein gp120 does not bind to galactosylceramide-expressing rat oligodendrocytes. AB - It may be postulated that the encephalopathy induced by the human immunodeficiency virus HIV-1, in particular, the characteristic "myelin pallor," may result from binding of the envelope glycoprotein gp120 to galactosylceramide and/or its metabolite sulfatide in the plasma membrane of oligodendrocytes, the myelin forming cells in the central nervous system. (1) gp120 has been reported to have a high affinity for these molecules in vitro. (2) The binding of antibodies to these molecules increases intracellular free calcium levels, which may be cytotoxic. (3) The binding of gp120 to the CD4 receptor in the immune system has the same effect. We have investigated the binding of gp120 to rat oligodendrocytes in vitro by indirect immunofluorescence and have monitored changes in intracellular free calcium with the calcium-sensitive dye INDO-1, in individual oligodendrocytes exposed to the glycoprotein. Antibodies against galatosylceramide and sulfatide bound to the cell membrane, but gp120 did not. The antibodies also increased intracellular free calcium levels in the oligodendrocytes, whereas gp120 did not. It, therefore, seems highly improbable that the demyelination observed during HIV encephalopathy is a direct cytotoxic effect of gp120 on oligodendrocytes. PMID- 7856084 TI - A suboptimal src 3' splice site is necessary for efficient replication of Rous sarcoma virus. AB - Regulation of splicing of Rous sarcoma virus (RSV) RNA primary transcripts is necessary, as with other retroviruses, to allow for the accumulation of unspliced RNA and approximately equivalent amounts of spliced env and src mRNAs. Previous studies have indicated that the env 3' splice site is suboptimal because it has a nonconsensus branchpoint sequence and that this suboptimal splice site is required for virus replication (R. A. Katz and A. M. Skalka, 1990, Mol. Cell Biol. 10:696-704). We show in this report that the RSV src 3' splice site is also suboptimal. Mutagenesis of the src polypyrimidine-rich tract, which is interspersed with purines, to an uninterrupted 14-nt pyrimidine tract resulted in a three- to fourfold increase in the level of src splicing. Concomitant with this increase in src splicing, a cryptic 5' splice site within the env gene was activated. Splicing at this splice site is normally detected in nonpermissive mammalian cells were src splicing is elevated but occurs at low levels in permissive chicken embryo fibroblasts (CEF). In CEF, mutant viruses with the improved src 3' splice site replicated significantly slower than the wild-type virus. Transformation-defective revertants lacking the src 3' splice site were rapidly selected after passage of the chicken cells infected with the mutant virus. Thus, an inefficient src 3' splice site appears to be necessary for the efficient replication of RSV. PMID- 7856085 TI - Identification of structural features of heparin required for inhibition of herpes simplex virus type 1 binding. AB - Binding of HSV-1 to cells is mediated by interactions of virion glycoproteins gC and/or gB with heparin sulfate (HS) glycosaminoglycans on cell surface proteoglycans. HS and the related glycosaminoglycan, heparin, comprise a family of heterogeneous carbohydrates composed of long, unbranched polysaccharides modified, for example, by sulfations and acetylations. To define the specific features of HS important for viral binding, we took advantage of the structural similarities between heparin and cell surface HS and compared the ability of chemically modified heparin compounds to inhibit the binding of viral particles to the cell surface and subsequent plaque formation. Because binding presumably involves multiple, complex interactions between both known heparin-binding glycoproteins, gC and gB, and cell surface HS, we compared the effects of modified heparin compounds on the binding and subsequent plaque formation of wild type and gC-negative strains of HSV-1 and, in select cases, the binding of gB negative virus to cells. We identified specific structural features of heparin essential for the inhibition of viral binding. For example, both N-sulfation and 6-O-sulfation must be important determinants since desulfation of heparin at these sites abolished or decreased the antiviral activity of heparin. Moreover, we found that the antiviral activity of heparin was independent of its anticoagulant activity. Carboxyl-reduced and 2,3-O-desulfated heparin selectively inhibited binding of gC-positive viruses (wild-type or a gB-negative strain) to cells, but had little or no inhibitory effect on binding and subsequent plaque formation for a gC-deletion virus. These results suggest that gC and gB interact with different structural features of HS. PMID- 7856086 TI - A recombinational event in the history of luteoviruses probably induced by base pairing between the genomes of two distinct viruses. AB - Alignments of luteovirus readthrough protein amino acid sequences show they consist of two distinct regions, here named the N domain and the C domain. N domain sequences were classified, and comparison of this gene phylogeny to phylogenies of other luteovirus genes revealed an anomaly in the relationships between beet western yellows luteovirus, cucurbit aphidborne yellows luteovirus (CABYV), and pea enation mosaic RNA1 (PEMV1). Together with alignments of virion protein and readthrough protein amino acid sequences, these gene phylogenies indicate the anomaly to be the result of two recombinational events, probably between ancestors of CABYV and PEMV1 and leading to the transfer of RNA coding for the N domain to an ancestor of CABYV. Two likely recombination sites were identified from the alignments, one at the 5' end of the readthrough protein gene and the other at the 5' end of the sequence coding for the C domain. Alignments of the nucleotide sequences encompassing the probable recombination sites suggest that base-pairing between the genomes of the two ancestral luteoviruses, resulting from local sequence similarity at the 5' end of the readthrough protein gene, probably induced one of the interspecies recombinational events. PMID- 7856087 TI - Phylogeny of TYU, SRE, and CFA virus: different evolutionary rates in the genus Flavivirus. AB - The nucleotide and deduced amino acid sequence of the envelope (E) gene of Tyuleniy (TYU) and Saumarez Reef (SRE) virus have been determined and the data used to classify these viruses in relation to the other tick- and mosquito-borne viruses in the genus Flavivirus. The phylogenetic trees obtained by maximum parsimony and distance methods for 22 flavivirus E genes showed that TYU and SRE virus are a sister group of the TBE virus complex. The trees were consistent with the Flavivirus serological classification and are compatible with the proposition that Cell Fusing Agent could be another genus in the family Flaviviridae. Comparison of the phylogeny and mutational regime of the E gene with the RNA dependent RNA polymerase (NS5) gene shows the validity of the E gene as a phylogenetic marker and suggests that the mosquito-borne flaviviruses are evolving twice as fast as the tick-borne flaviviruses. The implications of these observations are discussed. PMID- 7856088 TI - Mapping and sequence of the gene encoding protein p17, a major African swine fever virus structural protein. AB - The gene encoding protein p17, a major structural protein of African swine fever virus, has been mapped and sequenced. Protein p17 was purified from dissociated virus by reverse-phase HPLC and the amino acid sequence of a peptide obtained after digestion of protein p17 with cyanogen bromide was determined by automated Edman degradation. To map the gene encoding protein p17, a mixture of 17-mer oligonucleotides based upon a part of the amino acid sequence was hybridized to cloned African swine fever virus DNA restriction fragments. This allowed the location of the gene in the fragment EcoRI D of the viral genome. The nucleotide sequence of a Sa/l/KpnI fragment revealed an open reading frame designated D117R encoding a protein of 117 amino acids with a deduced molecular mass of about 13,000 Da. A transcriptional analysis revealed that the p17 gene is expressed late in the viral infection cycle. PMID- 7856089 TI - Identification of the cauliflower mosaic virus movement protein RNA-binding domain. AB - The in vitro RNA-binding activity of the movement protein (P1) of cauliflower mosaic virus was studied after its expression in Escherichia coli, purification, and uv-crosslinking to a radioactive probe. It was found that insoluble P1 aggregates were involved in RNA-binding activity. A series of deletion mutants were used to identify a domain within P1 required for binding activity. The RNA binding domain is located between amino acids 120 and 197 and includes the region of homology between P1 and the movement protein (P30) of tobacco mosaic virus (TMV). The homologous region corresponds to part of RNA-binding domain "A" in TMV P30, but unlike domain A, the P1 domain is able to bind RNA out of the context of the complete protein. The P1 RNA-binding domain shows some structural similarity with RNA-binding domains of other proteins. The conservation of this domain in the caulimo- and badnaviruses provides support for the view that this activity has biological relevance. PMID- 7856090 TI - Functional similarities between HIV-1 Tat and DNA sequence-specific transcriptional activators. AB - The Tat regulatory protein encoded by human immunodeficiency virus type 1 (HIV-1) induces high levels of transcription from the viral long terminal repeat (LTR) promoter element after interacting with a promoter proximal RNA target sequence. In the wild-type HIV-1 LTR, this activation is facilitated by the synergistic interaction of Tat with the NF-kappa B and, particularly, SP1 regulatory proteins that bind to DNA sequences within the LTR promoter element. Using a synthetic Tat responsive indicator construct, we here demonstrate that NF-kappa B and SP1 are not uniquely or even unusually competent to synergize with HIV-1 Tat. Instead, these proteins can be functionally replaced by several, but not all, of the heterologous cellular and viral transcriptional activators tested. Tat therefore shares the ability to functionally synergize with a range of transcriptional activators, which is characteristic of DNA-sequence-specific regulatory proteins. PMID- 7856091 TI - Key role of a CCAAT element in regulating hepatitis B virus surface protein expression. AB - Two separate promoters, the upstream preS1 and the downstream S promoters, give rise to transcripts encoding three forms of the hepatitis B virus surface protein. Overproduction of large surface protein because of increased preS1 transcripts leads to a block in secretion of all forms of the surface protein and of virion particles. We show here that a CCAAT element in the S promoter not only increases the amount of S transcripts, but also decreases the amount of preS1 transcripts by up to fivefold. Consequently, mutations in this element cause intracellular accumulation of surface proteins because of the secretory block. Therefore, this CCAAT element appears to be critical for maintaining the high ratio of S versus preS1 transcripts that is necessary for the viral life cycle. PMID- 7856092 TI - Probing the structure of influenza B hemagglutinin using site-directed mutagenesis. AB - The crystal structure of the hemagglutinin (HA) of influenza virus A/Aichi/68 (H3N2) from the X-31 reassortant virus was reported in 1981, but as yet there are no X-ray diffraction structures for hemagglutinins of other types or even subtypes of influenza virus. We have used site-directed mutagenesis to probe the structure of the hemagglutinin of influenza B/Hong Kong/8/73. We investigated a region in the globular head domain that is helical in the influenza A HA structure, targeting sidechains that in the H3 HA point toward solvent (Thr196) or into the receptor-binding pocket (Gln197). None of the mutations affected hemagglutination activity, but mutations T196P or Q1971 eliminated binding of a monoclonal antibody. The data suggest that this region of the influenza B HA forms a surface structure different from the alpha-helix of the influenza A HA structure and that it accounts for much of the antigenic activity of influenza B HA. PMID- 7856093 TI - Differences in feline immunodeficiency virus host cell range correlate with envelope fusogenic properties. AB - Feline immunodeficiency virus (FIV) establishes persistent infections in cats inducing an acquired immunodeficiency syndrome. Differences in cell tropism have been observed among isolates of FIV (T. R. Phillips et al., J. Virol. 64, 4605 4613, 1990). The progeny of the infectious molecular clone of FIV p34TF10 was able to productively infect a feline fibroblast cell line, Crandell feline kidney cell, (CrFK), while the progeny of the molecular clone pPPR was not. However, pPPR, after transfection of CrFK cells, did produce virions which were able to productively infect feline lymphocytes. To analyze the mechanisms responsible for such differences in tropism and particularly the role of the envelope glycoproteins (Env), Env expression vectors were constructed by deletion of gag and pol genes from 34TF10 and PPR proviral clones. Env expression and function were studied by using a syncytium-formation assay and a quantitative ELISA. After transfection of CrFK, both 34TF10 and PPR Env precursors were correctly processed and Env surface glycoprotein, gp100, was released in culture supernatants. However, the Env of 34TF10 caused a dramatic syncytial effect in CrFK cells, while PPR Env did not induce any syncytium formation. The Env of 34TF10 placed under the control of the long terminal repeat of PPR maintained its ability to induce CrFK fusion. These results suggest that the inability of FIV PPR to infect CrFK fibroblasts is related to a restriction of virus entry mediated by the viral envelope. PMID- 7856094 TI - Minimal sequence requirements for synthetic peptides derived from the V3 loop of the human immunodeficiency virus type 1 (HIV-1) to enhance HIV-1 binding to cells and infection. AB - We previously demonstrated that a 23-mer peptide (DB3) derived from the V3 loop of the surface glycoprotein of HIV-1 MN strain was able to bind to soluble CD4 and enhance HIV-1 infection. The mechanism and structural features required for these biological activities were studied by using shortened DB3 derivatives and DB3 analogs carrying single amino acid substitutions. We found that peptides in which the aromatic amino acid in position 15 or 16 had been replaced by an uncharged hydrophobic residue (DB3-I15 and DB3-I16), analogs in which positively charged amino acids were replaced by corresponding D-enantiomers, and shortened DB3-derivatives lost both enhancing activity and ability to bind to soluble CD4. Other peptide variants in which a positively charged amino acid was replaced by asparagine at positions 3 (DB3-N3), 6 (DB3-N6), and 19 (DB3-N19), respectively, retained both enhancing and binding activities, although with different efficiencies. The CD4 binder peptides DB3 and DB3-N19, but none of the CD4 nonbinder peptides, enhanced CD4 expression on peptide-treated cells as well as gp120 binding to both CD4+ cells and soluble CD4. These findings strongly suggest that the peptide/CD4 interaction induced an increase in both CD4 expression and CD4/gp120 binding affinity, which in turn mediated the enhancement of viral infection. A model of the structural conformation of DB3 peptide required for its biological activities is discussed. PMID- 7856095 TI - Complete sequence (20 kilobases) of the polyprotein-encoding gene 1 of transmissible gastroenteritis virus. AB - The entire nucleotide sequence of cloned cDNAs containing the 5'-untranslated region and gene 1 of Purdue-115 strain of transmissible gastroenteritis virus (TGEV) was determined. This completes the sequence of the TGEV genome, which is 28,579 nucleotides long. The gene 1 is composed of two large open reading frames, ORF1a and ORF1b, which contain 4017 and 2698 codons, respectively (stop excluded). A brief, three-codon-long ORF is present upstream of ORF1a. ORF1b overlaps ORF1a by 43 bases in the (-1) reading frame. In vitro experiments indicated that translation of the ORF1a/b polyprotein involves an efficient ribosomal frameshifting activity, as previously shown for other coronaviruses. Analysis of the predicted ORF1a and ORF1b translation products revealed that the putative functional domains identified in infectious bronchitis virus (IBV), mouse hepatitis virus (MHV) and human coronavirus 229E (HCV 229E) are all present in TGEV. The amino-terminal half of the ORF1a product exhibits greater divergence than the carboxyl-terminal half, including within the TGEV/HCV229E pair. The ORF1b protein is overall highly conserved among the above four coronaviruses, except a divergent region situated near the carboxy terminus. PMID- 7856096 TI - Varicella-zoster virus open reading frame 1 encodes a membrane protein that is dispensable for growth of VZV in vitro. AB - Varicella-zoster virus (VZV) encodes 69 unique open reading frames, 5 of which do not have herpes simplex virus type 1 (HSV-1) homologs. One of the 5, ORF1, is predicted to encode a protein of 108 amino acids. We identified a 470-base RNA corresponding to ORF1. To determine whether ORF1 encodes a protein, an 11-amino acid epitope was inserted in frame after the ninth codon of the ORF1 open reading frame. A recombinant virus carrying this epitope expressed a protein that was immunoprecipitated with monoclonal antibody to the epitope. The ORF1 protein was detected in the membrane of infected cells. The size of ORF1 protein expressed in VZV-infected cells was slightly larger than the size expressed by translation in vitro, suggesting that the protein may undergo post-translational modification in infected cells. Insertion of stop codons immediately before the epitope in the ORF1 gene resulted in a recombinant virus that did not express ORF1 protein and that was not growth impaired in cell culture. Thus, ORF1 encodes a protein that localizes to the membrane of VZV-infected cells and that is dispensable for virus growth in vitro. PMID- 7856097 TI - Identification of the rubella virus nonstructural proteins. AB - Five segments of the rubella virus (RUB) nonstructural protein open reading frame (NSP-ORF) were cloned into pATH (trpE) bacterial fusion protein expression plasmid vectors. Antisera raised in rabbits against these fusion proteins were used to identify RUB nonstructural polypeptides in lysates from RUB-infected Vero cells and from BHK cells transfected with pTM3/nsRUB, a vector from which the RUB NSP-ORF is expressed. In both systems, three polypeptides were immunoprecipitated. A 200-kDa polypeptide (P200) was immunoprecipitated by all of the antisera and therefore is the primary translation product of the ORF. A 150 kDa polypeptide (P150) was immunoprecipitated by antisera against fusion proteins containing N-terminal regions of the ORF, and a 90-kDa polypeptide (P90) was immunoprecipitated by sera against fusion proteins containing C-terminal regions of the ORF. The order of these polypeptides within the NSP-ORF is thus NH2-P150 P90-COOH. It was shown in a previous study that a protease within P200 catalyzes cleavage of P200 (L. D. Marr et al., Virology 198, 586-592, 1994). When hypertonic block was used to synchronize initiation of translation in RUB infected cells, P200 was detected within 10 min following release of the block, while P150 and P90 were not detected until 20 min, indicating that translation of the precursor is completed before proteolytic cleavage occurs. Pulse-chase experiments showed that cleavage of the P200 precursor was complete within 90 min of synthesis. P150 was stable for 24 hr following processing, while turnover of P90 was detected within 90 min. In immunofluorescence experiments on RUB-infected cells, antisera that recognized P150 stained a perinuclear focus, a thread-like cytoplasmic structure, and the nuclear membrane. PMID- 7856098 TI - Overexpression of human immunodeficiency virus type 1 protease increases intracellular cleavage of Gag and reduces virus infectivity. AB - Here we have investigated if human immunodeficiency virus type 1 (HIV-1) protease expressed in trans can interfere with production of infectious HIV-1 particles. Protease produced from a Tat and Rev inducible expression plasmid specifically cleaved HIV-1 p55Gag in a dose-dependent manner. Coexpression of protease and an infectious HIV-1 proviral clone resulted in increased intracellular cleavage of p55Gag. As a consequence, virus production and virus infectivity was significantly reduced. These results suggest that overexpression of HIV-1 protease in HIV-1-infected cells is a powerful way to inhibit production of infectious virions. PMID- 7856099 TI - Efficient EBV superinfection of group I Burkitt's lymphoma cells distinguishes requirements for expression of the Cp viral promoter and can activate the EBV productive cycle. AB - Group I Burkitt's lymphoma cell lines conditionally expressing the CD21 receptor for EBV infection were superinfected with EBV. The incoming EBV entered its normal program of gene expression, producing EBNA-2 and LMP-1 and activating the Cp EBNA promoter, but the endogenous virus in the BL lines was not induced to express EBNA-2 or transcribe RNA from Cp. LMP-1 was, however, expressed from the endogenous genome in response to superinfection. In a proportion of the superinfected Akata cells, the productive cycle antigen BZLF1 was induced and the ability of infecting virus to cause this was sensitive to inactivation by uv light. The results show that the restricted latent pattern of EBV gene expression observed in Group I BL cells is not a consequence of lack of appropriate transcription factor activity but results from inactivation of part of the viral genome, probably by methylation. Induction of BZLF1 in some of the cells also indicates a novel pathway for activation of the virus productive cycle. PMID- 7856100 TI - Small amino acid sequence changes within the V2 domain can affect the function of a T-cell line-tropic human immunodeficiency virus type 1 envelope gp120. AB - Prior studies with recombinant viruses constructed in vitro showed that the V2 domain of envelope gp120, in addition to the required V3 domain, enhances the efficiency of infection of primary macrophages by HIV-1. Present structural studies on the gp120s of these recombinant viruses using three human monoclonal antibodies directed to the V3 loop indicate that the V2 domain affects cell tropism by modulating the conformation of the V3 loop. Additional mutational analyses of the V2 domain of the T-cell line-tropic virus HIV-1SF2 reveal that single amino acid sequence changes, mainly those affecting the location of potential N-linked glycosylation sites and the positive charge of this region, can also alter tropism. These amino acid substitutions in the V2 domain, however, do not appear to alter the conformation of the V3 loop. Thus, the V2 domain of gp120 can influence cell tropism through both an effect on V3 as well as via a V3 independent mechanism. PMID- 7856101 TI - Mutations of conserved cysteine residues in the CWLC motif of the oncoretrovirus SU protein affect maturation and translocation. AB - The envelope glycoprotein complex is composed of two polypeptides, an external heavily glycosylated polypeptide (SU) and a membrane-spanning protein (TM). Together they form a heterodimer on the surface of the virion. These proteins are synthesized in the form of a polyprotein precursor which is glycosylated and proteolytically processed during its maturation in the secretory pathway. A highly conserved stretch of four amino acids, CWLC, has been identified in most known oncoretroviral SU proteins, about two-thirds of the distance from the amino terminus. To study the significance of this sequence for the structure and/or function of SU, cysteine to serine mutations were made in reticuloendotheliosis virus strain A. Initial studies showed that substitution of either one or both cysteines resulted in the production of noninfectious virus. Furthermore, immunoprecipitations and pulse-chase analysis demonstrated that the mutants yielded envelope polyprotein precursors which were stable. However, the polyprotein precursors were not proteolytically processed into SU and TM, and immunoprecipitations indicate that the immature polyproteins form aggregates, suggesting that the mutations interfere with proper folding. Although not proteolytically processed, at least one of the mutant glycoproteins appeared to be efficiently transported to the cell surface. These studies indicate that changing either cysteine residue abrogates viral infectivity by affecting folding, inhibiting normal maturation of the envelope glycoproteins. PMID- 7856102 TI - Assembly functions of vesicular stomatitis virus matrix protein are not disrupted by mutations at major sites of phosphorylation. AB - The matrix (M) protein of vesicular stomatitis virus (VSV) plays a central role in virus assembly by binding the nucleocapsid core to the viral envelope during the budding process. A small percentage of M protein molecules are phosphorylated in vivo, but the role of phosphorylation in M protein function is unknown. Using limited proteolysis, we previously determined the sites of in vivo phosphorylation for VSV M protein to be Thr 31 (and possibly Ser 32) and a site N terminal to position 19 (Ser 2, Ser 3, or Ser 17) (P. E. Kaptur et al., J. Virol. 66, 5384-5392, 1992). M protein mutants were constructed using site-directed mutagenesis by substituting Ala for Ser or Thr at these sites in the M gene of the San Juan strain of VSV. One mutant had substitutions at the major in vivo phosphorylation site(s) at positions 31 and 32 (M31.32) while two others had additional substitutions at positions 2 and 3 (M2.3.31.32) or at position 17 (M17.31.32). Mutant M proteins were expressed in BHK cells using the vaccinia/T7 system, radiolabeled with 32Pi, and then analyzed for 32P content by PAGE and autoradiography. The data show that the site of phosphorylation near the N terminus is at Ser 2 or 3 and not Ser 17. Further, Ser 38 was not phosphorylated. Mutation of the major phosphorylation site enhanced phosphorylation at alternative sites in the M protein C-terminal to amino acid 43 and at Ser residues 2 and 3. Mutant M proteins were tested for their ability to complement growth of the temperature-sensitive M protein mutant virus tsO23 at the nonpermissive temperature. Mutant M2.3.31.32 was further tested for its ability to assemble into VSV-defective interfering (DI) particles, using a replication system in which the DI genome and all five VSV proteins were expressed from plasmid DNA. Assembly of tsO23 virions or DI particles in the presence of mutant M proteins was similar to that observed for wild-type M proteins. These data indicate that phosphorylation of M protein at the major in vivo sites is not essential for virus assembly. PMID- 7856103 TI - Strain-specific determinants of beet curly top geminivirus DNA replication. AB - The Logan and CFH strains of the geminivirus beet curly top virus (BCTV) possess cis- and trans-DNA replication factors which exhibit specificity and are not functionally interchangeable. We demonstrate that the cis-acting replication specificity element is entirely contained within a 82- to 97-bp fragment which includes most of the viral DNA origin of replication. We also demonstrate that the strain-specific trans-acting replication determinant is located within amino acid residues 3-89 of the BCTV C1 replication protein. Transient replication assays indicated that chimeric BCTV genomes containing reciprocally exchanged regions of the CFH and Logan genomes were replication competent when the cis- and trans-replication specificity elements were derived from the same strain. Two reciprocal chimeric viral genomes with heterologous cis- and trans-replication elements were incapable of self-replication, yet could trans-replicate one another in a coinoculation experiment. Only chimeric genomes possessing the Logan trans-replication element were capable of mobilizing and amplifying a transgenic Logan derived DI-DNA. DI-DNA mobilization and amplification occurred in transient replication assays even when the helper virus genome was incapable of self replication, providing that the trans-replication element was derived from the Logan strain. These results genetically define specific regions of the BCTV C1 replication protein determining viral DNA replication origin recognition and provide clear evidence that strains of BCTV have evolved specific cis- and trans replication factors which functionally define the Logan and CFH strains as distinct viral agents. PMID- 7856104 TI - Activation of the interferon-inducible enzymes, 2',5'-oligoadenylate synthetase and PKR by human T-cell leukemia virus type I Rex-response element. AB - In vitro-synthesized human T-cell leukemia virus type 1 (HTLV-I) Rex response element (Rex-RE) activates the interferon-induced 2',5'-oligoadenylate synthetase (2-50AS) in a dose-dependent manner. In addition, Rex-RE at 1 microgram/ml activates a second interferon-induced enzyme, p68 kinase (PKR); however, at 50 micrograms/ml, Rex-RE inhibits PKR activity. Poly(rl)-poly(rC) (10 micrograms/ml) dissociates the ribonucleoprotein complexes, Rex-RE/2-5OAS, or Rex-RE/PKR, whereas poly(rC) (100 micrograms/ml) does not, indicating the presence of high affinity interactions between Rex-RE and these two enzymes. To further characterize the interaction of Rex-RE with 2-5OAS and PKR, [32P]Rex-RE was uv cross-linked to 2-5OAS and PKR present in interferon-treated HeLa cell extracts. The affinity of Rex-RE to highly purified 40-kDa human recombinant 2-5OAS was determined to be Kd = 4.7 nM. The relevance of these results to the pathogenesis of HTLV-I-associated adult T-cell leukemia/lymphoma is discussed. PMID- 7856105 TI - Stem-loop structure synergy in binding cellular proteins to the 5' noncoding region of poliovirus RNA. AB - Picornavirus RNAs interact with host cellular proteins to direct viral translation initiation by internal ribosome entry. In this study, we analyzed the RNA-protein interactions involving computer-predicted stem-loops F and G (also referred to as V and VI, respectively) of the 5' NCR of poliovirus RNA. This region of the 5' NCR harbors part of the putative internal ribosome entry site. We show that a ribonucleoprotein complex involving stem-loop G RNA is composed, at least in part, of a 39-kDa HeLa cell polypeptide which contacts the viral RNA directly. Interestingly, the binding site of a neuronal cell 60-kDa protein, not present in HeLa cells, was mapped specifically to stem-loop G. We also determined that a subset of cellular factors requires a higher order structure synergy before binding to poliovirus RNAs. This was demonstrated by using a longer RNA encompassing both stem-loops F and G in the binding assays. Indeed, a protein with an approximate molecular weight of 36 kDa was shown to interact specifically with these poliovirus sequences. In addition, the role of a cellular polypeptide (p57 or PTB) in poliovirus replication functions was studied. Our results suggest that p57 interactions with stem-loops F-G are not required for internal ribosome binding on poliovirus RNAs. PMID- 7856106 TI - Readthrough protein associated with virions of barley yellow dwarf luteovirus and its potential role in regulating the efficiency of aphid transmission. AB - Purified particles of barley yellow dwarf luteovirus (BYDV) contain a major 22 kDa protein and a minor protein of approximately 58 kDa. The 22-kDa capsid protein is encoded by open reading frame (ORF) 3. ORF 5 is immediately downstream and in frame with ORF 3 and a 72-kDa protein can be translated via a readthrough suppression of the ORF 3 termination codon. Antibodies were produced against two Escherichia coli expressed polypeptides that represent the amino- and carboxyl terminal halves of a putative 50-kDa protein encoded by ORF 5. Immunological analyses indicated that the 58-kDa protein associated with purified virions contained sequences encoded by ORF 3 and ORF 5. The carboxyl terminal portion of the full-length (72 kDa) readthrough protein was absent from the 58-kDa protein. The full-length readthrough protein was detected in infected oat protoplasts and plant tissue, but was not associated with virus particles purified from plants. The carboxyl-terminal portion of the 72-kDa readthrough protein was not required for aphid transmission; however, virus was transmitted more efficiently from protoplast extracts containing virions and soluble 72-kDa readthrough protein than from mock-inoculated protoplast extracts to which plant purified virus was added. The full-length readthrough protein, although not required for transmission, may increase the transmission efficiency of BYDV by aphids. PMID- 7856108 TI - Complete nucleotide sequences of the M and S segments of two hantavirus isolates from California: evidence for reassortment in nature among viruses related to hantavirus pulmonary syndrome. AB - We report the complete nucleotide sequence of the M and the S genome segments and a portion of the L segments of two hantavirus isolates from Peromyscus maniculatus trapped in eastern California. The isolates, Convict Creek 107 and 74 (CC107 and CC74) are genetically similar to viruses known to cause hantavirus pulmonary syndrome in New Mexico. CC107 and CC74 each have an M segment consisting of 3696 nucleotides with a coding potential of 1140 amino acids in the virus complementary-sense RNA (cRNA). The S segments of CC107 and CC74 are 2083 and 2047 nucleotides long, respectively, and each has an ORF in the cRNA capable of encoding a protein of 428 amino acids. Unusually long 3' noncoding regions of 757 and 721 nucleotides follow the S segment ORF of CC107 and CC74, respectively, and include numerous imperfect repetitive sequences. Whereas the M and S segments of any given hantavirus typically appear to diverge at comparable rates from homologous genes of any other hantavirus, CC107 and CC74 have M segments that differ by only 1% from one another but S segments that differ by 13%. After trivial explanations are rendered improbable, i.e., by consideration of the genetics of closely and distantly related hantaviruses, the most likely explanation for our data is that hantavirus genome segment reassortment occurred within rodent populations in California. PMID- 7856107 TI - Isolation and initial characterization of a newfound hantavirus from California. AB - A fatal case of hantavirus pulmonary syndrome (HPS) in northern California prompted our attempt to isolate viruses from local rodents. From tissues of two deer mice, Peromyscus maniculatus, two hantaviruses (Convict Creek virus 107 and 74, CC107 and CC74) were established in cell culture. Viral antigens, proteins, and RNAs of the first and archetypical isolate (CC107) were examined, and portions of the medium (M) and small (S) genome segments of both isolates were sequenced. Antigenically, CC107 virus and the second isolate, CC74 virus, were more closely related to Puumala virus than Hantaan (HTN) virus, though distinct from both. Northern blots of viral RNAs showed the large and M segments of CC107 to be the same size as those of HTN virus, whereas the S segment was larger. Protein gels did not reveal CC107 to have a substantially larger nucleocapsid protein than HTN virus. Partial nucleotide sequence comparisons of CC107 and CC74 viruses revealed their M segments to be highly similar to one another, while their S segments differed by more than 10%. Nucleotide and deduced amino acid sequence comparisons showed the California isolates to be closely related to the newfound hantaviruses first detected in the Four Corners area and since incriminated in HPS through wide areas of the United States. PMID- 7856109 TI - Restriction of vaccinia virus replication in CHO cells occurs at the stage of viral intermediate protein synthesis. AB - Vaccina virus (VV) and cowpox virus (CPV) differ in their abilities to replicate in Chinese hamster ovary (CHO) cells because VV has a disrupted host range (hr) gene. To facilitate an examination of the molecular events associated with abortive infection of CHO cells with VV, we constructed two sets of recombinant viruses that contain a viral early promoter regulating the cat gene encoding chloramphenicol acetyltransferase and viral intermediate or late promoters regulating the lacZ gene encoding beta-galactosidase. The first set has the disrupted hr gene and the second set has the intact CPV homolog, allowing replication in CHO cells. Reporter chloramphenicol acetyltransferase and beta galactosidase assays demonstrated that early gene expression was unperturbed, whereas intermediate and late gene expression were severely inhibited under abortive conditions. Metabolic labeling studies confirmed the absence of viral late protein synthesis. The accumulation of viral DNA under abortive conditions was consistent with the synthesis of viral early proteins and established that inhibition of late protein synthesis was not primarily due to a replicative block. Analysis of steady state levels of viral mRNAs revealed substantial quantities of early and intermediate species but only very small amounts of late mRNAs under nonpermissive conditions. Despite the presence of viral intermediate mRNAs, the corresponding intermediate proteins, which function as late transcription factors, were not detected by immunoprecipitation of lysates from metabolically labeled infected CHO cells. Furthermore, when expression of lacZ was regulated by an intermediate promoter, no beta-galactosidase was detected even though lacZ transcripts were present. Thus, the abortive phenotype in CHO cells can be explained by a block to translation of intermediate mRNAs which prevents the synthesis of late transcription factors. PMID- 7856111 TI - [Adenovirus vector]. PMID- 7856110 TI - Specific restrictions in the progression of Venezuelan equine encephalitis virus induced disease resulting from single amino acid changes in the glycoproteins. AB - The pathogenesis of Venezuelan equine encephalitis virus (VEE) was examined in the mouse model using V3000, a virus derived from a molecular clone of the Trinidad donkey strain of VEE. These results were compared in parallel experiments with avirulent mutants of VEE derived by site-directed mutagenesis of the clone. Adult mice, inoculated subcutaneously in their left rear footpad with V3000, were followed in a time course study for 6 days in which 15 organs were tested for histopathological changes, for the presence of viral antigen by immunohistochemical staining, for the presence of viral nucleic acid by in situ hybridization analysis, and for content of viable virus. Virus was detected in the footpad inoculation site, but until 12 hr postinoculation (pi), the level of virus did not suggest early viral replication. By 4 hr pi, however, replication of V3000 was evident in the draining popliteal lymph node. At this early time point, no virus could be isolated from any other organ examined. At 12 hr, a significant serum viremia was observed, and virus was detected at a low level in a number of well vascularized organs, including spleen, heart, lung, liver, kidney, and adrenal gland. By 18 hr, high virus titers were present in serum and all the lymphoid organs examined, and these tissues appeared to be the major peripheral sites of V3000 replication. Virus in serum and peripheral organs was cleared by 3-4 days pi. In a second phase of the infection, V3000 invaded the central nervous system (CNS), replicated predominantly in neurons, and persisted in the brain until death by encephalitis. Pathologic findings as well as the results of immunocytochemical and in situ hybridization examination were generally coordinate with virus titration. A site-directed mutant of V3000, V3010, contained a mutation in the gene for the E2 glycoprotein at codon 76 (Glu to Lys) which rendered it avirulent after footpad inoculation. Detection of V3010 replication in the draining lymph node was sporadic and was sometimes delayed to as long as 3 days pi. Infrequent and/or delayed virus spread to other sites also was observed. Analogous experiments were performed with other mutants which were avirulent by the footpad inoculation route: V3014, a mutant differing from V3000 at three loci (E2 Lys 209, E1 Thr 272, and E2 Asn 239), as well as single-site mutants V3032 (E2 Lys 209) and V3034 (E1 Thr 272).(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7856112 TI - [Retrovirus vector]. PMID- 7856113 TI - [Movement proteins of plant viruses]. PMID- 7856114 TI - [Development of genetic recombination and expression system using Sendai viruses]. PMID- 7856115 TI - [Ambisense RNA genome of rice stripe virus]. PMID- 7856116 TI - [The structural and functional similarity between viroid and hepatitis delta RNA]. PMID- 7856117 TI - [Studies on the replication mechanisms of plant RNA viruses]. PMID- 7856118 TI - [Comparison between hepatitis B virus and cauliflower mosaic virus, which have gap structure in the genomic DNA]. PMID- 7856119 TI - [Beet necrotic yellow vein virus transmitted by the fungus Polymyxa betae]. PMID- 7856120 TI - [Tungro virus agents of rice and their transmission by vector leafhoppers]. PMID- 7856121 TI - [Plant response to viruses]. PMID- 7856122 TI - [Molecular bases of naturally occurring virus resistance genes]. PMID- 7856123 TI - [Transgenic resistance to plant viruses]. PMID- 7856124 TI - [Tumors induced by human papillomavirus --special reference to role of the E 6 gene]. PMID- 7856125 TI - [Tumors caused by human papillomavirus]. PMID- 7856126 TI - [Hepatitis B virus and liver neoplasms]. PMID- 7856127 TI - [Recent progress on study of EB virus tumors]. PMID- 7856128 TI - [Development of new virus vectors for gene therapy]. PMID- 7856129 TI - [Outpatient and inpatient methods for treating surgical patients in an enclosed garrison]. PMID- 7856130 TI - [Deontology in dermatovenereology]. PMID- 7856131 TI - [The medical and procedural classification of catastrophes]. PMID- 7856132 TI - [The reactions of the upper respiratory pathways to low doses of ionizing radiation]. AB - The state of upper respiratory tract, non-specific cell resistance and immune status were studied in persons who participated in liquidation of the Chernobyl APS disaster consequences. The prolonged influence of factors caused by small doses of ionizing irradiation leads to mucosa affection of upper respiratory tract, considerable reduction of phagocytic and antiviral activity of monocytes and worsening of the immune status of organism. The data obtained during researches explains the considerable increase of ARD among these persons. PMID- 7856133 TI - [Gunshot injuries to the wrist joint]. PMID- 7856134 TI - [The combined treatment of patients with atherosclerosis of the distal arterial bed of the lower extremities]. AB - The authors summarize the experience of treatment of 178 patients with distal type of obliterated atherosclerosis of arteries of lower limbs. The 2nd stage of this malady was diagnosed in 91 (51.1%) patients; the 3rd stage--in 50 (28.1%); the 4th stage--in 37 (20.8%). 79 (44.4%) patients have received only conservative method of treatment, in 66 (37.1%) patients this method was accompanied by lumbar sympathectomy. Reconstructive operations with connection of one of the shin arteries to bloodstream were conducted in 33 (18.5%) patients. With the aim of improvement of distal artery channel visualization it is necessary to apply the digital subtraction angiography with the help of non-ionic roentgen-contrast preparations after the advanced application of spasmolytics. PMID- 7856135 TI - [Experience in giving anesthesiological and resuscitation care to therapeutic patients in Afghanistan]. AB - The article analyses the experience of reanimatological care to medical patients in Afghanistan. These patients comprised 3% of all the contingency from anaesthesia/reanimation/intensive care unit. The experience obtained in these researches made it possible to reevaluate some principles concerning the improvement of work in this unit, as far as professional qualities of its specialists, organic structure and material support are concerned. PMID- 7856136 TI - [The efficacy of isolated ultrafiltration and Capoten in the combined treatment of chronic heart failure]. PMID- 7856137 TI - [The antibiotic therapy of complicated forms of dermatomycoses of the feet]. PMID- 7856138 TI - [The chemoprophylaxis of influenza in troop units]. AB - Materials concerning the existing and perspective drugs for chemoprophylaxis of flu and its application schemes are described in this article. From the point of view of modern epidemiological theory, and on the basis of mechanism of action, all described medications are subdivided according to their influence on the elements of "influenza virus--human organism" parasitic system. Application of these drugs is in conformity with the modern complex system of non-specific prophylaxis of flu and acute respiratory diseases. Basic conditions for its successful application in military contingency are also described. PMID- 7856139 TI - [The role of disorders in the coagulation and lytic systems of the body in the occurrence of the intestinal complications of amebiasis]. PMID- 7856140 TI - [The outlook for improving specialized medical care for servicewomen]. PMID- 7856141 TI - [The methodology and principles for the complex psychological assessment of the professional fitness of military specialists]. PMID- 7856142 TI - [The assessment of military and professional work capacity]. PMID- 7856143 TI - [The effect of the professional activities of flight personnel on their tolerance for the rebreathing test]. AB - The return breathing test (rerespiration) developed by the authors makes it possible to conduct testing on the efficiency of compensatory reactions and disclose the reserve capacities of cardiorespiratory system in pilots. 82 pilots were examined in the process of their professional activity. The major part can be subdivided into 3 groups with middle, good and high tolerance to rerespiration, having 1/3 of pilots under 30 years old a high tolerance to test. This test substantiates the expediency to subdivide the flight personnel into the groups of tolerance. The low tolerance can be explained by changes of functional state of organism under the influence of endogenic or exopathic factors. PMID- 7856144 TI - [An information model of the adaptation process in sailors under the conditions of the polar regions on the Kola Peninsula]. AB - On the basis of information concept an attempt to create a model of adaptation process was made with the purpose of revealing the general features of man's adaptation for the conditions of the Kola [correction of Kolsk] Peninsula polar region. In the authors' opinion it is necessary to study this problem from the point of view of thermodynamic approaches. The model obtained in the result of studies reflects the process of adaptation and gives the possibility to prognosticate the health status of sailors depending on their "polar continuous service". PMID- 7856145 TI - [The work of the medical service of the Air Force at the beginning of World War II]. PMID- 7856146 TI - [An outstanding organizer of Soviet military public health (on the centenary of the birth of N. I. Zavalishin)]. PMID- 7856147 TI - [Lev Evgen'evich Poliakov (on his 70th birthday)]. PMID- 7856148 TI - [The contribution to military medicine of Prince A. P. Ol'denburgskii during World War I]. PMID- 7856149 TI - [The organization of medical care for those with mild illness and infectious pathology in aviation commands in wartime]. AB - Infectious diseases are the major cause of casualties in aviation in war time. The present system of casualty staging for infectious patients in an air force doesn't give the possibility for the AF Command and its medical service to execute stable control over minimally sick pilots and aviation technicians with infectious pathology who abandon the air force tactical zone. This fact delays their return to duty. The authors propose to alter the system of casualty staging for these patients by providing medical care right during the stages of medical evacuation. PMID- 7856150 TI - A case study of abdominal angina secondary to celiac compression syndrome. AB - Celiac compression syndrome occurs when the median arcuate ligament of the diaphragm and/or periarterial neural tissue causes extrinsic compression of the celiac axis. In rare cases, this syndrome can cause upper abdominal angina. The classic triad of celiac compression syndrome consists of abdominal pain, an epigastric bruit, and angiographic evidence of celiac compression. Operative therapy consists of thorough exploration, transection of the median arcuate ligament, and either celiac dilatation or a bypass. This article describes a case of celiac compression syndrome which was treated successfully by transection of the median arcuate ligament and aortosplenic bypass. PMID- 7856151 TI - Keep the change, doc!: coins in the upper GI tract of children. AB - Many children are brought to the Emergency Room each year because they have swallowed foreign bodies (FBs), particularly coins. Whether to remove these foreign bodies or let them pass through naturally is a constant dilemma for ER physicians. This article reviews our experiences in treating pediatric patients who underwent FB retrieval for coins, food particles and toy parts, and discusses their clinical and endoscopic findings. The vast majority (82%) of the swallowed FBs were lodged in the esophagus. A review of the literature and a suggested medical protocol to manage patients who have swallowed coins are also discussed in this article. PMID- 7856152 TI - Acute renal failure due to ofloxacin. AB - Fluoroquinolone antibiotics have rarely been associated with renal failure (1). However, temafloxacin, a member of this drug class, was voluntarily withdrawn from the U.S. market in 1992 after reports of renal failure and other adverse reactions (2). In this article, we report one of the first published cases of renal failure resulting from the administration of ofloxacin (Floxin, Ortho Pharmaceutical Corporation), one of the newest fluoroquinolone antibiotics. PMID- 7856153 TI - HMO business. PMID- 7856154 TI - National survey states more mothers are breastfeeding babies. PMID- 7856155 TI - Why health care reform must still be addressed: a medical student's inside look at Washington. PMID- 7856156 TI - Firearm violence in California. Information and ideas for creating change. AB - Homicides have been on the rise in California in recent years, almost entirely as a result of increased firearm activity, resulting in one of the highest homicide rates in the country. With increasing morbidity and mortality from guns, health care professionals have called the situation an epidemic. In the past decade, attention from the health care profession has resulted in a new focus on the public health issues surrounding firearms. There is considerable confusion among policy makers regarding what should be done to stem firearm violence. I discuss morbidity and mortality trends, academic research, and legal issues surrounding firearm violence, affording insight into the seriousness and complexity of this rapidly growing problem and providing policy ideas for addressing the role of firearms. Such policy ideas include removal of the California Legislature's preemptive authority on firearms licensing and registration; the formation of an information and advisory body within the California Department of Health; increased liability for manufacturers, distributors, dealers, and owners; and a statewide registration system. PMID- 7856157 TI - Physician management of hypercholesterolemia. A randomized trial of continuing medical education. AB - To determine the effect of continuing medical education (CME) on compliance with the recommendations of the National Cholesterol Education Program Expert Panel on high serum cholesterol levels in adults, we randomly assigned primary physicians in 174 practices to 3 groups, 2 that underwent either standard or intensive CME and a control group. The standard CME group was offered a free 3-hour seminar on high serum cholesterol levels; the intensive CME group was offered in addition follow-up seminars and free office materials. After 18 months, we audited 13,099 medical records from the 140 practices that remained in the study. There were no significant differences (P > .15) in screening for high serum cholesterol or compliance with guidelines between the groups receiving continuing medical education (51% screening; 33% compliance) and the control group (57% screening; 37% compliance). In the prespecified subgroup of patients with hypercholesterolemia, there was a trend toward a modest benefit from the continuing medical education interventions: compliance was 21% in the control group, 23% in the standard CME group, and 27% in the intensive CME group (P = .07 overall). These results emphasize the need for better ways to change behavior in practicing physicians and the importance of studying the implementation of preventive health recommendations. PMID- 7856158 TI - Antibiotic therapy for ocular infection. AB - Infections of the eye can rapidly damage important functional structures and lead to permanent vision loss or blindness. Broad-spectrum antibiotics should be administered to the appropriate site of infection as soon as a diagnosis is made. Topical drops are preferred for corneal and conjunctival infections. Intravitreal antibiotics, and possibly subconjunctival and parenteral antibiotics, are preferred for endophthalmitis. Parenteral antibiotics are recommended for infection in deep adnexal structures. We review specific aspects of antibiotic therapy for ocular and periocular infection. PMID- 7856160 TI - Keratorefractive surgery. AB - The Council on Scientific Affairs of the California Medical Association presents the following epitomes of progress in ophthalmology. Each item, in the judgment of a panel of knowledgeable physicians, has recently become reasonably firmly established, both as to scientific fact and clinical importance. The items are presented in simple epitome, and an authoritative reference, both to the item itself and to the subject as a whole, is generally given for those who may be unfamiliar with a particular item. The purpose is to assist busy practitioners, students, researchers, and scholars to stay abreast of progress in medicine, whether in their own field of special interest or another. The epitomes included here were selected by the Advisory Panel to the Section on Ophthalmology of the California Medical Association, and the summaries were prepared under the direction of Alfred C. Marrone, MD, and the panel. PMID- 7856161 TI - Updated recommendations from the Optic Neuritis Treatment Trial. PMID- 7856159 TI - Increased erythrocyte sedimentation rate and a splenic mass. AB - This discussion was selected from the weekly Grand Rounds in the Department of Medicine, University of Washington School of Medicine, Seattle. Taken from a transcription, it has been edited by Jonathan G. Drachman, MD, Chief Medical Resident; Henry Rosen, MD, Professor and Associate Chair; and Paul G. Ramsey, MD, Professor and Chair of the Department of Medicine. PMID- 7856164 TI - Risk of corneal infection and extended wear of contact lenses. PMID- 7856162 TI - Do sunglasses protect the retina from light damage? PMID- 7856163 TI - Nonsteroidal eye drops for ocular allergy. PMID- 7856165 TI - Massive hemoptysis in pregnancy due to a solitary pulmonary arteriovenous malformation. PMID- 7856166 TI - Electrocardiographic changes associated with anaphylaxis in a patient with normal coronary arteries. PMID- 7856168 TI - Do guns matter? PMID- 7856169 TI - Ocular infections--a rational approach to antibiotic therapy. PMID- 7856170 TI - Medical practice guidelines. PMID- 7856167 TI - Dietary antioxidants, cancer, and atherosclerotic heart disease. PMID- 7856172 TI - Oregon Health Plan--clarification. PMID- 7856171 TI - The FDA and terfenadine. PMID- 7856173 TI - Physicians and health care reform. PMID- 7856174 TI - Using the fax--concerns about patient confidentiality. PMID- 7856176 TI - Apolipoprotein (a) levels in patients with type 1 diabetes mellitus are unrelated to metabolic control or vascular disease. AB - Increased serum levels of lipoprotein (a) have been found to be an independent risk factor for coronary heart disease. The major protein constituents of lipoprotein (a) are apolipoprotein B 100 und apolipoprotein (a) (apo(a)). We determined the serum levels of apo(a) and several lipid (cholesterol, HDL- and LDL-cholesterol, triglycerides, apolipoproteins A, A1 and B) and glycaemic (HbA1c, fasting blood glucose) parameters in 40 patients with type 1 diabetes mellitus and in 103 age- and sex-matched control subjects. The median serum levels of apo(a) were significantly increased in the type 1 diabetic patients (142.7 vs. 80.0 U/L; P = 0.03), whilst HDL, LDL-cholesterol, and apolipoprotein A, A1 and B levels were lower (P < 0.01). No significant correlation was found between parameters of metabolic control and apo(a) levels. After subdivision of the diabetic patients according to different stages of diabetic nephropathy (DN), determined by urinary albumin excretion, significant relationships were found between DN and triglycerides (P = 0.04), LDL (P = 0.03) and apolipoprotein B (P = 0.008, Kruskal-Wallis test) levels. Apo(a) levels were significantly higher than normal values in patients without DN (P < 0.05), but unrelated to the degree of DN. Patients with diabetic macroangiopathy had significant higher levels of cholesterol (P = 0.0001), triglycerides (P = 0.026), LDL (P = 0.0003), and apoB (P = 0.002) than patients without. Apo(a) levels were unrelated to diabetic macroangiopathy. The significantly elevated levels of apo(a) even in patients without DN or macroangiopathy are noteworthy.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7856175 TI - The RED-LIP study--pravastatin in primary isolated hypercholesterolemia--an open, prospective, multicenter trial. AB - The therapeutic effects of the HMG-CoA reductase inhibitor pravastatin on plasma lipids were assessed in an open, prospective, multicenter trial over a treatment period of 3 months. Of a total of 1111 patients, the overall results were calculated from 715 evaluable patients (352 men and 363 women, mean age: 56.1 +/- 11.3 years) with primary isolated hypercholesterolemia (hyperlipoproteinemia type IIa according to Fredrickson) being at high risk for cardiovascular disease according to the classification of the national cholesterol consensus, whose guidelines are distinguishing between three risk levels (low, moderate, and high, respectively) of total-cholesterol (total-c) as well as LDL-c. The treatment period was preceded by a 3-month dietary counselling phase. Treatment with pravastatin significantly reduced total-c (23.8%, p < 0.001), LDL-c (31.9%, p < 0.001) and triglyceride (16.9%, p < 0.001) levels, concomitantly those of HDL-c were significantly raised (15%, p < 0.001). Pravastatin lowered the total-c/HDL-c ratio by nearly 36% from a mean of 8.1 +/- 2.5 to a mean of 5.2 +/- 1.6. At the end 476 patients (66.6%) received the standard dosage of 10 mg/day whereas 140 patients (19.6%) were recorded to take a dose of 20 mg/day. When comparing those patients (n = 456) having maintained consistently a dose of 10 mg pravastatin per day from week 0 to week 12 with patients (n = 113) who received 20 mg/day from week 4 to 12 similar efficacy was observed in both groups (reduction of total-c: 24.5% vs. 22.2%, n.s., reduction of LDL-c: 33.0% vs. 30.0%, n.s.).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7856177 TI - [Prevalence of cardiac autonomic neuropathies in uremia and diabetes mellitus]. AB - In the absence of relevant data, the prevalence of cardiac autonomic neuropathy was investigated in patients with diabetes mellitus or uremia due to other causes and diabetic patients with endstage renal failure. 117 patients (40 on a dialysis program without diabetes, 32 with diabetes mellitus type 1 but no nephropathy, 16 type 1 and 13 type 2 diabetic uremic patients, 16 diabetic patients with a kidney graft) and 25 healthy control subjects underwent assessment of the cardiorespiratory reflexes. The evaluation of parasympathetic damage was of particular interest. Definite parasympathetic dysfunction was detected in 32% of the non-diabetic uremic and in 19% of the non-uremic type 1 diabetic patients. Furthermore, 88% of type 1 and 77% of type 2 diabetic patients on dialysis and 75% of diabetic patients after kidney transplantation had evidence of autonomic neuropathy. PMID- 7856179 TI - [High altitude lung edema in the East Alps]. AB - We present a case of high-altitude pulmonary edema in a trained skier who undertook a three-day tour in the eastern Alps. This clinical condition can occur in hitherto healthy, predisposed persons at a critical altitude of 2500-3000 m and has to be differentiated above all from pneumonia. Extreme physical exertion, especially at low temperatures, the intake of alcohol or hypnotics and, presumably, preceding infection of the respiratory tract favor the occurrence of high-altitude pulmonary edema. The history of having spent the night at or above the critical altitude and the spontaneous restitutio ad integrum with rapid clinical recovery and dissolution of the radiographic pulmonary infiltrates within a few days after evacuation to lower altitudes are decisive features in establishing the diagnosis. Without therapy or evacuation the mortality rate is 50%. In spite of the low incidence in the eastern Alps, as opposed to the western Alpine countries, the potentially fatal course of high-altitude pulmonary edema should make it mandatory to equip huts and refuges above 3000 m even in the eastern Alps with the first-aid medicament nifedipine and therapeutic oxygen. PMID- 7856178 TI - [Clinical evaluation of the blood glucose monitors Accutrend, Companion 2, Glucometer 3 and One Touch II in comparison with the glucose oxidase reference method]. AB - New small, light-weight and fast-acting meters for measuring blood glucose have been developed recently. To determine their accuracy and precision we compared Accutrend, Companion 2, Glucometer 3 and One Touch II with the reference glucose oxidase method. For determination of accuracy 150 measurements were performed on two meters of each brand, together with measurement on the Beckman 2 Analyzer, which served as our reference. Capillary blood samples were obtained from patients with type 1 and type 2 diabetes attending our outpatient clinic. All measurements were performed by one experienced technician. Precision in series was determined by 15 measurements of venous EDTA samples. The coefficient of variance was used for statistical analysis. Accuracy was evaluated according to recommendations of the American Diabetes Association and clinically useful criteria such as the error grid analysis. We found that One Touch II performed best overall, followed by Accutrend. Companion 2 and Glucometer 3 showed higher deviations in both accuracy and precision, but nonetheless met the clinical criteria of accuracy and reliability measured by error grid analysis in 87% and 90.5% of measurements, respectively. In conclusion, all four blood glucose meters can safely be used, after proper training, by patients and medical staff for self measurement of blood glucose. PMID- 7856180 TI - [Propter- or post-thrombotic? Quo vadis?]. PMID- 7856181 TI - [The incidence of post-thrombotic syndrome]. AB - To evaluate the clinical and socio-economic importance of the postthrombotic syndrome (PTS), the following epidemiologic parameters are to be known: The incidence of deep vein thrombosis (DVT) in the population, the incidence of PTS after DVT, the prevalence of the PTS, the socio-medical consequences and the mortality. The DVT-incidence in the literature is about 3/1000 per year in the adult population. In our own follow-up study we found a global PTS-incidence of 40% (10% with, 30% without ulcer) 13 years after DVT. The PTS-incidence was correlated with the initial DTV-extent. The risk of PTS after 3- and 4-level DVT is significantly reduced by a successful fibrinolysis in the acute stage (p = 0.01). The mortality of patients with PTS is 3 times higher than in the population. 4% of the patients with PTS get disabled. To our knowledge an adequate study with direct assessment of the PTS-prevalence does not exist, but the PTS-prevalence can be deduced from large epidemiologic studies, such as the Basel-Study, in which the global chronic venous insufficiency is assessed. It amounts in the adult population between 0.5 to 1% for the PTS with and 3 to 5% for the PTS without ulcer. PMID- 7856182 TI - [The pathophysiology of post-thrombotic syndrome]. AB - The acute stage of venous thrombosis is characterized by an inflammatory process, therefore the term phlebitis is often erroneously equated with venous thrombosis. In most cases, however, the inflammatory reaction or phlebitis is a secondary phenomenon, associated with the process of fibrinolysis and phlebitis as a primary cause is rare. Postthrombotic sequelae such as edema, varicose veins and ulcers usually are late complications and can take a long time to develop. The primary cause of the postthrombotic syndrome is related to an injured venous wall, including damaged valves or stenosis due to incomplete recanalisation. The amount of damage is dependent on the extent of the primary thrombosis and the degree and rapidity of thrombolysis. When postthrombotic changes are suspected, functional evaluation can be performed with ambulatory venous pressure measurement in a foot vein or with the aid of non-invasive methods such as volumetry. PMID- 7856183 TI - [The current concept of the pathogenesis of trophic skin lesions in chronic venous insufficiency from the morphologic viewpoint]. AB - Disturbances of the venous macrocirculation are the main cause of trophic skin lesions in primary and secondary chronic venous insufficiency. The microcirculatory process initiates with functional and organic endothelial alterations in the cutaneous and subcutaneous capillaries, followed by increased permeability for blood plasma and erythrocytes, and later by edema and micronecroses in the interstitial tissue. Subsequently a reactive chronic inflammation develops. A vicious circle consisting of repeated tissue necrosis alternating with repair processes and later with tissue fibrosis may develop. This injury and repair process is non-specific and characteristic for all types of tissue necrosis. Intensity and duration of the process depend on degree and persistence of the underlying disorder. PMID- 7856185 TI - Morphological and functional skin changes in postthrombotic syndrome. AB - After a period of deep venous thrombosis a lot of patients will develop chronic venous insufficiency. In time different skin alteration will occur. Several hypothesis have been proposed to explain the pathogenesis behind these skin changes. In this paper we will briefly discuss the most important theories. We concentrate on microcirculation and the different skin changes. PMID- 7856184 TI - [Micromorphologic changes in the skin in primary and secondary (post-thrombotic) chronic venous insufficiency]. AB - The micromorphological alterations in chronic venous insufficiency are characterized by a patchlike distribution. At least in the initial stages, normal skin areas may alternate with regions containing severe alterations. The capillaries may be rarified, or elongated and dilated with formation of glomerulus-like clusters, or they may show proliferation within a granulomatous repair tissue. Pericapillary accumulation of fibrin may be observed only within necrotic tissue surrounding an ulcer. The pericapillary space which is enlarged and edematous in chronic venous insufficiency, cannot be anatomically defined. The interstitial tissue may contain a secondary chronic inflammation with repair function. Finally a hyaline scar tissue with so-called "avascular" fields and dystrophic calcification/ossification may result. PMID- 7856186 TI - [Significance of cutaneous microangiopathy for the pathogenesis of dermatitis in venous congestion due to chronic venous insufficiency]. AB - Skin damage due to chronic venous insufficiency is preceded by severe microangiopathy of skin. With increasing clinical symptoms like edema, hyperpigmentation, induration, ulcer and atrophy blanche number of nutritive capillaries and transcutaneous oxygen-tension decreases, transcapillary, and interstitial leakage increases and cutaneous vascular reserve disappears. These congruent results were found by means of capillaroscopy, fluorescence videomicroscopy, transcutaneously measured oxygen partial pressure and Laser Doppler Fluxmetry. Most of capillaries are elongated and tortuous, especially in ulcer stage they look glomerular. Compared to pin-shaped capillaries glomerular capillaries contribute less to nutrition because of functional AV-shunts. As dilated capillaries are already seen in skin areas without any trophic skin changes, cutaneous microangiopathy seems to be first consequence of venous hemodynamic disturbances which then is followed by skin disease. As severe microangiopathy still remains after healing of ulcer, it explains frequent recurrencies. PMID- 7856187 TI - [Involvement of the lymphatic system in post-thrombotic syndrome]. AB - The involvement of the lymphatic drainage in patients with postthrombotic syndrome can be verified by (quantitative) isotopic lymphography (99m Tc labelled microcolloids) and by indirect lymphography (water-soluble contrast medium Iotrolan). Both methods point to an augmented praefascial lymph-transport. In the region of lipodermatosclerotic skin changes dermal backflow can be explained by a local damage of peripheral skin-lymphatics ("localized lymphoedema"). No working lymphatics can be found in the border of ulcers. As could be demonstrated by intramuscular injection of the radioactive tracer subfascial lymphtransport is decreased not only in the postthrombotic stage but already in the acute phase of a deep vein thrombosis. The alterations of the lymph-drainage in a postthrombotic syndrome may have some pathophysiological importance for the development of the tissue changes and may also explain some clinical signs. PMID- 7856188 TI - [Clinical features in post-thrombotic syndrome]. AB - Signs which follow deep vein thrombosis and which develop as a feature of deep venous insufficiency caused by incomplete recanalization and of destruction of valves and endothelium are defined as a postthrombotic syndrome. The clinical symptoms range between no objective signs, severe oedema and ulceration. They depend on the amount of valvular and endothelial damage during the acute phase, localization of the deep vein thrombosis and on several other factors outside the venous macrocirculation which are poorly understood until now. PMID- 7856190 TI - [The value of measuring reflux by color duplex in post-thrombotic syndrome]. AB - Until now, the diagnosis of the postthrombotic syndrome is based upon venography. This study compares the diagnostic value of the CW-Doppler with the sonographic signs in the deep venous system observed in B-mode sonography and with the quantitative measurement of venous reflux by color Doppler sonography. 84 venous sections of 21 patients with phlebographically diagnosed PTS and substantial clinical signs were examined. CW- Doppler and B-mode sonography did not show significant differences compared to phlebographic findings. Color doppler sonography, however, showed signs which significantly went beyond those seen in venography. PMID- 7856189 TI - Incidence and time of occurrence of valvular incompetence following deep vein thrombosis. AB - Commencing December 1986 and over the course of 4 years, the diagnosis of acute deep vein thrombosis (DVT) was established by duplex scanning in 286 patients referred to the University of Washington Medical Center in order to rule out this problem. From this group 107 patients (123 legs with DVT) were placed in a long term follow-up program. The documentation of valvular reflux and its site was demonstrated by duplex scanning. The duplex studies were done at intervals of 1 and 7 days, 1 month, every 3 months for the first year and then yearly thereafter. The mean follow-up time was 341 days. The presence of reflux was also determined in 502 patients with a negative duplex study and no previous history of DVT or chronic venous insufficiency. In the patients with acute DVT, valvular incompetence was noted in 17 limbs (14%) at the time of the initial study. Reflux was absent in 106 limbs (86%). In this last group reflux developed in 17% of the limbs by day 7. By the end of the first month, 37% demonstrated reflux. By the end of the first year, more than two-thirds of the involved limbs had developed valvular incompetence. The distribution of reflux at the end of the first year of follow-up was: 1) popliteal vein, 58%; 2) superficial femoral vein, 37%; 3) common femoral vein, 33%; and 4) posterior tibial vein, 18%. Reflux in the greater saphenous vein occurred in 25% of the limbs after 1 year. Reflux developed more frequently in thrombosed venous segments.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7856191 TI - [Duplex ultrasound of post-thrombotic syndrome--quantification of venous flow parameters]. AB - In the last years Duplex-Sonography established itself in the diagnosis of venous diseases. This noninvasive method combines Doppler-ultrasound and real-time sonography. In this way an exact quantitative interpretation of the Dopplersounds in relation to the examined blood vessel is possible. Especially the venous bloodflow of postthrombotic veins will be explored. It will be discussed whether the data measured by Duplex-sonography allow a staging of venous diseases. PMID- 7856192 TI - [From thrombosis to post-thrombotic syndrome--plethysmography studies of venous function]. AB - 46 patients with deep vein thrombosis have been investigated by strain gauge plethysmography and by foot-volumetry in the acute state, after 4 weeks, and after every year up to 5 years. The primary therapy consisted in anticoagulation, compression-bandages and walking exercises. Venous drainage measured by venous occlusion plethysmography showed in average a normalisation after one year, while expelled volume as a parameter for the venous pumping function (assessed by foot volumetry) remained in the pathological range. Since the clinical outcome- ulceration in 6.5%, lipodermatosclerosis in 15% and no major signs in 78%--does not correspond to these functional findings it is concluded that venous refluxes which are the main cause for the impeded pumping function lead to skin changes only in specially predisposed cases. PMID- 7856193 TI - [Site of phlebographically determined venous changes in postphlebitic syndrome with varicose ulcer]. AB - In 207 legs with venous leg ulcers and postthrombotic syndrome proved by phlebography, the frequency of involvement of the 4 levels of deep venous system was assessed. Level A: deep veins of the lower leg. Level B: poplieal vein and gastrocranial veins. Level C: femoral veins. Level D: iliac veins. Our investigations showed that in 35% damages of the deep veins only in level A (lower leg) were responsible for venous ulcer. In cases with combinations of levels, Level A in 95% also was involved. One can say that postthrombotic leg ulcer correlates above all with the pathomorphological alterations of the lower leg veins. PMID- 7856194 TI - [Discussion comment: surgical therapy of thrombosis of leg and pelvic veins]. AB - Referring to a survey of the literature and the own clinical series the open problems in the surgical treatment of acute iliofemoral venous thrombosis are discussed. Only 2 reports have been published, which test 2 therapeutical options, surgery versus oral anticoagulant treatment in a randomised trial. Nevertheless there have been some shortcomings. Therefore a further clinical trial, with multicentre design, probably guided by a scientific society, seems justified to settle the remaining questions. PMID- 7856195 TI - [Compression therapy in post-thrombotic syndrome]. AB - The most important aim of compression therapy in postthrombotic legs is prevention of dermatosclerosis and ulcus cruris. For the acute stage of leg swelling and for venous ulceration we prefer compression bandages ("therapy phase"). The effect of compression therapy with bandages depend on the material of the used bandages (short or long-stretch bandages), the stretching the bandages are applied with, the number of layers, the local pads and on well done application of the bandages. After removal of oedema compression therapy should be continued with medical compression stockings ("maintenance phase"). Compression stockings should be fit on carefully and be checked from time to time to guarantee their application by the patient. PMID- 7856196 TI - [Combined compression and electric stimulation therapy]. AB - The use of compression- or Neuromuscular electrostimulation therapy (NMES) for the treatment of venous and lymphatic disorders has been known for a long time. Furthermore, NMES is being used for the treatment of arterial circulatory disorders as well as for neuromuscular lesions. More and more often, external pneumatic intermittent compression therapy is being used for the prophylaxis of postoperative thromboembolic complications. If both methods are used simultaneously, a synergic effect is being obtained, where as the possible deficits of one technique are being counteracted by the advantage of the other. The KKRT is being described and the outcome of 2 trials performed in gynecological and dermatological field is being presented. PMID- 7856197 TI - [Compression stockings in treatment of lower leg venous ulcer]. AB - AIM: of the study was to evaluate the efficiency of medical compression stockings, which do not require special application techniques, compared with short stretch bandages for treating leg-ulcers. STUDY-DESIGN AND PATIENTS: Prospective trial on a total of 50 out-patients with leg-ulcers randomly allocated into two therapy-groups: 25 patients got firm compression bandages using short stretch material (Rosidal K), 25 patients were treated by medical compression stockings (Thrombo+Sigvaris 503). Due to the statistically significantly lower mean age and longer duration of the ulcers in the Sigvaris group only restricted comparison of the treatment groups is possible. Local dressings in both groups consisted of a nonadherent, absorbing material (Vliwin) with an individually modelled rubber foam pad on top. The end-point was complete ulcer-healing, in a period of 3 months. METHODS: The following parameters were measured: area of ulceration, compression-pressure, tcPO2 and Laser-Doppler Fluxmetry at the ulcer border before and after 3 minutes of arterial occlusion, venous volume and venous filling index by air plethysmography (APG) with and without compression. RESULTS: After 3 months 21 cases (84%) were healed in the Sigvaris-group and 13 (52)% in the Rosidal-group. This significant difference may be partly explained by the more favorable starting condition of the stocking patients. However, one major advantage of stockings over short stretch bandages is the maintenance of an adequate pressure if they are not renewed for several days. CONCLUSION: Therapy of venous ulcers by medical compression stockings may be an effective approach for fit and cooperative patients. PMID- 7856198 TI - [Varicose ulcer: healing in conservative therapy. A prospective study]. AB - In a prospective study 105 consecutive patients with leg ulcers were recruited (causes: 77% venous, 4% arterial, 9.5% mixed, 9.5% other). 70 (67%) had a history of previous ulceration. 83 patients could be followed for 1 year. The healing rate for the whole group was 41 (49%) after 3 months and 61 (73%) after 1 year. The corresponding figures for the 67 venous patients are 44 (66%) and 52 (78%) respectively. From 61 healed ulcers 18 (30%) reoccurred during the 1st year. At the primary examination several factors were investigated which might have influenced the healing rate. Age, ulcer-size, the duration of the ulcer, lateral localization, absence of foot-pulses and lymphoedematous skin changes on the forefoot could be shown to have negative influence on healing. PMID- 7856199 TI - [Saphenous vein stripping in post-thrombotic syndrome]. AB - Some patients with a history of deep venous thrombosis have intact valves in the deep venous system. For these patients a diagnostical examination is important to prove the falling high venous pressure. According to several functional tests the decline of venous pressure indicates the surgical treatment of the insufficient superficial veins. Step by step we show the diagnostical and therapeutical procedure in a patient with a history of deep venous thrombosis. Then we discuss an alternative decision and ask the question, if the absence of increasing venous pressure according to the phlebodynamometry indicates the surgical sanitation of the insufficient superficial veins. PMID- 7856200 TI - [Excision of perforating veins]. AB - Excision of perforating veins is performed under local anesthesia and approached through a 10 to 15 mm incision. The superficial vein and the perforator are prepared and excised with scissors. Digital compression instead of ligatures is applied to arrest bleeding. No sutures, but wound closure strips. A strong compression bandage is then applied. Adverse effects are rare and not severe. The resulting scars are bare noticeable. Long term results are satisfactory compared with other radical procedures. The operation only takes a few minutes and is also recommended in daily phlebological practice. PMID- 7856201 TI - [Prognosis in endoscopic perforans vein excision in postphlebitic syndrome]. AB - In the presence of leg ulcer endoscopic treatment is particularly indicated as it permits reliable diagnosis and treatment of incompetent perforator veins from a small incision away from the contaminated zone. Lately 3 surgeons have developed special instruments for this type of endoscopy. Hauer was the 1st to develop a specialized technique with the Wolf Company. He uses an angulated optic system and a double cautery clamp. It permits excellent vision. Sattler works with a Storz thoracoscope and specially built instruments controlled by a monitor. This means agreeable and motivating handling. Fischer uses direct vision through a Wolf or similar endoscope shaft and a set of instruments produced by Storz and Ulrich Co for him for swift, simple and reasonable treatment. Each surgeon will chose his method on the ground of his education, his special liking and his set up. PMID- 7856202 TI - [Endoscopic venous surgery in postphlebitic syndrome]. AB - Endoscopy of the subfascial space of the lower medial calf is able to demonstrate the morphological changes of perforators in patients with postthrombotic syndrome. Inspection of the subfascial space allows the differentiation of competent and incompetent perforators and a following complete dissection of only incompetent perforators. By means of this method more information about the texture of the fascia cruris can be achieved. PMID- 7856203 TI - [Para-tibial fasciotomy]. AB - Since 1981 the paratibial fasciotomy is being increasingly used in the treatment of chronic venous congestion with persisting ulcers and severe dermatosclerosis. We now overlook more than 1800 successful operations. In a prospective study on patients who underwent paratibial fasciotomy, we are still finding a high healing quotient in respect to the leg ulcers. The construction of a special fasciotomy has led to the elimination of serious complications. PMID- 7856204 TI - [Surgical therapy of ulcus cruris. Significance of extension of the damage to deep veins for incidence of ulcus cruris recurrence]. AB - 2 retrospective studies illustrate the importance of the extent of damage to the deep venous system governing the recurrence rate of stasis ulcers treated surgically. 1. In patients with recurrent venous stasis ulcerations associated with superficial varicosis of the great or lesser saphenous veins and incompetent perforators operative treatment of the varicose veins resulted in a 100% long term healing rate of the ulcerations (5-year results). This was the case for 25 legs with venous ulcers in 229 consecutive cases operated for varicose veins. 2. In 76 patients with rebellious ulcers presenting without operable superficial varicose veins the treatment was a localized one consisting of wide and deep excision of the ulcer with ligature of underlying perforators and surrounding varicose veins. The 2-year success rate was 87% in 39 patients with intact deep veins, but only 59% in 37 patients with postphebite damage to the deep veins (p < 0.05). For 1 and 2 level deep vein disease the success rate was still high at 80%, but fell to 20% if damage to the deep veins extended to 3 or 4 levels! Thus, the degree of damage to the deep veins correlates well with the propensity to recurrence of venous ulceration following surgical treatment. Venous hypertension measured by phlebodynometry is the single most powerful predictor of success or failure of surgical treatment. Patients at risk should therefore be encouraged to wear compression stockings or hosiery to offset recurrencies. PMID- 7856205 TI - [The role of skin transplantation in the treatment plan of venous (post thrombotic) varicose ulcer]. AB - Under both inpatient and outpatient conditions several skin grafting techniques (eg. split-skin meshgraft, postage stampgrafts) can be useful in treating already phlebosurgically operated venous ulcers. 82 already phlebosurgically longterm treated venous ulcers were skin grafted under clinical conditions in the time from 1983 to 1992. Various characteristics of this patient-group (eg. age, sex, duration of disease, localization and size of venous ulcer) were put retrospectively into comparison with those of 72 patients suffering from venous ulcers treated exclusively in a conservative manner. Patients of the skin grafted group - aged mostly 55 to 65 years - suffered longer from chronic venous ulcers, of which 15 were circulatory. The time interval between clinical admission and skin grafting (16th to 28th day), the index of healing dependent indicator for the dermato-surgical intervention, as well as short and long term results, were investigated. In contrast to favourable short term results (39 patients with complete, 17 with > 50% settlement of skin graft) long term results were rather disappointing. 27 of 39 operated patients with initially successfully treated venous ulcers answered a questionnaire in which, as a result, only 15 did not suffer a relapse one to nine years after the dermatosurgical intervention. Despite of these results, simple techniques of skin grafting will still be in future of great value. PMID- 7856206 TI - [Local therapy of ulcus cruris]. AB - The primary step of local ulcer therapy consists in debridement. Cleaning the ulcers from necrotic tissue can be achieved by surgical, mechanical, osmotic, autolytic and enzymatic means. The introduction of (semi-)occlusive wound dressings for moist wound healing has significantly improved ulcer treatment, since critical steps of wound healing, such as fibroblast proliferation, angiogenesis and epithelialisation are markedly accelerated. In contrast, topical antimicrobial therapy and traditional local treatment with "wound ointments" are of diminishing value because of frequent side effects such as inhibition of granulation tissue or allergic sensitization. PMID- 7856207 TI - Klinefelter's syndrome as a model for skin changes in venous insufficiency. AB - Chronic venous insufficiency is a common disease with skin changes, varicosity and leg ulceration. Several theories have been proposed to explain all the changes that occur. We recently saw several patients with Klinefelter's syndrome complicated by leg ulceration and all the typical skin changes of venous insufficiency. The underlying disease was however lacking. They all showed disturbances in their fibrinolytic parameters. In this article we discuss (local) fibrinolytic disturbances as a possible factor in the pathogenesis of the skin changes in chronic venous insufficiency. PMID- 7856208 TI - [Pyoderma gangraenosum: differential diagnosis in ulcus cruris and postoperative exacerbating processes]. AB - A case of pyoderma gangrenosum that was initially misdiagnosed as postthrombotic ulcers is described. Surgical debridement triggered postoperative exacerbation. Dermatologic examination was then initiated and the diagnosis pyoderma gangrenosum was established. No underlying illness was detectable. Immunosuppressive therapy stopped disease activity promptly and as previously reported low-dose cyclosporine was also effective in our exceptionally therapy resistant case. Pyoderma gangrenosum should be considered as a rare, but important differential diagnosis of leg ulcers and postoperative progressive exacerbation. Timely diagnosis based on clinical suspicion is pertinent for correct therapy and to avoid iatrogenic deterioration of the disease. PMID- 7856209 TI - [Postpartum ovarian vein thrombophlebitis--case report]. AB - Because of the low incidence and the lack of clinical symptomatology, puerperal ovarian vein thrombophlebitis has constituted a diagnostic problem now as ever, and diagnostic errors are frequent. With the help of US and CT, however, the chances of early detection have improved. On the 26-year old patient P. C. a section had to be performed in the 34th week of pregnancy because of premature rupture of the bag of waters. On the 7th postoperative day, the patient developed pyrexia inspite of antibiotic therapy. Sonographical examinated lead us to suspect a floating thrombus in the vena cava inferior. It was in the CT that the diagnosis of ovarian vein thrombosis was made for the first time. On the 13th day post partum a laparotomy and exstirpation of the v.ovarica dextra with removal of the thrombus plug from the v.cava inferior infrarenally was performed. Primarily, conservative treatment is given preference if the development is uncomplicated; operative sanitation is undertaken in case of difficulties only. PMID- 7856210 TI - [How should I photograph the legs?]. PMID- 7856211 TI - [The myth of the lust for free life and so-called self-realization]. AB - There exists a present tendency for immediate satisfaction of desires and pleasures, as well in our western civilization in general, as propagated by some commercialized psychotherapy (with good sales results of books with title and contents as "Don't be good!" [?]; interrogation-mark set by me). Such educational tendency is opposed to a number of human inborn laws such as 1) need of getting to know one's limits and to accept them, 2) evolution of tolerance for frustration without which interhuman communication can not be kept alive, 3) the law that human beings are social beings. By no means we want to propagate a rigid doctrinary and mainly frustrating system of education. The golden path in between the extremes is here (as always) the most difficult. The "integrated psychotherapy", inaugurated and advocated by us, wants to show this way in psychotherapy. Outside psychotherapy too, within the general rules of (academic) education, the here given words may help to find this "golden path in between". PMID- 7856212 TI - [The carbohydrate theory]. AB - We can get the full range of our health only if our genome and our environment are compatible. After we had adapted through millions of years to the diet of scavengers and hunters we could not--up to now--adapt to the farming (to the carbohydrates) in a small fraction of this time. The author sees in this the cause of our "Western" diseases. Evidence can be gathered from the rates for cancer and myocardial infarctions in areas where farming came late (Scotland, Scandinavia, Ireland), and from the good results of a return to the (low carbohydrate) Paleolithic diet in many of our civilization diseases. The genetic substratum for this incomplete adaptation to carbohydrates can be seen in the so called gene polymorphism, incomplete genes for ACE etc, which are more frequent in areas where farming came later. PMID- 7856213 TI - [Magnetic resonance mammography--even today a routine procedure]. AB - Magnetic resonance imaging of the breast is at this time superior to all other methods of breast cancer diagnosis. Within a few short years since its introduction, magnetic resonance mammography (MRM) can be labelled the "golden standard" for breast imaging and carcinoma detection. Nevertheless, in a certain percentage of high risk patients, there remains an unacceptable number of unclassifiable findings on MRM examination. We were able to demonstrate in 10% of our examined patients small (< 8 mm), occasionally solitary, but usually multiple lesions that exhibited with the use of contrast material an appearance characteristic of carcinoma. Yet in merely half of these cases, that were subsequently surgically examined, significant pathology was found. We assume that some false-negative findings are a matter of the lack of broad acceptance of this diagnostic method by surgeons and pathologists. In order to further the development of MRM in the diagnosis of breast cancer and to ascertain the relevance of these borderline findings, it is important to perfect the techniques of MRM-guided localization of lesions and MRM-guided fine needle biopsies. We except that this would also deepen our knowledge of the pathogenesis of breast carcinoma. MRM is today, however, the examination method of choice for young, high-risk patients, patients with solitary lesions of unknown dignity and patients with markedly fibrocystic breasts. PMID- 7856214 TI - [Chronic fatigue syndrome: immune dysfunction, role of pathogens and toxic agents and neurological and cardial changes]. AB - 375 patients with chronic fatigue syndrome (CFS) were examined using a standardized questionnaire and subsequent interview on 11 risk factors and 45 symptoms. Additionally immunologic, serologic, toxicologic, neuroradiologic, neurophysiologic and cardiologic investigations were performed. Immunologic tests showed cellular immunodeficiences particularly in functional regard (pathological lymphocyte stimulation in 50% of the patients, disorders of granulocyte function in 44%). Furthermore variable deviations were found in the lymphocyte subpopulations (CD3, CD4, CD8, CD19, DR, Leu 11 + 19). In the humoral part tendencies to low IgG-3- and IgG-1-subclass-levels occurred (59% respectively 11% of the patients) also as decreases in complement system (CH50, C3, C4, C1 esterase-inhibitor). In the group of activation markers and cytokines 42% of the investigated patients had circulating immune complexes (CIC), 47% increases of tumor-necrosis-factor (TNF-a) and 21% increases of soluble interleukin-2-receptor (IL-2-R). The increased occurrence of autoantibodies in the CFS-patients (specially antinuclear anti-bodies [ANA], microsomal thyroid antibodies) suggest, that CFS is associated with or the beginning of manifest autoimmune disease. Under the pathogens 78% of the patients had a striking serological constellation of Epstein-Barr-Virus (EBV-EA positive, low EBNA-titers), in the HHV-6-Virus 47% showed increased antibody-titers. Tests on further herpes viruses and on Borreliae, Chlamydiae, Candida and Amoebae were positive in 8 to 36% of the examined patients. Furthermore there were found variable deficits of vitamins and trace elements also as hormonal disturbances.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7856215 TI - Effects of fatty acids and lipids in health and disease. Proceedings of the 1st International Congress of the International Society for the Study of Fatty Acids and Lipids (ISSFAL). Lugano, Switzerland, June 30-July 3, 1993. PMID- 7856216 TI - Some effects of omega 3 fatty acids on coronary heart disease. PMID- 7856217 TI - Essential fatty acid status is altered in pregnancies complicated by intrauterine growth retardation. PMID- 7856218 TI - The relationship between the essential fatty acid status of mother and child and the occurrence of pregnancy-induced hypertension. Intermediate results of a prospective longitudinal study. PMID- 7856219 TI - The role of fatty acid peroxidation and antioxidant status in normal pregnancy and in pregnancy complicated by preeclampsia. PMID- 7856220 TI - Does the long chain polyunsaturated fatty acid (LCPUFA) status at birth affect the postnatal LCPUFA status? PMID- 7856221 TI - Effects of fish oil supplementation in late pregnancy on prostaglandin metabolism. PMID- 7856222 TI - Plasma total phospholipid arachidonic acid and eicosapentaenoic acid in normal and hypertensive pregnancy. PMID- 7856223 TI - The epidemiology of omega 3 fatty acids. PMID- 7856224 TI - Omega 3 fatty acids in renal diseases. PMID- 7856226 TI - Omega 3 fatty acids and respiratory disease. PMID- 7856227 TI - Fatty acids and diabetes mellitus. PMID- 7856225 TI - Placebo-controlled trials of omega 3 fatty acids in chronic inflammatory bowel disease. PMID- 7856228 TI - Chylomicron metabolism and omega 3 and omega 6 fatty acids. PMID- 7856229 TI - VLDL metabolism and omega 3 fatty acids. PMID- 7856230 TI - Low density lipoprotein metabolism and omega 3 fatty acids. PMID- 7856231 TI - Effects of unsaturated fatty acids on high density lipoprotein metabolism. PMID- 7856232 TI - Unsaturated fatty acids in the management of hyperlipidemias. PMID- 7856233 TI - Future directions in omega 6 and omega 3 fatty acid research. PMID- 7856234 TI - Omega 3 fatty acids have multiple antithrombotic effects. PMID- 7856235 TI - Omega 3 fatty acids and cardiovascular risk factors. PMID- 7856237 TI - Platelet effects of omega 3 fatty acid ethyl esters. PMID- 7856236 TI - Effects of omega 3 fatty acid ethyl esters on monocyte tissue factor expression. PMID- 7856238 TI - Omega 3 fatty acids as anticarcinogens: cellular and molecular studies. PMID- 7856239 TI - Isoprenoids and neoplastic growth. PMID- 7856240 TI - Polyunsaturated fatty acids in the treatment of weight-losing patients with pancreatic cancer. PMID- 7856241 TI - Unsaturated lipids: a new approach to the treatment of cancer. PMID- 7856242 TI - Possible applications of polyunsaturated fatty acids in cancer therapy. PMID- 7856243 TI - Effects of eicosapentaenoic acid on tumour growth and cachexia in mouse colon cancer. PMID- 7856244 TI - Omega 3 fatty acids in the regulation of cytokine synthesis. PMID- 7856245 TI - Fatty acids and hypertension. PMID- 7856247 TI - [Autoantibodies in the clinic and in research: 2nd Dresden Autoantibody Symposium 21 to 23 April 1993]. PMID- 7856248 TI - [The natural polyspecific autoantibody repertoire of man]. PMID- 7856246 TI - Alleviation of autoimmune disease by omega 3 fatty acids. PMID- 7856249 TI - [Reactivity of a natural human monoclonal polyreactive antibody with exogenous and endogenous antigens and its possible role in an idiotypic-anti-idiotypic network]. PMID- 7856251 TI - [Recombinant Ro-, La- and U1-n-RNP antigens: detection of autoantibodies with ELISA and clinical association in SLE]. PMID- 7856250 TI - [Genetic association of autoantibodies against recombinant antigens of the ENA group and cardiolipin in systemic lupus erythematosus (SLE)]. PMID- 7856252 TI - [Ribosomal protein L7 as an autoantigen in patients with systemic lupus erythematosus, mixed collagen disease and rheumatoid arthritis]. PMID- 7856253 TI - [Antibodies against topoisomerase I (Scl-70)--comparative studies on detection with recombinant protein antigens and natural enzyme]. PMID- 7856255 TI - [Modification of B-cell precursor frequencies by systemic photochemotherapy (PUVA) in patients with systemic scleroderma]. PMID- 7856254 TI - [Association between HLA-D alleles and scleroderma-specific autoantibodies in quartz dust exposed persons]. PMID- 7856257 TI - [Autoantibodies in kidney diseases]. PMID- 7856256 TI - [Clinical relevance of antiphospholipid antibodies in rheumatology]. PMID- 7856261 TI - [Autoantibodies in type 1 diabetes mellitus]. PMID- 7856259 TI - [Anti-endothelial cell antibody as a marker of disease activity in Wegener's granulomatosis]. PMID- 7856262 TI - [Clinical relevance of autoantibodies in chronic liver diseases]. PMID- 7856260 TI - [Humoral autoreactivity in cardiac diseases]. PMID- 7856263 TI - [Humoral autoimmune response to nuclear Sp100 autoantigen in patients with primary biliary cirrhosis]. PMID- 7856258 TI - [Anti-myeloperoxidase antibodies in kidney and systemic diseases]. PMID- 7856265 TI - [Brain antibodies in schizophrenia]. PMID- 7856264 TI - [Autoantibodies in neurologic diseases]. PMID- 7856269 TI - [From general practice of expert assessment: growth disorders after inadequate treatment of an epicondylar joint fractures]. PMID- 7856268 TI - [Humoral immune reactivity in inflammatory eye diseases--an overview]. PMID- 7856267 TI - [Serum antibodies against brain tissue in multiple sclerosis patients: a frequent phenomenon in chronic progressive, but not relapsing disease course]. PMID- 7856266 TI - [Polyspecific immune reaction in the central nervous system in autoimmune diseases with CNS involvement]. PMID- 7856271 TI - [Theodor Billroth (1829-1894) on the 100th anniversary of his death]. PMID- 7856270 TI - [Chemical warfare since ancient times? Early "military toxicology" problems]. PMID- 7856272 TI - [Famous students of the Dresden Surgical Medical Academy]. PMID- 7856273 TI - [Response to Prof. U. Korner: Brain death and organ transplantation--the controversial control of dying]. PMID- 7856275 TI - [ACE inhibitors in cardiovascular diseases symposium. Colon, January 1994]. PMID- 7856274 TI - [Endothelial mechanisms in vasomotor effects of ACE inhibitors]. AB - The beneficial cardiovascular effects of ACE inhibitors are thought to be based primarily on a reduction in vascular angiotensin II formation. However, since ACE also degrades the potent endothelium-dependent vasodilator bradykinin, it has been proposed that the local accumulation of this peptide in the vascular wall represents an additional mechanism by which ACE inhibitors exert their cardiovascular effects. In this context it has been demonstrated that incubation of cultured endothelial cells with ACE inhibitors leads to an enhanced formation of nitric oxide (NO) and prostacyclin (PGI2). This effect is believed to be the consequence of an accumulation of endothelium-derived bradykinin in the vicinity of the endothelial cells. Moreover, by virtue of an as yet unidentified mechanism, ACE inhibitors may also enhance the potency of bradykinin at the receptor level and/or activate the B2-kinin receptor following pre-exposure to bradykinin. Both of these effects may enhance or sustain the bradykinin-induced formation of NO and PGI2 by the endothelium. ACE inhibition also leads to the accumulation of angiotensin I which can be metabolized to angiotensin-(1-7) by another endothelial enzyme, the neutral endopeptidase 24.11. Activating an as yet unidentified receptor, angiotensin-(1-7) (but not other known angiotensin peptides) stimulates endothelial NO release in coronary arteries from different species as well as in the isolated perfused rat heart. This effect also seems to involve the release of vasoactive kinins from the endothelium. The shift in angiotensin I metabolism towards an enhanced formation of angiotensin-(1-7) in the presence of an ACE inhibitor may thus also contribute to the hypotensive action of this class of compounds. PMID- 7856276 TI - [ACE inhibition and atherosclerosis in the animal model]. AB - The goals of rational antihypertensive medication should embrace the alleviation of atherosclerosis, the clinical consequences of which pose a major health problem and hence socio-economic concern for industrialized countries. Angiotensin converting enzyme (ACE) inhibitors are endowed with pharmacodynamic features which may help to attain this aim. Various animal experiments with cholesterol-fed rabbits, pigs and monkeys, as well as with rabbits with inherent disorder of lipid metabolism (WHHL-rabbit), demonstrated endothelial protection against loss of function due to hyperlipidemia and attenuation of lipid deposition in conduit blood vessels with ACE-inhibition. The alleviation of progressive atherosclerosis, which is a common feature of restenosis development following angioplasty, was shown in hypercholesterolemic rabbits and normal rats, but did not occur in clinically more relevant porcine models nor in large clinical trials. Circumstantial evidence from miscellaneous experiments is in line with the view that it is enhancement of bradykinin activity which causes the endothelial protection against the consequences of hypercholesterolemia. Furthermore, loss of relaxation of coronary resistance vessels without overt atherosclerosis despite hypercholesterolemia can be restored by augmentation of the EDRF-pathway as has been demonstrated with ramiprilat in vitro. This is being substantiated in preliminary clinical reports with different ACE-inhibitors. The possible association between improvement in both insulin sensitivity and endothelial function requires further investigation. The critical analysis of present experimental findings on a beneficial influence on both the spontaneous and the progressive development of atherosclerosis indicates ACE-inhibition to be more likely to preserve or restore the function of an intact endothelium than to interfere with the complex reaction occurring after injury of an already affected blood vessel. PMID- 7856279 TI - [Modification of re-stenosis with drugs]. AB - In the treatment of patients with symptomatic coronary artery disease using PTCA, success is limited due to restenosis rates ranging from 30-50% of the lesions treated. Medical approaches to reduce the rate of restenosis were therefore tested in a number of trials. However, in only a few randomized and controlled trials were positive effects reported. Inhibiting platelet aggregation through the use of anti-glycoprotein IIb/IIIa monoclonal antibody 7E3 and, in some studies, with 3 omega fatty acids, a significant reduction in the rate of restenosis was observed. Many trials testing less potent inhibitors of platelet aggregation, such as acetylsalicylic acid, prostacyclin, thromboxane A2 receptor antagonists, and ticlopidine as well as anticoagulants such as heparin or coumarin, calcium antagonists, ACE-inhibitors, antiproliferative agents such as colchicine, methylprednisolone, and angiopeptin were inconclusive or without a positive treatment effect. The results of a hirudin multicenter trial on the rate of restenosis (Helvetica Trial) will soon be reported. There are many possible reasons for these disappointing results, such as poor standardization of the invasive studies, in analyzing the degree of coronary artery stenoses, the inadequate sample size in many trials, and insufficient local drug concentrations as well as the lack of beneficial effects of the study medication. Thus, at present there is no effective treatment to reduce the restenosis rate following PTCA. However, it can be expected that potent antithrombins, or inhibitors of platelet aggregation, may be useful. PMID- 7856277 TI - [ACE inhibitor in metabolic syndrome]. AB - The metabolic syndrome is characterized by cluster-like occurrence of various risk-factors for vascular disease: overweight, hypertension, hyperlipidemia, hyperproteinuria. In the pathogenesis of this syndrome the peripheral resistance to insulin leading to hyperinsulinemia plays most likely a central role, as the development of individual components of the metabolic syndrome may causally be explained in this way. Various possible explanations exist for the development of insulin resistance: on the receptor level, as a result of changes in the capillary bed or in muscle fiber composition, or resulting from disturbed circulation of muscles. Clinical symptoms of hyperinsulinemia are hypertension, lipodystrophy, and type II diabetes. Patients with metabolic syndrome represent a group at high risk for arteriosclerotic vascular disease. Therapy aims primarily at reduction of hyperinsulinemia as the underlying factor. In particular non medical intervention plays an important role (reduction of body weight, exercise). In drug therapy of hypertension only such antihypertensives which remain neutral to metabolism should be applied, i.e., ACE-inhibitors which even improve the metabolic condition. PMID- 7856278 TI - [Mechanisms of re-stenosis after angioplasty]. AB - Restenosis post angioplasty is a segmentally limited, wound healing response to a circumscript traumatization of the vascular wall associated with the therapeutic intervention, which also comprises residual or recoiling plaque components at the time of initial revascularization. Studies with animal models and the analysis of human plaque tissue harvested by autopsy or atherectomy indicate a cascade-like course of this wound healing reaction, in which initially different cell types such as thrombocytes, endothelial cells, monocytes/macrophages and smooth muscle cells (SMCs), later predominantly SMCs are involved. In the first phase of inflammation, angioplasty as a multifactorial stimulus induces a sequence of (a) destruction of endothelial and subendothelial structures, (b) traumatization of medial regions with rupture of the internal elastic lamina, (c) exposition of thrombogenic factors such as collagen or tissue factor, (d) stretching of smooth muscle cells with subsequent expression of proto-oncogens (c-fos, c-myc, c-myb), (e) release of growth factors from cells of the bloodstream, endothelial cells and SMCs by direct traumatization and segmental thrombus formation, and (f) thrombin production with autocatalytic activation of the SMC thrombin receptor. Overlapping the inflammation period, granulation begins 3 days after angioplasty. Proteinases such as plasmin as well as collagenases induce the disintegration of extracellular matrix structures, thereby modulating plaque formation, and lead to an organelle-rich SMC phenotype within the intima and media. The phenotypic alteration of SMCs is considered to be the prerequisite for mitogenic and migratory stimulation. This stage shows different expression patterns of growth factors and their receptors; however, there is only limited knowledge about spatiotemporal and maximal expression as well as their coordination for human vascular wall tissue (PDGF, PDGF-R, EGF-R, FGF, FGF-R, TGF-beta). Overlapping with the granulation period, induction of different components of the extracellular matrix occurs 1-2 weeks after angioplasty, possibly mediated by TGF beta (phase of matrix formation). Smooth muscle cells produce and secrete matrix proteins such as tenascin, fibronectin, collagens and proteoglycans, and thereby induce a marked increase of the neointimal plaque volume. Angiographic restenoses of coronary and peripheral arteries histologically exhibit tissue with high cellularity (> 500 cells/mm2), associated with SMC activity markers such as PCNA or NMMHC-B. Proliferative and migratory activities of these cells in vitro are augmented by a factor of 2 to 3 as compared to those from chronic primary lesions. Transmission electron microscopic analysis proves that within the media a nearly complete re-differentiation of SMCs occurs, whereas intimal SMCs persist in the intermediate phenotype.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7856284 TI - Coronary endothelial vasodilator dysfunction: clinical relevance and therapeutic implications. AB - Endothelial function of epicardial arteries and coronary resistance vessels, as well as endothelial dysfunction and clinical symptoms of coronary artery disease and their therapeutic implications are reviewed including the presentation of the author's own results. Coronary endothelial vasodilator dysfunction represents a fundamental functional disturbance in vascular biology with the development of atherosclerosis. This functional alteration in coronary vascular reactivity appears to play an important integral part in the clinical presentation of coronary artery disease. Humoral and neuronal factors in favour of vasoconstrictor influences affect the balance between myocardial oxygen supply and demand, thus, facilitating the manifestation of myocardial ischemia. In order to identify more selective therapies the potential mechanisms underlying an impaired release or activity of EDRF/NO must be considered. Dysfunction of the endothelial L-arginine/NO pathway may involve decreased activity of NO synthase, increased inactivation of NO formed from its precursor L-arginine, impaired signal transduction mechanisms and reduced intracellular availability of L arginine. Currently, initial therapeutic strategies include the supplementation of L-arginine, the use of antioxidants, as well as ACE-inhibitors. ACE-inhibitors have been shown not only to reduce vascular tone (and hypertrophy) by inhibition of angiotensin II formation, but also by increasing the endothelial production of NO and prostacyclin most likely due to the local accumulation of endothelium derived bradykinin. Thus, ACE-inhibition appears to provide the potential to improve endothelial NO synthesis. Indeed, study results demonstrate that chronic ACE-inhibition is associated with an increased coronary blood flow response to acetylcholine suggesting an improvement in endothelial vasodilator functioning of coronary resistance vessels.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7856285 TI - [Indications for ACE inhibitors in chronic heart failure]. AB - Chronic systolic heart failure after coronary heart disease or dilated cardiomyopathy is characterized by an increasing dilatation of the left ventricle and raised intracardial pressures. The higher the NYHA class, the higher are usually preload and afterload of the left ventricle. Concomitantly, the renin angiotensin-aldosterone-system is stimulated, leading to neurohormonal activation of vasoconstrictive hormones. This will reduce the already depressed myocardial function even more. The addition of ACE-inhibitors to diuretics and digitalis has improved the prognosis of patients with severe and moderate heart failure. Thus, there is no question today that ACE-inhibitors are needed in chronic heart failure, irrespective of the origin. New investigations indicate that diuretics and digitalis are also needed in severe or moderate heart failure. They certainly lead to a decrease of symptoms. The significance of the local ACE-system seems to be greater than that of the circulating ACE-system, when chronic heart failure after myocardial infarction has to be treated. The prophylactic use of ACE inhibitors after myocardial infarction with decreased ejection fraction will reduce the necessity of admittance to hospital and will also improve the prognosis. PMID- 7856282 TI - [Reduction of infarct size and remodeling after ramipril]. AB - It is known that angiotensin converting enzyme (ACE) inhibitors not only prevent the formation of angiotensin II, but also potentiate the activity of bradykinin. We investigated the effects of the ACE-inhibitor ramipril in two models of cardiac ischemia. In anesthetized dogs with a coronary occlusion of 6-h duration, both ramiprilat and bradykinin significantly reduced infarct-size. This effect was prevented by the co-administration of the bradykinin antagonist HOE 140. In rats with a coronary occlusion of 6-weeks duration, ramipril administration significantly reduced infarct-size and prevented the development of left ventricular hypertrophy. Thus, ramipril showed a cardioprotective activity in models of acute as well as of chronic myocardial ischemia. These effects are probably mediated by the potentiation of bradykinin. PMID- 7856283 TI - [Indications for ACE inhibitors in the postinfarct period]. AB - Prognosis of patients post-myocardial infarction depends largely on the degree of left ventricular dysfunction, which results from loss of contractile tissue and remodeling of infarcted and surviving myocardium. This remodeling process may result in chronically progressive dysfunction and ultimately in heart failure. Next to mechanical determinants humoral control of hypertrophy, dilatation and qualitative changes of surviving myocardium are discussed. A major determinant of the extent of remodeling is infarct size. Efficacy of angiotensin-converting enzyme (ACE) inhibitors on infarct size was tested in animal experiments with conflicting results. Recent clinical studies also report beneficial (GISSI-3 and ISIS-4) or no (CONSENSUS II) effects on survival post-myocardial infarction when ACE-inhibitors were used in the acute phase. Up to date it remains unsettled which patients may benefit from acute therapy with ACE-inhibitors. Three days after myocardial infarction hemodynamically stable patients with heart failure may be treated with ACE-inhibitors (AIRE study). Prognosis may be improved and manifestation of heart failure prevented or delayed also in patients without heart failure treated in this phase of myocardial infarction with ACE-inhibitors (SAVE study). Prevention of heart failure may also be observed in patients treated later (at least 4 weeks) after myocardial infarction (SOLVD prevention arm). It is essential for this indication that patients are carefully selected for treatment depending on left ventricular function. Duration of treatment in patients with severe left ventricular dysfunction probably has to be lifelong, the doses of ACE-inhibitors used have to be relatively high (e.g. 3 x 50 mg captopril or 2 x 10 mg enalapril).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7856280 TI - [Cardioprotective effects by ramipril after ischemia and reperfusion in animal experiment studies]. AB - ACE inhibitors induce an increase in kinin levels with subsequent release of nitric oxide (NO) and prostacyclin, as shown in cultured endothelial cells and isolated rat hearts. Isolated perfused working rat hearts continuously release kinins and prostacyclin. During ischemia after ligation of the left coronary artery kinin and prostacyclin concentrations in the venous effluent of the hearts are increased. ACE inhibition with ramiprilat increases kinin concentrations during normoxia, ischemia and reperfusion, whereas deendothelialization markedly reduces kinin and prostacyclin outflow in controls as well as in ACE inhibitor treated hearts. Rat hearts with postischemic reperfusion arrhythmias are protected by ramiprilat- and bradykinin perfusion, cardiodynamics and metabolism of treated hearts are improved. These effects are observed in concentrations too low to increase coronary flow. The cardioprotective effects of ramiprilat and bradykinin are abolished by the specific B2-kinin receptor antagonist icatibant and by an inhibitor of NO-synthase. Long-term treatment (20 weeks) with ramipril in a blood-pressure-lowering dose (1 mg/kg/day) and a subantihypertensive dose (10 micromg/kg/day) protects spontaneously hypertensive rats (stroke prone) against hypertension and left ventricular hypertrophy in the high dose. In addition, both treatment regimens induce myocardial capillary growth. Isolated hearts of these animals show increased myocardial contractility and coronary flow, reduced release of cytosolic enzymes into the coronary effluent, and improved myocardial metabolism. These changes are observed even at a dose of ramipril which does not affect blood pressure and left ventricular hypertrophy. They are abolished by chronic blockade of kinin receptors with icatibant.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7856289 TI - Immunogenicity of rabies vaccines used during an urban epizootic of rabies in Mexico. AB - From 1 July 1987 to 31 December 1988, 30% of 247 rabid dogs in Hermosillo, Mexico had a positive history of rabies vaccination. Serosurveys suggested that inactivated suckling mouse brain vaccine (INACT-SMBV) and inactivated tissue culture vaccine (INACT-TC) used before and during the epizootic were poor immunogens. Prospective studies showed that only about one-third of dogs vaccinated with INACT-SMBV were seropositive 5 weeks after vaccination. Lack of vaccine potency was the most likely cause of poor immunogenicity. Rabies vaccines should be evaluated periodically by measuring antibody responses in animals. In some circumstances, minimum seroconversion rates and antibody titres in vaccinated animals may be better measures of immunogenicity than relative potency. PMID- 7856287 TI - Vaccinoprophylaxis of mumps using mumps vaccine, strain Sofia 6, in Bulgaria. AB - A mumps vaccine, using strain Sofia 6 prepared in guinea-pig kidney primary cell cultures, was gradually introduced in Bulgaria to vaccinate 1- to 12-year-old children between 1972 and 1976. It was included in the national vaccine programme in 1977. The vaccine showed a slight reactogenicity, a good immunogenicity and a high epidemiological efficacy. Due to the increased morbidity of mumps, revaccination was carried out in 4- to 12-year-old children in 1982. A high level of side-effects, mainly meningitis, was registered, and led to suspension of the mumps vaccine in Bulgaria. PMID- 7856288 TI - Enhancing effects of pertussis toxin B oligomer on the immunogenicity of influenza vaccine administered intranasally. AB - Influenza vaccines together with pertussis toxin B oligomer (PTB) purified from a culture supernatant of Bordetella pertussis were administered intranasally into mice to test for an adjuvant effect of the PTB. An inactivated virus vaccine and an ether-treated HA vaccine prepared from influenza virus A/Yamagata/120/86 (H1N1) and formulated with PTB, stimulated production of serum haemagglutinin inhibition (HI) antibody and pulmonary and endotracheal secretory IgA antibody to high titres. In addition, mice immunized with the influenza vaccines formulated with PTB were protected against exposure with a challenge virus. These results demonstrate that PTB can enhance the immunogenicity of influenza vaccines administered intranasally. PMID- 7856286 TI - [Therapy with ACE inhibitors in chronic heart failure and limited kidney function]. AB - Renal function in 31 patients with mild to moderate heart failure (NYHA Classes II-III) was studied before and during treatment with ACE-inhibitors. Maximal treatment doses were based on randomization: captopril 3 x 12.5 mg or lisinopril or enalapril, both 1 x 10 mg. Before therapy and at the end of titration phase (after 6 days) glomerular filtration rate and renal blood flow were determined from inulin and PAH clearance (steady-state method). In the total study group the median arterial pressure significantly decreased from 94 mmHg to 84 mmHg (p < 0.01), whereas glomerular filtration rate was only moderately, however, significantly reduced from 103 ml/min to 97 ml/min (median values, p < 0.01). Renal blood flow, however, increased from 372 ml/min to 403 ml/min (p < 0.01). Changes in glomerular filtration rate (GFRd) were significantly dependent on those of renal blood flow (GFRd = 0.07 RPFd - 9.2; p < 0.05). All three ACE inhibitors showed similar changes in glomerular filtration rate and renal blood flow. Ten of the patients had additionally received cyclooxygenase inhibitors. With respect to severity of heart failure and renal function these patients did not differ from the remaining 21 patients of the group. In both groups, a decrease of glomerular filtration rate was found, however, in those patients who had received acetylsalicylic acid there was no increase of renal blood flow. CONCLUSION: A small, however significant decrease of glomerular filtration rate is already seen in patients with mild to moderate heart failure treated with ACE inhibitors. Increase of renal blood flow counteracts the decrease of glomerular filtration rate. During concomitant application of acetylsalicylic acid the increase of renal blood flow remains absent. PMID- 7856294 TI - A subunit gIV vaccine, produced by transfected mammalian cells in culture, induces mucosal immunity against bovine herpesvirus-1 in cattle. AB - A truncated version of bovine herpesvirus-1 (BHV-1) glycoprotein IV (tgIV) was produced in a novel, non-destructive expression system based upon regulation of gene expression by the bovine heat-shock protein 70A (hsp70) gene promoter in Madin Darby bovine kidney (MDBK) cells. In this system, up to 20 micrograms ml-1 of secreted tgIV, which is equivalent to the yield from 4 x 10(6) cells, was produced daily over a period of up to 18 days. Different doses of tgIV were injected intramuscularly into seronegative calves. Virus-neutralizing antibodies were induced by all doses of tgIV, both in the serum and in the nasal superficial mucosa. However, the low dose (2.3 micrograms) induced significantly (p < 0.05) lower antibody titres than the medium (7 micrograms) and high (21 micrograms) doses. The medium and high doses of tgIV conferred protection from BHV-1 infection, as demonstrated by a significant (p < 0.05) reduction in clinical signs of respiratory disease and virus shedding in the nasal secretions postchallenge. However, the 2.3 micrograms group, although partially protected, was not significantly (p > 0.05) different from the placebo group. This study demonstrated the potential of an intramuscularly administered tgIV subunit vaccine to induce mucosal immunity to BHV-1 using an economic protein production system and an acceptable vaccine formulation. In addition, a strong correlation was observed between neutralizing antibodies in the serum and nasal superficial mucosa, virus shedding and clinical disease. Thus, serum neutralizing antibody levels in tgIV-immunized animals may be a good prognosticator of protection from BHV-1 infection and disease. PMID- 7856290 TI - Enteral immunization and challenge of volunteers given enterotoxigenic E. coli CFA/II encapsulated in biodegradable microspheres. AB - The development of a safe and effective vaccine against enterotoxigenic Escherichia coli (ETEC) would be useful for travellers and for young children in endemic areas. A feasibility study of an enteral ETEC vaccine prototype consisting of colonization factor antigen II (CFA/II), containing two component antigens CS1 and CS3, encapsulated in biodegradable polymer microspheres (BPM) was conducted in healthy volunteers. Ten adult volunteers swallowed intestinal tubes on days 0, 7, 14 and 28; after collection of jejunal fluid samples, 1 mg of CFA/II in BPM was administered via the tube. Volunteers kept a diary of symptoms after each dose. Secretory IgA in jejunal fluids, serum responses and circulating antibody-secreting cells (ASC) were measured before and after vaccination. The vaccine was well tolerated. Five of ten volunteers developed IgA anti-CFA/II ASC by 7 days after the last dose of vaccine; these same five vaccinees had IgA anti CS3 ASC, and three of these five vaccinees had IgA anti-CS1 ASC. Five of ten vaccinees developed rises in jejunal fluid sIgA anti-CFA/II with peak GMT of 1:42. About 8 weeks after the first dose of vaccine, ten vaccinees and ten unvaccinated control volunteers underwent challenge with 10(9) c.f.u. ETEC E24377A (O139:H28 LT+ST+CS1+CS3+). Ten of ten controls and seven of ten vaccinees developed diarrhoea (p = 0.11, 30% vaccine efficacy). Two of the three protected vaccinees had the highest numbers of ASC and highest sIgA titres during the course of immunization, suggesting that these responses were protective and that this vaccine development strategy has merit. Future studies with higher dosages and a different dosing schedule are planned. PMID- 7856281 TI - ACE-inhibitor therapy after myocardial infarction--a new treatment strategy. AB - Potential benefit or harm of drug therapy in patients with chronic congestive heart failure and those later presenting to hospital after an acute myocardial infarction (AMI) have been studied in a number of large-scale survival studies during the last few decades. Currently available data are reviewed in order to consider both methodology and also the clinical relevance of findings with emphasis on trials with ACE-inhibitors like CONSENSUS-II, the ISIS-4, GISSI-3 and Chinese mega-trials, TRACE, SAVE and AIRE. Results of SAVE and AIRE show a clear survival benefit for the patients. Furthermore, the benefit of both trials was in addition to any other benefit which resulted from aspirin, thrombolytic and beta blocker therapies. In absolute terms, treatment of 1,000 patients with ramipril (AIRE) for 1 year would be expected to result in the prevention/delay of 40 premature deaths. The beneficial effects of ramipril were clearly apparent by 30 days though additional benefit beyond this point was also present. Furthermore, prespecified subgroup analysis revealed significant benefit for patients at risk like women and the elderly. A selective approach is argued for the treatment of patients with ACE-inhibitors after myocardial infarction. PMID- 7856291 TI - Phase 1 trial of immunological adjuvant QS-21 with a GM2 ganglioside-keyhole limpet haemocyanin conjugate vaccine in patients with malignant melanoma. AB - Increasing doses of saponin fraction QS-21 were administered as immunological adjuvant in a Phase 1 trial with a constant dose of the melanoma ganglioside GM2 covalently attached to keyhole limpet haemocyanin (KLH). Twenty-eight patients with AJCC Stage III or IV melanoma who were free from disease after surgery were treated with six vaccinations administered subcutaneously over a 5-month period. Local and systemic reactions were QS-21 dose-related. Doses of < or = 100 micrograms induced mild local tenderness and inflammation at vaccination sites lasting 2-4 days and occasional brief low-grade fever and malaise, but no significant incapacitation. The 200 micrograms dose induced low-grade fever and malaise after 30% of vaccinations and local reactions as large as 20 cm in diameter were seen in all patients, resulting in discomfort with usage of the injected extremity for 5-10 days. The titres of IgM and IgG antibodies against GM2, and IgG antibodies against KLH, were highest at the 100 and 200 micrograms QS-21 doses. No antibodies against QS-21 were detected. This trial identifies the 100 micrograms dose of QS-21 as the optimal well tolerated dose for induction of antibodies against both the melanoma ganglioside/GM2 and the protein KLH in melanoma patients. PMID- 7856295 TI - Developments in mucosal influenza virus vaccines. AB - Immunogenicity and efficacy of aerosol inactivated split influenza virus vaccines, which are threefold the strength of the vaccines for parenteral use, and cold-adapted reassortant live influenza virus vaccines were evaluated. Mucosal immune responses were evaluated by quantifying specific IgA antibody of the nasal swab solution, and systemic immune responses were evaluated by determining serum haemagglutination inhibition antibody levels. Efficacy of the aerosol inactivated vaccine was evaluated by a challenge test using live vaccine virus. It was concluded that mucosally administered inactivated influenza virus vaccine stimulated systemic and mucosal immune responses more strongly than live influenza virus vaccine and manifested a much stronger booster effect than live vaccine. Mucosal administration of inactivated influenza virus vaccine was effective in preventing infection by live vaccine virus. PMID- 7856293 TI - Phase 1 trial of a 24-valent Klebsiella capsular polysaccharide vaccine and an eight-valent Pseudomonas O-polysaccharide conjugate vaccine administered simultaneously. AB - A Klebsiella (K) vaccine consisting of 24 capsular polysaccharide antigens and a Pseudomonas aeruginosa (P) vaccine consisting of eight O-polysaccharide antigens conjugated to P toxin A have been developed to prevent sepsis by means of active or passive immunoprophylaxis. In search for a practical immunization schedule, the two vaccines were injected in opposite arms simultaneously (20 volunteers) or 14 days apart (21 volunteers). The vaccines were similarly well tolerated by both volunteer groups. Geometric mean antibody concentrations and mean fold antibody rises to the 33 vaccine antigens (including toxin A) were similar in the two groups at 2 months, and the decline in antibody measured at 18 months was also similar. Because the two vaccines were safe and similarly immunogenic in the two vaccine groups, they can be administered simultaneously to patients or plasma donors in a practical vaccination schedule. PMID- 7856296 TI - Immunogenicity of high-titre AIK-C or Edmonston-Zagreb vaccines in 3.5-month-old infants, and of medium- or high-titre Edmonston-Zagreb vaccine in 6-month-old infants, in Kinshasa, Zaire. AB - The effect of measles vaccine potency was evaluated among 485 children aged 6 months, and the effect of vaccine strain was evaluated among 538 children aged 3.5 months, in Kinshasa, Zaire. Children aged 6 months were randomly assigned to receive either high-titre Edmonston-Zagreb (EZ-H), potency 5.7 log10/dose, or medium-titre EZ (EZ-M), potency 4.7 log10/dose, those aged 3.5 months were randomly assigned to receive either AIK-C, potency 5.5 log10/dose, or EZ-H, and were revaccinated with EZ-M vaccine at age 9.5 months. Measles antibodies were measured using the plaque reduction neutralization assay. Among children vaccinated at age 6 months, the seroresponse was significantly higher after EZ-H than EZ-M vaccine, with 92 and 83% seroconverting by 6 months postvaccination and 59 and 40% respectively having antibody titres > 200 mIU. Among children vaccinated at age 3.5 months, only 24% (AIK-C) and 22% (EZ-H) attained antibody titres > or = 200 mIU 6 months postvaccination. After revaccination at age 9.5 months, 81% of children in the AIK-C group and 73% in the EZ-H group had antibody levels > 200 mIU (p = 0.056). A retrospective survey was conducted in January 1993 to determine the mortality experience of vaccine groups, and information was obtained for 94% of the children. A total of 44 deaths (4%) were identified, with no significant differences between groups when stratified by age at vaccination.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7856292 TI - Effects of influenza virus-specific cytotoxic T-lymphocyte responses induced by a synthetic nucleoprotein peptide on the survival of mice challenged with a lethal dose of virus. AB - Even though virus-induced cytotoxic T lymphocytes (CTLs) recognize antigens as peptides presented on infected cells, short synthetic peptides without any modifications are generally considered unsuitable for inducing antigen-specific CTLs in vivo. Our results demonstrate rapid induction of influenza virus-specific CTLs in Balb/c mice by an unmodified core protein peptide known to be a dominant H-2d-restricted CTL epitope. Additionally, the immunization procedure we employed in these studies produced significant influenza virus-specific CTLs in lymph nodes, spleen and lungs. When challenged with a lethal dose of influenza virus, a statistically significant delay in the day of death was observed in peptide immunized mice. However, viral clearance was only slightly different from that in control mice. While these results are encouraging, they suggest a requirement for multiple CTL-inducing peptides, helper T cell-inducing peptides and/or virus specific IgA responses in order to achieve protection from influenza infection. PMID- 7856297 TI - Mixed populations in influenza virus vaccine strains. AB - Human influenza viruses used for vaccine production have previously been adapted to grow in eggs. During egg adaptation, variants are selected and we have observed that more than one variant may derive in a single egg resulting in a mixed population. We have now investigated the extent of heterogeneity, due to host cell selection, of virus strains used for the manufacture of influenza vaccine for the 1991/1992 and 1992/1993 seasons. The A(H1N1) vaccine virus was homogeneous with respect to substitutions in the haemagglutinin deriving from egg adaptation. However, two A(H3N2) vaccine strains and the influenza B component, B/Yamagata/16/88, consisted of mixed populations, apparently due to their cultivation in eggs. The individual variants within B/Yamagata were isolated and found to be antigenically distinct. The ratios of these variants within different manufacturers' seed stocks varied to the extent that vaccine derived from them could be distinguished antigenically. Furthermore, derivation of high-growth reassortants from the A(H3N2) strains which involves passaging at limit dilution did not necessarily lead to a homogeneous virus population. The significance of these findings for the efficacy of vaccine is not known at present. PMID- 7856298 TI - Immunogenicity of two different dosages (10 and 5 micrograms) of recombinant DNA hepatitis B vaccine in healthy neonates. AB - The immunogenicity of a half (5 micrograms) and a full (10 micrograms) dosage of recombinant DNA yeast-derived hepatitis B vaccine (HB-Vax-DNA) in healthy neonates was assessed in order to compare two candidate dosages of vaccine. After randomization 174 newborns of HBsAg-negative mothers entered the study. Neonates received four doses of either 10 or 5 micrograms hepatitis B vaccine, according to the DTP-polio immunization schedule at months 3, 4, 5 and 11. No serious adverse reactions were observed; 15.5% of vaccinated newborns suffered mild transient local symptoms. The vaccine was highly immunogenic irrespective of dosage of vaccine; all infants developed anti-HBs levels > or = 10 IU l-1, 99% > or = 100 IU l-1. A dosage of 10 micrograms hepatitis B vaccine produced higher antibody levels than 5 micrograms hepatitis B vaccine after primary vaccination (first three doses) but not after booster vaccination (fourth dose) (p = 0.06 and 0.75, respectively). Either vaccine dosage can be recommended for incorporation in the Expanded Programme on Immunization in the Netherlands. PMID- 7856300 TI - Immunogenicity of Vibrio cholerae ghosts following intraperitoneal immunization of mice. AB - The immunogenic potential of Vibrio cholerae ghosts (VCG) in comparison with heat killed whole-cell vibrios (WCV) was evaluated after intraperitoneal immunization of adult mice. Swiss white mice received four doses of VCG or WCV intraperitoneally, consisting of 500 micrograms of lyophilized material in 200 microliters of phosphate-buffered saline (PBS), pH 7.4. The control group received 200 microliters of PBS. Serum samples were collected from all mice on the day of immunization and on days 14, 24, 35 and 62 postimmunization. Sera were examined for vibriocidal antibodies by the microtitre and tube-dilution methods and Vibrio-specific serum IgG antibodies were assessed by ELISA. IgG antibodies to intact WCV were detected in sera from all animals immunized with VCG or WCV. The response was specific and of high magnitude. Significantly higher antibody responses were obtained when sera from both VCG- and WCV-immunized mice were titrated against VCG. The immunogenicity of VCG in evoking serum IgG responses was higher than that of WCV. However, the immunogenicity of the two antigen preparations was comparable in terms of seroconversion for vibriocidal antibodies. These results demonstrate that VCG administered intraperitoneally evoke Vibrio-specific serum IgG responses as well as vibriocidal antibody activity in mice. PMID- 7856299 TI - Hepatitis A vaccine. A new convenient single-dose schedule with booster when long term immunization is warranted. AB - A total of 162 anti-HAV-negative healthy adults were immunized with a single high dose (1440 ELISA units = 1 ml) of inactivated hepatitis A vaccine and a booster was given at month 6. Antibodies were measured after modification of a commercial ELISA kit, enabling quantification of titres down to 6 mIU ml-1. After 14 days, 96% of vaccinees had positive anti-HAV titres (> 20 mIU ml-1), and after 30 days all vaccinees had seroconverted. The geometric mean titres were 150 mIU ml-1 and 380 mIU ml-1 respectively. The booster dose at month 6 elicited a dramatic (25 fold) increase in antibody titres from 125 to 3090 mIU ml-1. Thus a single dose may be a convenient alternative to immunoglobulin for inducing rapid seroprotection, with a booster dose at month 6 ensuring long-lasting protection. PMID- 7856304 TI - Intradermal hepatitis B vaccination of hospital personnel in developing countries. PMID- 7856301 TI - Oral administration of an antigenic synthetic lipopeptide (MAP-P3C) evokes salivary antibodies and systemic humoral and cellular responses. AB - Parenteral immunization with a tetravalent multiple antigen peptide (MAP) containing a gp120 sequence coupled to a synthetic lipophilic moiety (MAP-P3C) has been previously found to produce systemic antibody and cellular responses in mice. This study demonstrates that oral administration of MAP-P3C induced IgA antibodies in mucosal secretions and protein-specific IgG in the sera of the immunized mice. Moreover, intragastric delivery of MAP-P3C generated systemic T lymphocyte stimulation and specific cytotoxic T-lymphocyte (CTL) activity. The CTL response was eliminated by treatment with CD8-specific antibody plus complement and was MHC class I-restricted. Therefore, presentation of lipid linked synthetic peptides to the intestinal mucosal surface is effective in initiating humoral and cellular immunity both at mucosal sites and systemically. PMID- 7856303 TI - Delivery of pseudorabies virus envelope antigens enclosed in immunostimulating complexes (ISCOMs); elicitation of neutralizing antibody and lymphoproliferative responses in swine and protection in mice. AB - An experimental subunit vaccine that consisted of pseudorabies virus (PRV) envelope glycoproteins enclosed into immunostimulating complexes (PRVenv/ISCOM) was constructed, and evaluated in DBA/2 mice and inbred swine of the SLA haplotype c/c. Two to three weeks after the first vaccine dose, specific anti-PRV antibodies could be demonstrated by ELISA or virus neutralization (VN) assays. Booster PRVenv/ISCOM vaccinations resulted in rapid and significant increases in antibody titres in both mice and swine. In addition, a week after receiving the third PRVenv/ISCOM vaccine dose swine peripheral blood mononuclear cells exhibited significant proliferation in response to stimulation with PRV virion antigen. Moreover, two doses of vaccine sufficed to protect mice fully against lethal virus challenge. Therefore, the data presented here support the ISCOM as a viable antigen delivery system for subunit PRV vaccines. PMID- 7856305 TI - [Analyses of the rearrangement of T-cell receptor- and immunoglobulin genes in the diagnosis of lymphoproliferative disorders]. AB - Rearrangements are developmentally regulated genetic recombinations in T and B cells which generate functional T cell receptor (TcR) and immunoglobulin genes, respectively. Different variable, sometimes diversity, and joining gene segments which are discontinuously spread out within their chromosomal location in germline configuration, are randomly assembled in individual lymphocytes. These rearrangements can be detected by Southern Blot analysis if more than 5% of a total lymphocyte population in a biopsy specimen carries the same clonal rearrangement. We analyzed DNA from 324 snap-frozen biopsy specimens from lympho proliferative disorders. None of the 20 reactive lesions and four malignant myelomonocytic tumors had a clonal antigen receptor gene rearrangement. All 117 malignant B cell lymphomas of different subtypes and 95 of 97 malignant T cell lymphomas showed a clonal gene rearrangement. Only two angioimmunoblastic lymphadenopathy(AILD)-type T cell lymphomas did not have immune receptor gene rearrangements. They were morphologically indistinguishable from the other 47 T/AILD lymphomas with clonal rearrangement patterns. In most cases TcR beta and immunoglobulin heavy chain (IgH) gene probes were sufficient for lineage assignment of the clonal T or B lymphocyte population. In 18% of B lymphomas, however, a cross-lineage rearrangement of TcR beta genes, and in 20% of the T cell lymphomas a clonal IgH gene rearrangement was detected. After exclusion of centrocytic, large cell anaplastic lymphomas (LCAL) of B-type, and T/AILD lymphomas which are overrepresented in our study, only 10% of the remaining 147 T and B cell lymphomas had aberrant rearrangements. TcR rearrangements other than those of the beta chain genes were extremely rare in B cell lymphomas, as were Ig kappa rearrangements in T lymphomas. Only two T/AILD lymphomas had IgH and Ig kappa rearrangement in addition to their clonal T cell receptor gene rearrangements. Both samples likely contain a clonal B and a clonal T cell proliferation in the same tumor. In other cases with cross-lineage rearrangements additional investigations with probes for the TcR gamma and Ig kappa genes readily assigned the lymphoproliferations to their proper lineage. Exceptions were two CD30 positive high-grade malignant B cell lymphomas, one medium-sized pleomorphic T lymphoma, and one T/AILD lymphoma. Taken together, 207 of 214 lymphoproliferative disorders (97%) could be assigned to T or B lineage by genotyping alone. In most of the other cases lineage assignment was successful if the immunohistochemical results were considered as well. In two cases was no lineage assignment possible.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7856306 TI - In vivo recombination of pseudorabies virus strains in mice. AB - We studied in vivo recombination of pseudorabies virus (PRV) by inoculating mice with non-lethal mutants that carry a small deletion or insertion in the thymidine kinase (TK) gene or the ribonucleotide reductase (RR) gene. After co-inoculation of mice with two different mutants, homologous recombination between the viral genomes resulted in the generation of wild-type PRV that was highly lethal for mice. Thus, recombination could easily be assessed by monitoring survival of inoculated animals. Our results demonstrated that recombination was only detectable when high doses of virus were used. Intragenic recombination was more efficient between mutations in the TK gene than between mutations in the RR gene. Efficient intragenic recombination in the TK gene occurred between mutations which were separated by as few as 266 nucleotides. When two mutants were inoculated with an interval of 2 h, recombination still occurred. No recombination could be detected when the viruses were inoculated at the same time but in separate parts of the body. When inoculated separately, none of the mutants tested could be isolated from the brains of mice. Virus could be recovered from the brain, however, after co-inoculation. Surprisingly, of these viruses 36-39% possessed the parental mutant genotype. This observation indicates that complementation enables these mutants to replicate in the brain and suggests that complementation may contribute to pathogenicity of PRV. PMID- 7856302 TI - Influenza A subtype cross-protection after immunization of outbred mice with a purified chimeric NS1/HA2 influenza virus protein. AB - Influenza A/PR/8/34-derived chimeric (D) protein (SK&F 106160) composed of the first 81 amino acids (aa) of NS1 fused to the conserved 157 C-terminal aa of HA2 (NS1 1-81-HA2 65-222) was previously shown to induce H-2d-restricted protective cytotoxic T-lymphocyte (CTL) immunity in inbred mice. However, D protein, like other small peptides, exhibited haplotype dependence and was not immunogenic in H 2b and H-2K mice. A potential use of this antigen in humans and the role of T cells in any protection were evaluated in outbred Swiss and inbred CBF6F1 (H 2d/b) mice. Mice immunized with D protein and challenged by small-particle aerosol with a lethal dose of influenza virus were significantly protected against mortality from influenza A/H1N1 and A/H2N2 (p < 0.05-< 0.0000001), but not from A/H3N2 and influenza B viruses when compared with control mice. D protein did not induce serum virus-neutralizing antibody but caused virus to be cleared faster in immunized mice. Protection was long-lasting. In vivo depletion of either Lyt2 (CD8+) or L3T4 (CD4+) T cells with monoclonal antibodies led to abrogation of in vitro-generated CTL activity in CF6F1 mice and significant reduction in the protective efficacy of D protein against virus challenge in both Swiss and CF6F1 mice. These results suggest that protection was mediated by CD8+ and/or CD4+ cells and not antibody. Thus D protein, via a conserved sequence on the HA2 polypeptide, has the potential to induce partially cross-reactive CTL that may protect against influenza virus disease in humans. PMID- 7856307 TI - Elements in the long terminal repeat of HIV-1 that interact with nuclear extracts from Jurkat cells persistently infected with vaccinia virus. AB - Previous reports showed transactivation of the long terminal repeat (LTR) of HIV 1 in Jurkat cells persistently infected with vaccinia virus. In this communication, electrophoretic mobility shift assays were used to characterize the elements in HIV-1 LTR which might be responsible for the mechanism of transactivation. The results indicated that two elements, those for binding NF-kB and NFAT-1, were able to interact with nuclear extracts derived from Jurkat cells persistently infected with vaccinia virus, suggesting that they may play a role in the transactivation of HIV-1 LTR. PMID- 7856312 TI - Analysis of the nucleotide sequence of 53 kbp from the right terminus of the genome of variola major virus strain India-1967. AB - Sequencing and computer analysis of a variola major virus strain India-1967 (VAR IND) genome segment (53,018 bp) from the right terminal region has been carried out. Fifty-nine potential open reading frames (ORFs) of over 60 amino acid residues were identified. Structure-function organization of the VAR-IND DNA segment was compared with the previously reported sequences from the analogous genomic regions of vaccinia virus strains Copenhagen (VAC-COP) and Western Reserve (VAC-WR) and variola virus strain Harvey (VAR-HAR). Multiple differences between VAR-IND and the strains of VAC but the high identity of VAR-IND with VAR HAR in the genetic maps are revealed. Possible functions of the predicted viral proteins and the effect of their differences on the features of orthopoxviruses are discussed. PMID- 7856310 TI - Expression of the mutagenic peptide of herpes simplex virus type 1 in virus infected cells. AB - A fragment of DNA from within the minimum transforming region (mtr-1) of herpes simplex virus type 1 (HSV-1) is known to raise the mutation frequency of cells. This activity has been attributed to a viral protein whose properties are largely unknown. Antiserum was raised to a synthetic peptide of a predicted amino acid sequence from the protein, and was found to react with cells that were infected by HSV-1 in an ELISA and by immunocytochemical staining. A combination of immunoprecipitation and immunoblotting techniques confirmed that the epitope is located at the carboxy terminus of the UL26 gene product and is downstream of epitopes that are recognized by two monoclonal antibodies. The mutagenic peptide was different from the conventional gene product of UL26 in that: (a) It was expressed from a different reading frame, (b) It was expressed earlier in infection, and (c) It bound DNA, and thus could be separated by DNA-cellulose chromatography. An RT-PCR experiment revealed two deletions in the cDNA, suggesting that RNA splicing could account for the frameshift. Examination of the DNA sequence of the region also revealed a potential ribosomal frame-shift site. The mutagenic peptide of HSV-1 is therefore a product of the UL26 gene which is expressed with a different carboxy terminus early in infection, and this could be due either to RNA splicing or to ribosomal frame-shifting. PMID- 7856309 TI - High level expression of the envelope glycoprotein (gp53) of bovine viral diarrhoea virus (Singer) and its potential use as diagnostic reagent. AB - A 1.74-kb cDNA fragment containing the gp53 coding region has been cloned from bovine viral diarrhoea virus (BVDV) strain Singer by reverse transcription polymerase chain reaction (RT-PCR). Sequence analysis indicated that gp53 of BVDV strains Singer, NADL and SD-1 shared extensive sequence homology at both the RNA (85-94%) and protein (82-91%) levels. Nineteen cysteine residues and five potential N-linked glycosylation sites were identified within the sequenced region, all of which were conserved. These observations suggest that although the homology at the nucleotide sequence level may vary, there was strong structural conservation among bovine viral diarrhoea virus envelope proteins. Full-length gp53 was expressed in Escherichia coli as a fusion protein with glutathione-S transferase (GST). The N-terminal half of gp53 was also synthesised in E. coli as a 28-KDa recombinant protein using the T7 RNA polymerase-directed expression system. Both recombinant proteins were expressed at high levels (approximately 30 50 mg/l). The recombinant proteins were recognised in ELISA and Western blot analyses by polyclonal serum raised against a mixture of BVDV and classical swine fever virus (CSFV). Rabbit antiserum raised against the 28-kDa recombinant protein reacted with different BVDV strains in ELISA and immunofluorescent antibody test, but not with CSFV in the same tests. These results demonstrated that the bacterial recombinant proteins have similar immunological properties to that of the native viral protein and, in conjunction with its homologous antisera, can be useful as diagnostic reagents. PMID- 7856311 TI - Functional analysis of human cytomegalovirus polymerase accessory protein. AB - The human cytomegalovirus (HCMV) UL44 gene product, polymerase accessory protein, was cloned and expressed in Escherichia coli as a 53,000 MW protein. The activity of HCMV DNA polymerase (Pol) alone and Pol/UL44 complex was evaluated in Pol assays designed specifically to elucidate Pol/UL44 interactions. Addition of UL44 to HCMV Pol with primed, single-stranded DNA resulted in increased incorporation of nucleotides into DNA, which was correlated with enhanced enzyme processivity. Several deletion mutants which span the UL44 sequence were constructed and examined for the ability to stimulate Pol activity and to bind double-stranded DNA. The functional domains of UL44 protein were determined to reside within the N-terminal 309 amino acids of the wild type sequence, since deletions within this region resulted in loss of DNA binding and the ability to stimulate Pol. Deletion of C-terminal amino acids 310-433 had no effect on the ability of UL44 protein to increase the processivity of HCMV DNA Pol. PMID- 7856313 TI - Persistence of the SV40 early region without expression in permissive simian cells. AB - SV40 containing recombinant vectors were introduced into permissive simian, non permissive rodent and semi-permissive human cell lines, and assayed for transformation. All mouse and human cell clones expressed T-antigen (T-Ag) and were morphologically transformed when they contained only the wt T-Ag gene (E SV40) or the entire wt viral genome with an interrupted late region. However, of 63 simian clones with these recombinant vectors, none became morphologically transformed and T-Ag containing cells were rare or absent. Nearly all simian cell lines made either no detectable early SV40 RNA or only small amounts of viral RNA but contained viral DNA restriction fragments similar to those in the original recombinant vectors. Functional T-Ag genes were recoverable from several cell clones and used to regenerate infectious virus. Hence, T-Ag gene expression had been suppressed. We found two conditions where T-Ag expression was activated. In a BSC-1 cell line containing E-SV40 DNA, subsequent introduction of a vector with a functional viral late coding region (L-SV40) resulted in the appearance of T-Ag and transformation. These findings suggest that L-SV40 sequences activate or enhance T-Ag expression and that this activation requires a functional Vpl gene. We found also, that vectors with E-SV40 DNA from the bipartite variant EL-SV40 consistently transformed simian CV-1 cells. Transformation was shown to be effected by the multiple alterations present in the regulatory region of this variant. PMID- 7856315 TI - Sequence analyses of the p24 gene of Borna disease virus in naturally infected horse, donkey and sheep. AB - By reverse transcriptase/PCR amplification and subsequent sequence determination of the p24 gene, the relatedness of Borna disease virus (BDV) in various naturally infected animal species was determined. These results are indicative of a common ancestral virus pool and a remarkably low species barrier of BDV. Comparison of 11 sequences to that of tissue culture adapted virus revealed that the homology among all isolates was at least 96.2% at the nucleotide level, and 97% at the amino acid level. Viral sequences from sheep, donkey and horse were found to be not more distantly related to each other than sequences from different infected horses. Tissue-specific virus variants were detected in one horse: the sequences established from infected cerebrum and kidney showed 10 mutations, whereas sequences obtained from parotid gland contained 20 mutations in comparison to the nucleotide sequence of MDCK cell adapted BDV. PMID- 7856314 TI - The herpes simplex virus type 2 gene which encodes the large subunit of ribonucleotide reductase has unusual regulatory properties. AB - Expression of herpes simplex virus type 2 (HSV-2) encoded ribonucleotide reductase (RR) is required for growth of the virus in non-dividing cells. The functional enzyme is composed of a large (RRA) and small (RRB) subunit and the enzyme is expressed as a delayed early activity. The promoter of RRA contains a cis-acting motif (TAATGARAT) which resembles those found in immediate early (IE) genes suggesting RRA is an IE gene. When primate cells were infected with HSV-2, low levels of RRA transcripts were expressed in the presence of cycloheximide indicating RRA is not a true IE gene. Conditions which allow for efficient RRA RNA expression in the presence of cycloheximide were identified in human cells. A phorbol ester, 12-O-tetradecanoyl phorbol-13- acetate (TPA), and hydroxyurea increased the level of RRA RNA expression in the presence of cycloheximide. Hydroxyurea and TPA also stimulated RRA promoter activity in transient assays suggesting these agents induced factors which transactivated the RRA promoter. Expression of an intact c-myc gene transactivated the RRA promoter more than 30 fold in transient assays. Although expression of an intact retinoblastoma gene (Rb) had a slight stimulatory effect on the RRA promoter, mutant Rb proteins also stimulated the RRA promoter. These studies demonstrated that inducible factors in permissive cells increase the steady state levels of RRA RNA in the presence of cycloheximide. PMID- 7856308 TI - Detection of negative-stranded subgenomic RNAs but not of free leader in LDV infected macrophages. AB - The mechanism of synthesis of the seven subgenomic mRNAs of lactate dehydrogenase elevating virus (LDV) was explored. One proposed mechanism, leader-primed transcription, predicts the formation of free 5'-leader in infected cells which then primes reinitiation of transcription at specific complementary sites on the antigenomic template. No free LDV 5'-leader of 156 nucleotides was detected in LDV-infected macrophages. Another mechanism, independent replication of the subgenomic mRNAs, predicts the presence of negative complements to all subgenomic mRNAs in infected cells which might be generated from subgenomic mRNAs in virions. Full-length antigenomic RNA was detected in LDV-infected macrophages by Northern hybridization at a level of < 1% of that of genomic RNA, but no negative polarity subgenomic RNAs. Negative complements to all subgenomic mRNAs, however, were detected by reverse transcription of total RNA from infected macrophages using as primer an oligonucleotide complementary to the antileader followed by polymerase chain reaction amplification using this sense primer in combination with various oligonucleotide primers complementary to a segment downstream of the junction between the 5' leader and the body of each subgenomic RNA. It is unclear whether these minute amounts of negative subgenomic RNAs function in the replication of the subgenomic mRNAs. They could also be by-products of the RNA replication process. Finally, no subgenomic mRNAs were detected in LDV virions. PMID- 7856317 TI - Intracellular processing and transport of Junin virus glycoproteins influences virion infectivity. AB - The influence of glycoprotein processing, cleavage and transport on Junin virus (JV) infectivity was investigated using monensin combined with lectin binding assays. Yields of extracellular virus were more significantly reduced than cell associated virus, indicating that monensin inhibited the transport of infectious virus to the extracellular space on a late stage of the replicative cycle. Shown by lectin reactivity and immunoprecipitation, the intracellular processing of JV glycoproteins involved first the maturation of GPC oligosaccharides to a complex form and then the precursor cleavage which might occur late in transit through or exit from the Golgi cisternae. Cleavage of GPC to yield the mature GP38 as well as cell surface immunofluorescence were blocked by monensin. Thus, GP38 production together with glycoprotein transport to the cell membrane seemed to be required for the release of infectious virus from JV-infected cells. PMID- 7856319 TI - [Schizophrenic psychosis in childhood and adolescence]. PMID- 7856318 TI - Evolutionary implications of genetic variations in the S1 gene of infectious bronchitis virus. AB - The large number of phenotypically distinct strains of infectious bronchitis virus (IBV) provide a broad genetic background for examining naturally occurring coronavirus variation. Comparisons of the published nucleotide sequence of S1 genes of strains isolated in Europe, Japan and the USA and four additional American strains described in this report identified 4 genetically distinct groups. The Dutch group was the most divergent sharing only about 60% identity with the American, Mass and European groups which were about 80% homologous with each other. Whereas the strains within the Mass, European and Dutch strains were at least 95% homologous, the strains within the American group were most variable, sharing about 80% identity. The hypervariable region (HVR) which tended to correlate with serotype extended from amino acid residue 53 to 148. In addition to the previously described putative recombination events in the S1 gene of PP14 and SE17, we have now described similar shifts in homology in the corresponding gene of the Gray, Holte, 6/82 (European strain), and Iowa strains. Although minor cross-over sites were identified in the more conserved 3' end at approximately nt 1000 and 1400, a frequently used hot-spot for recombination extended from nt 25 to a region immediately upstream of, but not including, the hypervariable region (HVR). In addition to point mutations, deletions, and insertions, recombination often involving Mass-like and Ark-like sequences, is a commonly used mechanism responsible for the evolution of IBV. PMID- 7856320 TI - [Early manifestations of schizophrenic psychoses]. AB - Schizophrenic disorders in childhood are rare. Only about 0.5 to 1% of all such disorders have their onset before age 9 and about 4% before age 14. In puberty and early adolescence, however, there is a marked increase in the frequency of such disorders. In childhood more boys seem to be affected, but during adolescence this difference seems to disappear. Possible etiological factors currently under discussion are genetic factors, neurointegrative deficits, attentional deficits, communication deficits and conspicuous premorbid features. With regard to the latter, the authors could show that positive and negative symptoms appear months or even years before the first manifestation of the disorder requiring inpatient treatment. From this perspective schizophrenic disorders in general and those with early onset in particular fit a dimensional model of illness better than a categorical one. In the development of preventive measures more attention to premorbid features is essential. PMID- 7856316 TI - Modulation of the activities of HN protein of Newcastle disease virus by nonconserved cysteine residues. AB - Comparisons of the sequences of the hemagglutinin-neuraminidase (HN) protein from thirteen different strains of Newcastle disease virus (NDV) show that while 12 cysteine residues are conserved in all strains, two cysteine residues are variably present (Sakaguchi et al. (1989) Virology 169, 260-272). One of these residues, at amino acid 6, is in the cytoplasmic domain. The other cysteine is at amino acid 123 in the ectodomain and is responsible for disulfide-linked HN dimers detected in some NDV strains (McGinnes and Morrison (1994) Virology 200, 470-483). To explore the role of these nonconserved residues in the structure and function of the protein, cysteine residues at amino acid 6 and 123 in the HN protein of the AV strain of NDV were mutated individually and in combination by site specific mutagenesis to serine and tryptophan, respectively. Proteins with mutations in either residue (C6S or C123W) or in both residues (C6S,123W) were transported to the cell surface. However, all three mutants had reduced attachment, neuraminidase, and fusion promotion activities. All three mutant proteins also showed an alteration in an antigenic site specific for oligomers of HN protein while all other antigenic sites were present at wild type levels. These results suggest that the nonconserved cysteine residues in the HN sequence may modulate the biological activities of the protein by affecting the oligomeric structure of the protein. PMID- 7856322 TI - [Follow-up dynamics of schizophrenic diseases in adolescence]. AB - In the present study the clinical features of the first episode of schizophrenia were investigated retrospectively and the initial symptomatology was compared with follow-up findings. The study group consisted of 40 adolescents with chronic schizophrenia. During a one-year follow-up period positive and negative symptoms of schizophrenia and depressive symptomatology were evaluated every six weeks. When the patients entered the follow-up study the mean duration of their illness was 4.3 years. Our data revealed a close link between positive and negative symptoms during the period studied. Persistent positive symptomatology at the end of the first treatment period was predictive of high scores for positive and negative symptoms during the entire follow-up period. Furthermore, we were able to demonstrate that negative symptoms can be distinguished from depressive symptoms in the context of the schizophrenic symptomatology. Depressive states (Brief Psychiatric Rating Scale, BPRS) were closely related to the positive symptoms (assessed with the Andreasen scale SAPS), and the negative symptoms (SANS) were correlated with the anhedonia score on the BPRS. Our results suggest that productive symptomatology should be treated aggressively both initially and for a prolonged period of time thereafter. Positive and negative symptoms appear to be related to each other longitudinally. Thus we postulate a single disease process rather than two distinct types of adolescent schizophrenia. PMID- 7856321 TI - [Follow-up of schizoaffective psychoses in adolescence]. AB - Of 156 adolescent inpatients with psychotic disorders (ICD-9: 295.0 to 296.9), 25 had a schizoaffective psychosis with onset before age 18. Of these, 21 were followed up an average of 6.5 years later. Six of the subjects had had only one schizoaffective episode and 15 had had a second episode an average of 14 months later. Half of the subjects had had schizoaffective episodes only. More of the patients with an initial affective episode developed schizoaffective psychosis than of those with an initial schizophrenic episode. On average there had been 0.91 episodes per year during the follow-up period. Seventy-one percent of the subjects had been unable to continue their education or work at the previous level and most had marked deficits in social adaptation. The level of social competence at the end of the first episode was of predictive value for the later social handicap. A comparison with other groups of patients of the same age showed that those with affective disorders had faired better and those with schizophrenia appeared to have the poorest outcome. The schizoaffective group tended to resemble the schizophrenic group more closely than the affective group. Patients whose schizoaffective disorder began in adulthood had fewer problems on the educational and occupational level, better social adaptation and fewer episodes per year and had spent less time in inpatient treatment than those whose disorder had begun before age 18. PMID- 7856323 TI - [Psychotherapeutic and sociotherapeutic aspects in schizophrenic psychoses in childhood and adolescence]. AB - A critical review is given of modern psychotherapeutic and sociotherapeutic approaches used with children and adolescents with schizophrenic disorders. Therapeutic strategies are evaluated within the framework of emprical data on biological and psychosocial facets of schizophrenia. Major treatment goals are discussed that go beyond differences in psychotherapeutic methodology, e.g. attainment of biographical continuity, improvement of strategies for social interaction and conflict resolution, stabilization of self-structures, mastery of age-dependent developmental tasks and, finally, coordination of different therapeutic interventions. It is stressed that psychotherapy and sociotherapy are equally important in the treatment of children and adolescents with schizophrenia. PMID- 7856324 TI - [Effect of clozapine on biogenic amines within the scope of drug treatment of schizophrenic psychoses in adolescence]. AB - Longitudinal assessments (every six weeks for one year) were made of plasma norepinephrine, dopamine, epinephrine and 3-methoxy-4-hydroxyphenylglycol (MHPG) in 40 adolescents with schizophrenia, 20 on clozapine therapy and 20 on conventional medication. In addition to the plasma catecholamine determinations, serum levels of 5-HT were determined as a measure of serotoninergic status. All analyses were performed by HPLC-ECD (high-performance liquid chromatography with electrochemical detection). Clinical ratings of symptomatology were obtained with the Brief Psychiatric Rating Scale (BPRS) and the Andreasen scales for negative and positive symptoms (SANS and SAPS). Compared with the typical neuroleptic medication, clozapine administration was accompanied by a significant increase in plasma norepinephrine and MPHG and serum serotonin levels. The fluctuations in the biogenic amines were closely associated with the observed symptomatology. Plasma MHPG was linked to depressive symptoms (BPRS), and negative symptoms (SANS) were related to changes in the serum serotonin levels. The pathophysiological implications and clinical consequences of these findings are discussed. PMID- 7856325 TI - [Dimensions of psychological disorders in children and adolescents with psychiatric disorders based on clinical observations]. AB - Up to now dimensional classification systems for psychiatric disorders in children and adolescents have been developed exclusively on the basis of parent, teacher and self-report questionnaires. In the present study a dimensional classification system for psychiatric disorders was developed that is based on clinical ratings and involves factor, reliability and correlational analyses. The ratings are made with a special documentation system for psychopathology in children and adolescents. Four primary symptom scales (aggressive symptoms, antisocial symptoms, hyperkinetic symptoms and social-emotional impulsivity) are combined into the secondary scale external symptoms. Two symptom scales (social and achievement anxiety, depressive symptoms) make up the scale internal symptoms. Two other symptom scales cover language and eating disturbances. Reliability coefficients are given and correlational structures discussed. PMID- 7856326 TI - [Experimental techniques for developing new drugs acting on dementia (5)- Screening method in drug evaluation on neurite regeneration in primary cultured neurons]. AB - Neurite regeneration is one of the important processes in the reconstruction of neuronal networks. We observed neurite elongation and branching of an individual neuron cultured at a comparatively low cell density. We also observed neurite re elongation and branching of neurites amputated by a laser beam. Screening method in drug evaluation on neurite regeneration in primary cultured neurons and effects of basic fibroblast growth factor (bFGF) and astrocyte-derived conditioned medium (ACM) are explained in this report. PMID- 7856328 TI - [Experimental techniques for developing new drugs acting on dementia (7)--A water finding task for use with mice: utility for evaluating latent learning]. AB - This article describes a water-finding (WF) task for use with mice in which the animals are not required to perform a special behavior and are not reinforced positively by water or feed during the training stage. The test apparatus consists of a rectangular open field with an alcove in the middle of one of the long walls of the enclosure. A metal drinking tube is inserted into the center of the alcove ceiling. Nonwater-deprived mice are placed individually into the test apparatus and are allowed to explore the environment freely during the training trial. In the test session, each mouse is placed back into this environment and the time between onset of exploration and initiation of drinking from the water tube is scored as a drinking latency. Learning is inferred if the animal finds the water tube more rapidly than an animal that had not been exposed previously to this environment. At that time, the WF task provides a measure of memory related mainly to the spatial construction of the test apparatus and to the specific object (water tube) in it. The water-finding performance during the test trial is thought to be based on latent learning, because the animals are deprived of water only before the test trial in order to promote recall of the location of the water tube to which they had been exposed in the training trial. Thus, the WF task may be advantageous in evaluating memory without manipulating reinforcers, although it can be improved upon. PMID- 7856327 TI - [Experimental techniques for developing new drugs acting on dementia (6)--Carbon monoxide-induced amnesia model in experimental animals]. AB - Cell death, neuronal dysfunction and deterioration of memory function can be produced after carbon monoxide exposure in mice as in human. These deficiencies are developed in a delayed manner (delayed amnesia). The neurotoxicity of excitatory amino acids may be involved in this model, since dizocilpine (MK-801) fully protects against carbon monoxide-induced cell death, learning impairment and delayed amnesia. In the present paper, we described the method of carbon monoxide exposure and the characteristic of behavioral and biochemical changes after carbon monoxide exposure. These data indicate that carbon monoxide can provide an amnesic model for the investigation of memory deterioration and the development of new anti-amnesic drugs. PMID- 7856330 TI - [Effects of carbamazepine and zonisamide on dopaminergic system in rat striatum and hippocampus]. AB - The effects of zonisamide and carbamazepine on extracellular and intraneuronal levels of monoamine, its precursor and metabolites were determined in rat striatum and hippocampus. DA re-uptake and monoamine oxidase activities were also determined. Acute administrations of therapeutic doses of zonisamide and carbamazepine increased the extracellular and intraneuronal levels of monoamine, however, supratherapeutic doses of zonisamide and carbamazepine decreased extra- and intracellular monoamine levels. Chronic administrations of therapeutic doses of zonisamide and carbamazepine increased intraneuronal levels of monoamine, while supratherapeutic doses of zonisamide and carbamazepine decreased. Monoamine oxidase type B activity was inhibited by zonisamide, and the IC50 values of inhibition by zonisamide for type B monoamine oxidase were 660 microM, however, carbamazepine did not affect monoamine oxidase activity. Zonisamide and carbamazepine showed no effect on monoamine re-uptake within therapeutically relevant concentrations. These results suggest that therapeutic doses of zonisamide and carbamazepine enhance monoamine turnover, while supratherapeutic doses of zonisamide and carbamazepine inhibit monoamine turnover. Those effects of zonisamide and carbamazepine on monoamine metabolism are at least partly involved in the mechanisms of action of zonisamide and carbamazepine. PMID- 7856329 TI - [Experimental techniques for developing new drugs acting on dementia (8)- Characteristics of behavioral disorders in senescence-accelerated mouse (SAMP8): possible animal model for dementia]. AB - Experimental methods to assess age-related behavioral disorders such as impairments of learning and memory, emotional disorder and abnormality of circadian rhythms in senescence-accelerated mice (SAMP8), and the characteristics of the behavioral disorders are described. SAMP8 shows age-related impairments of learning and memory assessed by passive avoidance, two-way active avoidance and Morris water maze tasks, and the impairments are significant even at 2 months of age and become obvious with aging. Age-related emotional disorder is also observed in SAMP8 mice. SAMP8 mice exhibit age-related emotional changes as compared with the SAMR1 control; they show apparent increases in the number of entries into open arms and time spent on open arms in the elevated plus-maze test. In addition, punished drinking in SAMP8 is markedly increased in the water drinking conflict test. It is implicated that the reduced anxiety-like behavior is closely related to learning impairments in the strain. Cholinergic drugs and a sustained formulation of thyrotropin-releasing hormone ameliorate impairments of learning behavior and the emotional disorder in SAMP8. Furthermore, SAMP8 shows an age-dependent abnormality of circadian rhythms of spontaneous motor activity (SMA) and ingestive behavior compared with the SAMR1 control, diurnal SMA and water intake in SAMP8 being higher than those of SAMR1. These findings suggest that the SAMP8 strain is a useful animal model for learning and memory impairments, emotional disorder and abnormality of circadian rhythms in patients with dementia. PMID- 7856331 TI - [Call recognition in neuron network formation]. PMID- 7856332 TI - [Function of dopamine receptor subtypes in striatum]. PMID- 7856333 TI - [Brain potentials following painful stimulation in humans]. AB - When a CO2 laser beam is applied to the skin, subjects feel a "pin-prick" sensation. We have investigated somatosensory evoked potentials following CO2 laser stimulation (laser SEP) in normal subjects, and confirmed that signals following CO2 laser stimulation ascend through A-delta fibers and the spinothalamic tract. Its conduction velocity is approximately 10 m/s. Change in pain perception produced by the application of movement and various modalities of sensation to areas adjacent to, and remote from, the painful stimulus was investigated by means of laser SEPs. We investigated pain SEPs and conventional electrically stimulated SEPs in patients with various neurological diseases including peripheral neuropathies, syringomyelia, multiple sclerosis and HTLV-I associated myelopathy (HAM), and found a good correlation between laser SEP findings and the degree of impairment of pain-temperature sensations. Laser SEPs could be used to find subclinical abnormalities in some patients. PMID- 7856334 TI - [Involvement of immune mechanism in the progressive brain damage]. AB - No definitive evidence for the participation of the immune system in progressive brain damage has been previously reported. However, glial cells continue to accumulate after degeneration of neurons appears to be completed, and a recent study showed that microglia and leukocytes also accumulate after brain damage. Thus, it seemed possible that immune responses might play a role in the delayed effects. Cyclosporin A (CsA) is a cyclic undecapeptide of fungal origin with a strong immunosuppressive action but low myelotoxicity. We examined the effect of CsA administration on three different kinds of animal models for neurological deficits. Late onset reduction of muscarinic receptors after transient forebrain ischemia in gerbils was prevented by daily post-ischemic administration of CsA. This indicates that an immune mechanism may be involved in the progressive brain damage occurring after transient ischemia. On the other hand, CsA exacerbated iminodipropionitrile-induced dyskinesia both behaviorally and biochemically. CsA also mimicked pentylenetetrazol-induced seizures. These findings suggest that immune mechanisms may play important roles in the progression of brain damage and possibly that immunosuppressants might open a new chapter in the pathophysiology and treatment of chronic progressive neurodegenerative diseases. Further investigations on the immune response in the progressive brain damage are needed. PMID- 7856335 TI - [Experimental and clinical studies of the effect of pectin on the causative agents of acute intestinal infections]. AB - The effect of alimentary pectin obtained from different raw materials (apple, tomato, cotton-wool) on the causative agents of infectious diarrheal diseases, belonging to the genera Shigella, Salmonella, Klebsiella, Enterobacter, Proteus and Citrobacter, was studied under experimental conditions and in clinical observations. The study revealed that pectin, irrespective of raw material used for its production, produced an inhibiting effect on these microorganisms. This effect was most pronounced, both under experimental and clinical conditions, when 5% pectin solution was used. A rapid suppress of diarrhea and other manifestations of the infectious syndrome was observed in patients. The patients treated with pectin stayed in the hospital, on the average, 2-3 days less than the control group of patients treated with antibiotics and other chemotherapeutic preparations. PMID- 7856336 TI - [Spontaneous coronavirus infection in monkeys]. AB - A high level of the spread of coronavirus (CV) infection among hamadryas baboons and macaques of different species (about 50%), both resident in the animal house and imported, has been established. The tropism of CV to the gastrointestinal and respiratory tracts has been demonstrated. The course of spontaneous CV infection is accompanied by enterocolitis and/or pneumonia with periodic exacerbations, or takes the inapparent form. Cases of virus persistence have also been noted. Infected macaques exhibited an increase in the titers of antibodies to their own CV strain isolated from these animals, as well as to antigenically related human CV strain 0043. Spontaneous CV infection in monkeys may be used for solving some obscure problems of the pathogenesis and epidemiology of CV infection in humans. PMID- 7856337 TI - [Immune system indices for the prediction of the course of human immunodeficiency virus infection]. AB - In 25 persons having HIV infection with different dynamics of the progress of the disease the content of lymphocyte populations was studied (by the methods of rosette formation and with the use of monoclonal antibodies) and the rosette forming and functional metabolic activity of neutrophils was determined. In comparison with patients with a stable course of HIV, patients with relatively rapid progress infection were found to have a significantly lesser amount of E rosette-forming cells (E-RFC), active E-RFC, theophylline resistant E-RFC, E rosette-forming neutrophils (E-RFN) and active E-RFN in combination with a significantly higher neutrophil and phosphatase activity and a significantly higher content of cation proteins. These characteristics may be used as criteria for prognosis of HIV infection progression. PMID- 7856339 TI - [The pathogenic properties of the causative agent and the immunological indices in an experimental Yersinia infection]. AB - In experiments on guinea pigs infected enterally with Y. enterocolitica isogenic strains of serovar O3 (pYV+ and pYV-) with known properties some characteristics of their cell-mediated and humoral immunity and nonspecific resistance were studied. The development of the localized infectious process and the corresponding immune shifts were noted only in infection with plasmid-containing Yersinia; in these cases a rise in the amount of T- and B-lymphocytes in the immunocompetent organs (the thymus, the spleen, lymph nodes), an increase in the functional activity of T-lymphocytes, a decrease in the ingestive activity of neutrophils and in the levels of nonenzymatic cation proteins and leukocytes, as well as the active production of specific agglutinins, were registered. PMID- 7856338 TI - [The role of hyaluronidase in the occurrence of a generalized pneumococcal infection]. AB - The hyaluronidase activity of pneumococcal strains isolated from 39 patients with purulent meningitis, 26 patients with acute internal otitis and 130 healthy carriers was studied. All strains isolated from patients with purulent meningitis and meningoencephalitis and 84.6% of strains isolated in cases of otitis were found to have hyaluronidase, while in healthy children hyaluronidase-synthesizing strains were detected only in 11.5% of cases. Hyaluronidase titers in pneumococcal strains isolated from patients with meningitis and meningoencephalitis were significantly higher than in strains causing purulent otitis. At the same time strains with high hyaluronidase titers were also isolated from 7% of healthy carriers. Noncapsular pneumococcal strains had no hyaluronidase. The average value of the reverse correlation between hyaluronidase activity and the virulence of strains for mice was established. Hyaluronidase activity did not correlate with different serotypes of pneumococcal strains. The intranasal administration of hyaluronidase in high titers (> or = 1:8) to mice and rats led to the penetration of the infective agent through the hematoencephalic barrier of the animals and to their death from generalized pneumococcal infection. The role of hyaluronidase as the invasiveness factor of pneumococci was confirmed in experiments on the intranasal infection of mice with low active strains mixed with the preparation of exogenous hyaluronidase. PMID- 7856340 TI - [The mechanisms of the in-vivo persistence of mycoplasmas and L-form bacteria]. PMID- 7856341 TI - [Viral persistence and 10 aspects of research into it]. PMID- 7856342 TI - [The antilysozyme factor in Klebsiella pneumoniae: its nature, biological functions and genetic control]. AB - The article deals with the data obtained as the result of the comprehensive study of K. pneumoniae antilysozyme factor, playing an essential role in the infectious pathology of weakened children and adults, as it was recently established. The study has revealed that the genes that determine the synthesis of the antilysozyme factor can be localized on the plasmid, tentatively designated pAlz60 and expressed in a wide circle of hosts of the family Enterobacteriaceae, belongs to type fi-, compatibility group Pl. Experiments with genetically related pairs of strains, differing by the presence of plasmid pAlz60, have demonstrated that factor ALz has no influence on the interaction of bacteria with the epithelium, but contributes to the suppression of phagocytosis, the preservation and multiplication of strains having this factor in the phagolysosome. Alz character has been classified with pathogenicity factors ensuring longer persistence of the infective agent in the body. The characterization of the chemical structure of the antilysozyme factor functioning as an inhibitor of lysozyme is presented. The method for the rapid determination of the antilysozyme activity of bacteria has been developed. This method may be used for the evaluation of isolated strains as regards their clinical and epidemic importance. PMID- 7856343 TI - [The biological significance of the anticomplement activity of bacteria]. AB - The occurrence and the average levels of anticomplementary activity among the representatives of bacterial species as Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, mainly reflecting differences between their ecovariants, were established. In connection with the fact that some of E. coli uropathogenic strains with high anticomplementary activity were found to be capable of inhibiting the activity of C5 in a hemolytic system and with the presence of correlation between the property under study and complement resistance, the existence of common mechanisms for the realization of these properties was supposed. Extracellular products of S. aureus were shown to be capable of inhibiting the functional activity and opsonic action of C3 component of the complement, which was related to the presence of anticomplementary activity in these bacteria. Experimental staphylococcal infection in mice revealed the predominant accumulation of bacteria possessing this property. Clinico-bacteriological studies demonstrated that the anticomplementary activity of E. coli contributed to the increased risk of postoperative complications in cholecystitis and to the prolongation of bacteriuria in chronic pyelonephritis. PMID- 7856344 TI - [The heterogeneity of the antilysozyme activity in populations of opportunistic enterobacteria]. AB - 1,484 clones of 104 strains representing 11 genera of the family Enterobacteriaceae and having different levels of lysozyme activity were tested for the presence of this activity. In the populations of 53.9% of strains under study the heterogeneity of the levels of antilysozyme activity was noted. In 13.4% of strains under study clones having no antilysozyme activity were detected. Among Escherichia, Hafnia and Enterobacter strains without antilysozyme activity individual clones having such activity were detected; these clones constituted 3-17% of the total number of the studied clones. PMID- 7856345 TI - [The persistence of Shigella sonnei in epithelial tissue in Sereny's model]. AB - The duration of persistence of S. sonnei in the tissues of a guinea pig eye (Sereny's model) has been studied. Bacteriological and histological investigations made with the use of fluorescent antibody techniques have revealed that S. sonnei can be preserved in macrophages (histiocytes) and intercellular space of the eye epithelium for a long time (up to 277 days). The injection of ACTH or Shigella vaccine into the animals may provoke the exacerbation of the infectious process and the release of the infective agent. PMID- 7856346 TI - [An immunological analysis of bacterial persistence in the bone marrow]. AB - A method for the evaluation of bacterial persistence in the bone marrow in association with particular clonogenic target cells was developed. The method was based on the negative selection of cells expressing microbial antigens after treatment with hyperimmune antiserum specific to a given infective agent and the subsequent quantitation of target cells thus eliminated in appropriate assays. Using this approach, we demonstrated that Mycoplasma arthritidis and L-forms of Streptococcus strain L-406 were capable of persisting in murine bone marrow in close association with CFUs-7 (a subpopulation of hematopoietic stem cells) for at least several months after experimental infection. Francisella tularensis was also found to be capable to express on the CFUs-7 membranes. Persisting microorganisms enhanced both proliferation and migration of CFUs-7. PMID- 7856347 TI - [The biomedical aspects of the persistence of bacteria]. AB - A correlation between the structure and function of bacteria was analyzed in the process of their persistence in the host body. A variety of persistent forms of bacteria was shown to be based on the isolation of their morphological substrate, peptidoglycane, which a cell "masked" (screening by surface bacterial structures, antigenic mimicry), "lost" (L-forms of bacteria, mycoplasmas) or protected against the system of host immunity by secreted factors. A new group of secreted bacterial (antilysozyme, anti-interferon, anti-immunoglobulin, anticomplement) factors, permitting microbial persistence in the host body, was described. Different methodological approaches to their determination were developed on the basis of the principle of "delayed antagonism". Applied aspects of the problem of persistence of bacteria were reviewed. The efficacy of new methods developed for the isolation and identification of a causative agent under the control of persistence markers was demonstrated on facultative microflora in different surgical, obstetrical, gynecological, urological diseases and diseases of internal organs. The facts concerning the use of the factors of bacterial persistence were presented for the solution of therapeutic (selection of means for controlling cell parasites), prognostic (development of carrier state in convalescents) and ecological (microbiological monitoring of the environment) problems. PMID- 7856348 TI - [The effect of changes in the cultivation conditions on the amplification of different Mycoplasma pneumoniae genes]. AB - In experiments carried out with the use of the polymerase chain reaction the inhibition of the amplification of several regions of M. pneumoniae genome, depending on the conditions of their cultivation, has been observed. We suggest that protein, selectively binding with individual sites of DNA, is capable of inhibiting the expression of genes coding pathogenicity factors and thus contributes to the transformation of mycoplasmas into persistent forms. PMID- 7856349 TI - [The Neisseria meningitidis serotypes and subtypes circulating among bacterial carriers in Moscow (1989-1991)]. AB - N. meningitidis strains isolated from 218 healthy carriers in 1989-1991 in closed communities of adults, irrespective of cases of meningococcal infection registered in these communities, were characterized with a variety of different type and subtype antigens. Only in 139 strains (63.76%) their types and/or subtypes could be determined with the use of a set of 6 serotypes and 11 subtypes of monoclonal antibodies. 26 group B strains and 31 group C strains had multiple antigenic composition. 13 group A strains were found to be more homogeneous: 8 of them, isolated in one area, belonged, according to Dr. Achtman's data, to a definite clone VI-1, heretofore unknown. No prevailing serotype/subtype could be revealed, which reflected the wide heterogeneity of N. meningitidis at the period of the decrease of morbidity in meningococcal infection. The observed stability of serotype/subtype of strains, isolated from the same carriers and circulating in the same communities, suggests that the serotype/subtype of N. meningitidis is a valuable epidemiological marker. PMID- 7856350 TI - [The characteristics of the formation of the staphylococcal landscape in the nasal mucosa of different types of bacterial carriers]. AB - The complex study of factors of persistence, virulence and antagonism in 473 coagulase-positive (CP) staphylococci and 489 coagulase-negative (CN) staphylococci inhabiting the nasal mucosa of resident and transitory carriers, and not carriers of CP staphylococci, was made. In the selection of virulent strains of CP staphylococci the factor of anti-interferon activity seemed to be of greater importance than the factor of antilysozyme activity, but the latter was preferable in the selection of virulent strains of CN staphylococci. Biovars of CP staphylococci with a set of factors of persistence, virulence and antagonism were isolated from resident carriers 1.6-3.1 times more frequently than from transitory ones. The selection of virulent biovars could be made among strains of CN staphylococci with pronounced persistent properties, isolated from subjects carrying no CP staphylococci. PMID- 7856351 TI - [Streptococcal group A carriage: new data on the characteristics of the biology of the causative agent and of the immune response of the host]. AB - Carriership of group A streptococcus (A-STR) was registered with significantly greater frequency among children of preschool and early school age (29.8%) than among adults (4.0%). Cultures of A-STR isolated from carriers were characterized by their low capacity for secreting erythrogenic toxin of type A (ET-A), lipoteichoic acid and by lower content of surface proteins than those isolated from tonsillitis and scarlet fever patients. Highly hydrophobic strains of A-STR prevailed in long-time carriers and patients. Elevated immunological characteristics for group-specific polysaccharide A and ET-A were more frequently detected in children than in adults, which correlated with frequency of A-STR carriership in these groups and the capacity of the infective agent to produce ET A. Some specific features in the character of humoral immune response in carriers, manifested mainly by defects of local immunity (a low level of SIgA to polysaccharide A), were established. PMID- 7856352 TI - [The features of Haemophilus influenza and Streptococcus pneumoniae carriage and the comparative characteristics of strains isolated from healthy children and from patients with acute and chronic respiratory infections]. AB - The biological properties (serotypes, biotypes and adhesive activity) of 839 H.influenzae strains isolated from healthy children and from patients with acute and chronic respiratory infections, as well as the serotype composition of 739 S.pneumoniae isolated from the same groups of children, were studied. The occurrence of H.influenzae carriership among healthy children varied between 13% and 78%, decreasing among older children. In 98% of cases the respiratory tract of healthy children was colonized by noncapsular forms of H.influenzae. The isolation frequency of pneumococci in healthy children was 16%, but during the period of 2 years 45% of children were found to be the transitory carriers of this infective agent. The persistence of H.influenzae and S.pneumoniae with the same biological properties lasted for 1-4 months. Repeated infections were caused, as a rule, by bacteria with other properties. S.pneumoniae persisting in healthy children and causing a chronic bronchopulmonary process had no differences in their serological composition (19, 6, 3). At the same time in acute pneumonia, complicated by pleuritis and pneumonia destruction, pneumococci of serotypes 1, 3, 5 and 14 were more frequently isolated. H.influenzae isolated from healthy children and from patients with chronic pneumonia had little difference in the occurrence of their capsular variants, but in the biotype composition of H.influenzae isolated from chronic pneumonia patients biotype 1 occurred more frequently. PMID- 7856353 TI - [The use of an amplification test system for detecting persistent mycoplasmas]. AB - A DNA amplification test system for the detection of Mycoplasma fermentans in clinical specimens was developed. The system was used for the analysis of biological specimens obtained from experimentally infected animals. The infective agent could be detected during the whole period of observation (6 months). High sensitivity of the polymerase chain reaction made it possible to detect M.fermentans in much greater number of cases than with the use of serological techniques. PMID- 7856354 TI - [Is sarcoidosis a chronic persistent infection?]. AB - The study carried out with the use of microbiological diagnostic methods has revealed that in 67% of cases specimens obtained from sarcoidosis patients for analysis contain different forms of mycobacteria (typical Mycobacterium tuberculosis and granular forms of mycobacteria). The content of typical and granular forms of mycobacteria detected in diagnostic specimens has been shown to differ, depending on the clinical form of sarcoidosis: as a rule, in cases of the sluggish course of sarcoidosis granular forms of mycobacteria are detected, while during the exacerbation of the disease and in cases of the acute course of newly diagnosed sarcoidosis the proportion of typical M.tuberculosis increases. To verify M.tuberculosis with greater certainty, two highly sensitive and specific amplification test systems have been developed on the basis of polymerase chain reaction. In this article the goals of microbiological and molecular genetic investigations which may jointly give direct proofs of the etiological importance of mycobacteria in sarcoidosis are considered and discussed; sarcoidosis may probably be regarded as chronic persistence infection. PMID- 7856355 TI - [The results of a 15-year study of the persistence of Yersinia pestis L-forms]. AB - New diagnostic preparations for the detection of L-forms, immunoglobulin erythrocyte diagnosticum and luminescent antimembrane immunoglobulins, are described. Proofs indicating that Y.pestis L-forms are constantly isolated from wild rodents and their ectoparasites in the natural foci of plague are given. To control the effectiveness of the sanitation of such natural foci, the use of the radioimmunoassay and the enzyme immunoassay, known to be the most sensitive techniques, are recommended. The facts indicating that Y.pestis contaminating ticks and fleas are converted into L-forms, capable of persisting for several years, are presented. After their reversion to back the initial rod-shaped form the transmission of infection is possible. A suggestion is put forward that the persisting forms of Y.pestis play an important role in the preservation of this infective agent in the natural focus of infection. PMID- 7856356 TI - [The screening diagnosis of intestinal dysbiosis]. AB - A screening method for the evaluation of the state of intestinal microbiocenosis by monitoring the persistence sign of bacteria, their anti-interferon activity, was proposed. The examination of patients with dysbiosis of the intestine has shown that their intestinal microflora was found capable of inactivating the preparation of human leukocytic interferon at a definite concentration 8.7 times more often than the intestinal microflora of healthy persons. The number of interferon-active colonies correlated with the severity of changes in intestinal microbiocenosis and the degree of clinical manifestations of the disease. PMID- 7856357 TI - [The clinico-bacteriological characteristics of urinary system infection in children]. AB - 317 children with pyelonephritis and cystitis were examined. The persistence properties of urological flora were determined. In most patients with infections of the urinary system, irrespective of the localization of the inflammatory process, enterobacteria (and more often Escherichia) prevailed. The clinico bacteriological relationship between the antilysozyme activity of isolated bacteria and the form and course of the disease was established. In patients with chronic pyelonephritis urological strains with antilysozyme activity prevailed (88.6%); among children with the relapsing and latent course of pyelonephritis urological strains with such activity were isolated 4 times as frequently as from patients with the cyclic course of the disease. The prognostic value of the latent course of pyelonephritis was the prolonged isolation of urological flora with high antilysozyme activity. PMID- 7856358 TI - [The differential microbiological diagnosis of bacteremia and sepsis and the results of its practical use]. AB - A rapid method for the detection of classical forms of bacteria and their cell wall defective (CWD) variants in the blood has been developed and approved. The method is based on the kinetic analysis of bacterial growth with the use of nephelometry. The analysis lasts 3-10 hours. The method permits the differential microbiological diagnosis of bacteremia and sepsis, as well as the rapid control of the effectiveness of antibacterial therapy. The rapid method has revealed that in the presence of antibacterial therapy infective agents persist in the blood as CWD variants and not in the classical bacterial form, which sharply decreases the reliability of the traditional diagnostic method. CWD variants have been detected in the blood of patients treated with the preparations of cephalosporin, chinolon, aminoglycoside, dioxydin, etc. PMID- 7856359 TI - [Bacterial pathogenicity factors: their functions in the environment]. AB - On the basis of literature data and the results of experimental studies the concept of the universal character of the main pathogenicity factors of bacteria (adhesion, enzymes, toxins, resistance to phagocytosis) as the adaptive mechanisms of bacterial populations under different ecological conditions, including their existence in the environment, has been put forward. Resistance of bacteria to phagocytosis as the mechanism of their protection from predators (protozoa, etc.), necessary for the existence bacteria in the ecological systems of water and soil, is considered in detail. PMID- 7856360 TI - [The lysozyme-antilysozyme functional system in hydrobionts and its role in forming aqueous biocenoses]. AB - Lysozyme activity has been evaluated in hydrobionts of different trophic levels: algae, zooplankton and germs. The existence of the functional system "Lysozyme of hydrobionts--antilysozyme of germs", functioning as a regulating element in the formation of aqueous microbiocenosis, has been substantiated on the basis of data provided by laboratory experiments and investigations carried out in natural water pools. PMID- 7856362 TI - [Quality problems in psychiatric care]. PMID- 7856361 TI - [The effect of the characteristics of the interaction of their determinant of virulence with the metabolic and specific mechanisms of immunity on the persistence of infectious causative agents]. AB - The persistence of the causative agents of infections depends on the effectiveness of the function of their virulence determinants ensuring their nutrition in the host body and resistance to its nonspecific and specific mechanisms of protection. The presence of antigens, effective mechanisms of antigenic reconstruction and, probably, the optimum ratio of strong and weak antigens in pathogenic microorganisms facilitates their persistence in the body of an immune host. PMID- 7856363 TI - [The postgraduate training of physicians in neurology (notes on the internship)]. PMID- 7856364 TI - [The antibacterial and antiviral immunity of patients with trigeminal neuralgia]. AB - The levels of antibodies to bacterial (tuberculin, staphylococcus, pneumococcus, streptococcus) and viral (herpes, measles, rubella, parotiditis, influenza) antigens were determined in 39 patients with trigeminal neuralgia (TN) aggravation of which 25 were untreated, while 14 had received a course of the cadaveric nerve specific tissue therapy, 46 healthy subjects and 31 patients with trigeminal neuropathy served control. The study proved that TN patients had significantly increased levels of herpes virus antibodies (p < or = 0.01). The above tissue therapy stimulated production of antibodies to rubella and parotiditis viruses. PMID- 7856365 TI - [The dynamic clinico-physiological indices of sexual function during the management of vertebrogenic pain syndromes]. AB - Sexual changes were registered electrophysiologically in 52 patients with low back pain of vertebrogenic origin. M-response of the bulbocavernous muscle emerged at low threshold. There were shifts in the latency and amplitude of the somatosensory evoked potentials of the brain. These confirm participation of disintegrated functioning of the segmentary and central nervous structures in the genesis of sexual diseases. Treatment-induced positive trends in the above parameters may be used prognostically in relation to the patients' sexual activity. PMID- 7856366 TI - [The strength of the elements of the human spinal column and the problems of the etiology, pathogenesis and principles of the treatment of degenerative spinal lesions]. AB - The study was made of strength characteristics of the vertebra and intervertebral disks of moving parts of human spine in postembryonic ontogenesis. The authors have obtained statistically significant data on degenerative dystrophic changes and lesions of human spine. Pathogenetic issues, conservative and surgical treatment policies in degenerative lesions are considered. The authors hold, that osteochondrosis is not the right term to denote degenerative lesions of the spine. PMID- 7856367 TI - [Hormonal disorders in women with prosopalgia in osteochondrosis of the cervical spine and the possible means for their correction]. AB - Radioimmunoassay was employed to determine basal levels of LH, FSH, prolactin, total testosterone and 17 beta-estradiol in plasma from 52 pre- or postmenopausal women with prosopalgia consequent to cervical osteochondrosis. The measurements were made before and after laser treatment. Different from the control, basal levels of the hormones and the trends in their changes due to laser therapy depended on the patients' age and the disease stage. PMID- 7856368 TI - [The diagnosis of the levels of peroneal nerve compression in spinal osteochondrosis]. PMID- 7856369 TI - [The surgical treatment of muscle tonus disorders by the destruction of the input areas of the posterior spinal nerve roots]. AB - Stereotactic cryodestruction of the subcortical ganglions for microdestruction of the inlets of the radices spinales was conducted in resistant to drug and surgical treatment patients with impaired muscular tension and spastic pain syndrome (infantile cerebral paralysis, dystonia musculorum deformans, postencephalitic spastic-hyperkinetic syndrome). A total of 8 patients aged 19-46 were treated. The destruction of the segments depended on the site of the tension impairment. In cervical, upper extremity, lumbar, lower extremity involvement the segments to be destroyed were, respectively: SV--SVII, SVIII, LII--LIII, LIV, LV and SI. The surgery aimed at breaking the centripetal nociceptive and myotactic tracts. The treatment reduced muscular hypertonicity and hyperkinesis, relieved spastic pain. The paper presents anatomic and neurophysiological grounds for the procedure application. PMID- 7856370 TI - [The clinical picture and pathogenesis of polyradiculoneuropathy in tick-borne encephalitis]. AB - Based on examination of tick-borne encephalitis patients with ascending polyradiculoneuropathy the authors describe the character of the disease, its clinical picture and the results of laboratory studies, etc. Differential diagnosis is made between the indicated syndrome associated with tick-borne encephalitis and sporadic polyradiculoneuropathies. A detailed description is given for the first time of the clinical and pathomorphological picture of that gravest form of tick-borne encephalitis. As regards the character of the clinical and pathomorphological alterations, the ascending polyradiculoneuropathy associated with tick-borne encephalitis is meningoencephalomyelitis with the radicular syndrome which often determines the disease gravity and prognosis. PMID- 7856372 TI - [Peroxide chemiluminescence of the cerebrospinal fluid in spinal cord tumors]. AB - Spontaneous and initiated by hydrogen peroxide chemiluminescence was evaluated before and after freezing of the CSF from 20 patients with various spinal tumors and 10 controls with intervertebral lumbar osteochondrosis. The intensity of the above chemiluminescence was found significantly different in tumors and osteochondrosis. Cryotreatment induced marked changes in CSF chemiluminescence, especially in extramedullary spinal tumors. CSF treatment with hydrogen peroxide entailed alterations in free radical oxidation which can serve an additional criterion in combined diagnosis of spinal cord tumors. PMID- 7856371 TI - [Migraine and epilepsy: clinical comparisons and the characteristics of the cerebral blood circulation]. AB - Clinical, electroencephalographic, rheoencephalographic and linear cerebral circulation findings were compared for 71 epileptics (group 1), 62 migraine patients (group 2) and 6 patients with epilepsy which had developed in the presence of severe migraine with aura (group 3). One-third of migraine patients, mostly of young age, suffering from migraine with aura and basilar migraine had such consciousness disorders as stupefaction and syncopes. EEG changes in migraine patients were considered nonspecific, paroxysmal spike activity arose only in addition of epileptic seizures. Cerebral blood flow measured by radionuclide tracing in migraine-free interval tended to speeding up, while in groups 1 and 3 hemocirculation was slow. Epileptogenic provocation in group 1 patients accelerated cerebral blood flow on the side of the focus, but decelerated it in group 3. The authors hold that the nature of migraine and epilepsy is different. By disintegration of cerebrovascular regulation and vascular supply of the neuron, migraine may promote secondary epileptogenesis. PMID- 7856373 TI - [The neurological aspects of chromaffinoma]. AB - Vegetative dysfunction with episodes of tachycardia, hypertension, paleness, general hyperhidrosis, subfebrile condition, hyperglycemia manifest first among clinical symptoms of chromaffinoma. In respect to these symptoms severity the crises observed in chromaffinoma are classified as minor or major. Major crises may be cerebral, epileptiform, cardial and abdominal. The crises are attributed to hypercatecholaminergic arterial hypertension. A reliable laboratory diagnosis of the disease involves urinary measurements of catecholamines and their metabolites. Manifold increase of the latter concentrations may serve the diagnostic indication. The only effective treatment is the removal of the tumor from the adrenals. PMID- 7856375 TI - [Leakadin immunotherapy in the combined therapy of acoustic neurinomas]. AB - The paper specifies the role of leacadin immunotherapy in combined treatment of acoustic nerve neurinomas. The antitumor immunomodulator leacadin contributes to establishment and consolidation of the tumor carrier's immunological adaptation which results in uneventful postoperative developments and recurrent-free survival. PMID- 7856374 TI - [Changes in the immunobiochemical composition of the cerebrospinal fluid and the antitumor reactions of the local immune system in astrocytic brain tumors]. AB - Pre- and postoperative immunochemical indices of cerebrospinal fluid (CSF) were investigated in 10 patients with fibrillary-protoplasmic astrocytoma and 10 patients with glioblastoma multiforme. Malignant neoplastic developments in the brain are associated with appearance of marked humoral reaction. Tumor-specific CSF changes observed comprise registration of ceruloplasmin immunomodulating proteins and alpha 2-macroglobulin. It is emphasized that biochemical antioxidant, antiprotease, energy-supplying systems are related directly to humoral immune reactions in the process of relevant postoperative rehabilitation. PMID- 7856377 TI - [The validation of rational therapy in the sequelae of closed craniocerebral trauma]. AB - Validating their approach to rational treatment of closed brain injury (CBJ), the authors take into account clinical features of posttraumatic psychovegetative syndrome resultant from dysfunction of nonspecific brain systems. The authors formulate two key tasks for the physicians faces with CBI aftereffects: 1) psychic correction, 2) reinforcement of the body adaptive-compensatory potential by enhancing sympathetic effects in cardiovascular system. On demand, the treatment may include additional nootropics and other metabolic drugs, resorption and dehydration drugs. An adjuvant stimulation of the adrenals with decimeter microwaves may potentiate drug correction of posttraumatic vegetative and emotional personality disturbances. PMID- 7856376 TI - [The intrathecal synthesis of G-class immunoglobulins in neurological cancer patients]. AB - The authors show that brain tumors onset and relevant recurrences are closely related to enhanced synthesis of IgG in the liquor and of circulating immune complexes as well as to blocking factors registered in the liquor. The above facts illustrate autoimmune reactions involved in pathogenesis and recurrent growth of brain tumors. Surgical removal of the latter inhibits the intensity of IgG intrathecal synthesis. PMID- 7856378 TI - [Combined therapy using actovegin and instenon in encephalopathies of different origins]. PMID- 7856379 TI - [The prediction of the development of circulatory encephalopathy in hypertension patients with the initial manifestations of brain blood supply insufficiency]. AB - The principal risk factors conducive to the development of cardiovascular diseases in young and middle-aged subjects with chronic cerebrovascular insufficiency due to Stage I or II essential hypertension were under study. Thirty-four male patients with the initial manifestations of inadequate blood supply to the brain (IMIBS), 35 male patients with stages I or II dyscirculatory encephalopathy (DE), and 32 and 33 female patients with the same conditions, respectively, were examined. Hypertensive cerebral crises were significantly more frequent in DE patients of both sexes than in IMIBS patients, and a tendency to a longer standing of arterial hypertension was observed in DE patients as against those with IMIBS. The results of the examinations evidence that excessive body mass, hypokinesia and psychoemotional stress, as well as an 'accumulation' of risk factors were conducive to the development of DE in essential hypertension patients with IMIBS. Basing on the discriminant analysis of risk factors, the authors have developed a method for predicting the development of DE in patients with IMIBS of a hypertensive origin. Use of this method will essentially improve the efficacy of prophylactic and therapeutic measures in IMIBS patients. PMID- 7856380 TI - [Carbohydrate metabolism and acid-base balance in the development of the diencephalic areactive syndrome]. PMID- 7856381 TI - [The volumetric blood flow in the carotid arteries of healthy subjects]. AB - Using ultrasonic duplex scanning, volumetric blood flow (VBF) in the common carotid artery (CCA) was studied in 119 healthy subjects (73 males and 46 females), aged 20-75. With age, mean linear flow rate seems to undergo slowing down, while CCA diameter becomes wider. However, VBF in CCA in the middle-aged and elderly subjects decreased insignificantly. Males have larger CCA diameters and, consequently, greater VBF. A correlation exists between head circumference measured horizontally 2 cm above the superciliary arches and CCA diameter. This explains higher VBF in CCA in subjects with greater head circumference. PMID- 7856382 TI - [Hormonal interrelationships in symptomatic epilepsy]. AB - The serum and cerebrospinal fluid (CSF) from patients with epilepsy resultant from cerebral leptomeningitis in the fit-free intervals were examined for some hypophyseal and adrenal hormones with reference to the disease course, severity and duration, frequency of the seizures. The levels of hydrocortisone, aldosterone and STH were found stable, while those of prolactin got elevated, especially in males. Hormonal shifts in the serum and CSF appeared significantly different. STH lowered, but prolactin went up only in CSF. The latter increase was related to the seizures frequency. PMID- 7856383 TI - [The use of magnetic stimulation in organic and psychogenic diseases]. PMID- 7856384 TI - [Mental and somato-autonomic disorders from long-term exposure to low doses of radiation]. AB - The paper presents the results of psychopathological and clinical examinations of the subjects exposed to low-dose radiation consequent to the Chernobyl accident. Relevant psychic disorders are specified. A close correlation was found between some psychopathological syndromes and somatovegetative disturbances. PMID- 7856385 TI - [The mental and neurological health status of the pediatric population in some regions of Ukraine after the accident at the Chernobyl Atomic Electric Power Station]. AB - Psychic, neurological and speech characteristics were studied in a comparative epidemiological survey of 910 schoolchildren aged 6-7 and 11-12. Of them 470 children lived in the Zhitomir region which had suffered radioactive contamination after the Chernobyl accident, 440 children lived in the Kharkov region which had not been exposed to radionuclide contamination. It was established that 74-79% of the children examined had borderline psychic, neurological or speech disorders. The children from the "clear" territories had more serious disturbances which say about the role of other ecological hazards in development of large-scale prevalence of borderline neuropsychic pediatric conditions. The radiation-exposed children received adequate treatment which produced positive shifts in their health. PMID- 7856386 TI - [The clinical, neurophysiological and differential diagnostic aspects in a study of severe forms of early childhood autism]. AB - Clinical, pathopsychological and neurophysiological studies have been carried out in 85 children with infantile autistic psychosis and in 38 girls with Rett's syndrome. New improved differential diagnostic criteria between these two forms of early childhood autism have been suggested. EEG spectral density values in alpha-1, alpha-2, beta and theta subbands are established to be their neurophysiological markers. Special attention was paid to close relationship between ontogenetic neuromorphogenesis of the brain cortical structures (e.g. physiological lysis of cortical cell populations at the age 8-30 months of the child's life) and the defect severity in the onset of illness at the same age range in patients with the studied forms of early childhood autism. The data obtained are discussed in terms of new approaches to understanding pathogenesis of different forms of early childhood autism. PMID- 7856387 TI - [Motor disorders and their correction in children from a high-risk group for the development of schizophrenia at an early age]. AB - A 7-year study of locomotor function in 103 children born in the families where one of the parents suffered from schizophrenia has found no locomotor abnormalities only in 20% cases. The rest of them had: disorders of the general locomotor activity, disorders of the static and locomotor development, symptoms of extrapyramidal and cerebral regulation dysfunctions, changes of the muscle tone, ataxia, pathologic locomotor phenomena, speech disorders. The severity of the above disturbances and their variability correlated with the child's general and mental development. Attempts of relevant locomotor correction including massage provided good results. PMID- 7856389 TI - [The mental health status of the population in the Russian Federation]. PMID- 7856388 TI - [Experience in using ketamine preparations in the psychotherapy of alcoholism]. AB - After careful clinical examination 64 alcoholics (48 males and 16 females) aged 21-52 were assigned to ketamin aversive psychotherapeutic procedure supposed to make the patients emotionally concerned with their disease and suggestible of alcohol intolerance. Ketamin caused in 55 patients (85.5%) oneiroid clouding of consciousness with occasional catatonic inclusions, 9 patients (14.5%) became delirious. Ketamin-induced high suggestibility created beneficial conditions for psychotherapy. A 2-year follow-up of 42 patients registered complete abstinence in 15 patients. The results obtained with ketamin are comparable to those achieved with conventional methods. This alternative approach needs further research, especially as analytical opportunities are concerned. PMID- 7856390 TI - [The use of Lamiktal in treating epilepsy in children and adolescents]. AB - Antiepileptic effects of lamiktal (lamotrigine) produced in Great Britain (Wellcome) was tried in 7 children aged 3-14 and 3 adults aged 18-30. Of them 6 patients and 4 patients suffered from temporal polymorphic fits and general paroxysms, respectively. Upon 3-month follow-up it was found that the fits discontinued in 4 patients, frequency of the paroxysms reduced or they became abortive in 6 cases. EEG changes were insignificant. No side effects occurred. Lamiktal is recommended in polymorphic seizures in children and adults, in failure of other anticonvulsants in patients frequently affected with epileptic paroxysms. PMID- 7856391 TI - [The Sturge-Weber-Krabbe syndrome]. PMID- 7856392 TI - [The organization of the work of child development departments in the state of Israel]. PMID- 7856393 TI - [The autonomic nervous system and aging]. PMID- 7856394 TI - [The prevalence and detectability of mental disorders]. PMID- 7856395 TI - The search for plant polyprenols. PMID- 7856396 TI - Disturbances in lipid metabolism in human hepatocellular carcinomas. PMID- 7856397 TI - Is there a "dolichol recognition sequence" in enzymes that interact with dolichols and other polyisoprenoid substrates? AB - Yeast dolichyl-P-mannose synthase and a number of other enzymes that interact with dolichol or dolichyl-P as substrates contain a highly conserved amino-acid sequence that has been proposed as a potential dolichol recognition sequence [Albright, C.F., Orlean, P. & Robbins, P.W. (1989) Proc. Natl. Acad. Sci. U.S.A. 86, 7366-7369]. In dolichyl-P-mannose synthase, the most highly conserved amino acid residues of this domain were modified by site directed mutagenesis, and for one construct the sequence was completely deleted. Enzymes containing the site directed modifications, and the deletion mutant, were found to retain catalytic activity, and all of the modified enzymes had the same apparent affinity for Dol P as wild type enzyme when assayed in a phospholipid matrix. Based on these results, the amino-acid composition and sequence of the conserved domain are not critically important for the recognition and binding of Dol-P when the synthase is reconstituted in a lipid matrix. PMID- 7856398 TI - A recent approach to the study of dolichyl monophosphate topology in the rough endoplasmic reticulum. AB - Amphomycin though withdrawn as an antibiotic against the gram-positive bacterial infection, can certainly serve as an excellent tool for determination of the topology of Dol-P in the endoplasmic reticulum membranes which has been otherwise impossible. PMID- 7856399 TI - Thermostable farnesyl diphosphate synthase of Bacillus stearothermophilus: crystallization and site-directed mutagenesis. AB - The gene for thermostable farnesyl diphosphate synthase from Bacillus stearothermophilus was cloned, sequenced, and overexpressed in Escherichia coli. The synthase was purified to homogeneity and crystallized. The enzyme carried only two cysteine residues in contrast to its counterparts from other sources, which have four to six cysteine residues. Either or both of the cysteine residues can be replaced with serine without causing a loss of the catalytic activity. The conserved arginine residue that occupies the third position from the C-terminus was also replaced with valine without significant loss of activity, but the valine mutant showed a weakened affinity for isopentenyl diphosphate. PMID- 7856401 TI - Structure of cis-polyisoprene from Lactarius mushrooms. AB - Sporophores from five species of Lactarius mushrooms had a liquid rubber content of 0.1% to 7% based on the dry weight. Rubber from L. volemus, L. chrysorrheus and L. hygrophoroides was found to be a homologue of polyprenol being composed of dimethylallyl group, two trans isoprene units, 160-300 cis isoprene units, and terminal hydroxyl or ester group aligned in that order by 13C-NMR analysis. The ratio of fatty acid ester group to hydroxyl group was about 9/1 to 5/5. The number of both terminal groups and trans units decreased during aging of sporophores. Rubber from L. piperatus, L. vellereus and L. subpiperatus was found to be cis polyisoprene having very small quantities of both terminal groups and trans units. The biosynthesis of cis polyisoprene in Lactarius mushrooms was found to start from trans, trans-farnesyl pyrophosphate. The termination was assumed to occur by esterification of polyisoprenyl pyrophosphate. Occurrence of some chemical modifications on both terminal groups was presumed during aging of sporophores. PMID- 7856400 TI - Purification of geranylgeranyl diphosphate synthase from bovine brain. AB - Geranylgeranyl diphosphate (GGPP) synthase was purified to homogeneity from bovine brain in a one-step affinity column procedure. For the construction of the affinity column, a farnesyl diphosphate (FPP) analog, O-(6-amino-1-hexyl)-P farnesylmethyl phosphonophosphate, was synthesized and linked to the spacer of the matrix of Affigel 10 via the amino group. The native enzyme appeared to be homooligomer (150-195 kDa) with a molecular mass of the monomer of 37.5 kDa. The pI for the enzyme was 6.2. The Km values for dimethylallyl diphosphate (DMAPP), geranyl diphosphate (GPP) and FPP were estimated to be 33 microM, 0.80 microM and 0.74 microM, respectively. The Km value for isopentenyl diphosphate (IPP) in the presence of both IPP and FPP mixture was 2 microM. The ratio of the reaction velocity for formation of GGPP from DMAPP, GPP or FPP was 0.004:0.145:1. The intermediate FPP was formed in the reaction with GPP as an allylic primer. FPP synthase catalyzing the formation of FPP from DMAPP and IPP was also purified to homogeneity from the same organ by a similar affinity chromatography procedure using a GPP analog, O-(6-amino-1-hexyl)-P-geranylmethyl phosphonophosphate as a ligand. The enzyme was a homodimer with a monomeric molecular mass of 40.0 kDa. These results indicate that GGPP, a lipid precursor for the biosynthesis of a majority of prenylated proteins, is synthesized from DMAPP and IPP by the action of FPP synthase catalyzing the reactions C5-->C15 followed by the action of GGPP synthase catalyzing the reaction C15-->C20. PMID- 7856402 TI - Intracellular trafficking of dolichol: on the presence of dolichol transfer activity in bovine liver supernatant. AB - A protein catalyzing dolichol transfer between membranes has been purified from bovine liver up to 600-fold by acid precipitation, ammonium sulfate precipitation, ion-exchange chromatography and hydrophobic interaction chromatography. The protein displays a relative molecular mass of 15000 on SDS gel electrophoresis. Kinetics as well as the influence of a series of effectors were studied. The transfer activity is inhibited by sphingomyelin, sulfhydryl groups and cationic amphiphilic amines with a bulky heterocyclic aromatic function. High salt concentration decreases the transfer efficiency. Transfer of dolichol between vesicles and mitochondria is not affected by the presence of moderate amounts of cholesterol in the donor vesicles. The overall characteristics of dolichol transfer activity are discussed in comparison to these of other lipid transfer proteins. PMID- 7856403 TI - Clofibrate and di(2-ethylhexyl)phthalate increase ubiquinone contents without affecting cholesterol levels. AB - Induction studies were performed on liver, muscle, heart, brain and blood by feeding Sprague-Dawley rats a diet containing a peroxisome proliferator, clofibrate or di(2-ethylhexyl)phthalate. Ingestion of these drugs resulted in an increase in the amount of two different types of ubiquinone homologues UQ9 and UQ10 found in rat. Phthalate proved to be the more effective drug, leading to a highly increased amount of ubiquinone in the liver. Increases were also found in all the above-mentioned organs except the brain. The UQ9 levels were raised to 400, 200, 120 and 120%, of the respective normal values. The antioxidant and hypolipidemic agent, probucol, was used as a control to evaluate whether the increased ubiquinone level constituted a response to the elevated hydrogen peroxide pressure, resulting from the induced increase in fatty acid beta oxidation. In the presence of probucol, ubiquinone levels were decreased in all the above-mentioned organs except heart and brain. Probucol had limited effects on the amount of cholesterol and did not significantly alter the amount of dolichol. The two peroxisome proliferators differed in their effects on cholesterol, as well as on dolichol levels which was induced by phthalate but not by clofibrate. The possible mechanisms involved, and the importance of low toxicity drugs which could elevate ubiquinone levels in various tissues, are discussed. PMID- 7856404 TI - Modulation of mannosylphosphodolichol synthase and dolichol kinase activity in Trichoderma, related to protein secretion. AB - It has been postulated that exoprotein secretion in Trichoderma is related to their O-glycosylation. In the present paper the involvement of phosphodolichol in this process is described and the key role of mannosylphosphodolichol (MPD) synthase in protein O-mannosylation is discussed. The effect of water soluble phospholipid precursors such as choline and Tween 80, known also to increase secretion of cellulases when added to the medium, on MPD-synthase activity is presented. This effect is positive in the Trichoderma reesei QM 9414 (a low producing strain) but has no influence on the enzyme activity from the RUT C-30 strain selected to overproduce secretion of exoproteins and known to contain an increased cellular amount of endoplasmic reticulum. The positive effect of addition of choline and Tween to the medium on the level of dolichol kinase activity is also demonstrated. The influence of cultivation temperature on the activity of the various enzymes involved in dolichol-dependent protein glycosylation i.e. MPD-synthase, dolichyl kinase and MPD/Protein mannosyl transferase was tested. For all enzymes cultivation at 35 degrees C led to the elevated activity, which was most striking for dolichol kinase, whereas for MPD synthase and MPD/Protein mannosyl transferase the difference was only apparent in the assay when endogenous phosphodolichol was used as a substrate. Furthermore, lipid extract from the membranes cultivated at elevated temperature, when added to the enzyme obtained from Trichoderma grown at 25 degrees C, enhanced the dolichol kinase activity measured in the absence of exogenous dolichol.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7856405 TI - Dolichols and proliferating systems. AB - The results obtained on dolichol metabolism, in two in vivo model systems, the developing rat liver and the regenerating rat liver, which provide different timing and interplay of proliferation and differentiation processes, have been reported. The regenerating liver presents a marked increase of both synthesis and content of dolichol, a decreased cholesterol/dolichol ratio, unchanged synthesis and content of dolichyl phosphate, or dolichol-kinase and dolichyl phosphate phosphatase activities; no significantly modified distribution of dolichol homologs, with respect to the control. Total content of dolichols is growing during perinatal development. At fetal stages only short chain dolichols are detectable, while the content of dolichyl phosphate is very low and the activity of dolichyl phosphate-phosphatase is high. The study of the role of liver in dolichol supply to the body in the partially hepatectomized rat shows an increased content of dolichol in the blood; blood dolichol is essentially provided by the release from liver and dolichol traffic in the blood is mediated by multiple carriers. PMID- 7856406 TI - Mass spectrometric analysis of prenyl phosphates and their glycosylated forms. AB - Three different mass spectrometric method suitable for the analysis of polyprenyl and dolichyl phosphates and their glycosylated forms are described. Fast atom bombardment mass spectrometry (FAB MS) of glycosyl monophosphopolyprenols produces negative ions characteristic of the intact molecule. Tandem mass spectrometry of (M-H)- anions allows the determination of masses of both glycosyl and lipid moieties. Thus, for example, FAB-MS/MS of a mixture of native glycosyl monophosphopolyprenols isolated from ethambutol-treated Mycobacterium smegmatis enabled us to detect two novel pentosyl monophosphopolyprenols. Two other methods are proposed for the analysis of prenyl phosphates, as these compounds do not produce fragments in FAB-MS/MS at low collisional energy. By Desorption Electron Impact ionization (DEI) an intense (M-H3PO4)+ ion as well as fragments corresponding to the successive loss of isoprene residues (68 Da) can be observed. Alternatively, Desorption Chemical Ionization yields ions corresponding to the loss of 66, 78 and 98 Da (i.e. of a part or the entire phosphate moiety) of a prenyl phosphate molecule. Tandem mass spectrometry of the (M-H-98)- ion gives a series of intense fragments differing by 68 mass units over the whole mass range. PMID- 7856407 TI - The effect of undecaprenol on bilayer lipid membranes. AB - The influence of undecaprenol on phosphatidylcholine macrovesicular bilayer lipid membranes has been studied by electrophysiological techniques. The current voltage characteristics, ionic transference numbers, the membrane conductance temperature relationships and the membrane breakdown voltage were measured. The permeability coefficients for Na+ and Cl- ions, the activation energy of ion migration across the membrane, the membrane hydrophobic thickness and the membrane Young's modulus were determined. Undecaprenol increases membrane conductance, membrane capacitance, membrane ionic permeability and membrane elastic deformability, decreases the activation energy, membrane hydrophobic thickness and membrane electromechanical stability, and does not change membrane selectivity. The formation by undecaprenyl molecules of fluid microdomains modulating membrane hydrophobic thickness is postulated. The data suggest that the behaviour of undecaprenol in membranes is regulated by transmembrane electrical potential. PMID- 7856408 TI - Immunohistochemical localization of different forms of somatostatin in the gastrointestinal tract of the calf. AB - The presence of two peptides that belong to the somatostatin family has been investigated in the calf gut. Somatostatin-14-like and Somatostatin-28-like peptides have been localized by a light microscopic immunohistochemical method. The method employed antibodies linked to colloidal gold particles that were revealed by a silver-enhancement step. Somatostatin-14-like peptide was only present in mucosal endocrine cells, which were detectable along the entire gut with the exceptions of the abomasal gastric proper glands and caecum. The cells were most abundant in cardiac and pyloric glands. Langerhans' islets also contained this type of endocrine cell. Somatostatin-28-like-immunoreactive endocrine cells were more abundant than the former cell type. They were present in the gastric proper glands and caecum where Somatostatin-14-like-immunoreactive cells were absent. They were as numerous as the former type of cell in the endocrine pancreas. The Somatostatin-28-like peptide was also detectable in the intramural nervous components of the abomasum and the intestine, in both perikarya and terminals. Our results show a possible heterogeneity of an endocrine cell type, which synthesizes and secretes somatostatin peptides. Our results also support the hypothesis that somatostatin-14 and somatostatin-28 peptides may have distinct functional roles, particularly in different species. PMID- 7856409 TI - Immunohistochemical localization of the beta subunit of prolyl 4-hydroxylase in human alveolar epithelial cells. AB - The beta subunit of prolyl 4-hydroxylase, the protein-disulfide isomerase (PDJ), catalyzes the hydroxylation of proline residues of collagens and proteins with collagen-like structure, a step essential for the folding of the procollagen chains to form triple-helices. In the present study, we report the selective immunohistological localization of PDI in type II alveolar and bronchial epithelial cells. The detection of the hidden antigen with the monoclonal antibody 5B5 is usually not successful in paraffin sections but was possible after microwave pretreatment of tissue sections. In cases of severe lung injury (fibrosing alveolitis) enhanced immunoreactivity was found for this enzyme in epithelial, endothelial as well as interstitial cells and in alveolar macrophages. The results indicate a possible involvement of the pulmonary epithelial cells in the upregulation of collagen production during the process of fibrosis. PMID- 7856410 TI - Light microscopic visualization of transport ATPase in the chick kidney and intestine using catalytic histochemistry. AB - To visualize the enzyme Na+/K(+)-ATPase (transport ATPase) in the chick kidney and intestine two recent methods of catalytic histochemistry were modified using capture of inorganic phosphate with lead according to Mayahara et al.(1980) or cerium after Kobayashi et al. (1987). For light microscopy a new step for the visualization of the reaction product was added; lead phosphate was visualized with (NH4)2S and cerium phosphate with the DAB-H2O2-Ni-hexamonium sulfate method. Reaction product was specifically found in the basolateral plasma membrane region of enterocytes and renal epithelial cells (distal tubules, thick ascending limbs of Henle's loops, cortical collecting ducts). Treatment of the sections with 8 mM levamisole and 40 mM L-phenylalanine before and during incubation was necessary to suppress the co-reaction of non-specific alkaline phosphatase in the microvillous zone of proximal tubules and enterocytes. The reaction specificity was controlled with 10 mM ouabain which completely inhibited the basolateral activity in enterocytes and renal epithelial cells. The described methods for transport ATPase are reliable and provide reproducible results in the chick. PMID- 7856411 TI - Nursing as a profession. PMID- 7856412 TI - The "Tate" family. PMID- 7856413 TI - Understanding the political process. PMID- 7856414 TI - Should nurses be unionized? PMID- 7856415 TI - Could a hospital-based nurse educator be charged with negligence? PMID- 7856416 TI - Caring circles and nursing in the nineties. PMID- 7856417 TI - Ten ways to know... PMID- 7856418 TI - Nurses key to healthy Albertans. Discussion paper on a model of community health centres within the health care system. Alberta Association of Registered Nurses August 1994. PMID- 7856419 TI - How the attitudes of health professionals towards breastfeeding are shaped and their impact on breastfeeding. PMID- 7856420 TI - Working together for a safer workplace: employers find that safety pays. PMID- 7856421 TI - Health care reform--an opinion. PMID- 7856422 TI - Perceptions of preceptors toward preceptorship in nursing undergraduate education programs. PMID- 7856423 TI - Dr. Jenifer Wilson-Barnett: an interview. Interview by Eve Henderson. PMID- 7856424 TI - Inservice education needs in geronotological nursing. AB - This study in the field of gerontological nursing, identified perceived geronotological learning needs of RNs employed in long term care (LTC) facilities in Alberta to obtain a data base upon which the planning and development of inservice education in gerontological nursing could be based. Several conclusions were reached. Many highly perceived gerontological learning needs exist among RNs working in LTC in Alberta. Perceived learning needs remained high throughout the stages of resident flow. Priorities for program development in gerontological nursing were established. Although inservice education attendance over the previous two years was low, programs that address these needs should be available on a regular basis. Time to attend inservice programming is a problem that needs to be addressed. This study has provided useful information upon which inservice programming in gerontological nursing in LTC may be based. PMID- 7856425 TI - Acta fifty years ago. The fate of prematurely born children. Finland 1919-1935. PMID- 7856426 TI - Use of antenatal care services in a controlled ultrasound screening trial. AB - BACKGROUND: The purpose of the present study was to evaluate whether systematically organized ultrasound screening would have an effect on the uptake of antenatal care services. METHODS: A total of 9310 women were randomised to an ultrasound screening (4691) or to a control (4619) group. The screening group had an ultrasound examination between the 16th and 20th week of gestation, but otherwise both groups had identical antenatal care. RESULTS: Antenatal outpatient clinic visits were significantly fewer (2.3 compared to 2.6, p < 0.0001) in the screening group. On the other hand women in the screening group had more visits to maternal health centers than those in the control group (12.9 compared to 12.6, p < 0.0001). No difference was noted between the groups with respect to days in hospital, rest at home on sick leave and visits for medical check-ups. CONCLUSION: Ultrasound screening reduced the need for specialist services and increased the use of basic maternal health care services. PMID- 7856427 TI - Paternal influences on birthweight. AB - OBJECTIVE: To assess the influence of paternal size on birthweight after suitable control for maternal and fetal factors. DESIGN: Prospective observational study. SETTING: Delivery suite, City Hospital, Nottingham. SUBJECTS: 571 husbands/partners of unselected women delivering August 1992 to February 1993. MAIN OUTCOME METHODS: Individualised birthweight ratio and thereby an adjusted birthweight for a typical mother. The results of a multiple regression analysis with the individualised birthweight ratio as the dependent variable. RESULTS: When considered in isolation both paternal height and weight are significantly positively associated with crude and adjusted birthweight (p < 0.01, analysis of variance). Due to correlations of paternal size with maternal size and smoking habit, only paternal height is significant in the multiple regression analysis (p = 0.01). CONCLUSION: If the partner of an average woman is short (mean-2s.d.) then the baby will be 183 g lighter than if he is tall (mean + 2s.d.). This effect of paternal height on birthweight must be genetic and therefore should be taken into account when defining intra-uterine growth retardation and macrosomia. PMID- 7856428 TI - Interleukin-1, interleukin-6 and tumor necrosis factor at delivery in preeclamptic disorders. AB - BACKGROUND: To examine if preeclamptic disorders lead to altered concentrations of tumor necrosis factor, interleukin-1 and interleukin-6 at delivery compared to normal pregnancy. METHODS: Amniotic fluid, placenta, maternal and cord serum were collected at delivery by cesarean section or spontaneous labor. Samples were retrieved from 53 women with normal pregnancy, 54 with preeclamptic disorders and 15 who delivered a small for gestational neonate of unknown cause. Cytokines were measured by bioassays. Statistics were performed with nonparametric tests. RESULTS: Interleukin-1 in amniotic fluid tended to be lower with preeclamptic disorders than in normal pregnancy irrespective of labor. There was an increase in amniotic fluid tumor necrosis factor, interleukin-1 and interleukin-6 with onset of labor in preeclamptic disorders just as in normal pregnancy. There was a similar increase in interleukin-6 in cord and maternal serum in the same groups, even if concentration of interleukin-6 in cord serum in labor of preeclamptic disorders was lower than in normal pregnancy. CONCLUSIONS: No major differences were seen in concentrations of interleukin-1, interleukin-6 and tumor necrosis factor in amniotic fluid, placenta, maternal or cord serum at delivery with preeclamptic disorders compared to normal pregnancy. PMID- 7856430 TI - Evaluation of breast stimulation for induction of labor in women with a prior cesarean section and in grandmultiparas. AB - BACKGROUND: Information on the efficacy of breast stimulation for inducing labor in grandmultiparas and in women with a previous cesarean section with or without premature rupture of membranes is limited. METHODS: Retrospective study of labor data from 135 women of grand multiparity or those with a previous section with or without premature rupture of the membranes in whom labor was induced by breast stimulation. RESULTS: The success rate in achieving vaginal delivery was 84%. The duration of breast stimulation, length of labor, vaginal delivery rate, and Apgar score did not differ significantly among the four groups studied. CONCLUSION: Breast stimulation in grandmultiparas and in women with a previous cesarean section is efficacious and safe. PMID- 7856429 TI - Infection markers during labor at term. AB - Serum levels of C-reactive protein (CRP), white blood cell count (WBC), amniotic fluid white blood cells (Gram staining) and leukocyte esterase (LE) activity were measured serially and prospectively in 30 pregnant women in labor at term. Results were retrospectively compared with amniotic fluid bacterial culture results. Leukocyte esterase activity was measured by the dipstick test (Nephurtest) and an in vitro photometric method. Amniotic fluid samples were collected through an intrauterine transvaginal pressure catheter. The serial CRP and WBC levels from admission to the delivery and CRP levels from delivery to the first post partum day increased statistically significantly. Levels of both markers correlated significantly with duration of labor. Both amniotic white blood cells and leukocyte esterase activity increased during labor. Bacterial colonization of amniotic fluid was not clearly associated with amniotic LE activity or leukocyte count as determinated by Gram stain. The tests evaluated cannot be regarded as reliable methods in distinguishing intra-amniotic infection during labor and vaginal delivery at term. PMID- 7856431 TI - Fertility, miscarriage and pregnancy after vertical banded gastroplasty operation for morbid obesity. AB - Vertical banded gastroplasty (VBG) is today the most widely performed bariatric operation. The procedures used previously for the same purpose resulted in metabolic derangements and other pathologies during pregnancy. In a retrospective study we compared the reproductive performance of nine women prior to VBG and after it. Of eighteen pregnancies prior to the operation, seven ended with miscarriage, while only one of fourteen pregnancies conceived after the operation was aborted. The rate of spontaneous conception was greatly increased after the operation and there were fewer complications in the course of the pregnancies. From the obstetrician and gynecologist's point of view VBG seems to be a good treatment for morbid obesity. PMID- 7856432 TI - Psychosocial aspects of donor insemination. Attitudes and opinions of Danish and Swedish donor insemination patients to psychosocial information being supplied to offspring and relatives. AB - BACKGROUND: The purpose of this study was to evaluate the attitudes and opinions among donor insemination recipient couples with respect to the informing of offspring and relatives, the effects of donor insemination on sexual life and marital status, and their concerns about the risk of getting a sexually transmitted disease. METHODS: A questionnaire study design. Three hundred and sixteen (194 Danish and 122 Swedish) couples were included. RESULTS: Answering rate among the Danish couples was 89% and among the Swedes 75%, (p < 0.01). Fifty percent of the Danish couples and 66% of the Swedes were of the opinion that the treatments should be kept secret from good friends, (p < 0.05). Sixty-seven percent of the Danes and 87% of the Swedes found it important that knowledge about the inseminations was not made common knowledge to all interested parties, (p < 0.005). Parameters in which there were no differences between Danes and Swedes: Fifty-one percent of the couples would withhold information about the insemination from the child even when it was old enough to understand this information. Seventy percent of the couples would prefer not to know themselves, whether they had been conceived by donor insemination. Nineteen percent of the Danish couples would not have accepted donor insemination if the legislation guaranteeing donor anonymity had not been in existence. Eighty percent thought that their sexual life was unaffected during the course of the treatment. When asked, 95% were still married to the same partner with whom they began the treatment. Eighty-five percent of the couples were worried about getting a sexually transmitted disease through the treatment. CONCLUSION: The results suggest that secrecy about the treatment and donor anonymity have a high priority among Danish and Swedish recipient couples, irrespective of the different legislation in the two countries. PMID- 7856433 TI - Sexual life in women after colectomy-proctomucosectomy with S-pouch. AB - In a consecutive series, 30 women were interviewed and gynecologically examined after pelvic pouch operation because of inflammatory bowel disease. The examination displayed: colpitis in two, bacterial vaginosis in one and cervical cancer in situ in one of the women. Unwanted infertility was reported by five women, probably due to female factors in three. Sixteen women had felt sexually unattractive by the temporary ileostomy. At follow-up, after closure of the ileostomy, 23 women experienced a considerable sexual desire, 28 could experience orgasm and 20 nearly always had orgasm at intercourse. Insufficient vaginal lubrication during intercourse was reported by seven women. This could be explained by hormonal or other factors in four women and might be owing to side effects of the operation in three. Four women reported slight deep dyspareunia and one superficial dyspareunia. The result indicated a low frequency of sexual problems after pelvic pouch operation. PMID- 7856435 TI - Endometrial adenocarcinoma with clinical evidence of cervical involvement: accuracy of diagnostic procedures, clinical course, and prognostic factors. AB - BACKGROUND: The accuracy of clinical staging is known to be insufficient in stage II endometrial carcinoma. Also the optimal management of this disease is controversial. In this study we evaluate diagnostic accuracy and prognostic factors with special reference to treatment modalities of stage II endometrial carcinoma. METHODS: Of 1297 patients with endometrial adenocarcinoma (EAC) treated between 1970 and 1980 at Departments of Obstetrics and Gynecology, Helsinki University Central Hospital, 140 (11%) cases represented clinical stage II and were retrospectively analyzed. RESULTS: Median age of the patients was 63.5 years (range 40-85 years). Accuracy of Papanicolaou smear was 50%, and that of endocervical curettage 51%. Most of the tumors were histopathologically pure adenocarcinomas (88%), well differentiated (43%), and superficially invaded to myometrium (44%). Thirty-four (24%) of the patients developed a recurrent disease during the first five years afterwards. Median time of recurrency was 17 months (range 4-35 months). The disease free 5- or 10-year survival were 72% and 67%. Survival was significantly correlated with menopausal state (p < 0.01), tumor grade (p < 0.05), myometrial invasion (p < 0.001), surgical stage (p < 0.0001), and mode of treatment, i.e. operation done or not (p < 0.05). Survival was not affected by the radical nature of the operation (radical vs. simple hysterectomy). When all prognostic variables were analyzed by Cox's regression model (multivariate analysis) in 10-years follow-up, only menopausal state, myometrial invasion, and mode of treatment, i.e. operation done or not (p < 0.01), were independent prognostic factors. CONCLUSIONS: The only relevant staging procedure is the histological examination of cervix without the preoperative irradiation. According to our results it seems that simple hysterectomy instead of radical (Wertheim operation) hysterectomy may be a sufficient operative treatment of stage II endometrial carcinoma. PMID- 7856434 TI - Effects of long-term administration of an oral contraceptive containing ethinylestradiol and cyproterone acetate on lipid metabolism in women with polycystic ovary syndrome. AB - BACKGROUND: The effects of an oral contraceptive pill containing cyproterone acetate on lipid metabolism in women with polycystic ovary syndrome (PCOS) was studied. MATERIALS AND METHODS: Seventy-two women with PCOS were treated for 36 consecutive cycles with an oral contraceptive containing 0.035 mg of ethinylestradiol and 2 mg of cyproterone acetate. Hormonal, lipid and glucose profiles were studied before and after 12 and 36 cycles of treatment. Lipid, lipo and apolipoprotein values were compared to a healthy control group. Statistical analysis was by one way analysis of variance and Bonferroni's t tests. RESULTS: The treatment suppressed gonadotropin and androgen values and increased the levels of sex hormone binding globulin. After 12 and 36 cycles a significant increase in triglycerides, high density lipoprotein (HDL) cholesterol system, and apoprotein B levels was seen. Low density lipoprotein (LDL) cholesterol and LDL cholesterol/HDL cholesterol ratio were reduced. Insulin and glucose plasma concentrations did not change. During treatment triglycerides, total cholesterol and apoprotein B values were higher than in the control group. There were no differences in plasma levels of LDL-C and HDL-C in PCOS and in the control group. CONCLUSION: Lipid and lipoprotein changes observed after treatment could be due to the estrogen dominance of the treatment. The plasma concentration of triglycerides and total cholesterol during treatment does not change appreciably and the LDL-C/HDL-C ratio improved. PMID- 7856436 TI - Detection of bacterial vaginosis in wet mount, Papanicolaou stained vaginal smears and in gram stained smears. AB - In a prospective study of 107 women, bacterial vaginosis was clinically diagnosed in 34 women. Compared with clinical diagnosis of bacterial vaginosis, detection of clue cells in Papanicolaou stained vaginal smears showed a sensitivity of 88.2%, a specificity of 98.6%, a positive predictive value of 96.8% and a negative predictive value of 94.7%. The corresponding values for detection of bacterial vaginosis in Gram stained smears compared with the clinical diagnosis were 100%, 97.3%, 94.4% and 100%, respectively. Compared with clue cells in wet smears, identification of clue cells in Papanicolaou stained vaginal smears showed a Kappa index of 0.87 and compared with Gram stain criteria a Kappa index of 0.94. The correlation between Gram stain and Papanicolaou stained vaginal smears showed a Kappa index of 0.89. In contrast to the results of earlier investigators our studies indicate that the demonstration of clue cells in Papanicolaou stained vaginal smears correlate reasonably well with the conventional clinical criteria. However, the Gram stain method may be more reliable than the Papanicolaou method. PMID- 7856437 TI - Intracranial blood flow during laparoscopic hysterectomy. AB - AIM OF THE STUDY: To examine intracranial blood flow during major laparoscopic gynecologic operation and the effects of a deep Trendelenburg position and pneumoperitoneum on the flow. MATERIAL: Fifteen patients scheduled for laparoscopic hysterectomy. METHODS: Trans-cranial Doppler examination of blood flow velocity waveforms in the middle cerebral artery during operation. RESULTS: Trendelenburg position and pneumoperitoneum were followed by a decrease in cardiac output and an increase of central venous pressure and pulmonary capillary wedge pressure. No significant changes in the pulsatility index or maximal or mean blood flow velocities in the middle cerebral artery occurred during operations. A negative correlation between percentual changes in the pulsatility index and mean arterial pressure existed. CONCLUSIONS: Uncomplicated laparoscopic hysterectomy is not associated with harmful changes in intracranial circulation in spite of a Trendelenburg position, pneumoperitoneum and changes in the patient's extracranial hemodynamics. PMID- 7856439 TI - Adenoid cystic carcinoma of Bartholin's gland--a review of the literature and report of a patient. AB - A case of adenoid cystic carcinoma of the Bartholin's gland, a rare vulval tumor, is reviewed with respect to clinical and pathological characteristics. Histological transition from normal Bartholin gland to adenoid cystic carcinoma was evident in this case. Local recurrences are common and often precede distant metastases. The recommended primary treatment is vulvectomy, obtaining clear margins and bilateral inguinofemoral node dissection. PMID- 7856438 TI - Regression of hepatic tumors during transdermal estradiol replacement therapy. AB - A 39 year-old patient with long-standing diagnosis of pelvic endometriosis had been treated for over twenty years with oral contraceptives (OCs). A year prior to admission to the gynecological ward, an ultrasonographic examination revealed three hepatic lesions, which were not reported in previous liver sonography. These lesions progressed during OC use, over the next six months. Liver function tests were normal. Liver scan, CT and ultrasound imaging techniques supported the diagnosis of solid hepatic tumors. These lesions developed concomitantly to long term use of OCs, therefore discontinuation of therapy was mandatory. Six months later, the patient was hospitalized due to pelvic pain. She underwent total abdominal hysterectomy and left salpingo-oophorectomy (the right adnexa had been removed years before). Due to the patient's young age, hormone replacement therapy was indicated. The preferred preparation was transdermal estradiol due to the fact that systemic absorption has no hepatic first-pass effect and therefore exerts minimal influence on liver enzymes and functions. Serial ultrasonographic examinations, performed while under treatment with transdermal estradiol, showed complete regression of the hepatic lesions over a period of two years. Our report demonstrates regression of multifocal hepatic tumors despite transdermal estradiol replacement therapy. PMID- 7856440 TI - Expectant management of ectopic pregnancy in the presence of ovarian hyperstimulation syndrome. AB - Cases of coexisting ovarian hyperstimulation and ectopic pregnancy are rare, and pose a difficult diagnostic problem. The routine attempts at laparoscopic diagnosis and treatment of these pregnancies may prove to be hazardous. Such cases may be better managed nonsurgically either by methotrexate or, in selected cases, by expectant management while monitoring the beta-hCG level and clinical status. PMID- 7856441 TI - Swallowing dysfunction and aspiration in neonates and infants. AB - In children, swallowing dysfunction and aspiration are common causes of recurrent pneumonia and can be fatal. The underlying mechanism is still unknown. In this study, we evaluated the swallowing function in 72 neonates and infants by fluoroscopy and followed the course of 39 patients for more than one year. The results of all the examinations were recorded on videotape or a digital imaging system. All 10 patients with neurologic disorder presented cricopharyngeal dysfunction. Of the 12 patients with near miss sudden infant death syndrome, 10 showed nasopharyngeal reflux, and 5 demonstrated cricopharyngeal dysfunction. In the 50 patients without neurologic disorder, 29 revealed cricopharyngeal dysfunction. Laryngeal elevation was not seen in 75%. Three of these 29 patients had no other abnormality. All patients without neurologic disorder recovered well. Seven patients demonstrated prolonged aspiration. Four of them had neurologic disorder, and the rest had near miss sudden infant death syndrome. Fluoroscopic examination showed two types of aspiration: one was caused not only by pharyngeal but also by lingual muscles. It was not associated with any neurologic disorders and the symptoms were transient. The other was caused by cricopharyngeal dysfunction and most of these patients had neurologic diseases and prolonged symptoms. PMID- 7856442 TI - Obstructive sleep apnea attack in complex craniosynostosis. AB - For treatment of patients with complex craniosynostosis, increased intracranial pressure, severe exophthalmos, and apnea attacks are important indications for operative intervention. Little has been reported on obstructive sleep apnea in complex craniosynostosis. Obstructive sleep apnea attacks in complex craniosynostosis are evaluated in relation to the upper and middle pharyngeal space and to the dimensions of the maxilla and mandible measured on cephalograms. The value of the pharyngeal air space in craniosynostosis had no relationship with either the frequency of sleep apnea attack or with severity of snoring. The dimensions had a close relationship with obstructive sleep apnea attack. PMID- 7856443 TI - Development of the pharynx in normal and malformed fetuses. AB - We studied the development of the pharynx in human embryos and fetuses. Embryos and fetuses from 4.5 mm crown-rump length (CRL) to 40 mm CRL were processed for microscopic examination. Normal fetuses from 32 mm CRL to 250 mm CRL and fetuses with malformations of the central nervous system (CNS) were cut sagittally through the midline and their pharyngeal regions were examined macroscopically. Our observations suggested that, at an early embryonic stage, the notochord and basicranium might play important roles in the formation of the human pharynx. At a later stage, the growth of the maxillomandibular portion also appears to be important in the formation of the pharynx. The finding of malformation of the pharynx in fetuses with maldevelopment of the CNS suggests that the brain may play an important role in the formation of the pharynx. PMID- 7856444 TI - Choanal atresia and congenital pharyngeal stenosis. AB - From 1980 to 1992, 8 patients with choanal atresia were treated in our facility. The female to male ratio was 5:3. One patient, a girl, had unilateral osseous obstruction with membranous closure of the opposite naris while the other 7 had bilateral osseous obstruction. Seven of the 8 had other congenital anomalies, CHARGE association (2 cases), Apert's syndrome (1 case), meningocele and banded fingers (1 case), omphalocele (1 case), subdural hematoma (1 case), and nasal fistula (1 case). Of the 7 patients who underwent endonasal surgical repair, 3 (40%) experienced reclosure. The remaining one patient, whose obstruction was of the bilateral osseous type, was successfully operated on via a transpalatal approach. Surgical correction is particularly difficult in those with craniofacial abnormalities, e.g. Apert's syndrome and maxillary hypoplasia. We treated 5 congenital pharyneal stenosis cases (CPS). Our CPS cases were divided into Types 1, 2 and 3, the latter being a new type not previously reported on. We consider Type 3 to be the result of fetal tissue remnants. We performed uvula splitting surgery in 4 cases and obtained good results in 3. PMID- 7856445 TI - Laser beam in treating congenital choanal atresia in three patients. AB - We present the results of 3 patients with congenital unilateral choanal atresia who were treated surgically at our department. We report a method of surgical approach for repair of choanal atresia. A transpalatal procedure offers an approach which is straightforward. The use of carbon dioxide or Nd:YAG laser seemed better for recurrent cases. A tube stent should be placed for at least 6 weeks postoperatively. PMID- 7856446 TI - Tornwaldt's disease. AB - Tornwaldt's disease was first described by Tornwaldt as one of the causes of epipharyngitis, and is an inflammation or abscess of the embryonic remnant cyst of the pharyngeal bursa appearing at the posterior median wall of the nasopharynx. Although many cases are symptom-free, symptoms can often be caused by nasal tamponade, trauma, adenotomy, or other mechanical stimuli. Only a few cases have been reported in Japan between 1929 and 1992. At about the 10th week of embryonic development, the pouch, which forms by adhesion of the pharyngeal ectoderm to the notochord at the most cranial end of the notochord, becomes closed at the orifice (cystic type), or crusts adhere to the orifice without closing (crust type). Symptoms are those of upper respiratory tract infection with obstinate occipital pain, purulent choanal discharge, nasal obstruction, halitosis, feeling of ear fullness, clearing of the throat, etc. Posterior rhinoscopy, simple lateral view X-ray tomography, nasopharyngeal fiberoscopy, CT scan and MRI are useful in showing adhesion to the cervical vertebrae. While complete extirpation via a transpalatal approach is desirable, incision or excision of the cyst can also be performed. PMID- 7856448 TI - Morphologic changes in superior vestibulo-ocular neurons and vestibular nerve following labyrinthectomy in the cat. AB - Morphologic changes in ipsilateral superior vestibulo-ocular neurons (SVON) and the vestibular nerve were measured in 4 cats 8 weeks after labyrinthectomy and 4 cats 1 year after labyrinthectomy. There is a 20% decrease in SVON size and 30% decrease in rough endoplasmic reticulum and ribosomes with no change in the volume fractions of Golgi apparatus or mitochondria. In the central nervous system degeneration of the vestibular nerve terminals ipsilateral to the labyrinthectomy was represented by a 25% loss of synaptic profiles (SP) on SVON at 8 weeks and 57% loss of SP at 1 year after labyrinthectomy. There was no significant loss of fiber number in the vestibular nerve at 8 weeks post lesion but a 35% loss of fibers primarily of the large size at 1 year post lesion. PMID- 7856447 TI - Sleep apnea and sleep-related breathing disorders in patients with craniofacial synostosis. AB - Seventeen patients with craniofacial synostosis (CFS) have been treated at the Department of Plastic and Reconstructive Surgery at Osaka Medical College during the past 10 years. Six patients were thoroughly evaluated at the Department of Otolaryngology by polysomnography (PSG), cephalometric X-ray and nasopharyngoscopy during sleep. In 4 of the patients PSG showed obstructive sleep apnea syndromes (OSAS). Heavy snoring without apnea and paradoxical respiration were noted in the other 2 patients. Thus, all of the patients had sleep-related breathing disorders (SRBD). It is assumed that the incidence of SRBD in CFS is high. Cephalometric analysis and profilogram showed maxillomandibular hypoplasia in each patient, and it was assumed that the main cause of SRBD in CFS was stenosis of the upper airway tract caused by maxillo-mandibular hypoplasia. Nasopharyngoscopy was performed during sleep in 2 patients with OSAS secondary to CFS. One patient with adenotonsillar hypertrophy had nasopharyngeal obstruction and another patient whose posterior airway space (PAS) on cephalometric radiograph was 3 mm (normal value: 11 mm) had obstruction at the tongue base. PMID- 7856449 TI - [Disability: a proposal for an anamnestic questionnaire in the evaluation of the degree of disability caused by disorders of equilibrium]. AB - Correct identification and evaluation of balance disorders and an assessment of their repercussions on a patient's life are common problems faced by the otoneurologist. These symptoms may not infrequently have a chronic or recurrent course and can lead to in restrictions in the patient's everyday life and even have consequences for the patient' mental health. In the doctor-patient relationship anamnesis is of crucial importance in diagnosis as well as in establishing a relationship of professional confidence with the patient which may influence the outcome of the treatment. An awareness of those situations of daily life which bring about or aggravate the symptoms provides the doctor with valuable information in formulating an etiopathogenetic hypothesis. This observation led us to design the anamnestic self-questionnaire "Disability" whose purpose is to describe the type of disability or impairment to daily life suffered by the patient as a result of the pathology, while at the some time measuring their effects. Our history questionnaire has confirmed the importance of careful history in assessing balance disorders, has highlighted the striking extent of disability and impairment caused by these disorders, and has enabled us to identify the chief features of all pathologies encountered in the specific field of balance disorders. The questionnaire enables us, in particular, to highlight the interference of extra-vestibular factors (muscle-strain, states of irritation, phobias, drugs, dietary factors, etc.). The use of this questionnaire has proved to be of great assistance, therefore, in carrying out routine clinical diagnosis, in the absence of complex technical equipment. Moreover, it constitutes a valuable method in monitoring the outcome of the therapy, or the natural course of the balance disorders. PMID- 7856450 TI - [Noise exposure in neonatal intensive care units]. AB - This study evaluates the exposure of newborn babies in neonatal intensive care units (NICU) to noise which can cause hearing lesions directly (acoustic trauma) as well as indirectly (hypoxia). Moreover, noise can have an aggravating effect when combined with other potentially harmful factors in the NICU, such as ototoxic medication or stress due to other external stimuli, such as excessively bright light, lack of a day/night rhythm or pain. Sound pressure levels were measured in the NICU and inside the cribs in various experimental conditions, classified under 3 different types of sound events: constant background noise, variations in background noise and impulsive events. The main sources of noise detected were crib noise generated by ventilation and temperature control systems, ambient noise in the room, noise caused by the staff in the NICU, noise generated by crib alarm systems and NICU apparatus and noise caused by activity on the crib cover or on its plexiglas top. Findings revealed that the influence of ambient noise is fairly irrelevant. Background noise and its variations concerned with activities in the department never exceeded the limits considered potentially harmful to adults (DRC), whereas the impulsive noise generated by staff on the cribs or on the plexiglas tops was considerable and potentially harmful. These findings demonstrate that it is feasible and relatively easy to control noise in the NICU and significantly reduce the impulsive noise component by training staff to be more careful and avoid any unnecessary jolting and rough handling on and near the cribs. PMID- 7856451 TI - [Early signs of occupational ototoxicity caused by inhalation of benzene derivative industrial solvents]. AB - People exposed to industrial solvents may suffer from disturbances of different psycho-physiological and vestibulo-oculomotor function. Therefore an investigation was performed testing vestibular and oculomotor reactions in workers exposed to solvents. It also seemed to be of interest to study if the auditory pathways were affected in these workers. 53 men aged 27-54 (Md = 37.7) were studied. They had been exposed to aromatic solvents in their work as colour mixers, painters, printers and petrol truck drives. Time of working was between 4 25 (Md = 15.2) years. At the time of this investigation none of the men had been exposed to solvents for at least the last four years. The clinical investigation included cerebellar tests and a general ENT investigation. Electronystagmography was performed and comprised the following functions: 1) spontaneous and caloric vestibular tests; 2) a sinusoidal swing test in darkness, the patient sitting in a rotatory chair; 3) visual suppression test; 4) a saccade test; a slow pursuit eye movement test. In addition all the patients were subjected to an audiological test battery including pure tone threshold, conventional vocal audiometry, speech discrimination used interrupted speech 10 interruptions per second, acoustic reflex thresholds and reflex decay. The clinical investigation showed in 19 patients balance problems in the balance test. The sinusoidal test was normal in all cases. The caloric test showed 8 cases of asymmetry in vestibular reactions. 10 of the patients had pathological spontaneous nystagmus. 17 of the patients had a pathologically decreased ability for visual suppression. The saccades were abnormal in 25 patients. The patients who were subjected to audiological testing all had pure tone thresholds and conventional vocal thresholds as expected with regard to age. 31 patients showed decreased discrimination scores at the interrupted speech. The acoustic reflex thresholds were normal and there was not pathological reflex decay. Results show the prevalently pathologic concern for C.N.S. Authors, last, give prominence to the significant relationship between the exposure time to solvents' vapour and changing of several parameters, connection conditioned by constitution and life habits in predisposing workers to a greater susceptibility at damages caused by organic solvents. PMID- 7856452 TI - [Distortion products in Meniere's disease]. AB - Distortion Product Otoacoustic Emissions (DPOAEs) are elicited by simultaneous application of two tones to the ear canal. These emissions are a result of nonlinear mechanical characteristics of the cochlea at a specific point and have a precise mathematical relation with the frequencies of the two eliciting primary tones f1 and f2. This frequency-selective property of DPOAEs suggests that they should be regarded as useful monitor of localized cochlear function at any predetermined frequency. The present study was designed to investigate DPOAEs in patients with Meniere's disease. DPOAEs were recorded before and after glycerol administration to verify if the fluctuation of the hearing threshold induced by this hyperosmotic agent causes selective changes in the activity of the outer hair cells. DPOAEs were present in patients in which the mean duration of the disease was shorter compared to those patients without measurable DPOAEs. An improvement of DPOAEs after glycerol intatte was observed in a half of our cases. The improvement of DPOAEs does not appear to be brought about by modifications of the auditory threshold induced by glycerol. PMID- 7856453 TI - [Cervical electrostimulation in some vestibular diseases]. AB - Vestibular disorders may be treated by means of drugs, surgical tools or rehabilitation. Cervical electrostimulation may be regarded as physical therapy and its activity is connected to neural pathways between cervical receptors and vestibular nuclei. In present study electrodes were placed lateral to cervical column on the opposite side of vestibular deficit as pointed by electronystagmography; stimulus duration was 18 msec and frequency 100 Hz. Every stimulation lasts for 30 minutes and were repeated twice a week for a total number of 10. The ability to adjust vestibulo-ocular reflex was evaluated by means of a Compensatory Index. The following materials were enrolled in the study: 20 normal subjects were observed before and after a cycle of stimulations: 24 patients suffering from acute labyrinthitis or neuritis, 48 cervical vertigo, 8 cervical traumatic injures and 3 patients operated for acoustical neuroma. All these groups were coupled with control groups composed of the same pathology and the same number of subjects. Statistical treatment of reports was evaluated by t student test before therapy after one month and after 3 months. Results point out good effects of electrostimulation on vestibulo-ocular reflex compensation, especially in cervical vertigo and labyrinthitis or neuritis with respect to control groups. No important results were obtained in neuroma group and in normal subjects. Electrostimulation may act on vestibular nuclei by direct spino vestibular pathway but also by repeated decompensations mainly mediated via the cerebellum or spino-reticular connections. PMID- 7856454 TI - [Non-recurrent inferior laryngeal nerve]. AB - The Authors describe a case of non recurrent inferior laryngeal nerve located on the right side observed during anatomical studies of the innervation of the larynx. The description is accompanied by photographic documentation which shows the anomalous course of the nerve and its abnormal relationship with the right subclavian artery, also anomalous. The embryological nature of such anatomical variations is discussed followed by considerations concerning possible consequences with regard to clinical aspects and thyroid surgery. Furthermore, the Authors indicate clinical signs that may suggest the presence of such anomaly so as to avoid anatomical or functional damage of the nerve which, although anomalous, plays an important role in coordinating breathing and phonation. PMID- 7856455 TI - [Evaluation of the T parameter of TNM classification of tumors of the tonsillar region. Correlation of MR and pathological data]. AB - The purpose of this study was to define MR accuracy in the evaluation of T Stage of tumors in the tonsillar region. Twenty-two patients with a squamous cell carcinoma of the tonsillar region were studied utilizing a superconductive scanner operating at 1.5 T. The study was performed with SE T1 and T2 images before contrast and short SE T1 after Gd-DPTA infusion. MR results were correlated with pathological data on T Stage (TNM classification) and on the relationships between tumors and surrounding structures. A positive correlation between MR and pathological data was obtained in 19/22 cases, with an MR accuracy of 86%. MR did not show the presence of 2 superficial lesions (MR T0, pathological T1), while one lesion was classified T2 with MR, instead of pathology T1. The accuracy of MR was 95% in the evaluation of the relationships between tumors and the base of the tongue and 100% for body of the tongue, retromolar trigone, valleculae, epiglottis, pre-epiglottis, parapharyngeal and masticator space. MR showed high accuracy in the evaluation of T Stage, above all utilizing Gd-DPTA infusion, with short SE T1 sequences. MR did not show the superficial lesions, but in these cases a deep extension of the disease was excluded. PMID- 7856457 TI - [Therapy of epistaxis during the ages]. PMID- 7856456 TI - [Association of the cytogenetic pattern and latero-cervical metastasis of laryngeal cancer]. AB - Although solid tumors, in particular carcinomas, play a much larger part in human morbidity and mortality than hematological neoplasias do, much less is known about the cytogenetic abnormalities that characterize them. Numerous classification schemes have been used in the subdivision of human tumors. Most often the tumors are classified according to the presumed cell of origin (epithelial, mesenchymal, neurogenic or germ cell tumors), their benignity or malignancy, differentiation features and histological growth pattern or anatomical site or organ of origin. In the following discussion, we analyse 12 cases of squamous cell carcinoma of the larynx. All teh sample were karyotyped using a direct chromosome analysis method. The method reported was highly successful and in several types of tumors showed the possibility of obtaining good banded metaphases. The purpose of this research was to attempt to define the chromosomal pattern of laryngeal carcinomas and, consequently, to correlated, it to histological grading and clinical evolution. In all the cases studied we found several chromosomal anomalies. In five of them clonal anomalies, such as the loss of chromosome 4; Robertsonian translocation t(13,14); rearrangement of chromosome 1 and chromosome 17 and the presence of similar markers, were observed. The characterization of the markers was made with an IN SITU hybridization technique using specific probes, followed also in order to define two particular markers involving chromosome 1 and t(13,14). We did not reveal a correlation between histological grading and karyotype, but we did find a correlation between tumor ploidy and latero-cervical metastases. The most important result seems to correlate the presence of latero-cervical metastases with a hypodiploid cell line (with less than 46 chromosomes) in the primary tumor. This could be an index of the ability of the tumor to invade the latero-cervical lymph nodes. If this correlation is confirmed, conservative neck dissection could be limited to N0 patients with a hypodiploid pattern. In conclusion, we feel that, if confirmed, the results of this research, may be widely applied in clinical medicine. PMID- 7856458 TI - [Evaluation of medical schools and universities]. PMID- 7856459 TI - [Macrocheilitis and Melkersson-Rosenthal syndrome. Review of 19 cases]. AB - Melkersson-Rosenthal syndrome is an uncommon condition of unknown cause. The classical triad includes recurrent orofacial oedema involving predominantly the lips (macrocheilitis), intermittent peripheral facial palsy and scrotal tongue. Some authors consider Miescher's cheilitis as a monosymptomatic form of the syndrome. Nineteen cases (11 females and 8 males) of macrocheilitis seen at the Dermatologic Clinic, University of Coimbra, between 1966 and 1992, are reviewed. The complete triad of signs was present only in 4 patients (21%) and two features of the classic triad in 3 (16%) (macrocheilitis and lingua plicata in two; macrocheilitis and facial palsy in one). Twelve patients had only recorrent or persistent orofacial swelling. All 19 patients had macrocheilitis. Less commonly, the check, nose, forehead, eyelid, chin and buccal mucosa were also involved. Peripheral facial paralysis was present in 5 cases (26%), and scrotal tongue occurred in 6 (32%). Lip biopsies, performed in 17 patients, revealed the typical pathologic picture of granulomatous cheilitis only in 8 cases. Systemic corticosteroids and clofazimine were the most efficacious treatment. PMID- 7856460 TI - [Epidemiologic study of bronchial asthma in schoolchildren from the Azores (Faial)]. AB - Epidemiologic data on prevalence of bronchial asthma among childhood in the Azores have been unknown so far. In October of 1993 a study was carried out to determine the prevalence of bronchial asthma in children aged 6-12 years on the island of Faial. Nine hundred and twenty seven schoolchildren, representing more than 95% of children within this age group, were studied. A questionnaire was distributed to be filled out by their parents and returned to the schools. Children were considered to have bronchial hyperreactivity when they had an episodical wheeze, spontaneous or related to cold, exercise, airway infections or allergic exposure, and to have asthma when they had been diagnosed by a doctor or had consulted their physicians for dispnea accompanied by wheezing and had received asthma medication in the last year or in their lifetime. The cumulative prevalence of asthma was 8% (CI 95%: 7-9%). Asthma was significantly more common in males (69%; CI 95%: 57-78%) than in females (31%) (p < 0.001). Seventy percent of the diagnoses were made in the first 5 years of life. Allergy was reported more often among asthmatic children (71%: CI 95%: 59-81%) than in the non asthmatic group (29%) (p < 0.001). Seventy seven percent (CI 95%: 65-85%) of asthmatic subjects had a family history of asthma. Asthma was not reported significantly more often in households with smokers than in those without smokers. PMID- 7856461 TI - [Life tables. An approximation to their construction]. AB - The method suggested by the World Health Organization on constructing current life tables is described in order to analyse the mortality by age groups and to estimate life expectancy for the Grandola community, between 1990 and 1992. Mortality rates seem to be high in some younger age groups, but a more detailed investigation should be made about their causes and, if possible, appropriate measures should be taken to correct the above situation. Life expectancy at birth was estimated in 67.75 years for males and 77.42 for females, the first being lower than the average of this country. The described method has the main advantage of being mathematically and conceptually simpler than many others existing in literature, with similar final results. PMID- 7856462 TI - [Thoracic drainage tubes]. AB - The invasive procedures handled by the pulmonologist in the diagnosis of lung disease have greatly expanded over the last decade (transbronchial, percutaneous or thoracoscopic pulmonary biopsy and needle aspiration). The growing number of intensive care units with facilities in mechanical ventilation and hemodynamic support has also modified the approach of the critically ill patient. Pneumothorax and hemothorax are well-known complications related to these diagnostic and therapeutic techniques. Other areas of interest and up-to-date are diagnostic thoracoscopy in pleural disease, chemical pleurodesis in patients with pneumothorax or malignant pleural effusion, and the administration of intrapleural fibrinolytics in the treatment of empyema. This evolution implicates that the pulmonologist and the intensivist be skilled in the management of chest tubes. In this article we review the indications, some technical topics and the principal complications related to the placement of thoracic drains. PMID- 7856463 TI - [Angiosarcoma of the breast]. AB - Angiosarcoma of the breast is a rare but highly malignant neoplasm of vascular origin. The median survival in previously reported cases is 22 months. The treatment of choice is simple mastectomy. Although the value of irradiation or chemotherapy as the only form of treatment is limited, their role as adjuvant therapy should be explored. One case is presented and a review of the literature is made. PMID- 7856464 TI - [Myxoma of the left atrium presenting as repeated cerebrovascular disorders]. AB - Infarction of the central nervous system secondary to embolism from a left atrial myxoma is a recognized phenomenon. However, a myxoma as the source of an embolus may be overlooked, if, during the evaluation of a patient with a stroke of unknown etiology, an index of suspicion is not present. We report a case of a 57 year old woman presenting three episodes of cerebral infarction always in the same brain territory, suggesting a carotid pathology. The physical examination of the patient only showed a loud S1 with no other sounds and neurologic alterations, namely, right hemiparesia and aphasia. Diagnosis was made by two dimensional echocardiography and better delineation was obtained by magnetic resonance imaging (MRI). The patient subsequently received a successful ressection of the myxoma. Eighteen months later the patient was well. PMID- 7856465 TI - [Sjogren's syndrome]. AB - This paper consists the theorical review and the current concepts of the subject and the second includes the casuistry of the Stomatology Department of the Pulido Valente Hospital. From April 1989 to 1991 (2 years), a study was made on Sjogren Syndrome (Primary and Secondary) of multiple character with the particular co operation of the Portuguese Institute of Rheumatology. With this paper we wish to point out the importance of the oral evaluation of the study of the plurisystemic diseases as well as to establish criterions of diagnosis for the Portuguese population. Eighty cases of suspected Sjogren's Syndrome have been assessed, 66 of which have been fully. The reason for the consultation was dry mouth, dry eyes and enlargement of parotid glands. The symptoms were isolated or in association with other pathologies after other causes had been excluded. We had to establish the salivary reference values for the Portuguese population in 22 healthy volunteers. The xerostomia was evaluated by the Sialochemistry, Sialography, Cintigraphy and biopsies of the lower lip and of the sublingual gland. The ophthalmologic examination took place in the Ophthalmology Department of Santo Antonio dos Capuchos Hospital by means of Shirmer test, Rosa Bengala and B.U.T. In spite of Sjogren's Syndrome being, up to now, so remotely determined in connection with the treatment, these patients need medical care and Stomatology plays a fundamental role as far as the diagnosis and the therapeutic points of view are concerned. We maintain the notion that the Syndrome is not as infrequent as one would believe and the evaluation of the oral field is important to establish the degree of the disease and its treatment. PMID- 7856466 TI - [Evaluation of medical schools and universities. Not postponable options, unavoidable risks]. AB - 1. The evolution of the relations between the Portuguese universities and the State is presented. It is considered that over the last 30 years the most important policies were the creation of new universities and the legal recognition of Ph.D.s obtained abroad. These measures influenced engineering much more than medical schools. 2. Multiple mechanisms of assessment covering the quality of teaching in conformity with international standards, research and post graduate activity should be established by medical schools themselves. It is also proposed that Medical Schools should embark on an ambitious post-graduate program so as to establish closer links with the medical profession. 3. It is considered that the assessment method under consideration by the Ministry of Education is dangerous, inadequate and unjustified. 4. It is considered that the present level of investment in tertiary education will cause our standards, in that area, to fall even more when compared with those of other European countries. PMID- 7856467 TI - [Francisco Goncalves Ferreira]. PMID- 7856468 TI - Hyperthermic reaction to haloperidol with rigidity, associated to central core disease. AB - A 21-year-old female patient with psychotic symptoms developed hyperthermia, muscular rigidity and hypertension after administration of haloperidol. A muscle biopsy showed some atrophic and necrotic fibers, and a great number of fibers with central cores in the oxidative enzyme preparations. A related syndrome, Malignant Hyperthermia (MH), is sometimes associated with central core disease. The present case shows an association of a hyperthermic syndrome related to haloperidol with central core disease. PMID- 7856469 TI - Intramedullary cavernoma: a case report and review of the literature. AB - A case of spinal cord cavernoma is presented. The pertinent literature is reviewed and the problems of diagnosis and management of this rare condition are discussed. PMID- 7856470 TI - Crow-Fukase syndrome: a case associated with vasospastic angina. AB - The patient is a 60-year-old man who developed numbness of the extremities, paralysis, hyperpigmentation of the skin, hypertrichosis, anasarca and chest pain at the age of 58 years. The diagnosis of Crow-Fukase syndrome was made and myeloma was not found. Prednisolone therapy was effective but chest pain reappeared every morning when prednisolone was tapered to 30 mg alternate day. Coronary arteriogram showed no stenosis but administration of acetylcholine into the coronary artery produced ST elevation in electrocardiogram, chest pain and coronary artery stenosis which were relieved by administration of nitrates into the coronary artery. PMID- 7856472 TI - Nicardipine versus propranolol in essential tumor. AB - To evaluate effect of the calcium-channel blocker nicardipine in essential tremor (ET), 14 patients with ET affecting upper limbs underwent a cross-over study with nicardipine (1 mg/Kg/day) and propranolol (160 mg/day). Evaluation (baseline and 1 month after each drug) was done by using the Fahn-Tolosa-Marin scale. Two patients withdrawed nicardipine (pretibial edema and palpitations) and other 2 propranolol (dyspnea and hypotension). Both drugs improved ET, with a non significantly higher efficacy of propranolol. These results suggest that nicardipine might be efficacious for ET. PMID- 7856471 TI - Subarachnoid hemorrhage of unknown origin. A 44 cases study. AB - 44 cases (20 men and 24 women) of subarachnoid hemorrhage (SAH) of unknown origin were studied: the mean age was 54.1 yrs. Highest frequency of the disease was observed in 51-70 years old patients. There was only a slight involvement of consciousness (I-II grade of HESS and HUNT). Vascular hypertension was noticed in 45.5% of patients, but outcome did not differ in hypertensive and normotensive subjects. The CT findings showed a typical picture of SAH. 4 cases of perimesencephalic and peripontine hemorrhage were noticed. 24 patients underwent lumbar puncture. The angiographic study was normal in all patients. 14 subjects repeated four-vessel angiography. Transient hydrocephalus was found in 22.7% of patients. Approximately 70% of patients received antifibrinolytic therapy, either with or without calcium entry-blockers (nimodipine). Neither ischemic complications nor rebleeding were observed. Follow-up showed that all patients had survived 7-88 months after SAH. All subjects made a complete recovery and have since been able to resume work. PMID- 7856473 TI - Dietary habits and multiple sclerosis. A retrospective study in Ferrara, Italy. AB - In a retrospective case-control study of multiple sclerosis (MS), set up with the aim of verifying the role of environmental factors in pathogenesis, we included a section on dietary habits. We compared the frequency and pattern of food consumption by cases and controls. We found an association between. MS and high consumption of bread and "pasta", butter and lard, legume soup, horse flesh, coffee and tea in the period from infancy to adolescence. A different pattern of consumption of eggs, wine and mineral water between cases and controls was found during adulthood. Our results support, at least partially, the data already reported in the international literature on an association between certain dietary factors and MS. Some foods consumed at certain "critical" ages could play a causal role in the onset of MS. PMID- 7856474 TI - Activated lymphocytes in glioblastoma: significance for anti-tumoral immunity. AB - Interaction between immune cells and tumoral cells of a case of glioblastoma was studied. Tissue fragments obtained during neurosurgery from different areas of the tumor were examined before and after rIL-2 treatment in vitro. The same morphofunctional type of cells usually activated by rIL-2, which show antitumoral reactivity, was observed both in the glioblastoma imprints and in tumoral fragments cultured with rIL-2. This cytokine stimulated the proliferation of tumor infiltrating lymphocytes in vitro. This preliminary study shows that IL-2 potentiates the differentiation of HMS cells in peripheral blood which probably pass through the blood brain barrier and infiltrate the tumor. PMID- 7856475 TI - Hypothalamic-pituitary-adrenal axis and immune system. AB - Complex and bidirectional relationships operate between the hypothalamic pituitary-adrenal (HPA) axis and the immune system (IS) and either in vivo or in vitro evidence supports a physiological role of the HPA axis-IS network. A part of the well-known pharmacological effects of glucocorticoid hormones (GC) as immunodepressive agents, the direct effects of many HPA axis hormones on IS functions are actually documented also in physiologic conditions. Conversely, numerous IS soluble mediators are reported to affect the HPA axis functions at various steps of HPA axis regulation, in both physiologic and pathologic conditions. Stress and aging may represent two paradigmatic conditions to show the relevance of the bidirectional network between HPA axis and IS, as in both HPA activation and IS impairment are frequently coexistent. Finally, in the context of the wide spectrum of HIV-related HPA axis abnormalities, a case of a Cushing's syndrome associated to an acquired immunodeficiency syndrome (AIDS related complex) in a 24-year-old homosexual drug abuser is reported. PMID- 7856476 TI - Leptomeningeal carcinomatosis: review of the literature. AB - Metastases from solid tumors that seed the leptomeninges (meningeal carcinomatosis) are an important neurologic complication of systemic cancer. Recently many authors have reported that its incidence is increasing; particularly it has been demonstrated for breast cancer and small cell bronchogenic carcinoma. A cytologic examination of cerebrospinal fluid (CSF) establishes the diagnosis. Gadolinium-enhanced MRI has demonstrated superiority over other imaging with the clinical context and CSF analysis may lead to a rapid diagnosis and treatment of leptomeningeal carcinomatosis. Despite all measures, prognosis remains poor because of the presence of multiple metastases elsewhere. PMID- 7856477 TI - [Synonyms, antonyms and...paronyms of urothelial lesions. Historic evolution of the concept]. PMID- 7856478 TI - [Do patients want to know the truth of their disease? Study on urologic patients]. AB - Presentation of a study, based on a survey conducted among urology patients on the extend of their wish to know the truth of their illness. The results indicate that the majority of patients DO want to know the truth, although such option is mediated by many environmental factors (such as age, sex, place of residence, education level, etc.). Some remarks are made on the lack of literature on the subject and the belief that awareness of this fact may be useful in the currently difficult physician-patient relationship. PMID- 7856479 TI - [The use of kidney grafts++ from donors of the same age or below 3 years (weight equal or below 15 Kg)]. AB - Over the last few years an impasse has been seen in the number of donors for organ transplantation. This has prompted a re-statement on the use of a group of grafts which, historically, were considered suboptimal: those from donors aged 3 years or under (weight less than or equal to 15 kg). 124 transplantations from corpse donors performed in adults over a 36 months period (Jun 90/July 93) were revised. 24 grafts (19.3%) from donors aged 3 years or under were used. Thirteen (54%) of these grafts were from donors aged 24 months or under, and six (27%) from donors aged 12 months or under. A comparative analysis is made on the clinical and functional evolution of these grafts, as well as their current survival status versus those from donors aged between 3 and 60 years (n = 86, 69.3%). Transplants made with grafts from donors older than 60 years (n = 14, 11.2%) were excluded from the analysis. Our results suggest that use of kidneys from donors aged 3 years or under--weight less than or equal to 15 kg--, implanted as units is acceptable when compared to grafts from older donors. Considering the current impasse in donations for organ transplantation we believe use of this type of donors, as a useful source of grafts, should be advocated. PMID- 7856480 TI - [Usefulness of nuclear morphometry as predictive factor of progression in bladder papillary carcinoma]. AB - Lately, nuclear morphometry methods are being used to analyze the malignant potential of tumoral cells. This paper presents a retrospective study of a series of 163 patients with the three histological grades (WHO), of superficial papillary transitional cell carcinoma (pTa-pT1) of the bladder with a mean follow up of 60 months. A morphometric analysis of the initial tumour biopsies was made. Mean nuclear area (NA) and its standard deviation (NASD) were measured in a semi automatic image analyzer (MOP-videoplan, Kontron). NA and NASD show increasingly higher values with increased grade (p < or = 0.0001). NA and NASD values raise in those progressing to muscle-infiltrant stage; tumours were, then, divided into two morphometric groups: small NA (< 50 microns 2) and large NA (> 50 microns 2); the difference between them being statistically significant. The likelihood of no tumoral progression at 30, 60 and 90 months was, respectively, 96, 94 and 92 percent, form small NAs, and 76, 65 and 64 percent for large NA (p < or = 0.0001). PMID- 7856481 TI - [Scrotal ultrasound in inflammatory lesions]. AB - Ultrasounds were performed in 45 patients with scrotal inflammatory processes. 12/15 patients with epididymitis had hypoechoic areas and 3/15 hyperechoic ares in the epididymis; hyperechoic areas were seen in 13/15 cases with epididymo orchitis, while in 2/15 patients we found hypoechoic areas in the testicle and hyperechoic in the epididymis; and in 15/15 cases with epididymo-testicular abscesses the areas found were hypoechoic of heterogeneous patterns. PMID- 7856482 TI - [Conservative approach in total multicystic renal dysplasia. Our experience]. AB - Contribution of 14 patients with Unilateral Total Multicystic Renal Dysplasia treated with conservative criteria, with particular emphasis in the absence of clinical complications, as well as the natural tendency to involution of the affected organs. Five dysplastic kidneys disappeared in the ultrasound, 4 decreased in size, 3 remained the same and 2 have been removed. Review of the literature and discussion of all the reasons why nephrectomy was traditionally indicated, explaining the reasons why we support an expecting attitude. PMID- 7856483 TI - [Urologic manifestations in patients with acquired immunodeficiency syndrome]. AB - In order to know the incidence and nature of urological conditions in the Acquired Immunodeficiency Syndrome, a revision was made of 223 clinical histories from patients admitted to our hospital between 1998 and 1992. Some 24.6% developed urological conditions with prevalence of unspecific urinary infections, though several types of specific infections, immunological, neoplastic, neurourological and nephrological changes were also found as well as other conditions not caused by the disease, such as renal lithiasis. We noted that, although involvement of urinary tract in AIDS is not well defined, its frequency is high, since up to one fourth of patients are affected by different disorders. PMID- 7856484 TI - [Functional and economic impact of the use of Wisconsin University conservation solution versus Eurocollins in relation to the period of cold ischemia in renal transplantation of cadaveric donor]. AB - Comparison of the effect of the Wisconsin University (WU) conservation solution in the graft's functional evolution and survival, and its cost-benefit relationship versus the Eurocollins (EC) solution with regard to cold ischaemia duration in a series of 142 consecutive adults renal transplantations from corpse donor, removed with beating heart. Of 142 kidneys, 92 (64.7%) were kept in WU and 50 (35.2%) in EC. Of the WU group, 62 (67.3%) kidneys were transplanted after a cold ischaemia of under 24 hours and 30 (32.6%) after cold ischaemia of more than 24 hours. In the EC group, 23 (46%) were kept in cold ischaemia for an interval shorter than or equal to 24 hours and 27 (54%) for more than 24 hours. Incidence of initial graft dysfunction (IGD) was greater in the EC groups (65% and 78%) versus the WU groups (39% and 50%), the difference being statistically significant (p). The graft function, as indicated by the creatinine levels was always better in the WU groups. There was a decreased need for complementary dialysis sessions, less days of oliguria and shorter hospitalization in the WU groups (p). There were no significant differences in the four series with regard to rejection episodes, cyclosporin-related nephrotoxicity, and vascular and urinary tract complications. All of which turn cost-effective the higher cost per litre of the WU versus the EC solution. Graft survival at 12 and 24 months was also significantly (p) higher for grafts kept in WU. This paper presents the results obtained in the analysis of our transplanted patients. In our experience, the WU solution allows better conservation of renal grafts, with less IGD and better graft survival at 12 and 24 months. These results turn cost-effective the higher cost per litre of the WU versus the EC solution. PMID- 7856485 TI - [The role of vascular radiology in the diagnosis of "suspicious" images of the upper urinary tract]. AB - Accurate diagnosis of "suspect" lesions from the Upper Urinary Tract (U.U.T.) is of major significance for implementing an appropriate treatment. There are many diseases and situations which may condition the occurrence of a suspect image, i.e., of a repletion defect of the U.U.T., in the U.I.V., the vascular imprints being just one of them. This paper contributes two cases where the suspect lesion was due to this cause and vascular radiology was decisive to reach a diagnosis. PMID- 7856486 TI - [Renal hydatidosis. Our experience]. AB - Presentation of five cases of renal hydatidic cysts. Revision of literature with regard to their clinical presentation form, diagnostic methods and surgical approach for management. PMID- 7856487 TI - [Castleman's disease, plasma-cellular variety: unusual finding in our specialty]. AB - Castleman's disease is a disorder of the lymph tissue, of undetermined etiology and with preferentially mediastinal location, although other lymphatic and extra lymphatic locations are also possible. This entry appears under two varieties: the most frequent, hyalovascular type which generally does not have associated systemic symptoms, and the plasmocellular type associated to multisystemic symptoms in up to 50% cases, such as fever, anaemia, hypergammaglobulinemia, etc. Additional examinations beyond those usually available are not enough to establish a certainty diagnosis against other types of tumours, so an histopathological study is required prior to arrive to this definite diagnosis. Surgery is the choice therapy, although sometimes a favourable response to radiotherapy, used as alternating or adjuvant therapy, can be obtained. Corticoid therapy can be an effective option when dealing with systemic symptoms. The paper submits one case of Castleman's disease of the hyalinovascular type with retroperitoneal location which forced us to establish a differential diagnosis with other disorders in that region more frequent in our specialty. Definite clinical diagnosis was not possible surgery was chosen and the entire lesion removed. As certainty diagnosis was therefore histologic and, up to this point, the patient has shown no signs or symptoms of relapsing. PMID- 7856488 TI - [Urinary retention in a child secondary to urethral uric lithiasis]. AB - Urinary lithiasis in children is less frequent than in adults. The incidence of uric acid lithiasis in adult population is between 5 to 39% of all lithiasis. Only a third part of the urinary calculi in infancy are compound of uric acid. The most frequent uric lithiasis is that so called endemic. Usually appears in the lower urinary tract and it is not related to metabolic disturbances. We present the exceptional case of an Arabian boy 4 years old who came to the Hospital because he suffered urinary retention secondary to the fixation of uric acid stone in bulbous urethra. The treatment performed was the external urethrotomy and we could removed the stone. We emphasize that the postoperative control was done by uroflowmetry. After one year, the result is satisfactory. PMID- 7856489 TI - [Cysts of the ejaculatory ducts. Diagnosis and clinical course after treatment]. AB - Confusion surrounding diagnosis of central prostate cysts is explained for the rarity of the condition. Deferento-vesiculography is diagnostic and must be performed independently (right-left) for a better anatomical evaluation of the area. The endoscopic images do not allow differential diagnosis from other prostate cysts. Recovery of bearer's fertile ability following endoscopic resection does not result, in our experience, as effective as it could be expected from resolving the obstructive cause. PMID- 7856491 TI - The American Roentgen Ray Society, 95th annual meeting. Washington, D.C., April 30-May 5, 1995. Programs and abstracts. PMID- 7856490 TI - [Superficial and infiltrating bladder tumor. Epidemiologic differences in a study of incident cases]. AB - An attempt has been made to identify the epidemiological factors associated with occurrence of biologically aggressive vesical tumours. In the Autonomous Community of La Rioja, a survey was conducted between 1975-1991 of incidental vesical tumours, recording in each case the patient's sex, age and occupation. It was found that the male sex, the sixth decade of life and being a farmer were associated to a higher incidence of vesical tumour. All this data was subsequently analyzed, segregating surface from infiltrant tumours depending on whether they affected (infiltrant) or not affected (surface) the vesical muscle layer. After both groups had been compared, no statistically significant differences were identified with regard to age, sex or occupation. The epidemiological factors associated to the occurrence of vesical tumours have no influence on its biological aggressiveness at the time of diagnosis. PMID- 7856492 TI - The price of the ticket. PMID- 7856493 TI - Congratulations Robarts parents. PMID- 7856494 TI - The interaction of race, gender and social class effects in the education of deaf students. AB - While racial effects have been noted in the education of the deaf in a variety of ways, gender effects are difficult to identify and social class effects are not discussed at all. Further, it is possible that these effects interact to produce unique effects. To examine these issues, a re-analysis of data from a longitudinal study of 451 deaf adolescents in local public schools was conducted. Results support previous observations about racial and gender effects and suggest that social class is an effect in the education of the deaf. In addition, there is very limited evidence to suggest an interaction of the effects. What is perhaps more critical is that the concept of race in relation to deaf education is an ambiguous concept and needs to be considered in light of parental income, educational attainment, and language attitudes rather than as a global concept. PMID- 7856495 TI - Educational interpreting and teacher preparation. An interdisciplinary model. AB - Educational interpreting remains the fastest growing area in the field of interpreting largely due to the Individual with Disabilities Education Act and the Americans with Disabilities Act. The United States Department of Education, Personal Preparation and Special Topics, has awarded grants to a number of organizations, agencies, colleges and universities to establish preparation programs for educational interpreters. This article describes how resources, namely the curriculum, extant in a teacher preparation program in deafness are used in establishing a four year preparation program for educational interpreters leading to a Bachelor of Science degree. The interdisciplinary model outlined follows the curriculum recommendations of the Council on Education of the Deaf/Registry of Interpreters for the Deaf Ad Hoc Committee for Educational Interpreting. PMID- 7856496 TI - Making science accessible to deaf students. The need for science literacy and conceptual teaching. AB - Upon examination of current literature, there is a noticeable disparity between suggested science teaching practice and what actually happens in the classroom. This disparity may be more pronounced in science classrooms of deaf students for several reasons discussed in this paper. Science education professionals recommend conceptual teaching, but rote, procedural teaching is often the reality. This is a call to arms for teachers of the deaf to teach science conceptually in an effort to afford deaf students more opportunities to grasp meaning and not function merely at the recall level. PMID- 7856497 TI - Issues in the use of cochlear implants with prelingually deaf children. AB - Approved for use by the Food and Drug Administration with deaf adults and prelingually deafened children above age two, the success of cochlear implants lacks supporting independent evaluative documentation. Allen et al (1993) compared hearing thresholds of profoundly deaf children with and without implants. Children with implants had an unaided threshold of 109.8 dB, which improved with the implant to 56.0 dB. Children without implants had an unaided threshold of 105.1 dB, which improved to 61.8 dB with conventional aids. Pure tone thresholds of 56.0 dB or 61.8 dB does not mean a child can process speech at that level. Lennenberg's critical stage theory (1967) represents the theoretical rationale for early implanting of prelingually deaf children. The flaw in this rationale rests on the fact that prelingually deaf children would not be acquiring English as a second language, even if the implant gave them adequate perception of English. There are strong, legitimate reasons to question the experimental implantation of prelingually deaf children, just as there are factual reasons to support it that should be considered by parents along with the possible benefits. PMID- 7856498 TI - A case study in planning staff development. What do teachers really need? AB - Through individual interviews and small focus groups, teachers, support staff, parents, students and administrators participated in a training needs assessment (TNA). The purpose of the TNA was to seek information about actual or current performance of teachers signing skills, the optimal performance desired, feelings, causes of performance problems and possible solutions from a variety of perspectives. All TNA participants provided information about how the program may help to motivate, facilitate and enhance teachers' communication skills in the classroom. The use of the TNA was an effort to collaborate with teachers rather than criticize them for their level of signing skills. The case study demonstrated that staff development alone was not the remedy for performance problems and that other factors contributed to teacher performance. PMID- 7856499 TI - Emotional indicators of deaf children on the Draw-A-Person test. AB - The purpose of this study was to test the validity of the Draw-A-Person: Screening Procedure for Emotional Disturbance (DAP:SPED; Naglieri, McNeish, & Bardos, 1991) when used with deaf children ages 9 through 12. Subjects were children with severe to profound prelingual hearing losses and at least low average intelligence. They were divided into two groups: emotionally disturbed and not emotionally disturbed based on a combination of factors. DAP:SPED group mean scores were not significantly different. In fact, the not emotionally disturbed group scored higher, or more pathological, than the emotionally disturbed group. More than half of the subjects from each group were misclassified using the DAP:SPED system. Results indicate that the DAP:SPED is not a valid screening instrument for use with deaf children and that there is a need for separate normative data for this group. PMID- 7856500 TI - Metacognitive strategies in a college world literature course. AB - Students at most reading levels in the World Literature Survey at Gallaudet University benefitted from the inclusion of metacognitive exercises in the course. These exercises emphasized pre-reading, reading, and post-reading strategies designed to improve reading comprehension and retention, but they also proved valuable as prompts to group discussion and to teacher-student communication. Results of this class approach suggest the usefulness of such exercises in "content" courses in general to improve attendance, discussion, and grades. PMID- 7856501 TI - Communicative interactions of deaf and hearing children in a day care center. An exploratory study. AB - Interactions were observed in a day care center serving deaf and hearing children. Observations focused on eight children (two deaf with deaf parents, two deaf with hearing parents, two hearing with deaf parents and two hearing with hearing parents) between 2 and 3 years of age. Center classes included deaf and hearing teachers and all children were encouraged to sign. Deaf and hearing children alike frequently interacted with other children and teachers whose hearing status differed from their own. However, each group showed a stronger tendency to initiate communication with same hearing status peers. Hearing children displayed the ability to modify their communications modes to match the hearing status of their intended communication partner. Language ability, not hearing status, was associated with the frequency of communication experienced by each child. PMID- 7856502 TI - FDA 'remains committed' to quick approval of AIDS drugs. PMID- 7856503 TI - Gene therapy and pharmacy practice: Part 2. PMID- 7856504 TI - Problems with using pharmacy computer systems--Part 2. PMID- 7856505 TI - Finding time for counseling. AB - To implement patient counseling, pharmacists must integrate new services into a significantly restructured prescription dispensing process to prevent marked reductions in efficiencies. Trying to add on counseling services--without changing existing systems--will reduce efficiency and increase unnecessary frustrations. Most pharmacy restructuring will require little or no additional expense--just changes in work flow, procedures, and functions, and/or small changes in physical layout. In a few situations, increasing efficiency may require major physical and design changes. PMID- 7856506 TI - The women's health movement: political, social, and medical issues. PMID- 7856507 TI - Management of thyroid disorders. PMID- 7856508 TI - Caution with preparing suspensions. PMID- 7856509 TI - Drawing the line: a case study in sexual harassment. Report of the American Pharmaceutical Association. PMID- 7856510 TI - Managed care: staying ahead of the pack. PMID- 7856511 TI - Bone marrow transplantation--Part 2. PMID- 7856512 TI - American Industrial Hygiene Association position statement: health care reform. PMID- 7856513 TI - The particle size distribution, density, and specific surface area of welding fumes from SMAW and GMAW mild and stainless steel consumables. AB - Particle size distributions were measured for fumes from mild steel (MS) and stainless steel (SS); shielded metal arc welding (SMAW) and gas metal arc welding (GMAW) consumables. Up to six samples of each type of fume were collected in a test chamber using a micro-orifice uniform deposit (cascade) impactor. Bulk samples were collected for bulk fume density and specific surface area analysis. Additional impactor samples were collected using polycarbonate substrates and analyzed for elemental content. The parameters of the underlying mass distributions were estimated using a nonlinear least squares analysis method that fits a smooth curve to the mass fraction distribution histograms of all samples for each type of fume. The mass distributions for all four consumables were unimodal and well described by a lognormal distribution; with the exception of the GMAW-MS and GMAW-SS comparison, they were statistically different. The estimated mass distribution geometric means for the SMAW-MS and SMAW-SS consumables were 0.59 and 0.46 micron aerodynamic equivalent diameter (AED), respectively, and 0.25 micron AED for both the GMAW-MS and GMAW-SS consumables. The bulk fume densities and specific surface areas were similar for the SMAW-MS and SMAW-SS consumables and for the GMAW-MS and GMAW-SS consumables, but differed between SMAW and GMAW. The distribution of metals was similar to the mass distributions. Particle size distributions and physical properties of the fumes were considerably different when categorized by welding method. Within each welding method there was little difference between MS and SS fumes. PMID- 7856514 TI - Estimation of regional pulmonary deposition and exposure for fumes from SMAW and GMAW mild and stainless steel consumables. AB - The particle size distributions and bulk fume densities for mild steel and stainless steel welding fumes generated using two welding processes (shielded metal arc welding [SMAW] and gas metal arc welding [GMAW]) were used in mathematical models to estimate regional pulmonary deposition (the fraction of each fume expected to deposit in each region of the pulmonary system) and regional pulmonary exposure (the fraction of each fume expected to penetrate to each pulmonary region and would be collected by a particle size-selective sampling device). Total lung deposition for GMAW fumes was estimated at 60% greater than that of SMAW fumes. Considering both the potential for deposition and the fume specific surface areas, it is likely that for equal exposure concentrations GMAW fumes deliver nearly three times the particle surface area to the lungs as SMAW fumes. This leads to the hypothesis that exposure to GMAW fumes constitutes a greater pulmonary hazard than equal exposure to SMAW fumes. The implications of this hypothesis regarding the design of future health studies of welders is discussed. PMID- 7856515 TI - Acute exposure to acid fog: influence of breathing pattern on effective dose. AB - Concern about the possible adverse health effects of acid fog has been fed by two observations: air pollution disasters earlier in this century were typically associated with fog, and current samples of fog water can be strongly acid. To study the acute effects of acid fog on the lung, the authors generated a monodisperse 10 microM MMAD aerosol of H2SO4 with a pH of 2.0 and a nominal concentration of 500 micrograms/m3. They exposed seven healthy young men on alternate days to acid or control equiosmolar NaCl aerosol during 40 min of resting ventilation and 20 min of exercise; the latter was sufficiently intense to induce oronasal breathing. Exposure was by means of a head dome, a head-only exposure device that permitted continuous measurement (unfettered breathing) of Vr, f, VE, and the onset and persistence of oronasal breathing. In this article the authors compare the relative importance of parameters contributing to the between-subject variability in estimated hydrogen ion dose to the lower airways (H+LAW), based on analysis of variance. Physiologic parameters accounted for 70% of the variability, of which 34% was due to differences in duration of oronasal breathing (tON) and 36% to differences in ventilation rate during oronasal breathing (VE(ON)); inhaled hydrogen ion concentration [H+], the environmental parameter, contributed only 30%. Minute ventilation at the time of transition from nasal to oronasal breathing varied significantly among subjects even if normalized to FVC, an index of lung size. PMID- 7856516 TI - Evaluation of an infrared open-path spectrometer using an exposure chamber and a calibration cell. AB - This study evaluated the use of a controlled exposure chamber and calibration cell to investigate the performance of open-path remote sensing instruments for workplace monitoring of pollutants. An open-path infrared spectrometer was deployed in a chamber, and a range of homogeneous air concentrations were generated using the tracer gas sulfur hexafluoride (SF6). Open-path measurements were compared with point-sample measurements taken along the beam and analyzed using an infrared (IR) and electron capture detector (ECD). A five-compartment calibration cell placed in the optical path was used to simulate heterogeneous concentrations of pollutants. Fifteen concentration patterns were created by injecting different volumes of SF6 into each compartment. Open-path spectrometer measurements were compared with compartment concentrations measured using an ECD. Results indicated that stable homogeneous and heterogeneous concentrations of SF6 were generated in the controlled exposure chamber and five-compartment calibration cell, respectively. Overall, individual open-path measurements were within 20% of point samples measured with the IR and ECDs. The open-path spectrometer measurements had a consistent positive bias of about 12%. Exposure chamber experiments uncovered remote sensing instrument design aspects that could adversely impact its use for indoor monitoring. The weight and size of the instrument make it useable only in a fixed position, thus limiting spatial coverage of the beam in a room. The instrument components were not air-tight, resulting in overestimation of some open-path concentrations. A controlled test chamber and a long calibration cell placed in the optical path are useful tools for evaluating a variety of open-path spectrometer instrument performance issues relevant to industrial hygiene monitoring. PMID- 7856518 TI - A case study of dermatitis based on a collaborative approach between occupational physicians and industrial hygienists. AB - An example of interdisciplinary problem solving by occupational health professionals is presented. Approximately one dozen employees in an aircraft wire harness assembly line complained of dermatitis, alleging workplace exposures as causation. The plant's and consulting industrial hygienists prepared toxicology and exposure assessments for all process materials, manufacturing procedures, and protective equipment used. They identified no common elements in the work environment that may have caused the dermatitis, suggesting multiple causation and possible individual worker sensitivities. An investigative team composed of the industrial hygienists and physicians in outside practice, including dermatologists and occupational medicine physicians, conducted a review of plant operations and proposed that workers with dermatitis complaints receive diagnostic medical examinations. An initial examination medically documented each worker's complaint, and a follow-up included patch testing for selected process materials. The physicians diagnosed a variety of mainly nonoccupationally induced illnesses such as fungal infections, skin cancer (solar induced), acne, etc., confirming the industrial hygienists' original assessment. One case appeared directly work-related and to be a specific assembly component sensitivity. Although several cases with a nonoccupational origin could have been aggravated by working conditions, these workers showed no sensitivity to the component when patch tested. PMID- 7856517 TI - Toxicological and chemical evaluation of emissions from carpet samples. AB - This study investigated findings that the off-gassing of certain carpets caused sensory and pulmonary irritation, changes in neurobehavioral signs, and death in exposed mice. Two standard test method measures--one for estimating sensory irritancy (ASTM-E981-84), the other for evaluating the neurotoxic potential of chemicals (functional observational battery)--were coupled with a postmortem assessment to ascertain the mechanism of toxicity. The postmortem evaluation included measurements of hemoglobin, serum clinical chemistries, blood and lung lavage white cell counts and differential, organ weights, and a gross necropsy with a microscopic evaluation of all major organs. The study evaluated three treatment groups composed of two preheated carpet emission exposures and one preheated air-control exposure. No toxic effects were associated with exposure to the off-gassing of the two tested carpets. Clinical chemistry and histopathological alterations were observed with exposure to either filter-air or carpet when compared to nonexposed unrestrained control mice, indicating that the exposure procedure caused significant effects unrelated to carpet emissions. A detailed chemical and microbial evaluation of the carpets and carpet emissions showed volatile organic compounds, pesticide residues, and microbiological flora, but at insufficient quantities to result in acute toxicity. Based on this assessment, there was no indication that exposure to emissions from these two carpets poses a serious health risk. PMID- 7856519 TI - Time-dependent hematological changes in workers exposed to electromagnetic fields. AB - A World War II-era study, involving the effects of electromagnetic fields (EMFs) emanating from radars and high-frequency radios on the blood of exposed workers, was analyzed for evidence of the effect of time in the manifestation of changes in the hematological system. Statistically significant correlations between increasing white blood cell count and average daily exposure, months of exposure, and total duration of exposure to EMFs were found. Changes in cell count were within the normal range, and thus their relation to epidemiological studies linking EMFs and leukemia, if any, is unclear. Results suggest that the time of exposure may be an additional factor (along with field strength, and perhaps frequency) in ascertaining the safety of EMF exposure. PMID- 7856520 TI - Magnesium therapy in acute myocardial infarction when patients are not candidates for thrombolytic therapy. AB - Thrombolytic therapy reduces in-hospital mortality. However, 70% to 80% of patients do not receive thrombolysis and their in-hospital mortality is high. During the last decade some clinical trials demonstrated that magnesium sulfate reduced in-hospital mortality. The aim of this study was to evaluate the effects of magnesium sulfate in patients with acute myocardial infarction (AMI) who were considered unsuitable for thrombolytic therapy. Intravenous magnesium sulfate was evaluated in 194 patients with AMI ineligible for thrombolytic therapy in a randomized, double-blind, placebo-controlled study. Group I consisted of 96 patients who received 48-hour intravenous magnesium. Group II consisted of 98 patients who received isotonic glucose as a placebo. Magnesium reduced the incidence of arrhythmias, congestive heart failure, and conduction disturbances compared with placebo (27% vs 40%, p = 0.04; 18% vs 23%, p = 0.27; 10% vs 15%, p = 0.21, respectively). Left ventricular ejection fraction 72 hours and 1 to 2 months after admission was higher in patients who received magnesium sulfate than in those taking placebo (49% vs 43% and 52% vs 45%; p = 0.01, respectively). In hospital mortality was significantly reduced in patients receiving magnesium sulfate than in those receiving placebo (4% vs 17%; p < 0.01), and also in the subgroup of elderly patients (> 70 years) (9% vs 23%; p = 0.09). In conclusion, magnesium sulfate should be considered as an alternative therapy to thrombolysis in patients with AMI. PMID- 7856521 TI - Regional myocardial sympathetic dysinnervation in patients with coronary vasospasm. AB - The purpose of this study was to assess the presence and location of impaired myocardial sympathetic innervation by using 123I metaiodobenzylguanidine (123I MIBG) in 15 patients with coronary vasospasm induced by intracoronary acetylcholine. The results were compared with those using thallium-201 (Tl-201). We also examined 14 patients with severe coronary stenosis (> 90%) and 8 control subjects without significant coronary stenosis (< 50%) and provokable coronary vasospasm. Regional myocardial sympathetic dysinnervation was detected by 123I MIBG single-photon emission computed tomography (SPECT) in all patients with coronary vasospasm, despite normal uptake during Tl-201 SPECT. This regional uptake-mismatch between 123I MIBG and Tl-201 Spect occurred specifically in the vasospasm group (p < 0.001 vs stenosis and control groups). Moreover, regional myocardial sympathetic dysinnervation was located in the distribution of perfusion in 25 of the 27 vasospasm-induced vessels. Normal uptake of 123I MIBG was observed in the perfused areas in 16 of the 18 non-vasospasm-induced vessels. The sensitivity ans specificity of 123I MIBG for detection of coronary vasospasm were 92% and 88% respectively. In patients with coronary vasospasm, we found regional myocardial sympathetic dysinnervation to be present. Furthermore, we were able to distinguish these patients from patients with critical coronary stenosis by 123I MIBG and Tl-201 SPECT. PMID- 7856522 TI - Balloon angioplasty versus rotational angioplasty in chronic coronary occlusions (the BAROCCO study). AB - Chronic total coronary occlusion remains one of the limitations of percutaneous transluminal coronary angioplasty, and few therapeutic devices are specifically designed to address this problem. Among such devices, low-speed rotational angioplasty could improve the primary success rate of the procedure but has never been studied in a controlled trial. One hundred consecutive patients with total coronary occlusion (duration 10 days to 1 year) and an indication for myocardial revascularization were randomized to either rotational or conventional angioplasty if the occlusion morphology was judged suitable for either technique. All baseline variables were evenly distributed among the 2 groups. The primary success rate in the rotational angioplasty groupo was 66% (33 of 50) compared with 52% (26 of 50) in the conventional angioplasty group before crossover to the rotational technique (p=NS). According to lesion morphology, the respective primary success rates were 77% (10 of 13) versus 92% (11 of 12) for tapered occlusions (p=NS), and 61% (22 of 36) versus 38% (14 of 37) for "stump-like" occlusions (p < 0.05). After taking into account the crossovers after failed conventional angioplasty, there was no benefit in performing rotational angioplasty first versus conventional angioplasty first (primary success rates 66% vs 60%, p=NS). Thus, in chronic coronary occlusions of tapered morphology, rotational angioplasty is not superior to conventional angioplasty. In stump-like occlusions, the primary success rate is higher with the rotational angioplasty technique; however ther is a disadvantage in using rotational angioplasty as a second-line device if the conventional technique is unsuccessful. PMID- 7856523 TI - Microvascular angina pectoris in hypertensive patients with left ventricular hypertrophy and diagnostic value of exercise thallium-201 scintigraphy. AB - In a series of 120 hypertensive patients, 60 were found to have echocardiographic left ventricular (LV) hypertrophy (Devereux's method). Of these, 18 (30%) had typical stress-induced angina and underwent coronary angiography, which showed that 11 (61%) had normal coronary arteries, and 7 (39%) (p < 0.05) had coronary stenosis of the epicardial arteries. Stress-rest thallium-201 scintigraphy (Burow's quantitative method) yielded abnormal results in 21 of the 60 patients with LV hypertrophy. Five of 30 (17%) were asymptomatic, 14 of 18 (78%) had angina, and 2 of 12 (17%) had dyspnea on exertion. In 5 normal patients used as a control group, coronary flow reserve after administration of papaverine (10 coronary arteries) was 6.25 +/- 1.4 versus 3.7 +/- 0.8 in 10 thallium-negative, asymptomatic hypertensive patients with LV hypertrophy (p < 0.001). The mean coronary flow reserve of 21 patients with abnormal thallium-201 results was 2.71 +/- 0.96 (p < 0.01 compared with the group with normal thallium-201 findings) and 2.5 +/- 0.6 in the segments with lowest uptake (p < 0.05 compared with normal segments in these same patients). Thus, stress-induced angina pectoris in hypertensive patients with LV hypertrophy was due to small-vessel disease in over half of our patients (62%). PMID- 7856524 TI - Effects of cardiac rehabilitation and exercise training on exercise capacity, coronary risk factors, behavioral characteristics, and quality of life in women. AB - Despite the known benefits of cardiac rehabilitation, limited data are available on the outcome of this treatment in women, and this secondary prevention strategy may be underutilized. To assess the gender differences in baseline exercise capacity, indexes of obesity, lipid profiles, behavior characteristics, and components of quality of life, as well as the improvements in these components after a secondary prevention program, we retrospectively reviewed data from 458 patients (83 women and 375 men) enrolled in a phase II cardiac rehabilitation and exercise program after a major cardiac event. At baseline (6 weeks after the cardiac event and before rehabilitation), exercise capacity (-9%, p = 0.08) and ratio of low-density lipoprotein cholesterol/high-density lipoprotein cholesterol (-14%, p < 0.01) were lower, but total cholesterol (+7%, p < 0.01), high-density lipoprotein cholesterol (+25%, p < 0.0001), low-density lipoprotein cholesterol (+8%, p < 0.01), and percent body fat (+15%, p < 0.0001) were higher in women than in men with coronary artery disease. In addition, with regard to quality of life, women had lower scores for energy (p = 0.06), function (p < 0.01), and total quality of life (p < 0.05) than men. After cardiac rehabilitation and exercise training, women had significant improvements in exercise capacity (+33%, p < 0.0001) and percent body fat (-7%, p < 0.001), which compared favorably with the improvements (+40% and -5%, respectively) seen in men, but improvements in body mass index and lipids were not statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7856525 TI - Coronary stenting with angioscopic guidance. AB - Coronary angioscopy can directly visualize luminal morphology and stent architecture. This new technology may provide insights into the stent mechanism of action and help guide stent procedures. Visualization of the target vessel segment with a 4.5Fr angioscope was attempted before and/or after Palmaz-Schatz coronary stent implantation in 50 patients. The target vessel segment was successfully visualized in 48 patients (96%). In 24 patients, angioscopy was performed both after balloon angioplasty and then again after stenting. In 16 of these 24 patients a dissection was documented by angioscopy after balloon angioplasty, and in each patient the dissection was absent after stenting. Angioscopy influenced the clinical management of 18 (37.5%) patients. Clinical decisions directly influenced by angioscopy included intracoronary thrombolytic therapy for thrombus visualized angioscopically, which had been unsuspected by angiography (n = 7), withholding intracoronary thrombolytic therapy for patients with suspected thrombus not confirmed by angioscopy (n = 4), repeat angioplasty in patients in whom plaque was found to be bulging into the lumen at the stent articulation site (n = 4), additional stents placed when angioscopy revealed significant proximal or distal disease (n = 4), or an unsuspected gap between 2 tandem stents (n = 1). Coronary angioscopy safely visualized stented vessel segments in most patients. Angioscopic observations provided insights into the stent mechanism of action and, in some cases, influenced clinical management. PMID- 7856527 TI - Neurohumoral variability in left ventricular dysfunction. SOLVD Investigators. Studies of Left Ventricular Dysfunction. AB - The immediate and longer term variability of selected vasoactive- and volume regulating neurohormones were measured in patients entering a substudy of the Studies of Left Ventricular Dysfunction--a randomized clinical trial in patients with left ventricular ejection fraction < or = 35%. The variability of these hormones has not been determined in a large cohort of patients. Immediate (short term) variability was assessed by systematically comparing levels after 15 and 30 minutes of supine rest at the initial visit, and longer term variability was assessed by comparing 30-minute supine rest values at the initial visit with corresponding values taken at 30 minutes after 16 to 24 days of stable therapy. Initial values obtained at the first visit after 30-minute supine rest for all 209 patients were (mean +/- SEM) 512 +/- 21 pg/ml pg/ml for plasma norepinephrine, 1.9 +/- 0.2 ng/ml/hr for plasma renin activity, 3.0 +/- 0.1 pg/ml for plasma arginine vasopressin, and 129 +/- 5.3 pg/ml for plasma atrial natriuretic peptide. All variables were moderately increased relative to established normal values. There was a small but significant decrease from 15- to 30-minute supine posture in all neurohormones, except arginine vasopressin. In the presence of stable background therapy, no significant differences were found between measurements obtained after 30 minutes supine rest at the initial visit and 16 to 24 days later. Spearman correlation coefficients corresponding to immediate and longer term variability were high (range 0.55 to 0.79) (p < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7856526 TI - Comparison of gemfibrozil versus simvastatin in familial combined hyperlipidemia and effects on apolipoprotein-B-containing lipoproteins, low-density lipoprotein subfraction profile, and low-density lipoprotein oxidizability. AB - We evaluated in a double-blind, placebo-controlled, randomized trial of 45 well defined patients with familial combined hyperlipidemia, the effect of gemfibrozil (1,200 mg/day) or simvastatin (20 mg/day) on apolipoprotein-B (apo-B)-containing lipoproteins, low-density lipoprotein (LDL) subfraction profile, and LDL oxidizability. Although both drugs reduced plasma cholesterol and triglyceride concentrations, gemfibrozil reduced plasma triglycerides more effectively and simvastatin reduced plasma cholesterol more effectively. LDL cholesterol was reduced with simvastatin. With both drugs, total serum apo-B concentration decreased. With gemfibrozil, this was due to an exclusive reduction (-46%) of very low/intermediate-density lipoprotein (VLDL + IDL) apo-B, whereas simvastatin decreased apo-B in both VLDL + IDL and LDL (34% and 15%, respectively). Initially, a dense LDL subfraction profile was present in all patients. The decrease in LDL cholesterol with simvastatin was due to a decrease in all isolated LDL subfractions except LDL2; gemfibrozil increased LDL1 and LDL2 cholesterol (p = 0.001) and reduced LDL4 cholesterol, resulting in a more buoyant LDL subfraction profile compared with simvastatin. In both groups, a predominance of small dense LDL remained despite therapy. LDL fatty acid composition showed a shift from oleic acid to linoleic acid after gemfibrozil; arachidonic acid increased after simvastatin. Vitamin E was lower after gemfibrozil. In the measurements of LDL oxidation, only the oxidation rate was significantly reduced with simvastatin. Thus, quantitative and qualitative changes of LDL cholesterol had only a small effect on total in vitro LDL oxidizability in this population with familial combined hyperlipidemia. PMID- 7856528 TI - Hemodynamic and energetic comparison of bucindolol and metoprolol for the treatment of congestive heart failure. AB - Although beta blockers have demonstrated a salutary effect on ventricular function in patients with heart failure, it is unclear whether a nonselective third-generation beta blocker produces different hemodynamic and energetic effects than a second-generation beta 1 selective agent. In 30 male patients with heart failure, we retrospectively analyzed hemodynamic data from 2 protocols examining the effects of a nonselective beta antagonist bucindolol (n = 15), and a highly selective beta 1 antagonist metoprolol (n = 15). Both studies were conducted in a similar fashion with patients undergoing cardiac catheterization before and after receiving 3 months of beta blockade. Both groups were matched at baseline in terms of ventricular function. beta blockade resulted in similar reductions in heart rate and similar improvements in ejection fraction, ventricular volumes, stroke and minute work, peak +dP/dt, and isovolumic relaxation in both groups. Only patients taking bucindolol had a significant within-group decrease in resting left ventricular end-diastolic pressure. The metoprolol group had a greater decrease in coronary sinus blood flow and myocardial oxygen consumption. Bucindolol increased cardiac index more than metoprolol, but did not increase stroke volume index more than metoprolol. The bucindolol group had an increase in systolic elastance, whereas the metoprolol group had a parallel left shift in this relation. Thus, metoprolol reduces coronary blood flow and myocardial oxygen consumption more than bucindolol, whereas bucindolol produces slightly more favorable improvements in resting cardiac index and end-diastolic pressure. Otherwise, these 2 agents produced similar hemodynamic changes. PMID- 7856529 TI - Evaluation of mitral stenosis with velocity-encoded cine-magnetic resonance imaging. AB - Velocity-encoded cine-magnetic resonance imaging (VEC-MRI) is a new method for quantitation of blood flow with the potential to measure high-velocity jets across stenotic valves. The objective of this study was to evaluate the ability of VEC-MRI to measure transmitral velocity in patients with mitral stenosis. Sixteen patients with known mitral stenosis were studied. A 1.5 Tesla superconducting magnet was used to obtain velocity-encoded images in the left ventricular short-axis plane. Images were obtained throughout the cardiac cycle at 3 consecutive slices beginning proximal to the mitral coaptation point. To determine the optimal slice thickness for MRI imaging, both 10 mm and 5 mm thicknesses were used. Echocardiography including continuous-wave Doppler was performed on every patient within 2 hours of MRI imaging. Peak velocity was determined for both VEC-MRI and Doppler-echo images. Two observers independently measured the VEC-MRI mitral inflow velocities. Of the 16 patients, imaged data were incomplete in only 1 study, and all images were adequate for analysis. Strong correlations were found for measurements of mitral valve gradient for both 10 mm (peak r = 0.89, mean r = 0.84) and 5 mm (peak r = 0.82, mean r = 0.95) slice thicknesses. Measurements of peak velocity with VEC-MRI (10 mm) agreed well with Doppler: mean 1.46 m/s, mean of differences (Doppler MRI) 0.38 m/s, standard deviation of differences 0.2 m/s. These findings suggest that VEC-MRI can noninvasively determine the severity of mitral stenosis. PMID- 7856530 TI - Single-stage repair of aortic arch obstruction and associated intracardiac defects in the neonate. AB - The effectiveness of a single-stage anterior approach for the repair of aortic arch obstruction and associated intracardiac defects has not been well evaluated. We therefore reviewed our experience with 60 neonates (median age 8 days, range 1 to 28) who underwent a single-stage repair by way of a median sternotomy at our institution between 1986 and 1994. Nineteen (32%) had coarctation with ventricular septal defect, 18 (30%) had interrupted aortic arch with ventricular septal defect, and 23 (38%) had coarctation or interrupted aortic arch with complex intracardiac anatomy. The arch obstruction was repaired using resection and primary anastomosis in 54 patients, synthetic patch aortoplasty in 3, subclavian flap aortoplasty in 2, and an interposition gortex graft placement in 1. Total circulatory arrest time was 48 +/- 3 minutes (mean +/- SEM). There were 7 early postoperative deaths (11.7%; 70% confidence limit 8% to 16.6%). The 53 survivors were followed for a mean of 23 months (range 1 to 78), for a total of 1,219 patient-months. Recurrent arch obstruction > or = 20 mm Hg has occurred in 2 of 53 patients (3.8%; 70% confidence limit 1.9% to 7.5%); both underwent successful balloon angioplasty. There were 2 late deaths, 1 of which was noncardiac. We conclude that repair of aortic arch obstruction and intracardiac defects by a single-stage approach through median sternotomy can be accomplished with low mortality in infancy, even with associated complex intra-cardiac anatomy. Recurrent coarctation is relatively uncommon and can be successfully managed with balloon angioplasty. PMID- 7856531 TI - Understanding right and left ventricular systolic function and interactions at rest and with exercise in primary pulmonary hypertension. AB - The effort limitation in primary pulmonary hypertension (PPH) is thought to result from an inability to increase cardiac output with exercise. The precise mechanism, however, is unknown. We studied right ventricular (RV) and left ventricular (LV) function and interactions in 16 patients with PPH with electron beam computed tomography (EBCT) at rest and during supine bicycle exercise. RV and LV volumes and masses were measured at systole and diastole, and ejection fraction and cardiac index computed. Resting RV end-diastolic volume (215 +/- 72 ml) and mass (110 +/- 45 g) were increased, whereas stroke volume (65 +/- 26 ml) and ejection fraction (31 +/- 8%) were decreased. LV end-diastolic volume (80 +/- 31 ml) was decreased, whereas ejection fraction remained normal (66 +/- 9%). Cardiac index was at the lower limit of normal (2.26 +/- 0.72 L/min/m2). During exercise, RV end-diastolic volume was unchanged (196 +/- 63 ml, p = NS) but stroke volume (52 +/- 29 ml, p < 0.05) and ejection fraction (26 +/- 10%, p = 0.08) decreased. LV end-diastolic (52 +/- 22 ml, p < 0.001), end-systolic (17 +/- 8 ml, p < 0.001), and stroke volumes (35 +/- 20 ml, p < 0.001) decreased, whereas ejection fraction (65 +/- 15%, p = NS) and cardiac index remained unchanged (2.17 +/- 0.93 L/min/m2, p = NS). the ratio of RV/LV stroke volume at rest (1.21 +/- 1.06) increased with exercise (1.74 +/- 1.13, p = 0.09).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7856532 TI - Incidence of specific etiology and role of methods for specific etiologic diagnosis of primary acute pericarditis. AB - To assess the incidence of a specific etiology and the role of methods for specific etiologic diagnosis in patients with primary acute pericarditis, we studied 100 patients with primary acute pericarditis consecutively admitted to our hospital between 1991 and 1993. A general diagnostic protocol was performed in all patients, whereas only pericardiocentesis was performed in patients with clinical cardiac tamponade or an unfavorable course with anti-inflammatory drugs. Surgical drainage and pericardial biopsy was performed in patients with tamponade relapse. A specific etiology was discovered in 22 patients (22%) (neoplasms in 7, tuberculosis in 4, other infections in 3, collagen diseases in 3, thyroid disorders in 4, and dissecting aortic aneurysm in 1). The general diagnostic protocol led to a specific diagnosis in 15 patients (68% of all patients with specific acute pericarditis) and pericardiocentesis in the other 7 patients (32%). The role of a diagnostic protocol, therapeutic pericardiocentesis, and diagnostic pericardiocentesis was similar and complementary. Pericardial biopsy results were negative in the 5 patients in whom it was performed. Cardiac tamponade and an unfavorable clinical outcome were significantly (p < 0.001) associated with the finding of a specific etiology; when both features were combined, sensitivity was 86% and specificity 85%, positive predictive value 63% and negative predictive value 96%. We conclude that the specific etiology in patients with primary acute pericarditis is about 20% to 25%, and that about 90% of these specific cases can be discovered by using the described systematic diagnostic protocol only in patients with an unfavorable outcome (cardiac tamponade or poor clinical course). PMID- 7856533 TI - Noninvasive estimation of pulmonary arterial wedge pressure with Doppler transmitral flow velocity pattern in patients with known heart disease. AB - Pulmonary arterial wedge pressure (PAWP) is an important marker of cardiac function. Regrettably, it requires catheterization, which can occasionally result in serious complications. A noninvasive method of estimating PAWP would thus be helpful. Recent studies have indicated that the Doppler transmitral flow velocity pattern was strongly dependent on preload and could provide an estimate of PAWP. This study was therefore designed to evaluate the relation between doppler transmitral flow velocity indexes and measured PAWP in 91 patients (learning group: 73 men, mean age 57 +/- 13 years) with ischemic heart disease (n = 41), dilated (n = 29) or hypertrophic cardiomyopathy (n = 4), or aortic stenosis (n = 17). Multiple regression analysis was used to derive an equation for estimation of PAWP, which was subsequently tested in a separate group of 33 patients (testing group: 28 men, mean age 58 +/- 12 years) with similar cardiac conditions. PAWP ranged from 4 to 48 mm Hg in the learning group and from 7 to 40 mm Hg in the testing group. In the learning group, PAWP correlated with the E/A ratio (r = 0.95), atrial filling fraction (r = -0.80), peak E velocity (r = 0.79), isovolumic relaxation period (r = -0.75), and deceleration time (r = 0.61). In the learning group, PAWP was best predicted as PAWP = 18.4 + [17.1.In(E/A ratio)]. This equation allowed prediction of PAWP within 3 mm Hg of the measured value in 24 of 33 patients (73%) in the testing group. In 8 additional patients, the equation also accurately predicted the changes in PAWP induced by volume loading or intravenous nitrates (r = 0.98).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7856534 TI - Supervision of clinical exercise testing by exercise physiologists. PMID- 7856535 TI - Randomized trials of magnesium in acute myocardial infarction: big numbers do not tell the whole story. PMID- 7856536 TI - Usefulness of coronary wedge pressure in evaluating coronary collateral circulation in anterior wall acute myocardial infarction. PMID- 7856537 TI - Myocardial perfusion pattern in patients with cocaine-induced chest pain. PMID- 7856538 TI - Serial intravascular ultrasound studies fail to show evidence of chronic Palmaz Schatz stent recoil. PMID- 7856539 TI - Abnormal uptake and washout of thallium-201 in patients with syndrome X and normal-appearing scans. PMID- 7856540 TI - Monomorphic versus polymorphic ventricular tachycardia after coronary artery bypass grafting. PMID- 7856541 TI - Natural history and management strategies of automatic atrial tachycardia in children. PMID- 7856542 TI - Acquired coronary artery fistulae after right ventricular myotomy and/or myomectomy for congenital heart disease. PMID- 7856543 TI - Characteristics and outcome in arrhythmogenic right ventricular dysplasia. PMID- 7856544 TI - Effects of paced counterpulsation on exercise capacity and hemodynamics after heterotopic heart transplantation. PMID- 7856545 TI - Diminished respiratory muscle endurance persists after cardiac transplantation. PMID- 7856546 TI - Reversal of hirudin-induced bleeding diathesis by prothrombin complex concentrate. PMID- 7856547 TI - Exercise-induced precordial ST depression in prior inferior myocardial infarction. PMID- 7856548 TI - Trans-fatty acid patterns in patients with demonstrated coronary artery disease. PMID- 7856549 TI - The future of clinical pathology. Arbiter of quality and gatekeeper of laboratory resources. PMID- 7856550 TI - Histologic grading of breast cancer. Let's do it. PMID- 7856551 TI - Monitoring blood glucose meters. PMID- 7856552 TI - Graylyn Conference Report. Recommendations for reform of clinical pathology residency training. Conjoint Task Force of Clinical Pathology Residency Training Writing Committee. AB - The Graylyn Conference Report of the conjoint ACLPS, ASCP, APC, and CAP task force is prompted by the growing realization that without reform of the clinical pathology residency curriculum the future of clinical pathology practice may be in jeopardy. The conclusions reached at the ASCP-sponsored Colorado Springs IV Conference on Clinical Pathology Residency Training laid the groundwork for this report on curriculum reform. The goal is the creation of scientifically oriented clinical pathology practitioners capable of serving as consultants to other physicians of managing laboratory resources, and of playing leadership roles in an increasingly complex health-care system. Recommendations are described under the headings of patient care roles, graduated responsibility, analytical and technical training, laboratory management and informatics, and basic and applied research. In terms of reforming the structure and content of the curriculum, it is recommended that basic laboratory rotations be preceded by either a single didactic general 4- to 6-week orientation, or a series of shorter orientations incorporated into each rotation. The introductory and rotation phase should be 9 to 12 months in duration. It is further recommended that the remaining 6 to 9 months of the 18-month core be an integrated experience in which the resident practices Clinical Pathology by assuming service responsibilities for several laboratory sections simultaneously. PMID- 7856553 TI - Specific immunohistochemical identification of Candida albicans in paraffin embedded tissue with a new monoclonal antibody (1B12). AB - In invasive candidiasis, the identification of Candida organisms in tissue samples or in normally sterile fluids is essential for an accurate diagnosis. Species identification is an important clue for the source of infection and in epidemiological studies. In this article, the authors have tested the value of a new monoclonal antibody (1B12) to detect C albicans in culture by immunofluorescence, and in tissue samples by immunohistochemistry. MAb 1B12 was found to specifically recognize C albicans, does not cross-react with other Candida species or other structurally similar fungi, and is very sensitive and specific in paraffin-embedded tissue, having no reactivity in normal human tissues or necrotic areas. Therefore, MAb may be a valuable tool in the evaluation of fungal infections in paraffin-embedded tissue, particularly when Candida species identification is needed. PMID- 7856554 TI - Hepatitis B E antigen detection in formalin-fixed liver biopsy specimens. A tool to investigate wild-type and E-minus variant HBV infection. AB - The aim of this study is to investigate whether hepatitis B e antigen (HBeAg) reactivity can be detected on formalin-fixed, paraffin-embedded liver tissue, and whether immunohistochemical detection of intrahepatic HBeAg may help to distinguish between "wild-type" and "eminus" hepatitis B virus (HBV) infection. Liver biopsy specimens were analyzed from 27 patients with chronic type B hepatitis: 12 patients had serum HBeAg (group A), and 15 patients were anti-HBe positive (group B). Part of each biopsy fragment was processed for histologic and immunohistochemical studies, and a part was used for HBV-DNA analysis. Dewaxed sections from each specimen were tested with a specific monoclonal anti-HBe antibody; then a Biotin-Streptavidin kit was used as detection system. HBeAg was revealed in 10 of 12 cases of group A and in 6 of the 15 cases of group B. Pre core region of HBV genomes, isolated from each biopsy specimen, was analyzed by direct sequencing: 10 cases of group A were found to be infected by wild-type HBV alone and 2 cases by both wild and e-minus HBV types. In group B, all the 6 cases with intrahepatic HBeAg reactivity were found to be infected by mixed viral population, whereas the 9 cases negative for such reactivity were found to be infected by e-minus HBV alone. These results show that HBeAg can be detected in formalin-fixed, paraffin-embedded liver specimens, and the method is sensitive and specific. Because the presence of HBeAg in the liver indicates a wild-type HBV infection, and the lack of detection of such antigen in the hepatocytes of anti-HBe positive subjects correlates with unmixed e-minus HBV infection, the authors conclude that this technique is a useful tool for recognizing the viral strains that infect patients with chronic type B hepatitis. PMID- 7856555 TI - Evaluation of culture conditions used for isolation of Chlamydia pneumoniae. AB - As only a few viable strains of the frequent respiratory pathogen Chlamydia pneumoniae have been isolated worldwide, improvement and standardization of isolation procedures is mandatory for adequate diagnosis and recovery of strains for further investigation. Growth rates of eight C pneumoniae strains were assessed for five host cell lines, for the growth-promoting effect of host cell cytostasis, for infection of adherent or suspended host cells, for optimal first passage incubation time, and for use of multiple blind passages. Cycloheximide treated HEp-2 or NCI-H 292 monolayers appeared most sensitive for isolation of C pneumoniae. No significant improvement of sensitivity was achieved by extending first passage incubation periods from 3 to 7 days. In contrast, continuous propagation in 4 culture passages yielded on average a 7-fold enhanced chlamydial recovery. Additional comparative isolation of two wild-type strains showed highest inclusion counts in HEp-2 cells, but subculture was necessary for optimal sensitivity. A widely applicable protocol using tissue culture plates for isolation of C pneumoniae is suggested. PMID- 7856556 TI - Practice guidelines for ordering stool cultures in a pediatric population. Alberta Children's Hospital, Calgary, Alberta, Canada. AB - A comprehensive utilization review was done of all stool culture tests performed at a pediatric hospital during a 3-year period from June 1, 1989 through to July 1, 1992. A total of 4,460 stool culture specimens were surveyed from 3,420 children. Sixty percent (2,692) of the workload was from inpatients, 22% (1,001) was from emergency room (ER) visits and 18% (767) was from outpatient clinic/office visits. A total of 9% (294 of 3,420) of the children were confirmed to have enteric bacterial infection. Enteric infections in Southern Alberta follow a typical pattern, where most cases of Escherichia coli O157:H7, Salmonella sp and Campylobacter jejuni are diagnosed in the summer months between June and September. Marked differences were found in the overall stool culture positivity rate between hospitalized children (94 of 2,141, 4%), and ambulatory children attending the ER (176 of 892, 19%). Although a significant number of children had more than one stool culture done, most cases of enteric bacterial infections were diagnosed on the first stool sample (290 of 294, 98%). Most children (89 of 94, 95%) who were hospitalized because of an acute diarrheal illness had a bacteriological diagnosis confirmed within the first 4 days after admission (90 of 94, 96%), including immunocompromised children in the Oncology ward. Over the past year, significant sustainable cost savings have resulted from the implementation of practice guidelines for ordering pediatric stool cultures. PMID- 7856557 TI - Robotics in the hematology laboratory. An evaluation of the productivity of the Sysmex HS-330. AB - The productivity of a robotic hematology system (Sysmex HS-330) was compared with that of existing automated, semi-automated, and manual systems (Coulter Counter Model STKS; Sysmex R-1000 reticulocyte counter. Geometric Data Miniprep slide maker, respectively) in the clinical hematology laboratory of a large hospital. On average, for a batch of 50 samples, the HS-330 performed a blood count with a 5-part differential, a reticulocyte count, and prepare a blood smear 23 minutes faster than could trained technologists using existing equipment. An estimated 1.8 medical technologists could be assigned to other tasks; however, because of the equipment's high cost, in a laboratory processing 1,000 samples per day, 4.6 years would be needed before any actual cost savings were experienced. PMID- 7856558 TI - Quality team approach in evaluating three automated hematology analyzers with five-part differential capability. AB - Three modern hematology analyzers (Abbott Cell-Dyn 3000, Coulter STKS, and Sysmex NE-8000) with high throughput and 5-part differential capability were evaluated using a protocol designed by a quality team. Effective use of the team process to evaluate instrumentation empowers laboratory personnel to share in decision making activities, improves job satisfaction, and produces the best purchasing decision. Instruments were compared using a combination of statistical analysis and written evaluations provided by team members. Tools and concepts from this study provide a comprehensive model for an effective multi-instrument evaluation. PMID- 7856559 TI - Comparison of PCR with southern hybridization for the routine detection of immunoglobulin heavy chain gene rearrangements. AB - The development of a reliable polymerase chain reaction (PCR) technique for the routine detection of clonal immunoglobulin heavy chain (IgH) gene rearrangements would represent an attractive alternative to Southern hybridization analysis because of the relative simplicity of PCR protocols, and because the requirements for both quality and quantity of DNA would be considerably less stringent. To assess the utility of PCR for the routine detection of clonal IgH gene rearrangements, samples from 123 adult patients were evaluated and analysis by PCR amplification using IgH Framework 1 or Framework 3 variable region consensus primers was compared with analysis by restriction endonuclease digestion and Southern hybridization with genomic, IgH probes. The authors found that 90% of IgH genes found to be rearranged by Southern hybridization are detected by the PCR technique. An additional 9 patient samples had clonal IgH gene rearrangements that were detectable by PCR alone. Eight of these nine patients had a history of a clonal hematopoietic process at either the morphologic or molecular level, and six had a history of a B-cell malignancy. It is likely that these specimens contained clonal lymphoid populations undetected by the Southern hybridization technique. Thus, the diagnostic sensitivity and specificity of the PCR method for the detection of B-cell tumors were 91% and 95%, respectively. The combination of improved analytical sensitivity and specimen flexibility of the IgH PCR assay could make it the method of choice for the routine detection of clonal IgH gene rearrangements, if minor improvements in the diagnostic sensitivity of the assay can be achieved. PMID- 7856560 TI - Promyelocytic blast crisis of chronic myelogenous leukemia. A rare subtype associated with disseminated intravascular coagulation. AB - Two patients with chronic myelogenous leukemia (CML) developed blast crisis that morphologically appeared to be the microgranular variant of acute promyelocytic leukemia. This represented 8% of CML patients developing blast crisis from 1984 to 1993. Cytogenetic studies revealed translocation 15;17 in addition to translocation 9;22 that had been documented at initial diagnosis. Both patients had evidence of disseminated intravascular coagulation at the onset or during treatment of blast crisis, which was not documented in any other patients with CML blast crisis. One patient died of sepsis during intensive chemotherapy. The second returned to a chronic phase of the disease after therapy. Although rare, a promyelocytic blast crisis of CML can occur which, as in de novo acute promyelocytic leukemia, has a propensity to produce disseminated intravascular coagulation. PMID- 7856562 TI - Interobserver reproducibility of the Nottingham modification of the Bloom and Richardson histologic grading scheme for infiltrating ductal carcinoma. AB - The interobserver reproducibility of the Nottingham modification of the Bloom and Richardson histologic grading scheme for invasive breast carcinoma was tested. Six surgical pathologists from four institutions independently evaluated histologic grade and each of its three components for 75 infiltrating ductal carcinomas. The number of slides per case ranged from one to nine (median 3). Pairwise kappa values for agreement ranged from moderate to substantial (0.43 0.74) for histologic grade. Generalized kappa values indicated substantial agreement for tubule formation (0.64), moderate agreement for mitotic count (0.52), and near moderate agreement for nuclear pleomorphism (0.40). Normalizing the mitotic counts per mm2 showed only slight improvement in agreement over the published range of mitotic counts for three different field areas. The results suggest that steps to discriminate between categories for nuclear pleomorphism would likely be of benefit for improving the interobserver reproducibility of histologic grade. Nevertheless, the Nottingham modification of the Bloom and Richardson grading system is recommended as a suitable scheme for evaluating invasive breast carcinomas in the routine clinical setting. PMID- 7856561 TI - Virus-associated hemophagocytic syndrome characterized by clonal Epstein-Barr virus genome. AB - Virus-associated hemophagocytic syndromes are a heterogeneous group of disorders in which viral infection is associated with a proliferation of hemophagocytic histiocytes throughout the reticuloendothelial system. The authors report the case of a 24-year-old Vietnamese male who developed a hemophagocytic syndrome associated with Epstein-Barr virus (EBV) and who died following a rapidly progressive course. A proliferation of reactive-appearing lymphoid cells was associated with an extensive proliferation of erythrophagocytic histiocytes. Immunophenotypically, the lymphoid infiltrate consisted of CD56+ natural killer cells, predominantly CD8+ T-cells and rare B-cells (CD20+). Double-label immunohistochemical studies showed CD3+ T-cells and CD56+ natural killer cells to be distinct cell populations. Combined immunohistochemical-in situ hybridization studies localized EBV to CD43+, CD3-, CD68-, lymphoid-appearing cells, indicating the presence of EBV within natural killer cells. Southern hybridization analysis of EBV genomic termini revealed clonal EBV genome. However, there was no detectable immunoglobulin or T-cell receptor gene rearrangements. The findings indicate that this case of hemophagocytic syndrome represents a clonal proliferation of natural killer cells containing EBV and highlights the importance of the analysis of EBV genomic termini for determination of clonality in EBV-associated proliferations. It is possible that other cases of fulminant EBV-associated hemophagocytic syndromes represent clonal natural killer cell proliferations. PMID- 7856563 TI - Accuracy and reliability of frozen section diagnosis in a series of 672 nonpalpable breast lesions. AB - Frozen section (FS) diagnosis was routinely performed in a large series of nonpalpable breast lesions from 1977 through 1991. The original FS diagnoses of 672 patients were classified in four categories (1 = benign lesion, 2 = in situ carcinoma, 3 = invasive carcinoma, 4 = deferred diagnosis) and compared with the diagnoses obtained at review of the permanent paraffin sections to estimate the accuracy of FS. A review of the mammographic pattern of the lesion was also performed. Frozen section diagnostic conclusion was deferred to permanent paraffin sections in only 22 cases (3.3%). Benign or malignant (grouping in situ and invasive carcinomas) FS diagnoses were accurate in 623 of 650 cases (95.8%). Overall, the prevalence of malignant lesions was 44.8% with a benign/malignant ratio of 1.2. The diagnosis was modified on the basis of permanent sections in 27 cases (4.2%) with three false positives and 24 false negatives. Sensitivity and specificity of FS diagnoses were 91.7 and 99.2%, respectively. When the comparison between FS and histologic diagnoses was analyzed according to the mammographic pattern, sensitivity among patients with microcalcifications as the only alteration was lower (88.8%) than among patients with opacities (94.9%). On the basis of these results, FS is to be considered a feasible and reliable diagnostic procedure in nonpalpable breast lesions, particularly in cases excised because of a mammographic opacity that is identifiable on gross examination of the surgical specimen. PMID- 7856564 TI - Tumor oncogenic expression in malignant effusions as a possible method to enhance cytologic diagnostic sensitivity. An immunocytochemical study of 87 cases. AB - The diagnostic ability of cytological preparations can be hampered by specimen inadequacy and the presence of representative cells, which may result in a diagnostic accuracy of only 70%. An immunocytochemical battery (ICC), which included anti-p53, anti-c-erbB-2, and B72.3 MoAbs, was used to enhance sensitivity in 87 specimens of body effusions. Thirty-six cases were positive for malignancy using conventional cytology. Forty cases were negative and 11 cases were inconclusive or had an equivocal diagnosis. Sensitivity was 65%, and there was a negative predictive value (NPV) of 62%. p53 was expressed in 50 cases (56%, sensitivity = 83%, NPV = 73%), and B72.3 MoAb was positive in 36 cases (37%, sensitivity = 66%, NPV = 64%). Forty-eight cases (56%) displayed reactivity with anti-c-erbB-2 (sensitivity = 75%, NPV = 63%). The authors concluded that application of an ICC panel of anti-p53, B72.3 and c-erbB-2 to complement conventional cytology increases sensitivity to 98% (P < .0005) with an NPV of 96% (P = .001). PMID- 7856565 TI - Testicular mass as a presenting symptom of isolated polyarteritis nodosa. AB - Isolated polyarteritis nodosa (PAN) of the male testes has rarely been reported. The authors describe two young men with testicular mass as a presenting symptom of isolated PAN, which was diagnosed following orchiectomy. The clinical features of the reported cases are reviewed. PMID- 7856566 TI - Adenomyosis with sparse glands. A potential mimic of low-grade endometrial stromal sarcoma. AB - Most cases of adenomyosis are easily recognized by the presence of intramyometrial aggregates of endometrial glands and endometrial stromal cells surrounded by hypertrophic smooth muscle. The authors report seven cases of adenomyosis with sparse glands, which was a finding that initially caused difficulties in diagnosis and raised the question of low-grade endometrial stromal sarcoma (LGESS). The patients' ages ranged from 51 to 81 years. All were postmenopausal. Each had undergone hysterectomy for a variety of reasons unrelated to the adenomyosis. Microscopic examination of the uteri disclosed multiple intramural nests of adenomyotic endometrial stromal cells without endometrial glands, ranging from 0.5 mm to 8.0 mm in maximum dimension. The percentage of adenomyotic foci without glands in each case ranged from 40% to 94%. Two cases also had foci of intravascular intrusion by the gland-poor adenomyotic stroma. The most useful features for differentiating adenomyosis with sparse glands from LGESS include: (1) its occurrence as an incidental finding in uteri removed for other reasons; (2) the microscopic size of the adenomyotic foci without grossly evident tumor nodules; (3) a distinctive concentric zonal organization of the gland-poor stromal aggregates, with less cellular pale centers surrounded by a thin rim of stromal or smooth muscle cells with increased cellularity, often with a thicker, but less well-defined, peripheral zone of hypertrophic myometrial smooth muscle; (4) the atrophic appearance of the stromal cells and absence of nuclear atypia and mitotic figures; (5) an absence of sclerotic areas, foam cells, sex cordlike structures, hemangiopericytoma-like vascular pattern, prominent vascular invasion and extrauterine extension commonly found in LGESS; (6) the presence of typical adenomyosis with glands elsewhere in the myometrium; and (7) the postmenopausal age of the patient. PMID- 7856567 TI - Alteration of the p53 tumor suppressor gene and activation of c-K-ras-2 protooncogene in endometrial adenocarcinoma from Colorado. AB - The authors previously reported a significant frequency of activating point mutations in codon 12 and 13 of the K-ras gene in endometrial carcinoma and endometrial atypical hyperplasia from Osaka, Japan. They also showed that alterations of the p53 gene are found frequently in those tumors. This study was designed to reveal possible demographic differences in the prevalence of K-ras and p53 mutations in endometrial carcinoma. Tumor-enriched areas of paraffin embedded histologic sections obtained through the Colorado Central Cancer Registry were isolated and extracted for DNA. Fragments amplified by polymerase chain reaction (PCR) were screened for transforming mutations in codon 12, 13, or 59-63 of K-ras by direct sequencing. Of 38 endometrial adenocarcinomas that were analyzed, K-ras activation was detected in 4 cases (11%), three in codon 12 (a single case with a GGT-->AGT transition, a single case with a GGT-->GAT transition, and a single case with a GGT-->TGT transversion) and one in codon 13 (a GGC-->GAC mutation). The prevalence of K-ras mutations was significantly lower in endometrial carcinomas from Colorado (4 of 38, 11%) than in those from Osaka, Japan (17 of 57, 31%; P = .02). Mutations in exons 5-8 of p53 were screened by PCR-SSCP analysis, and subsequently confirmed by direct sequencing. Mutations in the p53 gene were detected in 5 of 38 endometrial carcinomas from Colorado (13%), including a single base substitution mutation in 3 cases (60%) and a deletion mutation in 2 cases (40%). Mutations in the p53 gene were significantly more frequently found in G3 cancers (3 of 7, 43%) than G1-G2 cancers combined (2 of 31, 6%; P = .025). Although the prevalence of p53 mutations in endometrial carcinomas from Colorado was not significantly different compared to that from Osaka, Japan (9 of 40, 23%), a G:C-->A:T transition at a CpG site, which was the most common base substitution mutation among Japanese, was not included in any tumors from Colorado. A rare polymorphism in codon 213 (CGA-->CGG) was observed in three cases. These observations may indicate that genetic or environmental factors may significantly influence the pathway of endometrial carcinogenesis. PMID- 7856568 TI - Aspiration cytopathology of malignant melanoma in children. A morphologic spectrum. AB - Malignant melanoma (MM) is an uncommon neoplasm in the practice of pediatric cytopathology. The clinical and morphologic features of three white children with this neoplasm diagnosed by fine needle aspiration biopsy are described. All cytologic diagnoses were subsequently confirmed histologically. Two children were 16 years old and one was 9 years old. Two patients had metastatic MM to head and neck lymph nodes. In one of these children, a prior diagnosis of MM was known, whereas in the other it was unsuspected. A primary melanoma of the iris developed in the third child. The cytopathology of these children are similar to that described in adults. With the cytologic similarities, some striking differences were seen. Principal among these was the abundance of melanin in one case, its uneveness in another, and its absence in a third. The variation in individual cell morphology among the three cases is also described. Malignant melanoma is a rare neoplasm of children that can be recognized by fine-needle aspiration cytopathology. PMID- 7856569 TI - Carcinosarcoma (malignant mixed mullerian tumor) of the uterus with a rhabdoid tumor component. An immunohistochemical, ultrastructural, and immunoelectron microscopic case study. AB - A case of uterine carcinosarcoma (malignant mixed mullerian tumor) of the uterus containing a rhabdoid tumor element is described. In addition to a malignant glandular component and anaplastic sarcomatous areas, this tumor had multiple foci with histologic and ultrastructural features of malignant rhabdoid tumor. Vimentin positivity by immunohistochemistry was confirmed by immunoelectron microscopy. Although three malignant rhabdoid tumors of the uterus have been previously described, in addition to rhabdoid differentiation in an endometrial stromal sarcoma, to our knowledge this is the first report of rhabdoid tumor differentiation occurring within a uterine carcinosarcoma. PMID- 7856570 TI - Cost analysis of point-of-care laboratory testing in a community hospital. AB - Point-of-care testing (POCT) is a means of providing patient services more rapidly. Most evaluations of bedside laboratory testing devices have emphasized analytical performance in tertiary care settings. In contrast, the authors compare the operating cost of POCT for glucose and an electrolyte/glucose/blood urea nitrogen chemistry panel with the cost of central laboratory stat testing in a 204-bed community hospital. In scenarios studied, POCT costs exceed central laboratory stat costs from 1.1 to 4.6 times. The more POCT is used, the greater the excess costs compared to the central laboratory. Cost analysis demonstrates that the investment in acquiring automated transport and data management systems for the authors' hospital was far less expensive than POCT for both an individual stat test and on an annual cost basis. The authors urge fiscal caution before indiscriminately implementing POCT. PMID- 7856571 TI - Laboratory and bedside evaluation of portable glucose meters. AB - A two-phase, laboratory and bedside, evaluation of blood glucose meters was conducted in this study. Four meters, the AccuData Easy (Boehringer-Mannheim, Indianapolis, IN), HemoCue Glucose (HemoCue, Mission Viejo, CA), LifeScan One Touch II (LifeScan, Milpitas, CA), and Miles Encore QA (Miles, Elkhart, IN) systems, were compared to the Nova Stat Profile 5 (Nova, Waltham, MA) as the laboratory reference. Precision, linearity, correlation to the laboratory method, interference from hematocrit, data management, and operator preference were examined. None of the meters were found to satisfy all of the study's evaluation criteria. Therefore, institutions must weigh which criteria are most important to their individual settings. Although the HemoCue Glucose was found to be technically superior, this meter had no data management capabilities. The Encore QA had greater variance and low bias, whereas the AccuData Easy had bias affected by hematocrit and glucose concentration, and the One Touch II had a negative hematocrit bias and limited linear range when compared to the Nova. Only meters meeting both minimal analytical performance and computerization requirements, the One Touch II and AccuData Easy, were selected for further evaluation. At the bedside, the One Touch II demonstrated performance consistent with the lab evaluation, whereas the AccuData Easy showed greater imprecision in the low glucose range and a correlation that varied with sample type: capillary, venous, or arterial blood. This evaluation indicates that the clinician must interpret near-patient glucose results with respect to meter limitations. FDA approval and marketing statistics, alone, are insufficient to judge the performance of the meters in routine institutional use. Independent method validation, under actual operating conditions, is a better means of predicting future performance of the meters. PMID- 7856572 TI - Measurement of the intensity of cell surface antigen expression in B-cell chronic lymphocytic leukemia. PMID- 7856574 TI - Reduced drug coverage saved Medicaid 'pennies,' cost state 'pounds'. PMID- 7856573 TI - The utility of latex agglutination assays in the diagnosis of pediatric viral gastroenteritis. PMID- 7856575 TI - Complying with OSHA's Hazard Communication Standard. PMID- 7856576 TI - Agreeing on a keep-vein-open infusion rate. PMID- 7856577 TI - Hard times. PMID- 7856578 TI - Emergence of multidrug-resistant isolates of Acinetobacter baumannii. AB - Patterns of antimicrobial resistance during an outbreak of nosocomial infections caused by Acinetobacter baumannii were studied. The medical records of all patients admitted to the hospital between February 1993 and February 1994 from whom A. baumannii was cultured were reviewed for demographic data, confirmation of the isolation report, admission date, date of first isolation of the organism, and antimicrobial use before and after the culture and susceptibility test results were obtained. The culture and susceptibility test data were reviewed for all specimens submitted to the laboratory during the review period. A total of 87 patients (mean +/- S.D. age, 37.9 +/- 8.7 years) with nosocomial infection or colonization with A. baumannii were identified. All the patients were surgical intensive care unit residents and had predisposing factors for acinetobacter infection. A total of 107 isolates of the organism were cultured from various sites; sputum was the most common source. The number of isolates per month increased steadily beginning in September 1993 and then declined over the winter. The median time between admission and first isolation of resistant A. baumannii was 11 days. Infections were manifested clinically as pneumonia (36 patients), bacteremia (8), wound infection (6), and urinary-tract infection (2). Of the 107 isolates, all were resistant to formulary cephalosporins, extended-spectrum penicillins, quinolones, and aztreonam. Only nine isolates were susceptible to one or more aminoglycosides. All the isolates were susceptible to imipenem cilastatin. During an outbreak of nosocomial infections with A. baumannii, all or nearly all of the 107 isolates were resistant to a broad range of antimicrobials with the exception of imipenem-cilastatin, to which all the isolates were susceptible. PMID- 7856579 TI - Survey of clinical pharmacy services in United Kingdom National Health Service hospitals. AB - The extent to which clinical pharmacy services are provided in National Health Service (NHS) hospitals in the United Kingdom was studied by means of a questionnaire. Questionnaires inquiring whether and to what extent certain clinical pharmacy services were provided were mailed to all NHS hospital pharmacies in 1992. The questionnaires also requested information about the hospital and the number and qualifications of pharmacists employed. The results were compared with those of a survey of pharmaceutical services in the United States. Of 508 questionnaires mailed, 416 usable responses were returned. Services commonly provided were inpatient drug therapy monitoring (96%), clinical trials support (92%), formulary management (89%), participation in drug and therapeutic committees (97%), and an on-site drug information center (60%). Services infrequently provided were therapeutic drug monitoring (21%), medication history-taking (16%), and a 24-hour on-site pharmacist (10%). Several services were associated with pharmacies that employed many pharmacists, pharmacists with advanced education, or specialist clinical pharmacists and pharmacies located in medical school teaching hospitals. U.K. hospital pharmacies provided fewer patient-oriented services and more drug information, therapy monitoring, and pharmacist education services than U.S. hospital pharmacies. Provision of clinical pharmacy services in the United Kingdom was associated with employment of many pharmacists, pharmacy clinical specialists, and pharmacists with advanced education. PMID- 7856580 TI - Establishment of a 900 telephone number at a university-based drug information service. AB - Effects of converting a free drug information service at a university medical center to a 900 telephone number are described. Calls to a university medical center drug information service had increased beyond the capacity of staff. A telephone survey to recent users of the service indicated that callers outside the institution would be willing to pay a fee for the service, so a 900 number was instituted for outside calls in January 1993. Staff recorded data on all questions they answered; data for 1993 were compared with those from 1992. Question volume decreased by 48% after the 900 number was instituted, with questions from outside the institution dropping by 55%, questions from outside health care professionals dropping by 72%, and questions from the lay public increasing slightly. One severe impediment to callers from local hospitals was that many hospitals block access to 900 numbers from their telephone systems. The average length of a call was three minutes and the average cost per call was $6. Net income during the first year of operation was $6698. The 900 number provided some income, but it did not completely offset operating costs. A 900 telephone number is a workable, but imperfect, method of providing drug information to outside callers. Early notification of users before implementing a 900 number is essential to allow time for them to arrange telephone access. PMID- 7856581 TI - Mild theophylline-related adverse reactions and serum theophylline concentration. AB - The relationship between theophylline-associated adverse drug reactions (ADRs) and serum theophylline concentration (STC) was studied. Patients with obstructive airway disease who received theophylline on the pulmonary ward of a large urban hospital over a 10-month period were included in the study. Each patient was interviewed within two hours after collection of a sample for determining STC and, without knowing the STC, the interviewer classified each patient into one of the following categories: ADR, no ADR, or indeterminant (symptoms similar to a theophylline-associated ADR but possibly caused by concomitant drugs or comorbidities). ADRs were also classified as to their severity. The interviewer identified 340 ADRs during 201 interviews of 126 patients. All but four of the ADRs were mild. In half of the interviews, patients reported at least two concurrent ADRs. Not including the indeterminant group, ADRs occurred in 69% of the patients, a much higher frequency than previously reported. The mean +/- S.D. STCs for the ADR and no-ADR groups were 6.5 +/- 1.7 and 7.7 +/- 2.0 micrograms/mL, respectively. When the indeterminant ADRs were added to the theophylline-associated ADRs, the resulting group had a mean +/- S.D. STC of 11.5 +/- 3.3 micrograms/mL. No significant association was found between STC and occurrence of ADRs. Theophylline-associated ADRs occurred more frequently than expected at STCs within and below the usually accepted therapeutic range. PMID- 7856582 TI - Stability of esmolol hydrochloride in intravenous solutions. AB - The stability of esmolol hydrochloride in a variety of i.v. solutions was studied. Solutions of esmolol hydrochloride 10 mg/mL were prepared separately in 0.45% sodium chloride injection, 0.9% sodium chloride injection, 5% dextrose injection, 5% dextrose and 0.45% sodium chloride injection, 5% dextrose and 0.9% sodium chloride injection, 5% dextrose with lactated Ringer's injection, lactated Ringer's injection, 5% sodium bicarbonate injection, and 5% dextrose injection with potassium chloride 40 meq/L. One glass and one polyvinyl chloride container of each solution (except glass only in the case of the solution in 5% sodium bicarbonate injection) were stored in the dark at 5 degrees C, under ambient room light at 23-27 degrees C, in the dark at 40 degrees C, and under intense light at 25-30 degrees C. At storage intervals up to 168 hours, samples were tested for esmolol hydrochloride concentration by high-performance liquid chromatography. Optical density and pH were also measured. Esmolol hydrochloride was stable in the various i.v. fluids for at least 168 hours when stored at 5 degrees C or 23 27 degrees C, for at least 24 hours when stored under intense light, and, with one exception, for at least 48 hours when stored at 40 degrees C. When mixed with 5% sodium bicarbonate injection, the drug was stable for only about 24 hours at 40 degrees C. There were no substantial changes in optical density or pH. The type of container had no effect on stability. With one exception, esmolol hydrochloride was stable in all the i.v. solutions under all the conditions tested. PMID- 7856583 TI - Effect of coadministration of a nutritional supplement on ciprofloxacin absorption. PMID- 7856585 TI - Effect of sodium chloride concentration and temperature on melphalan stability during storage and use. PMID- 7856584 TI - Optimal volume of anticoagulant citrate dextrose solution in the preparation of technetium Tc 99m-labeled red blood cells. PMID- 7856586 TI - Stability of paclitaxel and fluconazole during simulated Y-site administration. PMID- 7856587 TI - Stability and compatibility of etoposide in 0.9% sodium chloride injection in three containers. PMID- 7856588 TI - Visual compatibility of neuroleptics with anticholinergics or antihistamines in polyethylene syringes. PMID- 7856589 TI - Hospital pharmacists and collective bargaining. PMID- 7856590 TI - Creating your future. PMID- 7856591 TI - Nontraditional doctor of pharmacy program: one graduate's experience. PMID- 7856592 TI - Comparison between respondents and nonrespondents in the ASHP national survey. PMID- 7856593 TI - New clinical skills program. PMID- 7856594 TI - Correction to Cancer Therapy Protocols. PMID- 7856595 TI - More Americans should take action to control their blood pressure. PMID- 7856596 TI - Maryland pharmacy students aid community health workers. PMID- 7856597 TI - Premature infants, missed doses are subjects of new hepatitis B vaccination guidelines. PMID- 7856598 TI - International working group standardizes drug testing requirements in the elderly. PMID- 7856599 TI - Factors to consider in exchanging night-shift services for a clinical position. PMID- 7856600 TI - Digging up details on residency and fellowship programs. PMID- 7856601 TI - Epidural administration of methylprednisolone for back pain. PMID- 7856602 TI - Accuracy of dispensing in a high-volume, hospital-based outpatient pharmacy. AB - Accuracy of dispensing was studied in the outpatient pharmacy setting, and error rates were compared with workload. All prescriptions filled in an outpatient pharmacy over 12 weekdays were audited to determine the rate of dispensing errors. In this pharmacy, pharmacists filled prescriptions and technicians delivered the medications to the patients. Before the medication reached the patient, the auditors recorded any dispensing errors and determined whether they were potentially serious. Of the 9846 prescriptions filled, 1229 (12.5%) contained a total of 1371 errors. Of these errors, 155 (1.6%) were potentially serious. Statistical analysis of the data revealed differences between error rates and (1) the total number of prescriptions dispensed per hour and (2) the number of prescriptions filled per pharmacist hour. However, no correlation existed between the number of prescriptions dispensed per hour and the total number of errors made. No significant correlation was found between the rate of potentially serious errors and increasing work volume, suggesting that important factors in error avoidance are continuous quality improvement mechanisms and minimal interruption of dispensing. No association was found between work volume and the number of dispensing errors or potentially serious errors. Error rates were consistent with published estimates. PMID- 7856603 TI - Morphine use and adverse effects in a neonatal intensive care unit. AB - Prescribing patterns and appropriateness of morphine use in a neonatal intensive care unit (NICU) were evaluated in a concurrent drug-use evaluation (DUE). Data were collected for 99 infants who received morphine over a six-month period. Patient charts were reviewed to collect the following data: patient's age, weight, dosage schedule, concurrent sedatives, ventilatory status, whether adequacy of analgesia was documented, and descriptions of adverse drug reactions (ADRs). The physicians' orders were reviewed to determine whether NICU morphine dosage guidelines were followed and whether the indication for use was noted. Seven ADRs occurred in six of the patients; three of the ADRs occurred after ophthalmic cryosurgery. Indications for use were noted in 79 of 285 physician orders (27.7%). The adequacy of sedation or analgesia was documented on 60 of the 360 patient days (16.7%). The DUE results prompted several changes: physicians were asked to select indications from a list in the computerized order-entry system, an analgesia or sedation assessment scale was added to nursing flow sheets, and endotracheal intubation became a requirement before ophthalmic cryosurgery. A follow-up DUE showed nearly complete compliance with the new guidelines for morphine use and a reduction in the number of adverse reactions to morphine. A DUE prompted policy changes that improved documentation of indications for and efficacy of morphine use and reduced adverse reactions to the drug in an NICU. PMID- 7856604 TI - Compatibility of paclitaxel injection vehicle with intravenous administration and extension sets. AB - The compatibility of paclitaxel injection vehicle with a variety of i.v. administration and extension sets was studied in terms of the amount of diethylhexyl phthalate (DEHP) leached from the sets. Test solutions of paclitaxel injection vehicle corresponding to paclitaxel injection 0.3 and 1.2 mg/mL were prepared in polyolefin bags of 5% dextrose injection. The solutions were delivered in triplicate over 24 hours through 26 models of administration sets and 24 models of extension sets and collected in glass containers. Portions were removed after delivery and analyzed in duplicate for DEHP concentration by high performance liquid chromatography. All the extension sets were compatible with paclitaxel injection vehicle. Most of the administration sets were also compatible. However, two administration sets were incompatible with paclitaxel vehicle corresponding to either drug concentration, and five sets were incompatible with the vehicle simulating the high (1.2-mg/mL) concentration. Some of the incompatible sets were labeled as not containing polyvinyl chloride (PVC). Solutions of paclitaxel vehicle leached DEHP from administration sets containing PVC and from some sets labeled as not containing PVC. PMID- 7856605 TI - Stability of midazolam hydrochloride and morphine sulfate during simulated intravenous coadministration. PMID- 7856606 TI - Antecedents of the American hospital pharmacist. PMID- 7856607 TI - American hospital pharmacy from the Colonial period to the 1930s. AB - The history of hospital pharmacy in the United States from the Colonial period to the 1930s is explored. America's first hospital pharmacist was Jonathan Roberts, hired in 1752. Like most other early hospital apothecaries, Roberts was an apprentice physician. His successor, John Morgan, proposed that the practices of medicine and pharmacy be separate. By 1811 the New York Hospital had a full-time pharmaceutical practitioner. The niche available for hospital pharmacy was small during the nineteenth century because most Americans were treated at home. Two pioneers who advanced the profession during the nineteenth and early twentieth centuries were Charles Rice and Martin Wilbert. Hospital pharmacists were sought out during the Civil War because of their experience in manufacturing drug preparations and as buyers. Immigration after the Civil War soon doubled the number of hospitals. The post-Civil War expansion of hospitals also coincided with the reform movement in nursing and the rise of scientific medicine. Hospital pharmacists became indispensable as supply masters and manufacturers. Physicians demanded professional pharmaceutical services for handling more complex therapies. Administrators learned that it was more economical to fill inpatient prescriptions inhouse. While community pharmacy had long since abandoned manufacturing and some compounding, hospital pharmacists retained these roles. However, the image of pharmacists as corner druggists was hard to shake. During the 1920s voices called for hospital pharmacists to organize. Edward Spease led in aligning schools of pharmacy with hospitals. In 1927 the first hospital pharmacy internship program was begun. A section for hospital pharmacists within the American Pharmaceutical Association was established in 1936, and the first state associations were founded during the 1920s. By the end of the 1930s, the stage was set for the national movement that followed. By the 1930s, American hospital pharmacists had reached the critical mass necessary for group identity on a national level. PMID- 7856608 TI - Pharmacist's duty to warn. PMID- 7856609 TI - Restructuring pharmacy departments for survival. PMID- 7856610 TI - Should the use of total nutrient admixtures be limited? PMID- 7856611 TI - Precipitation of calcium phosphate from parenteral nutrient fluids. PMID- 7856612 TI - Criteria for use of hypolipidemic agents in adults. PMID- 7856613 TI - Protocol for Mrs. C. PMID- 7856614 TI - Cost-effective use of cytomegalovirus immune globulin in recipients of orthotopic liver transplants. PMID- 7856615 TI - Pharmacists' responsibilities amplified. PMID- 7856616 TI - Simpler approaches to aminoglycoside monitoring. PMID- 7856617 TI - Final rule issued on Medicaid DUR and patient counseling. PMID- 7856618 TI - Federal task force advises on zidovudine use during pregnancy. PMID- 7856619 TI - Staffing pharmacies to meet the demands of patient-oriented care. PMID- 7856621 TI - Improving care and reducing costs in the ICU. PMID- 7856620 TI - Zidovudine-associated myopathy. PMID- 7856622 TI - Venlafaxine: a heterocyclic antidepressant. AB - The pharmacology, pharmacokinetics, and clinical efficacy of venlafaxine hydrochloride, a new antidepressant, are described. Venlafaxine inhibits the reuptake of serotonin, norepinephrine, and, to a lesser extent, dopamine. In animal models, it does not significantly inhibit muscarinic, histaminic, or adrenergic receptor activity and does not inhibit monoamine oxidase. Venlafaxine is rapidly absorbed and metabolized in the liver to its active metabolite, O desmethylvenlafaxine (ODV). Time to peak concentration is one to two hours for the parent compound and four to five hours for ODV. The pharmacokinetics of venlafaxine might be dose-dependent, although pharmacokinetic studies have had conflicting results. The major route of elimination is renal; thus, patients with renal dysfunction may require lower doses. In double-blind, placebo-controlled trials of venlafaxine for maintenance therapy, venlafaxine has shown effective antidepressant activity in severely ill patients with major depression. Antidepressant effectiveness may be apparent within two weeks; this finding needs to be replicated. The dosage is 75-375 mg/day administered in two or three divided doses. The strength of the antidepressant response may be correlated with increasing dosage. Nausea is the most commonly reported adverse drug reaction (ADR). Others include somnolence, dizziness, dry mouth, and sweating. All ADRs have commonly occurred at the beginning of therapy and decreased with time. Overall, venlafaxine is well tolerated. Venlafaxine is as effective as other available antidepressants. It may cause fewer anticholinergic, antihistaminic, and antiadrenergic ADRs and may have a quicker onset of therapeutic action than existing antidepressants. PMID- 7856623 TI - Clozapine therapy for Parkinson's disease and other movement disorders. AB - Recent research on the role of clozapine in the treatment of Parkinson's disease and other movement disorders is discussed. Most clinical trials have shown resolution of or improvement in psychotic symptoms accompanying Parkinson's disease without worsening of parkinsonian symptoms. Adverse effects appear to be mild at dosages of < 100 mg/day; sedation is the most frequent problem. Most of these studies have serious limitations, however; until better studies have been completed, the decision to use clozapine for Parkinson's disease-related psychosis should be made on a case-by-case basis, with thorough evaluation of risks, benefits, and other therapeutic options. Some patients with Parkinson's disease have shown improvement in tremor and other abnormal movements when given clozapine. Clozapine cannot be recommended for treating tardive dyskinesia on the basis of the research done so far; some trials show dramatic resolution of symptoms, others no benefit. Anticholinergics or dopamine-reuptake inhibitors should be considered before clozapine is given to patients with tardive dyskinesia because of clozapine's potential for serious adverse effects. A few patients with Huntington's disease have responded to clozapine, but again no conclusions can be drawn. Clozapine appears to offer no real advantage over haloperidol for treating choreiform movements in Huntington's disease. The frequency of tics in Tourette's syndrome does not seem to be reduced by clozapine. Clozapine has shown some efficacy as a treatment for psychosis and abnormal movements in Parkinson's disease. Results have been less promising for other movement disorders. Further study in larger populations is needed before any definitive conclusions about clozapine's place in movement disorder therapy can be made. PMID- 7856624 TI - Program for controlling the use of ondansetron injection. PMID- 7856625 TI - System for ranking injectable antimicrobials for empirical therapy. PMID- 7856626 TI - Stability of paclitaxel in 5% dextrose injection or 0.9% sodium chloride injection at 4, 22, or 32 degrees C. PMID- 7856627 TI - Opportunities for alliances between industry and pharmacy. PMID- 7856628 TI - Subtleties of managing acetaminophen poisoning. PMID- 7856629 TI - Infection rates in adult and pediatric inpatients when i.v. sets are changed every 72 hours. PMID- 7856630 TI - Paclitaxel diluent and the case of the slippery spike. PMID- 7856631 TI - Improved extemporaneous formulation of cyclosporine ophthalmic drops. PMID- 7856632 TI - Hydralazine injection still available. PMID- 7856634 TI - Validity of originality assessment. PMID- 7856633 TI - Unit dose dispensing of chromic phosphate P 32 suspension. PMID- 7856635 TI - National health care reform, Part 2: Response to pharmacists. PMID- 7856636 TI - Bartsocas-Papas syndrome with internal anomalies: evidence for a more generalized epithelial defect or new syndrome? AB - We report on two Dutch sibs with external anomalies compatible with Bartsocas Papas syndrome, who also had internal anomalies: bilateral renal agenesis in one, and esophageal atresia, hypoplastic diaphragma, unilateral renal agenesis, agenesis of the shaft of the penis, and anal atresia in the other patient. Several possible patterns for the pathogenesis of this combination of anomalies are discussed. We propose a generalized epithelial defect, affecting both epidermis and other lining epithelia, as the most probable cause in the present patients. PMID- 7856637 TI - Phenotype/karyotype correlations of Y chromosome aneuploidy with emphasis on structural aberrations in postnatally diagnosed cases. AB - Over 600 cases with a Y aneuploidy (other than non-mosaic 47,XYY) were reviewed for phenotype/karyotype correlations. Except for 93 prenatally diagnosed cases of mosaicism 45,X/46,XY (79 cases), 45,X/47,XYY (8 cases), and 45,X/46,XY/47,XYY (6 cases), all other cases were ascertained postnatally. Special emphasis was placed on structural abnormalities. This review includes 11 cases of 46,XYp-; 90 cases of 46,XYq- (52 cases non-mosaic; 38 cases 45,X mosaic); 34 cases of 46,X,r(Y) (9 cases non-mosaic and 25 cases 45,X mosaic); 8 cases of 46,X,i(Yp) (4 non-mosaic and 4 mosaic with 45,X); 12 cases of 46,X,i(Yq) (7 non-mosaic and 5 mosaic); 44 cases of 46,X,idic(Yq); 80 cases of 46,X, idic(Yp) (74 cases had breakpoints at Yq11 and 6 cases had breakpoints at Yq12); 130 cases of Y/autosome translocations (50 cases with a Y/A reciprocal translocation, 20 cases of Y/A translocation in 45,X males, 60 cases of Y/DP or Y/Gp translocations); 52 cases of Y/X translocations [47 cases with der(X); 4 cases with der(Y), and 1 case with 45,X with a der(X)], 7 cases of Y/Y translocations; 151 postnatally diagnosed cases of 45,X/46,XY; 14 postnatally diagnosed cases of 45,X/47,XYY; 18 cases of 45,X/46,XY/47,XYY; and 93 aforementioned prenatally diagnosed cases with a 45,X cell line. It is clear that in the absence of a 45,X cell line, the presence of an entire Yp or a region of it including SRY would lead to a male phenotype in an individual with a Y aneuploidy, whereas the lack of Yp invariably leads to a female phenotype with typical or atypical Ullrich-Turner syndrome (UTS). Once there is a 45,X cell line, regardless of whether there is Yp, Yq, or both Yp and Yq, or even a free Y chromosome in other cell line, there is an increased chance for that individual to be a phenotypic female with UTS manifestations or to have ambiguous external genitalia. This review once again shows a major difference in reported phenotypes between postnatally and prenatally diagnosed cases of 45,X/46,XY, 45,X/47,XYY, and 45,X/46,XY/47,XYY mosaicism. It appears that ascertainment bias can explain the fact that all known patients with postnatal diagnosis are phenotypically abnormal, while over 90% of prenatally diagnosed cases are reported to have a normal male phenotype. Further elucidation of major Y genes and their clinical significance can be expected in the rapidly expanding gene mapping projects. More, consequently better, phenotype/karyotype correlations can be anticipated at both the cytogenetic and the molecular level. PMID- 7856638 TI - Female infant with oncocytic cardiomyopathy and microphthalmia with linear skin defects (MLS): a clue to the pathogenesis of oncocytic cardiomyopathy? AB - A infant girl had red stellate skin lesions on the cheeks and neck, and mildly short palpebral fissures. Her skin abnormality was typical of microphthalmia with linear skin defects (MLS), a newly recognized syndrome consisting of congenital linear skin defects and ocular abnormalities in females monosomic for Xp22. She died suddenly and unexpectedly at age 4 months; the cause of death was ascribed to oncocytic cardiomyopathy. Oncocytic cardiomyopathy occurs only in young children, who present with refractory arrhythmias leading to cardiac arrest. The coexistence of two rare conditions, one of which is mapped to the X chromosome, and an excess of affected females with oncocytic cardiomyopathy, make it likely that oncocytic cardiomyopathy is also X-linked, with Xp22 being a candidate region. Overlapping manifestations in the two conditions (ocular abnormalities in cases of oncocytic cardiomyopathy and arrhythmias in MLS) offer additional support for this hypothesis. PMID- 7856639 TI - Psychosocial functioning in the Ehlers-Danlos syndrome. AB - Ehlers-Danlos Syndrome (EDS) is a group of related genetic disorders of connective tissue presenting with joint hypermobility, skin extensibility, and tissue fragility. Although the pathophysiology of EDS is increasingly understood, the psychosocial effects of having EDS have not been examined. We psychologically tested and interviewed 41 adults and 7 children with EDS. Anxiety, depression, anger, and interpersonal concerns were significantly elevated, varying from one quarter to one-third of patients; over 70% had a history of some mental health care use. Psychological difficulties appear to result from chronic pain and disability, ostracism or avoidance of relationships and social activities, sexual difficulties and reproductive concerns, and frustration with the medical system. Specific types of EDS (e.g., EDS Type I) are associated with greater pain and psychological distress. Psychological intervention, prescribed with the recognition that psychiatric features are secondary to EDS, is recommended for some patients. PMID- 7856640 TI - Ectodermal dysplasias: a clinical classification and a causal review. AB - We present a casual review of 154 ectodermal dysplasias (EDs) as classified into 11 clinical subgroups. The number of EDs in each subgroup varies from one to 43. The numbers of conditions due to autosomal dominant, autosomal recessive, and X linked genes are, respectively, 41, 52, and 8. In 53 conditions cause is unknown; 35 of them present some causal (genetic) suggestion. PMID- 7856641 TI - New case of the Carey-Fineman-Ziter syndrome. AB - We present a further case, the fourth known to us, of the Carey-Fineman-Ziter syndrome. The emergence of a consistent and recognisable phenotype, characterised by hypotonia, weakness, ophthalmoplegia, and a Mobius-like clinical picture, is emphasised. PMID- 7856642 TI - De novo 17q paracentric inversion mosaicism in a patient with Beemer-Langer type short rib-polydactyly syndrome with special consideration to the classification of short rib polydactyly syndromes. AB - A de novo 17q paracentric inversion mosaicism is detected in a fetus with type IV short rib (polydactyly) syndrome (Beemer-Langer). The cytogenetic finding in our case suggests a possible location of the gene or cluster of linked genes responsible for SR (P) S type IV to 17q21 or 17q23. Since this chromosome abnormality has not been described in short rib polydactyly syndromes and the existence of type IV SR (P) S has been controversial, the literature of this entity is reviewed with special consideration to the classification of short rib polydactyly syndromes. PMID- 7856643 TI - Possible protection against asthma in heterozygotes for familial Mediterranean fever. AB - To identify a specific heterozygote advantage in familial Mediterranean fever (FMF), responsible for the high carrier rate of 1/6 in North African Jews, we studied the morbidity and mortality of 148 parents of affected patients and of 148 ethnically matched control persons. Our data demonstrate an apparently reduced prevalence of asthma in the heterozygotes compared with the control persons (3 vs. 6). There were no significant differences between the 2 groups in fertility rate, number of pregnancies and deliveries, or the prevalence of common diseases. Our data are in agreement with previous studies which demonstrated decreased asthma prevalence in FMF patients. It further confirmed, these findings suggest that identification of the FMF gene on 16p may provide an insight into asthma. PMID- 7856644 TI - Lethal Pallister-Killian syndrome: phenotypic similarity with Fryns syndrome. AB - The Pallister-Killian syndrome is a sporadic multiple congenital anomaly syndrome characterized by "coarse" face, profound mental retardation, and epilepsy. Chromosomes of peripheral lymphocytes are usually normal, but tissue cultures show varying degrees of mosaicism for isochromosome 12p. In babies who die neonatally of severe malformations, including diaphragmatic hernia, and who also have a "coarse" face, acral hypoplasia, and other internal anomalies, Fryns syndrome is more likely to be suspected than Pallister-Killian syndrome, especially if karyotyping is unavailable or if peripheral lymphocytes have a normal chromosome constitution. An initial diagnosis of Fryns syndrome had to be modified in 3 successive newborn infants since chromosome analysis or in situ hybridization with a chromosome 12 probe on kidney tissue demonstrated the mosaic aneuploidy characteristic of Pallister-Killian syndrome. These 3 patients confirm that a similar pattern of malformations can be present in both conditions at birth. It consists of "coarse" face, acral hypoplasia, diaphragmatic hernia, and other defects. Newborn infants who present this phenotype, but lack a conclusively normal chromosome test, may not have Fryns syndrome. A diagnosis of Fryns syndrome should be made carefully to avoid the risk of inappropriate genetic counseling. PMID- 7856645 TI - Chorionic villus sampling and transverse limb deficiencies: maternal age is not a confounder. AB - Advanced maternal age is a frequent indication for performing chorionic villus sampling (CVS) and it might be a confounder of the association between transverse limb deficiencies (TLD) and early CVS. We have first analyzed the maternal age specific rates of TLD in the population monitored by the Italian Multicentric Birth Registry; then we updated a case control study controlling for maternal age. The rate of all limb deficiencies (LD) was 5.9 per 10,000 births. No trend for an excess risk for TLD or other LD with advancing maternal age was found. The relative risk for women 35 years of age and older vs. those under 35 was 0.92 (95% CI, 0.72-1.19) for any LD and 0.99 (95% CI, 0.71-1.39) for TLD. In the case control study, 11 mothers of case patients with a TLD had been exposed to CVS out of a total of 206 (5.3%), compared to 54 mothers of control patients with defects other than TLD out of a total of 12,140 (0.4%). The risk estimate for TLD associated with CVS was high in the overall analysis (OR, 12.63) and did not decrease after stratification, both in the overall sample (Mantel-Haenszel OR, 14.01) and in each gestational age stratum. Thus, advanced maternal age does not explain the association between CVS and TLD found in this study and it is unlikely to explain that observed in the several other positive studies. We recommend that any study addressing the relationship between CVS and LD should include a careful evaluation of the type of LD and the timing of CVS, and present the results for specific gestational age periods. PMID- 7856646 TI - Clinical and molecular studies in a large Dutch family with Noonan syndrome. AB - We describe the largest Noonan syndrome (NS) family reported to date. The manifestations of the affected relatives are discussed. In the absence of a biochemical marker NS is still a clinical diagnosis. The diagnostic criteria that were used are presented compared with other published criteria for diagnosing NS. The large size of this family enabled us to test the possible involvement of candidate regions by multipoint linkage analysis. Both the region surrounding the NF1 locus on chromosome 17 and the proximal part of chromosome 22 could be excluded. Since NS may well be heterogeneous, the use of such a large family in linkage studies of NS should prove indispensable. PMID- 7856647 TI - Epidemiological and genetic studies of congenital profound deafness in the general population of Sichuan, China. AB - People with congenital profound deafness (CPD) were surveyed in the general population of Sichuan. The prevalence was 0.082% (104/126, 876) of the general population, male 0.086%, female 0.078%. There was no significant difference in prevalence between urban and rural populations. However the population living in the mountains had a much higher prevalence than people from the foothills and plains (P < 0.05). Amongst the nationalities investigated, there were significant differences in prevalence. Non-Chinese, except for Tibetans, presented a significantly higher prevalence than Han Chinese. There was a significantly higher prevalence among the inbred population (0.82%) than among the non-inbred population (0.72%). An effect of parental age was demonstrated, but no effect of birth order was found. There was a significant seasonal variation in prevalence. Inherited cases could account for 71.2% of all cases, of which 92% were autosomal recessive (AR) and 8% autosomal dominant (AD). Heterogeneity in AR was found with at least 8 different loci. The fitness was 60.26%, the coefficient of selection was 0.3974, mutation rate was estimated to be 2.0 x 10(-4), and no heterozygote advantage was proven. PMID- 7856648 TI - Oral-facial-digital syndrome: report on a transitional type between the Mohr and Varadi syndromes in a fetus. AB - Oral-facial-digital syndromes (OFDS) constitute a heterogeneous group of entities whose clinical manifestations are often overlapping. We report on a 23-week-old aborted fetus who showed a transitional phenotype between OFD II and OFD VI syndromes. PMID- 7856649 TI - Pitfalls of genetic counselling in brachydactyly type C. AB - A familial case of brachydactyly type C is presented in which hand radiographs of the proposita's parents was considered normal. The metacarpophalangeal profile pattern of the mother's hands demonstrated minimal manifestations typical of brachydactyly type C. PMID- 7856650 TI - Cohen syndrome is neither uncommon nor new. PMID- 7856651 TI - Kabuki (Niikawa-Kuroki) syndrome and paracentric inversion of the short arm of chromosome 4. PMID- 7856652 TI - Microcephaly, lymphedema, and chorioretinal dysplasia: report of two additional cases. AB - In recent years, several patients with microcephaly, lymphedema and chorioretinal dysplasia have been described. We have studied two additional patients with similar findings. The question of whether microcephaly with lymphedema and microcephaly with chorioretinal dysplasia and lymphedema are distinct entities remains unanswered. Identification of other patients in the future may provide additional information. PMID- 7856653 TI - Polydactyly in a carrier of the gene for the Meckel syndrome. AB - Much of the Meckel syndrome literature has been concerned with the criteria for diagnosis but little has been said concerning heterozygote expression. We describe 3 affected brothers whose father and his paternal first cousin had postaxial polydactyly of both feet. A review of the literature was undertaken with regard to possible manifesting heterozygotes. We conclude that it is important to examine the relatives of patients with the Meckel syndrome for mild abnormalities, as these may be evidence of a manifesting heterozygote. Such information may be useful for genetic counselling. PMID- 7856654 TI - Deformations in infants of diabetic and control pregnancies. AB - Severe and mild deformations in newborn infants of insulin dependent diabetic mothers (IDDMs) and control mothers were evaluated with respect to the types of anomalies and previously hypothesized constraint factors. Factors evaluated were gestational length, birth weight, corrected birth weight for gestation (weight ratio), maternal height and parity, and severe deformations. Newborn infants from 81 control and 133 insulin dependent diabetic pregnancies were recruited periconceptually as part of a larger study of diabetes in early pregnancy. Examinations were done at 48 to 72 hours of life by one examiner blinded to maternal status using a checklist of major and minor deformations and malformations. Mild deformations were found to be common and were present in 84% of newborn infants. Severe deformations occurred in three (1.4%) IDMs, with two of three newborn infants having major malformations involving the CNS and/or musculoskeletal system which affected fetal movement. There was no significant difference between IDMs and control newborn infants with respect to the number with deformations; however, fetal macrosomia was not present in study participants. Using the entire cohort, a significantly greater number of deformations were present in newborn infants with a gestation > 36 weeks (P < 0.001), birth weight > 3,000 g (P < 0.001), and weight ratio > or = 1.2 (P = 0.05). There was no significant association with primiparous mothers or women with a height < 165 cm and the presence of deformations. For gestational age and birth weight, mild deformations were apparent only after 33 weeks gestation (P << 0.001) and/or birth weights of 2.0 kg or more (P << 0.001).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7856655 TI - De novo translocation involving chromosomes 1 and 4 resulting in partial duplication of 4q and partial deletion of 1p. AB - We describe an infant boy with a unique de novo translocation involving chromosomes 1 and 4, resulting in dup(4q) and del(1p). His karyotype was 46,XY, 1,+der(1)t(1;4) (p36.2;q31.2). He had minor anomalies, congenital heart defect, respiratory distress, seizures, and central nervous system abnormalities. He died at age 11 weeks. The patient had manifestations of dup(4q) del(1p), and he was more seriously affected than patients having only one of these. No other patient with an identical chromosomal finding has been reported. PMID- 7856656 TI - Oblique facial clefts: report on 4 Brazilian patients. Evidence for clinical variability and genetic heterogeneity. AB - Oblique facial clefts are rare and include types 2-6 of Tessier's classification. Here we report on 4 patients with oblique facial clefts and a strikingly similar facial appearance. The pattern of facial involvement, the presence of consanguinity in 3 of them, as well as the entire clinical picture, suggest a unique dysmorphogenetic process which could represent, in some instances, an oculomaxillofacial dysostosis. PMID- 7856657 TI - Dermatoglyphic peculiarities in patients with Williams-Beuren syndrome. AB - The dermatoglyphic patterns of fingertips and palms of 115 patients with Williams Beuren syndrome (WBS) were analysed and compared with the data from 199 control individuals from Germany. The following combination of dermatoglyphic patterns appears to be characteristic to WBS: an excess of whorls on all fingertips; high termination values of the main lines D, B, and A; frequent absence of C triradius (C0); high frequencies of ulnar loops on the hypothenar and distal loops on the 2nd, 3rd, and 4th interdigital areas, of distal axial triradii t", and of abnormal palmar creases such as simian crease and Sydney lines. The combination of fingertip and palmar patterns expressed by a "Log.Score-Index," provides a high degree of discrimination between the WBS patients (92%) and the control group (88%). A "phantom picture" for WBS was constructed, which can be used for its diagnosis. PMID- 7856658 TI - Distinguishing genetic disease and genetic susceptibility. AB - With the increasing awareness of the involvement of genetic factors in disease, questions arise as to what distinguishes genetic from non-genetic disease, and what constitutes a genetic susceptibility. A general framework, reflecting the structure of biological explanations, is presented in which such distinctions can be made. We conclude that such distinctions are objective and are based on the biological facts; they are not "social constructions" nor do they presuppose resolution of philosophical problems regarding causation. PMID- 7856659 TI - Sanfilippo syndrome type A in two adult sibs. AB - We report on 2 adult sibs with Sanfilippo syndrome type A (MPS IIIA; deficiency of heparin sulfamidase) who were less functionally impaired than other reported individuals with this disorder. These individuals expand our understanding of the range of clinical expression that one may see in Sanfilippo syndrome type A. PMID- 7856660 TI - Clinical spectrum and genetic studies of Fukuyama congenital muscular dystrophy. AB - The association of congenital muscular dystrophy (CMD) with type II lissencephaly and ocular anomalies is found in Fukuyama CMD (FCMD), the Walker-Warburg syndrome (WWS), and muscle-eye-brain disease (MEBD). The classification of these disorders remains controversial. Between 1972 and 1992, we performed clinical and genetic studies in 41 families of FCMD, which is particularly frequent in Japan. Nine families (22%) had multiple affected children ("familial" FCMD). The other 32 families had only one affected child ("sporadic" FCMD). Parental consanguinity was documented in 5 sporadic FCMD families and in none of the familial cases. In total, 48 patients, including 7 sib pairs, were evaluated with regard to maximum motor ability, mental and convulsion states, cranial CT or MRI findings, and EEG and ophthalmological data. A difference between the sibs in motor ability was apparent in 4 families. Mental status also showed wide variation. Two of 7 sib pairs differed in EEG findings. The familial FCMD patients showed relatively more severe motor disability than that in the sporadic FCMD patients, while in mental and convulsion states no significant difference was found in both groups. Interestingly, in one family hydrocephalus was found in only one of the sibs. In addition, this patient showed encephalocele and retinal detachment at birth. Based on these observations, we consider the clinical spectrum of FCMD to be much broader than previously described and to overlap with that of "mild" WWS and MEBD. PMID- 7856661 TI - Non-immune hydrops fetalis associated with impaired fetal movement: a case report and review. AB - Non-immune hydrops fetalis (NIHF) is due to many different causes. Fetal hypomobility has been alluded to as a possible cause. We present a preterm fetus with NIHF secondary to fetal hypomobility. Fetal movements were undetected after the 20th week of gestation. The infant was born 8 weeks later and was edematous, had pleural effusions, and no spontaneous movements. He died on day four of life. Diffuse massive central nervous system (CNS) destruction found on post-mortem examination was thought to be the origin of the hypomobility. As all other causes of NIHF were eliminated, we propose that the NIHF in this infant was due to the hypomobility. This case then gives support to the assertion that fetal hypomobility is another cause of NIHF. The cause of the CNS catastrophy remains unelucidated. PMID- 7856662 TI - Molecular analysis of a complex chromosomal rearrangement and a review of familial cases. AB - A complex chromosome rearrangement (CCR) involving chromosomes 7, 8, and 13 was detected in a phenotypically normal woman ascertained through her mentally retarded son with abnormal phenotype. He had a karyotype with 47 chromosomes including an extra der(13). In initial banding studies the CCR in the mother was interpreted as a three-way translocation. Fluorescence in situ hybridization with whole chromosome libraries and a telomere-specific probe was used to better characterize the rearrangement. Combined data allowed us to reinterpret the CCR as a translocation and an insertion. A review of 35 familial CCRs involving at least three chromosomes led to the following observations: 1) familial CCRs tend to have fewer chromosomes involved and fewer break-points than do de novo CCRs; 2) familial transmission is mainly observed through female carriers although the origin of de novo cases is paternal; 3) an apparent excess of balanced female carriers among the offspring of index carriers was noted; and 4) meiotic segregation resulting in malformed liveborn infants is most frequently due to adjacent-1 segregation, followed by 4:2 segregation; no adjacent-2 segregation was observed. PMID- 7856663 TI - Encomium: Theodore Puck, a life in biophysics applied to medicine. PMID- 7856664 TI - Living history biography. PMID- 7856665 TI - Confirmation that the conotruncal anomaly face syndrome is associated with a deletion within 22q11.2. AB - The so-called "conotruncal anomaly face syndrome" (CTAFS) is characterized by a peculiar facial appearance associated with congenital heart disease (CHD), especially cardiac outflow tract defects such as tetralogy of Fallot (TOF), double outlet right ventricle (DORV), and truncus arteriosus (TAC). CTAFS and the DiGeorge anomaly (DGA) have many similar phenotypic characteristics, suggesting that they share a common cause. In many cases DGA is known to be associated with monosomy for a region of chromosome 22q11.2. Fifty CTAFS patients and 10 DGA patients, 11 parents couples and 10 mothers of CTAFS patients, and 3 parents couples and 2 mothers of DGA patients were examined by fluorescent in situ hybridization (FISH) using the N25 (D22S75) DGCR probe (Oncor). Monosomy for a region of 22q11.2 was found in 42 CTAFS, 9 DGA, 4 mothers, and 1 father who had CTAF without CHD. The remaining 8 CTAFS patients 1 DGA patient and 1 mother who had questionable CTAF without CHD, showed no such chromosome abnormality. For the control, 60 patients who had CHD without CTAF or other known malformation syndromes were examined and had no deletion of 22q11.2. Therefore, we conclude that CTAFS is a part of the CATCH 22 syndrome; cardiac defects, abnormal faces, thymic hypoplasia, cleft palate, and hypocalcemia (CATCH) resulting from 22q11.2 deletions. PMID- 7856666 TI - 18q- and 18q+ mosaicism in a mentally retarded boy. AB - A mentally retarded boy was found to have an unusual chromosomal mosaicism [46,XY, del(18) (q22)/46,XY,iso psu dic(18)(q23)]. The clinical manifestations are compatible with the 18q- syndrome. The chromosome alteration was defined by high resolution banding and fluorescence in situ hybridization (FISH). A mechanism to explain the origin of the two cell lines is presented and discussed. PMID- 7856667 TI - Lowry-Maclean syndrome does exist. PMID- 7856668 TI - Renal agenesis, multicystic dysplasia, and uretero-pelvic junction obstruction--a common pathogenesis? PMID- 7856669 TI - Cayler cardiofacial syndrome and del 22q11: part of the CATCH22 phenotype. PMID- 7856670 TI - Very-low-birth-weight outcomes of the National Institute of Child Health and Human Development Neonatal Network, November 1989 to October 1990. AB - OBJECTIVE: Our purpose was to describe the neonatal outcomes of 1804 very-low birth-weight (< or = 1500 gm) infants delivered between November 1989 and October 1990 in the participating centers of the National Institute of Child Health and Human Development Neonatal Research Network. STUDY DESIGN: In an observational study sociodemographic, pregnancy, and delivery data were collected soon after birth, and neonatal and outcome data at discharge, at 120 days, or at death. RESULTS: Maternal and birth weight characteristics included 64% black, 29% white; 71% single mothers; 18% no prenatal care; 17% antenatal steroids; and 12% multiple gestations. Birth weight distributions included 18% weighing 501 to 750 gm, 23% 751 to 1000 gm, 28% 1001 to 1250 gm, and 31% 1251 to 1500 gm. Survival was 39% at < 751 gm birth weight, 77% at 751 to 1000 gm, 90% at 1001 to 1250 gm, and 93% at 1251 to 1500 gm. Survival was 15% to 18% at < or = 23 weeks' gestation, 54% at 24 weeks, 59% at 25 weeks, and 71% at 26 weeks. Surfactant was administered to 45% of the 56% of infants with respiratory distress syndrome. Morbidity, including intraventricular hemorrhage (40%), septicemia (24%), symptomatic patent ductus arteriosus (22%), and necrotizing entercolitis (8%), increased with decreasing birth weight. Oxygen was administered for > or = 28 days to 82% of < 751 gm infants, 49% of 751 to 1000 gm infants, and 10% of > 1001 gm infants. Steroids were administered to 28% of infants who required oxygen for > or = 28 days. Mean hospital stay was 62 days for survivors and 18 days for infants who died. There were large intercenter variations in mortality and morbidity. CONCLUSION: Mortality and morbidity in very-low-birth-weight infants improved in 1989 to 1990 without an increase in morbidity or length of hospital stay. The threshold of the improved survival was > or = 24 weeks and 601 to 700 gm. Although such data are reassuring, the rate of major morbidity in < 1001 gm birth weight infants continues to be high. PMID- 7856671 TI - The effect of maternal oxygen administration during the second stage of labor on umbilical cord blood gas values: a randomized controlled prospective trial. AB - OBJECTIVE: Our aim was to determine whether supplemental oxygen during the second stage of normal labor affects cord blood gas and cooximetry values. STUDY DESIGN: Patients at term pregnancy were prospectively randomized to the control or treatment group at the onset of the second stage of labor. The treatment group received 10 L/min oxygen by face mask, which result in a mean fractional inspired oxygen concentration of 0.81. RESULTS: There were 86 patients randomized into the study. In the oxygen group there were significantly more cord arterial pH values < 7.20 (9/41 vs 2/44, p < 0.05). The control group was compared with two subgroups of patients receiving oxygen: those receiving oxygen therapy for < or = 10 minutes and those receiving oxygen for > 10 minutes. Analysis of variance demonstrated significant differences (7.285 +/- 0.058, 7.312 +/- 0.056, 7.237 +/- 0.064; F test 8.3, p = 0.0005). Among several independent variables, regression analysis demonstrated that only duration of oxygen therapy had a significant inverse relation to cord arterial pH (F test = 15.6, p = 0.0002). CONCLUSIONS: Prolonged oxygen treatment during the second stage of normal labor resulted in a deterioration of cord blood gas values at birth. PMID- 7856672 TI - Alloimmune thrombocytopenia: fetal and neonatal losses related to cordocentesis. AB - OBJECTIVE: This report describes the increased risks of cordocentesis in fetuses affected with alloimmune thrombocytopenia. STUDY DESIGN: As part of a multicenter treatment study clinical and laboratory data from five pregnancies with alloimmune thrombocytopenia in which there was a fetal or neonatal loss associated with cordocentesis were reviewed. The fetal or neonatal deaths were all thought to be a result of exsanguination. These fetuses were compared with a group of 44 affected fetuses who underwent the same procedure but who survived. The data were analyzed by the Wilcoxon rank-sum test and the two-tailed Fisher's exact test. A p value < 0.05 was considered significant. RESULTS: The mean platelet count at cordocentesis was significantly lower in the cases than in the controls (5.8 vs 32.8 x 10(9)/L, p = 0.005). The incidence of antenatal intracranial hemorrhage in the untreated sibling of the prior affected pregnancy was significantly greater in the cases than in the controls (two of five vs one of 42, p = 0.02). CONCLUSION: Fetuses affected with alloimmune thrombocytopenia are at increased risk for fatal exsanguination associated with cordocentesis. PMID- 7856673 TI - Antenatal diagnosis of urinary tract abnormalities by ultrasonography after 28 weeks' gestation: incidence and outcome. AB - OBJECTIVE: The objective was to establish the likelihood that antenatal upper urinary tract dilatation identified after 28 weeks of gestation will progress to significant postnatal uropathy. STUDY DESIGN: In 5 years, 3856 fetuses had ultrasonography after 28 weeks of gestation when the mothers were first seen in advanced pregnancy for delivery appointments or for other obstetric indications. Fetuses with urinary tract anomalies had ultrasonographic surveillance after 6 days and 6 weeks of life with further evaluation as necessary. RESULTS: Renal tract anomalies were identified in 313 fetuses, and 55 infants had significant renal tract abnormalities. There were 7 deaths; 2 infants were anephric and 5 with hydronephrosis had lethal congenital abnormalities. Dilatation of the upper urinary tract was identified in 7.7% of the fetuses (298/3856) but was transient in 216 of them (72%). Follow-up of children with transient renal pelvis dilatation found only one with a history of urinary tract infection. Obstruction occurred in 23 infants (6.0/1000) and 16 required surgical correction. Vesicoureteric reflux was identified in 14 infants (3.6/1000) and resolved by age 2 years in 64%. Unilateral multicystic renal dysplasia occurred in 8 and posterior urethral valves occurred in 3 infants. CONCLUSION: Antenatal ultrasonography after 28 weeks' gestation identified significant renal tract abnormalities with a frequency of 14.3 per 1000 births, permitting early treatment of the asymptomatic newborn and reducing later renal damage. PMID- 7856674 TI - Antepartum surveillance for a history of stillbirth: when to begin? AB - OBJECTIVE: A history of stillbirth is universally accepted as an indication for antepartum fetal heart rate testing. Our goal was to examine when fetal testing should begin in an otherwise healthy patient with a history of stillbirth. STUDY DESIGN: This is a nonconcurrent cohort study of patients who were seen for antepartum surveillance from January 1979 to December 1991 with a history of stillbirth as the only indication for testing. Subsequent pregnancies were evaluated for adverse outcomes and abnormal antepartum test results. RESULTS: There was one case of recurrent stillbirth among the 300 study patients. Nineteen patients (6.4%) had one or more positive antepartum surveillance tests (positive contraction stress test or biophysical profile < or = 4). Three patients (1%) had positive tests before 32 weeks, all of whom were subsequently delivered without incident at term. Three patients were delivered for positive tests at < 36 weeks, one by cesarean section for fetal distress. We could not detect a relationship between the gestational age of the previous stillborn and the incidence of abnormal tests or fetal distress in subsequent pregnancies. CONCLUSION: Antepartum surveillance should begin at > or = 32 weeks in the healthy pregnant woman with a history of stillbirth. PMID- 7856676 TI - A stereologic study of postmature placentas fixed by dual perfusion. AB - OBJECTIVE: Placental insufficiency has been considered the cause of increased morbidity in infants delivered postmaturely. Former quantitative studies have indicated a decrease in some placental structures just before term. In this study we describe a method of dual perfusion fixation to provide tissue for stereologic examination. Postmature placentas were examined with this method. STUDY DESIGN: Eleven postmature placentas and 14 placentas delivered at term were fixed by dual perfusion. The volume and the surface area of villi, the trophoblast volume, and the volume, surface area, and length of villous capillaries were estimated by stereologic examination. The Mann-Whitney test (p < or = 0.05) was used for statistical analysis. RESULTS: Morphologic features were normal in all placentas. No significant differences were disclosed in the stereologic estimates of placentas delivered at term and postmature placentas. CONCLUSION: No morphologic or significant quantitative changes were found in postmature placentas. PMID- 7856675 TI - Expression of inflammatory cytokines (interleukin-1 beta and interleukin-6) in amniochorionic membranes. AB - OBJECTIVE: This study was designed to investigate the expression of inflammatory cytokines (interleukin-1 beta and interleukin-6) by fetal membranes in response to infection in vivo and to endotoxin in organ culture. STUDY DESIGN: Amniochorionic membranes were collected from infected and uninfected women and analyzed for cytokine messenger ribonucleic acid and protein. Normal membranes were cultured and exposed to endotoxin. Messenger ribonucleic acid expression was analyzed by reverse transcriptase-polymerase chain reaction. Cellular localization of messenger ribonucleic acid and protein was determined by in situ hybridization and immunocytochemical evaluation, respectively. RESULTS: Messenger ribonucleic acid for interleukin-1 beta appeared to be increased in infected or endotoxin-stimulated amniochorionic membranes, whereas interleukin-6 messenger ribonucleic acid was only observed in infected membranes or after endotoxin stimulation. Interleukin-1 beta messenger ribonucleic acid was localized exclusively to chorionic cells, whereas protein was observed in both chorion and amnion. Interleukin-6 messenger ribonucleic acid and protein were produced in both amniotic and chorionic cells. CONCLUSION: Amniochorionic membranes are a site of inflammatory cytokine production. These findings may have significance in preterm labor or premature rupture of membranes. PMID- 7856677 TI - Biophysical profile testing as an indicator of fetal well-being in high-order multiple gestations. AB - OBJECTIVE: The purpose of this investigation was to determine the value of biophysical profile testing in preventing intrapartum death in patients with high order multiple gestations (triplets or quadruplets). STUDY DESIGN: A retrospective review was performed of patients with triplets and quadruplets cared for by Phoenix Perinatal Associates from October 1988 to December 1991. Biophysical profile testing was used as the primary method of fetal surveillance in these pregnancies. Fetal heart rate monitoring on an external monitor was used as back-up and in cases sent to labor and delivery for problems. The ultrasonographic parameters of the biophysical profile score were used without the nonstress test component because of technical difficulty with that test in high-order multiple pregnancies. A score of 6 to 8/8 was therefore considered reassuring, 4/8 equivocal, and 0 or 2/8 possibly abnormal. Testing was done twice per week. RESULTS: Eighteen patients with triplets and six patients with quadruplets constituted the study group. The last biophysical profile before delivery was examined to evaluate the value of the test. There were no antepartum deaths in these 78 babies. The last biophysical profile score was 2/8 in nine fetuses of five triplet pregnancies and two fetuses of one quadruplet pregnancy. These six pregnancies (25%) were delivered on the basis of biophysical profile results and clinical circumstances. There was no morbidity or mortality in the 19 babies delivered because of abnormal biophysical profile testing. Four pregnancies had poor outcome at delivery in spite of 8/8 biophysical profile scores on all babies within 4 days of delivery. Of these four, two patients had worsening pregnancy-induced hypertension, one had abruptio placentae, and one had a severely growth-retarded infant. CONCLUSION: There were no stillbirths in this series. Twenty-five percent of these pregnancies eventually were delivered for nonreassuring biophysical profile testing, with good outcome. Four pregnancies had poor neonatal outcome in spite of normal biophysical profile testing. All of these pregnancies had active changes in physiologic features leading to delivery (two worsening pregnancy-induced hypertension, one abruptio placentae, one spontaneous rupture of membranes and labor). The biophysical profile appears to be a reliable antepartum test of fetal well-being in triplets and quadruplets. PMID- 7856678 TI - Delivery of uncomplicated triplet pregnancies: is the vaginal route safer? A case control study. AB - OBJECTIVE: Our purpose was to evaluate the safety of vaginal delivery of triplets. STUDY DESIGN: A retrospective case-control study on 69 consecutive triplet pregnancies delivered in the same institution between 1981 and 1992. Vaginal delivery was attempted in 23 otherwise uncomplicated triplet pregnancies, which form the study group. They were compared with 23 controls undergoing routine cesarean section and matched for gestational age at birth. Maternal hospital stay, neonatal mortality, hospitalization in the neonatal intensive care unit, and 5-minute Apgar scores were compared by means of paired t tests. RESULTS: In the vaginal delivery group there was one neonatal death related to prematurity (32 weeks) after intrapartum cesarean section for failure to progress. However, neonatal mortality was not significantly increased in comparison with controls (1 of 69 vs 0). In the study group Apgar scores were significantly higher (9.5 vs 8.4) and hospitalization in the neonatal care intensive unit was significantly shorter (6 vs 18 days) than in the cesarean section group (p < or = 0.002). CONCLUSION: In carefully selected cases vaginal delivery of triplets may be safe. PMID- 7856679 TI - Reduced placental villous tree elaboration in small-for-gestational-age pregnancies: relationship with umbilical artery Doppler waveforms. AB - OBJECTIVE: Our purpose was to investigate the three-dimensional architecture of placental villi from normal and growth-restricted fetuses and relate findings to umbilical artery blood flow velocity waveforms. STUDY DESIGN: Placentas from term (n = 15) and preterm (n = 5) appropriately grown and term (n = 9) and preterm (n = 7) growth-restricted fetuses (birth weight < 10th percentile) were examined to determine the number of arteries per stem villus and the three-dimensional configuration of the villous trees and their vessels. Umbilical blood flow before delivery was assessed by Doppler ultrasonography. The effects of age and growth restriction were determined by two-way analyses of variance. RESULTS: Growth restriction was associated with reduced large vessel wall thickness (p < or = 0.05) but no reduction in the number of these vessels per stem villus. The volumes and surface areas of intermediate and terminal villi were reduced (p < or = 0.001), especially in preterm growth-restricted cases, where a marked reduction in diastolic blood flow velocity was observed in the umbilical artery. CONCLUSIONS: Reduced villous development may contribute to abnormal umbilical artery blood flood flow, as assessed by Doppler ultrasonography, in some cases of intrauterine growth restriction. PMID- 7856680 TI - Safety of metronidazole in pregnancy: a meta-analysis. AB - OBJECTIVE: Our purpose was to determine from published experience in humans whether metronidazole exposure during the first trimester of pregnancy is associated with an increased teratogenic risk. STUDY DESIGN: All published articles reporting on metronidazole use during pregnancy were screened by two independent reviewers to select those including pregnant patients exposed during the first trimester and comparing the outcomes of their pregnancies with that of patients either not exposed to metronidazole or exposed only during the third trimester. The outcome under consideration was the occurrence of birth defects in live-born infants. The overall odds ratios of first-trimester exposure versus no first-trimester exposure was calculated by combining the selected studies in a meta-analysis according to the procedure of Mantel and Haenszel. RESULTS: From 32 identified studies, 7 met the inclusion criteria for meta-analysis. Six were prospective and included 253 women exposed to the drug in the first trimester of pregnancy; one was retrospective and reported on 1083 exposed women. The overall weighted odds ratio of exposure versus no exposure during the first trimester calculated by meta-analysis of the 7 studies was 0.93 (95% confidence interval 0.73 to 1.18). The odds ratio calculated from the 6 prospective studies was 1.02 (95% confidence interval 0.48 to 2.18). CONCLUSION: Metronidazole does not appear to be associated with an increased teratogenic risk. PMID- 7856681 TI - Ex vivo human placental transfer of human immunodeficiency virus-1 p24 antigen. AB - OBJECTIVE: Our purpose was to determine whether human immunodeficiency virus-1 p24 antigen crosses the human placenta and, if so, to determine its clearance index relative to antipyrine. STUDY DESIGN: Eight term human placentas from uncomplicated vaginal or cesarean section deliveries were studied by ex vivo placental perfusion to determine the incidence and concentration required to obtain passage of p24 antigen into the fetal circulation. The concentration of p24 antigen was determined by antigen-capture enzyme immunoassay. RESULTS: The passage of p24 antigen into the fetal circulation was observed in three of five placentas studied when the p24 antigen concentration in the maternal circulation was 2942.8 +/- 401 pg/ml. When the p24 concentration in the maternal circulation was raised approximately fourfold to 14506 +/- 4124 pg/ml, p24 antigen passed to the fetal circulation in two of three placentas and in three of three placentas in the closed perfusion system. CONCLUSIONS: p24 antigen crossed the human placenta to the fetal circulation in what appears to be a concentration-dependent manner. PMID- 7856682 TI - Single-cell analysis of the RhD blood type for use in preimplantation diagnosis in the prevention of severe hemolytic disease of the newborn. AB - OBJECTIVE: Our purpose was to develop a molecular assay to determine the fetal RhD blood type on single diploid cells, including blastomeres. STUDY DESIGN: Polymerase chain reaction amplification of a 99 bp deoxyribonucleic acid fragment of the RhD gene or a 113 bp fragment from the RhCE gene was performed from 20 venous blood samples and 20 amniotic fluid samples and from 60 single-cultured lymphoblasts and 12 media blanks mixed in a blinded fashion. This reaction was similarly tested after whole-genome amplification on 10 lymphoblasts and seven human blastomeres. RESULTS: Deoxyribonucleic acid amplification was successful and correct from all genomic deoxyribonucleic acid samples. Ninety-seven percent of single cells amplified; correct diagnosis was made in 96%. Five blastomeres successfully amplified. No media blanks produced amplified, contaminating deoxyribonucleic acid. CONCLUSIONS: The RhD blood type can be determined reliably from single cells and can be used for preimplantation genetic diagnosis for the prevention of rhesus hemolytic disease. PMID- 7856683 TI - First-trimester multifetal pregnancy reduction: acute and persistent psychologic reactions. AB - OBJECTIVE: Our purpose was to determine acute and persistent psychologic impacts of multifetal pregnancy reductions and patients' ability to cope with fetal loss while simultaneously bonding to surviving infants. STUDY DESIGN: The first 100 women to undergo a multifetal reduction were invited to participate in a retrospective telephone study assessing their emotional reactions and attitudes toward multifetal reduction. The semistructured interview elicited demographic and obstetric data and contained scales used in previous studies of reproductive loss, which assessed repetitive thoughts about reduced fetuses, catastrophic fears, and lingering depressive feelings. RESULTS: More than 65% of the sample recalled acute feelings of emotional pain, stress, and fear during the reduction procedure. Mourning for the lost fetuses was reported by 70% of women, but most grieved for only 1 month. Thoughts about reduced fetuses occurred moderately frequently after the reduction but rarely at follow-up. Persistent depressive symptoms were mild, although moderately severe levels of sadness and guilt continued for many. Nonetheless, 93% would make the same decision again. Emotional reactions of patients who miscarried differed little. The small subsample who continued to be most affected were younger (p < 0.02), were more religious (p < 0.003), and had viewed the multifetal pregnancy on ultrasonography more often (p < 0.009). CONCLUSIONS: Multifetal reductions, although highly stressful psychologically, are well tolerated. Sadness and guilt may persist, especially for an identifiable subgroup. Normal maternal bonding and achievement of parenthood goals facilitate grief resolution. The large majority were reconciled to the termination of some fetuses to perserve the lives of a remaining few. PMID- 7856684 TI - A prospective comparison of transvaginal ultrasonography and diagnostic hysteroscopy in the evaluation of patients with abnormal uterine bleeding: clinical implications. AB - OBJECTIVE: We determined the diagnostic value of transvaginal ultrasonography for endometrial and intrauterine abnormalities in patients with abnormal uterine bleeding. STUDY DESIGN: Between June 1, 1992, and June 1, 1993, 279 consecutive patients underwent transvaginal ultrasonography. Findings were compared with the final diagnosis established by diagnostic hysteroscopy and histologic examination. RESULTS: Transvaginal ultrasonography demonstrated a sensitivity of 0.96 and a specificity of 0.89. With a pretest probability (prevalence) of 0.42, this resulted in posttest probabilities of 0.03 in the case of a normal sonogram and 0.87 for an abnormal sonogram. The corresponding likelihood ratios were 0.04 and 9.09, respectively. CONCLUSION: Transvaginal ultrasonography seems to be an effective procedure to exclude endometrial and intrauterine abnormalities. Its use could be implemented as a routine first-step procedure in patients with abnormal uterine bleeding, and it selects those in need of further diagnostic evaluation in the case of an abnormal or inconclusive sonogram. PMID- 7856685 TI - Genital ulcer disease in women infected with human immunodeficiency virus. AB - OBJECTIVE: The purpose of this study was to determine the prevalence and microbiologic characteristics of genital ulcer disease in a population of human immunodeficiency virus-infected women. STUDY DESIGN: A retrospective cohort study was performed in university-affiliated, hospital-based women's human immunodeficiency virus clinics. A total of 307 women with human immunodeficiency virus infection were followed up during 20 months. There were no interventions. Age, race, CD4+ cell counts, bacteriologic and virologic analyses in cases of ulcers, serologic testing for syphilis, and histopathologic examination in selected cases (n = 6). RESULTS: Among 307 women followed up over a 20-month period, 43 ulcers were detected with a prevalence of 14%. Among the ulcer cases the average absolute CD4+ lymphocyte number was 210/mm3. Diagnostic evaluation yielded no proven etiologic agent in 26 (60%) of the cases. Twelve of the 43 cases (28%) were positive for herpes simplex-2. Five cases (12%) yielded unusual or mixed bacteriologic types. No cases were attributable to primary syphilis infection. One case each of an ulcer infected with cytomegalovirus, Chlamydia trachomatis, and Gardnerella vaginalis, as well as three unusual presentations of herpetic ulcers, is analyzed in detail. CONCLUSION: These cases exemplify the often dramatic presentation of human immunodeficiency virus-related genital ulcers and the clinical complexity of both diagnosis and management. The frequent lack of an infectious or neoplastic cause in human immunodeficiency virus infected women with genital ulcer disease suggests that human immunodeficiency virus may play a local role in causation or exacerbation. Biopsies of atypical genital ulcers should be considered to aid diagnosis. Further studies are needed to elucidate the pathogenesis of genital ulcer disease in human immunodeficiency virus-infected women. PMID- 7856686 TI - Sustained-release estradiol implants and a levonorgestrel-releasing intrauterine device in hormone replacement therapy. AB - OBJECTIVE: Efficacy and acceptability of continuous combined parenteral hormone replacement consisting of subdermal estradiol delivery and intrauterine progestin delivery was studied. STUDY DESIGN: Thirty-six volunteer postmenopausal women seeking treatment for climacteric symptoms participated in this open, randomized study. The subjects received either one or three subdermal implants with a controlled daily release of estradiol in vitro. Progestin therapy was carried out with a levonorgestrel-releasing intrauterine device. Climacteric symptoms and serum concentrations of estrone, estradiol, follicle-stimulating hormone, and sex hormone-binding globulin were followed up for 1 year. The subjects kept daily records of bleeding. RESULTS: Serum estradiol concentrations with the set of three implants were stable during the follow-up period; the range of mean serum estradiol concentrations was 45 to 57 pg/ml. Four women, all from the group with one implant, discontinued the study after 6 months because of the return of climacteric symptoms. In spite of different daily estradiol doses, the patterns of bleeding were similar in both groups. At the end of the follow-up year 72% of the women had had no bleeding or spotting in the previous 3 months. CONCLUSION: Our results suggest that by combining subdermal and intrauterine steroid delivery systems postmenopausal hormone replacement therapy can be carried out successfully without daily effort and with minimal or no bleeding. PMID- 7856687 TI - Does "incessant" ovulation increase risk for early menopause? AB - OBJECTIVE: We attempted to determine whether gynecologic histories differ in women who have and have not experienced an early menopause. STUDY DESIGN: A group of 344 "case" women whose average age at menopause was 42.2 years and an age matched group of 344 "control" women still menstruating or menopausal after age 46 were selected from a survey of 10,606 women aged 45 to 54 years for interviews about their reproductive history. RESULTS: Case women were more likely to have had menarche at or before age 11, had shorter cycle lengths, had fewer pregnancies with live births, and had more frequent pelvic operations including unilateral oophorectomy and multiple cesarean sections. Case women had a greater number of presumed ovulatory cycles, as estimated from age at menarche, average cycle length, and years of anovulation associated with pregnancies or oral contraceptive use. In a multivariate model including smoking status and body mass index, ovulatory cycles were a significant predictor of early menopause, especially after an estimated 300 ovulations. CONCLUSION: The reproductive histories of women who experienced an early menopause suggest a pattern of more rapid oocyte loss ("incessant" ovulation). PMID- 7856688 TI - Single-agent methotrexate chemotherapy for the treatment of nonmetastatic gestational trophoblastic tumors. AB - OBJECTIVE: Our purpose was to evaluate the efficacy and toxicity of single-agent methotrexate chemotherapy and to identify factors associated with chemotherapy resistance in patients with nonmetastatic gestational trophoblastic tumors. STUDY DESIGN: A total of 337 patients with nonmetastatic gestational trophoblastic tumors (choriocarcinoma and invasive mole) received treatment at the Brewer Trophoblastic Disease Center of Northwestern University Medical School from 1962 through 1990. Of the 337 patients, 253 (75.0%) were treated initially with single agent methotrexate 0.4 mg/kg intravenously daily for 5 days per treatment course repeated every 14 days. RESULTS: All 337 patients with nonmetastatic gestational trophoblastic tumors were cured. Of the 253 patients initially treated with methotrexate, resistance developed in 27 (10.7%), 22 (8.7%) required a second agent (actinomycin D), 3 (1.2%) required multiagent chemotherapy, and 2 (0.8%) had a hysterectomy to achieve complete remission. Factors associated with the development of resistance were pretreatment human chorionic gonadotropin level > or = 50,000 mlU/ml (36%, p < 0.001), nonmolar antecedent pregnancy (26%, p < 0.02), and clinicopathologic diagnosis of choriocarcinoma (20.5%, p = 0.02). Significant methotrexate toxicity requiring a change to a second agent occurred in only 12 patients (4.7%), the most common side effect being severe stomatitis. CONCLUSIONS: In a large series of patients with nonmetastatic gestational trophoblastic disease, single-agent methotrexate chemotherapy proved to be an extremely well-tolerated and effective treatment. PMID- 7856689 TI - Genital tract abnormalities and female sexual function impairment in systemic sclerosis. AB - OBJECTIVE: Our purpose was to determine the involvement of the female genital tract and its functional consequences on menstrual and sexual aspects in systemic sclerosis. STUDY DESIGN: Sixty women with systemic sclerosis and 23 age- and disease duration-matched women with either rheumatoid arthritis or systemic lupus erythematosus were surveyed with a comprehensive questionnaire addressing problems before and after disease onset. Fourteen systemic sclerosis patients also had gynecologic evaluations. RESULTS: Vaginal dryness (71%), ulcerations (23%), and dyspareunia (56%) were significantly more frequent in patients with systemic sclerosis after disease onset than before and also in comparison with control subjects. Vaginal tightness and constricted introitus were present in 5 of 60 systemic sclerosis patients. More than half of systemic sclerosis patients reported a decrease in the number (p = 0.04) and intensity (p = 0.02) of orgasms, compared to < 20% of control subjects. The desire and frequency of coitus and the sexual satisfaction index were impaired equally in each group. Skin tightness, reflux-heartburn, and muscle weakness adversely affected sexual relations more in systemic sclerosis than in control subjects. On gynecologic examination 5 of 11 systemic sclerosis patients had small-sized uteri, and 3 of them had early menopause at 29, 38, and 43 years. Seven of 16 (44%) women with systemic sclerosis, compared with 6% of normal women in the United States, attained natural menopause before age 45. CONCLUSIONS: Although impairment in various indexes of sexual function occurs in a number of autoimmune diseases, decreased orgasmic function appears to be limited to systemic sclerosis. Vaginal involvement and other systemic sclerosis-related systemic symptoms adversely influence sexual relations. Menstrual abnormalities, including early menopause, affect many patients. Genital tract involvement occurs in a substantial proportion. Prospective longitudinal studies are warranted. PMID- 7856690 TI - The squirrel monkey: an animal model of pelvic relaxation. AB - OBJECTIVE: Casual observations of pelvic prolapse have previously been made in adult female squirrel monkeys. We objectively observed and described the pelvic findings of the adult females in our colony to evaluate their potential as an animal model for studies of pelvic relaxation. STUDY DESIGN: Subsets of a group of 28 adult female squirrel monkeys were examined on three separate occasions and photographed to document perineal findings. Four areas of loss of support in the vagina were described, including the urethra, anterior segment, cervix, and posterior segment. The degree of loss of support at each specific site was documented. Also, three measurements were obtained from each animal, including the distance from the base of the clitoris to the posterior edge of the perineal body and the length and width of the introitus. The length of the perineal body was calculated. RESULTS: Fifty percent of the animals had at least one site of pelvic prolapse at rest or on straining. With straining 50% had urethral prolapse, 21% had anterior segment prolapse, and 11% had posterior segment prolapse. None of the animals had evidence of cervical prolapse. Of the animals with findings of pelvic relaxation, 43% had combined prolapse at two or more sites. Of the measurements obtained, only the width of the introitus was significantly different between the group of normal animals and those found to have pelvic prolapse (p < 0.0005). CONCLUSION: On the basis of observations of our colony of squirrel monkeys, a significant number of animals demonstrated findings of pelvic support loss with defects similar to those observed in humans. Although limitations to some techniques of evaluation and surgical intervention exist, the squirrel monkey is an animal model that may provide new opportunities for basic investigation of the pathophysiologic features and the management of pelvic relaxation. PMID- 7856691 TI - Cytokine-induced secretion of monocyte chemotactic protein-1 by human endometriotic cells in culture. The Groupe d'Investigation en Gynecologie. AB - OBJECTIVE: Local secretion of chemotactic factors could contribute to the attraction of macrophages into the peritoneal cavity of women with endometriosis. The purpose of this study was to investigate the ability of endometriotic cells to produce monocyte chemotactic and activating protein-1 in response to interleukin-1 beta and tumor necrosis factor-alpha, which are found in elevated levels in the peritoneal fluid of patients with endometriosis. STUDY DESIGN: Cultures of fibroblast-like and epithelial cells isolated from endometriotic tissue were incubated with different concentrations of cytokines for varying periods of time. The de novo secretion of monocyte chemotactic protein-1 in the culture supernatants was analyzed by immunoprecipitation and electrophoresis after metabolic labeling with sulfur 35-labeled cysteine. RESULTS: The incubation of endometriotic fibroblast-like cells with interleukin-1 beta and tumor necrosis factor-alpha resulted in a time- and dose-dependent release of monocyte chemotactic protein-1 into the culture supernatant. Coincubation of the cells with tumor necrosis factor-alpha and interferon gamma resulted in a synergistic and dose-dependent increase of the monocyte chemotactic protein-1 secretion, whereas interferon gamma alone had no significant effect. Preliminary results indicate that monocyte chemotactic protein-1 is also produced by endometriotic epithelial cells in response to the same cytokines. CONCLUSIONS: Cytokine stimulated endometriotic cells synthesize and secrete monocyte chemotactic protein-1 in culture, and they may play a relevant role in the recruitment of macrophages to the peritoneal cavity of patients by the local production of chemotactic factors. PMID- 7856693 TI - Toward universal criteria for gestational diabetes: the 75-gram glucose tolerance test in pregnancy. AB - OBJECTIVES: The purpose of this study was to determine the distribution of values for the 75 gm glucose tolerance test in pregnancy and to define glucose intolerance by the relationship between maternal glucose values and neonatal macrosomia. STUDY DESIGN: A total 3505 unselected pregnant women were given a 75 gm, 2-hour glucose tolerance test. Diet or insulin therapy was offered only to patients with a fasting plasma glucose level > or = 105 mg/dl or a 2-hour post glucose-load value > or = 200 mg/dl. Birth weights of live-born singletons delivered from 36 to 42 weeks whose mothers had a fasting plasma glucose level < 105 mg/dl and 2-hour post-glucose-load value < 200 mg/dl were used to calculate relationships between glucose levels and birth weights. RESULTS: At 24 to 28 weeks' gestation the mean and SD plasma glucose values were fasting 83.6 (8.9) mg/dl, 1 hour 128.4 (32.9) mg/dl, and 2 hour 108.4 (24.8) mg/dl. In a multiple logistic regression model the factors found to be statistically significantly associated with macrosomia were maternal race, parity, prepregnancy body mass index, weight gain, gestational age at testing, fasting plasma glucose level, and 2-hour post-glucose-load value. A positive association was found between maternal glucose values and birth weight percentiles. No clinically meaningful glucose threshold values relative to birth weight or macrosomia were found. CONCLUSION: In the absence of a meaningful threshold relationship between glucose tolerance test values and clinical outcome, criteria defining gestational diabetes will probably be established by consensus. PMID- 7856692 TI - Suppression of gelatinase production with decreased invasiveness of choriocarcinoma cells by human recombinant interferon beta. AB - OBJECTIVE: Choriocarcinoma is a highly invasive gynecologic tumor, and hematogenous metastases frequently develop. To establish a molecular basis for antiinvasion therapy of choriocarcinoma, we examined the effects of human recombinant interferons on gelatinase production and invasion by choriocarcinoma cells. STUDY DESIGN: Using five choriocarcinoma cell lines, we measured gelatinase activity by gelatin zymography. The effects of recombinant interferons (rIFN-alpha, rIFN-beta, and rIFN-gamma) were then analyzed by Western blot analysis and chemoinvasion assay. RESULTS: High levels of 72 kd gelatinase activity were detected in the highly invasive choriocarcinoma cell lines, two of which also contained an active form of 72 kd gelatinase with an apparent molecular mass of 68 kd. Gelatinase production was decreased by incubation with rIFN-beta. In the chemoinvasion assay, only rIFN-beta had an inhibitory effect on the invasiveness of tumor cells without a cytotoxic effect. CONCLUSION: Choriocarcinoma cells showed high 72 kd gelatinase activity, which suggested a role for the enzyme in vascular metastasis. Studies on the use of rIFN-beta to inhibit metastasis of choriocarcinoma via suppression of gelatinase production are warranted. PMID- 7856694 TI - Gestational diabetes survey. AB - OBJECTIVE: Our purpose was to determine how residents in obstetrics and gynecology and fellows in maternal-fetal medicine are currently being trained to diagnose and manage gestational diabetes mellitus. STUDY DESIGN: Questionnaires were mailed to 202 obstetrics and gynecology residency program directors and 78 maternal-fetal medicine fellowship directors. RESULTS: Sixty-four (82%) of the maternal-fetal medicine directors versus 142 (70%) of the residency directors responded. Universal screening, use of a 50 gm glucose challenge with a 1-hour postingestion sample, no requirements for fasting before the screening test, use of two abnormal values on the 3-hour glucose tolerance test to define gestational diabetes mellitus, and initiation of insulin for elevated fasting glucose levels in spite of diet therapy were each recommended by > 90% of the respondents. CONCLUSION: Although the optimal management of gestational diabetes mellitus remains controversial, program directors are in general agreement with many aspects of the diagnosis and management. PMID- 7856695 TI - Gestational diabetes diagnostic criteria: long-term maternal follow-up. AB - OBJECTIVE: The purpose of this study was to determine if the risk of having diabetes later in life was different in those who were gestational diabetic by Coustan criteria and not by National Diabetes Data Group criteria and those who are gestational diabetic only by National Diabetes Data Group criteria. STUDY DESIGN: Between 1988 and 1990, 331 patients from the Springfield area who were diagnosed as gestational diabetic by either criteria since 1975 were examined for the development of diabetes by history or by 2-hour, 75 gm glucose tolerance test. National Diabetes Data Group criteria were used to determine normality or diabetic abnormality. Variables associated with diabetes were obtained. The data were analyzed using three groups: (1) gestational diabetic by National Diabetes Data Group criteria, (2) gestational diabetic by Coustan's criteria only, and (3) both groups 1 and 2. RESULTS: Group 1 had 190 (57.4%) and group 2 had 141 patients (42.6%), of which 25.3% and 25.5% had diabetic abnormality, respectively. Variables predictive for the development of diabetic abnormality were glucose tolerance test fasting value, number of gestational diabetic pregnancies, time to follow-up, and prepregnancy weight index. There were no differences in these variables between the normal patients or those with diabetic abnormality in groups 1 and 2. CONCLUSION: Because Coustan criteria classify an additional 68.9% patients who have the same risk and risk factors for later development of diabetic abnormality and pregnancy complications compared with patients who are gestational diabetic by National Diabetes Data Group criteria, the criteria of Carpenter and Coustan should be adopted as the standard for diagnosing gestational diabetes. PMID- 7856696 TI - A new model of diabetic pregnancy with genetic hypertension: pregnancy in spontaneously hypertensive rats with neonatal streptozotocin-induced diabetes. AB - OBJECTIVE: We designed this study to develop a new animal model of high-risk pregnancy complicated by hypertension and diabetes mellitus. STUDY DESIGN: Female spontaneously hypertensive rats were injected intraperitoneally with 75 mg/kg streptozotocin or vehicle as control at 2 days of age. They were mated with untreated male spontaneously hypertensive rats at 4 to 5 months of age. RESULTS: Hyperglycemia, defined as > 20 mmol/L plasma glucose level, was maintained during pregnancy in streptozotocin-treated spontaneously hypertensive rats, and systolic blood pressure was significantly higher in the streptozotocin-treated group than in controls before delivery (p < 0.01). Furthermore, urinary albumin excretion was significantly increased in the streptozotocin-treated group during and after pregnancy compared with the prepregnant level (p < 0.05), whereas in controls it remained unchanged. The incidence of low birth weight was significantly higher in male neonates from streptozotocin-treated mothers than those from control mothers (p < 0.05). CONCLUSION: Neonatally streptozotocin-treated spontaneously hypertensive rats may be useful for studying the combined effect of hypertension and diabetes mellitus during pregnancy. PMID- 7856697 TI - Impact of a nurses' strike on the cesarean birth rate. AB - OBJECTIVE: Our purpose is to describe the impact of a 31-day nurses' strike on the cesarean birth rate in the province of Manitoba, Canada. STUDY DESIGN: Computerized hospital records, obtained for all births over a 24-month period, were used to identify complications of labor indicating cesarean section, method of delivery, and adverse maternal and newborn outcomes. The strike interval was compared with a 16-month prestrike period. RESULTS: The cesarean section rate in the strike interval, 12.5 per 100 deliveries, was significantly lower than the prestrike rate of 14.6 per 100 deliveries (p < 0.05). Reductions occurred primarily among breech deliveries and among women with a previous cesarean section. No differences were observed in the rates of individual adverse maternal or newborn outcomes. However, the pooled incidence of adverse newborn outcomes was significantly higher during the strike than during the prestrike period (10.2 vs 8.1/100 deliveries, odds ratio 1.27, 95% confidence interval 1.07 to 1.52). CONCLUSION: In response to constraints imposed by a reduced nursing complement, physicians increased the frequency of vaginal birth in breech presentation and among women with previous cesarean section. PMID- 7856698 TI - The impact of mandated in-hospital coverage on primary cesarean delivery rates in a large nonuniversity teaching hospital. AB - OBJECTIVE: Our purpose was to determine whether attending physician call status affected the primary cesarean delivery rates of the resident or private services after institution of in-hospital coverage. STUDY DESIGN: Data for the study year, during which in-hospital attending coverage was in place, were compared with those of the previous year, during which in-hospital attending coverage of residents was not in place. Birth records were analyzed retrospectively for physician and patient factors. RESULTS: For the year before in-hospital coverage the institutional total cesarean rate was 24.9%, with a primary cesarean section rate of 17.6%. In the first year of coverage the total cesarean delivery was 21.7%, with a decrease in the primary rate to 15.3%. The resident service primary cesarean delivery rate was 10.6% during the study year, which was unchanged from 10.9% the prior year and did not contribute to the overall decrease. Conversely, the private service primary cesarean rate decreased from 18.0% in the prestudy year to 13.4% when the attending physician was on call in the hospital but remained higher at 17.5% when the attending physician was on call not in the hospital. CONCLUSIONS: In-hospital attending physician coverage lowered individual attending physicians' private service primary cesarean rates. Resident service primary cesarean rates were lower than private service and were unaffected by the initiation of in-hospital coverage. PMID- 7856699 TI - Risk factors for preeclampsia in healthy nulliparous women: a prospective multicenter study. The National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. AB - OBJECTIVE: We conducted a large clinical trial to evaluate the effect of low-dose aspirin on the frequency of preeclampsia in nulliparous women. A secondary objective of the trial was to identify those clinical characteristics that might be predictive for the development of preeclampsia. STUDY DESIGN: A total of 2947 healthy women with a single fetus were prospectively followed up from randomization at 13 to 27 weeks' gestation to the end of pregnancy. Of these, 1465 women were assigned to low-dose aspirin and 1482 to placebo. Baseline maternal blood pressure and demographic characteristics were examined for the prediction of preeclampsia. RESULTS: Preeclampsia developed in 156 women (5.3%). Four characteristics predicted the development of preeclampsia: in order of importance, systolic blood pressure at entry, prepregnancy obesity (weight as a percentage of desirable weight), number of previous abortions or miscarriages, and smoking history. Contrary to previous reports, black race was not a risk factor for preeclampsia. Systolic blood pressure was a better predictor of preeclampsia than either diastolic or mean arterial blood pressure. The greater the blood pressure or prepregnancy weight, the greater was the risk for preeclampsia. If the woman had never smoked or had never been previously pregnant, her risk was also higher than average. A multivariate logistic regression equation based on these four factors was able to define a tenth of the population at very high risk and another tenth at very low risk; the ratio of risk between these two groups was 12:1. The p value for each of the multivariate coefficients of the risk equation was systolic blood pressure (p < 0.001), prepregnancy weight (p < 0.01), smoking history (p < 0.01), and gravidity (p < 0.05). There were no statistically significant differences in the predictive values of these risk factors between women receiving low-dose aspirin or placebo. CONCLUSIONS: These risk factors should be of value to practitioners counseling women regarding preeclampsia. Moreover, such risk factors should be considered in the design of future studies dealing with preeclampsia. PMID- 7856700 TI - Fetal fibronectin levels are elevated in maternal plasma and amniotic fluid of patients with severe preeclampsia. AB - OBJECTIVE: Our purpose was to investigate levels of fetal fibronectin in maternal plasma, amniotic fluid, and umbilical cord plasma from patients with severe preeclampsia. STUDY DESIGN: The study group comprised 20 patients with severe preeclampsia (group A). An antepartum comparison group was composed of 20 healthy patients matched for gestational age (group B). An intrapartum control group consisted of 20 term normotensive patients (group C). Maternal plasma samples were collected before labor (groups A and B), then immediately after delivery, and again at 20 to 24 hours post partum (groups A and C). Amniotic fluid was also collected in early labor, and umbilical cord blood was collected at delivery (groups A and C). Samples were assayed for fetal fibronectin by a specific enzyme linked immunoassay. RESULTS: Before labor maternal plasma levels of fetal fibronectin were significantly elevated in preeclamptic patients compared with patients in group B (p < 0.0001). Plasma levels of fetal fibronectin were also increased in preeclamptic patients compared with patients in group C at delivery (p < 0.0001) and post partum (p < 0.05). Additionally, amniotic fluid levels of fetal fibronectin in the preeclamptic patients were significantly increased (p < 0.05). In contrast, umbilical cord plasma fetal fibronectin concentrations from the preeclamptic and control patients were similar. CONCLUSIONS: Fetal fibronectin is elevated in the maternal plasma and amniotic fluid, but not umbilical cord plasma, of patients with severe preeclampsia. These findings suggest an increase in production of fetal fibronectin from chorionic trophoblast in patients with preeclampsia or an abnormal interaction between chorionic trophoblast and decidua with resultant increased leakage into the maternal circulation and amniotic fluid. PMID- 7856701 TI - Platelet intracellular free calcium response to arginine vasopressin is similar in preeclampsia and normal pregnancy. AB - OBJECTIVE: Our purpose was to compare the effect of arginine vasopressin stimulation on platelet free intracellular calcium levels in normal pregnancy, incipient preeclampsia, and established preeclampsia. STUDY DESIGN: Cross sectional and prospective observational study designs were used. Platelet free intracellular calcium was measured by flow cytometry in 10 nonpregnant female volunteers, 10 women with established preeclampsia and their normal pregnant matched controls, and 64 normal pregnant women at 28 weeks' gestation. All pregnant women were nulliparous. RESULTS: Increased response to arginine vasopressin stimulation was observed in nonpregnant compared with pregnant women (p < 0.001). No differences were observed between women with normal pregnancy, incipient preeclampsia, or established preeclampsia. CONCLUSION: The platelet intracellular free calcium response to arginine vasopressin is not a feature of incipient or established preeclampsia. Therefore, in contrast to a previous report, it does not appear to have value as a predictive test for preeclampsia. PMID- 7856702 TI - Corticotropin-releasing hormone and pituitary-adrenal hormones in pregnancies complicated by chronic hypertension. AB - OBJECTIVE: We hypothesized that maternal plasma corticotropin-releasing hormone levels are elevated in chronic hypertension and that elevations modulate maternal and fetal pituitary-adrenal function. STUDY DESIGN: Venous blood samples and 24 hour urine specimens were obtained in normal and hypertensive pregnancies at 21 to 40 weeks of gestation. Corticotropin-releasing hormone, corticotropin, cortisol, dehydroepiandrosterone sulfate, and total estriol levels were measured by radioimmunoassay. Mean hormone levels were compared by unpaired t test or two way analysis of variance. RESULTS: Plasma corticotropin-releasing hormone levels were elevated early in hypertensive pregnancies but did not increase after 36 weeks. Levels of pituitary and adrenal hormones were not different in normal and hypertensive women. However, maternal plasma estriol levels were lower in hypertensive pregnancies compared with normal pregnancies. CONCLUSIONS: Fetal 16 hydroxy dehydroepiandrosterone sulfate, the major precursor to placental estriol production, has been reported to be lower than normal in hypertensive pregnancies, possibly explaining the decreased plasma estriol levels reported here. Early stimulation of placental corticotropin-releasing hormone production or secretion may be related to accelerated maturation of placental endocrine function in pregnancies complicated by chronic hypertension. PMID- 7856703 TI - Cervical examination and tocodynamometry at 28 weeks' gestation: prediction of spontaneous preterm birth. AB - OBJECTIVE: We determined the value of cervical examination and tocodynamometry in identifying nulliparous women at risk for spontaneous preterm delivery. STUDY DESIGN: At 27.5 +/- 0.8 weeks' gestation 589 women underwent 30 minutes of tocodynamometry, and 570 of these had a cervical examination. Positive findings on these examinations were compared to the rate of spontaneous preterm delivery, defined as those deliveries following the onset of spontaneous labor or premature rupture of membranes. RESULTS: The two best predictors of spontaneous preterm birth were two or more contractions in 30 minutes and the presence of a soft or medium consistency on cervical examination. As the contractions increased from zero to four or more, the rate of spontaneous preterm delivery rose from 4.2% to 18.2%. CONCLUSION: In nulliparous women at 28 weeks' gestation, uterine contractions and several components of the cervical examination predicted spontaneous preterm birth. PMID- 7856705 TI - Costs of triplet pregnancy. AB - OBJECTIVE: Our purpose was to describe the total costs involved in the delivery, prenatal, and neonatal care for triplet pregnancies. STUDY DESIGN: Twenty triplet pregnancies were born at our institution over the 1-year period between July 1, 1992, and June 30, 1993. Total charges for prenatal care, physician fees, antepartum admissions, delivery, postpartum inpatient and outpatient care, and neonatal inpatient and outpatient care were extracted from the hospital billing computers. RESULTS: Our 20 triplet pregnancies were delivered of 54 live born infants at an average gestation of 30.2 weeks. Mothers averaged 16.7 inpatient hospital days. Total cost of prenatal care, outpatient laboratories and ultrasonography, delivery, and maternal inpatient care averaged $27,491. Neonates averaged 13.7 hospital days. Total neonatal costs for the inpatient stay and short term-postpartum (< 6 week) outpatient period was $36,856 per family. Total average cost per family was $64,347. CONCLUSION: Combined maternal and neonatal costs per individual baby delivered was approximately $21,000. Although expensive, this cost is far from prohibitive, even in times of close attention to health care expenditures. PMID- 7856704 TI - Preterm premature rupture of membranes and abruptio placentae: is there an association between these pregnancy complications? AB - OBJECTIVE: Our purpose was to determine whether the incidence of abruptio placentae is increased in pregnancies with preterm premature rupture of membranes and to assess whether certain clinical risk factors in this group predispose them to have abruptio placentae. STUDY DESIGN: A retrospective cohort study over a 2.5 year period was performed. The study group consisted of 756 singleton pregnancies between 20 and 36 weeks' gestation complicated by preterm premature rupture of membranes and managed expectantly. The control group consisted of 11,240 pregnancies not complicated by preterm premature rupture of membranes and delivered during the same time period. The incidence of abruptio placentae was compared between the two groups. The study group of patients with preterm premature rupture of membranes was further subdivided into cases with (n = 38) and without abruptio placentae (n = 718) and compared. Clinical factors such as admission amniotic fluid index, history of bleeding before or after rupture of membranes, incidence of intrapartum fetal distress, and low 5-minute Apgar scores (< 6), latency-to-delivery interval, gestational age and weight at delivery, and incidence of amnionitis and endometritis were compared. RESULTS: The incidence of abruptio placentae in the study group (38/756, 5%) was significantly higher than that in the control group (97/11, 240, 0.9%) (p < 0.001, odds ratio = confidence interval). Comparison of cases with preterm premature rupture of membranes with and without abruptio placentae demonstrated both groups to have a similar gestational age at delivery, birth weight, latency-to-delivery interval, amniotic fluid index, and infectious morbidity. The group with abruptio placentae had a significantly higher incidence of bleeding before rupture of membranes (six of 38, 15% vs eight of 718, 1%; p < 0.005) and of intrapartum fetal distress (18/38, 46% vs 49/718, 7%; p < 0.0009). CONCLUSIONS: Pregnancies complicated by preterm premature rupture of membranes that are managed expectantly are at significant risk for abruptio placentae. Preterm premature rupture of membranes in such cases is more often preceded by bleeding. These abruptions may predispose the patient to intrapartum fetal distress. PMID- 7856706 TI - The "dangerous multipara": fact or fiction? AB - OBJECTIVE: Our purpose was to compare the intrapartum complication incidence among grand multiparous women with that of age-matched control multiparous women. STUDY DESIGN: A total of 382 grand multiparous women (para > or = 5) were compared with 382 age-matched control subjects (para 2 to 4), all delivering between July 1989 and September 1991. Intrapartum complications classically associated with grand multiparity (abruptio placentae, dysfunctional labor, fetal malpresentation, postpartum hemorrhage, and shoulder dystocia) were compared. RESULT: Both groups had comparable antepartum complications and gestational ages at delivery. The overall intrapartum complication incidence for grand multiparous women was 33% (127/382 patients), not significantly different from that of the control multiparous women, 27% (103/382). Grand multiparity was associated with an increased incidence of macrosomia (16% vs 11%) and a decreased incidence of operative delivery (14% vs 21%). Macrosomia increased the incidence of intrapartum complications from 31% to 46% (p < 0.03) in the grand multiparous patients, and a trend was observed in the multiparous patients, from 26% to 37%. However, when properly controlled, this was noted to be a confounding variable and was not related to parity. CONCLUSIONS: In a largely Hispanic population grand multiparous patients do not have an increased incidence of intrapartum complications. PMID- 7856707 TI - Preinduction cervical ripening: a comparison of intracervical prostaglandin E2 gel versus the Foley catheter. AB - OBJECTIVE: Both prostaglandin E2 gel and an intracervical balloon catheter have been shown to be effective for cervical ripening. The purpose of this study is to compare the efficacy of intracervical prostaglandin E2 gel with an intracervical Foley catheter for preinduction cervical ripening. STUDY DESIGN: A randomized, prospective study was conducted in the Maternity Care Center at the Foothills Hospital at Calgary, Alberta, Canada. Patients with a Bishop score < or = 4 and meeting inclusion and exclusion criteria were included. Thirty patients were randomized to receive prostaglandin E2 gel and 36 to receive an intracervical Foley catheter on the evening before induction. Induction then proceeded the following morning by the preferred method of the attending physician. RESULTS: The groups were comparable with respect to maternal age, parity, gestational age, reason for induction, and initial Bishop scores. Both groups had a significant change in Bishop score (4.1 +/- 0.4 and 4.8 +/- 0.5, respectively, p < 0.001); however, there was no significant difference between the groups. There was no significant difference in side effect profile, intrapartum complications, or delivery mode. Six cesarean sections (17.6%) were performed in the Foley group and seven (25%) in the prostaglandin E2 gel group (not significant). The induction-to-delivery interval was 16.0 +/- 1.7 hours in the Foley group and 21.5 +/- 3.2 hours in the prostaglandin E2 gel group (p = 0.014). Apgar scores, cord gases, and neonatal birth weight showed no difference between the groups. CONCLUSION: This study has shown that for preinduction cervical ripening there is no difference in efficacy between intracervical prostaglandin E2 gel or an intracervical Foley catheter. PMID- 7856708 TI - Intravenous immunoglobulin therapy for the antiphospholipid syndrome in pregnancy. AB - OBJECTIVE: Our purpose was to study the influence of intravenous immunoglobulin on pregnancy outcome. STUDY DESIGN: Pregnancy outcomes were evaluated in five patients with 17 unsuccessful previous pregnancies. Each patient received 400 mg/kg immunoglobulin for 5 days monthly beginning in the first or early second trimester. Four patients with previous thromboembolic events were treated with concomitant heparin prophylaxis. Four patients received 81 mg of aspirin daily. RESULTS: Short- and long-term decreases of anticardiolipin immunoglobulin G were noted in three patients. Four patients were delivered of healthy infants at term, one at 32 weeks' gestation with a diagnosis of fetal distress. Neither preeclampsia nor fetal intrauterine growth retardation were observed. The immunoglobulin therapy was not associated with major side effects. Significant placental histologic anomalies were not identified. CONCLUSIONS: The observations suggest that immunoglobulin therapy may improve pregnancy outcomes beyond that observed with heparin and aspirin. A prospective trial is encouraged. PMID- 7856709 TI - Serum CA 125 levels and spontaneous abortion. AB - OBJECTIVE: Previous reports have suggested that serum CA 125 levels in patients who spontaneously abort in the first trimester of pregnancy differ from the levels of patients who successfully complete their pregnancies. Low CA 125 levels have been suggested to predict spontaneous abortion, although an increased rate of first-trimester spontaneous abortion has also been reported in women with elevated CA 125 levels early in pregnancy. The purpose of this study was to prospectively compare serum CA 125 levels of women who abort in the first trimester with levels of those women whose pregnancies progress beyond 12 gestational weeks. STUDY DESIGN: A total of 188 pregnant patients had weekly serum CA 125 levels obtained after a prepregnancy baseline value was determined. Levels of the antigen in women who ultimately had a first-trimester spontaneous abortion were compared with CA 125 levels from women whose pregnancies continued past the first trimester. RESULTS: There was no statistically significant difference in the CA 125 levels of patients who aborted compared with those of women whose pregnancies continued. In addition, among patients with CA 125 values > 150 U/ml there was also no statistically significant difference in the proportion of patients who aborted compared with controls. CONCLUSION: Serum CA 125 levels are not predictive of spontaneous abortion in the first trimester of pregnancy. PMID- 7856710 TI - Risk factors for mother-to-child transmission of human immunodeficiency virus-1 infection. AB - OBJECTIVE: Our aim was to examine maternal, obstetric, and infant characteristics of mother-to-child transmission of human immunodeficiency virus-1 in Nairobi, Kenya. STUDY DESIGN: Proviral human immunodeficiency virus-1 was detected by polymerase chain reaction in peripheral blood samples taken between 6 weeks and 3 months of age from 107 children born to human immunodeficiency virus-1 seropositive women. The association of maternal, infant, and obstetric variables with human immunodeficiency virus-1 transmission was examined. RESULTS: The mother-to-child transmission rate was 31% (95% confidence interval 21.6 to 40.2) as defined by the presence of proviral human immunodeficiency virus-1 in the infant. Variables associated with transmission in a univariate analysis included placental inflammation (7/12 in the transmitting group as compared with 2/22 in nontransmitters, p = 0.006), low maternal CD4 and high CD8 percentages (21% and 52%, respectively, in transmitting mothers and 32% and 40% in nontransmitting mothers; p = 0.001), and the gender of the neonate (20/29 infected neonates were female as compared with 26/65 noninfected children, p = 0.02). Sexually transmitted diseases were found more often in transmitting mothers but the differences were not significant. Birth weight and gestational age were not related to vertical transmission of human immunodeficiency virus-1. CONCLUSION: Risk factors for mother-to-child transmission of human immunodeficiency virus-1 included chorioamnionitis, an impaired maternal immune status, and female gender. PMID- 7856711 TI - Gestational weight gain among average-weight and overweight women--what is excessive? AB - OBJECTIVE: Our purpose was to determine the association between increased gestational weight gain and birth weight outcomes for low-income women. STUDY DESIGN: A total of 53,541 single, live infants delivered from 1990 to 1991 to white, black, and Hispanic women in eight states were evaluated. Multiple logistic regression was used to calculate risk of low and high (> 4500 gm) birth weight, adjusting for selected factors. RESULTS: The association between gestational weight gain and birth weight varied by prepregnancy body mass index. Risk for low birth weight decreased with increasing weight gain for average weight women. There was no reduction in risk for low birth weight, however, beyond weight gains of 30 to 34 pounds for overweight women and 15 to 19 pounds for very-overweight women. Risk for high birth weight, however, increased with increasing weight gain in all three groups. CONCLUSION: Very-overweight women (body mass index > 29 kg/m2) may benefit from an upper guideline of 25 pounds of weight gain to help reduce risk for high birth weight. PMID- 7856712 TI - Der Swangern Frawen und hebamen Rosegarten. [A garden of roses for pregnant women and midwives]. PMID- 7856714 TI - Unusual ultrasonographic appearance of uterus in postmenopausal patients receiving tamoxifen. PMID- 7856713 TI - Fetal thoracentesis for cystic adenomatoid malformation of the lung. PMID- 7856715 TI - A photographic look at umbilical cord vessel variation. PMID- 7856716 TI - Effects of binding on human transplacental transfer of cocaine. PMID- 7856717 TI - Questionable research methods. PMID- 7856718 TI - Redefining cell death. PMID- 7856719 TI - Constitutive expression and modulation of the functional thrombin receptor in the human kidney. AB - Thrombin exerts procoagulant effects and has also many cellular effects mediated by cell surface receptors. A functional thrombin receptor from human platelets has been cloned and sequenced. In the present study, by reverse transcription and polymerase chain reaction, using specific primers designed from the thrombin receptor cDNA sequence, we show that the mRNA encoding for this receptor can be amplified from freshly isolated human glomeruli obtained by microdissection of normal kidney cortex. By immunohistochemistry using a specific monoclonal antibody, ATAP2, directed against the extracellular N-terminus of this receptor, we find that this functional thrombin receptor is constitutively expressed in the normal human kidney. The three glomerular cell types, endothelial, mesangial, and epithelial cells, were positively stained, as were the endothelial cells of renal arteries, arterioles, venules, and peritubular capillaries. Occasionally, interstitial cells and smooth muscle cells in the media of renal arteries were also stained. Proximal and distal tubular cells were not stained. By in situ hybridization, using a digoxigenin-labeled cDNA probe specific for thrombin receptor, the thrombin receptor mRNA was found to have the same distribution as the thrombin receptor protein detected by immunohistochemistry. A lighter staining of glomerular endocapillary cells was observed in cases of thrombotic microangiopathy and extracapillary glomerulonephritis, two renal diseases associated with in situ thrombin generation and fibrin formation. In one case of thrombotic microangiopathy, we observed an increase in thrombin receptor mRNA. This suggests that thrombin receptor protein is not always correlated with thrombin receptor mRNA level. Internalization and degradation of thrombin receptor protein have been demonstrated in vitro and could also occur after activation in vivo. This is the first demonstration of the constitutive expression of the functional thrombin receptor in the human kidney. These results suggest that thrombin may exert glomerular and vascular effects within the kidney in normal and in pathological conditions. PMID- 7856720 TI - Effects of energy intake on type 1 plasminogen activator inhibitor levels in glomeruli of lupus-prone B/W mice. AB - Calorie restriction (CR) and/or reduced energy intake ameliorates the progression of autoimmune renal disease in (NZB x NZW)F1 (B/W) female mice and increases life span. Like other forms of glomerulonephritis, the lupus-like kidney disease observed in these animals is frequently accompanied by glomerular deposition of fibrin and increased accumulation of mesangial matrix. Because alterations in plasminogen activator inhibitor type 1 (PAI-1) expression or function may be involved in both fibrin deposition and accumulation of extracellular matrix, we have studied the effects of CR on the expression of PAI-1 in kidneys from female B/W mice fed either ad libitum or on a 40% CR diet. By immunohistochemistry and immunoblotting, we found that the glomerular levels of PAI-1 antigen were highest in older ad lib fed animals with more advanced glomerular disease. Increased levels of PAI-1 protein were paralleled by increased levels of PAI-1 mRNA in total RNA extracted from renal cortex and in diseased glomeruli as detected by in situ hybridization. CR diminished the accumulation of PAI-1 protein and reduced the expression of PAI-1 mRNA. Thus, glomeruli from animals fed ad lib showed much greater deposition of PAI-1 protein, increased expression of PAI-1 mRNA, and more severe histological abnormalities than animals on a CR diet. The differences between CR and ad lib animals were more pronounced in animals studied at 9 to 10 months versus those at 3 to 4 months of age. These observations indicate that the ameliorating effects of CR include diminished PAI-1 gene expression and decreased localization of PAI-1 in glomeruli. PMID- 7856721 TI - Myofibroblasts in experimental hydronephrosis. AB - Interstitial fibrosis is a common outcome of longterm ureteral obstruction. One pathological arm of the fibrotic reaction in diverse tissue loci and experimental models is the retraction of granulation tissue. The role of the myofibroblast in granulation tissue contraction and fibrocontractive diseases has been well established, but the mechanisms leading to differentiation of fibroblastic cells into myofibroblasts during the evolution of inflammation are not yet fully clarified. Investigators using other model systems have shown that macrophage derived transforming growth factor-beta 1 (TGF-beta 1) may be pivotal in the process of myofibroblast modulation. Our laboratory has shown that the unilateral ureteral obstruction in the rat is characterized by a 20-fold increment in infiltrating renal cortical interstitial macrophages, an increase in cortical TGF beta 1 gene expression, which parallels the infiltrating macrophage burden, and immunolocalization of this peptide growth factor in close proximity to resident interstitial fibroblasts. Because of this model's features, it was our aim to assess whether a myofibroblastic modulation was operant in the renal cortex of obstructed rat kidneys versus the control contralateral unobstructed kidney specimens. Immunolabeling for alpha-smooth muscle actin and the intermediate filament protein, desmin, was detected and steadily intensified from 24 to 96 hours after unilateral ureteral obstruction in obstructed kidneys only. In temporal concert with the detection of alpha-smooth muscle actin protein, the mRNA expression for this cytoskeletal component exhibited 3.7-, 15.7-, and 4.1 fold increments in the renal cortex of obstructed kidneys versus the contralateral unobstructed kidney specimens at 24, 48, and 96 hours after unilateral ureteral obstruction, respectively. Whole body X-irradiation, administered to rats 11 days before proximal left ureteral ligation, significantly lowered cortical interstitial macrophage number, cortical TGF-beta and alpha-smooth muscle actin mRNA levels as well as the intensity of immunolabeling for alpha-smooth muscle actin from 12 to 96 hours after unilateral ureteral obstruction. These data support a postulate that renal cortical TGF-beta 1, derived from the infiltrating macrophage, in part, contributes to the subsequent interstitial fibrosis response to renal injury by fostering the modulation of fibroblasts to myofibroblasts within the renal cortex after ureteral obstruction. PMID- 7856722 TI - Monocyte chemotactic protein expression during schistosome egg granuloma formation. Sequence of production, localization, contribution, and regulation. AB - The present study explored the role of murine monocyte chemotactic protein (MCP) in the T cell-mediated hypersensitive granulomatous response to Schistosoma mansoni eggs. The study examined the time course of local production, contribution to cellular infiltration, and the role of T cells in endogenous regulation. Synchronized pulmonary granulomas were induced under conditions of primary and secondary states of immunity. Primer-directed polymerase chain reaction analysis showed increased MCP mRNA expression in granulomatous lungs, mainly in the secondary response. Levels of MCP were measured by enzyme-linked immunosorbent assay in cultures of intact granulomas. Spontaneous MCP production was modest in primary granuloma cultures, reaching a maximum of 5.7 +/- 0.9 ng/ml by 16 days. In contrast, the secondary response showed augmented and accelerated production, achieving 13 +/- 2.0 ng/ml by 2 days. Immunohistochemical staining revealed the strongest MCP expression within microvascular adventitial cells or pericytes as well as in scattered mononuclear cells associated with granulomas. Staining was not detected in normal lungs. Passive immunization with anti-MCP-1 antibodies caused a 40% reduction in the secondary granuloma area but did not significantly affect the primary response. With adoptive cell transfer and T cell subset depletion, it was shown that Thy-1+ and CD5+ cells augmented, whereas CD8+ cells appeared to impair, MCP production. This provides direct evidence that MCP is involved in secondary Th2-mediated response to schistosome eggs and is subject to regulation by T cells. PMID- 7856723 TI - Distribution of unesterified cholesterol-containing particles in human atherosclerotic lesions. AB - The objective of the study was to characterize unesterified cholesterol particles in human aorta and to correlate the findings with the severity of aortic atherosclerosis. Human tissues were processed under conditions that preserve deposits of unesterified cholesterol agglomerates. Filipinfluorescence was determined by using a novel triple band pass filter. The pattern of unesterified cholesterol deposits was age related and correlated with the severity of atherosclerosis. We found three types of deposits: 1), small spherulites (3 to 5 mu), which were depicted in both the media and intima in individuals as early as age 16, and which, in more advanced ages, showed an increase in density and a tendency to aggregate extracellularly throughout the intima in clusters; 2), elongated structures (10 to 30 mu in the middle zone of the intima), the density of which was directly related to the severity of atherosclerosis; and 3), large (100 mu), irregular deposits found mainly in the core of atherosclerotic plaques. The medium size deposits, compared with those found in the core of atherosclerotic plaques, retain their overall size (10 to 30 mu), uniformity (oval elongated), and localization (middle zone of the intima). On the basis of these observations we hypothesize cholesterol deposition in two stages of aggregation: 1), early degradation of infiltrating low density lipoprotein particles forming unesterified cholesterol-rich vesicles in the vessel wall, followed by aggregation to spherulites in the lower part of the intima; and 2), more massive agglomeration of particles containing unesterified cholesterol and calcium phosphate in the midzone of the intima. Because in the second stage of aggregation the transition of cholesterol to the solid state has already occurred, it is irreversible. PMID- 7856724 TI - 92-kd type IV collagenase (matrix metalloproteinase-9) activity in human amniochorion increases with labor. AB - To determine whether specific collagenolytic enzymes are expressed in human fetal membranes with labor, we examined gelatinase activity in extracts of amniochorion by zymography. The 92-kd gelatinase (MMP-9) was barely detectable in extracts of fetal membranes before the onset of labor but was readily demonstrable in extracts prepared from membranes isolated from laboring women or membranes collected immediately after delivery. In contrast, the 72-kd gelatinase (MMP-2) was detectable in extracts from pre- and post-labor membranes. Ethylenediaminetetracetic acid and the tissue inhibitor of metalloproteinases, TIMP-1, inhibited the gelatinase activities detected by zymography, confirming that the enzymes are metalloproteinase. Assay of amniochorion gelatinase activity using a radiolabeled denatured collagen substrate revealed a more than twofold increase in activity comparing pre-labor with post-labor fetal membrane extracts. A function-blocking anti-MMP-9 monoclonal antibody inhibited pre-labor membrane gelatinase activity by approximately 11.5%, which was only slightly greater inhibition than observed with irrelevant monoclonal antibodies. However, post labor membrane gelatinase activity was reduced by 53% by the function-blocking antibody, indicating that MMP-9 is a major contributor to the increased gelatinase activity extractable from post-labor membranes. Western blot analyses demonstrated increased MMP-9 protein in amniochorion extracts after onset of labor. MMP-9 protein and mRNA were co-localized in amnion epithelium, underlying macrophages and chorion laeve trophoblast and decidual cells after labor. We conclude that 1) MMP-9 activity and protein in human amniochorion increases with labor and 2) MMP-9 is expressed by amnion epithelium, macrophages and chorion laeve trophoblast and decidual cells. The increased expression of MMP-9 may result in degradation of the extracellular matrix of the fetal membranes and facilitate their rupture under both physiological and pathological conditions. PMID- 7856725 TI - Defining apoptosis. PMID- 7856726 TI - Mutations of the Ki-ras oncogene in carcinoma of the endometrium. AB - Mutations of the Ki-ras oncogene in endometrial carcinoma have been reported in Japan, but the prevalence and clinical significance of such mutations in the United States remains unclear. DNA extracted from paraffin sections of 112 carcinomas of the endometrium was amplified by the polymerase chain reaction with mismatched primers that generated a BstNI recognition site with the wild-type codon 12. Loss of this recognition site indicating Ki-ras codon 12 mutations was observed in 13 tumors (11.6%), including 11 endometrioid carcinomas, one undifferentiated carcinoma, and one carcinosarcoma. None of 17 papillary serous clear cell carcinomas contained Ki-ras codon 12 mutations. These mutations were confirmed and characterized by direct sequencing. We found no evidence of correlation of the presence of Ki-ras mutations with stage, grade, depth of invasion, or clinical outcome. Our results indicate that Ki-ras oncogene mutations in carcinoma of the endometrium may be less prevalent in the United States than in Japan. PMID- 7856727 TI - Ultrastructural localization of the C-terminus of the 43-kd dystrophin-associated glycoprotein and its relation to dystrophin in normal murine skeletal myofiber. AB - We used single and double immunogold labeling electron microscopy to investigate ultrastructural localization of the C terminus of the 43-kd dystrophin-associated glycoprotein (43-DAG) and its relationship to dystrophin in normal murine skeletal myofibers. Single immunolabeling localized the antibody against the C terminus of 43-DAG to the inside surface of the muscle plasma membrane and the sarcoplasmic side of plasma membrane invaginations. Double immunolabeling co localized antibodies against dystrophin and the C terminus of 43-DAG to the same site noted in the single immunolabeling localization of 43-DAG. In particular, dystrophin and the C-terminal 43-DAG antibody signals were often observed as doublets separated by less than 30 nm. We compared these results with those obtained from double immunogold labeling with anti-dystrophin and anti-beta spectrin, as well as anti-C-terminal 43-DAG and anti-beta-spectrin antibodies. The antibodies against dystrophin and beta-spectrin, or beta-spectrin and 43-DAG, also co-localized to similar sites in skeletal muscle fibers. Signals of doublet formations were noted but their frequency was significantly lower than the doublet frequency of antidystrophin and anti-43-DAG antibodies. The results support the presence of dystrophin and 43-DAG linkage at the inside surface of the murine skeletal muscle plasma membrane. PMID- 7856728 TI - The bcl-2 proto-oncogene and the gastrointestinal epithelial tumor progression model. AB - We report overexpression of the proto-oncogene bcl-2 in gastrointestinal adenocarcinoma and its precursor lesions. The bcl-2 proto-oncogene is centrally involved in the oncogenesis of human follicular lymphoma via a chromosomal translocation t(14;18)(q32;q21) and is also expressed in the epithelial regenerative compartment or the basal crypts of the normal colon and small intestine. We describe an immunohistochemical analysis of fixed, paraffin embedded tissue using both a polyclonal rabbit and a monoclonal mouse antibody to the Bcl-2 protein. In addition to confirming bcl-2 expression in normal colonic and small intestinal crypts, we also observed expression in the gastric epithelial regenerative compartment, the mucous neck region. No increased expression was found in nonneoplastic or inflammatory gastrointestinal conditions, including ulcerative colitis, Crohn's disease, or inflammatory or hamartomatous polyps. Increased bcl-2 expression, however, was present in hyperplastic colonic polyps and in the majority of dysplastic lesions, from the earliest precursors through large adenomas, high grade flat dysplasia, and adenocarcinoma, all in comparison with adjacent internal control normal epithelium. Increased expression was present in dysplastic glandular lesions from all gastrointestinal sites, including colon, small bowel, and stomach. Furthermore, bcl-2 expression was frequently abnormal in nondysplastic epithelium surrounding dysplastic lesions, suggesting that altered expression occurred before the development of morphological dysplasia. Specifically, directly contiguous morphologically nondysplastic epithelium often showed abnormal bcl-2 expression throughout the full length of the crypt-villus axis. This expression pattern gradually diminished to involve only the crypt base (the normal pattern of expression), proceeding away from malignant or dysplastic lesions. Abnormal bcl-2 immunoreactivity in 1), the earliest precursor dysplastic lesions and its persistence throughout neoplastic progression and 2), contiguous morphologically unaltered nondysplastic epithelium suggests that bcl-2 alterations occur early during the morphological and molecular sequence of events leading to gastrointestinal epithelial neoplasia. PMID- 7856729 TI - Human skin in organ culture. Elaboration of proteolytic enzymes in the presence and absence of exogenous growth factors. AB - Proteinase levels were assessed in organ culture fluids from human neonatal foreskin maintained under growth factor-free conditions and in the presence of a combination of growth factors (ie, epidermal growth factor, insulin, hydrocortisone, pituitary extract, and all-trans-retinoic acid). Analysis of culture fluids by gelatin zymography revealed the presence of 92-kd and 72-kd gelatinases. There was a greater amount of 92-kd gelatinase activity in the presence of growth factors whereas the levels of 72-kd gelatinase were similar in growth factor-free and growth factor-containing media. Experiments with keratinocytes and fibroblasts in monolayer culture and with isolated dermal tissue in organ culture indicated that the epithelial component was responsible for most of the 92-kd gelatinase activity whereas fibroblasts were primarily responsible for the 72-kd gelatinase activity. Activation with aminophenyl mercuric acetate, requirement for divalent cations, inhibition with EDTA, and insensitivity to inhibition with phenylmethyl sulfonyl fluoride indicated that both gelatinases were metalloproteinases. In additional studies, culture fluids were examined for the presence of plasminogen activator activity. This was detected in culture fluids from tissues maintained under both conditions but was increased in the growth factor-containing medium. The increased amount seen in the growth factor-containing medium appeared to be due almost entirely to a single factor, ie, all-trans-retinoic acid. In monolayer culture, both keratinocytes and fibroblasts produced plasminogen activator; the level was higher in keratinocyte culture fluids than in culture fluids from fibroblasts. PMID- 7856730 TI - Detection of a Cdc2-related kinase associated with Alzheimer paired helical filaments. AB - By immunocytochemical staining and Western blotting, we detected a Cdc2-related kinase in human brains. The kinase is recognized by antibodies against the carboxyl and the amino termini of p34Cdc2 but is not recognized by antibodies against the PSTAIRE motif. It is slightly smaller than p34Cdc2 in molecular mass (approximately 33 kd). This 33-kd Cdc2-related kinase is present in intracellular neurofibrillary tangles in neurons of elderly humans and in Alzheimer's disease, and it is associated with paired helical filaments (PHF) from Alzheimer's disease brains. Unlike the antibodies to the carboxyl and amino termini of p34Cdc2, antibodies to an abundant brain Cdc2-related kinase PSSLARE/Cdk5 did not immunolabel Alzheimer's disease neurofibrillary lesions. PHF preparations were demonstrated to contain kinases capable of phosphorylating histone H1, PHF-Tau, and a synthetic peptide (VAVVRTPPKSPSSAK). By virtue of its physical association with PHF, the 33-kd Cdc2-related kinase may play a role in transforming normal Tau proteins to PHF-Tau characteristic of Alzheimer's disease. PMID- 7856731 TI - Role of interleukin 1 in antigen-induced exacerbations of murine arthritis. AB - The mechanism underlying the chronic and intermittent course of rheumatoid arthritis is not elucidated. In the present study, the role of interleukin 1 (IL 1) was investigated in exacerbations of antigen-induced arthritis in mice. A flare-up of smoldering inflammation (weeks 3 to 4 of antigen-induced arthritis) was inducible by injection of a small amount of methylated bovine serum albumin into the hypersensitive knee joint. Immunohistochemistry showed IL-1 expression in the synovial lining layer and in focal areas of the inflamed synovium during the flare-up. IL-1 was also measured in 1-hour culture supernatant of synovial tissue taken during the flare-up by a bioassay. The expression of both immunoreactive and bioactive IL-1 in the hypersensitive joint peaked around 6 hours after antigen (2 micrograms of methylated bovine serum albumin) injection and declined thereafter. Antigen rechallenge induced an acute joint swelling of the arthritic joint but not in the naive joint of the sensitized mouse, yet synovia of both joints produced IL-1 after antigen injection. Remarkably, a single intravenous injection of rabbit anti-IL-1 alpha and -beta antibodies 1 hour before antigen rechallenge neutralized IL-1 in the joint. Anti-IL-1 treatment significantly reduced the antigen-induced joint swelling (30 to 40%) but did not affect the profound influx of polymorphonuclear cells in the onset of the exacerbation. However, a profound relief of the inflammation (synovitis) was obtained by IL-1 blockade on day 4 of the exacerbation. Chondrocyte proteoglycan synthesis was markedly suppressed in the antigen-challenged naive knee joints suggesting that this was a direct IL-1 effect as the inflammation was insignificant. Anti-IL-1 treatment was able to maintain chondrocyte proteoglycan synthesis in the antigen-rechallenged joint, which was highly suppressed in the control group. Furthermore, the enhanced proteoglycan breakdown in the antigen rechallenged joints was significantly decreased in the anti-IL-1 group. We concluded that IL-1 is an important mediator in exacerbations of murine arthritis, and amelioration of cartilage pathology was obtained with anti-IL-1 antibody treatment. PMID- 7856732 TI - Transforming growth factor-beta 1 null mice. An animal model for inflammatory disorders. AB - Approximately 40% of transforming growth factor-beta 1 null (knockout) mice generated in our laboratory develop normally to term, but 60% die in utero. The animals appear normal during the first 2 weeks of life but develop a rapid wasting syndrome and die by 3 to 4 weeks of age. All of the knockout mice have a multifocal inflammatory disease in many tissues. The heart and lungs are most severely affected. Increased adhesion of leukocytes to the endothelium of pulmonary veins is the initial lesion seen at day 8 postnatally and is soon followed by perivascular cuffing as well as inflammatory infiltrates in lung parenchyma. The lesions in the heart begin as endocarditis and then progress to myocarditis and pericarditis. Within the lung, chronic inflammatory infiltrates consist of T and B lymphocytes, including plasma cells, whereas macrophages are the primary inflammatory cell type in the heart. Increased expression of major histocompatibility complex class I and II proteins is seen in pulmonary vascular endothelium as early as day 8. An immunoblastic response in mediastinal and mandibular lymph nodes and spleen is also seen. In the absence of any pathogens, this massive inflammatory disease, together with overexpression of major histocompatibility complex class I and II proteins and overproduction of immunoglobulins by lymphocytes, offers circumstantial evidence for an autoimmune etiology. PMID- 7856733 TI - Disparate localization of 55-kd and 75-kd tumor necrosis factor receptors in human endothelial cells. AB - We have used confocal immunofluorescence microscopy and immunogold electron microscopy to localize tumor necrosis factor (TNF) receptors in cultured human umbilical vein endothelial cells. The 75-kd receptor is largely expressed on the cell surface and undergoes endocytosis and transport to lycosomes through coated pits and coated vesicles. TNF may accelerate receptor clustering and internalization. The 55-kd receptor is expressed at much lower levels on the cell surface than the 75-kd receptor but is more abundant overall. It is predominantly localized to the Golgi apparatus and, to a lesser extent, cytoplasmic vacuoles. The cellular distribution of the 55-kd receptor is largely unaffected by TNF. These results have implications for TNF-mediated endothelial cell activation and for interactions between 75- and 55-kd TNF receptors. PMID- 7856734 TI - Onset and progression of pathological lesions in transforming growth factor-beta 1-deficient mice. AB - Null-mutant (knockout) mice were obtained through disruption of the sixth exon of the endogenous transforming growth factor-beta 1 allele in murine embryonic stem cells via homologous recombination. Mice lacking transforming growth factor-beta 1 (mutants) were born grossly indistinguishable from wild-type littermates. With time, mutant mice exhibited a wasting phenotype that manifested itself in severe weight loss and dishevelled appearance (between 15 and 36 days of age). Examination of these moribund mice histologically revealed that transforming growth factor-beta 1-deficient mice exhibit a moderate to severe, multifocal, organ-dependent, mixed inflammatory cell response adversely affecting the heart, stomach, diaphragm, liver, lung, salivary gland, and pancreas. Because of the known multifunctional nature of transforming growth factor-beta 1 on the control of growth and differentiation of many different cell types, it is important to determine the degree to which the inflammatory response interacts with or masks other deficiencies that are present. To this end, we examined the extent and nature of the inflammatory lesions in different ages of neonatal knockout mice (5, 7, 10, and 14 days of age) and older moribund mice (> 15 days of age) and compared them with the histology seen in wild-type normal animals. Mild inflammatory infiltrates were first observed in 5-day mutant mice in the heart, by day 7 in the lung, salivary gland, and pancreas, and by day 14 inflammatory lesions were found in almost all organs examined. Moderate to severe inflammation was not present until the mice were 10 to 14 days old. In the older animals, there was a slight increase in the severity of the inflammatory lesions as the mice aged. PMID- 7856735 TI - Apoptosis, oncosis, and necrosis. An overview of cell death. AB - The historical development of the cell death concept is reviewed, with special attention to the origin of the terms necrosis, coagulation necrosis, autolysis, physiological cell death, programmed cell death, chromatolysis (the first name of apoptosis in 1914), karyorhexis, karyolysis, and cell suicide, of which there are three forms: by lysosomes, by free radicals, and by a genetic mechanism (apoptosis). Some of the typical features of apoptosis are discussed, such as budding (as opposed to blebbing and zeiosis) and the inflammatory response. For cell death not by apoptosis the most satisfactory term is accidental cell death. Necrosis is commonly used but it is not appropriate, because it does not indicate a form of cell death but refers to changes secondary to cell death by any mechanism, including apoptosis. Abundant data are available on one form of accidental cell death, namely ischemic cell death, which can be considered an entity of its own, caused by failure of the ionic pumps of the plasma membrane. Because ischemic cell death (in known models) is accompanied by swelling, the name oncosis is proposed for this condition. The term oncosis (derived from onkos, meaning swelling) was proposed in 1910 by von Reckling-hausen precisely to mean cell death with swelling. Oncosis leads to necrosis with karyolysis and stands in contrast to apoptosis, which leads to necrosis with karyorhexis and cell shrinkage. PMID- 7856736 TI - Frequent expression of IL-7 gene transcripts in tumor cells of classical Hodgkin's disease. AB - Interleukin-7 (IL-7) is a pleiotropic cytokine acting mainly on cells of the hematolymphoid system. In vitro studies have shown enhanced proliferation of acute lymphoblastic leukemia cells in response to IL-7. On the other hand, tumor cell lines transfected with a functioning IL-7 gene and subsequently transplanted into mice resulted in a prominent inflammatory infiltrate and reduced tumorigeneicity. These data suggest an important role of this cytokine in the pathophysiology of lymphoid neoplasms. Because little is known about the in vivo expression of this cytokine in various neoplastic and nonneoplastic lesions of the lymphoid system, we examined frozen and paraffin-embedded tissue samples of normal, reactive, and malignant lymphoid lesions using in situ hybridization with a 35S-labeled RNA probe specific for IL-7. Tumor cells of nodular sclerosing and mixed cellularity type of Hodgkin's disease displayed IL-7-specific signals in 24 of 31 cases. Among reactive lesions, only thymic tissue showed labeling within both cortex and medulla (4 of 7 cases), whereas in tonsils clear-cut IL-7 specific signals could not be found. Tissues infiltrated by B-type chronic lymphocytic leukemia or T- or B-type lymphoblastic lymphoma showed cytokine specific signals in only one case of lymphoblastic lymphoma in rare reactive cells. In conjunction with the finding of elevated levels of IL-7 in the serum of many patients with Hodgkin's disease, our data suggest an important role of this cytokine in the pathogenesis of Hodgkin's disease. The prominent reactive infiltrate observed in most cases of Hodgkin's disease could be a consequence of elevated local levels of this cytokine as similar infiltrates are also observed in tumors in mice resulting from injection of tumor cell lines transfected with a functioning IL-7 gene. PMID- 7856737 TI - Comparative in situ hybridization analysis of PAX2, PAX8, and WT1 gene transcription in human fetal kidney and Wilms' tumors. AB - Wilms' tumor (WT) is a childhood renal neoplasm with histological features resembling fetal kidney development. Two members of the paired box family of genes, PAX2 and PAX8, are expressed in WT and are potentially involved in its induction. A zinc finger gene, WT1, which is involved in WT induction, encodes a DNA binding protein, and like PAX2 and PAX8 proteins is a transcription factor with an important role in kidney development. We have compared the expression patterns of PAX2, PAX8, and WT1 in fetal kidney and WTs by in situ hybridization. The PAX2, PAX8, and WT1 genes were transcribed in the condensed mesenchyme and early stages of epithelial differentiation in fetal kidney. WT1 gene transcription was observed in the glomeruli of fetal kidney until a later stage in development than PAX genes. In WTs all three genes were expressed in the condensed blastema, but WT1 expression was not detectable in the epithelial structures in two WTs. No evidence of attenuation of PAX gene expression was found in WT. These results suggest that in some WTs the expression of WT1 is attenuated in structures that continued to express PAX genes. It is unlikely that both PAX2 and PAX8 genes would be mutated in WT. However, failure of PAX gene expression to attenuate in WTs may result from mutations involved in the onset of the tumor. PMID- 7856738 TI - Analysis of T cell receptor-gamma gene rearrangements by denaturing gradient gel electrophoresis of GC-clamped polymerase chain reaction products. Correlation with tumor-specific sequences. AB - We describe a modified denaturing gradient gel electrophoresis (DGGE) procedure with a 40-nucleotide GC clamp in the polymerase chain reaction to improve resolution in amplifying T cell receptor-gamma (TCR-gamma) rearrangements. DNA from 46 cases of lymphoblastic leukemia/lymphoma, 5T cell lines, 2 B cell lines, 7 normal lymphocytes, and 3 cases of Hodgkin's disease was amplified by polymerase chain reaction. In addition, 20 cases of paraffin-embedded T cell lymphomas and 5 cases of reactive hyperplasia were also studied. Clonal TCR-gamma rearrangements were identified on DGGE by the presence of a predominant band. Results obtained from 5 T cell lines and 12 lymphoblastic leukemia/lymphomas containing known TCR-gamma gene rearrangements revealed 100% concordance in detecting clonal rearrangements between DGGE and traditional Southern blot analysis. Of the remaining 34 lymphoblastic leukemia/lymphoma cases studied by DGGE alone, 30 were positive. DGGE analysis of 10 lymphoblastic leukemia/lymphoma cases with known group IV gamma to J gamma 1 or J gamma 2 rearrangement sequences confirmed that the electrophoretic migration was dependent on the tumor-specific rearranged TCR-gamma sequence. In addition, 17 of 20 cases of paraffin-embedded T cell lymphomas were positive by DGGE, 6 of which had the clonal population also identified in fresh tissue DNA. DGGE analysis of GC-clamped polymerase chain reaction products can provide a way to more accurately detect TCR-gamma clonality of lymphoid tumors and can be applied to archival tissues. PMID- 7856739 TI - Apoptosis mediates the decrease in cellularity during the transition between granulation tissue and scar. AB - Granulation tissue formation and contraction is an important step of second intention wound healing. Granulation tissue develops from the connective tissue surrounding the damaged or missing area and its cellular components are mainly small vessel and inflammatory cells as well as fibroblasts and myofibroblasts. As the wound closes and evolves into a scar, there is an important decrease in cellularity; in particular myofibroblasts disappear. The question arises as to which process is responsible for this cellular loss. During a previous investigation on the expression of alpha-smooth muscle actin in myofibroblasts (Darby I, Skalli O, Gabbiani G, Lab Invest, 1990, 63:21-29), we have observed that in late phases of wound healing, many myofibroblasts show changes compatible with apoptosis and suggested that this type of cell death could be responsible for the disappearance of myofibroblasts. We have now tested this hypothesis by means of morphometry at the electron microscopic level and by in situ end labeling of fragmented DNA. Our results indicate that the number of myofibroblastic and vascular cells undergoing apoptosis increases as the wound closes and support the assumption that this is the mechanism of granulation tissue evolution into a scar. The regulation of apoptotic phenomena during wound healing may be important in scar establishment and development of pathological scarring. PMID- 7856740 TI - Chondrocyte apoptosis induced by nitric oxide. AB - Chondrocytes stimulated with IL-1 produce high levels of nitric oxide (NO), which inhibits proliferation induced by transforming growth factor-beta or serum. This study analyzes the role of NO and IL-1 in the induction of chondrocyte cell death. NO generated from sodium nitroprusside induced apoptosis in cultured chondrocytes as demonstrated by electron microscopy, 4',6-dianidino-2 phenylindole dihydrochloride staining, FACS analysis, and histochemical detection of DNA fragmentation. Similar results were obtained with two other NO donors, 3 morpholinosynonimide-hydrochloride and s-nitroso-N-acetyl-D-L-penicillamine. In contrast, oxygen radicals generated by hypoxanthine/xanthine oxidase caused necrosis but did not induce chondrocyte apoptosis. To analyze whether endogenously generated NO induces apoptosis, chondrocytes were stimulated with IL 1, but there was no evidence for apoptotic changes. Combinations of NO inducers such as IL-1, lipopolysaccharide, tumor necrosis factor, and interferon-gamma also failed to trigger apoptosis. IL-1-stimulated chondrocytes are known to produce oxygen radicals that react with NO to form products that can induce cell death in other systems. We thus tested IL-1 in combination with the oxygen radical scavengers N-acetyl cysteine, dimethyl sulfoxide, or 5,5' dimetylpyrroline 1-oxide. Under these conditions IL-1 was able to induce apoptosis, which was inhibited in a dose-dependent manner by the NO synthase inhibitor N-monomethyl L-arginine. Conversely, endogenous oxygen radicals induced by inflammatory mediators caused necrosis under conditions in which the simultaneous production of NO was reduced. These results suggest that NO, but not oxygen radicals, is the primary inducer of apoptosis in human articular chondrocytes. PMID- 7856741 TI - Increased expression of osteonectin and osteopontin, two bone matrix proteins, in human breast cancer. AB - Microcalcifications are a common phenomenon associated with breast cancer and are often the only mammographic sign of a malignant breast disease. Although microcalcifications are not restricted to breast cancer and can be also associated with benign lesions, it is noteworthy that they are composed exclusively of hydroxyapatite in breast carcinoma. Hydroxyapatite is the bone associated phosphocalcic crystal the deposition of which in bone tissue requires the coordinated expression of several molecules such as osteonectin (OSN) and osteopontin (OPN), synthesized by cells of the osteoblastic lineage. In this study, we evaluated the expression of these two bone matrix proteins, using an immunoperoxidase technique and specific antibodies, in 79 breast lesions including 28 benign and 51 cancerous specimens. We found that normal mammary tissue associated with the lesions examined expressed generally undetectable or lightly detectable (0 or 1+) amounts of OSN and OPN (92 and 81%, respectively). Benign breast lesions, including fibroadenoma and fibrocystic dysplasia, were generally weakly stained (0 or 1+) with both anti-OSN and anti-OPN antibodies (96.4 and 60.7%, respectively). Interestingly, the majority of both in situ and invasive breast carcinoma lesions showed a strong expression (2+ or 3+) for OSN or OPN (74.5 and 84.3%, respectively). High expression of these two bone matrix proteins was associated with frequent microcalcification deposition in the lesion. This study is the first extensive study of OSN and OPN expression in mammary cancers. Our data suggest that OSN and OPN could play a role in the formation of ectopic microcalcifications often associated with breast cancer. It is also tempting to speculate that the expression of these two glycoproteins by breast cancer cells play a role in the preferred bone homing of breast metastases. PMID- 7856742 TI - Influence of inflammatory bowel disease on the distribution and concentration of pancreatic secretory trypsin inhibitor within the colon. AB - Gastrointestinal epithelia contain a powerful protease inhibitor called pancreatic secretory trypsin inhibitor (PSTI). Patients with inflammatory bowel disease have changes in mucus structure suggestive of increased proteolysis. We therefore examined the distribution and concentration of PSTI in the colon of normal subjects and patients with inflammatory bowel disease. In normal subjects (N = 12), mucosal levels of PSTI were approximately 200 ng/mg protein in all regions of the colon and was localized to goblet and endocrine cells. Mucosal PSTI levels in the (affected) left side of the colon of patients with active (N = 12) or quiescent (N = 10) ulcerative colitis were reduced (approximately 80% of control in descending colon, 55% of control in sigmoid colon, and 50% of control in rectum, all P < 0.01), whereas levels in the (unaffected) right side of the colon were normal. PSTI levels were also reduced to approximately 65% of control in colonic tissue affected by Crohn's disease (N = 6, P = 0.01) and immunostaining showed PSTI positivity within the ulcer-associated cell lineage. As the mucous layer is important in preserving mucosal integrity, our finding of prolonged reduction in mucosal PSTI levels after an episode of ulcerative colitis probably represents a long-term reduction in a mucosal defense mechanisms that could lead to increased susceptibility to episodes of inflammation. PMID- 7856743 TI - Messenger RNA expression of the immunosuppressive cytokine IL-10 in human gliomas. AB - Interleukin 10 (IL-10) was initially discovered on the basis of its ability to suppress cytokine synthesis. Additionally, it can exert immunosuppressive effects on a variety of cell types. Because patients with malignant gliomas present with a general impairment of the immune system, we investigated IL-10 expression in the glioma tissue. Because expression of IL-10 and IL-6 is associated in hematopoietic cells and IL-6 can act as an autocrine growth stimulator for glioblastoma cell lines, we looked in addition for a relationship between IL-10 and IL-6 expression. Using a quantitative reverse transcriptase polymerase chain reaction, IL-10 and IL-6 mRNA levels were determined in 37 glial tumors of different grades including 2 recurrencies, 3 specimens from normal brain tissue, and 3 glioblastoma cell lines. Expression of IL-10 mRNA was demonstrable in all tumors as well as in normal brain. High grade tumors and recurrent cases expressed significantly higher amounts of IL-10-specific mRNA compared with low grade tumors, whereas 2 of 3 cell lines showed only weak constitutive expression, mRNA for IL-6 was found in 86.5% of all gliomas with a correlation concerning the expression levels for both cytokines in 69% of gliomas. We suggest that IL-10 may contribute to the progression of astrocytomas by suppressing the patient's immune response, whereas IL-6 provides an additional growth advantage. PMID- 7856744 TI - Low frequency association of the t(2;5)(p23;q35) chromosomal translocation with CD30+ lymphomas from American and Asian patients. A reverse transcriptase polymerase chain reaction study. AB - Although cytogenetic data suggest that the t(2;5)-(p23;q35) translocation occurs in many cases of CD30+ lymphomas, the exact frequency of this event is still unknown. To clarify this issue and its epidemiological characteristics, we examined 37 formalin-fixed, paraffin-embedded specimens of CD30+ lymphomas from the United States and Hong Kong by reverse transcriptase-polymerase chain reaction (RT-PCR) for the status of the NPM and ALK genes, which are typically juxtaposed by the t(2;5) translocation. Thirty-four cases were classified as anaplastic large cell lymphomas (ALCL), 2 cases as non-anaplastic large cell lymphomas (LCL), and 1 case as the small cell variant of CD30+ lymphoma. The t(2;5) translocation was detected in 6 cases (16%), including 3 of 18 American patients and 3 of 19 cases from Hong Kong. All cases had a 185-bp NPM RT-PCR product as detected by Southern blot analysis, indicating adequate preservation of mRNA. The 6 positive cases were among 4 of 34 adult lymphomas, as compared with 2 of 3 childhood cases. Five of 17 T-lineage cases were t(2;5)-positive, compared with 1 of 15 B-lineage cases and none of the 5 null-cell or mixed lineage cases. Our results therefore show that t(2;5) occurs at a low frequency among CD30+ lymphomas, at least in our adult-dominated series. PMID- 7856745 TI - Alterations in glucose transporter proteins in alcoholic liver disease in the rat. AB - We used the intragastric feeding rat model for alcoholic liver disease to investigate alterations in glucose transporter isoforms GLUT 1 and GLUT 2 in response to different dietary fats and ethanol. Six groups of rats (three rats/group) were fed ethanol or dextrose with either saturated fat, corn oil, or fish (menhaden) oil. All control animals were pair fed the same diets as ethanol fed rats except that ethanol was isocalorically replaced by dextrose. In all animals, the following were assessed: pathological changes in the liver, immunohistochemical and Western blot analysis of GLUT 1 and GLUT 2 isoforms, and glycogen distribution. The most severe pathological changes were seen in fish oil/ethanol fed rats, moderate changes were seen in the corn oil/ethanol group and no changes were observed in the dextrose-fed or saturated fat/ethanol groups. In the groups of rats showing pathological liver injury (corn oil/ethanol and fish oil/ethanol), the depletion in liver glycogen was accompanied by decreased GLUT 2 expression and increased GLUT 1 expression. A decrease in glycogen and GLUT 2 expression was also seen in the fish oil/dextrose-fed rats. We hypothesize that the shift in glucose transporters from GLUT 2 to GLUT 1 probably reflects a compensatory response to attenuated gluconeogenic activity and to meet the increased intracellular demand for glucose. This demand for glucose in the presence of depleted glycogen may serve to provide a source for ATP synthesis in the centrilobular zone where hypoxia occurs secondary to ethanol metabolism. PMID- 7856746 TI - Detection of mouse mast cell-associated protease mRNA. Heparinase treatment greatly improves RT-PCR of tissues containing mast cell heparin. AB - The reverse transcriptase polymerase chain reaction (RT-PCR) procedure is markedly inhibited in specimens of blood that contain commercial heparin as an anticoagulant or in cell preparations containing rat or mouse peritoneal mast cells. However, it was not known whether the levels of endogenous, mast cell associated heparin that are present in some mammalian tissues are sufficient to interfere with the use of RT-PCR in these settings. We show that RT-PCR detects little or no mRNA transcripts for either mast cell-associated products, such as mouse mast cell-associated protease-2 or -4 (MMCP-2 or MMCP-4) or mast cell carboxypeptidase A, or for mast cell-nonspecific products, such as glyceraldehyde 3-phosphate dehydrogenase, in routinely prepared specimens of cells or tissues that include populations of heparin-containing mast cells. However, signals for mast cell-associated or mast cell-nonspecific transcripts can be readily detected in such specimens if they are treated with heparinase before RT-PCR. RT-PCR after heparinase treatment appears to represent an extremely sensitive method for detecting mast cell-associated transcripts in tissue specimens, permitting the identification of transcripts for mast cell-specific proteases in the skin of genetically mast cell-deficient WBB6F1-W/WV mice, a tissue that contains few or no mast cells according to histological analysis. PMID- 7856747 TI - Wilms' tumor 1 susceptibility (WT1) gene products are selectively expressed in malignant mesothelioma. AB - The distinction between malignant mesothelioma and other neoplastic processes involving the pleura is difficult, partly due to the lack of specific markers expressed on mesothelioma. Because of evidence suggesting that the Wilms' tumor susceptibility gene (WT1), unlike other tumor suppressor genes, is restricted mostly to mesenchymally derived tissues, we hypothesized that the WT1 gene products could serve as a potential marker for mesothelioma. The expression of WT1 mRNA was analyzed in 19 malignant mesothelioma cell lines and 9 tumors and compared with the expression of WT1 in 10 non-small cell lung cancer lines and 9 lung cancer specimens. WT1 mRNA was detectable by Northern analysis in 16 of 19 mesothelioma cell lines and in 5 of 8 malignant mesothelioma tumors. In contrast, WT1 mRNA was not detected by Northern analysis in non-small cell lung cancer lines or carcinomas. Immunoprecipitation with an anti-WT1 monoclonal antibody showed that a 52- to 54-kd protein was present in 4 mesothelioma cell lines. Immunostaining with this antibody localized the WT1 protein to the nucleus in two mesothelioma lines and in 20 of 21 mesothelioma tumors examined. This distinctive pattern of nuclear immunoreactivity was absent in 26 non-mesothelioma tumors involving the lung, including 20 non-small cell lung carcinomas. The detection of WT1 mRNA or protein may thus provide a specific molecular or immunohistochemical marker for differentiation of mesothelioma from other pleural tumors, in particular, adenocarcinoma. PMID- 7856748 TI - Localization of superoxide dismutases in Alzheimer's disease and Down's syndrome neocortex and hippocampus. AB - Abnormalities in the cellular regulation and expression of antioxidant enzymes may have a role in mechanisms of central nervous system aging and neurodegeneration. We therefore examined, using isozyme-specific antibodies and immunohistochemistry, the localization of copper, zinc-superoxide dismutase and manganese-superoxide dismutase in the frontal and temporal neocortices and hippocampi of aged controls and individuals with Alzheimer's disease or Down's syndrome. Two different antibodies to copper, zinc-superoxide dismutase and one antibody to manganese-superoxide dismutase were evaluated by immunoblotting of homogenates of human brain before use in immunohistochemistry. The copper, zinc superoxide dismutase antibodies recognized a single band of proteins at 16 kd. The manganese-superoxide dismutase antibody detected a single band of proteins at 25 kd. Immunohistochemically, copper, zinc-superoxide dismutase and manganese superoxide dismutase immunoreactivities were localized predominantly to neocortical and hippocampal pyramidal neurons and scarcely seen in glial cells in controls. In Alzheimer's disease and Down's syndrome, the distributions and intensities of these two forms of superoxide dismutase immunoreactivities were different as compared with controls. Copper, zinc-superoxide dismutase was enriched in pyramidal neurons undergoing degeneration, whereas manganese superoxide dismutase was more enriched in reactive astrocytes than in neurons. In senile plaques, copper, zinc-superoxide dismutase-positive globular structures were surrounded by astrocytes highly enriched in manganese-superoxide dismutase. By double label immunohistochemistry, some pyramidal neurons coexpressed superoxide dismutases and tau, and a few copper, zinc-superoxide dismutase positive structures in senile plaques colocalized with tau. Amyloid cores, diffuse plaques, and microglia scarcely showed colocalization with superoxide dismutase-positive structures. The observed changes in the cellular localization of superoxide dismutases in neocortex and hippocampus in cases of Alzheimer's disease and Down's syndrome support a role for oxidative injury in neuronal degeneration and senile plaque formation. The differential localization of copper, zinc-superoxide dismutase and manganese-superoxide dismutase in cerebral sites of degeneration suggests that cellular responses to oxidative stress is antioxidant enzyme specific and cell type specific and that these two forms of superoxide dismutase may have different functions in antioxidant mechanisms. PMID- 7856750 TI - Pulmonary artery adventitial changes and venous involvement in primary pulmonary hypertension. AB - Primary pulmonary hypertension (PPH) is associated with a spectrum of structural changes in the pulmonary arteries: increased medial thickness, eccentric and concentric intimal thickening, obliteration and recanalization of arteries, and appearance of plexiform and dilatation lesions. The purpose of the present study was to further characterize these structural changes with particular emphasis on arterial adventitial thickness and alterations in the walls of the pulmonary veins. In addition, to determine whether the characteristic structural changes of PPH were size related, each was related to external diameter. With quantitative techniques, the pulmonary vasculature of 19 patients with PPH and 7 controls was examined by light microscopy. In all 19 patients, we found a striking increase in adventitial, as well as intimal and medial, thickness in arteries of all sizes when compared with controls (P < 0.05). In addition, we found intimal and adventitial thickening of pulmonary veins < 250 mu in diameter in approximately half of the PPH cases (P < 0.05). The frequency of arterial obliteration, concentric intimal thickening, and recanalization was 16, 18, and 11 of 19 cases, respectively. These changes were most prevalent in arteries less than 200 mu in diameter whereas eccentric intimal thickening and plexiform lesions occurred in 15 and 6 of the patients, respectively, and were most widespread in arteries > 200 mu. We conclude that remodeling of the pulmonary vasculature in PPH routinely includes thickening of the arterial adventitia and frequently also includes changes in the walls of the pulmonary veins. The finding that recanalization occurs predominantly in the smaller arteries whereas eccentric intimal thickening occurs mainly in the larger ones suggests that recanalization should not be considered a consequence of thromboemboli but may also occur at sites of more fibrotic intimal change. PMID- 7856749 TI - Expression of endothelial cell-specific receptor tyrosine kinases and growth factors in human brain tumors. AB - Key growth factor-receptor interactions involved in angiogenesis are possible targets for therapy of CNS tumors. Vascular endothelial growth factor (VEGF) is a highly specific endothelial cell mitogen that has been shown to stimulate angiogenesis, a requirement for solid tumor growth. The expression of VEGF, the closely related placental growth factor (PIGF), the newly cloned endothelial high affinity VEGF receptors KDR and FLT1, and the endothelial orphan receptors FLT4 and Tie were analyzed by in situ hybridization in normal human brain tissue and in the following CNS tumors: gliomas, grades II, III, IV; meningiomas, grades I and II; and melanoma metastases to the cerebrum. VEGF mRNA was up-regulated in the majority of low grade tumors studied and was highly expressed in cells of malignant gliomas. Significantly elevated levels of Tie, KDR, and FLT1 mRNAs, but not FLT4 mRNA, were observed in malignant tumor endothelia, as well as in endothelia of tissues directly adjacent to the tumor margin. In comparison, there was little or no receptor expression in normal brain vasculature. Our results are consistent with the hypothesis that these endothelial receptors are induced during tumor progression and may play a role in tumor angiogenesis. PMID- 7856751 TI - Relationship between P-glycoprotein expression and cyclosporin A in kidney. An immunohistological and cell culture study. AB - P-glycoprotein (P-gp), encoded in humans by the mdr-1 gene, acts physiologically as an efflux pump to expel hydrophobic substances from cells. This glycoprotein is closely related to multidrug resistance in tumor cells and can be modulated by cyclosporin A (CsA). We investigated the relationship between CsA and P-gp in 52 renal allograft biopsies and in cultures of Madin-Darby canine kidney (MDCK) renal tubule cells to determine whether the intrarenal accumulation of CsA or chronic stimulation with the drug modified the expression of P-gp. Expression of P-gp and CsA was analyzed by immunohistochemistry. Immunostaining was evaluated semiquantitatively. Modulation of P-gp in MDCK cells after chronic stimulation with CsA for 7, 30, and 60 days was analyzed by flow cytometry. P-gp and CsA immunostaining in renal post-transplant biopsies showed considerable overlap in all cases (Spearman's test, r = 0.577, P < 0.001). After 7 days in vitro, the number of cells expressing P-gp increased progressively; a further increase in mean fluorescence was found after 60 days (P < 0.001, Student's t-test). Our findings suggest that in non-neoplastic cells, CsA may stimulate P-gp as a mechanism of detoxification. Individual differences in the adaptive responses to glycoprotein may be responsible for the appearance of nephrotoxicity or a CsA resistant rejection reaction in cases of overexpression on lymphocytes and macrophages. PMID- 7856752 TI - Cytokine mRNA expression in postischemic/reperfused myocardium. AB - While the role of cytokines in mediating injury during hind limb skeletal muscle ischemia followed by reperfusion has recently been described, the role of cytokines in myocardial infarction and ischemia/reperfusion have remained relatively unexplored. We hypothesize that cytokines play an important role in the regulation of postischemic myocardial inflammation. This study reports the temporal sequence of proinflammatory cytokine gene expression in postischemic/reperfused myocardium and localizes interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha)-protein by immunostaining. Rats were subjected to either permanent left anterior descending (LAD) occlusion or to 35 minutes of LAD occlusion followed by reperfusion and sacrificed up to 7 days later. Rat-specific oligonucleotide probes were used to semiquantitatively assess the relative expression of mRNA for TNF-alpha, IL-1 beta, IL-2, IL-6, interferon gamma (IFN-gamma), and transforming growth factor-beta 1 (TGF-beta 1) utilizing the reverse transcriptase-polymerase chain reaction amplification technique. Increased cardiac mRNA levels for all cytokines except IL-6 and IFN-gamma were measurable within 15 to 30 minutes of LAD occlusion and increased levels were generally sustained for 3 hours. During early reperfusion, mRNA levels for IL-6 and TGF-beta 1 were significantly reduced compared with permanent LAD occlusion. In both groups, cytokine mRNA levels all returned to baseline levels at 24 hours, while IL-1 beta, TNF-alpha, and TGF-beta 1 mRNA levels again rose significantly at 7 days only in animals with permanent LAD occlusion. Immunostaining for IL-1 beta and TNF-alpha protein revealed two patterns of reactivity: 1) microvascular staining for both IL-1 beta and TNF-alpha protein only in postischemic reperfused myocardium in early post-reperfusion time points; and 2) staining of infiltrating macrophages in healing infarct zones which was most prominent at 7 days after permanent LAD occlusion. These results provide evidence for local expression of cytokine mRNA in postischemic myocardium and suggest that regulation of local cytokine release is altered during the postischemic period. PMID- 7856753 TI - Differential permeability and quantitative MR imaging of a human lung carcinoma brain xenograft in the nude rat. AB - This study characterized agent differential permeability, three-dimensional tumor volume, and survival in an LX-1 human small cell lung carcinoma intracerebral xenograft model in the nude rat. The percent accessible tissue space (distribution volume) and the permeability x capillary surface product for aminoisobutyric acid (M(r) 103), methotrexate (M(r) 454), dextran 10 (M(r) 10,000), and dextran 70 (M(r) 70,000) were measured between 8 and 16 days after inoculation of tumor. Magnetic resonance imaging and histology were used to quantitate intracerebral tumor volume (mm3). Accessible tissue space (ml/g) and permeability x capillary surface product in intracranial tumor, surrounding brain, and subcutaneous tumor decreased with increasing molecular weight of the agent, regardless of the number of days after inoculation. Accessible tissue space in intracranial tumor increased between 8 and 16 days for all agents except dextran 70. There was little change in the subcutaneous tumor or other tissues with time. Tumor volume calculations from imaging studies correlated with volumetric measurements from histological sections (r2 = 98.5%) and illustrated natural tumor progression (9 to 225 mm3). These results provide a basis for therapeutic design based on differential permeability of specific agents and the ability to quantitatively measure brain tumor volume for accessing tumor response. PMID- 7856754 TI - Regulatory roles of tumor necrosis factor-alpha and interleukin-1 beta in monocyte chemoattractant protein-1-mediated pulmonary granuloma formation in the rat. AB - Intravenous infusion of particulate yeast cell wall glucan into rats results in the synchronous development of angiocentric pulmonary granulomas that are composed almost entirely of monocytes and macrophages. Previous studies indicate that locally produced monocyte chemoattractant protein-1 (MCP-1) is required for full granuloma development. Because tumor necrosis factor-alpha (TNF-alpha) and interleukin 1 (IL-1) can induce MCP-1 production in a variety of cell types, we sought to determine their potential regulatory roles in this model. A single infusion of anti-TNF-alpha antibody at the time of glucan infusion (time 0) markedly reduced MCP-1 mRNA levels at 1 and 6 hours but not at later time points; there was no effect on granuloma size or number measured at 48 hours. When multiple infusions of anti-TNF-alpha antibody were administered over a 23-hour period (0 to 23 hours), MCP-1 mRNA was reduced through 24 hours, there was a significant reduction in peak bronchoalveolar lavage fluid MCP-1 activity at 48 hours, and there were marked reductions in granuloma size and number at 48 hours. Similar results were observed in animals that received infusions of anti-IL-1 beta. Infusion of anti-IL-1 beta at time 0 resulted in moderate reductions in MCP 1 mRNA at 1 and 6 hours and had no effect on granuloma size or number measured at 48 hours. When multiple infusions of anti-IL-1 beta were administered over a 23 hour period (0 to 23 hours), MCP-1 mRNA was reduced through 24 hours, there was a moderate reduction in peak bronchoalveolar lavage fluid MCP-1 activity at 48 hours, and there were marked reductions in granuloma size and number at 48 hours. A single infusion of anti-TNF-alpha and anti-IL-1 beta together at time 0 resulted in marked reductions in whole lung MCP-1 and mRNA at 1 and 6 hours, but not at 24 hours. Multiple combined infusions of anti-TNF-alpha and anti-IL-1 beta over a 23-hour period resulted in additive reductions in MCP-1 mRNA through 24 hours, bronchoalveolar lavage fluid MCP-1 activity at 48 hours, and granuloma size and number at 48 hours. These data suggest that locally produced TNF-alpha and IL-1 beta play regulatory roles in glucan-induced pulmonary granulomatous vasculitis through the modulation of local MCP-1 production. PMID- 7856755 TI - CD30 antigen in embryonal carcinoma and embryogenesis and release of the soluble molecule. AB - The expression, serological detection, and possible functional role of the CD30 antigen in Hodgkin's disease and anaplastic large cell lymphoma is well documented. In embryonal carcinoma (EC), the expression of this cytokine receptor has been demonstrated only by immunohistology. Because the CD30 monoclonal antibody Ki-1 was found to cross-react with an unrelated molecule, we examined by in situ hybridization testicular germ cell neoplasms for the presence of CD30 specific transcripts. CD30 mRNA was detectable in the tumor cells of 9 of 9 cases of EC or mixed germ cell tumors with an EC component but in no other nonlymphoid tumors. Thus, the CD30 transcript expression pattern proved to be identical to the immunostaining pattern seen with the CD30-specific monoclonal antibody Ber H2. By Northern blot analysis, CD30 transcripts could be demonstrated in the EC cell line Tera-2. Employing a highly sensitive second generation sandwich enzyme linked immunosorbent assay, we could detect the soluble CD30 molecule in 8 of 8 sera from patients with a diagnosis of EC but not in 8 of 10 sera from patients with other testicular germ cell tumors. In fetal tissue, no CD30-expressing germ cells or epithelial cells could be observed. Thus, the cellularly expressed CD30 marker for testicular neoplasms of EC type. Moreover, the serum levels of soluble CD30 antigen seem to be a promising parameter for monitoring patients with EC. PMID- 7856756 TI - Correlation of loss of heterozygosity at chromosome 9q with histological subtype in medulloblastomas. AB - Patients with the nevoid basal cell carcinoma syndrome (NBCCS) are at increased risk for medulloblastomas as well as for basal cell carcinomas. The gene for NBCCS has been mapped to chromosome 9q22.3-q31 by linkage analysis, and loss of heterozygosity (LOH) in this region has been demonstrated in approximately one half of sporadic basal cell carcinomas. In the present study, LOH for chromosome 9q22.3-q31 microsatellite markers was investigated in medulloblastomas occurring among children with NBCCS and in sporadic medulloblastomas. Histologically, all 3 NBCCS medulloblastomas were noted to have a desmoplastic phenotype, and LOH was detected in both of the 2 cases for which microsatellite markers were heterozygous in normal tissues. LOH was also detected in a subset of sporadic medulloblastomas, each of which were found to display the desmoplastic phenotype. In all, 3 of the 6 sporadic desmoplastic tumors showed LOH, whereas LOH was not seen in any of the 11 sporadic, non-desmoplastic medulloblastomas studied. Additionally, desmoplastic tumors lacking detectable LOH each showed histological features of so-called cerebellar neuroblastoma, a subgroup of desmoplastic medulloblastoma with extensive neuroblastomatous differentiation. The data are consistent with a role for inactivation of a tumor suppressor gene at chromosome 9q in the development of medulloblastomas in patients with NBCCS and of sporadic medulloblastomas characterized by a desmoplastic phenotype similar to that found in patients with NBCCS. Restriction of chromosome 9q loss to non neuroblastomatous desmoplastic tumors suggests that this variant of medulloblastoma maybe pathogenetically distinct from tumors having other histological phenotypes. PMID- 7856757 TI - Regulation and function of Bcl-2 during differentiation-induced cell death in HL 60 promyelocytic cells. AB - Polymorphonuclear leukocytes are generated by differentiation of early myeloid precursors. Once fully differentiated, blood neutrophils are programmed to die rapidly and are removed by tissue macrophages. In normal myeloid cells, the death mechanism seems to be coupled to the differentiation pathway and is accomplished by a process termed apoptosis. In the present study, we have examined the role of Bcl-2 in the differentiation pathways of the promyelocytic cell line HL-60. Treatment of HL-60 with retinoic acid or phorbol ester, which induced neutrophil or macrophage-like cell differentiation, respectively, resulted in progressive loss of cellular viability and internucleosomal DNA degradation. In HL-60, differentiation and apoptosis were coupled to down-regulation of the Bcl-2 protein. Overexpression of Bcl-2 by gene transfer inhibited apoptosis triggered by terminal differentiation of HL-60. Yet, Bcl-2 did not alter the expression of surface markers or other phenotypic changes that are induced upon myeloid differentiation. In contrast to HL-60, another immature myeloid cell line, K562, did not produce Bcl-2 but expressed a related protein, Bcl-xL, that functions as a repressor of apoptotic cell death. K562 has been shown to be relatively resistant to a variety of apoptotic stimuli. Incubation of HL-60 and K562 with inhibitors of macromolecular synthesis induced apoptosis, which appeared earlier in HL-60 than in K562. Interestingly, Bcl-2 overexpression protected K562 cells from apoptosis induced by inhibitor of macromolecular synthesis but it had little or no effect on HL-60 cells. We conclude that although differentiation and apoptosis proceed simultaneously, they can be uncoupled by expression of Bcl-2. Down-regulation of Bcl-2 appears to be part of the differentiation pathway and may serve to facilitate the apoptotic response. PMID- 7856758 TI - Aromatase in human endometrial carcinoma and hyperplasia. Immunohistochemical, in situ hybridization, and biochemical studies. AB - The expression of P450 aromatase and other steroidogenic enzymes were evaluated in 42 endometrioid endometrial carcinomas, 23 endometrial hyperplasias, and 7 normal endometrial specimens. These findings were correlated with clinicopathological findings to elucidate the possible biological significance of in situ estrogen production in the development of human endometrial carcinoma. Only weak aromatase immunoreactivity was observed in vascular walls and myometrial cells. In contrast, strong aromatase stromal immunoreactivity was observed in 28 of 42 (66.7%) endometrial carcinomas. However, no stromal immunoreactivity was seen in normal or hyperplastic endometrial specimens. Immunoreactivity in the carcinoma stromal cells was significantly increased at sites of invasion. These aromatase-positive cells were immunohistochemically negative for other steroidogenic enzymes involved in estrogen biosynthesis. In situ hybridization studies revealed aromatase mRNA hybridization signals in stromal cells but not in carcinoma cells. The distribution of aromatase mRNA correlated well with the immunohistochemical localization of aromatase enzyme. Quantitation of aromatase activity demonstrated 8.75 +/- 2.75 pmol/hour/mg of protein for endometrial carcinomas (22 specimens) and 0.98 +/- 1.95 pmol/hour/mg of protein for normal endometrial specimens (4 specimens). Aromatase activity was found in both estrogen receptor-positive and -negative endometrial carcinomas. Aromatase did not vary with respect to the menopausal status of patients with endometrial carcinoma. These results suggest that estrogen is produced in situ in endometrial carcinoma but not in benign endometrial lesions. Such locally synthesized estrogen may act on carcinoma cells in a paracrine fashion to promote tumor growth. Additional investigations are necessary, but increased aromatase expression in the stromal cells of endometrial carcinoma may therefore play an important role in the development of human endometrioid endometrial carcinoma. PMID- 7856759 TI - A polymerase chain reaction assay for non-random X chromosome inactivation identifies monoclonal endometrial cancers and precancers. AB - We hypothesize that endometrial carcinoma and their precursors share a monoclonal growth pattern and tested this thesis with archival paraffin-embedded tissues using a polymerase chain reaction-based assay for non-random X chromosome inactivation. Of the 10 well-differentiated endometrial adenocarcinoma cases with heterozygous markers (HUMARA, X-linked androgen receptor gene), 9 had skewed X inactivation consistent with a monoclonal process, and one contained a structurally altered HUMARA gene. X inactivation skewing similar to that of the tumor was seen in matched control polyclonal tissues of 4 (of 9) cases, caused by the small number of endometrial stem cells at the time of embryonic X inactivation. When the polymerase chain reaction assay was applied to four potential endometrial precancers (atypical endometrial hyperplasia) and matched control tissues, two were inconclusive, and two were found to be monoclonal. We conclude that 1) it is essential to include polyclonal control tissues in X inactivation analyses to determine whether skewing is a specific indicator of monoclonality; and 2) endometrial adenocarcinomas and some putative precancers, atypical endometrial hyperplasia, are monoclonal. PMID- 7856760 TI - Study of the immunohistochemistry and T cell clonality of enteropathy-associated T cell lymphoma. AB - Specimens from 23 patients with enteropathy-associated T cell lymphoma were studied by immunohistochemistry after antigen retrieval. Specimens from 14 of these patients were investigated for the presence of clonal T cell gene rearrangements in both the tumor and the adjacent enteropathic intestine by the polymerase chain reaction. Primers for T cell receptor beta and gamma genes were used in a combination that permits the identification of approximately 90% of T cell receptor rearrangements. Clonal rearrangements of the T cell receptor were found in 13 of the 14 tumors studied. Specimens of enteropathic bowel resected with the tumor, but showing no morphological or immunohistochemical evidence of tumor involvement, showed clonal T cell receptor gene rearrangements in 11 cases. In 10 of these, the amplified DNA was of the same molecular weight in the enteropathic bowel as in the corresponding tumor. In 2 cases, sequencing the polymerase chain reaction product showed identical T cell receptor gene rearrangements in the tumor and in the adjacent intestine. Uniform staining for p53 was seen in 22 of the 23 tumors. In 9 of 19 cases studied, collections of small lymphocytes in the enteropathic bowel expressed p53. In all but one of these specimens, a clonal rearrangement of the T cell receptor genes was identified. We interpret these findings as support for the concept that enteropathy-associated T cell lymphoma arises on a background of gluten-sensitive enteropathy with evolution of neoplastic T cell clones from the reactive T cell population present in the enteropathic bowel. PMID- 7856761 TI - Source of peritoneal proteoglycans. Human peritoneal mesothelial cells synthesize and secrete mainly small dermatan sulfate proteoglycans. AB - This study describes experiments that compare the proteoglycans (PGs) extracted from the dialysate from patients receiving continuous peritoneal ambulatory dialysis (CAPD) with those secreted by metabolically labeled human peritoneal mesothelial cells in vitro. The PGs isolated from both sources were predominantly small chondroitin sulfate/dermatan sulfate PGs. Western blot of the core proteins obtained after chondroitin ABC lyase treatment with specific antibodies identified decorin and biglycan. With [35S]sulfate and [35S]methionine as labeling precursors it was shown that dermatan sulfate rather than chondroitin sulfate were the major glycosaminoglycan chains and that decorin was the predominant species. These data provide the first evidence that human peritoneal mesothelial cells may be the principal source of PGs in the peritoneum. Given the proposed functions of decorin and biglycan, the results suggest that these PGs may be involved in the control of transforming growth factor-beta activity and collagen fibril formation in the peritoneum. PMID- 7856762 TI - Sarcoglycan complex is selectively lost in dystrophic hamster muscle. AB - We recently reported that the dystrophin-associated glycoprotein (DAG) complex is biochemically divided into two subcomplexes: one is the dystroglycan complex comprised of 156DAG and 43DAG and the other is the sarcoglycan complex comprised of 50DAG, A3b, and 35DAG. A3b is a novel dystrophin-associated glycoprotein with an approximate molecular mass of 43 kd but is distinct from 43DAG. In the present study, we examined the striated muscles of the dystrophic hamster with anti-A3b antibody in addition to anti-50DAG, anti-43DAG, anti-35DAG, anti-dystrophin, and anti-laminin antibodies by both immunohistochemistry and immunoblot analysis and found that 50DAG, A3b, and 35DAG are selectively lost. This selective defect of the sarcoglycan complex in dystrophic hamster muscles may give rise to dystrophic changes in striated muscles. Thus, the differentiation of the dystrophin associated glycoprotein complex into the dystroglycan and sarcoglycan complexes is important not only from a biochemical standpoint but also in understanding the cause of muscular dystrophy in the hamster. Our findings further show that the dystrophic hamster may serve as an animal model for a human disease, severe childhood autosomal recessive muscular dystrophy, which has recently been shown to result from a selective defect in the sarcoglycan complex. PMID- 7856764 TI - Craniometric variation, genetic theory, and modern human origins. AB - Recent controversies surrounding models of modern human origins have focused on among-group variation, particularly the reconstruction of phylogenetic trees from mitochondrial DNA (mtDNA) and the dating of population divergence. Problems in tree estimation have been seen as weakening the case for a replacement model and favoring a multiregional evolution model. There has been less discussion of patterns of within-group variation, although the mtDNA evidence has consistently shown the greatest diversity within African populations. Problems of interpretation abound given the numerous factors that can influence within-group variation, including the possibility of earlier divergence, differences in population size, patterns of population expansion, and variation in migration rates. We present a model of within-group phenotypic variation and apply it to a large set of craniometric data representing major Old World geographic regions (57 measurements for 1,159 cases in four regions: Europe, Sub-Saharan Africa, Australasia, and the Far East). The model predicts a linear relationship between variation within populations (the average within-group variance) and variation between populations (the genetic distance of populations to pooled phenotypic means). On a global level this relationship should hold if the long-term effective population sizes of each region are correctly specified. Other potential effects on within-group variation are accounted for by the model. Comparison of observed and expected variances under the assumption of equal effective sizes for four regions indicates significantly greater within-group variation in Africa and significantly less within-group variation in Europe. These results suggest that the long-term effective population size was greatest in Africa. Closer examination of the model suggests that the long-term African effective size was roughly three times that of any other geographic region. Using these estimates of relative population size, we present a method for analyzing ancient population structure, which provides estimates of ancient migration. This method allows us to reconstruct migration history between geographic regions after adjustment for the effect of genetic drift on interpopulational distances. Our results show a clear isolation of Africa from other regions. We then present a method that allows direct estimation of the ancient migration matrix, thus providing us with information on the actual extent of interregional migration. These methods also provide estimates of time frames necessary to reach genetic equilibrium. The ultimate goal is extracting as much information from present-day patterns of human variation relevant to issues of human origins.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7856765 TI - Major gene for percent of oxygen saturation of arterial hemoglobin in Tibetan highlanders. AB - This report employs a statistical genetic approach to analyze quantitative oxygen transport variables in a high-altitude (4,850-5,450 m) native Tibetan population and demonstrates the presence of a major gene influencing % O2 saturation of arterial hemoglobin. This result suggests the hypothesis that individuals with the dominant allele for higher % O2 saturation have a selective advantage at high altitude. Studies of the biologically distinctive Himalayan and Andean populations have greatly influenced thinking about ongoing human evolution and adaptation; this is the first statistical evidence for a major gene enhancing oxygen transport in a high-altitude native population. PMID- 7856763 TI - Characterization of biliary epithelial cells isolated from needle biopsies of human liver in the presence of hepatocyte growth factor. AB - Current methods for the isolation of intrahepatic biliary epithelial cells from human liver rely upon relatively large segments of tissue, thereby limiting studies to cells isolated from patients with end-stage disease. To investigate a greater range of diseases and those at an earlier stage, we have developed a method to isolate biliary epithelial cells from biopsy-sized fragments of human liver. Tissue explants are cultured for > 4 weeks, and, in approximately 50% of samples incubated with medium containing hepatocyte growth factor, biliary epithelial cells begin to migrate from the fragments and proliferate. With time they form confluent pavements of cells that express cytokeratin 19 and gamma glutamyl transpeptidase and are negative for markers of non-biliary cell phenotype. After subculturing, cells can be expanded, yielding substantial numbers for subsequent study in vitro. Cells can be isolated with a similar degree of success from adult normal liver, from a variety of liver diseases, and from post-transplant liver biopsies. Overall, pediatric tissue yielded cells less frequently than adult tissue. This novel technique is likely to have a major impact on the study of biliary pathophysiology, as small fragments of tissue removed from biopsies taken for diagnostic purposes can be used. PMID- 7856766 TI - Phylogenetic, paleodemographic, and taphonomic implications of Victoriapithecus deciduous teeth from Maboko, Kenya. AB - More than 240 milk teeth of Victoriapithecus macinnesi, representing all elements of the deciduous dentition, are described. Their morphology is intermediate between that of hominoids and cercopithecids. Unlike colobine and cercopithecine milk teeth, Victoriapithecus dp3s, dp4s, and at least 7 (14%) dp4s lack transverse distal loph(id)s and are not bilophodont. Victoriapithecus also differs from cercopithecids in having less elongated deciduous premolars, a dp3 metacone set mesial to a very small hypocone, a dp4 crista obliqua, and a dp4 hypoconulid. The deciduous canines and incisors of Victoriapithecus are like those of other cercopithecids in having an uneven distribution of enamel around a compressed (rather than cylindrical) root, but differ from cercopithecids and resemble hominoids in being more elongated. Since Colobinae and Cercopithecinae share features of the deciduous dentition that are derived relative to Victoriapithecus and hominoids, extant Old World monkeys are interpreted as representing the sister-taxon of the middle Miocene cercopithecoids. Due to a dramatic increase in the number of deciduous teeth found at Maboko Island, juvenile individuals represent a much larger proportion of recently excavated Victoriapithecus collections than is true of pre-1987 assemblages which mainly derive from sediment first excavated during the 1930s and 1940s. Age distribution differences between pre- and post-1987 samples indicate that paleontological collection procedures were more important than taphonomic biases in determining the paleodemographic profile of the Maboko fossils. Since the Victoriapithecus assemblage from Maboko is strikingly similar to that of fossil Theropithecus oswaldi from Olorgesailie in terms of the large number of specimens and high representation of juvenile and infant individuals, the latter can no longer be viewed as unique among cercopithecoid fossil assemblages. Rather than being related to a specific cause of death, such as selective hunting of T. oswaldi by Homo (Shipman et al. [1981] Curr. Anthropol. 22:257-268), the large number of cercopithecoids at both sites is attributed to the fact that both assemblages represent excavated samples and that the preferred habitats of the extinct monkeys were probably at or near the site of deposition. The greater number of young adult male than female canines in the apparently attritional Maboko Bed 5 assemblage, indicate that the social organization of V. macinnesi may have been similar to that of modern macaques, with males migrating out of their natal group and suffering higher death rates than females at puberty. PMID- 7856767 TI - "Giant" tamarin from the Miocene of Colombia. AB - A nearly complete but badly crushed skull and mandible of Lagonimico conclucatus, gen. et sp. nov. is described from the La Victoria Formation, Colombia. The specimen is of middle Miocene age and dates from about 13.5 Ma. Features of the dentition suggest Lagonimico is a sister group to living Callitrichinae (Saguinus, Leontopithecus, Callithrix, and Cebuella). These features include having elongate compressed lower incisors, a reduced P2 lingual moiety, and the absence of upper molar hypocones. The new taxon also has autapomorphies, such as a relatively deep jaw, that rule it out of the direct ancestry of any living callitrichine. This animal is assigned to a new tribe of the callitrichine clade. The orbits of L. conclucatus are small, suggesting diurnal habits. Inflated, low crowned (bunodont) cheek teeth with short, rounded shearing crests, as well as premolar simplification and M3 size reduction, suggest fruit- or gum-eating adaptations, as among many living callitrichines. Procumbent and slightly elongate lower incisors suggest this species could use its front teeth as a gouge, perhaps for harvesting tree gum. Estimates from jaw size suggest Lagonimico weighed about 1,200 g, about the size of Callicebus, the living titi monkey of South America. Judged from tooth size and jaw length, Lagonimico would have been slightly smaller than Callicebus, but still larger than Callimico or any living callitrichine. Therefore, many of the distinctive anatomical features of the callitrichine clade, sometimes explained by phyletic dwarfing, may have evolved at larger body size. Evolutionary size reduction may have occurred in parallel in callitrichines and Callimico. PMID- 7856768 TI - Endocasts and meningeal vascular patterns. PMID- 7856769 TI - The tribulations of trials--intervention in communities. PMID- 7856770 TI - The results of the COMMIT trial. Community Intervention Trial for Smoking Cessation. PMID- 7856771 TI - Smoking cessation treatment and the good doctor club. PMID- 7856772 TI - Annotation: accounting for the effects of both group- and individual-level variables in community-level studies. PMID- 7856773 TI - Annotation: confounding in epidemiologic research. PMID- 7856774 TI - Annotation: protection of the public interest, allegations of scientific misconduct, and the Needleman case. PMID- 7856775 TI - Emerging diseases and ecosystem instability: new threats to public health. AB - Ecologists have begun to describe an environmental distress syndrome, whereby widespread loss of top predators and harsh environmental conditions are encouraging the selection of opportunistic pests and pathogens across a wide taxonomic range of plants and animals. Environmental change and pollutants stress individuals and populations, and this may be reflected in the global resurgence of infectious disease as these stresses cascade through the community assemblages of species. In 1993, the sudden appearance of a virulent, rodent-borne hantavirus in the arid US Southwest accompanied anomalous weather patterns, and a novel Vibrio cholerae variant (O139 Bengal) emerged in Asia where marine ecosystems are experiencing a pandemic of coastal algal blooms, apparently harboring and amplifying the agent. This paper suggests a framework for integrating the surveillance of health outcomes and key reservoir and vector species, with ecological and climatic monitoring. PMID- 7856776 TI - Seven chronic conditions: their impact on US adults' activity levels and use of medical services. AB - OBJECTIVES: This paper analyzes the impact of seven chronic conditions (three nonfatal: arthritis, visual impairment, hearing impairment; four fatal: ischemic heart disease, chronic obstructive pulmonary disease, diabetes mellitus, malignant neoplasms) on US adults aged 18 and older. Impact refers to how readily a condition prompts activity limitations, physician visits, and hospital stays. METHODS: Data come from three national health surveys and vital statistics. For comparability, a single disease classification scheme was applied, and new rates were estimated. Frequency, impact, and prominence of the target conditions are studied via rates, ratios of rates, and ranks, respectively. RESULTS: In young adulthood, the nonfatal conditions prompt limitations less readily than do the fatal ones, but by older ages, arthritis and visual impairment have a limiting impact equivalent to that of fatal conditions. Despite high prevalence and limitations, nonfatal conditions stand well below fatal conditions for health services use. CONCLUSIONS: Although statistics on frequency, impact, and prominence all indicate conditions "importance," they give only weak clues about specific service needs of affected persons. The persistent finding that nonfatal conditions do not receive health services care commensurate with their prevalence and impact reflects long-standing imbalanced attention on fatal conditions in research and medical care. PMID- 7856777 TI - Community Intervention Trial for Smoking Cessation (COMMIT): I. cohort results from a four-year community intervention. AB - OBJECTIVES: The primary hypothesis of COMMIT (Community Intervention Trial for Smoking Cessation) was that a community-level, multi-channel, 4-year intervention would increase quit rates among cigarette smokers, with heavy smokers (> or = 25 cigarettes per day) of priority. METHODS: One community within each of 11 matched community pairs (10 in the United States, 1 in Canada) was randomly assigned to intervention. Endpoint cohorts totaling 10,019 heavy smokers and 10,328 light-to moderate smokers were followed by telephone. RESULTS: The mean heavy smoker quit rate (i.e., the fraction of cohort members who had achieved and maintained cessation at the end of the trial) was 0.180 for intervention communities versus 0.187 for comparison communities, a nonsignificant difference (one-sided P = .68 by permutation test; 90% test-based confidence interval (CI) for the difference = -0.031, 0.019). For light-to-moderate smokers, corresponding quit rates were 0.306 and 0.275; this difference was significant (P = .004; 90% CI = 0.014, 0.047). Smokers in intervention communities had greater perceived exposure to smoking control activities, which correlated with outcome only for light-to moderate smokers. CONCLUSIONS: The impact of this community-based intervention on light-to-moderate smokers, although modest, has public health importance. This intervention did not increase quit rates of heavy smokers; reaching them may require new clinical programs and policy changes. PMID- 7856778 TI - Community intervention trial for smoking cessation (COMMIT): II. Changes in adult cigarette smoking prevalence. AB - OBJECTIVES: COMMIT (Community Intervention Trial for Smoking Cessation) investigated whether a community-level multichannel intervention would decrease the prevalence of adult cigarette smoking and increase quitting, with heavy smokers (> or = 25 cigarettes per day) receiving the highest priority. METHODS: One community within each of 11 matched community pairs (10 in the United States, 1 in Canada) was randomly assigned to intervention. Baseline (1988) and final (1993) telephone surveys sampled households to determine prevalence of smoking behavior. RESULTS: Among the target population aged 25 to 64 years, there was no intervention effect on heavy smoking prevalence, which decreased by 2.9 percentage points in both intervention and comparison communities. Overall smoking prevalence decreased by 3.5 in intervention communities vs 3.2 in comparison communities, a difference not statistically significant, while the mean quit ratios were 0.198 versus 0.185, respectively, a difference of 0.013 (90% test-based confidence interval = -0.003, 0.028). CONCLUSIONS: Results are consistent with the cohort analysis reported separately, although the more powerful cohort design showed a statistically significant intervention effect upon light-to-moderate smokers. This community-based intervention did not have a significant impact on smoking prevalence beyond the favorable secular trends. In future efforts, additional strategies should be incorporated and rigorously evaluated. PMID- 7856779 TI - Changes in adult cigarette smoking in the Minnesota Heart Health Program. AB - OBJECTIVES: The Minnesota Heart Health Program was a research and demonstration project designed to reduce risk factors for heart disease in whole communities. This paper describes smoking-specific interventions and outcomes. METHODS: Three pairs of matched communities were included in the study. After baseline surveys, one community in each pair received a 5-year education program, while both cross sectional and cohort surveys continued in all sites. Adult education programs for smoking cessation included Quit and Win contests, classes, self-help materials, telephone support, and home correspondence programs. RESULTS: Encouraging short term results were obtained for several adult education programs. Overall long term outcomes were mixed, with evidence of an intervention effect only for women in cross-sectional survey data. Unexpectedly strong secular declines in smoking prevalence were observed in comparison communities. CONCLUSIONS: The findings suggest that community education may be unlikely to exceed dramatic secular reductions in smoking prevalence. The success of several key interventions and the incorporation of Minnesota Heart Health Program interventions by education communities are encouraging, however. PMID- 7856780 TI - Take heart: results from the initial phase of a work-site wellness program. AB - OBJECTIVES: The purpose of this study was to evaluate the short-term effects of a low-intensity work-site heart disease risk reduction program using a matched pair design with work site as the unit of analysis. METHODS: Twenty-six heterogeneous work sites with between 125 and 750 employees were matched on key organization characteristics and then randomly assigned to early or delayed intervention conditions. Early intervention consisted of an 18-month multifaceted program that featured an employee steering committee and a menu approach to conducting key intervention activities tailored to each site. RESULTS: Cross-sectional and cohort analyses produced consistent results. At the conclusion of the intervention, early and delayed intervention conditions did not differ on changes in smoking rates, dietary intake, or cholesterol levels. There was considerable variability in outcomes among work sites within each condition. CONCLUSIONS: Despite documented implementation of key intervention activities and organization level changes in terms of perceived support for health promotion, this intervention did not produce short-term improvements beyond secular trends observed in control work sites. Research is needed to understand determinants of variability between work sites. PMID- 7856781 TI - Integrating smoking cessation into routine public prenatal care: the Smoking Cessation in Pregnancy project. AB - OBJECTIVES: In 1986, the state health departments of Colorado, Maryland, and Missouri conducted a federally-funded demonstration project to increase smoking cessation among pregnant women receiving prenatal care and services from the Women, Infants, and Children (WIC) program in public clinics. METHODS: Low intensity interventions were designed to be integrated into routine prenatal care. Clinics were randomly assigned to intervention or control status; pregnant smokers filled out questionnaires and gave urine specimens at enrollment, in the eighth month of pregnancy, and postpartum. Urine cotinine concentrations were determined at CDC by enzyme-linked immunosorbent assay and were used to verify self-reported smoking status. RESULTS: At the eighth month of pregnancy, self reported quitting was higher for intervention clinics than control clinics in all three states. However, the cotinine-verified quit rates were not significantly different. CONCLUSIONS: Biochemical verification of self-reported quitting is essential to the evaluation of smoking cessation interventions. Achieving changes in smoking behavior in pregnant women with low-intensity interventions is difficult. PMID- 7856782 TI - Gender differences in smoking cessation after 3 years in the Lung Health Study. AB - OBJECTIVES: An analysis of gender differences in smoking cessation was conducted among 3923 participants in the Special Intervention group of the Lung Health Study. This report focuses on gender differences in sustained quit rates at 12 and 36 months. METHODS: Special Intervention participants were offered a 12 session, 12-week smoking cessation program using nicotine gum and were followed for 3 years. Self-reported smoking status was validated with carbon monoxide and salivary cotinine. RESULTS: Men had higher sustained quit rates at 12 and 36 months; gender differences were found in baseline variables that also predicted sustained abstinence; and controlling for selected baseline variables reduced the association between gender and sustained abstinence. When other variables were controlled, gender predicted sustained abstinence at 36 months (odds ratio [OR] = 1.24, 95% confidence interval [CI] = 1.04, 1.48) but not 12 months (OR = 1.08, 95% CI = 0.92, 1.27), reflecting more late relapse among women. CONCLUSIONS: Demographics and smoking history were more important than gender per se in sustained smoking cessation in the Lung Health Study. Programs tailoring smoking cessation by gender need to include coping skills for problems associated with less education and social support and for improving persistence with quit attempts. PMID- 7856783 TI - Making the most of a teachable moment: a smokeless-tobacco cessation intervention in the dental office. AB - OBJECTIVES: Primary care medical clinics are good settings for smoking interventions. This study extends this strategy with a smokeless tobacco intervention delivered by dentists and dental hygienists in the course of routine dental care. METHODS: Male users of moist snuff and chewing tobacco (n = 518) were identified by questionnaire in clinic waiting rooms and then randomly assigned to either usual care or intervention. The intervention included a routine oral examination with special attention to the part of the mouth in which tobacco was kept and an explanation of the health risks of using smokeless tobacco. After receiving unequivocal advice to stop using tobacco, each patient viewed a 9-minute videotape, received a self-help manual, and was briefly counseled by the dental hygienist. RESULTS: Long-term success was defined as no smokeless tobacco use at both 3- and 12-month follow-ups, with those lost to follow-up counted as smokeless tobacco users. The intervention increased the proportion of patients who quit by about one half (12.5% vs 18.4%, P < .05). CONCLUSIONS: These results demonstrate the efficacy of a brief dental office intervention for the general population of smokeless tobacco users. PMID- 7856784 TI - Fruit and vegetable intake among adults in 16 states: results of a brief telephone survey. AB - A brief food frequency questionnaire was used to assess daily fruit and vegetable consumption among 23,699 adults in 16 US states sampled in a random-digit dialing telephone survey. Men consumed fewer servings per day (3.3) than did women (3.7). Only 20% of the population consumed the recommended 5 or more daily servings. Intakes varied somewhat by state and were lower among the young and the less educated. Efforts are needed to improve fruit and vegetable consumption among all Americans, especially younger adults and those with lower levels of education. PMID- 7856786 TI - Serial mass-media campaigns to promote physical activity: reinforcing or redundant? AB - Changes associated with two serial, nationwide, mass-media-based campaigns to promote physical activity conducted by the National Heart Foundation of Australia in 1990 and 1991 were examined. Surveys conducted before and after each campaign found statistically significant differences in message awareness (46% vs 71% in 1990; 63% vs 74% in 1991). In 1990, there were significant increases in walking, particularly among older people, and in intentions to exercise. No such changes were apparent in 1991. In the case of these two campaigns, conducted 1 year apart, the second may have been redundant. PMID- 7856785 TI - The association between leisure-time physical activity and dietary fat in American adults. AB - Relations between leisure-time physical activity and dietary fat were examined in a population-based probability sample of 29,672 adults in the 1990 Behavioral Risk Factor Surveillance System. Consumption of 13 high-fat food items and participation in physical activities were measured, and fat and activity scores were calculated. Dietary fat and physical activity were strongly and inversely associated. This association was independent of nine other demographic and behavioral risk factors. Etiologic researchers should consider that diet and physical activity can potentially confound each other, and creators of public health messages that target one behavior should consider including the other. PMID- 7856787 TI - Home pesticide use and childhood cancer: a case-control study. AB - The association between childhood cancer and home pesticide use was examined in a case-control study of children under 15 years of age. Parents of 252 children diagnosed with cancer in the Denver area between 1976 and 1983 and of 222 control subjects were interviewed regarding use of home pest extermination, yard treatment, and pest strips. The strongest associations were found for yard treatments and soft tissue sarcomas (odds ratios [ORs] around 4.0) and for use of pest strips and leukemias (ORs between 1.7 and 3.0). These results suggest that use of home pesticides may be associated with some types of childhood cancer. PMID- 7856788 TI - The limits of thresholds: silica and the politics of science, 1935 to 1990. AB - Since the 1930s threshold limit values have been presented as an objectively established measure of US industrial safety. However, there have been important questions raised regarding the adequacy of these thresholds for protecting workers from silicosis. This paper explores the historical debates over silica threshold limit values and the intense political negotiation that accompanied their establishment. In the 1930s and early 1940s, a coalition of business, public health, insurance, and political interests formed in response to a widely perceived "silicosis crisis." Part of the resulting program aimed at containing the crisis was the establishment of threshold limit values. Yet silicosis cases continued to be documented. By the 1960s these cases had become the basis for a number of revisions to the thresholds. In the 1970s, following a National Institute for Occupational Safety and Health recommendation to lower the threshold limit value for silica and to eliminate sand as an abrasive in blasting, industry fought attempts to make the existing values more stringent. This paper traces the process by which threshold limit values became part of a compromise between the health of workers and the economic interests of industry. PMID- 7856789 TI - Community incorporation of quit and win contests in Bloomington, Minnesota. PMID- 7856790 TI - A collaborative regional model for obstetrical care in New York State. PMID- 7856791 TI - The perceived needs of child care center directors in preventing injuries and infectious diseases. PMID- 7856792 TI - Day care, infant feeding, and ear infections. PMID- 7856793 TI - What does a decline in child pedestrian injury rates mean? PMID- 7856794 TI - More on folic acid and neural tube defects. PMID- 7856795 TI - Outcomes research in the AOSSM. PMID- 7856796 TI - The prevalence of abnormal magnetic resonance imaging findings in asymptomatic knees. With correlation of magnetic resonance imaging to arthroscopic findings in symptomatic knees. AB - The purpose of this study was to prospectively evaluate the prevalence of abnormal magnetic resonance imaging scans of the knees of asymptomatic subjects. A prospective analysis of magnetic resonance imaging to arthroscopic findings in symptomatic knees was also performed. The prevalence of meniscal tears found in asymptomatic knees was 5.6% (medial meniscus, 1.9%; lateral meniscus, 3.7%). Other abnormal findings included a prevalence of 1.9% for degenerative changes of the medial femoral condyle and 3.7% both for ganglion cysts and patellofemoral joint articular cartilage degenerative changes. There was also a prevalence of 24.1% of Grade II signal changes of the posterior horn of the medial meniscus. Statistical comparison of our results to previous studies revealed that the magnetic resonance imaging scan readings on the asymptomatic knees in this study were accurate and lesions were correctly identified. We recommend that clinicians match clinical signs and symptoms with magnetic resonance imaging findings before instituting surgical treatment because of a 5.6% prevalence of meniscal tears in the asymptomatic population. The significance of the high percentage of posterior horn medial meniscal Grade II signal changes is unknown. PMID- 7856797 TI - Upper extremity physical factors affecting tennis serve velocity. AB - Forty tournament-level tennis players with expert serve technique volunteered to have their serve evaluated to determine relationships between anthropometric data, extremity strength, and functional serve velocity. All players underwent a complete physical examination, a video taped serve analysis, a radar measurement of serve velocity, and a series of upper extremity strength measurements. Statistical analysis was performed to determine which factors were related to serve velocity. Statistically significant relationships were found between serve velocity and several flexibility measurements including increased dominant wrist flexion (P < 0.05), increased dominant shoulder flexion (P < 0.05), and increased dominant shoulder internal rotation at 0 degrees of abduction (P < 0.05). Several strength measurements were also related to serve velocity including elbow extension torque production (P < 0.01) and the ratios of internal to external rotational torque production for both low- and high-speed measurements (P < 0.01 concentrically and P < 0.05 eccentrically). These findings relate strength and flexibility to serve velocity, suggesting that it may be possible to increase a tennis player's serve velocity through specifically directed muscular strengthening or stretching regimens. However, prospective studies must be undertaken to demonstrate these possibilities. PMID- 7856798 TI - Stimulation of bone growth through sports. A radiologic investigation of the upper extremities in professional tennis players. AB - This contribution addresses the following questions: Does unilateral sports specific strain affect the skeletal system of the athlete? Specifically, can any differences be found in longitudinal growth of the bones of the forearm and hand in professional tennis players between the stroke arm and the contralateral arm? An investigation was conducted involving 20 high-ranking professional tennis players (12 male and eight female players) between 13 and 26 years of age as well as 12 controls of the same age range. The radiologic examinations of the bones of the forearm and hand yielded an increase in density of bone substance and bone diameter as well as length in the stroke arm as compared with the contralateral arm. Whereas the first results confirm previous findings, the stimulation of longitudinal growth has never been reported. This change in bone structure and size can be attributed to two factors: mechanical stimulation and hyperemia of the constantly strained extremity. It may thus be regarded as a biopositive adaptation process. PMID- 7856799 TI - Arthroscopy-assisted anterior cruciate ligament reconstruction using patellar tendon substitution. Two- to four-year follow-up results. AB - The purpose of this retrospective study was to evaluate clinically, functionally, and objectively our initial experience using free, autogenous middle third patellar tendon for anterior cruciate ligament reconstruction without extraarticular augmentation in 62 of 75 patients (80% followup) who were available for clinical review at a minimum 2-year followup. Subjective, clinical, functional, Cybex dynamometer, and KT-1000 arthrometer tests were performed along with modified tests of the Hospital for Special Surgery, Noyes Cincinnati, Tegner, and Lysholm knee rating scales. Ninety-two percent had a negative pivot shift at followup. The mean Cybex dynamometer extension deficits postoperatively were 9% and 7% at 180 and 240 deg/sec. Mild patellar pain symptoms were noted in 18%. The reoperation rate was 10% with a mild flexion contracture as the most common reason. The Hospital for Special Surgery scoring scale postoperatively was 88; Noyes, 86; Lysholm, 88; and Tegner, 6. Mean postoperative single-legged and vertical jump indices were 88% and 87%, respectively. The KT-1000 arthrometric evaluation postoperatively revealed a mean maximum manual difference of 0.3 mm; 92% of the patients had a maximum manual difference of < or = 3 mm. Subjectively, 95% indicated that they would undergo the procedure again. Early results demonstrate excellent stability, preservation of motion, and encouraging evaluations by scoring scales and arthrometric evaluation. PMID- 7856800 TI - The effect of the squat exercise on anterior-posterior knee translation in professional football players. AB - Although the squat exercise is considered essential for optimal athletic performance, controversy exists regarding the effect on knee stability. The purpose of this prospective study was to determine the effect of squat exercises on in vivo knee joint stability of professional football players. Thirty-two subjects with normal knees participated in a 21-week off-season training program. Subjects performed power squat exercises with barbell loads of 130% to 200% body weight twice weekly. Both knees of each subject were tested by a single examiner with a knee ligament arthrometer before the training program and at 12 and 21 weeks. Passive displacements were recorded at 67, 89, and 133 N with the knee at 30 degrees and 90 degrees of flexion. Active testing was performed with the knee in the same positions. Student's paired t-tests were used to compare pre- and postexercise measures. For all subjects, no significant differences were found between pre- and postexercise results for active and passive tests. Of the 2440 measurements taken, only 8 demonstrated increased excursions greater than 2 mm. This study demonstrates no significant increases in anterior-posterior tibiofemoral translation in athletes using the squat exercise as part of their off-season training program. PMID- 7856801 TI - Correlation of remaining patellar tendon width with quadriceps strength after autogenous bone-patellar tendon-bone anterior cruciate ligament reconstruction. AB - One hundred twenty-one patients were prospectively studied to determine whether the different remaining patellar tendon widths after central 10-mm bone-patellar tendon-bone graft harvest influenced the rate and level of quadriceps strength achieved during rehabilitation. Size of the patellar tendon width, measured at the same location in each patient, ranged from 24 to 35 mm. For this study, patients were grouped according to their remaining tendon size into small (14 to 17 mm; mean, 15.8), medium (18 to 20 mm; mean, 19.2), and large (21 to 25 mm; mean, 22.5) widths. Postoperatively, the patient's isokinetic quadriceps scores were determined at 6 weeks, 3 months, 6 months, and 1 year. At 6 weeks, the small and medium-width tendon groups were significantly weaker than the large-width tendon group. At 3 months, only the small-width tendon group continued to be significantly weaker than the large-width tendon group. At and beyond 6 months, no statistically significant differences were seen between remaining patellar tendon width groups and their isokinetic quadriceps scores. A constant-sized autogenous patellar tendon graft may be harvested for anterior cruciate ligament reconstruction without compromising ultimate postoperative quadriceps strength recovery. PMID- 7856802 TI - Excursion of the rotator cuff under the acromion. Patterns of subacromial contact. AB - Nine fresh-frozen, human cadaveric shoulders were elevated in the scapular plane in two different humeral rotations by applying forces along action lines of rotator cuff and deltoid muscles. Stereophotogrammetry determined possible regions of subacromial contact using a proximity criterion; radiographs measured acromiohumeral interval and position of greater tuberosity. Contact starts at the anterolateral edge of the acromion at 0 degrees of elevation; it shifts medially with arm elevation. On the humeral surface, contact shifts from proximal to distal on the supraspinatus tendon with arm elevation. When external rotation is decreased, distal and posterior shift in contact is noted. Acromial undersurface and rotator cuff tendons are in closest proximity between 60 degrees and 120 degrees of elevation; contact was consistently more pronounced for Type III acromions. Mean acromiohumeral interval was 11.1 mm at 0 degrees of elevation and decreased to 5.7 mm at 90 degrees, when greater tuberosity was closest to the acromion. Radiographs show bone-to-bone relationship; stereophotogrammetry assesses contact on soft tissues of the subacromial space. Contact centers on the supraspinatus insertion, suggesting altered excursion of the greater tuberosity may initially damage this rotator cuff region. Conditions limiting external rotation or elevation may also increase rotator cuff compression. Marked increase in contact with Type III acromions supports the role of anterior acromioplasty when clinically indicated, usually in older patients with primary impingement. PMID- 7856804 TI - Arthroscopic evaluation of meniscal repairs. Factors that effect healing. AB - Fifty-one patients with 54 meniscal repairs were evaluated with second-look arthroscopy and physical examination at an average of 11 months (range, 4 to 30) after repair. Thirty-five of 54 repairs (65%) were completely healed and 9 repairs were incompletely healed, for an overall satisfactory healing rate of 81% (44 of 54 repairs). Ten repairs did not heal (19%). An anterior cruciate ligament reconstruction combined with meniscal repair increased meniscal healing--36 of 40 (90%) healed versus 8 of 14 (57%) in cruciate stable knees. Rim width was a significant factor; no meniscal repair with a rim width greater than 4 mm healed. Meniscal repair with anterior cruciate ligament reconstruction in patients less than 30 years old and performed within 19 weeks of injury resulted in improved healing rates. In patients with simultaneous meniscal repair and anterior cruciate ligament reconstruction, a higher rate of complete healing (16 of 19 repairs, 84%) was observed after the conservative rehabilitation program. Those who followed the aggressive program had a complete healing rate of 63% (12 of 19 repairs). Satisfactory healing (complete plus incomplete arthroscopic healing) was similar for both groups, 89% and 90%, respectively. PMID- 7856803 TI - The normal and the painful shoulders during the breaststroke. Electromyographic and cinematographic analysis of twelve muscles. AB - The purpose of this study was to describe and compare electrical activity patterns in 12 shoulder muscles during the breaststroke in 25 competitive swimmers who had normal shoulders and in 14 who had painful shoulders while they performed this stroke in a pool. The electromyographic analysis was synchronized with high-speed cinematography to discern phases of the breaststroke. Means, standard deviations, and t-tests were done for each phase. The differences in muscle activity between the two groups of swimmers demonstrated an increase in the internal rotators in the group with painful shoulders. They also demonstrated a decrease in the teres minor, supraspinatus, and the upper trapezius muscles. These factors increase the risk of impingement. Both the serratus anterior and teres minor muscles in the swimmers with normal shoulders consistently fired at or above 15% manual muscle test throughout the breaststroke cycle and were thus subject to fatigue. Based on these results, exercises for the breaststroke swimmer should be directed toward endurance training of the serratus anterior and teres minor muscles while balancing the internal and external rotators of the shoulder as well as the deltoid and supraspinatus muscles. PMID- 7856805 TI - The influence of immobilization versus exercise on scar formation in the rabbit patellar tendon after excision of the central third. AB - There is much discussion about the appropriate timing and intensity of rehabilitation after reconstruction of the anterior cruciate ligament with a patellar tendon autograft. The purpose of this study was to look at two extremes (complete immobilization and vigorous, forced exercise) on the extent of scar formation and mechanical properties of the host tendon. Three groups of six Flemish Giant rabbits had the central third patellar tendon removed in one limb. Group I was sacrificed immediately after surgery. Group II was exercised on a treadmill for 12 weeks. In Group III the limb was immobilized for 12 weeks. After 3 months, average length and cross-sectional area from Group II were greater than those of the controls and Group III tendons. Structural properties of all tests limbs were similar to each other but different from controls. Tensile modulus of Group III tendons did not decrease as much that of Group II tendons. Histology revealed a clear demarcation between the central defect and host tendon in Group III, whereas Group II tendons remodeled throughout their cross-sections. We propose that early joint mobility produces large multiaxial stresses in original tendon leading to microdamages and repair processes within the entire host tissue. Less aggressive exercise or delay in joint mobility may help control tissue remodeling. PMID- 7856806 TI - The relationship between anterior-posterior knee laxity and the structural properties of the patellar tendon graft. A study in canines. AB - We studied the relationship between anterior-posterior knee laxity and the structural properties of autogenous patellar tendon grafts used to replace the anterior cruciate ligaments in dogs 1 year after reconstruction. At 30 degrees (full extension for the dog), 60 degrees, and 90 degrees of flexion a significant inverse correlation was found between anterior-posterior knee laxity and the ultimate failure strength of the graft. Likewise, at 60 degrees and 90 degrees of flexion a significant inverse correlation was found between knee laxity and the linear stiffness of the graft. In all cases, as knee laxity increased, the ultimate failure load and linear stiffness values of the graft were found to decrease. There was also a significant increase in anterior-posterior knee laxity of the reconstructed knees (produced by an increase in anterior translation of the tibia relative to the femur) compared with the contralateral control knee. The group of dogs that underwent a sham operation without reconstruction of the anterior cruciate ligament had no change in anterior-posterior knee laxity or the structural properties of the anterior cruciate ligament. The clinical significance of this investigation is that knee laxity measurements demonstrating an increase in anterior translation of the tibia relative to the femur during graft healing may indicate that the graft has weakened and reduced structural properties. PMID- 7856807 TI - Deterioration of mechanical properties of the autograft in controlled stress shielded augmentation procedures. An experimental study with rabbit patellar tendon. AB - Effects of partial and complete stress shielding on mechanical properties and histology of in situ frozen patellar tendons were studied in 120 mature female Japanese White rabbits that were divided into three groups: completely stress shielded, partially stress-shielded, and sham-operated groups. In the former two groups, tendon tension was reduced to 0% and about 30% of normal force, respectively, with a polyester artificial ligament. Tensile tests were conducted on patella-patellar tendon-tibia complexes harvested 1, 2, 3, 6, or 12 weeks after surgery. Tensile strength significantly decreased compared with the sham group to 17% and 28% at 3 and 6 weeks, respectively, in the completely stress shielded group, and to 54% and 63% at 3 and 12 weeks, respectively, in the partially stress-shielded group. Patellar tendon cross-sectional area significantly increased to 156% and 157% at 2 and 3 weeks, respectively, in the completely stress-shielded group and to 133% at 2 weeks in the partially stress shielded group, compared with the sham group. Stress shielding significantly changed tensile strength, tangent modulus, and cross-sectional area of in situ frozen patellar tendon; these changes depended on degree of stress shielding. Histologic observations indicated that remodeling occurred in the patellar tendon while there were no cells in the fascicle. PMID- 7856808 TI - Effects of a functional knee brace on leg muscle function. AB - The effects of a functional knee brace on local intramuscular pressures and on calculated blood perfusion pressure in the tibialis anterior muscle of the legs of six volunteers were determined. Torque generation during dorsiflexion of the ankle joint was measured with a Kinetic Computerized ergometer, and the time to elicit muscle fatigue during exercise was recorded. For each experimental subject studies compared right with left unbraced legs, then right braced with left unbraced legs, and finally right unbraced with left braced legs. In the braced leg, intramuscular pressure at rest and muscle relaxation pressure during exercise were significantly higher, and the time to elicit muscle fatigue was 35% shorter. The calculated local blood perfusion pressure was lower because of the increased muscle relaxation pressure. We conclude that the increased muscle relaxation pressure during exercise caused by a knee brace is a possible explanation for the premature development of muscle fatigue in the braced leg. PMID- 7856809 TI - Profiles of exercise history and overuse injuries among United States Navy Sea, Air, and Land (SEAL) recruits. AB - This prospective study examined running history as a risk factor for subsequent overuse injury in Navy Sea, Air, and Land (SEAL) recruits. Recruits preparing to be Navy SEALs undergo 6 months of rigorous physical training programs, which place these recruits at high risk for developing an overuse injury. We assessed the independent variables of age; prior running frequency, duration, and pace; and training surface. Univariate and multivariate estimates of risk were determined for each variable. We observed an incidence of 3.4 overuse injuries per 1000 recruit-days. Assessing the physical activity of the recruits in the 6 months before entrance into basic training, we found that the recruits who ran at a pace slower than 8 minutes per mile and on softer training surfaces were more likely to sustain an overuse injury during basic training, in both univariate and multivariate estimates of risk. Recruits who ran fewer weekly miles and for shorter durations before basic training were also more likely to sustain an overuse injury according to univariate estimates of risk. Our findings suggest that risk of overuse injuries can be reduced by adjusting exercise routines before training. Running on different type surfaces with a gradual increase in speed, duration, and weekly mileage in the period preceding basic training may reduce risk of overuse injury. PMID- 7856810 TI - Lunate and perilunate dislocations in professional football players. A five-year retrospective analysis. AB - The purpose of this retrospective study was to review the treatment and prognosis of lunate and perilunate carpal dislocations in professional football players in the National Football League over a 5-year period. There were 7 lunate and 3 perilunate dislocations in 10 players. The mechanism of injury was hyperextension in 9 of 10 players. Five players were subsequently treated by closed reduction and percutaneous pinning; the others were treated by open reduction and K-wire fixation. No player was treated by cast immobilization alone. Intraoperative techniques, postoperative immobilization and protection, return to play, final follow-up physical examination, radiographic evaluation, and complications were reviewed. Results of this study clearly demonstrate that lunate and perilunate carpal dislocations do not mean the end of a career in professional football, although a minimum of 4 weeks of playing time is lost. Treatments varied with respect to open or closed reductions, placement of pins, casts, and time of immobilization. None of the variations was clearly superior or detrimental, although four of the five players who returned to play in the same season were treated by closed reduction with percutaneous pinning. PMID- 7856811 TI - Gymnast wrist: an epidemiologic survey of ulnar variance and stress changes of the radial physis in elite female gymnasts. AB - The ulnar variance in female gymnasts attending the World Championship Artistic Gymnastics Rotterdam 1987 was measured. There was a marked increase in the ulnar length in adult as well as immature gymnast compared with nonathletes. The changes in relative ulnar length were correlated to weight, height, and skeletal age of the athletes. In 10% of the gymnasts' wrists we noted so-called "stress related changes" of the distal physis of the radius. Repetitive injury and compression of the wrist leads to a premature closure of the distal radial growth plate resulting in secondary ulnar overgrowth. PMID- 7856812 TI - Magnetic resonance imaging of iliotibial band syndrome. AB - Seven cases of iliotibial band syndrome and the pathoanatomic findings of each, as demonstrated by magnetic resonance imaging, are presented. These findings were compared with magnetic resonance imaging scans of 10 age- and sex-matched control knees without evidence of lateral knee pain. Magnetic resonance imaging signal consistent with fluid was seen deep to the iliotibial band in the region of the lateral femoral epicondyle in five of the seven cases. Additionally, when compared with the control group, patients with iliotibial band syndrome demonstrated a significantly thicker iliotibial band over the lateral femoral epicondyle (P < 0.05). Thickness of the iliotibial band in the disease group was 5.49 +/- 2.12 mm, as opposed to 2.52 +/- 1.56 mm in the control group. Cadaveric dissections were performed on 10 normal knees to further elucidate the exact nature of the area under the iliotibial band. A potential space, i.e., a bursa, was found between the iliotibial band and the knee capsule. This series suggests that magnetic resonance imaging demonstrates objective evidence of iliotibial band syndrome and can be helpful when a definitive diagnosis is essential. Furthermore, correlated with anatomic dissection, magnetic resonance imaging identifies this as a problem within a bursa beneath the iliotibial band and not a problem within the knee joint. PMID- 7856813 TI - Dynamic ankle ultrasonography. A new imaging technique for acute ankle ligament injuries. AB - We have developed a noninvasive ultrasound technique that may be used to differentiate complete and incomplete acute tears of the anterior talofibular ligament. Direct visualization of the ligament will demonstrate the lesion in most cases and can be supplemented by an anterior drawer test with the ligament under direct vision. Seventeen athletes involved in sports and work that put high demand pressure on their ankles underwent ultrasonic examination of their acute lateral ankle ligament injuries before surgical exploration. Fourteen scans demonstrating a complete lesion of the anterior talofibular ligament were confirmed at operation. Three scans were equivocal; two of these patients had incomplete lesions of their anterior talofibular ligaments and one patient had a complete tear that was not detected. We have found that the dynamic ultrasound test is a simple and reliable examination. We suggest that this technique is indicated where the extent of an acute lateral ligament injury requires further definition. Ankle ultrasonography may reduce the need for ankle arthrography. PMID- 7856814 TI - Physical and performance characteristics of successful high school football players. AB - The purpose of this investigation was to determine the performance and physiologic characteristics of a "successful" American high school football team, and to compare the present values with values reported for other groups of high school, college, and professional players. For descriptive purposes, players were divided into two groups: backs (N = 8) and linemen (N = 10). Maximal aerobic power (VO2max) was determined from a maximal treadmill test, and body composition was evaluated by hydrostatic weighing. Maximal strength values were evaluated by one-repetition maximum bench press and squat test; the sit-and-reach test was used to measure flexibility. Speed and power were evaluated by a vertical jump and a 36.6-meter sprint. Results indicate that compared with other groups of college and professional players, as the level of competition increases so do height, weight, and fat-free weight of the players. Similar maximum oxygen consumption values were found for the present group when compared with other groups of these players. From the strength and power standpoint, football players at all levels are becoming stronger. Incorporation of strength training programs has greatly improved strength and performance profiles of football players at all levels of competition. PMID- 7856815 TI - Recurrent anterior shoulder instability. PMID- 7856816 TI - The acromion-splitting approach for large and massive rotator cuff tears. PMID- 7856817 TI - The slow fix: communities, research, and disease control. PMID- 7856818 TI - Sequence and phylogenetic analyses of human T cell lymphotropic virus type 1 from a Brazilian woman with adult T cell leukemia: comparison with virus strains from South America and the Caribbean basin. AB - Human T cell lymphotropic virus type 1 (HTLV-1) is endemic in South America and the Caribbean basin. To clarify the genetic and phylogenetic relationship between an HTLV-1 strain isolated from a Brazilian woman with adult T cell leukemia and viral isolates from elsewhere in South America and from other geographic regions, selected regions of the gag, pol, env, and pX genes were amplified and directly sequenced. The overall sequence similarities between the Brazil-R-1 strain and the Japanese prototype ATK strain were 98.7% based on 1,295 nucleotides and 99.1% based on 429 amino acids. Phylogenetic analysis indicated that strain Brazil-R-1 clustered with other Brazilian and South American HTLV-1 isolates and was more closely related to Caribbean isolates from Martinique and Guadeloupe than to virus strains from other geographic regions. These data suggest a common source of HTLV-1 infection in the Caribbean basin and South America. PMID- 7856819 TI - The risk of Helicobacter pylori infection among U.S. military personnel deployed outside the United States. AB - To determine whether military personnel deployed outside the United States are at increased risk of Helicobacter pylori infection, 1,000 male U.S. Navy and Marine Corps personnel (mean age 22 years) were evaluated. Study subjects included 200 recruits, 500 shipboard personnel deployed for six months to South America, West Africa, and the Mediterranean, and 300 ground troops deployed for five months to Saudi Arabia. Among all 1,000 subjects, 247 (25%) were seropositive for H. pylori IgG antibody by an enzyme-linked immunosorbent assay; 24% of new recruits and 25% of troops who had been on active duty for a mean of four years. The prevalence of H. pylori antibody was higher among subjects who were older, nonwhite, foreign born, and seropositive for antibody to hepatitis A virus. Among the 601 initially seronegative subjects evaluated before and after a 5-6 month deployment outside the United States, five seroconverted, for a rate of infection of 1.9% per person year of exposure. As found in other populations in developed countries, these data indicate that among U.S. military personnel a large proportion of H. pylori infections occur before adulthood and infection is related to demographic factors. These preliminary findings also suggest that deployed U.S. military personnel may be at increased risk of H. pylori infection compared with adult populations in developed countries either from exposure in developing countries or from crowding. PMID- 7856820 TI - Dracunculiasis eradication: March 1994 update. AB - Substantial progress has been realized in the global campaign to eradicate dracunculiasis by the end of 1995 since a previous review of the subject was published in this journal a year ago. All known endemic countries are now engaged in the eradication effort, and one or more control measures are now in place in 93% of endemic villages. Despite improved surveillance for the disease, the number of reported cases of the disease has been reduced by 41% (to about 221,000), and the number of known endemic villages has been reduced by 28% (to about 16,500) in the past year. Priorities for national eradication programs in 1994 include increasing the use of vector control and intensifying the case containment strategy in endemic villages. It is still possible to achieve the eradication target of December 1995, but greatly intensified efforts this year will be required to do so. PMID- 7856821 TI - Measures to control Toxocara egg contamination in sandpits of public parks. AB - We investigated measures to prevent Toxocara egg contamination of sandpits. Replacement of contaminated sand was not effective because 1-9 new fecal deposits per sandpit were found daily, with eggs reappearing in the sand 6-9 weeks after the replacement. When the sandpit was covered with a clear vinyl sheet, the temperature of the sand to a depth of 3 cm was 42 degrees C or more for 3 hr when the air temperature was higher than 30 degrees C. This procedure prevented contamination by fecal deposits and also resulted in the destruction of existing eggs because the sandpit was kept dry on rainy days. The method seemed safe and inexpensive. The effectiveness of a fence around a sandpit depended on user behavior, which could not be relied upon. Therefore, a practical method for the prevention of Toxocara egg contamination of sandpits is to cover the sandpit with a clear vinyl sheet at night and on rainy days. PMID- 7856822 TI - Electroencephalographic abnormalities in patients with snake bites. AB - Electroencephalograms (EEGs) were obtained for 26 patients with snake bite to observe the cerebral impact of snake venom. All snakes were identified; 19 (73%) were Russell's vipers, one (4%) was a common cobra, five (19%) were hump-nosed vipers, and one (4%) was a dog-faced fresh water snake. The EEG was abnormal in 25 patients (96%) and these results included all the snake species identified. The EEG abnormalities observed were reduced alpha activity, increased theta/beta activity or sharp waves (grade 1), sharp waves or spikes and slow waves (grade 2), or diffuse delta activity (grade 3). Grade 1 changes occurred in 16 patients (62%), grade 11 in eight patients (31%), and grade 111 in one patient (4%). Thus, grade 2 and 3 changes, which were moderately severe to severe abnormalities, occurred in nine patients (35%). One patient had acute renal failure and two others had mild jaundice and hyponatremia. These three patients had EEG abnormalities that were similar to those observed in the remaining 22 patients. The altered EEG, suggestive of an encephalopathy, appeared within hours of the bite and persisted for several days without clinical neurologic effects. The changes were seen mainly in the temporal lobe. Similar changes occurred in both patients with and without antivenom therapy. It appeared that the EEG abnormalities are a consequence of the effects of venom from the bites of a variety of snakes. PMID- 7856823 TI - Second recorded case of human infection by Echinococcus oligarthrus. AB - The paper reviews a previously published case of hydatid disease in the human heart of a Brazilian person who died of tetanus. Based on present knowledge about the distinguishing characteristics of Echinococcus granulosus, E. vogeli, and E. oligarthrus, it was recognized that the infection was due to E. oligarthrus, mainly based the morphologic features of the hooklets of the protoscolex. This is the second human infection due to E. oligarthrus and the first showing wall features of cysts. Therefore, some human infections of polycystic hydatid disease observed outside the range of the bush dog, the only definitive host of E. vogeli (Panama to Northern Argentina), may be due to E. oligarthrus rather than to E. vogeli. PMID- 7856824 TI - The diagnosis of Plasmodium falciparum infection using a new antigen detection system. AB - With the widespread emergence of drug-resistant Plasmodium falciparum infection, febrile patients in the tropics can no longer be empirically treated with inexpensive yet effective antimalarials. The substitution of newer and more costly drugs brings with it the need for rapid, accurate, and inexpensive diagnostic procedures so that directed therapy can be used. We report a field trial comparing standard microscopic malaria diagnosis and quantitative buffy coat analysis to a new P. falciparum antigen detection system. The ParaSight F test (PFT) was found to be easy to learn, rapid to perform, and highly accurate. If confirmed, the use of the PFT in endemic areas may aid in the identification of patients requiring therapy for drug-resistant malaria. PMID- 7856825 TI - Specific and nonspecific responses to Plasmodium falciparum blood-stage parasites and observations on the gametocytemia in schoolchildren living in a malaria endemic area of Mozambique. AB - We have observed specific and nonspecific reactivities to the asexual states and gametocytes of Plasmodium falciparum and examined the effect of chloroquine and Fansidar (pyrimethamine/sulfadoxine) on the dynamics of gametocytemia. Schoolchildren peripheral blood films positive for P. falciparum gametocytes were identified in a malaria-endemic area of Mozambique. The children were randomly allocated into two groups to receive chloroquine or pyrimethamine/sulfadoxine, and were followed for 28 days after treatment. In patients harboring drug sensitive parasites, asexual parasitemias were cleared by day 4, but gametocytes persisted for an additional 17 days. The prevalence of the asexual parasites was 67.6% in the chloroquine-treated group at day 0 and 61.1% at day 28, whereas in the pyrimethamine/sulfadoxine treated group, the initial parasite prevalence of 70.7% was reduced to 2.4% at day 28, suggesting a high prevalence of chloroquine resistant parasites. On day 0, gametocyte prevalence was 59.5% in the chloroquine treated group and in 68.3% in the pyrimethamine/sulfadoxine-treated group; these values were reduced to 5.6% and 2.4%, respectively, at day 28. Our results suggest strongly that there is no induction of gametocytogenesis by either course of chemotherapy. PMID- 7856826 TI - A comparison of transmission-blocking activity with reactivity in a Plasmodium falciparum 48/45-kD molecule-specific competition enzyme-linked immunosorbent assay. AB - Monoclonal antibodies (MAbs) 32F1 and 32F3 react with two independent epitopes of a protein doublet with molecular weights of 48 and 45 kilodaltons (kD) expressed on the surface of Plasmodium falciparum (Pfs48/45) macrogametes and zygotes; only 32F3 blocks transmission. These MAbs were used to develop a Pfs48/45-specific competition enzyme-linked immunosorbent assay (ELISA) using 32F1 to capture antigen and labeled 32F3 for quantification and analysis of the contribution of antibodies in human serum to transmission-blocking activity. A comparison analysis was used to determine agreement of competition ELISA titers and transmission-blocking activity as observed in the bioassay in three groups of serum samples: 37 from European travelers with previous exposure to malaria, 56 from gametocyte carriers, and 66 from schoolchildren from a malaria-endemic area in Cameroon. The index of agreement between outcomes of the ELISA and transmission-blocking assay in gametocyte carriers and in travelers was specifically defined as fair-to-moderate; in schoolchildren the agreement was not significant. The combined analysis of all sera showed a significant and fair-to moderate agreement between the results of the competition ELISA and the transmission-blocking assay, with a relative specificity of 94% (of 105 cases negative in the transmission-blocking assay, 99 were also negative in the competition ELISA) and a relative sensitivity of 44% (of 54 cases positive in the transmission-blocking assay, 24 were also positive in the competition ELISA). This study shows that a positive C48/45-ELISA is indicative for transmission blocking activity in the mosquito assay, while a negative result does not exclude transmission-blocking activity. PMID- 7856827 TI - Humoral response to Plasmodium falciparum ring-infected erythrocyte surface antigen in a highly endemic area of Papua New Guinea. AB - The prevalence and concentration of antibodies to ring-infected erythrocyte surface antigen (RESA) were measured in blood samples collected during a cross sectional survey conducted in Papua New Guinea. Antibodies were measured by enzyme-linked immunosorbent assay to the recombinant RESA protein in 1,398 subjects and to RESA 8 and RESA 11 synthetic peptides in a subsample of 200 adults. Overall, the seropositivity rate to recombinant RESA was 66% and the geometric mean antibody concentration was 28 micrograms/ml. There was a slow increase in antibody prevalence and concentration with age that continued to occur even after 40 years of age. In children less than 10 years of age, there was a significant positive correlation between both RESA antibody prevalence and concentration and concurrent infection with Plasmodium falciparum. The opposite was true in adults more than 20 years of age, with those having a high antibody concentration to RESA being less likely to be parasitemic at the time of the survey. This observation was consistent with the finding of a weak but significant negative correlation between log antibody concentration and log P. falciparum density, which was mainly found in adults. No consistent correlation was found between humoral immune response to RESA and morbidity indicators. PMID- 7856828 TI - Short report: mode of action of protective immunity to Lyme disease spirochetes. AB - To determine whether protective immunity against the agent of Lyme disease may be expressed mainly within its tick vector prior to transmission, we passively immunized mice at various intervals after infected ticks had attached, and assayed such mice for evidence of spirochetal infection by xenodiagnosis one month after challenge. Groups of CD-1 mice were intraperitoneally infused with 0.5 ml of hyperimmune rabbit or mouse serum, reagents and quantities previously determined to protect against syringe-challenge with 10(6) low-passage JD1 spirochetes 12 hr after passive transfer. Comparison groups received normal rabbit serum or saline. All mice were protected from infection when infused no more than one day after infective ticks were allowed to attach. However, if infused three or five days post-tick attachment, 60-100% of the mice became infected. All mice became persistently infected when infused with saline or normal rabbit serum. We conclude that antibody is protective against tick transmitted spirochetal infection only when passively administered before the spirochetes are deposited in the skin of the host. Ingested antibody may destroy spirochetes or interfere with activation and replication within the tick gut, or with dissemination to the salivary glands. Lyme disease vaccines may thus be uniquely effective because of the vulnerability of the spirochetal agent within its vector. PMID- 7856829 TI - Phenotypic analysis of yellow fever virus derived from complementary DNA. AB - A thorough phenotypic characterization of yellow fever (YF) virus generated from cDNA is a necessary prerequisite for mapping virulence/attenuation determinants and exploring the potential of YF attenuated virus 17D as a carrier for heterologous protective epitopes. In this study, YF virus was produced from 17D cDNA clones after lipofectin-mediated RNA transfection of certified primary cultures of chicken embryo fibroblasts (YFiv5.2/SL). This virus was passaged once in embryonated chicken eggs according to current YF vaccine manufacture methodology to produce the experimental virus (YFiv5.2/VL). These viruses were characterized in established monkey neurovirulence safety tests and quantitative clinical and histologic scores were derived for each virus. The experimental vaccine viruses (YFiv5.2/SL and VL) compared favorably with another well-known YF vaccine strain (17DD) used as control virus for the histologic score. Although slightly higher clinical neurovirulence was observed for YFiv5.2 as compared with the 17DD virus, it should not preclude the use of YFiv5.2 for mapping YF virus virulence determinants. PMID- 7856830 TI - The economic burden imposed by a residual case of eastern encephalitis. AB - To estimate the economic burden imposed by eastern encephalitis (EE), we identified a series of residents of eastern Massachusetts who had survived EE infection and enumerated any costs that could be attributed to their experience. The records of three people who suffered only a transient episode of disease were analyzed as well as those of three who suffered severe residual sequelae. Transiently affected subjects mainly required assistance for direct medical services; the average total cost per case was $21,000. Those who suffered persistent sequelae remained at home and seemed likely to live a normal span of years, but without gainful employment. Early in the course of their chronic illness, costs ranged as high as $0.4 million per year, but plateaued at about $0.1 million after three years. Hospital costs, which dominated early in the disease experience, approached $0.3 million per patient. Educational costs tended to replace hospital costs after two years as the dominant economic burden and totaled about $0.3 million per patient during the first six years. Total costs then averaged almost $0.8 million. By the time that these subjects will have reached 22 years of age, disease-related costs will have totaled about $1.5 million. Institutionalization will impose an additional lifetime cost of $1.0 million. Insecticidal interventions designed to avert outbreaks of human EE infection cost between $0.7 million and $1.4 million, depending on the extent of the treated region. The direct costs of an intervention are less than the $3 million imposed on one person suffering residual sequelae of EE. PMID- 7856831 TI - Age-dependent carriage of multiple Plasmodium falciparum merozoite surface antigen-2 alleles in asymptomatic malaria infections. AB - Genetic diversity of the merozoite surface antigen-2 gene of the human malaria parasite Plasmodium falciparum has been analyzed in a Senegalese village where malaria is holoendemic. A cross-sectional survey of 65 residents was performed in 1992 during the high transmission season. Plasmodium falciparum was detected both by microscopy (77% positive samples) and DNA amplification using a single (29% or 38% positive samples, depending on the primers used) or nested polymerase chain reaction (PCR) (78% positive samples). The overlap between the positive nested PCR and microscopic examination was not complete. The PCR fragments were analyzed for size polymorphism on agarose gels, and were subsequently assigned to the major allelic families 3D7 or FC27 by hybridization with family-specific probes. Both allelic families were found, with a slightly higher prevalence for FC27. Chimeric alleles that failed to hybridize under stringent conditions to the reference probes were also observed. Some were typed using a novel PCR approach, using hybrid pairs of primers, consisting of a family-specific sense oligonucleotide combined with an antisense oligonucleotide specific for the other family. Combining typing techniques, 82% of the positive PCR results yielded more than one band. Both the overall number of fragments and the number of allelic types per carrier were markedly reduced around the age of 15 years. The number of DNA fragments decreased abruptly from an average of four per carrier before the age of 15 years to an average of two in individuals more than 15 years of age.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7856832 TI - Use of cross-reactive antigens of the microsporidian Glugea atherinae for the possible detection of Enterocytozoon bieneusi by western blot. AB - The microsporidia Enterocytozoon bieneusi is reported in 10-30% of those infected with the human immunodeficiency virus. The parasite appears to be a cause of gastralgia, malabsorption, and diarrhea. A Western blot technique using another microsporidian species, Glugea atherinae, has demonstrated an antigenic similarity between this parasite and E. bieneusi. Preliminary results show the variability of the antigenic profiles obtained from the sera of immunodeficient patients infected with E. bieneusi and also of the cross-reactivity to Glugea sp. antigens of some sera from patients with cryptosporidiosis. The origin of this cross-reactivity is undetermined. The possibility of coinfection with undetected microsporidia is not excluded. These results raise questions concerning the interpretation of serologic data and of the potential immunodiagnostic value of microsporidian antigens. PMID- 7856833 TI - Ivermectin detection in serum of onchocerciasis patients: relationship to adverse reactions. AB - Ivermectin treatment of onchocerciasis patients can be accompanied by adverse reactions. Not much is known concerning the pathogenesis of these reactions. Previous studies have demonstrated that the occurrence and extent of adverse reactions are related to infection intensity. However, some severely infected patients experience relatively few adverse effects. The aim of the present study was to investigate whether this seeming discrepancy could be due to diminished ivermectin absorption. Ivermectin concentrations one and two days after treatment were measured by high-performance liquid chromatography in sera of 71 skin snip positive onchocerciasis patients (21 without reactions, 25 with mild reactions, 14 with moderate reactions, and 11 with severe reactions). The overall mean +/- SD ivermectin concentrations one and two days after a single oral dose (150 micrograms/kg) were 16.4 +/- 6.4 and 6.6 +/- 3.1 ng/ml, respectively. The overall mean +/- SD half-life was estimated to be 19.9 +/- 8.6 hr. The data presented did not show a relationship between ivermectin concentrations and the grade of adverse reactions. PMID- 7856834 TI - Expanding the potential of restriction endonucleases: use of hapaxoterministic enzymes. AB - A new class of restriction endonucleases called hapaxoterministic enzymes, hapaxomers for short, has been defined. A hapaxomer cleaves DNA outside the recognition site or within an interrupted "palindrome" at bases which are not specified producing fragments with asymmetric, staggered ends. Such termini are unique; in the general case, the protrusions of a fragment obtained with the aid of a hapaxomer cannot self-hybridize, nor can the fragment be ligated to the vast majority of other fragments produced by the same enzyme. When the fragments generated by a hapaxoterministic enzyme are mixed, they can reassemble in only one configuration--that of the original structure from which they were derived. Hapaxomers, then, are characterized not by their recognition sites, which may be symmetric or asymmetric, but by their cleavage sites. The ability to reunite once contiguous fragments efficiently means that hapaxomers cleaving DNA at many locations are virtually equivalent to restriction enzymes cutting at unique sites. These properties can be exploited for applications such as site-specific mutagenesis or the isolation of large intact DNA fragments. PMID- 7856835 TI - A continuous fluorescence-based assay for the human high-molecular-weight cytosolic phospholipase A2. AB - A sensitive method for continuously monitoring the activity of the human cytosolic phospholipase A2 (cPLA2) is described. Recombinant cPLA2 efficiently hydrolyzes fatty acid esters of 7-hydroxycoumarin, producing the free fatty acid and the highly fluorescent 7-hydroxycoumarin. All of the observed 7 hydroxycoumarinyl ester hydrolase activity (7-HCEase) in a preparation of the purified recombinant cPLA2 was due to this enzyme since: (1) all of the ester hydrolase activity comigrated on nondenaturing polyacrylamide gel with a protein characterized as the cPLA2 by Western analysis; (2) the immunoreactive protein also possessed both phospholipase A2 and lysophospholipase activities; and (3) arachidonyl trifluoromethyl ketone, a potent inhibitor of the phospholipase A2 activity of cPLA2, also inhibited the 7-HCEase activity. A study of the 7-HCEase activity demonstrated that when 7-hydroxycoumarinyl gamma-linolenate was dispersed in a phospholipid matrix it was hydrolyzed by cPLA2 at a rate comparable to that of an arachidonyl-containing phospholipid substrate and with an identical reaction progress curve. In the presence of phospholipid vesicles, the cPLA2-catalyzed hydrolysis of hydrophobic 7-hydroxycoumarinyl esters was stimulated by submicromolar concentration of free calcium and showed a preference for polyunsaturated substrates. The cPLA2-catalyzed hydrolysis of the water soluble substrate 7-hydroxycoumarinyl 6-heptenoate was catalyzed by cPLA2 in the absence of calcium and other lipids. PMID- 7856836 TI - Enzymatic assay for quantification of deoxynucleoside triphosphates in human cells exposed to antiretroviral 2',3'-dideoxynucleosides. AB - Quantification of intracellular 2'-deoxynucleoside-5'-triphosphates (dNTPs) is of importance in studies of antiretroviral 2',3'-dideoxynucleoside analogs (ddNs) and a highly sensitive enzymatic assay for dNTPs has frequently been used for this purpose. However, the susceptibility of the assay to interference from the corresponding substrate analogs, ddNTPs, is still undefined. Ideally, DNA polymerases used in the assay should meet at least two criteria: (i) high fidelity to the template even in the presence of ddNTPs and (ii) low affinity for ddNTPs. None of the currently used exonuclease-free Klenow and Sequenase enzymes met both criteria. However, Sequenase had higher fidelity to the template than did the Klenow enzyme in the presence of pyrimidine-ddNTPs, and its reaction followed first order kinetics. We have, therefore relying primarily on Sequenase, designed a dNTP proportional reduction assay to correct the ddN-induced deviation in the enzymatic assay. With the use of high-fidelity exonuclease-free DNA polymerase and the application of correction factors, we now can accurately quantify dNTPs with a minimum detection limit as low as 0.1 pmol, using as few as 1 x 10(4) peripheral blood mononuclear cells. The method described should be useful in the study and development of antiretroviral ddNs. PMID- 7856837 TI - Analysis of multiple heterogeneous mRNAs in single cells. AB - We describe a two-stage amplification procedure designed to analyze multiple heterogeneous mRNA from single cells. Using an oligo(dT) primer with an attached phage promoter, the whole mRNA pool from a single cell was first transcriptionally amplified. This step brings the weak signal from one cell to a range in which it can be reliably picked up by the polymerase chain reaction (PCR) procedure. The cDNA was then divided for separate PCR amplification to obtain an unambiguous signal for each gene product. The linear amplification of phage transcription increased the convenience and reliability of detecting multiple messengers in the second stage. The procedure is extremely sensitive because it combines the amplification generated by both phage transcription and PCR. Using a pAW109 artificial RNA, we demonstrated that this procedure detects 10 copies of pAW109 RNA per original sample with 90% confidence and 50 copies per sample with > 95% confidence. This procedure of multiple mRNA analysis allows "phenotyping" of any cell for its mRNA composition. Examples involving several immediate early genes and subunits of the gamma-aminobutyric acidA receptor genes are given. The method should greatly facilitate the analysis of combinatorial expression of various regulatory or channel molecules in their native environments. The procedure should also provide a direct and efficient way of decoding the developmental instruction coded through combinatorial transcriptional regulation. PMID- 7856838 TI - A substrate recycling assay for phenolic compounds using tyrosinase and NADH. AB - A substrate recycling assay for phenolic compounds was developed using tyrosinase, a copper-containing enzyme, in excess NADH. The reaction of various phenols with the enzyme produced an o-quinone, which was then detected by recycling between reactions with the enzyme and NADH. The recycling of quinones by excess NADH to their original reduced forms prevented the problems of subsequent quinone polymerization and product inactivation which occur in nonrecycling assays. Absorbance measurements of the NADH consumption rate enhanced the assay sensitivity for catechol 100-fold compared to nonrecycling o quinone detection, giving a detection limit of 240 nM. Fluorescence NADH monitoring permitted a 10-fold improvement over absorbance, with a detection limit of 23 nM. The recycling reaction was selective for o-quinones, and no interference was noted for p-quinones or quinoneimines. The two-step oxidation of phenols was observed as an initial lag phase (ca. 10 min), requiring a higher enzyme concentration to achieve the same sensitivity as that for catechol. The procedure was most useful for assaying catechol, 4-chlorocatechol, phenol, p cresol, and 4-chlorophenol and may provide selective detection of these components in mixtures. Several other derivatives of catechols, including amine derivatives, were also detected, with relative sensitivity being related to substrate activity of the enzyme. PMID- 7856839 TI - High-molecular-weight polypeptide substrates for phospholysine phosphatases. AB - The detection and characterization of the phosphatases responsible for the dephosphorylation of N-phosphoryl groups, such as phospholysine, in proteins has been frustrated in large measure by a lack of suitable substrates for the assay of these enzymes. Herein we describe the preparation of phospholysine-containing amino acid homo- and heteropolymers by chemical means, and their use in a simple, nonradioactive assay for phospholysine phosphatase activity. PMID- 7856840 TI - Affinity retardation chromatography: characterization of the method and its application. The description of low affinity laminin self-interactions. AB - Affinity retardation chromatography (ARC), a method for the examination of low affinity interactions, is mathematically described in order to characterize the method itself and to estimate binding coefficients of self-assembly domains of basement membrane protein laminin. Affinity retardation was determined by comparing the elutions on a "binding" and on a "nonreacting" column. It depends on the binding coefficient, the concentrations of both ligands, and the nonbinding elution position. Half maximal binding of the NH2-terminal domain of laminin B1-short arm to the A- and/or B2-short arms was estimated to occur at 10 17 microM for noncooperative and at < or = 3 microM for cooperative binding. A model of the laminin polymerization, postulating two levels of cooperative binding behavior, is described. PMID- 7856841 TI - Direct covalent attachment of small peptide antigens to enzyme-linked immunosorbent assay plates using radiation and carbodiimide activation. AB - Direct adsorption of small peptide antigens to unaltered, commercially available polystyrene surfaces may be too weak to permit suitable assay by ELISA. We therefore developed a simple method for the covalent attachment of small, potentially single epitope antigens to polystyrene surfaces. Chemical activation of polystyrene plates with carbodiimide considerably improves the total and covalent attachment of radioactive octapeptides. The covalent attachment was demonstrated by washing with hot detergent. A 3.5 Mrad gamma-irradiation of plates also increases total binding, particularly in combination with chemical activation. The covalent attachment presumably occurs through formation and chemical activation of carboxylate functions on the polystyrene surface which form amide bonds with peptides. ELISA test was performed with CGRP and successive smaller CGRP fragments. Covalent attachment of C-terminal peptide fragments as detection antigens allows optimal recognition and sensitivity even for hexapeptides, while decapeptide antigens were already poorly recognized using a conventional antigen plating technique. Repetitive detergent washes and/or prolonged storage of plates with covalently bound antigens did not reduce their ELISA sensitivity. The method with storage and reutilization capacities that we present here will be useful for the development of preplated antibody screening test. PMID- 7856842 TI - Facile methods for isolation and determination of gangliosides in a small scale: age-related changes of gangliosides in mouse brain synaptic plasma membranes. AB - A quantitative isolation method for gangliosides from small sizes of samples has been developed. Total lipids were separated into gangliosides and other lipids using Phenyl Sepharose column chromatography. Gangliosides were recovered in a yield of 99%. Determination of gangliosides was performed by gas chromatography- mass spectrometry using a selected ion-monitoring technique. These combined methods can provide quantitative isolation and determination of gangliosides from as little as 10 mg fresh brain tissues or 0.5 mg protein of membrane fractions. The present methods were successfully applied to the analysis of gangliosides from mouse brain synaptic plasma membranes to reveal that the ganglioside contents and composition remain constant from adult to senescence. PMID- 7856843 TI - Inhibition of in vivo transcription by actinomycin D treatment of ethylenediaminetetraacetic acid-permeabilized Escherichia coli: effects on bacteriophage proliferation. AB - Rifampicin, which is able to block DNA-dependent RNA synthesis, has been widely used to selectively inhibit host protein synthesis in RNA bacteriophage-infected Escherichia coli without affecting the viral specific protein synthesis. However, in many cases it is necessary to increase rifampicin levels to 200 micrograms/ml in order to obtain an almost complete suppression of bacterial protein synthesis, and these high antibiotic concentrations cause at the same time a strong inhibition of phage proliferation resulting in a 50- to 100-fold reduction of phage yields. We have partially avoided this difficulty by using actinomycin D after permeabilization of bacteria by a brief incubation with EDTA. To optimize the method the effects of changing EDTA and actinomycin concentrations as well as the duration of the permeabilization period have been studied. With this procedure it has been possible to shut off bacterial RNA and protein synthesis with phage yields about 10 times higher than those observed in the presence of high levels of rifampicin. The usefulness of the described method is particularly evident when working with rifampicin-resistant strains of E. coli. PMID- 7856845 TI - Determination of protein tertiary structure class from circular dichroism spectra. AB - Fifty-three circular dichroism (CD) spectra consisting of the spectra of 46 native proteins, 3 denatured proteins, and one oligopeptide (the spectra of two denatured proteins and oligopeptide were taken at two different temperatures) were investigated in order to examine the correlation between the shape of the CD spectrum and the tertiary structure class of the protein. Five classes were considered--all -alpha, all -beta, alpha+beta, alpha/beta, and denatured proteins. Spectra from 190 to 236 nm with 2 nm interval were described as points in 24-dimensional hyperspace, where coordinates were values of ellipticities at fixed wavelengths. This allows the spectra to be treated as patterns and subsequently analyzed using pattern recognition algorithms. Cluster analysis, which does not need predefined information about protein structure, divides spectra into several compact groups or clusters with good correlation with tertiary structure class. To visualize these results, orthogonalization procedures were imposed on the original data set in 24-dimensional space. The new 3-dimensional coordinate system demonstrated well-separated all-beta class and denatured proteins. Regions corresponding to all -alpha and especially alpha+beta and alpha/beta proteins were not as well resolved. The following approach was then applied to the original data set to obtain an objective mathematical algorithm for the determination of a protein's tertiary structure class from its CD spectrum. Regions in 24-dimensional hyperspace corresponding to all of the tertiary structure classes were found by calculating the decision functions, or equations of hyperplanes, which separate groups of spectral patterns of different classes.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7856844 TI - Development of an assay method for purine catabolic enzymes in the mouse and its adaptation for use on an autoanalyzer. AB - An assay method has been developed for the purine catabolic enzymes adenosylhomocysteinase, adenosine deaminase (ADA), purine-nucleoside phosphorylase (PNP), and urate oxidase in mice. The assay links H2O2 produced during purine catabolism to the production of a dye complex. The assay method has been developed for ADA and PNP in erythrocytes and for all four enzymes in liver. The assay is cheap, sensitive, and easy to perform. The dye complex absorbs in the visible range, negating the need for an expensive ultraviolet spectrophotometer and allowing the use of an autoanalyzer. PMID- 7856846 TI - Capillary electrophoresis of nucleotides on ucon-coated fused silica columns. AB - Ucon-coated columns have been used to isolate nucleotides, such as ribonucleotides, deoxyribonucleotides, and pyridine nucleotides, by capillary zone electrophoresis. This neutral, hydrophilic column coating (Ucon) significantly reduced macromolecule adsorption and electroosmotic flow, which provides the maximum resolution of the nucleotides separated under moderate buffer conditions (pH about 5-6). The relative standard deviations of the nucleotides were less than 1%. Low minimum detectable concentrations (about 2-8 microM) and quantities (about 70-360 fmol) of the ribonucleotides were obtained. A qualitative and quantitative analysis of the ribonucleotides in hybridoma cell extracts shows the applicability of the developed methodology for the determination of intracellular nucleotide pools under the desirable buffer conditions. PMID- 7856847 TI - Comparison of amino acid analyses by phenylisothiocyanate and 6-aminoquinolyl-N hydroxysuccinimidyl carbamate precolumn derivatization. AB - An extensive retrospective comparison was conducted of the long-term repeatability and consistency of amino acid analyses using phenylisothiocyanate and 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (AQC) precolumn derivatization. Amino acid standards were analyzed more than 130 times on more than 60 independent occasions by each of these two precolumn derivatization methodologies, during routine amino acid analysis procedures. Similar coefficients of variation were seen only when very freshly prepared derivatives were analyzed. When realistic aging for < 20 h was taken into account, the extreme stability of the AQC derivatives stood out. Chromatography of AQC derivatives using HPLC solvents prepared on a large scale provided the lowest coefficients of variation. The superiority of AQC over PTC methodology was clearly apparent. PMID- 7856848 TI - A spectrophotometric assay for glucosidase I. AB - A spectrophotometric assay for glucosidase I using the synthetic trisaccharide alpha-D-Glc 1-->2 alpha-D-Glc 1-->3 alpha-D-Glc-O(CH2)8COOCH3 is reported. The terminal glucose is released from the substrate by the enzyme and quantitated using glucose oxidase, peroxidase, and o-dianisidine. The trisaccharide is specific for glucosidase I and provides all the necessary structural features for correct interaction in the enzyme active site. The utility of the assay for monitoring enzyme activity during isolation and for use in kinetic and inhibition studies (i.e., with 1-deoxynorjirimycin) is demonstrated. PMID- 7856849 TI - Drying from phosphate-buffered solutions can result in the phosphorylation of primary and secondary alcohol groups of saccharides, hydroxylated amino acids, proteins, and glycoproteins. AB - Drying (e.g., freeze-drying) aqueous phosphate-buffered solutions of organic compounds containing primary and/or secondary alcohol groups promotes esterification, producing orthophosphate esters. The reaction is accelerated by heat and by pH values < 7 and is affected by residual moisture content. The same preparations as solutions, similarly treated, produced little or no phosphorylated materials. The promotion of esterification in the dry state can, in part, be rationalized in terms of a mass-action effect because of the resulting low-water activity in dried preparations. When metaphosphates are used, esterification proceeds at a greatly increased rate and to a greater extent. Because of the relatively facile interconversion of phosphorus oxyacid salts, it is possible that a "metaphosphate species" may be responsible for the esterification reaction in all cases. We conclude that care should be exercised when hydroxylated organic compounds are dried from phosphate buffers so as to avoid the formation of phosphorylated artifacts. PMID- 7856850 TI - Amino acid analysis and protein database compositional search as a rapid and inexpensive method to identify proteins. AB - The identification of protein samples in minute quantities of protein samples, e.g., from two-dimensional polyacrylamide gel electrophoresis analysis, is an everyday problem in biology laboratories. Here we show that computer-assisted amino acid analysis can fulfill this task. Amino acid analysis data can be used to compare the amino acid composition of an unknown protein with protein compositions in a database (compositional search). Routine amino acid analysis data can, despite a certain margin of error, be used to identify a protein. Compared to protein sequencing, amino analysis is much cheaper, faster, and allows higher sample throughput. Thus, the method may replace protein sequencing as a first attempt in identification, provided a homolog can be found in the database. PMID- 7856851 TI - A method for selective isolation of the amino-terminal peptide from alpha-amino blocked proteins. AB - A method for selective isolation of the amino N-terminal peptide from an alpha amino (N alpha)-blocked protein is presented. The method consists of four steps. First, epsilon-amino groups of lysine residues in the protein are succinylated. Second, the derivatized protein is digested by either enzymatic or chemical cleavage. Third, the digest is subjected to reaction with cyanogen bromide activated Sepharose. Only the N-terminal-blocked peptide fails to react, while the other peptides are covalently bound to the Sepharose. Fourth, uncoupled peptides are purified by reversed-phase chromatography. The amino acid sequence of the peptide including the blocking group can be determined by mass spectrometry. These procedures were successfully tested with three known N alpha blocked proteins including bovine brain S100 protein, horse cytochrome c, and ovalbumin. PMID- 7856852 TI - Simultaneous measurement of cytochrome P4501A catalytic activity and total protein concentration with a fluorescence plate reader. AB - A method for simultaneous measurement of the cytochrome P4501A-associated enzyme, ethoxyresorufin-O-deethylase (EROD), and total protein concentration in liver microsomes is described. EROD assays were carried out in multiwell plates, and the fluorescent product (resorufin) and total proteins were quantified within the same wells with a fluorescence plate reader. Fluorescamine was used for protein assays. PMID- 7856853 TI - Chemiluminescent detection of mRNAs on northern blots with digoxigenin end labeled oligonucleotides. AB - To establish a simplified, nonradioactive approach for identifying mRNAs on Northern blots, antisense oligonucleotides have been used as probes in combination with chemiluminescence-based detection. Oligonucleotides (approximately 32-mer) were end-labeled with digoxigenin (DIG) and used in conjunction with adamantyl 1,2-dioxetane aryl phosphate substrates (Lumigen PPD and CSPD). Oligonucleotides were designed as probes for several mRNAs in tissues of rats and mice, including the mitochondrial uncoupling protein, lipoprotein lipase, GLUT1, GLUT4, and beta-actin. Uncoupling protein mRNA was detected in total RNA from brown adipose tissue with a 32-mer DIG-labeled oligonucleotide, within 2 min of exposure to film. This mRNA could also be detected when as little as 250 ng of total RNA was applied to the gel, following 4 h exposure to film, and was present only in brown fat. The mRNA for lipoprotein lipase was detectable with a 30-mer DIG-labeled oligonucleotide in 1 micrograms of total RNA from mouse heart, within 2 h of exposure. The mRNA for the GLUT1 glucose transporter was detected in total RNA from rat midbrain using a 32-mer DIG-labeled oligonucleotide, while beta-actin mRNA was detected with a 30-mer oligonucleotide. The mRNA for the insulin-sensitive glucose transporter GLUT4 was detected with a 32-mer DIG-labeled oligonucleotide and found only in those tissues in which glucose uptake is stimulated by insulin. The speed of detection was greater with CSPD and was augmented by exposure of membranes to film at 37 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7856854 TI - Analytical and preparative separation of anionic oligosaccharides by weak anion exchange high-performance liquid chromatography on an inert polymer column. AB - The use of ammonium formate buffers for analytical and preparative weak anion exchange high-performance chromatography of anionic sugars is described. The method can be used for structures containing sulfate, phosphate, sialic acid, and uronic acid moieties. Excellent separation of the anionic sugars was achieved from pH 5.5 to 9. In contrast to silica matrix columns the polymer matrix column used can tolerate a wide range of pH values for the eluting buffer and it does not shed material into the eluent. The use of a single volatile buffer avoids additional purification steps to recover separated sugars suitable for further structural and functional analyses. PMID- 7856855 TI - DNA damage by anticancer agents and its repair: mapping in cells at the subgene level with quantitative polymerase chain reaction. AB - The quantitative polymerase chain reaction (QPCR)-based assay was used to measure DNA damage and repair to a small (523 bp) fragment of the single-copy human N-ras gene in K562 cells. Compared with previous methods DNA preparation from treated cells and the subsequent detection of the radioactive product were considerably simplified. The results demonstrated that QPCR can be used to measure damage in a small gene segment, caused by cisplatin, nitrogen, and quinacrine mustards. Drug DNA adducts produced by two novel minor groove binding, sequence-specific molecules (AT-486 and DSB-120) could be detected at physiologically relevant concentrations of drug. For both cisplatin and nitrogen mustard the concentrations required to cause damage in cells were higher than those needed to cause equivalent damage in isolated DNA. In contrast both AT-486 and quinacrine mustard caused more damage at equimolar concentrations in cells than in isolated DNA. DSB-120, which is closely related to AT-486, was found to be 15-fold less effective than the latter at causing damage in treated cells despite similar reactivity with isolated DNA. Repair of damage caused by quinacrine mustard to the same small gene fragment was found to proceed at a constant rate over 24 h. The QPCR assay presented here is a simple quantitative method to measure damage and repair in subgene functional units such as promoters, introns, and exons. PMID- 7856856 TI - Reversal of tyrosinamide-oligosaccharide derivatization by Edman degradation. AB - In a previous report (Tamura, T., Wadhwa, M.S., and Rice, K.G. (1994) Anal. Biochem. 216, 335-344) we described the derivatization of N-linked oligosaccharides with Boc-tyrosine resulting in the formation of tyrosinamide oligosaccharides. Attachment of Boc-tyrosine to the reducing-end of an oligosaccharide through a glycosylamide linkage provides a hydrophobic chromophore that facilitates the purification of individual N-linked oligosaccharides derived from glycoproteins on preparative reverse-phase HPLC. In the present report we extend the utility of tyrosinamide-oligosaccharides by demonstrating two additional attributes of these glycoconjugates. Edman degradation was used to reverse both sialyl and asialyl tyrosinamide oligosaccharide derivatives resulting in the formation of reducing oligosaccharides. These can be used as analytical standards for chromatography or can be further derivatized with other probes that react with the reducing-end of an oligosaccharide. Second, we report that the fluorescence of tyrosinamide oligosaccharides allows their sensitive detection (5 pmol) on HPLC. These two attributes expand the versatility of tyrosinamide-oligosaccharides as glycoconjugates suitable for both analytical and biological studies. PMID- 7856857 TI - Comparative binding studies of cyclophilins to cyclosporin A and derivatives by fluorescence measurements. AB - The interaction of cyclosporin A and cyclosporin derivatives with cyclophilins A, B, and C has been investigated by means of fluorescence measurement techniques. Since Trp-121 of cyclophilin A is in close contact with bound cyclosporins and changes its fluorescence emission upon binding, direct estimation of Kd values for cyclosporins is straightforward in this case. Cyclophilins B and C, however, display no evident binding-dependent fluorescence changes suitable for the estimation of their binding affinities. This problem can be circumvented by measuring the variations of fluorescence emission intensities of a mixture of cyclophilin A and the fluorescence measurements unsuitable for cyclosporin binder as a function of ligand concentration. Application of a mixed-mode kinetic analysis then allows the calculation of the cyclosporin binding affinity of the second binder in the system. The dissociation constant for cyclosporin A/cyclophilin A was found to be 36.8 nM. Mixed-mode kinetic calculations yielded Kd values of 9.8 and 90.8 nM for cyclophilins B and C, respectively. The analysis was extended to noncyclophilin (weak) cyclosporin binders such as calmodulin and actin, resulting in approximate Kd values of 1.2 and 5.7 microM, respectively. Using the same approach, the Kd values of a series of different cyclosporin derivatives were determined. PMID- 7856858 TI - Development of a high-performance liquid chromatographic method for the analysis of enatiomer/enantiomer interaction in oxidative metabolism of bunitrolol in rat liver microsomes. AB - A high-performance liquid chromatographic method for the assay of enantiomeric 4 hydroxybunitrolol (4-OH-BTL) formed from racemic bunitrolol (BTL) in rat liver microsomes was developed. Racemic bunitrolol was incubated with rat liver microsomes fortified with an NADPH-generating system. Metabolites extracted with ethyl acetate were converted to acetyl derivatives with acetic anhydride in pyridine. The derivatives of 4-OH-BTL were well separated by the liquid chromatography equipped with a chiral column. Using this method, the metabolic interaction of BTL enantiomers was examined. The 4-OH-BTL-forming activities from enantiomeric BTL were higher than those from racemic BTL in rat liver microsomes, while the formation of ratios of 4-OH-BTL enantiomer to its antipode were the same under the two conditions. The Ki values obtained from kinetic studies using each BTL enantiomer as an inhibitor of its antipode were almost the same (ca 0.9 microM), which were close to their Michaelis constants (Km values). Oxidative activities of enantiomeric and racemic BTL were almost equally inhibited by debrisoquine and quinidine, a typical substrate and a selective inhibitor of the CYP2D subfamily, respectively. These results indicate that a BTL enantiomer is a mutual metabolic inhibitor of its antipode and BTL enantiomers compete for the same CYPD2D isozyme in rat liver microsomes. PMID- 7856859 TI - Practical instructions for radioactively labeled ligand receptor binding studies. AB - This paper represents a practical guide to ligand receptor binding studies with special emphasis on the detailed characterization of radiolabeled ligands prior to receptor binding experiments. The effects due to labeled ligand inactivated by the labeling procedure are included. The inactive ligand may contribute as much as the active ligand to nonspecific binding. A method for measuring the fraction of active ligand in the initial sample and for determining the specific radioactivity and bindability is presented in detail. A straightforward procedure for extracting the concentration of bound and free active ligand from the measured crude binding data is then presented. The dissociation constant and the number of receptors are obtained by fitting the binding equation to the free and bound ligand concentrations. As a practical example, interleukin-8 binding to human neutrophils was used. The experiments are discussed with respect to possible errors, and specific conditions (concentrations of ligand and receptors) necessary for accurate determination of the respective binding parameters are given. PMID- 7856860 TI - Analysis of glycosphingolipids by fluorophore-assisted carbohydrate electrophoresis using ceramide glycanase from Mercenaria mercenaria. AB - Polyacrylamide gel electrophoresis of fluorophore-labeled saccharides is a simple and sensitive separation method for glycan analysis. This method requires an aldehydic reducing carbon on the saccharide in order to react with the amine group of the fluorophore (8-aminonaphthalene-1,3,6-trisulfonic acid or 2 aminoacridone). We have used exoglycosidase-free ceramide glycanase from hard shelled clam to expose the reducing terminal of the glycan in glycosphingolipid by cleaving the linkage between the glycan and the ceramide. The released glycan was used for fluorophore-assisted carbohydrate electrophoresis, in order to qualitatively determine its monosaccharide composition, chain length, and glycosidic linkages using linkage-specific glycosidases, including a beta 1-3,4 galactosidase from clam. PMID- 7856861 TI - Farnesyl-protein transferase and geranylgeranyl-protein transferase assays using phosphocellulose paper absorption. AB - Farnesyl-protein transferase catalyzes the reaction of farnesyl pyrophosphate and its acceptors to yield farnesyl protein and pyrophosphate. Geranylgeranyl-protein transferases are distinct enzymes that catalyze the reaction of geranylgeranyl pyrophosphate and their acceptors. We used tritiated isoprenoid pyrophosphate donors and synthetic peptide acceptors to measure enzyme activities. The peptide acceptors contained basic amino acid residues on the amino terminus of tetrapeptide substrate determinants specific for each enzyme. Following the incubation, portions of the reaction mixture were applied to numbered phosphocellulose paper strips that were immersed in 95% ethanol/75 mM phosphoric acid (1/1; v/v). Acid promoted binding of positively charged peptide substrates and products to the negatively charged paper, and alcohol eluted the radioactive prenyl groups. Paper strips were processed in the same container in batches for 40 min, and radioactivity adsorbed to the strips was then measured by liquid scintillation spectrometry. The use of peptides makes the expression and purification of recombinant substrates in bacteria unnecessary. However, most proteins bind quantitatively to phosphocellulose at acidic pH, and the washing procedure developed for peptide substrates is applicable for measuring prenyltransferase activities with recombinant Ras proteins as acceptor. PMID- 7856862 TI - Flow injection immunoassay for albumin using thiophilic gels. PMID- 7856863 TI - Enzymatic synthesis of [32P]acyl-sn-glycerol 3-phosphate using diacylglycerol kinase. PMID- 7856864 TI - Isolation and identification of rare and differentially expressed genes using subtractive hybridization. PMID- 7856865 TI - Membrane proteins lose activity on freezing because of adsorption: implications for activity and protein assay. PMID- 7856866 TI - Purification of humanized murine and murine monoclonal antibodies using immobilized metal-affinity chromatography. AB - An affinity purification technique has been developed using mild elution conditions for the isolation of humanized murine and murine IgG1. This technique is based on the innate affinity of IgG1 for metal and utilizes immobilized metal affinity chromatography. Antibody bound to the metal-affinity column is eluted with a descending pH gradient and IgG1 elutes around pH 6.0. Humanized murine IgG1 isolated from cell culture media using this procedure is approximately 90% pure and does not contain any free light chain, light-chain dimer, or contaminating serum albumin. In addition, murine IgG1 has been isolated from ascites fluid by direct application to the metal-affinity column. Murine IgG1 is recovered essentially free from albumin in approximately 60% purity, the principal contaminant being transferrin. This method facilitates further purification which is easily achieved by cation-exchange chromatography. The near complete removal of albumin makes metal-affinity chromatography an alternative to salt precipitation of antibody from ascites fluid. Recoveries of antibody from the column are high, typically greater than 90%. We have identified the location of the metal affinity in the IgG1 as being near the carboxy terminus of the heavy chain. A histidine-rich sequence is present in this region which offers the possibility of genetically engineering this sequence to form an even higher affinity metal binding site for potential application in antibody imaging and therapeutics. PMID- 7856867 TI - Rescue of a failed polymerase chain reaction catalyzed by vent or deep vent DNA polymerase with 10% dimethyl sulfoxide. PMID- 7856868 TI - The preparation and use of biotinylated trypsin in western blotting for the detection of trypsin inhibitory proteins. AB - Methods were developed for the preparation of biotinylated trypsin of high specific activity. This was used as a probe for the detection of serine proteinase inhibitory proteins which had been separated by sodium dodecyl sulfate polyacrylamide gradient slab gel electrophoresis and electroblotted to nitrocellulose. The method was extremely sensitive and specific and could detect 0.15 ng of the serine proteinase inhibitor, trasylol (0.023 pmol active inhibitor). The method was also widely applicable and could be used to detect a range of serine proteinase inhibitors in human serum with molecular weights of 50 to approximately 180 kDa, soybean trypsin inhibitor variants, and secretory leukocyte proteinase inhibitor extracted from human intervertebral disc and articular cartilage. The identity of several of the serine proteinase inhibitors detected using biotinylated trypsin was verified by Western blotting using specific antibodies. Under the conditions used, electrotransfer of trasylol was quantitative; densitometric examination of blots indicated that there was a linear relationship between the amount of active trasylol electrophoresed (1-50 ng) and the intensity of the blot obtained with biotinylated trypsin as probe, indicating that serine proteinase inhibitory proteins may also be quantified by this technique using densitometric scanning. PMID- 7856869 TI - Acrylamide in polyacrylamide gels can modify proteins during electrophoresis. AB - Many notable discoveries have resulted from the characterization or purification of compounds by electrophoresis. The results reported here show that when polyacrylamide gels are used as the support matrix for electrophoresis, proteins can be modified by reaction with unpolymerized monomers of acrylamide, forming covalent acrylamide adduction products. This was demonstrated by electrophoresis of human and rat hemoglobins and subsequent analysis by electrospray ionization mass spectrometry. The degree of covalent acrylamide binding can be appreciable. The degree of adduction is dependent upon the condition of the gel matrix, the amount of material applied, and the reactivity of the material under investigation. PMID- 7856870 TI - Separation and analysis of 4'-epimeric UDP-sugars, nucleotides, and sugar phosphates by anion-exchange high-performance liquid chromatography with conductimetric detection. AB - An anion-exchange HPLC method coupled with conductimetric detection was developed for the analysis of UDP-sugars, nucleotides, and sugar phosphates, each in a single chromatographic run. The analysis was applicable to concentrations over 50 pmol. The utility of this technique was demonstrated by the measurement of UDP sugar 4'-epimerase activity of cell-free extracts from wild-type and mutant Neisseria meningitidis serogroup B strains. Additionally, the method has been applied to the analysis of the intermediates of glycolysis in human erythrocytes. PMID- 7856871 TI - Selective determination of adenine-containing compounds by capillary electrophoresis with laser-induced fluorescence detection. AB - Capillary electrophoresis coupled with laser-induced fluorescence detection provides a selective analysis of mixtures of adenine-containing compounds (adenine, adenosine, cAMP, AMP, ADP, and ATP) that are derivatized using chloroacetaldehyde as a fluorogenic reagent. The components can be detected with linear response over the concentration range of 10(-4) to 10(-9) M, and the detection limit corresponds to 5 to 10 x 10(-19) mol for each nucleotide. Analysis is achieved in less than 10 min with high separation efficiencies (up to 400,000 theoretical plates) and shows good reproducibility for migration times (0.5 to 1.0%) and peak heights (2.8 to 7.7%). To demonstrate the rapid analysis of small-volume samples, the adenine-containing compounds present in an oocyte from Xenopus laevis are determined. PMID- 7856872 TI - Directional immobilization of heparin onto beaded supports. AB - Heparin was immobilized in a defined orientation on Sepharose, agarose, and polyacrylamide supports by coupling through its reducing end. This is expected to mimic the attachment of heparin to the protein core in the naturally occurring proteoglycan and impart better ligand binding efficiency by exposing all the binding sites available in the naturally occurring heparin. The coupling chemistry was accomplished by modifying heparin at its reducing end to introduce reactive functionality that can react with appropriately functionalized supports. Three reducing end modified heparins were synthesized and characterized: 2,6 diaminopyridinyl heparin, containing a reactive amino group at the reducing end; omega-hydrazido-adipyl-azo heparin, containing a hydrazido group at the reducing end; and heparin lactone, containing a reactive ester functionality at the reducing end. These heparin derivatives were then reacted with the supports to give directionally immobilized heparin using different coupling chemistries: coupling of reducing end modified heparins to amine-containing supports (i.e., omega-aminohexyl Sepharose and omega-aminobutyl agarose), hydrazide-containing supports (i.e., Emphaze hydrazide), and activated carboxy-containing supports (i.e., activated 6-aminohexanoic acid Sepharose, Emphaze azlactone). The heparinized matrices were prepared and analyzed for their heparin content and protamine binding capacity. PMID- 7856873 TI - Analysis of factors affecting functional assays for estimating IF1, the mitochondrial ATPase inhibitor. AB - Functional assays for IF1 have been in use for more than 30 years, i.e., since the initial report of Pullman and Monroy in 1963 on the inhibition of soluble F1 ATPase by the purified bovine heart inhibitor. However, beginning with the report of Horstman and Racker in 1970 and for approximately 17 years thereafter, workers in many laboratories routinely used IF1-depleted bovine heart submitochondrial particles (SMP) prepared from slaughterhouse material for the assay of IF1 containing extracts and preparations. Then, in 1987 we introduced the use of submitochondrial particles prepared from a species naturally poor in IF1 for this purpose. Thus, rat heart SMP which are largely depleted of IF1 in their native state were found to allow the performance of particularly linear and reproducible IF1 titration assays regardless of the species source of the IF1 titrated on them. The present study presents the first systematic comparison of the effects of a variety of factors upon functional assays for IF1. These include variations in IF1 functional assays due to seasonal effects on bovine A particles as well as to the species source of the IF1-depleted particles used in the assays. Interestingly, bovine heart A particles prepared during cold weather were considerably more active than those prepared during warmer weather. Moreover, the more active cold-weather particles allowed the performance of better IF1 assays. Also, the larger the species of origin of the IF1-depleted heart muscle SMP, the less IF1 was required to produce a given amount of ATPase inhibition regardless of both seasonal effects and the species source of the IF1.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7856874 TI - Chemolabeling of frozen cerebral tissue proteins and immunopurified products with biotin and digoxigenin: physicochemical characteristics of biotinylated and digoxigeninated products. AB - Biotinylation and digoxigenination have been compared for labeling proteins from a total frozen tissue extract and from products of immunopurification with anti RAR beta (retinoic acid receptor beta). The detection of biotinylated and digoxigeninated proteins was found to be easier and more sensitive than detection of silver-stained proteins after two-dimensional electrophoresis. Although biotinylated or digoxigeninated proteins can be detected with avidin conjugates or anti-digoxigenin antibodies, they can also be detected with specific antibodies such as anti-RAR beta antibodies. Previously, coimmunoprecipitates could be visualized only by radioactive amino acid incorporation in cell culture, whereas biotinylation and digoxigenination enable the study of specific protein expression in frozen tissues by immunoprecipitation and the visualization of coimmunoprecipitates. Chemolabeling presents the two major advantages of limiting the use of radioisotopes and allowing the use of frozen tissues in all types of protein expression studies. PMID- 7856875 TI - Quantitative analysis of 2-oxoglutarate in biological samples using liquid chromatography with electrochemical detection. AB - This paper describes a technique for quantitative analysis of 2-oxoglutarate (alpha-ketoglutarate) in biological samples using liquid chromatography with electrochemical detection (LC-EC). This method utilizes a simplified, efficient sample preparation designed to select for 2-oxoglutarate and similar compounds by derivatization with phenylhydrazine. The response was linear over the range from 62.5 to 1000 ng/ml. The least quantifiable concentration was 62.5 ng/ml and the least detectable concentration was 25 ng/ml. To test the ability of the assay to measure 2-oxoglutarate in biological samples, this method was used to quantitate the 2-oxoglutarate content in chick osteoblast cultures and to determine the ability of the assay to accurately measure a standard addition of 500 ng/ml 2 oxoglutarate when added to a sample of the forementioned groups. The 2 oxoglutarate content of these cells was 6.67 +/- 1.20 ng/micrograms DNA or 105 +/ 18 ng/cell layer (mean +/- 95% confidence interval) and the assay accurately measured the standard addition. This method was also used to quantitate 2 oxoglutarate content in whole embryonic chick calvariae containing 6.40 +/- 0.95 ng/mg dry bone weight or 37.5 +/- 5.5 ng/bone. This assay provides significantly lower detection limits than the currently available procedures and is suitable for determination of 2-oxoglutarate in biological samples where very low amounts of 2-oxoglutarate are found. This method is the first application of LC-EC for quantitating 2-oxoglutarate. PMID- 7856876 TI - Quantitative electrophoretic analysis of proteins labeled with monobromobimane. AB - Protein cysteine residues were labeled with the thiol-specific fluorescent probe monobromobimane prior to electrophoresis. Labeling was rapid and complete under the conditions employed. Scanning the negative films of photographed gels with a laser densitometer provided quantitation. Analysis of five different cysteine containing proteins demonstrated that the fluorescence was dependent on the total number of cysteine residues present for each protein and independent of the protein species. The method allowed the construction of two nomograms for the universal quantitative analysis of cysteine-containing proteins. One nomogram calculated the limit of detection for each protein based on the protein's molecular mass, the protein's molar ratio of cysteine, and a nominal detection limit of 10 pmol cysteine. The second nomogram determined the quantity of the class 4 protein in outer membrane extracts of Neisseria meningitidis from the protein's molecular mass, its molar ratio of cysteine, and its total cysteine content. Additional applications for the analysis of protein cysteine and cystine content are discussed. PMID- 7856877 TI - Determination of theophylline metabolites in human liver microsomes by high performance liquid chromatography. AB - A method for the quantitation of three metabolites of theophylline, 1 methylxanthine (1 MX), 3-methylxanthine (3MX), and 1,3-dimethyluric acid (13DMU) in human liver microsomes has been developed. The method is based on a simple one step extraction followed by isocratic, reversed-phase high-performance liquid chromatography with uv detection (detection wavelength: 273 nm). The detection limit was 0.03 nmol.mg-1.h-1, which corresponds to 10 pmol per sample for all three metabolites. Linear standard curves were obtained for all three compounds within a concentration range of 0.6-6.0 nmol.mg-1.h-1 for 3MX and 1MX and 2.4 24.0 nmol.mg-1.h-1 for 13DMU. The absolute recoveries ranged from 61 to 80%, 68 to 74%, and 74 to 85% for 1MX, 3MX, and 13DMU, respectively, within the concentration range of the standard curve. The reproducibility and repeatability showed a coefficient of variation < 12% at five concentrations within the standard curve range. The accuracy for all three metabolites was within +/- 5% at three concentrations, except for 1MX in the lowest concentration (12%). The simple but sensitive method developed is highly suitable as a probe for cytochrome P4501A2 (CYP1A2) and probably also CYP2E1 function in human liver microsomes. PMID- 7856879 TI - Location of an amphipathic alpha-helix in peptides using reversed-phase HPLC retention behavior of D-amino acid analogs. AB - The reversed-phase HPLC retention behavior of D-amino acid replacement sets of an amphipathic model peptide, neuropeptide Y, and corticotropin releasing factor has been studied. The results demonstrate that D-amino acid substitutions destabilized the amphipathic alpha-helix, leading to a decrease of fractional helicity as determined by circular dichroism. The effect is enhanced by substitution of two adjacent D-amino acids and correlates well with a decrease of hydrophobic interaction during reversed-phase HPLC, caused by disturbance of the preferred binding domain of the stationary phase-bound peptide. In contrast, D amino acid substitutions in nonamphipathic or disordered regions of peptides do not influence the retention time to the same extent. Thus, the "retention profile" that results from plotting the retention time vs the position of the double D-amino acid replacements provides an indication of the presence and location of an amphipathic alpha-helical secondary structure in peptides. PMID- 7856878 TI - Glutathione disulfide variability in normal human blood. AB - A prevailing opinion is that glutathione disulfide (GSSG) levels in human blood are very low, but many studies have reported variable results. Therefore, our objective was to determine valid processing conditions for GSSG measurement and apply them to normal human blood samples. Reproducibility and stability of GSSG were demonstrated in acid extracts of a single sample of fresh whole blood by repetitive measurements during a 6-h period in which the %CVs were < 10. In contrast, in normal subjects tested repeatedly over several years, GSSG values ranging from < 2 to 166 nmol per 10(10) red blood cells were obtained and the overall %CV was 46. Lower GSSG values were obtained in hemolysates and ultrafiltrates. Thus, these results indicate that blood GSSG concentrations differ due to biological variation using optimal processing conditions. PMID- 7856880 TI - Mediated, thin-layer cell, coulometric determination of redox-active iron on the surface of asbestos fibers. AB - Redox-active iron on the surface of asbestos fibers was detected and quantified using a thin-layer cell, coulometric method with soluble mediators to shuttle electrons between the mineral fibers and the solid electrode. The working and counter electrodes consisted of gold films on a glass slide with reference electrodes of silver. Asbestos fibers were entrapped in a thin-layer cell of 25 microns thickness. Hexaammineruthenium(II) or o-dianisidine (dication) was used as the reducing or oxidizing mediator, respectively. Hexaammineruthenium(III) undergoes a one-electron reduction, and protonated o-dianisidine undergoes a sequential two-electron oxidation. The measurement involved determination of the total charge for the oxidation or reduction of surface-immobilized Fe(II) or Fe(III) on the asbestos fibers. Analysis of the results showed that crocidolite and amosite have 4.3 +/- 0.7 and 3.3 +/- 0.7 nmol/mg of total redox-active iron that is accessible to the mediators, respectively. This corresponded to a surface coverage of accessible redox-active iron of approximately 4.3 x 10(-11) mol/cm2 for crocidolite and 9.5 x 10(-11) mol/cm2 for amosite. Furthermore, Fe(II) constituted 76% or 25% of the accessible redox-active iron on the surface of crocidolite or amosite, respectively. The method may be applied to other types of solid materials with redox-active species on their surfaces. PMID- 7856881 TI - High-mass analysis using quadrupolar excitation/ion cooling in a Fourier transform mass spectrometer. AB - Quadrupolar axialization has been applied to matrix-assisted laser desorption/ionization Fourier transform mass spectrometric analysis of singly charged polymer and protein ions. When a quadrupolar excitation is applied in the presence of argon collision gas, ions are driven to the center of the cell, where they can traverse the conductance limit and be detected in the lower pressure analyzer cell of a dual cell instrument. It is shown that single frequency quadrupolar excitation permits highly selective detection of single oligomers of poly(ethylene glycol) 6000. Resolution enhancement is demonstrated for bovine insulin and ubiquitin, where spectra with resolving powers of 92,000 and 25,000, respectively, are obtained. Finally, quadrupolar axialization is demonstrated to be effective for molecules with masses as large as 13,000 Da. PMID- 7856882 TI - Durable gold-coated fused silica capillaries for use in electrospray mass spectrometry. AB - A simple procedure for preparing gold-coated silica capillaries for use in electrospray ionization mass spectrometry is described. The tip of the capillary is mechanically tapered to a fine point, and a thin film of gold is vapor deposited on the outer surface following treatment with an organofunctional silane. The performance characteristics of these durable capillaries as continuous infusion sources are examined, and their utility in on-line capillary electrophoresis mass spectrometry is demonstrated. PMID- 7856883 TI - Mass spectrometric identification of amino acid transformations during oxidation of peptides and proteins: modifications of methionine and tyrosine. AB - Liquid chromatography/electrospray ionization mass spectrometry (LC/ESI-MS), tandem mass spectrometry with on-line liquid chromatography (LC/ESI-MS/MS) and high-resolution mass spectrometry with liquid secondary ionization (LSI-MS) were utilized to identify the modified amino acids in peptides and proteins formed during oxidation with performic acid. The procedure of protein oxidation was chosen to assist in protein unfolding by oxidizing the cystines to cysteic acids to allow for more complete proteolytic digestion and to create additional cleavage sites for endoproteinase Asp-N. Investigation of the Asp-N peptide map of oxidized superoxide dismutase (SOD) by LC/ESI-MS revealed that an expected proteolytic fragment of the protein was missing. In its place, two peptides with molecular weights 66 and 100 higher than that calculated for the missing peptide were observed. To identify the modified amino acids in the unexpected peptides, a model peptide with some amino acid similarities (tyrosine, arginine, methionine, lysine) to the missing peptide was chosen and was subjected to similar oxidation and enzymatic digestion steps, conditions, and reactions. After oxidation and digestion, the model peptide (TAP; sequence, Ac-MDKVLNRY) showed three major peaks in LC/MS. The peptides in the three peaks were identified as the unmodified peptide and two peptides whose molecular weights were 66 and 100 higher than that of TAP.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7856884 TI - Irradiated (15N)DNA as an internal standard for analysis of base-oxidized DNA constituents by isotope dilution mass spectrometry. AB - A simple and convenient procedure for the preparation of isotopically labeled DNA enriched in oxidized deoxynucleosides is described. 15N-Labeled DNA was isolated from Escherichia coli cells grown in an isotopically enriched medium, and the level of oxidative damage was increased by in vitro irradiation under oxygen. The resulting DNA was hydrolyzed and subsequently analyzed by GC/MS. Results indicated that the DNA was 99% 15N-enriched and that 1% of the total 2' deoxyguanosine was converted into 8-hydroxy-2'-deoxyguanosine (8-OHdG). When applied to the analysis of 8-OHdG, [15N]DNA as internal standard gave a better reproducibility (CV, 7.9%; n = 5) as compared to the monomeric 8-[18O]hydroxy-2' deoxyguanosine (CV, 16%; n = 4). Background levels of 8-OHdG in rat colon DNA determined with [15N]DNA and 8-18OHdG as internal standard were 26 +/- 11 and 15 +/- 7 8-OHdG per 10(6) deoxynucleosides, respectively. PMID- 7856885 TI - Cell geometry considerations for the Fourier transform ion cyclotron resonance mass spectrometry remeasurement experiment. AB - Three cell geometries, closed cubic, closed elongated, and open elongated, are evaluated for optimum remeasurement performance in the Fourier transform ion cyclotron resonance mass spectrometry (FTICR) experiment. The advantages and disadvantages of each cell during normal FTICR operation are discussed. Unit remeasurement efficiency is obtained for the closed elongated cell at approximately 71% of the cell radius, whereas the open elongated cell achieves unit remeasurement at only approximately 18% of the cell radius. The closed cubic cell does not achieve unit remeasurement efficiency at a detectable signal level. A correlation between remeasurement efficiency and the characteristic radial electric field of each trapped ion cell is established. Radial dispersion of the ion cloud is considered the dominant signal loss mechanism in the remeasurement experiment, and cell geometries are examined for optimized sensitivity and unit remeasurement efficiency. PMID- 7856886 TI - Affinity purification and microcharacterization of recombinant DNA-derived human growth hormone isolated from an in vivo model. AB - A procedure has been developed for the isolation and purification of trace amounts of unlabeled proteins from biological solutions. Using a combination of affinity chromatography and reversed-phase HPLC, microgram amounts of recombinant DNA-derived human growth hormone (rhGH) were purified from an in vivo rat model. Microcharacterization techniques were developed, and picomole amounts of the recovered protein were digested with trypsin and characterized using capillary HPLC peptide mapping. The described procedures were used to study the chemical changes that occur in rhGH following intravenous administration. The study demonstrated that both deamidation and oxidation can occur in vivo, although the former would occur to a significant extent only in proteins with an extended half life. PMID- 7856887 TI - Estimation of liquid-vapor critical loci for CO2-solvent mixtures using a peak shape method. AB - Critical-mixture curves for 13 CO2-solvent binary mixtures were estimated using the peak-shape method. Mixture critical points were determined within 1 degrees C and 1 atm. The results for CO2-toluene and CO2-methanol were compared to previously reported data from high-pressure view cell studies. No more than a 3% difference was observed in the data generated by the two different techniques. A few abnormalities encountered while using the peak-shape method are also discussed. PMID- 7856888 TI - Improvement in the long-term stability of an amperometric glucose sensor system by introducing a cellulose membrane of bacterial origin. AB - Classical amperometric glucose sensors that use cellulose membranes of wood origin (Cuprophan) suffer from the fact that their long-term stability in blood is short; therefore, their clinical use is limited. In the present study, a classical amperometric glucose sensor was covered with a bacterial cellulose (BC) membrane. Its surface in comparison to that of the classical glucose sensor (Cuprophan) and its long-term stability were tested in vitro and in vivo. The surface element composition was approximately 44% oxygen and approximately 56% carbon in both membranes and thus typical for cellulose. BC membranes exhibited fiber structure, whereas cup membranes did not. There was also a qualitative difference in protein adsorption between both membranes on exposure to bovine serum albumin. Treatment with Trogamid of one site of the BC membranes allowed linear glucose detection between 0 and 40 mM. Hemocompatibility of BC membranes was improved in comparison to cup membranes on the basis of complement activation (C3a and C5a). In diluted blood (1:10), the BC-covered sensor exhibited a long term stability of more than 200 h; in undiluted blood it was stable for about 24 h, which is about 6-7 times longer than the stability of the classical Cup membrane-covered sensor. In in vivo studies, where the BC membrane-covered sensors were connected to the jugular vein of rats, blood glucose levels could be monitored for at least 24 h. In summary, the use of a modified bacterial cellulose membrane to cover the classical amperometric glucose sensor significantly improves the sensor's long-term stability both in vitro and in vivo. PMID- 7856889 TI - Spinally administered neostigmine--something to celebrate. PMID- 7856890 TI - Estimating brain temperature during hypothermia. PMID- 7856891 TI - Phase I safety assessment of intrathecal neostigmine methylsulfate in humans. AB - BACKGROUND: In dogs, sheep, and rats, spinal neostigmine produces analgesia alone and enhances analgesia from alpha 2-adrenergic agonists. This study assesses side effects and analgesia from intrathecal neostigmine in healthy volunteers. METHODS: After institutional review board approval and informed consent, 28 healthy volunteers were studied. The first 14 volunteers received neostigmine (50 750 micrograms) through a #19.5 spinal needle followed by insertion of a spinal catheter. The remaining 14 volunteers received neostigmine through a #25 or #27 spinal needle without a catheter. Safety measurements included blood pressure, heart rate, oxyhemoglobin saturation, end-tidal carbon dioxide, neurologic evaluation, and computer tests of vigilance and memory. Analgesia in response to ice water immersion was measured. RESULTS: Neostigmine (50 micrograms) through the #19.5 needle did not affect any measured variable. Neostigmine (150 micrograms) caused mild nausea, and 500-750 micrograms caused severe nausea and vomiting. Neostigmine (150-750 micrograms) produced subjective leg weakness, decreased deep tendon reflexes, and sedation. The 750-micrograms dose was associated with anxiety, increased blood pressure and heart rate, and decreased end-tidal carbon dioxide. Neostigmine (100-200 micrograms) in saline, injected through a #25 or #27 needle, caused protracted, severe nausea, and vomiting. This did not occur when dextrose was added to neostigmine. Neostigmine by either method of administration reduced visual analog pain scores to immersion of the foot in ice water. CONCLUSIONS: The incidence and severity of these adverse events from intrathecal neostigmine appears to be affected by dose, method of administration, and baricity of solution. These effects in humans are consistent with studies in animals. Because no unexpected or dangerous side effects occurred, cautious examination of intrathecal neostigmine alone and in combination with other agents for analgesia is warranted. PMID- 7856892 TI - Do standard monitoring sites reflect true brain temperature when profound hypothermia is rapidly induced and reversed? AB - BACKGROUND: Brain temperature is closely approximated by most body temperature measurements under normal anesthetic conditions. However, when thermal autoregulation is overridden, large temperature gradients may prevail. This study sought to determine which of the standard temperature monitoring sites best approximates brain temperature when deep hypothermia is rapidly induced and reversed during cardiopulmonary bypass. METHODS: Twenty-seven patients underwent cardiopulmonary bypass and deep hypothermic circulatory arrest in order for each to have a giant cerebral aneurysm surgically clipped. Brain temperatures were measured directly with a thermocouple embedded in the cerebral cortex. Eight other body temperatures were monitored simultaneously with less invasive sensors at standard sites. RESULTS: Brain temperature decreased from 32.6 +/- 1.4 degrees C (mean +/- SD) to 16.7 +/- 1.7 degrees C in 28 +/- 7 min, for an average cerebral cooling rate of 0.59 +/- 0.15 degrees C/min. Circulatory arrest lasted 24 +/- 15 min and was followed by 63 +/- 17 min of rewarming at 0.31 +/- 0.09 degrees C/min. None of the monitored sites tracked cerebral temperature well throughout the entire hypothermic period. During rapid temperature change, nasopharyngeal, esophageal, and pulmonary artery temperatures corresponded to brain temperature with smaller mean differences than did those of the tympanic membrane, bladder, rectum, axilla, and sole of the foot. At circulatory arrest, nasopharyngeal, esophageal, and pulmonary artery mean temperatures were within 1 degree C of brain temperature, even though individual patients frequently exhibited disparate values at those sites. CONCLUSIONS: When profound hypothermia is rapidly induced and reversed, temperature measurements made at standard monitoring sites may not reflect cerebral temperature. Measurements from the nasopharynx, esophagus, and pulmonary artery tend to match brain temperature best but only with an array of data can one feel comfortable disregarding discordant readings. PMID- 7856893 TI - An evaluation of the effect of anesthetic technique on reproductive success after laparoscopic pronuclear stage transfer. Propofol/nitrous oxide versus isoflurane/nitrous oxide. AB - BACKGROUND: Laparoscopic pronuclear stage transfer (PROST) is the preferred method of embryo transfer after in vitro fertilization in many infertility programs. There are scant data to recommend the use or avoidance of any particular anesthetic agent for use in women undergoing this procedure. The authors hypothesized that propofol would be an ideal anesthetic for laparoscopic PROST because of its characteristic favorable recovery profile that includes minimal sedation and a low incidence of postoperative nausea and vomiting. The purpose of the study was to compare propofol and isoflurance with respect to postanesthetic recovery and pregnancy outcomes after laparoscopic PROST. METHODS: One hundred twelve women scheduled for laparoscopic PROST were randomized to receive either propofol/nitrous oxide or isoflurane/nitrous oxide for maintenance of anesthesia. RESULTS: Visual analog scale scores for sedation were lower in the propofol group than in the isoflurance group at all measurements between 30 min and 3 h after surgery. More women experienced emesis and were given an antiemetic during recovery in the isoflurance group than in the propofol group. However, the percentage of pregnancies with evidence of fetal cardiac activity was 54% in the isoflurane group compared with only 30% in the propofol group (P = 0.023). Also, the ongoing pregnancy rate was greater in the isoflurane group than in the propofol group (54% vs. 29%, P = 0.014). CONCLUSIONS: Propofol/nitrous oxide anesthesia was associated with lower clinical and ongoing pregnancy rates compared with isoflurane/nitrous oxide anesthesia. PMID- 7856894 TI - Distribution of cerebral blood flow during anesthesia with isoflurane or halothane in humans. AB - BACKGROUND: Halothane and isoflurane have been shown to induce disparate effects on different brain structures in animals. In humans, various methods for measuring cerebral blood flow (CBF) have produced results compatible with a redistribution of CBF toward deep brain structures during isoflurane anesthesia in humans. This study was undertaken to examine the effects of halothane and isoflurance on the distribution of CBF. METHODS: Twenty ASA physical status patients (four groups, five in each) anesthetized with either isoflurane or halothane (1 MAC) during normo- or hypocapnia (PaCO2 5.6 or 4.2 kPa (42 or 32 mmHg)) were investigated with a two-dimensional CBF measurement (CBFxenon, intravenous 133xenon washout technique) and a three-dimensional method for measurement of the regional CBF (rCBF) distribution with single photon emission computer-aided tomography (SPECT; 99mTc-HMPAO). In the presentation of SPECT data, the mean CBF of the brain was defined as 100%, and all relative flow values are related to this value. RESULTS: The mean CBFxenon level was significantly influenced by the PaCO2 as well as by the anesthetic used. At normocapnia, patients anesthetized with halothane had a mean CBFxenon of 40 +/- 3 (SE) ISI units. With isoflurane, the flow was significantly (P < 0.01, 33 +/- 3 ISI units) less than with halothane. Hypocapnia decreased mean CBFxenon (P < 0.0001) during both anesthetics (halothane 24 +/- 3, isoflurane 13 +/- 2 ISI units). The effects on CBFxenon, between the anesthetics, differed significantly (P < 0.01) also during hypocapnia. There were significant differences in rCBF distribution measured between the two anesthetics (P < 0.05). During isoflurane anesthesia, there was a relative increase in flow values in subcortical regions (thalamus and basal ganglia) to 10-15%, and in pons to 7-10% above average. Halothane, in contrast, induced the highest relative flow levels in the occipital lobes, which increased by approximately 10% above average. The rCBF level was increased approximately 10% in cerebellum with both anesthetics. Changes in PaCO2 did not alter the rCBF distribution significantly. CONCLUSIONS: There is a difference in the human rCBF distribution between halothane and isoflurane with higher relative flows in subcortical regions during isoflurane anesthesia. However, despite this redistribution, isoflurane anesthesia resulted in a lower mean CBFxenon than did anesthesia with halothane. PMID- 7856895 TI - Death and other complications of emergency airway management in critically ill adults. A prospective investigation of 297 tracheal intubations. AB - BACKGROUND: Hospitalized patients outside of the operating room frequently require emergency airway management. This study investigates complications of emergency airway management in critically ill adults, including: (1) the incidence of difficult and failed intubation; (2) the frequency of esophageal intubation; (3) the incidence of pneumothorax and pulmonary aspiration; (4) the hemodynamic consequences of emergent intubation, including death, during and immediately following intubation; and (5) the relationship, if any, between the occurrence of complications and supervision of the intubation by an attending physician. METHODS: Data were collected on consecutive tracheal intubations carried out by the intensive care unit team over a 10-month period. Non anesthesia residents were supervised by anesthesia residents, critical care attending physicians, or anesthesia attending physicians. RESULTS: Two hundred ninety-seven consecutive intubations were carried out in 238 adult patients. Translaryngeal tracheal intubation was accomplished in all patients. Intubation was difficult in 8% of cases (requiring more than two attempts at laryngoscopy by a physician skilled in airway management). Esophageal intubation occurred in 25 (8%) of the attempts but all were recognized before any adverse sequelae resulted. New infiltrates suggestive of pulmonary aspiration were present on chest radiography after 4% of intubations. Seven patients (3%) died during or within 30 min of the procedure. Five of the seven patients had systemic hypotension (systolic blood pressure < or = 90 mmHg), and four of the five were receiving vasopressors to support systolic blood pressure. Patients with systolic hypotension were more likely to die after intubation than were normotensive patients (P < 0.001). There was no relationship between supervision by an attending physician and the occurrence of complications. CONCLUSIONS: In critically ill patients, emergency tracheal intubation is associated with a significant frequency of major complications. In this study, complications were not increased when intubations were accomplished without the supervision of an attending physician as long as the intubation was carried out or supervised by an individual skilled in airway management. Mortality associated with emergent tracheal intubation is highest in patients who are hemodynamically unstable and receiving vasopressor therapy before intubation. PMID- 7856896 TI - Epidural and intravenous fentanyl produce equivalent effects during major surgery. AB - BACKGROUND: The benefit of epidural versus intravenous fentanyl administration for postoperative analgesia is controversial. In the current study, the intraoperative effects of epidural versus intravenous fentanyl administration were compared during major surgery. METHODS: Twenty elective patients scheduled for thoracoabdominal esophagectomy under general anesthesia with propofol infusion were randomly allocated to receive either intravenous or epidural boluses of 50-100 micrograms fentanyl in a double-blind fashion to maintain hemodynamic stability. Plasma cortisol and fentanyl, as well as total urinary catecholamines, were obtained at the end of the operations. RESULTS: Hemodynamic variations were similar except that patients receiving epidural fentanyl had a lower incidence of heart rate reduction (> 20% reduction from baseline, P < 0.05). There were no differences in mean intraoperative fentanyl (1,115 +/- 430 and 1,010 +/- 377 micrograms, epidural and intravenous, respectively) or propofol (2,281 +/- 645 and 2,452 +/- 1,169 mg) doses, number of boluses of fentanyl (nine in both groups), plasma fentanyl concentration (1.13 +/- 0.4 and 1.02 +/- 0.46 ng/ml), or number of anesthesiologists correctly identifying the site of fentanyl administration. Similarly, there were no differences in plasma glucose (8.9 +/- 1.8 and 9.3 +/- 1.8 mM) and cortisol (696 +/- 446 and 846 +/- 257 mM), or urinary epinephrine (12 +/- 3.7 and 13.1 +/- 9.2, micrograms/sample) and norepinephrine (42.7 +/- 26.7 and 39.1 +/- 27.6, micrograms/sample). CONCLUSIONS: There appears to be no clinical advantage to epidural administration of fentanyl over intravenous administration during anesthesia for major surgery. PMID- 7856897 TI - The dose-response relationship of tranexamic acid. AB - BACKGROUND: Prophylactic administration of the antifibrinolytic drug tranexamic acid decreases bleeding and transfusions after cardiac operations. However, the best dose of tranexamic acid for this purpose remains unknown. This study explored the dose-response relationship of tranexamic acid for hemostatic efficacy after cardiac operation. METHODS: In prospective, randomized, double blinded fashion, 148 patients undergoing cardiac operation with extracorporeal circulation were divided into six groups: a placebo group and five groups receiving tranexamic acid in loading doses before incision (range 2.5 to 40 mg.kg 1) and one-tenth the loading dose hourly for 12 h. The mass of blood collected by chest tubes over 12 h represented blood loss. Allogeneic transfusions within 12 h and within 5 d of surgery were tallied. RESULTS: The six groups presented similar demographics. Patients receiving placebo had increased postoperative D-dimer concentration compared to groups receiving tranexamic acid. Patients receiving at least 10 mg.kg-1 tranexamic acid followed by 1 mg.kg-1.h-1 bled significantly less (365, 344, and 369 g.12 h-1, respectively, for those three groups) compared with patients who received placebo (552 g, P < 0.05). Tranexamic dose did not affect transfusions. Only initial hematocrit affected whether a patient received an allogeneic transfusion within 5 days of operation (odds ratio 2.08 for each 3% absolute decrease in hematocrit). CONCLUSIONS: Prophylactic tranexamic acid, 10 mg.kg-1 followed by 1 mg.kg-1.h-1, decreases bleeding after extracorporeal circulation. Larger doses do not provide additional hemostatic benefit. PMID- 7856898 TI - Cerebral metabolism during propofol anesthesia in humans studied with positron emission tomography. AB - BACKGROUND: Although the effects of propofol on cerebral metabolism have been studied in animals, these effects have yet to be directly examined in humans. Consequently, we used positron emission tomography (PET) to demonstrate in vivo the regional cerebral metabolic changes that occur in humans during propofol anesthesia. METHODS: Six volunteers each underwent two PET scans; one scan assessed awake-baseline metabolism, and the other assessed metabolism during anesthesia with a propofol infusion titrated to the point of unresponsiveness (mean rate +/- SD = 7.8 +/- 1.5 mg.kg-1.h-1). Scans were obtained using the 18fluorodeoxyglucose technique. RESULTS: Awake whole-brain glucose metabolic rates (GMR) averaged 29 +/- 8 mumoles.100 g-1.min-1 (mean +/- SD). Anesthetized whole-brain GMR averaged 13 +/- 4 mumoles.100 g-1.min-1 (paired t test, P < or = 0.007). GMR decreased in all measured areas during anesthesia. However, the decrease in GMR was not uniform. Cortical metabolism was depressed 58%, whereas subcortical metabolism was depressed 48% (P < or = 0.001). Marked differences within cortical regions also occurred. In the medial and subcortical regions, the largest percent decreases occurred in the left anterior cingulate and the inferior colliculus. CONCLUSION: Propofol produced a global metabolic depression on the human central nervous system. The metabolic pattern evident during anesthesia was reproducible and differed from that seen in the awake condition. These findings are consistent with those from previous animal studies and suggest PET may be useful for investigating the mechanisms of anesthesia in humans. PMID- 7856899 TI - The magnitude and time course of vecuronium potentiation by desflurane versus isoflurane. AB - BACKGROUND: Preliminary studies suggest that desflurane and isoflurane potentiate the action of muscle relaxants equally. However, variability between subjects may confound these comparisons. A crossover study was performed in volunteers on the ability of desflurane and isoflurane to potentiate the neuromuscular effect of vecuronium, to influence its duration of action, and on the magnitude and time course of reversal of potentiation when anesthesia was withdrawn. METHODS: Adductor pollicis twitch tension was monitored in 16 volunteers given 1.25 MAC desflurane on one occasion, and 1.25 MAC isoflurane on another. In eight subjects, vecuronium bolus dose potency was determined using a two-dose dose response technique; the vecuronium infusion dose requirement to achieve 85% twitch depression also was determined. Also in these subjects, the magnitude and time course of spontaneous neuromuscular recovery were determined when the anesthetic was withdrawn while maintaining a constant vecuronium infusion. In the other eight subjects, the time course of action of 100 micrograms/kg vecuronium was determined. RESULTS: Vecuronium's ED50 and infusion requirement to maintain 85% twitch depression were 20% less during desflurane, compared to isoflurane, anesthesia; vecuronium plasma clearance was similar during the two anesthetics. After 100 micrograms/kg vecuronium, onset was faster and recovery was longer during desflurane anesthesia. When the end-tidal anesthetic concentration was abruptly reduced from 1.25 to 0.75 MAC, twitch tension increased similarly (approximately 15% of control), and time for the twitch tension to reach 90% of the final change was similar (approximately 30 min) with both anesthetics. Decreasing anesthetic concentration from 0.75 to 0.25 MAC increased twitch tension by 46 +/- 10% and 25 +/- 7% of control (mean +/- SD, P < 0.001) with desflurane and isoflurane, respectively; 90% response times for these changes were 31 +/- 10 min and 18 +/- 7 min (P < 0.05), respectively. CONCLUSIONS: Desflurane potentiates the effect of vecuronium approximately 20% more than does an equipotent dose of isoflurane. PMID- 7856900 TI - Studies on the safety of chronically administered intrathecal neostigmine methylsulfate in rats and dogs. AB - BACKGROUND: The spinal delivery of the cholinesterase inhibitor neostigmine yields analgesia in rats and augments the analgesic effects of alpha 2 agonists in sheep. To assess its activity in humans, preclinical toxicology studies to define its safety were required in two species. METHODS: Rats with chronic intrathecal catheters received daily injections of saline (vehicle) or 5 micrograms/10 microliters or 10 micrograms/10 microliters neostigmine HCl (n = 6/group) for 4 days and were observed for general behavior and nociception (52.5 degrees C hot plate). On day 6, rats were anesthetized and submitted to whole body perfusion/fixation. For dog studies, male beagles were prepared following rigid aseptic precautions with catheters passed from the cisterna magna to the lumbar intrathecal space. Catheters were connected to an external vest-mounted pump. Based on preliminary studies, ten implanted dogs were randomly assigned to receive infusions of neostigmine for 28 days (4 mg/4 ml/day; n = 6) or saline (4 ml/day; n = 4). At 28 days, dogs were anesthetized, cisternal cerebrospinal fluid was obtained, and dogs were submitted to perfusion-fixation. Rat and dog spinal cords were embedded, sectioned, stained, and assessed by the pathologist without knowledge of treatment. RESULTS: In rats, neostigmine produced a dose-dependent increase in hot plate latency, and no tolerance was observed. Mild tremor was observed but was not debilitating. Histopathology revealed a mild fibrotic reaction to the catheter with mixed signs of moderate, acute, and chronic inflammation with no differences between saline or drug groups. In dogs, neostigmine had no effect on blood pressure or on the skin twitch response but produced bradycardia and an increase in muscle tone. At sacrifice, cerebrospinal fluid protein, specific gravity, and glucose were elevated in both saline and neostigmine groups. Histopathology displayed a local reaction to the spinal catheter and a mixed acute and chronic inflammatory reaction. No group differences were observed. These results suggest that, at the neostigmine concentration of 1 mg/ml in the rat and dog and in doses up to 4 mg/day in the dog, there is no evidence of spinal tissue toxicity that can be attributed to the drug. This result, observed in two species, suggests that intrathecal neostigmine given in this manner is without distinguishable toxicity in these two models. PMID- 7856901 TI - Cardiorespiratory and spinal cord blood flow effects of intrathecal neostigmine methylsulfate, clonidine, and their combination in sheep. AB - BACKGROUND: Intrathecal neostigmine may produce analgesia by itself and may enhance analgesia from spinal clonidine. Before clinical trials, the spinal cord blood flow effects of these drugs alone and in combination should be examined in animals. METHODS: Conscious, nonpregnant ewes with indwelling vascular and thoracic spinal catheters received intrathecal injection of 0.2 or 2 mg neostigmine, 0.2 mg clonidine, or 2 mg neostigmine plus 0.2 mg clonidine. Mean systemic and pulmonary arterial and central venous pressures, heart rate, and cardiac output were monitored, arterial blood was sampled for blood gas tensions and pH, and spinal cord blood flow was determined by colored microsphere injection before and at 15, 60, and 240 min after spinal study drug injection. RESULTS: Neostigmine alone did not affect cardiorespiratory variables or spinal cord blood flow. Intrathecal clonidine alone decreased systemic arterial and central venous pressures, whereas these effects were not observed with addition of neostigmine. Clonidine or neostigmine alone or the combination of clonidine and neostigmine did not affect spinal cord blood flow. CONCLUSIONS: Intrathecal neostigmine alone or in combination with clonidine does not reduce spinal cord blood flow, an important preclinical toxicity issue. These results provide additional support for initial clinical trials of intrathecal neostigmine for analgesia. PMID- 7856902 TI - Mechanism of the negative inotropic effect of thiopental in isolated ferret ventricular myocardium. AB - BACKGROUND: Thiopental's myocardial depressant effects are well known and most likely involve some alteration in intracellular Ca2+ homeostasis. The aim of this study was to investigate the mechanisms of thiopental's negative inotropic effects and its underlying mechanism in isolated ferret ventricular myocardium (which shows physiologic characteristics similar to human ventricular myocardium), and in frog ventricular myocardium, in which Ca2+ ions for myofibrillar activation are derived almost entirely from transsarcolemmal influx. METHODS: The authors analyzed the effects of thiopental after beta-adrenoceptor blockade on variables of contractility and relaxation, and on the free intracellular Ca2+ transient detected with the Ca(2+)-regulated photoprotein aequorin. Thiopental's effects also were evaluated in ferret right ventricular papillary muscles in which the sarcoplasmic reticulum (SR) function was impaired by ryanodine and in frog ventricular strips with little or no SR function. RESULTS: At concentration > or = 10(-4) M, which is in the high range of the clinically encountered free plasma thiopental concentrations, thiopental decreased contractility and the amplitude of the intracellular Ca2+ transient. At equal peak force, peak aequorin luminescence in 10(-4) M thiopental and [Ca2+]0 > 2.25 mM was slightly smaller than that in control conditions at [Ca2+]o = 2.25 mM. This indicates that thiopental causes a small increase in myofibrillar Ca2+ sensitivity. After inactivation of sarcoplasmic reticulum Ca2+ release with 10( 6) M ryanodine, a condition in which myofibrillar activation depends almost exclusively on transsarcolemmal Ca2+ influx, thiopental caused a further decrease in contractility and in the amplitude of the intracellular Ca2+ transient, and thiopental's relative negative inotropic effect was not different from that in control muscles not exposed to ryanodine. Thiopental, > or = 10(-4) M, decreased contractility in frog ventricular myocardium. CONCLUSIONS: These findings indicate that the direct negative inotropic effect of thiopental results from a decrease in intracellular Ca2+ availability. At least part of thiopental's action is caused by inhibition of transsarcolemmal Ca2+ influx. These effects become apparent at concentrations routinely present during intravenous induction with thiopental. PMID- 7856903 TI - In vitro effects of fentanyl, methohexital, and thiopental on brain endothelial permeability. AB - BACKGROUND: The use of anesthetics can lead to changes of the permeability of the blood-brain barrier (BBB). To eliminate those factors, such as varying hemodynamic effects that are associated with anesthesia, an in vitro model of the BBB consisting of brain microvascular endothelial cells (BMEC) was used to study the direct effects of the opiate, fentanyl, and the barbiturates methohexital and thiopental, which are widely used in the clinical setting, on the permeability of confluent monolayers. METHODS: BMEC isolated from porcine brains were grown to confluence on collagen-coated polycarbonate membranes, which were placed into 24 well dishes, thus forming a two-compartment chamber. The permeability of the BMEC monolayer to ions--determined by measurements of the transendothelial resistance (TER)--the passage of sucrose, Evans Blue albumin (EBA), and alpha aminoisobutyric acid (AIB) across the BMEC monolayer were assessed in the presence and absence of fentanyl (25-100 ng/ml), methohexital (10-50 micrograms/ml), and thiopental (25-100 micrograms/ml). RESULTS: The permeability of cultured BMEC to the tracers used increased significantly after exposure of the monolayer to arabinose and after removal of calcium ions. Fentanyl, methohexital, and thiopental did not change the permeability of the cell monolayer to ions, sucrose, albumin, and AIB. Only thiopental at the concentration of 100 micrograms/ml increased the flux of AIB. CONCLUSIONS: At the concentrations tested, there is little evidence of changes in the permeability of the in vitro BBB caused by fentanyl, methohexital, and thiopental regarding the para- and transcellular route of ions, sucrose, and albumin. Only thiopental at a concentration of 100 micrograms/ml increased the passage of AIB across the BMEC monolayer. PMID- 7856904 TI - Bupivacaine transfer across the human term placenta. A study using the dual perfused human placental model. AB - BACKGROUND: Bupivacaine is widely used for obstetric analgesia, yet published information on the mechanism of human placental bupivacaine transfer is sparse. The dual perfused human placental model was used to elucidate the factors governing the placental transfer of bupivacaine. METHODS: Bupivacaine transfer was studied using the recirculating (closed) model and the single pass (open) model. Single placental cotyledons were perfused with either heparinized Krebs Ringer's buffer (KRB) supplemented with human albumin (fetal and maternal circuits) or 100% fresh frozen plasma (maternal circuit) to control the bupivacaine protein binding in those circuits. In the open model, bupivacaine clearance was compared before and after being subjected to either increasing concentrations of bupivacaine or its structural analog, mepivacaine. RESULTS: For those studies in which the maternal and fetal protein binding was equal, the maternal to fetal (M-->F) transfer was significantly greater (P < 0.05) than that in the fetal to maternal (F-->M) direction. When the perfusates were modified to simulate actual in vivo plasma protein concentrations, bupivacaine transfer was shown to be related to the degree of protein binding found in the two circuits. In the open studies, bupivacaine transfer was similar at all concentrations investigated, unaffected by mepivacaine, and related to the pH of the fetal perfusate. A concentration effect was seen within the placental tissue at the end of the experiment. CONCLUSIONS: Bupivacaine placental transfer characteristics suggest passive diffusion rather than active drug transport and appear to be influenced by the maternal and fetal plasma protein binding, fetal pH, and placental uptake. PMID- 7856905 TI - Anesthetics and automaticity of dominant and latent atrial pacemakers in chronically instrumented dogs. III. Automaticity after sinoatrial node excision. AB - BACKGROUND: Management of patients with sinus node dysfunction must consider the stability of subsidiary pacemakers during anesthesia and treatment with antimuscarinic or sympathomimetic drugs. Baroreflex regulation of atrial pacemaker function is known to contribute to the interactions between inhalation anesthetics and catecholamines. Sinoatrial (SA) node excision can be a model for intrinsic SA node dysfunction. Subsidiary atrial pacemakers are expected to emerge after SA node excision, but they may respond differently to humoral and neural modulation. Isolated and combined effects of epinephrine and methylatropine should help characterize subsidiary pacemaker function during anesthesia with halothane, isoflurane, and enflurane. METHODS: In eight dogs, SA nodes were excised and epicardial electrodes implanted at the atrial appendages, the His bundle, and along the sulcus terminalis. Spontaneous pacemaker automaticity and subsidiary atrial pacemaker recovery time were measured in the conscious state, in the presence of methylatropine, with 1 and 2 micrograms.kg 1.min-1 epinephrine and during 1.25 and 2 MAC halothane, isoflurane, and enflurane. RESULTS: After SA node excision, a stable and regular subsidiary atrial pacemaker rhythm emerged. Each anesthetic prolonged subsidiary atrial pacemaker recovery times. This prolongation was greater in the presence of methylatropine. Without methylatropine, isoflurane and enflurane, but not halothane, further enhanced the baroreflex-mediated negative chronotropic effects of epinephrine, whereas with methylatropine, each anesthetic reduced the direct positive chronotropic effects of epinephrine. CONCLUSIONS: Halothane, isoflurane, and enflurane have significant depressant effects on the spontaneous and epinephrine-altered automaticity of subsidiary atrial pacemakers. Depression of subsidiary atrial pacemaker automaticity was most apparent in dogs with muscarinic blockade. PMID- 7856906 TI - Halothane and isoflurane decrease the open state probability of K+ channels in dog cerebral arterial muscle cells. AB - BACKGROUND: Both halothane and isoflurane evoke cerebral vasodilation. One of the potential mechanisms for arterial vasodilation is enhanced K+ efflux resulting from an increased opening frequency of membrane K+ channels. The current study was designed to determine the effects of volatile anesthetics on K+ channel current in single vascular smooth muscle cells isolated from dog cerebral arteries. METHODS: Patch clamp recording techniques were used to investigate the effects of volatile anesthetics on macroscopic and microscopic K+ channel currents. RESULTS: In the whole-cell patch-clamp mode, in cells dialyzed with pipette solution containing 2.5 mM EGTA and 1.8 mM CaCl2, depolarizing pulses from -60 to +60 mV elicited an outward K+ current that was blocked 65 +/- 5% by 3 mM tetraethylammonium (TEA). Halothane (0.4 and 0.9 mM) depressed the amplitude of this current by 18 +/- 4% and 34 +/- 6%, respectively. When 10 mM EGTA was used in the pipette solution to strongly buffer intracellular free Ca2+, an outward K+ current insensitive to 3 mM TEA was elicited. This K+ current, which was reduced 51 +/- 4% by 1 mM 4-aminopyridine, was also depressed by 17 +/- 5% and 29 +/- 7% with application of 0.4 and 0.9 mM halothane, respectively. In cell attached patches using 145 mM KCl in the pipette solution and 5.2 mM KCl in the bath, the unitary conductance of the predominant channel type detected was 99 pS. External application of TEA (0.1 to 3 mM) reduced the unitary current amplitude of the 99 pS K+ channel in a concentration-dependent manner. The open state probability of this 99 pS K+ channel was increased by 1 microM Ca2+ ionophore (A23187). These findings indicate that the 99 pS channel measured in cell attached patches was a TEA-sensitive, Ca(2+)-activated K+ channel. Halothane and isoflurane reversibly decreased the open state probability (NPo), mean open time, and frequency of opening of this 99 pS K+ channel without affecting single channel amplitude or the slope of the current-voltage relationship. CONCLUSIONS: Halothane and isoflurane suppress the activity of K+ channels in canine cerebral arterial cells. These results suggest that mechanisms other than K+ channel opening likely mediate volatile anesthetic-induced vasodilation. PMID- 7856907 TI - Halothane selectively inhibits nonshivering thermogenesis. Possible implications for thermoregulation during anesthesia of infants. AB - BACKGROUND: During halothane anesthesia, infants fail to increase oxygen consumption in response to a cold stimulus in the form of an increase in temperature gradient between body and environment. Based on recent observations with isolated brown-fat cells, it seemed feasible that this inability to respond could be due to an inhibition of nonshivering thermogenesis during halothane anesthesia. METHODS: The rate of oxygen consumption was measured in cold acclimated hamsters and rats. The rate evoked by norepinephrine injection in hamsters at an environmental temperature of approximately 24 degrees C was used as a measure of the capacity for nonshivering thermogenesis. Anesthesia was induced by 3% halothane and maintained by 1.5% halothane. One experimental series with spontaneously breathing hamsters and a second control series with spontaneously breathing rats and with rats whose lungs were mechanically ventilated were conducted. RESULTS: Norepinephrine injection led to a fourfold increase in the rate of oxygen consumption in control hamsters; after this response had subsided, a second injection led to a similar effect. Halothane anesthesia caused an approximately 20% decrease in resting metabolic rate (P < 0.05) and a 70% inhibition of the thermogenic response to norepinephrine (P < 0.001). The halothane concentration yielding half-maximal inhibitory effect was estimated to be less than 1.0%. After the animals had recovered from halothane anesthesia, a completely restored thermogenic response to norepinephrine was observed. The inhibitory effect of halothane also was observed in hamsters maintained at normothermia and was therefore not secondary to the slight hypothermia that otherwise developed during anesthesia. In a series of control experiments, it was confirmed that rats also showed large thermogenic responses to norepinephrine injections, and it was found that, in spontaneously breathing halothane-anesthetized rats, the thermogenic response to norepinephrine was also much inhibited. Further, in halothane-anesthetized rats whose lungs were mechanically ventilated, and where blood gases were kept at virtually normal levels, the thermogenic response to norepinephrine was found to be similarly markedly inhibited. CONCLUSIONS: A much diminished or abolished thermogenic response to injected norepinephrine was demonstrated in halothane-anesthetized animals. This implies that there would be a diminished ability to elicit nonshivering thermogenesis even when this process is physiologically induced. Such a diminished ability could in part explain the susceptibility of neonates and infants to hypothermia during halothane anesthesia. PMID- 7856908 TI - Anesthetics affect the uptake but not the depolarization-evoked release of GABA in rat striatal synaptosomes. AB - BACKGROUND: Numerous classes of anesthetic agents have been shown to enhance the effects mediated by the postsynaptic gamma-aminobutyric acid A (GABAA) receptor coupled chloride channel in the mammalian central nervous system. However, presynaptic actions of anesthetics potentially relevant to clinical anesthesia remain to be clarified. Therefore, in this study, the effects of intravenous and volatile anesthetics on both the uptake and the depolarization-evoked release of GABA in the rat striatum were investigated. METHODS: Assay for specific GABA uptake was performed by measuring the radioactivity incorporated in purified striatal synaptosomes incubated with 3H-GABA (20 nM, 5 min, 37 degrees C) and increasing concentrations of anesthetics in either the presence or the absence of nipecotic acid (1 mM, a specific GABA uptake inhibitor). Assay for GABA release consisted of superfusing 3H-GABA preloaded synaptosomes with artificial cerebrospinal fluid (0.5 ml.min-1, 37 degrees C) and measuring the radioactivity obtained from 0.5 ml fractions over 18 min, first in the absence of any treatment (spontaneous release, 8 min), then in the presence of either KCl alone (9 mM, 15 mM) or with various concentrations of anesthetics (5 min), and finally, with no pharmacologic stimulation (5 min). The following anesthetic agents were tested: propofol, etomidate, thiopental, ketamine, halothane, enflurane, isoflurane, and clonidine. RESULTS: More than 95% of 3H-GABA uptake was blocked by a 10(-3)-M concentration of nipecotic acid. Propofol, etomidate, thiopental, and ketamine induced a dose-related, reversible, noncompetitive, inhibition of 3H-GABA uptake: IC50 = 4.6 +/- 0.3 x 10(-5) M, 5.8 +/- 0.3 x 10(-5) M, 2.1 +/- 0.4 x 10(-3) M, and 4.9 +/- 0.5 x 10(-4) M for propofol, etomidate, thiopental, and ketamine, respectively. Volatile agents and clonidine had no significant effect, even when used at concentrations greater than those used clinically. KCl application induced a significant, calcium-dependent, concentration-related, increase from basal 3H-GABA release, +34 +/- 10% (P < 0.01) and +61 +/- 13% (P < 0.001), respectively, for 9 mM and 15 mM KCl. The release of 3H-GABA elicited by KCl was not affected by any of the anesthetic agents tested. CONCLUSIONS: These results indicate that most of the intravenous but not the volatile anesthetics inhibit the specific high-affinity 3H-GABA uptake process in vitro in striatal nerve terminals. However, this action was observed at clinically relevant concentrations only for propofol and etomidate. In contrast, the depolarization evoked 3H-GABA release was not affected by anesthetics. Together, these data suggest that inhibition of GABA uptake, which results in synaptic GABA accumulation, might contribute to propofol and etomidate anesthesia. PMID- 7856909 TI - Hyperglycemia during hypothermic canine cardiopulmonary bypass increases cerebral lactate. AB - BACKGROUND: Hyperglycemia frequently occurs during cardiopulmonary bypass (CPB), although its direct effects on cerebral perfusion and metabolism are not known. Using a canine model of hypothermic CPB, we tested whether hyperglycemia alters cerebral blood flow and metabolism and cerebral energy charge. METHODS: Twenty anesthetized dogs were randomized into hyperglycemic (n = 10) and normoglycemic (n = 10) groups. The hyperglycemic group received an infusion of D50W, and the normoglycemic animals received an equal volume of 0.9% NaCl. Both groups underwent 120 min of hypothermic (28 degrees C) CPB using membrane oxygenators, followed by rewarming and termination of CPB. Cerebral blood flow (radioactive microspheres) and the cerebral metabolic rate for oxygen were measured intermittently during the experiment and brain tissue metabolites were obtained after bypass. RESULTS: Before CPB, the glucose-treated animals had higher serum glucose levels (534 +/- 12 mg/dL; mean +/- SE) than controls (103 +/- 4 mg/dL; P < 0.05), and this difference was maintained throughout the study. Cerebral blood flow and metabolism did not differ between groups at any time during the experiment. Sagittal sinus pressure was comparable between groups throughout CPB. Tissue high-energy phosphates and water contents were similar after CPB, although cerebral lactate levels were greater in hyperglycemic (37.2 +/- 5.7 mumol/g) than normoglycemic animals (19.7 +/- 3.7 mumol/g; P < 0.05). After CPB, pH values of cerebrospinal fluid for normoglycemic (7.33 +/- 0.01) and hyperglycemic (7.34 +/- 0.01) groups were similar. CONCLUSIONS: Hyperglycemia during CPB significantly increases cerebral lactate levels without adversely affecting cerebral blood flow and metabolism, cerebrospinal fluid pH, or cerebral energy charge. PMID- 7856910 TI - Glutamate release from the ovine fetal brain during maternal hemorrhage. A study using chronic in utero cerebral microdialysis. AB - BACKGROUND: Glutamate has been implicated in the pathophysiology of neuronal injury associated with cerebral hypoxia-ischemia. A model using chronic in utero microdialysis was developed to sample the extracellular space of the fetal brain. Using this model, we tested the hypothesis that glutamate efflux from the parasagittal parietal cortex of near-term fetuses would increase during maternal hemorrhage. METHODS: Twelve near-term fetal sheep were instrumented with vascular catheters, and a microdialysis probe(s) was implanted into the parasagittal parietal cortex. After a 3-day recovery period, the animals were subjected to maternal hemorrhage until either the fetal pH was < 7.00 or the fetus died. The extracellular glutamate concentration in the collected dialysate was determined by high pressure liquid chromatography (HPLC). RESULTS: Maternal hemorrhage resulted in an 80-90% decrease in uterine blood flow, a decrease fetal po2, and a mixed metabolic and respiratory fetal acidosis. There were two groups of fetuses, survivors (n = 5) and nonsurvivors (n = 7). The nonsurvivor group showed a large increase (10-30-fold) in peak glutamate release (P = 0.0015). Survivors demonstrated a small (threefold) increase that was not statistically significant (P = 0.065), unless one animal with very low probe recovery was excluded (P = 0.0048). CONCLUSIONS: Extracellular glutamate release from the fetal brain can occur during maternal hemorrhage with fetal acidemia. The pathophysiologic role (if any) of glutamate release in the survivors remains to be elucidated. Our results are consistent with the hypothesis that in utero release of glutamate occurs during periods of fetal asphyxia. This experimental preparation of chronic fetal brain microdialysis can be used to monitor the brain extracellular concentration of any dialyzable substance in response to stress, including maternal hemorrhage. PMID- 7856911 TI - The effect of pentoxifylline on acid-induced alveolar epithelial injury. AB - BACKGROUND: Acid instillation into one lung is known to cause an increase in the permeability of the endothelium to protein in both the instilled and the contralateral lungs. Activated neutrophils are believed to be involved in causing this increased permeability. Pentoxifylline, a drug used in clinical practice, has multiple effects on neutrophils, including inhibition of phagocytosis, degranulation, and superoxide generation. This study investigated whether pretreatment with pentoxifylline would protect the alveolar epithelium or lung endothelium from injury. METHODS: The effect of acid instillation into one lung of anesthetized rabbits using several quantitative parameters was investigated. The quantification of the bidirectional movement of the alveolar (125I-albumin) and the circulating protein tracers (131I-albumin) was used as a measurement of the permeabilities of the lung epithelium and the lung endothelium in the acid instilled lung. Bronchoalveolar lavage and measurement of the entry of the circulating protein tracer were used to assess the permeabilities of these barriers in the noninstilled lung. RESULTS: The instillation of HCl (pH 1.25, 1.2 ml/kg) into the right lung resulted in an increase in the protein permeability of the right lung's alveolar epithelium and endothelium as well as an increase in the permeability to protein of the left lung's endothelium. Pentoxifylline pretreatment attenuated the increase in the endothelial permeability of both lungs by 50% and restored the PaO2/FIO2 to normal in the pretreated animals exposed to acid injury. CONCLUSIONS: Acid aspiration causes a dramatic increase in the alveolar epithelial permeability of the acid-instilled lung, but the permeability of the alveolar epithelium of the contralateral lung remains normal. In contrast, unilateral acid instillation causes an increase in the permeability of the endothelium of both lungs. The increase in endothelial permeability can be attenuated by pretreatment with pentoxifylline administration, and this leads to restoration of normal gas exchange. PMID- 7856912 TI - Coronary vasodilation by isoflurane. Abrupt versus gradual administration. AB - BACKGROUND: Under certain circumstances, isoflurane is associated with coronary artery vasodilation. The objective of the current study was to ascertain whether the rate of administration of isoflurane influences its vasodilating effect in the coronary circulation. METHODS: Seven open-chest dogs anesthetized with fentanyl and midazolam were studied. The left anterior descending coronary artery was perfused via either of two pressurized (80 mmHg) reservoirs; reservoir 1 (control) was supplied with arterial blood free of isoflurane, and reservoir 2 was supplied with blood from an extracorporeal oxygenator, which was provided with 95% O2/5% CO2 gas that passed through calibrated vaporizer. Coronary blood flow (CBF) was measured with Doppler flow transducer. In each dog, isoflurane was administered according to two protocols; abrupt (isoflurane-A) or gradual (isoflurane-G). In isoflurane-A, the left anterior descending coronary artery was switched from reservoir 1 to reservoir 2 after the latter was filled with blood previously equilibrated with 1.4% (1 MAC) isoflurane. In isoflurane-G, the left anterior descending coronary artery was switched to reservoir 2 with vaporizer set at 0% isoflurane; then the vaporizer was adjusted to 1.4% isoflurane, which produced a gradual increase in isoflurane concentration within reservoir 2 that reached a level equivalent to that in isoflurane-A (as evaluated by gas chromatography) by 30 min. CBF during maximally dilating, intracoronary infusion of adenosine served as a reference to assess effects of isoflurane. RESULTS: Isoflurane-A caused marked increases in CBF, which, at constant perfusion pressure, reflected pronounced reductions in vascular resistance. These increases in CBF were 80% of those with adenosine. Although isoflurane-G also caused increases in CBF, the increases were only 45% of those caused by isoflurane-A. CONCLUSIONS: The current findings demonstrate that the extent of coronary vasodilation by isoflurane was not dependent only on its blood concentration but also on the rate at which this blood concentration was achieved; a gradual increase in blood concentration blunted the vasodilator effect. Differences in the rate of administration of isoflurane likely contributed to its widely variable coronary vasodilating effects in previous studies. PMID- 7856913 TI - Hypoxic contraction of isolated rabbit mesenteric veins. Contribution of endothelium and attenuation by volatile anesthetics. AB - BACKGROUND: Acute systemic hypoxia induces mesenteric venoconstriction in intact rabbits in part because of an increase in chemoreflex-mediated sympathetic efferent nerve activity. Inhaled anesthetics attenuate this reflex response. The direct effects of hypoxia on mesenteric veins are unknown. The purpose of the current study was to examine the effects of hypoxia on isolated rabbit mesenteric capacitance veins and to determine the effects of halothane, isoflurane, and enflurane on the responses to hypoxia. METHODS: Isometric tension was measured before, during, and after 10 min of hypoxia in the rings of either quiescent or norepinephrine contracted veins, with or without endothelium. Effects of various pharmacologic agents and volatile anesthetics on the responses to hypoxia were examined. RESULTS: Hypoxia augmented contractions to norepinephrine and phenylephrine only in endothelium-intact veins. The hypoxic response was inhibited by phentolamine (alpha-adrenoceptor antagonist) and abolished in the absence of extracellular Ca2+. There were no effects of propranolol (beta adrenoceptor antagonist), ryanodine (a sarcoplasmic reticulum Ca2+ depleter), indomethacin (cyclooxygenase inhibitor), or nordihydroguaiaretic acid (lipoxygenase inhibitor). L-NAME (an inhibitor of nitric oxide synthase) enhanced basal sensitivity of veins to norepinephrine but had no effect on the response to hypoxia. Nicardipine (a blocker of voltage-gated calcium channels) depressed the hypoxic contraction by 86 +/- 5%, phosphoramidon (an inhibitor of endothelin converting enzyme) by 82 +/- 8%, and BQ-123 (a specific endothelin-1 receptor antagonist) by 47 +/- 10%. Volatile anesthetics (1.0 MAC) inhibited responses to hypoxia in the absence as well as presence of L-NAME. CONCLUSIONS: These results suggest that in mesenteric capacitance veins of rabbits an intrinsic vascular mechanism contributes to endothelium-dependent hypoxic augmentation of contraction to alpha-adrenergic agonists that involve activation of endothelin-1, an endothelium-derived constricting factor. Inhibition of hypoxic contraction by volatile anesthetics is not mediated by endothelium relaxing factor. PMID- 7856914 TI - Effects of sevoflurane on contractile responses and electrophysiologic properties in canine single cardiac myocytes. AB - BACKGROUND: The effects of sevoflurane was examined on the contractile response, membrane potential, membrane ionic currents, and intracellular cyclic adenosine monophosphate (cAMP) in canine single ventricular myocytes. METHODS: Contraction was measured by a video-edge detector, and membrane ionic currents were recorded using whole-cell voltage clamp technique. Intracellular cAMP was measured with radioimmunoassay method. RESULTS: Sevoflurane (1.0-4.0%) decreased the contraction of single ventricular cells in a dose-dependent and reversible manner. Also, sevoflurane decreased the action potential plateau and shortened the duration of action potential. Sevoflurane reduced the peak Ca2+ currents (ICa) but did not show the use-dependent block. On the other hand, sevoflurane slightly reduced the Na+ currents (INa) only at a high concentration (4.0%). Intracellular cAMP concentration was reduced only at 4.0% sevoflurane. CONCLUSIONS: The negative inotropic effect of sevoflurane is mediated via the inhibition of ICa in canine ventricular myocyte but not associated with reduced intracellular cAMP except at a high dose (4.0%). PMID- 7856915 TI - Myocardial effects of propofol in hamsters with hypertrophic cardiomyopathy. AB - BACKGROUND: Propofol is a short-acting intravenous induction agent that induces cardiovascular depression but without significant effect on intrinsic myocardial contractility in various species. However, its effects on diseased myocardium remain unknown. METHODS: The effects of propofol (1, 3, and 10 micrograms.ml-1) on the intrinsic contractility of left ventricular papillary muscles from normal hamsters and those with hypertrophic cardiomyopathy (strain BIO 14.6, aged 6 months) were investigated in vitro (Krebs-Henseleit solution, 29 degrees C, pH 7.40, Ca++ 2.5 mmol.l-1, stimulation frequency 3/min). RESULTS: Cardiac hypertrophy (143 +/- 13%, P < 0.001) was observed in cardiomyopathic hamsters. The contractility of papillary muscles from hamsters with cardiomyopathy was less than that of controls, as shown by the decrease in maximum shortening velocity ( 29%, P < 0.03) and active isometric force (-51%, P < 0.001). Propofol did not induce any significant effect on contraction, relaxation, and contraction relaxation coupling under low and high loads in normal hamsters. The effects of propofol were not significantly different between normal hamsters and those with cardiomyopathy. A slight but significant increase in maximum unloaded shortening velocity was observed in cardiomyopathic hamsters at 3 micrograms.ml-1 (4 +/- 6%, P < 0.05) and 10 micrograms.ml-1 (7 +/- 6%, P < 0.05). CONCLUSIONS: Propofol did not modify intrinsic myocardial contractility in normal hamsters, and no significant differences were observed between normal and cardiomyopathic hamsters. These results may be useful because, unlike propofol, most anesthetics decrease myocardial contractility. Nevertheless, indirect cardiac effects of propofol may be more important than its direct cardiac effects in patients with impaired cardiac function. PMID- 7856916 TI - Effect of vasoconstrictive agents added to lidocaine on intravenous lidocaine induced convulsions in rats. AB - BACKGROUND: Epinephrine is reported to decrease the threshold of intravenous lidocaine-induced convulsions. However, the mechanism underlying this effect is not clear. Therefore, we carried out a study to examine the role of vasopressor induced hypertension. METHODS: Fifty-six awake Wistar rats were assigned to seven groups of eight. All groups received a continuous intravenous infusion of lidocaine at a rate of 4 mg.kg-1.min-1 until generalized convulsions occurred. The control group (group C) received plain lidocaine. The acute hypertensive groups received lidocaine with epinephrine (group E), norepinephrine (group N), or phenylephrine (group P) to increase mean arterial blood pressure (MAP) to 150 +/- 5 mmHg. Sodium nitroprusside (SNP) was added to prevent an increase in mean arterial pressure in the remaining three groups (vasopressor-SNP groups). RESULTS: The acute hypertensive groups required significantly smaller cumulative doses of lidocaine to produce convulsions compared with control (C = 41.5 +/- 2.9 > E = 24.1 +/- 2.7, N = 27.1 +/- 2.8, P = 26.7 +/- 2.5 mg.kg-1; values are mean +/- SD, P < 0.01). In addition, plasma lidocaine concentrations (C = 11.0 +/- 0.7 > E = 7.4 +/- 0.5, N = 7.9 +/- 0.6, P = 8.1 +/- 0.8 micrograms.ml-1, P < 0.01) and brain lidocaine concentrations (C = 50.9 +/- 4.5 > E = 32.6 +/- 4.2, N = 34.5 +/- 4.8, P = 37.1 +/- 4.5 micrograms.g-1, P < 0.01) were less in the acute hypertensive groups at the onset of convulsions. In the vasopressor-SNP groups, the plasma and brain lidocaine concentrations at the onset of convulsions returned to the control values, although epinephrine and norepinephrine, but not phenylephrine, still decreased cumulative convulsant doses of lidocaine significantly (P < 0.01) compared with control (E + SNP = 30.8 +/- 2.9 < N + SNP = 34.8 +/- 2.8, P < 0.01) < P + SNP = 40.2 +/- 3.0 mg.kg-1, P < 0.01). The brain/plasma concentration ratios were similar for the seven groups. CONCLUSIONS: An equal degree of acute hypertension induced by these three different vasopressors may play a role in reducing the threshold (plasma and brain lidocaine concentrations) as well as the cumulative convulsant doses associated with lidocaine-induced convulsions. PMID- 7856917 TI - Hypopharynx perforation by a transesophageal echocardiography probe. PMID- 7856918 TI - Early thrombus formation on heparin-bonded pulmonary artery catheters in patients receiving epsilon aminocaproic acid. PMID- 7856919 TI - Tension pneumothorax presenting as ischemia of the hand. PMID- 7856920 TI - Inhaled nitric oxide improves hepatic tissue oxygenation in right ventricular failure: value of hepatic venous oxygen saturation monitoring. PMID- 7856921 TI - Nonconvulsive status epilepticus as a cause for delayed emergence after electroconvulsive therapy. PMID- 7856922 TI - Large doses of topical lidocaine during microvascular surgery are not associated with toxic blood concentrations. PMID- 7856923 TI - Pulmonary artery catheter migration causing venous cannula obstruction during cardiopulmonary bypass. PMID- 7856924 TI - Failure of the proportioning system to prevent hypoxic mixture on a Modulus II Plus anesthesia machine. PMID- 7856925 TI - Improvement of the accuracy of references in Anesthesiology. PMID- 7856926 TI - More on barbiturate-related hyperalgesia. PMID- 7856927 TI - Intravenous alcohol in 1831. PMID- 7856928 TI - Safekeeping of nasogastric tube connectors. PMID- 7856929 TI - Measurement of cerebral blood flow during hypothermic cardiopulmonary bypass. PMID- 7856930 TI - Laryngeal mask airway and fiberoptic endoscopy in an infant with Schwartz-Jampel syndrome. PMID- 7856931 TI - [Alpha-thalassemia]. AB - alpha-Thalassaemias are probably the most common genetic disorder worldwide. alpha-Thalassaemias are haemolytic anaemias resulting from inherited deficient synthesis of alpha-globin chains. In this paper, the classification and nomenclature of alpha-thalassaemias are developed. Procedures to ensure the laboratory diagnosis are explained. The heterozygous carrier states for these disorders are, in most cases, not associated with any easily discernible change in the haemoglobin pattern, except, sometimes, a reduced MCV in the blood picture. Heterozygotes for alpha-thalassaemia deletions are now detectable by the accurate PCR method. Because of the high prevalence of these disorders in large segments of the world population, alpha-thalassemia and haemoglobinopathies often occur in the same individual. The laboratory features of these interactions and, particularly, the role of alpha-thalassaemia as a potential modulator of sickling haemoglobinopathies are discussed. PMID- 7856932 TI - [Enzymatic determination of sodium, potassium and chloride in plasma]. AB - The Boehringer enzymatic reagents for Na, K and Cl determination on a Hitachi 717 automatic analyser at 37 degrees C were evaluated. Except for Na, the within-run and between-run precision assays gave CV within the SFBC ranges but were higher than those of the comparison analysers: Ektachem 500 Kokak, Dimension Ars Du Pont De-Nemours and flame photometry. The linear ranges were larger than the usual clinical results. Accuracy, estimated from human controls, was 99 to 103% for Na and K, and 105% for Cl. Comparison of plasma from 102 to 152 patients showed a good concordance for sodium with the Dimension ARS (y = 1x + 0). On the contrary, with Ektachem Kodak, differences appeared, particularly for high values (y = 0.91x + 13.6). For potassium, the concordance was good with flame photometry (y = 1x + 0.1) and Ektachem Kodak (y = 0.94x - 0.16). For chloride, comparison was satisfactory except for high values which were underestimated by the enzymatic method: Dimension ARS (y = 1.03x - 4.8), Ektachem Kodak (y = 0.91x + 9.8). The enzymatic methods were very easy to perform and can be adapted on any autoanalyser at 37 degrees C. We conclude that they are suitable for routine clinical determination. Urinary assays are currently being developed. PMID- 7856933 TI - Early detection of antibodies to human immunodeficiency virus 1 by a third generation enzyme immunoassay. A comparative study with the results of second generation immunoassays and western blot. AB - The aim of the study was to examine the sensitivity and the specificity of a HIV 1/HIV-2 third-generation enzyme immunoassay, the Abbott recombinant HIV-1/HIV-2 third-generation enzyme immunoassay, which is reported to detect simultaneously IgG and IgM. Sensitivity was evaluated with sera from seropositive subjects and a series of samples from eight HIV-1 seroconverting subjects. Results were compared with Western blot, second-generation immunoassays (including Vidas HIV-1 + 2) and an HIV-1 antigen assay. Specificity was studied with sera collected from a low risk population and sera with false-reactive enzyme immunoassays results. In seven cases, the third-generation immunoassay detected HIV-antibodies several days earlier (range 4 to > or = 9 days) than the Western blot test according to the criteria proposed by the Association of State and Territorial Public Health Laboratory Directors, ie, positive with two of the three bands-gp160 or gp120, gp41, and p24. In the last case detection occurred at the same time as Western blot. The second-generation tests generally detected HIV-antibodies at the same time as Western blot. Antigaenemia was positive in the first samples tested in most cases, prior to or simultaneously with the Abbott third-generation test first reactivity, before the second generation tests and the Western blot test. In most cases, the disappearance of detectable HIV antigen was observed, and was concurrent with the development of the antibodies immune response. For our low risk population, the current third-generation EIA test obtained a false-reactive rate of 0.26%. Our data indicate that the Abbott third-generation immunoassay is more sensitive than the Western blot test and the second-generation tests. The addition of a third-generation assay to the strategy for HIV-antibody screening may indeed be of interest and could make it possible to decrease the number of false-negative results. PMID- 7856934 TI - [Evaluation of an immunological new kit used in the toxicological screening of benzodiazepines in hospital emergency care units]. AB - Benzodiazepines are mostly used for their antianxiety and sedative effects. In recent years, new compounds have been developed with a hypnotic action. Although marked toxicity is uncommon with the use of these compounds, the clinician requires a rapid laboratory report in emergency and intensive care units in case of self-poisoning. To reduce the incidence of false-negative results routinely observed with our enzyme immunoassay kit (Emit tox benzodiazepine), the performance of a new kit (Emit dau benzodiazepine) was evaluated in 57 patients who had taken an overdose of benzodiazepines. Results were compared with those obtained by high performance liquid chromatography (HPLC) using a diode array detector and giving a semi-quantitative result. Seventy-four percent of the patients studied gave readings above the cut-off value, which was consistent with benzodiazepine intoxication, according to the results of the specific HPLC analysis (bromazepam, triazolam, alprazolam and flunitrazepam were clearly identified). No false negatives were obtained in this study with the Emit dau benzodiazepine. Finally, HPLC is unsuitable in the emergency setting; the enzyme multiplied immunoassay technique is the most appropriate method used in cases of self-poisoning with benzodiazepines having a low therapeutic index. PMID- 7856935 TI - Measuring urinary protein with the new BioRad reagent kit: evaluation and comparison with five other methods. AB - Total urinary protein was measured by five methods: BioRad Total Protein Test (TPT), pyrogallol red, benzethonium chloride, sulfosalicylic acid, trichloroacetic acid, and the results compared to those obtained by a method combining preparative ultrafiltration and the biuret reaction. TPT was linear to 1.5 g protein/l, the detection limit 0.0135 g/l, and it was 3-5 times more sensitive than the other methods. Within-day precision (CV) was 4.3%, (0.60 g/l), the day-to-day precision was 4.5%. The protein contents of 35 selected urine samples assigned to one of five groups according to their electrophoretic pattern were assayed by the five methods. No method accurately measured physiological proteinuria, but the values for light chain (Bence Jones), glomerular, tubular and overload proteinurias measured by TPT did not differ significantly from the biuret value. The other methods differed significantly for at least three groups. Alpha 1 acid glycoprotein slightly inhibited TPT, but peptones, amino acids, antibiotics or normal urine constituents had little or no effect. The TPT method has been automated (Kone Progress); normal 24-h urinary protein excretion was 36 mg/day (range 12-114), the protein creatinine ratio was 34 mg/g (12-106 mg/g). PMID- 7856936 TI - [Physiological variations of LpA1, HDL2 and principal lipid markers in athletes]. AB - An original approach of the influence of physical activities on lipid metabolism is presented in this work: the authors studied the physiological variations of the lipoparticle LpA1, high-density lipoprotein subfraction HDL2 and the most important lipid markers in serum of a presumably healthy population of 55 high level sportsmen. They were 18-45 years old and practised endurance sports, whether individual (cycling, long-distance running), or collective activities (soccer, basketball). The authors observed an important increase of LpA1 (+20%, p < 0.001) and C-HDL2 (+23.3%, p < 0.01) after an intense physical activity (CK = 430 +/- 312 U/l); they also found a good correlation between LpA1 and HDL2 (r = 0.85, p < 0.0001) and between LpA1 and CK (r = 0.62, p < 0.001). PMID- 7856937 TI - [Conclusions of the first French workshop of standardization of anticardiolipin antibody determination associated with autoimmune pathology]. AB - Anticardiolipine antibodies are a marker of the antiphospholipid syndrome. They are detected by Elisa. Despite its simplicity, the results obtained by this assay are not always reproducible despite several worldwide standardizations and the distribution of calibration sera by EN Harris. On 4 December 1992, the First French Anticardiolipin Antibodies Standardization Workshop was held in Paris. Eight coded standards were sent to 33 laboratories in France, one in Switzerland and one in Luxembourg. Some of them used several assays. Agreement between qualitative results was good for samples with high and moderate level of antibodies. But the results expressed in IgG antiphospholipid units were scattered, the interlaboratory coefficient of variation for each of the eight standards was higher than 70%, though the within-run coefficient of variation had a median value of 10%. Assays using bovine serum for the blocking buffer and for the dilution buffer seemed to give more reproducible results than assays using purified bovine serum albumin (p < 0.001). For only nine assays out of 38 which expressed results quantitatively, was a linear regression observed between the dilutions of a sample and the results expressed in IgG antiphospholipid units. Absence of linearity is an obstacle which must be overcome if we wish to compare quantitative results obtained by different laboratories. PMID- 7856938 TI - [Anti-mitochondrial antibodies type 5 are markers of antiphospholipid syndrome]. AB - In order to investigate the clinical value of anti-mitochondrial antibodies type 5 (anti-M5), we carried out a retrospective study on 48 patients with these antibodies. Seventeen of these 48 patients (35%) satisfied at least 4 criteria of the revised American Rheumatism Association classification of SLE. Twenty-nine (61%) had at least one clinical manifestation of anti-phospholipid syndrome; thirteen had symptoms consistent with primary anti-phospholipid syndrome; five had isolated recurrent thrombosis; five had Evans' syndrome; four had auto-immune haemolytic anaemia; two had immunologic thrombocytopenia. Two of the 48 patients had no clinical manifestations, but only anti-M5 and a false laboratory test for syphilis (FBTS). Our data confirm that patients with anti-M5 have a high prevalence of: 1) thrombosis (42% had three or more deep thromboses) and fetal loss (21%); 2) auto-immune cytopenia with idiopathic thrombocytopenic purpura (29%) and auto-immune haemolytic anaemia (54%); 3) laboratory markers of anti phospholipid syndrome (lupus anticoagulant (71%), FBTS (95%) and anticardiolipin antibodies (aCL) (71%). For 32 patients with anti-M5, anti-beta 2 glycoprotein I antibodies were also tested; 12 (38%) were positive, all of whom had IgG aCL, ie none had anti-beta 2GPI antibodies without aCL. There was no association between the presence of anti-beta 2GPI antibodies and recurrent thrombosis among patients with anti-M5. All these findings suggest that anti-M5 is another marker of the antiphospholipid syndrome. Even though the prevalence of anti-M5 is low, especially in SLE, it was the only marker of the anti-phospholipid syndrome in two patients; this appears to justify routine screening for these antibodies. PMID- 7856939 TI - [Antiphospholipid and anti beta 2-glycoprotein I antibodies]. AB - Recent studies have shown that beta 2glycoprotein I (beta 2GPI), a plasma inhibitor of coagulation with affinity for anionic phospholipids, is frequently required for the formation of the epitopes recognized by some anti-phospholipid antibodies. Six murine monoclonal antibodies directed against human beta 2GPI were compared with anti-beta 2GPI antibodies associated with systemic lupus erythematosus and primary anti-phospholipid syndrome. The beta 2GPI-dependent binding properties to neutral and anionic phospholipids were studied, as well as the target epitopes on the beta 2GPI molecule and the effect of various beta 2GPI treatments to get rid of contaminating phospholipids or to block the beta 2GPI phospholipid interaction. The results are in favour of a direct binding of patient's antibodies to beta 2GPI, in the absence of phospholipids. Anti-beta 2GPI monoclonal antibodies, two of which inhibited beta 2GPI recognition by the antibodies from patients, possessed lupus-like anticoagulant properties, thereby constituting an interesting model for a subset (beta 2GPI-dependent) of anti phospholipid antibodies. PMID- 7856940 TI - [A stable and high-titre reference serum for bilirubin assay]. PMID- 7856941 TI - [Role of the determination of serum fructosamine in the screening of glucose intolerance]. PMID- 7856942 TI - [Potassium perchlorate interference in the determination of carbon dioxide using the CHEM 1 analyzer]. PMID- 7856943 TI - Increasing the biosafety of analytical systems in the clinical laboratory. International Federation of Clinical Chemistry (IFCC). PMID- 7856944 TI - [Why are some allergens enzymes?]. AB - In the last ten years, progress in the field of allergy research has led to the purification of some of the major allergens and to a better knowledge of their physico-chemical properties. A number of studies have shown that some allergens have enzymatic activities. Molecular biology has provided the means to clone and sequence genes encoding these allergens and to produce recombinant allergens in yeast and bacteria. Epitope mapping of natural and synthetic allergens, using polyclonal or monoclonal antibodies and cell-stimulation tests, has also contributed greatly to the understanding of their immunogenicity and allergenicity. Analysis of these new data allow us to explain why some allergens are enzymes. PMID- 7856945 TI - Chromatographic separation of eight progesterone receptor isoforms in human breast tumors, and detection by radioligand and monoclonal antibodies. Association with hsp90 and hsp70 heat shock proteins. AB - It has been shown previously that untransformed molybdate-stabilized breast cancer progesterone receptor (PR) complexes can be dissociated by KCl (0.4 to 1M) into eight different intermediate forms, or isoforms (680-600-361-224-193-119-88 52 kDa), separated by high performance size exclusion chromatography and with the use of computer assisted smoothing and deconvolution procedures (H Cren et al [1993] J Chromatogr 615, 23-36). The purpose of this work was to study the constitution of each isoform by using different monoclonal antibodies (mabs) raised against PR-A/B (JZB39 and KD68), against PR-B (PR6 and KC 146), and against hsp90 and hsp70 heat shock proteins (9D2 and Ab72, respectively). The differential recognition of nontransformed molybdate-stabilized PR isoforms by either radioligand (RLA, 3H-Org2058) or by an enzyme immunoassay (PgR-EIA Abbott) showed the presence of two different PR isoforms in the non-dissociated PR heteropolymeric peak eluted from a TSK-3000 SW column. After PR dissociation by 0.4 M KCl and interaction of PR isoforms with the different mabs, the presence of PR-A, PR-B, hsp90 and hsp70 was studied. Results showed that hsp90 was present in isoforms 1 (680 kDa), 2 (600 kDa) and 3 (361 kDa) exclusively, whereas hsp70 remained strongly bound to isoforms 4 (224 kDa) and 5 (193 kDa). Isoforms 6 (119 kDa) reacted with PR6 antibody and represented the PR-B protein, whereas isoform 7 (88 kDa) represented PR-A protein. Isoform 8 (52 kDa) was not detected by mabs and represented a truncated form of PR. Detection of isoform 1 either by RLA or by EIA showed ratios EIA/RLA approximately 1 or 2, and these values suggested that this heteropolymeric form may contain a dimeric structure. From these observations, a model is proposed for the composition of each PR isoform obtained from dissociation of breast tumor PR. PMID- 7856946 TI - Evaluation of the ATB 32C, automicrobic system and API 20C using clinical yeast isolates. AB - The ATB 32C (bioMerieux, Spain), AMS-YBC (Vitek System, bioMerieux, Spain) and API 20C (bioMerieux, Spain) systems were evaluated for their reliability in identifying 100 clinical yeast isolates. The ATB 32C, AMS-YBC and API 20C systems correctly identified 97%, 98% and 100% of the isolates respectively. There were no significant differences in incubation periods between ATB 32C and AMS-YBC systems. One isolate of Candida tropicalis was wrongly identified by the ATB 32C and the AMS-YBC systems. The Saccharomyces cerevisiae isolate was wrongly identified by the ATB 32C system while the AMS-YBC failed to identify it and a third isolate of Candida krusei was wrongly identified by the ATB 32C system. The overall accuracy and rapidity of the ATB 32C and AMS-YBC systems were sufficient to permit recommendation of either of these systems for routine use in the clinical microbiology laboratory, although the first system enjoys the advantages of having a wider data-base and the possibility of manual reading. PMID- 7856947 TI - [Computer-assisted validation system applied to hematology: Valab-hemato]. AB - Validation of laboratory reports is the ultimate step before transmission of results to the clinician. The biologist checks the intrinsic consistency of the data as well as their possible medical value that is liable to lead to other investigations. Such a policy, when performed on all the data, is time-consuming, boring and uncertain. This step may be simplified by the use of a computerized expert system. The computer assisted validation system presented here concerns routine haematology data (Valab-haemato). Like its predecessor devoted to clinical chemistry (Valab-Biochem) it is based on the performance of a powerful inference engine which generates a decision-making tree for each report according to the data. This adaptability gives the system a capacity very close to human reasoning. In its haematology version the system deals with many variables including sex, age, origin of the patient (hospital ward), and the haematological data (blood cell count, differential, reticulocyte count, various information drawn from microscope examination of the blood smear as well as any report concerning the blood sample, erythrocyte sedimentation rate). Previous data are also taken into account, as well as the normal ranges, the values beyond which no result can be automatically validated and the delta-check. Some information definitely prevents validation of the results, others can be validated if they have been previously approved. Whereas the method of reasoning is fixed, all items are changeable in order to adapt the system to the type of activity of the laboratory.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7856949 TI - Quality system in the medical laboratory: the role of a quality manual. AB - A quality system for a medical laboratory should be directed on all fundamental aspects of its function. This implies the obligation to join the External Quality Assessment schemes, and to make use of its results. It means the setting-up of a quality system according to a medical translation of the items of the EN 45001 standard. And it means taking into account such professional aspects as registration and post-doctoral education, regular contacts with physicians and paying special attention to the suitability of tests. This whole process can be instituted on the basis of an ISO 9000 approach, which means specific standards for the medical laboratories, and inspection, in which the professionals should play an important role. The use of a quality manual facilitates the whole process. It should eventually lead to an accreditation system for medical laboratories. Cooperation in Europe on these aspects is important. An overview is given on the way the system works in the Netherlands. PMID- 7856948 TI - Oxidative modification of protein structures under the action of myeloperoxidase and the hydrogen peroxide and chloride system. AB - Myeloperoxidase of neutrophilic leukocytes (MPO) at pH 4.0 to 6.5 mediated oxidation of Cl- ions, yielding hypochloride (OCl-) which then reacted with amino acids and polypeptides. Thiol and thioether groups may be oxidized to disulfide or to sulphoxides and sulphonic acids respectively. Tryptophanyl residues yielded 2-oxoindole. Epsilon amino groups of lysine produced chloramine which, however, decomposed, yielding aldehyde residues. Bovine serum albumin treated with MPO-Cl H2O2 system yielded derivatives with a decreased affinity to antialbumin antibodies and increased electrophoretic mobility. Albumin aldehyde derivatives were also obtained. At H2O2 molar ratio with albumin 20:1, a precipitation of albumin occurred, due to the formation of new polymeric albumin derivatives. The lysozyme (LZM) lost its enzyme activity when 1.4 to 1.8 mol of H2O2 per 1 mol of LZM was used. Addition of H2O2 above molar ratio 5:1 produced LZM polymerization to di-, tri-, tetra and pentameric derivatives. IgA exposed to the MPO-Cl-H2O2-Cl system split into light chains (molecular weight: 25.8 kDa), heavy chains (molecular weight: 81.8 kDa) and a third polypeptide which size was half the light chain size (molecular weight: 13.9 kDa). The IgA exceeding the HOCl ratio 1:350 (mg/mumol) produced both precipitation and degradation of the IgA polypeptide structure. The treatment of IgG with HOCl released a fragment corresponding to half the light chain size, the light chain, and the heavy chain, whereas HOCl treatment of IgM released only a fragment which size was smaller than the heavy chain and another fragment which size was the same as the light chain. The MPO-Cl-H2O2 system produced many specific changes in protein structures.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7856950 TI - [Determination of alcoholemia by the Emit ST method. Comparison with the gas chromatography method]. PMID- 7856951 TI - [Research of meprobamate in emergency toxicology: identification in urine]. PMID- 7856952 TI - IFCC methods for the measurement of catalytic concentration of enzymes. Part 8: IFCC method for lactate dehydrogenase (L-lactate: NAD+ oxidoreductase, EC 1.1.1.27). PMID- 7856953 TI - [Reference values of serum ferritine in adults]. PMID- 7856954 TI - [Etiopathogenic bases of insulin-dependent diabetes]. PMID- 7856955 TI - Survey finds loss of RNs jeopardized patient safety. PMID- 7856956 TI - Newsletter tracks needlestick injuries. PMID- 7856957 TI - A new message to Congress. PMID- 7856958 TI - Oncology nursing: the toughest job you'll ever love. PMID- 7856959 TI - Waging a battle against cancer pain and fatigue. PMID- 7856960 TI - Partnerships at work. PMID- 7856961 TI - Continuing education program. Integrating an understanding of sleep knowledge into your practice. Part 2. Helping people manage primary insomnia (continuing education credit). PMID- 7856962 TI - Survey assesses RN management of genetic information. PMID- 7856963 TI - NIH must value nursing's contribution. PMID- 7856964 TI - Whatever happened to nursing? (and where in the world is my key ring?) PMID- 7856966 TI - Thoracoscopy for spontaneous pneumothorax 2.10 version with bleb stapling and pleurectomy. AB - A series of 25 Thoracoscopy procedures were performed for spontaneous pneumothorax over the past 2 1/2 years. The indications for the procedure were recurrent pneumothorax or choice of patient for definitive care. The procedure developed over the period of 2 1/2 years, and the procedure included a thoracoscopy, stapling of apical blebs, and apical pleurectomy. The complication rate was 3% and limited to local wound problems. There was one recurrent pneumothorax in a patient who did not have the pleurectomy as a part of the procedure. This was early on in the experience, when it was felt that pleural abrasion would be adequate. Since that time, a formal apical pleurectomy has been done with each of these procedures. No further recurrences have been noted over the 2 1/2 year period of time. The procedure includes one port at the anterior axillary line, fifth intercostal space, one port in the axilla, third intercostal space, and one port in the midclavicular line, fourth intercostal space. A 30 degree and angled scope is sometimes used for better visualization. The Endo GIA (US Surgical or equivalent Ethicon stapler) is used to staple the blebs, and the pleurectomy is done through the two non-video ports. PMID- 7856965 TI - Latex allergies on the rise among health care workers. PMID- 7856967 TI - The laparoscopic approach reduces the endocrine response to elective cholecystectomy. AB - The purpose of this study was to prospectively determine and compare the effect of laparoscopic cholecystectomy (LC) versus open cholecystectomy (OC) on the neuroendocrine response to surgical trauma. Twenty-three evenly matched patients were assigned to either OC (11) or LC (12). Plasma concentrations of norepinephrine (NEPI), epinephrine (EPI), dopamine (DOPA), total catecholamine (TCAT), cortisol, and glucose were measured before and up to 9 hours after skin incision. Compared with preoperative values, significant (P < 0.05) increases in the plasma concentrations of catecholamines, cortisol, and glucose occurred shortly after skin incision following both LC and OC. Compared to post-incision values for OC patients, the increases in NEPI (3-9 hrs), EPI (2-9 hrs), DOPA (1-9 hrs), cortisol (4-9 hrs) and glucose (4-9 hrs) were significantly (P < 0.05) less following LC. Levels of these stress indicators returned to baseline by 4-5 hrs after LC but remained elevated for 9 hrs after OC. The laparoscopic approach results in a significantly reduced neuroendocrine response to surgical trauma following cholecystectomy. The laparoscopic technique may be the best surgical approach in critically ill patients requiring cholecystectomy or other intraabdominal procedures. PMID- 7856968 TI - Abdominal stab wound protocol: prospective study documents applicability for widespread use. AB - Traditionally, stab wounds violating the abdominal wall fascia led to exploratory celiotomy that was often nontherapeutic. In an attempt to limit the number of nontherapeutic celiotomies (NTC), we devised a protocol to prospectively study stab wounds violating the anterior abdominal wall fascia. Through protocol, abdominal stab wounds were explored in stable adults. If the anterior fascia was violated, paracentesis and, if necessary, peritoneal lavage was undertaken in the absence of previous abdominal surgery. If evisceration was noted, it was reduced and the patient lavaged. Fascial penetration was noted in 72 patients. 46 patients underwent celiotomy: because of shock/peritonitis in 8 (2 NTC), fascial penetration with a history of previous celiotomy in 7 (5 NTC), positive paracentesis in 20 (5 NTC), or positive lavage in 10 (4 NTC). One patient underwent late celiotomy without ill-effect after a negative lavage because she subsequently developed fever and localized peritonitis (ice pick injury to cecum). Eleven patients had evisceration; nine underwent celiotomy. Patients with abdominal stab wounds can be selectively managed safely. More than one-third with fascial penetration, some with evisceration, avoided exploration. Only one patient underwent delayed celiotomy and did so without detriment. Nontherapeutic celiotomy rates were highest in patients with previous abdominal surgery who, thereby, could not undergo paracentesis/lavage; excluding these patients, the nontherapeutic celiotomy rate was 17% (11/65) for those with fascial penetration. PMID- 7856969 TI - Missed pathology following laparoscopic cholecystectomy: a cause for concern? AB - Although many have recorded the incidence of complications after laparoscopic cholecystectomy, few have discussed the possibility of missing intra-abdominal pathology after this procedure. We have evaluated the first two years, September 1990-September 1992, of laparoscopic cholecystectomy in our community. Readmissions within 10 months of the original surgery with another diagnosis similar to gallbladder disease were considered "missed pathology" at the original surgical procedure. For the first 12-month period, 465 laparoscopic cholecystectomies were performed. Seventy-seven patients were readmitted, with 13 of these patients having other intra-abdominal pathology. These readmissions were for carcinoma (6), inflammatory bowel disease (2), diverticular disease, esophageal varices, and appendicitis. In the second year 429 laparoscopic cholecystectomies were performed; 59 patients were readmitted, with 10 of these patients having other intra-abdominal pathology. These readmissions were for carcinoma (3), inflammatory bowel disease (2), strongyloides, peptic ulcer disease, and abdominal pain of unknown etiology (3). Although intra-abdominal pathology was found in only 2%-5% of all patients having surgery for gallbladder disease, of the patients who were readmitted for "missed pathology," 46% the first year and 30% the second year were readmitted for carcinomas. Several other diseases were found in patients whose symptoms mimicked gallbladder disease. It is therefore possible that in the zeal to perform a new procedure, other diagnoses may be overlooked. PMID- 7856970 TI - Inflammatory breast cancer. AB - Inflammatory breast cancer has historically carried a poor prognosis. This has led to the development of multimodal protocols in an attempt to improve survival. Twenty-three women were treated for inflammatory breast cancer at our institution between 1979 and 1992. The mean age at diagnosis was 55.8 years (40 to 77 years). Eighteen women (78%) presented clinically with an erythematous or swollen and tender breast, and 19 (80%) had pathologically demonstrated dermal lymphatic invasion. Five (21.7%) had evidence of distant metastasis at the time of presentation. Treatment consisted of modified radical mastectomy in 65% of patients in combination with preoperative or postoperative chemotherapy. The most common chemotherapeutic regimen was 5-Fluorouracil, Adriamycin, and Cyclophosphamide. Eleven women (48%) also received chest wall irradiation (4,200 to 6,000 cGy). Eleven women had classic multimodality therapy (surgery, chemotherapy, and radiation therapy). Median survival is 23.4 months (6 to 77 months). We concluded that with combination therapy, selected patients can experience long-term survival; however, overall prognosis remains poor, with eventual disease recurrence and death resulting from the disease. PMID- 7856971 TI - Partial portal decompression alleviates thrombocytopenia of portal hypertension. AB - Thrombocytopenia due to splenic sequestration of platelets occurs commonly in patients with portal hypertension. Partial portal decompression for bleeding esophagogastric varices, via the small diameter H-graft portacaval shunt (HGPS), is intended to partially decompress the portal system below bleeding threshold but also to maintain a degree of portal hypertension sufficient to maintain prograde portal perfusion. This study was undertaken to determine whether the reduction of portal pressures seen in patients undergoing HGPS is sufficient to relieve the thrombocytopenia seen in patients with portal hypertension. A total of 74 patients underwent small diameter HGPS for bleeding esophagogastric varices not amenable to medical management. Thirty-four (46%) patients had thrombocytopenia (platelet count < 80,000/mL) before shunting. Platelet counts were obtained preshunt, at discharge, and from 1 to 3 years after shunting. Portal pressures decreased significantly from 30mm Hg +/- 5.6 (SD) pre shunt to 19mm Hg +/- 5.8 (SD) after shunting (P < 0.001). Platelet counts increased from a pre-shunt value of 61,000/mL +/- 2,700 (SEM) to a platelet count of 139,000/mL +/ 21,800 (SEM) at discharge (P < 0.006) and to 102,000/mL +/- 17,500 (SEM) 1 to 3 years after shunting (P < 0.001). Patients undergoing portasystemic shunting for bleeding esophagogastric varices are frequently thrombocytopenic. Partial portal decompression using the 8 mm HGPS is sufficient to alleviate thrombocytopenia associated with portal hypertension immediately following HGPS and for years to follow. The presence of thrombocytopenia does not preclude the use of partial portal decompression in patients with bleeding varices requiring operative intervention. PMID- 7856972 TI - Selective management of pediatric esophageal foreign bodies. AB - Esophageal foreign body is a relatively common consultation from the Pediatric Emergency Room. This study evaluates optimal selective management of esophageal foreign bodies in the pediatric patient. Eighty-six children have been referred for esophageal foreign body. Fifteen had been symptomatic for 48 or more hours before being seen. In eight, there was a known history of previous repair for esophageal atresia. In 88%, the foreign body was opaque, most frequently a coin. The most common nonopaque foreign body was retained food. Upon diagnosis, 72 children were taken to radiology, where balloon extraction under fluoroscopic control was attempted. Fourteen children went directly to the operating room for endoscopy and foreign body removal. Balloon extraction was successful in 62 cases (86%), and the children were discharged directly from the Emergency Department. The foreign body was successfully removed at esophagoscopy in the 10 cases that failed attempts at balloon extraction. Since 1990, successful extraction has been accomplished in 100% of cases (29/29). Neither balloon extraction nor endoscopy was associated with morbidity or mortality. Endoscopy was, however, associated with total hospital charges approximately 400% higher than balloon extraction. Fluoroscopically guided balloon extraction of appropriate esophageal foreign bodies is a safe and cost-effective alternative to endoscopy. Failure of nonoperative management does not complicate subsequent endoscopic removal. Patients with symptoms > 48 hours, a history of prior esophageal atresia, and/or nonopaque esophageal foreign bodies do not preclude attempt at balloon extraction. PMID- 7856973 TI - Malrotation in the older child: surgical management, treatment, and outcome. AB - Malrotation in the neonate is an anomaly for which there are clear indications for surgery. However, the management of the older patient with this entity is not well defined. At Arkansas Children's Hospital, we reviewed our patients who were older than two years of age with malrotation. Between 1978 and 1993, 22 cases ages 2-23 years were identified. The most common presenting symptoms were vomiting 15 (68%), colicky abdominal pain 12 (55%), and diarrhea 2 (9%). Other symptoms were hematemesis 1 (5%), and constipation 1 (5%). The duration of symptoms averaged 28 months, range 2-96 months. All diagnoses were made by upper gastrointestinal (UGI) series, except for one that was recognized during an exploratory laparotomy for an intestinal duplication. A Ladd's procedure with appendectomy was performed in all cases. A significant number of patients in our series (41%) were found to have either a volvulus or internal hernia at exploration that was not clearly demonstrated by the diagnostic studies. Intestinal resection was performed in two patients for ischemic bowel. There were no perioperative deaths. Postoperative complications consisted of a wound infection in one patient. Total relief of symptoms occurred in 64% of patients. All patients with volvulus or internal hernia had resolution of symptoms, and all patients reported partial relief of their chronic symptoms. Surgical therapy eliminates the possibility of loss of bowel from volvulus or internal hernia, which is not always evident on diagnostic radiographic examination. Surgery is also highly effective in alleviating the chronic symptoms in these children. We believe, therefore, that surgical treatment is clearly indicated in the older child with proven malrotation. PMID- 7856974 TI - Venous injury: to repair or ligate, the dilemma revisited. AB - Controversy continues over management of major venous injuries. The records of 322 patients with venous injury were reviewed. Isolated venous injury was present in 83 patients; 54 (65%) underwent ligation of the injured vein. Combined arterial and venous injuries were present in 239 patients; 170 (71%) patients had ligation. Injured were the inferior vena cava, iliac, femoral, popliteal, distal leg, and arm veins; all were confirmed at surgery. Arterial injuries were repaired with standard techniques; venous injuries were ligated or repaired by end-to-end or lateral phleborrhaphy. Adjunctive fasciotomy was used as clinically indicated. The patients were followed an average of 32 months. No patient with isolated venous injury developed permanent sequelae, although 29 (35%) had transient extremity edema. Transient edema developed in 86 (36%) patients with combined injury, and permanent edema occurred in 4 (2%). Edema developed regardless of vein injury ligation or repair. No extremity was lost after venous injury ligation. While repair of all venous vascular injuries is still the surgical ideal, in civilian practice permanent sequelae of venous injury ligation are rare and in patients with hemodynamic instability from blood loss, extensive local injury, associated organ injury, anesthesia requirements, or other concerns venous ligation is acceptable. PMID- 7856975 TI - Occult vascular injuries following gunshot wounds resulting in long bone fractures of the extremities. AB - The routine use of arteriography following penetrating injuries to the extremities has declined in popularity in recent years. A careful physical examination coupled with Doppler-derived blood pressure has been shown to be sufficient to determine the presence of significant vascular injuries in most circumstances. Evaluating for occult vascular injuries in the presence of a complex wound involving the fracture of a long bone, however, seems to be an exception to this trend in management. This study was undertaken to ascertain the incidence of occult versus clinically apparent vascular injuries in patients suffering gun shot wounds (GSW) to the extremities that were associated with a long bone fracture. To address the value of invasive arteriographic evaluation, physical examination (pulse palpation, Doppler-derived limb blood pressure) was compared to arteriography in 75 consecutive patients following a GSW that resulted in fracture of the tibia/fibula (n = 28), femur (n = 19), humerus (n = 17), or radius/ulna (n = 11). Fourteen patients (19%) had an abnormal physical examination, with 13 (93%) of these also having an abnormal arteriogram. Of the 61 (81%) patients with a normal physical examination, an occult vascular injury was found on subsequent arteriography in 17 (28%). These occult injuries were classified as minor (intimal flap less than one-fourth the diameter of the vessel, segmental narrowing, noncritical branch vessel injury) or major (large intimal flap, occlusion, pseudoaneurysm, A-V fistula). The majority (83%) of occult injuries were minor and did not require operative intervention.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7856976 TI - Predictive value of AMES scoring system in selection of extent of surgery in well differentiated carcinoma of thyroid. AB - The extent of surgical resection continues to be controversial for treatment of well-differentiated thyroid carcinoma (WDTC). It has been proposed that age, distant metastases, extent, and size (AMES) are prognostic indicators for WDTC. In this retrospective study, the role of AMES in selection and extent of surgical resection was evaluated. A total of 155 patients with WDTC treated between 1970 and 1990 at this institution were reviewed. The mean follow-up was 9 years. Patients were divided into low risk (Group A), and high risk (Group B) based on AMES. Group A had 141 patients, and Group B had 14 patients. Ninety-eight patients underwent total or subtotal thyroidectomy; 87 of these were in Group A and 11 in Group B. Fifty-seven patients had lesser surgical resection (53 lobectomy and isthmusectomy, three excision of nodule, and one needle biopsy). Five of the 11 in Group B who had more extensive surgery and none of 3 who had lesser surgery have died of their disease. Three patients in Group A have died of WDTC, of which two had total thyroidectomy and one had lobectomy with isthmusectomy. This study suggests that conservative resection is an adequate treatment in low risk patients based on AMES. This treatment may be enough for high risk patients, although the number of patients is small to make definitive recommendations. PMID- 7856977 TI - Molecular oncology and the surgeon. AB - The last 20 years have witnessed a flood of new developments and discoveries in the fields of molecular biology and oncology. Dozens of human genes associated with cancer predisposition syndromes and the malignant and metastatic process have been identified and characterized. These findings have led to a greater understanding of this complex disease and inaugurated a new era of investigations seeking more effective diagnostic protocols and therapies. This review summarizes a few of the many salient discoveries and discusses the clinical implications for the surgeon. PMID- 7856978 TI - Fibromuscular dysplasia of the brachial artery: an endovascular approach. AB - Fibromuscular dysplasia (FMD) is a nonatherosclerotic segmental disease of unknown etiology primarily affecting muscular arteries of intermediate size. The pathology affects the renal arteries in the majority of cases, followed by the carotid, vertebral, and ilio-femoral arteries. There have been only six reported cases of FMD involving the brachial artery. This case report describes the seventh case and illustrates an endovascular approach to this clinical entity. A 63-year-old female with a history of hypertension presented to vascular surgery clinic with a 4-day history of numbness, pain, and coolness of her left hand. On physical exam, the patient had a normal axillary and brachial pulse, but had only a Doppler signal of the left ulnar artery. There was no Doppler signal of the radial artery. Segmental pressures and PVR waveforms were normal in the upper arm, but there was a significant blunting of the waveform and decrease in pressure at the level of the wrist. An arteriogram revealed significant narrowing and irregularity of the brachial artery with a characteristic "string-of-beads" appearance. There was complete thrombosis of the radial artery and evidence of fresh thrombus in the distal brachial artery. The patient was treated with intra arterial infusion of urokinase with restoration of the radial pulse and resolution of her symptoms. Subsequently, the patient had a percutaneous transluminal balloon angioplasty of the involved segment of brachial artery, with normal PVR's and segmental pressures upon completion. FMD of the brachial artery and its sequelae are extremely rare, and therefore, there is no consensus on proper management.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7856979 TI - Biloma and biliary fistula following hepatorraphy for liver trauma: incidence, natural history, and management. AB - From 1986-1992, more than 6250 patients were admitted to a Level I Trauma Center, with 175 patients requiring hepatorraphy. Eleven patients (6%) developed either a biloma (1), biliary fistula (2), or both (8 patients). Patients' ages ranged from 15-40 years with a mean Injury Severity Score of 23. Seven patients (64%) suffered penetrating injury and four (36%) were victims of blunt trauma. The right lobe was injured in 10 patients (91%), with one patient (9%) sustaining left lobe injury. All liver injuries were either grade 3 (seven patients, 64%) or grade 4 (four patients, 36%). No patient sustained extrahepatic biliary tract injury. Bilomas and fistulas were diagnosed 14-30 days post injury (mean 24 days) by CT and HIDA scans. All were managed by CT-guided percutaneous drainage. One patient also required percutaneous transhepatic cholangiography with biliary stent placement due to bile ascites. Fistulas persisted from 5-120 days (mean 44 days). No patient required further operative intervention and all fistulas closed spontaneously without complication. PMID- 7856981 TI - Crucial anatomic lessons for laparoscopic herniorrhaphy. AB - Laparoscopic herniorrhaphy is generally performed using a transabdominal approach, an approach to hernia repair that is unfamiliar to most general surgeons. There is sufficient published anecdotal experience to indicate that the relationships of structures near the internal ring are not generally known and that this may predispose to their injury. There is considerable variability of nerves that pass through, or deep to, the iliopubic tract lateral to the internal inguinal ring, making it potentially hazardous to place staples or sutures in this region. Medially, the surgeon must be conscious of the possible presence of an aberrant obturator artery or vein and unexpected iliopubic vessels and take appropriate precautions to avoid unexpected sources of hemorrhage. The human cadaver, especially in the unfixed state, can be an ideal model to learn the surgical anatomy for laparoscopic hernia repair and to avoid neurovascular injuries. PMID- 7856982 TI - Optimal exposure for hepatobiliary operations using the Bookwalter self-retaining retractor. AB - With the increasing application of hepatic resections for both primary and metastatic tumors and the growth of liver transplantation, safe and reliable exposure to all surfaces of the liver is routinely required. In the past, many surgeons thought the resection of hepatic lesions, especially those located in the posterior right lobe of the liver, required a thoraco-abdominal incision for adequate exposure. However, the Bookwalter retractor, together with the bilateral subcostal incision with extension in the midline to the xiphoid, provides outstanding exposure to the upper quadrants of the abdomen and all surfaces of the liver. We found that certain technical details of its use provided superior exposure during more than 158 hepatic resections and orthotopic liver transplantations in a 36 month period at Vanderbilt University Medical Center. No thoracotomies were required. Only a few patients noted transient postoperative costal pain, and there have been no significant complications with the use of this system. This retractor provides optimal exposure for hepatic operations without the need for thoracotomy. It is versatile and easy to use, decreasing manpower use, time, and cost. By providing steady, unobstructed exposure to all surfaces of the liver, this system facilitates the procedure and increases safety for the patient. PMID- 7856980 TI - Laparoscopic cholecystectomy in children with sickle cell disease. AB - Since 1991, laparoscopic cholecystectomy has been utilized in children with sickle cell disease, predominantly because of the decreased pain and shorter hospitalization. We believe that outpatient laparoscopic cholecystectomy or even a 24 hour hospitalization is not indicated in the patient with sickle cell disease. Perioperative complications include bleeding diathesis, vaso-occlusive phenomena, and delayed hemolytic transfusion reactions, although clotting parameters can be normal. PMID- 7856983 TI - Octreotide versus pyloric exclusion in reducing gastrointestinal secretions entering the duodenum in a canine model. AB - Pyloric exclusion is advocated in the treatment of duodenal injury. The beneficial effect is thought to be due to diversion of gastric secretions and resultant reduction of biliary and pancreatic secretions. The long-acting somatostatin analog, Octreotide, makes the inhibitory actions of somatostatin on gastric, biliary, and pancreatic secretions a potential alternative to pyloric exclusion. We compared the effect of pyloric exclusion to the effect of Octreotide on the volume of gastrointestinal secretions entering the duodenum by creating a duodenal fistula using a canine model. Five animals had modified Thomas cannulas placed in the duodenum. Two animals had staple closure of the pylorus with a gastrojejunostomy in addition to the cannula. Gastrointestinal secretions were measured in 2- or 3-hour collection periods performed every third or fourth day. Animals were administered saline or Octreotide (100 micrograms/hour) intravenously during each collection. Up to 9 hours of collections under both saline and Octreotide (18 hours total) were done on each dog. Octreotide alone reduces gastrointestinal secretions entering the duodenum more than pyloric exclusion alone. Pyloric exclusion and Octreotide together offered no additional reduction in gastrointestinal secretions entering the duodenum over Octreotide alone. PMID- 7856984 TI - Use of the inferior epigastric artery to revascularize a lower pole renal artery in renal transplant. AB - The increasing use of living-related donors has increased the incidence wherein the transplant surgeon is required to use special vascular surgical techniques to transplant kidneys with anomalous arterial anatomy. One of the most commonly encountered arterial anomalies is the presence of a lower pole renal artery. In many cases, this artery can be anastomosed to the main renal artery, and the main renal artery can then be anastomosed into the recipient vessel. However, there are cases where the lower pole renal artery is too distant from the main renal artery to allow an anastomosis to be performed. The lower pole renal artery of the graft must be revascularized to avoid ischemic injury to the ureter. Thus, alternate methods for the revascularization of this vessel must be found. We describe the use of the recipient inferior epigastric artery as an arterial supply for the donor lower pole artery. In our case report, this method provided excellent flow to the lower kidney and was documented by later studies. PMID- 7856985 TI - Diagnostic laparoscopy for suspected appendicitis. AB - One hundred consecutive patients who underwent diagnostic laparoscopy for suspected appendicitis were evaluated to assess the appropriate clinical setting for laparoscopic appendectomy. The usefulness of diagnostic laparoscopy in the setting of acute abdominal pain has been well documented. However, there is debate about the use of laparoscopy for definitive therapy. The purpose of this study is to evaluate the decision making process during diagnostic laparoscopy for suspected appendicitis. When pathology is identified other than in the appendix, the majority of patients can be treated without converting to an open procedure. In patients found to have no obvious pathology, incidental appendectomy can be performed laparoscopically. When appendicitis was identified, the majority of patients could be treated safely without converting to an open technique. However, there were certain clinical situations that necessitated conversion to an open operation. Involvement of the cecum or perforation at the base of the appendix puts the appendiceal stump at risk for leak and abscess formation. Evaluation of the cecum by palpation for a mass should also be performed in this situation. Another situation in which conversion to an open technique is warranted is an appendiceal abscess with adherent small bowel. The friability of bowel wall greatly increases the risk for bowel injury in this setting. Laparoscopy is a useful technique for the diagnosis and treatment of abdominal pain even if the appendix is normal on inspection. Conversion to an open operation should be employed when inflammation or perforation occurs at the base of the appendix and when bowel is found to be adherent to an appendiceal abscess. PMID- 7856986 TI - The identification and mapping of melanoma regional nodal metastases: minimally invasive surgery for the diagnosis of nodal metastases. AB - The most controversial part of melanoma surgical care involves the role of elective lymph node dissection (ELND). Whereas proponents cite retrospective studies demonstrating the ability to control regional metastases and more accurate staging, opponents cite the unnecessary morbidity of a complete node dissection for the majority of patients. The technology of sentinel node mapping and selective lymphadenectomy, defined as the identification and removal of the first node into which the primary melanoma drains, may revolutionize melanoma care. If the sentinel node is negative, then theoretically the remainder of the nodes should also be negative (no "skip" metastases), and a complete lymphadenectomy would not be required to control occult nodal disease. The location of the sentinel node may be variable in the lymphatic basin. Ideally, the surgeon needs a map of the position of the sentinel node in reference to the other nodes in the basin in order to do the procedure under local anesthesia with small incisions. In this way, patients are subjected to minimal morbidity and the procedure can be performed as an out-patient. Twenty-nine patients with clinically negative nodes and melanomas greater than 0.76 mm in thickness were judged to be candidates for ELND. Preoperative lymphoscintigraphy in two planes was used to mark the sentinel node, and the patients were taken to the operating room for intraoperative lymphatic mapping and sentinel node biopsy followed by complete dissection.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7856987 TI - Zidovudine resistance and HIV-1 disease progression during antiretroviral therapy. AIDS Clinical Trials Group Protocol 116B/117 Team and the Virology Committee Resistance Working Group. AB - OBJECTIVE: To evaluate the association between resistance of human immunodeficiency virus type 1 (HIV-1) to zidovudine and clinical progression. DESIGN: Retrospective analysis of specimens from patients in the AIDS Clinical Trials Group (ACTG) protocol 116B/117, a randomized comparison of didanosine with continued zidovudine therapy in patients with advanced HIV-1 disease who had received 16 weeks or more of previous zidovudine therapy. SETTING: Participating ACTG virology laboratories. PATIENTS: 187 patients with baseline HIV-1 isolates. MEASUREMENTS: Zidovudine susceptibility testing and assays for syncytium-inducing phenotype were done on baseline HIV-1 isolates. Relative hazards for clinical progression or death associated with baseline clinical, virologic, and immunologic factors were determined from Cox proportional hazards regression models. RESULTS: Compared with other patients, 15% (26 of 170) with isolates showing high-level zidovudine resistance (50% inhibitory zidovudine concentration > or = 1.0 microM) had 1.74 times the risk for progressing to a new AIDS-defining event or death (95% CI, 1.00 to 3.03) and 2.78 times the risk for death (CI, 1.21 to 6.39) in analyses that controlled for baseline CD4+ T-lymphocyte count, syncytium-inducing HIV-1 phenotype, disease stage, and randomized treatment assignment. The clinical benefit of didanosine was not limited to patients with highly zidovudine-resistant baseline HIV-1 isolates. CONCLUSIONS: High-level resistance of HIV-1 to zidovudine predicted more rapid clinical progression and death when adjusted for other factors. However, patients with advanced HIV-1 disease may benefit from a change in monotherapy from zidovudine to didanosine whether high-level HIV-1 resistance to zidovudine is present or absent, and laboratory assessment of zidovudine resistance is not necessary for deciding when to switch monotherapy from zidovudine to didanosine. PMID- 7856988 TI - Bone density in non-insulin-dependent diabetes mellitus. The Rotterdam Study. AB - OBJECTIVE: To investigate the relation between non-insulin-dependent diabetes mellitus and bone mineral density at the lumbar spine and hip. DESIGN: Population based study with a cross-sectional survey. SETTING: A district of Rotterdam, the Netherlands. PARTICIPANTS: 5931 residents (2481 men, 3450 women) of the district aged 55 years or more. MEASUREMENTS: Participants were classified as having non insulin-dependent diabetes mellitus if they were receiving antidiabetic medication or if they had a serum glucose level of 11.1 mmol/L or more after a nonfasting oral glucose tolerance test. Bone mineral density, measured at the lumbar spine and proximal femur using dual-energy x-ray absorptiometry and the frequency of nonvertebral fractures during the preceding 5 years were compared between persons with and without non-insulin-dependent diabetes mellitus. RESULTS: 243 men and 335 women had non-insulin-dependent diabetes mellitus. Both men and women with this condition had substantially higher mean bone mineral density values at all four sites measured than those with normal glucose tolerance. The increase could not be explained by age; obesity; use of estrogens, thiazides, or loop diuretics; impairment in abilities of daily living; smoking; or osteoarthritis. Women with non-insulin-dependent diabetes mellitus reported having had fewer fractures in the 5 preceding years than women without this condition (adjusted odds ratio, 0.63; 95% CI, 0.44 to 0.90). The frequency of fractures in men was similar for those with and without non-insulin-dependent diabetes mellitus (adjusted odds ratio, 0.96; CI, 0.60 to 1.52). CONCLUSIONS: Men and women with non-insulin-dependent diabetes mellitus have increased bone mineral density. Non-insulin-dependent diabetes mellitus in women is associated with a lower frequency of nonvertebral fractures. PMID- 7856989 TI - The association between the quality of inpatient care and early readmission. AB - OBJECTIVE: To determine whether the quality of care during a hospital stay is associated with unplanned readmission within 14 days. DESIGN: Case-control study. SETTING: 12 Veterans Affairs hospitals. PATIENTS: Men discharged after a hospitalization for diabetes (n = 593), chronic obstructive lung disease (n = 1172), or heart failure (n = 748). The ratio of controls (men without an unplanned readmission within 14 days to any Veterans Affairs hospital) to cases (men with such a readmission) was 3:1. MAIN OUTCOME MEASURES: Unplanned readmission to any of the 159 Veterans Affairs hospitals within 14 days of discharge. Quality of care during the index stay was assessed by chart review using disease-specific explicit criteria for the process of inpatient care, which were developed by panels composed of expert physicians. Adherence scores (the percentage of applicable criteria that were met) were calculated for the admission workup, evaluation and treatment, and readiness for discharge. RESULTS: After adjustment was made for demographic characteristics, severity of illness, and need for care, adherence scores correlated with early unplanned readmission (P < 0.05). For patients with diabetes and heart failure, decreased readiness-for discharge adherence scores correlated with increased risk for readmission (P = 0.001 and P = 0.016, respectively). In patients with obstructive lung disease, decreased admission-workup scores correlated with increased risk for readmission (P = 0.013). One of 7 readmissions in patients with diabetes, 1 of 5 readmissions in patients with heart failure, and 1 of 12 readmissions in patients with obstructive lung disease were attributable to substandard care. CONCLUSIONS: Lower quality of inpatient care increases the risk for unplanned early readmission in patients with heart failure, diabetes, or obstructive lung disease. Under certain circumstances, readmission is associated with remediable deficiencies in the process of inpatient care. PMID- 7856990 TI - Documentation and evaluation of cognitive impairment in elderly primary care patients. AB - OBJECTIVE: To describe the prevalence of cognitive impairment among elderly primary care patients and to compare diagnostic evaluations and use of health services among patients with and those without cognitive impairment. DESIGN: Prospective cohort study. SETTING: Academic primary care group practice. PATIENTS: 3954 patients aged 60 years and older who completed the Short Portable Mental Status Questionnaire during routine office visits. MEASUREMENTS: Demographics and comorbid illness at baseline, diagnostic evaluations for cognitive impairment, use of standard and preventive health services, use of psychoactive drugs, and death in the year after the screening date. RESULTS: The prevalence of cognitive impairment among all patients aged 60 years and older at baseline was 15.7%; 10.5% had mild impairment and 5.2% had moderate to severe impairment. Patients with moderate to severe impairment were significantly older than patients with no impairment (76.2 years and 67.4 years, respectively), were more likely to be black (85.8% and 61.3%), had fewer years of education (7.3 years and 9.2 years), and were more likely to have cerebrovascular disease (20.4% and 6.3%) and evidence of undernutrition (30.6% and 16.9%). Dementia was recorded as a diagnosis for less than 25% of patients with moderate to severe cognitive impairment, but patients with documented impairment were more likely to have been evaluated for reversible causes. In the year after screening, patients with moderate to severe impairment were more likely than those with no impairment both to be hospitalized (29.1% and 16.5%) and to visit the emergency department (55.8% and 38.5%) but had fewer outpatient visits (6.0 and 7.6) and greater mortality (8.2% and 2.8%). CONCLUSIONS: Cognitive impairment is associated with increased use of health services and increased mortality. Patients with undocumented cognitive impairment were significantly less likely to be evaluated for reversible causes. Research is needed to determine if better documentation of cognitive impairment would improve not only diagnostic evaluations but also patient management, counseling, and outcomes. PMID- 7856991 TI - Postmenopausal estrogen therapy and the risk for developing systemic lupus erythematosus. AB - OBJECTIVE: To examine the relation between postmenopausal hormone use and development of systemic lupus erythematosus. DESIGN: Prospective cohort study. SETTING: Nurses' Health Study. PATIENTS: 69,435 women aged 30 to 55 years in 1976 who reported that they had completed menopause and did not have systemic lupus erythematosus or any connective tissue disease were followed every 2 years from 1976 to 1990. These women were classified as never- or ever-(current and past) users of postmenopausal hormones. MEASUREMENTS: Incidence rates of systemic lupus erythematosus and classification criteria from the American College of Rheumatology that were confirmed by chart review. RESULTS: With never-users of postmenopausal hormones as the reference group, age-adjusted relative risks for systemic lupus erythematosus (n = 45 women) were 2.1 (95% CI, 1.1 to 4.0) for ever-users, 2.5 (CI, 1.2 to 5.0) for current users, and 1.8 (CI, 0.8 to 4.1) for past users. A proportional increase in the risk for systemic lupus erythematosus was observed that was related to the duration of use of postmenopausal hormones (test for trend, P = 0.011). CONCLUSIONS: Postmenopausal hormone therapy is associated with an increased risk for developing systemic lupus erythematosus. PMID- 7856992 TI - Failure of information as an intervention to modify clinical management. A time series trial in patients with acute chest pain. AB - OBJECTIVE: To test whether a low-intensity, nonintrusive intervention improved the efficiency of management of patients with acute chest pain. DESIGN: Time series trial with six 14-week cycles, each including a 5-week intervention period and a 5-week control period separated by 2-week "washout" periods. SETTING: Urban teaching hospital. PATIENTS: 1921 patients aged 30 years or older with acute chest pain unexplained by local trauma or chest radiograph. INTERVENTION: Risk estimates and triage recommendations were made available to physicians at the time of emergency department evaluation and, for hospitalized patients, on a daily basis before morning rounds. Flowsheets and stickers, but no direct human contact, were used to transmit this information. MEASUREMENTS: Rates of admission to the hospital and coronary care unit, inpatient costs, and lengths of stay. RESULTS: Rates of admission during intervention and control periods were similar in both the hospital (52% and 51%, respectively) and the coronary care unit (10% and 10%, respectively). Total lengths of stay in the hospital were similar (4.9 +/- 5.9 days and 4.9 +/- 5.7 days, respectively), as were average total costs ($7822 +/- $13,217 and $7955 +/- $13,400, respectively). No differences in management were detected for the subgroup of patients with low clinical risk for acute myocardial infarction. CONCLUSIONS: The use of information alone--without direct human contact--did not affect management of patients with acute chest pain at this hospital. Although this low-intensity intervention might be more effective for other conditions and in other settings, our data support the use of other strategies to affect physician decision making. PMID- 7856993 TI - Incontinence in the nursing home. AB - Urinary and fecal incontinence are prevalent, disruptive, and expensive health problems in the nursing home population. Nursing home residents who are incontinent of urine should have a basic diagnostic assessment, including a focused history and bladder record, a targeted physical examination, a urinalysis, and a determination of postvoid residual urine volume done by catheterization or ultrasonography. Potentially reversible conditions, such as fecal impaction and drug side effects, should be identified and treated. Selected residents should have further urodynamic evaluation or other diagnostic tests. Prompted voiding, a simple, noninvasive behavioral intervention, is effective in managing daytime urinary incontinence in one quarter to one third of incontinent nursing home residents. If it is to be effective over a long period of time, this intervention must be targeted to those residents most likely to respond. Selected nursing home residents will benefit from other behavioral interventions, drug therapy, or surgery. Because of the morbidity associated with it, long-term catheterization should only be used for specific indications. Like urinary incontinence, fecal incontinence may be caused by potentially reversible conditions. After such conditions have been excluded, fecal incontinence can generally be managed effectively by avoiding fecal impaction and by using a systematic bowel-training protocol. PMID- 7856994 TI - Practice guidelines and malpractice litigation: a two-way street. AB - OBJECTIVE: To understand how practice guidelines are used in malpractice litigation. DESIGN: Review of the open and closed malpractice claims of two medical malpractice insurance companies, and a mailed survey of attorneys who litigate malpractice claims. SETTING: United States. PARTICIPANTS: Two insurance companies and 960 randomly selected malpractice attorneys. MEASUREMENTS: Frequency and nature of the use of practice guidelines in litigation; understanding and frequency of the use of practice guidelines by attorneys in malpractice cases. RESULTS: 259 claims opened in 1990-1992 at two insurance companies, including all obstetrics and anesthesia claims and a random sample of other claims, were reviewed. Seventeen of these claims involved practice guidelines, which were used as exculpatory evidence (exonerating the defendant physician) in 4 cases and as inculpatory evidence (implicating the defendant physician) in 12 cases. The only physician or patient factors associated with use of a guideline was a longer physician-patient relationship (P = 0.021). Nine hundred and sixty surveys were mailed and 578 were returned (response rate, 60.1%). Attorneys reported that once a suit is initiated, practice guidelines are likely to be used for inculpatory purposes (inculpatory in 54% of cases; exculpatory in 22.7% of cases). However, guidelines that seem to offer exculpatory value induce attorneys not to bring suits. The only attorney factor associated with increased use of guidelines was a practice in which more than 50% of business was in medical malpractice. CONCLUSIONS: Guidelines are used both by plaintiffs' and defendants' attorneys in malpractice cases. The emphasis in health reform proposals on guidelines as exculpatory evidence should be carefully considered. PMID- 7856995 TI - Elixirs, diluents, and the passage of the 1938 Federal Food, Drug and Cosmetic Act. AB - The Elixir Sulfanilamide disaster of 1937 was one of the most consequential mass poisonings of the 20th century. This tragedy occurred shortly after the introduction of sulfanilamide, the first sulfa antimicrobial drug, when diethylene glycol was used as the diluent in the formulation of a liquid preparation of sulfanilamide known as Elixir Sulfanilamide. One hundred five patients died from its therapeutic use. Under the existing drug regulations, premarketing toxicity testing was not required. In reaction to this calamity, the U.S. Congress passed the 1938 Federal Food, Drug and Cosmetic Act, which required proof of safety before the release of a new drug. The 1938 law changed the drug focus of the Food and Drug Administration from that of a policing agency primarily concerned with the confiscation of adulterated drugs to a regulatory agency increasingly involved with overseeing the evaluation of new drugs. The Elixir Sulfanilamide tragedy, its effect on drug regulations, and the history of other diethylene glycol and diluent mass poisonings are discussed. PMID- 7856996 TI - No-fault and enterprise liability: the view from Utah. PMID- 7856997 TI - Will hepatitis A become a vaccine-preventable disease? PMID- 7856998 TI - Beyond MICRA: new ideas for liability reform. American College of Physicians. AB - The existing medical liability system does not work. It does not deter negligence, provide timely compensation to injured persons, or resolve disputes fairly. Studies show that a large percentage of injured patients are not compensated and that physicians feel vulnerable to a lawsuit whether or not they practice high-quality medicine. The arbitrariness and inefficiency of the system disrupts the physician-patient relationship, increases health care costs, and, in some cases, hurts access to care. As a result, comprehensive changes to the liability system must be made. The American College of Physicians makes the following recommendations. 1. Congress should immediately pass the tort reforms contained in the California Medical Injury Compensation Reform Act (MICRA), particularly caps on noneconomic damages, as necessary short-term changes to a flawed system. 2. Federal legislation should be enacted that overturns recent court decisions that have relied on the Employee Retirement Income Security Act of 1974, a federal law that regulates pensions and other benefit plans, to bar plaintiffs from suing their health plan for negligence if the plan's benefits or treatment decisions lead to an injury. 3. Demonstration projects should be created and funded to examine the feasibility of using a set of caps for noneconomic damage awards that are based on the severity of injury suffered and the injured party's age. A set of caps could be seen as fairer to injured persons than flat caps but would still protect physicians from unlimited awards. 4. Demonstration projects should be authorized and funded to test enterprise liability and no-fault systems. These systems could take many forms, including administrative approaches; lists of accelerated compensation events; "early offer of settlement" approaches; and organizational liability for health plans, hospitals, or health systems. Such long-term reforms are consistent with trends in health care delivery and are necessary to promote quality of care, compensate injured persons, and protect physicians. PMID- 7856999 TI - Eradication of hepatitis C virus after interferon-alpha therapy. PMID- 7857000 TI - Eradication of hepatitis C virus after interferon-alpha therapy. PMID- 7857001 TI - Triglyceride levels in sons of patients with coronary artery disease. PMID- 7857002 TI - Pituitary adenomas. PMID- 7857003 TI - Pituitary adenomas. PMID- 7857004 TI - Smoking while wearing a nicotine patch. PMID- 7857005 TI - Study of internal medicine manpower XX. PMID- 7857006 TI - Study of internal medicine manpower: XX. PMID- 7857007 TI - Adult immunizations 1994. PMID- 7857008 TI - Historical perspectives on psychotherapy. PMID- 7857009 TI - Christine Ladd-Franklin's color theory: strategy for claiming scientific authority? PMID- 7857010 TI - Recurrent pleomorphic adenoma of the parotid gland: report of 126 cases and a review of the literature. AB - The records of 126 patients with recurrent pleomorphic adenoma of the parotid gland treated at our institution from 1965 to 1985 were retrospectively reviewed. Multiple variables were analyzed to determine tumor behavior and treatment results. Of the study patients, 61% were female and 39% male, with a mean age of 35.6 years at the time of treatment at our institution. The average follow-up period was 14.5 years. Tumor recurrence was 32.5% after one operation at our institution, 7.1% after two operations, and 1.6% after three. Malignant disease occurred in 9 (7.1%) patients. After all surgical procedures, partial facial nerve paralysis was noted in 13.5% and total paralysis in 5.5%. These results suggest low morbidity and good success in tumor eradication with an aggressive surgical approach. PMID- 7857011 TI - Management of posterior cranial fossa meningiomas. AB - Posterior cranial fossa meningiomas are relatively common extra-axial tumors with important relationships to the cochleovestibular system, facial nerve, and/or cranial base. Nevertheless, objective reporting of auditory and vestibular function is rare for this patient population, and a full discussion of the nonsurgical management is all but totally discounted in the otolaryngology literature. Nine cases (8 operative cases) are presented, with the purpose of correlating neurotologic function with precise anatomic tumor location, available by magnetic resonance imaging and computed tomography. The usefulness of this information for diagnosis and meaningful scrutiny of the operative results is discussed. A comprehensive review of posterior fossa meningiomas in terms of epidemiology, etiology, and pathology, as well as nonsurgical treatment alternatives, is provided. PMID- 7857013 TI - Surface morphology of the endolymphatic duct in the rat. A scanning electron microscopy study. AB - Following intracardiac vascular perfusion fixation of 8 rats with glutaraldehyde in a buffered and oxygenated blood substitute, the vestibular aqueduct and endolymphatic duct were opened by microsurgery of the resulting 16 temporal bones. Optimum preservation of the epithelium for scanning electron microscopy was attained by coating of the specimens with osmium tetroxide and thiocarbohydrazide followed by a continuous dehydration procedure. This technique permitted, for the first time, an investigation of the surface morphology of the epithelial cells in the endolymphatic duct. Three types of cells were identified with the scanning electron microscope. A polygonal and oblong epithelial cell was observed in the largest number throughout the duct, and in the juxtasaccular half of the duct, two additional types of epithelial cells were observed. The scanning electron microscopic observations are compared and discussed with reference to previous transmission electron microscopic studies of the endolymphatic duct. PMID- 7857012 TI - Glutathione in the upper respiratory tract. AB - Glutathione (GSH), a major extracellular antioxidant, has been found in high concentrations in the epithelial lining fluid of the lower respiratory tract. The GSH concentrations in nasal fluid, in normal and pathologic conditions, were investigated and found to be very low. A GSH aerosol (600 mg daily for 10 days) increased GSH levels in the nasal mucosa and induced a statistically significant improvement in nasal obstruction, rhinorrhea, and ear fullness. Thus, GSH administered by aerosol could be a means of defending the epithelial respiratory cells against a toxic oxidant. PMID- 7857015 TI - Peritonsillar abscess: an unlikely cause of necrotizing fasciitis. AB - Cervical necrotizing fasciitis is a devastating polymicrobial soft tissue infection characterized by gas formation and extensive necrosis of subcutaneous fat and fascia with extension to skin and muscle. Involvement of the head and neck is rare and is typically dental in origin. Despite broad-spectrum antibiotics, mortality rates for this disease remain high. We report a successfully treated case of necrotizing fasciitis arising from a peritonsillar abscess. Review of the literature reveals only 6 other cases, with 3 successful outcomes. Early diagnosis, broad-spectrum antibiotics, and aggressive surgical debridement are the cornerstones of therapy. The pathophysiology is typically a mixed aerobic and anaerobic infection. Supportive treatment options such as hyperbaric oxygen therapy and high-calorie supplemental nutrition may be of benefit. A comprehensive literature review of craniocervical necrotizing fasciitis is presented. Factors associated with poor outcomes include diabetes mellitus, mediastinitis, cardiovascular disease, and peritonsillar abscess. PMID- 7857014 TI - Revascularization of a salvage supraglottic laryngectomy. Preliminary report. AB - After supraglottic laryngectomy, particularly if there has been a large preoperative dose of radiotherapy, significant ischemia at the suspension anastomosis site may ensue. Neovascularization may play a major role in the healing of this salvage horizontal laryngectomy anastomosis. We have analyzed the process of angiogenesis and neovascularization from a fascial flap in a case of salvage supraglottic laryngectomy. PMID- 7857016 TI - Histologic investigation of the macula flava of the human vocal fold. AB - An investigation was carried out to determine the histologic structure of the maculae flavae of human adult vocal folds. Excised human adult larynges served as the materials for this study. Light microscopic, scanning, and transmission electron microscopic observations were made. The results are summarized as follows. 1) The maculae flavae are located at the anterior and posterior ends of the bilateral vocal folds. Vocal fold ligaments run between the anterior and posterior maculae flavae. 2) The maculae flavae are elliptical in shape and about 1.5 x 1.5 x 1 mm in size. 3) The maculae flavae are composed of fibroblasts, elastic fibers, collagenous fibers, and ground substance. 4) Fibroblasts in the maculae flavae synthesize, and occasionally engulf, the elastic and collagenous fibers. 5) The maculae flavae seem to control the synthesis of fibrous components in the vocal ligament. PMID- 7857017 TI - Intervascular smooth muscle fibers and muscular bolsters in nasal swell bodies of humans. AB - There is strong clinical evidence that the cavernous tissue (swell bodies) of nasal mucosa plays an important role in congestion of the nose. Still, the complex mechanisms responsible for the unique behavior of these vessels have not yet been identified, and even the morphology of these structures is still a matter of controversy. The present study was performed on nasal mucosal specimens from inferior turbinates of humans by means of histology and transmission electron microscopy. Besides the evaluation of the vascular wall structure of the nasal swell bodies, special attention was given to two morphological peculiarities: intervascular smooth muscle fibers and muscular bolsters. Intervascular smooth muscle fibers are composed of bundles of smooth muscle cells varying in diameter between 14 and 35 microns; they are attached to the muscular coat of the vessels of the cavernous tissue. Muscular bolsters are distinct protrusions of the vascular wall in nasal swell bodies; they are found not only at the transition between different vessels, but also irregularly within the course of veins of the cavernous tissue. The authors report on their understanding of the functional significance of intervascular smooth muscle fibers and muscular bolsters within the cavernous tissue for swelling mechanisms in the nose and discuss their results in light of the literature. PMID- 7857018 TI - Disturbance of regulation of sodium by cis-diamminedichloroplatinum in perilymph of the guinea pig cochlea. AB - We studied the acute effects of cis-diamminedichloroplatinum (CDDP) on the cochlear partition and inner ear fluid in the guinea pig. At 48 hours after the administration of a single intramuscular injection of CDDP, 12.5 mg/kg of body weight, the endocochlear resting potential (EP) was significantly decreased to 32.1 +/- 1.8 mV in the treated animals, versus 80.6 +/- 1.0 mV in the control animals. There was a significant rise in potassium (K+), sodium (Na+), and chlorine (Cl-) in the endolymph of the animals treated with CDDP as compared with the control animals. Only Na+ was found to increase significantly in the perilymph, reaching more than twice the level of the control animals; both K+ and Cl- remained within the normal range. Serum electrolytes also remained within the normal range. Evaluation of modified ionic permeabilities across the endolymph perilymph barrier showed an apparent increase in Na+ permeability and a normal range of K+ and Cl- permeabilities. Histopathologic examination of the cochlea showed a moderate collapse of the endolymphatic space, with atrophy of the stria vascularis and destruction of the outer hair cells. The findings suggest that the acute changes produced in the cochlea by administration of CDDP were attributable to a breakdown in the regulation of Na+ metabolism in the perilymph. PMID- 7857019 TI - Degeneration of vestibular sensory cells caused by ablation of the vestibular aqueduct in the gerbil ear. AB - The vestibular aqueduct of the gerbil has a unique anatomic feature that makes it possible to selectively obliterate the endolymphatic sac with or without interfering with its venous drainage. In animals in which only the endolymphatic sac was ablated, endolymphatic hydrops was slight in the cochlea and was absent in the vestibular labyrinth. The cochlear and vestibular sensory cells were normal. In animals in which both the endolymphatic duct and the vein were obliterated, hydrops was slight, with the exception of a few cochleas that showed moderate hydrops. The sensory cells of the posterior canal cristae had degenerated in all specimens, while varied pathologic changes in cochlear and vestibular sensory cells were present in some specimens. These results suggest that hydrops is primarily due to blockage of the endolymphatic duct and sac and that degeneration of sensory cells occurs when blood flow in the vestibular aqueduct is impeded. Pathologic changes in the endolymphatic sac, including the vascular plexus at the endolymphatic sac, may play an important role in the production of endolymphatic hydrops and vestibular symptoms in Meniere's disease. PMID- 7857020 TI - Sinus within a sinus: a mammoth extramural ethmoid air cell. PMID- 7857021 TI - Sialoadenitis: a rare but well-recognized complication of iodinated glycerol. PMID- 7857022 TI - Computed tomographic detection of necrotizing soft tissue infection of dental origin. PMID- 7857023 TI - Pituitary gland involvement of the sinonasal tract. AB - Involvement of the upper aerodigestive tract by a pituitary adenoma is due either to downward extension of an intracranial tumor or to a tumor arising from ectopic (Rathke's pouch) remnants. Sites of predilection for the ectopic adenoma are headed by the sphenoid bone and sinus, followed by the soft tissue of the dorsal pharynx and clivus. Both invasive sellar and ectopic adenomas can be destructive, with the extracranial extension of pituitary adenomas being more locally aggressive. There have been no examples of metastasizing ectopic pituitary tumors. PMID- 7857024 TI - Laryngeal hamartoma: a rare congenital abnormality. AB - Hamartoma is a rare congenital abnormality of the larynx that must be considered in the differential diagnosis of benign lesions of the larynx. Presenting symptoms may include changes in voice, eating, and activity levels, and respiratory complaints. We treated a 2 1/2-year-old boy with an 8-month history of upper airway compromise. Radiographic studies showed a rounded, right-sided, supraglottic soft tissue mass. Direct laryngoscopy revealed a well-mucosalized, encapsulated, firm 3 x 2.5-cm mass that originated from the right supraglottic structures. The mass was excised endoscopically. Histologic examination revealed a hamartoma. At 18 months, the patient has had an uneventful postoperative course. PMID- 7857025 TI - Head and neck manifestations of eosinophilia-myalgia syndrome. AB - Eosinophilia-myalgia syndrome (EMS) is a multisystemic disease that occurs in patients who have consumed products containing L-tryptophan. Prominent features include incapacitating myalgias, arthralgias, neuropathies, and eosinophilia. Despite the frequent association of dysphagia, dyspnea, and the potential for aspiration, the otolaryngology literature is devoid of information on EMS. In order to determine the frequency of otolaryngic symptoms, questionnaires were distributed to patients with EMS in 33 different US states. Among the 28 various head and neck manifestations studied, 70% of EMS patients complained of generalized muscle spasms, 66% xerostomia, 62% dyspnea, and 56% dysphagia. In addition, the epidemiology, clinical presentation, diagnostic criteria, and treatment options are discussed. This paper assesses the frequency of otolaryngic manifestations of EMS, as well as introduces this syndrome to the otolaryngologist-head and neck surgeon. It is important for the otolaryngologist to be aware of EMS and its manifestations and treatments so that patients with this potentially lethal disease can receive appropriate evaluation and expeditious treatment. PMID- 7857026 TI - [Human articular chondrocyte culture. Value in pharmacotoxicology]. AB - Inflammatory and degenerative joint diseases are a major health problem of today. Research is aimed at understanding the processes that bring about degeneration and at the pharmacotoxicological studies of new compounds. Articular cartilage is a connective tissue consisting of an organized extracellular matrix, composed of collagen and proteoglycan aggregates, in which chondrocytes are embedded. Chondrocyte culture has been developed since 1971. However, the use of human chondrocytes for pharmacotoxicology studies is much more recent. The effect of agents can be studied on a number of aspects of chondrocyte metabolism. The most studied are: cell proliferation, proteoglycan degradation and release of matrix proteolytic enzymes or cytokines in the culture medium. Several types of chondrocyte culture can be used for in vitro studies. Organ culture of cartilage slices permits investigation on intact tissue. Chondrocytes can also be released from the articular tissue by serial enzymatic digestions and cultured in a monolayer or tridimensional system. Monolayer culture is easy to set up and allows the culture of large amounts of cells. However, this type of culture is hindered by the phenotypic instability of the chondrocytes. Culture in suspension or within a gel (agarose, collagen) or alginate beads is more suitable for the maintenance of the differentiated phenotype. Chondrocyte immortalization by transfection with oncogenes has been described, but the immortalizing agent still needs to be improved to permit the maintenance of some differentiative properties. The most studied agents are non-steroidal anti-inflammatory drugs. Chondroprotective drugs should also be mentioned. The type of chondrocyte culture for pharmacotoxicological study should be chosen keeping in mind the expected goals of the research undertaken. PMID- 7857027 TI - Synthesis and separation of optically active compounds. Part I. AB - Biological processes involve a high degree of stereoselectivity. Considering that pharmacological activity is very often associated with only one enantiomer, regulation authorities have defined new guidelines in requiring chiral drugs to be marketed as pure individually safe and effective enantiomers. If large scale production of pure stereoisomers has met until recently a great difficulty to become economically acceptable, the current state of the art in asymmetric synthesis and chiral separation, provides however many industrial applications. Among the methods currently used, asymmetric synthesis, using chiral auxiliaries or chiral catalysts such as enzymes or metal complexes, allows to create new asymmetric centers, starting from prochiral molecules. Regarding racemate resolution, asymmetric synthesis offers the real economical advantage to produce exclusively the targeted enantiomer. However, resolution methods allowing access to both enantiomers, are very useful at preparative scale for new chiral drugs when preclinical studies are requested for each enantiomer. Large scale racemate resolution can be achieved by crystallization, enzymatic resolution and even more recently by liquid chromatography. Although the "unwanted" enantiomer is also produced, the feasibility of its racemization for recycling has made resolution methods widely used in industry. It is clear today that in most cases, pharmacologically active molecules having an asymmetric center will have to be marketed as optically pure drugs. PMID- 7857028 TI - [Particle state: divided solids and functionality]. AB - Physical and physico-mechanical properties of powder particles, in the field of pharmacy, as drugs, excipients, microparticles and so on... are one of the main element in quality of dosage forms. The aim of this work is to insist on the importance of packing and rheological properties of divided solids and on his influence on compacting behaviour in drug development and industrial process, to avoid difficulties due to the variability of physical properties batch to batch. But as the physical quality of material raw is induced up to the crystallization operation, it is necessary to know, before, what use it will be done. PMID- 7857029 TI - [International harmonization of regular requirements for the registration of drugs: necessity, frena limitations]. AB - Considering the necessity of internationalisation, the Pharmaceutical Industry fears the regulatory variations that may result from national evolutions, parallel or divergent, which sometimes impose on it some repeated works, hence causing an undesirable extension of development duration and also higher costs. Therefore it is quite evident to that Industry that a worldwide harmonization is necessary. For the whole collectivity, such an harmonization allows a better utilization of manpower, of animal experimentation, and also of the material means available for the new pharmaceutical products development. The strong interest showed by the Pharmaceutical industry in France for the International regulatory harmonization, confirms that this Profession has effectively taken into account the worldwide dimension for the medicinal products of the year 2000. PMID- 7857030 TI - [Maurice Vigneron (1904-1993)]. PMID- 7857031 TI - [Contrast products in magnetic resonance imaging]. AB - Contrast agents MRI (Magnetic Resonance Imaging) have been developed to improve the diagnostic information obtained by this technic. They mainly interact on T1 and T2 parameters and increase consequently normal to abnormal tissues contrast. The paramagnetic agents which mainly act on longitudinal relaxation rate (T1) are gadolinium complexes for which stability is the main parameter to avoid any release of free gadolinium. The superparamagnetic agents that decrease signal intensity by an effect on transversal relaxation rate (T2) are developed for liver, digestive and lymph node imaging. Many area of research are now opened for optimal use of present and future contrast agents in MRI. PMID- 7857032 TI - [Demonstration of molecular combinations of alpha cyclodextrin (ACD) with dioctanoyl glycerol]. AB - The molecular association of dioctanoyl glycerol (DOG) with the natural alpha cyclodextrin molecule (ACD) was studied using small unilamellar vesicles (SUV) by proton and 13C NMR. While no classic inclusion complex was found, a molecular association exists, leading to the formation of an insoluble precipitate. The possibility of a polar head group implication is discussed about the dimyristoyl phosphatidyl choline model. PMID- 7857033 TI - Synthesis and separation of optically active compounds. Part II. AB - This review is the second part of an article devoted to the synthesis and separation of optically active compounds. This article deals mainly with chiral chromatography which represents an important component of the state of art for the preparation of enantiomers, as illustrated by a description and a classification of the main packing materials available to date. The various phases are based on different principles of molecular recognition and show advantages and drawbacks according to the molecules to separate. The preparative aspect of this method is particularly emphasized here and in the same context, trends and future developments are mentioned. PMID- 7857034 TI - [Plant poisoning cases in Turkey]. AB - In Turkey, the majority of the population live in rural areas where they use wild plants as food and medicine. The confusion of an edible plant with a poisonous one give rise to serious poisoning which may even result in death. The incidence of plant poisoning in Turkey is about 6% and especially high among children between ages of 2 and 11 living in rural areas. The number of species that cause poisoning is around twenty and Hyoscyamus niger (Solanaceae), Colchicum species (Liliaceae), Conium maculatum (Umbelliferae) and Prunus species (Rosaceae) are the most important. Mushroom poisoning is more frequent in spring and fall. The main reasons are their widespread usage as food and the inexperience of the gatherers in distinguishing the edibles from the poisonous. Amanita phalloides, A. verna, A. muscaria, A. pantherina are responsible for severe cases of poisoning. PMID- 7857035 TI - [Vaccinal prospect in cancerology]. PMID- 7857036 TI - [Drugs in Europe]. PMID- 7857037 TI - [Raoul Mestre (1903-1993)]. PMID- 7857039 TI - Endoscopic mandibular angle surgery: a swine model. AB - The improvement of endoscopic technology has revolutionized surgery, and endoscopy has become a trend in recent years. In plastic surgery, endoscopic release of the carpal tunnel and endoscopic face-lifting have been used clinically. However, no report has been noted that deals with the bone of the face. Using pigs as the animal model, endoscopic resection of the mandibular angles was undertaken. The result was satisfactory; it appears that it can also be effective in humans. PMID- 7857038 TI - Early clinical experience in endoscopic-assisted muscle flap harvest. AB - Two cases of endoscopic-assisted muscle harvest for lower extremity reconstruction are presented. Each case involved resurfacing the distal leg and dorsum of the foot with a split-thickness skin graft over a latissimus dorsi free flap. An endoscope with a video monitor and modified thoracoscopic instruments were used to assist in the muscle harvest. The principles of endoscopic muscle harvest include an incision long enough to remove the muscle, placed in the least conspicuous area that is within the reach of the instrumentation; retraction to optimize the optical cavity or visual working area; and use of video monitors to allow for coordinated assistance. The decrease in visible scarring is dramatic and represents the primary advantage over open techniques. We believe that the role of endoscopy will continue to expand as our experience increases and technology improves. PMID- 7857040 TI - Efficacy of prophylactic antibiotics in reduction mammoplasty. AB - The use of prophylactic antibiotics in reduction mammoplasty has been random and its efficacy unproven. This study reviewed 106 consecutive inferior pedicle technique reduction mammoplasties. Two groups were identified; 47 patients received prophylactic antibiotics and 59 patients did not. The decision of who received prophylactic antibiotics was random based on resident rotation and resident preoperative orders. The demographics were equal between the antibiotic group and the control group. The wound infection rate and the rate of delayed healing were examined in both groups. There were no statistically significant differences in the infection rate or the rate of delayed wound healing in either the antibiotic group or the control group. Individual risk factors were also studied in each group. These risk factors included obesity, older age, smoking history, and large reductions. The use of prophylactic antibiotics did not reduce the infection rate in any of these high-risk groups. Comparing the individual risk factors for the remainder of the patient population showed that the infection rate was higher in obese patients but was unaffected by prophylactic antibiotics. Delayed healing was also higher in larger reductions but also was unaffected by the use of prophylactic antibiotics. We conclude that the use of prophylactic antibiotics in reduction mammoplasty is not efficacious in reducing the rate of wound infection or delayed healing. PMID- 7857041 TI - Lower lid reconstruction with a chondromucosal alar graft and upper lid musculocutaneous flap. AB - Partial or total lower lid reconstruction implies the repair of three layers: the skin, the tarsus, and the conjunctiva. The method of reconstruction must, therefore, aim at three objectives: ensuring the stability of the lid by repairing the tarsoconjunctival layer, achieving an aesthetic result with the repair of the skin, and taking into consideration the primary role of the upper lid in the ocular protective system. We recommend a musculocutaneous flap, taken from the upper lid, with a single lateral or medial pedicle combined with a chondromucosal alar graft. During the last 10 years, 41 patients were operated on with malignant skin tumors requiring marginal, partial, and total lower lid reconstruction. The results were quite satisfactory from a functional and aesthetic point of view. We noticed two cases of partial flap necrosis and two cases of ectropion needing revision. We believe that the procedure described can be a tool in the armamentarium of the plastic surgeon involved in the field of the orbitopalpebral area. PMID- 7857042 TI - Correction of the cleft nasal deformity with an L-shaped iliac bone graft. AB - We describe our technique for correcting a cleft lip nasal deformity using L shaped iliac bone grafts to achieve additional structural support and the desired nasal projection and profile. Augmenting the nasal bridge creates the illusion of a narrower nose. Further, the columellar portion of the L-shaped graft provides stabilization, eliminating the "see-saw" effect of the bridge graft on the fulcrum of the bony bridge, which can lead to a depressed tip and loss of the root indentation. Clinical and radiographic observation has revealed that this method of correction has consistently produced satisfactory results. PMID- 7857043 TI - Temporalis muscle sling revisited: a technique to restore ocular sphincter function. AB - Five patients with unilateral facial palsy with moderate to severe lagophthalmos (less than 70% eyelid closure) and duration of palsy expected to last more than 2 years were selected for the study. In all patients, a temporalis muscle-fascia sling was used to restore ocular sphincter function. A few modifications in the original technique as described by Gillies have been recommended: namely, harvesting of a narrow strip of temporalis muscle to avoid a bulge in the temporal region, submuscular passage of temporalis fascial strip in the eyelid to avoid eversion of the lid margins, and tenorrhaphy of fascial strips at the medial aspect of the lower eyelid to avoid webbing of the medial canthus. Average duration of follow-up was 3 years. All patients showed excellent eyelid closure. Advantages of the temporalis muscle sling, which is a dynamic procedure using autogenous tissue, are discussed. PMID- 7857044 TI - Viability of adipose tissue injected and treated by different methods: an experimental study in the rat. AB - Fat injection is being used for the correction of various soft-tissue defects. In this study, the manner of fat injection yielding the greatest transplant viability was examined. Autologous fat was obtained from the inguinal area of rats and subsequently reinjected to the nuchal region, an area naturally poor in subcutaneous fat. Before injection, the fat was processed by one or more of the following methods: suture of the recipient area, repeated washing to remove residual blood, and addition of insulin. Transplant status was evaluated by both macroscopic and microscopic examination of the recipient sites 2 weeks and 12 weeks after the injection. The results demonstrated that the injected fat remained in part as viable new fatty tissue in the nuchal area. No statistically significant improvement in the viability of the injection fat was noticed at 2 weeks and 12 weeks after its processing by the different methods just described. Significant positive correlation was demonstrated between the volume of the injected fat and the size of the bulging at the injection area only 2 weeks after the injection. PMID- 7857045 TI - Vascularized allogeneic nerve transplantation with cyclosporine immunosuppression. AB - Allogenic grafts have many advantages over autogenous grafts. An experimental rat model using the great saphenous nerve was developed to study the reconstruction of long peripheral nerve defects with vascularized allogeneic nerve grafts, and the effects of cyclosporine therapy on graft survival were assessed. In animals receiving short-term immunosuppression, the number of regenerated axons increased steadily during the treatment, but rejection began immediately after cyclosporine was discontinued. As the tissues transplanted with the nerves underwent necrosis, the grafts showed demyelination. In contrast, in animals receiving long-term cyclosporine therapy, nerve regeneration assessed in terms of the myelinated axon count was excellent until at least 12 weeks postoperatively but was less active than in vascularized autografts or conventional allografts. These results indicate that the short-term immunosuppressive therapy with cyclosporine cannot produce immunological tolerance of vascularized nerve allografts. In addition, even when administration of cyclosporine was prolonged, nerve regeneration did not exceed that in autografts. PMID- 7857046 TI - Experimental study of delay of venous island flaps. AB - If a stable and reliable venous island flap can be elevated, it may enable us to make various flaps everywhere on the body surface by using subcutaneous veins. We have carried out an experimental study to investigate the possibility of increasing the survival area of a venous island flap by a delay procedure. In a proximally based venous island flap, survival area increased when a delay procedure was used, especially with ligation of the distal vein. In a distally based venous island flap, survival area increased when a delay procedure was used without ligation of the proximal vein. PMID- 7857047 TI - Extended use of scrotal septal island skin flap for the repair of penile hypospadias. AB - In this article, one-stage repair of complicated cases of penile hypospadias when there is no penile skin available for safe reconstruction is described. An island of the most median hairless part of the scrotal skin around the median raphe was used as a skin flap based on its scrotal septal pedicle with an extended and free arc of rotation for repair of distant urethral defects. The bilaterally stretched, most median area of scrotal skin is almost hairless. This well vascularized flap was used in reconstruction of 18 patients with recurrent, complicated, proximal, and distal penile hypospadias from January 1989 through July 1993. Of these, 17 patients were post pubertal and 1 was prepubertal. A maximum of 5 years and a minimum of 8 months follow-up showed no hair growth problems. Complications were sacculation of the reconstructed urethra in 1 patient, meatal stenosis in 1 patient, and urethral fistula in 1 patient. Technique refinements and encouraging results as well as complications are discussed. PMID- 7857048 TI - Effect of storage on osteoinductive properties of demineralized bone in rats. AB - A requirement for the clinical use of demineralized bone is the possibility of storing the material without loss of its osteoinductive properties. Seventy-five 8-week-old male Wistar rats were randomly assigned to one of five groups of 15 rats each. Lyophilized demineralized allogeneic bone was prepared and implanted in the abdominal muscle either without prior storage (control group) or after storage for 9 or 14 months at -70 degrees C or 4 degrees C (four experimental groups). Bone formation in the implants was evaluated quantitatively 4 weeks postoperatively by measuring the strontium 85 uptake of the recovered implants. Storage for 9 months at both temperatures did not affect the osteoinduction, whereas storage for 14 months at both temperatures led to a statistically significant decrease in osteoinduction. PMID- 7857049 TI - Reverse-flow radial forearm flap for reconstruction of the hand. AB - Soft-tissue injuries of the hand often require flap coverage to achieve primary wound closure and a good functional result. The use of the reverse radial forearm fasciocutaneous flap in the reconstruction of the hand is discussed. This flap offers thin, pliable, hairless skin and has proved very reliable because of its excellent vascular supply. The anatomy and vascular basis of this flap are presented along with its application in three patients. PMID- 7857050 TI - Reconstruction of the lips, oral commissure, and full-thickness cheek with a composite radial forearm palmaris longus free flap. AB - Reconstruction of the lower and upper lips, commissure, and full-thickness cheek defects using a composite radial forearm palmaris longus free flap with secondary commissuroplasty is described. This flap is useful for reconstruction of the total lower lip as well as larger defects that include full-thickness cheek and the commissure. PMID- 7857051 TI - Closure of multiple pressure sores with split total thigh flap. AB - Pressure sores remain a pervasive and recurrent problem in the chronically bedridden and immobilized insensate patient populations, such as those with spinal cord injury. Various musculocutaneous flaps based on muscles of the buttock and thigh are routinely used to close primary, uncomplicated ulcers. The gluteus maximus, tensor fascia lata, and posterior thigh muscles, for example, can be used to close the majority of primary defects. In the case of extensive and recurrent ulceration, however, particularly when the hip joint or proximal femur is infected or marked heterotopic ossification is present, these conventional flaps are inadequate. The total thigh flap offers a solution to some of these problems by providing a large volume of tissue as a unit to cover the defects, particularly in cases in which other reconstructive options have been exhausted. We describe a modification in the total thigh flap procedure by splitting the flap according to its vascularity to achieve closure of multiple pressure ulcers in a one-stage procedure. PMID- 7857052 TI - Revascularization of free mandibular reconstruction after early emergency arterial ligation. AB - A 70-year-old man with a squamous cell carcinoma involving the anterior arch and body of the mandible underwent resection and reconstruction with a 10-cm free vascularized iliac crest bone graft, preserving periosteum and minimal adjacent soft tissue. On postoperative day 12, he experienced bleeding from an orocutaneous fistula, requiring emergency ligation of the arterial pedicle to control hemorrhage. After ligation, continued bleeding was noted from the margin of the graft, with active filling of the venous pedicle. The 10-cm mandibular bone graft survived without appreciable resorption during a period of follow-up of 5 years. We believe that bone graft survival in the present case was due to early vascular communication between the periosteum and adjacent soft tissues of the graft with the recipient bed. This mechanism may serve to maintain bone graft viability after early arterial disruption, when repeat arterial anastomosis is believed to be contraindicated. PMID- 7857053 TI - Treatment of paralytic ectropion with composite chondrocutaneous graft. AB - We present our experience with correction of paralytic ectropion in 10 patients with a composite chondrocutaneous graft obtained from the scapha of the ear. This large composite graft is sutured to the tarsal plate to support the lower lid. It prevented exposure keratitis in all patients. Two patients needed minor secondary revisions of the corners of the cartilage graft. The donor defect healed satisfactorily without deforming the ear. There were no other complications and no other lid or visual problems. At 3-year follow-up, the results thus far appear long lasting. PMID- 7857054 TI - Reduction mammaplasty for gigantomastia using inferiorly based pedicle and free nipple transplantation. AB - Patients with gigantomastia have severely distorted anatomical breast structures. Reduction mammaplasty in such cases using the inferiorly based pedicle containing the nipple-areola complex can be technically difficult, yield poor results, and cause postoperative complications such as nipple necrosis and loss. Alternative traditional methods such as amputation mammaplasty with free nipple-areola transplantation usually results in a flattened, nonaesthetic breast with poor projection. This unacceptable result is due to the lack of central breast tissue required for normal anatomical projection. Herein, we describe a method of reduction mammaplasty for gigantomastia combining free nipple transplantation and an inferiorly based pyramidal parenchymal flap for augmentation of breast fullness and nipple projection. PMID- 7857055 TI - Composite gastric seromuscular and omental pedicle flap for urethral and scrotal reconstruction after Fournier's gangrene. AB - A new composite gastric seromuscular and omental pedicle flap is described that can provide immediate airtight or watertight closure in the repair of complex defects involving the urethra. This flap was used to repair defects of the urethra, scrotum, and abdominal wall in a patient with Fournier's gangrene. The seromuscular patch was sutured to the urethral defect, and the omentum was applied over the defects of the scrotum and abdominal wall. This new procedure made it possible to close the skin primarily without leakage or infection. The patient had an uncomplicated recovery. Postoperative urethrography demonstrated no leakage or stenosis. PMID- 7857056 TI - Avoiding the boiled frog syndrome. PMID- 7857057 TI - Re: Analysis of suturing techniques in the microvascular anastomosis of vessels of unequal diameter. PMID- 7857058 TI - Re: Secondary reconstruction of abdominal wall defects associated with exstrophy of the bladder. PMID- 7857059 TI - Re: Cross-finger flap: how to design its shape accurately. PMID- 7857060 TI - Volar foot skin grafts do work! PMID- 7857061 TI - Physiology and measurement of tissue perfusion. AB - Sufficient tissue perfusion and oxygenation are vital for all metabolic processes in cells and the major influencing factor of tissue repair and resistance to infectious organisms. The concept of tissue perfusion has been aliked with blood flow, oxygen delivery or a combination of flow and nutritional supply including that of oxygen. A concept covering both oxygen delivery, tissue oxygen transport and oxygen consumption of the cells could be named tissue oxygen perfusion. This concept could be useful for clinicians describing tissue perfusion and oxygenation of the patient. Tissue perfusion must be evaluated on local tissue level. A single tissue that would represent the situation in all tissues of the body and be easily available for measurements, would be ideal. Subcutis and mucosa of the gastrointestinal tract are such types of tissue. Many monitoring systems are available for measuring tissue perfusion and oxygenation. However, only measurement of tissue oxygen tension and pH the gastrointestinal mucosa fulfil the criteria of tissue oxygen perfusion. Future evaluation of tissue perfusion will be of fundamental importance for the outcome of medical treatment. Presently measurements of tissue oxygen tension, and in intensive care units also gastrointestinal mucosal pH, seem to be the best monitoring systems clinically available for this purpose. PMID- 7857062 TI - Pancreatic trauma with proximal duct injury. AB - A retrospective study of patients with traumatic injuries to the head of the pancreas involving the main pancreatic duct but not the duodenum identified five cases comprising 0.5% of all abdominal, and 21% of pancreatic injuries managed operatively. Four of the injuries resulted from penetrating, and one from blunt trauma. Two patients treated with pancreaticoduodenal resection died of septic complications caused by the pancreatic procedures. Three patients undergoing duodenum-preserving pancreatic resection survived without developing diabetes during five months follow-up. CONCLUSIONS: Pancreatic trauma with proximal duct injury can in some cases be managed with distal subtotal pancreatectomy. If the resection would include more than 80% of the gland, a duodenum preserving resection of the head of the pancreas with distal Roux-en-Y pancreaticojejunostomy is a viable option providing the duodenum with its vasculature, the common bile duct, and the ampulla of Vater are uninjured. Unstable patients with severe associated injuries can be managed with external drainage alone. PMID- 7857063 TI - Operative treatment of severe pancreatitis in the Paijat-Hame Central Hospital during 1986-1990. A retrospective analysis of 35 patients. AB - Thirty-five of 556 (6.3%) patients with acute pancreatitis were treated with standard operative technique in our hospital between 1986 and 1990. All of the operated patients had necrotizing course of the disease. The aetiology was alcohol in 80.0%, biliary disease in 11.4%, postendoscopic retrograde cholangiopancreatography (ERCP) in 5.7% and postoperative in 2.8% of the patients. The median delay from admission to hospital to operation was only one (mean 1.9; range 0-10) day. The operative technique consisted of careful debridement of necrotic tissue and continuous high volume lesser sac lavage. The overall mortality was 8.6% (3/35) and morbidity 68.6% (24/35). The low overall mortality rate in necrotizing pancreatitis in this retrospective study supports our concept that our operative technique is effective and early operative intervention is justified in the treatment of necrotizing pancreatitis even if there may have been some unnecessary laparotomies. PMID- 7857064 TI - Parathyroid re-exploration in patients with primary hyperparathyroidism. AB - In a prospective study fifteen consecutive patients underwent re-exploration for persistent or recurrent primary hyperparathyroidism. We aimed at definite preoperative localization of enlarged, abnormal parathyroid glands in all patients. Ultrasound guided fine needle aspirations for parathyroid hormone assay had the highest accuracy rate of 100%, those for cervical ultrasound and thallium technetium, scintigraphy were similar, both 86%. Normocalcaemia was achieved in all patients, but five (33%) patients required more than one re-exploration. Permanent unilateral vocal cord injury occurred in two (13%) patients, but none had permanent hypocalcaemia. We conclude that the results of re-exploration are good but one third of the patients required more than one reoperation. Localization studies aiming at definite localization are mandatory before re exploration. On the basis of our results we suggest a protocol for preoperative localization which takes into consideration both the accuracy rates and the costs of localization examinations. PMID- 7857065 TI - Periprosthetic leakage after aortic valve replacement. AB - During the period 1968-1985, aortic valve replacement was performed in 871 patients, 617 males and 254 females aged 49.6 years in mean (15 to 75). Up to the end of 1988, 42 patients (4.8%) were reoperated on because of periprosthetic leakage. In primary surgery, annular calcification was found in 27 of these patients (64%), 17 patients (40%) had a bicuspid valve, and a positive culture from the excised valve was diagnosed in one of three patients with active native endocarditis. Two patients had Marfan's syndrome and two others postendocardial regurgitation. At primary surgery, mechanical prostheses were inserted in every case. Differences between the prosthetic models used could not be shown as regards to the occurrence of periprosthetic leakage. To implant the valve, interrupted everted U-mattress sutures with pledgets appeared to be the best method. Leakage occurred in 21 patients (50%) during their hospital stay and in 18 patients (43%) during the follow-up period of four months. Three others developed leakage two to four years from primary surgery. The main indication for reoperation was congestive heart failure alone or combined with heamolytic anaemia in 37 (88%) of cases. Four patients required the reoperation due to infectious dehiscence. Preoperatively, 34 patients (81%) were in NYHA (The New York Heart Association) Class III-IV. A new prosthetic valve was implanted in 23 cases, a composite graft once and in 18 cases refixation was performed. Two patients died in association with surgery, both due to the low output syndrome. During the follow-up time of 6.4 years, eight patients developed recurrent leakage. Four of them were found during their hospital stay and four others later. The role of prosthetic infection was remarkable in these eight cases; three patients with preoperative infectious dehiscence of the prosthesis had recurrence and one patient developed prosthetic endocarditis with leakage later. Three patients required more reoperations. At follow-up study, leakage was diagnosed in five of 28 living patients. Three of them were not significant and two moderate. 24 patients (86%) were in NYHA Class I-II. PMID- 7857066 TI - Atrial versus ventricular pacing in sick sinus syndrome: the role of retrograde ventriculoatrial conduction. AB - This study compares the acute haemodynamic effect of atrial versus ventricular pacing, and ventricular pacing in the presence versus absence of retrograde ventriculoatrial conduction. Twenty-two patients with symptomatic sick sinus syndrome were tested: 12 with ventriculoatrial conduction (Group 1) and 10 without it (Group 2). Cardiac haemodynamics were measured by thermodilution technique at spontaneous rhythm as baseline and during atrial versus ventricular pacing at two different pacing rates. Atrial pacing offered an average augmentation for 20% in cardiac index from spontaneous rhythm in both groups (P < 0.05). The presence of ventriculoatrial conduction was the crucial determinant of cardiac performance during ventricular pacing. The change in cardiac index from the baseline was towards decrease in Group 1 and towards increase in Group 2. The difference between the groups was significant (P < 0.05). We conclude that atrial pacing is superior to ventricular and should be preferred in symptomatic sick sinus syndrome patients without atrioventricular conduction defects. However, ventricular pacing can be considered for preventing clinical symptoms associated with attacks of severe bradycardia or temporary cardiac arrest in patients without ventriculoatrial conduction. PMID- 7857067 TI - Is horse riding a dangerous recreation for young girls? A study at emergency departments of Lahti City Hospital and Paijat-Hame Central Hospital, Lahti. AB - Horse-related injuries form a notable part of sports and leisure time accidents. 54% of the injured were female riders under the age of 20 years. The most serious injuries were upper extremity ones. Over one third of the riders had suffered previously from horse-related injuries. PMID- 7857068 TI - Knee laxity in carpet and floor layers and painters. AB - The knees of 154 carpet and floor layers and 131 painters were examined clinically and the anteroposterior displacement of the knees was measured with a computer-based arthrometer. The drawer test, the pivot shift and the thigh muscle stretching tests showed greater mobility among carpet and floor layers than among painters. The arthrometric examination showed equal anteroposterior tibiofemoral displacements in the two groups. Two percent of the subjects had a right knee/left knee difference indicating a cruciate ligament insufficiency. Tightness in the rectus femoris stretching test, and among carpet and floor layers also radiographic tibiofemoral osteophytosis predicted small arthrometric changes. PMID- 7857069 TI - Adduction moment of the knee compared to radiological and clinical parameters in moderate medical osteoarthrosis of the knee. AB - The purpose of this study was to investigate the relationship between clinical symptoms, static radiographic measurements, and of load distribution during walking at the knee, in 54 patients with moderate medial osteoarthrosis of the knee. Varus deformity of the knee was assessed from static radiographic measurements as the Hip-Knee-Ankle (HKA) angle, and range of moments at the knee in the frontal plane were assessed using a Kistler force plate system. No correlations between clinical symptoms and radiographic parameters or moments at the knee were found. The adduction moment in mid stance was more important than the peak adduction moment in differentiating between patients and normal controls. The amplitude of the peak adduction moment depended on the sex and body mass of the patients, while the amplitude of the mid stance adduction moment depended on body mass and the varus deformity of the knee. There was a weak correlation between the peak adduction moment and the HKA-angle (r = 0.32, P < 0.05) and there was a moderately high correlation between the peak adduction moment in mid stance, i.e 50% of the stance phase, and the HKA angle (r = 0.46, P < 0.001) even after normalization of the mid stance moment to body mass. Accordingly, 20% of the medio-lateral knee load in mid stance during walking could be explained by the varus deformity of the osteoarthrotic knee in our patients. PMID- 7857070 TI - Three years' audit of a bone bank. AB - A three years' practice of a hospital-based non-commercial bone bank is presented. Altogether 121 allografts were collected from primary hip arthroplasties for osteoarthritis. Altogether 41 of the grafts were used in our hospital, 47 grafts were transported to other hospitals at a non-profit basis. The grafts were stored fresh-freezed at -80 degrees C. The allograft recipient patients in our hospital were reviewed. Main indication for the use of allografts was revision arthroplasty of the hip or knee. Other indications included difficult nonunions, arthrodeses of the knee or spine, difficult major primary fractures in osteoporotic bone and a large bone cyst. Of the nonunions, 3/10 failed to unite and of the revision arthroplasties, 1/19 had to be reoperated on. Three infections were recorded, all of which were unrelated to the allograft transplantation. The infections all healed without surgical intervention. PMID- 7857071 TI - Coagulation abnormalities in diabetic patients undergoing renal transplantation. AB - Nineteen diabetic (DM) and twenty-two non-diabetic (NDM) uraemic patients undergoing renal transplantation were studied to evaluate coagulation abnormalities. Thirty-three healthy patients admitted for minor surgery served as controls. Antithrombin III (AT III), thromboelastogram (TEG), other haemostatic parameters and the influence of dialysis treatment were assessed in DM and NDM uraemic patients. All uraemic patients were anaemic and bleeding time was slightly prolonged (NS). The level of AT III was raised in the DM group when compared in the healthy controls (P < 0.001). Prothrombin time (PT) percentage was increased in both uraemic groups (P < 0.001) in comparison with the controls. Thrombocytosis was marked in DM patients (P < 0.001) when compared with controls and NDM patients. TEG parameters were similar in all groups. Continuous peritoneal dialysis treatment (CAPD) was associated with elevated total platelet count in NDM (P < 0.05) and DM group (P < 0.05) when compared with haemodialysis (HD) patients. Also, the PT was shortened in DM patients on CAPD vs HD (P < 0.05). AT III level was elevated in NDM patients on CAPD compared with those on HD (P < 0.05). There was no difference in clinical bleeding tendency during renal transplantation. Postoperatively, one patient in NDM group suffered from thrombosis of the graft artery and transplantectomy had to be performed. Our study showed a prethrombotic state in diabetic uraemic patients admitted for renal transplantation. The increased AT III activity may protect these patients against thrombotic complications. The role of CAPD treatment requires further studies. PMID- 7857072 TI - Treatment of hypothermic circulatory arrest with thoracotomy and pleural lavage. AB - We describe a successful case of severe hypothermia due to coldwater immersion. An eight-year-old boy was saved from cold water (4 degrees C) after forty minutes. Open rewarming and resuscitation was performed by thoracotomy and pleural lavage for cardiac arrest due to the low core temperature (25 degrees C). The patient recovered primarily well without any postoperative complications. The follow-up of two years shows good state of physical health but some neuropsychological defects disturbing normal progress in school work. PMID- 7857073 TI - Choledochal cyst in childhood. AB - During a two years period, four children were operated on because of choledochal cysts. All four patients were girls aged 9, 9, 8 and 6 years at operation. The symptoms at presentation were mainly episodic abdominal pain, mild jaundice and tenderness under the right costal curvature. Ultrasonography of the biliary tract revealed a cystic dilatation of the choledochus. Endoscopic retrograde cholangiopancreatography (ERCP) confirmed the cystic dilatation and, importantly, delineated the junction of the pancreatic duct. The surgical procedure in all four patients consisted of complete excision of the choledochal cyst and extrahepatic biliary tree combined with a Roux-en-Y hepaticojejunostomy. The postoperative course of all patients was uneventful. Ultrasonography of the abdomen should be performed liberally in case of biliary tract symptoms in children. PMID- 7857074 TI - Sulindac therapy for familial adenomatous polyposis after colectomy and ileorectal anastomosis. AB - Preventive colectomy for familial adenomatous polyposis is indicated for inevitable malignant change after the age of 30 years. We describe two patients of the same family with familial adenomatous polyposis, who underwent colectomy with ileorectal anastomosis and were treated with sulindac after operation. Sulindac causes regression of size and number of adenomas but discontinuation of treatment seems to lead to recurrence of adenomas. PMID- 7857075 TI - Association between medically induced achlorhydria of the stomach and a severe postoperative infection? A report of two cases. AB - Two cases are reported, where severe postoperative septic infection developed after gastric resection without surgical technical complication. Both patients had had long preoperative therapy with omeprazole and no perioperative antibiotic prophylaxis was given in either of the cases. The other of the cases was fatal. The need for an effective perioperative prophylaxis in gastric surgery together with drugs creating gastric achlorhydria is discussed. PMID- 7857076 TI - [Regulation of synthesis and secretion of parathyroid hormone (PTH) and of tumor hypercalcemia hormone (PTHrP)]. AB - PTH is a peptidic hormone which regulates blood calcium level. The PTH gene has been characterized and has 3 exons and 3 introns. PTH is synthetized as a precursor (pre-pro-PTH). The sequence "pre" is the signal peptide. The role of the sequence "pro" is still unknown. Main factors which regulate PTH synthesis are the level of extra-cellular calcium, vitamin D, and to a lesser extent steroid hormones. Calcium is the main factor influencing PTH secretion. Very recently, a "calcium sensor" has been purified and cloned. It is present on the membrane of parathyroid cells and some specific agonists of these receptors are already purified and could modulate PTH secretion. PTH-RP is responsible of hypercalcemia of tumors and has structural homologies with PTH. But, whereas PTH is only secreted by parathyroid cells, PTH-RP is synthetized by several different cell types and seems to act as an autocrine factor. Two major questions are still unanswered: 1) Is there only one receptor for PTH and PTH-RP? Some studies concluded that there are probably at least 2 different receptors, 2) And what is the role of PTH-RP? Many effects have already been published: pth-RP is involved in placental physiology, keratinocyte differentiation, or vascular smooth cell relaxation. PMID- 7857077 TI - [Mode of action of parathyroid hormone (PTH) and PTH-related peptide (PTHrP) in target organs]. AB - Calcium and phosphorus metabolism is mainly regulated by PTH through its actions on kidney and bone. PTHrP, which is associated with the hypercalcemia of malignancy syndrome, binds to and activates the same receptor that PTH does. cDNA clones of PTH/PTHrP receptors from rat osteosarcoma (ROS 17/2.8) and opossum kidney (OK) cells are highly homologous and are members of a novel G protein linked receptor family that includes calcitonin, glucagon, GLP-1, GHRH, VIP, and secretin receptors. Analysis of the protein sequence predicts a receptor with 7 transmembrane domains, a 155 amino acids (aa) extracellular (EC) N-terminal, and 130aa intracellular C-terminal domaina. The extracellular domain has 6 conserved cysteines and 4 potential glycosylation sites. When transfected in COS cells, both receptors are able to bind PTH and PTHrP active fragments with equal affinity. Likewise, agonists activate both adenylate cyclase and phospholipase C efficiently. The N-terminal EC domain and the first EC loop seem to determine the receptor binding capacity with the agonists. Activation of adenylate cyclase and phospholipase C might involve multiple sites between the 3rd helix and the C terminal tail. Partial characterization of the rat PTH/PTHrP receptor gene demonstrates the existence of at least 15 exons. The first six transmembrane domains are encoded by separated exons. The PTH/PTHrP receptor mRNA is expressed mainly in kidney and bone, and also is widely expressed in many tissues, but not all. A major 2.3-2.5 kb transcript is observed in all these tissues. Nevertheless, 2 larger transcripts are observed in kidney and liver, and multiple smaller mRNA species are observed in kidney, skin, and testis.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7857078 TI - [Primary hyperparathyroidism. Clinical, epidemiological and histological aspects]. AB - Primary hyperparathyroidism is most frequently caused by a single parathyroid adenoma and is more frequent in females than in males. Its frequency increases with age. Its annual incidence has been estimated at 41 per 100,000 in Rochester, and its prevalence at 4.3 per 1000 in Stockholm. Since the introduction of automated serum calcium measurements, the recognition of primary hyperparathyroidism has increased and the clinical presentation of the disease has changed. Classical osseous and renal features of the disease have become rare, due to the increased proportion of asymptomatic forms and to earlier diagnosis. Primary hyperparathyroidism is nowadays usually recognized because serum calcium is measured either systematically or in the clinical setting of mild manifestations, such as arthenia, anxiety, hypertension... Bone histology gives evidences of an accelerated bone turn-over, without major unbalance between formation and resorption. Bone densitometry has shown only minor decrease of mineral content of the lumbar spine in several modern series, so that the deleterious effect of mild or asymptomatic hyperparathyroidism on cancelous bone is presently questioned by several authors. PMID- 7857079 TI - [Hyperparathyroidism secondary to renal insufficiency. Physiopathology, clinicoradiological aspects and treatment]. AB - Stimulation of PTH secretion and synthesis in chronic renal failure involves direct and indirect factors. The indirect ones are those contributing to a decrease of plasma ionized calcium concentration which stimulates the release of PTH (1) primarily the negative calcium balance due to the iatrogenic reduction of dietary calcium intake associated with an inadequate synthesis of calcitriol, this latter being explained by a reduction in the nephronic mass, the phosphate retention, the acidosis and the retention of uremic toxins (2) more accessorily, the physicochemical dysequilibrium induced by the late occurring hyperphosphatemia. The factors acting directly on the parathyroid gland stimulating synthesis of prepro PTH at its transcription level: not only hypocalcitriolemia but also hypocalcemia and hyperphosphatemia. The clinicoradiological manifestations appear late, mostly only after the patient has been put on dialysis. The most precocious sign is the subperiosteal resorption assessed on the hand X-rays. Therefore diagnosis of hyperparathyroidism relies mainly on the measurement of plasma concentration of intact PTH. In dialysis patients the optimal range corresponding to the best bone histology is between 1 an 3 times the upper limit of normal. No such data exist for predialysis patients. Medical treatment of hyperparathyroidism should primarily be preventive, probably in predialysis lipin patient as soon as plasma intact PTH is greater than the normal upper limit. This treatment is based primarily on the prevention of phosphate retention, of negative calcium balance and acidosis by the use of oral alkaline salts of calcium given with the meals in association with appropriate dietary protein and phosphate restriction. Native vitamin D depletion should also be prevented but use of 1 alpha OH vitamin D3 metabolites in controversial: it is reasonable to administer them only when plasma intent PTH is above 3-7 the normal upper limit and when plasma phosphate is below 1.2 in predialysis patients below 1.5 mmol/l in dialysis patients and plasma calcium remains below 2.3 mmol/l in spite of CaCO3 administration. This situation is encountered in less than 50% of the dialysis patients and rarely in predialysis patients. In dialysis patients the calcium concentration in the dialysate should be chosen in relation to the dose of oral calcium and the use of 1 alpha OH vitamin D3. The superiority of the intermittent (oral or intravenous) over the daily oral administration is not yet clinically proven. The surgical parathyroidectomy is indicated when hypercalcemia and/or hyperphosphatemia occur under medical treatment, whereas the intact PTH levels remain very high (> 500 pg/ml).(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7857080 TI - [Imaging of parathyroid glands]. AB - Ultrasonography (US) has become the gold standard of the preoperative detection of parathyroid masses. Provided that it is performed by sonographists aware of the normal and pathological anatomy of the neck, US can detect more than 80 per cent of the parathyroid masses. Ectopic masses, especially when they are intramediastinal, are rare but their diagnoses rely on more sophisticated procedures such as TI-Tc scintigraphy, CT, arteriography, MR, superselective venoius sampling. The specialized surgeons emphasize the lack of reliability of parathyroid US because of its operator-dependance. However, the accuracy of the technique enables some new treatments, percutaneous alcoolization and focal surgery under local anesthesia. One can regret that US is too often used as a diagnostic criterion of hyperparathyroidism, but this trend is explainable because of the difficulty to interpret monosymptomatic hypercalcaemia, especially in the elderly. The contribution of diagnostic imaging is undoubtfully worthwhile in persisting or recurrent hyperparathyroidisms, which are more often related with intracervical masses than with intramediastinal ones. PMID- 7857081 TI - [Surgical treatment of primary hyperparathyroidism]. AB - The authors report their experience with treatment of primary hyperparathyroidism in a series of 1496 patients (September 1991). The clinical profile of the disease has changed in the past few years, incomplete or even asymptomatic forms of the disease are now more common. The results of treatment have considerably improved (99% cure rate), progress is essentially due to two factors: surgeons have gained in experience and diagnostic errors have disappeared thanks to the reliability of laboratory tests and hormone level determination. PMID- 7857082 TI - [Surgery of primary hyperparathyroidism by unilateral approach under local anesthesia and intraoperative determination of PTH 1-84]. AB - Between July 89 and June 92, 70 patients with primary hyperparathyroidism underwent adenomectomy by unilateral incision under local anesthesia (Ul/LA), without exploration of the remaining glands. The procedure was carried out with intraoperative monitoring of urinary cyclic AMP (n = 35), Calcemia was measured 6 monthly for one year in every patient. 62 (88.6%) patients were cured after Ul/LA, whereas 5 patients required conversion to bilateral cervicotomy under general anesthesia because of abnormal hormonal levels, thus giving an overall success rate of 97% (67/70). The reasons for treatment failure of Ul/LA included misleading conclusions of cervical ultrasonography (n = 5), agitation of the patient (n = 1) and deep localization of the adenoma (n = 1). When cervical ultrasonography is suggestive of a parathyroid adenoma in expert hands, the probability of a second localization or associated hyperplasia is very low, so that adenomectomy by Ul/LA can be attempted safely, provided that the serum level of intact parathyroid hormone returns to normal values within one hour following resection. In our experience, parathyroidectomy by Ul/LA should not be considered in case of non conclusive ultrasonography, familial history pf hyperparathyroidism of MEN-I, ultrasonic evidence of several enlarged glands or associated thyroid nodule requiring simultaneous treatment. PMID- 7857083 TI - [Evaluation of vertebral bone mass in anorexia nervosa]. AB - Lumbar bone mineral content (BMC) of 33 female patients aged 14-30 years (19 +/- 4.1 (mean +/- SD) with anorexia nervosa (duration 31 +/- 37 months) was studied using dual X-ray absorptiometry. Results were compared with the data obtained in a population of 26 women aged 17-38 years without bone disease. BMC was significantly decreased (0.872 +/- 0.107 g/cm2 hydroxyapatite) in anorectic patients as compared to controls (1.008 +/- 0.098 hydroxyapatite). A single patient had a non traumatic vertebral compression fracture. A statistically significant negative correlation was found between BMC and duration of amenorrhea (r = 0.48; p < 0.01). There was no significant correlation between BMC and body mass index or daily calorie intake. Ovarian steroid deficiency might thus be a major factor--among other ones--in the development and the degree of bone loss in anorexia nervosa. PMID- 7857084 TI - [Mid-term and long-term outcome in Leydig cell estrogen tumors]. AB - A study has been realized in six patients with estrogen secreting Leydig cell tumors from 18 to 120 months after hemicastration. Testicular contralateral volume is normalized, gynecomastia can be completely reduced, sex steroids are normalized while gonadotropins can be temporary increased. Spermogram which is abnormal can be normalized. These results confirm the heterogeneity of these tumors. PMID- 7857085 TI - [Basedow disease following autoimmune primary hypothyroidism. Apropos of 7 cases]. AB - The evolution of Graves' disease following auto immune hypothyroidism appears to be rather infrequent. We present seven female patients with autoimmune thyroiditis, 2 with goiter and 5 with hypothyroidism who, after a few months or years, presented signs of Graves'. Therefore it is usefull to carefully monitor TSH in patients treated for autoimmune thyroiditis to detect a possible evolution towards Graves' disease. This should be mostly true in patients with TBII positive antibodies autoimmune thyroiditis. During hyperthyroidism, 123 lodine uptake is much lower than usually observed in Graves' nevertheless, it is always increased compared to the uptake measured during hypothyroidism. This could be in favor of residual functional capacity of these often small thyroid glands. The alternate action of blocking or stimulating antibodies upon the TSH receptor would probably explained the switch from hypo to hyperthyroidism, even if there is usually no correlation between antibodies levels and clinical signs. PMID- 7857086 TI - [Diabetic pregnancy in Senegal (years 1980 to 1989)]. AB - INTRODUCTION AND OBJECTIVES: Diabetic Pregnancy Prognosis in Seventies is it better in Eighties because of Patient Education? METHODOLOGY: Retrospectively, since 1980 to 1989, in Women in status to breed, Diabetic Pregnancy was screened in our Department. W.H.O.'s (1980) Diabetes Mellitus Criterias, PEDERSEN's Criterias, White's Classification were used. Studied Parameters were etiologic factors (age, type, Diabetes oldness and control), former and present Evolution of Pregnancies (term and pregnancy's product). RESULTS: A--In Global Study, 15.07% Diabetic Pregnancies were observed: 22 (37%) Insulin Dependent and 38 (63%) Non Insulin Dependent. The global mean of age was 31 years; Diabetic Mellitus was less than 10 years old in 90% cases whatever the type. Their control was not good (Glycemic Control < 1.4 g/l in less than 50%). Diabetes complications were nephropathy (13.6% and 8%), retinopathy (13.6% and 18.5%), arterial hypertension (0% and 26.32%), cetoacidosis (31.42% and 0%), urinary tract infection (18% and 0%) respectively in Insulin Dependent and Non Insulin Dependent Pregnancies. Near a third (31.6%) of Insulin Dependent and a third (33.41%) for Non Insulin Dependent were of D, F, H White's Class. Multipares were often Non Insulin Dependent and inversely Insulin Dependent frequently paucipare. Former Pregnancies had near 25.5% interrupted term in Insulin Dependents. Present Pregnancies have given 28.5% and 32% of Normal Children: 14.25 and 12% of Abortions and 14.25% and 6% of Spontaneous Premature Parturitions respectively in Insulin Dependents and Non Insulin Dependents. B--In Analytic Study of Foetopathies, bad Prognosis Factors were high Maternal Age, Multiparity, bad Glycemic Control whatever Diabetes type. For Insulin Dependent, Negligency was added and for Non Insulin Dependent, Obesity, Arterial Hypertension and all PBSP. DISCUSSION AND CONCLUSION: A relatively mild Diabetic Pregnancy Prognosis in our areas with limited means has been observed despite of Patients Education. PMID- 7857087 TI - Seasonal changes in liver and serum proteins, serum calcium, inorganic phosphate and magnesium levels in relation to vitellogenesis in a freshwater catfish, Heteropneustes fossilis (Bloch). AB - Female specimens of Heteropneustes fossilis show marked seasonal changes in liver and serum proteins, serum calcium, inorganic phosphate and magnesium levels in relation to the ovarian cycle. Their levels increase with the ovarian maturation, record the maximum values during the prespawning phase and gradually decline during spawning and postspawning phases. Thus, a positive correlation exists between liver and serum proteins, serum calcium, inorganic phosphate and magnesium levels during the annual ovarian cycle which seems to be related with vitellogenin synthesis. PMID- 7857088 TI - [Helicobacter pylori in peptic ulcer and gastric cancer]. AB - Recently many reports have shown a strong association between Helicobacter pylori infection in the stomach and recurrent peptic ulcer. Moreover, prospective cohort serological studies showed that H. pylori infected individuals have significantly increased rate of gastric cancer in the USA. H. pylori is a gram-negative spiral organism which has urease activity and produces ammonia and CO2 from urea, and nestles in the gastric pits and overlaying mucus gel layer. Many diagnostic methods of H. pylori infection are available; ie bacterial culture, 13C-urea breath test, histology, serum IgG antibody against H. pylori. We developed a new method, ie tissue IgA antibody against H. pylori and detection of H. pylori DNA in the gastric juice by PCR method. Triple therapies with metronidazole, bismuth compounds, and amoxicillin or tetracyclin are difficult to use in Japan because of their sever side effects. Thus, new methods with proton pump inhibitor (PPI) and amoxicillin have been introduced. We treated 14 patients of whom were H. pylori positive-active peptic ulcer with 30 mg/day of lansoprazole, a new PPI, plus 1,500 mg/day of amoxicillin for 2 weeks and 8 (57%) patients were eradicated. Gastric carcinogenesis are multi-steps and multifactorials process. Hypothetical sequence of intestinal type of gastric cancer is that superficial gastritis-->atrophic gastritis-->intestinal metaplasia-->dysplasia-->gastric cancer and H. pylori infection may play a role in the early stage of the sequence. We examined mucosal IgA antibody against H. pylori in chronic gastritis and intestinal metaplasia detected by the Tes-Tape method in 25 resected specimens after gastrectomy for gastric cancer. Positivity rates of tissue H. pylori IgA antibody were lower in the mucosa of intestinal metaplasia than in non metaplastic gastric mucosa and were negative in carcinoma. Causal relationship between H. pylori infection and gastric cancer is not proven and factors other than H. pylori infection are also important in the gastric carcinogenesis. Finally we introduce 2 reports: (1) NIH Consensus Conference: Helicobacter pylori in peptic ulcer disease (JAMA. 1994; 272: 65-69). The consensus panel concluded that 1. ulcer patients with H. pylori infection require treatment with antimicrobial agents in addition to antisecretory drugs whether on first presentation with the illness or on recurrence; 2. the value of treating nonulcerative dyspepsia patients with H. pylori infection remains to be determined; and 3. the interesting relationship between H. pylori infection and gastric cancer requires further exploration. (2) World Health Organization: Working Group Meeting (Reported in World Congress of Gastroenterology, Los Angeles, 1994). H. pylori plays a causal role in the chain of events leading to cancer of the stomach. Group I: definite carcinogen. PMID- 7857089 TI - [Laser bronchoscopic therapy of lung cancer]. AB - Laser endoscopic therapy has now achieved status as an effective treatment modality for lung cancer. The usefulness of Nd-YAG laser as palliative treatment for obstructive tracheobronchial tumors has been recognized. Our experience consisted in 205 YAG laser cases, including 184 obstructive tracheobronchial tumors, and the airway gauge was improved in 88.3%. On the other hand, the effectiveness of photodynamic therapy (PDT) using photofrin as a photosensitizer was demonstrated in our institution in 1979 for the treatment of lung cancers, and increasing attention has focused on this new treatment technique. Over the past decade, 211 patients with central lung cancers, including 66 cases of early stage lesions, have been treated at Tokyo Medical College Hospital, and a complete remission rate of 65.2% was achieved. We gave an overview of laser endoscopic therapy, including Nd-YAG laser treatment and photodynamic therapy, for lung cancer as well as an evaluation of the effectiveness of these therapies. PMID- 7857090 TI - [Thoracoscopic surgery of lung cancer]. AB - Thoracoscopic surgery is a dream that was realized by the remarkable progress achieved in the video equipment system and the development of advanced surgical tools, in particular the endoscopic stapler. The main reasons for the rapid and wide introduction of thoracoscopic surgery are that patient injury is much less than with the traditional chest operation, there is no need for blood transfusion, the physical and mental loads on the patient are much less, and recovery from surgery is much faster. When performed by a skilled surgeon, it is a safe surgical operation, and this surgical technique may become applicable to about one-half of thoracic surgery. The application of robotics and the use of artificial satellites in the sector of thoracoscopic surgery may be possible in the future. PMID- 7857091 TI - [Endoscopic mucosal resection of esophageal cancer]. AB - Limited surgery, esophagectomy without thoracotomy or endoscopic mucosal resection (EMR), is indicated for mucosal cancer of the esophagus without lymph node metastasis. Mucosal cancer less than 2 cm in size or less than a third of the circumference of the esophagus, is suitable for EMR. However, mucosal cancer invasive to the muscularis mucosa is excluded. As for postoperative complications, a small fissure, two cases of stenosis and 3 cases of oozing bleeding, were experienced. Conservative treatment was performed for all patients except one. The 5-year survival rate of EMR was 95%-100% in several institutions in Japan. Recurrence was observed in 3%-7%, however, it was cured by means of local treatment of esophageal cancer. PMID- 7857092 TI - [Endoscopic surgery for early gastric cancer by endoscopic mucosal resection (EMR)]. AB - Endoscopic mucosal resection (EMR) enables one to examine resected specimens histologically and judge the curability by the histological findings. A mucosa and a part of submucosa can be resected by EMR. Therefore, mucosal cancers are indications for EMR. The present study showed that better indications for EMR were as follows: lesions less than 10 mm in size, lesions without ulceration, and lesions in the antrum or at the greater curvature. However, it is difficult to judge correctly before EMR whether the lesions are completely resected or not. The lesions with better indications are not always resected completely, and, conversely, the lesions more than 11 mm in size are completely resected at times. Therefore, it is most important to know how to deal with resected specimens. Specimens must be dealt with in strict conformity with the regulations. At present, when EMR may be regarded as the least invasive modality of curative sugeries, a new systematic treatment combining surgical laparotomic treatment and EMR is desirable for curative treatment of early gastric cancer. PMID- 7857093 TI - [Endoscopic treatment of colorectal cancer]. AB - Endoscopic polypectomy should be applied only for early colorectal carcinomas. Intramucosal carcinoma do not have a risk of lymph node metastases. However, there is an about 10% risk of lymph node metastases among carcinomas showing submucosal invasion (sm carcinoma). When risk factors revealed to be positive after polypectomy, subsequent surgical resection of the large bowel with lymph nodes dissection is needed, because these sm carcinomas are considered to have a high risk of lymph node metastases. Therefore, accurate diagnosis of depth of invasion is essential to prevent subsequent surgical resection following endoscopic polypectomy. Endoscopy, barium enema and endoscopic ultrasonography (EUS) are all considered to be effective for an accurate diagnosis of depth of invasion. Endoscopic polypectomy includes hot biopsy, snare polypectomy and endoscopic mucosal resection (EMR). Appropriate maneuver must be chosen, considering the characteristics of the lesion. Major complications after endoscopic polypectomy are bleeding and perforation of the large bowel. Including an establishment of a new risk factors, further efforts must be made to prevent unnecessary additional surgical resection of the large bowel following endoscopic polypectomy. PMID- 7857094 TI - [Evaluation of new drug delivery system for primary lung cancer: intermittent intra-arterial injection therapy with implantable port system (reservoir)--II. Evaluation of technical methods for cannulation of feeding arteries of lung cancer with implantation of implantable port system]. AB - As mentioned in the first of the present series of reports, lung cancers were fed by various arteries such as bronchial arteries, internal mammary arteries, inter costal arteries and branches of subclavian arteries such as thyro-cervical truncus or thoraco-dorsal arteries, according to the size and stages of tumors and the processes of therapy. On the basis of these anatomical findings of the feeders of lung cancers, we tried several effective and reasonable ways of cannulation of catheters, which were connected with an implantable port system. PMID- 7857095 TI - [Effect of intraperitoneal chemotherapy with implantable reservoir against unresectable gastric cancer]. AB - Intraperitoneal chemotherapy was applied for eight unresectable gastric cancer patients, including two exploratory laparotomy and six gastrojejunostomy. Chemotherapeutic agents were given ip at a dose of 75 mg/body of cisplatin and 150 mg/body etoposide and iv at a dose of 10 mg/body of mitomycin C as well as orally 5-FU. This treatment was repeated three to ten times. An overall response rate against primary lesion was 40%. Six month and 1 year survival rate of this therapy were 87.5% and 75% respectively, while those of control group were 42% and 0%. Median duration of survival was 518 days in this chemotherapy group and 172 days in the control. In this study, intraperitoneal chemotherapy group showed a significant improvement of survival compared to the control. All patients were able to stay home between therapies. This method seemed to be beneficial to the unresectable gastric cancer patients. PMID- 7857096 TI - [Continuous intraarterial infusion of 5-fluorouracil plus leucovorin for liver metastases from colorectal cancer]. AB - Between September 1990 and August 1994, 11 patients (pts) with liver metastases (mets) from colorectal cancer were treated with continuous hepatic arterial infusion chemotherapy of 5-fluorouracil (FU) plus leucovorin (LV). Eight pts had non-resectable liver mets (H3: 7, H2: 1), and 3 had residual small mets after resection of major mets. Drugs were administered via an extracorporeal infusion device connected to the hepatic arterial infusion port. 5-FU and LV were given through a 5- to 7-day continuous infusion at 500-750 mg/body/day and 30 mg/body/day, respectively, with a 3- to 4-week rest period. In the recent 6 pts, cisplatin was administered as a 2-hour infusion at 25 mg/body, one or two times simultaneously. Grade 2 toxicity was noted in two pts (18%). One was stomatitis and another was uncontrolled ascites in an advanced cirrhotic pt. The response rate in the 9 evaluable pts was 67% with 6 PR and no CR. The duration of the response was 5 to 9 months. One- and two-year survival rates were 75% and 22%, respectively. These results were superior to those of the intermittent bolus injection of 5-FU plus MMC (or epirubicin) in 40 pts from 1977 to 1994. These results suggest that continuous 5-FU plus LV arterial infusion is an effective regimen in pts with liver metastases from colorectal cancer. However, the infusion with an extracorporeal device limits the pts' quality of life. Further investigation is needed for a schedule that can be practiced for a longer period. PMID- 7857097 TI - [Study on prognostic factors in twenty-five patients with myelodysplastic syndrome]. AB - Twenty-five consecutive patients with myelodysplastic syndrome (MDS) were followed in the Second Department of Internal Medicine, Miyazaki Medical School from 1984 to 1993. The diagnosis of MDS was morphologically based on the criteria of FAB. At the time of diagnosis, 9 patients had refractory anemia (RA), 1 had RA with ring sideroblasts (RARS), 6 had RA with excess blasts (RAEB), 6 had RAEB in transformation (RAEB-t), and 3 had chronic myelomonocytic leukemia (CMMoL). Prognostic factors involved in survival times and progression to leukemia were analyzed in these patients; FAB classification of MDS, age, sex, peripheral blood cell counts, bone marrow examination, karyotype, numbers of blasts. None of these prognostic factors had a significant effect on the prognosis of MDS patients. Study of the therapeutic effects on MDS patients revealed no significant increase of survival time in treated MDS patients compared to non-treated patients. Further, no significant difference in survival time was found between MDS patients treated with or without anticancer drugs. These results indicated that MDS patients were pathologically and therapeutically heterogeneous. PMID- 7857098 TI - [The prevention of cancer chemotherapy-induced emesis with granisetron and clonazepam]. AB - The antiemetic efficacy of a combination of granisetron and clonazepam was investigated in 39 gynecological cancer patients treated with cisplatin. Granisetron (3 mg/body/day) was administered by intravenous drip infusion before and 24 hours after anticancer drug administration, and clonazepam was taken orally twice a day. With a combination of granisetron and clonazepam, excellent efficacy was found in 87% (34/39) of the cases. Delayed emesis occurred in 38% (13/34), but the degree of nausea was mild. Clinically, antiemetic therapy with a combination of granisetron and clonazepam demonstrated superior antiemetic effects and seems to be useful for controlling nausea and vomiting associated with cancer chemotherapy. PMID- 7857099 TI - [Pharmacokinetic study of UFT in cancer patients receiving maintenance dialysis]. AB - Six post-operative cancer patients receiving chronic dialysis (4 colorectal and 2 gastric cancer) were given daily UFT (300 mg/day tid). To determine the clearance of UFT with dialysis, the plasma concentration of tegafur, 5-FU and uracil were measured on the day with dialysis and without dialysis. The plasma concentrations of tegafur at 2 hours after oral administration of UFT showed no difference between the day with dialysis and without dialysis. The concentration of 5-FU on the next day with dialysis was almost same as that of the patients with normal renal function because of the clearance of 5-FU with dialysis, although that on the 2nd day after dialysis was higher than that with dialysis. It was difficult to compare the plasma concentrations of uracil, because they are different in each patient. Therefore, it was considered to be difficult to maintain the suitable plasma concentration of uracil. However, clearance of UFT with dialysis was good and no severe side effect was observed in administration of UFT. These data suggest that UFT can be useful drug for gastrointestinal cancer patients receiving dialysis in a post-operative adjuvant chemotherapy. PMID- 7857100 TI - [Pharmacokinetic study in biochemical modulation therapy of UFT with leucovorin tablet]. AB - Preoperative oral treatment with UFT and leucovorin tablet was performed. Pharmacokinetics, degree of degeneration in the tumor tissue and side effects were studied in 34 patients with colorectal cancer preoperatively given 400 mg/day of UFT with 20 mg/day of leucovorin tablet or 400 mg/day of UFT alone. Results were as follows; 1) there was no significant difference between UFTL group and UFT group regarding concentration of FdUMP in the tumor tissue. In UFTL group, concentration of FdUMP was higher in the tumor tissue of moderately differentiated adenocarcinoma than that of well differentiated adenocarcinoma. No significant differences regarding concentration of FdUMP were obtained between diploid and aneuploid groups. 2) TS inhibition rate in the tumor tissue was 66.8% in UFTL group and 53.2% in UFT group, and there was a significant difference between these two groups. TS inhibition rate in the tumor tissue was higher than that in the normal tissue either in UFTL group or UFT group. However, there were no significant differences of TS inhibition rates regarding differentiation of tumor tissue or DNA ploidy pattern. 3) Degree of degeneration of more than Grade 2 was not obtained in any patients of either UFTL or UFT group. 4) There was no change in blood laboratory data between before and after medication. Only one patient complained Grade 1 pruritus in UFTL group. These results suggest that oral biochemical modulation therapy of UFT with leucovorin tablet is effective because of pharmacokinetically high anti-tumor effect and minimal side effects. PMID- 7857101 TI - [5-FU concentrations in the blood and tumor tissue after 5'-DFUR or UFT administration in the patients with uterine cervical cancer]. AB - In order to verify the antitumor activity of fluorinated pyrimidine drugs, we conducted an investigation of the clinical pharmacology with two drugs, 5'-DFUR and UFT. Total 21 cases of cervical cancer were alloted randomly into 5'-DFUR group (daily dose 800 mg for 3 days) consisting of 11 patients and UFT group (daily dose 600 mg for 3 days) consisting of 10 patients, the unchanged substances (5'-DFUR in the 5'-DFUR group and tegafur concentrations in the UFT group) and 5-FU concentrations in serum and tissues were measured 6 hours after administration of the drugs. The 5'-DFUR concentration in the 5'-DFUR group was not detected in serum and less than a detectable limit for all of cancerous tissues, normal cervical tissues, and lymph nodes. The tegafur concentrations in the UFT treated group was 13.8 +/- 7.0 micrograms/ml for serum, 10.4 +/- 6.4 micrograms/g for cancerous tissues, 14.1 +/- 7.3 micrograms/g for normal cervical tissues, and 4.5 +/- 4.2 micrograms/g for lymph nodes. The 5-FU concentrations in the 5'-DFUR treated group were 0.018 +/- 0.046 micrograms/g for cancerous tissues, but less than a detectable limit for serum and normal cervical tissues. On the other hand, in the UFT group, 0.271 +/- 0.247 micrograms/g for a cancerous tissue, 0.035 +/- 0.018 micrograms/ml for serum, 0.125 +/- 0.073 micrograms/g for normal cervical tissues, showing significantly high values (p < 0.01, p < 0.001, and p < 0.01, respectively) compared to those in the 5'-DFUR treated group. These results suggest that UFT is a promising drug for the treatment of cancer of the uterine cervix. PMID- 7857102 TI - [The clinical phase I study of TNP-351. The TNP-351 Research Committee]. AB - The clinical phase I study of TNP-351, an antifolate drug having a novel structure, was performed through a multicenter cooperative program in 40 patients with solid tumors. The test drug was used on dosage schedules of single and daily doses for 5 or 3 days (by intravenous drip over 30 minutes, respectively). From the daily administration for 5 days, severe adverse reactions such as myelosuppression, became manifest at 5 mg/m2 (1n). This schedule was then switched to daily administration for 3 days. Administration of the test drug was initiated at a dose of 5 mg/m2. On a single-dose schedule, the dose was increased up to 100 mg/m2 (20 n), and on the 3-day daily administration schedule, up to 10.8 mg/m2 (2.2 n). Consequently, 26 of the study patients received single doses; three of them the 5-day daily administration, and 11 the 3-day daily administration. The dose-limiting factors were leukopenia and thrombopenia on both the single-dose and 3-day daily administration schedules. MTD was 100 mg/m2, and MAD, 75 mg/m2 for the single-dose schedule; and 10.8 mg/m2 and 9 mg/m2 for the 3-day daily administration schedule. WBC and platelet counts fell to nadirs at 1-2 weeks on either the single-dose or 3-day daily administration schedule, and it took the respective parameters about 1 week to recover. Subjective and objective adverse reactions to the test drug consisted of digestive tract disorders manifested as stomatitis, anorexia, nausea and vomiting; and laboratory abnormalities such as elevations of GOT and GPT in addition to the myelosuppression. Many of these adverse reactions subsided within 3 weeks after initiation of TNP-351 treatment. On the single-dose schedule, the test drug occurred chiefly in unchanged form in the blood, and in this form it disappeared from the blood biphasically with an alpha phase of 0.29-0.95 hours, and a beta phase of 7.8-14.4 hours. This disappearance pattern did not vary with an increase in dose. The 24-hour urinary excretion rate of the unchanged form amounted to 42 62% of the administered doses. On the 3-day daily administration schedule, the test drug was not accumulated in vivo. In the present study, two patients with malignant fibrous histiocytoma responded to the test drug with tumor regression. The results suggested that the recommended dosage regimen for the clinical early phase II study of the test drug should comprise a course of 9 mg/m2/day (by intravenous drip infusion over 30 minutes) every day for 3 days, which should be repeated every 3 weeks. PMID- 7857103 TI - [A case of gastric cancer with multiple liver metastasis responding to combined therapy with UFT and mitomycin C]. AB - A 66-year-old female was admitted to our hospital with the complaint of anorexia and epigastric pain. Examination of the gastrointestinal tract revealed Borrmann III type gastric carcinoma, 5 cm x 5 cm in size, in the lesser curvature of the stomach. Multiple liver metastases were detected on abdominal computed tomography. In January 1993, she underwent subtotal gastrectomy as a palliative therapy. Pathological diagnosis of the resected specimen was poorly differentiated adenocarcinoma. Two weeks after operation, administration of UFT (300-450 mg/day, orally) and mitomycin C (12 mg/three months, intravenously) was started. This chemotherapy had to be discontinued within six months because of its severe side effects, such as leukopenia and acral erythema. However, a marked reduction in the size of the metastatic liver tumors was observed on abdominal computed tomogram, and the patient is now (15 months after operation) alive without local recurrence or re-growth of liver metastatic tumors. PMID- 7857105 TI - [A case report: postoperative recurrence of peritoneal dissemination of gastric cancer responding to sequential methotrexate and 5-FU (5-fluorouracil)]. AB - In a 61-year-old female patient, the recurrence of peritoneal dissemination after total gastrectomy due to gastric cancer responded well to chemotherapy of sequential methotrexate and 5-FU. A total of 10 courses of this chemotherapy diminished ascites, normalized the value of CA 19-9, and re-opened the left obstructed ureter. During this therapy, the patient's condition was good, with no experience of nausea or leukopenia. PMID- 7857104 TI - [A case of advanced gastric remnant carcinoma with Virchow's metastasis treated with neoadjuvant chemotherapy (low dose CDDP + 5-FU) followed by surgical resection]. AB - The patient was a 64-year-old woman. At hospitalization she had gastric remnant carcinoma with Virchow's and paraaortic lymph node metastases, extensive local infiltration and obstructive jaundice. The lesions were considered nonresectable, and the patient was placed on neoadjuvant chemotherapy consisting of low-dose CDDP and 5-FU, which resulted in the disappearance of Virchow's and paraaortic lymph node metastases. She was considered to have a partial response (PR) and underwent lower esophageal resection, total remnant gastrectomy and splenectomy. Eight months after surgery, however, she died of disseminated carcinomatosis of bone marrow. Since this therapy was associated with only slightly adverse events (< or = Grade 1), this treatment modality appears to be safe. However, further studies will be necessary to identify what type of recurrence is responsive to this therapy and to evaluate its effect on patient survival. PMID- 7857106 TI - [Delayed clearance of methotrexate in a patient with malignant lymphoma who developed renal failure]. AB - Malignant lymphoma of diffuse large cell type, was diagnosed in a 70-year-old man with tumors of the nasal cavity and right testis. He was treated with Epi-VEPA regimen and relapsed in the right thalamus just after achieving remission. Total cranial irradiation was effective, but multiple skin lesions were present at the time. He then suffered from renal failure and delayed clearance of MTX after high dose methotrexate (MTX) administration with citrovorum factor (CF). The serum concentration of MTX decreased to 0.09 microM within 285 hours by multi-clearance techniques as continuous arteriovenous hemoperfusion (CAVH), plasma exchange (PEX), peritoneal dialysis (PD) and charcoal hemoperfusion (CH). Better MTX clearance was observed in CH and PEX than in CAVH and PD, with higher effect in PEX than in CH or CAVH. The patient suffered severe mucositis and myelosuppression, but fatal harm of MTX was prevented. CH and PD were considered the best combination of clearance techniques for removing serum MTX in delayed methotrexate clearance with renal disturbance. PMID- 7857107 TI - [Acute necrotizing gastritis associated with adult T-cell leukemia in the course of chemotherapy]. AB - A 63-year-old man with smoldering adult T-cell leukemia (ATL) which became acute was admitted. During chemotherapy, he experienced epigastric pain and fever due to neutropenia. The combination therapy of antimicrobials and rhG-CSF was ineffective and he died. Autopsy revealed systemic invasion of ATL cells. The stomach findings resembled those of phlegmonous gastritis, a rare form of bacterial gastritis, along with diffuse, mucosal necrosis with hemorrhage. The pathogenesis of necrotizing gastritis remains to be elucidated. The patient had also received histamine H2 antagonist for gastric ulceration, which might have influenced the gastric bacterial flora. PMID- 7857108 TI - [Evaluation of new style of drug delivery system for primary lung cancer; intermittent intra-arterial injection therapy with subcutaneous infusible port- III. Evaluation of effects of intra-arterial chemotherapy through subcutaneous infusible port]. PMID- 7857109 TI - Focal dermal hypoplasia (Goltz's syndrome). Treatment of cutaneous lesions with the 585-nm flashlamp-pumped pulsed dye laser. PMID- 7857110 TI - Is dermatology slipping into its anec-dotage? AB - In recent issues, the Archives has run a feature entitled "In the Archives a Century Ago" in which a portion of a very old article is reprinted. These articles seem often to be chosen for comic interest and make good reading, seeing how widely our forefathers missed the mark. It is even better when the author is a familiar name. How could they think such crazy things? Usually a short while after feeling so smug, one of our residents, or perhaps a visiting internist, will give me a strange look after I state some dermatologic concept and ask how we have come to such a conclusion. Sometimes, it can be tough to defend (why do so many people get "insect bite reactions" in the dead of winter?), and I am left wondering how we know what we know. PMID- 7857111 TI - Sunlight exposure, pigmentary factors, and risk of nonmelanocytic skin cancer. I. Basal cell carcinoma. AB - BACKGROUND AND DESIGN: Basal cell carcinoma (BCC) of the skin is the most common neoplasm in white populations, and solar radiation is generally accepted to be the dominant environmental risk factor for this disease. However, little information is available on the nature of the relationship between BCC and sunlight. The purpose of this study was to evaluate the nature of the relationship between sunlight exposure, pigmentary factors, and BCC of the skin. A population-based case-control study of 226 male patients with BCC diagnosed from January 1, 1983, through December 31, 1984, and 406 randomly selected male control subjects was conducted in Alberta, Canada. The study was conducted using a standardized questionnaire, administered in person by trained interviewers. Data were analyzed using conditional logistic regression methods. RESULTS: After controlling for other host and pigmentary factors, the risk of BCC was increased in subjects with light skin color and those who freckled in childhood. A history of severe sunburn in childhood also increased risk. Subjects of southern European ethnic origin were at significantly lower risk of BCC. Surprisingly, no association was seen between mean annual cumulative summer sunlight exposure and risk of BCC. A significantly increased risk of BCC was seen in subjects with increased recreational sunlight exposure in adolescence and childhood (age, 0 to 19 years), although an inverse relationship was seen with lifetime recreation exposure. The relationship with childhood sun exposure was most pronounced among sun-sensitive subjects whose skin tended to burn rather than tan in the sun. CONCLUSIONS: The lack of association between cumulative sun exposure and BCC contradicts conventional wisdom about the cause of this tumor, and the increased risk with sun exposure at age 0 to 19 years suggests that childhood and adolescence may be critical periods for establishing adult risk for BCC. PMID- 7857112 TI - Sunlight exposure, pigmentation factors, and risk of nonmelanocytic skin cancer. II. Squamous cell carcinoma. AB - INTRODUCTION AND DESIGN: Squamous cell carcinoma of the skin (SCC), a common cancer in white populations, is related to sunshine exposure; however, relatively little information is available on how timing and character of exposure affect the relationship. The purpose of this study was to investigate the nature of the relationship of SCC to individual solar UV exposure after control for phenotype and pigmentary factors. All newly diagnosed cases of SCC were in men aged 25 through 79 years, ascertained in the province of Alberta from January 1, 1983, through December 31, 1984, who were approached for participation; 80% completed a standardized etiologic interview that was conducted in their homes by a trained interviewer. Control subjects were chosen at random from the Alberta Health Care Insurance Plan subscribers list, matched only by sex (male) and age (within a 5 year age group). The response rate among controls was 71%. RESULTS: Subjects with pale skin and red hair had an elevated risk of SCC. Subjects whose mother was of southern European ancestry had a reduced risk of SCC. After accounting for pigmentary factors, no association was seen between risk of SCC and cumulative lifetime sun exposure. However, a strong trend toward increasing risk was seen with increasing chronic occupational sun exposure in the 10 years prior to diagnosis. CONCLUSION: The results suggest that recent sun exposure (in the 10 years prior to diagnosis) may be important in accounting for individual risk of SCC. PMID- 7857113 TI - High sun protection factor sunscreens in the suppression of actinic neoplasia. AB - BACKGROUND AND DESIGN: A controlled trial was undertaken from December 1987 to December 1990 to test the hypothesis that a strong sunscreen can reduce the number of cancerous and precancerous skin lesions. Candidates were selected from a high-risk population attending either a university- or Veterans Affairs-based dermatology practice in Lubbock, Tex, for a prospective, double-blind, controlled trial of daily application of sunscreen vs placebo over a 2-year period. Participants were asked to volunteer if they had demonstrated premalignant changes (actinic keratoses) or nonmelanoma skin cancer (basal cell carcinoma or squamous cell carcinoma), had continuing sun exposure, and were not using sunscreen on a regular basis. Fifty-three volunteers were initially enrolled in the study, and 37 came for the final 24-month visit. RESULTS: The rate of appearance of new precancerous skin lesions was less for the treatment group than for control subjects. People with darker skin had fewer actinic keratoses, women had fewer lesions than men, and people with fewer lesions at enrollment had fewer lesions during the study. The numbers of new nonmelanoma skin cancers appearing during the study period were too small for statistical analysis. CONCLUSIONS: The regular use of sunscreens can significantly reduce cutaneous neoplasia, as indicated by its suppression of precancerous lesions. A longer and/or larger study would be necessary to demonstrate an effect on malignant lesions. PMID- 7857114 TI - A comparison of the efficacy and safety of Jessner's solution and 35% trichloroacetic acid vs 5% fluorouracil in the treatment of widespread facial actinic keratoses. AB - BACKGROUND AND DESIGN: We compared the efficacy and safety of a medium-depth chemical peel with those of the standard regimen of topical fluorouracil in the treatment of widespread facial actinic keratoses (AK). Fifteen patients with severe facial actinic damage and similar numbers of AK on both sides of the face were treated on the left side with a single application of Jessner's solution and 35% trichloroacetic acid and on the right side with twice daily applications of 5% fluorouracil cream for 3 weeks. Evaluations were conducted before treatment and at 1, 6, and 12 months after treatment. Visible AK were counted, random skin biopsies performed, adverse effects monitored, and patients questioned about preference and perception of efficacy. RESULTS: Both treatments reduced the number of visible AK by 75% and produced equivalent reductions in keratinocyte atypia, hyperkeratosis, parakeratosis, and inflammation, with no significant alteration of preexisting solar elastosis and telangiectasia. Except for erythema that lasted 3 months in one patient, no untoward side effects were observed with the chemical peel. The majority of patients preferred the peel over fluorouracil because of the single application and less morbidity. CONCLUSION: The medium depth peel induced by Jessner's solution and 35% trichloroacetic acid is a useful alternative therapeutic option for widespread facial AK, particularly for poorly compliant patients, because it equals fluorouracil in efficacy while being superior in terms of the convenience of a single application with little associated morbidity. PMID- 7857115 TI - Late irradiation damage to the skin caused by soft X-ray radiation therapy of cutaneous tumors. AB - BACKGROUND: Although radiotherapy of skin tumors has lost its former preeminence, there is still need for this modality. The aim of this study was, therefore, to determine the frequency of radiogenic ulcers and tumors following soft x-ray therapy of skin lesions. STUDY DESIGN: A total of 612 radiation sites in 522 patients were retrospectively analyzed by means of medical records. All patients received at least a total dose of more than 12 Gy and had a minimum follow-up time of 10 years. The average radiation dose was about 80 Gy, ranging from 56 to 184 Gy. Determined was occurrence of radiogenic tumors after more than 10 years and of ulcers during the entire follow-up period. The frequency of radiogenic tumors and ulcers was related to the total dose applied and the patient's age at the time of irradiation. RESULTS: In the 612 radiation fields used, 58 ulcers (9.4%), 12 basal cell carcinomas (2%), and nine squamous cell carcinomas (1.5%) were observed. There was no relationship between the total dose of radiation and the frequency of tumors; in contrast, radiogenic ulcers increased with a higher total dose. Radiogenic ulcers occurred more often in patients who were of a younger age at the time of irradiation. CONCLUSIONS: The risk of developing radiogenic ulcers and tumors after soft x-ray therapy is not very high. Since most of the ulcers can be prevented by modern dose recommendation (time dose fractionation factor), soft x-ray therapy can be considered as a safe and effective means of therapy, especially in older patients. PMID- 7857116 TI - Langerhans' cells in skin tumors. AB - DESIGN: We studied 58 skin specimens of normal skin (NS), basal cell epithelioma, squamous cell carcinoma, seborrheic keratosis, and malignant melanoma for the presence of Langerhans' cells (LCs) in and above the tumor. Anti-CD1 was used as a marker for LCs. All specimens were also incubated with anti-CD4, which also labels a certain number of LCs. RESULTS: All tumors contained LCs in the tumor and overlying epidermis. The number of LCs over basal cell carcinoma, squamous cell carcinoma, and malignant melanoma was significantly lower than in normal skin and seborrheic keratosis. These results are presented in detail and are compared with former studies discussing the different methodological approaches. CONCLUSIONS: Langerhans' cells were present in the epidermis of all the examined tumors. A certain percentage of LCs express CD4 surface antigen. This percentage varies from tumor to tumor. PMID- 7857117 TI - The role of genetic variation in thiopurine methyltransferase activity and the efficacy and/or side effects of azathioprine therapy in dermatologic patients. AB - BACKGROUND: Thiopurine methyltransferase (TPMT) is one of three major enzymes involved in the metabolism of azathioprine and its active metabolite 6 mercaptopurine. Thiopurine methyltransferase activity is determined by an allelic polymorphism for either high (TPMTH) or low (TPMTL) enzyme activity. Homozygotes for the low activity allele are known to be at risk for profound myelosuppression with azathioprine. Heterozygotes may be at risk for myelosuppression. Homozygotes for the high activity allele may be inadequately immunosuppressed with conventional, empiric doses of azathioprine. We analyzed TPMT activity in red blood cell (RBC) lysates and determined the TPMT genotypes (based on normal population screening) of 28 dermatologic patients. This information was correlated with the observed efficacy and side effects of azathioprine therapy. OBSERVATIONS: Two patients with TPMT levels of less than 12.5 U/mL RBCs (both TPMTH heterozygotes) experienced leukopenia (white blood count < 4.0 x 10(9)/L) with azathioprine doses around 1.5 mg/kg. A third patient who experienced leukopenia had a TPMT level at the lower end of the homozygous range (15.5 U/mL RBCs) but received the highest dose of azathioprine (2.6 mg/kg) of all patients in this series. Ten patients with TPMT levels of more than 18.5 U/mL RBCs (all TPMTH homozygotes) receiving less than 1.5 mg/kg of azathioprine were judged to have a poor clinical response. In comparison, seven patients with TPMT levels between 12.5 and 18.5 U/mL RBCs (six TPMTH homozygotes and one TPMTH heterozygote) receiving 0.9 to 1.8 mg/kg of azathioprine had a favorable clinical response. Adverse effects of gastrointestinal upset and liver function test abnormalities did not appear to correlate with TPMT activity. CONCLUSION: The TPMTH heterozygotes may be at increased risk for myelosuppression with standard, empiric doses of azathioprine. On the other hand, homozygotes for TPMTH, particularly those with TPMT levels at the upper end of the homozygous range, may have a poor clinical response to azathioprine due to inadequate empiric dosing. PMID- 7857118 TI - Trichoblastic fibroma. A series of 10 cases with report of a new plaque variant. AB - BACKGROUND: Trichoblastic fibroma is a benign trichogenic tumor that has both epithelial and mesenchymal components and exhibits partial to complete follicular induction. We studied 10 cases of trichoblastic fibroma and reviewed their clinical and histologic features. OBSERVATIONS: All 10 tumors were located on the face. Nine of 10 patients were women. The mean age at presentation was 63.8 years (range, 35 to 81 years). Two distinct subsets of trichoblastic fibroma were identified: the nodular variant and the plaque variant. The nodular variant is well circumscribed, while the plaque variant is poorly circumscribed, has significant subclinical extension, and may represent the low-grade malignant counterpart of the classic nodular trichoblastic fibroma. Histologically, both variants demonstrate mesenchymal induction with keratin cysts, papillary mesenchymal bodies, and an inductive fibroblastic stroma. CONCLUSIONS: Trichoblastic fibroma may be confused clinically and/or histologically with basal cell carcinoma. Identification of the mixed epithelial-mesenchymal components is helpful in tumor recognition. The plaque variant trichoblastic fibroma has not been previously reported. Familiarity with this variant is important because of the potential for infiltrative growth. PMID- 7857119 TI - Acute cutaneous reactions to docetaxel, a new chemotherapeutic agent. AB - BACKGROUND: Docetaxel (RP 56976) is a new chemotherapeutic agent that has shown promise in a number of animal studies and is currently undergoing phase I and phase II trials. Early in the phase I trials, it was noted that a significant number of patients were experiencing a variety of cutaneous complaints, so we elected to prospectively evaluate the cutaneous reactions occurring during the first three courses of therapy in the first 12 patients enrolled for phase I chemotherapy at our institutions. OBSERVATIONS: All but one patient had some type of cutaneous eruption over the three courses of therapy. Of the 27 evaluable courses of docetaxel given, 19 (70%) resulted in a cutaneous eruption with four (21%) being asymptomatic and 15 (79%) being at least mildly symptomatic. The most common reaction seen was characterized by discrete erythematous to violaceous patches or edematous plaques similar to acral erythema. CONCLUSION: Although a majority of patients receiving docetaxel experience some degree of cutaneous reaction, the eruptions are usually mildly symptomatic and almost always self limiting. PMID- 7857120 TI - A solitary, erythematous, hyperkeratotic papule. Acantholytic acanthoma. PMID- 7857121 TI - Pedal papule. Eccrine porocarcinoma (EPC) in association with poroma. PMID- 7857122 TI - Long-standing subcutaneous nodule in a young woman. Plexiform fibrohistiocytic tumor. PMID- 7857123 TI - Solitary facial plaque of long duration. Desmoplastic trichoepithelioma. PMID- 7857124 TI - Sunscreens for cancer prevention. PMID- 7857125 TI - Pseudolymphoma? PMID- 7857126 TI - Occlusion of potent topical steroids. PMID- 7857127 TI - Occlusion of potent topical steroids. PMID- 7857128 TI - Diascopy, the lips, and vitiligo. PMID- 7857129 TI - Recurrent leg ulcerations as the initial clinical manifestation of Klinefelter's syndrome. PMID- 7857130 TI - Failure of livedoid vasculitis to respond to tissue plasminogen activator. PMID- 7857131 TI - [Neurothekeoma. General review apropos of an anatomoclinical case with immunohistochemical and ultrastructural study]. AB - The authors report a case of neurothekeoma in a 16-year-old woman. The tumor was located in the dermis of the chin and exhibited a plexiform and multinodular architecture with dense lobules admixed with myxoid areas. Tumor cells were pleomorphic and few atypias and mitoses were seen. On immunohistochemical study, intracytoplasmic staining was observed with anti-vimentin antibody, and, to a lesser extent, with KP1 antibody. Few elements expressed S100 protein. Ultrastructural analysis showed undifferentiated mesenchymal cells. A review of 156 cases (of which 123 cases are reported in two main series) shows that neurothekeoma preferentially affects dermis in cervicofacial areas and shoulders in young women. It has a benign course and recurrence is not seen provided excision is complete. Two main histological varieties are described, i.e. cellular and myxoid, the latter being referred to as nerve sheath myxoma. Diagnostic problems can be raised with other nerve sheath tumors and melanocytic and fibrohistiocytic proliferations. Transition forms between neurothekeoma and neurinoma or neurofibroma are described. Despite confusing immunohistochemical and ultrastructural data, most authors admit that neurothekeoma can express schwannian or perineurial differentiations, and may also be derive from an undifferentiated mesenchymal cell of neural crest origin. PMID- 7857132 TI - [Seven cases of subependymoma. Anatomoclinical study and review of the literature]. AB - Subependymomas are uncommon, benign, slowly growing lesions usually located in the fourth ventricle. Their morphology is characteristic, but their histogenesis remains controversial. Seven cases observed in our laboratory over a period of 7 years are reported. Most tumors were located axially in the brain stem, and symptoms were more variable than usually reported. The histological appearance was fairly uniform. Immunohistochemistry showed that the fibrillary component was composed of glial fibers. Ependymary differentiation is inconstant on electron microscopy. The pathogenesis of the lesion (tumor, hamartoma or reactive proliferation) is debated in the literature as is the histogenesis. PMID- 7857133 TI - [Collagenous enterocolitis. Apropos of a case and review of the literature]. AB - Collagenous enterocolitis is a recent entity of which only two cases have been published. The authors report the association of collagenous colitis and collagenous sprue in a 67-year-old woman. The diagnosis of collagenous enterocolitis is based on the presence of a duodenal collagen deposit with partial villous atrophy associated with collagenous colitis. The symptom appeared one month after non-steroidal antiinflammatory treatment. The authors discuss the role of drug toxicity in the pathogenesis of collagenous enterocolitis. PMID- 7857134 TI - [Adenoid cystic carcinoma (cylindroma) of the uterine cervix. Histology, immunohistochemistry, ultrastructure in a case, with review of the medical literature]. AB - The authors report a case of adenoid cystic (cylindromatous) carcinoma of the endocervical canal associated with an intraepithelial squamous cell carcinoma of the cervical os in a 60-year-old woman suffering from metrorrhagia. Immunohistochemical study demonstrated labeling of cylindromatous cells with anti actin, anti-vimentin and anti-keratin antibodies. Ultrastructural study provided significant findings to confirm that the hyaline material surrounded by tumor cells was derived from the remnants of the lamina densa of the basement membrane of tumor lobules. These morphological data are similar to those observed in adenoid cystic carcinomas (cylindromas) of salivary glands. They support the hypothesis that adenoid cystic carcinoma of the cervix may develop from the multipotent reserve cells. PMID- 7857135 TI - Perinatal death and thymus gland. AB - Three hundred (300) cases of perinatal death were autopsied and the thymus was removed for histologic examination. The histologic findings were classified into five groups: a) normal-mature thymus, b) involutional changes--"Starry sky" pattern, c) involutional changes--intense lymphocytic depletion, d) hypoplasia- aplasia, e) agenesis. The perinatal deaths were classified into five groups according to Wigglesworth's classification: 1) normally formed macerated stillborn neonates, 2) congenital malformations, 3) conditions associated with immaturity, 4) asphyxial conditions developing in labor, 5) other specific conditions (e.g. known-beta-hemolytic streptococcal infection or a fatal inborn error of metabolism). The main objective was to identify a possible correlation between sex, gestational age, birth weight, thymus weight, histologic features of the thymus and cause of death. In conclusion, a strong correlation was found between: a) weight of thymus and gestational age, b) weight of thymus and birth weight, c) weight of thymus and its histologic features, d) histologic features of thymus and cause of death, e) weight of thymus and cause of death, f) gestational age and cause of death. No correlation was found between: a) gestational age and histologic features of thymus, b) birth weight and histologic features of thymus, c) weight of thymus and sex, d) histologic features of thymus and sex, e) cause of death and sex. PMID- 7857136 TI - [Charcot, anatomo-pathologist]. AB - Charcot (1825-1893) brought new vigor to the clinicopathologic tradition of the Paris school by adding to macroscopic anatomy the new dimension of histology- still marginal in France when, in 1862, he came to the Salpetriere and undertook the exploration of its enormous resources in pathology. Vulpian was the initiator. Cornil, Charcot's intern in 1863, taught him the techniques which he had acquired from Virchow's laboratory. Within a decade, Charcot established the bases for a neurological classification which have endured. He described multiple sclerosis. He attributed progressive and acute muscular atrophy to lesions of anterior horns of the spinal cord; locomotor ataxia to the posterior horn and spinal root. He gathered together the data leading to the description of amyotrophic lateral sclerosis. In 1872 (in fact 1873) he replaced Vulpian in the chair of pathological anatomy which he held for ten years. His lessons in pathology of the viscera; kidney, liver, and bile ducts, lung, make up several volumes of his Completes Works. In the study of Localizations of diseases of the spinal cord (1873-74), he specified the anatomy and physiology of the cord. In 1875, and then in 1880, the Cerebral localizations of motor activities marked a decisive step. By 1882, when the clinical chair for the diseases of the nervous system was inaugurated, Charcot was already substantially involved in the study of hysteria. He approached that subject from a perspective that remained loyal to pathology setting up by analogy an ongoing correspondence in terms of anatomical sites, between the "dynamic lesion" assumed to be responsible for manifestations of the neurosis, and organic lesions which produced the same symptoms. PMID- 7857137 TI - [Adenomatoid odontogenic tumor. A case with an unusual mandibular site]. AB - An adenomatoid odontogenic tumor located in the mandible was studied in a 28 year old woman. The clinical, histological and ultrastructural characteristics of this rare tumor are described out and the histogenesis is discussed. PMID- 7857138 TI - [Acute phlegmonous gastritis. Apropos of a case]. AB - Phlegmonous gastritis is a rare bacterial infection of the stomach. Its diagnosis is difficult and has a poor prognosis. The authors report a case of phlegmonous gastritis occurring in a 50 year-old woman in whom the diagnosis was made by microscopic examination after surgery for intestinal occlusion. The patient died a few hours after the operation. PMID- 7857139 TI - [Granular cell tumors of the breast. Apropos of two cases]. AB - Granular cell tumors of the breast are rare. The clinical presentation, the poor macroscopical delimitation and the infiltrating appearance of the tumor cells between the mammary lobules and within the adipose tissue may lead to a diagnosis of carcinoma, especially on frozen section. The authors present two cases of granular cell tumor of the breast occurring in two women aged 19 and 59 respectively. Before surgery, the diagnosis was that of a malignant tumor. In both cases, frozen section suggested the diagnosis of a granular cell tumor, which was confirmed by immunohistochemical study in one patient. PMID- 7857140 TI - Cytoreductive surgery and intraperitoneal chemotherapy for peritoneal carcinomatosis. PMID- 7857141 TI - Prognostic features of 51 colorectal and 130 appendiceal cancer patients with peritoneal carcinomatosis treated by cytoreductive surgery and intraperitoneal chemotherapy. AB - OBJECTIVE: A treatment plan to be used in patients with peritoneal carcinomatosis was devised and tested as a Phase II study. BACKGROUND: Peritoneal carcinomatosis from appendical or colorectal cancer has been regarded as a fatal clinical entity. Treatment protocols have not been reported previously. METHODS: The authors used cytoreductive surgery and intraperitoneal chemotherapy to treat 181 consecutive patients with peritoneal carcinomatosis. There were 51 patients with colorectal cancer and 130 patients with appendiceal cancer. Mean follow-up is 24 months, with a range of 0 to 149 months. RESULTS: Clinical features that showed prognostic significance included appendiceal versus colorectal primary tumors (p = 0.0001), grade 1 versus grades 2 and 3 histopathology (p = 0.0003), complete versus incomplete cytoreductions (p = 0.0001), lymph node-negative versus lymph node-positive primary tumors (p = 0.0001), and volume of peritoneal carcinomatosis present preoperatively for colon cancer (p = 0.0006). Features with no statistical prognostic significance included preoperative tumor volume for appendiceal cancer, age, sex, number of cycles of chemotherapy, operative time, complications, blood loss, and institution providing treatment. From these prognostic features, four prognostic groups were identified, and 3-year survival was estimated by the product-limit survival method. Group I patients (n = 76) were those with grade 1 histology, no lymph node metastases, and complete cytoreductions (survival at 3 years = 99%). Group II patients (n = 23) were those with grade 2 or 3 histology, no lymph node metastases, and complete cytoreductions (65%). Group III patients (n = 24) had any histology, lymph node metastases, and complete cytoreductions (66%). Group IV patients (n = 58) had incomplete cytoreductions (20%). PMID- 7857142 TI - Laparoscopic antegrade sphincterotomy. A new technique for the management of complex choledocholithiasis. AB - OBJECTIVE: Laparoscopic antegrade sphincterotomy represents a new technique that expands the ability of the surgeon to manage complex choledocholithiasis at the time of laparoscopic cholecystectomy. The authors describe their experience with six patients with cholelithiasis and complex common bile duct stone disease who underwent successful laparoscopic cholecystectomy and antegrade sphincterotomies. SUMMARY BACKGROUND DATA: Patients with complex choledocholithiasis have represented a technical challenge to the minimally invasive surgeon. Recently, a laparoscopic technique of antegrade biliary sphincterotomy has been reported by DePaulo in Brazil. This technique has been successful at clearing the common bile duct at the time of laparoscopic cholecystectomy. METHODS: Laparoscopic antegrade sphincterotomy was performed in six patients with multiple common bile duct stones. A standard endoscopic sphincterotome was introduced antegrade via the cystic duct or common bile duct and guided through the ampulla. A side-viewing duodenoscope was used to confirm proper positioning of the sphincterotome. Then a blended current was applied until the sphincterotomy was complete. RESULTS: There was no mortality or morbidity associated with laparoscopic antegrade sphincterotomy. The mean additional operative time to complete laparoscopic antegrade sphincterotomy was 19 minutes. Three of the six patients were noted to have transient, asymptomatic elevation in serum amylase levels immediately after surgery (average 252 international units/L; normal < 115), which normalized within 72 hours. The mean postoperative hospital stay was 2.9 days. At a mean follow-up of 5 months (range 1 to 10 months), five patients remain asymptomatic. One individual with acquired immune deficiency syndrome had persistent symptoms, and a diagnosis of cytomegalovirus pancreatitis was eventually made. CONCLUSIONS: Laparoscopic antegrade sphincterotomy appears to be a safe and effective technique for the management of complex biliary tract disease. PMID- 7857143 TI - Carcinoma of the pancreatic head and periampullary region. Tumor staging with laparoscopy and laparoscopic ultrasonography. AB - OBJECTIVE: The authors performed a prospective evaluation of staging laparoscopy with laparoscopic ultrasonography in predicting surgical resectability in patients with carcinomas of the pancreatic head and periampullary region. SUMMARY BACKGROUND DATA: Pancreatic resection with curative intent is possible in a select minority of patients who have carcinomas of the pancreatic head and periampullary region. Patient selection is important to plan appropriate therapy and avoid unnecessary laparotomy in patients with unresectable disease. Laparoscopic ultrasonography is a novel technique that combines the proven benefits of staging laparoscopy with high resolution intraoperative ultrasound of the liver and pancreas, but which has yet to be evaluated critically in the staging of pancreatic malignancy. METHODS: A cohort of 40 consecutive patients referred to a tertiary referral center and with a diagnosis of potentially resectable pancreatic or periampullary cancer underwent staging laparoscopy with laparoscopic ultrasonography. The diagnostic accuracy of staging laparoscopy alone and in conjunction with laparoscopic ultrasonography was evaluated in predicting tumor resectability (absence of peritoneal or liver metastases; absence of malignant regional lymphadenopathy; tumor confined to pancreatic head or periampullary region). RESULTS: "Occult" metastatic lesions were demonstrated by staging laparoscopy in 14 patients (35%). Laparoscopic ultrasonography demonstrated factors confirming unresectable tumor in 23 patients (59%), provided staging information in addition to that of laparoscopy alone in 20 patients (53%), and changed the decision regarding tumor resectability in 10 patients (25%). Staging laparoscopy with laparoscopic ultrasonography was more specific and accurate in predicting tumor resectability than laparoscopy alone (88% and 89% versus 50% and 65%, respectively). CONCLUSIONS: Staging laparoscopy is indispensable in the detection of "occult" intra-abdominal metastases. Laparoscopic ultrasonography improves the accuracy of laparoscopic staging in patients with potentially resectable pancreatic and periampullary carcinomas. PMID- 7857144 TI - Superior nitrogen balance after laparoscopic-assisted colectomy. AB - BACKGROUND: Although early resumption of enteral feeding after gastrointestinal surgery results in improved nitrogen balance and lower infectious complications, no postoperative nutritional data after laparoscopic-assisted colectomy exists. OBJECTIVE: The authors prospectively compared nitrogen balance after laparoscopic assisted colectomy versus open colectomy. METHODS: This is a series of colon resections (open, N = 10; laparoscopic-assisted, N = 9) at the Ferguson-Blodgett Hospital, Grand Rapids, Michigan, between January and March 1993. Nitrogen intake and 24-hour urine collections were performed on postoperative days 1, 3, and 7 for the analysis of total urinary nitrogen and urinary 3 methylhistidine-(3mH). RESULTS: The time to passage of flatus (4.7 +/- 0.6; 2.0 +/- 0.2), resumption of oral intake (6.1 +/- 0.7; 1.4 +/- 0.2; p < 0.05, Student's test), first bowel movement (5.2 +/- 1.0; 3.0 +/- 0.3; p < 0.05, Student;s t test), and discharge (10.3 +/- 1.3; 4.1 +/- 1.8; p < 0.05, Student's t test) occurred significantly earlier in the laparoscopic-assisted colectomy group. Overall hospital charges were lower in the laparoscopic-assisted colectomy group ($11,572 +/- $823 vs. $13,961 +/- $1050). The operative time was higher in the laparoscopic-assisted colectomy group (176 +/- 12 hours vs. 105 +/- 17 hours, p < 0.05,Student's test). Blood loss was higher in the open group (805 +/- 264 mL vs 217 +/- 32 mL, p < 0.05, Student's test). Urinary nitrogen losses were similar between the two groups; however, significantly more patients in the laparoscopic-assisted colectomy group achieved net positive nitrogen on day 3 (6/9; 0/10; p < 0.05, Fisher's exact test), and day 7 (9/9; 4/10; p < 0.05, Fisher's exact test). Infectious complications occurred less frequently in the laparoscopic-assisted colectomy group (0/9 vs. 4/10; p < 0.05, Fisher's exact test). CONCLUSIONS: Patients undergoing laparoscopic-assisted colectomy can achieve early resumption of enteral nutrition with earlier return to positive nitrogen balance compared with open colectomy. This may offer benefits of fewer infectious complications and lower cost of care. PMID- 7857145 TI - Comparison of manually constructed and stapled anastomoses in colorectal surgery. West of Scotland and Highland Anastomosis Study Group. AB - OBJECTIVE: The authors compared both the initial and the long-term outcomes of patients undergoing stapled and sutured colorectal anastomoses. SUMMARY BACKGROUND DATA: Sutured and stapled large bowel anastomoses are perceived to be equally safe, but concern has been raised about increased rates of tumor recurrence with the use of stapling instruments. METHODS: The outcome of patients with sutured and stapled colorectal anastomoses were compared in a prospective, multicenter, randomized study. Factors affecting long-term outcomes were assessed by both univariate and multivariate analysis. RESULTS: Seven hundred thirty-two patients were recruited. There was a significant increase in radiologic leakage in the sutured group (14.4% vs. 5.2%, p < 0.05), but there was no difference in clinical anastomotic leak rates, morbidity, or postoperative mortality. Tumor recurrence and cancer-specific mortality were higher in the sutured patients (7.5% and 6.7%, respectively) and in patients with anastomotic leaks. CONCLUSIONS: This study shows that suturing or stapling are equally safe in large bowel surgery. However, it also shows a long-term benefit of stapling in colorectal cancer patients. PMID- 7857147 TI - Contributions of the Mayo Clinic in World Wars I and II. PMID- 7857146 TI - Prognostic factors predictive of survival for truncal and retroperitoneal soft tissue sarcoma. AB - OBJECTIVE: The authors identified prognostic factors relevant to clinical outcomes (especially survival) in truncal and retroperitoneal soft-tissue sarcoma. SUMMARY BACKGROUND DATA: These results can be used to optimize surgical management and select patients most likely to benefit from novel therapeutic strategies in future trials. METHODS: A retrospective analysis was performed of a prospectively compiled database of 183 consecutive patients with truncal and retroperitoneal sarcomas seen at the Brigham and Women's Hospital and the Dana Farber Cancer Institute between 1970 to 1994. RESULTS: For truncal sarcoma, multivariate analysis showed that high-grade histology was associated with an eightfold increased risk of death compared with low-grade histology (p = 0.001). In addition to grade, gross positive margin of resection (p = 0.001), microscopic positive margin (p = 0.023), and tumors greater than 5 cm in size (p = 0.018) were important independent prognostic factors for survival. In this series, postoperative radiation therapy for truncal sarcoma was associated with a 2.4 fold decreased risk of death compared with truncal sarcoma patients receiving no adjuvant radiation therapy, having adjusted for the other prognostic factors (p = 0.030). In contrast, for retroperitoneal sarcoma, multivariate analysis showed that high-grade and intermediate-grade histology were associated with a five- to sixfold increased risk of death compared with low-grade histology (p = 0.009). In addition to grade, gross positive margin of resection (p = 0.001) and microscopic positive margin (p = 0.004) were important independent prognostic factors for survival in retroperitoneal sarcoma. Patients who received either preoperative or postoperative chemotherapy for retroperitoneal sarcoma had a 4.6-fold (p = 0.002) and 3-fold (p = 0.010) increased risk of death, respectively, compared with patients receiving no adjuvant chemotherapy, having adjusted for the other prognostic factors. CONCLUSIONS: The histologic grade and the margin of resection are prognostic for survival in both truncal and retroperitoneal soft-tissue sarcoma. Tumor size was an independent prognostic factor for truncal sarcoma, but not for retroperitoneal sarcoma. Postoperative adjuvant radiation was beneficial to overall survival for truncal sarcoma. In this series of patients receiving a heterogeneous mixture of chemotherapeutic regimens-either as preoperative "neoadjuvant" therapy or as postoperative "adjuvant" therapy, there were no beneficial effects on survival compared with nonrandomized patients not receiving chemotherapy. PMID- 7857148 TI - Appendicular adenocarcinoma. PMID- 7857149 TI - Treatment of rectal cancer by low anterior resection with coloanal anastomosis. PMID- 7857150 TI - Patients with soft-tissue sarcomas. PMID- 7857151 TI - Injection sclerotherapy in patients with extrahepatic portal venous obstruction. PMID- 7857152 TI - Preoperative visceral angiography for mapping the midgut arterial anatomy. PMID- 7857153 TI - Incidence, timing, and management of biliary tract complications after orthotopic liver transplantation. PMID- 7857155 TI - [Experimental study of the effect of antimicrobial substances on the dissemination of solizyme during its purification]. AB - Microorganisms of different taxonomic groups were isolated from intermediate products of microbial lipase and shown to be able to multiply in them. Therefore, the intermediates forming during solizyme production could be potential nutrient media for growth of the contaminating microflora. The effect of chlorhexidine active against the contaminating microorganisms on the growth of the microbial biomass was studied and it was shown that chlorhexidine could lower the dissemination of the intermediates in production of solizyme. Neomycin added at the stage of the solizyme chemical purification retarded solely the growth of staphylococci contaminating the solizyme intermediate products. The use of antimicrobial agents for the solution of the problem of the solizyme microbial contamination requires the consideration of the contamination level, temperature conditions of the production process and susceptibility of the microflora to the antimicrobial agent used. PMID- 7857154 TI - [Use of electrodialysis in the technology of desalinization of chromatographic eluates of proteins]. AB - In a model of recombinant protein as an intermediate in production of rRNA-origin insulin, electrodialysis was shown to be useful in demineralization of protein chromatographic eluates. The operation conditions were developed. It was demonstrated that the electrodialysis provided higher purity of the recombinant protein. PMID- 7857156 TI - [Experimental substantiation of population heterogeneity in methicillin resistant Staphylococcus aureus]. AB - A comprehensive intraspecies typing of the cultures of MRSA collected during inspection of drug resistance in causative agents of intrahospital infections was performed. The following parameters were investigated: antibiotic resistance, toxin production, sensitivity to the phages of the International Set and the phages of an experimental collection providing the isolation of strains with definite specificity of the restriction-modification system. Different clones of methicillin resistant S. aureus were found to be circulating on the territory of the CIS. PMID- 7857157 TI - [Actinomycete plasmid and integrative vectors based on DNA of the temperate Phi C31 actinophage, determining limitation of lytic development of phage Phi C31, not dependent on repressor]. AB - Bireplicon plasmids were constructed. The plasmids consist of DNAs of the streptomycete plasmid pIJ702, the Escherichia coli plasmid pUC19 and the phi C31 actinophage genome fragment encoding the function of the site-specific integration into the chromosome. Part of the plasmids transformed Streptomyces lividans TK64 to thiostreptone resistance. The DNA transforming activity depended on the mutual orientations of the blocks used for the construction and probably depended on the structural stability of the plasmids in S. lividans. The integrative vectors consisting of the pUC19 plasmid DNA and the phage genome fragment with the integrative function efficiently transformed S. lividans. No phage plagues were detected with the standard procedure of integrants' infection by phi C31 phage, despite the absence of the phi C31 phage repressor gene in the integrated DNA. The phi C31 phage mutants including clear and virulent ones were not capable of lytic growth on the integrants. The region determining the limitation of the phi C31 phage lytic development was localized by the deletion analysis of the bireplicon plasmids. As a result actinomycete monoreplicon plasmids were formed. The region is the 1.3 kb phage fragment whose right end maps at 0.2 kb preceding the right end of the phi C31 phage genome linear map. PMID- 7857158 TI - [Sensitivity of Pseudomonas mallei to tetracyclines and their effectiveness in experimental glanders]. AB - MICs and MBcCs of minocycline, doxycycline, methacycline and chlortetracycline for 8 strains of Pseudomonas mallei were determined. The chemotherapeutic efficacy of minocycline and doxycycline was studied on golden hamsters and their efficacy indices were estimated in comparison with those of chlortetracycline in the prophylaxis and treatment of experimental malleus. Minocycline was shown to be the most efficient drug in the treatment of malleus. Doxycycline in a dose of 0.25 mg/kg practically had the same efficacy as chlortetracycline in a dose of 25 mg/kg. Methacycline was inefficient. PMID- 7857159 TI - [Combined use of quinolones with other antibiotics in treatment of experimental plague infection]. AB - The efficacy of combinations of fluoroquinolones (ciprofloxacin and pefloxacin) with betalactams (ampicillin, azlocillin and cefotaxime), aminoglycosides (amikacin) and rifampicin was studied on albino mice infected subcutaneously with plague. The drugs were used in deliberately ineffective or insufficiently effective doses. Synergism was observes with the use of ciprofloxacin and pefloxacin in combinations with amikacin, cefotaxime or rifampicin. The combinations of ciprofloxacin with ampicillin or azlocillin had no synergistic action though the therapeutic effect was not lower. With using the specifically determined doses the efficacy of the combinations could be increased by comparison with that of the drugs used alone. PMID- 7857160 TI - [A method of sequential administration of antibiotics in preventive treatment of experimental plague in albino mice]. AB - Combination of a betalactam antibiotic (ampicillin or azlocillin) or polymyxin B with rifampicin were studied with their administration in succession at various intervals in an experimental model of plague infection of albino mice. It was shown that when the administration of the betalactams or polymyxin B preceded the administration of rifampicin, the efficacy of the preventive therapy considerably increased. The time of the intervals was noted to be of importance and should be predetermined for every subsequent administration. PMID- 7857161 TI - [In vitro activity of surgical suture materials containing cephalosporin antibiotics]. AB - Surgical threads containing cefazolin and cefoperazone were studied comparatively. Cefazolin was shown to incorporate into the structure of caproamide threads in an amount of 20 per cent by the thread weight while the cefoperazone incorporation amounted only to 3.7 per cent. The dynamics of the antibiotic release from the threads was investigated in detail and it was found that cefazolin had no advantages over cefoperazone. In spite of the equal value with respect to the antibiotic release, cefoperazone proved to be a better drug, its use was more economic and the spectrum was broader. Therefore, the threads containing cefoperazone could be considered more promising for the prophylaxis of surgical infections. PMID- 7857162 TI - [Effectiveness of comprehensive therapy of broncho-obstructive syndrome]. AB - Patients with chronic obstructive diseases of the lungs and bronchial asthma were treated with terbutaline sulfate in combination with cefotaxime. The results of the treatment were found to be favourable. PMID- 7857163 TI - [New achievements in the fluoroquinolone problem: possibilities of increasing activity and expansion of the spectrum of action]. AB - Studies of antibacterial compounds and drugs belonging to the derivatives of 6 fluoroquinolones are reviewed. The structure-function dependencies, the introduction of additional fluorine atoms to the structure and the cycle substitutions at positions 5 and 8 are discussed from the viewpoint of the antibacterial activity increasing and the spectrum broadening. The data on the activity of new 6-fluoroquinolones against gram positive bacteria, including pneumococci, anaerobic organisms, mycobacteria, chlamydia, and mycoplasma are presented. Compounds belonging to 6-fluoroquinolones substituted at positions 2 and 3 are discussed. The activity of 6-fluoroquinolones and their nonfluorinated derivatives is compared in general. PMID- 7857164 TI - Effects of selected hormones on the motility of spermatozoa in the mouse vas deferens. AB - Acting in vivo, adrenalin and noradrenalin cause a statistically significant and permanent decrease in the motility of mouse spermatozoa remaining in the vas deferens. Intratesticular injection of vasopressin, oxytocin, insulin, and glucagon results in a decrease in spermatozoa motility in vas deferens, removal the spermatozoa to PBS in vitro, and an increase in percentage of motile spermatozoa on incubation medium. Thyroxine, calcytonin, and TRH did not affect motility of mouse spermatozoa in vivo. PMID- 7857165 TI - Reproducibility of sperm motility measurements in asthenozoospermic and normozoospermic individuals using the Hamilton-Thorn motility analyzer. AB - Computer-assisted semen analysis provides a useful, quantitative method for analyzing sperm movement parameters. However, few experimental data have been published on the measurement characteristics of CASA. This study measured the reproducibility of measurements of sperm motility using a Hamilton-Thorn motility analyzer. Twenty normozoospermic and 20 asthenozoospermic patients provided semen samples. Ten samples from each group were analyzed as unprocessed semen; the remainder were analyzed after washing. An aliquot from each sample was analyzed by CASA 10 times over an 18-min period. The mean coefficient of variation for all sperm motility parameters was less than 10%, except for the percentage of motile cells in the asthenozoospermic unprocessed samples, which was 17.1%. The mean coefficient of variation for percentage motility was reduced to 9.6% in the washed asthenospermic group. Other motility parameters were unaltered by washing in the asthenospermic samples. There were no substantial differences between the washed and unwashed normospermic measurements. Normospermic samples showed better reproducibility in measurement than asthenozoospermic samples. Washing reduced the difference, probably because of the removal of debris in the asthenozoospermic samples. The results indicate that serial measurements of sperm motility in both unprocessed and washed semen samples can be reliably made using the Hamilton-Thorn motility analyzer, and that reproducibility can be improved in asthenospermic samples by washing. PMID- 7857166 TI - Effect of sperm washing on levels of reactive oxygen species in semen. AB - The possibility was evaluated that the production of reactive oxygen species (ROS) by human sperm is stimulated by the repeated cycles of centrifugation and resuspension involved in conventional sperm preparation. ROS generation by human sperm was monitored before and after the washing of sperm from 55 men (43 men with suspected subfertility and 12 normal volunteers). The ROS activity of all 55 specimens before washing was inversely correlated with original sperm motility (r = .278, p < .05). The mean level of ROS activity was significantly higher after washing than before processing (p < .05) for the 26 specimens with normal sperm motility, the 20 specimens with normal sperm morphology, and the 12 specimens with both normal motility and normal morphology. In contrast, the mean ROS level was not significantly changed after washing in the 27 specimens with poor sperm motility, the 16 specimens with abnormal sperm morphology, or the 13 specimens with both abnormal motility and abnormal morphology. It would appear that repeated centrifugation, resuspension, and vortexing cause excessive generation of ROS in the motile sperm population of the washed specimen. Washing procedures involving excessive manipulation of sperm may, in fact, cause the most harm to motile sperm, i.e., those that the method is trying to select. Procedures that minimize multiple centrifugation, resuspension, and vortexing steps should therefore be used for the preparation of semen specimens for assisted reproduction techniques. PMID- 7857167 TI - Effects of cigarette smoking on human semen quality. AB - The effects of cigarette smoking on sperm quality were evaluated from a group of males undergoing initial screening for infertility. Out of a total of 674 males, 618 (selected based on established criteria) were studied. Detailed smoking history was obtained by direct interview. Tests were conducted on semen characteristics (volume, sperm density, viability, motility, and morphology). Smokers had significantly poorer sperm density (p < .04), a lower percentage of normal sperm morphology (p < .001) and a higher percentage of headpiece spermatozoa defects (p < .01) compared with the nonsmokers. Significant trends were also observed for different categories of cigarette-years with sperm density, percentage of normal spermatozoa morphology, and percentage of spermatozoa with headpiece defect. Cigarette smoking appears to affect sperm density and the morphology of spermatozoa, especially the headpiece. A dose response relationship of cigarette smoking and spermatogenesis is suggested. PMID- 7857168 TI - Restoration of testicular transferrin, insulin-like growth factor-1 (IGF-1), and spermatogenesis by exogenously administered purified FSH and testosterone in medically hypophysectomized rats. AB - To investigate the relation between testicular transferrin and insulin-like growth factor-1 (IGF-1) secreted by Sertoli cells and the differentiation of germ cells in the rat, testosterone and/or purified FSH was administered to rats medically hypophysectomized by an LH-RH agonist. Spermatogenesis was quantitatively analyzed and concentrations of intratesticular transferrin and IGF 1 were measured by radioimmunoassays. The last step of spermatogenesis was quantitatively restored by combined administration of testosterone and purified FSH. Intratesticular IGF-1 concentrations were significantly increased by combined administration of testosterone and purified FSH. From these observations, it is surmised that IGF-1 may have a stimulatory effect on the last step of spermatogenesis. PMID- 7857169 TI - Glutathione and gamma-glutamyl cycle enzymes in rat testis during sexual maturation. AB - The main enzymes of the gamma-glutamyl cycle in the testis were studied during the onset of spermatogenesis. The activities of gamma-glutamyl transpeptidase, 5 oxoprolinase, and gamma-glutamyl cysteine synthetase, and levels of glutathione were measured in testis homogenates and Sertoli cell preparations obtained from 10-, 18-, and 26-day-old rats. A significant increase of all enzyme activities with the animal age was observed. Level of glutathione also increased in an age dependent manner. Since the gamma-glutamyl cycle is involved in the cellular incorporation of amino acids, the present findings suggest that this uptake mechanism may be relevant during spermatogenic onset in which synthesis and secretion of specific proteins are essential for germ cell development. PMID- 7857171 TI - [Islet and hybrid islet transplantation: clinical trial and future prospect]. PMID- 7857170 TI - Steroidogenesis in the two enriched-Leydig cell populations of human testis: evidence for a positive control by seminiferous tubules secreted factor(s). AB - In two different enriched populations of Leydig cells (called FI and FII) obtained from human testes (young patients: mean age 36 +/- 3 years, n = 6; aged men: mean age 73 +/- 2 years, n = 5), the dehydroepiandrosterone and testosterone in vitro outputs were increased in a dose- and time-related manners by hCG. Similar results were obtained when the Leydig cells were incubated in presence of either dbcAMP or 22R-hydroxycholesterol. In presence of either hCG or dbcAMP, the coefficient of stimulation (in terms of steroid outputs) was higher in FII when compared to FI. Conversely, the basal production of steroids was greater in FI than in FII, mainly for testosterone. The addition of increasing amounts of seminiferous tubule culture medium (STM) to the Leydig cell incubation medium led to a dose-related enhancement of the steroid production in both enriched-Leydig cell fractions under basal and hCG-stimulated conditions. Similar results were obtained in presence of increased seminiferous tubules length. Additional experiments realized with either concentrated STM or the coculture of seminiferous tubules with purified Leydig cells have confirmed the existence of a paracrine control of Leydig cell steroidogenesis by seminiferous secreted factor(s). A paracrine factor (or factors) from seminiferous tubular origin influences positively and with a high efficiency the Leydig cell function in humans, whatever the age. PMID- 7857172 TI - Clinical study of extracorporeal shock wave lithotripsy (ESWL) for biliary stones. PMID- 7857173 TI - End colostomy using stapling device. AB - Our experiences concerning the end colostomy using the stapling method are reported. The anvil which has been inserted to the proximal end of the colon and purse string suture with the skin is engaged the anvil shaft, and then, is fired. This operative procedure is simple, safe and convenient, and we can expect a uniform and satisfactory outcome. We applied this technique on 6 cases and have had no postoperative complications. PMID- 7857174 TI - [A clinical study on acute mesenteric arterial occlusion]. AB - Thirteen patients with acute occlusion of superior mesenteric artery are presented. Eight of them presented with sudden abdominal pain as the initial complaint while the others did with vomiting, abdominal distension or general fatigue. Arterial blood gas and deficit determinations revealed metabolic acidosis in 45.5% and large deficit in 100%, which was considered to be a reliable method for accurate early diagnosis of acute mesenteric arterial occlusion. Eleven patients underwent laparotomy and massive bowel resection, two of which had treatment with selective intraarterial infusion of urokinase prior to operation. One of two remaining patients did not need operation because she went on to complete recovery after fragmentation of embolus in the superior mesenteric artery by the percutaneously inserted catheter on angiography. The other one was inoperable because of poor general condition. The overall mortality in this series was 53.8%. PMID- 7857175 TI - Calcification in carcinoma of the stomach: report of a case. AB - By upper gastrointestinal series, a 57 years-old woman was pointed out to have scattered calcifications along the greater curvature of the stomach. On computerized tomography, the calcifications distributed in the irregularly thickened gastric wall. With a diagnosis of calcified mucinous adenocarcinoma showing Borrmann type III, total gastrectomy with splenectomy was carried out. The characteristics of this lesion were briefly presented with a review of the literature. PMID- 7857176 TI - [From Paris to Berlin: what is the purpose of world congresses?]. PMID- 7857177 TI - [Residual shunt after percutaneous occlusion of patent ductus arteriosus by Rashkind's device. Echographic aspects, outcome, prognostic factors and management]. AB - Percutaneous occlusion of patent ductus arteriosus with the double umbrella Rashkind prosthesis is an alternative to surgery. The authors report the results of a series of 40 patients aged 16 to 203 months, who underwent transcatheter occlusion of patent ductus arteriosus between January 1989 and March 1993. These children were followed up regularly, clinically and by echocardiography to determine the presence or absence of a residual shunt. Immediately after implantation, angiography showed a residual shunt in 75% of cases. However, the shunt progressively regressed during follow-up. Three types of shunt were described using colour Doppler based on the diameter of the transductal jet at its origin and its extension in the pulmonary artery: type I, a wide jet (> 3 mm), type II, or minimal shunt, with a jet diameter of 2 to 3 mm and an extension to the pulmonary valve (flame-like), and finally the type III, or punctiform shunt with a jet diameter < 2 mm and extension in the main pulmonary artery < 1.5 cm. During follow-up, a transition between the 3 types was observed in 37% of cases. Kaplan-Meier actuarial analysis showed a residual shunt rate of 33% at one year and 19% at 2 years after implantation. The search for predictive factors of residual shunt showed that very young patients at the time of catheterisation was the only indicator of a residual shunt (p = 0.03). Occlusion of a patent ductus arteriosus with a Rashkind device is a reliable method which gives good results. The essential problem remains that of a residual shunt but this disappears in 3/4 of patients during follow-up. When the shunt persists, a 1 to 2 year interval is advised before considering implantation of a second occluder. PMID- 7857178 TI - [Re-stenosis of aortic coarctation in children. Comparison between aortic angioplasty and surgery]. AB - The use of aortic angioplasty rather than surgery for restenosis of coarctation of the aorta after initial surgery remains controversial. The efficacy and complications of these two techniques have never been compared in prospective and retrospective studies. Between 1976 and 1992, 56 patients were treated for secondary restenosis of coarctation of the aorta: 29 by angioplasty and 27 by surgery. The case reports of these patients were reviewed retrospectively. The average follow-up was 1.5 +/- 0.3 years of the angioplasty group and 5.4 +/- 0.8 years for the surgical group. The reduction of systolic blood pressure in the right arm was significant and identical in the two groups (p < 0.05). The residual pressure gradient was less immediately and at term in the surgical group (p < 0.05). No fatalities were observed in either group. There were no aneurysmal complications. A neurological complication (posterior column syndrome) was observed after surgery (3.7%). The global rate of complications was higher after surgery (6.7% vs 33%). The rate of further restenosis was higher after angioplasty (18.5% vs 3.7%). The low rate of complications, the shorter hospital stay without repeat thoracotomy were in favour of the angioplasty procedure but the greater immediate and long-term efficacy of surgery on the pressure gradient was in favour of the latter solution. A prospective long-term study is necessary. PMID- 7857179 TI - [Risk factors of coronary graft disease following heart transplantation in children]. AB - Coronary disease after cardiac transplantation is a major medium and long-term complication in adult patients. In childhood, this is reputed to be rare and, therefore, the authors undertook a study to evaluate its incidence and the role of potential risk factors in this age group. The study included 30 children followed up at least one year after cardiac transplantation and investigated by at least one selective coronary angiography after the first postoperative year. Seventeen patients (57%) had a normal coronary angiography but 13 had coronary lesions (43%). The two groups were compared for age, sex, HLA groups of the donor recipient couple, the duration of ischaemia of the transplants, cytomegalovirus serology, lipid profile, number of episodes of acute rejection that were treated, the necessity for steroid therapy for more than 3 months, and the blood pressure. The only significant differences, probably inter-related, were the number of rejections treated, greater in the group with coronary lesions (2.23 +/- 1.01 per patient) than in the group with normal coronary arteries (1.53 +/- 1.01 per patient) (p < 0.05) and the necessity of triple therapy with addition of prednisone, greater in the first group (9/13) than in the second (4/17) (p < 0.02). These results show that coronary disease after cardiac transplantation is as common and as early in children as in adults. They strongly suggest an important role of immunological factors. On the other hand, the authors' experience did not confirm the role of other potential risk factors. PMID- 7857180 TI - [Echocardiographic evaluation of the growth of cardiac graft in children with heart transplantation]. AB - The evaluation of the growth of the cardiac transplant in children was studied in four young children and three infants by echocardiography after orthotopic transplantation. These children were all under 13 years of age at the time of transplantation and have been followed up for more than two years. The age of the recipients ranged from 2 days to 12.8 years (average 10.7 years) and that of the donors from 7 days to 27 years (average 6.7 years). All patients received triple immunosuppressor therapy. The follow-up was 29 to 48 months (average 39.7 months) in the infants and 28 to 71 months (average 50.25 months) in the children. In the 7 patients the global follow-up period ranged from 28 to 71 months (average 45.8 months). No episodes of acute rejection or hypertension were observed during the study period. The echocardiographic parameters studied were the left ventricular end diastolic dimension, left ventricular end systolic dimension, left ventricular mass, left ventricular mass index. The date was gathered prospectively during the study at monthly intervals after the 3rd postoperative month. The donor/recipient weight ratio varied from 0.83 to 5 (average 1.89). The growth of the recipients was normal in 5 out of 7 cases and moderately retarded in 2 cases. The left ventricular end diastolic dimension, left ventricular end systolic dimension and left ventricular mass increased linearly with the body surface area of all patients. The growth was faster in the infant patients.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7857181 TI - [Cardiac transplantation for old congenital heart diseases after multiple surgery]. AB - Of the 100 consecutive patients undergoing cardiac transplantation between January 1988 and October 1993, 4 patients had terminal cardiac failure related to congenital heart disease after multiple prior palliative procedures (transposition of the great arteries, N = 1, tricuspid atresia, N = 1, single ventricle, N = 2). The prior palliative or curative operations (average 3.75 procedures per patient) modified essentially the systemic venous return and the pulmonary arteries. The technique of "subtotal" cardiac transplantation enabled anatomical reconstruction without prosthetic material in all cases by extensive usage of the donor tissue. There was no hospital mortality. There were no specific postoperative complications. The long-term results were comparable to those of the rest of the transplanted population. Patients with congenital heart disease in a terminal condition should be considered as candidates for cardiac transplantation. The difficulties related to anatomical abnormalities caused by prior surgery may be overcome and should not be considered a contra-indication to transplantation, providing pulmonary arterial resistances are taken into consideration. PMID- 7857182 TI - [Scimitar syndrome complicated by stenosis of the right pulmonary vein. Apropos of 4 cases]. AB - The authors report 4 cases of the scimitar syndrome with pulmonary hypertension by stenosis of an abnormally draining right pulmonary vein and they also review the literature. All cases were symptomatic from infancy. The diagnosis was confirmed by catheterisation which showed a significant pressure gradient between the right pulmonary vein and the inferior vena cava, and by angiography which demonstrated the stenosis. None of the treatments proposed (interventional catheterisation with dilatation and eventual implantation of a stent, surgery with treatment of the stenosis and reimplantation of the right pulmonary vein in the left atrium, or pneumonectomy) were satisfactory. However, it is possible that earlier treatment could be effective as changes in the pulmonary vascular bed seem to occur very early in these patients. PMID- 7857183 TI - [Prognostic study of single ventricle with respect of anatomical and clinical data]. AB - The authors analysed the anatomical and clinical prognostic factors of single or common ventricle. This retrospective study was based on a series of 185 patients hospitalised between 1/2/70 and 31/12/91 in the paediatric cardiological unit of the Cardiological Hospital of Lyon with this condition. A number of anatomical and clinical parameters were identified in this population. For each parameter, a given patient could only relate to single modality and a survival graph determined by Kaplan-Meier analysis was established for each modality. For each variable, the survival curve of the most frequently encountered modality served as a reference and the other modalities were compared with it using a logrank test. The different modalities potentially related to patient survival were then entered into a multivariable model using logistic regression. The results of this study of multivariable analysis using the Odds-Ratio (OR) independently suggest that four variables may influence negatively survival of patients with a single ventricle: pH < or = 7.3 on admission (OR = 3.55), a non-left ventricular morphology of the main ventricular chamber (OR = 3.11), the presence of an obstacle on the aortic outflow (OR = 5.58) and a total anomalous pulmonary venous drainage (OR = 26.88). PMID- 7857184 TI - [Prognostic study of 3 main palliative surgical procedures in patients with single ventricle]. AB - In emergency cases of babies with a single ventricle and an obstruction to aortic outflow, low pulmonary flow or, on the contrary, high pulmonary flow, only palliative surgical procedures can be proposed. The authors set out to determine the prognosis of a population with this type of lesion having undergone one of the three following procedures: systemic pulmonary shunt, pulmonary artery banding, repair of the aortic arch (usually associated with pulmonary banding). One hundred and nineteen (63%) of the 185 patients hospitalised between 1/01/1970 and 31/12/1991 in the paediatric cardiology unit of the Cardiac Hospital of Lyon with a diagnosis of single ventricle, underwent one of these three procedures as a treatment of first intention. The survival of the 22 patients who underwent pulmonary artery banding (90 +/- 6%, 85 +/- 8%, 85 +/- 8% at 1.5 and 10 years respectively) was significantly better than that of the patients undergoing systemico-pulmonary shunt (63 +/- 6%, 53 +/- 6% and 49 +/- 6% at 1.5 and 10 years respectively). On the other hand, repair of an obstacle of the aortic arch was a precarious procedure as the survival was only 23 +/- 11%, 16 +/- 11% and 16 +/- 11% and 1.5 and 10 years respectively). These results suggest, with the reserve inherent to the methodology of retrospective studies of small populations, that it is not illogical to continue to propose pulmonary artery banding for babies with single ventricle associated with high pulmonary flow. This procedure should only be envisaged after strict selection of candidates and providing there are facilities for intensive postoperative care.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7857185 TI - [Total cavopulmonary shunts. Short- and mid-term results apropos of 19 cases]. AB - Experimental and clinical studies show that total cavopulmonary shunt operations may prevent certain complications of the Fontan atriopulmonary procedure. The authors have used the total cavopulmonary shunt instead of the Fontan procedure since February 1990. Nineteen consecutive patients were operated by three different surgical teams; 18 patients had undergone prior palliative surgery. The shunt was carried out by Puga's modified Kreutzer technique or by the construction of an extracardiac autologous pediculated pericardial tube. There were two deaths (10.5%) attributed to severe stenosis of the left pulmonary artery. The postoperative course was complicated in most of the 17 survivors but after a follow-up of 3 to 57 months (average 24.9 +/- 13.6 months) all were in the NYHA functional classes I (N = 15) or II (N = 2) with an arterial saturation over 85% in 15/17 cases and a cardiothoracic index less than 53% in 14/17 cases. All were in sinus rhythm. Doppler echocardiography showed no obstruction of the bypass. Pulmonary flow in 11 cases had a venous morphology. The function of the single ventricle was slightly depressed in 3 cases (2 of which were operated late, at 16 years of age). Catheterisation and cavography in 13 children showed uniform pressures in the cavopulmonary connection with no pressure gradient, except in 1 child. A right atrial'a'wave transmitted to the pulmonary arteries and inferior vena cava accompanied by retrograde vena cava flow was observed in 4 of the 6 cases with a Puga or modified Kreutzer procedure. Fenestration of the connection was closed by a Sideris button device in one case; reoperation was required in another.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7857186 TI - [Pulmonary atresia with open septum: analysis of therapeutic management apropos of 47 cases]. AB - Pulmonary atresia with ventricular septal defect (VSD) accounts for 2% of all congenital heart disease. The prognosis is poor (30% survival at 1 year) and early medico-surgical management is essential. A natural history of retrospective analysis of 47 consecutive patients with this abnormality born between 1962 and 1992, hospitalised between 1971 and 1992 and followed up for an average of 9.6 years (range: 1 month to 24 years) allowed identification of several anatomical groups: Group I (N = 19, 40.4%) comprised patients who underwent complete correction; Group II comprised patients who had undergone one or more palliative procedures. In Group II, there were 13 survivors at the end of the study (Group IIA); 14 patients died (Group IIB) and one was lost tot follow-up. The global mortality was 38% (21% in Group I and 52% in Group II). Overall management was intense: 166 cardiac catheter studies, 109 surgical operations including 48 systemico-pulmonary anastomoses, 34 right ventricular outflow reconstructions, I Ilbawi procedure. The survival was higher in Group I (79%) than in Group II (48%) indicating a clear advantage in reestablishing as normal as possible anatomic and haemodynamic status. Patients in Group I had a higher incidence of pulmonary artery confluence, patent ductus and an anatomically simple form of pulmonary atresia with VSD, all good surgical prognostic factors. The first palliative procedure was performed on average at 35 months in Group I, 46 months in Group IIA and 24 months in Group IIB; complete correction, when possible, was performed at about the 10th year, after an average of 3 operative procedures per patient.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7857187 TI - [Mitral valve replacement in infants using the "Saint-Jude Medical" prosthesis]. AB - The authors report their experience of mitral valve replacement in infants under 2 years of age. A St Jude medical mitral prosthesis was implanted in 8 children, 7 with mitral regurgitation and 1 with mitral stenosis. The average age at surgery was 9 months with an average body weight of 6.6 Kg. Two children had prior mitral valvuloplasty. All patients were in the NYHA functional Class IV. One patient died after surgery (12.5%). There was one secondary death during follow-up. Six children were followed up for an average of 61 months (range 34 to 104 months). The 6 survivors are asymptomatic and receive oral anticoagulant therapy. Regular postoperative Doppler echocardiographic assessment has shown a gradual increase of the mean transprosthetic pressure gradient in all children. To date, no reoperation on the prosthetic valve has been necessary. Mitral valve replacement is an effective option in infants with severe cardiac failure in whom mitral valve repair is impossible. In these cases, the St. Jude medical prosthesis is a good choice. Effective anticoagulation is recommended, even at this age. Growth of the child will necessitate changing the prosthesis in later years. PMID- 7857188 TI - [Outcome of Wolff-Parkinson-White syndrome in children. Transesophageal study of anterograde permeability of the accessory pathway and of atrial vulnerability]. AB - Twenty-nine children with the Wolff-Parkinson-White syndrome (WPW) were evaluated by transoesophageal electrophysiological studies to determine the quality of anterograde-conduction in the accessory pathway and the atrial vulnerability. The study group included 15 neonates, 1 to 30 days old, and 14 children from 5 to 15 years of age; Anterograde conduction through the bundle of Kent was tested by incremental transoesophageal atrial pacing and by the determination of the shortest conducted cycle with preexcited RR waves; bursts of atrial pacing were then used to try to trigger an atrial arrhythmia. In the group of the 15 neonates, 11 had accessory pathways capable of conduction to the ventricules at frequencies > 300/min (stimulation cycle < or = 2.00 ms) but no atrial arrhythmias could be induced. The older children had slower conduction in the accessory pathways with the shortest conducted cycle length > 200 ms in 11/14 cases; on the other hand, atrial fibrillation was easily induced in 4 children, all over 12 years of age. The risk of syncope by rapid conduction of an atrial arrhythmia through the accessory pathway is negligeable in young children, including those on digoxin. This study suggests that this low risk is explained more by the absence of atrial vulnerability than by the electrophysiological properties of the accessory pathways. PMID- 7857189 TI - [Natural history and prognostic factors in primary endocardial fibroelastosis in infants]. AB - Over a 33 year period, 127 patients under 2 years of age with dilated cardiomyopathies and appearances compatible with the diagnosis of primary endocardial fibroelastosis were admitted to the paediatric cardiac unit of the CHRU of Lille. The average follow-up was 8.9 +/- 6.7 years. Ninety-four children (74%) were cured, 16 (13%) had persistent cardiomegaly and/or left ventricular dysfunction on echocardiographic examination, and only 17 (13%) patients died (10 in the year following their initial hospital admission including 5 in the first week). The outcome of patients was not related to age at diagnosis, sex, cardiothoracic index, initial shortening fraction of the left ventricle or the period at which the patients were seen for the first time. On the other hand, the presence of a family history of cardiomyopathy was associated with a significantly worse prognosis. A recurrence of symptoms was the factor most closely correlated with a bad prognosis: 12 of the 19 patients (63%) with this evolution died, and 4 others (21%) had persistent myocardial dysfunction at the end of the study. These recurrences were often observed after premature withdrawal or after use of ineffective dosages of digitalis. In the authors' experience, dilated cardiomyopathy in neonates with clinical features of primary endocardial fibroelastosis is associated with a relatively high number of cures. Prolonged treatment with high doses of digitalis seems a determining prognostic factor.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7857190 TI - [Search for 22q11 deletion and linkage study in familial cases of non-syndromic conotruncal defects]. AB - Conotruncal malformations are one of the major criteria of the Di George syndrome. Nearly 90% of subjects with this syndrome have been shown to have a 22q11 deletion of a part of the long arm of chromosome 22. The authors set out to determine the role of the 22q11 region in the genesis of non-syndromic familial conotruncal malformations. The families were selected on the following criteria: at least 2 members affected; the members had to have a "conotruncal malformation" (truncus arteriosus, tetralogy of Fallot, interruption of the aortic arch,...). Typing with a microsatellite (x) marker localised in the region usually deleted, deletion was searched for in affected and non-affected members. A study of the transmission of the alleles from generation to generation was made with x and three other microsatellite markers (w, y, z) which cover the pericentromeric region of 22q. Six families fulfilling the inclusion criteria were presented. Of the 11 affected members, 9 had no deletion in the region where the microsatellite x is localised. In 2 cases it was not possible to arrive at a formal conclusion at this stage of the study. All individuals of the 6 recruited families were typed with the 4 microsatellites. Computer analysis (Linkage program) of the results obtained showed that the markers w and x were very close to each other (a recombination rate between these two markers theta = 0.001). Linkage analysis seems to infirm the 22q11 region in the genesis of conotruncal malformations (total lodscore-2.74 for x, for theta = 0), at least in the 6 families studied to date.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7857191 TI - [Idiopathic dilatation of the pulmonary artery. Echocardiographic aspects]. AB - The authors compared 30 patients with at least one clinical sign of idiopathic dilatation of the pulmonary artery, with a group of 20 normal control subjects in order to establish diagnostic criteria for this condition. In the first group, 17 had characteristic radiological findings and 13 others had clinical signs of idiopathic dilatation of the pulmonary artery. Comparison with the control group showed significant differences (p < 0.05) in 4 parameters: 1) the diameter of the pulmonary artery at the bifurcation/m2 body surface area (2.8 +/- o.4 cm versus 2.4 +/- 0.4 cm), 2) the diameter of the aorta 2 cm beyond the aortic valve/m2 of body surface area (1.7 +/- 0.3 cm versus 2.1 +/- 0.7 cm), 3) the ratio of pulmonary artery/aortic diameters at the valve rings (1.4 +/- 0.2 versus 1.1 +/- 0.02); 4) the ratio of the aorta 2 cm beyond the valve/aortic ring (1.02 +/- 0.07 versus 1.09 +/- 0.09). The diagnostic criteria of idiopathic dilatation of the pulmonary artery in the absence of cardiac or pulmonary disease are: 1) ratio of pulmonary artery diameter at its bifurcation/aortic ring diameter or 2 cm beyond the aortic valve of > or = 1.4; 2) ratio of pulmonary/aortic ring diameters > or = 1.5. PMID- 7857192 TI - [Surgical indications and results in 50 cases of isolated ventricular septal defects during the first year of life]. AB - Surgical indications of isolated ventricular septal defects (VSD) with large shunts are a common problem in paediatric cardiology. The present study was undertaken retrospectively and continuously over 5 years in 50 patients in whom the age of diagnosis varied from birth to 1 year. The surgical results are presented and the clinical and paraclinical parameters used for determining the surgical indications are reviewed. Only 16 out of 50 children (32%) were operated without catheter study. However, since February 1992, when colour Doppler echocardiography became a routine investigation in the department, 75% of children have been operated on echocardiographic data alone. Knowing that the risk of pulmonary vascular disease is practically nil in this condition at this age, the most important problem lies in distinguishing between single and multiple VSDs. Until recently, angiography has always been the reference investigation. In this series, it did not appear to be superior to a good colour Doppler study. The surgical results showed a hospital mortality of 4%, the persistence of a well tolerated VSD in 16% of cases, none of which required reoperation. Two cases of complete atrioventricular block required permanent cardiac pacing. The authors conclude that when echocardiography provides all the necessary data concerning site, number, size and haemodynamic consequences of VSD, catheterisation may be dispensed with at this age. The surgical indication is, generally, closure of the VSD by a patch, usually possible by a right atrial approach; pulmonary artery banding is an exceptional necessity in infants with a precarious haemodynamic status and/or with multiple apical VSD. PMID- 7857193 TI - [Surgical repair of common truncus arteriosus with homograft. Short- and mid-term results]. AB - Between July 1987 and July 1993, 25 consecutive children with truncus arteriosus underwent complete surgical correction with homografts. Nineteen were under 6 months of age and 4 had an associated interruption of the aortic arch. Ten pulmonary and fifteen aortic homografts were implanted. They were cryopreserved with the exception of two, fresh aortic homografts. The diameters of the homografts varied from 8 to 19 mms. Two children who had an interruption of the aortic arch, aged 24 and 31 days, died in the peroperative period. The postoperative course was uncomplicated in only 3 cases; 20 patients had complications, including 9 cardiogenic shocks and 8 pulmonary hypertensive crises. The medium-term results included one death 4 months after surgery in an infant with an interruption of the aortic arch, and 2 successful homograft replacements 3 and 12 months after the initial repair for mycotic infection in 1 case and valvular stenosis in the other. The mean follow-up of the other 20 patients was 23 months: 14 were in NYHA functional Class I, 4 are on the waiting list for replacement of their homograft for obstruction after an average period of 47 months. The authors strategy is to perform surgical correction of truncus arteriosus very early: immediately in the neonatal period in cases with uncontrollable cardiac failure, at 6 months at the latest. Small homografts make this aggressive attitude feasible, but with an operative mortality in the first 6 months of life of 10.5% (2/19).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7857194 TI - [Interruption of the left aortic arch with right descending thoracic aorta disclosed in adulthood]. AB - Evaluation of hypertension, in a 30 years old man, revealed an interruption of a left aortic arch beyond the origin of the left subclavian artery, associated with a right descending thoracic artery. Surgical restoration of the continuity between the ascending aorta and the low descending aorta was successfully achieved by interposition of a graft. Survival in adulthood without bronchial compression, is explained by the absence of ventricular septal defect and patent ductus arteriosus. PMID- 7857195 TI - [Calcified constrictive pericarditis in an adolescent]. AB - The authors report the case of an adolescent with no previous medical history with calcific pericarditis which rapidly progressed to constriction. The disease was diagnosed several months after an episode of chest pain very suggestive of acute viral pericarditis. Surgery was necessary and resulted in a complete cure of the constrictive pericarditis. The aetiologies of constrictive pericarditis are reviewed; previously, tuberculosis used to be the most common cause but it is being progressively supplanted by other pathologies. PMID- 7857196 TI - [Calcification and healing of infectious myocardial pseudoaneurysms. Apropos of 2 cases]. AB - The authors present two cases of infectious myocardial pseudo-aneurysms: the first was secondary to an intracardiac foreign body with mitral valve endocarditis; the second to septicaemia of urinary origin. Both cases progressed to calcification of the pseudo-aneurysm which appeared to be a mode of healing. Reviewed 20 and 19 years respectively after the initial episode, both patients have normal cardiac appearances apart from the residual myocardial calcification. PMID- 7857197 TI - Genetic characterization of ompH mutants in the deep-sea bacterium Photobacterium sp. strain SS9. AB - OmpH is an outer membrane protein produced by the deep-sea bacterium Photobacterium species strain SS9 in response to elevated hydrostatic pressure. In order to facilitate studies of the function of this protein, a series of OmpH+ and OmpH- strains were obtained from SS9 by Tn5 gene replacement mutagenesis. A previously isolated ompH::lacZ strain and a derivative of this strain harboring a plasmid expressing the wild-type ompH gene were also utilized. The acridine mutagen ICR 191 preferentially inhibited the growth of OmpH+ over OmpH- cells. Indeed, OmpH+ cultures treated with the mutagen rapidly accumulated mutants producing reduced levels of OmpH. In addition, OmpH+ cells took up the peptide Met-Leu-Phe approximately 15 times more rapidly than OmpH- cells. The results are consistent with the hypothesis that OmpH functions as a relatively large, nonspecific diffusion channel. PMID- 7857198 TI - Induction by nitrate of cytoplasmic and periplasmic proteins in the photodenitrifier Rhodobacter sphaeroides forma sp. denitrificans under anaerobic or aerobic condition. AB - The synthesis of nitrate, nitrite, and nitrous oxide reductases is highly enhanced by the addition of nitrate during growth of Rhodobacter sphaeroides forma sp. denitrificans. Contrary to what is observed in many denitrifiers, the synthesis of these enzymes is not repressed by oxygen at concentrations as high as 37% air saturation. When oxygen concentration is increased up to 100% air saturation, the synthesis of nitrite and nitrous oxide reductases is repressed while the nitrate reductase is still synthesized. Two proteins, one periplasmic (35 kDa) and the other cytoplasmic (32 kDa), are also induced by nitrate, but not by trimethylamine-N-oxide or oxygen. Although their function is not yet known, these two proteins appear to be specifically linked to the denitrification pathway. The amino acid sequences of tryptic peptides and of the N-terminal ends of these proteins indicate no significant similarity with the sequences in the Swiss Prot Data Bank. However, a very good alignment is obtained between the amino acid sequences of the periplasmic nitrate reductase of Alcaligenes eutrophus H16 and those of various tryptic peptides of the nitrate reductase of R. sphaeroides forma sp. denitrificans. PMID- 7857199 TI - The biometric evaluation of the acute-toxic-class method (oral). AB - The acute toxic class method (ATC method) is an alternative to the LD50 test, with the use of substantially fewer animals needed for the classification of substances. Like the classical LD50 test the biometry of the ATC method is based on the probit model. The biometric calculations of the ATC method were carried out not only for the classification categories of the European Union but also for the classification criteria of various countries and organizations, currently in use. It is demonstrated that in comparison with the LD50 test in general the same classification is obtained with the ATC method and with the use of substantially fewer animals. Substances with high slopes are likely to be allocated to the predicted toxicity class in comparison with substances having low slopes, with both the ATC method and the LD50 test. Substances are more likely to be allocated into a lower toxicity class with the LD50 test than with the ATC method. PMID- 7857200 TI - Comparative metabolism and disposition of acrylonitrile and methacrylonitrile in rats. AB - Aliphatic nitriles are a class of chemicals used in high volumes in the production of plastics and elastomers, in organic synthesis, and in production of a number of food packaging containers. Toxicity and metabolism of acrylonitrile (AN) are well characterized. On the other hand, minimal information is available on the toxicity or fate of structurally related, methacrylonitrile (MAN). In an attempt to predict the toxicity of MAN, the present studies were designed to compare the disposition of both nitriles in rats. After gavage administration of equimolar doses (0.87 mmol/kg) of 2-14C-MAN or 2-14C-AN to male F344 rats, both chemicals were well absorbed from the GI tract and distributed to all major tissues. However, major differences in the disposition of the two nitriles were observed. While approximately 39% of the administered MAN dose was eliminated as CO2 in 24 h after dosing, only 11% of an equimolar dose of AN was eliminated as such. In addition, 31% of the MAN dose was exhaled as organic volatiles in 24 h compared to less than 2% of an equivalent AN dose. MAN and acetone were identified by HPLC analysis of expired organic volatiles from MAN-treated rats. HPLC analysis showed that AN is the only organic volatile exhaled by AN-treated rats. Urinary excretion of MAN was 22% compared to 67% of an equivalent dose of AN. The major urinary metabolite from AN results from direct conjugation with GSH, whereas the major urinary metabolite from MAN results from conjugation of the epoxide with GSH.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7857201 TI - Effects of recombinant human interleukin 6 (rhIL-6) in marmosets (Callithrix jacchus). 1. General toxicity and hematological changes. AB - The physiological and toxicological properties of recombinant human interleukin 6 (rhIL-6) were assessed in marmoset monkeys (Callithrix jacchus). Two experimental series were performed with daily subcutaneous administration: (a) 5 or 1000 micrograms rhIL-6/kg per day for three weeks and (b) 25, 100 or 500 micrograms rhIL-6/kg per day for 3 months. RhIL-6 was well tolerated and did not induce fever or any other non-specific signs of toxicity. The main findings were: (1) A two- to threefold increase in platelet counts at 2-4 weeks, which decreased following further continuous rhIL-6 administration; (2) increase in total white blood cells between 1 and 4 weeks of administration, including an absolute increase in granulocytes (including band forms) and basophils. A change in the number of monocytes was not detected; (3) an increase in total red blood cells, which peaked at 4 weeks, sustained elevation of red cell distribution width and a slight decrease in hemoglobin between week 1 and 4, concurrent with a distinct decrease in mean corpuscular hemoglobin at 4 weeks. This effect persisted for 9 weeks in the 100 micrograms/kg and 500 micrograms/kg groups; (4) decrease in plasma AST activity and increase in plasma protein concentration after 2 weeks of treatment; (5) no clinical or biochemical signs of renal glomerular dysfunction; (6) RhIL-6 after s.c. administration was detectable in the plasma, peak levels (mean values +/- SD) of 9.4 +/- 6.3 and 72.4 +/- 7.7 ng/ml were measured after a single dose of 100 or 1000 micrograms/kg; (7) antibodies against rhIL-6 developed within 2 weeks, increased during administration and neutralized the biological effect of rhIL-6 progressively from 4 to 9 weeks. In conclusion, aside from a mild anemia, rhIL-6 was well tolerated in marmosets and had a profound and sustained effect on thrombopoiesis. Due to the formation of neutralizing antibodies, the chronic biological effect of rhIL-6 is lost in marmosets and studies beyond 4 weeks are rendered less meaningful. The analyses of antibody formation, induction of acute phase proteins, histological changes and alterations on lymphocyte receptors will be reported in two following publications. PMID- 7857202 TI - Hypoproduction of erythropoietin contributes to anemia in chronic cadmium intoxication: clinical study on Itai-itai disease in Japan. AB - Itai-itai disease is a condition caused by long-term exposure of the inhabitants of Toyama prefecture, Japan, to cadmium intoxication. The characteristic clinical features of this disease include renal tubular dysfunction, osteomalacia, and anemia. In order to clarify the pathogenesis of the anemia, the red blood cell count, hemoglobin concentration, hematocrit, serum iron level, total iron-binding capacity, serum ferritin level, serum erythropoietin level, creatinine clearance, fractional excretion of beta 2-microglobulin, and bone marrow morphology were determined in ten patients with Itai-itai disease. Low serum iron or ferritin levels were not observed, and bone marrow aspiration did not reveal any specific hematological disorders. A close relationship was observed between the decrease in the hemoglobin level and the progression of renal dysfunction. Low serum erythropoietin levels were detected despite the presence of severe anemia. These results suggest an important role of renal damage in the anemia which develops in Itai-itai disease. PMID- 7857203 TI - Metallothionein expression during liver regeneration after partial hepatectomy in cadmium-pretreated rats. AB - Metallothionein is a low molecular mass protein inducible mainly by heavy metals, having high affinity for binding cadmium, zinc and copper. In the present study we investigated the expression of metallothionein in regenerating liver, at different time intervals, in cadmium pretreated partially hepatectomized rats. Liver metallothionein is highly expressed during regeneration induced by partial hepatectomy in rats, providing zinc within the rapidly growing tissue. Cadmium pretreatment caused inhibition of the first peak of liver regeneration, while metallothionein expression was markedly more prominent in the liver residues of cadmium-pretreated rats. These results demonstrate that although metallothionein able to bind temporarily metal ions as zinc and cadmium has been highly expressed, the liver regenerative process was inhibited possibly due to the effects of cadmium on other pivotal events necessary to the DNA replication. PMID- 7857204 TI - Effect of gentamicin-induced nephrotoxicity on some carbohydrate metabolic pathways in the rat renal cortex. AB - Rats were injected with gentamicin at doses of 20, 40 and 80 mg/kg per day for 6 consecutive days. The treatment caused nephrotoxicity as evidenced by dose related increases in serum creatinine concentration and renal tubular necrosis. The nephrotoxicity was accompanied by reduced renal cortical and fasting blood glucose levels, and by increases in serum lactate concentrations. The activities of cortical malate dehydrogenase and alanine transaminase were significantly reduced by the three doses of gentamicin. On the other hand, aspartate transaminase activity was lowered only by the highest dose of antibiotic used. However, the activity of cortical glucose-6-phosphate dehydrogenase was altered by the 20 and 40 mg/kg doses of gentamicin, but not by the 80 mg/kg dose. The two lower doses reduced the lactate content of the cortex but activated lactate dehydrogenase. The activity of isocitrate dehydrogenase was not altered by any of the gentamicin doses used. PMID- 7857206 TI - [Value of computerized exercise stress test in the differential diagnosis of ischemic phenomena of obstructive versus nonobstructive origin]. AB - PURPOSE: To describe groups of patients who have obstructive and non-obstructive coronary artery disease, through computadorized exercise stress test. METHODS: The test was done in 121 patients, all male, divided into 3 groups: GN group, 50 patients with normal electrocardiographic response to exercise; GLO group, 40 patients with obstructive coronary artery disease and GNO group, 31 patients with normal coronary arteries, showing one or more of the following entities: intramural coronary traject, coronary tortuosity, slow flow, mitral valve prolapse or left ventricular hypertrophy. GLO and GNO groups presented with abnormal response of the ST segment during exercise. The quantitative variables registered by computer were particularly analyzed as follows: STL (point Y depression), slope, index and ST segment integral. The magnitude of ST vector was visually measured and quantified. The statistic study was made through ANOVA and multiples comparison by the Scheffe's method, Fisher's test, quisquare and sensibility, specificity and accuracy calculation. RESULTS: There was a significant statistic difference among the 3 groups relative to slope and index (p < 0.05). The integral variable of ST segment did not allow us to differentiate the GLO and GNO groups. In the association study between the ST vector magnitude and abnormal T loop, there was an increase in sensibility of 15% in the exercise stress test. CONCLUSION: The ST segment slope below zero values, define patients having obstructive disease, and the opposite, non-obstructive disease. Values of ST segment index lower than -2 are linked to obstructive disease and higher than 2 linked to non-obstructive. Values of ST segment lower than -7 microV. s separate individuals with normal exercise stress test from those with ischemic type response. The magnitude of ST vector equal to or lower than 0.20mV define normal vectorcardiographic response to the exercise. PMID- 7857205 TI - In vitro oxime-induced reactivation of various molecular forms of soman-inhibited acetylcholinesterase in striated muscle from rat, monkey and human. AB - The purpose of this study was to compare the in vitro reactivation of the various molecular forms of soman-inhibited acetylcholinesterase by oximes such as HI-6, toxogonin and PAM, in striated muscle tissue from three species-rat, monkey and human. To simulate the various in vivo conditions the oxime was present either 5 min before and after (Pre-Post) or 5 min after (Post) exposure to the nerve agent soman. In the Pre-Post mode the oxime effects would result from a combination of not only shielding of acetylcholinesterase from soman inhibition but also from immediate reactivation of soman-inhibited acetylcholinesterase. In the Post experimental group the increase in soman-inhibited acetylcholinesterase activity was due to reactivation. HI-6 (Pre-Post) increased significantly the activity of soman-inhibited acetylcholinesterase in the rat, human and monkey muscle. HI-6 (Post) was a highly effective reactivator of soman-inhibited acetylcholinesterase in the rat muscle and moderately so in the human and monkey muscle. Toxogonin (Pre-Post) and toxogonin (Post) were effective in increasing soman-inhibited acetylcholinesterase activity in rat muscle but were relatively ineffective in the human and monkey muscle. PAM (Pre-Post) and PAM (Post) were ineffective in increasing soman-inhibited acetylcholinesterase activity in muscle from all species examined. Effectiveness of oxime-induced reactivation of soman-inhibited acetylcholinesterase could be estimated from the total acetylcholinesterase activity which appears to reflect the results found with the individual molecular forms of acetylcholinesterase. In addition, SAD-128, a non-oxime bispyridinium compound, appeared to enhance significantly the HI-6 induced reactivation of soman-inhibited acetylcholinesterase in human but not rat striated muscle. PMID- 7857208 TI - [Cardiopulmonary exercise test in the evaluation of healthy elderly men]. AB - PURPOSE: To study methodological aspects and results of cardiopulmonary exercise tests in elderly. METHODS: Twenty-five men (mean age 65 +/- 5 years) performed a cardiopulmonary exercise test using a bicycle ergometer and a progressive continuous work load increase protocol was employed. A computadorized system (2001 CAD/Net System-MGC), which includes a gas analyser and a pneumotacograph, was used for on line monitoring of oxygen and carbon dioxide expired fraction and also of pulmonary flow. RESULTS: We observed the following values of oxygen uptake, pulmonary ventilation and respiratory gas exchange: rest=4 +/- 1 ml/kg 1/min-1, 11 +/- 2 l/min-1 and 0.80 +/- 0,1, respectively: anaerobic threshold=12 +/- 3 ml/kg-1/min-1, 29 +/- 6 l/min-1 and 0.90 +/- 0.1, respectively: respiratory compensation point=18 +/- 4ml/kg-1/min-1, 47 +/- 1 l/min-1 and 1.07 +/- 0.1, respectively, and peak of exercise = 13 +/- 5 ml/kg-1/min-1, 76 +/- 18 l/min-1 and 1.21 +/- 0.2, respectively. The anaerobic threshold and the respiratory compensation point were achieved at 53 +/- 11 and 77 +/- 9% of peak oxygen uptake respectively. The elderly shown slightly increased values of the relation volume dead/tidal volume at rest with a slightly smaller decrease of its values during exercise in comparison to data obtained from young healthy untrained subjects. The heart rate prescription for exercise based on the heart rate reserve was higher than that based on the cardiorespiratory and metabolic responses (113 126bpm vs 96-114bpm). CONCLUSION: The cardiorespiratory and metabolic responses pattern in the elderly is quite heterogeneous. The heart rate prescription for exercise based on conventional stress tests seems to overestimate cardiorespiratory and metabolic capacity in healthy elderly men. The determination of anaerobic threshold and respiratory compensation point from cardiopulmonary exercise test data optimize exercise prescription for healthy elderly men. PMID- 7857207 TI - [Role of blood pressure in rest and exercise conditions and importance of clinical factors in left ventricular hypertrophy in arterial hypertension]. AB - PURPOSE: To evaluate the role of casual and exercise blood pressure as well as the importance of clinical factors on the presence and degree of left ventricular hypertrophy in hypertension. METHODS: Fifteen normotensives (control group) and 30 hypertensives, 14 of them with and 16 without left ventricular hypertrophy (groups with LVH and without LVH, respectively) were studied. LVH diagnosis was established when mass index was higher than 2 standard-deviations of the mean values calculated for each sex in control group. Resting, casual determined, and bicycle exercise systolic and diastolic blood pressures along with age, body surface area, sex and race distribution were compared between groups. In addiction, their relation with mass index as independent variables were also tested. RESULTS: Hypertensives in group with LVH had higher diastolic septal, posterior wall, and relative wall thicknesses. No significant statistical difference was observed neither in sex and race distribution, nor in age and body surface area between groups. Otherwise, there were significant differences in both resting and exercise blood pressure. In the entire population studied, left ventricular mass index significantly correlated with age (r=0,33, p=0,03) as well as with both casual (systolic - r=0,72, p=0,0001; diastolic - r=0,69, p=0,0001) and exercise (systolic - r=0,62, p=0,0001; diastolic - r=0,66, p=0,0001) blood pressures. However, linear regression analysis demonstrated that only resting systolic (p=0,0001) and exercise diastolic (p=0,0303) blood pressures were significant and independent determinants of mass index. CONCLUSION: Resting and exercising blood pressures are the main determinants of left ventricular hypertrophy in hypertension. PMID- 7857209 TI - [Hemodynamic behavior of the right ventricle in acute inferior wall myocardial infarction: comparison between patients with and without cardiogenic shock]. AB - PURPOSE: To evaluate the hemodynamic profile of patients (pts) with acute inferior wall myocardial infarction (AMI) and dysfunction of right ventricle (RV). METHODS: Ninety nine consecutive pts (aged 56.6 +/- 3.4 years), 47 men, with inferior AMI and RV dysfunction were studied. RV infarction was diagnosed based on ST segment elevation (> lmm) in precordial V4R lead and RV abnormalities found in echocardiography. All pts were undergone to bedside hemodynamic studies, by measuring mean right atrial (RAP), pulmonary artery (PAP), wedge pulmonary (PWP), and radial artery (AP) pressures and cardiac output (CO). Cardiac index (CI), pulmonary (PAR) and systemic arterial resistance (SAR) were calculated in dynes x sec x cm-5. Left ventricle (LV) ejection fraction (EF) and RV-EF were obtained by contrast ventriculography. Cardiogenic shock was diagnosed based on AP < or = 70 mmHg, RAP > or = 7 mmHg, PWP < or = 20mm Hg, CI < or = 1.8l/min/m2 and oliguria. Pts were then subdivided in 2 groups: with cardiogenic shock (group A, n = 41) with a mean age of 55.4 +/- 2.1 and without shock (group B, n = 58) with a mean age of 57.2 +/- 1.7. RESULTS: No significant differences between groups regarding RAP, PWP, AP and LVEF were observed, but compared to group B, group A had lower CI (1.3 +/- 0.3 vs 2.6 +/- 0.5 l/min/m2, p < 0.05), higher SVR (2314 +/- 252 vs 1324 +/- 324 dynes.sec.cm-5, p < 0.01), and lower RVEF (0.27 +/- 0.08 vs 0.41 +/- 0.11%, p < 0.05). CONCLUSION: Pts with inferior AMI and RV dysfunction, cardiogenic shock depends on of RV failure and is independent of a preserved LV function. PMID- 7857210 TI - [Thrombolytic therapy in thrombosis of prosthesis]. AB - PURPOSE: To relate our experience with thrombolytic therapy in 8 patients with cardiac metal prosthesis complicated with thrombosis. METHODS: Eight patients with clinical and echocardiographic diagnosis of cardiac valvar prosthesis thrombosis were treated. RESULTS: The treatment efficacy was evaluated by clinical and echocardiographic improvement. The authors recognized improvement in all 8 patients. One case of hemorrhage was observed (coxo-femoral articulation). Late death were observed twice: 24 months after, sudden death and 30 months later by hemorrhagic stroke. CONCLUSION: The results indicated that thrombolytic therapy is best way to treat patients with cardiac valve thrombosis, instead of surgical treatment. PMID- 7857211 TI - [Diagnosis of papillary muscle rupture in acute myocardial infarction by transesophageal Doppler echocardiography]. AB - Three patients, two females, ages ranging from 62 to 78 years were studied, evolving with hypotension, acute pulmonary edema and cardiogenic shock. One had anterior myocardial infarction, and in two, infero-posterior. Due to severe hemodynamic instability and necessity of vasoactive drug therapy to maintain adequate arterial pressure, coronary angiography was performed in two, showing total occlusion of the circumflex artery and severe mitral regurgitation. In one case, angioplasty on the circumflex artery was successfully achieved. No hemodynamic improvement was observed, however. Doppler echocardiography depicted mild to moderate mitral regurgitation in the three cases. Transesophageal echo confirmed the clinical suspicion of papillary muscle rupture: total rupture of antero-lateral papillary muscle in one patient, as well as total and partial rupture of the postero-medial papillary muscle in the other two patients. Two patients were submitted to mitral valve replacement, and the surgical findings confirmed the transesophageal echo conclusions. One of them died in the immediate pos-operative period, whereas the other was discharged from the hospital and is doing well. The third patient died before operation. Differential diagnosis of acute mitral regurgitation due to papillary muscle dysfunction or rupture was not possible by left ventriculography or by transthoracic echo. Transesophageal echo was the only exam to clearly confirm papillary muscle rupture, as should be done promptly after clinical suspicion of this severe condition arises. PMID- 7857212 TI - [Case 4/94 (Instituto do Coracao do Hospital das Clinicas)]. PMID- 7857213 TI - [Reactivity of blood pressure during physical exercise]. PMID- 7857214 TI - [The dilemma of the Brazilian cardiologist: should the thrombolytic agent be changed?]. PMID- 7857215 TI - [Tissue plasminogen activator is the best thrombolytic agent]. PMID- 7857216 TI - [Efficacy of sotalol in idiopathic ventricular arrhythmia originating in the right ventricular outflow tract]. AB - PURPOSE: To evaluate the effects of sotalol in patients (pts) with idiopathic ventricular arrhythmias (VT) from right ventricular outflow tract. METHODS: Eighteen pts with VT were enrolled (five with monomorphic repetitive ventricular tachycardia - MRVT). Pts were submitted to a double-blind crossover randomized study (placebo vs. 320 mg/po/d/sotalol; four weeks each), after a wash-out control period. Holter recording were recorded in control and placebo and drug periods. Eligible pts have > 50/h isolated ventricular premature beats (VPB) in control, with or without paired VPB or nonsustained VT (NSVT- > 3 beats, > 100bpm). Drug efficacy criteria was: > 75% reduction in isolated VPB and > 90% of paired VPB or NSVT. The effects of the drug on uncorrected QT interval was evaluated and also on circadian rhythm of VT through the hourly pNN50/VPB ratios. Values are given as mean +/- SD. Three recordings were compared by using paired Student's "t" test. Statistical significance was assumed for p < 0.05. RESULTS: Differences between control and placebo were NS. Drug was effective in 61% of pts, reducing the 3 types of ET (VPB: placebo = 23.508 +/- 34.537; drug: 975 +/- 1357; paired placebo = 443 +/- 587; drug = 9 +/- 20). The drug was evaluated in 4 pts with MRVT, reducing all ectopic events, with efficacy of 60% over VPB and paired and 80% over NSVT (VPB: placebo = 52.639 +/- 42.207; drug: 1631 +/- 2062; paired: placebo = 796 +/- 754; drug: 20 +/- 30; NSVT: placebo = 4287 +/- 6343; drug: 9 +/- 11). Mean QT interval was 0.40 +/- 0.01s in control and 0.50 +/- 0.04s in the drug period, with no correlation between duration and efficacy. Sotalol modified the circadian rhythm of VPB in the non-responders group, mainly during the morning. CONCLUSION: Sotalol was effective in control of VT, mainly the MRVT. Its effect on VPB circadian rhythm may independently contribute to the overall efficacy profile and myocardial protective effect of this drug. PMID- 7857217 TI - [Brazilian consensus on dyslipidemia. Detection--assessment--treatment. Brazilian Society of Cardiology]. PMID- 7857218 TI - [Hemodynamic evaluation during isotonic exercise of patients with orthotopic heart transplantation]. AB - PURPOSE: To evaluate the hemodynamic response of patients submitted to orthotopic heart transplantation during progressive isotonic exercise. METHODS: Eight patients who underwent orthotopic heart transplantation have been evaluated through invasive hemodynamic study during isotonic exercise. The mean right atrial pressure (RAP), pulmonary artery pressure (PAP), pulmonary artery wedge pressure (PAWP), arterial blood pressure (ABP), systemic vascular resistance (SVR), pulmonary vascular resistance (PVR), heart rate (HR) and cardiac output (CO) have been determined in three distinct situations: at rest in the supine position (R), at rest with the legs up (RU) and during progressive isotonic exercise (E). The hemodynamic results at rest have been compared to the ones before transplantation. Phase RU and E results have been compared with each other. RESULTS: Comparing to the phase before transplantation at the R phase we found normalization of mean PAP (34.9 +/- 14.0 to 17.0 +/- 3.5 mmHg), RAP (7.3 +/ 4.3 to 2.9 +/- 1.9 mmHg) and CO (2.9 +/- 0.98 to 5.7 +/- 0.99 l/min), otherwise there was an increase in HR (89 +/- 15 to 94 +/- 13 bpm) mean ABP (84 +/- 25 to 115 +/- 12 mmH) and SVR (30 +/- 15 to 22 +/- 7 units Wood), (p < 0.05). Comparing phase E to phase RU, there was a significant increase in RAP (3.1 +/- 1.8 to 9.4 +/- 3.9 mmHg), mean PAP (21.0 +/- 2.8 to 37.0 +/- 10.0 mmHg), PAWP (8.1 +/- 2.1 to 15.0 +/- 5.8 mmHg), CO (5.8 +/- 0.8 to 9.9 +/- 2.4 l/min), HR (93 +/- 8 to 116 +/- 18 bpm) and a decrease in SVR (22.0 +/- 3.0 to 13.3 +/- 3.8 units Wood), (p < 0.05), otherwise there was no statistically significant modifications in PVR (2.2 +/- 0.7 to 2.3 +/- 1.2 units Wood) and mean ABP (129 +/- 12 to 129 +/- 15 mmHg), (p = NS). CONCLUSION: Patients submitted to heart transplantation may improve cardiac output mainly from increasing in stroke volume, associated with an increase in RAP and PAP. Nevertheless, the improvement increase in CO is compatible to exercise capacity after heart transplantation. PMID- 7857219 TI - Anal stricture following haemorrhoidectomy: early diagnosis and treatment. AB - Anal stricture is an uncommon but well recognized complication following haemorrhoidectomy. Twenty-seven (3.8%) out of 704 (500 elective and 204 emergency) cases of haemorrhoidectomy performed at the Singapore General Hospital over a 24 month period had clinical evidence of anal stricture post haemorrhoidectomy. Of the 27 cases, 15 had haemorrhoidectomy as an elective procedure while 12 had it performed as an emergency procedure (chi 2 = 3.26, 1 d.f., P > 0.05, not significant). The mean interval between surgery and presentation of anal stricture was 6 weeks (range 3-12 weeks). Eighteen of the patients were managed by anal dilatation in the outpatient clinic combined with bulk laxatives and a local anaesthetic agent. The other nine patients required a minor surgical procedure comprising either a lateral internal sphincterotomy (five) or an anoplasty (four) procedure. All patients were well, following treatment. None of these patients developed a recurrent stricture at follow up 3 months after treatment. It was concluded that although anal stricture following haemorrhoidectomy is rare, it should be detected and treated early in order to avoid pain and suffering, and treatment is usually successful. PMID- 7857220 TI - The ileal pouch-anal anastomosis in challenging patients: stretching the limits. AB - Total proctocolectomy and ileal pouch-anal anastomosis (IPAA) is the best option in the surgical treatment of ulcerative colitis, and for some patients with familial polyposis. Contraindications to the procedure include old age, obesity, weak sphincters, perianal sepsis and previous enterectomy. In this study the results of IPAA in five patients with one or more of these contraindications are presented and ways of dealing with them are discussed. All patients had a favourable outcome showing that such contraindications are relative, and IPAA may be attempted as long as patients are fully informed and understand the risks to which they are subject. PMID- 7857221 TI - Fissure in ano. AB - The present study documents a 15 year experience with anal dilatation in patients with fissure in ano. Patients who were unable to tolerate rectal examination were admitted urgently for anal dilatation. Patients in whom rectal examination and proctoscopy was possible were offered an anal dilator and were reviewed after 4 weeks. Patients who preferred not to use an anal dilator or who had not become asymptomatic were admitted for elective anal dilatation. Four finger anal dilatation was performed under general anaesthesia. Between 1975 and 1990 104 patients underwent 111 procedures. The male to female ratio was 1.3:1. Five patients were re-operated because of failure of resolution of symptoms. Three patients with anal fissures and Crohn's disease were successfully managed by anal dilatation. Nine patients had excision of a 'sentinel pile' in addition to anal dilatation. Ten patients were admitted acutely. One patient developed a perineal haematoma. Seventy-four procedures were performed as day cases. There was no mortality associated with the procedure. At the time of discharge from the clinic no patient complained of problems with continence. These results support our policy of gentle anal dilatation as first management choice in the treatment of anal fissure. PMID- 7857222 TI - The effect of recombinant growth hormone on nitrogen balance in malnourished patients after major abdominal surgery. AB - The effect of recombinant growth hormone (rGH) on nitrogen balance was studied in malnourished patients receiving total parenteral nutrition after major abdominal surgery. Fifteen patients were randomized to receive either subcutaneous rGH (0.2 iu/kg) or placebo (saline) injection daily for seven days after surgery. Positive nitrogen balance was achieved throughout the treatment period with rGH administration and was significant on days 3 and 6. This was associated with increase in mid-arm muscle circumference and significant weight gain. Plasma insulin-like growth factor-1 (IGF-1) concentration was significantly raised in the rGH group at day 7, suggesting its role in the anabolic effect of growth hormone. Plasma pre-albumin and retinol-binding protein concentrations were raised in both the rGH and control groups, indicating improvement in the nutritional status. We conclude that the postoperative catabolic response can be attenuated using recombinant growth hormone. PMID- 7857223 TI - A reproducible model of chronic rejection in rat renal allografts. AB - A reproducible animal model is essential for the study of the pathogenesis of chronic rejection. This study investigates: (i) the optimal pre-transplant blood transfusion conditions to induce tolerance in a strongly rejecting rat kidney allograft model (Dark Agouti to Albino-Surgery) and avoiding post-transplant immunosuppression; (ii) the functional and histological changes that occur in long-term surviving kidneys and their similarity to chronic rejection; and (iii) the maintenance of tolerance. Prolonged survival occurred after administration of at least two donor blood transfusions with concomitant cyclosporin A (5 mg/kg per day). The time-span between transfusions appeared to be critical: 4 days was more effective than 2 or 7 days. Ineffective treatment led to death within the first 2 weeks post-transplant with histological evidence of acute graft rejection. Seventy-five per cent of long-term survivors experienced impaired renal function in the first week which improved spontaneously and remained stable in 93% of the surviving animals after 100 days and in 66% after 200 days. The morphology of long-term allografts was extremely variable from minor to extensive tubular atrophy, interstitial fibrosis, glomerular hypertrophy, focal and segmental glomerulosclerosis and vascular changes. Glomerular hypertrophy occurred in uninephrectomized controls and probably denoted a response to uninephrectomy. Glomerulosclerosis increased with time and was absent in controls. Although chronic damage was evident, the rats remained tolerant to fresh donor skin. Replacement of the original kidney allograft with a fresh donor kidney resulted in 70% survival. These second grafts showed less severe renal dysfunction and morphological damage than the original allografts in the long-term follow up. PMID- 7857224 TI - Primary neonatal Duhamel procedure using the ENDO GIA stapler. AB - The technique of performing the Duhamel procedure in the neonate with Hirschsprung's disease using the ENDO GIA stapler (originally designed for laparoscopic surgery) is described. This technique overcomes the problem of conventional staplers being too large to introduce into the neonatal anus. PMID- 7857225 TI - Frederic Wood Jones: his academic medals and those they honoured. PMID- 7857226 TI - The diagnosis and treatment of psoas abscess: a 12 year review. PMID- 7857227 TI - Neoplastic obstruction of the abdominal aorta. AB - Obstruction of major arteries by neoplastic tissue is rare. A case of symptomatic obstruction of the distal abdominal aorta by metastatic carcinoma of the cervix, presenting 6 years after initial diagnosis, is described. PMID- 7857228 TI - Ureteric ischaemia following major colorectal resection. AB - An ischaemic injury of the ureter following major colorectal surgery is reported. The aetiology and incidence of this unusual complication is reviewed. Surgical techniques for prevention of such an injury are discussed. PMID- 7857229 TI - Granulomatous lobular mastitis. AB - Two cases of benign lobular granulomatous mastitis, both clinically felt to be carcinoma, are reported. One patient was cured by local excision of the mass while the other was cured by oral prednisolone, demonstrating the variable ways to treat this entity. The clinical and histological features were similar to those noted in previous reports. Immunological studies revealed predominantly stromal T lymphocytes and only duct intra-epithelial T lymphocytes. PMID- 7857230 TI - Chest wall actinomycosis in association with the use of an intra-uterine device. AB - A 31 year old woman presented with a chest wall abscess due to Actinomyces israellii and Porphyromonas asaccharolytica (previously Bacteroides asaccharolyticus). She was a long-term user of an intra-uterine device (IUD) and, although asymptomatic, had radiological evidence of pelvic infection. Actinomyces like organisms were seen on cervico-vaginal smears. The abscess was surgically drained, the IUD removed, and a prolonged course of amoxycillin/clavulanic acid given. PMID- 7857231 TI - Appendicocutaneous fistula: a hazard of incomplete appendicectomy. PMID- 7857232 TI - Assessment of blunt abdominal trauma. AB - Computerized tomography (CT) scanning and diagnostic peritoneal lavage have often been seen as competing modalities in the assessment of blunt abdominal trauma. Each has its own strengths and weakness. A judicious use of both modalities can result in improved diagnostic accuracy. An algorithm for their appropriate use is suggested. PMID- 7857233 TI - Molecular genetics of thyroid and parathyroid neoplasia. AB - There have been several recent advances in the understanding of the process of carcinogenesis in the thyroid and parathyroid glands. The specific abnormal molecules are, in many instances, well understood. This review provides an overview of the molecules in the cell that regulate cell growth and proliferation and identifies the molecules that have been found to be abnormal (or mutant) in various types of thyroid and parathyroid neoplasia. PMID- 7857234 TI - Hypothermia and severe trauma. AB - During the period from May 1992 until April 1993, 108 patients were admitted to Liverpool Hospital with Injury Severity Scores (ISS) > 15. Temperatures had been recorded in 100. Of these, 17 had a core temperature of less than 35 degrees C documented within 24 h of arrival. The hypothermic group presented with more severe injuries and contained a disproportionate number of females. Hypothermia was found to be more common in the winter months, but it was not associated with a delay in reaching hospital from the time of injury. When injuries were ranked by ISS, both hypothermic and normothermic patients were equally likely to have received a blood transfusion; however, the mean number of units of packed cells transfused was greater for the hypothermic group with ISS < 41 than for the similarly injured normothermic group. Two patients in the hypothermic group had sustained burns, and both of these were hypothermic on arrival. All of the hypothermic patients who required surgery developed hypothermia in the operating theatre. PMID- 7857235 TI - Outcome of patients with neurotrauma: the effect of a regionalized trauma system. AB - A system of regionalized trauma care was introduced to Sydney in early 1992. This study was carried out to assess the effect of regionalization on the outcome of patients suffering major head injury within the central Sydney area. A prospective before and after study extending over 3 years and centred on the time of designation of Royal Prince Alfred Hospital (RPAH) as a trauma centre, was the methodology used. The study group consisted of all patients admitted with head injury (Glasgow Coma Score < 9; admission systolic blood pressure > 90 mmHg; Injury Severity Score > 15) to RPAH from the central Sydney area. Outcome criteria include survival rates, transfer numbers, and time to definitive neurosurgical care. Fifty patients were entered during the first 18 months of the study, and 38 during the second 18 months. Fifteen in the first group required evacuation of intracranial mass lesions, as did nine in the second group. The overall mortality fell from 42 to 26% (P = 0.13). During the study period there were 77 primary retrievals and 20 required evacuation of mass lesions. The median time from injury to commencement of operation in these patients was 2 h 13 min (range 1 h 3 min-5 h 35 min). There were 11 transfers, four requiring craniotomy. The median time from injury to surgery was 7 h 24 min (range 3 h 2 min-10 h 25 min; P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7857236 TI - Obstructed defecation: current status of pathophysiology and management. AB - Obstructed defecation poses a challenging clinical problem and in many patients presenting with this syndrome the underlying pathophysiology cannot be determined. Up to now, attempts to diagnose and treat obstructed defecation (anismus) have focused on the function of the somatic pelvic floor musculature surrounding the anorectum, and concepts such as 'puborectalis paradox' and 'spastic pelvic floor' have gained widespread acceptance despite there being no objective data to support such concepts. New evidence showing that defecation is an integrated process of colonic and rectal emptying suggests that anismus may be much more complex than a simple disorder of the pelvic floor muscles. In a small number of patients obstructed defecation is caused by a more simple mechanism, such as internal sphincter hypertonia or a large rectocele, which is easily corrected surgically. Careful selection of patients for treatment, based on identifying the underlying pathophysiological disorder, is emphasized. PMID- 7857237 TI - Solitary rectal ulcer syndrome: the clinical entity and anorectal physiological findings in Singapore. AB - The clinical pattern and physiological abnormalities in solitary rectal ulcer syndrome (SRUS) occurring in Singapore, were investigated. Since April 1989, 25 patients have presented with histologically proven SRUS. There were 13 males and 12 females (20 Chinese, 4 Malay and 1 Indian) with a mean age of 47.5 (+/- 3.1) years. Ninety-six per cent presented with rectal bleeding, 92% strained at stools, 40% had mucus discharge, 40% felt incomplete defecation and 32% digitated to defecate. Four had previous haemorrhoidectomies that did not cure their symptoms. The lesions were at a mean 6.8 (+/- 0.5) cm above the anal verge, usually anteriorly (64%) but one was circumferential. Anorectal physiology performed on 14 patients was compared with 13 age and gender matched normal controls. The measured mean resting perineum level in SRUS (1.4 +/- 0.3 cm) was significantly lower than in normals (P < 0.01). The mean anal electrosensory threshold (2.5 +/- 0.52 mV) was also significantly higher than in the controls (P < 0.05). Fifteen patients were successfully treated with a high fibre diet and avoidance of straining. Three patients required surgery and the most recent seven patients have responded well to biofeedback treatment. Awareness of this uncommon anorectal condition is necessary for early diagnosis and appropriate management. The physiological findings support a pelvic straining pathophysiology resulting in perineal descent, with less sensitive rectal mucosa prolapsing into, and raising, the anal canal electrosensory threshold. Treatment strategies aimed at correcting the straining have usually been successful. PMID- 7857238 TI - Hartmann's operation: a personal experience. AB - This paper documents a 15 year experience with Hartmann's operation in the Colorectal Service at the Wellington School of Medicine, New Zealand. There were 31 male and 30 female patients. The majority had either complicated diverticular disease (27) or rectal cancer (27). Fifty-six patients were discharged home and five patients died within 30 days of surgery (8.2%). Of the 27 patients with complicated diverticular disease 19 proceeded to stoma closure with no mortality. Of the 27 patients who had complicated colorectal cancer only 2 had their stoma closed. There were 41 patients in whom bowel continuity was restored following construction of a Hartmann's stoma. Thirty-nine anastomoses were hand-sewn and two anastomoses were stapled. One patient developed a major anastomotic leak and one patient died postoperatively. Hartmann's operation has a definite place in the management of patients with complicated diverticular disease and recto sigmoid cancer. The operation can be performed and the stoma closed safely in the former group but is less likely to be followed by restoration of continuity in the latter group. PMID- 7857239 TI - Mechanisms of alcohol abuse and alcoholism in adolescents: a case for developing animal models. AB - This paper reviews the ontogeny of neurotransmitter systems and neuropharmacological challenge within transmitter systems and discusses the actions of alcohol on such systems during the juvenile through adolescent periods. To place the animal research within the context of human development, an attempt is made to first examine some fundamental principles of developmental research as they relate to the adolescent period. Evidence presented from animal studies indicates that unique neurochemical and behavioral changes are occurring during postnatal development, including adolescence, that could mediate the response to alcohol. The limited number of studies on the neurochemical and behavioral response to alcohol during adolescence has employed rats and has been restricted by the relatively brief adolescent period in that species. While one alternative is to use primates, it is suggested that innovative behavioral paradigms be developed for adolescent animals in other species to study behaviors such as alcohol self-administration or alcohol stimulus discrimination. It is also suggested that existing behavioral models that are more easily adapted to younger age ranges (e.g., conditioned place preference, conditioned taste aversion, thermal response to ethanol) be extended to make ontogenetic comparisons through adolescence and adulthood. This may further our understanding of alcohol's immediate consequences during each maturational stage and, more important, the contribution of early alcohol exposure to excessive drinking and abnormal cognitive and social functioning during subsequent stages of development. PMID- 7857240 TI - Place navigation in the Morris water maze under minimum and redundant extra-maze cue conditions. AB - Complex relational processes underlying place navigation learning were analyzed by minimizing the relational elements available to rats. The animals navigated in a standard water maze in darkness using controlled remote visual cues (back-lit shapes in opaque buckets aimed at the pool to keep the background dark) while being tracked by an infrared camera and computer. Learning was similar with 2 (AB) or 4 (ABCD) cues and as good as in a fully lit room with many cues (asymptotic escape time t = 5-7 s). The ABCD-trained rats were not impaired by removal of any 2 cues (t = 7). For AB-trained rats, adding 2 new cues (ABEF) or replacing AB with EF (EF) caused small (t = 11) or big disruptions (t = 20), respectively. By block 2, both groups (ABEF, EF) returned to asymptotic performance. But testing the ABEF rats on block 2 with only EF indicated that EF was learned (t = 12) but not as well as when only EF was present (t = 5). Thus transfer from a redundant to a minimal cue condition is immediate and easier than vice versa. Theoretical implications are discussed. PMID- 7857241 TI - Beta-adrenergic receptor antagonist antihypertensive medications impair arousal induced modulation of working memory in elderly humans. AB - It is well-established that administration of moderate doses of the adrenal catecholamines epinephrine or norepinephrine shortly after training results in the enhancement of later retention performance in laboratory animals. These substances, released endogenously as a result of arousal, are thought to modulate memory processes by stimulating peripheral receptors that send neural messages to the brain, thus altering the memory storage process. The applicability of this hypothesis to the modulation of memory processes in humans was tested in this experiment by using elderly subjects who were chronically taking beta-receptor antagonist medications to control hypertension. A moderate level of muscle tension-induced arousal was produced by having subjects squeeze a hand dynamometer during the initial storage and recall of highlighted words in short 200-word paragraphs. Twenty young normal individuals, 22 normotensive elderly subjects, 21 elderly subjects taking either calcium-channel blockers or angiotensin-converting enzyme inhibitors to control hypertension, and 21 elderly subjects taking beta-blocker antihypertensive medications served as subjects. The young subjects, normal elderly subjects, and those taking non-beta-blocker medications all showed enhanced long-term recognition performance as a result of the arousal manipulation. However, those subjects chronically taking beta receptor-antagonist medications showed no enhancement of memory. PMID- 7857243 TI - Food-induced arousal and nonassociative learning in honeybees: dependence of sensitization on the application site and duration of food stimulation. AB - Stimulus-induced arousal (sensitization) of a component of appetitive behavior in honeybees, the proboscis extension reflex (PER), was used to investigate different aspects of nonassociative memory. The sensitizing stimulus (sucrose solution) was applied to one antenna, as a compound to antenna and proboscis, and to the proboscis. Stimulus duration was either 1 or 3 s. Sensitization was evaluated by monitoring PER toward an odor before (pretest) and after (test) application of the sensitizing stimulus. All responses were quantified by recording from muscle M17 which represents the motor program of PER. Data were analyzed by determining (1) the response probability to the odor and (2) the response strength by determining the number of M17-spikes and the percentage of licking bees per trial. The analysis of the response probability led to two main results: the proportion of animals responding to the test odor depended on stimulus site, and, dependent on stimulus site, a longer application of the sensitizing stimulus resulted in different sensitization rates. The strength of the sensitized response, however, did not correspond to the probability, with which it was elicited, but rather to the strength of the response to the sensitizing stimulus itself. Furthermore, the three groups were not equally affected by the short and long stimulation. The analysis of the proportion of animals licking during test confirmed the data obtained using the number of muscle spikes as a measure of response strength. These results suggest an internal evaluation of the sensitizing stimulus depending on its quality and intensity. The differential effects after antennal and proboscis stimulation may be realized via an arousal system which has two independent functions, a permissive one modulating response probability and one modulating response strength. The permissive function of arousal may be regulated via an intervening inhibitory system whose activation critically depends on the functional significance of the arousing stimulus. The content of this short-term form of memory may be interpreted as an expectation for food which is regulated according to experienced consequences. PMID- 7857242 TI - Context and tone conditioning are selectively impaired by ethanol in the preweanling rat: effects of dose and time of administration. AB - Depending on dose and task requirements, ethanol can have either a facilitative or an impairing influence on learning. Some explanations for this dichotomy have considered ethanol's suppression of behavioral variability and processing of incidental stimuli (e.g., context). The present study examined the effect of ethanol on context and conditioned stimulus (CS) learning in the preweanling rat. To assess state-dependent effects, a drug dissociation design was used. Learning to both context and CS were analyzed within each dose of ethanol (0, 1.2, 1.6, or 2.0 g/kg) and a trend analysis was conducted to determine dose-response relationships as a function of train-test state. The 1.2 g/kg dose of ethanol did not affect conditioning to either the context or the CS. A 1.6 g/kg dose tended to disrupt context, but not CS, conditioning. The influence of 2.0 g/kg ethanol depended on train-test conditions. Ethanol administration prior to training resulted in the stronger impairment of CS learning while context conditioning was most disrupted if ethanol was given only prior to testing. The results suggest that ethanol selectively attenuates processing of stimuli, possibly dependent on relative saliency at the time of testing. PMID- 7857244 TI - Color learning and memory in honey bees are not affected by protein synthesis inhibition. AB - The role of protein synthesis was tested for memory formation after color learning in honey bees. Free flying bees were trained to a feeding place. Before the color conditioning started, foragers accustomed to flying to the feeding place received an injection of either cycloheximide in bee ringer or bee ringer alone into the brain. Afterward, the animals were trained appetitively to a specific colored target by three training trials. During the test situation, two targets with different colors and no reward were presented. The choice behavior toward the two targets was evaluated. The first test immediately followed the last trial, the second test 24 h later. A comparison between cycloheximide- and ringer-injected bees showed no significant difference in choice behavior in either test. Although the injection of cycloheximide causes the inhibition of protein synthesis (> 95%) for a period of 3 h, the memory for the learned color signal is not affected. These results corroborate those found for the olfactory conditioning of the proboscis extension reflex in bees (Wittstock, Kaatz, & Menzel, 1993, Menzel, Gaio, Gerberding, Nemrava, & Wittstock, 1993). PMID- 7857245 TI - Effects of estradiol on radial arm maze performance of young and aged rats. AB - Gonadectomized male and female Sprague-Dawley rats, given estradiol (E2) via sc Silastic capsules that generated proestrus levels of hormones, were tested for spatial memory performance on an 8-arm radial maze. Performance of males, with or without E2, exceeded that of females, with or without E2, for choice accuracy parameters over 20 trials. In addition, males reached criterion earlier than females (6 vs 11 trials). There were no significant effects of E2 on performance of either sex. When a 1-h delay was instituted between the 4th and 5th choices, the performance of males remained better than that of the females, and E2 administration was associated with a small, but significant, improvement in performance of the males but not the females. E2 administration to 25-month-old males also did not affect performance in regular trials, but performance was enhanced in trials with delays of 1-3 h after the 4th choice. These results show that estradiol can influence spatial memory performance and suggest that E2 may be beneficial for age and/or disease-related memory impairments. PMID- 7857246 TI - Memory-improving actions of glucose: involvement of a central cholinergic muscarinic mechanism. AB - Post-training intraperitoneal administration of alpha-D[+]-glucose (10-300 mg/kg) facilitated 24-h retention, in male Swiss mice, of a one-trial step-through inhibitory avoidance task. The dose-response curve was an inverted U. Glucose did not increase the retention latencies of mice that had not received a footshock during training. The effect of glucose (30 mg/kg, ip) on retention was time dependent, which suggests that the drug facilitated memory storage. The memory facilitation induced by glucose (30 mg/kg, ip) was prevented by atropine (0.5 mg/kg, ip) administered after training, but 10 min prior to glucose treatment. In contrast, neither methylatropine (0.5 mg/kg, ip), a peripherally acting muscarinic receptor blocker, nor mecamylamine (5 mg/kg, ip) or hexamethonium (5 mg/kg, ip), two cholinergic nicotinic receptor antagonists, prevented the effects of post-training glucose on retention. Low subeffective doses of the central acting anticholinesterase physostigmine (35 micrograms/kg, ip), administered immediately after training, and glucose (10 mg/kg, ip), given 10 min after training, acted synergistically to improve retention. The effects of glucose (10 mg/kg, ip) were not influenced by the peripherally acting anticholinesterase neostigmine (35 micrograms/kg, ip). Considered together, these findings suggest that the memory facilitation induced by post-training administration of glucose could result from an enhancement of brain acetylcholine synthesis and/or its release that, in turn, might modulate the activity of muscarinic cholinergic mechanisms that are critically involved in memory storage. PMID- 7857247 TI - Hypobaric hypoxia impairs spatial memory in an elevation-dependent fashion. AB - The effects of various levels of hypobaric hypoxia, exposure to reduced atmospheric pressure, on spatial memory in rats were examined. Hypobaric hypoxia simulates high altitude conditions where substantial deficits in human cognitive performance occur. However, few studies have measured cognitive changes in animals during exposure to this type of hypoxia. Male Fischer 344 rats were tested in the learning set version of the Morris water maze, a test known to assess spatial memory. Rats were tested at 2 and 6 hours while exposed to a range of simulated altitudes: sea level, 5500 m, 5950 m, and 6400 m. Altitude exposures at 5950 or 6400 m decreased both reference and working memory performance, as demonstrated by latency, distance, and speed measures, in an elevation-dependent fashion. During sea level testing on the day following hypobaric exposure, decrements in reference memory were still observed on all dependent measures, but only speed was impaired on the working memory task. These results agree with human studies that demonstrate elevation-dependent impairments in spatial memory performance during exposure to hypobaric hypoxia. The deficits may be attributable to changes in hippocampal cholinergic function. PMID- 7857248 TI - Infusion of the GABAergic antagonist bicuculline into the medial septal area does not block the impairing effects of systemically administered midazolam on inhibitory avoidance retention. AB - This experiment investigated the effect of intraseptal administration of the GABAergic antagonist bicuculline methiodide on benzodiazepine-induced amnesia. Male Sprague-Dawley rats were implanted with cannula aimed at the medial septal area and allowed to recover for 1 week. Ten minutes prior to training in a continuous multiple trial inhibitory avoidance task, buffer solution or bicuculline methiodide (56 or 100 pmol/0.5 microliter) was injected into the medial septal area. This infusion was immediately followed by systemic (ip) administration of saline or midazolam (1.5 or 3.0 mg/kg). In comparison with saline controls, animals given the higher dose of midazolam (3.0 mg/kg), required more trials to reach acquisition criterion (remaining in the starting chamber for 100 s). This midazolam-induced acquisition deficit was blocked by an intraseptal infusion of bicuculline methiodide (100 pmol). On a 48-h retention test the performance of animals given either dose of midazolam was significantly impaired relative to vehicle controls. Furthermore, although intraseptal infusion of bicuculline methiodide prior to systemic injection of midazolam blocked the midazolam-induced acquisition impairment, bicuculline did not block the midazolam induced retention impairment. These results suggest that although the medial septal area may be involved in midazolam-induced acquisition deficits, this area is not a critical site of action for benzodiazepine-induced effects on inhibitory avoidance retention. PMID- 7857249 TI - Development and experience lead to increased volume of subcompartments of the honeybee mushroom body. AB - The mushroom bodies of insects are believed to be involved in higher order sensory integration and learning. In the honeybee, the mushroom body can be separated into three different, modality-specific input compartments and several morphologically inseparable output regions. By means of morphometric analysis we show that the volumes of these subcompartments depend on both the age of the adult bee and its experience. For the most part a significant, age-dependent increase in neuropile volume is observed. Additionally, the olfactory and visual input regions show experience-related differences. Unlike other subcompartments, the visual input region does not change in volume with age, but only with experience. We thus suggest that experience is an important factor in the structural development of higher order brain regions of an insect, the honeybee. PMID- 7857250 TI - Activin induces the expression of the Xenopus homologue of sonic hedgehog during mesoderm formation in Xenopus explants. AB - The Xenopus homologue of sonic hedgehog (Xhh) was detected in Xenopus embryos at stages 13 and 31 by RT-PCR, but it was not expressed in explants isolated from the animal hemisphere of Xenopus embryos at stage 8-9. Treatment of the animal cap with activin (1-100 ng/ml) induced the expression of Xhh. However, it was not induced by 100 ng/ml basic fibroblast growth factor (bFGF). Whole mount in situ hybridization confirmed the expression of Xhh in the animal cap treated with activin. The expression of Xhh induced by activin was not inhibited in the presence of cycloheximide, suggesting that Xhh is an early response gene induced by activin. PMID- 7857251 TI - Oleic acid blocks EGF-induced [Ca2+]i release without altering cellular metabolism in fibroblast EGFR T17. AB - EGFR-T17 cells were pretreated with oleic acid and 5-10 minutes later stimulated with EGF, to study if early ionic signals are instrumental in inducing metabolic cellular response. Oleic acid blocks EGF-induced [Ca2+]i rise and Ca2+ influx without altering 2-deoxyglucose and 2-aminobutiryc acid uptake nor acute, nor chronically. Oleic acid it is shown, in the first minutes favors the entrance of both molecules to modify the physico-chemical membrane state. On the other hand, oleic acid is unable to block protein synthesis. The results suggest that EGF induced Ins(1,4,5)P3/Ca2+ pathway does not seem to be decisive in the control of cellular metabolic activity. PMID- 7857252 TI - Genomic structure of the mouse delta opioid receptor gene. AB - Using mouse delta opioid receptor (DOR) cDNA sequence to probe genomic libraries in bacteriophage lambda and P1 vectors, clones traversing the entire DOR coding sequence and 5' and 3' flanking regions were isolate. Genomic sequence encoding mature DOR message, including 5' and 3' untranslated sequence, is divided by two introns of 26 kb and 3 kb, resulting in the gene occupying 32 kb of chromosomal DNA. Multiple putative transcription initiation sites were located, by RNase protection assay, in TATA-less G+C rich sequence between 390 and 140 nucleotides upstream from the ATG translation start codon. A polyadenylation site was located 1.24 kb downstream from the TGA translation stop codon. Examination of 1.3 kb of 5'flanking sequence revealed potential binding sites for several known transcription factors including: Sp1, Ap-2, NF-kappa B, NF-IL6, and NGFI-B. PMID- 7857253 TI - Nitric oxide modulates the synthesis of extracellular matrix proteins in cultured rat mesangial cells. AB - Nitric oxide (NO) is an important effector molecule of the inflammatory response. It is synthesized by mesangial cells and has been proposed to contribute to glomerular injury in various disease states. We studied whether NO modulates extracellular matrix production in cultured rat mesangial cells. Stimulation of rat mesangial cell NO release with gamma-interferon and lipopolysaccharide resulted in reduced production of collagen (by 35%) fibronectin (by 48%) (P < 0.05). In contrast, laminin synthesis was enhanced two-fold by the same maneuver (P < 0.05). These changes were reversed by the addition of L-NAME, a selective inhibitor of inducible nitric oxide synthase. This is the first demonstration that NO regulates the synthesis of extracellular matrix by mesangial cells. The results indicate that increased renal production of NO in glomerular diseases may attenuate the production and accumulation of matrix proteins and limit the severity of glomerulosclerosis. PMID- 7857254 TI - Potassium channel opener, RP 66471, induces membrane depolarization of rat liver mitochondria. AB - Effect of potassium channel openers on membrane potential of rat liver mitochondria was studied. It has been found that potassium channel opener RP 66471 induces depolarization of the mitochondrial membrane. Since neither the inhibition of mitochondrial respiration nor the uncoupling of mitochondria was observed concomitantly, the specific effect on the mitochondrial potential is postulated. Most likely the effect is caused by the increase of permeability of the inner mitochondrial membrane to potassium ions. Interestingly, however, it was found that no other potassium channel openers tested but RP 66471 was able to induce depolarization of mitochondrial membrane. PMID- 7857255 TI - Beta-adrenergic receptor function in cultured AT-1 cardiomyocytes. AB - AT-1 cells are highly differentiated, contracting cardiomyocytes derived from atrial tumours in transgenic mice. The aim of this study was to characterize beta adrenergic receptor function and associated intracellular calcium regulation in AT-1 cells. Equilibrium binding experiments with [3H]-CGP-12177 showed a Kd = 0.30 +/- 0.08nM and a Bmax = 2.25 +/- 0.47 fmol/10(5) cells. Competition binding experiments with CGP-20712A showed presence of predominantly beta 1 adrenoreceptors. S-(-)propranolol, atenolol and R-(+)propranolol showed a competitive inhibition of binding with successively lower affinity. Isoproterenol, 2 microM, for 48 hours down-regulated the number (p < 0.05) of beta-adrenergic receptors/cell by about 50%; 10 microM for one hour increased the cAMP concentration (p < 0.05) by about 100%. Cytosolic [Ca2+] was measured flourimetrically in spontaneously and synchronously beating AT-1 cells. The resting cytosolic concentration was 94 +/- 10 nM. The observed sinusoidal Ca2+ oscillation frequency increased after addition of 10 microM isoproterenol (p < 0.02). This effect was antagonized by 10 microM alprenolol (p < 0.01). In conclusion, AT-1 cells have functional beta-adrenoreceptor signalling pathways and constitute an important tool in cardiac biology. PMID- 7857256 TI - Amylin stimulates osteoblast proliferation and increases mineralized bone volume in adult mice. AB - Amylin, a 37-amino-acid peptide co-secreted with insulin from the beta-cells of the pancreatic islets, has previously been demonstrated to inhibit bone resorption in vitro. However, its effects on bone formation and bone mass have not been assessed. We report that periphysiological concentrations of amylin stimulate proliferation of fetal rat osteoblasts in vitro. When amylin is injected daily for 5 days over the calvariae of adult mice in vivo, there are substantial increases in histomorphometric indices of bone formation, a reduction in bone resorption, and a significant increase in mineralized bone area. Equimolar doses of calcitonin in this in vivo model produced an inhibition of bone resorption but no significant effect on bone area. These findings support a role for amylin as a physiological regulator of bone and suggest that it should also be evaluated as a potential treatment for osteoporosis. PMID- 7857257 TI - Phosphorylation/activation of phosphorylase b kinase by cAMP/Ca2(+)-independent, autophosphorylation-dependent protein kinase. AB - Phosphorylase b kinase from rabbit skeletal muscle can be phosphorylated and activated by a cyclic nucleotide- and Ca2(+)-independent protein kinase previously identified as an autophosphorylation-dependent multifunctional protein kinase (auto-kinase) from brain and liver (Yang et al., J. Biol. Chem. 262, 7034 7040 (1987) and Yang et al. J. Biol. Chem. 262, 9421-9427 (1987)). This independent kinase phosphorylates both alpha and beta subunits of phosphorylase b kinase and results in a approximately 5-fold activation of the kinase when 0.55 and 0.5 mol of phosphate are incorporated into the alpha and beta subunits, respectively. Activation of phosphorylase b kinase catalyzed by auto-kinase is about 70% of that observed with cAMP-dependent protein kinase. Analysis of phosphopeptide maps of alpha and beta subunits further reveals that both kinases phosphorylate almost the same sites on both alpha and beta subunits, suggesting that activation of phosphorylase b kinase by the two kinases may be through a common molecular action mechanism. Taken together with the previous result that auto-kinase can inactivate glycogen synthase, the present study provides initial evidence that a coordinate control mechanism for simultaneous regulation of glycogenolysis and glycogenesis can be modulated by autophosphorylation-dependent protein kinase in a cAMP- and Ca2(+)-independent pathway, representing a new mode of control mechanism for the regulation of glycogen metabolism in cells. PMID- 7857258 TI - HDL3 activates phospholipase D in normal but not in glycoprotein IIb/IIIa deficient platelets. AB - Glycoprotein IIb/IIIa has been proposed as the platelet receptor for high density lipoproteins (HDL3). We characterized the HDL3-induced second messenger response in normal and glycoprotein IIb/IIIa-deficient platelets. In normal platelets physiological concentrations of HDL3 induced the time-dependent generation of phosphatidic acid in the absence of phosphoinositide turnover. The rise in phosphatidic acid preceded that of diacyglycerol which was inconsistent with phospholipase C/diacylglycerol kinase pathway being the source of phosphatidic acid and suggested the involvement of phospholipase D. In the presence of butanol, HDL3 stimulated the accumulation of phosphatidylbutanol, an unequivocal indicator of phospholipase D activity. No increase in phosphatidic acid, diacylglycerol, and phosphatidylbutanol was observed upon addition of HDL3 to glycoprotein IIb/IIIa-deficient platelets. We conclude that phosphatidic acid is generated in HDL3-stimulated platelets by phospholipase D and that glycoprotein IIb/IIIa is the receptor involved in this process. PMID- 7857259 TI - Different oxidant sensitivities of the alpha 1 and alpha 2 isoforms of Na+/K(+) ATPase expressed in baculovirus-infected insect cells. AB - Inhibition of Na+/K(+)-ATPase by partially reduced oxygen metabolites is an early event in the course of cell injury caused by oxidative stress. We showed before that isoforms of the enzyme obtained from different sources have different oxidant sensitivities. To evaluate the role of tissue-specific impurities in this difference, cDNAs of alpha 1 and alpha 2 isoforms were expressed in Sf-9 insect cells, and the effects of H2O2 on the resulting isolated enzymes were studied. The expressed alpha 2 was significantly more sensitive than alpha 1 to H2O2. These findings, together with our previous data showing different oxidant sensitivities of alpha 1 and alpha 3 in a cardiac enzyme preparation, indicate that differential oxidant sensitivities of Na+/K(+)-ATPase isoforms of various tissues are dictated by the primary sequences of alpha 1, alpha 2, and alpha 3 subunits. PMID- 7857260 TI - Differential control of the metal-mediated activation of the human heme oxygenase 1 and metallothionein IIA genes. AB - Heme oxygenase-1, an essential enzyme in heme catabolism, and metallothionein IIA, a small metal-binding protein with clusters of cysteins, are remarkably induced in HeLa cells following the treatment with cadmium or zinc. Both proteins are considered to be involved in the defense system against metal toxicity. Here we showed by transient expression assays that the cadmium-responsive element (CdRE) of the human heme oxygenase-1 gene is not responsive to zinc, whereas a metal-regulatory element (MRE) of the human metallothionein IIA gene is able to respond to either cadmium or zinc. The CdRE is recognized by a certain nuclear protein(s) which is however unable to bind to an MRE of the metallothionein IIA gene. These results suggest that the metal-selective activation of each gene promoter is mediated by a separate mechanism. PMID- 7857261 TI - Muscle undergoes atrophy in association with increase of lysosomal cathepsin activity in interleukin-6 transgenic mouse. AB - Interleukin(IL)-6 transgenic mice were produced by microinjection of human IL-6 cDNA fused with H-2Ld promoter into the pronucleus of fertilized eggs from C57BL/6J mice. At 16 weeks old, the gastrocnemius muscles of the IL-6 transgenic mice became atrophic as compared to those of the normal mice, while the body weights increased significantly. The activities and mRNA levels of lysosomal cathepsins B and L were increased in the muscles of the transgenic mice. Immunohistochemical study on the muscles showed increased staining of both cathepsins B and L in the transgenic mice. IL-6 is responsible for enhanced muscle catabolism by activating the lysosomal cathepsin (B and L) system. PMID- 7857262 TI - Glycerol-3-phosphate dehydrogenase activity in human lymphocytes: effects of insulin, obesity and weight loss. AB - Insulin exposure stimulates an increase in glycerol-3-phosphate dehydrogenase (G3PDH) activity in isolated human lymphocytes that correlates to an increase in G3PDH mRNA and requires new protein synthesis. Synthetic diacylglycerol or phorbol ester can mimic the effect of insulin on G3PDH activity, suggesting that protein kinase C may be involved in regulation of G3PDH levels. In addition, lithium chloride, an inositol phosphate phosphatase inhibitor, and calcium uptake inhibitors can abolish insulin stimulation of G3PDH activity. For obese subjects in whom insulin resistance in vitro can be demonstrated, the extent of insulin stimulation of G3PDH activity is decreased compared to normal weight individuals, and treatment by a very low calorie diet restores insulin stimulation of G3PDH activity. Thus, insulin stimulation of G3PDH activity is dependent upon the metabolic state of the subject from whom the cells are obtained. PMID- 7857263 TI - Hepoxilin binding in human neutrophils. AB - Hepoxilins have previously been shown to release intracellular calcium in human neutrophils. We show herein that tritium-labeled hepoxilin A3 of high specific radioactivity binds to human neutrophils, and this binding is reversed by the addition of unlabeled compound, demonstrating that specific binding for these compounds exists in these cells. Specific binding of both the methyl ester derivative as well as the free acid form of the hepoxilin takes place in broken membrane fragments. In contrast only the methyl ester derivative binds specifically to the intact cells. We also show that intact neutrophils form hepoxilin A3 when incubated in the presence of the hepoxilin precursor, 12(S) HPETE. These data demonstrate that hepoxilin synthesis can occur in the neutrophil and that hepoxilin binding sites, which appear to be located intracellularly, exist in these cells. PMID- 7857264 TI - The nitroso-donor S-nitroso-cysteine regulates IsK expressed in Xenopus oocytes via a c-GMP independent mechanism. AB - In Xenopus oocytes expressing slowly activating IsK channels superfusion with the nitroso-donor S-Nitroso-Cysteine (SNOC) resulted in an increase of IsK, which was greatly enhanced when the amino acid-exchanger rBAT was coexpressed. The effects of SNOC on IsK could not be prevented by the guanylate cyclase inhibitor LY 83,583 and the cGMP kinase inhibitor H8, but was abolished in the presence of staurosporine. SNOC also increased the currents induced by the expression of protein mutants lacking intracellular sites, previously described to be involved in IsK regulation by oxidation and phosphorylation. These data suggest that the NO-donor SNOC regulates IsK indirectly via a cGMP independent, but staurosporine sensitive, pathway. PMID- 7857265 TI - Improvement of thermal stability of subtilisin J by changing the primary autolysis site. AB - The thermostability of subtilisin J, an extracellular serine protease secreted from Bacillus stearothermophilus, has been improved by changing the primary autolysis site of the Asp-49 mutant protein. Previously we have shown that the Asp-49 mutant protein has proteolytic activity, but so unstable that it was primarily autolyzed in Tyr-58-Gln-59 peptide bond during cultivation (Jang et al. Biochim. Biophys. Acta. 1162, 233-235 1993). In the present study, to mitigate the autolytic degradation and increase the thermostability, we deleted the Tyr-58 residue using the Asp-49 mutant as a template. This mutant (Asp-49/delta Tyr-58 mutant) protein showed an improved resistance to heat treatment without changing the catalytic efficiency of the enzyme. These results show that change of primary autolysis site can stabilize the subtilisin. PMID- 7857266 TI - The type II hemopexin interleukin-6 response element predominates the transcriptional regulation of the hemopexin acute phase responsiveness. AB - Hemopexin (Hx) is induced during the acute phase response (APR) by the cytokine interleukin (IL)-6. A type II IL-6 response element (RE) of the Hx gene has been characterized recently (J. Biol. Chem. (1994); 269, 12654-12661). To assess Hx gene regulation by other agents, various cytokines and growth factors were tested for their ability to induce Hx in rat hepatoma H-35 cells. IL-6-type cytokines, IL-1 beta and TNF-alpha, in contrast to transforming growth factor-beta (TGF beta), hepatocyte growth factor and insulin significantly increased Hx gene expression. Chloramphenicol acetyltransferase (CAT) activity in H-35 cells transfected with constructs that contained the 5'-flanking Hx promoter region or multiple copies of the Hx IL-6-RE fused to the CAT gene was upregulated only by IL-6-type cytokines, although to varying degrees. These data indicate that signal transduction pathways mediated by IL-6-type cytokines but not those by IL-1 beta and TNF-alpha converge on the common Hx IL-6-RE. PMID- 7857267 TI - Aggregation state-dependent binding of beta-amyloid peptide to protein and lipid components of rat cortical homogenates. AB - Beta-amyloid peptide (A beta) is the primary protein component of senile plaques in Alzheimer's disease. A beta is toxic to neuronal cell cultures, although the mechanism of neurotoxicity is unknown. Neurotoxicity has been correlated to the aggregation state of the peptide. In this work, the synthetic beta-amyloid peptide A beta(1-39) was radioiodinated and fractionated into samples containing varying degrees of aggregated material. Binding of the peptide to rat cortical homogenates (containing both lipids and membrane-associated protein) and to artificial neuronal membrane (containing only lipids) was measured. Binding increased with increasing percent aggregated peptide in the solutions. Aggregated peptide bound to both cortical homogenate and membrane, whereas monomeric peptide bound to homogenate only. These results may help discriminate among alternative mechanisms of neurotoxicity of A beta. PMID- 7857268 TI - Increased expression of heparin binding epidermal growth-factor-like growth factor mRNA in the kidney of streptozotocin-induced diabetic rats. AB - Heparin binding epidermal growth factor (HB-EGF), a new member of the EGF family, is a potent mitogen for smooth muscle cells, fibroblasts, and mesangial cells. To study whether the HB-EGF is involved in the development of diabetic nephropathy, we measured the expression of the HB-EGF gene in the kidney tissues of streptozotocin-induced diabetic rats by Northern blot analysis. The mean kidney weight of diabetic rats without strict blood sugar control was significantly increased as compared to that of the control group. Renal HB-EGF mRNA expression was also increased in diabetic rats without strict blood sugar control at 7 days after induction of diabetes and remained elevated for the entire 3-month study period. Strict insulin treatment abolished the elevation of HB-EGF mRNA expression and kidney growth. As HB-EGF is a mitogen for mesangial cells, our results suggest that HB-EGF may be involved in the development of diabetic nephropathy. PMID- 7857269 TI - Nucleotide sequence and expression of UDP-glucose dehydrogenase gene required for the synthesis of xanthan gum in Xanthomonas campestris. AB - Xanthomonas campestris pv. campestris, producing large amounts of exopolysaccharide xanthan gum, has a mucoid phenotype. Strain SD7 was a non mucoid mutant deficient in UDP-glucose dehydrogenase. A DNA fragment able to complement the mutation of SD7 was cloned from the parental wild-type strain Xc11. Sequence analysis of the region required for the complementation revealed an open reading frame which could encode a polypeptide of 445 amino acids with a calculated molecular weight of 48,432, a size similar to that of the product produced by maxicell. The amino acid sequence had significant homology to that of the GDP-mannose dehydrogenase from Pseudomonas aeruginosa. PMID- 7857270 TI - Oxidized low-density lipoprotein stimulates nitric oxide release by rabbit aortic endothelial cells. AB - Incubation of rabbit aortic endothelial cells (RAEC) with oxidized low-density lipoprotein (LDL) for 16 h resulted in stimulation of calcium uptake and increased release of nitric oxide (NO) by these cells. Accompanying inhibition of protein tyrosine phosphatase (PTP) activity in these cells was also observed. Conversely, native LDL was unable to produce any of those effects. These observations suggest that oxidized LDL could modulate two major signalling processes in endothelial cells: tyrosine dephosphorylation and NO synthesis. Such modulation may be of importance in the early phase of the atherogenic process. PMID- 7857271 TI - Calcium ionophore A23187 inhibits ACTH secretion from a human small cell lung cancer cell line, COR-L103. AB - The mechanism of ectopic adrenocorticotrophic hormone (ACTH) secretion was examined by studies on the effects of corticotropin-releasing hormone (CRH), dexamethasone, interleukin (IL)-1 beta and 2, somatostatin, calcium ionophore A23187, 12-O-tetradecanoylphorbol-13-acetate (TPA) and 8-bromo-cAMP on pro opiomelanocortin (POMC) expression and ACTH secretion from a human small cell lung cancer cell line COR-L103. None of these agents except TPA and A23187 had any effect on ACTH secretion from the cell line in short (0-8 hrs) or long term (1-4 days) cultures. In long term cultures, 1-100 nM TPA stimulated ACTH secretion dose-dependently, whereas 500nM A23187 inhibited ACTH secretion completely. When the cells were incubated with 10nM TPA plus 500 nM A23187, the inhibitory action of A23187 on ACTH secretion was suppressed by TPA. These results suggest that the mechanisms of ACTH secretion by COR-L103 cells and normal pituitary cells are different. PMID- 7857272 TI - Involvement of preferential formation of apurinic/apyrimidinic sites in dimethylarsenic-induced DNA strand breaks and DNA-protein crosslinks in cultured alveolar epithelial cells. AB - We previously found that lung-specific DNA damage induced by administration of dimethylarsinic acid (DMAA), a main metabolite of inorganic arsenics in mammals, in mice might be due to dimethylarsenic peroxyl radical [(CH3)2AsOO.] produced in the further metabolic processing of DMAA. Further analysis of DNA damage was performed in the present study using a human embryonic cell line of alveolar epithelial (L-132) cells. Alkali-labile sites in DNA were produced prior to DNA single-strand breaks (SSB) and DNA-protein crosslinks (PC) in L-132 cells by exposure to 10mM DMAA. An experiment using methoxyamine (MA), an agent reacting with the aldehyde group of apurinic/apyrimidinic (AP) sites in DNA, indicated that, of the alkali-labile sites formed by exposure to DMAA, major ones were AP sites. These findings suggest that SSB and PC induced by exposure of L-132 cells to DMAA occurred via the formation of AP sites in DNA. That is, SSB were produced by a beta-elimination reaction on AP sites in the DNA and PC by a Schiff-base reaction between amino groups of nuclear proteins and aldehyde groups of AP sites. PMID- 7857273 TI - Interleukin-1, tumor necrosis factor and lipopolysaccharide additively stimulate production of adrenomedullin in vascular smooth muscle cells. AB - To elucidate physiological functions of adrenomedullin (AM) secreted from vascular smooth muscle cells (VSMCs), we examined the effect of cytokines, growth factors and related substances on AM production in cultured rat VSMC. Among them, interleukin-1 alpha (IL-1 alpha), IL-1 beta, tumor necrosis factor-alpha (TNF alpha) and TNF-beta, as well as lipopolysaccharide (LPS), markedly augmented production and gene expression of AM. Although maximal stimulation levels of these substances were not greatly different, ED50 values of IL-1s (0.3 ng/ml) were about 1/10 that of TNFs and LPS. AM mRNA levels maximized at 3-6 h after stimulation with IL-1 beta and LPS, while TNF-alpha increased the AM mRNA level up to 48 h. Furthermore, IL-1 alpha, TNF-alpha and LPS additively increased AM production in VSMC. AM production was slightly augmented by fibroblast, epidermal and platelet derived growth factors. These results suggest that AM secreted from VSMC actually exerts a vasorelaxant effect under physiological conditions such as endotoxin shock, atherosclerosis and inflammation. PMID- 7857274 TI - Alpha-lipoic acid increases intracellular glutathione in a human T-lymphocyte Jurkat cell line. AB - The addition of exogenous alpha-lipoic acid to cellular medium causes a rapid increase of intracellular unbound thiols in Jurkat cells, a human T-lymphocyte cell line. The rise of cellular thiols is a result of the cellular uptake and reduction of lipoic acid to dihydrolipoic acid and a rise in intracellular glutathione. Although the level of dihydrolipoic acid is 100-fold lower than glutathione, the cellular concentration of dihydrolipoic acid might be responsible for the modulation of total cellular thiol levels. Rises in glutathione correlate with the levels of intracellular dihydrolipoic acid (p < .01). This increase in glutathione is not the result of expression of new proteins like gamma-glutamylcysteine synthetase, since the rise in glutathione was not inhibited by cycloheximide, a protein synthesis inhibitor. Lipoic acid administration is therefore a potential therapeutic agent in an array of diseases with glutathione anomalies including HIV infection. PMID- 7857275 TI - Expression of rat liver AdoHcy hydrolase in a Rhodobacter capsulatus ahcY mutant restores pigment formation and photosynthetic growth. AB - An amino acid alignment of fourteen S-adenosylhomocysteine hydrolases shows that sequences from six photosynthetic species and one species possibly derived from algae have an internal 36 to 41 amino acid sequence that is not present in hydrolase sequences from seven non-photosynthetic species. In the photosynthetic eubacterium Rhodobacter capsulatus, the StLB1 strain has a disrupted hydrolase gene, and hydrolase activity is not detectable. Photopigment synthesis and photosynthetic growth are significantly reduced in the StLB1 strain. Introduction of rat hydrolase cDNA into the StLB1 strain restored hydrolase activity, photopigment synthesis and photosynthetic growth. The results show that the 36 amino acid sequence of Rhodobacter capsulatus S-adenosylhomocysteine hydrolase does not have a photosynthesis specific function. PMID- 7857276 TI - 5-15-diHETE and lipoxins generated by neutrophils from endogenous arachidonic acid as asthma biomarkers. AB - 5-Lipoxygenase (5-LO) activation of human blood polymorphonuclear cells (PMN) from healthy subjects (HS) and from asthmatic patients (AP) was investigated comparing their respective capacities to produce lipoxins, 5,15 dihydroxyeicosatetraenoic acid (5,15-diHETE) and leukotrienes, under in vitro stimulation by ionophore A23187. PMN from AP were able to generate higher leukotriene levels from endogenous sources than PMN from HS. Moreover they produced 5,15-diHETE (from 50 to 280ng/10(7) cells) and lipoxins (from 1 to 30ng/10(7) cells), in a linear manner, whereas in the same experimental conditions no detectable amounts of these compounds appeared in PMN from HS. The enhanced 5-LO activation of blood PMN may reflect transcellular signalisation priming indicating that lipoxins and 5,15-diHETE could be much more specific inflammatory state biomarkers than leukotriene B4. PMID- 7857277 TI - The role of reactive oxygen intermediates in osteoclastic bone resorption. AB - Osteoclasts have been shown to produce reactive oxygen intermediates (ROI) and it has been suggested that ROI are involved in the process of bone resorption. ROI have also been shown to play a central role in the activation of the multisubunit transcription factor NF-kappa B that enhances the transcription of genes encoding defence and signaling proteins. Therefore, we have assessed the effect of pyrrolidine dithiocarbamate (PDTC), an oxygen-radical scavenger and metal chelator that is a selective and potent inhibitor of NF-kappa B activation, on osteoclastic bone resorption in the bone slice assay. PDTC (0.001-0.1 mM) dose dependently and non-cytotoxically inhibited osteoclast activity with an IC50 of 0.01 mM. PDTC (0.01 mM) caused no change in the ratio of resorption pit area to resorption pit depth as measured by Lasertec confocal microscopy, indicating that ROI are not involved in the resorptive process per se. This view is supported by time-course studies showing that addition of PDTC or N-acetyl cysteine (NAC; an ROI scavenger, but not metal chelator), 6 hr after the start of the assay had no significant effect on subsequent bone resorption. Desferal (100 microM), a chelator of iron and other metal ions, had no significant effect on bone resorption, indicating (along with the results with NAC) that ROI-scavenging rather than metal chelation is responsible for inhibition of osteoclastic bone resorption by PDTC. Taken together these results indicate that ROI produced by osteoclasts in the bone slice assay are not involved in the process of bone resorption, but are important during osteoclast activation for bone resorption, possibly being involved in activation of the transcription factor NF-kappa B. PMID- 7857278 TI - Cytokines and evolution: in vitro effects of IL-1 alpha, IL-1 beta, TNF-alpha and TNF-beta on an ancestral type of stress response. AB - Invertebrate hemocytes are immune-neuroendocrine cells which contain a variety of cytokines [Ottaviani et al. (1993) Biochem. Biophys. Res. Commun. 195, 984-988] and release biogenic amines when added to corticotropin-releasing factor (CRF), a phenomenon we have described as an evolutionary proto-type stress response [Ottaviani et al. (1991) Proc. R. Soc. Lond. B 245, 215-218]. Here we show in two molluscs, Planorbarius corneus and Viviparus ater, that this response is significantly reduced when hemocytes are pre-incubated with IL-1 alpha, IL-1 beta, TNF-alpha and TNF-beta before the addition of CRF. These results confirm and extend the hypothesis that a deep evolutionary relationship exists between cytokines and stress response. Moreover, these data offer an evolutionary basis for understanding the promiscuity of cytokine receptors. PMID- 7857279 TI - Mg(2+)-ADP protects against inactivation of sarcoplasmic reticulum Ca2+,Mg(2+) ATPase by N-cyclohexyl-N'-(4-dimethylamino-alpha-naphthyl) carbodiimide. AB - N-cyclohexyl-N'-(4-dimethylamino-alpha-naphthyl) carbodiimide (NCD-4) inactivates the sarcoplasmic reticulum Ca(2+)-ATPase by covalent labelling at or near the high affinity (transport) Ca2+ sites. Mg(2+)-ADP protects against the inactivation of the Ca(2+)-ATPase produced by NCD-4, with a K0.5 of Mg(2+)-ADP of 28 +/- 6 microM for purified Ca(2+)-ATPase. With native and solubilized sarcoplasmic reticulum membranes millimolar Mg(2+)-ADP concentrations are needed to produce an effective protection of the Ca(2+)-ATPase against inactivation by NCD-4. These results suggest a tight structural interconnection between catalytic and transport Ca2+ sites in the Ca(2+)-ATPase, modulated by protein-protein interactions in the SR membrane. PMID- 7857280 TI - Inhibition by glucose and deoxyglucose of phosphatidylserine synthesis in Ehrlich ascites tumor cells: a possible relation to the Crabtree effect and depletion of endoplasmic reticulum Ca2+ stores. AB - Incorporation of [14C]serine into phosphatidylserine by the base exchange reaction in Ehrlich ascites tumor cells is inhibited by 30% by glucose and by 60% by 2-deoxyglucose (10 mM each). The inhibition by thapsigargin (0.2 microM) amounts to 80%. This inhibition is interpreted as being due to depletion of calcium stores in the endoplasmic reticulum and is compatible with the previous observation [Teplova, V. V., Bogucka, K., Czyz, A., Evtodienko, Yu.V., Duszynski, J., and Wojtczak, L. (1993) Biochem. Biophys. Res. Commun. 196, 1148-1154] that glucose and deoxyglucose elicit an increase of cytoplasmic [Ca2+] at the expense of intracellular Ca2+ stores and with the finding [Baranska, J. (1989) FEBS Lett. 256, 33-37] that the base exchange reaction requires high concentration of Ca2+ within the endoplasmic reticulum lumen. PMID- 7857281 TI - Regulation of signalling by receptor tyrosine kinases in HeLa cells involves the q-base. AB - The nutrition factor queuine (q; the q-base) is a modulator of mammalian cell proliferation: it can be inhibitory or stimulatory, depending on the metabolic state of the cell. The mechanism underlying this growth-modulating activity was investigated. It was found that the q-base acts antagonistic to epidermal growth factor (EGF) but synergistic with platelet-derived growth factor (PDGF) in HeLa cells. Binding of either growth factor to its receptor resulted in the activation of distinct cellular kinases. The activities of these kinases were profoundly affected by q. The results suggest that the q-base is involved in the homologous regulation of signalling by receptor tyrosine kinases. PMID- 7857282 TI - Modulation of endogenous opiate production: effect of fasting. AB - The endogenous opiate alkaloid content in tissues from fed, 24 h and 48 h fasted rats was determined. Plasma morphine and codeine concentrations did not change in response to fasting. Morphine levels in the spleen increased 3-fold after 24 h of fasting and were lower than fed rats by 48 h of fasting; no change was detected in spleen codeine levels. Brain morphine levels were elevated 5-fold after 24 h of fasting and were two-fold higher than those of fed rats after 48 h of fasting. Brain codeine levels did not change with fasting. These results indicate that opiate alkaloids are endogenously produced in rodent tissues, particularly in the spleen, liver, and adrenals. The synthesis of morphine, in the spleen and brain, is maximally stimulated after 24 h of fasting, without alterations in tissue codeine synthesis. These suggest differential regulation of the endogenous synthetic pathways of morphine and codeine in response to the stress of fasting. PMID- 7857284 TI - Kunitz-type trypsin inhibitor prevents LPS-induced increase of cytosolic free Ca2+ in human neutrophils and HUVEC cells. AB - The protease inhibitor part of inter-alpha trypsin inhibitor is identical to urinary trypsin inhibitor (UTI). Preincubation of neutrophils and HUVEC cells with UTI inhibited increase of cytosolic free Ca2+ induced by LPS. Increase of cytosolic free Ca2+ induced by LPS in the presence of EGTA was also inhibited by UTI. In contrast, UTI did not inhibit increase of cytosolic free Ca2+ in cells stimulated by Ca2+ ionophore with or without EGTA. The effects of nine synthetic peptides of UTI on the concentration of cytosolic free Ca2+ in the neutrophils induced by LPS were examined. Preincubation with a peptide of UTI domain 2, NLPIVRGPCRAFIQL (83-97), was completely inhibited by the increase of cytosolic free Ca2+ in neutrophils. This region is identical to the trypsin inhibitor site of UTI. We propose that a function of UTI other than as a protease inhibitor is in regulation of intracellular Ca2+ and that this is due to its trypsin inhibitor region. PMID- 7857283 TI - Isolation and characterization of the HC8 subunit gene of the human proteasome. AB - For study of the molecular basis of regulation of proteasome gene expression, we isolated the gene encoding the alpha-type HC8 subunit of the human proteasome. About 2.3 kb of the 5' flanking region of this gene was tested for promoter function by chloramphenicol acetyltransferase assay. This analysis revealed that CAAT and TATA boxes, but not a GC box, are essential for its promoter activity. These results differed from previous findings that the genes for the alpha-type HC3 and beta-type HC5 subunits of the human proteasome have a TATA-less promoter and that two or three GC boxes function as the promoter sequences (Tamura, T. et al. (1994) J. Mol. Biol. 244, 1117-1124). We mapped the HC8 gene at q23 on human chromosome 14, which differs from the chromosomal locations of nine other proteasomal subunit genes mapped so far. PMID- 7857285 TI - Glucagon-like peptide-1 modulates Ca2+ current but not K+ATP current in intact mouse pancreatic B-cells. AB - The influence of GLP-1 on electrical activity and ion currents of mouse pancreatic B-cells was studied with intracellular microelectrodes and the whole cell configuration of the patch-clamp technique. In the presence of 15 mmol/l glucose 5, 50 and 100 nmol/l GLP-1 slightly increased electrical activity. This effect may be caused by the slowing of Ca2+ channel inactivation observed with GLP-1. Thus, changes in Ca2+ channel kinetics are suggested to contribute to the insulinotropic action of the hormone. The most prominent effect of GLP-1 on the membrane potential was the conversion of irregular electrical activity into regular oscillations of the membrane potential. At the threshold concentration for insulin secretion (7 mmol/l glucose) GLP-1 did not alter the membrane potential. Accordingly, in patch-clamp experiments GLP-1 had no effect on the whole-cell K+ATP current. PMID- 7857286 TI - Glucose 6-phosphate dehydrogenase from human erythrocytes: identification of N acetyl-alanine at the N-terminus of the mature protein. AB - Glucose 6-phosphate dehydrogenase from human erythrocytes has a blocked amino terminus and no information could be obtained by direct sequencing of the intact protein. The peptide corresponding to the amino-terminal region was isolated from a tryptic digest of the whole protein and identified on the basis of its amino acid composition and of the failure to obtain Edman degradation. Determination of peptide mass by fast atom bombardment mass spectrometry allowed identification of the blocked amino-terminal residue as N-acetyl-alanine. PMID- 7857287 TI - A polyomavirus enhancer mutant confers ubiquitous high transcriptional efficiency to the SV40 late promoter. AB - To identify expression plasmids with high efficiency of transcription and with a broad tissue and cell range, we have constructed a recombinant vector combining the late SV40 promoter and the polyomavirus regulatory region derived from a mutant (PyNB11/1) which displays a very wide host range. We show that these recombinant enhancer-promoters are efficient drivers for heterologous gene transcription and expression in vitro in all mouse and human cells tested. The most active combination we identified contained the mutant enhancer (PyNB11/1) in the late orientation. This construct was able to promote a high efficiency of expression without significant fluctuation between cells of different tissutal origin or different differentiative stage. A possible interpretation of these results is discussed. PMID- 7857288 TI - Vascular endothelial growth factor causes endothelial proliferation after vascular injury. AB - Vascular endothelial growth factor was infused into rat carotid arteries for 3 minutes immediately after endothelial denudation by balloon injury. Endothelial proliferation was determined by immunohistochemical labelling of proliferating cell nuclear antigen using Hautchen preparations. The proliferation index, or number of proliferating cells/total cells, measured at 25.5 or 30 hours was markedly increased after infusion of vascular endothelial growth factor. In addition, the total number of proliferating cells increased with increasing doses up to 100 micrograms total dose per infusion. These data indicate that infusion of vascular endothelial growth factor increases endothelial cell proliferation after mechanical denudation injury of the vascular wall. PMID- 7857290 TI - A study of the mitochondrial F1-ATPase tryptophan phosphorescence at 273 K. AB - The bovine heart mitochondrial F1-ATPase complex exhibits an intrinsic tryptophan phosphorescence that can be used to monitor structural changes of the epsilon subunit. The phosphorescence decay rate of F1 containing the tightly bound nucleotides increases upon addition of adenine nucleoside triphosphate in the presence of magnesium. The average phosphorescence lifetime of this enzyme preparation decreases from 10.2 to 7.8 ms upon Mg-ATP addition. Since increasing phosphorescence decay rate is related to increasing flexibility of proteins, Mg ATP added to the F1-ATPase complex can enhance the flexibility of the protein structure surrounding the chromophore. Experiments carried out on F1 prepared with the three noncatalytic sites filled and the three catalytic sites vacant show a significant increase of the phosphorescence lifetime from 6.4 ms to 7.6 ms upon Mg-ATP addition. These results suggest that the mitochondrial F1-ATPase epsilon-subunit conformation senses differently the nucleoside triphosphate binding to catalytic or noncatalytic sites. PMID- 7857289 TI - A simple method for isolating human endothelin converting enzyme free from contamination by neutral endopeptidase 24.11. AB - Subcellular fractionation of the phosphoramidon sensitive membrane-bound endothelin converting enzyme (ECE-1) activity from homogenates of bovine aortic endothelial cells and the human endothelial cell line EA.hy 926, combined with studies of intact cells, shows ECE-1 to be localised primarily to the plasma membrane with the topology of an ectoenzyme. To overcome the problem of neutral endopeptidase 24.11 contaminating the human ECE-1 activity solubilised from the plasma membrane fractions of EA.hy 926, we have used isoelectric focusing to simultaneously solubilise and separate these activities. The metallopeptidase ECE 1 obtained displayed a neutral pH optimum, a molecular weight of 250 kDa on gel filtration chromatography and was inhibited by phosphoramidon with an IC50 of 0.8 microM. PMID- 7857291 TI - An atypical anion transporter functioning at acid pH in neuroblastoma cells. AB - At pH 7.4, 36Cl- uptake by neuroblastoma cells was Na(+)-independent, saturable and blocked by submicromolar concentrations of DIDS. This suggests that at this pH, Cl- transport is mediated by an exchanger analogous to erythroid band 3. At pH 6.2, 36Cl- uptake was markedly activated by external carboxylate anions such as acetate. Acetate-stimulated 36Cl- uptake was blocked by DIDS (IC50 = 0.15 microM). Saturation by external 36Cl- was observed with K0.5 = 8 mM. K0.5 was not modified by acetate. As 36Cl efflux is also activated by acetate, we suggest the presence, in neuroblastoma cells, of an anion exchanger activated by carboxylic anions. This exchanger is active when the extracellular pH is 6.0-6.5. PMID- 7857292 TI - Induction of apoptosis by acyclic retinoid in the human hepatoma-derived cell line, HuH-7. AB - HuH-7 cells, a human hepatoma-derived cell line, underwent apoptosis in response to all-trans 3, 7, 11, 15-tetramethyl- 2, 4, 6, 10, 14-hexadecapentaenoic acid, or acyclic retinoid. The retinoid-induced apoptosis was verified by a characteristic step-wise fragmentation of genomic DNA and chromatin condensation. The induction of apoptosis was detected as early as 8 hrs after the addition of the retinoid and was concentration dependent (0.1-10 microM). Neither the natural retinoid all-trans retinoic acid nor 9-cis retinoic acid induced apoptosis. These data strongly indicate that the antitumor activity of the acyclic retinoid may be partly explained by the induction of apoptosis in tumor cells. PMID- 7857293 TI - The binding of HB-EGF to tumour cells is blocked by mAbs which act as EGF and TGF alpha antagonists. AB - Heparin binding EGF (HB-EGF), a newly discovered member of the EGF family of mitogens, binds to the EGF receptor (EGFR) and to heparan sulfate proteoglycans on the cell surface. Here, we show that the binding of HB-EGF to the EGFR is inhibited by mAbs which prevent the interaction of EGF and TGF alpha with the receptor. Also, we show that, like EGF and TGF alpha, treatment with HB-EGF inhibits the growth in vitro of tumours (HN5, HSC-4) that overexpress the EGFR. We conclude that mAbs which act as EGF and TGF alpha antagonists should also be effective therapeutic agents for blocking the growth of EGFR overexpressing tumours induced by HB-EGF. PMID- 7857294 TI - A plant steroid, diosgenin, a new megakaryocytic differentiation inducer of HEL cells. AB - We investigated the effect of plant steroids 5 alpha-spirosten-3 beta-ol (diosgenin), 5 alpha-spirostan-3 beta-ol (tigogenin) and 5 alpha-spirostan-3 beta ol-12-one (hecogenin) on the human erythroleukemia cell line (HEL TIB 180) and found that diosgenin addition to HEL cell cultures induces morphological and biochemical changes characteristic for megakaryocyte cells. Diosgenin-treated cells exhibit, at the ultrastructural level, increases in size in cytoplasmic and nuclear complexity. At the biochemical level, we demonstrated that diosgenin treated HEL cells increased glycoprotein Ib (GpIb) expression as previously described in the megakaryocytic differentiation of HEL cells induced by nanomolar dose phorbol myristate acetate treatment. PMID- 7857295 TI - Cleavage of DNA to large kilobase pair fragments occurs in some forms of necrosis as well as apoptosis. AB - In a number of cellular systems, DNA in apoptotic cells in initially degraded into large fragments of 30-50, 200-300 and > or = 700 kilobase pairs, which may subsequently give rise to oligonucleosomal fragments often considered as the biochemical hallmark of apoptosis. In this study, necrosis was induced in U937 cells by incubation with water. Cells yielded large DNA fragments similar in size to those found in apoptosis, but the DNA was then degraded to a continuous spectrum of small fragments, confirming that death was necrotic. The results demonstrate that kilobase pair DNA fragments are formed in some instances of necrosis as well as in apoptosis. This indicates that apoptosis should not simply be assessed by the formation of kilobase pair DNA fragments, but that other criteria, such as cellular morphology, must also be used to verify apoptosis. PMID- 7857296 TI - Cloning of a gene of the DEAD box protein family which is specifically expressed in germ cells in rats. AB - The cloning of a rat cDNA, RVLG, which encodes a novel protein of 713 amino acid residues with a molecular mass of 77,953, is described. The putative RVLG protein shares amino acid domains that are conserved in the DEAD protein family. It is approximately 52% identical and 85% similar in amino acid sequence to the XVLG1, a product which we previously cloned from Xenopus ovaries, suggesting it is the homologue of XVLG1. The size of the mRNA for RVLG is 3.1kb and can be detected specifically in the gonads of male and female adult rats. PMID- 7857298 TI - Putative hydrogen bond network in the heme distal site of horseradish peroxidase. AB - The N delta 1 atom of the distal His of several peroxidases is known to make a hydrogen bond with the side chain oxygen of Asn. Thus, a mutant horseradish peroxidase, in which Asn70 is replaced by Val, has been expressed in Esherichia coli to disrupt the putative hydrogen bond. Substitution of Asn70 to Val reduces the rate constant for the compound I formation from 1.6 x 10(7) (native) to 6 x 10(5) M-1s-1. The rate constant for reduction of compound I of N70V by guaiacol has been also reduced from 7.8 x 10(6) (native) to 1.2 x 10(5) M-1s-1. While compound I of N70V is stable and reduced to the resting state of the mutant without apparent formation of compound II at neutral pH, compound II of N70V is obtained as a stable intermediate at alkaline pH. Similar alteration of the reactivity has been observed in the reaction with guaiacol. PMID- 7857297 TI - Signal transduction in SF9 insect cells: endocytosis of recombinant CD4 after phorbol ester treatment. AB - In Spodoptera frugiperda (Sf9) insect cells infected with a recombinant baculovirus carrying a gene construct encoding human CD4 endocytosis of CD4 is induced after stimulation with phorbol-12-myristate-13-acetate (PMA). Stimulation of endocytosis with PMA reduced the amount of full-length CD4 on the plasma membrane of Sf9 cells by 50% after 2 hours. Endocytosis of CD4 is blocked after intracellular delivery by cationic liposomes of a monoclonal antibody directed against a cytoplasmic sequence of CD4. Endocytosis is also blocked by the calmodulin inhibitor W7. The PKC inhibitor H7 does not inhibit PMA-induced endocytosis. A truncated CD4, in which the last 32 C-terminal amino acids were deleted did, not respond to PMA. Our results show that PMA can stimulate the calmodulin-dependent signal transduction for endocytosis of full-length CD4 in Sf9 cells. Phosphorylation of CD4 in Sf9 cells was not detectable after PMA treatment and PKC is not required for endocytosis. PMID- 7857299 TI - Complete nucleotide sequence of a gene prtR of Porphyromonas gingivalis W50 encoding a 132 kDa protein that contains an arginine-specific thiol endopeptidase domain and a haemagglutinin domain. AB - We have purified from Porphyromonas gingivalis W50 a 45 kDa arginine-specific, thiol-activated, EDTA-sensitive endopeptidase, designated prtR. Oligonucleotide probes based on the N-terminal amino acid sequence were used to isolate a genomic fragment containing an open reading frame (3654 bp) with the potential to encode a 132 kDa protein including the prtR N-terminus. Analysis of this prtR gene revealed that the predicted nascent product contains a protease domain followed by a haemagglutinin domain and is post-translationally processed by proteolytic (possibly autolytic) events to produce a 43-54 kDa arginine-specific, thiol protease and a 41-53 kDa haemagglutinin. Comparison of the prtR with the P. gingivalis prtH gene suggests that the prtH gene product also contains protease and haemagglutinin domains but in the reverse order to that in the prtR. An overlapping but shifted reading frame at the 3' end of the prtR encodes the 5' region of the prtH. PMID- 7857300 TI - Stabilization of ribonuclease B activity by concentrated xylose solutions. AB - Ribonuclease B has become a paradigm as a simple example of an N-linked glycoprotein. We have found that certain affinity-purified preparations of this enzyme demonstrated a pronounced tendency to lose activity if stored as dilute aqueous solutions. Such inactivation is accelerated by the presence of NaCl, but can be counteracted by inclusion of high (1 mol/l) concentrations of xylose. Enzyme activity cannot be restored by addition of xylose after storage of the enzyme. In marked contrast to alpha-methyl-mannoside, xylose does not prevent ribonuclease B from binding to concanavalin A and so may be used to stabilize the enzyme during purification by lectin affinity chromatography. PMID- 7857301 TI - Fatty acid hydroperoxide lyase is a heme protein. AB - Fatty acid hydroperoxide lyase (HPO lyase) is an enzyme that cleaves hydroperoxides of polyunsaturated fatty acids to form short chain aldehydes and omega-oxoacids. Spectrophotometric analyses of HPO lyase highly purified from green bell pepper fruits indicate that it is a heme protein. The heme species was revealed to be heme b (protoheme IX) from the absorption spectrum of the pyridine hemochromogen. Although the spectrum highly resembles that of a plant cytochrome P450, allene oxide synthase from flaxseed, CO treatment of the enzyme caused no appearance of a peak at 450 nm, which is an essential diagnostic feature of a cytochrome P450. Internal amino acid sequences determined with peptide fragments obtained from the lyase showed no homology with any reported sequences. PMID- 7857302 TI - Determination of the photoaffinity-labeled site on the ligand-binding domain of retinoic acid receptor alpha. AB - The ligand-binding domain of human retinoic acid receptor alpha (hRAR alpha) was photoaffinity-labeled with a fluorescent retinoid, ADAM-3, by the use of a recombinant fused protein constructed from a maltose-binding protein and the E/F domain of hRAR alpha (MBP-RAR alpha/E), which was expressed in E. coli. The labeled site was identified as Arg-589 (this corresponds to amino acid residue 385 of hRAR alpha) or a residue in its vicinity. PMID- 7857303 TI - Polymorphic tandem repeats in dopamine D4 receptor are spread over primate species. AB - The human dopamine D4 receptor has polymorphic tandem repeats in the third cytoplasmic loop. However, these repeats are not present in the rat counterpart. To determine whether the tandem repeats are specific to humans or not, we analyzed genomic DNA sequences for the D4 receptor of six primate species (human, chimpanzee, gorilla, orangutan, macaque, marmoset). Sequencing data revealed that all primates have the 48-bp tandem repeats in the D4 receptor gene. This finding suggests that these repeats originated before the separation of the New World monkey lineage from the Old World monkey and ape-human lineages. PMID- 7857304 TI - Channeling behavior and activity models for Escherichia coli K-12 acetohydroxy acid synthases at physiological substrate levels. AB - The channeling behavior of acetohydroxy acid synthases I and III (EC 4.1.3.18; AHAS) was studied by computer simulation of activities over a wide range of concentrations for the substrates pyruvate and 2-ketobutyrate. The ratios of reaction rates for both channels and three-dimensional plots of single-channel reaction rates versus substrate concentrations were introduced to compare the substrate channeling properties of the isozymes. Substrate ranges were identified in which AHAS I and III operated both channels, and in which they used only one. Kinetic constants were varied to simulate whether and how AHAS might be made channel-specific. Our study suggests that AHAS might be made channel-specific for acetolactate but not for acetohydroxybutyrate. We postulate specific physiological roles for AHAS I and III to support cell growth under conditions that vary the levels and balance of substrates. PMID- 7857305 TI - Terminal oxidases of the bb- and caa3-types in Bacillus sp. FTU. AB - We previously identified two oxidases in the membranes of bacterium Bacillus sp. FTU. One of them slowly (caa3) and the other rapidly (bo) recombines with carbon monoxide (CO) after laser flash photolysis, in this respect resembling the Escherichia coli bo- and bd-type oxidases, respectively. In the present study we found three copper atoms in the slowly CO-recombining oxidase from Bacillus sp. FTU. In the other oxidase, the copper content is very low and clearly substoichiometric. Reversed-phase chromatography revealed the presence of haems A and C in the Bacillus sp. FTU copper-containing oxidase and haems B and C in the non-copper-containing one. We thus suggest that the Bacillus sp. FTU oxidase rapidly reacting with CO previously attributed to bo-type by analogy in redox spectrum with the E. coli enzyme be redefined as bb-type oxidase. PMID- 7857306 TI - Genomic organisation and expression of mouse deoxyribonuclease I. AB - Deoxyribonuclease I (DNase I) has recently been implicated in cell death by apoptosis, a process which is frequently accompanied by chromatin DNA degradation. Despite extensive studies on DNase I, its genomic organisation remained unknown. Here we report for the first time on the intron-exon structure of the DNase I gene. The coding region of mouse DNase I is composed of eight introns and eight exons, spanning 2315 base pairs. The deduced protein sequence is 91.5% identical to its rat counterpart, but does not carry the two mutations (Glu13 to D and V67 to I) responsible for the decrease in actin-binding of rat DNase I. The enzymatic activity of mouse DNase I is found in striated muscle, kidney, intestine, liver, lymphnodes, but not in the heart, spleen or pancreas. PMID- 7857307 TI - Induction of erythroid differentiation in leukaemic K562 cells by an S adenosylhomocysteine hydrolase inhibitor, aristeromycin. AB - We have isolated an unusual nucleoside, aristeromycin, from the culture filtrate of Actinomycetes as a compound that induces normal morphology in v-ablts-NIH3T3 cells. Aristeromycin also induced erythroid differentiation in abl-expressing human chronic myelogenous leukaemia K562 cells. It did not affect the amount of Abl or the Abl-associated tyrosine kinase activity in either v-ablts-NIH3T3 or K562 cells. As a potent inhibitor of S-adenosylhomocysteine hydrolase, aristeromycin inhibited methylation of phosphatidylethanolamine to form phosphatidylcholine in K562 cells. Among aristeromycin analogues, the activity to inhibit S-adenosylhomocysteine hydrolase was paralleled with the induction of erythroid differentiation. Thus, aristeromycin inhibits abl functions indirectly, possibly by inhibiting biological methylations. PMID- 7857308 TI - Augmented expression of atrial myosin light chain 1 in ventricular aneurysms of human: enzyme immunoassay for atrial myosin light chain 1. AB - We established an enzyme immunoassay (EIA) for atrial myosin light chain 1 (ALC1) using monoclonal antibodies KA1 and KB1, which were specific for ALC1 and for both ALC1 and ventricular myosin light chain 1, respectively. The serum ALC1 levels of healthy subjects were 0.28 +/- 0.14 ng/ml (mean +/- SD). The tissue ALC1 levels of normal adult human atria were much higher than those of ventricles (p < 0.01, 2,120 +/- 1,200 in right atria, 2,180 +/- 1,450 in left atria vs. 36.0 +/- 20.2 in right ventricles, 37.7 +/- 15.3 in left ventricles, ng/mg of proteins). The tissue ALC1 levels of ventricular aneurysms were significantly higher than those of normal ventricles (p < 0.01, 206.7 +/- 101.8). These results indicate that ALC1 is augmented in aneurysms and that the EIA provides a useful tool to investigate the roles of ALC1. PMID- 7857309 TI - Cationic multilamellar liposome-mediated gene transfer into primary myoblasts. AB - To transfer foreign genes into myoblasts in primary culture, we found cationic multilamellar liposomes to be a useful mediator. When the cells were transfected with 2 micrograms of the plasmid pRSV-luc encapsulated into 50 nmol of our cationic multilamellar liposomes that had been prepared from N-(alpha trimethylammonioacetyl)-didodecyl-D-glutamate chloride, dilauroyl phosphatidylcholine, and dioleoyl phosphatidylethanolamine in a molar ratio of 1:2:2, luciferase was expressed with high efficiency without cytotoxicity. When the cells were transfected with the plasmid pRSV-lacZ encapsulated into the same liposomes, 0.7% of the cultured myoblasts expressed beta-galactosidase without cytotoxicity. This is the first successful instance of introducing foreign genes into primary cultures of myoblasts by means of liposomes. PMID- 7857311 TI - Synthesis, conformation and opioid activity of deltorphins. AB - A series of deltorphin analogues was prepared by solid-phase peptide synthesis. Their opioid activity was evaluated in rat opiatic assay and their conformation was determined by two-dimension Nuclear Magnetic Resonance Spectroscopy. The analogues containing D-alanine acid at position 2 were much more potent in the assay than their corresponding isomers containing L-alanine acid at this position. The conformational analysis on NMR study in DMSO showed that C-terminal tetrapeptides of both deltorphin II and its L-alanine analog might form a 3(10) helix, which confirms that the substitution of D-amino acid at position 2 decreased the opioid activity. PMID- 7857310 TI - Retroviral suicide vector does not inhibit neointimal growth in a porcine coronary model of restenosis. AB - We attempted to attenuate neointimal formation following vascular injury using a retroviral suicide vector. Epicardial coronary arteries of adult miniature swine were injured by deployment of oversized tantalum stents. One week later, injured segments were exposed to packaged retroviral constructs with or without the herpes simplex virus thymidine kinase gene. Ganciclovir treatments were initiated 48 hours later in both control and experimental swine and continued for two weeks. Four weeks following vascular injury, both control and experimental arteries were harvested and histologically prepared for image analysis. Despite adequate marker gene expression, there was no significant difference in the neointimal area or neointimal/media ratio between control and experimental groups. While the HSVtk ganciclovir system attenuates cell proliferation in other systems, retroviral vector targeting of vascular smooth muscle cells for elimination may be too inefficient to prevent restenosis following angioplasty. PMID- 7857312 TI - Current approaches to the therapy of fibrotic diseases. PMID- 7857313 TI - Involvement of NF-kappa B in the induction of NAD(P)H:quinone oxidoreductase (DT diaphorase) by hypoxia, oltipraz and mitomycin C. AB - The activity of the two-electron bioreductive enzyme DT-diaphorase (DTD) is induced by heat shock, hypoxic stress, oltipraz, and mitomycin C (MMC). Transcriptional induction is associated with nuclear factor binding to elements mediating immediate early response including AP-1, though the DTD mRNA peaks at 24 hr. Electrophoretic mobility shift assays revealed that nuclear protein extracts from hypoxia-, oltipraz-, and MMC-treated cells bound a specific oligonucleotide probe corresponding to the NF-kappa B transcriptional binding site in two human cancer cell lines, HT29 and HepG2. The binding activity for the NF-kappa B site was induced with a time-course similar to that of the induction of DTD, and was delayed in comparison to the induction of AP-1 binding proteins. The time-courses of the NF-kappa B binding response to MMC, oltipraz and hypoxic treatment were similar, and binding was most pronounced at 24 hr. All three stimuli were associated with the late appearance of a higher molecular weight complex in HT29 but not in HepG2 cells, suggestive of the participation of additional rel family proteins in DNA binding in this cell line. Competition experiments indicated that the bound protein complex was specific for the NF kappa B binding site. An immunodepletion assay showed that in each case the bound complex consisted of a heterodimer of the NF-kappa B proteins p50 and p65. These data suggest that hypoxia, oltipraz and MMC may each induce the overexpression of DTD through a mechanism involving the NF-kappa B response element in the DTD 5' flanking region, and support a role for this element in the control of detoxication responses to environmental changes. PMID- 7857314 TI - Inhibitory effect of the antioxidant ethoxyquin on electron transport in the mitochondrial respiratory chain. AB - Ethoxyquin (6-ethoxy-2,2,4-trimethyl-1,2-dihydroquinoline, EQ) is an antioxidant used as a preservative in animal and human foods. In a previous work, we demonstrated that EQ induces an inhibition of renal secretory mechanisms that are dependent on metabolic energy; EQ inhibits renal ATPases. In the present study, we analyzed the effects of EQ on the metabolic pathways of renal and hepatic rat cells, as well as on mitochondrial and submitochondrial particles isolated from bovine heart and kidney. EQ induced a mild inhibition of oxygen uptake when it was added to whole homogenates of rat renal cortex in the presence of glucose. In contrast, a strong concentration-dependent inhibition was produced when EQ was added to preparations of intact liver mitochondria or to submitochondrial particles isolated from renal cortex. In the presence of NADH, 90% inhibition was attained at a final concentration of 1 mM EQ. The direct inhibitory effect of EQ on NADH dehydrogenase was a most relevant finding, since no inhibitor for the partial reaction of NADH-ferricyanide on this complex has been reported previously. PMID- 7857315 TI - Effects of metalloprotease inhibitors on smooth muscle endothelin-converting enzyme activity. AB - The enzyme responsible for the conversion of exogenous big endothelin-1 to endothelin-1 by porcine coronary arterial smooth muscle has been shown to be a metalloprotease. The potencies of eight metalloprotease inhibitors for this endothelin-converting enzyme were determined. CGS 25015, CGS 26129, and thiorphan inhibited the enzyme activity monophasically with IC50 values of 2.6, 2.4, and 190 microM, respectively. In contrast, the data obtained using phosphoramidon as an inhibitor were best fit by a two-site model. The biphasic concentration response curve had IC50 values of 4.6 microM and 2.2 mM. Three analogs of phosphoramidon were also tested for enzyme inhibition. Removal of the rhamnose moiety of phosphoramidon reduced the potency (IC50 = 15 microM), whereas substitution of the rhamnose by N-[2-(2-naphthyl)ethyl] improved the potency (IC50 = 2.0 microM). These results identify a thiol and a phosphonyl series of compounds as smooth muscle endothelin-converting enzyme inhibitors. The structure activity relationships revealed that an aromatic or aliphatic group in the P2' position or an aromatic group in the P1 position of the inhibitor significantly increased the potency. PMID- 7857316 TI - Different pathomechanisms of altered biliary leukotriene C4 elimination in isolated perfused rat livers. AB - Hepatic retention of cysteinyl leukotrienes is a consequence of impaired bile secretion and may be involved in the pathogenesis of intrahepatic cholestasis. In order to assess the mechanisms of altered biliary leukotriene elimination, we studied the secretion and metabolic pattern of leukotriene C4 (LTC4) in bile early in the alterations of bile formation by xenobiotics. To this end, rats were pretreated with alpha-naphthylisothiocyanate (ANIT), ethionine (ETH), or estradiol valerate (EV) at doses which did not increase serum marker enzymes of cholestasis. Bile secretion was assessed in perfused livers isolated from the treated rats. In all models, the access of [14C]sucrose into bile was increased, indicating increased permeability of the bile tract. Biliary recovery of radioactivity infused as [3H]LTC4 was decreased by ANIT and ETH while 3H-efflux into the perfusate was increased concomitantly. The secretion rate of 3H radioactivity into bile was correlated with that of [14C]taurocholate infused at the same time. After pretreatment with ANIT (but not in the other models) the venous efflux of [3H]LTC4-ANIT pretreatment was increased [14C]sucrose clearance into bile associated with greatly enhanced biliary access of [32P]phosphate. Thus, altered charge selectivity of the paracellular pathway appears to be a prerequisite for reflux of cholephilic anions. HPLC analysis of [3H]LTC4-derived radioactivity in bile revealed that in all models of altered bile secretion the relative amount of LTD4 in bile was elevated. These results demonstrate differential changes in hepatobiliary transport and metabolism of LTC4 in developing cholestasis. ANIT inhibits leukotriene secretion by increasing paracellular permeability with loss of charge selectivity. In contrast, ETH treatment inhibits transcellular transport while treatment with EV only results in enhanced LTC4 metabolism. PMID- 7857317 TI - Aurintricarboxylic acid, a putative inhibitor of apoptosis, is a potent inhibitor of DNA topoisomerase II in vitro and in Chinese hamster fibrosarcoma cells. AB - Aurintricarboxylic acid (ATA) is a polyanionic, polyaromatic compound which has been shown to inhibit apoptotic cell death in various cell types induced by a variety of factors. Since ATA is known to be a general inhibitor of nuclease activities in vitro (ID50S ranging from 2 to 50 microM), the in vivo effects are usually attributed to inhibition of endogenous endonuclease activities. We show herein that ATA is a potent inhibitor of the nuclear enzyme DNA topoisomerase II. ATA inhibits the catalytic activity of purified yeast topoisomerase II with an ID50 of approx. 75nM as measured by relaxation assays. ATA does not stabilize the covalent DNA-topoisomerase II reaction intermediate ("cleavable complex") as do other inhibitors of this enzyme such as 4'-(9-acridinylamino)-methane sulfon-m anisidide (amsacrime), 4'-demethyl-epipodophyllotoxin-9-(4,6-O-ethylidine-beta-D gluco pyr anoside) (etoposide) and ellipticines. In contrast, cleavable complex formation induced by amsacrine and etoposide is trongly inhibited in the presence of ATA. ATA also prevents the binding of topoisomerase II to DNA and inhibits topoisomerase II-catalysed ATP hydrolysis. The ability of ATA to interfere with more than one step in t he catalytic cycle of DNA topoisomerase II may explain its unusual potency as an inhibitor of this enzyme. ATA reduces the number of amsacrine-induced DNA-protein complexes in intact DC-3F Chinese hamster fibrosarcoma cells and protects these cells from the cytotoxic action of amsacrine. The effects of ATA on DNA-protein complex formation in living cells appear to be due to the direct interaction of the drug with topoisomerase II, since similar results are found when nuclei from untreated DC-3F cells are exposed to amsacrine after a short preincubation with ATA. Cells resistant to 9 hydroxyellipticine, which have been shown to possess altered topoisomerase II activity, are approx. 5-fold more resistant to ATA than the sensitive parental cells as shown by colony formation essays. We conclude that ATA is a potent inhibitor of topoisomerase II and that the drug interacts with topoisomerase II in living cells. Our findings raise the possibility that the protective effects of ATA towards apoptotic cell death might, at least in part, involve DNA topoisomerase II. PMID- 7857318 TI - Heterogeneity of circulating and exudated polymorphonuclear leukocytes in superoxide-generating response to cyclic AMP and cyclic AMP-elevating agents. Investigation of the underlying mechanism. AB - It has been found that cyclic AMP and cyclic AMP-elevating agents inhibit formyl methionyl-leucyl-phenylalanine (fMLP)-stimulated superoxide production from polymorphonuclear leukocytes (PMNs). The quantitative differences of this inhibitory effect on human and rabbit blood versus human salivary and rabbit peritoneal (tissue) PMNs were investigated. PMNs from all sources showed the same pattern of fMLP-stimulated superoxide generation, although it was slightly higher in tissue PMNs. However, treatment with salbutamol differentially blunted fMLP stimulated superoxide production from blood PMNs compared with tissue PMNs in both human and rabbit. While it could inhibit production from blood PMNs by 30 60%, it had only a negligible effect on generation from tissue PMNs. Similarly, forskolin, phosphodiesterase IV inhibitor Ro-201724, and dibutryl cyclic AMP showed significantly higher inhibitory effects on superoxide generation from blood PMNs than tissue PMNs in both species. beta-Adrenergic receptors, cyclic AMP accumulation, and protein kinase A activity were investigated in blood versus tissue PMNs to clarify the mechanism underlying the above-mentioned differences. At the beta-adrenergic receptor level, no significant changes were detected in the number or the binding affinity of the receptors in tissue versus blood PMNs of human and rabbit. On the other hand, cyclic AMP accumulation was significantly higher in response to salbutamol and Ro-201724 in fMLP-stimulated blood versus tissue PMNs in human and rabbit. At the same time, blood PMNs showed significantly higher cyclic AMP-dependent protein kinase A activity than tissue PMNs in human and rabbit. We concluded that tissue PMNs are less responsive to the effect of cyclic AMP-elevating agents in terms of fMLP-stimulated superoxide inhibition. This is due to differences, at least, at two levels. The first is lower accumulation of cyclic AMP and the second is lower protein kinase A activity in tissue versus blood PMNs. PMID- 7857319 TI - Decreased hypothalamic epinephrine concentration by quipazine and other serotonin agonists in rats. AB - Epinephrine concentrations in rat hypothalamus were decreased after the injection of quipazine, a direct-acting serotonin (5-HT) agonist. The decrease was statistically significant and dose-dependent from 0.1 to 10 mg/kg, s.c., was apparent within 1 hr, and persisted for 8 hr but not 24 hr. There was no decrease in epinephrine concentrations in rat medulla oblongata, a region containing epinephrine cell bodies. Epinephrine concentrations in rat hypothalamus were also decreased by 1-(m-trifluoromethylphenyl)-piperazine (TFMPP) and by 8-hydroxy-2 (di-n-propylamino)-tetralin (8-OH-DPAT), other direct-acting 5-HT agonists, and by d-fenfluramine, a 5-HT-releasing drug. The decrease evoked by quipazine was prevented by pretreatment with metergoline, ketanserin or LY53857 (6-methyl-1 [methylethyl]-ergoline-8-carboxylic acid 2-hydroxy-1-methyl-propyl ester), centrally acting 5-HT antagonists. The lowering of rat hypothalamic epinephrine concentrations by 8-OH-DPAT was prevented by pretreatment with pindolol, a centrally acting 5-HT1A receptor antagonist. These data suggest that serotonergic drugs affect epinephrine concentrations in rat hypothalamus. PMID- 7857320 TI - A glutathione depletion selectively imposed on mu glutathione S-transferase overproducing cells increases nitrogen mustard toxicity. AB - Glutathione (GSH) contributes to the detoxification of anticancer drugs through the operation of specific glutathione S-transferases (GST) and innate, or acquired, overexpression of this enzyme family has been frequently observed in tumor cell lines. In the GMA32 line of Chinese hamster fibroblasts, we showed that GSH starvation produced by exposing cells to buthionine sulfoximine (BSO) increased the toxicity of chlorambucil and melphalan, but not that of N,N'-bis(2 chloroethyl)-N-nitrosourea (BCNU), cisplatine and doxorubicin. This indicates that efficient mechanisms of detoxification using GSH operate for chlorambucil and melphalan, but not for the other drugs in these cells. We then showed that GSH depletion could be selectively and transiently induced in the mu GST overexpressing cell line derived from GMA32, HC474, by exposing cells to substrates specific to the overexpressed isozyme. Exposing cells to such a substrate, trans-stilbene oxide, does not alter the sensibility of GMA32 cells to melphalan and chlorambucil, but increases that of HC474 cells to these drugs, to an extent comparable to that obtained with BSO. This observation highlights the possibility of exploiting GST overexpression, a frequent feature of tumor cells, to selectively sensitize these undesirable cells to anticancer drugs. PMID- 7857322 TI - Tamoxifen and its active metabolite inhibit growth of estrogen receptor-negative MDA-MB-435 cells. AB - Tamoxifen (TAM), the non-steroidal anti-estrogen most widely administered to breast cancer patients, acts, at least in part, by competing with estrogen receptors (ER). However, the existence of an alternative mechanism of action for this drug is supported by the clinical observations that: (a) 30% of patients with ER-negative cancer cells respond to TAM, and (b) 30% of patients with ER positive cancer cells are not sensitive to this anti-estrogen. In this study, we observed that growth of the human ER-negative breast cancer cell line MDA-MB-435 was inhibited by TAM and 4-hydroxytamoxifen (4OH-TAM) in a concentration dependent fashion. Both monoclonal enzymoimmunoassay and Dextran Charcoal Coated Scatchard radioimmunoassay analysis demonstrated that this MDA-MB-435 cell line does not express ER. The absence of ER in MDA-MB-435 cells was also demonstrated at the mRNA level by both northern blot hybridization and reverse transcription polymerase chain reaction techniques. MDA-MB-435 cell proliferation was not affected by 17 beta-estradiol or by the pure anti-estrogen ICI 164384, further demonstrating that the observed effects of TAM and its active metabolite on the proliferation of MDA-MB-435 cells were due to an ER-independent mechanism, yet to be identified. MDA-MB-435 thus appears to be a promising original model for the study of the alternative ER-independent mechanisms of action of TAM. PMID- 7857321 TI - Translocation of dopamine and binding of 2 beta-carbomethoxy-3 beta-(4 fluorophenyl) tropane (WIN 35,428) measured under identical conditions in rat striatal synaptosomal preparations. Inhibition by various blockers. AB - Translocation of [3H]dopamine and binding of 2 beta-carbomethoxy-3 beta-(4 fluorophenyl)[3H]-tropane ([3H]WIN 35,428) were measured in crude synaptosomal preparations from rat striatum under identical conditions of assay buffer (phosphate-Krebs) and temperature (25 degrees). [3H]Dopamine uptake as a function of time was close to linear for at least 8 min, whereas [3H]WIN 35,428 binding had reached equilibrium within 1 min and remained at its plateau value for at least 20 min. The following inhibitors were tested in uptake and binding assays run in parallel with the same synaptosomal preparation: cocaine, WIN 35,428, benztropine, nomifensine, mazindol, methylphenidate, N-[1-(2-benzo[b] thiophenyl)cyclohexyl]piperidine (BTCP), Lu 19-005 (Indatraline), 1-(2-(di(4 fluorophenyl)-methoxy)-ethyl)-4-(3-phenyl-2-propyl)piperazine (GBR 12909), 1-(2 (diphenylmethoxy)-ethyl)-4-(3-phenyl-2-propyl)piperazine (GBR 12935) and 7 trifluoromethyl-4-(4-methyl-1-piperazinyl)-pyrrolo [1,2-a]quinoxaline (CGS 12066B). When present together with [3H]dopamine or [3H]WIN 35,428 for 8 min, the observed binding IC50 values were generally higher (average 1.4-fold) than the uptake IC50 values, with a significant y-axis intercept in linear regression analysis of binding on uptake IC50. For slowly equilibrating inhibitors, estimates of uptake IC50 values were overestimates, and relatively lower values were obtained by monitoring [3H]dopamine uptake for 1 min only during the last minute of the 8-min presence of inhibitor; under these conditions, binding over uptake IC50 ratios were on the average 2.3. Kinetic calculations, taking into account both radioligand and inhibitor equilibration kinetics, indicated that the latter comparison between binding and uptake measurements was most relevant, and suggested the involvement of complexities beyond simple competitive inhibition of dopamine transport, such as different binding domains for substrate and blocker recognition, or spare receptors for blockers. The present data indicate that binding over uptake IC50 ratios should be interpreted with caution, depending on the experimental conditions used to measure these ratios. PMID- 7857323 TI - Characterization of the potential antioxidant and pro-oxidant actions of some neuroleptic drugs. AB - It has been suggested in the literature that neuroleptic drugs may be able to exert antioxidant and/or pro-oxidant actions in vivo. The feasibility of this was tested by measuring the ability of chlorpromazine, prochlorperazine, metoclopramide, methotrimeprazine and haloperidol to scavenge biologically relevant oxygen-derived species in vitro. None of the drugs reacted with superoxide radical at a significant rate. Chlorpromazine, prochlorperazine, metoclopramide and methotrimeprazine were very powerful scavengers of hydroxyl radicals, reacting at almost a diffusion-controlled rate. Chlorpromazine showed some ability to inhibit iron ion-dependent hydroxyl radical formation. Chlorpromazine, methotrimeprazine, promethazine and prochlorperazine were powerful inhibitors of iron ion-dependent liposomal lipid peroxidation, scavengers of organic peroxyl radicals and inhibitors of haem protein/hydrogen peroxide-dependent peroxidation of arachidonic acid. Chlorpromazine, prochlorperazine, metoclopramide, methotrimeprazine and haloperidol were powerful scavengers of hypochlorous acid. Haloperidol showed no ability to inhibit lipid peroxidation or to scavenge peroxyl radicals, and reproducibly increased lipid peroxidation catalysed by haem proteins, in both the presence and absence of hydrogen peroxide. The relevance of these in vitro observations to events in vivo is discussed. PMID- 7857324 TI - Radioimmunoassay evidence that the pressor effect of big endothelin-1 is due to local conversion to endothelin-1. AB - Compared with endothelin-1 (ET-1), big endothelin-1 (big ET-1) is only weakly active on isolated vascular smooth muscle preparations. However, on systemic administration high doses of big ET-1 (1 nmol.kg-1) are approximately equipotent to ET-1, indicating the existence of an endothelin converting enzyme in the circulation that rapidly converts big ET-1 to ET-1. In this study arterial blood levels of big ET-1 and ET-1 immunoreactivity were measured after bolus i.v. administration of big ET-1 (1 or 3 nmol.kg-1) or ET-1 (1 nmol.kg-1) in anaesthetised male Wistar rats. In addition, the effect of phosphoramidon (10 mg.kg-1) on the pressor response to big ET-1 and its disappearance rate from the circulation were examined. After big ET-1 injection, circulating ET-1 concentrations did not exceed 2% of the big ET-1 level. Phosphoramidon reduced the pressor response to big ET-1 by 93%, but did not alter its rate of clearance from the circulation. Thus exogenous big ET-1 is converted locally in the vasculature and its disappearance from the circulation is not dependent on conversion to ET-1. PMID- 7857325 TI - Antibodies having markedly different effects on enzymatic activity and induction of acetylcholine release by two presynaptically-acting phospholipase A2 neurotoxins. AB - The enzymatic and acetylcholine-releasing activities of two presynaptically acting phospholipase A2 neurotoxins (pseudexin B and scutoxin) were studied in a synaptosomal fraction. Scutoxin (100 nM) induced greater [14C]acetylcholine release than did pseudexin B (100 nM). Both toxins caused fatty acid production in the synaptosomal fraction, although pseudexin B was more active than scutoxin. One monoclonal antibody raised against pseudexin B (#4) had no effect on the enzymatic activity of either pseudexin B or scutoxin. Two other monoclonal antibodies (#3 and #7), also raised against pseudexin B, antagonized the enzymatic activity of pseudexin B and scutoxin. Monoclonal antibody #3 was more effective than #7 in reducing the amount of acetylcholine released by the toxins, whereas #7 was more effective than #3 in reducing fatty acid production. Although antibody #3 caused complete inhibition of phospholipase A2 activity of pseudexin B on purified substrates, it only reduced phospholipase A2 activity by 35% in synaptosomes. These findings support the hypothesis that gross phospholipase A2 activity does not play a role in stimulation of acetylcholine release by the presynaptically-acting phospholipase A2 neurotoxins. PMID- 7857326 TI - Effect of verapamil and nifedipine on cholesteryl ester metabolism and low density lipoprotein oxidation in macrophages. AB - Using mouse macrophage cultures, the effects of verapamil and nifedipine on cholesteryl ester and low-density lipoprotein (LDL) metabolism were studied with special reference to the following parameters: (a) incorporation of [14C]oleate into cholesteryl esters (ChE), (b) contents of total and free cholesterol (FCh), (c) liberation of [14C]oleate from ChE and incorporation of [3H]FCh into ChE, (d) excretion of [3H]Ch from the cells, and (e) LDL oxidation. Verapamil and nifedipine (10-100 microM) were shown to decrease in a dose-dependent manner the incorporation of [14C]oleate into ChE and to increase the concentration of FCh but had no appreciable effect on the concentration of total cholesterol in macrophages cultured in the presence of acetylated LDL. The drugs stimulated the liberation of [14C]oleate from cellular ChE. The pharmacological concentrations (25-75 microM) of verapamil and nifedipine increased the excretion of [3H]FCh from ChE of macrophages in the presence of serum and high-density lipoproteins. The same concentrations of the drugs inhibited both LDL-derived malonyldialdehyde like products and nitroblue tetrazolium dye reduction in a dose-dependent fashion. The results obtained suggest that verapamil and nifedipine exert their macrophage-mediated antiatherosclerotic effect via reduction of LDL oxidative modification, reduction of intracellular ChE synthesis, stimulation of ChE hydrolysis and cholesterol excretion from the cells. PMID- 7857327 TI - Taurine analog modulation of taurine uptake by two different mechanisms in cultured glial cells. AB - Previous data have shown that HEPES, a taurine structural analog, inhibits the uptake of taurine by cultured cells differently, depending on its addition either to the culture medium or to the Krebs-Ringer buffer used for cell incubation during taurine uptake measurements (Lleu and Rebel, J Neurosci Res 23: 78-86, 1989). An extensive study of the effect of numerous other taurine structural analogs on taurine uptake by cultured glial cells was carried out. Our results show that taurine uptake modulation by structural analogs follows two different mechanisms. For the first mechanism, observable after the simultaneous presence of taurine and of its analog during the incubation time of the uptake experiment (10 min), the amine function on the molecule is essential. The sulfonate group could be replaced either by a sulfinic group or by a carboxylic group. beta Alanine, hypotaurine, acetyltaurine, guanidinoethanesulfonate and guanidinopropionate are the most potent inhibitors in this first mechanism. For the second mechanism, which requires the presence of the analog in the culture medium during the 48 hr preceding the taurine uptake measurement, the simultaneous presence of an amine and of a sulfonate group or of an amine and a sulfinate group is required. Carboxylates are ineffective in modulating taurine uptake in this mechanism. The sulfonate buffers synthesized by Good et al. (Biochemistry 5: 467-477, 1966) also affect taurine uptake in both mechanisms. PMID- 7857328 TI - Inhibition of glutathione-related enzymes and cytotoxicity of ethacrynic acid and cyclosporine. AB - Glutathione (GSH) is an endogenous thiol that detoxifies active oxygen and reactive species formed during intermediary metabolism and drug detoxification. Compounds with a range of potential toxicities were tested for their abilities to affect GSH reductase and GSH S-transferase activities, which are each components of the two principal detoxification pathways in which GSH participates. A high performance liquid chromatographic method for determining oxidized and reduced GSH was modified to assay GSH reductase activity. With this method it was possible to demonstrate that ethacrynic acid, which inhibits GSH S-transferase, also inhibits the activity of GSH reductase. Inhibition of GSH reductase by ethacrynic acid was similar to that seen with carmustine (BCNU). GSH reductase activity was not affected by cis- or transplatin, buthionine sulfoximine, other loop diuretics, cyclosporine A or aminoglycosides. Cyclosporine inhibited GSH S transferase at 50 microM and higher concentrations. These results support a role for GSH-mediated detoxification mechanisms in ethacrynic acid- and cyclosporine associated cytotoxicity, which may mediate their toxicities and their potential as adjunctive agents in antineoplastic therapy. A better understanding of the mechanism of their toxicity can greatly extend the clinical usefulness of these agents, as this toxicity is the basis of both their therapeutic and antitherapeutic actions. PMID- 7857330 TI - Pidotimod. A new biological response modifier. Introduction. PMID- 7857331 TI - Synthesis and preliminary pharmacological evaluation of pidotimod, its enantiomer, diastereomers and carboxamido derivatives. AB - A new compound with a peptide-like structure, (R)-3-[(S)-(5-oxo-2 pyrrolidinyl)carbonyl]-thiazolidine-4-carboxylic acid, its enantiomer, diastereomers and carboxamido derivatives were synthesized and tested for immunostimulant activity. Synthesis, preliminary, pharmacological data and structure-activity relationships are reported. (R)-3-[(S)-(5-Oxo-2 pyrrolidinyl)carbonyl]-thiazolidine-4-carboxylic acid (Ib, Pidotimod, PGT/1A, CAS 121808-62-6) was selected for further research. PMID- 7857332 TI - Analytical and chemical profile of pidotimod. AB - Pidotimod ((R)-3-[(S)-(5-oxo-2-pyrrolidinyl)carbonyl]-thiazolidine- 4-carboxylic acid, PGT/1A, CAS 121808-62-6) is a new synthetic immunostimulant, which has proved to possess a high activity. This paper describes its physico-chemical properties, structural identification including polymorphism, detection of impurities, determination of related compounds, separation, quantification and purity assay using high-performance liquid chromatography (HPLC). PMID- 7857329 TI - Aminoacetone metabolism by semicarbazide-sensitive amine oxidase in rat aorta. AB - High speed (105,000 g/60 min) membrane fractions from rat aorta homogenates metabolized the aliphatic amine aminoacetone (AA) to methylglyoxal (MG) with a Km of 19 +/- 3 microM, and Vmax of 510 +/- 169 nmol MG/hr/mg protein. This deaminating activity appears to be due to a semicarbazide-sensitive amine oxidase (SSAO), which is associated with smooth muscle cells in blood vessels of the rat and other species. AA was a competitive inhibitor (Ki of 28 +/- 6 microM) of the metabolism of benzylamine, a synthetic amine often used as an assay substrate for SSAO. AA is produced endogenously from mitochondrial metabolism of threonine and glycine, and thus could be a physiological substrate for SSAO, whereas the production of MG by SSAO could have cytotoxic implications for cellular function. PMID- 7857333 TI - Experimental immunological screening tests on pidotimod. AB - Pidotimod ((R)-3-[(S)-(5-oxo-2-pyrrolidinyl) carbonyl]-thiazolidine-4-carboxylic acid, PGT/1A, CAS 121808-62-6), a new biological response modifier, was administered to immunodepressed (by prednisolone, cyclophosphamide or methotrexate) mice by oral and intraperitoneal route (respectively up to 400 and 200 mg/kg) during several days (up to 9 days). The stimulatory action of the drug on cell-mediated immunity is investigated by measuring the rosette formation by the murine splenic lymphocytes ex vivo, by T- and B-lymphocytes ex vivo proliferative response to mitogens, by dinitrochlorobenzene delayed hypersensitivity induced on the ear, by the graft-versus-host reaction with immunodepressed mice as donors. In all tests pidotimod reveals a potent action in restoring the depressed reactivity. The action of pidotimod on humoral immunity is showed in two tests where the antibody response is induced by a thymus dependent (sheep erythrocytes) or a thymus independent (lipopolysaccharide) antigen. Pidotimod was active in both tests. Macrophage functions, anion superoxide production and the non-stimulated ex vivo chemotaxis reveal that pidotimod significantly reduces the immunodepressant action of prednisolone; particularly in i.p. treated mice the chemotaxis is likely to be restored to the levels of the non-immunodepressed controls. The colloidal china ink blood clearance in vivo in immunodepressed mice, after pidotimod treatment, results similar to that found in the control mice. PMID- 7857334 TI - Protective effects of pidotimod against experimental bacterial infections in mice. AB - Pidotimod ((R)-3-[(S)-(5-oxo-2-pyrrolidinyl) carbonyl]-thiazolidine-4-carboxylic acid, PGT/1A, CAS 121808-62-6) protected mice against experimental bacterial infections in different experimental models. In all tests the drug's effect was measured as protection from death. The activity of pidotimod was evident and statistically significant after 5 administrations before the bacterial challenges. Pidotimod was active against many bacterial species infections, its active dosages ranging from 0.01 to 100 mg/kg i.p. x 5 times. Pidotimod showed against some bacterial infections a protection similar or better than those of bestatin, N-acetylmuramyl-L-Ala-D-isoGlu-OH and tuftsin. It showed high protection against bacterial infections in cyclophosphamide-immunodepressed mice. Finally, pidotimod showed an additive or synergic activity in combination with beta-lactam antibiotics (cefotaxime, ampicillin) against bacterial infections in mice. PMID- 7857335 TI - Immunomodulating activity of pidotimod. AB - Experiments were performed to analyze the effect of the immunomodulating agent pidotimod ((R)-3-[(S)-(5-oxo-2-pyrrolidinyl) carbonyl]-thiazolidine-4-carboxylic acid, PGT/1A, CAS 121808-62-6) on the mouse splenic proliferative response to Con A and IL-2, natural killer (NK) cell activity and thymocyte apoptosis. The results indicate that in vivo treatment with pidotimod (200 mg/kg i.p. for 5 days) causes a significant increase in the proliferative response to mitogens (including Con-A and IL-2) and the cytotoxic activity mediated by NK cells. Pidotimod inhibits in vitro thymocyte apoptosis caused by other inducing agents such as protein kinase C activator 12-O-tetradecanoyl-phorbol-13-acetate, Ca(++) ionophore A23187, genistein and interleukin-2 (IL-2). PMID- 7857337 TI - In vivo antiviral effects of pidotimod. AB - The effect of pretreatment with pidotimod ((R)-3-[(S)- (5-oxo-2-pyrrolidinyl) carbonyl]-thiazolidine-4-carboxylic acid, PGT/1A, CAS 121808-62-6) was evaluated in mice infected with two challenging doses of three different viruses. Mengovirus, Herpes simplex, influenza virus were used. The mice were treated 15 days before the virus challenge. The antiviral effect of pidotimod was evaluated as difference in survival time versus control groups challenged with viruses but not pretreated with pidotimod. In groups pretreated and challenged with the lower dose of each virus strain a statistically significant increase in survival time was observed. On the basis of the known effects of pidotimod on immune system, this effect is due to an immunostimulating effect of this drug. PMID- 7857336 TI - Effects of pidotimod on macrophage functions in methylprednisolone-treated mice. AB - CD-1 mice were treated with methylprednisolone (mPDN) 2-5 mg/kg s.c., for 11 or 6 days, in order to achieve an immunosuppressed state. For the same length of time a group of mice also received pidotimod ((R)-3-[(S)-(5-oxo-2-pyrrolidinyl) carbonyl]-thiazolidine-4-carboxylic acid. PGT/1A, CAS 121808-62-6) i.p. at 100 or 10 mg/kg. At the end of treatment, peritoneal macrophages (MO) were recovered, purified by adherence to plastic and activated in vitro with different stimuli. After 24 h of incubation, the supernatants were collected and assayed for the presence of tumor necrosis factor-alpha (TNF-alpha) and nitrite (NO2-), which is the stable derivative of nitric oxide (NO) in acqueous solution. It is well known that TNF-alpha and NO represent two out of many molecules secreted by activated MO which are essential for killing microorganisms and for natural response to infections. It was observed that MO from mPDN-treated mice were unable to produce sufficient levels of both TNF-alpha and NO when stimulated in vitro with lipopolysaccharide, IFN-gamma or conidia from an opportunistic fungus, Aspergillus fumigatus, confirming that corticosteroids are able to inhibit the antimicrobial activity of MO. However, MO from mice received mPDN plus pidotimod fully recovered the capacity to produce TNF-alpha and NO in response to the same stimuli. Optimal dose of pidotimod was 100 mg/kg. In addition, pidotimod was also able to reconstitute the cellularity of the peritoneum and of the spleens of mice immunodepressed by mPDN.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7857338 TI - Effects of pidotimod on the immune and the neuroendocrine system in the aging rat. AB - The effects of pidotimod ((R)-3-[(S)-(5-oxo-2-pyrrolidinyl)carbonyl]-thiazolidine 4-carboxylic acid, PGT/1A, CAS 121808-62-6), a synthetic thymic dipeptide, on immune response in 2 and 24 month-old rats were investigated. Peripheral blood lymphocytes and splenocytes of aging rats treated for 1 week with different doses of pidotimod showed increased rates of mitogen-stimulated proliferation. Also, interleukin-2 production by 24 month-old rat lymphocytes was significantly increased after treatment with the drug. In addition, the response of the hypothalamic-pituitary-adrenal (HPA) axis to interleukin-1 in 2 and 24 month-old Sprague-Dawley rats previously treated with pidotimod was studies. Blood samples were withdrawn--30, 0, 30, 60, 90 and 120 min after interleukin-1 injection. Interleukin-1 injection stimulated ACTH secretion in a dose-related manner, in both 2 and 24 month-old rats. Peak of the effect was 60 min after the injection. ACTH levels returned to baseline within 120 min in 2 month-old rats, whereas they were still high in untreated 24 month-old rats. However, plasma ACTH levels at 120 min were significantly lower in 24 month-old rats treated with pidotimod. Results suggest that pidotimod possesses immunomodulating properties, such as enhancement of splenocyte and peripheral blood lymphocyte proliferation, and improvement of the deficitary feedback mechanism between the hypothalamic pituitary-adrenal axis and cytokines and, namely, interleukin-1 in the aging rat. PMID- 7857339 TI - General pharmacology of pidotimod and testing for drug interactions. AB - Pidotimod ((R)-3-[(S)-(5-oxo-2-pyrrolidinyl) carbonyl]-thiazolidine-4-carboxylic acid, PGT/1A, CAS 121808-62-6) is a new biological response modifier. General pharmacology and interactions with some drugs were tested. The drug, at doses of 200 mg/kg i.p. and 400 mg/kg p.o., did not affect the normal behaviour, did not modify the responses to stimulation of autonomic nervous system or central nervous system. Pidotimod did not display any cardiovascular or respiratory effect up to 125 mg/kg i.v. in 3 animal species. The drug did not show antimicrobial or antifungal activities nor interact with some of the most common therapeutics (antibiotics, tolbutamide, pentobarbital, antihypertensives, chlorothiazide, warfarin, non-steroidal antiinflammatory agents). On the basis of these results pidotimod shows a safe profile; moreover it does not interact with many therapeutic agents. PMID- 7857340 TI - Toxicological evaluation of pidotimod. AB - This paper reports the toxicological evaluation of pidotimod ((R)-3-[(S)-(5-oxo-2 pyrrolidinyl) carbonyl]-thiazolidine-4-carboxylic acid, PGT/1A, CAS 121808-62-6). Its acute toxicity in mice, rats and dogs was very low after oral, i.v., i.m. and i.p. administration. The repeated administration studies in rats were performed for 4 months via the i.p. route and for 12 months via the oral route. Pidotimod did not show toxic effects at dosages up to 200 mg/kg i.p. and 800 mg/kg p.o. These dosages correspond to 32.5 times the maximum dosage intended for clinical use. The repeated administration studies in dogs were performed for 26 weeks via the i.m. route and for 52 weeks via the oral route. Pidotimod did not show toxic effects at dosages up to 300 mg/kg i.m. and 600 mg/kg p.o.. It did not affect male or female rat fertility at dosages up to 600 mg/kg by oral and 500 mg/kg by i.v. route. The compound was not teratogenic in rats (600 mg/kg p.o. and 1000 mg/kg i.v.), with no effects on subsequent embryofoetal development at dosages up to 1000 mg/kg/day, and in rabbits (300 mg/kg p.o. and 500 mg/kg. i.v.). There were no peri- and postnatal toxic effects in rats (600 mg/kg p.o. and 500 mg/kg i.v.). Local tolerability of pidotimod after i.m. administration was very good. In conclusion pidotimod is characterized by a high safety margin in all animal species. PMID- 7857341 TI - Genotoxicity testing of pidotimod in vitro and in vivo. AB - The mutagenic potential of pidotimod ((R)-3-[(S)-(5-oxo-2- pyrrolidinyl)carbonyl] thiazolidine-4-carboxylic acid, PGT/1A, CAS 121808-62-6) was assessed in a series of five assays designed to measure gene mutation, chromosomal damage and primary DNA damage. All tests were carried out in accordance with appropriate EEC and OECD Guidelines. No indications of mutagenic potential were observed in any of the assays. PMID- 7857342 TI - Pharmacokinetics of pidotimod in rats and dogs. AB - The pharmacokinetic studies on pidotimod ((R)-3-[(S)-(5-oxo-2-pyrrolidinyl) carbonyl]-thiazolidine-4-carboxylic acid, PGT/1A, CAS 121808-62-6) a new biological response modifier, following intravenous, intramuscular or oral administrations in rats and dogs are reported in this paper. Plasma, urine and organ concentrations were determined by HPLC. Analytical methods were validated for specificity, sensitivity, recovery, accuracy and reproducibility; recovery was very close to 100%, the coefficients of variation of accuracy and reproducibility showed low values. In the rat the pharmacokinetic parameters obtained after oral administration demonstrate that pidotimod is a very fast absorbed, distributed and eliminated drug (t1/2el = 1 h) and that it shows high total clearance and distribution volume. Bioavailability was 100% in the intramuscular route and 27% in the oral route. Pidotimod distributes quickly in the main organs, in particular in kidneys and liver; the time course of the levels in organs follows that of plasma levels after intramuscular administration. After repeated intramuscular administrations no phenomena of accumulation or autoinduction were evident. The urinary excretion of the unmodified drug is 75.6% after intravenous and 31.1% after oral administration. The behaviour of pidotimod in dog after oral administration is quite similar to that observed in rat, with a t1/2el of 1.47 h, absolute bioavailability of 37%, high total clearance and distribution volume. Also in the dog the repeated intravenous and oral administrations do not cause any accumulation or autoinduction phenomena. PMID- 7857343 TI - Pharmacokinetics and oral bioavailability of pidotimod in humans. AB - Pidotimod ((R)-3-[(S)-(5-oxo-2-pyrrolidinyl) carbonyl]-thiazolidine-4-carboxylic acid, PGT/1A, CAS 121808-62-6), a new biological response modifier, was investigated in 3 different pharmacokinetic experiments in healthy volunteers. A first trial was carried out with a cross-over design in 12 subjects, given the drug in single administration by intravenous route (200 mg in bolus) and by oral route at 3 dose levels: 200, 400 and 800 mg (tablets). The second experiment was performed in 36 subjects, by intramuscular route at 50, 100 and 200 mg (12 volunteers/group) twice a day for 15 days. Blood samples were drawn and urine collected at different times after the first and the last administration (29th) of the compound. The third experiment was done in 12 subjects given the product at the same single oral dose (800 mg) in different galenic formulations: sachets, vials and tablets, to assess the relative bioavailability, with a cross-over design. Pidotimod plasma and urinary levels were measured by HPLC. The plasma levels after parenteral administration followed a second-order pharmacokinetic, while after oral administration they were processed by a first order input-output model.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7857344 TI - Pharmacokinetics of pidotimod in elderly volunteers and in renal failure patients. AB - The pharmacokinetics of pidotimod ((R)-3-[(S)-(5-oxo-2-pyrrolidinyl) carbonyl] thiazolidine-4-carboxylic acid, PGT/1A, CAS 121808-62-6) in elderly volunteers and in patients with renal failures were investigated. No differences in absorption, excretion and pharmacokinetic parameters was evident between old volunteers and the youngs of a previous work. Patients with impaired renal function showed different pharmacokinetic parameters of pidotimod in relation to different grade of kidney function. There were linear relationships between elimination half-lives and plasma levels of creatinine and urea; longer half lives correspond to higher levels of creatinine and urea. As the half-life of the compound did never exceed 8-9 h, the data do not support any change of pidotimod administration schedule (every 24-12 h). PMID- 7857345 TI - Effect of food on the bioavailability of pidotimod in healthy volunteers. AB - Pidotimod ((R)-3-[(S)-(5-oxo-2-pyrrolidinyl) carbonyl]-thiazolidine-4-carboxylic acid, PGT/1A, CAS 121808-62-6) is a dipeptide-like molecule with immunostimulating activity in animals and in men. According to a cross-over randomized study design, 12 healthy volunteers received pidotimod both as 800 mg sachets and 800 mg ampoules after fasting and after a standard meal. The intake of a standard meal before pidotimod administration, either as sachet or as ampoule, reduced the bioavailability of the drug, probably due to an interference at the absorption level. After eating, the time of maximum plasma level was significantly longer than that observed after fasting, while AUC values and the maximum concentration were reduced by 50%. On the contrary, the pharmacokinetics after absorption phase were not influenced by food: as a matter of fact, half life and MRT did not differ significantly when the drug was taken after fasting or after a standard meal. Finally, the two formulations used in this study resulted bioequivalent. PMID- 7857346 TI - Ex vivo evaluation of pidotimod activity on cell-mediated immunity. AB - The activity of pidotimod ((R)-3-[(S)-(5-oxo2-pyrrolidinyl) carbonyl] thiazolidine-4-carboxylic acid, PGT/1A, CAS 121808-62-6) on immunological parameters was evaluated in a double-blind trial, involving two Research Centres. 16 patients with a primary or metastatic neoplasm, 16 elderly patients under immunodeficiency conditions and 11 healthy volunteers were enrolled in the present study. The patients, randomized within each centre, were assigned to one of the following treatments lasting 15 days: one vial i.m. of pidotimod 50 mg, 100 mg, 200 mg twice a day, respectively; one vial i.m. of physiological saline twice a day. The lymphocyte PHA-stimulation test evidenced a significant variability due to the different treatment groups (p = 0.004). The analysis of the stimulation index (SI), computed from the mean c.p.m. before and after PHA stimulation, showed a significant difference, dose-independent, between saline and active treatment (p = 0.002). The SI analysis, on the basis of the data of the allogenic stimulation test (mixed lymphocyte culture), confirmed the difference between saline and active treatment (p = 0.05) with a significant linear component in the time-effect curve (p = 0.001) but not in the dose-effect curve. A 12% increase in CD 3 lymphocytes compartment was observed with pidotimod 400 mg/day. The drug was well tolerated by all the patients included in the study. PMID- 7857347 TI - Efficacy and safety of pidotimod in the treatment of recurrent respiratory infections in children. AB - The activity of pidotimod ((R)-3-[(S)-(5-oxo-2-pyrrolidinyl) carbonyl] thiazolidine-4-carboxylic acid, PGT/1A, CAS 121808-62-6) was evaluated in a double-blind, placebo-controlled, randomized, multicentre trial, on 120 pediatric patients affected by recurrent respiratory infections. The clinical course of acute infections was favourable both in placebo and in treatment group, but recovery was quicker with pidotimod than with placebo. Antibiotic therapy and time of hospitalization were shorter in the patients taking pidotimod, and main symptomatic parameters (pharyngalgia, dysphagia, mucous membrane inflammation, adenopathy, anorexia) receded quickly. In patients receiving the drug as well as in placebo group changes in laboratory parameters, indicating recovery from the acute infectious events, were observed. A significant trend to normalization of the immune response, evidenced by chemotaxis and leukocyte phagocytosis index, was found only in patients treated with pidotimod. A significant decrease in the risk of relapses was observed in patients treated with pidotimod (35%), as well as a reduction of hospitalization (86%) and a decreased antibiotic therapy (47%). If a relapse occurred, the response of treated patients was quicker (fever, antibiotic therapy, hospitalization). These findings allow to correlate the individual immune response activation to the resistance to recurrent infections and also to a better response to therapy in case of clinically relevant disease. No side effects were observed. Only in 12 patients (5 pidotimod, 7 placebo) mild reactions were observed, but they were attributed to concomitant antibiotic treatment or other factors. No alterations in main laboratory parameters were seen.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7857348 TI - Pidotimod in the treatment of recurrent respiratory infections in paediatric patients. AB - 50 young patients suffering from recurrent respiratory infections (RRI) were treated with pidotimod ((R)-3-[(S)-(5-oxo-2- pyrrolidinyl) carbonyl]-thiazolidine 4-carboxylic acid, PGT/1A, CAS 121808-62-6) (one 400 mg ampoule twice a day) or placebo, according to a double-blind experimental design. The treatment period was 20 days and there was then a 60-day follow-up period. Evaluation was both clinical (number and severity of the respiratory infectious episodes) and immunological, investigating the OKT 4 and OKT 8 lymphocyte sub-populations and OKT 4/OKT 8 ratio. The group of children treated with pidotimod showed a decrease in the number of infections. Patients free from RRI episodes, after 20 days of therapy, were 68% of the group treated with pidotimod compared with 8% of the placebo group. In addition, the mean duration of the episodes was lower in treated patients than in patients of the control group. Such differences were statistically significant. It was also observed that administration of the drug potentiated the immune response such that the clinical picture remained improved for a further 60 days after treatment cessation. Furthermore, only in the pidotimod group there were improving changes of OKT 4 and OKT 8 percentages which affected the OKT 4/OKT 8 ratio. PMID- 7857349 TI - Therapeutic efficacy and safety of pidotimod in the treatment of urinary tract infections in children. AB - The activity of pidotimod ((R)-3-[(S)-(5-oxo-2-pyrrolidinyl) carbonyl] thiazolidine-4-carboxylic acid, PGT/1A, CAS 121808-62-6) was studied vs. placebo in a double-blind, randomized, multicentre trial, involving 60 pediatric patients with recurrent urinary tract infections. Recovery from acute events was quicker with pidotimod than with placebo (9.6 vs. 12.3 days). In treated patients antibiotic therapy was shorter (6.9 vs. 8.3 days) and main symptomatic parameters (body temperature, vesical tenesmus, stranguria, pollakiuria, total number of symptoms, total symptomatic intensity, rate of asymptomatic patients, haematuria, leukocyturia, positive urinary culture) receded quickly. In patients receiving the drug as well as in patients treated with placebo changes in laboratory parameters were observed, indicating recovery from the acute infectious disease. A significant trend to normalization of the immune response, expressed by chemotaxis and index of leukocyte phagocytosis, was found only in patients treated with pidotimod. After the acute episode a significant decrease of risk of relapses (69%) was observed in these patients. If a relapse occurs, the response of treated patients is quicker (duration of fever, total time of relapses) than for control patients. These findings allow to correlate the individual immune response activation to the resistance to recurrent infections and also to a better response to therapy if the disease occurs and becomes clinically relevant. No side effects were observed. Mild reactions (4 nausea/vomiting, 1 erythema) occurred only in 5 patients (2 pidotimod, 3 placebo) but were attributed to concomitant antibiotic therapy. No alterations of main laboratory parameters were found. These findings confirm the tolerability of the drug also in long-term treatment.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7857350 TI - Pidotimod in the treatment of patients affected by bacterial exacerbations of chronic bronchitis. AB - A multicentre double-blind placebo-controlled study was conducted in order to assess the effects of pidotimod ((R)-3-[(S)-(5-oxo-2-pyrrolidinyl) carbonyl] thiazolidine-4-carboxylic acid, PGT/1A, CAS 121808-62-6), a new synthetic biological response modifier, on the clinical picture of bacterial exacerbations of chronic bronchitis. Seven centres of respiratory diseases participated in the trial. A total of 137 patients, 103 males and 34 females (mean age: 65.0 years) were admitted to the study. The trial was subdivided into 3 phases. During the first 8-day phase (D0-D8), 68 patients received 800 mg pidotimod orally (one sachet) twice daily and an antibiotic treatment (amoxycillin plus clavulanic acid: 1 g twice daily), while 69 patients received placebo (one sachet) and antibiotic according to the same dosage schedule. In the second 7-day phase (D8 D15), while the double-blind therapy proceeded, the antibiotic treatment was stopped. The third phase (D15-D45) consisted of a 30-day follow-up period. Five clinical observations, at D0, D4, D8, D15 and D45, were scheduled. The Skin test, to evaluate immunocompetence, was carried out at D0, D15 and D45. The faster improvement of symptomatology (dyspnoea, cough, sputum, hyperpyrexia) in the patients in the pidotimod group compared with the placebo group was reflected in recovery time: mean 8.9 days in the pidotimod group versus 10.7 days in the placebo group (p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7857351 TI - Evaluation of the efficacy of pidotimod in the exacerbations in patients affected with chronic bronchitis. AB - The efficacy and safety of pidotimod ((R)-3-[(S)-(5-oxo-2-pyrrolidinyl)carbonyl] thiazolidine-4-carboxylic acid, PGT/1A, CAS 121808-62-6), a new oral synthetic immunostimulating agent, were investigated in a multicentre study, performed in 10 university and hospital centres of pneumophthisiology and respiratory physiopathology, according to a double-blind vs. placebo experimental design. Primary objective of the investigation was to verify the efficacy of pidotimod against infectious exacerbations in patients affected with chronic bronchitis. 181 inpatients or outpatients (117 male, 64 female; mean age: 62.5 years), affected with chronic bronchitis, were enrolled in the study. Pidotimod 800 mg/die or placebo sachets were administered by oral route for 60 consecutive days, followed by a 60-day follow-up period. Clinical observations were performed at baseline (D 0), after 30 (D 30) and 60 (D 60) days of treatment, as well as at the end of the follow-up (D 120). Time and frequency of infectious relapses were considered as the target variable for the evaluation of the efficacy of the drug. Clinical picture, expectoration characteristics, spirometric parameters and laboratory tests were monitored to evaluate patients' conditions. The results indicate that pidotimod is significantly more effective than placebo against infectious relapses in patients suffering from chronic bronchitis. During the first month, 9% of patients treated with pidotimod were affected with an infectious relapse vs. 39.5% of patients treated with placebo (chi 2, p < 0.001). In the second month, infectious episodes were reported by 1.2% of patients treated with the drug vs. 46.1% of patients treated with placebo (chi 2, p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7857352 TI - Ex vivo evaluation of pidotimod activity in patients with chronic obstructive pulmonary disease. AB - The aim of this study was to evaluate the activity of pidotimod ((R)-3-[(S)-(5 oxo-2-pyrrolidinyl)carbonyl]-thiazolidine-4-carboxylic acid, PGT/1A, CAS 121808 62-6) on 52 patients affected with chronic obstructive pulmonary disease (COPD). The study was carried out in a randomized, parallel, double-blind trial, followed by incomplete blocks design. Pidotimod 800 mg was administered orally twice a day for 30 days. The follow-up period was 5 weeks. Our results show that in patients with COPD pidotimod potentiates T-cell activity. The effects on T-cells appear after 15 days of treatment and last for 5 weeks after the end of therapy. Since other studies demonstrated that pidotimod displays an immunopotentiating activity also on macrophages and granulocytes, the drug is useful to increase the immune defense during infections. The drug has a good compliance and is well tolerated also during long-term treatment. PMID- 7857353 TI - Role of immunoactivation with pidotimod in recurrent respiratory infections in childhood. AB - The efficacy and safety of pidotimod ((R)-3-[(S)-(5-oxo-2-pyrrolidinyl)carbonyl] thiazolidine-4-carboxylic acid, PGT/1A, CAS 121808-62-6) were rated in a child population with a remote history of recurrent respiratory infections (RRI). This randomized double-blind multicenter clinical trial versus placebo, stratified by age groups, involved 748 children recruited in 69 Medical Centres. The trial consisted of a 60-day treatment period and a 90-day follow-up. At the end of the treatment period the pidotimod group showed a significant decrease in the number of RRI episodes and associated symptoms vs control group. As a consequence, there was a significant decrease in the number of days of absence from kindergarten or school and in the consumption of antibiotics and symptomatic drugs. Safety was good. The effect of the drug persisted after its withdrawal throughout the whole 90-day follow-up period. During this period there was a significantly lower RRI incidence rate in the pidotimod group than in the placebo group (p < 0.01). Because of its efficacy and safety, pidotimod may be rated as an excellent drug in the RRI management in children. PMID- 7857354 TI - Pidotimod in the management of recurrent pharyngotonsillar infections in childhood. AB - The efficacy and safety of a new synthetic immunostimulant pidotimod ((R)-3-[(S) (5-oxo-2-pyrrolidinyl) carbonyl]-thiazolidine-4-carboxylic acid, PGT/1A, CAS 121808-62-6) in recurrent infections of the primary airways were assessed in a group of 416 children with a history of recurrent respiratory infections (RRI). This was a double-blind randomized trial of pidotimod vs. placebo, consisting of a treatment period of 60 days and a follow-up period of 3 months. A reduction in the duration and frequency of infectious episodes in the group of children treated with pidotimod (one 400 mg oral bottle daily) was observed which was statistically different from the placebo group. The protective effect produced by pidotimod was also confirmed by a series of recordings made over the five-month observation period, which showed a significant reduction in the number of days of fever, the severity of the signs and symptoms of acute episodes, use of antibiotics and antipyretic drugs and absence from school or nursery school. Safety was excellent. PMID- 7857355 TI - Pidotimod activity against chronic bronchitis exacerbations. AB - The efficacy of pidotimod ((R)-3-[(S)-(5-oxo-2-pyrrolidinyl) carbonyl] thiazolidine-4-carboxylic acid, PGT/1A, CAS 121808-62-6) in the management of infectious exacerbations of chronic bronchitis was evaluated in a double-blind, placebo-controlled study in parallel groups over 5 months (60 days of treatment and 90 days of follow-up). The study enrolled 580 patients, of whom 514 could be evaluated. The pidotimod group had fewer and shorter infectious episodes, fewer days of antibiotic therapy and fewer days unable to undertake normal activities. The difference vs. placebo was significant during the follow-up period and, in those subjects with a less severe history, during the treatment period also. Pidotimod was well tolerated. PMID- 7857356 TI - Immunoactivity of pidotimod against episodes of recurrent tonsillitis in childhood. AB - The therapeutic efficacy of the synthetic immunostimulant pidotimod ((R)-3-[(S) (5-oxo-2-pyrrolidinyl) carbonyl]-thiazolidine-4-carboxylic acid, PGT/1A, CAS 121808-62-6) was evaluated in a double-blind placebo-controlled study in parallel groups in the management of recurrences in 235 children with recurrent tonsillitis. The ambulant study provided for 15 days of treatment with two oral vials of pidotimod 400 mg or placebo daily, in accordance with a randomisation list, 60 days of treatment with one oral vial of pidotimod 400 mg or placebo daily, and a 90-day follow-up period. The total trial period was 165 days. In addition to evaluating the number of tonsillitis recurrences which occurred during the 75 days of treatment and the 90-day follow-up period, the number of days on which the principal symptoms of the illness were present and on which drugs such as antibiotics or anti-inflammatory agents were used concomitantly, as well as the number of days' absence from school, were analyzed. The findings showed that, taking the treatment phase and the three-month follow-up period together, pidotimod significantly reduces the incidence of inflammatory upper airways episodes. The very low incidence of adverse effects, which was the same as that in the placebo group, confirmed the excellent safety of the product. PMID- 7857358 TI - HMOs contracting under Medicare and Medicaid. PMID- 7857359 TI - Judith Montgomery. An up-close look at ASHA's 1995 president. Interview by Russell L. Malone. PMID- 7857357 TI - Immunoactivation by pidotimod in children with recurrent respiratory infections. AB - The therapeutic activity and safety of pidotimod ((R)-3-[(S)-(5-oxo-2 pyrrolidinyl) carbonyl]-thiazolidine-4-carboxylic acid, PGT/1A, CAS 121808-62-6), a new synthetic "biological response modifier", were examined in a double-blind, placebo-controlled, multicentre trial in 101 children, including 53 boys and 48 girls aged 2-13 years (mean +/- SD: 4.7 +/- 2.1 years) with a history of recurrent respiratory infections (RRI). Pidotimod (400 mg/day) or placebo were administered orally for 60 consecutive days, followed by a further 60-day follow up period. The trial was completed by 89.1% of patients. The results indicate that pidotimod has a beneficial effect in children with recurrent respiratory infections: the percentage of patients presenting symptoms affecting the upper and lower airways was significantly lower after treatment with the active drug than after treatment with placebo. Relevant side effects were not reported during the trial. An evaluation of the expression of CD25 (after in vitro stimulation of circulating mononuclear cells with PHA) before and after treatment with the two products revealed a significant increase in CD25+ cells in the group treated with pidotimod but not in the group treated with placebo. PMID- 7857360 TI - The transformation age: the sky's the limit. PMID- 7857361 TI - Fast forward. ASHA leaders imagine where we'll be in the year 2005. PMID- 7857362 TI - Learning disabilities and dyslexia. PMID- 7857363 TI - Changes in composition and distribution of LDL subspecies in hypertriglyceridemic and hypercholesterolemic patients during gemfibrozil therapy. AB - The effect of gemfibrozil (GEM) on composition and distribution of LDL subspecies in 10 hypertriglyceridemic (HTG) patients with triglyceride (TG) levels of 300 750 mg/dl and low density lipoprotein cholesterol (LDL-C) < 160 mg/dl, and 8 hypercholesterolemic (HC) patients with LDL-C > or = 190 mg/dl and TG < 200 mg/dl was investigated. Patients were randomized in a double-blind, crossover design to 12 week periods of placebo and 1200 mg/day GEM with an intervening washout period. All 7 LDL subspecies in the density range of 1.029 to 1.063 g/ml in the HTG group contained more TG (P < 0.01) and less free cholesterol (P < 0.05), while the proportion of cholesterol ester was lower only in LDL subspecies 1 to 3 (P < 0.05) as compared to the HC group. In HTG patients, GEM increased the proportion of cholesterol ester (P < 0.05) in all subfractions, while the proportion of free cholesterol was increased and TG was decreased in LDL subspecies 1 to 4 only (P < 0.05). GEM decreased the LDL subspecies score from 4.8 +/- 0.7 to 4.2 +/- 0.5, and the major LDL subclass density from 1.048 +/- 0.006 to 1.043 +/- 0.002 g/ml (P < 0.01) in HTG patients. GEM decreased TG levels to mean of 228 +/- 52 mg/dl in HTG patients, but there was no change in LDL phenotype. No significant changes in composition and distribution of LDL subspecies were noted in HC patients with GEM. We conclude that GEM significantly altered the composition and distribution of LDL subspecies with a shift from small dense LDL particles to large, less dense particles in HTG patients. PMID- 7857364 TI - Inhibition of cholesteryl ester transfer protein activity in hamsters alters HDL lipid composition. AB - We investigated the role of cholesteryl ester transfer protein (CETP) in hamsters by using a monoclonal antibody (MAb) that inhibited hamster CETP activity. MAbs were prepared against partially purified human CETP and screened for inhibiton of 3H-cholesteryl oleate (CE) transfer from LDL to HDL in the presence of human plasma bottom fraction (d > 1.21 g/ml). Antibody 1C4 inhibited CE transfer activity in both human plasma bottom fraction (IC50 = approximately 4 micrograms/ml) and in whole plasma from male Golden Syrian hamsters (IC50 = approximately 30 micrograms/ml). Purified MAb 1C4 was injected into chow- and cholesterol-fed hamsters, and blood was collected for analysis of plasma CETP activity and HDL lipid composition. Plasma CETP activity was inhibited by 70%-80% at all and HDL lipid composition. Plasma CETP activity was inhibited by 70%-80% at all times up to 24 h following injection of 500 micrograms MAb 1C4 (approximately 3.7 mg/kg). The amount of antibody required for 50% inhibition at 24 h post-injection was 200 micrograms (approximately 1.5 mg/kg). Inhibition of hamster CETP activity in vivo increased hamster HDL cholesterol by 33% (P < 0.0001), increased HDL-CE by 31% (P < 0.0001) and decreased HDL-triglyceride by 42% (P < 0.0001) (n = 36) as determined following isolation of HDL by ultracentrifugation. An increase in HDL cholesterol and a redistribution of cholesterol to a larger HDL particle were also observed following fast protein liquid chromatography (FPLC) gel filtration of plasma lipoproteins.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7857365 TI - Elastase enhances cAMP accumulation and the inhibition of DNA synthesis induced by OP-41483, a stable prostacyclin analogue, in vascular smooth muscle cells. AB - To define the physiological roles of elastase in the vascular wall, we examined whether elastase at low concentrations can modulate the proliferation of vascular smooth muscle cells (VSMC). Elastase itself at low concentrations from 1 to 50 ng/ml inhibited DNA synthesis dose-dependently in VSMC. However, phenylmethylsulfonyl fluoride-inactivated elastase failed to induce this inhibition. OP-41483, a stable analogue of prostacyclin, inhibited DNA synthesis and stimulated accumulation of cAMP in VSMC. Preincubation of VSMC for 24 h with 50 ng/ml elastase enhanced both inhibition of DNA synthesis and the accumulation of cAMP induced by OP-41483. Preincubation of VSMC with 12-O-tetradecanoylphorbol 13-acetate, an activator of protein kinase C (PKC), also enhanced cAMP accumulation induced by OP-41483. On the other hand, elastase failed to enhance OP-41483-induced cAMP accumulation in PKC down-regulated cells. Furthermore, coincubation with chelerythrine, an inhibitor of PKC, inhibited the enhancement of cAMP accumulation induced by preincubation with elastase. These results suggest that elastase at low concentrations can enhance the inhibition of VSMC proliferation induced by prostacyclin through the activation of protein kinase C. PMID- 7857367 TI - Gender and diet interactions with simvastatin treatment. AB - Twelve men and thirteen women with hypercholesterolaemia participated in a 20 week controlled cross-over trial to assess the interaction between dietary fat intake, gender and an HMGCoA reductase inhibitor, simvastatin. Subjects were matched for total cholesterol, age, body mass index (BMI) and plasma triglyceride. Gender-drug interactions were noted with men demonstrating only a 27% fall in LDL cholesterol with simvastatin when consuming a high fat (40% energy) diet compared to women with a 35% fall. In men, the lowest LDL/HDL ratio was achieved with simvastatin on a low fat diet (22% energy). Gender differences in the effect of simvastatin on HDL were confined to HDL3 cholesterol, although the drug raised HDL2 in both sexes on the low fat diet. Simvastatin was responsible for an 11% increase in HDL3 cholesterol in men particularly when on a low fat diet but did not affect HDL3 in women. An important diet-drug interaction was seen in triglyceride response, with a lowering of 17%-20% only when subjects were on a low fat diet. There was a gender difference in response to dietary fat change with men demonstrating a 19% decrease in triglycerides with dietary fat reduction while on simvastatin, whereas women showed a 9% increase which did not reach significance. Men also responded more favourably to dietary fat reduction with at least two-fold greater falls in plasma cholesterol than was seen in women.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7857366 TI - Influence of lipoprotein lipids, dietary fat and smoking on macrophage degradation of native and oxidized low density lipoprotein. AB - Relatively little is known about the biological mechanisms by which lipoproteins promote atherogenesis. It has, however, been shown that structural modification of low density lipoprotein (LDL), such as by oxidation, results in their uptake and degradation by intimal macrophages and consequently leads to formation of lipid-rich atherosclerotic lesions. The aim of the present investigation was to study the influence of dietary intake of fat, lipoprotein lipid composition, smoking and gender on macrophage degradation of LDL before and after oxidation. The study group consisted of 48 males and 56 females with hyperlipidemia taking part in the open prerandomization phase of the Probucol Quantitative Regression Swedish Trial (PQRST). Analysis including lipoprotein determinations, dietary and smoking habit interviews, LDL degradation by macrophages, LDL receptor binding and LDL thiobarbituric acid reactive substance (TBARS) levels before and after copper ion-induced oxidation was done during the pre-andomization phase of the study. Increased plasma and very low density lipoprotein (VLDL) triglyceride levels were associated with an increased macrophage degradation of native LDL, whereas no such association was found after oxidation of LDL. The dietary intake of polyunsaturated fatty acids (PUFA) was also inversely related to the degradation of native LDL by macrophages, but increased the rate at which oxidized LDL was degraded. Smoking and gender did not influence the rate of macrophage degradation of native or oxidized LDL. It is concluded that hypertriglyceridemia is associated with an increased macrophage degradation of LDL. This may represent a mechanism by which hypertriglyceridemia promotes atherosclerosis. PMID- 7857368 TI - Relation of polymorphisms in the cholesteryl ester transfer protein gene to transfer protein activity and plasma lipoprotein levels in alcohol drinkers. AB - We investigated the interaction between genetic and environmental factors in the regulation of plasma HDL cholesterol concentration by determining TaqI and EcoN I restriction fragment length polymorphisms at the cholesteryl ester transfer protein (CETP) gene locus in 93 male alcohol drinkers and 82 control men. The highest plasma CETP activity and the lowest HDL cholesterol concentration were in the control subjects who were homozygous for the presence of the TaqI B restriction site (genotype 1-1). The lowest CETP activity and the highest HDL cholesterol among the control subjects were in those with genotype 2-2. These associations were, however, evident only in the non-smokers (P = 0.03 for CETP activity and P = 0.05 for HDL cholesterol). The non-smoking control subjects with genotype 1-1 had 19% higher CETP activity and 16% lower HDL cholesterol than those with genotype 2-2 (mean +/- S.D., 113 +/- 25 nmol/h/ml and 1.16 +/- 0.30 mmol/l vs. 95 +/- 16 nmol/h/ml and 1.38 +/- 0.34 mmol/l, respectively), and CETP activity and HDL cholesterol were negatively correlated (r = -0.280, P = 0.03, n = 59). The alcohol drinkers had 30% lower CETP activity (P < 0.001) and 48% higher HDL cholesterol (P < 0.001) than the controls. CETP activity was not affected by the TaqI B genotype in the alcohol drinkers. The lowest HDL cholesterol was in subjects with genotype 1-1 (1.68 +/- 0.60 mmol/l), but those with genotype 2-2 had lower HDL cholesterol than those with genotype 1-2 (1.78 +/ 0.59 and 1.93 +/- 0.66 mmol/l, respectively). The data of the alcohol drinkers fitted better with the quadratic regression model than with the linear one, suggesting a trend towards a curved relationship between the TaqI B genotype and HDL cholesterol in both the non-smoking and smoking alcohol drinkers. Total, LDL or VLDL cholesterol, total or VLDL triglycerides did not differ between the TaqI B genotypes either in the alcohol drinkers or the controls. Lipid and lipoprotein levels and CETP activities were likewise similar in the TaqI A and EcoN I polymorphisms. Our data indicate that CETP TaqI B polymorphism is related to plasma CETP activity and HDL cholesterol concentration in non-smoking men, but these associations are affected by smoking and alcohol drinking. PMID- 7857369 TI - Influence of apolipoprotein H polymorphism on levels of triglycerides. AB - Human apolipoprotein H (apo H) displays a genetically determined structural polymorphism: three alleles (H*1, H*2 and H*3) on chromosome 17 code for the six phenotypes (three homozygotes and three heterozygotes). The effect of apolipoprotein polymorphism on individual variations in plasma lipoprotein levels has been underscored in recent years. Since apo H is involved in metabolism of triglycerides (Tg), its phenotype could affect Tg levels. This paper reports an investigation of apo H phenotypes in a sample of 217 subjects of the Italian population by means of isoelectrofocussing followed by immunoblotting. The levels of the main lipid parameters were evaluated in relation to phenotype and other influential factors. Analysis of covariance disclosed a significant association between Tg levels (log transformed) and phenotype (F = 8.27, P = 0.004). Comparison of Tg levels between bearers of the two most frequent phenotypes (H2/2 and H3/2) divided by sex and age classes revealed significantly higher levels in male H3/2 heterozygotes (P = 0.0053) and in H3/2 subjects aged less than 50 (P = 0.0095). Our data support the view that there is an association between hypertriglyceridaemia and apo H polymorphism, especially with the H*3 allele. PMID- 7857370 TI - Histamine as an activator of cell growth and extracellular matrix reconstruction for human vascular smooth muscle cells. AB - Atherosclerosis is characterised by unusual growth of vascular smooth muscle cells (VSMCs) in the intima. We examined the effects of histamine on human VSMCs and the VSMC-derived cell line, ISS10. Histamine enhanced phosphoinositide hydrolysis, increased cytoplasmic Ca2+ level and stimulated the transcription of c-fos protooncogene, which resulted in DNA synthesis and the enhancement of proMMP-1 expression. These results indicate that histamine may play some roles in the pathological process of atherosclerosis and raise the possibility that mast cells migrating into the atherosclerotic foci are involved in the process of atherosclerogenesis. PMID- 7857371 TI - Correlations between platelet aggregation, fibrinolysis, peripheral and central serotonergic measures in subhuman primates. AB - We have studied the relationships between whole blood and plasma serotonin (5 hydroxytryptamine, 5-HT), its major metabolite 5-hydroxyindoleacetic acid (5 HIAA) and serum lipids, platelet aggregation in the whole blood and in the platelet-rich plasma (PRP), and some fibrinolytic parameters in monkeys. Plasma 5 HT was found to be positively related to 5-HT- and ADP-induced platelet aggregation, tissue plasminogen activator (tPA) activity, serum cholesterol and LDL-cholesterol, whereas 5-HT in cerebrospinal fluid correlated inversely with serum cholesterol. Plasminogen activator inhibitor (PAI) activity was positively related to LDL. Euglobulin clot lysis time was related to both tPA and PAI activities. The significance of these findings and the possible role of 5-HT in atherogenesis and hemostasis are discussed. PMID- 7857373 TI - Effects of supplementing with vitamin E on the uptake of low density lipoprotein and the stimulation of cholesteryl ester formation in macrophages. AB - Vitamin E supplementation has been reported to protect low density lipoprotein (LDL) from copper-induced oxidation and macrophage-mediated oxidation. We investigated the effect of in vitro vitamin E enrichment of LDL on the accumulation of [3H]cholesteryl ester (CE)-LDL and stimulation of cholesteryl ester formation in J774 macrophages. Vitamin E supplementation prolonged lag time (2.9-fold) before the initiation of copper-induced LDL oxidation. LDL, preincubated with 5 microM copper or with macrophages in Ham's F10 medium, accumulated in macrophages much more than did native LDL. However, following vitamin E enrichment, LDL accumulation was significantly reduced following oxidative stress. Vitamin E-enriched LDL also reduced the stimulation of cholesteryl ester formation in macrophages. Moreover, vitamin E enrichment of macrophages reduced the ability of the cells to oxidize LDL. The present results indicate that vitamin E supplementation protects LDL against copper-induced and macrophage-mediated oxidation, inhibits oxidation-dependent accumulation of LDL in macrophages, and prevents stimulation of cholesteryl ester formation in macrophages. Additionally we have provided evidence that intra-cellular enrichment with vitamin E prevents oxidative modification of LDL by macrophages. PMID- 7857372 TI - Glucocorticoid inhibits cAMP production induced by vasoactive agents in aortic smooth muscle cells. AB - It is well-known that atherosclerotic change and hypertension are common manifestations in patients with glucocorticoid excess. We previously reported that pituitary adenylate cyclase activating polypeptide (PACAP), prostaglandin E2 (PGE2) and carbacyclin, a stable analog of prostacyclin, have suppressive effects on vasopressin-induced DNA synthesis of rat aortic smooth muscle cells through cAMP production (Murase et al., J. Hypertens., 10 (1992) 1505; Oiso et al., Biochem. Cell. Biol., 71 (1993) 156). In the present study, we investigated the effect of glucocorticoid on cAMP production induced by PACAP, PGE2 and carbacyclin in aortic smooth muscle cells. The pretreatment with dexamethasone significantly inhibited cAMP accumulation induced by these vasoactive agents in a dose dependent manner in the range between 10 pM and 10 nM. These inhibitory effects of dexamethasone were dependent on the time of pretreatment up to 8 h. Dexamethasone inhibited cAMP accumulation induced by NaF, a GTP-binding protein activator, and forskolin which directly activates adenylate cyclase. Moreover, forskolin-induced adenylate cyclase activity was significantly reduced in membranes prepared from the cells treated with dexamethasone. These results strongly suggest that glucocorticoid inhibits cAMP production induced by vasoactive agents in primary cultured rat aortic smooth muscle cells and the inhibitory effect is exerted at the level of adenylate cyclase. PMID- 7857374 TI - Involvement of LDL receptor in the proliferation of vascular smooth muscle cells. AB - To study the involvement of the low-density lipoprotein (LDL) receptor in the growth of vascular smooth muscle cells (VSMC), we compared the proliferation of cultured VSMC from Watanabe heritable hyperlipidemic (WHHL) rabbits, which lack the LDL receptor, and VSMC from normal Japanese white rabbits in response to platelet derived growth factor (PDGF). The increase in the number of VSMC from WHHL rabbits in response to PDGF (10(-8) M) was significantly lower than that of VSMC from normal rabbits. PDGF stimulated the synthesis of DNA in VSMC from both normal rabbits and WHHL rabbits, but the response was significantly lower in the latter. To determine the involvement of the LDL receptor in the decreased mitogenic response of WHHL rabbit VSMC, we used an anti-LDL receptor monoclonal antibody (MAb) to normal rabbit VSMC; DNA synthesis of VSMC was stimulated by PDGF, but the effect was significantly blocked by the anti-LDL receptor MAb. Mitogen-activated protein (MAP) kinase activity in normal rabbit VSMC was increased by exposure to PDGF, but the effect was significantly suppressed in the presence of the MAb. The anti-LDL receptor MAb markedly inhibited LDL binding to the surface of normal rabbit VSMC. These results suggest that the LDL receptor influences the proliferation of VSMC and thus might be involved in the pathogenesis of atherosclerosis. PMID- 7857376 TI - 4th International Workshop on Lipid Metabolism. Dijon, France, 15-16 April 1994. Proceedings and abstracts. PMID- 7857375 TI - Hyperlipidaemia does not impair vascular endothelial function in glycogen storage disease type 1a. AB - Patients with glycogen storage disease type 1 (GSD-1) often have marked hyperlipidaemia with abnormal lipoprotein profiles. This metabolic abnormality improves, but is not fully corrected, with dietary therapy and therefore these patients may be at high risk for the development of atherosclerosis. Endothelial dysfunction is an early event in atherogenesis and can be detected in children and young adults at high risk. We studied endothelial function, using a non invasive ultrasonographic method, in the brachial arteries of 6 adult GSD-1a patients (aged 23-33 years) with mean cholesterol of 7.9 mmol/l (range 4.7 to 14.6) and mean triglycerides of 9.1 mmol/l (range 4.1 to 21.3), and 12 age- and sex-matched normolipidaemic controls. Flow-mediated (endothelium-dependent) dilation was similar in patients and controls (8.2% vs. 10.5%; P = 0.20). Although the patient numbers are small, these results are consistent with the surprising lack of clinically evident atherosclerosis in GSD-1. The reasons these patients appear less susceptible to the damaging arterial effects of hyperlipidaemia are unknown. These results may have implications for others with secondary hyperlipidaemias. PMID- 7857377 TI - Atherosclerosis, a multifactor lesion justifying multirisk care. PMID- 7857378 TI - Identification of individuals at high risk for myocardial infarction. AB - The incidence of atherosclerotic coronary heart disease (CHD) was assessed in 4559 male participants of the Prospective Cardiovascular Munster (PROCAM) study, aged 40-64 years, over a 6 year follow-up period. In this time, 186 study participants developed atherosclerotic CHD (134 definite nonfatal myocardial infarctions and 52 definite atherosclerotic CAD deaths including 21 sudden cardiac deaths and 31 fatal myocardial infarctions). In multiple logistic function (MLF) analyses, age, cholesterol, HDL cholesterol, systolic blood pressure, and the binary (yes/no) criteria of cigarette smoking, angina pectoris, diabetes mellitus or hyperglycaemia, and family history of myocardial infarction showed a significant association with the incidence of atherosclerotic CHD after adjustment for the other risk factors. In the subgroup of individuals, in whom clotting factors were measured, fibrinogen was found to be an independent additional risk indicator for CHD by multiple logistic function analysis (P < 0.05). The relationship between a variable and total mortality or some of its components was described by dividing the patient series into quintiles of the studied variable and then calculating the age-standardized death rate for each quintile. Lowest risk of total mortality occurs in men with lowest risk of CHD, though relationships between total mortality and levels of single risk factors are 'J'-shaped or even 'U'-shaped. PMID- 7857379 TI - Triglyceride-rich lipoproteins and atherosclerosis. AB - Plasma triglyceride (TG)-rich lipoproteins are related to high density lipoprotein (HDL)-cholesterol and risk of coronary artery disease (CAD). Two major hypotheses on the role of HDL in the development of CAD have been proposed: a 'causalist' view assigns a protective effect against atherosclerosis to HDL and a 'non-causalist' view states that HDL do not interfere directly with development of atheroma but reflect metabolism of TG-rich lipoproteins. HDL exist as two major subfractions: small, lipid-poor, dense HDL3, and larger, lipid-rich, less dense HDL2, with variable levels of total-HDL cholesterol. Rapid lipolysis of TG rich lipoproteins produces increased lipid uptake, formation of HDL2 and may protect the arterial wall; delayed lipolysis increases transfer of TG from TG rich lipoproteins into HDL. Cholesteryl ester transfer protein (CETP) catalyzes lipid exchange and may be the mechanism for switching 'good cholesterol' into 'bad cholesterol'. According to this view, the driving force for the switch is the metabolism of TG-rich lipoproteins. Rapid clearance of TG-rich lipoproteins promotes formation of HDL2, low levels of TG-rich lipoproteins prevent transfer of HDL-cholesteryl esters into TG-rich lipoproteins keeping HDL-cholesterol high. The net effect is antiatherogenic. Accumulation of TG-rich lipoproteins leads to transfer of cholesteryl esters from HDL into lipoprotein fractions associated with high CAD risk. PMID- 7857380 TI - The dyslipoproteinemias of diabetes. AB - Atherosclerosis is the most frequent complication of diabetes. There are many potentially atherogenic factors in diabetes that may underlie this problem. Of these, one is the group of dyslipoproteinemias. In diabetes there are both qualitative and quantitative changes in the plasma lipoproteins. Based on pathophysiological and epidemiological data, these may be among the many factors that can result in early macrovascular disease. Furthermore, at least one of the dyslipoproteinemias--hypertriglyceridemia--is associated with insulin resistance and therefore could aggravate glucose intolerance. Thus, on theoretical grounds it is reasonable to postulate that treating the dyslipoproteinemias of diabetes would reduce atherosclerotic disease. However, to date there have been no intervention studies specifically designed to test this postulate in the diabetic population. One such study, the Diabetes Atherosclerosis Intervention Study, is currently in progress. PMID- 7857381 TI - Recent concepts of lipoprotein pathophysiology. AB - Molecular genetic approaches have added greatly to the understanding of the human hyperlipoproteinemias. Studies in mice have added interesting new information. Transgenic mice over-expressing or deficient in various individual proteins important in lipoprotein metabolism have reproduced some dyslipidemias and permitted further pinpointing of the functions of apolipoproteins, lipoprotein receptors, lipid transfer proteins and enzymes. Cross-breeding of mice with single defects has reproduced certain dyslipidemia syndromes and permits examination of the combined etiologic effects of more than one gene. PMID- 7857382 TI - Apolipoprotein A-I-containing particles and reverse cholesterol transport: evidence for connection between cholesterol efflux and atherosclerosis risk. AB - It is now clearly established that apo A-I-containing lipoproteins exist as two major families, those containing apo A-I and apo A-II (LpA-I:A-II) and those containing apo A-I but free of apo A-II (LpA-I). Metabolic studies utilizing radiolabeled lipoprotein particles suggested that there is a kinetic difference between LpA-I and LpA-I:A-II family and support the concept that there may be important functional differences between the lipoprotein particles present within HDL. Of considerable significance was the finding that proteins stimulating reverse cholesterol transport (lecithin:cholesterol acyltransferase (LCAT), cholesteryl ester transfer protein (CETP)) are mainly present in LpA-I and not in LpA-I:A-II family. Cholesterol efflux mediated by A-I-containing particles has been studied in different cells. Long term exposure to LpA-I family promoted cholesterol efflux whereas less efflux was observed in the presence of LpA-I:A-II family. The fact that LpA-I:A-II family can inhibit the LpA-I promoted cholesterol efflux strongly supports the role of apo A-II as an antagonist in the production of cholesterol efflux. These results which emphasize that LpA-I and LpA-I:A-II families behave as distinct entities have been confirmed in other studies showing that they have different clinical significance. The results in mice transgenic for apo A-I indicate that overexpression of apo A-I induces more cholesterol efflux and protects C57BL/6 mice from atherosclerosis. Increased expression of apo A-II in mice appears to decrease cholesterol efflux and to promote rather than retard aortic fatty streak development.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7857383 TI - Comparison of European and USA guidelines for prevention of coronary heart disease. AB - This paper deals with the comparison of European and American guidelines for prevention of CHD, screening and management of hyperlipidemia. The revised EAS guidelines consist of 4 chapters: the scientific basis of CHD prevention; strategies for prevention of CHD; setting up a primary care system for CHD prevention, and the fourth focuses on clinical management with healthy diet, lifestyle and drug treatment of risk factors for CHD. The EAS guidelines emphasize that therapeutic decisions are based on the assessment of the global risk of CHD. In both EAS and American guidelines, optimal total plasma cholesterol and triglyceride target values recommended are < 200 mg/dl for both parameters. Both guidelines state that the initial approach to the treatment of hyperlipidemia should involve diet, increased physical activity, and weight reduction. If target levels are not achieved, the physician should determine whether drug therapy is appropriate. Conservative measures (diet and exercise) are recommended in particular for premenopausal women, elderly subjects and adolescents. There is complete agreement on the importance of secondary prevention of CHD. PMID- 7857384 TI - Micronised fenofibrate. AB - Rationale and development of a new fenofibrate formulation is described. A lower dispersion of particles size and thereby a better absorption rate leads to a decrease of the daily dose and provides a better control of the amount absorbed. Improved reproducibility of the pharmacological and therapeutic effect is expected. PMID- 7857385 TI - Efficacy and tolerance of 200 mg micronised fenofibrate administered over a 6 month period in hyperlipidaemic patients: an open Belgian multicenter study. AB - The authors report the results of a large open multicenter study using 200 mg micronised fenofibrate once a day. Among 1545 selected patients who underwent a 3 month period with nutritional advice, 1334 were included in a 6-month drug study. Inclusion criteria were total serum cholesterol equal to or above 250 mg/dl and/or serum triglycerides equal to or above 200 mg/dl. At 6 months, average changes from inclusion levels were -20.5, -26.1. -7.5 and +15.2% for total cholesterol, LDL-cholesterol > or = 160 mg/dl on inclusion, plasma fibrinogen and HDL-cholesterol, respectively. Median decrease of serum triglycerides was 46.5%. Trial discontinuation for clinical and biological adverse events were 5 and 1%, respectively. In conclusion, micronised fenofibrate at a daily dose of 200 mg had significant lipid-modifying properties but also exhibited a beneficial effect on other related risk factors such as fibrinogen reduction. The safety profile was very satisfactory providing an excellent benefit/risk ratio. PMID- 7857386 TI - The fibrates in clinical practice: focus on micronised fenofibrate. AB - Dietary measures, including calorie restriction and reduced fat intake, remain the mainstay of management in prevention of coronary heart disease (CHD). When this fails, drug therapy should be considered. Fibrates, a family of lipid lowering drugs, decrease plasma triglycerides and inhibit their synthesis. They are also reported to suppress cholesterol production in the liver. A disadvantage of fenofibrate is the poor solubility of the principal ingredient, with subsequent incomplete absorption after oral administration. Micronized fenofibrate, a new formulation chemically identical to the parent compound, has improved pharmacokinetic parameters which increase absorption, provide more stable plasma levels, and thus dosage can be decreased. The micronized formulation has been shown to be effective in reducing LDL cholesterol and triglycerides in patients with types IIa and IV hyperlipidemia, with increasing responsiveness to therapy in proportion to elevated baseline values of these parameters. This formulation has also been compared to simvastatin, an HMG-CoA reductase inhibitor. Results of a double-blind crossover study showed that both drugs reduced plasma cholesterol levels by similar amounts, and both produced similar increases in HDL cholesterol. The micronized formulation of fenofibrate thus provides improved efficacy in the prevention of CHD. In comparison to the standard formulation, micronised fenofibrate thus provides improved efficacy in the control of dyslipidemia and the prevention of CHD. PMID- 7857387 TI - Dietary monounsaturated fatty acids and serum lipoprotein levels in healty subjects. AB - Effects of monounsaturated fatty acids on serum total cholesterol levels in man are often described as 'neutral'. The term neutral, however, is often misinterpreted. It does not mean that one can simply add monounsaturates to the diet without changing the serum total cholesterol level but that, under iso caloric conditions, monounsaturated fatty acids have similar effects on serum total cholesterol as carbohydrates. Diets high in monounsaturated fatty acids, however, have a more favourable effect on the distribution of cholesterol over the various lipoproteins as compared with diets high in carbohydrates. Thus, the term neutral is misleading. In addition, in contrast with earlier studies, recent studies suggest that at realistic intakes, polyunsaturates and monounsaturates have comparable effects on serum lipoprotein levels. At present, there is no unequivocal explanation to resolve this discrepancy. However, these findings offer subjects on cholesterol-lowering diets a larger choice of food items to choose from to replace products high in the serum cholesterol-raising saturated fatty acids. PMID- 7857388 TI - Lipoprotein (a): implication in atherothrombosis. AB - Substantial experimental evidence now implicates lipoprotein (a) as an independent risk factor for premature cardiovascular disease. Both plasma Lp(a) levels and apo(a) phenotype are strong predictors of risk for ischaemic heart disease. The accumulation of apo(a) in vascular wall tissue and in atherosclerotic plaques and the potential inhibition of fibrinolysis by Lp(a) underlie the enhanced risk of premature cardiovascular disease associated with this cholesterol-rich particle. Recent studies of the capacity of purified Lp(a) isoforms to inhibit fibrinolysis in an in vitro system have revealed that small isoforms of Lp(a) (< or = 500 kDa) are efficient inhibitors of plasminogen activation and bind with high affinity to fibrin. Conversely, large isoforms exert little or no inhibitory effect in this system (> 500 kDa). These data suggest that the potential, high affinity interaction of Lp(a) particles containing small isoforms with fibrin introduces a new, third dimension to the atherothrombotic risk associated with these cholesterol-rich particles. PMID- 7857389 TI - Studies of lipoprotein (a) and high density lipoproteins in transgenic mice. AB - The many genetic components contributing to atherosclerosis in humans have been difficult to untangle, due in part to the lack of genetically defined model systems. To investigate the in vivo properties of two particularly puzzling human lipoproteins, lipoprotein (a) (Lp(a)) and high-density lipoprotein (HDL), we have engineered mice to produce human-like analogues in their plasma. In these studies, we have examined the effect that protein composition has on the antiatherogenic properties of HDL and the interaction of human apolipoprotein(a) (apo(a)) and human apolipoprotein B (apo B) in forming Lp(a). PMID- 7857390 TI - Effects of estrogens on lipoprotein metabolism and cardiovascular disease in women. AB - Estrogen use is associated with protection from cardiovascular disease in postmenopausal women. This benefit appears to be magnified among women with pre existing heart disease. The possible bias of intrinsically better health in women using estrogen has not been ruled out in observational studies. Therefore, two double-blind randomized clinical trials are underway in postmenopausal women. One in women with coronary disease is known as HERS (Heart Estrogen-progestin Replacement Study) and another in predominantly healthy women is the WHI (Women's Health Initiative). Several mechanisms of estrogen mediated protection from cardiovascular disease have been identified including increased HDL, lower LDL, lower VLDL-cholesterol/triglyceride ratio, increased clearance of intermediate density lipoprotein (IDL) and LDL via an upregulated LDL receptor, diminished penetration and degradation of LDL in the arterial wall, an inhibition of LDL oxidation by various estrogens and a reversal of inappropriate acetylcholine (EDRF)-mediated vasoconstriction in arteriosclerotic vessels. The predominating mechanism is not known, but estrogen replacement therapy is both likely to be beneficial to female health, pending randomized trials, as well as a tool to understand mechanisms of prevention of coronary artery disease. PMID- 7857392 TI - Difficulty finding and removing a Norplant system capsule. PMID- 7857393 TI - Keloid formation from levonorgestrel implant (Norplant System) insertion. AB - It is possible that women of certain ethnic backgrounds, specifically those more prone to keloid formation, are also more prone to the insertion site complications of levonorgesterel implants. Failure to recognize the potential for this complication and to provide adequate guidance to the patient could result in unwarranted cost and complications. It is possible that intralesional steroid injection at the first sign of a local reaction will minimize the formation of a keloid; however, specific research will need to be done before a change in practice can be recommended. PMID- 7857394 TI - Germ-cell migration. Finding the way to the gonad in Drosophila. AB - Transplantation experiments show that the timing of germ-cell migration in Drosophila embryos is determined by the surrounding somatic tissue. PMID- 7857391 TI - Current diagnosis and management of sinusitis. PMID- 7857395 TI - Replication and transcription. Silence of the ORCs. AB - The origin recognition complex, a multi-protein complex known to bind to replication origins, has now been implicated in transcriptional silencing, providing another link between DNA replication and transcription. PMID- 7857396 TI - T-cell immunity. How gamma delta T cells make a living. AB - New evidence indicates that gamma delta T cells, like alpha beta T cells, provide immunity to infectious diseases; but the two cell types may differ in that MHC molecules may not play a critical role in antigen presentation to most gamma delta T cells. PMID- 7857397 TI - P-glycoprotein. To flip or not to flip? AB - The phenotype of mice homozygous for mutations of the mdr2 gene suggests that the mdr2 protein, which is closely related to the multidrug resistance P glycoprotein, has a role in phospholipid transport. PMID- 7857398 TI - Apoptosis. Breaking the ICE. AB - Structural and functional similarities have been discovered between two mammalian proteins. Bcl-2 ang interleukin 1 beta-converting enzyme, and proteins encoded by nematode cell-death genes. PMID- 7857399 TI - Photosynthesis. Many chlorophylls make light work. AB - The structure of a plant light-harvesting complex at atomic resolution, determined recently by electron crystallography, helps to explain the efficiency and speed of the light-gathering process. PMID- 7857400 TI - Category learning. Learning the general but not the specific. AB - Amnesia patients have a normal ability to learn categories from examples, even though they fail to learn the examples themselves; computational models of brain function suggest how and why. PMID- 7857401 TI - Developmental timekeeping. Marking time with antisense. AB - Post-transcriptional regulation of the heterochronic gene lin-14 by the binding of a natural antisense RNA controls the temporal pattern of larval development in the nematode Caenorhabditis elegans. PMID- 7857402 TI - Multifunctional proteins. Calmodulin clarified. AB - Genetic analysis in yeast is helping to dissect the multiple functions of calmodulin: mutations have been made that uncouple calmodulin from single targets among many. PMID- 7857403 TI - Time-resolved X-ray diffraction studies of myosin head movements in live frog sartorius muscle during isometric and isotonic contractions. AB - Using the facilities at the Daresbury Synchrotron Radiation Source, meridional diffraction patterns of muscles at ca 8 degrees C were recorded with a time resolution of 2 or 4 ms. In isometric contractions tetanic peak tension (P0) is reached in ca 400 ms. Under such conditions, following stimulation from rest, the timing of changes in the major reflections (the 38.2 nm troponin reflection, and the 21.5 and 14.34/14.58 nm myosin reflections) can be explained in terms of four types of time courses: K1, K2, K3 and K4. The onset of K1 occurs immediately after stimulation, but that of K2, K3 and K4 is delayed by a latent period of ca 16 ms. Relative to the end of their own latent periods the half-times for K1, K2, K3 and K4 are 14-16, 16, 32 and 52 ms, respectively. In half-times, K1, K2, K3 lead tension rise by 52, 36 and 20 ms, respectively. K4 parallels the time course of tension rise. From an analysis of the data we conclude that K1 reflects thin filament activation which involves the troponin system; K2 arises from an order disorder transition during which the register between the filaments is lost; K3 is due to the formation of an acto-myosin complex which (at P0) causes 70% or more of the heads to diffract with actin-based periodicities; and K4 is caused by a change in the axial orientation of the myosin heads (relative to thin filament axis) which is estimated to be from 65-70 degrees at rest to ca 90 degrees at P0. Isotonic contraction experiments showed that during shortening under a load of ca 0.27 P0, at least 85% of the heads (relative to those forming an acto-myosin complex at P0) diffract with actin-based periodicities, whilst their axial orientation does not change from that at rest. During shortening under a negligible load, at most 5-10% of the heads (relative to those forming an acto myosin complex at P0) diffract with actin-based periodicities, and their axial orientation also remains the same as that at rest. This suggests that in isometric contractions the change in axial orientation is not the cause of active tension production, but rather the result of it. Analysis of the data reveals that independent of load, the extent of asynchronous axial motions executed by most of the cycling heads is no more than 0.5-0.65 nm greater than at rest.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7857404 TI - Case 5--1994. Cardiac herniation: a severe postoperative complication of intrapericardial pneumonectomy. PMID- 7857405 TI - The punaglandins: 10-chloroprostanoids from the octocoral Telesto riisei. AB - Telesto riisei, an octocoral from Hawaii, produces nineteen highly functionalized prostanoids, the punaglandins, which are characterized by various oxygenation at C-5, -6, -7, and -12, and a 10-chloro-9-cyclopentenone moiety. The absolute stereochemistry of the 10-chloroprostanoids is epimeric to that of the Pacific marine prostanoids without halogen. The punaglandins have shown anti-inflammatory and antitumor activity. A synthetic 10-thiomethyl derivative enhances in vivo mineralization in human osteoblasts. PMID- 7857406 TI - Some haemorheological factors and transcutaneous PO2 in patients with a peripheral arterial occlusive disease after treatment with naftidrofuryl. AB - The aim of the present study was to investigate the influence of long term intravenous administration of naftidrofuryl (Dusodril-Lipha Arzn) twice daily in a dose of 200 mg in continuous, 4-hour infusion in 500 ml 0.9% NaCl to the patients suffering from a peripheral arterial occlusive disease (PAOD) in a clinical condition with special attention paid to transcutaneous partial oxygen pressure measurements (tcPO2) and rheographic parameters. Also the effect of treatment with naftidrofuryl on the platelet adhesion to the bovine extracellular matrix, the leukocyte adhesion to nylon fibres, and the number of platelet leukocyte aggregates has been studied. We have found that after the naftidrofuryl treatment tcPO2 significantly increased from 38.5 +/- 0.8 mm Hg to 54.6 +/- 11.5 mm Hg, and the impedance plethysmography indexes, such as the height of the rheographic wave, the area of the rheographic wave and the rheographic index were also slightly increased. The leukocyte adherence to nylon fibres, the platelet adhesion to the extracellular matrix and the total number of platelet-leukocyte aggregates were significantly reduced after the treatment with Dusodril. On the basis of this study it seems that the observed influence of naftidrofuryl on leukocyte function in patients with PAOD is an additional mode of action of this drug that can be of new clinical value in the treatment of patients with a peripheral occlusive arterial disease. It seems that tcPO2 measurements in ischaemic legs can be recommended as a very sensitive method of monitoring the efficacy of vasoactive drugs in patients with PAOD. PMID- 7857407 TI - Patients' perceptions of the quality of informed consent for common medical procedures. PMID- 7857410 TI - [Consultation in pathology. The pathologist's view point]. PMID- 7857408 TI - Authenticity and autonomy in the managed-care era: forensic psychiatric perspectives. PMID- 7857409 TI - Blinded prospective evaluation of sensitivity of MR angiography to known intracranial aneurysms: importance of aneurysm size. AB - PURPOSE: To determine the sensitivity of time-of-flight and phase-contrast MR angiography for the detection of intracranial aneurysms. METHODS: Sixteen patients with 27 intracranial aneurysms previously identified with conventional angiography and 19 control patients were examined with three-dimensional time-of flight, three-dimensional phase-contrast MR angiography, and standard MR imaging. Subvolumes of the carotid and posterior circulations, source images, and standard MR images were blindly interpreted by three experienced neuroradiologists. RESULTS: Detection of an aneurysm by a given sequence was defined as at least two of the three blinded readers identifying the aneurysm. The sensitivities of the sequences based on all 27 aneurysms were: transaxial T1, 25.9%; T2, 48.1%; PC, 44.4%; and TF, 55.6%. Two of 3 aneurysms detected with T2 but not MR angiography had adjacent blood products. Five millimeters appeared to be a critical size; the sensitivities for aneurysms greater than or equal to 5 mm were: T1, 37.5%; T2, 62.5%; PC, 75%; and TF, 87.5%. CONCLUSIONS: Three-dimensional time-of-flight MR with 512 x 256 matrix is more sensitive than three-dimensional phase-contrast or standard MR imaging for detection of aneurysms. Retrospectively, aneurysms 3 mm or larger can be identified with MR angiography; however, prospectively, 5 mm is the critical size for detection. PMID- 7857411 TI - [Oncogenes and lymphoma]. PMID- 7857412 TI - [Malignancy markers in the cytodiagnosis of thyroid nodules. Thyroid peroxidase]. AB - The enzyme thyroid-peroxidase (TPO) possesses in thyroid malignancy an immunological alteration disclosed by an anti-TPO monoclonal antibody termed MoAb47: a negative immunostaining with MoAb47 thus represent a marker of malignancy for thyroid tumors. The present work has been intended to investigate the ability of TPO immunodetection to assist the diagnosis of malignancy in fine needle aspirates (FNA) of thyroid nodules. The study concerns 300 patients with histologically proven thyroid nodules. The results of TPO immunodetection have been compared to the final histological diagnosis and in 279 cases, to the results of standard cytological analysis. From 248 benign nodules, 215 yielded more than 80% positive cells. All malignant nodules had less than 80% positive cells and most of them less than 40%. According to these results, with 80% positive cells as the threshold between benign and suspicious or malignant results, the sensitivity of the method for the screening of malignancy is 100%, its specificity 86.7% and its overall accuracy 89%. PMID- 7857413 TI - [Association of Castleman's disease and Hodgkin's disease. Eight cases and review of the literature]. AB - We have recorded 8 patients presenting a Hodgkin's disease associated with Castleman's disease. Four men and 4 women with a 44 years mean age (15-60), presented as a solitary mass (2/7) or as a multicentric tumoral disease (5/7). One of our patients was HIV. Histological studies showed typical features of Castleman's disease. Nodular sclerosing Hodgkin's disease with numerous lacunar cells were present in 3 cases, interfollicular Hodgkin's disease in 4 cases and nodular paragranuloma in one case. Hodgkins' and Reed Sternberg cells were positive for CD15 (4/7), CD30 (5/7), EMA (3/6) and LMP-1 (4/5). In situ hybridization on tissue sections demonstrate presence of EBV DNA in one case and EBER1-RNA in 2 of 4 cases. The difficulty in making the diagnosis of Hodgkin's disease the relation between both diseases, and the role of IL-6 are discussed. PMID- 7857414 TI - [Cellular (juvenile) fibroadenoma of the breast. A clinico-pathologic and immunohistochemical study of 7 cases]. AB - A review of 82 fibroadenomas, collected over a period of 18 years, from female patients aged below 20 years, revealed 7 cases of cellular (juvenile) variant. The tumors are solitary, with an average diameter of 4 cm, these are characterized by a rich cellular stroma and a prominent glandular epithelium. Cellular fibroadenomas often pose to the pathologist serious problems of differential diagnosis, especially with phyllodes tumors. The patient's age together with the histological criteria that we have underlined should make the diagnosis more obvious. As the cellular fibroadenoma is seen essentially during adolescence, surgeons have tendency to preserve the maximum amount of breast tissue. The 2 cases in which we have observed recurrences were seen after incomplete resection of the primary tumor. Therefore, we are of the opinion that a security zone of mammary parenchyma is mandatory. PMID- 7857416 TI - [Granular cell tumor of the gingiva in the newborn. Report of a case in Martinique]. AB - The authors report a case of a gingival granular cell tumor, also called "congenital epulis", occurring in a female newborn. It is a rare congenital, benign tumor of uncertain histogenesis, with marked predilection for female newborn. The tumor arises, as a polypoid mass, on the gingiva of the anterior maxillary or mandibular alveolar ridge. Typical histologic features are represented by sheets of large cells with pale granular cytoplasm. Despite remarkable similarities between gingival granular cell tumors and others ubiquitous granular cell tumors (granular cell myoblastoma or Abrikossoff's tumor), histogenesis of the gingival granular cell tumors seems different. Unlike those of granular cell myoblastoma, granular cells of gingival granular cell tumor do not express S-100 protein and Neuron-Specific-Enolase. Considering the positivity for oestrogen and progesterone receptors, a hormonal factor may be important in the development of gingival granular cell tumor. The generally accepted treatment is simple excision. PMID- 7857415 TI - [An immunohistochemical and ultrastructural study of granular cell tumor of the neurohypophysis]. AB - We describe the histopathological examination of a granular cell tumor of the neurohypophysis (GCTN). The immunohistochemical study revealed a focal positivity for GFAP within rare neoplastic cells. The electron microscopy study characterised two types of cells: some contained spindles of intermediate filaments and a few granules in their cytoplasm whereas others cells only contained granules. These findings are compatible with the astrocytic origin of the GCTN, which have been suggested by many authors but never proved up to day. PMID- 7857418 TI - [Primary carcinoid tumor of the kidney associated with cystic malformation of the kidney]. AB - We report a case of primary renal carcinoid tumor associated with kidney malformation. The carcinoid tumor contained cells which stained with anti chromogranin, anti-serotonin and anti-somatostatin antibodies. The carcinoid tumor was developed on a cystic malformation with transitional epithelium. Immunohistochemical studies revealed positive chromogranin and serotonin cells within the epithelium. The 21 other cases of primary renal carcinoid were reviewed with a particular emphasis on the 2 other cases associated with renal lesions containing endocrine cells. These 3 cases could help to explain the development of primary renal carcinoid tumor. PMID- 7857419 TI - [Latent forms of parathyroid cysts. Report of two cases]. AB - The authors report two cases of non functional parathyroid cyst both found by a systematic clinical examination in two women of 56 and 67 years. In the first case, the cyst was associated to a thyroid dystrophy; the other patient had a history of thyroid dystrophy but also of pituitary prolactin adenoma. PMID- 7857420 TI - [Iatrogenic glaucoma]. PMID- 7857417 TI - [Breast metastasis from an ovarian adenocarcinoma]. AB - We report the case of a 74 year-old woman who presented nodules of the breast 3 years after the diagnosis of a papillary adenocarcinoma of the ovary. The diagnosis of breast metastasis from the ovary was made by histologic examination. PMID- 7857421 TI - [Coexistence in the same lobe of the thyroid of a macrofollicular papillary carcinoma and a medullary micro-carcinoma]. PMID- 7857422 TI - [Small intestinal tumors with skenoid fibers and von Recklinghausen neurofibromatosis]. PMID- 7857423 TI - [Pulmonary involvement in the course of infection by human immunodeficiency virus]. PMID- 7857424 TI - [Histologic classification of soft tissue tumors (WHO, 1994)]. PMID- 7857425 TI - Prevalence of prematurity, low birthweight, and asphyxia as perinatal risk factors in a current population of children with cerebral palsy. AB - To test the hypothesis that increasing survival of infants at highest risk for long-term neurological sequelae has strengthened the associations between perinatal events and subsequent cerebral palsy (CP), we compared the prevalence rates for prematurity, low birthweight, congenital malformations, and perinatal asphyxia from a current population of children with CP with those reported nearly 30 years ago by the National Collaborative Perinatal Project (NCPP, 1959-1966) of the National Institute of Neurologic and Communicative Disorders and Stroke. Although we saw no differences in the proportion of children who were born prematurely, we did find a significant shift in the birthweight and gestational age distribution, with a nearly threefold greater prevalence of births less than 1501 g in our population (31.1% and 95% confidence interval [CI] of 20.6 to 41.7% vs 9.1% and 95% CI of 5.0 to 13.2%). Nearly half (43.5%) of these very low birthweight infants had evidence of brain injury (intraventricular hemorrhage), a diagnosis not commonly recognized in the NCPP. On the other hand, birth asphyxia and congenital malformations occurred no more frequently in our population than that reported earlier. Furthermore, the majority (60%) of full-term infants who develop CP continue to be the products of normal pregnancies and have no perinatal events that may have caused their neurological impairment. The increasing prevalence of births less than 1501 g among children with CP may well reflect the improving survival of very small infants over the last 30 years.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7857426 TI - Acute effects of synthetic surfactant replacement on pulmonary blood flow in neonatal respiratory distress syndrome. AB - To assess the acute effects of surfactant replacement therapy on the pulmonary blood flow in neonatal respiratory distress syndrome (RDS), 23 distressed infants were studied before and for 1 hour after either synthetic surfactant instillation (n = 13) or endotracheal suctioning (n = 10). Doppler ultrasound was used to measure blood flow velocity and flow velocity integral, representing volumetric flow, of the left pulmonary artery branch, ductal left-to-right shunt, and ascending aorta. Surfactant instillation increased the left pulmonary artery and ductal shunt flow velocity and flow velocity integral for 1 hour in 10 of 13 treated infants, whereas no change was found after endotracheal suctioning. There was a significant (P < 0.05) correlation between the changes in the pulmonary artery and ductal flow values at 1 hour after surfactant treatment. The mean increase during 1 hour after treatment in the pulmonary artery flow ranged from 15 to 25% and in the ductal left-to-right shunt from 28 to 33%. No change in the aortic flow or heart rate was found in either group. Our results thus suggest that synthetic surfactant therapy may acutely increase pulmonary blood flow and ductal left-to-right shunting in infants with RDS. PMID- 7857427 TI - Recurrent miscarriage. AB - The perinatologists are emerging as the physicians who evaluate and treat women with recurrent pregnancy loss. Recurrent miscarriage, previously referred to as habitual abortion, affects almost 1% of couples. The etiologies of recurrent miscarriage are diverse and may be divided into genetic defects, such as chromosomal anomalies; maternal reproductive anatomic disease, both developmental and acquired, such as septate uterus or cervical incompetence; and systemic maternal disease such as antiphospholipid antibody syndrome or maternal diabetes. A cause for recurrent miscarriage can be identified approximately 60% of the time. We emphasize the tremendous psychological impact of recurrent miscarriage. We contrast any proposed treatments with the empiric fact that with no treatment after recurrent losses, couples still have a 60 to 70% chance of delivering a viable infant. PMID- 7857428 TI - Clinical significance of human parvovirus B19 infection in pregnancy. AB - We present a case of human parvovirus B19 infection in a term pregnancy that resulted in rapid development of hydrops fetalis and death. Clinical aspects of this virus in pregnancy and therapeutic options are discussed. PMID- 7857429 TI - Blunted fetal response to vibroacoustic stimulation associated with maternal intravenous magnesium sulfate therapy. AB - Maternal intravenous magnesium sulfate (MgSO4) therapy has been associated with decreased fetal heart rate (FHR) variability and reactivity, resulting in an increased incidence of nonreactive nonstress tests, frequently requiring further assessment of fetal well-being. This study was designed to assess fetal response to vibroacoustic stimulation in association with maternal intravenous MgSO4 therapy. Five gravidas with singleton gestations with normal fetal anatomy, intact membranes, and normal amniotic fluid volume at 31 weeks or more presenting with preterm labor were included. Vibroacoustic stimulation was performed prior to and during subsequent intravenous MgSO4 therapy so that each fetus served as its own control. Ultrasound was applied during vibroacoustic stimulation to assess fetal movement response. Response to vibroacoustic stimulation was considered normal if a FHR acceleration of at least 15 beats/min for at least 15 seconds occurred within 15 seconds after the stimulation with prolonged fetal movements. Maternal serum magnesium levels were obtained prior to each stimulation. All fetal responses prior to treatment were normal. All subsequent fetal responses in association with intravenous MgSO4 were abnormal, consisting of blunted FHR accelerations of 10 to 15 beats/min and ranging between 10 and 15 seconds in duration associated with brief limited fetal movements. Mean maternal serum magnesium levels (+/- standard error) during vibroacoustic stimulation, prior to and following intravenous MgSO4, were 1.4 +/- 0.1 and 5.2 +/- 0.4 mEq/L, respectively (P = 0.008). All 5-minute Apgar scores were 8 or higher. This occurrence may reflect an effect of magnesium on the fetus as either a central nervous system depressant or alternatively as a peripheral neuromuscular relaxant.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7857430 TI - Accurate gestational dating: revisited. AB - Using first trimester fetal crown-rump length (CRL) measurements as the criterion for gestational dating, rather than menstrual history or neonatal gestational age evaluation after birth, may be a more accurate way of evaluating the accuracy of second or third trimester ultrasonic measurements for gestational age estimation. This hypothesis was tested using two study groups to evaluate the accuracy of second or third trimester ultrasound measurements for the estimation of gestational age. Three hundred twenty normal obstetric patients who had first trimester CRL measurements were evaluated in the first study. Stepwise multiple regression analysis was used to determine the best combination of multiple ultrasonic parameters for calculation of gestational age, using each patient's CRL as his or her own control. The best formula derived from the first set of patients was used in a second set of 138 high-risk patients to determine the accuracy of multiple ultrasonic parameters obtained during the second or third trimester to date gestation accurately. The analysis confirmed the accuracy of multiple ultrasonic parameters for gestational dating and indicated that the use of two parameters (head circumference and femur length) was as accurate as the traditional four-parameter technique. PMID- 7857431 TI - Cysticercosis as a cause of seizure disorder in pregnancy: case report and review of literature. AB - Neurocysticercosis has become a very important cause of first time convulsions in pregnant patients. It should be considered in the differential diagnosis of seizure at the time of presentation. Patients may be initially controlled on anticonvulsive medications. If they are not controlled on antiepileptic drugs alone, praziquantel should be considered during pregnancy despite limited data because a clear decrease is seen in the number of neurocysticerci in the brain and improvement in seizure disorder has been demonstrated with anticysticidal treatment. If seizures are well controlled, antihelminthic treatment can be withheld until postpartum. PMID- 7857432 TI - Reherniation and pseudoreherniation of a congenital diaphragmatic hernia. AB - The differential in growth is apparent between lobes within the lung as well as between the two lungs. Any catch-up has clearly not corrected the hypoplasia present at birth. In addition, the small size and distorted shape as well as the abnormal proportions between the trachea and between the two main bronchi point to further functional irregularities based on structural distortion. PMID- 7857433 TI - Preterm premature rupture of membranes: experience with latent periods in excess of seven days. AB - The purpose of this study was to review the maternal and neonatal outcomes of patients with preterm premature rupture of membranes (PPROM) with a latency period greater than 7 days. Using the perinatal database, there were 11,007 deliveries in a 25-month period, in which 81 patients (0.7%) with singleton pregnancies were admitted with documented PPROM between 20 and 30 weeks' gestation. Twenty-one patients (26%) remained undelivered after 1 week, and 19 of these patients were discharged to outpatient care. Twelve patients (57%) delivered at term and nine patients (43%) delivered prematurely. In the preterm group all reported increased leaking prior to delivery and all neonates had 5 minute Apgar scores higher than 7. Length of stay in the neonatal intensive care unit for all the preterm neonates ranged from 12 to 117 days. The majority of patients with PPROM will deliver within 1 week, but there is a subset of patients with PPROM (one of every seven), characterized by the absence of labor or infection, who may be managed as outpatients and delivered at term. PMID- 7857434 TI - Prenatal diagnosis, clinical significance and management of fetal intracranial teratoma: a case report and literature review. AB - We report the prenatal ultrasonographic diagnosis of a massive intracranial teratoma in a 32-week breech intrauterine pregnancy associated with polyhydramnios and enlarged fetal head circumference. Ultrasound appearance, clinical significance, and how the prenatal diagnosis affects management and prognosis for both mother and fetus are discussed. PMID- 7857435 TI - Risk of thrombocytopenia in the infants of mothers with idiopathic thrombocytopenia. AB - Twenty-nine of 27,662 pregnant women had autoimmune thrombocytopenia at the time of delivery at King Khalid University Hospital over 6 years starting June 1986. Twenty-six had idiopathic thrombocytopenic purpura (ITP), gave birth to 33 infants, of which 22 were by spontaneous vaginal delivery, eight by lower segment cesarean section, and two by forceps. Fourteen (44%) of the 32 living infants had platelets less than 150 x 10(9)/L and four (12.5%) had severe thrombocytopenia (platelets less than 50 x 10(9)/L). The mothers' platelets of less than 50 x 10(9)/L at delivery were found to be predictive of thrombocytopenia in their infants (P < 0.027), compared with mothers' platelet of more than 50 x 10(9)/L. Maternal treatment with prednisone did not seem to have significant effect on infants' platelets (P < 0.89). All infants with severe thrombocytopenia (less than 50 x 10(9)/L) at birth had ultrasound done and were found to be normal. We conclude that: (1) steroid given to pregnant women with ITP does not increase infants' platelet counts, (2) severe thrombocytopenia in the mothers (platelet counts less than 50 x 10(9)/L) is highly predictive of thrombocytopenia in their infants; (3) cesarean section should be limited to the mother with severe thrombocytopenia if fetal scalp platelets are less than 50 x 10(9)/L. PMID- 7857436 TI - Erythropoietin umbilical serum levels during labor in women with preeclampsia, diabetes, and preterm labor. AB - In this study we determine the erythropoietin levels and hematocrit in 22 women with preterm labor, 21 with insulin-dependent diabetes, 22 with preeclampsia, and 20 with normal gestation. The erythropoietin level was higher in the preeclamptic group than in the diabetic group compared with the normal and premature groups. There were no hypoxic fetuses. From this study, we found that the mechanism of increased erythropoietin levels in neonates can be different from fetal hypoxia. Further studies are needed on this subject. PMID- 7857437 TI - Reversal of fetal distress following intensive treatment of maternal diabetic ketoacidosis. AB - Diabetic ketoacidosis during pregnancy is frequently associated with fetal distress that may result in fetal death in utero. A patient at 33 weeks of pregnancy with diabetic ketoacidosis and evidence of fetal distress is presented. Following intensive medical treatment, maternal metabolic state improved along with improvement of fetal heart rate tracing. A healthy infant was delivered by cesarean section at 36 weeks of gestation. PMID- 7857440 TI - Nonimmune hydrops fetalis secondary to premature closure of the foramen ovale. AB - Premature closure of the foramen ovale is a rare cardiac anomaly. Severe right sided heart failure accounts for the hepatomegaly, ascites, pleural and pericardial effusions, and generalized edema of these hydropic fetuses. Premature closure of the foramen ovale should be a part of the differential diagnosis when unexplained fetal hydrops is encountered. PMID- 7857438 TI - Pulmonary interstitial emphysema treated by selective bronchial obstruction and high-frequency oscillatory ventilation. AB - A 30-week preterm infant ventilated for respiratory distress syndrome developed severe right-sided pulmonary interstitial emphysema, pneumomediastinum, and subcutaneous emphysema involving the neck. Selective bronchial obstruction and high-frequency oscillatory ventilation showed dramatic improvement in the clinical and radiographic condition of the infant. PMID- 7857439 TI - Intracervical prostaglandin E2 for induction of labor in patients with premature rupture of membranes and an unripe cervix. AB - The efficacy and safety of intracervical prostaglandin E2 (PGE2) gel for induction of labor in patients with premature rupture of the membranes (PROM) at term and with an unripe cervix were evaluated. Fifty-two patients who did not start labor 6 to 12 hours after PROM and who had an unripe cervix were randomized to one of two management protocols. Patients randomized to PGE2 received a single intracervical application of 0.5 mg PGE2. Patients randomized to the conservative protocol were managed expectantly for 24 hours. If labor was not established 6 hours after randomization in patients receiving PGE2 or 24 hours after PROM in patients managed expectantly, labor was induced with intravenous oxytocin. Of the patients receiving PGE2, 93% began labor after a single application, and the mean interval between prostaglandin application and delivery was 6.6 hours. In the conservative group, only 57% began labor within 24 hours, and more than half of them required augmentation with oxytocin. The mean latency between PROM and delivery was 15 hours in patients managed with PGE2 and 30 hours in patients managed conservatively (P < 0.01). There were no complications and pregnancy outcome was similar in the two groups. Intracervical PGE2 is safe and effective for inducing labor in patients with PROM and an unfavorable cervix. PMID- 7857442 TI - Electronic fetal monitoring in the United States. PMID- 7857441 TI - Electronic fetal heart rate monitoring during labor: information from randomized trials. PMID- 7857443 TI - Electronic fetal monitoring in the United Kingdom. PMID- 7857444 TI - Clinical issues in electronic fetal monitoring. PMID- 7857445 TI - Identifying newborn babies who test positive for the human immunodeficiency virus. PMID- 7857446 TI - Information related to the Maternal and Child Health Bureau (MCHB), Health Resources and Services Administration, and the United States government contained in your editorial on the Baby Friendly Hospital Initiative. PMID- 7857447 TI - United States Baby Friendly Hospital Initiative feasibility study. PMID- 7857448 TI - The issue of breastfeeding promotion. PMID- 7857450 TI - Health status and timing of onset of prenatal care: is there an association among low-income women? AB - We examined medical obstetric conditions predating pregnancy and current symptoms as predictors of the timing of the start of prenatal care among low-income women in Snohomish County, Washington. The investigation was a cross-sectional survey with retrospective record review. Subjects were 473 women who sought care through the community health center network, which was the only provider of prenatal care for low-income women in the county at the time of the study. Women with a history of two or more medical or obstetric conditions were more likely than those without such histories to seek prenatal care early in pregnancy. Women who, in the current pregnancy, had few physical symptoms were more likely to delay seeking prenatal care than symptomatic women. Among this relatively homogeneous group, sociodemographic characteristics were not associated with the timing of entry into prenatal care. The findings help to explain the patterns of prenatal care use of certain groups, and suggest avenues for intervention to improve use among low-income women. PMID- 7857449 TI - Controversies in maternity care: where do physicians, nurses, and midwives stand? AB - Through a mail survey in 1991, we compared the opinions of 597 physicians practicing obstetrics, 723 maternity care nurses, and 70 midwives from the province of Quebec, Canada, about selected maternity care issues, including the practice of midwifery. Results showed that divergent points of view existed between and within the three groups on many maternity care issues. Physicians were more divided over the routine use of obstetric intervention than the approach to care or their opinion about midwives. Midwives held more client centered and less interventionist attitudes than nurses or physicians. Nurses were much more open to midwives than physicians, but 20 to 30 percent of physicians saw some advantages in legalizing the practice of midwifery. Physicians and nurses generally considered midwives as a greater professional threat to the other group than to themselves. The fact that many physicians were critical of current maternity care is difficult to reconcile with their general opposition to midwives. How and to what extent physicians will respond to women's desire for more humanized and less interventionist care remains an open question. Given the problems facing maternity care in North America, expanding midwifery services is an alternative to examine seriously. PMID- 7857451 TI - What makes a mother? Interviews with women involved in egg donation and surrogacy. AB - In recent years it has become possible to use eggs from one woman to bring about a pregnancy in another. This led to new definitions of who can be considered the mother of a child. Despite much speculation about the problems that may ensue from this situation, it is not at all clear that the women who have made the active decision to involve themselves in egg donation or gestational surrogacy will share these concerns. This paper reports on the interpretive frameworks used by 13 women who experienced either egg donation or gestational surrogacy, to define their relationships to any children (actual or potential) conceived as a result of their actions. PMID- 7857453 TI - Breastfeeding preterm twins: a case report. AB - This case report describes a primipara who successfully breastfed 35-week gestation twins for over six months. Positive interactions, research-based management strategies, and innovative problem solving helped her avoid the individual, interpersonal, and system factors that can influence lactation failure. PMID- 7857454 TI - Risk in pregnancy: the reality, the perception, and the concept. PMID- 7857452 TI - Exercise and pregnancy: a review. AB - The effects of pregnancy on the maternal cardiorespiratory system include increases in oxygen consumption, cardiac output, heart rate, stroke volume, and plasma volume. The increase in oxygen reserve seen in early pregnancy is reduced later, suggesting that maternal exercise may present a greater physiologic stress in the third trimester. Evidence suggests that weight-bearing exercise produces a greater decrease in oxygen reserve than nonweight-bearing exercise. Furthermore, to maintain a heart rate below 140 beats per minute during pregnancy, the intensity of weight-bearing exercise must be reduced. Nonweight-bearing, water based exercise results in smaller fetal heart rate changes and a lower maternal heart rate than the same exercise performed on land. Exercising in the supine position in late pregnancy has raised concerns because cardiac output in the supine position is lower than in the lateral position at rest, presumably because the gravid uterus partially obstructs the inferior vena cava. Sustained exercise produces a training effect on the mother, although reported associations between this effect and the experience of labor are not consistent. Short-term changes in fetal heart rate provide circumstantial evidence that physical activity can influence the fetus. Acute effects of exercise that can potentially affect the fetus include hyperthermia, changes in uteroplacental flow, reduced levels of maternal glucose, and increased uterine contractions. Moderate to high levels of sustained maternal exercise have been associated with reduced birthweight. Much research remains to be done on the effects of specific exercise regimens during pregnancy, the effects on previously sedentary women, and the long-term health consequences to the offspring of women who perform vigorous exercise during pregnancy. PMID- 7857456 TI - Licensed midwife-attended, out-of-hospital births in Washington state: are they safe? AB - The safety of out-of-hospital births attended by midwives who are licensed according to international standards has not been established in the United States. To address this issue, outcomes of births attended out of hospital by licensed midwives in Washington state were compared with those attended by physicians and certified nurse-midwives in hospital and certified nurse-midwives out of hospital between 1981 and 1990. Outcomes measured included low birthweight, low five-minute Apgar scores, and neonatal and postneonatal mortality. Associations between attendant and outcomes were measured using odds ratios to estimate relative risks. Multivariate analysis using logistic regression controlled for confounding variables. Overall, births attended by licensed midwives out of hospital had a significantly lower risk for low birthweight than those attended in hospital by certified nurse-midwives, but no significant differences were found between licensed midwives and any of the comparison groups on any other outcomes measured. When the analysis was limited to low-risk women, certified nurse-midwives were no more likely to deliver low birthweight infants than were licensed midwives, but births attended by physicians had a higher risk of low birthweight. The results of this study indicate that in Washington state the practice of licensed nonnurse-midwives, whose training meets standards set by international professional organizations, may be as safe as that of physicians in hospital and certified nurse-midwives in and out of hospital. PMID- 7857455 TI - The psychological effects of counting fetal movements. AB - By identifying a change in fetal activity state, fetal movement counting may help to reduce the possibility of stillbirth. Concern has arisen that such a focus on fetal activity may cause undue maternal anxiety. A prospective, controlled trial was conducted to determine whether fetal movement counting induced anxiety or other deleterious psychological effects in low-risk primigravidas. A sample of 613 healthy pregnant women was randomly assigned at 28 weeks' gestation to fetal movement counting, sleep recording, or a nonrecording control group. State and trait of anxiety, belief in sources of personal control, and attitudes toward pregnancy and infant were assessed at 28 and 37 weeks' gestation. Participation rates were high (91.4%) across all groups. Most women (90%) assigned to count fetal movements did so on a daily basis (95% of days). No significant changes in psychological status occurred in the three groups as a result of self-monitoring conditions. Independent of group assignment, all women showed a slight increase in transient state and decrease in trait of anxiety from 28 to 37 weeks. Internal locus of control and positive attitudes toward the infant increased slightly, and feelings of well-being decreased slightly for all women. It was concluded that women are willing to record fetal activity, and that fetal movement counting does not cause deleterious psychological effects in low-risk pregnant women. PMID- 7857457 TI - Postpartum depression: how much do obstetric nurses and obstetricians know? AB - Postpartum depression affects 10 to 15 percent of all mothers. A study of 725 obstetric nurses and 204 obstetricians was conducted using a reliable two-factor scale to measure their knowledge and awareness of postpartum depression. Nurses were more aware than physicians of the emotional impact of postpartum depression. Nurses who demonstrated more empathy and who believed education of postpartum depression does not increase a mother's risk were more aware of the postpartum phenomenon than nurses who were less empathic and who did not hold the same belief. Younger and women physicians recognized the psychosocial antecedents to postpartum depression to a greater degree than did older and men physicians. These findings offer potential use in the training of perinatal health care professionals and in the education of pregnant women about postpartum depression. PMID- 7857458 TI - Smoking among low-income, pregnant women: prevalence rates, cessation interventions, and clinical implications. AB - Smoking has a significant effect on the major causes of death and disability among women, including coronary heart disease, stroke, cancer, and osteoporosis. When pregnant women smoke, it adversely affects not only them but also the health, development, and functioning of their unborn and young children. Of the general population of pregnant women, between 20 and 45 percent smoke. Furthermore, among low-income and less educated pregnant women, the increase in prevalence of postpartum smoking relapse rates, continued smoking, and initiation of smoking underlies the need for developing effective interventions for prevention and cessation. Although self-help, stop-smoking materials demonstrated success in several trials, interventions used in conjunction with these materials were brief with little follow-up, and did not address the need for continued intervention to help maintain abstinence or cessation after birth. This article reviews the smoking cessation trials that have assessed the effects of various interventions on cessation rates among low-income pregnant women, and describes future research needs for clinic-based smoking interventions for those women and the clinical implications for health professionals. PMID- 7857460 TI - Sheila Kitzinger's letter from England: prison babies. PMID- 7857459 TI - A time to be born: implications of animal studies in maternal-fetal medicine. AB - Recent studies on the capabilities of the fetus in the last third of gestation demonstrated that the fetus actively prepares for its journey to the extrauterine environment. The most remarkable of these preparations is that the fetal brain gives the signal to begin the birth process. Several studies, particularly those conducted in sheep, showed that endocrine signals from the fetal brain are sent to the placenta to stimulate increased estrogen production. The increased estrogen production initiates uterine contractility, and starts the labor process. The mother's oxytocin production also plays a role by determining the precise time of the day that the baby is born. These studies produced fascinating insights into fetal and uterine physiology that have already begun to be employed in clinical care. One primary example in the application of this new knowledge obtained originally from studies on fetal sheep is in understanding the endocrine regulation of fetal production of surfactant to treat women in preterm labor and to produce artificial surfactants for the treatment of babies delivered too early. It is important to obtain and use reproducible data gained from carefully controlled animal experiments to rationalize clinical management practices. Basic research should precede changes in clinical management, rather than follow them, as is so often the case. PMID- 7857461 TI - Transmission of the human immunodeficiency virus (HIV) by artificial insemination. PMID- 7857462 TI - "Crisis in primary care: will midwives meet the challenge?". PMID- 7857463 TI - "Infant formula distribution and advertising in pregnancy: a hospital survey". PMID- 7857464 TI - Family physicians and maternity care: high tech or high touch? PMID- 7857465 TI - Cesarean section rates in teaching hospitals: a national survey. AB - This survey investigated the cesarean section rate in teaching hospitals in the United States and the factors that may influence it. A national survey was performed by mailing a questionnaire to 277 accredited residency programs in obstetrics and gynecology. The estimated cesarean rate in all hospitals with residencies in obstetrics and gynecology in the United States in 1990 was 20.3 percent, compared with an overall national rate of 23.5 percent. Women delivering in teaching hospitals were less likely to have a cesarean section than those delivering in hospitals without residency programs (odds ratio = 0.77, 95% CI 0.77-0.78, p = 0.0001). As centers for training and research, teaching hospitals represent an appropriate setting to begin the process of lowering the United States cesarean section rate. PMID- 7857466 TI - A comparison of outcomes between joint and physician-only obstetric practices. AB - Since 1981, the cesarean birth rate of a joint practice has been consistently lower than that of physician-only practices at a private community hospital in Yolo County, California. This study sought to determine whether differences in perinatal outcomes were influenced by women's use of a joint versus a physician only practice or were associated with parity, maternal age, or newborn birthweight. Data from the hospital's 1634 consecutive singleton births in 1990 were examined, using a prospective concurrent analytic cohort study design. Chi square statistics and stepwise logistic regressions were used for data analysis. The joint practice had a significantly lower rate of total cesarean births (9.3%) compared with the physician-only practices (17.7%); the frequencies of severe lacerations were 1.0 percent and 6.4 percent, respectively. No significant differences were found in parity, birthweight, or newborn outcomes in the two types of practice. Type of practice was the major determinant of cesarean birth (p < 0.0001). All variables studied, including type of practice, were significant determinants of primary cesarean birth. Parity and practice type were significant determinants of third- and fourth-degree lacerations (p < 0.0001). The type of practice from which women receive care is significantly associated with both method of birth and possibility of severe perineal trauma. PMID- 7857467 TI - Women's experiences with breastfeeding longer than 12 months. AB - This prospective, longitudinal study was conducted to describe the experiences of 82 primiparas who breastfed longer than 12 months. They were compared with 541 primiparas who weaned their infants within the first year. Greater age, education, and weeks of exclusive breastfeeding were associated with longer duration of breastfeeding. More than two-thirds (68%) of the women who breastfed longer than one year returned to employment before their infant was 1 year old. The most frequently chosen reason for long-term breastfeeding was that breastfeeding was a special time for mother and baby that the mother was not ready to give up. Nearly half of the women reported breastfeeding their babies on demand. At 12 to 15 months, 54 percent of the babies slept in a crib in a separate room, and 37 percent slept in the same bed with their mother all or part of the night. Most mothers (57%) considered their support group to be slightly or moderately important in influencing their decision to breastfeed beyond a year, and 10 percent considered it to be extremely important. The major themes that emerged from women's comments were the importance of being strong in the face of social unacceptability, development of a close mother-child bond, and the naturalness of breastfeeding beyond 12 months. Health caregivers should recognize the emotional and interpersonal aspects of long-term breastfeeding, support the breastfeeding relationship, and avoid contributing to the development of "closet nursers" so that women may feel free to discuss their concerns about their child's health. PMID- 7857468 TI - Labor experiences of childhood sexual abuse survivors. AB - This field study used the ethnographic method to describe and analyze the labor experiences of childhood sexual abuse survivors. The sample included seven sexual abuse survivors, five nurse-midwives, and three labor and delivery nurses. Data collection included in-depth interviews, participant observation in labor and delivery over a period of six years, and anecdotal material from the literature. Analysis followed Spradley's Developmental Research Sequence and included domain, taxonomic, componential and theme analysis. Women reported both forgetting and remembering abusive incidents, and described labor sensations reminiscent of sexual abuse. A heuristic for appraising labor styles suggestive of past sexual abuse includes fighting, taking control, surrendering, and retreating. These styles are considered extremes of women's reactions to labor and are directly linked to posttraumatic stress disorder. This study demonstrated that it is important for perinatal caregivers to understand the link between childhood sexual abuse and childbirth so that they can assist women to have a positive birth experience. PMID- 7857469 TI - Female genital mutilation: perspectives from a Somalian midwife. PMID- 7857470 TI - Miscarriage: a historical perspective. AB - Ancient cultures have applied a variety of fascinating therapies to prevent the occurrence and reoccurrence of miscarriage. Ceremonies of ritual purification, special prayers, and a variety of medicinal therapies were employed throughout the ages to prevent this feared event. Rituals to memorialize and help mourn the lost pregnancy were developed in many cultures. These rituals reinforce how deeply men and women are affected by early pregnancy loss. PMID- 7857471 TI - The controversy over AIDS testing of newborns. PMID- 7857472 TI - Electronic monitoring: who needs a trojan horse? PMID- 7857473 TI - The published randomized controlled trial (RCT) of fetal heart rate monitoring by Vintzileos et al. PMID- 7857474 TI - Home care for chronic obstructive pulmonary disease: impact of the Iqaluit program. AB - The Iqaluit home care program, which began in February 1987, has a five year history. Data about hospitalization of five elderly persons with chronic obstructive pulmonary disease (COPD) are available for the five years before and the five years after the program. Data for some of these years are available for four other COPD clients who joined the program in 1987 and for seven others who joined the program after its inception. The health histories of these sixteen people presented an excellent opportunity to demonstrate the effects of Home Care programs in the Northwest Territories. Home care in Iqaluit was evaluated by interviews with clients and care givers, by analyzing the trend in admission to hospital and hospitalization days for each client. The study showed that home care 1) improved health and reduced the economic impact of COPD by reducing the average number of days in hospital for each episode of hospitalization; 2) allowed clients with COPD to experience a better quality of life than they would if in hospital or institutional long term care; 3) allowed people to live in their homes, with their families, taking part in their usual age and role appropriate cultural activities, language and daily life. PMID- 7857475 TI - Growth patterns of Labrador Inuit youth: II. Skeletal age. AB - Few studies have been conducted on skeletal maturity of circumpolar populations despite its importance as background knowledge to orthopedic and orthodontic procedures or for other medical problems involving endocrine disturbances. The purpose of this study was to compare skeletal age with chronological age of Labrador Inuit youth aged between 5-18 years and to compare these results with data from a national survey of United States youth. The sample included 32% (n = 100) of the Inuit youth living in Nain, Labrador, Canada (Male = 41, female = 59). Hand wrist radiographs, collected during a field study in 1991, were used to estimate bone age using the Greulich and Pyle bone specific method. The mean relative Inuit skeletal ages increased almost consistently with chronological age but showed considerable individual variation as shown by the 95% confidence intervals. The pattern of growth of skeletal vs chronological age was similar to the National Center for Health Statistics data but the tempo was slower. The Z scores for mean male relative bone ages ranged from -0.7 to -1.9 and for females from -0.6 to -1.4. The results indicated that Inuit males started to reach adult skeletal maturity levels by the chronological age of 17 years 9 months, and Inuit females by 15 years 8 months. Generally, Inuit skeletal ages were delayed by 10 24 months behind the reference atlas skeletal ages and 9-22 months behind the Inuit chronological ages.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7857476 TI - Ectopic pregnancies in Greenland 1981-1990 verified by histology. AB - From 1981 to 1990 503 cases of ectopic pregnancy (EP) among Greenlandic females were confirmed by histologic examination. The yearly number more than tripled from 26 in 1981 to 89 in 1990. When correction for age distribution and the total number of conceptions were made the increase in incidence rates for the population age 15-44 as a whole, was statistically significant. The rate of EP/100,000 females increased from 223 in 1981 to 581 in 1990 (slope 34/yr, p < 0.01, degrees of freedom 8, t = 4.996). EP/100 pregnancies increased from 2.08 in 1981 to 4.51 in 1990 (slope 0.22/yr., p < 0.01, degrees of freedom 8, t = 4.784). However, we did not find a significant increase in rates for females aged 15-24 years. Possible etiological factors behind the high and increasing incidence are discussed. The incidence rates of ectopic pregnancy in Greenland found in this study are among the highest ever reported. PMID- 7857477 TI - Snowmobile injuries in Kiruna, northern Sweden. AB - Snowmobile injury events in Kiruna, northern Sweden, have been studied over a 3 year period. The area is large and fairly isolated with centrally located health facilities which provides a study population that reflects the actual incidence of injury events in the area. It is also a region with an extremely frequent use of snowmobiles. A series of 109 persons injured in snowmobiling crashes were analysed. The number of injury events per registered vehicles was 5/1000. There were 88 males and 21 females with the peak injury frequency in the age group 20 29 years. Six persons were under the age of 16. Most of the patients were drivers and the most common accident mechanism was falling off the machine and sudden stops. The total number of injuries were 1.1/patient. The lower extremities were the most commonly injured sites (32%). In 26% of the cases there were non-minor injuries. Nineteen patients needed in-patient care with a mean duration of hospital stay of 5.7 days. We also report four fatalities that occurred during the time of the study. PMID- 7857478 TI - Would a helmet law for snowmobile riders reduce head injuries? AB - Swedish authorities have discussed making the use of helmets for snowmobile riders compulsory. To evaluate the possible injury-reducing potential of such a law, 245 non-fatally injured riders and 104 fatalities were analyzed. Non-minor (AIS > 1) head injuries were far less common than in motorcycling, and many fast driving young snowmobile riders seem to use helmets regardless of a law. The persons with head injuries who had not used helmets, or whose helmet use was unknown, had violated other laws, most often the Traffic Temperance Law, or the law forbidding driving on public roads. A helmet law for snowmobile riders will probably not increase the helmet use in this group and consequently have a negligible injury-reducing effect. Helmets are, however, strongly recommended, especially for riders who favour fast driving. PMID- 7857479 TI - "Which sweater to choose in the cold: knitted or fleece". AB - The aim of the present study was to investigate the influence of two common wool sweaters in a clothing ensemble on sweat production, sweat accumulation and sweat distribution in the clothing ensemble, as well as on other thermoregulatory responses together with comfort of man. A further aim was to investigate the influence of the two different sweaters on the temperature and the humidity gradient through the clothing ensemble in order to describe the different avenues and forms of heat exchange. Thick woolen middle layer sweaters manufactured in two different constructions, fleece and knitted, were tested as part of a 3-layer clothing system. The test was performed on eight male subjects (Ta = 10 degrees C, RH = 85%, Va < 0.1 m/s), and comprised a twice repeated bout of 40-min cycle exercise followed by 20 min rest. Skin temperatures, rectal temperature, weight loss and humidity near the skin and in the clothing layers were recorded during the test. Total changes in body and clothing weight were measured separately. Furthermore, subjective ratings on thermal comfort and on sensation of temperature and humidity were collected. The results demonstrated that there were no significant physiological and subjective differences when the two sweaters were worn, apart from higher sweat production and accumulation when the knitted sweater was used. It is assumed that this is a result of a larger thickness rather than different construction. Choosing the knitted sweater or the fleece wool sweater for work in an ambient temperature of 10 degrees C will be of minimal significance in practice. However, a sweater with more sweat accumulated will be heavier and this reduces the air layer between the garments, decreasing the clothing ensemble's insulation value. PMID- 7857480 TI - [Withdrawal of life-sustaining means]. PMID- 7857482 TI - Resting energy expenditure in children after major surgery. AB - Resting energy expenditure (REE) is reported to increase by 24% in adults following elective operations. We studied REE in 12 children after major surgery to check if they had a similar response. REE was measured by indirect calorimetry. All subjects (6 males, 6 females; age range 6 to 12 years) were measured supine in bed, and after overnight fast. REE was expressed as kilocalories per unit body surface area (BSA) per day. In addition, respiratory quotient (RQ) was calculated for each patient. Contrary to adults, these children did not demonstrate a significant increase in REE following major operative procedures. Furthermore, there was no change in RQ postoperatively. These data demonstrate that children might have a different response to surgical stress than adults. We believe that children are able to convert energy expended on growth to energy spent on wound repair and healing, thus avoiding the overall increase in energy expenditure seen in the adult population. PMID- 7857481 TI - Genitourinary tuberculosis: the importance of early diagnosis and management. Case presentation. AB - Genitourinary tuberculosis is the second most common form of extrathoracic tuberculosis. The most common signs are persistent sterile pyuria in up to 90% of patients, irritative voiding symptoms and painless hematuria in up to 80% of the patients. In Puerto Rico the incidence of tuberculosis is rising, being 9.2 per 100000 population in 1992. A.I.D.S. has had a steady rise since 1983. With the rise in the incidence of both diseases and with the influx immigrants from countries were tuberculosis is endemic we should expect a rise in the number of cases of genitourinary tuberculosis. Chemotherapy is the mainstay of treatment. Surgery is performed less often. Early recognition and management is important to avoid irreversible damage to the genitourinary tract. The cases of a 43 y/o man and a 30 y/o male with A.I.D.S. are discussed. PMID- 7857483 TI - [Infections of penile prosthesis: treatment and prevention]. AB - To date, there are 10,000,000 men with impotence in the United States and it is estimated that at least 17,000 penile prosthesis are implanted annually. The most fearsome complication is the infection of the prosthesis which is usually caused by Staphylococcus epidermidis (in 40-80% of the cases). In general, the incidence of infection is actually 0.8-8.3%, but it can increase to 37% in patients with tertiary implants. The initial empiric treatment is usually with vancomycin and aminoglycosides and prophylaxis is recommended with a penicillinase-resistant synthetic penicillins, first generation cephalosporins, or vancomycin in case of penicillin allergy. PMID- 7857484 TI - [A proposal: the humanized physician and medical ethics]. PMID- 7857485 TI - [Letter on abortion]. PMID- 7857486 TI - Orientation in road traffic. Age-related differences using an in-vehicle navigation system and a conventional map. AB - Forty-eight drivers of different ages (35-50 years old, 61 years and older) took part in our study, which tested a marketable navigation system (TRAVELPILOT IDS). Driving and navigation performance, as well as mental workload and the acceptance of innovative technology, were investigated. A limited range of findings will be presented in this paper. The results show that older and middle-aged drivers differ in only a few aspects. Both age groups reveal comparable results in driving. However, regarding the operation of the navigation system and concerning its effectiveness, older drivers performed worse. Age-related differences being rather small, analyses revealed significant global differences between the navigation system and a common road map: usage of the TRAVELPILOT influenced driving behavior negatively with respect to traffic safety. Also, the drivers' orientation was not any better using the navigation system. Based on this experimental work and on results derived from the literature, conclusions are drawn regarding future navigation systems in general and with respect to needs of elderly drivers. PMID- 7857487 TI - Head-up displays and their automotive application: an overview of human factors issues affecting safety. AB - In response to the recent innovations to use head-up displays (HUDs) in vehicles, this paper discusses the relevant human factors issues arising from this display format and the potential safety implications. A review is made of the relevant HUD literature, primarily from the aviation field. The primary issues for automotive HUDs relevant to system performance and safety in the driving task involve interference from background scene complexity, system novelty, user perceptual style, cognitive disruption, and perceptual tunnelling. Basic research is necessary to investigate the extent of these issues as well as to resolve fundamental design specifications (e.g. HUD size, shape, placement, information content). It is suggested that the introduction of HUDs into vehicles be carefully considered. This will necessitate not only the reconsideration what constitutes an in-vehicle display, but also what constitutes the information to be conveyed. PMID- 7857488 TI - The external costs of traffic injury: definition, estimation, and possibilities for internalization. AB - The external costs of traffic injury in Norway are estimated. External costs are all costs that are imposed on others and not borne by the person whose activity generates the costs. Three types of external cost are identified: system externalities, physical injury externalities, and traffic volume externalities. System externalities are costs that road users impose on the rest of society. Physical injury externalities are costs that one group of road users impose on the rest of society. Physical injury externalities are costs that one group of road users imposes upon another in crashes in which both groups are involved. Traffic volume externalities are the costs imposed on other road users when an additional road user joins traffic. System externalities are estimated to be about 30% of the total cost of traffic injury. Physical injury externalities are estimated to be about 10% of the total cost of traffic injury. No precise estimate can be given for traffic volume externalities. Possibilities for internalizing the external costs are discussed. In Norway, current taxes on ownership and use of motor vehicles cover the external costs of traffic injury, although the taxes were not designed with this purpose in mind. PMID- 7857489 TI - Models of driving behavior: a review of their evolution. AB - This paper reviews models that emphasize the cognitive components of driving behavior. Studies of individual differences have sought predictors of accident histories. Typically low correlations and reliance on post hoc explanations reflect theoretical deficiencies and problems with the use of accident measures. Motivational models emphasize transient, situation-specific factors rather than stable, individual predictors. However, neither testable hypotheses nor suitable methods have been developed to study situational factors and motives that influence driving. More recent models have incorporated a hierarchical control structure, which assumes concurrent activity at strategic, maneuvering, and operational levels of control. At the same time, automaticity has emerged as a central construct in cognitive psychology. All activities are assumed to combine fast, automatic components with slower, more deliberate, controlled processing. It is argued that identifying the situational factors that increase drivers' uncertainty and thus trigger a shift in attention from automatic to controlled processing will help integrate concepts of automaticity and motivational models. Finally, recent theorizing has suggested that errors associated with the inherent variability of human behavior may be more important to roadway crash causation than systematic errors, which are attributable to the known limits of the human information-processing system. Drivers' abilities to recover from errors may also be important to crash causation. It is concluded that the hierarchical control structure and theories of automaticity and errors provide the potential tools for defining alternative criterion measures, such as safety margins, and developing testable theories of driving behavior and crash causation. Two examples of models that integrate information-processing mechanisms within a motivational framework are described. PMID- 7857490 TI - An experimental study to evaluate the effectiveness of different methods and intensities of law enforcement on driving speed on motorways. AB - Two field experiments were conducted to establish the most effective method of enforcement in reducing driving speed and to establish the most efficient strategy in terms of police force personnel required. In the first experiment, the effect of three variables on driving speed on motorways was studied. The first variable, intensity of enforcement, was manipulated by creating three different objective levels of apprehension for detected speeding drivers. The second variable was method of enforcement. On-view stopping and ticketing of offenders was compared to mailing of fines on the basis of the car's licence plate number. The third variable manipulated was the time delay in the mailing of fines. Time delay between detection of the offence and feedback to the driver was shortened in one condition. In a second experiment, police enforcement effort was optimized by relating intensity level of enforcement to the proportion of speeding vehicles. In the first experiment, police enforcement was applied for four weeks; in the second experiment, enforcement activities were continued for 12 consecutive weeks. In both cases the main dependent variable was driving speed. Before, during, and after the application of enforcement, speed was registered using induction loops. In addition, driver opinion about speeding and speed enforcement was studied using postal questionnaire surveys. The results show the largest and longest lasting reduction in driving speed in the highest intensity level-condition, giving support for a relation between objective chance of apprehension and speed choice. On-view stopping of offenders was shown to be a more effective method to reduce driving speed than mailing of fines. Some of these results are discussed in the light of game theory. The questionnaire surveys indicated that most drivers did not notice the recurrence in enforcement activities due to infrequent passing of the sections of motorways studied. The preventive effect of police enforcement appeared to be far more substantial than its repressive effect. Enforcement primarily deters the current nonoffender from speeding. PMID- 7857491 TI - Mechanisms of brain injury related to mathematical modelling and epidemiological data. AB - Measurements of the frequency response of head impact points on the exterior and the interior of a car were used to characterize the dynamic behavior of the object that was struck. These points were then arranged in a hierarchy of increasing stiffness. Thirty-two cases in which the distribution of injury to the brain had been recorded were grouped according to the stiffness of the object struck and by the location of the impact on the head. The distribution of the brain lesions were determined for each class of stiffness and location of impact. Three probable mechanisms of brain injury were distinguished: relative motion between the brain and the skull, local bone deformation, and intracerebral stresses. Each mechanism was related to a range of stiffness and natural frequency of the structure impacted. These theories of brain injury mechanisms are consistent with observed epidemiological data and with conclusions drawn from mathematical modelling. PMID- 7857492 TI - Measuring the safety effect of road measures at junctions. AB - The effects of road measures implemented at main road junctions in 1984-1986 were studied on the basis of police-reported accidents that had occurred at the junctions in 1983-1987. The data were obtained from an extensive junction inventory performed by the District Offices of the Finnish National Road Administration in 1988. A total of 325 three-arm and 298 four-arm junctions were included in the study. The number and type of accidents were studied at each junction both before and after the implementation of the measure. The effects of the measure were determined by comparing the observed number of accidents after the measure with the number that would have been expected to occur at the junction if the measure had not been implemented. The expected number of accidents was calculated on the basis of the observed number of accidents in the before period and the expected number of accidents as predicted by an accident model, utilizing at the same time the information on the variation of the number of accidents at similar junctions revealed by the model. Likelihood functions determined for the effects of the measures were used for studying the accuracy of the estimates of the effects. The likelihood functions can also be utilized later when new before-and-after studies are performed. Road lighting, stop signs, signal control, and lowering of the speed limit value were found to decrease the number of accidents. Through-flow junction widenings, additional lanes for turning vehicles, and road widenings, however, did not seem to affect the safety at junctions to any marked extent. If we had not accounted for the regression-to the-mean effect, these measures would have seemed to have a positive effect on safety. The study method also enabled us to quantify the regression-to-the-mean effect. The magnitude of the regression effect was on average 20%, i.e. the number of accidents would have decreased by 20% at the junctions studied even if the measures had not been implemented. The magnitude of the regression-to-the mean varied greatly between the different measures. PMID- 7857493 TI - Evaluation and replication of impact damage to bicycle helmets. AB - A group of 72 impacted bicycle helmets were collected, primarily from manufacturers with a crash replacement policy that encourages the return of damaged helmets. Each damaged helmet was thoroughly inspected and measured to determine the construction details and collision damage. Laboratory replication tests were then performed on selected samples using exemplar helmets to determine impact velocity and peak headform aceleration. The predominant impact location was the front left quarter and the replication studies indicate that the majority of impacts took place on flat surfaces from drop heights of 1 meter or less. Overall, it is evident that a large number of bicycle helmet users who have benefited from the use of a bicycle helmet, and future bicycle helmet standards must incorporate the protective requirements of this unique group. PMID- 7857494 TI - Seat-belt legislation and risk homeostasis: further analysis of the British data. AB - It has been suggested that seat-belt legislation may result in drivers' feeling overprotected and their consequent riskier driving may lead to more injuries to other road users (the risk homeostasis or compensation theory). We have examined data in Britain before and after legislation made seat-belt use compulsory for front-seat occupants of specified vehicles. The relative numbers of injuries to cyclists and pedestrians in collisions with vehicles requiring and not requiring seat-belt use were compared, using a log-linear analysis taking into account possible confounding variables. It was not possible directly to incorporate vehicle distance travelled for the two categories of vehicle. However, a simple adjustment for differential vehicle use accounted for most of an apparent effect. The revised odds ratio (for mandated seat-belt use vehicles versus nonmandated, post- versus prelegislation) was 1.04 for cyclists and 1.06 for pedestrians, showing minimal, if any, evidence for the theory. PMID- 7857495 TI - Driver experience with antilock brake systems. AB - Antilock brakes provide the capability for shorter stopping distances and the ability to steer and maintain control during hard braking, especially on wet and slippery surfaces. Owners of late model cars equipped with antilock brakes were surveyed in North Carolina and Wisconsin regarding their experiences with antilocks. The survey results indicated that more than 50% of the drivers in North Carolina and 40% in Wisconsin incorrectly indicated how to brake a car in an emergency situations on wet and slippery pavements in a way that will effectively activate the antilock feature. More drivers in Wisconsin than in North Carolina reported that their cars' antilock feature had been used, but more than 33% of the Wisconsin drivers and 62% of North Carolina drivers said they had never used the antilock feature of their cars' brakes. PMID- 7857496 TI - The seat belt syndrome in children. AB - Lap belts, fitted to the centre seats of Australian cars for the past 22 years, have come under criticism as being injurious to children. The weight of evidence is that lap belts provide substantial protection, though less than three-point belts. A specific injury, the seat belt syndrome (SBS), to abdominal viscera and/or lumbar spine has been particularly associated with lap belts, an association confirmed by a hospital-based study in Melbourne. Roadside observations of belt use and Transport Accident Commission claims permitted the calculation of the incidence of SBS and the relative risks of SBS by seated position. The centre rear seat (lap belt) carried about twice the risk of SBS as outboard rear seats (three-point belts), which in turn have 2.7 times the risk of the outboard front seat. The number of SBS cases in Victoria has increased with penetration of the car fleet by 1971 and later cars. Suggestions are made for improvements in the restraint system. PMID- 7857497 TI - Prenatal nutritional deprivation as a risk factor in schizophrenia: preclinical evidence. AB - We will review evidence from preclinical literature that prenatal nutritional deprivation produces neurochemical, morphological, and electrophysiological effects reminiscent of those seen in clinical studies of schizophrenia. We will focus on effects of nutritional deficiency that are likely to have implications for schizophrenia. These include disruption of neurotransmitter systems such as dopamine and serotonin and dysgenesis of the hippocampal formation. Preclinical studies show enhanced release and turnover of dopamine and serotonin following prenatal and early postnatal nutritional deficiency. Morphology of the hippocampus, as well as electrophysiology and hippocampally-mediated behaviors are also altered. Although intriguing, these studies have not been conducted with schizophrenia in mind, and thus, outcome measures that may be more specifically related to schizophrenia have not been examined. We propose that further preclinical studies that examine the consequences of prenatal nutritional deficiency, which may lead to altered neuronal migration and other developmental abnormalities, may be useful in understanding the etiology of schizophrenia. PMID- 7857498 TI - Dynamics of slow-wave activity and spindle frequency activity in the human sleep EEG: effect of midazolam and zopiclone. AB - Electroencephalographic slow-wave activity (SWA; power density in the 0.75 to 4.5 Hz band) and spindle frequency activity (SFA; 11.25 to 15.0 Hz) exhibit a typical time course and a distinct mutual relationship during sleep. Because benzodiazepines (BDZ) suppress SWA and enhance SFA, we investigated the effect of two BDZ-receptor agonists on the dynamics of these EEG parameters. A single dose of midazolam (15 mg), zopiclone (7.5 mg), or placebo was administered before bedtime to healthy young men. Although the two drugs reduced SWA and enhanced SFA, their time course across and within sleep cycles as well as their mutual relationship were little affected. The results constitute further evidence that hypnotics acting as BDZ-receptor agonists do not substantially interfere with the homeostatic aspect of sleep regulation. PMID- 7857499 TI - Special section from the XIXth Collegium Internationale Neuro Psychopharmacologiucum (CINP) Congress. Washington, D.C., June 27-July 1, 1994. Abstracts. PMID- 7857500 TI - Hypericum treatment of mild depressions with somatic symptoms. AB - In a randomized, placebo-controlled, double-blind study, 39 patients with depression with somatic symptoms were treated with hypericum extract LI 160. The therapy lasted for 4 weeks; the dosage was 300 mg three times daily. At the onset of the study as well as after 2 and 4 weeks, the following criteria were analyzed: HAMD, B-L, CGI, and vegetative symptoms. The results show a significant improvement in the active treatment group at the 5% level as compared to placebo. Seventy percent of the patients treated with LI 160 were free of symptoms after 4 weeks. Typical symptoms of the depression such as lack of activity, tiredness, fatigue, and disturbed sleep, were especially responsive. In no case were any undesirable side effects observed. PMID- 7857501 TI - Multicenter double-blind study examining the antidepressant effectiveness of the hypericum extract LI 160. AB - Seventy-two depressive patients of 11 physicians' practices were treated in a double-blind study for a period of 6 weeks either with hypericum extract LI 160 or with placebo. Inclusion criterion was a major depression in accordance with DSM-III-R. The changes were assessed using four psychometric scales (HAMD, D-S, BEB, CGI). After 4 weeks of therapy, the statistical evaluation revealed a significant improvement in all four psychometric tests in the active group as compared to the placebo group. After switching the placebo group to active treatment (5th to 6th week of therapy), significant improvements were found in the original placebo group. No serious side effects were observed. PMID- 7857502 TI - Effectiveness and tolerance of the hypericum extract LI 160 in comparison with imipramine: randomized double-blind study with 135 outpatients. AB - In a double-blind comparative study, 135 depressed patients were treated in 20 centers. Inclusion diagnoses were typical depressions with single episode (296.2), several episodes (296.3), depressive neurosis (300.4), and adjustment disorder with depressed mood (309.0) in accordance with DSM-III-R. The dosage was 3 x 300 mg hypericum extract LI 160 or 3 x 25 mg imipramine daily. The treatment lasted for 6 weeks. Main assessment criteria were the Hamilton Depression Scale (HAMD), the Depression Scale according to von Zerssen (D-S) and the Clinical Global Impressions (CGI). In both treatment groups, a parallel reduction of the Hamilton score from 20.2 to 8.8 (LI 160, n = 67) or from 19.4 to 10.7 (imipramine, n = 68), and the transformed D-S point values from 39.6 to 27.2 (LI 160) and 39.0 to 29.2 (imipramine) were found. The analysis of CGI revealed comparable results in both treatment groups. Clinically relevant changes of the safety parameters were not found. In the LI 160 group fewer and milder side effects were found as compared to imipramine. PMID- 7857503 TI - Effectiveness and tolerance of the hypericum extract LI 160 compared to maprotiline: a multicenter double-blind study. AB - A randomized, double-blind study examining the effectiveness and tolerance of a standardized hypericum preparation when compared to maprotiline was performed in a group of 102 patients with depression, in accordance with ICD-10, F 32.1. The study was conducted in the offices of neurology and psychiatry specialists. The patients received, over a period of 4 weeks, either 3 x 300 mg of the hypericum extract or 3 x 25 mg maprotiline pills of identical appearance. Effectiveness was determined using the Hamilton Depression Scale (HAMD), the Depression Scale according to von Zerssen (D-S), and the Clinical Global Impression Scale (CGI). The total score of the HAMD scale dropped during the 4 weeks of therapy in both treatment groups by about 50%. The mean values of the D-S scale and the CGI scale showed similar results, and after 4 weeks of therapy, no significant differences in either treatment group were noticed. The onset of the effects occurred up to the second week of treatment, but were observed earlier with maprotiline than with the hypericum extract. On the other hand, maprotiline treatment resulted in more cases of tiredness, mouth dryness, and heart complaints. PMID- 7857504 TI - Hypericum in the treatment of seasonal affective disorders. AB - Seasonal affective disorder (SAD) represents a subgroup of major depression with a regular occurrence of symptoms in autumn/winter and full remission in spring/summer. Light therapy (LT) has become the standard treatment of this type of depression. Apart from this, pharmacotherapy with antidepressants also seems to provide an improvement of SAD symptoms. The aim of this controlled, single blind study was to evaluate if hypericum, a plant extract, could be beneficial in treating SAD patients and whether the combination with LT would be additionally advantageous. Patients who fulfilled DSM-III-R criteria for major depression with seasonal pattern were randomized in a 4-week treatment study with 900 mg of hypericum per day combined with either bright (3000 lux, n = 10) or dim (< 300 lux, n = 10) light condition. Light therapy was applied for 2 hours daily. We found a significant (MANOVA, P < .001) reduction of the Hamilton Depression Scale score in both groups but no significant difference between the two groups. Our data suggest that pharmacologic treatment with hypericum may be an efficient therapy in patients with seasonal affective disorder. PMID- 7857505 TI - Treatment of depression. AB - Depressions are the most common psychiatric diseases. For treatment, plant extracts have been used for thousands of years: examples are extracts from the (sleeping) poppy (opium), deadly nightshade (Atropa belladonna), Indian hemp (hashish), henbane (hyoscyamine), thorn apple (scopolamine), and St. John's wort (hypericum oil). In addition, psychotherapeutic measures, like playing music, dancing, playing theatre, and also the temple sleep, were used. In the 19th century, the introduction of brome (1826), codeine (1832), chloral hydrate (1869), and paraldehyde (1882), as well as the barbiturates (at the turn of the century) introduced significant improvements in pharmacotherapy. The modern thymoleptica therapy started in 1957 with the introduction of imipramine. Now about 40 active antidepressants are marketed. New drug developments should be characterized mainly by an improvement in tolerance. PMID- 7857506 TI - Benefits and risks of the hypericum extract LI 160: drug monitoring study with 3250 patients. AB - Effectiveness and acceptance of a 4-week treatment with hypericum extract LI 160 were investigated by 663 private practitioners. The results of the 3250 patients (76% women and 24% men), were recorded using data sheets. The age of the patients ranged from 20 to 90 years (mean 51 years). Of the patients, 49% were mildly depressed, 46% intermediate, and 3% severely depressed. In about 30% of the patients, the situation normalized or improved during the therapy. Undesired drug effects were reported in 79 (2.4%) patients and 48 (1.5%) discontinued the therapy. Most frequently noted side effects were gastrointestinal irritations (0.6%), allergic reactions (0.5%), tiredness (0.4%), and restlessness (0.3%). PMID- 7857507 TI - Effects of hypericum extract on the sleep EEG in older volunteers. AB - The effects of treatment with high doses (300 mg three times daily) of hypericum extract LI 160 on sleep quality and well-being were investigated over a 4-week period. The double-blind, placebo-controlled study was conducted with 12 older, healthy volunteers in a cross-over design, which included a 2-week wash-out phase between both treatment phases. A hypostatic influence of the REM sleep phases, which is typical for tricyclic antidepressants and MAO inhibitors, could not be shown for this phytopharmacon. Instead, LI 160 induced an increase of deep sleep during the total sleeping period. This could be shown consistently in the visual analysis of the sleeping phases 3 and 4, as well as in the automatic analysis of slow-wave EEG activities. The continuity of sleep was not improved by LI 160; this was also the case for the onset of the sleep, the intermittent wake-up phases, and total sleep duration. PMID- 7857508 TI - Effects of hypericum extract LI 160 compared with maprotiline on resting EEG and evoked potentials in 24 volunteers. AB - In a randomized double-blind study, the effect of hypericum extract was compared to that of maprotiline in 24 healthy volunteers. The investigations included measurements of resting EEG as well as visual and acoustic evoked potentials. In resting EEGs, both medications revealed oppositely directed changes in the theta frequencies, and mainly similarly directed changes in alpha and beta frequencies. Measurements of evoked potentials in the theta and beta frequencies supported these results. The results indicate improved cognitive functions mainly with the treatment of hypericum extract. PMID- 7857509 TI - Pharmacokinetics of hypericin and pseudohypericin after oral intake of the hypericum perforatum extract LI 160 in healthy volunteers. AB - The single- and multiple-dose pharmacokinetics of the naphthodianthrones hypericin and pseudohypericin derived from St. John's wort (Hypericum perforatum, LI 160, Lichtwer Pharma GmbH, Berlin) were studied in 12 healthy male subjects. After a single oral dose of 300, 900, or 1800 mg of dried hypericum extract (250, 750, or 1500 micrograms hypericin and 526, 1578, or 3156 micrograms pseudohypericin), plasma levels were measured with a modified highly sensitive high-pressure liquid chromatography (HPLC) method (lower detection limit 0.1 ng/mL) up to 3 days. The median maximal plasma levels were 1.5, 4.1, and 14.2 ng/mL for hypericin and 2.7, 11.7, and 30.6 ng/mL for pseudohypericin, respectively, for the three doses given above (interim evaluation of four volunteers). The median elimination half-life times of hypericin were 24.8 to 26.5 hours, and varied for pseudohypericin from 16.3 to 36.0 hours. Ranging between 2.0 to 2.6 hours, the median lag-time of absorption was remarkably prolonged for hypericin when compared to pseudohypericin (0.3 to 1.1 hours). The areas under the curves (AUC) showed a nonlinear increase with raising dose; this effect was statistically significant for hypericin. During long-term dosing (3 x 300 mg/day), a steady-state was reached after 4 days. Mean maximal plasma level during the steady-state treatment was 8.5 ng/mL for hypericin and 5.8 ng/mL for pseudohypericin, while mean trough levels were 5.3 ng/mL for hypericin and 3.7 ng/mL for pseudohypericin. In spite of their structural similarities there are substantial pharmacokinetic differences between hypericin and pseudohypericin. PMID- 7857510 TI - Inhibition of MAO and COMT by hypericum extracts and hypericin. AB - The influence of hypericin, hypericum total extract, and hypericum fractions on the activity of MAO and COMT, prepared in vitro from pork liver, were investigated in several concentration steps. An inhibition of MAO could be shown in the following concentrations (extract correlated to a mean molecular value of 500): hypericin to 10(-3) mol/L, hypericum total extract to 10(-4) mol/L, one extract fraction up to 10(-5). A COMT inhibition could not be shown for hypericin, with hypericum extract to 10(-4) mol/L and with two extract fractions also up to 10(-4) mol/L. The MAO inhibiting fraction contained hypericins as well as flavonols, the COMT-inhibition fraction being mainly flavonols and xanthones. The concentrations of inhibition shown might not be sufficient to explain the clinically proven antidepressive effect of hypericum particularly with regard to the inhibition of MAO activity. PMID- 7857511 TI - Inhibition of MAO by fractions and constituents of hypericum extract. AB - The inhibition of monoamine oxidase (MAO) by six fractions from hypericum extract and three characteristic constituents (as pure substances) were analyzed in vitro and ex vivo to study the antidepressive mechanism of action. Rat brain homogenates were used as the in vitro model, while the ex vivo analysis was performed after intraperitoneal application of the test substances to albino rats. Massive inhibition of MAO-A could be shown with the total extract and all fractions only at the concentration of 10(-3) mol/L. At 10(-4) mol/L, one fraction rich in flavonoides showed an inhibition of 39%, and all other fractions demonstrated less than 25% inhibition. Using pure hypericin as well as in all ex vivo experiments, no relevant inhibiting effects could be shown. From the results it can be concluded that the clinically proven antidepressive effect of hypericum extract cannot be explained in terms of MAO inhibition. PMID- 7857512 TI - Clinical investigation of the antidepressant effectiveness of hypericum. AB - To date, 25 controlled therapy studies have investigated the antidepressive effectiveness of hypericum extracts. A total of 1592 treatment cases have been included. The dosage was typically 300 to 900 mg total extract daily; the therapy duration was 2 to 6 weeks. Fifteen studies were performed comparing hypericum extracts with placebo, 10 studies as comparative studies. This paper presents an overview of their results. PMID- 7857513 TI - Modulation of cytokine expression by hypericum extract. AB - The effect of hypericum extract LI 160 on the stimulated cytokine expression was investigated in vitro in a whole blood culture system. Blood samples were taken from five healthy volunteers and four depressive patients. The release of interleukin-6 (IL-6), interleukin-1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF-alpha) was measured quantitatively after an incubation time of 24 hours on microtiter plates. A massive suppression of the interleukin-6 release was found for PHA-stimulated hypericum extract. Possible relations to the antidepressive effects of hypericum extract are discussed. PMID- 7857514 TI - Effects of hypericum extract on the expression of serotonin receptors. AB - The influence of hypericum extract LI 160 on the expression of serotonin receptors was investigated using a neuroblastoma cell line to establish a model for the regulation of neurotransmitters by immunologically active compounds such as cytokines. The cells were incubated with hypericum extract LI 160 in kinetic form for 2, 4, 6, 8, and 10 hours, then washed. The serotonin receptor expression analysis was compared to that of a placebo control solution. The neuroblastoma cells showed a clearly reduced expression of the serotonin receptors under treatment with hypericum extract. First stimulation experiments with interleukin 1 (IL-1) and hypericum extract suggest that a further reduction of the serotonin receptors is possible when IL-1 is added. PMID- 7857515 TI - Pharmaceutical quality of hypericum extracts. AB - Hypericum extracts contain at least ten constituents or groups of components that may contribute to the pharmacological effects. It is not yet possible to correlate the antidepressive mode of action with specific constituents; therefore, the pharmaceutical quality of the extracts was characterized on the basis of typical leading substances and especially the hypericins. For the analysis and improvement of the production procedure, the content of hypericin and pseudohypericin was measured experimentally. The drug material was extracted with different solvents and the yield was analyzed for each kind of solvent, its concentration and extraction temperature. Optimal yields were obtained with 80% methanol at temperatures of 80 degrees C. PMID- 7857516 TI - Placebo-controlled double-blind study examining the effectiveness of an hypericum preparation in 105 mildly depressed patients. AB - One hundred and five outpatients with mild depressions of short duration were treated in a double-blind study with either 3 x 300 mg hypericum extract or placebo. The therapy phase was 4 weeks. The effectiveness was judged according to the Hamilton Depression Scale after 2 and 4 weeks. The values of the mean basic score in these periods fell from 15.8 to 9.6 or 7.2 in the active group, and in the placebo group, from 15.8 to 12.3 and 11.3. The differences between active and placebo groups were statistically significant with P < .05 and P < .01 achieved after 2 and 4 weeks, respectively. In the active group, 28 of 42 patients (67%) and, in the placebo group, 13 of 47 patients (28%) responded to treatment. Notable side effects were not found. PMID- 7857517 TI - Heat-resistant fungi of importance to the food and beverage industry. AB - Spoilage of pasteurized and canned fruit and fruit products caused by heat resistant molds have been reported repeatedly in recent years. Species most commonly implicated in fruit and fruit product disintegration are Byssochlamys fulva, Byssochlamys nivea, Neosartorya fischeri, Talaromyces flavus, and Eupenicillium brefeldianum. These organisms are saprophytic rather than parasitic and usually contaminate fruits on or near the ground. They can survive heat treatments used for fruit processing and can grow and spoil the products during storage at room temperature, which results in great economic losses. Mold heat resistance is attributed to the formation of sexual spores, ascospores. Ascospores have a wide range of heat resistance, depending on species, strain, age of organism, heating medium, pH, presence of sugars, fats, and acids in heating medium, growth conditions, etc. The mechanism(s) of thermoresistance are not clear; probably some very stable compound(s) critical to germination and outgrowth are present in the heat-resistant ascospores. Besides spoilage, the heat-resistant molds produce a number of toxic secondary metabolites, such as byssotoxin A; byssochlamic acid; the carcinogen, patulin, the tremorgenic substances, fumitremorgin A and C, and verruculogen; fischerin, which caused fatal peritonitis in mice; and eupenifeldin, a compound possessing cytotoxicity as well as in vivo antitumor activity. Growth of heat-resistant fungi can be controlled by lowering the water activity, adding sulfur dioxide, sorbate, or benzoate; washing of fruits in hypochlorite solution before heat treatment reduces the number of ascospores and makes the heat destruction more successful. More research is needed to elucidate the mechanism(s) of thermoresistance and develop new methods for the complete inactivation of resistant ascospores. PMID- 7857518 TI - Microbial degradation of explosives and related compounds. AB - The pollution of soil and water with explosives and related compounds caused by military activities has been known for a long time, but progress in understanding the environmental fate of such substances has only been made in the last few years. Microbial processes could be used for the remediation of explosives contaminated soils and waste waters because it has been shown that a variety of different microorganisms are able to metabolize these chemical compounds. In some cases even a complete mineralization has been found, whereas in others only biotransformation reactions took place, producing more or less toxic and/or recalcitrant metabolites. Studies with pure cultures of bacteria and fungi have given detailed insights into the biodegradation pathways of at least some nitroorganic compounds. Additionally, some of the key enzymes have been isolated and purified or studied in crude extracts. This review summarizes information on the biodegradation and biotransformation pathways of several important explosives. This may be useful in developing microbiological methods for a safe and economic clean-up of soil and water contaminated with such compounds. It also shows the necessity of further investigations concerning the microbial metabolism of these substances. PMID- 7857519 TI - Microbial fatty acids and thermal adaptation. AB - The existing literature on the role of fatty acids in microbial temperature adaptation is reviewed. Several modes of change of cellular fatty acids at varying environmental temperatures are shown to exist in yeasts and fungi, Gram negative bacteria, and bacteria containing iso- and anteiso-branched fatty acids, as well as in a few Gram-positive bacteria. Consequently, the degree of fatty acid unsaturation and cyclization, fatty acid chain length, branching, and cellular fatty acid content increase, decrease, or remain unaltered on lowering the temperature. Moreover, microorganisms seem to be able to change from one mode or alter the cellular fatty acid profile temperature dependently to another on lowering the temperature, as well as even within the same growth temperature range, depending on growth conditions. Therefore, the effect of the temperature on cellular fatty acids appears to be more complicated than known earlier. However, similarities found in the modes of change of cellular fatty acids at varying environmental temperatures in several microorganisms within the above mentioned groups support the existence of a limited amount of common regulatory mechanisms. The models presented enable the prediction of temperature-induced changes occurring in the fatty acids of microorganisms, and enzymatic steps of the fatty acid biosynthesis that possibly are under temperature control. PMID- 7857520 TI - Intragenomic heterogeneity of DNA damage formation and repair: a review of cellular responses to covalent drug DNA interaction. AB - Chemical DNA interaction and its processing can now be studied at the level of specific genomic regions. Such investigations have revealed important new information about the molecular biology of the cellular responses to genomic insult and especially of the repair processes. They also have demonstrated that both the formation and repair of DNA damage display patterns of intragenomic heterogeneity. Therefore, mechanistic studies should involve examination of DNA damage formation and repair in specific genomic sequences besides in the overall genome to provide clues to the way in which specific modifications of DNA or chromatin could have specific biological effects. This review primarily focuses on studies done to elucidate the nature of DNA damage induction and intragenomic processing provoked by covalent drug-DNA modification in mammalian cells. The involvement of DNA damage formation and cellular processing as critical factors for genomic injury is exemplified by studies of the novel alkylating morpholinyl anthracyclines and the bifunctional alkylating agent nitrogen mustard as a prototype agent for covalent drug DNA interaction. PMID- 7857521 TI - The role of mitotic recombination in carcinogenesis. AB - Genetic recombination systems are present in all living cells and viruses and generally contribute to their hosts' flexibility with respect to changing environmental conditions. Recombination systems not only help highly developed organisms to protect themselves from microbial attack via an elaborate immune system, but conversely, recombination systems also enable microorganisms to escape from such an immune system. Recombination enzymes act with a high specificity on DNA sequences that either exhibit extended stretches of homology or contain characteristic signal sequences. However, recombination enzymes may rarely act on incorrect alternative target sequences, which may result in the formation of chromosomal deletions, inversions, translocations, or amplifications of defined DNA regions. This review describes the characteristics of several recombination systems and focuses on the implication of aberrant recombination in carcinogenesis. The consequences of mitotic recombination on the inappropriate activation of protooncogenes and on the loss of tumor suppressor genes is discussed. Cases are reported where mitotic recombination clearly has been associated with carcinogenesis in rodents as well as humans. Several test systems able to detect recombinagenic activities of chemical compounds are described. PMID- 7857522 TI - Toxicology of selected nitric oxide-donating xenobiotics, with particular reference to azide. AB - Nitric oxide (NO) has been discovered recently to be a ubiquitous, endogenous mediator, which is responsible for a variety of normal physiological functions. However, NO also has been implicated in several pathophysiological processes. For example, the pulmonary toxicity of various nitrogen oxides, including NO, found in photochemical smog has been studied for decades; endogenous NO also is associated with bleomycin-induced lung damage, as well as other adverse effects. Recently, a variety of xenobiotics have been shown to owe their biological activity in vivo to their biotransformation to NO. Thus, the therapeutic vasodilatation produced by drugs such as nitroglycerin and sodium nitroprusside is now believed to result from their release of NO, which then mimics the effects of endogenously synthesized NO. The toxic effects of NO prodrugs are, therefore, a matter of concern, especially the extent to which, if any, NO contributes to their toxicity. As reviewed here, NO does not appear to contribute importantly to the toxicity of the NO donors nitrite, hydroxylamine, or nitroprusside. However, it is by no means clear whether or not the NO generated in vivo from sodium azide contributes in a major way to its toxicity. Azide is almost as acutely toxic as cyanide, with which it shares a number of biological effects; yet, azide also has certain cardiovascular actions in common with nitrite. Unlike either cyanide or nitrite, some evidence suggests a tendency for azide to produce low-grade cumulative toxicity. In laboratory animals, azide frequently produces nonasphyxial convulsions, whereas most human deaths appear to be the result of cardiovascular collapse. Neither of these azide-induced syndromes appears to be due to the inhibition of cytochrome c oxidase. Azide is widely used as a preservative in aqueous laboratory reagents and as the propellant in automobile air bags and aircraft escape chutes. Both of these inflable systems are generally safe, and will prevent untold numbers of injuries and deaths. However, to protect workers who handle these devices and others who may come into contact with the sodium azide propellant in these systems, our rudimentary knowledge of azide toxicity needs to be expanded. PMID- 7857523 TI - Self-determinant selection and selective regulation. PMID- 7857524 TI - Idiotypic regulation directed at T-cell receptor determinants. PMID- 7857525 TI - Antigen-specific immunosuppression: oral tolerance for the treatment of autoimmune disease. PMID- 7857526 TI - Treatment of autoimmune disease: to activate or to deactivate? PMID- 7857527 TI - Selective targets for immunotherapy in autoimmune disease. PMID- 7857528 TI - Selective immunosuppression of tumour necrosis factor-alpha in rheumatoid arthritis. PMID- 7857529 TI - MHC blocking peptides and T-cell receptor antagonists: novel paths to selective immunosuppression? PMID- 7857530 TI - Modified T-cell receptor ligands: moving beyond a strict occupancy model for T cell activation by antigen. PMID- 7857531 TI - The neurosurgeon and the foetus. PMID- 7857532 TI - Ruptured intracranial aneurysms--learning from experience. AB - The outcome of treatment of 400 consecutive patients with ruptured intracranial aneurysms was assessed at 1 year. The patients were treated by a single surgeon over a period of 13 years. Data sheets completed as each patient was treated included a contemporary analysis of the reasons for any unsatisfactory outcome. Surgery was usually delayed for over 10 days from the last haemorrhage. Over the four successive 100-patient cohorts, in which the composition of the patient population remained unaltered, 1 year overall management mortality fell steadily from 38 to 24%. One year surgical mortality fell from 19 to 3%. The population of those operated on who were in Glasgow Outcome Score 5 at 1 year rose from 73 to 90% (from 51 to 71% for all patients). Of the 123 deaths, 89 occurred prior to operation, 24 after it. Thirty-five patients died from rebleeding prior to operation, but only eight of these occurred in patients judged fit for surgery at the time. All but one of the postoperative deaths resulted from technical problems related to the surgery. Over the successive cohorts, several factors indicated an improvement in operative efficiency, notably a fall in the proportion of cases with technical problems from 15 to 1%. We have demonstrated a steady improvement in management results, resulting largely from increasing operative experience. We do not believe that changes in overall management strategy, such as early surgery, would have any effect on overall outcome. PMID- 7857533 TI - Advances in image-directed neurosurgery: preliminary experience with the ISG Viewing Wand compared with the Leksell G frame. AB - Because of the limited application of frame-based stereotaxy to general neurosurgical procedures, we have carried out a preliminary evaluation of the ISG Viewing Wand, a frameless image-directed surgical system that is based on the rapid reformat and accurate three-dimensional reconstruction capability of parallel processor-based computer technology. We have compared the first 36 cases carried out with the system in the Frenchay Neurosurgery Department with a retrospective analysis of the previous 36 cases carried out using the Leksell G frame. The stereotactic cases were completed over a period of 15 months, representing 2.8% of intracranial procedures. The wand cases were completed in 3 months, 13% of the intracranial practice during that time. The wand was used for 28 supratentorial craniotomies (76%), four infratentorial procedures (11%) and five biopsy procedures (13%). Conventional stereotaxy was not used for posterior fossa or skull base procedures. Supratentorial craniotomy was carried out in nine cases (25%), while the remaining 27 cases involved point source localization within the cranium (75%). The mean preparation time prior to surgery was 65 min for the stereotactic cases and 37 min for the wand cases. We therefore conclude that the indications for frame-based stereotaxy and Viewing Wand use are mutually exclusive. Leksell stereotaxy remains the method of choice for point source localization deep within the cranium. All other procedures requiring an image directed minimally invasive surgical approach are more appropriately carried out using the Viewing Wand. The system has potential immediate application in supratentorial, skull base and infratentorial tumour surgery, vascular surgery, epilepsy surgery and upper cervical spine surgery. PMID- 7857534 TI - Actinomycotic brain abscess successfully treated by burr hole aspiration and short course antimicrobial therapy. AB - Three cases of brain abscess caused by Actinomyces israelii are reported which were successfully treated by burr hole aspiration and a short course of antibiotics (3-4 weeks). The clinical response of the patients, as well as the serial serum C-reactive protein levels and CT findings were used as a guideline for stopping antimicrobial therapy relatively early. PMID- 7857535 TI - The pathogenesis and fate of traumatic subdural hygroma. AB - We present a series of 61 traumatic subdural hygromas, and discuss the pathogenic mechanisms and natural history of this condition. It commonly occurred in patients over 50 years of age and before 5 years of age. Fifty-two cases (85.2%) were diagnosed 3 days after head injury. Glasgow Coma Score (GCS) on admission was 3-8 in 24 (39.3%), 9-12 in 15 (24.6%) and 13-15 in 22 patients (36.1%). Although three patients (4.9%) showed slow deterioration, most hygromas were clinically 'silent'. Thirty-eight patients (62.3%) were managed conservatively and 23 patients (37.7%) underwent surgery. Only five patients (21.7%) showed gross improvement after surgery, even though surgery was performed only for enlarged hygromas shown by serial computed tomography. In five patients (8.2%), a chronic subdural haematoma subsequently developed from a hygroma. A favourable outcome (good recovery or moderate disability) occurred in 59%, an unfavourable outcome (severe disability and vegetative state) in 28%, and death resulted in 13%. Outcome was closely related to the severity of primary head injury. PMID- 7857536 TI - Endoscopic-guided clipping of cerebral aneurysms. AB - An endoscopic probe has been used intraoperatively to facilitate the obliteration of cerebral aneurysms. This method has been used in 24 patients with 30 arterial aneurysms. There were 13 males and 11 females. They ranged in age from 22 to 73 years (mean age 48 years). The mean time of surgery was 7.3 days after subarachnoid haemorrhage (ranging from 2 to 24 days). In three cases there was intraoperative rupture of the aneurysm and with one patient the operation had to be abandoned because of severe brain oedema. The follow-up ranged from 12 to 48 weeks (average 31.8 weeks). The overall outcome was good in 14 cases (58.3%), eight patients (33.3%) showed moderate disability, severe disability occurred in one patient (4%) and one patient (4%) died. In all cases when the endoscope was used, there was a striking improvement in the visualisation of the anatomy of the aneurysm and surrounding structures. Furthermore, the position of the clip and the state of the vessels leading to and from the aneurysm could be easily examined. PMID- 7857537 TI - Spinal cord stimulation for the treatment of progressive systemic sclerosis and Raynaud's syndrome. AB - Progressive Systemic Scleroderma (PSS) is a generalized disease of connective tissue involving the skin, as well as other internal organs. The cutaneous signs are characterized by a progressive sclerosis and loss of function or dexterity in the hands. Between 1987 and 1992, 15 patients affected by scleroderma were treated by means of spinal cord stimulation (SCS) in order to reduce signs and symptoms related to vascular damage. The follow-up ranged from 12 months to 6 years. The study confirms that SCS is an effective therapy in patients with PSS and Raynaud's phenomenon because of its beneficial effects on the Raynaud episodes, ulcers, pain, vascular sclerosis and hand function. This method may have a primary role in the treatment of this chronic disorder because of the high probability of failure of other medical or surgical therapy. PMID- 7857538 TI - The use of transcranial Doppler ultrasonography as a method of assessing intracranial pressure in hydrocephalic children. AB - Previous studies in children have shown a strong correlation between raised intracranial pressure (RICP) and the Gosling pulsatility index (PI) as determined by transcranial Doppler ultrasonography (TCD). This diagnostic modality can, therefore, be used as a non-invasive method for the indirect evaluation of shunt function in children with hydrocephalus. Transcranial Doppler waveform analyses were done in 15 children with hydrocephalus, before and after insertion of a ventriculo-peritoneal shunt. All had clinical evidence of raised intracranial pressure (ICP) prior to surgery. CT had demonstrated dilated ventricles and, in some, additional features of RICP. Fifteen children without clinical and CT evidence of hydrocephalus were examined in an identical manner to act as a control group. The results clearly demonstrated that TCD may be a useful, non invasive means of assessing the need for a cerebrospinal fluid (CSF) diversionary procedure and also for follow-up and monitoring. PMID- 7857539 TI - Teaching image-guided stereotactic methodology and functional neuroanatomy of the thalamus and pallidum: a simple ex vivo technique. AB - A simple and cheap model that enables on site, ex vivo, but very practical, learning of frame-based image-guided stereotactic technique and methodology, and the functional anatomy of the pallidum and thalamus is described. Using a cadaver skull, a specially prepared, formalin-fixed cadaver brain, and a modified stereotactic probe application of a stereotactic frame to the cranium, fiducial point acquisition, target point acquisition, computation of both arc and probe depth settings, and verification of target point accuracy can all be practiced. If diencephalic targets are selected for targeting with ball bearings then section of the cadaver brains, and study of a human thalamic stereotactic atlas provides an excellent and clinically relevant method of learning functionally important thalamic and pallidal anatomy. The method and techniques are described for CT imaging using the Brown-Roberts-Wells frame, but they are equally applicable to other frame types. PMID- 7857540 TI - Multidrug resistance gene (MDR 1) expression in neuro-axial tumours of children and young adults. AB - Drug resistance in many cancers outside the CNS has been associated with over expression of the multidrug resistance gene (MDR1), which codes for the transmembrane efflux pump P-glycoprotein (Pgp). To determine whether tumours of the neuroaxis over-express MDR1 and to identify the site of Pgp expression we examined 50 tumour specimens from 46 children and young adults using immunocytochemistry. Pgp was not expressed by any neoplastic cells, but was detected in the endothelium of tumour blood vessels in 35 of the 50 samples (70%). 11/35 (31%) were Pgp positive in the majority of vessels, 11/35 (31%) in a proportion, but < 50% of vessels, and 13/35 (37%) in one or two vessels. Pgp was also detected in surrounding normal brain capillaries. MDR1 may play a role in the chemoresistance of neuro-axial tumours either by its expression in the normal blood-brain barrier or by forming a blood-tumour barrier. The proportion of vessels expressing Pgp may determine the degree of resistance. PMID- 7857541 TI - Technique of extended transcranial approach for massive nasopharyngeal angiofibroma. AB - Various surgical approaches have been described to deal with extensive nasopharyngeal angiofibromas. These lesions, particularly those with a large intracranial extension and involving the cavernous sinus, pose a formidable surgical challenge. An extended transcranial approach was employed to resect successfully 2 such lesions. PMID- 7857542 TI - False aneurysm following intracranial surgery. AB - A false aneurysm of the pericallosal artery formed following resection of a colloid cyst. The aneurysm presumably resulted from arterial damage during surgery and its enlargement may have been facilitated by the surgical defect in the corpus callosum. A spherical hyperdense lesion on postoperative CT may indicate a false aneurysm. PMID- 7857543 TI - Subgaleal haematoma resulting in extradural compression following craniotomy. Report of two cases. AB - We describe two patients who underwent intracranial aneurysm surgery and developed postoperative subgaleal haematomas which, in the presence of an unfixed bone flap, resulted in significant extradural compression and a marked clinical deterioration. The application of a pressure dressing to tamponade a developing scalp haematoma is unwise unless the bone flap has been rigidly fixed in place. PMID- 7857544 TI - Cerebral astrocytoma and cavernous angioma: a case report. AB - The authors report a case of cerebral astrocytoma associated with a cavernous angioma. The patient presented with seizures and progressive hemiparesis. Diagnostic studies suggested the presence of a cavernous malformation with signs of previous haemorrhage. Surgery disclosed a complex tumour, which on histological examination revealed to be an anaplastic astrocytoma associated with a cavernous angioma. PMID- 7857545 TI - Brown-Sequard syndrome and an intradural arteriovenous fistula in a child. AB - A case of spinal dural arteriovenous fistula presenting in a 7-year-old child as a Brown-Sequard syndrome is reported. Spinal arteriovenous fistulae are reviewed with emphasis on classification, pathophysiology, investigations and management. PMID- 7857546 TI - Synchronous dural and cutaneous metastases along the distribution of the external carotid artery. AB - Dural metastases in the posterior fossa are relatively rare. We report a combination of cutaneous metastases in the scalp of the occiput with ipsilateral dural metastasis in the posterior fossa, on the inferior surface of the tentorium. It is suggested that all the metastases spread via the external carotid artery. PMID- 7857547 TI - Post-operative central sleep apnoea complicating cervical laminectomy: case report. AB - Breathing disorders following decompressive laminectomy for cervical stenosis are rare. We report a case of postoperative central apnoea following cervical laminectomy, and discuss the aetiology, management and potential relationship between upper cervical surgery and sleep apnoea. Preoperative evaluation of respiratory function, intraoperative monitoring and caution with sedative and anaesthetic drug use is important and the need for postoperative apnoea monitoring in cases with critical upper cervical compression with compromised breathing is emphasized. PMID- 7857548 TI - Interhemispheric subdural haematomas. AB - Eight cases of interhemispheric subdural haematomas (ISDHs) are described. Trauma was the most common cause. Two patients were hydrocephalic and one of them had also agenesis of the corpus callosum. The diagnoses were established by CT. In one of the cases with chronic ISDHs, CT findings suggested a subdural empyema. Conservative treatment was preferred for neurologically stable patients. In one of the patients, the haematoma migrated to the cerebral convexity after liquefaction. PMID- 7857549 TI - Academic productivity in neurosurgery. PMID- 7857550 TI - Consequences of prolonged inhalation of ozone on F344/N rats: collaborative studies. Part V: Effects on pulmonary function. AB - The impact of a 20-month exposure to ozone on the pulmonary function of rats was assessed from a single series of measurements made after exposures were completed. Four to ten male and female F344/N rats per group were exposed six hours per day, five days per week, for 20 months to ozone at 0.12, 0.5, or 1.0 parts per million (ppm), or to clean air as controls. One to three days after the last exposure, the rats were anesthetized using halothane, fitted with oral endotracheal and esophageal catheters, and measured using plethysmographic techniques. The differences between mean values for control and treated rats were tested for significance by multiple comparisons. The values and intersubject variability for more than 30 measured and calculated parameters were similar to those reported previously for rats of similar age. The only consistent exposure related effect was a small reduction of residual volume measured during slow lung deflation. This trend was observed in most exposure groups, but was most significant in females exposed to ozone at the 0.5 ppm level. Fibrosis and epithelial changes were observed in the terminal bronchiole-alveolar duct region in parallel studies of different rats from the same exposure groups. We hypothesized that these changes stiffened airspace walls and acted to maintain the patency of the air pathway at a lower than normal lung volume during deflation. Overall, the exposures had little impact on the integrated pulmonary function of the lung as measured in anesthetized rats. PMID- 7857551 TI - The emerging epidemic of HIV infection and AIDS in Asia and the Pacific. PMID- 7857552 TI - HIV/AIDS in Myanmar. PMID- 7857553 TI - AIDS in the Pacific Islands. PMID- 7857554 TI - HIV/AIDS prevention and control in Papua New Guinea. PMID- 7857555 TI - HIV/AIDS in the Philippines. PMID- 7857556 TI - The molecular epidemiology of HIV in Asia. PMID- 7857557 TI - The recent epidemiology of HIV and AIDS in Thailand. PMID- 7857558 TI - Risk factors for HIV infection in Thailand. PMID- 7857559 TI - The Thai response to the HIV/AIDS epidemic. PMID- 7857560 TI - HIV and AIDS in Asia and the Pacific: an epidemiological overview. PMID- 7857562 TI - Governments of Asia and the Pacific responding to the HIV/AIDS pandemic. PMID- 7857561 TI - Risk factors for HIV transmission in Asia and the Pacific. PMID- 7857563 TI - Non-governmental organization and community responses to HIV/AIDS in Asia and the Pacific. PMID- 7857564 TI - Social policy, human rights, and HIV/AIDS in Asia and the Pacific. PMID- 7857565 TI - Early HIV infection. PMID- 7857566 TI - AIDS pathogenesis. PMID- 7857567 TI - Late manifestations of HIV in Asia and the Pacific. PMID- 7857568 TI - Involving the communities: AIDS in Australia and New Zealand. PMID- 7857569 TI - AIDS and HIV infection in China. PMID- 7857570 TI - Epidemiology of HIV and AIDS in India. PMID- 7857571 TI - Risk factors for HIV transmission in India. PMID- 7857572 TI - Government response to HIV/AIDS in India. PMID- 7857573 TI - HIV and AIDS in Indonesia. PMID- 7857574 TI - Summary of the epidemiology of HIV/AIDS in Japan. PMID- 7857575 TI - AIDS in Malaysia. PMID- 7857576 TI - Lithium perbromate monohydrate at 296 and 173 K. AB - Lithium tetraoxobromate(1-) monohydrate, LiBrO4.-H2O, whose perchlorate analog has not yet been described, is found to be isomorphic with NaBrO4.H2O and NaClO4.H2O. Each of the two inequivalent Li ions is coordinated by six O atoms, thus forming distorted octahedra, each of which has three inequivalent Li-O distances. At room temperature, the average Li(1)-O and Li(2)-O distances are 2.150 and 2.164 A, respectively. The perbromate ion displays very nearly regular tetrahedral geometry, although it is not subject to symmetry constraints. At 296 K the average observed Br-O distance is 1.610 (4) A and the average O-Br-O angle is 109.5 (6) degrees, while at 173 K the corresponding values are 1.613 (4) A and 109.5 (7) degrees. The perbromate ion shows rigid-body behavior but the lithium coordination polyhedra do not. At 296 K, the average rigid-body corrected Br-O distance in the perbromate ion is 1.624 (3) A, in excellent agreement with the corresponding value reported for NaBrO4.H2O. Refinement of the two inequivalent H atoms allowed detailed analysis of the hydrogen bonding, which is more extensive than in NaBrO4.H2O or in NaClO4.H2O. The average observed B values for the H atoms [2.9 (3) A2 at 296 K and 2.8 (3) A2 at 173 K] are sufficiently small to suggest that dynamic disordering of the H atoms (determined by magnetic resonance methods for NaClO4.H2O) is not significant in the title salt. PMID- 7857577 TI - Medical ethics series. PMID- 7857578 TI - The role of ethics in rehabilitation medicine. Introduction to a series. PMID- 7857579 TI - Ethical issues in physical medicine and rehabilitation. Conclusion to a series. PMID- 7857581 TI - Quality of life never in the eyes of the beholder! PMID- 7857580 TI - A message to Dr. Death from a physiatrist. PMID- 7857583 TI - Behavioural actions of prolactin locally applied into the hippocampus of adult female rats. AB - The probable behavioural effects of rat prolactin (rPRL) locally applied into the ventral hippocampus (HPC) were studied in cycling female rats. Three experiments were performed examining the behavioural responses of rats subjected to three different situations: (i) Exploratory activity in an enriched holeboard (ii) exploratory activity under conflicting situation and (iii) escape behaviours in a forced swimming test. Behavioural parameters studied were: underground and object directed exploration and locomotion (Experiment 1); latency time and exploration behaviours (Experiment 2); swimming time and escape behaviours (Experiment 3). In Experiment 1 results showed that rPRL decreased the underground exploration and also locomotion but increased the object-directed exploration and had no effect on non-ambulatory activity. In Experiment 2 results showed that treatment of rPRL increased the latency time but did not modify the exploratory activity. In Experiment 3 results showed that rPRL augmented the swimming time and one of two parameters (frequency of immersions intents) of the escape behaviour. Results are interpreted as local actions of PRL on hippocampal neuron affecting expression of behaviours of rats depending on the stressful conditions of the environment. PMID- 7857582 TI - Effect of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin on in vivo L-[beta-11C]dopa turnover in the rat striatum with infusion of L-tyrosine. AB - L-[11C]DOPA, combined with positron emission tomography (PET), has made possible the assessment of dopamine turnover in vivo. Before the evaluation of PET study with L-[11C]DOPA in the primate, the effect of 6R-L-erythro-5,6,7,8 tetrahydrobiopterin (6R-BH4) and/or L-tyrosine infusion on L-[11C]DOPA turnover was analyzed in the rat striatal tissue and in the striatal extracellular fluid using microdialysis. L-[11C]DOPA was rapidly taken up into the brain after intravenous injection and converted to [11C]dopamine, [11C]DOPAC and [11C]HVA in the striatal tissue. Small amount of 3-O-methyl-[11C]DOPA, a product of DOPA by 3 O-methylation in peripheral tissues, was also detected in the striatal tissue. The striatum/cerebellum ratio of total radioactivity uptake was linear against time up to 40 min after L-[11C]DOPA injection. The uptake ratio, increased by 6R BH4 administration, was further increased by L-tyrosine infusion. The in vivo microdialysis technique was further applied to determine L-[11C]DOPA and its metabolites in striatal extracellular fluid (ECF). The peripheral administration of 6R-BH4 (50 mg/kg) induced elevation of [11C]DOPA concentration in ECF in the early phase after injection, following higher radioactivity in [11C]dopamine and [11C]HVA fractions than those in control animals at late phase. The 6R-BH4 induced elevation of [11C]DOPA uptake and the radioactivity of its metabolites was further enhanced by the continuous infusion of L-tyrosine at a dose of 1.0 mumol/min/kg. L-Tyrosine infusion alone did not induce the elevation of radioactivity. The results suggest that [11C]DOPA might be a useful probe to evaluate the effect of 6R-BH4 and/or L-tyrosine loading in the primate. PMID- 7857584 TI - Immunochemical quantification of sarcoplasmic reticulum Ca(2+)-ATPase and calsequestrin in muscle biopsies from patients with myotonia congenita and paramyotonia congenita Eulenburg. AB - A sensitive enzyme-linked immunoadsorbant assay was developed to quantify Ca(2+) ATPase and calsequestrin from sarcoplasmic reticulum in human muscle biopsies. Tissue levels of Ca(2+)-ATPase and calsequestrin averaged 51.5 +/- 28.1 and 6.4 +/- 1.8 mg/g muscle protein, respectively, in control muscles (means +/- SD, n = 12). The high sensitivity and specificity of the antibodies make the assay a useful tool in the diagnosis of human neuromuscular disorders where defects in sarcoplasmic reticulum function may be expected. The assay was applied to muscle biopsies from patients with myotonia congenita and paramyotonia congenita Eulenburg. The calsequestrin concentration was normal in all patient muscles. The Ca(2+)-ATPase content was also within the normal range but varied considerably with the percentage distribution of slow-twitch fibres. This indicates that the prolonged relaxation observed in the muscles of patients with these disorders is not caused by faulty expression of Ca(2+)-ATPase and calsequestrin. PMID- 7857585 TI - Influence of chronic beta-adrenoreceptor blocker treatment on melatonin secretion and sleep quality in patients with essential hypertension. AB - The nocturnal production of melatonin synthesis has been associated with circadian mechanisms of the organization of sleep. It is well known that the synthesis of melatonin is under the control of pineal beta 1-adrenoreceptors. In this study the effect of ten weeks treatment with the beta-adrenoreceptor (beta AR) blockers propranolol and ridazolol on melatonin synthesis and on sleep quality was examined in 42 patients suffering from essential hypertension. Before and after 6 and 10 weeks of beta-AR-blocker administration urinary sulfatoxymelatonin excretion rates were measured and sleep factors were evaluated by using a standardized sleep inventory consisting of self-rating sleepiness scales. After 6 and 10 weeks of treatment, a significant about 50 percent reduction of sulfatoxymelatonin was measured. No relationship between these reductions and changes in sleep factors was found. The results indicate that a reduced nightly amplitude of melatonin has minor significance for the organization of physiological sleep. Furthermore, it is suggested that pineal mechanisms beside the beta 1-adrenergic receptor transduction system serve to maintain the melatonin signal to a considerable extent during a chronic beta 1-AR blockade. PMID- 7857586 TI - Persistent psychosis after reduction in pre- and post-synaptic dopaminergic function. AB - The purpose of this study was to evaluate the hypothesis that neuroleptic non response in the face of "adequate" DA post-synaptic receptor blockade reflects failure of regulatory mechanisms to decrease DA pre-synaptic activity. Eight chronic schizophrenics, meeting rigorous criteria for neuroleptic non-response, were treated for four weeks with alpha-methylparatyrosine as an adjunct to their previously stable neuroleptic dose. Treatment with AMPT produced a prompt decrease in plasma HVA that was, on average, 72% lower at the end of the study. While there was also strong clinical evidence of reduction in central dopaminergic activity (both a significant reduction in dyskinetic movements and increase in extrapyramidal symptoms), there was virtually no change in severity of psychotic symptoms. Thus, in this group of non-responders, psychotic symptoms persisted despite both extensive dopamine post-synaptic receptor blockade and marked reduction of presynaptic activity. These symptoms may not be directly DA dependent. PMID- 7857587 TI - Tiagabine inhibits haloperidol-induced oral dyskinesias in rats. AB - Chronic administration of haloperidol to male Sprague Dawley rats for 6 months at a dosage of 1.5 mg/kg/day produces oral dyskinesias in a significant percent of the treated group. This has been used as an animal model of tardive dyskinesia in several laboratories, because the rat movements display characteristics reminiscent of the human dyskinetic condition. Previously, we have reported a reduction in these haloperidol-induced oral dyskinesias with the coadministration of a direct acting GABA agonist progabide. Here, we have tested an indirect acting GABA agonist, tiagabine, coadministered with haloperidol, for its effect on the oral dyskinesias. At a dosage of 75 mg/kg/day tiagabine significantly inhibited the onset of vacuous chewing movements (VCMs), decreasing the average movement severity from 11.2 +/- 2.0 to 4.4 +/- 1.4, compared with a placebo rate of 1.3 +/- 0.5 (VCMs/5 min). These data support the proposition that an effective, potent GABAmimetic coadministered with haloperidol, will block the onset of rat oral dyskinesias. This conclusion has important implications for the treatment and prevention of tardive dyskinesia in humans. PMID- 7857588 TI - Locomotor inhibition by the D3 ligand R-(+)-7-OH-DPAT is independent of changes in dopamine release. AB - The dopamine D3 preferring ligand R-(+)-7-OH-DPAT induced strong hypolocomotion in rats. Doses producing reduction of locomotion failed to affect dopamine release or synthesis rate. These data support the hypothesis that the dopamine D3 receptor is a postsynaptic receptor with an inhibitory influence on rat locomotor activity. PMID- 7857589 TI - Bilateral reciprocal organisation in man: focus on IA interneurone. AB - The H reflex of flexor carpi radialis and radial-induced reciprocal inhibition were recorded in normal subjects during conditioning stimulation of the contralateral median or radial nerves. It was found that stimulation of the contralateral median nerve enhanced the degree of reciprocal inhibition exerted by the radial nerve on the median nerve, while contralateral radial nerve stimulation reduced the reciprocal inhibition exerted by the extensor on the flexor. In two subjects in which a pure extensor H reflex was recorded specular features were observed following contralateral median and radial stimulation. These findings are considered to be the electrophysiological manifestation of contralateral modulation of reciprocal inhibition, which is likely to act at the level of the IA interneurone. PMID- 7857590 TI - Peripheral autonomic regulation of gonadotropin secretion in pubertal rats. Inhibition of post-castration rise of gonadotropins during wallerian degeneration after sympathetic superior cervical ganglionectomy. AB - Shortly after superior cervical ganglionectomy (SCGx) peripheral sympathetic nerve terminals in the median eminence degenerate, the neurotransmitter is released, and a transient period of increased postsynaptic ensues. The present experiments were undertaken to examine, in the anterograde degeneration paradigm after SCGx, the participation of peripheral sympathetic nerves in feedback regulation of gonadotropin release in pubertal rats. Groups of 18 days old or 26 days old rats of both sexes were subjected to castration or its sham-operation, and 4 h later to SCGx or sham-SCGx. Twenty-four h later, the rats were decapitated and serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels were measured by RIA. In 19 days old male rats, the post-castration increase of circulating LH, but not of FSH, was prevented by the wallerian degeneration of sympathetic nerves after acute SCGx. At the 27th day of life, acute SCGx prevented FSH, but not LH, post-orchidectomy rise. In female rats, SCGx blunted the oophorectomy-induced increase of gonadotropin levels at both examined ages. SCGx brought about a significant decrease of serum LH levels in 19 days old, sham-castrated female rats. At the 19th day of life, acute SCGx decreased serum LH and FSH in neonatally orchidectomized rats, but not in neonatally androgenized female rats. The data are in favor of a negative influence of peripheral sympathetic neurons on gonadotropin release in prepubertal rats, predominantly in female rats. PMID- 7857591 TI - 1,2,3,4-Tetrahydro-2-methyl-4,6,7-isoquinolinetriol inhibits tyrosine hydroxylase activity in rat striatal synaptosomes. AB - 1,2,3,4-tetrahydro-2-methyl-4,6,7-isoquinolinetriol (TMIQ), a tetrahydroisoquinoline derivative of adrenaline, was tested for potency as an analog of the dopamine depleting agent 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) in assays of tyrosine hydroxylase (TH) activity in the striatal synaptosome preparation. TMIQ inhibited TH activity with an IC50 (4 x 10(-6)M) similar to that found for MPTP (IC50 1 x 10(-6)M). TH inhibitions produced by IC50 concentrations of TMIQ were reversed by monoamine oxidase (MAO) A or MAO-B inhibitors (clorgyline or deprenyl), or the dopamine reuptake blocker nomifensine, or excess cofactor (6R)-5,6,7,8-tetrahydro-L-biopterin. TMIQ did not appear to act at the presynaptic D2 sulpiride sensitive autoreceptor for dopamine synthesis modulation. These in vitro data are consistent with earlier findings that TMIQ acts as a dopamine depleting agent, and with the possibility that TMIQ may have a degree of MPTP-like activity in vivo. PMID- 7857592 TI - Modifications of mesolimbic and nigrostriatal dopaminergic activities after intracerebroventricular administration of prolactin. AB - In the present study we examined the effects of intracerebroventricular (i.c.v.) injections of prolactin (PRL) on the presynaptic activity and post-synaptic sensitivity of mesolimbic and nigrostriatal dopaminergic neurons. In addition, the effects of PRL on in vitro release of dopamine (DA) from perifused striatal fragments were examined. Tyrosine hydroxylase (TH) activity and D2 receptor density in the striatum decreased after i.c.v. PRL administration; this was accompanied by an increase in D2 receptor affinity. These effects occurred after i.c.v. administration of PRL to normoprolactinemic rats, although normally they did not appear after administration to animals with pituitary grafting-induced hyperprolactinemia. Thus, in these animals, i.c.v. PRL failed to decrease TH activity and D1 and D2 receptor densities to a significant extent. In the case of D2 receptors, this was probably due to the fact that pituitary grafting-induced hyperprolactinemia itself was able to reduce the density of this receptor. No changes were observed in DA or L-3, 4-dihydroxyphenylacetic acid (DOPAC) contents after i.c.v. administration of PRL to both normo-and hyperprolactinemic animals. Basal and K(+)-evoked DA release in vitro from perifused striatal fragments of normoprolactinemic rats were not affected by the addition of PRL, whereas this hormone enhanced K(+)-evoked DA release when added to perifused striatal fragments from hyperprolactinemic animals. In the limbic forebrain, i.c.v. administration of PRL to normoprolactinemic animals produced a decrease in DA and DOPAC contents and D1 receptor density. Interestingly, none of these effects appeared when PRL was injected to hyperprolactinemic animals. In summary, our results suggest a possible inhibitory role of PRL on the activity of both the nigrostriatal and mesolimbic dopaminergic neuronal systems. These inhibitory effects were reflected in the decreases elicited in a set of neurochemical parameters, indicating either presynaptic activity or postsynaptic sensitivity, after i.c.v.-administered PRL. This observation supports the hypothesis of a possible neuromodulatory role for an extrapituitary PRL on the activity of these neurons, although the fact that most of these effects did not appear when i.c.v. administration was performed in hyperprolactinemic rats also suggests that they are influenced by peripheral PRL levels. PMID- 7857593 TI - Mecamylamine reverses physostigmine-induced attenuation of scopolamine-induced hyperactivity. AB - It has previously been demonstrated that the muscarinic antagonist scopolamine induces hyperactivity in rodents, which is reversed by physostigmine but not by directly acting agonists such as pilocarpine. This may suggest that non muscarinic actions of physostigmine may be responsible for its reversal of scopolamine-induced hyperactivity. We have found, in male Wistar rats, whose activity was measured on electromagnetic detector plates, that the central nicotinic receptor antagonist mecamylamine (3 mg/kg) reverses the blockade of scopolamine-induced behavioural activation induced by physostigmine. This suggests that activation of nicotinic receptors can counteract the effects of muscarinic blockade. Interestingly, however, treatment with nicotine does not block scopolamine-induced hyperactivity, suggesting that the exogenous and endogenous ligands may have different receptor or neuronal substrates. PMID- 7857594 TI - 6-Fluoro-serotonin as a substrate for the neuronal serotonin transporter. AB - 6-Fluoro-serotonin (6F-5-HT) was previously identified in the rat brain after peripheral administration of 6-fluoro-DL-tryptophan, a serotonin (5-HT) synthesis inhibitor. These present studies, performed with rat brain synaptosomes show that: i-neuronal 6F-5-HT uptake partly involved the 5-HT transporter since it was inhibited by clomipramine, a 5-HT uptake inhibitor, ii-6F-5-HT blocked the synaptosomal uptake of 3H-5-HT, with an IC50 value of 98 +/- 13 nM, and iii- 6F-5 HT induced 3H-5-HT release from preloaded synaptosomes, with an EC50 value of 95 +/- 6 nM; this release was decreased in the presence of clomipramine, suggesting the involvement of the 5-HT transporter. This release was also reduced when using synaptosomes from reserpinized rats, suggesting that the vesicular pool also participates to the 3H-5-HT release induced by 6F-5-HT. So, 6F-5-HT behaved as a substrate for the 5-HT neuronal transporter. PMID- 7857596 TI - Adrenergic receptors in the cerebellum of olivopontocerebellar atrophy. AB - Using autoradiographic techniques we studied the changes that in adrenergic receptors occurred in the cerebellum of two olivopontocerebellar atrophy (OPCA) patients as compared with a control group. In OPCA cerebellum the densities of total beta-adrenoceptors were reduced along the cortex but increased in the white matter. Although mainly the beta 1 subtype was decreased along the cerebellar cortex, the increase of beta-receptors over the white matter was due to a selective raise in the beta 2 subtype. These findings suggest a postsynaptic neuronal location for the beta 1 subtype and a glial location for the beta 2 adrenoceptor. On the other hand, alpha 2-adrenoceptors were clearly reduced all along the cerebellar cortex of these OPCA brains, this probably being secondary to the loss of presynaptic adrenergic terminals arising from the locus coeruleus. These results help clarify both the subcellular location of adrenoceptors in human cerebellum and the neurochemical pathophysiology of OPCA. PMID- 7857595 TI - Effects of the altered serotonergic signalling by neonatal treatment with 5,7 dihydroxytryptamine, ritanserin or clomipramine on the adrenocortical stress response and the glucocorticoid receptor binding in the hippocampus in adult rats. AB - The aim of the present study is to investigate the effect of neonatal alterations in 5-HT signalling on the regulation of endocrine stress response in adult rats. The neonatal blockade of 5-HT transmission by 5,7-DHT or ritanserin treatment did not alter the density of glucocorticoid receptor (GR) binding sites in the hippocampus, although a 5,7-DHT-induced lesion was clearly shown to decrease in 5 HT content by greater than 80% in the hippocampus. In addition, the animals pretreated with the blockade of 5-HT transmission during early life did not exhibit a hyperresponsiveness of the adrenocortical response to stress. On the other hand, the neonatal administration of the 5-HT uptake inhibitor, clomipramine, was shown to lower the stress responsiveness of the adrenocortical axis in adulthood. PMID- 7857597 TI - Monoamine activity reflected in urine of young patients with obsessive compulsive disorder, psychosis with and without reality distortion and healthy subjects: an explorative analysis. AB - Positive psychotic symptoms are reported to be associated with high, negative symptoms with low dopamine (DA) activity and serotonin (5HT) activity may be altered in obsessive-compulsive disorder (OCD). We analysed 24 h urine samples in these patient groups and in healthy controls for supportive evidence. Young unmedicated OCD subjects excreted more adrenaline (AD) and homovanillic acid (HVA) and showed a higher HVA/MHPG ratio and metabolic rate than healthy controls. Independent of general metabolic rate they showed higher HVA concentrations which suggests that the relative activity of catecholamine systems in OCD (HVA/MHPG) is due more to high DA than to low noradrenergic (NA) activity. Concentrations of 5HT were also high in OCD patients. In psychotic patients low levels of DA, HVA, NA and MHPG probably resulted from neuroleptic medication. Patients diagnosed with paranoid psychosis showed higher DA utilization than controls and those with few paranoid symptoms showed high 5HT utilization. These results support studies suggesting that paranoid psychosis is associated more with increased DA activity (discussed in the context of neuroleptic reactivity), that non-paranoid forms are associated more with increased 5HT activity and that OCD patients are unusually aroused with high levels of Ad, 5HT and HVA. PMID- 7857598 TI - Expression of human tyrosine hydroxylase-chloramphenicol acetyltransferase (CAT) fusion gene in the brains of transgenic mice as examined by CAT immunocytochemistry. AB - We have produced transgenic (Tg) mice carrying 5.0-kb fragment from the 5' flanking region of the human tyrosine hydroxylase (hTH) gene fused to a reporter gene, chloramphenicol acetyltransferase (CAT) [Sasaoka et al. (1992) Mol Brain Res 16: 274-286]. In the brain of the Tg mice, CAT expression has been observed in catecholaminergic (CAnergic) neurons and also in non-CAnergic neurons. The aim of the present study is to examine in detail the cell-type specific expression of the hTH-CAT fusion gene in the brain of the Tg mice, by use of immunohistochemistry for CAT, TH, and aromatic L-amino acid decarboxylase (AADC). CAT-immunoreactive cells were found in CAnergic brain regions which contained TH positive cells, and also in non-CAnergic brain regions which contained no TH labeled cells. The non-CAnergic brain regions that represented CAT-stained cells were further divided into two groups: (i) regions containing AADC-labeled cells, for example, bed nucleus of the stria terminalis, nucleus suprachiasmaticus, mammillary body, nucleus raphe dorsalis, inferior colliculus, and nucleus parabrachialis, and (ii) regions containing no AADC-positive cells, for example, main olfactory bulb (except A16), accessory olfactory bulb, nucleus olfactorius anterior, caudoputamen, septum, nucleus accumbens, hippocampus, medial nucleus of the amygdala, entorhinal cortex, nucleus supraopticus, and parasubiculum. The results indicate that the 5.0-kb DNA fragment flanking the 5' end of the hTH gene may contain the element(s) specific for neuron-specific TH expression but which may be insufficient to attenuate ectopic expression. PMID- 7857599 TI - Glyoxylate for affinity labelling of 6-phosphogluconate dehydrogenase. AB - In order to find a new reagent for the affinity labelling, 6-phosphogluconate dehydrogenase was treated with glyoxylate, a versatile metabolite with a carboxyl and a reactive aldehydic group. High concentrations of glyoxylate inhibit the enzyme, while in the presence of the reducing agent cyanoborohydride, the enzyme is irreversibly inactivated by only millimolar glyoxylate. This indicates the formation of a Schiff base between the aldehydic group of glyoxylate and one enzyme lysine residue. The kinetics and substrate competition suggest that inactivation is due to affinity labelling. In the first step the inhibitor carboxylic group binds to the substrate carboxyl binding site, and in the second slower step the aldehydic group binds a nearby lysine. We have also found that other enzymes are inactivated by the combined actions of glyoxylate and cyanoborohydride, with a saturation kinetics. Hence, glyoxylate can be helpful to identify specific lysines at the carboxyl binding sites in proteins. PMID- 7857600 TI - HPLC separation of toxic fraction components extracted from planktonic and benthic Cnidaria. AB - HPLC separation of crude extract components derived from nematocysts and extranematocystic tissues of macroplanktonic jellyfish Aequorea aequorea and Rhizostoma pulmo and benthic sea-anemones Actinia equina and Anemonia sulcata was carried out by different columns. A satisfactory peak separation was obtained analyzing the toxin of Rhizostoma pulmo by cationic and C18 columns. Low molecular weight fragments were separated by C18 column and U.V. monitored varying pH values and obtaining the displacement of significant peaks. Clear differences between chromatographic plots concerning planktonic and benthic species was evidenced by anionic column; this result can point out a clear ecological analogy between species living in the same environment and a similar toxin biosynthesis, due to selective actions related to both the environment and the phylogenetic relationships; these organisms could have developed similar mechanisms useful to tackle the environment. PMID- 7857601 TI - Analytical profile of zolpidem. AB - The paper present an analytical profile of Zolpidem. The applications of chromatographic methods (HPLC and HPTLC) and non-aqueous titrimetry in the analysis of this drug are described. Partition coefficients at pH 2.0 and 7.4 and absorptivity values have been determined. Reversed phase HPLC and HPTLC systems have been successfully performed utilizing methanol/water mixtures as eluent and octadecylsilane as stationary phase. Acidimetric and alkalimetric methods in non aqueous titrimetry have been applied for quantitative analysis. The suggested procedures are proposed as an effective tool for quality control on pure compound and pharmaceutical formulations. PMID- 7857602 TI - Hypoglossal responses elicited by periodontal afferent activation in the rat. AB - Mechanical stimulation of the ipsilateral incisor tooth in the rat evoked reflex discharges in the hypoglossal nerve branch innervating the intrinsic and extrinsic tongue muscles. Stimulation elicited biphasic potentials in the whole XIIth nerve and influenced the unitary firing rate in 54 out of 80 fibers tested. The fiber responses were characterized by excitation or inhibition in frequency discharge or sequences of excitation-inhibition or inhibition-excitation. The results observed suggest that the periodontal-hypoglossal reflexes play a role in the control of tongue position during mastication. PMID- 7857604 TI - Morphometric analysis of Sardinian breed donkeys. AB - The main somatometric characteristics of 15 Sardinian breed adult donkeys (6 male and 9 female) were studied. Analysis of the somatic measurements and zoometric indexes show subjects of small build of a mesomorph constitutional type. Dimorphism between the sexes is slight and is limited to the rump area. The number of donkeys still to be found in Sardinia is greatly reduced and urgent measures are needed to safeguard its animal genetic resource. PMID- 7857603 TI - HCV-RNA survival as detected by PCR in the environment. AB - We have shown that HCV-RNA is resistant to drying at room temperature for at least 48 hours. This is a factor which could influence the diffusion of the virus in the general population, which epidemiological studies have shown to be surprisingly high. It should be considered in evaluating the importance of the inapparent parenteral routes of transmission. PMID- 7857605 TI - X-ray densitometry applied to the study of prenatal ossification. AB - To evaluate bone mass (BMC) and bone density (BMD) it is possible to utilize x ray absorptiometry. This method is usually employed in clinical practice for the evaluation of metabolic osteopathies. The authors describe an application of this diagnostic technique to the study of the ossification pattern of the human vertebral column in pre- and post-natal life. On this regard, an ultra high resolution software allowed to analyze quantitative aspects of the ossification of small size vertebral bodies by lateral scans directly performed on bone specimens. PMID- 7857606 TI - Methodological problems in determining the relationship between handedness and immune system function. PMID- 7857607 TI - Allergy and the Geschwind-Behan-Galaburda model. PMID- 7857608 TI - Evaluating support for the Geschwind-Behan-Galaburda model: with a rubber ruler and a thumb on the scale. PMID- 7857609 TI - Anomalous cerebral lateralization and Down syndrome. AB - Contrary to Bryden, McManus, and Bulman-Fleming's claim, the dichotic listening and handedness literature indicate that persons with Down syndrome exhibit a unique pattern of cerebral specialization. This pattern creates difficulty for any model of laterality that proposes random specialization of function in the absence of a predisposition toward left hemisphere lateralization for language and motor control. PMID- 7857610 TI - Anomalous brain and anomalous model. PMID- 7857611 TI - Evaluating the Bryden-McManus-Bulman-Fleming critique of the Geschwind-Behan Galaburda model of cerebral lateralization. PMID- 7857612 TI - Anomalous dominance, incidence rate studies, and other methodological issues. PMID- 7857613 TI - Anomalous dominance, sex, and laterality. PMID- 7857614 TI - If you can replicate the handedness-immune disorder effect, the more power to you. AB - Bryden, McManus, and Bulman-Fleming's (1994) meta-analysis of studies examining the Geschwind-Behan-Galaburda hypothesis indicates that the original data set supports the hypothesis significantly more than the body of replication attempts. We present data on 2256 subjects that clearly fail to support the hypothesis and describe practical and statistical reasons suggesting why the original data cannot be easily replicated. A power analysis suggests that to find the effect in a general sample, one should plan to have 17,000 to 40,000 subjects. PMID- 7857615 TI - Babies, bath water, and the chicken's way out. AB - Bryden, McManus, and Bulman-Fleming (1994) have provided a thoughtful critique of the developmental model of cerebral lateralization proposed by Geschwind, Behan, and Galaburda. Although it is clear that many particular aspects of the Geschwind Behan-Galaburda (GBG) model have not withstood empirical test, the GBG model has had an important and useful impact by encouraging others to conceptualize cerebral laterality in an appropriately developmental way. Consequently, although the present commentary reinforces some of the criticisms leveled by Bryden et al., it also points out why it would be unwise to throw out the baby (i.e., a developmental perspective) with the bath water (i.e., particular details of the GBG model). PMID- 7857616 TI - Geschwind's legacy. PMID- 7857617 TI - Life after birth: the influence of steroid hormones on cerebral structure and function is not fixed prenatally. AB - Bryden, McManus, and Bulman-Fleming conclude that available empirical evidence does not support the Geschwind-Behan-Galaburda model of cerebral lateralization. One of the central assumptions of the model is that fetal testosterone plays a determinant role in the development of anomalous specialization and is associated with various behavioral, cognitive, and immunological disorders. The influence of testosterone, however, is not limited to the perinatal period. We show that hormonal effects constitute lifelong influences on aspects of brain architecture and function. These influences represent a little-known and discussed--but extremely relevant--dimension of our understanding of the biological bases of behavior. PMID- 7857618 TI - A linguistic approach to developmental dyslexia. PMID- 7857619 TI - Is testosterone related to spatial cognition and hand preference in humans? PMID- 7857620 TI - The Geschwind-Behan-Galaburda theory of cerebral lateralization: thesis, antithesis, and synthesis? PMID- 7857621 TI - The search continues: casual relationships among dyslexia, anomalous dominance, and immune function. PMID- 7857622 TI - Comments on immune aspects of the Geschwind-Behan-Galaburda model and of the article of Bryden, McManus, and Bulman-Fleming. AB - The goal of this article is to reconsider the links among immune disorders, testosterone, and left-handedness made originally by Geschwind and Behan (1982) and by Geschwind and Galaburda (1985). We demonstrate that an excess of testosterone in utero is not a prerequisite for immune disorders, because of its destructive action on thymus, and that allergy and autoimmune disorders are not primarily thymo-dependent but B-lymphocyte-dependent. We furthermore study the HLA proposed by Yeo and Gangestad (1993) and retained by Bryden, McManus, and Bulman-Fleming as a possible variable that could explain, in replacement of testosterone, the link among allergy, asthma, and ulcerative colitis. We conclude that the HLA of lefthanders and the meta-analysis of Bryden et al. do not fit together as well as hoped for. PMID- 7857623 TI - The GBG model: is there more to consider than handedness? AB - It is peculiar that Bryden and his colleagues admit to the inadequacy of handedness as an index for cerebral anomalous dominance and then attack a model of anomalous dominance using primarily handedness data. In reality, the GBG model (which was intended to be "a hypothesis and program for research," to quote the exact titles of the 1985 articles) is not nearly as narrow as Bryden's worldview. We present here the rest of the literature on the link between immune disorders and language disorders which Bryden et al. neglected and argue that the data are sufficient to have warranted a +2 in their evaluation. The strength of this link is worthy of further investigation, even though the hormonal mechanism proposed in the GBG model may be erroneous. PMID- 7857624 TI - Neuroanatomical lateralization of language: sexual dimorphism and the ethology of neural computation. PMID- 7857626 TI - Early structural changes in the rat tympanic membrane during pneumococcal otitis media. AB - The early inflammatory reaction in the rat tympanic membrane was studied during the first 36h following inoculation of Streptococcus pneumoniae type 3 in the middle ear cavity. Otomicroscopic examination showed only minor signs of inflammation in the early stages although changes at the light microscopic level were pronounced. This reaction differed significantly between the pars flaccida and pars tensa of the tympanic membrane. Three hours after inoculation, edema and infiltration with polymorphonuclear leukocytes and macrophages were found in the pars flaccida whereas in the pars tensa no polymorphonuclear leukocytes were noted until after 12h. This reaction was most prominent after 36h. In the pars flaccida, mitoses occurred frequently among the cells of the simple squamous epithelium, which changed into a double-layered cuboidal epithelium. These findings demonstrate that an inflammatory reaction starts earlier in the pars flaccida than in the pars tensa of the tympanic membrane. PMID- 7857627 TI - A cohort study of point prevalence of eardrum pathology in children and teenagers from age 5 to age 16. AB - The aim of this prospective study was to estimate the prevalence of different types of eardrum pathology in a cohort of children and teenagers up to the age of 16. Among this initial group of 373 subjects, repetitive screening trials including otomicroscopy and tympanometry were performed from age 5 to 16 years. All clinical pathology of Shrapnell's membrane and the pars tensa was recorded systematically. At age 5 years, pathology of the eardrum was found in 19% of ears examined. At succeeding follow-ups until the age of 16 years, the prevalence of eardrum pathology increased to 33%. The tympanometric profile improved significantly from 49% of children with negative middle ear pressure at age 5 years to 4% at age 16 years. The patency of the eustachian tube was estimated in the group with eardrum pathology and compared to the group with no eardrum pathology. Our findings show that, despite improvement of middle ear ventilation through childhood, the prevalence of pathological changes of the eardrum seems to increase. The reason for this increase is discussed. PMID- 7857628 TI - Recurrent cervical lymphadenopathy: differential diagnosis with color-duplex sonography. AB - In this prospective study 45 patients with cervical lymphadenopathy treated by operation, radiation and/or chemotherapy were examined by color-duplex sonography. The aim was to investigate the lymph node perfusion and to find out whether differentiation between benign and malignant nodal disease after therapy was possible by resistance and pulsatility indices. In 200 of 245 lymph nodes (82%) color-duplex sonography was able to detect perfusion. Using a pulsatility index (PI) threshold of 1.6 and resistance index (RI) threshold of 0.8, differentiation between reactive nodal enlargement and metastases was possible with an accuracy of 96%. Differentiation between lymphomas and metastases by RI and PI was not possible. Qualitative assessment of perfusional patterns was useful in detecting malignancy because reactively enlarged nodes showed greater hilar perfusion whereas metastases showed an increased peripheral perfusion. Lymphomas had both increased central and peripheral perfusions. PMID- 7857625 TI - Experimental, clinical and preventive aspects of ototoxicity. AB - Ototoxicity is an important clinical problem and accounts for a significant proportion of sensorineural hearing loss in some parts of the world. Ototoxicity is predominantly an iatrogenic condition. However, with proper dosing, prudent monitoring of serum levels of ototoxic medications and serial audiometry, ototoxicity can be prevented. A number of the more common ototoxic medications, including aminoglycosides, erythromycin, loop diuretics, salicylates, cisplatin, deferoxamine and ototopical agents, are outlined in this review. Their pharmacology, mechanisms of action and methods of preventing complications are discussed together with animal and clinical studies. PMID- 7857630 TI - Prognostic significance of lymph node reactivity in patients with laryngeal carcinoma. AB - Apart from the presence or absence of metastases in patients with laryngeal carcinoma, there are changes of reactivity in cervical lymph nodes that are seen histologically as nonspecific reactive lymphadenitis. These changes are morphological manifestations of the regional lymphatic system reactivity in relation to tumor, and their presence may be of prognostic value. To test this hypothesis, 45 patients with laryngeal carcinoma were examined for the evidence of node reactivity. The classification applied by Tsakraklides et al. was used, defining patterns of lymphocyte predominance, germinal center appearance (indicating lymph node stimulation) and whether or not lymphocyte depletion had occurred. The presence of node reactivity was compared with long-term (5-year) survivals in the group of patients studied. By applying statistical analysis it was found that lymph node stimulation was a favorable prognostic factor, while its absence worsened prognosis. PMID- 7857629 TI - Differences in glial, synaptic and motoneuron responses in the facial nucleus of the rat brainstem following facial nerve resection and nerve suture reanastomosis. AB - Transection and reanastomosis of the facial nerve with microsurgical sutures in rats (facial-facial anastomosis) results in the complete regeneration of the facial nucleus, whereas resection of a 10 mm length of the peripheral facial nerve leads to degeneration and loss of neurons in the nucleus. Nerve sutures or resections were performed in 84 female Wistar rats, and the time course and differences between regenerative and degenerative reactions in the facial nuclei were compared after survival times of 4-112 days. The volume of the facial nucleus, number of facial motoneurons and motoneuron density were estimated stereologically by the physical dissector method. Synaptic plasticity, activation of astroglia and microglia were studied cytochemically with anti-synaptophysin, anti-glial fibrillary acidic protein and the isolectin Griffonia simplicifolia I B4 (GSA I-B4). After facial-facial anastomosis the volume of the facial nucleus and its number of motoneurons remained constant, whereas resection of the facial nerve caused shrinkage of the facial nucleus and loss of one-third of facial motoneurons within 112 days post-operation. Synaptic stripping, activation of microglia and astroglia occurred in the same sequence and were reversible after both operations, but these reactions were more severe and prolonged after resection, i.e. without suture of the facial nerve. It appears to be most important clinically that differences between de- and regeneration become clear within 7 days post-axotomy. Our results strongly support reconstruction of the facial nerve as early as possible after a nerve lesion. PMID- 7857631 TI - Tonsillectomy and the immune system: a long-term follow up comparison between tonsillectomized and non-tonsillectomized children. AB - Immunological functions of the tonsils and possible effects of their removal are still controversial. One reason for this is the lack of long-term follow-up investigations after tonsillectomy. In the present study selected parameters of the cellular and humoral immune systems of 160 children 0.5-11 years after tonsillectomy (mean 6.6 +/- 2.1 years) were compared to those of 302 age-matched non-tonsillectomized children. In tonsillectomized children the incidence of infections of the upper respiratory tract was not increased compared to the non tonsillectomized control group. Slightly increased percentages of CD 21 + cells, raised counts of CD4+ cells, absolute and relative increases in DR+ cells and a raised CD4+ DR count was found mainly in tonsillectomized boys, while lymphocyte subpopulations of tonsillectomized girls remained unaffected. Tonsillectomized children had lower IgA levels, but the complement system was not altered in either sex. These findings show that while tonsillectomy may lead to certain changes in the cellular and humoral immune systems, these alterations are clinically insignificant and no increased frequency of immunomodulated diseases should be expected. PMID- 7857632 TI - The effect of adenosine on cochlear potentials in the guinea pig. AB - The effect of adenosine on cochlear potentials was examined in the guinea pig. Perilymphatic perfusion with 10(-4) M adenosine produced a significant decrease in the amplitudes of cochlear microphonics, negative summating potential (-SP) and compound action potential (CAP) and significant prolongation of N1 latency with no change in the endocochlear potential. The decreases in the amplitudes of SP and CAP caused by adenosine were dose-dependent. Perilymphatic perfusion with an inactive analogue, 8-bromoadenosine, produced no changes in the cochlear potentials. The A1-receptor agonist, 2-chloro-adenosine, produced a similar change in cochlear potentials to adenosine, while no changes were produced by the A2-receptor agonist, 5'-(N-ethylcarboxamido)-adenosine. These results suggest that adenosine may have a modulatory function through an A1 receptor in the cochlea. PMID- 7857633 TI - Postnatal developmental changes in facial nerve morphology. Computer-aided 3-D reconstruction and measurement. AB - Accurate measurements of the lengths and angles of the facial nerve were obtained in eight normal human temporal bones of varying ages from 7 days to 76 years. Measurements were made on serial histological sections, using computer-aided three-dimensional (3-D) reconstruction. The most noteworthy of the findings demonstrated that both the mastoid portion of the facial nerve and the segment of the facial nerve between the second genu and the divergence of the chorda tympani nerve lengthened with age. The mastoid segment lengthened more significantly than the latter, indicating the facial canal grows more than the facial nerve in its mastoid portion. This difference in growth rates results in the site of the chorda tympani nerve divergence shifting with age relative to the stylomastoid foramen. PMID- 7857634 TI - Principles of human brain organization derived from split-brain studies. PMID- 7857635 TI - Mutations disrupting neuronal connectivity in the Drosophila visual system. AB - The photoreceptor neurons (R cells) of the Drosophila compound eye elaborate a precise array of neuronal connections in the brain. These projections exhibit target specificity and create topographic maps (retinotopy). We have screened histologically for mutations disrupting R cell connectivity in developing tissue. Eighty mutations were isolated from over 6000 ethylmethane sulfonate-mutagenized lines. Characterization of these mutations included genetic mosaic analysis to determine whether the gene is required in the retina or in the optic ganglia. Most mutations were found to affect connectivity indirectly by disrupting development more generally in the eye or brain. Genes were identified as candidates for playing direct roles in R cell connectivity by affecting axonal outgrowth (eddy), target recognition (limbo and nonstop), and retinotopy (limbo). PMID- 7857636 TI - Regulation of c-fos expression in transgenic mice requires multiple interdependent transcription control elements. AB - Transcription control regions of eukaryotic genes contain multiple sequence elements proposed to function independently to regulate transcription. We developed transgenic mice carrying fos-lacZ fusion genes with clustered point mutations in each of several distinct regulatory sequences: the sis-inducible element, the serum response element, the fos AP-1 site, and the calcium/cAMP response element. Analysis of Fos-lacZ expression in the CNS and in cultured cells demonstrated that all of the regulatory elements tested were required in concert for tissue- and stimulus-specific regulation of the c-fos promoter. This implies that the regulation of c-fos expression requires the concerted action of multiple control elements that direct the assembly of an interdependent transcription complex. PMID- 7857637 TI - Molecular cloning of TOPAP: a topographically graded protein in the developing chick visual system. AB - Topographically graded molecules representing position-specific differences among otherwise similar cells are thought to play a role in the patterning of the developing nervous system. In the embryonic chick visual system, a 40 kDa protein, TOPAP, is expressed in a posterior > anterior gradient in the retina and in an inverted anterior > posterior gradient in the optic tectum, the major retinal projection area. Here we report the isolation and nucleotide sequencing of a complementary DNA clone encoding the chick TOPAP protein and demonstrate that the mRNA encoding this coiled-coil integral membrane protein is topographically graded within the retina and is present in a variety of chick tissues. PMID- 7857638 TI - Localized collapsing cues can steer growth cones without inducing their full collapse. AB - Collapsing factors are proteins that induce growth cone collapse and paralysis when added in a soluble form to cultured embryonic neurons. Here we examine the responses of growth cones to localized collapsing signals. Temporal retinal ganglion cell growth cones exposed to a localized collapsing stimulus from nasal retinal ganglion cell axons frequently turn smoothly away from the axons without collapsing. Turning is rare on contact with retinal axons that are unable to induce collapse. In a separate series of experiments, dorsal root ganglion growth cones tend to turn away from beads coated with a brain extract enriched for the motility-inhibiting protein collapsin. Many turns are accomplished with filopodial contact alone. Growth cones do not turn away from control beads coated with heat-inactivated collapsin. These results suggest that inhibitory guidance cues can steer growth cones through a localized inhibition of lamellipodial protrusion. PMID- 7857639 TI - minibrain: a new protein kinase family involved in postembryonic neurogenesis in Drosophila. AB - The development of the adult central nervous system of Drosophila requires a precise and reproducible pattern of neuroblast proliferation during postembryonic neurogenesis. We show here that mutations in the minibrain (mnb) gene cause an abnormal spacing of neuroblasts in the outer proliferation center (opc) of larval brain, with the implication that mnb opc neuroblasts produce less neuronal progeny than do wild type. As a consequence, the adult mnb brain exhibits a specific and marked size reduction of the optic lobes and central brain hemispheres. The insufficient number of distinct neurons in mnb brains is correlated with specific abnormalities in visual and olfactory behavior. The mnb gene encodes a novel, cell type-specific serine-threonine protein kinase family that is expressed and required in distinct neuroblast proliferation centers during postembryonic neurogenesis. The mnb kinases share extensive sequence similarities with kinases involved in the regulation of cell division. PMID- 7857640 TI - Superoxide dismutase delays neuronal apoptosis: a role for reactive oxygen species in programmed neuronal death. AB - Sympathetic neurons in culture die by apoptosis when deprived of nerve growth factor (NGF). We used this model of programmed cell death to study the mechanisms that mediate neuronal apoptosis. Cultured sympathetic neurons were injected with copper/zinc superoxide dismutase protein (SOD) or with an expression vector containing an SOD cDNA. In both cases apoptosis was delayed when the neurons were deprived of NGF. The delay was similar to that seen when a bcl-2 expression vector was injected. SOD, injected 8 hr after NGF deprivation, provided no protection, indicating that superoxide production may occur early in response to trophic factor deprivation. We have demonstrated, with a redox-sensitive dye, an increase in reactive oxygen species (ROS) that peaked at 3 hr after sympathetic neurons were deprived of NGF. If NGF was added back to the culture medium after the period of peak ROS generation, apoptosis was completely prevented, suggesting that ROS production serves as an early signal, rather than a toxic agent, to mediate apoptosis. PMID- 7857641 TI - Myoblast fusion and innervation with rat motor nerve alter distribution of acetylcholinesterase and its mRNA in cultures of human muscle. AB - To elucidate the mechanisms underlying acetylcholinesterase (AChE) localization, we analyzed the distribution of AChE and Ache mRNA during myogenesis in cocultures of human muscle and fetal rat spinal cord. We observed a temporal coincidence in alterations of AChE localization and nuclei expressing the message, suggesting developmental regulation at the mRNA level. Nonuniform mRNA staining among nuclei suggests asynchronous regulation, also supporting an earlier proposal that transcription proceeds intermittently. Asynchrony seems to be overridden by generally acting factors during myoblast fusion, when message is up-regulated, and at the onset of muscle contractions, when it becomes restricted to some nuclei in the junctional region and focal patches of AChE appear near nerve contacts. Coincidence of mRNA down-regulation and synthesis of stable basal lamina-bound AChE suggests coordinated adaptation, so that sufficient enzyme may be derived from low message levels. PMID- 7857642 TI - Regulation of the acetylcholine receptor epsilon subunit gene by recombinant ARIA: an in vitro model for transynaptic gene regulation. AB - Structural specialization of the postsynaptic skeletal muscle membrane is in part mediated by the motor neuron-induced transcriptional regulation of synaptic muscle nuclei. ARIA, a factor that stimulates production of acetylcholine receptors (AChRs), is a candidate signaling molecule for such regulation. Here we examine the transynaptic inducing potential of this polypeptide factor. ARIA immunoreactivity is detectable at synaptic sites in vivo. In vitro, recombinant heregulin beta 1 (rHRG beta 1), the human homolog of ARIA, induces expression of the AChR epsilon gene, the subunit most sensitive to synaptic input. The inducing property of rHRG beta 1 is demonstrated most dramatically in primary muscle cultures from transgenic mice bearing an epsilon promoter-nuclear lacZ reporter transgene. Transient transfection experiments using the Sol 8 muscle cell line indicate that sequences that confer responsiveness to ARIA are located within a 150 bp epsilon subunit promoter region and are E box-independent. These results suggest that ARIA performs a vital role by directing spatially restricted gene expression at the neuromuscular junction. PMID- 7857643 TI - Targeted expression of tetanus toxin light chain in Drosophila specifically eliminates synaptic transmission and causes behavioral defects. AB - Tetanus toxin cleaves the synaptic vesicle protein synaptobrevin, and the ensuing loss of neurotransmitter exocytosis has implicated synaptobrevin in this process. To further the study of synaptic function in a genetically tractable organism and to generate a tool to disable neuronal communication for behavioural studies, we have expressed a gene encoding tetanus toxin light chain in Drosophila. Toxin expression in embryonic neurons removes detectable synaptobrevin and eliminates evoked, but not spontaneous, synaptic vesicle release. No other developmental or morphological defects are detected. Correspondingly, only synaptobrevin (n-syb), but not the ubiquitously expressed syb protein, is cleaved by tetanus toxin in vitro. Targeted expression of toxin can produce specific behavioral defects; in one case, the olfactory escape response is reduced. PMID- 7857644 TI - Chromaffin cell cortical actin network dynamics control the size of the release ready vesicle pool and the initial rate of exocytosis. AB - Morphological, biochemical, and membrane capacitance measurements were used to study the role of cortical filamentous actin (F-actin) in exocytosis. Fluorescence and electron microscopy of resting chromaffin cells revealed a cortical actin network that excluded secretory vesicles from the subplasmalemmal area. Phorbol ester (PMA) treatment disrupted cortical F-actin and increased both the number of vesicles within the 0-50 nm subplasmalemmal zone and the initial rate of stimulated catecholamine release. In PMA-pretreated cells, membrane capacitance studies showed an increased number of vesicles fusing with the plasmalemma during the first two depolarizations of a train. PMA did not affect voltage-dependent Ca2+ influx. The total number of vesicles fused with the plasma membrane correlated well with the number of vesicles occupying the 0-50 nm cortical zone. Therefore, cortical F-actin disassembly allows translocation of vesicles to the plasmalemma in preparation for exocytosis. PMID- 7857645 TI - Temporally regulated nuclear entry of the Drosophila period protein contributes to the circadian clock. AB - The Drosophila period protein (PER) is a predominantly nuclear protein and a likely component of a circadian clock. PER is required for daily oscillations in the transcription of its own gene and thus participates in a circadian feedback loop. In this study, key pacemaker neurons of the Drosophila brain were examined to determine whether the subcellular distribution of PER changes with the time of day. Indeed, PER was found to accumulate in the cytoplasm for several hours before entering the nucleus during a narrow time window. Three long-period mutations (perL) cause a delay in the timing of nuclear translocation and a further delay at elevated temperature. The data indicate that regulation of PER nuclear entry is critical for circadian oscillations by providing a necessary temporal delay between PER synthesis and its effect on transcription. PMID- 7857646 TI - Topology profile for a glutamate receptor: three transmembrane domains and a channel-lining reentrant membrane loop. AB - We investigated the transmembrane topology of the GluR3 subunit that was translated in rabbit reticulocytes supplemented with microsomal membranes. A prolactin reporter epitope was fused to GluR3 at six locations, bracketing each of the proposed transmembrane domains. The sidedness of the epitope in the microsomal membrane was then assessed by proteinase K sensitivity. The N terminus and the entire region between M3 and M4 was extracellular, and the C terminus was intracellular by this method. Four native N-linked glycosylation sites in the amino terminus and one introduced site between M3 and M4 were utilized, confirming the extracellular location of these regions. Epitopes inserted upstream and downstream of M2 were protease sensitive and thus intracellular. Our results support a topological model for glutamate receptor subunits that consists of three transmembrane domains, M1, M3, and M4, and another domain, the proposed channel-lining M2, which forms a reentrant membrane segment with both ends facing the cytoplasm. PMID- 7857647 TI - Bradykinin excites rat sympathetic neurons by inhibition of M current through a mechanism involving B2 receptors and G alpha q/11. AB - Bradykinin (BK) is a peptide mediator released in inflammation that potently excites sympathetic neurons. We have studied the mechanism of this excitation in dissociated rat sympathetic neurons and found that at low nanomolar (EC50 = 0.9 nM) concentrations, BK inhibited the M-type K+ current IK(M). Studies with the selective antagonist Hoe140 revealed that this effect was mediated via the B2 receptor subtype, and mRNA encoding this receptor was identified in these neurons by RT-PCR. IK(M) inhibition was unaffected by Pertussis toxin or microinjection of antibodies to G alpha o but was selectively inhibited by microinjection of antibodies to G alpha q/11. Thus, BK is the most potent M current inhibitor yet described in mammalian neurons, and BK inhibition of M current is mediated by a G protein pathway similar to that activated by muscarinic acetylcholine receptors. PMID- 7857648 TI - Persistent activation of min K channels by chemical cross-linking. AB - Expression of the structurally and functionally distinct min K channel in Xenopus oocytes results in voltage-dependent potassium currents that activate with a characteristic slow time course. Application of a membrane-impermeable chemical cross-linking agent to oocytes expressing min K decreased the time-dependent current, increased its rate of activation, and induced persistently activated inward and outward potassium currents. These effects required membrane depolarization, demonstrating use dependence. Persistently activated channels retained potassium selectivity and sensitivity to block by clofilium and barium. These results suggest that a major conformational change occurs during min K channel gating, which can be stabilized by chemical cross-linking, and are consistent with a model in which min K channels activate by voltage-dependent subunit aggregation. PMID- 7857649 TI - A novel intermediate stage in the transition between short- and long-term facilitation in the sensory to motor neuron synapse of aplysia. AB - A major difference between short- and long-term memory is that long-term memory is dependent on new protein synthesis. Long-term memory can be further subdivided into a transient, initial phase that is readily susceptible to disruption and a later, more stable and persistent stage. To analyze this transition on the cellular level, we have examined the steps whereby short-term facilitation is converted to a long-term form in the sensorimotor connection of the Aplysia gill withdrawal reflex. We found that stable long-term facilitation (at 24 hr) requires a higher concentration (100 nM) of serotonin (5-HT) than does short-term facilitation (10 nM). By using low concentrations of 5-HT, which do not produce long-term facilitation, we now have been able to explore the intermediate phases between the short- and long-term processes. By this means we have uncovered a new transient phase that involves three mechanistically different mechanisms- covalent modification, translation, and transcription--each of which can be recruited as a function of the concentration of 5-HT. PMID- 7857650 TI - Sorting mechanisms of tau and MAP2 in neurons: suppressed axonal transit of MAP2 and locally regulated microtubule binding. AB - Tau is abundant in the axon, whereas MAP2 is found in the cell body and dendrites. To understand their differential localization, we performed transfection studies on primary cultured neurons using tagged tau, MAP2, MAP2C, and their chimeric/deletion mutants. We found that MAP2 was prevented from entering the axon by its N-terminal projection domain and that microtubule binding of tau was stronger in the axon than in the cell body and dendrites, whereas that of MAP2/MAP2C was tighter in the cell body and dendrites than in the axon. These binding properties were determined by their microtubule-binding domains and were suggested to be regulated by phosphorylation, at least in the case of tau. Thus, the suppressed axonal transit of MAP2 and locally regulated microtubule binding may play important roles for their sorting in neurons. PMID- 7857651 TI - Arc, a growth factor and activity-regulated gene, encodes a novel cytoskeleton associated protein that is enriched in neuronal dendrites. AB - Neuronal activity is an essential stimulus for induction of plasticity and normal development of the CNS. We have used differential cloning techniques to identify a novel immediate-early gene (IEG) cDNA that is rapidly induced in neurons by activity in models of adult and developmental plasticity. Both the mRNA and the encoded protein are enriched in neuronal dendrites. Analysis of the deduced amino acid sequence indicates a region of homology with alpha-spectrin, and the full length protein, prepared by in vitro transcription/translation, coprecipitates with F-actin. Confocal microscopy of the native protein in hippocampal neurons demonstrates that the IEG-encoded protein is enriched in the subplasmalemmal cortex of the cell body and dendrites and thus colocalizes with the actin cytoskeletal matrix. Accordingly, we have termed the gene and encoded protein Arc (activity-regulated cytoskeleton-associated protein). Our observations suggest that Arc may play a role in activity-dependent plasticity of dendrites. PMID- 7857652 TI - Expression of the Alzheimer amyloid-promoting factor antichymotrypsin is induced in human astrocytes by IL-1. AB - The amyloid deposits of Alzheimer's disease contain, in addition to the beta protein (A beta), lesser amounts of other proteins including the protease inhibitor alpha 1-antichymotrypsin (ACT). We have recently shown that ACT acts as a pathological chaperone, binding to the beta protein and strongly promoting its polymerization into amyloid filaments in vitro. The data of this paper show that ACT synthesis is induced in cultured human astrocytes by IL-1, a lymphokine whose expression is strongly up-regulated in microglial cells in affected areas of Alzheimer's disease brain. Furthermore, unfractionated glial cultures containing both astrocytes and microglia from human cortex (which develops amyloid in Alzheimer's disease) spontaneously express IL-1 and ACT as they reach confluence. In contrast, confluent mixed glial cultures similarly prepared from human cerebellum or brain stem, or from rat brain-tissues not prone to amyloid formation-do not express ACT unless supplemented with exogenous IL-1. The same regional difference in IL-1 expression by microglia is seen in vivo in Alzheimer's disease. These results indicate that the IL-1-induced expression of ACT may help direct the region-specific production of mature amyloid filaments in the Alzheimer brain. PMID- 7857653 TI - Dominant and differential deposition of distinct beta-amyloid peptide species, A beta N3(pE), in senile plaques. AB - We analyzed an amino-terminal modification of beta-amyloid (A beta) peptide in brain, using anti-A beta antibodies that distinguish distinct molecular species. Examination of cortical sections from 28 aged individuals with a wide range in senile plaque density revealed that a molecular species distinct from the standard A beta is deposited in the brain in a dominant and differential manner. This modified A beta peptide (A beta N3(pE)) starts at the 3rd aminoterminal residue of the standard A beta, glutamate, converted to pyroglutamate through intramolecular dehydration. Because plaques composed of A beta N3(pE) are present in equivalent or greater densities than those composed of standard A beta bearing the first amino-terminal residue (A beta N1) and because deposition of the former species appears to precede deposition of the latter, as confirmed with specimens from Down's syndrome patients, the processes involved in A beta N3(pE) production and retention may play an early and critical role in senile plaque formation. PMID- 7857654 TI - The precursor protein of non-A beta component of Alzheimer's disease amyloid is a presynaptic protein of the central nervous system. AB - Non-A beta component of Alzheimer's disease amyloid (NAC) is the second component in the amyloid from brain tissue of patients affected with Alzheimer's disease. Its precursor protein (NACP) was shown to be a brain-specific protein. In rat brain, NACP was more abundant in the neocortex, hippocampus, olfactory bulb, striatum, thalamus, and cerebellum and less abundant in the brain stem. Confocal laser microscopy analysis revealed that anti-NACP immunostaining was colocalized with synaptophysin-immunoreactive presynaptic terminals. Ultrastructural analysis showed that NACP immunoreactivity was associated with synaptic vesicles. NACP sequence showed 95% identity with that of rat synuclein 1, a synaptic/nuclear protein previously identified in rat brain, and good homology with Torpedo synuclein from the electric organ synapse and bovine phosphoneuroprotein 14 (PNP 14), a brain-specific protein present in synapses. Therefore, NACP is a synaptic protein, suggesting that synaptic aberration observed in senile plaques might be involved in amyloidogenesis in Alzheimer's disease. PMID- 7857655 TI - Localization of mRNA for basic fibroblast growth factor in human placenta. AB - The site of basic fibroblast growth factor (bFGF) gene expression in human placenta is not known. In situ hybridization using [35S]-labelled riboprobe was employed to localize the sites of expression of bFGF mRNA in placental sections from early and late gestation. Autoradiographic hybridization signal was present in all placental tissue examined, with no significant hybridization with sense control. Basic FGF expression was seen in the syncytiotrophoblast surrounding the placental villi and in or around cytotrophoblast cells in first trimester placenta. At term, the bFGF gene expression was detected in the syncytiotrophoblast and fetal membranes. Strong expression of bFGF mRNA was localized in the smooth muscle cells around the mid and large sized placental vessels. The detection of bFGF mRNA in the placenta during early pregnancy suggests a role for bFGF in angiogenesis, whereas, its expression at term suggests that bFGF may be associated with differentiated functions of the trophoblast. PMID- 7857656 TI - Processing of epidermal growth factor in the rat submandibular gland by Kallikrein-like enzymes. AB - Epidermal growth factor (EGF) is synthesized as a precursor which is processed intracellularly to a 6 kDa EGF in the rat submandibular gland. This gland contains very high amounts of kallikrein-like enzymes, and the purpose of the present study was to examine whether any of five such enzymes, rK1, rK2, rK7, rK9 or rK10, can process the rat EGF precursor. Molecular weight forms of EGF, that were N- or C-terminally extended compared to submandibular gland EGF were obtained from rat urine. These extended forms of EGF were incubated with each of the enzymes for 24 h at 37 degrees C. Two enzymes, rK7 and rK10, were able to cleave N- and C-terminally extended EGF, releasing a form of EGF which eluted similarly to submandibular gland EGF upon gel filtration, and which was recognized both by antibodies against rat EGF and by the EGF receptor. One enzyme, rK1, cleaved C- but not N-terminally extended EGF. Neither rK2, nor rK9 cleaved the extended forms of EGF. In previous immunohistochemical studies rK1, rK7 and rK10 have all been demonstrated in the EGF containing cells of the rat submandibular gland. EGF and rK1 are also synthesized in the rat kidney but the present study demonstrated that EGF and rK1 are not colocalized in this organ. Based on the cleavage of the extended forms of rat EGF by rK1, rK7 and rK10 and on the fact that the enzymes are abundant and colocalized with EGF in the rat submandibular gland, we suggest that rK1, rK7 and rK10 can be involved in the processing of the EGF precursor in the rat submandibular gland. PMID- 7857657 TI - Isolation of a receptor tyrosine kinase (DTK) from embryonic stem cells: structure, genetic mapping and analysis of expression. AB - Analysis of receptor tyrosine kinases expressed during mouse embryonic stem cell differentiation resulted in the cloning of a receptor designated developmental tyrosine kinase (DTK). The 850 amino acid mature receptor protein comprises an extracellular domain with two immunoglobulin-like motifs and two fibronectin type III modules, a 25 amino acid transmembrane domain and a cytoplasmic region with a catalytic kinase domain. In embryonic stem cells growing in the presence of leukemia inhibitory factor DTK is abundantly expressed and this level of expression is maintained in differentiating embryonic stem cells and cystic embryoid bodies. In mid-gestational embryos (E14.5), DTK RNA is expressed in many tissues including brain, eye, thymus, lung, heart, gut, liver, testis and limbs. In contrast, expression of DTK in adult mice becomes restricted to brain, portions of the gastrointestinal tract, bladder, testis and ovary. There is enrichment of transcripts encoding DTK in purified fetal liver hematopoietic stem cells, when compared with unfractionated fetal liver. The DTK gene maps to mouse chromosome 2, band F. PMID- 7857658 TI - Isolation and characterization of the human DTK receptor tyrosine kinase. AB - A cDNA encoding the human homologue of the murine DTK receptor tyrosine kinase has been isolated from a human brain library. The DTK cDNA encodes a mature protein of 850 amino acids with similar structural features to those of the murine receptor. The extracellular domain contains two immunoglobulin-like motifs and two fibronectin type III modules; features which define a new class of receptor tyrosine kinase. The human DTK gene has been mapped by fluorescent in situ hybridization to chromosome 15q15, and a DTK-related gene identified at chromosome 15q24. In fetal tissues, transcripts for DTK were detected in brain, kidney, lung and heart. Prominent expression was observed in the embryonal carcinoma cell line NT2/D1. Expression of the gene is up-regulated in adult tissues with high levels of expression in many regions of the adult brain. DTK is also abundantly expressed in adult kidney, testis, and ovary. PMID- 7857659 TI - Production of a bioactive high molecular weight transforming growth factor beta like molecule by human malignant glioma cell lines. AB - The present study describes identification and partial characterization of a glioma-derived high molecular weight transforming growth factor beta-like molecule (HMW-TGF beta) that requires no activation for biological activity. HMW TGF beta, constitutively produced by the human glioma cell line, D54MG, is not acid- or heat-labile; is relatively resistant to denaturation, reduction, and high salt treatment. Monoclonal antibody 12A12.D7, produced against partially purified HMW-TGF beta, was used both to deplete and to neutralize directly a > 158 kDa HMW-TGF beta activity from gel filtration fractions; the antibody also directly neutralized purified mature TGF beta 1. 12A12.D7 recognized a single protein species of 186 kDa from unlabeled glioma cell conditioned media and 35S labeled lysates. HMW-TGF beta is not due to complex formation between TGF beta and any of the known carrier molecules. Production of HMW-TGF beta by glioma cells could facilitate tumor cell proliferation, and thus contribute to the inexorable and rapid progression that characterizes malignant gliomas. PMID- 7857660 TI - LIF and OM directly interact with a soluble form of gp130, the IL-6 receptor signal transducing subunit. AB - Oncostatin M and LIF are related members of a cytokine family that also includes IL-6, CNTF and G-CSF. These proteins exhibit overlapping biological properties and with the exception of G-CSF, they all appear to utilize gp130 as a signaling component of their high affinity receptor complexes. Recently it has been demonstrated that monomeric, membrane bound gp130 can directly bind OM. To further investigate the binding properties of gp130 we generated a soluble form of gp130, sgp130-Rg, to investigate potential gp130 interactions with OM and other members of this cytokine family. Using chemical crosslinking techniques we demonstrate that OM and LIF but not CNTF or IL-6 directly interact with sgp130 Rg. Since OM signaling can be prevented by binding gp130 with anti gp130 mAbs we also investigated the potential of sgp130-Rg to prevent the biological activities of both LIF and OM. Here we demonstrate that sgp130-Rg can bind LIF and OM preventing their biological activities on the TF-1 erythroleukemia cell line. This property suggests that sgp130-Rg may have therapeutic value in the specific prevention of LIF or OM mediated pathologies. PMID- 7857661 TI - Identification of functional domains of interleukin-3 by construction of primate interspecies chimera. AB - Interleukin-3 (IL-3) is involved in regulation of proliferation and differentiation of multipotent hemopoietic cells and stimulates the production of most blood cell types. The observed functional specificity across species concurs with an extreme rate of IL-3 amino acid substitutions during mammalian evolution. Tamarin IL-3 exhibited 70.5% sequence identity with human IL-3 and was severely impaired in supporting proliferation of human IL-3-dependent cells. In contrast, chimpanzee IL-3 displayed high amino acid sequence homology (98.5%) and could substitute for human IL-3. A panel of interspecies chimera between the chimpanzee and tamarin IL-3 genes has been constructed and expressed in Escherichia coli and eukaryotic cells to investigate the role of substitutions in different protein domains on the functional species specificity. Our analyses show that substitutions at residues encoded by the first two exons appear crucial in the functional species specificity, whereas C-terminal alterations show only moderate effects. PMID- 7857662 TI - IgG subclass levels and southern analysis of DNA in primary immunodeficiency diseases including IgG subclass deficiency. AB - Serum IgG subclass levels are reported for twenty patients with primary immunodeficiency diseases, including four patients with IgG subclass deficiency, using an enzyme-linked immunosorbent assay with monoclonal antibodies. The disorder of each patient with IgG subclass deficiency seemed to be heterogeneous immunologically and clinically. One had complete IgG2-IgG4 deficiency, another had IgG2-IgG4-IgA deficiency and the other two had IgG2-IgA deficiencies. We did not find any structural-gene deletions in the constant region of the human immunoglobulin heavy-chain locus. Although the possibility of defects in genes controlling immunoglobulin expression, or small mutations, remains, these results suggest that IgG subclass deficiency is not always linked to particular structural-gene deletions. PMID- 7857663 TI - Viral antibody titers are influenced by HLA-DR2 phenotype. AB - Antibody serum levels against herpes simplex type 1 virus, cytomegalovirus, viral capsid antigens of Epstein-Barr virus, and rubella virus were evaluated in a sample of the Sicilian population. Results demonstrated that HLA-DR2-positive individuals showed a significant increase in antibody titers, when compared to HLA-DR2-negative individuals. These observations seem to be in contrast with the reported association of the HLA-DR2 phenotype with an ineffective immune response against several infectious pathogens. On the other hand, an increased humoral response to viral antigens need not be interpreted as a marker for effective control of virus infections. In fact, the response to virus infections is related to the T-cell-mediated immune response restricted by class-I- or class-II-encoded proteins. Thus, the above-mentioned HLA-DR2-related susceptibility to certain viral infections could be associated with a preferential induction of an increased (although ineffective) antibody synthesis against viral antigens. PMID- 7857664 TI - Oligonucleotide genotyping of HLA-DRB1 04 and HLA-DQB1 03 among Russians in west Siberia suffering from rheumatoid arthritis. AB - To determine the HLA-DRB1 04 and HLA-DQB1 03 variants associated with rheumatoid arthritis (RA) among Russians who live in West Siberia, we studied patients with RA using the polymerase chain reaction and dot-blot hybridization with oligonucleotide probes. A significant increase was seen only for DRB1 0404/08, although the predominant variant in DR4+ RA patients was DRB1 0401. We found no significant difference in the DQB1 03 variants in RA cases when compared with controls. The results suggest that in the Russian-Siberian population RA is primarily associated with several DRB1 04 variants that share sequence identity in the third hypervariable region. PMID- 7857665 TI - Genetic variability of the MHC class III complement proteins C2, BF, C4A and C4B in southern Brazil. AB - We describe here the genetic variability of C2, C4 and BF in 225 healthy adult individuals from southern Brazil, including 172 Caucasoids, 47 Mulattos, 3 Blacks and 1 Amerindian. C2 gene frequencies were in accordance with those described for other populations, and two rare variants were observed. The BF allotype frequencies were slightly different between the Caucasoids and Mulattos, the latter having a higher BF*F frequency. A new BF*S variant, identified as S05 was observed in a Caucasoid individual. The frequencies of C4A and C4B in the Caucasoids were similar to other reported Caucasoid populations; a decrease of the silent allele B*Q0, and several rare variants were observed. A higher C4A*3 frequency and a remarkable decrease of C4A*Q0 were observed in the Mulattos. In addition, several C4 heteroduplications and aberrant allotypes were observed. Considering the high genetic variability found in a limited number of individuals, one may conclude that due to genetic admixture much heterogeneity might be expected for the MHC class III region in different Brazilian populations. PMID- 7857666 TI - TCR/CD3 ligation of a TCR-transgenic T lymphoma blocks its proliferation in vitro but does not affect its growth in vivo. AB - A backcrossed mouse line was established homozygous for the autosomal recessive mutation scid (severe combined immunodeficiency) and carrying T cells which express transgenic (tg) T cell receptor (TCR) alpha and beta chains that mediate H-2 class I (Db)-restricted recognition of a male (H-Y) determinant (TCR-tg SCID mouse). A thymoma arose 'spontaneously' in one of the TCR-tg female SCID mice and the thymoma cells were adopted to factor-independent, in vitro growth in long term tissue culture. The thymic lymphoma cell line was cloned and one of the subclones, TL1, was studied. The ultrastructure of TL1 cells resembled that of small-to-medium lymphoblasts. The cells had the following phenotype: CD3 + TCR alpha T+TCR beta T+CD4-CD8- CD44-CD45RB+LECAM-1 + IL-2R- and low H-2 expression. Exposure of TL1 cells to TCR-binding monoclonal antibodies or lectins blocked in their in vitro proliferation. In addition, TL1 cell proliferation was inhibited by coculture with male and female H-2b+ cells. Following adoptive transfer into both H-2b+ and H-2d+ SCID recipient mice, TL1 cells showed rapid, malignant growth and infiltrated lymphoid and nonlymphoid organs. Expression of the tg TCR complex was selectively downregulated in TL1 cells growing in H-2b+ male SCID recipients. However, the malignant in vivo growth potential of TL1 cells was comparable, irrespectively of the sex and haplotype of the SCID recipient. In conclusion, our data show that the growth of TL1 cells in vitro is suppressed by physiological ligation of their TCR complex, whereas TL1 cells, by downregulation of their TCR, may escape TCR-ligation-induced suppression in vivo. PMID- 7857667 TI - Molecular basis of human band-3 mutation associated with increased anion transport. AB - Band 3, the anion transporter, is a ubiquitous protein. It is present in brain and all other tissues. Not only is band 3 present in cell membranes, but also in nuclear, Golgi, and mitochondrion membranes. Band 3 is involved in respiration, acid-base balance, and is the major structural protein linking the plasma membrane to the cytoskeleton. Thus, alterations/mutations in the transport segment of the band-3 molecule might be expected to be of major importance. We discovered and sequenced a mutation of band 3, high-transport band 3 (HTbd3), that exhibits anion transport that is 2-3 time above normal. Anion transport studies of the family members revealed that red cells from the proposita, one of two siblings, and both parents had abnormally increased anion transport (increased Vmax). We used synthetic peptides of band 3 to help localize the change along the band-3 molecule. Results suggest that high-transport band 3 is altered in or near residue 869-883. This places the alteration toward the carboxyl terminal of band 3. cDNA sequencing demonstrated that the mutation was a proline to leucine at residue 868. A peptide was synthesized corresponding to residues 853-870 for testing in the anion transport inhibition assay. This peptide significantly inhibited anion transport (p < or = 0.001) indicating that it is an anion transport/binding region of band 3. Thus, DNA technology confirms the validity of the anion transport inhibition assay for localizing transport regions. Glucose transport is decreased in affected individuals. The HTbd3 mutation appears benign as determined by the red cell aging panel. IgG binding, creatinine, and glyceraldehyde-3-phosphate dehydrogenase are normal. Our studies indicate that the most rapid and sensitive techniques for detecting band-3 alterations are polyacrylamide gel electrophoresis, IgG binding, and anion transport studies. This is the only mutation of band 3 discovered to date the affects the transmembrane, anion transport region of band 3. PMID- 7857668 TI - Definition of a sequence-tagged site for the human immunoglobulin IGLV9S1 gene located at chromosome 22q11. AB - We have compared the sequences of the nine human immunoglobulin V lambda gene subgroups in order to define specific sequences for the IGLV9S1 gene. The oligonucleotides corresponding to these regions, in both forward and reverse positions, were used in polymerase chain reactions from human genomic DNA. A unique fragment of 177 base pairs was amplified from positions 136-312 of the IGLV9S1 gene and cloned in pUC18. When used as a probe in Southern hybridization with human genomic DNA, a unique band was detected, indicating that IGLV9S1 is a single-copy gene. We have defined this fragment as a sequence-tagged site designated IGLV9S1 [/22q11] for the IGL locus. PMID- 7857669 TI - Molecular analysis of cis-regulatory sequences of the alpha-amylase gene in D. melanogaster: a short 5'-flanking region of Amy distal gene is required for full expression of Amy proximal gene. AB - The structural locus for alpha-amylase (AMY) in Drosophila melanogaster is duplicated and divergently transcribed. These two genes are designated as Amy-p and Amy-d, respectively. We searched for the cis-acting regulatory elements for full expression of the duplicated Amy-p and Amy-d loci, by injecting plasmid constructs containing sequences from the Amy locus into preblastoderm embryos of an AMY-null strain and measuring exogenous AMY activity produced in transformed host larvae (i.e., the transient expression assay). Relative activities of endogenous amylase isozymes, AMY-1 and AMY-3, in extracts of AMY1,3 larvae of a Canton-S are almost the same. However, three independently isolated Amy-p1 constructs with only the 5' upstream regions of Amy-p1 expressed a very low AMY-1 activity. Two other Amy-p1 constructs with the 5' upstream region of Amy-d3 in addition to that of Amy-p1 produced a high activity. Thus, the 5' upstream region of Amy-d3 is necessary for full expression of Amy-p1. In order to locate cis regulatory elements within the 5' region of Amy-d3, a series of hybrid constructs including this region were tested to locate them. Our results clearly show that the cis-acting regulatory sequences required for full expression of Amy-p1 are located between the base pairs at -304 and -372 upstream of Amy-d3 gene. In other words, only a short region located upstream of Amy-d3 was found to be necessary and sufficient for the full expression of Amy-p1 in addition to its promoter. This region seems also necessary for the expression of Amy-d3. PMID- 7857670 TI - Placental glucose dehydrogenase polymorphism in Koreans. AB - The genetic polymorphism of placental glucose dehydrogenase (GDH) was investigated in 300 Korean placentae using horizontal starch gel electrophoresis. The allele frequencies for GDH1, GDH2 and GDH3 were 0.537, 0.440 and 0.005, respectively, which were similar to those in Japanese. We also observed an anodal allele which was similar to the GDH4 originally reported in Chinese populations at a low frequency of 0.015. An additional new cathodal allele (named GDH6) was observed in the present study with a very low frequency of 0.003. PMID- 7857671 TI - Cloning of the cDNA and genomic DNA that correspond to the recA-like gene of Drosophila melanogaster. AB - We have isolated a cDNA homologous to the yeast DMC1 and RAD51 genes from Drosophila melanogaster. The DMC1 and RAD51 genes of Saccharomyces cerevisiae are known to play crucial roles during meiosis and during both meiosis and mitosis, respectively, and their gene products are homologous to each other and to the RecA protein of Escherichia coli. The cDNA cloned here contains an open reading frame that encodes 336 amino acids. Sequence analysis of the corresponding genomic DNA fragment showed one short intron existing in the coding region as in the DMC1 gene, but not in the RAD51 gene. By in situ hybridization to the salivary gland chromosomes, the recA-like gene was cytologically mapped to 99D of the third chromosome. PMID- 7857672 TI - Molecular cloning and characterization of a fission yeast gene responsible for supersensitivity to the spindle poison, isopropyl N-3-chlorophenyl carbamate. AB - The cps3 gene of the fission yeast, Schizosaccharomyces pombe, was previously identified as a mutation conferring supersensitivity to the spindle poison, isopropyl N-3-chlorophenyl carbamate (CIPC). A 3.2 kb DNA fragment that complements the mutant phenotype was cloned from a S. pombe genomic library. The base sequence analysis showed that the fragment contains a maximum 1086 nucleotide open reading frame and that the putative product consists of 362 amino acids, having a molecular weight of 39.3 KDa. No significant homology of the potential product with known proteins could be found by database searches. A disruptant of the gene, produced by insertion of a ura4+ fragment was able to germinate, but not to undergo cell division, suggesting that the gene to be essential for the cell cycle progression. The disruption experiment suggests that the gene is an extragenic suppressor of cps3 mutation. PMID- 7857673 TI - Chromosomal localization of human, rat, and mouse protein phosphatase type 1 beta catalytic subunit genes (PPP1CB) by fluorescence in situ hybridization. AB - Using fluorescent in situ hybridization (FISH) method, gene encoding the catalytic subunit of protein phosphatase type 1 beta (PPP1CB) in human and its corresponding gene in rat (PP1 delta) and mouse (dis2m2) were mapped to human 2p23, rat 6q21-q23, and mouse 12D, respectively. These results indicate that PPP1CB is a member of conserved syntenic group. It is shown that the genes encoding catalytic subunit of protein phosphatase type 1 family (PP1 alpha, PP1 beta, and PP1 gamma in human and those corresponding genes in rat and mouse), in spite of their high identity, are located to different chromosomes in these three species. PMID- 7857674 TI - Genetic characterization of Drosophila RBP-J kappa (suppressor of hairless) as a neurogenic gene in adult PNS development. AB - Drosophila RBP-J kappa is a novel sequence-specific DNA binding protein encompassing the integrase motif which is highly conserved in various organisms. Its gene has been shown to be identical to Suppressor of Hairless which regulates adult peripheral nervous system (PNS) development. To elucidate the precise function of the RBP-J kappa protein in adult PNS development, we analyzed transgenic files that misexpress the RBP-J kappa protein. Such studies have shown that RBP-J kappa regulates PNS cell fate in at least two steps: commitment to sensory mother cell by lateral inhibition and terminal differentiation into the socket and shaft cells. Taken together with analysis of phenotypes of Suppressor of Hairless mutants, RBP-J kappa shows the synergistic activity with neurogenic genes. PMID- 7857675 TI - Genetic variation estimated in three Shorea species by the RAPD analysis. AB - Three species of Shorea (S. leprosula, S. acuminata and S. cursitii) were collected from a natural forest reserve of Malaysia and analyzed for genetic variation using the technique of random amplification of polymorphic DNA (RAPD) by the polymerase chain reaction (PCR). The average number of nucleotide substitutions was estimated. The nucleotide diversities within species were very similar and larger than those found in Drosophila melanogaster. The nucleotide divergences between these species are about 1.5 times the nucleotide diversities within the species, indicating that these species diverged from a common ancestor relatively recently. PMID- 7857677 TI - Homozygous presence of the crossover (fusion gene) mutation identified in a type II Gaucher disease fetus: is this analogous to the Gaucher knock-out mouse model? AB - Gaucher disease (GD) is an inherited deficiency of beta-glucocerebrosidase (EC 3.1.2.45, gene symbol GBA). In type I GD, the CNS is not involved (nonneuronopathic), whereas in type II GD (acute neuronopathic) CNS involvement is early and rapidly progressive, while in type III GD (subacute neuronopathic) CNS involvement occurs later and is slowly progressive. The T6433C (L444P) substitution is prevalent in type GD II. It may occur alone as a single base-pair mutation but often is found as part of a complex allele containing additional GBA nucleotide substitutions, G6468C (A456P) and G6482C (V460V), without (recNciI) or with (recTL) G5957C (D409H). This complex allele is presumed to have formed by recombination (crossover, fusion) of the structural gene with the pseudogene, which contains the mutated sequences. Two complex alleles have never been demonstrated to coexist in any individual. We devised a selective PCR method for the specific amplification of the normal and/or fusion gene. Using this procedure we demonstrated the fusion gene in homozygous form for the first time, in a Macedonian/Ashkenazi Jewish GD type II fetus. Both parents were carriers of the recombination. This was confirmed by direct sequence analysis. A previous conceptus in this family was stillborn at 36 weeks, with features of severe type II GD. Neonates showing a severe clinical phenotype, analogous to the early neonatal lethal disease occurring in mice homozygous for a null allele produced by targeted disruption of GBA, have been described elsewhere, but the specific mutations in these cases have not yet been characterized.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7857676 TI - Mannose-coated liposomal hamycin in the treatment of experimental leishmaniasis in hamsters. AB - Liposomal hamycin was found to elicit enhanced microbicidal activity and reduced toxicity in experimental leishmaniasis in a hamster model under in vivo conditions. Mannose-coated liposomal hamycin was seen to produce increased therapeutic efficacy as judged from the lowering of spleen parasite load. At an equivalent dose of 0.5 mg/kg, every 3 days for a total of three doses in 7 days, the mannose-coated liposomal hamycin was found to be most effective compared to either of the liposomal hamycin or the free hamycin. Because of the reduced toxicity as judged from the blood pathology, tissue histology, and specific enzyme level related to normal liver function, mannose-coated liposomal hamycin resulted in 80 to 100% survival for a period of 15-18 days. Hamycin intercalated in sterol-rich liposomes showed reduced hemolytic activity but comparable therapeutic efficacy as was found with ordinary liposomes. PMID- 7857678 TI - Insulinotropic action of formycin A. AB - The adenosine analogue formycin A is phosphorylated to its triphosphate ester in a sequence of reactions catalyzed by adenosine kinase and adenylate kinase. Formycin A triphosphate is an ATP analogue that is currently used to probe for ATP binding sites. Considering the key role ascribed to ATP in the coupling of metabolic to cationic events in the process of glucose-stimulated insulin release, we investigated whether formycin A displays insulinotropic action in rat pancreatic islets. Formycin A (10 microM to 1.0 mM) caused a concentration related increase of insulin release evoked by 8.3 mM D-glucose and prevented the fall in insulin output otherwise observed over two successive incubations of 90 min each. Formycin A (1.0 mM) also augmented insulin secretion at low (5.6 mM) and high (16.7 mM) concentrations of D-glucose. At the low hexose concentration, the secretory response to formycin A was comparable to that evoked by either glibenclamide or glipizide. At higher concentrations of D-glucose, however, formycin A was more potent than the hypoglycemic sulfonylureas in enhancing insulin output. These findings support the role of ATP in glucose-stimulated insulin release and, therefore, suggest that ATP mimetics represent a new class of insulinotropic agents that have potential utility in the treatment of non insulin-dependent diabetes mellitus. PMID- 7857679 TI - Platelet-derived growth factor (PDGF) rapidly stimulates binding of glycolytic enzymes to muscle cytoskeleton, prevented by calmodulin antagonists. AB - Glycolytic enzymes are known to be controlled by reversible binding to cytoskeleton. Our previous experiments have shown that insulin, epidermal growth factor (EGF), and Ca2+ induce a rapid and transient stimulation of binding of glycolytic enzymes to muscle cytoskeleton. We show here that platelet-derived growth factor (PDGF) exerts a similar action. Incubation of rat diaphragm muscle in the presence of PDGF resulted in rapid and transient stimulation of binding of phosphofructokinase (EC 2.7.11) and aldolase (EC 4.1.2.13) to muscle cytoskeleton. The increase in cytoskeleton-bound glycolytic enzymes induced by PDGF was prevented by treatment with the calmodulin antagonists trifluoperazine or CGS 9343B (a potent and selective inhibitor of calmodulin activity), which strongly suggests that Ca(2+)-calmodulin is involved in this effect of PDGF. Similarly, we previously found that stimulation of cytoskeleton-bound glycolytic enzymes exerted by insulin, EGF, or Ca2+, was also calmodulin mediated. The present and previous results suggest that the rapid, Ca(2+)-calmodulin-mediated increase in cytoskeleton-bound glycolytic enzymes, may be a general mechanism in the cell, in signal transduction of insulin, growth factors, and other Ca(2+) mobilizing hormones. The accelerated cytoskeletal glycolysis will provide local ATP, which is required for the rapid cytoskeletal-membrane rearrangements following binding of growth factor or hormone to its receptor. PMID- 7857680 TI - Protective action of succinic acid monomethyl ester against the impairment of glucose-stimulated insulin release caused by glucopenia or starvation: metabolic determinants. AB - The monomethyl ester of succinic acid (SME) was recently found to protect pancreatic islet B-cells against the impairment of glucose-stimulated insulin release caused by either glucopenia or starvation. The possible metabolic determinants of such a protective action are now scrutinized. After 180 min preincubation at 2.8 mM D-glucose in the presence of SME (10 mM), the oxidation of D-[U-14C]glucose, relative to either the utilization of D-[5-3H]glucose or the generation of 14C-labeled acidic metabolites, was higher than that after preincubation in the absence of SME and became close to that otherwise found after preincubation at 16.7 mM D-glucose. Likewise, after 3 days of culture at a low concentration of D-glucose (2.8 mM), the presence of SME in the culture medium tended to increase the subsequent oxidation of D-[6-14C]glucose and utilization of D-[5-3H]glucose. These two variables increased as a function of the concentration of D-glucose in the culture medium, this coinciding with a modest increase in hexokinase activity and a more pronounced increase in glucokinase activity. The presence of SME in the culture medium failed, however, to exert any obvious effect upon the respiration of the islets, suggesting that the protective action of the ester against glucopenia may also involve variables distinct from the metabolism of either endogenous or exogenous nutrients. Likewise, the fact that SME infusion to starved rats prevents the impairment of glucose-induced insulin release otherwise attributable to starvation may involve enzymatic determinants, such as a less severe decrease in glucokinase activity, metabolic variables, such as a greater relative increase in D-[U-14C]glucose oxidation relative to D-[5-3H]glucose utilization in response to a rise in extracellular D-glucose concentration, and other factors yet to be identified that participate in the secretory sequence at a site distal to those metabolic events triggered by D-glucose in the islet cells. PMID- 7857681 TI - Nonkallikrein arginine endopeptidase in the human submaxillary gland: purification and characterization of the enzyme. AB - The two major species of arginine endopeptidase present in the soluble fraction of human submaxillary gland are glandular kallikrein and another enzyme tentatively named nonkallikrein arginine endopeptidase. In this study, we purified the latter enzyme to homogeneity and examined its catalytic properties. The newly found enzyme was clearly distinguishable from human tissue kallikrein in its molecular nature, action toward various synthetic substrates, and kinin generated activity. The specificity of the action of the enzyme was further investigated using various basic amino acid-containing peptides as model substrates. HPLC analysis of peptide fragments produced, followed by their amino acid analysis, revealed that the enzyme preferentially hydrolyzed the Arg-Arg or Arg-Lys bonds in dynorphins A 1-10, 1-9, and 1-8, beta-neoendorphin, adenorphin, and neurotensin. PMID- 7857682 TI - Immunochemical characterization of feline and human N-acetylgalactosamine 4 sulfatase. AB - Maroteaux-Lamy syndrome (mucopolysaccharidosis type VI; MPS VI) is a disorder which results from a deficiency in the lysosomal associated enzyme N acetylgalactosamine 4-sulfatase (4-sulfatase). A feline model of human MPS VI has previously been described and provides a system for the evaluation of enzyme replacement therapy protocols. As a preliminary study to human 4-sulfatase enzyme replacement therapy in feline we have compared the immunochemical properties of human and feline 4-sulfatase. By SDS-PAGE the molecular mass of purified feline and human 4-sulfatase were similar under both reducing and nonreducing conditions. There was, however, a detectable conformation difference between human and feline 4-sulfatase indicating some structural variation. Feline 4 sulfatase reacted weakly with a panel of monoclonal antibodies in an immunobinding assay (interacting with 4-sulfatase in free solution), but the same monoclonal antibodies reacted strongly with feline 4-sulfatase in an immunoquantification assay where the feline 4-sulfatase was bound to a polyclonal antibody (which presumably induces a conformation change in the feline 4 sulfatase to closer approximate the structure of human 4-sulfatase). A monoclonal antibody which selectively reacts with human 4-sulfatase has been used to develop an assay suitable for evaluating human 4-sulfatase enzyme replacement in cat tissues. PMID- 7857683 TI - 13C NMR study of C2- and C3-deuterated lactic acid production by parotid cells exposed to 13C-labeled glucose in the presence of D2O. AB - The generation of C2- and C3-deuterated lactic acid produced by rat parotid cells exposed to [1-13C] glucose, [2-13C]glucose, and [6-13C]glucose in the presence of D2O was assessed by 13C NMR. The results indicated that the escape from deuteration amounted to about 46% at the phosphoglucoisomerase level, 100% at the phosphomannoisomerase level, 65% in the reactions catalyzed by phosphofructoaldolase and triose phosphate isomerase, and 58% at the level of glutamate pyruvate transaminase. Such high values are considered to support a possible enzyme-to-enzyme tunneling of metabolic intermediates at selected sites in the glycolytic pathway. PMID- 7857684 TI - Effect of protein kinase C on the plasma membrane calcium pump in purified beta cells. AB - The effect of protein kinase C activation on (Ca(2+)-Mg2+)-ATPase and 45Ca2+ uptake in purified plasma membranes and membrane vesicles from beta cells was examined. PKC activation was achieved by incubating cells for 10 or 30 min in 100 nM or 1 microM of the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA) and evident by translocation of the alpha-isoform from the cytosolic to the membrane fraction. (Ca(2+)-Mg2+)-ATPase had a Km for Ca2+ of 0.56 +/- 0.17 microM and the Vmax was 120 +/- 12 nmol/min*mg protein in membranes from cells treated with TPA, while it was 0.66 +/- 0.14 microM and 135 +/- 19 nmol/min*mg protein, respectively, in its absence. In inside-out vesicles 45Ca2+ uptake had a Km for Ca2+ of 79 +/- 19 nM and a Vmax of 1.68 +/- 0.43 nmol/min*mg protein in the presence of TPA. In the absence of TPA, the Km was 71 +/- 17 nM, and the Vmax was 1.59 +/- 0.39 nmol/min*mg protein, respectively. It is concluded that in beta cells PKC activation does not regulate (Ca(2+)-Mg2+)-ATPase activity or Ca2+ transport directly. PMID- 7857685 TI - Myocardial adaptation to long-term action of substances associated with decreased intensity of cardiac function. AB - The effect of prolonged treatment of rats with 6-n-propyl-2-thiouracil (PTU), verapamil, or propranolol on cardiac pump function and the properties of myofibrils and mitochondria was studied. After 6-8 weeks of treatment, the heart rate and maximal cardiac output of the isolated heart of rats treated with verapamil or propranolol were higher than those in the control group. The PTU treatment was followed by lower heart rate and maximal work. Calcium sensitivity (pCa50 value) of skinned ventricular fibers was higher in all experimental groups compared to the control by 0.07-0.15 units. Myofibrillar Mg2+, Ca(2+)-ATPase activity measured in isolated Triton-skinned cardiomyocytes was considerably lower after PTU treatment than that in respective controls (0.128 +/- 0.013 vs 0.178 +/- 0.010 mumol Pi/min/mg protein). In contrast, long-term treatment with verapamil or propranolol was accompanied by increased activity to 0.223 +/- 0.018 and 0.254 +/- 0.015 mumol Pi/min/mg protein, respectively. Neither the basal mitochondrial respiration rate of saponin-skinned cardiac fibers nor its enhancement after addition of low ADP concentration or creatine was significantly altered in any experimental group. Also no difference between control and experimental groups was observed in the total activity of creatine kinase or relative percentage of its isoenzymes extracted from cardiac tissue. Thus the changes in cardiac pump function after prolonged treatment with agents decreasing cardiac function may be attributed to concomitant alterations of myofibrils while mitochondria remain relatively intact. PMID- 7857686 TI - Rapid screening of point mutations in the protein C gene by multiperpendicular temperature gradient gel electrophoresis. PMID- 7857687 TI - FISH technique. What's all the fuss about? PMID- 7857688 TI - Genetic analysis: techniques and applications bibliography. PMID- 7857689 TI - Accelerated screening of cDNA libraries using the polymerase chain reaction and Southern blotting. AB - cDNA libraries are normally constructed in either phage or plasmid vectors and screened for sequences of interest using antibodies or, more commonly, nucleic acid probes. To clone a sequence of interest from a library generally involves at least three rounds of hybridization with 32P-labeled probes. This approach is highly labor intensive, and no information about the size of the hybridizing insert is obtained until the clones have been purified and the insert DNA analyzed by restriction enzyme digestion. We report on a rapid screening protocol for libraries constructed in bacteriophage lambda vectors involving polymerase chain reaction amplification of the insert from hybridizing phage plaques and on its analysis by agarose gel electrophoresis and Southern blotting. This can take place after only one round of conventional screening, and phage from a large number of positively hybridizing plaques can be analyzed by a "one-tube" reaction. PMID- 7857691 TI - Alu-based vectorettes and splinkerettes. More efficient and comprehensive polymerase chain reaction amplification of human DNA from complex sources. AB - Alu-polymerase chain reaction (PCR) is widely used to amplify human specific fragments from complex heterologous DNAs, such as somatic cell hybrids or yeast artificial chromosome (YAC) recombinants, but the fragments amplified are limited in number and are nonrepresentative. This report describes a modified one-sided alu-PCR technique, which offers better representation of amplified sequences while maintaining human specificity. The method relies on the ligation of partially mismatched double-stranded oligonucleotides (vectorettes or splinkerettes) to endonuclease-restricted DNA and universal priming with a single alu-consensus primer, the complement to which is the unpaired region. Alu vectorette and alu-splinkerette-PCR of two somatic cell hybrids results in a greater complexity of products than alu-PCR alone. The advantage of alu splinkerette over alu-vectorette-PCR is the elimination of nonspecific priming owing to the presence of the vectorette primer and to an increase in the product size range, a consequence of the difference in the splinkerette design. Alu splinkerette-PCR is a useful technique for generating new and more comprehensive markers of the human sequences contained in somatic cell hybrids and YACs. PMID- 7857690 TI - Development of a sensitive, highly controlled assay for molecular detection of the Philadelphia chromosome in patients with chronic myelogenous leukemia. AB - The Philadelphia chromosome (Ph1), present in > or = 95% of chronic myelogenous leukemia (CML) patients, is a well-characterized translocation that results in a unique chimeric gene product (BCR/ABL) with transforming capability. Molecular methods utilizing the polymerase chain reaction (PCR) to detect BCR/ABL mRNA transcripts has been useful for detecting minimal residual disease (MRD) after treatment, as well as for establishing the diagnosis of CML. Amplification-based assays for the BCR/ABL transcript, however, have shown variable reproducibility and sensitivity. This variability may be largely due to technical differences and insufficient controls. In this report, we describe the development of a highly controlled, reproducible, and sensitive PCR assay to detect Ph1 that is well suited to clinical and research applications. A validation study of 82 samples was performed consisting of 25 dilutions of K562 cells (Ph1+) into normal cultured B cells, 26 pre- and post-transplant peripheral blood samples from CML patients, 16 peripheral blood samples for diagnosis of CML, and 15 peripheral blood samples from healthy individuals. RNA isolated from 3 to 5 million leukocytes was reverse transcribed (RT) and amplified by nested primer PCR. The products were characterized using agarose gel electrophoresis. Approximately 1000 Ph1-positive cells admixed with 10(6) normal cells were detectable after one round of amplification. In 60% of assays where one Ph1-positive cell was admixed with 10(6) normal cells, a BCR/ABL product was detectable after nested primer PCR. Specific measures to ensure accurate results in routine testing included (a) assessing RNA integrity and adequate cDNA preparation by detection of the constitutively expressed ABL mRNA, (b) monitoring sensitivity with the addition and detection of K562 RNA mixed with RNA from unknown samples (failure to detect the "spiked" K562 RNA indicates the presence of inhibitors or ribonucleases within the unknown RNA sample), (c) detection of nucleic acid contaminants by using negative controls in every assay, and (d) duplicate analysis of all samples and controls. Internally, this assay was 100% reproducible. Our results verify that nested primer RT-PCR is a fast, sensitive alternative to cytogenetic or Southern blot analysis for monitoring MRD after treatment and for diagnosis of CML. In addition, the highly controlled detection scheme presented here can be used as a general model for the development of other amplification-based detection assays. PMID- 7857692 TI - Lead poisoning from retained lead projectiles. A critical review of case reports. AB - Case reports demonstrate that embedded lead projectiles (bullets, pellets) have the potential to cause lead poisoning. They also show that the relationship between blood lead concentration and lead poisoning is the same as in lead poisonings of occupational origin and that latent periods between lodgement and the onset of lead poisoning varies from less than a half year to several decades. Nevertheless neither the quantitative relationships between projectiles and blood concentrations nor the number at risk and the number affected are known. The aim of this review is to show the limitations of case studies through the analysis of negative and positive case reports, diagnostic and monitoring methods, differences between bullets and pellets, and factors affecting the disintegration of projectiles and the distribution of released lead. PMID- 7857693 TI - Cysteine esters protect cultured rodent lung slices from sulphur mustard. AB - 1. In previous studies an in vitro rat lung slice system was used to investigate the metabolic and structural changes after exposure to known lung toxicants. 2. In this study, the same system was used to identify the ability of cysteine esters to protect against sulphur mustard toxicity. 3. The cyclopentyl (CCPE), cyclohexyl (CCHE), isopropyl (CIPE), methyl (CME) esters of cysteine, cystine dimethyl ester (CDME), cysteine (CySH) and N-acetyl cysteine (NAc) were all non toxic to cultured rat lung slices at 5 mM (equivalent cysteine concentration) after a pretreatment time of 30 min. 4. Pretreatment with the isopropyl, cyclohexyl, cyclopentyl and methyl esters of cysteine at concentrations higher than 1 mM protected against an IC50 of sulphur mustard, however, neither cysteine nor N-acetylcysteine protected. 5. We propose that the extent of protection is directly related to increased levels of intracellular cysteine provided by the esters of cysteine. PMID- 7857695 TI - Selective inhibition of gastrointestinal beta-glucuronidase by poly(vinylbenzyl D glucaro(1,4)lactonate). Part 2. Poly(vinylbenzyl D-glucaro(1,4) lactonate) in vitro inhibition studies. AB - In vitro inhibition studies with beta-glucuronidase from purified E. coli and mouse intestinal contents indicated that the polymer, poly(vinylbenzyl D glucaro(1,4)lactonate, is an effective beta-glucuronidase inhibitor. Purified E. coli beta-glucuronidase was inhibited by 99.6% with 177 mM D-glucaro(1,4)lactone using the polymer-inhibitor. Similarly, 95% inhibition of beta-glucuronidase activity of mouse intestinal contents was obtained with 177 mM and 50% inhibition was obtained with 31.5 mM D-glucaro(1,4)lactone based on the modified polymer. The structural requirements of an effective beta-glucuronidase inhibitor based on the structure of the polymer-inhibitor are also discussed. PMID- 7857694 TI - Development of a rabbit model to investigate the effects of acute nitrogen dioxide intoxication. AB - 1. In previous studies a rat inhalation model was developed to investigate the effects of intervention after acute NO2 exposure. The object of the present study was to investigate whether acute NO2 intoxication induced comparable effects in rabbits as it does in rats. Where the effects of intervention in both species are similar, then the conclusions drawn from these studies may have more relevance for the treatment of man. 2. Biochemical variables in bronchoalveolar lavage and supernatant from lung homogenate, which may be relevant for the evaluation of lung injury and repair, were investigated and compared with histology. 3. After NO2 exposure for 10 min, the pulmonary effects observed became more pronounced with increasing NO2 concentrations (0, 125, 175, 250, 400, 600 or 800 ppm) [1 ppm NO2 is 1.88 mg m-3]. The effects in rabbits were found to be broadly comparable with those in rats. 4. To achieve severe lung injury in rabbits without mortality, enabling investigations of the effects of intervention over several days, exposure to a NO2 concentration of 600 ppm for 10 min was most appropriate, while a concentration of 175 ppm NO2 was needed to attain comparable effects in rats. 5. The repair phase starts later, namely at 3 days after exposure in rats, compared to 5 days in rabbits. PMID- 7857696 TI - Evaluation of the genetic toxicity of the peroxisome proliferator and carcinogen methyl clofenapate, including assays using Muta Mouse and Big Blue transgenic mice. AB - The rodent liver carcinogen and hepatic peroxisome proliferator methylclofenapate (MCP) has been evaluated for genetic toxicity in a range of in vitro and rodent genotoxicity assays. It gave a negative response in each of the following assays: mutagenicity to S. typhimurium and E. coli (+/- S9 mix, plate and pre-incubation assays), clastogenicity to cultured human lymphocytes and CHO cells (+/- S9 mix), a mouse bone marrow micronucleus assay (24h and 48h sampling), a rat liver assay for UDS in vivo (12h sampling), assays for lac I (Big Blue) and lac Z (Muta Mouse) mutations in the liver of transgenic mice, and an assay of the ability of MCP to modify the mutagenicity to the liver of dimethylnitrosamine in both transgenic mutation assays. The micronucleus and UDS assays were conducted using a single administration of MCP at its maximum tolerated dose, while the transgenic assays were conducted using nine daily administrations of MCP at its cancer bioassay dose level. These nine daily administrations were shown to double the weight of the liver of non-transgenic, Big Blue and Muta Mice, as well as leading to a dramatic proliferation of peroxisomes (electron microscopy) in the livers of each strain. These changed parameters had returned to control levels when the mutation analyses were conducted (10 days after the final dose of MCP). Despite the liver enlargement observed following MCP administration, no evidence of mitotic activity was observed in treated livers, although an increased number of cells were undergoing replicative DNA synthesis during the final 3 days of the 9 days of administration (BUdR assessment of S-phase). Liver biochemistry parameters (ALT, AST, AP, CK, GGT and albumin) were unaffected by the chronic (9 day) administration of MCP indicating an absence of hepatic toxicity. These combined observations favour a non-genotoxic mechanism of action for the hepatic carcinogenicity of MCP. The clastogenicity in vitro of the perixisome proliferator Wyeth 14,643 has been confirmed in CHO cells, but it is noted that this chemical is more soluble than is MCP. In particular, at the highest dose level at which MCP could be tested, Wy 14,643 was also non-clastogenic. PMID- 7857697 TI - Thiol levels in rat bronchio-alveolar lavage fluid after administration of cysteine esters. AB - 1. The intraperitoneal administration of cysteine, N-acetylcysteine, the methyl, isopropyl, cyclo pentyl, neo pentyl, cyclo hexyl and tertiary butyl esters of cysteine and of cystine dimethyl ester increased the levels of total non-protein sulphydryls and cysteine in the bronchioalveolar lavage fluid and plasma of rats. In all cases the non-protein sulphydryl levels reflected the increased cysteine levels. 2. Cysteine, N-acetylcysteine, the cysteine esters and cystine dimethyl ester raised the levels of non-protein sulphydryls and hence cysteine in the bronchioalveolar lining fluid as follows: CIPE > CCPE > CME > CDME > CneoPE > CCHE > Nac > CySH > CTBE. 3. Plasma levels of NPSH were increased as follows: Nac > CySH > CCPE > CCHE > CneoPE > CIPE > CME > CDME > CTBE. 4. All except CTBE have been shown to protect against the lethal effects of inhaled perfluoroisobutene, a pyrolysis product of polytetrafluoroethene which induces a fulminating pulmonary oedema. 5. This study showed that by raising the levels of thiols in the bronchioalveolar lavage fluid (BALF), the epithelial cells lining the bronchiolar, alveolar regions of the lung could be protected against inhaled toxicants. 6. It is proposed that increased thiol levels in the BALF may contribute to the overall protection induced by these compounds by reacting with inhaled electrophiles to prevent or reduce damage to tissue in close proximity to the airways. PMID- 7857698 TI - Mechanistically-based human hazard assessment of peroxisome proliferator-induced hepatocarcinogenesis. AB - In this review we have evaluated the relationship between peroxisome proliferation and hepatocarcinogenesis. To do so, we identified all chemicals known to produce peroxisome proliferation and selected those for which there are data (on peroxisome proliferation and hepatocarcinogenesis) which meet certain criteria chosen to facilitate comparison of these phenomena. The summarised data and definition of the methodology used has been collected in appendices. These comparisons enabled us to evaluate the relationship between these phenomena using reliable data. As there is a good correlation between them, we further explored the mechanisms of action that have been proposed (direct genotoxic activity, production of hydrogen peroxide, cell proliferation and receptor activation). The relationship between these events in other species, including humans, was also reviewed and finally an overview of the assessment of human hazard is presented in section IX. Some of the first chemicals which were shown to produce peroxisome proliferation were also hepatocarcinogens whose carcinogenicity could not be readily explained by genotoxic activity. This raised the suggestion that the unusual phenomenon of peroxisome proliferation was intricately linked to the carcinogenic activity of these agents. Three questions have exercised the attention of regulatory, industrial and academic toxicology since then; are chemicals which elicit peroxisome proliferation in the liver actually a coherent class of chemical carcinogens?; does the early biological phenomenon of peroxisome proliferation have real predictive value for and mechanistic association with rodent carcinogenesis?; and what hazard/risk do these agents pose to humans that may be exposed to them? Whether peroxisome proliferators are indeed a discrete class of rodent carcinogens would appear to be the single, most important question. If so, then the assumptions and procedures relevant to human hazard and risk assessment should be applied to the class and should be essentially generic; if not, each chemical should be considered independently. Our critical analysis of the published data for over 70 agents which have been shown to possess intrinsic ability to induce peroxisome proliferation in the livers of rodents has led to the conclusion that there exists a strong correlation between peroxisome proliferation as n early effect in the liver and hepatocarcinogenicity in chronic exposure studies. An almost perfect correlation was observed between the induction of peroxisomes in the rodent liver and the eventual appearance of tumours following chronic exposure The few exceptions to this were largely explainable (section II).(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7857699 TI - Clinical reversal of the multidrug resistance phenotype: true tumour modulation or pharmacokinetic interaction? PMID- 7857700 TI - Cathepsin D, both a prognostic factor and a predictive factor for the effect of adjuvant tamoxifen in breast cancer. South Sweden Breast Cancer Group. AB - Cathepsin D is a lysosomal protease implicated in cancer metastasis. Its concentration in breast tumours has also been shown to be of prognostic importance, although to what extent this is subject to lymph node status, the use of adjuvant therapy and menopausal status has not been clearly evaluated. At a cut-off level of 45 pmol/mg protein (61% of the 623 samples were classified as high cathepsin D tumours; immunoradiometric assay), we found cathepsin D to be of prognostic importance only among breast cancer patients with lymph node-positive (N+) disease not treated with adjuvant tamoxifen. When the series was stratified according to cathepsin D content of their tumours, progesterone receptor (PgR) status and lymph node involvement, adjuvant tamoxifen was found to have a significant beneficial effect only among patients with N+ and PgR-positive breast cancer whose tumours had a high cathepsin D content. PMID- 7857701 TI - In vivo stimulation by tamoxifen of cathepsin D RNA level in breast cancer. AB - We have previously shown that 3 weeks of treatment with tamoxifen, of patients with primary breast carcinomas, increased cytosolic cathepsin D protein in oestrogen receptor (ER) positive tumours [Maudelonde et al., Cancer 1989, 63, 1265-1270]. In order to investigate the mechanism of this increase and to eliminate a transient flare-up effect, we semi-quantified cathepsin D RNA levels by in situ hybridisation in 32 breast carcinomas from patients treated with tamoxifen for 3 weeks prior to surgery and in 35 breast cancer patients receiving no tamoxifen. We found that tamoxifen increased cathepsin D RNA level regardless of the ER status of the tumours. In ER positive tumours, tamoxifen increased the cathepsin D RNA level to the same extent as cytosolic cathepsin D protein but not in ER negative tumours. The induction of cathepsin D RNA by tamoxifen in ER positive tumours was probably due to its agonist activity, also observed in vitro in breast cancer cell lines. These results suggest that the cathepsin D gene is inducible by oestrogens in ER positive breast cancer as it is in breast cancer cell lines. PMID- 7857702 TI - Phase II trial of procarbazine, vincristine and lomustine (POC) chemotherapy in metastatic cutaneous malignant melanoma. AB - 40 patients with symptomatic metastatic melanoma were treated with procarbazine, vincristine and lomustine (POC). 4 patients had received chemotherapy previously. Responses were seen in 8 patients (20%), 4 of whom had a complete remission. All responding patients had some tumour shrinkage after one cycle. The median duration of response was 27 weeks, with 2 patients remaining in complete remission at 6 and 6.5 years. The median survival for the whole group was 22 weeks, whilst that of the responding patients was 35 weeks. Using conventional anti-emetics, the principal toxicities were nausea and vomiting, severe in 15% of cycles. Other nonhaematological toxicity was uncommon. Neutropenia (WHO grade 3 or 4) occurred in 11% of cycles and thrombocytopenia in 8%. The response rate of metastatic melanoma to POC chemotherapy was similar to other cytotoxic regimens though toxicity, other than nausea and vomiting, was minimal. The rapid response allows patients with unresponsive disease to be identified early, avoiding continuing toxicity. PMID- 7857703 TI - Cytotoxic effects of long-term circulating ultrafiltrable platinum species and limited efficacy of haemodialysis in clearing them. AB - We applied haemodialysis to clear platinum (Pt) circulating species following renal insufficiency due to an accidental cisplatin overdosage (205 mg/m2 instead of 100 mg/m2). Serum samples were repeatedly obtained during this clinical episode from day 5 up to day 30 after cisplatin dosing. A serum aliquot taken at day 22 after cisplatin administration was tested to assess the possible cytotoxicity exhibited by the circulating Pt species on a head and neck tumour cell line. The profile of ultrafiltrable (UF) Pt during successive haemodialysis cycles was striking. After each haemodialysis cycle, a marked decrease in UF Pt, occurred but was followed by more or less pronounced rebounds. Cisplatin concentration-cytotoxic effect curves obtained in vitro from patient serum before cisplatin administration and healthy control serum exhibited very similar concentration effect profiles. In contrast, the patient serum taken at day 22 after cisplatin administration resulted in marked cytotoxic effects, which were much greater than those which could have been anticipated considering the Pt concentration of this serum sample. The present report underlines the limited usefulness of haemodialysis for rescuing cisplatin treated patients, exhibiting unanticipated postinfusion renal failure with overexposure to the drug. The in vitro investigations suggest that pharmacological effects of Pt derivatives may not only be attributable to short-term effects of the drug diffusion into tissues, but also to more delayed effects from Pt circulating species. PMID- 7857704 TI - Prognostic factors for local control, regional control and survival in oropharyngeal squamous cell carcinoma. AB - We have performed univariate and multivariate analysis to identify the clinical and treatment-related prognostic factors in a series of 254 patients with newly diagnosed, histologically proven, oropharyngeal squamous cell carcinoma treated with radical radiation therapy. The probabilities of local control, regional control, disease-free survival (DFS) and adjusted survival (AS) were calculated using the Kaplan-Meier method and differences between curves were evaluated by the Mantel-Cox test. The obtained significant variables in the univariate analysis were analysed using the Cox proportional hazards model. In the Cox multivariate analysis, four variables significantly influenced local control probability in the following order: tumour diameter, N stage, alcohol intake and weight loss. N stage significantly influenced the probability of regional control. Five variables influenced both DFS and AS: N stage, tumour diameter, weight loss, alcohol intake and tumour origin within the posterior oropharyngeal wall. PMID- 7857705 TI - Apoptosis in breast cancer as related to histopathological characteristics and prognosis. AB - Apoptotic cells were quantitated by light microscopy in a series of 288 breast carcinomas, and their number (cells/mm2 of neoplastic epithelium, i.e., the apoptotic index, AI) was related to various histopathological features and disease outcome. High AI was associated with tumour necrosis (P = 0.003), lack of tubule formation (P = 0.03), dense stromal lymphocyte infiltration (P = 0.0009), high grade of the tumour (P < 0.0001), DNA aneuploidy (P = 0.049), high S-phase fraction (P = 0.010), high mitotic rate (P < 0.0001), lack of sex steroid receptors (P = 0.004), expression of p53 tumour suppressor gene (P = 0.004), and high values of morphometrically measured nuclear factors (P < 0.05). In survival analysis, an AI greater than 3/mm2 was related to short recurrence-free survival in the entire cohort (P = 0.0079) as well as in the axillary lymph node-negative tumours (P = 0.0253). Survival of the patients with node-negative tumours (P = 0.0356), node-positive tumours (P = 0.0085) and in the entire cohort (P = 0.004) was related to AI. Recurrence-free survival was related to the mitotic index (P = 0.0012), ductal type (P = 0.011), S.D. of the nuclear area (P = 0.075), and axillary lymph node status (P = 0.096). Cox's analysis showed that only the tumour diameter (P < 0.001), axillary lymph node status (P = 0.001), progesterone receptor content (P = 0.004) and ductal type (P = 0.041) had independent prognostic value, whereas AI did not. PMID- 7857706 TI - Patient population analysis in EORTC trial 22881/10882 on the role of a booster dose in breast-conserving therapy. AB - The changing composition of the patient population in breast cancer, which has been reported over the last decade, has important consequences for prognosis. In the present trial, an analysis of the population in an EORTC trial (22881/10882) on breast-conserving therapy was conducted. A shift towards earlier stages has been seen stage per stage, therefore better survival and local control rates are likely to be expected in comparison to previously published series. The majority of tumours in this trial were small, with a median clinical size of 2 cm and a median pathological size of 1.5 cm. A substantial number of lesions were detected in a pre-clinical stage (17.8%). Nodal involvement was present in only 19% of all patients and usually in only a low number of nodes (only 4% of all patients had four or more nodes invaded). The median number of nodes examined was 12, the difference between institutions was large. There was a significant correlation between the number of nodes examined, the percentage of patients with positive nodes (P = 0.03) and the percentage of patients with massive axillary invasion (P = 0.003). The correlation between clinical evidence and pathological invasion of the axillary nodes showed that 15% of the clinical examinations were false negative and 51% were false-positive. Pathological nodal invasion could be clinically predicted in only 31% of patients, and consequently clinical examination of the axilla was a poor predictor of prognosis in this study. Pathological invasion of axillary lymph nodes was better correlated to pathological tumour size than clinical or radiological size. PMID- 7857707 TI - Prognostic value in predicting overall survival of two mucinous markers: CA 15-3 and CA 125 in breast cancer patients at first relapse of disease. AB - The role of circulating tumour markers in providing prognostic information has been scarcely studied. We evaluated the prognostic significance of two mucinous markers: CA 15-3 and CA 125 in 115 breast cancer patients at first recurrence of disease. At diagnosis of advanced disease bone involvement was found in 64 patients, lung in 57, skin lymph nodes in 21, liver in 20, and brain in 5. Patients were recruited and treated in the same institution with conventional chemo- or endocrine therapy. The follow-up ranged from 3 to 54+ months (median 35). Serum samples were drawn at first recurrence of disease before the start of any endocrine and/or chemotherapy. Patients with CA 15-3 < 30 U/ml survived significantly longer than those with CA 15-3 > 30 U/ml (median 50+ versus 26 months, P < 0.02). Similarly, overall survival of patients with CA 125 < 35 U/ml was significantly higher in comparison with patients with CA 125 > 35 U/ml (median 34.5 versus 18.5 months, P < 0.001). CA 125, but not CA 15-3, maintained its prognostic value in the subgroup of patients with visceral metastases. Both markers were found to be independent prognostic variables in multivariate analysis according to Cox's model. CA 15-3 and CA 125 appeared to be powerful prognostic indicators, in addition to visceral metastases, in patients with advanced breast cancer. PMID- 7857708 TI - Therapy for small cell lung cancer using carboplatin, ifosfamide, etoposide (without dose reduction), mid-cycle vincristine with thoracic and cranial irradiation. AB - The aim of this study was to assess the efficacy and toxicity of intensive chemotherapy, administered without dose reduction, with cranial and thoracic radiotherapy given when possible as a single fraction in small cell lung cancer. 87 patients were eligible on the basis of good performance status, normal or near normal biochemistry and clinical staging, 73 limited and 14 extensive stage, computed tomography scanning was not mandatory. Six cycles of carboplatin, ifosfamide and etoposide with vincristine on day 15 at 4 weekly intervals were planned. Dosages were not reduced in response to myelosuppression. Prophylactic cranial irradiation (PCI) as a single fraction after the first cycle and thoracic irradiation (when possible as a single fraction) following the third cycle were delivered. Seventy-two per cent of patients completed the protocol. Complete response rate was 55% and 26% of patients had a partial response. The median nadirs of neutropenia were 0.5 x 10(9)/l and thrombocytopenia 14 x 10(9)/l, with 6% probable treatment-related deaths. Performance status and dyspnoea improved markedly to normal or near normal levels following the second course. Brain metastases occurred in 13% of patients. The median survival was 16.2 months with a 2-year survival of 31% (95% confidence interval, 24-41%) for a minimum follow up of 26 months. These results compare favourably with other combined modality studies, using multiple radiotherapy fractions with cisplatin-based combinations and dosage reduction for patients staged in more anatomical detail. The toxicity spectrum and efficacy data could lead to the use of this chemotherapy regimen with haematopoietic growth factors and, in the future, peripheral blood progenitor cell rescue. PMID- 7857709 TI - Phase II study of protracted infusional 5-fluorouracil combined with cisplatinum for advanced gastric cancer: report from the Japan Clinical Oncology Group (JCOG). AB - A phase II study of protracted infusional 5-fluorouracil (5FU) combined with cisplatin (CDDP) was conducted in patients with advanced gastric carcinoma. 55 previously untreated patients, including 40 patients with measurable disease, were treated with 5FU (800 mg/m2, days 1-5, protracted infusion) and CDDP (20 mg/m2, days 1-5, drip infusion). Objective tumour responses were observed in 17/40 (43%) patients with measurable disease. Median survival was 7 months. WHO grade 3 or 4 leucopenia occurred in 10/55 patients (18%) and grade 3/4 thrombocytopenia was observed in 4 patients (7%). A randomised trial including this regimen is now underway in a JCOG study. PMID- 7857710 TI - A phase II study of the sequential administration of dacarbazine and fotemustine in the treatment of cerebral metastases from malignant melanoma. AB - 34 patients with cerebral metastases from malignant melanoma received sequential dacarbazine at 250 mg/m2 followed 2 h later by fotemustine at 100 mg/m2; this was repeated on day 8. Maintenance therapy was given every 4 weeks to patients with radiological evidence of response or stable disease until a maximum response was achieved plus two more cycles. A 12% response rate was obtained for cerebral metastases, with 2 complete responses lasting 12 and 36+ months, and 2 partial responses lasting 2.5 and 3.75 months. Toxicity was mainly haematological with grade 3-4 leucopenia and thrombocytopenia in 23.5% of patients. No pulmonary toxicity was seen. This schedule of sequential dacarbazine and fotemustine has low activity against metastatic melanoma, and the response rate for cerebral metastases is not superior to that shown in other studies with single agent fotemustine, but the treatment was well tolerated and can be delivered on an outpatient basis. PMID- 7857711 TI - Trends in cancer mortality in young adults in Europe, 1955-1989. AB - Trends in mortality in the age group 20-44 years for the 16 most common cancers or groups of cancer in young adults are presented for 24 European countries (i.e. those with > or = 1,000,000 inhabitants). The largest (up to 9-fold) and most frequent increases were recorded for cancer of the mouth and pharynx (> or = 2 fold increase from 1955-1959 to 1985-1989 in 10 countries), and oesophagus (in eight countries) in males, and for cancer of the skin, chiefly of melanomatous type, in males and females (in nine and eight countries, respectively). Consistent declines were observed for cancer of the stomach and uterus (chiefly, cervix), and for Hodgkin's disease, most notably in northern European countries. Little change emerged in the last 30 years or so in young adult mortality rates for cancer of the colon-rectum, pancreas, non-Hodgkin's lymphoma, leukaemias and cancers of the breast and ovaries in women. More than 2-fold elevations in lung cancer mortality rates in men aged 20-44 years were found only in a few previously non-market economy countries, and in Spain and Portugal. In some northern European countries, favourable downward trends in young males were accompanied by more than 2-fold increases in lung cancer mortality rates in young women. Overall, total cancer mortality rates in women at aged 20-44 years have declined over the last 35 years by more than 20% in 12 countries, and have not increased anywhere. Total cancer mortality rates in young males showed similar decreases in nine northern European countries, but increases of the same magnitude were also observed in most formerly non-market economy countries, and in Spain and Portugal. PMID- 7857712 TI - Expression of functional very late antigen-alpha 1, -alpha 2, -alpha 3 and -alpha 6 integrins on Ewing's sarcoma and primitive peripheral neuroectodermal tumour cells and modulation by interferon-gamma and tumour necrosis factor-alpha. AB - Twelve different human primary and metastatic Ewing's sarcoma (ES) and primitive peripheral neuroectodermal tumour (pPNET) cell lines were examined by fluorocytometric analysis for the expression of alpha 1, alpha 2, alpha 3 and alpha 6 very late antigen (VLA) beta 1-integrins. VLA-alpha 1, was abundantly expressed on all typical ES cell lines and pPNET cell lines, while absent from atypical (large cell) ES cells. VLA-alpha 2 was displayed on some ES and pPNET cell lines. In two different pPNET cell lines, derived from the same patient, VLA alpha 2 expression was considerably higher on primary cells compared with metastatic cells. VLA-alpha 3 was exclusively expressed on pPNET cell lines. Expression of VLA-alpha 6 was higher on metastatic than on primary ES and pPNET cells. Adhesion assays on purified extracellular matrix (ECM) proteins, using monospecific adhesion-blocking antibodies, disclosed VLA-1 (alpha 1 beta 1) on typical ES cells and pPNET cells, and VLA-2 (alpha 2 beta 1) on atypical ES cells, as dual collagen type IV (COIV)/laminin (LM) binding sites, and VLA-6 (alpha 6 beta 1) as a specific LM binding site. Treatment of typical ES cells and pPNET cells for up to 48 h with recombinant human interferon-gamma (rhIFN gamma) and tumour necrosis factor-alpha (rhTNF alpha) upregulated alpha 1 and beta 1 expression, concomitant with an increase in cell adhesion to COIV and LM. Alternatively, these cytokines downregulated the expression of alpha 2, alpha 6 and beta 1 on atypical ES cells, concomitant with a decrease in the adhesion to COIV and LM. In conclusion, these findings suggest that the difference in repertory of CO and LM integrin receptors on ES cells and pPNET cells reflects tumour status and degree of differentiation. Furthermore, our data indicate that IFN gamma- and TNF alpha-mediated alteration in the level of expression of distinct VLAs on ES and pPNET cells is correlated with changes in the adhesive behaviour of these tumour cells. PMID- 7857713 TI - Constitutive secretion of bioactive transforming growth factor beta 1 by small cell lung cancer cell lines. AB - We investigated effects of soluble mediators secreted by small cell lung cancer (SCLC) cell lines on modulation of cytokine-induced growth of lymphocytes. We found that interleukin-2 (IL-2)-mediated T-cell growth was inhibited by a cytokine constitutively secreted by the SCLC cell line, NCI-N417. Of several cytokines tested, only transforming growth factor beta 1 (TGF beta 1) severely suppressed IL-2-dependent T-cell growth. Using a specific anti-TGF beta 1 antibody, we found that this antibody blocked the immunosuppressive activity secreted by NCI-N417. Thus, the NCI-N417-derived immunosuppressive molecule was serologically identified as TGF beta 1. Further experiments showed that TGF beta 1 was secreted by four of eight SCLC lines tested. mRNA for TGF beta 1 was expressed in NCI-N417 and in SCLC-22H. Constitutive secretion of biologically active TGF beta 1 by SCLC lines suggests that tumour-derived immunosuppression may have clinical relevance. PMID- 7857714 TI - Aldehyde dehydrogenase involvement in a variant of the brown Norway rat acute myelocytic leukaemia (BNML) that acquired cyclophosphamide resistance in vivo. AB - The development of drug resistance is an important factor contributing to failure of chemotherapy in cancer patients. Cyclophosphamide (CP) is a cytostatic drug widely used in the treatment of haematological malignancies and solid tumours. Because CP requires bioactivation to become cytotoxic, an in vivo approach was chosen to generate a subline of the Brown Norway rat acute myelocytic leukaemia (BNML/CPR) highly resistant to CP to serve as a model to investigate the molecular mechanism(s) of cyclophosphamide resistance. The role of the CP detoxifying enzyme aldehyde dehydrogenase (ALDH) in the molecular mechanism of CP resistance in this subline of the BNML has been investigated. Compared to the parent BNML cell line, the BNML/CPR cell line displayed an approximately 6-fold higher level of ALDH enzyme activity. Pretreatment of leukaemic rats with the ALDH inhibitor disulfiram resulted in a restoration of CP sensitivity of animals carrying the BNML/CPR cells. Furthermore, in vitro incubation of BNML/CPR cells with disulfiram prior to incubation with the activated CP derivative mafosfamide resulted in an extra 2-3 log cell kill as indicated by the survival time of rats which were injected with disulfiram pretreated BNML/CPR cells compared to non pretreated BNML/CPR cells. Data on the glutathione S-transferases (GSTs) isozyme profiles of cytoplasmic liver and spleen extracts of BNML- and BNML/CPR-carrying leukaemic rats indicated that the total GST enzyme amount was lower in BNML/CPR cells than in parent BNML cells. Furthermore, the BNML/CPR subline proved to be sensitive to phosphoramide mustard, both in vivo and in vitro. PMID- 7857715 TI - Molecular and cellular effects of hexadecylphosphocholine (Miltefosine) in human myeloid leukaemic cell lines. AB - The molecular and cellular effects of the anti-neoplastic alkylphospholipid hexadecylphosphocholine (Miltefosine, MIL) on parameters associated with growth and differentiation of human myeloid leukaemic cell lines U937, KG1 and KG1a were investigated. On a cellular level, MIL has dose-dependent differentiation inducing growth-promoting and cytotoxic activities exemplified by induction of respiratory burst activity, stimulation of interleukin-3 (IL-3)/granulocyte macrophage colony stimulating factor (GM-CSF)-dependent growth of the KG1 cell line in soft agar culture, inhibition of cellular net growth and finally cell death. By northern blot analysis, transcription of functional receptors for IL-3, GM-CSF, G-CSF and FcRI were studied. It was shown that MIL has stimulatory activity on IL-3 and GM-CSF receptor gene transcription. In addition, the transcription of proliferation- and differentiation-associated proteins, namely histone subtypes, c-myc and NF-kappa B p50, were studied. MIL suppressed c-myc and enhanced NF-kappa B p50 transcription in the U937 cell line, comparable to the well-characterised differentiation-inducing phorbolester 12-O tetradecanoylphorbol-13-acetate (TPA). We conclude that the interaction of MIL with its molecular target(s) in myeloid cells induces molecular and cellular effects associated with induction of differentiation, distinct from its cytotoxic activity. PMID- 7857716 TI - Expression of pi-glutathione S-transferase gene (GSTP1) in gastric cancer: lack of correlation with resistance against cis-diamminedichloroplatinum (II). AB - Class pi-glutathione S-transferase (GSTP-1) is one of several factors proposed to affect drug sensitivity to cisdiamminedichloroplatinum (II) (CDDP). It has also been investigated as a potential marker for the serodiagnosis of various types of cancers. In this study, attempts were made to quantify mRNA levels of the enzyme in healthy and cancerous gastric mucosa specimens, and to evaluate their significance in inherent drug resistance to CDDP. Thirty gastric cancer specimens were analysed by northern blotting with radiolabelled GSTP1 cDNA. Of these, the chemosensitivities of 22 specimens were evaluated by the succinic dehydrogenase inhibition (SDI) test. GSTP-1 mRNA was detected in all the specimens, with slightly increased, but non-significant expression in the neoplasms. Comparison of these drug sensitivities with results of northern blotting analysis showed no inverse correlation, as was expected from the widely investigated role of the enzyme in drug resistance. PMID- 7857717 TI - Technical evaluation of thymidine kinase assay in cytosols from breast cancers. EORTC Receptor Study Group Report. AB - Pilot retrospective studies have pointed to the prognostic value of thymidine kinase (TK) in breast cancer. We studied the Prolifigen TK-REA assay (Sangtec Medical, Sweden), usually applied to serum, for TK analysis in breast cancer cytosols. Reproducibility was good, provided that small volume pipetting was performed carefully. The TK assay was not influenced by the short-term storage of cytosols in liquid nitrogen or at -80 degrees C. However, some steps appeared critical for good laboratory practice. The TK level was affected by thawing the cytosols more than twice. Tumour storage in liquid nitrogen should be preferred over storage at -80 degrees C. The components of the homogenisation buffer, especially sodium molybdate and KCl can have a marked influence on results. Finally, linearity problems arose with some cytosols. Thus, although assay of TK in cytosols is apparently simple, care must be taken in practice. The TK-REA kit should be standardised before widespread use in breast cancer. PMID- 7857719 TI - Protease inhibitors: role and potential therapeutic use in human cancer. AB - Proteases and protease inhibitors have been increasingly recognised as important factors in the physiopathology of human diseases, and our understanding of their role in cancer has dramatically increased over the last decade. We have obtained causal evidence linking proteases to tumour invasion and metastasis, and have become aware of genuine mechanisms used by tumour cells to optimise the use of proteases in the pericellular matrix. Many synthetic and natural inhibitors of these proteases have also been characterised, and their mechanisms of interaction with their corresponding enzymes are progressively unveiled as the X-ray crystal structures of these enzymes and their inhibitors are now reported. It has also become evident that many of these inhibitors, in addition to preventing the dissemination of cancer cells, have an inhibitory effect on tumour growth. Thus protease inhibitors are emerging as potentially therapeutic tools to treat cancer. In this article, recent studies on the role of proteases and their inhibitors in cancer are reviewed, and current ideas on their potential use as therapeutic agents are discussed. PMID- 7857718 TI - Colorectal cancer and the integrin family of cell adhesion receptors: current status and future directions. AB - Tumour progression is thought to be determined, at least in part, by the balance between available cell surface receptors and the nature of the surrounding extracellular matrix. The integrin family of transmembrane adhesion receptors involved in tumour cell-matrix interactions mediates cell adhesion, migration, and differentiation. Certain patterns of integrin receptor expression on normal and malignant colon epithelial cells are emerging, and it is now clear that integrins can also regulate such divergent processes as cell proliferation and programmed cell death in this tumour type. This implies that integrins are involved in signal transduction events within colon carcinoma cells consequent upon their adhesive interaction with matrix molecules. A better understanding of the mechanisms involved in these events may lead to useful therapeutic strategies in the management of this disease. PMID- 7857720 TI - Interferon-alpha-carboplatin combination therapy for metastatic melanoma: phase II study. PMID- 7857721 TI - Lymphomas associated with the endemic (African) variant of Kaposi's sarcoma: a chemosensitive but fatal entity. PMID- 7857722 TI - Thyroid-stimulating hormone (TSH) suppression in differentiated thyroid carcinoma: combined treatment with triiodothyronine and thyroxine. PMID- 7857723 TI - Prognostic significance of phagocytic functions in breast cancer patients. PMID- 7857724 TI - A new model for the interaction of EGF-like ligands with their receptors: the new one-two. PMID- 7857725 TI - Treatment of interleukin-2-induced thrombocytopenia by intravenous immunoglobulin. PMID- 7857726 TI - Mitoxantrone and ifosfamide as second-line therapy of epithelial ovarian cancer. A pilot study by the I.T.M.O. Group. PMID- 7857727 TI - Informed consent and truth in medicine. PMID- 7857728 TI - Use of B mode ultrasound of peripheral arteries as an end point in clinical trials. PMID- 7857729 TI - Effect of ACE inhibitors on the atrial natriuretic peptides in heart failure. PMID- 7857730 TI - Value of the chest radiograph before cardiac catheterisation in adults. PMID- 7857731 TI - Heart rate variability in left ventricular dysfunction and heart failure: effects and implications of drug treatment. AB - OBJECTIVE: To review the importance of heart rate variability analysis in left ventricular dysfunction and heart failure and to assess the effects of drug treatment. In patients with left ventricular dysfunction or heart failure, a low heart rate variability is a strong predictor of a low probability of survival. Because drug treatment in these patients has rapidly changed over the past two decades, the effect of these drugs on heart rate variability needs special attention. DESIGN: A study of published reports to give an overview of heart rate variability in patients with left ventricular dysfunction or heart failure and how it is affected by drug treatment. RESULTS: Analysis of heart rate variability provides an easily obtained early marker for progression of disease. It seems to be more closely related to the degree of neurohumoral activation than to haemodynamic variables. Cardiovascular drugs may either stimulate or inhibit the degree of neurohumoral activation, and the effects of pharmacological intervention can be closely monitored with this method. CONCLUSIONS: The analysis of heart rate variability, including spectral analysis, is a novel non-invasive way to obtain potentially useful clinical information in patients with reduced left ventricular function. The effects of drug treatment on heart rate variability are in general consistent with their long-term effects in left ventricular dysfunction and heart failure. PMID- 7857732 TI - Association between reduced heart rate variability and left ventricular dilatation in patients with a first anterior myocardial infarction. CATS Investigators. Captopril and Thrombolysis Study. AB - BACKGROUND: Reduced heart rate variability has been identified as an important prognostic factor after myocardial infarction. This factor is thought to reflect an imbalance between sympathetic and parasympathetic activity, which may lead to unfavourable loading conditions and thus promote left ventricular dilatation. PATIENTS AND METHODS: 298 patients in a multicentre clinical trial were randomised to captopril or placebo after a first anterior myocardial infarction. All patients were treated with streptokinase before randomisation. In the present substudy full data including heart rate variability and echocardiographic measurements were available from 80 patients. Patients were divided into two groups: those with a reduced (< or = 25) heart rate variability index and those with normal heart rate variability index (> 25). Heart rate variability was evaluated by 24 h Holter monitoring before discharge. Left ventricular volumes were assessed by echocardiography before discharge and three and 12 months after myocardial infarction. Extent of myocardial injury, severity of coronary artery disease, functional class, haemodynamic variables, and medication were also considered as possible determinants of left ventricular dilatation. RESULTS: Before discharge end systolic and end diastolic volumes were not different in the two groups. After 12 months in patients with a reduced heart rate variability, end systolic volume (mean (SD)) had increased by 6 (14) ml/m2 (P = 0.043) and end diastolic volume had increased by 8 (17) ml/m2 (P = 0.024). Left ventricular volumes were unchanged in patients with a normal heart rate variability. Also, patients with left ventricular dilatation had a larger enzymatic infarct size and higher heart rates and rate-pressure products. A reduced heart rate variability index before discharge was an independent risk factor for left ventricular dilatation during follow up. Measurement of heart rate variability after three months had no predictive value for this event. CONCLUSION: Assessment of the heart rate variability index before discharge, but not at three months, gave important additional information for identifying patients at risk of left ventricular dilatation. PMID- 7857733 TI - Influence of angiotensin converting enzyme inhibition on relation of atrial natriuretic peptide concentration to atrial pressure in heart failure. AB - OBJECTIVE: To examine the relation between haemodynamics and atrial natriuretic peptide concentration during short term angiotensin converting enzyme inhibition. DESIGN: Patients were randomly allocated to receive placebo or one of three doses of the angiotensin converting enzyme inhibitor ramipril. SETTING: Cardiac units of two tertiary referral hospitals. SUBJECTS: 38 Patients with stable congestive heart failure caused by ischaemic heart disease. METHODS: Data were collected over a 24 hour period and assessed with the aim of distinguishing between the haemodynamic effects on plasma concentrations of atrial natriuretic peptide and the direct effects of the study drug, vasopressin concentrations, and angiotensin converting enzyme activity. RESULTS: Pulmonary capillary wedge pressure was the main predictor of the plasma concentration of atrial natriuretic peptide. A higher plasma concentration of this peptide with a given pulmonary capillary wedge pressure was found after 24 hours of treatment with 2.5 mg and 5 mg of ramipril. Plasma concentration of the active metabolite, change in arginine vasopressin concentration or degree of angiotensin converting enzyme inhibition did not significantly predict change in plasma concentration of atrial natriuretic peptide or in the ratio of atrial natriuretic peptide concentration to pulmonary capillary wedge pressure. CONCLUSIONS: A gradual increase in plasma concentration of atrial natriuretic peptide with a given pulmonary capillary wedge pressure, occurs during short term high degree inhibition of angiotensin converting enzyme. The causative mechanisms are yet to be identified. Such a change in the relation between central haemodynamics and atrial natriuretic peptide concentration may contribute to the beneficial effects of angiotensin converting enzyme inhibition in patients with congestive heart failure due to ischaemic heart disease. PMID- 7857736 TI - Prospective assessment of the value of a chest radiograph in the performance of diagnostic cardiac catheterisation in adults. AB - OBJECTIVE: To assess the value of a chest radiograph in the performance of diagnostic cardiac catheterisation in adults. PATIENTS AND METHODS: 340 consecutive diagnostic cardiac catheter procedures in adults at one institution. It is normal practice for primary operators to report the results of catheterisation using a graphical user interface database system. Data entry screens were modified to present a study questionnaire to assess the use made of the chest radiograph in the performance of the catheter procedure. SETTING: Tertiary referral cardiac centre. RESULTS: The chest radiograph was judged of value in only 12/340 procedures (4%). The radiograph influenced catheter selection in six procedures, the volume of injected radiographic contrast medium in five, and showed an abnormality important to the planning or conduct of the procedure in six procedures. A dual benefit was reported in five procedures. Utility of the radiograph was related to the pre-catheter diagnosis. It proved of value in only 2/283 (0.7%) procedures with a working diagnosis of ischaemic heart disease, influencing only catheter selection. Its utility was greater in congenital heart disease, contributing in 3/4 (75%) procedures, dilated cardiomyopathy in 2/6 (33%) procedures, and valvar heart disease in 4/35 (11.5%) procedures. CONCLUSIONS: In the performance of diagnostic cardiac catheterisation in adults access to a recent chest radiograph contributes little to the conduct of investigations performed for suspected ischaemic heart disease, but may be of greater value in congenital disease, valve abnormalities, and dilated cardiomyopathy. PMID- 7857734 TI - Responses of plasma concentrations of A type natriuretic peptide and B type natriuretic peptide to alacepril, an angiotensin-converting enzyme inhibitor, in patients with congestive heart failure. AB - BACKGROUND: Plasma concentrations of A type or atrial natriuretic peptide (ANP) and B type or brain natriuretic peptide (BNP) are increased in patients with congestive heart failure (CHF). OBJECTIVE: To examine the haemodynamic and hormonal responses, especially of ANP and BNP, to oral administration of an angiotensin-converting enzyme (ACE) inhibitor in patients with CHF and in controls. PATIENTS: 12 patients with CHF and 11 controls. METHODS: Haemodynamic variables and plasma concentrations of ANP, BNP, and other hormones were serially measured for 24 hours after alacepril (37.5 mg) was given by mouth. RESULTS: Pulmonary capillary wedge pressure and systemic vascular resistance decreased significantly in both groups. The cardiac index increased only in the CHF group. In patients with CHF pulmonary capillary wedge pressure, systemic vascular resistance, and cardiac index were significantly changed from 1 to 12 hours after alacepril administration. Plasma ANP and BNP decreased significantly after alacepril was given to the CHF group: neither concentration changed in the control group. In the CHF group plasma ANP was significantly lower between 1 and 6 hours and was highly significantly correlated with pulmonary capillary wedge pressure. Plasma BNP, however, was significantly lower between 6 and 24 hours after alacepril and was not correlated with pulmonary capillary wedge pressure. CONCLUSIONS: The response of plasma BNP after alacepril administration occurred later and lasted longer than the plasma ANP response. This may indicate that the mechanisms of synthesis, secretion, or degradation of the two peptides are different. PMID- 7857735 TI - Apparent paradox of neurohumoral axis inhibition after body fluid volume depletion in patients with chronic congestive heart failure and water retention. AB - BACKGROUND: Hypovolaemia stimulates the sympathoadrenal and renin systems and water retention. It has been proposed that in congestive heart failure reduction of cardiac output and any associated decrease in blood pressure cause underfilling of the arterial compartment, which promotes and perpetuates neurohumoral activation and the retention of fluid. This study examined whether an intravascular volume deficit accounts for patterns that largely exceed the limits of a homoeostatic response, which are sometimes seen in advanced congestive heart failure. METHODS AND RESULTS: In 22 patients with congestive heart failure and water retention the body fluid mass was reduced by ultrafiltration and the neurohumoral reaction was monitored. A Diafilter, which was part of an external venous circuit was regulated to produce 500 ml/hour of ultrafiltrate (mean (SD) 3122 (1199) ml) until right atrial pressure was reduced to 50% of baseline. Haemodynamic variables, plasma renin activity, noradrenaline, and aldosterone were measured before and within 48 hours of ultrafiltration. After ultrafiltration, which produced a 20% reduction of plasma volume and a moderate decrease in cardiac output and blood pressure (consistent with a diminished degree of filling of the arterial compartment), there was an obvious decrease in noradrenaline, plasma renin activity, and aldosterone. In the next 48 hours plasma volume, cardiac output, and blood pressure recovered; the neurohumoral axis was depressed; and there was a striking enhancement of water and sodium excretion with resolution of the peripheral oedema and organ congestion. The neurohumoral changes and haemodynamic changes were not related. There were significant correlations between the neurohumoral changes and increase in urinary output and sodium excretion. CONCLUSIONS: In advanced congestive heart failure arterial underfilling was not the main mechanism for activating the neurohumoral axis and retaining fluid. Because a decrease in circulating hormones was associated with reabsorption of extravascular fluid it is likely that hypoperfusion and/or congestion of organs, such as the kidney and lung, reduce the clearance of circulating noradrenaline and help to keep plasma concentrations of renin and aldosterone raised. A positive feedback loop between fluid retention and plasma hormone concentrations may be responsible for progression of congestive heart failure. PMID- 7857737 TI - Comparative study of risk factors in patients undergoing coronary or femoropopliteal artery bypass grafting. AB - OBJECTIVE: To compare risk factors in two populations of patients with advanced atheroma requiring coronary or femoropopliteal artery bypass grafting to try to account for the different localisations of vascular disease. DESIGN: Cross sectional epidemiological study. SETTING: Cardiovascular surgery department of a university hospital. SUBJECTS: 464 men (mean age 59.25 (SD 8.57) years) undergoing coronary artery bypass grafting; 74 men (mean age 56.28 (13.3) years) undergoing femoropopliteal artery bypass grafting; and 204 control men (mean age 45.07 (6.59) years) who had been recruited in a preventive medicine department. INTERVENTIONS: Blood samples were drawn 24 hours before surgery. METHODS: Lipid and lipoprotein concentrations were measured for each patient and with adjustment for age were compared by analysis of covariance. The main risk factors (smoking, arterial hypertension, obesity, and diabetes) were determined by a standardised history, and the chi 2 test was used to compare the results in the two patient groups. Pairwise comparisons between the three populations were performed by logistic discriminant analysis. RESULTS: Both patient groups showed a significant rise in triglyceride concentration and in the ratio of total cholesterol to high density lipoprotein cholesterol (R1) and a drop in apolipoprotein AI and high density lipoprotein cholesterol concentrations. Disturbances were greater in patients undergoing coronary artery bypass grafting than in those undergoing femoropopliteal artery bypass grafting for the R1 ratio, apolipoprotein B concentration, and the ratio of apolipoprotein AI to apolipoprotein B (R2). A higher proportion of smokers was found in the femoropopliteal bypass group than in the coronary bypass group, whereas were often obese. Logistic discriminant analysis with adjustment for age and with the coronary bypass as the reference group selected three factors: smoking, the R2 ratio, and obesity. CONCLUSION: Disturbances in lipid and apoprotein concentrations varied with respect to bypass site. Other risk factors played a part in accelerating the atherogenic process, especially smoking in patients undergoing femoropopliteal artery bypass grafting and, to a lesser degree, obesity in patients undergoing coronary artery bypass grafting. PMID- 7857738 TI - Non-cardiac chest pain and benign palpitations in the cardiac clinic. AB - OBJECTIVES: To assess the characteristics of consecutive patients referred from general practice with the presenting disorder of chest pain or palpitations, and to determine the outcome at six months and three years. SETTING: A single consultant teaching hospital cardiac clinic receiving new referrals from a health district. DESIGN: 94 consecutive referrals by general practitioners to a cardiac clinic with the presenting disorder of chest pain or palpitations were assessed at first attendance (research interview, cardiologists' ratings, systematic medical case note information), home interview six months later, and by a postal questionnaire at three years. OUTCOME MEASURES: Physical and psychological symptoms, limitation of activities, satisfaction with care, and use of health care resources. RESULTS: 39 patients were given a cardiac diagnosis and 51 patients were not given a cardiac or other major physical diagnosis. The non cardiac group was more likely to be young women, and to report other physical symptoms and previous psychiatric problems. The cardiac and non-cardiac groups reported progressive improvement in presenting symptoms and disability at the six months and three year follow up, but little change in mental state. Even so, three quarters of the non-cardiac subjects described continuing limitation of activities, concern about the cause of their symptoms, and dissatisfaction with medical care. CONCLUSIONS: A substantial proportion of the consecutive referrals continued to describe symptoms and disability throughout the three years after clinic attendance. Outcome was poor for those who had negative investigations and were reassured that they had no cardiac disorder or other serious physical finding. These results have implications for defining the role of psychological assessment and for the formulation of cost effective clinical measures to (a) minimise disability associated with cardiac disorder; and (b) prevent and treat handicaps in those without major physical diagnoses. PMID- 7857739 TI - Influence of increased adrenergic activity and magnesium depletion on cardiac rhythm in alcohol withdrawal. AB - OBJECTIVE: To investigate the prevalence of arrhythmias in alcoholic men during detoxification and its relation to neuroendocrine activation and electrolyte disturbances. DESIGN: Consecutive case-control study. SETTING: Primary and secondary care, detoxification ward. PATIENTS AND CONTROLS: 19 otherwise healthy alcoholic men (DSM-III-R) with withdrawal symptoms necessitating detoxification in hospital. 19 age matched, healthy non-alcoholic men as controls for Holter recordings. INTERVENTIONS: Treatment with chlomethiazole; additional treatment with carbamazepine in patients with previous seizures. MAIN OUTCOME MEASURES: Computer based analyses of mean heart rate and arrhythmias from 24 hour Holter recordings, 24 hour urinary excretion of adrenaline and noradrenaline, magnesium retention measured by means of intravenous loading test, and serum concentrations of electrolytes. RESULTS: The 24 hour mean heart rate was higher in the alcoholic men (97.4 beats/minute, 95% confidence interval (CI) 91.2 to 103.6) than in the controls (69.6 beats/minute, 95% CI 65.4 to 73.8, P < 0.001). However, there was no difference in diurnal heart rate variation. The prevalence of premature supraventricular depolarisations was lower in the alcoholic men (P < 0.05). Neither atrial fibrillation nor malignant ventricular arrhythmias occurred. The sinus tachycardia in the alcoholic men correlated with the concomitant urinary excretion of catecholamines (P < 0.05). The mean serum magnesium concentration was 0.78 mmol/l (95% CI 0.73 to 0.83) in the alcoholic men and 0.83 mmol/l (95% CI 0.81 to 0.85) in a reference population of 55 men aged 40. Magnesium depletion (defined as magnesium retention > 30%) was detected in 10 alcoholic men (53%). Three alcoholic men had serum potassium concentrations < or = 3.3 mmol/l on admission. CONCLUSION: Increased adrenergic activity, magnesium depletion, and hypokalaemia are often seen after heavy drinking, but in alcoholic men without clinical heart disease these changes were not accompanied by arrhythmias other than sinus tachycardia during detoxification in hospital. PMID- 7857741 TI - Comparisons between female and male patients with mitral stenosis. AB - OBJECTIVE: To compare Doppler, echocardiographic, and clinical variables in female and male patients with mitral stenosis. DESIGN: Observational study in consecutive patients with mitral stenosis of cross sectional and Doppler echocardiographic and clinical variables and a retrospective search for a history of systemic embolism. SETTING: A medical centre with 3000 beds, serving both urban and rural populations. PATIENTS: 500 consecutive patients with an echocardiographic mitral valve area of 2 cm2 or less. 331 (66.2%) were female and 169 (33.8%) male (mean (SD) ages of 49 (13) and 48 (14) respectively). MAIN OUTCOME MEASURES: Mitral valve areas by echocardiographic planimetry and Doppler pressure half-time method, peak early diastolic mitral velocity and pressure gradient, echocardiographic score of mitral valve, left atrial end systolic diameter, frequency of left atrial thrombus and smoky echoes as well as various valve lesions detected with Doppler and echocardiography, cardiac rhythm, symptomatic functional class of heart failure, and history of systemic embolism. RESULTS: The prevalence of significant tricuspid (22% v 9%, P < 0.001) and pulmonary regurgitation (5% v 1%, P = 0.018) was higher in the female patients than in the male patients. Female patients also had a higher peak regurgitant velocity (3.2 (0.7) v 2.9 (0.7) m/s, P = 0.007) and pressure gradient (41 (21) v 36 (19) mm Hg, P = 0.010) across the tricuspid valve. However, the male patients had a higher echocardiographic score (9.7 (2.4) v 7.0 (2.3), P < 0.001) and a smaller Doppler-derived mitral valve area (0.9 (0.4) v 1.0 (0.4) cm2, P = 0.027). There were no differences between the female and the male patients in mitral valve area measured by planimetry, peak early diastolic mitral velocity and pressure gradient, and left atrial end systolic diameter or in the prevalence of atrial fibrillation, left atrial thrombus, left atrial smoky echoes, significant aortic stenosis, aortic regurgitation, or heart failure of New York Heart Association class III or IV. CONCLUSIONS: Female patients not only had a higher prevalence of mitral stenosis but also had a higher prevalence of associated tricuspid and pulmonary regurgitation along with a higher velocity and gradient of tricuspid regurgitation. The echocardiographic score was higher in male patients, however. These findings suggest that the pathophysiology of mitral stenosis is different in the two sexes and that gender should be taken into account when therapeutic strategies are formulated. PMID- 7857740 TI - Increased circulating cytokines in patients with myocarditis and cardiomyopathy. AB - OBJECTIVES: To elucidate the potential role of cytokines in the pathogenesis of cardiomyopathy and myocarditis. BACKGROUND: Experimental studies show that certain cytokines depress myocardial contractility and that tumour necrosis factor-alpha plays an important part in the pathogenesis of myocardial injury in animal models of viral and autoimmune myocarditis. METHODS: Plasma interleukin 1 alpha, interleukin 1-beta, interleukin-2, interleukin-6, tumour necrosis factor alpha, tumour necrosis factor-beta, granulocyte-macrophage colony stimulating factor, granulocyte colony stimulating factor, macrophage colony stimulating factor, interferon-alpha and interferon-gamma were measured in 13 patients with acute myocarditis, 23 patients with dilated cardiomyopathy, 51 patients with hypertrophic cardiomyopathy, nine patients with acute myocardial infarction, 18 patients with angina pectoris, 12 patients with essential hypertension and 17 healthy controls. RESULTS: Increased concentrations of cytokines were not detected in the controls. In patients with acute myocarditis, interleukin 1-alpha was detected in 23% (mean (SD) 25 (11) pg/ml), tumour necrosis factor-alpha in 46% (61 (31) pg/ml), and macrophage colony stimulating factor was 2.5 (1.8) ng/ml (normal 1.9 (0.4)). In patients with dilated cardiomyopathy, tumour necrosis factor-alpha was detected in 35% (402 (555) pg/ml). In patients with hypertrophic cardiomyopathy, interleukin-2 was detectable in 14% (2318 (4738) pg/ml) and tumour necrosis factor-alpha ws detected in 20% (992 (1517) pg/ml). The concentration of macrophage colony stimulating factor was raised in patients with acute myocardial infarction. Granulocyte colony stimulating factor was often increased in myocarditis, cardiomyopathies, acute myocardial infarction, and angina pectoris--suggesting activation of macrophages and/or endothelial cells- but this increase was not specific to these diseases. Increased concentrations of cytokines were not found in patients with essential hypertension. CONCLUSION: These results suggest that cytokines may play a part in the pathogenesis of myocardial injury in myocarditis and cardiomyopathies and that further studies to explore the potential pathogenetic role of cytokines in myocardial diseases may be warranted. PMID- 7857742 TI - Recurrence rate after accessory pathway ablation. AB - OBJECTIVE: To evaluate characteristics of patients and accessory pathways as well as additional technical factors involved in the reappearance of accessory pathway conduction after successful ablation. DESIGN: Analysis of recurrences after radiofrequency ablation. SETTING: 163 consecutive patients with 167 accessory pathways. SUBJECTS: 97 men and 66 women with a mean (SD) age of 36 (14) range (11 to 75) years. RESULTS: After a mean (SD) follow up of 14 (7) range (2 to 27) months, conduction recurred in 13 out of 167 (7.8%) accessory pathways. The initial manifestation of recurrence was circus movement tachycardia in 7 patients and reappearance of delta waves on a 12 lead electrocardiogram in 6 patients. The interval to the return of accessory pathway conduction ranged from 3 hours to 90 days. Age, sex, presence of multiple accessory pathways, criteria to determine the target ablation site, number and duration of radiofrequency applications, and cumulative energy did not significantly differ between the groups with recurrence and without. Recurrence was less common with concealed accessory pathways (2/44) than with overt accessory pathways (11/110). The difference was not significant. The only variable to influence the recurrences in this study group was the location of the accessory pathway. Reappearance of conduction through right sided accessory pathways occurred significantly more often than through left sided ones (8/40 v 5/114, P = 0.01). CONCLUSION: After radiofrequency ablation the recurrence rate of accessory pathways is low and there are no predictors of the risk of reappearance of conduction apart from the right sided location of the accessory pathway. PMID- 7857743 TI - Ventricular late potentials and spontaneous ventricular arrhythmias after surgical repair of tetralogy of Fallot: do they have prognostic value? AB - OBJECTIVE: To determine the prognostic significance of ventricular late potentials and spontaneous ventricular arrhythmias detected early after surgical repair of tetralogy of Fallot. DESIGN: Prospective observational. SETTING: Cardiology department of a teaching hospital. METHODS: Between June 1984 and June 1991, 104 children (63 boys, 41 girls) were studied by signal averaging and 24 hour ambulatory monitoring after surgical repair of tetralogy of Fallot. Mean (SD) age at operation was 6 (3) years, mean interval between operation and evaluation was 8 (25) months, and the follow up after evaluation was one to 88 (mean 30) months. RESULTS: Ventricular late potentials were detected in 24/104 patients (23%) and spontaneous ventricular arrhythmias in 39/96 patients (38%); usually (in 81%) these were unifocal and rare. Patients with ventricular late potentials were older at operation than patients without late potentials (9 (3) v 6 (3) years, P = 0.002). No correlation was found between the presence of ventricular late potentials and the presence or complexity of spontaneous ventricular arrhythmias early after operation. During the mean follow up of 2.5 years no case of sudden death or sustained ventricular tachycardia was found. CONCLUSION: Short-term prognosis after surgical repair of tetralogy of Fallot is good; ventricular late potentials and spontaneous ventricular arrhythmias are often detected shortly after operation, but in the medium term follow up they do not predict sudden death or serious ventricular arrhythmias. PMID- 7857745 TI - Effect of percutaneous fenestration of the atrial septum on protein-losing enteropathy after the Fontan operation. PMID- 7857744 TI - Cardiac involvement in tuberous sclerosis. AB - OBJECTIVE: To assess the incidence, importance, and history of cardiac involvement in infants and children with tuberous sclerosis. DESIGN: Prospective study; clinical examination, sector and Doppler echocardiography, standard and ambulatory electrocardiography. SETTING: A tertiary referral centre. PATIENTS: 21 patients with tuberous sclerosis aged 1 day to 16 years (mean 6.3 years); follow up investigations were available in 14 cases (10 retrospective, 4 prospective; mean follow up 4.3 years). RESULTS: Multiple cardiac rhabdomyomas in the right ventricle (11) and left ventricle (14) as well as in the right atrium (1) were present in 14/21 patients. Two of them had obstruction of the left ventricular inflow and outflow tract related to a tumour. In the remaining 7 patients, echocardiography was normal in 4 and equivocal in 3 cases. The standard electrocardiogram (n = 20) showed ventricular hypertrophy (2), ventricular pre excitation (1), arrhythmias (2), and repolarisation disturbances (4) in 7/13 patients with rhabdomyomas but was normal in all patients with a normal or equivocal echocardiogram. The ambulatory electrocardiogram (n = 19) showed frequent premature atrial (2) and polymorphous ventricular (2) contractions. The polymorphous ventricular contractions coexisted with rhabdomyomas. No arrhythmias that needed medical treatment were found. Follow up investigations showed return to a normal standard electrocardiogram in 3 patients. Definite regression or complete disappearance of the tumour occurred in 6 infants. CONCLUSIONS: Cardiac rhabdomyomas, although often present in these patients with tuberous sclerosis, caused neither major arrhythmias nor haemodynamic obstruction except in the neonatal period. The indication for operation is limited to cases with life threatening obstruction or arrhythmias refractory to medical treatment. PMID- 7857746 TI - Diagnosis, treatment, and long-term follow up of a patient with a hydatid cyst of the left ventricle. PMID- 7857747 TI - Evidence of inadequate investigation and treatment of patients with heart failure. PMID- 7857748 TI - Heart rate variability and clinical cardiology. PMID- 7857749 TI - Long-term results of the corridor operation for atrial fibrillation. PMID- 7857750 TI - Neurostimulation and myocardial ischaemia. PMID- 7857751 TI - [The role of ACE inhibitors in heart failure. Lessons of CONSENSUS, SOLVD and V HeFTII]. AB - Heart failure is today one of the most serious health problems of modern industrialized societies. The increase in the mean age of the population is an additional factor which favours a high incidence of episodes of heart failure. Age is also a relevant factor in mortality linked with heart failure. On this basis more emphasis has been given by researchers and physicians to improve a preventive and therapeutic approach to heart failure. For many years the pharmacological treatment of heart failure patients was based on the increase in inotropism through the digitalis and on the reduction in sodium-water retention through diuretics, while less importance was given to the improvement of the afterload. We have had knowledge of vasodilatory drugs in chronic heart failure for at least 20 years but only 10 years ago with the Vasodilator-Heart Failure Trial (V-HeFTI), it was proved that the combination of hydralazine and nitrates in addition to the conventional treatment, improved the survival of patients affected by moderate-severe heart failure. With the advent of the ACE-inhibitors, in the '80s, the first studies concerning the role of such drugs in heart failure were carried out. In the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS I) it was proved for the first time that an ACE-inhibitor (enalapril), added to the conventional heart failure therapy, improved the survival of patients with severe congestive heart failure (NYHA class IV). The result was so extraordinary that the study was interrupted for ethical reasons. However, it has raised a considerable interest in the study of the ACE-inhibitors in heart failure and now it has been proved that such drugs are a milestone in a correct pharmacological approach to heart failure. PMID- 7857752 TI - [Variability of heart rate in hypertensive patients: clinical and physiopathological implications]. AB - Heart rate variability has been investigated in essential hypertension by studies combining 24-hour ambulatory blood pressure and heart rate monitoring techniques. These studies have shown a clear circadian pattern of heart rate fluctuations. By means of spectral analysis it has also been possible to describe the changes over the 24 hours of specific heart rate fluctuations occurring at various frequencies, which, at least in mild to moderate hypertensives, are not different from those of normotensive subjects. Laboratory studies have also shown the important role exerted by arterial baroreflexes in modulating heart rate variability. Finally, recent methods have been developed to dynamically monitor changes in baroreflex sensitivity in daily life conditions through the time domain or frequency domain analysis of spontaneous blood pressure and heart rate fluctuations. PMID- 7857753 TI - [An Italian study on heart rate in hypertensives]. AB - Epidemiological studies performed in the last few years have demonstrated a positive association between resting heart rate, cardiovascular disease incidence and mortality. The aim of the study was to evaluate the extent to which a frequent heart rate is associated with arterial hypertension and its relative risk. For 6 consecutive months 3500 physicians throughout the country have checked blood pressure and heart rate, anthropometric measurement--height, weight, hip-waist ratio, body mass index--and then have filled in a specific questionnaire focussed on family history and living habits. All the Operating Units have participated in a special training programme to ensure standardization of the methods. The study has collected data so far on 50,000 hypertensive individuals; the results of the ongoing analysis will be illustrated and discussed. A 5-year follow-up is ensured in order to make a step forward in the knowledge of the role played by heart rate in the development of cardiovascular diseases. PMID- 7857754 TI - [Pharmacological control of heart rate]. AB - Heart rate, an important risk factor of coronary mortality, is highly correlated with numerous anthropometric and biochemical variables: height, body weight and hyperlipidemia; it varies, furthermore, with smoking and age and can be modified during pharmacotherapy for hypertension. From meta-analyses on different cardiovascular treatments, given after coronary events, only the efficacy of drugs significantly reducing heart rate is borne out (beta-blockers with sympathomimetic activity, or calcium-antagonists with a prevalent vasodilatory action do not provide a protective effect). Among calcium-antagonists, while the mechanism of action is similar at the cell level (delay of opening of voltage operated slow channels), the distribution of activity within the vascular system varies markedly. Dihydropyridines (e.g., nifedipine) exert a dominant peripheral effect, with consequent vasodilation, whereas phenylalkylamines (verapamil) have both peripheral vasorelaxant and cardiac negative chronotropic activity, because of a reduced sinus node action potential. A relative tachycardia may occur with dihydropyridines, secondary to the activation of baroreceptors; the compensatory heart mechanism operated by verapamil antagonizes this reflex tachycardia. The activity of verapamil on the atrioventricular conduction allows both a slowing of functional recovery of the channel in hyperexcitable conditions (supraventricular tachycardia), and, moreover, increased diastolic intervals, with consequent improvement of coronary flow. New molecules can selectively reduce the sinus node activity without exerting other effects (hypotensive, anti-arrhythmic). From a comparative evaluation of these molecules with verapamil, it clearly emerges how this latter can provide a more acceptable pharmacodynamic profile, both for the hypotensive activity, and also for the control of reflex tachycardia, with a consequently improvement of coronary flow. PMID- 7857755 TI - Neurogenic factors in hypertension: therapeutic implications. AB - This manuscript reviews the evidence supporting a role for neurogenic factors in the pathophysiology of essential hypertension. The available evidence in human subjects is largely indirect and suggests a role for the sympathetic nervous system primarily in younger patients with borderline hypertension. In predisposed subjects, environmental factors, such as stress and high dietary salt intake, may activate the sympathetic nervous system and cause hypertension. With advancing age, vascular structural changes may contribute to the maintenance of hypertension despite a seemingly normal sympathetic nerve activity. The evidence supporting a role for neurogenic factors in the genesis of hypertension in patients with chronic renal failure has also been reviewed. Afferent stimuli from the scarred or diseased kidneys into the central nervous system may activate the sympathetic nervous system and contribute to the genesis of hypertension in patients with chronic renal failure. These observations may explain the efficacy of antiadrenergic agents in the management of hypertension in these patients. PMID- 7857756 TI - [Epidemiology of arterial hypertension and organ damage]. AB - In this review prevalence of hypertension and target organ damage related to hypertension were analyzed. The prognostic role of blood pressure variability in hypertensive patients was also discussed. Prevalence of hypertension has been related to several factors that could influence it. They included environmental and racial factors, sodium and alcohol intake, age, gender and concomitant diseases. Moreover the importance of left ventricular hypertrophy and structural vascular abnormalities in the developing of cardiovascular disease induced by hypertension were evaluated. On the other hand the role of microalbuminuria as marker of renal impairment in hypertensive patients has been reported. At last cerebral and retinal involvement in hypertensives was discussed. PMID- 7857757 TI - [Molecular biology and cardiac and vascular changes in hypertension: focus on the renin-angiotensin system]. AB - Arterial hypertension is the leading cause of cardiovascular disease in Western countries. In the last few years a widespread application of molecular medicine techniques has led to unprecedent progress in unravelling both the pathogenetic mechanisms of cardiac hypertrophy and accelerated atherosclerosis as well as the genetical markers of susceptibility to cardiovascular disease. Available data demonstrate the presence of all components of the renin-angiotensin system in the heart and arterial wall and suggest that they may play a crucial role in causing both myocardial hypertrophy and atherosclerosis in hypertension. The current research strategies along with the most recent results in this field are reviewed. PMID- 7857758 TI - [Problems in the treatment of arterial hypertension]. AB - During the last 20 years antihypertensive treatment has given excellent results in terms of prevention of cardiovascular complications. However these results, for some reasons, are less satisfactory than those theoretically possible. The problems we need to solve are many and all contribute to reduce the efficacy of therapy. First of all it is necessary to make a correct diagnosis of hypertension to avoid treating normotensive subjects. The use of continuous ambulatory blood pressure monitoring in some cases can be useful to clarify these situations and also to better evaluate the efficacy of therapeutic regimens. In the vast majority of cases, however, the traditional blood pressure recordings, if correctly performed, can give satisfactory and sufficient information. After a correct diagnosis is made the physician must start with the patient an open minded cooperation based on confidence. He must clearly explain the goals and the methods of therapy and encourage, instead of frighten, the patient. The next step is the choice of the kind of treatment in which many factors must be kept in mind and in which the physician must have a deep knowledge of the patient and of the drugs. Treatment has a high probability rate of a good patient's compliance only if it does not cause adverse reactions and if the therapeutic scheme is simple. Studies on compliance have shown that it is possible to identify those patients at risk of low compliance even before the beginning of therapy and it has been shown that adverse reactions especially if the patient has not been informed by the doctor, can cause a dramatic fall in compliance.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7857759 TI - [Transdermal therapy of arterial hypertension: a new approach in the management of hypertensive patients]. AB - Hypertension remains one of the most important cardiovascular risk factors: the excess of mortality in hypertensive patients is due in 70% of cases to mild hypertension. A therapy able to reduce this risk has to be free from any even negligible negative effect, to control blood pressure 24 hours over 24 hours and to reduce the blood pressure variability to a minimum. The transdermal preparation of clonidine (TTS) permits a continuous and constant administration of the drug by applying a patch on the skin once a week. The serum concentration of clonidine reaches the steady-state in 2-4 days and it remains constant during a 7-day period and at the time of the change of the patch. Blood pressure reduction is completed in 1-2 weeks without any interference with the orthostatic control and with the haemodynamic response to exercise. After discontinuation of treatment there is neither a blood pressure nor a plasma catecholamine rebound: both indexes return to pre-treatment values after 3 to 5 days. Systemic side effects of TTS are markedly reduced as compared to oral preparation due to the absence of peak plasma concentration. Cutaneous reactions in the site of application of the patch are present in 14-16% of patients. The total percentage of both systemic and cutaneous side effects is around 22%. In conclusion, TTS is a safe and efficacious therapeutic means to reach a constant blood pressure control in hypertension. PMID- 7857760 TI - [Neurohumoral mechanisms in cardiocirculatory decompensation]. AB - Congestive heart failure is characterized by profound alterations in systemic haemodynamics as well as in neurohumoral profile with activation of the sympathetic nervous system, reninangiotensin axis, plasma vasopressin and atrial natriuretic peptides, i.e. factors involved in homeostatic control of the cardiovascular system. The sympathetic stimulation, which has been documented by a variety of methodological approaches (plasma norepinephrine measurement, norepinephrine spillover technique, microneurographic recording of efferent post ganglionic muscle sympathetic nerve traffic) is already evident in the initial stages of the disease (NYHA classes I-II) and more manifest in severe heart failure (NYHA classes III-IV). Although representing in mild heart failure a compensatory mechanism aimed at preserving cardiac output, the sympathetic and neurohumoral activation, which can be likely ascribed to arterial baroreceptor dysfunction, may represent, in the clinical course of the disease, a maladaptative phenomenon. Thus pharmacological treatment of heart failure should be aimed not only at improving systemic haemodynamics but also at reversing neurohumoral activation and baroreflex impairment. Recent experimental clinical evidence suggests that these therapeutical goals can be satisfactorily achieved by digitalis glycosides and ACE-inhibitors. PMID- 7857761 TI - [New knowledge on the subject of therapy in cardiac decompensation in the light of large trials]. AB - Although an underlying disturbance in cardiac function can be identified in most patients with congestive heart failure, manifestations of the disease are greatly influenced by other factors, particularly neurohumoral and peripheral adaptive responses which occur secondary to impaired cardiac function. Until recently diuretic agents and digoxin formed the basis of conventional treatment of this condition. The majority of clinical trials published since 1980, indicate that digoxin lessens symptoms and reduces morbidity associated with congestive heart failure particularly in patients with more advanced symptoms and ventricular dysfunction. The efficacy of digitalis in congestive heart failure may in part result from sympathoinhibitory properties such as the activation of baroreceptorial mechanisms. At present there is no conclusive evidence that cardiac glycosides improve survival. Several trials clearly indicate that angiotensin converting enzyme inhibitors (enalapril, captopril) can reduce both morbidity and mortality in symptomatic congestive heart failure. Asymptomatic patients like those with severe left ventricular dysfunction and those who are at high risk for left ventricular remodeling after anterior wall myocardial infarction may also benefit from ACE-inhibition therapy. Increasing evidence suggests that beta-adrenergic blockade can produce symptomatic and hemodynamic improvement in heart failure of idiopathic and ischemic aetiology. Appropriately powered randomized controlled trials are required to determine the impact on survival of beta-blockers. PMID- 7857762 TI - The mitogen activated protein kinase signal transduction pathway: from the cell surface to the nucleus. AB - Activation of the mitogen activated protein kinase (MAPK) plays essential roles in many signal transduction pathways. MAPK has been demonstrated to phosphorylate and regulate numerous cellular proteins, including growth factor receptor, transcription factors, cytoskeletal proteins, phospholipase and other protein kinases. Activation of MAPK requires phosphorylation of both threonine and tyrosine residues, which are catalysed by a single protein kinase known as MAPK kinase or MEK. MEK itself is activated by phosphorylation on two conserved serine residues. Three distinct mammalian Ser/Thr kinases, including Raf, Mos and MEKK (for MEK kinase), have been demonstrated to phosphorylate and activate MEK. The MAP kinase cascade is highly conserved in all eukaryotes and involved in numerous cellular responses. Activation of MAPK is a transient event that is tightly regulated by both kinases and phosphatases. A growth factor induced dual specific phosphatase is likely to play an important role in MAPK regulation. PMID- 7857763 TI - Cyclic ADP-ribose: a new member of a super family of signalling cyclic nucleotides. AB - Cyclic nucleotides are second messengers exerting their cellular effects mainly through protein phosphorylation. A new member of this family, cyclic ADP-ribose, is involved, instead, in mediating mobilization of Ca+2 from internal stores. The structure of this nucleotide has now been determined by X-ray crystallography and accumulating evidence indicates it may be an endogenous modulator of the Ca+2 induced Ca+2 release mechanism. This article summarizes the current knowledge of the structure, the mechanism of action and the metabolic enzymes of this novel nucleotide. With this new addition, the signalling functions of the cyclic nucleotide family are now extended from protein phosphorylation to Ca+2 signalling. PMID- 7857765 TI - Control of secretory function in mammary epithelial cells. PMID- 7857764 TI - The visual transduction and the phosphoinositide system: a link. PMID- 7857766 TI - Phosphorylation of phospholamban in aortic smooth muscle cells and heart by calcium/calmodulin-dependent protein kinase II. AB - Phospholamban is a negative regulator of the sarcoplasmic reticulum Ca(2+) pumping ATPase. Phosphorylation of phospholamban activates the ATPase and decreases the level of cytosolic calcium. Phospholamban is phosphorylated in heart by cAMP-dependent protein kinase, cGMP-dependent protein kinase and calcium/calmodulin-dependent protein kinase II (CM-kinase-II) and in smooth muscle cells by cGMP-dependent protein kinase. In contrast to heart muscle, phospholamban is poorly phosphorylated by CM-kinase-II in extracts of rat aortic smooth muscle cells. Rat aorta phospholamban amino acid sequence was identical to dog heart. The peptide substrate specificity of CM-kinase-II from rat aorta was the same as that from rat heart. The lack of phosphorylation of rat aorta phospholamban by the CM-kinase-II appears to result from the relatively low abundance of phospholamban in smooth muscle. PMID- 7857767 TI - The epidermal growth factor mitogenic signal is modulated by protein kinase C in T51B rat liver cells. AB - The regulation of cell proliferation involves a complex interplay between several signal transduction pathways. The effect of EGF on DNA synthesis in serum starved quiescent, synchronized T51B cells was investigated by [3H]thymidine incorporation and flow cytometry. 1 nM EGF or readdition of serum initiated G1 progression and entry into S phase by 18 h and DNA synthesis reached a maximum by 28 h. Low concentrations of EGF markedly stimulated DNA synthesis, but EGF was not as potent as readdition of serum. The effect of EGF on DNA synthesis was only partially blocked by the tyrosine inhibitors genistein and tyrphostin, suggesting that other signalling pathways play a role in EGF-stimulated mitogenesis. 1 nM EGF caused a rapid, transient increase in the activity of membrane-associated protein kinase C (PKC) followed by a longer sustained increase that continued into S phase. TPA (12-O-tetradecanoyl-phorbol-13-acetate) did not mimic EGF, rather it caused a slight stimulation of membrane-associated PKC activity within 1 h followed by a dramatic downregulation of PKC within 4 h. TPA was without effect on DNA synthesis alone, but when added along with EGF or serum TPA caused a significant enhancement of DNA synthesis. Pretreatment of quiescent, serum deprived T51B cells with TPA reduced the basal level of DNA synthesis; however, under these conditions EGF became as potent a mitogen as serum. We hypothesize that EGF via activation of PKC regulates the activity of its receptor by switching from high affinity to low affinity states. Downregulation of PKC by long term treatment with TPA removes this regulation thus rendering T15B cells more sensitive to exogenous EGF. PMID- 7857768 TI - Dual modulation of the L-type calcium current of rat osteoblastic cells by parathyroid hormone: opposite effects of protein kinase C and cyclic nucleotides. AB - Using whole-cell voltage-clamp recording of rat osteoblastic cells, we show that PTH-(1-34), known to stimulate protein kinase C (PKC) and adenylate cyclase, has a dual effect on the L-type calcium current. It induces a long-lasting increase and a superimposed reversible decrease, which can be separated by repeating hormone applications. The stimulatory effect is the only effect induced by the (3 34) fragment, able to stimulate PKC but unable to stimulate adenylate cyclase. The L current is stimulated by an active phorbol ester and is reduced by permeable analogues of cyclic AMP. Thus, the effect of PTH-(1-34) can be explained by the opposite effects of PKC and cyclic AMP. Dibutyryl cyclic GMP reduces the L current even more potently than dibutyryl cyclic AMP. The above modulations are all voltage-insensitive. These results led us to reinvestigate the effects of some vitamin D3 metabolites known to stimulate PKC and/or guanylate cyclase, and previously reported to affect the voltage-sensitivity of the L current. We only detected voltage-insensitive effects. PMID- 7857769 TI - Interferon mediated phosphatidylinositol uptake and processing in nuclei isolated from Burkitt lymphoma cells. AB - The kinetic analysis of exogenous [3H]phosphatidylinositol (PI) uptake and processing by nuclei isolated from Daudi lymphoma cells upon interferon alpha treatment has been performed. Results have disclosed that, with respect to controls, interferon induces an evident stimulation of label incorporation into nuclei. The incorporated [3H] PI has been found for phosphorylation and hydrolytic cleavage, indicating that the intranuclear transduction system activated by interferon at plasma membrane level, might involve the PI cycle as a possible route of intracellular signalling. PMID- 7857770 TI - Lateral mobility of tetramethylrhodamine (TMR) labelled G protein alpha and beta gamma subunits in NG 108-15 cells. AB - Multi-step signal transducing events, such as those mediated by G proteins, have been difficult to study in intact cells. We prepared fluorescently labelled G protein subunits, tetramethylrhodamine-alpha o (TMR-alpha o) and TMR-beta gamma, in order to study their subcellular distribution and lateral mobility. Heterotrimeric G proteins labelled in the alpha (TMR-alpha o/beta gamma) or beta (TMR-beta gamma/alpha o) subunit were reconstituted into lipid vesicles and fused to NG-108-15 cells using polyethylene glycol (PEG). Vesicles fused completely to the cells as determined by dequenching of a fluorescent lipid probe, octadecyl rhodamine B. The orientation of G protein beta gamma subunits after fusion followed the expected random distribution; the quenching of surface fluorescence with anti-fluorescein antibodies showed that about 50% of the label was accessible extracellularly. G proteins incorporated by the fusion method were able to couple to endogenous alpha 2 adrenergic receptors based on the restoration of high affinity agonist binding to pertussis toxin-treated cells. The subcellular localization of TMR-alpha o and TMR-beta gamma determined by differential centrifugation and confocal microscopy indicated that TMR-alpha o was present in the plasma membrane and in intracellular membranes, whereas TMR beta gamma was mainly localized in the plasma membrane. The lateral mobility of TMR-alpha o and TMR-beta gamma measured using fluorescence recovery after photobleaching (FRAP) demonstrated low mobile fractions of 0.34 +/- 0.03 and 0.16 +/- 0.03, respectively. The translational diffusion coefficients of the mobile components were similar, 4.0 x 10(-9) and 2.0 x 10(-9) cm2/s, for alpha and beta gamma respectively. Neither activation of Gi-linked receptors nor cytoskeletal disruption with nocodozole or cytochalasin D changed the mobile fraction or diffusion coefficient of the alpha or beta gamma subunits. The FRAP data combined with the localization of fluorescent subunits by confocal microscopy suggest that the beta gamma subunits are highly constrained to localized regions of the plasma membrane while the alpha subunit may diffuse in intracellular regions to transmit signals from receptors to effector proteins. PMID- 7857771 TI - The GTP-binding protein Gi alpha 2 is directly linked to and substrate of a serine kinase in Balb/c3T3 cells. AB - Mitosis of Balb/c3T3 cells induced by epidermal growth factor and insulin is inhibited by pertussis toxin. Pertussis toxin inactivates certain GTP-binding proteins, of which only Gi is present in Balb/c3T3 cells. Therefore, Gi was implicated as important in the signal transduction of EGF and insulin receptors leading to mitosis. Our previous studies of the role of Gi in cell division have shown that the alpha-subunit of Gi(Gi alpha) is induced to translocate from the cell periphery to the nucleus by these growth factors, and in the nucleus of dividing cells Gi alpha binds to the separating chromatin. As protein phosphorylations are essential components of the messenger systems from these receptors, we have examined whether Gi could be functionally coupled to protein kinases in the activated cell. We have found that Gi alpha 2 is directly linked to a serine kinase in Balb/c3T3 fibroblasts, and that Gi alpha 2 itself is a substrate for phosphorylation in vitro. This phosphorylation of Gi alpha 2 is inhibited if the G-protein is first activated with GTP or inactivated with GDP, suggesting that the phosphorylation may be occurring in the guanine nucleotide binding region. We present evidence that the kinase is not a protein kinase C. Such a phosphorylation of Gi alpha 2 could represent either a negative feedback mechanism of signal transduction, or a GTP-independent pathway of G-protein signal transduction in fibroblasts. PMID- 7857772 TI - Insulin-stimulated phosphatidylcholine hydrolysis, diacylglycerol/protein kinase C signalling, and hexose transport in pertussis toxin-treated BC3H-1 myocytes. AB - Pertussis toxin was used to block insulin-stimulated phosphatidylinositol (PI) glycan hydrolysis, consequent de novo synthesis of phosphatidic acid (PA) and the diacylglycerol (DAG) production that results from these two related processes in BC3H-1 myocytes. In contrast, pertussis toxin pretreatment did not inhibit insulin-stimulated hydrolysis of phosphatidylcholine (PC) which was found to be at least partly due to activation of a phospholipase D. Moreover, pertussis toxin insensitive PC hydrolysis was accompanied by rapid biphasic increases in DAG and translocative activation of protein kinase C (PKC). Insulin-stimulated glucose transport was also insensitive to pertussis toxin pretreatment. Our findings suggest that insulin-stimulated PC hydrolysis pays an important role in DAG/PKC signalling during insulin action. PMID- 7857773 TI - In vitro inhibition of aromatase by the enantiomers of aminoglutethimide and analogs. AB - The in vitro aromatase activity in microsomal fractions from rat ovary and its inhibition by enantiomers of aminoglutethimide (AG), rogletimide (RG), and cyclohexylaminoglutethimide (ChAG) were studied by analysing the [3H]H2O released when [1 beta-3H]androstenedione was converted to estrone. Maximum velocity (Vmax) and the Michaelis-Menten constant (Km) of the microsomal aromatase enzyme were 17.40 +/- 0.45 pmol/ml/mg protein/min and 1.02 +/- 0.06 microM, respectively. The IC50s for the enantiomers were similar for (+)-R-AG and (-)-R-ChAG (0.86 +/- 0.06 and 0.89 +/- 0.15 microM, respectively. (+)S-ChAG was most potent with IC50 of 0.075 +/- 0.003 microM. The IC50s for (-)-S-AG, (+)-R-RG, and (-)-S-RG were in the same range (23.15 +/- 2.74, 24.58 +/- 2.46, and 24.43 +/- 2.20 microM, respectively. PMID- 7857774 TI - Optically active analogues of ebastine: synthesis and effect of chirality on their antihistaminic and antimuscarinic activity. AB - A series of optically active analogues of the H1-antihistamine ebastine, with chiral center(s) at the benzhydryl and/or phenylbutyl part of the molecule, have been synthesized. Their in vitro antihistaminic and antimuscarinic activities were investigated, along with a molecular modelling study. It was found that introduction of the benzhydryl chiral center yielded significant stereoselectivity for both antihistaminic and antimuscarinic activities. The steric preferences of the benzhydryl chiral center for antihistaminic and antimuscarinic actions were mirror images of each other. The (-)-isomer of 4 methylebastine (6d) showed more than 10-fold higher in vitro antihistaminic potency than ebastine. Meanwhile the selectivity of 6d for histamine H1-receptors was also increased by more than 20 times in comparison with ebastine. The chirality at the phenylbutyl part of the molecule does not significantly alter the antihistaminic or antimuscarinic activity of the compounds although the (S) isomers showed slightly but unanimously higher antihistaminic activity than the (R)-isomers. These results have been discussed with existing stereoselectivity data of antihistamines and an asymmetric pharmacophore model for H1-antagonists has been described. PMID- 7857775 TI - Marked enantioselective protein binding in humans of ketorolac in vitro: elucidation of enantiomer unbound fractions following facile synthesis and direct chiral HPLC resolution of tritium-labelled ketorolac. AB - The protein binding of the enantiomers of the nonopiate analgesic, ketorolac, was investigated in vitro using human plasma and solutions of human serum albumin (HSA) at physiological pH and temperature. In order to detect the very low levels of unbound enantiomers in protein solutions, tritium-labelled rac-ketorolac was synthesised by regiospecific isotopic exchange of the parent drug with tritiated water as the isotope donor. Radiochemical purification of this compound by reversed-phase HPLC followed by direct resolution using a chiral alpha 1-acid glycoprotein (Chiral-AGP) HPLC column afforded labelled enantiomers of high specific activity. The in vitro use of (R)- and (S)-[3H4]ketorolac enabled reproducible radiometric detection of enantiomers in protein solution ultrafiltrate. The unbound fractions of (R)- and (S)-ketorolac [fu(R) and fu(S), respectively] were determined when drug was added to various plasma or albumin solutions as either the separate enantiomers or as the racemate. Over an enantiomeric plasma concentration range of 2.0-15.0 micrograms/ml, fu(S) (mean range: 1.572-1.795%) was more than 2-fold greater (P < 0.001) than fu(R) (mean range: 0.565-0.674%). Both fu(R) and fu(S) were constant over this concentration range, and each was unaffected by the presence of the corresponding antipode (P > 0.05). At a concentration of 2.0 micrograms/ml in 40.0 g/liter fatty acid-free HSA, fu(R) and fu(S) were approximately 0.5 and 1.1%, respectively, and both values declined with increasing concentrations of the long chain fatty acid, oleic acid.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7857776 TI - Synthesis and enantiomeric purity determination of chiral 3-benzylglycidol, a key synthon for HIV protease inhibitors. AB - The detailed synthesis of (2R,3R)-3-benzylglycidol by the Sharpless asymmetric epoxidation route is described. The enantiomeric purity determination of this compound is complicated by the presence of small quantities of the diastereometric (2R,3S)-3-benzylglycidol from the asymmetric epoxidation of the cis-allylic alcohol, and the unreacted allylic alcohols that are not removed in the product isolation steps. We have developed a direct chiral HPLC method that can resolve all these components for the precise determination of enantiomeric excesses of chiral 3-benzylglycidols. PMID- 7857777 TI - kappa-Opioid activity of the four stereoisomers of the peripherally selective kappa-agonists, EMD 60,400 and EMD 61,753. AB - The four stereoisomers of the two peripherally selective kappa-opioid agonists EMD 60,400 and EMD 61,753 were synthesized, tested for stereoisomeric purity, and examined for affinity to the kappa opioid receptor. The relationships between the configuration of these molecules and their biological activity are discussed. PMID- 7857778 TI - Distribution of the vesicular acetylcholine transporter (VAChT) in the central and peripheral nervous systems of the rat. AB - Expression of the acetylcholine biosynthetic enzyme choline acetyltransferase (ChAT), the vesicular acetylcholine transporter (VAChT), and the high-affinity plasma membrane choline transporter uniquely defines the cholinergic phenotype in the mammalian central (CNS) and peripheral (PNS) nervous systems. The distribution of cells expressing the messenger RNA encoding the recently cloned VAChT in the rat CNS and PNS is described here. The pattern of expression of VAChT mRNA is consistent with anatomical, pharmacological, and histochemical information on the distribution of functional cholinergic neurons in the brain and peripheral tissues of the rat. VAChT mRNA-containing cells are present in brain areas, including neocortex and hypothalamus, in which the existence of cholinergic neurons has been the subject of debate. The demonstration that VAChT is a completely adequate marker for cholinergic neurons should allow the systematic delineation of cholinergic synapses in the rat nervous system when antibodies directed to this protein are available. PMID- 7857780 TI - Occurrence of prosaposin as a neuronal surface membrane component. AB - Prosaposin is a precursor of four saposins that are required for the lysosomal hydrolysis of sphingolipids by specific hydrolases. Besides its precursor role, prosaposin also exists as a secreted protein. The present investigation reveals that prosaposin also exists as an integral component of the surface membranes of neuronal cells. Subcellular fractionation studies demonstrate that the membrane bound prosaposin occurs specifically in plasma membranes of NS20Y rat neuroblastoma cells. An immunohistochemical study of the neuroblastoma cells using rat prosaposin-specific antibodies also showed that a portion of prosaposin is located on the surface of neurites as well as on cell bodies. Similar histochemical studies with antibodies that specifically recognized human prosaposin revealed the presence of prosaposin in dendrites, axons, and cell bodies of subcortical and spinal cord neurons in both human adult brain and in fetal brain (24-wk gestation). These findings suggest an important role of prosaposin in neuronal development. PMID- 7857779 TI - Nerve growth factor-induced differentiation of PC12 cells employs the PMA insensitive protein kinase C-zeta isoform. AB - To elucidate the role of protein kinase C (PKC) in nerve growth factor (NGF) induced differentiation, PMA downregulation of pheochromocytoma (PC12) cells was undertaken. Prolonged treatment (2 d) of PC12 cells with PMA (1 microM) resulted in depleting the cells of alpha, beta, delta, and epsilon-PKC isoforms, but had no effect on the expression of the atypical PKC isoform zeta. PC12 cells, which expressed only PKC zeta, were evaluated for their responses to NGF. Removal of the PMA-sensitive PKC isoforms enhanced the ability of NGF to promote neurite extension. Both the percentage cells with neurites and length of neurites were increased in the PMA-treated cells, whereas no effect was observed on the number of neurites per cell or branching of individual neurites. In addition, PMA downregulation resulted in an increase in the incorporation of 3H-thymidine without any significant effect on the expression of c-fos. Addition of NGF to PC12 cells depleted of the PMA-sensitive PKC isoforms resulted in the activation of PKC zeta (Wooten et al., 1994). To test whether the transient activation of PKC zeta is a necessary component of the neuritogenetic pathway, antisense oligonucleotide strategy was utilized to remove this particular PKC isoform. The addition of a 20-bp antisense oligonucleotide directed against the 5' coding sequence of PKC zeta attenuated NGF-induced neurite outgrowth in PC12 cells lacking PMA-sensitive PKC isoforms. Sense oligonucleotide directed at the same site was without effect on NGF responses. These data indicate that PKC zeta comprises a portion of the NGF pathway and underscores the importance of this isoform in neuronal differentiation. Moreover, these findings demonstrate that the PMA-insensitive pathway, which was previously characterized as PKC independent, and the neurite induction pathway are synonymous and mediated by PKC zeta. PMID- 7857781 TI - Early discharge in febrile neutropenia. PMID- 7857782 TI - Birth characteristics of childhood cancer cases, controls, and their siblings. AB - Reproductive characteristics of childhood cancer cases, controls, and their siblings were examined using data from a case-control study in the Denver, Colorado metropolitan area. Childhood cancer patients (n = 356) diagnosed from 1976 to 1983 were identified, and 242 were interviewed. Controls were selected by random digit dialing, with 212 interviews being completed (60% of eligibles). Extremes of birth weight were more common only among brain cancer cases. Patients were more often born preterm, particularly those with brain tumors [odds ratio (OR) = 6.1; 95% confidence interval (CI), 1.6-23.4] and were more likely to have birth defects (OR = 2.1; 95% CI, 0.9-5.0). Twins were more common among case siblings (OR = 2.6; 95% CI, 0.8-8.2). Low birth weight and preterm delivery among siblings were related only to soft tissue sarcoma. Birth defects were more common among case siblings, particularly leukemia cases (OR = 3.2; 95% CI, 1.3-7.7). Previous reports of elevated birth weight among cases and increased risk of miscarriage in case mothers were not corroborated, but associations with preterm delivery, high birth order, and birth defects among cases and birth defects and twinning among cases siblings encourage additional evaluation. PMID- 7857783 TI - Diarrhea and weight loss after bone marrow transplantation in children. AB - To define the determinants of diarrhea after bone marrow transplantation (BMT) and its nutritional sequelae, the medical records of 20 consecutive children (median age, 9 years; 13 boys and 7 girls) undergoing BMT at Children's Hospital in Birmingham, UK were surveyed. All patients who received total body irradiation (TBI) required parenteral nutrition (PN). Seventy-eight percent of TBI patients and 73% of children who received allografts developed diarrhea compared with only 27% of non-TBI patients and 22% of those who received autografts (P < 0.05). Ninety percent of children with diarrhea required PN. Duration of PN in these children was longer than in those without diarrhea who requested PN (P < 0.05). Despite PN, weight loss at discharge was still greater in the study group (P < 0.05). Diarrhea was associated with a significant fall in serum albumin (P < 0.005). Diarrhea and weight loss occur in children after BMT despite active PN support. Pretransplant TBI and the use of allografts are important determinants of these complications. PMID- 7857784 TI - High-dose cyclophosphamide, adriamycin, and vincristine (HD-CAV) in children with recurrent solid tumor. AB - A dose-intensive regimen of cyclophosphamide (140 mg/kg over 2 days), doxorubicin (Adriamycin, 75 mg/m2 over 3 days), and vincristine (1 mg/m2 on days 1, 2, and 3 and 1.5 mg/m2 on day 9) was tested in 18 children and adolescents with poor prognosis recurrent or refractory solid tumors. Nine were affected by neuroblastoma, 3 by Ewing's tumors, 2 by rhabdomyosarcoma, 2 by synovial sarcoma, 1 by hepatocellular carcinoma, and 1 by osteogenic sarcoma. All enrolled patients were heavily pretreated, including 2 patients after bone marrow transplantation. Forty courses were applied (median, 2). The overall response rate was 33% (2 complete remissions and 4 partial remissions). Responses were obtained in children with neuroblastoma, Ewing's tumors, and hepatocellular carcinoma. Myelosuppression [World Health Organization (WHO) grade IV after all courses] and cardiac toxicity (3 WHO grade I, 5 WHO grade III, and 3 WHO grade IV) were the main side effects. Nephrotoxicity and hepatoxicity were not observed. With further therapy consisting of surgery, radiotherapy, and high-dose chemotherapy [cisplatin, carboplatin/etoposide (VP16), or ifosfamide/VP16 with or without autologous stem cell reinfusion after conditioning with melphalan/VP16/carboplatin], 3 complete remissions and 5 very good partial remissions were obtained. Ten of 18 patients are alive after a median follow-up of 16 months. PMID- 7857785 TI - Enrichment of residual tumor cells in bone marrow or peripheral blood cells in a neuroectodermal tumor model. AB - To enrich a small population of malignant cells contaminating human bone marrow or peripheral blood, a method of immunomagnetic depletion of the normal nucleated cells was developed. In a model using neuroectodermal cell lines, contaminations between 0.1% and 1.4% of tumor cells could be increased by a factor of 7.5 (median; range, 3.8 to 18.0; n = 10). Because incubation with antibodies is restricted to the magnetic beads in this method, the cell population after removal of the beads has not been incubated with antibodies. The risk of unspecific staining of the tumor cells during the enrichment procedure is minimal. This simple method is therefore well suited to the study of the characteristics of a minimal residual disease population. PMID- 7857786 TI - Hematopoietic progenitors in children with end-stage renal disease. AB - Bone marrow and circulating erythroid progenitors (BFU-E) in six anemic children with end-stage renal disease (ESRD) were 2.0 and 1.9 times as abundant, respectively, as in six age-matched normal controls and were significantly more responsive in vitro to low concentrations of recombinant human erythropoietin (rHuEpo) than those from the controls. After 4 weeks of rHuEpo therapy, both the number and the in vitro rHuEpo response of circulating BFU-E in the ESRD patients returned to normal control values. The numbers of bone marrow and circulating granulocyte-monocyte progenitors in the ESRD patients before and after rHuEpo therapy were comparable to those of normal controls. There was no inhibition of in vitro erythropoiesis by either the patients' serum or medium conditioned by their mononuclear cells. These results demonstrate a significant abundance and an increased rHuEpo sensitivity of BFU-E in anemic children with ESRD with no evidence of the presence of uremic inhibitors to erythropoiesis. PMID- 7857787 TI - Apoptosis as a possible way of destruction of lymphoblasts after glucocorticoid treatment of children with acute lymphoblastic leukemia. AB - Apoptosis (programmed cell death) is a physiologic phenomenon wherein the dying cell plays an active part in its own destruction. It has an important role in regulation of the balance of cell proliferation and cell death. The pharmacologic manipulation of apoptosis offers new possibilities for the prevention and treatment of cancer. One of the independent prognostic factors in the treatment of acute lymphoblastic leukemia is the sensitivity of the leukemic cells to corticosteroids. Apoptosis after glucocorticoid therapy is suggested as a prognostic factor in children with leukemia. Peripheral blood of children with acute leukemia was taken for morphologic and flow cytometric studies before and after the onset of prednisolone monotherapy. In most of the cases a positive correlation was observed between the decrease of blast numbers and the increase in apoptotic ratio in peripheral blood. In one case no response was observed either clinically or regarding apoptosis. PMID- 7857788 TI - Unusual case of leukoencephalopathy after bone marrow transplantation. AB - A girl with chronic myeloid leukemia received bone marrow transplantation with total body irradiation as part of a conditioning regimen. She developed leukoencephalopathy about 50 days after transplant. There was permanent neurologic impairment afterward. She had not received any cranial irradiation or intrathecal chemotherapy before transplant. She had received 10 months of interferon treatment before transplant, which might have played a part in the development of leukoencephalopathy. PMID- 7857789 TI - Proposals to unify the genera Grahamella and Bartonella, with descriptions of Bartonella talpae comb. nov., Bartonella peromysci comb. nov., and three new species, Bartonella grahamii sp. nov., Bartonella taylorii sp. nov., and Bartonella doshiae sp. nov. AB - Polyphasic methods were used to examine the taxonomic positions of three newly identified Grahamella species. A comparison of the 16S rRNA gene sequences of these organisms with the sequences available for other bacteria revealed that these three species form a tight monophyletic cluster with members of the genus Bartonella. This cluster is only remotely related to other members of the order Rickettsiales. Determinations of the levels of DNA relatedness between Grahamella species and Bartonella species (by using a modified hydroxyapatite method) revealed that all of the species belonging to these two genera are distinct but closely related. On the basis of these data and the results of guanine-plus cytosine content and phenotypic characterization studies, we propose that the genera Grahamella and Bartonella should be unified and that the latter name should be retained. Bartonella talpae and Bartonella peromysci, new combinations for former Grahamella species, are created, and the following three new Bartonella species are described: Bartonella grahamii, Bartonella taylorii, and Bartonella doshiae. A taxonomic analysis of Grahamella species complete the study of all members of the family Bartonellaceae, and the results of this study support the proposal that the family should be transferred out of the order Rickettsiales. PMID- 7857790 TI - Phylogenetic analysis of mycoplasma strain ISM1499 and its assignment to the Acholeplasma oculi strain cluster. AB - A mycoplasma strain designated ISM1499 was used to develop a mycoplasma genetic system (G. G. Mahairas and F. C. Minion, J. Bacteriol. 171:1775-1780, 1989; G. G. Mahairas, C. Jian, and F. C. Minion, Gene 93:61-65, 1990), but phenotypic inconsistencies led to the conclusion that this organism had been classified incorrectly as a member of the species Mycoplasma pulmonis. Studies were initiated to determine the proper taxonomic position of ISM1499, and on the basis of the results of our genetic analysis, this strain was assigned to the Acholeplasma oculi strain cluster. The base composition of strain ISM1499 was identical to the base composition of A. oculi 19L, but not to the base composition of Acholeplasma laidlawii PG8 (28.3 and 30.7 mol% G+C, respectively). The taxonomic position of ISM1499 was examined by performing a parsimony analysis with 16S ribosomal DNA sequence data, and the results were compared with previous phylogenetic reconstructions. Our results indicated that ISM1499 is more closely related phylogenetically to A. oculi 19L than to A. laidlawii PG8 and JA1. Heterogeneity in the 16S ribosomal DNA sequences of A. oculi 19L and ISM1499 and in the 16S ribosomal DNA sequences of A. laidlawii PG8 and JA1 may indicate that unusual dissimilarities occur in the 16S ribosomal DNA sequences of members of the genus Acholeplasma. PMID- 7857791 TI - Amino acid sequence analysis of ribosomal protein AT-L30 from members of the family Pseudonocardiaceae. AB - The phylogenetic relationships of the genera belonging to the family Pseudonocardiaceae were examined by a novel approach, amino acid sequencing of ribosomal AT-L30 proteins. The results of partial amino acid sequencing of AT-L30 preparations revealed that the members of the family Pseudonocardiaceae are divided into four clusters; the first cluster contains the genus Actinopolyspora, the second cluster contains the genus Saccharopolyspora, the third cluster contains the genus Amycolatopsis, and the fourth cluster contains the genera Amycolata, Pseudonocardia, Saccharomonospora, and Kibdelosporangium, indicating a close phylogenetic relationship between the genera Amycolata and Pseudonocardia. The genus Actinokineospora is closely related to the genus Saccharothrix, and these two genera formed a cluster separate from the clusters for the genera of the Pseudonocardiaceae. These results agree in almost all respects with previous 16S rRNA sequencing work by Embley et al. (T. M. Embely, J. Smida, and E. Stackebrandt, Syst. Appl. Microbiol. 11:44-52, 1988) and Warwick et al. (S. Warwick, T. Bowen, H. McVeigh, and T. M. Embley, Int. J. Syst. Bacteriol. 44:293 299, 1994), thus supporting the proposal of Warwick et al. that the genera Amycolata and Pseudonocardia should be combined in an emended genus, Pseudonocardia. However, a discrepancy was found between the present study and that of Warwick et al. In the present study, the Nocardia-Rhodococcus group and the Saccharothrix-Actinokineospora group were both recovered within the clade for the family Pseudonocardiaceae. PMID- 7857792 TI - Cycloclasticus pugetii gen. nov., sp. nov., an aromatic hydrocarbon-degrading bacterium from marine sediments. AB - Three heterotrophic bacterial strains were isolated from different locations in Puget Sound, Washington, by using biphenyl as the principal carbon source. These strains grow by using a limited number of organic compounds, including the aromatic hydrocarbons naphthalene, phenanthrene, anthracene, and toluene, as sole carbon sources. These aerobic, gram-negative rods are motile by means of single polar flagella. Their 16S rRNA sequences indicate that they are all members of the gamma subdivision of the Proteobacteria. Their closet known relatives are the genera Methylobacter and Methylomonas (genera of methane-oxidizing bacteria), uncultured sulfur-oxidizing symbionts found in marine invertebrates, and clone FL5 containing 16S ribosomal DNA amplified from an environmental source. However, the Puget Sound bacteria do not use methane or methanol as a carbon source and do not oxidize reduced sulfur compounds. Furthermore, a 16S rRNA base similarity comparison revealed that these bacteria are sufficiently different from other bacteria to justify establishment of a new genus. On the basis of the information summarized above, we describe a new genus and species, Cycloclasticus pugetti, for these bacteria; strain PS-1 is the type strain of C. pugetti. PMID- 7857793 TI - Genomic diversity and phylogenetic relationships among lipid-requiring diphtheroids from humans and characterization of Corynebacterium macginleyi sp. nov. AB - DNA relatedness experiments were performed with 38 clinical isolates and 13 reference strains of coryneform taxa exhibiting a lipid requirement for optimal growth. Forty-five of these strains split into five genomic groups at the species level, whereas six other strains remained unclustered. Genomospecies II fits Corynebacterium accolens, but the other genomospecies were not genetically related to any of the defined Corynebacterium species. Phylogenetic analyses of genes coding for small-subunit rRNA sequences revealed that two genomospecies (I and III) and C. accolens form a tight cluster within the robust branch that groups all Corynebacterium species presently sequenced. Reference strains of biotypes C-1, C-2, and C-3 of "Corynebacterium pseudogenitalium" were found to fall into genomospecies I, as well as "Corynebacterium tuberculostearicum," Centers for Disease Control and Prevention (CDC) coryneform group G-1, and CDC coryneform group G-2 reference strains. Biochemical tests allowed differentiation between genomospecies except between genomospecies IV and V and between six unclustered strains and genomospecies I. We propose a new classification for these lipid-requiring diphtheroids within the genus Corynebacterium with the delineation of some CDC coryneform group G-1 strains (genomospecies III) as a new species for which the name Corynebacterium macginleyi is proposed. The type strain is strain JCL-2 (CIP 104099), isolated from a human corneal ulcer. PMID- 7857794 TI - Chemotaxonomic analyses of Bacteroides gracilis and Bacteroides ureolyticus and reclassification of B. gracilis as Campylobacter gracilis comb. nov. AB - The cellular fatty acids, respiratory quinones, and proteins of the generically misnamed taxa Bacteroides gracilis and Bacteroides ureolyticus were analyzed and compared with the corresponding chemotaxonomic features of their closest relatives, the campylobacters. Our results and previously published data for genotypic and phenotypic characteristics were used in a polyphasic approach to reconsider the classification of these organisms. We transfer B. gracilis to the genus Campylobacter as Campylobacter gracilis comb. nov. B. ureolyticus can be considered a campylobacter on genotypic grounds; in contrast, the proteolytic metabolism and fatty acid components of this taxon exclude it from the genus Campylobacter. We prefer to consider this taxon a species incertae sedis pending the isolation and characterization of additional B. ureolyticus-like bacteria. PMID- 7857795 TI - Characteristics of Rhizobium tianshanense sp. nov., a moderately and slowly growing root nodule bacterium isolated from an arid saline environment in Xinjiang, People's Republic of China. AB - We performed a numerical analysis of 148 phenotypic characteristics of 20 strains of root nodule bacteria isolated from an arid saline desert soil in the Xinjiang region of northwestern People's Republic of China and compared these organisms with 28 Rhizobium and Bradyrhizobium strains obtained from different regions of the People's Republic of China and from other countries, including nine type strains of different species. All of the strains examined clustered into two groups at a similarity level of more than 63%. Group I included all of the previously described Rhizobium species and was divided into eight subgroups, which corresponded to previously described Rhizobium species, at a similarity level of more than 82%. Group II was divided into the following three subgroups at a similarity level of more than 80% Bradyrhizobium japonicum, a cluster containing 17 moderately and slowly growing strains isolated in the Xinjiang region, and a small subgroup containing three fast-growing strains. The generation times of the moderately and slowly growing strains were 5 to 15 h, and these organisms produced acid in medium containing mannitol. The DNA G+C contents of the members of this group ranged from 59 to 63 mol%. DNA-DNA hybridization experiments revealed that the levels of DNA homology among all of the moderately and slowly growing strains obtained from Xinjiang were more than 70% and that the levels of DNA homology between representative strains of this group and the type strains of all previously described species of root- and stem-nodulating bacteria were low.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7857796 TI - Staphylococcus pulvereri sp. nov., isolated from human and animal specimens. AB - A new coagulase-negative species of the genus Staphylococcus, Staphylococcus pulvereri, was isolated from human and animal specimens. The complete 16S rRNA sequence of the type strain of S. pulvereri, NT215, was determined and compared with the sequences of 16S rRNAs from the other staphylococci. Strains of S. pulvereri were differentiated from other novobiocin-resistant Staphylococcus species by their biochemical activities, cell wall composition, and levels of genetic relatedness. The type strain of this species is NT215 (= PCM 2443T). PMID- 7857797 TI - Microlunatus phosphovorus gen. nov., sp. nov., a new gram-positive polyphosphate accumulating bacterium isolated from activated sludge. AB - Polyphosphate-accumulating bacteria that were previously isolated from activated sludge and exhibited high phosphate removal activity were studied taxonomically and phylogenetically. These organisms were gram-positive, coccus-shaped, aerobic chemoorganotrophs that had a strictly respiratory type of metabolism in which oxygen was a terminal electron acceptor. They accumulated large amounts of polyphosphate under aerobic conditions. The major quinone was menaquinone MK 9(H4). The cell wall peptidoglycan contained LL-diaminopimelic acid. The guanine plus-cytosine content of the DNA was 67.9 mol%. Our isolates were similar phenotypically and chemotaxonomically to Luteococcus japonicus, which was proposed recently as a new genus and species. However, our isolates differed from L. japonicus in cellular fatty acid composition and some other traits. A phylogenetic analysis based on 16S rRNA sequences showed that our isolate differ from the genus Luteococcus and other genera belonging to the high-G+C-content gram-positive group. Accordingly, we concluded that our strain NM-1T (T = type strain) should be assigned to a new genus and species, for which we propose the name Microlunatus phosphovorus. PMID- 7857798 TI - Isoenzyme, restriction fragment length polymorphism, and random amplified polymorphic DNA characterization of Phaffia rhodozyma Miller et al. AB - The validity of the species concept was examined with strains of Phaffia rhodozyma by comparing the isoenzyme profiles, ribosomal DNAs, and random amplified polymorphic DNA (RAPD) patterns of the strains. The isoenzyme profiles appeared to be more stable than the RAPD patterns or the electrophoretic karyotypes determined previously (A. Nagy, N. Garamszegi, C. Vagvolgyi, and L. Ferenczy, FEMS Microbiol. Lett., in press). The ribosomal DNA patterns revealed only a limited degree of variability, while RAPD analysis proved to be the most useful method for differentiating the strains studied. Strain CBS 5905T (T = type strain) produced characteristic RAPD patterns, which were different from those produced by the other strains. However, despite the high degree of variability observed, the isoenzyme data and the slightly variable ribosomal DNA hybridization profiles confirmed that the strains which we examined belong to one species. PMID- 7857799 TI - Heterogeneity of genome sizes within the genus Spiroplasma. AB - Organisms belonging to the genus Spiroplasma are currently classified into 23 groups, 17 of which have been assigned species epithets. We determined the genome sizes of representatives of 20 groups by using pulsed-field gel electrophoresis. Each genome size was deduced from the mobility of linear nonrestricted DNA, as well as from the sum of the sizes of restriction fragments obtained after digestion with NotI, a restriction endonuclease with a limited number of restriction sites in spiroplasma DNA. The values which we obtained indicated that the genome sizes of members of the genus Spiroplasma range from 940 to 2,220 kbp. PMID- 7857801 TI - Taxonomic note: implementation of the provisional status Candidatus for incompletely described procaryotes. AB - The International Committee on Systematic Bacteriology recommended that the category Candidatus, recently proposed by Murray and Schleifer (Int. J. Syst. Bacteriol. 44:174-176, 1994) to record the properties of putative taxa of procaryotes, should be implemented. This category should be used for describing procaryotic entities for which more than a mere sequence is available but for which characteristics required for description according to the International Code of Nomenclature of Bacteria are lacking. In addition to genomic information, such as sequences apt to determine the phylogenetic position of the organism, all information, including structural, metabolic, and reproductive features, should be included in the description of a provisional taxon, together with the natural environment in which the organism can be identified by in situ hybridization or other similar techniques for cell identification. PMID- 7857800 TI - The phylogenetic position of the family Methylococcaceae. AB - The 16S ribosomal DNA-based phylogenetic positions of various members of the Methylococcaceae (group I methanotrophs) were investigated. The Methylococcaceae as a whole formed a distinct branch in the gamma subdivision of the Proteobacteria, and this branch had five distinct subbranches. On the basis of a number of phenotypic traits, phospholipid fatty acid patterns, and the results of a 16S ribosomal DNA analysis, we determined that the species belonging to one subbranch, Methylobacter albus, Methylobacter agilis, and Methylobacter pelagicus, formed a distinct group that could be differentiated from other members of the genus Methylobacter, which grouped in an adjacent subbranch. We propose that these species belong to a new taxon, Methylomicrobium gen. nov. PMID- 7857802 TI - Taxonomic note: the potential of dead bacterial specimens for systematic studies. AB - Consideration should be given to preserving nonliving bacterial specimens as dried material in herbaria for use in future systematic studies. Nucleic acid sequences can be recovered from such material, and it may be possible to utilize it in other techniques. Dried specimens are cheap to prepare and preserve and would record much bacterial variation without the expense of maintaining living cultures. They would also be useful for uncultivable microorganisms. Some technical suggestions are offered. PMID- 7857803 TI - Spiroplasma ixodetis sp. nov., a new species from Ixodes pacificus ticks collected in Oregon. AB - Eight strains of mollicutes were isolated from pooled suspensions prepared from western black-legged ticks (Ixodes pacificus) collected in Oregon. Morphologic examination by electron and dark-field microscopic techniques showed that each strain consisted of a mixture of motile, tightly coiled helical cells, small coccoid cells with diameters ranging from 300 to 500 nm, and pleomorphic, straight or branched filamentous forms. All cellular forms were surrounded by a single cytoplasmic membrane, and there was no evidence of a cell wall. The organisms were filterable and fastidious in their growth requirements. The optimum temperature for growth was 30 degrees C, but multiplication occurred at temperatures ranging from 23 to 32 degrees C. The strains catabolized glucose but did not hydrolyze arginine or urea. The genome size of strain Y32T (T = type strain) was 2,220 kbp, and the DNA base composition (guanine-plus-cytosine content) of this organism was 25 +/- 1 mol%. The eight isolates were serologically related to each other but were not related to 37 other type or representative strains belonging to the genus Spiroplasma. Strain Y32 (= ATCC 33835) is the type strain of Spiroplasma ixodetis sp. nov. PMID- 7857804 TI - Mycoplasma adleri sp. nov., an isolate from a goat. AB - Mycoplasma sp. strain G145T (T = type strain) was isolated from a goat's abscessed ankle. Strain G145T required cholesterol or serum for growth and possessed characteristics similar to those of other members of the genus Mycoplasma. This strain was serologically distinct from previously described Mycoplasma species and from a group of currently unnamed strains thought to belong to the genus Mycoplasma. Strain G145T hydrolyzed arginine, but did not hydrolyze urea or ferment glucose. The guanine-plus-cytosine content of the DNA was 29.6 mol%. We propose that strain G145 (= ATCC 27948) is the type strain of a new species, for which we propose the name Mycoplasma adleri. PMID- 7857805 TI - Dietzia, a new genus including Dietzia maris comb. nov., formerly Rhodococcus maris. AB - Sequencing of the 16S ribosomal DNAs (rDNA) of two strains of Rhodococcus maris was performed to determine the relationship of this species to other mycolic acid containing actinomycetes. For this purpose we also determined the 16S rDNA sequences for the type species of the genus Rhodococcus, Rhodococcus rhodochrous, and for Mycobacterium chlorophenolicum (formerly Rhodococcus chlorophenolicus), Rhodococcus erythropolis, Gordona bronchialis, and Gordona terrae, for which only partial sequence data have been available previously. The sequences of the two strains of R. maris were identical. The results of a distance matrix analysis indicated that R. maris is not a member of the genus Rhodococcus but is located between members of the genus Corynebacterium and members of the Rhodococcus Nocardia-Mycobacterium-Gordona-Tsukamurella cluster. The finding that R. maris is phylogenetically isolated is supported by the presence of N-acetyl residues in the glycan moiety of the peptidoglycan and the lack of phosphatidylinositol and phosphatidylinositol mannosides, characteristics which distinguish this taxon from related taxa. On the basis of our results and previous findings, we propose that R. maris should be reclassified in a new genus, Dietzia. The type species is Dietzia maris comb. nov. PMID- 7857806 TI - Bordetella hinzii sp. nov., isolated from poultry and humans. AB - A polyphasic taxonomic study that included DNA-rRNA hybridizations, DNA-DNA hybridizations, DNA base ratio determinations, whole-cell protein and fatty acid analyses, and an examination of classical phenotypic characteristics was performed in order to classify human and veterinary isolates that resemble Bordetella avium. Twelve poultry isolates and two human isolates were assigned to a new species, for which we propose the name Bordetella hinzii. The position of this organism in the family Alcaligenaceae and various genotypic, phenotypic, and chemotaxonomic characteristics are described. PMID- 7857807 TI - Dermatophilus chelonae sp. nov., isolated from chelonids in Australia. AB - Three isolates of a previously undescribed Dermatophilus sp. obtained from chelonids (two strains obtained from turtles and one strain obtained from a tortoise) were compared with 30 Dermatophilus congolensis isolates obtained from Australian mammals. The microscopic appearance, the colony morphology, and most biochemical test results for the chelonid isolates were characteristic of the genus Dermatophilus. Our isolates differed from the mammalian D. congolensis isolates in a number of cultural characteristics, including faster growth at 27 degrees C than at 37 degrees C, formation of two hemolysis zones around colonies on blood agar at 37 degrees C in the presence of 10% CO2, poor motility, and production of a distinctive odor. The DNA restriction enzyme digestion and protein electrophoresis patterns of our strains were distinct. The electrophoretic mobilities of 11 enzymes differed from the mobilities observed with D. congolensis strains. A monoclonal antibody to a surface antigen of an ovine isolate did not react with zoospores or filaments of the chelonid isolates. Biochemical differences between our isolates and D. congolensis included the ability of the chelonid isolates to reduce nitrate to nitrate and the fact that the chelonid isolates exhibit collagenase activity in vitro. We propose that the chelonid isolates should be placed in a new species, Dermatophilus chelonae. Strain W16, which was isolated from a nose scab on a snapping turtle, is the type strain; a culture of this strain has been deposited in the American Type Culture Collection as strain ATCC 51576. PMID- 7857808 TI - Description of human-derived Centers for Disease Control coryneform group 2 bacteria as Actinomyces bernardiae sp. nov. AB - Biochemical, chemotaxonomic, and molecular methods were used to establish the precise taxonomic position of the Centers for Disease Control (CDC) coryneform group 2 bacteria. The results of a comparative 16S rRNA sequence analysis demonstrated that the CDC coryneform group 2 bacteria constitute a distinct species within the genus Actinomyces. Actinomyces pyogenes was found to be the closest genealogical relative of the CDC coryneform group 2 bacteria, although these taxa were readily distinguished from each other and other Actinomyces spp. by using phenotypic criteria. On the basis of our findings we propose the name Actinomyces bernardiae sp. nov. for the CDC coryneform group 2 bacteria. The type strain is DSM 9152 (CCUG 33419). PMID- 7857809 TI - Campylobacter hyoilei sp. nov., associated with porcine proliferative enteritis. AB - Campylobacter hyoilei sp. nov. is the name proposed for an organism formerly described as strain RMIT 32AT (T = type strain) and a group of similar bacteria isolated from intestinal lesions of pigs with proliferative enteritis. The phenotypic characteristics of these organisms indicated that they are closely related to each other and are not strains of other Campylobacter spp. commonly isolated from pigs. The results of probing of ClaI-, EcoRV-, or BglII-cleaved genomic DNAs from C. hyoilei strains with a radiolabeled DNA probe that distinguishes between Campylobacter jejuni and Campylobacter coli indicated that C. hyoilei and C. coli are closely related. However, the 16S rRNA sequence of the reference strain of C. hyoilei, RMIT 32AT, was four bases different from the 16S rRNA sequence of C. jejuni CCUG 11284T and five bases different from the 16S rRNA sequence of C. jejuni subsp. doylei CCUG 24567T, suggesting that C. hyoilei is more closely related to C. jejuni than to C. coli. Hybridization between DNA from C. hyoilei type strain RMIT 32A and DNAs from selected type and reference strains of other Campylobacter species and subspecies, including C. jejuni, C. jejuni subsp. doylei, C. coli, Campylobacter mucosalis, and Campylobacter hyointestinalis, as well as the other C. hyoilei strains (the RMIT 32AT-like isolates), revealed that high levels of DNA hybridization (> 70%) occurred only between the reference strain and other strains of C. hyoilei. PMID- 7857811 TI - Brevinema andersonii gen. nov., sp. nov., an infectious spirochete isolated from the short-tailed shrew (Blarina brevicauda) and the white-footed mouse (Peromyscus leucopus). AB - A spirochete which infects short-tailed shrews (Blarina brevicauda) and white footed mice (Peromyscus leucopus) has been shown previously to be ultrastructurally and serologically distinct from other spirochetes. Two of the original isolates from Connecticut and Minnesota and 16 new isolates obtained from shrews captured in Minnesota were characterized phenotypically and genetically in this study. A comparative analysis of the 16S rRNA sequences of two shrew isolates and one mouse isolate and the 16S rRNA sequences of 16 other spirochetes and Escherichia coli revealed that these organisms exhibited low levels of similarity (range of similarity values, 73.9 to 77.8%; average level of similarity, 74.7%). The shrew and mouse isolates which we examined formed a deeply branching subgroup that was clearly distinct from the other genera of spirochetes examined. These and other results indicated that the new spirochetes represent a unique taxon in the order Spirochaetales. Accordingly, we propose that they should be classified as members of a new genus, Brevinema. The three strains of Brevinema which we examined had 16S rRNA sequences that were nearly identical. We also compared these isolates by using sodium dodecyl sulfate polyacrylamide gel electrophoresis, fatty acid and enzyme analyses, restriction endonuclease analysis, and Southern hybridization and found that the levels of genetic and phenotypic homogeneity among the strains were very high. We concluded that the isolates which we examined were members of a single species, for which we propose the name Brevinema andersonii. The type strain of Brevinema andersonii is CT11616 (= ATCC 43811).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7857813 TI - [Beliefs and superstition in medicine at the end of the 20th century]. PMID- 7857810 TI - Thermocrispum gen. nov., a new genus of the order Actinomycetales, and description of Thermocrispum municipale sp. nov. and Thermocrispum agreste sp. nov. AB - Ten strains of thermophilic actinomycetes were isolated from waste and mushroom composts, as well as from the air of compost plants and a refuse incineration plant in Germany. These organisms produce white aerial mycelia and form hyphae with so-called pseudosporangia that fragment into rod-like structures. The organisms have type III cell walls (meso-diaminopimelic acid and whole-cell sugar type C), the phospholipid type is type PII, and mycolic acids are not present. The major menaquinone is MK-9(H4), and the fatty acids are mainly iso- and anteiso-branched fatty acids, hydroxy fatty acids, and 10-methyl-branched fatty acids. The guanine-plus-cytosine content of the DNA is 69 to 73 mol%. The chemotaxonomic markers (especially whole-cell sugar type C) and 16S ribosomal DNA sequence data indicated that these organisms represent a new genus of the order Actinomycetales, for which the name Thermocrispum is proposed. On the basis of phylogenetic and phenotypic data, this new genus is closely related to members of the family Pseudonocardiaceae and related taxa and contains two species: Thermocrispum municipale sp. nov. and Thermocrispum agreste sp. nov. The type species of the genus is T. municipale, with type strain MKD 35 (= DSM 44069), and the type strain of T. agreste is CHB 77 (= DSM 44070). PMID- 7857815 TI - [Therapeutic care and compression therapy for burns in children]. PMID- 7857814 TI - [Giving a good start to breast feeding]. PMID- 7857812 TI - Bacillus thermoamylovorans sp. nov., a moderately thermophilic and amylolytic bacterium. AB - A moderately thermophilic, facultatively anaerobic, amylolytic bacterium was isolated from palm wine, a tropical alcoholic beverage that was sampled in Senegal. The cells were gram positive, catalase positive, non-spore forming, rod shaped, and slightly motile with peritrichous flagella. The strain which we examined did not possess cytochrome and produced L-(+)-lactate, acetate, ethanol, and formate but not hydrogen during carbohydrate fermentation. Growth occurred at pH values ranging from 5.4 to 8.5, and optimum growth occurred at around pH 7.0. The optimum temperature for growth was around 50 degrees C, and the upper temperature limit for growth was 58 degrees C. The guanine-plus-cytosine content of the DNA was 38.8 +/- 0.2 mol%. A sequence analysis of the 16S rRNA gene revealed that the new organism is closely related phylogenetically to members of genus Bacillus. Despite the lack of spores, we propose that on the basis of phylogenetic characteristics, the new isolate should be classified as a new Bacillus species, Bacillus thermoamylovorans. The type strain is strain DKP (= Collection of Institut Pasteur CNCM I-1378). PMID- 7857817 TI - [Help for the patient overcoming a bone marrow transplantation]. PMID- 7857816 TI - [Caring for the dying in a pediatric intensive care unit]. PMID- 7857818 TI - [Experiences with the ruling on nursing personnel]. PMID- 7857819 TI - [Ethics is ... many things]. PMID- 7857820 TI - [Every-day-nursing with our patients' parents]. PMID- 7857821 TI - [Timely patient information]. PMID- 7857822 TI - [First aid and care of burns and scalds]. PMID- 7857823 TI - [Introduction to the program of the "25 years of the Krefeld pediatric intensive care unit" symposium]. PMID- 7857824 TI - [The importance of care in the prevention of brain hemorrhages in premature infants]. PMID- 7857825 TI - ["Much too early and much too small". Difficulties and prospects for the mother of a premature infant]. PMID- 7857826 TI - [Pediatric home nursing in type 1 diabetes mellitus]. PMID- 7857827 TI - [Work in the refugee camp of Mogunga/Goma-Zaire]. PMID- 7857828 TI - [Compulsion exemplified in eating disorders (anorexia nervosa)]. PMID- 7857829 TI - [Treatment of respiratory syncytial virus infections--a review. Part 1]. PMID- 7857830 TI - [The new labor legislation (ArbZG). Simplification and more flexibility was the legislator's motto. Part 1]. PMID- 7857831 TI - [Toxic and less toxic plants. Part 17]. PMID- 7857832 TI - Erythropoietic protoporphyria. AB - Erythropoietic protoporphyria (EPP) is an inherited inborn error of porphyrin metabolism caused by decreased activity of the enzyme ferrochelatase, the terminal enzyme of the haem biosynthetic pathway, which catalyses the insertion of iron into protoporphyrin to form haem. EPP is characterized clinically by photosensitivity to visible light commencing in childhood, and biochemically by elevated red cell protoporphyrin levels. Although the majority of papers and reviews have classified EPP as an autosomal dominant disorder, the inheritance has now been shown to be more complex, and both autosomal dominant and recessive patterns of inheritance have been demonstrated using ferrochelatase activity. Further molecular studies should clarify the exact mode of inheritance. It seems likely that in the majority of families a defective allele from the apparently normal parent will be required for disease expression, but another possibility is autosomal dominant inheritance with low clinical penetrance. Exposure to bright sunlight, for as little as a few minutes in the worst affected patients, causes burning pain in exposed skin, which may be so severe and persistent that it prevents sleep for several nights. Patients usually attempt to relieve the pain by cold water or cold compresses. Apart from sun avoidance, the mainstay of prophylactic treatment has been beta-carotene. Although the published evidence for the effectiveness of beta-carotene is impressive, no controlled trials using adequate doses have been performed to unequivocally confirm its usefulness. The most serious complication of EPP is acute hepatic failure, which is due to accumulation of protoporphyrin in the liver. If jaundice develops, a rapidly fatal outcome often follows, unless liver transplantation is undertaken. Regular monitoring of liver function and red cell porphyrin levels is advisable, but this does not always identify patients before serious liver damage has occurred. Even when patients are identified at an early stage in the development of liver disease the therapeutic options available to prevent further damage are limited, and have not been fully evaluated. The gene for ferrochelatase has been cloned, sequenced and mapped to the long arm of chromosome 18. As mutations continue to be identified, phenotype/genotype correlations should become apparent, and it may eventually be possible to identify those patients at risk of developing hepatic failure. In addition, as the basic enzymatic defect in EPP is at the level of the bone marrow stem cells, which are the target cells of choice in the development of retroviral-mediated gene transfer, definitive treatment of EPP by gene therapy is a distinct hope for the future.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7857834 TI - T lymphocytes in lesional skin of patients with dermatitis herpetiformis. AB - Ten patients with dermatitis herpetiformis had biopsies taken from involved and uninvolved skin. Monoclonal antibodies and the avidin-biotin peroxidase staining technique were used to stain for T cells and Langerhans cells in skin sections. A significant increase in the number of CD3-positive T cells was observed in the upper dermis of involved compared with uninvolved skin (P < 0.0005). Most of the T cells in involved skin were CD45RO-positive memory cells; CD4-positive T cells exceeded the number of CD8-positive T cells by a ratio of 4:1. In addition, CD1a positive dendritic cells were observed within the clumps of T cells in involved dermis in nine of the 10 patients, but were absent from the dermis of uninvolved skin. Double immunofluorescent staining demonstrated that approximately 20-40% of the CD3-positive T cells were activated, and expressed the HLA-DR antigen. These findings suggest that activated T cells are involved in the pathogenesis of dermatitis herpetiformis skin lesions. PMID- 7857833 TI - Immunohistochemical characterization of the 'intimal proliferation' phenomenon in Sneddon's syndrome and essential thrombocythaemia. AB - Cellular changes were immunocytochemically characterized in skin vessels of five patients with idiopathic generalized racemose livedo (Sneddon's syndrome), and one patient with localized racemose livedo associated with essential thrombocythaemia. Antibodies against alpha-smooth muscle-actin, tropomyosin, desmin, vimentin, factor VIII-related antigen, human endothelial cells (CD31), human macrophages (CD68), and HLA-DR positive cells (CR3/43) were used. Conventional light microscopy showed, in all cases, intimal thickening of ascending arteries and arterioles as a result of an accumulation of cells and extracellular hyalinized material. None of the specimens showed infiltration with polymorphonuclear leucocytes or macrophages. The cells in the region of the intimal hyperplasia showed intense positive immunostaining for alpha-smooth muscle actin and tropomyosin. Staining for the intermediate filament desmin was localized to the resident smooth muscle cells of the media, whereas staining for vimentin was found in all types of cells in both the intima and media. Positive immunostaining for factor VIII-related antigen and CD31 was strictly confined to the endothelial cells lining the narrowed lumina of the vessels. No positive staining with either antibody was observed in totally occluded vessels. Cells in the subintimal space did not show reactivity for CD68 in any of the specimens, but two cases showed solitary cells with positive staining for HLA-DR in this region. There were no differences in staining pattern between Sneddon's syndrome and essential thrombocythaemia with any of the antibodies. Our results support the assumption that the 'intimal proliferation' in both diseases is caused by colonization of the subendothelial space with contractile cells of possible smooth muscle origin.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7857835 TI - Sheep vibrissa dermal papillae induce hair follicle formation in heterotypic skin equivalents. AB - Cultured skin equivalents were constructed by combining keratinocytes, outer root sheath cells or isolated epidermis, in vitro, with a matrix composed of collagen and cultured fibroblasts. When equivalents were grafted on to host animals, the epidermis thickened considerably, and tongues of cells penetrated the dermis, giving the dermal/epidermal junction a deeply sculptured profile. No cutaneous appendages were found in these grafts. We explored the possibility of inducing hair follicles by incorporating ovine hair follicle dermal papillae into constructs composed of an isolated epidermal sheet and a contracted dermal equivalent. In vitro, no morphogenetic changes associated with follicle formation were observed in the recombinants, but when grafted on to nude mice, follicle like structures were identified. The follicles were large, and had developed adjacent to the epidermis, indicating that the matrix environment of the induced follicles may not have been compatible with the downgrowth of the epidermal plugs normally observed during follicle formation in living skin. Nevertheless, in histological sections, the induced structures displayed many of the morphological characteristics of follicles in vivo, including the production of keratinized hairs. These results indicate that skin equivalents provide a useful model for the study of the chemical and structural features of matrices that facilitate hair follicle development. PMID- 7857836 TI - Extracellular matrix derived from hair and skin fibroblasts stimulates human skin melanocyte tyrosinase activity. AB - There is indirect evidence that both skin and hair melanocytes are regulated by the activity of adjacent cells. In hair, the specialized fibroblasts (dermal papilla cells) appear to play a role in the regulation of hair growth. Hair pigmentation may relate to hair growth. In skin, melanocytes are located adjacent to the basement membrane zone. As far as we are aware, direct interactions of fibroblasts with melanocytes have not previously been investigated. Accordingly, the objective of this study was to develop co-culture conditions in which to investigate whether dermal fibroblasts from skin or hair could influence melanocyte differentiation. The influence of fibroblast-conditioned media, co culture with fibroblasts, and fibroblast-derived extracellular matrix (ECM) on normal human skin melanocyte tyrosinase activity was examined. Fibroblasts from both skin and hair were capable of altering melanocyte morphology and significantly increasing tyrosinase activity when melanocytes were cultured in the absence, but not the presence, of the major proliferative drives. Although stimulation of tyrosinase activity was detectable with conditioned medium and co culture with fibroblasts, the most striking result was obtained with the fibroblast-produced ECM which, on average, produced a four-fold increase in tyrosinase activity within 6 days. Thus, the study describes co-culture conditions in which the stimulatory effect of the fibroblast on melanocyte differentiation can be examined. PMID- 7857837 TI - Morphological and quantitative analyses of normal epidermal Langerhans cells using confocal scanning laser microscopy. AB - Confocal scanning laser microscopy (CSLM), when used in conjunction with computerized image processing systems, provides a powerful tool for morphological and quantitative analyses of biological tissues. In this study, normal human epidermal sheets were stained by an indirect immunofluorescence method using anti CD1a monoclonal antibody. Positively stained epidermal Langerhans cells (LCs) were visualized using the Bio-Rad MRC-600 Confocal Imaging System. Images obtained from the confocal microscope were volumetrically rendered and quantitatively analysed using ANALYZE (Version 4.0) running on a Sun SPARC 2 Workstation. Normal epidermal LCs were shown to be large disc-like structures with five to nine long dendritic processes per cell, orientated with their flat surfaces parallel to the skin surface. LCs form a monolayer network of cells distributed evenly throughout the suprabasal layers of the epidermis, with no direct physical contact between dendritic processes. Mean LC density was estimated to be 582 per mm2 (95% confidence intervals, CI = 233-940), and mean cell volume was 612 microns3 (95% CI = 257-1020). LCs in sun-exposed sites were significantly lower in mean cell density, but larger in mean cell volume, than in covered sites. Mean surface area projected by LCs was estimated to be 26.8% (95% CI = 18.9-34.2), and this value did not show significant regional or individual variation. Our data support the notion that epidermal LCs are organized in such a way as to maximize their surface area for efficient trapping of antigens, and a reduction in LC density per unit area in sun-exposed sites is compensated for by an increase in the mean cell volume. PMID- 7857838 TI - Age-related diurnal changes of dermal oedema: evaluation by high-frequency ultrasound. AB - Using high-frequency ultrasound, we measured the influence of gravitational stress on skin echogenicity in 22 young (age range 17-27; median 19) and 22 elderly (age range 75-100; median 87) healthy adults. B-mode ultrasound images were obtained from the medial malleolus, lateral calf, anterior thigh, volar forearm and the medial aspect of the arm three times daily: in the morning, immediately before rising, and 2 and 12 h later. The echogenicity was measured by counting the number of low echogenic pixels in the image. Pronounced changes of low echogenic pixel numbers were seen in the areas exposed to high gravitational stress, i.e. the ankle and calf. In the young age-group echogenicity of the skin increased steadily during the day, whereas in the elderly population echogenicity decreased 2 h after getting up in the morning, and subsequently returned to the baseline level. In a control group of 10 people (aged 17-83; median 18), who remained in the supine position throughout the day, the echogenicity of the skin remained unchanged. As the echogenicity of the dermis is inversely related to the amount of fluid it contains, our results indicate that young skin responds to gravitational stress by fluid depletion. In the skin of the elderly, the mechanism of fluid removal appears to be defective. The impaired protection against the development of intradermal oedema in the elderly may predispose to the development of lipodermatosclerosis and leg ulceration. PMID- 7857839 TI - Fumaric acid derivatives evoke a transient increase in intracellular free calcium concentration and inhibit the proliferation of human keratinocytes. AB - Systemic administration of fumaric acid (FA) derivatives was originally an empirical antipsoriatic treatment, which showed promising clinical results. In the present study, FURA-2-loaded suspensions of cultured normal keratinocytes and SV40-transformed keratinocytes (SVK-14 cells) were used to study the effects of FA derivatives on the intracellular free calcium concentration ([Ca2+]i). Monomethylfumarate (MMF), dimethylfumarate (DMF) and monoethylfumarate (MEF) induced a rapid, transient [Ca2+]i increase in both cell types. This immediate increase reached maximal values of 396 nmol/l 10s after addition of MMF, and fell to basal values within 90-120 s (173 nmol/l for normal keratinocytes and 68 nmol/l for transformed keratinocytes). This increase was not affected by the prior addition of EGTA, indicating that FA derivatives released Ca2+ mainly from intracellular stores into the cytoplasm. Subsequently, dose-dependent inhibitory effects of FA derivatives on keratinocyte proliferation were demonstrated. The results of these experiments revealed that DMF was the most potent, MMF and MEF intermediate, and FA and malonic acid the least potent growth inhibitors. These antiproliferative effects of FA derivatives might be linked to the observed, transient [Ca2+]i elevations. PMID- 7857840 TI - Determination of density of follicles on various regions of the face by cyanoacrylate biopsy: correlation with sebum output. AB - The density of follicles on various regions of the human face has received scant attention. We used cyanoacrylate follicular biopsies to determine the number of follicles on the forehead, cheek, chin and nose of 12 healthy adult white women. Sebum output was assessed on the same regions by means of Sebutape. The density of follicles and sebum output followed a centrolateral decreasing gradient. There was no correlation between these two parameters. These regional patterns are important for studies of the pathogenesis of common disorders of the face and their response to treatment. PMID- 7857841 TI - Idiopathic trachyonychia (twenty-nail dystrophy): a pathological study of 23 patients. AB - We report the clinical features and pathological findings in 23 patients with idiopathic trachyonychia (twenty-nail dystrophy). Clinically, the nail changes in the majority of patients consisted of the typical 'sandpapered' appearance, with a rough, lustreless nail plate. In some, however, the nail plate abnormality was less severe, with numerous small, superficial pits, which imparted a shiny appearance to the surface of the nail. Histology of nail biopsy specimens showed spongiotic changes in 19 patients, psoriasiform features in three, and features of lichen planus in one patient. The mean follow-up of these patients was 2 years, during which time none developed alopecia areata or mucocutaneous lesions. Idiopathic trachyonychia is therefore a consequence of several inflammatory disorders, which produce a disturbance of nail matrix kinetics. The course of the inflammation and the extent of the inflammatory process within the nail matrix produce two different patterns of nail plate surface abnormalities. PMID- 7857842 TI - The practice of ultraviolet phototherapy in the United Kingdom. AB - A survey, using a postal questionnaire, was carried out to examine the current practice of UVB phototherapy in dermatology centres in the U.K. The questionnaire was sent to 115 dermatology departments, and sought information regarding the type and age of each machine used for ultraviolet B (UVB) phototherapy, methods of prescribing, recording and terminating patient exposure, and the skin conditions treated. Completed questionnaires were received from 87 of the 115 centres, giving a response rate of 76%. The survey showed that an appreciable number of U.K. phototherapy centres are using equipment which is both old, and suboptimal in producing a therapeutic response. There appeared to be a wide variation in the approach to phototherapy, both in terms of prescribing initial and incremental exposure, and in terminating treatment. The findings suggest that effectiveness and efficiency might be improved, and the risk/benefit ratio of phototherapy further reduced, by some rationalization of treatment protocols. PMID- 7857843 TI - Ocular toxicity of antimalarials in dermatology: a survey of current practice. AB - A questionnaire sent to 325 U.K. dermatologists regarding toxicity of antimalarials had a 70% response rate. Hydroxychloroquine (HCQ) was used by 168 respondents, chloroquine (CQ) by 66, and mepacrine by 89 (only 111 always chose one of these). HCQ was considered to be the most effective by 59%, and to have the least cutaneous side-effects by 66%; mepacrine was considered to have the lowest frequency of ocular side-effects by 50%. Thirty respondents had encountered ocular side-effects, but in most cases these were mild. Maculopathy after short-term therapy was identified as a side-effect which is rarely considered. Ocular side-effects were believed to be due to cumulative dose alone by 31%, to dose/body weight alone by 8%, to duration of treatment alone by 3%, and to combinations of these by 58%. Overall, cumulative dose was considered relevant by 85%, duration of treatment by 52%, and dose/body weight by 41%. Referral for ophthalmology screening was always performed at baseline or after an initial trial of therapy by 56%; 17% never referred patients for baseline screening; 60% routinely requested ophthalmological follow-up. In comparison, 14% of respondents routinely referred patients for baseline ophthalmological screening before PUVA therapy (only 52% of whom routinely referred patients before antimalarial therapy). The most important factor contributing to an individual's current practice was experience in training posts (52%), followed by advice of local ophthalmologists (45%), personal experience (19%), specific publications (16%), and manufacturers' recommendations (14%).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7857844 TI - Value of a second freeze-thaw cycle in cryotherapy of common warts. AB - A study of open, randomized, parallel-group design was performed to investigate the impact of a second freeze-thaw cycle on the cure rate, at 3 months, from cryotherapy of common warts on the hands and feet. Cryotherapy was performed at 3 week intervals, and subjects were randomized to receive either one or two freeze thaw cycles. In addition, all subjects used keratolytic wart paints throughout the study, and plantar warts were pared prior to freezing. Three hundred subjects were recruited. At 3 months, 124 were cured, 83 were not cured, and 93 had defaulted. Among those who did not default the cure rate was 57% from the single freeze technique, and 62% from the double freeze technique, a difference of 5% (P = 0.53, 95% CI-8.1-18.6). Separate analyses for subjects with warts on the hands and on the feet demonstrated no effect of double freezing on hand warts. In contrast, for plantar warts, the cure rate was 41% from single freezing and 65% for double freezing, a difference of 24% (P = 0.04, 95% CI 2.9-44.4). The use of a double freeze-thaw cycle confers little or no advantage over a single freeze in the treatment of hand warts, but may be considerably more effective for plantar warts. PMID- 7857845 TI - Is lipoatrophia semicircularis induced by pressure? AB - Ten patients suffering from lipoatrophia semicircularis are reported. It is suggested that pressure from a chair on the posterior aspect of the thighs, possibly in combination with direct pressure from a desk on the anterior aspect, caused the condition in these patients. Lipoatrophia semicircularis may be quite common, but most patients do not present to a dermatologist. PMID- 7857846 TI - The value of a baseline liver biopsy prior to methotrexate treatment. AB - Two patients with severe disabling psoriasis were treated with methotrexate (MTX). As a short course of treatment was envisaged, a pretreatment liver biopsy was not performed. Although both patients developed similarly abnormal levels of hepatic enzymes after low cumulative doses of MTX (440 and 450 mg), subsequent liver biopsies revealed contrasting findings. In one patient the histological features were normal. However, in the second, there was hepatic fibrosis, and the absence of a pretreatment biopsy led to problems with interpretation of these histological findings. As a liver biopsy is by far the most reliable method of detecting liver disease, we suggest that it is still of value to include a baseline liver biopsy in the pretreatment assessment of patients even when only a short course of MTX is planned. PMID- 7857847 TI - Specific skin lesions in a patient with Niemann-Pick disease. AB - We report a patient with Niemann-Pick disease who developed papular lesions on the face. These showed ultrastructural findings typical of this disorder. Specific skin lesions such as these are an extremely rare manifestation of Niemann-Pick disease. PMID- 7857849 TI - Bubble hair: a cosmetic abnormality caused by brief, focal heating of damp hair fibres. AB - Following investigation of two individuals with bubble hair abnormality, a reproducible cause has been established. Simple experiments showed that brief, focal heating of damp hair is sufficient to cause bubbles to form inside the hair fibres. This in turn results in weak, dry and brittle hair which breaks easily. PMID- 7857848 TI - Childhood epidermolysis bullosa acquisita. AB - We report a 6-year-old boy suffering from acquired epidermolysis bullosa, who presented with extensive lesions of the mucous membranes and disseminated, herpetiform and 'cluster of jewels'-like vesicles and bullae arising on erythematous plaques. Direct immunofluorescence showed linear deposits of IgG and C3 at the epidermal basement membrane zone. Indirect immunofluorescence demonstrated circulating autoantibodies (titre 1:128-1:256) directed at the blister floor of human NaCl-split skin, and reacting specifically with collagen VII of the anchoring fibrils, as demonstrated by immunoblotting. The disease was controlled with a combination of dapsone and prednisone. This case demonstrates the importance of modern immunological techniques in classifying childhood autoimmune bullous diseases, as precise diagnosis is important in determining an appropriate therapeutic regimen. PMID- 7857850 TI - Oral fluconazole treatment of fungating candidiasis in the keratitis, ichthyosis and deafness (KID) syndrome. AB - We report a patient with a congenital ichthyosiform eruption, sensorineural deafness, vascularizing keratitis and pannus formation, and hypotrichosis, who developed recalcitrant fungating candidal plaques on the skin. There was no family history of similar disease, or of consanguinity. The steroid sulphatase level in the keratin was within normal limits, and this finding excluded a diagnosis of X-linked recessive ichthyosis. Treatment with oral fluconazole for 14 weeks resulted in complete resolution of the fungating lesions, and there has been no evidence of recurrence during a 12-month follow-up period. PMID- 7857851 TI - Suncheck patches and monitoring of UVR exposure. PMID- 7857852 TI - Withdrawal symptoms after discontinuation of long-acting brompheniramine maleate. PMID- 7857853 TI - New antimicrobials against Mycobacterium marinum infection. PMID- 7857854 TI - The increasing incidence of basal cell carcinoma. PMID- 7857855 TI - Kaposi-like acroangiodermatitis induced by a suction-socket prosthesis. PMID- 7857856 TI - Paraneoplastic dermatomyositis: efficacy of intravenous gammaglobulin. PMID- 7857857 TI - Linear IgA disease exacerbated by topical iodine preparations. PMID- 7857858 TI - Pyoderma gangrenosum associated with IgA paraproteinaemia and ocular vasculitis. PMID- 7857859 TI - Aquagenic pruritus, PUVA and capsaicin treatments. PMID- 7857860 TI - The Melkersson-Rosenthal syndrome and food additive hypersensitivity. PMID- 7857861 TI - Pediatric cerebellar medulloblastoma and extraneural metastases: a case study. AB - Brain tumors, the most common solid tumors affecting children, account for nearly 20% of all pediatric neoplasms. They occur second in incidence only to leukemia and are the leading cause of cancer-related death in children under 15 years of age. Of the many different brain tumors, medulloblastoma is one of the most common, accounting for 20% of all intracranial neoplasm. Once a reportable event, extraneural metastases of this tumour now occur at a rate of 7% and reports suggest the prevalence may be increasing. These children represent a major therapeutic challenge, that for optimal results require the coordinated efforts of a multidisciplinary approach. The nurse may play a vital role in the mobilization and coordination of many specialists. The intent of this case study is to highlight the essential link in the role of the nurse as a facilitator, coordinator and liaison, within the context of caring for a child with a malignant brain tumour. PMID- 7857862 TI - Issues for nurses who care for patients in persistent vegetative states. AB - In a series of interviews, personal stress was identified as the most significant problem for neuroscience nurses who care for patients in persistent vegetative states. Other issues included inconsistent medical care, demanding physical care requirements, quality-of-life, ordinary versus extraordinary treatments, and the impact of this condition on patients' families. Some recommendations are presented that should help to alleviate some of these concerns. PMID- 7857863 TI - How a nursing licensing body responds to a complaint that is received against a nurse. PMID- 7857864 TI - Patient restraint: choosing the proper equipment. AB - In response to the Ontario Hospital Association's position paper describing the use of restraints, the Toronto Hospital responded by developing a "least restraint" policy and procedure. In the developmental stages, various types of equipment were evaluated. This paper describes the equipment selected by the safety task force and the rationale for its use. PMID- 7857865 TI - Length of hospital stay and contributing variables in supratentorial craniotomy patients with brain tumour: a pre-care map study. AB - The study included 70 patients admitted to Neurosurgical ICU (NICU) with the diagnosis of Supratentorial Craniotomy for Brain Tumour. These patients were followed throughout their hospitalization in NICU, to the ward and until discharge from hospital. The purposes of the study were (a) to indicated the NICU and floor length of stay (LOS) in this group of patients, prior to the use of care map and compare it to a developed care map, and (b) to identify the variables that contribute toe overall prolonged hospital LOS. The findings indicated that, prior to the use of care map, 68.8% of Supratentorial Craniotomy Patients with Brain Tumour had an ICU LOS of one day. However, only 38.6% of these patients were discharged from hospital within the care map indicated 5 day post ICU, floor LOS. The findings also showed that the overall hospital LOS, in 71.4% of the patients, was over 7 days, as indicated on the developed care cap. Several variables such as patient complications, consults, rehab/placement, patient falls and additional diagnostic tests contributed to the overall pronged hospital LOS. Thus, by monitoring these variables with the use of a care map, may produce measurements to evaluate cost effectiveness, and allow health care professionals to provide more effective and quality patient care. PMID- 7857866 TI - Sumatriptan in acute migraine therapy. PMID- 7857867 TI - The role of neuroscience nurses in organ and tissue donation, retrieval and transplantation. Developed by the specialization committee of the Canadian Association of Neuroscience Nurses. PMID- 7857868 TI - Subcellular distribution of the glucocorticoid receptor and evidence for its association with microtubules. AB - The cellular distribution of the glucocorticoid receptor (GR) has not yet been firmly established. The extensive literature indicates that GR is present both in the cytoplasm and the cell nucleus, however, some studies have failed to detect cytoplasmic GR. It is still controversial as to whether GR is randomly diffusing in the cytoplasm and nucleus, or if the GR-distribution is organized or controlled in some way, which may be of importance for the transduction of glucocorticoid effects to cells. There is evidence that both non-activated and activated GR is associated with the plasma membrane, a number of cytoplasmic organelles and the nucleus. Both morphological and biochemical evidence show that GR is associated with microtubules during different stages of the cell cycle, i.e. GR co-localizes, co-purifies and co-polymerizes with tubulin. This indicates that GR is structurally linked to the intracellular MT-network which may be of importance in the mechanism of action of glucocorticoid hormones. The literature in this field is reviewed including the reported data on subcellular GR localization. PMID- 7857869 TI - Feedback regulation of gonadotropins by androgens in rats: is 5 alpha-reduction involved? AB - The action of testosterone (T) on the sex accessory organs, such as ventral prostate (VP) and seminal vesicles (SV) is amplified by its 5 alpha-reduction to dihydrotestosterone (DHT). This does not happen in the case of muscle (levator ani, LA) which contains little or no 5 alpha-reductase activity. It has been suggested that the regulation of gonadotropins by T may also be mediated by its 5 alpha-reduced metabolites. We investigated this question by utilizing two types of androgens: (1) T and 17 alpha-methyl-testosterone (17MT), whose potency increases following 5 alpha-reduction; and (2) 19-nortestosterone (NT) and 17 alpha-methyl-19-nortestosterone (17MNT) whose potency decreases following 5 alpha reduction. Castrated rats were used to investigate the ability of these androgens to stimulate VP, and SV (androgenic action) and LA growth (anabolic action) and to suppress the post-castration rise in LH levels. In addition, modification of these actions by a 5 alpha-reductase inhibitor (5 alpha-RI) was studied. Compared to T, NT was approximately 5 times less potent in stimulating VP and SV. By contrast, it was twice as potent as T in stimulating LA growth. Similarly, 17MNT was 5 times less androgenic but twice as anabolic as 17MT. The antigonadotropic potency of both the 19-nor compounds was 2-3 times greater than that of their respective 19-methylated parent compounds. The similarity in their anabolic and antigonadotropic potency suggested that 5 alpha-reduction is not a factor in their antigonadotropic action. This was confirmed by the use of the 5 alpha-RI. Treatment of rats receiving the androgens with 5 alpha-RI showed that it decreases the androgenic activity of T and 17MT while it increases the androgenic activity of NT and 17 MNT. In all cases the anabolic activity and the antigonadotropic potency remained unchanged. It is concluded that the regulation of pituitary gonadotropin secretion by T does not depend upon its 5 alpha reduction to DHT. PMID- 7857870 TI - Enzyme-activated inhibitors of steroidal hydroxylases. AB - Cytochrome P450 monooxygenases (CYP450) of the steroid biosynthetic pathways are highly substrate specific in comparison to the variable specificities of hepatic CYP450 enzymes. Both groups of enzymes catalyze the reductive cleavage of molecular oxygen with transfer of oxygen to the substrate to form hydroxylated derivatives. Those steroids formed in endocrine tissues represent highly specific endocrine/autocrine hormones with enhanced biological potency, while hepatic hydroxylation of steroids reduces their endocrine bioactivities and enhances urinary elimination. Changes of the hormonal milieu of endocrine and peripheral tissues are associated with the development of hyperplastic and/or malignant conditions. Hormone deprivation induces regression of endocrine dependent growth via apoptosis and may also alter growth of hormone insensitive cells by the induction of negative growth factors. Biosynthetic CYP450 enzymes of those steroids that mediate specific disease processes are potential therapeutic targets for selective intervention. This objective can be accomplished by the design of specific pseudo-substrate analogs that will be activated during enzyme directed catalysis to produce a reactive functional group in the enzyme's active site that will either tightly or irreversibly bind and inactivate the host enzyme. The CYP450 enzymes that hydroxylate the C19 carbon of androgens (aromatase) and the C18 carbon of corticosterone (aldosterone synthase) were selected as target enzymes because they are terminal enzymes of biosynthetic pathways which hydroxylate specific angular methyl groups. Hypersecretion of their respective hormonal products, estrogens and aldosterone, are associated with specific disease conditions. Substrate analogs containing ethynyl, vinyl, or nitrile groups attached to the C19 or C18 methyl groups were enzyme-activated inhibitors. The ethynyl analogs, 19-acetylenic androstenedione (Plomestane) and 18-acetylenic deoxycorticosterone, had nanomolar inhibitory constants (Ki values) and were irreversible inactivators of their target enzymes in animal models. PMID- 7857871 TI - Isolation and expression of an isoform of rat estrogen sulfotransferase. AB - A new isoform of rat liver estrogen sulfotransferase (EST), rEST-6, which is distinct from the previously reported rat EST [Demyan et al., Molec. Endocrinol. 6 (1992) 589], has been cloned, expressed, purified and characterized. A PCR procedure using oligonucleotide primers synthesized to the 5'-nontranslated and 3'-nontranslated regions of the published rEST sequence was used to isolate rEST 6 cDNA. The cloned DNA is 1000 bp in length and encodes a protein of 295 amino acids with a calculated molecular mass of 35,300 Da. rEST-6 is selectively expressed in male rats, as confirmed by Northern blot and immunoblot analyses. Northern blot analysis of male and female rat liver RNA with the rEST-6 cDNA as a probe shows a band with male RNA but not with female RNA. Similarly, immunoblot analysis of male and female rat liver cytosols with an antibody to rat EST yields a strong immunoreactive band in rat liver cytosol from male rats but not from females. Subsequent to bacterial expression and purification of rEST-6, the enzyme was analyzed kinetically and shown to sulfate estrogens but not dehydroepiandrosterone, pregnenolone, cortisol or testosterone. Maximal sulfation activity towards both beta-estradiol and estrone occurred at a concentration of 1 microM with substrate inhibition at higher concentrations. These results indicate that multiple, closely related forms of EST are present in rat liver. Analysis of the activity and regulation of these different EST enzymes is important in understanding estrogen metabolism in rats. PMID- 7857872 TI - Changes in the levels of 11 beta-hydroxysteroid dehydrogenase mRNA over the oestrous cycle in the rat. AB - The NADP dependent enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta HSD) metabolizes glucocorticoids to their inactive 11-keto-metabolites in a wide range of tissues. To date very little is known about the regulation of this enzyme at the level of gene transcription. In this study we show significant changes in the uterine, renal, ovarian and hepatic levels of 11 beta HSD1 mRNA over the oestrous cycle. Uterine and renal message levels followed the same pattern, with the highest levels observed at dioestrus and the lowest levels at oestrus, a pattern that correlates with plasma oestrogen levels during the cycle. In both the uterus and kidney 11 beta HSD1 message levels more than halved from dioestrus to oestrus, while renal levels than doubled at metoestrus. In contrast, hepatic 11 beta HSD1 message levels at prooestrus were twice those observed at metoestrus. Ovarian levels remain constant until metoestrus when a marked decrease in message levels was seen. 11 beta HSD1 mRNA levels are thus differentially regulated in a tissue specific manner throughout the oestrous cycle. PMID- 7857874 TI - Molecular modelling of the human estrogen receptor and ligand interactions based on site-directed mutagenesis and amino acid sequence homology. AB - A molecular model of the human estrogen receptor is reported based on a new alignment with the alpha 1-antitrypsin sequence, a homologous protein of known crystal structure. The putative ligand binding site is situated roughly equidistant between the DNA binding and dimerization regions. This binding site contains a number of amino acid residues shown by site-directed mutagenesis to be associated with the binding of agonists and antagonists. This putative ligand binding pocket is well-defined within a loop of peptide, containing complementary amino acids for binding interactions with agonists and antagonists. A leucine rich region, common to most steroid-binding proteins, is in an optimum position for dimerization leading to DNA interaction. It is likely that ligand binding influences dimerization and DNA interaction by a conformational change in the receptor via the transcriptional activation residues. This model suggests that ligand binding may affect the hydrogen bonding pattern such that transpeptide signalling is initiated. The model accommodates steroidal estrogens and antiestrogens as well as the non-steroidal partial antagonist, hydroxytamoxifen. PMID- 7857873 TI - An essential role of androgen-induced growth factor in glucocorticoid-dependent autocrine loop in Shionogi carcinoma 115 cells. AB - Androgen-induced growth factor (AIGF) is essential for the androgen-induced autocrine growth of a mouse mammary Shionogi carcinoma cell line (SC-3 cells). Because glucocorticoid and estrogen have been observed to weakly stimulate DNA synthesis in SC-3 cells, the expression of AIGF mRNA after stimulation with various concentrations of androgen, glucocorticoid, or estrogen was examined by Northern blot analysis. Testosterone, dexamethasone, and estradiol-17 beta (E2) induced AIGF mRNA expression, although the maximum AIGF mRNA expression levels induced by dexamethasone or E2 were lower than that by testosterone. Yet, diethylstilbestrol showed no induction, suggesting that the effect of E2 could be mediated through the androgen receptor. The induction levels of AIGF mRNA by each steroid hormone were correlated positively with hormone-induced DNA synthesis. In addition, the DNA synthesis induced by each steroid hormone was almost completely inhibited by AIGF antisense oligonucleotides, indicating that AIGF is an obligatory component in not only the androgen- but also the glucocorticoid inducible autocrine loop in SC-3 cells. PMID- 7857876 TI - Human 17 beta-hydroxysteroid dehydrogenase: optical properties of its complex with NADP+. AB - The apoenzyme of the human placental 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) and its complex with NADP+ were prepared from two alternative procedures. The apoenzyme (Form I) has an absorption maximum at about 279 nm, and an absorption ratio at 280 and 260 nm of 1.65 +/- 0.1; whereas the complex (Form II) has a broad absorption peak between 268-278 nm, and a 280 to 260 nm ratio of 1.1 +/- 0.05. Upon addition of the substrate estradiol to the complex, an absorption increase at 340 nm and a fluorescence emission at 450 nm, following NADPH formation, were produced. Both changes indicate that one cofactor is tightly bound to the 17 beta-HSD molecule in this complex. No significant optical change can be produced in this way for the apoenzyme. Convenient analyses of cofactor content of the enzyme are thus provided. The optical analyses and the homogeneous apo- or holo-enzyme preparations are important in the study of the enzyme's function and crystallization. This is the first human steroid converting enzyme which has yielded X-ray quality crystals. PMID- 7857875 TI - The effect of aromatase inhibitor 4-hydroxyandrostenedione on steroid receptors in hormone-dependent tissues of the rat. AB - In previous studies, we observed that aromatase inhibitor 4-hydroxy androstenedione (4-OHA) treatment significantly decreased estrogen (ER) and progesterone receptor (PR) concentrations in the uterus of ovariectomized (OVX) rats. To investigate whether similar effects occur in mammary tumors, we have studied the hormone-dependent, carcinogen (DMBA)-induced tumors of the rat. After 2 weeks of 4-OHA treatment both ER and PR were reduced in mammary tumors, as well as in uteri of intact animals (P < 0.05). Following ovariectomy, receptor levels were also reduced. A further reduction in receptor concentration in mammary tumors occurred with 4-OHA treatment in OVX animals (P < 0.001). Treatment of OVX rats with estradiol (0.2 microgram/ml) restored tumor PR concentrations to the level of the control, whereas ER levels were increased to concentrations slightly higher than the control. 4-OHA treatment partially inhibited this increase in ER in mammary tumors of OVX rats treated with estradiol. In contrast to ER concentrations, mRNA ER levels in the uterus were not decreased significantly by ovariectomy although mRNA levels were reduced in the tumors. Ovariectomy was without effect on mRNA PR in either tissue. Treatment with 4-OHA reduced mRNA levels of ER and PR in uterus and tumors in intact and OVX animals. Levels of tumor mRNA of both ER and PR were inhibited by 4-OHA treatment in estradiol treated OVX rats. Thus, 4-OHA appears to inhibit ER and PR concentrations in mammary tumors of the rat by reducing transcription. Although aromatase inhibition which results in decreased estrogen production, is the major antitumor effect of 4-OHA, reduction in ER and PR could contribute to effective estrogen blockade and limit tumor growth by antagonizing estrogen action as well as production. PMID- 7857877 TI - Regulation of the cholesterol ester cycle and progesterone synthesis by juvenile hormone in MA-10 Leydig tumor cells. AB - We had previously reported that juvenile hormone III (JH III) and the JH analogue 2-(4-phenoxy phenoxy)-ethoxytetrahydropyran exert inhibitory effects on progesterone synthesis by blocking cAMP production in hCG-stimulated MA-10 Leydig tumor cells. In the present study, the effects of JH analogue upon the biosynthetic pathway of progesterone synthesis have been examined. Our results demonstrated that JH analogue inhibited progesterone production even in the presence of 20-hydroxycholesterol or 25-hydroxycholesterol. Furthermore, although JH analogue inhibited pregnenolone production in hCG-stimulated MA-10 cells the activity of the 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) was unaffected. These data suggest that JH analogue might inhibit the steroidogenic pathway in Leydig tumor cells by inhibiting the activity of the cholesterol side chain cleavage (CSCC) enzymatic complex. The JH analogue was also evaluated for inhibitory actions on cholesterol availability. An important effect of this compound was the interference with the cellular process of plasma membrane cholesterol internalization. Moreover, JH analogue inhibited not only the use of cholesterol ester for steroid biosynthesis under Bt2cAMP stimulation, but also the cholesterol ester hydrolase (CEH) activity in MA-10 Leydig tumor cells. PMID- 7857878 TI - Murine steroid sulfatase (mSTS): purification, characterization and measurement by ELISA. AB - The murine steroid sulfatase (mSTS) is a microsomal enzyme, important in steroid metabolism. In the mouse, the gene encoding mSTS is pseudoautosomal and thus escapes X-inactivation. We have purified steroid sulfatase approximately 30-fold from mouse liver microsomes and its properties have been investigated. The major steps in the purification procedure included solubilization with Triton X-100, gel filtration chromatography, DEAE-Sephadex chromatography and HPLC gel filtration chromatography. The purified sulfatase showed a relative molecular weight of 128 kDa on HPLC gel filtration, whereas the enzyme migrated as two bands of 60 and 68 kDa on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The isoelectric point of steroid sulfatase was estimated to be 6.2 by column chromatofocusing. Polyclonal antibodies to the purified protein were prepared. An Enzyme Linked Immunosorbent Assay (ELISA) was developed using purified monospecific anti-mSTS antibodies labelled with peroxidase. The standard criteria of precision and reproducibility were satisfied. The assay was applicable to routine determination of mSTS samples in research laboratories. Differences in mSTS liver concentrations were used to identify putative alleles for the mSTS gene (Sts). Results in ELISA confirmed the polymorphism previously demonstrated for an enzymatic mSTS activity assay in two inbred mouse strains. PMID- 7857879 TI - Lignan and isoflavonoid conjugates in human urine. AB - Lignans and isoflavonoids are two groups of diphenolic phytoestrogens of plant origin which have gained increasing interest because of their possible cancer protective properties. High excretion of these compounds occur in populations at low risk of breast, prostate and colon cancer consuming either high amounts of whole-grain (lignans and some isoflavonoids) or soy products (isoflavonoids and some lignans). We determined the pattern of conjugation of the phytoestrogens in four urine samples from vegetarian or semivegetarian women and in two samples from men. Seven compounds were investigated: enterodiol, enterolactone, matairesinol, diadzein, equol, genistein and O-desmethylangolensin. The fractions quantified are the free fraction, mono- and disulfate, as well as the mono-, di- and sulfoglucuronide fractions. For the fractionation and purification we used ion-exchange chromatography and the determination of the concentrations of each compound in all fractions was done by isotope dilution gas chromatography-mass spectrometry (GLC-MS) using deuterated internal standards of all diphenols. More than 60% of all compounds determined, occurred in the monoglucuronide fraction. Daidzein, enterodiol and equol are excreted to a relatively high extent as sulfoglucuronides and genistein as diglucuronide. We conclude that the general pattern of lignan and isoflavonoid conjugates in urine is similar to that of endogenous estrogens. PMID- 7857880 TI - Neuronal Intestinal Dysplasia. Proceedings of the International Symposium of the Hospital of Pediatric Surgery of the Cologne Municipal Clinical Center and International Association for Gastrointestinal Motility in Children. Cologne, Germany, November 11-13, 1993. PMID- 7857881 TI - Hirschsprung's disease and allied disorders--a review. AB - Despite scepticism in the English speaking literature today there is international agreement on the existence of neuronal intestinal dysplasia and other intestinal malformations which may well be differentiated from classical aganglionosis. In large series of patients with neuronal intestinal malformations it was found that only one fourth suffers from Hirschsprung's disease. Therefore this article presents the state of our recent knowledge of classical aganglionosis and allied disorders which include hypoganglionosis, neuronal intestinal dysplasia type A and B, immaturity of ganglion cells and not classifiable dysganglionosis. We want to emphasize the morphological differentiation of these neuronal intestinal malformations. However, the relationship between morphological findings, clinical symptoms and bowel motility remain to be clarified by further studies. PMID- 7857882 TI - The neuropathological diagnosis of neuronal intestinal dysplasia (NID B). AB - Between 1986 and 1991 773 infants were investigated by biopsy. 209 children suffered from a neuronal dysplasia of the submucous plexus (NID B). 64 of these 209 cases had concomitant Hirschsprung's disease with NID. The combination of Hirschsprung's disease with NID was established at biopsy not earlier than at 12 +/- 6 months of age. The classical form of an isolated aganglionosis had a median age at diagnosis of 4 +/- 2 months. The preconditions for a reliable diagnosis of NID are mucosal biopsies with submucosa taken 1, 3 and 9 cm above the pectinate line, the preparation of 15 microns thick serial sections, a acetylcholinesterase and lactate-reaction and a systematic examination of all serial sections. Giant ganglia, which are 2-3 times as large as normal ganglia and having more than 7 LDH-positive nerve cells (10 +/- 3 nerve cells in the mean), are the most relevant parameters in the diagnosis of NID. They can be observed in infants as well as in adults. The NID proximal to aganglionosis is in principle not different from an isolated form of NID. Increase of acetylcholinesterase-activity in muscularis mucosae and lamina propria mucosae and a "hyperplasia" of the submucous plexus in early infancy disappears with advancing age and are very seldom observed at 2 years of age or in adulthood. NID B is the mildest form of a developmental abnormality of the autonomic nervous system, which shows in most cases a spontaneous normalization of gut motility.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7857883 TI - Immunohistochemistry of markers of the enteric nervous system in whole-mount preparations of the human colon. AB - In this study we tested the immunohistochemical reactions of various markers for the enteric nervous system in whole-mount preparations of the human colon. For that purpose we used polyclonal antibodies against the neuronal markers--protein gene product 9.5 (PGP), neuron-specific enolase (NSE), neurofilament protein 200 (NFP), microtubule-associated proteins (MAPs); and the glial markers--S-100 protein and glial fibrillary acidic protein (GFAP) for the immunoperoxidase reaction. Whole-mount preparations are more suitable for histopathological evaluation and interpretation than sections, because the enteric nervous system consists of three-dimensional plexuses lying within the layers of the intestinal wall. Sections show only a part of the plexuses, neurons and glial cells. On the other hand, whole-mount preparations reveal the morphology of the plexuses as a whole. Among the neuronal and glial markers used, S-100 protein, the neurofilament protein, and the protein gene product 9.5 (PGP) produced the best results. Furthermore, this developing method provides new possibilities for the histopathological analysis of defects in the enteric nervous system, such as neuronal intestinal dysplasia (NID). PMID- 7857884 TI - Neuronal intestinal malformations: a retro- and prospective study on 203 patients. AB - A total of 203 patients with neuronal intestinal malformations were analyzed. A retrospective study was performed on 122 patients who had been treated from 1963 1988 and 119 (97.5%) of these patients underwent follow-up examination after a mean of 11.5 years. Subsequently 81 patients treated from 1989-1993 were included in a prospective trial. These patients were investigated preoperatively by standardized questionnaires, x-ray examination, electromanometry, transit time studies, and underwent follow-up after a mean of 3.2 years. All biopsy specimens of the prospective trial were analyzed by the Institute for Pathology of the University of Basel. Before 1989 the incidence of neuronal intestinal malformations was 4.9 per year as compared to 18 per year from 1989-1993. The percentage of classical aganglionosis decreased from 77.9% to 35.8% and aganglionosis associated with NID B was increased from 9% to 29.6% (p < 0.001). The prospective trial showed that only 54.7% of 53 children with aganglionosis had classical Hirschsprung's disease, 45.3% were combined with NID B. Out of 37 patients with NID 64.9% had associated aganglionosis. Preoperative symptoms showed no pathognomonic criteria for any specific neuronal intestinal disorder. However, 75% of the patients with aganglionosis combined with NID suffered from ileus as compared to 41.1% of the patients with classical aganglionosis and 23.1% of patients with isolated NID (p < 0.05). This indicates an additive effect of both lesions. X-ray examinations, electromanometry, and transit time studies did not show pathognomonic criteria for specific neuronal intestinal malformations.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7857885 TI - Neuronal intestinal dysplasia: clinical experience in Italian patients. AB - The authors present a review of 431 children biopsied and studied with the following histochemical and immunohistochemical techniques: 1) acetylcholinesterase activity; 2) alphanaphthylesterase activity; 3) S-100 protein immunohistochemical technique; 4) glyoxylic acid method. Two hundred forty-eight patients of our series presented different forms of dysganglionosis, 12 of them (4.8%) presenting neuronal intestinal dysplasia type B. In 7 cases, NID type B was diffuse, whereas in 5 recto-colonic NID type B was confined to the splenic flexure. Male:female ratio was 9:3. Familial recurrence was present in 2 of the 12 cases of our series, affected by severe neuronal intestinal dysplasia extended to the small intestine, associated with intestinal malrotation and short bowel syndrome. Four of the 7 cases of diffuse NID type B and 2 of the 5 cases of rectocolonic NID type B were surgically treated. Three patients with diffuse NID died from sepsis within the 2nd year of life. This study confirms that NID type B is a form of dysganglionosis which can be diagnosed in a Mediterranean country if histochemical techniques are applied in the study of a large series of constipated and pseudo-Hirschsprung patients. From a pathogenetic point of view, the authors compared the histochemical findings of biopsies from their series of NID patients with those of recto-colonic biopsies from patients with MEN II B syndrome. The similarity of GI symptoms in MEN II B and NID pediatric patients suggests that the two disorders could be the result of mutations affecting the same domain of the RET proto-oncogene. PMID- 7857886 TI - A histological grading system for the evaluation of co-existing NID with Hirschsprung's disease. AB - The significance of dysplastic features in the surgical pullthrough segment of bowel in patients with Hirschsprung's disease (HD) has not yet been clarified. The aim of this study was to evaluate prospectively the ganglionated proximal bowel in 26 patients with HD (January 1988 through January 1991). The significance of dysplastic features and their influence on post operative outcome were evaluated by means of a newly devised histological scoring system based on the morphological features. Functional outcome was assessed clinically at follow up interview. Comparison was with control specimens from 22 patients undergoing unrelated bowel surgery and a further 5 patients with neuronal intestinal dysplasia (NID). Results indicated a wide spectrum of histologically identified dysplastic features in patients with NID, the ganglionated bowel of HD and controls. Although individual abnormal features were noted in the control group, significant degrees of dysplasia were absent. The overall degree of dysplasia was less striking than that observed in NID and in the 5 patients in whom NID co existed with HD. Dysplasia of the ENS in residual bowel could be correlated with postoperative dysfunction in 4 out of 5 patients (80%) with HD and features of co existing NID. In addition, milder symptoms were noted in 50% of patients having a borderline score (5-6/12). This study emphasizes the relationship between clinical obstructive symptoms and a high degree of dysplasia within the ENS. A histological grading system is of value in evaluating the spectrum of abnormal findings and prospectively identifying those with functional significance in patients with NID co-existing with HD. PMID- 7857887 TI - Experience with neuronal intestinal dysplasia (NID) in adults. AB - In paediatrics neuronal intestinal dysplasia (NID) has frequently been described, but in adults the clinical picture was not recognised. NID has been diagnosed in adults as well as children with impaired colonic motility since enzymehistochemical methods became available. Patients with primary chronic constipation (n = 41) and with diverticulosis of the sigmoid colon (n = 23) showed neuronal colonic dysplasia, whereas healthy controls (n = 15) had a normal innervation of the intestinal wall (p < 0.001). The results of this clinical study make a worthwile contribution to the understanding of the aetiology and pathogenesis of primary chronic constipation and diverticulosis of the colon in adults. Conservative treatment is usually unavailing and surgical intervention is needed. Hence, where strictly indicated, resection of the pathologically disturbed colon segment is often the only successful therapeutic procedure. PMID- 7857888 TI - Results in the treatment of anorectal malformations with special regard to the histology of the rectal pouch. AB - The results of surgery for anorectal malformation (ARM) in 536 children treated between 1962 and 1993 are presented. Before 1985, patients underwent an abdominoperineal pullthrough for high and intermediate type of ARM, whereas cut back procedures or perineoproctoplasty were performed in low type. Since 1985, we have changed our policy and performed a modified posterior sagittal anorectoplasty (PSARP) for intermediate type of ARM, eventually combined with an abdominal mobilization for high type. Perineoproctoplasty was reserved for low type of ARM. Data of 143 patients of Group 1 and 85 patients of Group 2 were available for follow-up. Continence was compared using a clinical score. Good or fair continence was found in 82% of patients operated on before 1985 (low type 85% good, 15% fair, intermediate type 17% good, 50% fair, high type 12% good, 37% fair), comparing to 93% in children treated after 1985 according to the new regimen (low type 88% good, 6% fair, intermediate type 59% good, 35% fair, high type 43% good, 47% fair). Liquid stools and inability to retain bowel contents were the main problem in the older series, whereas incontinence could often be attributed to constipation with overflow incontinence in the recently treated group of patients. Analysis of the innervation of fistula and distal rectal pouch in a prospective study comprising 40 of our most recent patients showed normal innervation in only 5% of patients, whereas 66% had neuronal intestinal malformations (NIM) including aganglionosis, NID and hypoganglionosis.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7857889 TI - Electromanometrical investigations in patients with isolated neuronal intestinal dysplasia (NID). AB - In a retrospective study the manometrical findings of 27 patients with histochemically confirmed isolated NID were compared with the findings of 14 patients with habitual constipation. In a second group NID or other neuronal disorders of the distal colon were excluded by histology/histochemistry. Significant differences were found only for the amplitude and frequency of anorectal fluctuations and for presence or absence of rectoanal inhibitory reflexes (RAIR). All other investigated parameters were not significant. In conclusion a reliable diagnosis of isolated NID is only possibly by combined use of anorectal manometry and histochemistry. Nevertheless anorectal manometry remains an important tool for screening in constipative disorders and should be performed prior to other investigations i.e. radiology or biopsy. PMID- 7857890 TI - Value of a score in the electromanometrical diagnosis of neuronal intestinal dysplasia. AB - Anorectal manometry was performed in a series of 8 children where NID was histochemically confirmed or suspected. The results were transferred to a electromanometric score theoretically worked out previously. Clinical symptoms as well as histological and manometric findings have been compared concerning the meaningfulness of the electromanometric score in the diagnosis of NID. It was impossible to make a statistical statement due to the small number of patients we examined. It seems, however, that certain electromanometric parameters in NID appear regularly which, when combined in a score, make manometric diagnosis of NID sufficiently reliable. PMID- 7857891 TI - Hypersensitivity to an orthodontic bonding agent. A case report. AB - A case report of a 14-year-old male who developed an allergic reaction shortly after the placement of Edgewise stainless steel orthodontic brackets with Unite, a composite bonding agent, is reported. Patch testing revealed that he was allergic to the set composite and the catalyst paste. The brackets were replaced by stainless steel orthodontic bands cemented with Poly F Zinc polycarboxylate cement which allowed treatment to progress without further incident. PMID- 7857892 TI - Orthodontic rare earth magnets--in vitro assessment of cytotoxicity. AB - The aim of this study was to assess and compare in vitro the cytotoxic effects of uncoated and parylene-coated rare earth magnets, used in orthodontics. Cytotoxicity of samarium-cobalt magnets (SmCo5 and Sm2Co17) and neodymium-iron boron magnets (Nd2Fe14B) was assessed by two in vitro methods, the millipore filter method and an extraction method. Orthodontic stainless steel brackets served as controls. Uncoated SmCo5-magnets showed high cytotoxicity while uncoated Sm2Co17-magnets demonstrated moderate cytotoxicity. Uncoated neodymium iron-boron magnets, as well as parylene coated Sm2Co17-magnets and parylene coated neodymium-iron-boron magnets, showed negligible cytotoxicity. Short-term exposure to a static magnetic field did not cause any cytotoxic effect on the cells. PMID- 7857893 TI - Finite element analysis for stresses in the craniofacial sutures produced by maxillary protraction forces applied at the upper canines. AB - The purpose of this study was to investigate the nature of stress distributions in the craniofacial sutures produced by orthopaedic maxillary protraction forces applied to the upper canines. A three-dimensional finite element model of the craniofacial complex was developed for finite element analysis. An anteriorly directed force of 1.0 kg was applied to the upper canines in three different directions, i.e. parallel, 30 degrees upwards and downwards to the functional occlusal plane. Normal stresses acting on the sutural systems were greatest when force was applied in the 30 degrees upward direction. Furthermore, relatively large compressive stresses were induced in the frontonasal and frontomaxillary sutures, indicating that forward and upward rotation of the nasomaxillary complex was produced with substantial distortion of the complex, by the forces applied in both parallel and 30 degrees upward directions. A 30 degrees downward force produced almost uniform tensile stresses in the zygomaticotemporal and zygomaticomaxillary sutures, with least compressive stresses in the frontonasal and frontomaxillary sutures located in the superior region of the complex. This would indicate a uniform stretch of the nasomaxillary complex in both anterior and inferior directions, with negligible distortion of the complex and would be appropriate for accelerating natural growth of the nasomaxillary complex. PMID- 7857894 TI - A study of frictional forces between orthodontic brackets and archwires. AB - The differences in magnitude of static and kinetic frictional forces generated by 0.022 x 0.030-inch stainless steel (Dentaurum) and polycrystalline ceramic (Transcend) brackets in combination with archwires of different sizes (0.018 inch and 0.019 x 0.025 inch) and materials (stainless steel, nickel-titanium, and beta titanium) at a constant ligature force were investigated. A friction-testing assembly using the Instron machine was used. In all cases, the static frictional force was greater than the kinetic frictional force. There were no significant differences in the frictional forces generated by stainless steel and polycrystalline ceramic brackets. Beta-titanium archwires produced greater frictional forces than the other two materials. Increasing the archwire diameter increased the frictional force. PMID- 7857895 TI - A study to compare the effects of simulated torquing forces on pre-adjusted orthodontic brackets. AB - The transmission of torquing forces between three types of preadjusted bracket was investigated. 0.022-inch Roth prescription 'A'-Company (stainless steel), Silkon (reinforced polycarbonate), and Allure III (polycrystalline ceramic) brackets were used. A selection of stainless steel archwires were chosen, 0.018 x 0.025, 0.019 x 0.025, and 0.021 x 0.025 inch. The brackets were torqued with respect to the archwire and force v. angular deflection was recorded on an Instron machine. The dimension of angular change was in part dependent on the ability of the bracket to elastically or plastically deform. There were no significant differences between bracket types with the 0.018 x 0.025-inch archwire. 'A'-Company brackets demonstrated a significantly lower resistance to loading compared to Silkon brackets in the 0.019 x 0.025-inch group. The greatest amount of distortion was seen in Silkon brackets with an 0.021 x 0.025-inch archwire. Allure III brackets demonstrated the greatest resistance to loading in all groups. As no apparent distortion under loading is seen in Allure III brackets, it is assumed that the load is largely transmitted to the tooth. Full thickness stainless steel rectangular wires should be avoided with these brackets, in order to prevent overloading. PMID- 7857896 TI - A comparison of the forces required to produce tooth movement ex vivo through three types of pre-adjusted brackets when subjected to determined tip or torque values. AB - Friction in fixed appliance systems has received considerable attention in recent literature, although that attributable to varying second order (tip) and third order (torque) adjustments in either the bracket or the archwire has not been fully investigated. The ex vivo study of 0.022 x 0.028-inch slot Minitwin, Activa, and Standard Straight Wire brackets investigates friction when known values of tip or torque were applied to 0.018 x 0.025-inch stainless steel wires. The resistance to sliding of the wire through the ligated brackets was measured on a vertically-mounted Instron testing machine. The results showed that the self ligating Activa brackets consistently produced less friction than the other conventionally tied brackets. Minitwin brackets were slightly more resistant to movement than the Standard brackets during torquing, but the converse was found when tip was applied. Increasing tip and torque (ranges tested 0-6 degrees and 0 25 degrees, respectively) produced almost linear increases in friction for all brackets, although increasing tip had the more profound effect on friction, particularly in Activa brackets. PMID- 7857897 TI - The influence of fluoride-releasing bonding composites in the development of artificial white spot lesions. An ex vivo study. AB - This study investigates the effects of fluoride-releasing bonding composites on the development of artificially created white spot lesions ex vivo. The severity of the lesions was estimated visually using the von der Fehr Caries Index. The integrated mineral loss of the lesions (delta z) was measured using microradiography/microdensitometry. The results of the visual assessment indicated that teeth bonded with Reliance exhibited more Grade 2 lesions than expected. Teeth bonded with Mirage Dual Cure, however, showed a high prevalence of teeth with no lesions (Grade 0) and few with Grade 2. Microdensitometric analysis found 17 subsurface lesions; 14 of these were in the non-fluoridated groups (Right-On and Heliosit), and 3 and 1 in the fluoridated groups (Reliance and Mirage Dual Cure), respectively. Lesion mineral content ranged from 64.93 to 20.43 per cent for Right-On, from 32.53 to 26.72 per cent for Heliosit, from 19.52 to 19.58 per cent for Reliance, and 23.58 per cent for Mirage Dual Cure. The results of this study suggest that fluoride-releasing composites may have a caries preventive effect around orthodontic brackets. PMID- 7857898 TI - Late lower arch crowding: the role of differential horizontal growth. AB - Eighty-five subjects, recorded soon after eruption of second permanent molars, were followed longitudinally for 3 or 4 years. Correlation and multiple regression analyses were used to examine the relationship between the change in lower arch space condition and (1) the horizontal component of the change in position of various points on or near the anterior borders of the maxilla and mandible, (2) the differential horizontal-vertical change in these points and (3) differences in horizontal change between maxillary and mandibular, and between intramandibular points. No significant differences in amount or direction of growth were found between the maxillary and mandibular teeth or jaws. Pogonion changed more in a horizontal direction than B point. Increased lower arch crowding was weakly associated with differential horizontal growth of the teeth and jaws. Reduced horizontal growth and greater vertical as opposed to horizontal growth of the maxilla and teeth, and increased growth of the mandibular base were to some extent related to the crowding increase. PMID- 7857899 TI - The incidence of cleft lip and palate in Northern Ireland from 1980-1990. AB - This study reports the incidence of the various types of cleft lip and/or palate drawn from a regional database of all affected children born in Northern Ireland during the period 1980-1990. The incidence of these anomalies was 1.28 per 1000 live births (1:781). Fifty-three per cent of clefts involved the secondary palate only, 16 per cent the primary palate only, 26 per cent involved both primary and secondary palate, and 5 per cent were unconnected. Overall, more males than females were affected and there were more males than females in the group having complete clefts. Separate clefts of lip and palate occurred exclusively in males with only one exception. Unilateral clefts were more common on the left side. Within the group showing complete unilateral cleft of the primary and secondary palate, left-sided clefts were more commonly male, right-sided clefts were more commonly female. There were no statistically significant sex differences between sides in the unilateral primary palate cleft group. PMID- 7857900 TI - An alternative method of occlusal registration for functional appliances. AB - Although wax is commonly used to record the protrusive occlusal registration for functional appliances, it is not without its disadvantages. In restorative dentistry silicone occlusal registration materials have been developed to overcome some of the drawbacks of wax. This paper presents a method of utilizing these new materials in orthodontics. PMID- 7857901 TI - Products for prevention during orthodontics. AB - The potential for iatrogenic damage following fixed orthodontic treatment has been well documented for many years. Enamel decalcification and gingival inflammation are preventable if good practice is followed. Patients with gingivitis or active caries should not be considered for fixed orthodontics until the disease is controlled. Diet advice, oral hygiene, and topical fluorides are the basic elements of any preventive regime, and while they need to be individually tailored for each patient, fluoride mouthrinses should be routinely used by all patients with fixed appliances. The susceptibility of enamel adjacent to an orthodontic attachment remains a problem which future improvements in adhesive materials may help to address. PMID- 7857902 TI - Yashica Dental Eye II. PMID- 7857903 TI - Fear of boredom. PMID- 7857904 TI - Guidance on presentation of cephalometry-based research studies. PMID- 7857905 TI - Orthodontic treatment and isolated gingival recession: a review. PMID- 7857906 TI - Digestion of raw banana starch in the small intestine of healthy humans: structural features of resistant starch. AB - The digestion of freeze-dried green banana flour in the upper gut was studied by an intubation technique in six healthy subjects over a 14 h period. Of alpha glucans ingested, 83.7% reached the terminal ileum but were almost totally fermented in the colon. Structural study of the resistant fraction showed that a small part of the alpha-glucans which escaped digestion in the small intestine was composed of oligosaccharides from starch hydrolysis, whereas the rest was insoluble starch in granule form with physical characteristics similar to those of raw banana starch. Passage through the small intestine altered granule structure by increasing susceptibility to further alpha-amylase hydrolysis. Compared with resistant starch values in vivo, those obtained with the in vitro methods tested were inadequate to estimate the whole fraction of starch reaching the terminal ileum. PMID- 7857907 TI - Calcium solubilization and retention in the gastrointestinal tract in chicks (Gallus domesticus) as a function of gastric acid secretion inhibition and of calcium carbonate particle size. AB - In chicks, immature pullets and laying hens, the inhibition of gastric acid secretion by omeprazole, an H+,K(+)-transporting ATPase (EC 3.6.1.36) inhibitor, greatly increased proventricular and gizzard pH values. Consequently, gizzard soluble Ca concentration deceased and the insoluble Ca fraction increased. Inhibition of acid secretion increased duodenal pH values in immature pullets and laying hens but not in chicks. Duodenal soluble and ionic Ca concentrations were lowered by gastric acid inhibition in chicks and to a larger extent in immature pullets and laying hens. The use of Ca of coarse particle size increased the gizzard insoluble Ca fraction in chicks and pullets. However, it did not influence its soluble Ca fraction in chicks but tended to reinforce the negative effect of omeprazole on soluble Ca in the gizzard and duodenum of chicks and laying hens. Coarse particles of Ca led to an increase in gizzard and duodenal soluble Ca at the end of eggshell calcification in laying hens. An enhancement in the level of Ca in the diet from 10 to 36 g/kg increased gizzard soluble Ca and duodenal soluble and ionic Ca concentrations in immature and adult hens. Intestinal Ca retention and bone mineralization was unaffected by gastric acid inhibition in chicks but were largely diminished by the use of coarse particles of Ca. Gastric acid inhibition was associated in laying hens with decreased Ca retention to a small extent and with reduced eggshell quality. These observations confirm that gastric acid secretion is of importance for CaCO3 solubilization but question its role as a prerequisite for intestinal Ca retention in chicks and even in hens fed on a high Ca diet. PMID- 7857908 TI - Morphological changes in the rat small intestine in response to riboflavin depletion. AB - Female Wistar rats were weaned onto a diet deficient in riboflavin and compared with weight-matched and ad lib.-fed controls. The effects of riboflavin deficiency on villus morphometry and enterocyte number on the villi in the upper small intestine were studied. Riboflavin depletion was associated with increased villus length and a proportional increase in the number of cell positions along the villi. The total DNA, RNA and protein contents in the intestinal mucosa were not significantly different between any of the groups. Villus hypertrophy in the absence of increased cell number in the small intestine suggests that villus number may be reduced in riboflavin deficiency. Riboflavin deficiency did not influence the number of mucus-producing goblet cells or the amount of mucosal glycoprotein in the small intestine. Impaired production of mucus appeared not to be involved in the structural and functional changes seen in riboflavin deficiency. PMID- 7857909 TI - Trends in fat consumption. PMID- 7857910 TI - Bioavailability of nutrients. Conceptual aspects of definition and problems of determination. PMID- 7857911 TI - Consumption of diets containing raw soya beans (Glycine max), kidney beans (Phaseolus vulgaris), cowpeas (Vigna unguiculata) or lupin seeds (Lupinus angustifolius) by rats for up to 700 days: effects on body composition and organ weights. AB - Feeding trials have been done with rats to assess the effects of long-term (700 d) consumption of diets based on raw cowpeas (Vigna unguiculata; moderate Bowman Birk inhibitor content, low lectin content), lupin seeds (Lupinus angustifolius; low lectin and protease inhibitor content) or soya beans (Glycine max; high Kunitz inhibitor content, moderate Bowman-Birk inhibitor content, moderate lectin content) or diets containing low levels of raw kidney bean (Phaseolus vulgaris; high lectin content, low Bowman-Birk inhibitor content) on body weight and composition and organ weights. All the legume-based diets reduced feed conversion efficiency and growth rates during the initial 250 d. However, after 250 d the weight gains by rats given legume-based diets were similar to those of controls given the same daily feed intake. Long-term consumption of diets containing low levels of kidney bean significantly altered body composition of rats. The levels of lipid in the body were significantly reduced. As a result, carcasses of these rats contained a higher proportion of muscle/protein than did controls. Small intestine relative weight was increased by short- and long-term consumption of the kidney-bean-based diet. However, the increase in relative pancreatic weight observed at 30 d did not persist long term. None of the other legume-based diets caused any significant changes in body composition. However, long-term exposure to a soya-bean- or cowpea-based diet induced an extensive increase in the relative and absolute weights of the pancreas and caused an increase in the incidence of macroscopic pancreatic nodules and possibly pancreatic neoplasia. Long-term consumption of the cowpea-, kidney-bean-, lupin-seed- or soya-bean based diets by rats resulted in a significant increase in the relative weight of the caecum and colon. PMID- 7857912 TI - A non-linear compartmental model to describe forage degradation kinetics during incubation in polyester bags in the rumen. AB - A new model for describing forage degradation kinetics during incubation in the rumen using polyester bags is presented. Attention is given to dealing with the problem of deviations from exponential behaviour in the early stages of degradation by devising a function capable of representing exponential or sigmoidal trends. This is achieved by allowing part of the fractional degradation rate to vary with time of incubation, thus enabling responses other than those expected under simple first-order kinetics to be described. Seven sets of data consisting of 620 curves were analysed to study the performance of the new model compared with a commonly used exponential model. The proportion of significantly better fits varied from set to set. The new model deals successfully with sigmoidal behaviour and, thus, provides a means of analysing the degradation profiles of low-quality forage feeds. PMID- 7857913 TI - Dietary effects of faba-bean (Vicia faba L.) tannins on the morphology and function of the small-intestinal mucosa of weaned pigs. AB - The objective of the present study was to evaluate effects of condensed tannins in faba beans (Vicia faba L.) on morphological and functional variables of the small-intestinal mucosa of piglets. In an experiment with young piglets (8-17 kg body weight), fed on either a control diet or a diet containing 200 g/kg of low- or high-tannin faba bean hulls (with < 0.10 and 3.3% catechin equivalents of condensed tannins respectively), morphological and functional characteristics of the jejunal mucosa were determined. Results of the study showed that the morphological variables of the mucosa of the three groups of piglets were similar. Also, no changes due to dietary tannins were observed in sucrase (EC3.2.1.48)-isomaltase (EC 3.2.1.10) activity in homogenates of mucosa plus submucosa. However, aminopeptidase (EC 3.4.11.2) activity in these homogenates in the proximal part of the small intestine of the animals of the group fed on the high-tannin diet was significantly lower than that in the animals fed on the control diet or the diet with low-tannin hulls (P < 0.05). PMID- 7857914 TI - Passage rate and total clearance rate from the rumen of cows fed on grass silages differing in cell-wall content. AB - Four non-lactating, rumen-fistulated cows were fed ad lib. on two grass silages (first cut (FC) and second cut (SC) harvested at different growth stages, resulting in different crude-protein (CP) and neutral-detergent-fibre (NDF) contents (FC, 152g CP/kg, 515g NDF/kg and SC, 210g CP/kg, 442g NDF/kg). Voluntary intake and rumen contents, total as well as organic matter were higher for silage FC. Fractional passage rate from the rumen, calculated from the logarithmic decline in Cr-NDF rumen pool, was higher for silage FC (0.0395/h and 0.0446/h for silages SC and FC respectively). When fractional passage rates from the rumen were calculated by dividing the intake of indigestible organic matter by the mean rumen pool of this fraction, the same differences between silages were found, although the actual levels were much lower (0.0258/h and 0.0300/h for silages SC and FC respectively). The results from the present experiment suggest that disappearance rate from the rumen of particles with a size between 1.25 and 0.071 mm is the rate-limiting step in the control of rumen fill. PMID- 7857915 TI - The effect of protein degradation products in grass silages on feed intake and intake behaviour in sheep. AB - The effects of NH3 and amines on grass-silage intake, intake behaviour and rumen characteristics were studied in sheep. From a single sward, two direct-cut grass silages were prepared, either untreated (WAS) or with 4.51 formic acid/tonne (FAS). Four experimental diets: WAS, FAS, FAS with addition of 2.9 g NH3/kg DM (FAS + N) and FAS with 2.8 g amines/kg DM (FAS + A), were offered ad lib. once daily to four rumen-cannulated wethers in a 4 x 4 Latin square design. Daily DM intake (DMI) tended to be influenced by dietary treatment (P = 0.09). Compared with FAS, DMI was lower for WAS. Addition of NH3 did not alter DMI, whereas amine addition slightly lowered daily DMI. Reduced DMI resulted from lower intake rates during both the principal meal and the subsequent small meals. Lower initial intake rate during the principal meal suggested reduced palatability of WAS and FAS + A. Amines and NH3, however, did not influence chewing efficiency. No treatment effects were observed on total rumen pool size, DM and neutral detergent fibre content. Furthermore, NH3 and amines did not alter rumen pH, NH3 and volatile fatty acid concentrations to the extent that they could act on chemostatic intake regulation. Amine addition, however, lowered osmolality of the rumen liquid. No treatment effects on rumen motility were observed. In conclusion, daily DMI was not reduced by the addition of NH3, suggesting that NH3 per se is not the causal factor in the negative correlations between silage NH3 content and intake observed by other authors. Amines, however, tended to reduce DMI only by their effect at the oro-pharyngeal level of intake control. PMID- 7857916 TI - Protein v. enzymic protein hydrolysates. Nitrogen utilization in starved rats. AB - The present study was carried out to compare the effects of four isoenergetic and isonitrogenous diets on the N utilization, total serum protein concentration and serum amino acid profile in starved rats at weaning. These diets differed only in the molecular form of two milk proteins (whey protein and casein), which were either native or partly hydrolysed. Male Wistar rats at weaning were fasted for 3 d and then refed with one of the four diets for 48 h. No differences were observed in the body weight gain, protein digestibility and total serum protein concentration between groups after the refeeding period and all the N balances were positive. N retention was higher in the two groups of rats given the protein hydrolysate-based diets compared with those given the intact-protein-based diets. This was associated with a lower urinary N excretion in rats, given the whey protein-hydrolysate and the casein-hydrolysate diets. Despite this fact, the serum amino acid pattern of rats given the hydrolysed protein diet was very similar to that of those given the corresponding native protein diet. In conclusion, we have proved that enzymic hydrolysates from milk proteins have equivalent effects to native proteins in recovery after starvation in rats at weaning, on N absorption, total serum protein concentration and serum amino acid profile, and even give a higher N retention. We did not observe any harmful effect in using protein hydrolysates instead of native proteins. PMID- 7857917 TI - Protein and energy relationships in the broiler chicken. 12. Dietary protein and triiodothyronine (T3) effects on the response of broilers to isoproterenol and cyclic adenosine monophosphate in vitro. AB - Indian River male broiler chickens (7-d-old) were fed on diets containing 120, 210 or 300 g crude protein/kg + 0 or 1 mg triiodothyronine (T3)/kg diet (Expt 1) and 120, 150, 180 or 210 g crude protein/kg + 0 or 1 mg T3/kg diet (Expt 2) to determine the effects of crude protein level and T3 on growth and metabolism. Body composition of chickens was determined by a combination of dissection of muscle and abdominal fat pads, and chemical extraction (Expt 1). In vitro lipogenesis (IVL) was determined in both experiments by incubating liver explants for 2 h at 37 degrees in the presence of 10(-4) M-dibutyryl cyclic AMP (cAMP) or 10(-5) M isoproterenol (ISO) and 10(-2) M-[2-14C]acetate. Acetate incorporation into total lipid was an indication of IVL. Activity ratios for each of these additions relative to control (-cAMP-ISO) were calculated to ascertain basal v. inhibited rates of IVL. The relative muscle mass was increased by increasing crude protein from 120 to 210 g/kg diet but not from 210 to 300 g/kg diet. Dietary T3 decreased total body lipid regardless of the dietary crude-protein level. Increasing dietary crude protein decreased (P < 0.05) basal IVL (-cAMP ISO) but not IVL (+cAMP). Dietary T3 decreased basal IVL in birds fed on the diets containing 120 and 210 g crude protein/kg but had little effect on the two inhibited states of lipogenesis (+cAMP or +ISO). The component of lipogenesis sensitive to in vitro inhibition is also the component under dietary control. PMID- 7857918 TI - Immunological changes in growing mice fed on diets containing casein or peas (Pisum sativum var. Belinda) as the source of protein. AB - The effects of two different sources of protein: peas (Pisum sativum var. Belinda) and casein on immunocompetence, nutritional utilization and growth performance have been investigated in recently weaned mice. Feeding these animals on a pea diet resulted in an impairment in growth and significant decreases in the weights of liver, muscle, kidneys and femur, while intestine weights increased. No differences in food consumption were observed, but food conversion efficiency (food intake: weight gain) was increased in pea-fed animals compared with those offered the casein diet. Packed cell volume and serum Fe and Zn levels fell significantly after legume-protein intake, and, by contrast, Cu values increased slightly. Serum albumin levels showed a statistically significant reduction in mice fed on the diet containing peas. However, gamma-globulins and immunoglobulin G titres were markedly increased. The characterization of spleen cell subsets using monoclonal antibodies revealed a significantly higher percentage of T-lymphocytes in the pea group compared with casein-fed animals, while no changes were observed in the proportions of B-lymphocytes and macrophages. In vitro mitogenic responses to phytohaemagglutinin, concanavalin A and Escherichia coli lipopolysaccharide S were slightly, but not significantly, lower in the pea-fed animals. Our results describe, apparently for the first time in mice, some immunological disturbances after peak intake. These results may lead to a better understanding of the possible role of antigenic proteins in gastrointestinal disorders and the poor individual performance after legume intake. PMID- 7857919 TI - Influence of antibiotics and food intake on liver glutathione and cytochrome P 450 in septic rats. AB - Experimental sepsis in rats induces a restriction in spontaneous food intake and a drop in liver glutathione, cytochrome P-450 (P-450) and aminopyrine demethylase (AD) activity. The present study was designed to assess the effects of antibiotics alone or when combined with food deprivation on these variables. Eighty-nine male Sprague-Dawley rats were assigned to six groups: control (C), acute infection (experimental pyelonephritis, I), acute infection with antibiotics and food given ad lib. (IA), control with antibiotics (CA), acute infection with antibiotics pair-fed to I (IAR), and sham-operated pair-fed to I (SR). Liver glutathione, P-450 and AD activities were reduced by 45.2, 79.8 and 41.2% respectively in group I. Glutathione and AD significantly increased only in those infected rats given antibiotics and allowed free access to food. P-450 did not normalize within the study period in infected rats receiving antibiotics and food repletion. The risk of drug hepatotoxicity in acute septic states is therefore closely related to the nutritional status. From this point of view, nutritional support is almost as important as treatment of infection. PMID- 7857920 TI - Recovery of native structure by calcium binding site mutants of calmodulin upon binding of sk-MLCK target peptides. AB - The calcium-dependent binding of two synthetic 18-residue peptides derived from the calmodulin binding region of skeletal myosin light chain kinase to wild-type Drosophila melanogaster calmodulin and four calcium binding site calmodulin mutants has been investigated using optical spectroscopy. The WFF peptide (with W4 and F17) and the FFW peptide (with F4 and W17) both bind to wild-type calmodulin with 1:1 stoichiometry and Kd values of < or = 0.2 and 1.6 nM, respectively. Near-UV CD spectra of the protein-peptide complexes suggest that both peptides bind in the same orientation, with the side chain of residue 4 interacting with the C-domain of calmodulin and that of residue 17 with the N domain [as in the structure of the calmodulin-M13 peptide complex determined by Ikura et al. [Ikura, M., Clore, G. M., Gronenborn, A. M., Zhu, G., Klee, C. B., & Bax, A. (1992) Science 256, 632-638]]. Both peptides have lower affinities for all the mutant calmodulins than for the wild-type protein. Fluorescence measurements suggest that mutation of calcium binding site 2 in the N-domain does not affect the interaction of the W4 side chain of the WFF peptide with the C domain of calmodulin. However, the E67Q (B2Q) but not the E67K (B2K) mutation (site 2, N-domain) alters the interaction of W17 of the FFW peptide with the protein. In contrast, the E140K (B4K) mutation has a much greater effect than the E140Q (B4Q) mutation (site 4, C-domain) on the interaction of calmodulin with both peptides.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7857921 TI - A divalent metal ion binding site in the kinase insert domain of the alpha platelet-derived growth factor receptor regulates its association with SH2 domains. AB - To investigate the effects of metal ion binding to the alpha-PDGFR kinase insert domain, a PCR product representing amino acid residues 691-795 (104 amino acids) was bacterially expressed and purified. Secondary structure prediction and circular dichroism spectroscopy indicated this domain to be a mixed alpha + beta protein with a large coil/turn contribution. This 16 kDa, soluble, nonphosphorylated domain bound to 45Ca2+ and 65Zn2+ through a common shared site. Of the unlabeled divalent and trivalent metal ions tested, Ho3+ = Zn2+ > Ni2+ > Ca2+ = Mn2+ > Mg2+, Ba2+ in competing for 45Ca2+ binding to this domain. In the presence of Ca2+ ions, the conformation of the KI domain changed significantly, and this changed conformation was resistant to subtilisin proteolysis. However, in the presence of Zn2+ ions, the conformation of the KI domain changed only slightly. Nevertheless, Zn2+ ions were more effective in rendering the KI domain resistant to proteolysis as compared to that shown by Ca2+ ions. In vitro binding studies using purified baculovirus-expressed alpha-PDGFR showed a marked increase in binding the p85 N-SH2 domain in the presence of Ca2+ or Zn2+ ions (KD = 0.5 microM), suggesting that metal ion binding enhances association of the p85 N-SH2 domain with the receptor. To confirm this, association of the alpha-PDGFR with the p85 N-SH2 domain was tested in the presence of the KI domain. The nonphosphorylated KI domain was effective in competing with the alpha-PDGFR for the binding of the p85 N-SH2 domain. This effect was more pronounced in the presence of Ca2+ ions. Microinjection of this domain into Xenopus oocytes delayed maturation in the presence of insulin but not progesterone. This suggests that the KI domain has a correctly folded three-dimensional structure compatible with biological activity. Together these findings indicate that the recombinant alpha PDGFR KI domain binds the p85 N-SH2 domain and this binding is modulated by the presence of a novel divalent metal ion binding site within its structure. PMID- 7857922 TI - 1H NMR characterization of myoglobins where exogenous ligands replace the proximal histidine. AB - The role of the proximal ligand in determining the structure and ligand binding properties of sperm whale myoglobin has been investigated using the mutant H93G(L), where the proximal histidine has been replaced with glycine, creating a cavity which can be occupied by a variety of exogenous ligands, L, to the iron [Barrick, D. (1994) Biochemistry 33, 6546-6554; DePillis, G.D., Decatur, S.M., Barrick, D., & Boxer, S.G. (1994) J. Am. Chem. Soc. 116, 6981-6982]. In this report, we present the assignments of selected protons of the heme and heme pocket residues in the metcyano complexes of H93G with Im and a series of methyl substituted Ims [H93G(Im)CN, H93G(N-MeIm)CN, H93G(2-MeIm)CN, H93G-(4-MeIm)CN]. Each complex has a unique 1H NMR spectrum, providing a fingerprint for documenting the ligand exchange phenomenon. Moreover, the identification of NOEs between the protons of proximal ligands and protons of proximal pocket amino acid residues confirms that the new ligand occupies the proximal cavity in solution. The pattern of hyperfine-shifted heme methyl resonances in H93G(Im)CN is very different from that of wild-type Mb, consistent with the differences compared to wild-type in is very different from that of wild-type Mb, consistent with the differences compared to wild-type in orientation of the proximal imidazole observed in the X-ray crystal structure of H93G(Im) [Barrick, D. (1994) Biochemistry 33, 6546-6554]. Addition of deuterated Im to H93G(Im)CN permits direct observation of exchange of proximal ligands with ligands from solution; exchange of Im for deuterated Im in the metcyano complex occurs with half-life of around 10 min.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7857923 TI - Stoichiometry of the atrial natriuretic factor-R1 receptor complex in the bovine zona glomerulosa. AB - The atrial natriuretic R1 receptor is a membrane protein that is present as an apparently preassociated noncovalent oligomer in the absence of ligand as suggested by steric exclusion studies and cross-linking experiments in physiological and recombinant receptor expression systems. The association state of this receptor oligomer was studied in the presence of amiloride and ATP, two known modulators of the R1 receptor functions with both the intact receptor and a cytoplasmic domain-deleted form obtained by limited proteolysis with trypsin. It was shown by steric exclusion on Superose 6 column that amiloride increased the affinity of ANF for the native and truncated receptor, in contrast with ATP, whose destabilizing effect on ANF binding was abolished by truncation of the cytoplasmic domain. Neither amiloride nor ATP exerts its effects by altering the aggregation state of the receptor. Comparison of the measured number of ANF binding sites with immunoassayable receptor protein revealed that the stoichiometry of ANF binding to the R1 receptor was 1:2. This was confirmed by using an ANF analog that bears a photoactivatable group at both of its ends, showing that ANF, as for the growth hormone/receptor complex, interacts with both the receptor subunits and specifically cross-links a dimeric form of the receptor. The potential pharmacological consequences of this 1:2 stoichiometric ratio of the ANF-receptor complex are discussed. PMID- 7857924 TI - NMR behavior of the aromatic protons of bovine neurophysin-I and its peptide complexes: implications for solution structure and for function. AB - The NMR behavior of the aromatic protons of bovine neurophysin-I and its complexes was interpreted with reference to the 2.8 A crystal structure of the dipeptide complex of bovine neurophysin-II and to mechanisms underlying the thermodynamic linkage between neurophysin dimerization and peptide binding. Large binding-induced shifts in the ring proton signals of Tyr-2 of ligand peptides (approximately 0.5 ppm upfield and approximately 0.35 ppm downfield at 25 degrees C for the 3,5- and 2,6-ring protons, respectively) were demonstrated. Consistent with the crystal structure, and in disagreement with conclusions by other investigators, evidence is presented indicating the absence of dipolar contact between Tyr-2 ring protons and protein Phe ring protons. The large binding induced shifts are attributed to a strong influence of proximal neurophysin carbonyl and disulfide groups on the bound Tyr-2 ring, of potential importance in binding specificity. Resolution of the behavior of neurophysin Phe residues -22 and -35 and of their proton NOE contacts provided insights into the conformational changes associated with peptide binding and with dimerization. Within the amino domain of the protein, as evidenced by the behavior of interface residue Phe-35 and its NOE contacts, binding-induced changes in the subunit interface appeared to involve principally the junction between this interface region and the 3,10-helix that connects it to the binding site in the liganded state. By contrast, as judged by the NOE contacts of His-80, the corresponding interface participant of the carboxyl domain, peptide binding induced a marked decrease in side-chain mobility within the carboxyl domain segment of the interface. Interactions of Phe-22 with protons assigned to Ala-68, neither of which is an interface participant, were demonstrated to be markedly altered both by dimerization in the unliganded state and by peptide binding to the dimer. Since Phe-22 is adjacent to the peptide-binding site, the results collectively support a model in which conformational differences between unliganded monomer and dimer are important contributors to the preferential binding of peptide to the dimer and indicate that the amino and carboxyl domain segments of the interface, which are homologous, are affected differently by peptide binding. PMID- 7857925 TI - Substitution of charged residues into the hydrophobic core of Escherichia coli thioredoxin results in a change in heat capacity of the native protein. AB - Two site-directed mutants of Escherichia coli thioredoxin (L78K and L78R) were designed to study the effect of placing a charged residue in the hydrophobic core of the protein. Both mutants retain catalytic activity in the assembly of phage M13. Thermal denaturation of both these mutant proteins at pH 7.0 shows a reduction of stability of approximately 4 kcal.mol-1 with respect to the oxidized wild-type form. The thermal denaturation of the protein fits a dimeric state model. A significant reduction in the change in heat capacity (delta Cp) on unfolding is observed compared to oxidized wild-type thioredoxin. We present data to indicate that this reduction in delta Cp is attributable to structural perturbations resulting in localized unfolding of the native protein and exposure to solvent of residues that are buried in the wild-type protein. PMID- 7857926 TI - Folding and stability of the N-terminus of human carbonic anhydrase II. AB - Truncations and mutations in the N-terminus of human carbonic anhydrase II were constructed in order to establish what role this part of the protein plays in the folding and stability of the protein. When incubated in various concentrations of guanidine hydrochloride (GuHCl), HCAII unfolds in two transitions, with an intermediate state at about 1.3 M GuHCl. N-Terminal truncations of 5, 17, or 24 amino acid residues destabilize the native state by 4-5 kcal/mol, relative to the intermediate state, but these amino acid residues have virtually no effect on the stability of the intermediate state relative to the unfolded state. These truncated variants of HCAII still have a high enzymatic activity. Deletion of 28 or more amino acid residues, however, results in inactive enzyme variants. The rates at which the active site is formed are practically unaffected by the removal of the 24-amino acid segment, i.e., the active site forms independently of the N-terminus. By using the tryptophans in positions 5 and 16 as intrinsic probes, we conclude that the structure of the N-terminal region is formed very late in folding. The results strongly indicate that this process is dependent on the prior formation of an enzymatically active native-like structure of the rest of the protein. PMID- 7857927 TI - Three-dimensional structure of butyryl-CoA dehydrogenase from Megasphaera elsdenii. AB - The crystal structure of butyryl-CoA dehydrogenase (BCAD) from Megasphaera elsdenii complexed with acetoacetyl-CoA has been solved at 2.5 A resolution. The enzyme crystallizes in the P422 space group with cell dimensions a = b = 107.76 A and c = 153.67 A. BCAD is a bacterial analog of short chain acyl-CoA dehydrogenase from mammalian mitochondria. Mammalian acyl-CoA dehydrogenases are flavin adenine dinucleotide (FAD)-containing enzymes that catalyze the first step in the beta-oxidation of fatty acids. Although specific for substrate chain lengths, they exhibit high sequence homology. The structure of BCAD was solved by the molecular replacement method using the atomic coordinates of pig liver medium chain acyl-CoA dehydrogenase (MCAD). The structure was refined to an R-factor of 19.3%. The overall polypeptide fold of BCAD is similar to that of MCAD. E367 in BCAD is at the same position and in a similar conformation as the catalytic base in MCAD, E376. The main enzymatic differences between BCAD and MCAD are their substrate specificities and the significant oxygen reactivity exhibited by BCAD but not by MCAD. The substrate binding cavity of BCAD is relatively shallow compared to that of MCAD, as consequences of both a single amino acid insertion and differences in the side chains of the helices that make the binding site. The si-face of the FAD in BCAD is more exposed to solvent than that in MCAD. Therefore solvation can stabilize the superoxide anion and considerably increase the rate of oxidation of reduced flavin in the bacterial enzyme. PMID- 7857928 TI - Engineered metal regulation of trypsin specificity. AB - Histidine substrate specificity has been engineered into trypsin by creating metal binding sites for Ni2+ and Zn2+ ions. The sites bridge the substrate and enzyme on the leaving-group side of the scissile bond. Application of simple steric and geometric criteria to a crystallographically derived enzyme-substrate model suggested that histidine specificity at the P2' position might be achieved by a tridentate site involving amino acid residues 143 and 151 of trypsin. Trypsin N143H/E151H hydrolyzes a P2'-His-containing peptide (AGPYAHSS) exclusively in the presence of nickel or zinc with a high level of catalytic efficiency. Since cleavage following the tyrosine residue is normally highly disfavored by trypsin, this result demonstrates that a metal cofactor can be used to modulate specificity in a designed fashion. The same geometric criteria applied in the primary S1 binding pocket suggested that the single-site mutation D189H might effect metal-dependent His specificity in trypsin. However, kinetic and crystallographic analysis of this variant showed that the design was unsuccessful because His189 rotates away from substrate causing a large perturbation in adjacent surface loops. This observation suggests that the reason specificity modification at the trypsin S1 site requires extensive mutagenesis is because the pocket cannot deform locally to accommodate alternate P1 side chains. By taking advantage of the extended subsites, an alternate substrate specificity has been engineered into trypsin. PMID- 7857929 TI - Location of the catalytic site for phosphoenolpyruvate formation within the primary structure of Clostridium symbiosum pyruvate phosphate dikinase. 1. Identification of an essential cysteine by chemical modification with [1 14C]bromopyruvate and site-directed mutagenesis. AB - Pyruvate phosphate dikinase (PPDK) catalyzes the interconversion of adenosine 5' triphosphate (ATP), orthophosphate (Pi), and pyruvate with adenosine 5' monophosphate (AMP), pyrophosphate (PPi), and phosphoenolpyruvate (PEP). The reaction takes place according to the following steps: (1) E+ATP+P(i)<-->E PP.AMP.P(i), (2) E-PP.AMP.P(i)<-->E-P+AMP+PP(i), and (3) E-P+pyruvate<-->E+PEP, where E represents free enzyme; E-PP, pyrophosphorylenzyme; and E-P, phosphorylenzyme. Steps 1 and 2 comprise the nucleotide partial reaction, and step 3 comprises the pyruvate partial reaction. The present studies were carried out to locate amino acid residues within the primary structure of Clostridium symbiosum PPDK participating in the catalysis of the pyruvate partial reaction. The enzyme was treated with the affinity label [1-14C]bromopyruvate, reduced with NaBH4, proteolyzed with trypsin, and chromatographed on an HPLC column. The radiolabeled tryptic peptide isolate was sequenced to reveal Cys 831 as the site of alkylation. Using PCR techniques Cys 831 was replaced by Ala, and the C831A PPDK mutant formed was then subjected to kinetic analysis. Rapid quench studies of single turnover reactions on the enzyme showed that the mutant is as efficient as wild-type PPDK in catalyzing the nucleotide partial reaction while it is unable to catalyze the pyruvate partial reaction. These results were interpreted as evidence for a role of Cys 831 in pyruvate/PEP binding and/or catalysis. PMID- 7857930 TI - Location of the catalytic site for phosphoenolpyruvate formation within the primary structure of Clostridium symbiosum pyruvate phosphate dikinase. 2. Site directed mutagenesis of an essential arginine contained within an apparent P loop. AB - Pyruvate phosphate dikinase catalyzes the interconversion of adenosine 5' triphosphate (ATP), orthophosphate (P(i)), and pyruvate with adenosine 5' monophosphate (AMP), pyrophosphate (PP(i)), and phosphoenolpyruvate (PEP). The Arg 561 residue of Clostridium symbiosum PPDK is contained within a Gly-rich stretch of sequence spanning positions 553-563 (viz., GAEGIGLCRTE) located in the 35 kDa C-terminal domain of the enzyme. The possible role of this stretch of sequence as a phosphate binding loop participating in catalysis of the PEP/pyruvate partial reaction (viz., E+PEP<-->E-P+pyruvate, where E-P represents enzyme phosphorylated at the catalytic histidine) was deduced from the similarity of this sequence to other known phosphate binding loops and by its location in the 35 kDa PEP/pyruvate binding domain of PPDK. To test the proposed role of Arg 561, and hence, the signature sequence, in catalysis of the E+PEP<-->E-P+pyruvate partial reaction, the C. symbiosum PPDK site-directed mutants Arg 561-->Leu 561 and Arg 561-->Lys 561 were constructed and expressed in Escherichia coli JM101. Neither mutant catalyzed the full PPDK reaction, ATP+P(i)+pyruvate<- >AMP+PP(i)+PEP, but both catalyzed the E+ATP+P(i)<-->E-P+AMP+PP(i) partial reaction as efficiently as wild-type PPDK. Both mutants were shown to be unable to catalyze the PEP/pyruvate partial reaction. On the basis of these results it was proposed that Arg 561 and, possibly, the Gly-rich stretch of sequence spanning positions 553-563 are essential components of the active site of the PEP/pyruvate partial reaction. PMID- 7857931 TI - Separate site catalysis by pyruvate phosphate dikinase as revealed by deletion mutants. AB - Previous studies had indicated that pyruvate phosphate dikinase (PPDK), an enzyme which catalyzes the interconversion of adenosine 5'-triphosphate (ATP), orthophosphate (P(i)), and pyruvate with adenosine 5'-monophosphate (AMP), pyrophosphate (PP(i)), and phosphoenolpyruvate (PEP), is made up of 25, 13, 18, and 35 kDa domains [Carroll, L. J., Xu, Y., Thrall, S. H., Martin, B. M. & Dunaway-Mariano, D. (1994) Biochemistry 33, 1134]. The catalytic histidine (which mediates the phosphoryl group transfers from ATP to P(i) and pyruvate) is located on the 18 kDa domain while the 25 and 13 kDa domains appear to contain the ATP binding site and the 35 kDa domain appears to contain the pyruvate binding site, respectively. The goal of this investigation was to examine functional interdependency of the putative ATP and pyruvate binding domains. Two truncated forms of PPDK were created by using recombinant DNA techniques. The 35 kDa (C terminal) deletion mutant was found to catalyze the E+ATP+P(i)<-->E-P+AMP+PP(i) partial reaction but not the E-P+pyruvate<-->E+PEP partial reaction. The 25 kDa (N-terminal) deletion mutant was found to catalyze the E-P+pyruvate<-->E+PEP partial reaction but not the E+ATP+P(i)<-->E-P+AMP+PP(i) partial reaction. Neither mutant catalyzes the full ATP+P(i)+pyruvate<-->AMP+PP(i)+PEP reaction. These results are interpreted to mean that the ATP and pyruvate binding domains in PPDK are functionally independent, thus providing evidence for separate active sites for catalysis of the two partial reactions. PMID- 7857932 TI - Substoichiometric binding of taxol suppresses microtubule dynamics. AB - We have measured the effects of taxol (10 nM to 1 microM) on the growing and shortening dynamics at the ends of individual bovine brain microtubules in vitro and have correlated the effects both with the stoichiometry of taxol binding to tubulin in microtubules and with the changes in the microtubule polymer mass. The results indicate that taxol suppresses microtubule dynamic instability differently depending upon the stoichiometry of taxol binding to the microtubules. At the lowest effective concentrations (< or = 100 nM), substoichiometric binding of taxol to tubulin in microtubules (between 0.001 and 0.01 mol of bound taxol/mol of tubulin in microtubules) potently and selectively suppresses the rate and extent of shortening at plus ends in association with some increase (28% to 60%) in the mass of microtubule polymer. At intermediate taxol concentrations (between 100 nM and 1 microM), the binding of additional taxol molecules to the microtubules (between 0.01 and 0.1 mol of taxol bound/mol of tubulin in microtubules) inhibits both growing and shortening events at both microtubule ends with no additional increase in microtubule polymer mass. At high taxol concentrations and high taxol binding stoichiometries (> or = 1 microM taxol and > or = 0.1 mol of taxol bound/mol of tubulin in microtubules), microtubule mass increases sharply and dynamics is almost completely suppressed. The data support the hypothesis that binding of a molecule of taxol to a tubulin subunit in microtubules induces a conformational change in that subunit that strongly reduces its ability to dissociate when the subunit becomes exposed at the microtubule end. PMID- 7857933 TI - Site-directed mutation of the putative catalytic residues of endoglucanase CenA from Cellulomonas fimi. AB - The catalytic domains of beta-1,4-glucanases can be grouped into families of related amino acid sequences. The endoglucanase CenA from Cellulomonas fimi is a member of family B. All enzymes from this family are believed to hydrolyze beta 1,4-glucosidic bonds using a general acid-base catalytic mechanism resulting in inversion of anomeric configuration at the scissile bond. Three-dimensional structures for two cellulases from family B have been determined by X-ray crystallographic analysis. These structures show that there are four Asp residues which are in a position to function as acid catalyst, base catalyst, and/or transition state stabilizers. These aspartates are conserved in all members of family B. The roles of Asp216, Asp252, Asp287, and Asp392, the corresponding amino acids in CenA, were determined. These aspartates have been systematically replaced with alanine and glutamate via site-directed mutagenesis, and the resulting effect on activity, substrate specificity, and overall structure has been determined. Changes in overall structure were monitored using circular dichroism spectroscopy, and no significant differences between the wild-type and mutant proteins were found. Active site structure was also found to be intact as all proteins bound to a cellobiose affinity column. The Michaelis-Menten parameters of the enzyme were determined on 2,4-dinitrophenyl cellobioside as well as (carboxymethyl)-cellulose and phosphoric acid-swollen cellulose. Initial characterization of mutant proteins indicates that Asp252 and Asp392 are the acid and base catalysts, respectively, in CenA. Residue Asp287 appears to aid Asp252 in acid catalysis, and Asp216 is not absolutely required for catalysis. PMID- 7857934 TI - Backbone dynamics of chymotrypsin inhibitor 2: effect of breaking the active site bond and its implications for the mechanism of inhibition of serine proteases. AB - The backbone dynamics of uniformly 15N-labeled chymotrypsin inhibitor 2 (CI2) and of the complex formed by the association of two fragments consisting of residues 20-59 and 60-83 have been studied. A data set consisting of 15N longitudinal (T1) and transverse (T1 rho) relaxation times and (1H)-15N NOE enhancements has been measured for all backbone NH groups in both proteins. Information on internal motions has been extracted from these data using the model-free approach to determine order parameters (S2) and effective internal correlation times (tau e). The data indicate that most of the backbone of CI2 is highly constrained (S2 approximately 0.9) with the exception of residues in the binding loop (residues 54-64), which have slightly lower order parameters. Most of the residues in the CI2(20-59).(60-83) complex are also highly constrained (S2 approximately 0.9). However, the loss of the covalent bond between Met59 and Glu60 leads to a large increase in the mobility of residues in the loop region. The residues in the first half of the loop region have significantly lower order parameters than those in the second half of the loop. This observation suggests that the NH2 group that is released on cleavage of the scissile bond remains anchored in its original position, inhibiting the attack of water on the acyl-enzyme that is formed between the protease and the cleaved inhibitor. More importantly, the NH2 group is optimally placed for reversing the formation of the acyl-enzyme so that the equilibrium between the cleaved and uncleaved inhibitor, bound to the protease, greatly favors the uncleaved complex. PMID- 7857935 TI - X-ray structure of cyclodextrin glycosyltransferase complexed with acarbose. Implications for the catalytic mechanism of glycosidases. AB - Crystals of cyclodextrin glycosyltransferase (CGTase) from Bacillus circulans strain 251 were soaked in buffer solutions containing the pseudotetrasaccharide acarbose, a strong amylase- and CGTase inhibitor. The X-ray structure of the complex was elucidated at 2.5-A resolution with a final crystallographic R value of 15.8% for all data between 8.0 and 2.5 A. Acarbose is bound near the catalytic residues Asp229, Glu257, and Asp328. The carboxylic group of Glu257 is at hydrogen bonding distance from the glycosidic oxygen in the scissile bond between the B and C sugars (residue A is at the nonreducing end of the inhibitor). Asp328 makes hydrogen bonds with the 4-amino-4,6-dideoxyglucose (residue B), and Asp229 is in a close van der Waals contact with the C1 atom of this sugar. From this we conclude that in CGTase Glu257 acts as the proton donor and Asp229 serves as the general base or nucleophile, while Asp328 is involved in substrate binding and may be important for elevating the pKa of Glu257. On the basis of these results it appears that the absence of the C6-hydroxyl group in the B sugar is responsible for the inhibitory properties of acarbose on CGTase. This suggests that the C6-hydroxyl group of this sugar plays an essential role in the catalytic mechanism of CGTase.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7857936 TI - The major, N2-Gua adduct of the (+)-anti-benzo[a]pyrene diol epoxide can be unstable in double-stranded DNA. AB - The mechanisms of mutagenesis by the (+)-anti diol epoxide of benzo[a]pyrene [(+) anti-B[a]PDE] was investigated in supF of the Escherichia coli plasmid pUB3 [Rodriguez & Loechler (1993) Biochemistry 32, 1759]. pUB3 was reacted with (+) anti-B[a]PDE, then either (1) transformed immediately into E. coli or (2) heated at 80 degrees C for 10 min prior to transformation--the latter to probe mechanism. Qualitatively, heating did not have a statistically significant effect on the mutagenic pattern, except at the major base substitution hot spot, G115, in supF; principally, G115-->T mutations were obtained prior to heating, while after heating, G115-->A and G115-->C mutations became more prevalent. Quantitatively, heating caused an approximately 2-fold decrease in mutation frequency. Heating released a small fraction of adducts (approximately 5%), and the chemistry and implications of this reaction are investigated herein. Although the major adduct of (+)-anti-B[a]PDE (formed at N2-Gua) is generally regarded to be heat stable, it can be quite unstable in double-stranded (but not single stranded) DNA at low [Mg2+]. Heating releases the corresponding tetraols from (+) anti-B[a]P-N2-Gua in approximately the same ratio as for simple hydrolysis of (+) anti-B[a]PDE itself. This and other results suggest that guanine remains in DNA when (+)-anti-B[a]P-N2-Gua adducts are hydrolyzed. [No evidence for any other chemical change in (+)-anti-B[a]PDE adducts was found.] While no general acid/base or nucleophilic catalysis was observed, adduct hydrolysis was specific acid catalyzed down to pH approximately 5.6, where the pH-rate profile showed a break to a slope of approximately 0.0. This break probably indicates the pKa of (+)-anti-B[a]P-N2-Gua protonated at the N2-position, which is higher than expected.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7857937 TI - Specific binding of the biradical analog of neocarzinostatin chromophore to bulged DNA: implications for thiol-independent cleavage. AB - The enediyne anticancer antibiotic neocarzinostatin chromophore generates a single, site-specific break at a bulge in DNA in a thiol-independent reaction, involving intramolecular drug activation under general base catalysis [Kappen, L. S., & Goldberg, I. H. (1993) Biochemistry 32, 13138-13145]. As part of an effort to elucidate the three-dimensional structure of the active complex formed between the labile drug and bulged DNA, we have studied the binding of stable drug products generated in the course of the cleavage reaction with oligodeoxynucleotides containing the bulged structure. By use of fluorescence quenching, we have found that one drug product, which is also formed in the absence of bulged DNA and most closely resembles the biradical intermediate in the cleavage reaction, specifically binds bulged DNA with a Kd in the low micromolar range and competitively inhibits the cleavage reaction. Other drug products, including one formed only in the presence of bulged DNA, fail to bind to the bulged DNA. Implications of these results for the proposed mechanism of bulge-specific cleavage and for the role of the DNA bulge in generating a unique drug product are discussed. PMID- 7857938 TI - Stringent and relaxed specificities of TaqI endonuclease: interactions with metal cofactors and DNA sequences. AB - We have studied the roles of metal cofactors Mg2+ and Mn2+ in modulating substrate specificities during the enzymatic cycle of TaqI endonuclease using steady state and single-turnover kinetics. In the presence of Mg2+, stringent discrimination of TaqI against single base-pair changes (star sites) is manifested by the loss of tight, specific binding in the early stage of the enzymatic cycle. In the presence of Mn2+, relaxed specificity for a star site sequence is attributed to formation of three distinct classes of the ternary complexes: the highly activated TaqI-cognate-Mn2+ complex; the partially activated TaqI-star-Mn2+ complex; and the ground state, inactive TaqI-nonspecific Mn2+ complex. In addition to a high affinity for a TaqI-DNA complex, Mn2+ also binds to TaqI in a DNA-independent fashion. This may facilitate enzyme activation, which could account for the observed relaxation in substrate specificity. Thus, the TaqI-DNA-Mn2+ complex could be formed by either of two pathways: TaqI binding to DNA followed by the binding of Mn2+ or TaqI first binding to Mn2+ followed by the addition of DNA. The inactive, nonspecific TaqI star-Mg2+ complex virtually prohibits transition state interactions, but a TaqI star-Mn2+ complex attains a measurable single-turnover rate. In the late stages of the enzymatic cycle, high affinity of Mn2+ to a TaqI-DNA complex and to the TaqI enzyme may also account for a slower rate of product release. PMID- 7857939 TI - Photoinduced spin-polarized radical pair formation in a DNA photolyase.substrate complex at low temperature. AB - Electron spin polarization is a phenomenon characterized by anomalous line intensities (emission or enhanced absorption) in the EPR spectrum. It is highly diagnostic of radical pairs, such as those formed in photoinduced electron transfer reactions. Electron spin polarization behavior (E/A pattern) is observed in light-modulated EPR spectra obtained at 4 K with fully reduced DNA photolyase.substrate complexes. Similar results are obtained with complexes formed with native enzyme or reconstituted enzyme containing fully reduced flavin as its only chromophore. No signal is observed for fully reduced enzyme or substrate alone. The results suggest that the electron spin polarization signal is due to photoinduced formation of a flavin/substrate radical pair (FADH./T < > T.-); splitting of T < > T.- does not occur at 4 K, and the radical pair can only undergo back-electron-transfer reactions. The data are consistent with the proposal that electron transfer initiates DNA repair in the photolyase reaction. PMID- 7857940 TI - Differential expression of alternatively spliced forms of MAP4: a repertoire of structurally different microtubule-binding domains. AB - We previously reported that the microtubule (MT)-binding domain of microtubule associated protein 4 (MAP4) contains three 18-amino acid imperfect repeats that are homologous to the repeats found in the MT-binding domains of the neuronal MAPs, MAP2 and tau [Chapin, S. J., & Bulinski, J. C. (1991) J. Cell Sci. 98, 27 36]. Here we report the isolation of clones encoding additional isoforms of MAP4, which differ in the number of repeated elements contained within their MT-binding domains. In addition to clones encoding three repeats, we isolated clones encoding a four-repeat isoform, whose MT-binding domain bears a striking similarity to the four-repeat isoform of tau. Other MAP4 clones that we isolated encode five repeats. The additional repeat in the five-repeat isoform of MAP4 is quite unusual in its amino acid sequence; this unusual repeat was also found by Aizawa et al. [Aizawa, H., et al. (1990) J. Biol. Chem. 265, 13849-13855] among the repeats encoded by bovine MAP4 clones possessing four repeats. In humans, MAP4 was recently shown to be encoded by a single-copy gene [West, R. R., et al. (1991) J. Biol. Chem. 266, 21886-21896]; we demonstrated that the human MAP4 gene is located on human chromosome 3p21. Expression of multiple MAP4 isoforms from this gene, which appears to result from alternative RNA splicing, was investigated by RNase protection analysis of mammalian cell lines and rat tissues. The five-repeat isoform was the only form detectable in most cell lines, and it was the most abundant isoform expressed in rat lung, liver, kidney, spleen, and testis. However, in rat brain, heart, and skeletal muscle, although the five-repeat isoform was expressed at all developmental stages examined, the tau-like four-repeat isoform was also expressed, and its expression increased during development. The three-repeat isoform was expressed in heart and, to a lesser extent, in brain, skeletal muscle, and lung. Our results demonstrate that several different MAP4 isoforms are expressed in the rat in different tissues and at various developmental stages. Furthermore, our data suggest that differential expression of MAP4 isoforms possessing distinct MT-binding domains may be involved in the changes in MT dynamics or function that are known to accompany differentiation. PMID- 7857941 TI - In vitro assembly of microtubule protein with GTP and 2'dGTP: kinetic evidence for a preassembly conformational change. AB - The assembly of chick brain microtubule protein in a NaCl-supplemented buffer has been examined with respect to nucleation and the subsequent elongation as a function of the nucleotide (GTP vs 2'dGTP), and the protein and nucleotide concentrations. The kinetics suggest that unassembled tubulin can exist in two conformational states (termed Tu1,GTP and Tu2,GIP when GTP is bound to the exchangeable site), with Tu1,GTP contributing to nucleation and Tu2,GTP participating in elongation. The extent of self-nucleation is proposed to be determined, in part, by the rate constant governing this conformational change. This analysis contrasts with that of earlier studies, which concluded that the number of subunits interacting to form an effective nucleus could be estimated from the dependency of self-nucleation on the initial concentration of unassembled tubulin. PMID- 7857942 TI - Contributions of troponin I and troponin C to the acidic pH-induced depression of contractile Ca2+ sensitivity in cardiotrabeculae. AB - Acid pH diminishes the Ca2+ sensitivity for force generation in both cardiac and skeletal muscles, but the mechanisms for these remain undetermined. In permeabilized (skinned) single myofibers of fast-twitch skeletal muscle of the rat, we find that pCa50 of the pCa-force relationship was 5.73 in pH 7 and 5.02 in pH 6.2 (delta pKskeletal = pCa50 in pH 7-pCa50 in pH 6.2 = 0.71 pCa unit); on the other hand, in skinned cardiotrabeculae, the hpCa50 was 5.79 in pH 7 decreasing to 4.14 in pH 6.2 (delta pKcardiac = 1.65 pCa units). We have used this large differential between cardiac/skeletal delta pKs to probe the mechanisms of the pH effects. Since troponin C (TnC) and troponin I (TnI) each have a central role in the Ca2+ switch, we exchanged these proteins in cardiac muscle with their skeletal counterparts and reinvestigated the pH effects. Firstly, with fast-twitch skeletal muscle (sTnC) substituting for 80% of the endogenous cardiac TnC (cTnC), the cardiac pH effect was decreased marginally (modified delta pK = 1.39 pCa units). This TnC-mediated change was further probed with two distinct cardiac-skeletal TnC chimeras, c1/s and CBc1/s (the Ca(2+) binding c1/s), in which a majority of the N-terminal 41 amino acid residues was made cardiac and the rest skeletal [Gulati, J., & Rao, V. G. (1994) Biochemistry 33, 9052-9056]. The phenotype shift following sTnC/cTnC exchange in the trabeculae was blocked when c1/s was used in lieu of sTnC; on the other hand, interestingly, CBc1/s exactly mimicked sTnC.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7857943 TI - Superoxide contributes to the rapid inactivation of specific secondary donors of the photosystem II reaction center during photodamage of manganese-depleted photosystem II membranes. AB - The role of superoxide in the mechanism of photoinactivation of the secondary donors of the reaction center of photosystem II membranes depleted of Mn by extraction with NH2OH plus EDTA (NH2OH/EDTA-PSII) was assessed. EPR analyses (g = 2 region) in continuous light, optical kinetic spectrophotometric analyses of P680+ and Car+, and AT-band emission measurements were made after various durations of weak and strong light treatment of NH2OH/EDTA-PSII in the presence and absence of superoxide dismutase, or of PSII electron acceptors to suppress superoxide formation. Additionally, flash-induced variable fluorescence of chlorophyll a and the capabilities of the membranes of photooxidize Mn2+ (in the presence of H2O2) via a high-affinity site (Km approximately 180 nM) and to carry out the photoactivation of the Mn-cluster were determined. In the absence of any additions to the NH2OH/EDTA-PSII membranes which were highly depleted of Mn, weak light treatment caused rapid (t1/2 approximately 20 s) and parallel losses of (a) the approximately 10 microseconds phase of P680+ reduction, which reflects the TyrZ-->P680+ reaction, (b) the amplitude of chlorophyll a variable fluorescence, (c) the capability to accumulate the TyrZ(+)-radical in continuous light, and (d) the capability to photooxidize Mn2+/H2O2 in continuous light. As reported previously [Blubaugh et al. (1991) Biochemistry 30, 7586-7597], a dark-stable 12 G-wide featureless EPR signal centered at g = 2.004 was formed rapidly during illumination. This signal previously was tentatively identified as a Car+ radical and was suggested to contribute to the quenching of chlorophyll a variable fluorescence and to the slowing of the TyrZ-->P680+ reaction. However, we failed to detect Car+ formation by sensitive optical spectrophotometry and obtained no definable evidence for either a quencher of fluorescence other than P680+ itself or a slowing of the TyrZ-->P680+ reaction. Addition of a saturating concentration (96 units/mL) of superoxide dismutase diminished the rate of photodamage(s) by approximately 30-fold, but did not abolish it completely. Superoxide dismutase similarly suppressed strong light-induced photodamages, causing the loss of capability to photooxidize Mn2+/H2O2, to carry out photoactivation, and to generate the AT-band emission as well as TyrZ+ EPR signal. In contrast to others, we found no evidence that the initial target(s) of photodamage is (are) different in weak versus strong light treatment. The totality of the results suggests that the initial event in either weak light or strong light photodamage of NH2OH/EDTA PSII is a decoupling of the redox activity of TyrZ from P680.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7857944 TI - Resonance Raman spectroscopy of the photosystem II light-harvesting complex of green plants: a comparison of trimeric and aggregated states. AB - Resonance Raman spectroscopy was performed on photosystem II light-harvesting complex (LHCII) in trimeric and oligomeric states with various excitation conditions. From these studies, it can be concluded that the structure of LHCII is altered during the trimer/oligomer transition. These structural changes affect the conformation of a population of carotenoid within the complex, which becomes twisted in the oligomeric form. Moreover, the interactions assumed by a chlorophyll a and a chlorophyll b are modified during the oligomerization process. This induces the formation of an H-bond to a formyl group of a chlorophyll b molecule and to a keto group of a chlorophyll a molecule. The extent to which these H-bonds to chlorophyll relate to the formation of the quencher cannot yet be precisely established. However, the structural changes they evidence may play a role in the control of the energy flux by LHCII complexes. PMID- 7857945 TI - Peptide models of helical hydrophobic transmembrane segments of membrane proteins. 1. Studies of the conformation, intrabilayer orientation, and amide hydrogen exchangeability of Ac-K2-(LA)12-K2-amide. AB - The secondary structure, amide hydrogen exchangeability, and intramembrane orientation of the hydrophobic peptide Ac-K2-(LA)12-K2-amide [(LA)12] were studied by a combination of circular dichroism (CD), Fourier transform infrared (FTIR), and proton nuclear magnetic resonance (1H NMR) spectroscopic techniques. All three techniques indicate that (LA)12 adopts predominantly helical conformations in various organic solvents, detergent micelles, and phospholipid bilayers. Also, attenuated total reflectance FTIR studies of oriented phospholipid bilayers demonstrate that (LA)12 is arranged with the long helical axis perpendicular to the bilayer plane. FTIR and 1H NMR studies of the exchangeability of the amide protons of (LA)12 indicate that in all media there are at least two populations of amide protons which exchange with the bulk solvent at markedly different rates. Moreover, the 1H NMR spectroscopic studies indicate that, in organic solvents and micellar dispersions, amide proton exchange rates decrease progressively from the N- or C-terminus of the peptide toward the central region. Our results are thus consistent with (LA)12 retaining a predominantly helical structure with so-called frayed ends in all media. The amide proton exchange studies also indicate that when (LA)12 is dispersed in lipid bilayers, the slowly exchanging population of amide protons is larger than that observed in organic solvents or in micellar dispersions and that most of that proton population is virtually unexchangeable. Such observations are consistent with the sequestration of the central regions of the peptide in the hydrophobic domains of the lipid bilayer. The CD and FTIR data indicate that although (LA)12 seems to retain conformations with a high alpha-helical content in all media examined, its conformation is sensitive to the composition of the surrounding medium, in contrast to the polyleucine-based analogues which have been studied previously. In particular, the FTIR spectroscopic data indicate that (LA)12 may exhibit an amide I absorption band between 1633 and 1639 cm-1 under some circumstances. The relative intensity of this band changes with the composition of the surrounding medium and its appearance has previously been correlated with the formation of 3(10)-helical structures [Miick et al. (1992) Nature 359, 653-655]. Thus (LA)12 may be interconverting between different helical conformations in response to changes in the physical properties of the medium in which the peptide is dispersed. Our results suggest that (LA)12 should serve as a good peptide model of hydrophobic, transmembrane helices which are conformationally sensitive to the properties of the lipid bilayer in which they reside. PMID- 7857946 TI - Peptide models of helical hydrophobic transmembrane segments of membrane proteins. 2. Differential scanning calorimetric and FTIR spectroscopic studies of the interaction of Ac-K2-(LA)12-K2-amide with phosphatidylcholine bilayers. AB - The interactions of the hydrophobic helical transmembrane peptide Ac-K2-(LA)12-K2 amide [(LA)12] with a series of n-saturated diacylphosphatidylcholines (N:0 PC) were studied by high-sensitivity differential scanning calorimetry (DSC) and Fourier transform infrared (FTIR) spectroscopy. The incorporation of (LA)12 into these lipid bilayers results in a broadening of the chain-melting phase transitions of the lipids and progressive decreases in the characteristic temperatures and enthalpies of their gel/liquid-crystalline phase transitions. At low peptide/lipid ratios, the DSC thermograms exhibited by mixtures of (LA)12 with the short chain PCs (13:0 and 14:0) and with very long chain PCs (21:0 and 22:0) appear to be a summation of sharp and broad components, the former diminishing in intensity with increases in peptide concentration. This behavior can be approximated by that of a macroscopic mixture of peptide-poor and peptide rich lipid domains, the relative proportions of which change with changes in peptide concentration. For peptide mixtures with the medium-chain PCs, the hydrocarbon chain-melting phase transition endotherms are not clearly resolvable into similar sharp and broad components. Instead, at all finite peptide concentrations the DSC heating thermograms appear as broad and highly asymmetric endotherms, the transition temperatures of which decrease significantly with increases in peptide concentration. For mixtures of (LA)12 with each of the lipids studied, the total hydrocarbon chain-melting transition enthalpy decreases with increasing peptide concentration but does not vanish at high peptide/lipid ratios. The FTIR spectra of (LA)12 in these PC bilayers indicate that the peptide retains a predominantly alpha-helical conformation in both the gel and liquid crystalline phases of the short to medium chain PCs studied (N < 18). However, when incorporated into bilayers composed of the longer chain PCs (N > or = 18), (LA)12 undergoes a reversible conformational change at the gel/liquid-crystalline phase transition of the mixture. In the liquid-crystalline phase, the amide I regions of the FTIR spectra of these mixtures are indicative of a predominantly alpha-helical peptide conformation. However, upon freezing of the lipid hydrocarbon chains, populations and/or domains of (LA)12 giving rise to a sharp conformationally unassigned band near 1665 cm-1 are formed.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7857947 TI - DNA duplexes flanked by hybrid duplexes: the solution structure of chimeric junctions in [r(cgcg)d(TATACGCG)]2. AB - Hybrid duplexes and chimeric duplexes containing hybrid segments linked to pure DNA (or pure RNA) segments are involved in transcription and replication, as well as reverse transcription. A complete understanding of the mechanism of these processes requires detailed information on such duplexes and the junctions between duplexes of differing structure. Using two-dimensional NMR, restrained molecular dynamics and mechanics, and back-calculation refinement against the nuclear Overhauser effect spectra at various mixing times, we have determined the solution structure of the chimeric duplex [r(cgcg)d-(TATACGCG)]2 containing a pure DNA segment in the center of a hybrid duplex. The solution structure differs from the previously determined X-ray structure of the analogous duplex [r(gcg)d(TATACGC)]2, which was found to be A-form throughout [Wang, A.H.-J., et al. (1982) Nature 299, 601-604]. The basic features of the solution structure are (a) the RNA residues are all A-form with C3'-endo sugar conformations, (b) the central DNA segment is B-form, (c) the transition from A-form RNA sugar conformations to B-form DNA sugar conformations involves only the dT5 base step, and (d) although the sugar conformations of the DNA residues A6-G12 are closer to B-form, the basic helical properties of the peripheral RNA.DNA hybrid segments are closer to typical A-form than to B-form. PMID- 7857948 TI - Proximal and long-range alterations in chromatin structure surrounding the Chinese hamster dihydrofolate reductase promoter. AB - The chromatin structure of the dihydrofolate reductase (DHFR) gene was examined by DNA/protein cross-linking, chemical DNA methylation, and micrococcal nuclease digestion. The 5' promoter region of the gene displays two nucleosome-free zones (-550 to -300 and -150 to +100 bp relative to the ATG codon), each of which contains a number of micrococcal nuclease-hypersensitive sites. Regions upstream from the distal hypersensitive zone (-900 to -550 bp), downstream from the proximal hypersensitive zone (+100 to +400 bp), and between these two zones (-300 to -150 bp) appear either to be more than 80% histone-free or to contain histones whose globular domains have lost most of their contacts with DNA. Overall, a broad zone extending from -4300 to +4700 bp is altered relative to bulk chromatin, and within this region there are positioned nucleosomes and/or nucleosome-free zones in which the DNA appears to interact with a number of different non-histone proteins. By comparison, the chromatin in the 3' end of the gene (including the right end of the 5th intron and the 6th exon) contains randomly positioned nucleosomes, and its structure is intermediate between that of the 5' end of the gene and a downstream matrix attachment region that contains regularly organized chromatin. A 2.3 kb zone in the central part of the 5th intron reveals some features similar to the 5' end of the gene, suggesting a hitherto unrecognized functional role. PMID- 7857949 TI - A review of social support theories and instruments used in adolescent mothering research. AB - This article reviews the theories and instruments used in 14 studies that measured social support levels of adolescent mothers. Two general trends were revealed, a tendency for researchers to: (1) avoid stating their theoretical perspective of social support and (2) develop new social support instruments rather than take advantage of those already in existence. Strategies are offered to match the social support theories and instruments with the particular study purpose and outcome variables. Use of both an established and a new social support instrument within the same study is recommended as a method of providing concurrent validation for the new instrument and promoting comparability across studies in different situations. Assessment of confounding among variables, construct overlap between measures, and the validity of social support and outcome instruments with adolescent mothers will promote a more accurate description of the role of social support in adolescent mothering. PMID- 7857950 TI - Patterns and covariates of tobacco use in a recent sample of pregnant teenagers. AB - PURPOSE: Little is known about the prevalence and patterns of smoking among pregnant teenagers. We provide a comprehensive description of the prevalence, patterns and correlates of smoking from a recent sample of 199 pregnant adolescents. METHODS: We interviewed pregnant teenagers at mid-pregnancy and delivery to obtain information on tobacco and other substance use before and during pregnancy and on demographic, medical and psychosocial status. RESULTS: The average age was 16.1 years (range 12-18); 70% were African-American. Smoking was prevalent and increased from first (59%) to third (62%) trimesters. This increase was in sharp contrast to decreases in other substances. Caucasians had higher rates of smoking and heavier smoking. For Caucasians, third trimester smoking was predicted by peer smoking and early onset of sexual activity. For African-Americans, third trimester smoking was related to older age, not living with parent(s), dissatisfaction with social support, early pregnancy binge drinking, peer smoking, and early onset of sexual activity. CONCLUSIONS: The high prevalence and increasing pattern of prenatal smoking in teenagers is a major public health concern. Effective education and cessation programs must be targeted at pregnant teenagers. PMID- 7857952 TI - Factors influencing self-esteem and self-consciousness in adolescents with spina bifida. AB - PURPOSE: To identify the demographic, personal, familial, attitudinal, and social factors that influence the self-esteem of adolescents with spina bifida. METHODS: A structured face-to-face interview, that included the Rosenberg Self-Esteem Inventory, was conducted with 107 adolescents with spina bifida. Discriminant analyses were performed to identify the factors that discriminate between adolescents with spina bifida who have low vs. high self-esteem and low vs. high self-consciousness. The discriminant functions included variables from the following domains: sociodemographics, personal biography, family interaction, peer relationships and activities, school and work experiences, attitudes toward spina bifida, sexuality and sexual education, and future aspirations. RESULTS: The factors contributing most positively to adolescents' self-esteem were age appropriate treatments by parents and parental permissiveness in social participation, as perceived by the adolescents. Factors negatively associated with self-esteem included school problems, a perception of disability by others, and living in a medium-sized town (i.e., population 10,000-49,999). The discriminant models correctly identified 57.8% of adolescents who had low self esteem and 50.4% of those with high self-consciousness, and accurately classified 92.6% and 88.4% of those who had high self-esteem and low self-consciousness, respectively. CONCLUSION: Parents' relationships with their adolescents have important associations with the self-image of the youth. PMID- 7857951 TI - Factors affecting number of prenatal care visits during second pregnancy among adolescents having rapid repeat births. AB - PURPOSE: To examine factors associated with the number of prenatal care visits during second pregnancy for adolescents having a short interval between pregnancies. METHODS: The sample includes all adolescents aged 13 to 17 years whose first pregnancy resulted in a birth at a regional medical center in southeastern North Carolina from January 1983 to December 1989 and who had a repeat pregnancy within 24 months which resulted in a birth. We abstracted data from medical records and birth certificates. We fit a negative binomial regression model to determine the effects of various factors on the number of prenatal care visits during second pregnancy. RESULTS: The number of prenatal care visits during the first pregnancy, poor first birth outcome, interval between first and second pregnancy, and care provided by health department staff during first pregnancy were all positively associated with number of prenatal care visits during second pregnancy when controlling for gestation age of second birth. Other independent variables in the model included maternal age, education, black race, and being unmarried at the time of second birth. CONCLUSIONS: Because prenatal care is important for healthy mothers and babies, adolescents should be encouraged to seek prenatal care early in the first pregnancy. This could be an important time to implement interventions aimed at increasing prenatal care utilization in this and subsequent pregnancies. PMID- 7857953 TI - Medical clinics in junior high school: changing the model to meet demands. AB - PURPOSE: To document the development of an initiative undertaken by the Columbia University School of Public Health to provide medical, mental health, and social services in inner city junior high school-based clinics. METHODS: Review of records, reports, and foundation proposals from 1984-1993. Site visits, interviews with clinic staff, school personnel, and students. RESULTS: Years of planning and community development produced four clinics in the Washington Heights area of New York City, the first school-based clinics located in junior high schools in the country. After seven years, the program has the capacity to serve over 4,000 students who present an overwhelming array of physical, psychological, social, and family problems. Almost 23,000 visits were made to the clinics this year: 49% for medical services, 38% for social services, and 13% for health education. As the demand multiplied, a form of triage was implemented that tracked the highest risk students into intensive individual and group interventions. Primary health screening, mental health services, and pregnancy prevention were identified among the critical needs in this deprived community. CONCLUSIONS: Over the years, the clinics have become integrated into the fabric of the schools. Strategies for working in urban junior high schools must be broad, encompassing medical and mental health services, group counseling, life planning and career orientation, along with enhancement of the total school and learning environment. PMID- 7857954 TI - Transfer as a component of the transition of adolescents with sickle cell disease to adult care: adolescent, adult, and parent perspectives. AB - PURPOSE: There are no empirical studies which access the transfer needs/concerns of adolescents and young adults with sickle cell disease (SCD) and their primary caretakers. The overall purpose of this research was to determine the issues, concerns, and expectations of adolescents, young adults and primary caretakers with regard to transfer to adult care. METHODS: Participants were recruited from clinics and programs participating in the Duke/UNC Comprehensive Sickle Cell Program. Using a cross-sectional survey design, young adults (n = 60), adolescents (n = 36) and primary caretakers (n = 25) were administered the Sickle Cell Transfer Questionnaire (SCTQ). RESULTS: Adolescents and young adults with SCD were primarily concerned about how they would pay for medical care and how they would be treated by adult providers. Caretakers were concerned about their teens leaving pediatric care and assuming responsibility for medical care. All three groups reported mixed emotions about leaving pediatric care. There was consensus among the respondents regarding the need for transfer programs and what they should offer. Bivariate analysis revealed that age, education level, and disease severity were statistically significant co-factors influencing the feelings, concerns and opinions of the study participants. CONCLUSION: Future longitudinal experimental research is needed to corroborate the results of this study and to assess the effectiveness of transition-related intervention programs for adolescents with SCD and their families. PMID- 7857955 TI - Predictors of HIV testing among runaway and homeless adolescents. AB - PURPOSE: Although runaway and homeless adolescents are at high risk for acquiring HIV infection, little is known about which of these youth obtain HIV testing or whether those considered to be at highest risk are being tested. The purpose of our study was to determine demographic characteristics and risk profiles of runaway and homeless adolescents who had obtained an HIV test and compare them to those who had not been tested. METHODS: We analyzed data collected by the State of California from a survey of 202 San Francisco Bay area runaway and homeless youth aged 13-18 years conducted in 1990-1991. Adolescents were interviewed about AIDS-related knowledge, attitudes, beliefs, and behaviors, including HIV testing experience. RESULTS: Most subjects were 16 years or older (80%), white (61%), sexually active (91%) and heterosexual (82%). Twenty-three percent reported a previous sexually transmitted disease (STD); 27% had used injection drugs. Over half (54%) had been HIV antibody tested. Free/community clinics were the most common site for testing. In a logistic regression model, four variables were independent predictors of having obtained an HIV antibody test: history of an STD (p = 0.01), 5 or more years of sexual activity (p = 0.01), injection drug use (P = 0.04), and age (p = 0.04). CONCLUSIONS: Our study demonstrates that many runaway and homeless adolescents have obtained an HIV antibody test and that those with known risk factors are more likely to have been tested. These data support the need for community-based expansion of HIV-related services for homeless youth. The effects of HIV antibody testing on subsequent beliefs and behaviors need further study. PMID- 7857956 TI - Body size and the menarche: the Dunedin Study. AB - PURPOSE: We wished to elucidate the relationships among body size variables and age of menarche for New Zealand girls. METHODS: Body size variables were measured repeatedly over eighteen years and age of menarche recorded for 415 girls enrolled in the Dunedin Multidisciplinary Health and Development Study. RESULTS: Girls who were taller and heavier with a higher body mass index than their peers from 7 years of age reached menarche early: height was the most important determinant. Early maturing girls were overtaken in height by the later-maturing girls by fifteen but remained heavier even at eighteen. The daughters of tall mothers matured later. The mean weight at menarche was 41.4 kg, height 149.4 cm, body mass index 18.4, and age 12.9 years. CONCLUSIONS: The daughters of short women matured early and continued growing heavier, but they stopped growing taller and were overtaken in height by the later-maturing daughters of tall women. PMID- 7857957 TI - Prevalence and risk factors for HBV infection among street youth in central Brazil. AB - PURPOSE: A seroprevalence survey was carried out among 496 street adolescents from 9 to 20 years old in central Brazil to determine the prevalence of hepatitis B (HBV) markers, as well as to assess the role of potential risk factors. RESULTS: The findings reveal that 20.4% of the participants were homeless adolescents without family links, living and/or working on the streets. The age at first sexual intercourse was as low as 9 years old, and approximately 60% of this population had had at least one sexual relationship by the age of thirteen, indicating prepubertal initiation of sexual experiences among street adolescents. 13.5% were HBV marker-positive (anti-HBc) and 2.0% had antigenemia. Street-based youth had a higher HBV marker-positive rate when compared to home-based teens (OR = 4.1, 95% CI: 2.1-8.5) and, similarly, higher HBV prevalence was obtained for those reporting sexual activity versus the group without sexual activity (OR = 2.1, 95% CI: 1.1-3.9), even after adjusting for potential confounders. CONCLUSIONS: We have found that street youth, particularly street-based adolescents, should be considered at-risk group for hepatitis B infection in our region. These findings may be used as a baseline information for policy changes not only in hepatitis B prevention but also to reverse the scenario of adolescents sexual abuse. PMID- 7857958 TI - Evaluating a school-based intervention for STD/AIDS prevention in Peru. AB - PURPOSE: In a context of increasing HIV/STD risks among adolescents in Latin America, new conceptions of sequential "sex education" are needed. However, older adolescents must be reached through shorter programs. A quasi-experimental study was conducted to evaluate the impact of a short school-based STD/AIDS prevention program on knowledge, attitudes, and intended behavior among secondary students in Lima. METHODS: Aimed at empowering adolescents regarding their sexuality, improving knowledge and attitudes, and developing skills and prevention-oriented behavioral intentions, the program consisted of seven weekly two-hour sessions. Cost exclusive of research expenses was $3 per student reached. RESULTS: 1213 students from 14 schools participated in either the intervention or control groups. Significant changes in knowledge on sexuality and AIDS, erotophilia, acceptance of contraception, machismo, and discrimination against persons with HIV/AIDS were found in the intervention group, as compared to the control group. Self-efficacy and prevention-oriented behavioral intentions were significantly better in the intervention group. CONCLUSIONS: Owing to its effectiveness, acceptability, and low cost, this program may become useful in reaching adolescents unable to participate in longer-term sex education programs in Peru and elsewhere. PMID- 7857959 TI - Effect of high-sugar intake by low-income pregnant adolescents on infant birth weight. AB - PURPOSE: The objective of this study was to determine the effect of total sugar intake by pregnant adolescents from low-income families on infant birth weight and small-for-gestational-age (SGA) infants. METHODS: The study sample consisted of 337 adolescents, enrolled in a county-wide demonstration project in Camden, New Jersey, who delivered live, singleton newborns. The adolescents were divided into two groups at the 90th percentile for the study sample total sugar intake (206 g): high-sugar intake (> or = 206 g, n = 34) and low-sugar intake group (< 206 g, n = 303). RESULTS: The sample was 46% black, 30% white, and 24% Hispanic. The sample gestational age and birth weight (mean +/- SD) were 39 +/- 3 weeks and 3189 +/- 666 g, respectively. After adjusting for energy intake, the high- compared with the low-sugar intake group was more likely to consume higher total sugar and carbohydrate but lower protein and fat. Likewise, the high-compared to the low-sugar intake group consumed significantly more calcium and magnesium. After adjusting for possible confounding variables such as maternal age, ethnicity, marital status, parity, smoking, net weight gain, body mass index, energy intake, and gestational age at birth, adolescents on high- compared to low sugar diets gave birth to infants weighing 215 +/- 104 g less (p = 0.04). The adjusted odds ratios were 3.41 (95% confidence interval, 1.14 to 10.23) for delivering a SGA infant among adolescents with high- compared with low-sugar intakes. CONCLUSIONS: Low-income adolescents consuming high-sugar diets are at increased risk for delivering lower birth weight and SGA infants. PMID- 7857960 TI - Forces and factors that contribute to the structural stability of membrane proteins. AB - While a considerable amount of literature deals with the structural energetics of water-soluble proteins, relatively little is known about the forces that determine the stability of membrane proteins. Similarly, only a few membrane protein structures are known at atomic resolution, although new structures have recently been described. In this article, we review the current knowledge about the structural features of membrane proteins. We then proceed to summarize the existing literature regarding the thermal stability of bacteriorhodopsin, cytochrome-c oxidase, the band 3 protein, Photosystem II and porins. We conclude that a fundamental difference between soluble and membrane proteins is the high thermal stability of intrabilayer secondary structure elements in membrane proteins. This property manifests itself as incomplete unfolding, and is reflected in the observed low enthalpies of denaturation of most membrane proteins. By contrast, the extramembranous parts of membrane proteins may behave much like soluble proteins. A brief general account of thermodynamics factors that contribute to the stability of water soluble and membrane proteins is presented. PMID- 7857961 TI - Enzymatic activities of mitochondrial respiratory complexes from children muscular biopsies. Age-related evolutions. AB - Measurements were performed to determine maximum enzymatic activities of citrate synthetase and respiratory complexes I, III, and IV of mitochondria obtained from muscular biopsies in control children. The significant number of determinations carried out (43 different biopsies in controls aged 3.8 to 19.1 years) permits the formulation of a table of statistically validated reference values for these activities. These values are independent of sex of the controls, and of the studied muscles. Citrate synthetase activity, which remains stable in this age range, thus constitutes a good internal indicator of mitochondrial activity. Complexes I and III manifest activity which does not vary with age. On the other hand, cytochrome oxidase activity shows a highly significant decrease in this age group. This decrease may be correlated with qualitative changes (subunits VIa and VIIa) in composition of this complex. PMID- 7857962 TI - Mapping of the pyrophosphate binding sites of beef heart mitochondrial F1-ATPase by photolabelling with azidonitrophenyl [alpha-32P]pyrophosphate. AB - 4-Azido-2-nitrophenyl [alpha-32P]pyrophosphate (azido-[alpha-32P]PPi) mimics ADP and PPi by some of its binding properties when assayed in the absence of photoirradiation with mitochondrial F1-ATPase. Upon photoirradiation, both alpha- and beta-subunits of F1-ATPase were covalently labelled. Following chemical and enzymatic cleavages of each of the two photolabelled subunits, peptides containing the covalently bound radioactivity were separated by HPLC and identified by amino acid sequencing. Bound azido-[alpha-32P]PPi was found to be concentrated in two distant sequences of the alpha-subunit, namely Asp194-Thr221 and Lys386-Met437, and in a single sequence of the beta-subunit Glu294-Met358 with most of the photoprobe bound to beta-Tyr-311 and beta-Tyr-345. These results are discussed in terms of a model in which the pyrophosphate binding sites of F1 are located in regions of the alpha- and beta-subunits exposed at the interface between the two subunits and correspond to non-catalytic and catalytic adenine nucleotide binding sites, respectively. PMID- 7857963 TI - The nuclear-encoded MSS2 gene is involved in the expression of the mitochondrial cytochrome-c oxidase subunit 2 (Cox2). AB - Saccharomyces cerevisiae cells carrying the mss2-1 pet mutation contain no Cox2 protein (cytochrome-c oxidase subunit 2), through COX2 transcripts are synthesized and processed normally. Gene MSS2 was cloned and sequenced. It is localized on chromosome IV. The Mss2 protein does not show any significant homology with published sequences. PMID- 7857965 TI - Oxidation of low-density lipoproteins: effect of antioxidant content, fatty acid composition and intrinsic phospholipase activity on susceptibility to metal ion induced oxidation. AB - The oxidative modification of low-density lipoprotein (LDL) may play an important role in atherogenesis. Our understanding of the mechanism of LDL oxidation and the factors that determine its susceptibility to oxidation is still incomplete. We have isolated LDL from 45 healthy individuals and studied the relationship between LDL fatty acid, vitamin E and beta-carotene composition, intrinsic phospholipase A2-like activity and parameters of LDL oxidation. LDL was exposed to a copper ion-dependent oxidising system and the kinetics of oxidation studied by monitoring formation of fatty acid conjugated dienes. The length of the lag phase of inhibited lipid peroxidation was measured as well as the rate of lipid peroxidation during the propagation phase. There was no significant correlation between LDL antioxidant vitamin or fatty acid composition and lag time to LDL oxidation. Oleic acid was negatively correlated with the rate of LDL oxidation (r = -0.41, P < 0.01) whilst linoleic acid was significantly correlated with the extent of LDL oxidation measured by the production of total dienes (r = 0.34, P < 0.05). Interestingly, LDL vitamin E content was positively correlated with both the rate (r = 0.28, P < 0.05) and extent of LDL oxidation (r = 0.43, P < 0.01). LDL isolated from this group of subjects showed significant intrinsic phospholipase-like activity. The phospholipase activity, whilst not correlated with lag time, was significantly correlated with both rate (r = 0.43, P < 0.01) and total diene production (r = 0.44, P < 0.01) of LDL oxidation. We conclude that antioxidant content, fatty acid composition and intrinsic phospholipase activity have little influence on the lag time of Cu-induced LDL oxidation. These components do however, significantly influence both the rate and extent of LDL oxidation, with increased vitamin E, linoleic acid content and phospholipase activity associated with faster and more extensive oxidation. The possible pro oxidant effect of vitamin E has interesting implications for the postulated 'protective' effects of vitamin E on atherogenesis. PMID- 7857964 TI - Platelet-activating factor and its analogs: metabolic pathways and related intracellular processes. PMID- 7857966 TI - Modulation of lipid metabolism at rat hepatic subcellular sites by female sex hormones. AB - The present studies examine the modulation of lipoprotein metabolism at subcellular sites in the liver by female sex hormones. Subcutaneous injection of ethinyl estradiol (5 mg/kg) decreased both triacylglycerol (TG) lipase activity and neutral cholesteryl ester (CE) hydrolase activity in hepatic endosomes while increasing lysosomal lipid hydrolysis. These data suggest that estrogen may induce a shift in the site of intracellular lipid catabolism similar to that found in fasting animals [1]. This work also shows that TG-lipase activity is increased in the CURL and MVB endosomal fractions of ovariectomized rats compared to that found in the equivalent endosomal compartments of age-matched intact female controls. These observations are consistent with an inhibition of endosomal lipase by female sex hormones under physiologic conditions. PMID- 7857967 TI - Stilbene disulfonic acids inhibit synexin-mediated membrane aggregation and fusion. AB - Stilbene disulfonic acids inhibit surfactant secretion from lung epithelial type II cells by an undefined mechanism, and inhibit CD4 mediated cell-cell fusion. We have previously shown that lung synexin promotes in vitro fusion of lamellar bodies and plasma membranes, an obligatory process for surfactant secretion. This study investigates the effect of stilbene disulfonic acids, 4,4' diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS), 4-acetamido-4' isothiocyanatostilbene-2,2'-disulfonic acid (SITS), and 4-acetamido-4' maleimidylstilbene-2,2'-disulfonic acid (AMDS), on synexin-mediated liposome aggregation and fusion. Structurally, these three stilbene compounds differ in the number of isothiocyano groups present (DIDS = 2, SITS = 1, and AMDS = 0). At 10 micrograms synexin/ml, DIDS and SITS inhibited synexin-mediated liposome aggregation with an EC50 of 3.5 microM and 148 microM, respectively. In comparison, AMDS was least inhibitory (EC50 > 1 mM). Thus, the inhibitory potency (DIDS > SITS > AMDS) was partly dependent upon the number of isothiocyano groups. The EC50 was also dependent on synexin concentration. Stilbene disulfonic acids were also inhibitory for arachidonic acid-enhanced synexin-mediated liposome fusion. The EC50 for DIDS and SITS for fusion were similar to that for liposome aggregation. Ca(2+)-induced synexin polymerization, measured by 90 degrees light scattering, was increased by DIDS, suggesting binding of stilbene disulfonic acids to synexin. The binding of DIDS to synexin was dependent on the molar ratio of synexin to DIDS. These results indicate that stilbene disulfonic acids interact directly with synexin to inhibit membrane aggregation and fusion. Our results suggest that such inhibition of synexin activity may contribute towards inhibition of surfactant secretion by DIDS, and support a physiological role for synexin in lung surfactant secretion. PMID- 7857968 TI - Translocation of both lysosomal LDL-derived cholesterol and plasma membrane cholesterol to the endoplasmic reticulum for esterification may require common cellular factors involved in cholesterol egress from the acidic compartments (lysosomes/endosomes). AB - Using a stable cell line 25-RA derived from wild-type Chinese hamster ovary (CHO) cells as the parental cell, this laboratory previously reported the isolation and characterization of CHO cell mutants (cholesterol-trafficking or CT) defective in transporting LDL-derived cholesterol out of the acidic compartment(s) (lysosomes/endosomes) to the endoplasmic reticulum (ER) for esterification. In this report, we show that the CT mutation can be complemented by fusion with human cells; however, attempts to complement the CT defect through DNA transfection have resulted in a collection of stable cell lines designated as ST cells. Under cholesterol starvation condition, the ST cells exhibit an elevated rate of cholesterol ester biosynthesis (by 3- to 5-fold) compared to both the parental CHO cells and the CT cells. The phenotypes of the ST cells are stable. ST cells are thus new cell lines arisen from the CT cells. When the plasma membranes of the parental, CT, and ST cells are labelled with [3H]cholesterol, ST cells show rates of [3H]cholesterol esterification much higher than that observed in CT cells but lower than that observed in the parental CHO cells. This result shows that translocation of plasma membrane cholesterol to the ER for esterification is defective in the CT cells. This result also suggests that ST cells acquire increased cholesterol trafficking activity between the lysosome and the ER without mixing the plasma membrane cholesterol pool. The characteristics of CT cells and ST cells reported here suggest that translocation of both lysosomal LDL-derived cholesterol and plasma membrane cholesterol to the ER for esterification may require common cellular factors involved in cholesterol egress from the acidic compartment(s) (lysosomes/endosomes). PMID- 7857969 TI - The CoA-independent transacylase in PAF biosynthesis: tissue distribution and molecular species selectivity. AB - Microsomal membranes from six different rat tissues (spleen, lung, kidney, brain, testis, and liver) were found to possess CoA-independent transacylase activity that could both acylate lyso-[3H]PAF (1-[3H]hexadecyl-2-lyso-sn-glycero-3 phosphocholine) and then deacylate the 1-[3H]hexadecyl-2-acyl-sn-glycero-3 phosphocholine product via the transacylation of added exogenous 1-alk-1'-enyl-2 lyso-sn-glycero-3-phosphoethanolamine. Platelet-activating factor (1 [3H]hexadecyl-2-acetyl-sn-glycero-3-phosphocholine) was produced when acetyl-CoA was added to the spleen microsomes during generation of lyso-[3H]PAF by the transacylases. More extensive studies with subcellular fractions from spleen revealed that, in addition to microsomes, the transacylase activities were also present in the 15,000 x g membrane fraction but not in the cytosol. Analysis of molecular species of 1-[3H]hexadecyl-2-acyl-sn-glycero-3-phosphocholine before and after addition of 1-alk-1'-enyl-2-lyso-sn-glycero-3-phosphoethanolamine as the acyl acceptor demonstrated a high selectivity for polyunsaturated fatty acids (> 3 double bonds/acyl group) in both the acylation and deacylation processes that occurred in testicular microsomal membranes. The transfer of acyl groups by the transacylase appeared to be equally effective for either arachidonic or docosapentaenoic(n - 6) fatty acids, whereas linoleic and oleic fatty acids were not transferred from 1-[3H]hexadecyl-2-acyl-sn-glycero-3-phosphocholine following the addition of 1-alk-1'-enyl-2-lyso-sn-glycero-3-phosphoethanolamine. Similar experiments with the membrane fraction of undifferentiated HL-60 cells showed that arachidonic acid supplementation of intact cells enhanced both the CoA independent transacylation of lyso-[3H]PAF and the subsequent deacylation of 1 [3H]hexadecyl-2-acyl-sn-glycero-3-phosphocholine caused by addition of 1-alk-1' enyl-2-acyl-sn-glycero-3-phosphoethanolamine. Differentiation of the HL-60 cells into a neutrophil-like form had no effect on the transacylase activity. Our results indicate the PAF-related transacylase is widely distributed among tissues and, although highly selective for polyunsaturated acyl groups, does not discriminate selectively among the polyunsaturates. PMID- 7857970 TI - Regulation of mRNA levels for pulmonary surfactant-associated proteins in developing rabbit lung. AB - Gene transcriptional activities and steady-state mRNA levels have been examined for the surfactant-associated proteins SP-A, SP-B and SP-C in developing rabbit lung. It was observed SP-C mRNA levels increase early in gestation, while SP-A and SP-B mRNA levels increase rapidly between 26 and 30 days gestation. Transcriptional activities for all three surfactant apoproteins increase between 26 and 30 days. Studies conducted with fetal lung explants of 26 days gestation demonstrated exposure to low doses of dexamethasone increases SP-A and SP-C mRNA levels, while high doses stimulate transcription, although this only significant for SP-C. Time course studies revealed different temporal patterns and glucocorticoid responses for SP-A and SP-C mRNAs. SP-A and SP-C mRNA production and steady-state levels were reduced after treatment with cycloheximide. In contrast, SP-B gene transcription was selectively stimulated, suggesting involvement of a labile negative regulatory factory. It is concluded that expression of the three surfactant apoproteins is independently regulated. Early in gestation, SP-C mRNA levels may be regulated in vivo through message stabilization. Glucocorticoids can affect SP-A and SP-C mRNA levels in culture at both transcriptional and post-transcriptional levels. The ability of glucocorticoids to influence these processes declines during fetal development. PMID- 7857971 TI - Characterization of a partially purified diacylglycerol lipase from bovine aorta. AB - A partially-purified diacylglycerol (DG) lipase from bovine aorta has been characterized with respect to the effects of lipid metabolites and two lipase inhibitors, phenylboronic acid and tetrahydrolipstatin (THL). DG lipase activity was determined by the hydrolysis of the sn-1 position of 1-[1-14C]palmitoyl-2 oleoyl-sn-glycerol. The products of the lipase reaction, 2-monoacylglycerol (2 monoolein) and non-esterified fatty acids (oleate, archidonate) produced a concentration-dependent (20-200 microM) inhibition of DG lipase activity. Oleoyl CoA and dioleoylphosphatidic acid also inhibited aortic DG lipase activity, but lysophosphatidylcholine had little or no effect. The inhibition of aortic DG lipase by phenylboronic acid was competitive, with a Ki of approx. 4 mM. THL was a very potent inhibitor of aortic DG lipase; the concentration required for inhibition to 50% of control was 2-6 nM. THL inhibition was reduced when the concentration of substrate in the assay was increased. Attempts to identify the aortic DG lipase by covalent-labelling with [14C]THL were unsuccessful. Immunoblotting experiments revealed that hormone-sensitive triacylglycerol lipase (HSL) could not be detected in bovine aorta. PMID- 7857972 TI - Incorporation of acetyl-CoA generated from peroxisomal beta-oxidation into ethanolamine plasmalogen of rat liver. AB - We have reported that peroxisomal beta-oxidation has an anabolic function, supplying acetyl-CoA for biosyntheses of bile acids and phospholipids. Here we deal with its role in the biosynthesis of the subclasses of ethanolamine- and choline-containing phosphoglycerides (EPG, CPG, respectively). Rats were fed for 2 weeks on chow containing 0.25% clofibrate, which inhibits cholesterol and bile acid biosyntheses, but stimulates peroxisomal beta-oxidation. [1-14C]Lignoceric acid, which is exclusively degraded by peroxisomal beta-oxidation to acetyl-CoA, was intravenously injected, and 3 h later the rats were killed. The EPG-rich and CPG-rich fractions were prepared from the liver. When they were treated with phospholipase A2, the radioactivity was predominantly recovered in the 1-radyl group. The radioactivity in EPG was easily dissociated with HCl vapor, and the lipid containing radioactivity was found to be a fatty aldehyde mixture consisting of steary aldehyde (approx. 58%) palmityl aldehyde (approx. 40%) and oleyl aldehyde (approx. 2%). Thus, in the case of EPG, acetyl-CoA from peroxisomal beta-oxidation is incorporated mainly into the 1-alkenyl group of ethanolamine plasmalogen. The radioactivity in CPG, however, was found in fatty alcohol (formed from fatty acid), but not in alkylglycerol after reduction of the fraction with Vitride. Thus, in the case of CPG, acetyl-CoA from peroxisomal beta oxidation is exclusively incorporated into the 1-acyl group of diacyl glycerophosphocholine, but not into the 1-alkyl group. The above results were supported by the results of phospholipase C treatment. The above data indicate that peroxisomal beta-oxidation plays a role in supplying acetyl-CoA for 1 alkenyl group of plasmalogen-type phospholipid, but this channel may open only to synthesis of EPG, and almost not to CPG. PMID- 7857973 TI - Characterization of a dimeric canine form of surfactant protein C (SP-C). AB - Canine pulmonary surfactant protein C (SP-C) is a small hydrophobic peptide which has one palmitoylated cysteine residue. SP-C enhances the insertion of phospholipids into a monolayer. Two forms of canine SP-C were isolated using Sephadex LH-60 chromatography. It was found that canine SP-C exists in a palmitoylated monomeric form of 3.5 kDa, and a non-acylated dimeric form of 7 kDa. Circular dichroism showed that both forms of SP-C exhibit similar secondary structures at the air/water interface. Both forms of SP-C were able to induce the insertion of phospholipids into a monolayer as measured with the Wilhelmy plate technique. In contrast to the palmitoylated monomeric form of SP-C, the non acylated dimeric form of SP-C does not require calcium ions to insert phospholipids into a monolayer without the negatively charged phosphatidylglycerol. It is concluded that two forms of canine SP-C exist, but the physiological significance of these different forms remains to be established. PMID- 7857974 TI - Immunological studies of human constitutive cyclooxygenase (COX-1) using enzyme immunometric assay. AB - Polyclonal antisera and six distinct monoclonal antibodies (mAbs) were raised against constitutive cyclooxygenase (COX-1) purified from ram seminal vesicles. Immunoblotting experiments revealed that the polyclonal antisera and 4 of the mAbs strongly recognized human COX in platelet extracts. Different two-site immunometric assays of ram COX-1 were established using different combinations of mAbs. The assays were performed in 96-well microtiter plates coated with one mAb, with another mAb (covalently labeled with acetylcholinesterase (AChE)) as tracer. One combination (solid phase CX-101 + CX-105-AChE) exhibited the best sensitivity, with significant detection of concentrations as low as 23 pg/ml (0.3 fmol/ml of sheep COX-1). Unfortunately, this assay poorly cross-reacted with human COX-1 from platelet extracts. Another combination (solid phase CX-111 + CX 110-AChE) exhibited good recognition of human COX-1 but poor cross-reactivity with ram COX-1. Finally, purified anti-COX-1 IgG coated and CX-110-AChE were chosen as the best compromise since both good sensitivity (limit of detection, 113 pg/ml of ram COX-1) and significant cross-reactivity between COX-1 from both species were observed. In parallel, polyclonal antibodies were raised in rabbits against a peptide of 12 amino acids corresponding to the aminoterminal part of human COX-1. These polyclonal antibodies were affinity-purified and used in development of another two-site immunometric assay of COX-1 with CX-110-AChE as tracer. These two assays were used to analyze the COX-1 content of human platelets and cultured human umbilical vein cells (HUVEC). The results obtained with each assay were compared in terms of sensitivity and specificity. The validity of both assays was checked by analyzing platelets and HUVEC extracts previously fractionated by molecular sieve chromatography. PMID- 7857975 TI - Differential measurement of constitutive (COX-1) and inducible (COX-2) cyclooxygenase expression in human umbilical vein endothelial cells using specific immunometric enzyme immunoassays. AB - We have produced and characterized monoclonal antibodies (mAbs) directed against a specific carboxyterminal sequence of human cyclooxygenase-2 (residues 580-598). A rabbit polyclonal antiserum was also raised against another sequence of 10 amino acids (residues 570-581) not present in human constitutive cyclooxygenase 1. Affinity-purified polyclonal antibodies, coated on microtiter plates, were used as capture antibodies in a two-site immunometric assay, with an mAb acetylcholinesterase conjugate used as tracer. The detection limit was 500 fmol/ml of peptide C3-COX2 (residues 570-595). The assay was specific for the cyclooxygenase-2 (COX-2) isoform, since no immunoreactivity could be detected in platelet extracts known to be rich in cyclooxygenase-1 (COX-1). In contrast, extracts from cultured human umbilical vein endothelial cells challenged with 20 nM phorbol myristate acetate (PMA) showed an increase in COX-2 immunoreactivity related both to the increase in enzyme activity and the variations observed by Western blot analysis. Under these conditions, analysis of the same cell lysates with another immunometric assay specific for COX-1 revealed insignificant variation of this enzyme. The specificity of detection was further assessed by measuring the immunoreactivity of the fractions obtained after molecular sieve chromatography of control and stimulated cell extracts, and corroborated the marked enhancement of COX-2 by comparison with COX-1. Treatment of PMA-activated cells with H-7 or actinomycin D totally abolished the COX-2 signal and had little effect on COX-1. No significant variation in COX-2 immunoreactivity was observed using the inactive isomer 4 alpha-PMA, even at 100 nM. These assays constitute the first quantitative analysis of constitutive COX-1 and of inducible COX-2 in nucleated cells at the protein level. PMID- 7857976 TI - Quantification of the interactions among fatty acid, lysophosphatidylcholine, calcium, dimyristoylphosphatidylcholine vesicles, and phospholipase A2. AB - The rate of hydrolysis of phosphatidylcholine bilayers by soluble phospholipase A2 (PLA2) is greatly enhanced by the presence in the bilayer of a threshold mole fraction of the reaction products: fatty acid and lysophosphatidylcholine (lyso PC). The threshold requirement of these products appears to vary as a function of vesicle and calcium concentration. To further identify the roles of myristic acid, lyso-PC, and calcium in promoting optimal PLA2 activity, we have quantified the various interactions among these components and dimyristoylphosphatidylcholine large unilamellar vesicles. The bilayer/water partition coefficient for myristic acid was obtained by competition of vesicles for the binding of the fatty acid to an acrylodan conjugate of an intestinal fatty acid binding protein as monitored by the acrylodan fluorescence emission spectrum. The partition coefficient for lyso-PC was obtained by a similar procedure using the tryptophan emission spectrum of bovine serum albumin. The effect of calcium concentration on these interactions was also quantified. These results were incorporated into an empirical model to describe the threshold requirements for these products in the bilayer. This information is vital for elucidating the mechanism of activation of PLA2 by the hydrolysis products. PMID- 7857977 TI - Inhibition of phorbol ester-stimulated arachidonic acid release by alkylglycerols. AB - Although synthetic analogs of alkylglycerol (AG), such as dodecylglycerol, possess potent biological activities, their mechanism of action has not been determined. We recently detected substantial amounts of AG in unstimulated MDCK cells (Warne, T.R. and Robinson, M. (1991) Anal. Biochem. 198, 302-307) raising the possibility that the endogenous compound may act as a biological mediator. In this study, we examined the effects of synthetic AG on the release of arachidonic acid and arachidonate metabolites (AA) from Madin Darby canine kidney (MDCK) cells in response to 12-O-tetradecanoylphorbol-13-acetate (TPA) in order to characterize its effects on this signalling pathway. Treatment of MDCK with AG potently inhibited the release of AA during subsequent stimulation with TPA. Dodecylglycerol, the most effective of a series of alkyglycerols tested, was active at concentrations as low as 3 microM. The sn-1 and sn-3 forms of AG were found to be equally potent inhibitors. The effects of AG on AA release were not the result of arachidonic acid redistribution among cellular lipids and were independent of the phospholipid source of the released AA. AG did not inhibit the release of AA from MDCK cells when bradykinin was used as a stimulus, indicating selectivity for the effects produced by phorbol esters. These results show that AG can function as a potent and specific inhibitor of TPA-mediated AA release. The ability of AG to regulate this signalling pathway in intact MDCK cells, together with its natural occurrence, suggests a potential bioregulatory role for the endogenous compound as an inhibitor of protein kinase C. PMID- 7857978 TI - 13C-NMR spectroscopic studies of 2-mercaptoethanol-stimulated glutathione synthesis in the intact ocular lens. AB - 13C-NMR spectroscopy was employed non-invasively for the real-time measurement of the rates of glutathione synthesis in intact rabbit lenses supported in organ culture containing L-[3-13C]cysteine. Supplementation of the organ culture medium with 2-mercaptoethanol resulted in a dose- dependent enhancement of lenticular glutathione synthesis rates (dose for 50% maximal effect = 125 microM). At the most effective concentration (400 microM) 2-mercaptoethanol increased the rate of glutathione synthesis 163% relative to the rate observed under control conditions. The mechanism of action for this effect was investigated in intact lenses using antagonists of specific amino acid uptake systems. These experiments demonstrated that the enhanced rates of glutathione synthesis observed in the presence of 2-mercaptoethanol were due to the affinity of the mixed-disulfide formed between cysteine and 2-mercaptoethanol for L system amino acid uptake, thereby providing a mechanism for increasing intracellular cysteine levels by circumventing normal cellular cysteine uptake pathways in the lens. Because of the role of cysteine as the rate limiting substrate in lenticular glutathione biosynthesis, these results suggest a potential strategy to prevent tissue opacification associated with depleted glutathione levels. PMID- 7857979 TI - The allosteric enhancer, PD 81,723, stabilizes human A1 adenosine receptor coupling to G proteins. AB - 2-Amino-3-benzoylthiophenes such as PD 81,273 (PD) have been shown to increase agonist, but not antagonist, radioligand binding and to enhance functional effects of A1 adenosine receptor (A1AR) activation in tissues derived from rats and guinea-pigs. The mechanism by which PD produces this allosteric enhancement, and its effect on human A1ARs was not known. In this study, we demonstrate that PD modifies recombinant human A1AR binding and function in stably transfected CHO cells. In membranes, PD (20 microM) causes: (i) a 3-fold increase in the fraction of receptors found in a high affinity G-protein coupled conformation as assessed by the binding of [125I]N6-(3-iodo-4-aminobenzyladenosine) (125I-ABA), an A1AR agonist; (ii) a 2.44-fold increase in the potency of the agonist R-N6 phenylisopropyladenosine (R-PIA) to compete for binding with the antagonist radioligand, [3H]8-cyclopentyl-1,3-dipropylxanthine ([3H]CPX); (iii) a 1.5-fold increase in the t1/2 of 125I-ABA to dissociate from A1AR; and (i.v.) a 2.2-fold increase in the concentration of guanosine-5'-3-O-(thio)triphosphate (GTP gamma S) required to half-maximally uncouple receptor-G-protein complexes. In intact CHO cells expressing A1AR, PD increases the potency of R-PIA to decrease forskolin-stimulated cAMP accumulation by 3.3-fold. We speculate that PD binds to A1AR at a site distinct from the agonist binding site and stabilizes agonist-R-G complexes. PMID- 7857980 TI - Multiple protein kinases are required for basal Kv1.5 K+ channel gene expression in GH3 clonal pituitary cells. AB - The role of protein kinases in maintaining basal expression of voltage-gated K+ channel mRNA was examined in GH3 clonal pituitary cells. Nonspecific inhibition of protein kinases with H7 or staurosporine markedly decreases Kv1.5 K+ channel gene transcription and mRNA without producing a substantial change in Kv1.4 mRNA. Selective inhibitors for protein kinase C, Ca(2+)-calmodulin kinases, and tyrosine kinases do not affect Kv1.5 mRNA expression. In contrast, the Rp diastereomer of adenosine 3',5'-cyclic monophosphorothioate, a specific inhibitor of protein kinase A, partially inhibits Kv1.5 mRNA expression (approximately 40%), and this effect was antagonized by 8-bromo-adenosine 3',5'-cyclic monophosphate. Thus, protein kinase A and at least one other kinase are required for basal Kv1.5 mRNA expression in pituitary cells. PMID- 7857981 TI - Intracellular degradation of apolipoprotein B generates an N-terminal 70 kDa fragment in the endoplasmic reticulum. AB - Regulated apoB degradation in HepG2 cells occurs in the endoplasmic reticulum (ER), is catalyzed by an N-acetylleucylleucylnorleucinal (ALLN)-sensitive proteinase, and generates a specific 70 kDa fragment (Adeli, K., 1994, J. Biol. Chem. 269, 9166-9175) [corrected]. In the present report, we have characterized the 70 kDa fragment by immunoprecipitation of permeabilized HepG2 cells with a battery of monoclonal antibodies against various sites on the apoB molecule. N Terminal monoclonal antibodies (1D1 and 2D8) were capable of binding to the 70 kDa fragment suggesting that this polypeptide is an N-terminal fragment of the intact apoB. Subcellular fractionation of permeabilized cells and carbonate extraction resulted in the detection of the 70 kDa fragment in the ER lumen. Endoglycosidase H treatment confirmed that the fragment is N-linked glycosylated. We hypothesize that the ALLN-sensitive proteinase which may be located on the luminal side of the ER membrane, catalyzes an initial cleavage of apoB near the N terminus generating a 70 kDa fragment, which is then released into the ER lumen. PMID- 7857982 TI - Characteristics of the signal transduction system activated by ATP receptors in the hepatoma cell line N1S1-67. AB - The transmembrane transduction mechanism coupled to purinergic receptors has been studied in a rat hepatoma cell line (N1S1) at the single cell level by a combination of microfluorimetric and electrophysiological techniques. ATP in the micromolar range causes release of Ca2+ from internal stores and consequent opening of Ca(2+)-activated K+ channels, leading to membrane hyperpolarization. The order of potency of the various nucleotides tested is UTP = ATP = ADP >> AMP, and ATP > beta, gamma-CH2 ATP, indicating that these receptors belong to the P2U subtype. The Ca2+ rise induced by various amounts of ATP exhibits an all-or-none behaviour already observable at 10 microM ATP. Intracellular injection of (10-20 microM) InsP3 or of its non-metabolizable analogue 3-F-InsP3 through the patch pipette, does not always result in a Ca2+ rise. These results may be interpreted assuming that the InsP3 receptors-Ca2+ release channels involved in the purinergic/pyrimidinergic stimulation are located in a subcellular compartment not easily accessible from the bulk cytosol and that a positive feedback loop occurs in this restricted space. PMID- 7857983 TI - Interleukin-4 suppresses the expression of macrophage NADPH oxidase heavy chain subunit (gp91-phox). AB - The production of superoxide anion by NADPH oxidase is a principal nonspecific bactericidal activity of macrophages and neutrophils in host defense. However, exuberant production of superoxide anion also damages host tissues. Cloning and DNA sequencing of the 91 kDa subunit (gp91-phox) open reading frame indicated a high degree of sequence conservation, greater than 90% in nucleotide and amino acid sequences, between the porcine and human cDNAs. We show in pigs that interleukin-4 (IL-4), a T lymphocyte cytokine which plays a major role in mediating antibody responses to pathogens, suppresses superoxide anion production in macrophages by specifically reducing the level of mRNA encoding gp91-phox. Messenger RNA levels are suppressed approx. 70% within 4 h and persist for 24 h without any change in the rate of mRNA turnover. Nuclear run-on analysis showed that IL-4 did not alter the rate of gp91-phox gene transcription under conditions in which IL-1 beta transcription was inhibited. These results indicate that IL-4 suppresses the inflammatory response of macrophages by mechanisms that include post-transcriptional regulation of the 91 kDa catalytic subunit of NADPH oxidase, and transcriptional regulation of inflammatory cytokine expression. PMID- 7857984 TI - Temporal segregation in signalling: a novel mechanism in human neutrophils. AB - The ability of neutrophils to carry out chemotaxis in response to low chemoattractant concentrations, but arrest their motility when exposed to higher concentrations of the same substance, has fascinated investigators for years. By analyzing the temporal characteristics of the morphological responses, corresponding to chemotaxis and cell arrest, we have recently discovered that the choice between them is made by transduction of the continuous binding process into either single or multiple stimuli within defined time intervals, initiating chemotaxis or cell arrest, respectively. Both experimental and theoretical lines of evidence are presented to support the validity of this unique mechanism. PMID- 7857985 TI - PAF and haematopoiesis: III. Presence and metabolism of platelet-activating factor in human bone marrow. AB - Platelet-activating factor (PAF) is a phospholipid compound with major immunoregulatory activities. The present study shows that human bone marrow contains 576 +/- 39 pg PAF/ml (n = 35). Bone marrow-derived PAF exhibits the same biophysical and biological properties that synthetic PAF. PAF concentrations in bone marrow are correlated with the granulocyte (r = 0.4, P = 0.02) but not with the lymphocyte (r = 0.24, P = 0.17) and the monocyte (r = 0.12, P = 0.48) counts. In bone marrow PAF is inactivated by a plasma PAF acetylhydrolase activity (48.0 +/- 2.3 nmol/min per ml, n = 34). Experiments with [3H]PAF indicate that human bone marrow cells actively metabolize this potent molecule by the deacetylation transacylation pathway. Results of this investigation indicate the permanent presence of significant amounts of PAF in bone marrow suggesting its putative involvement in the processes of bone marrow cell proliferation and maturation. PMID- 7857986 TI - Hydrogen peroxide activation of cytosolic phospholipase A2 in vascular smooth muscle cells. AB - We have reported previously that hydrogen peroxide induces arachidonic acid release from prelabeled vascular smooth muscle cells. Here, we studied the effect of hydrogen peroxide on the phosphorylation of cytosolic phospholipase A2 in these cells. Hydrogen peroxide induced a rapid, time-dependent increase in the phosphorylation of cytosolic phospholipase A2. Hydrogen peroxide also increased arachidonic acid release from prelabeled cells in a time-dependent manner similar to that of phosphorylation of cytosolic phospholipase A2. Protein kinase C depletion significantly inhibited the hydrogen peroxide-stimulated cytosolic phospholipase A2 phosphorylation and arachidonic acid release. Hydrogen peroxide caused a time-dependent increase in mitogen activated protein kinase activity. Taken together, these findings suggest that cytosolic phospholipase A2 may, at least in part, contribute to arachidonic acid release induced by hydrogen peroxide and this effect appears to be mediated by protein kinase C and mitogen activated protein kinase. PMID- 7857987 TI - Insulin action on cardiac glucose transport: studies on the role of protein kinase C. AB - Isolated ventricular cardiomyocytes from adult rat have been used to elucidate a possible relationship between protein kinase C (PKC) and the stimulatory action of insulin on cardiac glucose transport. Cells were incubated in the presence of either insulin or phospholipase C from Clostridium perfringens (PLC-Cp) and intracellular sn-1,2-diacylglycerol (DAG) levels and initial rates of 3-O methylglucose transport were determined. Insulin had no effect on the DAG mass level, whereas it was elevated by PLC-Cp to 200% of control. Under these conditions the hormone produced a 2.7-fold stimulation of glucose transport with no significant effect of PLC-Cp. Insulin was unable to produce a redistribution of PKC, whereas phorbol 12-myristate 13-acetate (PMA) increased membrane associated PKC twofold. The PKC inhibitors tamoxifen and staurosporine did not interfere with glucose transport stimulation by insulin. Furthermore, cells treated with PMA exhibited unaltered basal and maximally insulin stimulated rates of glucose transport. In contrast, at physiological concentrations of insulin the stimulatory action of the hormone was significantly reduced. We conclude from our data that PKC is not involved in insulin action on cardiac glucose transport. However, activation of this enzyme may lead to a modified insulin sensitivity of the cardiac cell. PMID- 7857989 TI - Effect of extracellular Mg2+ concentration on agonist-induced cytosolic free Ca2+ transients. AB - The modulating effects of extracellular Mg2+ concentration ([Mg2+]o) on vascular contraction are well known. In the present study it was tested how the changes in cytosolic free Ca2+ concentration ([Ca2+]i) induced by various agonists are modified by changes in [Mg2+]o. Extracellular Mg2+ deprivation increased the [Ca2+]i response to arginine vasopressin, to angiotensin II and to thapsigargin, but not to 5-hydroxytryptamine and noradrenaline. Withdrawal of extracellular Ca2+ revealed that extracellular Mg2+ deprivation increased Ca2+ influx, but not Ca2+ release from cellular stores. The findings demonstrate that different responses of [Ca2+]i to agonists may underlie the modulating effect of [Mg2+]o on vascular contraction. PMID- 7857988 TI - Differential release of histamine and prostaglandin D2 in rat peritoneal mast cells: roles of cytosolic calcium and protein tyrosine kinases. AB - We studied how the release of histamine and prostaglandin D2 (PGD2) were connected in stimulated rat peritoneal mast cells, and to what extent these processes were controlled by the cytosolic Ca2+ concentration, [Ca2+]i, and protein tyrosine kinases. In the presence of 1 mM CaCl2, the G-protein activating compound 48/80 (10 micrograms/ml) evoked a transient rise in [Ca2+]i and a relatively high secretion of histamine, but only a low release of PGD2. In contrast, 5 microM thapsigargin (an inhibitor of endomembrane Ca(2+)-ATPases) and 5 microM ionomycin evoked high and prolonged rises in [Ca2+]i, and stimulated the cells to release relatively small amounts of histamine and high amounts of PGD2. Stimulation of the cells with CaCl2 and 10 microM ATP4- gave only minor quantities of histamine and PGD2, despite of the micromolar level of [Ca2+]i reached. When CaCl2 was replaced by EGTA, rises in [Ca2+]i as well as release of histamine and PGD2 were reduced with each agonist, but the preference of agonists to release more histamine or PGD2 remained unchanged. In mast cells with depleted Ca2+ stores, the addition of CaCl2 stimulated the store-regulated Ca2+ entry resulting in a prolonged rise in [Ca2+]i. However, simultaneous addition of compound 48/80 and CaCl2 was required for release of histamine and PGD2. In cells with full stores, PGD2 release evoked by compound 48/80 was greatly reduced by genistein and methyl-2,5-dihydroxycinnamate, two structurally unrelated inhibitors of protein tyrosine kinases, whereas histamine secretion was not influenced by these inhibitors. Similarly, with thapsigargin or ionomycin as agonist, PGD2 release was more sensitive to the tyrosine kinase inhibitors than histamine secretion. We conclude that in activated rat peritoneal mast cells: (i) the influx of extracellular Ca2+ potentiates agonist-evoked rises in [Ca2+]i as well as histamine secretion and PGD2 release; (ii) the amplitude of the [Ca2+]i rise does not determine the preferential effect of agonists to release more histamine or more PGD2; (iii) the relatively high PGD2 release evoked by thapsigargin and ionomycin is probably due to their potency to evoke a prolonged rise in [Ca2+]i and to activate protein tyrosine kinases. PMID- 7857990 TI - The bisindolylmaleimide GF 109203X, a selective inhibitor of protein kinase C, does not inhibit the potentiating effect of phorbol ester on ethanol-induced phospholipase C-mediated hydrolysis of phosphatidylethanolamine. AB - In fibroblasts, the protein kinase C (PKC) activator phorbol 12-myristate (PMA) either inhibits or stimulates phospholipase C-mediated hydrolysis of phosphatidylethanolamine in the absence or presence of ethanol, respectively. Here, we demonstrate that the specific PKC inhibitor bisindolylmaleimide GF 109203X prevents only the inhibitory, but not the stimulatory, PMA effect. PMID- 7857991 TI - A protein kinase from Dictyostelium discoideum with an unusual acidic repeat domain. AB - DdKinX codes for 1093 amino acids which are organized in four regions: the N terminal catalytic domain, a region containing 30% acidic amino acids, tandem repeats of the motif VKVEEPVEE and the C-terminus. Identity with other protein kinases is 25 to 30%. Descendent trees show that DdKinX does not belong to any of the known kinase branches. PMID- 7857992 TI - Occupational therapy management of a patient with severe polymyositis. AB - The purpose of this article is to illustrate with a case study the process through which a patient with polymyositis taking part in an occupational therapy program achieved functional improvement in spite of persistent muscle weakness. Although the focus is on the occupational therapy program, close monitoring of patient improvement or regression by the total rehabilitation team was essential in order to adjust the patient's weekly activity level for maximum benefit. PMID- 7857993 TI - Wrist splints in rheumatoid arthritis: what do we know about efficacy and compliance? PMID- 7857994 TI - Clinical implications of depression in rheumatoid arthritis. AB - The clinical implications of depression in the context of rheumatoid arthritis are described. An overview of the diagnostic criteria for depression is provided, with specific focus on major depression and the associated subtypes. The neurobiological literature on major depression is briefly reviewed and the implications of the depression literature for the care of persons with rheumatoid arthritis are discussed. PMID- 7857995 TI - Pain behavior of rheumatoid arthritis patients enrolled in experimental drug trials. AB - OBJECTIVE: This study examined the sensitivity of a behavioral observation method for the assessment of arthritis pain as an outcome measure in clinical drug trials. METHODS: The subjects were 33 rheumatoid arthritis patients who were receiving either an active experimental drug or a placebo. Disease activity measures, self-reports of pain, and pain behavior observations were completed for each subject prior to drug initiation, 6 weeks after drug initiation, and 12 weeks after drug initiation. RESULTS: Significant reductions in measures of disease activity and self-report of pain were found for the subjects who received an active drug, relative to those who received the placebo. The pain behavior scores produced by both groups of subjects remained relatively stable during the study. CONCLUSION: The lack of change in pain behavior suggests that arthritis pain behavior may lack sensitivity to short-term changes accompanying drug therapy. PMID- 7857996 TI - Life activities of persons with rheumatoid arthritis with and without depressive symptoms. AB - OBJECTIVE: Persons with rheumatoid arthritis (RA) report more activity losses than persons without RA. Persons with RA who report depressive symptoms experience lower levels of functioning. We integrated these findings and examined the association of depressive symptoms with the activities in which persons with RA participate. METHODS: We surveyed 726 persons with RA and 192 matched controls. Within each group, we examined the perceived importance and actual performance of 65 life activities by individuals with and without depressive symptoms. RESULTS: Significantly more individuals with RA reported depressive symptoms. Among persons with RA, those who had depressive symptoms performed fewer activities, particularly fewer valued activities. In contrast, among controls, those who were depressed rated fewer activities as important, but exhibited few significant differences in the performance of activities. CONCLUSIONS: Depressive symptoms and life activities are associated differently among persons with RA and controls. The higher rate of depression among persons with RA may be partially due to the inability to perform valued activities. PMID- 7857997 TI - A tool for measuring functional outcomes after total hip arthroplasty. AB - PURPOSE: To describe a functional milestone scale (FMS) for measuring functional progression following total hip arthroplasty and to demonstrate that this scale meets accepted standards of scale construction. METHODS: Inter-observer reliability of the scale was determined for 30 patients using a kappa coefficient of concordance (k) for ordinal data, representing 221 pairs of observations. There were 79, 54, 44, and 44 pairs of observations for transfer, walker, crutch, and stair ambulation, respectively. RESULTS: The k coefficient ranged from 0.82 to 0.91. Agreement between therapists was almost perfect according to the criteria of Feinstein. CONCLUSIONS: The FMS exhibits substantial inter-observer reliability and moderate to substantial validity. We have demonstrated its clinical applications as well as showing it to be a useful management and research tool. PMID- 7857998 TI - Characteristics of participants in water exercise programs compared to patients seen in a rheumatic disease clinic. AB - PURPOSE: To determine if community-based water exercise programs are serving people with significant levels of disability and pain. METHODS: Eighty-seven participants in water exercise classes and 174 patients from a rheumatic disease clinic were matched for age, sex, and diagnosis and comparisons were made between the groups for the study variables. RESULTS: Patients had significantly higher disability, pain, global disease severity, anxiety, and depression and lower grip strength than participants. Osteoarthritis (OA) patients (n = 126) compared to OA participants (n = 63) had similar significant differences for all variables. Rheumatoid arthritis (RA) patients' (n = 48) scores were all more severe than RA participants' scores (n = 24), and these differences were similar in magnitude to OA differences, but only global disease severity and grip strength were statistically significantly different. CONCLUSIONS: Water exercise classes are reaching persons with important levels of dysfunction and pain, but more severely affected patients are underrepresented in such programs. PMID- 7857999 TI - Continuation of group physical therapy is necessary in ankylosing spondylitis: results of a randomized controlled trial. AB - PURPOSE: Group physical therapy in patients with ankylosing spondylitis was studied to determine whether beneficial effects persisted after cessation of the intervention. METHODS: After a 9-month period of supervised group physical therapy, 68 patients were randomized for another 9 months to unsupervised daily exercises at home (discontinuation group) or continuation of weekly sessions of supervised group physical therapy (continuation group). Endpoints were spinal mobility (thoraco-lumbar flexion and extension, chest expansion, cervical rotation), fitness (maximum work capacity), functioning (Sickness Impact Profile (SIP), Health Assessment Questionnaire for the Spondylarthropathies [HAQ-S], Functional Index [FI]), and patient's global health assessment on a visual analogue scale. RESULTS: Time for exercises at home was significantly higher in the continuation than in the discontinuation group (mean duration 1.9 versus 1.2 hr per week, P < 0.05). The continuation group improved in global health (mean improvement 1.6; 32%) and in SIP score. Scores for thoraco-lumbar mobility and HAQ-S did not change very much, whereas chest expansion, cervical rotation, fitness, and FI deteriorated. The average attendance for group therapy sessions was 62%. The discontinuation group improved only marginally (0.2; 4%) in global health, whereas all other endpoints decreased. Only for global health and HAQ-S were the differences statistically significant in favor of the continuation group. CONCLUSIONS: Global health and functioning are sustained or even improved further if group physical therapy is continued. Spinal mobility decreased slightly in both groups. PMID- 7858000 TI - Anatomical urinary stress incontinence in women with rheumatoid arthritis: its frequency and coping strategies. AB - OBJECTIVE: The objectives of this study were to develop a valid screening tool for anatomical urinary stress incontinence (AUSI), to use it to determine the frequency of AUSI in women with RA, and to identify the cognitive, behavioral, and psychological coping strategies used by these women to deal with incontinence. METHODS: A screening tool concerning AUSI was validated by comparing self-reported incidences of AUSI with clinical evaluation. Questionnaires regarding presence of AUSI and cognitive, behavioral, and psychological coping strategies were sent to 750 women clinically diagnosed with RA. RESULTS: Of the 262 respondents (35% response rate), 21% had characteristics of AUSI, a rate similar to general population studies. Coping strategies varied depending on whether the women were at home or away from home and whether the women were alone or with others. CONCLUSIONS: There is a need for women with incontinence and the health care workers who serve them to be educated about AUSI and its treatments. PMID- 7858001 TI - Celiac disease: a review. AB - Celiac disease is relatively rare in the United States and many of the facets of this complex disorder are not completely understood. In the gluten-sensitive individual, celiac disease is activated by ingestion of cereal glutens. An abnormal immune system response to dietary gluten causes damage to the small bowel mucosa, which results in nutrient malabsorption. When gluten is removed from the diet, malabsorption resolves. Nursing intervention in celiac disease requires careful nutritional assessment and dietary instruction. PMID- 7858002 TI - The impact of OSHA regulations on nursing care cost and compliance. AB - The Occupational Safety and Health Administration (OSHA) requires health care facilities to protect employees from bloodborne pathogens. One of the mandates is to provide personal protective equipment (PPE) to employees at no cost to the employee. In this article, the authors explore the cost and compliance of implementing the new OSHA regulations for nursing staff assisting with colonoscopies over a 6-month period. The data were collected on a total of 461 procedures. The cost of implementing PPE for the nursing staff was $2.98 per procedure. The PPE available for the nursing staff included goggles, splash-proof gown, face mask, shoe covers, and latex gloves. The total cost of implementing the new regulations for the nursing staff assisting with colonoscopies was $2,747.56 and was projected to cost approximately $50,000 yearly if implemented for all GI procedures in the institution. Staff compliance rates for the five pieces of PPE ranged from 6.5 to 97.8%. PMID- 7858003 TI - Listening to the customer: implementing a patient satisfaction measurement system. AB - Patient satisfaction is an important issue in positioning ambulatory medical services. An effective patient satisfaction measurement program not only helps hospital managers improve the quality of clinical and administrative activities, but also helps the hospital remain viable in increasingly competitive markets. A method for the design and measurement of patient satisfaction with outpatient Endoscopy Lab services is described in this article. The survey focuses on the sequence of events experienced by the patient. Outcome measures of primary interest include global patient satisfaction and the likelihood of using the service again if given a choice. Analysis of patient responses shows that global satisfaction with the outpatient experience is positively associated with service return intention. Additional analysis shows that facility cleanliness, privacy and nurse attention are most strongly associated with global patient satisfaction. Results underscore the importance of various service attributes on patient satisfaction and return intention and of the need to further expand the uses of patient satisfaction measurement in the outpatient Endoscopy Lab. PMID- 7858004 TI - Data analysis for repeated measures studies. AB - Many research questions in nursing can best be answered by designing studies using repeated measures representing pretreatment and posttreatment observations on the same subject. In this article, the author discusses both a parametric statistical test and its nonparametric counterpart and provides guidance regarding when it is appropriate to use each. The steps used in computing both statistics are also provided. PMID- 7858005 TI - Endoscopy nursing education competency: romazicon administration for IV conscious sedation reversal. PMID- 7858006 TI - Cigarette smoking and inflammatory bowel disease. PMID- 7858007 TI - Transjugular intrahepatic portosystemic shunt (TIPS): a pediatric perspective. AB - The TIPS (transjugular intrahepatic portosystemic shunt) procedure is a relatively new therapeutic treatment option for variceal bleeding secondary to portal hypertension. The TIPS procedure evolved in response to the need for a safe, nonoperative shunting procedure, and is becoming a practical alternative to surgically placed shunts. Possible complications of a TIPS include hemorrhage, postprocedure sepsis, shunt encephalopathy or decompensation. Development of shunt stenosis or occlusion is associated with re-bleeding. Three children (ages 10-13) with recurrent, significant variceal bleeding were referred for the TIPS procedure. Two had recurrent GI hemorrhage despite sclerotherapy. To date, all have maintained shunt patency for up to 1 year. None of these children have had significant re-bleeding episodes, and the only recurrence of varices was associated with an obstructed shunt. In this article, the author reviews both conventional treatment and the TIPS procedure for the child with bleeding varices. Nursing implications from a pediatric perspective are emphasized. Pediatric GI nurses must understand TIPS in order to prepare the child and family and to monitor for complications or shunt failure afterward. PMID- 7858008 TI - Patients' attitudes towards TIA. AB - Transient ischemic attacks (TIA) are an important forewarning of stroke. By means of questionnaire, information was sought from patients who suffered a stroke regarding whether or not they had a preceding transient ischemic attack. Those with a preceding transient ischemic attack were polled for their response to the TIA; 47% of patients with a transient ischemic attack did not seek medical attention. The reasons behind failure to seek medical advice are analyzed. PMID- 7858009 TI - Deathstorm. The yellow fever epidemic of 1855. PMID- 7858010 TI - Tuberculosis is back. PMID- 7858011 TI - A method for determination of optimal image enhancement for the detection of mammographic abnormalities. AB - We present a paradigm for empirical evaluation of digital image enhancement algorithms for mammography that uses psychophysical methods for implementation and analysis of a clinically relevant detection task. In the experiment, the observer is asked to detect and assign to a quadrant, or indicate the absence of, a simulated mammographic structure characteristic of cancer embedded in a background image of normal breast tissue. Responses are indicated interactively on a computer workstation. The parameter values for the enhancement applied to the composite image may be varied on each trial, and structure detection performance is estimated for each enhancement condition. Preliminary investigations have provided insight into an appropriate viewing duration, and furthermore, suggest that nonradiologists may be used under this methodology for the tasks investigated thus far, for predicting parameter values for clinical investigation. We are presently using this method in evaluating several contrast enhancement algorithms of possible benefit in mammography. These methods enable an objective, clinically relevant evaluation, for the purpose of optimal parameter determination or performance assessment, of digital image-processing methods potentially used in mammography. PMID- 7858012 TI - Developing a new picture archiving and communication system for the new Osaka University Hospital. AB - Osaka University Hospital moved into a new hospital building on the suburban Suita campus in October 1993. A newly developed hospital information system, a new radiologic information system and phase I of a completely new Picture Archiving and Communication System (PACS) also began operating. Work began in 1986 on this PACS. The PACS effort has been guided by one working group and two committees during the last 7 years. A survey of the previous diagnostic and image delivery system was performed as part of the preamble to designing an optimal PACS. Extensive analysis and measurement of pre-existing operational conditions was undertaken. These studies and technical research projects are described in a companion paper in this issue. The phase I hardware installation and initial testing were completed in March 1994. Subsequent phases will build incrementally until the completely new, hospital-wide PACS is realized. PMID- 7858013 TI - Initial data-element selection for the evaluation of picture archiving and communication system performance. AB - The completely new, hospital-wide picture archiving and communication system (PACS) now being implemented at Osaka University Hospital is described elsewhere in this issue. This paper lists the many studies of the department and hospital that were performed before the PACS for the purpose of identifying data elements for use in evaluating a PACS system. A second purpose of the initial data-element collection was to assist in the overall Osaka University PACS design. Selected studies from this work are presented here. PMID- 7858014 TI - Noise removal from multiple MRI images. AB - We introduce a novel technique for magnetic resonance image (MRI) restoration, using a physical model (spin equation). We determine a set of three basis images (proton density and nuclear relaxation times) from the MRI data using a nonlinear optimization method, and use those images to obtain restorations of the original image. MRIs depend nonlinearly on proton density, two nuclear relaxation times, T1 and T2, and two control parameters, echo time (TE) and relaxation time (TR). We model images as Markov random fields and introduce a maximum a posteriori restoration method, based on nonlinear optimization, which reduces noise while preserving resolution. PMID- 7858015 TI - Eye movement during computed tomography interpretation: eyetracker results and image display-time implications. AB - Stacked displays hold the potential for accurate interpretation of multiple computed tomography (CT) studies on a low-cost workstation. But can such a display scroll as quickly as radiologists can move their eyes to the next image on a film? To address this question, eye-movement duration during CT chest interpretation was recorded using an electronic eye tracker. Adjacent eye movements (+/- 1 image in sequence) averaged 0.54 seconds. Time motion analysis indicates that a CT workstation using a stacked approach with a 0.2-second image display time and a simple interaction can display the next image in less than 0.4 seconds, so a stacked approach should allow a low-cost workstation to facilitate acceptable interpretation of multiple CT or magnetic resonance studies. However, nonadjacent eye movements is likely to take longer and radiologist behavior may be effected. PMID- 7858016 TI - A comparison of conventional screen-film radiography and hard copy of computed radiography in full and two-thirds sizes in detection of interstitial lung disease. AB - This study examined whether hard-copy radiographs produced from computed radiography (CR) images show the subtle interstitial pulmonary disease equally well to conventional screen-film radiographs, because a digital radiography should be chosen for introduction of the digital picture archiving and communication system (PACS) for the new Osaka University Hospital. Eleven radiologists examined 20 abnormal and 20 control chest radiographs presented in each of three groups: conventional screen-film radiographs and two sizes of hard copy radiographs made from CR images. This study of digital image quality of chest examinations found that some findings on conventional screen-film radiography images are not reproduced by current CR (2,000 x 2,000 x 10 bits in matrix), especially when the experienced radiologists were observed. This finding suggested improvements are needed in CR before CR of chest should fully replace conventional screen-film radiography. PMID- 7858017 TI - Reduction of false positives in computerized detection of lung nodules in chest radiographs using artificial neural networks, discriminant analysis, and a rule based scheme. AB - A computer-aided diagnosis (CAD) scheme is being developed to identify image regions considered suspicious for lung nodules in chest radiographs to assist radiologists in making correct diagnoses. Automated classifiers--an artificial neural network, discriminant analysis, and a rule-based scheme--are used to reduce the number of false-positive detections of the CAD scheme. The CAD scheme first detects nodule candidates from chest radiographs based on a difference image technique. Nine image features characterizing nodules are extracted automatically for each of the nodule candidates. The extracted image features are then used as input data to the classifiers for distinguishing actual nodules from the false-positive detections. The performances of the classifiers are evaluated by receiver-operating characteristic analysis. On the basis of the database of 30 normal and 30 abnormal chest images, the neural network achieves an AZ value (area under the receiver-operating-characteristic curve) of 0.79 in detecting lung nodules, as tested by the round-robin method. The neural network, after being trained with a training database, is able to eliminate more than 83% of the false-positive detections reported by the CAD scheme. Moreover, the combination of the trained neural network and a rule-based scheme eliminates 96% of the false positive detections of the CAD scheme. PMID- 7858018 TI - Application of polymerase chain reaction to detect animals latently infected with agents of malignant catarrhal fever. AB - Oligonucleotide primers derived from alcelaphine herpesvirus 1 (AHV-1) isolate WC11 DNA, the first identified agent of malignant catarrhal fever (MCF), were used to assay blood lymphocyte DNA using the polymerase chain reaction (PCR). Multiple species of exotic ruminants were examined to determine the suitability of this technique for detecting animals that may be latently infected. To correlate the PCR results with those of serology, serum samples were obtained from each animal concurrently with lymphocyte collection and subjected to an AHV 1 virus-neutralization assay (VNA). A total of 86 MCF-susceptible animals were tested, and the results of the VNA and PCR assays were compared. PCR results were positive for 44 animals. Of these, 13 were positive by VNA. Animals positive by both VNA and PCR were all wildebeest, the asymptomatic carriers of AHV-1, confirming the ability of the primers to amplify AHV-1 sequence. Positive PCR results from species other than wildebeest may represent sequence amplified from viruses related to AHV-1, which may not induce antibodies capable of neutralizing the WC11 isolate used in the VNA. This study demonstrates that PCR is capable of detecting the presence of MCF agents in various populations of captive ruminants prior to the appearance of clinical MCF so that the sources of infection can be more reliably ascertained. PMID- 7858019 TI - Serum immune responses to the proteins of porcine reproductive and respiratory syndrome (PRRS) virus. AB - The antibody responses of pigs to porcine reproductive and respiratory syndrome virus (isolate VR-2332) were evaluated by indirect immunofluorescence, virus neutralization, and immunoblotting. All pigs in each group were positive by indirect immunofluorescence 14-21 days postexposure (DPE), and antibodies to specific viral proteins (15, 19 or 26 kD) were initially demonstrated by immunoblotting at 7-21 days DPE. Neutralizing antibodies were detected in only 2 pigs that were inoculated intranasally and given additional parenteral injections with adjuvant. These antibodies appeared much later, 51-70 DPE, than did antibodies detected by indirect immunofluorescence. The titer of the neutralizing antibodies increased until 127 DPE, after which the titers decreased, and 1 animal became seronegative for neutralizing antibody by 262 DPE. PMID- 7858020 TI - Evaluation of rotavirus infection and diarrhea in Iowa commercial pigs based on an epidemiologic study of a population represented by diagnostic laboratory cases. AB - Group A, B, and C rotaviruses were identified in 9% (96/1,048) of pig fecal specimens submitted to the Iowa State University Veterinary Diagnostic Laboratory during 1987 and 1988. Six of the rotaviruses were group B, 5 were group C, and the remaining 89% were group A. Of the rotavirus cases with more than 1 serotype, 5 were multiple group A serotypes, 1 involved a group A and B serotype, and 1 included 2 group C serotypes. A retrospective epidemiologic evaluation of pig diarrhea in herds of origin was done using data obtained from the accession records of the rotavirus and 88 matched nonrotavirus pig diarrhea control cases. Herds from which rotavirus cases were derived experienced lower morbidity, mortality, and case fatality rates than matched control herds. The incidence of diarrhea decreased rapidly among all pigs from birth to 3 weeks of age. The peak incidence for piglet diarrhea occurred in February, and a moderate rise occurred in August-September. Definitive evidence for transmissible gastroenteritis virus was found in 12% of nonrotavirus cases but none of the rotavirus cases in which it was sought. Other pathogenic microorganisms were identified less frequently and inconsistently. PMID- 7858021 TI - Mycoplasma infection in a commercial goat dairy caused by Mycoplasma agalactiae and Mycoplasma mycoides subsp. mycoides (caprine biotype). AB - A commercial dairy goat herd of 600 animals experienced sudden onset of arthritis/polyarthritis, clinical mastitis, and sudden death in does. The offending infectious agents were Mycoplasma agalactiae and M. mycoides subsp. mycoides (caprine biotype). The disease syndrome began approximately 4 weeks following the 1) introduction into the herd of a lactating doe with no apparent clinical signs and 2) a breakdown of proper hygienic conditions in the milking parlor. Over a period of 3 weeks, 90 does (15%) either died or were culled because of arthritis/polyarthritis and mastitis. A management decision resulted in only the does affected with M. mycoides subsp. mycoides being submitted for necropsy; those affected with M. agalactiae, which were in a different "string," were not submitted for evaluation. Gross necropsy of the does affected with M. mycoides subsp. mycoides showed purulent discharges from the udders, enlarged supramammary lymph nodes, enlarged and firm spleens, and swollen livers. Microscopic findings were characterized by a loss of vascular integrity and diffuse fluid leakage in multiple organs. Antibiotic therapy with tylosin was attempted but was not successful. The outbreak was terminated following the removal or segregation of affected does and implementation of hygienic conditions in the milking parlor. PMID- 7858022 TI - A PCR-based test for the specific identification of Mycoplasma mycoides subspecies mycoides SC. AB - The polymerase chain reaction (PCR) was used to develop a test for the detection of Mycoplasma mycoides subspecies mycoides SC in the tissues of animals infected with contagious bovine pleuropneumonia (CBPP). Two sets of primers were designed; one set (MC323/MC358) to amplify a approximately 1.5-kbp DNA fragment from all the members of the M. mycoides 'Cluster' and the other set (MM450/MM451) specifically amplified a 574-bp DNA fragment from M. mycoides subspecies. The PCR products could be differentiated further by digestion with the restriction enzyme AsnI. Enzyme digestion of amplification products from M. m. mycoides SC produced 2 fragments, whereas the other 2 M. mycoides subspecies, M. m. mycoides LC and M. m. capri, produced 3 fragments. This test was shown to be very sensitive, being able to detect between 10 and 100 organisms. Cattle were experimentally infected with the Gladysdale strain of M. m. mycoides SC, and samples of serum and mucus were taken periodically, as were postmortem samples of lung, lymph node, pleural fluid, synovial fluid, and tracheal swabs. Complement fixation test on serum samples, culture of postmortem tissues, and histopathologic examination confirmed disease. DNA was extracted from postmortem samples and amplified by PCR using primers MM450 and MM451. Digestion of products using AsnI allowed the specific identification of M. m. mycoides SC. This test could confirm CBPP in 48 hours and was thus capable of giving a more rapid result than the traditional methods of culture, isolation, and identification using biochemical and serological techniques. PMID- 7858023 TI - Molecular and biological characterization of a newly isolated Anaplasma marginale strain. AB - Anaplasma marginale, a rickettsial hemoparasite of cattle and other ruminants, results in significant economic losses worldwide. Distinct strains of A. marginale have been identified based on differences in tick transmissibility, molecular size of surface proteins and DNA restriction fragments, and reactivity to a panel of monoclonal antibodies. These different strains vary considerably in their virulence, antigenic composition, and ability to protect against heterologous challenge. In this paper, we report on the molecular characterization of a newly isolated strain of A. marginale, designated St. Maries, recovered from an acutely infected cow in northern Idaho. Dermacentor andersoni ticks taken from the infected animal were tested for infection by RNA probe analysis. The infection rate of male ticks (as determined by midgut infection) was 100%, and the infection rate of female ticks was 83%. Infected male ticks were able to transmit the St. Maries strain to a susceptible calf. The high infection rate in male ticks may be particularly relevant, given that male ticks are believed to be epidemiologically important in transmission of A. marginale because of their intermittent feeding behavior, which promotes interhost transfer. The newly isolated strain differs from other US strains, including strains previously isolated in Idaho and Washington, based on reactivity to a panel of monoclonal antibodies and restriction fragment length polymorphisms. These results imply that antigenically distinct strains of A. marginale may arise within the same region.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7858024 TI - Characteristics of a Brucella species from a bottlenose dolphin (Tursiops truncatus). AB - A culture isolated from an aborted fetus of a bottlenose dolphin (Tursiops truncatus) was characterized. The isolate was a gram-negative coccobacillus, and the colonial morphology was typical of a smooth Brucella. The isolate was positive for catalase, oxidase, nitrate reduction, and urease. Hydrogen sulfide was not produced. It grew in air at 37 C but required 72 hours for good growth. There was growth on media containing basic fuchsin, thionin, thionin blue, penicillin, and erythritol. The M antigen was dominant, and the isolate was lysed by 4 of 10 brucellaphages tested. The oxidative metabolic profile of the isolate was similar to that for B. abortus but differed in utilization of L-asparagine, L glutamic acid, and DL-citrulline. Whole-cell lysates were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The protein profiles were markedly different from the protein profiles of reference strains of Brucella species. Biochemical and oxidative metabolism profiles indicated that the isolate belongs in the genus Brucella but did not match the profiles of any established species or biovars. This isolate may be an atypical strain of a recognized Brucella species or a new biovar or species of Brucella. PMID- 7858025 TI - In situ analysis of cellular proliferation in canine, feline and equine tumors by immunohistochemistry: a comparison of bromodeoxyuridine, proliferating cell nuclear antigen, and interchromatin-associated antigen immunostaining techniques. AB - Cell proliferation in canine, feline, and equine tumors was evaluated using immunohistochemical detection of in vitro 5-bromodeoxyuridine (BrdU) incorporation, proliferating cell nuclear antigen (PCNA), and interchromatin associated antigen (p105). Ten tumors in each species were analyzed. The tumor proliferative fraction (PF) was defined as the percentage of labeled nuclei for 5,000 tumor nuclei counted. Immunoreactivity was observed with all techniques in all species. A good correlation was observed between the proliferative fractions measured with the BrdU (PFBrdU) and PCNA (PFPCNA) techniques (rs = 0.523, P = 0.0026). There was no correlation between the PFs measured with the BrdU (PFBrdU) and p105 (PFP105) techniques. Using the median values obtained from the different approaches as cutoff points to define slowly and rapidly proliferating tumors, there was an 80% agreement (P = 0.009) between PFBrdU and PFPCNA and no agreement between PFBrdU and PFP105. The results of this study indicate that both BrdU and PCNA labeling methods can be used reliably for identifying proliferating cells in animal tumors. In addition, PCNA could be used to replace the BrdU method to assess tumor proliferative fraction because it does not require pretreatment of tissues. PMID- 7858026 TI - Multifocal subacute necrotizing encephalomyelopathy in Simmental calves. AB - In 24 cases of multifocal necrotizing encephalopathy (MNE) in Simmental and Simmental-cross cattle, clinical features varied, consisting of mild rear limb ataxia, caudal paresis, and, less often, sudden death. Bilateral and symmetric malacic lesions were present in the brain stem (olivary nucleus) of all affected calves. Foci of malacia affecting thoracic spinal cord and additional brain stem sites were common. Neuronal cell bodies and hypertrophied capillaries were present within malacic foci. Rarefaction of neuropil, progressing to complete parenchymal loss, characterized advanced lesions. Pathologic features were similar to those of Leigh syndrome in humans, and a similar defect in aerobic metabolism is hypothesized. Occurrence of the syndrome within 1 breed over a wide geographic area suggests that hereditary factors contribute to development of MNE. PMID- 7858027 TI - Serum alpha-mannosidase activity and the clinicopathologic alterations of locoweed (Astragalus mollissimus) intoxication in range cattle. AB - Subclinical intoxication of livestock with Astragalus and Oxytropis species (locoweeds) results in decreased animal feed conversion, reduced weight gains, and reproductive failure. Sensitive diagnostic methods to definitively diagnose and monitor intoxication are needed to minimize these losses and better manage locoweed-infested pastures and rangelands. Sera from cattle grazing locoweed were evaluated for alpha-mannosidase activity, serum biochemical values, electrolytes, and thyroid hormone concentrations. As the cows began to ingest locoweed, the mean serum alpha-mannosidase activities dropped significantly (400.0 microM to 72.5 microM). Changes in other serum chemistry values were less specific; however, individual animals (generally those ingesting more locoweed) had elevated levels of alkaline phosphatase (ALP), aspartate aminotransferase, and lactate dehydrogenase, with decreased serum total protein (5.8 +/- 0.8 g/dl) and albumin (2.3 +/- 0.3 g/dl). Mean serum thyroid concentrations (both T4 and T3) were lower in animals that were ingesting locoweed. The calculated swainsonine dose correlated statistically with serum alpha-mannosidase activity, ALP, albumin, Cl, CO2, and thyroid hormone T3. This correlation suggests that serum alpha-mannosidase activity along with potential changes in ALP, albumin, and thyroid hormone concentrations is a sensitive indicator of locoweed exposure and intoxication. These parameters may also be useful for monitoring intoxication and allowing subclinically affected cattle to be removed from infested areas before irreversible damage occurs. PMID- 7858028 TI - Pulmonary lesions in fetuses exposed in utero to porcine reproductive and respiratory syndrome virus. PMID- 7858029 TI - Detection of the large latency transcript of pseudorabies virus by RNA-PCR and its potential in diagnosis. PMID- 7858030 TI - Severe autolysis does not prevent scrapie diagnosis in sheep. PMID- 7858032 TI - Western equine encephalitis virus in emus in Oklahoma. PMID- 7858031 TI - Experimental epizootic hemorrhagic disease virus infection in calves: virologic and serologic studies. PMID- 7858033 TI - Disseminated equine herpesvirus-1 infection in a two-year-old filly. PMID- 7858034 TI - Endometrial polyps and endometritis in a thoroughbred filly. PMID- 7858035 TI - Histoplasmosis in a miniature Sicilian burro. PMID- 7858036 TI - Comparison of a commercial antigen-capture ELISA with enrichment culture for detection of Salmonella from fecal samples. PMID- 7858037 TI - Lethal nicotine intoxication in a group of mules. PMID- 7858038 TI - Endocarditis and pulmonary aspergillosis in a horse. PMID- 7858039 TI - Neospora abortion storm in a midwestern dairy. PMID- 7858040 TI - Systemic neosporosis in a California black-tailed deer (Odocoileus hemionus columbianus). PMID- 7858041 TI - Pathology in a dog associated with elevated tissue mercury concentrations. PMID- 7858042 TI - Retrobulbar teratoma in a great blue heron (Ardea herodias). PMID- 7858044 TI - Impaired healing of cervical oesophagogastrostomies can be predicted by estimation of gastric serosal blood perfusion by laser Doppler flowmetry. AB - OBJECTIVE: To assess the value of relative blood perfusion of the gastric tube in prediction of impaired healing of cervical oesophagogastrostomies. DESIGN: Prospective study. SETTING: University hospital, The Netherlands. SUBJECTS: Thirty patients undergoing transhiatal oesophagectomy and partial gastrectomy for cancer of the oesophagus or oesophagogastric junction, with gastric tube reconstruction and cervical oesophagogastrostomy. MAIN OUTCOME MEASURES: Operative measurement of gastric blood perfusion at four sites by laser Doppler flowmetry and perfusion of the same sites after construction of the gastric tube expressed as a percentage of preconstruction values. RESULTS: The relative perfusion at the most proximal site of the gastric tube was significantly lower than at the more distal sites (p = 0.001). Nine of 18 patients (50%) in whom the perfusion of the proximal gastric tube was less than 70% of preconstruction values developed an anastomotic stricture, compared with only 1 of 12 patients (8%) with a relative perfusion of 70% or more (p = 0.024). A reduction in perfusion of the gastric tube did not predict leakage. CONCLUSION: Impaired anastomotic healing is unlikely if relative perfusion is 70% or more of preconstruction values. Perfusion of less than 70% partly predicts the occurrence of anastomotic stricture, but leakage cannot be predicted. Factors other than blood perfusion may have a role in the process of anastomotic healing. PMID- 7858043 TI - Local intra-arterial thrombolysis with urokinase combined with balloon angioplasty in the lower extremities. AB - OBJECTIVE: To assess the effect of thrombolysis with urokinase in the treatment of acute and subacute arterial thrombosis or graft occlusion. DESIGN: Open study. SETTING: County hospital, Sweden. SUBJECTS: 20 selected patients with lower limb arterial or graft occlusions of less than six months' duration, 17 of whom presented with rest pain (four with ulceration) and the rest with claudication. INTERVENTIONS: High dose urokinase (4,000 IU/minute for up to 8 hours) given intra-arterially, followed by oral anticoagulation for 6 months. MAIN OUTCOME MEASURES: Patency at one month and one year, morbidity and mortality. RESULTS: At one month 6/17 who presented with rest pain could walk unlimited distances, 8 had claudication between 50 and 500 m, and 3 had no improvement; 2 had had below knee amputations. At one year only 4 could walk unlimited distances, 5 had claudication between 50 and 500 m, 2 had rest pain, 4 had had major amputations, and 1 was dead and 1 was lost to follow up. Five patients had had 10 additional procedures. Of the 3 who presented with claudication, 2 improved their walking distance to at least 100 m, and one had total relief of symptoms after one month; after a year one had no symptoms, one had mild claudication, and one had severe claudication (120 m). Three developed complications: one bleeding 12 hours after treatment was successfully treated by transfusion, one embolism to the midpopliteal artery was successfully treated by embolectomy, and one episode of bleeding during lysis ceased when treatment was stopped. CONCLUSION: Thrombolysis is at best only an adjunct to balloon angioplasty or traditional vascular operations. PMID- 7858045 TI - Trends in incidence, clinical findings and outcome of acute and elective cholecystectomy, 1970-1986. AB - OBJECTIVE: To assess time trends in the incidence, clinical findings, and outcome of conventional acute and elective cholecystectomy. DESIGN: Single-institution time series analysis. SETTING: University hospital, Sweden. SUBJECTS: A consecutive series of 2926 patients operated on for acute or chronic gallbladder disease in a defined Swedish population. MAIN OUTCOME MEASURES: Changes in the incidence and outcome of acute and elective cholecystectomy. RESULTS: From period I (1970-1978) to period II (1979-1986), the mean rate of acute operations increased from 10 to 30/100,000 inhabitants/year and that of elective operations decreased from 190 to 120/100,000 inhabitants/year. There was therefore a negative correlation between the rate of elective and acute operations (r = 0.58, p < 0.02). This was strongest when the rate of elective operations in any one year was correlated with the rate of acute operations two years later (r = 0.71, p < 0.01). In both groups the proportion of patients over 70 years old increased significantly. The female:male ratio decreased significantly for acute but not elective operations (mean 2.6 in period I and 1.0 in period II). The length of history and the number of previous admissions to hospital with gallstone disease decreased significantly for both groups, as did prevalence of common bile duct stones detected at cholecystectomy. Morbidity did not seem to change, though a general improvement may have been concealed, because patients were older in period II and postoperative mortality was lower than in period I. Complications were least common among patients with a short or no previous history of symptoms attributable to gallstones. CONCLUSIONS: The rate of elective cholecystectomy seems to have some influence on the future rate of acute cholecystectomy. When symptoms of gallstone disease develop, treatment should not be delayed unnecessarily. PMID- 7858046 TI - Quality of life after treatment of gallstones: results of a randomised study of lithotripsy and open cholecystectomy. AB - OBJECTIVE: To compare quality of life after extracorporeal shock wave lithotripsy (ESWL) and open cholecystectomy for symptomatic gallstones. DESIGN: Randomised study. SETTING: University hospital, The Netherlands. SUBJECTS: 49 Patients, 23 of whom were randomized to undergo ESWL and 26 to undergo open cholecystectomy. INTERVENTIONS: Health questionnaires were filled out before, and at 3, 6 and 12 months after treatment. MAIN OUTCOME MEASURE: Improvements of quality of life after one year. RESULTS: Both treatments improved quality of life. Open cholecystectomy improved quality of life significantly better than ESWL (median percentage gains in Nottingham Health Profile scores at 1 year 17.1 and 10.5, respectively, p = 0.003). CONCLUSION: Open cholecystectomy is superior to ESWL in improving quality of life, so cholecystectomy remains the treatment of choice for symptomatic gallstones. For patients who are unfit or unwilling to undergo operation, however, ESWL is adequate because most patients have some benefit from it in terms of quality of life. PMID- 7858047 TI - Methyl tert-butyl ether improves the efficacy of extracorporeal shock wave lithotripsy of human gallstones implanted in pigs. AB - OBJECTIVE: To investigate the contribution of contact dissolution with methyl tert-butyl ether (MTBE) to the success of extracorporeal shock wave lithotripsy (ESWL) of human gallstones implanted in pigs. DESIGN: Experimental study of matched pairs. SETTING: Laboratory for experimental surgery, The Netherlands. MATERIAL: 30 pigs. INTERVENTIONS: Couples of similar human gallstones were surgically implanted into the gallbladders of 30 pigs. All pigs underwent ESWL with an electromagnetic lithotriptor. Half the animals were given adjuvant treatment with MTBE for 2 hours immediately after the ESWL. All pigs were killed a week after treatment. RESULTS: Adjuvant MTBE dissolution led to superimposed damage of the gallbladder. One pig died of biliary leakage and peritonitis. For all kinds of stones, adjuvant MTBE treatment increased the median (range) percentage of stone dissolved by ESWL from 31 (0-58) to 60 (11-81) (p < 0.01), whereas for pure cholesterol stones the increase was from 23 (0-58) to 61 (11-81) (p < 0.01). CONCLUSIONS: These data warrant clinical evaluation of the applicability of combined ESWL and MTBE dissolution of symptomatic gallstones in selected patients. PMID- 7858049 TI - Late results of postanal repair for idiopathic faecal incontinence. AB - OBJECTIVE: To assess the long term clinical results of postanal repair for idiopathic faecal incontinence. DESIGN: Retrospective study. SETTING: University hospital, The Netherlands. SUBJECTS: 38 patients with idiopathic faecal incontinence. MAIN OUTCOME MEASURES: Clinical outcome and its correlation with anorectal manometry. RESULTS: After a median follow up of 43 months (15-126) 19 patients were classified grades 1 and 2 (satisfied) and 19 patients grades 3 and 4 (dissatisfied). Six patients deteriorated and went from grades 1 or 2 to grade 3 or 4. Satisfied patients had a significant rise in resting pressure (median 13.5 mmHg, p = 0.01, 95% CI 5 to 25) and dissatisfied patients did not. CONCLUSION: Long term follow up of patients after postanal repair shows that half the patients have a good result, although only 21% are fully continent. Long term follow up is necessary as a number of patients deteriorate. PMID- 7858048 TI - Late results of anterior sphincter plication for traumatic faecal incontinence. AB - OBJECTIVE: To assess the long term clinical results of anterior sphincter plication for traumatic rupture of the anal sphincters. DESIGN: Retrospective study. SETTING: University hospital, The Netherlands. SUBJECTS: 28 consecutive patients with traumatic faecal incontinence after injury to the anal sphincters. MAIN OUTCOME MEASURES: Clinical outcome and its correlation with anorectal manometry. RESULTS: After a mean (SD) follow up of 50 (37) months 21 patients were classified grades 1 and 2 (satisfied) and seven patients were grades 3 and 4 (classified). There were significant differences after operation between the 21 patients in grades 1 and 2 compared with the 7 in grades 3 and 4 in median resting pressure (43 compared with 25 mmHg, p = 0.004, 95% CI 9 to 40), and squeeze pressure (100 compared with 40 mmHg, p = 0.001, 95% CI 15 to 80) but not in length of high pressure zone (3.5 compared with 2.3 cm, p = 0.14, 95% CI -0.2 to +2.2). (Mann Whitney U test was used.) CONCLUSION: Long term follow up of patients after anterior sphincter plication showed good results in three quarters of patients, and 57% were fully continent. Good postoperative results correlate with significant increases in resting and squeeze pressures. PMID- 7858050 TI - Retention mesh: an alternative to retention sutures. PMID- 7858051 TI - Recurrent giant granuloma of the buttock after intramuscular injection. PMID- 7858052 TI - Treatment of medial tangential osteochondral fractures of the patella, with resorbable materials. PMID- 7858053 TI - The Comox Valley Nursing Centre. PMID- 7858054 TI - Megatrends in professional regulation: towards the year 2000. PMID- 7858055 TI - Standards in action. Maintaining fitness to practice. PMID- 7858056 TI - A blueprint for new technologies. PMID- 7858057 TI - Too afraid to care. PMID- 7858058 TI - Alice Wright. PMID- 7858059 TI - Hyperthermia induces IL-1 alpha but does not decrease release of IL-1 alpha or TNF-alpha after endotoxin. AB - Heat treatments administered prior to the onset of sepsis or endotoxemia markedly increase survival. A potential mechanism for the beneficial effect of heat could be effects on IL-1 alpha and TNF-alpha, important mediators of sepsis and endotoxemia. Administration of IL-1 or TNF prior to development of sepsis and endotoxemia increases survival; thus, prophylactic heat treatments may protect by releasing IL-1 or TNF. Paradoxically, an alternative mechanism of protection of prophylactic heat treatments could be to decrease the amount of IL-1 and TNF released during sepsis or endotoxemia. Cells pretreated with heat do not produce as much IL-1 or TNF in response to endotoxin as cells that have not been pretreated with heat. The purpose of this investigation was to determine if hyperthermia caused release of cytokines and/or blunted the rise in cytokines occurring after endotoxin. Mice were anesthetized with ketamine/xylazine and immersed in a water bath at 37.0 or 42.0 degrees C for sham or heat treatments. At 6-7 h after recovery from anesthesia and immersion, sham and heat-treated mice were injected with Escherichia coli endotoxin. Both heat-treated and sham mice had elevated plasma IL-1 alpha 2 h after anesthesia and immersion but IL-1 alpha was approximately 3-fold greater in the heated mice, 732 +/- 50 vs. 256 +/- 76 pg/ml (p < 0.01). Blood samples obtained after endotoxin revealed no difference in levels of TNF-alpha (5477 +/- 742 vs. 6514 +/- 652 pg/ml) or IL-1 alpha (546 +/- 72 vs. 603 +/- 121 pg/ml) in the sham vs. heated mice.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7858060 TI - Expression of TGF-beta isoforms by Thy-1+ and Thy-1- pulmonary fibroblast subsets: evidence for TGF-beta as a regulator of IL-1-dependent stimulation of IL 6. AB - Transforming growth factor-beta (TGF-beta) and interleukin-1 (IL-1) are essential participants in the development of pulmonary fibrosis. Administration of inhibitors to either cytokine can prevent the onset and progression of lung fibrosis in animal models. In this report, stable Thy-1+ and Thy-1- murine lung fibroblast subpopulations were analyzed for expression of the three mammalian TGF beta isoforms. TGF-beta 1, TGF-beta 2, and TGF-beta 3 mRNA transcripts were detected by reverse transcriptase-PCR in both murine fibroblast subsets. Most of the TGF-beta produced by fibroblasts is latent; however, a small amount of active TGF-beta can be detected using a sensitive mink lung cell bioassay. By incorporating neutralizing anti-TGF-beta isoform-specific antibodies, it was determined that TGF-beta 1 is the predominant isoform present in both the active and the latent forms. Overall, Thy-1- fibroblasts secrete twice as much latent TGF-beta as the Thy-1+ subset. To investigate whether a link exists between TGF beta and IL-1, the effect of TGF-beta 1 on the expression of IL-1 receptor type I (IL-1RtI) by fibroblast subsets was assessed by flow cytometry and Scatchard analysis. TGF-beta 1 significantly down-regulates the expression of IL-1RtI by Thy-1+ fibroblasts, but not by Thy-1- fibroblasts. A functional consequence of this down-regulation of the IL-1RtI is that it makes Thy-1+ fibroblasts less responsive to IL-1-mediated induction of IL-6 protein synthesis.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7858061 TI - Regulatory role of nitric oxide in the IL-4-induced IgE production by normal human peripheral blood mononuclear cells. AB - An in vitro study was performed in order to assess a possible regulatory role of nitric oxide (NO), a short-lived biologic mediator that displays immunoregulatory properties, in the IL-4-driven synthesis of IgE by normal human peripheral blood mononuclear cells (PBMC). In addition to induce IgE production, IL-4 was found to elicit nitrite (NO2-) release by PBMC. A marked correlation was observed between IgE secretion and nitrite release by PBMC stimulated with an optimal concentration of IL-4. The IL-4-dependent IgE production was significantly reduced (p < 0.001) in the presence of N omega-monomethyl-L-arginine (LNMMA), an inhibitor of the NO-synthase pathway; this inhibition was partially reverted with an excess of L-arginine. Addition to PBMC cultures of the chemical NO donor Sin 1, inactive alone, was found to result, depending on the concentration of IL-4, in either potentiation (suboptimal concentration of IL-4, 10 ng/ml) or inhibition (optimal concentration of IL-4, 50 ng/ml) of IgE synthesis. The potentiating effect of Sin-1 was dose dependent, with a maximal effect for 300 microM, whereas its metabolite Sin-1c was inactive. In both cases, Sin-1 markedly reduced the IL 4-induced release of the soluble form of the low affinity IgE receptor (sCD23). Together, these data strongly suggest that NO may display biphasic immunoregulatory properties on the IL-4-induced IgE production by PBMC. PMID- 7858062 TI - Coexpression of the human TNF receptors TR60 and TR80 in insect cells: analysis of receptor complex formation. AB - For investigation of a possible physical interaction between the two human tumor necrosis factor receptors, TR60 (type I) and TR80 (type II), the baculovirus expression system was used. Each of the receptors was expressed as a membrane integrated protein in insect cells, able to specifically bind the two ligands, tumor necrosis factor (TNF) and lymphotoxin (LT alpha). Typically, about 150,000 membrane receptors per cell could be detected 40 h after infection, exerting high affinity ligand binding capacity with Kd values virtually identical to that of human cell lines. The baculovirus system allowed coexpression of both TNF membrane receptors at very high and about equal numbers to investigate the existence of heteromultimeric receptor complexes, either formed spontaneously or ligand induced. Neither saturation binding studies nor immunoprecipitation experiments gave an indication for the existence of TNF receptor heteromers. These data are in accordance with the current view of TNF signaling, in which homonultimerization, rather than heteromer formation of TNF receptors is the initial activating event. PMID- 7858063 TI - Identification of HLA-DRB1 and HLA-DQB1 identical individuals by a cytokine-based mixed lymphocyte culture. AB - Cytokine determination in MLC is under discussion as providing more sensitive and specific information regarding host-graft compatibility, and is therefore suggested to represent a new method for transplantation medicine. Little is known, however, about the stimulatory influence of HLA class II antigens and minor lymphocyte-stimulating antigens (Mls). Our results demonstrate that cytokine determination in MLC is suitable to detect identical alleles of HLA-DRB1 and HLA-DQB1. Among more than 100 random MLC experiments, we observed one cytokine pattern similar to the cytokine release detected in a control MLC of HLA identical siblings, which showed marginal or no secretion of IL-2, sIL-2R, IFN gamma, TNF-alpha, and IL-6. HLA-typing of these two nonreactive individuals elevated identical HLA-DRB1 and HLA-DQB1 regions, while they differed in the HLA DP locus. This suggests that HLA-DP has no stimulatory influence on cytokine release. Further investigation of the stimulatory capacity of HLA-DR and DQ showed that HLA-DR is more effective in inducing IFN-gamma release than HLA-DQ. To evaluate the stimulatory influence of human Mls, i.e., human endogenous retroviruses (HERV), we analyzed HERV sequences of nonreactive individuals. Both individuals showed identical HERV patterns. A third individual, who had shown distinct cytokine release in MLC with both nonreactive individuals, differed in the HERV fragments. In conclusion, cytokine determination in MLC is a new method of evaluating the biological relevance of stimulatory antigens after allogeneic stimulation detecting all individual diversities in one experiment. PMID- 7858064 TI - Pathways of heat shock protein 28 phosphorylation by TNF in human fibroblasts. AB - Treatment of human diploid FS-4 fibroblasts with TNF or IL-1 led to a rapid increase in the phosphorylation of a approximately 28-kDa protein. Increased phosphorylation was seen after 5 min of TNF treatment, it reached a plateau between 10 and 30 min, and decreased thereafter. Immunoprecipitation with specific antibodies identified the 28-kDa protein as a member of the family of small heat shock proteins (Hsp28). Treatment of cells with different kinase inhibitors (staurosporine, H7, H8, HA-1004, or chelerythrine chloride) failed to inhibit TNF-induced Hsp28 phosphorylation, suggesting that neither protein kinase C nor other common protein kinases were involved. Treatment of FS-4 cells with sodium arsenite led to a very strong increase in the phosphorylation of Hsp28 demonstrable after 5 min and persisting for at least 4 h. Tyrosine phosphorylation of pp42 and pp44 MAP kinases was increased by TNF treatment, whereas arsenite produced a modest increase in tyrosine phosphorylation of pp44 while decreasing that of pp42 MAP kinase. The finding that sodium arsenite strongly increased Hsp28 phosphorylation, together with the resistance of TNF induced phosphorylation to kinase inhibitors, supports the notion that increased serine phosphorylation of Hsp28 in this system involves inhibition of protein phosphatase activity. PMID- 7858065 TI - Antiidiotypic antibodies mimic molecular and functional properties of human IL-1 beta in vitro and in vivo. AB - We obtained affinity-purified polyclonal anti-id antibodies against mAb MhC1 and BrhC3, which recognize amino acids 133-147 at the N-terminus of mature human IL-1 beta. mAb MhC1 and BrhC3 have been shown to inhibit binding of IL-1 beta to type I IL-1R, and to neutralize IL-1 beta bioactivity in a number of in vitro assays. We show that affinity-purified antibodies against the MhC1 and BrhC3 idiotypes specifically bind to type I IL-1 beta IL-1R and that this binding is inhibited by both IL-1 beta and IL-1ra; anti-id antibodies were also able to trigger IL-1R dependent events, such as IL-8 secretion by human skin fibroblasts and pyrogenic effect after injection in mice. These anti-id antibodies, therefore, behave as structural and functional "images" of IL-1 beta, both in vivo and in vitro. These data indicate the idiotypic strategy as a powerful tool to study the fine specificity of receptor-ligand interactions. Moreover, this is, to our knowledge, the first report showing that the "internal image" of a cytokine can be active in vivo. PMID- 7858066 TI - Meeting report of the International Symposium of Molecular Cell Biology of Macrophages '94. AB - The International Symposium of Molecular Cell Biology of Macrophages '94 was held on February 10-11, 1994 at Kanazawa University, Kanazawa, Japan. Fifteen speakers including 4 speakers from Europe and the United States were invited to this symposium. In spite of unusual heavy snow and chilly weather, 150 macrophage scientists gathered and had hot discussions. In the meeting reception, a special recognition speech entitled "Dawn of Cytokines--Discovery of a Blastogenic Factor in the Early 1960's" was given by a discoverer of blastogenic factor, Dr. Shinpei Kasakura. This symposium was initiated in 1991 with the intention of bringing together experts of macrophage investigation once a year to discuss progress in the field of molecular cell biology of macrophages. PMID- 7858067 TI - The comparative efficacy and long-term effect of clozapine treatment on neuropsychological test performance. AB - Previous studies have suggested that clozapine may improve neuropsychological test performance. The current study was designed to examine the comparative efficacy and the long-term effect of clozapine (versus haloperidol), on neuropsychological test performance. Neuropsychological measures of executive/attention, visuospatial, and memory function were administered to schizophrenic patients at baseline, at the end of a 10-week double-blind study, and after 1 year of open clozapine treatment. Symptoms and function ratings were obtained at the same time points. The 10-week double-blind study revealed significant group-by-time interactions for two measures: Categorical Fluency and WAIS-R Block Design. At the end of 1 year of open treatment there were significant improvements in Verbal Fluency, Mooney Faces Closure, and WAIS-R Block Design performance, and trend improvements in Stroop Color-Word Interference, Category Fluency, and WMS-R Logical Memory performance. Improvements in neuropsychological performance were unrelated to symptom changes. Change in selected neuropsychological measures were significantly correlated with improvement in quality of life. The results suggest that long-term clozapine treatment may have beneficial effects on a broad range of cognitive functions. PMID- 7858068 TI - An empirical analysis of latent structures underlying schizophrenic symptoms: a four-syndrome model. AB - Various models of schizophrenia have postulated two syndromes (i.e., positive and negative), although other exploratory factor analyses have suggested a disorganization syndrome. We conducted a confirmatory factor analysis (CFA) on Schedule for the Assessment of Positive Symptoms (SAPS) and Schedule for the Assessment of Negative Symptoms (SANS) items and subscales to assess the latent structure of symptoms reflecting underlying pathological processes. The sample included 253 DSM-IIIR schizophrenic inpatients. Fourteen different models with one, two, three, or four syndromes were compared using CFA for "goodness of fit." The three-syndrome models displayed better fitness than any of the one- or two syndrome models. All of the three-syndrome models shared the positive and negative dimensions; the third dimension in these three-syndrome models was either the disorganization or Strauss' relational dimensions. In the reported data, a four-syndrome model, including positive, disorganization, negative, and relational dimensions, showed excellent fitness. Despite its limitations, this study suggests the need to explore the validity of a four-syndrome model. The positive-negative model fits poorly with the data. PMID- 7858070 TI - Varied psychiatric manifestations of acute intermittent porphyria. AB - Acute Intermittent Porphyria (AIP) is an autosomal dominant metabolic disorder that has various psychiatric manifestations. This is a report of a case who had six brief psychotic episodes of varying nature within a 2-month period. The psychotic manifestations included catatonic stupor, hypomania, and delirium in different episodes. The management aspects of the case have been highlighted. PMID- 7858069 TI - Temporal lobe abnormalities in multigenerational families with schizophrenia. AB - Brain structure in familial schizophrenia was studied with computerized tomography in 42 individuals from six multigenerational families. Sulcal enlargement in the lateral temporal cortex, and ventricular and cisternal enlargement in the medial temporal region were observed in psychotic individuals compared to unaffected family members. Genetic factors in familial schizophrenia may exert part of their effect through determining or altering temporal lobe structure. PMID- 7858071 TI - Effects of treatment with imipramine and clonazepam on an animal model of panic disorder. AB - Tonic GABAergic inhibition in the dorsomedial hypothalamus (DMH) has been shown to regulate a constellation of behavioral and physiological responses that resemble a human panic attack. The present study was aimed at testing if the panic-like response elicited by injecting gamma-aminobutyric acid (GABA) antagonists into the DMH can be blocked by pretreating the animals with the antipanic drugs, imipramine and clonazepam. Rats were fitted with arterial catheters and bilateral chronic microinjection cannulae in the DMH. Their baseline heart rate, respiratory rate, blood pressure and "anxiety" (measured by the social interaction test) responses to injection of the GABAA antagonist bicuculline methiodide (BMI) into the DMH were recorded. After treatment in a double-blind manner with vehicle, imipramine (5 and 15 mg/kg, 7 days), and clonazepam (5 mg/kg, 3 days), the response to BMI microinjection into the DMH was once again recorded. Both imipramine and clonazepam, but not vehicle treatments blocked the BMI response. PMID- 7858072 TI - Myoclonic seizures and "leg folding" phenomena with clozapine therapy: report of two cases. PMID- 7858073 TI - MDMA ("ecstasy") abuse: psychopathological features and craving for chocolate: a case series. PMID- 7858074 TI - Clozapine for polydipsia and hyponatremia in chronic schizophrenics. PMID- 7858075 TI - Effects of lithium on thyroid hormone metabolism in rat frontal cortex. PMID- 7858076 TI - Effects of tryptophan depletion in panic disorder. PMID- 7858078 TI - Further evidence for an association between electrodermal unresponsiveness and structural brain abnormalities. PMID- 7858077 TI - A comparison of the effects of imipramine and fluvoxamine on the thyroid axis. PMID- 7858079 TI - CYP2D6 genotype and possible susceptibility to the neuroleptic malignant syndrome. PMID- 7858080 TI - Candida and oral candidosis: a review. AB - Candida species are the most common fungal pathogens isolated from the oral cavity. Their oral existence both as a commensal and an opportunist pathogen has intrigued clinicians and scientists for many decades, and recent investigations have revealed many attributes of this fungus contributing to its pathogenicity. In addition, the advent of the human immunodeficiency virus infection and AIDS has resulted in a resurgence of oral Candida infections. Clinicians are witnessing not only classic forms of the diseases but also newer clinical variants such as erythematous candidosis, rarely described hithertofore. Therefore, this review is an attempt at detailing the current knowledge on Candida and oral candidoses together with the newer therapeutic regimes employed in treating these mycoses. PMID- 7858081 TI - HIV-related tumors of the oral cavity. AB - In HIV-infected patients with AIDS the most frequent malignancies are Kaposi's sarcoma and non-Hodgkin's lymphoma. In these patients, the natural history of these tumors is quite different from those of HIV-negative subjects. These tumors may present atypical clinical aspects, may be very aggressive, and the coexistence of immunosuppression and opportunistic infections may render their treatment more difficult. The aim of this article is to provide updated information on the epidemiology, pathogenesis, natural history, and management of tumors that develop in the oral cavity of patients with AIDS. PMID- 7858082 TI - Cell adhesion molecules in inflammation and immunity: relevance to periodontal diseases. AB - Inflammatory and immune responses involve close contact between different populations of cells. These adhesive interactions mediate migration of cells to sites of inflammation and the effector functions of cells within the lesions. Recently, there has been significant progress in understanding the molecular basis of these intercellular contacts. Blocking interactions between cell adhesion molecules and their ligands has successfully suppressed inflammatory reactions in a variety of animal models in vivo. The role of the host response in periodontal disease is receiving renewed attention, but little is known of the function of cell adhesion molecules in these diseases. In this review we summarize the structure, distribution, and function of cell adhesion molecules involved in inflammatory/immune responses. The current knowledge of the distribution of cell adhesion molecules is described and the potential for modulation of cell adhesion molecule function is discussed. PMID- 7858083 TI - [Sjogren's syndrome: a prevailing clinical concept]. PMID- 7858084 TI - [A pleuropulmonary tuberculosis study in a pneumology service]. AB - We reviewed the records of 125 patients admitted in our Service of Pneumology from January 1985 to December 1992, which were diagnosed of pleural or pulmonary tuberculosis. Several characteristics are described, with the following findings: 1) Higher incidence among men. 2) Relevant incidence among young people. 3) Frequent association with risk factors or concomitant diseases, mainly tobacco and alcohol consumption. 4) Delay in the diagnosis, probably due to the unspecific symptoms observed; fever, cough, constitutional syndrome. 5) The must frequent radiological findings were pleural leakage and cavitated infiltrations affecting the upper lobes. 6) Sputum microbiological exam still has a high diagnostic profitability. PMID- 7858085 TI - [The solitary pulmonary nodule. An analysis of the experience over 6 years in a medical service]. AB - We conducted a retrospective analysis of the epidemiological, etiological, clinical and radiological characteristics, and mainly of those related to the diagnosis and treatment, of all the patients with radiological criteria of solitary pulmonary nodule (SPN) studied in our environment during a period of six years (1984-1989). The incidence of SPN was 3.1% (123/3953). Among the 117 cases of filiated etiology, 83 (71%) were malignant and 34 (29%), benign thoracotomy was used as diagnostic method in 11 (32%) benign cases and in 8 (9.6%) malignant cases. Due to several causes, only 31 out of the 75 (41.3%) malignant nodules diagnosed prior to the thoracotomy underwent resection surgery. According to the selection criteria applied in our medium, a high number of the SPN were malignant; in most of these cases, the diagnosis was established without the need of thoracotomy and in less that half of them, curative surgery was attempted. PMID- 7858086 TI - [The length of stay in hospital emergency medical care]. AB - The length of stay in emergency services has been considered as a quality control and evaluation index of emergency care. The impact of several factors on its magnitude is analyzed. The age of the patient, the time of admission, the performance of complementary explorations (simple radiology, analytic tests, abdominal echography), as well as the disease group including the diagnosis of the emergency service, significantly modify the length of stay. The age and performance of such tests seem to be the most relevant factors, although they may not be independent. The length of stay of the patients in the emergency service may be shortened by reducing the complementary explorations just to the ones mentioned above. The adequacy of the functional organization, the material and human resources, as well as the adequate staff skills and attitudes, may also reduce the length of stay of these patients in the hospital emergency care. PMID- 7858087 TI - [An epidemiological study of alcohol consumption habits in La Foz de Morcin (Asturias)]. AB - OBJECTIVE: To determine the prevalence of alcoholism in a rural area of Asturias and the correlation between this disease and several disorders, symptoms and clinical signs, as well as personal and social factors. DESIGN: We conducted a cross-sectional descriptive study on a sample of 200 persons divided into two groups according to alcohol consumption, stating as limit for the classification of a person as hard-drinker, the consumption of 80 or more grams of ethanol/day in the case of men and 50 gr/day in the case of women, during at least 10 years. Through a specially designed survey and the data on physical explorations and blood biochemistry, the results in both groups were compared. RESULTS: The prevalence of alcoholism in the area under study was 19.5%, with domination of males (12/1) and a mean age of 47.4 +/- 12.8 years, this being globally greater than the national average. The most sensitive analytical parameters a indicators of hard alcohol consumption were Hct, Hb, TGO, TGP, FA, bilirubin and gamma-GT. The main physical signs observed among the hard-drinkers were: malar telangiectasias, parathyroid hypertrophy, conjunctival jaundice and hepatomegaly. There were no significant differences between both groups with respect to mean age, marital status or labour activity. A greater prevalence of depressive-type psychiatric problems were observed in the group of hard-drinkers. In this group, there was also a greater proportion of traumatic antecedents, judicial-type problems and accidents, as well as a greater work absenteeism. CONCLUSIONS: All these findings support the already known idea of the severity of the problem caused by excessive consumption of alcohol, both at the individual, public health and socio-economical level; as well as the usefulness of several hematological and hepatic biochemical parameters for its detection. The high prevalence of excessive alcohol consumption in this rural area of Asturias, its population being characterized by a great proportion of miners, has also been demonstrated. PMID- 7858088 TI - [Angioimmunoblastic lymphadenopathy. Apropos a case with unusual clinical manifestations and evolution to T-cell lymphoma]. AB - We present the case of a 67-years-old patient which, after treatment with ciprofloxacin, developed fever, exanthema, arthralgias, polyadenopathies, hepatosplenomegaly, autoimmune hemolytic anemia, hypergammaglobulinemia and severe inversion of the CD4/CD8 ratio. Latter, he developed ischemic signs in several locations (splenic and cerebral infarcts), as well as polyneuropathy and inflammatory myopathy. The diagnosis of angioimmunoblastic lymphadenopathy was established through ganglionary biopsy. The patient improved initially with the administration of corticoids, but in a few months, he developed pleomorphic T lymphoma with quick fatal evolution. We discuss the rarity of some of the clinical and laboratory manifestations in this patient and we comment on the association of ciprofloxacin and the angioimmunoblastic lymphadenopathy, which has never been previously described in the international literature. PMID- 7858089 TI - [The pseudothrombophlebitic syndrome: a new diagnostic approach]. AB - The clinical manifestation of popliteal or Baker's cysts, either intact or complicated due to rupture or dissection, can be a thrombophlebitis (pseudothrombophlebitis), greatly difficulting the differential diagnosis and the management of these patients, being their treatment completely different. The doppler echography is a reliable, quick and low-cost method which allow to differentiate between this two types of pathology and the magnetic resonance (MR) is the ideal technique to assess the complications of popliteal cysts. We present a case of pseudothrombophlebitis due to compression of the popliteal vein by a Baker's cyst. PMID- 7858090 TI - [Bronchiolitis obliterans organizing pneumonia: the usefulness of the transbronchial biopsy as a diagnostic technic]. AB - Bronchiolitis obliterans organizing pneumonia (BOOP) is a recently described entity characterized by cough, fever and dyspnea. To date, only a few cases have been published in the literature. Currently, the diagnosis is established by open lung biopsy. We hereby present a case of BOOP diagnosed through transbronchial biopsy (TBB); we discuss the potential benefits of the thoracic radiography and computerized tomography scan (CT scan). Finally, we underline that in our patient, the bronchoalveolar lavage fluid (BAL) restored to normal before the resolution of the radiological images. PMID- 7858091 TI - [Familial thyroid medullary carcinoma without associated neoplasms]. AB - Each of three patients with thyroid medullary carcinoma (TMC) presents the tumor as a family feature. Most of them have other associated endocrinous neoplasias. Through the study of baseline plasmatic calcitonin and after stimulus with calcium and pentagastrin, patients with silent TMC can be detected. We present the results of the study of a family including 70 members and with hereditary TMC, between 1988 and 1992. Six new cases of TMC were diagnosed starting from the case index. Their average age was 31.7 years. Five of them underwent surgery. None of them had other associated endocrinous neoplasias, which is extremely rare. In addition, we present data on the postoperative follow-up of the patients, two of which had high calcitonin and CEA levels. PMID- 7858092 TI - [Charcot-Marie-Tooth disease, dilated myocardiopathy and cardiac conduction disorders]. AB - We describe the case of two brothers with Charcot-Marie-Tooth disease, dilated cardiomyopathy and disorders in the cardiac conduction. We review the literature in order to find physiological grounds for these associations. Despite the absence of consolidated data on this question, the genetic grounds could play some role here. In this sense, our cases contribute with the novelty that the disease affects two brothers. This has never been described before and could contribute, along with future observations, to clarify some etiopathogenic aspects of the disease. PMID- 7858093 TI - [Selenium: the physiopathological and clinical implications]. AB - Selenium is an ultra-trace element widely distributed in the environment, although its consumption varies significantly depending on the region. Its daily requirements range between 50 and 200 micrograms/day (or a minimum of 1 microgram/kg/day), which are supplied by animal and vegetal foods. Its essentiality in human nutrition is derived from its antioxidative action, being a part of the glutation-peroxidase system (GPx). Thus, it is a protective agent against the harmful action of free radicals. Determination of the selenium dependent GPx activity seems to be the best index for the assessment of nutritional status. A deficit of selenium will result in a decrease of the GPx activity and, therefore, in a increase of cell damage which cannot be counter balanced by other antioxidative systems. Diet has a relevant role for the maintenance of selenium status. Deficiency conditions may appear in different population groups when the selenium content in the diet is inadequate. Toxicity states are rare, but some diseases are sensitive to this element, which is mainly involved in cancer prevention. PMID- 7858094 TI - [A splenic abscess due to Salmonella enteritidis in a neutropenic patient treated with percutaneous drainage and antibiotic therapy]. PMID- 7858095 TI - [Splenic hematoma as a complication of infectious mononucleosis. A favorable evolution with a conservative approach]. PMID- 7858096 TI - [The indicators of health care activities in an internal medicine service. The importance of this type of analysis]. PMID- 7858097 TI - [Primary hyperparathyroidism in adolescence]. PMID- 7858098 TI - [Deep venous thrombosis of the upper limb in IVDA patients with HIV infection: a report of 3 cases]. PMID- 7858099 TI - [Noonan's syndrome and aortic coarctation]. PMID- 7858100 TI - Prolactin modulates the incidence of diabetes in male and female NOD mice. AB - The nonobese diabetic (NOD) mouse develops diabetes spontaneously due to autoimmune destruction of the pancreatic islets with a higher incidence in the female than the male. Prolactin (PRL), a hormone whose role has been previously focused on reproduction and lactation has been demonstrated to influence immune responses. In this study, we investigated the effect of hypoprolactinemia and hyperprolactinemia on the incidence of diabetes in male and female NOD mice. Our hypoprolactinemia model was induced from the time of weaning (21 days of age) to 112 days of age by daily injections of 200 micrograms of bromocriptine (CB-154). A hyperprolactinemic model was induced by a syngeneic anterior pituitary transplant (APT) to the kidney capsule at 35 days of age and maintained until 112 days of age. Additional experimental groups were also investigated. A group of males received pituitary transplants combined with daily subcutaneous injections of CB-154. A group of females treated with CB-154 was also given daily subcutaneous injections of 30 micrograms of oPRL. An ovariectomized (OVX-Control) group of females was also established to serve as a second control for the OVX APT group. Bromocriptine administration did not significantly decrease plasma PRL levels compared to controls (CTRL) while APT animals had plasma PRL levels that were significantly higher (P < 0.01) than those of CTRL and CB-154 animals. These differences were observed in animals of both sexes. Bromocriptine treatment of APT groups significantly lowered plasma PRL levels from their respective controls. Plasma PRL from the OVX-Control group was markedly lower than the intact female control. The incidence of diabetes was significantly lower in female mice receiving CB-154 injections compared to the intact female CTRL group at 84, 98 and 112 days of age.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7858101 TI - Endogenous TNF production differs between high and low diabetes incidence non obese diabetic (NOD) mice. AB - Tumour necrosis factor (TNF) has been implicated in the pathogenesis of insulin dependent diabetes mellitus (IDDM). To investigate a possible role for TNF in IDDM we compared endogenous TNF production in two lines of non-obese diabetic (NOD) mice, NOD/Lt and NOD/WEHI, that have a high and low incidence of diabetes, respectively. Preliminary experiments had shown that the lower syngeneic mixed lymphocyte reaction (SMLR) in NOD/Lt mice could be corrected by TNF-alpha. Plasma TNF-alpha was measured in 8 week-old female non-diabetic mice primed with 1000 units IV of murine interferon gamma (IFN-gamma) followed after 3 hours by 5 micrograms IV of lipopolysaccharide (LPS). Two hours later plasma was collected and TNF measured by ELISA. Plasma TNF in NOD/Lt mice was 9.2 +/- 2.4 ng/ml (mean +/- SEM, n = 16) compared to 2.5 +/- 0.5 ng/ml in NOD/WEHI mice (n = 15) and 7.6 +/- 1.0 ng/ml in BALB/c mice (n = 14). Time course studies demonstrated higher levels of both immunoreactive and bioactive TNF in NOD/Lt compared to NOD/WEHI mice up to 4 hours post-stimulation. A separate group of female NOD/Lt mice had IFN-gamma/LPS-stimulated plasma TNF-alpha measured at 10 weeks and were followed to age 30 weeks. The mean stimulated plasma TNF-alpha level was consistently higher in those mice that developed diabetes compared to those that remained non diabetic, the difference being significant when mice were 21 weeks of age. These results suggest that endogenous TNF-alpha production may be a trait marker of IDDM susceptibility. PMID- 7858103 TI - Exacerbation of collagen-induced arthritis in rats by rat cytomegalovirus is antigen-specific. AB - Collagen-Induced Arthritis (CIA) is an experimentally induced and genetically controlled animal model of chronic joint inflammation. In rats, there are informative strain differences in susceptibility to CIA. DA rats (RT1avl) develop severe CIA after immunization with bovine (BII), chick (CII), or homologous rat (RII) type II collagens. In contrast, the MHC-congenic DA. 1N(BN) and WF.1N(BN) rats (RT1n) are relatively resistant to CIA and develop moderate CIA in response to immunization with CII but not BII or RII. We previously found that simultaneous infection with rat cytomegalovirus (RCMV) greatly exacerbates the severity of arthritis that develops in BII-immunized DA rats. To examine the mechanism of RCMV amplification of CIA, the effect of simultaneous infection with RCMV on arthritis and autoimmunity to type II collagen was determined in WF.1N and DA.1N rats after immunization with BII, CII and RII. RCMV increased the incidence of CIA and the level of autoimmunity to type II collagen (skin-testing and IgG antibody titer) selectively in DA.1N and WF.1N rats immunized with CII, but not in littermates immunized with BII, although the transient reversal of CD4+/CD8+ mononuclear cell ratios in peripheral blood that is associated with RCMV infection occurred equally in both BII- and CII- immunized DA.1N rats. Likewise, RCMV infection moderately increased the levels of anti-RII autoimmunity and arthritis in DA rats sub-optimally immunized with RII but had no consistent effect on either anti-RII immunity or arthritis in RII-immunized DA.1N and WF.1n rats. The data show that RCMV augments arthritis only in rats that are genetically susceptible to CIA and that are appropriately immunized with a species of type II collagen that is arthritogenic for the MHC-haplotype being tested. Two possible mechanisms are suggested by these data: RCMV-associated increases in anti-RII autoimmunity in rats with CIA may result from amino acid sequence homologies between RCMV and type II collagen; alternatively, virus induced pro-inflammatory cytokines may activate RII-reactive lymphocytes thereby potentiating autoimmunity and arthritis. PMID- 7858102 TI - The study of anticardiolipin antibodies and interleukin-6 in cerebrospinal fluid and blood of Chinese patients with systemic lupus erythematosus and central nervous system involvement. AB - Anticardiolipin (ACL) antibodies and interleukin-6 (IL-6) in cerebrospinal fluid (CSF) may be involved in the mechanism of lupus patients with central nervous system (CNS) involvement. ACL antibodies of 3 isotypes and IL-6 were measured in paired CSF and serum samples from 14 lupus patients with CNS involvement, 5 lupus patients without CNS involvement and 7 patients with non-inflammatory neurological diseases. ACL antibodies, IgG and IgM isotypes, and IL-6 were significantly increased in CSF from lupus patients with CNS involvement as compared with other 2 groups of patients. Both ACL antibodies and IL-6 decreased after neurological activity subsided. These results suggest increased ACL antibodies and IL-6 in CSF are involved in immune responses within CNS in lupus patients. Quantitation of CSF ACL antibodies may be helpful in evaluating neurological activity of lupus patients with CNS involvement. PMID- 7858104 TI - Additive susceptibility to insulin-dependent diabetes conferred by HLA-DQB1 and insulin genes. AB - Several genomic polymorphisms at the insulin (INS) gene and its flanking regions were analyzed in 197 unrelated Caucasian patients affected by insulin-dependent diabetes (IDDM) and 159 ethnically matched, normal controls ascertained from the South-Eastern United States. We found that the frequency of homozygotes for the common variant at the insulin gene was significantly increased in the diabetic population (RR = 2.0, p < 0.005). However, the polymorphisms in the 5' and 3' regions flanking the INS were not significantly associated with IDDM. These results suggest that the IDDM susceptibility locus on chromosome 11p is located within the region extending from the 5' VNTR to the 3' end of the INS gene. We determined the HLA-DQB1 genotypes by denaturing gradient gel electrophoresis (DGGE) and/or sequence-specific primers (SSP) techniques to assess the possible interactions between INS and HLA. DQB1*0302 had the strongest predisposing effect on IDDM susceptibility (RR = 9.3) and DQB1*0602 the strongest protective effect (RR = 0.02). However, a significant predisposing effect of DQB1*0201 could be demonstrated only after removal of the effects of DQB1*0302 and DQB1*0602. Analyses of the genotypes revealed that all genotypes containing 0602 were protective and that the heterozygous genotype 0201/0302 and homozygous genotype 0302/0302 confer the highest risk (RR = 20.9 and 12.9 respectively). However, heterozygous genotypes 0302/X (X excludes 0201, 0302 and 0602) have a significantly lower predisposing risk. Similarly, there is heterogeneity in risk between predisposing 0201/0201 homozygous individuals and protective 0201/X individuals. When subjects were stratified by HLA genotypes, the relative risks conferred by INS did not vary, thus suggesting that the susceptibility effects conferred by HLA and INS are additive rather than interactive. PMID- 7858105 TI - Anti-nuclear, anti-neutrophil cytoplasmic and anti-glomerular basement membrane antibodies in HIV-infected individuals. AB - Many autoantibodies have been described in HIV-infected individuals. We have examined the incidence, associations and prognostic significance of anti-nuclear antibodies (ANA), anti-neutrophil cytoplasmic antibodies (ANCA) and anti glomerular basement membrane (GBM) antibodies in individuals with HIV infections. One hundred and five patients, with asymptomatic infections (n = 37), AIDS related complex (n = 32) or AIDS (n = 36) were studied. Plasma from 24 of these (23%) were positive for ANA: most demonstrated speckled fluorescence (n = 21) and were of low titre (1+ in 18). ANCA were demonstrated by IIF in 18 individuals (17%) and all fluorescent patterns were seen; 6 of these plasma were also positive in the ELISAs for antibodies to proteinase 3, myeloperoxidase or elastase. Thirteen plasma were positive for ANCA in the neutrophil cytoplasm ELISA; 10 of these were also positive in the specific ELISAs. A total of 30 plasma bound to proteinase 3, myeloperoxidase or elastase in specific ELISAs, in 6 cases with 2 specificities. Finally, 18 plasma (17%) contained anti-GBM antibodies by ELISA, but none of 4 plasma tested in inhibition assays was specific. ANA, ANCA and anti-GBM antibodies were not uncommon in HIV-infected individuals but the presence of these antibodies was not associated with the clinical manifestations of the corresponding autoimmune diseases. In addition, there was no correlation between the demonstration of these antibodies and the immunological status of the individual (apart from a correlation between CD4 counts less than 400/microliters with anti-GBM antibodies), the presence of an opportunistic infection, the development of malignancy or reduced survival. Some of these antibodies may arise from polyclonal activation, or be due to "sticky" serum since we have shown that the presence of anti-GBM antibodies correlated with the demonstration of ANCA by ELISA. These antibodies are not more common in hypergammaglobulinemic plasma but some may be due to heat-treatment of the plasma. The clinician caring for HIV-infected individuals needs to be aware of these "false-positive" antibody results. PMID- 7858106 TI - High prevalence of thyroid autoimmunity in idiopathic Addison's disease. AB - We have determined the incidence of autoimmune thyroid disorders in patients with Addison's disease. The material comprised 212 patients, 128 women and 84 men, aged 9-74 years. In 58 patients tuberculosis and in six patients other adrenal disorders were diagnosed. In the remaining 148 patients the auto-immune mechanism was the most probable cause of adrenocrotical insufficiency. In order to evaluate the thyroid abnormalities seen in patients with Addison's disease the T3, T4 (RIA), TSH (ELISA) and anti-thyroid autoantibodies were determined apart from routine clinical examination. Antimicrosomal, anti-thyroglobulin and anti thyroperoxidase antibodies were measured in 91, 188 and 81 cases respectively. Thyrotoxicosis was diagnosed in 17 and primary hypothyroidism in 18 cases. Moreover, eight patients had evidence of subclinical hypothyroidism. The anti thyroglobulin antibodies with titer ranging from 1:80 to 1:10,000 were detected in 66 patients, whereas antimicrosomal antibodies were found in 51 patients at a titer ranging from 1:80 to 1:9720. Autoantibodies against thyroid peroxidase were found in sera of 67 patients, with titer ranging from 1:2000 to 1:25,6000. PMID- 7858107 TI - Relationship between antigens and IgG subclasses in bullous pemphigoid. AB - Bullous pemphigoid (BP) is an autoimmune blistering disease characterized in part by the presence of tissue-bound and circulating antibodies (mostly of IgG) to the basement membrane zone (BMZ). We previously reported that IgG subclasses of BP antibodies were IgG1, IgG2 and IgG4, and that only BP IgG1 fixed complements. In this study, we examined whether BP IgG sub-classes bound to the same epitope of BP antigen or a different epitope. In an inhibition immunofluorescence studies, the complement fixing capability of IgG1 was inhibited by the pretreatment with IgG4 and partially inhibited by IgG2. On immunoblot analysis, IgG1 and IgG4 were bound to the same MW of BP antigen. In enzyme-linked immunosorbent assay (ELISA), the binding capability of IgG subclass fractions from patients with BP to synthetic peptide P1-2, exceeding normal IgG subclass fractions was seen in five IgG1, one IgG2 and two IgG4, from eight BP patients. The binding capability of IgG subclass fractions from the patients with BP to P1-1, exceeding the normal IgG fractions was seen in two IgG1, three IgG2 and one IgG4 from ten BP patients. On inhibition ELISA, the binding activity to P1-2 of IgG4 was partially inhibited by the pretreatment of IgG1 and IgG2. These findings suggest that BP IgG1, IgG2 and IgG4 could bind to the same epitope though considerable variation occurred between patients. PMID- 7858108 TI - Influence of K+ channel openers on interferon-gamma dependent immune response in experimental allergic neuritis (EAN). AB - We examined the influence of the K+ channel opening drugs BRL 38227, pinacidil and diazoxide on cellular immune response and clinical course of experimental allergic neuritis (EAN) actively induced in Lewis rats by bovine peripheral myelin (BPM). T cell functions of EAN lymph node cells were assessed by measurement of proliferation and by counting of interferon-gamma secreting cells (IFN-gamma sc) in response to the specific antigen BPM and the T cell mitogen phytohemagglutinin (PHA). BRL 38227 and diazoxide at concentrations of 10(-5)M 10(-6)M and pinacidil at concentrations of 10(-5)M-10(-7)M enhanced the proliferative response to both BPM and PHA. The number of IFN-gamma sc was suppressed by the K+ channel openers in the same concentration range. There was a tendency of stronger suppression of cultures with high numbers of BPM-reactive IFN-gamma sc than of cultures with low numbers of BPM-reactive IFN-gamma sc. The applied K+ channel openers are primarily acting on ATP-sensitive K+ channels, which have not been found in T cells so far. The drugs may, therefore, exert non selective effects on conventional voltage- and/or Ca(++)-dependent channels of T cells. A first trial with in vivo administration of 2.5 mg/kg x day of the drugs resulted in more severe neurological deficits in the early phase of EAN with BRL 38227, whereas pinacidil and diazoxide had no significant effects. PMID- 7858109 TI - Polymorphism in the human complement C4 genes and genetic susceptibility to autoimmune hepatitis. AB - Susceptibility to autoimmune hepatitis is associated with the HLA-DR3 and DR4 haplotypes, but which genes are directly involved in the pathogenesis, has not been established. Low levels of complement component C4 and elevated frequencies of C4 null allotypes have been described in patients, suggesting that the C4 genes, which are closely linked with the HLA loci, may play a role. We therefore examined restriction fragment length polymorphisms in the C4 and 21-hydroxylase genes, and determined HLA-A and B phenotypes, and HLA-DR, DQ and DP genotypes in a large series of Caucasoid patients with autoimmune hepatitis and matched controls. A DNA deletion of the C4A gene and the 21-hydroxylase A pseudogene was found to be present in 50% of patients compared to 23% of controls (Pc < 0.005, relative risk = 3.3). This increase, however, appears to be due to linkage disequilibrium with HLA-DR52a which was most strongly associated with the disease. Complete C4A deficiency, determined by homozygosity for the deletion increased the risk to 18.1 (16% versus 1%, Pc < 0.005), suggesting an additional role for C4 in disease susceptibility. C4 deletions were associated with an increased mortality and tendency to relapse whilst on treatment but did not correlate with age of onset of disease. Our data suggest that MHC-encoded susceptibility to autoimmune hepatitis is polygenic, involving the HLA-DR genes plus other loci, and C4 deficiency may be a marker of disease susceptibility and/or severity. PMID- 7858110 TI - Expression of rheumatoid factor idiotypes 17.109, 6B6.6 and 4C9 in the sera of Pima Indians. AB - This study was undertaken to determine whether the expression of 17.109, 6B6.6 and 4C9 rheumatoid factor (RF) idiotypes is predictive of the development of rheumatoid arthritis (RA) and whether the RF response is idiotypically restricted in an inbred population of Pima Indians who have a genetic predisposition for the disease. Serial sera were obtained from 25 subjects who developed RA and 25 RF positive subjects who did not develop RA over the course of a longitudinal community health survey. RF titers and titers of the RF-associated idiotypes 17.109, 6B6.6 and 4C9 were determined by ELISA, and the relationship between 6B6.6 and 4C9 was analyzed by cross-absorption studies. Expression of the three RF-associated idiotypes was found in both the subjects who developed RA and those who did not. The amount of idiotype expressed was variable, but a few subjects in both groups had high levels indicative of an oligoclonal RF response. Reactivity with 6B6.6 and 4C9 antiidiotypes overlapped, with 4C9 appearing to mark a broader spectrum of RF than 6B6.6. Thus, even in an inbred and genetically predisposed population, the RF-associated antiidiotypes studied here did not identify a dominant idiotypic response and were no better markers for the development of RA than was RF itself. PMID- 7858111 TI - The target antigen of anti-tubular basement membrane antibody-mediated interstitial nephritis. AB - Our previous studies showed that 54 kD and 48 kD tubular basement membrane (TBM) proteins were the major form of the target antigen involved in anti-TBM antibody mediated tubulo-interstitial nephritis in humans. In those studies, we isolated the 54 kD glycoprotein (named gp54) from collagenase-digested bovine TBM. NH2 terminal amino acid sequencing indicated that gp54 represented a newly defined glycoprotein. In this study, we further characterized the target antigen, using mouse monoclonal antibodies to gp54 and polyclonal anti-gp54 peptide antibody. Two monoclonal antibodies (H79 and H80) were established, and they reacted, by immunofluorescence, predominantly with the proximal TBM of humans, rabbits, and Wistar, Sprague-Dawley, and Brown-Norway rats, but not with that of Lewis rats. They were also fixed by blotting intensely to the 54 kD component and weakly to the 48 kD component of collagenase-digested human TBM. In vivo transfer of H79 to Wistar rats showed extensive linear binding of mouse IgG to the TBM and the basal membrane of the small intestine; however, no pathologic changes were seen by light microscopy. The anti-gp54 peptide antibody reacted with both the 54 kD and 48 kD TBM components of human TBM. mRNA was prepared from rabbit kidneys, and fractionated to enrich mRNA encoding the 54 kD and 48 kD peptides. On in vitro translation experiments with the mRNA fraction, the 54 kD and 48 kD peptides were immunoprecipitated with anti-gp54 antibodies. These findings indicate that the 54 kD and 48 kD components are encoded with different mRNA, but that they share the same antigenic epitope.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7858112 TI - Marked gamma delta T-cell decrease in peripheral blood of patients with primary biliary cirrhosis (PBC). AB - PBC is a cholestatic liver disease of unknown etiology with autoimmune features that is often associated with other autoimmune diseases. We analyzed peripheral blood T-cell subsets in patients groups with PBC (n = 11), non-PBC hepatobiliary disease (n = 11) and an age and sex matched control group (n = 11) by two color FACS-analysis. Seven out of eleven PBC patients exhibited markedly lowered and nearly undetectable levels of gamma delta T-cells (< 0.8%). None of the individuals in the non-PBC hepatobiliary disease (HBD) group or the normal control group had gamma delta values below 1%. The other four individuals in the PBC group had gamma delta values within the normal range. Overall, the PBC group had a statistically significant, lowered mean percentage of gamma delta T-cells (1.50%) as compared to the hepatobiliary disease group (3.76%) and the control group (4.22%, p = 0.01). The percentages of CD4+ and CD8+ and alpha beta TCR+ CD4 CD8- double negative cells in PBC patients did not differ from the control group. PBC patients with normal gamma delta cell counts did not differ from the PBC group with low gamma delta values in autoantibody titers, liver tests or treatment of the disease. As a possible cause for the observed decrease of gamma delta T-cells three sera of PBC patients with low gamma delta T-cell counts were screened by single color, indirect immunofluorescence for antibodies to gamma delta T-cell enriched lymphocytes, but no differences to control sera were observed.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7858113 TI - Tumor necrosis factor-alpha alters the metabolism of endothelial cell proteoglycans. AB - Cytokines play an important role in modulating cellular function. The effect of tumor necrosis factor alpha (TNF-alpha) on the metabolism of proteoglycans (PGs) was studied in mouse aortic endothelial cells (MAE). Confluent and exponentially growing cells were labeled with [35S] sulfate and [3H] glycine, and PGs isolated from the secreted, the pericellular, and intracellular pools. TNF-alpha influenced the metabolism of MAE PGs. This effect of TNF-alpha was dependent on the growth state of the cells. Nondividing MAE secrete PGs that have higher net negative charge than PGs from exponentially growing cells. TNF-alpha treatment further increased the net negative charge of PGs secreted from nondividing cells. Treatment of MAE with TNF-alpha caused a substantial decrease in the sulfation of PGs isolated from pericellular pool of nondividing cells, while it had the opposite effect on pericellular PGs isolated from dividing cells. Our results indicate that changes in PGs metabolism induced by TNF-alpha may contribute to the disturbance of vascular endothelial homeostasis associated with vascular injury in a variety of disease states. PMID- 7858114 TI - Nitric oxide and pancreatic beta-cell destruction in insulin dependent diabetes mellitus: don't take NO for an answer. AB - A major surge of interest has recently focused upon nitric oxide (NO) as a mediator of autoimmune destruction of beta-cells in insulin-dependent diabetes mellitus (IDDM). It has been proposed that insulin producing cells in response to cytokines are induced to produce self destructing amounts of NO, and that endothelial cells or islet infiltrating macrophages may induce beta-cell death by releasing cytotoxic levels of NO within the islet. Recent findings in this field are presently discussed and we conclude that although NO might have a role in rodent IDDM, any putative role of NO in the pathogenesis of human IDDM remains to be clarified. PMID- 7858115 TI - Cell cycle-associated autoantibodies: markers for autoimmunity and probes for molecular cell biology. AB - Antinuclear autoantibodies are useful diagnostic markers for systemic autoimmune diseases and as probes for the molecular cell biology of nuclear proteins. Here, we review a subset of autoantibodies to nuclear and cytoplasmic proteins involved in the cell cycle. We propose a classification of these autoantibodies into S phase (DNA Synthesis) and M-phase (Mitosis) autoantibodies. S-phase autoantibodies are represented by autoantibodies to PCNA (Proliferating Cell Nuclear Antigen), the auxiliary protein of DNA polymerase delta. M-phase autoantibodies are represented by autoantibodies to mitotic spindle components viz. centrosomes, condensed chromosomes, centromeres, mitotic spindle proper and intercellular bridge. We have included autoantibodies to nuclear lamins as M phase autoantibodies as lamins play a key role in reversible breakdown and reformation of nuclear membranes during mitosis. The usefulness of these autoantibodies as diagnostic markers in systemic autoimmune disease is tempered by their presence in patients with "atypical" autoimmune diseases and in normal individuals. However, as molecular probes, they have proven to be unique and invaluable tools for shedding new light on the workings of the cell cycle. PMID- 7858116 TI - Human Th1 and Th2 cells: functional properties, regulation of development and role in autoimmunity. AB - Evidence has accumulated suggesting the existence in humans of polarized T helper (Th) cell subsets, coded as Th1 and Th2, with defined cytokine secretion profiles. Immune responses to intracellular bacteria and viruses result in the preferential development of the Th1 cell subset. Th1 cells express cytolytic activity against antigen-presenting cells and provide helper function for IgM, IgG and IgA synthesis only at low T/B cell ratios. In contrast, Th2 cells develop in response to allergens or helminth antigens, provide help for all immunoglobulin classes, including IgE, and lack cytolytic potential. The cytokine milieu in the microenvironment plays a fundamental role in determining the functional phenotype of the subsequent antigen-specific Th1 or Th2 responses. In recent years it has become clear that Th1 and Th2 cells play different roles not only in protection against exogenous offending agents, but also immunopathology. Th2 cells are involved in immunopathology induced by helminths and are responsible for the initiation and maintenance of allergic disorders. Th1 cells seem to be involved in contact dermatitis, acute allograft rejection and organ specific autoimmunity, such as thyroid autoimmune disorders, diabetes mellitus or multiple sclerosis, whereas less polarized patterns of Th cells are detectable in target organs of patients with rheumatoid arthritis. Sjogren's syndrome or systemic lupus erythematosus. PMID- 7858117 TI - New dimensions in two dimensions. PMID- 7858118 TI - Microhydrodynamics simulation of protein crystallization. I. Static calculations. AB - A computer simulation method is proposed to study the effects of hydrodynamic interactions on protein crystallization. It is a combination of Stokesian dynamics and continuum hydrodynamics and is referred to as "microhydrodynamics." The method is checked against analytical expressions for Stokes drag and diffusion coefficients for unit spheres. For a number of protein molecules the diffusion coefficients have been calculated and compared with experimental values. It is shown that the method works well for stationary calculations. Using dynamical calculations interacting protein molecules will be simulated to study the events in the early stages of protein crystallization. PMID- 7858119 TI - The relation between ion permeation and recovery from inactivation of ShakerB K+ channels. AB - We have studied the relation between permeation and recovery from N-type or ball and-chain inactivation of ShakerB K channels. The channels were expressed in the insect cell line Sf9, by infection with a recombinant baculovirus, and studied under whole cell patch clamp. Recovery from inactivation occurs in two phases. The faster of the two lasts for approximately 200 ms and is followed by a slow phase that may require seconds for completion. The fast phase is enhanced by both permeant ions (K+, Rb+) and by the blocking ion Cs+, whereas the impermeant ions (Na+, Tris+, choline+) are ineffective. The relative potencies are K+ > Rb+ > Cs+ > NH4+ >> Na+ approximately choline+ approximately Tris+. Ion permeation through the channels is not essential for recovery. The results suggest that cations influence the fast phase of recovery by binding in a site with an electrical distance greater than 0.5. Recovery from fast inactivation is voltage-dependent. With Na+, choline+, or Tris+ outside, about 15% of the channels recover in the fast phase (-80 mV), and the other 85% apparently enter a second inactivated state from which recovery is very slow. Recovery in this phase is not influenced by external ions, but is speeded by hyperpolarization. PMID- 7858120 TI - Attempts to define functional domains of gap junction proteins with synthetic peptides. AB - To map the binding sites involved in channel formation, synthetic peptides representing sequences of connexin 32 were tested for their ability to inhibit cell-cell channel formation. Both large peptides representing most of the two presumed extracellular loops of connexin32 and shorter peptides representing subsets of these larger peptides were found to inhibit cell-cell channel formation. The properties of the peptide inhibition suggested that the binding site is complex, involving several segments of both extracellular loops. One of the peptides (a 12-mer) did not inhibit but instead was found to form channels in membranes. Both in oocyte membranes and in bilayers, the channels formed by the peptide were asymmetrically voltage dependent. Their unit conductances ranged from 20 to 160 pS. These data are discussed in the form of a model in which the connexin sequence represented by the peptide is part of a beta structure providing the lining of the channel pore. PMID- 7858122 TI - Charged tetracaine as an inactivation enhancer in batrachotoxin-modified Na+ channels. AB - Two distinct types of local anesthetics (LAs) have previously been found to block batrachotoxin (BTX)-modified Na+ channels: type 1 LAs such as cocaine and bupivacaine interact preferentially with open channels, whereas type 2 LAs, such as benzocaine and tricaine, with inactivated channels. Herein, we describe our studies of a third type of LA, represented by tetracaine as a dual blocker that binds strongly with closed channels but also binds to a lesser extent with open channels when the membrane is depolarized. Enhanced inactivation of BTX-modified Na+ channels by tetracaine was determined by steady-state inactivation measurement and by the dose-response curve. The 50% inhibitory concentration (IC50) was estimated to be 5.2 microM at -70 mV, where steady-state inactivation was maximal, with a Hill coefficient of 0.98 suggesting that one tetracaine molecule binds with one inactivated channel. Tetracaine also interacted efficiently with Na+ channels when the membrane was depolarized; the IC50 was estimated to be 39.5 microM at +50 mV with a Hill coefficient of 0.94. Unexpectedly, charged tetracaine was found to be the primary active form in the blocking of inactivated channels. In addition, external Na+ ions appeared to antagonize the tetracaine block of inactivated channels. Consistent with these results, N-butyl tetracaine quaternary ammonium, a permanently charged tetracaine derivative, remained a strong inactivation enhancer. Another derivative of tetracaine, 2-(di-methylamino) ethyl benzoate, which lacked a 4-butylamino functional group on the phenyl ring, elicited block that was approximately 100 fold weaker than that of tetracaine. We surmise that 1) the binding site for inactivation enhancers is within the Na+ permeation pathway, 2) external Na+ ions antagonize the block of inactivation enhancers by electrostatic repulsion, 3) the 4-butylamino functional group on the phenyl ring is critical for block and for the enhancement of inactivation, and 4) there are probably overlapping binding sites for both inactivation enhancers and open-channel blockers within the Na+ pore. PMID- 7858123 TI - Membrane stress increases cation permeability in red cells. AB - The human red cell is known to increase its cation permeability when deformed by mechanical forces. Light-scattering measurements were used to quantitate the cell deformation, as ellipticity under shear. Permeability to sodium and potassium was not proportional to the cell deformation. An ellipticity of 0.75 was required to increase the permeability of the membrane to cations, and flux thereafter increased rapidly as the limits of cell extension were reached. Induction of membrane curvature by chemical agents also did not increase cation permeability. These results indicate that membrane deformation per se does not increase permeability, and that membrane tension is the effector for increased cation permeability. This may be relevant to some cation permeabilities observed by patch clamping. PMID- 7858121 TI - Phosphorylation modulates the function of the calcium release channel of sarcoplasmic reticulum from skeletal muscle. AB - The modulation of the calcium release channel (CRC) by protein kinases and phosphatases was studied. For this purpose, we have developed a microsyringe applicator to achieve sequential and multiple treatments with highly purified kinases and phosphatases applied directly at the bilayer surface. Terminal cisternae vesicles of sarcoplasmic reticulum from rabbit fast twitch skeletal muscle were fused to planar lipid bilayers, and single-channel currents were measured at zero holding potential, at 0.15 microM free Ca2+, +/- 0.5 mM ATP and +/- 2.6 mM free Mg2+. Sequential dephosphorylation and rephosphorylation rendered the CRC sensitive and insensitive to block by Mg2+, respectively. Channel recovery from Mg2+ block was obtained by exogenous protein kinase A (PKA) or by Ca2+/calmodulin-dependent protein kinase II (CalPK II). Somewhat different characteristics were observed with the two kinases, suggesting two different states of phosphorylation. Channel block by Mg2+ was restored by dephosphorylation using protein phosphatase 1 (PPT1). Before application of protein kinases or phosphatases, channels were found to be "dephosphorylated" (inactive) in 60% and "phosphorylated" (active) in 40% of 51 single-channel experiments based on the criterion of sensitivity to block by Mg2+. Thus, these two states were interconvertable by treatment with exogenously added protein kinases and phosphatases. Endogenous Ca2+/calmodulin-dependent protein kinase (end CalPK) had an opposite action to exogenous CalPK II. Previously, dephosphorylated channels using PPT (Mg2+ absent) were blocked in the closed state by action of endogenous CalPK. This block was removed to normal activity by the action of either PPT or by exogenous CalPK II. Our findings are consistent with a physiological role for phosphorylation/dephosphorylation in the modulation of the calcium release channel of sarcoplasmic reticulum from skeletal muscle. A corollary of our studies is that only the phosphorylated channel is active under physiological conditions (mM Mg2+). Our studies suggest that phosphorylation can be at more than one site and, depending on the site, can have different functional consequences on the CRC. PMID- 7858124 TI - Hydration force parameters of phosphatidylcholine lipid bilayers as determined from 2H-NMR studies of deuterated water. AB - The continuous decrease of the quadrupolar splitting of deuterated water interacting with phosphocholine lipid bilayers with growing water concentration is analyzed as a function of the water activity. From the apparent linear dependence on water activity a measure for hydration forces is obtained. The forces calculated are in the range of published data using sorption isotherms and osmotic stress technique in combination with SAXS. A simple interaction potential which includes orientational order of water adsorbed on surfaces gives a physical base for these findings. Therefore, deuterium NMR may become a powerful tool for hydration force analysis complementing well-known methods. PMID- 7858125 TI - Alcohol induction of interdigitation in distearoylphosphatidylcholine: fluorescence studies of alcohol chain length requirements. AB - Although it is now well established that the fully interdigitated phase is induced in saturated like-chain phosphatidylcholines (PCs) by a variety of amphipathic molecules including alcohols, no systematic study of the properties of the inducing molecules has been reported. To elucidate the stereochemical features that lead to the alcohol induction of interdigitation in PCs, we have investigated the induction of interdigitation in distearoylphosphatidylcholine (DSPC) by a series of alcohols. Our previously established DPH (1,6-diphenyl 1,3,5-hexatriene) fluorescence intensity method has been expanded (P. Nambi, E. S. Rowe, and T. M. McIntosh (1988), Biochemistry 27:9175-9182) and used to determine which of the alcohols induce interdigitation and to determine the threshold concentrations for each. We have found that each of the n-alcohols up to heptanol and several branched alcohols are capable of inducing interdigitation in DSPC; octanol and nonanol do not appear to induce interdigitation by these criteria. The threshold concentrations for interdigitation for each of these alcohols up to heptanol were found to be correlated with the membrane: buffer partition coefficients. The mole fraction of bound alcohol at the threshold concentration was similar for each of the alcohols up to pentanol. These results are discussed in terms of a general mechanism of the formation of the interdigitated phase. PMID- 7858126 TI - Surface shape change during fusion of erythrocyte membranes is sensitive to membrane skeleton agents. AB - We previously reported that the induction of membrane fusion between pairs of erythrocyte ghosts is accompanied by the formation of a multipore fusion zone that undergoes an area expansion with condition-dependent characteristics. These characteristics allowed us to hypothesize substantial, if not major, involvement of the spectrin-based membrane skeleton in controlling this expansion. It was also found that the fusion zone, which first appears in phase optics as a flat diaphragm, has a lifetime that is also highly condition-dependent. We report here that 2,3-diphosphoglycerate, wheat germ agglutinin, diamide, and N ethylmaleimide, all known to have binding sites primarily on skeleton components (including spectrin), have condition-dependent effects on specific components of the fusion zone diameter versus time expansion curve and the flat diaphragm lifetime. We also report a pH/ionic strength condition that causes a dramatic stabilization of flat diaphragms in a manner consistent with the known pH/ionic strength dependence of the spectrin calorimetric transition, thus further supporting the hypothesis of spectrin involvement. Our data suggest that the influence of the membrane skeleton on cell fusion is to restrain the rounding up that takes place after membrane fusion and that it may have variable, rather than fixed, mechanical properties. Data show that WGA, a known ligand for sialic acid, and DPG, a known metabolite, influences the flat diaphragm stability and late period expansion rates, raising the possibility that some of these mechanical properties are biologically regulated. PMID- 7858127 TI - Detection of phase separation in fluid phosphatidylserine/phosphatidylcholine mixtures. AB - The nonideal mixing of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoserine, (16:0, 18:1)PS, and 1,2-didodecenoyl-sn-glycero-3-phosphocholine, (12:1, 12:1)PC, in fluid lamellar model membranes was studied by measuring binding of aqueous Ca2+ ions and by x-ray diffraction. A region of two-phase coexistence was found by invariance of the aqueous concentration and by the appearance of two sets of lamellar spacings. The phases were identified as fluid from the diffuse x-ray diffraction in the wide-angle region. The width of the two-phase coexistence region was greater at higher ionic strength. In 800 mM KCl, the phase boundaries were at PS mole fraction 0.5 and 0.8. In 100 mM KCl, the phase boundaries were at PS mole fraction 0.52 and 0.62. Monte Carlo simulations of the lateral distributions of these PS/PC mixtures show pronounced clustering of the lipids. PMID- 7858128 TI - Activity of creatine kinase in a contracting mammalian muscle of uniform fiber type. AB - We investigated whether the creatine kinase-catalyzed phosphate exchange between PCr and gamma ATP in vivo equilibrated with cellular substrates and products as predicted by in vitro kinetic properties of the enzyme, or was a function of ATPase activity as predicted by obligatory "creatine phosphate shuttle" concepts. A transient NMR spin-transfer method was developed, tested, and applied to resting and stimulated ex vivo muscle, the soleus, which is a cellularly homogeneous slow-twitch mammalian muscle, to measure creatine kinase kinetics. The forward and reverse unidirectional CK fluxes were equal, being 1.6 mM.s-1 in unstimulated muscle at 22 degrees C, and 2.7 mM.s-1 at 30 degrees C. The CK fluxes did not differ during steady-state stimulation conditions giving a 10-fold range of ATPase rates in which the ATP/PCr ratio increased from approximately 0.3 to 1.6. The observed kinetic behavior of CK activity in the muscle was that expected from the enzyme in vitro in a homogeneous solution only if account was taken of inhibition by an anion-stabilized quaternary dead-end enzyme complex: E.Cr.MgADP.anion. The CK fluxes in soleus were not a function of ATPase activity as predicted by obligatory phosphocreatine shuttle models for cellular energetics. PMID- 7858129 TI - Transient contraction of muscle fibers on photorelease of ATP at intermediate concentrations of Ca2+. AB - We isometrically activated skinned fibers in rigor by flash photolysis of caged ATP at various [Ca2+] at 8 degrees C. On release of ATP, tension initially decreased with the same time course at all [Ca2+]. At high [Ca2+] (pCa < or = 5.8), tension rose to the steady-state plateau after the brief relaxation. When the [Ca2+] was intermediate (7.0 < or = pCa < or = 6.0), tension temporarily overshot the final steady-state level. The half-time during this tension transient was longer at higher [Ca2+]. The transient contractions could be simulated by a simple kinetic model: R + ATP-->Q, and X<-->Q<-->A, where R, X, and A are the rigor, relaxed, and active-tension states, respectively; Q is a "pre-active" state where tension is very low; and Ca2+ affects only the X-Q transition. This scheme was also useful for predicting the tension transients in Ca(2+)- and P(i)-jump experiments at various [Ca2+]. ADP enhanced the Ca2+ sensitivity of the ATP-induced transient contraction, which was not in the scope of the model. PMID- 7858130 TI - Activation of skinned trabeculae of the guinea pig induced by laser photolysis of caged ATP. AB - The kinetics of force production in chemically skinned trabeculae from the guinea pig were studied by laser photolysis of caged ATP in the presence of Ca2+. Preincubation of the tissue during rigor with the enzyme apyrase was used to reduce the population of MgADP-bound cross-bridges (Martin and Barsotti, 1994). In untreated tissue, tension remained constant or dipped slightly below the rigor level immediately after ATP release, before increasing to the maximum measured in pCa 4.5 and 5 mM MgATP. The in-phase component stiffness, which is a measure of cross-bridge attachment, exhibited a large decrease before increasing to 55% of that measured in rigor. Neither the rate of the decline nor of the rise in tension was sensitive to the concentration of photolytically released ATP. The rate of the decline in stiffness was found to be dependent on [ATP]: 1.8 x 10(4) M-1/s-1, a value more than four times higher than that previously measured in similar experiments in the absence of Ca2+. The rate of tension development averaged 14.9 +/- 2.5 s-1. Preincubation with apyrase altered the mechanical characteristics of the early phase of the contraction. The rate and amplitude of the initial drop in both tension and stiffness after caged ATP photolysis increased and became dependent on [ATP]. The second-order rate constants measured for the initial drop in tension and stiffness were 8.4 x 10(4) M-1 s-1 and 1.5 x 10(5) M-1 s-1. These rates are more than two times faster than those previously measured in the absence of Ca2+. The effects of apyrase incubation on the time course of tension and stiffness were consistent with the hypothesis that during rigor, skinned trabeculae retain a significant population of MgADP-bound cross bridges. These in turn act to attenuate the initial drop in tension after caged ATP photolysis and slow the apparent rate of rigor cross-bridge detachment. The results also show that Ca2+ increases the rate of cross-bridge detachment in both untreated and apyrase-treated tissue, but the effect is larger in untreated tissue. This suggests that in cardiac muscle Ca2+ modulates the rate of cross bridge detachment. PMID- 7858131 TI - Spatial non-uniformities in [Ca2+]i during excitation-contraction coupling in cardiac myocytes. AB - The intracellular calcium ([Ca2+]i) transient in adult rat heart cells was examined using the fluorescent calcium indicator fluo-3 and a laser scanning confocal microscope. We find that the electrically evoked [Ca2+]i transient does not rise at a uniform rate at all points within the cell during the [Ca2+]i transient. These spatial non-uniformities in [Ca2+]i are observed immediately upon depolarization and largely disappear by the time the peak of the [Ca2+]i transient occurs. Importantly, some of the spatial non-uniformity in [Ca2+]i varies randomly in location from beat to beat. Analysis of the spatial character of the non-uniformities suggests that they arise from the stochastic nature of the activation of SR calcium-release channels. The non-uniformities in [Ca2+]i are markedly enhanced by low concentrations of Cd2+, suggesting that activation of L-type calcium channels is the primary source of activator calcium for the calcium transient. In addition, the pattern of calcium release in these conditions was very similar to the spontaneous calcium sparks that are observed under resting conditions and which are due to spontaneous calcium release from the SR. The spatial non-uniformity in the evoked [Ca2+]i transient under normal conditions can be explained by the temporal and spatial summation of a large number of calcium sparks whose activation is a stochastic process. The results are discussed with respect to a stochastic local control model for excitation contraction (E-C) coupling, and it is proposed that the fundamental unit of E-C coupling consists of one dihydropyridine receptor activating a small group of ryanodine receptors (possibly four) in a square packing model. PMID- 7858133 TI - Lattice spacing changes accompanying isometric tension development in intact single muscle fibers. AB - The myosin lattice spacing of single intact muscle fibers of the frog, Rana temporaria, was studied in Ringer's solution (standard osmolarity 230 mOsm) and hyper- and hypotonic salines (1.4 and 0.8 times standard osmolarity respectively) in the relaxed state, during "fixed end" tetani, and during shortening, using synchrotron radiation. At standard tonicity, a tetanus was associated with an initial brief lattice expansion (and a small amount of sarcomere shortening), followed by a slow compression (unaccompanied by sarcomere length changes). In hypertonic saline (myosin lattice compressed by 8.1%), these spacing changes were suppressed, in hypotonic saline (lattice spacing increased by 7.5%), they were enhanced. During unloaded shortening of activated fibers, a rapid lattice expansion occurred at all tonicities, but became larger as tonicity was reduced. This expansion was caused in part by the change in length of the preparation, but also by a recoil of a stressed radial compliance associated with axial force. The lattice spacing during unloaded shortening was equal to or occasionally greater than predicted for a relaxed fiber at that sarcomere length, indicating that the lattice compression associated with activation is rapidly reversed upon loss of axial force. Lattice recompression occurred upon termination of shortening under standard and hypotonic conditions, but was almost absent under hypertonic conditions. These observations indicate that axial cross-bridge tension is associated with a compressive radial force in intact muscle fibers at full overlap; however, this radial force exhibits a much greater sensitivity to lattice spacing than does the axial force. PMID- 7858132 TI - Structural connectivity in actin: effect of C-terminal modifications on the properties of actin. AB - In this study, we use fluorescent probes and proteolytic digestions to demonstrate structural coupling between distant regions of actin. We show that modifications of Cys-374 in the C-terminus of actin slow the rate of nucleotide exchange in the nucleotide cleft. Conformational coupling between the C-terminus and the DNasal loop in subdomain II is observed in proteolytic digestion experiments in which a new C-terminal cleavage site is exposed upon DNasel binding. The functional consequences of C-terminal modification are evident from S-1 ATPase activity and the in vitro motility experiments with modified actins. Pyrene actin, labeled at Cys-374, activates S-1 ATPase activity only half as well as control actin. This reduction is attributed to a lower Vmax value because the affinity of pyrene actin to S-1 is not significantly altered. The in vitro sliding velocity of pyrene actin is also decreased. However, IAEDANS labeling of actin (also at Cys-374) enhances the Vmax of acto-S-1 ATPase activity and the in vitro sliding velocity by approximately 25%. These results are discussed in terms of conformational coupling between distant regions in actin and the functional implications of the interactions of actin-binding proteins with the C-terminus of actin. PMID- 7858134 TI - Formation of two-dimensional complexes of F-actin and crosslinking proteins on lipid monolayers: demonstration of unipolar alpha-actinin-F-actin crosslinking. AB - A method is described for forming two-dimensional (2-D) paracrystalline complexes of F-actin and bundling/gelation proteins on positively charged lipid monolayers. These arrays facilitate detailed structural studies of protein interactions with F-actin by eliminating superposition effects present in 3-D bundles. Bundles of F actin have been produced using the glycolytic enzymes aldolase and glyceraldehyde 3-phosphate dehydrogenase, the cytoskeletal protein erythrocyte adducin as well as smooth muscle alpha-actinin from chicken gizzard. All of the 2-D bundles formed contain F-actin with a 13/6 helical structure. F-actin-aldolase bundles have an interfilament spacing of 12.6 nm and a superlattice arrangement of actin filaments that can be explained by expression of a local twofold axis in the neighborhood of the aldolase. Well ordered F-actin-alpha-actinin 2-D bundles have an interfilament spacing of 36 nm and contain crosslinks 33 nm in length angled approximately 25-35 degrees to the filament axis. Images and optical diffraction patterns of these bundles suggest that they consist of parallel, unipolar arrays of actin filaments. This observation is consistent with an actin crosslinking function at adhesion plaques where actin filaments are bound to the cell membrane with uniform polarity. PMID- 7858135 TI - Unloaded shortening of skinned muscle fibers from rabbit activated with and without Ca2+. AB - Unloaded shortening velocity (VUS) was determined by the slack method and measured at both maximal and submaximal levels of activation in glycerinated fibers from rabbit psoas muscle. Graded activation was achieved by two methods. First, [Ca2+] was varied in fibers with endogenous skeletal troponin C (sTnC) and after replacement of endogenous TnC with either purified cardiac troponin C (cTnC) or sTnC. Alternatively, fibers were either partially or fully reconstituted with a modified form of cTnC (aTnC) that enables force generation and shortening in the absence of Ca2+. Uniformity of the distribution of reconstituted TnC across the fiber radius was evaluated using fluorescently labeled sTnC and laser scanning fluorescence confocal microscopy. Fiber shortening was nonlinear under all conditions tested and was characterized by an early rapid phase (VE) followed by a slower late phase (VL). In fibers with endogenous sTnC, both VE and VL varied with [Ca2+], but VE was less affected than VL. Similar results were obtained after extraction of TnC and reconstitution with either sTnC or cTnC, except for a small increase in the apparent activation dependence of VE. Partial activation with aTnC was obtained by fully extracting endogenous sTnC followed by reconstitution with a mixture of aTnC and cTnC (aTnC:cTnC molar ratio 1:8.5). At pCa 9.2, VE and VL were similar to those obtained in fibers reconstituted with sTnC or cTnC at equivalent force levels. In these fibers, which contained aTnC and cTnC, VE and VL increased with isometric force when [Ca2+] was increased from pCa 9.2 to 4.0. Fibers that contained a mixture of a TnC and cTnC were then extracted a second time to selectively remove cTnC. In fibers containing aTnC only, VE and VL were proportional to the resulting submaximal isometric force compared with maximum Ca(2+)-activated control. With aTnC alone, force, VE, and VL were not affected by changes in [Ca2+]. The similarity of activation dependence of VUS whether fibers were activated in a Ca(2+)-sensitive or -insensitive manners implies that VUS is determined by the average level of thin filament activation and that, with sTnC or cTnC, VUS is affected by Ca2+ binding to TnC only. PMID- 7858136 TI - Isometric force redevelopment of skinned muscle fibers from rabbit activated with and without Ca2+. AB - Fiber isometric tension redevelopment rate (kTR) was measured during submaximal and maximal activations in glycerinated fibers from rabbit psoas muscle. In fibers either containing endogenous skeletal troponin C (sTnC) or reconstituted with either purified cardiac troponin C (cTnC) or sTnC, graded activation was achieved by varying [Ca2+]. Some fibers were first partially, then fully, reconstituted with a modified form of cTnC (aTnC) that enables active force generation and shortening in the absence of Ca2+. kTR was derived from the half time of tension redevelopment. In control fibers with endogenous sTnC, kTR increased nonlinearly with [Ca2+], and maximal kTR was 15.3 +/- 3.6 s-1 (mean +/- SD; n = 26 determinations on 25 fibers) at pCa 4.0. During submaximal activations by Ca2+, kTR in cTnC reconstituted fibers was approximately threefold faster than control, despite the lower (60%) maximum Ca(2+)-activated force after reconstitution. To obtain submaximal force with aTnC, eight fibers were treated to fully extract endogenous sTnC, then reconstituted with a mixture of a TnC and cTnC (aTnC:cTnC molar ratio 1:8.5). A second extraction selectively removed cTnC. In such fibers containing aTnC only, neither force nor kTR was affected by changes in [Ca2+]. Force was 22 +/- 7% of maximum control (mean +/- SD; n = 15) at pCa 9.2 vs. 24 +/- 8% (mean +/- SD; n = 8) at pCa 4.0, whereas kTR was 98 +/- 14% of maximum control (mean +/- SD; n = 15) at pCa 9.2 vs. 96 +/- 15% (mean +/- SD; n = 8) at pCa 4.0. Maximal reconstitution of fibers with aTnC alone increased force at pCa 9.2 to 69 +/- 5% of maximum control (mean + SD; n = 22 determinations on 13 fibers) and caused a small but significant reduction of kTR to 78 +/- 8% of maximum control (mean +/- SD; n = 22 determinations on 13 fibers); neither force nor krR was significantly affected by Ca>2(pCa 4.0). Taken together, we interpret our results to indicate that kTR reflects the dynamics of activation of individual thin filament regulatory units and that modulation of kTR by Ca> is effected primarily by Ca>+ binding to TnC. PMID- 7858137 TI - Femtosecond pump-probe spectroscopy of bacteriochlorophyll a monomers in solution. AB - One- and two-color absorption difference profiles were obtained for BChl a in 1 propanol with approximately 50-fs resolution, using a self-mode-locked Ti:sapphire laser system. Time evolution in the BChl a absorption difference spectrum produces nonexponential photobleaching/stimulated emission (PB/SE) decay kinetics in 800-nm one-color experiments. Nonexponential PB/SE rise behavior occurs for some combinations of pump and probe wavelengths in two-color experiments. Optimized parameters from triexponential fits to the absorption difference profiles depend markedly on the fitting time window; they typically include a minor component with lifetime in the hundreds of fs. Much of the latter component is due to vibrational relaxation and/or intramolecular vibrational redistribution, rather than solvent dielectric relaxation. Measurements of the pump-probe anisotropy indicate that the electronic transition moment for the broad Qy excited state absorption band that overlaps the Qy steady-state absorption spectrum makes an angle of at most 20 degrees from that of the ground- >Qy state transition. No coherent oscillations are observed at early times. Our results bear directly on the interpretation of fs pump-probe experiments on BChl a-containing pigment-protein complexes. PMID- 7858138 TI - The pH dependence of the subpicosecond retinal photoisomerization process in bacteriorhodopsin: evidence for parallel photocycles. AB - The pH dependence of the subpicosecond decay of the retinal photoexcited state in bacteriorhodopsin (bR) is determined in the pH range 6.8-11.3. A rapid change in the decay rate of the retinal photoexcited state is observed in the pH range 9 10, the same pH range in which a rapid change in the M412 formation kinetics was observed. This observation supports the previously proposed heterogeneity model in which parallel photocycles contribute to the observed pH dependence of the M412 formation kinetics in bR. PMID- 7858139 TI - Similarity of fluorescence lifetime distributions for single tryptophan proteins in the random coil state. AB - The picosecond time-resolved fluorescence decay data of nine single-tryptophan (trp) proteins and two multi-trp proteins in their native and denatured states were analyzed by the maximum entropy method (MEM). In the denatured state (6 M guanidine hydrochloride) a majority of the single-trp proteins show bimodal (at 25 degrees C) and trimodal (at 85 degrees C) distributions with similar patterns and similar values for average lifetimes. In the native state of the proteins the lifetime distributions were bimodal or trimodal. These results (multimodal distributions) are contradictory to the unimodal Lorentzian distribution of lifetimes reported for some proteins in the native and denatured states. MEM analysis gives a unimodal distribution of lifetimes only when the signal-to-noise ratio is poor in the time-resolved fluorescence decay data. The unimodal distribution model is therefore not realistic for proteins in the native and denatured states. The fluorescence decay components of the bi- or trimodal distribution are associated with the rotamer structures of the indole moiety when the protein is in the random coil state. PMID- 7858140 TI - Theory of light quenching: effects of fluorescence polarization, intensity, and anisotropy decays. AB - Experimental studies have recently demonstrated that fluorescence emission can be quenched by laser light pulses from modern high repetition rate lasers, a phenomenon we call "light quenching." We now describe the theory of light quenching and some of its effects on the steady-state and time-resolved intensity and anisotropy decays of fluorophores. Light quenching can decrease or increase the steady-state or time-zero anisotropy. Remarkably, the light quenching can break the usual z axis symmetry of the excited-state population, and the emission polarization can range from -1 to +1 under selected conditions. The measured anisotropy (or polarization) depends upon whether the observation axis is parallel or perpendicular to the propagation direction of the light quenching beam. The effects of light quenching are different for a single pulse, which results in both excitation and quenching, as compared with a time-delayed quenching pulse. Time-delayed light quenching pulses can result in step-like changes in the time-dependent intensity or anisotropy and are predicted to cause oscillations in the frequency-domain intensity and anisotropy decays. The increasing availability of pulsed laser sources offers the opportunity for a new class of two-pulse or multiple-pulse experiments where the sample is prepared by an excitation pulse, the excited state population is modified by the quenching pulse(s), followed by time- or frequency-domain measurements of the resulting emission. PMID- 7858141 TI - Photoelectron imaging of viruses and DNA: evaluation of substrates by unidirectional low angle shadowing and photoemission current measurements. AB - Photoelectron imaging (photoelectron emission microscopy, PEM or PEEM) is a promising high resolution surface-sensitive technique for biophysical studies. At present, image quality is often limited by the underlying substrate. For photoelectron imaging, the substrate must be electrically conductive, low in electron emission, and relatively flat. A number of conductive substrate materials with relatively low electron emission were examined for surface roughness. Low angle, unidirectional shadowing of the specimens followed by photoelectron microscopy was found to be an effective way to test the quality of substrate surfaces. Optimal results were obtained by depositing approximately 0.1 nm of platinum-palladium (80:20) at an angle of 3 degrees. Among potential substrates for photoelectron imaging, silicon and evaporated chromium surfaces were found to be much smoother than evaporated magnesium fluoride, which initially appeared promising because of its very low electron emission. The best images were obtained with a chromium substrate coated with a thin layer of dextran derivatized with spermidine, which facilitated the spreading and adhesion of biomolecules to the surfaces. Making use of this substrate, improved photoelectron images are reported for tobacco mosaic virus particles and DNA-recA complexes. PMID- 7858142 TI - Phosphorescence lifetime analysis with a quadratic programming algorithm for determining quencher distributions in heterogeneous systems. AB - A new method for analysis of phosphorescence lifetime distributions in heterogeneous systems has been developed. This method is based on decomposition of the data vector to a linearly independent set of exponentials and uses quadratic programming principles for x2 minimization. Solution of the resulting algorithm requires a finite number of calculations (it is not iterative) and is computationally fast and robust. The algorithm has been tested on various simulated decays and for analysis of phosphorescence measurements of experimental systems with descrete distributions of lifetimes. Critical analysis of the effect of signal-to-noise on the resolving capability of the algorithm is presented. This technique is recommended for resolution of the distributions of quencher concentration in heterogeneous samples, of which oxygen distributions in tissue is an important example. Phosphors of practical importance for biological oxygen measurements: Pd-meso-tetra (4-carboxyphenyl) porphyrin (PdTCPP) and Pd-meso porphyrin (PdMP) have been used to provide experimental test of the algorithm. PMID- 7858143 TI - Dynamics of platelet glycoprotein IIb-IIIa receptor expression and fibrinogen binding. I. Quantal activation of platelet subpopulations varies with adenosine diphosphate concentration. AB - We have previously reported that maximal platelet activation with adenosine diphosphate (100 microM ADP) causes rapid expression of all GPIIb-IIIa receptors for fibrinogen (FgR) (< 1-3 s), measured with FITC-labeled PAC1 by flow cytometry. We have extended these studies to examine the effects of ADP concentration on the graded expression and Fg occupancy of GPIIb-IIIa receptors. Human citrated platelet-rich plasma, diluted 10-fold with Walsh-albumin-Mg+2 (2 mM), was treated with ADP (0.1-100 microM). The rates of GPIIb-IIIa receptor expression or Fg binding were measured in unstirred samples by flow cytometry, using FITC-labeled monoclonal antibodies (mAb) PAC1 and 9F9, respectively, from on-rates, using increasing times between mAb and ADP additions. Fibrinogen receptors were all expressed rapidly at low (1 microM) or high (100 microM) ADP (few seconds), whereas Fg occupancy was 50% of maximal by about 2 min. The maximal extent of GPIIb-IIIa receptor expression and Fg occupancy was determined from maximal binding (Flmax) at 30 min incubation with PAC1 or 9F9. On-rates and maximal extents of binding for either PAC1 or 9F9 probes showed identical [ADP] response profiles ("KD" approximately 1.4 +/- 0.1 microM). However, Flmax studies showed bimodal histograms consisting of "resting" (Po) and maximally "activated" (P*) platelets for both PAC1 and 9F9 binding, with the fraction of "activated" platelets increasing with ADP concentration. The data best fit a model where platelet subpopulations are "quantally" transformed from Po to P*, expressing all GPIIb-IIIa receptors, rapidly filled by Fg, but "triggered" at critical ADP concentrations. Larger, but not the largest, platelets appear to be the most sensitive subpopulation. The implications for clinical studies are discussed, and the relationship to dynamics of aggregation are described in a companion paper. PMID- 7858144 TI - Dynamics of platelet glycoprotein IIb-IIIa receptor expression and fibrinogen binding. II. Quantal activation parallels platelet capture in stir-associated microaggregation. AB - There is broad agreement that platelet aggregation is generally dependent on fibrinogen (Fg) binding to the glycoprotein (GP) IIb-IIIa receptor expressed on the activated platelet surface. We therefore compared rates and extents of aggregation and of fibrinogen receptor expression and specific Fg binding to activated platelets, as a function of ADP concentration. Human citrated platelet rich plasma (diluted 10-fold) was stirred with adenosine diphosphate (ADP) for 10 s or 2 min to measure rates and extent of aggregation, respectively, determined from the decrease in the total number of particles. The number of fibrinogen receptors and bound Fg were measured from mean fluorescence values obtained with FITC-labeled IgM monoclonal antibody PAC1 and the IgG monoclonal antibody, 9F9, respectively, using flow cytometry as presented in part I (Frojmovic et al., 1994). Because flow cytometric and aggregation measurements were routinely determined at room temperature and 37 degrees C, respectively, we also compared and found temperature-independent initial rates of aggregation. The fraction of platelets with fluorescence values above one critical threshold value, corresponding to maximally "activated" platelets (P*), increased with increasing activator concentration and correlated linearly with the fraction of platelets recruited into aggregates for ADP (r > 0.9). Aggregation was not rate-limited by fibrinogen receptor expression or by Fg binding. It appears that each platelet expresses its maximal Fg receptors at a critical ADP concentration, i.e., occupancy of ADP receptors. This, in turn, leads to rapid Fg occupancy and capture of such "quantally activated" platelets into aggregates. PMID- 7858146 TI - Preferred negative geotactic orientation in mobile cells: Tetrahymena results. AB - For the protozoan species Tetrahymena a series of airplane experiments are reported, which varied gravity as an active laboratory parameter and tested for corresponding changes in geotaxic orientation of single cells. The airplane achieved alternating periods of low (0.01 g) and high (1.8 g; g = 980 cm/s) gravity by flying repeated Keplerian parabolas. The experimental design was undertaken to clearly distinguish gravity from competing aerodynamic and chemical gradients. In this way, each culture served as its own control, with gravity level alone determining the orientational changes. On average, 6.3% of the Tetrahymena oriented vertically in low gravity, while 27% oriented vertically in high-gravity phases. Simplified physical models are explored for describing these cell trajectories as a function of gravity, aerodynamic drag, and lift. The notable effect of gravity on turning behavior is emphasized as the biophysical cause of the observed negative geotaxis in Tetrahymena. A fundamental investigation of the biological gravity receptor (if it exists) and improved modeling for vertical migration in important types of ocean plankton motivate the present research. PMID- 7858145 TI - Free calcium concentrations in bullfrog rods determined in the presence of multiple forms of Fura-2. AB - We employed the fluorescent calcium indicator Fura-2, loaded into intact retinas of the bullfrog Rana catesbeiana, to measure free calcium concentrations in the rod outer-segment cytosol. We determined that traditional methods of calculation yielded erroneous values of calcium. This error results from the presence of at least two distinct pools of Fura-2 in rod outer segments. Application of manganese quenches each pool, but quenching occurs at different rates. Using this fact, we show that the pools can be isolated by brief exposure to manganese and examined separately. One of these pools has the same fluorescent properties as the free salt of Fura-2 we use in our in vitro calibrations. The other source of fluorescence has more unusual properties. Although insensitive to calcium concentrations in the physiological range, it contributes significant anomalous fluorescence when cytosolic free calcium concentrations are elevated by application of IBMX. Nevertheless, the experimentally isolated, classic pool of Fura-2 is well behaved and allows us to calculate calcium concentrations relative to the Kd of Fura-2 by the usual ratio method. We show that when rods are exposed to saturating light, the free calcium concentration in their outer segments falls to a level not significantly different from zero within 20-30 s. PMID- 7858147 TI - Hemoglobin affinity for 2,3-bisphosphoglycerate in solutions and intact erythrocytes: studies using pulsed-field gradient nuclear magnetic resonance and Monte Carlo simulations. AB - The diffusion coefficient (D) of 2,3-bisphosphoglycerate (DPG) was measured using pulsed-field gradient (PFG)-31P nuclear magnetic resonance spectroscopy in solutions containing 2.7-5.0 mM hemoglobin (Hb) and a range of DPG concentrations. The dependence of the measured values of D on the fraction of the total DPG in the sample that is bound to Hb enabled the estimation of the dissociation constants (Kd) of complexes of DPG with carbonmonoxygenated, oxygenated, and deoxygenated Hb; the values of Kd (mM), measured at 25 degrees C, pH 6.9 and in 100 mM bis Tris/50 mM KCl, were 1.98 +/- 0.26, 1.8 +/- 0.5 and 0.39 +/- 0.26, respectively. In intact erythrocytes the apparent diffusion coefficient, Dapp, of DPG was larger in oxygenated and carbonmonoxygenated cells (6.17 +/- 0.20 x 10(-11) m2s-1) than in deoxygenated cells (4.10 +/- 0.23 x 10( 11) m2s-1). Changes in intracellular DPG concentration (5-55 mM) in erythrocytes, brought about by incubation in a medium containing inosine and pyruvate, did not result in significant changes in the value of Dapp; this result supports the hypothesis that DPG binds to other sites in the erythrocyte. Monte Carlo simulations of diffusion in biconcave discs were used to test the adequacy of the values of Kd estimated in solution to describe the binding of DPG to Hb in oxygenated and deoxygenated erythrocytes. The results of the simulations implied that the value of Kd estimated for deoxygenated Hb-DPG was greater than expected from the experiments involving intact erythrocytes. This difference is surmised to be at least partly due to the difficulty of measuring D at low-ligand concentrations. Notwithstanding this shortcoming, the PFG method appears to be suitable for probing interactions between macromolecules and ligands when the Kd is in the millimolar range. It is one of the few techniques available in which these interactions can be studied in intact cells. In addition, the Monte Carlo simulations of the diffusion experiments highlighted important differences between theory and experiment relating to the nature of molecular motion inside the cells. PMID- 7858148 TI - Single-particle tracking: models of directed transport. AB - Single-particle tracking techniques make it possible to measure motion of individual particles on the cell surface. In these experiments, individual trajectories are observed, so the data analysis must take into account the randomness of individual random walks. Methods of data analysis are discussed for models combining diffusion and directed motion. In the uniform flow model, a tracer simultaneously diffuses and undergoes directed motion. In the conveyor belt model, a tracer binds and unbinds to a uniform conveyor belt moving with constant velocity. If a tracer is bound, it moves at the velocity of the conveyor belt; if it is unbound, it diffuses freely. Trajectories are analyzed using parameters that measure the extent and asymmetry of the trajectory. A method of assessing the usefulness of such parameters is presented, and pitfalls in data analysis are discussed. Joint probability distributions of pairs of extent and asymmetry parameters are obtained for a pure random walk. These distributions can be used to show that a trajectory is not likely to have resulted from a pure random walk. PMID- 7858150 TI - Are recombinant interleukins more or less therapeutically effective than their exogenous inducers? PMID- 7858149 TI - "Simulated molecular evolution" or computer-generated artifacts? AB - 1. The authors define a function with value 1 for the positive examples and 0 for the negative ones. They fit a continuous function but do not deal at all with the error margin of the fit, which is almost as large as the function values they compute. 2. The term "quality" for the value of the fitted function gives the impression that some biological significance is associated with values of the fitted function strictly between 0 and 1, but there is no justification for this kind of interpretation and finding the point where the fit achieves its maximum does not make sense. 3. By neglecting the error margin the authors try to optimize the fitted function using differences in the second, third, fourth, and even fifth decimal place which have no statistical significance. 4. Even if such a fit could profit from more data points, the authors should first prove that the region of interest has some kind of smoothness, that is, that a continuous fit makes any sense at all. 5. "Simulated molecular evolution" is a misnomer. We are dealing here with random search. Since the margin of error is so large, the fitted function does not provide statistically significant information about the points in search space where strings with cleavage sites could be found. This implies that the method is a highly unreliable stochastic search in the space of strings, even if the neural network is capable of learning some simple correlations. 6. Classical statistical methods are for these kind of problems with so few data points clearly superior to the neural networks used as a "black box" by the authors, which in the way they are structured provide a model with an error margin as large as the numbers being computed.7. And finally, even if someone would provide us with a function which separates strings with cleavage sites from strings without them perfectly, so-called simulated molecular evolution would not be better than random selection.Since a perfect fit would only produce exactly ones or zeros,starting a search in a region of space where all strings in the neighborhood get the value zero would not provide any kind of directional information for new iterations. We would just skip from one point to the other in a typical random walk manner. PMID- 7858151 TI - Anti-cytokines: promising tools for diagnosis and immunotherapy. AB - Anti-cytokines belong to a new family of biological response modifiers which interfere with the biological functions of cytokines. An imbalance between cytokines and natural anti-cytokines may represent an important factor to explain the pathogenesis of some human diseases. Indeed, dysregulation of anti-cytokine serum levels was observed in cancers and auto-immune and infectious diseases. It was sometimes associated with disease activity and in some circumstances they may help to predict clinical response to treatment. Control of disease activity in septic shock and auto-immune diseases was demonstrated after administration of anti-cytokines such as soluble TNF receptors and IL1ra inhibitors. Therefore these agents are promising tools for diagnosis and immunotherapy. PMID- 7858152 TI - Cytokines as mediators in the central nervous system. AB - Cytokines are soluble mediators involved in cell-cell regulations in the immunological and the hematopoietic system. We review various cytokine effects on the central nervous system, including growth-promoting activity, neuro-modulatory action, fever induction, sleep and decreased food intake. In addition, cytokines, neuropeptides, neurotransmitters and hormones all participate in an intricate inter-relationship to contribute to the development and maintenance of brain homeostasis. Cytokines are also involved in the wounding responses of injured brain after trauma, infection or neuro-degenerative processes. Pharmacological modulation of the expression and/or actions of cytokines in the brain may represent a new field of research of therapeutic benefit in the treatment of central disorders. PMID- 7858153 TI - Autocrine and paracrine functions of cytokines in malignant lymphomas. AB - Cytokines play important roles in the pathogenesis of lymphomas via an autocrine or a paracrine mechanism, or both. The characteristic clinical and histopathological features of malignant lymphomas may be due in part to elevated serum or tissue levels of cytokines. Determination of the effects of cytokines on the growth or differentiation of lymphoma cells is often complicated by the fact that more than one cytokine is responsible, and by the failure of anti-cytokine antibodies or antisense oligonucleotides to block the proliferation in vitro of lymphoma cells. However, it appears that IL-6 and/or IL-9 may play a prominent role in the tumor cell proliferation of Hodgkin's disease (HD), anaplastic large cell lymphoma, or immunoblastic lymphoma. IL-6 may also be responsible for the plasmacytoid differentiation of lymphoma cells in polymorphic immunocytoma. The histopathological changes as a result of paracrine effects are most noticeable in HD. The malignant (H-RS) cells of HD have been shown to express IL-1, IL-5, IL-6, IL-9, TNF-alpha, M-CSF, TGF-beta, and CD80, and, less frequently, IL-4 and G-CSF. These cytokines may be responsible for the increased cellular reaction and fibrosis observed in tissues involved by HD and for the immunosuppression found in patients with HD. In contrast to H-RS cells, most non-HD lymphoma cells do not produce cytokines in excess amounts and reveal only a minimal cellular reaction. Exceptions include T-cell-rich B-cell lymphoma, angiocentric T-cell lymphoma, and angio-immunoblastic lymphadenopathy (AILD-like T-cell lymphoma. IL-4 is responsible for the T-cell reaction in T-cell-rich B-cell lymphoma, whereas IL-6 accounts for the plasma cell reaction in AILD-type T-cell lymphoma. The authors extensively review the role of cytokines in lymphomas because this may lead to major advances in the understanding of the molecular processes involved in the histopathogenesis of lymphomas. PMID- 7858154 TI - Cytokines and macrophages. AB - Macrophages, within the cytokine network, are a major source of many cytokines involved in immune response, hematopoiesis, inflammation and many other homeostatic processes. Upon stimulation by micro-organisms, microbial products or endogenous factors including cytokines, macrophages can de novo synthesize and release a large variety of cytokines (ie IL-1, IL-1ra, IL-6, IL-8, IL-10, IL-12, TNF alpha, IFN alpha, IFN gamma, MCP-1, MCP-3, MIF, M-CSF, G-CSF, GM-CSF, MIP-1, MIP-2, LIF, OSM, TGF beta). Some cytokines can upregulate the production of cytokines by macrophages (IL-3, GM-CSF, IFN gamma) while others can inhibit it (IL-4, IL-10, IL-13, TGF beta). In addition, these cytokines can modulate most of the macrophage functions and cell surface marker expression. Other cytokines (the chemokines such as MCP-1,2,3, MIP-1,2 and RANTES) contribute to the recruitment of circulating monocytes within tissues. It is worth noting that macrophages can be their own source of regulatory cytokines. PMID- 7858156 TI - Cancer versus Alzheimer risks. Health is not moral. PMID- 7858157 TI - Alzheimer's disease: rhythm, timing and music as therapy. AB - Active music-making provides a form of therapy for the Alzheimer's patient which may stimulate cognitive activities such that areas subject to progressive failure are maintained. Anecdotal evidence suggests that quality of life of Alzheimer's patients is significantly improved with music therapy, accompanied by the overall social benefits of acceptance and sense of belonging gained by communicating with others. Music therapy, when based on clear treatment objectives can reduce the individual prescription of tranquilizing medication, reduce the use of hypnotics and help overall goals of rehabilitation. Mood improvement and self-expression, the stimulation of speech and organisation of mental processes; and sensory stimulation and motor integration are promoted. Given that the rate of deterioration in Alzheimer's disease is not predictable, a series of single case experimental designs would generate valuable empirical data concerning treatment outcome and promote basic research into the timing functions required for the co ordination of cognition, physiology, motor ability and the integrity of behaviour. PMID- 7858158 TI - Endosome-lysosomes and neurodegeneration. AB - A number of the major human and animal neurodegenerative diseases, such as Alzheimer's disease and sheep scrapie, are characterised by deposits of amyloid, arising through incomplete breakdown of membrane proteins. Although our knowledge concerning these diseases is increasing, they remain largely untreatable. Recently, attention has focussed on the mechanisms of production of different types of amyloid and the likely involvement within cells of acid compartments called endosome-lysosomes. These organelles may be 'bioreactor' sites for the unfolding and partial degradation of membrane proteins to generate the amyloid materials. These subsequently become expelled from the cell, or are released from dead cells, and accumulate as pathological entities. Common features of the disease processes give new direction to therapeutic intervention. PMID- 7858155 TI - Inhibitory effect of bombesin/gastrin-releasing peptide (GRP) antagonists RC-3950 II and RC-3095 on MCF-7 MIII human breast cancer xenografts in nude mice. AB - Bombesin/gastrin-releasing peptide (GRP) may be involved in the growth of human breast cancers. Nude mice bearing xenografts of MCF-7 MIII human breast cancer cell line were treated for 7 weeks with bombesin/GRP antagonists RC-3950-II and RC-3095. RC-3950-II, administered sc twice daily at a dose of 10 micrograms, produced significant inhibitory effects on tumor growth after 2 weeks of administration. RC-3095 acetate (D 22213), injected sc twice daily at the same dose of 10 micrograms, suppressed tumor growth after 4 weeks. Both RC-3950-II and RC-3095 significantly decreased the final tumor volume and tumor weights. RC-3950 II appeared to be somewhat more efficacious than RC-3095 in inhibiting the growth of MCF-7 MIII breast cancers. Chronic treatment with either bombesin/GRP antagonist caused down-regulation of receptors for epidermal growth factor (EGF) in tumor cell membranes, which might be related to inhibition of tumor growth. These findings suggest that bombesin/GRP antagonists should be considered for a new endocrine therapy of breast cancer. PMID- 7858159 TI - Pathological Tau proteins of Alzheimer's disease as a biochemical marker of neurofibrillary degeneration. AB - Paired Helical Filaments (PHF) accumulate in the degenerating neurons from the associative cortical brain areas during Alzheimer's disease. They are composed of a triplet of hyperphosphorylated microtubule-associated protein Tau, called Tau 55, 64, 69 or PHF-Tau. The distribution of PHF-Tau in the different brain areas corroborates neuropathological observations and specifies that: the entorhinal cortex and hippocampus are vulnerable regions specifically affected by Alzheimer type neurofibrillary degeneration during aging, the temporal cortex is already affected at the very first stage of clinical manifestations, almost the whole brain is concerned by neurofibrillary degeneration at the end-stages of the disease. Tau-PHF are also observed in the cortical areas from Parkinson patients with dementia, and more especially in the prefrontal cortex. Tau pathology for Progressive Supranuclear Palsy is significantly different, with a doublet of pathological Tau, namely Tau 64 and 69, in almost all cortical and subcortical areas. Therefore, the presence of pathological Tau proteins in several associative cortical areas is always associated with severe intellectual impairment. Finally, PHF-Tau are powerful biochemical markers of the degenerating process which could be used for setting up an early biological diagnosis test of Alzheimer's disease based upon the immunodetection of PHF antigens in the CSF, as well as for developing experimental models of neurodegeneration. PMID- 7858160 TI - Serine proteases and their serpin inhibitors in Alzheimer's disease. AB - Our article documents recent studies in the proteolytic processing of the Alzheimer's beta-amyloid protein precursor (beta-APP), as well as the role of thrombin and its potent inhibitor, protease nexin I in Alzheimer's disease (AD). Since synapse loss correlates best with cognitive decline in AD, we also present in detail, our model of synapse formation and elimination, reviewing recent findings related to the subject as well as our own original data. Recent exciting findings concerning the involvement of thrombin-like activity in synapse elimination, which we feel to be important in neural plasticity are also discussed. PMID- 7858161 TI - Modulation of AMPA receptor function in relation to glutamatergic abnormalities in Alzheimer's disease. AB - Abnormalities in the excitatory glutamate neurotransmitter system appear to be a prominent factor in Alzheimer's disease (AD). Whereas hypoactivity of this system is observed in some areas of Alzheimer brains, hyperactivity may play a role in the degenerative processes in other brain areas. This apparently paradoxical situation makes therapeutic intervention in the glutamatergic system in AD difficult and demands the development of unique therapeutic approaches. The involvement of the (RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) subtype of glutamate receptors in AD brain dysfunctions seems to be important, and compounds showing different modulatory activity at AMPA receptors are discussed in relation to therapeutic possibilities. Compounds enhancing excitatory activity at AMPA receptors may have beneficial effects on the learning and memory deficits observed in AD, whereas agents showing antagonistic or partial agonist profiles may block or delay the progressive neurodegeneration, which is a key phenomenon in AD. In vitro experiments with compounds capable of enhancing AMPA receptor activity have been performed. Such compounds without excitatory activity on their own may not show the excitotoxic properties characteristic of glutamate agonists. Another possibility for therapeutic intervention is the use of a partial agonist. The concept of "functional partial agonism" at the AMPA receptors is described with a specific example. PMID- 7858162 TI - Alzheimer's disease: a review of recent findings. AB - The recent development of biological research on dementias of the Alzheimer's type has lead to a better understanding of their pathophysiology. We know the nature of the proteins present in senile plaques and in the neurofibrillary degeneration. Pathophysiological hypotheses are more precise, and clearly involve genetic factors. The rapid progress in this field raises the hope that more efficient treatments will appear in the near future. PMID- 7858163 TI - The use of lipid-linked oligosaccharides (neoglycolipids) in the identification of carbohydrate receptors for microbial pathogens. AB - Specific oligosaccharide chains on the host cell surface act as receptors for many microbial pathogens. Identification of receptor structures is an important step in the understanding of the pathogenesis of infection. Glycolipid receptors have been identified by direct binding assays. However, technical difficulties have prevented demonstration of bacterial binding to the oligosaccharides of glycoproteins; these have been identified mainly by inhibition assays. By a novel technique developed in our laboratory, oligosaccharides released from glycoproteins are linked to lipids to form neoglycolipids. These can be used in bacterial binding assays. The feasibility of this approach has been demonstrated using type 1 fimbriated Escherichia coli binding specifically to neoglycolipids rich in mannose residues. The application of the method has resulted in a demonstration of a new type of adhesive specificity for E. coli and differences in the binding specificities of E coli and Pseudomonas aeruginosa. Further application of this technique by generating oligosaccharides purified from mucus glycoproteins from patients with cystic fibrosis to use in binding assays with P aeruginosa is currently being undertaken. The basic knowledge gained by this approach may in time see the development of novel therapy in the form of receptor blocking agents. PMID- 7858164 TI - Anti-HIV effect of immunomodulating agent, levamisole, in vitro. AB - An anthelminthic agent, levamisole, also known as a potent immunomodulator, has been successfully used for adjuvant therapy of malignancies and chronic infections underlined by immunodeficiency. We have tested the effect of this drug on de novo viral infection by exposing MT-4 T lymphocytes to HIV in the presence of serial ten-fold dilutions of levamisole (range 10(-3)-10(-9) M). The results indicate that 50% reduction in viral infectivity (IC50) of levamisole starts from as low as 10(-7) M, whereas even the highest millimolar dose of the drug has not shown any appreciable cytotoxicity. Although the mechanism of levamisole action remains unknown, our observation in vitro suggests that levamisole, a clinically established immunomodulator, can be potentially effective for treatment of HIV infection. PMID- 7858165 TI - A new mode of cancer cell death induced by hyperthermia and non specific (macrophagic) cancer immunotherapy: lysosomal exocytosis. PMID- 7858166 TI - Chromosome rearrangements: from embryopathies and cancer, to species evolution: in memoriam of Jerome Lejeune, the founder of human genetics. PMID- 7858167 TI - Waardenburg syndrome in man and splotch mutants in the mouse: a paradigm of the usefulness of linkage and synteny homologies in mouse and man for the genetic analysis of human congenital malformations. AB - The use of chromosomal segments with conserved homologous linkage groups found in different species provides one method of predicting the location of genes causing congenital malformations in man. For example, homology between man and mouse involves 241 homologous autosomal genes spread on 68 homologous chromosomal segments. In addition, the similarities of phenotypic expression of human congenital malformations and mouse mutations indicate the possible involvement of an homologous gene implicated during ontogeny of the two species. The identification of a single gene defect in the mouse and comparative mouse-human gene mapping provides therefore another approach for selecting candidate loci for inborn error of morphogenesis in man. Further molecular studies can then be performed to show that the loci are identical. The human Waardenburg syndrome and the splotch (Sp) mouse mutant represent the first example of the potential of this approach for the understanding of human congenital malformations at the molecular level. PMID- 7858168 TI - Molecular epidemiology of Tay-Sachs disease in Europe. AB - The abnormalities in the gene coding for the beta-hexosaminidase alpha subunit were analysed from fibroblast's RNAs of 42 Tay-Sachs patients (seven with adult or late onset of Tay-Sachs disease and 35 with infantile Tay-Sachs disease). After first strand synthesis by random priming, PCR was used to amplify in two overlapping fragments (868 and 949 bp) the entire coding region. These amplified products were first studied for changes in size by agarose gel electrophoresis to screen for splicing mutations leading to exon skipping or cryptic splice site activation. For each patient, the two overlapping cDNA fragments were subjected to chemical mismatch cleavage analysis using hydroxylamine to modify C-containing mismatches and osmium tetroxide to modify T-containing mismatches. DGGE was used to screen for mutations in the coding region spanning exon 2 to exon 6, a region putatively encompassing the active site and therefore a potential hot spot of mutations associated with Tay-Sachs disease. To increase the sensitivity of the technique, a 30 bp GC-clamp has been added at the 5' end of the sense oligonucleotide to amplify a fragment of 629 bp. The computerized analysis found that single base changes in domain spanning from nt 313 to nt 693 can be distinguished. Fragments displaying an altered melting behavior or a cleaved product were further analysed by direct sequencing of the amplified material. These methods as a whole allowed us to identify 30/38 alleles studied (79%) with 15 point mutations and one 4 bp insertion detected.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7858169 TI - Late infantile metachromatic leukodystrophy in Israel. AB - Metachromatic Leukodystrophy (MLD) is a neurodegenerative disease in which the lysosomal enzyme, Aryl sulfatase A (ARSA) is deficient. The disease is inherited as an autosomal recessive trait and its frequency is estimated to be 1/40,000 live births. The gene of ARSA has been cloned and up to now eight mutations causing MLD have been reported. Another mutation, PD, leads to the deficiency of the enzyme in vitro (pseudodeficiency) without any known clinical effect. The PD mutation is frequent in all populations. In Israel, late infantile MLD was found to be very frequent in a small Jewish isolate, the Habbanite Jews (1/75 live births). The molecular analysis demonstrated that in the Habbanite population, the mutation occurred on an allele with the PD mutation. The loss of ARSA activity is due to a point mutation C > T leading to a change of proline to leucine. MLD is also frequent among Moslem Arabs in Jerusalem. The mutation is a transition G > A destroying the splice donor site of exon 2. This mutation has been reported in patients with the late infantile MLD from different ethnic groups. The Christian Arabs in Israel also have a high incidence of the disease (1/10,000 live births); the mutation in this population is still unknown. Knowledge of the different mutations causing MLD in these defined populations will allow a carrier screening program to be carried out and prevent the birth of additional affected children. PMID- 7858170 TI - High incidence of central nervous system malformations associated with marked parental consanguinity in an Israeli Arab community. AB - It is common among Israeli Arabs who live in villages to prefer consanguineous marriages, particularly among first cousins. In addition, such villages are populated by a few (< 20) original families, and inter-family/inter-village marriages are infrequent. The purpose of this study was to examine the incidence of congenital malformation of the central nervous system associated with such "consanguinity" in Taibe, a large Arab village, 30 km from Tel Aviv. Six hundred and ten families were prospectively ascertained through infants who were routinely seen in the local "Well Baby Clinics". A significant increase in the incidence of major malformations was noted in relation to the closeness of the parental relationship. For the index cases group, the prevalence of individuals with major malformations was 5.8% in the product of inter-village marriages, 8.3% in the intra-village non-related matings, 15.1% in the distant consanguineous group, and up to 15.8% in the progeny of first-cousin marriages (P < 0.001). Malformations of the central nervous system consisted of 1/3 to 1/2 of the total malformations in the consanguineous group versus less than 1/5 in the non consanguineous groups. The study demonstrates a marked high rate of consanguineous marriages, the effect of which leads to a marked increase in major malformations and especially those of the central nervous system. This requires a unique genetic counseling approach. PMID- 7858171 TI - Molecular genetic detection of Xp21 muscular dystrophy carriers in Cyprus. AB - Multiplex Polymerase Chain Reaction (PCR) for 18 different exons of the dystrophin gene was used to characterize the mutations in 29 Cypriot families with Duchenne or Becker Muscular Dystrophy. Deletions were detected in 21 out of 28 families from which DNA was available for an affected patient (75%). Quantitative Multiplex PCR further enabled the identification of a duplication in one of our families (3.6%). Quantitative Multiplex PCR also enabled carrier diagnosis in families where a deletion or a duplication was detectable in an affected patient. Out of 69 at-risk females examined in these families, 20 were shown by Quantitative Multiplex PCR to be carriers, including three obligatory carriers. In the remaining six families with a surviving patient, carrier diagnosis was based on haplotype analysis using microsatellite polymorphisms from the 5'- and 3'-ends of the dystrophin gene. Haplotype analysis was informative in three of the above families (10.7%). Thus, deletions or duplications were detected in 78.6% of our families with a surviving patient, while carrier diagnosis was possible in 89.3% of these families. In the single family without a surviving patient, Quantitative Multiplex PCR indicated the absence of a deletion or duplication in the mother, while haplotype analysis could not be carried out in the absence of an affected patient. The high rate of new mutations in the dystrophin gene of which only about 80% are directly detectable by Quantitative Multiplex PCR, and the difficulty of haplotype analysis in some of our families, restricts the usefulness of these techniques to about 90% of our families. PMID- 7858172 TI - A molecular survey of Israeli Duchenne and Becker muscular dystrophy patients. AB - Duchenne (DMD) and Becker (BMD) muscular dystrophy are allelic X-linked recessive diseases caused by a mutation in the dystrophin gene located on the short arm of chromosome X (Xp21). The dystrophin gene is the largest gene known in humans, extending over 2300 kb and containing more than 70 exons coding for a 420 KD protein comprising 3685 amino acids. The gene is highly unstable, with a high percentage of deletions and rearrangements. A third of dystrophin mutations are new mutations. The frequency of DMD is 1:3500 liveborn males, and that of BMD 1:10000. These dystrophies are severe, progressive, and lethal. BMD/DMD patients and 2/3 of female carriers have high levels of creatine phosphokinase (CK). During the past 5 years, 169 families with patients affected by progressive muscular dystrophy were examined and counselled. We were able to exclude the diagnosis of DMD/BMD in 49 families on the basis of clinical symptoms and signs, normal dystrophin on biopsy (11 families) and/or the absence of linkage to chromosome X by analysis of RFLP derived haplotypes. Molecular analysis was performed on 111 DMD/BMD families (five BMD and 106 DMD) with 81 available probands. This study resulted in the establishment in Israel of an integrated diagnostic protocol for DMD/BMD, employing genetic, biochemical and molecular techniques. Molecular analysis provided most of the families with new and essential information. PMID- 7858173 TI - Tissue-specific alternative splicing of neurofibromatosis 1 (NF1) mRNA. AB - The neurofibromatosis 1 gene NF1 appears to play a crucial role in regulating the proliferation of cells of neural crest origin. The NF1 gene is a 300 kbp gene, encoding a complex pattern of mRNA related to the presence or absence of two alternative splices. The first splice, in the centre of the coding region of the gene, results in the addition of 63 bp in the GAP-related domain. The second splice located 4203 bp downstream, near the 3' terminus of the coding region of the gene, consists of a 54 bp insert. RT-PCR analysis demonstrates that the most prevalent splice variant in human tissues is the one which contains the GAP related splice and omits the 3' terminal splice. It is also the form expressed in the peripheral nerve, adrenal medulla, benign NF1 neurofibromas and NF1 neurosarcomas. Conversely, a few organs (brain, muscle) exhibit extensive alternative splicing leading to the co-expression of four distinct transcripts. The reproducibility of the relative levels of each of the splice types in the different organs indicates a tissue-specific splicing pattern of the NF1 gene. PMID- 7858174 TI - Myotonic dystrophy: molecular analysis of Israeli patients. AB - Myotonic dystrophy (DM) is an autosomal dominant, multisystem disorder and the most common adult form of muscular dystrophy. The age of onset and degree of severity of DM is highly variable. The biochemical defect in DM is unknown. DM was the first autosomal disorder to be localised by genetic linkage to protein markers (Lu, Se, C3), and assigned to chromosome 19. Linkage studies in DM families using RFLPs as polymorphic markers refined the mapping position to 19q13.1-13.2 distal to the BCL3, apoCII, CKM and ERCCI genes. Based on the linkage data, healthy individuals from DM families request a pre-symptomatic test. The information is of use in planning their family, if at high risk they can choose to have prenatal diagnosis. We have studied ten unrelated DM families by linkage analysis. The DNA probes to detect the various RFLPS were either from the vicinity of BCL3, ApoCII, CKMM and ECCRI genes or anonymous DNA probes. Linkage analysis in the DM families enabled us to determine the carrier status of healthy individuals and to perform prenatal diagnosis at a confidence of > 99%. In two families the DM diagnosis was in doubt and we did not include them in the combined analysis. Linkage disequilibrium was noted with two RFLPs pDIO/Pst1 and p37.1/BamH1. Both DNA probes were isolated by Shaw and his group in Cardiff. In six out of eight families, the DM chromosome was associated with allele 3 of pDIO/Pst1 and allele 1 of p37.1/BamH1.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7858175 TI - Hunter syndrome among Jews in Israel. AB - Hunter syndrome (mucopolysaccharidosis II) is an X-linked lysosomal storage disorder caused by the deficiency of iduronate sulfatase (IDS), the gene of which is located at Xq28. A relatively high frequency of Hunter disease among Ashkenazi and Moroccan Jews in Israel was observed. Genetic analysis of the patients with Hunter disease in these ethnic groups indicated the absence of new mutations and a two-fold excess of individuals with the mutant allele over non carriers. This unusual phenomenon is unique to these ethnic groups and is suggestive of a prenatal selection process favoring the Hunter allele. Studies of the IDS gene structure and its flanking region are performed with the aim of detecting the mutations causing the disease in these patients and thus develop the most accurate diagnostic procedure for carrier identification among female relatives in these families. Furthermore, these studies are also aimed at identifying the unique molecular structure in the IDS gene or its flanking region which is the basis for the selection process. RFLP analysis using the cDNA gene (pc2S15) and DNA probes closely linked to the IDS gene, as well as the study of CA repeats in a closely linked region, indicated the absence of common haplotypes among Ashkenazi or Moroccan patients, excluding a linkage disequilibrium between a putative advantageous linked gene to the Hunter mutation in our patients. Studies of the IDS gene indicated a partial deletion in two patients while the other 12 patients had an apparent intact gene.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7858176 TI - Genetics and biochemistry of Creutzfeldt-Jakob disease in Libyan Jews. AB - A focus of Creutzfeldt-Jakob disease (CJD) among Jews from Libyan origin was identified in Israel 20 years ago. The incidence of the disease in this ethnic group is about 100 times more than in the worldwide population. The consumption of lightly cooked sheep brain has been invoked to explain the high incidence of CJD in this community. The discovery of mutations in the PrP gene which segregates with other familial prion diseases such as Gerstmann-Straussler syndrome (GSS) lead us to perform a molecular genetic study and compare it to an epidemiological survey among the Libyan community. The epidemiological data suggests a very high familial incidence of CJD in this population and a molecular genetic research elucidated that CJD segregates with a point mutation at codon 200 of the PrP gene resulting in the substitution of Lysine for Glutamate. This mutation was found in some 40 CJD patients of Libyan origin and was not found in one Moroccan Jew suffering from CJD. It was also absent in almost 100 healthy Libyan controls above the age of 60. This result strongly supports a genetic etiology for CJD pathogenesis in the Libyan Jewish community and disregards the previous culinary hypothesis. The disease is vertically transmitted in autosomal dominant inheritance with unknown penetrance. All our patients were heterozygote for the mutation except one homozygote patient. The course of the disease in this patient was identical to the heterozygote patients, strongly arguing that inherited CJD displays complete phenotypic dominance.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7858177 TI - Neurologic genetic diseases of Jewish people. AB - Three important dominantly-inherited neurological diseases were discovered to be particularly common among various Jewish ethnic groups. For idiopathic torsion dystonia (ITD), previously thought to be recessively transmitted among Ashkenazi Jews, we have established an autosomal dominant mode of inheritance. This finding resulted from a country-wide survey of ITD in Israel and its subsequent genetic analysis. In Creutzfeldt-Jakob disease (CJD) the focus among Libyan Jews was previously thought to be related to culinary habits; a point mutation of the prion-protein gene was first described by us. The factors leading to the preservation of these disadvantageous genes in the communities are however unknown. Genetic analysis shows reduced penetrance in ITD and age-related expression in CJD. Factors leading to the expression of the genes were looked for. Data for ITD suggest that laterality of onset depends on motor dominance. Data on anticipation are presented. Factors possibly involved in the expression of the CJD codon 200 mutation are also discussed. A focus of myotonic dystrophy was documented among Yemenite Jews. The preservation of this disadvantageous, dominantly-inherited gene (which leads to diminished reproductive abilities), was found to be social rather than biological, related to reduced age of marriage and number of offspring in this ethnic group. These data show an interaction between genetic and other biological and external factors in the expression of these three diseases. PMID- 7858178 TI - Histamine receptors in an experimental mammary carcinoma. AB - An experimental mammary carcinoma was induced in Sprague-Dawley rats by the ip administration of N-nitroso-N-methylurea (NMU) in three doses of 50 mg/kg. In order to study the expression of histamine receptors in these experimental tumors, the presence of specific binding sites for histamine was studied. Using [3H]-histamine as a radioligand, two specific binding sites were characterized on the cell membrane. The first site, of high affinity, Kd = 4 +/- 2 nM, was further characterized as an H2 type using [3H]-cimetidine and [3H]-tiotidine as radioligands and by displacement experiments with different histamine agonists and antagonists. The second one of low affinity, Kd = 35 +/- 14 nM, needs further characterization. The determination of cAMP levels showed that histamine and the H2 agonist dimaprit, produced a significant decrease in the nucleotide concentration 6 minutes after stimulation, in a response that was specifically abolished by H2 antagonists. Based on these results, we conclude that neoplastic cells from NMU induced tumors express H2 histamine membrane receptors which are coupled to a transductional pathway different from cAMP production, which may be involved in the regulation of tumor growth. PMID- 7858179 TI - A human monoclonal antibody with the capacity to neutralize Staphylococcus aureus alpha-toxin. AB - A human monoclonal antibody, CB STL-1, against staphylococcal alpha-toxin has been established by hybridoma technology. It is of IgG1 subclass with lambda light chain and possesses a dissociation constant of 8 x 10(-10) mol/l. 1 mg of purified antibody neutralizes the hemolytic activity of 800 micrograms/ml alpha toxin in an in vitro hemolysis assay using rabbit erythrocytes. The antibody does not bind to overlapping (7 residues) decapeptides spanning the sequence of alpha toxin, thus it might bind to a conformational epitope. The epitope recognized by the antibody is not accessible in oligomeric toxin. The antibody binds both to the hydrophilic and amphipathic forms of the monomeric toxin Fab fragments of the antibody are stable and show no significant loss of activity. CB STL-1 was able to protect mice in vivo from i.p. challenge with alpha toxin. Thus, the antibody is a candidate for passive immunotherapy. The variable regions of the antibody secreted by CB STL-1 were sequenced and found to be encoded by a VH gene segment belonging to the VH1 family, and a Vlambda segment most likely belonging to the VlambdaIII subgroup. Further analysis concerning the third complementarity determining region (CDR3) of the heavy chain is presented. PMID- 7858180 TI - Human monoclonal Fab fragments from a combinatorial library prepared from an individual with a low serum titer to a virus. AB - An IgG1k lambda Fab library was generated on the surface of phage beginning with bone marrow RNA from a healthy 22-year-old human donor. The donor had been immunized to measles in his early childhood but had only a low serum titer to a measles antigen preparation. The resulting library of approximately 10(7) clones was panned against the measles antigen preparation and three positive Fab producing clones identified by ELISA. One of the Fabs was found to be specific to measles and to bind with high apparent affinity (10(8) M-1). The other two bind with lower affinity and show marked cross-reactivity with a number of other antigens. They possess heavy chains derived, with extensive somatic modification, from the single member gene family VH6. The study indicates that both high affinity specific antibodies and lower affinity polyreactive antibodies can be derived from the library approach under appropriate conditions. PMID- 7858181 TI - Secretion of human monoclonal antibody after fusion of an immortal T cell line and lymphocytes from the peripheral blood of a patient with colon carcinoma. AB - A series of human hybridomas were derived by the fusion of the immature T cell line, JM, and lymphocytes from the peripheral blood of a colon carcinoma patient in long term remission who was shown to produce anti-tumor antibody. Five of the hybridomas have been selected for further study. These hybridomas express the T cell surface markers CD2, CD3, CD4, and CD8. The human IgG2/kappa antibody produced by these clones has been purified using affinity chromatography and has been used in immunohistiologic staining procedures. Biotinylated monoclonal antibody (MAb) stained colon carcinoma tissue but did not stain normal colon. Positive immunostaining was also seen utilizing colon carcinoma cell lines but not with other cell lines tested. These hybrids were constructed without using the conventional fusion technology which employs 8-azoguanine resistant, HAT sensitive malignant fusion partners. Because the fusion partner was a T cell, we were able to select hybrids on the basis of surface immunoglobulin. This approach was accompanied by stringent selection of patients as lymphocyte donors. Utilizing these unique methods, we have successfully produced hybridomas with T cell surface markers that produce human MAb with reactivity to colon carcinoma. PMID- 7858182 TI - Humanization of the murine anti-human CD3 monoclonal antibody OKT3. AB - OKT3 is a murine monoclonal antibody which recognizes an epitope on the epsilon subunit within the human CD3 complex. OKT3 possesses potent immunosuppressive properties in vivo and has been proven effective in the treatment of renal, heart and liver allograft rejection. Despite its efficacy, significant problems remain associated with OKT3 therapy, i.e. T-cell activation and the anti-murine antibody response. To address the problem of the anti-murine antibody response we have constructed humanized versions of OKT3. One of the humanized derivatives, gOKT3-7 incorporating the OKT3 complementarity determining regions plus a small number of alterations to the human framework, has an affinity of 1.4 x 10(9) M-1 compared with 1.2 x 10(9) M-1 for the murine OKT3. A humanized antibody (gOKT3-1) incorporating only the CDRs from OKT3 was found to be functionally inactive, confirming the requirement for nonCDR substitutions. gOKT3-7 retains the ability of mOKT3 to induce T cell proliferation in vitro and appears to be a good candidate for further development for in vivo therapy. PMID- 7858183 TI - Phage surface presentation and secretion of antibody fragments using an adaptable phagemid vector. AB - Phagemid vectors have been developed which promise to supersede hybridoma technology for the selection and production of human antibodies. We have modified an existing phagemid vector to improve the stability of synthesized soluble antibody fragments. The vector allows the antibody fragment to be produced: i) as a soluble protein incorporating a stable carboxyl terminal octapeptide (FLAG) or, ii) on the surface of a bacteriophage fused to a minor coat protein (the gene III protein). The antibody gene encoding the well characterized monoclonal antibody NC10 (an antibody that recognizes the neuraminidase of the influenza strain N9) was inserted as a single chain Fv construct into the phagemid vectors pHFA and pHFA/SacII. Western blotting, ELISA and electron microscopy studies showed that recombinant clones could be manipulated to either synthesize soluble protein into the periplasm or present the protein on the surface of bacteriophage. Cosynthesis of GroEL and GroES chaperonins resulted in complete proteolysis of the scFvNC10 FLAG-gIIIp fusion product and did not improve total phage production. Coexpression of chaperonins should be used with caution for library construction due to the expected selection pressure for protease resistant gene III fusions. PMID- 7858184 TI - Design and analysis of PCR primers for the amplification and cloning of human immunoglobulin Fab fragments. AB - We have developed PCR primers for the amplification and cloning of the genes encoding human antibody fragments. Two sets of primers were designed to amplify the coding sequence of the complete variable region and the first constant domain of immunoglobulin heavy chains. One set of primers was designed to amplify the coding sequence of complete kappa light chains. These three sets of primers were used in PCR amplifications with cDNA prepared from EBV transformed B cells as the template. The amplified fragments were cloned and their nucleotide sequences were determined. Analysis of the DNA sequences of such PCR generated antibody fragments suggested that our primer sets were able to amplify the major subsets of the heavy and light chain variable region genes. Comparison between the estimated frequency of the different subsets of heavy chain variable region genes and the distribution of our subclones further indicated that one set of our primers was able to proportionally amplify the subsets of the heavy chain family. PMID- 7858185 TI - Serum preparation and methods for the large-scale production of IgG monoclonal antibody. AB - In this study we demonstrated that fetal calf serum (FCS) depleted of IgG by protein G affinity chromatography (G-FCS) is superior to whole FCS or serum-free culture media as a culture supplement for the production of purified IgG monoclonal antibodies (MAb). One hundred ml FCS was applied to a 25 ml protein G Sepharose 4 Fast Flow Column, which was shaken gently for 2 days at 4 degrees C. The procedure was repeated using a protein G column for an additional day. G-FCS was used at a concentration of 5% in RPMI 1640 medium to grow the mouse myeloma cell line P3X63.Ag8.653, which secretes an IgG-1 mouse-human chimeric monoclonal antibody (TVE-1). Cell density, viability, doubling time, and antibody production were used as indices to compare the efficacy of this medium with that of whole FCS medium, AIM-V (Gibco, USA) and other serum-free media. The results demonstrate that cell growth and antibody production in -GFCS medium did not differ significantly from that in FCS medium, but were significantly better than in the serum-free media (p < 0.001). TVE-1 antibody in the spent tissue culture media was purified by 50% ammonium sulfate precipitation and Protein A affinity chromatography. An antibody that was more than 99% pure was obtained. Endotoxin analysis revealed that the IgG depletion process does not generate a significant level of endotoxin in FCS (< 0.06 EU/ml).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7858186 TI - Human monoclonal antibodies recognize early and late viral proteins of human cytomegalovirus. AB - Human monoclonal antibodies directed against human cytomegalovirus were generated by fusion of in vitro stimulated human spleen lymphocytes from an HCMV seropositive 53-year-old organ donor with the mouse myeloma cell line Ag8.653. Fourteen human/mouse hybridomas producing anti-cytomegalovirus IgG were screened by an ELISA technique and four selected clones have been established since March 1988, generating about 5-40 micrograms/24 h IgG per ml culture supernatant. Reference and local cytomegalovirus strains were stained by the antibodies without showing cross-reactivity to other herpes viruses. Three monoclonal antibodies, A4B4 (IgG11), A6B3 (IgG1k) and A6A2 (IgG1k), immunoprecipitated a 68 kDa early viral protein which appears during the infectious cycle, first in the nucleus (18-24 h) and then also in the cytoplasm (24-96 h) of infected cells. Inhibition of DNA replication restricted the detection of the 68 kDa viral protein to the nucleus of infected cells. Staining of unfixed infected cells showed that two of the antibodies bound at the surface of a few cells. The fourth monoclonal antibody A3C5 (IgG11) immunoprecipitated a 34/38 kDa late viral protein which appears in the nucleus (48-72 h) of infected cells. These antibodies enable us to study the human host response to human cytomegalovirus and to elucidate the functions of human antibodies especially in their interaction with the T-cell response. PMID- 7858187 TI - Construction and characterization of chimeric and humanized forms of a broadly neutralizing monoclonal antibody to HIV-1. AB - Murine monoclonal antibody (MAb) G3-519 has been shown to recognize a conserved neutralizing epitope in the fourth constant (C4) region of the external glycoprotein gp120 of HIV-1. Inasmuch as this antibody effectively neutralized the infectivity of diverse HIV-1 isolates, it has been selected to be developed for passive immunization against HIV-1 infection in humans. In order to minimize the problem of immunogenicity of murine antibodies and to confer additional accessory immune functions, we have constructed mouse/human chimeric and humanized forms of the antibody. The chimeric antibody was constructed by cloning the murine variable regions and replacing the mouse constant regions with those from human Ig gamma 1,kappa. The humanized antibody was constructed using the human KAS variable region framework sequences as template. Engineering was guided by a three dimensional model of the murine variable region. The murine, chimeric and humanized forms of the antibody exhibited similar reactivity with the peptidic antigen in ELISA, and comparably neutralized the infectivity of HIV-1 in vitro. Taken together, our results show that the chimeric and humanized forms of G3-519 essentially retain the binding activity of the mouse parental antibody. Clinical development is planned to assess the prophylactic and therapeutic usefulness of these reshaped antibodies in humans. PMID- 7858188 TI - Anti-bacterial specificities in the human fetal B cell repertoire. AB - To study the human fetal B cell repertoire, liver and spleen lymphocytes were fused with the human x mouse heteromyeloma line CB-F7. Initially, 2310 IgM and 181 IgG producing hybridoma lines were established. Culture supernatants were analysed for binding activity to antigens from both the exogeneous and the endogeneous environments. For IgG secreting cell lines no antigenetic specificity has been detected. However, independently from the gestational age, monoclonal IgM antibodies binding to bacterial antigens (tetanus toxoid, lipid A, N. meningitidis antigens) were found. In particular, nearly 10% of the hybridomas obtained from fetal liver produced antibodies binding to lipid A (endotoxin). Among the IgM antibodies with anti-bacterial specificities approximately 30% were found to be polyspecific, i.e. these antibodies recognized auto-antigens of different molecular origin as well (ssDNA, keratin, myosin, actin). We conclude that polyreactive natural IgM antibodies may be generated during fetal life, which may take part in the formation of a humoral anti-infectious first line defense barrier in the neonate. PMID- 7858190 TI - Signal transduction in the sexual life of Chlamydomonas. AB - Several signal transduction pathways play important roles in the sexual life cycle of Chlamydomonas. Nitrogen deprivation, perhaps sensed as a drop in intracellular [NH4+], triggers a signal transduction pathway that results in altered gene expression and the induction of the gametogenic pathway. Blue light triggers a second signalling cascade which also culminates in gene induction and completion of gametogenesis. New screens have uncovered several mutants in these pathways, but so far we know little about the biochemical events that transduce the environmental signals of nitrogen deprivation and blue light into the changes in gene transcription that produce gametes. Cell-cell contact of mature, complementary gametes elicits a number of responses that prepare the cells for fusion. Contact is sensed by the agglutinin-mediated cross-linking of flagellar membrane proteins. An increase in [cAMP] couples protein cross-linking to the mating responses. In C. reinhardtii the cAMP signal appears to be generated by the sequential stimulation of as many as 3 distinct adenylyl cyclase activities. Although the molecular mechanisms of adenylyl cyclase activations are poorly understood, Ca2+ may play a role. Most of the mating responses appear to be triggered by a cAMP-dependent protein kinase, but here too, Ca2+ may play a role. Numerous mutants are facilitating studies of the signalling pathways that trigger the mating responses. Cell fusion triggers another series of events that culminate in the expression of zygote specific genes. The mature zygote is sensitive to a light signal which stimulates the expression of genes whose products are essential for germination. The signal transduction pathways that trigger zygospore formation and germination are ripe for investigation in this experimentally powerful system. PMID- 7858191 TI - Control of cell proliferation during plant development. AB - Knowledge of the control of cell division in eukaryotes has increased tremendously in recent years. The isolation and characterization of the major players from a number of systems and the study of their interactions have led to a comprehensive understanding of how the different components of the cell cycle apparatus are brought together and assembled in a fine-tuned machinery. Many parts of this machine are highly conserved in organisms as evolutionary distant as yeast and animals. Some key regulators of cell division have also been identified in higher plants and have been shown to be functional homologues of the yeast or animal proteins. Although still in its early days, investigations into the regulation of these molecules have provided some clues on how cell division is coupled to plant development. PMID- 7858192 TI - Signal molecules involved in plant embryogenesis. AB - In plant embryogenesis, inductive interactions mediated by diffusable signal molecules are most likely of great importance. Evidence has been presented that at late globular stages in plant embryogenesis, perturbation of the polar auxin transport results in abberrant embryo morphology. Rhizobium lipooligosaccharides or Nod factors are a newly discovered class of bacterial molecules that are able to trigger initial steps in root nodule development in legumes. Part of the activity of Nod factors may be directed towards alteration of endogenous plant growth regulator balance. The same bacterial Nod factors promoted the formation of globular embryos in the carrot cell line ts11. Whether there exist plant analogues of the Nod factors and whether these molecules are active as a more universal control system perhaps designed to initiate and or mediate gradients in auxin and cytokinin remains to be determined. PMID- 7858189 TI - Transmembrane signalling in eukaryotes: a comparison between higher and lower eukaryotes. PMID- 7858193 TI - Initial events in phytochrome signalling: still in the dark. PMID- 7858194 TI - Mechanical signalling, calcium and plant form. AB - Calcium is a dynamic signalling molecule which acts to transduce numerous signals in plant tissues. The basis of calcium signalling is outlined and the necessity for measuring and imaging of calcium indicated. Using plants genetically transformed with a cDNA for the calcium-sensitive luminescent protein, aequorin, we have shown touch and wind signals to immediately increase cytosol calcium. Touch and wind signal plant cells mechanically, through tension and compression of appropriate cells. Many plant tissues and cells are very sensitive to mechanical stimulation and the obvious examples of climbing plants, insectivorous species as well as other less well-known examples are described. Touch sensing in these plants may be a simple evolutionary modification of sensitive mechanosensing system present in every plant. The possibility that gravitropism may be a specific adaptation of touch sensing is discussed. There is a growing appreciation that plant form may have a mechanical basis. A simple mechanical mechanism specifying spherical, cylindrical and flat-bladed structures is suggested. The limited morphological variety of plant tissues may also reflect mechanical specification. The article concludes with a discussion of the mechanisms of mechanical sensing, identifying integrin-like molecules as one important component, and considers the specific role of calcium. PMID- 7858195 TI - Genetic analyses of signalling in flower development using Arabidopsis. AB - Flower development can be divided into four major steps: phase transition from vegetative to reproductive growth, formation of inflorescence meristem, formation and identity determination of floral organs, and growth and maturation of floral organs. Intercellular and intracellular signalling mechanisms must have important roles in each step of flower development, because it requires cell division, cell growth, and cell differentiation in a concerted fashion. Molecular genetic analysis of the process has started by isolation of a series of mutants with unusual flowering time, with aberrant structure in inflorescence and in flowers, and with no self-fertilization. At present more than 60 genes are identified from Arabidopsis thaliana and some of them have cloned. Although the information is still limited, several types of signalling systems are revealed. In this review, we summarize the present genetic aspects of the signalling network underlying the processes of flower development. PMID- 7858197 TI - Role of rhizobial lipo-chitin oligosaccharide signal molecules in root nodule organogenesis. AB - The role of oligosaccharide molecules in plant development is discussed. In particular the role of the rhizobial lipo-chitin oligosaccharide (LCO) signal molecules in the development of the root nodule indicates that oligosaccharides play an important role in organogenesis in plants. Recent results of the analyses of structures and of the biosynthesis of the LCO molecules are summarized in this paper. The knowledge and technologies that resulted from these studies will be important tools for further studying the function of LCO signals in the plant and in the search for analogous signal molecules produced by plants. PMID- 7858196 TI - Oligosaccharins: structures and signal transduction. PMID- 7858198 TI - Fatty acid signalling in plants and their associated microorganisms. PMID- 7858199 TI - The salicylic acid signal in plants. PMID- 7858200 TI - Plant hormone conjugation. PMID- 7858201 TI - Cytokinin metabolism: implications for regulation of plant growth and development. PMID- 7858202 TI - Activation tagging: a means of isolating genes implicated as playing a role in plant growth and development. AB - Activation T-DNA tagging has been used to generate a variety of tobacco cell lines selected by their ability to grow either in the absence of auxin or cytokinin in the culture media, or under selective levels of an inhibitor of polyamine biosynthesis. The majority of the cell lines studied in detail contain single T-DNA inserts genetically co-segregating with the selected phenotype. While most of the plants regenerated from the mutant cell lines appear phenotypically normal, several display phenotypes which could be inferred to result from disturbances in the content, or the metabolism, of auxins and cytokinins, or polyamines. The tagging vector is designed to allow the isolation of tagged plant genes by plasmid rescue. Confirmation that the genomic sequence responsible for the selected phenotype has indeed been isolated is provided by PEG-mediated protoplast DNA uptake of rescued plasmids followed by selection for protoplast growth under the original selective conditions. Several plasmids have been rescued from the mutant lines which confer on transfected protoplasts the ability to grow either in the absence of auxin or cytokinin in the culture media, or under selective levels of an inhibitor of polyamine biosynthesis. This review describes the background to activation tagging and our progress in characterizing the genes that have been tagged in the mutant lines we have generated. PMID- 7858203 TI - Gibberellins: perception, transduction and responses. PMID- 7858204 TI - Current advances in abscisic acid action and signalling. AB - Abscisic acid (ABA) participates in the control of diverse physiological processes. The characterization of deficient mutants has clarified the ABA biosynthetic pathway in higher plants. Deficient mutants also lead to a revaluation of the extent of ABA action during seed development and in the response of vegetative tissues to environmental stress. Although ABA receptor(s) have not yet been identified, considerable progress has been recently made in the characterization of more downstream elements of the ABA regulatory network. ABA controls stomatal aperture by rapidly regulating identified ion transporters in guard cells, and the details of the underlying signalling pathways start to emerge. ABA actions in other cell types involve modifications of gene expression. The promoter analysis of ABA-responsive genes has revealed a diversity of cis acting elements and a few associated trans-acting factors have been isolated. Finally, characterization of mutants defective in ABA responsiveness, and molecular cloning of the corresponding loci, has proven to be a powerful approach to dissect the molecular nature of ABA signalling cascades. PMID- 7858205 TI - Ethylene biosynthesis and action: a case of conservation. PMID- 7858206 TI - Structure and function of the receptor-like protein kinases of higher plants. AB - Cell surface receptors located in the plasma membrane have a prominent role in the initiation of cellular signalling. Recent evidence strongly suggests that plant cells carry cell surface receptors with intrinsic protein kinase activity. The plant receptor-like protein kinases (RLKs) are structurally related to the polypeptide growth factor receptors of animals which consist of a large extracytoplasmic domain, a single membrane spanning segment and a cytoplasmic domain of the protein kinase gene family. Most of the animal growth factor receptor protein kinases are tyrosine kinases; however, the plant RLKs all appear to be serine/threonine protein kinases. Based on structural similarities in their extracellular domains the RLKs fall into three categories: the S-domain class, related to the self-incompatibility locus glycoproteins of Brassica; the leucine rich repeat class, containing a tandemly repeated motif that has been found in numerous proteins from a variety of eukaryotes; and a third class that has epidermal growth factor-like repeats. Distinct members of these putative receptors have been found in both monocotyledonous plants such as maize and in members of the dicotyledonous Brassicaceae. The diversity among plant RLKs, reflected in their structural and functional properties, has opened up a broad new area of investigation into cellular signalling in plants with far-reaching implications for the mechanisms by which plant cells perceive and respond to extracellular signals. PMID- 7858210 TI - Closing lecture--ISPMB Congress. PMID- 7858209 TI - Sugar transport across the plasma membranes of higher plants. AB - The fluxes of carbohydrates across the plasma membranes of higher-plant cells are catalysed mainly by monosaccharide and disaccharide-H+ symporters. cDNAs encoding these different transporters have been cloned recently and the functions and properties of the encoded proteins have been studied extensively in heterologous expression systems. Several of the proteins have been identified biochemically in these expression systems and their location in plants has been shown immunohistochemically or with transgenic plants which were transformed with reporter genes, expressed under the control of the promoters of individual transporter genes. In this paper we summarize the current knowledge on the molecular biology and biochemistry of higher-plant sugar transport proteins. PMID- 7858207 TI - GTP-binding proteins in plants: new members of an old family. AB - Regulatory guanine nucleotide-binding proteins (G proteins) have been studied extensively in animal and microbial organisms, and they are divided into the heterotrimeric and the small (monomeric) classes. Heterotrimeric G proteins are known to mediate signal responses in a variety of pathways in animals and simple eukaryotes, while small G proteins perform diverse functions including signal transduction, secretion, and regulation of cytoskeleton. In recent years, biochemical analyses have produced a large amount of information on the presence and possible functions of G proteins in plants. Further, molecular cloning has clearly demonstrated that plants have both heterotrimeric and small G proteins. Although the functions of the plant heterotrimeric G proteins are yet to be determined, expression analysis of an Arabidopsis G alpha protein suggests that it may be involved in the regulation of cell division and differentiation. In contrast to the very few genes cloned thus far that encode heterotrimeric G proteins in plants, a large number of small G proteins have been identified by molecular cloning from various plants. In addition, several plant small G proteins have been shown to be functional homologues of their counterparts in animals and yeasts. Future studies using a number of approaches are likely to yield insights into the role plant G proteins play. PMID- 7858208 TI - Transporters for nitrogenous compounds in plants. PMID- 7858211 TI - Coordinate expression of antibody subunit genes yields high levels of functional antibodies in roots of transgenic tobacco. AB - To explore the feasibility of employing antibodies to obtain disease resistance against plant root pathogens, we have studied the expression of genes encoding antibodies in roots of transgenic plants. A model monoclonal antibody was used that binds to a fungal cutinase. Heavy and light chain cDNAs were amplified by PCR, fused to a signal sequence for secretion and cloned behind CaMV 35S and TR2' promoters in a single T-DNA. The chimeric genes were cloned both in tandem and in a divergent orientation. The roots of tobacco plants transformed with these constructs produced antibodies that were able to bind antigen in an ELISA. Immunoblotting showed assembly to a full-size antibody. In addition, a F(ab')2 like fragment was observed, which is probably formed by proteolytic processing. Both antibody species were properly targeted to the apoplast, but the full-size antibody was partially retained by the wall of suspension cells. The construct with divergent promoters showed a better performance than the construct with promoters in tandem. It directed the accumulation of functional antibodies to a maximum of 1.1% of total soluble protein, with half of the plants having levels higher than 0.35%. The high efficiency of this construct probably results from coordinated and balanced expression of light and heavy chain genes, as evidenced by RNA blot hybridization. PMID- 7858212 TI - Expression of the BnmNAP subfamily of napin genes coincides with the induction of Brassica microspore embryogenesis. AB - Brassica napus cv. Topas microspores can be diverted from pollen development toward haploid embryo formation in culture by subjecting them to a heat stress treatment. We show that this switch in developmental pathways is accompanied by the induction of high levels of napin seed storage protein gene expression. Changes in the plant growth or microspore culture conditions were not by themselves sufficient to induce napin gene expression. Specific members of the napin multigene family were cloned from a cDNA library prepared from microspores that had been induced to undergo embryogenesis. The majority of napin clones represented three members (BnmNAP2, BnmNAP3 and BnmNAP4) that, along with a previously isolated napin genomic clone (BngNAP1), constitute the highly conserved BnmNAP subfamily of napin genes. Both RNA gel blot analysis, using a subfamily-specific probe, and histochemical analysis of transgenic plants expressing a BngNAP1 promoter-beta-glucuronidase gene fusion demonstrated that the BnmNAP subfamily is expressed in embryogenic microspores as well as during subsequent stages of microsporic embryo development. PMID- 7858213 TI - Functional complementation of a yeast vesicular transport mutation ypt1-1 by a Brassica napus cDNA clone encoding a small GTP-binding protein. AB - A cDNA clone (bra) encoding a small GTP-binding protein was isolated from Brassica napus by screening a root cDNA library with a degenerate oligonucleotide probe that corresponds to a highly conserved GTP-binding domain of the Ras superfamily. Sequence analysis shows that the clone contains an open reading frame of 219 amino acid residues with the estimated molecular mass of 24379 Da and this coding region contains all the conserved motifs of the Ras superfamily. The deduced amino acid sequence of the bra gene is most closely related to the Ypt/Rab family that functions in the vesicular transport (46% and 47% amino acid identity to the yeast Ypt1 and to the human Rab1, respectively) and is more distantly related to the other Ras-related families. The protein encoded by the bra gene, when expressed in Escherichia coli, shows the ability to bind GTP. Furthermore, when the bra gene is introduced into Saccharomyces cerevisiae under the regulation of the yeast GAL1 promoter, the gene can complement the temperature-sensitive yeast mutation ypt1-1 that has defects in vesicular transport function. The amino acid sequence similarity and the functional complementation of the yeast mutation suggest that this gene is likely to be involved in the vesicular transport in plants. Genomic Southern analysis shows that this gene is a member of a small gene family in Brassica napus. PMID- 7858214 TI - Molecular characterization of rice genes specifically expressed in the anther tapetum. AB - In situ localization of mRNA was carried out on two cDNAs (Osc4 and Osc6) that had been isolated from rice anthers at the microspore stage. The mRNA corresponding to each cDNA was shown to be localized only in the tapetal cells of the rice immature anthers, but not in the microspores or the mature pollen. The corresponding genomic clone, Osg6B, was isolated, and its 5'-upstream region was found to regulate beta-glucuronidase expression in the tapetum of transgenic tobacco. A set of 5' deletions was also generated and a 1095 bp 5' region was revealed to be necessary for activation of the Osg6B promoter in transgenic tobacco. PMID- 7858215 TI - Characterization of the tobacco eIF-4A gene family. AB - Characterization of cDNAs encoding eukaryotic translation initiation factor 4A (eIF-4A) indicates the expression of a minimum of ten related genes in tobacco leaf cells. The ten groups fall into two gene families, NeIF-4A2 and NeIF-4A3. The majority of the cDNAs exhibit significant sequence similarity to the NeIF-4A2 family at both the DNA and deduced amino acid levels. Northern analysis using specific probes indicates variable expression of four family members in various tobacco organs. Western analysis, using an anti-tobacco eIF-4A polyclonal antibody, reveals a complex pattern of immunologically related polypeptides of approximately 46 kDa. Subcellular fractionation suggests that at least one eIF-4A related polypeptide is located in the chloroplast where it is ribosome associated. PMID- 7858217 TI - In vivo analysis of intron processing using splicing-dependent reporter gene assays. AB - The mechanisms of intron recognition and processing have been well-studied in mammals and yeast, but in plants the biochemistry of splicing is not known and the rules for intron recognition are not clearly defined. To increase understanding of intron processing in plants, we have constructed new pairs of vectors, pSuccess and pFail, to assess the efficiency of splicing in maize cells. In the pFail series we use translation of pre-mRNA to monitor the amount of unspliced RNA. We inserted an ATG codon in the Bz2 (Bronze-2) intron in frame with luciferase: this construct will express luciferase activity only when splicing fails. In the pSuccess series the spliced message is monitored by inserting an ATG upstream of the Bz2 intron in frame with luciferase: this construct will express luciferase activity only when splicing succeeds. We show here, using both the wild-type Bz2 intron and the same intron with splice site mutations, that the efficiency of splicing can be estimated by the ratio between the luciferase activities of the vector pairs. We also show that mutations in the unique U-rich motif inside the intron can modulate splicing. In addition, a GC rich insertion in the first exon increases the efficiency of splicing, suggesting that exons also play an important role in intron recognition and/or processing. PMID- 7858216 TI - The C3 plant Flaveria pringlei contains a plastidic NADP-malic enzyme which is orthologous to the C4 isoform of the C4 plant F. trinervia. AB - To study the molecular evolution of NADP-dependent malic enzyme (NADP-ME) in the genus Flaveria a leaf-specific cDNA library of the C3 plant F. pringlei was screened for the presence of sequences homologous to the C4 isoform gene (named modA) of the C4 plant F. trinervia. The cDNAs isolated contained varying numbers of identical restriction fragments suggesting that they were derived from a single gene. This was supported by Southern hybridisation experiments with genomic DNA from F. trinervia and F. pringlei. Nucleotide sequence analysis of a full-size clone identified the presence of a typical plastidic transit peptide and revealed that the mature modA proteins of F. trinervia (C4) and F. pringlei (C3) are 90% similar. These findings indicate that C3 plants, like C4 species, possess a plastidic isoform of NADP-ME and that the modA genes of the two species represent orthologous genes. Northern analyses showed that modA transcripts accumulate to similar levels in leaves, stems and roots of F. pringlei. The expression of this gene in F. pringlei thus appears to be rather constitutive. In contrast, the modA gene of F. trinervia is abundantly expressed in leaves, but maintains its expression in stems and roots. It has to be concluded from these data that the leaf-specific increase in the expression level was a key step which was taken during the evolution of the C4 isoform modA gene starting from a C3 ancestral gene. PMID- 7858218 TI - A putative O-methyltransferase from barley is induced by fungal pathogens and UV light. AB - A cDNA clone, pBH72-F1 (F1), was isolated from a cDNA library prepared from barley leaves 72 h after inoculation with Erysiphe graminis f.sp. hordei. The 1388 bp nucleotide sequence of pBH72-F1 contains an open reading frame encoding a 42.3 kDa polypeptide of 390 amino acids which shows sequence similarity to O methyltransferases (OMTs) from different plant species; the highest identity (41%) was observed with a putative OMT expressed in roots of maize. A phylogenetic analysis shows that the barley and maize sequences are distinctly different from the ortho-diphenol-OMTs involved in lignin formation. A putative S adenosyl-L-methionine-binding motif (KELVDDSITN) determined for a rabbit protein carboxyl OMT is partially conserved in the encoded amino acid sequence. Genomic Southern blot hybridization shows that pBH72-F1 probably represents a single copy gene. The F1 clone corresponds to a gene transcript exhibiting a relatively late accumulation in mildew-infected barley leaves compared to other pathogen-induced transcripts, such as transcripts encoding PR proteins, a peroxidase, and transcripts homologous to a maize caffeic acid OMT. No transcript was detected in plants exhibiting papilla resistance at time points when resistance is thought to be manifested. The atypical transcript accumulation pattern for F1 was also observed after infection by other pathogens and after UV-light treatment. PMID- 7858219 TI - Biphasic and differential expression of cytosolic glutamine synthetase genes of radish during seed germination and senescence of cotyledons. AB - Three structurally distinct cDNA clones for cytosolic glutamine synthetase (GS1) were isolated from libraries prepared from senescing radish cotyledons. Northern blot analysis showed that transcripts from two of the three genes encoding GS1, Gln1;1 and Gln1;3, accumulated in the cotyledons during both dark-induced and natural senescence. Transcripts from the last gene, Gln1;2, remained at a low level during both processes. Transcripts from all three Gln1 genes accumulated in cotyledons of germinating seeds. We infer from these findings that GS1 enzymes function in both germination and senescence to convert ammonium to glutamine to remobilize nitrogen from source to sink organs. We have also examined the pattern of expression of these genes in different tissues. All three genes are expressed in roots. A large amount of transcripts from Gln1;1 accumulated in hypocotyls. Whereas none were transcribed in flowers. During dark-induced senescence of cotyledons, application of inorganic nitrogen delayed chlorophyll degradation. Inorganic nitrogen enhanced the accumulation of Gln1;1 transcripts, but decreased those of Gln1;3. In contrast, application of glutamine promoted yellowing of cotyledons during the dark treatment, and slightly increased the amounts of transcripts from Gln1;3 but decreased those of Gln1;1. Transcription of the three Gln1 genes appears, therefore, to be differentially regulated in radish cotyledons during senescence and germination. PMID- 7858220 TI - Characterisation and expression of the mitochondrial genome of a new type of cytoplasmic male-sterile sunflower. AB - A new cytoplasmic male sterile sunflower, CMS3 [44], was characterised in relation to the Petiolaris (PET1) cytoplasmic male-sterile sunflower, CMS89 [25]. Southern blot analysis showed that the mitochondrial genome of CMS3 contains unique rearrangements in at least five loci (atp6, atp9, atpA, nad1 + 5 and coxIII) compared to the PET1 sterile and the fertile cytoplasms. Transcripts of two (coxIII and atp6) of the five rearranged loci differed in CMS3 when compared to the corresponding loci in the PET1 and fertile cytoplasms. In organello protein synthesis experiments showed that the ca. 15 kDa mitochondrial polypeptide, characteristic of PET1, is not present in the CMS3 line. These data suggest that the molecular basis of male sterility in the CMS3 line differs from that of the PET1 cytoplasm. The nucleotide sequences of the coding and the immediate flanking regions of the coxIII and atp6 genes of CMS3 were compared to the corresponding regions from the fertile sunflower. In CMS3 the ORFB-coxIII locus is located immediately 3' to the atpA gene whereas in the fertile cytoplasm these two loci are ca. 60 kb apart. This DNA rearrangement probably involved a 265 bp repeat which may be implicated in the DNA recombination associated with PET1 CMS. The atp6 gene in CMS3 contains a 5'-terminal extention which results in an extended ORF. The potential involvement of the rearrangements associated with the coxIII and atp6 loci in relation to the CMS phenotype is discussed. PMID- 7858221 TI - Expression of a single gene encoding microbody NAD-malate dehydrogenase during glyoxysome and peroxisome development in cucumber. AB - A full-length cDNA clone encoding microbody NAD(+)-dependent malate dehydrogenase (MDH) of cucumber has been isolated. The deduced amino acid sequence is 97% identical to glyoxysomal MDH (gMDH) of watermelon, including the amino terminal putative transit peptide. The cucumber genome contains only a single copy of this gene. Expression of this mdh gene increases dramatically in cotyledons during the few days immediately following seed imbibition, in parallel with genes encoding isocitrate lyase (ICL) and malate synthase (MS), two glyoxylate cycle enzymes. The level of MDH, ICL and MS mRNAs then declines, but then MDH mRNA increases again together with that of peroxisomal NAD(+)-dependent hydroxypyruvate reductase (HPR). The mdh gene is also expressed during cotyledon senescence, together with hpr, icl and ms genes. These results indicate that a single gene encodes MDH which functions in both glyoxysomes and peroxisomes. In contrast to icl and ms genes, expression of the mdh gene is not activated by incubating detached green cotyledons in the dark, nor is it affected by exogenous sucrose in the incubation medium. The function of this microbody MDH and the regulation of its synthesis are discussed. PMID- 7858222 TI - Cloning and characterization of maize herbicide safener-induced cDNAs encoding subunits of glutathione S-transferase isoforms I, II and IV. AB - Several GSTs have been characterised in maize. GST I is a homodimer of 29 kDa subunits, GST II a hetrodimer of 27 kDa and 29 kDa subunits and GST IV a homodimer of 27 kDa subunits. We report the isolation and characterization of a herbicide-safener inducible cDNA clone, GST-27. Based on partial amino acid sequence, GST-27 encodes the 27 kDa subunit present in both glutathione S transferase isoforms GST II and IV. Northern blotting was used to compare the expression patterns of GST-27 with that of GST-29. Transcripts corresponding to GST-27 were found to be constitutively expressed in RNA isolated from the root, but no expression was detected in RNA isolated from aerial parts of the plant. The application of herbicide safener caused a dramatic increase in the expression of GST-27 in all aerial plant parts tested. GST-29 was found to be constitutively expressed in RNA isolated from a number of maize tissues. The basal level of GST 29 expression showed a minimal increase upon herbicide safener treatment. Although a range of hormonal, environmental and physiological stimuli failed to elevate GST-27 levels, some increase in GST-27 mRNA was observed in the late stages of leaf senescence and after treatments resulting in phytotoxic effects. PMID- 7858223 TI - Cloning of an Arabidopsis thaliana cDNA coding for farnesyl diphosphate synthase by functional complementation in yeast. AB - A cDNA encoding farnesyl diphosphate synthase, an enzyme that synthesizes C15 isoprenoid diphosphate from isopentenyl diphosphate and dimethylallyl diphosphate, was cloned from an Arabidopsis thaliana cDNA library by complementation of a mutant of Saccharomyces cerevisiae deficient in this enzyme. The A. thaliana cDNA was also able to complement the lethal phenotype of the erg20 deletion yeast mutant. As deduced from the full-length 1.22 kb cDNA nucleotide sequence, the polypeptide contains 343 amino acids and has a relative molecular mass of 39,689. The predicted amino acid sequence presents about 50% identity with the yeast, rat and human FPP synthases. Southern blot analyses indicate that A. thaliana probably contains a single gene for farnesyl diphosphate synthase. PMID- 7858224 TI - A novel anther-expressed adh-homologous gene in Lycopersicon esculentum. AB - Two novel tandemly-oriented open reading frames (ORFs) with homology to alcohol dehydrogenase (ADH) were isolated from tomato. The predicted amino acid composition for each of the two tandem adh genes indicates the presence of 22 and 21, respectively, of 22 amino acids conserved in ADH proteins from plants and animals. However, comparison to known plant adh genes reveals a significantly lower similarity indicating that they belong to a novel class of ADHs. According to mapping data, the adh-homologous ORFs do not represent either of the previously studied adh1 or adh2 genes of tomato. The tandem genes, termed adh3a and adh3b, mapped to a distal region of the long arm of chromosome 4, unlike adh1, which maps closer to the centromere. Adh3a and adh3b have over 90% similarity to each other at the nucleotide and putative peptide levels. The adh3a gene has ten exons and nine introns with the transcription initiation site 57 bp upstream of the translation start. A putative TATA box and polyadenylation site have been identified. Adh3a is transcribed and, according to cDNA sequence analysis, fully processed in the late stages of anther development. According to transformation analysis, tissue-specific regulatory elements reside within the 448 to +724 region. The termination codon of adh3a is separated from the putative adh3b translation start site by 789 bp of intervening sequence. The 5' untranscribed sequences of each gene contain a stretch of 68 bp with 78% similarity. Within this stretch are sequences which are homologous to sequences found in anaerobically-induced or pollen-expressed genes from various plant species. PMID- 7858225 TI - Narrow A/T-rich zones present at the distal 5'-flanking sequences of the zein genes Zc1 and Zc2 bind a unique 30 kDa HMG-like protein. AB - Nuclear extracts from maize endosperm were used to investigate protein-DNA interactions in the 5'-upstream region of the Zc1 and Zc2 genes. These genes encode for zeins of apparent molecular mass (MWapp) 16 and 28 kDa, respectively, which accumulate in the endosperm during seed maturation. Binding assays revealed specific binding of a nuclear protein to three A/T-rich elements, 0.9-1.0 kbp upstream from the initiation codon. One of these elements (41 bp, 88% A/T), present in Zc1, contained a 13 nucleotide duplication. The other two (28 bp, 86% A/T; 42 bp alternating A-T) are consecutive elements in Zc2. Competition experiments strongly suggest that the three elements bind to the same protein. Protein-DNA interaction was detected in endosperm nuclear extracts of 8 to 21 days after pollination (DAP), as well as in 25 DAP embryos and in different tissues from plantlets. The protein factor has an MWapp of ca. 30 kDa. This factor has properties suggesting it is an HMG-like protein. These results are consistent with a growing accumulation of data for a number of genes indicating that A/T-rich elements, located at distal and proximal zones of the 5'-flanking sequences, interact with HMG-like proteins. PMID- 7858226 TI - HMG protein binding to an A/T-rich positive regulatory region of the pea plastocyanin gene promoter. AB - Gel retardation assays using pea nuclear extracts have detected specific binding to regions of the promoter of the pea plastocyanin gene (petE). Several complexes which differ in sensitivity to competition with unlabelled promoter fragments and various DNA alternating copolymers, to heat treatment and to digestion with proteinase K have been detected. A protein factor, PCF1, forming one of these complexes was heat-stable and most sensitive to competition with poly(dAdT).poly(dAdT) compared to other alternating copolymers. DNase I footprinting assays showed that tracts of A/T-rich sequence within the -444 to 177 positive regulatory region of the petE promoter were protected in the presence of the pea nuclear extract. The factor PCF1 copurified with a high mobility-group (HMG) protein preparation from pea chromatin. DNase I footprinting with the HMG protein preparation demonstrated that similar tracts of A/T-rich sequences within the promoter were protected. Southwestern-blot analysis of pea HMG proteins purified by gel filtration through Superose 12 detected a single DNA binding species of 21 kDa. The properties of the factor PCF1 suggest that it is likely to be an HMG I protein. PMID- 7858227 TI - Expression, tissue distribution and subcellular localization of dehydrin TAS14 in salt-stressed tomato plants. AB - We previously isolated and characterized TAS14, and mRNA that is induced in tomato upon osmotic stress or abscisic acid (ABA) treatment and that shares expression and sequence characteristics with other dehydrin genes in different species. Affinity-purified antibodies against TAS14 protein were used to study the expression of TAS14 protein, both in seedlings and mature plants, its tissue distribution and its subcellular localization. TAS14 protein was not detected in 4-day-old seedlings but accumulated after ABA, NaCl or mannitol treatments. In NaCl-treated seedlings, some protein was detectable after 6 h of treatment and reached maximal levels between 24 and 48 h. Concentrations ranging from 5 to 12.5 g/l NaCl induced the protein to similar levels. In salt-stressed mature plants, TAS14 was expressed abundantly and continuously in aerial parts, but only slightly and transiently in roots. Immunocytochemical analysis of salt-treated plants showed TAS14 accumulated in adventitious root primordia and associated to the provascular and vascular tissues in stems and leaves. Immunogold electron microscopy localized TAS14 protein both in the cytosol and in the nucleus, associated to the nucleolus and euchromatin. Since TAS14 is a phosphoprotein in vivo, the classes of protein kinases potentially responsible for its in vivo phosphorylation were tested in in vitro phosphorylation assays. TAS14 protein was phosphorylated in vitro by both casein kinase II and cAMP-dependent protein kinase. PMID- 7858228 TI - Root- and shoot-specific responses of individual glutamine synthetase genes of maize to nitrate and ammonium. AB - The responses of the five cytosolic-type glutamine synthetase (GS1) genes of maize to treatment of hydroponically grown seedlings with 10 mM KNO3 or 10 mM NH4Cl were analyzed. Non-coding 3' gene-specific hybridization probes and radioanalytic imaging were used to quantitate individual gene transcript levels in excised roots and shoots before treatment and at selected times after treatment. Genes GS1-1 and GS1-2 exhibited distinct organ-specific responses to treatment with either nitrogen source. The GS1-1 transcript level increased over three-fold in roots, but changed little if any in shoots. In contrast, the GS1-2 transcript level increased over two-fold in shoots, but decreased in roots after treatment. Increased transcript levels were evident at 4 h after treatment with either nitrogen source, with maximum accumulations present at 8 h after treatment with ammonium and at 10-12 h after treatment with nitrate. The GS1-3 gene transcript level showed little or no change after treatment with either nitrogen source. The GS1-4 gene transcript level remained constant in shoots of treated seedlings, whereas in roots, it exhibited relatively minor, but complex responses to these two nitrogen sources. The GS1-5 gene transcript is present in very small amounts in seedlings, making it difficult to analyze its response to metabolites in young plants. These results provide support for the possibility that different cytosolic GS genes of maize play distinct roles in nitrogen metabolism during plant growth and differentiation. PMID- 7858229 TI - Identification of domains in an Arabidopsis acyl carrier protein gene promoter required for maximal organ-specific expression. AB - Deletions were made in the promoter of the acyl carrier protein (ACP) Acll.2 gene from Arabidopsis to investigate the nature of the cis-acting elements that direct its expression. These constructs, which included the untranslated leader region, were fused to a reporter gene coding for beta-glucuronidase (GUS) and transformed into tobacco. Quantitative fluorometric analysis of GUS activity in transgenic plants showed that expression in young leaves drops to a basal level when a 85 bp domain, from -320 to -236 relative to transcription initiation, is deleted. Maximum promoter activity in roots also depends on this domain, but two other regions are also important. In total, deletion of the sequences from -466 to -55 caused an ca. 80-fold reduction in Acl1.2 promoter activity in roots. The -320 to -236 domain forms a complex with a protein factor found in leaves and roots, which was not detectable in seeds. The formation of this protein-DNA complex was abolished by mutation of a bZIP core motif, ACGT, found within the context AAGACGTAG, which is dissimilar to the other bZIP-binding sites thus far characterized in plants. Previously we showed that Acl1.2 promoter activity is highest in seeds [2]. Here we find, in contrast to leaves and roots, that deletion to position -236 has no effect on GUS levels in seeds. However, nearly a 100-fold drop was observed when the -235 to -55 region was removed. Hence, this 180 bp domain contains all the cis-acting information necessary for Acl1.2 promoter activity in seeds. The same region is necessary for Acl1.2 activity in the receptacle, stigma, tapetum and pollen of the flower, as demonstrated by histochemical staining. PMID- 7858230 TI - Chloroplast and cytosolic triosephosphate isomerases from spinach: purification, microsequencing and cDNA cloning of the chloroplast enzyme. AB - Chloroplast and cytosolic triosephosphate isomerases from spinach were separated and purified to homogeneity. Both enzymes were partially sequenced by Edman degradation. Using degenerate primers designed against the amino acid sequences, a homologous probe for the chloroplast enzyme was amplified and used to isolate several full-size cDNA clones. Chloroplast triosephosphate isomerase is encoded by a single gene in spinach. Analysis of the chloroplast cDNA sequence in the context of its homologues from eukaryotes and eubacteria reveals that the gene arose through duplication of its preexisting nuclear counterpart for the cytosolic enzyme during plant evolution. PMID- 7858231 TI - Isolation and characterization of two beta-tubulin cDNA clones from rice. AB - Two cDNA clones encoding two different beta-tubulins, RTUB-1 and RTUB-2, were isolated from a rice cDNA library and their nucleotide sequences were analyzed. The deduced amino acid sequences showed amino acid sequence identity between 92% and 97% with other plant beta-tubulins. Southern blot analysis using gene specific and coding-region probes suggested that beta-tubulins in rice are encoded by multigene families. The two cDNA clones represent two subfamilies of rice tubulins, RTUB-1 and RTUB-2, consisting of 3 to 4 genes and a single gene, respectively. The transcript levels of RTUB-1 and RTUB-2 genes were higher in actively elongating tissues such as etiolated shoot tissues and light-grown root tissues of four-day old seedlings. PMID- 7858232 TI - Genes encoding oleosins in maize kernel of inbreds Mo17 and B73. AB - We have investigated all three oleosin genes which are expressed in the kernel of maize (Zea mays L., Mo17). Oleosin genes, ole16, ole17, and ole18, encode OLE16, OLE17, and OLE18, respectively, in proportional amounts of approximately 2:1:1 in isolated oil bodies. None of the three genes has an intron or a sequence encoding an N-terminal signal peptide. The three genes are expressed coordinately during seed maturation, and their encoded oleosins are present in similar proportional amounts in oil bodies isolated from the embryonic axis, scutellum, and aleurone layer. OLE16 represents one oleosin isoform, whereas OLE17 and OLE18 are close members of another oleosin isoform. ole16 and ole18 have been mapped to single loci on chromosomes 2 (near b1 gene) and 5S (near phya2), respectively. We predict that ole17 is located on chromosome 1 (near phya1), in a chromosomal segment duplicated on chromosome 5. PMID- 7858233 TI - Cotton (Gossypium hirsutum L.) pollen-specific polygalacturonase mRNA: tissue and temporal specificity of its promoter in transgenic tobacco. AB - A gene (G9) expressed during late microsporogenesis in cotton (Gossypium hirsutum L.) was isolated. Sequence analysis of the cDNA (1.3 kb) as well as the gene (2.6 kb) revealed an open reading frame of 1233 bases encoding a protein of 43.9 kDa. The coding region of the gene is interrupted by three introns. Northern analysis of the RNA from developing anthers showed that the transcripts appear 12 days before anthesis and that the maximal concentration of RNA occurs in pollen on the day of anthesis. This pattern of gene expression suggests functions in post anthesis events. Sequence comparisons with other known plant genes indicated that G9 is homologous to polygalacturonases. The G9 promoter conferred tissue and temporal specificity of beta-glucuronidase (GUS) expression in transgenic tobacco plants. Thus, the G9 promoter can be used to drive gene expression in homologous as well as heterologous plants in a tissue-specific manner. PMID- 7858234 TI - The expression of a chimeric Phaseolus vulgaris nodulin 30-GUS gene is restricted to the rhizobially infected cells in transgenic Lotus corniculatus nodules. AB - In Phaseolus vulgaris there is a nodulin family, Npv30, of ca. 30 kDa, as detected in an in vitro translation assay [2]. We isolated a gene (npv30-1) for one of the members of this family. The nucleotide sequence of the promoter of npv30-1 contains nodule-specific motifs common to other late nodulin genes. The promoter was fused to the GUS reporter gene; this chimeric fusion was introduced into Lotus corniculatus via Agrobacterium rhizogenes transformation. GUS activity was only detected in the infected cells of the nodules of transgenic plants. By contrast, the expression of a 35S-GUS construct was restricted to the uninfected cells and the vascular tissue. PMID- 7858235 TI - Isolation and expression analysis of two rice genes encoding the major intrinsic protein. AB - We isolated two rice cDNAs (rMip1 and rTip1) which are homologous to the genes encoding the major intrinsic protein (Mip) (soybean nod-26 and Arabidopsis gamma Tip), respectively. Expression of rTip1 in shoots and roots of rice seedlings was enhanced by water stress, salt stress and exogenous ABA. rMip1 was expressed only in shoots. Although mRNA level of rMip1 in shoots was induced to a small extent by exogenous ABA, it did not show any increase under water or salt stress over the course of 12 h. On the basis of the differential expression patterns and evolutional distinctions, it is suggested that the possible channel proteins encoded by rMip1 and rTip1 genes may function in different transport systems. PMID- 7858236 TI - A 6' gentamicin acetyltransferase gene allows effective selection of tobacco transformants using kanamycin as a substrate. AB - 6' gentamicin acetyltransferases detoxify aminoglycoside antibiotics containing a 6' amino group. We tested whether a 6' gentamicin acetyltransferase gene (6' gat) of Shigella sp. is suitable as selectable gene in plant transformation using kanamycin (Km) as a substrate. A comparative transformation experiment using Nicotiana tabacum SR1 protoplasts showed that 6' gat is as effective for selection of transformants as the commonly used neomycin phosphotransferase II (nptII). In stably transformed plants we detected moderate levels of the 6' gat mRNA. An enzymatic assay was developed with which the acetyltransferase activity of the protein is easily demonstrated. PMID- 7858237 TI - Overview of the hematopoietic growth factors and cytokines--past, present and future. PMID- 7858238 TI - CD43 expression by murine lymphohemopoietic progenitors. AB - CD43 is expressed by many types of mature blood cells including T-lymphocytes, activated B-lymphocytes, neutrophils, monocytes, and platelets but not non hemopoietic cells. Defective CD43 is seen in patients with Wiscott-Aldrich syndrome. We have investigated CD43 expression by hemopoietic progenitors of normal and 5-fluorouracil(5-FU)-treated mice. Bone marrow cells were enriched for progenitors by a combination of density centrifugation and negative immunomagnetic selection using lineage-specific monoclonal antibodies. They were then separated based on expression of Ly-6A/E and CD43. Approximately 50% of the Ly-6A/E+ cells of both normal and 5-FU-treated mice were CD43neg-low, while the rest of the cells were CD43bright. The majority of the colony-forming cells including lymphohemopoietic progenitors that gave rise to both myeloid and B lymphoid lineages were present in the Ly-6A/E+CD43bright cell population. Therefore, Ly-6A/E+CD43bright cells were approximately 2-times enriched for the progenitors relative to Ly-6A/E+ cells. Anti-CD43 antibody is useful in isolation of primitive murine hemopoietic progenitors. PMID- 7858240 TI - Percentages of bone marrow blasts and chromosomal changes in patients with refractory anemia help to determine prognoses. AB - We statistically analyzed the hematologic findings of patients with refractory anemia (RA) to identify parameters associated with a poor prognosis. We first separated the RA patients into two groups: one group with disease progression and one without. The patients with disease progression were predominantly male and had a significantly higher percentage of bone marrow (BM) blasts at the time of diagnosis (3.06 +/- 1.29% vs. 1.44 +/- 1.38%, P < 0.005). This finding was confirmed when the patients were separated into the two groups; those who survived and those who expired (BM blasts: 2.68 +/- 1.59% vs. 1.37 +/- 1.27%, P < 0.005). The survival probabilities were calculated depending on whether or not the RA patients had > or = 3% BM blasts. The RA patients with > or = 3% BM blasts had a significantly worse prognosis (P < 0.01) than the patients with < 3% BM blasts. Notably, the RA patients with > or = 3% BM blasts did not show any significant differences in the incidence of disease progression, mortality rate, or survival probability, when compared with the patients with RA with an excess of blasts (RAEB). The present findings indicate that RA patients are heterogeneous with regard to prognosis, and the RA patients with > or = 3% BM blasts might have a poorer prognosis than those with fewer BM blasts. Thus we propose a general approach in predicting the prognosis of RA patients: those with complex chromosomal changes will expire shortly. Secondly, when the patients do not have any complex changes, the prognosis might be linked to the percentage of BM-blasts at the MDS diagnosis. PMID- 7858239 TI - PML-RAR alpha fusion transcripts by RNA PCR in acute promyelocytic leukemia in remission and its correlation with clinical outcome. AB - Molecularly defined specific chromosomal translocation in leukemia allows detection of minimal residual leukemia cells by the reverse transcription polymerase chain reaction (RT-PCR). However, the positivity of the specific fusion transcripts in chronic myelogenous leukemia and acute myelogenous leukemia with t(8;21) is reportedly not directly correlated with the predictability of relapse. We analyzed seven patients with acute promyelocytic leukemia (APL) in hematological remission for PML-retinoic acid receptor alpha (PML-RAR alpha) fusion transcripts by RT-PCR with the sensitivity level of one APL cell in 10(5) bone marrow mononuclear cells. Two of the four patients with chemotherapy-induced remission had detectable PML-RAR alpha only before treatment. In the other two patients with chemotherapy-induced remission, the PML-RAR alpha was detectable when their remission was first confirmed and became negative after consolidation chemotherapy. Two patients were resistant to chemotherapy and achieved remission by all-trans-retinoic acid; PML-RAR alpha was detectable in them for a few months during consolidation chemotherapy. Two patients whose PML-RAR alpha had become continuously positive had relapse 2 and 8 months later, but the other five patients with continuously negative or only transiently positive PML-RAR alpha remained in remission during follow-up for 11 to 35 months. These findings suggest the relevance of detectable PML-RAR alpha by RT-PCR to the predictability of relapse in acute promyelocytic leukemia. PMID- 7858241 TI - 3,5,3'-Triiodothyronine nuclear receptors and their role in the thyroid hormone action. PMID- 7858242 TI - Effects of thyroid hormones on the lymphocyte phenotypes in rats: changes in lymphocyte subsets related to thyroid function. AB - The effects of hyperthyroidism and hypothyroidism on the immune function were assessed in rats by the changes in lymphocyte subsets in peripheral blood and spleen. Hyperthyroidism was induced in rats by intraperitoneal injection of large doses of T4. Hypothyroid rats were prepared by total thyroidectomy followed by 131I administration. In the hyperthyroid rats, the peripheral blood helper/suppressor T cell ratio was decreased, while in hypothyroidism this ratio was increased. However, in spleen cells, this ratio was increased in hypothyroid rats as compared to normal controls. The most striking finding was an augmentation of activated T cells (transferrin receptor positive lymphocytes) in both peripheral blood and spleen cells in the hypothyroid rat. These results suggested that thyroid hormone suppressed the immune response and that a deficiency of this hormone was associated with an increase of activated T cells. These effects of thyroid hormone on the lymphocyte subsets in rats were at variance with the abnormalities that have been observed in humans with such autoimmune thyroid disease as Graves' disease. PMID- 7858243 TI - Effects of hypophysectomy on TRH and its related peptides concentrations in various rat organs. AB - The effects of hypophysectomy on thyrotropin releasing hormone (TRH), TRH-glycine (TRH-Gly) and pre-pro-TRH (178-199) concentrations in the rat hypothalamus, cerebrum, cerebellum, brain stem, stomach and retina were studied 7 days after the operation. The hypophysectomized rats were administered a single i.p. injection of T4 (500 micrograms/kg), T3 (100 micrograms/kg) or bovine TSH (1.25 IU/kg), and 5 rats of each subgroup were decapitated at 4 hours later. After hypophysectomy, TRH-Gly and pre-pro-TRH (178-199) concentrations in the hypothalamus increased significantly and TRH concentrations decreased after hypophysectomy. After the injection of T4, T3, TRH or TSH TRH-Gly and pre-pro-TRH (178-199) concentration in the hypothalamus of hypophysectomized rats decreased significantly, while that of TRH significantly increased. No changes in TRH, TRH Gly and pre-pro-TRH (178-199) concentration in other tissues were observed after hypophysectomy or hormone treatment. The findings suggest that hypophysectomy stimulated TRH synthesis and release in the hypothalamus, that TRH, TSH, T3 and T4 regulate hypothalamic TRH levels, and that pro-TRH synthesis in the tissues except the hypothalamus may not be regulated by thyroid hormone. PMID- 7858244 TI - Elevated serum cortisol and glucose and liver glycogen in juvenile fish Clarias lazera after exposure to acid stress. AB - The exposure of juvenile Clarias lazera to acute (pH 3.1 for 96 h) and chronic (pH 5.4 or 4.7 for 12 weeks) acid stress (H2SO4) resulted in a number of physiological responses which could be considered as adaptive to the effects of stress. These responses were evident in the rapid rise of serum cortisol level from 43.0 +/- 0.76 microgram/dl in the control to 71.0 +/- 1.06 micrograms/dl (P < 0.001) 24 h after acute exposure. Also serum glucose level was increased from 123.66 +/- 1.85 mg/dl in the control and reached 295.0 +/- 2.89 mg/dl (P < 0.001) by the end of the experimental period (96 h). Chronic exposure of the fish to the two levels of pH (5.4 and 4.7) caused significant increase in serum cortisol and serum glucose level starting from the first week of exposure and lasted throughout the study period (12 weeks). As to the liver glycogen content, a slight but significant drop was found from 11.06 +/- 0.03 mg/100 mg tissue dry weight in the control to 10.80 +/- 0.06 mg/100 mg tissue dry weight (P < 0.025) 24 h after acute acid exposure. However, the values at 72 and 96 h were significantly higher than those in the control. In the chronic exposure study, the fish maintained at pH 5.4 showed a marked increase in liver glycogen content starting from week 2 and lasted till the end of experimental period (12 weeks). As early as after one week of treatment, in fish maintained in pH 4.7, liver glycogen content surged and remained significantly high till the twelfth week. PMID- 7858245 TI - Methylene blue inhibits the stimulation of bone mass by high doses of estradiol in male rats. AB - To elucidate the effect of methylene blue on bone metabolism we examined the rats treated with estradiol, with methylene blue alone and with estradiol and methylene blue. The mineral bone mass in the femurs of the animals was measured quantitatively. A significant increase of bone density and bone mineral content was found in the estradiol treated animals compared to animals without estradiol. The rise in bone mineral content after estradiol was inhibited by methylene blue. Methylene blue alone did not affect bone mineral mass. From our work the possibility arose that beside well known effect of estradiol on osteoblast receptors also other mechanism of estrogen action exists which possibly may include the effect of estrogen on cytosolic guanylate cyclase producing cGMP. PMID- 7858246 TI - Specific radioimmunoassay of oxytocin in rat plasma. AB - Sensitive, specific and reproducible radioimmunoassay (RIA) was developed for the measurement of oxytocin (OXT) in rat blood plasma after various extraction methods. The assay is based on an antiserum raised against OXT in rabbit. The sensitivity, affinity constant, and cross-reactivity of the antiserum were determined. The 125I-labelled OXT for RIA was produced by chloramine-T method and purified with high pressure liquid chromatography (HPLC). Two extraction procedures were employed: 1. adsorption to an artificial silicate, Lichroprep Si 60 (Merck); 2. immunoextraction of the hormone applying a magnetic bearer covered with purified antibodies against OXT. The specificity of the extraction methods was characterized in comparative HPLC/RIA studies of specimens extracted from blood plasma in different ways. The basal level of the peptide measured after the extraction with thermally activated Lichroprep Si 60 or after the immunoextraction method was found to be 9.6 +/- 2.3 pg/ml (mean +/- S.E.) and 15.3 +/- 0.9 pg/ml (mean +/- S.E.), respectively. Various well known factors (ether exposure, hyperosmotic stress and suckling) appeared to be potent peripheral stimuli of OXT release, and thus indicated the suitability of the RIA method for the measurement of OXT in blood plasma. PMID- 7858247 TI - The biology and treatment of acute lymphoblastic leukemia in adults. AB - Despite reports to the contrary, only a small minority of adults with ALL are currently cured. Results have improved modestly with more intensive postremission chemotherapy and with tailoring of protocols in individuals with specific subsets of ALL. The use of growth factors may further improve treatment results. The performance of allogeneic BMT in first remission is clearly effective in some individuals, eg, those with Ph1-positive ALL, but it is unclear whether it is advantageous in most individuals. There are little data supporting the effectiveness of autotransplantation, as currently performed in ALL, despite its theoretical potential. Advances in understanding the biology of ALL have led to new approaches currently under basic and clinical investigation. These include serial studies of minimal residual disease by a variety of techniques to tailor treatment, the development of conjugated MoAbs to lymphoid cell antigens and immunologic and biochemical approaches to chimeric RNA and peptides generated by abnormal fusion genes. It seems likely that substantial improvement in the treatment of adult ALL awaits better characterization of the biology of this disease. However, some improvement will occur through empirical clinical research. It is critical that physicians recognize the poor results with current therapeutic approaches and enter patients into large well-designed clinical trials. PMID- 7858248 TI - Acute promyelocytic leukemia cases with nonreciprocal PML/RARa or RARa/PML fusion genes. AB - Tumor-associated chromosome translocations usually lead to the formation of two reciprocal fusion genes: one thought to be involved in the transformation process, the other the mechanical consequence of the translocation event. In the case of acute promyelocytic leukemia (APL) blasts, the 15;17 chromosome translocation generates the putatively transforming PML/RARa fusion gene and its reciprocal RARa/PML. We report APL cases with submicroscopic 15;17 recombinations leading to the formation of nonreciprocal PML/RARa or RARa/PML fusion genes. Therefore, each of the two reciprocal translocation products may be independently formed and selected by the leukemic phenotype, implying that both are involved in tumorigenesis. PMID- 7858249 TI - Induction of phagocytosis by a protein tyrosine kinase. AB - The transmission of extracellular signals to cellular targets by many noncatalytic surface receptors is dependent on interaction between cytoplasmic protein tyrosine kinases (PTKs) and tyrosine-containing sequences in the cytoplasmic domain of the receptor or an associated subunit. Isoforms of each of the three classes of the noncatalytic Fc gamma receptors, Fc gamma RI, Fc gamma RII, and Fc gamma RIII, are able to transmit a phagocytic signal in transfected COS-1 cells. Both Fc gamma RI and Fc gamma RIIIA require the gamma subunit for this signaling event. The protein tyrosine kinase Syk dramatically enhances phagocytosis mediated by both these receptors and increases the number of cells able to mediate phagocytosis. Two gamma chain cytoplasmic YXXL sequences are required for this effect. The action of Syk is less pronounced on the phagocytic Fc gamma RII receptor, Fc gamma RIIA, which does not require the gamma chain for phagocytosis. However, Syk allows phagocytosis by the nonphagocytic Fc gamma RII receptor Fc gamma RIIB2, which contains only a single YXXL sequence, when an additional tyrosine-containing sequence, YMTL, is introduced. These studies indicate that the efficiency of phagocytosis is markedly enhanced by the presence of a specific protein tyrosine kinase. PMID- 7858250 TI - All-trans retinoic acid for the treatment of newly diagnosed acute promyelocytic leukemia. Japan Adult Leukemia Study Group. AB - We conducted a multicenter trial of treatment with all-trans retinoic acid (ATRA) for newly diagnosed acute promyelocytic leukemia (APL) in the AML-92 study and compared it with our previous study with standard intensive chemotherapy, the AML 89 study, in the view of complete remission (CR) rate, incidence of early death, and event-free survival (EFS). Patients were scheduled to receive oral ATRA 45 mg/m2 daily until CR. If patients had leukocyte counts above 3 x 10(9)/L at the start of therapy, they received daunorubicine (DNR) 40 mg/m2 for 3 days and behenoyl cytosine arabinoside (BHAC) 200 mg/m2 for 5 days in addition to ATRA. During the ATRA therapy, if patients showed myeloblast plus promyelocyte counts higher than 1 x 10(9)/L in the peripheral blood, they received additional DNR and BHAC in the same schedule, as well. A total of 110 patients were entered into the study. Median age was 43 years (range, 16 to 74). Twenty-eight (26%) of 109 patients (one died before the start of therapy) received ATRA alone. Ninety-seven patients (89%) achieved CR; 48 of 49 (98%) aged less than 40 years, 44 of 52 (84%) aged between 40 and 69, and 5 of 8 (63%) aged above 70 achieved CR, respectively; 25 of 28 (89%) with ATRA alone, 46 of 51 (90%) with ATRA plus initial chemotherapy and 26 of 30 (87%) with ATRA plus later chemotherapy attained CR, respectively. Nine (8%) patients died within 28 days after the start of therapy. In contrast, 44 of 62 patients (71%) attained CR, and 13 (21%) died within 28 days in the AML-89 study with the combination of DNR, BHAC, 6 mercaptopurine and prednisolone. Seven developed retinoic acid syndrome and one died of it in the present study. Other toxicities associated with this drug included cheilitis, desquamation, muscle pain, and hypertriglyceridemia. Predicted 23 months EFS for all ATRA-treated patients and disease-free survival (DFS) in the CR cases were 75% and 81%, respectively, in a median follow-up period of 21 months. Compared to the AML-89 study, there was a highly significant difference in remission rate (P = .004), EFS (P = .0007), and also early mortality rate (P = .02). Present results demonstrated that ATRA with or without chemotherapy gives a statistical improvement in CR rate and early mortality rate, as well as superior survival in newly diagnosed APL. PMID- 7858251 TI - Transient increase in circulating donor leukocytes after allogeneic transfusions in immunocompetent recipients compatible with donor cell proliferation. AB - Donor leukocytes in therapeutic blood components are implicated in transfusion related complications ranging from alloimmunization to graft-versus-host disease (GVHD) to viral transmission and reactivation. To further characterize the kinetics of donor leukocyte clearance after allogeneic transfusion, we developed allele-specific polymerase chain reaction (PCR) assays directed at a single-copy Y chromosome gene and HLA class II alleles. These assays enable sensitive detection and quantitation of donor leukocytes at concentrations ranging from one cell to greater than 1,000 cells per 125 microL of recipient blood. When applied to serial samples from five consecutive orthopedic surgery patients who met study criteria, we observed 99.9% clearance of donor leukocytes over the initial 2 days posttransfusion, followed by a transient, 1-log increase in circulating donor leukocytes on days 3 to 5. This phenomenon was reproduced in a canine transfusion model, where the transient donor leukocyte expansion phase was prevented by gamma irradiation of donor blood, and was not observed after transfusions into alloimmunized dogs. We hypothesize that this transient increase in circulating allogeneic donor cells represents one arm of an in vivo mixed lymphocyte reaction, with activated donor T lymphocytes proliferating in an abortive GVHD reaction to HLA-incompatible recipient cells. Further investigation of this phenomenon should provide insight into the mechanisms involved in donor-recipient leukocyte interactions posttransfusion and the relationship of these interactions to leukocyte-induced complications. PMID- 7858252 TI - The 175 antigen expressed on myeloid and erythroid cells during differentiation is associated with serine protease activity. AB - Monoclonal antibody 175 recognizes a cell-surface antigen on more than 80% of nucleated ovine bone marrow cells (BMC). The distribution is unusual, as the majority of differentiated myeloid and erythroid cells express the antigen (175 antigen), whereas mast cells, basophils, and the majority of lymphocytes do not. The level of 175 antigen expression has been shown to increase as BMC differentiate during hematopoiesis. Previous attempts to identify the 175 antigen have been unsuccessful. In this study, the 175 antigen was affinity-purified and shown to contain serine protease activity. Immunoblot analysis following sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE) of bone marrow cell lysates run under reducing or nonreducing conditions showed two closely adjacent protein bands (a doublet) of 28 to 30 kD molecular weight. N-linked deglycosylation showed that the 30-kD band was a glycosylated form of the 28-kD protein. Both protein bands shared the same N-terminal amino acid sequence over 20 residues, with high homology with serine proteases. Affinity-purified 175 antigen was proteolytic in substrate gels, the activity being inhibited by the 175 monoclonal antibody (Mab) and the serine protease inhibitor phenylmethylsulfonyl fluoride (PMSF), but not by metallo, thiol, or acid protease specific inhibitors. The 175 antigen is therefore part of a growing family of cell-surface proteases associated with hematopoietic cell differentiation. PMID- 7858253 TI - N- and O-glycosylation muteins of recombinant human erythropoietin secreted from BHK-21 cells. AB - Single-site glycomuteins of recombinant human erythropoietin (rhuEpo) were constructed and transiently and stably expressed in BHK-21 cells. The transient expression levels varied among muteins, being highest for mutein rhuEpoGln24 followed by wild-type rhuEpo (rhuEpowt). All other glycomuteins, including rhuEpoGln38, rhuEpoGln83, rhuEpoThr126, and rhuEpoGly126, were secreted at lower levels than rhuEpowt. Muteins expressed in stable cell lines showed similar differences in expression levels. Also each mutein could be affinity-purified from culture supernatants, and was biologically active in vivo. Based on secretion rates from BHK-21 cells, the most potent erythropoietin was rhuEpoGln24. This mutein is also considered to have biologic activities that are superior to rhuEpowt. PMID- 7858254 TI - Differential expression of a novel proline-rich homeobox gene (Prh) in human hematolymphopoietic cells. AB - Proline-rich homeobox (Prh) is a novel human homeobox-containing gene recently isolated from the CD34+ cell line KG-1A, and whose expression appears mainly restricted to hematopoietic tissues. To define the pattern of Prh expression within the human hematopoietic system, we have analyzed its constitutive expression in purified cells obtained from normal hematopoietic tissues, its levels of transcription in a number of leukemia/lymphoma cell lines representing different lineages and stages of hematolymphopoietic differentiation, and its regulation during in vitro maturation of human leukemic cell lines. Prh transcripts were not detected in leukemic cells of T-lymphoid lineage, irrespective of their maturation stage, and in resting or activated normal T cells from peripheral blood and lymphoid tissues. In contrast, high levels of Prh expression were shown in cells representing early stages of B lymphoid maturation, being maintained up to the level of circulating and tissue mature B cells. Terminal B-cell differentiation appeared to be conversely associated with the deactivation of the gene, since preplasmacytic and plasmocytoma cell lines were found not to express Prh mRNA. Prh transcripts were also shown in human cell lines of early myelomonocytic, erythromegakaryocytic, and preosteoclast phenotypes. Prh expression was lost upon in vitro differentiation of leukemic cell lines into mature monocyte-macrophages and megakaryocytes, whereas it was maintained or upregulated after induction of maturation to granulocytes and osteoclasts. Accordingly, circulating normal monocytes did not display Prh mRNA, which was conversely detected at high levels in purified normal granulocytes. Our data, which show that the acquisition of the differentiated phenotype is associated to Prh downregulation in certain hematopoietic cells but not in others, also suggest that a dysregulated expression of this gene might contribute to the process of leukemogenesis within specific cell lineages. PMID- 7858255 TI - The murine interleukin-3 receptor alpha subunit gene: chromosomal localization, genomic structure, and promoter function. AB - The interleukin-3 receptor (IL-3R) is composed of alpha and beta subunits, members of the class I cytokine receptor family. Here we describe isolation and characterization of the chromosomal gene for the mouse IL-3R alpha subunit (mIL 3R alpha). Whereas the human IL-3R alpha gene is tightly linked with the granulocyte-macrophage colony-stimulating factor receptor alpha subunit (GM-CSFR alpha) gene in the pseudoautosomal region of the X and Y chromosomes, the mIL-3R alpha gene (II3ra) is located in the proximal region of mouse chromosome 14, separated from the mouse GM-CSFR alpha gene, which is on chromosome 19. The mIL 3R alpha gene spans about 10 kb and is divided into 12 exons. All the exon-intron boundaries possess the splicing junction consensus sequences (5'GT-AG3'), and the whole genomic structure is similar to those of the previously reported class I cytokine receptor genes. There are two major transcription initiation sites that are located at 215 and 188 nucleotides upstream of the initiator codon. The promoter region is GC-rich and contains potential binding sites for GATA, Ets, c myb,, Sp1, Ap-2, and G-C boxes, but not a typical TATA or CAAT sequence. A fusion gene containing 0.8 kb of the 5' noncoding sequence linked to the firefly luciferase gene directed the transcription in mouse mast cells but not in fibroblasts or T cells, suggesting that this promoter functions in a cell type specific manner. Further sequential deletion of the 5' region suggests two potential regulatory regions for transcription of the mIL-3R alpha gene. PMID- 7858256 TI - Heterogeneity of hepatitis C virus genotypes in hemophilia: relationship with chronic liver disease. AB - In this study we have determined the hepatitis C virus (HCV) serotype and genotype in a cohort of 96 HCV-infected hemophiliacs and have examined the relationship between HCV genotype and severity of chronic liver disease as determined by liver biopsy. HCV serotype was determined by specific enzyme-linked immunosorbent assays (ELISAs) and genotype by restriction fragment length polymorphism (RFLP) and HCV viral sequencing. The pattern of genotype distribution was quite unlike that of HCV-infected United Kingdom (UK) blood donors in that five of the six known HCV genotypes were represented, 50% were type 1, 13% type 2, and 18% type 3. An unexpected observation was the presence of HCV genotype 4 in four patients and type 5 in two patients. An additional feature was the presence of mixed infection, detected in 14% and 7% by serotype and genotype analysis, respectively. Liver biopsies were available from 51 patients. Cirrhosis was present in five of 27 (19%) of individuals with type 1, in 2 of 9 (22%) with type 2, and 5 of 8 (63%) of those with type 3. The heterogeneous pattern of HCV genotype distribution in this cohort of patients and the observed relationship between the severity of the related liver disease and specific HCV genotype may have important implications with respect to the natural history and treatment of HCV-related chronic liver disease in infected hemophiliacs worldwide. PMID- 7858257 TI - Immunosuppressive effect of human herpesvirus 6 on T-cell functions: suppression of interleukin-2 synthesis and cell proliferation. AB - Human herpesvirus-6 (HHV-6), the etiologic agent of roseola, is ubiquitous, establishes latency in the host, and can infect a variety of immunocompetent cells, with CD4+ T lymphocytes being the targets in which it replicates most efficiently. The present study was undertaken to learn more about specific immunobiologic effects of HHV-6 infection on T-lymphocyte functions. Our data demonstrate that infection of peripheral blood mononuclear cells (PBMC) by HHV-6 results in suppression of T-lymphocyte functions, as evidenced by reduced interleukin-2 (IL-2) synthesis and cellular proliferation. In fact, HHV-6 infected PBMC secreted 50% less IL-2 than mock-infected cells after mitogenic stimulation with OKT3 antibody or phytohemmaglutinin (PHA). The inhibition of IL 2 by HHV-6 was also observed in enriched T-cell cultures, suggesting a direct effect of this virus on this cell type. Messenger RNA (mRNA) analysis by reverse transcriptase polymerase chain reaction (PCR) indicated that HHV-6 diminishes IL 2 mRNA levels in mitogen-stimulated peripheral blood T cells. These results were also confirmed by Northern blot using the leukemic T-cell line Jurkat. This inhibitory effect of HHV-6 did not require infectious virus, as the use of UV irradiated HHV-6 produced similar results. Moreover, HHV-6-infected PBMC showed up to an 85% reduction in their mitogen-driven proliferative response, as compared with sham-infected cells. Proliferation of both CD4+ and CD8+ T cells was affected by HHV-6. Taken together, our data show that infection of T cells by HHV-6 results in immune suppression characterized by a downregulation of IL-2 mRNA and protein synthesis accompanied by diminished cellular proliferation. PMID- 7858258 TI - Involvement of CD31 in lymphocyte-mediated immune responses: importance of the membrane-proximal immunoglobulin domain and identification of an inhibiting CD31 peptide. AB - CD31 (PECAM-1) is an immunoglobulin gene superfamily cell adhesion molecule found on vascular endothelium, platelets, and leukocytes. Lymphocyte expression of CD31 is most closely associated with the CD45RA+CD8+ naive T phenotype. CD31 has recently been shown to play a role in leukocyte egress to inflammatory sites. The mechanism of CD31 adhesion remains under investigation. Several investigators have reported evidence for a heterotypic ligand. We have previously shown that CD31 is phosphorylated with cell activation, which suggests a possible role for CD31 in cell activation events. We therefore studied the effects of CD31 antibodies on in vitro assays of lymphocyte activation. One CD31 antibody, LYP21, inhibited the mixed lymphocyte reaction (MLR) in a specific and dose-dependent fashion. An LYP21 epitope was localized to the sixth Ig domain of CD31. This peptide and a scrambled control peptide were synthesized and used to study effects of this epitope on lymphocyte activation. The CD31 peptide strongly inhibited the MLR. Because CD31 is expressed on both stimulator and responder populations, stimulator peripheral blood leukocytes and responder lymphocyte populations were separately incubated with CD31 peptide or control peptide and then washed before mixing. The CD31 peptide inhibited the MLR equally when either stimulator or responder cells were preincubated with the CD31 peptide. We further sorted responder cells into CD31-high and CD31-low populations and separately incubated these subsets with peptides. The CD31 peptide strongly inhibited MLRs, regardless of level of responder-cell CD31 expression. Examination of MLR reactions involving the CD31 peptide showed dispersed small aggregates of cells, rather than the single large aggregate observed in control MLRs. The CD31 peptide did not affect activation of lymphocytes by phorbol myristate acetate (PMA) and ionomycin. These results suggest that a surface CD31-ligand interaction may have a functional role in alloimmune lymphocyte activation and identify a functionally important domain of CD31. PMID- 7858259 TI - Expression of recombination activating genes (RAG-1 and RAG-2) in Epstein-Barr virus-bearing B cells. AB - Recombination activating genes 1 and 2 (RAG-1 and RAG-2), are the only lymphoid specific genes required for the site-directed recombination reaction leading to generation of B-cell receptors and T-cell receptors (TCRs). RAGs are normally expressed during a narrow window of precursor lymphocyte development. RAG expression was examined in Epstein-Barr virus (EBV)-infected B cells. No steady state RAG RNA was found in EBV immortalized cells, including newly established B lymphoblastoid cell lines derived from precursor lymphocytes that transcribed RAGs at the time of infection. RAG RNAs were detected in some endemic (EBV+) and also in some sporadic (EBV-) Burkitt's lymphoma lines that had been infected with EBV in vitro. The RAG+, EBV+ Burkitt's lines were unusual in that they were SIgM+ (one was SIgG+, SIgM-), CD10+, and lacked terminal deoxynucleotidyl transferase. In EBV+ Burkitt's lymphoma lines, transcription of virus latent membrane protein 1 (LMP-1) was correlated with downregulation of RAG-1 and RAG-2. Conversely, absence of LMP-1 in clones of EBV+ tumor lines was associated with increased RAG transcription. Translocation of c-myc into V(D)J loci has been observed in endemic Burkitt's lymphomas, and heptamer-nonamer recombination signal sequences have been identified at some chromosomal breakpoints. Association of RAG transcription with EBV infection raises the possibility that, under certain conditions, virus might predispose to aberrant V(D)J recombination reactions. PMID- 7858260 TI - Interleukin-9 is a major anti-apoptotic factor for thymic lymphomas. AB - We have recently shown that interleukin-9 (IL-9) strongly stimulates the proliferation of mouse thymic lymphomas in vitro. Here we report that this factor is also one of the most potent inhibitors of apoptosis induced by dexamethasone (DEX) in such cell lines, even if they do not depend on exogenous factors for growth. For the murine thymic lymphoma BW5147, protection against apoptosis was also obtained with IL-4 and less strongly with IL-6, whereas IL-2, IL-7, and IL 10 were inactive. Moreover, IL-4 and IL-9 maintained proliferation of these cells in the presence of DEX. Analysis of eight other factor-independent thymic lymphoma lines showed significant protection in seven and six cell lines with IL 9 and IL-4, respectively, whereas only three were protected by IL-7 and only two by IL-2. Comparison of the responses to IL-2 and IL-9 in a factor-dependent cell line that responds to both cytokines showed that IL-2 is a stronger inducer of proliferation, while IL-9 is more efficient in protecting the cells against apoptosis. Taken together, our observations suggest that, for thymic lymphomas, proliferation and apoptosis involve distinct regulatory mechanisms and can be differentially regulated by cytokines. PMID- 7858261 TI - Detection of the chromosome 16 CBF beta-MYH11 fusion transcript in myelomonocytic leukemias. AB - Karyotypic detection of chromosomal 16 abnormalities classically associated with AML M4Eo can be difficult. Characterization of the two genes involved in the inv(16)(p13q22), CBF beta and MYH11, has allowed the detection of fusion transcripts by reverse-transcriptase polymerase chain reaction (RT-PCR). We have analyzed CBF beta-MYH11 fusion transcripts by RT-PCR in myelomonocytic leukemias, with or without eosinophilia, to determine whether their presence correlates with morphology. Fifty-three cases (11 AML M4Eo; 1 AML M4 with atypical abnormal eosinophils (AML M4 "Eo"); 29 AML M4; 8 AML M5; 3 CMML; and 1 AML M2 with eosinophilia) were analyzed. All 11 typical AML M4Eo were CBF beta-MYH11 positive. The single case of AML M4 with distinctive eosinophil abnormalities was negative by karyotype, RT-PCR and fluorescent in situ hybridization (FISH). Three of 29 (10%) AML M4 without abnormal eosinophils were CBF beta-MYH11 positive, 1 of which did not show any apparent chromosome 16 abnormalities by classical metaphase analysis (2 not tested). Both cases tested also showed MYH11 genomic rearrangement. None of the other leukemias were RT-PCR positive. Follow-up of three patient showed residual positivity in apparent complete remission. These data show that CBF beta-MYH11 fusion transcripts occur not only in the vast majority of typical AML M4Eo, but also in approximately 10% of AML M4 without eosinophilic abnormalities, a much higher incidence than the sporadic reports of chromosome 16 abnormalities in AML M4 would suggest. Taken together with the detection of CBF beta-MYH11 transcripts in the absence of apparent chromosome 16 abnormalities by classical banding techniques, these data show that additional screening by either RT-PCR or FISH should be performed in all AML M4, regardless of morphologic features, to allow accurate evaluation of the prognostic importance of this fusion transcript. PMID- 7858262 TI - Characterization of plasma lipids in patients with malignant disease by 13C nuclear magnetic resonance spectroscopy and gas liquid chromatography. AB - The purpose of this study was to characterize possible changes in fatty acid composition of plasma lipids associated with malignancy. The very low, low, and high-density lipoproteins were isolated by gradient density ultracentrifugation of plasma from 16 patients with malignant disease and from 15 controls. The triglyceride, esterified cholesterol, and phospholipid constituents of each lipoprotein fraction were isolated, and the fatty acid composition within each lipid component was determined by gas liquid chromatography (GLC). In the 10- to 45-parts-per-million (ppm) region of the carbon-13 (13C) nuclear magnetic resonance (NMR) plasma spectrum, differences were found between patients with malignant disease and controls. The ratio of the 31.6/32.1 ppm resonance intensities was lower in the group of cancer patients. The ratio of the 24.4/24.9 ppm resonance intensities in patients with malignant disease was different from the nonpregnant controls. The NMR changes were interpreted in light of GLC data that indicated derangements in the composition of fatty acids within lipoprotein lipids. In total plasma esterified cholesterol, the relative amount of linoleic acid (18:2, n-6) was lower, whereas oleic acid (18:1, n-9) was higher in the group of patients with malignant disease. In total plasma triglycerides, the amount of oleic acid was higher in the cancer patient group. For total plasma phospholipids, no differences in fatty acid composition between patients and controls were found. Throughout the lipoprotein fractions, the same differences in oleic acid and linoleic acid distribution for triglyceride and esterified cholesterol were found when comparing cancer and control subjects. In conclusion, we found that there are certain differences in the 13C NMR spectra and fatty acid profiles between a small and heterogeneous group of cancer patients after they have received their initial treatment and a group of healthy controls. We suggest that carbon NMR spectroscopy could be useful in characterizing malignancy associated lipid changes. PMID- 7858263 TI - Is there a critical gestational age in neutrophil superoxide production activity? AB - We studied superoxide (O2-) production in neutrophils from 78 normal pregnant women at 7 to 39 weeks' gestation to determine whether there is a critical gestational age in O2- production activity of maternal neutrophils. The O2- production was measured by determining the rate of superoxide dismutase inhibitable reduction of ferricytochrome c at 550 to 540 nm. A scattergram of neutrophil O2- production value versus gestational age was analyzed using the least median of squares regression, leading to a statistical stratification in which the median values of O2- production for outlying and nonoutlying points were 6.60 nmol/10(6) cells and 2.72 nmol/10(6) cells, respectively. All of the outlying points were concentrated at 19 to 22 gestational weeks. There was the significant difference in FMLP-induced O2- production in neutrophils of nonpregnant subjects when incubated with the sera from 10 cases (selected among 60 cases with nonoutlying points) (3.86 +/- 0.77 nmol/10(6) cells) compared with 5 cases with outlying points (5.62 +/- 1.19 nmol/10(6) cells) (P < .05) These results suggest that during the normal course of pregnancy, the production of O2- from the function of circulating neutrophils can be dissociated from such neutrophil functions as adherence, chemotaxis, and phagocytosis. PMID- 7858264 TI - Downregulation of proinflammatory cytokine release in whole blood from septic patients. AB - Using animal models or healthy volunteers, injection of lipopolysaccharide (LPS) or bacteria causes activation of macrophages with excessive synthesis and secretion of proinflammatory cytokines. Although these models mimic the effects of LPS in the host, they may represent more of an experimental expression of endotoxemia than natural infection itself. Therefore, as an ex vivo model of sepsis, whole blood from 15 patients with severe sepsis and 20 control patients without infection was stimulated with LPS to study the kinetics of mRNA expression and release of proinflammatory cytokines, tumor necrosis factor (TNF) alpha, interleukin (IL)-1 beta, and IL-6. Stimulation of whole blood with 1 microgram/mL LPS resulted in a maximum increase of cytokine secretion in the control group, while a marked (P < .01) depression of TNF-alpha, IL-1 beta, and IL-6 release was observed in the septic group, which persisted up to 10 days after study enrollment. While IL-1 beta mRNA expression was similar in peripheral blood mononuclear cells (PBMCs) harvested from LPS-stimulated whole blood in septic and control patients, the half-life and consequently the expression of TNF alpha and IL-6 mRNA were strongly reduced in the septic group. These data indicate a downregulatory mechanism of cytokine release in whole blood from patients with severe sepsis that occurs on different levels. Although excessive secretion of proinflammatory cytokines has been considered deleterious for the host, the reduced capacity of PBMCs in whole blood from septic patients to synthesize and secrete proinflammatory cytokines to an inflammatory stimulus may result in immunodeficiency, because these cytokines in low concentrations are involved in the upregulation of essential cellular and humoral immune functions. PMID- 7858265 TI - Aplastic anemia and paroxysmal nocturnal hemoglobinuria: search for a pathogenetic link. AB - The association of paroxysmal nocturnal hemoglobinuria (PNH) and aplastic anemia (AA) raises the yet unresolved questions as to whether these two disorders are different forms of the same disease. We compared two groups of patients with respect to cytogenetic features, glycosylphosphatidylinositol (GPI)-linked protein expression, protein C/protein S/thrombomodulin/antithrombin III activity, and PIG-A gene expression. The first group consisted of eight patients with PNH (defined as positive Ham and sucrose tests at diagnosis), and the second, 37 patients with AA. Twelve patients with AA later developed a PNH clone. Monoclonal antibodies used to study GPI-linked protein expression (CD14 [on monocytes], CD16 [on neutrophils], CD48 [on lymphocytes and monocytes], CD67 [on neutrophils and eosinophils], and, more recently, CD55, CD58, and CD59 [on erythrocytes]) were also tested on a cohort of 20 normal subjects and five patients with constitutional AA. Ham and sucrose tests were performed on the same day as flow cytometric analysis. Six of 12 patients with AA, who secondarily developed a PNH clone, had clinical symptoms, while all eight patients with PNH had pancytopenia and/or thrombosis and/or hemolytic anemia. Cytogenetic features were normal in all but two patients. Proteins C and S, thrombomodulin, and antithrombin III levels were within the normal range in patients with PNH and in those with AA (with or without a PNH clone). In patients with PNH, CD16 and CD67 expression were deficient in 78% to 98% of the cells and CD14 in 76% to 100%. By comparison, a GPI-linked defect was detected in 13 patients with AA, affecting a mean of 32% and 33% of CD16/CD67 and CD14 cell populations, respectively. Two of three tested patients with PNH and 1 of 12 patients with AA had a defect in the CD48 lymphocyte population. In a follow-up study of our patient cohort, we used the GPI-linked molecules on granulocytes and monocytes investigated earlier and added the study of CD55, CD58, and CD59 on erythrocytes. Two patients with PNH and 14 with AA were studied for 6 to 13 months after the initial study. Among patients with AA, four in whom no GPI-anchoring defect was detected in the first study had no defect in follow-up studies of all blood-cell subsets (including erythrocytes). Analysis of granulocytes, monocytes, and erythrocytes was performed in 7 of 13 AA patients in whom affected monocytes and granulocytes were previously detected. A GPI-anchoring defect was detected on erythrocytes in five of six.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7858266 TI - Organization of the gene encoding the human Kell blood group protein. AB - Kell is one of the major blood group systems in human erythrocytes. It is a complex system containing a large number of different antigens. Previously we cloned the Kell cDNA, which was predicted to encode an integral membrane protein with 731 amino acids. Now we have isolated overlapping genomic clones and determined the exon-intron structure of the KEL gene; it spans approximately 21.5 kb with its coding sequence being organized in 19 exons that range in size from 63 bp to 288 bp. The size of introns ranges from 93 bp to approximately 6 kb. The donor and acceptor splice sites all conform to the consensus splicing sequences. Exon 1 encodes only the initiation amino acid, methionine, and contains a consensus Sp1 binding site. The single membrane spanning region of Kell protein is encoded in exon 3 and the putative zinc endopeptidase active site is in exon 16. The amino acids encoded by the 19 exons are identical to those of a person with a common Kell phenotype, as determined by RNA polymerase chain reaction of peripheral blood. Amplification of cDNA 5' ends, derived from human fetal liver, indicated three transcription initiation sites located 30, 81, and 120 bp upstream of the initiation codon. The 5' flanking region of KEL from -176 does not contain a TATA sequence, but has possible GATA-1 binding sites and has significant promoter activity when determined by chloramphenicol acetyltransferase activity in K562 cells. PMID- 7858267 TI - New glucose-6-phosphate dehydrogenase mutations associated with chronic anemia. AB - We have identified the glucose-6-phosphate dehydrogenase mutations responsible for enzyme deficiency in nine individuals with chronic nonspherocytic hemolytic anemia. We found the variants Tokyo, Iowa, Shinshu, and Guadalajara in British subjects and Kobe in an Italian. In addition we have determined the variant Corum has the mutation 820 G-->A and have found in British subjects the mis-sense mutations 224 T-->C, 488 G-->A and 833 C-->T which have not been described before. Some, but not all, of the mutations involve amino acids located near putative substrate binding sites. PMID- 7858268 TI - High-dose chemotherapy with or without total body irradiation followed by autologous bone marrow and/or peripheral blood stem cell transplantation for patients with relapsed and refractory Hodgkin's disease: results in 85 patients with analysis of prognostic factors. AB - Eight-five consecutive patients with relapsed or refractory Hodgkin's disease (HD) underwent high-dose chemotherapy or chemo/radiotherapy followed by autologous bone marrow (ABMT) and/or peripheral blood stem cell (PBSC) transplantation. Two preparative regimens were used. Twenty-two patients (26%) without prior radiation received fractionated total body irradiation (FTBI) 1,200 Gy in combination with high-dose etoposide (VP-16) 60 mg/kg and cyclophosphamide (CTX) 100 mg/kg. Sixty-three patients (74%) with prior radiotherapy received carmustine (BCNU) 450 mg/m2 instead of FTBI. The median age was 32 years (range, 16 to 56). The median number of prior chemotherapy regimens was three (range, 1 to 7). Forty-three patients (51%) received transplants in first relapse or second complete remission (CR), whereas 33 (39%) received transplants after second or subsequent relapse. All relapsed patients, except one, received conventional salvage chemotherapy and/or radiotherapy in an attempt to reduce tumor bulk before transplant. At the time of analysis in April 1994, fifty-seven patients (67%) are alive, including 44 (52%) in continuous CR, with a median follow-up for the surviving patients of 28 months (range, 7 to 66). Thirty patients (35%) relapsed at a median of 9 months (range, 1 to 43). Eleven patients (13%) died of transplant-related complications including veno-occlusive disease of the liver (VOD) in five, acute and late interstitial pneumonitis in three, graft failure in one, cerebral hemorrhage in one, and therapy-induced myelodysplasia (MDS)/acute leukemia in one patient. At a median follow-up of 25 months (range, 0.6 to 66), the cumulative probability of 2-year overall and disease-free survival (DFS) of all 85 patients is 75% (95% confidence interval [CI] 64% to 84%) and 58% (95% CI 47% to 69%), respectively. Three independent prognostic variables were identified by univariate analysis: number of prior chemotherapy regimens, prior radiotherapy, and extranodal disease at ABMT. Multivariate stepwise Cox regression identified the number of prior chemotherapy regimens as the only significant prognostic factor predicting for both relapse and DFS. There were no significant differences in the outcome of the treatment between the two preparative regimens. Our results confirm that high-dose therapy and ABMT is an effective therapy for patients with relapsed or refractory HD. Earlier transplantation is recommended before the development of drug resistance and end organ damage that results from repeated attempts of salvage therapy. PMID- 7858269 TI - High-dose etoposide, cyclophosphamide, and total body irradiation with allogeneic bone marrow transplantation for patients with acute myeloid leukemia in untreated first relapse: a study by the North American Marrow Transplant Group. AB - Relapse is a major cause of treatment failure following allogeneic bone marrow transplantation (BMT) for acute myeloid leukemia (AML). To reduce the risk of relapse following BMT for patients with hematologic malignancy, our group developed a novel preparative regimen which combines high-dose etoposide with cyclophosphamide and total body irradiation (VPCyTBI). We now report the outcome of therapy with VPCyTBI followed by allogeneic BMT for 40 patients with AML in untreated first relapse. With the exception of increased stomatitis, the toxicity of this regimen was similar to that reported by others for CyTBI. Forty-four months after transplant the actuarial probabilities of disease-free survival (DFS), persistent or recurrent leukemia, and transplant related mortality were .29, .44, and .47 respectively. DFS was improved (P < .01) and risk of persistent or recurrent leukemia reduced (P = .005) among patients with significant (grade > or = 2) acute GVHD. Patients with 30% or more blasts on pre-BMT bone marrow examination were not at increased risk for persistent or recurrent leukemia. We conclude that VPCyTBI with allogeneic BMT is effective therapy for AML in untreated first relapse and that a randomized trial comparing this regimen with CyTBI is warranted. PMID- 7858271 TI - Cyclophosphamide/antithymocyte globulin conditioning of patients with severe aplastic anemia transplanted with bone marrow from HLA-identical related donors. PMID- 7858270 TI - Posttransplantation lymphoproliferative disorders frequently contain type A and not type B Epstein-Barr virus. AB - Two families of Epstein-Barr virus (EBV), type A and type B, have been defined on the basis of sequence divergence in the EBNA-2 gene. Type A EBV immortalizes B cells more efficiently in vitro and infects immunocompetent individuals more commonly than type B EBV. However, increased rates of infection by type B EBV are seen in immunocompromised hosts and in many lymphoid neoplasms associated with immunocompromise. The posttransplantation lymphoproliferative disorders (PT-LPDs) are a heterogeneous group of B-cell neoplasms that arise in the setting of immunosuppressive therapy, and are associated with EBV infection. Whether type A and/or type B EBV are associated with PT-LPDs is unknown. Therefore, we investigated 27 PT-LPD lesions from 22 solid-organ transplant recipients by polymerase chain reaction (PCR) at the EBNA-2 and EBNA-3c loci to detect sequence deletions that distinguish the two EBV families. Another locus, EBER, was examined by single-strand conformation polymorphism analysis (SSCP), in conjunction with direct sequencing in selected cases. Type A EBV was found in 24 of 27 cases (89%) as seen by amplification of the EBNA-2 and EBNA-3c regions. Four different EBER polymorphisms were detected, confirming the presence of different type A EBV isolates among these cases. Three cases were negative for infection by EBV. Surprisingly, despite the immunocompromised state of the hosts, none of the 27 PT-LPD lesions harbored type B EBV. Thus, although type B EBV may commonly infect peripheral blood lymphocytes in immunocompromised individuals, they do not appear to induce readily PT-LPD formation. PMID- 7858272 TI - Procoagulant triggers during cardiopulmonary bypass. PMID- 7858273 TI - Cyclosporin A therapy of immune-mediated thrombocytopenia in children. PMID- 7858274 TI - Importance of PF4 in heparin-induced thrombocytopenia: confirmation with gray platelets. PMID- 7858275 TI - Nomenclature of human platelet alloantigens. PMID- 7858276 TI - The Functional Independence Measure: a comparative validity and reliability study. AB - The majority of measurement scales used to evaluate outcome in rehabilitation are ordinal in nature and consequently statistically valid assessments of change are difficult to make. The Functional Independence Measure (FIM) can be weighted to possess interval properties, potentially allowing more accurate analysis of change. In this study the FIM was compared to the Barthel Index (BI) to determine its validity, reliability and ease of use in two groups of 25 patients undergoing neurorehabilitation. The FIM was considered to be more valid than the BI, and equally reliable in the assessment of disability. When the two disability scores were compared using subjective and objective assessment the agreement between them was comparable, although neither was high. PMID- 7858277 TI - Competence and performance in activities of daily living of patients following rehabilitation from stroke. AB - Indices of activities of daily living (ADL) are commonly criticized for failing to yield other than functional information. We suggest an alternative approach in which tested functional ability (ADL competence) is distinguished from actual behaviour (ADL performance). A method of making these assessments, based on the Australian ADL Index, was trialled in a longitudinal study involving 130 patients admitted for rehabilitation following stroke. Twelve months after discharge from rehabilitation the total ADL performance score was higher, that is to say worse, than the total ADL competence score; further, there was no significant agreement between the competence and performance ratings for nine of the 17 activities. It appears that ADL competence and ADL performance can be distinguished both theoretically and empirically. Two case studies illustrate the usefulness of the performance assessment. We recommend the ADL performance assessment as an outcome measure in rehabilitation. PMID- 7858278 TI - Assessing inter- and intrapersonal resources: social support and coping among adults with a disability. AB - A promising model for addressing community reintegration and adjustment following disability is the stress-outcome model. In spite of demonstrated applicability, this model has found little support among clinicians and researchers in the rehabilitation field. One reason for this may be the lack of explicit conceptual and operational definitions for the central constructs of the model. This paper presents theoretical and measurement models for two such constructs which are considered buffers or mediators in the stress-outcome relationship: social support and coping. Issues associated with each construct are explored, with reference particularly to people with disabilities. Following a synthesis of the literature, models for each construct were proposed that represented the two constructs as each having a parallel three-factor structure. Using a sample of 120 spinal cord-injured adults from across Ontario, data were collected on existing instruments which measure the two constructs of interest (Interpersonal Support Evaluation List, Ways of Coping Questionnaire). Face-to-face interviews were conducted in participants' homes at 1, 4, and 12 months post-discharge from rehabilitation, in order to capture the period of initial community readjustment and reintegration. Psychometric evaluation of the measurement models included item analysis, factor analysis, and reliability assessment. These analyses provided empirical support for the three-factor structure for both constructs, as well as a second-order general factor for social support. Recommendations for revisions of the scales and further development of the measurement models were made, and the revised measures were discussed in terms of theoretical and research implications. PMID- 7858279 TI - Patients' experience of rehabilitation after stroke. AB - In this study patients were interviewed concerning their experience of rehabilitation in an experimental stroke unit. The patients reported positive effects of being together with other stroke patients and used the unit in a self help group fashion. They felt that they could have used more rehabilitation, even though they were hospitalized for longer than reported in other studies. Patients felt that there were important non-physical problems in connection with their rehabilitation, and that sufficient attention was not given to all of these. Finally patients underlined the positive effects of the rehabilitation process in helping them organize their coming life in the community. PMID- 7858280 TI - Disability in late adolescence. I: Introduction, methods, and overview. AB - The research sought to describe the nature and severity of disability and its impact in a large sample of 18-year-olds. It was conducted as part of a larger longitudinal study of the health and development of a cohort of approximately 1000 children. This paper presents an overview of the methods used together with the results on the prevalence of specific disabilities. The three leading disabilities were: coping with dust, pollens, or chemicals (rate: 272 per 1000), equipment dependence (186), and disability in endurance (160). PMID- 7858281 TI - Environmental modifications in the homes of elderly Canadians with disabilities. AB - This study was performed to (1) determine if the use of architectural modifications in the homes of the disabled elderly can reduce the level of disability; (2) determine the predictors of the use of architectural modifications; and (3) estimate the degree of need for environmental modifications. The degree of need was estimated using data from 8895 respondents (55 years and older) from the Canadian Health and Disability Survey (1983-84). A subgroup of 1520 respondents who needed architectural modifications was selected to predict: (1) the ability to perform instrumental activities of daily living (IADL) and (2) the use of architectural modifications. These data were analysed using multiple linear regression. Approximately 37.9% of the disabled elderly required at least one modification to their home. About 40% did not have the architectural modification that was needed. Income was found to be a predictor of the use of architectural modifications (p = 0.0273). Users of architectural modifications were more independent in IADL than non-users (p < 0.0312). In conclusion, there is a substantial need for environmental modifications in the homes of the disabled elderly. Furthermore, architectural modifications should be available at a low cost. PMID- 7858282 TI - Endocrine tumors of the gastrointestinal tract: systemic treatment. AB - Neuroendocrine gut and pancreatic tumors are neoplasms that present distinct features from other malignant tumors. Firstly, in most patients, tumor growth is rather slow, and even in advanced metastatic disease, there is very little impairment of the general well-being of the individual, e.g. appetite and weight. Secondly, these tumors are known to produce specific peptide hormones which may be factors in some clinical conditions e.g. carcinoid, Zollinger-Ellison and hypoglycemic syndromes. These conditions can be critical to the patients and can occasionally be lethal. Therefore, the treatment of neuroendocrine tumors must control the clinical symptoms related to hormone over-production and prevent further tumor growth. These two features are not always in parallel. Systemic treatment of neuroendocrine tumors mainly consists of chemotherapy, interferon and somatostatin analog administration. Chemotherapy has been used for at least 30 years; the most effective combination has proved to be streptozotocin with 5 fluorouracil or adriamycin. This combination produces biochemical responses in up to 60% of patients with endocrine pancreatic tumors; the results in carcinoid patients are very poor and response rates are < or = 10%. Alpha-interferon (IFN alpha) produces biochemical responses in approximately 50% of patients with malignant carcinoid tumors, significant reductions in tumor size in 15% and a further 39% of patients have disease stabilization with no further tumor growth. Somatostatin analogs have only been used clinically within the last 10 years, but produce symptomatic improvement in 70% of cases, biochemical responses in 40-60%, but rarely produce any significant reduction in tumor size. These analogs are particularly useful to control severe clinical symptoms and are the first-line therapy for the management of carcinoid patients both peri- and intra operatively. Patients with endocrine pancreatic tumors, particularly those with glucagon and vasointestinal peptide-producing tumors, benefit most from this type of treatment. Recently, a combination of IFN-alpha and a somatostatin analog has showed an additive effect of these two drugs. The side effects of streptozotocin and 5-fluorouracil are mainly nausea and vomiting which can be controlled with 5 HT3 receptor blocker therapy. Another significant adverse reaction is impaired renal function. The adverse reactions to IFN-alpha are mainly flu-like symptoms, fatigue, mild impairment of liver and bone marrow function and autoimmune reactions in 15% cases. Somatostatin analog treatment causes a low frequency of adverse reactions, those which do occur include gall stone formation and steatorrhea. Future systemic treatment should be based on increased knowledge of the tumor biology, particularly growth-regulatory mechanisms.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7858283 TI - Phase I clinical trial of ormaplatin (tetraplatin, NSC 363812). AB - Ormaplatin is a platinum analog that was developed because of an altered toxicity profile and non-cross resistance to cisplatin in both in vitro and in vivo models. To determine the toxicities and maximum tolerated dose of ormaplatin on a daily times five schedule, patients with refractory solid tumors received ormaplatin on five consecutive days at nine dose levels ranging from 1.0 to 15.0 mg/m2/day. A total of 35 patients received 70 cycles of therapy. Nausea and vomiting and myelosuppression were moderate and not dose-limiting. Dose-limiting neurotoxicity, consisting of a sensory peripheral neuropathy, was seen in all five patients who received cumulative doses greater than or equal to 165 mg/m2. This neurotoxicity was symptomatic in all patients and caused significant functional impairment in four patients with inability to walk in two patients. A sensitive atomic absorption spectroscopy analysis performed for one patient at the 13.0 mg/m2/day dose level showed a Cpmax of 163 ng/ml and a t1/2 of 10.9 min for free platinum. A phase II dose could not be determined due to the onset of peripheral neuropathy at low cumulative doses and not at absolute dose levels. PMID- 7858284 TI - A dosing scheme for carboplatin in adult cancer patients based upon pre-infusion renal function and platelet count. AB - The most important risk factors for the development of carboplatin-induced thrombocytopenia are total dose, glomerular filtration rate (GFR) and pre infusion platelet count (P0). Pharmacokinetic and toxicity data from 23 patients with ovarian or testicular cancer were combined with published values from four other centers and the relationships between plasma clearance of ultrafilterable platinum and GFR, and between percentage reduction in platelet count and area under the plasma platinum curve were determined. The scatter in the data was estimated and used in a Monte-Carlo computer simulation to derive the following five-level dosing scheme. [table: see text] The scheme is based on 5% of patients incurring grade IV thrombocytopenia. Using this scheme, the majority of patients with ovarian or testicular cancer receiving carboplatin will be given an initial dose of 900 mg. PMID- 7858285 TI - Structure-activity studies on 2-aryl-4H-3,1-benzoxazin-4-ones. AB - Eight benzoxazin-4-ones related in structure to NSC 341964 (1) have been tested for cytotoxicity in two different cell systems. Two of the benzoxazin-4-ones (3 and 10) showed good cytotoxicity (ID50 = 9.9 and 8.9 microM) in P388 cells. The nitrobenzoxazin-4-one (10) caused a significant alteration in cell cycle distribution when administered to P388 cells and was an inhibitor of porcine pancreatic elastase. Structure-activity relationships are discussed. PMID- 7858286 TI - Pharmacokinetic studies on Elobromol in children with brain tumors. AB - Systemic pharmacokinetics of high dose (500 mg/m2), orally administered Elobromol (dibromodulcitol, DBD) were studied in 16 chemotherapeutic courses administered to five patients. Cerebrospinal fluid (CSF) DBD levels were also analyzed in two patients. Bromoepoxydulcitol (BED), dianhydrodulcitol (DAD) are cytotoxic, whereas bromoanhydrodulcitol (BAD) and anhydroepoxydulcitol (AED) are inactive metabolites detectable during the biotransformation of DBD. The HPLC method, developed by our team, is suitable for the determination of both DBD and its main metabolites (DAD and BAD). Our publication is the first in the literature to describe the pharmacokinetic properties of these three hexitol derivatives in pediatric patients. With the exception of one patient, concentration time curves were analyzed by the one-compartment model. From 30 min following administration, DBD was detectable in all plasma samples for at least 12 h; its concentration, however, was usually undetectable by 24 h. Though highly variable in value, DAD concentrations were detectable during all but one of the therapeutic courses. The following peak concentrations were observed: DBD = 3.46-30.63 microM, DAD = 1.70 6.17 microM and BAD = 0-5.63 microM. The correlation of AUCBAD and AUCDBD values were exponential up to 200 microM h with no additional increase detectable above this limit: the distribution of AUCBAD and AUCDBD was described by a maximum curve. The possibility of enterohepatic recirculation could not be excluded for any of the compounds studied. Each of the three hexitol derivatives was detectable in CSF even if the concentration of the individual metabolite remained undetectable in plasma. DBD CSF concentrations were almost constant in the period from 2.5 to 8 h following administration.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7858287 TI - Antiproliferative effects of sodium butyrate in adriamycin-sensitive and resistant human cancer cell lines. AB - The proliferation of the MCF7 and MCF7-A (adriamycin-resistant) and KB-3-1 and KB A (adriamycin-resistant) cell lines was arrested by sodium butyrate (NaBut) at 1 mM or higher concentrations. In the MCF7 and MCF7-A cell lines, an accumulation in the G1 phase was observed, whereas the KB-3-1 and KB-A cell lines accumulated in both G1 and G2/M phases. The level of the mRNA coded by the 'early G1' gene c myc was high in all these cell lines, and was only transiently decreased by NaBut treatment. The 'late' mRNA coding for the proliferating cell nuclear antigen (PCNA) was also strongly expressed in all the cell lines studied; incubation with NaBut caused a decrease of the PCNA mRNA in the MCF7 and MCF7-A cells but not in the KB-3-1 and KB-A cells. The anti-oncoprotein p105RB was undetectable in the MCF7 and MCF7-A cells, while the KB-3-1 as well as KB-A cells contained a high level of this protein. Neither the content nor the apparent state of phosphorylation of the RB protein were affected by incubation (up to 48 h) with NaBut. PMID- 7858288 TI - Topoisomerase II-dependent novel antitumor compounds merocil and merodantoin induce apoptosis in Daudi cells. AB - Three photoproducts of merocyanine 540 have been isolated, chemically characterized and synthesized. Two of these photoproducts, merocil and merodantoin, show significant antitumor activity in vitro and in vivo while demonstrating minimal toxicity to normal cells and tissues. Treatment of lymphoma cells with these compounds resulted in a rapid decline in macromolecular synthesis, DNA fragmentation inhibitable by actinomycin D and cycloheximide, and a marked rise in intracellular calcium. In vitro analysis revealed that activity of these compounds is dependent on topoisomerase II. These results are discussed in terms of the novel class of topoisomerase II-dependent compounds for potential use in chemotherapy. PMID- 7858289 TI - Chemopreventive action by an extract from Ocimum sanctum on mouse skin papillomagenesis and its enhancement of skin glutathione S-transferase activity and acid soluble sulfydryl level. AB - We report the chemopreventive property of an ethanolic extract of the leaves of Ocimum sanctum (a traditional medicinal plant) on 7,12-dimethylbenz[a]anthracene induced skin papillomagenesis in male Swiss albino mice. A significant reduction in the values of tumor incidence, average number of tumors per tumor bearing mice and the cumulative number of papillomas was observed in mice treated topically with the leaf extract of O. sanctum at either the peri-initiational, post initiational stages or continuously at peri- and post-initiational stages of papillomagenesis as compared to the corresponding control group. Topical application of Ocimum leaf extract for 15 days resulted in significant 2-fold elevation of reduced glutathione content in the skin of mice (p < 0.05). Similarly, glutathione S-transferase activity was also observed to be significantly elevated by 25% compared with the control group (p < 0.05) following Ocimum extract treatment. PMID- 7858290 TI - Pharmacokinetics of hydroxyurea in nude mice. AB - Extrachromosomal DNA is the predominant form of gene amplification in human tumors. Hydroxyurea (HU) concentrations of 100-150 microM have been promising in vitro for extrachromosomal DNA elimination. The study objective was to determine the HU dose-concentration relationship in nude mice with HU doses from 0 to 200 mg/kg. For HU t1/2 determination, mice were injected with HU 100 mg/kg. A plasma concentration of 159 microM was achieved and a t1/2 of 11.3 min determined. Based on these findings, In vivo elimination studies will require frequent administration of HU to maintain plasma concentrations from 100 to 150 microM. PMID- 7858291 TI - Liposome encapsulated vincristine: preclinical toxicologic and pharmacologic comparison with free vincristine and empty liposomes in mice, rats and dogs. AB - A preclinical toxicology study of liposome encapsulated vincristine, free vincristine and empty liposomes was carried out in mice and dogs by single and multiple (daily for 5 days) intravenous injection. Single and multiple dose intravenous injection studies in mice showed the encapsulated form of vincristine to be less toxic than free vincristine. Empty liposomes injected intravenously into dogs were without significant toxicity. In dogs, the toxicities seen with liposomal vincristine were qualitatively similar to those of free vincristine with only minor quantitative differences. The principal toxicities of free and liposomal vincristine in dogs were anorexia, weight loss, pyrexia, myelosuppression and gastrointestinal toxicity. After single high doses of either formulation gastrointestinal toxicity was the dose-limiting toxicity, while either hematologic or gastrointestinal toxicity was dose limiting after multiple dose administration of either drug. Histopathologic lesions of importance were bone marrow atrophy, necrosis and atrophy of the lymphoproliferative tissues, necrosis of gastrointestinal tract mucosa, liver and pancreas, and hemorrhage. Distribution studies in rats showed significantly higher vincristine levels in serum, spleen, liver, trachea, jejunum, cerebrum, lung, ischiatic nerve and heart, and significantly lower levels in colon, stomach, salivary gland, thymus esophagus and pancreas after injection of the liposome-associated agent. No toxicities were seen that should preclude safe clinical trial of liposomal vincristine in man. PMID- 7858292 TI - Inhibitory effects of the gastrin receptor antagonist CR2093 on basal, gastrin stimulated and growth factor-stimulated growth of the rat pancreatic cell line AR42J. AB - AR42J, a rat pancreatic cell line expressing receptors for both gastrin and epidermal growth factor (EGF), has been used to examine the effect of the gastrin receptor antagonist CR2093 on basal, gastrin-17 (G17), EGF and transforming growth factor (TGF)-alpha stimulated growth in vitro. In serum-free conditions, CR2093 reduced the basal growth of AR42J at a concentration known to displace physiological levels of G17 from gastrin receptors and this effect was reversed by G17 at 1 x 10(-9) M. Alone, G17 had little effect on growth, but EGF and TGF alpha stimulated growth to 181 and 176% of control values, respectively, and marked synergy was observed when G17 was used in combination with both EGF (212%) and TGF-alpha (259%). When CR2093 was added, the synergistic effects of the G17/EGF and G17/TGF-alpha combinations were reduced to basal levels. In addition, CR2093 inhibited the growth stimulation induced by EGF and TGF-alpha alone. When the ability of CR2093 to bind to EGF receptors was assessed in a ligand binding assay, it was found that the antagonist displaced up to 23% of labeled EGF. Thus CR2093 has potent inhibitory effects on the basal growth of AR42J which can be reversed by G17. It can also inhibit type 1 growth factor-stimulated growth, but although this action may in part be related to the antagonist's ability to inhibit binding to the EGF receptor, other mechanisms may be involved. PMID- 7858293 TI - Effects of lovastatin on a human myeloma cell line: increased sensitivity of a multidrug-resistant subline that expresses the 170 kDa P-glycoprotein. AB - Using a fluorometric microculture cytotoxicity assay for measuring cell viability and proliferation we examine the cytotoxic effect of lovastatin on a drug sensitive myeloma cell line (RPMI 8226) and a multidrug resistant (MDR) clone (8226/Dox40), that was approximately 100-fold less sensitive to doxorubicin. The RPMI 8226 cells were sensitive to lovastatin with an IC50 of 15.8 micrograms/ml. However, the MDR subline exhibited a collateral sensitivity to lovastatin, with an IC50 of 1.7 microM, thus having a 9.3-fold greater sensitivity to lovastatin than the parental cell line. The combination of doxorubicin and lovastatin did not show any synergistic or antagonistic effects on any of the cell lines. The increased sensitivity to lovastatin of the P-gp 170-expressing MDR cells 8226/Dox40 might be part of a more general phenomenon that merits further investigation. PMID- 7858294 TI - Interferon-beta does not change the level of O6-alkylguanine-DNA alkyltransferase in cancer patients' lymphocytes. PMID- 7858295 TI - Safe administration of oral etoposide after hypersensitivity reaction to intravenous etoposide. PMID- 7858296 TI - Development of hearing. Part II. Embryology. AB - We humans hear the way we do because of at least three major forces. The first is phylogeny, the evolutionary changes in the auditory system since its beginnings. Another is embryology, the development of the system in each individual. Finally, there is the biologically determined mechanism we are born with and our interaction with the environment in early postnatal life. This series of articles reviews each aspect so that we may have a fuller appreciation of how it is we come to hear the way we do. Part I described the phylogeny of the auditory system. Part II traces the development in prenatal life of the internal, middle, and external ear and the nervous system by days, weeks, and months. Wherever possible, parallels are drawn between phylogenetic and embryologic development. Part III considers the postnatal aspects of auditory development. PMID- 7858298 TI - Sound pressure in the external auditory canal during bone-conduction testing. AB - Sound pressure levels (SPLs) were measured in the external auditory canals (EACs) of 16 subjects with normal hearing and normal middle ear immittance. SPLs were the result of bone-conduction (BC) stimulation at 500, 1000, 2000, and 4000 Hz, with the oscillator placed either on the forehead or on the mastoid process. At 1000, 2000, and 4000 Hz, significantly higher SPLs were measured when the head was stimulated from the mastoid than from the forehead. When SPLs were compared between right and left EACs, forehead placement of the oscillator produced no interaural differences, while mastoid placement resulted in significantly greater EAC SPLs ipsilateral to the oscillator at 2000 and 4000 Hz. We conclude that forehead placement of a BC vibrator may help to lessen the (unwanted) contribution of the EAC to measurements of hearing sensitivity by BC. PMID- 7858297 TI - Deriving passage difficulties for a tracking study via the Cloze technique. AB - The current report demonstrates the importance of formally accounting for passage difficulty when using the tracking procedure. Cloze responses to 82 encyclopedia excerpts (343-349 words each) were obtained from a large pool of normal-hearing adults and scored verbatim. Passage difficulty, derived via ANOVA, was then defined as the deviation of a passage's mean Cloze score from the score for all passages, corrected for differences among respondents. The passage difficulties were applied in an alternating conditions tracking experiment with one adult cochlear implant user. Conditions included conventional auditory-visual and auditory-only tracking and experimental mode-switching techniques in which the talker changed modalities during the correction phase. An ANCOVA of the word-per minute scores was conducted, with passage difficulty as a covariate and passage adjustment values as the output. Tracking rates and percentage of words correct from the beginning and end of training were examined. Use of adjusted data reversed the interpretation of performance change, demonstrating the need for determining passage difficulties a priori. PMID- 7858299 TI - ENG in the emergency room: subtest results in acutely dizzy patients. AB - A retrospective analysis of electronystagmography (ENG) subtests performed on 93 acutely dizzy patients in the emergency room (ER) shows that "pendular tracking" has high sensitivity and specificity for determining central pathology. Small combinations of subtests altered sensitivity or specificity only slightly over pendular alone. Detection of spontaneous nystagmus was also helpful in ruling out "other" diagnoses such as hyperventilation syndrome, psychogenesis, or malingering. Popularity of the shortened ENG in the ER was evidenced by the high rate of charting of results and the frequency with which the test was requested after the study terminated. ENG also identified four cases of previously unsuspected central nervous system (CNS) lesion. PMID- 7858300 TI - Intersubject variability of real-ear sound pressure level: conventional and insert earphones. AB - Measures of the sound pressure level (SPL) near the eardrum were determined at discrete frequencies between 500 and 4000 Hz on 50 ears using TDH-39P and ER-3A earphones with the attenuator of an audiometer fixed at 90 dB HL. Results revealed significant differences in the measured SPL between the two earphones at all test frequencies. Results also revealed large intersubject differences in the SPL measured near the eardrum for both earphones. The results of this study highlight the large intersubject variability associated with measuring the SPL at the eardrum and point out the difficulty in accurately predicting individual performance from averaged group data. PMID- 7858301 TI - Test-retest reliability of high-frequency thresholds at bedside with sensorineural hearing-impaired listeners. AB - Previous investigations have established the reliability of high-frequency thresholds performed in a sound suite using headphones. In addition, test-retest reliability of high-frequency thresholds in adults with normal hearing in a hospital room versus a sound-treated booth has also been established. The current study evaluated the test-retest reliability of thresholds in the 8000- to 18000 Hz range in 15 hearing-impaired adults (26 ears) with varying degrees of sensorineural hearing loss. A high-frequency audiometer and supra-aural earphones were used to measure thresholds in a typical hospital room. Results revealed no significant difference between repeated threshold measures. This study represents the third phase of an ongoing project to develop reliable bedside monitoring of patients undergoing ototoxic medical treatment. PMID- 7858302 TI - Prediction of 8-hour noise dose from brief duration samples. AB - The purpose of this study was to determine whether brief duration samples of noise dose measurements could predict the noise exposure levels of employees as measured by 8-hour dosimetry. Sampled noise dose measurements were obtained for 1, 5, 10, 15, and 20 minutes and 8 hours for four workers at each of four industrial sites. Statistical analyses indicated no significant differences or interactions among trials and sample durations. A simple linear prediction model provided the best fit for the four shortest of the five abbreviated sample durations, whereas an exponential regression model provided the best predictions using the 20-minute sample duration. The high variance and low correlations across all measures permitted only poor predictions from these abbreviated sample data. Based on these results, sampled noise measurements of short duration (1 to 20 minutes) do not appear to be a valid means for predicting the amount of noise exposure during an 8-hour shift. PMID- 7858303 TI - Autonomy of audiologists in educational settings. AB - Professional autonomy continues to be an issue of major concern for practicing audiologists. Members of the Educational Audiology Association completed a written survey covering the amount of independence and authority they experience when employed in an educational setting. Four areas were explored: scope of practice; referral procedures; assessment and management activities; and employment conditions. Responses indicated that educational audiologists have a great deal of autonomy in matters relating to the scope of their practice and the implementation of daily activities. Autonomy in the area of employment conditions was much less widespread. This report provides a detailed description of the survey responses, conclusions, and implications for future training needs for audiologists who may be employed in an educational setting. PMID- 7858304 TI - Evaluation of a behavioral audiometry simulator for teaching visual reinforcement audiometry. AB - Eight audiology students with little or no visual reinforcement audiometry (VRA) experience each performed a VRA test on an infant. Four of the students received approximately 5 hours of behavioral audiometry simulator (BAS) training, and 1 week later, after the first VRA test, all eight students tested a second infant. Student performance was rated by three audiologists who were experienced in performing VRA with infants. The performance of the group that received BAS training improved significantly while the performance of the control group did not. Among the students who received BAS training, those who improved the most during stimulated testing also showed the greatest improvement in VRA with real infants. PMID- 7858305 TI - Qualitative and quantitative determination of mRNA. AB - Many environmental pollutants, xenobiotics, as well as endobiotics cause modulation in gene expression which may change the transcriptional activities of the gene. A reliable, sensitive method to determine the mRNA level qualitatively or quantitatively is essential for the study of gene expression. Since the early seventies many methods have been available for the qualitative as well as quantitative measurement of steady-state level of mRNA (Thomas, 1989; Friedberg et al., 1990; Hoof et al., 1991). The choice of method depends largely upon the level of mRNA expression, amounts of cells or tissues available for the analysis, and the level of sensitivity required for the study. This review outlines some of the methods available for the qualitative and quantitative measurement of mRNA, their suitability for various purposes, and their limitations. Northern blot analysis, solution hybridization methods, Polymerase Chain Reaction and in situ hybridization are some of the major categories of the methods largely used for mRNA detection and/or quantitation. Each is described in the following sections. PMID- 7858306 TI - Neurotoxins in the study of neural regulation of membrane proteins in skeletal muscle. AB - The discovery and purification of several neurotoxins, including alpha bungarotoxin and tetrodotoxin has provided very high-affinity ligands which have proved to be central to the elucidation of the neural control of skeletal muscle membrane proteins and to the purification and characterization of the nicotinic acetylcholine receptor (AChR) and the Na+ channel, respectively. This review describes the use of neurotoxins for quantification and localization of receptors and ion channels in normal and denervated skeletal muscles with particular emphasis on the appropriateness of the muscle preparation and ligand used in the studies. It is now clear that the nerve controls the synthesis and spatial distribution of AChRs and Na+ channels by regulating gene expression in extrajunctional and subjunctional nuclei. The down-regulation of extrajunctional AChRs is primarily mediated by neuromuscular activity and the concentration of AChRs and Na+ channels in specific membrane domains at the neuromuscular junction is controlled by a number of neurotrophic substances at the neuromuscular junction. These include agrin, ARIA, and CGRP. PMID- 7858307 TI - The six-day-old rat air pouch model of inflammation: characterization of the inflammatory response to carrageenan. AB - Inflammation was induced in the 6-day-old rat air pouch by injection of carrageenan. The model was characterized in terms of exudate volume, leucocyte influx, cell free protein, prostaglandin E2 levels, and granuloma formation. The time course of all these inflammatory markers, except prostaglandin E2, showed a 3-hr lag followed by a rapid increase to 8 hr. Thereafter, the rate of increase was much slower to 48 hr. Differential cell counts indicated a predominantly polymorphonuclear cell response (75%) during the first 48 hr. Prostaglandin E2 levels increased rapidly after a 3-hr lag, to a maximum of 440 +/- 140 ng/mL at 15 hr and thereafter quickly declined to 140 +/- 60 ng/mL at 21 hr. Prostaglandin E2 levels were the most sensitive inflammatory marker to (S+)-ibuprofen and were reduced dose dependently in the range 0.05 to 1 mg/kg. We have demonstrated the time course for duration of NSAID-induced reduction of prostaglandin E2 levels during inflammation in an individual animal. Rac-ibuprofen (0.1-1 mg/kg) reduced leucocyte influx at 3 and 5 hr, after which drug effects gradually diminished by 24 hr. Rac-ibuprofen at 1 mg/kg significantly reduced the volume of air pouch exudate recovered at 24 hr but had no effect on protein levels. PMID- 7858308 TI - Application of microdialysis to the pharmacokinetics of analgesics: problems with reduction of dialysis efficiency in vivo. AB - Microdialysis in freely moving rats coupled to high-performance liquid chromatography (HPLC) was used to measure the free concentration of acetaminophen (APAP) in blood and cerebrospinal fluid (CSF) after an intravenous bolus dose (25 mg/kg). In vitro calibration of two commercially available probe types was performed in 0.9% NaCl solution and blood. The influence of these media on recovery was tested by retrodialysis. This technique was also used for in vivo calibration and to monitor the dynamics of the performance of implanted probes. The results were compared with data obtained from conventional sampling techniques of direct withdrawal of blood and CSF, and also with the results obtained by correcting dialysate concentrations using in vitro recovery values. The data demonstrate that whole blood lowers recovery not only by reducing the free concentration of drug, but also by directly influencing dialysis efficiency (mean reduction of recovery: 50.1%). By contrast, low transport capacities of CSF surrounding the implanted probe lead to suboptimal conditions and, therefore, to a reduction of in vivo recovery (mean reduction of recovery: 65.5%). After correction of recovery values using in vivo retrodialysis prior to dosing the animal, we obtained similar data as compared to conventional sampling techniques. These results demonstrate that microdialysis may provide a minimally invasive method to monitor the free concentrations of drugs, such as acetaminophen, in different compartments, and allow a multitude of pharmacokinetic data to be obtained from freely moving animals. PMID- 7858309 TI - A new computer-assisted two-way avoidance conditioning equipment for rats: behavioral and pharmacological validation. AB - A new PC-controlled two-way avoidance conditioning equipment for rats is described. The position of the rat within the two-compartment shuttle-box is monitored by means of 4 + 4 horizontal photocell beams. Experimental conditions and procedures, such as CS-UCS interval, photocell operations, shock strength, and so on, can conveniently be preset by the experimenter. The successful operation of the shuttle-box is evidenced by rapid and efficient acquisition of the avoidance behavior, and approximately 100% median avoidance performance was obtained within 5 successive days of training (20-25 trials per day). In a separate experiment, different groups of rats received avoidance training (0-5 sessions) at 8 weeks of age, and a retention test was performed at 14 weeks of age. The correlation between acquisition and retention avoidance performance was weak (r = 0.33, NS), and performance during the acquisition process appears to be a poor predictor of final performance. As expected, a number of dopamine (DA) receptor blocking agents (DA D1 and/or D2 selective) produced a selective suppression of the avoidance behavior, that is, the suppression of avoidance responding was matched by a corresponding increase in escape responding (with no escape failures). PMID- 7858310 TI - An animal model for the assessment of gingival lesions. AB - A model of gingival inflammation was performed in Sprague-Dawley rats weighing 180-200 g. Mechanical bamboo stick-induced injury was inflammatory when bacteria contaminated the sticks. Bacteria were first obtained from gingival fluid collected from a patient with adult periodontitis. Another strain from Institut Pasteur (IP 6444) induced similar inflammation. Inflammation was then quantified 10 days later by means of elastase assays performed in gingival extracts. In parallel, elastic structures were observed and elastic fibers were quantified by automated image analysis. This technique of "impaction" was able to induce a gingival inflammatory reaction characterized by a significant increase of gingival elastase content, infiltration of gingival tissues by elicited cells, and gingival elastic fiber breakdown. These parameters were correlated, and measurement of one of them might be useful for pharmacological studies applied to the treatment of periodontal lesions. An example of results obtained from animals treated by heparine was shown. PMID- 7858311 TI - Estimation of blood sampling errors resulting from metabolism and solute exchange between plasma and formed elements. AB - The origin and magnitude of potential errors in whole-blood sampling are predicted on the basis of a mathematical model. The model describes the kinetics of solute metabolism, breakdown, and interphase distribution (i.e., partitioning and exchange between formed elements and plasma) within a blood sample during sample withdrawal and storage. The model is applied to the determination of the integral over time of solute concentration in the plasma (area-under-the-curve, or AUC) from a sample withdrawn through an arterial or venous catheter. Errors in AUC determination can be substantial and are strongly dependent on the duration of sampling (T), the rate constants for solute degradation processes, the rate constant for solute exchange between the formed elements and the plasma (ke), and the equilibrium ratio for distribution of the solute between formed elements and plasma (R). When the value of the dimensionless group keT/R is small, little solute exchanges between plasma water and formed elements before the two phases of the blood are separated. When keT/R is large, the solute distribution is close to equilibrium at all times. In these two keT/R limits, the contribution of solute redistribution to sampling error is small. Sizable errors resulting from redistribution are associated with intermediate values of keT/R, even in the absence of metabolism and despite rapid separation of the phases at the end of the withdrawal period. Chemical conversion within either of the blood phases introduces additional sampling error under most circumstances. PMID- 7858312 TI - Cross-flow membrane plasmapheresis technique for continuous ex vivo plasma sampling. AB - A technique is described for plasma sampling by continuous membrane plasmapheresis performed on blood flowing through an extracorporeal arteriovenous shunt. The plasmapheresis sampler in the shunt employs replaceable commercial planar membranes 2.5 cm in diameter. Validation tests were conducted for 0.6 micron pore diameter microporous membranes with several low-molecular-weight, nonmetabolized solutes that either rapidly equilibrate between plasma and formed elements or remain extracellular. Ex vivo tests were performed for bolus intravenous administration to rabbits. The technique yielded values for time averaged plasma concentrations comparable to those obtained with serial blood and continuous blood withdrawal methods. The new technique should be particularly advantageous when the distribution of the solute of interest between plasma and formed elements of the blood undergoes significant changes during the sampling interval as a result of binding, exchange, or metabolism in the formed element phase. PMID- 7858314 TI - Hyaluronate distribution in the regenerating retinal pigment epithelium of the rabbit: a study using confocal laser scanning microscopy. AB - The distribution of hyaluronate (HA) in regenerating retinal pigment epithelium (RPE) of the rabbit was examined using immunohistochemistry and confocal laser scanning microscopy. The goal was to determine if there is a correlation between differentiation and HA expression, like that seen in developing tissues, where HA accumulates and then disappears as the tissue matures. In normal RPE cells HA is associated mainly with the apical surface. In regenerating RPE (produced by i.v. injection of sodium iodate to damage the epithelium, regeneration arising from spared cells), HA exhibits a patchy distribution among the more immature cells and is especially prominent where they overlap or pile up on each other. Where cells are more mature and form a compact monolayer of cells, HA is expressed mainly on the apical surface, as in normal RPE. The accumulation of HA among the more immature cells in the regenerating epithelial sheet supports the hypothesis that HA influences differentiation by suppressing cell-cell associations until the proper time for their formation. PMID- 7858315 TI - In vivo human corneal confocal microscopy of identical fields of subepithelial nerve plexus, basal epithelial, and wing cells at different times. AB - A technique is described to obtain time-lapse reflected light confocal images of cells in the basal epithelium and adjacent wing cell layer from the in vivo human cornea. The technique is based on the sequential relocation of the unique patterns of the subepithelial nerve plexuses immediately posterior to Bowman's membrane. The patterns of individual subepithelial nerve plexuses, as well as perforation points where nerves traverse Bowman's membrane, serve as fixed landmarks. A real-time, scanning slit, confocal microscope is used to obtain reflected light images of a subepithelial nerve plexus, and the anterior and adjacent fields of basal and wing cells in the in vivo human cornea. All of the photographs are obtained from single video frames without the necessity of frame averaging or digital image processing. The instrument and relocation technique are prerequisites for applying a time-lapse observation technique to investigate the dynamics of basal cell proliferation and differentiation in the living eye. PMID- 7858313 TI - Construction and analysis of a database representing a neural map. AB - We describe the development and analysis of a quantitative database representing the global structural and functional organization of an entire sensory map. The database was derived from measurements of anatomical characteristics of a statistical sample of typical mechanosensory afferents in the cricket cercal sensory system. Anatomical characteristics of the neurons were measured quantitatively in three dimensions using a computer reconstruction system. The reconstructions of all neurons were aligned and scaled to a common standard set of dimensions, according to a highly reproducible set of intrinsic fiducial marks. The database therefore preserves accurate information about spatial relationships between the neurons within the ensemble. Algorithms were implemented to allow the integration of electrophysiological data about the stimulus/response characteristics of the reconstructed neurons into the database. The algorithms essentially map a physiological function onto a "field" representing the continuous distribution of synaptic terminals throughout the neural structure. Subsequent analysis allowed quantitative predictions of several important functional characteristics of the sensory map that emerge from its global organization. First, quantitative and testable predictions were made about ensemble response patterns within the map. The predicted patterns are presented as graphical images, similar to images that might be observed with activity dependent dyes in the real neural system. Second, the synaptic innervation patterns from the sensory afferent map onto the dendrites of a postsynaptic target interneuron were predicted by calculating the overlap between the interneuron's dendrites with the afferent map. By doing so, several aspects of the stimulus/response properties of the interneuron were accurately predicted. PMID- 7858316 TI - Three-dimensional organization of neuronal and glial processes: high voltage electron microscopy. AB - Neurons and glia cells in the mammalian central nervous system have many complicated processes. They are too fine for light microscopic study and too complicated and widely spread for thin section electron microscopy. High-voltage electron microscopic (HVEM) stereo observation of thick Golgi preparation provides detailed 3-D images of their processes. Three-dimensional fine structures of astocytic processes in the neuropile and on the surface of neuronal somata, and those of the ruffed cell axon initial segment and thorny excrescences of CA3 pyramidal cell dendrites, are elucidated with the aid of HVEM stereoscopy of thick Golgi preparations. In addition, some results obtained by 3-D morphometrical analysis of dendritic spines using HVEM stereo images are shown. The examples presented here clearly show the usefulness of high-voltage electron microscope stereo observation of thick specimens for detailed morphological and morphometric study of the central nervous system. PMID- 7858317 TI - Understanding the neostriatal microcircuitry: high-voltage electron microscopy. AB - High voltage electron microscopy (HVEM) and HVEM tomography of selectively stained cell processes in the neostriatum have offered an alternative to serial thin section reconstruction for accurate 3-D visualization and measurement of axons, dendrites, and dendritic spines. Tissue preparation is simple and rapid, allowing examination of large numbers of specimens required for quantitation of neuronal morphology. The resolution of the images exceeds that available from any light microscopic technique and is appropriate for measurement of the finest axons and dendritic spine necks. HVEM tomography allows the direct measurement of dendritic surface area, required for computational modeling of synaptic integration. PMID- 7858318 TI - Application of serial sectioning and three-dimensional reconstruction to the study of taste bud ultrastructure and organization. AB - The lingual taste buds of mammals are complex organs containing dozens of cells of varying morphology and numerous nerve fibers that are intermingled among the cellular processes. Some of the taste bud cells form synaptic contacts with these nerve fibers. Important questions remain to be answered regarding the structure and function of the cells of various types within taste buds and the means by which responses to gustatory stimuli are transmitted to the nerve fibers that communicate with the brain. Using both conventional and high voltage electron microscopy, we have examined serially sectioned taste buds from the tongues of mice and rabbits in order to address these issues and to obtain more complete information than that available from sampling of sections. The technique of computer-assisted 3-D reconstruction was used to generate models of whole taste buds and individual cellular and neural elements within taste buds from the serial sections. Analysis of serially sectioned taste buds from mice and rabbits has revealed that in both of these species relatively few (30% or less) of the cells within the taste buds form synaptic contacts with nerve fibers. In the foliate taste buds of rabbits, all of the cells that are presynaptic to nerve fibers are of a single morphological type (type III). The cells that are presynaptic to nerve fibers within the taste buds of mice are morphologically diverse. A pattern of synaptic connectivity exists within murine taste buds such that a given nerve fiber receives synaptic input only from taste cells that are ultrastructurally similar. In the taste buds of both mice and rabbits, we have observed both divergence and convergence of synaptic input from the putative taste receptor cells onto nerve fibers, suggesting that at the level of the taste bud there is some integration of the information generated by individual receptor cells. In addition to typical chemical synapses, other cytoplasmic specializations (such as subsurface cisternae and atypical mitochondria) may be involved in interactions between taste bud cells and nerve fibers. PMID- 7858319 TI - Parameter estimation in six numeric models of transperitoneal transport of glucose. AB - Six competing kinetic models of transperitoneal glucose transport were formulated and validated. The models were designed to elucidate the presence or absence of diffusive, nonlymphatic convective and lymphatic convective solute transport. The validation procedure included an assessment of theoretical and practical identifiability, goodness of fit, residual error analysis, and plausibility of parameter estimates. Experimental results were obtained from 21 patients without diabetes. The validation procedure demonstrated that the model that only included diffusion was superior to the other models. Theoretically, both nonlymphatic convective and lymphatic convective transports might exist. However, neither the ultrafiltration sieving coefficient nor the lymphatic flow rate were practically identifiable, probably because any amount of glucose transported by nonlymphatic convective and lymphatic convective transport mechanisms was negligible compared with the amount transported by diffusion. Based on these results, there appear to be problems measuring convective solute transport parameters when the solute transport is in the dialysate-to-blood direction while the fluid transport is in the blood-to-dialysate direction. PMID- 7858320 TI - Contamination of dialysis water and dialysate. A survey of 30 centers. AB - The concentration of bacteria and endotoxin in dialysis water and dialysate of 30 dialysis centers in western Germany was examined. Water samples were obtained after treatment by reverse osmosis or other processing methods. Collection of dialysis samples for bacterial, fungal, and endotoxin analysis was conducted before and 2 hours after start of hemodialysis. In 17.8% of all water samples analyzed, the AAMI standard was exceeded and bacterial and fungal counts greater than 200 colony forming units/ml were found. In 11.7% of all dialysate samples, higher contamination than the recommendations for dialysate of 2000 colony forming units/ml were found. The concentration of endotoxin in water and dialysate varied between 0 and 95 endotoxin units in the water samples and 0 and 487 endotoxin units/ml in the dialysate samples. In 12.2% of all water sampled, and 27.5% of all dialysate samples, values of 5 endotoxin units/ml were found. No correlation was found between the level of contamination of either water or dialysate in a specific center and the following factors: water processing method (reverse osmosis or others), type of dialysate (acetate of bicarbonate), type of dialysate machine, or method of machine disinfection. In view of these results it is suggested that endotoxin testing, especially in the dialysate, be a part of regular quality control in dialysis. PMID- 7858321 TI - Extracorporeal Life Support Organization 1994. AB - The annual report of the Extracorporeal Life Support Organization is presented for 1994. The aggregate experience of neonatal, pediatric pulmonary, and neonatal/pediatric cardiac patients treated with extracorporeal membrane oxygenation is presented for data collected to April 1994. In addition, the Registry now includes a large number of adult extracorporeal membrane oxygenation cases. Rates of survival for each patient group remained unchanged from previous years with 81% neonatal, 50% pediatric, and 44% cardiac survival. Complete data are available through 1992, with increasing case numbers each year as a basis for this growing registry. PMID- 7858322 TI - National surveillance of dialysis associated diseases in the United States, 1992. AB - To determine trends in a number of hemodialysis associated diseases and practices, the Centers for Disease Control and Prevention, in collaboration with the Health Care Financing Administration, completed a mail survey of chronic hemodialysis centers in the United States in 1992. Of 2,321 centers surveyed, 2,170 (93%) representing 170,028 patients and 43,535 staff members responded. In 1992, 2,049 (94%) centers used bicarbonate dialysate as the primary method of dialysis, 765 (35)% used high flux dialysis, and 1,569 (72%) reused dialyzers, continuing the trends toward increased use of these methods. Central (subclavian or jugular) venous catheters were used in > or = 1 patient as permanent vascular access for hemodialysis at 69% of dialysis centers. Hepatitis B surface antigen was present at low frequency in patients (incidence = 0.1%, prevalence = 1.2%) and staff members (incidence - 0.03%, prevalence = 0.3%). Among centers that had > or = 1 hepatitis B surface antigen positive patient, the incidence of hepatitis B virus infection was lower in those centers that used a separate room for dialysis of patients positive for hepatitis B surface antigen. From 1991 to 1992, reported hepatitis B vaccine coverage increased from 17% to 24% among patients and from 56% to 69% among staff members; in absolute terms, these were the largest single year increases since introduction of hepatitis B vaccine. The prevalence of antibody to hepatitis C virus was 8.1% among patients and 1.6% among staff members. Pyrogenic reactions in the absence of septicemia were reported by 19% of centers and associated with use of high flux dialysis. New dialyzer syndrome was reported by 24% of centers, most frequently by centers using regenerated cellulose or cuprophan membranes. Human immunodeficiency virus was known to be present in 1.5% of patients; 34% of centers reported providing hemodialysis to one or more patients infected with HIV. PMID- 7858323 TI - Assessment of the response of right ventricular performance to decreasing levels of mechanical assistance by on-line pressure area relationships. AB - The rapid assessment of the response of right ventricular (RV) performance to decreasing levels of mechanical assistance may be an important adjunct in determining if a patient can tolerate the removal of such a device. This report describes the use of on-line pressure area relationships to assess RV function in a patient supported with an RV assist device (RVAD). Mid RV short axis cross sectional area was measured on-line by transesophageal echocardiography with an automated endocardial border detection feature. RV pressure was measured with a high fidelity catheter. Pressure and area were plotted simultaneously on a computer workstation interfaced with the pressure and echo systems to yield on line pressure area loops. The following indices of RV performance were calculated while RVAD flow was decreased in 1 L/min increments: stroke work' (SW' = integral of PdA)[mmHg*cm2], stroke area (SA = Maximum Area-Minimum Area)[cm2], and fractional area change (FAC = SA/Maximum Area*100)[%]. SW', SA, and FAC significantly increased with decreasing RVAD flow: SW'(from 32 to 61 mmHg*cm2), SA (from 2.58 to 4.37 cm2), and FAC (from 20 to 32%). In conclusion, the increase in these parameters of RV performance with decreasing mechanical assistance suggested that this patient would tolerate removal of the RVAD, which was subsequently successful. This method of on-line pressure area relationships may be useful to predict the need for further mechanical assistance. PMID- 7858324 TI - It's time to reconsider the implantable insulin pump. PMID- 7858325 TI - Artificial vision for the blind. The summit may be closer than you think. PMID- 7858326 TI - The early development of the arteriovenous fistula needle technique for hemodialysis. PMID- 7858327 TI - Continuous renal replacement therapy in the critically ill patient with acute renal failure. Pros and cons. PMID- 7858328 TI - Anticoagulation during continuous renal replacement therapy. AB - Proper anticoagulation is an important factor in the function and life of the filter in CAVH or CAVHD and is the Achilles heel for CRRT. Several options now exist for anticoagulation and can be selected based on individual patient characteristics, availability of various anticoagulants, and local expertise. The choice of anticoagulant should be based on multiple factors, including A) the access site and whether an external pump is being used; B) the nature and geometry of the membrane; C) whether enhancements for ultrafiltration, such as predilution, are used; and D) the clinical status of the patient and preexisting coagulation abnormalities. Since anticoagulation in continuous therapy lasts longer than in intermittent hemodialysis, careful selection and monitoring are essential to prevent complications. PMID- 7858329 TI - Continuous venovenous hemofiltration for acute renal failure in the intensive care setting. Technical considerations. PMID- 7858330 TI - Continuous renal replacement therapies. Whom, how, and why. PMID- 7858331 TI - Physical characterization of unimplanted gel filled breast implants. Should old standards be revisited? AB - Physical characterization of unimplanted gel filled mammary prostheses was undertaken using both destructive and non-destructive test methods. Physical properties measured included mass, volume, optical transmittance, coefficient of kinetic friction, mechanical stiffness, dynamic response to a stationary random vibration, bursting strength, elasticity of the envelopes, and nuclear magnetic resonance relaxation times. The data obtained from this study will provide reference points for quantifying the rate of degradation of prostheses in past and current clinical use. Some of the test methods are suitable for use as routine quality control procedures to improve the uniformity of the properties and performance of breast prostheses. This investigation also showed that some currently used prostheses do not comply with the relevant American Society for Testing and Materials standards, or even with the manufacturers' own stated claims or specifications. PMID- 7858332 TI - A sheep model for the study of hemorheology with assisted circulation. Effect of an axial flow blood pump. AB - Hemorheologic investigations were performed on nine sheep during the in vivo evaluation of a new axial flow ventricular assist device, the Nimbus AxiPump (Nimbus, Inc., Rancho Cordova, CA). Blood hematocrit, plasma and whole blood viscosity, red blood cell (RBC) deformability and aggregation, plasma fibrinogen, and free hemoglobin (hemolysis) levels were measured. Changes in the main rheologic parameters of sheep blood relative to the pre-implant values were minor and transient. The exception was RBC aggregation, which appeared on the third day of implantation. (Sheep blood does not normally demonstrate RBC aggregation.) Sheep RBCs started to form classic rouleaux typically on the third post-operative day simultaneously with increasing fibrinogen level. To investigate the relative effects of mechanical stress and elevated fibrinogen levels on RBC aggregability, in vitro studies were conducted with blood from control sheep. These studies indicated that neither mechanical trauma nor elevated fibrinogen alone caused RBC aggregation as seen in vivo. However, combined mechanical stress and elevated fibrinogen did cause this unusual effect for sheep blood. PMID- 7858333 TI - The plasma glutathione peroxidase enzyme in hemodialyzed subjects. AB - The kidney is probably the major site of production of the plasma enzyme glutathione peroxidase (GSHPx-P). For this study, GSHPx-P activity was determined in 40 healthy people, in 34 patients with differing degrees of renal impairment, and in hemodialysis patients from whom blood samples were withdrawn either before or after each session (18 patients) or throughout the dialysis session (27 patients). Hemodialysis patients were treated by means of different techniques (bicarbonate hemodialysis, hemodiafiltration, and acetate free biofiltration), and different membranes (cuprophane, polyacrylonitrite, and polymethylmethacrylate). The following results were obtained: 1) GSHPx-P activity was significantly decreased in renal impairment patients; 2) GSHPx-P activity negatively correlated with serum creatinine values in renal impairment patients (r = -0.55; p < 0.001); and 3) the enzyme activity slightly increased after the session in hemodialysis patients. The following conclusions can be drawn: GSHPx-P activity could be new index of renal function, because it was decreased in patients with renal failure; the decrease in GSHPx-P activity paralleled the severity of renal impairment, and was maximal in hemodialysis patients; GSHPx-P activity was slightly raised at the end of the hemodialysis session, concomitant with other enzyme activities (aspartate transaminase, alanine transaminase, and alkaline phosphatase) and total protein concentration. This seems to be attributable to the process of water loss rather than other hypothetical mechanisms, such as A) enzyme activation by either peroxide generation during blood-membrane contact, or by the removal of a hypothetical inhibitor; and B) de novo synthesis in the residual renal mass or in other sites of production. PMID- 7858334 TI - Heparin coated percutaneous cardiopulmonary support for the treatment of circulatory collapse after cardiac surgery. AB - To overcome the hemorrhagic complications that may occur during extracorporeal circulatory support for post cardiotomy shock patients, a heparinized circuit was introduced into the percutaneous cardiopulmonary support system and decreased systemically administered heparin during bypass. Heparin coated percutaneous cardiopulmonary support with low dose systemic heparinization was instituted in 13 patients (6 men and 7 women, mean age 62.2 +/- 8.5 years) who experienced circulatory collapse after cardiac surgery. Of the 13 patients, 9 could not be weaned from cardiopulmonary bypass and 4 had circulatory collapse in the operating room or in the intensive care unit. The duration of support ranged from 1 to 66 hr (mean 27.4 +/- 26.7), and the flow rate ranged from 1 to 3 L/min (2.2 +/- 0.5). An activated coagulation time of about 150 sec was maintained with or without minimal systematically administered heparin. Of the patients cannulated, 77% (10 of 13) were successfully weaned from percutaneous cardiopulmonary support and 39% (5 to 13) were long-term survivors. The causes of death were sepsis in three, progressive heart failure in three, lower leg ischemia in one, and vital infection in one. From the results of clinical or post mortem examinations, there was no massive bleeding or evidence of thromboembolism in the major organs. From observations made within 12 hr of initiation of percutaneous cardiopulmonary support, there was no significant decrease in the number of platelets, but platelet count had significantly decreased 24 hr after initiation.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7858335 TI - Use of hemodiafiltration to enhance delivered dialysis. AB - Patients on hemodialysis for end-stage renal disease frequently have increased levels of lipoproteins and beta-2 microglobulin (B2M). In an effort to assess the effect of hemodiafiltration on TACUrea, delivered Kt/VUrea, normalized protein catabolic rate, and B2M level, 6 chronic hemodialysis patients (mean age 63.3 +/- 17 years; 3 men, 3 women) were randomly selected to undergo 4 weeks of hemodiafiltration. The therapy consisted of Qb: 400 ml/min, Qd: 800 ml/min, time: 3.5 hours and 10 L hemofiltrate exchanges with either Ringer's lactate or combination of Ringer's solution and saline using polysulfone membrane dialyzer. TACUrea, Kt/VUrea delivered, normalized protein catabolic rate, serum electrolytes, liver enzymes, lipoproteins, and B2M clearance were evaluated before and after hemodiafiltration. Kt/V increased significantly [pre: 1.3 +/- 0.2 vs post: 1.8 +/- 0.3; p < 0.05], and TACUrea decreased (pre: 44.3 +/- 15 vs post 32 +/- 6.7 mg/dl; p < 0.1). There was no change in normalized protein catabolic rate (pre: 0.88 +/- 0.21 vs post: 0.80 +/- 0.15). B2M clearance was greatly enhanced (pre: 22 +/- 11 vs post: 110 +/- 36 ml/min; p < 0.001) together with a reduction in serum B2M level (pre: 43.6 +/- 11.4 vs 31.2 +/- 6.4 mg/L; p < 0.05). There was no significant increase in total cholesterol, low density lipoprotein, high density lipoprotein, or triglyceride levels, nor was there a change in electrolyte, CO2, or liver enzyme levels. Blood pressure control was satisfactory throughout hemodiafiltration therapy. Hemodiafiltration using a polysulfone membrane dialyzer raised delivered Kt/VUrea and reduced TACUrea and B2M levels significantly. PMID- 7858336 TI - Effect of respiration on the arterial pressure wave in calves with nonpulsatile biventricular bypass. AB - The possibility of idioperipheral pulsation in calves with chronic nonpulsatile biventricular bypass has been previously reported. To test the hypothesis that both spontaneous respiration and mechanical ventilation are the cause of pulsation in the arterial pressure recording in calves with nonpulsatile biventricular bypass, two protocols were used to generate data. Both right and left ventricles were bypassed using two centrifugal pumps followed by electrical fibrillation in seven calves. In protocol 1, the spontaneous respiratory rate was increased in awake calves by carbon dioxide gas inhalation. In protocol 2, the animals were anesthetized and intubated to control ventilation, and data were collected as the ventilation rate or tidal volume was changed in a stepwise fashion, as well as when the ventilation was stopped for several seconds. The results of protocol 1 showed good correlation between the arterial pulse rate and spontaneous respiratory rate (Y = 1.03 X, r = 0.822, p < 0.001). The results of protocol 2 showed that the relationship between the ventilation rate and the arterial pulse cycle was identical (Y = X, r = 1.000, p < 0.001), and no pulsation was seen when the ventilator was stopped. The authors conclude that the arterial pulsation observed in calves with nonpulsatile biventricular bypass is caused by respiration. PMID- 7858337 TI - General anesthesia with isoflurane for diaphragmatic hernia repair during ECMO. AB - Isoflurane has been administered via the oxygenator of the extracorporeal membrane oxygenation (ECMO) circuit to provide anesthesia and prevent hemodynamic instability during surgical repair of congenital diaphragmatic hernia. A comparison of a series of patients treated with isoflurane demonstrates that there is less fluctuation in heart rate and blood pressure than when surgery is performed under fentanyl analgesia alone. PMID- 7858338 TI - Use of a mathematical model to predict oxygen transfer rates in hollow fiber membrane oxygenators. AB - A semi-empirical theoretical model of oxygen transfer is used to predict the rates of oxygen transfer to blood in hollow fiber membrane oxygenators over a wide range of inlet conditions. The predicted oxygen transfer rates are based on performance of the devices with water, which is more cost effective and easier to handle than blood for in vitro evaluations. Water experiments were conducted at three different flow rates to evaluate oxygen transfer performance in three commercially available membrane oxygenators. Data obtained from these experiments were used in a computer model to predict the rate of oxygen transfer to bovine blood at specified inlet conditions. Blood experiments were conducted at three different flow rates at a wide variety of inlet conditions, including different pH levels, hemoglobin concentrations, and oxyhemoglobin saturations for the three types of oxygenators. The measured and predicted oxygen transfer rates are closely correlated, which suggests that we have an accurate, reliable method for predicting oxygen transfer in hollow fiber membrane lungs. PMID- 7858340 TI - The transforming principle: a tribute to Maclyn McCarty. PMID- 7858339 TI - Simple Kt/V formulas based on urea mass balance theory. AB - The ratio Kt/V (K is patient clearance, t dialysis time, V urea space) has become the standard measure of dialysis adequacy. In this article simple Kt/V equations are developed theoretically from the urea mass balance equation. Two approximations lead to the most precise equation: [formula: see text] where R is the post to pre dialysis urea ratio, BW/V is the amount of fluid removed during dialysis (delta BW) expressed as a fraction of urea distribution space (V) at dry body weight (BW), and t is dialysis length in hours. A second equation arises with V approximated as 58% of BW. One further approximation leads to a simpler but slightly less precise Kt/V formula: [formula: see text] These and earlier published equations were tested with two sets of data: 1) 49 sessions involving 17 patients on maintenance dialysis and 2) 540 computer simulations spanning all likely values of Kt/V (0.6-1.6), protein catabolic rate (0.6-1.6), interdialytic weight gain (0-4% of BW per day) and dialysis session length (2-4 hr). The most precise formula (upper equation above) had a maximum error of 0.031 and 0.035 Kt/V units for the clinical and simulated data, respectively, whereas the lower equation was slightly less accurate with maximum Kt/V errors of 0.079 and 0.081, respectively. The proposed Kt/V equations are considerably more accurate than previously published formulas. PMID- 7858341 TI - Expression and plasmid transfer of genes coding for the fimbrial antigen F107 in porcine Escherichia coli strains. AB - Expression of the fimbrial antigen F107 of porcine E. coli strains on agar plates was achieved by microaerobic cultivation. For part of the strains of some types, addition of alizarin yellow and eosin to the agar medium proved to be necessary. Some of these strains reacted distinctly positive only when the small colonies growing between the larger ones on alizarin-yellow agar were tested. The fimbrial antigen of the Swiss strain 107/86 was provisionally designated the F107ab variant and that of the Hungarian strain 2134P and the Czech strain 8813, the F107ac variant. The F107 genetic determinants were found to be often linked with those encoding haemolysin production and are frequently carried by plasmids. PMID- 7858342 TI - Expression of capsular polysaccharide determines serum resistance in Escherichia coli K92. AB - The amount of capsular polysaccharide expression has been shown to be the major determinant of serum resistance in Escherichia coli K1. E. coli K92, like K1, is a polymer of sialic acid molecules. It differs from K1 by containing both alpha (2.8) and alpha (2.9) linkages. Four strains of E. coli K92 were tested for serum resistance. Three strains were serum-resistant (50% normal human serum), one strain was moderately serum-sensitive. The serum-resistant strains expressed significantly more capsular polysaccharide than did the serum-sensitive strain. For each of the serum-resistant strains, six mutants were isolated by selection for resistance against infection with a K92-specific bacteriophage. All of the mutants expressed less capsular polysaccharide than the respective wild-type strains. All mutants were more sensitive to serum killing than the wild-type strains. In all groups, the mutants with lowest expression of capsular polysaccharide were highly serum-sensitive. Changes of outer membrane proteins or lipopolysaccharide patterns that were present in some mutants did not correlate with serum resistance properties of the mutants. Furthermore, it was investigated whether the presence of active serum had an influence on capsule expression. In the serum-sensitive strain, the presence of serum induced a significant and concentration-dependent increase of capsule expression. Serum had no effect on capsule expression by the serum-resistant strains. We conclude from the data that the expression of K92 capsular polysaccharide determines serum resistance in the strains examined. PMID- 7858343 TI - Kinetics of growth and product formation in cultures from streptococci of groups A and C. AB - During growth of streptococci of Lancefield groups A and C in a culture medium containing glucose, yeast extract and peptone, two main growth phases occur: growth phase I and growth phase II (diauxic growth). They are separated by a short stationary phase (1st stationary phase). The diauxic growth is caused by transient limitations as well as the availability of new sources of the amino acids L-serine and L-arginine. Growth phase I consists of an exponential and a nearly linear part. These growth kinetics are reflected by the kinetics of gas metabolism as well as by product formation. Hyaluronic acid is formed during the nearly linear phase whereas the enzyme alkaline phosphatase, is exclusively excreted in the 1st stationary phase. Also carbon dioxide and L-lactate are mainly produced in a growth phase-dependent mode. In the late stationary phase (2nd stationary phase) more oxygen is consumed whereas the demand for oxygen in the 1st stationary phase is nearly zero. PMID- 7858344 TI - Molecular typing of Actinomyces pyogenes isolates. AB - The molecular characterization of 28 clinical Actinomyces pyogenes strains was attempted. SDS-PAGE protein profiles did not allow to distinguish isolates. Restriction endonuclease analysis of total DNA gave the finest differentiation between strains but the profiles were difficult to read. Ribotypes after DNA digestion by Bst EII or Sma I have a high discriminatory power and are more helpful epidemiological markers. No relationship could be demonstrated between molecular types and clinical sources. PMID- 7858345 TI - Comparison of dark-field microscopy, culture, and polymerase chain reaction (PCR) for detection of Borrelia burgdorferi in field-collected Ixodes ricinus ticks. AB - In a study based on 100 field-collected female Ixodes (I.) ricinus ticks from the surroundings of Giessen, dark-field microscopy (DFM), culture, and PCR were compared as procedures for detecting Lyme borreliosis spirochetes in ticks. By DFM, 16 ticks were found to be infected with spirochetes. From the midgut of 18 ticks (including 14 microscopically positive specimens), spirochetes were cultured in BSK II medium and in BSK II medium supplemented with either co trimoxazole (500 micrograms/ml) or 5-fluorouracil and kanamycin (200 micrograms/ml and 8 micrograms/ml). Using these selective media, the isolation rate was increased by 50% compared to BSK II medium without additives. Midgut homogenates of 22 ticks (including 13 ticks positive by culture and 12 microscopically positive ticks) were found to contain Borrelia (B.) burgdorferi specific DNA by PCR using a primer set based on sequences of the flagellin gene of B. burgdorferi. PMID- 7858346 TI - Fecal shedding of Listeria monocytogenes during murine listeriosis after intravenous infection. AB - Female NMRI SPF-Mice were intravenously infected with L. monocytogenes and the feces and urine samples were cultured to detect a possible presence of the bacterium. In 6 out of 10 mice, the bacteria occurred in the feces, but not in the urine samples. Listerial shedding was detected only during acute listeriosis from day 2 to day 9 post infectionem. Thus, listerial shedding after infection via routes other than the gastrointestinal tract is possible not only in newborns, but also in adult experimental animals. PMID- 7858347 TI - Transfer, by conjugation and transduction, of resistance to ceftazidime and cefotaxime from the same clinical isolate of Pseudomonas aeruginosa. AB - A strain of Pseudomonas aeruginosa No. 4870 was isolated at the Pediatric University Hospital in Bratislava which transferred, by conjugation, the resistance to cefotaxime (CTX), ceftazidime (CTZ) and aztreonam (AZA) and to more classical anti-pseudomonadal antibiotics. This strain was also lysogenic and contained a temperate bacteriophage which was isolated and used to transduce determinants of resistance to susceptible P. aeruginosa strains. The phage, designated as AP-271 (Aeruginosa phage) transduced determinants of resistance to CTX CTZ AZA as well as to kanamycin and, in one case, also to streptomycin to four susceptible recipient strains of PAO and ML series. The block of resistance to three new betalactam drugs was not separated by transduction. Results obtained indicate that both conjugation and transductional transfer of antibiotic resistance from the same strains of P. aeruginosa seem to be possible. PMID- 7858348 TI - Prevalence of attaching and effacing Escherichia coli in stool samples from patients and controls. AB - Enteropathogenic E. coli (EPEC) and enterohemorrhagic E. coli (EHEC) have the ability to cause 'attaching and effacing' (AE) lesions; the genes necessary to cause AE in both of these pathogroups have been identified and termed eae. Using colony hybridization, we screened 237 stool samples from patients with diarrhea, and 237 stool samples from age-matched controls for the presence of E. coli carrying eae. Individual colonies harbouring eae could be recovered from 7 (2.9%) of the patient stools, as well as from 6 (2.5%) of the control stools. All these E. coli isolates were positive in the fluorescence actin staining (FAS) test. In addition, all the samples were also probed for Shiga-like toxin (slt) genes and the EPEC adherence factor (EAF) to evaluate whether testing for eae identified all EHEC and class I EPEC. Of the 7 patient samples harbouring E. coli with eae, 4 had E. coli with eae and slt genes, and 2 had E. coli with eae and EAF sequences. In 2 of the 237 patient stools, E. coli which were eae and EAF negative but slt probe positive could be recovered. These 2 E. coli strains were non-reactive in the FAS test. Of the control samples, none of the E. coli strains, including the 6 samples containing eae positive strains, possessed EAF or slt-sequences. In concrete terms, the similar eae incidence found in both E. coli isolates from patients and controls is currently of limited clinical diagnostic value and more importantly, the eae probe could not identify all slt harbouring E. coli. On the basis of these results, the use of the eae-probe cannot be recommended in preference to the slt probes for the detection of EHEC. PMID- 7858349 TI - Bacteriophages presence in human faeces of healthy subjects and patients with gastrointestinal disturbances. AB - The variation of the content of enteric bacteria and their bacteriophages in faeces from the different types of diarrhoeal processes has been studied. A total of 122 samples of human faeces from both healthy individuals and patients with diarrhoeal diseases of functional or infectious origin were tested. Detection rates for all microbial parameters tested decreased in the faeces of individuals with functional gastrointestinal disturbances. On the contrary, no significant differences of the microbial detection frequency was observed in faeces containing pathogenic microorganisms compared to faeces of healthy subjects. Human faeces were a poor source of F-specific, Salmonella, and Bacteroides bacteriophages, whereas specific Escherichia coli phages were isolated in most samples tested. Coliphage concentrations in faeces of healthy individuals were not directly correlated with levels of faecal coliforms. On the basis of their high correlation, faecal streptococci and coliphages were the most adequate indicators of the intestinal ecosystem variations in subjects with diarrhoeal processes. PMID- 7858350 TI - Adherence properties of Bacteroides vulgatus, the preponderant colonic organism of adult humans. AB - Bacteroides vulgatus is the predominant intestinal bacterium of adult humans. The adhesins of this species were studied by using haemagglutination of rabbit erythrocytes and inhibition of this haemagglutination. Eleven haemagglutinating strains were tested after incubation with chicken albumin, bovine serum albumin, human serum fibronectin, fibronectin fragment and N-acetyl neuraminic acid, and after they had been heated, treated with NaIO4, trypsin and D(+)-mannose. Rabbit erythrocytes treated with neuraminidase served as controls. Four different types of adhesins could be distinguished as characterized by different substrate specificities. PMID- 7858352 TI - The singer not the song. PMID- 7858351 TI - Frequency of Clostridium perfringens types in Jordanian sheep. AB - 778 fecal samples from 29 Jordanian sheep flocks were examined for the presence of Clostridium perfringens. 252 field strains were isolated and typed by the enzyme immunosorbent assay. The presence of C. perfringens types B, C and D in Jordanian sheep was confirmed. Type D was found in 55% of the flocks examined. Types B and C were each isolated from 7% of the flocks examined. The proteinase activity of isolated type B field strains was similar to that of type B reference strains. According to the results, it does not seem to be necessary to include locally isolated C. perfringens strains in the Jordanian vaccine production. PMID- 7858353 TI - Free choice of care: have we ever really had it? Do we want it? PMID- 7858354 TI - The short form of the Beck Depression Inventory: validity issues with chronic pain patients. AB - OBJECTIVE: To investigate the validity of the Beck Depression Inventory short form when used to screen for depression in chronic pain patients. SETTING: A multidisciplinary pain management center located in a major university medical center. PATIENTS: Seven hundred sixty-five persons presenting for evaluation of chronic pain, including low back pain, head/neck pain, and extremity pain. MEASURES: Beck Depression Inventory short form, McGill Pain Questionnaire, Pain Disability Index, pain drawing, and Quality of Life Scale. RESULTS AND CONCLUSIONS: Items on the Beck Depression Inventory short form reflecting pain related interference with function (i.e., disability) were endorsed to a greater degree than affective and cognitive items. A factor analysis of the inventory yielded two affective/cognitive factors and one "disability" factor (work inhibition and fatigue). The correlations between the factor scores and the Pain Disability Index suggested that endorsement of the work inhibition and fatigue items by chronic pain patients may not be indicative of affective disturbance. The results suggest that these items should be evaluated critically for their contribution to the total score of the Beck Depression Inventory short form when assessing depression in chronic pain patients. PMID- 7858355 TI - Prediction of treatment outcome from clinically derived MMPI clusters in rehabilitation for chronic low back pain. AB - OBJECTIVE: The aim of this study was to assess the ability of specific and clinically relevant Minnesota Multiphasic Personality Inventory (MMPI) profile types to predict outcomes in a structured interdisciplinary pain-management program for patients with low back pain. DESIGN: Subjects were divided into clusters representing MMPI profiles yielding similar clinical interpretation. Analyses of variance and chi-square testing assessed the effect of cluster group on a variety of outcome measures at pretreatment, posttreatment, and 6- to 66 month follow-up. Fisher's Least Significant Difference Test assessed the significance of differences between pairs of cluster groups. SETTING: A university-based comprehensive interdisciplinary pain-management program serving both inpatients and outpatients. PATIENTS: 122 subjects with chronic low back pain who completed the program, provided follow-up data, and fit into the definition of one of seven clusters. MAJOR OUTCOME MEASURES: Self-reports of subjective pain intensity, pain-related medication intake, and activity level at pretreatment, posttreatment, and follow-up; employment status at pretreatment and follow-up. RESULTS: Cluster groups did not differ significantly at any time on activity level and medication intake and differed on employment status only at pretreatment. There was a significant (p < 0.05) effect of cluster group on subjective pain intensity, but only two pairwise group comparisons were significant: subjects with a normal MMPI profile and those with no elevations except T = 71-80 on Hypochondriasis and Hysteria reported less pain at follow-up than did subjects with extreme elevations (T > 80) on both Hypochondriasis and Hysteria. CONCLUSION: Even when subjects with chronic pain are divided into cluster groups associated with highly similar clinical interpretations, the MMPI for the most part fails to predict self-reported outcomes in an interdisciplinary pain-management program. PMID- 7858356 TI - Childhood abuse, depression, and chronic pain. AB - OBJECTIVE: To investigate the relationships among history of childhood abuse, type of pain, and depression. DESIGN: Survey, consecutive sample, correlational. SETTING: An interdisciplinary pain-management center in a rehabilitation hospital. PATIENTS: The participants were 201 consecutive patients with chronic pain complaints, 68% women, mean age 38 years, of whom 28% complained of pain in more than three major sites, 26% had low back pain, 19% had craniofacial pain, and 25% had pain in other regions. OUTCOME MEASURES: Beck Depression Inventory, Childhood History recorded presence or absence of abuse, age of onset, age when abuse was acknowledged, duration and frequency of abuse, relationship of abuser to the participant. Pain type was classified by IASP. RESULTS: Patients with history of both sexual and physical abuse in childhood had more depression. The differences among abuse groups was significant (p < 0.03). The impact of childhood abuse and type of pain on depression was tested by a two-factor analysis of variance. The influence of childhood abuse was significant (p < 0.04), whereas the influence of type of pain (p < 0.76) and the interaction between type of pain and childhood abuse (p < 0.40) were not significant. CONCLUSIONS: There is a positive, significant relationship between depression and history of childhood sexual and physical abuse. The influence of type of pain on depression was not significant. Prevailing research explained depression as an expected, natural consequence of chronic pain. Our research suggests that the relationship between chronic pain and depression may be attributable in part to childhood abuse history. PMID- 7858357 TI - Pain in young adults: I. Relationship to gender and family pain history. AB - OBJECTIVES/DESIGN: Two studies were carried out to examine how gender and family pain history related to pain and activity interference in young adults. The first study (n = 252 college students) examined how gender and family pain history related to pain intensity and the second study (n = 206 college students) examined how these variables related to pain intensity, location, and activity interference. Whenever possible, data from the two studies were combined for purposes of data analyses. RESULTS: Results indicated that more than half of the young adults studied reported experiencing some type of pain at the time of the investigation. The intensity of the pain was in the low range and the most frequent sites of pain were in the head and legs or feet. Gender differences were noted, with women reporting a greater number of sites of pain. Family pain history was found to be related to pain and activity interference. Subjects who had a strong family history of pain problems reported a greater number of pain sites, and higher levels of pain-related activity interference. CONCLUSIONS: Generalizability of results is limited due to the group of young adults studied, yet several conclusions relative to this group may be suggested. First, this group of young adults do appear to experience pain. Second, there may be gender differences in the types of pain they report and the ways they react to pain. Third, family history of pain may be related to the pain experiences of this group of young adults. PMID- 7858358 TI - Acupuncture and subtypes of chronic pain: assessment of long-term results. AB - OBJECTIVE: To determine patients' opinions of pain relief for a longer time after one treatment period of acupuncture for chronic pain. PATIENTS AND SETTING: Two hundred and eleven patients had acupuncture treatment for chronic pain at the Pain Clinic of Malmo University Hospital during 1983-5. Their mean duration of pain was 10.4 years prior to treatment. INTERVENTION: The patients were treated with needle acupuncture with a combination of local and distal points every 1-2 weeks. Both manual and electrical stimulation was utilized. The mean number of treatments was 7.8. DESIGN: In 1988, all patient documents were screened, and the pain conditions were classified as nociceptive, neurogenic, or psychogenic. Of the 211 treated patients, initial results could be evaluated from the clinic records in 202 cases. Eighty-five of these patients (42.1%) experienced pain relief immediately after the treatment period. These patients were sent a 1-page questionnaire by mail in 1988. OUTCOME MEASURES: Pain relief over defined time periods (yes/no); do more work at home or at workplace (yes/no); analgesic consumption. RESULTS: Only 35 patients (17.3% of all patients) still experienced pain relief 6 months after treatment. Among those with nociceptive pain, 70 of 142 (49%) had experienced initial pain relief, while those with neurogenic or psychogenic pain experienced relief in only 11 of 34 and four of 26 of the cases, respectively. Pain relief for > 6 months was experienced by 33 of 142 of the cases with nociceptive pain, but by only two of 34 of those with neurogenic pain, and by none of those with psychogenic pain. CONCLUSION: Only patients with nociceptive pain can be expected to get pain relief for > 6 months after one treatment period of acupuncture, and of these only a small proportion will be helped. PMID- 7858359 TI - Effect of spiritual healing on chronic idiopathic pain: a medical and psychological study. AB - OBJECTIVE: To study over a period of one and a half years the effect of spiritual healing on patients with idiopathic pain syndrome using several psychological and medical parameters. DESIGN: Randomized clinical trial. SETTING: Outpatient pain clinic. PATIENTS: Twenty-four patients with idiopathic chronic pain who had passed a pretreatment psychological interview were allocated randomly to receive spiritual healing or no active treatment. MAIN OUTCOME MEASURES: Medical interview (Visual Analog Scale and Pain Clinic Investigation Formula); International Association for the Study of Pain (IASP) Data Base Outline; psychological interview (Hopkin's Symptom Checklist, Middlesex Hospital Questionnaire, Beck's Depression Inventory, Coping Strategy Questionnaire, Health Locus of Control scale). Patients were evaluated at baseline and at 2 weeks posttreatment. Final assessment at 1 year posttreatment was done with a modified form of IASP Data Base Outline. RESULTS: There was a minor decrease in analgesic drug intake and an improvement in sleep patterns in patients treated by the healer. Generally, clinical variables remained unchanged. Attitudes toward spiritual healing improved. There was a decrease in the feeling of hopelessness (p < 0.05) and an increased acceptance of psychological factors as reasons for pain (p < 0.05). Other scores of the psychological tests were unaffected by the healing. However, half (n = 6) of the treated patients felt that spiritual healing gave them some relief. CONCLUSION: Spiritual healing appears harmless and was subjectively helpful to some patients suffering from idiopathic chronic pain syndrome. PMID- 7858360 TI - Primary care physicians and pain: education during residency. AB - OBJECTIVE: This study examines whether family practice residents are receiving adequate training in the evaluation and treatment of pain during their residencies. DESIGN: A survey of the training directors of all family practice residency programs in the United States (n = 390) was conducted by mail. Questions were included regarding the residency programs and training in and knowledge of common pain conditions and therapies. PARTICIPANTS: Of all the training directors surveyed, 258 (66%) responded. MAIN OUTCOME MEASURE: The relationship between adequate training in pain and the characteristics of the residency programs was examined. RESULTS: Twenty-nine percent of the training directors who responded considered that their residents received adequate training in the recognition and treatment of pain. Adequate training correlated with rotation through pain services and the number of hours of lecture on pain provided. While the majority of program directors reported that their trainees were receiving training in many of the common pain syndromes and the use of analgesic medications, significantly fewer (p < 0.001) considered it to be adequate. CONCLUSIONS: Family practice training directors do not believe their residents are receiving adequate training in pain. In light of previous studies indicating the importance of providing proper pain treatment, enhanced teaching on this subject during residency appears to be needed. PMID- 7858361 TI - The value of the provocation response in lumbar zygapophyseal joint injections. AB - OBJECTIVE: To determine the relationship between pain provocation and the analgesic response in lumbar zygapophyseal joint blocks. DESIGN: Consecutive patients undergoing intraarticular zygapophyseal joint blocks for the investigation of low back pain were included in this prospective study. SETTING: The referred sample was from the metropolitan areas of New Orleans and San Francisco. PATIENTS: Ninety patients with low back pain of > 3 months' duration and no history of lumbar surgery. INTERVENTIONS: All patients underwent one or more intraarticular injections of radiographic contrast followed by lignocaine (lidocaine) 2% into zygapophyseal joints between L2-3 and L5-S1. Those with definite responses at one or more levels underwent confirmatory blocks using 0.5% bupivacaine. OUTCOME MEASURES: Provocation of familiar pain and relief of pain after the injection of local anesthetic. Patients were assessed by an independent observer. RESULTS: A total of 203 joints were studied. Adopting liberal criteria, either exact or similar reproduction of pain on the one hand correlated with either definite or complete relief of pain after a single, analgesic block on the other (p < 0.0001). However, when more stringent criteria were adopted, such as response to a confirmatory block using bupivacaine, there was no significant association. CONCLUSIONS: This study calls into question the validity of pain provocation alone as a criterion standard in patients undergoing diagnostic lumbar zygapophyseal joint blocks. PMID- 7858362 TI - Comparison of morphine and ketorolac for intravenous patient-controlled analgesia in postoperative cancer patients. AB - OBJECTIVE: To compare the effectiveness of intravenous patient-controlled (i.v. PCA) ketorolac to i.v.-PCA morphine in the treatment of postoperative pain in cancer patients. DESIGN: In a double-blind, prospective, randomized trial, patients received either morphine in 1 mg/ml concentration or ketorolac 5 mg/ml for postoperative pain control. On arrival to the postanesthesia care unit (PACU), the patients received 2 ml of medication every 5 min, until satisfactory analgesia was achieved. If pain persisted after 20 ml of study drug had been administered, 0.1 mg/kg morphine was given i.m. On discharge from the PACU, the patients were placed on an i.v.-PCA pump. All patients received a basal infusion of 1 ml/h with a 1-ml on-demand bolus and a lockout interval of 10 min. Patients were offered 0.1 mg/kg morphine IM every 6 h, which they could refuse. SETTING: University Cancer Center. PATIENTS: Seventy patients scheduled for abdominal or truncal cancer operations. MAIN OUTCOME MEASURES: Visual analog pain scores (VAPS) and Visual analog sedation scores (VASS) were used to measure the quality of pain control achieved either with ketorolac or morphine. The incidence of side effects was documented. RESULTS: The VAPS were comparable between the groups. Patients in the ketorolac group requested more supplemental i.m. morphine. However, the total morphine dose and incidence of side effects was significantly higher in patients receiving i.v.-PCA morphine. CONCLUSIONS: These results indicate that ketorolac supplemented with small doses of morphine is associated with a lower incidence of nausea, vomiting, and pruritus compared to morphine alone. This combination should be considered where immunosuppression from operation and administration of morphine is undesirable. PMID- 7858363 TI - Epidural morphine pretreatment for postepisiotomy pain. AB - OBJECTIVE/DESIGN: A randomized double-blind controlled study was conducted on two groups of 45 parturients to evaluate the importance of the timing of epidural morphine administration for the relief of postepisiotomy pain. Both groups had preemptive analgesia by continuous lumbar epidural bupivacaine blockade. Upon completion of the episiotomy repair and before the onset of pain, the patients received epidural injections of 3 ml saline with or without 2 mg morphine in groups A and B respectively. When pain appeared, group A patients received an epidural injection of 3 ml saline while group B patients received 2 mg morphine in 3 ml saline. Postepisiotomy pain level was evaluated by a visual analogue scale. RESULTS: The incidence of pain in group B women following epidural morphine administration was 68.6%. This was significantly higher than that of group A at 15.6% (p < 0.01). Furthermore, group B showed that the rate of effective pain relief after 2 mg epidural morphine significantly decreases as the level of pain intensity rises (p < 0.01). CONCLUSION: Epidural morphine for postepisiotomy pain is much more effective if administered before the onset of pain. PMID- 7858364 TI - Norepinephrine and epinephrine levels in affected versus unaffected limbs in sympathetically maintained pain. AB - OBJECTIVE: To test the hypothesis that there is relative sympathetic hyperactivity in the affected limb in patients with sympathetically maintained pain syndromes by measuring serum norepinephrine and epinephrine in the affected versus the unaffected sides. DESIGN: Venous pool samples were drawn just proximal to the affected area and from an identical site on the unaffected side. Serum norepinephrine and epinephrine were measured by high-pressure liquid chromatography with electrochemical detection. SUBJECTS: Sixteen women and seven men with a mean age of 44.4 years diagnosed as having sympathetically maintained pain on the basis of a positive response to paravertebral block and a criteria based diagnostic scheme. RESULTS: The serum norepinephrine level was significantly lower in the affected limbs than the unaffected limbs (p = 0.024). The serum epinephrine level was not significantly different. CONCLUSIONS: These results are not consistent with the hypothesis of segmental sympathetic hyperactivity in the affected limb in sympathetically maintained pain and support a hypothesis of peripheral receptor upregulation with pathologic response to circulating catecholamines. Other possible explanations are discussed. PMID- 7858365 TI - Occupational low back pain and intervertebral disc degeneration: epidemiology, imaging, and pathology. PMID- 7858366 TI - Labelling deficiencies and communication problems leading to medication misuse in the elderly. PMID- 7858367 TI - Post-herpetic neuralgia in older patients. Incidence and optimal treatment. AB - Post-herpetic neuralgia (PHN) is a disease caused by having had herpes zoster; it is not a continuation of shingles. Up to 50% of elderly patients who have had shingles may develop PHN. PHN is defined as pain recurring or continuing at the site of shingles, 1 or more months after the onset of the rash. Because many cases resolve spontaneously in the early stages, no claims of 'pharmacological cure' can be entertained before 3 months post-rash. In fact, some authorities will not accept claims made before 6 months. Antivirals administered systemically within the appropriate time-window greatly relieve the pain of acute shingles, and to a large extent prevent scarring. There is no evidence that they prevent the subsequent development of PHN. However, patients with PHN whose acute shingles were treated with aciclovir obtain pain relief with antidepressants in half the time required by those patients who did not receive aciclovir for their acute shingles. If patients with acute shingles are given low dose amitriptyline from the onset, only half as many are in pain at 6 months as a group not so treated, irrespective of the antiviral treatments given. The most effective treatment of established PHN to date consists of adrenergically active antidepressants. There is a strict correlation with the brevity of the interval between acute shingles and initiation of such treatment. 75% of patients starting treatment with antidepressants within 3 to 6 months after shingles obtain pain relief, whereas if antidepressants are not started for 2 years, only 25% obtain pain relief.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7858369 TI - Differential diagnosis of dementia, delirium and depression. Implications for drug therapy. AB - Dementia, delirium and depression are the 3 most prevalent mental disorders in the elderly. While dementia and depression are prevalent in the community, hospitals and nursing homes, delirium is seen most often in acute care hospitals. Much of the management of these syndromes is undertaken by primary care physicians rather than psychiatrists. Therefore, it is imperative that generalist physicians be adept at recognising, evaluating and managing patients with these syndromes. Because no diagnostic tests are pathognomonic of these syndromes, the differential diagnosis hinges on a careful clinical evaluation. The first step is to recognise which of the syndromes is present. Dementia is defined by a chronic loss of intellectual or cognitive function of sufficient severity to interfere with social or occupational function. Delirium is an acute disturbance of consciousness marked by an attention deficit and a change in cognitive function. Depression is an affective disorder evidenced by a dysphoric mood, but the most pervasive symptom is a loss of ability to enjoy usual activities. It is important to recognise that these syndromes are not mutually exclusive, as dementia frequently coexists with delirium and depression. Furthermore, physical diagnoses, such as chronic obstructive lung disease, congestive heart failure, stroke and endocrine disorders, are frequently associated with depressive symptoms. Given this, a comprehensive evaluation is mandatory. Laboratory tests are necessary to exclude concurrent metabolic, endocrine and infectious disorders, and drug effects. Imaging studies should be obtained selectively in patients with signs and symptoms, such as focal neurological findings and gait disturbances, which are suggestive of structural lesions: stroke, subdural haematoma, normal pressure hydrocephalus and brain tumours. Appropriate management involving pharmacological and nonpharmacological measures will result in significant improvement in most patients with these syndromes. Potentially offending drugs should be discontinued. In delirious patients the underlying illness must be treated concomitantly with the use of psychotropics, if necessary. Although no current medications have been shown to have a significant effect on the functional status of patients with the 2 most common causes of dementia, Alzheimer's disease and multi-infarct dementia, the management of concomitant illness in these patients may result in improved function for as long as a year. Tacrine, an anticholinesterase inhibitor, improves cognitive function slightly in selected patients with Alzheimer's disease over short periods. Finally, the treatment of depression with medications or electroconvulsive therapy (ECT) results in significant reductions in mortality and morbidity. PMID- 7858368 TI - Postsurgical complications in older patients. The role of pharmacological intervention. AB - The number of elderly patients undergoing surgery has been rapidly increasing during the last few years. Following surgical interventions, high rates of mortality and morbidity have been reported in the most advanced age groups. Nevertheless, perioperative evaluation and postoperative care are the major determinants of the overall outcome. Postsurgical complications are common in advanced age, since multiple pathology is often present in geriatric patients. Furthermore, the decreased efficiency of homeostatic mechanisms may facilitate the development of multiple organ failure (MOF), even as a consequence of apparently slight alterations in immune, cardiac or respiratory systems. Thus, prompt recognition and treatment of any complication often prevents the development of irreversible conditions. While cardiac and pulmonary complications account for 50% of early postoperative adverse events, infections, thromboembolism, renal failure, stress ulcers and coagulation disorders may occur well after surgical procedures. An important part of postoperative geriatric care is the diagnosis and correction of fluid, electrolyte and acid-base disturbances. These disturbances may manifest as mild, atypical signs, such as slight neuromuscular depression or delirium. Yet, they often constitute life-threatening conditions that should be rapidly and properly corrected. Finally, it should be remembered that, due to the frequent use of multiple drugs, elderly patients are at high risk of developing adverse drug reactions. Thus, the treatment of postoperative complications requires a strong rational effort to disentangle the combined effects of aging, drugs and pathology. PMID- 7858371 TI - Advancing the cause of academic minority physicians and scientists. AB - By every measure, we live in exciting times, when opportunity knocks and offers us the challenge to rise above ourselves, to achieve through our common efforts what we thought to be impossible. Let us renew our commitment to make things happen! PMID- 7858372 TI - Molecular analysis of genetic diseases: an overview for clinicians. AB - The identification of fetal genetic disease has, for the most part, relied on examination of an end product, such as analysis of factor VIII levels obtained from cord blood in fetuses at risk for hemophilia. Advances in molecular genetics have shifted our focus in prenatal diagnosis away from protein product analysis toward etiology, making new discoveries gleaned from the Human Genome Project relevant to clinicians. This review discusses the basic principles involved in gene-based diagnosis, highlighting the complexities of current approaches to molecular diagnosis of fetal genetic disease. Given an understanding of both the theory and practice of genetic analysis, the review covers the fundamental principles of molecular biology (structure, function, packaging, and regulation) and discusses recombinant DNA techniques presently used for the analysis of mutations. Clinical examples are presented to introduce the techniques most commonly employed in service laboratories: direct detection assays, where the specific mutation is recognized, and indirect detection assays, useful for the deduction of an inheritance pattern where the actual mutation or its gene is not known but may be closely linked to known DNA polymorphisms. PMID- 7858370 TI - Etidronic acid. A review of its pharmacological properties and therapeutic efficacy in resorptive bone disease. AB - Etidronic acid is an orally and intravenously active bisphosphonate, which is believed to inhibit resorption of bone via a number of cellular mechanisms, including alteration of osteoclastic activity. In studies of patients with symptomatic Paget's disease, etidronic acid 5 to 20 mg/kg/day administered orally rapidly decreased the biochemical indices of bone turnover. Mineralisation defects in forming bone may be avoided by the use of an initial dosage of 5 mg/kg/day for up to 6 months; dosages above 10 mg/kg/day should be limited to 3 months' duration, and dosages greater than 20 mg/kg/day should be avoided. Although 3-day intravenous therapy with etidronic acid 7.5 mg/kg/day has shown superior efficacy to rehydration and forced diuresis in the management of hypercalcaemia of malignancy, the efficacy of the drug is lower than that of the newer bisphosphonates, pamidronic acid and clodronic acid. Clinical studies involving postmenopausal women with established osteoporosis have indicated that oral etidronic acid 400 mg/day for 14 days as part of a 90-day cycle, repeated for up to 3 years, increases the bone mineral density (BMD) of the lumbar vertebrae and appears to reduce the incidence of vertebral fracture. Published data suggest that etidronic acid shows similar efficacy to hormone replacement therapy (HRT) in these respects. The above dosage also appears to be effective in preventing corticosteroid-induced osteoporosis when administered as part of an intermittent, cyclical regimen. Etidronic acid in higher dosages (10 to 20 mg/kg/day orally) is effective in reducing the incidence of heterotopic ossification and its ensuing complications in both neurological and post-surgical patients. Etidronic acid is well tolerated by the majority of patients, with gastrointestinal complaints reported most commonly, but tends to delay the normal mineralisation of forming bone when administered continuously at higher dosages for prolonged periods. This is of little consequence where short term treatment is involved, but may be detrimental to those patients receiving longer courses of therapy. This effect may be minimised or avoided by using the lowest effective dosage for as short a time as possible (as in the above recommendations for Paget's disease), or by the use of intermittent cyclical therapy (as in the management of osteoporosis). Etidronic acid therefore retains a role in the management of resorptive bone disease, particularly in the treatment of Paget's disease, the prevention of heterotopic ossification, and as a second-line option in postmenopausal osteoporosis. However, the development of newer bisphosphonates requires that these compounds be continually compared and re-evaluated. PMID- 7858373 TI - Invasive techniques for prenatal diagnosis: current concepts. AB - Recent dramatic advances have been made in our understanding of the genetic basis of diseases. One result will be an increase in the number of pregnant women considered potential candidates for prenatal diagnosis. At the same time, the invasive techniques by which fetal specimens for prenatal diagnosis are obtained have come under increasing scrutiny in the lay press. Practicing obstetricians must have sufficient knowledge of the benefits, risks, and limitations of these techniques to respond to patient inquiries. This article reviews the commonly used invasive prenatal diagnostic methods, including amniocentesis, chorionic villus sampling, and fetal blood sampling, as well as less widely available techniques, such as fetal skin and liver biopsies. Such relevant issues as indications, timing, and fetal risks are covered. PMID- 7858374 TI - Sonographic neuroembryology of the central nervous system. AB - In the last decade, strong emphasis has been placed on the structural evaluation of the fetus. Central nervous system anomalies are among the most common malformations affecting the developing fetus. As ultrasound equipment has improved, our demand for more resolute pictures has increased. The high frequency, transvaginal ultrasound probe allows us to access the fetal fontanel and produce high-resolution fetal brain images. When such transducer probes are aligned with the fetal anterior fontanel (much like neonatal brain scans), clear and clinically useful images in the sagittal and coronal planes are generated. In this article, we review the technique of transvaginal transfontanel scanning, discuss pertinent neuroembryology, and apply this information to the sonographic diagnosis of neural tube defects. PMID- 7858375 TI - Management of tuberculosis in pregnancy. AB - In the United States, escalating rates of homelessness and human immunodeficiency virus infection have provided a background for the resurgence of Mycobacterium tuberculosis. This scourge of tuberculosis has disproportionately affected groups of reproductive-age women who have limited access to health care. Despite wide reporting of an increased incidence of tuberculosis, a low index of suspicion continues to delay diagnosis of the disease in pregnant women. As a result, a newborn diagnosed with congenital infection often becomes the index case for maternal infection. To become proficient in the prenatal diagnosis of tuberculosis, clinicians must make an in-depth review of the clinical signs and symptoms consistent with tuberculosis a routine part of obstetrical screening. Once diagnosed, tuberculosis is treated as aggressively in pregnancy as it is in the nonpregnant patient. PMID- 7858376 TI - Lipid profile in women with preeclampsia: relationship between plasma triglyceride levels and severity of preeclampsia. AB - It has been hypothesized that, in preeclampsia, hypertriglyceridemia may lead to increased endothelial triglyceride accumulation that, in turn, may result in endothelial cell damage. The purpose of our study was to determine whether hypertriglyceridemia is associated with the severity of preeclampsia. We studied 29 preeclamptic patients and 46 normal pregnant women, aged 15 to 35 years, with singleton pregnancies, at 28 to 37 weeks' gestation. Total cholesterol, low density lipoprotein cholesterol, and triglyceride levels were measured enzymatically. High-density lipoprotein cholesterol was determined using a dextran sulfate-magnesium precipitation method. Patients with mild preeclampsia had a significant increase in plasma triglyceride levels (P < .001), while patients with severe preeclampsia had triglyceride levels comparable to controls. Our findings suggest that there is no direct relationship between triglyceride levels and severity of preeclampsia. PMID- 7858377 TI - Cocaine effects on pregnancy and infant outcome: do we really know how bad it is? AB - While cocaine abuse in pregnancy is associated with a number of negative outcomes for both mothers and infants, it is unclear to what extent cocaine is specifically responsible for these negative outcomes and how its effects are distinct from those associated with substance abuse in general. Use of other drugs commonly associated with cocaine abuse, such as alcohol, marijuana, and tobacco, has also been associated with adverse pregnancy outcomes. Untoward pregnancy effects often ascribed to cocaine abuse in pregnancy may be more appropriately attributed to these or other drugs or to the unhealthy life-style associated with the long-term abuser rather than to cocaine itself. Epidemiologic data concerning cocaine use in pregnancy describe only associations of drug use and do not prove causality. Future research and longitudinal studies are needed to examine the roles of maternal and environmental factors in predicting differences in cocaine-exposed and nonexposed pregnancies. PMID- 7858378 TI - Nursing assessment: more than merely 'doing the obs'. PMID- 7858379 TI - 'The use of relaxation for the promotion of comfort and pain relief in persons with advanced cancer'. PMID- 7858380 TI - 'Health assessment and the nursing process: a means to an end? PMID- 7858381 TI - 'Childhood immunization, homeopathy and community nurses'. PMID- 7858382 TI - Problem-based learning: a model for graduate transition in nursing. AB - This article is a discussion paper related to the use of problem-based learning to assist in the professional role socialization that occurs during the transition from student to graduate nurse. Through the use of a preceptorship program which incorporates the principles of problem-based learning this transition can be a positive experience for both the graduate and the health care setting. It encourages the graduate to develop independent problem-solving skills in order to make clinical judgements and develop and evaluate action plans with a client-centred focus. The graduate would be encouraged to critically evaluate and challenge ready-made principles and norms to develop creative approaches to care which are sensitive to the client's physical, psychological, social and spiritual needs. As a model of preceptorship it provides the graduate with the opportunity to explore clinical situations within a framework of critical reflection and problem resolution. PMID- 7858383 TI - The organization: a problem for the professionalization of nursing. AB - The re-constitution of the Australian labour force has seen the emergence of the organization as the dominant employment setting. This is the case for professions as well as non-professions. With organizations have come increasingly bureaucratic forms of controlling work. The 'ideal type' which characterises the work of professions is, it would seem, under threat from the organization, and this has significant implications for nursing. PMID- 7858384 TI - Mentors and preceptors in the nursing profession. AB - Mentoring and precepting are currently receiving attention in Australian nursing. Studies in private industry and corporate organizations reveal a high correlation between professional success and a positive mentoring experience. Frequently confused with preceptor relationships, mentoring differs in subtle and not-so subtle ways. This discussion paper aims to identify differences and similarities between the various experiences in an effort to appreciate the contribution such relationships can make to the novice nurse as well as to the mentor or preceptor. Nursing can use the concepts of mentoring and precepting in a variety of ways to facilitate the transition from novice to expert as well as career changes. PMID- 7858385 TI - To screen or not to screen: cancer of the prostate. AB - Prostatic cancer is a leading cause of mortality in Australian males and yet screening programs are accorded a low priority by the health professions. Literature to date suggests that there are strong cultural taboos to the effective implementation of a national screening program. Comparisons are made with screening programs for breast and cervical cancer, currently available to Australian women. PMID- 7858386 TI - The privilege of caring for the dying client. PMID- 7858387 TI - Families--an important part of client care. PMID- 7858388 TI - Phenomenology as a way of understanding in nursing. AB - This paper discriminates between Husserlian and Heideggerian phenomenology. It also discusses some of the implications of each of these phenomenological approaches for nursing research. Phenomenological research techniques offer nurses a valuable way to understand the lifeworld of nursing. While there has been a lot written by nurses about phenomenology as a nursing research technique, the essential differences between these two phenomenological schools have not adequately been documented. This paper suggests that each of these approaches offers nurse researchers significantly different perspectives about the human condition. PMID- 7858389 TI - Beyond the obvious. PMID- 7858391 TI - What about undergraduate nurse education? PMID- 7858390 TI - The positives and negatives of handover. PMID- 7858392 TI - Speaking out for nursing in the higher education sector: the Australian Council of Deans of Nursing. PMID- 7858393 TI - Animal models in diabetes research. AB - Animals can suffer from diabetes due to a wide variety of factors. The diabetic animals may be regarded as models of diabetes in man; however, the disease displays a wide diversity of pathophysiologic factors and occasionally does not correspond to diabetes in man. Diabetes in animals can be produced by surgery, viral infections, hormone administration and chemical agents. Some animals may develop spontaneous diabetes. Animal models could be useful in the study of acute and chronic complications of the disease. We present information that we think is useful to the researcher who is involved in the care, production or use of animal models of diabetes. PMID- 7858394 TI - Pancreatic lipid peroxidation in alloxan-induced diabetes mellitus. AB - The time-course of pancreatic lipid peroxidation and reduced glutathione, and blood glucose were studied in adult male CD-1 mice after each of three sequential injections of alloxan, administered at intervals of 48 h. Twenty four hours after alloxan administration an increment of blood glucose and pancreatic lipoperoxidation was observed. Lipoperoxidation partially recovered, while blood glucose was increased after the third administration to a value of 150 mg/100 ml. Pancreas reduced glutathione content remained without any significant change throughout the experiment. These results suggest that the establishment of alloxan-induced diabetes is preceded by an increment in pancreatic lipid peroxidation that could be associated with permanent damage to pancreatic tissue. PMID- 7858395 TI - Determination of oral rifampin pharmacokinetic parameters in Mexicans and comparison with other populations: absence of evidence for interethnic variability. AB - Oral pharmacokinetics of rifampin were studied in eight Mexican young healthy male volunteers after administration of a 600 mg oral dose. After an overnight fast, subjects received medication and blood samples were drawn at selected times over a 24-h period. Rifampin plasma levels were determined by HPLC. Pharmacokinetic parameters (mean +/- SEM) were: Cmax 13.514 +/- 1.775 micrograms/ml, tmax 1.88 +/- 0.30 h, AUC 73.61 +/- 9.48 micrograms.h/ml and half life 2.98 +/- 0.29 h. Results were compared with those obtained for other populations under similar conditions in order to explore the possibility of interethnic variability, since it has been reported that rifampin pharmacokinetics in Indonesian subjects differ from those found in Europeans. Pharmacokinetic data found in Mexicans were comparable with those observed in British, Indian, Japanese and Italian individuals. As the pharmacokinetics of rifampin seem to be similar in different populations, it is concluded that ethnic origin does not appear to play an important role. Therefore, dosing regimens designed for Caucasians can be extrapolated for other populations. PMID- 7858396 TI - The level of metabolic control in low income Mexico City Diabetics. The Mexico City Diabetes Study. AB - The importance of good metabolic control in the treatment of diabetes mellitus (DM) is unquestionable. Measurements of the level of control (LC) are available such as glycohemoglobin (GH) and fructosamine (FA). The aims of this study are: to estimate LC in a population based case series of type II DM patients, to assess the effect of clinical, metabolic and sociodemographic variables usually associated with the LC and to estimate the clinical impact of the LC on vascular complications of DM. A low income area of Mexico City was enumerated. All males and non-pregnant females between 35-64 years of age were considered eligible. Home interview was obtained in 2813 and a medical exam including an oral glucose tolerance test was performed in 2282 (65.1%). Three hundred and four subjects met the criteria (WHO) for DM. Three years later, 213 (70.1%) were located for GH and FA measurements. Cases were divided according to the level of GH: Group I, good LC (GH < or = 8.6%, n = 66); and group II poor LC (GH > or = 8.7%, n = 147). A significant difference was observed in the mean value of FA between groups (Group I 255 +/- 52.3 mumol/dl. Group II 306.4 +/- 51.1; p < 0.001). In comparison with subjects with good LC, patients with poor LC had higher values of duration of DM (p < 0.01), waist/hip ratio (p < 0.04), fasting glucose (p < 0.001) and lower values of fasting insulin (p < 0.07), LDL cholesterol (p < 0.006) and VLDL cholesterol (p < 0.09).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7858397 TI - Amebiasis in the epidemiologic transition in Mexico: its morbidity and mortality trends in the Mexican Institute of Social Security. AB - Amebiasis is one of the most common parasite-related diseases and one of those with the greatest impact on health. At the Instituto Mexicano del Seguro Social (Mexican Institute of Social Security-IMSS) approximately half a million cases per year are currently treated. Of these, more than 2500 correspond to the form which invades the liver. Within the process of epidemiologic transition which Mexico is undergoing, a progressive reduction has been observed in incidence of, and mortality due to, invading amebiasis in all its clinical forms. In turn, there is a significant decrease in its fatality rate. The social and economic development and improved sanitary conditions observed in Mexico, particularly in the second half of this century, may have conditioned this process. The improvement in availability, accessibility and utilization of medical care services could also explain the reduction which has been noted in its fatality rate and mortality. The model for epidemiologic transition proposed by Omran and adapted for Mexico by Frenk, offers a plausible explanation for the changes observed in the occurrence and mortality of invading amebiasis in Mexico. PMID- 7858398 TI - Infection of BALB/c, C57B1/6 mice and F1 hybrid CB6F1 mice with strains of Leishmania mexicana isolated from Mexican patients with localized or diffuse cutaneous leishmaniasis. AB - Mice from the syngeneic strains BALB/c, C57B1/6 and (BALB/cxC57B1/6)F1 hybrids (CB6F1) were infected in the footpad with six different strains of Leishmania mexicana mexicana isolated from Mexican patients. Three Leishmania strains were isolated from patients with localized cutaneous leishmaniasis (LCL, the benign form of the disease) and three from patients with diffuse cutaneous leishmaniasis (DCL, the malignant form of the disease). In BALB/c mice, four Leishmania strains showed a sustained fast growth from 4 to 5 weeks postinfection until the end of the experiment (15 weeks), and the other two grew slowly up to 10 or 12 weeks after infection and then started to grow faster. In C57B1/6 mice four Leishmania strains showed a limited to moderate growth up to 6 to 11 weeks postinfection and then started to decrease. One strain showed a moderate growth during the entire experiment and one strain grew as fast as in BALB/c mice up to 11 weeks postinfection and then started to decrease. The CB6F1 hybrid behaved like the C57B1/6 parent strain with five Leishmania strains but was much more resistant to one Leishmania strain than the C57B1/6 mice. Sex of the mouse did not influence the outcome of infection. One important purpose of this work was to see if the Leishmania strains that cause DCL are intrinsically more virulent than those that cause the benign form (LCL). Although important variations in virulence among the Leishmania strains were observed, especially in BALB/c mice, they were not correlated with the type of disease caused in humans. PMID- 7858399 TI - Ultrastructural localization of Giardia lamblia antigens by human IgA and IgG. PMID- 7858400 TI - Incidence of memory of transoperative events during total intravenous general anesthesia with propofol. AB - The incidence of memories of events during the total intravenous general anesthesia is studied in a 400 adult patient group in order to establish the influence of the included doses of drugs in this scheme, upon the mentioned incidence. The anesthetic method included propofol, fentanyl and vecuronium. Two groups of patients were constituted according to the propofol infusion rate (PIR) required for the anesthetic maintenance: group I required a PIR < 6.0 mg.kg-1.h 1, and group II required a PIR > 6.0 mg.kg-1.h-1. Transanesthetic monitoring was done with cardiac frequency, systolic and diastolic arterial pressures, ECG, pulse oximeter oxygen saturation and end tidal CO2. The memory incidence of transoperative events was obtained through postoperative interviews about intraoperative events. Patients in group I had a significantly greater remembrance incidence both in real events and in dreams than the patients in group II. We conclude that a PIR of propofol < 6.0 mg.kg-1.h-1 can be associated with a high incidence of remembrances of transoperative events. PMID- 7858401 TI - Effects of intrathecal administration of adrenergic agonists on the frequency of copulatory pelvic thrusting of the male rat. AB - The effects of the intrathecal perispinal administration of adrenergic agonists on the characteristics of frequency, duration, and vigor of pelvic thrusting displayed by male rats during copulation was assessed by an accelerometric technique. A different dose of one drug (noradrenaline, clonidine or isoproterenol) and saline as control was administered at the lumbosacral level of the spinal cord to sexually active male rats in tests of sexual behavior performed at weekly intervals. The intrathecal administration of noradrenaline (alpha-adrenoceptor agonist) increased the frequency of pelvic thrusting in mount and intromission responses, whereas both the alpha 2-adrenoceptor agonist clonidine (25 micrograms) and the beta-adrenoceptor agonist isoproterenol (40 micrograms) reduced the frequency of pelvic thrusting in these responses as compared to values obtained under the intrathecal administration of saline. On the other hand, the duration of the thrusting trains and the potency or vigor of pelvic thrusting in mounts and intromissions did not differ from values obtained under saline treatment. These findings indicate a possible participation of noradrenaline in the modulation of the spinal mechanisms involved in the generation of rhythmic pelvic thrusting performed by the male rat during copulation. PMID- 7858402 TI - Purkinje cell density in cerebella of alcoholized and non-alcoholized male rat offspring. AB - The effect of alcohol intake by male rats was evaluated on Purkinje cell morphology and number in their offspring. Forty five male Wistar rats, 45 days old, were used and divided into three groups of 15 rats each: control group (CG), fed with conventional Purina rodent feed (CPRF) and water ad libitum; experimental group (EG), fed with CPRF ad libitum and a mixture of water/ethanol, which represented 36% of kilocalories in food; and an equienergetic intake control group (ECG), which was given CPRF (in grams) and sugar in their drinking water, in order to substitute the energetic value provided by alcohol. Five subgroups (n = 3) were created to be used for different treatment periods: 60, 90, 120, 150 and 180 days; all groups started treatment when they were 70 days old. At the end of each treatment period, male rats were mated with nulliparous females not having undergone treatment. Offspring were obtained and studied at 14 and 21 days of age. The Purkinje cells of the cerebella of 14- and 21-day-old offspring belonging to the CG and ECG showed no morphological changes. On the other hand, in 14-day-old offspring belonging to the experimental group of parents alcoholized during 90, 120, and 180 days, a large number of hyperchromatic Purkinje cells were seen, forming zones of cells undergoing a degenerative process. No significant differences in cellular density were determined between the CG and the ECG. When comparing the CG vs. EG and the ECG vs. EG, significant differences were found in the 14-day-old offspring as well as in the 21-day-old ones with a p < 0.05 of rats belonging to parents alcoholized for 90, 120, and 180 days. The results may indicate that there are changes in the germinal plasma of males due to alcohol consumption; therefore, reflecting this effect on a decrease of Purkinje cells and probably on other cell populations. PMID- 7858403 TI - Pharmacological screening of some quinoline derivatives in canine vascular smooth muscle. AB - In order to develop drugs which can discriminate vascular 5-HT1-like receptors, this study analyzed the agonist/antagonist interactions of several quinoline derivatives in vascular tissues containing these receptors. 5-HT and several substituted quinolines were evaluated and compared in canine basilar artery rings and saphenous vein helical strips which were mounted in organ baths for monitoring isometric tension changes. Based upon the molecular features of quipazine, the main assayed variations included some substitutions at the 4 position of piperazine and miscellaneous substitutions at the 2-position of the quinoline nucleus. The results, in terms of agonist-induced contraction and/or antagonism of 5-HT-induced contraction revealed that: a) 4-alkylation of the piperazinyl moiety moderately increases the agonist efficacy; b) halogenation or methylation at 5- or 6-position of both 1-piperazinyl- and 4-methyl-1-piperazinyl quinolines completely abolishes agonist activity; c) introduction of larger substituents (i.e., alkyl, carbethoxy, acethoxyalkyl, aromatic and non-aromatic rings) at the 4-position of the piperazinyl moiety, notably decreases or even abolishes the agonist activity; d) replacement of the piperazinyl group by an amino-ethyl moiety importantly increases potency (more than threefold) and efficacy (more than twofold). These findings represent leads which may aid the subsequent design of vascular 5-HT1-like-selective agents. PMID- 7858404 TI - Evaluation of the toxic and teratogenic potential of the anticonvulsant drug 4 hydroxy, 4-ethyl, 4-phenylbutyramide in mice. AB - The toxicity profiles of the phenyl alcohol amides: 4-hydroxy, 4-ethyl, 4 phenylbutyramide (HEPB) and two lower homologous: 3-hydroxy, 3-ethyl, 3 phenylpropionamide (HEPP) and 2-hydroxy, 2-ethyl, 2-phenylacetamide (HEPA) were studied in mice. TD50 value was determined by oral administration and LD50 by oral and intraperitoneal routes. The results indicate that HEPP is less toxic than the others, both of which had very similar toxicity. Furthermore, the teratogenic potential of HEPB was investigated in mice after oral administration. The compound was administered on days 6-15 of gestation at doses of 0, 5, 25, 50 or 100 mg/kg of weight. On day 17 of pregnancy the mice were sacrificed and the pups examined. An increase of body weight in both mothers and fetuses was observed at 25 and 50 mg/kg and a decrease was found in mothers receiving 100 mg/kg, as a sign of maternal toxicity. Considering the litter data, embryotoxicity and fetotoxicity were only shown at the highest dose. However, the HEPB treatment did not result in malformations of live fetuses or resorptions when the implantations were considered as the individual entity. PMID- 7858405 TI - Yeast as an expression system for the production of bacterial and viral antigens. AB - To develop a yeast system that expresses bacterial and viral antigens in the future, we analyzed yeast secretion with a reporter system based on the cc1A gene of Clostridium thermocellum that encodes endoglucanase A. Sequences coding for the mature CelA protein were fused in frame to yeast promoters and secretion signals, introduced into different vectors and analyzed biochemically in yeast secretory mutants. Gene dosage had little effect, whereas expression from a weak promoter enhanced endoglucanase A secretion. In yeast secretory mutants, a major fraction of endoglucanase A piled up in the endoplasmic reticulum as a core glycosylated protein. PMID- 7858406 TI - Perspectives and limitations of the mycobacterial expression system. AB - To develop multivalent vaccines expressing foreign antigens in BCG strains, a genetic system for BCG and Mycobacterium smegmatis is being developed that uses vectors derived from the M. fortuitum pAL5000 plasmid. In this paper we present recent advances of our laboratory in this line of research: i) optimal conditions for M. fortuitum electroporation, ii) demonstration that host range properties of pAL5000-based vectors depend on certain open reading frames, iii) cloning of expression signals derived from the BCG Moreaux 65 kD antigen, and iv) construction of expression vectors for M. smegmatis. PMID- 7858407 TI - Evaluation of the efficacy of human antimeningococcal immunoglobulin G in infant rats experimentally infected with Neisseria meningitidis group B. AB - Infants rats, a well known model for the experimental reproduction of bacterial meningitis, were used by us to test the protective potential of antibodies developed in humans who had been vaccinated with the Cuban antimeningitis vaccine (VA-MENGOCBC). Newborn rats were inoculated by the intraperitoneal and intranasal routes with suspensions of Neisseria meningitidis group B bacteria. Bacteremia kinetics were evaluated from blood and brain-spinal fluid cultures. Samples of the central nervous system were taken and smears of backbone fluids prepared for histopathologic evaluations. Characterization of bacteremia evolution, as well as the mean lethal dose of germs and histopathologic features, were determined. After standardization of the model, therapeutic schemes were applied using passive immunization pre- and post-infection with N. meningitidis. A significant level of protection was obtained in relation to control animals that received the same challenge doses. PMID- 7858408 TI - Cloning of the gene encoding the p30 antigen of Toxoplasma gondii by PCR to insert it in transgenic mice. AB - The serum from virtually all people exposed to Toxoplasma gondii contains a high titer of antibodies against a major antigen called P30. It has been suggested that p30 antigen can be used as a good diagnostic tool during T. gondii infection. Polymerase chain reaction (PCR) is the most widely used method for amplifying a known of nucleic acid fragment. We have cloned the P30 gene by PCR using oligonucleotide primers, based on the reported sequence of the T. gondii p30 gene, and introduced it into the pEV142 expression vector. Work is in progress to explore the use of pEV142 expression vector in transgenic mice in order to study the immunological role of p30 antigen during T. gondii infection. PMID- 7858409 TI - Thymidine kinase in malignant melanoma. AB - Thymidine kinase (EC 2.7.1.21) is an enzyme supporting DNA synthesis under conditions of increased cell proliferation. Although it has proved to be a useful marker for various malignant diseases, it has not been tested in malignant melanoma. Thymidine kinase activity was measured by means of a radioenzymic assay in two classical animal models of melanoma disease--B16 and Cloudman S91 melanoma bearing mice. Tumour cell proliferation was assessed histochemically by measuring the expression of proliferating cell nuclear antigen (PCNA). Tumour cytosolic specific thymidine kinase activity was found to be higher in less pigmented Cloudman S91 melanoma than in differentiated, ie pigmented B16 melanoma, relative to the proliferative activity of the two tumours. Serum thymidine kinase levels were increased in melanoma-bearing animals of both types compared with healthy mice; this also reflected the efficacy of the therapy: cyclophosphamide-treated B16 melanoma-bearing mice in which the tumour development was slowed down had significantly lower serum enzyme levels in comparison with the non-treated group and the same levels compared with control, healthy mice. Our results suggest that serum thymidine kinase levels might be used as a marker to follow the effect of melanoma therapy. PMID- 7858410 TI - Swimming and the risk of cutaneous melanoma. AB - Recreational exposure to the sun may not explain fully current trends in melanoma incidence. The hypothesis was examined whether carcinogens in water play a role in the development of cutaneous melanoma. In a case-control study, 128 melanoma patients and 168 patients with other types of malignancy completed a detailed questionnaire on aquatic leisure time activities. All relative risk estimates were adjusted for age, gender, educational level, pigmentation characteristics, and exposure to sun habits. Regular swimming during the summer months in swimming pools and in open waters such as rivers and seas before the age of 15 years, was associated with odds ratios of 2.20 (95% confidence interval (CI), 1.05-4.62) and 2.41 (95% CI, 1.04-5.58), respectively, compared with no swimming at all or swimming in relatively unpolluted waters, such as lakes and fens. Melanoma patients learned to swim at a younger age; compared with those who never learned to swim or who learned to swim after the age of 12 years, the odds ratio was 1.87 (95% CI, 0.91-3.78) for those who learned to swim at ages 9-12 years, and 2.22 (95% CI, 1.16-4.26) for those who learned to swim before 9 years of age. Compared with persons who had no swimming certificates, an odds ratio of 1.25 (95% CI, 0.71-2.23) was found for persons with one or two certificates, and an odds ratio of 2.96 (95% CI, 1.25-6.96) for persons with three or more certificates. The positive association between a history of swimming and melanoma risk suggests that carcinogenic agents in water, possibly chlorination by products, play a role in melanoma aetiology. PMID- 7858411 TI - Levels of dopachrome tautomerase in human melanocytes cultured in vitro. AB - Several reports have been published about the level of activity and possible functions of dopachrome tautomerase (DCT) in mouse melanoma cells. Data about the levels of this activity in human melanocytes in culture are still scarce, and, as far as we know, a comparison between mouse and human melanocytes, or between normal and malignant melanocytes, has never been published. We have measured the tyrosinase and DCT activities, as well as the melanin content, in mouse Cloudman melanoma cells, two lines of human melanoma, and three lines of normal human melanocytes obtained from fetal skin. Although more cell lines should be tested to draw a general conclusion, our results suggest that normal melanocytes contained much higher tyrosinase activity and melanin content but lower DCT activity than malignant melanocytes. The two lines of human melanoma cells tested had lower levels of DCT activity than Cloudman melanoma cells. Finally, the low level of DCT activity found in normal human melanocytes cultured in vitro cannot be explained by any of the necessary stimulatory factors added to the cell culture media. PMID- 7858412 TI - Expression of proliferating cell nuclear antigen (PCNA): proliferative phase functions and malignant transformation of melanocytes. AB - The UV-dependent G2-phase functions of melanocytes include dendricity, the expression of melanocyte stimulating hormone (MSH) receptors and neural differentiation. The present report studied highly dendritic melanocytes in epidermis overlying tumours, seborrhoeic keratosis, basal cell carcinoma and melanomas. The expression of the proliferative protein PCNA was studied by immunohistochemistry, as this indicates cells in S/G2-phase. In the non neoplastic dendritic melanocytes, PCNA is retained in the cytoplasm, resulting in the arrest of the cells in the S/G2-phase for prolonged periods, as indicated by the length and complexity of the dendritic processes. In melanomas, this barrier is overcome with rapid proliferation of the cells and loss of dendricity. PCNA is produced in the cytoplasm and transported into the nucleus during the S-phase, as observed in melanomas. The arrest of melanocytes in the S/G2-phase for long periods associated with UV responsiveness makes these cells vulnerable to DNA damage and neoplasia. Pools of PCNA in the cytoplasm, when transported into the nucleus, would support the rapid proliferation observed in melanomas. PMID- 7858413 TI - Different sensitivities of the murine melanomas BL-6 and BL-6-beta m to local injections of interleukin-2 (IL-2). Analysis of gangliosides after the treatment. AB - The murine melanoma cell line BL-6-beta m, which is a stable cell line transfected with a gene coding a unique actin subspecies called beta m to the BL 6 cell line, has low metastatic potentials as compared with those of the parent cell line. BL-6-beta m melanomas were found to be sensitive to in vivo local injection of IL-2, while BL-6 melanomas showed almost no response. Ganglioside analysis of BL-6 and BL-6-beta melanomas revealed that the main ganglioside of both melanomas was GM3, which suggested that different sensitivities between BL-6 and BL-6-beta m melanomas to the injection of IL-2 did not relate to the different compositions of main gangliosides. However, minor components of the gangliosides such as GM2 and GM1 emerged only in BL-6-beta m melanomas after treatment with IL-2. Local injection of IL-2 caused considerable infiltration of anti-asialo GM1-positive cells into the nests as well as the interstitials of BL 6-beta m melanomas. In contrast, in the BL-6 melanomas treated with IL-2, infiltration of the anti-asialo GM1-positive cells was hardly seen, although anti Thy1,2 and anti-macrophage-positive cells were found to more or less the same extent as observed in BL-6-beta m melanomas. These results suggest that the murine metastatic variant melanoma cell lines BL-6 and BL-6-beta m have different properties in terms of sensitivity to in vivo IL-2 treatment, and a slight enhancement of the ganglioside components GM2 and GM1 expression only in BL-6 beta m after IL-2 treatment may play a role in the IL-2-mediated attraction of immune cells or may explain the different sensitivities of the two lines to treatment with IL-2. PMID- 7858414 TI - Step down heating and melphalan: cytotoxic interactions and clinical implications. AB - Step down heating from 41.8 degrees C (10, 15 and 20 min) to 40.5 degrees C (55, 50 and 45 min respectively) was studied in vitro in L929 sarcoma cells in the presence and absence of increasing doses of melphalan. Results for heat killing alone demonstrated that step down heating for 20 min (but not 10 or 15 min) at 41.8 degrees C was equivalent to 41.8 degrees C x 65 min. Heat enhancement of melphalan, however, was observed at 10, 15 and 20 min with thermal enhancement ratios of 8.3, 10.3 and 8.5 respectively (p < or = 0.01), consistent with the enhancement of 41.8 degrees C x 65 min. The relevance of these data to hyperthermic limb perfusions for the treatment of malignant melanoma and sarcoma are discussed. PMID- 7858415 TI - A radiolabelled iodobenzamide for malignant melanoma staging. AB - 123I-N-(di-ethylamino-2-ethyl) 4 iodobenzamide (I-BZA) has been put forward by the Clermont-Ferrand INSERM U71 group (France) as a tracer for malignant melanoma. We report on the clinical results obtained in 56 studies performed on 48 patients. Whole body scans along with spot views were obtained after injection of 185 MBq of I-BZA. The scans were read by three independent observers and correlated to the clinical findings and the other imaging modalities available, taking into account all lesions larger than 1 cm. Patients were classified into two groups on the basis of a post-treatment survey of patients: group I, in complete remission (24 scans); group II: documented metastases (32 scans). In group 1, 21 studies were truly negative. However, three studies showed positive results. Only one turned out to be a false positive (specificity 95%), the other two revealed unknown lesions and modified the patients' management. In group II, 73% of the known metastases were detected with higher sensitivities (> 80%) for eye and orbit, lung and abdomen. One false positive was reported and four new lesions were detected. I-BZA scintigraphy has the same sensitivity as immunoscintigraphy with higher specificity and without the risk of xenoimmunization. It is a useful tool for staging malignant melanoma which can improve patient management. PMID- 7858416 TI - Protein kinases in normal and transformed melanocytes. AB - Aberrant function of protein kinases has been implicated in the development of melanoma. In an effort to define the molecular events involved in initiation and progression of this malignancy, we used RT-PCR to identify protein kinases in both normal and transformed melanocytes. Collectively, we identified seven clones corresponding to previously characterized protein kinases (JAK-1, TYK02, AXL/UFO, IGF1-R, KDR and FER) as well as the recently identified MLK-3/PTK1 protein kinase. Northern analysis was used to determine the expression pattern of each protein kinase in both normal melanocytes and a variety of melanoma cell lines. Relatively abundant levels of UFO/AXL and KDR mRNAs were observed in a subset of the melanoma cell lines whereas most of the remaining protein kinases were expressed at similar levels in both normal and transformed melanocytes. PMID- 7858417 TI - Anti-proliferative activity of natural interferon-alpha, isotretinoin and their combination varies in different human melanoma cell lines. AB - Natural interferon alpha (nIFN-alpha) isotretinoin and their combination were tested for their capacity to modulate the proliferation of different human melanoma cell lines. Modulation of cell growth was measured using the MTT-assay. Isotretinoin and nIFN-alpha as single agents inhibited the proliferation in a dose dependent manner in the three cell lines: SK-Mel-30, SK-Mel-28 and MaRi. The combination of isotretinoin and nIFN-alpha led to a marked enhancement of the antiproliferative effect compared with either nIFN-alpha or isotretinoin alone in SK-Mel-30 cells. In contrast, there were no additive effects on growth inhibition of melanoma cell lines SK-Mel-28 and MaRi when nIFN-alpha and isotretinoin was combined. In one melanoma cell line (MaRi) proliferation was actually enhanced by isotretinoin in combination with nIFN-alpha. These results demonstrate the heterogeneous response of human melanoma cell lines to noncytotoxic concentrations of isotretinoin and nIFN-alpha alone and in combination. PMID- 7858418 TI - Mechanism of the anti-tumour effect of biochemotherapy in melanoma: preliminary results. AB - During the conduct of a biochemotherapy trial in which cisplatin, vinblastine and dacarbazine (CVD) were administered concurrently with interleukin-2 (IL-2) plus interferon-alpha 2a (IFN-alpha 2a) (biochemotherapy) in advanced melanoma, we performed a series of laboratory studies in an attempt to understand better the mechanism of anti-tumour effect of the regimen. We initially hypothesized that CVD enhanced the anti-tumour effect of the biotherapy. However, in the first 10 patients studied, of whom eight were responders, we observed no lymphokine associated killer cell (LAK) and minimal natural killer (NK) cell activities. This prompted us to change our initial hypothesis. Based on the work of others which showed a marked synergism between IL-1 alpha and cisplatin, apparently mediated by H2O2 derived from tumour-infiltrating macrophages, we reasoned that the biotherapy could enhance the cytotoxicity of the CVD regimen. To evaluate macrophage function, we measured serum neopterin levels in eight responders and seven non-responders. An increase of six or more times above baseline levels was observed in seven out of eight responders but in only two of seven non-responders (P = 0.041). We also examined the level of DNA inter-strand cross-link in peripheral blood mononuclear cells in four responders and four responders, as a means to evaluate the DNA repair process. A DNA cross-link index > or = 0.75 was observed in all four responders but only in one non-responder (P = 0.14). Our preliminary results suggest that concurrent biochemotherapy may exert its predominant anti-tumour effect by direct cytotoxicity and that macrophages may be involved in this process. PMID- 7858419 TI - International Melanoma Conference. Brisbane, Australia, 6-9 April 1994. PMID- 7858420 TI - A rapid, high-yield purification of L-alanine:4,5-dioxovalerate transaminase from rat kidney mitochondria using an improved enzyme assay method. AB - The present report documents an improved enzyme assay method for the mammalian L alanine:4,5-dioxovalerate transaminase which is of significant utility in work with crude tissue homogenates, cell cultures, or purified enzyme preparations. We also describe a new and rapid purification procedure for this enzyme from rat kidney mitochondria. The three-step procedure involves the use of digitonin and lubrol for mitochondrial matrix preparation and L-alanine-Sepharose 4B column chromatography followed by gel filtration on Sepharose 6B. By this procedure it is possible to obtain a highly purified enzyme preparation in a relatively short time with a 37.5% yield. PMID- 7858421 TI - A fermentor culture for production of recombinant phenol hydroxylase. AB - Fermentor cultures using the fed-batch technique produced the FAD-containing enzyme phenol hydroxylase (EC 1.14.13.7) originated in the lower eukaryote Trichosporon cutaneum, but expressed in Escherichia coli under the control of the tac promoter. At 30 degrees C and isopropyl beta-D-thiogalactopyranoside (IPTG) concentrations of 0.5-2 mM, the enzyme protein was expressed to high cellular content, but aggregated into inclusion bodies. At 25 degrees C similar levels of enzyme protein were synthesized after induction with 0.05 mM IPTG, but a soluble, active enzyme was obtained. The active enzyme was produced at up to 45% of total protein and constituted more than 50% of soluble protein. The total yield was 5 g x liter-1. The FAD content of the cells increased after induction at a rate not limiting the formation of active enzyme. The enzyme was purified in two chromatographic steps. The N-terminal amino acid residue and the kinetic properties of the purified recombinant enzyme were similar to those reported for the enzyme from T. cutaneum. PMID- 7858422 TI - Expression, purification, and functional characterization of the two zinc-finger domain of the human GATA-1. AB - The DNA-binding domain of the erythroid transcription factor GATA-1 consists of two closely related, but distinct zinc-fingers which are highly conserved among the members of the growing family of GATA-like factors. The DNA-binding domain of the human GATA-1 (F1F2) was expressed as a histidine-tagged fusion protein in Escherichia coli. The denaturated protein was purified by Ni(2+)-chelate affinity chromatography and renaturated in situ. The active recombinant protein was purified by DNA affinity chromatography. F1F2 displayed GATA-1 specific binding activity toward its DNA recognition sequences within the hypersensitive site 3 of the human locus control region and the human gamma-globin promoter. In contrast to GATA-1 protein purified from K562 nuclei, the recombinant F1F2 bound also the CCAAT-box region of the human gamma-globin promoter. PMID- 7858423 TI - An improved system for ribonuclease Ba expression. AB - The extracellular ribonuclease from Bacillus amyloliquefaciens (barnase, RNase Ba) is a well-characterized enzyme extensively used in structure-function studies. A new system for efficient expression and purification of barnase has been developed. The strong regulated expression cassette with the Pr promoter of lambda phage and the cooperative expression of barnase and barstar under its control have been applied to expression of these proteins in Escherichia coli. The expression cassette containing the Pr promoter of E. coli lambda phage under cI repressor regulation and the nucleotide sequence coding for barnase and barstar structural genes were merged into the plasmid pTN441, which was used for large-scale barnase production. The phoA signal peptide was used to express the target protein into cell periplasm. The purification of RNase Ba was carried out in two steps: the initial sample was concentrated followed by RP-HPLC. The system provides a stable yield of homogeneous protein of about 100-150 mg per liter of culture medium. PMID- 7858424 TI - Introduction of additional charges as an aid in protein purification: isolation of elongation factor 2 from Sulfolobus acidocaldarius by preparative isoelectric focusing before and after ADP-ribosylation. AB - Diphtheria toxin catalyzes the ADP-ribosylation of elongation factor 2 (EF-2) in eukaryotes and archae-bacteria. As the reaction is strictly EF-2 specific and introduces two negative charges into the molecule, the resulting shift in the isoelectric point (pI) by 0.2 pH units was used to establish a new purification method for EF-2 from Sulfolobus acidocaldarius. The cells were lysed with dithiothreitol at pH 9 and EF-2 was purified by ammonium sulfate precipitation, gel filtration on Sephadex G-200, and three isoelectric focusing steps. The EF-2 containing fractions from the first isoelectric focusing step at pH 4-9 were refocused in a more narrow pH-gradient (pH 5-7). The EF-2 peak from the second step was eluted, collecting only the fractions above the pH region where ADP ribosylated EF-2 would focus. The EF-2 was then ADP-ribosylated with diphtheria toxin and NAD and subjected to further isoelectric focusing (pH 5-7). The EF-2 was almost homogeneous since ADP-ribosylation had shifted it into a region of the pH gradient free of contaminating proteins. Diphtheria toxin was immobilized on CNBr-activated Sepharose to prevent a possible contamination by proteins from the diphtheria toxin preparation which might have the same pI as ADP-ribosylated EF 2. Finally, the ADP-ribosyl group was removed by equilibrium dialysis using diphtheria toxin and nicotinamide at pH 6.3. The obtained EF-2 was active in protein synthesis. PMID- 7858426 TI - Purification of proteins by the use of hydrophobic zeolite Y. AB - Hydrophobic zeolite Y can be used as a fast and efficient and inexpensive matrix in the purification of proteins from crude extracts. Preferably the zeolite can be used in the first purification step, replacing the commonly used precipitation techniques with (NH4)2SO4 or ethanol. The time required for the zeolite prefractionation was a few hours compared to the much more time consuming precipitation procedure which demands centrifugation and subsequent dialysis. Proteins can be absorbed on the zeolite either in order to remove undesired proteins or to be subsequently eluted from the zeolite in order to achieve purification and concentration. Removal of undesired proteins is exemplified by the purification of horseradish peroxidase from a crude extract. The zeolite procedure enhanced the specific activity five times and provided a yield similar to that which was obtained by the use of standard procedures, (NH4)2SO4 fractionation and ion-exchange chromatography. Binding and subsequent elution of proteins from the zeolite is exemplified by the purification of monoclonal antibodies from hybridoma culture supernatants. Proteins were desorbed from the zeolite by the use of polyethylene glycol 600 and this procedure yielded a purification factor of 5. PMID- 7858425 TI - High yield expression and purification of human endothelin-1. AB - A DNA construct encoding human big endothelin (Big ET) preceded by the factor Xa protease recognition site (Ile-Glu-Gly-Arg), fused in frame to the maltose binding protein sequence, has been introduced in DH5-alpha cells. The fusion product (MBP-Big ET) was expressed at a concentration close to 100 micrograms/ml of culture broth and constituted approximately 50% of the total protein content. Crude cell extracts containing the fusion product have been directly treated with trypsin under mild denaturing conditions in order to release big endothelin (1 37) from the adduct. Cleavage yield of the MBP-Big ET adduct was close to 70%. Big ET(1-37) was separated from unrelated peptides derived from the tryptic digest of the bacterial extract by affinity chromatography. The affinity column was prepared by immobilizing a protease resistant peptide ligand able to recognize Big ET with sufficient affinity, selectivity, and specificity. From the affinity step (recovery, 90%), recombinant Big ET(1-37) was obtained with a purity close to 80%. The affinity-purified recombinant product was then digested with alpha-chymotrypsin in order to release endothelin (1-21), which was then purified by RP-HPLC. With this two-step purification protocol, 3 micrograms of endothelin was recovered from 1 ml of bacterial broth, with a purity close to 95%. PMID- 7858427 TI - Isolation of yeast transcription factor IIA using a functional transcription assay. AB - TFIIA was extensively purified from a whole-cell transcription extract from yeast. Activity was followed throughout isolation utilizing a functional transcription assay. Transcription activity was found to copurify with polypeptides of 43 and 12.5 kDa, consistent with a previous purification that utilized a TBP/DNA gel mobility shift assay (J. Ranish and S. Hahn, J. Biol. Chem. 266, 19320-19327, 1991). The Stoke's radius of the purified protein was determined by gel filtration chromatography to be 44 A under native conditions. The solution molecular weight derived from this measurement, 110 kDa, is consistent with a heterotetrameric structure of TFIIA. PMID- 7858428 TI - Human pancreatic procolipase expressed in insect cells: purification and characterization. AB - A cDNA clone encoding human pancreatic procolipase was incorporated into a recombinant baculovirus. Spodoptera frugiperda insect cells infected with the recombinant baculovirus secreted procolipase into the medium, which could be isolated in a single step by immunoaffinity chromatography. The highly purified protein reactivated human pancreatic lipase in a concentration-dependent fashion and was efficiently converted to colipase by limited trypsin digestion. This expression system is suitable for producing amounts of procolipase adequate for biophysical studies. PMID- 7858429 TI - In vitro transcription of erythroid promoters using baculoviral-expressed human GATA-1: purification, physicochemistry, and activities. AB - GATA-1 is a cys-2/cys-2 zinc finger transcriptional activator that is required for erythrocyte development in chimeric mice and contributes to the expression of all erythroid genes studied to date, including the erythropoietin receptor, glycophorin B, and porphobilinogen deaminase genes. Transactivation by GATA-1 is mediated by either an amino-terminal acidic domain, R1, or an independent adjacent domain, R2, and may involve the coordinate action of cofactors (NF-E2, EKLF, and Sp1) which bind adjacent cis-elements. To directly assess mechanisms of transactivation, we have developed an efficient cell-free transcription system using recombinant human GATA-1 (rhGATA-1) expressed in SF9 cells. Levels of baculoviral expression of GATA-1 were > or = 200-fold higher than endogenous levels in erythroid K562 cells. Factors from each source were essentially equivalent in molecular weight and DNA binding properties, and highly similar in phosphotryptic peptide composition. Notably, DNA binding was inhibited following treatment with alkaline phosphatase. In both SF9 and K562 cells, GATA-1 occurred largely as heterogeneous multimers, thus complicating its isolation by standard procedures. However, significant purification of this factor (> or = 100-fold; > or = 75% purity) was accomplished via DNA affinity chromatography. In cell-free assays, this rhGATA-1 was shown to be remarkably active in transactivating model erythroid promoters. This work establishes an efficient in vitro system for direct analyses of mechanisms, cofactors, and functional domains of GATA-1 which regulate transcription at defined proximal promoters. PMID- 7858430 TI - Effects of co-expressing chaperone BiP on functional antibody production in the baculovirus system. AB - The assembly pathway of the insect cell Spodoptera frugiperda (Sf-9) was engineered to include expression of the murine chaperone immunoglobulin heavy chain binding protein (BiP) using the baculovirus vector. The impact of BiP coexpression on the production and secretion of functional and soluble recombinant immunoglobulin IgG levels was evaluated. Recombinant BiP was found to associate specifically with immunoglobulins in immunoprecipitation studies. Coinfection of insect cells with a BiP-containing baculovirus and baculoviruses coding for two different murine IgG proteins increased intracellular functional antibody activity levels substantially above the levels observed in the absence of BiP. Soluble intracellular immunoglobulin levels were found to increase as well. However, secreted functional antibody levels did not increase significantly. Also, degradation of heavy chain immunoglobulin in insect cells was indicated by the accumulation of lower molecular weight immunoglobulins at 4 days postinfection. Coexpression of light chains reduced the level of these lower molecular weight immunoglobulins while BiP coexpression led to enhanced levels. These findings suggest that coexpressed BiP can increase intracellular soluble and functional antibody yields but that secretion in the baculovirus-insect cell system must be limited at some post-translational step. PMID- 7858431 TI - Overexpression and rapid purification of rabbit fast skeletal troponin I from Escherichia coli: effect of different promoters, host strains, and culture conditions. AB - Rabbit fast skeletal troponin I (TnIf) cDNA was expressed using two Escherichia coli expression vectors, pRE1 containing the bacteriophage lambda pL promoter and pAED4, a T7 RNA polymerase-based vector. Although both vectors expressed TnIf, overexpression of the target protein was achieved with pAED4. The effect of several parameters such as culture condition, compatible host strain, and inhibition of protein synthesis by rifampicin on the expression of TnIf was investigated. The overexpressed target protein synthesized during a brief induction period of only 2 h was conveniently purified from inclusion bodies by a simple and rapid procedure involving extraction with urea, ultracentrifugation, DE-52 column chromatography, and gel filtration. About 50-75 mg of highly purified TnIf was obtained per liter E. coli culture by this method, which does not involve time-consuming multistep procedures such as affinity and ion exchange chromatography as previously reported in the literature. The isolated unfused protein is stable and is indistinguishable from native protein in all biological parameters examined. The parameters optimized in this report for overexpression of TnIf may also be applicable for other eukaryotic proteins. PMID- 7858432 TI - Comparison of the effects of nifedipine and nitroglycerin on coronary blood flow using intracoronary Doppler catheter. AB - Different effects of nifedipine and nitroglycerin on large coronary arteries measured by the Xenon washout method are well documented in early reports, but results of direct measurements of the flow velocity of the large vessels were inconsistent. The goal of this investigation was to compare the effects of nifedipine and nitroglycerin on coronary blood flow using an intracoronary Doppler catheter. Fourteen patients with normal coronary arteries (group 1) and eight (group 2) with coronary artery diseases (more than 75% concentric stenosis over the left anterior descending artery in the middle portion) were presented on diagnostic procedure for evaluation of chest pain or abnormal exercise tests after written informed consents. We compared the effects of nitroglycerin (0.6 mg) and nifedipine (10 mg) given sublingually on coronary blood flow velocity using a Doppler coronary catheter. The results indicated that the maximal increase in large coronary arterial diameter induced by nifedipine was similar to that induced by nitroglycerin. Nifedipine increased diastolic and systolic velocity area indices (DVAI and SVAI), and reduced diastolic and systolic coronary vascular resistance (DCVRI and SCVRI). In contrast, nitroglycerin reduced DVAI and SVAI and minimally increased DCVRI and decreased SCVRI in group 2 patients. The increased heart rate and decreased blood pressure induced by both drugs were similar. The differences in the rate-pressure product between the two drugs were not significant. Nifedipine increased flow velocity and decreased coronary vascular resistance, but nitroglycerin achieved the opposite effect, especially in patients with coronary artery disease. PMID- 7858433 TI - Findings of anomalous pulmonary venous return using MRI. AB - This study represents a preliminary retrospective assessment of the value of spin echo magnetic resonance imaging (MRI) in detecting and describing total or partial anomalous pulmonary venous return (APVR). MRI was performed in 21 cases of APVR; orthogonal planes were used in all. Of the 21 cases, 19 were classified as total APVR (TAPVR) and two were partial APVR (PAPVR). Of the 19 cases of TAPVR, seven supracardiac, nine cardiac, one infracardiac and two mixed type were noted. The detection rate of each pulmonary vein combined in all three planes was 57% in the right superior pulmonary vein (RSPV), 62% in the left superior pulmonary vein (LSPV), 76% in the right inferior pulmonary vein (RIPV), and 86% in the left inferior pulmonary vein (LIPV). The axial plane was most effective (RSPV: 38%; LSPV: 52%; RIPV: 71%; LIPV: 81%). The coronal plane offered a better detection rate than the axial plane in RSPV (43%) and additional information of bronchial and visceral situs. Imaging of the combined axial and coronal planes was sufficient to evaluate each individual pulmonary vein. The sagittal plane gave no additional information in this respect. Accurate identification of pulmonary venous confluence and anomalous pulmonary venous channel was 95% (20/21). Limitation of echocardiography and and angiocardiography makes cardiac MRI important in assessing pulmonary vein and pulmonary venous confluence. It obviates the need for invasive angiocardiography and is an important supplement to an inadequate echo. PMID- 7858434 TI - Childhood acute nonlymphocytic leukemia in 88 patients. AB - In this study, 88 newly diagnosed children with acute nonlymphocytic leukemia (ANLL) were retrospectively analyzed for their treatment outcome. The patients included 51 boys and 37 girls, aged from four months to 14 years 11 months (median, seven years one month). The treatment consisted of chemotherapy using protocols which were standard at the time of diagnosis (1978-1991). Cerebrospinal fluid was not routinely examined. Fever with neutropenia was treated with empiric combination antibiotics, and anemia and thrombocytopenia were treated with blood components. Non-compliance was frequent; it was estimated that only 35.6% of all patients followed the given instructions. For the overall group (n = 57), 50.9% achieved confirmed complete remission. Median remission duration was five months and survival time was 11 months. The probability of continuous remission at 24 months was 20.9%. For the compliant group (n = 31), 51.6% attained complete remission, with a median remission duration of 14 months. The probability of continuous remission at 24 months was 44.5%, and the median survival time was six months. Early death occurred in 21.1% of all patients, 38.7% of compliant patients and 85.7% of acute promyelocytic leukemia patients. This study demonstrates how supportive treatment, socioeconomic factors and chemotherapy interact and affect the treatment outcome of ANLL in children. PMID- 7858435 TI - An in vivo canine model for the study of phonation physiology by midbrain stimulation. AB - A versatile in vivo canine model is indispensable in studying the phonation function of the larynx. In this study, we attempted to build an in vivo phonation model in anesthetized dogs using stereotaxic electrical stimulation at a specific area in the midbrain. In each of the eight animals in this experiment, evoked phonation was successfully elicited by stimulating sites in the area ranging from 9 to 11 mm anterior, 3 to 5 mm lateral and 5 to 16 mm dorsal to the ear bar zero. This area was at the lateral border of the periaqueductal gray in the midbrain. The evoked-phonation process involved electrical stimulation of sites in this area, resulting in consistent responses by respiratory and laryngeal musculature accompanied by phonation. The evoked phonation could be consistently repeated. Different pitches of phonation were elicited by slightly moving the stimulation spots in this area. During evoked phonation, the subglottic aerodynamic power and individual laryngeal muscle action could be modified to study the effects of a single factor on the phonation process. The neuromuscular action for the control of phonation and the mechanical properties of the vocal folds can be investigated using an in vivo canine model. PMID- 7858436 TI - Intussusception in infants and children: risk factors leading to surgical reduction. AB - Intussusception is commonly the etiology of intestinal obstruction in infants and children. To investigate demographic data, clinicopathologic features and therapeutic prognosis of patients with intussusception, we reviewed 361 intussusceptions in 333 patients over an 11-year period. Most patients were below two years of age and there was a male preponderance of 1.6:1. There was no seasonal difference between the number of cases. The clinical triad of vomiting, abdominal colicky pain and bloody stools was manifested in only one-third of our patients. Secondary intussusception contributed to 6.6% of cases and Meckel's diverticulum was the most common pathologic cause. Positive findings were recorded in 82% of 67 patients undergoing sonographic examination. Intussusception of the ileo-colic type was most frequently encountered. Most patients (79%) were diagnosed within 48 hours and almost all cases underwent primary barium enema reduction. The success rate was 45%. Laparotomy was performed in 207 patients (57%) refractory to enema reduction or with critical illness, and intestinal resection was required in 28 (14%). Long-standing duration of illness (> 24 hours), positive clinical triad, positive pathologic lead point, and radiologic finding of bowel obstruction were identified as risk factors leading patients to surgical reduction (p < 0.001). Postoperative complications and recurrent intussusception developed in some patients, and the overall mortality was 0.6%. The clinical characteristics of intussusception in children generally remained unchanged as compared to previous reports. Early identification of patients with risk factors for surgical treatment is important to decrease the need for intestinal resection. PMID- 7858437 TI - Hyperammonemic encephalopathy due to essential amino acid hyperalimentation. AB - Hyperammonemic encephalopathy has occasionally been reported in uremic patients receiving hyperalimentation with essential amino acid (EAA) as a source of nitrogen as one of the remaining treatment options when the enteric routes were prohibited. We encountered this complication in a patient with normal renal function. A rat animal model was designed to elucidate the mechanism of hyperammonemia resulting from hyperalimentation with EAA as a source of nitrogen. Sixty-four male Long-Evan rats were divided into eight groups receiving feeds ad libitum or different formula of hyperalimentation. Hyperammonemia was found in every rat given hyperalimentation with EAA as the only nitrogen source. Using the Tukey honestly significant difference test, the results were significantly higher (p < 0.001) than that of the control group which were given feeds ad libitum and those groups given hyperalimentation for the same number of days but with mixed amino acid (MAA) as the nitrogen source. Adding arginine to EAA for a further four days after initial administration of EAA hyperalimentation for three days only slightly lowered the mean serum ammonia level. When compared to that of the three-day EAA hyperalimentation group, the difference was not statistically significant. Adding arginine, citrulline, and ornithine to EAA for a further four days significantly lowered the mean serum ammonia level. When we changed EAA hyperalimentation to MAA hyperalimentation for a further four days, the mean serum ammonia level decreased dramatically to nearly normal. Hyperalimentation using EAA as the exclusive source of nitrogen resulted in hyperammonemia. A deficiency of arginine or other amino acids of the urea cycle failed to account completely for the hyperammonemia observed.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7858438 TI - Isoelastic total hip replacement: clinical evaluation of prosthetic isoelasticity. AB - By using the lower modulus material, polyacetal, ie, prosthesis made by R. Mathys', isoelastic hip prosthesis is claimed to reduce stress shielding effects and secure long-term, stable fixation of prostheses. In Tri-Service General Hospital from October 1985 to October 1989, 23 patients (25 hips) were treated using this prosthesis. Twenty patients (22 hips) were followed for clinical and radiographic evaluation for an average of 44.8 months (29-58 months). In clinical evaluation, the overall results were comparable to other cemented or cementless hip prostheses. The Merle d'Aubigne and Postel score for pain, motion and walking were improved from 1.6, 3.9, and 2.4 to 4.6, 4.3, and 4.9, respectively. The acetabular cup showed more favorable radiographic evaluation with a total mean score by combined Charnley and Engh's system of 7.9. It was not optimal on the femoral side and it showed that 20 of the femoral stems were stable fibrous fixations with a mean score of 15.8. Early complications included two dislocations, two significant femoral shaft fractures, and five medial neck cracks at surgery. The late complications included one loosening, one screw breakage, and one screw back out. The isoelastic hip always gained an inferior score in clinical evaluation from the "self comparison" in three patients with one side isoelastic hip and the other side different cemented or cementless prosthesis. There is no obvious benefit in radiographic evaluation, both in elimination of stress shielding and enhancement of fixation stability. As a result, the theoretical advantages of the isoelasticity concept are difficult to justify in our clinical practice. PMID- 7858439 TI - Kyphectomy and segmental spinal instrumentation in young children with myelomeningocele kyphosis. AB - For children with myelomeningocele kyphosis, the ideal timing for spinal correction or the correct stabilization technique for preventing the recurrence of deformity are controversial issues. From 1988 to 1992, vertebral kyphectomy and long segment spinal fixation with a special lower-end contouring around the anterior aspect of the sacrum through the sacral foramina (the modified Gillespie's technique) were carried out on six young children with ages ranging from three years and four months to five years and 11 months (average, five years). The indications for surgery were recurrent skin breakdown and/or increasing functional deficits due to curve progression. A mean preoperative kyphosis of 126.3 degrees was reduced to 21.8 degrees postoperatively. There was one case of pseudarthrosis seen at the osteotomy site which was treated with anterior interbody grafting. With a mean follow-up period of 35 months (range, 10 48 months), all patients showed good maintenance of correction and no implant failure. The average loss of correction was 2.7 degrees. We believe that in these young, severely handicapped children, long segment fixation using the modified Gillespie's technique with full or partial segment fusion allows a quick resumption of upright activities, achieves satisfactory correction of kyphosis and minimizes the risk of recurrent deformity. PMID- 7858440 TI - Posterior slope angle of the medial tibial plateau. AB - The overall average of the posterior slope of the medial plateau of the tibia as determined from the lateral radiography of the knee was 10 degrees +/- 4 degrees, with a range from 0 degrees to 20 degrees. This value was independent of age and gender and was unaffected by arthrosis as long as the arcuate contours of the medial socket were not eroded and could be identified by lateral radiography. While the average value of this posterior slope was similar to that of a cadaveric study, the range was much greater. The current practice of neglecting the preoperative posterior tibial slope and arbitrarily setting the tibial component at a predetermined posterior tilt angle failed to take into account the wide variation in posterior tibial slope. PMID- 7858441 TI - Mitochondrial respiratory function in multiple symmetrical lipomatosis: report of two cases. AB - Madelung's disease is a rare benign disorder characterized by symmetrical deposition of adipose tissue on the neck and shoulders. The cause of Madelung's disease is obscure and may be associated with mitochondrial dysfunction. In this communication, we report two cases encountered at Cardinal Tien Hospital during 1992. Besides physical check-up and laboratory examination, adipose tissue and muscle biopsies from the biceps brachii were performed. As lipid metabolism is closely related to mitochondrial respiration, biochemical studies may be of great value in clarifying the pathogenetic mechanism of Madelung's disease. We thus determined the activities of mitochondrial respiratory enzymes (NADH cytochrome c reductase, succinate cytochrome c reductase, cytochrome c oxidase) in muscle and blood cells and revealed that the electron transport functions were all elevated. Molecular analysis of mitochondrial DNA from the muscle and blood cells of both patients failed to find large-scale deletion or point mutations. PMID- 7858442 TI - Mucocele of the sphenoid sinus with acute bilateral blindness: report of a case. AB - Paranasal sinus mucocele is not uncommon in Taiwan, but is relatively rare in the sphenoid sinus. The symptomatology of mucocele in the sphenoid sinus is quite vague, but it could be well explained by compressive neuropathy. Computed tomographic scanning is the diagnostic imaging study of choice if paranasal mucocele is suspected. This is a report of an unusual case of sphenoid sinus mucocele, presenting with sudden bilateral blindness. The bilaterla optic nerve neuropathy focused attention on the sphenoid sinus, and the patient's previous history of intranasal surgery further suggested the possibility of a mucocele. Computed tomography confirmed the suspicion. The patient recovered her visual function after sphenoidotomy. PMID- 7858443 TI - Multiple mediastinal ganglioneuromas: report of a case. AB - A 23-year-old male known to have an asymptomatic mediastinal mass for four years was admitted due to progressive pitting edema of his arms and legs lasting for one week. The edema subsided prior to surgical extirpation of the left paraspinal mass. Initially recognized radiologically as a well-defined soft tissue mass with mottled calcification, on operation the mass was seen to be two well-encapsulated ganglioneuromas. Another small, round, nodular lesion abutted the contralateral side of the vertebral body on a computed tomographic scan of the chest. The postoperative course was unremarkable except for subsequently developed but well tolerated regional anhidrosis involving the left side of the chest wall and the left upper limb. PMID- 7858444 TI - Occult breast carcinoma presenting with axillary lymph node metastases: report of two cases. AB - We report two unusual cases of occult breast carcinoma in which extensive axillary node metastasis was the first manifestation. A microscopic lesion of intraductal carcinoma was found in the tissue of one resected breast and a small infiltrative ductal carcinoma, 0.8 cm in size, in the greatest dimension in the other. Extensive metastasis was found in 26 out of 51 and 10 out of 15 axillary nodes, respectively. Results of immunohistochemical stains for estrogen and progesterone receptors on fresh frozen sections were negative for metastatic nodes in one case and both were positive for primary and metastatic tumors in the other. We review the literature and discuss the diagnosis, management and prognosis in female patients presenting with metastatic carcinoma in the axillary nodes. PMID- 7858445 TI - Congenital nephrotic syndrome with microcephaly: report of a case. AB - Congenital nephrotic syndrome is an uncommon disease with variable etiology, course and prognosis; its association with microcephaly is even more unusual. A case is reported here of congenital nephrotic syndrome because of focal glomerulosclerosis in a three-month-old female infant with microcephaly since birth. There were no known renal diseases nor hereditary disorders in her family. The serologic tests for syphilis, toxoplasmosis, rubella, and cytomegalovirus infections were negative. Magnetic resonance imaging of the brain showed diffuse atrophic change of the cerebral hemispheres and brain stem with a remarkable increase of extracerebral space. The infant died at the age of four months without any clinical cause other than congenital nephrotic syndrome. These findings, including congenital nephrotic syndrome and microcephaly accompanied by various other clinical symptoms, have been described as a clinical entity with an autosomal recessive mode of inheritance. PMID- 7858446 TI - Renal hypoplasia, Gartner's duct cyst and imperforated hemivagina: report of a case. AB - A girl with unilateral renal hypoplasia, ipsilateral Gartner's duct cyst and ipsilateral imperforate hemivagina is reported. She had a history of urinary drib bling since early childhood. Recently, a foul bloody vaginal discharge was noted. Diagnosis was highly suspected on pelvic sonography, computerized tomography and magnetic resonance imaging, and was confirmed by punctures in the genitourinary tract with contrast study during surgery. This anomaly is extremely rare. Although three patients with similar conditions have been previously reported, different clinical presentations were noted in this patient. PMID- 7858447 TI - Age-period-cohort analysis of pulmonary tuberculosis mortality in Taiwan: 1961 to 1990. AB - The specific aim of this study was to examine the effects of age, calendar period of death, and birth cohort in pulmonary tuberculosis (TB) mortality in Taiwan during the period 1961 to 1990. A log-linear Poisson regression model modified from the method of Osmond and Gardner was used and 79,881 deaths (58,025 males and 21,856 females) were included in the analysis. Birth cohort is the most significant predictor of pulmonary TB mortality according to the model. The earliest birth cohort from 1891 had a pulmonary TB mortality 17,327 and 6,186 times those born from 1986 for males and females, respectively. There was also a significant age effect. The youngest age group of zero to four years had a pulmonary TB mortality 7.10 and 5.87 times those for the age group of five to nine years for males and females, respectively. The oldest age group of 70 to 74 years had a risk of pulmonary TB mortality 2.89 and 1.88 times those for the five to nine-year age groups for males and females, respectively. Parameters of the period factor showed a decreasing pulmonary TB mortality from 1961 to 1990 that was less significant than those of age or cohort. In addition to the improvement in medical measures that influenced the effect of calendar year on TB mortality, year of birth is an important determinant in the trend of TB mortality in Taiwan. The result shows that the major focus for TB mortality in Taiwan is in the age groups born between 1891 and 1921. PMID- 7858448 TI - Atherosclerotic risk factors for peripheral vascular disease in non-insulin dependent diabetic patients. AB - The purpose of this study was to evaluate risk factors associated with peripheral vascular disease (PVD) in patients with non-insulin-dependent diabetes mellitus (NIDDM). A group of 100 patients (50 men and 50 women) aged 50 years or over with PVD and another group of 200 age-sex-matched patients (100 men and 100 women) without PVD were studied. The mean +/- standard error of ages for subjects with and without PVD were 60.8 +/- 0.6 years and 59.7 +/- 0.3 years, respectively. Doppler ultrasound was used to measure the systolic pressures of the brachial, posterior tibial and dorsal pedal arteries bilaterally. The diagnosis of PVD was made by an ankle-brachial index (ABI) < 0.90 and the diagnosis of non-PVD by an ABI > 1.00. The association of PVD with diabetic duration, body mass index (BMI), cerebral infarction (CI), coronary heart disease (CHD), proteinuria, diabetic retinopathy, neuropathy, hypertension, and cigarette smoking was evaluated. In addition, biochemical data including fasting plasma glucose, hemoglobin (HD)Alc, cholesterol, triacylglycerol, high- and low-density lipoprotein cholesterol, uric acid, blood urea nitrogen (BUN) and creatinine (Cr) were studied. In univariate analysis, PVD was associated with an increased level of systolic blood pressure (SBP), BUN and Cr, cigarette smoking, CI, CHD, proteinuria and retinopathy. In stepwise logistic regression analysis, the level of SBP, cigarette smoking and CI remained statistically significant. The log odds of PVD could be expressed as: 2.834 + 0.013 (SBP in mmHg) + 0.577 (cigarette smoking) + 1.320 (CI). PVD is the result of aggregation of atherosclerotic risk factors; among those factors noted in this study, SBP, cigarette smoking and CI are important. PMID- 7858449 TI - Effect of octreotide on hemodynamics and glucagon levels in portal hypertensive rabbits. AB - This study was designed to investigate the effect of octreotide (Sandostatin, Sandoz), an analogue of somatostatin, on the hemodynamics and glucagon level in portal hypertension. Sixteen portal hypertensive rabbits produced by partial ligation of the portal vein two weeks earlier received an intravenous infusion of octreotide at a dose of 30 micrograms/h. After infusion of octreotide, a significant reduction in portal venous pressure from 16.2 +/- 3.9 mmHg (mean +/- SD) to 13.3 +/- 4.3 mmHg at 21 minutes and 12.0 +/- 4.5 mmHg 42 minutes was noted. A persistent decrease in portal pressure to 11.0 +/- 4.5 mmHg 21 minutes after stopping infusion of octreotide was also observed. Portal venous blood flow was decreased significantly from 60.9 +/- 13.1 mL/min to 46.9 +/- 15.0 ml/min at 21 minutes and to 45.8 +/- 12.8 ml/min at 42 minutes. A slight elevation of portal blood flow to 49.0 +/- 14.1 ml/min was noted 21 minutes after cessation of octreotide infusion. Portal venous resistance was slightly elevated during infusion of octreotide (before infusion: 2.2 +/- 1.4 dyne.s.cm-5, 21 minutes after infusion: 2.4 +/- 1.4 dyne.s.cm-5 and 42 minutes after infusion: 2.3 +/- 1.3 dyne.s.cm-5), and decreased (1.9 +/- 1.0 dyne.s.cm-5, p < 0.1) with a forward significance after stopping infusion. There were no significant changes in systemic arterial pressure during this experiment. A significant decrease (p < 0.05) in glucagon level from 323 +/- 93 pg/dl to 267 +/- 62 pg/dl at 21 minutes and to 298 +/- 88 pg/dl at 42 minutes in the portal vein was noted during the infusion.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7858451 TI - Surgical treatment of acute type A aortic dissection with an intraluminal sutureless graft. AB - The surgical treatment of acute type A aortic dissection remains a great challenge to all cardiac surgeons. From January 1991 to June 1993, 21 consecutive patients (13 men and eight women, aged 34 to 74 years) underwent emergency operations to repair acute type A aortic dissection, with the aid of hypothermic circulatory arrest. The intima tear was located in the ascending aorta in 13 patients, in the aortic arch in five patients, and in the descending aorta in three patients. The dissected ascending aorta was replaced with sutureless, intraluminal vascular grafts in all 21 patients. The intima tears in the aortic arch of five patients were primarily repaired. Modified Cabrol's shunts were created in seven patients for hemostasis, and Dacron grafts were used to wrap the ascending aorta in 18 patients. Retrograde cerebral perfusion during circulatory arrest was performed on 15 patients. The circulatory arrest time was 37 +/- 10 minutes (mean +/- SD). All patients survived the operation and regained consciousness in the early postoperative period without neurologic deficit. Post treatment follow-ups (mean, 18.2 months) were completed in all patients except one, who died 12 months after the operation as a result of a traffic accident. All of the surviving patients are doing well without any further aortic operations. Our experience suggests that surgical repair of the acute type A aortic dissection can be a simple and safe procedure if sutureless intraluminal grafts are used and hypothermic circulatory arrest and retrograde cerebral perfusion are utilized. PMID- 7858450 TI - Comparison of the pharmacologic action of two isoquinoline alkaloids on rat cardiac tissue. AB - We investigated the action of two synthetic isoquinoline alkaloids, 3,4 dihydroxybenzyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (CSH109) and 2-bromo 3,4-dimethoxybenzyl 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (CSH118) on rat cardiac tissue. In the right atria, CSH109 increased the amplitude of contractions and spontaneous beats dose-dependently. In the driven left atria and right ventricular strips, CSH109 caused a similar increase in contractions. The positive inotropic and chronotropic actions of CSH109 were antagonized by propranolol. CSH118 caused the spontaneous beats in the right atria to slow down. CSH118, however, failed to antagonize the positive inotropic effect and positive chronotropic effect of isoprenaline. Electrophysiologic study revealed that 3 microM CSH118 markedly reduced fast action potential upstroke and prolonged the action potential duration (APD50) of rat ventricular cells from 34 +/- 8 msec to 122 +/- 29 msec (n = 6). CSH109 prolonged APD50 slightly from 24 +/- 4 msec to 38 +/- 7 msec (n = 4). Under voltage clamp conditions, CSH109 significantly increased the L-type calcium inward current (ICa). The TTX-sensitive sodium inward current (INa), transient outward (Ito) and late outward current (I800), however, were unaffected. The increase in ICa by CSH109 was effectively antagonized by propranolol. Contrary to the action of CSH109, CSH118 strongly suppressed INa, ICa, Ito and I400. The inhibition of INa by 1.5 to 9 microM CSH118 was associated with negative shifting of its steady state inactivation curve. It is concluded that CSH109 exerts a cardiac effect by activating the B adrenoceptor. CSH118, however, is a broad spectrum ionic channel blocker. PMID- 7858452 TI - Use of microwave tissue coagulator in hepatocellular carcinoma resection: compared with Lin's hepatic clamp. AB - Fifty-nine patients with hepatocellular carcinoma (HCC) underwent resection with the aid of a microwave tissue coagulator at the Department of Surgery, National Taiwan University Hospital from July 1987 to December 1992. There were 41 men and 18 women with an average age of 59.2 years (range, 32-79 years). The intraoperative blood transfusion included packed RBC 1.53 +/- 1.34 U, fresh frozen plasma 3.85 +/- 1.69 U and/or platelet 1.58 +/- 3.07 U. The operation time from skin incision to skin closure was 250 +/- 74.9 minutes (range, 125 range, 495 minutes) and the average hospital stay was 20 +/- 9.7 days (nine to 50 days, median 17 days). The complication rate was 16.9% (10/59), including two with biliary fistula, prolonged impaired liver function and pleural effusion. Subphrenic abscess was seen in one patient and ascites in three. There was no operative mortality. Compared to 34 patients who underwent similar hepatic resections for HCC carcinoma with the aid of Lin's hepatic clamp, there was no statistical difference between the operation time, and intraoperative blood transfusion. However, the hospital stay was shorter in the microwave group. The change in liver function was also less remarkable in the microwave group and the postoperative complication rate was lower. We conclude that the application of microwave tissue coagulator is useful and safe in the resection of HCC. PMID- 7858453 TI - Prediction of outcome in omphalocele and gastroschisis by intraoperative measurement of intravesical pressure. AB - A simple and accurate measurement of intraabdominal pressure is essential to predict a successful closure of defects in omphalocele and gastroschisis. Intravesical pressure (IVP) is a close estimation of intraabdominal pressure and can be measured safely by placing a catheter in the urinary bladder during surgery. Three neonates with gastroschisis and four with omphalocele were studied. Pressure-related complications such as ascites leakage, ventral hernia, impaired venous return of the lower extremities, and oliguria developed only in the patients with IVP > 20 mmHg after fascial closure. Prolonged hospitalization, ventilation support and intensive care were required for these patients. PMID- 7858454 TI - Endourologic management of impassable urethra stricture. AB - Visual internal urethrotomy with the help of suprapubic urethroscopy and rectal digital palpation is an effective method of treating impassable urethral stricture. This technique was used to treat 25 male patients with completely obstructed membranous urethral stricture and three female patients with total obliteration of the urethra. The technique is relatively easy and safe and has produced satisfactory results. This procedure should be the management of choice when the impassable urethral segment is shorter than 2.5 cm. It is also very effective and safe in treating urethra stricture in females. PMID- 7858455 TI - Trichophyton tonsurans infection in Tainan area. AB - We report a clinicomycologic study of eight culture-proven cases (diagnosed from May 1991 to June 1992) of Trichophyton tonsurans (T. tonsurans) infection in Tainan. T. tonsurans is the most common cause of tinea capitis in the United States and Mexico; Trichophyton violaceum (T. violaceum) is the most common cause in South Africa, India, Jordan and the Far East. To date, there has been no written report of infection caused by T. tonsurans in Taiwan. We report six cases of tinea capitis and two cases of tinea corporis which were proven to be T. tonsurans infection. In this small series, as in our previous series on T. violaceum infection, a predominance of adults of the female gender was noted. The median age of the adults was 58 years. The only child patient was an eight-year old girl with tinea capitis whose mother was also infected. We have observed T. tonsurans infection with an increasing frequency over the last two years in Tainan. In the future, one would expect an increased incidence of T. tonsurans infections in other parts of the country, especially in adjoining cities. Dermatologists should be increasingly alerted to the possibilities of T. tonsurans as an etiologic agent in fungal infection. PMID- 7858456 TI - Percutaneous lumbar discectomy: indications and surgical results in 35 consecutive cases. AB - Thirty-five patients (27 men and eight women) who met our criteria of case selection for percutaneous lumbar discectomy (PLD) were treated by this method during the period May 1992 to June 1993. Thirty-six spaces, including one man with double disc disease, were decompressed. Patients ranged in age from 14 to 64 years. All patients but one were followed up for a minimum of six months. The operative results, evaluated by a more objective functional grading system, revealed a short-term (two months) success rate of 83% and a mid-term (six months) success rate of 76%. This discrepancy resulted from two recurrences of sciatic symptoms. It indicates that the medical conditions of those who have received PLD are by no means static, but instead may fluctuate. The operative result was similar to that of open discectomy, averaging 81.1% in reported series. Our "functional grading system" reflects these fluctuations quantitatively. With respect to the operative success rate, there was a statistical difference between the very good, good and fair-poor indication groups of patients, as were categorized by our major criteria of indications that included three clinical manifestation criteria and the other three radiographic findings. This result emphasizes the critical role of case selection in the operative success rate. Complications consisted of one disc infection which cleared without sequelae. This study provides an objective means of selecting cases and evaluating surgical results which, in turn, makes the use of this procedure convincing and predictable. PMID- 7858457 TI - Adult Fanconi syndrome with proximal muscle weakness and hypophosphatemic osteomalacia: report of a case. AB - A 42-year-old female presented with progressive proximal muscle weakness, generalized hyperreflexia, marked bone pain, severe lumbago and knee arthralgia. Electromyographic study showed short-duration (5-10 msec), variable amplitude (200-2500 microV) polyphasic potentials. A muscle biopsy specimen revealed non specific type II fiber atrophy. After a comprehensive laboratory work-up, adult Fanconi syndrome was diagnosed. The patient's symptoms, including bone pain and proximal muscle weakness, were relieved after a six-week supplement of tricalcium phosphate, vitamin D3 and sodium bicarbonate. The hyperreflexia also became less brisk. PMID- 7858458 TI - Ischemic colitis caused by an isolated dissecting aneurysm of the left colic artery: a presumed case of segmental mediolytic arteriopathy. AB - A 54-year-old male suddenly developed cramping abdominal pain followed by diarrhea. A segmental narrowing with multiple mucosal ulcers of the colon near the splenic flexure was noted on both barium enema and fiberoptic colonoscopy. Cramping abdominal pain and diarrhea persisted, associated with a body weight loss of 13 kg. Four months later, angiography revealed an isolated, complete occlusion of the left colic artery near the point of branching from the inferior mesentery artery. The artery was biopsied and the severely strictured colon was removed. The artery showed an eccentric organized hematoma between the outer media and the adventitia. The lumen was occluded by organized thrombi. The pathologic findings were those of an organized dissecting hematoma (aneurysm), probably caused by segmental mediolytic arteriopathy. PMID- 7858459 TI - Acute confusion induced by a high-dose infusion of 5-fluorouracil and folinic acid. AB - A 61-year-old man was treated with combination chemotherapy incorporating cisplatinum, etoposide, high-dose 5-fluorouracil (2,250 mg/m2/24 hours) and folinic acid for an inoperable gastric adenocarcinoma. He developed acute neurologic symptoms of mental confusion, disorientation and irritability, and then lapsed into a deep coma, lasting for approximately 40 hours during the first dose (day 2) of 5-fluorouracil and folinic acid infusion. This complication reappeared on day 25 during the second dose of 5-fluorouracil and folinic acid, which were then the only drugs given. Because folinic acid was unlikely to be associated with this condition, neurotoxicity due to high-dose 5-fluorouracil was highly suspected. The pathogenesis of 5-fluorouracil neurotoxicity may be due to a Krebs cycle blockade by fluoroacetate and fluorocitrate, thiamine deficiency, or dihydrouracil dehydrogenase deficiency. High-dose 5-fluorouracil/folinic acid infusion therapy has recently become a popular regimen for various cancers. It is necessary that both oncologists and neurologists be fully aware of this unusual complication. PMID- 7858460 TI - Dupuytren's contracture: report of a Taiwanese case. AB - This case of Dupuytren's contracture was seen in a 65-year-old Taiwanese male farmer patient. The patient complained of a progressive inability to fully extend the ring and middle fingers of his dominant hand over the last three years. Clinically, a longitudinal cord-like mass surrounded the distal palmar crease of the hand and digital flexion contraction of the ring finger was more affected than the middle finger. Histopathologically, the excised tissue was of a mixed, moderate and scantily cellular type. After surgical treatment by limited fasciectomy, the patient's hand recovered fully. No recurrent contracture was noted after three years of follow-up. PMID- 7858461 TI - Unilateral cheiro-oral syndrome in a patient with bilateral subdural hematomas. AB - We report a 49-year-old man with acute intermittent perioral and distal hand sensory dysfunction on the left side (cheiro-oral syndrome). The responsible lesion was confirmed by magnetic resonance imaging to be bilateral subdural hematomas with the larger side compressing the middle and lower thirds of the right postcentral gyrus. We emphasize that subdural hematoma should be considered in the differential diagnosis of cheiro-oral syndrome. PMID- 7858462 TI - [The development of a graft of embryonic mediobasal hypothalamus in the 3rd cerebral ventricle of the adult rat]. AB - Development of the mediobasal hypothalamus from 15-day rat foetuses and 8-week human foetuses transplanted in the 3rd ventricle of the adult rat brain has been morphologically analyzed. The graft was shown to fill the ventral area of the 3rd ventricle and integrate with the host brain, as was especially distinct in the region of optic chiasma. The graft was abundantly vascularized and its vessels connected with the host brain vessels. The graft neurons were normally differentiating in situ. Some neurons migrated in the host brain. The graft neuropile ultrastructure was characterized by the abundance of synaptic contacts. Some graft neurons expressed dopaminergic phenotype by synthesizing tyrosine hydroxylase and DOPA-decarboxylase and displaying specific capture of 3H dopamine. Dopaminergic axons of the neurons were spreading both within the graft and penetrating in the host tissue, especially in the region of optic chiasma and tracts. Unlike allotransplantation in rats, survival of xenotransplants of the human embryonic nervous tissue in the 3rd ventricle of the adult rat brain was possible only under the conditions of constant immunosuppression. PMID- 7858463 TI - [The characteristics of eye regeneration in newts after complete retinal detachment induced by a change in the effect of gravitation in an experiment using a clinostat]. AB - Morphological changes and proliferative activity of the neural retina cells after the neural retina detachment were studied in the newts subjected to microgravity in a clinostat. According to theoretical calculations, simulated microgravity could vary from 3.21 x 10(-2) to 8.05 x 10(-3) g. These conditions had a positive effect on morphological and functional restoration of the neural retina according to various criteria. Specifically, the increased number of Mullerian glial cells, increased relative volume of the plexiform layers, decreased mortality of the detached neural retina cells and increased redifferentiation of the retinal pigment epithelium and reattachment of the neural retina were observed. These changes were mainly found in the dorsal and central areas of the neural retina. PMID- 7858464 TI - [The effect of chemical mutagens on mammalian spermatogenesis. A cytogenetic analysis]. AB - It was shown using the micronucleus test and estimating the defects of sperm heads that premeiotic and meiotic mammalian cells are genetically very sensitive to Dipin and nitrosomethylurea. In rats, unlike mice, the stem and differentiating spermatogonia with serious chromosomal defects are not eliminated and pass through a "sieve" of mitotic and meiotic divisions reaching the stage of round spermatids. Our observations suggest long-term preservation Dipin-induced, rather than nitrosomethylurea-induced, mutations in the stem cells of both mice and rats. PMID- 7858465 TI - [The molecular-cellular regulation of the mitochondrial respiratory chain]. AB - We propose a new concept of molecular-cellular regulation of the mitochondrial respiratory chain. According to this concept, the cell uses acetaldehyde (AcA) as a main regulator of the respiratory chain. AcA expresses its action by changing the structural-functional state of ubiquinone, the key component of the respiratory chain. Studies were made on white random bred rats using the Langendorff's model of isolated perfused heart. We comparatively estimated the mechanometabolic state of myocardium under the conditions of simulated hypoxia of various degree, as well as in the presence of exogenous ethyl alcohol. Both hypoxia and ethyl alcohol induced severe disturbances of energy metabolism in the myocardium, cells at the level of respiratory chain due, apparently, to the increased content of free AcA. Hydroxyquinone and glycine, capable of binding free AcA, were used for pharmacological protection of the cells. Application of these drugs markedly improved the functional-metabolic state of the cell. We propose that AcA exerts both regulatory (in low doses) and inhibitory (in high doses) effect on the respiratory chain. The results obtained allow a novel insight in the processes of alcoholic and hypoxic damage and their pharmacological correction. It is evident that prophylactic and therapeutic measures in case of hypoxia or alcoholic intoxication should be first directed at decreasing the level of free AcA in the cell. PMID- 7858466 TI - [The antithrombotic and thrombolytic activity of a plasminogen activator isolated from a monolayer cell culture]. AB - Plasminogen activator has been isolated from the culture of pig kidney cells by gel-filtration on Sephadex G-75. The plasminogen activator (181.9 MU/200 g body weight) protected the animals against thrombosis hazard in case of provocation by thromboplastin and exerted a thrombolytic effect in case of thrombus appearance. PMID- 7858467 TI - [The effect of insulin on protein synthesis and secretion in primary liver cultures]. AB - The effects of insulin on the rates of synthesis of intracellular and secreted proteins have been studied in primary cultures of fetal rat hepatocytes. During 3 h incubation with the hormone and 14C-L-leucine similar stimulation of synthesis of both intracellular and secreted protein was observed. Insulin did not affect significantly the proportion of 14C-labelled proteins destined for secretion in the cell cultures grown on standard nutrient medium, as well as on selective medium containing phenobarbital and cortisol. The results obtained show that the major part (85-90%) of newly synthesized proteins remains inside the cells. Therefore, biological testing of insulin or its synthetic analogs on hepatocyte cultures may be limited by the estimation of the rate of biosynthesis of intracellular proteins only. PMID- 7858468 TI - [The late sequelae from the body exposure of healthy animals to a superlow dose of nitrosomethylurea]. AB - Time-related changes in essential internal organs (spleen, thymus, liver, kidney, and lung) and peripheral blood cells (leucocytes and large granular lymphocytes) were studied in healthy mice for 50 days after a single injection of 10(-15) M water solution of nitrosomethylurea. Mass and cellularity fluctuations were induced. The longest fluctuation period was 45 days (for the lung) and the shortest one was 15-20 days (for the liver and blood cells). Possible consequences of treatment with extra low doses of the biologically active drug for the organism are discussed. PMID- 7858469 TI - [Cellular self-synchronization in a hepatocyte culture with antiphase fluctuations in the intensity of protein synthesis]. AB - A part of suspension with isolated hepatocytes was cooled and then warmed to normal temperature. In cultures formed with such cells, antiphase oscillations of the protein synthesis rate were detected concerning control cultures from another part the same hepatocyte suspension. Oscillations of protein synthesis were observed in the mixed cultures formed with equal parts of antiphase subpopulations of hepatocytes. The experiments established cell interactions in vitro resulted in synchronization of protein synthesis oscillations in different cells the same population. PMID- 7858470 TI - [The comparative characteristics of crystalline lens and limb regeneration in newts operated on before and after the completion of an orbital space flight]. AB - It has been already established that a tendency towards synchronization and acceleration of the forelimb and lens regeneration is observed in Pleurodeles waltlii under the effect of space flight factors. Here we present the results obtained after 16-day space flight of two groups of newts. In animals of group I forelimbs were amputated and lenses were removed 14 and 7 days before the space flight, respectively. Intact animals of group II were operated on the day of the sputnik landing. Regenerates of the flight and corresponding control animals were fixed at the same time after the operation. For evaluation of the regeneration rate morphological criteria were used: morphological stages of regeneration were compared in the experiment and the control. For quantitative assay of the regeneration rate we determined the index of nuclei labelled with 3H-thymidine in the blastema and lens rudiment cells and used morphometry of the lens regenerates. Acceleration of forelimb and lens regeneration was observed in both groups of animals. In group II more than two-fold increase of the index of labelled nuclei was found in the blastema cells at the comparable stages of development. The size of lens regenerates in flight groups I and II exceeded reliably those in the control animals. The results obtained suggest a prolonged effect of the space flight factors on forelimb and lens regeneration. Under the conditions of space flight the lens regenerates reached more advanced stages of regeneration, as compared with the control animals operated after the space flight. These results also suggest acceleration of regeneration in lower vertebrates. PMID- 7858471 TI - [The effect of chemical mutagens on mammalian spermatogenesis. A quantitative evaluation]. AB - A quantitative analysis of spermatogenesis in mice and rats has shown that the response of various germ cells to cytotoxic effects of Dipin or NMU differs. The spermatogonial compartment consisting of actively proliferating cells and some stem cells are the main targets for these drugs. The advanced I order spermatocytes, spermatids and spermatozoa proved to be less susceptible. Species specific differences have been established in the character of destructive and restorative processes during spermatogenesis. PMID- 7858472 TI - [The possible role of the harderian gland in the chemical communication of the hamster (Mesocricetus auratus Waterhouse, 1839)]. AB - The hypothesis was tested on involvement of the Harderian gland in chemical communication of the Syrian hamster (Mesocricetus auratus), a species in which smelling plays a leading role in initiation of many forms of social behavior. Experiments have been carried out, in which homo- and heterospecific olfactory stimuli were presented to recipients (adult males, n = 45). When the Harderian gland homogenates from males and females of the same species were presented in microtubes, the recipient males examine the female Harderian gland homogenates reliably longer. In an "open field" chamber the males spent more time near the box with the sawdust bedding from intact females than with the sawdust bedding from males or Harderectomized females. The control box was of least interest to them. When the immobile model was presented the frequency of behavioral elements of the male recipients characteristic of the reaction to a female decreased while that of elements typical for the reaction to a male increased in a sequence: female--male with applied vaginal secretory substance--male with the applied female Harderian gland homogenate--male. When the Harderian gland homogenates from the Syrian hamster and Campbell hamster female were presented, the homospecific stimulus was examined longer. Thus, the Harderian glands of the Syrian hamster produce olfactory stimuli with an attractive effect and containing information about species and sex. Besides, the Harderian gland homogenate masks the smell of an immobile male and stimulates, to some extent, elements of sexual behavior. PMID- 7858473 TI - [The lipid-secreting skin glands in the common hamster (Cricetus cricetus Linnaeus, 1758)]. AB - The Harderian gland and glands of the oral angle structure and processes of secretion in the common hamster have been studied under light and electron (scanning and transmission) microscopes. Both these glands were shown to be lipid producing. Nevertheless, their epithelial cells differ in ultrastructure. The Harderian gland has tubulo-alveolar architecture and consists of two types of epithelial cells. The oral angle gland is acinar and contains differentiating cells of the third type. The possibility of synthesis of various lipids by these three types of cells is discussed. PMID- 7858474 TI - [The fertility and age composition of the mammalian populations in a primary tropical forest in eastern Indochina]. AB - Stepanian (1991, 1992) proposed that the prosperity of avian populations in the tropical forest is based on preservation of the highest possible number of older generations during the longest possible period at the expense of youngs. We have tested this hypothesis with reference to mammals inhabiting some ecosystems. Comparison of the data on reproduction and abundance of mammalian populations (some species of the Sciuridae and Felidae) in the tropical forests and in the northern latitude areas suggests that this hypothesis is also valid for the mammalian populations of the tropical forests. PMID- 7858476 TI - Screening for colon cancer. PMID- 7858475 TI - [The distant interaction of the cells in a hepatocyte culture. The population rhythm of protein synthesis]. PMID- 7858477 TI - Serodiagnosis of Helicobacter pylori: evaluation of a rapid, miniaturized immunochromatographic test. AB - Diagnosis and successful eradication of Helicobacter pylori infection has been shown to be significantly related to symptom improvement in patients affected by chronic gastritis, duodenal and gastric ulcer. There is, therefore, an increasing need for the development of new, easy to use, reliable and non-invasive techniques to detect this organism. One such test is Flex-Sure (SmithKline Diagnostics Inc., United States), a new, rapid immunochromatographic test which requires a drop of the patient's serum to be placed on the absorbent pad of a strip. If specific antibodies to H. pylori are present a red colour line appears. The present study compared Flex-Sure with a homologous quantitative immunoenzymatic test (HM-CAP, EPI, US) using the same antigen (high molecular weight protein), the second generation GAP test (Bio-Rad, USA), a rapid urease test, culture and histology in a cohort of dyspeptic patients. We produced a semiquantitative visual scale with which to perform this comparison. Our results show that Flex-Sure possesses a sensitivity of 96.1%, a specificity of 73.9%, an overall accuracy of 78.8%, a positive predictive value of 72% and a negative predictive value of 91.6%. It showed a highly significant correlation with histological and cultural results (P < 0.001), and with the other serological tests (P < 0.0001). Based on our data we conclude that Flex-Sure may yield quick (within 4 min), simply readable, qualitative, and according to our colourimetric scale, even semiquantitative results. Furthermore, it does not require any sample dilution, any particular equipment, or any specialized training for the operator. PMID- 7858478 TI - Recreational physical activity and risk of benign proliferative epithelial disorders of the breast in women. AB - The association between recreational physical activity and the risk of benign proliferative epithelial disorders (BPED) of the breast was examined in a case control study conducted in Adelaide, Australia, between 1983 and 1985. The study included 383 incident, histologically confirmed cases of BPED identified through the major private pathology laboratory, 383 unbiopsied community controls matched to the cases for age and area of residence, and 192 controls whose biopsies did not show any signs of epithelial proliferation. Subjects reported their level of usual weekly physical activity in a self-administered questionnaire. When cases were compared with community controls, there was some evidence for a negative association between risk of BPED and total recreational physical activity. However, the reverse was observed when the cases were compared with biopsy controls. These patterns were essentially the same when examined by intensity of activity and by menopausal status. Despite the lack of an association between physical activity and risk BPED in this study, further investigation is warranted because of the potential benefits for the primary prevention of breast disease. PMID- 7858479 TI - DNA methylation as an intermediate biomarker in colorectal cancer: modulation by folic acid supplementation. AB - Several studies have suggested that DNA hypomethylation is an early step in colorectal carcinogenesis. However, it is not clear at which stage in carcinogenesis this hypomethylation occurs, what promotes it, the extent to which it can be reversed and the consequences of such reversal in affecting tumour development. In an attempt to address some of these questions, we studied three groups of subjects with similar age and gender distributions: a group of 12 patients with colorectal carcinomas; a group of 12 patients with colorectal adenomas; and a group of eight healthy control subjects. Two experimental protocols were employed. In the first protocol, intrinsic DNA methylation was evaluated in neoplastic and in normal-appearing rectal mucosa of patients with colonic carcinomas or adenomas, compared with a group of healthy controls. In the second protocol, we examined, in a prospective and controlled fashion, the effect of folic acid supplementation (10 mg/day) on the degree of DNA methylation of rectal mucosa from those same patients after removal of the neoplasms. The degree of intrinsic DNA methylation was assessed on the basis of the capacity of the DNA isolates to serve as methyl acceptors in in vitro incubations that contained DNA methylase and [3H-methyl] S-adenosylmethionine. Intrinsic DNA methylation was significantly lower in carcinomas than in adenomas (P < 0.005). In addition, normal-appearing rectal mucosa from patients with carcinomas was significantly less methylated than in healthy controls (P < 0.005); the mean value found in the latter was also greater than the value observed in patients with adenomas, but not significantly so (P > 0.05).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7858480 TI - Thyroid cancer: reproductive factors, previous diseases, drug intake, family history and diet. A case-control study. AB - An association between female sex hormones and thyroid cancer has been suggested, but the only well-established risk factor is ionizing radiation. This case control study was designed to evaluate the association between different aetiological factors and thyroid cancer and encompassed 180 cases aged 20-70 years at the time of diagnosis in 1980-89, and 360 controls. The response rate was 92%. A history of one pregnancy gave increased risk for papillary thyroid cancer, odds ratio (OR) = 3.1, 95% confidence interval (CI) = 1.0-11, whereas no increased risk was found for > or = four pregnancies. Age > or = 25 years at the time of the first pregnancy showed a non-significantly increased risk for papillary thyroid cancer, OR = 1.5, 95% CI = 0.8-3.0. Use of oral contraceptives before the age of 20 years gave an OR of 0.5, 95% CI = 0.1-1.3. A history of asthma or allergy, or the use of cortisone, significantly decreased the risk, while cardiovascular disease in men increased the risk of developing thyroid cancer. In the logistic regression, use of cortisone decreased the risk, while one pregnancy gave a significantly increased risk in papillary thyroid cancer. The results indicated that endogenous hormones may play a role in the aetiology of thyroid cancer in women. PMID- 7858481 TI - The application of different correlation coefficients to assess the reproducibility of a food frequency questionnaire. AB - We computed four different correlation coefficients to investigate the degree of reproducibility of the weekly consumption of 77 food items or groups of foods and of seven summary questions from a food frequency questionnaire developed in Italy for a case-control study on cancers of the breast and digestive tract. The questionnaire had been administered twice to 452 Italian men and women. These included Pearson correlation coefficients (a) using the weekly frequencies of consumption without any transformation (P1); (b) after applying the transformation log (x + 1) (P2); (c) after applying the transformation log (x + 0.01) (P3); and (d) the Spearman correlation coefficient (SP). The mean values were 0.55 for P1, 0.59 for P2, 0.56 for P3 and 0.59 for SP. All coefficients were positively correlated, although to variable extents: the Spearman correlation coefficient between P2 and SP was 0.92, and that between P1 and P3 was 0.53. Differences between the four coefficients were more marked for food items with a lower kappa statistic and lower intraclass correlation, ie for those items with more severe reproducibility problems. Thus, a single correlation coefficient may not be enough to detect zones of the distribution of a food item where misclassification problems are more severe. The correlation coefficients used to investigate reproducibility should therefore be chosen on the basis of subsequent data analyses. PMID- 7858482 TI - Effects of recombinant bovine somatotropin implants on serum concentrations of somatotropin, insulin-like growth factor-I and blood urea nitrogen in steers. AB - Four cross-bred beef steers averaging 346 kg were used in a 4 x 4 Latin square design to determine the effect of prolonged-release recombinant bovine somatotropin (rbGH) implants on serum concentrations of somatotropin (GH), insulin-like growth factor-I (IGF-I) and blood urea nitrogen (BUN). Recombinant bGH implants of 0, 40, 80 or 160 mg were administered subcutaneously in the tailhead during the 4 trial periods. Each steer received each treatment starting at 06:00 on day 0 with 21 days between treatments. Jugular vein blood samples were collected on days 0, 1, 2 and 3 (4 day time course for GH, IGF-I and BUN) and every 15 min (GH profile) for 6 h on day 3. Serum baseline GH values were higher (P < 0.10) for the 80 and 160 mg treatments than for the control, and peak amplitude was decreased (P < 0.05) by the 40 and 160 mg treatments. There was a trend (P < 0.11) for fewer GH peaks during the 160 mg treatment. Somatotropin concentrations decreased from day 1 to day 3 (P < 0.05) in a linear manner. Serum IGF-I concentrations increased (P < 0.05) in a linear dose-dependent manner from the 0 mg to the 160 mg treatment. BUN concentrations were not significantly altered by rbGH treatment. Results from this experiment indicate that rbGH implants significantly increase serum IGF-I and GH baseline concentrations while suppressing GH peak amplitude in finishing steers. PMID- 7858483 TI - TaqI restriction fragment length polymorphisms for growth hormone in bovine breeds and their association with quantitative traits. AB - The objectives of the present study were (1) to reveal GH-TaqI RFLPs in different bovine breeds and (2) to look for association between quantitative traits and GH TaqI RFLPs in bulls highly selected for growth and meat production. Blood was sampled from 269 Holstein heifers, 48 Italian and 45 Hungarian Simmental heifers, 30 Normande heifers and 41 bulls and 13 heifers of the double-muscled Belgian White Blue breed. Bulls were weighed from 7 until 13 months of age and the average daily gain, the feed efficiency, the height and the phenotypic index were determined at the end of the experiment. GH-TaqI RFLPs revealed 4 DNA fragments of 6 (A), 5.2 (B), 4.4 (C) and 4.2 (D) kbp. The distribution of genotypes was different between Normande and the other breeds (P < 0.001) and between Belgian White Blue and Holstein (P < 0.001) or Hungarian Simmental breed (P < 0.005). The Normande heifers were also characterized by a high frequency of the AB genotype (53%) compared with other experimental breeds (range values: 7-24%). In the statistical analysis of the relationships between quantitative traits and GH-TaqI RFLPs in double-muscled Belgian White Blue bulls, the AC genotypic class was not used because of its low distribution. The AA class showed greater records of weight at 7 (P < 0.07) and 13 (P < 0.06) months of age than the AB class. In conclusion, this study has shown a correlation between the GH-TaqI RFLPs and weight at 7 and 13 months of age in Belgian White Blue bulls.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7858484 TI - Hepatic growth induced by injection of the liver growth factor into normal rats. AB - Normal Wistar rats injected with the liver growth factor (LGF), a mitogen specific for liver cells, experienced hepatic growth. LGF shows two peaks of activity in vivo, both of them mitogenic. Rats injected either with 6.8 ng or 3.9 micrograms LGF/rat every 3-4 days experienced liver growth showing a see-saw profile. Dry liver weight usually peaked at day 2 (microgram doses) or at day 3 (ng doses) after each injection, with increases of about 30% over controls. Liver DNA synthesis, measured by [3H]-thymidine incorporation, peaked 24 h after LGF injection at both doses. Liver protein synthesis, measured by [14]C-leucine incorporation, usually peaked 24 h after DNA synthesis maximums. Mitogen stimulated cells were also assessed by immunohistochemical staining for proliferating cell nuclear antigen in livers of LGF-injected rats. Rats injected with rat serum albumin purified from normal rats to serve as controls showed a 6% increase in dry liver weight, but when serum albumin from 3-day fasted rats was injected instead, the increase was not statistically significant. The mild effect of rat serum albumin could be due to the lipid content of the solutions injected, but the level of lipids/mg protein in LGF solutions was half that determined with serum albumin from 3-day fasted rats. From the microscopic and ultramicroscopic studies carried out in rat livers injected with LGF at each dose, we observed: (1) an increase in the number of hepatocytes undergoing mitosis; (2) transient increases in lipid and glycogen contents, as occur after liver resection; (3) no signs of degeneration, such as the appearance of amyloids or fibrosis; (4) no increase in lysosome number, as in hepatotoxicity; (5) no alterations in endothelial or Kupffer cells; and (6) no ultrastructural signs of degeneration either in cytoplasmic organelles (rough endoplasmic reticulum, mitochondria) or in nuclei. One year after LGF injection, rat liver, pancreas, kidneys and spleen were normal, with no signs of degeneration or onset of fibrosis. PMID- 7858485 TI - Effects of growth hormone and insulin-like growth factor-I on the proliferation and differentiation of cultured pig bone cells and rat calvaria cells. AB - Growth hormone (GH) increases bone formation in vivo in pigs. The capacity of GH and its mediator insulin-like growth factor-I (IGF-I) to influence bone cell proliferation and differentiation was investigated in cells isolated from trabecular and cortical bone of growing pigs, from fetal pig bone and from newborn rat calvaria. GH enhanced the proliferation of confluent rat cells but did not affect that of either confluent or subconfluent porcine cells from trabecular, cortical or fetal bone. IGF-I increased the proliferation of confluent rat cells and subconfluent pig cells. GH slightly inhibited alkaline phosphatase (ALP) activity in pig cells of the three origins while IGF-I increased it in cortical cells. Collagen synthesis by pig cells was stimulated by IGF-I but not by GH. These results suggest that GH does not stimulate bone forming cells in pigs, and that GH and IGF-I affect cultured bone cells differently depending on the species or bone type they were isolated from. PMID- 7858486 TI - Growth hormone stimulates proliferation of normal human bone marrow stromal osteoblast precursor cells in vitro. AB - In this study the effects of growth hormone (GH) in human marrow stromal osteoblast-like [hMS(OB)] cell cultures containing a population of osteoblast precursors, were tested. GH (dose range 0.1-500 ng/ml) stimulated hMS(OB) cell proliferation in a dose-dependent fashion as evidenced by increased 3H-thymidine incorporation into DNA and increased cell number. Maximal stimulation was 173 +/- 35% (P < 0.001, n = 12) and 145 +/- 6% (P < 0.0001, n = 10) of no-treatment controls for 3H-thymidine incorporation and cell number, respectively. GH did not exert major effects on differentiation markers in hMS(OB) cell cultures. 1,25 dihydroxy vitamin D3 (10(-9) M) alone increased cellular production of alkaline phosphatase (AP) and induced expression of osteocalcin. When GH was tested in combination with 1,25(OH)2D3, it tended to inhibit vitamin D-stimulated effects on differentiation markers but these effects were not statistically significant. Our results suggest that GH induces proliferation of less differentiated cells in the osteoblast lineage and this mechanism may in part mediate the in vivo effects of GH on bone formation. PMID- 7858487 TI - Dyskeratosis congenita is a chromosomal instability disorder. AB - Dyskeratosis congenita (DC) is a rare inherited disorder characterized by dystrophic changes in the skin and mucous membranes, bone marrow failure, and a predisposition to malignancy. In the majority of families the pattern of inheritance of DC has been compatible with X-linkage, the most likely location being Xq28. The primary defect responsible for this disease remains unknown. As DC shares many features (congenital abnormalities, bone marrow failure) with the chromosomal instability disorder. Fanconi's anaemia (FA), several studies have focused on cytogenetic features in DC. Unlike in FA, cytogenetic studies on peripheral blood lymphocytes have shown no significant difference between DC and normal lymphocytes with or without prior incubation with clastogens (bleomycin, diepoxybutane, mitomycin-c, 4-nitroquinoline-1-oxide). However, studies on DC fibroblasts have shown abnormalities in both morphology (polygonal cell shape, ballooning, dendritic-like projections) and growth rate (doubling time about twice normal), as well as numerous unbalanced chromosomal rearrangements (dicentrics, tricentrics, translocations) in the absence of any clastogenic agents. Bone marrow metaphases from one out of three patients studied (the eldest of the three) also showed unbalanced chromosomal rearrangements in the absence of any clastogens. Cell-specific difference and a higher rate of chromosomal rearrangements in the older patients appear to correlate with the clinical evolution of the disease. These findings suggest that the DC defect predisposes DC cells to developing chromosomal rearrangements. PMID- 7858488 TI - Combined immunophenotyping and karyotyping in peripheral T cell lymphomas demonstrating different clonal and nonclonal chromosome aberrations in T helper cells. AB - Combined immunophenotyping and karyotyping was performed in seven cases of peripheral T cell lymphoma with complex aberrant clones. Various lymphocytic cell populations entered mitosis, whereas all aberrant cells belonged to the T helper/inducer cell population. Lymphomas with the same recurrent chromosome aberrations, i.e. inversion inv(14)(q11q32.1) and isochromosome i(8)(q10), had a very similar immunophenotype. The aberrant cells in these cases expressed CD3+, CD4+, CD7+, CD45RO+. The immunophenotypic similarity is underlined in one case of T prolymphocytic leukemia, in whom the aberrant cells lost the CD8 antigen originally present, during cultivation with PHA. In one case of Sezary's syndrome, two or possibly even three different clones as well as nonclonal aberrations were identified within the T (helper/inducer) cell population, providing further evidence that chromosomal instability is a characteristic feature of cutaneous T cell lymphoma. PMID- 7858490 TI - Aggressive chemotherapy for acute leukemia relapsed after transplantation. AB - Bone marrow transplantation procedure has emerged as an effective treatment for hematological malignancies. However, recurrence of leukemia is still the major cause of treatment failure. Subsequent treatment in this category of patients, generally considered incurable, has not been yet standardized. At our institution, 13 patients, 7 with acute non lymphoid leukemia (ANLL) and 6 with acute lymphoid leukemia (ALL), were treated at relapse after bone marrow transplantation either autologous or allogeneic (AuBMT 8, ABMT 4) performed in complete remission (CR). The interval between BMT and relapse was less than 9 months in 6 patients (2 ABMT and 4 AuBMT) and more than 9 months in 7 patients. Early relapsed patients showed no response to treatment and died at a median of 5.5 months (range 1-13) after relapse. Late relapse after BMT was characterized by a high percentage of response (5 CR and 1 PR), particularly after intensive chemotherapy and by a longer survival (median 14 months; range 2-36). Chemotherapy after transplantation should be carefully evaluated in patients relapsed after BMT in order to select a population that can achieve long term disease free survival. PMID- 7858489 TI - Idarubicin, high-dose cytarabine and etoposide for remission induction in therapy related acute myeloid leukemia. AB - Five patients with therapy-related acute myeloid leukemia received combination induction chemotherapy with idarubicin, high-dose cytarabine, and etoposide. Complete remission was achieved in all patients with a single course of therapy. Treatment-related toxicity included nausea, vomiting, mucositis, diarrhea, and liver and kidney function abnormalities, and was low in all patients. There were no deaths during induction therapy. We conclude that this combination is well tolerated in induction of remission in secondary acute myeloid leukemia, and warrants further assessment because of a very good complete remission rate. PMID- 7858491 TI - Expression and genomic configuration of GM-CSF, IL-3, M-CSF receptor (C-FMS), early growth response gene-1 (EGR-1) and M-CSF genes in primary myelodysplastic syndromes. AB - Peripheral blood mononuclear cells from seventeen patients with primary myelodysplastic syndromes (MDS) in advanced stage were enriched for blasts and tested for (1) karyotype, (2) genomic configuration and (3) expression of IL-3, GM-CSF, FMS and EGR-1 genes which are all located on the long arm of chromosome 5. The expression of the M-CSF gene, that has been recently reassigned to the short arm of chromosome 1 (lp), was also investigated. Aims of the study were to (1) assess the potential role of the expression of these genes in the maintenance and expansion of the neoplastic clones and (2) search for constitutional losses or rearrangements of one allele followed by a deletion of the second allele of the same genes in the leukemic cells. The latter issue was investigated by comparing, in 8 cases, constitutive DNA from skin fibroblasts with leukemic DNA. Eleven of the 17 patients had abnormal karyotypes. The M-CSF gene was expressed in 6 cases and the FMS and the EGR-1 genes were expressed in 2 of the latter cases. An autocrine mechanism of growth could be hypothesized only for the 2 patients whose cells expressed both the M-CSF and FMS genes. No germline changes or rearrangements were observed in any of the genes studied. Thus, deregulation of genes encoding for certain hemopoietic growth factors or receptors does not seem to represent a major mechanism of MDS progression. PMID- 7858492 TI - Pre-treatment with all-trans retinoic acid accelerates polymorphonuclear recovery after chemotherapy in patients with acute promyelocytic leukemia. AB - All-trans retinoic acid (ATRA) is currently being used as remission induction treatment for acute promyelocytic leukemia (APL). Conventional chemotherapy is added both during and after ATRA treatment, in order to avoid the occurrence of hyperleukocytosis, and to improve the duration of complete remission. In this study we analysed the hematopoietic recovery of 18 consecutive APL patients after standard Idarubicin or Daunorubicin +/- Cytosine-Arabinoside regimens. 9 of the patients were at the onset of the disease, (CHT group) while 9 had been pre treated with ATRA 45 mg/sqm/day for at least 3 months (ATRA group). 500 PMN/mmc were reached after 20.8 day from the end of treatment in CHT group and after 12.0 days in ATRA group (p = 0.007). Platelets recovery was faster, even though not significantly in ATRA group. Interestingly, PMN recovery in ATRA group was even shorter (p = 0.004) than that obtained in CHT group, after the first course of chemotherapy (treatment in CR vs treatment in CR). If these results are confirmed in a larger study, a protective effect of ATRA on normal residual hemopoiesis should be postulated. PMID- 7858493 TI - Recombinant human erythropoietin in the treatment of myelodysplastic syndromes- response patterns. AB - Different response patterns to recombinant human erythropoietin (rHuEpo) administration to anemic patients with myelodysplastic syndromes (MDS) are described. The biology of rHuEpo effect on erythropoiesis in patients with MDS has not been elucidated. However, until more biological information is obtained, it could be prudent to consider these response patterns as guidelines in the treatment of MDS. In the small but interesting series of nine patients with MDS only one responded to rHuEpo within the treatment period of eight weeks. Two additional patients continued the treatment on their own, and after 16 weeks a response was noted for the first time. A third patient was treated for only six weeks and a delayed response was recorded while off treatment for ten weeks. This response was also recorded 16 weeks from treatment initiation-as in the other two patients. A fourth patient with MDS developed transfusion related hemosiderosis and during iron chelation therapy the RBC transfusion rate dropped to a rate lower than the rate needed before the rHuEpo treatment. It is emphasized that in non responders, non-routine approaches should be considered. PMID- 7858494 TI - Low-grade lymphoma: clinical and prognostic studies in a series of 143 patients from a single institution. AB - Clinical and prognostic studies were carried out in a series of 143 patients with low-grade (small-lymphocytic, follicular small cleaved cell, follicular mixed small- and large-cell) lymphoma. After treatment with alkylating agents (21.5% cases), combination chemotherapy (73.3%) or other therapies (5.2%), complete response (CR) was obtained in 40.7% of cases and partial response (PR) in 43.7%. The stage of the disease was the most important factor for response. With a median follow-up of 6.5 years, 48.0% (95% Cl: 37.5-58.5) of patients were alive 10 years after diagnosis. Among the initial parameters, advanced stage. B symptoms, poor performance status, nodal involvement > 3 sites, extranodal involvement > or = 2 sites, WBC count > or = 10 x 10(9)/L, leukemic expression, high serum LDH levels, and bone marrow infiltration were all related to survival; treatment modality, however, had no influence on survival. In the multivariate analysis, stage (p = 0.008) and age (p = 0.053) were the most important prognostic factors. When considering response to therapy, both CR (p < 0.001) and PR (p = 0.003) emerged as the most important predictive variables, with only the absence of B-symptoms retaining its prognostic significance (p = 0.014) among the other parameters. In addition, in CR patients the duration of the response (< or = 1 year vs. > 1 year) was the most significant parameter for survival (p < 0.001). Finally, the initial stage (p = 0.011) and the histologic subtype (those patients with follicular mixed lymphoma relapsing less frequently than the others) (p = 0.052) were the only significant factors for relapse. PMID- 7858495 TI - Trisomy 12 in chronic lymphocytic leukemia and hairy cell leukemia: a cytogenetic and interphase cytogenetic study. AB - Fluorescent in situ hybridization (FISH) with a chromosome 12-specific pericentromeric probe was performed in 42 patients with B-cell chronic lymphocytic leukemia (CLL) and in 10 patients with hairy cell leukemia (HCL). In all cases, a normal karyotype in more than 10 metaphase cells was obtained by conventional chromosome study. FISH documented that 6/42 patients with CLL in fact had trisomy 12 in 15-49% interphase cells. Sequential FISH studies were performed in 2 cases, showing an increase of percentage of trisomic cells over a 2-month to 4-year period. Two out of 10 patients with HCL, one of whom had morphologic features consistent with a diagnosis of HCL variant, showed 5.5 and 10% interphase nuclei with three fluorescent signals, a finding suggestive of the presence of trisomy 12. Combined immunophenotyping and FISH staining in these patients with HCL documented that trisomic cells were CD11c-positive, CD13 negative, and CD2-negative. We conclude that FISH is a sensitive technique allowing for the detection of trisomy 12 in a fraction of cytogenetically normal patients affected with CLL and HCL. PMID- 7858496 TI - N- and K-ras oncogenes in plasma cell dyscrasias. AB - N- and K-ras oncogene mutations represent the most frequent molecular lesions in plasma cell dyscrasias. They are not randomly distributed since they are detectable in multiple myeloma (MM) (9-31%) and plasma cell leukemia (PCL) (30%), and not in monoclonal gammopathy of undetermined significance (MGUS) and solitary plasmacytoma (SP). Codons 12, 13 and 61 of N- and K-ras genes have been found mutated. Mutations affecting codon 61 of N-ras gene are the most frequent finding. A heterogeneous pattern of mutations is described with a prevalence of purine-pyrimidine transversions. Ras gene mutations have been predominantly detected in myelomas characterized by an advanced stage disease, and adverse prognostic parameters. These findings suggest that ras mutations represent a late molecular lesion and may be implicated in tumor progression rather than tumor initiation. PMID- 7858497 TI - Activity of fludarabine in refractory chronic lymphocytic leukemia and low grade non-Hodgkin's lymphoma--the Jerusalem experience. AB - Twenty four patients with refractory chronic lymphocytic leukemia (CLL) and advanced low grade lymphoma (LGL) were treated with Fludarabine given at a dose of 25 mg/m2, intravenously daily for 5 days, every 28 days. Ten of the patients with LGL were in terminal leukemic phase. All patients had received previous chemotherapy, most with multiple regimens. Patients received a mean of 5.1 cycles (range 1-9). 4 patients--one with CLL and 3 with LGL--achieved a complete remission, while 7 LGL and 3 CLL patients had a partial response. Two patients remain in complete remission 23 and 25 months after completion of therapy. One patient underwent successful autologous bone marrow transplantation after achieving a complete remission, while two others had marrow cryopreserved during complete remission. The drug was well tolerated and toxicity was mild. In 9 of the 122 given cycles patients required hospitalization. In conclusion, Fludarabine is active in refractory patients with CLL and LGL and induces complete and partial remissions in some. It seems that Fludarabine could be used as primary therapy in these disorders in the future. PMID- 7858498 TI - Parallel tubular granules in human immature neutrophils--an electron microscopic study. AB - Unique rounded granules consisting of clustered parallel tubules, 29-31 nm in diameter, with occasional, flocculent or amorphous electron-dense material (parallel tubular granules, PTGs) were found in immature neutrophils in the bone marrow in a case of chronic neutrophilic leukemia (CNL). PTGs were positive for electron microscopic myeloperoxidase. Since no structures similar to PTGs have been documented, we investigated the bone marrow of 65 adult patients with hematologic diseases, and 7 adult patients with miscellaneous non-hematologic diseases, by electron microscopy. The results showed that no PTGs were found in any cases other than the original CNL case. These findings suggest that PTGs are rare granules representing certain primary granules. In addition, the presence of PTGs might be helpful in diagnosing CNL. PMID- 7858499 TI - Recurrence of autoimmune thrombocytopenia after treatment with fludarabine in a patient with chronic lymphocytic leukemia. PMID- 7858500 TI - Apoptosis induced by DNA topoisomerase I and II inhibitors in human leukemic HL 60 cells. AB - The induction of apoptosis following topoisomerase inhibitors proceeds in at least three distinct steps: (1) induction of cleavable complexes (potentially lethal damage), (2) topoisomerase-induced DNA damage, and (3) a presently unknown sequence of events that must either lead to cell cycle arrest (G2-block, differentiation) or apoptosis. DNA degradation provides a convenient way to quantify apoptosis in HL-60 cells. Extensive apoptosis can be induced rapidly in undifferentiated HL-60 cells without prevention by cycloheximide or actinomycin D. Therefore, HL-60 cells appear to express constitutively the apoptotic machinery that may be kept under control of a yet unknown repressor. The absence of the tumor suppressor p53 and the presence of bcl-2 are in contrast with the sensitivity of these cells to apoptosis. Agents that modify chromatin structure (zinc, poly[ADPribose] inhibitors, spermine) can block DNA fragmentation without affecting cell survival. By contrast macrophage-like differentiation by phorbol esters suppresses apoptosis without affecting topoisomerase-induced DNA damage. Better understanding of the apoptotic regulation in the widely used and characterized HL-60 cell line should allow the identification of new mechanisms and parameters of cellular sensitivity and resistance to the cytotoxic activity of anticancer agents. PMID- 7858501 TI - Follicular dendritic cells in non-Hodgkin's lymphomas. AB - Follicular dendritic cells (FDC) are restricted to the B-cell regions of secondary lymphoid tissue and to non-Hodgkin's lymphomas derived from the follicular center or the mantle zone. With their cytoplasmic ramifications they form a dense network which contains the B-lymphocytes. In situ, FDC are only detectable at the ultrastructural level or when stained with anti FDC-reagents. On the surface of their dendritic extensions they express transferrin receptors (CD71), the B-cell epitope CD20, class II antigens, the myelomonocytic molecule CD14, the glycoprotein gp50 (CD40), and several receptors for components of the complement system (CD11b, CD21, CD35). Subsequent to an antigen challenge, FDC trap and retain immune-complexes for a long period of time. In vitro FDC and neoplastic lymphocytes spontaneously form small cellular aggregates. This adhesion is mediated by the LFA-1-alpha/beta = ICAM-1, the VLA-4 = VCAM-1, and the ICAM-1 = C3bi- receptor ligand pathways on B-cells and on FDC, respectively. The loss of LFA-1- alpha/beta and ICAM-1 molecules may enable neoplastic lymphocytes to detach from FDC. The monoclonal B-cells now invade new compartments. In vitro, FDC have the capacity to activate resting B-cells and to save them from dying by apoptosis. Signals involved in this activation include cell-surface immunoglobulin and CD40. Immunocytochemistry and autoradiography with single cell suspensions of neoplastic B cells suggest that FDC also provide signals leading to the continued stimulation of lymphoma lymphocytes. During the early stage of HIV infection lymph nodes show an immense follicular hyperplasia, with a massive increase of the dendritic network of FDC. In the later stage of the disease, the continuous involution of the germinal centers is associated with a progressive destruction of FDC. PMID- 7858502 TI - The role of immunophenotype in acute lymphoblastic leukemia of infant age. AB - The prognosis of acute lymphoblastic leukemia in infants is still significantly worse than that of older children. This is thought to be due to both clinical and biological factors, such as high white blood cell (WBC) counts at diagnosis, irregular or immature phenotypes, and molecular and cytogenetical abnormalities. In order to focus the significance of immunophenotypic analysis, we have reviewed the immunophenotypic studies of 145 infants under 18 months of age treated at the AIEOP centers from 1984 to 1992. Children have been divided in three age groups of six months each; WBC count at diagnosis has been evaluated both as mean values and within different categories (< 10.10(9)/L, > 100.10(9)/L). These have been studied in correlation with immunophenotype and with the expression of single, specific markers. A significant correlation has been found between young age, high WBC count and immature phenotypes. Common ALL was more frequent in older children and showed lower WBC counts. Moreover, event-free survival was significantly better in older children with WBC count < 100.00/mm3, with CD10+, MyAg- ALL. Therefore, we suggest that immunophenotypic analysis is still an important prognostic factor and can be usefully used, together with simple clinical data, to plan therapy for ALL in infants. PMID- 7858503 TI - Autoimmune thrombocytopenic purpura complicating lymphoproliferative disorders. AB - Thrombocytopenia in patients with lymphoproliferative disorders is usually multifactorial. In some patients, peripheral destruction of platelets by platelet autoantibodies may account in part for the thrombocytopenia. However, the diagnosis of autoimmune thrombocytopenic purpura in this group of patients can be difficult due to the splenomegaly and compromised bone marrows in some of these patients. The development of autoimmune thrombocytopenic purpura in these patients does not affect the eventual outcome of the underlying lymphoproliferative disorders. Unfortunately the current available therapy for this condition is unsatisfactory. Other innovative treatment modalities are therefore much needed. PMID- 7858504 TI - Late intensification therapy in adult acute lymphoid leukemia: long-term follow up of the Southeastern Cancer Study Group experience. AB - One hundred and ninety-two evaluable patients were treated on a multicenter protocol for adult acute lymphoid leukemia to determine in a prospective randomized fashion if late intensification chemotherapy beginning after about six months of treatment would improve remission duration and survival. The complete remission rate was 60%. The median remission duration from beginning of maintenance was 18.7 versus 25.9 months (P = 0.36) for standard maintenance therapy and late intensification, respectively, and the median survival from randomization was 25.8 versus 28.5 months (P = 0.94) respectively. There was a suggestion that the late intensification strategy was helpful with respect to remission duration, and this trend was sustained in long-term follow-up. However, relapse proved to be common during the earlier phases of treatment; thus, insufficient numbers of patients were available at the randomization point to conclusively address the possible value of late intensification. Intensive therapy earlier in the course of treatment should be evaluated, including transplantation in selected patients. PMID- 7858505 TI - The influence of induction chemotherapy dose and dose intensity on the duration of remission in acute myeloid leukemia. Australian Leukemia Study Group. AB - The aim of this study was to assess the influence of dose and dose intensity (DI) of induction and consolidation chemotherapy on relapse rates in 264 de novo patients with acute nonlymphocytic leukemia (ANLL). Patients were randomised to receive cytosine arabinoside (ARAC) 100 mg/m2 continuous infusion for 7 days and daunorubicin (DNR) 50 mg/m2 IV day 1-3 (7-3) or the same drugs with the addition of etoposide 75 mg/m2 IV days 1-7 (7-3-7). Cox proportional hazards regression models were used throughout to identify prognostic factors, including dose delivery parameters, influencing the rate of relapse. Of 152 patients who achieved a complete remission (CR), 104 have relapsed with a median duration of CR of 15.8 months. Actual dose delivered was prospectively documented. Cox regression analysis identified the most significant prognostic factors jointly influencing duration of CR as performance status groups (p < 0.0001), percentage peripheral blasts (p = 0.0015), 7-3-7 arm (p = 0.0075), age < 40 years (p = 0.022) and induction dose ARA-C plus DNR (p = 0.029). In this analysis patients randomized to the 7-3-7 arm had an estimated 43% reduction in the relapse rate and each 10% reduction of doses ARA-C and DNR was associated with an estimated 45% increase in the relapse rate. The number of induction courses, delays in treatment and induction dose intensity did not significantly influence the duration of CR nor did any of the consolidation treatment parameters.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7858506 TI - Benefit of high-dose cytarabine-based consolidation chemotherapy for adults with acute myelogenous leukemia. AB - Despite consolidation and/or maintenance chemotherapy most patients with newly diagnosed acute myelogenous leukemia relapse such that only 20-30% survive free of recurrence at five years. To evaluate the long-term effects of dose-intensive consolidation, we analysed 123 consecutive patients, age 16 to 84 (median 48 years), who received high-dose cytarabine-based consolidation chemotherapy. After a median follow-up of 88 months (range 26 to 126 months), 38 patients remain alive, with 26 in continued remission from 45 to 126+ months. Median remission duration for all eligible patients is 14 months (range 1.3 to 126 months) and actuarial leukemia-free survival at five years is 24 +/- 8%. Median survival from remission is 24 months (range 1.3 to 126 months) and actuarial survival from remission is 31 +/- 9%. Eighty-two patients (67%) have relapsed with an actuarial risk of relapse of 71 +/- 9% at five years. Adverse prognostic factors were age over 45 and male gender. When compared to historical controls (P = 0.02), dose intensive consolidation produced improved leukemia-free survival for patients age < 45, but compliance and enhanced toxicity in the older age groups may limit further dose intensification. PMID- 7858508 TI - [The quantitative relation between the mutagenic activity of heterocyclic analogs of pyrene and phenanthrene and their structure]. PMID- 7858509 TI - [From disorder to order: population waves of Escherichia coli bacteria in an isolated inoculation area]. PMID- 7858507 TI - EBV gene expression, EBNA antibody responses and EBV+ peripheral blood lymphocytes in post-transplant lymphoproliferative disease. AB - Epstein-Barr virus (EBV) is associated with the development of several B cell malignancies including Burkitt's lymphoma (BL), post-transplant lymphoproliferative disease (PTLD), and AIDS-related lymphomas. The latter two diseases result from EBV-driven B cell proliferation in the absence of normal immunosurveillance and as such, represent a heterogenous family of lymphoproliferative disorders. This article reviews studies on EBV gene expression and antibody development in PTLD and introduces recent information on the levels of EBV+ peripheral blood lymphocytes to discuss possible mechanisms of pathogenesis under varying conditions of immunosuppression. PMID- 7858510 TI - [Is the gamma frequency band of electrical activity in the brain homogeneous?]. PMID- 7858511 TI - [Dynamics of myocardial hypertrophy and status of left and right ventricular cardiomyocyte mitochondria in experimental renal arterial hypertension]. PMID- 7858512 TI - [Identification and ultrastructural characteristics of retrotransposon Tv1 virus like particles in Drosophila virilis cells]. PMID- 7858513 TI - [Genetic instability in inheritance of electrophoretic variants, coded by the Ldh B locus, in hybrid crosses of representatives of Rana esculenta L. complex (Amphibia, Ranidae)]. PMID- 7858514 TI - [The effect of temperature and chorionic gonadotropin on kinetic properties of lactate dehydrogenase from loach oocytes]. PMID- 7858515 TI - [Cytotoxic effect of viscumin on hybridoma cells, synthesizing an antibody against the viscumin A-subunit]. PMID- 7858516 TI - [Need-information basis for typical features of animal behavior]. PMID- 7858517 TI - [Age-related increase in the frequency of spontaneous and gamma-radiation-induced HPRT-mutations in murine spleen lymphocytes]. PMID- 7858518 TI - [Change in blood cell membrane permeability in animals after radioiodine irradiation]. PMID- 7858519 TI - [SegE--a new site-specific endodeoxyribonuclease from bacteriophage T4]. PMID- 7858520 TI - [Comparison of the activity of anit-CD25 immunotoxins based on the ricin A subunit and a toxin from mistletoe lectin MLI]. PMID- 7858521 TI - [Perception of small sizes in the normal state and during suppression of one hemisphere]. PMID- 7858522 TI - [Rhythmic activity of neurons of the tracheal plexus]. PMID- 7858523 TI - [Experimental evidence for using the binemic structure of the human chromosome]. PMID- 7858524 TI - Thrombotic microangiopathy following bone marrow transplantation. AB - Thrombotic microangiopathy (TMA) is a well-recognised disorder which may occur in up to 6% of patients following bone marrow transplantation (BMT). Reported cases of post-BMT TMA vary widely in their reported clinical features, severity and response to therapy. Several factors are important in the aetiology, including cyclosporin A (CsA), graft-versus-host disease, irradiation, intensive conditioning chemotherapy and infection. A unifying pathogenetic mechanism is suggested, wherein these factors may interact to produce post-BMT TMA. On the basis of differences in clinical features and prognosis, we propose the classification of post-BMT TMA into four distinctive although overlapping subtypes: multifactorial fulminant TMA, conditioning-associated haemolytic uraemic syndrome, CsA-associated nephrotoxicity with microangiopathic haemolytic anaemia (MAHA) and CsA-associated neurotoxicity with MAHA. Treatment of post-BMT TMA, especially of the poor-prognosis multifactorial fulminant subtype, is currently unsatisfactory, although occasional cases may respond to plasma exchange. PMID- 7858525 TI - Ultraviolet irradiation for the prevention of graft-versus-host disease and graft rejection in bone marrow transplantation. AB - This review describes an approach to the prevention of graft-versus-host disease (GVHD) and graft rejection following allogeneic BMT that differs from conventional methods. Ultraviolet (UV) irradiation inhibits the proliferative responses of lymphoid cells to mitogens and alloantigens by inactivation of T lymphocytes and dendritic cells, and in animal models this can prevent both GVHD and graft rejection. It is important that the marrow repopulating capacity of haemopoietic stem cells is not damaged by the irradiation process. We have found that polymorphic microsatellite markers are a sensitive way of assessing the impact of UV irradiation on chimerism after BMT in rodents. PMID- 7858526 TI - Distinct T cell populations distinguish chronic myeloid leukaemia cells from lymphocytes in the same individual: a model for separating GVHD from GVL reactions. AB - Donor lymphocyte responses to minor histocompatibility antigen (mHA) differences are involved in allo-responses between HLA matched pairs causing GVHD and graft versus-leukaemia (GVL). Since some mHA are tissue-restricted, GVHD and GVL responses may be separable. We studied donor lymphocyte responses to patients with CML in a series of 10 HLA-matched sibling and 10 unrelated donor-recipient pairs comparing proliferation to recipient PHA blasts and CML cells and attempting to selectively deplete responses to PHA blasts in vitro. Responses in counts per min (c.p.m) to CML cells and PHA blasts were, respectively, 2809 +/- 2205 (SD) and 7376 +/- 1877 in related and 12,107 +/- 7191 and 26,136 +/- 22,479 in unrelated pairs. Autologous responses to PHA blasts were significantly lower (mean 779 +/- 735) (p < 0.001). Results correlated with clinical outcome: higher responses to recipient cells correlated with transplant-related death (p = 0.02 for CML and p = 0.06 for PHA blasts). Higher responses to CML correlated with GVHD grade > or = II (p = 0.025). Donor lymphocytes exposed to recipient PHA blasts for 5 days and treated with a ricin-conjugated anti-CD25 antibody retained over 75% of their response to CML but < 10% to PHA blasts. Similarly, depletion of response to CML but not to PHA blasts occurred when CML was the primary challenge. These results indicate that distinct populations of donor T cells respond to recipient leukaemic and non-leukaemic cells, and provide the basis for a clinically applicable technique to selectively deplete donor GVHD reacting cells while conserving GVL. PMID- 7858528 TI - Prevention of lethal graft-versus-host disease in mice by monoclonal antibodies directed to T cells or their subsets. II. Differential effectiveness of IgG2a and IgG2b isotypes of anti-CD3 and anti-CD4 moAb. AB - The effects of rat anti-CD3 and anti-CD4 moAb, of the IgG2a as well as of the IgG2b subclass, on the development of lethal graft-versus-host disease (GVHD) in a fully allogeneic mouse strain combination were compared in vivo. After treatment with these moAb, mice recovered from an initial loss of body weight. Moreover, their survival significantly improved. A single dose of 200 micrograms moAb resulted in a complete and long-term survival, which was not the case after treatment with anti-CD4 IgG2a moAb. A dose of at least 1 mg anti-CD4 IgG2a was necessary to induce a tolerant state. Mice effectively treated were fully repopulated with donor-type cells. Flow cytometric analysis of the recipient spleen cells demonstrated that the moAb caused depletion, modulation or coating of T cells or a combination of these. The moAb with the highest depleting capacity appeared to be anti-CD4 IgG2b moAb. Anti-CD3 IgG2a as well as IgG2b treatment resulted in a strong modulation of CD3 surface proteins, which was found on all days examined. Modulation of CD4 surface antigens did not occur in the case of anti-CD4 IgG2a moAb treatment. Anti-CD4 IgG2b moAb treatment, on the other hand, not only caused some CD4 modulation, but also, quite unexpectedly, a significant modulation of the CD3 molecule. Coating was only observed after treatment with anti-CD4 IgG2a moAb and lasted at least 1 week.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7858527 TI - Generation of self HLA-DR-specific CD3+CD4-CD8+ cytotoxic T cells in chronic graft-versus-host disease. AB - To analyze the mechanism of chronic graft-versus-host disease (GVHD) characteristic of autoimmune disease, we used a cell-mediated lympholysis assay to study the autoreactivity of PBL from two patients after MHC-matched BMT. Our data indicate the induction of CD3+CD4-CD8+ autoreactive cytotoxic T lymphocytes (CTL) in the one patient with chronic GVHD and an important role for allo-non-MHC (minor histocompatibility) antigen-specific CD3+CD4+CD8- helper T cells in this induction. Experiments using HLA-DR gene-transfected mouse L cells as target cells and blocking assays with anti-HLA class I and class II antibodies provided evidence that autoreactive CTL recognized HLA-DR antigen on autologous cells. Analysis of antigen-specific T cell proliferative responses in these patients to examine the effect of self HLA-DR-specific CTL on the antigen presenting cell (APC)-T cell interaction suggested that donor bone marrow-derived self HLA-DR specific CTL are responsible for the decreased antigen-presenting ability of the patient's APC. These results suggest a new interpretation of the induction mechanism of chronic GVHD and its associated immunosuppression after MHC-matched BMT based on diminished APC function. PMID- 7858529 TI - Analysis of the alloreactive capacity of human umbilical cord blood: implications for graft-versus-host disease. AB - Hematopoietic reconstitution by bone marrow transplantation (BMT) is used as therapy for the treatment of various malignancies and genetic blood disorders. Allogeneic BMT is the most common application of this treatment but is frequently associated with graft-versus-host disease (GVHD). Recent clinical studies have shown that sibling transplant using umbilical cord blood (UCB) is an acceptable alternative to BMT and may involve fewer problems with GVHD. We have investigated the in vitro alloreactive capacity of UCB as it relates to allogeneic transplantation. Initial screening assays demonstrated that UCB T cells were functionally immature. It was not possible to generate significant levels of alloantigen-specific cytotoxic T lymphocytes (CTL) in either primary or secondary mixed lymphocyte cultures. Limiting dilution analyses revealed that cord blood T cells were 10-1000 x less alloreactive in terms of proliferative T cells (PTLp) and cytotoxic T cells (CTLp) compared with adult peripheral blood lymphocytes (PBL). However, UCB was equivalent to adult PBL in terms of natural killer (NK) and lymphokine-activated killer (LAK) cell precursors. Analysis of cells from alloantigen-stimulated MLC revealed that UCB generated primarily CD4+ and CD16+ cells that made little or no IL-4, IL-6, TNF-alpha or IFN-gamma on antigenic stimulation. Cold target inhibition analyses revealed that alloantigen-stimulated cord blood T cells had a fine specificity similar to NK cells. From these in vitro results cord blood would seem to be unlikely to mediate severe GVHD reactions in vivo and should be suitable for allogeneic transplantation. PMID- 7858530 TI - Short-term ex vivo activation of splenocytes with anti-CD3 plus IL-2 and infusion post-BMT into mice results in in vivo expansion of effector cells with potent anti-lymphoma activity. AB - We investigated the proliferation and therapeutic utility of anti-CD3 activated splenocytes infused into mice following BMT. Using congenic mouse strains we demonstrated that splenocytes activated briefly ex vivo with anti-CD3 plus IL-2 (T-activated killer cells or T-AK) and infused intravenously following BMT had a greater expansion in blood, spleen and BM compared with splenocytes stimulated with IL-2 alone. T-AK cells recovered from blood, spleen and BM consisted predominantly of CD8+ T cells. A single infusion of T-AK cells given on day +1 post-syngeneic BMT and sustained in vivo with liposomal encapsulated IL-2, significantly increased survival of mice with BDL-2 lymphoma when compared with mice receiving saline and those treated with IL-2 liposomes alone. The anti-tumor effect of T-AK cells was significantly enhanced when IL-2 was given by continuous infusion compared with bolus injections. Depletion studies confirmed that the CD8+ T-AK cells were mainly responsible for the anti-tumor effect against BDL-2 lymphoma. Our findings demonstrate that brief ex vivo activation of splenocytes with anti-CD3 plus IL-2 results in in vivo proliferation of effector cells with potent anti-tumor activity following BMT. PMID- 7858531 TI - Lack of efficacy of a short ex vivo incubation of human allogeneic donor marrow with recombinant human GM-CSF prior to its infusion into the recipient. AB - Ten patients with haematological malignancy receiving allogeneic transplants from donors other than HLA-identical siblings were prepared for marrow transplantation with antithymocyte globulin, cyclophosphamide 120 mg/kg and fractionated total body irradiation 12 Gy, and were given cyclosporin, methotrexate and prednisolone as prophylaxis against graft-versus-host disease post-transplant. The harvested T replete donor marrow was incubated with recombinant human (rh) GM-CSF 10 micrograms/ml (supersaturating concentration) for 1 h at 37 degrees C on a gently shaking rocker platform. After incubation the marrow was washed twice in 5% human serum albumin/normal saline and infused into the recipient. Before and after incubation, there was no significant difference in cell viability, the nucleated cell count, the CFU-GM content nor the proportion of cells in S phase of the cell cycle. Compared with a preceding cohort of 16 patients treated on the same protocol but in whom the marrow was not incubated with GM-CSF, there was no difference in the incidence of graft failure or rate of neutrophil recovery. PMID- 7858532 TI - Phase I study of recombinant human interleukin-1 beta (rhIL-1 beta) in patients with bone marrow failure. AB - The administration of recombinant human interleukin-1 beta (rhIL-1 beta) stimulates pluripotent cell growth and reduces mortality from infection in animal models. In this phase I trial, rhIL-1 beta (0.02-0.50 microgram/kg) was administered by 30-minute intravenous infusion once daily for 2 or 5 consecutive days. The dose was escalated with the subsequent cycle in the same patient if no hematologic response was observed. Nineteen patients with severe bone marrow failure received 60 courses of IL-1 beta. Diagnoses included autologous bone marrow transplant (BMT) (n = 5), allogeneic BMT (n = 7) or idiopathic aplastic anemia (n = 6) and 1 patient with chronic myeloid leukemia. Toxicities included fever (89%), chills (85%), hypertension (89%), hypotension (57%) and headache (95%). No complications were life-threatening and all either spontaneously resolved or were managed pharmacologically. In 8 of 19 patients there was an acute, transient increase in neutrophil counts. In 2 patients there was a transient increase in platelet count; however, no durable, clinically significant effects on peripheral blood counts were observed. In conclusion, administration of rhIL-1 beta in this population of patients had limited efficacy and moderate toxicity. PMID- 7858533 TI - Second bone marrow transplantation for leukemia in untreated relapse. AB - Seven patients with relapsed acute leukemia (4 ANLL, 3 ALL) and one with juvenile chronic myelomonocytic leukemia (JCMML) received a second BMT (BMT2). Patients were conditioned with CY/TBI (n = 7) or BU/CY (n = 1) for the first BMT (BMT1), with adequate recovery in all and without the appearance of acute GVHD (n = 3) or with mild forms (grade I, n = 2; grade II, n = 3). Relapse after BMT1 occurred in < 6 months (n = 2), between 6 and 12 months (n = 5) and > 12 months (n = 1), and the interval from BMT1 to BMT2 was < 6 months (n = 1), from 6 to 12 months (n = 5) or > 12 months (n = 2). Conditioning for BMT2 was done in untreated relapse and included combinations of BU/CY (n = 2), CY/TBI (n = 1) or BU 1 mg/kg at intervals of 6 h by mouth on days -7 to -4 and melphalan 180 mg/m2 i.v. on day 2, with the addition of VP-16 in the patient with JCMML. Two patients died on day +11 with no evidence of residual leukemia at autopsy. Six patients engrafted, one of whom had an uneventful BMT2, but he relapsed 6 months later. The other five developed severe acute GVHD (grades III-IV), with a fatal outcome in three cases, while two responded to treatment and are currently alive in continuous CR at 12 and 36 months. All patients had received conventional prophylaxis against acute GVHD.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7858534 TI - Carmustine, Ara C, cyclophosphamide and etoposide with autologous bone marrow transplantation in relapsed or refractory lymphoma: a dose-finding study. AB - The purpose of this study was to define the dose-limiting non-hematologic toxicity of carmustine, Ara C, cyclophosphamide and etoposide (BACE). Between October 1986 and March 1990, 37 patients with relapsed or refractory lymphoma received escalating doses of combination chemotherapy followed by autologous bone marrow transplant (ABMT). Twenty patients with Hodgkin's disease (HD) and 17 patients with intermediate or high grade non-Hodgkin's lymphoma (NHL) initially received conventional-dose therapy with either a 7 week course of modified MACOP B or a single dose of cyclophosphamide (CY) at 2 g/m2 depending on prior therapy and response. Regardless of response, patients then received escalating doses of BACE, toxicity permitting. Ten patients obtained complete responses (CR) and 12 patients were partial responders (PR), CR+PR (75%) with modified MACOP-B and 7 (64%) patients obtained PR with CY. The maximum-tolerated dose (MTD) for BACE was determined to be carmustine 700 mg/m2, Ara C 1500 mg/m2, CY 150 mg/kg and etoposide 1500 mg/m2. When Ara C was escalated from 1500 mg/m2 to 3000 mg/m2 holding the other drugs at the prior doses, the next two patients died secondary to diffuse alveolar damage. Overall and event-free survivals are identical with 14 of 37 patients (38%) alive with a median follow-up of 61 months (range 38-79 months). Ten patients were treated at the MTD, none of whom died a toxic death and 3 (30%) are alive with a median follow-up of 42 months (range 38-52 months). We defined the MTD and BACE showing pulmonary toxicity to be the dose-limiting non-hematologic toxicity.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7858535 TI - Treatment of moderate to severe acute graft-versus-host disease: a retrospective analysis. AB - Seventy-one patients with moderate to severe acute GVHD after BMT were analysed retrospectively. At the start of therapy 96% of the patients had rashes, 45% liver abnormalities and 54% gut dysfunctions. Forty-four patients (62%) had been treated for grade I GVHD with systemic corticosteroids. First therapy for moderate to severe acute GVHD was with corticosteroids (n = 59), psoralen with ultraviolet light (PUVA) (n = 14), cyclosporin (CsA) (n = 10), antithymocyte globulin (ATG) (n = 7), methotrexate (MTX) (n = 2), monoclonal antibodies (n = 1) or thalidomide (n = 1). In 18 of these patients two or more agents were combined. Resolution of skin disease and evaluable liver and gut disease were seen in 48%, 44% and 47% of cases, respectively. Overall complete resolution was seen in 37%. Thirty-two patients received a second treatment, resulting in complete resolution in 31%. Patients with a complete response had an actuarial transplant-related mortality of 37% compared with 82% or worse for patients with other outcomes (p < or = 0.003). Combined treatment was superior to ATG, but not better than corticosteroids. In multivariate analysis a low total sum severity score was the only factor associated with complete response (p = 0.02). AML diagnosis (p = 0.01) and GVHD of the liver (p = 0.02) were independent risk factors for treatment failure. PMID- 7858536 TI - Detection of residual leukaemia more than 10 years after allogeneic bone marrow transplantation for chronic myelogenous leukaemia. AB - The clinical status of a homogeneous cohort of long-term survivors of allogeneic marrow transplantation was assessed and residual leukaemia was studied by reverse transcription polymerase chain reaction for leukaemia specific BCR-ABL mRNA. The group comprised 34 consecutive patients with CML in chronic phase treated by chemoradiotherapy and transplantation of bone marrow from HLA-identical sibling donors between February 1981 and December 1983 in the joint Hammersmith-Northwick Park programme. The probability of survival at 10 years was 59 +/- 17%. Eighteen of the 19 surviving (95%) patients have Karnofsky scores of 90 or 100% indicative of a good performance status. One of the survivors had evidence of relapse 6.5 years after transplant but has since been restored to complete remission by treatment with interferon-alpha followed by donor leucocyte transfusions. Surprisingly, 2 of the 19 patients who have been in remission for over 10 years have molecular evidence of persisting leukaemic cells. Quantification by competitive PCR indicated that the malignant clone persisted at low levels. The data suggest that the majority of long-term survivors after BMT for CML are in good health and may be regarded as cured. Some long-term survivors, however, may still harbour residual leukaemic cells and continued monitoring for late relapse is warranted. Late relapse is amenable to further therapy with leukocyte transfusions from the original marrow donor. PMID- 7858537 TI - Late effects of bone marrow transplantation on pulmonary function in children. AB - This study was undertaken to evaluate in a primarily pediatric population whether the late effects of bone marrow transplantation (BMT) on pulmonary function in patients having undergone the procedure for treatment of acute leukemia or lymphoma are worse than that of patients having undergone transplant for treatment of aplastic anemia. Forty-six patients were studied. We did not demonstrate statistically significant differences in group mean forced expiratory flow in one second/forced vital capacity (FEV1/FVC) and percentage predicted forced expiratory volume in one second (FEV1), forced vital capacity (FVC), forced expiratory flow at 25-75% of the forced vital capacity (FEF25-75) and total lung capacity (TLC) values between the two groups of patients before BMT and to 7 years post-transplant. Individual patients with pulmonary function abnormalities were identified. Furthermore, there were no significant differences between the two study groups or within the group of patients with aplastic anemia from pre-transplant to 9-12 months and from pre-transplant to 18-24 months after BMT. However, within the group of patients treated for acute leukemia or lymphoma, there was a significant decline in the group mean percentage predicted FVC (p = 0.0001), FEV1 (p = 0.0006) and FEF25-75 (p = 0.0063) from pre-transplant to 9-12 months and in the FVC (p = 0.004) and FEV1 (p = 0.0006) from pre transplant to 18-24 months after BMT. The greater decline in the FVC relative to the FEV1 suggests the development of a restrictive process in this group of patients. PMID- 7858539 TI - Generalized granuloma annulare post autologous bone marrow transplantation in a Hodgkin's disease patient. AB - A case of generalized granuloma annulare is described in a patient with Hodgkin's disease 3 weeks after autologous bone marrow transplantation (BMT). This is, to our knowledge, the first report of generalized granuloma annulare post-BMT. Immunological pathogenesis is suggested and the association with delayed-type hypersensitivity reaction is discussed. PMID- 7858538 TI - Differential effect of pre-transplant cytoreduction on recovery of day zero host circulating cells. AB - Host lymphocytes, reactive against donor specific HLA antigens, emerge at the time of graft rejection following T cell-depleted BMT. Thirty patients receiving different cytoreduction regimens were evaluated for the presence of circulating residual, in vitro expandable, host cells on day 0. Twenty-five patients received TBI-containing regimens and 5 patients received non-TBI containing regimens. Patients prepared with thiotepa or TBI-containing regimens had 10-fold lower numbers of circulating host PBMC pre-transplant on day 0 compared with patients cytoreduced with BU/CY. Cell proliferation was observed only in patients who received BU/CY. The phenotype of the in vitro expanded cells was predominantly CD3+ (88-97%), CD8+ (45-70%), HLA-DR+ (43-88%), although natural killer cell function and phenotype (CD56+: 6-21%) was also documented. Host cells expanded from a patient who received BU/CY exhibited specific cytotoxicity against feeder cell targets, indicating that BU/CY cytoreduction might not be an optimal BMT preparative regimen for patients at high risk of graft failure. The published experience of similar studies to date is also summarized. PMID- 7858541 TI - Histiocytic cytophagic panniculitis: a rare late complication of allogeneic bone marrow transplantation. AB - Histiocytic cytophagic panniculitis (HCP) is the name given to the hemophagocytic syndrome when subcutaneous fat is involved. Histologically, it is characterized by phagocytosis of blood elements by histiocytes that appear to be benign. We report this rare skin disease in a 46-year-old patient that occurred 32 months after an allogeneic bone marrow transplantation. This skin disease could be a manifestation of graft-versus-host disease, although the connection remains speculative. PMID- 7858540 TI - Successful treatment of veno-occlusive disease with recombinant tissue plasminogen activator in a patient requiring peritoneal dialysis. AB - There have been encouraging reports of the use of recombinant tissue plasminogen activator (tPA) in established veno-occlusive disease (VOD). Haemodialysis has been considered a contraindication to this therapy in view of the potential haemostatic complications. We report a case of a woman who developed moderately severe VOD complicated by anuria following an allogeneic bone marrow transplant for relapsed acute myeloid leukaemia. Following initiation of peritoneal dialysis she received tPA at a dose of 10 mg/day for 5 days. There was rapid improvement in her urine output and liver function with no bleeding complications. This case suggests that the requirement of dialysis may not preclude the use of tPA in established VOD and therefore warrants further study. PMID- 7858542 TI - Graft-versus-host disease following interferon therapy for relapsed chronic myeloid leukaemia post-allogeneic bone marrow transplantation. AB - The combination of donor leucocytes, with or without interferon, has produced encouraging responses in patients with haematological relapse following allogeneic BMT for chronic myeloid leukaemia (CML). A 25-year-old male received low-dose interferon-alpha alone for haematological relapse occurring 10 months following an allogeneic BMT for Ph-positive CML. Interferon therapy was complicated by severe GVHD requiring immunosuppressive therapy. The patient was subsequently found to be in complete haematological and cytogenetic remission, raising the possibility of an immune-mediated antileukaemic action. PMID- 7858543 TI - Autologous bone marrow transplantation for cyclosporin-related lymphoma in a renal transplant patient. AB - The optimal treatment of post-transplantation lymphoma remains undefined. We report a case of high grade lymphoma occurring after a renal transplant treated with high-dose chemotherapy and ABMT leading to a 10 month CR. Relapse occurred 8 months after reintroduction of CsA, which may have been implicated in this relapse. PMID- 7858544 TI - Diagnosis of fungemia in bone marrow transplantation patients by examination of peripheral blood smears. AB - Two patients who received BMT for treatment of severe aplastic and AML-M2, developed fungemia during leukopenia. The organisms responsible for the infections were Candida parapsilosis and Rhodotorula glutinis, respectively. Early diagnosis of fungemia in these two patients was made by visualization of fungal blastospores in peripheral blood (PB) smears. These two cases illustrate that cytologic examination of PB smears is a useful method for early detection of fungus infection in BMT patients with leukopenia and unexplained fever in spite of appropriate antibiotic treatment. PMID- 7858545 TI - Severe rotavirus-associated diarrhoea following bone marrow transplantation: treatment with oral immunoglobulin. AB - Two patients developed acute severe rotavirus-associated diarrhoea following BMT. Both received treatment with oral immunoglobulin and in each case the diarrhoea substantially resolved within 3 days, and rotavirus became undetectable in their stool. Oral immunoglobulin may be a useful therapy for rotavirus gastroenteritis post-BMT. PMID- 7858546 TI - Long-term follow-up of a patient transplanted for Hunter's disease type IIB: a case report and literature review. AB - Unlike most other storage diseases and despite clinical experience, the indications for bone marrow transplantation in Hunter's disease remain controversial. The case of a 14-year-old male with mucopolysaccharidosis type IIB is presented, who received an allograft from his HLA-identical sibling. The donor had been off therapy for acute lymphoblastic leukemia for 3 years. The patient experienced minimal difficulties with his transplant and was fully engrafted by day 42, with no signs of acute or chronic graft-versus-host disease. Now, more than 3 years after BMT, the patient has experienced significant subjective and objective improvement in his disease. The iduronate-2-sulfatase levels in the serum are now approximately 10% of normal control. Urinary glycosaminoglycans were negative. The posttransplant marrow was evaluated for donor-recipient source using VNTR analysis with the polymerase chain reaction (PCR). This showed a PCR detectable subpopulation of residual patient marrow cells remaining, suggesting a state of stable mixed chimerism. The patient continues to show signs of amelioration of his disease. These results may be of value in determining the proper therapy for a patient with mild Hunter's disease, and may also be pertinent to the future application of recombinant enzyme therapy or gene therapy. PMID- 7858547 TI - Type I cryoglobulin with cold agglutinin activity complicating allogeneic bone marrow transplantation. AB - We report a case of type I cryoglobulinemia with cold agglutinin activity complicating allogeneic bone marrow transplantation. To our knowledge, this complication has not been previously reported. We also discuss possible etiologic mechanisms for this unusual event. PMID- 7858548 TI - Failure of ribavirin to clear adenovirus infections in T cell-depleted allogeneic bone marrow transplantation. PMID- 7858549 TI - Electrocardiographic alterations occurring during cryopreserved bone marrow infusion. PMID- 7858550 TI - Failure of high-dose alkylating agents in osteosarcoma. Solid Tumors Working Party. PMID- 7858551 TI - Committee to Advise on Tropical Medicine and Travel (CATMAT). Statement on travellers and rabies vaccine. PMID- 7858552 TI - Committee to Advise on Tropical Medicine and Travel (CATMAT). Statement on travellers and sexually transmitted diseases. PMID- 7858553 TI - Laboratory reports of human viral and selected non-viral agents in Canada--1993. PMID- 7858554 TI - Community surveillance for wild poliovirus in Ontario, 1993. PMID- 7858555 TI - Comparative and combined efficacy of doxazosin and enalapril in hypertensive patients. AB - Twenty patients with essential hypertension were randomised to a 7-week period of dose titration with doxazosin, 1-8mg/day or enalapril, 5-20mg/day. In a further 7 week period the dosage level reached with the initial drug was halved, and titration with the second agent was carried out. Blood pressure responses at the end of each treatment period were assessed by clinic measurements made 24 hours post-dose. In the first treatment period, enalapril (mean dose 19mg/day) reduced serum free ACE activity by 40% and had a greater effect than doxazosin (mean dose 5.2mg/day) on clinic supine blood pressure (systolic and diastolic). In the second period, the addition of enalapril to doxazosin was associated with a significant fall in clinic standing blood pressure (systolic and diastolic), despite the doxazosin dose reduction and consequent decrease in median plasma doxazosin concentration (from 10.6 to 5.2ng/ml). Alternatively, when doxazosin was added to enalapril, free ACE activity remained 40% decreased despite enalapril dose reduction, and blood pressure was not further affected. Plasma renin activity was increased by enalapril. No changes were observed in plasma aldosterone or lipid concentrations with either drug. The combination of doxazosin and enalapril was well tolerated and lowered blood pressure overall. Judged by clinic measurements 24 hours post-dose, most of the antihypertensive effect was attributable to the enalapril component. However, ambulatory blood pressure monitoring 0-12 hours post-dose in a subset of patients suggested a contribution of doxazosin earlier in the dose interval. PMID- 7858556 TI - Compliance with long-term dietary salt restriction in hypertensive outpatients. AB - Eighty hypertensive outpatients were recruited for a dietary salt restriction program to examine long-term compliance. Twenty-four-hour urine samples were collected repeatedly (7.9 +/- 2.6 times, mean +/- s.d.) during a follow-up period of 6.4 +/- 1.7 years. After initial urine collection, nutritional education was carried out by dietitians to reduce dietary salt intake to 8 g/day or less. After every urine collection, the subjects were given advice by doctors on salt restriction, if necessary. The mean 24-hour urinary salt excretion (U-NaCl) and the mean urinary salt/creatinine ratio (U-NaCl/U-Cr) varied considerably both among and within individuals. U-NaCl/U-Cr, but not U-NaCl, in females was significantly higher than that in males, and in middle-aged subjects than in young subjects. U-NaCl and U-NaCl/U-Cr tended to decrease in the summer. In spite of the repeated educational effort, neither U-NaCl nor U-NaCl/U-Cr was different in the first control samples from that in the last samples. When 57 subjects were divided into three groups according to the urinary salt excretion level, U-NaCl was consistently higher during a follow-up period in the high-salt excretion group than in the mid-salt excretion group, while U-NaCl in the low-salt excretion group was initially lower than, but finally similar to, that in the mid salt excretion group. These results suggest that: (1) multiple 24-hour urine samplings are required to assess urinary salt excretion in individuals; (2) the influence of age and sex should be taken into account in interpreting U-NaCl/U Cr; and (3) it seems difficult to achieve long-term dietary salt restriction as a non-pharmacologic treatment of hypertension in an outpatient clinic. PMID- 7858557 TI - Erythrocyte Na+/K(+)-ATPase and membrane and serum lipid profiles: as related to alcohol, body mass index and blood pressure. AB - Erythrocyte Na+/K(+)-pump activities have been measured in hypertensives, alcohol consumers and obese persons, but the results have been variously reported as decreased, increased or unchanged. We analyzed the relationships between erythrocyte Na+/K(+)-ATPase activities and the membrane and serum lipid profiles in 83 middle-aged men, to clarify the reasons for these inconsistencies. Increases in erythrocyte Na+/K(+)-ATPase activity related closely to decreases in cholesterol to phospholipid (C/P) ratio of the erythrocyte membrane. Decreases in the C/P ratio in turn related closely to elevations of serum triglycerides (TG) with increasing body mass index, and weakly to the volume of alcohol consumed. Thus, erythrocyte Na+/K(+)-ATPase activities depend largely on the membrane and serum lipid profiles as related to body weight and alcohol consumption, and which may be a cause of the previous conflicting findings. Erythrocyte Na+/K(+)-ATPase showed a positive association with blood pressure, independently of age, body mass index and serum gamma-glutamyl transpeptidase levels. Although the biological link of elevated erythrocyte Na+/K(+)-ATPase with the rise in blood pressure remains unclear, it may be a reflection of hyperinsulinemia in the subjects with a higher blood pressure due to overweight or excessive alcohol consumption. PMID- 7858558 TI - Role of glucocorticoid in the development of glycyrrhizin-induced hypertension. AB - Role of alterations of corticosterone metabolism in the expression of the mineralocorticoid activity of glycyrrhizin was explored in rats. While the mineralocorticoid actions of oral glycyrrhizin were not observed in bilaterally adrenalectomized rats and dexamethasone treated rats, the mineralocorticoid actions of glycyrrhizin were fully expressed in bilaterally adrenalectomized rats supplemented with physiological doses of corticosterone. Similar mineralocorticoid actions were observed in rats given glycyrrhizin, deoxycorticosterone and pharmacological doses of corticosterone. Although increases in mean blood pressure were suppressed only by concurrent administration of spironolactone to glycyrrhizin- and deoxycorticosterone-treated rats, increases in mean blood pressure were attenuated by both the glucocorticoid antagonist RU 38486 and spironolactone in pharmacological doses of corticosterone administered rats. Pressor responses to norepinephrine and angiotensin II infusions in rats given deoxycorticosterone and pharmacological doses of corticosterone were significantly higher than in glycyrrhizin-treated rats. These results confirmed the functional significance of 11-beta-hydroxysteroid dehydrogenase in expression of the mineralocorticoid activity of glycyrrhizin. PMID- 7858559 TI - Systemic and regional haemodynamic effects of 1-(2,5-dimethoxy-4-iodo-phenyl)-2 aminopropane (DOI) and alpha-methyl-5-HT, in the anaesthetised rat. AB - The present experiment was performed to investigate the haemodynamic effects of 1 (2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and alpha-methyl-5 hydroxytryptamine (alpha-methyl-5-HT) in the anaesthetised normotensive rat. DOI (1-300 micrograms/kg i.v.) increased mean arterial pressure (MAP), total peripheral resistance (TPR) and decreased cardiac output (CO) and heart rate (HR). DOI increased all vascular resistances investigated (hindquarters, mesenteric and renal). Alpha-methyl-5-HT (10-300 micrograms/kg i.v.) dose dependently increased MAP, TPR, all regional vascular resistances and decreased CO and HR. The bradycardia induced by alpha-methyl-5-HT was suppressed by bivagotomy. Both DOI and alpha-methyl-5-HT were more effective on renal vascular bed than hindquarters and mesenteric vascular beds. The effects of DOI and alpha methyl-5-HT were antagonised by spiperone (10 or 100 micrograms/kg i.v.) and LY 53857 (10 micrograms/kg i.v.). Intracerebroventricular administration of DOI (100 micrograms/kg) increased MAP, TPR, regional vascular resistances and did not change HR and CO. Pretreatment with xylamidine (10 micrograms/kg i.v.), a selective peripheral 5-HT2 receptor antagonist, blocked i.v. and i.c.v. effects of DOI. These results suggest that: 1) the increase in MAP induced by DOI and alpha-methyl-5-HT is due to an increase in TPR. All regional vascular beds and in particular the renal vascular bed participate in the increase of TPR. 2) Peripheral--and may be--central 5-HT2 receptors seem to be implicated in the control of regional vascular resistances. 3) Cardiac effects of alpha-methyl-5-HT are baroreflexly-mediated whereas those of DOI are--at least in part--centrally mediated. PMID- 7858560 TI - The role of kinins and atrial natriuretic peptide on the renal effects of neutral endopeptidase inhibitor in rats. AB - To further elucidate the natriuretic mechanisms of neutral endopeptidase 24.11 (NEP) inhibition, we employed a new specific NEP inhibitor, UK 73967 (UK), with or without a specific kinin receptor antagonist, Hoe 140 (Hoe), in Sprague-Dawley rats, and evaluated the renal NEP, kinins and plasma ANP simultaneously. There were no significant changes in urinary NEP, kinins, urine volume (UV) or urinary sodium excretion (UNaV) with vehicle treatment in anesthetized normotensive rats. Infused UK (10 mg/kg) significantly decreased NEP, and increased kinins, UV and UNaV. There was not a significant difference in plasma ANP between the vehicle and UK groups. Simultaneous administration of Hoe (20 nmol/kg) canceled the increases of UV and UNaV caused by UK. From these results, we conclude that inhibition of NEP may exaggerate the contribution of renal kinins to the renal water-sodium metabolism and overcome the contribution of ANP on that metabolism at least in normotensive rats. PMID- 7858561 TI - Biometrical genetic analysis of blood pressure level in the genetically hypertensive mouse. AB - Hypertensive mice of the inbred strain BPH/2 were mated to mice of the inbred hypotensive BPL/1, and their hybrid offspring were crossed and intercrossed. The systolic blood pressures of the resulting ten populations were then subjected to a biometrical genetic analysis to determine the mode of inheritance of genes regulating blood pressure in these strains. It was found that the inheritance of elevated blood pressure was due, primarily, to the additive effects of three to five genes. There was no evidence that genetic dominance or epistasis were involved in the genetic control of blood pressure in these strains. PMID- 7858562 TI - Cyclic AMP export from lymphocytes in hypertension. AB - While the importance of receptor-mediated intracellular cyclic AMP in blood pressure regulation is well documented, few studies have evaluated the physiologic relevance of cyclic AMP exported from cells. We report evidence of a relationship between blood pressure and the transport of intracellular cyclic AMP from lymphocytes. Twenty-eight hypertensive and 56 normotensive white and black volunteers (mean age 40 years) were studied. Both intra- and extracellular concentrations of cyclic AMP were determined in lymphocytes following incubation with 10(-5) M isoproterenol. Compared to normotensives, hypertensives (p = 0.001), particularly white hypertensives (p = 0.023) had higher levels of exported cyclic AMP. These values were independent of intracellular concentrations of cyclic AMP, which were similar across the groups. Exported cyclic AMP was independent of both sodium excretion and beta-adrenergic receptor sensitivity, the latter being lower in white hypertensives (p = 0.024). Across all subjects, exported cyclic AMP was correlated with MAP (r = .39, p < 0.001). These findings indicate that the active transport of cyclic AMP may be enhanced in hypertension and suggest a possible pathway which might explain existing data of increased cyclic AMP levels in hypertension. PMID- 7858563 TI - Differential effects of amiloride on the basal rate and the pressure overload induced increase in protein synthesis in perfused rat heart. AB - The purpose of the present study were to determine the contribution of Na+/H+ exchange to pressure overload-induced cardiac hypertrophy and to examine its potential interaction with cAMP-dependent signaling pathway. Isolated rat hearts were perfused as Langendorff preparations with aortic pressure of 60 mmHg. In pressure overload group, aortic pressure was increased to 120 mmHg. cAMP contents in the heart perfused at 2 min were examined by RIA. Rates of protein synthesis were examined by 14C-phenylalanine incorporation into myocardial protein during the second hour of perfusion. Expression of c-fos mRNA in the heart perfused at 1 hour was analyzed by Northern blotting. Elevation of aortic pressure from 60 mmHg to 120 mmHg in perfused rat hearts increased cAMP contents from 4.89 +/- 0.09 to 6.30 +/- 0.28 pmol/mg protein and accelerated rates of protein synthesis from 644 +/- 13 to 860 +/- 49 mmol Phe/g dry heart/hr. Expression of c-fos mRNA was induced by elevated aortic pressure. Amiloride, an inhibitor of Na+/H+ exchange, decreased rates of protein synthesis in a concentration-dependent manner (12.5, 25, 50, 100 microM) but did not change cAMP content (5.25 +/- 0.11 pmol/mg protein) or expression of c-fos mRNA. Furthermore, amiloride did not prevent the increases in cAMP (6.99 +/- 0.34 pmol/mg protein), protein synthesis rates (476 +/- 18 to 689 +/- 31 nmolPhe/g dry heart/hr) and expressions of c-fos mRNA that were induced by elevation of aortic pressure. These results indicate that amiloride, an inhibitor of Na+/H+ exchange system, while influencing rates of protein synthesis, does not play an important role in pressure overload-induced cardiac hypertrophy. The mechanism by which amiloride influences cardiac protein synthesis is independent of the cAMP-dependent mechanism by which pressure overload induces cardiac hypertrophy. PMID- 7858564 TI - Individualization of therapy for hypertension in the 1990's: the role of calcium antagonists. AB - The Joint National Committee Reports IV (1988) and V (1992) have emphasized individualization of drug therapy for patients with hypertension-a departure from the "stepped" care approach of initiating therapy with diuretics as advocated by the JNC I-III in the 1970's and 1980's. This review highlights individualization or "patient profiling" using calcium channel blockers as first-line treatment strategy for patients with primary hypertension--especially in the patient who has attendant risk factors and sequelae. The calcium channel antagonists, especially effective in elderly and Black patients, have proven efficacy in reducing left ventricular hypertrophy and improving diastolic function in patients with hypertensive heart disease. The heart rate limiting calcium antagonist, verapamil, has been found effective in outcome trials of reducing death and reinfarction rates post myocardial infarction and is an alternative therapy for the beta blocker intolerant hypertensive post myocardial infarction. More vascular specific dihydropyridines (felodipine, isradipine, and amlodipine) may be preferable to rate limiting agents in hypertensives with sinus node or AV conduction disorders and in those with impaired left ventricular systolic function. Verapamil and diltiazem have been effective in preliminary trials in reducing proteinuria and preserving renal function in both diabetic and non diabetic hypertensives. Calcium channel antagonists appear to prevent the progress of atherosclerosis independent of their antihypertensive properties. Further, they have theoretic value in improving endothelial mediated vasodilation. PMID- 7858565 TI - Effect of long term isradipine treatment on the morphology of the endothelium in the aorta of spontaneously hypertensive rats. AB - The influence of hypertension and of treatment with the dihydropyridine calcium channel blocker isradipine on the morphology of the thoracic aorta and of the aortic tunica intima were studied. Three experimental groups of male spontaneously hypertensive rats (SHR) of 10 weeks of age were used. Two groups were treated with a daily oral dose of 0.01 mg/kg or of 0.1 mg/Kg of isradipine respectively. A third group of SHR was left untreated and served as control. Age matched normotensive Wistar-Kyoto (WKY) rats were used as a reference group. Animals were allowed to survive for 12 weeks and were killed at 22 weeks of age. Systolic pressure values which did not change in WKY rats, significantly increased in SHR as a function of age. The dose of 0.1 mg/Kg/day isradipine reduced systolic pressure to normotensive values after the first week of treatment, whereas the lower one was ineffective. The area of the wall, the area of the tunica media and the wall-to-lumen ratio of the aorta significantly increased in SHR and decreased either with the antihypertensive and non antihypertensive doses of isradipine. Transmission and scanning electron microscope analysis of the tunica intima revealed hypertrophy of the endothelial cells with an increase in sub endothelial space in SHR. An improvement of the endothelial morphology and a decrease in sub endothelial space was noticeable in isradipine-treated SHR. Although the hypotensive dose of the compound was the most effective, the non-hypotensive dose was active was well. The above results suggest that isradipine treatment may counter structural changes of the aorta of SHR and has a protective action on the hypertension-dependent modifications of the endothelium. The endothelial effects are probably dependent only in part by the hypotensive activity of the compound. PMID- 7858566 TI - [Apropos of some risk factors for osteoporosis: high-intensity sports, smoking, alcoholism, hyperprolactinemia]. PMID- 7858567 TI - [Treatment of osteoporosis: current data and prospects]. AB - Postmenopausal osteoporosis is characterized not only by a reduction in bone mass but also by bone microarchitecture alterations, which result in greater bone frailty and in an increased fracture risk. Many drugs have been studied to determine whether they prevent bone loss or reduce the incidence of additional fractures in patients with established osteoporosis. Primary prevention of osteoporosis rests on regular exercising and adequate intake of dietary calcium. For secondary prevention in women undergoing menopause, replacement estrogen therapy given for at least ten years is associated with substantial reductions in fractures of the radius, hip, and spine. Other drugs capable of arresting postmenopausal bone loss include parenteral, nasal or rectal calcitonin and diphosphonates. However, the long-term safety of the latter requires further evaluation. Current studies are evaluating new molecules with potential preventive efficacy, such as ipriflavone. There is no general consensus about the efficacy of treatments for established osteoporosis with fractures. To date, no controlled studies have demonstrated a reduction in the incidence of further fractures in patients given calcium alone. Studies of hydroxylated vitamin D derivatives have been disappointing, although daily administration of vitamin D3 in combination with calcium significantly reduced the incidence of nonvertebral fractures in a population of elderly institutionalized subjects. Plausible explanations for this effect include increased vitamin D levels and reduced parathyroid levels in the bloodstream. Parenteral or nasal calcitonin stabilizes or increases bone mineral content in both cancellous and cortical bone. This effect is especially marked in high-turn-over patients. Several lines of evidence suggest that calcitonin therapy has a protective effect against vertebral and hip fractures. In patients with osteoporosis, oral or intravenous diphosphonates are associated with a significant increase in cancellous bone mass with no loss of cortical bone. Etidronate may be especially beneficial in severe osteoporosis with marked loss of bone and multiple vertebral crush fractures. Fluoride stimulates the growth and synthetic activity of osteoblasts. Accurate information is needed on the optimal dosage of fluoride, on the effects of fluoride on the appendicular skeleton, and, above all, on the biomechanical properties of the bone produced under fluoride therapy. In addition to these commercially available drugs, several other agents are at various stages of the development process.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7858568 TI - [Duration of use of non-steroidal anti-inflammatory agents in patients with rheumatoid arthritis]. AB - Many new nonsteroidal antiinflammatory agents are available for the treatment of rheumatoid arthritis. Although they all seem effective and reasonably safe, it is difficult to determine whether some are superior over others under real life conditions of use. Currently available study designs for answering this question were evaluated. Results demonstrated the value of treatment duration as a measure of the efficacy and safety of nonsteroidal antiinflammatory drugs. An earlier retrospective study using treatment duration is described and its results compared with those reported by other investigators. Treatment duration was subjected to survival analysis, and the Cox proportional hazards model was used to adjust for disease severity and concomitant treatments. One hundred sixteen patients with rheumatoid arthritis meeting American College of Rheumatology criteria received 188 courses of nonsteroidal antiinflammatory drugs over the four-year study period. Regardless of the nonsteroidal antiinflammatory agent used, treatment duration was longer in patients receiving steroid therapy, a second-line drug, or a narcotic analgesic. Treatment duration was not influenced by disease severity, the number of nonsteroidal antiinflammatory agents used, the number of previously used second-line drugs, the dosage, or the prescribing physician. Treatment duration was significantly (p < 0.001) longer for naproxen than for the other antiinflammatory agents (sulindac, piroxicam, indomethacin, tolmetin, and ibuprofen). This difference persisted after adjustment for concomitant use of prednisone, second-line drugs, or analgesics. Other studies support our findings, although they found no statistically significant differences, for a number of reasons. In our study, naproxen was used longer than any other nonsteroidal antiinflammatory drug. Continued work is needed to confirm our findings. PMID- 7858569 TI - [Cytokines and anti-cytokines in inflammatory rheumatism]. AB - Studies done over the last few years have demonstrated that interleukin-1 and tumor necrosis factor alpha, which are produced mainly by monocyte-macrophages, are the key mediators of inflammation and tissue destruction in rheumatoid arthritis. The synergistic effects of these factors lead to the production of large amounts of metalloproteases by the synovial cells, chondrocytes, and bone derived cells. Direct membrane-to-membrane contact between activated lymphocytes and monocyte-macrophages is one of the main factors activating the production of interleukin-1 and tumor necrosis factor alpha. This activation involves several glycoproteins expressed at the surface of activated lymphocytes (CD11, CD69). Antibodies can partially block this lymphocyte-monocyte interaction. Recent studies have identified two mechanisms capable of inhibiting macrophage and synovial cell activation. One calls into play the antiinflammatory cytokines, such as interleukin-4 and interleukin-10, which are potent inhibitors of the production of interleukin-1, tumor necrosis factor alpha, and the metalloproteases. Interleukin-10 also activates the tissue inhibitor of metalloproteases. The second mechanism, which is more specific, involves antagonists such as the interleukin-1 receptor antagonist and inhibitory soluble fragments derived from the extramembranous portion of the two receptors for tumor necrosis factor alpha (TNF-sR55 and TNF-sR75). These molecules, which we first studied in their naturally-occurring form, have been cloned and are being tested in several conditions including rheumatoid arthritis. Similar soluble fragments of the receptors for interleukin-1 alpha and beta can inhibit interleukin 1.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7858570 TI - [Non drug-induced connective tissue disease]. PMID- 7858571 TI - [Rheumatoid arthritis and neoplasms]. AB - The relationships between rheumatoid arthritis and malignant disease have been a focus of controversy for many years. The body of available data supports a relative decrease in the overall rate of occurrence of cancer, in particular of the colon, with no significant impact on mortality. However, increases have been demonstrated in the relative risks of lymphoma and, to a lesser degree, leukemia. The concomitant occurrence of rheumatoid arthritis and multiple myeloma seems fortuitous, with a relative risk of approximately 2. The effect of treatments, including methotrexate, remains unproven to date. PMID- 7858572 TI - [Corticosteroids and rheumatoid arthritis. Development of concepts]. AB - A step-by-step account is given of how corticosteroids were found to be beneficial in rheumatoid arthritis. Current hypotheses concerning the mechanism of action of corticosteroid therapy are reviewed. PMID- 7858573 TI - [Corticosteroid-induced osteoporosis]. PMID- 7858574 TI - [Substitution criteria]. PMID- 7858575 TI - [The risk/benefit ratio of low-dose cyclosporin in the treatment of severe rheumatoid arthritis]. AB - Although the efficacy of cyclosporine therapy in rheumatoid arthritis has been established, there have been no long term studies of the risk/benefit ratio of cyclosporine A in severe rheumatoid arthritis. A prospective, open-label one-year study included 106 patients (83 women and 23 men; mean age 53 years; mean disease duration, 11 years) with rheumatoid arthritis. Mean number of previous second line treatments was four and 69% of patients had failed methotrexate therapy. The initial dosage of cyclosporine was 3 mg/kg/d and was increased if needed up to 5 mg/kg/d. The dosage was reduced in the event of serum creatinine elevation (by more than 30% versus baseline) or diastolic blood pressure elevation (above 95 mmHg). The statistical analysis was performed on an intention-to-treat basis. In the 45 patients who completed the one-year study period, the mean dosage was 3.6 +/- 1 mg after six months and 3.3 +/- 1 mg/kg/d after one year. Significant improvements were seen in all the clinical efficacy parameters. The mean reduction in corticosteroid dosage was 0.5 mg/d. The study drug was discontinued prematurely in 61 patients (36 because of adverse events and 21 because of inefficacy). Twelve of the 56 patients with serum creatinine level elevation on at least one occasion and seven of the 35 patients with diastolic blood pressure elevation were taken off the study drug. PMID- 7858576 TI - [Functional ability and quality of life in rheumatoid arthritis: use of the Functional Independence Measure and the Reintegration to Normal Living Index]. AB - Functional disability and quality of life were evaluated using the Functional Independence Measure and the Reintegration to Normal Living Index, respectively, in 57 subjects (15 men and 42 women) with a mean disease duration of 15 years. Scores on both these nonspecific scales correlated with those obtained using instruments specifically designed for rheumatoid arthritis (ARA index, Lee index) and with a number of clinical parameters including patient age, disease duration and number of affected joints. Functional ability was correlated with quality of life in this study and in others performed using other evaluation tools. Nonspecific assessment scales are useful for comparing function and quality of life in various diseases. PMID- 7858577 TI - [Heterotopic ossification and vascular compression]. AB - Heterotopic ossification is common in patients with spinal cord or brain injury. Whereas the articular complications of heterotopic ossification have been well documented, the vascular complications are less well known. We report three cases with vascular compression and discuss the diagnosis and treatment in the light of a review of the literature. PMID- 7858578 TI - [Bone and joint sites of African histoplasmosis (Histoplasma duboisii). Apropos of a case and review of the literature]. AB - The authors report a case of disseminated African histoplasmosis with bone and joint involvement in a black 28-year-old citizen of the Central African Republic who presented with a 17-month history of multiple osteoarticular lesions (sternoclavicular joints, humerus, ribs), cutaneous lesions (face, scalp, thorax), and lymphadenopathy. Clinical manifestations resolved rapidly under treatment with ketoconazole (600 mg/d for 10 days then 400 mg/day for nine months). Persistent yeast cells were then found upon examination of a lymph node biopsy specimen. The characteristics and diagnosis of osteoarticular lesions due to African histoplasmosis are discussed on the basis of a review of the literature. Bone and joint lesions due to African histoplasmosis have not yet been reported in patients with the acquired immunodeficiency syndrome. However, the expanding epidemic of human immunodeficiency virus infection in Africa can be expected to result in an increase in the incidence of African histoplasmosis. Imidazole derivatives are easier to use on a long-term basis than amphotericin B and have significantly improved our ability to treat African histoplasmosis. PMID- 7858579 TI - [Chemonucleolysis of disk herniation with low back pain as the single symptom: 20 cases]. AB - Disk herniation can manifest as isolated low back pain, which is usually intermittent and accompanied with stiffness of the lumbar spine. There is almost general agreement that neither neurosurgical treatment nor chemonucleolysis is appropriate in patients with this clinical pattern. We used chemonucleolysis in 19 patients with recurrent episodes of isolated low back pain and one patient with severe permanent isolated low back pain dating back to a conservatively treated episode of sciatica. All 20 patients had disk herniation documented by imaging studies. A very good or satisfactory outcome was recorded in ten patients after three months, 11 after six months and 12 in March 1993 after a mean follow up of 72 months. The treatment was well tolerated, even in those patients who were not improved; a single patient developed an episode of acute low back pain that required surgical treatment. In patients with low back pain and disk herniation, there is currently no means of determining whether a causal relationship links these two abnormalities. Nevertheless, we believe that chemonucleolysis can be proposed in severe forms, provided the patients are apprised of current success rates. PMID- 7858580 TI - [Epidemiology of bone fluorosis of hydrotelluric origin]. AB - Although endemic fluorosis occurs in many countries, epidemiological studies have been limited by funding problems, a lack of awareness of the public health impact of the disease, and the absence of inexpensive defluoridation methods. The effects of fluorides on human bone are reviewed and the methodological problems raised by epidemiological studies of endemic skeletal fluorosis are discussed. PMID- 7858581 TI - [Adaptation of the skeleton to microgravity]. PMID- 7858582 TI - [Salmonella osteomyelitis. 2 cases]. PMID- 7858583 TI - [Double foci of spinal vacuum phenomenon in bone mastocytosis]. PMID- 7858584 TI - [Prolactin response to protirelin in reactive arthritis and ankylosing spondyloarthritis. Failure of treatment of 4 reactive arthritis with bromocriptine]. PMID- 7858585 TI - [Large rheumatoid synovial cyst of the psoas complicated by femoral vein thrombosis]. PMID- 7858586 TI - [Rhabdomyolysis complicating acute lumbar compartment syndrome]. PMID- 7858587 TI - [Nocardia asteroides-induced septic arthritis. A case, review of the literature]. PMID- 7858588 TI - [Histological demonstration of the process of paraspinal muscle denervation in a case of reducible lumbar kyphosis (camptocormia)]. PMID- 7858589 TI - [Chlamydia infections in rheumatology]. PMID- 7858590 TI - [Integrins]. PMID- 7858591 TI - [Involvement of the hip in systemic-onset forms of juvenile chronic arthritis. Retrospective study of 28 cases]. AB - The objective of this work was to evaluate the course of hip disease in patients with systemic-onset juvenile chronic arthritis. 59 patients with systemic-onset juvenile chronic arthritis followed-up for a mean of 15 years (+/- 6 years) were studied retrospectively. 28 patients (47.5%) had involvement of the hip. Mean age at onset of symptoms of hip disease was 9.5 years (+/- 5 years). Hip arthritis was always preceded by other manifestations of the disease, including arthritis of other lower limb joints. Mean time interval between onset of the disease and onset of hip symptoms was 6.3 years (+/- 3 years). In 66% of cases, symptoms occurred simultaneously in both hips. Eight of nine patients with initially unilateral hip arthritis subsequently developed arthritis of the other hip; in four patients, less than one year elapsed between involvement of the two hips. Roentgenographic changes were variable and included acetabular protrusion (25%), complex cervico-cephalic and acetabular growth disorders (21%), subdislocation (18%), a short femoral neck with varus deformity (14%), and a long femoral neck with valgus deformity (14%). Avascular necrosis of the femoral head occurred in three patients. Roentgenographic evidence of repair was seen in one patient. Among the ten patients who required surgery, two had corrective osteotomy with adductor tenotomy and eight had total hip arthroplasty (of both hips in six patients) with good short- and medium-term outcomes. After arthroplasty, a single patient required reoperation in the short term, for persistent flexion contracture. Loosening of the acetabular arthroplasty required revision in two patients 5 and 10 years, respectively, after the initial procedure.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7858592 TI - [Comparison of azathioprine and methotrexate in rheumatoid arthritis: an open randomized clinical study]. AB - Thirty-eight patients with active rheumatoid arthritis (RA) were entered in an open randomized 24-week study comparing azathioprine (AZA; initial daily dose 1 mg/kg) with methotrexate (MTX; initial weekly dose 7.5 mg). The patients had previously been treated with antimalarials, gold salts and/or D-penicillamine. The groups were well balanced in baseline characteristics. There were three premature withdrawals in each group, all of which were due to toxicity. The present study did not show any significant differences between AZA and MTX in ability to reduce activity in RA after 24 weeks of treatment. PMID- 7858593 TI - [Increase of CA 19.9 in dysimmune inflammatory rheumatism. Apropos of 6 cases]. AB - CA 19.9 is a marker for several cancers, including ductal adenocarcinomas of the pancreas. CA 19.9 elevation is rarely found in patients without benign or malignant digestive system disease. We studied serum CA 19.9 levels in patients with a variety of inflammatory joint diseases, including rheumatoid arthritis (n = 20), lupus, Sjogren's syndrome or U1RNP-associated connective tissue syndrome (Sharp's syndrome) (n = 11), dermatopolymyositis (n = 8), and giant cell arteritis or polymyalgia rheumatica (n = 8). The mean CA 19.9 level in each of these groups was not significantly different from the value seen in a group of patients with osteoporosis. Six patients had persistent marked elevation in serum CA 19.9 levels. Two had Sjogren's syndrome, two had Sharp's syndrome and two had dermatopolymyositis. None of these six patients had evidence of tumoral disease despite a follow-up of several years. Likely explanations for the CA 19.9 elevation were chronic pancreatitis in one case and lung disease in the other five. In patients with lung involvement due to inflammatory joint disease, CA 19.9 elevation may indicate severe disease and may be of use for monitoring the lung condition. PMID- 7858594 TI - [Neer's shoulder prosthesis: results according to etiology]. AB - The outcome of 80 glenohumeral arthroplasties with the Neer prosthesis in 77 patients with degenerative or inflammatory shoulder disease was evaluated after a mean follow-up of three years five months. The arthroplasties were performed because of intractable pain and functional disability due to destruction of the glenohumeral joint. The postoperative rehabilitation program focused on full recovery of joint motion and function in 65 cases and on joint stability with partial recovery of joint motion and function in 15 cases. According to the criteria developed by Neer, the outcome was excellent or satisfactory in 75% of cases and unsatisfactory in 25%. Constant's scores adjusted for age and gender varied widely across diagnostic categories, from a high of 76% in centered glenohumeral osteoarthritis (n = 40) to lows of 59% in rheumatoid arthritis (n = 21) and 45% in posttraumatic osteoarthritis (n = 10) or eccentric osteoarthritis due to cuff disruption (n = 9). At reevaluation, 70% of patients had little or no pain and 90% were satisfied with the outcome. The mean increase in flexion of the arm (39 degrees) was markedly influenced by the diagnosis. The increases in lateral rotation (mean 35 degrees) and medial rotation (four vertebral levels) of the arm were especially appreciated by the patients as having a very beneficial effect on the ability to perform everyday tasks. Complications included instability in three cases (two anterior dislocations and one posterior dislocation), glenoid component loosening in 11 cases (of which only four required reoperation) and rotator cuff tear in eight cases. Our results add to the existing evidence that nonconstrained shoulder implants, such as the Neer prosthesis, are both safe and effective in alleviating pain and improving joint function. They should be used in patients with refractory pain, disability due to restrictions in external and medial rotation of the arm and roentgenographic evidence of glenohumeral joint space loss. PMID- 7858595 TI - [Measurement of bone density in the wrist using X-ray absorptiometry: comparison with measurements of other sites]. AB - In order to validate a new technique to measure bone mineral density (BMD) of the forearm with a single X-ray absorptiometry device (DTX 100), we have measured the BMD of 195 women, aged 32 to 83 years, free of metabolic bone disease, simultaneously on two devices: 1. BMD of the ultradistal radius and of the distal radius and ulna on DTX 100, Osteometer, 2. BMD of the lumbar spine, of the proximal femur, of the whole body and of the distal and ultradistal radius by dual X-ray absorptiometry (DXA) on an Hologic 2000 device. The precision of DTX, assessed by 5 repeated measurements on 9 volunteers, was 1% for the distal site and 2% for the ultradistal site. There was a high correlation (r = 0.93) between radial BMD measurement by DTX and Hologic 2000. Correlations between forearm BMDs measured by DTX and whole body BMD were as high (r = 0.80-0.82) as between whole body BMD and lumbar spine (r = 0.82), femoral neck (r = 0.77) and femoral trochanter (r = 0.76). Age-related bone loss measured by DTX was 27% and 31% at the distal and ultra distal radius respectively, as compared to 17% for the lumbar spine, 21% for the femoral neck and 16% for the whole body BMD. In a group of 20 untreated osteoporotic women with vertebral fractures, forearm BMD was as sensitive (T score of -3.1 and -2.9 for distal and ultra distal) as was lumbar spine (T = -2.9) and femoral neck (T = -2.5).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7858596 TI - [Self tolerance]. PMID- 7858597 TI - [Osteomyelitis in the pagetic tibia]. AB - Osteomyelitis developing in pagetic bone is a very rare event, of which only one instance has been reported to date, in a patient with mandibular disease. We have managed three patients with osteomyelitis of a pagetic tibia. The portal of entry was a skin lesion in all three cases. A Gram-negative organism was found in all three cases and was associated with the anaerobe Bacteroides melaninogenicus in one case. One of the patients was lost to follow up before eradication of the infection. Amputation was required in the other two after unsuccessful antimicrobial therapy for 23 and four years, respectively. PMID- 7858598 TI - [Kawasaki's disease in a young adult]. AB - The authors describe a 29-year-old white male who fulfilled the diagnostic criteria for Kawasaki disease. Apart from the patient's age, this case is unusual in that there were a large number of manifestations including liver complications, epistaxis, Baker's cyst, and circulating anti-neutrophil cytoplasmic antibodies. PMID- 7858599 TI - [A case of Gougerot-Sjogren syndrome associated with diffuse interstitial calcinosis and Jaccoud's arthropathy]. PMID- 7858600 TI - [Peroperative anaphylactoid reaction in systemic mastocytosis]. PMID- 7858601 TI - [Longitudinal fatigue fissure of the femoral diaphysis: apropos of a first case]. PMID- 7858602 TI - [Use of criteria of Amor and European Spondylarthropathy Study Group in the United States]. PMID- 7858603 TI - [Study of algodystrophy using bone scintigraphy together with Doppler ultrasonography]. PMID- 7858604 TI - [Erosive polyarthritis in Crohn disease]. PMID- 7858605 TI - [Role of synovial inflammation, cytokines and IGF-1 in the physiopathology of osteoarthritis]. AB - The role of cytokines in the progression of arthritic diseases such as osteoarthritis (OA) has received particular attention because of the important interaction between articular cartilage and synovium in the pathology of the diseased state. Chondrocytes and synovial cells are targeted by cytokines such as interleukin 1 (IL-1) and tumor necrosis factor (TNF-alpha) to produce matrix proteases and to suppress the synthesis of collagen and proteoglycan. Thus, cytokines not only favor tissue destruction, but also inhibit tissue repair. Furthermore, growth factors such as insulin-like growth factor (IGF-1), may not be able to counteract the effect of cytokines on the synthesis of matrix components or natural inhibitors of cartilage degrading enzymes due to a resistance of the chondrocyte to the action of this hormone. This article discusses the action of cytokines and growth factor IGF-1 and their relationship to the pathophysiology of OA. PMID- 7858606 TI - [Importance of interleukin-I receptors in osteoarthritis]. AB - Osteoarthritis (OA) is a degenerative disease of the articular cartilage associated with a variable degree of synovial inflammation which appears to play an important role in the pathophysiological process by interacting with and thereby accelerating catabolism. Interleukin-1 (IL-1) is a main contributor to these changes. Its action is mediated via binding to specific receptors on target cells. In human cells, two types of IL-1 receptors (IL-1R) have been characterized: the type I and the type II. Extensive characterization of IL-1R on both chondrocytes and synoviocytes demonstrated that the type I is predominant. Recent data suggested the importance of these receptors in OA pathophysiology. A two-fold increase in the number of sites per cell was found in OA cells, which resulted in a higher sensitivity of the latter cell to stimulation by IL-1. Understanding the elements involved in the regulation of these receptors will, therefore, provide a better insight for therapeutic strategy. Findings regarding IL-1 inhibitors, such as soluble IL-1R (sIL-1R) and IL-1 receptor antagonist (IL 1ra) offer exciting possibilities for controlling cytokine biology. Recent investigation of the IL-1ra system by our laboratory has explored its role in OA. Results from two studies will be discussed. PMID- 7858607 TI - [Osteoarthritis of rare etiology]. AB - Although osteoarthritis is characterized by a uniform pattern of clinical and radiological manifestations, it is a syndrome that can be produced by a variety of causative factors. Rare causes of osteoarthritis can be categorized as follows: 1) systemic metabolic disorders due to known biochemical and/or genetic abnormalities, such as hemochromatosis, ochronosis, Wilson's disease, Ehlers Danlos syndrome (and probably the "idiopathic" joint hypermobility syndrome), sickle cell anemia, and thalassemia; 2) endocrine disorders, such as acromegaly, whose joint manifestations are now well-known, and hypothyroidism; 3) Paget's disease of bone, osteopetrosis (which induces changes in bone elasticity), and other systemic bone diseases; 4) dysplasias, which form a vast group including familial polyepiphyseal dysplasia, spondyloepiphyseal dysplasia congenita (especially its milder forms), Stickler's syndrome, osteo-onychodysplasia, Kniest's dysplasia, trichorhinopharyngeal syndrome, and a group of diseases that affect the epiphyses; 5) endemic forms of osteoarthritis, e.g., Mselini disease, Kashin-Beck disease, and Malnad disease, which are unknown in western Europe but have been reported to affect thousands of individuals in endemic areas. All these disorders are usually responsible for premature osteoarthritis, whose presentation sometimes bears the imprint of the causative abnormality but can be identical to that of common osteoarthritis. The effects of toxic substances (Kashin-Beck disease) or genetically-determined collagen II abnormalities (epiphyseal dysplasias) may explain the occurrence of these rare forms of premature osteoarthritis. PMID- 7858608 TI - [Rate of joint space pinching in coxarthrosis]. AB - Accurate measures of cartilage destruction are needed to evaluate the effects of chondroprotective agents in human osteoarthritis. Use of a digitalized image analyzer (HOLOGIC, ICMS software) to measure mean joint space width on roentgenograms of the hip is a simple, reliable method with a coefficient of variation of 3.3%. To determine the rate of joint space loss and to identify factors associated with this parameter, we retrospectively studied 56 hips with osteoarthritis in 39 patients (mean age at baseline 55.5 +/- 12 years; mean roentgenographic follow-up 5.2 +/- 3.6 years, mean number of roentgenograms per patient 3.7 +/- 1.1). Mean annual joint space loss was 13.5 +/- 16.6%, i.e., 0.42 +/- 0.38 mm, and was negatively correlated with the duration of roentgenographic follow-up (r = 0.95 and 0.97, p < 0.01). When only those subjects who were followed up for two to eight years were studied, mean joint space loss was only 6.7% with a considerably smaller standard deviation of 4.2%, i.e., 0.29 +/- 0.21 mm. No influence on the rate of joint space loss was found for age at onset of symptoms, age at the first roentgenographic study, side, gender, or location of the joint space narrowing. The roentgenographic stage or joint space width at baseline were positively correlated with the rate of joint space loss expressed as a percentage but not in mm. These data suggest that the absolute amount of cartilage lost is not influenced by the roentgenographic stage of the osteoarthritis at inclusion of the patient in the study.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7858609 TI - [Chondroscopy: a new method for measuring osteoarthritis?]. AB - Arthroscopy allows direct visual examination of joint cavity components and is useful for the diagnosis, treatment and evaluation of lesions. We investigated the contribution of arthroscopy to the evaluation of joint cartilage. The severity of cartilage lesions can be assessed using a total 100-mm visual analog scale (0 = no chondropathy; 100 = the worst possible lesions) or a more objective system based on the site, depth, and surface area of the lesions. This latter system was developed by the French Society for Arthroscopy (Societe Francaise d'Arthroscopie) and provides a score and a class (SFA score and SFA grade). We investigated whether this system has the characteristics required of an evaluation tool, i.e., simplicity, reproducibility, clinical relevance, sensitivity to change, and discriminant capacity. Arthroscopy is an invasive procedure. However, we introduced several simplifications, including use of local rather than general anesthesia, performance on an outpatient basis, elimination of the tourniquet (to avoid muscular dysfunction), and use of a small arthroscope. This simplified technique is called chondroscopy. Intra-observer reproducibility is far better than inter-observer reproducibility. We found a good correlation between the two arthroscopy scales (visual analog scale and SFA scale). Chondroscopy and roentgenographic evaluations of cartilage lesions were closely correlated. Changes in the severity of cartilage lesions were correlated with changes in functional impairment. Chondroscopy proved capable of demonstrating statistically significant changes in cartilage lesions due to knee osteoarthritis between two evaluations done only one year apart, even in a small sample of patients (less than 20). A preliminary study of repeated hyaluronic acid injections suggested that chondroscopy may be capable of identifying truly chondromodulating agents. PMID- 7858610 TI - [Methods for evaluating chondroprotective agents]. AB - A number of compounds have "chondroprotective" effects in animals or chondrocyte cultures. However, in humans, these drugs have not been convincingly shown to prevent, delay, arrest, or repair structural cartilage lesions due to osteoarthritis. In clinical trials, the main evaluation criterion should be the time-course of cartilage lesions. One parameter for assessing cartilage lesions is cartilage thickness, which can be measured at the site of greatest joint space loss using compasses and a magnifying glass. Alternatively, joint space surface area in the abnormal zone can be determined by automatic analysis of digitalized images. Use of echotomographic sections obtained using an intraarticular probe inserted during arthroscopy of the knee has been advocated. External measurements by magnetic resonance imaging or ultrasonography are technically difficult and most have been found inadequate during validation studies. Clinical trials should also include a clinical assessment of therapeutic benefits, without which chondroprotection would be pointless. Duration of these trials should be two to four years, since cartilage loss occurs slowly in osteoarthritis: mean values of 1/4 mm per year, with wide variations, have been reported at the hip and knee. A randomized, double-blind, placebo-controlled design should be used. PMID- 7858612 TI - [Various aspects of the epidemiology of osteoarthritis]. PMID- 7858611 TI - [Study of ART 50 in everyday rheumatic practice]. PMID- 7858613 TI - [Regulation of cartilage matrix synthesis by chondrocytes]. AB - Articular cartilage has important load bearing properties. These depend on the integrity of its matrix which is formed by a dense network of collagen fibres (mainly type II) and a high concentration of proteglycan (mainly aggrecan). The matrix is maintained by the chondrocytes, which control the production and turnover of matrix components and are greatly affected by cytokines (such as IL-1 alpha,beta and TNF alpha) and growth factors (such as IGF-1 alpha, beta TGF beta). They have strongly antagonistic effects. IL-1 alpha, beta and TNF alpha inhibit proteoglycan synthesis and at slightly higher concentration they enhance the rates of matrix degradation. In contrast the growth factor IGF-1 stimulates proteoglycan biosynthesis and reduces matrix proteinase action. TGB beta has less direct anabolic effect on matrix biosynthesis in normal cartilage, but does not induce an anabolic response in isolated chondrocytes or in explants following IL 1 treatment. We have also investigated the action of IL-1 in inflammatory arthritis in vivo by treatment with IL-1 receptor antagonist, the natural IL-1 inhibitor. In antigen-induced arthritis the effects of the injection of rh IL-1 ra was measured over 3 days. There was little effect on the induction of joint swelling, cellular infiltration into synovium or cartilage proteoglycan depletion, but when given over a similar time in more chronic arthritis, 14 days after induction it had a major effect on suppressing synovial fibrosis although it still did not affect parameters of joint inflammation. The results suggested that IL-1 was not the major factor inducing inflammation in the joint, but was responsible for the excessive collagen deposition in the synovium in this experimental model of arthritis. PMID- 7858614 TI - [Biological markers of osteoarthritis]. AB - The degradation of proteoglycans, collagens and proteins in the articular cartilage matrix produces fragments which diffuse out of the tissue and into the joint fluid. These fragments subsequently appear in the blood circulation and are eventually eliminated by the liver or the kidney. Recent studies have shown that the joint fluid and blood levels of these biological markers of degradation can be used to monitor abnormal metabolic processes in cartilages. The joint fluid level of a cartilage-derived marker provides information about the metabolism of that molecule in that joint. In blood, levels of specific markers have been shown to be helpful in identifying systemic changes affecting the metabolism of matrix constituents in all or most cartilages in the body. Measurement of different biological markers in body fluids have proved useful in identifying increased catabolic activities in articular cartilage during the preradiological stages of osteoarthritis. These markers have great potential for monitoring disease activity, assessing disease progression, examining responses to drug therapy and evaluating long-term prognosis. In addition, markers should prove most useful in prospective studies at identifying early changes in cartilage metabolism in humans at high risk of developing post-traumatic osteoarthritis. PMID- 7858615 TI - Endourologic management of complications in renal allografts. AB - Because of the altered anatomy, the presence of immunosuppression, the possibility of graft rejection, and the serious implications of a problem involving a solitary kidney, the transplanted kidney presents unique challenges in the diagnosis and treatment of urologic complications. Historically, the mortality rate in these patients has been as high as 68%, and as many as 15% of the allografts have been lost. Today, endourologic procedures are used for prompt diagnosis, temporization, and even definitive management of many urologic complications, and many patients and allografts are being saved. The authors review present techniques and suggest others that may be available in the future. PMID- 7858616 TI - Does respiratory gating improve extracorporeal shockwave lithotripsy results? AB - The reliability and efficacy of extracorporeal shockwave lithotripsy (SWL) has been established in urinary stone disease. Its combination with respiratory gating might be a useful method to increase the effectiveness of treatment and reduce the number of shocks required. For this purpose, the results of SWL combined with respiratory gating were compared with those of SWL without gating. There was no difference in the stone-free rates of the two groups or in the complication rate. It is concluded that this method neither decreases the number of shockwaves needed nor increases the effectiveness of SWL. PMID- 7858617 TI - Piezolith extracorporeal shockwave lithotripsy: the Hotel-Dieu de France experience. AB - A total of 1500 patients underwent treatment with the Wolf Piezolith 2300 extracorporeal shockwave lithotripter for renal, ureteral, and bladder stones. Follow-up data were available at 3 months for 1435 patients. At that time, the overall stone-free rate was 82.7%: 82.4% for patients with renal stones, 81.0% for those with ureteral stones, and 100% for those with bladder stones. The overall success rate was 92.3%: 93.8% for patients with renal stones, 87.1% for those with ureteral stones, and 100% for those with bladder stones. The auxiliary treatment rate was 14.9%, and the retreatment rate was 53%. The effectiveness quotient was 49.2%. The Wolf Piezolith 2300 is an effective treatment for most stones smaller than 30 mm. PMID- 7858618 TI - Clinical correlates of the gross, radiographic, and histologic features of urinary matrix calculi. AB - We present five patients with urinary matrix calculi, which, in contrast to the normally brittle calcigerous calculi, are soft, pliable, and amorphous. Common clinical features include a history of calcigerous stone disease, renal surgery, urinary obstruction or stasis, and chronic infection with Proteus species or coliforms. The diagnosis is usually made at surgery, but certain preoperative radiographic findings may be suggestive. Matrix calculi are radiolucent on plain abdominal films, although their appearance on nonenhanced CT scans is similar to that of calcigerous calculi despite their small mineral content. Extracorporeal shockwave lithotripsy is ineffective; open or percutaneous techniques are necessary. Histologic inspection reveals laminar concentric rings of organized matrix with an orderly, layered deposition of minerals. Histochemical investigation can provide insight into the possible sequence of events in normal calculogenesis. The successful management of urinary matrix calculi depends on a high index of suspicion and a thorough knowledge of their clinicopathologic features. PMID- 7858619 TI - Outpatient fragmentation of ureteral calculi with mini-ureteroscopes and laser lithotripsy. AB - Laser lithotripsy with mini-ureteroscopes is a minimally invasive method to fragment ureteral calculi. This study reviewed the efficacy and morbidity of outpatient laser lithotripsy for the treatment of ureteral calculi. The 248 patients were initially treated by outpatient ureteroscopy and laser lithotripsy with the Candela pulsed-dye laser over a period of 3 1/2 years. Thirty-six patients had prior unsuccessful fragmentation of ureteral calculi by SWL. Twenty eight patients had undergone unsuccessful ureteroscopy with attempted basket extraction or attempted fragmentation with methods other than laser. Calculi were located in the upper ureter in 31% and in lower ureter in 69% of these patients. The 1-month stone-free rate was 92% for upper ureteral calculi and 96% for lower ureteral calculi, with an overall success rate of 94.7%. Ninety per cent of the patients were discharged the same day and 96% within 23 hours. Hospital admission was needed in only 4% of patients. Parenteral analgesia was required in 18% of patients, and major complications occurred in 0.8%. The combination of mini ureteroscopes and laser lithotripsy is an effective method for fragmentation of ureteral calculi in outpatients with low morbidity and few complications. PMID- 7858620 TI - Endoscopic management of ureteral injury after cesarean section. AB - Ureteral injury is an uncommon complication of cesarean section. As with all iatrogenic ureteral injuries, if the problem is not recognized intraoperatively, the manifestations may be protean. The management of ureteral injury that is first recognized in the early postoperative period must be individualized. We present a case of ureteral injury during a cesarean section in which endoscopic techniques were employed successfully to establish kidney drainage and allow ureteral healing, obviating open surgical repair. PMID- 7858621 TI - Oliguria during laparoscopic surgery. AB - Oliguria is infrequently viewed as a complication of laparoscopic surgery. The rate of urine output in six healthy patients undergoing laparoscopic surgery was measured during the period of CO2 pneumoperitoneum and for several hours after desufflation. The average hourly urine output during insufflation was 0.30 +/- 0.14 mL/kg despite an average hourly intravenous infusion rate of lactated Ringer's solution of 13.0 +/- 4.0 mL/kg. After release of pneumoperitoneum, urine output increased 467% to 1.7 +/- 1.1 mL/kg per hour. Patients remained hemodynamically unchanged perioperatively. Preoperative and postoperative blood urea nitrogen and creatinine concentrations did not significantly differ. We discuss the potential etiologic factors in the development of oliguria in the setting of the increased intra-abdominal pressure of pneumoperitoneum and the implications of this acute but reversible renal dysfunction. PMID- 7858622 TI - Minilaparotomy for laparoscopy: not a foolproof procedure. AB - Minilaparotomy with placement of a trocar under direct vision has been felt to be a safe approach for establishing access to the intra-abdominal contents during laparoscopy. However, there is potential for hollow viscus injury. We report a case of a 23-year-old man whose small bowel was injured during placement of a Hasson trocar at the time of laparoscopic varix ligation. The literature on laparoscopic complications is reviewed, and recommendations for avoiding difficulties are outlined. PMID- 7858623 TI - Laparoscopic radical nephrectomy for renal cell carcinoma: early experience. AB - We developed a laparoscopic radical nephrectomy for malignant disease of the kidney and successfully performed the operation in six patients between July 1992 and October 1993. This procedure is basically derived from that of Clayman and associates. A CO2 pneumoperitoneum is induced, and five trocars are introduced into the abdominal cavity through the lateral abdominal wall. The kidney is removed en bloc together with the adrenal gland, perirenal fatty tissue, and Gerota's fascia. The free kidney is put into a laparoscopy sack, and the sack is pulled out through a 5- to 6-cm incision in the abdominal wall without morcellation to allow complete pathologic examination. By this procedure, right nephrectomy was performed in four patients and left nephrectomy in two patients. The mean operative time was 6 hours and 13 minutes, and the mean blood loss was 430 mL. There were no severe complications. The average hospital stay was 11 days, and the average time to full convalescence was 21 days. Pathologic examination revealed renal cell carcinoma in five patients and nephroblastoma in one. Of the patients with renal cell carcinoma, the stage was pT1pN0pM0 in three patients and pT2pN0pM0 in two. There has been no recurrent disease in these six patients with a mean follow-up period of 9.5 months. PMID- 7858624 TI - Laparoscopic management of testicular pain after embolotherapy of varicocele. AB - We report a patient who underwent embolization of a varicocele for chronic testicular pain with Gianturco coils and developed increased bilateral pain. Complete pain relief was achieved by laparoscopic resection of both spermatic cords. The case provides insights into the pathophysiology of testicular pain and may suggest alternative therapies for chronic orchialgia. PMID- 7858625 TI - Role of laparoscopic pelvic lymph node dissection in the management of patients with penile cancer and inguinal adenopathy. AB - Patients with invasive squamous cell carcinoma of the penis and tumor involvement of the inguinal nodes are at risk for pelvic lymph node metastases. When this spread occurs, the chance for patient survival is limited. Because the sensitivity of CT in detecting pelvic lymph node metastases is low, open surgical pelvic lymphadenectomy is frequently performed. We have utilized laparoscopic pelvic lymphadenectomy as a minimally invasive alternative to this open approach in three patients with Stage T3 (UICC staging system) squamous cell carcinoma of the penis who had persistent inguinal adenopathy after a standard course of postpenectomy antiobiotic therapy. There were no intraoperative or postoperative complications, and all patients were discharged within 24 hours after surgery. The mean number of nodes removed was eight, and all specimens were free of tumor. Laparoscopic pelvic lymphadenectomy should be considered in patients with persistent inguinal adenopathy after antibiotic therapy before proceeding with inguinal lymph node dissection. PMID- 7858626 TI - Response of renal intrahilar retroperitoneal fibrosis to immunosuppressive therapy. AB - We report the case of a 37-year-old woman who developed renal failure secondary to obstruction by renal intrahilar retroperitoneal fibrosis. Her disease proved to be sensitive only to high-dose immunosuppression. Our case illustrates an unusual course of this disease and the role of immunosuppression in its management. PMID- 7858627 TI - Laparoscopically implantable nerve-stimulating electrode (LINSE): application to the cavernous nerve in acute and chronic canine models. AB - Using a new laparoscopic procedure, we investigated stimulation of the cavernous nerves to achieve erection in a canine model. The technique was developed during acute experiments in four dogs, following which, chronic studies (4- to 6-weeks survival after surgery) were undertaken in three dogs. A monopolar cuff electrode was inserted laparoscopically by a transperitoneal approach and placed around the cavernous nerve. The leads were brought out to the subcutaneous space, where they were attached to stimulation receivers that could be activated by an external radiofrequency transmitter. An intracavernous pressure elevation indicative of successful stimulation was obtained acutely in five of eight cavernous nerves in the four acute-study dogs and in four of six nerves in the three chronic-study dogs. The implanted equipment associated with four of six cavernous nerves failed mechanically in the chronic-study animals, such that only two receiver-electrode sites were intact at the time of sacrifice 4 to 6 weeks later. Transmitter-driven stimulation of one of these two sets produced an intracavernous pressure rise above 100 cm H2O. We present this technique as part of the continuing evolution of laparoscopy as both a research and a clinical tool. The present use of the laparoscopically implantable nerve-stimulating electrode is a new animal research tool and a potential first step in the human application of the technology. PMID- 7858628 TI - [Current therapeutic modalities for cancer of the prostate]. AB - The treatment of prostatic adenocarcinoma is no longer limited to systematic and blind oestrogen therapy. Modern methods of investigation now allow us to determine with much greater precision the site, size and extent of the tumour as well as its histological features. Therapeutic modalities have also been improved and diversified and should now be selected according to the clinical stage of the tumour and, less precisely, according to its cellular aggressiveness potential (grade). Schematically, the major therapeutic approaches are as follows: because of their slow and uncertain natural history, incidental tumours (stage T1a and b) may not require any immediate treatment provided they are submitted to long-term surveillance. Cancers confined to the prostate gland (stages T1b, T2) warrant local therapy, which may be curative at this stage: radical prostatectomy or radiotherapy. The principal problem at this stage remains the difficult assessment of lymph node involvement. Locally more advanced cancers (stages T3 T4) are no longer amenable to curative treatment and opinions are divided between combined (and aggressive) local treatments and hormone therapy. Disseminated, metastatic cancers (stages D2, M+) are treated by hormone therapy which may consist of a combination of androgen deprivation by LHRH analogues or surgery and antiandrogens with a direct prostatic action. Although very effective in the majority of cases, the action of this treatment is limited in time. When the "hormone escape" phase is reached, no specific chemotherapy is available and only palliative measures can try to maintain an acceptable quality of life for a limited period of time. PMID- 7858629 TI - [Stenosis of the vesico-urethral anastomosis. Our experience with 114 radical prostatectomies]. AB - The authors report a retrospective series of 114 radical prostatectomies performed over a ten-year period. This study was designed to investigate the factors likely to cause complications in order to prevent them. Stenosis of the vesicourethral anastomosis was observed in 22 patients and represented the commonest complication (19.2%). It generally occurred before the 12th month, while late stenoses. An anastomotic leak after removal of the bladder catheter appears to be the most significant factor. The decreasing incidence of these stenoses over the ten-year study period illustrates the role of operator experience. The most effective treatment for these stenoses is mono-incision which, completed by dilatation sessions, prevents recurrence without compromising continence. PMID- 7858630 TI - [Extracorporeal lithotripsy for urinary calculi: a non invasive technique? Report of 150 patients treated with the Nova lithotriptor]. AB - The NOVA apparatus is an electrohydraulic lithotriptor not yet available in France. The authors present an evaluation of the first 150 patients treated with this machine. 92.2% of the 185 stones treated were fragmented. 141 patients were reviewed at 1 month and, if necessary, 3 months after the first session; 4/24 patients and 1/3 patients were not reviewed after their second and third treatment session, respectively. Evaluation of the 177 sessions performed (16% of second sessions and 2% of third sessions), 69.11% of patients did not have any residual stones. The success rate was 52% for renal stones; 96% for stones of the lumbar ureter and 50% for pelvic stones. The morbidity was low (10% of renal colic, 5% of obstructive stone) but in combination with second treatment sessions, it generated a risk of being rehospitalised after the first session of 26%. When the procedures performed under anaesthesia before and after ECL (apart from repeated sessions) are added, the risk of this supplementary anaesthetic for a given patient is 18.66%. Lastly, the risk of undergoing another anaesthetic after the 1st ECL was 33%. These data indicate the limits of the "noninvasive" nature of a modern and effective lithotriptor. PMID- 7858631 TI - [The use of the Babcock forceps for hemostasis of the pre-prostatic veins in radical prostatectomy of total cystoprostatectomy]. AB - Haemostasis of Santorini's venous plexus during radical prostatectomy or total cystoprostatectomy is a delicate phase of the procedure which facilitates the conditions of the surgery and the postoperative course. Based on a series of 150 prostatectomies, the authors describe their technique using Babcock forceps for "en bloc "ligation of the venous plexus. After opening the pelvic aponeurosis and section of the puboprostatic ligaments, a Babcock forceps is placed above the urethra and prostatic apex, including all of Santorini's plexus enclosed by its fibrous tissue, allowing exposure of the abascular plane of cleavage situated between the anterior surface of the urethra and this plexus. Klikenberg scissors are then introduced into the depression formed underneath the jaws of the Babcock forceps and are guided by the index finger into the symmetrical depression of the other side. The hypogastric connective tissue is perforated lateromedially and the scissors are gently opened to enlarge the passage. A right-angle dissector is then inserted and grips n.1 or 2 absorbable suture material which, after removing the Babcock forceps, is used to tie all of the anterior venous complex. This technical device allows a more reproducible and standardised approach to this operative step. PMID- 7858632 TI - [Sexuality in Ancient Egypt]. AB - The present article explores the sexuality in ancient Egypt. In particular in this article are presented the ways of concubinage (marriage, concubinage, adultery), the incest, loves of the pharaohs and of the common people, the freedom of choice in garments, the status of the hetairas and of the whores, the sexual perversions (male and female homosexuality, necrophilia, sodomism, bestiality, rape, masturbation, exhibitionism), the operations of the genitals (circumcision, excision, castration) and finally the level of knowledge in gynaecology, fertility, contraception and obstetrics that even today demands our admiration. PMID- 7858633 TI - [Radical prostatectomy. Report of the 88th Congress of the French Association of Urology 1994]. PMID- 7858634 TI - [How to control the Santorini's plexus easily]. AB - Control of Santorini's plexus is one of the main difficulties of prostatectomy and total cystectomy. Two procedures allow easy control of this plexus: Perform a running haemostatic suture in the bladder neck, from one edge of the pelvic aponeurosis to the other. Apart from ensuring haemostatis by bringing Santorini's plexus together in the midline, this suture also provides excellent exposure of the prostate. Prepare the passage of the dissector at the prostatic apex by disrupting the fibrous tissue with a finger. The urethra is easily identified as it is intubated by the bladder catheter. The avascular plane between the urethra and Santorini's plexus is open to the finger and the dissector can be easily introduced into the correct plane. Section of the venous plexus is performed precisely to reveal the urethroprostatic junction. PMID- 7858635 TI - [Vesico-urethral anastomosis after radical prostatectomy in cancer: Vest-Mayo's simplified technique]. AB - The authors describe the technique of anastomosis without vesicourethral suture after radical prostatectomy for cancer. The operative details are described with a brief analysis of the principal complications observed in the first 14 patients operated with preservation of the bladder neck. These results are compared with the in the literature concerning this old technique recently revised by the Mayo Clinic surgical team in 1988. PMID- 7858636 TI - [Color Doppler ultrasonography in urology]. AB - Due to the development of the duplex mode, combining ultrasound images with Doppler recording, and especially the development of flow colour coding. Doppler is now increasingly used to investigate the kidney and male genital tract. It is now the technique of choice in the initial diagnosis of certain renal diseases: primary renal vein thrombosis, iatrogenic and malformative arteriovenous anomalies, vascular complications of renal transplantation, and for examination of the scrotal contents in a context of acute scrotum or investigation of the cavernosal arteries in the case of erection disorders. It allows a rapid diagnosis and guides the subsequent radiological assessment. Doppler can also provide useful or even essential additional information in the case of a known abnormality such as renal cancer, in which it defines the venous extension when CT scan is technically insufficient. In certain fields, such as diagnosis of renovascular hypertension or exploration of the prostate, the place of Doppler is still poorly defined and remains controversial, except in a few specialised centres equipped with sophisticated apparatuses used by experienced operators. After briefly reviewing Doppler techniques and the basic steps in interpretation, the authors define the contribution and limitations of colour Doppler in the investigation of the urinary tract and male genital tract. Normal appearances and the results of Doppler-ultrasound in nephrourological disease are illustrated. PMID- 7858637 TI - [Tomodensitometry: current technique and perspectives]. AB - The inventors of computed tomography were rewarded by the Nobel Prize for Medicine in 1979. This apparatus, now used routinely, is based on the physical principle of attenuation of x-rays combined with computerised calculation to generate a tomographic image of the human body. This article describes the components of computed tomography, the mode of acquisition, calculation and image reconstruction and the criteria of image quality and artefacts. Continuous rotation of the x-ray tube, now available on the latest machines, allows rapid 3D acquisition of raw data, largely eliminating movement artefacts, particularly those related to respiration. It is also possible to reconstitute images in a different plane from the plane of acquisition and to obtain 3D representations of the volume studied. The advantages and disadvantages of this recent technique are discussed. PMID- 7858638 TI - [MRI: overview, technique, interpretation]. AB - The purpose of this paper is to describe the general principle of MRI, emphasising the practical conduct of the examination which consists of three main phases. The authors define the concepts of relaxation time and T1 and T2, essential parameters for the understanding of MRI. They simply explain how to recognise a predominance of T1- or T2-weighting on MRI images. They review the principal artefacts which must be recognised in order to avoid erroneous interpretation of the images. Lastly, they define the value of MRI in clinical urology, renal pathology, especially neoplastic, and prostatic and bladder disease. PMID- 7858639 TI - [Torsion of the spermatic cord. Current controversies]. AB - The diagnosis of torsion of the spermatic pedicle is primarily clinical, despite the many studies concerning the value of complementary investigations. Currently available imaging modalities are limited either by their lack of sensitivity or by their lack of availability. The absence of well established evidence of direct impairment of contralateral testicular exocrine function is in favour of conservative treatment whenever the local conditions are suitable. PMID- 7858640 TI - [Detubulized Z-shaped +enterocystoplasty following total prostato-cystectomy]. AB - After the completion of the radical cystoprostatectomy and a thorough survey of the dissected pelvis, a small bowel segment 50 to 60 cm long is resected, 20 cm proximal to Bauhin's valve. The small bowel resected is left as it is and as we find it, without rotation folding or twist, forming a Z. It is incised at its antimesenteric border and then the ileal plate is formed with running 3/0 vicryl sutures. The urethra is anastomosed in the lower part of the pouch and there after each ureter is implanted directly in a very simple way. The ureteral catheters are brought directly through the anterior abdominal wall lateral to the rextus muscle. When the omentum is large enough and covers all the dissected pelvis, drainage of the operative site will not be necessary. PMID- 7858641 TI - [Management of drug-induced prolonged erection]. AB - Prolonged pharmacological erection (PPE) is a blocked erection lasting for more than 4 hours after intracavernosal injection (ICI) of an erectogenic drug. This form of priapism is the commonest complication of ICI in the diagnosis and treatment of impotence. It carries a potential risk of acute ischaemia of the corpora cavernosa with subsequent destruction of the erectile tissues. Any blocked erection must therefore be treated within 4 hours. Medical treatment is sufficient in the very great majority of cases, provided it is performed early. The indication for each medical method (simple measures, oral or, more especially, intracavernosal alpha-stimulant treatment, decompressive cavernosal puncture) depends on the duration of PPE and/or the presence of signs of tissue ischaemia (pain). Surgery is only indicated in the rare cases of failure of medical treatment. PPE can now be prevented by means of selection and information of patients and the recent introduction of less dangerous drugs. PMID- 7858642 TI - [Vesico-sphinteral disorders in multiple sclerosis: value of urodynamic tests]. AB - Vesicosphincteric disorders are frequent in multiple sclerosis and lead to the diagnosis of this disease in 2 to 5% of cases. The clinical signs are dominated by urgency (60 to 80%), frequency (40 to 60%) and incontinence due to vesical disinhibition. Dysuria (15 to 30%) occurs in an areflexive or hyperactive bladder, associated with vesicosphincteric dyssnergia. These signs are frequently associated (50 to 80%). Cystomanometry shows detrusor hyperactivity in 50 to 78% of cases and hypoactivity in 20 to 40% of cases and dyssnergia is frequent (50 to 80%). There is no correlation between the clinical and urodynamic signs. Consequently, urodynamic studies are useful for establishing a precise urological diagnosis and to prescribe adapted and early treatment due to the long-term risk of upper tract damage. PMID- 7858643 TI - [Can we improve the selection of patients for curative radical prostatectomy?]. AB - The indication for curative radical prostatectomy in a patient with prostatic cancer clinically confined to the prostate (stage T1, T2) and the absence of any detectable metastases, is associated with a postoperative recurrence rate of 24 to 51% after a mean follow-up of 3 years. Certain preoperative criteria allow the selection of patient groups in which the risk of postoperative tumour recurrence is higher: presence of more than 4 positive biopsies out of 6 systematized biopsies associated with a Gleason score greater than or equal to 7 and a PSA higher than 15 ng/ml (normal value for monoclonal test < 4 ng/ml). The indication for curative radical prostatectomy is doubtful in this group of patients. PMID- 7858644 TI - Control of iron and other micronutrient deficiencies in the English-speaking Caribbean. AB - Most micronutrient deficiencies affect relatively few people in the Caribbean; however, many Caribbean residents are affected by anemia that appears due primarily to a lack of dietary iron. While generally substantial, the prevalences of such anemia have differed a good deal from place to place and study to study, observed rates ranging from 27% to 75% in pregnant women, 19% to 55% in lactating women, and 15% to 80% in young children. Severe anemia, defined by a blood hemoglobin concentration below 8 g/dl, has been found in approximately 6% of the pregnant women and 11% of the preschool children in some Caribbean countries. The principal ways of controlling iron deficiency anemia are through food fortification, control of intestinal parasites, direct oral supplementation, and dietary modification. Progress has been made in iron fortification of wheat flour and wheat products (the principal foodstuffs consumed by the general public in most of the English-speaking Caribbean). Data on control of relevant parasites in the Caribbean (primarily hookworm and to a lesser extent whipworm) are limited. Health services throughout the English-speaking Caribbean have been providing direct iron supplementation for pregnant women, but high levels of anemia during pregnancy still exist because of coverage, monitoring, and compliance problems. All the Caribbean countries also have education programs, which mainly advise pregnant women about iron-rich foods and iron absorption inhibitors and enhancers. PMID- 7858645 TI - HIV/AIDS and its interaction with tuberculosis in Latin America and the Caribbean. AB - At present, human immunodeficiency virus (HIV) is thought to have infected over 17 million people worldwide, over 1 million in North America and roughly 2 million in Latin America and the Caribbean. By comparison, infection with the tuberculosis (TB) agent Mycobacterium tuberculosis is far more common, current estimates indicating that roughly one-third of the world's population is infected. These two infections tend to aggravate each other. That is, HIV leads to a progressive immune system depression that favors reactivation of TB in people with latent tuberculous infections; it promotes progression of TB primary infections or reinfections to full-blown tuberculous disease; and it fosters TB transmission, because those simultaneously infected with HIV and M. tuberculosis tend to develop a bacilliferous and contagious TB that can be transmitted to other susceptible individuals, even though the latter are HIV-negative. In addition, this coinfection tends to promote circulation of drug-resistant M. tuberculosis and to produce peculiar manifestations that complicate TB diagnosis, treatment, and control. Overall, it seems clear that the growing threat posed by these associated agents demands effective action in the form of well-coordinated measures involving throughgoing participation by all countries. PMID- 7858646 TI - Lemon juice as a natural biocide for disinfecting drinking water. AB - The natural biocidal activity of lemon juice was studied in order to explore its possible use as a disinfectant and inhibitor of Vibrio cholerae in drinking water for areas lacking water treatment plants. From January through July 1993, water samples of varying alkalinity and hardness were prepared artificially, and underground and surface water samples were obtained from a number of different rural and urban areas in Argentina's Buenos Aires Province. After measuring the latter samples' hardness and alkalinity, a range of concentrations of lemon juice and other acidifiers were added to each sample, and the resulting pH as well as the samples' ability to destroy V. cholerae were determined. The results show that lemon juice can actively prevent survival of V. cholerae but that such activity is reduced in markedly alkaline water. For example, treatment of underground drinking water, which is characterized as having the greatest degree of alkalinity in our area, will typically destroy V. cholerae if the alkalinity of the water is the equivalent of that produced by 200 mg CaCO3 per liter, if enough lemon juice is added to bring the lemon juice concentration to 2%, and if the lemon juice is allowed to act for 30 minutes. All this points up the need to determine the alkalinity of water from any local source to be treated in the process of assessing the minimum concentration of lemon juice required. PMID- 7858647 TI - A basis for the formulation of policies on health science and technology in Latin America. PMID- 7858648 TI - Street food vending in Latin America. AB - Despite occasional attempts to repress it, street food vending in Latin America appears to be on the rise--encouraged by growing marginal urban populations, the unemployed status of innumerable potential street vendors, lengthening commutes for workers, public demand for cheap and culturally appropriate food near workplaces, and a shortage or absence of regular establishments serving such food. Besides placing a hidden burden on public services, the generally unregulated and quasi-clandestine street food industry tends to observe poor hygienic practices and to pose significant public health problems. Within this context, Latin America's cholera epidemics have drawn increasing attention to street food's potential for disease transmission and have created growing support for attempts to resolve these troubles. What appears needed at this point, rather than futile attempts at abolition, is a new and more positive approach wherein countries change their regulations so as to permit peaceful and constructive adaptation of street food vending to a new style of Latin American social life. This implies legal reorganization directed at structurally developing street food vending and permitting application of measures--especially provision and use of safe water--that will foster good hygiene and safe foods. It also implies creating programs to provide appropriate training for inspectors as well as health education for both vendors and consumers of street food; and it implies promoting and adopting improved methods for preparing and selling such food. There is no reason to suppose these measures will provide an immediate panacea for the street food vending problem; but there is good reason to think they can immensely improve the situation that exists today. PMID- 7858649 TI - Epidemiologic surveillance for substances banned from use in agriculture. PMID- 7858650 TI - Serving the underserved. PMID- 7858651 TI - Case study: Mary is a healthy 33-year-old woman concerned about her risk of breast cancer. PMID- 7858652 TI - Community-directed cancer screening program. AB - The Atlanta Project, one of six American Cancer Society demonstration projects, is a community-designed and -directed breast and cervical cancer screening program focused on empowering African-American women to accept responsibility for their health maintenance. This article reports the project's goals, objectives, intervention strategies, roles of key project personnel, and outcomes. A total of 3852 women older than 40 years received breast clinical examinations, were taught breast self-examination, and had a screening mammogram; 2689 women obtained a pelvic examination and were screened for cervical cancer with a Papanicolaou smear. Of those women screened, 12 breast and 1 cervical cancers were identified and treated. Important lessons learned and successes achieved from this project were: (1) there is a need for joint planning with community representatives and their involvement in all aspects of the program's implementation and evaluation; (2) in addition to the commitment of the major participants, the community must "buy in" to the proposed health intervention; (3) the focus of the intervention should be on positive health messages; (4) cancer education materials should be culturally and literacy-appropriate; (5) the project's activities were planned to be sustained after the project period; (6) women can be empowered to accept responsibility for and control over their health. PMID- 7858653 TI - Breast cancer screening of the medically underserved: results and implications. AB - Socioeconomic status is the most significant factor influencing the decreased survival associated with breast cancer in minority groups in the United States. Barriers to the use of early detection programs by low-income women often result in the detection of breast cancer at stages too advanced to assure optimum outcomes. In an effort to increase accessibility of breast cancer screening among such individuals, the Early Detection Program (EDP) was initiated in 1987. The program provided breast cancer screening to women 40 years of age and older who attended eight primary healthcare centers located in low-income neighborhoods throughout Dade County, Florida. From its inception in October 1987 through December 1993, 23,866 medically underserved women had mammography examinations, with more than 17,000 of these women undergoing baseline mammograms. Since the program's inception, 126 cancers were diagnosed in 123 women. A dramatic shift from later to earlier stage breast cancers was observed. These results warrant a greater inclusion of medically underserved and lower socioeconomic status women in screening programs for the early detection of breast cancer. PMID- 7858654 TI - Strategies for overcoming nurses' fear of radiation exposure. AB - Preparing an additional nursing unit to care for brachytherapy patients at our institution presented a challenge with regard to overcoming fears and misconceptions about radiation exposure. A collaborative effort among the nursing, radiation oncology, radiation safety, and social work departments was successful in educating and supporting the staff and overcoming potential barriers to providing quality care for patients receiving brachytherapy. PMID- 7858655 TI - Chronic venous access: bedside placement technique and complications. AB - Long-term tunneled venous access catheters have evolved into safe and useful tools. More than 80% of these are implanted in patients in operating rooms with fluoroscopic and anesthesia support. This article describes a technique for safely placing these catheters at the patient's bedside and focuses on how to identify, prevent, and manage common complications associated with this procedure. This article also summarizes 8 years of the authors' personal experience with bedside placement and describes a hospital quality assurance study that evaluated the efficacy of bedside placement. The role of appropriately trained personnel is highlighted. The possibility of cost savings, totaling millions of dollars, is raised. PMID- 7858656 TI - Development of a self-administered psychosocial cancer screening tool. AB - Among patients with cancer, psychosocial issues and problems are common, yet they often go unnoticed and thus untreated until they become severe and significantly interfere with the patient's comfort, quality of life, and potentially survival. Given the increasing complexity of cancer care, psychosocial support must assume a more prominent role in the care of individuals with cancer. Routine use of a screening tool for psychosocial assessment may help facilitate early identification and intervention for individuals who are at risk for psychosocial problems. Based on the prevalence of psychosocial problems described in the literature and the paucity of psychosocial screening instruments that can be applied practically in the clinical setting, the development of a new instrument to identify patients with cancer who have psychosocial problems in multiple domains and who thus are at risk for excessive psychosocial distress throughout the course of treatment is presented. This article provides background information, reviews the literature, including instruments that have been used to screen patients in the oncology setting for psychosocial problems, and presents a new instrument based on current deficiencies in this area. Pilot testing of the instrument demonstrates its feasibility for use in the clinical setting. PMID- 7858657 TI - Human immunodeficiency virus-associated neoplasms: epidemiology, pathogenesis, and review of current therapy. AB - The development of cancer in the setting of human immunodeficiency virus (HIV) infection is a devastating event and highlights the role of impaired immunity in the generation of various neoplasms. Improved strategies to suppress viral replication and prevent opportunistic infections generally have enabled patients with HIV to live longer and more productively. Unfortunately, acquired immune deficiency syndrome (AIDS)-associated neoplasia is increasing. Kaposi's sarcoma (KS), primary central nervous system lymphoma, intermediate- and high-grade B cell lymphoma, and invasive cervical carcinoma are AIDS-defining conditions and the most commonly encountered malignancies. Recent information suggests an indirect role for HIV in the pathogenesis of these tumors. Effective treatment involves addressing complex variables encountered specifically in patients with AIDS. This review focuses on the epidemiology, pathogenesis, and treatment of KS and non-Hodgkin's lymphoma. PMID- 7858658 TI - Strategies for assisting people 65 years of age and older. PMID- 7858659 TI - Professional boundaries: clarifying roles and goals. PMID- 7858660 TI - An object-oriented approach to knowledge representation in a biomedical domain. AB - An object-oriented approach has been applied to the different stages involved in developing a knowledge base about insulin metabolism. At an early stage the separation of terminological and assertional knowledge was made. The terminological component was developed by medical experts and represented in CORE. An object-oriented knowledge acquisition process was applied to the assertional knowledge. A frame description is proposed which includes features like states and events, inheritance and collaboration. States and events are formalized with qualitative calculus. The terminological knowledge was very useful in the development of the assertional component. It assisted in understanding the problem domain, and in the implementation stage, it assisted in building good inheritance hierarchies. PMID- 7858661 TI - Reusable influence diagrams. AB - Influence Diagrams have been recognized as a suitable formalism for building probabilistic expert systems. Nevertheless, the most part of applications consists in stand-alone systems, concerning a very limited domain. On the other hand, Artificial Intelligence research has outlined Blackboard Architectures as the basis for building expert systems in which several knowledge sources, in general built with different formalisms, cooperate to the solution of a complex task. This paper addresses the use of influence diagrams as knowledge sources of such a system, and particularly faces the problem of reusing the same influence diagram in different inference phases. We will show that, specially in planning tasks, the modularity requirement of keeping the knowledge sources separated, may imply that an influence diagram must call another influence diagram to solve itself and to maintain the coherence of the whole set of decisions underlying the plan. Conditions for the correctness of this concatenation of knowledge sources will be provided, and an example from the medical domain of therapy planning for Acute Myeloid Leukemia will be shown, as an implemented prototype exploiting these ideas. PMID- 7858662 TI - Towards productive Knowledge-Based Systems in clinical organizations: a methods perspective. AB - This paper discusses an approach towards Knowledge-Based Systems (KBS) development which emphazises fit in the clinical organization, utility and safety. KBS design is identified as a subset of Decision Support System (DSS) design, and experiences from use of development methods is made available from the more general field. Generic and specific issues related to making KBS development result in systems used in clinical practice are discussed, and an integration of the Logic Engineering KBS technique into the Action Design DSS requirements specification method is outlined. Group-based knowledge modeling is identified as the bridge between the methods. It is concluded that while Action Design provides organizational validation (Are we building the right system?), Logic Engineering adds on KBS design verification (Are we going to build the system right?). PMID- 7858664 TI - Hearing myself with others: sound levels in choral performance measured with separation of one's own voice from the rest of the choir. AB - The choir singer has two acoustic signals to attend to: the sound of his or her own voice (feedback), and the sound of the rest of the choir (reference). The balance in loudness between feedback and reference is governed mainly by the room acoustics. Although earlier experiments have shown that singers have a fairly large tolerance for imbalance, with references ranging from -23 to +5 dB, experience suggests that, when singers are given control over this parameter, their preferences are much narrower. A quantification of the optimum balance would be useful in the design of concert stages and rehearsal halls. A method is described for measuring the feedback and reference levels as experienced by singers under live performance conditions. Recordings were made using binaural microphones worn by choir singer subjects. With the given combination of choir and room, it was possible to achieve adequate separation of the feedback and reference signals with simple signal processing. The feedback-to-reference ratio averaged over the 12 singers was found to be +3.9 dB, with extremes of +1.5 and +7.3 dB. PMID- 7858663 TI - High-specificity neurological localization using a connectionist model. AB - Most previous connectionist models for diagnosis have been developed using error backpropagation. While these systems function reasonably well, they have been limited by their need for a large database of test cases, to situations where a single disorder is present, and by the large number of connections required between fully-connected sets of processing units. Here we describe a recently developed connectionist model that overcomes these limitations. This approach can reuse existing causal knowledge bases, works well in situations where multiple disorders can occur simultaneously, and does not require fully-connected sets of processing units. We demonstrate that the accuracy of this model is comparable to that of more conventional AI programs using the same knowledge base in determining precisely the site of brain damage in a group of 50 stroke patients. These results support the conclusion that connectionist models can effectively use pre-existing causal knowledge bases from AI systems, and that they can function accurately when handling actual clinical problems. PMID- 7858665 TI - An investigation of the laryngeal system as the resonance source of the singer's formant. AB - Since its introduction, the Sundberg model of the laryngeal system as the resonance source of the singer's formant has gained wide acceptance. However, no studies directly testing this hypothesis in vivo have previously been reported. Thus, the present study was undertaken to test this hypothesis on three classically trained professional male singers. The vocal behaviors of the singer subjects were evaluated during model and pulse register phonation via magnetic resonance imaging, strobolaryngoscopy, and acoustic analysis. Results indicated the subjects did not achieve the laryngopharyngeal/laryngeal outlet cross sectional area ratio requisite to the model and that the formant remained robust in pulse register phonation. It was concluded that these subjects' behaviors were not consistent with Sundberg's model and that the model was inadequate to account for the generation of the singer's formant in these three subjects. PMID- 7858666 TI - A real-time LPC-based vocal tract area display for voice development. AB - This article reports the design and implementation of a graphical display that presents an approximation to vocal tract area in real time for voiced vowel articulation. The acoustic signal is digitally sampled by the system. From these data a set of reflection coefficients is derived using linear predictive coding. A matrix of area coefficients is then determined that approximates the vocal tract area of the user. From this information a graphical display is then generated. The complete cycle of analysis and display is repeated at approximately 20 times/s. Synchronised audio and visual sequences can be recorded and used as dynamic targets for articulatory development. Use of the system is illustrated by diagrams of system output for spoken cardinal vowels and for vowels sung in a trained and untrained style. PMID- 7858667 TI - Spectral pattern recognition of improved voice quality. AB - The self-organizing map (a neural network) was applied to the spectral pattern recognition of voice quality in 34 subjects: 15 patients operated on because of insufficient glottal closure and 19 subjects not treated for voice disorders. The voice samples, segments of sustained /a/, were perceptually rated by six experts. A self-organized acoustic feature map was first computed from tokens of /a/ and then used for the analysis of the samples. The locations of the samples on the map were determined and the distances from a normal reference were compared with the perceptual ratings. The map locations corresponded to the degree of audible disorder: the samples judged as normal were overlapping or close to the normal reference, whereas the samples judged as dysphonic were located further away from it. The comparison of pre- and postoperative samples of the patients showed that the perceived improvement of voice quality was also detected by the map. PMID- 7858668 TI - Differential phonatory characteristics of four women with amyotrophic lateral sclerosis. AB - Patients with specific neural subsystem involvement are often reported to present with particular perceptual characteristics of voice. This has been true for diseases such as amyotrophic lateral sclerosis (ALS), a progressive disease in which mixed neurologic signs are present. This article reports acoustic data on the phonatory performance of four women diagnosed with ALS who had initial bulbar signs and progressive phonatory deterioration. The data presented here demonstrate that the phonatory characteristics of women with ALS are not uniform, but in fact may vary greatly from patient to patient. PMID- 7858669 TI - Studies on vocal fold injection and changes in pitch associated with alcohol intake. AB - The current study was carried out with particular emphasis on the association between phonetic function tests and alterations in the appearance of the hypopharyngeal and laryngeal mucosa, such as capillary dilatation, edema, and vocal fold injection after alcohol intake. The results demonstrated the occurrence of previously unrecognized pathophysiological changes associated with synchronous phonetic functions in the vocal pathway after alcohol intake. Serum ethanol and aldehyde concentration levels were evaluated hourly for 2.5 h after ingestion of alcohol. When an electronystagmogram showed the typical pattern of alcohol intake, the study was initiated. Occasionally, rhinography was performed on subjects complaining of a stuffy nose after alcohol intake. PMID- 7858670 TI - Botulinum toxin in the treatment of recalcitrant mutational dysphonia. AB - Mutational falsetto is the failure of the normal drop in vocal pitch at puberty. Voice therapy almost always achieves an appropriate pitch; however, in cases of failure, surgical treatment has also been recommended. We report a case of a 47 year-old man with an above-average fundamental frequency and a thin voice quality in the absence of any signs of androgen insufficiency. Laryngeal examination revealed atrophy of the vocalis muscle. Voice therapy was unsuccessful in achieving a stable voice. Injection of 15 units of botulinum toxin into each cricothyroid muscle initially resulted in aphonia, but the voice returned by 1 week. Average fundamental frequency was 84 Hz at 1 week, 104 Hz at 1 month, and 100 Hz at 1 year. We hypothesize that mutational dysphonia is an habitual dysfunction of the voice with inappropriate activation of the cricothyroid muscle and disuse of laryngeal adductor muscles. Temporary deactivation of the cricothyroid muscle enforces adoption of a more appropriate vocal mechanism. Botulinum toxin as an adjunct to voice therapy should be considered before surgical alteration of the glottis in patients with recalcitrant mutational falsetto. PMID- 7858672 TI - The integration of voice science, voice pathology, medicine, public speaking, acting, and singing. AB - The integration of voice science, voice pathology, medicine, public speaking, acting, and singing has been central to evolution in all fields. The Voice Foundation Symposia have played a seminal and central role in fostering integration among disciplines. The result has been an improvement in the knowledge and practice in each field. And the future promises to be even more informative and exciting. PMID- 7858671 TI - Nonspecific laryngeal granuloma: a case study of a professional singer. AB - A professional singer with laryngeal granuloma underwent surgery following failed response to conservative treatments. Two primary findings emerged. First, although a sizable lesion was present initially, presurgical voice measures were largely normal or superior. The exception was elevated phonatory effort during singing. Second, postsurgical voice functions were entirely normal or superior (including phonatory effort), despite demanding singing performances a few weeks following surgery. The results add to the limited corpus of quantitative, normative-referenced data on voice in patients with granulomas and are inconsistent with previous reports of voice abnormalities in such patients and poor functional response to surgery. PMID- 7858673 TI - Developing a charging system for a nursing specialty: ET nursing. AB - Because of limited resources and economic constraints, justifying the existence of ET nurses has become an economic challenge for hospitals and nurses. To justify the role of the ET nurse, a charging system for enterostomal therapy was developed at a corporate, for-profit hospital. Three months after implementation, an evaluation of the system demonstrated that revenue was generated in excess of the ET nurse's salary. PMID- 7858674 TI - Biotherapy for colon cancer: promise or progress? AB - In the United States, more than 149,000 new cases of colorectal cancer are expected in 1994. Surgery remains the most effective method of treatment for this disease. Because these operations often result in formation of an ostomy, ET nurses frequently care for patients with colorectal cancer. Many of these patients will receive additional types of therapy after operation, including such traditional therapies as radiation and chemotherapy. Biotherapy, one of the newest therapeutic modalities in cancer care, is increasingly being used in the treatment of colorectal cancer. Because the ET nurse may be one of the few nurses caring for patients throughout the course of their disease, knowledge of the various biotherapeutic agents and the management of patients receiving them is vital. PMID- 7858675 TI - The ileoanal reservoir: an alternative to ileostomy. AB - The ileoanal reservoir, or ileal pouch-anal anastomosis, is a relatively new, innovative surgical approach offering normal sphincter preservation to clients with familial adenomatous polyposis and ulcerative colitis. In most patients, the ileal pouch-anal anastomosis is performed in two stages. In stage one, the ET nurse must address such patient-education issues as an understanding of the surgical procedure, care of the temporary ileostomy, diet and electrolyte balance, care of the perirectal skin, and the restrengthening of bowel control. Stage two ET nursing interventions focus on perianal skin care, use of medications, sphincter reeducation, and prompt recognition of complications. Written instructions offer the best method of providing crucial information succinctly. Patients require significant physical and emotional support throughout the potentially complex, long-term course until an optimal steady state is achieved. PMID- 7858676 TI - Patient with pharyngostomy, esophagostomy, and tracheostomy. PMID- 7858677 TI - President's message: incontinence management and ET nursing practice. PMID- 7858678 TI - Risk takers and opportunity makers. PMID- 7858679 TI - Riding the wave of the future: an ET nurse's guide to surviving health care reform. AB - Historically, ET nurses have adapted to and grown professionally with change. Projected and current reform of the U.S. health care delivery system requires ET nurses to increase their knowledge base regarding reimbursement; to become proactive change agents in the reform process, to develop strategies to ensure that patients receive high-quality, cost-effective, affordable care; and to intertwine the reimbursement of services and supplies used in ET nurse practice with the development of patient care plans. ET nurses must understand the impact of proposed health care reform on their professional practice, join forces with other organizations to initiate the modification of outmoded policies and laws, and develop innovative strategies that will underwrite the future of ET nursing. PMID- 7858680 TI - Clinical preceptorships: strategies to enhance teaching and learning. AB - This article focuses on the practical aspects of clinical teaching. The teacher, preceptor, and mentor roles are defined and developed within the framework of adult learning principles. Guidelines for determining learning goals, choosing learning activities, facilitating learning during clinical practice, and evaluating knowledge and skill levels of both novice and experienced practitioners are included. PMID- 7858681 TI - Just say no ... welfare. PMID- 7858682 TI - Problems with the report of the Expert Panel on blood cholesterol levels in children and adolescents. AB - An Expert Panel convened by the National Cholesterol Education Program has recommended selective screening and treatment of children for high blood cholesterol levels, based on family history of cardiovascular disease or high blood cholesterol. This recommendation is problematic for several reasons. First, the recommended diets are likely to cause only a slight decrease in low-density lipoprotein cholesterol levels, the projected benefits of which will be offset by a similar decrease in high-density lipoprotein cholesterol levels. Lack of efficacy of the recommended diets could lead to use of more restrictive diets or to cholesterol lowering drugs. Second, even under optimistic assumptions, beneficial effects of cholesterol intervention will be small and delayed for many decades. As a result, childhood cholesterol-lowering efforts will not be cost effective. Third, the Expert Panel's recommendations do not address important gender differences. Girls have higher average cholesterol levels than boys. They will therefore qualify for more dietary and drug treatment despite their lower age-adjusted risk of heart disease and the lack of association between cholesterol levels and cardiovascular mortality in women. Finally, recent evidence from randomized trials, cohort studies, and animal experiments suggests that cholesterol lowering may have serious adverse effects. This evidence was not discussed in the Expert Panel's report. Given current evidence, any screening and treatment of children for high blood cholesterol levels is, at best, premature. PMID- 7858683 TI - Decision rules for roentgenography of children with acute ankle injuries. AB - OBJECTIVE: The Ottawa Ankle Rules (OAR) assist emergency physicians in the appropriate use of roentgenography in adults with acute ankle injuries. The OAR state that ankle roentgenograms are needed only if there is pain near the malleoli and one or more of the following exists: (1) age 55 years or older; (2) inability to bear weight; or (3) bone tenderness at the posterior edge or tip of either malleolus. This study assessed the utility of the OAR on pediatric patients with acute ankle injuries. DESIGN: Prospective, consecutive survey of pediatric patients with acute ankle injuries. SETTING: Pediatric emergency department of an urban university hospital. PARTICIPANTS: Seventy-one children with acute ankle injuries were enrolled from July 22, 1993, to December 1, 1993. INTERVENTIONS: Twenty-four standardized clinical variables were assessed and recorded by physicians in the pediatric emergency department. The OAR were applied to each patient by the investigator to determine which ones would qualify for roentgenography. MAIN OUTCOME MEASURES: Sensitivity and specificity of the OAR were calculated, as was percent reduction in roentgenograms ordered. RESULTS: Seventy-one of 73 eligible patients were enrolled. The two missed patients had open fractures of the tibia. Sixty-eight of 71 patients had ankle roentgenography during the visit. Fourteen patients (21%) (mean age, 11.8 +/- 4.0 years) had fractures noted on the roentgenograms. Fifty-four patients (79%) (mean age, 12.0 +/- 3.6 years) had no fracture. Application of the OAR would have reduced the number of roentgenograms ordered by 25% without missing any fractures. Sensitivity of OAR was 100% (95% confidence interval, 77% to 100%), specificity was 32% (95% confidence interval, 21% to 43%), negative predictive value was 100% (95% confidence interval, 80% to 100%), and positive predictive value was 28% (95% confidence interval, 17% to 39%). CONCLUSIONS: Initial testing suggests that the OAR may help determine which children with acute ankle injuries could safely forgo roentgenograms without risk of missing fractures. PMID- 7858684 TI - Urine concentration and enuresis in healthy preschool children. AB - OBJECTIVES: To determine whether children concentrate their urine overnight and to assess the correlation between specific gravity of a first morning urine specimen and the results of a questionnaire concerning bedwetting, voiding habits, and continence in 47 healthy children aged 3 to 6 years. DESIGN: A prospective observer-blinded consecutive sample. SETTING: Two San Francisco, Calif., preschools. PARTICIPANTS: Forty-seven children attending preschool during the study period. MEASUREMENTS/MAIN RESULTS: Forty of 47 children had a urine specific gravity greater than 1.020. None of these children wet the bed during this study, although four (11%) of 36 had a history of bedwetting. Furthermore, seven children with a urine specific gravity of 1.015 or lower had a history of bedwetting and wet the bed during this study. A voiding frequency of six or more times per day, by history, was associated with a 3:1 relative risk of bedwetting but did not segregate children with primary enuresis from those with secondary enuresis. CONCLUSIONS: Our results indicate that healthy children aged 3 to 6 years are able to concentrate their urine. In addition, urine specific gravity was an accurate predictor of the presence of nocturnal enuresis in this group of children. Our results suggest that a specific gravity of the first morning urine specimen should be correlated with appropriate history before extensive diagnostic evaluation or empiric therapy is performed in children with nocturnal enuresis. PMID- 7858685 TI - Omeprazole treatment of children with peptic esophagitis refractory to ranitidine therapy. AB - OBJECTIVE: To evaluate the cause of chronic abdominal pain lasting more than 3 weeks in 153 patients aged 6 to 18 years (mean, 9.9 years) who had undergone endoscopy. DESIGN: Those patients with peptic esophagitis as the cause of their chronic pain were treated with high-dose ranitidine hydrochloride, followed by the proton-pump inhibitor, omeprazole, for those who did not respond to a histamine2-receptor antagonist. RESULTS: Eighty-four percent of patients had peptic esophagitis, 3% had Helicobacater pylori gastritis, and 3% had ulcer disease. Seventy percent of the patients with peptic esophagitis responded to an 8-week course of high-dose ranitidine hydrochloride (4 mg/kg per dose, twice a day or three times a day). Of the 30% of patients who failed to respond to ranitidine therapy, 87% responded to an 8-week course of omeprazole (20 mg/d). The grade of esophagitis at initial endoscopy was a predictive factor for response to ranitidine therapy. Ninety percent of patients with grade 1 esophagitis responded to ranitidine therapy vs only 43% of those with grade 3 or 4 esophagitis. Only five patients (4%) failed to respond to both therapies; three of these subsequently underwent Nissen fundoplications. There were no side effects of either ranitidine or omeprazole therapy. CONCLUSIONS: These findings indicate that (1) peptic esophagitis was a common cause of chronic abdominal pain in pediatric patients and (2) omeprazole was effective in the treatment of esophagitis in children and adolescents that was resistant to high-dose histamine2-receptor antagonists. PMID- 7858686 TI - Gravid students. Characteristics of nongravid classmates who react with positive and negative feelings about conception. AB - OBJECTIVE: To determine whether gravid classmates affect nongravid students' feelings about conception. METHOD: Cross-sectional survey of a school-based clinic population. We asked 130 nulliparous high school students who were seeking routine health care at an urban school-based clinic to complete an anonymous questionnaire concerning risk factors for and attitudes about teen pregnancy. RESULTS: The respondents were grouped according to the effect that contact with gravid classmates had on their desire for conception: increased desire (n = 13), no change in desire (n = 59), and decreased desire (n = 49). The analysis disclosed no significant group differences for age (mean +/- SD, 16.3 +/- 1.2 years), sex (65% female), welfare use (20%), or living situation (85% lived with a parent). The increased-desire group had significantly more sociodemographic risk factors for teen pregnancy than did the groups with no change and decreased desire. The group with increased desire was significantly more likely than the other two groups to be failing in school (54% vs 44% and 12.2%; P < .001), to have low education goals (15.4% vs 3.4% and 0%; P = .02), to be unhappy with their family support (69.2% vs 27.1% and 29.8%; P = .01), to be concerned about sterility (30.8% vs 8.6% and 6.1%; P = .03), not to be using contraceptives (77% vs 35.6% and 30.6%; P < .01), to want a pregnancy within 2 years (61.5% vs 25.4% and 12.2%; P < .001), and to have a sexual partner who wanted a pregnancy within 2 years (61.5% vs 13.6% and 8.2%; P < .0001). CONCLUSIONS: Our findings support the study hypothesis that that never-pregnant students in the increased-desire group had more sociodemographic risk factors for teen pregnancy than did students in the groups with no change or decreased desire. The results of this study may help to ally concerns about the adverse effect that the increased prevalence of gravid students in American schools might have on the childbearing attitudes of never-pregnant students. PMID- 7858687 TI - Factors associated with prolonged hospitalization of children with asthma. AB - OBJECTIVE: To identify clinical features of asthma present before arrival in the emergency department, at the time of emergency department treatment, and during hospitalization that differ between children with asthma hospitalized for a prolonged period and those hospitalized for an average duration. DESIGN: Retrospective chart review. PATIENTS AND SETTING: Hospital records of patients with asthma (International Classification of Diseases, Ninth Revision, code 493) admitted to Children's Hospital and Medical Center, Seattle, Wash, from October 1989 to September 1991. RESULTS: The medical records of 23 children hospitalized from October 1989 to September 1991 for more than 4 days with acute asthma were compared with those of 62 sex- and age-matched children hospitalized for 2 days. Patients in the long-stay and short-stay groups had similar histories of home medication use. The presence of asthma symptoms before arrival in the emergency department was prolonged in the long-stay group (P < .001). Only one of the 23 patients in the long-stay group had augmented asthma treatment within 24 hours before hospitalization, compared with 39 of the 62 patients with short stays (P < .001). During hospitalization, a greater proportion of children in the long-stay group than the short-stay group received supplemental oxygen (P < .01). More children in the long-stay group than the short-stay group had residual hypoxemia (arterial oxygen saturation, < 94%) in room air at discharge, suggesting that hospital stay was not prolonged to reach normal oxygen saturations. None of the children were readmitted within 1 month of their index admission. CONCLUSIONS: Early augmentation of home therapy for acute asthma is associated with a reduced duration of hospitalization for children admitted with asthma. In addition, hypoxemia in children with acute asthma on presentation and during hospitalization is associated with prolonged hospital stay. PMID- 7858688 TI - Establishing clinically relevant standards for tachypnea in febrile children younger than 2 years. AB - OBJECTIVE: To determine values for defining tachypnea in febrile children younger than 2 years that best identify those at risk for pneumonia. DESIGN: Prospective case series. STUDY PATIENTS: Children younger than 2 years presenting to the emergency department of a children's hospital with a temperature of 38 degrees C or higher. INTERVENTIONS: Using a standardized method, respiratory rates were obtained on eligible children for 1 year. Study patients were classified as having pneumonia or no pneumonia based on clinical evaluation and chest radiograph findings. Receiver operating characteristic curves were constructed to select the values for respiratory rate that maximized sensitivity and specificity of tachypnea as a sign of pneumonia. RESULTS: Data were analyzed for 572 children; pneumonia was present in 42 (7%). The diagnostic utility of tachypnea was maximal when cutoff values for respiratory rates of 59/min in infants younger than 6 months, 52/min in those aged 6 through 11 months, and 42/min in those aged 1 to 2 years were selected. Based on these definitions, tachypnea as a sign of pneumonia had a sensitivity of 73.8%, specificity of 76.8%, positive predictive value of 20.1%, and negative predictive value of 97.4%. CONCLUSIONS: Tachypnea, as defined in this study, is an important predictive sign of pneumonia in febrile children younger than 2 years. Conversely, the absence of tachypnea obviates the need for chest radiography in most settings. PMID- 7858689 TI - A prospective study of femoral catheter-related thrombosis in children. AB - OBJECTIVES: To establish the incidence and correlate clinical findings of femoral venous catheter-related thrombus formation in critically ill children. RESEARCH DESIGN: Observational prospective blinded study. SETTING: University-affiliated pediatric hospital intensive care unit. PATIENTS: Twenty children admitted to the pediatric intensive care unit who had percutaneous femoral venous catheters placed while in the pediatric intensive care unit. INTERVENTIONS: None. MEASUREMENTS: Duplex Doppler ultrasonography evaluation of femoral vein catheters at 1 to 2, 3 to 5, and 7 to 10 days after placement was used to detect the presence of thrombus formation and venous occlusion. Demographic patient data, pediatric risk of mortality scores, and clinical findings, including leg swelling and whether catheters would aspirate blood, were also recorded. Continuous data were analyzed using the Mann-Whitney U Test, and categorical data were compared with Fisher's Exact Test. Statistical significance was assigned at a P value of .05 or less. CONCLUSIONS: The overall incidence of catheter-related femoral vein thrombus formation was 35% (7/20). Ipsilateral leg swelling and the inability to aspirate blood from the catheter were significantly associated with thrombus formation. Patients who developed thrombi were younger and smaller than those who did not. In six of seven patients, thrombus formation was clinically occult when first demonstrated by ultrasonography. PMID- 7858690 TI - Year-to-year variability of cholesterol levels in a pediatric practice. AB - OBJECTIVES: To study the impact of the variability of blood cholesterol levels, which are known to vary spontaneously. The impact of this variability on screening for hypercholesterolemia according to National Cholesterol Education Program (NCEP) guidelines was reviewed in a private pediatric practice. DESIGN: Retrospective chart review. SETTING: Private pediatric practice. PATIENTS: Children (N = 646) aged 3 to 19 years. INTERVENTION: Cholesterol measurements at a mean interval of 19 months between visits. MAIN OUTCOME MEASURES: Year-to-year change in cholesterol levels according to NCEP guidelines, regression to the mean, age, pubertal status, body mass index, hematocrit, interval between measurements, and season of the year were assessed for their contribution to cholesterol level variability. RESULTS: Cholesterol level varied significantly with both age (P < .001) and pubertal status (P < .01) with children aged 9 to 12 years; prepubertal children had the highest levels. Visit-to-visit consistency of NCEP classification was poorer for younger children than for older children (kappa = 0.21 for 3- to 6-year-olds, 0.39 for 6- to 10-year-olds, and 0.44 for those older than 10 years). Of children with initial total cholesterol levels of 5.17 mmol/L (200 mg/dL) or greater, only 40% continued to have high levels at follow-up. A child with an initial cholesterol value of 5.17 mmol/L (200 mg/dL) showed an average decline of 0.34 mmol/L (13 mg/dL) at follow-up by regression analysis. CONCLUSION: Year-to-year variability in total cholesterol level has a significant impact on the stability of NCEP classification. PMID- 7858691 TI - Pediatric computer-assisted instruction. PMID- 7858692 TI - Picture of the month. Atypical presentations of varicella with underlying skin disorders. PMID- 7858693 TI - Pathological case of the month. Mesenchymal hamartoma of the liver. PMID- 7858694 TI - Outcome of infants with birth weights less than 1000 g with respiratory distress syndrome treated with high-frequency ventilation and surfactant replacement therapy. AB - OBJECTIVE: To compare outcomes in premature infants with respiratory distress syndrome who received surfactant replacement therapy and were treated with either high-frequency or conventional mechanical ventilation. DESIGN: Retrospective chart review of patient series. SETTING: Tertiary academic medical center. PATIENTS: One hundred fourteen extremely low-birth-weight infants (< 1000 g) with respiratory distress syndrome treated with surfactant replacement therapy, consecutively admitted to the neonatal intensive care unit between September 1989 and August 1992. INTERVENTIONS: Treatment with either high-frequency ventilation (n = 46) or conventional mechanical ventilation (n = 68) after surfactant replacement therapy. MAIN OUTCOME MEASURES: Intraventricular hemorrhage and neurodevelopmental status. RESULTS: Infants who received high-frequency ventilation had significantly lower birth weights and were more premature than infants receiving conventional mechanical ventilation. Despite this, patients ventilated with high frequency had similar incidences of intraventricular hemorrhage and impaired neurodevelopmental outcomes when compared with the conventionally ventilated patients. As expected, the smaller and more premature infants receiving high-frequency ventilation required a longer duration of respiratory support (mechanical ventilation and nasopharyngeal continuous positive airway pressure). Additionally, multiple logistic regression analysis to control for differences in birth weight and gestational age between the two groups revealed a significant association between the combined use of high frequency ventilation and antenatal corticosteroids and the absence of either intraventricular hemorrhage or pneumothorax. CONCLUSION: We conclude that high frequency ventilation combined with surfactant therapy is as safe as conventional mechanical ventilation combined with surfactant therapy for treating respiratory distress syndrome in extremely low-birth-weight infants (< 1000 g) and does not increase the risk of either intraventricular hemorrhage or abnormal neurodevelopmental outcome. PMID- 7858695 TI - Epoetin alfa therapy in infants awaiting heart transplantation. AB - OBJECTIVE: To determine the safety and efficacy of epoetin alfa therapy in infants awaiting heart transplantation to minimize the need for blood transfusions. DESIGN: Prospective case series analysis. SETTING: Pediatric tertiary care center. PATIENTS: Eleven term infants (4 to 54 days old) awaiting heart transplantation. INTERVENTION: Infants received 16 courses of daily epoetin therapy and four subsequent courses of alternate-day epoetin therapy. RESULTS: Daily epoetin therapy was instituted at 23.6 +/- 4.5 days of age, and the duration of treatment was 13.8 +/- 3.9 days (mean +/- SEM). During daily epoetin therapy, the hematocrit increased from 0.42 +/- 0.015 to 0.50 +/- 0.019 (P < .001), and the reticulocyte count increased from 58 +/- 9 x 10(-3) to 105 +/- 16 X 10(-3) (P < .05). There were no significant changes in leukocyte count (13.4 +/ 1.0 X 10(9)/L vs 15.1 +/- 0.9 X 10(9)/L), platelet count (402 +/- 43 X 10(9)/L vs 387 +/- 39 X 10(9)/L), or creatinine (53 +/- 9 mumol/L [0.6 +/- 0.1 mg/dL] vs 53 +/- 9 mumol/L [0.6 +/- 0.1 mg/dL]) (not significant). Four patients received blood transfusions during daily epoetin therapy, but the amount of blood administered to patients was significantly less (0.9 +/- 0.5 mL/kg per day) than the phlebotomy losses (1.8 +/- 0.4 mL/kg per day) (P < .01). During alternate-day epoetin therapy, the hematocrit decreased from 0.53 +/- 0.014 to 0.43 +/- 0.019 (P < .05). CONCLUSIONS: Daily epoetin therapy appears to be effective in maintaining stable hematocrit in infants awaiting heart transplantation, who generally require multiple transfusions secondary to iatrogenic blood losses. PMID- 7858696 TI - Access to home apnea monitoring and its impact on rehospitalization among very low-birth-weight infants. AB - OBJECTIVE: To examine the relationship between home apnea monitoring and sociodemographic, socioeconomic, and medical factors and the risk for rehospitalization among very-low-birth-weight infants (birth weight < 1500 g). DESIGN AND SETTING: Analysis of live infants born weighing less than 1500 g; these data were obtained from the 1988 National Maternal and Infant Health Survey. Data from this survey were obtained by maternal questionnaires and from birth certificates and medical records. OUTCOME MEASURE: One or more hospitalizations after discharge from the hospital of delivery. RESULTS: Home apnea monitor use was strikingly lower among black infants (19.8%) compared with nonblack infants (43.7%) (P < .001). The rate of rehospitalization for blacks was 24.8%, which was lower than the rate of 34.3% for nonblacks (P = .001). Neither annual family income nor method of hospital payment was associated with rehospitalization. The use of an apnea monitor in the home was associated with an increased odds ratio for rehospitalization for both blacks (odds ratio, 2.56; 95% confidence interval, 1.56 to 4.21) and nonblacks (odds ratio, 2.28; 95% confidence interval, 1.51 to 3.45). With adjustment for the use of an apnea monitor, the odds ratio for rehospitalization of blacks vs nonblacks was no longer significant (odds ratio, 0.80; 95% confidence interval, 0.60 to 1.08). CONCLUSIONS: The use of an apnea monitor in the home was highly associated with an increased risk for rehospitalization. Whether this increased risk was attributable to a valid reason for rehospitalization or to closer scrutiny of the infant could not be determined. The lower prevalence of apnea monitor use among blacks is unexplained. PMID- 7858697 TI - Nutrient quality of fat- and cholesterol-modified diets of children with hyperlipidemia. AB - OBJECTIVE: To assess the nutritional adequacy of low-fat, low-saturated fat, low cholesterol-modified diets of children with hyperlipidemia. DESIGN: Case comparison study. SETTING: Tertiary care ambulatory pediatric atherosclerosis prevention center. PATIENTS AND OTHER PARTICIPANTS: White middle-class suburban children. Subjects were 54 consecutive children with hyperlipidemia (26 boys) with a mean (+/- SD) age of 10.8 +/- 3.4 years. Controls were 44 healthy children (19 boys) aged 10.8 +/- 0.9 years recruited from a local elementary school. INTERVENTION: The subjects received individual nutrition counseling on a National Cholesterol Education Program Step I Diet from a registered dietitian. MAIN OUTCOME MEASURE: The 3-day written food records were analyzed by a registered dietitian using the Minnesota Nutrient Data System. Outcome measures were intakes of energy, fat-soluble vitamins, and minerals as a percentage of the Recommended Dietary Allowance. The means between cases and controls were compared by Student's t test. RESULTS: There was no significant difference in consumption of energy, minerals, or vitamins D and E between the groups. The control group's diet contained significantly greater amounts of fat, saturated fat, and cholesterol. The children with hyperlipidemia consumed significantly more vitamin A (P < .005). CONCLUSION: The nutrient quality of fat- and cholesterol-modified diets of children who have received nutritional counseling compares favorably with the nutrient quality of controls on an unrestricted diet. Therefore, pediatricians can prescribe with confidence a Step I Diet for children with hyperlipidemia and adolescents when nutritional counseling is available. PMID- 7858698 TI - Lead mobilization test in children with lead poisoning: validation of a 5-hour edetate calcium disodium provocation test. PMID- 7858699 TI - Chlamydial infection and reactive airway disease. PMID- 7858700 TI - Empyema causing paralysis of hemidiaphragm. PMID- 7858701 TI - Determination of benzene and its metabolites: application in biological monitoring of environmental and occupational exposure to benzene. AB - Methods for the biological monitoring of benzene and its metabolites in exhaled air, blood and urine are reviewed. Analysis of benzene in breath can be carried out by using an exhaled-air collection tube and direct analysis by GC or GC-MS; however, this technique is less reliable when compared to analysis using blood or urine. For the determination of non-metabolized benzene in blood and urine, GC head-space analysis is recommended. Phenol, the major metabolite of benzene can be monitored by either HPLC or GC methods. However, urinary phenol has proved to be a poor biomarker for low-level benzene exposure. Recent studies have shown that trans,trans-muconic acid, a minor metabolite of benzene can be determined using HPLC with UV detection. This biomarker can be used for detection of low level benzene exposure. Urinary S-phenylmercapturic acid is another sensitive biomarker for benzene, but it can be detected only by GC-MS. Hydroquinone, catechol and 1,2,4-benzenetriol can be measured using HPLC with either ultraviolet or fluorimetric detection. Nevertheless, their use for low-level assessment requires further studies. Eventually, for the assessment of health risks caused by benzene, biological-exposure reference values need to be established before they can be widely used in a field setting. PMID- 7858702 TI - Determination of quinidine, dihydroquinidine, (3S)-3-hydroxyquinidine and quinidine N-oxide in plasma and urine by high-performance liquid chromatography. AB - A specific and sensitive method for the quantitation of quinidine, (3S)-3 hydroxyquinidine, quinidine N-oxide, and dihydroquinidine in plasma and urine has been developed. The method is based on a single-step, liquid-liquid extraction procedure, followed by isocratic reversed-phase high-performance liquid chromatography, with fluorescence detection. After extraction from 250 microliters plasma and 100 microliters urine, the limit of determination is 10 nM and 25 nM, respectively. For the use as standards, commercially available quinidine was purified from dihydroquinidine; quinidine N-oxide was synthesized. PMID- 7858703 TI - Determination of 4-hydroxycyclophosphamide in plasma, as 2,4 dinitrophenylhydrazone derivative of aldophosphamide, by liquid chromatography. AB - A reversed-phase liquid chromatographic method to determine the concentration of 4-hydroxycyclophosphamide, a labile cytotoxic metabolite of cyclophosphamide, in plasma is described. In order to stabilize 4-hydroxycyclophosphamide, as well as to increase the selectivity and the sensitivity, a 2,4-dinitrophenylhydrazone derivative was formed. Plasma proteins were precipitated with acetonitrile prior to the derivatization with 2,4-dinitrophenylhydrazine at pH 2. The derivatization was performed at 50 degrees C for 5 min. The chromatographic system consisted of an octadecyl silica column and a mobile phase containing phosphate buffer and acetonitrile. Quantitation was performed using an UV detector operating at 357 nm. Optimal derivatization was obtained by adding 0.2 ml 2,4 dinitrophenylhydrazine (3.8 mg/ml) to 0.5 ml of the deproteinized plasma supernatant. The relative recovery of 4-hydroxycyclophosphamide from plasma is > or = 97%. Concentration levels down to 22 mg/ml of 4-hydroxycyclophosphamide in plasma could be determined with a R.S.D. of about 13%. No degradation of the derivative was observed after 24 h at room temperature. The t1/2 for 4 hydroxycyclophosphamide in blood is ca. 4 min at 37 degrees C, whereas 4 hydroxycyclophosphamide is stable for at least 1 h at 4 degrees C. Application of the method for the pharmacokinetic monitoring of 4-hydroxycyclophosphamide is described. PMID- 7858704 TI - Determination of altretamine in human plasma with high-performance liquid chromatography. AB - A fast, simple, and sensitive isocratic HPLC method has been developed and validated for the determination of the anticancer drug altretamine in human plasma. Spiked serum samples and clinical plasma samples are extracted with acetonitrile at 4 degrees C and the precipitate removed by filtration. The plasma sample volume required (ca. 0.2 ml) is small and the total analysis time is less than 15 min per sample (including batch-wise pre-treatment). Recovery of altretamine is 99 to 106% for pooled human serum spiked with altretamine in the range 200 ng/ml to 10 mg/ml. In this concentration range, the R.S.D. varies from 1 to 8%. The limit of quantitation is ca. 150 ng/ml for an R.S.D. of 10%. The intra-day R.S.D. for human samples spiked at 5 mg/ml varied between 1.7 and 4%; the inter-day R.S.D. at this concentration was ca. 3%. A preliminary study with one patient receiving 260 mg/m2 by mouth indicated that the peak altretamine concentration was significantly lower after a standard breakfast than in the fasting state. PMID- 7858705 TI - High-performance liquid chromatographic method with electrochemical detection for the determination of idrapril, a novel angiotensin-converting enzyme inhibitor, in biological matrices. AB - A reversed-phase high-performance liquid chromatographic method for the determination of idrapril in human and rat plasma and urine and in rat tissue homogenates is described. The method is based on the electrochemical detection of idrapril without prior derivatization. Sample preparation simply consists in deproteinization with acetonitrile for plasma and tissue homogenates and in passage through a Sep-Pak C18 cartridge for urine. The limit of quantification is 12.5 ng/ml for plasma, 125 ng/g for tissues and 2.5 micrograms/ml for urine. The method is suitable for monitoring idrapril plasma pharmacokinetics in humans and its tissue distribution and urinary excretion in rats. PMID- 7858706 TI - Determination of the rifamycin-related hypolipidemic drug CGP 43371 in human feces, plasma and urine by high-performance liquid chromatography. AB - A simple, rapid and sensitive normal-phase high-performance liquid chromatographic (HPLC) method was developed and validated for the determination of a novel hypolipidemic agent in human feces, plasma and urine. This experimental drug candidate is structurally related to rifamycin. The compound and internal standard were isolated from biological matrices by a one step liquid liquid extraction. Separations were achieved on a mu Porasil silica gel column. Recovery and reproducibility assessments indicated good accuracy and precision. The overall mean relative recoveries were 93.3% from feces (0.2-20 micrograms/mg), 95.1% from plasma (20-500 ng/ml) and 97.5% from urine (20-500 ng/ml), with coefficients of variation ranging from 0.7 to 10.0% for feces, 3.0 to 12.7% for plasma and 2.3 to 10.6% for urine. The limits of quantification were 0.2 micrograms/mg for feces and 20 ng/ml for plasma and urine. The method has sufficient sensitivity to support clinical trials, and was utilized to measure concentrations of the compound in fecal, plasma and urine samples from healthy male volunteers who had received a single 800-mg oral dose. PMID- 7858707 TI - Simultaneous quantification of an anti-inflammatory compound (DuP 697) and a potential metabolite (X6882) in human plasma and urine by high-performance liquid chromatography. AB - A high-performance liquid chromatographic (HPLC) method using fluorescence detection has been developed for the simultaneous analysis of low nanogram concentrations of an anti-inflammatory drug, 5-Bromo-2-(4-fluorophenyl)-3-[4 (methylsulfonyl)phenyl]thiophene (DuP 697), and a potential metabolite (X6882) in human plasma and of DuP 697 in human urine. This assay method used an EM Separations Lichrospher C18 endcapped column. The mobile phase was acetonitrile water (75:25, v/v). The detection of DuP 697 and X6882 was by fluorescence at excitation and emission wavelengths of 256 and 419 nm, respectively. The chromatographic system could separate DuP 697 from X6882, the external standard (anthracene), and other endogenous substances present in human plasma. In human plasma the limits of quantification for DuP 697 and X6882 were 3 and 20 ng/ml, respectively; the limit of quantification for DuP 697 in human urine was 5 ng/ml. These compounds were shown to be stable in frozen (-20 degrees C) human plasma and urine for at least 9 weeks. The assay described has been used to characterize DuP 697 pharmacokinetics after oral administration in humans. PMID- 7858708 TI - Measurement of urinary free cortisol by stable isotope dilution mass spectrometry using a new cortisol derivative. AB - The reaction of the bismethylenedioxy derivative of cortisol (cortisol-BMD) with heptafluorobutyric anhydride to give the corresponding 3,5-dienol heptafluorobutyrate (cortisol-BMD-HFB) has been shown to proceed with dehydration. Acid-promoted dehydration of either cortisol-BMD or cortisol-BMD HFB, or concurrent dehydration of both, is the proposed reaction mechanism leading to a trienol heptafluorobutyrate, whose chromatographic properties and mass spectral data are consistent with the additional double bond in the C9-C11 position. Forming the 3,5-dienol heptafluorobutyrate of cortisol-BMD in benzene rather than acetone gave a compound whose chromatographic properties and mass spectral data were different to that of the 3,5,9(11)-trienol heptafluorobutyrate but consistent with that of a cortisol-BMD-HFB. The mass fragmentometry of this new cortisol derivative was found to be more suited to the technique of isotope dilution mass spectrometry than the 3,5,9(11)-trienol heptafluorobutyrate, and thus was applied to our intended goal of measuring urinary free cortisol by gas chromatography-mass spectrometry. An efficient and convenient solid-phase extraction technique is employed in our assay to isolate cortisol from 5 ml of urine. PMID- 7858709 TI - High-performance liquid chromatographic determination of hypotaurine and taurine after conversion to 4-dimethylaminoazobenzene-4'-sulfonyl derivatives and its application to the urine of cysteine-administered rats. AB - A method for the determination of urinary hypotaurine and taurine for the purpose of studying hypotaurine-taurine status in mammals is described. Hypotaurine and taurine were converted into 4-dimethylaminoazobenzene-4'-sulfonyl (dabsyl) derivatives under conditions minimizing hypotaurine oxidation. The dabsylhypotaurine and dabsyltaurine formed were determined by reversed-phase HPLC. Average excretions of taurine and hypotaurine in rat urine were 270.5 and 2.5 mumol/kg body mass per day, respectively. After intraperitoneal injection of 5 mmol of L-cysteine/kg body mass, the increased excretions of taurine and hypotaurine corresponded to 22.1 and 2.5%, respectively, of L-cysteine administered, indicating that hypotaurine production exceeded the capacity of hypotaurine oxidation in vivo. PMID- 7858710 TI - Determination of NG-nitro-L-arginine and NG-nitro-L-arginine methyl ester in plasma by high-performance liquid chromatography. AB - An HPLC method has been developed for the measurement of the nitric oxide synthase inhibitors, NG-nitro-L-arginine (L-NOLA) and NG-nitro-L-arginine methyl ester (L-NAME), in sheep plasma. Using an ion-exchange HPLC column (JWAS 150, 100 x 3.9 mm I.D., Millipore-Waters, Australia) and post-column ninhydrin detection, L-NOLA was separated from valine and other plasma amino acids. When added to sheep plasma, good recovery (mean 102%) and precision (mean coefficient of variation 2.7%) in the measurement of L-NOLA was obtained over the range 2-50 mg/l. L-NAME was unstable in sheep plasma at 37 degrees C, and was converted to L NOLA with a half-life of 250 min. This method will permit pharmacokinetic parameters to be determined for these potential drugs, and will allow plasma drug concentrations to be correlated with the pharmacodynamic effects of these compounds. PMID- 7858711 TI - Determination of orotic acid in serum by high-performance liquid chromatography. AB - A simple method for the determination of orotic acid in serum is described. The analyses were carried out using a strong anion-exchange column. Orotic acid was separated isocratically with 0.8 M formic acid (pH 2.8, adjusted with 10 M NaOH) methanol (65:35, v/v) at a flow-rate of 1.0 ml/min. Absorbance at 275 nm was recorded for quantification. Validation yielded a detection limit of 0.07 micrograms/ml and a quantification limit of 0.25 micrograms/ml. The maximum within-day and day-to-day coefficients of variation were less than 6%. The method has the advantage that samples can be easily prepared. PMID- 7858712 TI - Nitritocobalamin and nitrosocobalamin may be confused with sulfitocobalamin using cation-exchange chromatography. AB - The previously reported ability of SP-Sephadex C25 column chromatography for partitioning biologically important cobalamins has been modified to include analytical separation of nitritocobalamin (NO2-Cbl) and nitrosocobalamin (NO Cbl). Gel column dimensions (1.5 x 11.0 cm), a low eluent flow-rate (125 microliters/min), collection of small eluate fractions (160 microliters) plus maintenance of He saturated mobile and gel phases all combined to eliminate ordinarily confusing proximal elution of NO2-Cbl and NO-Cb1 with sulfitocobalamin (SO3-Cbl) and cyanocobalamin. Cobalamin elution profiles from the gel column were monitored by direct radiometric analysis of 57Co-labelled cobalamin standards or competitive intrinsic factor radioassays for cobalamin sample sizes up to 10.0 ng. Failure to implement the chromatographic conditions detailed here totally obscured analysis of NO2-Cbl coexisting with SO3-Cbl in brain tissues for chicks exposed to dietary sulfites and caused oversight of NO-Cb1 normally coexisting in prepared NO2-Cbl standards. PMID- 7858713 TI - Rapid column liquid chromatographic analysis of flucloxacillin in plasma on a microparticulate pre-column. AB - A rapid, sensitive, accurate and precise high-performance liquid chromatographic assay is described for flucloxacillin in plasma. Samples (100 microliters) containing dicloxacillin (internal standard) were extracted with ethyl acetate (2 ml). The mobile phase of acetonitrile (18%, v/v) in phosphate buffer (0.01 M, pH 7) was pumped at 1.2 ml/min through a 40 x 3.2 mm I.D. column (3 microns particles). Detection was at 220 nm. Calibration plots were linear (r > 0.9995) from 0.2 to 40 mg/l. Within-day and between-day coefficients of variation were less than 9% (n = 6). The detection limit was 0.05 mg/l and the limit of quantitation was 0.3 mg/l. Of 24 drugs tested, only phenytoin and carbamazepine may interfere in some patients' samples. PMID- 7858714 TI - High-performance liquid chromatographic assay for sematilide in plasma using solid-phase extraction microcolumn technology. AB - A simple and sensitive high-performance liquid chromatographic assay for quantification of sematilide in rabbit plasma was developed. After extraction of samples via solid-phase extraction on C8 microcolumns, baseline resolution was achieved on a reversed-phase 5 microns Inertsil ODS-2 column using isocratic conditions with mobile phase consisting of water-glacial acetic acid-acetonitrile methanol-triethylamine (93.5:4.0:1.5:0.5:0.5) and UV detection at 254 nm. The assay did not require evaporation or reconstitution steps. The injection interval was 8 minutes. The inter-day coefficient of variation for replicate analysis of spiked samples was less than 7.6% and the accuracy was more than 97% over the standard curve range (0.128 to 3.191 microM) using 0.5 ml of plasma. The assay has been successfully applied to pharmacokinetic studies in rabbits. PMID- 7858715 TI - Differential extraction of artemether and its metabolite dihydroartemisinin from plasma and determination by high-performance liquid chromatography. AB - A method is described for the separation of artemether (ARM) from its metabolite dihydroartemisinin (DHA) and determination by HPLC. The basis of the separation is differential extraction of the drugs from plasma as a function of plasma pH. Hexane extracted ARM from basiffied plasma and both ARM and DHA from normal plasma. Derivatized extracts were chromatographed on a 5-microns ODS column with water-acetonitrile (40:60) as mobile phase and detected at 254 nm. The method removes the need for expensive absorption cartridges (BondElut). Chromatography has been improved and the elution time shortened in comparison with previous methods. PMID- 7858716 TI - High-performance liquid chromatographic determination of busulfan in human serum with on-line derivatization, column switching and ultraviolet absorbance detection. AB - A high-performance liquid chromatographic (HPLC) method is described for the determination of busulfan in human serum using on-line derivatization and column switching. Busulfan was extracted from serum with a mixture of diethyl ether and dichloromethane. After the evaporation of the organic layer, the reconstituted residue was injected into the HPLC system and busulfan was derivatized with sodium diethyldithiocarbamate on the first short column. The back-flushed derivative was then separated on the second column. Finally, after column switching, the heart-cut fraction containing the derivative was further analysed on the third column and monitored with ultraviolet absorbance detection at 278 nm. The lower limit of quantitation in serum was 10 ng/ml. PMID- 7858717 TI - Simultaneous determination of granisetron and 7-hydroxygranisetron in human plasma by high-performance liquid chromatography with fluorescence detection. AB - A highly sensitive high-performance liquid chromatographic method for the determination of granisetron, a novel antiemetic agent for cancer therapy, and its pharmacologically active and major metabolite in human plasma is described. Methylation of the metabolite with trimethylsilyldiazomethane was employed for sample pretreatment. As a result of this treatment, the originally non fluorescent metabolite could be detected simultaneously with granisetron using fluorescence detection. Both the compounds and the internal standard added were isocratically well resolved from endogenous peaks in plasma on an ODS column. The concentrations of the compounds were proportional to the peak-area ratios over the practical determination ranges of 0.2-100 ng/ml for granisetron and 0.1-50 ng/ml for the metabolite. In tests, reproducibilities for granisetron at 1 ng/ml and the metabolite at 0.5 ng/ml as determined by the relative standard deviation (n = 3) were less than 3.98 and 7.23%, respectively, in a single run. PMID- 7858718 TI - Determination of a new H(+)-K+ ATPase inhibitor (E3810) and its four metabolites in human plasma by high-performance liquid chromatography. AB - A method for the simultaneous determination of E3810, 2-[(4-(3-methoxypropoxy)-3 methyl pyridine-2-yl)methyl sulfinyl]-1H-benzimidazole sodium salt and its four metabolites, demethylated-E3810 (DM), demethylated thioether-E3810 (DMTE), sulfone-E3810 (S), and thioether-E3810 (TE), in human plasma by high-performance liquid chromatography (HPLC) with UV absorbance detection has been established. The correlation coefficient for all the standard curves was 0.998 or greater. The quantitation limit was 5 ng/ml for E3810 and 20 ng/ml for each of its four metabolites. The recovery of E3810 and its four metabolites from human plasma was high, being greater than 80% when 100 ng of each substance was added per tube, except for DM (74.1%). The stability of E3810 and its four metabolites was evaluated and the following results were obtained: (1) when samples were centrifuged within 20 min after collection, there was no loss of E3810 or its metabolites; (2) when 100 microliters of a 1% aqueous solution of diethylamine was added within 20 min after plasma isolation, there was no loss of E3810 or its metabolites; and (3) there were no stability problems during storage for a period of 10 months at -20 degrees C. PMID- 7858719 TI - Solid-phase extraction method for the determination of diltiazem and its metabolites by high-performance liquid chromatography: fact or fallacy? PMID- 7858720 TI - Simultaneous determination of urinary free cortisol and 6 beta-hydroxycortisol by high-performance liquid chromatography to measure human CYP3A activity. AB - The ratio of the hydrophilic metabolite 6 beta-hydroxycortisol to its parent compound cortisol has recently been demonstrated to be a specific marker for human CYP3A oxygenase activity. We have developed a sensitive and simple single run high-performance liquid chromatographic method for the quantification of urinary free cortisol and 6 beta-hydroxycortisol using dexamethasone as internal standard. The urine samples (1 ml) are applied to Sep-Pak cartridges, which are washed with water and eluted with ethyl acetate-diethyl ether (4:1, v/v). The organic extracts are washed sequentially with alkaline and acidic solutions saturated with sodium sulfate and subsequently concentrated to dryness. After reconstitution in ethanolic water, the samples are analyzed on a reversed-phase gradient system using ultraviolet absorbance detection at 254 nm. The within- and between-day coefficients of variation (C.V.) for the assay where both in the range of 5-10%. The reference interval for the 6 beta-hydroxycortisol/cortisol ratio of eleven healthy non-smoking subjects was 2.77-26.88 with an average of 10.09 +/- 6.89 (S.D.). The method constitutes an improvement over previous methods and is suitable for routine assessment of the 6 beta hydroxycortisol/cortisol ratio requiring only 1 ml of urine or less. PMID- 7858721 TI - High-performance liquid chromatographic determination of taurine and hypotaurine using 3,5-dinitrobenzoyl chloride as derivatizing reagent. AB - A method for the determination of taurine and hypotaurine in biological samples involving the preparation of their 3,5-dinitrobenzoyl derivatives followed by HPLC was established. Taurine and hypotaurine in aqueous media were reacted with 3,5-dinitrobenzoyl chloride in the presence of triethylamine to prepare 3,5 dinitrobenzoyl derivatives. These derivatives were separated on a C18 reversed phase column and detected by recording the absorbance at 254 nm. Derivatives of taurine and hypotaurine were obtained in yields of 91.4 +/- 3.3 and 85.6 +/- 2.6%, respectively. The calibration graphs for taurine and hypotaurine were linear between 2.5 and 500 microM with correlation coefficients of 0.999. The method was applied to the determination of taurine and hypotaurine in human and rat urine and blood and in rat liver and heart. PMID- 7858723 TI - Simultaneous determination of vitamins D3, E and K1 and retinyl palmitate in cattle plasma by liquid chromatography with a narrow-bore column. AB - A reversed-phase high performance liquid chromatographic method is described for the simultaneous determination of vitamins D3, E and K1 and retinyl palmitate in plasma. Narrow-bore columns are recommended because this alternative provides a good separation efficiency, plus greater economy and sensitivity. Detection limits for individual vitamins range from 0.42 to 2.8 ng. All vitamins were separated in less than 9 min. Recovery studies showed good results for all solutes (88.8-100.3%) and the intra-day coefficients of variations ranged from 1.0 to 4.5%. This method permits the simple determination of fat-soluble vitamins using 1 ml of cattle heparinized plasma. PMID- 7858722 TI - Measurement of nucleoside diphosphate kinase-Nm23 activity by anion-exchange high performance liquid chromatography. AB - A first-order assay to detect the activity of nucleoside diphosphate kinase (NDP kinase; EC 2.7.4.6) was developed. In this assay, the activity of NDP-kinase is measured using various deoxy- and ribonucleotide triphosphates as phosphate donors and dADP as phosphate acceptor. The enzyme activity is determined by quantifying, after anion-exchange HPLC, the amount of newly synthesized dATP. Contrary to the most common coupled enzymic assays or isotopic assays the use of different donor-acceptor pairs is not restricted. The resolution of the procedure described is limited only by the chromatographic separation of substrate and product pairs participating in the reaction. PMID- 7858724 TI - Method for analysis of methyltetrahydrophthalic acid in urine using gas chromatography and selected ion monitoring. AB - A method for the determination of methyltetrahydrophthalic acid (MTHP acid), a metabolite of methyltetrahydrophthalic anhydride (MTHPA) in human urine, was developed. The investigated MTHP acid was obtained by hydrolysis of a commercial MTHPA mixture, composed of three major isomers. These were synthesized and identified as 3-methyl-delta 4-tetrahydrophthalic anhydride, 4-methyl-delta 4 tetrahydrophthalic anhydride and 4-methyl-delta 3-tetrahydrophthalic anhydride. The urine was worked up by a liquid-solid extraction technique using C18 sorbent columns. Esterification was performed with methanol and boron trifluoride. The derivative in toluene was analyzed with capillary gas chromatography and selected ion monitoring. Deuterium-labeled MTHP acid was used as internal standard. The intra-assay precision for the overall method was between 4 and 8% in the range 3 110 ng/ml and the inter-assay precision was between 4 and 7% in the range 30-110 ng/ml. The total recoveries of the MTHP acid at 19 and 190 ng/ml were 94 and 97%, respectively. The total detection limit for the three isomers was < 6 ng/ml. Analysis of urine from a worker exposed to MTHPA makes it reasonable to assume that the method may be used for biological monitoring of MTHPA exposure. PMID- 7858725 TI - Coupled-column high-performance liquid chromatographic method for the determination of four metabolites of polycyclic aromatic hydrocarbons, 1-, 4- and 9-hydroxyphenanthrene and 1-hydroxypyrene, in urine. AB - A coupled-column high-performance liquid chromatographic method applying system integrated sample processing on a copper phthalocyanine modified solid-phase material, gradient elution and fluorescence detection for the quantification of 1 , 4- and 9-hydroxyphenanthrene as well as for 1-hydroxypyrene in urine is described. The automated chromatographic system tolerates direct and repeated injection of urine samples. Validation results presented indicate quantitative and matrix-independent recoveries, low imprecisions in within-series and between series analysis in combination with broad linear working ranges (2-400 nmol/l) and low detection limits (< 0.1 nmol/l). PMID- 7858726 TI - Gas chromatographic-electron-impact chemical ionization mass spectrometric identification of cinmetacin and its metabolites in human urine. AB - Cinmetacin and its three metabolites were identified by gas chromatography electron-impact positive-ion chemical ionization-negative chemical ionization mass spectrometry. After a single oral dose of 30 mg of cinmetacin to a healthy man, urine was collected and hydrolysed. The three metabolites were identified as O-desmethylated, N-descinnamoyl and C-C double bond reduced cinmetacins. The identification of cinmetacin metabolites in human urine was established by comparison of their GC retention times and electron impact and methane chemical ionization mass spectra with those of the synthesized authentic standards. PMID- 7858727 TI - Gas chromatographic-mass spectrometric analysis of alfentanil metabolites. Application to human liver microsomal alfentanil biotransformation. AB - The short-acting synthetic opioid alfentanil undergoes extensive biotransformation to several metabolites. A gas chromatographic-mass spectrometric assay, using selected-ion monitoring and deuterated internal standards, was developed for quantitating the predominant metabolites of alfentanil. Optimal extraction and derivatization conditions are described. The assay was applied to the analysis of metabolites formed during alfentanil metabolism in vitro by human liver microsomes. Formation of known alfentanil metabolites was confirmed, and formation of a metabolite, not previously detected in vitro, is described. The assay represents a significant improvement over existing methods of alfentanil metabolite analysis, which use HPLC and radiochemical detection. PMID- 7858728 TI - Determination of chlordiazepoxide in mouse plasma by gas chromatography-negative ion chemical ionization mass spectrometry. AB - A gas chromatographic-negative-ion chemical ionization mass spectrometric (GC NCIMS) method for the determination of chlordiazepoxide (Librium) in mouse plasma is described. Chlordiazepoxide was not suitable for GC analysis because of its thermal instability. The specific derivatization technique described permits the analysis using GC-MS with high sensitivity and selectivity. The use of halazepam as an internal standard instead of an isotopic internal standard decreases the cost and time of the analysis. The detection limit for chlordiazepoxide was 0.1 ng/ml with an injection volume of 1 microliter at a signal-to-noise ratio > 5. The limit of quantification was 5 ng/ml. PMID- 7858729 TI - Osmoregulation, the secretion of arginine vasopressin and its metabolism during pregnancy. AB - This review stresses changes in osmoregulation as well as the secretion and metabolism of arginine vasopressin during pregnancy, focusing on human gestation. Pregnant women experience a decrease in body tonicity, plasma osmolality decreasing immediately after conception to a nadir approximately 10 mosmol/kg below non-pregnant levels early in pregnancy, after which a new steady state is maintained until term. Data from both human and rodent gestation have led to a formation of how these changes occur. The osmotic thresholds for thirst and antidiuretic hormone release decrease in parallel. Lowering the threshold to drink stimulates increased water intake and dilution of body fluids. Because arginine vasopressin (AVP) release is not suppressed at the usual level of body tonicity, the hormone continues to circulate and the ingested water is retained. Plasma osmolality declines until it is below the osmotic thirst threshold, and a new steady state with little change in water turnover is established. Pregnancy is characterized by increments in intravascular volume, but volume-sensing AVP release mechanisms appear to adjust as gestation progresses so that each new volume status is "sensed" as normal. The metabolic clearance of AVP increases fourfold, the rise paralleling that of circulating cystine aminopeptidase (vasopressinase), and enzyme produced by the placenta. Furthermore, the disposal rate of 1-deamino-8-D-AVP, and AVP analogue resistant to inactivation by vasopressinase, is unaltered in pregnancy. Thus, the increase in AVP's metabolism and the high circulating aminopeptidase levels have been implicated in certain forms of transient diabetes insipidus that occur in late pregnancy. Finally, mechanisms responsible for the altered osmoregulation in pregnancy are obscure, but chorionic gonadotropin and relaxin may be implicated in the changes. PMID- 7858730 TI - Diabetes insipidus and use of desmopressin (Minirin) during pregnancy. AB - With the use of two central health registries in Sweden, the Hospital Discharge Registry and the Medical Birth Registry, we identified 100 infants born of women who had been hospitalized for diabetes insipidus. By checking the medical records of these women, 29 infants were identified whose mothers had diabetes insipidus prior to the pregnancy and had been treated through the pregnancy with desmopressin. These infants had a normal birth weight and gestational length; there was only one congenital malformation identified (a ventricular septum defect with a patent ductus arteriosus and simian lines). This child died at the age of 14 years in a hypophyseal disease. This is the largest material published on desmopressin during pregnancy. The results suggest that maternal diabetes insipidus and treatment with desmopressin during the whole pregnancy does not constitute a major risk for the infant. PMID- 7858731 TI - Impaired response of atrial natriuretic peptide to acute water load in obesity and in anorexia nervosa. AB - Plasma atrial natriuretic peptide (ANP) concentrations were determined in basal conditions and after infusion of 1000 ml of 0.9% NaCl in women with anorexia nervosa, in normotensive obese women and in healthy women of the control group. Additionally, in the obese women and in the controls, plasma ANP was measured after iv injection of clonidine. Anorectic patients were investigated in the period of weight loss (mean deficit of body weight was 40%). The mean body mass index (BMI) in the obese women was 36.44 +/- 0.36 kg/m2. Basal plasma ANP concentrations were significantly higher in both anorectic and obese women (p < 0.001 and p < 0.01, respectively). The response of ANP to acute water load was markedly blunted in anorexia nervosa and in obesity (delta % = 232% in control group, 14% in anorexia nervosa and 21% in obesity. A significant increase of ANP was found after iv injection of clonidine in the control group and in obesity (p < 0.001 and p < 0.01, respectively). However, the increase of response (expressed as a percentage change) in obese patients was lower than that in the control group (delta % = 64% and 199%, respectively). The response of ANP to alpha 2 adrenergic stimulation was higher than to hemodynamic stimulus. Our results suggest that the disturbed control of neuropeptides and neurotransmitters as well as changes in peripheral metabolism may explain the impaired responsibility of ANP to hemodynamic stimuli in anorectic and obese patients. PMID- 7858732 TI - Lack of growth hormone response to acute administration of dexamethasone in anorexia nervosa. AB - High plasma growth hormone (GH) levels, associated with abnormal hormone responses to provocative stimuli, point to an altered GH secretion in anorexia nervosa. The GH-releasing effect of acutely administered glucocorticoids, firmly established in normal subjects, has not been reported in these patients. In this study, acute iv administration of 4 mg of dexamethasone, compared with saline, increased plasma GH in nine normal-weight women (AUC 848.2 +/- 127.95 vs 242.8 +/ 55.35 micrograms.l-1.min-1, p < 0.05, respectively) but was ineffective in 11 anorectic patients (AUC 3271.8 +/- 1407.11 vs 2780.0 +/- 1162.04 micrograms.l 1.min-1, NS). After dexamethasone, a significant lowering of plasma cortisol was observed in normal women (AUC 25367.0 +/- 3128.43 vs 47347.1 +/- 4456.61 nmol.l 1.min-1, after dexamethasone and saline, respectively, p < 0.05), but not in anorectic patients (AUC 77809.3 +/- 8499.92 vs 78454.9 +/- 7603.62 nmol.l-1.min 1, NS). In both groups, plasma adrenocorticotrophin (ACTH) displayed a significant decrease after dexamethasone (AUC 523.6 +/- 92.08 vs 874.2 +/- 115.03 pmol.l-1.min-1, p < 0.05, after dexamethasone and saline, respectively, in anorectic patients and 377.5 +/- 38.41 vs 1004.9 +/- 200.51 pmol.l-1.min-1, p < 0.05, in controls). However, when considering the hormonal decremental areas, a significant dexamethasone-induced ACTH inhibition, compared to saline, was evidenced in normal (delta AUC -414.4 +/- 65.75 vs 222.9 +/- 42.40 pmol.l-1.min 1, p < 0.05) but not in anorectic women (delta AUC -254.2 +/- 96.92 vs 2.9 +/- 132.32 pmol.l-1.min-1, NS).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7858733 TI - Effect of growth hormone therapy in men with severe idiopathic oligozoospermia. AB - Some studies have suggested that growth hormone (GH) may enhance folliculogenesis in women, and similarly may enhance spermatogenesis in men with hypogonadotrophic hypogonadism. In this prospective open-controlled pilot study, we investigated the effect of daily subcutaneous GH for 5 months in 12 endocrinologically normal men with severe idiopathic oligozoospermia (< 10 million/ml). All the men had normal karyotype and endocrine tests, including a GH response of > 20,000 mU/l to insulin hypoglycaemia. Nine men with similar sperm counts acted as controls. During treatment, each patient was examined monthly, asked for side effects and had glycosylated haemoglobin, glucose and blood counts monitored. Five semen samples were obtained in the 4 months before treatment, two samples per month during treatment and three samples after stopping treatment. The mean insulin like growth factor I (IGF-I) was normal before treatment and 1 month after ending treatment, at 206 and 182 micrograms/l, respectively, but increased significantly during treatment to 444 micrograms/l (p < 0.0001, ANOVA). The mean (SD) sperm counts were 2.6 (2.5), 2.5 (3.7) and 2.3 (2.1) million/ml before, during and after GH treatment, respectively, and did not show any statistically significant differences (ANOVA). We conclude that GH does not increase or decrease sperm counts in men with severe idiopathic oligozoospermia. PMID- 7858734 TI - Stimulatory effect of gonadotropin-releasing hormone (GnRH) on in vitro prolactin secretion and presence of GnRH specific receptors in a subset of human prolactinomas. AB - The purpose of this study was to determine whether gonadotropin-releasing hormone (GnRH) may exert a direct action on human prolactinomas. On a series of 17 adenomas, we studied the effect of GnRH on the in vitro prolactin (PRL) secretion of dispersed and perifused cells of 10 cases and the [125I]GnRH agonist binding on frozen sections of three out of the adenomas studied in perifusion and on the membrane preparations of seven other cases. Two 20-min pulses of GnRH (10(-7) mol/l) stimulated the in vitro PRL secretion of three adenomas out of 10 (increase of 200, 444 and 205%, respectively, above basal levels). The GnRH receptors of three adenomas bound GnRH agonist (Des-Gly10-(D-Ala6)-GnRH ethylamide). The binding was specific, with a high affinity (Kd = 0.60, 0.48 and 0.40 nmol/l) similar to that of two human anterior pituitaries obtained post mortem (Kd = 0.70 and 0.40 nmol/l). Indirect immunoperoxidase revealed that the majority of the cells (60-90%) in all the adenomas studied contained immunoreactive PRL. Four of them also contained cells immunoreactive to the alpha subunit of the glycoprotein hormones. In none of the prolactinomas were cells immunoreactive to antiserum of anti-beta-luteinizing hormone, anti-beta-follicle stimulating hormone or anti-beta-thyrotropin. All the prolactinomas that were responsive to GnRH in perifusion experiments and/or bound specifically to [125I]GnRH agonist were also immunoreactive for alpha-subunit. These results show that GnRH, via GnRH specific receptors, exerts a stimulation on in vitro PRL secretion in a subset of prolactinomas characterized by the presence of alpha subunit. PMID- 7858735 TI - Urinary iodine excretion and individual iodine supplementation among elderly subjects: a cross-sectional investigation in the commune of Randers, Denmark. AB - Several studies have demonstrated that the iodine intake is relatively low in Denmark. However, the results are difficult to interpret because no information has been given on the frequency of individual iodine supplementation. We performed a cross-sectional study of elderly subjects living in the commune of Randers, Denmark. Urinary iodine excretion was measured in the 423 participants (185 males, 238 females) and a careful history was taken on any possible intake of supplementary iodine. The median urinary iodine excretion was 48.3 micrograms/g creatinine for the whole population (40.8 micrograms/g creatinine in males, 53.2 micrograms/g creatinine in females). In the part of the population that did not take iodine supplementation (46.7%) the median value was 36.1 micrograms/g creatinine (males 33.8; females 38.8). Regular iodine supplementation taken as an iodine-containing vitamin/mineral tablet was found in 30.8% of the population. This increased the urinary iodine excretion to a median level of 80.5 micrograms/g creatinine (males 62.0; females 88.0). The study shows that the basic iodine intake level is overestimated if individual iodine supplementation is not taken into account. Such supplementation may lead to median iodine excretion values that seem reasonable, even if the iodine intake of the part of the population not taking iodine (in this study, nearly half of the population) is low. PMID- 7858736 TI - Impaired natural killer cytotoxicity in peripheral blood mononuclear cells in Graves' disease. AB - We studied the natural killer (NK) activity of peripheral blood mononuclear cells (PBMC) in patients with Graves' disease (GD). Peripheral blood mononuclear cells from 20 untreated hyperthyroid patients with GD showed a significantly reduced NK activity against 51 Cr-labeled K562 cells (33.9 +/- 15.9%), while in 32 euthyroid patients under antithyroid drug therapy. NK activity was similar to that of controls (46.9 +/- 17.3 and 49.9 +/- 20.2%, respectively). Furthermore, normalization of thyroid function with antithyroid drugs was associated with a significant increase and normalization of NK activity during the follow-up of nine GD patients (from 29.2 +/- 17.9 to 48.1 +/- 16.5%). This phenomenon could not be ascribed to a defective number of NK cells because the amounts of CD56+ and CD16+ cells in PBMC from both hyperthyroid and euthyroid GD patients were within normal ranges. Natural killer activity of PBMC from patients with toxic multinodular goiter was similar to that of normal controls (45 +/- 12.8 to 49.9 +/- 20%). No correlation was found between natural killer activity and serum levels of free thyroxine, TSH-inhibitory immunoglobulins, thyroidal antibodies to thryoglobulin and thyroidal microsomal antigen, dose or duration of antithyroid drug therapy. Natural killer activity from both controls and GD patients was enhanced in vitro by addition of recombinant interleukin 2 (IL-2), reaching control levels in hyperthyroid patients. These abnormalities were not associated with a defective IL-2 production by T cells, nor with a decreased IL-2R expression. We conclude that in untreated Graves' disease there is a decrease in NK cell activity in PBMC, probably dependent on the autoimmune process.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7858737 TI - Sulfoconjugated and free plasma catecholamine levels at rest and during exercise in patients with idiopathic dilated cardiomyopathy. AB - Plasma levels of sulfoconjugated (sc) catecholamines (CA) have been shown to be increased with activation of the sympathoadrenal system in a number of clinical settings. We evaluated the relation between scCA and clinical or hemodynamic parameters of patients with idiopathic dilated cardiomyopathy (IDC) at rest and during incremental exercise testing. Eleven healthy subjects, nine patients in New York Heart Association (NYHA) functional class I (IDC-A group) and 11 in NYHA functional class II and III (IDC-B group) performed a symptom-limited, graded bicycle exercise test. Resting, peak and various postexercise levels of plasma free and scCA were determined by high-pressure liquid chromatography. Resting CA levels obtained in the supine position were remarkable for elevations of free norepinephrine (NE) in IDC-B patients (355 +/- 157 ng/l) as compared to IDC-A patients (177 +/- 54, p = 0.006) or healthy controls (193 +/- 74, p = 0.007). Similarly, scNE was highest in IDC-B patients with 1856 +/- 1089 ng/l, followed by IDC-A (1028 +/- 187, p = 0.025) and control subjects (1109 +/- 440, p = 0.025). There was a highly significant correlation between free and scNE (r = 0.76, p < 0.0005). Whereas resting free dopamine (DA) levels were comparable in all three groups, scDA was found to be elevated clearly in IDC-B patients (8772 +/- 2097 ng/l) and significantly different to IDC-A (5786 +/- 2481, p = 0.01) or control subjects (4892 +/- 1575, p = 0.0005). The NYHA functional class and maximum exercise performance correlated best with resting scDA (r = 0.68, p = 0.001 and r = 0.56, p = 0.005, respectively). At peak exercise, IDC-B patients exhibited a significant decrease in scNE and sc epinephrine (E) (from 1856 +/- 1089 to 1495 +/- 932 ng/l, p < 0.005 and from 491 +/- 173 to 282 +/- 143 ng/l, p < 0.01) compared to controls (from 1109 +/- 444 to 1094 +/- 548 ng/l and from 379 +/- 200 to 329 +/- 134 ng/l). In IDC-B patients this decrease in scNE and scE at peak exercise was related inversely to the rise in free NE and E (r = -0.81, p < 0.005 and r = -0.68, p < 0.05). Resting hemodynamic indices generally were reflected better by some free CA rather than by conjugated forms or by parameters of clinical performance. These findings suggest that in addition to free or scNE levels, resting scDA is elevated in symptomatic patients with IDC.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7858738 TI - Biosynthetic growth hormone increases the collagen deposition rate in rat aorta and heart. AB - Disorders of the cardiovascular system often are associated with alterations in the metabolism of the collagens of these tissues. A method for in vivo determination of collagen deposition rate in small tissue samples is delineated and used for assessment of the effect of biosynthetic growth hormone (GH) injections on the collagen deposition rate in rat aorta and cardiac musculature. Rats were injected with GH, and the controls with saline, twice daily for 7 days. The in vivo collagen deposition rate was measured by injecting iv a large dose of [3H]-proline with a flooding dose of "cold" proline, followed by determination of the production of [3H]-hydroxyproline during a 4-h labelling period. Extractable collagens that were not bound in the tissue and therefore do not contribute mechanical strength to it were removed from the samples. 3H-Labelled- and "cold" amino acids were assessed by reversed-phase HPLC combined with simultaneous flow scintillation detection on the same sample. In the control group the deposition per hour was 0.13 +/- 0.02% (mean +/- SEM) in aortic intima media and 0.72 +/- 0.09% in cardiac left ventricular musculature. Growth hormone induced a threefold increase (p < 0.001 and p < 0.01, respectively) in the collagen deposition rate: 0.45 +/- 0.06% in aortic intima media and 2.43 +/- 0.45% in cardiac left ventricular musculature. The method described enables a rapid and sensitive determination of collagen deposition per hour in small tissue samples from experimental animals. The collagen deposition rate of cardiac musculature is fivefold higher compared with that of aortic intima media.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7858739 TI - Epidermal growth factor stimulates the cell growth of the PA-1 teratocarcinoma cell line in an autocrine/paracrine fashion. AB - In order to investigate the biological significance of epidermal growth factor (EGF) in the cell function of teratocarcinoma cells, we examined the production, binding and cell proliferative effect of EGF in PA-1 human ovarian teratocarcinoma cell line. The immunoreactivity of EGF in PA-1 cell-conditioned medium was detected by human EGF radioimmunoassay, and prepro-EGF mRNA was demonstrated in PA-1 cells by Northern blot analysis. An [125I]EGF binding study showed the presence of EGF receptor with very high binding affinity and relatively low numbers of binding sites in PA-1 cells. Furthermore, the growth of PA-1 cells was stimulated by EGF and inhibited by anti-EGF monoclonal antibody. These results suggest strongly that EGF plays an important role in controlling the growth of teratocarcinoma cells as an autocrine/paracrine growth factor. PMID- 7858740 TI - Increase in human placental glucose transporter-1 during pregnancy. AB - Glucose transporter-1 (GLUT1) has been found in high abundance in human placentas. The purpose of this study was to analyze the changes in the level of GLUT1 during pregnancy. We have analyzed the gestational changes in human placental GLUT1 by [3H]cytochalasin B binding assay, immunoblot analysis and Northern blot analysis. Levels of [3H]cytochalasin B binding to placental membrane in pregnancy at 7-10, 18-20 and 38-40 weeks were 4.2 +/- 0.47, 5.2 +/- 0.46 and 7.2 +/- 0.40 (mean +/- SEM, N = 4) mumol/kg protein, respectively. Amounts of 49-kD and 60-kD proteins detected in immunoblot analysis increased during pregnancy in parallel with [3H]cytochalasin B binding to placental membrane. The GLUT1 mRNA levels also increased during pregnancy. Immunohistochemical examination showed that GLUT1 was localized in the plasma membranes of trophoblast cells. These findings showed that the GLUT1 level increased during pregnancy in human placentas and suggest that GLUT1 may play an important role in fetal development. PMID- 7858741 TI - Identification of luteinizing hormone receptor binding inhibitor in bovine corpora lutea. AB - A 7000 g supernatant, obtained during the purification of luteinizing hormone (LH) receptor from bovine corpora lutea homogenate, was concentrated by ultrafiltration. The filtrate, containing < 50,000 molecular weight material, exhibited LH receptor binding inhibitor (LH-RBI) activity. The filtrate was ultrafiltered sequentially through Amicon PM-10, PM-30 and UM-2 filters to yield a LH-RBI-containing fraction in the higher molecular weight range of 30,000 10,000 and a LH-RBI-containing fraction in the lower molecular weight range of 10,000-1000. The higher molecular weight LH-RBI fraction was purified on Sephadex G-25 and the lower molecular weight LH-RBI fraction was purified on Sephadex G 50. Both the high- and the low-molecular-weight LH-RBI species inhibited the binding of 125I-labeled human chorionic gonadotropin (hCG) to bovine corpora lutea and to rat Leydig cell membrane receptors. Similarly, the production of testosterone by hCG-stimulated rat Leydig cells was inhibited in a dose-response manner by both the high- and the low-molecular-weight LH-RBI species. The LH-RBI activity in the low-molecular-weight species was stable at 4 degrees C for up to 6 months and at temperatures up to 90 degrees C for 15 mins, whereas the LH-RBI activity of the high-molecular-weight species was stable at 4 degrees C for 15 months and unstable at 60 degrees C after 15 min. The 7000 g supernatant provided a much-needed source to obtain larger than previously reported quantities of LH RBI for isolation as well as for structure and function studies. PMID- 7858742 TI - Pituitary-testicular axis in rats lacking testicular macrophages. AB - Testicular macrophages were depleted selectively in adult rats by intratesticular injections of liposome-entrapped dichloromethylene diphosphonate (Cl2MDP-Lp), whereas control animals received intratesticular injections of phosphate-buffered saline-containing liposomes or 0.9% NaCl. The absence of macrophages in Cl2MDP-lp injected rats was confirmed histologically. Rats lacking testicular macrophages showed significantly increased (twofold on average) serum concentrations of luteinizing hormone at 5 and 10 days after treatment. Serum luteinizing hormone concentrations drop to control values at 15 days after treatment. Serum testosterone concentrations were increased significantly (twofold on average) at 5, 10 and 15 days after treatment. No significant changes were found for follicle stimulating hormone serum concentrations, or for the weights of the testes and sex accessory organs. Testicular histology was unchanged, except for the absence of testicular macrophages in Cl2MDP-lp-treated animals. Rats treated with NaCl or Cl2MDP-lp were injected with 100 IU of human chorionic gonadotrophin and sacrificed 2 h later. Serum testosterone concentrations increased 8.6- and 3.5 fold in NaCl and Cl2MDP-lp-treated rats, respectively, in response to acute human chorionic gonadotrophin treatment. These results point out the relevance of testicular macrophages for the regulation of the pituitary-testicular axis. PMID- 7858743 TI - Beta-adrenergic receptors are involved in histamine-induced secretion of proopiomelanocortin-derived peptides and prolactin in rats. AB - The neurotransmitter histamine (HA) is involved in central regulation of secretion of prolactin (PRL) and the proopiomelanocortin (POMC)-derived peptides adrenocorticotropin (ACTH), beta-endorphin (beta-END) and alpha-melanocyte stimulating hormone (alpha-MSH). The effect of HA on POMC-derived peptides and PRL release is, at least in part, indirect and may involve activation of catecholaminergic systems. Therefore, we investigated the effect of beta adrenergic receptor blockade on HA or HA agonist-induced release of ACTH, beta END, alpha-MSH and PRL. Central administration of HA, the H1-receptor agonist 2 thiazolylethylamine (2-TEA) or the H2-receptor agonist 4-methylhistamine (4-MeHA) stimulated the secretion of ACTH, beta-END, alpha-MSH and PRL. Pretreatment with the beta-adrenergic antagonist propranolol inhibited secretion of the POMC peptides in response to HA, 2-TEA or 4-MeHA. Propranonol only inhibited the PRL response to HA or 2-TEA, but had no effect on the PRL response to 4-MeHA. Administration of the beta-receptor agonist isoproterenol stimulated ACTH, beta END, alpha-MSH and PRL two to five-fold. This effect was totally blocked by pretreatment with propranolol. We conclude that HA-induced secretion of POMC derived peptides from the anterior and intermediate lobe of the pituitary gland and of PRL from the anterior lobe is, at least in part, mediated via catecholamines. beta-Adrenergic receptors are involved in the mediation of the POMC response to H1- as well as H2-receptor activation, whereas beta-receptors are involved only in the mediation of the PRL response to H1-receptor activation. PMID- 7858744 TI - Epidermal growth factor (EGF)- and transforming growth factor alpha-stimulated invasion and growth of follicular thyroid cancer cells can be blocked by antagonism to the EGF receptor and tyrosine kinase in vitro. AB - We have shown recently that epidermal growth factor (EGF) enhanced invasion and growth of differentiated thyroid cancer cells in vitro and in vivo. The present study analyzed the effects of transforming growth factor alpha (TGF-alpha) on invasion and growth of a follicular thyroid cancer cell line (FTC133) and whether blocking the EGF receptor by a monoclonal antibody (Mab528) or blocking the tyrosine kinase of the receptor by genistein abolished the EGF- and TFG-alpha mediated effects. Growth and invasion (penetration of 8-microns pore polycarbonate membranes coated with Matrigel) were determined by the dimethylthiazol-diphenyltetrazolium bromide assay. Epidermal growth factor (10 ng/l) stimulated invasion of FTC133 by 42% and TGF-alpha (10 ng/l) stimulated invasion of FTC133 by 27% (p < 0.02). Both growth factors also enhanced growth by 62% (EGF) and 30% (TGF-alpha) (p < 0.003). Epidermal growth factor receptor antibodies (1 microgram/ml) abolished EGF-mediated stimulation of invasion and growth completely and that of TGF-alpha by 93%. At 100 ng/ml genistein reversed EGF and TGF-alpha stimulation, and at 1 microgram/ml it inhibited invasion (27%) and growth (40%) of unstimulated FTC133 (p < 0.02). We conclude that TGF-alpha stimulates invasion and growth of follicular thyroid cancer by binding to the EGF receptors, that EGF- and TGF-alpha-mediated effects can be blocked by antagonism to the EGF receptor and to tyrosine kinase, and that genistein not only neutralized EGF and TGF-alpha effects but also inhibited invasion and growth of unstimulated FTC133.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7858745 TI - Follow-up study on the effects of thyroid hormone administration on androgen metabolism of peripubertal rat Sertoli cells. AB - The inhibitory effect of triiodothyronine (T3) given in early postnatal life on Sertoli cell proliferative activity, leading to their precocious terminal differentiation, has been demonstrated previously. However, data concerning the role of thyroid hormone on androgen metabolism of Sertoli cells during the same period are still lacking. In this study we performed a time-course investigation on the effects of T3 treatment on testosterone metabolism in Sertoli cells isolated from 2-, 3- and 4-weeks-old euthyroid rats. Triiodothyronine (3 micrograms/100 g body wt) was given ip., during the last week prior to sacrifice. Sertoli cells from all animal groups initially were cultured under basal conditions during the first 24 h and subsequently in the presence of testosterone (0.5 mumol/l) with or without T3 (1 nmol/l) for an additional 24 h. This treatment given to 2-week-old animals resulted in reduced testicular growth. As far as androgen metabolism is concerned, T3 in vivo and in vitro treatment in 2- and 3-week-old animals induced a lowering of dihydrotestosterone + 3 alpha-diol with an enhancement of the two other 5 alpha-reduced androgens. The effect was much less pronounced in the oldest group. In both 2- and 3-week-old treated rats a marked reduction of oestradiol was observed, which indicates an inhibition of aromatase activity, mainly in younger animals. This enzyme has been reported to be extremely active in Sertoli cells of rats (of the same strain) between the age of 5 and 20 days, but it decreases rapidly thereafter.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7858746 TI - Effects of transforming growth factor alpha (TGF-alpha) on DNA synthesis and thyrotropin-induced iodine metabolism in cultured porcine thyroid cells. AB - Transforming growth factor alpha (TGF-alpha) is a potent mitogen that is similar structurally to epidermal growth factor (EGF). As EGF is a potent growth stimulator and an inhibitor of iodine metabolism in cultured thyroid cells of several species, we studied whether TGF-alpha has similar effects using porcine thyroid cells in culture. Recombinant human TGF-alpha dose-dependently stimulated DNA synthesis of thyroid cells, with maximal stimulation (eight- to ninefold above basal) occurring at 2 nmol/l. The potency was approximately 50% that of mouse EGF and correlated with the ability to compete with EGF for receptor binding, suggesting that the action of TGF-alpha is mediated by interaction with EGF receptors. When thyroid cells were cultured for 3 days with thyrotropin (TSH) in the presence of TGF-alpha, TSH-induced iodide uptake was inhibited in a dose dependent manner. The potency of TGF-alpha again was approximately 50% that of EGF. Transforming growth factor alpha did not inhibit TSH-stimulated cAMP production. Moreover, iodide uptake stimulated by either forskolin or 8-bromo cAMP also was inhibited by TGF-alpha. Thus, we conclude that TGF-alpha inhibits TSH-induced iodine metabolism largely by acting at the steps distal to cAMP production. Northern blot analysis revealed expression of TGF-alpha mRNA in porcine thyroid cells. These observations suggest that TGF-alpha acts as an autocrine modulator of growth and differentiated functions in porcine thyroid cells. PMID- 7858747 TI - Blood pressure and left ventricular mass in children and adolescents: the Hypertension in Pregnancy Offspring Study. AB - The etiology of essential hypertension is still a matter of some speculation. Research concerned with pre-hypertensive mechanisms of human essential hypertension usually includes subjects with either borderline hypertension or with a positive family history of hypertension. High blood pressure and increased left ventricular mass are risk factors for cardiovascular disease in adults. Much information about hypertension and other coronary artery disease risk factors in children and adolescents has been collected in the past two decades, and during the last years new evidence has emerged which indicates that essential hypertension originates early in life. Several studies have suggested that children and adolescents born following hypertensive pregnancies may constitute a risk group for future hypertension. The present study addresses the question concerning the future cardiovascular risk in offspring of women who had hypertension during pregnancy. The subjects in the present study were also studied in the search for early pre-hypertensive mechanisms. Fifty-nine children were studied, their mean age being 12.6 years. Forty-two children were born to mothers who had hypertension during pregnancy and 17 children were born after normotensive pregnancies by mothers who remained normotensive at follow-up 7-12 years after pregnancy. Blood pressure was measured at rest and during physical exercise. Left ventricular mass was calculated from M-mode echocardiogram. Erythrocyte concentrations of sodium and potassium and Na-K-ATPase activity were determined. Perinatal and maternal characteristics were collected from hospital records for all deliveries. Twenty-nine males and 23 females, of the initially studied children, were reexamined after 5.6 years. The present study demonstrates that children whose mothers had hypertension during pregnancy and were hypertensive at follow-up had higher blood pressure than children born following normotensive pregnancies. A familial factor for hypertension was an independent determinant of blood pressure, but not a determinant of left ventricular mass. Children born following hypertensive pregnancies had lower birth weight, shorter gestational period and higher blood pressure at follow-up. There was no relationship between birth weight and blood pressure in these children, but there were associations between maternal blood pressure during pregnancy and birth weight as well as blood pressure at follow-up. The difference in blood pressure persisted as the children matured. Particularly the children whose mothers had hypertension during pregnancy and were hypertensive at follow-up maintained their rank with regard to blood pressure and left ventricular mass during adolescence.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7858748 TI - Misconduct and the development of ethics in the biological sciences. PMID- 7858749 TI - Reflections of an IRB chair. PMID- 7858750 TI - Making research consent forms informative and understandable: the experience of the Indian Health Service. PMID- 7858751 TI - How much influence do various members have within research ethics committees? PMID- 7858752 TI - Women in clinical studies: a feminist view. PMID- 7858753 TI - Surrogate decision making for severely cognitively impaired research subjects: the continuing debate. PMID- 7858754 TI - Conflicts of interest in research on children. PMID- 7858755 TI - Review of legal instruments and codes on medical experimentation with children. PMID- 7858756 TI - CQ sources. PMID- 7858757 TI - Response of Buddhism and Shinto to the issue of brain death and organ transplant. PMID- 7858758 TI - Living related liver transplantation: request for an international ethics consultation from the Research Center for Surgery in Moscow. PMID- 7858759 TI - CQ interview with Sherwin Nuland on How we Die. Interview by Steve Heilig. PMID- 7858760 TI - Universal access on the American Commons. PMID- 7858761 TI - Honest mistakes. From the physician father of a young patient. PMID- 7858762 TI - Intravascular ultrasound imaging in patients with acute myocardial infarction: comparison with chronic stable angina pectoris. AB - BACKGROUND: Myocardial infarction is the result of acute thrombotic occlusion of a coronary artery, most likely secondary to rupture of an atherosclerotic plaque. Intracoronary ultrasonic (ICUS) examinations were performed in patients with acute myocardial infarction (AMI) in order to describe intraluminal ultrasonic findings at the site of acute coronary occlusion. METHODS: Coronary angiography and ICUS studies were performed consecutively within 6 h of the onset of chest pain in 30 patients with AMI prior to percutaneous transluminal coronary angioplasty (PTCA). The control group consisted of 30 patients with chronic stable angina pectoris (SAP). Following angiographic documentation of a proximal stenosis or occlusion, a 3.5 or 4.8 F mechanical ultrasound catheter (20 MHz) was advanced successfully through the lesion in 25 of 30 (83%) patients with AMI and in 15 of 30 (50%) patients with SAP (P < 0.01). RESULTS: Intracoronary ultrasound permitted differentiation between pulsatile, low-echogenic intraluminal material suggesting thrombus and mural highly echogenic atherosclerotic plaque in 22 of 25 (88%) patients with AMI. A negative imprint of the ICUS catheter was documented within the low-echogenic material in 17 of 25 (68%) patients with AMI. Low echogenic intraluminal material was found in 18 of 25 (72%) segments proximal and in 12 of 25 (48%) segments distal to the highly echogenic plaque, indicating prestenotic and post-stenotic thrombus in AMI. The plaque appeared eccentric in 22 of 25 (88%) patients with AMI. In comparison, stenotic lesions in chronic SAP patients were less frequently eccentric (5/15, 33%, P < 0.01) and contained a higher proportion of pure highly echogenic material (12/15, 80%). Cross-sectional area stenosis due to highly echogenic plaque averaged 52 +/- 13% in AMI and 82 +/ 3% in SAP (P < 0.01). Calcification of plaque was evident in 21 of 25 patients with AMI (SAP 12/15, 80%, NS). The surface of the plaque was rough in 13 of 25 (52%) AMI patients (SAP 4/15, 27%, P < 0.05). Fissures were detected in only seven (28%) patients and dissection was observed in two (8%) cases. The low incidence might be a result of the limited resolution of the ICUS system. CONCLUSION: This study demonstrates that ICUS with 4.8 or 3.5 F catheters is feasible and safe in selected patients with AMI, and adds little to the overall duration of the angioplasty procedure. The identification and demarcation of atherosclerotic plaque provided by ICUS could prove valuable in guiding PTCA, in deciding on appropriate therapy, and in acute and long-term follow-up of AMI patients. PMID- 7858763 TI - Apparently coronary heart disease-free patients in the coronary care unit: characteristics, medical care, and 1-year outcome. AB - BACKGROUND: Coronary care units (CCUs) have contributed significantly to the improved survival rates among patients with acute myocardial infarction. Many patients admitted to CCUs are certified to be free of coronary heart disease (CHD) at discharge. There is little literature on the hospital course and prognosis of such patients. METHODS: We identified and followed 594 patients admitted to six CCUs in the Minneapolis-St Paul metropolitan area in 1990 because of suspected acute myocardial infarction who were eventually discharged without evidence of acute or chronic CHD. Their baseline characteristics, medical care, and 1-year outcome were compared with those of 672 patients with confirmed acute myocardial infarction and 612 patients with a history of CHD but without evidence of an acute coronary event. RESULTS: Similar numbers of men and women were certified to be CHD-free on discharge from hospital. These patients were significantly younger than either patients with acute myocardial infarction or patients with a history of CHD (mean age 57, 65, and 67 years, respectively). CHD free patients commonly reported current smoking, hypertension, and hypercholesterolemia (26, 50, and 18%, respectively). These patients were less likely than those with acute myocardial infarction or a history of CHD to undergo diagnostic or therapeutic procedures, or to receive pharmacological treatment. Their 1-year mortality rate was 5%, significantly lower (P < 0.05) than the mortality among patients with either acute myocardial infarction (18%) or a history of CHD (13%) but 2.6 times greater than expected in the general population. Older age, previous or current smoking, chest pain leading to admission, and congestive heart failure were independent predictors of 1-year mortality. CONCLUSIONS: Patients certified to be CHD-free after admission to a CCU with suspected acute myocardial infarction have a lower 1-year mortality rate than patients experiencing acute myocardial infarction or chronic CHD. Their mortality rate, however, is substantially higher than expected, probably because of a high prevalence of cigarette smoking and hypertension. PMID- 7858764 TI - Early recurrence of ST-segment elevation in patients with initial reperfusion during thrombolytic therapy: impact on in-hospital reinfarction and long-term vessel patency. AB - AIM: To investigate the frequency and prognostic impact of early recurrent ST segment elevation after initial ST-segment resolution in patients with acute myocardial infarction who had been treated with intravenous thrombolysis. METHODS: Eighty-one patients with acute myocardial infarction underwent 24 h Holter monitoring of the infarct-related ST-segment elevation, at the initiation of thrombolytic therapy. Angiography was performed in 88% of the patients 9 +/- 4 days after infarction. RESULTS: Resolution of the ST-segment elevation during the first 4 h, suggestive of early reperfusion, occurred in 67 (83%) patients (group 1). Of these, 31 (46%) had subsequent re-elevations (group 1a), 26 during the first 4 h, and 20 later. Thirty-six (54%) patients had no recurrence of the ST segment elevation (group 1b). During follow-up, patients in group 1a experienced more in-hospital reinfarctions (26 versus 6%, P = 0.04) and had a higher rate of occluded infarct-related vessels at angiography than patients in group 1b (40 versus 17%, P = 0.01). CONCLUSION: During the first 24 h after initiation of thrombolytic therapy, recurrences of ST-segment elevation are frequent in myocardial infarction patients with ECG signs of an initially reperfused infarct related artery. Recurrence of ST-segment elevation indicates a higher risk of reinfarction during hospitalization and of long-term occlusion of the infarct artery. PMID- 7858765 TI - Lipoprotein (a) and other risk factors in patients with non-insulin-dependent diabetes mellitus. AB - BACKGROUND: Studies have established a relationship between lipoprotein (a) [Lp(a)] levels and cardiovascular disease, but few have studied Lp(a) in patients with non-insulin-dependent diabetes mellitus (NIDDM). METHODS: We determined Lp(a) concentrations, levels of glycated hemoglobin, and the personal and family history of atherosclerosis in 88 patients with NIDDM (53 men and 35 women; age, 33-70 years) and 90 age- and sex-matched controls. Twenty-three patients with NIDDM had cardiovascular disease (CVD group) and 65 did not (non-CVD group). RESULTS: Lp(a) levels were higher in CVD than non-CVD patients (P < 0.01). Triglyceride levels negatively correlated with Lp(a) (r = -0.51, P < 0.05), independently of the metabolic control of diabetes. Patients with poor metabolic control (glycated hemoglobin > 7.5%) had higher Lp(a) levels than the control group (P < 0.05). Lp(a) levels were higher than 0.30 milligram in 11% of patients without CVD and 55% of those with CVD (P < 0.05). Cluster analysis showed that Lp(a), as well as total cholesterol, triglycerides, apolipoprotein B100, and age were independently related to CVD in patients with NIDDM (P < 0.001 for triglycerides and P < 0.05 for the other variables). CONCLUSIONS: Lp(a) levels can be considered an independent risk factor for the development of atherosclerosis in NIDDM. PMID- 7858766 TI - Prostacyclin and thromboxane A2 levels in children and adolescents with an inherited predisposition to coronary heart disease: a family study. AB - BACKGROUND: The aim of this study was to trace the possible mechanisms of premature atherosclerosis in its early stages and to expand our knowledge of the genetic structure of an inherited predisposition to coronary heart disease (CHD) by monitoring of TXA2 and PGI2 levels in the children of fathers who have suffered a premature myocardial infarction. METHODS: Prostacyclin (PGI2) and thromboxane A2 (TXA2) levels were estimated by radioimmunoassay in 90 children (aged 7-18 years) of fathers who had suffered premature infarction and in both their parents (the 'main' group, n = 191), and in 59 of their healthy contemporaries with no family history of ischaemic events, hypertension, or diabetes, and both their parents (the 'control' group, n = 110). RESULTS: Sons of early infarction patients presented an average TXA2 level of 158.94 +/- 16.60 pg/ml (versus 86.88 +/- 12.71 pg/ml in the control group, P < 0.001), and daughters presented an average TXA2 level of 230.13 +/- 33.68 pg/ml (versus 69.67 +/- 14.99 pg/ml in the control group, P < 0.001). This hyperproduction was independent of the children's sex and could not be attributed to health problems. A significant increase (two-fold) of PGI2 in the boys but not in the girls of the main group was noted. Daughters of infarction patients had significantly higher levels of TXA2 than PGI2. The wives of early infarction patients presented a significantly higher level of both TXA2 and PGI2 (two and three times the level in the control group, P < 0.02 and P < 0.05, respectively). CONCLUSIONS: Spontaneous TXA2 hyperproduction is intrinsic among children with an inherited propensity for CHD and is strongly determined by genetic factors, which is evident from the structure of in-family phenotypic correlations of PGI2 and TXA2 levels. PMID- 7858767 TI - Effects of glibenclamide on ventricular fibrillation in non-insulin-dependent diabetics with acute myocardial infarction. AB - BACKGROUND: Glibenclamide, a hypoglycemic sulfonylurea, has shown antiarrhythmic effects in acutely ischemic myocardium. The aim of the present study was to evaluate the effectiveness of the drug in preventing ventricular fibrillation in diabetic patients with acute myocardial infarction. METHODS: We studied 232 patients with non-insulin-dependent diabetes mellitus (106 on glibenclamide, group A1; 126 treated with another hypoglycemic drug or with diet only, group A2) and 830 non-diabetic people. All the patients were admitted to our coronary care unit with their first myocardial infarction. RESULTS: Ventricular fibrillation occurred in 1.9% of group A1, 7.9% of group A2, and 9.9% of the non-diabetic (A1 versus A2, P < 0.05; A2 versus the non-diabetic group, NS; A1 versus the non diabetic group, P < 0.01). Sustained ventricular tachycardia was not significantly different among the groups. CONCLUSIONS: The antiarrhythmic effectiveness of glibenclamide might be related to its blocking action on the ATP dependent potassium channel, with consequent attenuation of the efflux of potassium induced by ischemia. We also observed a higher mortality rate resulting from heart failure in group A2 than in group A1 or the non-diabetic group. Since glibenclamide has never shown significant effects on myocardial contractility, this finding remains to be elucidated. Glibenclamide therefore appears to have an antifibrillatory effect in acute myocardial infarction; with respect to acute coronary events, the drug might be able to prevent ventricular fibrillation, which is most often fatal when it occurs before hospitalization. PMID- 7858768 TI - Intravenous diltiazem versus isosorbide dinitrate for unstable angina: comparison of coronary angiographic morphology in the unstable and stabilized states. AB - BACKGROUND: The efficacy of intravenous infusion of diltiazem was compared with that of isosorbide dinitrate (ISDN) for the early treatment of unstable angina. METHODS: Sixty-four patients with at least 70% organic stenosis of the culprit artery and prolonged rest angina were enrolled. Coronary angiography was performed on admission. Subsequently, patients were randomly assigned to receive either intravenous diltiazem or ISDN. Coronary angiography was repeated when the angina was under control, and the findings were compared with those on admission. RESULTS: Diltiazem was more effective than ISDN, and symptoms were resolved in 84% of the diltiazem group compared with 47% of the ISDN group (P = 0.0038). Repeat coronary angiography showed that the degree of stenosis remained unchanged in the majority of patients (n = 47, 75.8%). There was no difference between the two groups with regard to the coronary angiographic findings. CONCLUSIONS: Since diltiazem was more effective than ISDN even though the coronary angiographic findings of the two groups were similar, it is possible that some action other than vasodilatation (such as a direct protective effect on the myocardium) may be responsible for the remission of unstable angina. PMID- 7858769 TI - Lipofectin-mediated versus adenovirus-mediated gene transfer in vitro and in vivo: comparison of canine and porcine model systems. AB - BACKGROUND: Restenosis after coronary angioplasty might be prevented by locally delivered gene therapy in conjunction with percutaneous transluminal coronary angioplasty (PTCA), since this approach should provide a sustained source of therapeutic protein within the dilated lesion. However, the potential application of gene therapy is limited by the technical barrier of efficiently transferring genes to vascular cells. METHODS: We used cultured coronary smooth muscle cells of human, porcine, and canine origin to evaluate three methods of gene transfer: recombinant adenovirus, liposomal complexes (Lipofectin), and Lipofectin supplemented with hemagglutinin. We then compared Lipofectin- and adenovirus mediated direct gene transfer in canine and porcine coronary arteries. RESULTS: The lipofection of cultured smooth muscle cells was enhanced by adding hemagglutinin, yielding luciferase levels that were 631-fold (human), ninefold (porcine), and sevenfold (canine) higher than with Lipofectin alone. However, the recombinant adenovirus directed even higher levels of gene expression, yielding luciferase levels that were 113,000-fold (human), 450-fold (porcine), and 230 fold (canine) higher than with Lipofectin alone. After percutaneous transluminal local delivery to intact canine coronary arteries, the adenovirus produced 55 times more luciferase than did Lipofectin. In living porcine coronary arteries, adenovirus produced 95 times more luciferase than did Lipofectin. CONCLUSION: Recombinant adenovirus produces far more recombinant protein than does Lipofectin after percutaneous transluminal direct gene transfer to canine and porcine coronary arteries. Adenoviral vectors may therefore prove useful in evaluating the potential of gene therapy in large animal models of coronary restenosis. PMID- 7858770 TI - Head-to-head comparison between technetium-99m-sestamibi and thallium-201 tomographic imaging for the detection of coronary artery disease using combined dipyridamole-exercise stress. AB - AIM: The purpose of this study was a head-to-head comparison of tomographic imaging (SPECT) with technetium-99m (Tc-99m)-sestamibi and thallium-201 (Tl-201) using dipyridamole-low-level bicycle exercise stress for the assessment of coronary artery disease. METHODS: We studied 38 consecutive patients referred for the evaluation of chest pain who had undergone coronary angiography. The patients were randomly allocated to Tc-99m-sestamibi SPECT followed by Tl-201 SPECT or vice versa. The accuracy of both tracers in detecting significant coronary artery disease (> 50% luminal stenosis) was 87% (95% confidence interval 72-96%). Only two patients were classified differently by the two methods. RESULTS: On a segmental basis, good agreement was found between Tc-99m-sestamibi and Tl-201 for both the localization and the nature of perfusion defects (reversible or persistent) identified (Cohen's kappa = 0.67). CONCLUSION: No clinically relevant differences in diagnostic accuracy were demonstrated between Tc-99m-sestamibi and Tl-201 SPECT using combined dipyridamole-exercise stress for the evaluation of coronary artery disease. PMID- 7858771 TI - Clinical and angiographic determinants of ventricular remodeling after acute myocardial infarction. AB - BACKGROUND: Ventricular remodeling after acute myocardial infarction is a precursor of the development of overt heart failure and is an important indicator of mortality. However, clinical and angiographic determinants of ventricular remodeling have not been fully elucidated. The purpose of the present study was to evaluate the effects of long-standing preinfarction angina and the late reperfusion of the infarct-related coronary artery on ventricular remodeling and function. METHODS: Coronary angiography and left ventricular cineangiography were performed 35 +/- 16 days after the onset of acute myocardial infarction in 80 patients with a relatively recent anterior Q-wave myocardial infarction who had received conventional therapy. RESULTS: In patients with preinfarction angina that occurred more than 1 week before the onset of myocardial infarction, the left ventricular size and ejection fraction were better preserved than in those without preinfarction angina. On the other hand, the late reperfusion of the infarct-related coronary artery did not affect ventricular remodeling. CONCLUSION: Our results indicate that the presence of residual flow to the infarct area through the collateral circulation, presumably developed by repetitive ischemic stimuli, appears to be a crucial determinant of subsequent left ventricular size and function in patients with acute myocardial infarction who have had conventional therapy. PMID- 7858772 TI - Arterial conduits for coronary bypass. PMID- 7858773 TI - Bibliography of the current world literature. PMID- 7858774 TI - Cognitive psychology and the design of alarm sounds. AB - One of the less desirable features about technological advances in medicine is that individuals working with sophisticated monitoring equipment are often bombarded by warning sounds and signals. However, there are some basic cognitive psychological principles which suggest that the over-use of auditory warnings in such circumstances may be counter-productive. This review highlights some of these principles, arguing that future systems should place more emphasis upon cognitive capabilities and predispositions in their design. Upcoming alarms standards where issues such as the number of alarms, their recognizability, and the principle of 'urgency mapping' are discussed with relation to the cognitive psychology of sound. PMID- 7858775 TI - Modelling of the enteric nervous network: 3. Adrenergic neuron. AB - A mathematical model is developed to investigate the coupled electrochemical processes of nerve-pulse transmission via adrenergic synapse. Based on pharmacological and morphophysiological data, the model describes the dynamics of the propagation of the electric signal along the unmyelinated geometrically non uniform axon of the neuron and the chemical mechanisms of the transformation of the electrical signal in the synaptic zone into the post-synaptic output. The combined nonlinear system of partial and ordinary differential equations has been obtained and solved numerically. The results of computer simulation of the function of the idealized adrenergic neuron quantitatively and qualitatively describe the dynamics of Ca2+ ion influx into the terminal, noradrenaline release from the free 'releasable' store, its diffusion into the synaptic cleft, binding with the adrenoceptors on the pre- and post-synaptic structures with the generation of the inhibitory post-synaptic potential, and utilization of noradrenaline by neuronal and non-neuronal capture mechanisms. PMID- 7858776 TI - The closing velocity of mechanical heart valve leaflets. AB - The closing motion of the occluder leaflets in bileaflet type mechanical heart valves (MHV) was monitored with a laser sweeping technique. The angular displacements of the leaflets were registered with precision of 0.2 microsecond steps. Experimental measurements were made using five 29 mm Edwards-Duromedics including three original specification (EDOS) and two modified specification (EDMS), and two 29 mm St Jude Medical MHVs. The testing valve was installed in the mitral position of a physiologic pulsatile mock circulatory flow loop using water-glycerine solution as the testing fluid. Each valve was tested by: (1) direct mounting the valve on metal washers, and (2) mounting the valve with its sewing ring. Experiments were carried out at pulse rates of 70, 90, and 120 beats min-1, with the corresponding cardiac output of 5, 6, and 7.5 litres min-1, and maximum left ventricular pressure gradients (dp/dt) of 1,800, 3,000 and 5,600 mm Hg s-1, respectively. The maximum leaflet closing velocity of each of the tested valve types are presented. The difference in leaflet closing movements between the direct rigid mounting and the sewing ring mounting are discussed. The details of the laser sweeping technique are presented. PMID- 7858777 TI - A possible relation between pressure loading and thickened leaflets of the aortic valve: a model simulation. AB - A much smaller percentage of thickened leaflets of the aortic valve have been found in the right or left coronary leaflet than in the noncoronary leaflet. This study investigated the pressure loading transferring to the leaflets of the aortic valve and their effects on the valvular thickening. A simple ascending aorta model was established, and a simulation was made. The pressure loading in the coronary and noncoronary leaflets then were estimated. The simulation results showed that 5.8% to 17.% percentage of pressure loading to the coronary leaflet may be decreased by the coronary perfusion in diastole. The coronary arteries play an important role on pressures in the sinuses of Valsalva. The smaller pressure loading transferring to the coronary leaflet than that to the noncoronary leaflet is one reasonable explanation related to the thickened leaflets of the aortic valve. PMID- 7858778 TI - A synthetic leaflet heart valve with improved opening characteristics. AB - A new geometry for the design of polyurethane leaflet heart valves has been investigated. The geometry termed the 'alpharabola' has a radius of curvature that increases from the centre of the leaflet at the free edge towards the base of the valve and perimeter of the leaflet. The hydrodynamic function and leaflet opening characteristics of the new valve design have been compared to a valve with a spherical leaflet geometry using the same material. The pressure and flow required to open alpharabola leaflets in steady flow tests was markedly lower than for spherical leaflets. Under pulsatile flow conditions with the valve leaflets fully open, the pressure drop across the alpharabola and spherical leaflets was similar, but much lower than in a porcine bioprosthesis. High speed photography showed that the alpharabola leaflets opened in less than 30 ms with the leaflet opening initiating in the base of the leaflet where the radius of curvature was larger. The synthetic leaflet valve has demonstrated short term durability in accelerated fatigue tests to 100 million cycles. PMID- 7858779 TI - Automated measurement of the cyclic activity of respiratory muscles. AB - A microcomputer-based system developed for the automated analysis of the electromyogram (EMG) recorded from respiratory muscles in a variety of situations is described. In addition, an assessment of the performance of the system is presented, along with data relating intercostal EMG activity to ribcage movement in seated subjects. Studies were performed on sixteen normal subjects--non smokers, mean (+/- SD) age 31 (+/- 6) years, mean (+/- SD) mass 78 (+/- 8) kg--of which fifteen studies proved suitable for analysis. Each study lasted for a period of five minutes, during which time recordings of intercostal EMG, ribcage postero-anterior displacement (RCPA) and airflow were made. For every breath taken by each of the subjects, the peak integrated EMG activity (iEMGpeak) was measured both by hand and by the automated system. The automated and manual measurements of iEMGpeak, which ranged from 0.0 to 91.3 microV, differed by only 0.82 +/- 3.34 microV (mean +/- SD). The index iEMGpeak and two additional indices of iEMG activity (iEMGmean, iEMGarea) were evaluated with respect to RCPA, a measure of overall respiratory activity. The indices of iEMG were observed to show an exponential dependence on RCPAamp, the amplitude of ribcage motion. Following a log transformation to linearise the relationship, the correlation of each index with RCPAamp was evaluated; iEMGpeak and iEMGarea correlated similarly with RCPAamp (no significant difference at 5% level), but iEMGmean was found to be a significantly different (p < 0.001) and poorer correlate. We conclude that the automated analysis of respiratory iEMG as described in this paper can provide results showing consistency with manual measurement.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7858780 TI - A four-parameter linear model for analysing cardiorespiratory data in post operative cardiac patients. AB - This paper investigates the possibility of characterizing the differences between normal- and high-risk postoperative cardiac patients on the basis of four parameters related to a simple linear model of cardiorespiratory performances. The model comprises three subsystems representing cardiac, vascular and respiratory functions, respectively. These parameters, determined from physiological variables measured in the Intensive Care Unit, seem useful for clinical evaluation of patient status. In fact, their values quantify the improved cardiovascular and respiratory response that normal-risk patients exhibit to increasing metabolic needs after hypothermic treatment, with less utilization of blood oxygen reserve. In addition, a set of three parameters derived from the proposed four allows a prediction of patient class membership with an error lower than 7% when used with a Bayes quadratic classifier. PMID- 7858781 TI - ESTRACE--1: a stethoscope for functional checking of electrostimulators and low cost body surface mapping system. AB - In a project on the mapping of body surface potentials evoked by implanted spinal cord stimulators and transcutaneous electrostimulators, a simple device was developed for use in polyclinical practice for easy checking of the function of these stimulators. The device is an electrical stethoscope and consists of an instrumentation amplifier, bandpass filter, a distortion circuit and a headphone. In vivo measurements demonstrate the generation of an amplitude-dependent tone by the distortion circuit. The apparatus is in many aspects similar to a stethoscope: simple to understand and a practical tool for a fast Go/No-Go test. The device can be optionally connected with a PC and enables body surface mapping documentation within a few minutes. PMID- 7858782 TI - Sterilization of Fuji pressure-sensitive film. AB - Fuji Prescale film is a pressure-sensitive medium which produces a characteristic pink stain on the application of pressure. Up to a saturation level, increases in pressure will produce a denser stain, thereby providing a method of determining pressures within the interface between two articulating surfaces. The relationship between the magnitude of applied pressure and the optical density of the resulting stain is non-linear; this relationship also varies with ambient temperature and humidity, in addition to load rate, and therefore requires a calibration procedure prior to use. The use of Fuji prescale film for recording interface pressures within the joint space in vivo has been widely reported; however, the object of this study was to assess the effects of sterilizing this medium, with a view to future in vivo applications. Samples of Fuji film were sterilized using a standard ethylene oxide (ETO) gas process and their subsequent pressure-recording properties were compared to a control group of samples. The 'optical-density vs pressure' relationship for the sterilized group was significantly different from that of the control group (paired Student's t-test, P < = 0.001); however, both groups provided reliable data across the same pressure-range and both exhibited an excellent degree of repeatability (coefficient of variation < 2.5%). It was concluded that Fuji film will continue to produce pressure-stains following ETO sterilization; however, the calibration of this film will only be valid if it is conducted using film from the sterilized group. PMID- 7858783 TI - Measurement of soft tissue imbalance in total knee arthroplasty using electronic instrumentation. AB - The existence of soft tissue contractures in arthritis and the presence of soft tissue imbalance at the time of a total knee arthroplasty causing deformity in the coronal plane has been debated extensively. This discussion was based on the use of instrumentation which tensed the medial and lateral soft tissues in an uncontrolled manner during the operation. Previous work by this research team has developed a surgical instrument to quantify soft tissue imbalance independently of the compressive passive loads through the knee. In order to validate this assumption, an electronic measuring system was developed to record the soft tissue imbalance at 0.25 mm distraction intervals of the knee. This soft-tissue measuring system consists of a surgical instrument containing electronic transducers, an analogue conditioning unit and a portable computer. The surgical instrument introduces a pivot to the centre of the knee in the coronal plane so that the clockwise and counterclockwise moments produced by the collateral soft tissues produce an angular deviation at the equilibrium position. Measurements of angular deviation and separation gap are recorded by the electronic transducers. Eight patients were measured whilst undergoing total knee replacement at Bretby Hall Orthopaedic Hospital. The mean change in angular deviation over an average distraction of the knee of 7.15 mm was 0.4 degrees with a standard deviation of 0.4. It is concluded that this is an acceptable error band for surgical measurement, and soft tissue imbalance can be defined as angular deviation independently of the passive compressive loads through the knee. PMID- 7858784 TI - Fluid shear induced endothelial cell detachment from glass--influence of adhesion time and shear stress. AB - In this study, human umbilical vein and human saphenous vein endothelial cells were seeded on glass and exposed to fluid shear in a parallel-plate flow chamber. Cell retention, morphology and migration were studied as a function of shear stress and of adhesion time prior to exposure to shear. Three-hour and 24-h adhesion times gave rise to comparable cell retention values after 2 h of flow for both cell types. Cell retention decreased from 85 to 20% as shear stress increased from 88 to 264 dynes cm-2 (8.8 to 26 Pa). Mean spreading areas decreased after the onset of flow, but subsequently stabilized to plateau values, which were smaller at higher shear stresses. Shape factors increased faster to higher values as cells were exposed to higher shear stresses, without any obvious preference in orientation of the cells with respect to the direction of flow. Migration was unidirectional with flow and linear with time. Migration was faster for cells which had adhered for 24 h than for cells which had adhered for 3 h and was accompanied by the presence of fibrillar structures left behind on the surface upstream of migrating cells. It is concluded that after 3 h adhesion to glass, cells have adhered with an adhesion strength that does not substantially increase during the next 21 h. However, during this time changes in cell substratum interactions seem to occur judging by the differences in, e.g., migration rates. PMID- 7858785 TI - Discrimination of ventricular tachycardia from sinus tachycardia by antitachycardia devices: value of median filtering. AB - Rate and rate variation algorithms used by implantable devices designed for management of life-threatening arrhythmias have major limitations in separating physiologic sinus tachycardia (ST) from pathologic ventricular tachycardia (VT) requiring therapy. These algorithms presently utilize criteria such as simple heart rate, stability of rate, or derivative of rate (sudden onset) which assumes a gradual onset for ST and an abrupt onset for VT. An alternative method employing median filtering was designed, tested, and compared to a previously published sudden onset rate algorithm using the same data set for analysis of performance. In 50 patients, the onset of ST during exercise and onset of VT were analysed. To accommodate occasional outlying intervals which might affect rate derived by averaging, a five-cycle median filter was used to smooth heart rate. Results from using a 'fixed-interval' or a 'percent' change in the median gave better discrimination of ST and VT than previously published 'fixed-interval' or 'percent' change algorithms. The superiority of median filtering performance was validated by statistical measures. PMID- 7858786 TI - Spatial measurement and transformation of muscular attachments at the lower extremity. AB - A large number of spatial coordinates were directly measured on two wet anatomical muscle specimens with a measuring device specifically designed to collect cylindrical coordinates. Three-dimensional coordinates of muscle attachment circumferences, joint centres and bone landmarks were collected. All the measured points of a segment, including the adjacent joint centres, were referred to a reference system defined by three marked screw heads at the femur and tibia. The points of the pelvic segment were referred to three marks on a lumbar mounting plate. This approach allows one to define and to transform the data to any reference frame. PMID- 7858787 TI - Effect of suturing on the mechanical properties of bovine pericardium- implications for cardiac valve bioprosthesis. AB - In the fabrication of a bioprosthetic heart valve from bovine pericardial tissues, the tissues are subjected to suturing. The stress-strain response of sutured as well as unsutured strips of this tissue were examined. The stress strain response was determined using a tensile-testing machine. It was found that suturing weakens the tissue in that sutured strips are more extensible, exhibit a lower stress at rupture and a lower final elastic modulus. In addition, it was also found that the bigger the suture/needle size used the greater the decrease in tissue strength. In all, tissue strength was observed to decrease by 22 to 59% in this study. The weakening of the tissue is attributed to the puncture holes created by the surgeon's needle which create regions of weakness. This response of bovine pericardial tissue to suturing should be given due consideration in the fabrication of a bioprosthetic heart valve using this tissue. PMID- 7858788 TI - Eat, drink and be merry... PMID- 7858789 TI - Challenging stereotypes. PMID- 7858790 TI - A review of lay health beliefs research: insights for nursing practice in health promotion. AB - Recent sociological research in the field of lay health and illness beliefs is reviewed and discussed in the light of nursing practice in health promotion. How the findings might deepen nurses' understanding of difficulties in adhering to desired health behaviours is outlined. The distinctions between 'public' and 'private' accounts of health, the 'taken-for-grantedness' of health, the emotive nature of health and the difficulty of accessing 'unpolluted' lay views of health is considered. The implications for nurses working in health promotion are discussed. There is a need for further research into the relationship between health beliefs and behaviour, the health beliefs of various groups within society and a need to examine how health beliefs arise and change. PMID- 7858791 TI - Gram-negative bacteria. The challenge of preventing cross-infection in hospital wards: a review of the literature. AB - Gram-negative bacteria are responsible for a high proportion of nosocomial infections, particularly among the critically ill and those in hospital for long periods. Colonization (asymptomatic carriage on the skin) occurs before the emergence of overt clinical infection (appearance of the signs and symptoms of disease) and is therefore worth reducing. Spread is principally via the hands of staff, so handwashing is the chief method of prevention. Gram-negative bacteria survive best in a moist environment and are more readily transferred via damp than dry surfaces; hands and equipment should therefore be kept as dry as possible. Good skin can also help prevent cross-infection as Gram-negative bacteria colonize damaged skin more readily than if it is in good condition. PMID- 7858792 TI - Automating ward evaluations: a tentative first step. AB - Auditing nursing practice is a time-consuming, error-prone task. Feedback to individuals is highly desirable but usually is not offered. This is particularly difficult in large-scale studies. In this study of 654 wards a new method was attempted. Structured questionnaires were analysed by a computer program and feedback reports generated automatically. Informal evaluations by the initial recipients are positive and the method seems worthy of future development. PMID- 7858793 TI - The hospital health-promotion facilitator: an evaluation. AB - This 1-year study tested the transferability of the Primary Care Facilitator model to the hospital setting, and was designed to assess and enhance existing hospital health-promotion activity. From work with nurses on three wards in an acute general hospital, the Primary Health Care model was found to be appropriate for the hospital setting. There were demonstrable changes in attitudes to health promotion and an increase in health-promotion activity. It now appears appropriate to evaluate the role of the hospital health-promotion facilitator on a wider basis. Areas for further research, beyond the scope of this particular project, should be the quality of the health-promotion activity and exploration of factors that encourage or inhibit utilization of health-promotion opportunities. PMID- 7858794 TI - A telephone survey of medical patients 1 week after discharge from hospital. AB - The telephone is an effective means of communication and its use is growing as a means of offering members of the public access to health-care agencies for advice and support. Acute hospital beds are at a premium and as lengths of stay in hospital continue to fall there is an increasing need for effective discharge planning and post-discharge support. Eighty-five patients (58 men and 27 women) were interviewed over the telephone 1 week after discharge from a medical ward. Over half of the patients reported health problems and one-fifth reported social problems. Almost half of the patients sought advice. Telephone follow-up would appear to be a useful means of monitoring a patient's progress and providing an opportunity for patients seeking, or nurses offering, advice and support. PMID- 7858795 TI - Preventing heel pressure sores: a comparison of heel pressure relieving devices. AB - It has been widely recognized that elderly patients with an orthopaedic problem are predisposed to developing heel pressure sores. In this study four pressure reducing devices, commonly used in the prevention of heel ulcers, were objectively compared for their ability to decrease or remove pressure on the heels of patients with fractured necks of femurs and fractured femurs. Forty-one patients were randomly allocated a pressure relieving device. The efficacy of the device was evaluated by continuously assessing the skin integrity of both heels on a daily basis over a period of 12 days. Data were collected over a 30 month period. The four devices were foam splints, eggshell foam, duoderm and heel protector boots. Foam splints and eggshell foam proved to be more effective devices in relieving pressure exerted on the heel. This study recognizes that meticulous nursing care remains the critical element in prevention of heel ulcers; however, the use of eggshell foam and foam splints in conjuction with this enhances the maintenance of skin integrity. PMID- 7858796 TI - Fatigue and cancer: a phenomenological study. PMID- 7858797 TI - Problems with the ethics of medical research. PMID- 7858798 TI - Alcohol and cardiac risk. PMID- 7858799 TI - Epidemiology of mental illness among Asians in the UK. AB - With the passage of time, a British-born generation of New Commonwealth ethnic origin has emerged. They have received relatively less attention from researchers than their parents, because of the practice of using country of birth to identify subjects for research. A significant number of immigrants from India are in fact of British origin, and are not of Indian ethnicity. This article looks at the rate of psychiatric illness in the immigrant population and discusses whether or not studies reflect this. PMID- 7858800 TI - Hazards associated with the recreational drug 'ecstasy'. AB - The amphetamine analogue 'ecstasy' is a popular 'designer' drug and is perceived by its users to be relatively harmless. However, it has been associated with several fatalities through a disorder of thermoregulation, and severe reactions have been reported across many disciplines. This article emphasises the hazardous nature of the drug and highlights the urgency and nature of treatment in the acutely toxic state. PMID- 7858801 TI - Operative viva F. PMID- 7858802 TI - Slides in paediatrics 2. PMID- 7858803 TI - Acute aortic dissection. AB - Acute aortic dissection is a surgical emergency which, if not adequately treated, carries a high mortality. With appropriate early intervention, however, a significant percentage of patients can be salvaged. This article discusses how to approach and manage this condition. PMID- 7858804 TI - Clinical aspects of cyclosporin nephrotoxicity. AB - Nephrotoxicity is the most important side effect of cyclosporin therapy. Glomerular filtration rate is reduced in almost all patients and improves when cyclosporin is discontinued. Longterm studies in renal transplant recipients indicate that there is no progressive loss of renal function in the majority of patients treated with cyclosporin. Similar results are found in non-transplant recipients treated with low-dose cyclosporin. Approximately 10% of heart and heart-lung transplant patients develop a progressive deterioration in renal function which may not respond to stopping cyclosporin therapy. PMID- 7858805 TI - Preliminary evaluation of the effectiveness of a preoperative clinic for gynaecological surgery. AB - A preoperative clinic for gynaecological surgery was introduced primarily to provide counselling but with access to multidisciplinary support. Initial results showed a substantial reduction in the postoperative hospitalisation period and a significant improvement in attendance rates. PMID- 7858806 TI - Nimodipine. AB - Nimodipine is a lipophilic dihydropyridine calcium antagonist which is used to reduce the incidence and severity of delayed cerebral ischaemia in patients with subarachnoid haemorrhage. This article reviews its mechanism of action, pharmacology and indications for use. PMID- 7858807 TI - HCV infection in blood donors. PMID- 7858808 TI - HCV infection in blood donors. PMID- 7858809 TI - Postgraduate education. PMID- 7858810 TI - Air pollution and health: a problem for the standard setters? PMID- 7858811 TI - Sarcoidosis: when and how should we treat? PMID- 7858812 TI - Anaesthetic risks in rheumatoid arthritis. AB - Rheumatoid arthritis can be a major challenge to the anaesthetist, the principal problem being a difficult upper airway. Additional risks may arise because of cardiovascular and pulmonary involvement. The drugs used in the treatment of rheumatoid arthritis also affect the anaesthetic management of these patients. PMID- 7858814 TI - Human immunodeficiency virus medicine for the MRCP long case and viva. AB - Doctors should consider human immunodeficiency virus (HIV) disease as a possibility in patients both in the MRCP clinical examination and during daily clinical practice. Aspects relating to the MRCP long case and viva are dealt with in this article. PMID- 7858813 TI - Identification and immediate management of the oral changes associated with eating disorders. AB - Oral changes are often the first indication that an eating disorder is present. Although the effect of acid regurgitation on the teeth is well appreciated, other factors may also be involved. This article highlights the changes that may be observed in patients with eating disorders, together with the possible aetiological causes. PMID- 7858815 TI - The short child: clinical assessment and treatment. AB - In the majority of cases, short stature is due to normal physiological variations in growth and maturation. However, there are a significant number of other causes, some of which are amenable to treatment. This article reviews the clinical assessment and investigation of the short child in order to identify those children who might benefit from treatment. PMID- 7858816 TI - Surgical treatment of the rheumatoid hand. AB - Many rheumatoid patients either present late or are denied access to surgery which would benefit them if undertaken at an early stage. Combined clinics involving physicians, surgeons and therapists allow better assessment and help patients to receive maximum benefit from treatment. An understanding of the principles of surgery of the rheumatoid hand is important in the management of these patients. PMID- 7858817 TI - Oesophageal variceal haemorrhage: a practical approach. AB - Variceal haemorrhage is a common and frequently fatal presentation of cirrhosis. There have been several recent developments in endoscopic therapy, pharmacological therapy and portal shunting, offering new therapeutic options. These are reviewed and followed by a management strategy incorporating these developments with established therapies. PMID- 7858818 TI - Micrographic surgery for basal cell carcinoma. AB - Mohs' micrographic surgery is the most effective method of ensuring complete removal of basal cell carcinoma. It is particularly indicated for recurrent tumours and tumours in critical anatomical areas of the face. This article describes the technique and contrasts it with conventional surgical excision and tissue processing. PMID- 7858819 TI - Blindness with a normal erythrocyte sedimentation rate in giant cell arteritis. PMID- 7858820 TI - Inguinal hernia: an unusual cause of gastric outlet obstruction. PMID- 7858821 TI - Car pollution and asthma prevalence. PMID- 7858822 TI - The NHS's winds of change. PMID- 7858823 TI - Use of botulinum toxin to alleviate facial pain. PMID- 7858824 TI - Airway management after severe facial contractures. PMID- 7858825 TI - Infection with non-tuberculous mycobacteria. PMID- 7858826 TI - Lessons from the Concorde trial. PMID- 7858827 TI - Heel pain: diagnosis and management. AB - Chronic non-traumatic heel pain is not an uncommon symptom in patients presenting to GP, orthopaedic or rheumatological clinics. A full history and examination will provide a diagnosis in most cases. Rarer causes need to be excluded in certain patients. This article outlines the differential diagnosis and discusses the more common causes. PMID- 7858828 TI - Transanal endoscopic microsurgery. AB - Transanal endoscopic microsurgery is a minimally invasive technique for local excision of tumours in the rectum and lower sigmoid colon. It allows precise transanal dissection and suturing, and enables sphincter-preserving local resection to be performed without an abdominal or perineal incision. PMID- 7858829 TI - Management of the first stage of labour. AB - The management of delay in labour has been dominated by the use of oxytocin to augment the 'powers' of labour. However, this empirical approach has not been rigorously tested and 'failure to progress' remains a major clinical problem. A return to an analysis of the underlying pathophysiology is advocated. PMID- 7858830 TI - Surgical diathermy. PMID- 7858831 TI - Atopic dermatitis: new information from epidemiological studies. PMID- 7858833 TI - Bradycardia, hypotension and stroke: an unusual presentation of aortic dissection. PMID- 7858832 TI - Diltiazem hydrochloride. AB - Since their introduction in 1963, calcium-channel blockers, with their effectiveness and lack of side effects, have become widely used. Diltiazem hydrochloride, a benzothiazine, has its major role in the treatment of angina and is also used as an antihypertensive and antiarrhythmic. PMID- 7858834 TI - Is the increase in tuberculosis an epidemic. PMID- 7858835 TI - Is the increase in tuberculosis an epidemic? PMID- 7858836 TI - Is the increase in tuberculosis an epidemic. PMID- 7858837 TI - A gynaecological mistake. PMID- 7858838 TI - Anaesthetic priorities/safety. PMID- 7858839 TI - Keeping 'mum' on medical matters. PMID- 7858840 TI - Toe amputation following a recent myocardial infarct. PMID- 7858841 TI - Effect of cyclopiazonic acid, an inhibitor of sarcoplasmic reticulum Ca(2+) ATPase, on the frequency-dependence of the contraction-relaxation cycle of the guinea-pig isolated atrium. AB - 1. The relevance of a functional sarcoplasmic reticulum (SR) membrane system to the contraction-relaxation cycle and to the force-frequency relationship of guinea-pig atrial tissue was investigated. Cyclopiazonic acid (CPA) was used to inhibit selectively the activity of the SR Ca(2+)-ATPase. IC50 values of 0.2 microM or 1.0 microM were measured in guinea-pig isolated SR membranes in the absence or presence of millimolar ATP, respectively. CPA (0.3-30 microM) did not inhibit the activity of the sarcolemmal Na(+)-Ca(2+)-exchanger as measured in isolated cardiac cell membrane preparations. 2. In guinea-pig isolated left atrium paced at 2.5 Hz (30 degrees C), CPA (1-100 microM) produced a concentration-dependent reduction in developed tension and a fall in the maximum rate of tension increase (+dT/dtmax) and decrease (-dT/dtmax). The twitch duration was markedly increased due to a prolongation of the time to peak tension, and in particular, the relaxation phase. 3. The contraction-relaxation cycle of the left atrium showed a marked dependence on the frequency of stimulation. The developed tension and +dT/dtmax showed a progressive increase from 0.5 Hz, reaching peak values at a stimulation rate of 1.5-2.5 Hz, the positive staircase phenomenon. Higher frequencies of stimulation caused a fall in these parameters. Resting tension was unaffected. The time-course of the contraction-relaxation cycle was also frequency-dependent, with both time to peak tension and relaxation time showing a progressive fall from 2.0-3.5 Hz. 4. The addition of CPA (30 microM) caused marked alterations in the frequency-dependence of the contraction-relaxation cycle. The frequency-dependence of developed tension, + dr/dtmax and dT/dt max was shifted downwards, particularly at higher frequencies, and the frequency at which peak values of+ dT/dtmax and - dT/dtmax were reached was shifted leftwards. The resting tension of the tissues in the presence of 30 micro M CPA was increased markedly at frequencies greater than 2 Hz. The time-course of the contraction-relaxation cycle was markedly prolonged between 1.0 and 3.5 Hz, due to an effect on both time to peak tension and relaxation time.5. In conclusion, these results show that CPA is a highly selective inhibitor of the cardiac SR Ca2+-ATPase, without effect on the sarcolemmal Na+-Ca2+-exchanger, and suggest that a functional SR Ca2+-ATPase is necessary for the normal contraction-relaxation cycle of guinea-pig cardiac tissue.Additionally, the results suggest an increasing dependence of tension development on SR Ca2+-ATPase with increasing frequency, which may reflect either a frequency-dependent activation of this enzyme or the diminished contribution of the Na+-Ca2+ exchanger. These results also provide novel support for the mechanism of the depressed force-frequency relation found in cardiac tissue of heart failure patients, in which there is a reduced expression of Ca2+-ATPase. PMID- 7858842 TI - Induction of cyclo-oxygenase-2 by cytokines in human pulmonary epithelial cells: regulation by dexamethasone. AB - 1. Cyclo-oxygenase metabolizes arachidonic acid to prostaglandin H2 (PGH2) and exists in at least two isoforms. Cyclo-oxygenase-1 (COX-1) is expressed constitutively whereas COX-2 is induced by lipopolysaccharide (LPS) and some cytokines in vitro and at the site of inflammation in vivo. Epithelial cells may be an important source of prostaglandins in the airways and we have, therefore, investigated the expression of COX-1 or COX-2 isoforms in primary cultures of human airway epithelial cells or in a human pulmonary epithelial cell line (A549). 2. COX-1 or COX-2 protein was measured by western blot analysis using specific antibodies to COX-2 and selective antibodies to COX-1. The activity of COX was assessed by the conversion of either endogenous or exogenous arachidonic acid to four metabolites, PGE2, PGF2 alpha, thromboxane B2 or 6-oxo PGF1 alpha measured by radioimmunoassay. Thus, COX-1 or COX-2 activity was measured under two conditions; initially the accumulation of the COX metabolites formed from endogenous arachidonic acid was measured after 24 h. In other experiments designed to measure COX activity directly, cells were treated with cytokines for 12h before fresh culture medium was added containing exogenous arachidonic acid (30 microM) for 15 min after which COX metabolites were measured. 3. Untreated primary cells or A549 cells contained low amounts of COX-1 or COX-2 protein. Bacterial LPS (1 micro g ml-1 for 24 h) induced COX-2 protein in the primary cells, a process which was enhanced by interferon-gamma, with no further increase in the presence of a mixture of cytokines (interleukin-1 beta, tumour necrosis factor-alpha and interferon-gamma, 10 ng ml-1 for all). In contrast, A549 cells contained only low levels of COX-2 protein after exposure to LPS or LPS plus interferon-y, but contained large amounts of COX-2 protein after exposure to the mixture of cytokines.4. Untreated human pulmonary primary cells or A549 cells released low levels of all COX metabolites measured over a 24 h incubation period. This release was enhanced by treatment of either cell type with the mixture of cytokines (interleukin-1 beta , tumour necrosis factors- and interferon-gamma, 10 ng ml-1 for all).PGE2 was the principal COX metabolite released by cytokine-activated epithelial cells. The release of PGE2 induced by cytokines occurred after a lag period of more than 6 h.5. The glucocorticosteroid, dexamethasone (1 micro M; 30 min prior to cytokines) completely suppressed the cytokine-induced expression of COX-2 protein and activity in both primary cells and A549 cells.6. In experiments where COX-2 activity was supported by endogenous stores of arachidonic acid,treatment of A549 cells with interleukin-l beta but not tumour necrosis factor a or interferon gamma alone caused a similar release of PGE 2 to that seen when the cytokines were given in combination. However, both interleukin-l beta and necrosis factor- alone produced similar increases in COX-2 activity (measured in the presence of exogenous arachidonic acid) as seen when the mixture of interleukin-l beta, tumour necrosis factor- alpha and interferon-gamma were used to stimulate the cells.7. These findings show that COX-2 expression correlates with the exaggerated release of prostaglandins from cytokine-activated human pulmonary epithelial cells and that the induction of the enzyme is suppressed by a glucocorticosteroid. These findings may be relevant to inflammatory diseases of the lung, such as asthma. PMID- 7858843 TI - Vasoconstrictor and vasodilator responses to various agonists in the rat perfused mesenteric arterial bed: selective inhibition by PPADS of contractions mediated via P2x-purinoceptors. AB - 1. The effect of pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) on vasoconstrictor and/or vasodilator responses to various agonists and electrical field stimulation was investigated in the rat mesenteric arterial bed at basal tone and at tone raised by methoxamine (15-50 microM). 2. At basal tone, nucleotides produced vasoconstriction with the following rank order of potency: alpha,beta-methylene ATP >> 2-methylthio ATP > or = ATP = UTP. PPADS (0.3-10 microM) concentration-dependently antagonized alpha, beta-methylene ATP-, 2 methylthio ATP- and ATP-induced responses. UTP-, noradrenaline- and nerve mediated (4-32 Hz) increases in perfusion pressure remained unaffected by 10 microM PPADS. 3. In raised tone preparations, nucleotides produced vasodilations, their rank order of potency being 2-methylthio ATP > ATP > UTP. Responses to 2 methylthio ATP were slightly antagonized, whereas ATP- and UTP-induced responses remained unaffected by 10 microM PPADS. In addition, acetylcholine- and adenosine elicited relaxations were not influenced by 10 microM PPADS. 4. The present results confirm the previously described selective P2x antagonism by PPADS, this compound being ineffective at muscarinic M3- and adenosine P1-receptors as well as at alpha 1-adrenoceptors. There was some inhibition of P2y-purinoceptors but at a much higher concentration than required for inhibition of P2x-purinoceptors. 5. In addition, this study provides evidence for the ineffectiveness of PPADS at both vasoconstriction- and vasodilatation-mediating P2u-purinoceptors. PMID- 7858844 TI - Role of Ca(+)-dependent K-channels in the membrane potential and contractility of aorta from spontaneously hypertensive rats. AB - 1. Contractile responses to KCl and membrane potentials were determined in aortic rings from spontaneously hypertensive rats (SHR), normotensive Wistar rats (NWR) and Wistar Kyoto rats (WKY) both in the absence and in the presence of the Ca(2+) dependent K-channel blockers, apamin and tetraethylammonium (TEA). 2. Compared to NWR, aortic rings from WKY and SHR were less reactive and their Ca2+ uptake after stimulation with K+ was decreased. 3. Smooth muscle cell membrane potentials were higher in aortae from SHR and WKY than in NWR aortae, whereas SHR had higher K+ and lower Na+ intracellular activities than WKY and NWR, suggesting overactivity of the Na+/K+ pump in the hypertensive animals. 4. Treatment with apamin caused depolarization of WKY and SHR aortae, and increased their contractile responses to the same level as those of the NWR. Treatment with TEA also caused depolarization of aortae from WKY and SHR, but in the SHR the depolarization induced by TEA was smaller than that produced by apamin and the contractile responses to KCl did not reach the level of those of aortae from NWR. 5. It is concluded that overactivity of Ca(2+)-dependent K-channels in aortae of WKY and SHR contributes to their higher membrane potentials and lower responsiveness to vasoconstrictor stimuli. In SHR, an overactive Na+/K+ pump is also present, and the contribution of apamin-sensitive Ca(2+)-dependent K-channels to the membrane potential and reactivity appears to be more relevant than that of TEA-sensitive channels. PMID- 7858845 TI - Paired-pulse depression of the N-methyl-D-aspartate receptor-mediated synaptic potentials in the amygdala. AB - 1. An in vitro slice preparation of rat amygdala was used to study the paired pulse depression of the N-methyl-D-aspartate (NMDA) receptor-mediated synaptic potential e.p.s.p.NMDA. 2. The e.p.s.p.NMDA was isolated pharmacologically by applying a solution containing the non-NMDA receptor antagonist, 6-cyano-7 nitroquinoxaline-2,3-dione (CNQX) and the gamma-aminobutyric acidA (GABAA) blocker picrotoxin and increasing the stimulus intensity. 3. When two stimuli of identical strength were applied in close succession, the second e.p.s.p.NMDA was depressed. This paired-pulse depression was seen with interstimulus intervals of between 100 ms and 2000 ms; the maximal depression was observed at interval of 200 ms. 4. Superfusion of phaclofen or 2-hydroxy-saclofen inhibited the paired pulse depression indicating the involvement of GABAB receptors. 5. Bath applications of Ba2+ or intracellular injection of Cs+ to block post- but not presynaptic GABAB receptors failed to inhibit the paired-pulse depression (PPD). 6. Incubation of slices with pertussis toxin prevented the postsynaptic hyperpolarization induced by baclofen. The PPD of e.p.s.p.NMDA, however, was not affected by pertussis toxin treatment. 7. These results suggest that GABA released by the first stimulus acts on GABAB receptors to suppress the second e.p.s.p.NMDA via mechanisms other than activation of a postsynaptic GABAB receptor-coupled K+ conductance. PMID- 7858846 TI - Role of bradykinin in the hyperaemia following acid challenge of the rat gastric mucosa. AB - 1. This study examined whether the hyperaemia following acid challenge of the rat gastric mucosa involves bradykinin, a peptide formed in response to tissue injury. 2. Gastric mucosal blood flow in urethane-anaesthetized rats was assessed by the hydrogen gas clearance method. Infusion of a bradykinin solution (10 microM) into the gastric wall augmented gastric mucosal blood flow by a factor of 2.3, an effect that was prevented by the bradykinin B2 antagonist Hoe-140 (icatibant; 100 mumol kg-1, i.v.). 3. I.V. injection of bradykinin (20-60 nmol kg 1) caused a 2.3-3.5 fold increase in blood flow through the left gastric artery as measured by the ultrasonic transit time shift technique. The hyperaemic effect of bradykinin in this gastric artery was also prevented by Hoe-140 (100 mumol kg 1, i.v.). 4. Gastric acid back diffusion was evoked by perfusing the stomach with 15% ethanol, to break the gastric mucosal barrier, in the presence of luminal acid. Depending on the concentration of acid (0.05 and 0.15 M HCl), this procedure increased gastric mucosal blood flow by a factor of 1.6-2.8 and caused formation of gross damage in 1.5-3% of the glandular mucosa. Hoe-140 (100 mumol kg-1, i.v.) failed to alter the moderate vasodilatation seen in the presence of 0.05 M HCl but significantly (P < 0.05) attenuated the marked hyperaemia and enhanced the gross mucosal damage observed in the presence of 0.15 M HCl. 5. These data show that bradykinin is able to enhance gastric mucosal blood flow via activation of B2 receptors. It appears as if this kinin is formed during severe acid challenge of the rat gastric mucosa and participates in the hyperaemic reaction to gastric acid back diffusion. PMID- 7858847 TI - Pharmacological actions of the selective and non-selective beta-adrenoceptor antagonists celiprolol, bisoprolol and propranolol on human bronchi. AB - 1. The pharmacological actions of the beta-adrenoceptor antagonists, celiprolol, bisoprolol and propranolol were investigated in human lung tissue by radioligand binding experiments as well as in human isolated bronchi by functional experiments in organ baths. 2. Data from lung tissue were compared to those obtained from myocardial membranes. 3. Lung tissue was obtained from 10 patients having undergone lung resection for bronchial carcinoma and myocardial tissue from a patient who had received a heart transplantation. 4. In radioligand binding experiments, celiprolol exhibited a high affinity binding to beta 1 adrenoceptors in heart and a low affinity binding to beta 2-adrenoceptors in lung tissue. The selectivity obtained for the beta 1-adrenoceptor was calculated to a factor of eleven. 5. Compared to bisoprolol and propranolol, celiprolol elicited the lowest affinity for the beta-adrenoceptor, as judged from the K1-values. 6. In the absence and presence of the guanine nucleotide Gpp(NH)p celiprolol did not affect receptor binding. 7. In functional experiments on intact bronchi, celiprolol, bisoprolol and propranolol failed to produce relaxation (+/- forskolin) or a significant difference in efficacy in antagonizing the relaxant effects of isoprenaline. However, a rank order of potencies was revealed (propranolol:bisoprolol:celiprolol = 46:12:1). 8. Plasma concentrations for celiprolol and bisoprolol usually achieved in vivo were below the IC50 value obtained in vitro. In contrast, for propranolol, plasma concentrations were nearly identical with the IC50 value. 9. It is concluded that celiprolol is a selective beta 1-adrenoceptor antagonist on human heart and has no agonistic properties on intact human bronchi. Compounds such as celiprolol and bisoprolol may in comparison to propranolol, possess reasonable therapeutic advantages in the treatment of patients with obstructive lung disease due to their low affinity for beta 2-adrenoceptors. PMID- 7858848 TI - Substrate specificity of the di/tripeptide transporter in human intestinal epithelia (Caco-2): identification of substrates that undergo H(+)-coupled absorption. AB - 1. pH-dependent transepithelial transport and intracellular accumulation of the hydrolysis-resistant dipeptide glycylsarcosine (Gly-Sar) have been demonstrated in the model human intestinal epithelial cell line, Caco-2. 2. Experiments with BCECF (2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein)-loaded Caco-2 cells demonstrated that dipeptide (Gly-Sar) transport across the apical membrane is coupled to proton flow into the cell. 3. A range of postulated substrates for the intestinal di/tripeptide carrier were tested for their abilities to: (a) inhibit pH-dependent [14C]Gly-Sar apical-to-basal transport and intracellular accumulation and (b) stimulate H+ flow across the apical surface of BCECF-loaded Caco-2 cell monolayers. 4. A range of compounds (including Gly-Gly, Leu-Leu, Gly Gly-Gly, cefadroxil and cephalexin) caused marked acidification of intracellular pH when perfused at the apical surface of Caco-2 cell monolayers. In contrast leucine and D-Leu-D-Leu failed to induce proton flow. The ability to induce proton-flow across the apical surface by these compounds, in this intestinal epithelium, was directly correlated to the relative inhibitory effects on [14C] Gly-Sar transport and accumulation. 5. The determination of substrate-induced intracellular pH change in the Caco-2 cell system may provide a useful rapid screen for candidate substrates for absorption via H(+)-coupled transport mechanisms such as the intestinal di/tripeptide carrier in an appropriate physiological context. PMID- 7858849 TI - FPL 66096: a novel, highly potent and selective antagonist at human platelet P2T purinoceptors. AB - 1. ADP-dependent platelet aggregation is mediated by the P2T-purinoceptor and is specifically inhibited by ATP, which is a competitive P2T-purinoceptor antagonist. However, ATP functions as an agonist at other P2-purinoceptor subtypes in other tissues and is, therefore, non-selective. This paper describes the effects of the novel ATP analogue, FPL 66096 (2-propylthio-D-beta,gamma difluoromethylene ATP), on ADP-induced and ADP-independent aggregation of human washed platelets and in standard preparations containing P2X- (rabbit ear artery) and P2Y-purinoceptors (guinea-pig aorta). 2. In suspensions of human washed platelets, FPL 66096 (1-100 nM) produced concentration-dependent rightward displacement of concentration-effect (E/[A]) curves obtained for ADP-induced platelet aggregation. Logistic fitting of E/[A] data indicated that the effect of FPL 66096 was consistent with simple competition with a pKB value of 8.66. FPL 66096 (10-1000 nM) had no effect on aggregation produced by the thromboxane A2 mimetic, U46619 (0.1-10 microM) when the response to this agent was rendered ADP independent by inclusion of the non-selective P2-purinoceptor antagonist, suramin (100 microM). 3. The anti-aggregatory potency of FPL 66096 was not influenced by increasing the incubation time from 2 to 15 min nor by inclusion of the P1 purinoceptor antagonist 8-sulphophenyltheophylline at a concentration (300 microM) that produced a 68 fold rightward displacement of the anti-aggregatory E/[A] curve for the P1-purinoceptor agonist, 5'-N-ethylcarboxamidoadenosine (0.1 1000 microM). 4. FLP 66096 behaved as a weak (pA" 3.68) but full P2x-purinoceptor agonist in preparations of the rabbit isolated ear artery and as a weak, competitive antagonist (apparent pKB 4.71) at P2Y purinoceptors in the guinea-pig isolated aorta, indicating a selectivity of at least 9000 fold for the P2t subtype. In the latter preparation, non-specific relaxations were produced by concentrations of FPL 66096 >10M gM.5. These results indicate that FPL 66096 is a P2-purinoceptor antagonist of unprecedented potency and selectivity and that its effects are consistent with simple competition at the P2-purinoceptor. Therefore,FPL 66096 represents a novel pharmacological tool in the classification of P2-purinoceptors and in the elucidation of the mechanisms involved in activation of platelets by ADP. PMID- 7858850 TI - Haemodynamic actions of a novel sino-atrial node function modulator, ZENECA ZD7288, in the anaesthetized dog: a comparison with zatebradine, atenolol and nitrendipine. AB - 1. ZENECA ZD7288 (4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino) pyrimidinium chloride, formerly ICI D7288) is a novel sino-atrial node function modulator which selectively slows sinus node rate. Its effects on haemodynamic function have been studied in pentobarbitone anaesthetized dogs, in comparison with zatebradine, atenolol and nitrendipine. 2. ZD7288 lowered heart rate in the dose-range 0.02 to 1.0 mg kg-1 i.v. from 152 to 77 beats min-1. Myocardial contractile function (measured as both dPLV/dtmax and right ventricular free wall developed force) decreased along with rate. Stroke volume increased as rate decreased. Cardiac output decreased at doses in excess of 0.2 mg kg-1, i.v. 3. These haemodynamic changes were reversed when heart rate reduction was reversed by atrial pacing and are, therefore, considered to be indirect consequences of heart rate changes induced by ZD7288. 4. The effects of zatebradine paralleled those of ZD7288 (heart rate reduced from 149 to 60.5 beats min-1 over the dose range 0.02 to 1.0 mg kg-1, i.v.), except that dPLV/dtmax did not decrease with heart rate and increased during arial pacing. 5. Neither ZD7288 nor zatebradine had significant effects on atrio-ventricular conduction at intrinsic heart rates, but both significantly and dose-dependently prolonged the atrio-ventricular conduction interval during atrial pacing at 180 beats min-1. 6. The observed effects of atenolol were commensurate with removal of beta-sympathetic cardiac drive. Atrial pacing was found not to restore the pre-atenolol heamodynamic state completely. 7. Nitrendipine up to 0.2 mg kg- i.v. induced changes indicative of direct vasodilatation accompanied by reflex compensation, followed by cardiac depression at higher doses. Atrial pacing failed to compensate for the effects of vasodilatation, but caused atrio-ventricular conduction block at doses above 0.5mgkg-1, i.v.8.data show ZD7288 has marked heart rate slowing properties and that accompanying haemodynamic changes appear to be secondary to the rate changes, being reversed by atrial pacing even in the continued presence of the drug. Heart rate slowing without depression of contractile function should prove to be of benefit in the treatment of myocardial ischaemia, particularly in the presence of myocardial dysfunction. PMID- 7858851 TI - The haemodynamic actions of ZENECA ZD7288, a novel sino-atrial node function modulator, in the exercising beagle: a comparison with zatebradine and propranolol. AB - 1. ZENECA ZD7288 (4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino) pyrimidinium chloride, formerly ICI D7288) is a novel sino-atrial node function modulator which selectively slows heart rate. 2. The haemodynamic effects of ZD7288 (0.1, 0.3 and 1.0 mg kg-1, i.v.) have been evaluated and compared with those of placebo (physiological saline), zatebradine (ULFS 49, 0.1, 0.3 and 1.0 mg kg-1, i.v.) and propanolol (0.03, 0.1, and 0.3 mg kg-1, i.v.) in beagles chronically instrumented for measurement of heart rate, aortic pressure, aortic flow and dPLV/dtmax. The dogs were trained to run at 6.5 k h-1 on a level treadmill for 5 min at half hourly intervals over a period of 4 h. Drugs were dosed cumulatively after the second, fourth and sixth exercise periods. 3. Control experiments demonstrated a degree of accommodation to repeated exercise over a period of 4 h. Resting heart rate decreased by 21 beats min-1, but heart rate response to exercise was maintained, whereas dPLV/dtmax at rest remained steady while the response to exercise decreased significantly (by 25% after 2 h, P < 0.05). 4. ZD7288 and zatebradine both decreased heart rate during exercise in a dose-dependent manner, whilst heart rate at rest did not differ from resting heart rates in saline dosed control animals. In contrast, heart rate at rest and during exercise were lowered equally by the lowest doses of propranolol (approximately by 30 beats min-1), and additional doses caused only minor additional decreases. The exercise-induced tachycardia was maintained within 12% of pre-dose levels, presumably by withdrawal of vagal tone.5. Cardiac inotropism, as indicated by dPLv/dt max, was not affected by ZD7288 or zatebradine at rest,although the inotropic response to exercise decreased in proportion to the decreases in exercise-induced tachycardia. Propranolol caused a marked dose dependent decrease in the exercise-induced inotropic response (by 85% at 0.3mg kg 1).6. Whilst the sino-atrial node modulators increased stroke volume at rest, and augmented increases in response to exercise, propranolol did not affect resting stroke volume and decreased the responses to exercise.7. Cardiac output at rest and cardiac output increases during exercise were well maintained in the presence of ZD7288 and zatebradine in contrast to propranolol which induced a significant depression of cardiac output, both at rest and during exercise. Propranolol also caused significant systemic vasoconstriction.8. In conclusion, ZD7288 has haemodynamic actions comparable to those of zatebradine despite their chemical dissimilarity. ZD7288 may be of benefit in the treatment of ischaemic heart disease by reducing heart rate without impairing cardiac function. PMID- 7858852 TI - Activation of BKCa channels in acutely dissociated neurones from the rat ventromedial hypothalamus by NS 1619. AB - NS 1619 activates the large-conductance Ca(2+)-dependent K+ channel (BKCa) in membrane patches isolated from rat ventromedial hypothalamic neurones. The activation is concentration dependent, with a maximal effect at less than 30 microM, reversible and can be inhibited by application of iberiotoxin to the extracellular membrane. NS 1619 does not activate ATP-K+ channels present in the same neurones. PMID- 7858853 TI - AT1 receptor-mediated stimulation by angiotensin II of rat aortic fibronectin gene expression in vivo. AB - Fibronectin plays an important role in various vascular diseases. A subpressor (200 ng kg-1 min-1) or pressor (1000 ng kg-1 min-1) dose of angiotensin II was continuously infused into rats by osmotic minipump for various times, to investigate the effects on aortic fibronectin gene expression. In rats infused with a subpressor dose of angiotensin II in which blood pressure was normal for 3 days, aortic fibronectin mRNA levels started to increase by 1.4 fold at 12 h and reached the maximal levels (increased by 3.1 fold) at 3 days. Treatment with TCV 116 (3 mg kg-1 day-1), a non-peptide selective AT1 receptor antagonist, completely inhibited the angiotensin II-induced increase in aortic fibronectin mRNA, while hydralazine (10 mg kg-1 day-1) did not block this effect. Similar results were also obtained for a pressor dose of angiotensin II. Thus, angiotensin II directly stimulates aortic fibronectin gene expression in vivo, which is mediated by the AT1 receptor but not by blood pressure. PMID- 7858854 TI - Effects of cyclopiazonic acid on contractility and ecto-ATPase activity in guinea pig urinary bladder and vas deferens. AB - 1. Cyclopiazonic acid (CPA), an inhibitor of sarcoplasmic ATPase, was tested on guinea-pig urinary bladder and vas deferens for its ability: (1) to modify contractile responses to electrical field stimulation (EFS), exogenous ATP, alpha,beta-methylene ATP (alpha,beta-MeATP), carbachol, noradrenaline (NA), histamine, and KCl; (2) to affect ecto-ATPase activity; (3) to modify the release of ATP evoked by EFS. 2. In the urinary bladder, CPA (10 microM) potentiated contractile responses to EFS, exogenous ATP (100 microM), alpha,beta-meATP (1 microM), carbachol (0.5 microM), histamine (30 microM) and KCl (30 mM). In the vas deferens, CPA (10 microM) potentiated responses to EFS, ATP, alpha,beta meATP, NA (100 microM) and KCl. CPA at a concentration of 1 microM had no effect on ATP-induced relaxation of carbachol-precontracted guinea-pig taenia coli, and at a concentration of 10 microM it markedly increased spontaneous contractile activity of taenia. 3. Ecto-ATPase was estimated to have Vmax and Km values of 0.98 nmol Pi 30 min-1 mg-1 wet tissue and 881 microM ATP in the urinary bladder, and 0.75 nmol Pi 30 min-1 mg-1 wet tissue and 914 microM ATP in the vas deferens, respectively. CPA at a concentration of 10 microM significantly inhibited ecto ATPase activity by 18% in the urinary bladder and by 24% in the vas deferens. 4. In the guinea-pig vas deferens, CPA significantly potentiated ATP release evoked by EFS from 2.2 +/- 0.8 (6) pmol ATP min-1 g-1 wet tissue to 35.2 +/- 4.8 (6) pmol ATP min-1 g-1 wet tissue (P < 0.01). 5. In conclusion, the potentiation of contractile responses of the guinea-pig urinary bladder and vas deferens by CPA has a non-specific character. CPA inhibited ecto-ATPase activity and increased ATP release, but these effects do not appear to contribute to the potentiation of Pu-purinoceptor-mediated responses since the contractile actions of all the agonists studied were potentiated to the same extent. PMID- 7858855 TI - Modulation by endogenous prostanoids of the vasoconstrictor activity of endothelin-1 in the canine isolated, perfused spleen. AB - 1. Endothelin-1 (ET-1, 0.4-200 pmol) was injected into the arterial circuit of the isolated perfused spleen of the dog in which splenic arterial perfusion pressure and spleen weight were recorded continuously. 2. Serial collection was made of splenic venous effluent before and after intra-arterial injection of ET-1 and assayed by direct radioimmunoassay for prostaglandin E2 (PGE2), 6-oxo-PGF1 alpha and thromboxane B2 (TXB2). 3. ET-1 caused graded arterial vasoconstriction of prolonged duration with small reductions in spleen weight at higher doses. 4. ET-1 cause a dose-related release of PGE2, 6-oxo-PGF1 alpha and TXB2 into the splenic venous effluent. The mean peak increase above the basal levels following 200 pmol of ET-1 was 800% for PGE2, 233% for 6-oxo-PGF1 alpha and 205% for TXB2. 5. Intra-arterial infusion of indomethacin significantly reduced the basal release of all three eicosanoids and significantly elevated the basal splenic vascular resistance. The release of all three eicosanoids in response to ET-1 and adrenaline (Ad) was significantly reduced by indomethacin and the accompanying increases in the splenic arterial vascular resistance were significantly potentiated at low doses of ET-1. The splenic arterial vascular responses to Ad were unchanged by indomethacin infusion. 6. These results indicate that the release of eicosanoids may modulate the splenic vascular responses to ET-1. PMID- 7858856 TI - The interaction between salmeterol and beta 2-adrenoceptor agonists with higher efficacy on guinea-pig trachea and human bronchus in vitro. AB - 1. In guinea-pig tracheal preparations precontracted with 1 mumol l-1 carbachol, formoterol, procaterol, fenoterol, salmefamol, salbutamol and terbutaline (in that order of potency) caused a concentration-dependent and almost complete, relaxation. However, under these conditions, the maximum relaxation by salmeterol was approximately 30% of the maximum attainable relaxation. 2. We have therefore explored the ability of salmeterol to inhibit the relaxant response to beta 2 adrenoceptor agonists of different chemical structure and relatively higher efficacy in smooth muscle preparations from guinea-pig trachea and human bronchus. 3. With 1 mumol l-1 salmeterol in the organ bath, the concentration effect curves for the other agonists were shifted to the right in a variable way by 1.8-2.8 log units, fenoterol and salbutamol being the extremes. 4. When 20 mumol l-1 sulfonterol, another low efficacy beta 2-adrenoceptor agonist, was substituted for salmeterol, the difference in the magnitude of the rightward shift between fenoterol and salbutamol was eliminated. 5. In the human bronchus, formoterol and terbutaline had a higher apparent efficacy than salmeterol. With 1 mumol l-1 salmeterol in the organ bath, the concentration-effect curve for formoterol was shifted 2.7 log units to the right. 6. Salmeterol inhibits, competitively, relaxant responses to beta 2-adrenoceptor agonists with higher efficacy. The degree of inhibition seems to be dependent on the agonist used. This contrasts with results obtained with sulfonterol and suggests that salmeterol interacts with the beta 2-adrenoceptor in a complex way. PMID- 7858857 TI - Atypical beta-adrenoceptors in the rat isolated common carotid artery. AB - 1. The possible existence of atypical beta-adrenoceptors in vascular smooth muscle of the rat common carotid artery was examined in this study. 2. Isoprenaline produced concentration-dependent relaxation of noradrenaline (10(-7) M) precontracted ring segments of the carotid artery. The relaxation was not affected by endothelial denudation. 3. Propranolol (10(-8) M-3 x 10(-7) M) shifted the isoprenaline curve to the right without suppressing the maximum response. However, the slope (0.74) of the Schild plot was significantly (P < 0.05) less than 1. 4. Salbutamol (beta 2), CGP 12177 and BRL 37344 (beta 3) also concentration-dependently relaxed noradrenaline precontracted artery segments. These relaxations were not affected by propranolol (10(-7) M). Pretreatment of the artery segments with BRL 37344 did not desensitize the tissue to the relaxant effect of isoprenaline, CGP 12177 and salbutamol. 5. It is concluded that atypical beta-adrenoceptors exist in vascular smooth muscle of the common carotid artery. PMID- 7858858 TI - Electrophysiological subtypes of inhibitory P1 purinoceptors on myenteric neurones of guinea-pig small bowel. AB - 1. Conventional intracellular microelectrode techniques were used to subclassify P1 purinoceptors linked to reduction of cell input resistance, steady-state hyperpolarization of the membrane potential, or inhibition of fast e.p.s.ps, in neurones of microdissected myenteric plexus preparations from guinea-pig ileum. The potencies of P1 purinoceptor agonists were estimated in neurones that were current clamped to a fixed membrane potential. 2. In AH/Type 2 neurones, the A2 agonist, CGS 21680, the A1 agonist, CCPA or the mixed A1-A2 agonist, NECA, suppressed excitability by reducing input resistance (40-50% max.) and causing hyperpolarization (20-25 mV max.). CGS 21680 (0.1-1 microM) enhanced the after hyperpolarizing potential. 3. From cumulative dose-response data, the potency order for reducing input resistance was CCPA (IC50 = 5.1 +/- 2.2 nM) >>> CGS 21680 (IC50 = 5.6 +/- 2.5 microM). This effect was reversed by the A1 antagonist, CPT (EC50 = 65 +/- 11 nM). 4. In contrast, the potency order for membrane hyperpolarization was CCPA (IC50 = 61 +/- 23 nM) = CGS 21680 (IC50 = 290 +/- 90 nM) > or = NECA (IC50 = 450 +/- 100 nM). Hyperpolarization elicited by CCPA was sensitive to the A1-A2 antagonist, DPSPX. 5. Agonists suppressed fast e.p.s.ps, but not DMPP responses, with an order of CCPA (IC50 = 8.1 +/- 3.0 nM) >>> CGS 21680 (IC30 = 10 +/- 2.9 microM). 6. In conclusion, the excitability of AH/Type 2 neurones is suppressed by activation of high affinity A l receptors that may be linked to a cyclic AMP-dependent pathway, leading to increase in calcium dependent potassium conductance and enhancement of the after-hyperpolarizing potential. Activation of lower affinity non A1 receptors linked to a cyclic AMP independent pathway reduces excitability and leads mainly to a steady-state hyperpolarization. Adenosine also suppresses nicotinic cholinergic transmission by activating presynaptic high affinity Al receptors. PMID- 7858859 TI - Effects of bradykinin B2 receptor antagonism on the hypotensive effects of ACE inhibition. AB - 1. The aim of this study was to determine the participation of endogenous bradykinin (BK) in the antihypertensive effects of the angiotensin converting enzyme inhibitor (ACEI), perindoprilat, in the spontaneously hypertensive rat (SHR) on different salt diets. 2. Conscious SHRs receiving either a low or a high NaCl diet were used in order to evaluate the respective roles of angiotensin II suppression and bradykinin stimulation in the acute hypotensive effects of perindoprilat. Two different B2 receptor antagonists (B 4146 and Hoe 140) were used after bolus administration of 7 mg kg-1 of the ACEI, perindoprilat. In separate animals, Hoe 140 was administered before the injection of perindoprilat. In other experiments, the effects of Hoe 140 on the hypotensive effects of the calcium antagonist, nicardipine, were tested. 3. The different NaCl diets had no effect on baseline blood pressure. Hoe 140 injection before ACE inhibition did not modify blood pressure. Perindoprilat caused more marked hypotension in the low salt-fed rats than in the high salt animals (P < 0.01). Administration of Hoe 140 or B4146 after perindoprilat significantly reduced the antihypertensive effects of perindoprilat in the different groups, but this effect was more pronounced in high salt-fed rats. However, in SHRs receiving Hoe 140 before perindoprilat, the antihypertensive effect of perindoprilat was completely abolished in both high or low salt diet rats. In separate experiments we confirmed that Hoe 140 did not affect the hypotensive efficacy of the calcium antagonist, nicardipine. 4. Our study shows that inhibition of endogenous bradykinin degradation participates in the acute antihypertensive effects of perindoprilat in SHRs. The role of bradykinin is more pronounced following exposure to a high salt diet i.e., when the renin-angiotensin system is suppressed. Blockade of bradykinin B2 receptors by Hoe 140 before administration of perindoprilat completely abolished the hypotensive effect of perindoprilat suggesting an increased role of bradykinin in the onset of hypotensive action of ACE inhibitors. However, the exact mechanism of this interaction remains unclear. PMID- 7858860 TI - Pharmacological evidence of distinct alpha 1-adrenoceptor subtypes mediating the contraction of human prostatic urethra and peripheral artery. AB - 1. The alpha 1-adrenoceptor subtypes mediating contractions of the smooth muscle in human prostatic urethra and branches of internal iliac artery were characterized in isometric contraction experiments. 2. Phenylephrine produced concentration-dependent contractions in both the urethra and artery. These responses were competitively inhibited by prazosin, WB4101 and 5-methyl-urapidil, and the slopes of Schild plots for all these antagonists were close to unity. 3. The pA2 values for prazosin were not significantly different between the urethra (9.42 +/- 0.11; mean +/- s.d.) and artery (9.50 +/- 0.27), while the pA2 values for WB4101 and 5-methyl-urapidil in the human prostatic urethra (8.94 +/- 0.19 and 8.42 +/- 0.14, respectively) were significantly greater than in the branches of human internal iliac artery (7.94 +/- 0.21 and 7.43 +/- 0.22, respectively; P < 0.01). 4. Pretreatment with chlorethylclonidine (CEC) at concentrations ranging from 0.1 microM to 100 microM attenuated the maximum contraction to phenylephrine in a concentration-dependent manner in both the urethra and artery. However, the urethra was significantly less affected by CEC than the artery. The pD'2 values (negative logarithm of the molar concentration of antagonist which reduced the maximum contraction to one half) in the urethra and artery were 4.35 +/- 0.27 and 5.20 +/- 0.37, respectively (P < 0.01). 5. The present results indicate that there are distinct populations of alpha 1-adrenoceptor subtypes in the human prostatic urethra and branches of the internal iliac artery. The alpha 1 adrenoceptors responsible for the contraction of the human internal iliac artery branches are predominantly alpha 1 B-subtype, whereas those in the human prostatic urethra are considered to be not alpha 1 B, but alpha 1 c or possibly alpha 1 A or alpha 1A/D-subtype. PMID- 7858861 TI - The anticonvulsant and behavioural profile of L-687,414, a partial agonist acting at the glycine modulatory site on the N-methyl-D-aspartate (NMDA) receptor complex. AB - 1. The anticonvulsant and behavioural effects of the glycine/NMDA receptor partial agonist, L-687,414 (R(+)-cis-beta-methyl-3-amino-1-hydroxypyrrolid-2-one) have been investigated in rodents. 2. L-687,414 dose-dependently antagonized seizures induced by N-methyl-D,L- aspartic acid (NMDLA, ED50 = 19.7 mg kg-1), pentylenetetrazol (PTZ, ED50 = 13.0 mg kg-1) and electroshock (ED50 = 26.1 mg kg 1) when given intravenously 15 min before test, in male Swiss Webster mice but was most potent against audiogenic seizures induced by a 120 dB bell in DBA/2 mice (ED50 = 5.1 mg kg-1, i.p., 30 min before test). 3. L-687,414 also induced impairments of performance in a rotarod test in both Swiss Webster and DBA/2 mice and the ratio [rotarod MED:anticonvulsant ED50] varied between 0.9 and 5, depending on the convulsant used. 4. Similar behaviours to those seen after administration of the non-competitive NMDA receptor antagonist, MK-801 (head weaving, body rolling, hyperlocomotion) were seen in the mouse after giving L 687,414, although the peak effect occurred at a dose (100 mg kg-1) which was 5-20 times the anticonvulsant ED50S, depending on the convulsant used. Unlike MK-801, however, doses of L-687,414 that were behaviourally stimulant did not increase dopamine turnover in the nucleus accumbens. 5. Consistent with the interaction of L-687,414 with the glycine/NMDA receptor, the anticonvulsant, ataxic and motor stimulant effects of the compound were significantly attenuated by the glycine/NMDA receptor agonist, D-serine (10-100 micrograms per mouse, i.c.v.). 6. The results show that L-687,414 is a potent, orally active anticonvulsant with a more benign pharmacological profile than antagonists acting at the ion channel of the NMDA receptor complex. The compound is a useful tool with which to probe the functional role of the glycine co-agonist site in vivo. PMID- 7858862 TI - Neuropeptide Y inhibits potassium-stimulated glutamate release through Y2 receptors in rat hippocampal slices in vitro. AB - 1. We investigated the effects of neuropeptide Y (NPY), peptide YY (PYY), NPY13 36, NPY18-36, [Leu31][Pro34]NPY and of pancreatic polypeptide Y (PPY) on calcium dependent, potassium-stimulated glutamate release in superfused rat hippocampal slices. 2. NPY, PYY and the Y2 receptor agonist NPY13-36 equipotently inhibited the release of glutamate. The half-maximal response was observed at about 10 nM in a dose-dependent manner (3 to 100 nM). Maximal inhibition of 50 to 60% was obtained at 100 nM. At higher concentrations of the peptides (300 nM and 1 microM) this inhibition was partially or entirely reversed. Porcine NPY13-36 and NPY18-36 inhibited glutamate release by about 44% at 100 nM. 3. The specific Y1 receptor agonist, [Leu31][Pro34]NPY, caused an insignificant increase in glutamate release at 100 to 300 nM concentrations. PPY had no effect on potassium evoked glutamate release in hippocampal slices at concentrations of 30 nM to 1 microM. 4. The experiments support previous electrophysiological data. They suggest a potent inhibitory action of NPY through NPY-Y2 receptors on the release of the excitatory amino acid glutamate in rat hippocampus. Especially under conditions of increased NPY synthesis, such as in epilepsy, this mechanism may be of pathophysiological relevance. PMID- 7858863 TI - Failure of CGS15943A to block the hypotensive action of agonists acting at the adenosine A3 receptor. AB - 1. Adenosine receptor agonists were evaluated for their activity at the putative adenosine A3 receptor which mediates a 'xanthine-resistant' hypotensive response in the anaesthetized rat. The compounds tested were: the A1/A3 receptor agonist, N-[2-(4-aminophenyl)ethyl]adenosine (APNEA), the non-selective adenosine receptor agonist, 5'-N-ethylcarboxamidoadenosine (NECA), the adenosine A1 receptor selective agonists, N-[(1S,trans)-2-hydroxycyclopentyl]adenosine (GR79236) and N6 cyclopentyl adenosine (CPA), the A2a receptor-selective agonists, 2-[[2-[4-(2 carboxyethyl) phenyl] ethyl] amino]-N- ethylcarboxamidoadenosine (CGS21680) and 2 phenylaminoadenosine (CV1808), and the moderately A2b selective agonist, N-[(2 methylphenyl)methyl]adenosine (metrifudil). 2. In confirmation of literature findings, APNEA (1-1000 nmol kg-1) induced hypotension and bradycardia; the hypotension was not blocked by pretreatment with the xanthine antagonist, 8-P sulphophenyltheophylline (8-sPT; 40 mg kg-1, i.v.), whereas the bradycardia was attenuated. The non-xanthine antagonist, 9-fluoro-2-(2-furyl)-5,6-dihydro [1,2,4]triazolo[1,5-c]- quinazin-5-imine (CGS15943A; 3 mg kg-1 i.v.), also attenuated the bradycardia without affecting the hypotension. 3. The adenosine A1 receptor-selective agonists, GR79236 and CPA, both produced dose-dependent falls in blood pressure and heart rate which were antagonized by 8-sPT (40 mg kg-1) and CGS15943A (3 mg kg-1). 4. The adenosine A2a receptor-selective agonists, CGS21680 and CV1808, produced only a hypotensive response which was antagonized by 8-sPT (40 mg kg-1) and to a much greater extent by CGS15943A (3 mg kg-1), consistent with the response being mediated solely by A2a receptors. 5. The modestly A2b receptor-selective agonist, metrifudil, produced a dose-dependent fall in blood pressure and at higher doses a fall in heart rate. The hypotension induced by metrifudil was not antagonized by either 8-sPT (40 mg kg-1) or CGS15943A (3 mg kg 1) even though the bradycardia was abolished, suggesting that this agonist activates the putative A3 receptor.6. The non-selective adenosine receptor agonist, NECA, produced a hypotension and bradycardia that was attenuated by 8 sPT (40 mg kg-1), confirming previous work. The non-xanthine antagonist,CGS15943A (3 mg kg-'), also attenuated the hypotension and bradycardia. The bradycardia was blocked to a much greater extent, suggesting that NECA may therefore induce hypotension partly by activating the putative A3 receptor.7. In conclusion, we have confirmed that the putative A3 receptor mediating hypotension in the anaesthetized rat is not blocked by 8-sPT, and further shown that it is not blocked by CGS15943A. The A2a agonists CGS21680 and CV1808 showed no discernible activity at the A3 receptor, whereas APNEA,NECA, CPA and metrifudil appear to activate this receptor. The adenosine A1 receptor agonist,GR79236, shows considerable selectivity for the A1 receptor but may activate the A3 receptor at high doses. PMID- 7858864 TI - Role of interleukin-5 in enhanced migration of eosinophils from airways of immunized guinea-pigs. AB - 1. Platelet activating factor (PAF), leukotriene B4 (LTB4) and interleukin-5 (IL 5) are potent chemoattractants for guinea-pig eosinophils, which may be involved in eosinophil recruitment and up-regulation in allergic diseases. Eosinophils from the bronchoalveolar lavage fluid (BALF) of ovalbumin-sensitized guinea-pigs were collected 24 h after antigen provocation and migration induced by PAF, LTB4 and rhIL-5 was studied. 2. Total BALF content and distribution of eosinophils were greater in immunized, ovalbumin-challenged guinea-pigs (5.0 +/- 0.8 x 10(6)/guinea-pig; 12 +/- 1%) than in immunized, saline-challenged animals (3.0 +/ 0.7 x 10(6)/guinea-pig; 7 +/- 1%). 3. The chemoattraction of eosinophils isolated on a metrizamide gradient was studied in micro-Boyden chambers, results being expressed as the number of migrating cells (mean +/- s.e. mean). PAF and LTB4-induced migration of eosinophils from immunized and OA-challenged guinea pigs were significantly enhanced, as compared to immunized and saline-challenged animals (170 +/- 36 vs 35 +/- 9 migrating eosinophils for 10 nM PAF; 271 +/- 60 vs 110 +/- 19 for 1 nM LTB4). 4. The IL-5 antibody TRFK-5, in vivo, reduced eosinophil recruitment in BALF of antigen-challenged immunized animals as well as the enhanced responsiveness of eosinophils from the challenged animals, suggesting a role for IL-5 in the priming of eosinophils in vivo. 5. In contrast to TRFK-5, nedocromil sodium reduced to a similar extent eosinophil, macrophage and lymphocyte recruitment into the BALF of antigen-challenged, but failed to down-regulate the enhanced responsiveness of eosinophils from the challenged animals. 6. The increased eosinophil content in lungs from antigen-challenged guinea-pigs is thus selectively reduced by the anti-IL-5 antibody, which also attenuates the concomitant enhancement of the eosinophil responsiveness, supporting the concept that IL-5 is essential for recruitment and priming of eosinophils in vivo. In contrast, nedocromil sodium reduced non-selectively the total cell recruitment to the airways,but failed to attenuate the enhanced responsiveness of those eosinophils which migrated, indicating that its effects involve a different target. PMID- 7858865 TI - Dual effects of tetrandrine on cytosolic calcium in human leukaemic HL-60 cells: intracellular calcium release and calcium entry blockade. AB - 1. Tetrandrine (TET, a Ca2+ antagonist of Chinese herbal origin) and thapsigargin (TSG, an endoplasmic reticulum Ca2+ pump inhibitor) concentration-dependently mobilized Ca2+ from intracellular stores of HL-60 cells, with EC50 values of 20 microM and 0.8 nM, respectively. After intracellular Ca2+ release by 30 nM TSG, there was no more discharge of Ca2+ by TET (100 microM), and vice versa. 2. Pretreatments with 100 nM rauwolscine (alpha 2-adrenoceptor antagonist), 100 nM prazosin (alpha 1-adrenoceptor antagonist), 10 nM phorbol myristate acetate (PMA, a protein kinase C activator) or 100 nM staurosporine (a protein kinase C inhibitor) had no effect on 100 microM TET-induced intracellular Ca2+ release. 3. After intracellular Ca2+ release by 30 nM TSG in Ca(2+)-free medium, readmission of Ca2+ caused a substantial and sustained extracellular Ca2+ entry. The latter was almost completely inhibited by 100 microM TET (IC50 of 20 microM) added just before Ca2+ readmission. In Ca(2+)-containing medium, 30 nM TSG caused a sustained phase of cytosolic Ca2+ elevation, which could be abolished by 100 microM TET. TET was also demonstrated to retard basal entry of extracellular Mn2+ and completely inhibit TSG-stimulated extracellular Mn2+ entry. 4. TSG-induced extracellular Ca2+ entry was insensitive to the L-type Ca2+ channel blocker, nifedipine (1 microM), but was completely inhibited by the non-selective Ca2+ channel blocker La3+ (300 microM). Depolarization with 100 mM KCl did not raise the cytosolic Ca2+ level. 5. These data suggest that (a) TET and TSG mobilized the same Ca2+ pool and TET-induced intracellular Ca2+ release was independent of protein kinase C activity and ox-adrenoceptor activation,and (b) TET blocked the voltage-insensitive Ca2+ entry pathway activated by TSG. These dual effects on HL 60 cells were also observed with hernandezine (HER), a TET-like compound and in another cell type, murine B lymphoma M12.4 cells. PMID- 7858866 TI - Antagonism by (R)- and (S)-trihexyphenidyl of muscarinic stimulation of adenylyl cyclase in rat olfactory bulb and inhibition in striatum and heart. AB - 1. Activation of muscarinic receptors in rat olfactory bulb stimulates adenylyl cyclase activity. This response was competitively antagonized by the (R)- and (S) enantiomers of trihexyphenidyl with pA2 values of 8.84 and 6.09, respectively. 2. Similarly, in rat striatal homogenates, muscarinic inhibition of adenylyl cyclase activity was antagonized by the (R)- and (S)-enantiomers with pA2 values of 8.75 and 6.12, respectively. 3. In contrast, in rat myocardium the muscarinic inhibition of the adenosine 3':5'-cyclic monophosphate (cyclic AMP) formation was more weakly antagonized by trihexyphenidyl, with a particularly marked loss (15 fold) in activity of the (R)-enantiomer. The (R)- and (S)-enantiomers had pA2 values of 7.64 and 5.72, respectively. 4. Each muscarinic response was completely antagonized by increasing concentrations of (R)-trihexyphenidyl with a Hill coefficient not significantly different from unity. 5. The present study shows that the muscarinic receptors coupled to stimulation of adenylyl cyclase in the olfactory bulb display high stereoselectivity for the enantiomers of trihexyphenidyl. The affinities of these receptors for the antagonists are similar to those shown by the striatal receptors. This finding supports the hypothesis that both the muscarinic stimulation of adenylyl cyclase in the olfactory bulb and the muscarinic inhibition of the enzyme in striatum are mediated by activation of a receptor subtype pharmacologically equivalent to the m4 gene product. On the other hand, the weaker affinities and the lower stereoselectivity for the trihexyphenidyl enantiomers exhibited by the muscarinic inhibition of adenylyl cyclase in the heart are consistent with the involvement of M2 receptors in this response. PMID- 7858867 TI - Facilitation by procaterol, a beta-adrenoceptor agonist, of noradrenaline release in the pithed rat independently of angiotensin II formation. AB - 1. The effects of the beta 2-adrenoceptor agonist, procaterol, on sympathetic neuroeffector transmission were studied in the pithed adrenal demedullated rat to determine if generation of angiotensin II was involved in its effect. Pressor responses were elicited by either electrical stimulation (20 V, 2 Hz) of the entire spinal sympathetic outflow or methoxamine (0.1 mg kg-1, i.v.). 2. Sodium nitroprusside (3 and 5 micrograms kg-1 min-1, i.v.) produced hypotension and the pressor responses to both sympathetic nerve stimulation and methoxamine were reduced. This indicates that decreasing blood pressure in pithed rats reduces pressor responses. Procaterol (10 and 30 ng kg-1 min-1, i.v.) also produced hypotension but did not alter pressor responses to sympathetic nerve stimulation. Nevertheless, procaterol (10 and 30 ng kg-1 min-1, i.v.) did reduce pressor responses to to methoxamine. Together these results suggest that procaterol may have enhanced sympathetic neurotransmitter release. This was confirmed in another series of experiments where procaterol (30 ng kg-1 min-1, i.v.) increased plasma noradrenaline levels during sympathetic nerve stimulation. 3. Captopril (5 mg kg 1, i.v.) produced hypotension and as expected reduced pressor responses to sympathetic nerve stimulation. When the hypotensive effect of captopril was abolished by concomitant vasopressin infusion (1.5-4.5 i mu kg-1 min-1, i.v.), pressor responses to sympathetic nerve stimulation were restored to pre-captopril levels. In this situation procaterol (10 and 30 ng kg-' min', i.v.) reduced basal blood pressure and did not alter pressor responses to sympathetic nerve stimulation whereas the pressor responses were reduced by an equihypotensive infusion of sodium nitroprusside (3 and 5 jig kg-' min' , i.v.). The lack of reduction of pressor responses after procaterol in the presence of captopril is indirect evidence that procaterol may have enhanced noradrenaline release independently of angiotensin II.4. In another series of experiments, plasma noradrenaline levels elicited by sympathetic nerve stimulation were not altered by captopril (5 mg kg', i.v.). In the presence of captopril (5 mg kg-', i.v.),procaterol (30 ng kg- min-1, i.v.) no longer enhanced plasma noradrenaline levels during sympathetic nerve stimulation. However, since the dose of captopril is well above that required to block angiotens in converting enzyme (ACE) the effect may be non-specific. Therefore, the selective AT, receptor antagonist, losartan (10mgkg'1, i.v.), was also used. Losartan (10mgkg'1, i.v.) did not alter plasma noradrenaline levels during sympathetic nerve stimulation, and in the presence of losartan procaterol(30 ng kg-I min-', i.v.) enhanced plasma noradrenaline levels during sympathetic nerve stimulation. This result further suggests that 1-adrenoceptor facilitation of noradrenaline release from sympathetic nerves in the pithed rat occurs by a mechanism independent of angiotensin II generation. PMID- 7858868 TI - Enhancement of retinal acetylcholine release by DAMGO: possibly a direct opioid receptor-mediated excitatory effect. AB - 1. An eye-cup preparation in anaesthetized rabbits was used to examine opioid modulation of acetylcholine (ACh) release from cholinergic neurones in the retina. 2. The mu-opioid receptor agonist, [D-Ala2, MePhe4, Gly-ol5]-enkephalin (DAMGO), when applied locally to the retina at concentrations between 1-30 microM significantly increased the light-evoked release of ACh. The effect of DAMGO was completely blocked by the selective mu-receptor antagonist CTOP but the kappa receptor antagonist nor-binaltorphimine (norBNI) did not affect the action of DAMGO on ACh release indicating that the opioid produced its effect by activation of mu-receptors (the rabbit retina has negligible delta-receptors). 3. Blockade with bicuculline and strychnine of GABAergic and glycinergic inputs to the cholinergic neurones did not affect the action of DAMGO on ACh release. Also DAMGO did not reduce the potassium-evoked release of either GABA or glycine from rat isolated retinas. 4. Exposure of the rabbit retina to a combination of an A1 adenosine receptor antagonist, 8-cyclopentyl-1,3 dipropylxanthine (DPCPX), and adenosine deaminase did not affect the enhancing action of DAMGO on the light evoked release of ACh. 5. When the retina in the rabbit eye-cup was exposed to kainate, the release of ACh was increased by approximately three times the resting release. In the presence of DAMGO the kainate-evoked release of ACh was enhanced by 44%. 6. These experiments show that activation of mu-opioid receptors by DAMGO increases the release of ACh elicited by physiological stimulation (flickering light). Since we could find no evidence thatDAMGO reduces inhibitory inputs to the cholinergic neurones, it seems that the enhancing action ofDAMGO on the light-evoked release of ACh involves a direct excitatory effect rather than disinhibition.This conclusion is supported by the enhancing action of DAMGO on the kainate-evoked release of ACh because kainate is thought to act directly on the cholinergic neurones. PMID- 7858869 TI - Contribution of intra- and extracellular Ca2+ to noradrenaline exocytosis induced by ouabain and monensin from guinea-pig vas deferens. AB - 1. Contributions of intra- and extracellular Ca2+ to noradrenaline (NA) release evoked by increasing intracellular Na+ concentrations (ouabain plus monensin) from adrenergic nerves of guinea-pig vas deferens were evaluated under conditions eliminating carrier-mediated NA release (with 100 microM cocaine). 2. Ouabain (100 microM) plus monensin (10 microM), unlike 100 mM KCl, produced a marked NA release which was unchanged by Ca(2+)-removal. 3. In normal solution but not in Ca(2+)-free solution, the release of NA evoked by ouabain plus monensin was reduced by adenosine, clonidine and neuropeptide Y, and by Ca(2+)-channel blockers such as omega-conotoxin GVIA and nifedipine. The release of NA was also decreased by cromakalim in a glibenclamide-sensitive fashion. 4. In contrast, in the absence but not in the presence of Ca2+, the drug-evoked NA release was inhibited by mitochondrial inhibitors (carbonylcyanide-m-chlorophenylhydrazone and oligomycin) and further by immobilizers of intracellular Ca2+ (TMB-8 and BAPTA-AM) and calmodulin antagonists (W-7 and trifluoperazine). 5. These findings suggest that the release of NA evoked by elevation of [Na+]i from adrenergic nerves in the presence and absence of Ca2+ involves, in part, exocytotic processes which are triggered by depolarization-induced Ca2+ influx and by utilization of Ca2+ from intracellular Ca2+ store sites such as mitochondria, respectively. PMID- 7858870 TI - The effect of hyperglycaemia on function of rat isolated mesenteric resistance artery. AB - 1. Noradrenaline sensitivity and acetylcholine-induced relaxation were investigated in mesenteric resistance arteries from female Wistar rats (220-250 g) following exposure to isotonic supraphysiological glucose solutions (20 and 45 mM, in physiological buffer, 2 h incubation). 2. Arteries incubated in 20 mM glucose demonstrated enhanced noradrenaline sensitivity compared with those in physiological buffer. 3. Profoundly impaired endothelium-dependent relaxation to acetylcholine was observed in arteries incubated in 20 and 45 mM glucose. 4. Indomethacin (10 microM) normalized noradrenaline sensitivity in 20 mM glucose, but unmasked an enhanced maximum response in 20 and 45 mM glucose relative to controls. 5. Addition of L-arginine (0.1 mM) prevented the abnormality of acetylcholine-induced relaxation in the 20 mM glucose medium and significantly improved relaxation in 45 mM glucose. 6. The aldose reductase inhibitor, ponalrestat (10(-5) M, ZENECA Pharmaceuticals), prevented impaired acetylcholine mediated relaxation in 20 mM glucose and significantly improved relaxation in 45 mM glucose. 7. Indomethacin (10 microM) improved maximum relaxation but did not alter impaired sensitivity to acetylcholine in the high glucose media (20 and 45 mM). 8. Superoxide dismutase (SOD, 150 u ml-1) also prevented impaired acetylcholine-induced relaxation in 20 mM glucose but not in 45 mM glucose. 9. Endothelium-independent relaxation to sodium nitroprusside (SNP, 10(-9)-10(-5) mM) was normal in 20 mM glucose but was slightly, although significantly impaired by 45 mM glucose. 10. Enhanced responsiveness of rat isolated mesenteric resistance arteries to noradrenaline caused by elevated glucose would appear to be mediated through abnormal cyclo-oxygenase activity and the reduced tonic release of nitric oxide. 11. Hyperglycaemia may lead to abnormal endothelium dependent relaxation in these arteries through several mechanisms which include a role for increased free radical production, polyol pathway activation and altered L-arginine metabolism. PMID- 7858871 TI - The effect of non-steroidal anti-inflammatory drugs on the accumulation and release of interleukin-1-like activity by peritoneal macrophages from the mouse. AB - 1. The non-steroidal anti-inflammatory drugs (NSAIDs) indomethacin, 10 and 100 microM, piroxicam, 100 microM, and sodium meclofenamate, 1 and 100 microM, potentiated the lipopolysaccharide (LPS)-stimulated release of interleukin-1 (IL 1)-like activity from mouse peritoneal macrophages. Aspirin up to 100 microM was without effect. The drugs did not themselves stimulate the release of IL-1-like activity at the concentrations used. 2. LPS, 1 microgram ml-1, stimulated prostaglandin E2 production by mouse peritoneal macrophages and this was totally inhibited by aspirin, 100 microM, indomethacin, 1 microM, piroxicam, 10 microM and sodium meclofenamate, 0.1 microM. 3. The potentiation of LPS-stimulated release of IL-1-like activity produced by indomethacin, 100 microM, piroxicam, 100 microM, or sodium meclofenamate, 10 microM, was inhibited by prostaglandin E2, (PGE2) 10 ng ml-1. 4. Aspirin, 100 microM, indomethacin, 100 nM to 10 microM, piroxicam, 1 to 100 microM, and sodium meclofenamate, 10 nM, all potentiated cell associated IL-1-like activity in LPS- stimulated macrophages. The drugs had no effect on cell-associated IL-1-like activity by themselves. 5. Exogenous PGE2, 2 to 30 ng ml-1, inhibited the cell-accumulation of IL-1-like activity stimulated by LPS in the presence of indomethacin, 1 microM, or sodium meclofenamate, 0.1 microM. 6. The 5-lipoxygenase inhibitors BWA4C, 0.01 to 10 microM, and L-651,392, 0.01 to 10 microM, had no effect on LPS-stimulated released or cell-associated IL 1-like activity. Over the same concentration-ranges,neither of the 5-lipoxygenase inhibitors affected released or cell-associated IL-1-like activity in LPS stimulated mouse macrophages in the presence of indomethacin, 1 JM.7. The synthetic diacylglycerol, DiC8, 10 to 200 JAM, did not itself increase released or cell-associated IL-I-like activity but in the presence of the diacylglycerol kinase inhibitor, R59022, 10 JM, DiC8increased released and cell-associated IL-i like activity. The activity of DiC8 on released and cell associated IL-l-like activity was not increased by indomethacin, 100 micro M.8. NSAIDs increase LPS induced cell-associated IL-i-like activity in mouse macrophages by inhibiting the formation of cyclo-oxygenase products such as PGE2 but at higher concentrations the NSAIDs potentiate LPS-induced release of IL-I-like activity by a mechanism independent of cyclo-oxygenase inhibition. The potentiation of the release of IL i-like activity appears not to be related to an effect of NSAIDs on either 5 lipoxygenase or diacylglycerol metabolism. PMID- 7858872 TI - Evidence for P2-purinoceptor-mediated inhibition of noradrenaline release in rat brain cortex. AB - 1. Some postganglionic sympathetic axons possess P2Y-like P2-purinoceptors which, when activated, decrease the release of noradrenaline. We examined the question of whether such receptors also occur at the noradrenergic axons in the rat brain cortex. Slices of the brain cortex were preincubated with [3H]-noradrenaline, then superfused with medium containing desipramine (1 microM) and stimulated electrically, in most experiments by trains of 4 pulses/100 Hz. 2. The selective adenosine A1-receptor agonist, N6-cyclopentyl-adenosine (CPA; 0.03-3 microM) as well as the non-subtype-selective agonist 5'-N-ethylcarboxamido-adenosine (NECA; 0.3-3 microM) reduced the evoked overflow of tritium, whereas the adenosine A2a receptor agonist, 2-p-(2-carbonylethyl)-phenethylamino-5'-N-ethylcarboxamido-a denosine (CGS-21680; 0.003-30 microM) and the adenosine A3-receptor agonist N6-2 (4-aminophenyl)ethyl-adenosine (APNEA; 0.03-3 microM) caused no change. Of the nucleotides tested, ATP (30-300 microM), adenosine-5'-O-(3-thiotriphosphate) (ATP gamma S; 30-300 microM), adenosine-5'-O-(2-thiodiphosphate) (ADP beta S; 30-300 microM), P1,P4-di(adenosine-5')-tetraphosphate (Ap4A; 30-300 microM) and the preferential P2Y-purinoceptor agonist, 2-methylthio-ATP (300 microM) decreased the evoked overflow of tritium. The P2X-purinoceptor agonist, alpha,beta methylene-ATP (3-300 microM) caused no change. 3. The A1-selective antagonist, 8 cyclopentyl-1,3-dipropylxanthine (DPCPX; 10 nM) attenuated the effects of the nucleosides CPA (apparent pKB value 9.8) and NECA as well as of the nucleotides ATP (apparent pKB 9.3), ATP gamma S (apparent pKB 9.2) and ADP beta S (apparent pKB 8.7). CGS-21680 and APNEA were ineffective also in the presence of DPCPX. The A2-selective antagonist 1,3-dipropyl-8-(3,4-dimethoxystyryl)-7-methylxanthine (KF 17837) reduced the effects of CPA, NECA and ATP gamma S only when given at a concentration of 300 nM but not at 1O nM.4. The P2-purinoceptor antagonists, suramin (300 micro M), reactive blue 2 (30 micro M) and cibacron blue 3GA(30 micro M) did not change the effect of CPA. Suramin and cibacron blue 3GA shifted the concentration response curve of ATP gamma S to the right (apparent pKB values 3.7 and 5.0, respectively). Reactive blue 2 also attenuated the effect of ATPyS, and cibacron blue 3GA attenuated the effect of ATP, but in these cases the agonist concentration-response curves were not shifted to the right. There was no antagonistic effect of suramin against ATP and ADP beta S.5. The results indicate that rat cerebrocortical noradrenergic axons possess, in addition to the knownadenosine Al-receptor, a separate purinoceptor for nucleotides (P2) which, in contrast to the Al-receptor,is blocked by suramin, reactive blue 2 and cibacron blue 3GA. Nucleotides such as ATP and ATP gamma S activate both receptors. Inconsistencies in antagonist effects against nucleotides are probably due to this activation of two receptors. The presynaptic P2-purinoceptor is P2Y like, as it is in the peripheral sympathetic nervous system. PMID- 7858873 TI - Agonist-induced desensitization of histamine H1 receptor-mediated inositol phospholipid hydrolysis in human umbilical vein endothelial cells. AB - 1. The regulation of histamine-induced [3H]-inositol phosphate formation was studied in human cultured umbilical vein endothelial cells (HUVEC). 2. Histamine (EC50 4.8 microM) produced a 12.7 fold increase in [3H]-inositol phosphate formation over basal levels. Prior exposure to 0.1 mM histamine (2 h) produced a 78% reduction in the response to subsequent histamine (0.1 mM) challenge. The IC50 for this histamine-induced desensitization was 0.9 microM. 3. The inositol phosphate response to histamine (0.1 mM) was inhibited by phorbol dibutyrate (IC50 40 nM; maximal reduction 64%). This effect was antagonized by both staurosporine (100 nM) and Ro 31-8220 (10 microM). However, the histamine-induced desensitization of the H1-receptor-mediated inositol phosphate response was insensitive to the protein kinase inhibitors, staurosporine, Ro 31-8220, K252a and KN62. 4. Prior exposure to sodium nitroprusside (100 microM), forskolin (10 microM) or dibutyryl cyclic AMP (1 mM) had no effect upon histamine-induced [3H] inositol phosphate formation. 5. NaF (20 mM) and thrombin (EC50 0.4 u ml-1) also induced inositol phosphate formation in HUVEC. Histamine pretreatment (0.1 mM, 10 120 min) failed to modify the inositol phosphate response to a subsequent NaF or thrombin challenge. 6. We conclude that the desensitization of histamine H1 receptor-mediated [3H]-inositol phosphate formation occurs at the level of the receptor and involves a mechanism independent of activation of protein kinase A, G, or C, or calcium calmodulin-dependent protein kinase II. PMID- 7858874 TI - Effects of dihydropyridine calcium antagonists on rat midbrain dopaminergic neurones. AB - 1. The effects of the dihydropyridine calcium channel antagonists, nifedepine and nimodipine (300 nM-30 microM) were tested in vitro on intracellularly recorded dopaminergic neurones in the rat ventral mesencephalon. 2. Bath applied nifedipine and nimodipine inhibited in a concentration-dependent manner the spontaneous firing discharge of the action potentials, whereas, the dihydropyridine calcium channel agonist, Bay K 8644 increased the firing rate. 3. Pacemaker oscillations and bursts of action potentials were produced by loading the cells with caesium. Nifedipine and nimodipine reduced the rate and the duration of the caesium-induced membrane oscillations and decreased the number of action potentials in a burst. During the blockade of potassium currents the dopaminergic neurones often developed a prolonged (100-800 ms) afterdepolarization that was also inhibited by dihydropyridines. 4. The spontaneous discharge of calcium spikes was also inhibited by both dihydropyridine calcium antagonists. The apparent input resistance and the level of membrane potential were not affected by the dihydropyridine calcium antagonists. 5. If the action potential duration was less than 150 ms the shape of the spike was not clearly influenced by both calcium antagonists. However, when the duration of the action potential was longer than 150-200 ms due to the intracellular injection of caesium ions plus the extracellular application of tetraethylammonium (10-50 mM), both nifedipine and nimodipine reversibly shortened the plateau potential. 6. It is suggested that nifedipine and nimodipine depress the rhythmic and bursting activity of the dopaminergic cells and shorten the calcium action potential by blocking dihydropyridine-sensitive high-threshold calcium currents. PMID- 7858875 TI - The effects of clozapine on behavioural responses to the selective 'D1-like' dopamine receptor agonist, A 68930, and to the selective 'D2-like' agonist, RU 24213. AB - 1. The influence of the atypical antipsychotic clozapine on D1 dopamine receptor mediated function was examined in terms of its effects on behavioural responses to the new isochroman selective D1 agonist, A 68930, and to the selective D2 agonist, RU 24213. 2. In rat striatal membrane preparations, radioligand binding studies with [3H]-SCH 23390 and [3H]-spiperone confirmed clozapine to show weak and non-selective affinity for both D1 and D2 receptors. 3. Using a rapid time sampling behavioural check list technique, clozapine (4.0-36.0 mg kg-1) exerted only modest antagonism of RU 24213 (15.0 mg kg-1)-induced sniffing and locomotion, and weakly released some episodes of myoclonic jerking; such antagonism with release of jerking has been shown previously to occur only during concurrent stimulation of D2 receptors and attenuation of D1 function. 4. Over the same dose-range, clozapine completely blocked A 68930 (0.25 mg kg-1)-induced intense grooming but failed to influence the vacuous chewing response; this profile was similar to that demonstrated previously for selective D1 antagonists. 5. On the basis of complete blockade of typical D1 agonist-induced grooming and weak release of atypical jerking to D2 agonism in the face of modest reduction in typical D2-stimulated behaviours, clozapine appears to exert some preferential but not selective attenuation of D1 receptor-mediated function. Clozapine may attenuate activity through a classical D1 receptor at a level beyond the recognition site, for which it has little affinity, or by way of new, putative 'D1-like' site(s) that subserve distinct elements of dopaminergic behaviour. PMID- 7858876 TI - Characterization of receptors mediating vascular responses to endothelin-1 in the conscious rat. AB - 1. The present study has determined the receptors mediating the vascular responses (pressor and depressor actions and vascular permeability effect) to endothelin-1 (ET-1) in the conscious rat by using the novel non-peptide ETA/ETB receptor antagonist, bosentan (Ro 47-0203, 4-tert-butyl-N-[6-(2 hydroxyethoxy)-5 (2-methoxy-phenoxy)-2,2'-bipyrimidine- 4-yl]benzene-sulphonamide), the ETA receptor-selective antagonist, FR 139317 and the ETB receptor-selective peptide agonist, IRL 1620. 2. Bolus injection of ET-1 (1 nmol kg-1, i.v.) resulted in a prolonged pressor effect (maximum increase in mean arterial blood pressure (MABP) was 47 +/- 3 mmHg, n = 6) preceded by a transient depressor response (maximum decrease in MABP was 17 +/- 1 mmHg). Both these responses were inhibited by bosentan (1-20 mg kg-1, i.v. bolus) in a dose-dependent manner. The maximum inhibition of ET-induced depressor and pressor responses did not exceed 53 and 87%, respectively. FR 139317 (2.5 mg kg-1, i.v.) attenuated the pressor response to ET-1 by 75% without affecting the depressor response. Furthermore, FR 139317, but not bosentan, prolonged the depressor action of ET-1. Corresponding to changes in blood pressure, a small transient tachycardia (delta heart rate 15 +/- 5 beats min-1) followed by a sustained bradycardia (delta heart rate -48 +/- 10 beats min-1, n = 6) was observed following injection of 1 nmol kg-1 ET-1. FR 139317 and bosentan (10 mg kg-1) inhibited ET-1-induced bradycardia by 79% and 71%, respectively.ET-l-induced tachycardia was significantly attenuated by bosentan,but not FR 139317.3. The ETB receptor agonist, IRL 1620 (0.1-2 micro molkg-1, i.v.) produced biphasic dose-dependent changes in MABP with an initial transient fall followed by a prolonged pressor action. The maximum decrease and increase in MABP were 11 +/- 2 and 19 +/- 3 mmHg, respectively (n = 5). These changes in MABP were accompanied by a transient tachycardia (Delta heart rate 9+/ 3 beats min-1) and prolonged bradycardia (Delta heart rate -17+/-11 beats min 1), respectively. Pretreatment of the animals with FR139317 (2.5 mg kg-1, i.v.) did not affect IRL 1620 (1 nmol kg-1)-induced changes in MABP and heart rate, whereas both the depressor and pressor actions of IRL 1620 and the accompanying tachycardia and bradycardia were almost completely inhibited by bosentan (10mgkg 1).4. ET-1 (1 nmol kg-1) enhanced albumin extravasation in the upper and lower bronchi, spleen, kidney,stomach and duodenum (up to 246%) as measured by the extravasation of Evans blue dye. FR 139317(2.5mgkg-1) completely inhibited ET-l induced protein extravasation in the stomach and duodenum,whereas 40-75% inhibition was observed in the other vascular beds studied. The permeability effect of ET-l was almost completely inhibited by bosentan (10mgkg-1) in all vascular beds studied.5. IRL 1620 (0.4 or 1 nmol kg-1, i.v.) enhanced albumin extravasation (up to 219%) in the upper and lower bronchi, spleen and kidney in a dose-dependent manner. Unlike ET-1, IRL 1620 failed to increase albumin extravasation in the stomach and duodenum.6. The present study demonstrates in the conscious rat that ETA and ETB receptors are responsible for mediating the majority of the pressor response to ET-l and suggest that a small component of the ET-l pressor response might be mediated via a non-ETA, non-ETB receptor, whereas ETB and perhaps a non-ETA, non-ETB receptor may mediate the depressor action of ET-1. Furthermore, the ET-1 induced albumin extravasation is mediated solely via ETA receptors in the stomach and duodenum, whereas both ETA and ETB receptors are involved in the permeability effect of ET-l in the bronchial, splenic and renal vascular beds. PMID- 7858877 TI - Characterization of P2-purinoceptors in the smooth muscle of the rat tail artery: a comparison between contractile and electrophysiological responses. AB - 1. The electrophysiological actions of the P2-purinoceptor agonists, adenosine 5' triphosphate (ATP), 2-methylthioATP (2-meSATP), alpha, beta-methyleneATP (alpha, beta-meATP) and uridine 5'-triphosphate (UTP) were studied under concentration and voltage-clamp conditions in acutely dissociated rat tail artery smooth muscle cells. For comparison, their actions as vasoconstrictors were studied in intact ring preparations. 2. Rapid application of ATP (100 nM-1 microM) via a U-tube superfusion system activated concentration-dependent inward currents with a latency to onset of less than 3 ms. The inward current decayed by more than 95% during a 2 s application of 300 nM and 1 microM ATP. 3. 2-meSATP (100 mM-1 microM) and alpha, beta-meATP (100 nM-1 microM) also evoked transient inward currents. The agonist order of potency was ATP = 2-meSATP > or = alpha, beta meATP. UTP (300 nM-1 microM) did not produce a change in the holding current. 4. A second application of ATP (300 nM and 1 microM) 10 min after the first, evoked currents which were one third of the initial amplitude. This decline was dependent upon activation of the P2-purinoceptor. Similar results were seen with 2-meSATP and alpha, beta-meATP (both 300 nM and 1 microM). Cross-desensitization was seen between ATP and 2-meSATP or alpha, beta-meATP. 5. Inward currents evoked by ATP, 2-meSATP and alpha, beta-meATP (all 1 microM) were abolished by the P2 purinoceptor antagonist suramin (100 microM). 6. Alpha, beta-meATP (100 nM-30 micro M), 2-meSATP (3 micro M- 100 micro M), ATP (3 micro M-I mM) and UTP (3 ELM I mM)produced concentration-dependent contractions of rat tail artery rings. When measured at a level equal to 50% of the maximum response to noradrenaline, the rank order of agonist potency was alpha,beta-meATP>>2-meSATP >UTP >ATP.7. This study shows that the rank order of agonist potency at the P2X-purinoceptor which mediates contractions of the rat isolated tail artery is very different from the potency order for evoking the inward current which initiates the contractions. It is concluded that this difference may be due to the relative absence of breakdown of some of the agonists in the single cell system compared with artery rings. PMID- 7858878 TI - Inhibition by SK&F 96365 of Ca2+ current, IL-2 production and activation in T lymphocytes. AB - 1. By use of whole cell patch-clamp and Indo-1 fluorescence studies of the Jurkat T leukaemic cell line, we show that the new organic antagonist of receptor mediated Ca2+ entry, SK&F 96365, inhibits the T cell Ca2+ current in a dose dependent fashion, with an IC50 of 12 microM. 2. SK&F 96365 also inhibits [3H] thymidine incorporation and interleukin-2 (IL-2) synthesis in peripheral blood lymphocytes. 3. SK&F 96365 has no effect on Ca2+ stores release or K+ channels. 4. This is the first account of an organic inhibitor of the T cell Ca2+ current. The ability of SK&F 96365 to inhibit IL-2 synthesis and cell proliferation suggests that a new class of related Ca2+ channel blockers can be developed as immunosuppressive agents. PMID- 7858879 TI - Role of endogenous endothelin in myocardial and coronary endothelial injury after ischaemia and reperfusion in rats: studies with bosentan, a mixed ETA-ETB antagonist. AB - 1. Previous studies suggested that endothelin-1 (ET-1) may play a role in myocardial ischaemia and reperfusion. This study was designed to test the effect of a new nonpeptide antagonist of endothelin ETA and ETB receptors, bosentan, on myocardial infarct size, ventricular arrhythmias, and coronary endothelial dysfunction after ischaemia and reperfusion. 2. Anaesthetized male Wistar rats were subjected to 20 min ischaemia (left coronary artery occlusion) followed by 1 h (for the evaluation of coronary endothelial dysfunction) or 2 h (for the evaluation of infarct size) reperfusion, or 5 min ischaemia followed by 15 min reperfusion (for the evaluation of reperfusion arrhythmias). Vascular studies were performed on 1.5-2 mm coronary segments (internal diameter 250-300 microns) removed distal to the site of occlusion and mounted in wire myographs for isometric tension recording. Area at risk and infarct size were determined by Indian ink injection and triphenyl tetrazolium staining, using computerized analysis of enlarged sections after colour video acquisition. 3. Bosentan, administered at a dose which virtually abolished the pressor response to big ET-1 (3 mg kg-1, i.v. before ischaemia) did not affect heart rate, arterial pressure or the rate pressure product before ischaemia, during ischaemia and during reperfusion. Bosentan did not affect the incidence of reperfusion-induced ventricular fibrillation (controls: 86%, n = 14; bosentan: 93%, n = 15), and did not modify infarct size (% of area at risk: controls: 63 +/- 4, n = 10; bosentan: 60 +/- 6, n = 8). Ischaemia followed by reperfusion markedly reduced the endothelium-dependent relaxations to acetylcholine(maximal response: sham: 59 +/- 4%, n = 9; ischaemia-reperfusion: 26+/- 6%, n = 8; P<0.01), characteristic of reperfusion-induced endothelial dysfunction, and this dysfunction was not prevented by bosentan (maximal response to acetylcholine: 25 +/-5%, n = 9; P<0.01 vs sham; P = NS vs ischaemia/reperfusion).4. These experiments suggest that endogenous endothelin does not contribute to myocyte or coronary endothelial injury in this rat model of ischaemia and reperfusion. PMID- 7858880 TI - Presence of neuropeptide Y in the rat seminal vesicle and its effects on noradrenaline- and nerve-induced contractions. AB - 1. Immunohistochemical and functional studies have been performed to localize and determine the effects of neuropeptide Y (NPY) in the rat seminal vesicle. 2. An abundant presence of NPY-immunoreactive nerves, mainly concentrated in the smooth muscle layer of the seminal vesicle was found. Chronic 6-hydroxydopamine treatment (four doses of 50 mg kg-1 i.p. on days 1, 2, 4 and 6; rats killed one week after the last injection) led to a large reduction but not abolition of the NPY-immunoreactivity. 3. NPY (1-250 nM) did not affect the resting tone of the seminal vesicle. 4. The seminal vesicle was contracted by electrical field stimulation (EFS) and by exposure to 5 microM noradrenaline (NA). These contractions were abolished by phentolamine (1 microM). Tetrodotoxin (0.5 microM) abolished EFS-evoked contractions but did not affect NA-evoked contractions. 5. Seminal vesicles, from animals chronically-treated with reserpine (5 mg kg-1 i.p. on days 1 and 2; rats killed on day 3), were contracted by NA but not by EFS. 6. NPY (0.25-250 nM), concentration-dependently, inhibited EFS-evoked contractions by up to 70% maximum inhibition. Contractions evoked by EFS with short trains of pulses were inhibited by NPY to a greater degree than those with longer trains. 7. NPY had no significant effect on NA-evoked contractions. 8. These data provide strong evidence that the motor transmission in rat seminal vesicle is predominantly if not exclusively, adrenergic. It is further concluded that a rich NPY-containing innervation is present in the smooth muscle layer of rat seminal vesicle. The primary effect of NPY is modulation of adrenergic motor transmission by a prejunctional inhibition of NA release. PMID- 7858881 TI - Y2-receptor-mediated selective inhibition of slow, inhibitory postsynaptic potential in submucous neurones of guinea-pig caecum. AB - 1. The subtype of neuropeptide Y receptor mediating the selective inhibition of the slow inhibitory postsynaptic potential (i.p.s.p.) of submucous neurones in guinea-pig caecum was investigated by use of conventional intracellular electrophysiological recording techniques. 2. Neuropeptide Y (NPY) (1-300 nM) was found to depress or abolish reversibly the slow i.p.s.p. evoked by focal stimulation of internodal fibre tracts. At low concentrations (1-30 nM), a reduction in the duration of the slow i.p.s.p. was often apparent before any inhibition of the amplitude of this synaptic potential. 3. These inhibitory effects of NPY were mimicked by peptide YY (PYY; 0.3-100 nM), NPY13-36 (1-300 nM) and NPY22-36 (10-100 nM); [Leu31,Pro34]NPY ([Pro34]NPY) and bovine pancreatic polypeptide (bPP) were without pre- or postsynaptic effects at concentrations of up to 300 nM. The IC50 +/- s.e. mean values for PYY, NPY, and NPY13-36 were 2.7 +/- 0.3, 7.8 +/- 2.1 and 30 +/- 4.8 nM, respectively, and were significantly different from each other. Thus, the apparent rank order of potency was PYY > NPY > NPY13-36 >> [Pro34]NPY and bPP. 4. In concentrations of up to 300 nM, NPY and its analogues had no depressant effects on the active and passive properties of the impaled neurone and did not affect the amplitude or duration of either cholinergic fast synaptic potentials or non-cholinergic, slow excitatory postsynaptic potentials (e.p.s.ps). Furthermore, none of these peptides altered the amplitude or time-course of changes in membrane potential induced by focal application of acetylcholine or noradrenaline. 5. It is, therefore, concluded that the selective inhibition of the slow i.p.s.p. is mediated by Y2 receptors,located presynaptically on noradrenergic nerve terminals. PMID- 7858882 TI - Regional and species differences in glyburide-sensitive K+ channels in airway smooth muscles as estimated from actions of KC 128 and levcromakalim. AB - 1. The purpose of the present experiments was to elucidate the differences in actions of two K+ channel openers, KC 128 and levcromakalim, on the carbachol induced contraction, membrane potential and 86Rb+ efflux of the dog tracheal and bronchial smooth muscles. Furthermore, we compared the effects of these agents on guinea-pig and human airway smooth muscles. 2. In the dog tracheal and bronchial smooth muscle tissues, levcromakalim induced a concentration-dependent relaxation of the carbachol-induced contraction. The IC50 values were 0.35 microM (pIC50: 6.46 +/- 0.10, n = 9) and 0.55 microM (pIC50: 6.26 +/- 0.07, n = 5), respectively. KC 128 relaxed bronchial smooth muscles precontracted by carbachol with an IC50 value of 0.19 microM (pIC50: 6.73 +/- 0.10, n = 7). However, KC 128 had almost no effect on the contraction evoked by carbachol in the trachea (IC50 > 10 microM). The relaxations induced by levcromakalim and KC 128 were antagonized by glyburide (0.03-1 microM) but not by charybdotoxin (100 nM). 3. Levcromakalim (1 microM) hyperpolarized the membrane of both dog tracheal and bronchial smooth muscle cells, whereas KC 128 (1 microM) hyperpolarized the membrane of bronchial but not of tracheal smooth muscle cells. 4. Levcromakalim (10 microM) increased 86Rb+ efflux rate from both tracheal and bronchial smooth muscle tissues but KC 128 (10 microM) increased 86Rb+ efflux rate only from bronchial and not tracheal smooth muscle tissues. Glyburide (1 microM) prevented the hyperpolarization and the 86Rb+ efflux induced by these agents at the same concentration as observed for mechanical responses. 5. Both KC 128 and levcromakalim relaxed the guinea-pig isolated tracheal smooth muscles precontracted by carbachol (100 nM), histamine (3 micro M) or U46619 (10 nM). KC 128 was approximately 10 times more potent than levcromakalim for each agonist.6. In human bronchial smooth muscles, levcromakalim but not KC 128 induced a concentration dependent relaxation of the carbachol-induced contraction.7. It is concluded that KC 128 has relaxant and hyperpolarizing effects in the dog bronchial and guinea-pig tracheal smooth muscles, but not in the dog tracheal and human bronchial smooth muscles.On the other hand, levcromakalim acts consistently on all the above airway smooth muscle tissues.These results indicate that there are regional and species differences in distribution of K+ channels, and at least two different K+ channel opener- and glyburide-sensitive K+ channels are present in the dog airway smooth muscles. PMID- 7858883 TI - The sensitivity of nicotinic synapses in bullfrog sympathetic ganglia to alpha bungarotoxin and neuronal-bungarotoxin. AB - 1. The sensitivity of nicotinic synapses to alpha-bungarotoxin (alpha-Bgt) and neuronal-bungarotoxin (n-Bgt) was measured in the B and C cell systems of bullfrog paravertebral sympathetic ganglia 9 and 10 by recording extracellular compound postganglionic action potentials from the rami communicantes. 2. High concentrations (10 microM) of alpha-Bgt applied for up to 8 h had no effect upon synaptic transmission in either the B or C cell system. Ganglia pretreated with collagenase were also insensitive to alpha-Bgt. In control experiments on isolated sartorius muscle preparations, nerve-evoked twitches were fully blocked by 30-100 nM alpha-Bgt. 3. Nicotinic transmission in the B and C cell systems was reversibly blocked by 30-300 nM n-Bgt. Block appeared within 25-45 min of exposure to toxin and reversed fully with a half-time of 40-80 min. This was indistinguishable from washout times after block by 100 microM (+)-tubocurarine. 4. The results demonstrate close parallels between the bungarotoxin sensitivity of neuronal nicotinic receptors mediating ganglionic transmission in functional subclasses of bullfrog sympathetic neurones and the bungarotoxin sensitivity which has been reported for autonomic in avian and mammalian preparations. PMID- 7858884 TI - Location of the sulphonylurea receptor at the cytoplasmic face of the beta-cell membrane. AB - 1. In insulin-secreting cells the location of the sulphonylurea receptor was examined by use of a sulphonylurea derivative representing the glibenclamide molecule devoid of its cyclohexy moiety (compound III) and a benzenesulphonic acid derivative representing the glibenclamide molecule devoid of its cyclohexylurea moiety (compound IV). At pH 7.4 compound IV is only present in charged form. 2. Lipid solubility declined in the order tolbutamide > compound III > compound IV. 3. The dissociation constant (KD) for binding of compound IV to the sulphonylurea receptor in HIT-cells (pancreatic beta-cell line) was similar to the KD value for tolbutamide and fourfold higher than the KD value for compound III. 4. In mouse pancreatic beta-cells, drug concentrations inhibiting adenosine 5'-triphosphate-sensitive K+ channels (KATP-channels) half-maximally (EC50) were determined by use of the patch-clamp technique. When the drugs were applied to the extracellular side of outside-out or the intracellular side of inside-out membrane patches, the ratio of extracellular to intracellular EC50 values was 281 for compound IV, 25.5 for compound III and 1.2 for tolbutamide. 5. In mouse pancreatic beta-cells, measurement of KATP-channel activity in cell attached patches and recording of insulin release displayed much higher EC50 values for compound IV than inside-out patch experiments. A corresponding, but less pronounced difference in EC50 values was observed for compound III, whereas the EC50 values for tolbutamide did not differ significantly. 6. It is concluded that the sulphonylurea receptor is located at the cytoplasmic face of the beta cell plasma membrane. Receptor activation is induced by the anionic forms of sulphonylureas and their analogues. PMID- 7858885 TI - Contribution of intercellular adhesion molecule 1 (ICAM-1) to the pathogenesis of splanchnic artery occlusion shock in the rat. AB - 1. It has been suggested that leukocytes play a key role in the pathogenesis of splanchnic artery occlusion shock. Intercellular adhesion molecule 1 (ICAM-1) is an adhesion molecule of crucial importance in the phenomenon of leukocyte accumulation. 2. We investigated the involvement of ICAM-1 in the pathogenesis of splanchnic artery occlusion shock. Splanchnic artery occlusion (SAO) shock was induced in anaesthetized rats by clamping splanchnic arteries for 45 min. Sham operated animals were used as controls. Survival time, serum tumour necrosis factor-alpha (TNF-alpha), white blood cell (WBC) count, mean arterial blood pressure, myeloperoxidase activity (MPO; studied as a quantitative means to assess leukocyte accumulation) and the responsiveness to acetylcholine of aortic rings were investigated. SAO shocked rats had a decreased survival time (90 +/- 9.5 min, while sham-shocked rats survived more than 4 h), reduced mean arterial blood pressure, increased serum levels of TNF-alpha (201 +/- 10 mu ml-1) and MPO activity in the ileum (0.15 +/- 0.03 mu x 10(-3) per g tissue) and in the lung (1.9 +/- 0.8 mu x 10(-3) per g tissue), leukopenia and reduced responsiveness to acetylcholine (ACh, 10 nM-10 microM) of aortic rings. 3. Administration of monoclonal antibody raised against rat ICAM-1 significantly increased survival time (225 +/- 9 min), reduced leukopenia and MPO activity both in the ileum (0.031 +/- 0.003 mu x 10(-3) per g tissue) and in the lung 0.23 +/- 0.03 mu x 10( 3) per g tissue), improved the cardiovascular changes and restored the responsiveness to ACh of aortic rings. 4. Our findings are consistent with an involvement of adhesion mechanisms in vivo in the pathogenesis of SAO shock and suggest that specific adhesion mechanisms, which support leukocyte accumulation,may represent potentially important therapeutic targets in circulatory shock. PMID- 7858886 TI - Regulation of nicotinic receptors in rat brain following quasi-irreversible nicotinic blockade by chlorisondamine and chronic treatment with nicotine. AB - 1. Chronic administration of nicotinic agonists in vivo increases the density of brain nicotinic binding sites. It has been proposed that this up-regulation results from agonist-induced functional blockade of nicotinic receptors. This hypothesis was tested by examining post mortem [3H]-nicotine and [125I]-alpha bungarotoxin ([125I]-alpha BTX) binding following treatment in vivo with the quasi-irreversible and insurmountable CNS nicotinic blocker chlorisondamine, given either alone or in combination with chronic nicotine administration. 2. In rats that had not received chlorisondamine pretreatment, chronic nicotine administration (0.6 mg kg-1 s.c., twice daily for 12 days) increased [3H] nicotine binding density (Bmax) in forebrain tissue sections by 19%, with no change in the apparent dissociation constant (KD). Chlorisondamine (10 mg kg-1, s.c.), given once prior to the chronic treatment phase, neither increased [3H] nicotine binding by itself, nor altered the extent of nicotine-induced up regulation. Nevertheless, chlorisondamine pretreatment resulted in a persistent blockade of CNS nicotinic receptors, as demonstrated by complete block of acute locomotor responses to nicotine. 3. In a second experiment, [3H]-nicotine and [125I]-alpha BTX binding was measured in tissue homogenates prepared from several brain regions. In the absence of chlorisondamine pretreatment, chronic nicotine administration (1 mg kg-1 s.c., twice daily for 12 days) increased the Bmax of [3H]-nicotine binding in the cerebral cortex (by 34%), striatum (by 28%), midbrain (by 16%) and hippocampus (by 36%); KD was unchanged. As before, this up regulation was neither mimicked nor blocked by chlorisondamine pretreatment (10 mg kg-1, s.c., given twice), despite persistent blockade of acute locomotor responses to nicotine. Chronic nicotine treatment also increased the Bmax (but not KD) of [125I]-alpha BTX binding in cerebral cortex (by 35%), hippocampus (by 46%) and midbrain (by 35%). Chlorisondamine altered neither Bmax nor KD when given alone, but significantly attenuated the nicotine-induced up-regulation of toxin binding sites in midbrain, with a similar trend in the other two regions.4. The finding that chronic receptor blockade neither mimicked nor blocked the agonist-induced up-regulation of [3H]-nicotine binding sites suggests that up regulation of these receptors is not determined by their functional status. In contrast, it appears that chronic nicotine-induced up-regulation of[125I]-alpha BTX binding sites may result from receptor activation. PMID- 7858887 TI - Effect of cytoplasmic pH on Ca(2+)-stimulated eicosanoid biosynthesis in human platelets. AB - 1. We have investigated the effect of cytoplasmic pH (pHi) on the relationship between platelet cytoplasmic Ca2+ concentration ([Ca2+]i) and eicosanoid biosynthesis. Stirred gel-filtered human platelets loaded with fluorescent indicators of Ca2+ and H+ were suspended in balanced salt solutions at 37 degrees C. [Ca2+]i was controlled by calcium ionophore (ionomycin). Increased [Ca2+]i was associated with increased production of thromboxane A2 (TXA2) as determined by radioimmunoassay of its stable hydrolysis product TXB2, and of 12-hydroxy eicosatetraenoic acid (12-HETE) measured by high performance liquid chromatography. 2. Varying pHi with a K+/H+ ionophore (nigericin) in platelets suspended in K+ rich solutions of pH 6.8, 7.4 or 7.8 with subsequent resuspension in solution of pH 7.4 containing albumin (1 g l-1) and Ca2+ (1 mM) resulted in pHi of 6.72 +/- 0.05, 7.31 +/- 0.02 and 7.71 +/- 0.04 (mean +/- s.e. mean, n = 5). Ionomycin (1.2 microM) increased [Ca2+]i by 97.1 +/- 17.6, 191.9 +/- 48.7 and 322.8 +/- 55.7 nM at the different values of pHi respectively; TXB2 production was 0.7 +/- 0.2, 2.1 +/- 0.4 and 10.7 +/- 3.3 ng micrograms-1 protein, and 12 HETE production was 150.9 +/- 68.2, 184.4 +/- 77.9 and 302.3 +/- 62.8 ng micrograms-1 protein. 3. Ammonium chloride (50 mM) caused a small reduction in pHo while increasing pHi from 7.32 +/- 0.04 to 7.89 +/- 0.05 and increasing ionomycin (1.2 microM)-induced [Ca2+]i responses from 94.1 +/- 67.3 to 721.6 +/- 288.3 nM. TXB2 production increased from 3.1 +/- 2.1 to 17.3 +/- 8.2 and 12-HETE production increased from 100.5 +/- 26.7 to 203.2 +/- 36.4 ng microg-1 protein. Responses of [Ca2+]i and TXB2 production to epoxymethano prostaglandin H2 (U46619, an endoperoxide-thromboxane receptor agonist) increased significantly in the presence of NH4C1.4. Alterations of pHi (such as may occur under pathological conditions) influence [Ca2+]i responses and eicosanoid synthesis in human platelets. PMID- 7858888 TI - Identification of renal natriuretic peptide receptor subpopulations by use of the non-peptide antagonist, HS-142-1. AB - 1. The renal actions of natriuretic peptides are dictated by the distribution of guanylyl cyclase-linked (NPRA and NPRB) and non-guanylyl cyclase-linked (NPRC) receptors. Natriuretic peptide receptors have previously been distinguished on the basis of their differential affinity for peptide fragments and analogues; however, most of the available ligands are not fully selective. We have used the specific guanylyl cyclase-linked receptor antagonist, HS-142-1, to investigate the differential distribution of natriuretic peptide receptor subtypes in the human, bovine and rat kidney. 2. Specific, high affinity 3-([125I]-iodotyrosyl) rat-ANP-(1-28)([125I]-rANP1-28) binding sites were identified in all three species, localized to glomeruli, inner medulla, intrarenal arteries and regions in the outer medulla corresponding to vasa recta bundles. Binding sites were also identified in the smooth muscle lining of the hilar region in the bovine and rat kidney. 3. In the rat, [125I]-rANP1-28 binding was inhibited by unlabelled peptide sequences with a rank order of potency (rANP1-28 > pCNP1-22 > C-ANP4-23). The glomeruli exhibited a heterogeneous population of binding sites, C-ANP4-23 and pCNP1-22 producing a significantly better fit to a two component inhibition curve compared to the single component curve for rANP1-28. 4. Competitive inhibition experiments with the receptor selective ligands, C-ANP4-23 and HS-142 1, suggested that, like the rat, human and bovine glomeruli possessed a heterogeneous population of binding sites, whilst those in the inner medulla and intrarenal arteries of all three species represented a homogeneous population. Rat glomeruli exhibited a high proportion (>80%) of the NPRc receptor subtype whereas in human and bovine glomeruli this receptor represented less than 20% of the total population, the majority of binding sites being HS-142-1-sensitive.5. C ANP4-23 exhibited a significantly higher inhibitory potency for binding sites in rat glomeruli compared to those in human and bovine kidney whilst HS-142-1 was significantly more potent in the rat and bovine kidney compared to man. No evidence was found to suggest the presence of a renal NPRBreceptor subtype.6. The relative density, affinity and proportion of natriuretic receptor subtypes in the kidney exhibit significant species differences. HS-142-1 may be a valuable tool in further elucidating the localization and function of these receptors, but heterogeneity between species should be considered when selecting experimental models. PMID- 7858889 TI - The role of bradykinin B1 receptors in the maintenance of intra-articular plasma extravasation in chronic antigen-induced arthritis. AB - 1. The role of bradykinin B1 and B2 receptors in bradykinin- and des-Arg9 bradykinin-induced plasma extravasation in normal and inflamed rat knee joints was investigated by use of an antigen-induced model of chronic arthritis. A modification of an Evans blue extraction technique allowed the unstimulated (basal) plasma extravasation to be assessed in this model. The contributions of bradykinin B1 and B2 receptors towards basal synovial plasma extravasation were determined. 2. In normal knees, intra-articular injection of bradykinin (BK) induced plasma extravasation in a potent, dose-dependent manner with a threshold of 0.01 nmol and an ED50 of 0.1 nmol. In day 5 arthritic knees, basal plasma extravasation was substantially enhanced. Lower doses of BK had no demonstrable effect and increases above basal extravasation were first observed at 0.1 nmol. Thereafter the dose-response mirrored the response in normal knees and the maximal response was unaltered. 3. The B1 agonist, des-Arg9-BK, induced slight but significant plasma extravasation in normal knees but was less potent than bradykinin. This response was inhibited by the B1 receptor antagonist, des-Arg9, [Leu8]-BK. Lower doses of des-Arg9-BK bradykinin did not significantly increase basal extravasation in day 5 arthritic knees but, in contrast to BK, the maximal response was significantly enhanced. 4. The B2 antagonist, Hoe 140, inhibited BK induced plasma extravasation in normal joints over a dose-range of 0.1-1.0 nmol but was relatively inactive in day 5 inflamed knees. The B1 receptor antagonist, des-Arg9, [Leu8]-BK, was relatively inactive in normal joints but showed increased potency against BK-induced plasma extravasation in day 5 arthritic joints.5. Hoe 140 and des-Arg9,[Leu8]-BK both inhibited basal extravasation in arthritic joints on days 1 and 5 post-challenge in a dose-dependent fashion. Whilst Hoe 140 was the more potent inhibitor on day 1, it was less potent than des-Arg9,[Leu8]-BK on day 5.6. Although the majority of responses to BK in normal tissue are mediated via B2 receptors, a small population of B1 receptors may exist in normal joint tissues. The data presented in this study suggest an evolving role for B1 receptors in the mediation of plasma extravasation in inflamed joint tissues. A role for BK antagonists in the treatment of arthritis is also suggested. PMID- 7858891 TI - Role of K+ channels in the vasodilator response to bradykinin in the rat heart. AB - 1. The role of K+ channels in the nitric oxide (NO)-independent coronary vasodilator effect of bradykinin was examined in the Langendorff heart preparation in which nitroarginine was used to inhibit NO synthesis and elevate perfusion pressure; cyclo-oxygenase was inhibited with indomethacin. 2. The K+ channel inhibitors, tetraethylammonium, procaine and charybdotoxin, but not glibenclamide, further increased perfusion pressure suggesting a role for K+ channels, other than ATP-sensitive K+ channels, in the regulation of coronary vascular tone under the experimental conditions adopted here. 3. The non-specific K+ channel inhibitors, tetraethylammonium and procaine, reduced vasodilator responses to bradykinin and cromakalim but not those to nitroprusside in the perfused heart treated with nitroarginine and indomethacin. 4. Glibenclamide, an inhibitor of ATP-sensitive K+ channels, reduced vasodilator responses to cromakalim but did not affect those to bradykinin or nitroprusside. 5. Charybdotoxin, an antagonist of Ca(2+)-activated K+ channels, inhibited responses to bradykinin but did not affect those to cromakalim or nitroprusside. 6. Nifedipine inhibited vasodilator responses to bradykinin and cromakalim without affecting those to nitroprusside. 7. Inhibition of cytochrome P450 with clotrimazole reduced responses to bradykinin but did not modify those to cromakalim or nitroprusside. 8. These results suggest that bradykinin utilizes a Ca(2+)-activated K+ channel to produce vasodilatation in the rat heart. PMID- 7858890 TI - Inhibition by gomisin C (a lignan from Schizandra chinensis) of the respiratory burst of rat neutrophils. AB - 1. The possible mechanisms of action of the inhibitory effect of gomisin C on the respiratory burst of rat neutrophils in vitro was investigated. 2. The peptide formyl-Met-Leu-Phe (FMLP) induced superoxide anion (O2-) formation and O2 consumption, which was inhibited by gomisin C in a concentration-dependent manner (IC50 21.5 +/- 4.2 micrograms ml-1 for O2- formation). Gomisin C also suppressed O2- formation and consumption at low concentrations of phorbol myristate acetate (PMA) with an IC50 value of 26.9 +/- 2.1 micrograms ml-1 for O2- formation. However, gomisin C did not affect the responses induced by a high concentration of PMA. 3. Gomisin C had no effect on O2- generation and uric acid formation in the xanthine-xanthine oxidase system, and failed to alter O2- generation during dihydroxyfumaric acid (DHF) autoxidation, indicating that it does not scavenge superoxide. 4. Like trifluoperazine (TFP), gomisin C attenuated the activity of PMA-activated neutrophil particulate NADPH oxidase in a concentration-dependent manner. 5. Gomisin C reduced the elevations of cytosolic free Ca2+ in neutrophils stimulated by FMLP in the presence or absence of EDTA. Cyclopiazonic acid (CPA) induced the release of Ca2+ from intracellular stores and this was also reduced by gomisin C. However, the Ca2+ influx pathway activated by CPA was not affected by gomisin C. 6. The cellular cyclic AMP level was markedly increased by forskolin, but not by gomisin C. Moreover, the inositol phosphate levels in FMLP activated neutrophils were not affected by gomisin C. 7. These results show that the inhibitory action of gomisin C on the respiratory burst is not mediated by changes in cellular cyclic AMP or in inositol phosphates, or by scavenging O2- released from neutrophils, but may be mediated partly by the suppression of NADPH oxidase and partly by the decrease of cytosolic Ca2+ released from an agonist sensitive intracellular store. PMID- 7858892 TI - Blockade by dendrotoxin homologues of voltage-dependent K+ currents in cultured sensory neurones from neonatal rats. AB - 1. Homologues of dendrotoxin (Dtx) were isolated from the crude venom of Green and Black Mamba snakes and examined for K+ channel blocking activity in neonatal rat dorsal root ganglion cells (DRGs) by whole-cell patch clamp recording. 2. Outward potassium current activated by depolarization was composed of two major components: a slowly inactivating current (SIC, tau decay approximately 50 ms, 200 ms and 2s), and a non-inactivating current (NIC, tau decay > 2 min). Tail current analysis revealed two time constants of deactivation of total outward current, 3-12 ms and 50-150 ms (at -80 mV) which corresponded to SIC and NIC, respectively. 3. All the homologues (alpha-, beta-, gamma- and delta-Dtx and toxins I and K) blocked outward current activated by depolarization in a dose dependent manner. The most potent in blocking total outward current was delta-Dtx (EC50 of 0.5 +/- 0.2 nM), although there were no statistically significant differences in potency between any of the homologues. 4. Qualitative differences in the nature of the block were noted between homologues. In particular, the block by delta-Dtx was time-dependent, whereas that by alpha-Dtx was not. 5. alpha-Dtx was a much better blocker of SIC (EC50 = 1.0 +/- 0.4 nM) than was delta Dtx (EC50 = 17.6 +/- 5.8 nM). Furthermore, delta-Dtx was selective for NIC (EC50 +/- 0.24 +/- 0.03 nM) over SIC and reduced the slow component of tail currents (NIC), preferentially. On the other hand, a-Dtx did not significantly distinguish between SIC and NIC although tail current analysis showed that a Dtxpreferentially reduced the fast component of tail currents (SIC).6. The results confirm, using direct electrophysiological methods, that homologues of dendrotoxins from Mamba snake venom block K+ channels in rat sensory neurones. Furthermore, a-Dtx and 6-Dtx distinguish between sub-types of K+ channels in these cells and may thus be useful pharmacological tools in other neuronal K+ channel studies. PMID- 7858893 TI - Role of 5-HT3 receptors in basal and K(+)-evoked dopamine release from rat olfactory tubercle and striatal slices. AB - 1. The present study was aimed at examining the role of 5-HT3 receptors in basal and depolarization-evoked dopamine release from rat olfactory tubercle and striatal slices. [3H]-dopamine ([3H]-DA) release was measured in both brain regions and endogenous dopamine release from striatal slices was also studied. 2. The selective 5-HT3 receptor agonist 2-methyl-5-HT (0.5-10 microM) produced a concentration-dependent increase in [3H]-DA efflux evoked by K+ (20 mM) from slices of rat olfactory tubercle. 1-Phenylbiguanide (PBG) and 5-HT also increased K(+)-evoked [3H]-DA efflux. 3. 5-HT (1-100 microM) increased in a concentration dependent manner basal [3H]-DA release from olfactory tubercle and striatal slices as well as endogenous DA release from striatal slices. The selective 5-HT3 receptor agonists 2-methyl-5-HT and 1-phenylbiguanide were weaker releasing agents. In all cases, the release was Ca2+ independent and tetrodotoxin insensitive. 4. 5-HT3 receptor antagonists such as ondansetron, granisetron and tropisetron (0.2 microM) significantly blocked the enhanced K(+)-evoked [3H]-DA efflux from rat olfactory tubercle slices induced by 2-methyl-5HT. A ten fold higher concentration of the 5-HT2 receptor antagonist ketanserin was ineffective. 5. Much higher concentrations, up to 50 microM, of the same 5-HT3 receptor antagonists did not block the increase in basal [3H]-DA release from striatal or olfactory tubercle slices induced by 5-HT or the release of endogenous DA induced by 5-HT from striatal slices.2+ off PMID- 7858894 TI - Pharmacological profile of the ATP-mediated increase in L-type calcium current amplitude and activation of a non-specific cationic current in rat ventricular cells. AB - 1. The pharmacological profile of the ATP-induced increase in ICa amplitude and of ATP activation of a non-specific cationic current, IATP, was investigated in rat ventricular cells. 2. The EC50 values for ICa increase and IATP activation were 0.36 microM and 0.76 microM respectively. Suramin (10 microM) and cibacron blue (1 microM) competitively antagonized both effects of ATP. 3. The rank order of efficacy and potency of ATP analogues in increasing ICa amplitude was 2 methylthio-ATP approximately ATP approximately ATP gamma S. The derivatives alpha,beta-methylene-ATP, beta,gamma-methylene-ATP and beta,gamma-imido-ATP up to 500 microM had no significant effects. 4. The rank order of efficacy of ATP analogues in activating a non-specific cationic current, IATP, was 2-methylthio ATP > ATP >> ATP gamma S. The rank order of potency was 2-methylthio-ATP approximately ATP. The EC50 of ATP gamma S could not be determined owing to its very low efficacy. 5. The ATP analogues alpha,beta-methylene-ATP, beta,gamma methylene-ATP and beta,gamma-imido-ATP at 500 microM did not activate IATP but acted as antagonists of activation of IATP by ATP. 6. The results suggest that the increase in ICa amplitude induced by external ATP is due to activation of P2Y purinoceptors. 7. The mechanism of IATP activation remains to be determined before the receptor subtype involved can be deduced. PMID- 7858895 TI - The transhepatic action of ATP on the hepatic arterial and portal venous vascular beds of the rabbit: the role of nitric oxide. AB - 1. The effect of bolus administration of adenosine 5'-triphosphate (ATP) into the portal vein on hepatic arterial pressure (the transhepatic action of ATP) and portal venous pressure, and the contribution of nitric oxide towards these responses, was studied in the in vitro dual-perfused rabbit liver. 2. At basal tone, hepatic arterial and portal venous vasoconstriction followed ATP injection, while at a tone raised with methoxamine (10(-6)-10(-5) M) ATP caused hepatic arterial vasodilatation, and a phasic vasodilatation followed by vasoconstriction in the portal venous vascular bed. 3. To determine whether the transhepatic arterial dilatation was due to the diffusion of nitric oxide (NO) from the portal venous vasculature, NG-nitro-L-arginine methyl ester (L-NAME, 100 microM), an inhibitor of NO synthesis, was infused selectively into the portal vein. L-NAME infusion potentiated portal venous vasoconstriction to ATP (-log M ED50 5.32 +/- 0.31 to 6.51 +/- 0.43, P < 0.05, Student's paired t test) indicating the possible inhibition of a NO-mediated vasodilator component of the portal venous response to ATP. There was, however, no demonstrable difference in the transhepatic arterial vasodilatation induced by ATP during this infusion. 4. Simultaneous perfusion of both the hepatic arterial and portal venous inflows with L-NAME (100 microM) resulted in a significant decrease in the amplitude of hepatic arterial responses to ATP demonstrating that these responses were ultimately mediated by an NO-dependent mechanism. 5. This study has thus demonstrated a vasodilator component of the portal venous response to ATP that is NO-mediated. It also provides evidence that it is not portally-derived NO, but NO released from the hepatic arterial vascular bed, that accounts for the hepatic arterial vasodilatation to intra-portal administration of ATP. This implies that ATP itself, and not a second messenger, diffuses from the portal venous to hepatic arterial vascular bed to elicit the hepatic arterial response. PMID- 7858897 TI - Atherosclerosis: cell biology and lipoproteins. PMID- 7858896 TI - Long-lasting inhibitory activity of the hetrazepinic BN 50730 on exudation and cellular alterations evoked by PAF and LPS. AB - 1. Inhibitory effects of the hetrazepinic derivative BN 50730 on the rat pleural inflammatory response, triggered by PAF or lipopolysaccharides (LPS), were examined. The type of pharmacological blockade exerted by this antagonist in in vitro assays of eosinophil chemotaxis and platelet aggregation were also investigated. 2. Intrathoracic injection of PAF (1 microgram per cavity) caused a 4 fold increase in the extravasated protein within 15 min and led to a marked eosinophil accumulation 24 h post-challenge. BN 50730 (0.5-10 micrograms per cavity) inhibited exudation by PAF dose-dependently without modifying the response induced by histamine, bradykinin or 5-hydroxytryptamine (5-HT). 3. The kinetics of the inhibitory effect on exudation revealed that the actions of WEB 2086 and BN 52021 (10 micrograms per cavity) were over within 2 and 4 h respectively, whereas BN 50730 (10 micrograms per cavity) retained 80% of its inhibitory activity for 4 days. 4. Oral treatment with BN 50730 (10-20 mg kg-1, 1 h beforehand) suppressed the leucocyte accumulation and late eosinophilia observed 6 and 24 h after PAF respectively, but did not modify the eosinophilia induced by leukotriene B4 (LTB4) or bradykinin. BN 50730 also failed to reduce the eosinophil accumulation induced by LPS but drastically inhibited the neutrophil influx. 5. The pre-incubation of rat peritoneal eosinophils for 10 min with BN 50730 (30 nM-1 microM) dose-dependently inhibited the chemotaxis induced by PAF (0.1 microM) in vitro. The IC50 values for BN 52021, WEB 2086 and BN 50730 in this system were 5, 5 and 0.05 microM respectively. 6. In separate assays, rat peritoneal eosinophils and rabbit washed platelets were preincubated with BN 50730 or WEB 2086 (1 pM) then subjected to a series of at least two consecutive washings in order to remove the antagonist from the receptor environment. Under such conditions, only the cells pretreated with WEB 2086 recovered the sensitivity to the lipid.7. We conclude that BN 50730 is a potent, specific and long-acting PAF antagonist and its effect seems to result from a high affinity and non-competitive interaction of the drug with the PAF receptor. PMID- 7858898 TI - Nutrition and therapeutics. PMID- 7858899 TI - Genetics and molecular biology. PMID- 7858901 TI - Cardiovascular disease and hyperlipidaemia. PMID- 7858900 TI - Lipid metabolism. PMID- 7858902 TI - Atherosclerosis: cell biology and lipoproteins. PMID- 7858903 TI - Clinical chemistry and coagulation. PMID- 7858904 TI - Atherosclerosis: cell biology and lipoproteins. PMID- 7858905 TI - Endothelial cells and atherosclerosis: lipoprotein metabolism, matrix interactions, and monocyte recruitment. AB - The endothelial cell and subendothelial cell matrix provide a stage for several interactions that mediate lipoprotein transport, retention, and modification during atherogenesis. Many novel mechanisms in these processes have been uncovered. The endothelium regulates circulating plasma lipoproteins by acting as the site of action of the triglyceride hydrolyzing enzyme, lipoprotein lipase. Endothelial cells synthesize proteoglycans that anchor this enzyme, affect the actions of growth factors, and directly interact with some classes of lipoproteins. Recent studies have provided insights into the initiation of monocyte entry and the regulation of macrophage lipid uptake. Endothelial cell adhesion molecules are required for the recruitment of monocytes and, therefore, are essential to the atherosclerotic process. Understanding cellular and molecular pathways underlying the early stages of atherosclerosis may provide a rational basis for therapeutic intervention of this disease. PMID- 7858906 TI - The role of smooth muscle cells in atherosclerosis. AB - The smooth muscle cells within the human atherosclerotic plaque differ from the cells of the media. These phenotype changes, the mechanisms responsible, and their possible relevance to the formation of the plaque are discussed. PMID- 7858907 TI - Lipoprotein receptors and atherogenic receptor-mediated mechanisms. AB - The liver plays a decisive role in the regulation of the plasma levels of atherogenic lipoproteins. The primary liver interaction site of chylomicron remnants and VLDL remnants (beta-VLDL) is still unidentified, whereas the subsequent cellular uptake is likely to be mediated in concert by the LDL receptor-related protein and the LDL receptor. The nature of the primary interaction site of remnants (remnant receptor) might be a liver-specific proteoglycan or a liver-specific protein. Atherogenic modified LDL can be recognized by a family of scavenger receptors. A newly identified 95 kDa protein forms the most likely candidate for mediating the in-vivo uptake of oxidized LDL from the circulation and may, therefore, protect the body against the presence of oxidized LDL in the blood compartment. PMID- 7858908 TI - Heterogeneity of plasma low-density lipoproteins and atherosclerosis risk. AB - Increased levels of IDL and small, dense LDL are associated with the risk of coronary artery disease. Possible mechanisms include increased susceptibility of small, dense LDL to oxidation, and to other pathologic effects, such as increased retention in the arterial wall. Beneficial effects of a low-fat diet and certain lipid-lowering therapies on the levels and properties of small, dense LDL or their precursors may contribute substantially to the reductions in coronary atherosclerosis observed in several lipid-lowering trials. PMID- 7858909 TI - The role of native apolipoprotein B-containing lipoproteins in atherosclerosis: cellular mechanisms. AB - Apolipoprotein B-containing lipoproteins play a central role in the pathogenesis of atherosclerosis. The processes that determine the atherogenicity of these lipoproteins, however, remain unclear. A new development that involves the interactions of lipoproteins, enzymes, apolipoproteins, and cell-surface heparan sulphate may explain, at least in part, the enhanced atherogenicity of these lipoproteins. In addition, the development of specific transgenic apolipoproteins, and apolipoprotein-deficient mice models that develop atherosclerosis, provide new tools for studies on the role of native apolipoprotein-B containing lipoproteins in atheroma formation. PMID- 7858910 TI - The role of apolipoprotein A-I-containing lipoproteins in atherosclerosis. AB - The inverse relationship between HDL and apolipoprotein A-I concentrations and the risk for premature atherosclerosis is well established, but the mechanism whereby apolipoprotein A-I offers protection is still somewhat elusive. Recent studies suggest that a specific subpopulation within the lipoprotein (AI) subclass may be more effective than others in promoting cholesterol efflux from cells. In addition, it appears that the lipid-free form of apolipoprotein A-I may have an important role in the antiatherosclerotic process. Unique new functions of apolipoprotein A-I-containing particles in modulating cytokines and lipid hydroperoxide transport, together with their role in antiatherogenesis, are also discussed. Current research with transgenic mice, however, indicates that apolipoprotein A-II must be taken into consideration in understanding the development of atherosclerosis, because it appears to be a potent antagonist for the protective properties of apolipoprotein A-I. PMID- 7858911 TI - Lipoprotein modification: cellular mechanisms. AB - Oxidatively damaged LDL may be of pivotal importance in atherogenesis. This review focuses on the cellular pathways involved in LDL oxidation in vitro, the biological properties of oxidized LDL, and the implications of these findings for the role of LDL oxidation in the development of atherosclerosis. PMID- 7858913 TI - The arterial wall and the atherosclerotic lesion. AB - The role of the lipid-rich core region in atherogenesis is beginning to be understood, from its inception in early lesions to its catastrophic effects in promoting plaque rupture in late lesions. Besides the lipid-rich core, recent studies on human and animal atherosclerosis have drawn attention to atherogenic lipoproteins larger than LDL, unesterified cholesterol in lesions, apolipoprotein E as an antiatherogenic factor, macrophages as atherogenic effector cells, and unexpectedly slow rates of smooth muscle cell proliferation. PMID- 7858912 TI - Mechanisms of oxidation, antioxidants, and atherosclerosis. AB - The oxidation of LDL by a number of different cell types has been studied and described. Cells may be able to initiate and seed peroxides in LDL but, in the absence of metals or peroxidase activity, may not be able to oxidize the lipoprotein. Monocyte-derived macrophages and neutrophils are able to initiate and propagate lipid peroxidation. The oxidative role of smooth muscle cells and endothelial cells may be restricted solely to the generation of hydrogen peroxide or other oxidants. The above rationale presents a problem in using LDL preparations that already contain peroxides, and in using media that generate peroxides independently of cells. PMID- 7858914 TI - Relationships of thrombosis and fibrinolysis to atherosclerosis. AB - The importance of the haemostatic system in predisposing to or precipitating coronary heart disease has gained increasing recognition. Major advances have been made in our understanding of the mechanisms resulting in hypercoagulability and impaired fibrinolytic function. Emphasis is placed on the role of dyslipoproteinaemia and insulin resistance. PMID- 7858915 TI - Embryology of the cerebral vasculature. AB - Although much remains to be learned about the embryology of the intracranial vasculature, much of the developmental pathways of the intracranial vascular system are now apparent. Understanding these pathways offers the potential to appreciate the nature of such arterial anomalies as the azygos anterior cerebral artery and the trigeminal artery and such venous anomalies as the vein of Galen malformation and the venous angioma. PMID- 7858916 TI - Anatomy of the cerebral vasculature. AB - In this article, cerebral arterial and venous anatomy are reviewed. Although angiographic anatomy remains pertinent to neurosurgery and neurointerventional radiology, much of the previous concerns about vascular displacements (i.e., shifts) are no longer relevant in the age of MR imaging. Today, the MR anatomy of intracranial vessels is much more important. PMID- 7858917 TI - Hemorrhage and hemorrhagic infections in the brain. AB - Hemorrhage in the brain can be accurately staged using a combination of T1- and T2-weighted MR images. The MR appearance depends on the form of hemoglobin present and on whether hemolysis has occurred. The stages of hemorrhage distinguishable by MR imaging are: hyperacute (less than 1 day, intracellular oxyhemoglobin), acute (1-3 day, intracellular methemoglobin), late subacute (7-14 days, extracellular methemoglobin) and chronic (14+ days, hemosiderin rim). PMID- 7858918 TI - Cerebral ischemia and infarction. AB - Cerebral infarction is most commonly related to atherosclerotic disease in the carotid and vertebrobasilar circulations. TIAs are manifestations of this same disease process and may occur before a complete infarction. The transformation of pale to hemorrhagic infarction may result from reperfusion of an infarct or from migration of an embolus. CT is often the primary imaging study to exclude frank hemorrhage. The use of MR is increasing, in both the acute and the subacute phases of stroke. The combination of MR imaging and MR angiography is gradually replacing CT, particularly in patients with TIAs. In addition, the depiction of minute alterations in contrast and subtle mass effect is visualized with MR more often than with CT. The precise localization of brain stem and posterior fossa infarctions is improved by the ability of MR to view complex structures in two or more orthogonal planes. Vascular structures are readily identified both on the spin echo images and with MR angiography. Slow or obstructed flow in the venous channels may be recognized, which makes MR the ideal examination for the evaluation of cerebral ischemia and infarction. PMID- 7858919 TI - Trauma to the cerebrovascular system. AB - Trauma to the cerebrovascular system can result in vascular injuries, such as dissection, pseudoaneurysm, thrombosis, rupture, and arteriovenous fistula. Although the diagnosis of vascular injury is usually considered in all cases of penetrating trauma, it may be overlooked in patients with nonpenetrating trauma. The possibility of vascular injury should be considered in all patients with head and neck trauma, especially those patients with acute or delayed neurologic dysfunction. Although intra-arterial angiography remains the gold standard diagnostic tool, the combination of MR imaging and MR angiography may permit noninvasive diagnosis of vascular injury. Moreover, MR readily provides detection of intracranial sequelae, such as cerebral infarction and intracranial hemorrhage. PMID- 7858920 TI - Intracranial vasculitis. AB - The etiology and types of intracranial vasculitis are described, along with a neuroimaging-oriented classification system. Specific entities are discussed in detail. The role of various modalities is defined, as well as a practical approach to diagnosis. PMID- 7858921 TI - Cerebral aneurysms. AB - Concurrent improvements in neurosurgical treatment and neuroradiologic evaluation of intracranial aneurysms have altered the approach to this condition. Meticulous panangiography remains the procedure of choice in the patient presenting with SAH to rule out aneurysmal rupture. MR imaging can play a role in the evaluation of intraluminal thrombus and is the examination of choice in the evaluation of patients presenting with focal neurologic deficits, such as oculomotor palsy suspected of being due to mass effect related to an aneurysm. Currently, MR angiography is not sufficiently accurate to play a role in the evaluation of the patient with SAH but may be useful as a screening test. It is likely that, with expected technical innovations, MR imaging and MR angiography will play an increasingly important role in the imaging evaluation of intracranial aneurysms. PMID- 7858922 TI - Intracranial vascular malformations. AB - Magnetic resonance imaging is a useful process in the evaluation and follow-up examination of intracranial vascular malformations. Magnetic resonance imaging as related to the four subtypes of these malformations, arteriovenous malformations, venous angiomas, cavernous malformations, and capillary telangiectasis, is discussed. PMID- 7858923 TI - Intracranial vascular tumors. AB - The study of intracranial vascular tumors is of significant importance because these tumors may stimulate vascular malformations, infarctions, or infections. This article describes vascular tumors and discusses their appearance on MR imaging studies. Choroid plexus neoplasms, primitive neuroectodermal tumors, hemangioblastoma and other disorders are discussed. PMID- 7858924 TI - Cancer patients' attitudes to final events in life. PMID- 7858925 TI - Administration of chemotherapeutic agents. Techniques and controversies. AB - Safe and pain-free vascular access is now the achievable goal for every patient receiving systemic chemotherapy. The discomfort and anxiety that used to accompany multiple (often unsuccessful) venipunctures can be avoided by placement of a long-term central-venous-access device as part of the patient's early treatment plan. In the United States, approximately 5 x 10(5) such devices are now inserted each year. This review discusses and compares the different types of devices currently available, methods of insertion, and management of morbidity. Future studies should focus on the cost effectiveness of these devices, better selection of patients for the various types of access, and avoidance, recognition, and treatment of complications. PMID- 7858926 TI - Empirical therapy for bacterial infections in neutropenic patients. AB - Infection in neutropenic patients remains a continuing challenge as the modalities of cancer treatment evolve and new pathogens appear. Although the concept of empirical therapy remains valid, there is a need for adaptation of our therapeutic approaches to new clinical and microbiological evidence. PMID- 7858928 TI - Outpatient management of febrile episodes in neutropenic cancer patients. AB - Febrile neutropenic patients have traditionally received hospital-based parenteral antibiotic therapy because of the risk of serious complications and associated mortality. Recently a low-risk subset among febrile neutropenic patients has been identified. Several alternatives to hospital-based therapy have been evaluated in such patients. These include early discharge to home antibiotic therapy after initial stabilization in the hospital, or treatment of the entire febrile episode with intravenous and/or oral antibiotics in an ambulatory setting. A multidisciplinary approach involving the physician and other health care providers, the patients, and their families, ensures the success of this therapeutic modality. Careful patient selection, daily follow-up, close monitoring for the development of complications and/or adverse reactions, and informed consent along with detailed instructions to patients, minimize the risk of the development of serious complications. Outpatient antibiotic therapy for febrile episodes in low-risk neutropenic patients should now be considered an acceptable alternative to hospital-based therapy. PMID- 7858929 TI - Overview of the role of hematopoietic growth factors in bone marrow transplant recovery and bone marrow transplant failure. AB - Morbidity of bone marrow transplantation has been reduced by the prophylactic use of myeloid stimulating growth factors. Trials are current exploring the usage of hematopoietic growth factors in a variety of other potential clinical applications in bone marrow transplantations. These include stimulation of multipotent progenitor cells, enhancement of monocyte macrophage function, enhancement of lymphocyte function, and alteration of inflammatory mediators which are causal of nonhematologic toxicities of bone marrow transplantation. Hematopoietic growth factors, factors which induce production of stimulatory cytokines and/or factors which alter inflammatory pathways, may be effective in improving the tolerability of patients undergoing bone marrow transplant. PMID- 7858927 TI - Viral infections in severely immunocompromised cancer patients. AB - Immunocompromised cancer patients are susceptible to infection by many viral pathogens. The most serious morbidity results from active infection by members of the herpes virus family. Reactivation of latent virus occurs as a sequela of cytotoxic therapy and deficiency of cell-mediated immunity, especially cytotoxic responses, the major host protective defense. Herpes simplex virus and varicella zoster virus infections are problematic in patients with all types of cancer; cytomegalovirus infections cause life-threatening morbidity in bone marrow transplant patients. Several antiviral agents are highly active against these pathogens and different strategies of using them have resulted in reduced morbidity and mortality. Ultimately, the resolution of these infections is dependent on the control of the malignancy and the ability of the patient to mount an adequate immune response. PMID- 7858930 TI - Cytoprotection: concepts and challenges. AB - Clinical trials with several toxicity protectors (cytoprotective or chemoprotective agents) have been performed during the past decade. These trials are quite complex since they must include sufficient dose-limiting events for study, and assessment of both toxicity (and therefore the efficacy of protection) and antitumor effects must be carried out. However, it is inevitable that with greater understanding of drug actions, one seeks to manipulate these for greater antitumor activity (biochemical modulation) or for lesser dose-limiting toxicity (cytoprotection) or for both. Examples of cytoprotective agents include dexrazoxane (ICRF-187), protecting against doxorubicin cardiotoxicity, and amifostine protecting against the myelosuppression of platinum and alkylating agents. In spite of the challenges encountered in the clinical development of these drugs, studies of cytoprotectors have led to a considerable understanding of important therapeutic issues and tangible clinical benefit in specific clinical situations. PMID- 7858931 TI - Amifostine: potential for clinically useful cytoprotection. AB - The ability to target malignant cells for cytotoxicity while sparing normal host tissues has proven to be limited. These limitations have resulted in unacceptable toxicity or insufficiently effective therapy. Continuing investigation of new, potentially useful cytotoxic agents must continue. An alternative approach, also worthy of study, is the selective protection of normal tissues. This approach, used in conjunction with available therapeutic agents, may open the therapeutic window and incrementally enhance the effectiveness of cytotoxic therapy. A variety of methods have been used to protect normal tissues selectively. Regional protection can be used for certain organ systems, such as the oral mucosa. Selective protection on a systemic level is more difficult but agents that seem to protect normal but not malignant tissues selectively are being developed. Among these is amifostine, which was originally selected by the U.S. defense department for study as a radioprotectant. Pre-clinical studies have suggested that amifostine is differentially concentrated in normal tissues but not in malignant tissues. Tissue-specific differences in the activity of alkaline phosphatase, which dephosphorylates amifostine to its active metabolite WR-1065, and in pH are thought to be involved in this relative specificity. Clinical studies indicate that amifostine can reduce the myelosuppression produced by cyclosphosphamide, the combination of cyclophosphamide and cisplatin, and, perhaps, carboplatin. The protective effects of amifostine on nonhematopoietic toxicities are being investigated. Future trials will investigate the integration of amifostine with cytokine-based supportive care in order to define the role of this potentially clinically useful cytoprotectant agent. PMID- 7858933 TI - Efficacy and tolerability of nasally administered compared to parenterally administered metoclopramide in the symptomatic treatment of chemotherapy-induced emesis in cancer outpatients. A controlled clinical study. AB - The clinical efficacy and tolerability of a new nasal spray formulation of metoclopramide (MTC) was evaluated in terms of its ability to prevent the nausea and vomiting induced by a moderately emetic chemotherapy (cisplatin 20 mg/m2 weekly as radioenhancer+radiotherapy for a fractionated total of 60 Gy) in 12 patients with non-small-cell lung cancer, stage IIIB. The first chemotherapy cycle was administered without any prophylaxis in order to identify those patients who experienced grade 2 nausea and/or vomiting. As prophylaxis during the second cycle, these patients were given MTC 20 mg i.v. at time zero, and MTC 20 mg i.m. after 4 h and 8 h; during the third cycle, they received MTC 40 mg by nasal spray 2 h before chemotherapy, followed by the same dose at 4 h and 8 h. The two prophylactic treatments (parenteral injections and nasal spray) proved to be therapeutically equivalent: complete protection, 6 and 6 patients respectively; major protection, 2 and 3 patients; minor protection, 1 and 1 patient; no protection, 3 and 2 patients. The control of nausea was satisfactory, with 7 and 9 patients respectively experiencing grade 0-1 nausea. Comparative analysis of individual responses confirmed the similar anti-emetic efficacy of the two regimens. No adverse reactions were observed at any time during the course of the study, and all 12 patients judged the acceptability of the new formulation as optimal. It can thus be concluded that the use of metoclopramide nasal spray represents an effective, safe, easily managed and low-cost therapeutic alternative for the prophylaxis and treatment of emesis induced by low-dose chemotherapy.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7858932 TI - Association therapy as a prognostic factor in deep fungal infection complicating oncohaematological diseases. AB - A group of 31 oncohaemopathic patients (17 male, mean age 44 +/- 6 years), diagnosed as having primary deep fungal infection involving the lungs, were retrospectively evaluated. When infection was suspected on a clinical basis the major associated risks for death were the duration of bone marrow aplasia (12 +/- 7 versus 21 +/- 6 days, P < 0.001), increase in white blood cells and, in particular, prolonged granulocytopenia (11 +/- 5 versus 24 +/- 8 days, P < 0.001) when survivors were compared with patients, who died. Our therapeutic empirical approach was based on the association of i.v. amphotericin B, 1 mg kg-1 day-1, with oral 5-fluorocytosine (5-FC) 150 mg kg-1 day-1. Only 9 subjects received combination therapy for more than 7 days. For majority of them, oral 5-FC was interrupted because of altered compliance or sustained liver damage. A chi 2 test for independent parameters showed (P = 0.0021) a concentration of deaths among patients who received amphotericin B alone (15/22); none of the patients treated with amphotericin B + 5-FC (9 cases) died. Results generally suggest that a more favourable outcome was statistically associated with empirical antifungal combination therapy in deep fungal infection, although both treatment regimens showed effectiveness in terms of survival. Nevertheless the low 5-FC compliance and the small sample do not indicate the safe use of this drug in a large population. PMID- 7858934 TI - Tropisetron (Navoban) in the prevention of chemotherapy-induced nausea and vomiting--the Nordic experience. AB - An open, noncomparative, Nordic multicenter study was carried out during 1991 1992 to evaluate the 5-HT3 receptor antagonist tropisetron (Navoban) as an antiemetic agent for various types of cancer chemotherapy. A total of 630 patients were recruited from 15 centers in Sweden, Denmark, and Finland. Gynecological cancers (60%), breast cancer (15%), and lung cancer (10%) were the main diagnoses. Prior experience of chemotherapy was documented in 338 patients (54%). In 260 patients (41%), cisplatin was part of the cytostatic regimen. Carboplatin (23%), doxorubicin (27%), and epidoxorubicin (24%) were also frequently included. In all, 23 cytostatic agents were used in various combinations. The mean number of courses studied was 4.6 (range 1-19). Altogether, 394 of 619 evaluable patients (64%) were completely protected from acute nausea and vomiting during the first course of chemotherapy. Delayed nausea and vomiting were completely prevented in 45%-73% (days 2-6) in the complete series. Treatment efficacy remained stable (60%-79%) during ten consecutive courses of chemotherapy. With noncisplatin regimens, complete protection from acute nausea and vomiting was achieved in 72% compared with 52% for cisplatin regimens (P < 0.0001). Patients without prior experience of chemotherapy had higher control rates of acute nausea and vomiting (72%) compared to patients treated before (57%) during the first course, but not later on. There were no differences in delayed nausea and vomiting.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7858935 TI - Febrile neutropenia in cancer patients in Kuwait: microbial spectrum and outcome. AB - A sample of 100 consecutive febrile neutropenic episodes in cancer patients in Kuwait was studied. Acute leukaemias (44%) and lymphomas (29%) were the most frequent underlying cancers; 21 bacteraemis (gram-positive 10, gram-negative 9, polymicrobial 2) were encountered. Staphylococcous epidermidis and Escherichia coli were the commonest organisms. Urinary tract infection occurred in 30% of the microbiologically documented cases. A total of 84 episodes responded to therapy and 9 of the 14 deaths were secondary to infection. PMID- 7858936 TI - The management of cancer anemia. AB - Anemia is common in patients with cancer and is often exacerbated by myelosuppressive chemotherapy. If severe enough, the anemia may require red blood cell transfusion for symptomatic palliation. However, blood transfusion will never be completely safe. Inconvenience and acute transfusion reactions are a problem and there is still a small risk of hepatitis. In selected patients with cancer-related anemia, recombinant human erythropoietin is another option to consider for the symptomatic patient. PMID- 7858937 TI - Guidelines for the assessment of quality of life in oncology--implementing adequate methods and contents. PMID- 7858938 TI - Species difference in the resistibility of embryonic fibroblasts against oxygen induced growth inhibition. AB - The growth of fibroblasts, which were isolated from human, rabbit, rat, mouse, and chick embryos, was inhibited partially under 50% oxygen and nearly completely under 95% oxygen. There was species difference in the resistivity of these cells against oxygen-induced growth inhibition. The extent of the resistivity was in the following order: chick cells > rat cells > human cells > rabbit cells approximately mouse cells. The order of their ability to recover from oxygen induced growth inhibition was similar to the above order of species. There was also species difference in their antioxidant enzyme activities, including superoxide dismutase, catalase, and glutathione peroxidase activities, and their reduced glutathione concentration. Chick cells, having the highest resistivity against oxygen-induced growth inhibition, were at the lowest activity levels of antioxidant enzymes and at the highest concentration level of reduced glutathione. The species difference in resistivity against oxygen-induced growth inhibition seems to depend on the reduced glutathione concentration, but not on the antioxidant enzyme activities. PMID- 7858939 TI - Ecdysteroid titre and metabolism and cuticle deposition during embryogenesis of the ixodid tick Amblyomma hebraeum (Koch). AB - Three embryonic cuticles are formed before larval cuticle deposition during embryonic development of Amblyomma hebraeum. The quantity of radioimmunoassay positive material varied between 50 and 200 pg ecdysone equivalents per mg, but no significant peaks were detected. Maternally incorporated [3H]-20 hydroxyecdysone and [3H]-ecdysone contained in freshly laid eggs appear to be conjugated to C-22 fatty acid esters and 3 alpha epimers of those esters, and, thus, appear doubly inactivated. In addition, ecdysone is converted to an unknown product called 2'. The role of these maternally derived ecdysteroids is unknown. PMID- 7858940 TI - Effect of long term iron deficiency on the activities of hepatic and extra hepatic drug metabolising enzymes in Fischer rats. AB - Male Fischer rats were maintained for a period of 17 weeks on an iron-deficient diet along with suitable controls. The effect of long term deprivation of iron on xenobiotic metabolism was studied by the activities of various drug metabolising enzymes in both liver as well as extra-hepatic tissues like lungs, kidneys and intestinal mucosa (I.M.). The results show that among the Phase I (activating) enzymes, the hepatic activities of benzo(a)pyrene hydroxylase (AHH) and microsomal epoxide hydrolase (mEH) are significantly reduced in iron deficiency. The other parameters of the activating system, namely cytochrome P450, aminopyrene demethylase (ADM) and aniline hydroxylase (AH), are not altered. Of the two Phase II (conjugating) enzymes studied, only uridine diphospho glucuronyl transferase (UDPGT) is found to be depressed, but not glutathione S-transferase (GST) in liver in iron deficiency. Activities of Phase I enzymes are markedly lowered in extra-hepatic tissues compared to liver; such depression is not observed in conjugating enzymes. Iron deficiency does not seem to make much impact on the enzyme activities of extra-hepatic tissues. Overall, the hepatic results suggest a defect in detoxification mechanisms in iron deficiency. Such impairment may very well predispose an iron-deficient host to an increased risk of carcinogenesis. PMID- 7858941 TI - Evidence for DNA endonuclease activity in nuclear extracts from mosquito cells. AB - We describe a deoxyribonuclease activity from nuclear protein extracts of cultured Aedes albopictus mosquito cells. The nuclease cleaved linear and circular double-stranded DNA, first generating 3' OH single-stranded nicks followed by second strand cleavage, but had little or no exonucleolytic activity. Detection of this activity was optimal at pH 7.1, in the presence of a divalent cation (Mg2+, Ca2+, Mn2+, Ba2+). In the presence of Mg2+, Zn2+, Hg2+ and Cu2+ inhibited activity, sulfhydryl reagents and ATP had no effect. At physiological temperatures (18-35 degrees C), linear double-stranded DNA probes were preferentially cleaved near sites containing 3-6 consecutive deoxyadenine/thymine base pairs. Results from salt dependency and drug inhibition studies, combined with inspection of DNA sequence, suggested that DNA structure is among the parameters that determine preferred cleavage sites. PMID- 7858942 TI - Lipid metabolism in pigs fed beef tallow or high-oleic acid sunflower oil. AB - The objectives of this study were to establish the effects of high-oleic sunflower oil (HOSO) and beef tallow on tissue fatty acids and stearoyl-CoA desaturase activities in swine; and to compare effects of HOSO and tallow on swine plasma triglycerides and lipoprotein-cholesterol fractions. Sixteen gilts were divided into two groups: eight fed a control diet containing 10 g/100 g beef tallow, and eight fed a diet containing 10 g/100 g HOSO. Plasma samples were obtained before feeding began and at 4 weeks and 8 weeks of dietary treatment. Samples were obtained from longissimus dorsi muscle, liver, adipose and duodenal mucosa for the measurement of fatty acid composition and stearoyl-CoA desaturase activity. The HOSO diet increased (P < 0.05) the concentrations (mumol/g wet weight of tissue) of 18:1 and 18:2 (n-6) in adipose tissue. In muscle from pigs fed the HOSO diet, concentrations of 14:0, 16:0, 16:1, 18:0, 18:1, and 18:2 (n-6) decreased (P < 0.05) relative to muscle from pigs fed the beef tallow diet; only 14:0 and 16:1 were reduced in liver by the HOSO diet. Stearoyl-CoA desaturase specific activity [(pmol 7 min-1 mg-1 microsomal protein)] was 40 percent lower, and activity expressed as pmol 7 min-1 g-1 tissue) was 20 percent lower, in adipose tissue of pigs fed HOSO (P < 0.05). No differences due to dietary treatment were observed for desaturase activity from muscle, liver or intestinal mucosa. Plasma triglycerides declined steadily in the tallow-fed pigs, possibly reflecting the lower percentages of liver 18:0 and 18:1 acids, relative to the HOSO-fed pigs. The animals responded similarly to the addition of fat (beef tallow or HOSO) to their diets with increased (P < 0.05) plasma total, LDL- and HDL-cholesterol by 4 weeks of treatment. Total cholesterol, LDL-, VLDL- or HDL cholesterol were not different between pigs fed beef tallow or HOSO. Thus, differences in fatty acid composition of the diets were sufficient to alter tissue fatty acid composition and adipose tissue desaturase activity, but insufficient to alter plasma lipoprotein cholesterol. PMID- 7858943 TI - Oxygen affinities (P50) of myoglobins from four vertebrate species (Canis familiaris, Rattus norvegicus, Mus musculus and Gallus domesticus) as determined by a kinetic and an equilibrium method. AB - Rate constants of the reaction with oxygen of myoglobins from four vertebrate species (Canis familiaris, Rattus norvegicus, Mus musculus and Gallus domesticus) and the isolated alpha A and beta A chains of human adult hemoglobin (HbA) were determined by the stopped-flow-spectrophotomeric method. Half-saturation oxygen pressure (P50) of the proteins calculated from the rate constants, assuming a simple bimolecular reaction model, agreed very well with those directly determined by oxygen equilibria. The proteins used were freshly prepared, and fully characterized by electrophoretic and ultracentrifugal analyses. Sulphydryl groups in the Hb chains were ascertained to be completely regenerated. PMID- 7858944 TI - The compartmentation of nucleoside diphosphate kinase in mitochondria. AB - The compartmentation of nucleoside diphosphate kinase (NDPK) was studied in mitochondria isolated from heart and liver of rat, rabbit, and pigeon. Compartmentation was assessed by determining latencies of enzyme activities, fractionating mitochondria with digitonin, and treating mitochondria with trypsin in the presence and absence of digitonin. NDPK activity in pigeon liver mitochondria was five- and seven-fold higher than in rat and rabbit liver mitochondria. The ratios of NDPK activities in liver vs. heart mitochondria were about 15 for rat, 2 for rabbit, and more than 40 for pigeon. Nearly all NDPK in pigeon liver mitochondria is in the matrix space, but outside the matrix in rat and rabbit liver mitochondria. Most NDPK in pigeon heart mitochondria was located outside the matrix while a significant fraction may be in the matrix of rat and rabbit heart mitochondria. These results are discussed relative to the assumed role that mitochondrial NDPK transfers the phosphoryl group of GTP produced in the Krebs cycle to the adenine nucleotide pool. PMID- 7858945 TI - Serum lysozyme level in the European bison, Bison bonasus (L.). AB - From 168 European bison divided into four groups (group 1, 0-3-year-old males; group 2, 0-3-year-old females; group 3, mature bulls, over 2 years old; group 4, mature cows, over 3 years old) the serum lysozyme level was studied. The mean lysozyme level varied from 3.91 micrograms/ml in young males (group 1) to 4.02 micrograms/ml in young females (group 2) and mature bulls (group 3); the range was from 2.10 to 6.40 micrograms/ml (only in a few animals). Statistically significant differences between months were found only in young males (group 1). PMID- 7858946 TI - Comparison of structural protein and proteolytic enzyme levels in degenerating and regenerating rat muscle induced by Notechis scutatus venom. AB - To develop a clear understanding of the biochemical mechanism of muscle degeneration and regeneration induced by a single dose of Notechis scutatus scutatus venom, we have correlated changes in the levels of a series of muscle structural proteins and proteolytic enzymes. The degradation of structural proteins post-injection fell into two broad groups; those completely degraded within 3-6 hr (e.g. C- and M-proteins, skelemin), and within 1-2 days (e.g. myosin, actin, troponin), respectively. Similarly, activation of proteases followed two general patterns; those enzymes showing substantially increased activity after 12-24 hr (lysosomal cathepsins, leucyl aminopeptidase) and those enzymes showing decreased activity after 12-24 hr, with substantially increased activity after 3-4 days (mainly cytoplasmic proteases). The data suggest that activation of cathepsins B, L and D and in particular leucyl aminopeptidase, may be responsible for the early stages of structural protein catabolism, and are thus potential therapeutic targets to prevent myonecrosis following envenomation. PMID- 7858947 TI - Myocardial microdialysis of salicylic acid to detect hydroxyl radical generation during ischemia. AB - We examined in vivo monitoring of hydroxyl radical (.OH) generation during myocardial ischemia for 30 min by occluding the left anterior descending (LAD) in dog heart using a microdialysis technique. The hydroxyl radical reacts with salicylate and generates 2,3- and 2,5-dihydroxybenzoic acids (DHBA) which can be measured electrochemically in picomole quantity by a high pressure liquid chromatography-electrochemical (HPLC-EC) procedure. When the premature ventricular contraction (PVC) occurred at almost 25 sec intervals, marked elevation of the levels of 2,3- and 2,5-DHBA was observed in the heart dialysate of 30-min ischemia. This study demonstrated the generation of .OH in the canine heart subjected to 30-min ischemic insult. PMID- 7858948 TI - Effects of gonadectomy and temperature on the N-acetyltransferase activity in the harderian gland of the green frog Rana esculenta. AB - Since, in the Harderian gland (HG) of the hamster, the N-acetyltransferase (NAT), the specific enzyme involved in the biosynthesis of melatonin, exhibits a sexual dimorphism, in the present study, we investigated whether such a dimorphism is present also in the HG of the green frog Rana esculenta. In intact frogs, no significant differences emerged between males and females in the HG NAT activity under both cold (10 degrees C) and warm (22 degrees C) temperature conditions. In female frogs, the HG NAT activity was significantly decreased by both gonadectomy (P < 0.001) and warm temperature (P < 0.001), the two effects being not additive. In male animals, neither gonadectomy nor temperature alone significantly affected the activity of the NAT enzyme in the HG. However, gonadectomized male frogs exposed to warm temperature exhibited a significant drop in the HG NAT activity (P < 0.005). These data show that, in Rana esculenta, although no sexual dimorphism exists in the HG NAT activity, a sex difference is evident in the modulation of the enzyme activity by gonads and temperature, the female frogs being more sensitive to the impairing effects of both gonadectomy and higher temperature. PMID- 7858949 TI - Uptake of purine substrates shows major physiological variations in mammalian skin fibroblasts. AB - Uptake of the purine bases hypoxanthine and adenine were studied in skin fibroblast cultures from three different mammalian species. Marked variation in uptake was observed, and using an analysis of variance, the main component of this variation was found to be at the between experiment level as opposed to the between replicate or between individual level. After allowing for this variation, significant between species differences in uptake were found. Uptake of both purines decreased proportionately with passage number, and increased markedly after viral transformation of the fibroblast cultures. These results demonstrate significant metabolic differences in purine anabolic pathway fluxes between mammalian species but also have serious implications for the use of these methods in a diagnostic context. PMID- 7858950 TI - Comparative study of hepatic VLDL secretion in vivo in the growing turkey (Meleagris gallopavo) and chicken (Gallus domesticus). AB - Hepatic secretion of VLDL was compared in young turkeys and chickens (8 and 4 weeks of age, respectively) and older birds (11 and 8 weeks of age, respectively) reared together under the same nutritional conditions. VLDL, VLDL-TG and total TG secretion rates were higher in chickens than in turkeys. The cholesteryl ester content of turkey VLDL was higher than that of chicken. Differences in the fatty acid composition of the VLDL lipids were observed between the species: the proportion of linoleic acid was greater in turkeys, whereas monounsaturated fatty acids were more abundant in chickens. These results are consistent with the hypothesis of a positive relationship between hepatic lipogenesis, delta-9 desaturation, VLDL secretion and fattening in turkeys and chickens. PMID- 7858951 TI - Sequence-independent detection of gene family homologs: identification of a transcript encoding a molluscan serine protease homologous to the pancreatic enzymes of vertebrates. AB - Autoradiography of 32P-labeled cDNA, fractionated at high resolution by electrophoresis through thin (0.8-1.5 mm) vertical alkaline agarose gels, provides a sequence-independent screening procedure for gene family homologs. A screen of tissues of a marine mollusc revealed a prominent intestine-specific cDNA encoding a pancreatic serine protease homolog, which was not detectable as a discrete poly(A)+ RNA species on formaldehyde agarose gels. Discrete cDNA products are authentic, non-truncated transcripts of tissue-specific mRNA. A band sharpening effect is imparted to cDNA products due to (a) substitution of a uniform length 5'-oligo(dT) terminus for heterogeneous 3'-poly(A) termini and (b) the inherent superior resolution of alkaline-denatured DNA. PMID- 7858952 TI - Biochemical characterization of sheep platelet acetylcholinesterase after detergent solubilization. AB - The biochemical characterization of detergent-solubilized acetylcholinesterase (AChE) from subcellular particles of sheep platelets and the effects of different effectors on AChE activity from solubilized platelet crude membranes have been undertaken and studied. Solubilization of AChE with detergent increased the thermal stability of the enzyme from all particulate fractions. Solubilized AChE from the mitochondria-granule fraction was the most thermostable at 55 degrees C. The Km values against acetylthiocholine chloride and the Arrhenius plot obtained were very similar for the AChE from all the solubilized fractions. There were no differences in the ability of solubilized AChE from different subcellular fractions to bind concanavalin A (Con A). In solubilized platelet crude membranes, benzyl alcohol was a potent AChE inhibitor at a concentration of 10( 2) M, whereas ethanol was not. Mg2+ cations and, to a lesser extent, Ca2+ and Mn2+ cations, activated AChE at concentrations higher than 1 mM. Serine hydrolase inhibitors and cholinesterase-specific inhibitors were very effective in the inactivation of AChE, whereas EDTA and EGTA had no effect. Of all the monosaccharides tested, only N-acetylneuraminic acid exerted an inhibitory effect on AChE activity. Immobilized-lectin binding studies demonstrated the interaction of solubilized crude membrane-bound AChE with Con A, lentil lectin and wheat germ agglutinin. Taken together, these data suggest the presence of a unique form of the membrane-bound AChE which has at least alpha-mannose and N-acetylglucosamine residues in the glycan chain. PMID- 7858953 TI - In vivo evaluation of dosage forms: application of gamma scintigraphy to non enteral routes of administration. AB - The trend to deliver drugs to defined areas of the body involves sophisticated carriers systems. In addition to the in vitro drug release profile one must be aware of the in vivo behaviour of the dosage form and the drug. Gamma scintigraphy is an elegant way to gain insights of the actual in vivo distribution pattern of dosage forms. This technique relies on the use of radioactive tracers included into the medicament and selected so as to enable an optimum detection by a gamma ray camera. The choice of a convenient label enables the in vivo determination of the targeting of the formulation administered through a large number of routes. The present paper reviews applications of gamma scintigraphy for the evaluation of dosage forms administered by the parenteral, rectal, buccal, nasal, pulmonary, and ophthalmic routes. PMID- 7858954 TI - Polysulfone capillary fiber for intraocular drug delivery: in vitro and in vivo evaluations. AB - Studies were conducted to investigate the usefulness of polysulfone capillary fiber (PCF) as a drug delivery device for intraocular applications. Carboxyfluorescein (CF) was used as a model drug to prepare PCF-dye devices for both in vitro and in vivo kinetic studies. For the in vitro study, PCF-CF devices were incubated in 0.1 M phosphate buffer, pH 7.4 at 37 degrees C, and CF release was quantified at various times up to 5 weeks. In vitro results indicated a bi phasic, sustained-release profile of CF from the PCF device for over 30 days. PCF CF devices released 5% and 10% of their initial CF contents by the first and second day following incubation, respectively. By 10 days after incubation, approximately 50% of the dye content was released from the PCF-CF devices. The rate of dye release decreased thereafter, such that 65% and 90% of CF was released by 17 and 28 days after incubation, respectively. In a subsequent study, the in vivo kinetics of the PCF-CF device were determined in the rabbit eye. PCF dye devices were prepared with the following CF formulations: 1) microsphere incorporated CF; 2) lyophilized liposome-encapsulated CF; or 3) micronized CF powder. A PCF-dye device was implanted in the vitreous cavity, and fluorophotometry from the retina to the anterior chamber was performed at various times up to 45 days to quantify fluorescein level. At the conclusion of the study, eyes were enucleated and examined for histopathology. The time-course study showed fluorescein level for up to 45 days in the vitreous. The midvitreous concentration-time profile indicated a CF t1/2 of 10 and 30 days for the PCF-CF powder and PCF-CF liposome preparation, respectively. In contrast, the PCF device prepared with microsphere-incorporated CF showed fluorescein level with a t1/2 of less than one week in the vitreous. Histological examination of the eyes implanted with PCF or PCF-dye device showed no sign of ocular toxicity. Collectively, these results indicated that the PCF device is biocompatible and may be useful for the extended release of drugs in the posterior segment of the eye. PMID- 7858955 TI - Growth inhibition of macrophage-like and other cell types by liposome encapsulated, calcium-bound, and free bisphosphonates in vitro. AB - Bisphosphonates effectively inhibit osteoclastic bone resorption in diseases characterized by excessive bone loss. Liposome-encapsulated clodronate (dichloromethylene bisphosphonate) also is known to inactivate phagocytic cells in vivo, and inhibit the growth of macrophage-like RAW 264 cells in vitro. The macrophage suppressive effect of liposomal clodronate is of interest in autoimmune diseases, like rheumatoid arthritis, in which phagocytic cells are involved in inflammatory processes. Earlier in vivo studies suggested that liposomal clodronate is a far more potent inactivator of macrophages than liposomal forms of two other bisphosphonate compounds, pamidronate (3-amino-1 hydroxypropylidene bisphosphonate), and etidronate (1-hydroxyethylidene-1,1 bisphosphonate). We examined the growth inhibitory properties of these three bisphosphonates with macrophage-like RAW 264 cells and with other types of cells in vitro. All three bisphosphonates encapsulated in liposomes effectively inhibited the growth of RAW 264 and CV1-P cells, while free drugs were 20-1000 times less potent growth inhibitors. Also, high extracellular calcium concentrations enhanced the potency of bisphosphonates for RAW 264 cells, indicating that, in addition to liposomes, the uptake of bisphosphonates by macrophages is mediated also by calcium. In all formulations, pamidronate was the most potent compound for the cells, with the exception of CV1-P cells, for which liposomal clodronate was the most potent. The effects of liposomal drugs were selective for highly endocytotic cells. The results suggest that liposome encapsulated bisphosphonates could provide a specific tool to affect the function of macrophages and all three of these bisphosphonates are potentially effective as macrophage suppressors in autoimmune diseases. PMID- 7858956 TI - Synthesis and evaluation of a redox chemical delivery system for brain-enhanced dopamine containing an activated carbamate-type ester. AB - A chemical delivery system (CDS) for enhanced delivery of dopamine to brain tissue, based on a dihydropyridine<==>pyridinium salt redox system, was modified to include an activated carbamate ester. The dihydronicotinate moiety was chemically attached to the amino group of dopamine (DA) by acylation with chloroethyl chloroformate, followed by condensation with sodium nicotinate under mild conditions. The product was selectively N-alkylated at the pyridine ring and subjected to regioselective reduction to the corresponding 1,4-dihydropyridine derivative, DA-CDSac. In vitro stability of the new compound was studied in phosphate buffers at mild acidic, physiological, and mild alkaline pH values. Oxidation studies showed facile conversion of the dihydronicotinate, DA-CDSac, is readily converted to the corresponding quaternary salt, both chemically and enzymatically. In vivo studies in rats did not detect sustained increases in brain levels of the quaternary salt after i.v. dosing with DA-CDSac. However, the new CDS appeared to change spontaneous locomotor activity in rats after i.v. administration which may be due to altered central DA neuronal activity. PMID- 7858957 TI - Improvement of therapeutic effect of human recombinant superoxide dismutase on ischemic acute renal failure in the rat via cationization and conjugation with polyethylene glycol. AB - Therapeutic effect of superoxide dismutase (SOD) and three derivatives: a conjugate with polyethylene glycol (SOD-PEG2), a cationized derivative (cSOD), and a mannosylated derivative (Man-SOD), on acute renal failure induced by ischemia/reperfusion was studied in rats. SOD and derivatives were administered intravenously to the rat after nephrectomy of the right kidney and before and after 60 min occlusion of the left renal artery. At 48 hr after reperfusion, the renal function was evaluated by determining the urinary excretion rate of 14C inulin injected intravenously. No therapeutic effect on the impaired renal function was shown in the case of low dose SOD (2600 unit/kg) treatment. In contrast, administration of cSOD which was shown to be taken up by the isolated perfused kidney from its capillary side and SOD-PEG2 which maintained high plasma concentration exhibited significant therapeutic effect, as did SOD at ten-fold higher dose (26,000 unit/kg). On the other hand, renal damage was promoted by Man SOD. Thus, the present study demonstrated that chemical modification may improve the therapeutic effect of SOD on the ischemic acute renal failure and increased SOD concentration in the renal vascular space is an important factor for the improved effect. PMID- 7858958 TI - Experimental determination of a drug targeting index for S(+)ibuprofen using the rat air pouch model of inflammation. AB - We have used the rat air pouch model of inflammation and S(+)ibuprofen as an experimental model system to enable the quantitative assessment of the pharmacokinetic determinants of site specific drug delivery. S(+)ibuprofen (50 & 1mg/kg) was administered directly into six day old air pouches immediately following the injection of the irritant carrageenan. Serial exudate and plasma samples were collected and analysed for ibuprofen by HPLC. The procedure was repeated following administration of S(+)ibuprofen (20 & 5mg/kg) intravenously. The parameters describing events in the air pouch and plasma indicated linear kinetics over the doses employed. The dose normalised AUCs were then used to formulate a quantitative measure of benefit for S(+)ibuprofen delivered directly to the air pouch. A Drug Targeting Index (DTI) was calculated from the ratio of AUC in the air pouch and plasma following direct intrapouch administration divided by the same ratio following intravenous administration and gave a value of 130. This pharmacokinetic measure of benefit represents the maximum advantage afforded by the site specific delivery of S(+)ibuprofen as the whole of the administered dose is delivered directly to the site of action. PMID- 7858959 TI - A polymer-Triton X-100 conjugate capable of PH-dependent red blood cell lysis: a model system illustrating the possibility of drug delivery within acidic intracellular compartments. AB - Poly(amidoamines) are soluble polymers containing tertiary amino and amido groups regularly arranged along the macromolecular chain, and their net average charge alters considerably as pH changes from neutral to acidic leading to a change in conformation. This property provides the possibility to design polymer-drug conjugates that are, following intravenous administration, relatively compacted and thus protect a drug payload in the circulation, but following pinocytic internalisation into acidic intracellular compartments unfold permitting pH triggered intracellular drug delivery. To study the feasibility of this approach, a covalent conjugate of a poly(amidoamine) (MBI) was prepared to contain the membrane lytic non-ionic detergent Triton X-100 (as a model), and its ability to lyse red blood cells in vitro was used as an indicator of conjugate conformation at at different pHs. Although Triton X-100 was highly lytic at pH 5.5, 7.4 and 8.0, and the parent polymer MBI was not lytic under any conditions, the conjugate only showed concentration-dependent red blood cell lysis at pH 5.5. Moreover, incubation of human leukaemic cells (CCRF) with these substrates showed conjugate to be more toxic than MBI (IC50 values of 100 micrograms/ml and 650 micrograms/ml respectively) and less toxic than Triton X-100 (IC50 of 1 microgram/ml). PMID- 7858960 TI - Enzymes for the resolution of alpha-tertiary-substituted carboxylic acid esters. AB - Aromatic alpha-amino-alpha-methyl acids and alpha-hydrazino-alpha-methyl acids are known aromatic amino acid decarboxylase inhibitors. Specific derivatives such as 2-amino-2-methyl-3-(3,4- dihydroxyphenyl)propanoate, Aldomet, and 2-hydrazino 2-methyl-3-(3,4- dihydroxyphenyl)propanoate, Lodosyn, have been developed as therapeutic agents to treat hypertension and Parkinson's disease, respectively. We recently reported a method for the kinetic resolution of the racemic esters of such compounds using a crude preparation of a novel enzyme catalyst from the yeast Candida lipolytica (Yee, C.; Blythe, T.A., McNabb, T.J.; Walts, A.E. J. Org. Chem. 1992, 57, 3525-3527). Here we report the purification and initial characterization of the active enzyme component, an enzyme given the name Candida lipolytica ester hydrolase (CLEH). CLEH was purified to > 95% homogeneity by chromatography on Matrex Blue B resin. The enzyme was found to be a glycoprotein with M(r) = 80,000-300,000. In addition to esterolytic activity, the enzyme was found to catalyze the hydrolysis of amides, anilides and peptides. Sequence analysis of internal peptides of CLEH revealed striking homology to a number of enzymes belonging to the group of serine carboxypeptidases (E.C. 3.4.16.1). One peptide aligned with the canonical serine carboxypeptidase active site sequence, GESYAG. Based on the structural relationship of CLEH to serine carboxypeptidases, three representative serine carboxypeptidases were evaluated for their utility in resolving racemic alpha-tertiary ester substrates and compared with the activity of CLEH. All enzymes revealed similarly high activity and enantioselectivity towards the alpha-hydrazino-alpha-methyl ester precursor of the Parkinson-drug Carbidopa. However, differences in enantioselectivity were observed with other alpha-tertiary-substituted ester substrates. Serine carboxypeptidase-catalyzed ester resolutions thus offer a new route to many sterically hindered homochiral alpha-amino, alpha-hydrazino and alpha-hydroxy carboxylic acids. PMID- 7858961 TI - Resolution of racemic sterically hindered secondary alcohols via enzymatic alcoholysis of their esters. The first enzymatic preparation of optically pure 2,2,2-trifluoro-1-(9-anthryl)ethanols. AB - An approach has been developed which exploits the non aqueous enzymatic alcoholysis reaction for resolution of racemic sterically hindered secondary alcohols. The method was used effectively in the first enzymatic preparation of both enantiomers of the title compound via porcine pancreatic lipase catalysed alcoholysis of its butyrate ester. A considerable enhancement of the reaction rate was achieved by dispersion of the powdered enzyme preparation on aluminium oxide. A facile procedure was developed for separating the (R)-alcohol product from the unreactive (S)-butyrate ester and for the hydrolysis of the latter into the (S)-alcohol. The preparative usefulness of the resolution procedure is demonstrated by the convenience of the scaled-up enzymatic experiment carried out on 370 g of substrate in an ordinary flat bottom flask. PMID- 7858962 TI - Carba analogues of triglycerides--isosteric mimics for natural lipids. Novel substrates for the determination of regio- and enantioselectivities displayed by lipases. AB - The novel carba analogues 1a,b and 2 were synthesized and demonstrated to be isosteric identical mimics for natural triglycerides. They can be used for the system independent determination of regio- and enantioselectivities displayed by lipases. They are, moreover, attractive starting materials for novel carba analogues of phospholipids, PAF analogues and PAF antagonists. PMID- 7858963 TI - The utilization of 3-mercapto-2-methylpropionate as sulphur source by a phototrophic bacterium. AB - A bacterium (strain photoB) photoassimilated 3-mercapto-2-methylpropionate as sole source of sulphur with methacrylate accumulating in the medium. This was thought to be the product of a sulphur-lyase type enzyme attacking the 3-mercapto 2-methylpropionate. Detailed examination of the biochemistry of the utilization of 3-mercapto-2-methylpropionate showed however that the thiol was first activated to 3-mercapto-2-methylpropionyl CoA. It appeared that this CoA derivative then served as the substrate for a sulphur-lyase type enzyme, with methacrylyl-CoA as product. Further metabolism was via beta-hydroxyisobutyryl-CoA and beta-hydroxyisobutyrate. PMID- 7858964 TI - Microbial Baeyer-Villiger reaction of bicyclo[3.2.0]heptan-6-ones--a novel approach to sarkomycin A. AB - Racemic (1 alpha, 2 alpha, 5 alpha)- and (1 beta, 2 alpha, 5 beta)-2- bromobicyclo[3.2.0]heptan-6-one (rac-7, rac-10, respectively), (1 alpha, 2 alpha, 5 beta)- and (1 beta, 2 alpha, 5 beta)-2- benzyloxybicyclo[3.2.0]heptan-6-one (rac-15, rac-13, respectively), (1 beta, 2 alpha, 5 beta)-2 hydroxybicyclo[3.2.0]heptan-6-one (rac-17) and cis-bicyclo[3.2.0]hept-2-en-7-one (rac-18) were subjected to a microbial Baeyer-Villiger reaction by Acinetobacter calcoaceticus NCIB 9871. In each case both regioisomeric lactones were formed (67 93% yield) having always the opposite configuration (20 to > 99 % e.e.). Both the ratio of the regioisomers and the enantiomeric excess proved to be dependent on the type of substitution. Analogously cis-bicyclo[3.2.0]heptan-2,6-dione (rac-1) gave besides other products cyclosarkomycin (1b) (7 % yield, 97 % e.e.). Compound 1b was also obtained from the Baeyer-Villiger product of rac-17 by Swern oxidation (total yield starting from rac-17 9 %, > 98 % e.e.). PMID- 7858965 TI - A simple method for determination of stereospecificity of aminotransferases for C 4' hydrogen transfer of the coenzyme. AB - A simple method was established for determination of the stereospecificity of C 4' hydrogen transfer of the coenzymes (pyridoxal and pyridoxamine). The method is based on the findings that aspartate aminotransferase of pig heart and D-amino acid aminotransferase of Bacillus sp. YM-1 catalyze the abstraction of the pro-S and pro-R proton at C-4' of pyridoxamine, respectively. Pyridoxal is a poor coenzyme, but readily released from the enzyme. It reacts in 3H2O with a substrate amino acid and an apo-aminotransferase whose stereospecificity for C-4' hydrogen transfer is to be determined. The resultant pyridoxamine which is tritiated at C-4' is incubated with an apo form of aspartate aminotransferase or D-amino acid aminotransferase and a substrate, alpha-keto acid. The stereospecificity for the C-4' hydrogen transfer examined is determined by measurement of radioactivity retained in the pyridoxal formed. We showed by means of this method that C-4' hydrogen transfer of coenzyme occurs on the si face of the external Schiff base in the transamination reactions of two aspartate aminotransferases of Bacillus sp. YM-2 and Escherichia coli, and aromatic amino acid aminotransferase of E. coli. PMID- 7858966 TI - Microbiological transformations--XXIX. Enantioselective hydrolysis of epoxides using microorganisms: a mechanistic study. AB - The regio- and stereochemistry of the hydrolysis of styrene oxide 1 by two fungi: Aspergillus niger and Beauveria sulfurescens, were studied using H2(18)O labelling experiments. Also, the kinetic parameters of these hydrolyses were determined. We conclude that the epoxide hydrolases of these two fungi operate via different mechanisms. PMID- 7858967 TI - An enzymatic route to L-ornithine from arginine--activation, selectivity and stabilization of L-arginase. AB - The non-proteinogenic amino acid L-ornithine (L-Orn) can be conveniently obtained by enzymatic hydrolysis of arginine (Arg) with arginase (EC 3.5.3.1). Arginase from calf liver (Vmax = 459 mumol/(min.mg), Km = 25.5 mM) is inhibited competitively by L-Orn (Ki = 480 mM). The enzyme was found to be completely enantioselective (E-value > 100) so that D,L-Arg can be split into D-Arg and L Orn. Operational stability at 25 degrees C (deactivation rate constant kdeact = 3.8 x 10(-3) h-1; tau 1/2 = 182 h) is sufficient for use in a continuous process but is significantly smaller than temperature stability (kdeact = 4.1 x 10(-4) h 1; tau 1/2 = 1682 h); mechanical stress through stirring and unsteady Mn2+ supply owing to oxidation in the continuous process are believed to cause the difference. Addition of ascorbic acid stabilizes calf liver arginase at temperatures higher than 25 degrees C (at 60 degrees C, delta delta G not equal to = 2.9 kJ/mol). PMID- 7858968 TI - Selective inhibition of metabolic enzymes by enzymatically synthesized D-glucal-6 phosphate. AB - Yeast hexokinase (EC 2.7.1.1) catalyzes the phosphorylation of D-glucal and methyl alpha- and beta-D-glucopyranosides at 1-5% of the rates of phosphorylation of D-glucose and 2-deoxy-D-glucose. Maltose, cellobiose, D-galactal and tetrahydropyran-2-methanol are not substrates of hexokinase. Enzymatically synthesized D-glucal-6-phosphate inhibits rabbit muscle phosphoglucose isomerase competitively (KI = 1.94 mM) and phosphoglucomutase noncompetitively (KI = 0.122 mM). PMID- 7858969 TI - Enzymatic synthesis of isotopically labeled isoprenoid diphosphates. AB - Recombinant yeast isopentenyl diphosphate (IPP) isomerase and avian farnesyl diphosphate (FPP) synthase from overproducing strains of Escherichia coli were used to synthesize FPP from IPP and dimethylallyl diphosphate (DMAPP). [2,4,5 13C3]IPP and [2,4,5-13C3]DMAPP were synthesized from ethyl [2-13C]bromoacetate and [1,3-13C2]acetone. Thes compounds were used as substrates for enzymatic synthesis of FPP selectivity labeled at the first or third isoprene residue or at all three. PMID- 7858970 TI - Phosphoenolpyruvate as a dual purpose reagent for integrated nucleotide/nicotinamide cofactor recycling. AB - An efficient technique is presented which integrates cofactor dependent enzymic phosphorylation and dehydrogenation into a single, closed-loop system by employing phosphoenolpyruvate as the sacrificial reagent for sequential ATP and NAD+ recycling steps. Exemplary applications are developed for the synthesis of 6 phosphogluconate from glucose, and that of dihydroxyacetone phosphate from glycerol. The latter system is combined with exergonic diastereoselective aldol additions for the one-flask synthesis of a ketosugar (D-sorbose), thiosugar (L threo-5-thiopentulose), or a sugar acid (L-threo-pent-4-ulosonic acid) starting from a mixture of glycerol and simple aldehydes. PMID- 7858971 TI - Biotransformation of organic sulfides--IV. Formation of chiral benzyl alkyl and phenyl alkyl sulfoxides by Helminthosporium species NRRL 4671. AB - The fungus Helminthosporium species NRRL 4671 has been used for the biotransformation of a series of phenyl alkyl sulfides with alkyl groups ranging from methyl to n-hexyl, and benzyl alkyl sulfides with alkyl groups from methyl to n-nonyl. Several 2-phenylethyl and 3-phenylpropyl sulfides have also been examined as substrates, together with cyclohexyl methyl sulfide and 1- and 2 naphthyl methyl sulfides. For the majority of substrates, sulfoxide formation occurred in moderate yield and with predominant (S) chirality at sulfur; lesser amounts of sulfone product were also obtained in some cases. The data so obtained have been used to define the preparatively useful limits of S-oxidation of phenyl alkyl sulfides and benzyl alkyl sulfides by biotransformation using Helminthosporium. PMID- 7858972 TI - Polyclonal antibodies and catalysis. AB - Some recent results involving catalytic polyclonal antibodies are described. Polyclonal antibodies isolated directly from serum contain the complete distribution of different IgG antibodies elicited via immunization, so catalytic results obtained with polyclonal antibodies can be used to characterize the overall catalytic activity produced in an animal in response to a given hapten. This new window on catalytic antibodies should be especially useful for identifying general trends relating hapten structure to antibody catalytic activity, for monitoring the maturation of catalytic activity during immunization, and for studying the variability of catalytic activity elicited in different animals immunized with the same hapten. Furthermore, studying the catalytic activity of polyclonal antibodies in serum may aid in the development of novel immunization-based therapies. PMID- 7858973 TI - Thermostability and thermoactivity of enzymes from hyperthermophilic Archaea. AB - Enzymes from hyperthermophilic microorganisms are characteristically thermostable and thermoactive at extremely high temperatures. Information about the basis for the structure and function of these novel proteins is beginning to emerge. However, there are very few generalizations that can be drawn at this point that can be derived from the limited number of studies that have focused on biocatalysis and thermostability at extremely high temperatures. PMID- 7858974 TI - Combined chemical and enzymatic synthesis of the sialylated non reducing terminal sequence of GM1b glycolylated ganglioside, a potential human tumor marker. AB - N-Glycolylglucosamine 8 was synthesized in 4 steps from anisal glucosamine, via the new crystalline monochloracetyl derivatives 3, 4 and 7. N-Glycolylneuraminic acid 10 was prepared in 59% yield starting from pyruvate and a mixture of 8 and its manno epimer 9 in a 2:3 ratio, with immobilized sialic acid aldolase. Neu5Gc 10 was converted into CMP-NeuGc 11 in the presence of immobilized calf brain CMP sialate synthetase. Finally 11 was used as a donor in the transfer to the acceptor beta-D-Gal-(1-3)-beta-D-GalNAc-OBn 12 catalyzed by a preparation of porcine liver (2-3)-alpha-sialyltransferase, roughly purified by a chromatography on Cibacron Blue-agarose. alpha-Neu5Gc-(2-3)-beta-D-Gal-(1-3)-beta-D-GalNac-OBn 13 isolated in 56% yield was deprotected to give the non-reducing terminal sequence of GM1b glycolylated ganglioside, which might be expressed in human tumors. PMID- 7858975 TI - Use of N-acetylglucosaminyltransferases I and II in the synthesis of a dideoxypentasaccharide. PMID- 7858976 TI - Biocatalytic desulfurization of arylsulfonates. AB - A microbial strain, Klebsiella oxytoca KS3D, has been isolated which is capable of exploiting arylsulfonates as a sole source of sulfur during growth. The desulfurization catalyzed by intact K. oxytoca KS3D results in the conversion of arylsulfonates into the corresponding phenols. Even arylsulfonates carrying substituents which significantly alter steric and electronic characteristics are substrates. Only a single regioisomer is produced from substituted arylsulfonates. Based on the products formed from the biocatalytic desulfurizations and incorporation of isotopic oxygen in phenolic product when the desulfurization is run under 18O-enriched oxygen, hydrolysis mechanisms can be eliminated from consideration. Two reaction types which might mimic the chemistry occurring during microbial desulfurization of arylsulfonates were examined. The first reaction involved conversion of appropriately substituted arylsulfonates into phenols by single electron reduction followed by reaction of the radical anions with molecular oxygen. A second reaction using intramolecular reaction of arylsulfonates and arylsulfones with alkoxy radicals failed to achieve desulfurization. In addition to mechanistic evaluation, desulfurization of arylsulfonates catalyzed by K. oxytoca KS3D is examined from the perspective of its relevance to desulfurization of the organosulfur components of coal and its possible use for industrial manufacture of phenols. PMID- 7858977 TI - Solvent isotope effects and the nature of electrophilic catalysis in the action of the lactate dehydrogenase of Bacillus stearothermophilus. AB - Deuterium oxide at atom fractions of deuterium from 0.0 to 0.97 has an effect of less than 20% on the kinetic term kcat/KmB (believed to reflect the transition state for the hydride-transfer step) for the reduction of pyruvic acid by NADH at 55 degrees C, with catalysis by the tetrameric form of the lactate dehydrogenase of Bacillus stearothermophilus. This observation suggests that the hydride transfer event is not assisted by protonic bridging to the carbonyl group being reduced. The results are consistent with protonic bridging only if an opposing isotope effect is present, for example from a generalized conformation or solvation change. The results are consistent with other forms of electrophilic catalysis. PMID- 7858978 TI - Inhibition of lipases by phosphonates. AB - Ethyl hexylchlorophosphonate and analogues thereof were investigated as inhibitors of lipases. Both microbial and mammalian lipases were irreversibly inhibited. The inhibition could be monitored by p-nitrophenol release from the corresponding ethyl p-nitrophenyl hexylphosphonate inhibitor. Quantitative analysis of the data indicated that a 1:1 lipase-inhibitor complex was formed during inhibition. Enantioselective inhibition was found for the lipases derived from Candida antarctica and Rhizomucor miehei using pure enantiomers of ethyl p nitrophenyl hexylphosphonate as inhibitors. Using the same inhibitor, reversed enantioselectivity was found for the protease alpha-chymotrypsin as compared to the two lipases. PMID- 7858979 TI - Regioselectivity and fatty acid specificity of Chromobacterium viscosum lipase. AB - The fatty acid specificity of Chromobacterium viscosum lipase was studied by comparing the pseudo-first-order rate constants for the transesterification of different fatty acid methyl esters with 1-propanol in dry acetonitrile as solvent. It was found that this enzyme shows a significant preference towards long chain fatty acids and, for chains with the same length, towards saturated ones. The same enzyme was used to study the esterification of sorbitol and decanoic acid. A mixture of mono-, di-, tri- and tetraesters was obtained. The concentration of esters was strongly increased upon raising the temperature from 35 to 70 degrees C. The structures of the di-, tri- and tetraesters were determined using 13C NMR spectrometry. The diester appeared to be sorbitol 1,6 didecanoate, the triester was sorbitol 1,5,6-tridecanoate and the tetraester was the 1,2,5,6-tetradecanoate, which indicates that the C. viscosum lipase acylates sorbitol in a regioselective manner. PMID- 7858980 TI - Enzyme-catalysed enantioselective hydrolysis of racemic naproxen nitrile. AB - The bacterial strain Rhodococcus butanica (ATCC 21197), which exhibits nitrilase and nitrile hydratase/amidase activities, catalyses the enantioselective hydrolysis of racemic naproxen nitrile (R/S)-1 to furnish a moderate enantiomeric excess of (S)-naproxen (S)-3. Racemic naproxen amide (R/S)-2 is not a good substrate for this strain. Resting cells of the newly selected bacterial strain Rhodococcus sp. C3II catalyse the enantioselective hydrolyses of racemic naproxen nitrile (R/S)-1 and naproxen amide (R/S)-2 as well, to give (S)-3 in excellent optical (99% e.e.) and good chemical yields in aqueous medium and in the biphasic system of phosphate buffer/hexane. PMID- 7858981 TI - Kinetic resolution of substituted 1,3-4H-5,6-dihydrooxazines with carboxylesterase NP: synthesis of (3S,1'R)-3-(1'-hydroxyethyl)-azetidin-2-one. AB - The kinetic resolution of oxazinyl-ethyl carboxylates 4, is reported employing carboxylesterase NP as biocatalyst. Starting from the anti racemic stereoisomers 4c-d, the unreacted ester is obtained in 40% yield and 93% e.e. The enantiomeric acid is obtained in the open form. Cyclization of the latter and base equilibration allows recycling of the undesired stereoisomer. Compound 4d has the absolute configuration required in the azetidinone 3d, an intermediate in the synthesis of penems and carbapenems. PMID- 7858982 TI - Oxidation of 2-methoxynaphthalene by toluene, naphthalene and biphenyl dioxygenases:structure and absolute stereochemistry of metabolites. AB - 2-Methoxynaphthalene was subjected to biooxidation by whole cells of six organisms: Pseudomonas putida F39/D containing toluene dioxygenase, Escherichia coli JM109(pDTG601), containing recombinant toluene dioxygenase from Pp F39/D, Pseudomonas sp. NCIB 9816/11, containing naphthalene dioxygenase. E. coli JM109(pDTG141), containing recombinant naphthalene dioxygenase from NCIB 98161/11, E. coli C534(ProR/Sac) containing recombinant naphthalene dioxygenase from Pp G7, and Beijerinckia sp. B8/36, containing biphenyl dioxygenase. The major product of oxidation by the naphthalene and biphenyl dioxygenases has been isolated and identified as (1R,2S)-dihydroxy-7-methoxy-1,2-dihydronaphthalene, 2c. A minor product, (1R,2S)-dihydroxy-6-methoxy-1,2-dihydronaphthalene, 3c, has also been detected. Oxidation by the toluene dioxygenase-containing organisms led to the isolation of 3c as the major product. Minor products detected in these reactions were 2c, and a third compound, (1S,2S)-dihydroxy-3-methoxy-1,2 dihydronaphthalene, 4c. Structural studies and dehydration of the diols to a mixture of naphthols are described. The absolute stereochemistry of these new diols has been established by correlation with known compounds. The organisms' potential in the production of new metabolites as useful chiral synthons by biooxidation of 2-substituted naphthalenes is indicated. PMID- 7858984 TI - Factors influencing coronary artery bypass graft patency. AB - Coronary artery bypass surgery is one of the most frequently performed and successful operations in improving quality of life for patients with intractible angina. Unfortunately, there is accumulating evidence that angina will eventually return and consequently an increasing amount of repeat surgery is being undertaken. Subsequent operations have a reduced chance of benefit and many patients are only in early middle age at the time of initial surgery. It is obviously of paramount importance, therefore, to try and maintain graft patency for as long as possible. Various factors such as avoidance of certain surgical techniques, use of the internal mammary artery whenever possible, continued use of aspirin and attention to major risk factors are known to significantly influence graft patency. This review examines these factors in detail and provides practical advice on how to optimize long-term patency. PMID- 7858983 TI - The biomimetic oxidation of beta-1, beta-0-4, beta-5, and biphenyl lignin model compounds by synthetic iron porphyrins. AB - The degradation of four dimeric lignin model compounds by meso-tetra(2,6-dichloro 3-sulfonatophenyl)porphyrin iron chloride (TDCSPPFeCl) (2) are reported. 4-Ethoxy 3-methoxyphenylglycerol-beta-guaiacyl ether (3) (a beta-0-4 dimer) was cleaved to give 4-ethoxy-3-methoxybenzaldehyde (4) and guaiacol (5) as major products. The oxidation of 1-(4-ethoxy-3-methoxyphenyl)-2-(4-methoxyphenyl)-1,3-propandiol (6, a beta-1 dimer) gave 4, 4-methoxybenzaldehyde (7), and 4-methoxy-alpha hydroxyacetophenone (8) as major products. Side chain oxidation and aromatic ring cleavage reactions were found to occur for the phenylcoumaran (alpha-5) model compound, ethyl dehydrodiisoeugenol (12). A biphenyl model compound, 4,4' diethyldehydrodivanillin (20), was oxidized to give mono- and dicarboxy derivatives, as well as ring-cleaved products of the acid derivatives. PMID- 7858985 TI - Surgical priorities in the management of arteriopaths. AB - Coronary artery disease and its complications remain the leading cause of death in Western society. With an ageing population there is an increasing number of patients with severe multilevel atherosclerosis. Atheromatous disease affecting the coronary, carotid, abdominal aorta and peripheral vasculature may co-exist, and vascular surgical reconstruction is commonly indicated to more than one site. The investigation and sequence of surgical interventions to minimize morbidity and mortality in this group of patients are discussed. PMID- 7858986 TI - Comparative analysis of glutaraldehyde-preserved porcine xenografts and fresh or glutaraldehyde-treated human aortic valves by holographic interferometry. AB - Although calcification and degeneration are recognized as the main causes of bioprosthetic heart valve failure, the reasons for such failure are not well understood. Hidden tissue anomalies in the valves may be the origin of later calcification. Application of hologram interferometry for non-destructive testing enables the detection of such tissue anomalies. A comparative study by holographic interferometry of ten porcine bioprosthetic valves (seven Carpentier Edwards SAV, two BioImplant and one Valcor) with five human aortic valves before and after glutaraldehyde treatment is presented. Whereas irregularities were detected in the interferograms of eight out of ten bioprostheses, no similar distorted fringe pattern was found in the holographic interferograms of human specimens. The present results suggest that tissue abnormalities exist in standard bioprosthetic valves which are absent in human ones. These irregularities may be the origin of later calcification and valvular dysfunction. PMID- 7858987 TI - Effects of R80122, a new phosphodiesterase inhibitor, on liver and global haemodynamics in patients undergoing coronary artery bypass surgery. AB - R80122 (0.3 mg/kg body weight), a new phosphodiesterase inhibitor, was tested in ten patients undergoing coronary artery bypass surgery. Haemodynamic measurements were made and hepatic blood flow assessed by the indocyanine green infusion method using liver vein catheterization. Cardiac index increased by 63% and systemic vascular resistance decreased by 47%. Hepatic blood flow and intestinal vascular resistance were not significantly affected; nor was hepatic oxygen consumption. It is concluded that R80122 is a highly cardioselective phosphodiesterase inhibitor and that the reduction in systemic vascular resistance by this drug is not an effect of extensive intestinal vasodilatation. PMID- 7858989 TI - Pericarditis: a persisting surgical problem. AB - A study of pericarditis treated surgically over a period of 14.5 years was conducted to evaluate the current pattern and management of this disease in a tropical environment. The series comprised 86 patients (58 males and 28 females) aged from 5 months to 60 years (mean 21.1 years). Pericarditis was effusive in 41 patients, calcific in 33 and fibrous in 12. Aetiological or associated factors were non-specific, pyogenic infection, rheumatic heart disease, endomyocardial fibrosis, tuberculosis and amoebiasis in 36, 21, eight, eight, six and four patients, respectively. All the patients were in New York Heart Association (NYHA) functional class III or IV. Operative treatment involved pericardiotomy with tube drainage in 32 patients, pericardiectomy in 49, and pericardiotomy with subsequent pericardiectomy in five. The total hospital mortality rate was 8.0%, and was largely a result of severe pre-operative cardiac decompensation and multiple organ failure. Of the 79 early survivors, 91% reverted to NYHA functional class I or II. Surgical treatment remains the most effective management of chronic pericarditis which still constitutes a major clinical problem in some countries. PMID- 7858988 TI - Intraoperative assessment of internal mammary artery bypass graft patency by thermal coronary angiography. AB - Following early graft failure in some patients during routine use of the internal mammary artery in coronary bypass surgery, a thermal coronary angiography technique was used for direct intraoperative control of internal mammary artery graft patency. This non-invasive method allows the evaluation of graft patency, anastomotic integrity and initial flow patterns without compromising the conduct of the surgical procedure. Internal mammary artery graft patency was controlled by thermal coronary angiography in 348 patients undergoing coronary bypass surgery. Graft anatomy, perfusion and distal run-off in the recipient native coronary artery was delineated by thermal coronary angiography using the temperature gradient of the warm perfusing blood and the cold myocardium. Thermal coronary angiograms were evaluated for graft and anastomotic patency as well as for direction and magnitude of internal mammary artery flow in the native coronaries. Some 348 internal mammary artery grafts, including 13 sequential grafts, were evaluated. Thermal coronary angiography failed for technical or logistical reasons in seven of 348 cases (2.0%). Thermal coronary angiography documented optimal anterograde flow in 282 of 341 cases (82.7%), reduced anterograde flow in 38 of 341 (11.1%) and no anterograde flow in 21 of 341 (6.2%). Using this approach 21 internal mammary artery graft occlusions were discovered, 18 at the anastomotic site and three at the site of the previously placed bulldog clamp. In addition, six unexpected distal native coronary stenoses and three internal mammary artery graft spasms were detected by thermal coronary angiography and found to be responsible for impaired anterograde flow. Based on these findings, 16 anastomotic revisions, nine additional vein grafts and two additional vein patches were performed.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7858990 TI - Right ventricular rupture after coronary surgery. AB - A 70-year-old woman suffered a fatal right ventricular rupture 12 h after uneventful coronary surgery. Post-mortem examination revealed that the rupture had occurred through an area of fatty infiltration. Myocardium had been replaced by fat cells. The literature is reviewed and pathology of this condition discussed. PMID- 7858991 TI - Reperfusion injury in skeletal muscle: interaction of osmotic and colloid-osmotic pressure in the initial reperfusate for oedema prevention. AB - Previous studies from the authors' laboratory have shown that controlled limb perfusion after prolonged, acute ischaemia minimizes reperfusion injury. The present study was performed to investigate the role of osmotic and colloid osmotic pressure in the initial reperfusate in order to reduce postischaemic limb oedema and subsequent reperfusion injury. A total of 96 isolated rat hindlimbs were used: 18 were perfused immediately after amputation (no ischaemia; untreated) and 78 limbs were subjected to 4 h of warm ischaemia in a moist chamber. Thereafter eight limbs were used to investigate the effects of the addition of mannitol to the initial reperfusate. The remaining 70 limbs received controlled reperfusion (modified reperfusate with various osmotic (315-580 mosmol/l) and colloid-osmotic pressure (0-50 mmHg. perfusion pressure 50 mmHg) during the first 30 min after ischaemia. Controlled reperfusion was always followed by uncontrolled reperfusion (30 min. perfusion pressure 100 mmHg) to simulate the clinical condition where normal blood perfusion at systemic pressure will follow controlled reperfusion. Functional recovery, limb weight, water content of the soleus muscle, limb flow and tissue high-energy phosphates were assessed at the end of the experiment. Results show that a reperfusate without colloid-osmotic pressure (i.e. without macromolecules) produces severe limb oedema (84.6(2.0)% water content) and allows no functional recovery after prolonged warm ischaemia. Addition of mannitol to the initial reperfusate does not prevent severe reperfusion injury. In contrast, a hyperosmotic reperfusate with a colloid-osmotic pressure of 26 mmHg effectively prevents limb oedema (78.6(0.9)% water content, 110.8(2.4)% of control weight). Physiological osmotic pressure (315 mosmol/l), however, will not reduce oedema formation (82.7(0.4)% water content). Furthermore, colloid-osmotic pressure > 26 mmHg increases the viscosity of the reperfusate (flow decreases to < 50% of control) and does not allow an optimal functional recovery. Macromolecules used to create the colloid osmotic pressure should be of similar molecular weight to albumin (69,000 Da); those with a smaller molecular weight (e.g. hydroxyethyl starch40,000/0.5) produce excessive limb oedema (184.9(13.5)% control weight; 85.7(1.4)% water content) without functional recovery (0% control contractions). The present data suggest that after prolonged limb ischaemia: (1) addition of mannitol to a crystalloid solution does not prevent oedema; (2) hyperosmotic reperfusates (380 480 mosmol/l) with a colloid-osmotic pressure of 26 mmHg are most effective in preventing limb oedema; and (3) macromolecules used to achieve colloid-osmotic pressure should have a molecular weight similar to albumin. PMID- 7858992 TI - Reperfusion injury in skeletal muscle: controlled limb reperfusion reduces local and systemic complications after prolonged ischaemia. AB - Previous studies in isolated limbs using crystalloid perfusion solutions have shown that control of the initial reperfusion reduces postischaemic complications. However, no experimental study has been undertaken to evaluate the concept of controlled limb reperfusion experimentally in an in vivo blood perfused model and to assess the local as well as systemic effects of normal blood reperfusion and controlled limb reperfusion. Of 20 pigs undergoing preparation of the infrarenal aorta and iliac arteries, six were observed for 7.5 h and served as controls; 14 others underwent 6 h of complete infrarenal occlusion. Thereafter, embolectomy was simulated in eight pigs by removing the aortic clamp and establishing normal blood reperfusion at systemic pressure. In six other pigs, the composition of the reperfusate and the conditions of reperfusion were controlled during the first 30 min, followed by normal blood reperfusion. Some 6 h of infrarenal aortic occlusion leads to a severe decrease in high-energy phosphates and muscle temperature, together with a slight increase in creatine kinase and potassium in the systemic circulation. Normal blood reperfusion resulted in severe reperfusion injury: massive oedema developed, the tissue showed a marked decrease in oxygen consumption, glucose consumption, tissue ATP, total adenine nucleotides, muscle pH and total calcium in the femoral vein. Furthermore, a massive increase was seen in plasma creatine kinase concentration and potassium, together with the development of muscle rigidity. In sharp contrast, initial treatment of the ischaemic skeletal muscle by controlled limb reperfusion resulted in normal water content, oxygen consumption, glucose consumption, flow and muscle rigidity. Furthermore, controlled limb reperfusion resulted in higher total adenine nucleotides content, less tissue acidosis, markedly reduced creatine kinase release, and potassium release as compared with that of normal blood reperfusion. This study shows that 6 h of acute infrarenal aortic occlusion will result in severe reperfusion injury (postischaemic syndrome) if normal blood at systemic pressure is given in the initial reperfusion phase. In contrast, initial treatment of the ischaemic skeletal muscle by controlled limb reperfusion reduces the metabolic, functional and biochemical alterations. PMID- 7858993 TI - Role of neutrophil depletion and elastase inhibition in modifying skeletal muscle reperfusion injury. AB - This study investigated the effect of neutrophil depletion and neutrophil elastase inhibition on the severity of skeletal muscle reperfusion injury. In a rodent model, indices (experimental/normal limb) of gastrocnemius muscle viability (histochemical staining), oedema (wet:dry weight ratio) and myeloperoxidase content (neutrophil recruitment) were assessed in normal (no ischaemia), ischaemic (6-h unilateral hindlimb ischaemia), control (6-h ischaemia and 4-h reperfusion), neutrophil-depleted rats (given antineutrophil serum) and rats receiving the neutrophil elastase inhibitor Elafin. Neutrophil recruitment muscle infarction and oedema did not occur in normal limbs, or in those subjected to ischaemia without reperfusion. In contrast increased muscle myeloperoxidase levels (P < 0.001), muscle infarction (P < 0.01) and oedema (P < 0.001) all occurred in the reperfused limbs of control animals compared with those of normal and ischaemic rats. Antineutrophil serum and Elafin both reduced neutrophil recruitment during reperfusion (P < 0.001 and P < 0.01 respectively) and muscle viability was preserved. Reperfusion oedema still occurred however, suggesting that altered endothelial permeability is mediated by factors other than neutrophils. PMID- 7858994 TI - Relative risks of limb revascularization and amputation in the modern era. AB - A retrospective review of 266 patients undergoing infrainguinal revascularization for limb salvage and/or major amputation (transmetatarsal, below-knee or above knee) from 1984 to 1990 was conducted to determine comprehensive procedure specific 30-day operative morbidity and mortality rates. Some 211 patients underwent 295 infrainguinal vascular reconstructions (195 primary and 100 secondary reconstructions). There were 122 major amputations in 98 patients (29 above-knee, 70 below-knee and 23 transmetatarsal). Most amputations were performed in patients with unreconstructable vascular disease, including 39 patients (41 extremities) with failed infrainguinal reconstruction. Procedure specific morbidity and mortality rates were 48 and 2% for primary revascularization, 35 and 2% for secondary revascularization and 37 and 4%, for amputation, respectively. The difference in mortality between revascularization and amputation approached but did not achieve statistical significance. Cardiac, graft and wound complications were the major causes of morbidity in all groups. Nine of the 12 deaths were of cardiac etiology. Revascularization can be performed in almost all patients with advanced limb ischemia, with a mortality rate equivalent to, or perhaps lower than, that of amputation. When limb amputation is required, it can be performed with a mortality rate remarkably lower than that described in the older literature. PMID- 7858995 TI - Abdominal aortic hypoplasia: clinical and technical considerations. AB - Hypoplasia of the distal abdominal aorta, first described by Quain in 1847, is rarely associated with atherosclerotic occlusive disease. The condition usually occurs early in life; the principal clinical features are hypertension and arterial insufficiency of the lower extremities which is often well tolerated. Some 20 patients had operations for abdominal aortic hypoplasia; 16 underwent prosthetic reconstruction and four had aortoiliac endarterectomy with angioplasty. Reconstructive techniques were influenced by narrow renal arteries and by the presence of extensive atheroma. The long-term prognosis is often poor, especially in patients with extensive disease. PMID- 7858996 TI - Late occlusion of aortofemoral bypass graft: surgical treatment. AB - Surgical treatment for graft thrombosis is often difficult and its outcome is complicated by a high incidence of rethrombosis. The records of 803 patients (1261 limbs) treated with aortofemoral bypass graft for peripheral vascular disease were reviewed. Among these, 71 patients (63 men and eight women with a mean age of 60.2 years) needed an overall number of 125 reoperations. The mean follow-up was 6.3 years. Smoking was significantly higher in these patients compared with those who were not reoperated on. Intimal hyperplasia was the most common lesion responsible for graft thrombosis. Before 'redo' surgery 20 patients with recent thrombosis received thrombolytic treatment; one was subsequently treated with percutaneous transluminal angioplasty and the others underwent reoperation. The best patency rates were achieved with reconstruction of the distal anastomosis with a graft interposition or with a patch angioplasty. Isolated thrombectomy was complicated by early rethrombosis in 53.3% of cases. The overall amputation rate was 14%, the operative mortality rate 5.6%, and the incidence of complications 16.8%. At follow-up a cumulative secondary patency rate of 81.7% at 5 years (74.5% at 10 years), a limb salvage rate of 80.5%, and a survival rate of 89.2% at 10 years were recorded. It is concluded that the only indications for redo surgery following graft thrombosis are severe limb ischaemia or disabling claudication. PMID- 7858997 TI - Ex situ repair of complex renal artery lesions. AB - A total of 59 patients (from a personal series of 354) underwent ex situ repair of complex renal artery lesions. This series comprised 27 males and 32 females, of whom 15 were children and 44 adults, with ages ranging from 17 months to 70 years. The operated lesions were aneurysms with or without associated stenosis, spontaneous dissection, extensive fibrodysplasia and reoperations on the renal artery. In all patients, the kidney was exteriorized and cooled by perfusion of cold Collins' solution. The kidney was reimplanted after repair in either the loin or the iliac fossa. An arterial substitute was used in 42 patients. No mortality was observed. There were three cases of postoperative thrombosis of the repaired artery. Segmental thrombosis leading to partial atrophy of the kidney occurred in three patients. During long-term follow-up, one repeat stenosis and two fusiform dilatations of the venous autografts were observed. All other repairs (85%) were successful. Arterial hypertension in 46 patients was cured in 33 cases (72%) and improved in eight (17%). Renal function was improved after repair of severe stenotic lesions impairing renal blood flow restored normal circulation to the organ. Ex situ repair must be reserved for: (1) multiple lesions involving terminal branches of the renal artery for which prolonged circulatory arrest is required; and (2) lesions profoundly situated in the renal sinus that are difficult to treat by conventional surgery. PMID- 7858998 TI - Advantages of the lateral approach for re-exploration of the sapheno-femoral junction for recurrent varicose veins. AB - Re-exploration of the sapheno-femoral junction for recurrent varicose veins presents many problems. The lateral approach to the sapheno-femoral junction via a groin incision as previously described was performed in 109 lower limbs. The operative mortality rate was 0%. Functional outcome was good in 106 cases (97.2%) and only in three (2.8%) did recurrent varicose veins occur in the upper thigh. Complications were mainly lymphorrhoea (six cases, 5.5%). Cosmetic results were also satisfactory. This surgical procedure allows an easy and safe approach to the sapheno-femoral junction and avoids damage to femoral vessels. Recurrence was rare and caused by incompetent communicating veins in the upper thigh. These characteristics make the lateral approach the preferred technique for re exploration of the sapheno-femoral junction. PMID- 7858999 TI - Duplex ultrasonography of recurrent varicose veins. AB - Varicose veins are a common clinical finding with a high recurrence rate following treatment with either surgery or sclerotherapy. Patterns of incompetence in 100 limbs with recurrent varicose veins were determined using duplex ultrasonography. Saphenofemoral or recurrent groin tributary incompetence was present in 44 limbs, an incompetent long saphenous remnant in 20, saphenopopliteal incompetence in 28, perforator incompetence in 35 and deep venous incompetence in 22. No significant incompetence was detected in 15 limbs. The findings suggest an important role for deep venous incompetence in recurrent veins and show that a re-exploration of the groin is unnecessary in over half of limbs with recurrent veins. PMID- 7859000 TI - Subadventitial rupture of the splanchnic arteries as the result of blunt abdominal trauma presenting with acute gastric dilatation. AB - Two patients are reported who presented with intestinal ischaemia caused by a subadventitial rupture of the origin of the coeliac trunk and superior and inferior mesenteric arteries after blunt trauma from deceleration injury. In both cases the initial clinical examination revealed a painful abdomen without any 'peritonism'. Abdominal ultrasonographic examination showed no abnormality. Plain abdominal radiography showed gastric dilatation in both patients. In the first, the diagnosis was made by laparatomy but only after 2 days. In the second, diagnosis was made by aortography performed because of the early appearance of gastric dilatation. Both patients died as a result of extensive associated injuries and delay in diagnosis. PMID- 7859001 TI - Hematemesis as initial presentation of traumatic paraceliac pseudoaneurysm of the abdominal aorta. PMID- 7859002 TI - Esophageal physiology. AB - Esophageal peristalsis and sphincter function involve coordinated neuromuscular processes the nature of which differs according to regional muscular anatomy and, to a degree, according to whether motility is initiated by swallowing or esophageal distension. The physical characteristics of the bolus and the conditions of testing may alter the speed and force of the propulsive contraction. Neural control of these processes and their modulation involves parasympathetic, sympathetic and enteric innervation of the organ. In smooth muscle regions, myogenic mechanisms may also play a role. PMID- 7859003 TI - Medical and surgical treatment of uncomplicated gastroesophageal reflux. AB - It appears obvious from the literature that several different antireflux procedures yield good to excellent results when performed by practitioners skilled and experienced in their performance. However, even a good operation will provide poor results in untrained hands. The choice of operations for the treatment of uncomplicated gastroesophageal reflux should be based on the training and experience of the operator. PMID- 7859005 TI - Failed antireflux operations. Pathophysiology and treatment. AB - This article reviews the pathophysiology of failed antireflux operations and sets forth diagnostic and therapeutic strategies. Utilization of esophageal function tests is stressed. A thoracic rather than abdominal approach is recommended to provide all surgical options. PMID- 7859004 TI - Medical and surgical management of peptic esophageal strictures. AB - Peptic esophageal strictures usually respond to intensive medical therapy and dilation. Failure of such management necessitates surgical intervention, usually consisting of dilation and fundoplication, for which results are good. More complex problems require gastroplasty, acid suppression and alkaline diversion, or resection; outcomes of these operations are not as favorable. PMID- 7859006 TI - Barrett's esophagus. AB - The development of the columnar-lined lower esophagus, or Barrett's disease, is an acquired condition due to reflux of gastric and duodenal contents. The medical treatment of patients with reflux disease and Barrett's esophagus is currently the same as for patients with reflux without Barrett's disease which may indicate more aggressive antireflux control. Constant surveillance of the Barrett's mucosa remains important. The progression of squamous epithelium to Barrett's metaplasia and eventually invasive carcinoma in a subgroup of patients is well described and becoming more frequent. The discovery of this carcinogenic process is becoming extremely important as it may help improve the dismal long-term prognosis of patients with adenocarcinoma of the distal esophagus and gastroesophageal junction. PMID- 7859008 TI - Esophageal diverticula. AB - Diverticula disease of the esophagus is associated with specific motor dysfunctions. Motility disorders at the pharyngoesophageal junction result from a restrictive pathology of the upper esophageal sphincter. Hyperdynamic motor abnormalities are seen with distal esophageal diverticula. Treatment of the motor disorder is essential in the management of these conditions. PMID- 7859007 TI - Achalasia of the esophagus. AB - Achalasia, a disease of unknown cause, is characterized by absence of peristalsis in the esophagus body and incomplete relaxation of the lower esophageal sphincter (LES) in response to swallowing. This article reviews the history and pathogenesis of achalasia along with clinical manifestations, diagnosis and management options relating to the disease. PMID- 7859009 TI - Benign tumors of the esophagus. AB - Benign esophageal tumors and cysts are rare. Leiomyomas and various cysts account for about 80% of all lesions. Thoracic surgeons must be aware of the clinical, radiologic, and endoscopic features of benign lesions since treatment is usually simple and effective. PMID- 7859010 TI - Esophageal disease in the pediatric age group. AB - This article reviews the congenital disorder, esophageal atresia (EA) and tracheoesophageal fistula (TEF), and the acquired problem of gastroesophageal reflux (GER). Each can cause significant morbidity, but if treated appropriately can have gratifying results. EA and TEF anomalies exemplify a congenital disorder which is life threatening, but have been treated with improved success over the past three decades and continue to challenge pediatric surgeons. GER is an abnormal physiologic event which with overt emesis can present pulmonary problems or pathologies involving the esophagus alone. Recognition of GER as part of a foregut motility disorder enhances our understanding of the problem and its treatment. PMID- 7859011 TI - Penetrating and blunt injuries of the esophagus. AB - Though uncommon, the incidence of esophageal injury from external trauma is increasing in frequency and requires a thorough knowledge of the principles of esophageal surgery in general and familiarity with the options for repair of both the different anatomic locations of injury and the various types of injuring agents. Such knowledge and experience will avoid the potential for complications such as those described centuries ago by Richard Wiseman in the young man who impaled himself on his toy sword. PMID- 7859012 TI - Boerhaave's syndrome and barogenic injuries of the esophagus. AB - Herman Boerhaave clearly elucidated the pathology of barogenic esophageal perforation during the 18th century by describing the sad and fatal case of Baron John von Wassenauer. Although the science of the time had no treatment and surgery was considered a fool's venture, Boerhaave's description has stood the test of time and set the stage for modern surgical repair and treatment. The expeditious diagnosis, aggressive early repair, and vigilant attention to drainage of esophageal perforations in the 20th century all reduce the morbidity and are essential steps to obtaining the best outcome. Today, survival of barogenic esophageal perforation requires the surgeon to have the clarity of Boerhaave's observation of symptoms and to make use of modern surgical techniques to assure the patient's recovery from Boerhaave's syndrome. PMID- 7859013 TI - Long-term follow-up of humans with single kidneys: the need for longitudinal studies to assess true changes in renal function. PMID- 7859014 TI - Renal matrix and adhesion in injury and inflammation. AB - Over the past year, there have been major advances in the descriptive analysis of the extracellular matrix in the kidney. Several aspects of the interaction of matrix molecules with renal and, in particular with glomerular cells via specific integrin receptors, have also been studied. Most results on cell-matrix interactions have been obtained by in vitro investigations of glomerular mesangial cells in two-dimensional culture. The regulation of matrix formation and degradation has been shown to involve the concerted action of several soluble factors, notably transforming growth factor-beta, as well as the effects of nonsoluble matrix components themselves, such as collagens and proteoglycans. The mediation of such complex interactions between cells, matrix, and cytokines is facilitated by the tightly regulated expression of cell surface receptors, eg, cytokine receptors and integrins of the beta 1 series, which bind specific matrix molecules. New results have yielded more insight into the regulation not only of matrix formation but also of the specific interactions between cells and matrix and of the modulation of cytokine activity by matrix molecules. Using experimental rat models and transgenic mouse models of kidney disease, the first in vivo findings using immunohistochemistry and mRNA analysis have confirmed that major changes occur in the expression of matrix molecules, integrins, and cytokines in the process of glomerular inflammation. With the advent of specific modulators of the bioactivity of ligands and receptors, it is hoped that more information will be forthcoming on the functional relevance of various components of the cell-matrix-cytokine crosstalk in the normal and injured kidney. PMID- 7859015 TI - Hormonal disturbances of calcium metabolism in renal failure. PMID- 7859017 TI - The prevention of secondary hyperparathyroidism. AB - It has become increasingly evident that clear-cut disturbances of bone and mineral metabolism develop early in renal failure. Among these disturbances, hyperparathyroidism is well documented and is usually asymptomatic at that early stage. It is now accepted that early therapy using phosphate restriction, through diet and calcium-containing phosphate binders, and 1 alpha-hydroxylated vitamin D analogues is an effective means of preventing or even reversing hyperparathyroidism in early renal failure. The response to these therapies is both functional (reduced parathyroid hormone secretion) and structural (prevention of parathyroid gland hyperplasia). Parathyroid hyperplasia is largely irreversible; prevention is therefore important and can be achieved initially by a combination of diet and calcium-containing phosphate binders, with later addition of calcitriol or alfacalcidol if parathyroid hormone control cannot be achieved or sustained. PMID- 7859016 TI - Mechanisms underlying the regulation of parathyroid hormone secretion in vivo and in vitro. AB - Recent advances in our understanding of the regulation of parathyroid hormone secretion in vivo and in vitro are reviewed. The use of assays specific for immunoreactive intact parathyroid hormone has greatly improved our capacity to study parathyroid hormone dynamics in vivo. Such studies have emphasized the steep, inverse sigmoidal relationship between circulating intact parathyroid hormone and serum ionized Ca2+ concentrations, which can be modulated in a reciprocal fashion by 1,25 dihydroxyvitamin D. The use of the intact assay has also revealed additional complexities in the control of parathyroid hormone dynamics in vivo, including circadian and pulsatile patterns in parathyroid hormone as well as hysteresis and rate dependence in the relationship between intact parathyroid hormone levels and Ca2+. Studies in vitro have emphasized the role of a putative, extracellular Ca2+ receptor in regulating parathyroid function that is coupled by one or more G proteins to intracellular second messengers and parathyroid hormone secretion. Finally, the regulation of parathyroid hormone gene expression by extracellular Ca2+ and 1,25 dihydroxyvitamin D has been clarified at a molecular level by the description of specific motifs in the upstream region of the parathyroid hormone gene that mediate binding of specific inhibitory nuclear factors. PMID- 7859018 TI - Recent progress in management of secondary hyperparathyroidism of chronic renal failure. AB - Recent progress in cellular and molecular biology has had a great impact on our understanding of parathyroid hormone-vitamin D physiology and of the pathogenesis of secondary hyperparathyroidism in chronic renal failure and made possible the development of new therapeutic approaches for management of bone disease in dialysis patients. Management of parathyroid hyperplasia by calcitriol pulse therapy is one example. Suppression of parathyroid hyperfunction by other vitamin D analogues was also proposed, and some of these analogues are now under clinical trial. Further, percutaneous ethanol injection into hyperplastic parathyroid glands under ultrasonographic guidance has become the choice practical procedure under certain clinical settings and can be an effective alternate to surgical parathyroidectomy. In this article, we review selected and pertinent progress in the pathogenesis and management of secondary hyperparathyroidism and parathyroid hyperplasia, major causes of morbidity in chronic dialysis patients, emphasizing the important contributions made by laboratory research and critical clinical observations. PMID- 7859019 TI - Management of hyperphosphatemia in patients with renal failure. AB - Phosphate retention plays a major role in the pathogenesis of hyperparathyroidism at all stages of renal insufficiency. Dietary phosphate restriction is mandatory only for adults and is not advised for children because of the recommended diet allowance. Dietary restriction is usually not sufficient, and phosphate binders are almost always necessary when the glomerular filtration rate falls below 40 mL/min. Because long-term administration of aluminum phosphate binders is associated with risk of aluminum intoxication despite the use of so-called "safe doses", alternative phosphate binders should be used. Magnesium hydroxide and carbonate can be used only for dialysis patients because a low dialysate magnesium concentration is necessary to prevent the hazards of hypermagnesemia. Therefore, the major alternative is the use of alkaline salts of calcium. The most recently proposed salt, acetate, has a higher phosphate-binding capacity than carbonate but exposes patients to the same incidence of hypercalcemia despite the use of half the dose of elemental calcium. These salts should be taken with meals in order to complex more dietary phosphate and decrease calcium absorption and therefore the risk of hypercalcemia. Oral calcium alone, without 1 alpha OH-vitamin D3 derivatives, can prevent hyperphosphatemia and hyperparathyroidism in most uremic patients before dialysis and in about half of the patients dialyzed with a dialysate calcium of 1.5 to 1.65 mmol/L. 1 alpha OH vitamin D3 derivatives, which increase intestinal absorption of phosphate, should be used only when hyperphosphatemia has been prevented by oral calcium and diet and when plasma parathyroid hormone levels increase above three times the upper limit of normal. To decrease hypercalcemic risk, patients should be given 1 alpha OH-vitamin D3 derivatives, preferably at night, as an intermittent bolus (intravenous or oral). In dialysis patients, the dialysate concentration of calcium may have to be further decreased in order to prevent hypercalcemia when high doses of oral calcium are necessary to control hyperphosphatemia. PMID- 7859020 TI - Recent advances in the management of renal osteodystrophy in children. AB - Secondary hyperparathyroidism remains the predominant histologic lesion in pediatric patients undergoing regular dialysis, but recent evidence indicates that the regulation of parathyroid hormone secretion by calcium does not differ substantially between patients with osteitis fibrosa and subjects with normal renal function. Growth retardation and skeletal deformities are major findings in pediatric patients with renal osteodystrophy, and alterations in vitamin D metabolism and insulin-like growth factor almost certainly contribute to these findings. Avoidance of aluminum-containing medications and the introduction of intermittent calcitriol therapy provide newer approaches to the effective management of secondary hyperparathyroidism in pediatric patients with end-stage renal disease. PMID- 7859021 TI - Effects of metabolic and respiratory acidosis on bone. AB - Acidosis had long been thought to influence the bone mineral; however, there was little direct evidence to support this impression. When neonatal mouse calvariae are cultured for 3 hours in medium with a reduced bicarbonate concentration, a model of acute metabolic acidosis, there is net calcium efflux from bone in addition to a net influx of protons into bone lessening the magnitude of the acidosis. The protons appear to exchange for sodium and potassium on the bone surface. In these acute experiments, the calcium efflux appears to be due to mobilization of carbonated apatite through an alteration in the physicochemical driving forces for bone accretion and dissolution. In more chronic cultures (greater than 48 hours) metabolic acidosis induces calcium efflux by stimulating osteoclastic bone resorption and inhibiting osteoblastic bone formation. When calvariae are cultured acutely in medium with an elevated partial pressure of carbon dioxide, a model of respiratory acidosis, there is also calcium efflux, but at the same decrement in pH the magnitude is far less than that observed during metabolic acidosis. There does not appear to be any measurable influx of protons into bone, and during chronic cultures there is no measurable calcium efflux. Thus, acidosis influences the bone mineral; however, for the same decrement in pH there is a marked difference in the response of bone to models of metabolic and respiratory acidosis. PMID- 7859022 TI - Renal pathophysiology. PMID- 7859023 TI - Treatment of hyperlipidemia in chronic progressive renal disease. AB - Experiments in animal models suggest that correcting abnormalities in lipid metabolism could help slow the rate of functional decline in patients with chronic progressive renal disease. Circumstantial evidence in humans also suggests that lipids may play a role in the pathogenesis of glomerulosclerosis. Nevertheless, large controlled clinical trials examining the effect of lipid lowering strategies on renal disease progression have not been carried out. However, the recent development of antilipemic agents that appear to be safe and effective in patients with renal disease should make it possible to determine whether treating hyperlipidemia will reduce the rate of renal disease progression. PMID- 7859024 TI - Extracellular matrix gene expression in experimental glomerulonephritis. AB - Recent studies using animal models of glomerulonephritis indicate that steady state levels of mRNAs encoding basement membrane proteins are frequently, but not universally, increased in parallel and that mRNAs encoding interstitial matrix proteins represent a separate set of genes that may also display coordinate regulation. A variety of maneuvers that ameliorate progressive glomerulosclerosis may act, at least in part, by suppressing glomerular cell matrix protein gene expression. The observed coordinate regulation of matrix genes may be a consequence of shared genetic regulatory sequences. Future therapies designed to retard glomerulosclerosis may take advantage of similarities among the extracellular mediators and regulatory sequences that influence matrix gene expression. PMID- 7859025 TI - Cellular and molecular aspects of renal repair in acute renal failure. AB - Experimental data suggest that the recovery of renal function after ischemic or nephrotoxic acute renal failure is due to a replicative repair process dependent on predominantly paracrine release of growth factors. These growth factors promote renal proximal tubule cell proliferation and a differentiation phase dependent on the interaction between tubule cells and basement membrane. These insights identify the molecular basis of renal repair in ischemic and nephrotoxic acute renal failure and may lead to potential therapeutic modalities that accelerate renal repair and lessen the morbidity and mortality associated with these renal disease processes. PMID- 7859026 TI - Postischemic renal injury due to oxygen radicals. AB - Ischemia-reperfusion injury occurs in many organs and is the underlying cause of many disease processes, including myocardial infarction, stroke, and acute renal failure, which in total are responsible for the majority of deaths seen in developed countries. Most of the injury seen with this process is associated with the reperfusion phase in which the blood flow to the ischemic tissues is reinstituted. This reperfusion phase is associated with the formation of reactive oxygen species (ROS) in the tissues, and the sources of these oxidants are both the neutrophil as well as parenchymal cells such as endothelium. In the kidney as well as other organs, antioxidant therapy is protective, suggesting an important role for these agents. However, there is emerging evidence that ROS are not solely responsible for the reperfusion injury. In many of the kidney models of ischemia-reperfusion, antioxidants are only partially effective in ameliorating the functional and morphologic alterations. Furthermore, in vitro, ROS do not appear to be primarily involved in the killing of renal tubular epithelial cells, which is the morphologic hallmark of acute renal failure. Thus, reperfusion injury, like other types of tissue injury, appears to be mediated by more than one class of inflammatory mediator. PMID- 7859027 TI - Hyponatremia: epidemiology, pathophysiology, and therapy. AB - Despite several decades of research interest and productivity, many aspects of hyponatremia and hypo-osmolar disorders remain incompletely understood. Among these aspects are questions relating to the morbidity and mortality actually attributable to hyponatremia, possible hormonal and gender-associated risk factors underlying susceptibility to neurologic complications from hyponatremic encephalopathy, the stimuli to arginine vasopressin secretion in some atypical subsets of patients with the syndrome of inappropriate antidiuretic hormone secretion and other hyponatremic disorders, the contributions of natriuresis and natriuretic peptides to hyponatremic states, the pathologic determinants of brain demyelination that sometimes follow rapid correction of hyponatremia, and appropriate treatment guidelines for patients with acute and chronic hyponatremia. The recent literature confirms that acceptable answers to these questions and others are still not available, and a better understanding of basic issues regarding the pathophysiology of hyponatremia is needed. Several recent advances stand out as being likely to enhance our future understanding of hyponatremia and hypo-osmolar states. First are studies of cellular mechanisms of volume regulation in kidney and brain tissue in response to changes in osmolality. Many, though clearly not all, clinical observations can be better understood by considering them in the conceptual framework provided by knowledge of cell and body fluid compartment volume regulation. Second is the elucidation of several important protein structures via complementary DNA cloning, including the arginine vasopressin V1 and V2 receptors, several organic osmolyte transporters, and the CHIP28 water channel. Future application of these new tools to carefully designed and executed physiologic studies will likely add considerable new knowledge to our understanding of hyponatremia. Third is the development and increasing application of nuclear magnetic resonance spectroscopy and imaging methods that will allow more detailed analyses of acute changes in brain metabolism during hyponatremia and following correction. Finally, the recent development of nonpeptide antagonists to arginine vasopressin V1 and V2 receptors should enable clinical studies to assess more accurately the contribution of arginine vasopressin-induced antidiuresis to hyponatremia and more importantly holds the promise of more effective therapies for hyponatremic patients. PMID- 7859028 TI - Clinical relevance of the natriuretic peptides in edematous states. AB - The natriuretic peptide system, which comprises at least four related proteins: atrial natriuretic peptide; brain natriuretic peptide; C-type natriuretic peptide; and urodilatin, exerts important influences on central and renal hemodynamics and renal sodium excretion. Recent studies have examined the role of these peptides in the pathophysiology of edema formation in congestive heart failure, cirrhosis, and nephrotic syndrome and have explored the therapeutic value of manipulating their metabolic pathways. One striking feature appears common to all three states ie, a blunted response to the natriuretic effect of atrial natriuretic peptide, which becomes particularly severe in the late stages of each disease. However, whereas in congestive heart failure and cirrhosis the main mechanism responsible is enhanced proximal tubular reabsorption of sodium resulting in reduced distal sodium delivery to the major site of atrial natriuretic peptide action, in nephrotic syndrome a biochemical defect in the cellular response to atrial natriuretic peptide within the kidney is a more likely explanation. Most information regarding the efficacy of therapies that alter the metabolism or the local action of atrial natriuretic peptide pertain to congestive heart failure. However, continued investigation in this area may ultimately lead to interventions that play a valuable role in the future management of all three edematous states. PMID- 7859029 TI - OKT3 monoclonal antibodies induce interleukin-6 and interleukin-10: a possible cause of lymphoproliferative disorders associated with transplantation. AB - The risk of posttransplantation lymphoproliferative disorder (PTLD) has increased with the use of new, highly potent immunosuppressive agents. Monoclonal anti-T cell antibodies such as OKT3 have been associated with a particularly high risk of these frequently fatal Epstein-Barr virus (EBV)-related B-cell neoplasms. OKT3 is a powerful mitogen, raising the possibility that T-cell activation and cytokine release may facilitate the development of PTLD. Interleukin-6 and interleukin-10 have recently been shown to play major roles in B-cell neoplasia in general, and particularly in EBV-induced B-cell transformation and outgrowth. The development of PTLD after treatment with OKT3 might be mediated by the release of those cytokines. On the other hand, OKT3-related PTLD may simply be the result of the profound T-cell depletion induced by the drug, and the mechanisms for lymphomagenesis may be no different than those operative in PTLDs arising in other immunosuppressed patients. A clearer understanding of the relevant mechanisms will require further work with in vivo models of the disease and may have significant implications for the design of new immunosuppressive agents. PMID- 7859030 TI - Mineral metabolism. PMID- 7859031 TI - Renal pathophysiology. PMID- 7859032 TI - Transfer of exogenous genes into the kidney. PMID- 7859033 TI - Urodilatin: from cardiac hormones to clinical trials. PMID- 7859034 TI - Evaluation of nephrotoxicity in vitro using a suspension of highly purified porcine proximal tubular cells and characterization of the cells in primary culture. AB - Proximal tubular cells (PTC) were isolated from porcine kidney by collagenase treatment, subsequently purified on a discontinuous density gradient and finally cultured. Porcine PTC (PPTC) in primary culture expressed keratin, characteristics of epithelia and brush border specific glycoproteins (FX1A). In addition, vimentin was present. All cells were negative for the endothelial marker pal-E. Less than 0.1% expressed the Tamm-Horsfall protein, characteristic of the distal tubule, while less than 0.3% of all cells in culture expressed desmin, characteristic of connective tissue (i.e. fibroblasts) and mesangial cells. Ultrastructural analysis revealed microvilli, tight junctions and abundant mitochondrial and lysosomes, all characteristics of proximal tubular cells. Freshly isolated PPTC were validated as in vitro model to detect nephrotoxicity by studying the effect of mercuric chloride, cis-platin, p-aminophenol and the halogenated alkenes 1,2 dichlorovinyl-l-cysteine, S-(1,1-difluoro-2,2 dichloroethyl)-L-cysteine (DCDFE-cys) and the glutathione conjugate of DCDFE on viability and mitochondrial membrane potential. The cells responded, time- and dose-dependently, to the nephrotoxic compounds with a decrease in mitochondrial membrane potential and loss of viability. The sensitivity of the porcine cells in detecting toxic effects corresponded favorably with in vitro systems derived from other animals. PMID- 7859035 TI - Growth of proximal tubular cells in the presence of albumin and proteinuric urine. AB - The degree of interstitial scarring and proteinuria both correlate with renal function in progressive renal disease. Cellular hypertrophy and hyperplasia have been shown to occur under different experimental conditions. This study investigated the effect of protein on the growth of OK cells. Bovine serum albumin (BSA)- and fatty-acid-free BSA (FFBSA)-stimulated proliferation of OK cells and hypertrophy occurred when the cells were incubated with 10 mg/ml of BSA or FFBSA. Incubation with proteinuric urine from nephrotic rats resulted in much greater proliferation. Hence protein can alter proximal tubular cell growth in culture and the mixture of proteins in proteinuric urine has a greater effect than can be explained by albumin alone. These findings may be of significance in the progression of renal disease and indicate the potential importance of urinary proteins other than albumin in modulating tubular cell growth. PMID- 7859036 TI - Urodilatin inhibits sodium reabsorption in the isolated perfused rat kidney. AB - The effect of human urodilatin (hURO) on kidney function has been examined in stable recirculating isolated perfused rat kidney. The concentration-dependent effects of urodilatin (URO) on isolated perfused rat kidney were analyzed at different perfusion pressures. The experiments show that at perfusion pressures of 100 or 130 mm Hg, 100 nmol/l hURO cause a significant increase of urine flow and a significant decrease of the fractional sodium reabsorption from 95.2 (SD 0.9, n = 5) to 85.6% (SD 0.9, n = 5) and 86.8 (SD 1.6, n = 5) to 77.6% (SD 3.2, n = 5), respectively. In contrast, at a perfusion pressure of 80 mm Hg sodium excretion was not increased by URO. The glomerular filtration rate was unchanged. Furthermore, the renal effects of hURO were compared with rat urodilatin (rURO) and the circulating form of rat cardiodilatin/atrial natriuretic peptide (rCDD/ANP 99-126). hURO, rURO, and rCDD/ANP produced a concentration-dependent increase in sodium excretion. However, differences in natriuretic efficiency are observed. rCDD/ANP causes a decrease in fractional sodium reabsorption from 93.6 (SD 2.6, n = 5) to 86.8% (SD 2.4, n = 5), similar to hURO. rURO shows a significantly higher natriuretic effect decreasing fractional sodium reabsorption from 92.0 (SD 0.7, n = 5) to 79.1% (SD 1.2, n = 5). From these results we conclude that the response of the isolated kidney to URO is critically dependent on the perfusion pressure and that URO exhibits tubular action on renal sodium excretion. The observed differences among the tested peptides on renal function may be due to species differences in the peptide sequence. PMID- 7859037 TI - Effect of chronic renal failure on the abundance of mRNA for enzymes of intermediary metabolism in kidney and liver. AB - In chronic renal failure (CRF), renal ammoniagenesis and handling of ornithine cycle intermediates (ornithine, citrulline, and arginine) are disturbed. The present study examined the molecular mechanisms of these disturbances in kidney and liver of rats with moderate CRF induced by 5/6 nephrectomy. The steady state level of mRNA for phosphoenolpyruvate carboxykinase (PEPCK) and argininosuccinate synthetase (ASS) in both kidney and liver were unaffected by CRF. On the other hand, that for phosphate-dependent glutaminase (PDG) was increased while that for ornithine decarboxylase (ODC) was decreased in the diseased kidney. Combined with previously reported enzymatic activities, our findings suggest that, in CRF, gene expression is responsible for enzymatic changes of PDG and ODC, not of PEPCK and ASS. Underexpression of ODC, resulting in impaired renal polyamine synthesis, may contribute to progression of CRF. Finally, the significant increase in renal mRNA expression of beta-actin precludes the use of this molecule as a reference in CRF. PMID- 7859038 TI - Effect of morphine and naloxone on oxidative metabolism during experimental renal ischemia and reperfusion. AB - During experimental renal ischemia and reperfusion in rabbits, morphine as well as naloxone significantly inhibited the increased superoxide anion (O2-) generation by resting and opsonized zymosan-stimulated phagocytes in renal venous blood. Morphine with naloxone in combination inhibited O2- generation to a lesser extent than that observed when these drugs were used separately. Morphine and/or naloxone did not significantly affect erythrocyte superoxide dismutase (SOD-1), glutathione peroxidase (GPx) and catalase activities or malonyldialdehyde (MDA) concentrations in venous blood during renal ischemia. During reperfusion there was a tendency to a slight reduction of erythrocyte catalase activity in morphine treated animals, and to slight diminutions of erythrocyte SOD-1 and GPx activities and erythrocyte MDA concentrations in rabbits treated with naloxone and morphine in combination. These results indicate that opioid receptor agonists and antagonists modify the response of the kidney to acute injury. These effects may have relevance to the pattern of oxidative stress seen in patients with acute ischemic renal failure. PMID- 7859039 TI - Beyond benefits: the importance of a pediatric standard in private insurance contracts to ensuring health care access for children. PMID- 7859040 TI - Race and ethnicity--changes for children. PMID- 7859041 TI - The changing American family: implications for children's health insurance coverage and the use of ambulatory care services. PMID- 7859042 TI - Violence and today's youth. PMID- 7859043 TI - The health of Latino children in the United States. PMID- 7859044 TI - Public policy implications of HIV/AIDS in adolescents. PMID- 7859045 TI - Involuntary smoking and children's health. PMID- 7859046 TI - Prevention of neural tube defects with folic acid a success but... PMID- 7859047 TI - Particle size: the key to the atherogenic lipoprotein? AB - Using different analytical methods, up to 12 low-density lipoprotein (LDL) subfractions can be separated. LDL particle size decreases with increasing density. Smaller, denser LDL particles seem more atherogenic than the larger, lighter particles, based on the experimental findings that smaller LDL particles are more susceptible for oxidation in vitro, have lower binding affinity for the LDL receptors and lower catabolic rate, have a higher concentration of polyunsaturated fatty acids, and potentially interact more easily with proteoglycans of the arterial wall. Clinical studies have shown that a smaller LDL subfraction profile is associated with an increased risk of heart disease, even when total cholesterol level is only slightly raised. There is a strong inverse association between LDL particle size and triglyceride concentrations. Although LDL particle size is genetically determined, its phenotypic expression may also be affected by environmental factors such as drugs, diet, obesity, exercise or disease. Factors that shift the LDL subfractions profile towards larger particles may reduce the risk of heart disease. PMID- 7859048 TI - Pregnancy and its outcome in systemic lupus erythematosus. AB - In a multi-centre prospective study of systemic lupus erythematosus and pregnancy in France, 117 cases were identified from 1987 to 1992. We report significant morbidity and mortality for mother and fetus from an analysis of 103 cases. Pregnancy outcome was as follows: 28 full-term births, 48 premature births, 18 fetal losses (13 early and two late spontaneous abortions, three stillbirths), five therapeutic abortions and four elective abortions (for unwanted pregnancy). Four preterm neonates died. Lupus was active at pregnancy onset in 28 patients. Of 75 patients with inactive lupus at conception, 27 relapsed during pregnancy, and seven postpartum. Two patients with nephrotic syndrome treated with high-dose corticosteroids died from opportunistic infections. Fetal loss correlated with a history of proteinuria and absence of anti-SSA antibodies. Prematurity was related to a history of fetal loss, active lupus at pregnancy onset, hypertension and > or = 20 mg/day prednisone during pregnancy. Intrauterine growth retardation correlated with pregnancy of short duration, low serum C3 or C4, hypertension, and absence of SSA antibodies. Three of 22 newborns whose mothers had anti-SSA antibodies developed neonatal lupus: two with cutaneous involvement and one with complete atrioventricular block. PMID- 7859049 TI - Psychiatric outcome in alcoholic liver transplant patients. AB - We investigated drinking behaviour and psychiatric outcome of patients with alcoholic liver disease after liver transplantation, to help assess the advisability of the procedure in these patients. English-speaking patients (n = 20) transplanted for alcoholic liver disease and informants, and patients transplanted for non-alcoholic liver disease (n = 54), were assessed by semi structured interviews and standardized questionnaires 1-6 years following transplantation. All alcoholics were abstinent for several months after transplantation, but only one patient remained totally abstinent. Sixteen of the 20 alcoholics later returned to regular drinking; the mean daily alcohol consumption was 3.5 units. Forty percent of the group were drinking above the recommended safe levels for the general population and over 50% were 'binge' drinking intermittently. The alcoholic liver transplant patients did not have higher levels of psychiatric or physical morbidity than controls. Patients with alcoholic liver disease return to drinking after a period of abstinence following liver transplantation, although at lower levels than before. Their vulnerability to alcohol abuse is not explained by higher levels of physical or psychiatric morbidity. PMID- 7859050 TI - Plasminogen activator inhibitor activity in diarrhoea-associated haemolytic uraemic syndrome. AB - In the haemolytic uraemic syndrome (HUS), platelet microthrombi and deposition of fibrin in glomeruli may contribute to the development of renal failure. The balance of procoagulant and fibrinolytic activities in the renal vasculature may therefore have an important role. We measured plasminogen-activator inhibitor (PAI) activity in the plasma of 81 children with diarrhoea-associated (D+) HUS, and found elevated PAI activity in many patients. When we categorized patients by need for dialysis, only the dialysed group had significantly higher levels of activity, compared with a group of normal controls. We also compared PAI activity with patient outcome after one year, and found that those with a poor outcome had significantly higher PAI activity than those with a good outcome. We suggest that plasma PAI activity may be an acute marker for dialysis requirement in HUS, and may have prognostic value for long-term outcome. The possible role of PAI in the pathogenesis of HUS requires further investigation. PMID- 7859051 TI - Enalapril versus bendroflumethiazide in type 2 diabetes complicated by hypertension. AB - In a double-blind, double-dummy, randomized, multi-centre study, the effects of bendroflumethiazide vs. enalapril on blood pressure, glycaemic control, lipoprotein concentrations and albuminuria were compared in non-proteinuric, hypertensive type 2 diabetic patients; they were treated for 20 weeks with either bendroflumethiazide 2.5-5.0 mg (n = 59) or enalapril 10-20 mg (n = 55). Age, fasting plasma glucose, HbA1c and BMI were similar in the groups. Systolic and diastolic blood pressure were reduced in both groups. Bendroflumethiazide was accompanied by minor but significant elevations in fasting plasma glucose and serum C-peptide. HbA1c was increased during both treatments. Lipoproteins and urinary albumin/creatinine ratio were stable. Bendroflumethiazide caused a decrease in serum potassium and an increase in serum urate. No significant correlations were observed between the decline in blood pressure and changes in the metabolic risk factors. Baseline levels of age, sex, BMI, blood pressure or urinary albumin/creatinine ratio were not related to changes in blood pressure, metabolic parameters or urinary albumin/creatinine ratio. PMID- 7859052 TI - Staphylococcal tricuspid valve endocarditis in patients with structurally normal hearts and no evidence of narcotic abuse. AB - We report four cases of staphylococcal tricuspid valve endocarditis in patients with structurally normal hearts and no evidence of intravenous drug abuse. The only risk factor was superficial skin sepsis in three of these patients. Medical therapy was successful in all four cases. PMID- 7859053 TI - Teaching medical ethics. PMID- 7859054 TI - Aetiology of multiple sclerosis. PMID- 7859055 TI - Right hemisphere semantic performance and competence in a case of partial interhemispheric disconnection. AB - Various forms of right hemisphere (RH)-spontaneous or provoked--performance changes were observed in a partial split-brain patient. Variations in hemispheric activation levels and their interhemispheric balance were retained as the most plausible mechanisms for accounting for these facts. This article presents our attempts to obtain higher RH lexical semantic performance than that observed in a preliminary study where RH performance was at chance level: two forms of the dual task paradigm were used in order to improve the expression of an assumed RH potential for lexical semantics. Experiment 1 was aimed at activating the RH with a visuo-spatial task as a prior activity before each semantic decision trial. Experiment 2 was intended to overload LH processing systems with a concurrent verbal memory task and induce RH release from LH inhibition. As expected, better RH lexical semantic performance was obtained in these two conditions. Using pictures as stimuli, the aim of Experiment 3 was to observe the spontaneous temporal course of RH implementation in a semantic decision task devoid of written words. These results are discussed along with the issues of performance/competence and the dynamics of neurocognitive function. PMID- 7859056 TI - The efficacy of treatment for aphasic persons: a meta-analysis. AB - A meta-analysis of research findings is reported on the effectiveness of treatments for persons suffering aphasia. Twenty-one studies provided sufficient information for inclusion in the analysis. The magnitudes of three classes of effect sizes were estimated: untreated recovery, treated recovery, and treated versus untreated recoveries. The outcomes witness the clear superiority in performance of persons receiving treatment by a speech-language pathologist. PMID- 7859057 TI - Origins of paraphasias in deep dysphasia: testing the consequences of a decay impairment to an interactive spreading activation model of lexical retrieval. AB - This study investigates an account of atypical error patterns within the framework of an interactive spreading activation model. Martin and Saffran (1992) described a patient, NC, whose error pattern was unusual for the occurrence of higher rates of form-related than meaning-related word substitutions in naming and the production of semantic errors in repetition. They proposed that NC's error pattern could be accounted for by a pathologically rapid decay of primed nodes in the semantic-lexical-phonological network that shifts the probabilities of error outcome in lexical retrieval. In the present study, Martin and Saffran's account was tested and supported in a series of simulations that reproduce essential features of NC's lexical error pattern in naming and repetition. Also described here are the results of a longitudinal study of NC's naming and repetition, which revealed a shift in relative lexical error rates toward a qualitatively normal pattern. This change in error pattern was simulated by assuming that recovery reflects resolution of the rapid decay rate toward normal levels. The patient data and computational studies are discussed in terms of their significance for the understanding of aphasic impairments and their implications for models of lexical retrieval. PMID- 7859058 TI - Rhyme priming in aphasia: the role of phonology in lexical access. AB - The present experiment was conducted to explore the facilitory effects of rhyme in lexical processing in brain-damaged individuals. Normal subjects and non fluent and fluent aphasic subjects performed auditory lexical decision and rhyme judgement tasks, in which prime-target pairs were phonologically related (either identical or rhyming) or unrelated. Results revealed rhyme facilitation of lexical decisions to real-word targets for normal and non-fluent aphasic subjects; for fluent aphasic subjects, results were equivocal. In the rhyme judgement task, facilitory effects of rhyme were found for all three groups with real-word targets. None of the groups showed clear rhyme facilitation effects with non-word targets in either task. Findings are discussed with reference to the role of phonology in lexical processing in normal and aphasic populations. PMID- 7859059 TI - Influence of size and site of cerebral lesions on spontaneous recovery of aphasia and on success of language therapy. AB - Changes in linguistic competence were assessed with the Aachen Aphasia Test in 18 aphasic patients across 8 weeks of spontaneous recovery, 8 weeks of intensive language therapy, and after a follow-up period of 8 weeks without therapy. CT scans were obtained from all patients and were evaluated for size of lesion and for affection of Wernicke's area, adjacent regions of superior and middle temporal gyrus, inferior parietal lesions, and temporobasal lesions. Size of lesion had a negative influence on recovery in all phases. Patients with lesions to temporobasal regions showed less improvement during therapy and less total recovery, but a similar amount of spontaneous recovery than patients without such lesions. Lesions that affected the temporobasal regions were on average larger than those which spared them, but the dissociation between reduced therapy success and unaffected spontaneous recovery became even more conspicuous when the concurrent effect of lesion size was minimized by appropriate selection of patients. Possibly, temporobasal lesions cause a disconnection between the hippocampal formation and perisylvian language areas and hinder explicit learning of linguistic knowledge and compensatory strategies. PMID- 7859060 TI - Pituitary adenylate cyclase-activating polypeptide (PACAP) mobilizes intracellular free calcium in cultured rat type-2, but not type-1, astrocytes. AB - We investigated the effects of pituitary adenylate cyclase-activating polypeptide (PACAP38) on cytosolic free calcium ([Ca2+]i) at a single cell level in both type 1 and type-2 cultured rat astrocytes using a calcium-sensitive fluorescent dye, fura-2. Type-1 astrocytes were relatively silent during the 20 min observation of baseline [Ca2+]i and PACAP38 did not alter [Ca2+]i in type-1 astrocytes at concentrations up to 1 microM. In contrast, type-2 astrocytes could be divided into three subtypes (silent type, randomly-firing type and oscillatory type) based on the observation of baseline [Ca2+]i. Of 166 type-2 astrocytes tested, 145 (87.4%) were the silent type (stable basal [Ca2+]i levels) and 13 (7.8%) were the randomly-firing type (random increases in [Ca2+]i). PACAP38 could stimulate [Ca2+]i in subpopulations of all three subtypes. In the silent type-2 astrocytes (4 experiments with 255 cells/experiment), 54.4 +/- 3.6% of the total number responded to PACAP38. The half maximal concentration (ED50) of PACAP38 was 2.89 +/- 1.89 nM. Removing Ca2+ from the superfusion media did not alter the PACAP38 induced increase of [Ca2+]i. Neither 1-30 microM of forskolin nor 1-10 mM of dibutyryl cyclic AMP increased [Ca2+]i in the same type-2 astrocytes which responded to PACAP38. These findings suggest that PACAP increases [Ca2+]i in type 2, not type-1, rat astrocytes by mobilizing Ca2+ from intracellular stores, and that this action is not linked to activation of the cyclic AMP second messenger system. PMID- 7859061 TI - NMDA receptors in layers II and III of rat cerebral cortex. AB - Glutamate receptors are found in all layers of the cerebral cortex, but NMDA receptors are concentrated in layers II and III in the adult. We investigated the location of these receptors, and their contribution to the responses of cells in layers V and VI, by iontophoresing NMDA at various distances from the cell body along the apical dendrite of the cells, first in artificial CSF, then in TTX to abolish action potentials. Comparison of responses at various distances along the apical dendrite showed that the response generally increases as distance from the cell body decreases. Comparison of responses in layers II and III, before and after TTX, showed that TTX reduced the response considerably. We conclude first that NMDA receptors in layers II and III are located primarily on cells in layers II and III, rather than on the apical dendrites of cells in layers V and VI, and second that the contribution of NMDA receptors to the response of cells in layers V and VI comes primarily from receptors close to the cell body. PMID- 7859062 TI - The role of calcium and cAMP in the mechanism of action of two melanocortins: alpha MSH and the ACTH4-9 analogue Org 2766. AB - Melanocortins accelerate functional recovery after nerve crush and enhance neurite outgrowth in vitro. To get more insight in the mechanism of action of melanocortins, we studied the effects of two neurotrophic peptides: alpha melanocyte-stimulating hormone (alpha MSH) and an adrenocorticotropin4-9 analogue Org 2766 on second messengers in cultures of spinal cord (SC), dorsal root ganglion (DRG) and Schwann cells. alpha MSH (10 microM) enhanced the forskolin induced cAMP production in SC- (45%) and in DRG-cells (35%). Org 2766 (1 microM) induced an increase in cAMP only in SC-cells (39%). The peptides did not affect the cAMP levels in Schwann cells. Neither peptide evoked significant changes in the intracellular free calcium concentration ([Ca2+]i) in batch-measurements of all cell types, however, Ca(2+)-imaging revealed an infrequent occurrence of large [Ca2+]i-elevations in individual SC-neurons. The results indicate that SC- and DRG-cells are targets for both peptides, while Schwann cells are not or exploit different pathways. We observed for alpha MSH that cAMP production always coincides with outgrowth stimulation, whereas for Org 2766 cAMP production and outgrowth stimulation appear not causally related. These differences in second messenger stimulation could be explained by receptor heterogeneity. We suggest that alpha MSH and Org 2766 act through different receptors, each with its own signalling pathways. PMID- 7859063 TI - Evidence for volume transmission in the dopamine denervated neostriatum of the rat after a unilateral nigral 6-OHDA microinjection. Studies with systemic D amphetamine treatment. AB - In the present study the hypothesis has been tested if the dopamine releasing drug D-amphetamine via volume transmission can, at least partly, restore dopamine communication in the dopaminergically denervated neostriatum of rats. The experimental model used, has been a unilateral 6-hydroxydopamine-induced degeneration of the nigrostriatal dopamine neurons, based on nigral microinjections of this neurotoxin. Studies on c-fos like immunoreactivity after systemic D-amphetamine treatment demonstrated a wide-spread appearance of c-fos like immunoreactive neuronal nuclear profiles within the neostriatum on both the unlesioned and denervated side. In the unlesioned neostriatum a peak density of c fos like immunoreactive profiles was found within the central part of the neostriatum, while on the denervated side the distribution pattern of c-fos like immunoreactive profiles peaked medially and gradually declined in a lateral direction. The microdialysis experiments demonstrated, after systemic d amphetamine treatment, a marked and sustained increase of extracellular dopamine levels in the neostriatum on the unlesioned side, while no increases in the extracellular dopamine levels were observed on the dopaminergically denervated neostriatum. In the electrophysiological experiments, systemic D-amphetamine treatment produced an inhibition of the neuronal activity on the denervated side which showed a significant increase in basal discharge rate compared with the recordings obtained from the striata on the unlesioned side. The present immunocytochemical microdialysis and electrophysiological analysis provides evidence that in the unilaterally markedly dopamine depleted neostriatum with clearcut signs of dopamine receptor supersensitivity (rotational behaviour results), dopamine transmission may be partly restored via systemic D-amphetamine treatment through the release of dopamine, predominantly from the unlesioned neostriatum, which may diffuse into the cerebrospinal fluid to reach the contralateral dopaminergically denervated neostriatum. PMID- 7859064 TI - Effects of prenatal malnutrition and postnatal nutritional rehabilitation on CA3 hippocampal pyramidal cells in rats of four ages. AB - The effects of prenatal protein malnutrition and postnatal nutritional rehabilitation on CA3 hippocampal pyramidal cells were investigated in rats of 15, 30, 90 and 220 days of age. Female rats were fed either 6% or 25% casein diet 5 weeks before conception. Following delivery, litters born the same day to 6% and 25% casein diet rats were randomly cross-fostered to 25% casein diet dams and maintained on that diet until sacrificed. In 288 rapid-Golgi impregnated cells, we measured somal size, length of the longest apical dendrite, number of apical and basal dendrites intersecting 10 concentric rings 38 microns apart, synaptic spine density in three 50 microns segments of the largest apical dendrite and the thorny excrescence area. Prenatal protein malnutrition produced differential morphological changes on CA3 pyramidal cells. We observed significant decreases of somal size (at 90 and 220 days of age), of length of apical dendrites (at 15 days old), of apical (in 15 day animals) and basal (in 15, 90 and 220 day animals) dendritic branching and of spine density (in 30, 90 and 220 day animals). We also found significant increases of apical dendritic branching in 90 and 220 day old rats. These results indicate that prenatal protein malnutrition affects normal development and produces long-term effects on CA3 pyramidal cells. PMID- 7859065 TI - A midline area in the nucleus commissuralis of NTS mediates the phrenic nerve responses to carotid chemoreceptor stimulation. AB - The carotid body chemoreceptor afferents have been reported to project to a discrete area located in the nucleus commissuralis of nucleus tractus solitarius [A. Vardhan et al., Am. J. Physiol., 264 (1993) R41-R50]. The afore-mentioned study was done in spontaneously breathing rats and the afferents and efferents located in the chest wall and the respiratory tract of these animals were intact. In order to exclude the role, if any, of these afferents and efferents, in the present experiments respiratory changes were monitored by recording the phrenic nerve activity instead of tracheal airflow. Experiments were carried out in pentobarbital-anesthetized, bilaterally vagotomized, paralyzed and artificially ventilated rats with a pneumothorax. The carotid body chemoreceptors were stimulated with tracheal administration of nitrogen for 7-10 s. The chemoreceptor stimulation induced an increase in the frequency and amplitude of phrenic nerve bursts. A decrease in the duration of inspiratory (T1), expiratory (TE) and total cycles (TTOT) was observed in the phrenic nerve activity. Inhibition of neuronal cell bodies by microinjections of muscimol (140 pmol/20 nl) into a discrete area in the commissural subnucleus of the nucleus tractus solitarius (coordinates in mm: 0.3 rostral to 0.5 caudal, 0 to 0.5 lateral and 0.3 to 0.5 deep with respect to the calamus scriptorius), attenuated the phrenic nerve responses to the carotid body stimulation. On the other hand, control injections of saline (0.9%) into this site did not alter the phrenic nerve response to the carotid body stimulation.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859066 TI - Lesions of the pedunculopontine tegmental nucleus abolish catalepsy and locomotor depression induced by morphine. AB - The cataleptic and locomotor depressant effects of morphine are mediated by a series of neural structures, all of which project to the pedunculopontine tegmental nucleus (PPTg). To test the idea that the PPTg is also involved in mediating morphine's effect on these behaviours, we examined catalepsy and spontaneous motor activity following bilateral lesions of the PPTg (0.5 microliters of 0.1 M N-methyl-D-aspartate infused over 10 min). We also examined the effect of PPTg lesions on motor functioning by observing sensorimotor responses, limb use, muscle tone and locomotion. PPTg lesions completely abolished the catalepsy and decreased activity that normally follows morphine administration. In addition lesioned animals exhibited increased muscle tone, and impairments in limb use and righting reflexes. Although the deficits were subtle, these results confirm that damage to the PPTg is associated with motor abnormalities. PMID- 7859067 TI - Differential modulation of alpha 2-adrenergic and opioid spinal antinociception by cholecystokinin and cholecystokinin antagonists in the rat dorsal horn: an electrophysiological study. AB - Cholecystokinin (CCK) has been shown to reduce the spinal antinociceptive effects of opioid agonists such as morphine. The present study examined the effect of CCK and CCKB antagonists on the spinal antinociception mediated by the selective alpha 2-adrenergic agonist dexmedetomidine. Extracellular recordings of noxious evoked C fibre responses of dorsal horn convergent neurones were made in the halothane-anaesthetized rat. Alone, intrathecal dexmedetomidine (5 micrograms) profoundly inhibited C fibre-evoked responses (92 +/- 7%). In the presence of 1 microgram intrathecal CCK the antinociceptive effect of dexmedetomidine was reduced to 27 +/- 11%. Inhibitions of C fibre-evoked responses mediated by submaximal doses (0.5 and 2.5 micrograms) dexmedetomidine were not altered by CCKB antagonists L365,260 (0.2 mg/kg subcutaneous) or PD135158 (10 micrograms intrathecal). Both CCKB antagonists did increase the inhibition of C fibre-evoked responses by the mu opioid agonists DAGOL and morphine. The results suggest CCK is able to inhibit spinal antinociception mediated via the activation of alpha 2 adrenergic receptors in addition to its well-documented interaction with spinal opioid analgesia. However the antagonist studies indicate an endogenous CCK control of spinal mu opioid mediated antinociception which does not extend to alpha 2-adrenergic antinociception. PMID- 7859068 TI - An in vivo study of the effect of 5-HT and sympathetic nerves on transferrin and transthyretin mRNA expression in rat choroid plexus and meninges. AB - Brain expression of transferrin (Tf) and transthyretin (TTR) mRNA has been demonstrated in different species, TTR being found only in the choroid plexus. We report here that both these mRNAs are also expressed in the meninges. In vitro studies have shown that Tf secretion by the rat choroid plexus is stimulated by 5 hydroxytryptamine (5-HT) while sympathetic nerves regulate different transport functions in the same tissue. We have used various in vivo models to study the neuroendocrine regulation of Tf and TTR mRNA expression in the choroid plexus and meninges. Destruction of the serotonergic nerves in the brain by either raphe nuclei lesion or intraventricular injections of 5,7-dihydroxytryptamine (5,7 DHT), which both decreased brain 5-HT levels significantly, did not affect Tf or TTR mRNA levels in choroid plexus and meninges, but increased TTR mRNA in liver. Intraventricular injection of 10 or 100 pmol 5-HT did not change the expression of these proteins in any of the tissues studied. Removal of the sympathetic innervation to the choroid plexus by cervical sympathectomy did not affect Tf or TTR mRNA levels in choroid plexus and liver, nor the incorporation of radioactive leucine into protein in various parts of the brain. In conclusion, our results do not support a regulatory role in vivo for neuronally derived 5-HT or sympathetic nerve activity on Tf and TTR mRNA expression in rat choroid plexus and meninges. PMID- 7859069 TI - Basal forebrain control of cortical blood flow and tissue gases in conscious aged rats. AB - Cholinergic projections from the basal forebrain are capable of influencing local cortical blood flow (CoBF). The effect of age on this influence was investigated by measuring CoBF and tissue gas partial pressures (PtO2, PtCO2) by mass spectrometry in conscious young adult (2-4 months) and aged (22-28 months) Fischer 344 rats. Electrical stimulation (50 microA) of the substantia innominata (SI) increased frontal (+100.9%) and parietal (+28.4%) CoBF in young rats, but the effects were less in aged rats (frontal, +48.6%, P < 0.05; parietal, +18.9%, difference N.S.). Frontal PtO2 was increased in young but not aged rats (P < 0.01.). During standard hypercapnia, changes in CoBF, PtO2 and PtCO2 did not differ between young and aged rats. Under physostigmine infusion (0.15 mg/kg/h, i.v.), the CoBF increases to SI stimulation were approximately doubled in both cortices, in young and aged rats, and PtO2 increases were also significantly greater. However, frontal PtO2 increases were significantly smaller in aged (+7.6%) than in young (32.7%) rats, as were frontal PtCO2 reductions. We conclude: (i) the influence of the SI on frontal CoBF and PtO2 is substantially reduced with age; (ii) although physostigmine treatment potentiates this influence in both groups, the beneficial effects are relatively limited for aged rats. PMID- 7859070 TI - Fos synthesis in identified magnocellular neurons varies with phenotype, stimulus, location in the hypothalamus and reproductive state. AB - The present study compared Fos expression in identified hypothalamic magnocellular neurons in lactating and non-lactating female rats submitted to acute haemorrhage or 24 h of water deprivation, stimuli that induce the release of both oxytocin and vasopressin. Quantitative analysis of preparations doubly immunostained for Fos and either of the neuropeptides revealed that oxytocin and vasopressin neurons synthesise Fos in response to either stimulus but to a different degree, depending on the type of neuron, the type of stimulus, the location of the neurons and the reproductive state of the animal. Thus, in terms of number of cells, haemorrhage was significantly more potent than water deprivation in inducing Fos immunoreactivity in either type of neuron in the supraoptic, paraventricular and anterior commissural nuclei. However, the Fos reaction of vasopressin cells in response to either stimulus was greater than that of oxytocin cells in the supraoptic and paraventricular nuclei, and in the perifornical posterior nucleus and nucleus circularis in response to water deprivation. Moreover, when considering each neuronal population as a whole, it was obvious that Fos synthesis varied in relation to the location of the neurons in the different hypothalamic nuclei, suggesting the existence of functionally distinct neuronal subgroups. Finally, our analyses clearly indicated that Fos synthesis in either type of magnocellular neuron was closely linked to the reproductive state of the animal since after haemorrhage or water deprivation, the number of Fos-positive oxytocin cells in the supraoptic nucleus and Fos positive vasopressin cells in the paraventricular nucleus was significantly less in lactating than in virgin rats. PMID- 7859071 TI - The effects of interleukin 1 beta on the hypothalamic tachykinin, neurokinin A. AB - Interleukin-1 beta (IL-1 beta) is a pleiotropic cytokine that appears to be an integral component of the bidirectional signalling between the immune and central nervous systems. It is produced in the hypothalamus and has been shown to inhibit the hypothalamo-pituitary-gonadal axis and to activate the hypothalamo-pituitary adrenal axis. IL-1 beta is reported to up-regulate the tachykinin, substance P (SP), in the peripheral nervous system. We have recently observed that members of the hypothalamic tachykinin family including SP, neurokinin A (NKA) and two N terminal extended forms of NKA (neuropeptides kappa and gamma), inhibit hypothalamic LHRH and pituitary LH release and stimulate adrenal corticosterone secretion. The similarity in the endocrine effects of the tachykinins and the cytokine prompted us to test the hypothesis that IL-1 beta may stimulate the hypothalamic tachykinins, which would then mediate the neuroendocrine effects of IL-1 beta. First, the effects of IL-1 beta on the in vitro release of NKA-like immunoreactivity (NKA-li) from the hypothalamus was examined. Addition of 10 nM IL-1 beta significantly increased NKA-li release from the hypothalami of castrated rats, but not from the hypothalami of intact rats. To identify the site of IL-1 beta action, the effects of intraventricular IL-1 beta (100 ng) on NKA-li levels in various hypothalamic sites of intact and castrated rats were examined. The results showed that IL-1 beta increased NKA-li selectively in the median eminence (ME) and arcuate nucleus (ARC) of castrated rats only.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859073 TI - Modulation of catecholamine turnover rate in brain regions of rats exposed prenatally to morphine. AB - The concentration and turnover rate of brain catecholamines were measured in the hypothalamus, preoptic area (POA), frontal cortex, striatum and cerebellum of adult male and female rats exposed in utero to morphine (5-10 mg/kg/twice a day) during gestation days 11-18. Norepinephrine (NE) and dopamine (DA) turnover rates were estimated following alpha-methylparatyrosine (AMPT) administration. Prenatal morphine altered NE content and turnover in male and female rats in a regionally specific, sexually dimorphic manner. Basal NE content increased approximately 60% in the hypothalamus of male rats, but it decreased about 30% in the hypothalamus of female rats. NE turnover in the hypothalamus of morphine-exposed rats increased 50% in males and decreased 50% in females. Prenatal morphine had no effects on NE turnover in the male POA, but in female rats NE turnover decreased approximately 60%. Alterations in the frontal cortex of morphine-exposed male and female rats resembled the pattern in the hypothalamus; however, the differences did not reach statistical significance. In addition, prenatal morphine had no effect on striatal or cerebellar NE or on basal levels or turnover of DA in any brain regions. These results demonstrate that prenatal morphine alters the content and turnover of NE in a sexually dimorphic manner in specific brain regions of male and female rats, suggesting alterations in the density of terminals and/or utilization of NE. These sexually dimorphic alterations in hypothalamic NE induced by prenatal morphine may be related to the changes observed in adult male and female sexual behavior in our previous work. PMID- 7859072 TI - Impairment of integrin-mediated cell-matrix adhesion in oxidant-stressed PC12 cells. AB - Oxidants are believed to play an important and complex role in neuronal injury and death in the aging process and various neurode generative diseases. We studied the effect of oxidative stress on integrin-mediated cell-extracellular matrix (ECM) interactions using the PC12 neuronal cell line. In assays in which attachment was measured between 30 and 90 min, addition of hydrogen peroxide (H2O2) to the attachment medium resulted in a dose-dependent inhibition of initial cell attachment to collagen. Addition of H2O2 also caused previously attached cells to detach from collagen. The inhibition by H2O2 was specific for integrin-mediated adhesion, since attachment to substrata coated with non-ECM molecules was much less affected. Exposure of cells to H2O2 resulted in a rapid and profound reduction of intracellular ATP, accompanied by only a slight increase in intracellular free Ca2+ concentration ([Ca2+]i). Treatment of cells with the microfilament-disrupting agent, cytochalasin B, like that with H2O2, inhibited cell adhesion to collagen. We propose that integrin-mediated cell adhesion, which requires interactions between cytoplasmic portions of integrin subunits and cytoskeletal microfilaments, is impaired by oxidative stress as a result of the depletion of intracellular ATP and that such depletion is an early event in the process of oxidant-induced neuronal injury. PMID- 7859074 TI - Delayed treatment with 1,3-butanediol reduces loss of CA1 neurons in the hippocampus of rats following brief forebrain ischemia. AB - This study examined the effect of 1,3-butanediol on the selective loss of CA1 pyramidal neurons following a short period of near-complete forebrain ischemia. Injection of 55 mmol 1,3-butanediol/kg body weight at 24 h of recirculation and again at 36 h following 10 min of forebrain ischemia markedly reduced damage to CA1 neurons examined at 72 h of recirculation compared with that in saline treated rats. Comparable treatment with ethanol did not cause significant protection. Neuronal loss was also not reduced by 1,3-butanediol treatment when the ischemic period was extended to 15 min or by single treatments at 24 h or 36 h following 10 min of ischemia. However, a single treatment 5 min after reversal of 10 min of ischemia was effective in ameliorating cell loss. The difference in effectiveness of 1,3-butanediol following 10 min and 15 min of ischemia is consistent with a number of previous studies, indicating that the processes leading to loss of CA1 neurons are modified when the ischemic period is extended. Previous findings that 1,3-butanediol reduced damage in other ischemia susceptible neuronal subpopulations but not in CA1 neurons most likely reflected the longer period of ischemia which was used. The results of the present investigation demonstrate that administration of 1,3-butanediol offers a novel approach for interfering with post-ischemic loss of CA1 neurons following a brief ischemic period which is effective even when initiated after prolonged recirculation periods. PMID- 7859075 TI - Altered 9-O acetylation of disialogangliosides in cerebellar Purkinje cells of the nervous mutant mouse. AB - Some gangliosides in the nervous system are developmentally down-regulated, but many other gangliosides continue to be expressed in the adult nervous system. We have previously demonstrated that the 9-O-acetylated gangliosides recognized by a monoclonal antibody, P-path, confer unique compartmentation among Purkinje cell groups in the normal adult cerebellum. We have continued to explore the role of this group of gangliosides in cerebellar organization by investigating the biochemical and cellular expression of this unique epitope in the cerebellum of the mutant mouse, nervous, where postnatally, most Purkinje cells degenerate. Overall ganglioside composition of nervous cerebellum is similar to wild type cerebellum. However, quantitative analysis of gangliosides by TLC-immunostaining shows that the relative concentration of 9-O-acetylated gangliosides varies considerably. In nervous cerebellum, there is more than a three-fold increase in the concentration of 9-O-acetyl disialolactosyl ceramide (GD3), and 9-O-acetyl disialolactoneotetraosyl ceramide (LD1) is decreased to 25% of wild type. In addition, GD3 ganglioside, the immediate precursor of 9-O-acetyl GD3, is detected at 1/3 of the level of wild type cerebellum, and LD1 ganglioside, the precursor of 9-O-acetyl LD1, is virtually absent from nervous cerebellum. Thus, in nervous cerebellum the ratio of 9-O-acetyl GD3 to its disialoganglioside precursor is dramatically increased compared to wild type cerebellum. In accord with the altered expression of 9-O-acetyl gangliosides, immunoelectron microscopy demonstrates a change in the subcellular distribution in mutant Purkinje cells. Instead of being associated with the somatic and dendritic membranes, P-path immunoreactivity is located internally, in the cytoplasm of Purkinje cell bodies and their dendrites. In addition to the changes in the cerebellum, the other regions of the brain decreased in size by about 15% in the nervous mutant. In the ganglioside composition of these regions of nervous brain, 9-O-acetyl GD3 nearly doubled, but 9-O-acetyl LD1 and other gangliosides did not differ. Our findings of significant changes in 9-O-acetylated gangliosides, accompanied by the overall decrease in brain size, suggest that carbohydrate or glycolipid metabolism is abnormal in the nervous mutant mouse brain. PMID- 7859076 TI - Expression of c-fos mRNA after a mild focal cerebral ischemia in SOD-1 transgenic mice. AB - To clarify the role of oxygen free radicals in expression of the c-fos protooncogene, the distribution of c-fos mRNA was investigated in CuZn-superoxide dismutase (SOD-1) transgenic (Tg) mice compared to control nontransgenic (nTg) littermates after a mild (i.e. 10 min) focal cerebral ischemia. c-fos mRNA expression occurred at 1 to 6 h after reperfusion in the ipsilateral hippocampus and thalamus in Tg mice, whereas it did only at 1 h in the same regions in nTg mice. In the ipsilateral cortex, there were no significant differences in the pattern of the expression between nTg and Tg mice. These results suggest that oxygen radicals may suppress the expression of c-fos in the hippocampus and thalamus, the areas known to be without blood supply from the middle cerebral artery, following a mild focal cerebral ischemia and reperfusion. PMID- 7859077 TI - Neuron-specific human glutamate transporter: molecular cloning, characterization and expression in human brain. AB - A cDNA encoding a neuron-specific glutamate/aspartate transporter was isolated from human brain cDNA libraries and characterized. The new cDNA, designated human glutamate transporter III, is structurally distinct from two previously described brain specific glutamate transporters. This human cDNA is 90% and 95% homologous at nucleotide and amino acid level, respectively, with a previously reported rabbit glutamate/aspartate transporter. Northern blot analysis of human tissues revealed that the mRNA of this transporter is expressed in brain, liver, muscle, ovary, testis and in retinoblastoma cell lines. In situ hybridization in human brain sections showed that the mRNA is densely expressed in substantia nigra, red nucleus, hippocampus, and in cerebral cortical layers. Southern blot analysis revealed that the gene encoding this mRNA exists as a single copy in the human genome. PMID- 7859078 TI - Effect of codeine on the inspiratory and expiratory burst pattern during fictive cough in cats. AB - Experiments were conducted to study the effect of the opioid, codeine, on different components of the cough motor pattern. Midcollicular decerebrate cats were paralyzed and artificially ventilated by a pump triggered by the phrenic neurogram. Inspiratory (phrenic) and expiratory (cranial iliohypogastric) neurograms were recorded. Fictive cough was produced by mechanical stimuli applied to the intrathoracic trachea. Codeine (0.03-1.0 mg.kg-1, i.v.) decreased cough frequency (average number of coughs per stimulus trial), expiratory burst amplitude, and inspiratory burst amplitude in a dose-dependent manner. The maximum reduction in cough frequency and expiratory amplitude produced by codeine was 80-90% for both parameters. However, codeine was more potent in reducing cough frequency (ED50 = 0.1 mg.kg-1) than expiratory burst amplitude (ED50 = 0.35 mg.kg-1). The maximum observed reduction of inspiratory burst amplitude elicited by codeine was approximately 40%. There was a positive linear relationship between phrenic and cranial iliohypogastric burst amplitudes during fictive cough (r = 0.82, P < 0.001). Codeine destabilized the motor pattern during fictive cough by disrupting this relationship between inspiratory and expiratory burst amplitudes. We conclude: (a) the central pattern generator for cough is functionally organized into a cough frequency generator, an expiratory burst amplitude generator and an inspiratory burst amplitude generator, each of which have different sensitivities to codeine (b) there exists a specific codeine sensitive neural mechanism matching the relative magnitude of central drive to inspiratory and expiratory motoneurons during cough. PMID- 7859079 TI - Response of cytosolic Ca2+ to hypercapnic acidosis in cultured glomus cells of the adult rabbit carotid body. AB - The characteristics underlying the response of cytosolic Ca2+ ([Ca2+]i) to hypercapnic acidosis in clusters of cultured glomus cells of the adult rabbit carotid body were evaluated using fura-2 microscopic fluorometry. Application of CO2 by bubbling through both superfusions of bicarbonate-buffered saline and HEPES-buffered saline produced a rapid and sustained increase in [Ca2+]i. The [Ca2+]i response increased correspondingly with a rise in concentrations of CO2 to 20% but at a point between 20 and 50% adapted to CO2 and it decreased its linear assent. The hypercapnic acidosis-induced increase of [Ca2+]i was diminished by removing external Ca2+. Also the [Ca2]i response was reduced in dose-dependent fashion by the addition of the voltage-gated Ca2+ channel blocker D600. An additional response of [Ca2+]i to acetate was also diminished by Ca2+ removal. These results suggest that the [Ca2+]i response to hypercapnic acidosis involves an influx of external Ca2+ through voltage-gated Ca2+ channels. PMID- 7859080 TI - Amantadine increases the extracellular dopamine levels in the striatum by re uptake inhibition and by N-methyl-D-aspartate antagonism. AB - This study was performed to investigate the mechanism how amantadine increases the extracellular dopamine (DA) levels in the striatum in vivo. Local application of amantadine (1 mM, 40 min) to the striatum through the dialysis membrane significantly increased the extracellular DA levels. Coadministration of nomifensine (10 mM, 120 min), an inhibitor of neuronal DA uptake, into the perfusion fluid attenuated the amantadine-induced increase in DA outflow. The amantadine-induced increases in the extracellular DA levels were also inhibited by co-perfusion with Ringer containing high Mg2+ (15 mM, 120 min) or with MK-801 (1 microM, 80 min). These findings suggest that amantadine increases the extracellular DA levels in the striatum by inhibiting the re-uptake of DA and/or by blocking the channel in the N-methyl-D-aspartate (NMDA) receptor, which results in antagonism of NMDA receptor function. PMID- 7859081 TI - Flow cytometric analysis on cytotoxic action of amyloid beta protein fragment 25 35 on brain neurons dissociated from the rats. AB - Effects of amyloid beta protein fragment 25-35, A beta P(25-35), on membrane permeability and cell viability were examined in the brain neurons dissociated from the rats using a flow cytometer and two fluorescent dyes, fluo-3 to monitor intracellular Ca2+ concentration ([Ca2+]i) of neurons and ethidium which is impermeant to membranes of intact neurons to stain dead and dying neurons. A beta P(25-35) augmented fluo-3 fluorescence of some neurons at concentrations greater than 1 microM, indicating an increase in [Ca2+]i although other neurons (about 80% of total neurons) did not respond to A beta P(25-35) even at 10 microM. A beta P(25-35) at 1 microM or greater increased dose-dependently the number of ethidium-stained neurons, suggesting a dose-dependent increase in number of dead and dying neurons. Results suggest that A beta P(25-35) increases the membrane permeability of brain neurons, resulting in a destabilized intracellular homeostasis that leads to neuonal death. PMID- 7859082 TI - Evidence for activation of NMDA receptors when memory function is reinstated in rats with glutamatergic temporal systems disrupted. AB - Disruption of the fiber connections between the temporal cortex (TC) and lateral entorhinal cortex (LEC) results in impaired memory and decrease of glutamate in both denervated areas. Administration of glutamatergic agonists fully restores the mnemonic function in rats with TC/LEC lesions. The purpose of the present study was to examine whether the pharmacologically supported recovery of function may act via NMDA receptors. Rats with TC/LEC lesions either received saline, the NMDA antagonist HA-966, the NMDA agonist glycine or HA-966 + glycine. The results show that saline-treated rats are severely impaired in retention, whereas rats treated with glycine perform like normal controls. Rats pretreated with HA-966 are not able to profit from the beneficial effects of glycine. These data support the notion that the restoration of memory function obtained by glycine in lesioned animals involves activation of NMDA receptors. PMID- 7859083 TI - Single K+ channels closed by light and opened by cyclic GMP in molluscan extra ocular photoreceptor cells. AB - We report the first recordings of the light-sensitive channel which is active during dark and is closed by light in the Onchidium extra-ocular photoreceptor cells. This light-sensitive channel was K-selective and was not blocked by extracellular Ca2+ and Mg2+. Application of cyclic GMP to excised inside-out patches activated (opened) a channel that appeared to be the same as the light sensitive channel recorded from the same membrane in the intact cell. PMID- 7859084 TI - Synthesis of heat shock proteins in cultured chick pineal cells. AB - Chick pineal cells in static culture display a persistent, photosensitive, circadian rhythm of melatonin synthesis and release. Melatonin synthesis and its rhythm are also sensitive to temperature changes. By SDS-PAGE autoradiography, we found that several heat shock proteins (HSPs 25, 70, and 90) are synthesized under temperature conditions which also cause changes in melatonin production and rhythms. We did not see substantial phase-dependent differences in the induction of HSP synthesis, nor did we detect any clear effect of light on the synthesis of these proteins. PMID- 7859085 TI - An ultrastructural study of somal appositions in the suprachiasmatic nucleus and anterior hypothalamus of the rat. AB - Somatic appositions of glial and neuronal elements in the suprachiasmatic nucleus (SCN) and the anterior hypothalamus (AH) were evaluated. Neuronal somas in the SCN exhibited more coverage by astrocytes than did those in the AH. Conversely, somas in the AH showed more coverage by neuronal elements than those in the SCN. All measurements of somal appositions were independent of circadian influences. PMID- 7859086 TI - Actions of (+/-)-7-hydroxy-N,N-dipropylaminotetralin (7-OH-DPAT) on dopamine synthesis in limbic and extrapyramidal regions of rat brain. AB - The proposed D3-selective ligand (+/-)-7-hydroxy-N,N-dipropylaminotetralin (7-OH DPAT) inhibited tyrosine hydroxylase in vitro (IC50 = 0.6-0.7 microM) and dihydroxyphenylalanine (DOPA) accumulation in vivo (ID50 = 4.8-6.4 mg/kg) in two autoreceptor models in extrapyramidal and limbic tissue in rat forebrain, without consistent regional selectivity. Some limbic selectivity (ID50 = 10 vs. 29 mg/kg) was found in an in vivo model permitting expression of postsynaptic D3 and D2 receptor activity. The effects were partially blocked by S(-)-eticlopride alone, and fully after reserpine pretreatment. The results suggest that 7-OH-DPAT activates D3 or D2 autoreceptors, alters dopamine storage or release, and may interact with some limbic selectivity at postsynaptic D3 and D2 receptors as a partial agonist. PMID- 7859087 TI - Rapid decrease in ATP content without recovery phase during glutamate-induced cell death in cultured spinal neurons. AB - Glutamate neurotoxicity in the cultured neurons from rat spinal cord was evaluated on the basis of endogenous ATP content in the cells. A short exposure of the neurons to glutamate induced an immediate and rapid decrease in ATP content. Then, after removal of glutamate, no recovery of ATP content was observed for 24 h, eventually resulting in neuronal death. These findings suggest that the glutamate-induced neuronal death in vitro is apparently similar to but essentially different from so-called 'delayed' neuronal death in vivo after a brief ischemia in hippocampal CA1 neurons in which a transient recovery of ATP level occurs after its dramatic reduction. PMID- 7859088 TI - Glutamate and carnosine in the vestibular system of the frog. AB - We demonstrate that both glutamate-like and carnosine-like immunoreactivities are present in hair cells and in fibers of the vestibular organ of the frog inner ear. Comparison of the two immunoreactivity patterns indicates that glutamate and carnosine might be colocalized in some hair cells. The presence of glutamate-like immunoreactivity in hair cells is consistent with biochemical and pharmacological data indicating glutamate as the excitatory neurotransmitter in these sensory receptors. There is also evidence that carnosine might have a neuromodulatory function. PMID- 7859089 TI - Spontaneous activity of first- and second-order neurons in the frog olfactory system. AB - The spontaneous activity of first-order neurons (neuroreceptors of the mucosa) and second-order neurons (mitral cells of the bulb) was recorded extracellularly in the frog olfactory system. To assess the influence of peripheral inputs upon mitral cells, the bulb was either normally connected or partially deafferented. Our first set of findings concern the firing behavior. We found that most neurons generated interspike intervals (ISIs) that were stationary in mean and variance, and were not serially correlated at first and second order. Individual spikes in mitral cells and bursts of spikes in neuroreceptors were found to be generated by a Poisson process. Stochastic modeling suggests that the Poissonian behavior depends on the mean value of the membrane potential at the axon hillock. In these models, the mean potential in mitral cells would be far below the firing threshold and in neuroreceptors it would fluctuate at random between two states, one close to resting potential (between bursts) and the other close to the firing threshold with occasional crossings (within bursts). Secondly, partially deafferented mitral cells had significantly higher activity and lower variance than mitral cells receiving normal afferent input. This effect gives evidence that peripheral inputs influence mitral cells at rest not only through direct excitation but also through indirect inhibition exerted by local neurons. Thus, the unstimulated state of the olfactory bulb would not be qualitatively different from its stimulated state in the sense that both states involve the same types of synaptic interactions. Consequently, understanding the synaptic relationships that take place in the bulb network can benefit from studies of its spontaneous activity. PMID- 7859090 TI - Immunohistochemical mapping of angiotensin type 2 (AT2) receptors in rat brain. AB - Recently developed antisera selective for angiotensin Type 2 (AT2) receptors were used to localize AT2 receptors in rat brain by immunohistochemistry. While the results from these experiments were largely consistent with previous autoradiographic and radioligand binding analyses of AT2 receptor populations in brain, there were also some notable differences in the distribution of immunoreactivity. More specifically, in agreement with previous studies, AT2 antisera detected apparent receptor populations in the locus coeruleus and the bed nucleus of the accessory olfactory tract, whereas AT2 receptor immunoreactivity in the cerebellum was primarily associated with the Purkinje cell layer and the deep cerebellar nuclei rather than the molecular layer as has been previously reported in autoradiographic studies. Other regions with prominent immune-staining included all subfields of the hippocampus, which had been previously reported to contain exclusively AT1 receptors. Limbic structures such as the amygdala, thalamic areas such as the rhomboid thalamic nucleus, the paraventricular thalamic nucleus, hypothalamic areas such as the paraventricular hypothalamic nucleus, and the supraoptic nucleus also exhibited prominent AT2 immunoreactivity. In the paraventricular hypothalamic nucleus, AT2 receptor staining appeared to be associated primarily with the magnocellular neurons. In all regions examined, AT2 receptor immunoreactivity was associated with the cytoplasm and cell membrane and was not localized within the nucleus. Collectively, these results confirm and extend the neuroanatomical resolution of previous autoradiographic studies as well as identify new AT2 receptor populations in rat brain. PMID- 7859091 TI - An electrophysiological and immunohistochemical study of the hippocampus of the reeler mutant mouse. AB - The pyramidal cell layer in the CA1 subfield of the hippocampus of the reeler mouse is split into two laminae, the deep and the superficial. We examined the electrophysiological properties of double-layered CA1 pyramidal neurons in the reeler mouse hippocampal slice in vitro. We also studied cytoarchitectonic abnormalities in the hippocampus of this mutant by immunohistochemical methods using anti-parvalbumin and anti-F3/F11-protein antibodies. Laminar analysis of the postsynaptic field potentials in the CA1 subfield of the reeler hippocampus revealed broad negative field potentials with double negative peaks. In the CA1 subfield of the reeler mouse, tetanic stimulation of Schaffer collateral/commissural fibers induced long-term potentiation (LTP) in the majority of the deep layers (near alveus) examined, but very rarely in the superficial layer (near the molecular layer). Immunohistochemical study showed that parvalbumin-immunopositive neurons were densely concentrated in the hippocampus of the reeler mouse, especially in the stratum radiatum and the stratum lacunosum-molecular, in which only a few parvalbumin-immunoreactive neurons were seen in the normal mouse. Abnormal trajectories of axons arising from malpositioned pyramidal cells in the CA1 subfield of the reeler mouse were identified by F3/F11 immunohistochemistry. Interestingly, F3/F11-immunoreactive Schaffer collaterals were misdirected in the CA1 subfield of this mutant. The present electrophysiological and immunohistochemical data suggest that impairment of LTP in the superficial layer of the CA1 pyramidal neurons appears to be mainly due to strong inhibitory inputs to this malpositioned population of neurons. PMID- 7859092 TI - Motor fluctuations in levodopa treated parkinsonian rats: relation to lesion extent and treatment duration. AB - The pathogenesis of the motor fluctuations that complicate levodopa treatment of most parkinsonian patients remains uncertain. To evaluate the contribution of the degree of dopamine neuron loss and the duration of levodopa exposure, rats whose nigrostriatal system had been previously lesioned unilaterally by 6 hydroxydopamine received twice daily levodopa (25 mg/kg) injections for three weeks. The magnitude of the rotational response to levodopa more than doubled during the first week of treatment (P < 0.01), but remained essentially constant thereafter. Rats with over 95 percent loss of dopaminergic neurons evidenced a progressive shortening in the duration of levodopa's motor effects (P < 0.01) as well as a failure of nearly 8 percent of levodopa injections to elicit any response after the first week of treatment. In contrast, response changes resembling those associated with end of dose deterioration and on-off fluctuations in parkinsonian patients did not occur in the less severely lesioned rats. These results suggest that the extent of a dopamine neuron loss must exceed a relatively high threshold before intermittent levodopa treatment produces changes favoring the rapid appearance of motor fluctuations of the wearing-off and on-off types. PMID- 7859093 TI - Differential effects of polychlorinated biphenyl congeners on phosphoinositide hydrolysis and protein kinase C translocation in rat cerebellar granule cells. AB - Previous reports from our laboratory have suggested that the neuroactivity of some polychlorinated biphenyl (PCB) congeners is associated with perturbations in cellular Ca(2+)-homeostasis. We have characterized further the neurochemical effects of PCBs on signal transduction in primary cultures of cerebellar granule cells. The present experiments found that neither 2,2'-dichlorobiphenyl (DCBP), an ortho-substituted congener, nor 3,3',4,4',5-pentachlorobiphenyl (PCBP), a non ortho-substituted congener, affected basal phosphoinositide (PI) hydrolysis in cerebellar granule cells. However, at concentrations up to 50 microM, DCBP potentiated carbachol-stimulated PI hydrolysis, while decreasing it at 100 microM. PCBP, on the other hand, had no effect on carbachol-stimulated PI hydrolysis in concentrations up to 100 microM. [3H]Phorbol ester ([3H]PDBu) binding was used to determine protein kinase C (PKC) translocation. DCBP increased [3H]PDBu binding in a concentration-dependent manner and a twofold increase was observed at 100 microM in cerebellar granule cells. PCBP had no effect on [3H]PDBu binding at concentrations up to 100 microM. The effect of DCBP on [3H]PDBu binding was time-dependent and was also dependent on the presence of external Ca2+ in the medium. To test the hypothesis that DCBP increases [3H]PDBu binding by acting on receptor-activated calcium channels, the effects of DCBP were compared to those of L-glutamate. The effects of DCBP (50 microM) and glutamate (20 microM) were additive.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859094 TI - Serotonin depletion decreases the therapeutic effect of nicotine, but not THA in medial septal-lesioned rats. AB - The present study compares the effects of systemic pretraining trial injections of a cholinesterase inhibitor, tetrahydroaminoacridine (THA, 1, 3 and 5 mg/kg, i.p.) and nicotine (0.03, 0.1 and 0.3 mg/kg, i.p.) on spatial navigation water maze (WM) and passive avoidance (step-through PA) performance in medial septal (MS)--or MS+p-chlorophenylalanine (PCPA, a serotonin synthesis inhibitor) lesioned rats. MS-lesion impaired WM and PA acquisition, and serotonin depletion significantly aggravated PA failure of MS-lesioned rats. THA (3 mg/kg) and nicotine (0.1 and 0.3 mg/kg) promoted PA and WM navigation of MS-lesioned rats. THA at a dose of 3 mg/kg improved performance of MS+PCPA-lesioned rats in WM and PA tests, but nicotine did not promote test performance of combined-lesioned rats. This result demonstrates that serotoninergic pathology may decrease the therapeutic effect of nicotine. PMID- 7859095 TI - Locus coeruleus (LC)--target interaction and cAMP in control of LC development. AB - The epigenetic stimuli that regulate the development of noradrenergic LC neurons were studied in an vitro system of LC primary cultures. Noradrenergic cells were identified using immunocytochemical staining for tyrosine hydroxylase (TH). Maturation of noradrenergic neurons was assessed by measuring the high affinity uptake of norepinephrine (NE). Coculturing target cells with LC neurons exerts both stimulatory and inhibitory effects on NE uptake, depending on the density of plated cells. The target stimulatory effect may be mediated by glial soluble factors, whereas the inhibitory effect may be mediated by glial membranal molecules. In addition to target derived trophic factors, the effect of elevated cAMP levels was examined. cAMP analogs and forskolin dramatically increase the number of TH+ cells, possibly by supporting their survival. This phenomenon is not dependent on calcium or calcium requiring processes and is not mediated by glial cells. The trophic activity of cAMP appears to be exerted by protein phosphorylation via cAMP dependent protein kinase. Norepinephrine is suggested to be one signal that triggers cAMP elevation through the beta-adrenergic receptor and thereby affects LC development. Morphine, which is known to inhibit adenylate cyclase, reduces NE uptake and number of TH+ neurons. Morphine also inhibits the NT-3 induced increase in noradrenergic survival. We hypothesize that morphine exerts these effects by modulating the cAMP cascade. PMID- 7859096 TI - Regeneration of norepinephrine-containing fibers in occipital cortex of adult cats. AB - Regeneration of norepinephrine (NE)-containing nerve fibers in occipital cortex of adult cats was studied using morphological and biochemical methods. Initially, degeneration of cortical NE fibers was induced by direct infusion of 6 hydroxydopamine (6-OHDA) for a week. Cortical reinnervation by NE fibers continuously proceeded throughout 52 weeks, the longest survival period studied, after stopping 6-OHDA infusion. The rate of the reinnervation was slower in mature cortex than that obtained earlier in immature cortex. The present results indicate that the regenerative ability of the central NE neurons is universal, not limited to the immature brain. It is implied that the central NE neurons are equipped with a transmitter-specific repair mechanism throughout life. PMID- 7859097 TI - Coerulospinal fiber regeneration in transected feline spinal cord. AB - After complete cat spinal cord transection, a collagen matrix was used to bridge the gap. Vascular supply was increased to the transection site with an omental pedicle. Before hardening, either 4-aminopyridine, laminin, glia maturation factor, or lipid angiogenic factor were mixed into the collagen. Surgically reconstructed animals were compared to transection-only controls and observed for 90 days. Fluoro-Gold was injected distal to the transection site on day 75. Immunocytochemical examination of brain and spinal cord tissue was done on day 90. Examination revealed supraspinal catecholaminergic fibers present in the collagen bridge and distal cord tissue only in cats with surgical reconstruction. Fluoro-Gold particles were found localized in locus coeruleus and other noradrenergic pontine neurons. Distal to the transection, double immunostaining with synaptophysin and tyrosine hydroxylase or dopamine-beta-hydroxylase revealed dot-like deposits closely apposed to preganglionic sympathetic neurons suggestive of synaptic connectivity to these targets. Results indicate that considerable outgrowth of specific supraspinal fibers can be induced following spinal transection and reconstruction, and that such fibers may be extending and contacting appropriate distal target tissue in the cord. PMID- 7859098 TI - Locus coeruleus neuron growth cones and spinal cord regeneration. AB - One of the major impediments to successful recovery of function after a spinal cord injury is thought to be the reaction of the neuronal growth cone to inhibitory influences in the local environment in or around the site of the injury. The growth cones of locus coeruleus neurons studied in vitro collapsed upon contact with an extract of CNS myelin but did not collapse on contact with an extract of PNS myelin. Coincident with the collapse of the growth cone, was an increase in internal free calcium concentration that was predominantly the result of an influx of calcium through channels in the plasma membrane. Omega-conotoxin, which specifically blocks N-type voltage-gated calcium channels, blocked both the myelin-induced calcium influx and the coincident collapse of the growth cone. PMID- 7859100 TI - Noradrenergic agents in the cerebellar vermis affect adaptation of the vestibulospinal reflex gain. AB - In precollicular decerebrate cats, the vestibulospinal reflex (VSR) was intermittently recorded from the triceps brachii during sinusoidal roll tilt of the whole animal (at 0.15 Hz, +/- 10 degrees), leading to selective stimulation of labyrinth receptors. This reflex, tested during and after a 3-h period of sustained animal tilt at the same parameters indicated above, showed an adaptive increase in gain in some experiments but not in others. In a second group of experiments, however, rotation of the head (at 0.15 Hz, +/- 10 degrees) was associated with a synchronous body rotation (at 0.15 Hz, +/- 12.5 degrees) which led to an additional neck input, due to 2.5 degrees of out-phase body-to-head displacement. In these experiments, the VSR, tested every 10-15 min, consistently showed an adaptive increase in gain during and after a 3-h period of sustained vestibular and neck stimulation. Microinjection into the cerebellar anterior vermis of beta-adrenergic agents (0.25 microliters at 8 micrograms/microliters saline) produced slight and short-lasting changes in the basic amplitude of the VSR, due to the neuromodulatory influence of these agents on the Purkinje cells activity. In addition, the beta-adrenergic agonist isoproterenol brought to the light an adaptive process in those experiments in which no adaptation occurred during a sustained roll tilt of the whole animal. On the other hand, the beta adrenergic antagonists propranolol or sotalol either suppressed the increase in gain of the VSR which occurred in other experiments during sustained animal rotation, or prevented the occurrence of an adaptive increase in gain during a continuous out-phase head and body rotation. We conclude that the adaptive changes in gain of the VSR are facilitated by the noradrenergic system acting within the cerebellar cortex through beta-adrenoceptors. PMID- 7859099 TI - Cotransmitter-mediated locus coeruleus action on motoneurons. AB - This article reviews evidence for a direct noradrenergic projection from the dorsolateral pontine tegmentum (DLPT) to spinal motoneurons. The existence of this direct pathway was first inferred by the observation that antidromically evoked responses occur in single cells in the locus coeruleus (LC), a region within the DLPT, following electrical stimulation of the ventral horn of the lumbar spinal cord of the cat. We subsequently confirmed that there is a direct noradrenergic pathway from the LC and adjacent regions of the DLPT to the lumbar ventral horn using anatomical studies that combined retrograde tracing with immunohistochemical identification of neurotransmitters. These anatomical studies further revealed that many of the noradrenergic neurons in the LC and adjacent regions of the DLPT of the cat that send projections to the spinal cord ventral horn also contain colocalized glutamate (Glu) or enkephalin (ENK). Recent studies from our laboratory suggest that Glu and ENK may function as cotransmitters with norepinephrine (NE) in the descending pathway from the DLPT. Electrical stimulation of the LC evokes a depolarizing response in spinal motoneurons that is only partially blocked by alpha 1 adrenergic antagonists. In addition, NE mimicks only the slowly developing and not the fast component of LC-evoked depolarization. Furthermore, the depolarization evoked by LC stimulation is accompanied by a decrease in membrane resistance, whereas that evoked by NE is accompanied by an increased resistance. That Glu may be a second neurotransmitter involved in LC excitation of motoneurons is supported by our observation that the excitatory response evoked in spinal cord ventral roots by electrical stimulation of the LC is attenuated by a non-N-methyl-D-aspartate glutamatergic antagonist. ENK may participate as a cotransmitter with NE to mediate LC effects on lumbar monosynaptic reflex (MSR) amplitude. Electrical stimulation of the LC has a biphasic effect on MSR amplitude, facilitation followed by inhibition. Adrenergic antagonists block only the facilitator effect of LC stimulation on MSR amplitude, whereas the ENK antagonist naloxone reverses the inhibition. The chemical heterogeneity of the cat DLPT system and the differential responses of motoneurons to the individual cotransmitters help to explain the diversity of postsynaptic potentials that occur following LC stimuli. PMID- 7859101 TI - Plastic changes in Ara C-treated and "transplanted" coeruleocerebellar cultures. AB - Locus coeruleus axons project to cerebellar cortex in coeruleocerebellar cultures, where they make functional contacts, and also appear as fine fibers in the outgrowth zones. The predominant catecholamine of locus coeruleus neurons in culture is dopamine. When coeruleocerebellar cultures are exposed to cytosine arabinoside to destroy cerebellar granule cells and functionally compromise glia, there is a resultant increase of Purkinje cell survival and a sprouting of Purkinje cell recurrent axon collaterals, plus an increase of catecholaminergic axons accompanied by a doubling of tissue dopamine content. If such reorganized cultures are transplanted with granule cells and glia, a second round of plastic changes ensues in which the Purkinje cell population and the recurrent axon collaterals are reduced to control levels, but catecholaminergic axons and dopamine content remain increased. The maintenance of catecholaminergic axons does not appear to depend on the persistence of target neurons. PMID- 7859102 TI - The effects of selective alpha-2 adrenergic agents on the performance of rats in a 5-choice serial reaction time task. AB - The present study investigated how the systemic administration of alpha-2 adrenergic agents that modulate the function of the noradrenergic system in brain, affect rousal and sustained attention. Food-deprivated rats were trained to detect and respond to brief flashes of light presented randomly in one of five spatially diverse locations. The effects of single-dose administrations of dexmedetomidine, an alpha-2 agonist, and atipamezole, an alpha-2 antagonists, on the choice accuracy, errors of omissions, speed of responding, and collection of the reward could be assessed in this task. Dexmedetomidine increased the amount of omissions, speed of response, and decreased the number of premature responses, although it did not markedly lengthen response latencies and food collection latency. Atipamezole increased the number of premature responses. Neither dexmedetomidine nor atipamezole had any effect on choice accuracy of rats in this task. The results suggest that dexmedetomidine decreased behavioral activity and arousal of rats, whereas atipamezole had mild stimulant effect on behavior. PMID- 7859103 TI - Locus coeruleus-evoked responses in behaving rats: a clue to the role of noradrenaline in memory. AB - Neuromodulatory properties of noradrenaline (NA) suggest that the coreruleo cortical NA projection should play an important role in attention and memory processes. Our research is aimed at providing some behavioral evidence. Single units of the locus coeruleus (LC) are recorded during controlled behavioral situations, in order to relate LC activation to specific behavioral contexts. LC cells respond in burst to imposed novel sensory stimuli or to novel objects encountered during free exploration. When there is no predictive value of the stimulus or no behavioral response required, there is rapid habituation of the LC response. When a stimulus is then associated with reinforcement, there is a renewed response, which is transient. During extinction, LC neuronal responses reappear. Thus, LC cells respond to novelty or change in incoming information, but do not have a sustained response to stimuli, even when they have a high level of biological significance. The gating and tuning action of NA released in target sensory systems would promote selective attention to relevant stimuli at the critical moment of change. The adaptive behavioral outcome would result from the integration of retrieved memory with the sensory information selected from the environment. PMID- 7859104 TI - The locus coeruleus, norepinephrine, and memory in newborns. AB - Use of learned odor cues by newborn rats is critical for pup survival. Rat pups acquire approach responses to maternal odors through an associative conditioning mechanism. This learned behavioral response is accompanied by a modification of olfactory bulb neural response patterns to the learned odor. Both the behavioral and neural response changes involved and require norepinephrine release in the olfactory bulb. The source of this norepinephrine is the locus coeruleus. It is proposed that the unique response properties of the locus coeruleus during the early postnatal period in the rat may facilitate acquisition of these critical early memories. PMID- 7859105 TI - Noradrenergic modulation of synaptic transmission between olfactory bulb neurons in culture: implications to olfactory learning. AB - Noradrenergic modulation of the glutamatergic-GABAergic synapses between mitral/tufted (M/T) and granule cells has been implicated in some forms of olfactory learning (5), but the mechanism of action is unknown. Intracellular stimulation of M/T cells in primary culture, evoked glutamate-mediated excitatory postsynaptic potentials (EPSPs) in granule cells that were reversibly inhibited by approximately 50% during application of norepinephrine (NE). NE had no effect, however, on the membrane current evoked by the application of glutamate, indicating a presynaptic site of action. The effect of NE on EPSPs was mimicked by the alpha receptor agonist clonidine, but not by the beta receptor agonist isoproteronol. NE also inhibited spontaneous GABAergic inhibitory postsynaptic potentials recorded in M/T cells, by a presynaptic alpha-adrenergic mediated mechanism. NE and clonidine also inhibited high threshold calcium currents. The effects of NE on calcium currents were irreversible in the presence of internal GTP gamma S and prevented by pertussis toxin, suggesting a G protein-coupled mechanism. Pertussis toxin also prevented the effects of NE on synaptic transmission. These results support previous results suggesting a disinhibitory role for NE in the olfactory bulb. This action is, at least in part, due to a reduction in mitral cell mediated granule cell excitation through inhibition of presynaptic calcium influx. PMID- 7859106 TI - Hippocampal beta-amyloid reduces locus coeruleus glutamate and tyrosine hydroxylase. AB - The effects of intrahippocampally injected beta-amyloid protein (beta-AP) on glutamate- (Glu) and tyrosine hydroxylase (TH)-like immunoreactivities in the neurons of the locus coeruleus (LC) were studied in rats. A synthetic peptide or the vehicle alone was injected into the hippocampus as controls. All injections were made once a week (two or three injections; 3 nmol in 2 microliters of distilled water). Fluorescent microspheres (either alone or with one of the peptides) were also injected into the hippocampus to identify coeruleo hippocampal neurons. The results revealed cell loss in the hippocampus at the site near beta-AP or control peptide deposition. Furthermore, in beta AP/microsphere injected animals, only 22.4% and 49.6% of hippocampal projection neurons contained Glu and TH, respectively, compared to 88.4% and 85.3% in the animals that received control peptide with microspheres. Our results suggest that beta-AP has an effect on noradrenergic cells whose axons project to the hippocampus. These effects may contribute to the TH cell loss in the LC of Alzheimer's brains. PMID- 7859107 TI - Noradrenergic abnormalities in the genetically epilepsy-prone rat. AB - The genetically epilepsy-prone rat (GEPR) has central nervous system noradrenergic deficits as compared to normal rats. It is possible that these deficits contribute to seizure predisposition because they are exhibited by seizure-naive as well as by seizure-experienced GEPRs. On the basis of pharmacological studies, it is hypothesized that there is an inverse relation between seizure predisposition and levels of noradrenergic activity in brain. Neurochemical studies indicate that deficits exist in areas innervated by both the locus ceruleus and the lateral tegmental noradrenergic systems. These deficits exist in GEPRs without seizure experience and are more pronounced in the severe seizure strain as compared to the moderate seizure strain. We review eight experimental steps undertaken to identify more precisely the anatomical location of noradrenergic determinants of seizure predisposition. These steps illustrate the theoretical bases for the studies and describe the specific experiments completed. Evidence supports the hypothesis that noradrenergic deficits in the superior colliculus and/or ventrally adjacent regions are determinants of seizure predisposition. PMID- 7859108 TI - Existence of glutamate in noradrenergic locus coeruleus neurons of rodents. AB - This study distinguished three types of immunolabeled neurons in nucleus locus coeruleus (LC) of the rat and mouse: cells single labeled either for tyrosine hydroxylase-like immunoreactivity (TH-LI) or glutamate (Glu)-LI, and those double labeled for both antigens. Although the double labeled neurons tend to be located in the middle and ventral thirds of the rat LC nucleus, throughout its rostrocaudal extent, such feature was not apparent in the mouse. Quantitatively a majority of neurons cocontaining TH- and Glu-LI were commonly observed in the rat (62%) and mouse (77%) LC. Additional studies utilizing the combined retrograde and immunohistochemical labeling revealed that such a high incidence of coexistence of the TH- and Glu-LI was also represented by coeruleocortical neurons in the rat (69% and 75% of all ipsilateral and contralateral projection cells, respectively). A possible role of coeruleocortical neurons involvement in Glu- and norepinephrine-mediated target neuron dysfunction is discussed. PMID- 7859109 TI - Modulation of locus coeruleus neurons by extra- and intracellular adenosine 5' triphosphate. AB - The cell membrane of rat locus coeruleus (LC) neurons is sensitive to both extra- and intracellular ATP. Extracellular ATP or its enzymatically stable analogues activate membrane receptors of the P2 type. These receptors inhibit a persistent potassium current and simultaneously activate a nonselective cationic conductance. The resulting depolarization increases the spontaneous firing rate. A decrease in the concentration of intracellular ATP during hypoxia or hypoglycemia opens ATP-sensitive K+ (KATP) channels of LC neurons. The resulting hyperpolarization depresses the discharge of action potentials and conserved energy. The hypoxia-induced hyperpolarization is additionally due to the release of adenosine from neighboring neurons or glial cells. A certain class of compounds, termed potassium channel openers, also decrease the firing, while sulphonylurea antidiabetics known to block KATP channels increase it. Sulphonylurea antidiabetics antagonize the excitability decrease induced both by potassium channel openers and metabolic damage. PMID- 7859110 TI - Molecular and cellular mechanisms of opiate action: studies in the rat locus coeruleus. AB - We have studied the molecular and cellular mechanisms underlying the acute and chronic effects of opiate on neurons of the rat locus coeruleus (LC). Acutely, opiates inhibit LC neurons by activating K+ channels and inhibiting a novel sodium-dependent inward current. Both of these actions are mediated via pertussis toxin-sensitive G-proteins, and regulation of the sodium current occurs through inhibition of the cyclic AMP pathway. In contrast to the acute effects of opiates, chronic treatment of rats with opiates increases levels of specific G protein subunits, adenylate cyclase, cyclic AMP-dependent protein kinase, and a number of phosphoproteins (including tyrosine hydroxylase) in this brain region. Electrophysiological data have provided direct support for the possibility that this upregulation of the cyclic AMP system contributes to opiate tolerance, dependence, and withdrawal exhibited by these noradrenergic LC neurons. As the adaptations in G-proteins and the cyclic AMP system appear to occur at least in part at the level of gene expression, current efforts are aimed at identifying the mechanisms by which opiates regulate the expression of these intracellular messenger proteins in the LC. These studies will lead to an improved understanding of the molecular and cellular basis of opiate addiction. PMID- 7859111 TI - Possible noradrenergic dysfunction in schizophrenia. AB - In spite of extensive studies over the last 2 decades to find direct evidence in support of the dopamine hypothesis of schizophrenia, no undisputed experimental data has been obtained. In contrast, estimation of noradrenalin (another major catecholamine) and its metabolites in postmortem brain and in the cerebrospinal fluid appears to be producing consistent results. To understand the meaning of this change for the pathogenesis of the illness, we have carried out animal experiments in which reproducibility of schizophrenic signs and symptoms by noradrenergic dysfunction, and treatability of the disorder by modulation of noradrenergic activity were studied. First, psychophysiological signs in skin conductance responsiveness (nonhabituating or nonresponding change) and smooth pursuit eye movement (spiky or stepwise pursuit) could be reproduced by enhancing or suppressing central noradrenergic activity. Behavioral abnormalities resembling schizophrenic symptoms are known to be reproducible by over- or underactivity of the system (overarousal or underarousal syndrome). Secondly, the action of various drugs capable of modulating schizophrenic symptoms was analyzed in relation to noradrenergic activity. Haloperidol, in particular, had a potent suppressing effect on skin conductance activity (spontaneous fluctuation rate and habituation rate) when administered chronically, suggesting its inhibitory action on noradrenergic activity. PMID- 7859112 TI - Stress, antidepressant drugs, and the locus coeruleus. AB - This review presents a synthesis of a large body of seemingly inconsistent literature on the role of the locus coeruleus-norepinephrine (LC-NE) system and the corticotropin-releasing hormone (CRH)-median eminence system in mediating the CNS effects of stress and the therapeutic effects of antidepressant drugs. The clinical implications of these findings for the etiology and treatment of stress related psychiatric disorders such as depression will be discussed. PMID- 7859113 TI - Locus coeruleus activation by physiological challenges. AB - Studies were designed to elucidate the neurotransmitter(s) and circuitry involved in activation of noradrenergic locus coeruleus (LC) neurons by different physiological challenges in halothane-anesthetized rats, and to understand the functional consequences of LC activation by these stimuli. LC spontaneous discharge rate was increased by a hypotensive challenge and by bladder distention. The effect produced by hypotension, but not by bladder distention, was prevented by antagonists of the stress-related neurohormone, corticotropin releasing factor (CRF), administered ICV or directly into the LC. In contrast, ICV administration of excitatory amino acid antagonists prevented LC activation by bladder distention, but not by hypotension. These results suggest that LC activation by hypotension and bladder distention requires separate neurotransmitter systems, with CRF mediating activation by hypotension and excitatory amino acids mediating activation by bladder distention. Both physiological challenges activated forebrain electroencephalographic (EEG) activity, as indicated by a shift from low frequency, high amplitude activity to high frequency, low amplitude activity recorded from the frontal cortex. The EEG effects appeared to be temporally correlated with LC activation. Bilateral LC inactivation or microinfusion of CRF antagonists into the LC prevented both LC and EEG activation by hypotension. These results suggest that one consequence of LC activation during stress or physiological challenges may be to increase or maintain arousal. PMID- 7859114 TI - Depression and anxiety: role of the locus coeruleus and corticotropin-releasing factor. AB - Based on studies of depression and anxiety using animal (rat) models, it is suggested that, contrary to a widely accepted theory, increased activity of locus coeruleus (LC) neurons does not appear to potentiate anxiety; instead, the influence of LC activity may be opposite to this. First, studies are described that indicate that behavioral changes resembling what is seen in human clinical depression occur in rats exposed to highly stressful conditions, and the research is then traced, which links this stress-induced depression to disturbance of normal noradrenergic regulation of LC activity. Second, the potential role of corticotrophin releasing factor (CRF) in stress-induced behavioral depression is explored. CRF infused into the LC did not produce behavioral depression in the swim test but did increase anxiety; by comparison, CRF infused into the parabrachial nucleus lateral to LC increased both depression and anxiety. Finally, to further explore the relationship between LC activity and anxiety, drugs were infused into LC region to attempt to specifically activate or depress firing of LC neurons. In contrast to expectations, infusion to decrease firing of LC cells increased anxious behavior, while infusion to increase firing decreased anxious behavior. Several other studies are discussed that point to a similar conclusion. It is suggested that, at least in rats, the capacity of stress inducing or aversive stimuli to activate LC neurons does not potentiate anxiety under environmental conditions that elicit this response, but, rather, the increased activity of the LC/dorsal noradrenergic system under such conditions may exert a counterbalancing, antianxiety influence. PMID- 7859115 TI - Corticotropin-releasing factor neurotransmission in locus coeruleus: a possible site of antidepressant action. AB - Hypersecretion of corticotropin-releasing factor (CRF), has been hypothesized to occur in depression. Because CRF may serve as a neurotransmitter in the locus coeruleus (LC), it was proposed that CRF hypersecretion in the LC is responsible for some characteristics of depression, and that antidepressants act by interfering with CRF neurotransmission in the LC. To test this hypothesis, the acute and chronic effects of four antidepressants and cocaine were characterized on LC spontaneous and sensory-evoked discharge, LC activation by a stressor that requires CRF release, and LC activation by exogenously administered CRF. None of the antidepressants or cocaine altered LC activation by intracerebroventricularly administered CRF (3.0 microgram) after chronic administration. However, chronic administration of desmethylimipramine and mianserin inhibited LC activation by a hypotensive stress that requires endogenous CRF release, suggesting that they decrease CRF release in the LC. Chronic administration of sertraline and phenelzine altered LC responses to repeated sciatic nerve stimulation in a manner opposite to the effect produced by CRF, suggesting that these drugs may functionally antagonize CRF actions in the LC. Cocaine did not appear to interfere with CRF actions in the LC. In conclusion, chronic administration of antidepressants may have the potential to interfere with CRF neurotransmission in the LC. PMID- 7859116 TI - The locus coeruleus and immediate-early genes in spontaneous and forced wakefulness. AB - In this study, we mapped the expression of two immediate-early genes to examine the functional activation of the locus coeruleus and other regions of the rat brain after periods of spontaneous wakefulness or sleep and after sleep deprivation. c-fos and NGFI-A are two immediate-early genes that are rapidly induced by physiological stimuli and can be used as molecular markers of neural activation. We used immunocytochemical detection of Fos and NGFI-A proteins associated with double labeling for tyrosine hydroxylase to identify activated noradrenergic cells. We found that the expression of Fos and NGFI-A was markedly increased in the locus coeruleus and other brain areas both after spontaneous wakefulness and after short periods (3-24 h) of sleep deprivation. Several Fos positive cells and most NGFI-A positive cells found in the locus coeruleus after periods of spontaneous wakefulness were shown to be noradrenergic. This study demonstrates that wakefulness per se, whether spontaneous or induced by total sleep deprivation, results in the functional activation of identified noradrenergic locus coeruleus cells. PMID- 7859117 TI - Locus coeruleus-induced modulation of forebrain electroencephalographic (EEG) state in halothane-anesthetized rat. AB - The effects of reversible enhancement or suppression of locus coeruleus (LC) neuronal discharge activity on forebrain electroencephalographic (EEG) activity have been previously examined in two series of experiments in halothane anesthetized rats. Unilateral enhancement of LC activity increased EEG measures of arousal in frontal cortex and hippocampus. The EEG effects of LC activation were blocked by intracerebroventricular pretreatment with the noradrenergic beta antagonist, propranolol. Bilateral, but not unilateral, suppression of LC activity substantially increased EEG measures of sedation/anesthesia in cortex and hippocampus. In all experiments: a) EEG responses were only observed following changes in LC activity levels; b) onset of EEG responses closely followed changes in LC neuronal activity; c) recovery of EEG responses closely followed the recovery of LC neuronal activity. The present report integrates these previous results and considers their implications for the hypothesis that the LC may be an important modulator of behavioral state and/or state-dependent processes. Together, the two series of experiments yield complementary observations that have implications for LC function that are not apparent when considering each series in isolation. PMID- 7859118 TI - Locus coeruleus activity in monkey: phasic and tonic changes are associated with altered vigilance. AB - Impulse activity of individual neurons in the nucleus locus coeruleus (LC) was recorded from chair-restrained, unanesthetized cynomolgus monkeys. LC activity was closely related to the behavioral state of the animal. In alert waking, LC neurons displayed continuous, moderately irregular activity. In contrast, prolonged pauses in activity accompanied drowsiness. These pauses preceded eye closure and occurred 1-3 s before the onset of slow-wave EEG. At awakening, LC activation preceded by up to 3 s desynchronized EEG and eye opening. LC activity during alertness varied tonically. During behavioral agitation LC activity was higher than during goal-directed task behavior (described below). In addition to these changes in tonic activity, LC neurons were also phasically responsive to certain sensory stimuli. These cells responded selectively to unexpected, meaningful sounds. LC neurons were also recorded during a visual oddball discrimination task in which the monkey was required to selectively release a lever in response to an infrequent visual cue (target cue; CS+) to receive juice reward. LC neurons were selectively activated by CS+ cues in this task; no other task events evoked LC activity. The mean latency of CS+ response was 108 ms (90 ms for multicell recordings), more than 150 ms prior to the behavioral response (lever release). These responses became smaller in later epochs during the session, along with deteriorating task performance. It is proposed that these short-lasting stimulus-evoked LC responses may help optimize behavioral responses and increase vigilance to subsequent sensory stimuli. Together, LC may contribute both to maintaining tonic levels of vigilance and to phasically modulating the current vigilance level in a stimulus-dependent mode. PMID- 7859119 TI - A week in the life of a DON! PMID- 7859120 TI - Therapeutic options in the treatment of congestive heart failure. Part II. PMID- 7859121 TI - Pet therapy ... a pet project. PMID- 7859122 TI - A journey into TQM (total quality management). AB - Total quality management (TQM) which has been implemented for some time in industry and more recently in hospitals is just beginning to come to long term care organizations. Directors of Nursing can prepare themselves for such a program in their facility by learning from the experience of long term care facilities that have implemented TQM. This is part one of a two part series which describes the implementation process used and a discussion of problems encountered. The second article which will appear in a later issue describes the experience and findings of one project team-the nursing documentation team. PMID- 7859123 TI - LTC law: risk management primer for the director of nursing in LTC. PMID- 7859124 TI - Health care reform is on the front burner: help for nursing homes is not yet a part of it. PMID- 7859125 TI - Professional or perfectional? PMID- 7859126 TI - Federal nursing staff studies are to begin this spring ... get ready to contribute your thoughts and respond! PMID- 7859127 TI - Enteral tube selection in long term care. PMID- 7859128 TI - Assuring adequate staffing. PMID- 7859129 TI - A week in the life of a DON! Part II. PMID- 7859130 TI - LTC law: wandering residents: an emotional and legal nightmare. PMID- 7859131 TI - The role of the nursing home in nursing research of the elderly. AB - The greatest repository of knowledge of the elderly lies in the nursing home setting. Nurses who work in nursing homes acknowledge that the knowledge base that directs their practice is gerontological knowledge and over time they have evolved the most sophisticated care for older persons. Much of this care has evolved in trial and error response to needs. Many of the interventions have not been tested in rigorous research and therefore are difficult to justify in an atmosphere of cost cutting. Nursing home nurses have, therefore, a responsibility to be forerunners in the generation, testing and dissemination of the body of gerontological nursing knowledge to guide effective and efficient nursing practice with older persons. In a time of decreased resources this is no small challenge. To suggest approaches to encourage long term care research this article will explore the literature in this area, relate knowledge gained from the teaching nursing home projects and share the experience of a Director of Nursing in fostering research in a teaching nursing home setting without outside funding. PMID- 7859132 TI - Infection control: infection surveillance for long term care facilities. PMID- 7859133 TI - Uptake and binding of liposomal 2',3'-dideoxycytidine by RAW 264.7 cells: a three step process. AB - It was recently reported that the sequestration of virus by macrophages in reticuloendothelial system organs, such as lymph nodes, is possibly responsible for the clinical latency of disease in asymptomatic HIV-infected patients. Since macrophages may sequester HIV after phagocytosis, and because phagocytosis is a specialized function of any mammalian macrophage, a mouse-macrophage cell line (RAW 264.7) was used as a macrophage model to evaluate the uptake and binding of 2',3'-dideoxycytidine (ddC) encapsulated in liposomes of an average size of 300 nm containing 350 mumols of ddC per mmol of lipids. Liposomal ddC (L-ddC) was rapidly taken up by macrophages. In contrast, its free form (ddC) accumulated slowly in these cells. The accumulation of ddC from L-ddC into cells seemed to consist of two components: a saturable one, which fitted with the Michaelis Menten model, and a nonsaturable one, which proceeded linearly in the presence of an excess amount of unlabeled liposomes. Under these conditions, we found an apparent Michaelis-Menten constant (Km) of 40 microM and an initial velocity of 0.12 nmol ddC/mg protein/min for the saturable component and a constant rate of accumulation (KN) of 0.017/min for the nonsaturable component. The inhibition of uptake of ddC from L-ddC in the presence of phagocytosis inhibitors (deoxyglucose plus sodium azide) and nucleoside transport inhibitors (dipyridamole or nitrobenzylthioinosine) also confirmed the existence of several mechanisms in the liposome-mediated accumulation process of ddC into macrophages. Furthermore, studies of efflux of ddC in drug-free medium from cells preloaded with L-ddC or ddC established longer retention of ddC in cells preloaded with L-ddC than with ddC.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859134 TI - Detection of semen in cervicovaginal secretions. AB - Sperm were detectable by microscopic examination in human cervicovaginal lavage (CVL) specimens < or = 8 h after intercourse, whereas an enzyme-linked immunosorbent assay using the monoclonal antibody MHS-5, specific for a seminal vesicle antigen present in semen detected semen at a concentration of 1:2,500,000 (0.00004%) in CVL specimens and was positive < or = 24 h following unprotected intercourse. We recommend the routine use of semen detection assays to reduce false-positive results attributable to semen contamination in assays of pathogens, antibodies, or other factors in cervicovaginal secretions. PMID- 7859135 TI - Incidence and prognostic value of malnutrition and wasting in human immunodeficiency virus-infected outpatients. AB - Although malnutrition and wasting are known features of human immunodeficiency virus (HIV) infection, their incidence and possible association with immunologic impairment are largely unknown, as is the prognostic value of the nutritional state. Nutritional, clinical, and immunologic parameters were measured in 100 outpatients in different stages of HIV infection. In addition, 39 patients with AIDS were prospectively followed for a mean period of 343 (range, 53-650) days. Sixty-three percent of the patients showed evidence of malnutrition, 21% suffered from wasting. A reduced body cell mass and decreased serum albumin levels were observed in 32 and 14%, respectively, predominantly in more advanced disease stages. Fourteen of 39 AIDS patients died after a mean survival of 212 days. Survivors showed significantly larger initial body cell mass values and higher initial serum albumin levels compared with nonsurvivors, whereas CD4+ lymphocyte counts, disease complications, and medication were all similar in both groups. Kaplan-Meier analyses revealed a significantly prolonged survival in patients with a body cell mass > 30% of body weight or serum albumin levels exceeding 30 g/L. Factor analyses indicated that the parameters of nutritional state were independent from each other and from CD4+ lymphocyte counts. Malnutrition occurs frequently during HIV infection and increases with disease progress. It strongly predicts patient survival independent of CD4+ lymphocyte counts. PMID- 7859136 TI - The role of atovaquone tablets in treating Pneumocystis carinii pneumonia. AB - At the start of the AIDS epidemic, the only agents licensed for treatment of Pneumocystis carinii pneumonia (PCP) were trimethoprim-sulfamethoxazole (TMP-SMX) and pentamidine. Both are effective against PCP, but their use has been compromised by adverse reactions that necessitate discontinuing therapy in < or = 54% of patients. As a result of the limitations in the use of these therapies, research efforts have been directed toward the development of effective agents with an improved safety profile. Of these agents, one of the best studied is atovaquone, a hydroxynaphthoquinone that has been licensed by the U.S. Food and Drug Administration for use in the treatment of mild to moderate PCP in patients intolerant to TMP-SMX. Clinical studies have shown that atovaquone is associated with overall therapeutic success rates equivalent to those of intravenous pentamidine and TMP-SMX, although its therapeutic efficacy rates are somewhat lower. However, atovaquone is associated with fewer treatment-limiting side effects than the other drugs. The literature concerning the efficacy and safety of atovaquone for the treatment of PCP will be reviewed. PMID- 7859137 TI - Derivation and properties of a brief health status assessment instrument for use in HIV disease. AB - Health status measures adapted from the Medical Outcomes Study (MOS) scales have been shown to be useful and highly reliable in human immunodeficiency virus infected populations, but acceptance of these measures has been limited in part by concerns over investigator, patient, and data burden. We sought to address these concerns by reducing the number of items in the MOS scales rather than by reducing the number of domains covered. We selected items for the shorter scales based on the static and dynamic relationships to the longer scales and to indicators of clinical and functional status in 10,399 responses from 1,934 participants, as well as in relevant subpopulations. The resulting scales have a total of 21 items, as compared to 38 in the longer instrument. Correlations between the shorter and longer scales were excellent. At 0.78 to 0.85, the reliability of the subscales was lower than that of the full scales. However, compared to an index based on the longer scales, an index based on the subscales had identical reliability, yielded nearly identical values, and was as sensitive in detecting treatment differences in a clinical trial. The resulting instrument continues to cover disability, work, utilization, and health status, but is less than half the length of our previous comprehensive questionnaires. PMID- 7859138 TI - Serum beta 2-microglobulin and prediction of progression to AIDS in HIV-infected injection drug users. AB - Several immunological and serological variables have become established in recent studies as valuable markers to identify human immunodeficiency virus (HIV) positive individuals at the highest risk for rapid disease progression. These studies have been performed mainly in cohorts of homosexual men. In this study, we assessed the usefulness of CD4 lymphocyte count, serum beta 2-microglobulin concentration, and the presence of p24 antigen as predictors of AIDS in a cohort of 130 HIV-positive injection drug users (IDUs) followed-up for 1 to 67 months. Progression to AIDS was most strongly associated with reduced absolute numbers of CD4+ lymphocytes at baseline, but increases in beta 2-microglobulin levels at baseline were an independent predictor of outcome. After stratification by baseline CD4 count, beta 2-microglobulin concentration added significant prognostic information to CD4 count among IDUs with > 500/mm3 CD4 cells (Breslow statistic value, 5.84, p = 0.01). Thus among seropositive IDUs with normal CD4 counts, increases in beta 2-microglobulin may be used as an early marker of individuals with higher risk of progression to AIDS, who may benefit from more intensive laboratory monitoring or clinical management. PMID- 7859139 TI - HIV Dementia Scale: a rapid screening test. AB - HIV dementia has an annual incidence of 7% after AIDS development and eventually affects 20% of all HIV-infected persons. Accurate and early diagnosis of HIV dementia can lead to optimized therapeutic and management decisions. The purpose of this study was to design a valid instrument to identify HIV dementia. Five groups totalling 152 outpatients were evaluated; HIV-seronegative (SN) (n = 34); asymptomatic HIV-seropositive (ASX) (n = 38); AIDS, nondemented (AIDS) (n = 53); AIDS, mildly demented (Dm) (n = 39); and AIDS, severely demented (Ds) (n = 7). None had CNS opportunistic infections or delirium due to drug intoxication or systemic illness at the time of testing. Patients were evaluated with three different screening instruments: (a) the newly developed HIV Dementia Scale (HDS), (b) the Minimental State Exam (MMSE), and (c) the Grooved Pegboard (PB). Mean HDS scores (+/- SD) (maximum = 16) for each group were as follows: SN, 14.9 +/- 1.69; ASX, 14.1 +/- 1.72; AIDS, 12.8 +/- 3.17; Dm, 8.0 +/- 3.81; and Ds, 3.5 +/- 2.94. A Receiver-Operating Characteristic curve was used to derive an optimal HDS cut-off score of < or = 10 for identifying HIV dementia, with a sensitivity of 80%, specificity 91%, and positive predictive value 78%. The efficiencies of each instrument for identifying HIV dementia were as follows: HDS-84%, PB-86%, and MMSE-72%. The HDS is a reliable and quantitative scale that is superior to other widely used bedside tests such as the MMSE for identifying HIV dementia. PMID- 7859140 TI - Safety and efficacy of thymopentin in zidovudine (AZT)-treated asymptomatic HIV infected subjects with 200-500 CD4 cells/mm3: a double-blind placebo-controlled trial. AB - Thymopentin, 50 mg subcutaneously (s.c.) 3 times per week, was evaluated in a double-blind, randomized, placebo-controlled trial of zidovudine (AZT)-treated asymptomatic human immunodeficiency virus (HIV)-infected subjects with 200-500 CD4 cells/mm3 at entry. The 352 subjects were prestratified by prior AZT use into stratum I (235 subjects, > 6 months AZT at entry) and stratum II (117 subjects, < or = 6 months AZT at entry). Clinical end points, CD4 cell counts, serum p24, serum immune complex dissociated (ICD) p24, and safety variables were evaluated through 48 weeks, using an intent-to-treat analysis. The two strata were analyzed individually because they yielded different clinical outcomes, with a statistically significant treatment-by-stratum interaction. In stratum I (mean, 16 months AZT at entry) two AIDS or death events occurred in thymopentin and 10 in placebo recipients (p = 0.024; relative risk (RR) estimate, 4.9 [95% confidence limit (CI), 1.1 to 22.2]). There were three AIDS-related complex (ARC), AIDS, or death events in thymopentin and 18 in placebo recipients [p = 0.001; RR estimate, 5.9 (95% CI, 1.7 to 20.0)]. In stratum II (mean, 3 months AZT at entry), four AIDS or death events occurred in thymopentin and none in placebo recipients (p = 0.11), and four ARC, AIDS, or death events occurred in thymopentin and two in placebo recipients (p = 0.79). The treatment groups did not differ significantly with respect to changes in CD4 counts or p24 antigen levels or with respect to clinical adverse experiences or laboratory abnormalities. Thus, AZT-experienced placebo-treated subjects had relatively high progression rates to AIDS or death and to ARC, AIDS, or death, and these rates were reduced by thymopentin treatment. In contrast, placebo-treated subjects with little prior AZT experience had low progression rates; these were not significantly changed by thymopentin treatment. There was no increase in the incidence of adverse reactions with thymopentin. PMID- 7859141 TI - Failure of high-dose oral acyclovir to suppress CMV viruria or induce ganciclovir resistant CMV in HIV antibody positive patients. AB - Ninety-three symptomatic HIV antibody positive patients were randomized to receive zidovudine (ZDV) 600 mg/day and acyclovir (ACV) 4,800 mg orally per day versus ZDV 600 mg/day plus placebo. Urine was obtained at 3-month intervals and cultured for cytomegalovirus (CMV) in diploid fibroblast cells. The percent of urine specimens positive for CMV was 7.1% in the ZDV group and 5.8% in the ZDV plus ACV group (p = 0.55); 27% of patients had at least one urine culture positive for CMV while taking ZDV, versus 20% of patients taking the combination of ZDV plus ACV (p = 0.52). We conclude that ACV at a dosage of 4,800 mg/day does not suppress CMV excretion in urine of symptomatic HIV antibody positive patients taking concurrent ZDV. Use of ACV did not appear to induce resistance of CMV to ganciclovir since the ID50 of isolates from the two treatment groups did not differ. PMID- 7859142 TI - AIDS among the homeless of Boston: a cohort study. AB - We wanted to compare demographics, risk behaviors, AIDS-defining diagnoses, and survival between homeless and housed persons with AIDS in Boston from 1983 to 1991. Our retrospective cohort study used chart review to identify homeless AIDS cases and data from the Massachusetts AIDS Surveillance Program for comparison of homeless and nonhomeless cases. Seventy-two homeless and 1,536 nonhomeless Boston residents were reported to have AIDS between Jan. 1, 1983, and July 1, 1991. Homeless persons with AIDS were more likely to be African American or Latino (81 vs. 39%, p < 0.0001) and have i.v. drug use as a risk behavior (75 vs. 19%, p < 0.0001). The AIDS-defining diagnoses among the homeless were more commonly disseminated Mycobacterium tuberculosis (9 vs. 2%, p < 0.0001) and esophageal candidiasis (17 vs. 9%, p < 0.01). These differences were not seen when the populations were stratified by i.v. drug use. No significant difference in survival between the homeless and nonhomeless cohorts was found. Homeless individuals with human immunodeficiency virus are significantly different than housed persons, and at greater risk of invasive opportunistic infections. Appropriate clinical strategies can be developed to provide needed care to homeless persons with HIV. PMID- 7859143 TI - Trends in incidence and prevalence of HIV-1 infection in intravenous drug users in Valencia, Spain. AB - Our objective was to describe and compare the trends of incidence and prevalence of HIV-1 infection in intravenous drug users (IDUs) in Valencia, Spain in 1987 1992. A cohort study was carried out in AIDS Information Centers located in the Valencia Region (Spain). Point seroprevalence was calculated for in each year according to HIV status at the first contact. Incidence annual rates were calculated from those IDUs identified as seronegative in their first visit and who returned for a new testing. From a total of 4,207 IDUs who contacted these centers, 4,131 (98.2%) asked voluntarily for HIV-1 testing. The seroprevalence for the whole period was 48.4% (95% C.I., 46.88, 49.92). Follow-up information was available for 604 subjects of the total 2,130 subjects who were seronegative in their first visit. The incidence rate for the 1988-1992 period was 12.02/100 person-years (95% C.I., 9.62, 14.41). Prevalence showed an overall decreasing pattern with a minimum corresponding to the year 1992 (43.6%). Incidence rates increased mildly until 1990 (13.93 per 100 person-years), to stabilize beyond at approximately 10 per 100 person-years. Our incidence rates are very high regardless of the decline of prevalence. Effective risk reduction programs among IDUs have been almost nonexistent in Spain up to now and should become an immediate priority. PMID- 7859144 TI - Alcohol use, liberal/conservative orientations, and ethnicity as predictors of sexual behaviors. AB - The present study examined relationships among ethnicity, gender, alcohol consumption, and sexual behaviors in a community survey sample of 1,392 adults. Predictors included liberal versus conservative orientations (sex role orientation, religiosity); traditional versus liberal attitudes regarding sexuality, typical alcohol consumption patterns, expectancies regarding alcohol's effect upon one's sexuality, and frequency of alcohol use before sex. Findings are consistent with other studies indicating more sex partners among males than females and among Blacks (particularly males) than Anglos. Blacks also reported less involvement in oral sex than Anglos and Mexican-Americans--although observed differences for oral sex were more characteristic of females and less characteristic of unmarried nondrinkers. Unmarried Mexican-American males reported somewhat, though not significantly, more partners than did Anglos. Unmarried Black males (particularly nondrinkers) also reported more frequent risky behaviors than did Anglos. Divorced Black female drinkers reported significantly less frequent risky behavior than their Anglo counterparts. Alcohol use-sexual relationships were independent of psychosocial background characteristics and situated drinking (drinking before sex) was more strongly related to sexual behavior dimensions than were general drinking patterns. PMID- 7859145 TI - Apparent deficiency of glutathionine in the PBMC's of people with AIDS depends on method of expression. PMID- 7859146 TI - Flank abscess in AIDS and tuberculosis. PMID- 7859147 TI - Regional differences in human retroviral infections HIV-1, HIV-2, and HTLV-I/II in rural Guinea (west Africa) PMID- 7859148 TI - The Southern blot. An update. AB - This article is devoted to the recent advances made in the Southern blotting technique, which is used for the detection of gel-fractionated DNA molecules following transfer to a membrane. The latest practical improvements made to the techniques of Southern blotting, probe labeling, and hybridization are discussed. Among the most significant advances are: new membranes, transfer methods, probe labeling, and rapid hybridization. Detailed protocols show the application of these improvements in this widely used technique. PMID- 7859149 TI - Sepharose spin column chromatography. A fast, nontoxic replacement for phenol:chloroform extraction/ethanol precipitation. PMID- 7859150 TI - Catalytic antibodies. Conference overview. PMID- 7859151 TI - Forensic applications of DNA fingerprinting. AB - In many ways, DNA profiling technology is very similar to the conventional techniques used for forensic identification. As with, for example, blood grouping techniques, the molecular characteristics of the scene of crime sample may be determined and compared with those of the scene of reference samples from suspects and victim. If the molecular characteristics of the crime sample and the suspect are different, then they cannot be from the same person, whereas if they match, then the possibility remains that they may be from a single source. Similar material, such as blood or semen stains, may be used for both biochemical and genetic tests, and the main applications of identification and relationship testing are shared by both techniques. At this point, the similarity ends; DNA profiling has the following characteristics: 1. It is more sensitive, being able to generate sound data from only a tiny amount of even partially degraded biological material. 2. It is capable of resolving mixtures of semen or tissue from up to several individuals. 3. It has a far greater power of discrimination between individuals--sometimes up to 1 millionfold higher than conventional techniques. 4. It provides considerably more information on the nature of relationships, particularly in cases of incest. As such, the technique represents a quantum leap in forensic identification and relationship testing. PMID- 7859152 TI - Polybrene/DMSO-assisted gene transfer. Generating stable transfectants with nanogram amounts of DNA. AB - Polybrene/DMSO-assisted gene transfer is a simple and versatile transfection strategy capable of producing high numbers of stable transfectants from adherent monolayer cultures with low (nanogram) quantities of exogenous DNA. The procedure involves two stages: adsorption and internalization. The former is mediated by polybrene (a polycation polymer) and favors the uniform coating of target cells with polybrene-DNA complexes. Following adsorption, the cells are permeabilized by a brief exposure to dimethyl sulfoxide (DMSO) to facilitate the uptake of DNA complexes. Diverse cell types can be exposed to a wide range of polybrene concentrations without adverse effects. By contrast, the key determinant of success is the DMSO permeabilization regime, which must be configured independently for each cell line. Protocols optimized for gene transfer in murine and human fibroblasts are presented along with a guide for the rapid optimization of the method. The advantages and limitations of the method are also discussed. PMID- 7859153 TI - Immunoaffinity chromatography. AB - The basic procedure of immunoaffinity chromatography (IAC) is described. The insoluble support matrices available for IAC and their activation chemistries, including some of the most recently introduced, are reviewed. Means of selecting the most appropriate monoclonal antibody (MAb) are described, although an empirical approach is still required for the final choice of antibody. Precise methods of running IAC columns are surveyed including the binding, washing, and elution stages, although no precise recommendations can be made particularly for the elution step since this is unique to a particular MAb and antigen. All IAC sorbents lose activity with time through a combination of MAb inactivation and ligand leakage. The relative importance of the two phenomena is discussed, and suggestions are made to minimize the problem along with an indication of the relative stabilities of a range of coupling chemistries. A sample of the proteins purified by IAC is given together with pointers to the future of the technique. PMID- 7859154 TI - Catalytic antibodies: a critical assessment. AB - In the past few years, antibodies that catalyze a variety of reactions with enzyme-like properties have been produced. The present review is of a critical nature, rather than a survey or an introduction to the field of catalytic antibodies. Here, we examine the performance of catalytic antibodies in light of the features that define an enzyme: substrate specificity, rate enhancement, and turnover. We also refer to some limitations of the technologies currently used for their generation. In the future, antibodies may provide a new repertoire of tailor-made, enzyme-like, catalysts with possible applications in biology, medicine, and biotechnology. In the following sections, we emphasize that these applications will require far more efficient catalysts than are presently available, and we point to several trends for future research that may offer more efficient catalytic antibodies. PMID- 7859155 TI - Direct sequencing of PCR-amplified DNA. AB - This article describes the direct sequencing of PCR-amplified DNA, a technique that bypasses the problem of replication errors sometimes associated with other PCR procedures. The direct sequencing procedure produces an "average sequence" of all the copies of the target. Any miscopied molecule usually represents only a small proportion of the total. The technique described here is based on the "traditional" ddNTP sequencing method of Sanger et al. PMID- 7859156 TI - Expression vectors for the construction of hybrid Ty-VLPs. AB - Purification of expressed proteins can be facilitated by expressing the recombinant protein as a fusion with a carrier protein that assembles into particulate structures. This article describes the use of expression vectors in producing a hybrid of the yeast retrotransposon Ty, which self-assembles into virus-like particles (VLPs). Hybrid VLPs can be used in such laboratory applications as the production of polyclonal and monoclonal antibodies, structure/function analyses, the detection of important antigenic determinants, and epitope mapping of monoclonal antibodies. PMID- 7859157 TI - Production and purification of hybrid Ty-VLPs. AB - This article describes how pure Ty-VLPs (virus-like particles) can be prepared from hybrid Ty-VLPs. Many different hybrid Ty-VLPs have been produced and may be easily purified. Since the sedimentation properties of different hybrid Ty-VLPs are similar, a simple purification process can be used for any VLP. This fast, versatile, and easy process allows for the production of a variety of recombinant proteins. PMID- 7859158 TI - Immobilized metal ion affinity chromatography. AB - This article describes the technique of immobilized metal ion affinity chromatography (IMAC). The IMAC stationary phases are designed to chelate certain metal ions that have selectivity for specific groups in peptides and on protein surfaces. The number of stationary phases that can be synthesized for efficient chelation of metal ions is unlimited, but the critical consideration is that there is enough exposure of the metal ion to interact with the proteins, preferably in a biospecific manner. The versatility of IMAC is one of its greatest assets. An important contribution to the correct use of IMAC for protein purification is a simplified presentation of the various sample elution procedures. PMID- 7859159 TI - High-temperature gas chromatography and gas chromatography-mass spectrometry of glycoprotein and glycosphingolipid oligosaccharides. AB - High-temperature gas chromatography and gas chromatography-mass spectrometry for the analyses of oligosaccharides derived from glycoproteins or glycosphingolipids has been developed. Permethylated oligosaccharides with up to about 12 sugar residues and masses up to 2500 Daltons can be analyzed. This approach is discussed and exemplified. PMID- 7859161 TI - Universal primers for the PCR amplification of dicot-infecting geminiviruses. PMID- 7859160 TI - Yeast artificial chromosome cloning. AB - Yeast artificial chromosome (YAC) cloning systems enable the cloning of DNA stretches of 50 to well over 2000 kb. This makes it possible to study large intact regions of DNA in detail, by restriction mapping the YAC to produce a physical map and by examining the YAC for coding sequences or genes. YACs are important for their ability to clone the complete sequences of large genes or gene complexes that exceed the size limit for cloning in conventional bacterial cloning vectors like plasmids (up to 10 kb), bacteriophage (15 kb), and cosmids (50 kb). A major advantage of cloning in yeast, a eukaryote, is that many sequences that are unstable, underrepresented, or absent when cloned into prokaryotic systems, remain stable and intact in YAC clones. It is possible to reintroduce YACs intact into mammalian cells where the introduced mammalian genes are expressed and used to study the functions of genes in the context of flanking sequences. The correct protein processing mechanisms are present in the mammalian cells to ensure that a viable protein product is produced. PMID- 7859162 TI - Separation of proteins using cetyltrimethylammonium bromide discontinuous gel electrophoresis. AB - The gel electrophoresis system presented here allows the separation of proteins with the concomitant retention of detectable native activities. The system, referred to as CAT gel electrophoresis, uses the detergent cetyltrimethylammonium bromide in combination with a discontinuous gel matrix to resolve protein mixtures into discrete bands. Many proteins retain detectable levels of native activity after CAT electrophoresis, and gel bands can be easily identified using assays based on specific enzymatic activities or binding characteristics. The ability to identify protein bands based on Both M(r) and activity in a single gel makes the CAT system a powerful adjunct to existing biochemical techniques. PMID- 7859163 TI - Construction of yeast artificial chromosome libraries by pulsed-field gel electrophoresis. AB - Yeast artificial chromosome (YAC) libraries have been constructed from a variety of organisms using different approaches. This protocol outlines in detail the construction of YAC libraries with large inserts using size fractionation of partially digested DNA by pulsed-field gel electrophoresis. PMID- 7859164 TI - Expression of foreign genes in mammalian cells using an antibody fusion system. AB - An expression system is described whereby a gene product is expressed fused to an antibody Fab fragment to form an antibody-like molecule. The antigen binding function of the original antibody is retained and the foreign gene replaces the CH2 and CH3 regions of the heavy chain. The fusion protein is secreted as if it were an antibody, and can be purified using the antigen-binding function of the Fab-like part of the molecule. In principle, any open reading frame can be expressed and it is not necessary to develop an individual purification scheme, or any analytical reagents such as antibodies, for the expressed protein, as both these functions can be performed by the Fab part of the fusion protein. In practice, the nature of the nonantibody part of the fusion influences the efficiency of expression and secretion, and detailed guidance is given on trouble shooting and maximizing expression. PMID- 7859165 TI - Epitope mapping. AB - This article describes a strategy for the mapping of the binding site, or epitope, of a monoclonal antibody (MAb) using bacterially expressed protein products. An overall strategy is discussed. This includes an initial round of several parallel approaches to gain the greatest amount of information at this stage. The second round uses the mapping information generated to identify MAbs, which may bind to identical or overlapping epitopes. The third round involves the design of new constructs that express small defined regions of the protein to refine the position of the epitope. The final step leads to the identification of the epitope to a resolution of 10 amino acid residues or else. PMID- 7859166 TI - RAPD reactions from crude plant DNA. Adding RNase A as a "helper enzyme". AB - As opposed to standard polymerase chain reaction (PCR) using specific primers, genome analysis involving short random primers, for example RAPD, may yield inconsistent results if crude plant DNA preparations are used as the template. When RNase A, a thermostable enzyme, was added to such reactions, highly repeatable banding patterns were obtained from crude plant DNA, thus speeding up analyses substantially. PMID- 7859167 TI - "Without compromising in any particular": the success of medical coeducation in Cleveland, 1850-1856. PMID- 7859168 TI - Students and teaching in the clinical era, 1770-1860. PMID- 7859169 TI - Student culture at the turn of the nineteenth century: Edinburgh and Philadelphia. PMID- 7859170 TI - Students at the bedside in German universities, 1770-1830. PMID- 7859171 TI - [Progresses in medical sciences in China, 1994]. PMID- 7859172 TI - Ocular timolol levels after drug withdrawal: an experimental model. AB - Carbon 14-labelled timolol maleate was instilled into both eyes of 12 pigmented rabbits daily for 42 days. Drug levels in the aqueous humour and ocular tissues were measured up to 42 days after drug withdrawal. The results indicate that timolol concentrates mainly in melanotic tissues, with slow release. Even 42 days after withdrawal the drug was still present in pigmented ocular tissues. Timolol was detected in the aqueous up to 5 days after withdrawal. These findings explain the long-term depressant effect of topically administered timolol on aqueous production. We conclude that lower or less frequent doses of timolol should be considered in patients with glaucoma. PMID- 7859173 TI - Purpurogallin as a cytoprotector of cultured rabbit corneal endothelium. AB - We examined the protective properties of purpurogallin, a naturally occurring phenol, in delaying necrosis of cultured corneal endothelial cells caused by oxygen free radicals. Endothelial cell cultures were prepared from New Zealand white rabbits using microcarrier cell culture techniques. Corneal endothelial cells were treated with hypoxanthine (2 mM) and xanthine oxidase (67 IU/L) to generate free radicals. The criteria for cell necrosis were cytoplasmic shrinkage, dissolution of plasma membranes and presence of "haloes" around the cells on phase contrast microscopy, confirmed by transmission electron microscopy. More than 95% of second-generation cells exhibited morphologic evidence of necrosis within 4.62 +/- 0.82 minutes after exposure to oxyradicals. The addition of purpurogallin (0.25 or 1.0 mM) significantly increased time to cell necrosis to 8.18 +/- 0.83 and 11.59 +/- 1.71 minutes respectively (p < 0.05). Further studies are under way to determine whether purpurogallin may be useful in preventing endothelial cell damage in corneas preserved for corneal transplantation. PMID- 7859174 TI - Antiemetic prophylaxis for strabismus surgery. AB - Droperidol can reduce the high incidence of vomiting after pediatric strabismus surgery; however, its use may be associated with sedation, delayed hospital discharge, dysphoria and extrapyramidal signs. Midazolam, a short-acting benzodiazepine with antiemetic properties, has few side effects and may be a suitable alternative. We prospectively compared the antiemetic effect of these two drugs in 393 healthy children aged 18 months to 14 years undergoing outpatient strabismus surgery. The children were randomly assigned to receive midazolam hydrochloride (50 micrograms/kg) (199 patients) or droperidol (50 micrograms/kg) (194 children). The incidence rates of vomiting in the two groups were 45% and 37% respectively, a nonsignificant difference. The incidence of vomiting was not affected by the duration of anesthesia, but the number of muscles repaired was a significant predictor of postoperative vomiting (p < 0.001). PMID- 7859175 TI - Management of monocular cataract with long-term dilation in children. AB - We describe the use of long-term dilation and patching therapy in the management of three cases of pediatric monocular cataract. The cataracts were felt to be visually significant in the undilated state but consistent with good formed vision in the dilated state. One patient had a congenital cataract managed from 4 weeks of life, and two patients had late diagnosed cataracts of indeterminate onset presenting with dense deprivation amblyopia. The congenital cataract patient ultimately demonstrated recognition acuity of 20/40, and both the older children ultimately demonstrated an acuity of 20/30. We recommend considering long-term dilation and conventional amblyopia therapy rather than lensectomy in such cases if the cataract is felt to be consistent with development of good formed vision in the dilated state. PMID- 7859176 TI - Vocal cord paralysis with Nadbath facial block. PMID- 7859177 TI - Sjogren's syndrome in a child. PMID- 7859178 TI - Subconjunctival nodules: an unusual ocular complication of Crohn's disease. PMID- 7859179 TI - Metastatic meningococcal endophthalmitis treated by vitrectomy. PMID- 7859180 TI - Bilateral bullous retinal detachment as a complication of the HELLP syndrome. PMID- 7859181 TI - Private-sector funding and our health care system. PMID- 7859182 TI - Resuscitative interventions and "no-CPR" orders. PMID- 7859183 TI - Resuscitative interventions and "no-CPR" orders. PMID- 7859184 TI - Resuscitative interventions and "no-CPR" orders. PMID- 7859185 TI - Resuscitative interventions and "no-CPR" orders. PMID- 7859186 TI - Rural health care. PMID- 7859187 TI - Rural health care. PMID- 7859188 TI - Temporomandibular joint implants. PMID- 7859189 TI - Aluminum and Alzheimer's disease. PMID- 7859190 TI - Aluminum and Alzheimer's disease. PMID- 7859191 TI - Aluminum and Alzheimer's disease. PMID- 7859192 TI - Reports of steroid use needed. PMID- 7859194 TI - Information service on fetal alcohol syndrome launched. PMID- 7859193 TI - Caring for unhealthy lifestyles. PMID- 7859195 TI - Women's health: time for a redefinition. AB - Traditionally, women's health has been defined in mainly biologic terms. The various contexts within which women's health can be considered have been ignored, and many people have been unable to recognize the need for such a clinical entity as "women's health" in the first place. It is time for a change in attitudes and approaches. We need a more inclusive definition of women's health, one that takes into account social, cultural, spiritual, emotional and physical aspects of well being. Case histories that have recently received media attention and statistics on the impact of poverty and violence on women also show how urgently a redefinition of "women's health" is needed. Regardless of whether "women's health" will always have to be viewed as a separate discipline or whether it can be brought within mainstream medical practice, it is clear that, by altering their perception of women's health and of the problems unique to women, physicians can improve both health care and medical education to the benefit of all members of our society. PMID- 7859196 TI - Periodic health examination, 1995 update: 1. Screening for human papillomavirus infection in asymptomatic women. Canadian Task Force on the Periodic Health Examination. AB - OBJECTIVE: To develop recommendations for practising physicians on the advisability of screening for human papillomavirus (HPV) infection in asymptomatic women. OPTIONS: Visual inspection, Papanicolaou testing, colposcopy or cervicography, use of HPV group-specific antigen, DNA hybridization, dot blot technique, Southern blot technique or polymerase chain reaction followed by physical or chemical therapeutic intervention. OUTCOMES: Evidence for a link between HPV infection and cervical cancer, sensitivity and specificity of HPV screening techniques, effectiveness of treatments for HPV infection, and the social and economic costs incurred by screening. EVIDENCE: MEDLINE was searched for articles published between January 1966 to June 1993 with the use of the key words "papillomavirus," "cervix neoplasms," "mass screening," "prospective studies," "prevalence," "sensitivity," "specificity," "human" and "female." VALUES: Proven cost-effective screening techniques that could lead to decreased morbidity or mortality were given a high value. The evidence-based methods and values of the Canadian Task Force on the Periodic Health Examination were used. BENEFITS, HARMS AND COSTS: Potential benefits are to prevent cervical cancer and eliminate HPV infection. Potential harmful effects include the creation of an unnecessary burden on the health care system and the labelling of otherwise healthy people as patients with a sexually transmitted disease for which therapy is generally ineffective. Potential costs would include expense of testing, increased use of colposcopy and treatment. RECOMMENDATIONS: There is fair evidence to exclude HPV screening (beyond Papanicolaou testing for cervical cancer) in asymptomatic women (grade D recommendation). VALIDATION: The report was reviewed by members of the task force and three external reviewers who were selected to represent different areas of expertise. SPONSORS: These guidelines were developed and endorsed by the task force, which is funded by Health Canada and the National Health Research and Development Program. The principal author (K.J.) was supported in part by the National Health Research and Development Program through a National Health Fellowship (AIDS). PMID- 7859197 TI - Basic statistics for clinicians: 4. Correlation and regression. AB - Correlation and regression help us to understand the relation between variables and to predict patients' status in regard to a particular variable of interest. Correlation examines the strength of the relation between two variables, neither of which is considered the variable one is trying to predict (the target variable). Regression analysis examines the ability of one or more factors, called independent variables, to predict a patient's status in regard to the target or dependent variable. Independent and dependent variables may be continuous (taking a wide range of values) or binary (dichotomous, yielding yes or-no results). Regression models can be used to construct clinical prediction rules that help to guide clinical decisions. In considering regression and correlation, clinicians should pay more attention to the magnitude of the correlation or the predictive power of the regression than to whether the relation is statistically significant. PMID- 7859198 TI - The social context of women's health: goals and objectives for medical education. AB - The Women's Health Interschool Curriculum Committee of Ontario has developed goals and objectives for medical education based on a definition of women's health that includes emotional, social, cultural, spiritual and physical well being. The author presents background information on how women have been treated as "other" and sex-role stereotypes have been reinforced by some of the assumptions, terminology and attitudes used in medical practice and research. The objectives address the biologic and social context of women's health, the effect of power differentials (particularly the imbalance in power between physicians and patients), sex-role stereotyping in medical practice and teaching, and the effect of individual physicians' attitudes toward women on the care they provide. These objectives are the first published effort to define what physicians should know about the social context of women's health. The committee encourages readers to debate, discuss and use these objectives. PMID- 7859200 TI - What happens to donated blood? AB - Pursuing their chief work--gathering, processing and distributing blood--the blood donor centres of the Canadian Red Cross Society follow standard operating procedures like those in place at the Ottawa centre. Here, recruitment staff and volunteers work to recruit donors to meet needs at a time when the number of donors is falling. When they register, donors must show proof of identity. Each receives a permanent identification number that is linked to the numbers assigned to the units of blood each donates and to the date the unit was collected and the centre that collected it. Donors must answer questions about health and high-risk activity, and the blood of those who report high-risk activity is not accepted. Units are screened by automated instruments for syphilis, hepatitis B and C, HIV types 1 and 2, and human T-cell leukemia virus. Units with a negative test result are broken down into components for use in hospitals. A reactive test result prompts quarantining of the unit and a second screening test. If this test result is also reactive, a sample of the unit is sent to the National Testing Laboratory for confirmatory testing, and the unit is discarded. Once it has the results of the confirmatory test, the centre contacts the donor. Blood is now considered a drug. Red Cross practices in Canada and around the world have been changing since 1989 to reflect this. PMID- 7859199 TI - Adverse reaction to mefloquine associated with ethanol ingestion. AB - A 40-year-old man with no history of neuropsychiatric illness was taking one 250 mg tablet of mefloquine (MFQ) weekly for malaria prophylaxis while in Tanzania. He experienced no adverse reaction in association with his first two doses. Concurrently with both his third and his fourth dose he consumed about half a litre of whisky. On both occasions he experienced hallucinations, paranoid delusions and suicidal ideation. Thereafter he continued taking the MFQ, abstained completely from ethanol ingestion and had no recurrence of psychiatric symptoms. It is hypothesized that the combination of MFQ and ethanol caused the two episodes of severe psychiatric disturbance. PMID- 7859201 TI - Supplementary statement on newly licensed Haemophilus influenzae type B (Hib) conjugate vaccines in combination with other vaccines recommended for infants. PMID- 7859202 TI - Controversy still simmers over plan to build plasma-fractionation plant in Nova Scotia. AB - Controversy still simmers over a plan by the Canadian Red Cross Society and a US biopharmaceutical manufacturer to build a plasma-fractionation plant near Halifax. The unilateral decision to go ahead with the plant was taken as the Krever inquiry into Canada's blood-supply system was holding public hearings across the country. A panel created to evaluate the proposal has supported the fractionation plant, but made additional recommendations concerning product pricing, research and development, plasmapheresis centres and membership of the Board of Directors. PMID- 7859203 TI - Concern over fraud causes Ontario to invest $90 million in new health cards. AB - In an attempt to stop fraudulent use of Ontario's health care system, the province will soon begin issuing health-insurance cards containing the holder's photo. It is not known exactly how much fraud costs the system, but the cost may exceed $100 million annually. Dr. John Carlisle, deputy registrar of the College of Physicians and Surgeons of Ontario, warns that the government must be prudent in designing a system for reporting suspected health-card fraud. PMID- 7859204 TI - Physicians' fear of legal action becoming "pervasive," lawyer tells Ottawa conference. AB - Medical malpractice claims may be more common in the US than Canada, but that does not diminish the negative emotional, physical and professional consequences of legal action, delegates to the recent International Conference on Physician Health in Ottawa were told. Several US speakers described how physicians should employ risk-management strategies to avoid malpractice suits. They were also warned about what to expect during a legal action and the likelihood of facing subsequent suits alleging substandard care. PMID- 7859205 TI - The inhumanity of fairness: rationing resources for reconstructive breast surgery. AB - The Dr. William Logie Medical Ethics Essay Contest is open to undergraduate medical students studying at Canadian universities. The contest, named in honour of Canada's first medical graduate, is sponsored by CMAJ. In the following essay, which won second price in the 1994 competition, Dr. Agnes Wong examines how the state of Oregon reviewed the services it would insure under Medicaid, and why it determined that reconstructive breast surgery following mastectomy would not qualify. PMID- 7859206 TI - Economic hardship has put Nicaragua's health care system on the sick list. AB - Since Nicaraguans elected a conservative government to replace the Sandinistas in 1990, hospitals and health clinics have seen their budgets slashed and staff cut, and medical supplies have grown scarce. The poor are dying of treatable illnesses such as pneumonia and other respiratory infections, and malnutrition and mortality rates are rising. This report from the Central American country outlines how economic hardship has taken its toll on Nicaragua's health system in the 1990s. PMID- 7859207 TI - Persuasion techniques can motivate patients to change eating behaviours, symposium told. AB - Although surveys show that Canadians are concerned about good nutrition, they also reveal that taste and price outrank health concerns when consumers fill their shopping carts. Such attitudes are among the biggest barriers for health care practitioners who are trying to persuade patients to adopt a balanced diet that is low in fat and sugar and high in fibre. A marketing-communications expert says physicians and dietitians can fight fire with fire by adopting persuasion strategies that have been used successfully by advertisers to sell food products. PMID- 7859208 TI - Humour in the doctor's office. AB - Medical practice is a serious business, but Dr. Mel Borins thinks physicians sometimes take themselves and their profession too seriously and overlook the therapeutic value of joy and laughter. He thinks patients should be encouraged to laugh, and physicians should not overlook the benefits of humour in their personal lives. PMID- 7859209 TI - Bovine somatotropin and cow health--what are the facts? PMID- 7859210 TI - Options in dairy data management. AB - A great deal of progress has been made in the development of dairy herd management software in the last few years. At the same time, the speed, capacity, and portability of computer hardware have increased, while costs have decreased, thus encouraging use by veterinarians,dairy herd managers, and other industry support groups. A review of the literature indicates that an increasing number of producers, veterinarians, and other dairy industry service personnel are using computers and dairy herd management software in the delivery of their services (1 3,5,9-11,26-30,38,39). Wider adoption will occur if information generated through the use of these systems is directed towards the improvement of the profitability of dairy production. The quality of a decision is only as good as the information used to make it. In the past, the limited availability of reliable herd data has restricted our understanding of factors that influence herd performance. In essence, we must define what is normal before we can determine what is abnormal. More importantly, we must define what management practices are profitable and to what extent they increase revenue (3 1,32). Improved record keeping will benefit the dairy industry by allowing producers and dairy consultants to make profitable decisions based on more accurate and complete information. The ability to merge biological, management,and economic data may prove valuable in the evaluation of intervention at the herd and individual animal level. The impact of interventions is often as much a function of the unique combination of management factors on a dairy, as the biological effect that can be evaluated in a clinical trial. For example, the use of gonadotrophin-releasing hormone therapy at the time of service has been shown to be more successful in herds with better than average conception rates than in herds with poor conception rates. This difference in efficacy may be due to nutritional and other herd level management factors. Sophisticated dairy information management systems provide valuable herd specific management information, which allows more comprehensive understanding of the complex interaction of pharmaceutical,biological, and management factors that ultimately determine the profitability of veterinary intervention strategies. The use of electronic transfer of data will become essential in order to increase efficiency of use of information through data sharing. This will decrease transfer time and cost of information exchange between dairy herd managers and support industries. PMID- 7859211 TI - Canine distemper virus-like infection in a captive African lioness. PMID- 7859212 TI - An episode of diarrhea in calves of a well-managed dairy herd. PMID- 7859213 TI - Hepatic necrosis associated with halothane anesthesia in an alpaca. PMID- 7859214 TI - Treatment of canine sarcoptic mange using milbemycin oxime. PMID- 7859215 TI - Familial renal disease in Shih Tzu puppies. PMID- 7859216 TI - Black cherry poisoning in an Angora goat. PMID- 7859217 TI - Thrombocytopenia in weaned beef calves. PMID- 7859218 TI - Mucosal disease and acute bovine viral diarrhea go together. PMID- 7859219 TI - Ten key principles of veterinary management. PMID- 7859220 TI - Critical thinking: the perils of pattern recognition. PMID- 7859221 TI - Diagnostic ophthalmology. Exophthalmos. PMID- 7859222 TI - Selecting the right candidates for veterinary medicine in the 21st century. PMID- 7859223 TI - Selection of students for veterinary medicine. PMID- 7859224 TI - An ethicist's commentary on the case of shipping animals that have experienced heavy metal toxicosis. PMID- 7859225 TI - High-dose chemotherapy and autologous bone marrow transplantation for malignant lymphomas. PMID- 7859226 TI - Anticancer drug renal toxicity and elimination: dosing guidelines for altered renal function. AB - The narrow therapeutic index of anticancer drugs presents a clinical dilemma when these agents are administered to patients with impaired or unstable renal function. The purpose of this review is to (i) describe the nephrotoxicity of certain anticancer drugs, (ii) evaluate the fraction of renal clearance for pertinent anticancer drugs, and (iii) make general recommendations for the dosing of these drugs in the presence of impaired renal function. Pharmacokinetic, pharmacodynamic, and clinical toxicity information was obtained from current scientific and clinical literature. Recommendations for dosage adjustment of drugs is based on their nephrotoxicity, or renal clearance equal to or exceeding 30% of the administered dose. The specific formula used to calculate dosage adjustment of renally cleared anticancer drugs is based on fundamental pharmacokinetic principles. In addition, prospectively validated formulae for the dosage adjustment of specific agents, such as carboplatin are also reviewed. Forty-eight anticancer drugs are reviewed in this report. Nephrotoxicity is associated with 12 of these agents (Table 1). Renal clearance equal to or exceeding 30% of the administered dose is a characteristic of 17 of the drugs studied (Table 2), and a general recommendation for dose adjustment of these anticancer drugs is presented in Table 3. Renal clearance that is less than 30% of the administered dose is a feature of 31 anticancer drugs (Table 4) included in this review. This report provides general guidelines to adjust doses of renally excreted or nephrotoxic anticancer drugs in patients who present with altered renal function. PMID- 7859227 TI - Inhibition of cell signalling pathways. PMID- 7859228 TI - [The incremental prognostic value of the scintigraphic indices of myocardial hypoperfusion in patients with a maximal stress test]. AB - The additional prognostic value of thallium imaging in patients who are capable of performing a maximal, symptom-limited electrocardiographic stress test is still uncertain. Thus, we evaluated the incremental prognostic value of exercise thallium-201 indexes of myocardial hypoperfusion in 296 patients with suspected or known coronary artery disease who performed a maximal ECG stress test. At 2 year follow-up 20 hard events (16 cardiac deaths and 4 non fatal myocardial infarctions) and 44 soft events (myocardial revascularization procedures) occurred. Considering total events, thallium imaging provided significant additional prognostic information to clinical and exercise stress test data in all patients (p < 0.001) and in patients with previous myocardial infarction (p < 0.001); in patients without previous infarction, whichever the end-point considered, thallium imaging did not add incremental prognostic value. When only hard events were considered, thallium variables added further information only in patients with previous myocardial infarction (p < 0.05). The results of this study demonstrate that scintigraphic indexes of myocardial hypoperfusion obtained by qualitative planar thallium imaging give incremental prognostic information in patients with previous myocardial infarction but not in the subset of patients without previous infarction. PMID- 7859230 TI - [Supraventricular hyperkinetic arrhythmias in acute myocardial infarct: their prognostic assessment and correlation with the echocardiographic evolution]. AB - To assess the prognostic significance of supraventricular tachyarrhythmias (SVTA) during acute myocardial infarction (AMI), we studied 388 patients with first AMI, without ventricular preexcitation or chronic atrial fibrillation. The prevalence of SVTA was 14% (56/388), including atrial fibrillation (57%), atrial flutter (22%), polyfocal atrial tachycardia (14%), monofocal atrial tachycardia (7%). The arrhythmia appeared within 72 hours from the onset of chest pain in 61% of patients (early SVTA < 72 hours), while in 39% appeared later (late SVTA > 72 hours). Patients with SVTA (Group I n = 56) and without SVTA (Group II n = 232) were similar regarding prevalence of hypertension, dyslipidemia, diabetes, site of infarction and fibrinolysis, but SVTA was associated with a significant increase in death (Group I 18% versus Group II 9%; p < 0.05) and complications as pulmonary oedema and cardiogenic shock (Group I 25% versus Group II 14%; p < 0.05). Left atrial dimensions (LAD), end-diastolic left ventricular volume (EDLVV), end-systolic left ventricular volume (ESLVV) and echo-score, evaluated at admission, were not different between Group I and II (LAD 41.3 +/- 6 mm versus 40.1 +/- 5 mm, NS; EDLVV 181 +/- 34 ml versus 173 +/- 30 ml, NS; ESLVV 80 +/- 21 ml versus 75 +/- 18 ml, NS; echo-score 6.7 +/- 3.1 versus 6 +/- 2.7, NS) while pre-discharge echo-grams in Group I showed a trend towards the increase in volumes and echo-score (EDLVV from 181 +/- 34 ml to 194 +/- 36 ml, p = 0.052; ESLVV from 80 +/- 23 ml to 88 +/- 23 ml, p = 0.051; echo-score from 6.7 +/- 3.1 to 7.8 +/- 3.3, p = 0.070).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859229 TI - [Silent ischemia in patients on dialysis treatment]. AB - The authors carried out a perspective study to determine the frequency of silent ischemia (SI), in 50 consecutive patients with end stage renal failure, during dialysis by Holter monitoring. Twenty patients had SI. The number of cardiovascular risk factors, principally diabetes, smoking and the underlying renal disease was related to ischemic events. Dialysis may predispose to and facilitate the detection of myocardial ischemia by the simultaneous presence of hypotension, hypovolemia, hypoxia and tachycardia. Holter monitoring may allow the detection of ischemic events and the identification of a subgroup of dialytic patients with a high cardiovascular risk. PMID- 7859231 TI - [An echocardiographic analysis of the insufficient mitral valve: its intraoperative functional anatomy in relation to valvular reconstruction]. AB - Mitral valve repair in patients with mitral regurgitation requires a precise evaluation of the mechanism of valvular pathology before surgery. Transesophageal echocardiography has become the principal method for imaging valvular pathology, especially with the latest introduction of multiplanar transesophageal technology. Traditionally, echocardiographic analysis of regurgitant mitral valves has concentrated on the description of abnormalities of leaflet motion such as prolapse, while surgical correction aims at restoring the coaptation of the edges of the leaflets. To reconcile these different approaches, the echocardiographic features the findings on direct inspection, and the types of repair performed were analyzed in 37 incompetent mitral valves. The zone of coaptation of the mitral valve was studied in a series of left ventricular long axis views obtained with a transesophageal multiplanar echo-transducer from the anterolateral via the central, to the posteromedial segment. Four patterns of leaflet closure were found: normal apart from a dilated annulus (24%), normal apposition but absent coaptation (8%); asymmetrical apposition but intact coaptation (16%); and abnormal apposition and absent coaptation (52%). In addition leaflet motion was described (prolapse, retraction, normal), and the anteroposterior dimension of the mitral annulus was measured. There was a direct relationship between these echocardiographic findings and the types of reconstructive techniques used. The echocardiographic analysis offers a logical approach to the preoperative diagnosis of regurgitant mitral valves, with the possibility to predict the feasibility and the type of mitral repair. PMID- 7859232 TI - Risk stratification for restenosis after coronary angioplasty by means of exercise echocardiography. AB - To assess the prognostic contribution of exercise two-dimensional echocardiography in patients undergoing elective coronary angioplasty, 60 patients (44 males, 16 females, mean age 61 years) were enrolled in this study. The series included 31 patients with single-vessel disease, 23 with two vessel, and 5 with three vessel disease. After successful PTCA, they underwent stress echocardiographic testing either by treadmill (n = 23) or bicycle ergometry (n = 37), performed with digital continuous loop technique. A wall motion index (WMI) was calculated at rest and at peak stress. According to WMI values, the study population was divided into three groups: patients with normal WMI both at rest and stress (Group 1); patients with abnormal baseline WMI without change at stress (Group 2) and abnormal WMI diagnostic of stress-induced ischemia (Group 3). During the follow-up period, minimum of 1 year, 21 patients complaining of recurrent angina or chest discomfort, had repeat angiography: in 13 of these, typical restenosis of a previously dilated artery was found; 2 patients had progression of atherosclerotic plaque and in 6 the angiogram showed a good result of PTCA. Thirteen patients with restenosis or progressive disease underwent repeat PTCA. In this group, only 2 belonged to Group 1, 4 to Group 2, and 7 to Group 3. Thus, a linear correlation between the WMI value post-angioplasty and the clinical course could be documented (p = 0.001). Stress echocardiography was superior to stress ECG in both negative predictive value (88 and 77% respectively) and positive predictive value (73 versus 50%).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859233 TI - [Multiplanar transesophageal echocardiography in a case of hypernephroma]. AB - A 78-year-old man admitted to our hospital with signs and symptoms of right ventricular failure, consisting of severe edema of the scrotum and the penis, ankle edema, hepatomegaly, and a history of asthenia associated with a recent weight loss. Two-dimensional echocardiography showed an intracavitary mass in the right atrium and a moderate pericardial effusion; the remaining structures were normal. To better define the origin of this mass, transesophageal echocardiography was performed. The mass extended from the inferior vena cava with no sites of attachment to the atrial wall. The mass was elongated, mobile, with a triangular termination near the tricuspid valve, without signs of right ventricular obstruction. An abdominal-pelvic CT scan demonstrated the origin of the mass at the superior pole of the left kidney extending through the renal vein and the inferior vena cava into the right atrium. The mass was surgically removed and the pathological examination revealed a renal cell carcinoma (hypernephroma) of the clear cells subtype. After surgery, the patient did well with the resolution of the picture of right ventricular failure. PMID- 7859234 TI - Treatment of hypertension in the elderly. AB - This review discusses the pathophysiology and treatment of hypertension in the elderly. Evidence of the risks associated with systolic hypertension in particular is discussed in relation to the elderly population. The results of recent large-scale, placebo-controlled trials of hypertension in the elderly, including the Systolic Hypertension in the Elderly Program, the Swedish Trial in Old Patients with Hypertension, and the Medical Research Council trials, confirm the benefits of treatment in this population. However, pathophysiologic processes in the elderly may predispose them to drug side effects; therefore, selection of appropriate therapy is critical to the success of treatment. Various treatment options are available that may be suitable in subsets of the elderly population, particularly when low-dose regimens are used. Indapamide, a sulfonamide diuretic, may be particularly well suited for treatment of hypertension in the elderly because of its demonstrated efficacy and safety at low doses. PMID- 7859235 TI - A retrospective evaluation of imipenem use in bone marrow transplant patients. AB - A retrospective, open, 3-year trend analysis of imipenem use in bone marrow transplant (BMT) patients was conducted at a 1000-bed tertiary care hospital. Broad-spectrum antibacterial drugs are routinely used to treat infections in the febrile neutropenic host. The antibacterial activity and acceptable tolerance profile of imipenem makes this agent a potentially useful addition to the traditional armamentarium which includes aminoglycosides, cephalosporins, and glycopeptides. Some authorities recommend imipenem as monotherapy in the treatment of fever of unknown origin in this select patient population. Eighty three treatment courses (one treatment course per patient) were evaluated. The major indications for initiating therapy were fever of neutropenia (28%), suspected infection in the absence of fever (55%), and documented infection (17%). Imipenem was used as a first-line agent in 42% of patients, although imipenem monotherapy was not common. Concurrent antibacterials were usually vancomycin and tobramycin. Seventeen patients required modification of the initial regimen with vancomycin and/or tobramycin for additional coverage after an average of 8 days of imipenem therapy. Forty-eight bacterial isolates were obtained in cultures from 35 patients during the study, with gram-positive organisms predominating (in particular, staphylococci and streptococci). Pretherapy and superinfecting organisms were primarily gram-positive. Overall clinical success or improvement occurred in 42% of patients. Microbiologic outcome was indeterminate in 89% of patients, microbiologic eradication occurred in 1%, and superinfection occurred in 6%. Imipenem was relatively well tolerated. Rash and nausea/vomiting were reported most often; 29% of those patients who had adverse reactions discontinued therapy. PMID- 7859236 TI - The role of sertraline in the management of depression. AB - Sertraline is a highly specific, potent inhibitor of serotonin reuptake. It exerts no clinically significant effects on norepinephrine and dopamine uptake and possess negligible binding affinity for histaminergic, muscarinic, dopaminergic, and adrenergic receptors. Its pharmacologic profile permits once daily dosing while allowing plasma drug levels to equilibrate within 1 week. In multicenter, double-blind trials, sertraline proved superior to placebo and comparable to amitriptyline in ameliorating acute depression. Moreover, the drug has been shown to be effective in preventing relapses of the index episode and recurrence of further episodes over the long term. Sertraline has not been associated with sedating or anticholinergic effects, psychomotor impairment, or cardiovascular toxicity. Its principal side effects are generally transient and include mild-to-moderate nausea or diarrhea and sexual dysfunction (ejaculatory delay) in males. The safety margin of sertraline is wider than that of the tricyclic antidepressants. This serotonin reuptake inhibitor shows promise as an important therapeutic and prophylactic alternative in the pharmacologic management of depression. PMID- 7859237 TI - The inotropic and hemodynamic effects of intravenous milrinone when reflex adrenergic stimulation is suppressed by beta-adrenergic blockade. AB - Milrinone is an inotropic and vasodilator agent proven to be effective in the treatment of heart failure. This study evaluated whether milrinone produces inotropic and hemodynamic effects independent of reflex adrenergic stimulation. Eleven stable heart failure patients (New York Heart Association class II to III) undergoing cardiac catheterization received intravenous (i.v.) milrinone (50 micrograms/kg for 10 minutes followed by 0.5 micrograms/kg/min for 50 minutes) during beta-adrenergic blockade. After beta-blockade with a 50-mg oral dose of metoprolol, heart rate decreased by a mean of 16.6%. The peak inotropic response to i.v. milrinone measured using the maximum rate of rise of left ventricular pressure (LV dP/dt) was fully developed at 20 minutes. Mean absolute inotropic response of LV dP/dt from baseline was statistically significant at 10, 20, 30, and 40 minutes (P < 0.05). Mean percentage increase in cardiac index from baseline was statistically significant at 20 and 30 minutes, and mean absolute decline from baseline for pulmonary capillary wedge pressure was statistically significant at 20 and 40 minutes (P < 0.05). The inotropic and hemodynamic effects of i.v. milrinone were thus preserved during beta-adrenergic blockade. This finding is consistent with a mechanism of action of i.v. milrinone- myocardial phosphodiesterase inhibition--that is independent of reflex adrenergic stimulation. PMID- 7859238 TI - Long-term effects of pravastatin on serum lipid levels in elderly patients with hypercholesterolemia. AB - The purpose of this study was to evaluate the long-term efficacy and tolerability of pravastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, in elderly patients with hypercholesterolemia. Pravastatin was administered for 12 months at a mean final dose of 9.9 mg/d to 208 elderly patients (mean [+/- SD] age, 70 +/- 7 years) with levels of total serum cholesterol greater than 5.69 mmol/L. The mean total cholesterol level was significantly decreased from 6.85 +/ 0.80 mmol/L to 5.59 +/- 0.70 mmol/L after 3 months, and this decrease was maintained thereafter. A similar change was observed in the mean serum level of low-density lipoprotein cholesterol. Although the mean serum level of high density lipoprotein cholesterol in all the patients did not change significantly, the level in 34 patients with a value lower than 1.03 mmol/L was significantly increased after 3 months and thereafter. The serum level of triglycerides in all patients was significantly decreased after 3 months and thereafter and the decrease was more marked in 101 patients with levels greater than 1.73 mmol/L. In 168 elderly patients receiving 10 mg/d of pravastatin, there were significant negative correlations between the percent decrease in total cholesterol and both baseline total serum cholesterol level (r = -.354, P < 0.001) and age (r = -.208, P = 0.007). No serious side effects were observed. These results indicate that long-term administration of pravastatin is beneficial in the treatment of hypercholesterolemia in elderly patients. PMID- 7859239 TI - Effect of meals and dosage-form modification on theophylline bioavailability from a 24-hour sustained-release delivery system. AB - The bioavailability of theophylline from an extended-release formulation (Uni Dur) intended for once-daily administration was assessed in a randomized, single dose, five-way crossover study to determine the effects of food and breaking the tablet, and the bioequivalence of two dosage strengths. The five treatments given at 1-week intervals were (1) immediate-release theophylline (Slo-Phyllin) 5 x 100 mg to fasting subjects as a reference treatment; (2) sustained-release Uni-Dur 600-mg theophylline tablet to fasting subjects; (3) Uni-Dur 600-mg tablet after a high-fat meal; (4) Uni-Dur 600-mg dose administered as two half tablets to fasting subjects; and (5) Uni-Dur 400-mg tablet to fasting subjects. Serial blood samples were collected immediately before and for 57 hours after dosing. The mean relative extents of absorption for the four Uni-Dur treatments were not significantly different from Slo-Phyllin treatment or from each other (84.30 +/- 23.6%, 600 mg, fasting; 88.73 +/- 18.63%, 600 mg, fed; 93.65 +/- 19.67%, half tablet; and 92.87 +/- 19.5%, 400 mg, fasting). The maximum theophylline serum concentrations with Uni-Dur were significantly lower and the times to reach peak concentrations were significantly longer than with Slo-Phyllin. Differences noted among the four Uni-Dur treatments were as follows: the time to peak theophylline concentration was significantly longer in the fed state (17.09 hours) as were the times to 50% (11.73 hours) and 80% (18.46 hours) absorption compared with fasting (13.57 hours, 8.57 hours, and 14.07 hours, respectively). The Uni-Dur 400-mg treatment resulted in a significantly higher maximum theophylline serum concentration (6.64 mu g/mL) compared with the Uni-Dur 600-mg fasting treatment (5.33 mu g/mL); however, the correlation between in vivo and in vitro data supports the bioequivalence of the two strengths. This study shows that theophylline is slowly and consistently absorbed from the Uni-Dur 24-hour sustained-release form, and food or breaking the tablet does not alter the extent of absorption. Thus Uni-Dur potentially provides greater ease of administration and convenience for patients while maintaining therapeutic theophylline serum levels over the 24-hour dosing interval. PMID- 7859240 TI - Ofloxacin in the treatment of typhoid fever resistant to chloramphenicol and amoxicillin. AB - Twenty-five patients with typhoid fever, who were resistant to amoxicillin and chloramphenicol, were successfully treated with ofloxacin. Ofloxacin was administered at a dosage of 200 mg three times daily for 7 to 10 days. In a few seriously ill patients, a dosage of 400 mg three times daily for 3 days, followed by 200 mg three times daily for 4 to 7 days, was administered. This study confirmed the presence of resistant strains of Salmonella typhi. These strains were resistant to the commonly used drugs, chloramphenicol and amoxicillin. Ofloxacin was found to be well tolerated and effective in treating typhoid fever. PMID- 7859241 TI - Tosufloxacin in the treatment of nongonococcal urethritis, including Chlamydia trachomatis. AB - Sixty-three patients with nongonococcal urethritis were enrolled in an open, comparative study and assigned to 14 days of treatment with tosufloxacin 150 mg orally three times daily or doxycycline 100 mg orally twice daily. Chlamydia trachomatis was detected in 27 (42.9%) of the 63 patients: 13 (43.3%) of the 30 tosufloxacin-treated patients and 14 (42.4%) of the 33 doxycycline-treated patients. The clinical response between the two treatment groups was compared 7, 14, and 21 days after initiation of therapy. Clinical response to tosufloxacin was as good as that seen with doxycycline at the three follow-up visits. All C trachomatis-positive patients at baseline tested negative in both treatment groups at the three follow-up visits. Adverse reactions were observed in two patients treated with doxycycline. Although the number of study patients was small and the follow-up period short, these results indicate that tosufloxacin and doxycycline are equally effective in the treatment of nongonococcal urethritis. PMID- 7859243 TI - Role of eicosapentaenoic acid in lipid metabolism in the liver, with special reference to experimental fatty liver. AB - Choline-deficient feed was given to three groups (n = 7 in each) of male Sprague Dawley rats for 4 weeks to induce the development of fatty liver. In addition, two of the groups received eicosapentaenoic acid (EPA), 1000 mg/kg/d, administered orally either for all 4 weeks or for only the last 2 weeks of the study, respectively. The third group received the choline-deficient diet but no EPA. The untreated control group (n = 7) received only normal feed. The efficacy of EPA in preventing fatty liver was assessed based on the evaluation of pathologic and biochemical parameters and hepatic blood flow. EPA markedly improved fatty liver, probably due to both direct effects (inhibition of the synthesis of triglyceride in the liver) and indirect effects (increased hepatic blood flow). Decreased blood flow due to sinusoidal block is responsible for the progression of fatty liver. EPA has been shown to decrease thromboxane A2 production and blood viscosity and to enhance red cell deformability. These effects are thought to have contributed to the increases in hepatic blood flow. PMID- 7859242 TI - Effects of pravastatin treatment on vitamin D metabolites. AB - Hyperlipidemias, and notably hypercholesterolemia, represent important risk factors for atherosclerotic vascular disease. The enzymatic inhibitors of 3 hydroxy-3-methylglutaryl coenzyme A reductase, a selective and specific key enzyme involved in endogenous cholesterol synthesis, cause a significant mean reduction in low-density lipoprotein (LDL) cholesterol, both in familial and nonfamilial hypercholesterolemic forms. It has been hypothesized that these compounds might interfere with vitamin D endogenous synthesis secondarily to their effects on cholesterol. To verify this hypothesis, we studied 14 hypercholesterolemic patients treated as follows: 4 weeks of low-lipid, fiber rich diet followed by 8 weeks of pravastatin treatment at the oral evening dose of 20 mg/d and by a 1-month washout period. No significant changes in serum calcium, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D were noticed; on the contrary, significant (P < 0.01) reductions in total cholesterol and LDL cholesterol and a significant (P < 0.05) increase in high-density lipoprotein cholesterol were observed. After the final 1-month washout period, all values returned to baseline levels. In conclusion, our study confirms the clinical efficacy of pravastatin on lipid fractions and demonstrates the absence of any interference on the circulating levels of the main vitamin D metabolites. PMID- 7859244 TI - A postmarketing surveillance evaluation of quinapril in 3742 Canadian hypertensive patients: the ACCEPT Study. Accupril Canadian Clinical Evaluation and Patient Teaching. AB - The Accupril Canadian Clinical Evaluation and Patient Teaching (ACCEPT) study was a multicenter, 6-month, open-label, postmarketing surveillance study where the efficacy and safety of quinapril, an angiotensin-converting enzyme (ACE) inhibitor, was evaluated in a general population of patients with essential hypertension. Participating physicians followed their normal office procedures for the initiation of quinapril therapy (a dose of 10 mg QD in the majority of cases). The dose was titrated to blood pressure response, generally at 2-week intervals, for a maintenance dose of 10 mg QD to 20 mg QD in most cases (86% at 6 months) and not to exceed 40 mg QD. The use of concomitant antihypertensive medications was left to the discretion of the physician. By random assignment, physicians obtained patient informed consent on either a detailed form that listed possible quinapril side effects or a less specific form, which did not list particular side effects. The purpose of using two different forms was to assess any potential association between the frequency of adverse-event reporting and patient's awareness of quinapril side effects. The patients also received an educational package that provided general information on hypertension and lifestyle modifications known to reduce cardiovascular risk factors. An intent-to treat analysis included data from 3742 patients in whom the median age was 56 years and the median duration of hypertension was 5 years. The demographic characteristics of these patients were similar to those identified in Canadian hypertensive patients in a recent population-based survey. Nearly 80% of the ACCEPT study patients had more than one cardiovascular risk factor, in addition to hypertension. Among 2979 patients receiving quinapril at 3 months, 77% were stabilized. Among 2517 patients continuing to receive quinapril at 6 months, 84% were stabilized. Greater declines in both diastolic and systolic blood pressures were evident among patients who continued to receive quinapril as part of an antihypertensive regimen than among those who discontinued quinapril treatment. Blood pressure responses to quinapril were similar in newly diagnosed patients and those with a history of hypertension. A total of 980 patients (26.2%) reported one or more adverse events. Cough was most frequently reported and was deemed as definitely related to quinapril therapy by the treating physician in 3.6% of cases. Serious adverse events occurred in 55 patients (1.5%) and were assessed as possibly related to quinapril in only three patients.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7859245 TI - Prevalence of migraine headache and association with sex, age, race, and rural/urban residence: a population-based study of Georgia Medicaid recipients. AB - The estimates of migraine headache prevalence vary widely and fluctuate with the population examined and the methodologic factors used in studies examining this condition. As an alternative to survey techniques, a retrospective review of Medicaid claims data from 22 continuous months (January 1, 1989, to October 31, 1990) was used to detect medical episodes and physician-initiated pharmacologic therapy indicative of migraine headache. Specifically, the objectives of this study were to measure the prevalence of migraine headache in Georgia Medicaid recipients, estimate the prevalence in the US population, and describe the relationships between migraine and sociodemographic variables including sex, age, race, and rural versus urban residence. Logistic regression was used to isolate the independent effects of age, race, residence, and length of Medicaid eligibility on the presence or absence of migraine. The data consisted of adjudicated claims for 847,453 Georgia Medicaid recipients. Medicaid profiles for 678,079 recipients (468,448 female and 209,631 male) aged older than 4 years were analyzed as persons at risk of migraine. Migraine was identified in 6518 (1.39%) females and 991 (0.47%) males. Adjusting for eligibility, age, and race, the projected 22-month period prevalence for the United States was estimated as 3.83% (females) and 1.33% (males). Females, whites, and individuals residing in rural counties were more likely to suffer from migraine headache than their respective comparison groups. For both sexes, the peak prevalence was in the fourth and fifth decades of life. Migraine headache in the United States is estimated to afflict 4.5 million females and 1.4 million males. This prevalence is lower than previously reported and indicates that migraine headache may not be as common as previously believed. An alternative explanation is that many Medicaid recipients self-treat the condition, thus circumventing physician care and subsequent diagnosis and treatment. PMID- 7859246 TI - Economic effects of insomnia. AB - Insomnia affects up to 40% of the general population yearly and is a significant cause of morbidity and mortality. The direct and indirect costs of insomnia place a tremendous economic burden on society and employers. In addition to the cost of medical treatment and drugs, measurable costs of insomnia include reduced productivity, increased absenteeism, accidents, and hospitalization, as well as medical costs due to increased morbidity and mortality, depression due to insomnia, and increased alcohol consumption. This article reviews the literature on the economic costs and effects associated with insomnia. Based on the data reviewed, a conservative estimate of the total annual cost of insomnia was calculated at $92.5 to $107.5 billion. Early recognition and treatment of insomnia can reduce the costs associated with the condition, as well as possibly prevent other illnesses. PMID- 7859248 TI - Calcium-binding proteins in normal and transformed cells. PMID- 7859247 TI - Point-of-care versus central laboratory testing: an economic analysis in an academic medical center. AB - A cost-effectiveness study was conducted to determine time and labor costs for point-of-care (POC) versus central laboratory testing. A prospective, observational time and motion study was carried out at a teaching hospital located in Philadelphia, Pennsylvania. The cohort consisted of 210 patients presenting to the emergency department who were triaged at the urgent or emergent level during a 4-week period. Patients who had blood drawn for a seven-chemistry profile (Chem-7), which includes analysis of sodium, potassium, chloride, carbon dioxide, blood urea nitrogen, glucose, and creatinine, or for cell blood count (CBC) tests as part of regular care, also had an additional split sample drawn for POC analysis of sodium, potassium, chloride, blood urea nitrogen, glucose, and/or hematocrit. Blood drawn for POC analysis did not require additional needlestick(s), nor did it alter regular care procedures. Physicians and all emergency department staff participating in the care of the patients were blinded to POC test results. Main outcome measures included test turn-around time (TAT), physician determination of impact of rapid TAT and laboratory values on therapeutic approach, and cost per test for POC versus central laboratory testing. POC TAT was a mean of 8 minutes (time from blood drawn to results shown on the POC device display). Central laboratory TAT was a mean of 59 minutes (time from blood drawn to entry of results into mainframe computer). Therapeutic TAT was a mean of 1 hour and 25 minutes (time from blood drawn to analysis in central laboratory, to when the physician viewed test results). After therapeutic course of care was decided for the patient, physicians reported that POC testing, independent of other rate-limiting steps, would have resulted in earlier therapeutic action for 40 of 210 (19.0%) patients. The cost per test for Chem-7 and CBC tests was $11.14 and $9.48, respectively. The cost per test for POC analysis ranged from $14.37 to $16.67, depending on the POC test volume (estimated volume based on 20% to 50% of emergency department patients that had either Chem-7 or CBC test done applied over the useful life of the POC testing equipment) and the personnel (nurse or emergency department technician) who performed the test. With an increasing volume of POC tests performed per unit time, costs for POC testing would be reduced substantially. POC test costs are volume dependent under current reimbursement mechanisms for emergency department patient care services, for example, fee-for-service payment.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7859249 TI - Altered sarcolemmal calcium channel density and Ca(2+)-pump ATPase activity in tachycardia heart failure. AB - Whether sarcolemmal (SL) calcium handling is altered in endstage heart failure produced by chronic rapid pacing is not known. To investigate this we paced 7 rabbits at a rate of 400 beats/min for 35 +/- 11 days. 6 animals served as non paced controls. Purified left ventricular SL membranes were then prepared and tested for [3H]-nitrendipine binding and (Ca(2+) + Mg2+)-dependent ATPase (Ca(2+) pump) activity. Results show a 50% reduction in calcium channel antagonist binding sites with Bmax values reduced from 450 +/- 40 to 230 +/- 8 fmoles/mg protein in response to chronic rapid pacing (P < 0.01). This change was accompanied by a modest decrease in Kd from 0.29 +/- 0.09 to 0.22 +/- 0.03 nM (not significant). Vmax values for the SL Ca(2+)-pump ATPase were decreased from 387 to 164 nmoles/mg protein/min (P < 0.01) with KCa2+ values reduced from 0.91 to 0.28 microM Ca2+ (P < 0.05) in response to tachycardia induced failure as compared to controls. ATPase activity in both groups was very sensitive to 25 microM calmidazolium and 5 microM vanadate. Results from this study indicate that both a reduction in SL calcium channel density and decrease in SL Ca(2+)-pump ATPase activity are evident in tachycardia heart failure. We conclude that sarcolemmal calcium handling is altered in heart failure induced by chronic rapid pacing and that such changes may contribute to systolic dysfunction associated with this model to heart failure. PMID- 7859250 TI - Evolution of the Ca2+ current during dialysis of isolated bovine chromaffin cells: effect of internal calcium. AB - We have examined the internal Ca(2+)-dependence of the long-term evolution of whole cell high voltage activated Ca current in chromaffin cells. The evolution of the peak Ca current was characterized by 2 distinct phases: after an initial facilitation, there followed a rundown, which represented a reduction by 70% within some 10 min. The rundown process was shown not to depend on Ca2+ entry nor on membrane depolarization. It resulted from cell dialysis with a saline solution and, once initiated, it proceeded at a rate of 0.28 min-1 at 4 different Ca2+ concentrations (pCa 5-9). The facilitation is also initiated by cell dialysis but this process developed faster at higher internal Ca2+ concentrations. Thus, globally, high-voltage activated Ca2+ current runs down faster when using a recording pipette solution with a higher internal Ca2+ concentration (pCa 5 or 6). Some leupeptin-sensitive proteases may be involved in the initiation of facilitation and rundown processes. PMID- 7859251 TI - Calcium entry activated by store depletion in human umbilical vein endothelial cells. AB - We have used the patch clamp technique combined with simultaneous measurement of intracellular Ca2+ to record ionic currents activated by depletion of intracellular Ca(2+)-stores in endothelial cells from human umbilical veins. Two protocols were used to release Ca2+ from intracellular stores, i.e. loading of the cells via the patch pipette with Ins(1,4,5)P3, and extracellular application of thapsigargin. Ins(1,4,5)P3 (10 microM) evoked a transient increase in [Ca2+]i in cells exposed to Ca(2+)-free extracellular solutions. A subsequent reapplication of extracellular Ca2+ induced an elevation of [Ca2+]i. These changes in [Ca2+]i were very reproducible. The concomitant membrane currents were neither correlated in time nor in size with the changes in [Ca2+]i. Similar changes in [Ca2+]i and membrane currents were observed if the Ca(2+)-stores were depleted with thapsigargin. Activation of these currents was prevented and holding currents at -40 mV were small if store depletion was induced in the presence of 50 microM NPPB. This identifies the large currents, which are activated as a consequence of store-depletion, as mechanically activated Cl- currents, which have been described previously [1,2]. Loading the cells with Ins(1,4,5)P3 together with 10 mM BAPTA induced only a very short lasting Ca2+ transient, which was not accompanied by activation of a detectable current, even in a 10 mM Ca(2+)-containing extracellular solution. Also thapsigargin does not activate any membrane current if the pipette solution contains 10 mM BAPTA (ruptured patches). The contribution of Ca(2+)-influx to the membrane current during reapplication of 10 mM extracellular calcium to thapsigargin-pretreated cells was estimated from the first time derivative of the corresponding Ca2+ transients at different holding potentials. These current values showed strong inward rectification, with a maximal amplitude of 1.0 +/- 0.3 pA at -80 mV (n = 8; membrane capacitance 59 +/- 9 pF).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859252 TI - Lanthanum can be transported by the sodium-calcium exchange pathway and directly triggers catecholamine release from bovine chromaffin cells. AB - A comparison of the effectiveness of the trivalent cation, lanthanum (La3+) relative to Ca2+ in causing catecholamine release from bovine chromaffin cells has been made, together with a determination of the pathway by which La3+ enters these cells. In chromaffin cells maintained in tissue culture and permeabilised with digitonin, both La3+ and Ca2+ caused 3H release from cells preloaded with [3H]-noradrenaline; La3+ and Ca2+ caused similar maximal release but the EC50 for La3+ was an order of magnitude less than that for Ca2+. At maximal release caused by either La3+ or Ca2+ (approximately 14% of cell 3H content in 15 min), the other cation caused a small, but significant, further release. At submaximal effective concentrations the effects of the two cations were exactly additive. Using 3H release as an indicator of cytosolic La3+, its route of entry into intact chromaffin cells was investigated. With La(3+)-containing medium there was no release evoked by nicotine or by K(+)-depolarisation indicating that La3+ does not enter either via the nicotinic receptor linked ion channel or via voltage sensitive (Ca2+) channels. However, in sodium-loaded chromaffin cells (ouabain incubation in Ca(2+)-free medium for 15 min) exposure to bathing media containing either Ca2+ or La3+ caused 3H release. La3+ (0.1 mM) caused a release similar in magnitude to that caused by Ca2+ (about 1 mM). La3+ at low concentrations had an additive (0.1 mM La3+) or synergistic (0.25-0.45 mM La3+) action with Ca2+ (< 3.6 mM) on 3H release. At higher concentrations (> 0.9 mM) the effects of La3+ predominated and prevented the expected effects of Ca2+. In other experiments, La3+ (1 mM) blocked export of 45Ca2+ via both Nao-dependent and independent pathways, i.e. sodium-calcium exchange and the calcium pump. The results indicate that La3+ can enter bovine chromaffin cells via the Nai/Cao exchange pathway independently of, or together with, Ca2+ but, that concentrations above 0.9 mM block the influx or efflux of Ca2+. However, Ca2+, even at 3.6 mM, did not block the influx of La3+. The results further indicate that, within chromaffin cells, La3+ is at least as effective as Ca2+ in triggering catecholamine release and maintaining prolonged release. La3+ also appears to act cooperatively with Ca2+ at the release pathway. PMID- 7859253 TI - The initiation of a calcium signal in Xenopus oocytes. AB - Application of acetylcholine to Xenopus oocytes evoked increases in the cytosolic free calcium ion concentration ([Ca2+]i) after latencies of up to several seconds depending on the agonist dose. Higher acetylcholine concentrations evoked responses with larger amplitudes and shorter latencies. The latencies of responses to acetylcholine could be increased by application of caffeine, injection of calcium buffers or depletion of intracellular calcium stores. Acute inhibition of endoplasmic reticulum calcium pumps without substantial reduction of the calcium store content (by application of thapsigargin shortly before agonist stimulation) reduced the latencies of responses to acetylcholine. A schematic and mathematical model are presented to show a possible mechanism by which a calcium signal is initiated following a latent period after the elevation of the inositol trisphosphate concentration. During the latent period, calcium is slowly released from the intracellular stores. The released calcium is rapidly buffered by cytosolic calcium-binding proteins and some is resequestered into the stores by calcium pumps. The [Ca2+]i changes very little until the buffering is locally saturated. The [Ca2+]i then rises above a threshold concentration which evokes an explosive release of calcium due to positive feedback by calcium on the inositol trisphosphate receptor. PMID- 7859254 TI - Reduced PO2 alters the behavior of Fura-2 and Indo-1 in bovine pulmonary artery endothelial cells. AB - Calcium-sensitive fluorophores are used to estimate cytosolic free Ca2+ in many cell types under various conditions. We tested the effect of reduced PO2 on the behavior of Fura-2 and Indo-1 in cultured bovine pulmonary artery endothelial cells. Reduced PO2 (PO2 25-35 mmHg) caused a significant upward shift of in vivo calibration curves for both fluorophores. The in vivo emission spectrum of Fura-2 indicated that the effect was principally due to attenuated emission at the Ca(2+)-unbound 380 nm wavelength, with no shift in position of the emission maxima for either Ca(2+)-bound or unbound forms of the fluorophore. Reduced PO2 did not directly alter the behavior of the dyes, as no shift of in vitro calibration curves was seen. Neither decreased photobleaching nor altered autofluorescence accounted for the shift. We investigated several potential indirect effects, including cellular acidification, reduced viscosity, inhibition of oxidative energy production and reductive stress. In contrast to lowered PO2, acidification in vitro produced a leftward but not an upward shift. Estimation of intracellular pH with SNAFL-calcein under reduced PO2 showed no apparent acidification in these cells, further strengthening the argument that altered intracellular pH was not causing the shift. Others have shown that decreases in viscosity in vitro may shift the calibration curve for Fura-2 upward, similar to our finding with reduced PO2. However, for Indo-1 we found that decreased viscosity in vitro attenuated fluorescence emission at the Ca(2+)-bound 405 nm wavelength, thus producing the opposite effect on fluorescence ratio and indicating that reduced PO2 was not acting through changes in cellular microviscosity.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859255 TI - Delay in granular fusion evoked by repetitive cytosolic Ca2+ spikes in mouse pancreatic acinar cells. AB - Patch-clamp whole-cell recording in combination with a phase-sensitive detection method was applied to single, enzymatically isolated, mouse pancreatic acinar cells. Either muscarinic stimulation with a low concentration of ACh (50 nM) or cell infusion of inositol 1,4,5-trisphosphate (InsP3) induced repetitive spike like increases of membrane capacitance (delta C), membrane conductance (delta G) and membrane current (delta I). Cellular perfusion of InsP3, 10 microM in patch pipettes, induced baseline spikes in delta C and delta G, resembling those evoked by ACh. The result indicates that exocytotic granular fusion is primarily triggered by the InsP3-induced repetitive rise of [Ca2+]i. The ACh-induced delta C took off almost synchronously with delta G with an apparent delay of less than 40 ms in the initial spike response. This delay of delta C, however, becomes longer by a factor of 7-12 during repetitive Ca2+ spike cycles. Concomitantly a faster decrease in delta C spikes than delta G spikes was observed during the cycles. Two explanations are proposed. First, the Ca2+ sensitivity of granular fusion decreases during the repetitive Ca2+ spikes. This might be due to gradual washout of low molecular components responsible for exocytosis under the whole cell recording condition. Second, the pool of immediately releasable or of primed zymogen granules is easily exhausted or desensitized during the Ca2+ spike cycles, and has to be supplied from newly primed or sensitized resources. The progressive delay in delta C during the spike cycle is interpreted as a delay in the process of supplying fusible granules. PMID- 7859256 TI - [Survey on the current situation of epidemic of HIV infection in Yunnan Province]. AB - This paper summarized the results of routine surveillance, sentinel surveillance in Yunnan province during the period of 1986 to 1992. In 1992, HIV infection rates of intravenous drug users (IDUs) were 80.7% in Ruili city, 43.0% in Longchuan county, 17.4% in Yinjiang county, 3.7% in Luxi county and 0 in Kunming city respectively; the comparison of the change on the HIV infection rate of IDUs between 1990 and 1992 showed that the rate in Ruili city increased by 12.8%, the rate in Longchuan grew by 8.2%, but the rate in Luxi did not go up. On the sentinel surveillance, the rates in Longchuan drug treatment center went up. In Shimao, the HIV positive were detected in prostitutes and the HIV positive rate was 3.6%. In Xishuangbanna, the HIV positive percentage among sex clients was 9.1%. PMID- 7859257 TI - [Epidemiological study on the infections of Mycoplasma and Chlamydia in immoral persons and healthy controls in seven areas of China]. AB - 1,284 immoral persons and 1,161 healthy controls, from seven areas of China, were detected for the antibodies to Ureaplasma urealyticum (Uu), Mycoplasma hominis (Mh), and Chlamydia trachomatis (Ct) by indirect hemoagglutination (IHA). The results showed that: (1) in the immoral persons, the positive rates of antibody was the highest in Uu (25.47%), higher in Ct (18.22%), and lower in Mh (8.80%); (2) the levels of antibody to Mh, Uu, and Ct were significantly higher in the immoral persons than in the healthy controls; and (3) the immoral persons were commonly complicated with infections caused by Uu and Ct. It was indicated that the immoral persons were risk population of Mycoplasma and/or Chlamydial veneral diseases, and it must be noted for us controlling veneral diseases. PMID- 7859258 TI - [Study on factors affecting vaccination effect of poliomyelitis vaccine]. AB - We carried out this 1:2 matched case-control study in some counties and townships in Guangxi, Henan and Jiangsu provinces from June to October in 1992 to find the risk factors of poliomyelitis incidence among fully vaccinated children. Then we processed the collected data with individual and multiple condition logistic regression analysis and found the risk factors of poliomyelitis incidence among fully vaccinated children included two kinds, the community factors and the individual factors. The community factors which related to the cold chain and health services. They are the special risk factors for fully vaccinated children. The individual factors are the common risk factors for both fully vaccinated and unvaccinated children. In addition, children received five or more doses of TOPV was a favorable factor against poliomyelitis. It was showed that we must improve vaccination quality while rising TOPV coverage continually. PMID- 7859259 TI - [Comparative study on Legionella infection in different groups of population in Dalian area]. AB - Using a microagglutination test, the prevalence of antibodies against three species (10 groups) of Legionella was determined in 300 healthy donors, 120 non pneumonic patients with immunodeficiency and 158 patients with pneumonia. The results showed that there were significant differences among all groups on positive rate and GMT in three groups. Lp6 was the highest, Lp1 and Lp8 came second. There were significant differences among three groups in positive rate and GMT to Lp1, Lp2, Lp6 and Lp8, in the group of patients with pneumonia was highest, the group of non-pneumonic patients with immunodeficiency was second and healthy group was the lowest. It was suggested that the infection with Lp6, Lp1, Lp8 was predominant in population in Dalian area. The latent infection, subclinical infection and legionella pneumonia in population might be existence simultaneously. Using test-tube agglutination, the paired sera collected from 74 pneumonic patients were studied, it was showed that 5.4% of admitted pneumonic patients was legionellosis. PMID- 7859260 TI - [The case-control study of hepatitis risk factors in Shashi City]. AB - Hepatitis was regarded as a main health problem in Shashi city, Hubei province, according to DSP data at present. The case-control study of hepatitis risk factors were carried out among 115 hepatitis cases and 60 controls that all were negative serologically in Shashi city. The result indicates that economic status, way of having breakfast outside, habits of washing hands before meals and after feces, levels of knowing about route of infection of hepatitis are independently associated with morbidity probability of hepatitis A, the comprehensive preventive measures are presented in the light of these conclusions. PMID- 7859261 TI - [A study on seasonal variation of epidemic cerebrospinal meningitis with circular distribution method]. AB - In order to study the seasonal variation of epidemic cerebrospinal meningitis (ECM) incidence; the data of ECM incidence during the period 1959-1990 in Changde City were analysed with circular distribution method. The result showed that the seasonal variation was obvious. In 28 of these 32 years, the highest peak of the ECM incidence occurred in March. In 26 years, 95% of epidemic periods began from October to June of the next year. The annual incidence rate had positive correlation with the r value of circular distribution, negative correlation with angular deviation and no correlation with mean angle a. It is concluded that the annual incidence rate concerns with the seasonal variation and does not concern with the date of the highest peak. PMID- 7859262 TI - [An investigation on the distribution of leptospirae interrogans in water and soil in southwest of Yunnan Province]. AB - The conservation of pathogenic leptospirae in water and soil is one of the important problems of geography-epidemiological survey of leptospirosis. We have conducted this investigation by using of filtration-culture isolation method in five counties in the west and southwest of Yunnan during 1988-1992. The results showed that the isolates from samples of water and soil collected between July and September in Menglian and Huaping county were leptospirae biflexa while in the samples of water and soil collected between November and December in three counties, 8 strains of L. interrogans were isolated from the samples of Gengma and Baoshan county. The total positive rate was 3.31% (8/242). The positive rate of water and soil was 2.14% (3/140) and 4.9% (5/102) respectively. Strains obtained in this investigation belong to six serogroups: Icterohaemorrhagiae and Pyrogenes in 2 respectively. Canicola, Grippotyphosa, Sejroe and Australis in 1 respectively. These serogroups of leptospirae obtained from water and soil were corresponded with the serogroups obtained from the patients and animals with leptospirosis in local area. This survey provided new data for expounding the structure of the focus of leptospirosis. PMID- 7859263 TI - [Effects of high iodine and high fluorine on children's intelligence and the metabolism of iodine and fluorine]. AB - An investigation on children's intelligence and the metabolism of iodine and fluorine in high iodine and fluorine regions was carried out. The results were as follows. In high iodine and high fluorine areas, the thyroid enlargement prevalence rate among inhabitants and that among children were 3.8% and 29.8%, respectively. The dental fluorosis prevalence rate among inhabitants and that among children was 35.48% and 72.9%, respectively. The pupils' average intelligence quotient (IQ) was 76.67 +/- 7.75, slightly lower than the control point, but that of low intelligent pupils was 16.7%. The urinary iodine and urinary fluoride were 816.25 +/- 1.80 micrograms/L and 2.08 +/- 1.03 mg/L, respectively, markedly higher than the control point. The thyroid iodine-131 (131I) uptake rate was markedly lower than the control point. The values at 3 h and 24 h were 9.36 +/- 1.55% and 9.26 +/- 4.63%, respectively. The serum TSH was obviously higher than the control point. These results indicate that high iodine and high fluorine exert severe damage to human body. PMID- 7859264 TI - [Dietary factors and cancer of the colon and rectum in a population based case control study in Shanghai]. AB - The study was a population-based case control one, to compare possible difference in the risk factors between colonic and rectal cancer. This study showed that: (1) High intake of pork and saturated fat was an important risk factor for colon cancer, and only slightly related to rectal cancer. (2) Low consumption of vegetables especially cruciferous vegetables, rhizome vegetables, sea weeds, legume vegetables, dietary fiber and some vitamins mainly derived from vegetables, e.g. vitamin c and carotene, was associated with an increased risk for both colonic and rectal cancer, and these factors were closer relationship with rectal cancer than colon cancer. (3) High intake of the fried and pickled foods significantly increase the risk of occurrence of these cancers. (4) The ratio of bowel cancer in first degree relatives of colon cancer cases was 2.9 times of control group (P < 0.01), but the ratio for rectal cancer was only 1.6 times (P > 0.05) compared with control group. PMID- 7859265 TI - [The study of the dangerous factors of the simple heart disease in children and its action mode]. AB - The simple congenital heart disease is a multiple genetic disease. Its environmental factors are still unclear. The mode of action between the causes and congenital heart disease hasn't reported yet. This study used 1:1 case control study and multiple factors were investigated in 168 pairs of parent before conception and the period of conception. First, using single factor analysis, the 19 suspicious risk factors were obtained from 55 factors(alpha = 0.10). Second, using conditional logistic regression selected 8 risk factors from 19 factors(alpha = 0.05). Finally, analysis of 8 risk factors were carried out by path analysis to explore the mode of action between the causes and congenital heart disease. PMID- 7859266 TI - [Rapid detection for antigens of respiratory tract viruses by using series of monoclonal antibody]. AB - A series of monoclonal Antibodies (McAb) against six main respiratory tract viruses(RTV)--respiratory syncytial virus (RSV), Influenza A virus (FluA), influenza B virus(FluB), parainfluenza virus type 1.2.3 (PIV1.2.3) were developed, and were used in APAAP bridge-enzyme assay to rapidly detect the antigens of RTV. Total 260 samples of nasopharyngeal exfoliated cells were collected from young men in Beijing Army suffered from respiratory tract virus infections. The results showed that 18 cases were tested with FluA antigen; 10 with PIV2 antigen and 1 with FluB and another with RSV antigen, respectively. All the positive samples were determined by indirect immunofluorescence assay (IFA) and blocking test and replacement test. It is suggested that the method used in the study be effective in clinical rapid diagnosis and epidemiological survey. PMID- 7859267 TI - [Current status of application of monoclonal antibody to the diagnosis and differential diagnosis of brucellosis]. PMID- 7859268 TI - Condom use and the risk of HIV infection: who is being protected? AB - Descriptive baseline data at enrollment into a cohort of male factory workers who were tested for HIV serology and monitored for sero-conversion over time, were analysed for condom use. At recruitment, the 1,146 men were asked about their sexual behaviour, history of sexually transmitted diseases (STDs), condom use and circumstances under which condoms were used. HIV seroprevalence in the cohort was 18.2 pc. Self reported use of condoms was low, with only 5 pc of the men reporting using them all the time. Forty four pc reported that they had never used a condom, 11.5 pc tried a condom only once, and 30.5 pc used condoms less than half the time. HIV positive men were more likely (Odds Ratio [OR] = 2.2 95 pc CI: 1.3-3.3) to use condoms than those who tested negative. Men using a condom more than once were younger and had more education (p values < 0.0005). Univariate analysis showed that men with self reported risk factors for HIV infection were more likely to use condoms. Significantly more condom users reported paying for sex, multiple sex partners or (for married men) a girlfriend (p < 0.005). Condom users also more often had a history of genital ulcers, urethral discharge or other STDs. Few married men (24 pc) reported using a condom with their wives. Condom use was more commonly reported with commercial sex workers (44 pc) or other extramarital partners (36 pc). Some risk factors for HIV infection were also present amongst men who reported that they did not use condoms.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859269 TI - Plasma cholesterol distribution in a rural Nigerian population--relationship to age, sex and body mass. AB - Plasma cholesterol was measured in 417 healthy rural Nigerians consisting of 230 males (mean age 36.60 +/- 1.29 years) and 187 (mean age 34.60 +/- 1.38 years). Mean plasma cholesterol concentrations were found to be 2.91 +/- 0.22 mmol/l and 3.26 +/- 0.25 mmol/l in males and females respectively. These differences were highly significant (p < 0.025). The lowest plasma cholesterol levels were observed in the 11 to 20 year age group and the highest in the > 61 years age group. A strong correlation, which was higher in males than females was observed between plasma cholesterol and age (r = 0.48; p < 0.01). No significant correlation was observed between body mass index (BMI) and plasma cholesterol in both male female subjects. These results suggest that plasma cholesterol concentrations observed in rural Nigerians may be related to their physical activity and the consumption of a low fat diet. PMID- 7859270 TI - A cross-sectional sero epidemiological prevalence of polio virus antibodies post immunization with three doses of TOPV. AB - A cross-sectional sero epidemiological study to detect the presence of antibodies to polio virus types 1, 2 and 3 was undertaken. A total of 437 infants with an average of 40 subjects per province was enrolled in this study. All the subjects had completed the three doses of TOPV. Blood samples were aseptically collected by heel pricking on calibrated filter papers and immediately transported to the laboratory for processing. In the laboratory, standardized techniques were used to detect neutralizing antibodies to polio virus. Antibodies with a titre of > 1:32 were detected in all studied subjects. Some infants developed titres as high as 1:1024. However, polio virus type 3 showed a higher antibody titre than the other two types. Differences in titres were observed from province to province. PMID- 7859271 TI - Do traditional mosquito repellent plants work as mosquito larvicides? AB - Plant derived larvicides were evaluated in Kamhororo, an area of Zimbabwe. Twenty five third and fourth instar An. gambiae s.s mosquito larvae were used per test according to the method of WHO. All larvicides were effective against the An. gambiae s.s mosquito larvae and were comparable to studies done in Tanzania using Orange peel extracts. The extracts of the plant Ocimum canum (LC50 = 54, 94 x 10(3) ug/ml) were more effective in killing the larvae than Lippia javanica (LC50 = 125,34mg x 10(3) ug/ml). These concentrations are higher when considering commercial larvicides. PMID- 7859272 TI - A preliminary investigation into psychological disorders among Mozambican refugees: prevalence and clinical features. AB - Psychological disorders are common in refugee samples, with several studies showing high rates of Post Traumatic Stress Disorder. The present study examined the prevalence and factors associated with psychological disorders in Mozambican refugees in Zimbabwe. The findings indicated a very high prevalence rate (62 pc), which is considerably higher than that obtained from other settings within Zimbabwe. The demographic characteristics were similar in most respects to other Zimbabwean samples, but there was a trend towards greater social adversity (more relationship difficulties, less schooling and higher employment). Clinically, refugees were severe, with high scores on the SRQ-20, a presenting picture of multiple somatic complaints, and a high rate of rated suicidal risk. There were a significant number of refugees who had had an experience with violence in their recent past, as well as there having been frequent life events in the past six months. The implications of these findings are discussed with reference to Post Traumatic Stress Disorder, and the management of psychological disorders generally. PMID- 7859273 TI - Acute poisoning in a paediatric intensive care unit in Harare. AB - Forty two cases of acute poisoning were studied retrospectively over a two year period (1990 to 1991, inclusive) in the paediatric Intensive Care Unit (ICU), at Parirenyatwa Hospital in Harare. This formed 8.6 pc of the total admissions into the unit over the same period. The four commonest types of poisons were organophosphates, 38.1 pc; paraffin, 26.2 pc; traditional medicines (muti), 14.3 pc and miscellaneous drugs, such as chloroquine, aspirin, chloropromazine, diazepam and gama-benzene, 9.5 pc. The results suggest poor living conditions, local beliefs, customs and ignorance of the dangers of chemicals, as the risk factors associated with acute poisoning. Eighty eight pc of all admissions were children below the age of five years. The mortality rate in this series was 21 pc. Compared to the overall mortality rate of all ICU admissions of 30.9 pc over the same period, death due to acute poisoning was 1.8 pc of all ICU deaths. PMID- 7859274 TI - Umbilical hernia in Bulawayo: some observations from a hospital based study. AB - We present a retrospective study of 40 consecutive patients admitted with umbilical herniae to Mpilo Central Hospital between January 1990 and December 1993. The majority of the patients 95 pc (38/40) were children and only 5 pc (2/40) were adults. The study included 18 males and 22 females giving a M:F ratio of 1:1,2. In children the age range was from 1 month to 13 years with 63 pc (24/38) occurring in the zero to five year age group. The commonest indication for admission was obstruction of the umbilical hernia in 37.5 pc (15/40) of cases. Other indications included: large umbilical hernia 30 pc (12/40), recurrent discomfort and peri-umbilical pain 20 pc (8/40), incidental finding in patients admitted for some other problem 7.5 pc (3/40), one case of recurrent hernia and one case of accidental injury. Spontaneous reduction of obstructed umbilical herniae occurred in 86 pc (13/15) of cases and operative reduction was carried out in 14 pc (2/15) of cases. There was no mortality recorded in this series. It is clear from our findings in this study that obstruction of the umbilical hernia in children in our practice although relatively uncommon, is a well recognised surgical emergency. On the basis of our findings we would recommend that prophylactic umbilical hernia repair should be performed in all girls over two years of age and in all children over four years of age. PMID- 7859275 TI - Traveller's loiasis in Zimbabwe: a case report. AB - A case of loiasis diagnosed at Wankie Colliery Hospital is presented. The disease was suspected by the history of the patient and the presenting clinical signs, and it was confirmed by identification of Microfilariae loa loa in peripheral blood. The patient was successfully treated with a course of diethylcarbamazine. The paper gives a brief account of the clinical aspects of loiasis and emphasizes the importance of the laboratory methods to differentiate microfilariae. The case is discussed against the background of important diseases in Zimbabwe. PMID- 7859276 TI - Symptomatic polycystic liver disease: a case report and review of the literature. AB - A case of adult polycystic disease with an acute onset of intrahepatic cholangitis is presented. The diagnosis was made by ultrasonography and confirmed by histopathology. A wide unroofing-fenestration operation upon the liver was necessary in order to decompress the intrahepatic biliary duct system. The case is discussed against the background of congenital cysts of the liver with special reference to symptomatic polycystic liver disease. A review of the recent literature on the subject aims to summarise the current trends on diagnosis and treatment. PMID- 7859277 TI - Piece de Resistance: novel classes of plant disease resistance genes. PMID- 7859278 TI - FtsZ, a prokaryotic homolog of tubulin? PMID- 7859279 TI - Toward a molecular understanding of skeletal development. PMID- 7859280 TI - HIV-1 infection of nondividing cells: C-terminal tyrosine phosphorylation of the viral matrix protein is a key regulator. AB - The HIV-1 matrix (MA) protein contains two subcellular localization signals with opposing effects. A myristoylated N-terminus governs particle assembly at the plasma membrane, and a nucleophilic motif facilitates import of the viral preintegration complex into the nucleus of nondividing cells. Here, we show that myristoylation acts as the MA dominant targeting signal in HIV-1 producer cells. During virus assembly, a subset of MA is phosphorylated on the C-terminal tyrosine by a virion-associated cellular protein kinase. Tyrosine-phosphorylated MA is then preferentially transported to the nucleus of target cells. An MA tyrosine mutant virus grows normally in dividing cells, but is blocked for nuclear import in terminally differentiated macrophages. MA tyrosine phosphorylation thus reveals the karyophilic properties of this protein within the HIV-1 preintegration complex, thereby playing a critical role for infection of nondividing cells. PMID- 7859281 TI - The Epstein-Barr virus transforming protein LMP1 engages signaling proteins for the tumor necrosis factor receptor family. AB - The cytoplasmic C-terminus of Epstein-Barr virus (EBV) latent infection membrane protein 1 (LMP1) is essential for B lymphocyte growth transformation and is now shown to interact with a novel human protein (LMP1-associated protein 1 [LAP1]). LAP1 is homologous to a murine protein, tumor necrosis factor receptor-associated factor 2 (TRAF2), implicated in growth signaling from the p80 TNFR. A second novel protein (EBI6), induced by EBV infection, is the human homolog of a second murine TNFR-associated protein (TRAF1). LMP1 expression causes LAP1 and EBI6 to localize to LMP1 clusters in lymphoblast plasma membranes, and LMP1 coimmunoprecipitates with these proteins. LAP1 binds to the p80 TNFR, CD40, and the lymphotoxin-beta receptor, while EBI6 associates with the p80 TNFR. The interaction of LMP1 with these TNFR family-associated proteins is further evidence for their role in signaling and links LMP1-mediated transformation to signal transduction from the TNFR family. PMID- 7859282 TI - Mice deficient in IL-1 beta-converting enzyme are defective in production of mature IL-1 beta and resistant to endotoxic shock. AB - IL-1 beta-converting enzyme (ICE) cleaves pro-IL-1 beta to generate mature IL-1 beta. ICE is homologous to other proteins that have been implicated in apoptosis, including CED-3 and Nedd-2/lch-1. We generated ICE-deficient mice and observed that they are overtly normal but have a major defect in the production of mature IL-1 beta after stimulation with lipopolysaccharide. IL-1 alpha production is also impaired. ICE-deficient mice are resistant to endotoxic shock. Thymocytes and macrophages from the ICE-deficient animals undergo apoptosis normally. ICE therefore plays a dominant role in the generation of mature IL-1 beta, a previously unsuspected role in production of IL-1 alpha, but has no autonomous function in apoptosis. PMID- 7859283 TI - A fibrillar collagen gene, Col11a1, is essential for skeletal morphogenesis. AB - Mice that are homozygous for the autosomal recessive chondrodysplasia (cho) mutation die at birth with abnormalities in cartilage of limbs, ribs, mandible, and trachea. Limb bones of newborn cho/cho mice are wider at the metaphyses than normal bones and only about half the normal length. By linkage analysis, the cho gene and the gene encoding the alpha 1 (XI) chain of cartilage collagen XI were mapped to the same region of chromosome 3. Deletion of a cytidine residue about 570 nt downstream of the translation initiation codon in cho alpha 1 (XI) mRNA causes a reading frame shift and introduces a premature stop codon. The data demonstrate that collagen XI is essential for normal formation of cartilage collagen fibrils and the cohesive properties of cartilage. The results also suggest that the normal differentiation and spatial organization of growth plate chondrocytes is critially dependent on the presence of type XI collagen in cartilage extracellular matrix. PMID- 7859284 TI - Autosomal dominant and recessive osteochondrodysplasias associated with the COL11A2 locus. AB - Identifying mutations that cause specific osteochondrodysplasias will provide novel insights into the function of genes that are essential for skeletal morphogenesis. We report here that an autosomal dominant form of Stickler syndrome, characterized by mild spondyloepiphyseal dysplasia, osteoarthritis, and sensorineural hearing loss, but no eye involvement, is caused by a splice donor site mutation resulting in "in-frame" exon skipping within the COL11A2 gene, encoding the alpha 2(XI) chain of the quantitatively minor fibrillar collagen XI. We also show that an autosomal recessive disorder with similar, but more severe, characteristics is linked to the COL11A2 locus and is caused by a glycine to arginine substitution in alpha 2(XI) collagen. The results suggest that mutations in collagen XI genes are associated with a spectrum of abnormalities in human skeletal development and support the conclusion of others, based on studies of murine chondrodysplasia, that collagen XI is essential for skeletal morphogenesis. PMID- 7859285 TI - ATP-dependent accumulation and inositol trisphosphate- or cyclic ADP-ribose mediated release of Ca2+ from the nuclear envelope. AB - Uptake and release of Ca2+ from isolated liver nuclei were studied with fluorescent probes. We show with the help of digital imaging and confocal microscopy that the Ca(2+)-sensitive fluorescent probe Fura 2 is concentrated in or around the nuclear envelope and that the distribution of Fura 2 fluorescence is similar to that of an endoplasmic reticulum marker. The previously demonstrated ATP-dependent uptake of Ca2+ into isolated nuclei and release of the accumulated Ca2+ by inositol 1,4,5-trisphosphate (IP3) are therefore due to transport of Ca2+ into and out of the nuclear envelope and not the nucleoplasm. Dextrans labeled with fluorescent Ca2+ indicators (calcium-Green 1 and Fura 2) are distributed uniformly in the nucleoplasm and can be used to show that changes in the external Ca2+ concentration produce rapid changes in the nucleoplasmic Ca2+ concentration. Nevertheless, IP3 and cyclic ADP-ribose evoke transient intranuclear Ca2+ elevations. The release from the Ca2+ stores in or around the nuclear envelope appears to be directed into the nucleoplasm from where it can diffuse out through the permeable nuclear pore complexes. PMID- 7859286 TI - Neuronal pathfinding is abnormal in mice lacking the neuronal growth cone protein GAP-43. AB - GAP-43 has been termed a "growth" or "plasticity" protein because it is expressed at high levels in neuronal growth cones during development and during axonal regeneration. By homologous recombination, we generated mice lacking GAP-43. The mice die in the early postnatal period. GAP-43-deficient retinal axons remain trapped in the chiasm for 6 days, unable to navigate past this midline decision point. Over the subsequent weeks of life, most GAP-43-deficient axons do enter the appropriate tracts, and the adult CNS is grossly normal. There is no evidence for interference with nerve growth rate, and cultured neurons extend neurites and growth cones in a fashion indistinguishable from controls. Thus, the GAP-43 protein is not essential for axonal outgrowth or growth cone formation per se, but is required at certain decision points, such as the optic chiasm. This is compatible with the hypothesis that GAP-43 serves to amplify pathfinding signals from the growth cone. PMID- 7859287 TI - Control of Drosophila photoreceptor cell fates by phyllopod, a novel nuclear protein acting downstream of the Raf kinase. AB - The phyllopod (phyl) gene regulates the fates of a subset of cells in the developing Drosophila eye; in the absence of phyl function, the R1, R6, and R7 photoreceptors are transformed into additional cone cells, whereas ectopic phyl expression in the cone cell precursors transforms these cells into additional R7 cells. Within this group of cells, phyl expression thus mimics activation of the Raf pathway in its ability to induce photoreceptor rather than cone cell development. Furthermore, the transformation of cone cells into R7 cells in response to Raf activation is both accompanied by and dependent upon ectopic phyl expression. phyl thus represents a possible target gene of the Raf pathway during eye development, controlling the fates of a novel subset of photoreceptors. PMID- 7859288 TI - The SH2-containing protein-tyrosine phosphatase SH-PTP2 is required upstream of MAP kinase for early Xenopus development. AB - SH-PTP2, the vertebrate homolog of Drosophila corkscrew, associates with several activated growth factor receptors, but its biological function is unknown. We assayed the effects of injection of wild-type and mutant SH-PTP2 RNAs on Xenopus embryogenesis. An internal phosphatase domain deletion (delta P) acts as a dominant negative mutant, causing severe posterior truncations. This phenotype is rescued by SH-PTP2, but not by the closely related SH-PTP1. In ectodermal explants, delta P blocks fibroblast growth factor (FGF)- and activin-mediated induction of mesoderm and FGF-induced mitogen-activated protein (MAP) kinase activation. Our results indicate that SH-PTP2 is required for early vertebrate development, acting as a positive component in FGF signaling downstream of the FGF receptor and upstream of MAP kinase. PMID- 7859289 TI - Mutation in the silencing gene SIR4 can delay aging in S. cerevisiae. AB - Aging in S. cerevisiae is exemplified by the fixed number of cell divisions that mother cells undergo (termed their life span). We have exploited a correlation between life span and stress resistance to identify mutations in four genes that extend life span. One of these, SIR4, encodes a component of the silencing apparatus at HM loci and telomeres. The sir4-42 mutation extends life span by more than 30% and is semidominant. Our findings suggest that sir4-42 extends life span by preventing recruitment of the SIR proteins to HM loci and telomeres, thereby increasing their concentration at other chromosomal regions. Maintaining silencing at these other regions may be critical in preventing aging. Consistent with this view, expression of only the carboxyl terminus of SIR4 interferes with silencing at HM loci and telomeres, which also extends life span. Possible links among silencing, telomere maintenance, and aging in other organisms are discussed. PMID- 7859290 TI - OBF-1, a novel B cell-specific coactivator that stimulates immunoglobulin promoter activity through association with octamer-binding proteins. AB - Recent biochemical and genetic studies indicate that in addition to the octamer binding proteins Oct-1 and Oct-2, other B cell components are required for lymphoid-restricted, octamer site-mediated immunoglobulin gene promoter activity. Using a genetic screen in yeast, we have isolated B cell-derived cDNAs encoding Oct-binding factor 1 (OBF-1), a novel protein that specifically associates with Oct-1 and Oct-2. Biochemical studies demonstrate that OBF-1 has no intrinsic DNA binding activity and recognizes the POU domains of Oct-1 and Oct-2, but not those of Oct-4 and Oct-6. The OBF-1 mRNA is expressed in a highly cell-specific manner, being most abundant in B cells and essentially absent in most of the other cells or tissues tested. Furthermore, expression of OBF-1 in HeLa cells selectively stimulates the activity of a natural immunoglobulin promoter in an octamer site dependent manner. Thus, OBF-1 has all the properties expected for a B cell specific transcriptional coactivator protein. PMID- 7859291 TI - Interspecies gene exchange in bacteria: the role of SOS and mismatch repair systems in evolution of species. AB - Analysis of interspecies matings between S. typhimurium and E. coli indicates that the genetic barrier that separates these (and perhaps many other) related species is primarily recombinational. The structural component of this barrier is genomic sequence divergence. The mismatch repair enzymes act as potent inhibitors of interspecies recombination, whereas the SOS system acts as an inducible positive regulator. Interspecies mating triggers a RecBC-dependent SOS response in female bacteria that increases recombination mainly through overproduction of the RecA protein. Mismatch repair acts to reduce the mutation rate and recombination between similar sequences, whereas SOS acts to increase both. These opposing activities allow mismatch repair and SOS systems to determine both the rate of accumulation of sequence divergence and the extent of genetic isolation, which are the key components of the speciation process. PMID- 7859292 TI - Interactions among endoplasmic reticulum, microtubules, and retrograde movements of the cell surface. AB - Relationships among the endoplasmic reticulum (ER), microtubules, and bead movements on the cell surface were investigated in the thin peripheral region of A6 cells, a frog kidney cell line. ER tubules were often aligned with microtubules, as shown by double-labeling with DiOC6(3) and anti-tubulin in fixed cells. In living cells stained with DiOC6(3) and observed in time lapse, there were frequent extensions, but few retractions, of ER tubules. In addition, there was a steady retrograde (towards the cell center) movement of all of the ER at approximately 0.3 microns/min. Since microtubules are often aligned with the ER, microtubules must also be moving retrogradely. By simultaneous imaging, it was found that the ER moves retrogradely at the same rate as aminated latex beads on the cell surface. This indicates that the mechanisms for ER and bead movement are closely related. Cytochalasin B stopped bead and ER movement in most of the cells, providing evidence that actin is involved in both retrograde movements. The ER retracted towards the cell center in nocodazole while both ER and microtubules retracted in taxol. Time lapse observations showed that for both drugs, the retraction of the ER is the result of retrograde movement in the absence of new ER extensions. Presumably, ER extensions do not occur in nocodazole because of the absence of microtubules, and do not occur in taxol because taxol-stabilized microtubules move retrogradely and there is no polymerization of new microtubule tracks for ER elongation. PMID- 7859293 TI - Characteristics of pronuclear migration in Beroe ovata. AB - In the large eggs (approximately 1 mm) of the ctenophore Beroe ovata, female pronuclei migrate long distances to join stationary male pronuclei in the peripheral cytoplasm that surrounds the yolky interior. We have investigated the mechanism of nuclear migration using time lapse video recording, automated image analysis, visualization of microtubules by immunofluorescence and rhodamine tubulin injection, and electron microscopy. Female pronuclei migrated at average speeds of 0.2 microns/sec, and were found to show periodic oscillations in velocity. Alternating phases of acceleration and deceleration occurred with an average periodicity of 235 seconds covering distances of 47 microns (about 3 times the nuclear diameter). Migration velocities and velocity oscillations were similar in fertilized and unfertilized eggs; however, changes in migration direction were much more frequent in unfertilized eggs. Characteristic deformations of the pronuclear membrane and occasional rotation of the nuclear contents were observed during migration. Inhibitor studies indicated that microtubules are required for nuclear migration. In fertilized eggs the top of the nucleus was found to move through the dense layer of aligned sperm aster microtubules. The frequent changes in direction of pronuclear migration in unfertilized eggs reflect the random organization of the microtubule layer in the absence of sperm derived centrosomes. Densely packed endoplasmic reticulum was found intermeshed with sperm aster microtubules and connected extensively with the nuclear membrane during migration. Most nuclear pores were grouped in an infolding of the nuclear membrane. We suggest that in fertilized eggs the female pronucleus is transported to the minus ends of sperm aster microtubules using motor molecules attached either to the outer nuclear membrane and/or to the network of connecting ER. PMID- 7859294 TI - Myosin I localizes to the midbody region during mammalian cytokinesis. AB - During cytokinesis, daughter cells are cleaved in two by the constriction of an actin-rich contractile ring which encircles the equator of the dividing cell. Filamentous myosin II is present in the contractile ring and necessary for constriction of the furrow, as shown in several cell types [Satterwhite and Pollard, 1992: Curr. Opin. Cell Biol. 4:43-52]. However, no functional role nor distinctive localization has been previously identified for non-filamentous "unconventional" myosins, such as myosin I, during cytokinesis. Using antibodies to adrenal medullary myosin I, we report that myosin I is localized in 3T3 fibroblasts to the mid-equatorial plane during late-cytokinesis, as well as to the polar edges as previously described in ameboid cells [Fukui et al., 1989: Nature 341:328-331]. Confocal microscopy revealed that myosin I is concentrated at the midbody region in a nearly continuous transverse disk, extending from the cortical region of the furrow through the midbody itself. These findings suggest that, in addition to the accepted role of filamentous myosin II in constriction of the contractile ring, nonfilamentous myosin I might contribute to motile events occurring late in cytokinesis. PMID- 7859295 TI - Effect of protein kinase inhibitor H-7 on the contractility, integrity, and membrane anchorage of the microfilament system. AB - Addition of protein kinase inhibitor H-7 leads to major changes in cell structure and dynamics. In previous studies [Citi, 1992: J. Cell Biol. 117:169-178] it was demonstrated that intercellular junctions in H-7-treated epithelial cells become calcium independent. To elucidate the mechanism responsible for this effect we have examined the morphology, dynamics, and cytoskeletal organization of various cultured cells following H-7-treatment. We show here that drug treated cells display an enhanced protrusive activity. Focal contact-attached stress fibers and the associated myosin, vinculin, and talin deteriorated in such cells while actin, vinculin, and N-cadherin associated with cell-cell junctions were retained. Furthermore, we demonstrate that even before these cytoskeletal changes become apparent, H-7 suppresses cellular contractility. Thus, short pretreatment with H-7 leads to strong inhibition of the ATP-induced contraction of saponin permeabilized cells. Comparison of H-7 effects with those of other kinase inhibitors revealed that H-7-induced changes in cell shape, protrusional activity, and actin cytoskeleton structure are very similar to those induced by selective inhibitor of myosin light chain kinase, KT5926. Specific inhibitors of protein kinase C (Ro31-8220 and GF109203X), on the other hand, did not induce similar alterations. These results suggest that the primary effect of H-7 on cell morphology, motility, and junctional interactions may be attributed to the inhibition of actomyosin contraction. This effect may have multiple effects on cell behavior, including general reduction in cellular contractility, destruction of stress fibers, and an increase in lamellipodial activity. It is proposed that this reduction in tension also leads to the apparent stability of cell-cell junctions in low-calcium medium. PMID- 7859296 TI - Characterization of a monoclonal antibody prepared against plant actin. AB - Anti-actin monoclonal antibodies were prepared using phalloidin-stabilized actin that was purified from pea roots by DNase I affinity chromatography. One monoclonal antibody, designated mAb3H11, bound plant actin in preliminary screenings and was further analyzed. Immunoblot analysis showed that this antibody had a high affinity for plant actin in crude and purified preparations but a low affinity for rabbit muscle actin. In immunoblots of plant extracts separated on two-dimensional gels it appeared to bind all actin isoforms recognized by the JLA20 anti-chicken actin antibody. Using immunofluorescent cytochemistry, the antibody was used to observe actin filaments in aldehyde-fixed and methanol-treated tobacco protoplasts. These results indicate that mAb3H11 should be a useful reagent for the study of plant actins. PMID- 7859297 TI - Myosin reorganization in activated RBL cells correlates temporally with stimulated secretion. AB - Rat basophilic leukemia cells secrete histamine and serotonin in response to cross-linking of the IgE receptor by multivalent antigen [Metzger et al., 1986: Ann. Rev. Immunol. 4:419-470]. Receptor crosslinking also induces phosphorylation of the light and heavy chains of myosin II with kinetics similar to that of secretion [Ludowyke et al., 1989: J. Biol. Chem. 264:12492-12501]. Here we show that myosin II localization changes after activation with similar kinetics. Furthermore, these changes are coincident with changes in cell shape and increase in motile activity induced by activation. Within 2 min, activated cells begin to flatten, spread on their substratum, and extend lamellipodia which show active ruffling. Quantitation of the extent of cell spreading from video micrographs shows that 48% of the cells increase significantly in surface area by 5 min and 71% by 15 min. Myosin II is uniformly distributed in unactivated cells but is deficient in newly formed lamellipodia that start to appear at 2 min after activation. In contrast these lamellipodia show strong staining for actin. Further changes in myosin organization are detected by 15 min after activation when myosin reappears in the cell periphery, is concentrated in the perinuclear area, and is also organized in punctate linear arrays that extend from the nucleus to the cell periphery. The kinetics of the early cell shape changes and formation of the myosin-deficient lamellipodia correlate well with, and may relate to, the increase in the level of myosin II phosphorylation reported by Ludowyke et al. [1989: J. Biol. Chem. 264:12492-12501]. Changes in the distribution of cell surface-bound IgE also occur upon antigen activation, and they correlate with the myosin distribution in a manner that suggests that they may be driven by myosin II. PMID- 7859298 TI - Microtubules restrict plastid sedimentation in protonemata of the moss Ceratodon. AB - Apical cells of protonemata of the moss Ceratodon purpureus are unusual among plant cells with sedimentation in that only some amyloplasts sediment and these do not fall completely to the bottom of vertical cells. To determine whether the cytoskeleton restricts plastid sedimentation, the effects of amiprophos-methyl (APM) and cytochalasin D (CD) on plastid position were quantified. APM treatments of 30-60 min increased the plastid sedimentation that is normally seen along the length of untreated or control cells. Longer APM treatments often resulted in more dramatic plastid sedimentation, and in some cases almost all plastids sedimented to the lowermost point in the cell. In contrast, the microfilament inhibitor CD did not affect longitudinal plastid sedimentation compared to untreated cells, although it did disturb or eliminate plastid zonation in the tip. These data suggest that microtubules restrict the sedimentation of plastids along the length of the cell and that microtubules are load-bearing for all the plastids in the apical cell. This demonstrates the importance of the cytoskeleton in maintaining organelle position and cell organization against the force of gravity. PMID- 7859299 TI - Regulation of motility and cytoskeletal organization of rat bladder carcinoma cells by cyclic AMP. AB - Cyclic AMP (cAMP) has been implicated in the regulation of movement of certain cultured cell types. We have studied the effects of cAMP on epithelial cell motility using serum-free NBT-II cells, derived from a rat bladder carcinoma. The random movement of these cells on type I collagen was reduced upon elevation of intracellular cAMP by several means and this effect was reversible. Alterations in the organization of the cytoskeletal proteins F-actin and alpha-actinin occurred concurrently with the reduction in motility, and the arrangement of these proteins resembled that seen in non-motile cells on glass. In addition, pretreatment of cells with KT5720, a cAMP-dependent protein kinase (PKA)-specific inhibitor, prevented the dibutyryl cAMP-induced reduction in cell movement as well as the associated cytoskeletal changes. These results suggest that elevation of PKA is responsible for the observed effects on cell motility and cytoskeletal reorganization and demonstrate a role for PKA in the regulation of cell motility in this system. PMID- 7859300 TI - Oligonucleotide fingerprinting detects genetic diversity among Ascochyta rabiei isolates from a single chickpea field in Tunisia. AB - Fifty isolates of Ascochyta rabiei (Pass.) Labr. were hierarchically sampled from four well-separated locations of a single chickpea field in Beja (Tunisia), and single-spored. DNA was isolated from in-vitro-grown mycelia, digested with HinfI or RsaI, and hybridized to a set of synthetic oligonucleotides complementary to simple repetitive sequences. According to the fingerprint patterns derived from the probes (CA)8, (CAA)5, (CAT)5 and (GATA)4, 12 different fungal haplotypes were found at various frequencies within the investigated field. Seven haplotypes were confined to one location only, four occurred at two, one at three, and none at all four locations. Most of the genetic variability originated from diversity within, rather than between, locations. In some cases, more than one haplotype was isolated from the same lesion of a single host plant. Genetic distances between isolates, as calculated from band-sharing data, varied between 0.05 and 0.22. Relatedness between the different haplotypes was evaluated by cluster analysis using UPGMA. PMID- 7859301 TI - Centromere promoter factors (CPF1) of the yeasts Saccharomyces cerevisiae and Kluyveromyces lactis are functionally exchangeable, despite low overall homology. AB - The KlCPF1 gene, coding for the centromere and promoter factor CPF1 from Kluyveromyces lactis, has been cloned by functional complementation of the methionine auxotrophic phenotype of a Saccharomyces cerevisiae mutant lacking ScCPF1. The amino-acid sequences of both CPF1 proteins show a relatively-low overall identity (31%), but a highly-homologous C-terminal domain (86%). This region constitutes the DNA-binding domain with basic-helix-loop-helix and leucine zipper motifs, features common to the myc-related transcription factor family. The N-terminal two-thirds of the CPF1 proteins show no significant similarity, although the presence of acidic regions is a shared feature. In KlCPF1, the acidic region is a prominent stretch of approximately 40 consecutive aspartate and glutamate residues, suggesting that this part might be involved in transcriptional activation. In-vitro mobility-shift experiments were used to establish that both CPF1 proteins bind to the consensus binding site RTCACRTG (CDEI element). In contrast to S. cerevisiae, CPF1 gene-disruption is lethal in K. lactis. The homologous CPF1 genes were transformed to both S. cerevisiae and K. lactis cpf1-null strains. Indistinguishable phenotypes were observed, indicating that, not withstanding the long nonconserved N-terminal region, the proteins are sufficiently homologous to overcome the phenotypes associated with cpf1 gene-disruption. PMID- 7859303 TI - Heterologous transformation of Zalerion arboricola. AB - A heterologous DNA-mediated transformation system was developed for the pneumocandin-producing fungus Z. arboricola that was based on either conferral of hygromycin B resistance or complementation of a nitrate reductase mutant. Hygromycin-resistant transformants were selected with plasmid pCSN43 which contains the E. coli hygromycin B phosphotransferase gene under the control of Aspergillus nidulans trpC transcription signals. Transformation frequencies were about four transformants per microgram of circular DNA and could be improved four to six-fold by linearizing the transforming DNA. The transformants differed from one another with respect to the copy number of the integrated plasmid and the site of integration. Adding an autonomously-replicating sequence (AMA1) from A. nidulans to pCSN43 enhanced transformation three-fold and produced, in addition, numerous abortive transformants. However, it is unlikely that the AMA1 sequence promoted plasmid replication in Z. arboricola. Nitrate reductase mutants of Z. arboricola were isolated by positive selection on chlorate-containing medium, and one mutant was subsequently transformed with pSTA700 which contains the nitrate reductase gene (niaD) from Cephalosporium acremonium. Introduction of the niaD gene restored sensitivity to chlorate in the mutant; therefore, using the niaD gene as a selectable marker provides a system for both positive and negative selection. To our knowledge, this is the first report describing transformation of a member of the genus Zalerion. PMID- 7859302 TI - Molecular analysis of a leu2-mutant of Candida maltosa demonstrates the presence of multiple alleles. AB - Three different alleles of the beta-isopropylmalate dehydrogenase gene were cloned and sequenced from a leucine auxotrophic mutant, G587, of Candida maltosa. The cloning of functionally-intact wild-type genes from this mutant strain suggests the presence of silent gene copies. An interallelic-divergence comparison has provided evidence for new regulatory mechanisms. Sequence data and karyotype analysis argue for a highly-aneuploid genome of C. maltosa. An interpretation for the spontaneous auxotrophy-prototrophy-auxotrophy sequence of mutations in C. maltosa is suggested. PMID- 7859304 TI - Molecular karyotype alterations induced by transformation in Aspergillus nidulans are mitotically stable. AB - Clamped homogeneous electric field (CHEF)-gel electrophoresis was used to define the electrophoretic molecular karyotype of Aspergillus nidulans strain OC-1 before and after protoplast-based genetic transformation. The transforming DNA caused alterations in the molecular karyotypes in all transformants examined. Rather dramatic changes were observed in karyotypes, including apparent chromosome loss, massive size alterations, and the appearance of large chromosomes. Changes in molecular karyotype were mitotically stable. PMID- 7859305 TI - Isolation and characterization of a 1,4-beta-endoxylanase gene of A. awamori. AB - An enzyme with a particular 1,4-beta-xylanase activity was identified and purified from wheat-bran culture medium of an Aspergillus awamori strain. With oligonucleotides based on the N-terminal amino-acid sequence of the enzyme, the exlA gene of A. awamori, encoding 1,4-beta-xylanase A, has been cloned. Based on the deduced amino-acid sequence, 1,4-beta-xylanase A is produced as a 211 amino acid-residue-long precursor, which is converted post-translationally into a 184 aa residue-long mature protein. Transformation of the original A. awamori strain with multiple copies of the exlA gene resulted in a 40-fold overproduction of 1,4 beta-xylanase A. The overproduced enzyme has the same biochemical and enzymological properties as the wild-type enzyme. PMID- 7859306 TI - Additive action of partial heterokaryon incompatibility (partial-het) genes in Aspergillus nidulans. AB - We have observed partial heterokaryon-incompatibility reactions in combinations of field isolates of A. nidulans. We have demonstrated that partial heterokaryon incompatibility is genetically controlled by genes (partial-het genes) operating in the same manner as the previously-described het genes. Our results also reveal that partial-het genes can act additively in causing heterokaryon incompatibility and that partial heterokaryon incompatibility is not a barrier to the horizontal transfer of a mitochondrial marker. These results add to the growing body of evidence that vegetative-incompatibility reactions are not an absolute barrier to horizontal gene flow. PMID- 7859307 TI - The in-planta induced ecp2 gene of the tomato pathogen Cladosporium fulvum is not essential for pathogenicity. AB - During the colonization of tomato leaves, the fungal pathogen Cladosporium fulvum excretes low-molecular-weight proteins in the intercellular spaces of the host tissue. These proteins are encoded by the ecp genes which are highly expressed in C. fulvum while growing in planta but are not, or are only weakly, expressed in C. fulvum grown in vitro. To investigate the function of the putative pathogenicity gene ecp2, encoding the 17-kDa protein ECP2, we performed two successive disruptions of the gene. In the first of these, the ecp2 gene was interrupted by a hygromycin B resistance gene cassette. In the second gene disruption, the ecp2 gene was completely deleted from the genome, and replaced by a phleomycin resistance gene cassette. Both disruption mutants were still pathogenic on tomato seedlings, indicating that the C. fulvum ecp2 gene is not essential for pathogenicity in tomato. PMID- 7859308 TI - Transformation of Botrytis cinerea with the hygromycin B resistance gene, hph. AB - A transformation method has been developed for the phytopathogenic fungus Botrytis cinerea. Protoplasts were transformed with pAN7-1 plasmid carrying the Escherichia coli hygromycin phosphotransferase gene (hph), conferring hygromycin B resistance, downstream from an Aspergillus nidulans promoter. Molecular analysis, showed that transformation resulted in an integration of the plasmid into different regions of the B. cinerea genome and occurred through non homologous recombination. The frequency was 2-10 transformants per micrograms of DNA. Transformants expressed phosphotransferase activity confirming that the hph gene conferred the hygromycin-resistance phenotype. All transformants analysed so far proved to be stable after several subcultures without any selective pressure. PMID- 7859309 TI - Genes for components of the chloroplast translational apparatus are conserved in the reduced 73-kb plastid DNA of the nonphotosynthetic euglenoid flagellate Astasia longa. AB - The colourless, nonphotosynthetic protist Astasia longa is phylogenetically related to Euglena gracilis. The 73-kb plastid DNA (ptDNA) of A. longa is about half the size of most chloroplast DNAs (cpDNAs). More than 38 kb of the Astasia ptDNA sequence has been determined. No genes for photosynthetic function have been found except for rbcL. Identified genes include rpoB, tufA, and genes coding for three rRNAs, 17 tRNAs, and 13 ribosomal proteins. Not only is the nucleotide sequence of these genes highly conserved between A. longa and E. gracilis, but a number of these genes are clustered in a similar fashion and have introns in the same positions in both species. The results further support the idea that photosynthetic genes normally encoded in cpDNA have been preferentially lost in Astasia, but that the chloroplast genes coding for components of the plastid translational apparatus have been maintained. This apparatus might be needed for the expression of rbcL and also for that of still unidentified nonphotosynthetic genes of Astasia ptDNA. PMID- 7859310 TI - An atpE-specific promoter within the coding region of the atpB gene in tobacco chloroplast DNA. AB - The atpB and atpE genes encode beta and epsilon subunits, respectively, of chloroplast ATP synthase and are co-transcribed in the plant species so far studied. In tobacco, an atpB gene-specific probe hybridizes to 2.7- and 2.3-kb transcripts. In addition to these, a probe from the atpE coding region hybridizes also to a 1.0-kb transcript. The 5' end of the atpE-specific transcript has been mapped 430/431 nt upstream of the atpE translation initiation site, within the coding region of the atpB gene. In-vitro capping revealed that this transcript results from a primary transcriptional event and is also characterized by -10 and -35 canonical sequences in the 5' region. It has been found to share a common 3' end with the bi-cistronic transcripts that has been mapped within the coding region of the divergently transcribed trnM gene, approximately 236 nt downstream from the atpE termination codon. Interestingly, this transcript accumulates only in leaves and not in proplastid-containing cultured (BY-2) cells, indicating that, unless it is preferentially degraded in BY-2 cells, its expression might be transcriptionally controlled. PMID- 7859311 TI - Polymorphism for ribosomal RNA gene arrangement in the mitochondrial genome of fall rye (Secale cereale L.). AB - A restriction-fragment-length polymorphism (RFLP) in mitochondrial DNA (mtDNA) was detected between varieties of fall rye (Secale cereale L.) by Southern hybridization with rrn18, the gene encoding the mitochondrial 18S ribosomal RNA. Restriction mapping showed that the RFLP is based on differing numbers of genomic contexts (one vs three) for a recombining-repeat element (the "18S/5S repeat"). From examination of other Secale species, we conclude that the one-context state arose relatively recently, putatively by deletion of two of an ancestral set of three distinct genomic loci containing the mitochondrial 18S/5S repeat. This is consistent with our earlier conclusion that the 18S/5S repeat has probably existed in at least two genomic copies throughout much of the history of the grass family (at least 40 million years). Interestingly, the intervarietal difference in the number of distinct rrn18 loci is not accompanied by a major difference in the number of rrn18 copies per unit mass of mtDNA. This suggests the existence of a mechanism that can compensate rather precisely for differences in mitochondrial gene dosage, perhaps by over-replication or stabilization of specific subgenomic molecules. PMID- 7859312 TI - Linear plasmids, pLm9 and pLm10, can be isolated from the phytopathogenic ascomycete Leptosphaeria maculans by pulsed-field gel electrophoresis. AB - Two linear DNA plasmids (pLm9 and pLm10, sized 9 and 10 kb respectively) were isolated from the phytopathogenic ascomycete Leptosphaeria maculans, using pulsed field gel electrophoresis. pLm9 and pLm10 are found only in aggressive isolates of L. maculans but, because aggressive and non-aggressive strains appear to be different species, these plasmids are probably not involved in pathogenicity. pLm9 and pLm10 copurify with a mitochondrially-enriched cell fraction, and do not hybridise to chromosomal or mitochondrial DNA, or to each other. Exonuclease digestions suggest that both these molecules contain covalently-bound proteins at their 5' termini. pLm9 hybridises to the RNA polymerase of a linear plasmid from the ascomycete Podospora anserina, and pLm10 hybridises to the DNA polymerase from the same P. anserina plasmid, suggesting that pLm9 and pLm10 encode their own replication and transcription enzymes. PMID- 7859313 TI - Energy-dependent mitochondrial mutagenicity of antibacterial ofloxacin and its recombinogenic activity in yeast. AB - Ofloxacin, a specific inhibitor of bacterial topoisomerase II, is known to inhibit the growth of yeast cells and to induce rho- mutants in the yeast S. cerevisiae. The frequency of ofloxacin-induced petite mutants under non-growth conditions was found to be strongly diminished when the cells were depleted in intramitochondrial ATP. Under optimal conditions of mitochondrial mutagenesis the drug induced mitotic recombination and reverse mutation in diploid strains but failed to cure either killer plasmids or the 2 microns DNA of dividing cells. The sensitivity to ofloxacin of the strains deficient in the DNA strand-break repair pathway (rad52) was significantly higher then that of the wild-type strains and of the mutants deficient in excision or mutagenic DNA repair. The results are compatible with the idea that the cytotoxic and genetic activity of ofloxacin in yeast probably results from the inhibited DNA ligation function of topoisomerase II creating DNA breaks that are reparable through the recombination repair pathway. PMID- 7859314 TI - [Anaplastic Ki-1/CD30 positive lymphoma]. AB - Ki-1(CD30) positive lymphoma in its large cell variant represents a distinct histopathological entity. Its cells have a characteristic morphology, immunophenotype and karyotype. In the beginning the tumour infiltrates sinuses of the lymph node and it can be difficult to distinguish it from a metastatic carcinoma or melanoma. We present here six cases of this peculiar entity. PMID- 7859315 TI - [T-lymphocyte-rich large B-cell lymphoma--case report]. AB - A 60-year-old man presented with hepatosplenomegaly and signs of hepatic failure. The patient underwent splenectomy and liver biopsy. Histologic sections of the liver and the spleen showed nodular infiltrates composed of scattered large atypical cells that resembled Sternberg-Reed (SR) cells intermingled with abundant small T-lymphocytes. Large atypical cells showed B phenotype (CD20 positivity) and did not express CD15 and CD30 antigens typical of SR cells. PMID- 7859316 TI - [Non-Hodgkin's B-cell lymphoma resembling Hodgkin's lymphoma]. AB - Two bioptic cases of dual lymphomas in a single anatomic localization were described. In the first case supraclavicular lymph node and in the second case stomach were infiltrated. In both cases malignant non-Hodgkin's B cell lymphoma predominate. Hodgkin's-like lymphoma involved only part of organs and a few Reed Sternberg-like cells were found. Immunophenotype of these cells belonged to B cell line (CD15-, CD30-, CDw75+, CD74+, CD20+). Effect of lymphokins on the fibroproduction in both lymphomas was discussed. PMID- 7859317 TI - [Trephine biopsy of the bone marrow in hematologic tumors]. AB - A group of 1000 random trephine biopsies were evaluated according to their usefulness for typing and staging of haematological tumours. Trephine biopsy contributed someway to clinical data in half the cases. Primary medullary processes showed an excellent correspondence of clinical and bioptical data. Biopsy contributed substantially to specification of myeloproliferations and myodysplasias. There were only 24% of negative results (descriptive inconclusive). Malignant lymphomas presented situation analogical to leucaemias. Peripherical malignant lymphomas in medulla mostly did not follow diversity of lymph node phenomena and did not contribute to more detailed typing but enabled satisfactory staging. Malignant lymphomas were located, unlike leucaemia, intertrabeculary or peritrabeculary and often induced reactive myeloproliferation or scarring. Biopsy was usually good for separation of medullary carcinosis. Remarks to technology of getting and processing of bioptical sample were discussed. PMID- 7859318 TI - [Atypical decubital fibroplasia (ischemic fasciitis)--a new pseudosarcomatous entity]. AB - Two cases of atypical decubital fibroplasia (ischemic fasciitis) were presented. Both patients were immunocompromized and their lesions were located in usual decubital places (back shoulder, femorogluteal region). Histology was typical: 1. zone of fibrinoid necrosis, 2. neighbouring cellular parts reminding of proliferative fasciitis. Focal high cellularity with atypical ganglioid fibroblasts and mitotic activity imitated sarcoma. Immunohistochemistry showed expression of vimentin in all cells and of KP1 (CD 68), lysozym as well as F XIIIa in majority of them. There was not any expression of desmin, actin, S-100 protein, cytokeratin and epithelial membrane antigen. Importance of atypical decubital fibroplasia (ischemic fasciitis) is in its histological similarity to sarcoma-as it was in both the presented cases. PMID- 7859319 TI - [Experimental myocardial infarct in rats induced by ligation of the coronary vessels. Electrophysiologic and ultrastructural study]. AB - Ischemic damage of rat myocardium was produced by ligature of coronary arteries. Animals were studied in three groups: those dying of dysrhythmia, animals after ischemia lasting 10 minutes and 20 minutes. All of them were investigated by ECG and extrasystoles, bigeminia, trigeminia, salvos, ventricular tachycardia and fibrillation were found. Groups with ECG finding were sampled for electron microscopy. Ultrastructural findings documented ischemic damage of cardiomyocytes clearing of basal sarcoplasm, clearing of perinuclear zones, occurring of cytolytic regions and even necrotic disintegration of cardiocytes. PMID- 7859320 TI - [Eclectic, synthetic and integrative psychotherapy]. AB - Eclectic psychotherapy selects convenient techniques from various approaches. Synthetic psychotherapy combines various approaches both technically and theoretically. Integrative psychotherapy aims at putting diverse theoretical systems together under a system, which would be superordinated or metatheoretical. Following partial integrative hypotheses are stressed: 1. common factors are responsible for the effect of all important pure-form therapies, 2. different factors in diverse therapies have the same final effect, 3. different factors influence specifically certain symptoms, certain problems and certain patients. Following contemporary eclectic-integrative systems are seen as most influential: Lazarus's multimodal therapy. Beutler's systematic eclectic psychotherapy, Hart's functional eclectic therapy, Prochaska's transtheoretical approach, Garfield's eclectic approach, Driscoll's pragmatic therapy and Knobloch's integrated psychotherapy. Satisfactory integration still remains a goal to be achieved. Differentiation is viewed as an important part of the integration. It should offer to each patient specifically what he needs according to his symptoms, problems and personality. PMID- 7859321 TI - [Experience with the use of folk culture in rehabilitation in day care psychiatric units (preliminary information)]. AB - The author presents preliminary information on the orientation of rehabilitation in the day sanatorium of the Psychiatric Clinic of the Medical Faculty, Comenius University and Faculty Hospital in Bratislava on folk culture. She describes procedures and initial experience which is positive. The author reflects also on effective mechanisms in the orientation of activities on folk culture. PMID- 7859322 TI - [Alcohol tolerance and the clinical course of alcoholism]. AB - The authors investigated in 250 hospitalized men in different clinical stages of alcoholism the alcohol tolerance and described the phenomenon of primary extension and secondary reduction in the variety of abused alcoholic beverages. While an increased tolerance was found in all patients, a markedly increased tolerance was recorded in 22% and the actual tolerance dominates unequivocally in toxicomanic drug dependence. In reduced tolerance (36%) associated findings such as hepatopathies, craniocerebral injury, epilepsy, ulceration etc. were present in 10%. The variety of alcoholic beverages comprised in 66.8% drinking of liquor with beer or wine--described by the author as the obligatory variety. In 20.4% preference of liquors was recorded, in 4.8% preference of wine, in 3.6% preference of beer. During secondary reduction of the variety (14%) in the majority the patients abandoned liquor in favour of wine, beer etc. Changes in the alcohol tolerance along with changes of the variety of consumed drinks are more marked within the framework of clinical pictures described by the author in the monograph "Klinika alkoholismu" (Clinical aspects of alcoholism) (1988). In systematic alcohol abuse (developing dependence) the increase of tolerance takes place along with profilization of the variety (obligatory variety, preference of liquors etc.). In alcoholic toxicomania dominates secondary and in particular actual tolerance with a markedly increased tolerance and preference of liquors. In habitual ethylism despite the increase the tolerance is not extreme, the obligatory variety dominates.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859323 TI - [Clozapine--an atypical antipsychotic agents, its advantages and risks]. AB - The authors present a basic review on clozapine (Leponex, Clozaril) which is one of the atypical antipsychotic drugs. It is a derivative of dibenzodiazepine, which contrary to classical neuroleptic drugs, does not exert a marked effect on the extrapyramidal system and its long-term use is not associated with the risk of development of irreversible tardive dyskinesia or dystonia. It is effective also in patients who are resistant to treatment with other neuroleptics and it has a more favourable effect on the negative symptoms of schizophrenia than classical neuroleptics. Its disadvantage is the increased risk of granulocytopenia and agranulocytosis (2%) and therefore its use is justified only in patients where there is evidence that they are resistant to other treatment. The mentioned risk can be controlled effectively by regular checks of the haemogram in patients taking clozapine, along with recording in the central data bank which has a consulting and control function and guaranteeing the method of correct administration of this drug and early therapeutic provisions in case of granulocytopenia. Despite the cost of treatment and checks of the haemogram, clozapine reduces the sum total of expenditure associated with the treatment of chronic schizophrenia by reducing the number of re-admissions to hospital, by shortening the period of hospitalization and by cutting indirect costs, which are influenced by a greater sociability of the patient and a greater probability of successful comprehensive therapeutic procedures. PMID- 7859324 TI - [Psychotherapeutic methods beyond the scope of individual schools of psychotherapy]. AB - The author discusses four basic theoretical methodological approaches elaborated by H. Seiffert and R. Lay which were recommended by R. Vogt and in particular P. Hahn for medicine and psychology. The author explains also primary diagnostic methods used in psychotherapy. Due to the aspect of medical anthropology these basic methods are considered aspects of genetic epidemiology and at the same time as theoretical guidelines for the diagnosis and therapy of anthropological dimensions of diseases. Traditional combination of all diagnostic methods from the "clinical aspect" is then substituted by specific differentiation at the point of intersection of objective and subjective facts concerning the disease. PMID- 7859325 TI - [The mental disorder of Doctor Jonas Jeitteles]. AB - Doctor Jonas Mischel Jeitteles was born in Prague on May 5, 1735 and died in Prague on April 18, 1806. He was buried in the Old Jewish Cemetery in Prague. He studied medicine in Leipzig and Halle. He became the public health officer of the Jewish community. He was nominated chief supervisor of the guild of Jewish healers in Prague. In 1784 he obtained from the emperor Joseph in Vienna permission that not only he himself but also other Jewish doctors could pursue unrestricted medical practice. He suffered from periodic depressive disorders with several exogenously provoked attacks. PMID- 7859326 TI - Nucleosides and nucleotides. 131. Synthesis and properties of oligonucleotides containing 5-formyl-2'-deoxyuridine. AB - Thymidine was converted into 5-formyl-2'-deoxyuridine (1), which was incorporated into oligonucleotides, 5'd(GGAGA1CTCC)3' (I-1) and 5'd(GCTGC1GCGAAAGCTG)3' (II 1). To avoid side-reactions and degradation, protection of the formyl group of 1 using a newly developed protecting group, N,N-di-(3,5 dichlorophenyl)ethylenediamine, was necessary. Compound 1 was unstable under the conditions employed for enzymatic complete digestion of oligonucleotides, so that a peak corresponding to 1 was not detected clearly by HPLC analysis of a nucleoside mixture obtained by complete hydrolysis of I-1. Therefore, the oligonucleotide I-1 was treated with cyanomethylene-triphenylphosphorane to give an oligonucleotide containing (E) and (Z)-5-(2-cyanovinyl)-2'- deoxyuridine, which was then hydrolyzed, and the newly generated nucleosides were detected by HPLC analysis. The Tm of the self-complementary oligonucleotide I-1 (40 degrees C) was higher than that of the parent oligonucleotide, 5'd(GGAGATCTCC)3', (31 degrees C) in a buffer containing 0.01 M sodium phosphate (pH 7.0) and 0.1 M NaCl. DNA replication study on a template-primer system [primer, 5'd(32P CAGCTTTCGC)3'; template, 3'd(GTCGAAAGCGXCGTCG)5' (X = 1 or T)] showed that dATP was incorporated into the DNA strand at a site opposite to 1 by Klenow DNA polymerase, but with a reduced rate. The formyl group of 1 in the oligonucleotides reacted with amines to give Schiff base derivatives. PMID- 7859327 TI - Studies on chemical modification of monensin. V. Synthesis, sodium ion permeability, antibacterial activity, and crystal structure of 7-O-(4-substituted benzyl)monensins. AB - 7-O-(4-Substituted benzyl)monensins (3a-g) were synthesized from monensin (1), and their lipophilicity, antibacterial activity, and Na+ ion permeability were examined. 7-O-(4-Ethylbenzyl)monensin (3e) showed the largest Na+ ion permeability, but 3c,f,g showed smaller Na+ ion permeability than 7-O benzylmonensin (2) in spite of higher lipophilicity. An X-ray study of the sodium salt of 3e revealed that the benzyl group was located over the position between the D and E rings, and that the ethyl substituent on the benzyl group was close to the C(28) methyl group on the E ring. PMID- 7859328 TI - Amphoteric drugs. I. Synthesis and antiallergic activity of [4 (diphenylmethoxy)piperidino]-, [4-(diphenylmethyl)piperazinyl]- and [4 (diphenylmethylene)piperidino]alkanoic acid derivatives. AB - A simple method of transforming classical antihistaminics into nonsedative antiallergic agents with strong effects in rat models is described. Various [4 (diphenylmethoxy)piperidino]- (series A), [4-(diphenylmethyl)piperazinyl]-(series B) and [4-(diphenylmethylene)piperidino]alkanoic acid derivatives (series C) were synthesized and examined for antiallergic activities and effects on the central nervous system (CNS), in comparison with the corresponding N-methyl derivatives (1a--c). N-Alkylcarboxylic acids (5a--c) showed stronger inhibitory effects on compound 48/80-induced lethality in rats than the corresponding N-methyl derivatives (1a--c). In particular, N-alkylcarboxylic acids (5a) in series A exhibited approximately 100-fold stronger inhibitory effects than 1a, and were the least effective in prolonging the sleeping time on hexobarbital-induced anesthesia in mice in all series. As a result of chemical modification in series A, it was found that introduction of a methyl group at the para-position on one benzene ring in the (diphenylmethoxy)piperidine system effectively reduced CNS side-effects without reducing antiallergic activity. (+)-3-[4-[(4 Methylphenyl)phenylmethoxy]piperidino]propionic acid ((+)-5l), an optically active isomer of 5l, exhibited a stronger antiallergic effect (ED50 = 0.17 mg/kg, p.o.) than ketotifen and terfenadine in the 48 h homologous passive cutaneous anaphylaxis (PCA) test, and moreover exhibited no CNS side-effects, such as prolongation of the sleeping time on hexobarbital-induced anesthesia, at an oral dose of 30 mg/kg. Compound (+)-5l was thus proved to be a promising candidate as a nonsedative antiallergic agent. PMID- 7859329 TI - Xanthone C-glycoside and acylated sugar from Polygala tenuifolia. AB - A new xanthone C-glycoside, polygalaxanthone III (1), and a new acylated sugar, tenuifoliside E (2) were isolated from the roots of Polygala tenuifolia. Their structures were characterized as 4-C-[beta-D-apiofuranosyl-(1-->6)-beta-D glucopyranosyl]-1, 3,6-trihydroxy-7-methoxyxanthone (1) and beta-D-(1-O-acetyl-3 O-feruloyl-6-O-sinapoyl)-fructofuranosy l-alpha-D-(2,4,6- O triacetyl)glucopyranoside (2), respectively, on the basis of chemical and spectral evidence including two dimensional nuclear magnetic resonance (2D-NMR) studies. PMID- 7859330 TI - Triterpenoid saponins from Ardisia crenata and their inhibitory activity on cAMP phosphodiesterase. AB - Two novel triterpenoid saponins, ardisicrenoside C (1) [3 beta-O-(alpha-L rhamnopyranosyl-(1-->2)-beta-D-glucopyranosyl-(1-->4)- [beta-D-glucopyranosyl-(1- >2)]-alpha-L-arabinopyranosyl)-16 alpha, 28-dihydroxy-olean-12-en-30-oic acid 30 O-beta-D-glucopyranosyl ester] and ardisicrenoside D (2) [3 beta-O-(beta-D xylopyranosyl-(1-->2)- beta-D-glucopyranosyl-(1-->4)-[beta-D-glucopyranosyl-(1- >2)]-alpha-L- arabinopyranosyl)-16 alpha, 28-dihydroxy-olean-12-en-30-oic acid 30 O-beta-D-glucopyranosyl ester] were isolated from the roots of Ardisia crenata. Structure assignments are based on spectroscopic data including 2D-NMR (correlation spectroscopy (COSY), homonuclear Hartmann-Hahn spectroscopy (HOHAHA), heteronuclear correlated spectroscopy (HETCOR), heteronuclear multiple bond correlation (HMBC) and rotating frame NOE spectroscopy (ROESY)) experiments and some chemical reactions. In addition, the isolated saponins along with their prosapogenins and sapogenins have been evaluated for their inhibitory activity on cAMP phosphodiesterase as a primary screening test for new medicinal compounds. PMID- 7859331 TI - Application of calcium silicate for medicinal preparation. I. Solid preparation adsorbing an oily medicine to calcium silicate. AB - Calcium silicate (Florite RE, FLR), a fine porous powder, was recently approved as a medicinal additive. In this study we sought to make a solid preparation by absorbing an oily medicine to FLR; tocopheryl nicotinate (TN) was used as the oily medicine. TN adsorbed to FLR powder (TN-PO) was prepared by adsorbing TN ethanol solution to FLR and granulating with hydroxypropylcellulose (HPC) in order to improve the flowability. The results were as follows. FLR showed an excellent liquid holding ability compared with other excipients, and this was attributed to the high capillarity of the pores. In the adsorbing process, FLR particles were granulated with TN overflowing from the pores or adhering to the particle surface. The angle of repose was decreased with increasing TN content, which was attributed to the process of granulation, and the angle of repose of the granules with a binder (TN-GR) was below 40 degrees at any TN content. These results show that FLR is an useful additive for the solid preparation of an oily medicine. PMID- 7859332 TI - Characterization of the inclusion mode of beta-cyclodextrin sulfate and its effect on the chlorpromazine-induced hemolysis of rabbit erythrocytes. AB - The inclusion mode of beta-cyclodextrin sulfate (beta-CyD-sul) with a cationic drug, chlorpromazine, was investigated, and the effect of beta-CyD-sul on the hemolytic activity of chlorpromazine was compared with that of parent beta-CyD. The interaction of beta-CyD-sul with chlorpromazine was weaker than that of parent beta-CyD, probably because of the steric or electrostatic repulsion between anionic sulfate groups and hydrophobic phenothiazine moiety. Spectroscopic studies, including pH- and salt-effects, as well as thermodynamic parameters, suggested that both electrostatic and hydrophobic interactions are operative in the inclusion complexation of beta-CyD-sul with chlorpromazine. The inhibiting effect of parent beta-CyD on the chlorpromazine-induced hemolysis of rabbit erythrocytes was accounted for by the decreased fraction of free drug through the complexation. In the case of beta-CyD-sul, the hemolysis and binding of the drug to the erythrocyte membrane was higher than those estimated from the fraction of free drug, probably due to the increased hydrophobicity of the drug through the complexation. However, the chlorpromazine-induced shape change of the erythrocytes was significantly suppressed by beta-CyD-sul, and its inhibiting effect was greater than that of beta-CyD, because of the counterbalance of the opposite effects, i.e., internalization and externalization induced by chlorpromazine and beta-CyD-sul, respectively. PMID- 7859333 TI - New steroidal saponins from the rhizomes of Anemarrhena asphodeloides Bunge (Liliaceae). AB - From the rhizome of Anemarrhena asphodeloides Bunge (Liliaceae), four new steroidal saponins named anemarrhenasaponins I-IV (1-4) were isolated, together with known saponins, timosaponin A-III (5), marcogenin diglycoside (6) and timosaponin B-II (7) and a xanthone C-glycoside, mangiferin. These saponins are coprostane type steroidal glycosides. Their structures were established on the basis of spectroscopic and chemical evidence. PMID- 7859334 TI - A comparative ESR study of some paramagnetic materials as probes for the noninvasive measurement of dissolved oxygen in biological systems. AB - The ESR properties of three types of paramagnetic material, active charcoal, fusinite and a stable nitroxide radical 4-oxo-2,2,6,6-tetramethylpiperidine-1 oxyl (TEMPONE), were examined in order to evaluate their suitability as probes to measure dissolved intra- and extra-cellular oxygen. Although, with changes in oxygen concentration, a greater change in the linewidth of ESR signals was observed with fusinite or active charcoal, it took a long time (15 min for active charcoal and more than 6 h for fusinite) for equilibrium to be achieved. On the other hand, equilibrium was reached very rapidly in the case of the TEMPONE spectra although the sensitivity to changes in oxygen concentration was only moderate. Furthermore, since lipid bilayers are permeable to TEMPONE, this compound can be used to measure intracellular oxygen concentration when employed in combination with membrane-impermeable spin-broadening reagents which act on ESR signals arising from extracellular probes. A perdeuterated derivative of TEMPONE is useful in that it gives a greater signal-to-noise ratio and greater sensitivity to changes in oxygen concentration. In conclusion, active charcoal is suitable as a probe for extracellular oxygen in a system where changes are slow, while nitroxide is a versatile probe for measuring rapidly changing intra- and extra-cellular oxygen concentrations. PMID- 7859335 TI - Synthesis and antifertility activity of 1,5-diaryl-3-(3'-indolyl)formazans. PMID- 7859336 TI - Synthesis and biological activity of the metabolites of syn-3-ethyl-7-methyl-3,7 diazabicyclo[3.3.1]non-9-yl 4-chlorobenzoate hydrochloride. AB - Five metabolites of syn-3-ethyl-7-methyl-3,7-diazabicyclo[3.3.1]non-9-yl 4 chlorobenzoate hydrochloride (YUTAC) (1) were prepared and examined for Na+ current blocking activity in guinea pig ventricular myocytes. These metabolites showed lower inhibitory activities than the parent compound or were inactive. PMID- 7859337 TI - Dissolution behavior of phenytoin-bile salt complexes prepared by co-grinding. AB - The physicochemical properties of phenytoin (PHT)-bile salt complexes comprised of sodium dehydrocholate (DHCNa), sodium deoxycholate (DCNa) or sodium cholate (CNa) prepared by co-grinding were investigated by X-ray diffraction analysis, DSC and dissolution kinetics. All X-ray diffraction peak intensities of the co ground PHT-bile salt [1 mol: 1 mol] mixtures were decreased by grinding for 3 h, and showed a halo pattern of a noncrystalline solid. The solubility of ground products with DCNa, DHCNa and CNa were 212, 56, 68 times higher, respectively, than those of physical mixtures. PMID- 7859338 TI - Electrochemically accelerated adsorption of serum albumin on the surface of platinum and gold electrodes. AB - Adsorption of serum albumin on the surface of platinum and gold electrodes was highly accelerated by the application of a constant potential to the electrodes. The accelerated adsorption was significant at the electrode potential of 0.5-1.0 V vs. Ag/AgCl, even in the diluted solution of albumin (0.01%). PMID- 7859339 TI - TMS triflate induced synthesis of 1,1'-disaccharides from 1-hydroxy sugars. PMID- 7859340 TI - Ether lipids in biomembranes. AB - Plasmalogens (1-O-1'-alkenyl-2-acylglycerophospholipids) and to a lesser extent the 1-O-alkyl analogs are ubiquitous and in some cases major constituents of mammalian cellular membranes and of anaerobic bacteria. In archaebacteria polar lipids of the cell envelope are either diphytanylglycerolipids or bipolar macrocyclic tetraether lipids capable of forming covalently linked 'bilayers'. Information on the possible role of ether lipids as membrane constituents has been obtained from studies on the biophysical properties of model membranes consisting of these lipids. In addition, effects of modified ether lipid content on properties of biological membranes have been investigated using microorganisms or mammalian cells which carry genetic defects in ether lipid biosynthesis. Differential utilization of ether glycerophospholipids by specific phospholipases might play a role in the generation of lipid mediators that are involved in signal transduction. A possible function of plasmalogens as antioxidants has been demonstrated with cultured cells and might play a role in serum lipoproteins. Synthetic ether lipid analogs exert cytostatic effects, most likely by interfering with membrane structure and by specific interaction with components of signal transmission pathways, such as phospholipase C and protein kinase C. PMID- 7859341 TI - Divalent cation-dependent interaction of sulfated polysaccharides with phosphatidylcholine and mixed phosphatidylcholine/phosphatidylglycerol liposomes. AB - The Ca(2+)-dependent interaction of various polyanionic polysaccharides (chondroitin sulfate, heparin, dextran sulfate, beta-cyclodextrin sulfate, hyaluronic acid and carboxymethyldextran) with multilamellar dimyristoyl phosphatidylcholine (DMPC) liposomes was investigated by calorimetric and fluorescence spectroscopic measurements. It was found that an observed polysaccharide-induced phospholipid phase separation depends on the density of the sulfate groups along the polysaccharide chain independent of the presence of additional carboxyl groups. The phase separation resulting from the drastic dehydration of the covered membrane regions is monitored by the upward shift of the lipid phase transition and by the blue shift of the emission spectrum of a headgroup-dansylated phosphatidylethanolamine (DPE). This shift is only observable if the required polysaccharide chain length contains at least three glycosyl units. The Ca(2+)-mediated interaction of dextran sulfate with various phosphatidylcholines, differing in their compressibility, showed the maximal difference between the phase transition temperatures of the lipid phase covered by the polysaccharide and the uneffected lipid domains for dielaidinoyl phosphatidylcholine (DEPC), the most compressible phospholipid investigated here. Mixed negatively charged DMPC/dimyristoyl phosphatidylglycerol (DMPG) liposomes were found to compete with the likewise negatively charged dextran sulfate for the binding of Ca2+. At excess Ca2+ concentrations, the binding of the polysaccharide was strengthened, compared to pure DMPC liposomes. The monovalent cation sodium, was able to inhibit the interaction between the membrane surface and dextran sulfate. Various divalent cations were found to mediate the interaction, depending on their ionic radii and electron configuration. Within the second group of the periodic system Ca2+ is the most effective ion. However, within the horizontal forth period the ability to bind sulfated dextran to membrane surfaces decreases from Ca2+ to Ni2+, but then increases again if Cu2+ or Zn2+ was used as the mediating ion. PMID- 7859342 TI - Tirilazad mesylate protects stored erythrocytes against osmotic fragility. AB - The hypoosmotic lysis curve of freshly collected human erythrocytes is consistent with a single Gaussian error function with a mean of 46.5 +/- 0.25 mM NaCl and a standard deviation of 5.0 +/- 0.4 mM NaCl. After extended storage of RBCs under standard blood bank conditions the lysis curve conforms to the sum of two error functions instead of a possible shift in the mean and a broadening of a single error function. Thus, two distinct sub-populations with different fragilities are present instead of a single, broadly distributed population. One population is identical to the freshly collected erythrocytes, whereas the other population consists of osmotically fragile cells. The rate of generation of the new, osmotically fragile, population of cells was used to probe the hypothesis that lipid peroxidation is responsible for the induction of membrane fragility. If it is so, then the antioxidant, tirilazad mesylate (U-74,006f), should protect against this degradation of stored erythrocytes. We found that tirilazad mesylate, at 17 microM (1.5 mol% with respect to membrane lecithin), retards significantly the formation of the osmotically fragile RBCs. Concomitantly, the concentration of free hemoglobin which accumulates during storage is markedly reduced by the drug. Since the presence of the drug also decreases the amount of F2-isoprostanes formed during the storage period, an antioxidant mechanism must be operative. These results demonstrate that tirilazad mesylate significantly decreases the number of fragile erythrocytes formed during storage in the blood bank. PMID- 7859343 TI - Mechanistic data indicate that 1,3-butadiene is a human carcinogen. AB - A review of the epidemiological and mechanistic data on 1,3-butadiene indicates that this chemical is a human carcinogen for which the mouse is an appropriate model for assessing human cancer risk. Butadiene is carcinogenic at multiple organ sites in laboratory animals, including the induction of lymphomas in mice, while epidemiological studies have consistently found associations between occupational exposure to butadiene and increased mortality from lymphatic and hematopoietic cancers. Activated oncogenes and inactivated tumor suppressor genes in butadiene-induced tumors in mice are analogous to genetic alterations frequently observed in human cancers. Butadiene is metabolized to mutagenic and carcinogenic epoxides in all mammalian species studied, including humans. These metabolites form N7-alkylguanine adducts which have been detected in liver DNA of mice exposed to butadiene and in urine of exposed workers. Increases in hprt mutations were observed in lymphocytes from mice exposed to butadiene and in occupationally exposed humans. The mutational spectra for butadiene and its epoxide metabolites at the hprt locus in mouse lymphocytes are similar to the mutational spectrum of ethylene oxide; all of these chemicals exhibit a high percentage of frameshift mutations. Ethylene oxide, an alkylating agent that also forms an N7-alkylguanine adduct, was recently classified by the International Agency for Research on Cancer as a human carcinogen. Based on these data, we suggest that cancer induction by ethylene oxide and butadiene involve similar molecular mechanisms. PMID- 7859344 TI - Epidemiological and mechanistic data suggest that 1,3-butadiene will not be carcinogenic to humans at exposures likely to be encountered in the environment or workplace. AB - 1,3-Butadiene (BD) is a carcinogen in both rats and mice with mice being substantially more sensitive than rats. It is not known if BD poses a carcinogenic risk for humans. Findings from exposure assessment studies indicate that potential industrial exposure to BD in monomer, polymer, and end-user industries is typically < 2 p.p.m. Epidemiologic studies of persons occupationally exposed to BD are inconclusive. In vitro metabolism of BD in rats, mice and human tissues indicate that there are significant quantitative species differences in the metabolic activation of BD to butadiene monoepoxide (BMO) and butadiene diepoxide (BDE) and the detoxication of BMO. Activation/detoxication ratios calculated using in vitro kinetic constants reveal that ratios in mice were 12-fold greater than rats and humans. In rats and mice exposed to BD, concentrations of BMO in blood and tissues of mice were up to 14-fold higher than in rats and BDE was only detected in mice thereby providing a strong argument for why mice are highly sensitive to BD carcinogenicity. The fact that human tissues do not appear to metabolize BMO to BDE to any significant extent suggest that humans may not be sensitive to BD carcinogenicity. In mice, BDE is a more potent carcinogen than BMO. BDE is mutagenic in vitro at the hprt locus in human TK6 lymphoblasts at concentrations that were 100-fold less than the concentration of BMO required to yield a similar mutation frequency. Importantly, the concentrations of BDE that were genotoxic in vitro are nearly identical to the concentrations of BDE measured in blood and tissues of mice exposed to BD by inhalation. BD is genotoxic in mice, but not rats, following inhalation exposure and this is paralleled by species differences in observed tumor susceptibility. BD is not genotoxic in occupationally-exposed workers. The genetic basis for BD carcinogenicity appears to be primarily through induction of point mutations and deletion events mediated via the potent genotoxic metabolite, BDE. The genotoxic endpoints induced by BDE (e.g., deletion and point mutations) rather than BMO (e.g., point mutations) likely represent the underlying mechanism responsible for the striking species differences observed in the genotoxicity and carcinogenicity of BD in mice versus rats.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7859345 TI - Chemically induced mammary gland cancer in the National Toxicology Program's carcinogenesis bioassay. AB - Incidences of breast cancer change in populations as people migrate from one area of the world to another, suggesting that environmental factors contribute to this disease. There is a continuing effort to identify these environmental factors and the role that exposures to specific chemicals play in this disease. Results from experimental studies show that chemicals identified to cause mammary gland cancer in rodents are frequently mutagenic chemicals, suggesting that genetic damage is an important mechanism for the induction of this cancer. Prevalent classes of chemicals that were identified to cause mammary gland cancer in rodents in studies by the National Toxicology Program include halogenated hydrocarbons, aromatic amino/nitro compounds and epoxide-forming chemicals. Results from these experimental studies will help to elucidate mechanisms and possible causes of breast cancer in humans. PMID- 7859346 TI - Expression of gamma-glutamyl transpeptidase provides tumor cells with a selective growth advantage at physiologic concentrations of cyst(e)ine. AB - Cells from the GGT-negative mouse hepatoma cell line, Hepa 1-6, were transfected with a human GGT cDNA and stably transformed clones were isolated. In standard tissue culture medium the GGT-positive cells and GGT-negative controls grew equally well. However, when the cysteine concentration of the medium was reduced to physiologic levels the GGT-positive cells had a growth advantage. Further investigation revealed that the medium of the GGT-negative Hepa 1-6 cells contained glutathione that had been excreted by the cells, but no glutathione was present in the medium of the GGT-positive cells. We have previously shown that expression of GGT enables cells to use extracellular glutathione as a source of cysteine (Hanigan and Ricketts, Biochem., 32:6302, 1993). These new data reveal that physiologic levels of cysteine can be limiting for cell growth and expression of GGT can provide the cells with a selective growth advantage. These data explain the observation that cells transfected with GGT grow at the same rate as the GGT-negative controls in tissue culture medium which contains a high level of cysteine, but the GGT-positive cells grow more rapidly than the GGT negative cells when transplanted into animals (Warren et al., Proc. Soc. Exp. Biol. Med., 202:9, 1993). GGT-positive tumor cells have a selective growth advantage in vivo in comparison to GGT-negative tumor cells because they are able to use serum glutathione as a secondary source of cysteine thereby overcoming the growth restriction imposed by serum levels of cysteine. PMID- 7859347 TI - Inhibition of tumor promotion in benzo[a]pyrene-initiated CD-1 mouse skin by crocetin. AB - The effects of topical application of crocetin on 12-O-tetradecanoylphorbol-13 acetate (TPA)-induced promotion of skin tumors, hyperplasia, hydrogen peroxide, ornithine decarboxylase (ODC) and inflammation were evaluated in female CD-1 mice. Topical application of crocetin (0.2 or 1.0 mumol) with TPA (15 nmol) twice weekly for 20 weeks to mice previously initiated with benzo[a]pyrene (B[a]P) inhibited the number of TPA-induced tumors per mouse by 69 and 81% respectively. Pre-application of the same amount of crocetin also afforded significant protection against TPA-induced hyperplasia in the ear skin. Topical application of crocetin inhibited tumor promoter-caused induction of epidermal ODC activity by TPA (5 nmol). The topical application of crocetin (0.2 or 1.0 mumol) inhibited TPA-induced edema of mouse ears by 76 and 87% respectively. Pretreatment of mouse skin with various amounts of crocetin caused inhibition of hydrogen peroxide and myeloperoxidase production by TPA. These results indicate that crocetin possesses potential as a cancer chemopreventive agent against tumor promotion. PMID- 7859348 TI - Mechanisms involved in the immortalization of mammalian cells by ionizing radiation and chemical carcinogens. AB - Immortalization is a prerequisite for the clonal evolution and malignant transformation of normal mammalian cells in culture. In order to gain a mechanistic insight into the genetics of carcinogen-induced cellular immortality, a cell culture assay has been developed based on the use of freshly explanted Syrian hamster dermal (SHD) fibroblasts. The relative efficacies of a variety of chemical and physical carcinogens at immortalizing SHD cells (against a zero background of spontaneous immortalization) were compared. Ionizing radiation and nickel chloride appeared to be more effective as immortalizing agents than powerful point mutagens, suggesting (but not proving) that clastogenic damage may be more significant in the immortalization process than point mutation. Frequencies of induced immortality (10(-6)-10(-7)/treated cell) were arguably consistent with a direct mutational mechanism involving a single genetic target. However, detailed cytogenetic characterization of a panel of newly immortalized cell lines revealed no non-random chromosomal alterations in the cells at the level of G-banding. Furthermore, additional experiments with the SHD system have provided confirmatory evidence that immortalization can occur as an indirect consequence of carcinogen exposure following an induced high frequency change in the treated population, rather than through direct targeted mutagenesis. Previous somatic cell genetic studies have suggested the possibility that a target gene for immortalization exists on the human and Chinese hamster X chromosomes. Here we provide strong evidence that the normal SHD X chromosome displays powerful senescence-inducing properties when introduced, by microcell transfer, into newly immortalized SHD recipients. These results suggest that induction of the immortal phenotype in SHD cells by carcinogens results primarily from functional inactivation of a senescence gene which may be X-linked. One possible mechanism for senescence gene inactivation consistent with our observations is through a sub-microscopic interstitial genetic deletion. However, the considerable efficacy of nickel (a human carcinogen) as an immortalizing agent at nonmutagenic doses raises the alternative possibility that immortalization may occur through an epigenetic mechanism. PMID- 7859349 TI - Urine of tobacco/areca nut chewers causes genomic damage in Chinese hamster ovary cells. AB - The chromosome-damaging effects of urine concentrates (UCs) from tobacco plus areca nut (T/AN) chewers (a highly popular habit and a major risk factor for oral cancer in India) were evaluated on Chinese hamster ovary (CHO) cells employing two cytogenetic end-points, namely chromosome aberration (CA) and sister chromatid exchange (SCE) frequencies. Urine creatinine levels were comparable between controls and T/AN chewers. CA and SCE frequencies in CHO cells were found to be elevated significantly (P < 0.001) following treatment with UCs prepared from T/AN chewers (UC-T/AN chewers) as well as with UCs of non-chewer controls (UC-control subjects). Moreover, elevation of these two parameters by UC-T/AN chewers was significantly higher in comparison to that of UC-controls. The results of the present study indicated that besides the oral cavity, which is a target organ for T/AN chewers, mutagens/carcinogens in tobacco and areca nut might be playing a causative role in cancer of the urinary bladder as well. PMID- 7859350 TI - The effect of fibre source and fermentation on the apparent hydrophobic binding properties of wheat bran preparations for the mutagen 2-amino-3,8- dimethylimidazo[4,5-f]quinoxaline (MeIQx). AB - Preparations of dietary fibre have an ability to bind potentially toxic compounds in vitro, but it is unclear how the measured binding properties are a reflection of either the relative affinity of such compounds for fibre or the saturation binding capacity of the fibre. Cooking and processing of foods and fermentation activity in the colon can result in significant modification of the structure of the fibre matrix. Hence, binding properties measured in vitro may be significantly altered from those at the proposed site of fibre activity. Using cell wall material (CWM) prepared from three distinct wheat fibre sources, the effects of fermentation have been monitored and the consequences on the binding properties assessed. The CWM preparations were feremented for either 0, 6, 18 or 24 h in vitro, using a human faecal inoculum. The coarse bran CWM was also subjected to a simulated gastric treatment. Fermentation resulted in a loss of material from each CWM preparation, the loss being consistent with the bran source, and the maximum extent of fermentation was reached within 18 h. The in vitro binding of the mutagen 2-amino-3,8- dimethylimidazo[4,5-f]quinoxaline (MeIQx) to the unfermented and fermented fibre fractions showed fine bran CWM had a much higher affinity for MeIQx than coarse bran. A 6 h fermentation had little effect on the binding affinity to fine bran, but the affinity for coarse bran became similar to that of the fine bran. Further fermentation for 18 h or 24 h resulted in a further slight increase in the binding affinity for coarse and fine bran, but, more significantly, the binding capacity of each was increased. The binding properties of the beeswing bran were not significantly affected by fermentation. Wheat bran has the potential to bind hydrophobic mutagens in the diet and this potential can be enhanced after fermentation under colonic conditions. PMID- 7859351 TI - Chemoprevention of 2-amino-1-methyl-6-phenylimidazo[4,5-b]-pyridine (PhIP) induced mammary gland carcinogenesis by antioxidants in F344 female rats. AB - Chemopreventive effects of the antioxidants 1-O-hexyl-2,3,5- trimethylhydroquinone (HTHQ), 3-O-ethylascorbic acid (EAsA), 3-O dodecylcarbomethylascorbic acid (DAsA), green tea catechins (GTC) and ellagic acid on 2-amino-1-methyl-6- phenylimidazo[4,5-b]pyridine (PhIP)-induced mammary carcinogenesis were examined in female F344 rats. Groups of 20-21 6-week-old rats were maintained on a powdered diet containing 0.02% PhIP alone, PhIP together with 0.5% HTHQ, 1% EAsA, 1% DAsA, 1% GTC or 0.1% ellagic acid, these antioxidants alone or basal diet alone without supplement for 52 weeks. The survival rates of PhIP plus antioxidant groups at the end of the experiment were higher than that of the PhIP alone group. Sequential observation of palpable mammary tumors demonstrated only one tumor by week 52 in the PhIP plus HTHQ group, whereas 40% of the rats receiving PhIP alone had tumors by this time point. The final incidence of mammary adenocarcinomas was significantly decreased in the PhIP plus HTHQ group (4.8%, P < 0.01) as compared to the PhIP alone value (40%). Although statistically not significant, incidences of adenocarcinomas in the other antioxidant-treated groups (23.8-28.6%) were also lower than in the PhIP alone group. Furthermore, the incidence of large intestinal tumors in the PhIP plus HTHQ group (0%) showed a tendency to decrease relative to the PhIP alone group (16.7%). These results indicate that antioxidants, particularly HTHQ, exert a potent chemopreventive action against PhIP-induced carcinogenesis. PMID- 7859352 TI - A comparison of lymphocyte micronuclei and plasma micronutrients in vegetarians and non-vegetarians. AB - We performed a biochemical and cytogenetic epidemiological study to establish if there are significant differences between vegetarians (V) and non-vegetarians (NV) in their peripheral blood lymphocyte micronucleus (MN) index, which is a measure of chromosome damage rate. The levels of plasma vitamin C (VIT-C), vitamin E (VIT-E), vitamin B12 (B12) and folic acid were also analysed to assess if differences in chromosome damage rates were associated with these potentially antimutagenic micronutrients. Volunteers were classified as either 'vegetarian' if they had abstained from eating any flesh foods for at least 3 years prior to the study or 'non-vegetarian' if they consumed meat or meat products at least 5 days/week for at least 3 years before participation in the study. The volunteers in the study consisted of 47 male and 79 female V and 66 male and 72 female NV, all of whom were non-smokers for at least 3 years prior to the study. The age of the volunteers varied between 20 and 89 years. There was no significant difference in the slope of the age-related increase in MN index of V and NV of either sex. However, the MN index was significantly lower in NV males in the age group 20-40 years and significantly lower for V males in the 41-60 years age group. No difference between the MN index of older males was detectable and there also was no difference in the MN index of V and NV females across all age groups. V were generally found to have significantly higher plasma levels of VIT-C and folic acid, significantly lower levels of B12, and similar levels of VIT-E when compared with NV. VIT-C correlated positively with MN index in young males, but the reverse was true for B12. In young females folate and B12 appeared to correlate negatively with MN index. VIT-E had no apparent impact on MN index. These data suggest that the level of folate and B12 may be more important than VIT-C or VIT-E in minimizing chromosome damage rates in human lymphocytes. Overall, the data from this study do not support the hypothesis that V have a lower genetic damage rate than NV. PMID- 7859353 TI - Hormonal regulation of sex differentiated parameters in liver nodules from rats treated in the resistant hepatocyte model. AB - Sex differentiation of liver functions has been shown to be attenuated in preneoplastic rat liver nodules. The present study was performed to investigate whether nodules from male rats are to some extent withdrawn from the normal growth hormone (GH) regulation of these functions. Male and female Wistar rats were treated according to a modified resistant hepatocyte model (RH-model), with diethylnitrosamine initiation and promotion with intragastric administration of 2 acetylaminofluorene (2-AAF) combined with partial hepatectomy (PH). Eleven months post-initiation male rats were treated with either human (hGH) or bovine growth hormone (bGH) or ovine prolactin (oPRL) by continuous infusion for 1 week. The mRNA expression of a number of genes known to be sex differentiated in liver from adult control rats was compared in nodular and surrounding tissue from nodule bearing male, female and hormone-treated male rats. The basal mRNA expression of the female-predominant cytochrome P4502C12 (CYP2C12) was increased and the male predominant CYP2C11 was decreased in liver nodules from male rats compared with the surrounding liver. Expression of the prolactin receptor (PRL-r; female > male) and the steroid 5 alpha-reductase (female > male) genes was decreased in male nodules, whereas no difference was observed with respect to GH-receptor (GH r; female > male) expression in nodules versus surrounding tissue. Early nodules obtained from males treated according to the original RH-model (dietary 2-AAF, 0.02%) and isolated 2 weeks after completion of the 2-AAF/PH treatment showed significantly lower GH-r mRNA levels than the total liver tissue. In hepatocellular carcinomas from hormonally unmanipulated males 11 months post initiation the decrease in PRL-r expression was even more pronounced than in the nodules and a significant decrease in GH-r expression was seen. In female nodules the only significant difference with respect to the sex differentiated parameters was a lower 5 alpha-reductase expression than in the surrounding tissue. Continuous infusion of both hGH and bGH feminized the expression of all the sex differentiated genes in male tissues and eliminated the previously detected differences between nodules and surrounding tissue. oPRL also eliminated the differences between nodules and surrounding tissue in males and partly feminized the expression of both the 5 alpha-reductase and the PRL-r genes.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7859354 TI - Synergistic effects of chlordane and TPA in multistage morphological transformation of SHE cells. AB - The cyclodiene pesticide chlordane has been reported to be a non-genotoxic carcinogen in rodents. The effects of chlordane on SHE cell transformation were investigated in this study. It appeared that chlordane exhibited a weak transforming activity when applied repeatedly at 8 micrograms/ml. No effect resulted from the combination of benzo[a]pyrene-chlordane. In contrast, chlordane in the range 5-20 micrograms/ml and 12-O-tetradecanoylphorbol-13-acetate (TPA) (0.1 micrograms/ml) highly potentiated each other when applied sequentially. The synergistic effects could be inhibited by dexamethasone. These results led us to study the genotoxicity of chlordane on SHE cells: no DNA adduct formation could be detected in SHE cells treated with chlordane at a concentration potentiating the transforming effect of TPA. We also confirmed that this pesticide markedly inhibited intercellular communication between SHE as well as V79 cells. These results support literature data on the non-genotoxicity of chlordane. Overall, this study highlights the fact that interaction between-non genotoxic carcinogens may enhance the transformation frequency of SHE cells. Thus, combined effects must be taken into account in the evaluation of carcinogenic risk. PMID- 7859355 TI - Use of HT-29, a cultured human colon cancer cell line, to study the effect of fermented milks on colon cancer cell growth and differentiation. AB - Epidemiological and in vivo and in vitro experimental studies have suggested that fermented milks may interfere with the emergence and/or the development of colon cancer. The results, however, remain inconclusive. This prompted us to develop a new approach based on the use of HT-29, a cultured human colon cancer cell line, to study at the cellular level the effect of fermented milks on colon cancer cell growth and differentiation characteristics. Undifferentiated HT-29 cells have been grown in the continuous presence of milks fermented by one of the following bacterial populations: Lactobacillus helveticus, Bifidobacterium, L.acidophilus or a mix of Streptococcus thermophilus and L. bulgaricus. Penicillin G was added to the cell culture medium, resulting in a complete blockade of bacterial growth without significant effect on bacterial viability. One out of the four bacteria species studied, namely L.acidophilus, was without effect on both cell growth and differentiation. The three other bacterial strains induced a significant, although variable, reduction in the growth rate of HT-29 cells, which resulted in a 10-50% decrease in the cell number at steady-state (i.e. at cell confluency). The most efficient strains in lowering the HT-29 growth rate were L. helveticus and Bifidobacterium. Concomitantly, the specific activities of dipeptidyl peptidase IV (DPP IV), a sensitive and specific marker of HT-29 cell differentiation, and that of three other brush border enzymes (sucrase, aminopeptidase N and alkaline phosphatase) were significantly increased, thus suggesting that these cells may have entered a differentiation process. Altogether, these results indicate that the use of cultured colon cancer cells may be a useful tool to further study the effect of fermented milks on colon cancer and that bacterial strains may exert a different and specific effect on cancer cell growth and differentiation when used in fermented milk products. PMID- 7859356 TI - Improvements in the analytical method for 8-hydroxydeoxyguanosine in nuclear DNA. AB - Modifications at two points in the sequence of 8-hydroxy-2'-deoxyguanosine (8-OH dG) analysis have contributed to a more accurate and simplified determination of 8-OH-dG in DNA. The first was an improvement in the detection limit for 8-OH-dG in high-performance liquid chromatography analysis and the second was a pronase digestion and ethanol precipitation method (pronase/ethanol method) for DNA isolation which could minimize artificial formation of 8-OH-dG. Since the changes in background current from electrochemical detection are regularly periodical, it was possible to reduce this background change by connecting a pressure damper, degassing the eluent before use and finally subtracting its theoretical function. After this background correction, the detection limit for 8-OH-dG was improved one order of magnitude, from 20 fmol (5.68 pg) to 1.76 fmol (0.5 pg). Therefore, 0.005 8-OH-dG/10(5) dG can be detected from 50 micrograms DNA. This improvement will allow the analysis of small samples, tissues from needle biopsies, < 5 ml whole blood, etc., and will contribute to the accuracy of 8-OH-dG measurements. The pronase/ethanol method resulted in lower levels of 8-OH-dG than the phenol method in analyses of both rat liver and calf thymus DNA, even after 6 h incubation at 45 degrees C. The level obtained by the pronase/ethanol method with butylated hydroxytoluene was approximately equal to or lower than the 8-OH-dG levels reported in normal rat liver. The pronase/ethanol method for DNA isolation can replace the phenol or other methods in 8-OH-dG analysis. This method also omits the use of highly toxic organic solvents. PMID- 7859357 TI - Evaluation of dose and treatment duration on the esophageal tumorigenicity of N nitrosomethylbenzylamine in rats. AB - N-Nitrosomethylbenzylamine (NMBA) is a potent esophagus-specific carcinogen that has been utilized extensively in the study of esophageal carcinogenesis in rats. While many studies have focused on the pathogenesis of NMBA-induced esophageal tumors, the tumorigenicity of NMBA itself has not been thoroughly investigated in any single, systematic dose-response study. Therefore, in this study we evaluated NMBA tumorigenicity in rats following various short-term s.c. treatment regimens with the aim of developing an abbreviated treatment protocol which could be used in future studies. To assess the possible correlation of basal cell proliferation with NMBA tumorigenicity, we evaluated the expression of proliferating cell nuclear antigen (PCNA) in both control and NMBA-treated rats. In rats which received a cumulative NMBA dosage of 7.5 mg/kg over the course of 5 weeks, tumor incidence and multiplicity were as follows: 40% with 0.4 +/- 0.3 tumors/rat at week 10; 100% with 2.2 +/- 1.0 tumors/rat at week 20; and 100% with 2.3 +/- 1.0 tumors/rat at week 30. These rats exhibited marked increases in basal cell labeling, with indices that were 1.5- to 1.8-fold higher than controls. NMBA treatment regimens of shorter duration with equivalent or higher cumulative dosages were generally ineffective in producing esophageal tumors, even though significantly elevated levels of basal cell proliferation occurred. Together, these findings indicate that the duration of NMBA treatment is of critical importance in the tumorigenic potential of the carcinogen. PMID- 7859358 TI - Mutational spectrum of X-ray induced TK- human cell mutants. AB - Mutations induced by ionizing radiation have historically elicited significant public concern. However, only a limited database of ionizing radiation-induced point mutations is available, particularly at endogenous human cell loci. Here, we report the mutational spectrum for 184 X-ray induced TK- mutants derived from TK6 human lymphoblasts. This report represents the first large scale utilization of the tk locus for investigation of mutational specificity at the DNA sequence level. Rapid, single nucleotide sequencing assays at frameshift polymorphism sites in tk exons 4 and 7 were used to partition TK- mutants into two groups: 126 were attributed to either partial gene deletion or to loss of heterozygosity, and DNA sequence alterations were identified for 51. X-ray-induced point mutations included all classes of transitions and transversions, tandem base substitutions, frameshifts, small deletions and a small duplication. The distribution within tk was characterized by clustering at some sites. Twelve TK- point mutations, including five entirely within the coding sequence in exons 3 and 4, resulted in aberrant splicing of the tk transcript. The spectrum of X-ray-induced point mutations was found to be highly reproducible when TK- mutations were compared with HPRT- mutations in TK6. A statistically significant decrease in transitions (P = 0.04) was observed in the combined data set as compared to the spontaneous background. These findings suggest a reproducible pattern which may be utilized in recognizing radiation-induced mutations at other loci of interest. PMID- 7859359 TI - Cell type-specific expression of human 8-oxo-7,8-dihydroguanosine triphosphatase in normal breast and skin tissues in vivo. AB - 8-Oxo-7,8-dihydroguanosine triphosphate (8-oxo-dGTP) is formed from the oxidation of GTP in the nucleotide pools of cells during normal cellular metabolism and from exogenous sources. 8-Oxo-dGTP is a potent mutagenic substrate for DNA synthesis causing transversion mutations. In human cells this oxidized base is hydrolyzed to 8-oxo-7,8-dihydroguanosine monophosphate by 8-oxo-7,8 dihydroguanosine triphosphatase (8-oxo-dGTPase) to prevent the misincorporation of 8-oxo-dGTP into cellular DNA. In order to better understand specific human tissue and cell type responses to oxidative stress, we used colorimetric in situ hybridization, with an 8-oxo-dGTPase-specific antisense oligomer probe, to map, for the first time, the cellular distribution of 8-oxo-dGTPase mRNA in tissue sections of normal neonatal foreskin and adult human breast tissues. Paraffin embedded tissue sections were hybridized with a digoxigenin-labeled 39 base oligomer, antisense to 8-oxo-dGTPase cDNA. Hybridization of the probe to cells expressing the 8-oxo-dGTPase gene was visualized following immunodetection with an alkaline phosphatase-conjugated anti-digoxigenin antibody. Following color development, we were able to simultaneously identify tissue architecture and cell types with expression of the 8-oxo-dGTPase gene. There was no hybridization specific color when sections were 'mock' hybridized, hybridized with a sense probe or treated with RNase. In skin dermis, fibroblasts express high levels of 8 oxo-dGTPAse mRNA. Within the epidermis, a gradient of expression was observed, from high to moderate levels in the replicating basal epithelial cells to undetectable in the non-mitotic suprabasal and granular epithelial cells. In the breast tissue, fibroblasts in the loosely connective tissue and myoepithelial cells expressed high levels of 8-oxo-dGTPase mRNA, while expression in the luminal epithelial cells was not detectable. Our data suggest that expression of 8-oxo-dGTP is heterogenous between cell types within an organ and may help to explain cell type-specific responses to oxidative stress, especially in replicating and potentially replicating cells with low levels of this protective protein. PMID- 7859360 TI - Short-term carcinogenesis bioassay of genotoxic procarcinogens in PIM transgenic mice. AB - E mu-pim-1 transgenic mice, which overexpress the pim-1 oncogene in lymphoid tissues, have shown increased susceptibility to induction of T cell lymphomas by N-ethyl-N-nitrosourea, a direct-acting chemical carcinogen (Nature, 340, 61-63, 1989). We sought to further evaluate E mu-pim-1 transgenic mice as a potential test animal for a short-term carcinogenesis bioassay. We chose to test four genotoxic procarcinogens; 2-acetylaminofluorene (2-AAF), N-nitro-sodiethylamine (NDEA), 1,2-dichloroethane (1,2-DCE) and benzene (BEN). These compounds require metabolic activation and, with the exception of benzene, are not mouse lymphomagens. Compounds were administered by gavage daily for 38 (NDEA and 2-AAF) or 40 (BEN and 1,2-DCE) weeks to groups of 25-29 male and female PIM mice at 1 and 3 mg/kg for NDEA, 50 and 100 mg/kg for BEN, 25-100 mg/kg for 2-AAF and 100 300 mg/kg for 1,2-DCE. Small but statistically significant increases in the incidence of malignant lymphoma were seen for three of the four carcinogens tested; in high dose males treated with 2-AAF, high and low dose females treated with NDEA and high dose females treated with 1,2-DCE. Results for BEN, the only mouse lymphomagen tested, did not show a statistically significant increase in the incidence of malignant lymphomas in transgenic mice within the 40 week duration of the study. NDEA also produced a high incidence (> 70%) of hepatic hemangiosarcomas in both sexes at the low and high dose levels. These results demonstrate that over-expression of the pim-1 oncogene in lymphoid tissue can confer susceptibility of this tissue to chemical carcinogenesis by genotoxic procarcinogens. However, whereas potent genotoxic carcinogens produced only small increases in the incidence of lymphoma and since BEN, a mouse lymphomagen, was negative, PIM transgenic mice may lack sufficient sensitivity to established carcinogens to justify their routine use in a short-term carcinogenesis screening assay. PMID- 7859361 TI - Detection of deoxyadenosine-4-aminobiphenyl adduct in DNA of human uroepithelial cells treated with N-hydroxy-4-aminobiphenyl following nuclease P1 enrichment and 32P-postlabeling analysis. AB - To characterize the DNA adducts in human uroepithelial cells (HUC) exposed to 4 aminobiphenyl and its proximate N-hydroxy metabolites, we used 32P-postlabeling analyses following butanol extraction of the DNA hydrolysates. Using this method, we identified N-(deoxyguanosin-3',5'-bisphospho-8-yl)-4-aminobiphenyl (pdGp-ABP) as a major adduct and N-(deoxyadenosin-3',5'-bisphospho-8-yl)-4-aminobiphenyl (pdAp-ABP) as a minor adduct in an immortalized non-tumorigenic cell line of HUC following exposure to N-hydroxy-4-aminobiphenyl (N-OH-ABP). Towards characterization of pdAp-ABP, we postlabeled the synthetic N-(deoxyadenosin-3' phospho-8-yl)-4-aminobiphenyl (dAp-ABP) adduct to generate pdAp-ABP and determined its chromatographic (TLC and HPLC) properties and sensitivity to nuclease P1 digestion. In contrast to pdGp-ABP, which was cleaved to the corresponding 5'-monophosphate by nuclease P1, the pdAp-ABP adduct was unaffected when incubated with nuclease P1 under similar conditions. To test whether nuclease P1 digestion could be adopted for enrichment of the dAp-ABP adduct in HUC samples, postlabeling analyses were carried out after butanol extraction following nuclease P1 digestion of the DNA hydrolysate. Under these conditions, the pdAp-ABP adduct was detected in DNA from HUC E7 cells treated with N-OH-ABP and in calf thymus DNA reacted with N-OH-ABP under acidic (pH 5.0) conditions. These data indicate that pdGp-ABP and pdAp-ABP adducts are generated in HUC E7 on treatment with N-OH-ABP and that nuclease P1 enrichment may provide a method for qualitative and quantitative analyses of the pdAp-ABP adduct in DNA. PMID- 7859362 TI - A unique pattern of hepatocyte proliferation in F344 rats following long-term exposures to low levels of a chemical mixture of groundwater contaminants. AB - Most exposures of humans to environmental agents involve mixtures of chemicals, rather than individual chemicals. Some chemicals can cause hepatocellular proliferation and act as neoplastic promoters. Little is known concerning hepatocellular proliferation caused by chemical mixtures such as those found in groundwater at hazardous waste sites. Therefore, a 6 month study was performed to investigate hepatocellular proliferation and histopathological changes in F344 rats after long-term, low-level exposure to a mixture of groundwater contaminants. The seven chemicals used are among the most frequently detected contaminants associated with hazardous waste sites; arsenic, benzene, chloroform, chromium, lead, phenol and trichloroethylene. Male F344 rats were exposed to this mixture, or submixtures of the organic or inorganic chemicals, via drinking water for 6 months. The study design included a time-course experiment (i.e. 3 and 10 days and 1, 3 and 6 months) and a dose-response experiment. Hepatocellular proliferation studies were performed by subcutaneously implanting osmotic mini pumps to continuously deliver 5-bromo-2'-deoxyuridine for 7 days, which labeled nuclei of proliferating cells. In all groups, there were no differences in weight gain, body weight, liver weight ratios or liver-associated plasma enzymes. Light microscopic evaluation revealed no lesions related to the treatments in any animals. However, significant increases in hepatocellular labeling were observed at the 3 and 10 day and 1 month exposure time points after treatment with the full mixture, as well as the organic or inorganic submixtures. Proliferating hepatocytes expressed a unique labeling pattern surrounding large hepatic veins (0.5-2.0 mm), but not central veins. This did not appear to be a regenerative response due to cytotoxic mechanisms, as assessed by the absence of increased plasma enzyme activity and the absence of hepatocellular lesions. PMID- 7859363 TI - Inhibition of gap junctional intercellular communication and malignant transformation of rat liver epithelial cells by neu oncogene. AB - A retrovirus containing a neu oncogene was introduced into a Fischer F344 rat liver epithelial cell line (WB-F344) to study the effect of the expression of neu oncoprotein on gap junctional intercellular communication (GJIC), the ability to form colonies in soft agar and the ability to form tumors in rat liver by these cells. After viral infection, five different neu-transduced epithelial clones were randomly selected for further analysis. Southern blot analysis of HindIII digested genomic DNA hybridized with a neu-specific probe indicated that the neu oncogene carried by the retrovirus was integrated into different chromosomal locations in the five different neu-transduced WB cell lines. Using the fluorescence recovery after photobleaching (FRAP) assay, we found that GJIC was significantly reduced in neu-transduced WB clones, compared with control virus infected and parental WB cells. Western blot analysis of connexin 43 in the neu transduced cell lines showed altered phosphorylation patterns compared with the normal WB-rat liver cell line. Confocal image analysis of the neu-transduced cells showed that the connexin 43 protein, as detected by fluorescent immunostaining, was localized in the cell nucleus. The neu-transduced WB cell lines also acquired the ability to grow in soft agar. Furthermore, cells from three of the five neu-transduced cell lines, when injected into the liver of Fischer F344 rats through the portal vein, were highly tumorigenic (multiple focal hepatic tumors developed within 2 weeks). Cells derived from the tumor were shown to be G-418 resistant, demonstrating that the tumor was derived from the injected WB-neu cells. The results of this study demonstrate that the expression of the neu oncogene is able to block GJIC and to induce tumorigenicity in the rat liver WB-F344 cell line. PMID- 7859364 TI - The effect of iron binding on the ability of crocidolite asbestos to catalyze DNA single-strand breaks. AB - Crocidolite or crocidolite pretreated with desferrioxamine-B (DF crocidolite) was exposed to ferrous chloride solutions to determine whether iron could be bound from solution. Native crocidolite was capable of binding up to 57 nmol Fe2+/mg fiber in 60 min, while the DF crocidolite was capable of binding only 5.5 nmol Fe2+/mg fiber. The rate of iron binding for the first 5 min of exposure was independent of the concentration of iron in the solution, suggesting that there was a group of rapidly saturable sites, approximately 1.5 x 10(18) binding sites/m2 crocidolite surface, which were responsible for the immediate binding. This process was followed by a slower binding phase, likely occurring at other sites. Crocidolite and DF crocidolite, with various amounts of iron bound, were assayed for their abilities to catalyze the formation of DNA single-strand breaks (SSBs) in phi X174 RFI DNA. Native crocidolite with additional iron bound did not significantly change in its ability to cause DNA SSBs in 15 or 30 min incubations, even though more iron could be mobilized from the iron-treated crocidolite at 4 or 24 h. DF crocidolite, after the addition of iron, had a significantly increased ability to form DNA SSBs. DF crocidolite with 0, 3.0 or 5.5 mmol Fe2+/mg catalyzed the formation of DNA SSBs in 21, 42 or 51% of the DNA respectively in the presence of EDTA and ascorbate. Fibers were also incubated in tissue culture medium with or without iron salts. The fibers incubated in the iron-containing medium had an increased ability to form DNA SSBs. These results suggest that fibers such as crocidolite may be capable of binding iron from intracellular sources. This additional iron may be as reactive as the intrinsic iron and may increase the reactive lifetime of the fiber. PMID- 7859365 TI - Effects of prolonged (1 year) choline deficiency and subsequent re-feeding of choline on 1,2-sn-diradylglycerol, fatty acids and protein kinase C in rat liver. AB - Rats fed a choline-deficient diet develop foci of enzyme-altered hepatocytes with subsequent formation of hepatic tumors. They also develop fatty livers, because choline is needed for hepatic secretion of lipoproteins. We have previously reported that 1,2-sn-diradylglycerol accumulates in the livers of rats fed a choline-deficient diet for 1-27 weeks, and that protein kinase C activity in the hepatic plasma membrane is elevated during that time (da Costa et al., J. Biol. Chem., 268, 2100-2105, 1993). In the present study, we examined the changes that occur in rat liver at 52 weeks of choline deficiency and determined whether these changes were reversible when choline was returned to the diet of the deficient animals for 1 or 16 weeks. At 52 weeks, non-tumor liver samples from the experimental animals had increased 1,2-sn-diradylglycerol concentrations in the lipid droplets compared with control animals. Plasma membrane 1,2-sn diradylglycerol levels in the liver did not differ between the two groups, but an age-related increase in membrane 1,2-sn-diradylglycerol concentrations was observed. Unsaturated free fatty acids, another activator of protein kinase C, accumulated in the deficient livers. Protein kinase C activity associated with the plasma membrane remained significantly elevated at 52 weeks in deficient livers. Hepatic foci expressing gamma-glutamyltranspeptidase were detected only in the deficient rats (0.83% of liver volume) and 15% of these rats had hepatocellular carcinoma at 1 year on the diet. At 53 weeks (1 week after choline was returned to the deficient group), 1,2-sn-diradylglycerol concentrations in the lipid droplets and hepatic free fatty acids had dropped to control levels. By 68 weeks (16 weeks of re-feeding choline), the membrane protein kinase C activity had returned to normal. At this time, 14% of the experimental animals had hepatocellular carcinoma. We suggest that choline deficiency altered the protein kinase C-mediated signal transduction within liver and this contributed to hepatic carcinogenesis in these animals. PMID- 7859366 TI - Oxidative DNA damage induced by potassium bromate under cell-free conditions and in mammalian cells. AB - The oxidative DNA damage induced by the renal carcinogen potassium bromate (KBrO3) in cultured mammalian cells and in a cell-free system was characterized by means of various repair endonucleases. Under cell-free conditions, no modifications were induced by KBrO3 alone, but extensive DNA damage was observed in the presence of glutathione (GSH). The DNA damage was found to consist mostly of base modifications sensitive to Fpg protein (formamidopyrimidine-DNA glycosylase). HPLC analysis demonstrated that many of the modifications were 7,8 dihydro-8-oxoguanine(8-hydroxyguanine) residues. Single-strand breaks, sites of base loss (AP sites) and base modifications sensitive to endonuclease III (5,6 dihydropyrimidine derivatives) were formed in only low amounts. This 'damage profile' and experiments with various scavengers (catalase, superoxide dismutase, deferoxamine, azide, tert-butanol) and D2O as solvent excluded the involvement of hydroxyl radicals and single oxygen in the damage production, but were consistent with a radical mechanism involving bromine radicals. In L1210 mouse leukemia cells and LLC-PK1 porcine kidney cells, KBrO3 alone gave rise to a DNA damage profile similar to that observed after treatment of cell-free DNA with KBrO3 plus GSH, i.e. base modifications sensitive to Fpg protein were formed in high excess of all other lesions quantified. In LLC-PK1 cells (derived from the target organ of KBrO3-induced carcinogenesis) the level of DNA damage was twice that in the L1210 cells. DNA damage was partially prevented by depletion of intracellular GSH with diethylmaleate, indicating that GSH played an activating role in the cells similar to that seen under cell-free conditions. The Fpg-sensitive base modifications induced by KBrO3 were repaired with only moderate efficiency (38 +/ 10% of the lesions were still present after 18 h in full medium) under conditions that did not influence cell proliferation. PMID- 7859367 TI - Urinary and urothelial effects of sodium salts in male rats. PMID- 7859368 TI - Metal-mediated oxidative damage to cellular and isolated DNA by certain tryptophan metabolites. AB - The tryptophan metabolites 3-hydroxyanthranilic acid (3-HAA) and 3 hydroxykynurenine (3-HKyn) are carcinogens. DNA damage by 3-HAA and 3-HKyn in the presence of metal ions was investigated as a potential mechanism of their carcinogenicity. Pulsed field gel electrophoresis showed that in the presence of Mn(II), 3-HAA and 3-HKyn induced DNA double-strand breaks in cultured human cells. DNA single-strand breaks were observed with alkali treatment. The enhancing effect of catalase inhibitor and the inhibitory effect of o phenanthroline on the strand breakage indicated the involvement of H2O2 and endogenous transition metal ion. Damage to DNA fragments obtained from c-Ha-rds-1 protooncogene was investigated by a DNA sequencing technique. 3-HAA and 3-HKyn induced piperidine-labile sites frequently at thymine and guanine residues in the presence of Cu(II). The inhibitory effects of bathocuproine and catalase on Cu(II)-mediated DNA damage suggest that Cu(I) and H2O2 have important roles in the production of active species causing DNA damage. The Cu(II)-mediated DNA damage was enhanced by preincubation of 3-HAA with Mn(II). UV-visible spectroscopy showed that Mn(II) and Cu(II) enhanced the rate of autoxidation of 3 HAA in different ways. These results suggest that in the presence of Mn(II) or Cu(II), these tryptophan metabolites produce H2O2, which is activated by transition metal ion to cause damage to DNA both in the case of isolated DNA and cultured cells. PMID- 7859369 TI - Synthesis and characterization of covalent adducts derived from the binding of benzo[a]pyrene diol expoxide to a -GGG- sequence in a deoxyoligonucleotide. AB - Direct synthesis and purification procedures are described for the preparation of adducts derived from the covalent binding of 7R,8S-dihydroxy-9S,10R-epoxy 7,8,9,10-tetrahydro-benzo[a]pyrene [(+)-anti-BPDE or (+)-BPDE 2] to each of the three guanine residues (trans-N2-dG lesions) in the oligodeoxyribonucleotide d(CTATG1G2G3TATC). The positions of the modified Gs are defined by Maxam-Gilbert sequencing techniques. Six different oligonucleotides with one or two precisely positioned (+)-anti-BPDE residues are identified. The absorbance, circular dichroism and fluorescence characteristics are changed upon formation of duplexes with the complementary strands d(GATACCCATAG). In the doubly-modified oligonucleotides, a broad, excimer-like long wavelength fluorescence emission band is observed with a maximum near 455 nm only if the two (+)-anti-BPDE modified Gs are adjacent to one another. The covalently attached (+)-anti-BPDE residues decrease the thermodynamic stabilities of the duplexes; their melting points are markedly dependent on the position of the lesions, being highest with the (+)-anti-BPDE residue at G1 (Tm = 40 degrees C, only 2 degrees C lower than in the case of the unmodified oligonucleotide) and lowest when it is situated at G3 (Tm = 29 degrees C). The implications of these and other physical characteristics are discussed. The facile synthesis of these or similar site specific and stereochemically defined (+)-trans-anti-BPDE-N2-dG lesions in runs of contiguous guanines in oligodeoxyribonucleotides of specified base sequence should be useful for the design of site-directed mutagenesis studies in vitro and in vivo. PMID- 7859370 TI - Dose-response studies of MeIQx in rat liver and liver DNA at low doses. AB - 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) is a heterocyclic amine mutagen found in cooked meats and is carcinogenic in mice and rats at high doses (mg/kg body wt). Humans, however, are exposed to low amounts (p.p.b.) in the diet, and the effects caused by exposure to human equivalent doses of MeIQx have been difficult to determine accurately. We report on the effect of MeIQx exposure on liver bioavailability, hepatic DNA binding and MeIQx persistence in both liver tissue and liver DNA after acute (24 h), and subchronic (7 day and 42 day) exposures in male Sprague-Dawley rats. Male Sprague-Dawley rats were administered [2-14C]MeIQx either by gavage or in the diet for 1, 7 or 42 days (1 x 10(-6) mg/kg day up to 3.4 x 10(-2) mg/kg day dose) and the [2-14C]MeIQx was measured by accelerator mass spectrometry (AMS). Assessment of the kinetics of hepatic MeIQx DNA adduct formation over 42 days (1.1 x 10(-4) mg [2-14C]MeIQx kg daily dose) shows that steady-state [2-14C]MeIQx tissue concentrations of 138 +/- 15 pg/g liver and DNA adduct levels of 113 +/- 10 ag adduct/micrograms DNA were reached at 14-28 days and 28 days respectively. The relationship between administered dose and either hepatic MeIQx DNA adduct levels or MeIQx tissue levels are linear for the 24 h, 7 day and 42 day exposures. Furthermore, MeIQx adducts persist for at least 14 days after exposure ceases. These data suggest that bioavailability and DNA adduction by MeIQx increase linearly with increasing dose for both acute and subchronic exposures. These data also show that MeIQx DNA adducts are useful in predicting daily exposure and support a linear extrapolation in the risk assessment of MeIQx. However, the quantitative relationship between DNA adducts and tumor formation will also depend on the specific tissue and the subsequent steps needed for tumor progression. PMID- 7859371 TI - In vitro binding and functional studies comparing the human CYP1A1 negative regulatory element with the orthologous sequences from rodent genes. AB - In previous studies, we identified a 21 bp palindrome (-794 to -774) located within the negative regulatory element of the human CYP1A1 gene consisting of an 8 bp inverted repeat and 5 bp spacer. This element specifically binds protein(s) present in HepG2 nuclear extract preparations and is capable of down-regulating heterologous promoters and enhancers in transient expression assays. Conserved guanine/cytosine-rich regions which flank the palindrome also were implicated in this activity. In the present study, we examined similar regions from the rat ( 881 to -746) and mouse (-822 to -683) CYP1A1 genes for their ability to bind nuclear protein and down-regulate heterologous promoters and enhancers. These rodent DNA fragments contain the conserved guanine/cytosine-rich sequences, as well as half-sites similar to those found in the human CYP1A1 palindrome. However, each half-site is separated by approximately 40 bp. DNase I footprint analyses revealed the presence of rat and mouse nuclear proteins which gave a similar protection pattern as that observed with nuclear proteins from the human cell line, HepG2. Electrophoretic mobility shift assays with the human negative regulatory element demonstrated the formation of specific DNA-protein complexes with rat and mouse nuclear protein(s). Interestingly, two specific DNA-protein complexes were observed with rodent extracts as compared to the single specific complex seen with human extract. Specific binding was not observed with either the orthologous rat or mouse fragments using human or rodent extracts. In transient expression assays, the rat and mouse fragments were unable to down regulate enhancer/promoter activity. This absence of negative regulatory activity occurred whether transfections were performed in human, rat or mouse hepatoma cell lines. The human negative regulatory element, which was previously shown to down-regulate heterologous enhancers/promoters approximately 70% in human cells, did not exhibit this activity in rodent cell lines. UV cross-linking and southwestern blot analyses indicated a high degree of similarity between human and rodent NRE binding proteins, although some differences also were apparent. The possible implications of these findings with regards to species differences in the regulation of CYP1A1 expression are discussed. PMID- 7859372 TI - Effect of dietary retinyl palmitate on the promotion of altered hepatic foci by 3,3',4,4'-tetrachlorobiphenyl and 2,2',4,4',5,5'-hexachlorobiphenyl in rats initiated with diethylnitrosamine. AB - The purpose of this study was to determine the effects of dietary vitamin A on the tumor promoting effect of 3,3',4,4'-TCB and 2,2',4,4',5,5'-HCB in a two-stage rat hepatocarcinogenesis model with diethylnitrosamine (DEN, 150 mg/kg) as the initiator. Two weeks after DEN injection rats were fed a purified diet containing either 2000 or 100,000 IU of vitamin A in the form of retinyl palmitate. Rats received four biweekly injections of 3,3',4,4'-TCB, 2,2',4,4',5,5'-HCB (300 mumol/kg), or both (150 mumol/kg each) in corn oil (10 ml/kg) for 8 weeks. Control animals received vehicle only. Six rats in each group that received no DEN treatment were used as additional control animals. Ten days after the last injection the rats were killed. In rats fed the low retinyl palmitate diet, treatment with 3,3',4,4'-TCB, 2,2',4,4',5,5'-HCB or both compounds lowered hepatic retinyl palmitate content. This effect was prevented by high dietary retinyl palmitate supplementation in rats treated with 2,2',4,4',5,5'-HCB, but not 3,3',4,4'-TCB or both compounds together. Histopathological examination of the liver showed that high dietary retinyl palmitate lessened the severity of hepatocellular necrosis and fatty changes induced by 3,3',4,4'-TCB alone or in combination with 2,2',4,4',5,5'-HCB. The latter did not cause significant pathological lesions to the liver. However, high dietary retinyl palmitate was not able to prevent thymic involution caused by 3,3',4,4'-TCB. The number and volume of altered hepatic foci were increased by 2,2',4,4',5,5'-HCB and particularly 3,3',4,4'-TCB; no synergistic effect was seen. Supplementation with high dietary retinyl palmitate diminished the number and volume of foci. These results show that supplementation with high dietary retinyl palmitate protects against hepatocellular necrosis, fatty changes, and preneoplastic changes induced by 3,3',4,4'-TCB as well as against preneoplastic changes induced by 2,2',4,4',5,5'-HCB. In addition, these two agents did not synergistically induce preneoplastic changes in DEN-induced rats. PMID- 7859374 TI - Metabolic activation of the N-hydroxy derivative of the carcinogen 4 aminobiphenyl by human tissue sulfotransferases. AB - The role of human sulfotransferase(s) in the bioactivation of the N-hydroxy (N OH) metabolite of the human bladder carcinogen 4-aminobiphenyl (ABP) was investigated in vitro with human tissue cytosols. Using an enzymatic assay consisting of a PAPS-regenerating system, [3H]N-OH-ABP, calf thymus DNA and tissue cytosols, the sulfotransferase-mediated metabolic activation of N-OH-ABP was determined as the PAPS-dependent covalent binding of the N-OH substrate to DNA. With cytosols prepared from various tissues, we found that the sulfotransferase(s) in human liver, and to a lesser extent colon, can readily metabolize N-OH-ABP. No PAPS-dependent metabolic activation was detected with cytosols prepared from human pancreas or from the carcinogen target tissue, the urinary bladder epithelium. The N-OH-ABP sulfotransferase activities of liver and colon cytosols from different individuals were highly correlated with their thermostable phenol sulfotransferase (TS-PST) activity (liver, r = 0.99, P < 0.01; colon, r = 0.88, P < 0.01), but not with activities for the thermolabile phenol sulfotransferase (TL-PST; liver, r = 0.29; colon, r = 0.53), or for the dehydroepiandrosterone sulfotransferase (DHEA-ST; liver, r = 0.32; colon, negligible activity). N-OH-ABP sulfotransferase activity was highly sensitive to inhibition by a selective TS-PST inhibitor, 2,6-dichloro-4-nitrophenol (IC50 = 0.7 microM), and by p-nitrophenol, but was unaffected by competitive inhibitors of TL-PST (dopamine) or DHEA-ST (DHEA, DHEA-sulfate). The N-OH-ABP sulfotransferase activity also exhibited thermostability properties similar to that of the TS-PST. From these data, we conclude that human liver TS-PST but not TL-PST or DHEA-ST can metabolically activate the proximate human carcinogen N-OH ABP to a reactive sulfuric acid ester intermediate that binds covalently to DNA. In addition, in view of the putative role of N-OH-ABP as a major transport form of the carcinogen to the urinary bladder and of the absence of sulfotransferase activity in this tissue, we hypothesize that sulfotransferase activation in the liver may actually decrease the bioavailability of N-OH-ABP toward extrahepatic tissues and thus serve as an important overall detoxification mechanism for the urinary bladder. PMID- 7859373 TI - Cancer chemopreventive activity of brassinin, a phytoalexin from cabbage. AB - Brassinin [3-(S-methyldithiocarbamoyl)aminomethyl indole], a phytoalexin first identified as a constituent of cabbage, was synthesized and evaluated for cancer chemopreventive activity. Dose-dependent inhibition of 7,12 dimethylbenz[a]anthracene (DMBA)-induced preneoplastic lesion formation was observed with mouse mammary glands in organ culture, as was dose-dependent inhibition of DMBA-induced mouse skin tumors that were promoted by treatment with 12-O-tetradecanoylphorbol-13-acetate. Cyclobrassinin is a biologically derived product of the oxidative cyclization of brassinin, and was as active as the parent compound in inhibiting the formation of preneoplastic mammary lesions in culture; however, 2-methylbrassinin was not significantly active in this process. Therefore, oxidative cyclization may be an effective metabolic activation step. As judged by these tumor inhibition studies in conjunction with potential to induce phase II enzymes in mice or cell culture, brassinin may be effective as a chemopreventive agent during both the initiation and promotion phases of carcinogenesis. This is the first report documenting the chemopreventive potential of structurally novel indole-based phytoalexins that are naturally occurring in cruciferous vegetables, and the synthetic route described herein has proven amenable for scale-up production. The bifunctional structural nature of brassinin, bearing both an indole nucleus and a dithiocarbamoyl-aminomethyl moiety, is notably similar to the individual structural elements of other known chemopreventive agents such as indole-3-carbinol or benzylisothiocyanate. The favorable biological activity demonstrated by the compound may originate from the presence of these two moieties. PMID- 7859375 TI - Aflatoxin B1-induced 8-hydroxydeoxyguanosine formation in rat hepatic DNA. AB - A time- and dose-dependent increase in 8-hydroxydeoxyguanosine (8-OHdG) was observed in rat hepatic DNA after a single i.p. injection of aflatoxin B1 (AFB1). It was also found that pre-treatment with selenium or deferoxamine significantly reduced 8-OHdG level in AFB1-administered rats. In contrast, no reduction in 8 OHdG concentration was found in vitamin E-pre-treated rats. These results provide evidence that AFB1 causes oxidative DNA damage in rat liver, which may involve hydroxyl radicals as the initiating species. It is postulated that AFB1-induced oxidative DNA damage (8-OHdG formation) may constitute an important pathway in AFB1 hepatocarcinogenesis. PMID- 7859376 TI - Solid matrix, room temperature phosphorescence identification and quantitation of the tetrahydrotetrols derived from the acid hydrolysis of benzo[a]pyrene-DNA adducts from human lung. AB - A new method, suitable for human biomonitoring, that uses room temperature phosphorescence for the detection of DNA damage by carcinogenic metabolites of polycyclic aromatic hydrocarbons is described. Samples of human lung DNA (1 mg) that had been subjected to immunoaffinity chromatography (anti-benzo[a]pyrene diol-epoxide deoxyguanosine monoclonal antibodies) were acid hydrolyzed (0.1 N HCl, 90 degrees C, 3 h) and the resulting DNA lung hydrolyzates separated by high performance liquid chromatography. Relevant fractions were combined with a solid matrix support which consisted of a mixture of alpha-cyclodextrin (alpha-CD):NaCl (1:9) or alpha-CD:TINO3: aNO3 (1:1:8). The dried and powdered sample-matrix material was analyzed by phosphorescence spectroscopy at room temperature. Certain fractions of human lung samples were found to contain materials that yielded phosphorescence spectra that were indistinguishable from those produced when an authentic r-7, t-8, t-9, c-10-tetrahydroxy-7,8,9,10 tetrahydrobenzo[a]pyrene reference standard was analyzed. The data confirm previous studies that have reported the presence of r-7, t-8 dihydroxy-t-9,10 epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene-DNA adducts in human tissues at levels of 1 adduct/10(7)-10(8) nucleotides. The alpha-cyclodextrin solid matrix, room temperature phosphorescence technique was performed with a commercially available instrument, but is 50 times more sensitive than the synchronous fluorescence spectroscopic technique previously used. PMID- 7859377 TI - Chemoprevention by S-adenosyl-L-methionine of rat liver carcinogenesis initiated by 1,2-dimethylhydrazine and promoted by orotic acid. AB - Chemoprevention of liver carcinogenesis by S-adenosyl-L-methionine (SAM) was studied in F344 male rats. The rats were given 1,2-dimethylhydrazine (1,2-DMH) 2 HCl (100 mg/kg, i.p.) 18 h after two-thirds hepatectomy. One week later they were fed a semisynthetic basal diet containing 1% orotic acid (OA) for 29 weeks. At this time the rats were transferred to the basal semisynthetic diet and were killed 3 weeks later. SAM treatment (384 mumol/kg/day, i.m.), was started 1 week after 1,2-DMH and was continued up to the end of the experiment. Controls received solvent alone. SAM exerted an inhibitory effect on the induction of preneoplastic and neoplastic lesions. For example, nodules with diameters of 1-2 and 2-6 mm exhibited a decrease in both incidence and number per liver, while no such inhibitory effect was seen in the category of larger nodules. Furthermore, hepatocellular carcinoma (HCC) also exhibited a decrease in the SAM-treated group. The number/liver and incidence were 0.04 and 4.8% respectively in the SAM treated group, compared to 0.38 and 37.8% in the control group. Microscopic examination showed the presence of well-differentiated carcinomas and atypical nodules in control rats, while only one small, well-differentiated tumor and one nodule with patterns of initial transformation were seen in SAM-treated rats. No patchy staining of glutathione-S-transferase, indicative of remodeling, was observed in nodules of both SAM-treated and control rats. Nodules and HCCs developing in SAM-treated rats exhibited a relatively high number of apoptotic bodies. Apoptotic bodies count showed 2.8- and 1.8-fold increases in nodules and HCCs of SAM-treated rats with respect to controls. These results indicate that SAM exerts a chemopreventive effect on hepatocarcinogenesis induced by the OA model. SAM seems to be more effective in inhibiting nodule to HCC progression than on the growth of nodule per se. The inhibitory effect is associated with an increase in cell loss by apoptosis in nodules and HCC. PMID- 7859378 TI - Comparative tumorigenicity of benzo[a]pyrene, 1-nitropyrene and 2-amino-1-methyl 6-phenylimidazo[4,5-b]pyridine administered by gavage to female CD rats. AB - Agents that are ubiquitous in the environment and are known inducers of mammary cancer in rodents can be regarded as potential causes of human cancer and need to be evaluated more completely. Therefore, the purpose of this study was to determine under identical conditions the relative carcinogenic potency in the mammary glands of rats of benzo[a]pyrene (B[a]P), 1-nitropyrene (1-NP) and 2 amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Thirty-day-old female CD rats were gavaged once weekly for 8 weeks with B[a]P, 1-NP or PhIP. Each compound was given at 50 mumol/rat/week in 0.5 ml trioctanoin for a total dose of 400 mumol/rat. Forty-one weeks after the last carcinogen administration, rats were killed. In the 1-NP-treated rats, treatment elicited primarily benign tumors. In contrast, the B[a]P- and PhIP-treated rats developed both malignant and benign tumors. The incidence of adenocarcinomas in rats treated with B[a]P or PhIP was comparable and significantly higher than that in animals receiving trioctanoin only. The incidence of benign tumors (fibroadenomas, desmoplastic adenomas and adenomas) observed in animals treated with B[a]P or 1-NP was comparable and significantly higher than that in animals given PhIP or trioctanoin. This is the first report describing the carcinogenic activity of PhIP, given by gavage, in the mammary gland of CD rats and ranking the carcinogenic potency observed under identical conditions, of three agents (B[a]P congruent to PhIP > 1-NP) that are prevalent in the human environment. PMID- 7859379 TI - Functional consequences of sulfhydryl modification in the pore-forming subunits of cardiovascular Ca2+ and Na+ channels. AB - The structure and function of many cysteine-containing proteins critically depend on the oxidation state of the sulfhydryl groups. In such proteins, selective modification of sulfhydryl groups can be used to probe the relation between structure and function. We examined the effects of sulfhydryloxidizing and reducing agents on the function of the heterologously expressed pore-forming subunits of the cloned rabbit smooth muscle L-type Ca2+ channel and the human cardiac tetrodotoxin-insensitive Na+ channel. The known sequences of the channels suggest the presence of three or four cysteine residues within the putative pores of Ca2+ or Na+ channels, respectively, as well as multiple other cysteines in regions of unknown function. We determined the effects of sulfhydryl modification on Ca2+ and Na+ channel gating and permeation by using the whole-cell and single channel variants of the patch-clamp technique. Within 10 minutes of exposure to 2,2'-dithiodipyridine (DTDP, a specific lipophilic oxidizer of sulfhydryl groups), Ca2+ current was reduced compared with the control value, with no significant change in the kinetics and no shift in the current-voltage relations. The effect could be readily reversed by 1,4-dithiothreitol (an agent that reduces disulfide bonds). Similar results were obtained by using the hydrophilic sulfhydryl-oxidizing agent thimerosal. The effects were Ca(2+)-channel specific: DTDP induced no changes in expressed human cardiac Na+ current. Single-channel Ba2+ current recordings revealed a reduction in open probability and mean open time by DTDP but no change in single-channel conductance, implying that the reduction of macroscopic Ca2+ current reflects changes in gating and not permeation. In summary, the pore-forming (alpha 1) subunit of the L-type Ca2+ channel contains functionally important free sulfhydryl groups that modulate gating. These free sulfhydryl groups are accessible from the extracellular side by an aqueous pathway. PMID- 7859380 TI - Stable expression and coupling of cardiac L-type Ca2+ channels with beta 1 adrenoceptors. AB - A number of neurotransmitters modulate cardiac dihydropyridine-sensitive L-type Ca2+ channels through several homologous G protein-coupled receptors. Previous studies that have examined receptor-Ca2+ channel interactions have suffered because of the coexpression of various receptor subtypes in native cells. To study the functional coupling of a particular receptor subtype to these channels, rabbit cardiac Ca2+ channel alpha 1 and skeletal beta and alpha 2/delta subunits were stably expressed in baby hamster kidney cells. In this stable cell line, Ca2+ channels remained at high levels (> 1000 fmol/mg protein, or 2700 channels per cell) over extended times. The expressed recombinant Ca2+ channels displayed the voltage dependence of activation and inactivation, unitary conductance, and pharmacology characteristic of native cardiac L-type Ca2+ channels. Subsequent coexpression of the beta 1-adrenoceptors (150 to 300 fmol/mg protein) with the Ca2+ channels resulted in cell responsiveness to the extracellular application of isoproterenol. These results indicate that heterogeneous expression in mammalian cells provides a useful system for studying both biophysical analysis of Ca2+ channel properties and receptor-coupled regulatory processes. PMID- 7859381 TI - Cloning and functional expression of an inwardly rectifying K+ channel from human atrium. AB - The cardiac inward rectifier current (IK1) contributes to the shape and duration of the cardiac action potential and helps to set the resting membrane potential. Although several inwardly rectifying K+ channels (IRKs) from different tissues have been cloned recently, the nature and number of K+ channels contributing to the cardiac IK1 are presently unknown. To address this issue in human heart, we have used the reverse-transcriptase-polymerase chain reaction (PCR) technique with human atrial total RNA as a template to identify two sequences expressed in heart that are homologous to previously cloned IRKs. One of the PCR products we obtained was virtually identical to IRK1 (cloned from a mouse macrophage cell line); the other, which we named hIRK, exhibited < 70% identity to IRK1. A full length clone encoding hIRK was isolated from a human atrial cDNA library and functionally expressed in Xenopus oocytes. This channel, like IRK1, exhibited strong inward rectification and was blocked by divalent cations. However, hIRK differed from IRK1 at the single-channel level: hIRK had a single-channel conductance of 36 pS compared with 21 pS for IRK1. We have identified single channels of 41, 35, 21, and 9 pS in recordings from dispersed human atrial myocytes. However, none of these atrial inward rectifiers exhibited single channel properties exactly like those of cloned hIRK expressed in oocytes. Our findings suggest that the cardiac IK1 in human atrial myocytes is composed of multiple inwardly rectifying channels distinguishable on the basis of single channel conductance, each of which may be the product of a different gene. PMID- 7859382 TI - Characteristics of the delayed rectifier current (IKr and IKs) in canine ventricular epicardial, midmyocardial, and endocardial myocytes. A weaker IKs contributes to the longer action potential of the M cell. AB - Recent studies have described regional differences in the electrophysiology and pharmacology of ventricular myocardium in canine, feline, rat, guinea pig, and human hearts. In this study, we use standard microelectrode and whole-cell patch clamp techniques to examine the characteristics of the action potential and the delayed rectifier K+ current (IK) in epicardial, M region (deep subepicardial to midmyocardial), and endocardial cells isolated from the canine left ventricle. Cells from the M region displayed much longer action potential durations (APDs) at slow rates. At a basic cycle length of 4 s, APD measured at 90% repolarization was 358 +/- 16 (mean +/- SEM), 262 +/- 12, and 287 +/- 11 ms in cells from the M region, epicardium, and endocardium, respectively. Steady state APD-rate relations were steeper in cells from the M region. In complete Tyrode's solution, IK was smaller in myocytes from the M region when compared with those isolated from the epicardium or endocardium. Further characterization of IK was conducted in a Na(+)-, K(+)-, and Ca(2+)-free bath solution to isolate the slowly activating component of the delayed rectifier (IKs) from the rapidly activating component (IKr). IKs was significantly smaller in M cells than in epicardial and endocardial cells. With repolarization to -20 mV, IKs tail current density was 1.99 +/- 0.30 pA/pF (mean +/- SEM) in epicardial cells, 1.83 +/- 0.18 pA/pF in endocardial cells, and 0.92 +/- 0.14 pA/pF in M cells. Voltage dependence and time course of activation and deactivation of IKs were similar in the three cell types. The relative contribution of IKr and IKs among the three cell types was examined by using 6 mmol/L [K+]o Tyrode's solution with and without E-4031, a highly selective blocker of IKr. An E-4031-sensitive current was observed in the presence but not in the absence of extracellular K+. This rapidly activating component showed characteristics similar to those of IKr as described in rabbit and cat ventricular cells. Deactivation of IKr was significantly slower than that of IKs. IKr (E-4031-sensitive component) tail current density was similar in the three cell types, whereas IKs (E-4031-insensitive component) tail current density was significantly smaller in the M cells. Our results suggest that the distinctive phase-3 repolarization features of M cells are due in part to a lesser contribution of IKs and that this distinction may also explain why M cells are the main targets for agents that prolong APD in ventricular myocardium.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7859383 TI - The stochastic nature of cardiac propagation at a microscopic level. Electrical description of myocardial architecture and its application to conduction. AB - The object of this study is to present evidence that the myocardial architecture creates inhomogeneities of electrical load at the cellular level that cause cardiac propagation to be stochastic in nature; ie, the excitatory events during propagation are constantly changing and disorderly in the sense of varying intracellular events and delays between cells. At a macroscopic level, however, these stochastic events become averaged and appear consistent with a continuous medium. We examined this concept in a two-dimensional (2D) model of myocardial architecture by exploring whether experimentally observed Vmax variability reflected different patterns of intracellular excitation events and junctional delays. The patterns of Vmax variability at randomly chosen intracellular sites were similar experimentally and in the 2D model. The 2D cellular model produced marked variability in gap junction delays; however, on the average, different gap junctions were used for cell-to-cell charge flow during conduction in different directions. During longitudinal propagation (LP), the velocity increased from the proximal to the distal end of each myocyte, and Vmax was lowest proximally, increased to a maximum at the distal fourth of the cell, and decreased distally. Transverse propagation (TP) produced rapid intracellular conduction with variable intracellular excitation sequences. TP Vmax was greater than LP Vmax in most subcellular regions, but near the ends of some myocytes, a reversed "TP > LP Vmax" relation occurred. Total charge carried by the sodium current varied inversely with Vmax, demonstrating feedback effects of cellular loading on the subcellular sodium current and the kinetics of the sodium channels. The results suggest that the stochastic nature of normal propagation at a microscopic level provides a considerable protective effect against arrhythmias by reestablishing the general trend of wave-front movement after small variations in excitation events occur. PMID- 7859384 TI - Expression of multiple connexins in cultured neonatal rat ventricular myocytes. AB - Three gap junction proteins have been identified in mammalian cardiac myocytes: connexin43 (Cx43), connexin45 (Cx45), and connexin40 (Cx40). These proteins form channels with different electrophysiological properties and have different distributions in cardiac tissues with disparate conduction properties. We characterized the expression, phosphorylation, turnover, and subcellular distribution of these connexins in primary cultures of neonatal rat ventricular myocytes. Cx43, Cx45, and Cx40 mRNA were specifically detected in RNA blots. Immunofluorescent staining with antibodies specific for Cx43 and Cx45 revealed punctate labeling at appositional membranes, but no immunoreactive Cx40 was detected. Double-label immunofluorescence confocal microscopy of cultured myocytes revealed colocalization of Cx43 and Cx45. Cx43 and Cx45 were both identified by immunoprecipitation from [35S]methionine-labeled cultures, but anti Cx40 antibodies did not precipitate any radiolabeled protein. Phosphorylated forms of both Cx45 and Cx43 were immunoprecipitated from cultures metabolically labeled with [32P]orthophosphate. Phosphoamino acid analysis demonstrated that Cx45 was modified on serine residues, and Cx43 was phosphorylated on serine and threonine residues. Pulse-chase labeling experiments demonstrated that the half lives of Cx43 and Cx45 were 1.9 and 2.9 hours, respectively. Thus, both Cx43 and Cx45 turn over relatively rapidly, suggesting that myocardial gap junctions have the potential for dynamic remodeling. The results implicate multiple mechanisms of gap junction regulation that may differ for different connexins. PMID- 7859385 TI - Effects of hypoxanthine-xanthine oxidase on Ca2+ stores and protein synthesis in human endothelial cells. AB - We have investigated the effects of reactive O2 metabolites generated by the hypoxanthine-xanthine oxidase (HX-XO) system on intracellular Ca2+ and its relation with protein synthesis in human umbilical vein endothelial cells (HUVECs). Spectrofluorometry with fura 2 showed that the oxidative stress induced a rapid transient rise in cytosolic [Ca2+], followed by a sustained elevation above the baseline value. In the presence of La3+, which blocks Ca2+ influx from the extracellular medium, a transient [Ca2+] increase was still observed, but the sustained rise was suppressed. The HX-XO-related [Ca2+] changes were completely prevented by pretreatment with thapsigargin, which depletes intracellular Ca2+ stores. Hence, the effects of HX-XO on Ca2+ homeostasis were due to mobilization of Ca2+ from the intracellular stores with subsequent influx of extracellular Ca2+. HX-XO mobilized more of sequestered Ca2+ than did thrombin, a receptor agonist that depletes only a part of the intracellular Ca2+ stores (the hormone sensitive stores). To determine the relevance of the HX-XO-related depletion of Ca2+ stores for cell function, we investigated the role of Ca2+ mobilization in the regulation of protein synthesis. Overall protein synthesis in HUVECs was markedly reduced by thapsigargin, which depletes both hormone-sensitive and insensitive stores, but was not substantially affected by thrombin. Manipulation of the refilling of the Ca2+ stores via the availability of extracellular Ca2+ significantly influenced the thapsigargin-related and the HX-XO-related inhibition of overall protein synthesis. A corresponding effect of extracellular [Ca2+] was seen in polyribosome distribution profiles, which reflected an inhibition of translation initiation in both treatments.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859386 TI - Na(+)-Ca2+ exchange in intact endothelium of rabbit cardiac valve. AB - A new method of measuring cytoplasmic free Ca2+ ([Ca2+]i) of individual intact cardiovascular endothelial cells by using imaging fluorescence microscopy was designed. Application of agonist to the aortic or pulmonary valve of the rabbit triggered an increase in [Ca2+]i, which depended on the existence of endothelium on the surface of the valve. Under resting conditions, sudden reversal of the Na+ gradient by substituting external Na+ with N-methyl D-glucamine (NMDG) resulted in a [Ca2+]i spike, which then returned toward the resting level. Increasing intracellular Na+ concentration ([Na+]i) by application of ouabain or monensin induced a sustained [Ca2+]i increase. Na+ substitution by NMDG during the agonist or monensin-induced [Ca2+]i increase gave rise to a further [Ca2+]i spike, which subsequently declined to a level higher than that before removal of external Na+. A selective inhibitor of Na(+)-Ca2+ exchange, 3',4'-dichlorobenzamyl (DCB), abolished the transient [Ca2+]i increase induced by Na+ substitution, and Mg2+, an inorganic inhibitor of Na(+)-Ca2+ exchanger, markedly reduced this transient [Ca2+]i increase. On the other hand, the selective Na(+)-H+ exchanger blocker 5 (N,N-hexamethylene)amiloride (HMA) did not abolish the transient [Ca2+]i increase caused by Na+ substitution. In summary, decreasing the Na+ gradient of the endothelial cells through either receptor stimulation (agonist), Na(+)-K+ pump inhibition (ouabain), pretreatment with Na+ ionophore (monensin), or reversing the Na+ gradient through Na+ substitution (NMDG) all increased [Ca2+]i. This raised [Ca2+]i was antagonized by agents such as DCB or Mg2+, which are thought to inhibit Na(+)-Ca2+ exchange, but not by HMA, an inhibitor of Na(+)-H+ exchange.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859387 TI - Recombinant apolipoprotein A-IMilano dimer inhibits carotid intimal thickening induced by perivascular manipulation in rabbits. AB - Apolipoprotein A-IMilano (apoA-IM), a natural variant of apolipoprotein A-I (apoA I), confers to the carriers a significant protection against vascular disease. The antiatherogenic activity of a recombinant disulfide-linked apoA-IM dimer (rA IM/A-IM) was analyzed in vivo by evaluating its effect on neointimal formation induced by periarterial manipulation in 1% cholesterol-fed rabbits. A flexible collar was applied around the carotid artery 21 days after the beginning of the dietary regimen, and animals were killed 10 days later. Rabbits were injected five times with reconstituted high-density lipoprotein containing egg phosphatidylcholine (EPC) and rA-IM/A-IM (119 mg EPC + 40 mg protein per dose) or with EPC liposomes (119 mg EPC per dose) beginning either 5 days before or at the day of collar positioning. Neither treatment affected plasma cholesterol levels. A significant intimal thickening was observed in control animals; the intima-to media (I/M) ratio was 0.63 +/- 0.11 versus 0.03 +/- 0.05 for the sham-operated contralateral arteries. Neointimal formation was markedly inhibited in animals pretreated with rA-IM/A-IM before lesion induction (I/M, 0.26 +/- 0.19) but not in those in which treatment began the day of collar insertion (I/M, 0.74 +/- 0.14). EPC liposomes did not affect neointimal formation (I/M, 0.50 +/- 0.14 and 0.51 +/- 0.07 in the two treatment groups). Proliferation of smooth muscle cells, assessed by direct incorporation of bromo-2'-deoxyuridine (BrdU) into replicating DNA, was reduced by approximately 30% and 75% in the intimal and medial tissues of rA-IM/A-IM-pretreated rabbits.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859389 TI - Protective role of bradykinin in cardiac anaphylaxis. Coronary-vasodilating and antiarrhythmic activities mediated by autocrine/paracrine mechanisms. AB - Cardiac anaphylaxis, an acute ischemic dysfunction comprising coronary vasoconstriction and arrhythmias, is a model of clinically recognized immediate hypersensitivity reactions affecting the heart. Bradykinin, a mediator of hypersensitivity, is also a potent coronary vasodilator, acting via nitric oxide and prostacyclin production. Because ischemia increases bradykinin outflow from the heart, we questioned whether bradykinin might mitigate anaphylactic coronary vasoconstriction. Antigen challenge of hearts isolated from presensitized guinea pigs was associated with an approximately 30% increase in bradykinin overflow. Furthermore, (1) when the half-life of bradykinin was prolonged with the kininase II/angiotensin-converting enzyme inhibitors captopril and enalaprilat, anaphylactic coronary vasoconstriction was attenuated and reversed, and arrhythmias were alleviated; (2) the bradykinin B2-receptor antagonist HOE 140 prevented these effects; and (3) HOE 140 exacerbated both anaphylactic coronary vasoconstriction and arrhythmias. During cardiac anaphylaxis, the coronary overflow of cGMP, a marker of nitric oxide production, and 6-ketoprostaglandin F1 alpha, a stable prostacyclin metabolite, increased two-fold and fourfold, respectively. Because neither enalaprilat nor HOE 140 affected these changes, the enhanced overflow of cGMP and 6-ketoprostaglandin F1 alpha is likely to reflect the actions of other hypersensitivity mediators (eg, histamine and leukotrienes). We postulate that bradykinin plays a protective role in cardiac anaphylaxis by accumulating at the luminal surface of the coronary endothelium and promoting, in an autocrine mode, a B2-receptor-mediated production of nitric oxide and prostacyclin in concentrations sufficient to elicit a paracrine effect on coronary vascular smooth muscle, thus opposing the vasoconstricting effects of other anaphylactic mediators. PMID- 7859388 TI - Modulation of baroreceptor activity by nitric oxide and S-nitrosocysteine. AB - The goal of this study was to determine whether nitric oxide (NO) and the NO donor, S-nitrosocysteine (cysNO), modulate the activity of carotid sinus baroreceptors. Baroreceptor activity was recorded from the vascularly isolated carotid sinus in anesthetized rabbits. Baroreceptor activity decreased in a dose dependent manner after injection of either NO or cysNO as constant pressure was maintained, and activity recovered spontaneously over time, within seconds to minutes. The baroreceptor pressure-activity relation was shifted significantly to the right by cysNO, with a profound suppression of activity at high pressure. Baroreceptor activity at 160 mm Hg averaged 76 +/- 8%, 60 +/- 6%, and 36 +/- 5% of the control maximum during exposure to 10(-4), 2 to 3 x 10(-4), and 10(-3) mol/L cysNO, respectively. The inhibition of activity by the L and D isomers of cysNO was equivalent and was blocked by reduced hemoglobin, suggesting that the effect was mediated by NO. The suppression of baroreceptor activity by cysNO was not related to vascular relaxation as measured by videomicrometer. Inhibition of soluble guanylate cyclase with methylene blue or 6-anilinoquinoline-5,8-quinone (LY83583, 10(-5) mol/L) did not attenuate and dibutyryl cGMP (10(-3) mol/L) did not mimic the suppression of baroreceptor activity by cysNO, suggesting a cGMP independent mechanism. Activation of endogenous NO formation with thimerosal (10( 5) to 10(-4) mol/L) reduced maximum baroreceptor activity in five of eight experiments to 59 +/- 7% of the control maximum.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859390 TI - Heparin increases exercise-induced collateral blood flow in rats with femoral artery ligation. AB - The potential for heparin to enhance the training-induced increase in collateral dependent blood flow to the distal hind-limb muscles was evaluated after bilateral femoral artery ligation in adult male rats (approximately 350 g). Rats received either saline (n = 34) or heparin (n = 36) injections and were kept sedentary (limited to cage activity) or exercised on a treadmill 5 days per week up a 15% incline by one of two protocols: (1) exercise at a constant moderate speed (20 m/min) for approximately 6 wks or (2) exercise at a progressively increased speed for 7 to 8 weeks (started at 20 m/min, increased at 15 minutes to 25 m/min, and then increased at 30 minutes to 30 m/min). Heparin- and saline treated rats, exercised by the moderate-speed protocol, were run for the same time each day. Collateral-dependent blood flow to the distal limb tissue was determined by using 15-microns 85Sr-labeled microspheres in an isolated hindquarter preparation perfused in the descending aorta at 100 mm Hg. For comparison with the above groups, sedentary animals with acute femoral artery ligation and without femoral obstruction were included. Exercise tolerance increased from approximately 7 minutes initially to 30 to 40 minutes per bout; tolerance was greater in the heparin-injected rats than in the saline-injected rats (P < .05). Muscle performance of the gastrocnemius-plantaris-soleus muscle group (GPS) during isometric contractions in situ improved with training, was further increased by heparin administration (P < .001), and generally scaled with recovery of blood flow.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859391 TI - Role of lipoxygenase metabolites in ischemic preconditioning. AB - Preconditioning with brief intermittent periods of ischemia before a sustained period of ischemia has been shown to reduce infarct size and improve recovery of function in rat hearts. The mediators of this protective response are unknown in rats. We tested the hypothesis that a lipoxygenase metabolite might be involved in preconditioning, since lipoxygenase metabolites such as 12 hydroperoxyeicosatetraenoic acid have been shown to increase K+ channel activity and to decrease Ca2+ channel activity, which could have a protective effect on ischemic injury. In support of this hypothesis, we report that the lipoxygenase inhibitors nordihydroguaiaretic acid (NDGA, 5 mumol/L) and eicosatetraynoic acid (7 mumol/L) added just before and during preconditioning blocked the protective effects of preconditioning on recovery of function during reflow after 30 minutes of global ischemia. In addition, these lipoxygenase inhibitors partially blocked the ability of preconditioning to attenuate the rise in cytosolic free calcium during sustained ischemia. We also investigated the effects of preconditioning on eicosanoid metabolism by using high-performance liquid chromatography and found that 12-hydroxyeicosatetraenoic acid (12-HETE), the stable product of the lipoxygenase pathway, was made during the preconditioning protocol and that 12 HETE accumulation was blocked by NDGA. Thus, there is a correlation between functional recovery after ischemia and stimulation of the lipoxygenase pathway of arachidonic acid metabolism before the sustained period of ischemia; inhibition of the lipoxygenase pathway eliminates the protective effect of preconditioning on recovery of function after ischemia. PMID- 7859392 TI - Arterial wall mechanics in conscious dogs. Assessment of viscous, inertial, and elastic moduli to characterize aortic wall behavior. AB - To evaluate arterial physiopathology, complete arterial wall mechanical characterization is necessary. This study presents a model for determining the elastic response of elastin (sigma E, where sigma is stress), collagen (sigma C), and smooth muscle (sigma SM) fibers and viscous (sigma eta) and inertial (sigma M) aortic wall behaviors. Our work assumes that the total stress developed by the wall to resist stretching is governed by the elastic modulus of elastin fibers (EE), the elastic modulus of collagen (EC) affected by the fraction of collagen fibers (fC) recruited to support wall stress, and the elastic modulus of the maximally contracted vascular smooth muscle (ESM) affected by an activation function (fA). We constructed the constitutive equation of the aortic wall on the basis of three different hookean materials and two nonlinear functions, fA and fC: sigma = sigma E + sigma C + sigma SM + sigma eta + sigma M = EE. (epsilon - epsilon 0E) + EC.fC.epsilon + ESM.fA.epsilon + eta. [equation: see text] + M.[equation: see text] where epsilon is strain and epsilon 0E is strain at zero stress. Stress-strain relations in the control state and during activation of smooth muscle (phenylephrine, 5 micrograms.kg-1.min-1 IV) were obtained by transient occlusions of the descending aorta and the inferior vena cava in 15 conscious dogs by using descending thoracic aortic pressure (microtransducer) and diameter (sonomicrometry) measurements. The fC was not linear with strain, and at the onset of significant collagen participation in the elastic response (break point of the stress-strain relation), 6.02 +/- 2.6% collagen fibers were recruited at 23% of stretching of the unstressed diameter. The fA exhibited a skewed unimodal curve with a maximum level of activation at 28.3 +/- 7.9% of stretching. The aortic wall dynamic behavior was modified by activation increasing viscous (eta) and inertial (M) moduli from the control to active state (viscous, 3.8 +/- 1.3 x 10(4) to 7.8 +/- 1.1 x 10(4) dyne.s.cm-2, P < .0005; inertial, 61 +/- 42 to 91 +/- 23 dyne.s2.cm-2, P < .05). Finally, the purely elastic stress-strain relation was assessed by subtracting the viscous and inertial behaviors. PMID- 7859393 TI - Mechanism of impaired myocardial function during progressive coronary stenosis in conscious pigs. Hibernation versus stunning? AB - The major goal of this study was to determine whether impaired myocardial contractile function during the development of progressive coronary artery stenosis induced by ameroid constriction in conscious pigs reflected myocardial "hibernation" or "stunning." Minipigs were instrumented with a coronary ameroid constrictor and hydraulic occluder, regional wall thickness crystals, a left ventricular (LV) pressure gauge, and aortic and left atrial catheters. In the seven pigs in which it was measured, systolic wall thickening (WT) distal to the ameroid fell by a maximum of 56 +/- 6% at 20 +/- 3 days after ameroid implantation and then began to recover. At 1 day after ameroid implantation, brief complete coronary artery occlusion (CAO) resulted in wall thinning distal to the ameroid (-113 +/- 4%) and transmural decreases in myocardial blood flow in endocardial (from 0.82 +/- 0.08 to 0.02 +/- 0.01 mL/min per gram) and epicardial (from 0.73 +/- 0.13 to 0.03 +/- 0.02 mL/min per gram) layers. At 20 +/- 3 days, baseline myocardial blood flow was not altered either in endocardial (0.92 +/- 0.10 mL/min per gram) or epicardial (0.85 +/- 0.12 mL/min per gram) layers, whereas brief complete coronary artery occlusion still reduced WT (-83 +/- 12%) and myocardial blood flow in endocardial (to 0.21 +/- 0.03 mL/min per gram) and epicardial (to 0.43 +/- 0.12 mL/min per gram) layers, indicating that the coronary artery was not totally occluded. Pathology in four pigs demonstrated no gross necrotic myocardium shortly after this time point. Transient reductions in WT distal to the ameroid were observed during progressive coronary artery stenosis in response to spontaneous increases in activity. Beat-by-beat analysis of these episodes revealed that acute reductions in WT followed increases in LV dP/dt and heart rate and exhibited delayed recovery. These data suggest that the reduced function during ameroid-induced coronary stenosis reflected cumulative myocardial stunning rather than a primary deficit in coronary blood flow or "hibernating myocardium." PMID- 7859394 TI - Angiotensin II-induced growth responses in isolated adult rat hearts. Evidence for load-independent induction of cardiac protein synthesis by angiotensin II. AB - Cardiac myocyte hypertrophy often occurs in response to both hemodynamic and neurohumoral factors. To study whether activation of the renin-angiotensin system by itself may induce a cardiac growth response, the acute effects of angiotensin II on cardiac protein synthesis were studied in isolated rat hearts. New protein synthesis in isolated buffer-perfused adult rat hearts was measured by incorporation of [3H]phenylalanine into cardiac proteins during a 3-hour perfusion protocol. Angiotensin II (1 x 10(-8) mol/L), administered alone or in combination with the alpha 1-blocker prazosin (1 x 10(-7) mol/L), stimulated protein synthesis in both ventricles. The rate of [3H]phenylalanine incorporation into cardiac proteins was 3.9-fold (P < .005) and 2.6-fold (P < .01) higher in angiotensin II-perfused (n = 6) than in vehicle-perfused (n = 6) left and right ventricles, respectively. The induction of new protein synthesis by angiotensin II was blocked by the angiotensin II type 1 (AT1) receptor antagonist losartan (1 x 10(-7) mol/L, n = 5). To study the pathways of angiotensin signal transduction, protein kinase C (PKC)-epsilon as well as cardiac c-fos and c-jun mRNA levels were analyzed. Angiotensin II (1 x 10(-8) mol/L, n = 20) resulted in a transient translocation of PKC-epsilon from the cytosol to the cellular membrane. However, compared with phorbol ester stimulation (phorbol 12-myristate 13-acetate [PMA], 1 x 10(-7) mol/L; n = 20), angiotensin II effects on PKC translocation were significantly less pronounced and required a more prolonged stimulation.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859395 TI - Dye tracers define differential endothelial and smooth muscle coupling patterns within the arteriolar wall. AB - Dye tracers were chosen, based on net charge, chemical structure, and reactive groups, to test for the existence of and to provide novel insight into channel selectivities of junctional pathways connecting smooth muscle and endothelial cells of the arteriolar wall. Dyes were injected into individual smooth muscle or endothelial cells of hamster cheek pouch arterioles using microiontophoresis. Coupling, independent of tracer net charge, was seen both within and between cell layers. Endothelial cells were well coupled by all of the tested dyes. Smooth muscle junctions appeared less effective in dye transfer than endothelial junctions. Lucifer yellow was confirmed to be a poor tracer of smooth muscle gap junctions, and remarkably this dye and other related sulfate-containing molecules interfered with dye movement through smooth muscle but not endothelial junctions. Myoendothelial junctions showed a striking polarity of dye movement, with dye transfer from endothelial to smooth muscle cells but little or no transfer in the reverse direction. Because the dyes have size and charge characteristics similar to those of known cellular second messengers, these findings have important implications for cell-cell signaling in the vessel wall. PMID- 7859396 TI - Glaucoma therapy: implications for the internist. PMID- 7859397 TI - An abnormal chest finding in a 45-year-old man. PMID- 7859398 TI - Angioplasty or thrombolysis in acute myocardial infarction: dilate or dissolve? PMID- 7859399 TI - Hypertension in children and adolescents. AB - BACKGROUND: Children have lower blood pressure than adults do, and normal values for children have been established based on age and also on height and weight. Blood pressures in childhood correlate with blood pressures in adulthood, although weakly; a stronger correlation has been established between obesity in childhood and adulthood. Further, obese people are more likely to have high blood pressure than are slender people, both as children and adults. In hypertensive children, the higher the blood pressure and the earlier hypertension appears, the more likely is a secondary cause. KEY POINTS: Physicians should measure and record children's blood pressure, just as they do their height and weight. An algorithm can help physicians decide whether a child with high blood pressure needs further workup and treatment. Nonpharmacologic therapy includes dietary sodium restriction, weight reduction (if the child is overweight), aerobic exercise, and relaxation. In some cases pharmacologic therapy may be necessary. In general, all children should be encouraged to be physically active and to eat healthy foods. PMID- 7859400 TI - Managing hypertension in the elderly: dispelling the myths. AB - BACKGROUND: There are now more than 31 million people 65 years of age or older in the United States, at least half of whom have systolic blood pressure 140 mm Hg or higher or diastolic blood pressure 90 mm Hg or higher or both. By the year 2050, 16 million Americans will be over age 85. OBJECTIVE: To review the current data and recommendations regarding treating hypertension in elderly patients. SUMMARY: Randomized clinical trials have dispelled some of the myths that surround treatment of hypertension in the elderly by showing that judicious treatment of elevated blood pressure, both systolic and diastolic, will reduce the risk of cardiovascular morbidity and mortality, with an acceptable trade-off in terms of side effects and without sacrificing quality of life. CONCLUSIONS: Because most of the trials have used a diuretic as initial therapy, it is recommended that one of these agents be prescribed in low doses if life-style modifications do not reduce blood pressure to acceptable levels, unless there is a contraindication to diuretics or an indication for another class of agents. PMID- 7859401 TI - Chemotherapy in the management of breast cancer. AB - BACKGROUND: Breast cancer has become a national health problem, affecting more than 180,000 women each year. Although advances in early detection and treatment have been made, it remains the second leading cause of cancer-related death in women. KEY POINTS: The treatment of breast cancer requires the careful integration of systemic and local methods. Although the application of hormonal therapy or chemotherapy is becoming less distinct, this discussion will review the important clinical trials and future directions of chemotherapy in the management of breast cancer. Data support the use of chemotherapy in the adjuvant setting, for preoperative tumor reduction of locally advanced disease, and as palliation in metastatic disease. The optimal chemotherapeutic regimen is not known; however, data support a role for adjuvant doxorubicin in node-positive disease, neoadjuvant therapy for high-risk disease, and high-dose chemotherapy to consolidate responding metastatic disease. CONCLUSIONS: The clinician must determine the risks and potential benefits of systemic chemotherapy before recommending treatment strategies. Although progress has been made, future advances can only occur through active participation in clinical trials. PMID- 7859402 TI - Office evaluation and treatment of Raynaud's phenomenon. AB - BACKGROUND: Raynaud's phenomenon, an episodic vascular disorder induced by cold temperatures or stress and characterized by white, blue, and red discoloration of the fingers and toes, may affect up to 20% of the general population. KEY POINTS: Raynaud's phenomenon may exist independently (primary) or in association with an underlying disease (secondary), most commonly systemic sclerosis. The pathophysiologic features include vasospasm, endothelial cell changes, vessel obstructive features, and hemorrheologic factors. Raynaud's phenomenon is the initial manifestation of disease in 70% of patients with systemic sclerosis, in whom it may be present for many years before the development of the connective tissue disease. Patients with primary Raynaud's phenomenon need only conservative management and should be reassured that digital ischemia and loss of tissue occur extremely rarely. Pharmacologic agents that have been studied include vasodilators, platelet inhibitors, serotonin antagonists, and fibrinolytics. CONCLUSIONS: For prognostic and therapeutic reasons, it is important to determine if Raynaud's phenomenon is associated with an underlying condition and if the patient may develop a connective tissue disease. PMID- 7859403 TI - Stroke: prevention still the best treatment. PMID- 7859404 TI - Portal venous pressure and the serum-ascites albumin concentration gradient. AB - CLINICAL ISSUE: Other investigators have found the serum-ascites albumin concentration gradient to be 1.1 g/dL or greater in the presence of portal hypertension and less than that in its absence. OBJECTIVE: To determine if any correlation exists between the serum-ascites albumin concentration gradient (which reflects the net serum oncotic pressure) and the portal venous pressure. METHODS: The study group comprised 15 patients who had alcoholic cirrhosis. The portal venous pressure was calculated as the difference between the measured hepatic venous wedge and inferior vena cava pressures and was expressed as the hepatic venous pressure gradient. SUMMARY: All patients had portal hypertension; the mean hepatic venous pressure gradient was 14.81 +/- 6.91 (SD) mm Hg. Fourteen of the 15 patients had a serum-ascites albumin concentration gradient of at least 1.1 g/dL; the mean value was 2.168 +/- .709 g/dL. No correlation was found between these variables (r = .0459, P > .05). CONCLUSIONS: Although the serum ascites albumin concentration gradient is a sensitive indicator of portal hypertension in patients with alcoholic cirrhosis, it does not reflect the portal venous pressure. PMID- 7859405 TI - The effect of prolonged tourniquet application on serum bicarbonate. AB - BACKGROUND: Many clinicians believe that prolonged tourniquet application lowers the serum bicarbonate concentration in samples drawn from that limb, but this effect has never been examined prospectively. OBJECTIVE: To test the effect of prolonged tourniquet application before phlebotomy on serum bicarbonate concentration in healthy adults. METHODS: We drew blood samples from 27 healthy adult volunteers without a tourniquet and again 1, 3, and 5 minutes after applying a blood pressure cuff and inflating it to the mean arterial pressure. RESULTS: The mean bicarbonate concentration was 27.3 +/- 2.26 mmol/L (standard deviation) at baseline, 27.7 +/- 2.39 mmol/L at 1 minute, 27.7 +/- 2.05 mmol/L at 3 minutes, and 27.7 +/- 1.96 mmol/L at 5 minutes. The mean change in bicarbonate concentration from baseline was -0.04 +/- 1.02 mmol/L at 1 minute, 0.44 +/- 1.05 mmol/L at 3 minutes, and 0.44 +/- 1.31 mmol/L at 5 minutes. The mean lactate concentration was 1.1 +/- 0.28 mmol/L at baseline, 1.3 +/- 0.65 mmol/L at 1 minute, 1.2 +/- 0.52 mmol/L at 3 minutes, and 1.2 +/- 0.36 mmol/L at 5 minutes. The mean change in lactate concentration from baseline was 0.15 +/- 0.67 mmol/L at 1 minute, 0.11 +/- 0.11 mmol/L at 3 minutes, and 0.12 +/- 0.37 mmol/L at 5 minutes. CONCLUSIONS: Prolonged tourniquet application before phlebotomy does not lower the serum bicarbonate concentration in healthy adults. PMID- 7859406 TI - Calcium stones: calcium restriction not warranted. PMID- 7859407 TI - Drug metabolism in malnutrition and obesity: clinical concerns. AB - In general, patients who are malnourished tend to have prolonged effects from drugs metabolized by the MFOS. On the other hand, in obese patients, drugs that undergo phase II metabolism tend to be metabolized more rapidly, thus shortening their duration of action. Therefore, clinicians must remember that, in protein calorie malnutrition, drugs metabolized in the liver may be more likely to cause toxic effects due to the decreased rate of hepatic metabolism. Dose reduction could eliminate these adverse effects. Alternatively, drugs that undergo phase II metabolism may need to be administered at higher doses in obese patients, since the desired clinical effect may not be seen at a normal dose due to the obesity related increase in hepatic metabolism. This should be considered before discontinuing the drug as a result of its lack of effect. PMID- 7859408 TI - Fine-needle aspiration biopsy. PMID- 7859409 TI - Health effects of man-made mineral fibers. PMID- 7859410 TI - Role of the immune response in interstitial cystitis. AB - Interstitial cystitis (IC) patients present with irritative and painful bladder symptoms and are diagnosed clinically by their symptoms, negative urine cultures, absence of other diseases, and cytoscopic findings of glomerulations and/or ulcers. The histological evaluation usually is described as nonspecific chronic inflammation. Although numerous theories of pathogenesis have been proposed, the etiology of IC is unknown. The hypothesized causes of IC include infectious, lymphovascular obstruction and neurogenic, endocrinologic, psychoneurotic, inflammatory (especially mast cells), and autoimmune pathologies. In this Review we discuss the evidence supporting a role for autoimmunity in IC and link the mast cell to the expression of the disease. Moreover, we discuss newly developed animal models that may provide insight into the etiology of IC. PMID- 7859411 TI - Expansion of circulating gamma delta T cells in active sarcoidosis closely correlates with defects in cellular immunity. AB - The relationship between the level of gamma delta T cells and cellular immunity of T lymphocytes was assessed in the peripheral blood of active sarcoidosis patients and healthy controls. We divided the active sarcoidosis patients into two groups: a group of patients with a normal distribution of circulating gamma delta T cells (group A; n = 11, less than 8.2% lymphocytes) and another group with increased gamma delta T cell levels (group B; n = 11, greater than 8.2% lymphocytes). The proportion and absolute count of CD4+ lymphocytes in group B (28.6 +/- 11.2%, 374.1 +/- 193.8/microliters) were remarkably smaller than control subjects (45.7 +/- 6.8%, 818.3 +/- 290.2/microliters, P < 0.001, P < 0.002, respectively). Group A, however, showed a moderate reduction in CD4+ lymphocytes when compared with controls. Serial measurements of T cell subtypes were performed on five patients in group B. gamma delta T cells and CD4+ lymphocytes were inversely correlated over the observation period which ranged from 2 to 18 months. When peripheral blood T cells were stimulated with PHA or PPD in vitro, the responses were weaker in group B compared with both group A and control subjects. These results suggest that the increase in circulating gamma delta T cells in sarcoidosis closely relates to a defect in cellular immunity which progresses during the disease process. PMID- 7859412 TI - Interleukin-8 and granulocyte-macrophage colony-stimulating factor secretion in hepatocellular carcinoma and viral chronic active hepatitis. AB - Interleukin-8 (IL-8) and granulocyte-macrophage colony-stimulating factor (GM CSF) are important mediators of inflammation and immune response in human disease. To demonstrate their importance in pathophysiological processes in liver disease, we measured the circulating levels of IL-8 and GM-CSF in patients with hepatocellular carcinoma (HCC) and chronic active hepatitis (CAH). IL-8 and GM CSF levels in serum samples were determined with highly specific and sensitive enzyme-linked immunosorbent assays. IL-8 levels were more elevated in serum samples of patients with HCC and CAH associated with hepatitis C virus infection than HCC and CAH associated with hepatitis B virus infection. However, in all patients with autoimmune CAH and in some patients with HCC and CAH, GM-CSF levels were elevated over the baseline levels measured in all of the normals, but this difference was not statistically significant for any group. We conclude that IL-8 and GM-CSF are increased in some patients with liver diseases, and as such they may play a significant role in host defense and disease. PMID- 7859413 TI - Mast cells in accessory glands of experimentally induced prostatitis in male Wistar rats. AB - We studied the histological modifications in the accessory glands of autoimmune rats. Adult male Wistar rats were id immunized three times with saline extract of rat male accessory glands (RAG) chemically modified (MRAG) in complete Freund's adjuvant (CFA) (groups 1, 2, and 3). Prior to the first immunization with MRAG CFA groups 2 and 3 received peritoneal cells obtained from rats that had been injected 2 or 24 hr previously with low doses of RAG. Furthermore, an additional group (group 4) ip immunized with liposome-associated-RAG was incorporated. The delayed-type hypersensitivity response studied 10 or 15 days after first immunization was positive for rats of groups 1, 3, and 4, while it was negative for rats of group 2. Serum samples obtained on Day 45 and studied by ELISA showed high levels of autoantibodies in groups 1 and 2 and lower levels of autoantibodies in group 3, but did not show autoantibodies in group 4. The histological studies performed 10 days after the last immunization showed organ specific lesions in the accessory glands in animals of groups 1, 3, and 4. Infiltration of mononuclear cells was the main alteration in group 1, while infiltration of mast cells and polymorphonuclear leukocytes were present in specimens of groups 3 and 4. The main finding of this study was a significant increase (P < 0.0005) in the extent of mast cell degranulation in the specimens of accessory glands stained with toluidine blue. Our results suggest that mast cells are activated in our experimental model of autoimmune disease. PMID- 7859414 TI - A primary immunodeficiency syndrome in Shar-Pei dogs. AB - A multiple immunodeficiency, involving antibody- and cell-mediated responses in 10 Chinese Shar-Pei (CSP) dogs is described. Abnormal levels of serum IgM and IgA in most cases, and IgG in fewer cases characterized the immunoglobulin deficiencies. Decreased in vitro proliferative responses of pokeweed mitogen (PWM)-stimulated peripheral blood mononuclear cells (PBMC) were found in nine cases. Clinical presentation involved several organ systems and was associated with recurrent infections and malignancy. Sera from affected dogs suppressed PWM stimulated cell proliferation of affected and normal dogs, but not cultures stimulated with PWM followed by recombinant IL-2 (rIL-2). In vitro supplementation of PBMC cultures with immunomodulatory guanosine analogs (GA) resulted in increased de novo IgG and/or interleukin-6 (IL-6) synthesis. Cells from five immunodeficient dogs showed in vitro evidence of GA- or rIL-2-dependent enhanced immunological responses. Since rIL-2-mediated activation of the IL-2 receptor and GA-mediated immunomodulation are reported to act through protein kinase C (PKC)-independent pathways, it is concluded that the IL-2 receptor is functional in these dogs and that cell activation through alternative pathways may restore immune responses in affected CSP dogs. PMID- 7859415 TI - Anti-ribosomal P antibodies in systemic lupus erythematosus: a case-control study correlating hepatic and renal disease. AB - We report a case-control study of the occurrence of liver and kidney disease in 20 systemic lupus erythematosus (SLE) patients with anti-ribosomal P antibodies and 20 age-, sex-, and race-matched (control group) SLE patients without anti-P antibodies. In the group with anti-P antibodies, 7 patients were found to have had liver disease, compared with only 1 in the control group (P = 0.03), and 14 anti-P (+) patients have had kidney disease, compared with 4 in the control group (P = 0.01). A major serological difference between the groups was an increased prevalence of anti-dsDNA in the anti-P positive group (12/20) vs the control group (4/20), P = 0.02. These statistically significant differences suggest that antibodies to ribosomal P identify a subset of SLE patients at higher risk for liver and kidney involvement, in addition to the previously recognized risk for neuropsychiatric disease. PMID- 7859416 TI - Longitudinal study of anticentromere and antitopoisomerase-I isotypes. AB - The isotypes of anti-CENP-B, the major anticentromere antibody (ACA), and antitopoisomerase I in patients with scleroderma and Raynaud's disease were studied longitudinally in order to determine whether there was evidence of isotype switch. One hundred and three sera samples from 13 ACA(+) patients and 6 antitopoisomerase I patients were studied over a period from 3 to 17 years. Anti CENP-B was always IgG, whereas antitopo-I was IgG and IgA. IgM anti-CENP-B and IgM antitopoisomerase I, when present, were always found with IgG and/or IgA. Three patients developed IgG anti-CENP-B during the study. We conclude that anti CENP-B and antitopoisomerase I show evidence of isotype switch with persistence of IgG expression which suggests a continued antigen-driven immune response. PMID- 7859417 TI - Human recombinant IL-2 augments immunoglobulin and induces rheumatoid factor production by rheumatoid arthritis lymphocytes engrafted into severe combined immunodeficient mice. AB - Recombinant (r) human IL-2 was administered in vivo to improve homing and engraftment of rheumatoid arthritis (RA) patients' peripheral blood mononuclear cells (PBMC) into severe combined immunodeficient (SCID) mice. Human rIL-2 treatment resulted in augmented human Ig production and induced IgM rheumatoid factor (RF) of human origin in SCID-RA chimeras. The increment of human serum IgG in SCID-RA chimeras after IL-2 treatment ranged between 15 and 43% and for IgM between 50 and 98% during 2-8 weeks postengraftment. Human IgM-RF was detectable after 1 to 2 weeks after engraftment and persisted over a period of 10-13 weeks. No RF was produced in SCID mice engrafted with PBMC from healthy individuals with or without exogenous rIL-2 administration. Thus, human rIL-2 expanded autoreactive clones involved in the production of RF in the SCID-RA chimeras. The present study provides a novel approach to establish an in vivo SCID-RA model to study the cellular and molecular mechanisms involved in the production of RF and development of a RA-like lesion. PMID- 7859418 TI - The value of complement activation products in the assessment of systemic lupus erythematosus flares. AB - Complement activation products (CAP) have been reported as sensitive markers of disease activity in systemic lupus erythematosus (SLE). We have measured seven parameters of the complement system (C3, C4, factor B, C3a, C4a, iC3b, and the terminal complement complex-TCC-) in 61 SLE patients to study their interrelationship and relative efficacy as diagnostic indicators of lupus activity. Disease activity was judged according to a clinical index (SLEDAI) to be active in 22 and inactive in 39 patients. Subjects with active SLE showed increased levels of C3a, C4a, and TCC compared with those of stable lupus and normal controls, and plasma concentrations of these CAP manifested a positive correlation with disease activity scores. However, values of factor B and iC3b did not correlate with lupus flares. Serum C3 levels were a better reflection of the degree of SLE activity than were C4 levels. The anaphylatoxins were extremely sensitive markers of disease activity but they lacked enough specificity, and iC3b was not at all informative for this purpose. On the whole, TCC concentration was the most useful parameter (77% sensitivity, 80% specificity) to monitor lupus activity, correlating the best with the activity scoring system, and thus offers a better laboratory marker of lupus severity than conventional measurements of complement. PMID- 7859419 TI - Spontaneous luminol-dependent chemiluminescence of thrombocytes increases in hemorrhagic fever with renal syndrome. AB - Spontaneous luminol-dependent chemiluminescence (CL) of thrombocytes was studied in 12 patients with hemorrhagic fever with renal syndrome (HFRS) caused by Puumala virus. CL in the acute phase of HFRS (median, 61 mV/10 sec; range, 22-91) was higher than that of healthy controls (median, 22 mV/10 sec; range, 18-29; P < 0.01) and patients with acute hepatitis B infection accompanied by thrombocytopenia (median, 33 mV/10 sec; range, 13-45; P < 0.01). CL of thrombocytes in the convalescence phase of HFRS (median, 31 mV/10 sec; range, 12 80) was significantly lower than that during the acute phase (P < 0.01). Neither was there a difference in CL response between HFRS patients with or without thrombocytopenia, but both groups produced a higher CL response than that of the control groups. Both the complement-containing and complement-free sera from acute HFRS patients (final dilutions: range 1:10-1:2560) exhibited no effect on CL response of normal thrombocytes. A possible role of increased oxygen radicals production by thrombocytes in pathogenesis of HFRS is discussed. PMID- 7859420 TI - Myasthenia gravis: comparative autoantibody assays using human muscle, TE671, and glucocorticoid-treated TE671 cells as sources of antigen. AB - The use of acetylcholine receptors (AChR) from the readily available TE671 cell line as a practical alternative to human muscle for monitoring the anti-AChR antibody assay in sera of Myasthenia gravis patients has been recently proposed. Most of the TE671 culture protocols include the use of glucocorticoids. Glucocorticoids were shown to upregulate the acetylcholine receptor expression in TE671 cells. To confirm the advantage of using AChR from TE671 cells (AChRTE) and to validate the use of AChR from glucocorticoid-treated cells (AChRGT) in AChR antibody measurement, the three different antigens (muscle AChR (AChRMU), AChRTE, and AChRGT) were compared for radioimmunoprecipitation assay. We found that, despite a slight underestimation of the antibody titers using AChRTE and AChRGT compared to AChRMU, and considering the rare cases of AChRMU antibody titer category permutations, the correlations between the values were satisfactory. PMID- 7859422 TI - New therapies for otitis media. PMID- 7859421 TI - Single-dose ceftriaxone versus 10 days of cefaclor for otitis media. AB - We conducted a controlled clinical trial to determine the efficacy of single-dose intramuscular ceftriaxone for the treatment of acute otitis media. Fifty-four children aged 18 months to 6 years with clinical and tympanometric evidence of otitis media were randomized to receive either 50 mg/kg ceftriaxone or 10 days of oral cefaclor 40 mg/kg/day. Resolution of symptoms and clinical and tympanometric appearance of the tympanic membrane at follow-up visits were used to determine outcome. Thirty-one children received ceftriaxone and 23 received oral cefaclor. There were no treatment failures. There were no significant differences between groups in persistence of effusion or recurrence of acute otitis media. We conclude that a single intramuscular dose of ceftriaxone compares favorably with 10 days of oral cefaclor for the treatment of acute otitis media. PMID- 7859423 TI - Pediatric practice in a summer sleep-away camp. AB - Clinical practice was surveyed over a 4-week period at a sleep-away camp for children ages 9 to 16 years. The facility is located in the Pocono Mountains in Pennsylvania and has an enrollment of 694 campers and 266 adult staff members. There was a total of 895 visits to the infirmary; however, 190 children were evaluated on more than one occasion. Younger children and girls were more likely to seek medical help. The most common presenting complaints involved physical injuries related to sports activities, followed by a wide range of upper respiratory difficulties, such as sore throat, conjunctivitis, and stuffed nose. Tick bites were not observed in any campers. Significant psychosocial problems were not encountered among any children. Only one child had to be sent home from camp for specific treatment; this was a 14-year-old girl who suffered a lacerated nerve of the third finger on her right hand that required surgical correction. These data indicate that, aside from an increase in minor sports-related injuries, the health problems of children in camp are not significantly different in type or severity from those they experience at home. Furthermore, children attending camp can be relied upon to accurately report their complaints and receive appropriate medical attention. PMID- 7859424 TI - Behaviors associated with onset of gastroesophageal reflux episodes in infants. Prospective study using split-screen video and pH probe. AB - To identify behaviors associated with the onset of gastroesophageal reflux episodes in infants both systematically and prospectively, each of 10 patients (aged 2 to 32 weeks) was studied during 2 hours of intraluminal esophageal pH probe monitoring, using a split-screen audiovisual recording technique. Videotape analysis of eight infants who had scoreable reflux events revealed six discrete behaviors closely associated temporally (P < .001 to < .05) with the onset of reflux events: "discomfort" (crying or frowning), "emission" (of liquid or gas, i.e., regurgitation, drooling, or burping), yawning, stridor, stretching, and mouthing. Three behaviors (hiccuping, sneezing, and thumb-sucking) were infrequent but were significantly associated with onset of reflux events in one or two patients each. A tenth behavior, coughing or gagging, was significantly associated with onset of reflux events in two patients, but not in the rest, despite relatively frequent occurrence. Exploration of temporal relations between reflux and each behavior suggested that discomfort, emission, mouthing, and cough gag may have caused reflux episodes, and that all 10 of the behaviors may have been caused by reflux episodes. These findings and a "quiet period" immediately preceding episodes in six of the infants suggest interesting pathophysiologic mechanisms in infants which require further evaluation. PMID- 7859425 TI - The overdiagnosis of Lyme disease in children residing in an endemic area. AB - The medical records of 227 children ages 1 to 19 years referred to the Lyme disease pediatric clinic over a 32-month period since May 1990 were reviewed. Clinico-serologic criteria for a positive diagnosis were applied. One hundred thirty-eight of 227 referred children did not fulfill those criteria and became the study population. Four subsets of patients emerged: (1) 54 patients with predominantly subjective symptoms; (2) 52 patients with objective evidence for an alternative diagnosis; (3) eight patients who had documented infection in the past and continued with symptoms after antibiotic treatment; and (4) 24 patients with a history of tick attachment or prenatal/family history of Lyme disease. Serologic testing data from commercial laboratories were available for the 54 children from the "predominantly subjective" group; 50% were negative, and 50% were borderline or positive. Ninety-two percent of these patients were negative at retesting by our enzyme-linked immunosorbent assay (ELISA) and 100% were negative by Western blot. Fifty-seven percent of these patients had received treatment prior to our evaluation. Children residing in an endemic area who present with vague symptoms are being diagnosed with and treated for Lyme disease without clinical or serologic documentation. In addition, fear in the lay community may be inducing doctors to diagnose Lyme disease in patients with symptoms that may be suggestive of an alternative diagnosis. PMID- 7859426 TI - Carotid blood-flow velocity changes detected by Doppler ultrasound in determination of brain death in children. A preliminary report. AB - To investigate the value of Doppler ultrasonography of the carotid arteries as a diagnostic test for the determination of brain death in children, we enrolled 17 patients in a blinded fashion in the pediatric intensive care unit of Memorial Miller Children's Hospital of Long Beach between the period of December 1990 and October 1992. After institutional review board approval and parental consent, children who sustained severe brain injury underwent Doppler ultrasonography study of their carotid arteries. Seven of 17 patients were diagnosed as having brain death by clinical criteria (complete loss of cerebral and brainstem functions) and electroencephalogram (EEG). Five of seven (71%) patients with the diagnosis of brain death had bilateral reverse flow (characteristic of increased cerebrovascular resistance and absent cerebral circulation) on their Doppler ultrasonography, yielding a specificity of 100% and sensitivity of 71.4% (P = 0.01). All surviving patients (five) and the five who did not fulfill the brain death criteria at the time of Doppler ultrasonography and were later taken off life supportive measures had normal Doppler findings. These data indicate that Doppler ultrasonography of the carotid arteries is a very specific test and can be used as an adjunctive modality for determination of brain death in children. PMID- 7859427 TI - New strategies for the use of short polymers of glucose in diarrhea. PMID- 7859428 TI - Utility of laboratory screening in cocaine-exposed infants. PMID- 7859429 TI - Magnetic resonance imaging in staphylococcal osteomyelitis with negative bone scan. PMID- 7859430 TI - The prenatal pediatric visit and pediatric residency training. PMID- 7859431 TI - Reflections after 30 years on the relationship between academics and private practice. PMID- 7859432 TI - Intraperitoneal bladder rupture: an uncommon manifestation of child abuse. PMID- 7859433 TI - Permanently damaged: long-term follow-up of shaken babies. PMID- 7859434 TI - Cutaneous herpes simplex virus infection in a child with acquired immunodeficiency syndrome. PMID- 7859435 TI - Treatment of myocardial infarction in elderly patients. PMID- 7859436 TI - Retrospective assessment of fibromyalgia therapeusis. AB - An effective therapeutic intervention is documented for the most common source of back pain in clinical practice: As sleep disturbance is extremely common in and can even induce fibromyalgia, it seemed reasonable to explore the efficacy of specific quality sleep-inducing agents in its management. Timely hypnotic therapy appears effective in relieving symptoms in half of all patients afflicted with fibromyalgia. PMID- 7859437 TI - Delirium: a major diagnostic and therapeutic challenge for clinicians caring for the elderly. PMID- 7859438 TI - Metabolic and nutritional considerations for exercising older adults. AB - Age-associated declines in REE and the thermogenesis of activity result in lower energy requirements in older adults. Regular aerobic exercise and resistive exercise programs will increase ones daily energy expenditure and may preserve or increase the lean body mass which has been shown to decrease with increasing age. Further, regular resistive exercise programs may improve bone mineral density and ambulation in older adults. Normal age-associated changes in gastrointestinal function and the addition of exercise may require some modification of nutrient intake. However, in the absence of gastrointestinal disease, these modifications should not be great for healthy sedentary older adults. Protein intake should be at least 1.0 g/kg body weight for older adults especially, physically active older adults. PMID- 7859439 TI - Outcome of valvular heart disease with vasodilator therapy. PMID- 7859440 TI - Common blood disorders in the elderly. PMID- 7859441 TI - The menopause: benefits and risks of hormone replacement therapy. PMID- 7859442 TI - Leg edema in the elderly: a practical diagnostic approach. PMID- 7859444 TI - RBRVS 2.0: toward a special theory of resource-based relativity. PMID- 7859443 TI - Twenty most frequent DRG groups among Medicare inpatients age 65 or older in Connecticut hospitals, fiscal years 1991, 1992, and 1993. AB - This report provides data on the frequency of inpatient admissions for the 20 most frequent DRG categories among Medicare inpatients age > or = 65 years at Connecticut acute care hospitals during the three-year period FY1991 to FY1993. Frequency distributions of the numbers of discharges within these 20 DRG categories are provided, in aggregate and by gender and age subgroups. There were 199,680 discharges of elderly Medicare beneficiaries within the 20 most frequent DRG categories in the three-year study period, 55.7% of all Medicare discharges. Within this total, there was year-to-year stability in total numbers of discharges and in the distribution of DRGs. By gender, 43% of elderly Medicare patients discharged in the three year period were men; 57%, women. Forty-one percent, 41%, and 18% of the discharges occurred among beneficiary age groups 65 to 74 years, 75 to 84 years, and > or = 85 years, respectively. PMID- 7859445 TI - Bicycle injury in Connecticut. AB - We reviewed vital statistics (1987-92) and hospital discharge data (1987-91) for Connecticut residents to describe the epidemiology of bicycle-related injuries in the state. Each year there are approximately eight deaths (rate = 0.25/100,000) and 289 hospitalizations (rate = 8.8/100,000) due to bicycle related injury. Nonfatal bicycle injuries resulted in 1,500 hospital days at a cost of $1.7 million dollars. Death and hospitalization rates are highest among male children and adolescents five to 19 years of age. Most of the mortality and serious morbidity from bicycle-related trauma is due to head injuries. Both fatal and nonfatal bicycle head injury rates are highest in towns with a population less than 50,000 residents. Bicycle-related head injury is an important cause of mortality and morbidity of Connecticut children and youth and is largely preventable through the use of bicycle helmets. The data presented here allow for the development, implementation, and evaluation of community-based bicycle safety and helmet programs. PMID- 7859446 TI - Health-care reform: we all have a role to play. PMID- 7859447 TI - Mortality and morbidity of 22- to 27-week gestational age infants born at high risk perinatal units in Connecticut in the surfactant era: what conclusions do we draw from these data? PMID- 7859448 TI - The coming brave New World. PMID- 7859449 TI - Recovery of ovarian function after childbirth, lactation and sexual activity with relation to age of women. AB - The time for recovery of ovulation, lactation and initiation of sexual intercourse after childbirth was studied in 90 women, who were divided into three groups: 1) adolescents less than 19 years old (n = 30); 2) younger mothers 19 to 32 years old (n = 30); and 3) older women more than 32 years old (n = 30). No differences were found in the duration of breast-feeding or in the initiation of sexual intercourse among the three groups. The postpartum amenorrhea in lactating women was significantly longer than in nonlactating mothers. The amenorrhea was significantly less in younger women than in older mothers and tended to be lower than in adolescents. The time between delivery and detection of ovulation was significantly longer in women who breast-fed than in those who did not. Furthermore, this time was significantly shorter in younger women than in older mothers. The present work suggests that younger women had a quicker recovery of ovarian function than adolescents and older women. PMID- 7859450 TI - Use of multiple clips for tubal occlusion in interval laparoscopic sterilization: circumstances and consequences. AB - The use of multiple clips for the occlusion of the Fallopian tubes has been reported in interval laparoscopic sterilization, but the circumstances leading to the performance of the multiple-clip procedure and its effects on safety and efficacy have not been carefully studied. A data set from international multi center clinical trials of Filshie clips and Wolf (Hulka) clips was used to examine the possible reasons for performing this procedure for 102 women. Their complications, complaints, and surgical and post-surgical events before discharge and during one month of follow-up were compared with those of the 408 women whose tubes were occluded by single clip. Results indicate that multiple clips were most often used when surgical difficulties (and to a much lesser degree, tubal and/or mesosalpingeal injury) were encountered during the sterilization procedure. No increased risk of short-term complications or complaints (including pelvic pain) was found at one-month follow-up for those patients who received multiple clips. PMID- 7859451 TI - Clinical performance of the TCu 380A and TCu 220C IUDs in four developing country family planning clinics. AB - The clinical performance of the Copper T 380A (TCu 380A) and the Copper T 220C (TCu 220C) intrauterine devices (IUDs) were evaluated for 12 months in a group of women who had one of the two IUDs inserted. Results are from a randomized clinical trial conducted at four collaborating research sites located in two developing countries. The gross cumulative life-table pregnancy rate of the TCu 380A IUD was found to be lower than that of the TCu 220C IUD at 12 months (0.3 and 0.8, respectively), although this difference was not statistically significant (p > 0.05). Statistically significant differences between the two study IUDs were not found with regard to IUD expulsion or IUD removal due to bleeding/pain, personal reasons, medical reasons, or planned pregnancy. No statistically significant differences were observed in the frequency of experiencing menstrual disturbances (i.e., dysmenorrhea, intermenstrual pelvic pain or intermenstrual bleeding) between the two IUD groups. These data suggest that the TCu 380A and TCu 220C IUDs are both appropriate options for contracepting women. The TCu 380A IUD, however, may be a more appropriate option for those women wishing to space births over a longer period of time. PMID- 7859452 TI - Risk of cervical dysplasia in users of oral contraceptives, intrauterine devices or depot-medroxyprogesterone acetate. The New Zealand Contraception and Health Study Group. AB - Three cohorts of women aged 20-39 attending medical practitioners or family planning clinics in New Zealand for contraceptive advice were followed prospectively for five years. The three cohorts were defined by use (or at least prescription) of one of three study contraceptive methods at the time of beginning of follow-up--oral contraceptives (OC), intrauterine devices (IUD) or depot-medroxyprogesterone acetate (MPA)--and numbered 2469, 2072 and 1721 women, respectively. Follow-up was intended to be annual and included cervical smear as well as interim contraceptive and medical histories. A positive outcome (referred to here as 'dysplasia') was any degree of definite dysplasia or carcinoma of the cervix diagnosed cytologically by a central study laboratory, and confirmed by histology or analysis of DNA ploidy. In the three cohorts (OC, IUD and MPA, respectively), 12,839, 10,774 and 8,984 person-years of follow-up were accumulated and 125, 92 and 101 cases of dysplasia were confirmed. Crude annual rates of dysplasia per 1,000 person-years were approximately the same in the OC (9.6) and IUD (8.4) cohorts. Crude rates were higher in the MPA cohort (11.3 per 1,000 person-years). However, important confounding factors, principally smoking and sexual behavior, were identified with rate ratios ranging between 1 and 3 over the range of the potentially confounding variables, and multivariate analyses revealed no evidence of increased risk for the MPA cohort when these factors were taken into account. At least over the short term, there appears to be no difference in risk of cervical dysplasia between women using these three methods of contraception if differences between groups in respect to known confounding factors are taken into account. PMID- 7859453 TI - History of long-term use of depot-medroxyprogesterone acetate in patients with cervical dysplasia; case-control analysis nested in a cohort study. The New Zealand Contraception and Health Study Group. AB - Histories of use of depot-medroxyprogesterone acetate (MPA) given by women entering a previously-reported prospective study of risk of cervical dysplasia, including carcinoma, have been evaluated. Over a six-year follow-up period, 348 of the 7199 enrolled women developed cervical dysplasia diagnosed by cytology and confirmed by histology or DNA analysis. Use of MPA prior to entry into the study was reported somewhat more commonly and for somewhat longer periods by the women who developed confirmed dysplasia than by those who did not. However, this association was accounted for entirely by the fact that women who reported use of MPA, particularly at an early age, tended to carry a number of known strong risk factors for dysplasia, specifically, first intercourse at an early age, multiple sex partners and cigarette smoking. These findings indicate that the lack of relationship of MPA use to risk of cervical dysplasia, noted previously for women whose median duration of use within the formal study period was about 2 years, extended to the same women who used MPA prior to the study period--even to those whose duration of prior use was 4 years or more. PMID- 7859454 TI - Contraceptive outcomes among post-partum and post-abortal adolescents. AB - Between January 1992 and January 1993, there were 280 teens (ages 13-18) who either delivered a baby or terminated a pregnancy at Johns Hopkins Bayview Medical Center. Of these, 92 chose to contracept with Norplant implants, and 188 chose another method including "no" method. In July 1993, telephone interviews were conducted with 37 of those who chose Norplant implants and 41 of the non Norplant implants users. After 1 year, 47% of oral contraceptive (COC) users had discontinued the method compared to only 16% of Norplant implants users (P < 0.03). Reasons for discontinuation centered on side effects for both groups but with some COC and condom users, discontinuing use due to "forgetfulness" or failure (pregnancy). Among the COC group (which was the most common choice after Norplant implant), 25% of the adolescents had experienced a subsequent unplanned pregnancy compared to 0% of the Norplant implant group (P < 0.01). Norplant implants were clearly an acceptable and effective contraceptive for these post partum and post-abortal teens, who articulated a high motivation to avoid a subsequent unplanned pregnancy. However, it is clearly not the only method teens will choose to use, and more attention must be paid to adequate counseling of those choosing another method. PMID- 7859455 TI - Cervical ripening with mifepristone (RU 486) in late first trimester abortion. World Health Organization Task Force on Postovulatory Methods of Fertility Regulation. AB - In order to further evaluate the usefulness of the antiprogestogen, mifepristone, as a cervical ripening agent, a double-blind multicentre study was undertaken of 230 primigravid women with 10-12 weeks amenorrhoea who were randomly assigned to receive either 0 (placebo) or 200 mg of mifepristone 36 hours before surgical pregnancy termination. Fifteen women who did not fulfil all of the selection criteria were excluded from analysis. In the mifepristone group (N = 105) 12 women experienced some pre-operative vaginal bleeding as compared with only one subject in the placebo group (N = 110), but only one of these 12 women described the bleeding as more than her usual menstrual flow. In mifepristone-treated women the cervix was about 1 mm more dilated at operation and further mechanical dilatation was needed less frequently than in placebo-treated controls. High resistance during further mechanical stretching was encountered significantly more often and at a smaller cervical diameter in the placebo group than in the women given mifepristone. Also, dilatation was reported by the operating surgeons to be easier in women given the antiprogestogen. Other significant differences included a shorter operation time, lower peroperative blood loss and less frequent use of analgesic drugs post-operatively in the mifepristone group. Post operative complications, the duration of post-operative bleeding and the interval to the first menstruation were similar in both groups. The results confirm that the antiprogestogen, mifepristone, is an effective cervical ripening agent which deserves further study in comparison with the currently used methods, i.e. prostaglandins and osmotic dilators. PMID- 7859456 TI - Immunohistochemical staining of von Willebrand factor in endometrium of women during the first year of Norplant implants use. AB - The mechanisms responsible for Norplant implants-induced menstrual irregularities remain poorly understood. It is unclear whether local changes in endometrial haemostasis are involved. The aim of the present study was to examine the immunohistochemical staining for von Willebrand factor (vWF) in endometrial biopsies taken from 37 women exposed to Norplant implants for 3-12 months and to compare it with 73 controls at various phases of the normal menstrual cycle. The vWF staining intensity was quantified by subjective scoring and by objective computerised colour image analysis. Results from the Norplant implants group were additionally correlated with their bleeding patterns, endometrial histology, and plasma oestradiol (E2) and progesterone (P4) levels. No differences were found between control and Norplant implants subjects in the localization of vWF staining, which was specifically confined to the endothelium of endometrial blood vessels. vWF staining intensity in Norplant implants endometrium was significantly lower than in controls during mid cycle, and reached a mean (+/- SE) level (subjective staining score 2.05 +/- 0.13, n = 37) in the range of the early proliferative and mid secretory phase normal endometrium; nevertheless, it remained significantly higher than that of menstrual and late secretory phase normal endometrium. No significant variations in vWF staining could be related to either the histology of the endometrium or the bleeding pattern of the users. Correlation of vWF staining with either serum E2 or serum P4 prior to biopsy, or to the number of days of Norplant implants exposure revealed no significant relationships. However, vWF staining was positively correlated (r = 0.419, P < 0.01) to the number of bleeding/spotting days within a 90-day reference period prior to biopsies being taken. These results demonstrate that there are major differences in the mechanism responsible for normal menstruation and Norplant implants-induced intermenstrual bleeding and spotting, and show that menstrual disturbances associated with the use of Norplant implants are unlikely to be due to changes in vWF levels in endometrial endothelial cells. PMID- 7859458 TI - Evaluating quantitative research designs: Part 1. AB - This article has provided an overview of the three major types of quantitative designs commonly used in nursing research, as well as some criteria for evaluating the designs of published research. The next column will include additional criteria for critiquing quantitative research designs. PMID- 7859457 TI - The influence of vasectomy and vasovasostomy on testicular ATPases, cAMP, ABP and androgen receptor in rabbits. AB - The present study was performed to further clarify the influences of vasectomy on functions of testis and to disclose the possible mechanisms of infertility after vasovasostomy (VV). Thirty-one rabbits were divided into sham-operated control group (C), vasectomy control group (V), VV fertility group (VaF) and VV infertility group (VaI). Serum testosterone (ST) level, testicular cAMP, androgen binding protein (ABP), nuclear androgen receptor (NAR) concentrations, testis cell membrane Na(+)-, K(+)-ATPase, Mg(2+)-ATPase activities, sperm density and testis weight were measured. Vasectomy resulted in significantly reduced cAMP, Na(+)-, K(+)-ATPase, Mg(2+)-ATPase, testis weight and increased ABP; VV completely restore testis weight in VaF and VaI, Na(+)-, K(+)-ATPase, Mg(2+) ATPase in VaF, partly cAMP in VaF and VaI, Na(+)-, K(+)-ATPase, Mg(2+)-ATPase in VaI, but did not restore ABP. The NAR content in VaI was significantly lower than those in C, VaF and V. No statistical differences among 4 groups were seen in Kd values for [3H]-T. ST levels in VaF, VaI and V were insignificantly different compared with C, but the value in VaF was higher than that in VaI (p < 0.05). Sperm density after VV reached 122 +/- 62 x 10(6)/ml in VaF and 10 +/- 24 x 10(6)/ml in VaI, both in VaF and VaI were significantly low compared with C (p < 0.001), and the value in VaI was remarkedly lower than that in VaF (p < 0.001). It was shown that sperm density was positively correlated with cAMP content, Na(+)-, K(+)-ATPase, Mg(2+)-ATPase activities, but negatively with ABP. These results suggest that vasectomy gives rise to damage to the testis, and vasovasostomy does not appear completely effective in reversing testicular changes. PMID- 7859459 TI - Job satisfaction among critical care preceptors. PMID- 7859460 TI - The patient-driven system. PMID- 7859462 TI - A kinder, gentler ICU waiting room. PMID- 7859461 TI - Open forum--neuromuscular blockade to optimize ventilation is becoming common. How does your unit assess/monitor blockade level? PMID- 7859463 TI - Pain management: dispelling some myths. PMID- 7859464 TI - Readers offer comments on IABP waveform assessment. PMID- 7859465 TI - Peripheral intra-arterial thrombolytic therapy for acute arterial occlusion. AB - Because of the success of urokinase therapy, the expectation is that more patients with peripheral vascular disease will be treated with urokinase or another thrombolytic agent. For that reason, nurses must become proficient in caring for these patients. The standing orders and care map, along with the appropriate nursing diagnoses, offer the nurse concrete guidelines for the care of these patients. PMID- 7859466 TI - Interpleural analgesia: a new technique. PMID- 7859467 TI - Problem solving in pain management by expert intensive care nurses. PMID- 7859468 TI - Independent nursing interventions: relaxation and guided imagery in critical care. PMID- 7859469 TI - Saying goodbye. PMID- 7859470 TI - Noninvasive hemodynamic monitoring with thoracic electrical bioimpedance. AB - TEB is proving to be an exciting hemodynamic monitoring technique. It has been shown to accurately measure trends in the patient's volume and vasoactive state without the risks and discomfort of invasive monitoring. It can be applied easily and does not require specialized skill of nurses or physicians. A broad range of patient information can be displayed. However, continued education and implementation are important in helping nurses become adept at analyzing parameters that have not been measured with traditional monitoring. Further research is required to explore its possibilities and to determine which patients will benefit most from this form of monitoring. PMID- 7859471 TI - Sodium balance in very-low-birth-weight infants. AB - Maintaining sodium balance in the VLBW infant is not straightforward. Several predisposing factors appear in more than one imbalance constellation. In addition, the same patient circumstance can produce two types of imbalance. Understanding the physical properties of electrolytes and water enables critical care nurses to anticipate outcomes of specific situations in the neonatal ICU. Careful assessment of renal function, urine output, and water balance are crucial in determining proper treatment of sodium balance disorders. The high potential risk of errors in the neonatal ICU requires verification of all fluid and electrolyte orders, as well as serial safety checks of IV fluids and additives to avoid complications. An expert nurse's ability to predict the needs of VLBW infants places the nurse in a pivotal position to recognize subtle changes before actual physiologic change occurs. Although the multiple variations can be confusing to the bedside clinician, sorting through them helps in selecting interventions that are timely and improve the outcomes and morbidity of our smallest patients at risk. PMID- 7859472 TI - Epidural analgesia for effective pain control. AB - Over the past decade, awareness of the harmful effects of postoperative pain has increased. These effects seem to be intensified in critically ill patients. Epidural analgesia has been shown to improve pulmonary function in the critically ill, including a reduction in frequency of intubation and tracheostomies and decreased length of mechanical ventilatory support. In addition, the heightened metabolic-stress response associated with pain may be averted, thereby reducing problems with fluid retention that may further compromise pulmonary status. As a result, epidural analgesia can lead to: shortened length of stay in the ICU overall decreased mortality rate improvement in quality of life As a pain-control method, epidural analgesia is gaining popularity in a variety of ICU patient populations. Therefore, critical care nurses need to update their knowledge base and nursing practice to provide safe and effective nursing care. State nurse practice acts and agency policies dictate the amount and type of involvement nurses have in caring for patients receiving epidural pain therapy. Potential life-threatening problems with epidural analgesia are rare. Many side effects can be controlled or prevented with appropriate patient selection and nursing management. PMID- 7859473 TI - Beth Henneman's ICU passion is all in the family. Interview by Michael Villaire. PMID- 7859474 TI - Promoting collaboration in ethical decision making. PMID- 7859475 TI - Suicide and aging in Japan. PMID- 7859476 TI - Jail suicide in Mississippi. PMID- 7859477 TI - What are hotlines? PMID- 7859478 TI - Commitment decisions: identification of indeterminate cases. AB - Research shows that most involuntary commitments conform to legal criteria and that psychiatrists generally agree on which patients should be committed. There are many cases, however, that cause disagreement among psychiatrists making commitment decisions. No research has been done regarding types of cases causing disagreement. The authors developed 10 clinical vignettes termed "ambiguous case constructs" that could be proven to be indeterminate and explore what underlying themes these indeterminate cases might hold in common. A pilot study was conducted to develop a set of 10 clinical vignettes, which were found to be representative of psychiatric emergencies and likely to cause discordance among evaluating psychiatrists. These validated vignettes were then presented to 62 psychiatrists who were asked to determine the commitment disposition for each vignette patient. Seven of these vignettes elicited significant disagreement among respondents and were identified as indeterminate cases. The frequency and percentage of psychiatrists endorsing commitment for each vignette is listed. This study validates the existence of indeterminate cases which prompt disagreement among psychiatrists making commitment decisions. Upon retrospective review, disagreement evoked by the seven indeterminate cases is proposed to have originated from one of four themes. The implications for clinical practice are noted. PMID- 7859479 TI - Epidemiological aspects of attempted suicide--a case-control study in Gent, Belgium. AB - In order to study the distribution of attempted suicide among the population of Gent, exploratory and analytical case-control studies were carried out. The strength of the association between attempted suicide and marital and employment status was calculated taking into account the confounding and/or effect-modifying roles of age, gender, and the living situation. Unmarried individuals who were not living alone were at increased risk of attempted suicide compared to (cohabiting) married individuals. Young and middle-aged unemployed males and middle-aged unemployed females had significantly increased risks compared to employed individuals. In addition to a causal interpretation of the demonstrated associations, the roles of chance, reverse causality, and confounding or bias were considered. Selection and information biases may have accounted for the observed associations. For instance, in previous monitoring studies on attempted suicide, surprisingly little attention has been paid to the reliability of the information collected. The question of how one can reliably assess patients who may provide unreliable information remains unanswered. However, several findings support a role of causality in explaining the associations. The present studies therefore provide additional evidence for a detrimental affect of certain socio demographic or -economic conditions on the occurrence of attempted suicide. PMID- 7859480 TI - The epidemiology of attempted suicide in the Oxford area, England (1989-1992). AB - The epidemiological and clinical characteristics of attempted suicide in Oxford, United Kingdom, between 1989 and 1992 are reported on the basis of data collected as part of the WHO/EURO Multicentre Study of Parasuicide in Europe. Some further findings for the period 1976-1992 are also described. Rates of attempted suicide were particularly high among females aged 15-19 years. There was a very marked association in males and females between attempted suicide and both lower socioeconomic status and unemployment. The percentage of first-time attempters entering the attempted suicide population remained steady between 1976 and 1992, with approximately two-thirds of attempters each year making their first attempts. There was a great increase in the use of paracetamol (acetominophen) for self-poisoning between 1976 and 1992, this being involved in 14.3% of overdoses in 1976 and 43.2% in 1992. On the basis of the Oxford rates, there are approximately 100,000 general hospital admissions for attempted suicide each year in England and Wales, approximately 19,000 involving teenagers (mostly girls). Oxford has a similar pattern of attempted suicide to that in the rest of the UK. The findings indicate that the UK has one of the highest rates of attempted suicide in Europe. PMID- 7859481 TI - Attempted suicide and recent stressful life events: a report from India. PMID- 7859482 TI - Suicide in the Ukraine. PMID- 7859483 TI - Reconsidering prevention concepts. PMID- 7859484 TI - Befriending the suicidal in India--a column from Befrienders International. PMID- 7859485 TI - Familial combined hyperlipidemia in children: clinical expression, metabolic defects, and management. AB - The first evidence that elevation of plasma levels of cholesterol is a risk factor for the development of atherosclerosis in children came from the Bogalusa Heart Study in 1986, which reported an association between aortic fatty streaks in 3- to 26-year-old subjects and increased plasma levels of low-density lipoprotein cholesterol (LDL-C). The most compelling evidence of a cause-and effect relationship has come from the multicenter cooperative study called the Pathobiological Determinants of Atherosclerosis in Youth. When the investigators examined the abdominal aorta and the right coronary artery of adolescents and young adults who had died of trauma, they found a significant relationship between the sum of the very low density lipoprotein (VLDL) plus LDL-C level and both fatty streaks and raised atherosclerotic lesions. They also found an inverse relationship between those lesions and increased high-density lipoprotein cholesterol (HDL-C) levels. In addition, their studies showed that smoking (as assessed by the serum thiocyanate level) promotes atherogenesis in children as young as age 15 years. Thus many pediatricians have now accepted the importance of identifying children with significant hypercholesterolemia so that appropriate dietary and life-style modifications can be recommended. This is especially important because there is often a major genetic component to the hyperlipidemia seen in children. PMID- 7859486 TI - Effective well-child care. PMID- 7859487 TI - Rationale and prospects for rabies elimination in developing countries. PMID- 7859488 TI - Human rabies: clinical aspects, pathogenesis, and potential therapy. PMID- 7859489 TI - Current and future immunoprophylaxis against human rabies: reduction of treatment failures and errors. PMID- 7859490 TI - Production of human monoclonal antibodies against rabies virus. PMID- 7859491 TI - Bat lyssaviruses in Europe. PMID- 7859492 TI - Oral wildlife rabies vaccination field trials in Europe, with recent emphasis on France. PMID- 7859493 TI - Oral rabies immunization of wildlife and dogs: challenges to the Americas. PMID- 7859494 TI - The biology of southern African lyssavirus variants. PMID- 7859495 TI - Functional aspects of lyssavirus proteins. PMID- 7859496 TI - Rabies epidemiology: some ecological and evolutionary perspectives. PMID- 7859497 TI - Beyond Pasteur to 2001: future trends in lyssavirus research? PMID- 7859498 TI - Reproduction of lyssaviruses: ultrastructural composition of lyssavirus and functional aspects of pathogenesis. AB - Lyssaviruses are considerably adapted to neural tissue, although they can also be replicated in muscle and glandular cells. In neural tissue their reproduction takes place almost exclusively in neurons, and in the course of their dissemination they make use of the structural peculiarities of this highly differentiated cell type. The replication takes place completely in the cytoplasm, although rhabdovirus leader RNA enters the nucleus and by blocking host DNA and RNA synthesis promotes viral synthetic processes. In the cytoplasm the two phases of viral reproduction, the synthesis of nucleocapsids and the formation of the envelope together with the assembly of the virion, are separate in time and space. By this separation the transmission of infection by the incomplete form of the virus, i.e., by the synaptic transfer of ribonucleoprotein transcriptase complexes is also possible. The formation of viral envelope and assembly of full viruses on the cisternal system of the host neurons is a highly complex process, as presented here in a three-dimensional analysis. Due to the high complexity of virus assembly, defects in construction are frequent, accounting for the high yield of defective interfering particles in the course of the reproduction of lyssaviruses. PMID- 7859499 TI - The molecular basis for altered pathogenicity of lyssavirus variants. PMID- 7859500 TI - Animal models of rabies virus neurovirulence. PMID- 7859501 TI - The pathogenesis of rabies and other lyssaviral infections: recent studies. PMID- 7859502 TI - Epiphytic fitness of phytopathogenic bacteria: physiological adaptations for growth and survival. PMID- 7859503 TI - The genetic and chemical basis of recognition in the Agrobacterium: plant interaction. PMID- 7859504 TI - Does Rhizobium avoid the host response? PMID- 7859505 TI - Molecular and cellular mechanisms of Salmonella pathogenesis. PMID- 7859506 TI - Molecular and genetic determinants of the Listeria monocytogenes infectious process. PMID- 7859507 TI - Shigella flexneri: genetics of entry and intercellular dissemination in epithelial cells. PMID- 7859508 TI - Yersinia pathogenicity factors. PMID- 7859509 TI - Surface-associated and soluble components of Vibrio cholerae involved in bacteria host interactions. PMID- 7859510 TI - Biology of the pathogenic Neisseriae. PMID- 7859511 TI - Pathogenicity determinants and global regulation of pathogenicity of Xanthomonas campestris pv. campestris. PMID- 7859512 TI - Pathogenicity mechanisms of Bordetella. PMID- 7859513 TI - Erwinia chrysanthemi and Pseudomonas syringae: plant pathogens trafficking in extracellular virulence proteins. PMID- 7859514 TI - hrp genes of phytopathogenic bacteria. PMID- 7859515 TI - The enigmatic avirulence genes of phytopathogenic bacteria. PMID- 7859516 TI - Differential sensitivity patterns in small cell lung cancer cell lines: detection and circumvention of resistance to topoisomerase II targeting drugs. PMID- 7859517 TI - Anesthesia related hypoxemia. The effect of pulse oximetry monitoring on perioperative events and postoperative complications. AB - The objectives of the present investigation were to evaluate the extent of perioperative hypoxemia and to investigate the impact of pulse oximetry monitoring on the extent of hypoxemia and on perioperative morbidity in adults. To accomplish these objectives a number of prospective studies were carried out. The incidence, duration, and severity of hypoxemia were evaluated in two single blinded observer studies in the operating room (N = 296) (I) and in the Postanesthesia Care Unit (N = 200) (II). Pulse oximetry monitoring's effect on the extent of hypoxemia was evaluated in a randomized blinded observer study of 200 patients (III). The impact of pulse oximetry on the frequency of perioperative events, changes in patient care, and post-operative complications were studied in a randomized evaluation of 20,802 patients (IV-V). Finally, a subgroup of 736 patients already included in the randomized evaluation was psychologically evaluated pre- and postoperatively (VI). In the observer studies in the OR and PACU mild hypoxemia (SpO2 86-90%) was recorded in 53% and 55% of the patients, respectively. Severe hypoxemia with SpO2 values < 81% was recorded in 20% and 13% of the patients, respectively. In the randomized blinded observer study, patients with pulse oximeter data available had a significantly reduced incidence of perioperative hypoxemia when compared to patients where the data were unavailable. Most noteworthy was that in the available group extreme hypoxemia (SpO2 < 76%) was not encountered in the OR and both severe (SpO2 76 80%) and extreme hypoxemia were not observed in the PACU. In the randomized evaluation of pulse oximetry significantly more patients in the oximetry group experienced at least one respiratory event than did control patients in both the OR and in the PACU. This was a result of a 19 fold increase in the incidence of diagnosed hypoxemia in the oximetry group than in the control group. In the OR cardiovascular events were observed in a similar number of patients in both groups, except myocardial ischemia, which was detected in 12 patients in the oximetry group and in 26 patients in the control group (P < 0.03). Several changes in PACU care were observed in association with the use of pulse oximetry. These included higher flow rates of supplemental oxygen (P < 0.00001), increased use of supplemental oxygen at discharge (P < 0.00001), and increased use of naloxone (P < 0.02). One or more postoperative complications occurred in 10% of the patients in the oximetry group and in 9.4% in the control group (NS).(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7859518 TI - An evaluation of computer-aided differential diagnostic models in jaundice. PMID- 7859519 TI - Some aspects of lower esophageal sphincter (LES) physiology and pathophysiology. PMID- 7859520 TI - The microcirculation of the heart. With special reference to the role of reactive oxygen metabolites in the microvascular reperfusion injury. PMID- 7859521 TI - Chronic widespread musculoskeletal pain--the fibromyalgia syndrome. PMID- 7859522 TI - Bone banking in Denmark, results of a nationwide survey. AB - In a nationwide survey, all orthopaedic clinics were surveyed via a questionnaire about the use of bone allografts and how they managed their bone banks. Thirty two clinics (100 per cent) responded to the questionnaire (mid 1991). Seventeen clinics had established bone banks on the basis of femoral heads obtained from donors during primary hip replacement. Only five used bone substitutes. The mean consumption was 30 capita per year (10-132) and ten clinics estimated an increasing demand for allografts. The storage method was by freezing at temperatures varying from minus 20 to minus 80 degrees Celsius. Contraindications to procurement comprised history of infection and malignancy, all clinics tested donors for HIV antibodies and all but one for hepatitis B. Testing for hepatitis C was about to be introduced. All but one clinic developed cultures from the procured bone. Informed consent was employed by nearly all clinics, but very few obtained written consent. Since this survey, revised recommendations have been directed from the Danish National Board of Health, these listing that an HIV-test should be performed with a 90-day interval, and that testing should also be done for hepatitis B and C. International experience and this survey show that the establishment of more specific and general national recommendations would be preferable to present practice. PMID- 7859523 TI - Weight, length, head circumference, and growth velocity in a longitudinal study of Danish infants. AB - Two longitudinal studies of infant growth, performed from 1985 to 1988 in the Copenhagen area, have been combined to develop an up-to-date growth reference. Percentile curves were constructed and median growth velocities were calculated for monthly intervals, based on individually estimated growth curves. Compared with references based on data from periods when the prevalence of breast-feeding was low, these data support previous suggestions of a new growth pattern, with higher velocities during the first months and slower velocities during the remaining infancy. The growth of breast-fed infants differs from that of infants not being breast-fed, and special growth references for breast-fed infants have been suggested. We therefore examined growth patterns in the present study according to duration of breast-feeding. At 12 months, infants breast-fed > or = 9 months weighed less (400 g (95% CI: 70 g, 740 g) and were 1.0 cm shorter (0.3 cm, 1.8 cm) than infants breast-fed < 9 months. Part of this difference was already present at six months. Despite this we recommend a single growth reference for Danish infants regardless of mode of feeding. The slower growth in infants breast-fed > or = 9 months, which could be due to differences in composition of weaning foods, should be investigated further. PMID- 7859524 TI - Surgical treatment of primary hyperparathyroidism. AB - One hundred and two patients with primary hyperparathyroidism underwent a total of 108 bilateral neck explorations with attempted identification and biopsy of all four glands. Hypercalcaemia was surgically eliminated in 97 of 102 patients (95%). Of the remaining hypercalcaemic patients one was cured by percutaneous ethanol injection and one was reoperated and cured in another hospital. Three patients with persistent hypercalcaemia refused reoperation. Transitory hypocalcaemia with a median duration of 15 days was found in 36 patients, and permanent hypocalcaemia in two patients (1.9%). Permanent paralysis of the recurrent nerve occurred in three patients (2.9%). Twenty-one patients developed other postoperative complications from which they all recovered without sequelae. No postoperative deaths occurred. Our results show that surgical treatment of primary hyperparathyroidism--including bilateral neck exploration and attempted biopsies of all parathyroid glands--is safe with a high cure rate. PMID- 7859525 TI - Criterion-related validity of screening for exposure to torture. AB - Using an in-depth psychological assessment as reference, the aim of the study was to validate adult Middle Eastern refugees' own testimonies of their possible previous exposure to torture. The study group comprised 31 male and 43 female refugees, who accepted participation in a structured interview with closed questions and a following blinded in-depth psychological interview. According to the psychological interview, 30% (55% of males, 12% of females) had been exposed to torture. The sensitivity and the specificity of the structured interview in identifying previous torture was 82% and 92%, respectively, without significant differences concerning the refugee's gender. It is concluded that refugees' own testimonies of torture appear fairly valid. This enables anamnestic torture prevalence estimation in refugee groups, based on pre-structured interview techniques. Rehabilitation and Research Centre for Torture Victims (RCT), Copenhagen, and Department of Epidemiology and Social Medicine, Aarhus University. PMID- 7859526 TI - Swallowing therapy of neurologic patients: correlation of outcome with pretreatment variables and therapeutic methods. AB - The results of swallowing therapy in 58 patients with neurologic disorders are presented. All patients received tube feeding, either partially or exclusively, at admission, and successful outcomes, defined as exclusively oral feeding, were achieved in 67% of patients over a median treatment interval of 15 weeks. A subset of 11 patients who had experienced disease onset 25 weeks or more prior to admission nonetheless had a similar success rate of 64%. No other pretreatment variable, including age, localization of lesion, type or degree of aspiration, or cognitive status, correlated with successful outcome. Indirect therapy methods such as stimulation techniques and exercises to enhance the swallowing reflex, alter muscle tone, and improve voluntary function of the orofacial, lingual, and laryngeal musculature were utilized in all but 1 patient. Direct methods including compensatory strategies such as head and neck positioning, and techniques such as supraglottic swallowing and the Mendelsohn maneuver were additionally employed in nearly one-half of patients. Swallowing therapy is associated with successful outcome, as defined by exclusively oral feeding, among patients with neurogenic dysphagia, regardless of pretreatment variables including time since disease onset. Indirect treatment methods appear to be effective when used either alone or in combination with direct methods. Achievement of oral feeding is not associated with undue risk of pneumonia. Further rigorous scientific studies are needed. PMID- 7859527 TI - Surface electromyographic biofeedback and the patient with dysphagia: clinical opportunities and research questions. PMID- 7859528 TI - Manometric characteristics of the pharynx, upper esophageal sphincter, esophagus, and lower esophageal sphincter in patients with oculopharyngeal muscular dystrophy. AB - Improved techniques in esophageal manometry have made this test an attractive option for investigating pharyngeal or esophageal disorders in patients with dysphagia. We studied esophageal as well as upper esophageal sphincter/pharyngeal (UES/P) pressure dynamics in 11 patients with an established diagnosis of oculopharyngeal muscular dystrophy with modern solid-state manometric techniques and then compared manometric and clinical findings. Esophageal manometric abnormalities were found in 10/11 patients, with the most common being simultaneous contractions and incomplete lower esophageal relaxation. 9/11 patients showed abnormal UES/P manometrics, with the most common abnormalities found in the pharynx. The presence of manometric abnormalities closely paralleled clinical assessment of degree of disease severity. Modern manometric techniques offer an opportunity for a quantitative assessment of swallow abnormalities. PMID- 7859529 TI - Using cervical auscultation in the clinical dysphagia examination in long-term care. AB - The ability of the clinical dysphagia examination to identify patients who aspirate and to determine specialized diet management has been suspect. In long term care, however, the clinical examination can be the only assessment procedure available to clinicians. Cervical auscultation with stethoscope was incorporated into the clinical examination for dysphagia in an attempt to enhance the clinical examination's ability to detect aspiration and to determine specialized diet management in long-term care. Comparison of the clinical examination's results with results from videofluoroscopy revealed significant agreement in both areas. Results support the use of cervical auscultation as a highly sensitive and specific method of dysphagia assessment in long-term care. PMID- 7859530 TI - Dysphagia following strokes: clinical observations of swallowing rehabilitation employing palatal training appliances. AB - A retrospective study was undertaken to evaluate the progress of a group of dysphagic stroke patients for whom a dental prosthesis the Palatal Training Appliance (PTA), was used in the active rehabilitation of the swallowing mechanism. Patients selected were those who had sustained a stroke uncomplicated by other neurological illness, during one 12-month period, and whose dysphagia caused anxiety to the medical staff in the hospital ward. Thirty severely dysphagic stroke patients satisfied these criteria. The study recorded the duration and type of supplementary feeding required during hospitalization. Thirteen patients had evidence of aspiration before the PTA was fitted and 5 afterwards. Seven patients died, but only 1 was recorded as having a febrile illness which may have contributed to the death. At discharge, which averaged 10 weeks after admission, 22 of the 23 survivors were taking an adequate oral diet. It was also noted that almost half of the patients who wore dentures before the cerebrovascular event were unable to control them afterwards, adding to their neurological swallowing difficulties. The fitting of a PTA and correction of unstable dentures appeared to help both motivation and function. The results show an improvement in the rehabilitation of oral feeding compared with previous reports by other authors, who did not use the dental appliance. There did not appear to be any medical contraindication to its use. PMID- 7859532 TI - The unrealized potential of pharyngeal manometry. PMID- 7859531 TI - Simultaneous videoradiography and pharyngeal solid state manometry (videomanometry) in 25 nondysphagic volunteers. AB - Recent technological advances in manometry, including solid state transducers and computerized analysis, allows for reliable interpretation of intraluminal pharyngeal pressures. Simultaneous videoradiography (barium swallow) provides fluoroscopic control of the manometric sensors (videomanometry), thereby eliminating the uncertainty of sensor dislocation during laryngeal elevation. This is the first study describing normal manometric parameters in videomanometry during barium swallow. Seven manometric parameters and six videoradiographic parameters were analyzed. We included 25 nondysphagic volunteers with normal videoradiographic parameters in the study. The examination was performed in an upright physiologic position during 10-ml barium and dry swallows. Mean resting pressure in the upper esophageal sphincter was 89.6 +/- 32.6 (+/- 2 SD) mmHg. Mean residual pressure during relaxation of the upper esophageal sphincter was 7.2 +/- 8.0 (+/- 2 SD) mmHg during barium swallow and 3.8 +/- 6.2 (+/- 2 SD) mmHg during dry swallow. The mean duration of upper esophageal sphincter relaxation was 601 +/- 248 (+/- 2 SD) msec. The mean peristaltic contraction of the upper esophageal sphincter was 253.8 +/- 142.8 (+/- 2 SD) mmHg. Fourteen (56%) of the 25 had a measurable intrabolus pressure (mean 33.2 +/- 17.3 mmHg) at the level of the inferior pharyngeal constrictor. A specific finding was discovered when the epiglottis tilts down hitting the manometric sensor. This epiglottic tilt was identified in 7 subjects (28%) and caused pressures of around 600 mmHg. A standardized manometric technique is important in videomanometry, and normal values as described in this study are essential in clinical use. PMID- 7859533 TI - Autonomic nerve dysfunction in patients with bolus-specific esophageal dysmotility. AB - The pathogenetic mechanisms causing esophageal dysmotility is not well understood. We examined 13 patients with solid bolus dysphagia in a radiologic barium study including the swallowing of a 14-mm tablet. In all 13 patients the tablet was caught in the proximal or midesophagus. In 8 patients, the entrapment was associated with symptoms (Group 1) whereas in 5 patients (Group 2), no symptoms were reported. All 13 patients together with a control group of 56 healthy, nondysphagic subjects were tested for autonomic nerve function. Autonomic nerve function tests included registration of electrocardiographic R-R interval variation during deep breathing test (E/I ratio), a test of parasympathetic, vagal, nerve function. The results showed that the E/I ratio was significantly lower in patients with symptoms of bolus-specific esophageal dysmotility (-2,19 [1.76]) (median [interquartile range]) compared with patients without symptoms (0.05 [2, 87], p = 0.0192) and controls (-0.25 [1.26], p = 0.0009). In conclusion, symptomatic bolus-specific esophageal dysmotility is associated with vagal nerve dysfunction. PMID- 7859534 TI - Squamous cell carcinoma of the esophagus after partial gastrectomy. AB - Twelve patients (10.4%) had a history of partial gastrectomy among the 115 patients with squamous cell carcinoma of the esophagus. The clinical characteristics, nutritional parameters, and incidences of esophagitis of the resected specimens were investigated between 11 patients with esophageal carcinoma who had partial gastrectomy for peptic ulcer diseases (Group A) and 103 patients with esophageal carcinoma without any previous history of gastrectomy (Group B). Age, sex, tumor location, clinical stages, and cigarette and alcohol consumption were not different between the two groups. Hemoglobin, mean corpuscular volume, and mean corpuscular hemoglobin level in Group A were lower than those in Group B (p < 0.05). Serum zinc level in Group A was lower than that in Group B, but this difference was not significant. There was no difference in the incidences of esophagitis between the two groups. In conclusion, there is an association between partial gastrectomy and later development of squamous esophageal carcinoma. The role of malnutritional factors and gastroesophageal reflux, however, remain unclear. The long-term follow-up of patients after partial gastrectomy is warranted. PMID- 7859535 TI - Mediastinal histoplasmosis presenting with esophageal involvement and dysphagia: case study. AB - Esophageal involvement with histoplasmosis is uncommon, but has been recognized in two clinical settings. Most commonly, the esophagus becomes involved as a result of contiguous mediastinal lymphadenopathy. Such patients usually present with dysphagia secondary to midesophageal compression or stricture. The esophagus can also be involved in cases of disseminated histoplasmosis. Esophageal ulcers or nodular lesions are the usual clinical manifestations in this setting. We report a case of mediastinal histoplasmosis with esophageal narrowing and mucosal ulceration that presented with dysphagia. The diagnosis was established at thoracotomy by the histologic finding of necrotizing granulomas and a positive fungal stain. The case was successfully treated with amphotericin B. The literature on esophageal and gastrointestinal histoplasmosis is reviewed. PMID- 7859536 TI - Inflammatory fibroid polyp of the esophagus in an HIV-infected individual: case study. AB - We report an unusual case of a large esophageal inflammatory fibroid polyp in a man infected with the human immunodeficiency virus complaining of dysphagia. Barium studies and computed tomography demonstrated a long, submucosal-appearing, distal esophageal mass which extended into a hiatal hernia. Inflammatory fibroid polyps should be considered in the differential diagnosis of submucosal and polypoid esophageal masses, although distinctive radiographic features are not found. PMID- 7859537 TI - A direct intervention program for chronic neurogenic dysphagia secondary to brainstem stroke. AB - Little objective documentation is available regarding the efficacy of therapies for oropharyngeal dysphagia. Information specifying efficacy of treatment for chronic dysphagic conditions is almost nonexistent. This report describes a direct therapy program for chronic neurogenic dysphagia resulting from brainstem stroke, and provides information on immediate and long-term clinical outcome. Changes in swallowing physiology reflect goals of therapy. Long-term follow-up shows that functional benefits are long lasting without related health complications. PMID- 7859538 TI - Child welfare in fiction and fact. AB - This article deals with the treatment of the welfare of children in fiction, particularly in nineteenth century English and American literature. Novels and stories depicting the social condition of children and exploring their psychological problems played an important role in arousing concern for children at a time when childhood was virtually without rights or protection. The works discussed are worth recalling because they reflected prevailing attitudes and practices in child care, inspired sympathy for and understanding of children, and contributed to a hostile stereotype of adult child welfare workers. The authors' favorite remedy for children's problems--keeping them with or getting them back to their own parents or, if that was impossible, placing them in a loving family- accords with current policy objectives that are easier to attain in fiction than in real life. PMID- 7859539 TI - The dilemma in saving children from child labor: reform and casework at odds with families' needs (1900-1938). AB - Early in this century, reformers lobbied for regulation of child labor and compulsory school attendance. This article draws on their publications, agency case records, professional literature, and historical studies to examine the role of social workers in implementing the new reforms and the reactions of parents and children in low-income households who were affected by the legislative changes. The precarious nature of family self-sufficiency and social workers' ambivalence toward child labor led to conflict between professionals and client families. Missing at the time was professional acknowledgment of economic security for families as a fundamental necessity for children's welfare. PMID- 7859540 TI - An outrage to common decency: historical perspectives on child neglect. AB - Drawing on historical documents and case files, this article explores the roots of the perception that mothers are the parents primarily responsible for child neglect. It suggests that this focus on mothers has been at the expense of an understanding of, and efforts to change, the social and economic context in which child neglect occurs. PMID- 7859541 TI - Measuring socioeconomic status in studies of child development. AB - Income is more difficult to measure fully and accurately than occupation. Detailed occupational codes may be mapped into standard socioeconomic scales, and occupational status is related to other variables in much the same way as repeated or long-term measures of income. For these reasons, whether or not an attempt has been made to measure income, the measurement of socioeconomic status may be improved by ascertaining the occupation (and industry) of a job held by 1 or both parents. Income and household composition are preferable to the official poverty line in classifying economic standing, and housing tenure is a simple and powerful measure of economic consumption. Wherever possible, paternal as well as maternal education should be ascertained. However well they are measured, race ethnicity and socioeconomic status do not capture all of the effects of family background. PMID- 7859542 TI - Developing theories of mind: understanding concepts and relations between mental activities. AB - The purpose of the study was to expand our knowledge of older children's understanding of the unique features and potential relations existing among mental activities. 8- and 10-year-olds as well as adults were asked to rate the similarity of pairs of mental activity scenarios in terms of how their mind would be used for each one. The scenarios involved primarily Prospective Memory, List Memory, Recognition Memory, Comprehension, Interference, Planning, Comparison, or Selective Attention. There was a developing tendency to organize mental activities on the degree to which memory was a component of the activity. Several distinctions were also more likely to be made with age: the distinction between recall and recognition, the distinction between the roles of internal and external cues in mediating cognitive activity, and the distinction among the various roles of attentional processes in regulating input from the sensory world. Together, these findings suggest that a constructivist theory of mind develops in later childhood. PMID- 7859543 TI - The mind's "I": children's conception of the mind as an active agent. AB - 1 hypothesis about children's developing conception of the mind is that preschoolers are limited to an understanding that persons have internal, mental contents like thoughts and beliefs, whereas older children and adults conceive of the mind itself as an independent, active structure or processor. Adults' conception of the mind in this independent active fashion seems evident in their use of personified mental metaphor (e.g., "My mind tricked me"). 3 studies examined the development and consolidation of this active, personified view. Study 1 provided an analysis of natural language data regarding 1 child's uses of vision words such as see and look from age 2 1/2 to 8 years. We examined the child's use of such words to refer literally to perception (e.g., "I see the TV") and also to refer nonliterally to active mental processes such as comprehension and inference (e.g., "I see what you mean"). Studies 2 and 3 examined 6-, 8-, and 10-year-olds' comprehension and production of mental metaphors. In a metaphor comprehension task, we asked children to interpret personified metaphoric statements about the mind (e.g., "My mind wandered") and 3 comparison domains, mechanics (e.g., "The car is dead"), nature (e.g., "The wind is howling"), and emotion (e.g., "Her heart was smiling"). In an explanation task, we asked children to explain the processes underlying the making of both instant photos and mental images. The findings reveal a developing ability to interpret and produce statements personifying the mind and provide considerable evidence about children's movement toward a conception of the mind as an independent entity deserving reference and conceptualization in its own right. PMID- 7859544 TI - Children's understanding of knowledge acquisition: the tendency for children to report that they have always known what they have just learned. AB - Children's attention to knowledge-acquisition events was examined in 4 experiments in which children were taught novel facts and subsequently asked how long they had known the new information. In Experiment 1, 4- and 5-year-olds tended to claim they had known novel animal facts for a long time and also reported that other children would know the novel facts. This finding was replicated in Experiment 2, using facts associated with chemistry demonstrations. In Experiments 3 and 4, children were taught new color words. 5-year-olds, but not 4-year-olds, distinguished between novel and familiar color words, reporting they had not known the novel words before the test session, but they had always known the familiar words. 4-year-olds in Experiment 4 were better able to distinguish novel and familiar color words when the teaching of the novel words was an explicit and salient part of the procedure. PMID- 7859545 TI - Seeing is believing: children's explanations of commonplace, magical, and extraordinary transformations. AB - Children's magical explanations and beliefs were investigated in 2 studies. In Study 1, we first asked 4- and 5-year-old children to judge the possibility of certain object transformations and to suggest mechanisms that might accomplish them. We then presented several commonplace transformations (e.g., cutting a string) and impossible events (magic tricks). Prior to viewing these transformations, children suggested predominantly physical mechanisms for the events and judged the magical ones to be impossible. After seeing the impossible events, many 4-year-olds explained them as "magic," whereas 5-year-olds explained them as "tricks." In Study 2, we replaced the magic tricks with "extraordinary" events brought about by physical or chemical reactions (e.g., heat causing paint on a toy car to change color). Prior to viewing the "extraordinary" transformations, children judged them to be impossible. After viewing these events, 4-year-olds gave more magical and fewer physical explanations than did 5 year-olds. Follow-up interviews revealed that most 4-year-olds viewed magic as possible under the control of an agent (magician) with special powers, whereas most 5-year-olds viewed magic as tricks that anyone can learn. In a third study, we surveyed parents to assess their perceptions and conceptions of children's beliefs in magic and fantasy figures. Parents perceived their children as beliefs in magic and fantasy figures. Parents perceived their children as believing in a number of magic and fantasy figures and reported encouraging such beliefs to some degree. Taken together, these findings suggest that many 4-year-olds view magic as a plausible mechanism, yet reserve magical explanations for certain real world events which violate their causal expectations. PMID- 7859546 TI - Dimensional strategies dominate perceptual classification. AB - The nature of perceptual classification was investigated in children ranging between 4 and 10 years, and in young adults. Triad classification task responses were categorized as consistent or inconsistent with several classification rules, including: overall-similarity, size-dimensional, brightness-dimensional, pure identity, and all combinations of a switch from one rule to another midway through the experiment. The rule with the highest proportion of responses consistent with it reflected each person's best-fitting rule pattern. The higher this value, the higher the assumed consistency of rule usage. Data from the majority of individuals in every age group conformed best to one of the three dimensional rules. In addition, the consistency values for individuals' best fitting rule became significantly higher as age increased. It is concluded that most children have a tendency to attend selectively to one stimulus dimension when making perceptual classification judgments. The developmental trend in perceptual classification does not appear to be a holistic-to-analytic shift; instead, it is a trend toward greater consistency in following a given classification rule. PMID- 7859547 TI - Acquisition of the novel name--nameless category (N3C) principle. AB - Toddlers' acquisition of the Novel Name-Nameless Category (N3C) principle was examined to investigate the developmental lexical principles framework and the applicability of the specificity hypothesis to relations involving lexical principles. In Study 1, we assessed the ability of 32 children between the ages of 16 and 20 months to use the N3C principle (operationally defined as the ability to fast map). As predicted, only some of the children could fast map. This finding provided evidence for a crucial tenet of the developmental lexical principles framework: Some lexical principles are not available at the start of language acquisition. Children who had acquired the N3C principle also had significantly larger vocabularies and were significantly more likely to demonstrate 2-category exhaustive sorting abilities than children who had not acquired the principle. The 2 groups of children did not differ in either age or object permanence abilities. The 16 children who could not fast map were followed longitudinally until they attained a vocabulary spurt; at that time, their ability to fast map was retested (Study 2). Results provided a longitudinal replication of the findings of Study 1. Implications of these findings for both the developmental lexical principles framework and the specificity hypothesis are discussed. PMID- 7859548 TI - Developmental differences in infant attention to the spectral properties of infant-directed speech. AB - Across several independent studies, infants from a few days to 9 months of age have shown preferences for infant-directed (ID) over adult-directed (AD) speech. Moreover, 4-month-olds have been shown to prefer sine-wave analogs of the fundamental frequency of ID speech, suggesting that exaggerated pitch contours are prepotent stimuli for infants. The possibility of similar preferences by 1 month-olds was examined in a series of experiments, using a fixation-based preference procedure. Results from the first 2 experiments showed that 1-month olds did not prefer the lower-frequency pitch characteristics of ID speech, even though 1-month-olds were able to discriminate low-pass filtered ID and AD speech. Since low-pass filtering may have distorted the fundamental frequency characteristics of ID speech, 1-month-olds were also tested with sine-wave analogs of the fundamental frequencies of the ID utterances. Infants in this third experiment also showed no preference for ID pitch contours. In the fourth experiment, 1-month-olds preferred a natural recording of ID speech over a version which preserved only its lower frequency prosodic features. From these results, it is argued that, although young infants are similar to older infants in their attraction to ID speech, their preferences depend on a wider range of acoustic features (e.g., spectral structure). It is suggested that exaggerated pitch contours which characterize ID speech may become salient communicative signals for infants through language-rich, interactive experiences with caretakers and increased perceptual acuity over the first months after birth. PMID- 7859549 TI - The relations of children's emotion regulation to their vicarious emotional responses and comforting behaviors. AB - The purpose of the present study was to examine the relations of children's emotional and behavioral regulation (as indexed by heart rate variability and coping styles) to their emotional and prosocial responses to a crying infant. Kindergarten and second-grade children's vicarious emotional responses (e.g., facial reactions and heart rate slope) and comforting behaviors were recorded while children heard a crying infant. The mothers of these children completed a measure designed to assess their children's coping responses when exposed to others in distress. It was found that children who were able to regulate their arousal (as assessed with heart rate variance) and typically responded instrumentally when exposed to others' needy states and conditions were relatively unlikely to become distressed and relatively likely to talk to and comfort the crying infant. Compared to boys, girls were found to be more responsive to the crying infant and were reported to engage in more direct, active coping responses when exposed to others in distress. The results are discussed in relation to research on emotion regulation and coping in interpersonal contexts. PMID- 7859550 TI - The effect of relationship on children's distributive justice reasoning. AB - Kindergarten, third-grade, and sixth-grade children were told 2 stories about a group of children who made artwork that was subsequently sold at a craft fair. The characters in one story were described as friends, while the characters in the other story were described as strangers (relationship condition). 1 character in each story was presented as the oldest in the group, 1 as the most productive, and 1 as the poorest. Children were asked to allocate 9 dollars to the 3 characters under each relationship condition, provide rationales for those allocations, and rate the fairness of 4 different patterns of allocation. Older children allocated more money to needy friends than to needy strangers and more to productive strangers than to productive friends. Kindergartners' allocations and fairness ratings did not vary with relationship. Rationales for allocation judgments suggested that equality was the most salient principle for decisions at all ages, but the older children provided rationales based on benevolence more often than younger children when characters were presented as friends. PMID- 7859551 TI - Individual differences in achievement goals among young children. AB - Developmental research has generally not found evidence of helpless responses to failure in young children; a prevailing view is that young children lack the cognitive prerequisite for helplessness. However, recent evidence suggests that even preschoolers are vulnerable to helplessness in some situations. In the present study with 4- and 5-year-olds, we tested a goal-confidence model that predicts achievement behavior during failure for older children. We first categorized preschoolers' orientations toward "learning" or "performance" goals based on their preference for a challenging or nonchallenging task. As for older children, goal orientation was independent of ability and predicted cognitions and emotions during failure. Further, consistent with the model, within a learning goal, children displayed the mastery-oriented pattern regardless of confidence level, whereas within a performance goal, children with low confidence were most susceptible to helplessness. These behavior patterns were found on a second task as well. Thus, our findings show that individual differences in achievement goals emerge very early. PMID- 7859552 TI - Coping, stress, and the psychological symptoms of children of divorce: a cross sectional and longitudinal study. AB - The authors conducted a cross-sectional and prospective longitudinal study of stress, coping, and psychological symptoms in children of divorce. The sample consisted of 258 children (mean age = 10.1; SD = 1.2), of whom 196 were successfully followed 5.5 months later. A 4-dimensional model of coping was found using confirmatory factor analysis, with the factors being active coping, avoidance, distraction, and support. In the cross-sectional model avoidance coping partially mediated the relations between negative events and symptoms while active coping moderated the relations between negative events and conduct problems. In the longitudinal model significant negative paths were found from active coping and distraction Time 1 to internalizing symptoms Time 2, while Time 1 support coping had a positive path coefficient to Time 2 depression. Positive paths were found between negative events at Time 1 and anxiety at Time 2, and between all symptoms at Time 1 and negative events at Time 2. PMID- 7859553 TI - A study of friendship characteristics and problem behaviors among middle adolescents. AB - Exploratory and confirmatory factor analyses were used with a 15-item adolescent self-report measure to identify 4 salient friendship characteristics--Reciprocity of Relations, Overt Hostility, Covert Hostility, and Self-Disclosure--with a sample of about 1,100 middle adolescents. Higher levels of Overt and Covert Hostility and lower levels of Reciprocity of Relations with one's closest friend were associated with higher levels of alcohol consumption, percentage of friends who drink, delinquent activity, depressive symptoms, and suicidal behaviors. Self Disclosure was positively correlated with some adolescent problem behaviors, possibly reflecting developmental changes toward greater interpersonal involvement with friends in concert with age normative tasks such as increased alcohol use. Longitudinal, prospective analyses indicated that delinquent activity and depressive symptoms were significant lagged predictors of Overt and Covert Hostility, but that friendship characteristics were not significant lagged predictors of adolescent problem behaviors. PMID- 7859554 TI - "Birds of a feather...": behavioral concordances and preferential personal attraction in children. AB - The purpose of this study was to assess the extent to which preferential personal attraction was associated with behavioral similarity among newly acquainted children. Participants included 69 focal children, selected from a sample of 236 7-year-old children who met, for the first time, in same-sex quartets (n = 59) for a free-play session. Within each of these quartets, a "discriminating child" was identified; this child expressed a clear preference for one of his or her playmates over one other of her or his quartet playmates. Preference was determined sociometrically after the children became acquainted during free play. The results indicated that "discriminating" children were more behaviorally similar to preferred playmates than to nonpreferred playmates both in terms of cognitive play style and social participation. Implications of the findings are discussed in terms of the relation to the acquaintanceship process. PMID- 7859555 TI - Traits and relationship status: stranger versus peer group inhibition and test intelligence versus peer group competence as early predictors of later self esteem. AB - A 9-year longitudinal study of 99 children observed from ages 4 through 12 showed that inhibition toward strangers was strongly related to inhibition with peers, and test intelligence to social competence with peers, only in the first months of preschool socialization. These correlations decreased later on. Stranger inhibition and test intelligence were not predictive of social self-esteem in middle childhood. However, high inhibition and low competence in the peer group after 1 and 2 years of group socialization did predict low social self-esteem up to age 10. Discussion focuses on the processes that might mediate these correlative relations and on the role of relationship-unspecific traits and relationship-specific individual attributes for later social-emotional developmental outcomes. PMID- 7859556 TI - Children's academic and behavioral adjustment as a function of the chronicity and proximity of peer rejection. AB - The experience of peer rejection is associated with a number of concurrent and later problems for children. However, we know very little about differences in risk relative to different experiences of rejection over time. This study examined later academic and behavioral problems as a function of two dimensions by which rejection may vary over time: chronicity and temporal proximity. 622 second- through fourth-grade children (ages 7-12) were tested in the spring of 4 consecutive years. The results indicated that both chronicity and proximity directly influenced later adjustment. Taken together, the findings suggest that all levels of rejection were associated with greater absenteeism from school, and more chronic and proximal experiences of rejection were associated with elevated externalizing behavior problems and teacher-rated internalizing behavior problems. There was evidence that initial level of adjustment, gender, and development moderated the relation among these dimensions of rejection and later adjustment. PMID- 7859558 TI - Preparation of chromosome spreads for electron (TEM, SEM, STEM), light and confocal microscopy. AB - In the past, ultrastructural studies on chromosome morphology have been carried out using light microscopy, scanning electron microscopy and transmission electron microscopy of whole mounted or sectioned samples. Until now, however, it has not been possible to use all of these techniques on the same specimen. In this paper we describe a specimen preparation method that allows one to study the same chromosomes by transmission, scanning-transmission and scanning electron microscopy, as well as by standard light microscopy and confocal microscopy. Chromosome plates are obtained on a carbon coated glass slide. The carbon film carrying the chromosomes is then transferred to electron microscopy grids, subjected to various treatments and observed. The results show a consistent morphological correspondence between the different methods. This method could be very useful and important because it makes possible a direct comparison between the various techniques used in chromosome studies such as banding, in situ hybridization, fluorescent probe localization, ultrastructural analysis, and colloidal gold cytochemical reactions. PMID- 7859557 TI - The spindle pole body of yeast. AB - Microtubule organizing centers play an essential cellular role in nucleating microtubule assembly and establishing the microtubule array. The microtubule organizing center of yeast, the spindle pole body (SPB), shares many functions and properties with those other organisms. In recent years considerable new information has been generated concerning components associated with the SPB, and the mechanism by which it duplicates. This article reviews our current view of the cytology and molecular composition of the SPB of the budding yeast, Saccharomyces cerevisiae, and the fission yeast, Schizosaccharomyces pombe. Genetic studies in these organisms has revealed information about how the SPB duplicates and separates, and its roles during vegetative growth, mating and meiosis. PMID- 7859559 TI - High resolution detection of uncoated metaphase chromosomes by means of field emission scanning electron microscopy. AB - HeLa metaphase chromosomes were examined by means of "in lens" field emission scanning electron microscopy, which permits high resolution detection of uncoated biological samples. By using uncoated chromosomes as a model for comparison we report evidence of how traditional scanning electron microscopy techniques such as metal coating and conductive methods can generate errors in chromosome structure evaluation, since both give rise to morphological artifacts. By comparing the morphology of uncoated chromosomes obtained by two different isolation procedures, such as that utilized in standard cytogenetics and the polyamine method, we have drawn the following conclusions: (a) the standard cytogenetic method gives rise to a chromosome structure consisting of a flattened network of 10 nm fibers, in which higher order chromatin organization is absent. (b) Chromosomes obtained by the polyamine method show both three-dimensional profile and higher level folding of chromatin fibers, supporting the loop chromosome organization previously suggested by scanning electron microscopy observation of hexylene glycol isolated chromosomes. PMID- 7859560 TI - Organization of heterologous DNA inserts on the mouse meiotic chromosome core. AB - With simultaneous immunofluorescence and fluorescent in situ hybridization, we have determined the organization of native and heterologous DNA sequences relative to the cores of meiotic prophase chromosomes. The normal chromatin organization is demonstrated with probes of mouse sequences: a cosmid probe that identifies unique sequences and a 720 kb yeast artificial chromosome (YAC) probe that recognizes a specific region of the chromatin domain. The heterologous DNA consists of a 1.8 Mb insertion of 40 tandem head-to-tail phage lambda LIZ vectors and of 11.4 Mb of bacterial/mouse DNA repeats. The lengthy lambda insert is unusual in that it is not contained in the chromatin domain of chromosome 4 and in that it fails to form direct attachments to the chromosome core. The ends are attached indirectly, probably by means of the flanking mouse sequences. At late stages of meiotic prophase, while the terminal attachments remain the same, the lambda DNA becomes highly compacted. Apparently, higher order condensation and core attachment are independent processes. The condensed inserts relax precociously at metaphase I. In the mouse heterozygous for the insert, the two sister inserts are usually merged, as are all four inserts in the homozygous mouse. Evidently chromatin loops with identical sequences can become associated during meiotic prophase. Mouse sequences within a heterologous DNA insert (repeats of bacterial plasmid pBR322 with a mouse beta-globin insert) were observed to restore some degree of core attachment. PMID- 7859561 TI - Visualization of mitotic chromosomes in filamentous fungi by fluorescence staining and fluorescence in situ hybridization. AB - Mitotic chromosomes of the plant pathogenic filamentous fungi Botrytis cinerea and Alternaria alternata were observed. Chromosomes prepared by the germ tube burst method were stained with the fluorescent dye 4',6-diamidino-2-phenylindole (DAPI) to yield figures with good resolution. Using this method, component chromosomes were clearly distinguished and the chromosome number could be determined. Fluorescence in situ hybridization (FISH) was also successfully applied to the specimens, revealing one ribosomal RNA gene cluster, or nucleolus organizer region (NOR) in the genome of each fungus. A long attenuated chromatid thread expanding from a condensed metaphase chromosome, which had been called a thread-like structure in B. cinerea, was proved to be an NOR. This is the first report of the successful application of FISH to the chromosomes of filamentous fungi. PMID- 7859562 TI - Comparison of the two major ARS elements of the ura4 replication origin region with other ARS elements in the fission yeast, Schizosaccharomyces pombe. AB - We have previously reported that the replication origin region located near the ura4 gene on chromosome III of the fission yeast, Schizosaccharomyces pombe, contains three closely spaced origins, each associated with an autonomously replicating sequence (ARS) element. Here we report the nucleotide sequences of two of these ARS elements, ars3002 and ars3003. The two ARS elements are located on either side of a transcribed 1.5 kb open reading frame. Like 11 other S. pombe ARS elements whose sequences have previously been determined in other laboratories, the 2 new ARS elements are unusually A+T-rich. All 13 ARS elements contain easily unwound stretches of DNA. Each of the ARS elements contains numerous copies, at a higher than expected frequency, of short stretches of A+T rich DNA in which most of the Ts are on one strand and most of the As are on the complementary strand. We discuss the potential significance for ARS function of these multiple asymmetric A+T-rich sequences. PMID- 7859563 TI - Cytoplasmic localization of transcripts of a complex G+C-rich crab satellite DNA. AB - The primary sequence and higher order structures of a G+C-rich satellite DNA of the Bermuda land crab Gecarcinus lateralis have been described previously. The repeat unit of the satellite is approximately 2.1 kb. In exploring a possible function for this satellite, we asked whether it is transcribed. As a probe for transcripts, we used a segment of DNA amplified from a 368 bp EcoRI fragment from the very highly conserved 3' end of the satellite DNA. During polymerase chain reaction (PCR) amplification, the probe was simultaneously either radiolabeled or biotinylated. Tissue- and stage-specific transcripts were observed when blots of poly(A)+ mRNAs recovered from polysomes isolated from crab tissues [including midgut gland (hepatopancreas), limb bud, and claw muscle] were probed with the satellite DNA fragment. The presence of satellite transcripts in polysomal mRNAs is strong evidence that the transcripts had reached the cytoplasm. To corroborate the presence of transcripts in the cytoplasm, we investigated in situ hybridization of satellite probes with RNAs in tissue sections. Biotinylated satellite DNA probes were applied to sections of midgut gland, limb bud papilla, ovary, or testis of anecdysial crabs. Retention of RNAs in tissue sections was improved by UV-irradiation prior to hybridization. Transcripts were abundant in the cytoplasm of all tissues except testis. Sections of crab midgut gland treated with RNase A prior to hybridization and sections of mouse pancreatic tumor served as controls; neither showed any signals with the probe. PMID- 7859564 TI - Reorganization and condensation of chromatin in mitotic prophase nuclei of Allium cepa. AB - This paper studies the process and features of chromosome construction in mitotic prophase cells of Allium cepa. The results showed that a prominent reorganization of chromatin occurred during G2--early prophase. The 250-400 nm thick compact chromatin threads in G2 nuclei began to disorganize into about 30, 100 and 220 nm chromatin fibres which constituted the loosely organized chromosome outlines in early prophase before chromosome condensation. In middle prophase, chromosome condensation was characterized by the formation of many condensed regions (aggregates of chromatin), which increased in size (1-1.5 microns) when prophase proceeded. Meanwhile, the chromatin threads that constituted and connected the condensed regions became increasingly thicker (120-250 nm). In late prophase adjacent condensed regions fused to form cylinder-shaped chromosomes. Based on these observations, we come to the conclusion that the construction of prophase chromosomes is a two-step process, that is, the reorganization and condensation of chromatin. In addition, we report the study of silver-stained, DNA- and histone-depleted prophase chromosomes, describe morphological features of the non histone protein (NHP) residue in early, middle and late prophase chromosomes, and discuss the roles of NHPs in chromosome construction. PMID- 7859565 TI - [The diagnostic value of computed coronal tomography in maxillofacial tumors]. AB - CT images in both transverse axial and coronal planes of 52 cases of maxillofacial tumors were analyzed. The authors emphasized that coronal technique should not be neglected, especially when the tumor was near the base of the skull, the sphenoid sinus and the hard palate. Transverse axial scan alone could not demonstrate the exact extent of invasion and the adjacent relationship. Coronal scan affords exceptional visualization. In such conditions, the combination of scans in two planes is the most helpful in delineating such lesions. It provides important information for determining surgical or radiotherapeutic approaches. PMID- 7859566 TI - [Histopathological findings of 59 cases of cheilitis granulomatosa]. AB - By histopathological observations of 59 cases of CG, they are divided into 6 types according to pathological characteristics. Their differences are compared and discussed. The reason and significance of this classification from morphological point of view are discussed as well. It is suggested that the G is possibly resulted from different reactions of the body to the same pathogen or to the different pathogens. PMID- 7859567 TI - [Soft tissue changes after advancement genioplasty in Chinese adults]. AB - Twenty-five Chinese patients who had undergone advancement genioplasty were evaluated for soft tissue changes of chin. The effects of bony genioplastic advancement on soft tissues of profile were studied by means of computerized cephalometric analysis. The change ratios between soft tissue and hard tissue, as well as regression equations were calculated. The result of this study led to the following conclusions: The soft tissue chin point and labiomental sulcus moved by 85% and 41% of horizontal advancement of the mandibular symphsis. PMID- 7859569 TI - [Operative and pathological observations on secondary synovitis of temporomandibular joint dysfunction syndrome]. AB - 14 cases (16 joints) with temporomandibular joint dysfunction syndrome (TMJDS) were included in the present study. All the patients had severe pain of the joint for a long time and the conventional therapy was not effective. The operative and pathological findings of the 14 cases showed that synovitis secondary to microtrauma of the joint really existed and might be one of the reasons causing the severe pain of the joint in some patients with TMJDS. PMID- 7859568 TI - [An experimental study on dental pulp histology after the inferior alveolar nerve damage and autogenous nerve graft]. AB - The dental pulpal histology was studied experimentally in rabbits after the inferior alveolar neurovascularity damage and nerve graft. The results revealed that the dental vitality was gradually repaired at different intervals after the inferior alveolar neurovascularity damage. In the early damaged period the pulpal blood vessels were reduced in number and some of them were swollen and permeable, in the late period the structure of the microvascular system became normal and abundant. The pulpal architecture was altered in the initial stage and with the tendency to repair gradually. The pulpal axon degenerated in early stage and reinnervated later. The authors indicate that there are no evident affections for dental pulpal tissues whatever the inferior alveolar neurovascularity is damaged and repaired. This has an important clinical value to define the dental pulp vitality in mandibular subapical osteotomy and tumor resection. PMID- 7859571 TI - [Studies on endotoxin lipopolysaccharides of infected root canals in cytotoxicity in vitro]. PMID- 7859572 TI - [The clinical effects of human embryo demineralized bone on the periapical bone lesion in anterior and bicuspid teeth]. PMID- 7859570 TI - [Quantitative measurement of tolerance of deviations in facial appearance]. PMID- 7859573 TI - [Clinical observation on repair of bone defects in maxillofacial region by grafting hydroxylapatite combined with porcine bone morphogenetic protein]. PMID- 7859574 TI - [Clinical studies on implantation of metal implant and TPC+BMP for periodontal bone defects]. PMID- 7859575 TI - [The effect of different size of aluminoxide for sandblasting on bonding strength of porcelain to metal]. AB - In this article, 10um, 50um, 110um, 200um and 280um aluminoxide particles were used separatively for producing various roughness metal surfaces. The effects of different roughness of metal surface on porcelain--metal bonding strength were studied by porcelain--metal bonding strength measurement, scanning electron microscope (SEM) observation and energy-dispersive analysis of x-rays (EDAX). The result shows: the size of aluminoxide particles should be over 50 microns for non precious Ni-Cr allay Surface blasting. In certain range, the roughness of metal surface can increase bonding strength significantly. PMID- 7859576 TI - [Influence of anterior occlusal contacts of complete dentures on mastication]. AB - The photocclusion and mastication analysis of the complete dentures with or without the anterior occlusal contacts were made. The results indicated that there was no obvious differences among the maximum occlusal contact intensities of each tooth position in central occlusion. Under the functional condition the activity of the anterior temporal muscles was influenced and the mastication efficiency was decreased by the relatively stronger anterior occlusal contacts. PMID- 7859577 TI - [Effects of the orientation of occlusal plane on EMG of masticatory muscles in complete denture wearers]. AB - The occlusal plane was designed as parallel to Camper's line (the standard dentures) and 5 degree inclined upward, downward laterally and anterior-posterior for comparing the activities of masticatory muscles. Following results were obtained: (1) the amplitude of the masseter (Mm) and the anterior temporalis (Ta) muscles with standard dentures biting in intercuspal position were the highest among those with other dentures, (2) during unilateral chewing with standard dentures, the average amplitude of the anterior digastric muscles (Da) on the balanced side was higher than that on the working side, but the amplitude values of the Mm and the Ta on the working side were significantly lower than those on the opposite side, (3) to incline the plane forward or backward may cause the activity of the Da increased in the balanced side and (4) to incline the plane right or left the amplitude of Ta and Mm between the working and the balanced side was not significant different. PMID- 7859578 TI - [A preliminary study of intraoral fluoride controlled-release device applied to removable partial dentures]. PMID- 7859579 TI - [Scanning microradiographic study on the kinetics of enamel demineralization]. PMID- 7859580 TI - [The influence of lanthanum chloride on the acid resistant property of human enamel in vitro]. PMID- 7859581 TI - A review of the status of omeprazole: the Hambury workshop. PMID- 7859583 TI - Pharmacological aspects of acid secretion. AB - The secretion of gastric acid is regulated both centrally and peripherally. The finding that H2-receptor antagonists are able to reduce or abolish acid secretion due to vagal, gastrinergic, and histaminergic stimulation shows that histamine plays a pivotal role in stimulation of the parietal cell. In the rat, the fundic histamine is released from the ECL cell, in response to gastrin, acetylcholine, or epinephrine, and histamine release is inhibited by somatostatin or by the H3 receptor ligand, R-alpha-methyl histamine. The parietal cell has a muscarinic, M3, receptor responsible for [Ca]i regulation. Blockade of muscarinic receptors by atropine can be as effective as H2-receptor blockade in controlling acid secretion. However, general effects on muscarinic receptors elsewhere produce significant side effects. The different receptor pathways converge to stimulate the gastric H+,K(+)-ATPase, the pump responsible for acid secretion by the stomach. This enzyme is an alpha,beta heterodimer, present in cytoplasmic membrane vesicles of the resting cell and in the canaliculus of the stimulated cell. It has been shown that acid secretion by the pump depends on provision of K+Cl- efflux pathway becoming associated with the pump. As secretion occurs only in the canaliculus, this K+Cl- pathway is activated only when the pump inserts into the canalicular membrane. Transport by the enzyme involves reciprocal conformational changes in the cytoplasmic and extracytoplasmic domain. These result in changes in sidedness and affinity for H3O+ and K+, enabling active H+ for K+ exchange. The acid pump inhibitors of the substituted benzimidazole class, such as omeprazole, are concentrated in the canaliculus of the secreting parietal cell and are activated there to form sulfenamides. The omeprazole sulfenamide, for example, reacts covalently with two cysteines in the extracytoplasmic loops between the fifth and sixth transmembrane and the seventh and eighth transmembrane segments of the alpha subunit of the H+,K(+)-ATPase, forming disulfide derivatives. This inhibits ATP hydrolysis and H+ transport, resulting in effective, long-lasting regulation of acid secretion. Therefore, this class of acid pump inhibitor is significantly more effective and faster acting than the H2 receptor antagonists. K+ competitive antagonists bind to the M1 and M2 transmembrane segments of the alpha subunit of the acid pump and also abolish ATPase activity. These drugs should also be able to reduce acid secretion more effectively than receptor antagonists and provide shorter acting but complete inhibition of acid secretion. PMID- 7859582 TI - Optimizing acid suppression for treatment of acid-related diseases. AB - Gastric acid is of central importance in the pathogenesis of duodenal ulcer, gastric ulcer, and gastroesophageal reflux disease. Pharmacological reduction of acid secretion is, therefore, the mainstay of current treatment, but the optimal degree of acid suppression remains incompletely understood. This paper considers the ideal ways of assessing and reporting the pharmacological effectiveness of acid-inhibiting drugs and relating such data to clinical efficacy. Twenty-four hour intragastric pH measurements are widely used for this purpose, although this technique cannot measure secretion quantitatively. Data on suppression of 24-hr intragastric acidity for groups of subjects have been successfully correlated with healing rates for duodenal ulcer, gastric ulcer, and gastroesophageal reflux disease. Three primary determinants of healing have been derived from antisecretory data. These are the degree of suppression of acidity, the duration of suppression of acidity, and the duration of treatment. The order of importance of these determinants varies depending on the disease. Data on 24-hr intragastric acidity should be accompanied whenever possible by data on 24-hr plasma gastrin levels, as the relationship between suppression of acidity and a rise in gastrin varies widely between individuals. It is not possible to predict the plasma gastrin level from the intragastric pH or any other measurement of intragastric acidity. Comparative data sets in groups of subjects may provide useful information. Proton pump inhibitors produce a greater and longer-lasting degree of suppression of acidity than conventional doses of H2-receptor antagonists. For this reason, they are more effective in healing duodenal ulcer and gastric ulcer. However, in view of the importance of duration of treatment, healing rates with the H2-receptor antagonists approach those obtained with proton pump inhibitors if treatment is continued for a longer time. In gastroesophageal reflux disease in particular, although the optimal degree of acid suppression is not yet defined, the consistently superior performance of proton pump inhibitors demonstrates that increased suppression of acidity is clinically beneficial. PMID- 7859584 TI - Effects of hypochlorhydria and hypergastrinemia on structure and function of gastrointestinal cells. A review and analysis. AB - Since hypochlorhydria can induce hypergastrinemia, and gastrin has a trophic effect on some gastrointestinal cells, states that cause elevated plasma gastrin levels are of interest in terms of effects on cell growth and function. This article reviews the relationship between gastric mucosal cells during periods of acid stimulation and inhibition and analyses the effects of hypochlorhydria and hypergastrinemia on gastric and colonic cells and tumors. Hypochlorhydria releases the inhibitory effect of antral gastrin cells, inducing them to release gastrin in the presence of peptides or amino acids in the gastric lumen or in response to antral distension. Gastrin stimulates the oxyntic mucosa, which may lead to hyperplasia of enterochromaffin-like cells, resulting in enterochromaffin like carcinoid tumors in aged rats and, rarely, in patients with chronic atrophic gastritis or gastrinomas. In addition to hypergastrinemia, other factors appear to be required for the progression of enterochromaffin-like hyperplasia to carcinoids; genetic factors may be involved. Gastrin elevations due to antisecretory drug therapy are indirectly proportional to the degree of acid inhibition and are reversible upon cessation of therapy. The gastrin levels during omeprazole therapy are similar to those caused by gastric vagotomy. Available evidence does not support a relationship between hypergastrinemia and the occurrence or growth of gastric carcinoma or colonic tumors. PMID- 7859588 TI - Diabetes in Japan. PMID- 7859586 TI - Effects of acid suppression on microbial flora of upper gut. AB - Decreased acid secretion, due to therapy or disease, predisposes to increased bacterial counts in gastric juice. As bacterial numbers increase, the number of nitrate-reducing strains and the concentration of luminal nitrite usually also increase. However, there is controversy (mainly because of assay problems) about whether decreased acid increases generation of N-nitroso compounds: these may be produced by acid or by bacterial catalysis, and the relative contributions of each are still uncertain. Other potentially important factors include ascorbate secretion (can prevent nitrite conversion to nitroso compounds) and the particular spectrum of nitroso compounds produced. Nitrosation of several histamine H2-receptor antagonists has been demonstrated experimentally, but under conditions that are very unlikely to be encountered clinically. Some acid suppressant therapies have been claimed to aid eradication of Helicobacter pylori, but more work is needed to evaluate this. If ulcer treatment regimens do not also address eradication of H. pylori (when present), gastritis will progress, and the recently documented association between H. pylori and gastric carcinoma needs to be considered. Enteric flora probably also increase if acid secretion is markedly reduced: this does not appear to have nutritional consequences but probably reduces the resistance to occasional infections, of which cholera is the best documented. PMID- 7859589 TI - History of medicine and changes in concept of diabetes mellitus in Japan. AB - In Japan, diabetes mellitus was called 'Shoukachi', thirst disease, before the 18th century. Western medicine was first introduced by the Portuguese in the 16th century. During the period of National Isolation from the 16th to the middle of the 19th century, Nagasaki served as the sole window of Japan, through which Dutch medicine came into Japan. After the Meiji Reform in the 19th century, German medicine was actively introduced. There remains a record of a lecture by Prof. Aoyama on diabetes mellitus delivered in 1906, in which the restriction of carbohydrate intake and a meat-rich diet was recommended. Prof. Sakaguchi, the successor of Prof. Aoyama and a pioneer of diabetes research in Japan, studied blood sugar profiles in healthy and diabetic subjects and invented a rice-meal test to examine glucose tolerance. In 1928, he wrote 'diabetes occurs by the deficiency of insulin, genetic factors are important, and the bodily need for insulin is increased with obesity'. He and his colleagues found that too low an intake of carbohydrate may impair glucose tolerance. After the 2nd World War, Japanese doctors eagerly learned foreign medicine, especially from the United States. Since the 1940s, a new concept has arisen in which diabetes was defined by blood glucose values after glucose loading. But, in 1970, a Committee of the Japan Diabetes Society (JDS) expressed an opinion that diabetes should not be solely defined by the results of the glucose tolerance test but should be considered as a disease or diseases with characteristic metabolic and clinical features, based on deficient insulin action.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859585 TI - Safety of acid-suppressing drugs. AB - There is an extensive literature on the adverse effects of drugs that inhibit gastric acid secretion. This study presents a critical examination of interactions between antisecretory drugs and other compounds, the frequency of serious adverse effects relating to various body systems, the safety of antisecretory drugs in pregnancy, and longer-term safety data from postmarketing surveillance studies. While interactions with some other drugs, alcohol, and certain carcinogens are of potential concern, in practice clinically significant reactions appear to be rare if they occur at all. A small number of major side effects have been documented, but they occur rarely, and postmarketing surveillance has not detected other longer-term sequelae. Safety of these drugs in pregnancy is not established, as data are so few. It is concluded that antisecretory agents, by comparison with most other classes of drugs, are remarkably well tolerated. PMID- 7859590 TI - Insulin secretory response in Japanese type 2 (non-insulin-dependent) diabetic patients. AB - Insulin (immunoreactive insulin, IRI) response during a 100 g oral glucose tolerance test was studied in a large number of patients with definite diabetes, equivocal diabetes, and other pathological states causing glucose intolerance. Definite diabetes was diagnosed in patients with overt fasting hyperglycemia. Once the diagnosis of definite diabetes was made, IRI response remained low after improvement of glucose tolerance. Glucose intolerance caused by other pathological extra-pancreatic conditions was usually accompanied by increased IRI response. IRI response in equivocal diabetes was variable, but almost always decreased in those who developed definite diabetes later. In subjects with a strong family history of type 2 diabetes, the prevalence of a low IRI response was high. In non-diabetic subjects, weight gain caused a marked increase in IRI response and a small increase in blood glucose, while in those who developed diabetes, IRI increased little despite the marked increase in blood glucose. These data suggest that low IRI response is an important feature of type 2 diabetes, perhaps with a hereditary basis in part. It precedes the occurrence of overt hyperglycemia and persists after improvement of glucose tolerance. PMID- 7859591 TI - Pathophysiology and pathogenesis of visceral fat obesity. AB - Based on the analysis of fat distribution by CT scanning, we have proposed a classification of obesity: visceral fat obesity, in which fat accumulation is predominant in the intra-abdominal cavity. This type of obesity is more frequently accompanied by disorders of glucose and lipid metabolism, and also with hypertension, than subcutaneous fat obesity. We also showed that almost 90% of obese patients with ischemic heart disease have visceral fat accumulation. From clinical and basic experiments, aging, imbalance of sex hormone, overintake of sucrose and lack of physical exercise have been suggested to be major factors for visceral fat accumulation. Since intra-abdominal fat (mesenteric and omentum fat) have been show to have high activities of both lipogenesis and lipolysis, its accumulation induces a high content of free fatty acids, a product of lipolysis, in portal circulation which goes into the liver directly. Excess free fatty acid may cause the enhancement of lipid synthesis and gluconeogenesis as well as insulin resistance, resulting in hyperlipidemia, glucose intolerance and hypertension and finally atherosclerosis. PMID- 7859592 TI - NIDDM--genetic marker; glucose transporter, glucokinase, and mitochondria gene. AB - Candidate genes for NIDDM have been screened in Japanese. Mutations in the glucokinase gene were found in apparent late-onset NIDDM patients as well as in MODY patients. Clinical characteristics in the subjects with glucokinase gene mutations are similar to those in Caucasian subjects; diabetes mellitus is generally mild and some patients actually remain as having impaired glucose tolerance. Of great interest is that all affected subjects show blunted insulin secretion response to the glucose challenge, which is most commonly observed in Japanese NIDDM patients. Thus, it is possible that impairment in the regulation of glucokinase gene expression or its enzyme activity is associated with at least some Japanese NIDDM patients, though the prevalence of the mutations in the coding region is relatively low. In contrast, a mitochondrial tRNA(Leu(UUR)) gene mutation at np 3243 appears to be much more common, and diabetes due to this mutation has a progressive nature. Insulin secretory capacity progressively decreases, eventually reaching an insulin-dependent state in most patients. A surprising result is that this gene mutation is often observed in ICA-positive IDDM patients who were initially non-insulin-dependent, so called slowly progressive IDDM patients. These results suggest that the mitochondrial gene mutation may cause beta cell loss in addition to defects in glucose-induced signaling in pancreatic beta cells, which explains that the mitochondrial gene mutation manifests a wide range of diabetic phenotypes, from NIDDM to IDDM. PMID- 7859593 TI - Risk factors for the development of non-insulin-dependent diabetes mellitus (NIDDM) in Japan. AB - Follow-up studies of subjects with impaired glucose tolerance in Japan have shown that a higher level of blood glucose is a major predictor of the subsequent development of non-insulin-dependent diabetes mellitus (NIDDM). In addition, subjects with a lower insulin response to glucose show a higher risk for the development of NIDDM. In fact, most of the subjects who later develop diabetes show a lower insulin response to glucose at the initial examination. Moreover, obesity is generally associated with a higher risk of developing NIDDM. We conclude that low insulin secretion forms an important basis and obesity plays a precipitating role among low-insulin responders in the pathogenesis of the majority of NIDDM patients in Japan. PMID- 7859594 TI - Endocrine disorders and diabetes in Japan. AB - The frequency of glucose intolerance including diabetes and IGT in endocrine diseases was compared between Japan and foreign countries. It was revealed that the frequency of diabetes in endocrine diseases is generally higher in Japan than in foreign countries. In addition, plasma insulin response to glucose was exaggerated in Cushing's syndrome with glucose intolerance, but was impaired in acromegaly and pheochromocytoma with glucose intolerance. PMID- 7859595 TI - Abnormal insulinemia. AB - The recent development of molecular biology enables us to identify three abnormal insulins (insulin Chicago, insulin Los Angeles and insulin Wakayama). In Japan, three pedigrees in which affected individuals secrete [LeuA3] insulin (insulin Wakayama) have been identified. In each family, hyperinsulinemia associated with an abnormally elevated insulin to C-peptide molar ratio was demonstrated to occur in an autosomal dominant pattern of inheritance. In accordance with in vivo observations, semisynthetic [LeuA3] insulin demonstrated reduced in vitro receptor binding and biological activity relative to the human standard. The development of diabetes mellitus in affected family members was not uniform, was influenced by aging, and was different among families. Patients with impaired glucose tolerance demonstrated reduced insulin secretory reserve. Some of these features are thought to resemble the nature of non-insulin dependent diabetes mellitus (NIDDM). Therefore, insulin Wakayama may be a useful model for the study of the development of NIDDM. PMID- 7859587 TI - Pathophysiological effects of long-term acid suppression in man. AB - A critical evaluation has been made of the available evidence in man of the effects of prolonged low acid states on the structure and function of the stomach. Various human models have been examined. 1. Ageing does not affect acid output from the normal male stomach, and there may be an increase in women. With progressive atrophy of the corpus mucosa, which is more frequent and rapid in patients with gastric ulcer, there is an associated loss of secretory function. Chronic gastritis and atrophy are the most important age-related changes, which in many cultures are hypothesized to develop via a prior Helicobacter pylori related gastritis. However, H. pylori colonization of the mucosa decreases with increasing grades of gastric atrophy probably because intestinal metaplasia provides a hostile environment. Atrophy and intestinal metaplasia are associated with precancerous lesions and gastric cancer. Apparent hyperplasia of the gastric argyrophil endocrine cells is a common and spontaneous phenomenon in patients with atrophic gastritis, which in part may be related to the preferential loss of nonendocrine cells. 2. Pernicious anemia is associated with a complete lack of acid production, marked hypergastrinemia, and endocrine cell hyperplasia in the majority of patients. ECL-cell carcinoids and gastric cancer occur with a prevalence of 3-7%, and endoscopic surveillance in routine clinical practice is not warranted. 3. Gastric ECL-cell carcinoids are rare events that have been described in association with two diseases in man, pernicious anemia and Zollinger-Ellison syndrome as part of multiple endocrine neoplasia syndrome type I, and usually relate to marked hypergastrinemia and the presence of chronic atrophic gastritis with gastric antibodies or a genetic defect rather than the presence or absence of acid. Regression or disappearance of ECL-cell carcinoids, either spontaneously or after removal of the gastrin drive, has been recorded. Lymph node, and rarely hepatic, metastases are documented but death in these cases has been anecdotal. 4. Therapy with H2 antagonists may result in up to a twofold rise in serum gastrin levels but in man no endocrine cell hyperplasia has been recorded. However, the data for H2 antagonists on these aspects are very limited. There is no drug-related risk of gastric or esophageal cancer, although the incidence of the latter may be raised. Long-term treatment with omeprazole is associated with a two- to fourfold increase in gastrin levels over baseline values in one third of patients and apparent endocrine cell hyperplasia in 7% of cases overall.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 7859596 TI - Hyperproinsulinemia in Japan. AB - Four families with hyperproinsulinemia found in Japan were described. The details of the first case, who was investigated by Kanazawa et al., were reported and the similarity of the first case to the following cases was shown. Arginine 65 of the proinsulin molecule might be a hot spot of the insulin gene. A possible abnormality of insulin release in affected individuals was disclosed by investigation of the family members of the first case. PMID- 7859597 TI - Insulin receptor disorders in Japan. AB - The clinical features of insulin receptor disorders found in Japan are summarized. About 20 cases of primary receptor mutations (type A syndrome of insulin resistance, leprechaunism and Rabson-Mendenhall syndrome) and 16 cases of autoantibodies against insulin receptor (type B syndrome of insulin resistance) are described in Japan. There was a trial of IGF-1 for some of the patients, revealing its usefulness. PMID- 7859598 TI - Prevalence of diabetes mellitus in Japan compiled from literature. AB - This is an excerpt from the report (1992) of the Epidemiology Data Committee of the Japan Diabetes Society. Portions regarding the community-based prevalence data on adult diabetes and the data of official sources are shown. Data on the prevalence and incidence of diabetes were collected from Japanese medical literature from 1959-1991 by various means. In early studies, people were first screened by urine glucose test, and subjects positive for glucosuria were further evaluated by blood glucose test. Recent studies mostly used 75 g GTT without prior urine screening. Before 1984, the criteria of the JDS (1970) were chiefly used, while after 1985 the WHO criteria are used to define diabetes. Prevalence of diabetes in people older than 40 years was 1.3-4.7% in earlier studies, but it increased to 4-11% in recent studies despite the fact that the WHO criteria are more stringent in defining diabetes than the JDS criteria of 1970. The prevalence of diabetes was higher in men than in women in most reports. Some publications from the Ministry of Health and Welfare included the data on diabetes. They were based on the information of known diabetic patients seen by doctors, and gave much lower estimates of prevalence than community-based survey. The estimated prevalence of diabetes was 1.7% from the 1987 Patient Survey and 1.1% by the Comprehensive Survey of Living Conditions. There was a sharp 30-fold increase during these 30 years. Efforts are now being made to collect more accurate data on the prevalence of diabetes in Japan by the Epidemiology Study Group sponsored by the Ministry of Health and Welfare. PMID- 7859599 TI - Insulin autoimmune syndrome in Japan. AB - Since 1970, 197 patients with insulin autoimmune syndrome (IAS) showing severe spontaneous hypoglycemia have been reported in Japan. This is characterized by a high titer of anti-insulin autoantibodies without evidence of exogenous insulin administration. IAS is the third leading cause of spontaneous hypoglycemia in Japan, while only 21 cases have been reported in Europe and the United States. High levels of the extractable native human insulin and of the characteristic insulin autoantibodies in the sera of the IAS patients have been proved. Recently a significant association of HLA-DRB1*0406/DQA1*0301/DQB1*0302 with this syndrome has been found in the IAS patients in Japan. PMID- 7859600 TI - Prevalence of chronic complications in Japanese diabetic patients. AB - In November 1990, we carried out a survey of chronic complications of diabetes in more than 2000 diabetic patients who were seen on one day in 35 medical institutions including university hospitals, other hospitals and small clinics. More than 60% were aged 55-74 years. About 7% of patients had IDDM. Hypertension was present in 38.5%. Proteinuria was positive in 20% and 1% of patients were on dialysis therapy. 28% had visual disturbance and 2.9% had blindness in one or both eyes. Retinopathy was observed in 38% and proliferative retinopathy in 10%. The prevalences of myocardial infarction, angina pectoris, cerebral infarction and foot ulcer and gangrene were 2.1%, 4.7%, 5.7% and 2%, respectively, including the histories of these complications. Amputation of lower extremities was seen in only 0.6%. Microangiopathies were generally more frequent and more severe in IDDM than NIDDM. The prevalence of microangiopathy was as common as, but macroangiopathy seems less frequent than, the figures given in 'Diabetes in America'. PMID- 7859602 TI - Classification and treatment of diabetic retinopathy. AB - Diabetic retinopathy is the leading cause of blindness. In Japan about 45% of diabetic patients under medical care have retinopathy and 10% have proliferative retinopathy. Until recently, Scott's classification (1953, 1957) of retinopathy was commonly used in Japan. As there are several problems with this classification, I proposed a new classification in 1983. It aims to separate benign and malignant types and to be more useful clinically so that each stage corresponds better to the indication of specific treatment. Diabetic retinopathy is divided into benign (type A) and malignant (type B) retinopathy, and each type is subdivided into 5 stages. Benign retinopathy is unlikely to cause blindness unless maculopathy is present. It includes background retinopathy (A1 and A2) and interrupted proliferative retinopathy (A3, A4 and A5) after photocoagulation or vitrectomy. Malignant retinopathy is likely to get worse and may lead to blindness if left without specific treatment. It includes preproliferative retinopathy (B1), early (B2), advanced (B3) and end-stage (B4 and B5) proliferative retinopathy. The presence of specific findings is described by the addition of letters: maculopathy (M), tractional retinal detachment (D), neovascular glaucoma (G), and ischemic optic neuropathy (N). Systemic metabolic control of diabetes is the best means of treatment for benign retinopathy, but malignant retinopathy should immediately be seen by ophthalmologists for specific treatment: focal photocoagulation for B1, focal or panretinal photocoagulation for B2 and panretinal photocoagulation for B3-B5. Vitrectomy is indicated in B4 or more severe stages. PMID- 7859601 TI - Complications and prognosis of children with IDDM. AB - There was a marked reduction in the prevalence of complications in, and mortality status of, Japanese children with IDDM in the past 20 years. It is apparent that the improvement in medical treatment as well as social circumstance surrounding childhood diabetes in recent years contributed greatly to this change. However, when one compares Japanese data with those for Europe or the U.S., the present status is not yet satisfactory. In order to prevent the early development of diabetic complications followed by premature death associated with IDDM, an evenly distributed high-level medical system throughout Japan is required in addition to tight control of diabetes and patient education. Moreover, a population-based ongoing IDDM registry should be established from which risk factors for the progression of complications could be identified. PMID- 7859603 TI - Diabetic retinopathy and control of diabetes with special reference to blood glucose levels. AB - Data concerning diabetic retinopathy were collected prospectively in the Diabetes Clinic of the Third Department of Internal Medicine, University of Tokyo, from the beginning of the Clinic in 1957 until 1985. These data are analyzed here. The prevalence and severity of the retinopathy at the initial visit was strongly related to the duration of diabetes before examination. Pretreatment fasting blood glucose levels were also significantly related. During follow-up, the incidence of retinopathy was most strongly influenced by the degree of control of blood glucose, followed by other factors like blood pressure, age at diagnosis, etc. The effectiveness of sulfonylurea on retinopathy was not inferior to insulin so long as good control was obtained. It was deduced from the analysis of the chain of events that dot hemorrhage is the initial component of diabetic retinopathy, followed by hard exudate, blot hemorrhage, soft exudate and proliferative retinopathy. A six-year fluorescein angiography follow-up of well controlled non-insulin dependent cases with mild retinopathy showed that microaneurysms disappear rapidly during the first year and more slowly thereafter. The avascular areas once formed seem to progress despite the degree of control exerted here. The other Japanese results are discussed. PMID- 7859604 TI - Diabetic nephropathy in Japan. AB - According to a nation-wide survey of dialysis patients in Japan the number of diabetic patients with end-stage renal failure introduced to dialysis therapy has been increasing year by year, exceeding 6000 cases (28% of total cases) in 1991. A six-fold increase in numbers and a three-fold increase in percentages (DM/total) were observed in the past ten years. Although the medical technology and regimen in dialysis therapy have been greatly improved, the prognosis of those diabetic patients on maintenance dialysis has remained unsatisfactory. Their quality of life has been severely damaged mostly because of the impairment of visual acuity. The early detection and early introduction of effective therapy for diabetic nephropathy, therefore, may be the most imminent tasks necessary to prevent the various problems afflicting diabetic patients on end-stage renal failure. PMID- 7859605 TI - Ischemic heart disease in patients with diabetes mellitus in Japan. AB - The risk of death by ischemic heart disease (IHD) in patients with diabetes mellitus is higher than in non-diabetics, and the average life span of the diabetics is shorter than in non-diabetics in Japan. There is no direct correlation between the occurrence of IHD and severity or glycemic control of diabetes. However, the mortality by IHD increases in diabetic patients with severe retinopathy and/or massive proteinuria. Regarding the management of IHD, diabetes is not considered a contraindication to thrombolytic therapy. The indication and results of percutaneous transluminal coronary angioplasty and coronary bypass surgery are the same as in non-diabetics. PMID- 7859606 TI - Diabetes mellitus and cerebral vascular disease. AB - Non-fatal or small infarction, especially with multiple occurrence, is a feature of cerebrovascular disease complicating diabetes mellitus. The atherosclerosis of the cervical and cerebral arteries, especially in the posterior circulation, in diabetes is more severe than that in non-diabetics. We reviewed the incidence of vascular lesions, and clinical history in 25 male and 26 female diabetic autopsy subjects. In addition, the long-term effects of blood pressure and glucose values were evaluated in 267 stroke patients without cerebral embolism, 99 of whom had diabetes mellitus. Asymptomatic cerebral infarction is not rare in diabetic subjects, and can now be accurately pathologically and clinically evaluated using MRI. The results of our study indicate that high blood pressure and poor blood glucose control are associated with the higher incidence of cerebral infarction in the diabetic patients. PMID- 7859607 TI - Gangrene and ulcer of the lower extremities in diabetic patients. AB - In diabetic patients in Japan, gangrene, and ulcers of the lower extremities were found in 2% of out-patients and in 4% of hospitalized patients. This prevalence in Japan is much less than in Western countries, as already shown by the Multinational Study on Vascular Diabetic Diseases. The ratio of ulcers due to neuropathy is 3 or 4 times more than that caused by ASO. But recent trends showed a gradual increase in ASO among diabetic patients. According to the API measured by the ultrasonic Doppler method, the prevalence of ASO is estimated as being 10% of diabetic patients, and about one tenth of ASO patients will develop gangrene in future. PMID- 7859609 TI - Historical changes in diabetes therapy in Japan. AB - The origins of many aspects of ancient Japanese culture lie in knowledge brought from China, and medicine was no exception. Subsequently, however, in the middle of the 16th century, Portuguese missionaries introduced Western medicine to Japan along with Christianity. They were followed by the Dutch in the 17th century, who introduced Western culture while carrying on commerce at their Dejima outpost in Nagasaki. This was called the Dutch school in Japan, and although there was thus contact with Western culture and the Japanese eagerly studied Western medicine, it was not until after the establishment of the Meiji Reform government in the middle of the 19th century that there was aggressive incorporation and acceptance of modern Western medicine in Japan. The University of Tokyo was the first university in Japan. Preserved in the library of the Third Department of Internal Medicine are old records of hospitalized cases in Japan, and those documents form the basis of this review of the history of the treatment of diabetes mellitus in Japan. PMID- 7859608 TI - Plasma lipid abnormalities and risk factors for coronary artery disease in Japanese subjects with diabetes mellitus and glucose intolerance. AB - We evaluated the plasma lipid levels of 3163 subjects including subjects with non insulin-dependent diabetes mellitus (NIDDM), insulin-dependent diabetes mellitus (IDDM), impaired glucose tolerance (IGT), and normal glucose tolerance. Furthermore, we performed 100 g oral glucose tolerance tests on 2113 subjects, and analyzed the relationships of risk factors for coronary artery disease to glucose intolerance. Mean plasma cholesterol and triglyceride levels were highest in NIDDM (213 mg/dl and 148 mg/dl), and plasma HDL-cholesterol level was lowest in IGT and NIDDM (42 mg/dl), as compared to those in normal subjects (cholesterol, 200 mg/dl; triglycerides, 109 mg/dl; HDL-cholesterol, 52 mg/dl). Multiple regression analysis demonstrated a significant relationship of either blood pressure, plasma triglyceride or HDL cholesterol level to plasma insulin and glucose response after glucose loading. PMID- 7859610 TI - Systems for the treatment of diabetes in Japan. AB - Well-organized medical insurance systems cover all medical fees for diabetes mellitus, and diabetics can visit doctors quite freely in Japan. Also insulin therapy by self-injection became legal and covered by health insurance after 1981 in this country. Despite such good conditions for the patients, there are some problems such as the increase of patients with diabetes, poor education systems for diabetics and not enough systems to care for patients with severe diabetic complications. PMID- 7859611 TI - Prevalence and incidence of diabetes mellitus by WHO criteria. AB - The recent data on the prevalence and incidence of diabetes mellitus in Japan are presented. The data were obtained in 1989-1992 based on the 1985 WHO criteria. The prevalence and incidence for childhood IDDM (0-18 years) were chiefly derived from the records of patients who received free medical care for diabetes. The prevalence was 10-15 per 100,000 and incidence was 1.2-2.0 per 100,000 in most regions of Japan. There is no increasing tendency from south to north. The prevalence of diabetes (mostly NIDDM) in the population aged 40 years or older studied using the 75 g oral glucose tolerance test ranged from 4 to 12%. Men were affected more frequently than women in most areas. There are problems with the data on the incidence of NIDDM obtained so far. The nation-wide survey of HbA1c suggests about a 2-fold difference in abnormally high HbA1c in different regions of Japan. PMID- 7859612 TI - Diet therapy and food exchange lists for diabetic patients. AB - The present situation of diet therapy for diabetes in Japan is described in this chapter. The diabetic diet in Japan is based on Japanese traditional food and eating habits. So far, it has effectively contributed to the treatment of diabetes. The aim of diet therapy for the diabetic regimen in Japan is, as in other countries, firstly, to supply energy for maintaining adequate body weight and healthy social activities, and secondly, to attain glycemic control as close as possible to that of a non-diabetic person to prevent the occurrence of diabetic complications. The Japan Diabetes Society has elucidated the following principles of diet therapy for the accomplishment of the above purposes. (1) The proper amount of daily energy intake means the amount which affords physical activities. (2) The proportion of the 3 main nutrients should be: 60% as carbohydrate, 15-20% protein and 20-25% fat. (3) As to vitamins and minerals, an appropriate amount to meet the average requirement should be supplied daily. (4) It is recommended that a proper amount of fiber be taken. Furthermore, with regard to patient education, which is the most important aspect of adhering to diet therapy, an outline of the latest (1993) edition of the 'Food Exchange Lists', having been first edited in 1965 by the Japan Diabetes Society, is introduced together with its use. PMID- 7859613 TI - Exercise therapy in Japan. AB - The purpose of this report is to outline the exercise therapy of diabetes mellitus that has been administered in Japan during the past 10 years, with special emphasis on the results of studies on metabolic effects as well as on practical aspects of exercise therapy. The studies on the response to exercise clarified neuroendocrine mechanisms involved in the regulation of carbohydrate and fat metabolism in exercise and provided a basis for the indication of exercise therapy in view of the pre-existing metabolic abnormalities. Concerning the training effects, changes of insulin sensitivity have been chiefly studied in relation to metabolic improvement by physical training using the insulin clamp method. The improvement of glucose and lipid metabolism obtained during the training program, consisting of fast walking or jogging corresponding to 40-60% of predictive VO2 max for 30-60 min daily, was suggested to be related to improved insulin sensitivity in patients with NIDDM. Intensive studies have been made on exercise programs, and medical checks and guidelines for exercise prescription have been provided. Aerobic exercises with stretching and low-level callisthenics are recommended, and the usefulness of a multi-stage exercise loading test and the necessity of self-monitoring of blood glucose are stressed for the successful management of exercise therapy. PMID- 7859614 TI - Insulin treatment in Japan. AB - The therapeutic methods of treating Japanese cases of diabetes with insulin have been developed following the lead of the USA and European countries. With support from the National Health Care System, most clinics have been able to provide relatively good care of diabetic patients under treatment, but judging from the increase in the number of patients with chronic diabetic complications, the development of better methods of treatment and their wider application is a matter of great urgency. PMID- 7859615 TI - Artificial endocrine pancreas and optimal blood glucose regulation in diabetic patients--from bedside-type to wearable-type. AB - The artificial endocrine pancreas is a feedback control system regulating insulin delivery on a minute-by-minute basis according to the measured blood glucose levels. The bedside-type artificial endocrine pancreas has been proven to be useful not only as a therapeutic tool for diabetes mellitus but also as an elegant research tool for investigating the pathophysiology of the disease. With significant advances in the development of a subcutaneous tissue glucose monitoring system, the wearable-type artificial endocrine pancreas has been applied to diabetic patients. With this system, perfect glycemic control can be obtained for longer periods in ambulatory diabetic patients. The trend in the development of the artificial endocrine pancreas is now directed to implantable devices. Much efforts have been conducted to realize these devices. PMID- 7859616 TI - Serum 1,5-anhydroglucitol (1,5 AG): new clinical marker for glycemic control. AB - We review the use of 1,5-anhydroglucitol (1,5 AG) in diagnosing and monitoring patients with diabetes. This six-carbon chain monosaccharide is one of the major polyols present in humans. Its concentration in serum is normally about 12 to 40 micrograms/ml. This substance is derived mainly from food, is well absorbed in the intestine, and is distributed to all organs and tissues. It is metabolically stable, being excreted in the urine when its level exceeds the renal threshold. It is reabsorbed in the renal tubules, and is competitively inhibited by glucosuria, which leads to a reduction in its level in serum. The correlation between this reduction and the amount of glucose present in urine is so close that 1,5 AG can be used as a sensitive, day-to-day, real-time marker of glycemic control. It provides useful information on current glycemic control and is superior to both HbA1c and fructosamine in detecting near-normoglycemia. PMID- 7859617 TI - Self-monitoring of blood glucose, as a means of self-management. AB - In Japan, the study of the self-monitoring of blood glucose (SMBG) was started in 1976. After that, SMBG gradually became popular among the diabetes clinics, and was covered by health insurance in 1987. Although performers of SMBG constitute only 35% of all insulin-treated patients, it has been highly evaluated that 60% of patients with insulin-dependent diabetes perform SMBG. The results of this study of SMBG revealed that it was useful for the prevention of chronic complications and for the education of diabetes patients. New systems using an electrochemical technology are developing so rapidly that the newest model, with no wiping or blotting of a blood sample, will help the spread of SMBG. We must put emphasis on introducing SMBG as a means of self-management to all patients with diabetes. PMID- 7859619 TI - Patient education and educational activity in the general public. AB - In Japan, about 97% of diabetic patients suffer from non-insulin dependent diabetes. Because of its insidious onset, public education with regard to diabetes is very important. According to a survey in 1989, approximately 87% of diabetic patients were treated at hospitals. Considering the difficulty of organizing an educational team targetting small clinics, diabetes education should be provided with close cooperation between hospitals and local clinics. Since 1967, National Diabetes Week is annually held in the second week of November; in more than 150 cities and towns, lecture meetings, screening tests and consultation by physicians and health professionals are performed under the sponsorship of the Japan Diabetes Society and the Japan Association of Diabetes Care and Education. The Japan Diabetes Society has edited 'Diabetes Treatment Guide' and 'Meal Exchange List' since 1961 to provide the minimum requirement of knowledge and skill in the diabetes treatment regimen. More than 850 hospitals and clinics now have a particular educational program. Admission for the education of diabetic patients is provided by 366 hospitals. In 1991, summer camps for children were held at 37 sites, where about 1200 patients participated. For the training of the educators, the Japan Diabetes Society and several other organizations offer many lecture meetings and courses with experiential format; the curriculum for diabetes educators is expected to be much improved in the near future. PMID- 7859618 TI - Current status of pregnancy in diabetic women. A comparison of pregnancy in IDDM and NIDDM mothers. AB - Pregnancy in diabetic patients was uncommon before 1960 in Japan. It has increased recently and there has been a 3-fold increase since 1971. Only 26% of the cases of diabetic pregnancy had IDDM; the rest of cases had NIDDM. The perinatal mortality of infants decreased from 10.8% in 1971-1975 to 1.1% in 1986 1990, but the incidence of congenital malformations remained at 5.7-8.2% during this period. From 1988 to 1992, we experienced 207 deliveries at the Diabetes Center, Tokyo Women's Medical College. The ratio of IDDM to NIDDM of the mothers was 33:67. The onset of diabetes of pregnant women occurred earlier and the duration of diabetes was longer in IDDM than in NIDDM (mean onset, 17.8 vs. 26.0 years; mean duration, 11.5 vs. 5.6 years). The prevalence of maternal complications was similar between the IDDM and NIDDM mothers. Proliferative retinopathy in NIDDM was often detected for the first time during pregnancy. Major congenital malformations were found in none of the infants of IDDM mothers but in 5.8% of the infants of NIDDM mothers. This is probably related to the poor management of diabetes in NIDDM before pregnancy. PMID- 7859620 TI - Summer camp. AB - The first summer camp in Japan was held at a site near Tokyo in 1963. The guide book was edited by Japan Diabetes Society in 1984. In 1992, 1012 children with diabetes participated at 36 sites all across Japan. The programme is characterized by the smooth combination between education for the children and their experience of recreation. The term of the camp, staff member issues, camp operating fund are discussed. A pan-pacific international diabetes summer camp was successfully held at the Ehime prefecture site in 1989 with 56 patients from eight countries. The summer camp is evaluated for the achievement of good psycho physical growth of the participating children and the maintenance of good control of diabetes. The problems include the term length of the camp, finding a camp site and the national and local governmental subsidy. Finally, a more effective operation with a minimum number of educators should be another concern in the future. PMID- 7859621 TI - Trends in the prevalence of diabetes mellitus among Hiroshima atomic bomb survivors. AB - Mass screening for diabetes mellitus has been conducted on 64,000- 113,000 atomic bomb survivors resident in Hiroshima City since 1961. The trends in the number of diabetes mellitus patients from 1971 to 1992 based on the results of this mass screening and on death certificates are described. The prevalence of diabetes mellitus has shown an increase with age, but it peaked in the 8th decade and declined after the 9th decade. From 1971 to 1992 a 2.7-fold increase in the prevalence of diabetes mellitus was observed in males and a 3.2-fold increase in females. By age, in males the increase was high in those of less than 49 years of age, and in females the increase was predominant in those of 80 years of age and over. In males the prevalence of diabetes mellitus estimates by death certificates was in good agreement with that observed by mass screening, but in females the prevalence observed by death certificates gave a higher value. During a period of two decades, a 2.1-fold increase was observed in males and a 2.0-fold increase in females. PMID- 7859622 TI - Causes of death in Japanese diabetic patients examined by autopsy. AB - Autopsy records have been published annually by the Japan Society of Pathology. We collected diabetic autopsy cases from these records (1958-1985) and analysed the causes of death. Vascular diseases comprised 38-48% of all causes of death, malignant neoplasms 16-23% and infections 16-23%. Among vascular diseases, the incidence of coronary artery diseases has increased from 6.0 to 17%, but the frequency of nephropathy and cerebrovascular diseases has remained relatively stable since 1970. Diabetic coma and tuberculosis has decreased as a cause of death, while vascular diseases and malignant neoplasm have increased during these periods. These changes reflect the trend of changing disease structure in the general population, which is partly due to the changes in age distribution of the population. PMID- 7859623 TI - Mortality and causes of death in follow-up diabetic population in Japan. AB - There have been few reports of follow-up studies on mortality and causes of death from diabetics in Japan. One group of patients with non-insulin-dependent diabetes (NIDDM) was followed up in Osaka and the other group in Tokyo. Results from both studies were almost the same in which diabetic nephropathy and coronary heart disease were important as the causes of death. Because of a small number of patients with insulin-dependent diabetes (IDDM) follow-up studies are difficult in Japan, and only one study was reported from the Diabetes Epidemiology Research International (DERI) Mortality Study Group. Although a very large mortality of IDDM in Japan was reported in this study, this is now improving rapidly. PMID- 7859624 TI - Mortality and causes of death in patients with diabetes mellitus in Japan. AB - Although the mortality rate of diabetes mellitus in Japan is much lower than the rates in Western countries, an increasing trend has been evident over the last 40 years as a whole. However, the trend shows variations with age; there is an apparent decreasing trend in subjects of 0-35 years of age at death, while there is a remarkable increasing trend in subjects of 75 years of age and over. It appears that the increase in diabetes mortality is largely due to an elevation in the mortality rate in aged subjects and an increase in the size of the aged population in this country. A population-based study of causes of death, carried out in Osaka Prefecture for the period 1960-1989, indicates a remarkable increase in the age at death and significant changes in the causes of death of diabetic patients. Diseases of the circulatory system were found to be the major causes of death other than diabetes, and, among them, a rapid increase in the frequency of disease of the heart was observed. As a cause of death, tuberculosis decreased sharply, while malignant neoplasms, ischemic heart disease, and pneumonia and bronchitis increased during the same period. Among malignant neoplasms, an increase in neoplasm of the liver was marked. PMID- 7859625 TI - The NOD mouse. AB - The NOD mouse was discovered and established as an inbred strain in Japan. It is an excellent animal model for human Type 1 (insulin-dependent) diabetes mellitus in many aspects, including genetics, immunology, virology, and prevention and therapy. The diabetes and/or insulitis is controlled by at least 10 genes and results from the T cell-mediated destruction of beta cells. Retrovirus might also play a role in the pathogenesis. Insulitis and/or diabetes of the mice is easily prevented by a number of agents or manipulations, suggesting that diabetes of the mice develops only when many diabetogenic factors assemble. Some of the intervention trials using the mice are hoped to be applied to human Type 1 diabetes. PMID- 7859626 TI - KK mouse. AB - The KK mouse strain shows inherently glucose intolerance and insulin resistance. When KK mice become obese by aging, dietary means or other ways, such a chemical diabetic state is changed to overt diabetic state associated with frank hyperglycemia and glucosuria. Therefore, the KK mouse is a good model for investigating a process of expression of obesity-associated diabetes. PMID- 7859627 TI - OLETF (Otsuka Long-Evans Tokushima Fatty) rat: a new NIDDM rat strain. AB - The characteristic features of OLETF rats are: (1) late onset of hyperglycemia (after 18 weeks of age); (2) a chronic course of disease; (3) mild obesity; (4) clinical onset of diabetes mellitus (DM) mostly in males; (5) hereditary trait: (a) multiple recessive genes are involved in the induction of DM; (b) rat MHC, RT1 has no diabetogenic effect; (c) control strain, LETO appears to share some of diabetogenic genes with OLETF rats; (d) female OLETF rats also carry diabetogenic genes; and (e) one of the diabetogenic genes, designated as odb-1, is transmitted linked with the X-chromosome of OLETF rats, however testosterone is an important factor involved in developing diabetes; (6) the changes of pancreatic islets can be classified into three stages: (1) an early stage (at less than 9 weeks of age) mild lymphocyte infiltration; (2) a hyperplastic stage (10-40 weeks of age); hyperplastic change and fibrosis in or around islets; (3) a final stage (at more than 40 weeks of age) showing atrophy of islets; (7) diabetic nephropathy; (a) diffuse glomerulosclerosis; (b) nodular lesion (thickening of basement membranes, mesangial proliferation, fibrin cap). These clinical and pathologic features of disease in OLETF rats resemble those of human NIDDM. PMID- 7859628 TI - History and activities of Japan Diabetes Society. AB - After 1953, Dr. Y. Kobayashi organized a study group of chemotherapy of diabetes mellitus, and then a more broader 'Diabetes Study Group' sponsored by the Ministry of Education. During these group activities, the members felt the need to establish a forum to discuss various aspects of diabetology. In December 1957, an inaugural meeting of the Japan Diabetes Society (JDS) was held. The objectives of the Society were to promote the investigation and to spread the knowledge on diabetes and to thereby prevent the hazard arising from diabetes. Since that time, JDS has been admitted as a member of the International Diabetes Federation in 1958, and was approved as an incorporated association by the Ministry of Education in 1985. It has now seven regional branches. Members increased greatly and reached 7795 in March 1993. In every year, JDS has a 3-day nationwide general scientific meeting, and local meetings are held by each of its branches. The official journal 'Tonyobyo (Journal of the Japan Diabetes Society)' is being issued monthly. JDS edited educational books for diabetic patients, such as 'Guidebook for the Treatment of Diabetes', 'The Exchange List of Foods for the Treatment of Diabetes Mellitus' and 'The Guidebook of Summer Camp for Diabetic Children'. In 1967, JDS began to hold a 2-day post-graduate course named 'Progress in Diabetology' for physicians, nurses, dieticians and other health professionals. JDS has a close connection with the Japan Association of Diabetes Care and Education, co-sponsoring the 'diabetes week' every year.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859629 TI - History and current activities of the International Diabetes Federation-Western Pacific Region (IDF-WPR). AB - International Diabetes Federation (IDF) is one of the biggest non-governmental organizations with its 44-year history since 1950. In 1993, 114 diabetes associations in 96 countries participated in the IDF. In 1982, it was decided to divide the globe into seven regions and to promote the diagnosis, treatment, care and education of diabetes based on the environment, natural features, culture and race of the each region. On January 24, 1984, the IDF-WPR establishment meeting was held in Melbourne, Australia, with eight original member countries (Australia, New Zealand, Korea, The Philippines, Malaysia, Singapore, Fiji and Japan). In 1993, 13 diabetes associations in 12 countries joined the IDF-WPR. New member associations are from China (Beijing and Taipei), Hong Kong, Papua New Guinea and Indonesia. The IDF-WPR has been holding congresses and council meetings every 3 or 4 years since 1984 as well as formulating strategic action plans in the scientific, clinical, health care and education fields of diabetes. PMID- 7859630 TI - WHO Collaborating Centre for Diabetes Treatment and Education. AB - The World Health Organization (WHO) has a section for non-communicable diseases, where the public health problems related to diabetes are treated. The WHO has cooperated with the International Diabetes Federation for many years. The classification of diabetes and diagnostic criteria proposed by its committee is now widely used throughout the world. Many medical schools, hospitals and institutes have been designated as WHO Collaborating Centres, in order to gather and spread information, to moderate cooperative research and assist educational activities. In the field of diabetes, about 30 WHO Collaborating Centres were established. In Japan, one such Centre for Diabetes Treatment and Education was placed in Kyoto National Hospital. In April 1991, the First International Conference on Health Technology in the field of Diabetes was held under the auspice of the Centre (Chairman: Dr. Y. Akazawa). The Centre played a major role in the Japanese national diabetes program, particularly in the field of epidemiology. It is expected to make good contributions also to diabetes in other countries especially in Asia. PMID- 7859631 TI - The high prevalence of diabetes mellitus and hyperinsulinemia among the Japanese Americans living in Hawaii and Los Angeles. AB - A comparative epidemiologic investigations was conducted among Japanese immigrants and their offspring living in Hawaii and the Los Angeles area, and among Japanese living in Hiroshima. All subjects received an oral glucose tolerance test and the diagnosis of diabetes was made on the basis of WHO criteria. In the subjects aged 40 years or older, the age, sex, and obesity specific prevalence of diabetes was 2-3 times higher among Japanese living in America than those in Hiroshima. The fasting and post-glucose load serum immunoreactive insulin concentrations were higher in the Japanese-Americans compared to the Hiroshima inhabitants with the same degree of obesity and glucose tolerance. We suggest that a westernized lifestyle induces peripheral insulin resistance and promotes the development of diabetes among Japanese. PMID- 7859632 TI - Diabetes and diabetes risk factors in second- and third-generation Japanese Americans in Seattle, Washington. AB - In Seattle, Washington, the prevalence of diabetes was 20% in second-generation (Nisei) Japanese-American men and 16% in Nisei women 45-74 years old, while the prevalence of impaired glucose tolerance (IGT) was 36% in Nisei men and 40% in Nisei women. Hyperglycemia was less and duration of diabetes shorter in women. Related to diabetes and IGT in Nisei were higher fasting plasma insulin levels and central (visceral) adiposity. Prevalence of diabetes was low among the younger (34-53 years old) third-generation (Sansei) men and women. Among self reported non-diabetic Sansei, however, prevalence of IGT was 19% in men and 29% in women, and IGT was associated with both increased fasting plasma insulin levels and more visceral fat, suggesting that many Sansei are at risk of future diabetes. An important lifestyle factor in the development of NIDD in Japanese Americans appeared to be dietary saturated (animal) fat. Another factor may be physical inactivity. In Japanese-American women, menopause also appeared to be an important risk factor. These risk factors may be related to fostering the accumulation of visceral fat and the development of insulin resistance. Five-year follow-up examinations performed in non-diabetic Nisei men and women have yielded additional information concerning the prognosis of IGT. Of those women who were IGT at baseline, 34% were diabetic at follow-up while 17% returned to normal. In men who had been IGT at baseline, 18% were diabetic at follow-up while 36% returned to normal. Over the 5-yr follow-up interval, proportionally more women progressed from normal to IGT (54%) then went from IGT to normal (17%). For men, roughly equal proportions went from normal to IGT (37%) as from IGT to normal (36%). It would therefore appear that greater proportions of Nisei women are progressing to IGT and to NIDD than are Nisei men. This observation may be related to the increased risk of developing central obesity and insulin resistance following menopause. Prevalence of cardiovascular disease (hypertension, peripheral vascular disease, and/or coronary heart disease) was increased in Japanese Americans with IGT and NIDD. Neuropathy and retinopathy were associated only with NIDD. PMID- 7859633 TI - Self-reported prevalence of non-insulin-dependent diabetes mellitus in the 1st (Issei) and 2nd (Nisei) generation of Japanese-Brazilians over 40 years of age. AB - The immigration of Japanese people to Brazil began in 1908 with two major waves, from 1925 to 1940 and from 1952 to the 1960s. Brazil has the largest population (about 1,288,000) of Japanese origin outside Japan with varying age groups. A mortality study revealed that diabetes as an underlying cause of death was higher in the first-generation Japanese than in Japan (3.4 vs. 1.9 per 100,000 for men, and 7.2 vs. 1.9 for women). The self-reported prevalences of known diabetes in subjects aged 40 years or older were obtained by questionnaires from three sources. In six Japanese cultural associations in Sao Paulo city, the prevalences were 9.7% and 6.9% for the first generation (mean age 61.5 years) and for the second generation (mean age 40.0 years), respectively. Age-adjusted prevalences, according to the Brazilian population in the 1980 national census, were 6.9% and 8.1% for the first and second generations. According to a study carried out as a part of a socioeconomic census of the Japanese population in Brazil, the prevalences of diabetes were 7.4% and 5.2%, and the age-adjusted prevalences were 5.3% and 5.8% in the first and second generations, respectively. Another study carried out for employees of a bank, owned by Japanese-Brazilian community members, revealed crude prevalences of diabetes in the first and second generations of 7.1% and 4.2%, and age-adjusted prevalences of 7.3% and 8.2%, respectively. These data indicate an increased prevalence of diabetes in this population compared to Japan, suggesting the importance of environmental factors in the pathogenesis of diabetes. PMID- 7859635 TI - Diabetic twins in Japan. AB - By the cooperation of members of the Japan Diabetes Society, we collected data on 144 twin pairs with diabetes or glucose intolerance. By the diagnosis of reporting physicians, the concordance rate of diabetes in monozygotic twins (MZ) was 47% (9/10) for IDDM and 87% (68/78) for NIDDM. The concordance rate in dizygotic twins (DZ) was 8% (1/13) and 43% (9/21) for IDDM and NIDDM, respectively. The concordance rate was higher in MZ than in DZ and in IDDM than in NIDDM. In MZ, the concordance rate was higher in twin pairs in which probands developed diabetes at an older age. The discordant period for diabetes was not shorter in discordant pairs than in concordant pairs. The period of living together was irrelevant to concordance for diabetes. When co-twins of NIDDM twins were examined by oral glucose tolerance test, 98% of co-twins of MZ and 92% of co twins of DZ had diabetes or a milder degree of glucose intolerance, while in IDDM pairs 45% of MZ and 50% of DZ co-twins had normal glucose tolerance. The insulinogenic index (the ratio of the increment of insulin to that of blood glucose 30 min after a glucose load) in discordant NIDDM co-twins was similar to subjects with the same degree of glucose intolerance. PMID- 7859634 TI - Diagnostic criteria for diabetes mellitus in Japan--from a report of the Japan Diabetes Society (JDS) Committee on the Diagnosis of Diabetes Mellitus, 1982. AB - After the proposal of diagnostic criteria for diabetes mellitus by the National Diabetes Data Group (1979) and by WHO (1980), a committee was set up by the Japan Diabetes Society (JDS) to reconsider the old criteria by the JDS which had been proposed in 1970. Items covered by the report of the committee in 1982 included the concept of diabetes mellitus, describing it's features, and stating that it's diagnosis is a procedure of recognizing the disease 'diabetes' characterized by these features. Cutoff blood glucose values for fasting samples, after a 75 g oral glucose tolerance test, were proposed to define normal and diabetic types. The cutoff values for the diabetic type are identical to those of the WHO defining diabetes, whereas the values for the normal type (fasting < 110 mg/dl and 1-h < 160 and 2-h < 120 mg/dl for venous plasma) are much lower than those for the lower limit of IGT by the WHO. Subjects whose glucose tolerance is neither diabetic nor normal are classified as borderline type, which includes not only IGT but cases with milder glucose intolerance. The cutoff points for the normal type were selected based on the long-term follow-up data for mild glucose intolerance in Japan. The Committee further stated that the clinical diagnosis of diabetes should be made not only on the basis of the glucose tolerance data, but also after clinical consideration of the possibility of any other diseases which might impair glucose tolerance. PMID- 7859636 TI - Family history of diabetic patients in Japan. AB - The frequency of a positive family history of diabetes in diabetic patients has increased in recent studies. In this study, it was 16-33% for type 1 diabetes and 43-49% for type 2 diabetes. It was significantly higher than in non-diabetic subjects, and in type 2 than in type 1 diabetic patients. The prevalence of diabetes in parents and siblings of type 2 diabetic patients was higher than in those of type 1 patients, and it was particularly high in parents of young onset type 2 patients. Among type 2 diabetic patients, positive family history was somewhat lower in those with marked obesity in the past. Comparison of groups with varying degrees of glucose intolerance revealed that a family history of diabetes increased in parallel with the impairment of glucose tolerance. The results suggest that genetic factors in the pathogenesis of diabetes are more important in type 2 than in type 1 diabetes, and in the younger onset and less obese subjects than in older onset and more obese patients for type 2 diabetes. PMID- 7859637 TI - Epidemiology of type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus in Japanese children. AB - The overall annual IDDM incidence rates by area in Japan for 1985-1989 for children 0-14 years of age at diagnosis were from 1.65 to 2.07 per 100,000. The incidence in males and females did not show any temporal trends during the period between 1980 and 1989. The prevalence of IDDM was about 1 per 10,000. The clinical features at diagnosis among Japanese IDDM children identified during the 2-year period between 1979 and 1980 were as follows. Fourteen percent of the cases were in coma and 12% of the cases were asymptomatic at diagnosis. There is a suggestion that slow onset IDDM is often seen in Japan. In these children, the decline of serum CPR levels and the prevalence of ICA (islet cell antibodies) over the course of diabetes was slower than in those with an abrupt onset classical IDDM. During the period from 1975 through 1990 the incidence rates of NIDDM in school children showed as much as an approximate 1.5-fold increase along with a similar increase in the prevalence of obesity. About eighty percent of these NIDDM children were obese. A predominance of female children developing diabetes was seen in both type of diabetes, IDDM and NIDDM, in Japan. Non-obese type NIDDM in children was more common in females than in males. It is interesting to note that the mean height of Japanese children with IDDM was not different from the national average, but children with NIDDM were significantly taller than the national average. PMID- 7859638 TI - A multicenter study on HLA and autoimmunity in Japanese patients with early-onset insulin-dependent diabetes mellitus (IDDM): the JDS Study. AB - The Japan Diabetes Society (JDS) conducted a multicenter study on HLA and autoimmunity in Japanese patients with early-onset insulin-dependent diabetes mellitus (IDDM). HLA, immunoglobulin heavy-chain complex (Gm), properdin factor B (BF), and glyoxalase of erythrocytes (GLO) were typed, and organ-specific autoantibodies including islet cell antibodies (ICA) were assayed in 159 IDDM patients and their relatives and in 258 healthy Japanese subjects. The HLA-DRw9 phenotype and HLA-Bw61/DRw9 haplotype were significantly increased among the patients with autoantibodies other than ICA, whereas the DR4 phenotype and Bw54/DR4 haplotype were significantly increased in those without the autoantibodies. The DR4 phenotype was significantly increased in the patients with autoimmune thyroid diseases. The relative risk of the HLA-DRw9/DR4 genotype was highest among all DR genotypes. The Gm phenotype of g and gft were significantly increased in the patients with the autoantibodies. The BF-F phenotype was significantly decreased in the patients either with or without the autoantibodies. There was no association of GLO types with IDDM. The prevalence of ICA among IDDM patients was decreased with duration of IDDM. No significant association was found between the prevalence of ICA and sex, age at onset, or HLA type. On the other hand, the prevalence of the autoantibodies was not significantly changed with duration of the disease, and was significantly higher in females than in males. PMID- 7859639 TI - Genetic markers for insulin-dependent diabetes mellitus in Japanese. AB - Although the HLA class II genes are clearly associated with insulin-dependent diabetes mellitus (IDDM) in all ethnic groups, considerable variation in the associated haplotypes is observed among the ethnic groups. In Japanese, DRB1*0405 DQA1*0301-DQB1*0401, DRB1*0901-DQA1*0301-DQB1*0303 and DRB1*0802-DQA1*0301 DQB1*0302 are the major susceptibility haplotypes to IDDM, while DRB1*1501 DQA1*0102-DQB1*0602 and DRB1*1502-DQA1*0103-DQB1*0601 are the major resistance haplotypes. The hypothesis that alleles encoding amino acids other than aspartic acid at the DQB1 position 57 contribute to IDDM susceptibility is not applicable to the Japanese, mainly because the first and second susceptibility haplotypes listed above have aspartic acid at DQB1 position 57. In the 5' insulin gene polymorphism, the shorter insertion (class 1 allele) is predominant, and is not associated with diabetes in Japanese. Subdivision of the class 1 alleles also failed to show an association with IDDM in Japanese. The insulin gene region appeared to be of less value as a genetic marker for IDDM in Japanese. Little is known about other genetic markers. PMID- 7859640 TI - Autoantibodies to glutamic acid decarboxylase (GAD), 64,000-Mr islet cell protein (64K) antibodies and islet cell antibodies (ICA) in insulin-dependent diabetes mellitus with and without autoimmune diseases in Japan. AB - IDDM is known to be a heterogeneous disease which is frequently complicated with other autoimmune diseases (AID). We previously reported that IDDM patients with AID were characterized by late onset of diabetes, persistent ICA-positivity and increased association with DR9, while those without AID were characterized by rapid decline of ICA with duration of diabetes and increased association with DR4. The present study was performed to investigate the prevalence of autoantibodies to glutamic acid decarboxylase (GAD), autoantibodies to 64KDa islet cell protein (64K antibodies) and islet cell antibodies (ICA) in Japanese IDDM patients with and without AID. In short-duration diabetes (< 1 year), the prevalence of GAD antibodies, 64K antibodies and ICA were 100%, 100%, and 100%, respectively, in IDDM patients with AID, and 82%, 64% and 82%, respectively, in patients without AID. In long-standing diabetes (3-28 years), the prevalence of GAD antibodies were 76%, 48% and 33%, respectively, in IDDM patients with AID, and 48%, 28% and 16%, respectively, in patients without AID. The mean levels of GAD antibodies, 64K antibodies and ICA in IDDM patients with AID was significantly higher than in those without AID. Furthermore, the prevalence of GAD antibodies were detected more frequently than ICA and 64K antibodies in long standing IDDM patients. Our results demonstrate that the prevalence of GAD antibodies in IDDM patients were as high as those reported in Caucasians, and high levels of GAD antibodies were observed in IDDM patients with AID. PMID- 7859641 TI - Subtype of insulin-dependent diabetes mellitus (IDDM) in Japan: slowly progressive IDDM--the clinical characteristics and pathogenesis of the syndrome. AB - A prospective observation on the natural history of beta-cell function in islet cell antibody (ICA)-positive NIDDM disclosed characteristic findings of slowly progressive IDDM distinct from those of acute onset IDDM. The characteristic features includes: (1) late onset; (2) slow progression of beta-cell failure over several years with persistently positive low-titer ICA; (3) incomplete beta-cell loss; (4) frequent involvement of exocrine pancreas; (5) higher family history of NIDDM; and (6) association with some genetic predisposition including HLA DQA1*0301-DQB1*0401 and/or mitochondrial gene mutation at nucleotide pair 3243. PMID- 7859642 TI - [Laparoscopic surgery for hepatic, splenic and mesenteric cysts]. AB - Five women and one man (average age 62.5 [20-64] years) with symptomatic intraabdominal cysts at different sites (liver: n = 3; spleen: n = 2; mesentery: n = 1) had them removed by laparoscopic surgery. Broad fenestration was performed with the hepatic and splenic cysts, while the mesenteric cyst was enucleated from the mesentery. There were no intra- or postoperative complications. Median duration of operation was 60 (45-125) min, postoperative hospital stay was 5 (3 6) days. After a median follow-up period of 8 (1-12) months a 3 cm residual cyst was found in the patient with the splenic cyst, but all patients were free of symptoms. -Laparoscopic surgery is a low-stress alternative to conventional surgical removal of intraabdominal cysts. PMID- 7859643 TI - [Color Doppler-guided compression of pseudoaneurysms after arterial puncture. Early and late results]. AB - Sixteen pseudoaneurysms occurred after 1796 femoral arterial punctures for diagnostic coronary angiography and/or angioplasty, performed between 1. 1. 1993 and 25. 3. 1994. One additional patient with pseudoaneurysm had undergone a femoral arterial puncture at another hospital. Primary colour Doppler-directed compression of the pseudoaneurysm (15-minute compression followed by 10-minute compressions, as needed) was successful in 16 patients. There was one recurrence, after five days, which was successfully and lastingly treated by another compression. Primary thrombosing by compression of the pseudoaneurysm failed in only one patient, but after spontaneous thrombosis achieved by a compression bandage no flow was demonstrable on the following day. Clinical examination and/or colour Doppler sonography was performed on all patients a mean of 84 days (5 days to 6 months) after successful treatment: no recurrence was recorded. There were no significant early or late complications. These data indicate that colour Doppler-monitored compression of femoral-artery pseudoaneurysm can be considered the treatment of choice, with few exceptions, for this not rare complication of arterial catheterization. PMID- 7859644 TI - [Spontaneous hemothorax in dermatomyositis and long-term glucocorticoid treatment]. AB - A 65-year-old woman with dermatomyositis for which she had been treated for ten years with prednisone (latterly 15 mg daily) suddenly experienced severe pain in the left thoracolumbar region. Cardiovascular, pulmonary and vertebral causes of the pain were excluded. But serological tests indicated inflammatory disease and the haemoglobin concentration was low (10.4 g/dl). Left pleural effusions were repeatedly aspirated and some haemorrhagic fluid obtained (haematocrit 0.31 in blood, 0.28 in the pleural effusion). Five days after admission her cardiovascular status became unstable and she developed respiratory failure (haemoglobin 7.6 g/dl). Chest radiograph showed increased pleural effusion. Subsequent thoracotomy revealed a left coagulothorax which was removed and flushed. During this procedure severe bleeding occurred from a covered perforation of the descending aorta, 1.5 x 1.5 cm in size. Although the aortic wall was thin, there was no aneurysm but arteriosclerotic changes and an external erosion near an abscessing mediastinitis, originating from a chronic purulent pleuritis and bronchopneumonia. The severe blood loss caused circulatory failure from which the patient could not be resuscitated. PMID- 7859645 TI - [Systemic lupus erythematosus and silicosis]. AB - A 60-year-old stonemason, suffering for many years from joint pains and exertional dyspnoea, developed a high fever with weight loss. Physical examination revealed reddening of light-exposed skin areas, fine rales and overly warm and reddened hand and knee joints. Abnormal laboratory findings were increased erythrocyte sedimentation rate of 66 mm/h, C-reactive protein concentration of 1 mg/dl, haemoglobin of 9.4 g/dl and white cell count of 3300/microliters. Urine contained albumin (100 mg/dl) and cylinders. Titres of both antinuclear and anti-ds-DNA antibodies were elevated (1:2560 and > 97 U/ml, respectively). The chest radiography showed enlarged hili, as well as reticular and nodular shadows which histologically showed silicosis. Systemic lupus erythematodes was diagnosed and the patient was treated with prednisone (2 mg/kg daily), the dosage being reduced to 12 mg daily within 3 months. When the joint pains recurred, azathioprine (50 mg daily) was added for 24 months. At present he is receiving prednisone (12 mg daily) and there has been no recurrence for 4 years. PMID- 7859646 TI - [Virus-free preparations of factor VIII]. PMID- 7859647 TI - [Type II diabetes. Pathophysiology of insulin resistance, rules and goals of therapy]. PMID- 7859648 TI - [Omega-3 fatty acids (fish oil) in clinical practice]. PMID- 7859649 TI - [Magnesium in atrioventricular conduction disorders and intraventricular block]. PMID- 7859650 TI - [Allopurinol]. PMID- 7859651 TI - Educating and training doctors: are final year examinations necessary today? PMID- 7859653 TI - Utilisation of family planning services at the teaching hospital in Blantyre, Malawi. AB - In the whole of 1993, there were a total of 1533 new clients who attended the family planning clinic at the Queen Elizabeth Central Teaching Hospital in Blantyre, Malawi. They formed 23.0% of the total client-visits for the year. 305 women had surgical contraception (bilateral tubal ligation) for various reasons, but mainly on request for family limitation. The ages of the new clients ranged from 15 to 49 years. Adolescents (< 20 years old) formed only 9.0%, while those aged > 35 years formed 22.0%. Their parity ranged from 0 to 11, with 58.0% of them being para 1 to 4. The grandmultiparae (para > 5) formed 31.0%. The oral pill was the most favoured method (42.0%), followed by depo-provera (31.0%) and sterilisation (21.0%). Though the majority of the clients who chose the oral pill were aged less than 30 years, about 6.0% were aged > 35 years. Likewise about 15.0% of those who took oral pills were para > 5, i.e. grandmultiparae. These are women who should have either stopped producing a long time back or been counselled to have tubal ligation rather than these temporary methods, when seen in the clinic then. Amongst all the client-visits for the year, oral pill and depo-provera were the two most popular methods, 42.0% and 41.0%, respectively. The ratio, between the clients who discontinued the method they were on and the new clients was 1:6.8, and that of drop-out/new clients was 1:2.4, which are quite high. The rate of absenteeism was also high at 29.0% of the total client visits.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859654 TI - An intervention to reduce the risk of mother-to-infant HIV transmission: results of a pilot toxicity study. AB - Although unproven, vaginal cleansing with antiseptics during labour could be a practical approach to reducing the rate of transmission of HIV infection from mother to infant. Before initiating a large scale clinical trial of the antiseptic chlorhexidine, we conducted a study to assess possible toxic effects as well as beneficial outcomes in 160 women volunteers: 40 non-pregnant chlorhexidine washed, 40 pregnant not washed, 40 pregnant saline washed, and 40 pregnant chlorhexidine washed. The wash was easily administered by the nurse midwives. The participants generally felt better after the procedure, and had no complaints or adverse reactions in the subsequent 24 hours. Bacteriologically, the procedures lowered the carriage of Group B streptococcus and Staphylococcus aureus, but did not affect the frequency of T. vaginalis detection. No clinical problems were seen, and therefore the larger clinical trial of efficacy will proceed. Results of this trial are expected in late 1995. PMID- 7859655 TI - Knowledge, attitudes and practices of mothers regarding diarrhoea among children in a Sudanese rural community. AB - A survey of knowledge, attitudes and practices of mothers in the rural communities of two villages in Sudan regarding diarrhoeal diseases in children was conducted using a focus group research technique. Seven groups of literate mothers (87 mothers) and 13 groups of illiterate mothers (152 mothers) interviewed comprised 85% of mothers with children under 5 years of age in that community. The study showed that mothers can define and describe diarrhoea, however awareness about the aetiology and the importance of germs in its causation was low. The majority of mothers attributed diarrhoea to teething, milk of pregnant women, hot food and salty water. Less than 40% of mothers identify symptoms and signs of "dehydration" and the need for consultation. Only 10% could relate danger signs to severe dehydration. The ORS use rate was very low (2.1 4.3%). Although awareness about ORS was high (100%), only 25% prepared and used it correctly. However, home made fluids including rice water, custard, pap and tabaladi juice were used by 45% of the mothers. 45% of illiterate mothers stop breast feeding and food during diarrhoea compared to 30% of literate mothers. Harmful practices used in caring for children with diarrhoea included: fumigation (50%), cauterization and removal of teeth buds (45% illiterate mothers, 10% literate), withholding of breast feeding and indiscriminate use of drugs and herbs in 30%. PMID- 7859652 TI - Nutritional status of 3-6 year-old African children in the Cape Peninsula. AB - A survey was conducted in the Cape Town metropolitan area in 1990 to determine the dietary intake and anthropometric status of 3-6 year-old African children (N = 163). Dietary data obtained from 24-hour recalls revealed that mean energy intake (5200 kJ) was low and that mean intakes of most nutrients fell considerably below the recommended dietary allowances (RDAs). The average diet included an adequate number of portions from the meat and cereal groups, but was inadequate with respect to the milk and fruit/vegetable groups when compared with the recommendations of the Department of Health Services and Welfare. The macronutrient energy distribution was within prudent dietary guidelines, with 28.1% of energy (E) being obtained from total fat, 63.7% from carbohydrate and 13.2% from protein. Anthropometric profiles expressed in terms of the National Centre for Health Statistics' (NCHS) standards, revealed evidence of growth retardation and wasting in this population, coexisting with emergent obesity. The development of a nutrition and health policy to address the problems of both deficit and excess represents a pressing challenge. PMID- 7859656 TI - Secondary school students: a safer blood donor population in an urban with high HIV prevalence in east Africa. AB - We evaluated the enrollment of secondary school students as voluntary unremunerated blood donors in a city where the HIV-1 prevalence among the adult population is 11.8%. Between 1st July, 1992 and 1st December, 1993, consecutive blood donors were screened for anti-HIV-1, TPHA, HBsAg and anti-HBc. Test results were related to age, sex, voluntary or relative donor status. 525 (22.4%) of 2345 were voluntary donors aged 24 years or less and 529 (29.6%) of 1820 of the relative donors were of the same age group. Voluntary donors had statistically significant lower prevalence rates of anti-HIV-1, TPHA, and anti-HBc, 1.5%, 2.1% and 50.2% respectively, compared to relative donors of the same age group, 4.7%, 9.0% and 70.3% respectively. We conclude that secondary school students constituted a safer donor population. The student population offered the additional advantage of being easily accessible for donation and lesser blood units needed to be discarded. For a blood transfusion centre in an urban settlement, recruitment of secondary school students as voluntary unremunerated blood donors should be considered as a cost-effective strategy. PMID- 7859657 TI - Administration of first-aid and prevention of injuries in Kenyan soccer. AB - Appropriate scientific training demands the cooperation of the coach, player, doctor and physiotherapist. The training process involves the medical examination before a competitive season, the diagnosis and treatment of injuries when they occur, the prevention of injuries and the rehabilitation of the injured back into competitive play. It is in these respects that a coach requires the services of a doctor and/or a physiotherapist on the technical bench. This study therefore attempted to establish whether the soccer coaches were benefiting from the professional support of the doctors. The study sought the views of the Kenyan soccer coaches on the administration of first-aid and the preventive measures against injuries. Specifically, the study attempted to find out whether the Kenyan soccer clubs employed team doctors, whether the coaches had adequate knowledge in first-aid, the injury prevention measures that the coaches enforced, etc. A questionnaire was administered to 42 individual soccer coaches who were attending an advanced Confederation Africaine de Football (CAF) coaching course in Nairobi. Thirty-three (78.57%) were used in the study. The participants were drawn from all the provinces of Kenya except North Eastern. The findings were that 13 (39.4%) of the clubs represented did not have a qualified medical attendant; that in the absence of a team doctor, it is the coach who mostly administered first-aid (42.4%); that out of all the coaches only 15 (45.5%) were well versed in first-aid procedures, among others.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859658 TI - Incomplete abortion at the teaching hospital, Blantyre, Malawi. AB - A total of 444 women treated for incomplete abortion using the manual vacuum aspiration technique, at the Queen Elizabeth Central Teaching Hospital, Blantyre, between 10th January and 9th April, 1994, were interviewed by means of partially structured questionnaire, to determine among other things, their socio demographic profiles, contraceptive behaviour, as well as associated complications. These formed 56.0% of all abortion cases seen in the department during the study period. All abortion formed 68.0% of all the gynaecological admissions, and an abortion delivery ratio of 1:4. The ages of the patients ranged from 15 to 44 years with a mean of 24.4 years. Adolescents formed 21.2% of the total, while those aged 35 years and above formed 8.4%. Only 15.8% of the total were single. Their parities ranged from 0 to 12 with a mean of 2, while number of living children ranged from 0 to 9 with a mean of 1.7. 16.9% of them had had previous abortions, with the highest number of abortion being 6 and a mean of 1.6. 79.9% of the total group were housewives, and 10.6% students. Of their male partners (i.e. people responsible for the index pregnancy), only 4.2% were students and 25.0% of the school girls were involved with fellow school boys. Majority of the rest (56.3%) were involved with more mature self-sustaining males. The gestational ages ranged from 6 weeks to 20 weeks with a mean of 15 weeks.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859659 TI - Absence of neutropenia in African patients with AIDS and associated pyomyositis. AB - The association between AIDS and pyomyositis was recently pointed out in temperate and tropical countries. In Western countries, the patients affected by pyomyositis associated with AIDS in most cases are neutropenic. We compare a group of 17 patients with pyomyositis and AIDS living in temperate climates from the literature, and 11 patients affected by the same association seen by us in northern Uganda. The patients from Western countries were significantly more neutropenic and their mean of the neutrophil count was significantly lower when compared with our group. We suggest that the defective neutrophil function associated with HIV infection play a major role in the pathogenesis of pyomyositis in our patients. PMID- 7859660 TI - Cryptosporidium in Khartoum, Sudan. AB - Diarrhoea caused by the protozoan parasite Cryptosporidium has been shown in several tropical countries to be an important health problem, particularly in children. Although infection is often associated with contact with animals, it may also occur through person to person transmission and via contaminated water or food. We have undertaken a cross sectional study to determine the prevalence of Cryptosporidium in children with diarrhoea and in their family contacts, and also investigated its occurrence in adult food handlers. Sixteen of 100 children with diarrhoea and none of the controls, were positive for Cryptosporidium. In addition, seven children had one or more sibs with diarrhoea who also excreted Cryptosporidium. None of the food handlers or asymptomatic children were positive. The results confirm earlier findings that Cryptosporidium is an important cause of diarrhoea in children in Sudan, and suggest that intrafamilial spread occurs. PMID- 7859661 TI - Death registration on the Kenyan Coast. AB - District level statistics provide health care planners necessary information for both identifying priority areas and evaluating existing health care programmes. Since 1986 an upgraded civil registration system has been in operation in Kilifi district on the Kenyan Coast. For a one-year period (1992-1993) an independent, prospective surveillance for mortality events in a defined population of approximately 51,000 people was conducted as part of intensive demographic studies. Comparisons between the active surveillance and the civil registration system revealed marked under-reporting of deaths, particularly childhood deaths, to the civil authorities. Consideration needs to be given to methods of increasing the coverage of civil registration or of developing supplementary alternative methods of collecting the same information. PMID- 7859662 TI - The conjoined twins of Shinyanga, Tanzania: case report. AB - The first recorded set of conjoined twins in Tanzania was successfully separated on the 10th of February 1994 at the Muhimbili Medical Centre (MMC) in Dar es Salaam. The male omphalopagus twins were born to a 22-year-old para 1 gravida 2 mother by normal vaginal delivery at a Rural Health Centre in Shinyanga Region two months earlier, and had been transferred to the National Referral Hospital at the age of two weeks. At the age of about four months, the first twin died following multiple complications which necessitated several re-operations, while the second twin is still thriving and has been discharged to his home village since May 1994. This paper describes and discusses the medical, surgical and anaesthetic aspects of the management of these historic twins, and emphasizes the importance of teamwork in the evaluation, separation and care of such babies for a successful outcome. A brief review of the literature is also included, with special reference to the African experience. PMID- 7859663 TI - Blackwater fever at the Kenyatta National Hospital in Kenya: a case report. AB - Blackwater fever was an important cause of morbidity and mortality in the beginning of this century particularly in West and Central Africa. There has been a marked reduction in the incidence of blackwater fever since 1950 and only sporadic cases occur nowadays. At the Kenyatta National Hospital, three cases of blackwater fever have been seen in the past four years whereas not a single case had been reported between 1975 and 1988. Two of the patients fit into the classical description of blackwater fever and one was possibly due to drug induced haemolysis in a G6PD deficiency patient. PMID- 7859664 TI - Basal cell nevus syndrome: a case report. AB - A case is reported of a 13 year old Kenyan girl who presented at the Kenyatta National Hospital Dental Clinic with multiple mandibular and maxillary cysts, cutaneous lesions and mandibular prognathism. This combination of clinical and radiographic features led to a diagnosis of basal cell nevus syndrome. This paper is the first reported case of the syndrome in Kenya. The significance of thorough clinical inspection and radiographic screening of suspected cases is discussed. PMID- 7859665 TI - Repeated single fiber recordings do not affect the jitter and the fiber density. AB - The temporal variation of at least two muscle fibers of the same motor unit was recorded with the single fiber EMG technique (SFEMG) by means of special needles and filter settings. In the normal musculus extensor digitorum communis (EDC) the mean variation (jitter) is not longer than 37 microseconds, the fiber density not higher than 1.7 fibers in a 10 ms window. To determine whether these parameters are affected by repeated SFEMG recordings, we measured jitter and fiber density in 20 fiber pairs in the left extensor digitorum communis muscle on day 0, 3, 6, 9 and 30 in 5 healthy volunteers. The mean jitter and the fiber density did not change significantly from day 0 (30.1 +/- 3.6 microseconds; 1.4 +/- 0.07) to day 30 (34.5 +/- 2.7 microseconds; 1.6 +/- 0.13). We conclude that repeated SFEMG recordings do not influence jitter and fiber density. PMID- 7859666 TI - Neuropathy associated with Churg-Strauss syndrome (allergic granulomatous angiitis). AB - A patient with Churg-Strauss syndrome is described, in whom peripheral neuropathy was the principal finding on admission. A general description of allergic granulomatous angiitis is provided, and the clinical and technical (e.g. EMG) findings are discussed in detail. PMID- 7859667 TI - Changes in auditory P3 event-related potentials in uremic patients undergoing haemodialysis. AB - A study on event-related P300 potential (ERPs) was performed in 20 patients suffering from chronic uraemia and undergoing haemodialysis in order to assessing the functioning of their cognitive processes. The patients were evaluated before and after a standard treatment of haemodialysis. The P300 potential was studied by means of the "oddball" paradigm and the acoustic modality. Moreover the patients' performance was assessed on the basis of the following psychological tests: the Mini Mental Test, the Number Connection Test and the Digit Span of the Wechsler Adult Intelligence Scale. A significant improvement in the P3 latency was demonstrated following the dialysis treatment. Even though a slight improvement in the N2-P3 deflexion amplitude was recorded after dialysis, it was not statistically significant. These data indicate a positive modification in the speed of the cortical function as a consequence of dialysis. These results suggest that the P3 latency obtained from auditory stimuli can help to assess the benefits obtained through extracorporeal dialysis, especially in the follow-up to the illness. PMID- 7859668 TI - Electromyographic assessment of spasmodic dysphonia patients prior to botulinum toxin injection. AB - Electromyographic (EMG) evidence of inappropriate muscle activity (IMA) in the cricothyroid (CT) and vocalis (V) (thyroarytenoid) muscles was correlated with clinical voice measures in 32 patients with spasmodic dysphonia (SD). Subjective voice rating and quantified fluency and laryngeal diadochokinesis measures were obtained prior to botulinum toxin (Botox) injection into the V muscles. Pre-Botox EMG was performed using a monopolar needle electrode. Each muscle was sequentially examined at rest, during vocal click, scale, sustained "E" at different pitches, and repeated "E" voicings for brief periods. A three point EMG severity scale was used to grade the amount of IMA seen in each muscle. EMG evaluation showed no evidence of lower motor neuron involvement but did reveal IMA in 81.3% of the subjects. There were no significant correlations for the patients between different EMG-based IMA severity scales and the measures of voice quality and sound production. EMG did discriminate between predominantly adductor and abductor SD pattern types, but could not correctly differentiate a mixed SD group. Those patients with adductor SD displayed IMA in the V and CT muscles, while those with abductor SD displayed more IMA in the CT than the V muscles. Sequential EMG assessment of CT and V IMA in SD did not predict clinical severity or outcome following Botox injection into the V muscles. PMID- 7859669 TI - Auditory middle latency responses under different task conditions. AB - We examined the relationship between the Na and Pa components of human MLRs and the performance of different tasks. We also investigated whether MLRs are reliable indices of activity in the central motor-sensory system. The click stimuli we used consistently evoked the Na and Pa components. At CZ, the Na and Pa components significantly decreased for all tasks other than pegging with right hand while at FZ, these components were significantly decreased for all tasks. The Na and Pa latencies were slightly increased during task performances. These results indicate that the Na and Pa components of human MLRs decreased when various tasks were performed, while subjects were concentrating. A general principle of evoked potentials is that latencies decrease as amplitudes increase in excitation due to neural activation. Thus, it would appear that, under the conditions of this study, the pathways from the reticular formation and the thalamus to the primary auditory cortex were inhibited. Since the thalamus is considered to be the relay region for poly-sensory inputs, it is thought that the attenuation of the MLRs and SEPs occurs at the level of cerebral cortex, including the reticular formation, the thalamus, and the primary auditory cortex. Accordingly, since it is inferred that central factors are responsible for the attenuation of the MLRs, Na and Pa components observed during the performance of tasks carried out in the present experiment, it may be concluded that MLRs are reliable indices of activity in the central-motor system. PMID- 7859670 TI - Ankle spasticity is inversely correlated with antagonist voluntary contraction in hemiparetic subjects. AB - The correlation between the severity of spasticity and residual muscular activity is unclear, yet the latter is often used to investigate the effects of therapeutic interventions in spastic movement disorders. Our objectives were to compare the EMG and force generated by the ankle plantar- and dorsi-flexors in normal and spastic hemiparetic subjects, and to investigate their reproducibility and their correlation with clinical spasticity. Thirteen spastic hemiparetic and seven age-matched normal subjects generated maximal isometric ankle plantar- and dorsi-flexing contractions. Maximal force was significantly decreased to 33% of the non-affected leg during dorsiflexion and to 59% during plantarflexion. Measurements of force parameters (onset and magnitude) during both dorsi- and plantar-flexion and the EMG co-contraction ratios during dorsiflexion were highly reproducible (r = 0.78 to 0.99). Our most interesting finding was that the EMG co contraction ratio was inversely correlated with the amount of force produced by the paretic dorsiflexors (r = -0.91), and that the latter was in turn, inversely related to plantarflexor spasticity (r = -0.65). The high reproducibility of the force measurements suggested that they could be used to evaluate the long-term effects of therapeutic interventions. Furthermore, our findings demonstrated that the voluntary motor deficit in the paretic dorsiflexors but not the spastic plantarflexors was a reliable and valid indicator of the severity of ankle spasticity. PMID- 7859671 TI - Abnormal cortical unit activity of the reticular formation. AB - Many neurological disorders are accompanied by abnormal nerve activity. However, the exact causes of this abnormal nervous activity has never been determined. Based upon my research, I propose a theory that the underlying cause of many types of neurological disorders such as minor epilepsy and narcolepsy is an abnormally functioning Na+/K+ ATPase pump at the molecular framework of the brain, notably the brainstem reticular formation (locus coerulus) and cerebellum in this particular case. The excessive and repetitive nerve activity within localized areas of the brain caused by abnormally functioning molecular Na+/K+ ATPase ion pumps may be the primary and true causes of many different types of neurological disorders since constant depolarizations of the cell membrane causes abnormally excessive amounts of certain neurotransmitters to be released. The type of neurological disorder may be a function of the abnormally occurring Na+/K+ ATPase molecular ion pump's localization within the neurological framework of the brain. To focus on my theory of repetitive nervous activity from abnormal inhibitive or defective Na+/K+ ATPase pumps, I have chosen to analyze minor epilepsy and narcolepsy intentionally. What is found is that the abnormal release of neurotransmitters during epileptic seizures or narcoleptic sleep episodes is secondary to the abnormal neuronal systematic framework underlying Na+/K+ membrane potentials since an abnormally inhibited or defective Na+/K+ ATPase pump has a direct electrogenic effect on the membrane potential. PMID- 7859672 TI - Evaluation of erectile dysfunction with the sympathetic skin response in comparison to bulbocavernosus reflex and somatosensory evoked potentials of the pudendal nerve. AB - Sympathetic skin response (SSR) was investigated in 60 normal subjects (mean age 37.7 +/- 15.9) and 30 patients (mean age 47.2 +/- 12.0) referred from the department of urology for further electrophysiological evaluation of erectile dysfunction (ED). SSR was present in all normal subjects. Mean latency in the lower extremities was 2.16 +/- 0.20 sec. The coefficient of variance for repeated measurements in individual subjects was 10%. The latencies correlated slightly positively with the height of the subjects (r = 0.271, p < 0.05), but not with age. SSR in patients was compared to the bulbocavernosus reflex (BCR) and somatosensory evoked potentials (SSEP) of the pudendal nerve. All patients had a complete urological work-up with evaluation of hormonal function, pharmacotesting and Dopplersonography, as well as pharmacocavernosography and measurement of nocturnal penile tumescence if indicated. Six patients were diagnosed to have functional impotence, 4 dysfunctions were probably of vascular origin, 5 were neurogenic and 15 of the mixed type of vascular and neurogenic origin. Diabetes mellitus was the underlying disease in 14. In the two groups with neurogenic involvement (5 neurogen, 15 mixed) 14 of 20 patients had a pathological BCR, 12 had pathological SSEP and 9 had an absent SSR. Of these 9 patients two showed normal BCR and SSEP. Sensitivity for neurogenic dysfunction was 70% for the BCR, 60% for the BCR and SSEP, but that it detects some patients with erectile dysfunction, in whom other parameters are not pathological.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859673 TI - Artificial feedforward as preparatory motor control in postictal hemiparesis. AB - One of the most important disturbances in spastic hemiparesis is the lack of reciprocal inhibition and the insufficient and inadequate preparatory programming of this inhibition. In 40 patients with postical hemiparesis some preparatory procedures foregoing the volitional movement attempt were assumed. The movement was extension of the wrist and the intended reciprocal inhibition was that in the wrist flexors. The procedures were extensor muscle vibration or electrostimulation which produce contraction of the wrist extensors and reciprocal inhibition in the wrist flexors. A conditioning has been attempted of these effects achieved at spinal level to the existing ipsilateral and spared contralateral cortical influences during a volitional extension of the wrist. In this way an artificial feedforward have been created, with favourable results in motor reeducation of wrist movements. PMID- 7859674 TI - Frequency, location, and age and sex distribution of various types of gastric polyp. AB - Data on the frequency and location of the various types of gastric polyps are highly inconsistent. In a retrospective analysis of 5515 gastric polyps obtained from 4852 patients in the period between 1969 and 1989, including reexamination of 197 surgical, 1572 polypectomy, and 3746 biopsy specimens, the most frequent types found were Elster's glandular cysts (fundic gland polyps) (47.0%), followed by hyperplasiogenous polyp (28.3%), tubular adenoma (9.0%), adenocarcinoma (7.2%), inflammatory fibroid polyp (3.1%), carcinoid tumor (1.7%), Brunner's gland heterotopia (1.2%), and tubulopapillary adenoma (1.0%). Peutz-Jeghers polyps, juvenile polyps, and pancreatic heterotopia were found in younger patients (mean ages: 33.39 and 45 years, respectively), whereas the age of most patients (66%) with glandular cysts was between 40 and 69 years. Patients with any of the other types of gastric polyps were mostly (55-100%) over 60 years of age at the time of diagnosis. Glandular cysts, hyperplasiogenous polyps, inflammatory fibroid polyps, and carcinoid tumors were significantly more common in women, while all the other polyps were more or less equally distributed between the sexes. Glandular cysts and carcinoid tumors were relatively small (mean diameter 8 mm), and were mostly located in the corpus (100% and 83%, respectively). Medium-sized pancreatic heterotopias, Brunner's gland heterotopias, and inflammatory fibroid polyps (mean sizes 7-10 mm) were usually located in the antrum (100%, 81%, 80%, respectively), while the other polyps had an average size of between 10 and 16 mm and were distributed equally throughout the stomach.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859675 TI - One-stage gastrostomy button: an assessment. AB - Several types of gastrostomy tube are available. The gastrostomy button (GB) is a skin-level device that is easily used and acceptable to ambulatory patients. Previously, GB required the presence of a mature gastrocutaneous tract, necessitating a two-stage procedure for placement. We report our experience with one-stage GB placed in 24 patients. No difficulties with placement and no periprocedural complications occurred. GBs remained in place from 14 to 148 days (mean 71 days). Thirteen GBs were in place at follow-up. Four patients died from primary disease. Seven GBs were no longer needed, and were removed. No stomal infections occurred; no GBs were inadvertently removed; all GBs were convenient to use. Four complications occurred (17%): two tubes clogged, one colocutaneous fistula developed, and one tube migrated from the stomach into the abdominal wall. Complications were corrected without sequelae. One-stage GB is safe and feasible with comparable complication rates to standard PEG. PMID- 7859677 TI - Shape memory alloy catheter system for peroral pancreatoscopy using an ultrathin caliber endoscope. AB - Two types of a shape memory alloy (SMA) catheter system with a mechanism for tip control and irrigation were evaluated in performing peroral pancreatoscopy (PPS) using an ultrathin-caliber endoscope. The selective cannulation of SMA catheters into the papilla was made possible in 18 of 19 patients with pancreatic diseases. Endoscopic sphincterotomy was necessary in six of seven patients with the two directional catheter (2.6 mm) but in only one of 12 patients examined with the one-directional type (2.2 mm). In 17 of the 18 patients, the catheters were smoothly advanced to the desired positions in the main pancreatic duct, even to the distal pancreas, due to their controllable tip. PPS with adequate inspection of the ducts and lesions was successful in 16 of these 17 patients. Features of cancer (duct disruption, tumor infiltration) and chronic pancreatitis (smooth ductal surface, fine vascular network) could be distinguished. In this series, there were no obvious complications during or after the procedure. In our experience, the SMA catheter system is effective for PPS in patients with an intact papilla and without dilation of the main pancreatic duct. Further study will show the clinical benefits this technique may have in pancreatic diseases. PMID- 7859676 TI - A newly developed fine-caliber endoscope for peroral cholangiopancreatoscopy. AB - We have developed a new fine-caliber (2.09 mm outer diameter) endoscope for peroral cholangiopancreatoscopy. The endoscope contains one image transmission fiber, 12 light guide fibers (the transmitter of light from the light source) and a working channel (a lumen for the guide wire and rinsing). The working channel, whose bore is 0.72 mm, is located centrally within the endoscope. The endoscope can be introduced reliably into the bile and pancreatic ducts using the same techniques as those for endoscopic nasobiliary drainage through the instrumental channel of a duodenoscope for examination without pretreatment of the papilla of Vater. Two patients with lesions of the pancreatic duct and seven patients with lesions of the bile duct suspected or detected by endoscopic retrograde cholangiopancreatography (ERCP) were examined. Direct inspection of the biliopancreatic duct not only provided enough information to make a definite diagnosis, but also revealed lesions that were not detectable by ERCP or other examinations. PMID- 7859678 TI - Endoscopic Nd:YAG laser therapy in patients with early superficial carcinoma of the esophagus and the gastric cardia. AB - A group of 33 patients, 27 with early superficial esophageal cancer and six with early superficial carcinoma of the gastric cardia, were treated with endoscopic neodymium:yttrium aluminum garnet (Nd:YAG) laser from April 1989 to March 1993. Of the 33 patients, in 32 (97%) the disappearance of the cancer cells was noted. They were treated 1-6 times (average 2.6) with laser irradiation. No serious complications, such as perforation, occurred in the series. Twenty-two patients were followed up for 24-55 months. A negative biopsy was recorded in 16 (72.7%) of the 22 patients; the other six (27.3%) cases were found to have recurrent early cancer during the follow-up period from the 36th to the 40th months, and were treated with supplementary endoscopic therapy or surgical resection. It is suggested that endoscopic Nd: YAG laser may be a safe and effective therapy for early carcinoma of the esophagus and the gastric cardia, when the risks of surgery are too high or the patient has refused surgical resection. PMID- 7859679 TI - Identification and diameter assessment of gastric submucosal vessels using infrared electronic endoscopy. AB - In this study, an electronic endoscope was applied for observation of gastric submucosal vessels, with infrared illumination, in anesthetized dogs. An in-vivo spectrophotometry showed that infrared light at 620-820 nm penetrates the abdominal and gastric wall. During the endoscopy performed in dogs, the infrared radiation penetrated the abdominal wall and gastric wall from the outside, and was detected by the endoscope's charge-coupled device. A television monitor displayed a network of gastric vasculature, which was identified as veins in the gastric wall by injecting saline or indocyanine green into the vein. Using this system, it was possible to measure venous diameters of more than 0.2 mm by comparison with a reference wire. The diameter obtained by the image analysis correlated lineally to that of a vascular template prepared from the same stomach. Thus, it may become possible to assess gastric submucosal hemodynamics using infrared endoscopy, a new application in electronic endoscopy. PMID- 7859680 TI - Prevalence of Helicobacter pylori antibodies in the serum of gastroenterologists in Austria. AB - Eighty-eight endoscopists (mean age 41 years, range 29-76 years) and a control group of 100 persons of similar ages were investigated for the prevalence of antibodies (ABs) to Helicobacter pylori, using a quantitative enzyme-linked immunosorbent assay (ELISA) to IgG, two semiquantitative ELISAs to IgG and IgA, and a latex test to IgG and IgM antibodies. The prevalence of antibodies to H. pylori in endoscopists was 48% (quantitative ELISA), 56% (semiquantitative ELISA to IgG), 62% (latex test), and 57% by combined evaluation of semiquantitative ELISAS to IgG and IgA. The respective numbers in the control group were 47%, 48%, 48% and 51%. None of the differences was significant. In both groups, endoscopists and controls, there was a significantly higher H. pylori positivity in older subjects compared to younger persons, but there was no difference between the two groups. The prevalence of ABs was independent to the number of endoscopies previously performed, and independent of protective measures taken, such as wearing gloves during the procedures. Antibody titers as measured with quantitative ELISA showed a positive correlation with the length of time the subject had been active as an endoscopist, but no correlation with the total number of endoscopies performed. In conclusion, the prevalence of ABs to H. pylori in endoscopists follows the age-dependent pattern known from the general population. The regular performance of gastrointestinal endoscopies poses no additional risk of infection with H. pylori in Austria. PMID- 7859681 TI - Laparoscopic transcystic papillotomy under endoscopic control for bile duct stones. AB - We present here a laparoscopic transcystic papillotomy technique for the management of bile duct stones discovered either preoperatively or on intraoperative cholangiogram. Papillotomy is performed orthogradely with a hydrophilic wire-guided spincterotome inserted through the cystic duct. The correct position of the diathermic wire is verified with peroral duodenoscopy. The method has proved save and effective in our first 12 consecutive patients. Further evaluation is required to clarify its potential role in laparoscopic biliary surgery. PMID- 7859682 TI - Endoscopy of the pancreatic duct: endoscopic acrobatics or promising supplementary method in the diagnosis of pancreatic disorders? PMID- 7859683 TI - Laparoscopy-controlled suture closure of large stab wounds. PMID- 7859684 TI - Esophageal polyp as the sole manifestation of relapse seven years after treatment for Hodgkin's disease. PMID- 7859685 TI - Early primary duodenal carcinoma successfully treated by endoscopic polypectomy. PMID- 7859686 TI - Endoscopic diagnosis and treatment of an esophageal bezoar resulting from bulk laxative ingestion. PMID- 7859687 TI - Identification of a safe site for percutaneous endoscopic gastrostomy placement in patients with marked bowel distension: may octreotide have a role? PMID- 7859688 TI - Dyskeratosis congenita with esophageal stricture and dermatological manifestations. PMID- 7859689 TI - Common bile duct stone formation induced by tomato skin following endoscopic sphincterotomy. PMID- 7859690 TI - Idiopathic acute esophageal necrosis: report of a new case. PMID- 7859691 TI - Gastric mucosal tears occurring during endoscopy: might an endoscope defect be responsible? PMID- 7859692 TI - Options in the therapy of primary gastric lymphoma. PMID- 7859693 TI - Calcium nutrition and its implications for osteoporosis. Part I. Children and healthy adults. PMID- 7859694 TI - Digestion and absorption of sorbitol, maltitol and isomalt from the small bowel. A study in ileostomy subjects. AB - OBJECTIVE: To quantify small bowel digestion and absorption of sorbitol, isomalt and maltitol in ileostomy patients and estimate the metabolizable energy. SUBJECTS: Study A: Nine ileostomy patients, under a constant controlled diet, ate during three consecutive days 2 milk chocolate bars per day, containing 2 x 15 g of polyol, each day with another polyol in random order. The first bar was taken 30 min after breakfast, and the second bar, 7 h after breakfast. Effluents were recovered during the whole study. Study B: 5, 10 or 20 g of sorbitol or isomalt were consumed each day in a drink during two 3-day periods by two ileostomy subjects. The recovery in the ileal effluent was measured over 24 h. RESULTS: Study A: Carbohydrate recovery in ileostomy effluent was 26.8 +/- 2.8% (mean+SEM) for sorbitol, 24.8 + 5.7% for maltitol (2/3 as sorbitol) and 40.0 +/- 0.7% for isomalt (1/3 being sorbitol and mannitol). Ileal excretion, compared with a day without polyol, was compared in 4 subjects. The total volume excreted, as well as dry matter increased after polyol consumption. When taking this extra loss into account, the metabolizable energy value of the polyols for 2 x 15 g intake were: sorbitol, 12 kJ/g (2.8 kcal/g); maltitol, 13 kJ/g (3.1 kcal/g); isomalt, 9 kJ/g (2.1 kcal/g). Study B: The level of digestion and absorption of both sugar alcohols was dose dependent. CONCLUSIONS: These results indicate that sorbitol, maltitol and isomalt are rather extensively absorbed, but the digestibility of the other nutrients is also reduced, due to the osmotic load caused by the polyols in the small intestine. There are evidences of a dose dependency of the energy value of the polyols. PMID- 7859695 TI - The glycaemic index of spaghetti and gastric emptying in non-insulin-dependent diabetic patients. AB - OBJECTIVE: In the dietary treatment of non-insulin-dependent diabetes mellitus (NIDDM) great interest has been focused on foods with low glycaemic indices. Spaghetti has a low glycaemic index, but in NIDDM the underlying mechanism has not been elucidated. We investigated whether the low glycaemic index in spaghetti was the result of a retarded gastric emptying. DESIGN: Randomized study. SETTING: Department of Endocrinology & Metabolism, Aarhus County Hospital. SUBJECTS: Eight NIDDM in-patients participated without drop-outs. INTERVENTIONS: Paracetamol was used as a marker of the gastric emptying. On three different occasions the patients ingested 40 g of carbohydrate as: (1) spaghetti without paracetamol, (2) spaghetti containing 1.5 g paracetamol, and (3) mashed potatoes with 1.5 g paracetamol added. During the 4 h observation periods blood samples were drawn frequently. The spaghettis were industrially manufactured. RESULTS: The spaghetti meals induced similar glucose and insulin responses. The potato meal induced significantly higher glucose and paracetamol areas [607 +/- 108 vs 284 +/- 54 mmol/l*240 min (P = 0.02), and 18,668 +/- 999 vs 4979 +/- 369 mumol/l*240 min (P < 0.02)] as well as lower emptying index (time(peak)/peak concentration ratio of paracetamol) [2.1 +/- 0.3 vs 0.4 +/- 0.1 (P = 0.001)], as compared with the spaghetti meal. CONCLUSIONS: This study shows that the ingestion of spaghetti was associated with a slower gastrointestinal accessibility of the carbohydrates, which accounts for the low glycaemic index of spaghetti in NIDDM subjects. PMID- 7859696 TI - Comparisons between Hologic, Lunar and Norland dual-energy X-ray absorptiometers and other techniques used for whole-body soft tissue measurements. AB - OBJECTIVES: Assessment of the precision and accuracy of dual-energy X-ray absorptiometers (DXA) from three manufacturers, used for measuring soft-tissue composition, and comparability with each other and other techniques. DESIGN: Measurements of an anthropomorphic model of variable composition and thickness. 11 volunteers measured with each instrument and by underwater weighing (UWW) and three brands of bioelectric impedance analysis (BIA) apparatus. RESULTS: New software, introduced by each manufacturer during the course of the investigation, led to changes in measured fat proportion. The precision of determination of fat proportion by DXA in the (small) model was 3-4% (coefficient of variation), with little difference between brands. In vivo precision was 2-3%. In the model, measurements of % fat differed from the nominal values, but variation with thickness was small. There were significant mean differences of total fat proportion in the volunteers between pairs of DXA instruments of 2.6-6.3% fat. The SDs of the differences were 1.8-2.9% fat. Regional differences were greater, with trunk % fat being particularly underestimated by Hologic relative to Lunar and Norland. Compared with UWW, mean % fat was the same for Hologic, but higher for Lunar and Norland. SDs of 4% demonstrated inadequate agreement. The differences varied with proportion of bone in lean tissue, questioning the assumption of constant density of lean tissue in UWW. There were no mean differences of % fat between the BIA instruments and DXA and UWW, but SDs of 3-6% suggest that BIA using these instruments does not offer an acceptable accuracy in estimating fat proportion. CONCLUSIONS: UWW has limitations as a reference method. DXA is a useful technique, but its limitations, particularly regarding assumptions about fat distribution, must be borne in mind. The differences of fat proportion recorded by the three DXA instruments are such as to preclude interchangeability in measurements of individual subjects or in clinical trials. PMID- 7859697 TI - Reproducibility of a meal-based food frequency questionnaire. The influence of format and time interval between questionnaires. AB - OBJECTIVE: To compare the reproducibility and reported level of energy intake obtained using three versions of a meal-based food frequency questionnaire (FFQ) considering, firstly, the influence of FFQ format and, secondly, the influence of time interval between questionnaires. DESIGN: The study was conducted in two parts. In the first, subjects were randomly allocated to three groups (one for each FFQ) and sent, by mail, the same FFQ to complete on two separate occasions with a time interval of 4-6 weeks. In the second study, the reproducibility of one of the FFQs used in the initial study was compared, after an interval of 3 months, in a further group of people, matched as far as possible for gender, age and socio-economic status of area of residence. SUBJECTS: The study population was 651 supermarket shoppers from Geelong, a regional centre with a population of 150,000 situated in Victoria, Australia, who had previously responded to an in store survey about meat purchasing patterns. Of the 651 shoppers, 144 women and nine men (38% of those eligible) in part I and 98 women and two men (45% of those eligible) in part II of the study satisfactorily completed a FFQ on both occasions. RESULTS: While there were few statistically significant differences in terms of mean nutrient intake and nutrient density between the three FFQ formats, all under-estimated energy intake relative to the minimum estimated energy requirements for a sedentary population. A significant decrease in reported intake of approximately 10% was also observed, regardless of FFQ format used, when the same questionnaire was completed a second time after an interval of 4-6 weeks. In contrast, when the time interval between questionnaires was increased to 3 months, there were few significant differences in intake between the first and second administrations. Moreover those changes in food intake which were significantly different after the longer interval were, in general, consistent with expected seasonal changes in food intake patterns. CONCLUSION: Under the conditions of our study differences in FFQ format appeared to have less effect on estimates of mean intake than the length of the time interval between questionnaires. Our results suggest that motivation to complete a FFQ is significantly diminished on the second occasion, when the interval between FFQs is only 4-6 weeks and to a lesser extent when it is 3 months. Researchers planning studies which aim to assess short-term changes in food intake by means of a FFQ, for example after an intervention programme, need to be aware of this effect and to determine its magnitude, by assessing the reproducibility of their FFQ over the relevant time-interval prior to the proposed intervention and by including an appropriate non-intervention comparison group in the design of their study if seasonal effects are likely to occur in the course of the study. PMID- 7859698 TI - Diarrhoea and growth faltering in rural Zimbabwe. AB - OBJECTIVE: To assess the evidence that diarrhoea is an important cause of growth faltering in young children in developing countries. DESIGN: Prospective, longitudinal cohort study. SETTING: Worker's compounds on commercial farms in Shamva, rural Zimbabwe. SUBJECTS: 204 children < 12 months old were enrolled, 73 from birth. The median age at enrolment was 4 months. Eleven children died and 39 were lost to follow-up. INTERVENTIONS: Prospective weekly diarrhoea surveillance by farm health workers and monthly anthropometry. RESULTS: Growth faltering was severe, but there was little difference in average rates of growth between children with frequent diarrhoea and infrequent diarrhoea. The results of an interval-based data analysis were consistent with there being only a transient effect of diarrhoea on weight gain. Estimation of weight faltering following episodes of diarrhoea and the rate of return to the trend in the 9-14 month age range, indicated that weight loss associated with each episode was small (approximately 2%) and return to the child's trend was 90% complete within a month. At older ages than this, weight loss appeared to be less, and estimates were not statistically significant. CONCLUSIONS: These observations lend weight to the hypothesis that recurrent episodes of diarrhoea are not a potent cause of growth faltering in early childhood except in a small minority of largely catastrophic cases. Inadequate food intake is a more plausible explanation. PMID- 7859699 TI - Vitamin E and coronary heart disease: the European paradox. AB - OBJECTIVE: To relate premature mortality from coronary heart disease (CHD) to national food and nutrient supplies. DESIGN: Descriptive correlational study. SETTING: Nineteen western European and five non-European countries. METHODS: Premature mortality from CHD in men below 65 years was related to recalculated Food and Agriculture Organization (FAO) food, antioxidant vitamins and other nutrient supply data in 24 developed countries for 1985-87. Longitudinal analyses of death rates from CHD and supplies between 1970 and 1987 were carried out for all the countries. Correlational analyses of supplies that preceded mortality by up to 10 years were also undertaken. RESULTS: In 17 western European countries the inter-country association of dairy product supply with CHD was of moderate strength (r = 0.5) and the principal saturated fatty acids derived from dairy products: butyric, caproic and myristic acids (C4:0, C6:0 and C14:0) were the most strongly related with CHD (r = 0.5, 0.5 and 0.4 respectively). The phenolic antioxidant-rich foods, e.g. wine, vegetables and vegetable oils, were inversely related to CHD (r = -0.8, -0.7 and -0.6 respectively). Of the antioxidant vitamins, the alpha-tocopherol component of vitamin E was strongly related to CHD across Europe (r = -0.8). The major determinant of alpha-tocopherol supply was usually sunflowerseed oil. Vitamin C and beta-carotene gave moderate correlations (r = -0.6 and -0.5 respectively). Latency periods of 5 and 10 years between supplies and mortality rates did not markedly change the correlations. Longitudinal analyses of nutrient supplies and death rates within each country from 1970 to 1987 also showed that for the majority of countries there was an inverse association between supply of alpha-tocopherol and CHD. CONCLUSIONS: Dietary alpha-tocopherol may provide at least as good an explanation as does wine for the paradoxically low rates of CHD in several European countries which have a relatively high saturated fatty acid intake. PMID- 7859700 TI - Is gravity on our way? The case of polyacrylamide gel polymerization. AB - Potential gravity-induced deformations of polyacrylamide matrices during gelling were investigated in two different initiator systems based on (i) photopolymerization with 100 microM methylene blue, 1 mM sodium toluene sulfinate (reducer) and 50 microM diphenyliodonium chloride (oxidizer) (photopolymerization) and (ii) chemical polymerization, utilizing the standard persulfate N,N,N',N'-tetramethylethylenediamine. In both systems, it is seen that convective flows are imprinted in the final gel structure above a critical gelling layer thickness, set at ca. 3 mm. In both systems, progressive increments of the solution density, from normodense (density = 1.0) up to isodense with the growing polymer chains (density = 1.3) do not inhibit the appearance of strong convective flows. However, gel inhomogeneities are completely abolished even in 10 mm gelling layers if polymerization is performed in presence of density gradients, notably of sucrose, from 0 to 20%, 0 to 40% and 0 to 60%. Even the shallower gradient (0-20% sucrose) is able to completely abolish convective flows in persulfate-driven polymerization. It is hypothesized that such disturbances are not created by sedimentation of the growing polymer chains in the gravitational field, but are produced by the reaction exothermality, which produces strong buoyancy-driven flows. It is additionally demonstrated that persulfate polymerization is sensitive to oxygen absorbed from the top liquid layers, which should be carefully protected by an overlay of organic solvent. Methylene blue-induced polymerization appears to offer a series of unique advantages over chemical initiation with persulfate. PMID- 7859701 TI - Gradient polyacrylamide gel electrophoresis in presence of sodium dodecyl sulfate: a practical approach to muscle contractile and regulatory proteins. AB - Two gradient systems for polyacrylamide gel electrophoresis (PAGE) in the presence of sodium dodecyl sulfate (SDS) are described, with emphasis on improvements accumulated over two decades of studies on contractile proteins and regulatory enzymes from smooth muscle. The first "big slab" system utilizes 18 x 20 x 0.1 cm3 gels and a 10-18% acrylamide gradient, optimized for a high resolution of 10 to 500 kDa polypeptides. Eight (or more) gels are cast simultaneously with a gradient formation from "bottom to top" and 20% glycerol is added to the 18% acrylamide solution. The second "minislab" system represents an improved version of the system of Matsudaira and Burgess (Anal. Biochem. 1978, 87, 386-396), with 8 x 10 x 0.05 cm3 gels and 5-15% or 9-18% acrylamide gradient ranges. They are cast from "top to bottom" in 28-piece batches also with the addition of glycerol for improved gradient formation. Both types of gels can also be cast individually using a specially designed pestle-type gradient maker. For gel destaining, a convenient continuous hydrodynamic destainer is also described. PMID- 7859702 TI - Capabilities and potentialities of transverse pore gradient gel electrophoresis. AB - Transverse pore gradient gel electrophoresis is important as a tool for obtaining nonlinear Ferguson plots [log(mobility) vs. gel concentration], e.g. in application to DNA in polyacrylamide gels or to agarose gels, with the purpose of evaluating molecular properties (size, conformation, malleability) and gel fiber properties (fiber radius and length per unit volume). To date, it is capable of (i) yielding gel patterns ("Ferguson curves") of migration distance vs. predicted % T-range of the pore gradient, assuming its linearity; (ii) yielding information regarding molecular conformation from the intersection of Ferguson curves of unknowns (e.g. bent DNA) with those of standards; (iii) acquisition of Ferguson curves by computer, using prototype instrumentation; (iv) mathematical manipulation of acquired Ferguson curves to yielding Ferguson plots, providing that mobility in free solution has been assessed by capillary zone electrophoresis. The potentialities of the method remain unfulfilled to date due to (i) the unavailability, with a single exception, of an accurate and precise way to produce pore gradients of known shape; (ii) unavailability of a routinely applicable analysis for % T; (iii) unavailability of optimized, user-friendly and foolproof instrumentation for computer acquisition of Ferguson curves, including the present inapplicability of a commercially available electrophoresis apparatus with intermittent optical detection to transverse pore gradient gels; and (iv) unresolved problems in the statistical evaluation of Ferguson curves. PMID- 7859703 TI - Transverse pore gradient gel electrophoresis, using the PhastSystem. AB - The application of pore gradient gels prefabricated for the PhastSystem (Pharmacia) to transverse pore gradient gel electrophoresis is demonstrated. It has the twofold advantage of (i) horizontal positioning, avoiding gel stretching during the preparation of these gels and resulting pore size irreproducibility experienced with vertically applied pore gradient gels, which necessitate an orthogonal transfer of spacers, and (ii) miniaturized gel dimensions, which allow a small sample load and a short duration of electrophoresis and staining. PMID- 7859704 TI - Pulsed field electrophoresis for the separation of protein-sodium dodecyl sulfate complexes in polyacrylamide gels. AB - Polyacrylamide gel electrophoresis of proteins was studied using a pulsed-current mode. A new "local field" distribution was used to correct the gel patterns and optimize migration. A corrective field was applied at fixed 2 s intervals to a constant field, inducing a complex relaxation mechanism. Calculated variations in the local field directions decreased the electric strain on the gel during the run, with resultant optimum gel structure. The relaxation mechanism was found to enhance the absolute mobility of proteins with shorter running times compared to constant field gel electrophoresis (CFGE) and other pulsed field techniques. The enhancement of molecular mobility was explored by transverse pore gradient gel electrophoresis. Ferguson curves which exhibited a convex shape in CFGE were linearized by the new pulsed-field method named pulsed oscillatory high performance electrophoresis (POPE). PMID- 7859705 TI - Immobilized buffers for isoelectric focusing: from gradient gels to membranes. AB - Some major improvements to a pH gradient simulator for isoelectric focusing in immobilized buffers are here described. They allow creation of graphs (giving the profiles of pH gradient, deviation from ideal shape, buffering power and ionic strength) with up to 200 increments (which, in a 1 pH unit span means mapping of pH intervals at barely 0.005 pH increments per step). In addition, for preparative purification protocols, utilizing multicompartment electrolyzers with isoelectric, buffering membranes, this modified program allows easy calculation of the precise pI value at any point along the pH gradient used for the analytical assessment of the pI values of the proteins to be purified. At the desired pH value, reached by moving the cursor along the pH gradient, a simple clicking of the mouse button allows the display of the instant Immobiline composition responsible for that pH value. The molarity ratio of the various Immobilines present at this precise point of the pH scale in fact gives the composition (with the accompanying value of buffering power and ionic strength) of the membrane to be utilized as a pH-stat in the preparative scale run. This is the only method that allows reproducible and valid scaling up from the analytical to the preparative scale. PMID- 7859706 TI - Analysis of the HLA-DR gene locus by temperature gradient gel electrophoresis and its application for the rapid selection of unrelated bone marrow donors. AB - The human leucocyte antigen (HLA) class II compatibility of bone marrow donor and recipient is an essential prerequisite for the prevention of severe graft versus host disease and therefore for the successful outcome of bone marrow transplantation. In this study an efficient protocol was developed for the rapid analysis of the polymorphic HLA-DR gene locus, based on DNA-polymerase chain reaction (PCR) amplification of the variable exon II of the HLA class II DR genes and subsequent temperature gradient gel electrophoresis (TGGE). Computer-assisted melting map calculations were carried out to determine the melting behavior of the different HLA-DR fragments. Despite the high variability of the DR alleles on the nucleotide sequence level the calculations revealed a common melting domain structure of the different HLA-DR fragments, which was experimentally confirmed by perpendicular TGGE. On parallel TGGE, all samples were separated under the same electrophoretical conditions using a single PCR fragment without GC-clamp. TGGE was applied for the analysis of the DR alleles of numerous bone marrow receipt pairs and compared to the corresponding serological and DNA typing results. The TGGE patterns were found to be different for all samples with different HLA-DR typing results. Identical homoduplex and heteroduplex patterns occurred only in the case of complete genotypic HLA-DR identity as determined by direct sequencing of PCR products. PMID- 7859707 TI - Analysis of photoreceptor proteins of microorganisms by gradient gel electrophoresis and other biochemical separation methods. AB - Photoreceptor proteins for photoorientation in microorganisms are usually membrane bound and can be isolated by standard biochemical methods. Three examples are shown: the flagellates Euglena gracilis, Peridinum gatunense and the slime mold Dictyostelium discoideum. The photoreceptor of Euglena is attached to the basis of the flagellum and is composed of at least four chromoproteins which can be separated by gradient sodium dodecyl sulfate - polyacrylamide gel electrophoresis (SDS-PAGE) fast protein liquid chromatography (FPLC) and isoelectric focusing (IEF); it contains pterins and a flavin as chromophoric groups. The photoreceptor of Peridinium absorbs in the red wavelength band. Though not yet identified in detail, multiple receptors are probably involved, as indicated by fluorescence spectroscopy. Dictyostelium shows positive and negative phototaxis in its amoebal form and exclusively positive phototaxis in its pseudoplasmodial form. It is still open to discussion whether the two stages use separate photoreceptors. From amoebae two photoreceptor pigments have been isolated, showing an absorption which resembles the action spectrum, one membrane bound with a molecular mass of 45 kDa and one cytoplasmic fraction with a molecular mass of 27 kDa. PMID- 7859708 TI - Electrophoretic analysis of seed storage proteins from gymnosperms. AB - Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), pore gradient gel electrophoresis (PGGE) followed by SDS-PAGE and Western blot analysis were used to characterize the seed storage proteins from seven gymnosperm species from the families Pinaceae (Abies alba, Cedrus atlantica and Picea abies), Cupressaceae (Biota orientalis, Chamaecyparis lawsoniana and Cupressus arizonica), and Taxaceae (Taxus baccata). SDS-PAGE and PGGE X SDS-PAGE indicate the presence of proteins with characteristics similar to the 7S globulins in all the species studied. Antibodies to a 7S globulin subunit from Pinus pinaster cross-reacted with homologous polypeptides from Pinaceae species, but not with corresponding subunits from species belonging to other families. Also detected in each of the studied species, with the exception of A. alba and T. baccata, were those of C. atlantica may be extracted by saline buffer, while the remainder require a dissociating agent. Antibodies raised against the small subunit from P. pinaster 11S protein recognized only the corresponding polypeptides from Pinaceae species. Overall, these results help clarify our knowledge of gymnosperm seed storage proteins. PMID- 7859709 TI - Separation of chlorophyll-protein complexes by Deriphat polyacrylamide gradient gel electrophoresis. AB - An improved Deriphat polyacrylamide gradient gel electrophoresis system was developed for the separation of chlorophyll-protein complexes. The relatively good resolution of the starting discontinuous gel system was further improved by using glycerol in gels and an acrylamide gradient with high acrylamide-to-N,N' methylenebisacrylamide ratio in the separating gel. By applying mild but efficient glycosidic detergents for solubilization, and Deriphat to gels and buffers, the stability of complexes was increased, and only a low amount of pigment was removed. The advantage of our system is the better resolution of larger-size complexes, especially those of photosystem I. In addition, it makes possible an easier interpretation of results due to less overlapping of photosystem I and photosystem II bands when different plant species or the effects of different treatments are compared using whole thylakoid membranes. PMID- 7859710 TI - Electrophoretic analysis of coniferyl alcohol oxidase and related laccases. AB - Gradient gel electrophoretic methods enabled a distinction to be made between coniferyl alcohol oxidase (CAO) of lignifying cell walls and a pI approximately 9 pine "laccase" recently implicated in lignification (Science 1993 260, 672). Following treatment of a partially purified protein mixture from developing xylem of Pinus strobus with 2-[N-morpholine]ethanesulfonic acid (MES) buffer, isoelectric focusing and sodium dodecyl sulphate-polyacrylamide gel electrophoresis indicated that CAO had been selectively precipitated by MES and thereby purified to electrophoretic homogeneity. Purified CAO was determined to be a cell-wall-bound glycoprotein (38% glycan), M(r) 107,500, pI 7.6, pH and temperature optima 6.3 and 30 degrees C, respectively. By graphite-furnace atomic absorption analysis, CAO contained one copper atom per protein molecule. Proteins obtained from lignifying cambial derivatives of conifers (family Pinaceae) and from Rhus typhina bark were compared with CAO and the pI approximately 9 pine "laccase" following electrophoresis and Western blotting. For Abies balsamea, Larix laricina, Picea rubens, Pinus banksiana, Pinus taeda, and R. typhina, the isoelectric points of oxidatively active bands were identical to those of purified CAO. In addition, for all species only the pI 7.6 band was immunoreactive with antibodies against periodate-deglycosylated CAO. PMID- 7859711 TI - Separation of large DNA molecules with high voltage pulsed field gel electrophoresis. AB - We have developed two high voltage (3 kV and 10 kV) high speed pulsed field gel electrophoresis systems for the separation of DNA as large as 460 kbp. These systems enable us to combine the rapid speed of high voltages and the separation power of pulsed field electrophoresis to achieve high resolution and short run durations. We found that large DNA fragments can be separated at voltage gradients much higher than commonly used. Yeast chromosomes as large as 460 kbp can be separated in 4 h at 20 V/cm and 1-50 kbp DNA can be rapidly separated in 30 min at 55 V/cm. This is 25 times faster in mobility for the separation of relatively small DNA fragments (< 50 kbp). We have also found an inverse relationship between the voltage applied and the size separation limit at that particular voltage gradient (55 V/cm limits the separation to 50 kbp while 20 V/cm can separate up to 460 kbp). Depending on the size range, DNA can be separated 8- to 25-fold faster and with better resolution than existing electrophoretic systems. PMID- 7859713 TI - Detection of a single base mismatch in double-stranded DNA by electrophoresis on uncrosslinked polyacrylamide gel. AB - Uncrosslinked polyacrylamide forms gels in the concentration range of 15-40% acrylamide. Electrophoresis in these gels of a commercially available 350 bp heteroduplex DNA preparation separates it from the homoduplex DNA of the same size. The separation is qualitatively equivalent to that previously achieved in a commercial proprietary gel ("Mutation Detection Gel" of AT-Biochem), or in an equivalent 14% T, 0.15% C (N,N'-methylenebisacrylamide) gel, but the mechanical stability of mutation detection electrophoresis (MDE) gels or 0.15% C gels is better than that of uncrosslinked polyacrylamide gels. The separation in any of these three gel media can be carried out in short gel tubes within a few hours of electrophoresis time. In both uncrosslinked polyacrylamide and MDE gel media, the Ferguson plots [log(mobility) vs. gel concentration] and the plots of effective molecular radius vs. gel concentration ("T-plots") of both the heteroduplex and homoduplex DNA indicate an augmented size but similar flexibility upon passage through the gel than exhibited by the components of a DNA standard ladder. Homoduplex and heteroduplex DNA correspondingly exhibit a parallelism of their Ferguson curves in transverse MDE pore gradient gel electrophoresis, suggesting a surface net charge difference, possibly due to a conformational reorientation too subtle to be detected by a shift in the slope of the Ferguson plot, as has been observed once previously with a "kinked" DNA species. The gel fiber radius or length per unit volume of uncrosslinked polyacrylamide and MDE gels do not differ significantly within confidence limits, which are wide compared to unconventionally crosslinked gels, presumably because of their greater swelling. PMID- 7859712 TI - Separating field strength, temperature, and pulsing effects in pulsed field electrophoresis. AB - The utility of pulsed field electrophoresis for DNA sequencing is investigated. Previous studies have indicated a beneficial retardation of sequencing fragments when pulsed fields are employed. The interpretation of these results is complicated, however, by concomitant variations in electric field strength and/or temperature. Methods are presented here permitting discrimination of such mobility effects due to pulsing, field strength, and temperature. It is demonstrated that under the conditions employed here, observed mobility effects are due to electric field variations rather than pulsing. These conditions thus correspond to the low frequency/small molecule limit. The effect of temperature is estimated from the steady state solution to the heat conduction equation under appropriate boundary conditions. No temperature effect upon mobility is operative in the thin gel system employed, due to the high efficiency of heat transfer. However, it is shown that in conventional gel systems large temperature-related mobility effects can occur. These methods for dissecting and understanding mobility effects in pulsed field electrophoresis are expected to be of general utility. PMID- 7859714 TI - The relative separation efficiencies of highly concentrated, uncrosslinked or low crosslinked polyacrylamide gels compared to conventional gels of moderate concentration and crosslinking. AB - The joint report [1] has shown that the separation of heteroduplex DNA from homoduplex DNA can be achieved by uncrosslinked polyacrylamide gels or gels of a very low degree of crosslinking (0.15%) with N,N'-methylenebisacrylamide (Bis), while conventional polyacrylamide gels of 2-5% crosslinking with Bis are incapable of such a separation in the absence of added denaturing agents. This result raised the question whether in application to other separation problems the same superiority of uncrosslinked or low-crosslinked polyacrylamide existed. To test that question, Ferguson plots were determined for the members of a DNA ladder (50 to 1000 bp) in polyacrylamide with 0, 0.1, 0.2, 0.3, 0.5% C (Bis), and the separation efficiency function, S, was evaluated in comparison with that in conventional 2-5% C (Bis) gels. S was found to be lower, not higher, in gels of low crosslinking at the respective maximally effective gel concentrations. However, the range of gel concentrations in which gels of low or no crosslinking were effective extended over a range of at least 10% T, while conventionally crosslinked gels were most effective over a range of 3 to 1 units of %T. PMID- 7859715 TI - Molecular modeling of acrylamide derivatives: the case of N acryloylaminoethoxyethanol versus acrylamide and trisacryl. AB - Molecular mechanics (for evaluation of total energies of individual structures of monomers and oligomers) and molecular dynamics (for evaluating dynamic dependencies of structural features) were used for obtaining information on some unique chemical behavior of a novel N-substituted acrylamide (N acryloylaminoethoxyethanol; AAEE) vs. conventional acrylamide and trisacryl (N acryloyl-2-amino-2-hydroxymethyl-1,3-propane diol, an extremely hydrophilic derivative; Tris-A). As free monomers, Tris-A degrades with zero-order and acrylamide with first-order kinetics, whereas AAEE is highly resistant to hydrolysis. It is found that Tris-A (and its dideoxy derivative) is constantly forming hydrogen bonds between the -OH groups and the carbonyl of the amido group (bond distances of 1.64 to 1.70 A); this activates a mechanism of "N-O acyl transfer" which leads to quick degradation of the amido bond even under mildly alkaline conditions. Conversely, AAEE (which also contains an omega-OH group increasing its hydrophilicity) has no tendency to form H-bonds with the amido carbonyl, thus being resistant to the above degradation mechanism. In fact, the oxygen in the ethoxy moiety of the N-substituent chain acts as a preferential partner for H-bond formation with the omega-OH group. In the oligomeric state, it is found that Tris-A (tetrameric and dodecameric structures were simulated) tends to form inter-residue H-bonds (approximately parallel to the growing chain) competing with the intra-residue H-bonds (folding onto the amido carbonyl and approximately perpendicular to the oligomer chain), thus greatly increasing its stability.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859716 TI - Immobilized pH gradients: new pK values of acrylamido buffers in poly(N acryloylaminoethoxyethanol) matrices. AB - A novel matrix consisting of N-acryloylaminoethoxyethanol, a hydrophilic monomer extremely resistant to hydrolysis, was recently reported by Chiari et al. (Electrophoresis, 1994, 15, 177-186). When using it as a matrix for grafting immobilized pH gradients for isoelectric focusing, a shift in protein spot position was noticed. This was attributed to a shift in pK values of the Immobiline buffers when changing from the standard poly(acrylamide) to a poly(N acryloylaminoethoxyethanol) matrix. A series of 1 pH unit gradients was constructed, where a single buffering Immobiline was used and titrated with a counterion having a pK removed by at least 3 pH units from the nearest extreme of the generated pH interval. It was noted that all compounds became weaker acids and bases, with a delta pK ranging from -0.02 to -0.06 for the acids (pK 3.6, 4.4, and 4.6) and a delta pK ranging from -0.12 tp -0.20 for the bases. The new pK values for the seven commercially available buffers are thus pK 3.6-->pK 3.58, pK 4.4-->pK 4.36, pK 4.51-->4.45, pK 6.21-->6.09, pK 7.06-->6.94, pK 8.50-->pK 8.37, and pK 9.59-->pK 9.39. These values refer to 10 degrees C in the gel phase, the first value in poly(acrylamide) and the second in poly(N acryloylaminoethoxyethanol). PMID- 7859717 TI - The use of a hollow fiber membrane module in sample conditioning prior to electrophoresis. AB - A new method to continuously change the buffer conditions in samples prior to electrophoresis by counter-current dialysis has been developed using a hollow fiber membrane module (VariPerm M, bitop, Witten). It is demonstrated that the collected fractions of a column eluate after hydrophobic interaction chromatography cannot be analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) due to the high content of ammonium sulfate. In contrast, when the hollow fiber membrane module is used for on-line desalting of the eluate during chromatography, it is possible to detect distinct bands on SDS gels even after sample concentration by evaporation. Moreover, adding polyethyleneglycol 20,000 to the counter-current dialysis buffer the hollow fiber membrane module is suitable for combined on-line sample desalting and sample concentration of living organisms during free flow electrophoresis (FFE): a culture of Nitrosomonas eutropha which could not significantly be detected by FFE without conditioning was successfully analyzed when concentrated and desalted on line during sample application. PMID- 7859718 TI - Focused antigen capture immunoassay. AB - A new approach is described to immunoblotting in which antigens after isoelectric focusing are capture on nitrocellulose membranes coated with a specific antibody. The method has been applied to the analysis of human IgA kappa and lambda from whole blood and serum without prior purification. The visualized bands were quantified by laser densitometry in four pI ranges. It is concluded that, under the conditions used, close to 100% of serum IgA is captured. The method has a coefficient of variation of 4.5-12.8%, mean 8.0%. PMID- 7859719 TI - The validity of the Smoluchowski equation in electrophoretic studies of lipid membranes. AB - The Helmholtz-Smoluchowski theory, widely used for the calculation of zeta potential from the measured electrophoretic mobility (EPM), is known to be invalid in the region where the mobility is affected by the surface conductivity and polarization of the electrical double layer. In this region, the zeta potential found according to the Smoluchowski equation (zeta sm) is not identical to the true electrostatic potential at the hydrodynamic plane of shear (zeta), which is considered in the Gouy-Chapman-Stern theory of the electrical double layer. As a result, zeta sm cannot be used for the subsequent calculation of surface potential and surface charge density of a membrane studied. here we suggest a simple way, allowing one to decide between the validity and nonvalidity of the Smoluchowski equation in various sets of experimental conditions used in electrophoretic measurements on lipid membranes. We calculated the dimensionless criterion Rel, accepted in the Dukhin theory of electrophoresis as a measure of the extent of the influence of surface conductivity and double layer polarization on EPM. The Rel changes, with membrane charge density, ionic strength and vesicle radius, were found to be helpful in finding the combinations of these three parameters, corresponding to the validity of the Smoluchowski equation. PMID- 7859720 TI - Capillary zone electrophoresis of oligosaccharides derivatized with various aminonaphthalene sulfonic acids. AB - Malto-oligosaccharides were derivatized via their reducing ends with different aminoaphthalene mono-, di- and trisulfonic acids by reductive amination. The derivatives were then separated by capillary zone electrophoresis in uncoated fused silica capillaries, using 50 mM triethylammonium phosphate buffer, pH 2.5, as running electrolyte. The effect of degree of charge on speed of analysis and resolution was studied for different aminonaphthalene mono-, di- and trisulfonic acids. Under the conditions used, a higher degree of charge on the derivatives provided both faster analyses and higher resolution. Investigation of the electrophoretic behavior of derivatized oligosaccharides obtained from bovine pancreatic ribonuclease B gave insight into the possibility of applying such electrophoretic systems to the analysis of more complex carbohydrates. The resolution of positional isomers under the conditions described indicated that the high resolving power of this technique allows separations not strictly based on the effects of charge and mass of the analytes, but on structural characteristics as well. The relationship between electrophoretic mobility and molecular structure was investigated for the different derivatives. PMID- 7859721 TI - Electrophoretic mobilities of the complexes between sodium dodecyl sulfate and various peptides or proteins determined by free solution electrophoresis using coated capillaries. AB - Electrophoretic mobilities of various proteins or peptides complexed with sodium dodecyl sulfate (SDS) were determined by free solution capillary electrophoresis. The complexes formed between SDS and protein polypeptide showed electrophoretic mobilities virtually insensitive to the protein molecular weight. On the other hand, scattered and larger negative electrophoretic mobilities were observed for peptides of molecular weights less than 10000. Mobility differences as small as 0.3-3% among the three differently modified derivatives of bovine serum albumin could also be successfully determined due to the high resolving power of capillary electrophoresis. PMID- 7859723 TI - Separation of cis/trans isomers of a prolyl peptide bond by capillary zone electrophoresis. AB - On capillary electrophoresis of the chemically pure thioxo peptide Ala-Phe-psi[CS N]-Pro-Phe-4-nitroanilide a peak splitting was observed at a capillary temperature of 25 degrees C. By contrast, the oxo peptide analogue exhibits a single, sharp peak under these conditions. Both peaks of the thioxo compound coincided gradually when the temperature was increased to 60 degrees C. Peak fusion was reverted by cooling down the heated sample. This behavior could be attributed to the electrophoresis-mediated separation of the cis/trans prolyl bond isomers of the thioxo peptide, allowing data of this conformational equilibrium to be determined. Derived from computational data about molecular volume and the hydration energy of low-energy cis and trans isomeric structures, the more rapid migration of the cis form in comparison to trans may be explained by structural parameters. PMID- 7859722 TI - Micellar electrokinetic capillary chromatography analysis of water-soluble vitamins and multi-vitamin integrators. AB - Micellar electrokinetic capillary chromatography (MECC) was applied to the determination of water-soluble vitamins (WSV) in pharmaceutical preparations. The analytical procedure employed in the WSV separation by MECC showed a satisfactory average column efficiency (195,000 N) and resolution (more than 100 theoretical peaks separable). The mean reproducibility in the retention time of consecutive and day-to-day runs was 1.1% and 5.1%, respectively. Analyses were performed after extraction of active ingredients by solid phase extraction. Recoveries (92 103%) and relative variation coefficients (less than 5%) confirmed the potential of MECC in the field of pharmaceutical analysis. PMID- 7859724 TI - Quantitative studies of different injection systems in capillary electrophoresis. AB - For a rigorous assessment of the precise amount of sample loaded, for quantitation purposes, different sample injection systems were evaluated with two commercially available units, Waters Quanta 4000 and Beckman P/ACE 2100. In the first system, sample introduction by hydrostatic means (i.e., placing the sample vial at some height, usually 10.1 cm, above the other capillary end) was evaluated. It was found that in this system there is a constant positive bias, i.e. the amount of sample loaded lies on a curve parallel and above the theoretically predicted loading curve. However, the excess of mass loaded was constant along the injection times explored (covering from 5 to 35 s) and, for a 75 microns capillary, was found to be of the order of +6 nL (above the expected injected value). Thus it is easy to correct for this sample bias. In the electrokinetic mode, a very good correlation between expected and predicted sample loads was obtained for both units. In the pressure system (by positive pressure from a nitrogen tank, Beckman unit) a substantial discrepancy was found between experimental and predicted values (13.5% overload). Since the manufacturer claims a constant pressure of 0.5 psi, i.e. 3447.5 Pa, it would appear that the injection pressure is higher than the given value.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859725 TI - Fractionation of human serum proteins by capillary and recycling isotachophoresis. AB - The fractionation of human serum proteins using capillary isotachophoresis (CITP) and recycling isotachophoresis (RITP) in presence of low molecular mass spacer compounds is reported. Anionic CITP was performed in an instrument equipped with a Teflon capillary of 0.5 mm ID as well as in an apparatus which features an open tubular fused-silica capillary of 75 microns ID. RITP was performed in a recycling fast flow focusing apparatus in which fluid flows rapidly through a narrow, rectangular cell and the effluent from each outlet port is reinjected into the electrophoresis chamber through the corresponding input port. Typically, 1 mL serum was processed batchwise within about 2.5 h prior to collection of 30 fractions of about 4 mL each. The fractions were analyzed separately for conductivity, pH and UV absorbance and selected fractions were characterized by an immunoassay for transferrin, as well as by gel isoelectric focusing, two dimensional gel electrophoresis, CITP and capillary zone electrophoresis. The search for suitable electrolyte systems and spacers was executed by CITP and by computer simulation. For simple configurations, separations predicted by simulation are shown to qualitatively agree with fractionation performed by CITP and RITP. Configurations producing three protein subgroups, the first containing mainly albumin, the second transferrin and the third the globulins, are discussed. PMID- 7859726 TI - Isolation of human serum transferrin by free-fluid recycling electrophoresis in simple buffers. AB - The isolation of human serum transferrin (Tf) using recycling isotachophoresis (RITP) and recycling isoelectric focusing (RIEF) with simple buffers is described. Serum fractionation, the first step in the protocol for Tf purification, is shown to be easily performed either by RITP of filtered serum using low molecular mass spacers or by RIEF of dialyzed serum employing a binary mixture of a well-defined buffer pair covering the pH range between 5.2 and 6.2, called RIEF-OptiFocus. For polishing, Tf-containing fractions are reprocessed by RITP or RIEF-OptiFocus. Other RIEF approaches based on the use of single amino acids at high concentration and ternary amino acid mixtures are shown to constitute less effective methods for Tf isolation. With a four-step protocol, comprising in turn RITP, RIEF-OptiFocus, ultrafiltration and again RITP, "single band" purity (as assessed by two-dimensional gel electrophoresis) is obtained. Omission of the first step (RITP) and direct processing of dialyzed serum by RIEF OptiFocus, ultrafiltration and RITP, is shown to provide remarkable results as well. PMID- 7859727 TI - A large scale preparative gel electrophoresis separation of alpha 1 and alpha 2 subunits of the voltage-gated Ca2+ channel from rabbit skeletal muscle. AB - A large-scale preparative gel electrophoresis method effectively separates individual voltage-gated calcium channel (VGCC) subunits with high resolution, starting with up to 4 mg of rabbit skeletal muscle L-type VGCC complex. Using this method, we separated alpha 1 and alpha 2 subunits of rabbit skeletal muscle VGCC with a high efficiency and with protein recoveries of 83%. The separated alpha 1 and alpha 2 subunits eluted from the gel in a 1:1 molar ratio. The method should be applicable for separating the other VGCC subunits or subunits of other protein complexes. PMID- 7859728 TI - Molecular weight alterations of alpha-1 proteinase inhibitor in equine bronchoalveolar lavage fluid. AB - The equine alpha-1 proteinase inhibitor (alpha 1PI) system differs from that of man in that the equine system consists of four closely-linked genes (Spi1-Spi4) whereas in man, a single gene encodes for alpha 1PI. We have previously found differences in the proportion of the Spi proteins in equine serum and bronchoalveolar lavage fluid (BALF). We therefore wished to determine whether, as reported in man, there was any molecular weight difference between the Spi proteins in serum and BALF. alpha 1PI and albumin from equine BALF migrated further towards the anode compared with serum alpha 1PI on native polyacrylamide gel electrophoresis (PAGE) although the difference was only significant for alpha 1PI. Sodium dodecyl sulphate-PAGE (SDS-PAGE) showed that a mean decrease in molecular weight of 1.5 kDa for alpha 1PI and 1.3 kDa for albumin had occurred in BALF. These findings were observed in control animals and in those with symptomatic or asymptomatic chronic obstructive pulmonary disease. The mechanism of this decrease in molecular weight of alpha 1PI is likely to differ from reports of alpha 1PI cleavage by bacterial proteinases in man since the molecular weight change was relatively small and loss of trypsin inhibitory activity did not occur. Nor, in our system, was there evidence of bacterial infection. Damage by endogenous proteinases or glycosidases at a site other than the reactive site may be involved but the resultant effect on the efficiency of the antiproteinase screen of the lower respiratory tract is uncertain. PMID- 7859729 TI - The use of protein synthesis elongation factor EF-Tu as internal calibration standard in two-dimensional electrophoretic studies of differentiation in Streptomyces. AB - Protein synthesis elongation factor EF-Tu is presented as an internal calibration standard for quantitative analysis of two-dimensional (2-D) protein electrophoresis gels. EF-Tu was selected on the basis of concentration measurements in cell-free extracts from Streptomyces aureofaciens, grown under conditions leading to production of tetracyclines, and separated on one dimensional (1-D) and 2-D electrophoresis gels. The results demonstrated that the amount of EF-Tu synthesized in S. aureofaciens under conditions of slow growth during production of tetracyclines is constant in proportion to all other de novo synthesized proteins regardless of their total number. This makes EF-Tu an ideal internal protein standard for quantitation of protein spots on 2-D electrophoresis gels. For such quantitative analysis we developed a computer aided image analysis system which provides preparation of a gel image for further analysis including calibration, background subtraction and cleaning for streaking in both directions. The system can locate any resolvable spot in the gel and measure the integrated density of the spot, even in the case of irregular spot shape in crowded and overlapping spot regions. PMID- 7859730 TI - Polypeptide cartography of Spiroplasma taiwanense. AB - Spiroplasma taiwanense is the first member of the Class Mollicutes to be subjected to polypeptide cartography using computerized image analysis. The small genome size characteristic of this group was shown to code for low numbers of polypeptides when compared to other bacterial species. Silver-stained two dimensional electrophoresis gels, following separation by either isoelectric focusing and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (ISO-DALT) or nonequilibrium pH gradient electrophoresis (NEPHGE), were used to create databases from 10 and 6 gels, respectively, for each technique and produced, respectively, 263 and 287 replicated spots. Polypeptides were mapped with respect to molecular mass and glyceraldehyde-3-phosphate dehydrogenase carbamylation standards. Of interest was the unexpectedly high percentage (50.2%) of the total normalised optical intensity associated with all 263 spots detected by ISO-DALT electrophoresis, having been contributed by just 29 dominant protein spots. These 29 polypeptides are to be given priority in microsequencing and microanalysis aimed at their identification. PMID- 7859731 TI - Protein study of T and B acute lymphoblastic leukemia cell lines. AB - Two-dimensional polyacrylamide gel electrophoresis (2-D PAGE) was used to identify cellular proteins in T and B acute lymphoblastic leukemia (ALL) cell lines. Five lines, REH and BALL-1 of B-cell lineage, CCRF-CEM and HPB-ALL of T cell lineage, and a normal Epstein-Barr virus (EBV)-transformed line of B-origin (SKLN1) were studied. The lines were immunophenotyped using flow cytometry and lineage associated monoclonal antibodies. Whole cell lysates of the cell lines were subjected to 2-D PAGE analyses. 2-D gels were analyzed with an image scanning computer and the qualitative as well as quantitative differences of the protein patterns were studied. Despite the great similarities in the patterns of the B- and T-gels, three proteins were unique to B-cell lines, while eight were unique to T-cell lines. Using cell lines is the first step toward identifying potential markers in ALL and can provide important information regarding the human ALL databases. Whether these proteins are definite markers for B- or T-ALL or are unique to the cell lines studied needs further exploration. PMID- 7859733 TI - Two distinct regions of FC gamma RI initiate separate signalling pathways involved in endocytosis and phagocytosis. AB - Cross-linking of the high affinity receptor for IgG, Fc gamma RI, can result in both endocytosis of immune complexes and phagocytosis of opsonized particles in myeloid cells, although the cytoplasmic domain of the receptor lacks the tyrosine activation motif which has been implicated in signal transduction triggered by cross-linking of other Fc receptors. To identify the structural determinants of Fc gamma RI-mediated ligand internalization, we have expressed Fc gamma RI or truncated versions of Fc gamma RI in COS cells, either alone or in the presence of the Fc epsilon RI gamma subunit (which contains a classical tyrosine activation motif and associates with Fc gamma RI in myeloid cells), and assessed their ability to mediate endocytosis and phagocytosis. We have found that Fc gamma RI alone (in the absence of the gamma subunit) is capable of mediating endocytosis in COS cells and that the process occurs via a novel, tyrosine kinase independent signalling pathway. Activation of this pathway following cross linking appears to require only the receptor extracellular domain. In contrast, Fc gamma RI phagocytic function in COS cells is dependent on an interaction between the receptor transmembrane domain and the gamma subunit and is mediated by recruitment of tyrosine kinase activity. Our data therefore indicate that distinct domains of the receptor regulate ligand internalization following receptor cross-linking by either immune complexes (endocytosis) or opsonized particles (phagocytosis) and that these functions are mediated by different intracellular signalling pathways. PMID- 7859732 TI - Suppression of villin expression by antisense RNA impairs brush border assembly in polarized epithelial intestinal cells. AB - We have used an antisense RNA strategy to investigate the role of the actin associated protein, villin, in the brush-border morphogenesis of human intestinal CaCO2 cells. Stable expression of a cDNA encoding antisense villin RNA resulted in the permanent down-regulation of the endogenous villin message and dramatically affected brush-border assembly. Ultrastructural and immunolocalization studies revealed that epithelial cell polarity was largely maintained. However, in contrast to brush-border markers such as dipeptidyl peptidase IV, the apical localization of sucrase-isomaltase was specifically impaired. Retransfection of the villin antisense-expressing cell line with a cDNA encoding a partial sense villin RNA restored both brush-border assembly and sucrase-isomaltase apical expression. The suggestion that brush-border morphogenesis may be important for the trafficking of certain proteins is discussed. PMID- 7859734 TI - Phosphoglycerate kinase and triosephosphate isomerase from the hyperthermophilic bacterium Thermotoga maritima form a covalent bifunctional enzyme complex. AB - Phosphoglycerate kinase (PGK) from the hyperthermophilic bacterium Thermotoga maritima has been purified to homogeneity. A second larger enzyme with PGK activity and identical N-terminal sequence was also found. Surprisingly, this enzyme displayed triosephosphate isomerase (TIM) activity. No other TIM is detectable in T. maritima crude extracts. As shown by ultracentrifugal analysis, PGK is a 43 kDa monomer, whereas the bifunctional PGK-TIM fusion protein is a homotetramer of 240-285 kDa. SDS-PAGE indicated a subunit size of 70 kDa for the fusion protein. Both enzymes show high thermostability. Measurements of the catalytic properties revealed no extraordinary results. pH optima, Km values and activation energies were found to be in the range observed for other PGKs and TIMs investigated so far. The corresponding pgk and tpi genes are part of the apparent gap operon of T. maritima. This gene segment contains two overlapping reading frames, where the 43 kDa PGK is encoded by the upstream open reading frame, the pgk gene. On the other hand, the 70 kDa PGK-TIM fusion protein is encoded jointly by the pgk gene and the overlapping downstream open reading frame of the tpi gene. A programmed frameshift may be responsible for this fusion. A comparison of the amino acid sequence of both the PGK and the TIM parts of the fusion protein with those of known PGKs and TIMs reveals high similarity to the corresponding enzymes from different procaryotic and eucaryotic organisms. PMID- 7859735 TI - Glucocorticoid-induced apoptosis of human leukemic cells is caused by the repressive function of the glucocorticoid receptor. AB - Induction of apoptosis in lymphocytes, which may account for the therapeutic effects of glucocorticoids in various diseases including leukemia, depends on the glucocorticoid receptor. However, the events leading from the activated receptor to cell lysis are not understood. A prevailing hypothesis postulates induction of so-called 'lysis genes' by the activated receptor. In this study, we show that an activation-deficient glucocorticoid receptor mutant is as effective as the wild type receptor in repression of AP-1 activity, inhibition of interleukin-2 production, inhibition of c-myc expression and induction of apoptosis. Furthermore, we show that retinoic acid can also induce apoptosis in these cells through the retinoic acid receptor, whose repressive functions but not target site specificity, are similar to those of the glucocorticoid receptor. Therefore, the primary effect of the receptor in glucocorticoid-mediated apoptosis correlates with transcriptional repression rather than activation and could be mediated by interference with other transcription factors required for cell survival. PMID- 7859736 TI - Inhibition of apoptosis by the retinoblastoma gene product. AB - Tissue homeostasis and the prevention of neoplasia require regulatory co ordination between cellular proliferation and apoptosis. Several cellular proteins, including c-myc and E2F, as well as viral proteins such as E1A, have dual functions as positive regulators of apoptosis and proliferation. The product of the retinoblastoma tumor suppressor gene, pRb, binds these proteins and is known to function in growth suppression. To examine whether pRb may function as a negative regulator of both proliferation and apoptosis, we analyzed apoptosis induced in transfected derivatives of the human osteosarcoma cell line SAOS-2. Ionizing radiation induced apoptosis in a time- and dose-dependent manner in SAOS 2 cells, which lack pRb expression. In both a transient and stable transfection assay, SAOS-2 derivatives expressing wild-type (wt) pRb exhibited increased viability and decreased apoptosis following treatment at a variety of radiation doses. Expression in SAOS-2 of a mutant pRb that fails to complex with several known binding partners of pRb, including E1A and E2F, did not protect SAOS-2 cells from apoptosis. Radiation exposure induced a G2 arrest in SAOS-2 and in derivatives expressing pRb. Inhibition of DNA synthesis and cell cycle progression by aphidicolin treatment failed to protect SAOS-2 cells or pRb expressing isolates from undergoing apoptosis. Our data document a novel function for pRb in suppressing apoptosis and suggest that several proteins shown to induce apoptosis, including E1A, E2F and c-myc, may do so by interfering with the protective function of pRb. PMID- 7859737 TI - Proline-rich (PxxP) motifs in HIV-1 Nef bind to SH3 domains of a subset of Src kinases and are required for the enhanced growth of Nef+ viruses but not for down regulation of CD4. AB - Human immunodeficiency virus (HIV) and simian immunodeficiency virus Nef proteins contain a conserved motif with the minimal consensus (PxxP) site for Src homology region 3 (SH3)-mediated protein-protein interactions. Nef PxxP motifs show specific binding to biotinylated SH3 domains of Hck and Lyn, but not to those of other tested Src family kinases or less related proteins. A unique cooperative role of a distant proline is also observed. Endogenous Hck of monocytic U937 cells can be specifically precipitated by matrix-bound HIV-1 Nef, but not by mutant protein lacking PxxP. Intact Nef PxxP motifs are dispensable for Nef induced CD4 down-regulation, but are required for the higher in vitro replicative potential of Nef+ viruses. Thus, CD4 down-regulation and promotion of viral growth are two distinct functions of Nef, and the latter is mediated via SH3 binding. PMID- 7859738 TI - Counteractive roles of protein phosphatase 2C (PP2C) and a MAP kinase kinase homolog in the osmoregulation of fission yeast. AB - With the goal of discovering the cellular functions of type 2C protein phosphatases, we have cloned and analyzed two ptc (phosphatase two C) genes, ptc2+ and ptc3+, from the fission yeast Schizosaccharomyces pombe. Together with the previously identified ptc1+ gene, the enzymes encoded by these genes account for approximately 90% of the measurable PP2C activity in fission yeast cells. No obvious growth defects result from individual disruptions of ptc genes, but a delta ptc1 delta ptc3 double mutant displays aberrant cell morphology and temperature-sensitive cell lysis that is further accentuated in a delta ptc1 delta ptc2 delta ptc3 triple mutant. These phenotypes are almost completely suppressed by the presence of osmotic stabilizers, strongly indicating that PP2C has an important role in osmoregulation. Genetic suppression of delta ptc1 delta ptc3 lethality identified two loci, mutations of which render cells hypersensitive to high-osmolarity media. One locus is identical to wis1+, encoding a MAP kinase kinase (MEK) homolog. The Wis1 sequence is most closely related to the Saccharomyces cerevisiae MEK encoded by PBS2, which is required for osmoregulation. These data indicate that divergent yeasts have functionally conserved MAP kinase pathways, which are required to increase intracellular osmotic concentrations in response to osmotic stress. Moreover, our observations implicate PP2C enzymes as also having an important role in signal transduction processes involved in osmoregulation, probably acting to negatively regulate the osmosensing signal that is transmitted through Wis1 MAP kinase kinase. PMID- 7859739 TI - Lack of cyclin D-Cdk complexes in Rb-negative cells correlates with high levels of p16INK4/MTS1 tumour suppressor gene product. AB - D-type cyclins, in association with the cyclin-dependent kinases Cdk4 or Cdk6, regulate events in the G1 phase of the cell cycle and may contribute to the phosphorylation of the retinoblastoma gene product (Rb). However, in cells in which the function of Rb has been compromised, either by naturally arising mutations or through binding to proteins encoded by DNA tumour viruses, Cdk4 and Cdk6 are not associated with D cyclins. Instead, both kinases form binary complexes with a stable 16 kDa protein (p16) encoded by the putative tumour suppressor gene INK4/MTS1 on human chromosome 9p21. Here we show an inverse correlation between Rb status and the expression of p16. Since Rb-negative cells express high levels of p16, we suggest that in these cells p16 competes with D cyclins for binding to Cdk4 and Cdk6 and prevents formation of active complexes. In line with these predictions, DNA tumour virus oncoproteins do not disrupt cyclin D1-Cdk4 complexes in cells lacking p16. PMID- 7859740 TI - The dihedral symmetry of the p53 tetramerization domain mandates a conformational switch upon DNA binding. AB - The p53 tumor suppressor forms stable tetramers, whose DNA binding activity is allosterically regulated. The tetramerization domain is contained within the C terminus (residues 323-355) and its three-dimensional structure exhibits dihedral symmetry, such that a p53 tetramer can be considered a dimer of dimers. Under conditions where monomeric p53 fails to bind DNA, we studied the effects of p53 C terminal mutations on DNA binding. Residues 322-355 were sufficient to drive DNA binding of p53 as a tetramer. Within this region residues predicted by the three dimensional structure to stabilize tetramerization, such as Arg337 and Phe341, were critical for DNA binding. Furthermore, substitution of Leu344 caused p53 to dissociate into DNA binding-competent dimers, consistent with the location of this residue at the dimer-dimer interface. The p53 DNA site contains two inverted repeats juxtaposed to a second pair of inverted repeats. Thus, the four repeats exhibit cyclic-translation symmetry and cannot be recognized simultaneously by four dihedrally symmetric p53 DNA binding domains. The discrepancy may be resolved by flexible linkers between the p53 DNA binding and tetramerization domains. When these linkers were deleted p53 exhibited novel DNA binding properties consistent with an inability to recognize four contiguous DNA repeats. Allosteric regulation of p53 DNA binding may involve repositioning the DNA binding domains from a dihedrally symmetric state to a DNA-bound asymmetric state. PMID- 7859741 TI - Ultrabithorax protein is necessary but not sufficient for full activation of decapentaplegic expression in the visceral mesoderm. AB - To elucidate the mechanisms by which homeotic selector (HOM) genes specify the unique features of Drosophila segments, we have analyzed the regulation of decapentaplegic (dpp), a transforming growth factor (TGF)-beta superfamily member, and have found that the Ultrabithorax (Ubx) HOM protein directly activates dpp expression in parasegment 7 (PS7) of the embryonic visceral mesoderm. Other factors are also required, including one that appears to act through homeodomain protein binding sites and may be encoded by extradenticle (exd). The exd protein binds in a highly co-operative manner to regulatory sequences mediating PS7-specific dpp expression, consistent with a genetic requirement for exd function in normal visceral mesoderm expression of dpp. A second mechanism contributing to PS7 expression of dpp appears not to require Ubx protein directly, and involves a general visceral mesoderm enhancer coupled to a spatially specific repression element. Thus, even in an apparently simple case where visceral mesoderm expression of the dpp target gene mirrors that of the Ubx HOM protein, full activation by Ubx protein requires at least one additional factor. In addition, a distinct regulatory mode not directly involving Ubx protein also appears to contribute to PS7-specific expression. PMID- 7859743 TI - HIV-1 Tat potentiates TNF-induced NF-kappa B activation and cytotoxicity by altering the cellular redox state. AB - This study demonstrates that human immunodeficiency virus type 1 (HIV-1) Tat protein amplifies the activity of tumor necrosis factor (TNF), a cytokine that stimulates HIV-1 replication through activation of NF-kappa B. In HeLa cells stably transfected with the HIV-1 tat gene (HeLa-tat cells), expression of the Tat protein enhanced both TNF-induced activation of NF-kappa B and TNF-mediated cytotoxicity. A similar potentiation of TNF effects was observed in Jurkat T cells and HeLa cells treated with soluble Tat protein. TNF-mediated activation of NF-kappa B and cytotoxicity involves the intracellular formation of reactive oxygen intermediates. Therefore, Tat-mediated effects on the cellular redox state were analyzed. In both T cells and HeLa cells HIV-1 Tat suppressed the expression of Mn-dependent superoxide dismutase (Mn-SOD), a mitochondrial enzyme that is part of the cellular defense system against oxidative stress. Thus, Mn-SOD RNA protein levels and activity were markedly reduced in the presence of Tat. Decreased Mn-SOD expression was associated with decreased levels of glutathione and a lower ratio of reduced:oxidized glutathione. A truncated Tat protein (Tat1 72), known to transactivate the HIV-1 long terminal repeat (LTR), no longer affected Mn-SOD expression, the cellular redox state or TNF-mediated cytotoxicity. Thus, our experiments demonstrate that the C-terminal region of HIV 1 Tat is required to suppress Mn-SOD expression and to induce pro-oxidative conditions reflected by a drop in reduced glutathione (GSH) and the GSH:oxidized GSH (GSSG) ratio.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859742 TI - Functional analysis and regulation of nuclear import of dorsal during the immune response in Drosophila. AB - In addition to its function in embryonic development, the NF-kappa B/rel-related gene dorsal (dl) of Drosophila is expressed in larval and adult fat body where its RNA expression is enhanced upon injury. Injury also leads to a rapid nuclear translocation of dl from the cytoplasm in fat body cells. Here we present data which strongly suggest that the nuclear localization of dl during the immune response is controlled by the Toll signaling pathway, comprising gene products that participate in the intracellular part of the embryonic dorsoventral pathway. We also report that in mutants such as Toll or cactus, which exhibit melanotic tumor phenotypes, dl is constitutively nuclear. Together, these results point to a potential link between the Toll signaling pathway and melanotic tumor induction. Although dl has been shown previously to bind to kappa B-related motifs within the promoter of the antibacterial peptide coding gene diptericin, we find that injury-induced expression of diptericin can occur in the absence of dl. Furthermore, the melanotic tumor phenotype of Toll and cactus is not dl dependent. These data underline the complexity of the Drosophila immune response. Finally, we observed that like other rel proteins, dl can control the level of its own transcription. PMID- 7859744 TI - Identification of the active region of the DNA synthesis inhibitory gene p21Sdi1/CIP1/WAF1. AB - The cloning of the negative growth regulatory gene, p21Sdi1, has led to the convergence of the fields of cellular senescence, cell cycle regulation and tumor suppression. This gene was first cloned as an inhibitor of DNA synthesis that was overexpressed in terminally non-dividing senescent human fibroblasts (SD11) and later as a p53 transactivated gene (WAF1) and a Cdk-interacting protein (CIP1, p21) that inhibited cyclin-dependent kinase activity. To identify the active region(s) of p21Sdi1, cDNA constructs encoding various deleted forms of the protein were analyzed. Amino acids 22-71 were found to be the minimal region required for DNA synthesis inhibition. Amino acids 49-71 were involved in binding to Cdk2, and constructs deleted in this region expressed proteins that were unable to inhibit Cdk2 kinase activity in vitro. The latter stretch of amino acids shared sequence similarity with amino acids 60-76 of the p27Kip1 protein, another Cdk inhibitor. Point mutations made in p21Sdi1 in this region confirmed that amino acids common to both proteins were involved in DNA synthesis inhibition. Additionally, a chimeric protein, in which amino acids 49-65 of p21Sdi1 were substituted with amino acids 60-76 of p27Kip1, had almost the same DNA synthesis inhibitory activity as the wild-type protein. The results indicate that the region of sequence similarity between p21Sdi1 and p27Kip1 encodes an inhibitory motif characteristic of this family of Cdk inhibitors. PMID- 7859745 TI - Random activation of a transgene under the control of a hybrid hCD2 locus control region/Ig enhancer regulatory element. AB - Locus control regions such as those of human CD2 and beta-globin differ from classical enhancers in that, whereas the former confer high level, copy dependent, position-independent expression to linked genes in transgenic mice, the latter do not, expression levels being dependent on the site of integration. We report that the position independence of the CD2 locus control region is modified by coupling it to the immunoglobulin heavy chain enhancer. Whilst in the majority of transgenic lines the Ig heavy chain enhancer has little or no effect on T cell expression of the hCD2 transgene, in others transgene expression is non specifically extinguished in a proportion of lymphoid cells. The transgenic locus chromatin appears inaccessible to DNase I in these cells, which do not express the gene. Furthermore, mice homozygous for the hybrid hCD2-Ig heavy chain enhancer construct contain T cells with both an active and an inactive transgene. The 'decision' to express or repress the gene appears to be a random process which involves each chromosome separately, occurs at early stages in differentiation and is heritable by daughter cells. These data suggest the possibility that stochastic decisions might control a number of biological processes. PMID- 7859746 TI - Evidence for a novel mitochondrial promoter preceding the cox2 gene of perennial teosintes. AB - We have characterized two promoters of the cytochrome oxidase subunit 2 (cox2) gene in Zea perennis mitochondria present in maize lines. Initiation at a site 907 bases upstream of the start codon results in the major approximately 1900 nt cox2 transcript. A sequence just upstream of this site conforms to the consensus described for maize mitochondrial promoters and its transcription is correctly initiated in a maize mitochondrial in vitro transcription extract. A second transcription initiation site (-347) is used only when the dominant allele of a nuclear gene, Mct, is present and its use results in an additional, shorter major transcript. Sequences flanking the Mct-dependent transcription initiation site, which we have termed the conditional promoter of cox2 (cpc), do not fit the maize mitochondrial promoter consensus and do not function in the maize in vitro transcription extract. The cpc region does not hybridize with mitochondrial, chloroplast or nuclear DNAs from most maize or teosinte lines. However, the cpc sequence is found in the same position upstream of the cox2 gene in Zea diploperennis mtDNA and it has striking similarity to the previously reported 'ORF of unknown origin' fused to the ATPase subunit 6 gene in maize CMS-C mitochondria. cpc appears to represent a new type of mitochondrial promoter. Further analysis of both conditional and constitutive promoters should help us to better understand the control of transcription in plant mitochondria. PMID- 7859747 TI - Quantitative control of the stationary phase-specific sigma factor, sigma S, in Escherichia coli: involvement of the nucleoid protein H-NS. AB - In Escherichia coli, recent intensive studies revealed that expression of a certain subset of genes is under the control of the stationary phase-specific sigma factor, sigma S, which is encoded by the rpoS gene. Since sigma S functions predominantly under certain growth conditions, its activity and/or cellular content has accordingly to be tightly controlled, however, the underlying molecular mechanism is at present unclear. We previously demonstrated that expression of the cbpA gene, encoding an analogue of the DnaJ molecular chaperone, is largely dependent on sigma S function. Here we have found that a mutational lesion of the hns gene, which encodes one of the well-characterized nucleoid proteins, H-NS, affects the cellular content of sigma S remarkably and consequently affects the expression of cbpA. Enhanced accumulation of sigma S in hns deletion cells was particularly observed in the logarithmic growth phase and was demonstrated to result from an elevated translational efficiency of rpoS mRNA and also from an increased stability of newly synthesized sigma S. Although H-NS is known to influence the transcription of a number of apparently unlinked genes on the chromosome, in this study we provide a novel instance in which H-NS is deeply implicated in post-transcriptional regulation(s) of the expression of rpoS. As to physiological relevance, it was also demonstrated that hns deletion cells exhibit an extreme thermotolerance even in the logarithmic growth phase, presumably because of the enhanced accumulation of sigma S. PMID- 7859748 TI - Evidence for post-transcriptional regulation of cyclin B1 mRNA in the cell cycle and following irradiation in HeLa cells. AB - Cyclin B1 mRNA expression varies markedly through the cell cycle with its peak in G2/M and lowest level in G1. Cyclin B1 mRNA levels are also transiently reduced in HeLa cells after gamma-irradiation, coincident with the radiation-induced G2 block. In order to understand the mechanisms underlying these variations, we have measured cyclin B1 mRNA stability in HeLa cells during different phases of the cell cycle. The half-life of the mRNA measured after actinomycin D administration is 1.1-1.8 h in both early and late G1, 8 h in S and 13 h in G2/M. We therefore conclude that altered RNA stability is important in modulating cyclin B1 mRNA levels through the HeLa cell cycle. Furthermore, 3 h after irradiation of HeLa cells in S phase with 10 Gy, the half-life of cyclin B1 mRNA is reduced to 5 h; it is further reduced to 2-3 h at 14 h after irradiation. Thus, decreased stability contributes to the reduction in cyclin B1 mRNA following irradiation. PMID- 7859749 TI - The transketolase gene family of the resurrection plant Craterostigma plantagineum: differential expression during the rehydration phase. AB - Transketolases, key enzymes of the reductive and oxidative pentose phosphate pathways, are responsible for the synthesis of sugar phosphate intermediates. Here we report the first molecular analysis of transketolase genes from plants. Three distinct classes of transketolase-encoding cDNA clones were isolated from the desiccation-tolerant resurrection plant Craterostigma plantagineum. One class represented by the transcript tkt3 is constitutively expressed in leaves and roots under all physiological conditions tested. By biochemical analysis and protein sequencing of purified transketolase, it was shown that tkt3 is expressed in three enzymatically active isoforms. An intriguing discovery was that accumulation of the two other transketolase transcripts, tkt7 and tkt10, is preferentially associated with the rehydration process of the desiccated plant; whereas tkt10 is only expressed in leaves, tkt7 was detected in leaves and roots. This observation suggests a possible role for these transketolases in the conversion of sugars, which are a major phenomenon in the rehydration process. Despite an abundant level of tkt7 and tkt10 transcripts in rehydrating leaves, proteins could not be isolated. This is due in part to a translational control mechanism acting on the loading of mRNAs to polysomes. PMID- 7859752 TI - Anomalous origin of the posterior inferior cerebellar artery from the pre cavernous portion of the internal carotid artery--a primitive trigeminal artery variant. PMID- 7859750 TI - Termination of DNA replication in vitro: requirement for stereospecific interaction between two dimers of the replication terminator protein of Bacillus subtilis and with the terminator site to elicit polar contrahelicase and fork impedance. AB - The termination of DNA replication at a sequence-specific replication terminus in Bacillus subtilis is catalyzed by a dimeric replication terminator protein (RTP) of subunit mol. wt 14,500. RTP has become an attractive protein with which to study the molecular mechanism of termination because its crystal structure has now been solved and the previous lack of an in vitro replication system has been largely overcome by our discovery that the protein terminates replication in vivo and in vitro in the well-studied Gram-negative Escherichia coli system. We have exploited the surrogate in vitro system to show that RTP acts as a polar contrahelicase to DnaB helicase of E. coli only when two RTP dimers are bound co operatively to overlapping core and auxiliary sequences comprising the terminus. A core sequence by itself binds one dimer of RTP, but elicits no contrahelicase activity. Binding of two RTP dimers to a tandem head-to-tail core repeat also elicits no contrahelicase activity, thus suggesting that a specific stereochemical interaction between two RTP dimers and with the terminator site is essential for termination. RTP blocks unwinding of DNA substrates containing heteroduplex regions that include the terminus and are in the size range of approximately 50 to > 1000 bp in length. Thus, the protein blocks authentic helicase-catalyzed unwinding rather than just the translocation of the helicase on DNA. PMID- 7859751 TI - Prognostic features of Ewing's sarcoma on radionuclide bone scan after initial treatment. AB - OBJECTIVE: To study short-term changes in the radiopharmaceutical bone scan (BS) appearance of Ewing's sarcoma for indicators of decreased survival or future disease progression. METHODS: One-hundred and four patients with non-metastatic Ewing's sarcoma were evaluated at three time points: time of diagnosis (pre biopsy), after induction chemotherapy (13 weeks) and after radiation therapy (20 weeks). Radiographs, computed tomograms (CTs) and BSs were obtained at each interval. Primary lesion activity and size on BS were evaluated and compared to radiographic and CT findings. RESULTS: No significant relationship was found at any time point between absolute radiopharmaceutical activity within the primary lesion and either disease progression or patient survival. Relative changes in BS activity between time points were also not significantly related to disease progression or survival despite a significant decrease in activity among the three time points. The size of the BS abnormality compared to the CT abnormality at the primary lesion site was related to both survival and disease progression at the post-induction chemotherapy time point (P = 0.025 and P = 0.014, respectively) with larger BS abnormalities indicating worse prognosis and survival. This relationship lost its significance at the post-radiation time point. No other significant relationship between the relative size of the BS abnormality and the size of the plain radiographic or CT abnormality was detected. CONCLUSION: Our data suggest that BS imaging of the primary lesion of Ewing's sarcoma provides little information in terms of predicting long-term survival or disease progression in patients with non-metastatic Ewing's sarcoma. PMID- 7859754 TI - Renal aspergilloma, a rare manifestation in AIDS. PMID- 7859753 TI - Intraventricular neurocytoma: case report and review. PMID- 7859755 TI - Lhermitte-Duclos disease: a critical appraisal of different radiologic methods. PMID- 7859756 TI - CT angiography of the pelvic arteries. AB - A comparison was performed between CT angiography and digital subtraction angiography (DSA) on 55 patients with atherosclerotic obstructions of the pelvic arteries. Two post-processing algorithms were employed, maximum intensity projection (MIP) and 3D technique. RESULTS: (a) MIP: conformity with DSA: 20/23 occlusions and 24/36 stenoses; underestimation: three occlusions, seven stenoses; overestimation: five stenoses. (b) 3D display: conformity with DSA: 19/23 occlusions and 16/36 stenoses; underestimation: four occlusions, 17 stenoses; overestimation: three stenoses. The MIP technique proved to be the only method to display the localisation of vascular calcifications with their exact topographical relationship to the stenoses and occlusions. MIP also proved to be valuable in controlling the position of intravascular stents. Complementary to DSA, the MIP method therefore seems to be a clinically valuable technique for calcified and non-calcified stenoses, and for displaying intravascular stents. Its use in interventional procedures could therefore become increasingly important. PMID- 7859757 TI - Sarcoidosis of the pancreas mimicking pancreatic cancer: CT features. PMID- 7859758 TI - Migrating gallbladder in alcoholic liver cirrhosis mimicking true ectopia: CT findings. PMID- 7859759 TI - Intrahepatic cholangiocarcinoma: findings on spiral CT during arterial portography. AB - To attempt to determine the characteristic imaging features of intrahepatic cholangiocarcinoma on spiral CT during arterial portography (CTAP), spiral CTAP examinations of 17 patients with pathologically confirmed intrahepatic cholangiocarcinoma were reviewed in consensus by three radiologists. The diameter of the tumors ranged from 1 to 12 cm (mean diameter, 6.6 cm). All tumors (100%) were hypoattenuating masses on spiral CTAP. In 11 cases, the tumor was homogeneous in attenuation (65%). Tumor margins were smooth and regular in 11 cases (65%). Vascular invasion was found in 14 cases (82%). Intrahepatic bile duct dilatation was present in seven cases (41%). This review shows that intrahepatic cholangiocarcinoma is associated with a constellation of findings on spiral CTAP. The presence of a low attenuation homogeneous intrahepatic mass with vascular invasion and intrahepatic bile duct dilatation on spiral CTAP images should raise the possibility of intrahepatic cholangiocarcinoma. However, these findings can be associated with other types of primary and secondary malignant hepatic tumors. PMID- 7859760 TI - Magnetic resonance angiography in transjugular intrahepatic portosystemic stenting: comparison with contrast hepatic and portal venography. AB - In order to highlight the role of magnetic resonance angiography [MRA] in the assessment of patients pre-transjugular intrahepatic portosystemic shunt (TIPS) stenting, the MRA images of portal and hepatic veins of 21 patients were compared with the images from contrast portal and hepatic venograms performed on the same patients at the time of TIPS stenting (20 patients). MRA enabled accurate, non invasive, multiplanar imaging of portal and systemic venous anatomy in each of the patients studied. MRA facilitated accurate determination of vessel patency and flow direction, images correlating exactly with contrast venograms of hepatic and portal veins in each case. In one patient, identification of occult hepatocellular carcinoma extending to the portal vein lead to the postponement of the TIPS procedure. PMID- 7859761 TI - Diagnostic utility of color Doppler ultrasound in lower limb deep vein thrombosis in patients with clinical suspicion of pulmonary thromboembolism. AB - The diagnosis of pulmonary thromboembolism is frequently based on ventilation perfusion scintigraphy and ascending lower limb venography when pulmonary angiography is not available. The aim of this study is to compare color Doppler ultrasound against ascending venography in the evaluation of the lower limb deep vein system in patients with clinical suspicion of pulmonary embolism, with special attention to calf veins. We prospectively studied 30 patients with clinical suspicion of pulmonary embolism in whom a color Doppler ultrasound and venogram were performed with no more than a 3-h interval between both procedures. The diagnostic criteria was that of loss of venous compressibility. The 'color' ability was used to identify artery from vein. Out of 15 patients in whom a venogram proved positive (50%), 9 had isolated calf vein thrombosis (60%). In 5 patients, the color Doppler ultrasound of the calf was considered inconclusive. Overall sensitivity was 53%, specificity 100%, positive predictive value 100%, and negative predictive value 68%. In the femoropopliteal system, sensitivity was 83% and specificity 100%. Considering all patients, sensitivity in the calf system was 40%. Excluding the 5 patients who were difficult to assess, sensitivity increased to 60%. In conclusion, color Doppler ultrasound is not as sensitive as venography in dealing with patients with clinical suspicion of pulmonary embolism, due to its low sensitivity in the calf system when distal thrombi need to be excluded. However, a reasonable alternative is to begin by performing a compression ultrasonography of the femoropopliteal system. Color Doppler ultrasonography of the calf system represents a rarely sensitive and arduous task and does not seem justifiable in this type of patient.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859762 TI - Granular cell tumor of the breast: mammographic and histologic correlation. PMID- 7859763 TI - Assessment of blood flow in different segments of the penis by duplex sonography in subjects with normal erectile potency. AB - Correct evaluation of erectile potency requires careful assessment of the hemodynamics of the cavernous area. Pulsed Doppler flow velocity measurement of cavernous arteries after intracavernous injection of vasoactive drugs represents an effective, repeatable and minimally invasive technique. However, doubts remain concerning the procedures employed and the results obtained. Based on the assumption that all flowing viscous fluids are subjected to a significant decrease in pressure and, hence, velocity the smaller the vessel diameter is, the pulsed Doppler flow velocity measurement was used to evaluate such a decrease in three consecutive segments of the penis (a,b and c). A statistically significant decrease in velocity (P < 0.0001 on the right and left) was observed between the arterial segments a, b and c in cavernous arteries of subjects with normal erectile function. Therefore, we stress that in the vascular evaluation of the penis, one should take into account the values obtained in each penile segment because a reduction in flow velocity in a proximo-distal direction can be regarded as physiologic. Misinterpretation of results can thus be prevented, avoiding a wrong diagnosis of arteriogenic erectile insufficiency. PMID- 7859764 TI - Agenesis of the inferior vena cava associated with agenesis of the bilateral commune iliac vein. PMID- 7859765 TI - Radiology practice: British and American academic radiology compared. PMID- 7859766 TI - Non-Hodgkin's lymphoma of the skull vault. PMID- 7859767 TI - Localization of epileptic foci by single-photon emission tomography with new radiotracers. PMID- 7859768 TI - Autoradiography and density gradient separation of technetium-99m-exametazime (HMPAO) labelled leucocytes reveals selectivity for eosinophils. AB - Technetium-99m-Exametazime (HMPAO) is widely used for radiolabelling leucocytes for localization of infection. The subcellular distribution of radionuclide in the labelled cells and the distribution of radioactivity among the leukocyte population are incompletely understood. Frozen section autoradiography was used to determine quantitatively the distribution of 99mTc in leucocytes labelled with 99mTc-Exametazime. Sections of rapidly frozen suspensions of labelled leucocytes in plasma were autoradiographed on Ilford K2 emulsion and stained with haematoxylin and eosin. Neutrophils, eosinophils and mononuclear cells were separated by Percoll density gradient centrifugation. Cell nuclei were isolated by a rapid cell-breakage and fractionation method. In a typical experiment mean grain densities [grains/100 microns2 (ESD)] over cells were: eosinophils 31.2 (18.4), neutrophils 3.5 (3.5), mononuclear cells 4.2 (5.1). Mean grain numbers per cell (ESD) were: eosinophils 13 (6.8), neutrophils 1.3 (1.3), mononuclear cells 1.1 (1.3). These findings were confirmed by separation of labelled leucocytes on discontinuous density gradients. In four separation experiments, the mean activity-per-cell ratio for eosinophils to neutrophils was 10.1 (4.8):1, and for eosinophils to mononuclear cells, 14.1 (6.7):1. The subcellular distribution of the label was investigated using image analysis of autoradiographs and cell fractionation. This revealed no selectivity for nuclear or extranuclear compartments. It may be concluded that 99mTc-Exametazime has strong selectivity for eosinophils over other leukocytes but no selectivity for nuclear/cytoplasmic compartments. PMID- 7859769 TI - Effect of the route of administration on the biodistribution of radioiodinated OV TL 3 F(ab')2 in experimental ovarian cancer. AB - The effect of the route administration on the distribution of radioiodinated OV TL 3 F(ab')2 was studied in Balb/c female mice with intraperitoneal or subcutaneous ovarian carcinoma xenografts. In the intraperitoneal tumour model in which both ascites and solid tumour deposits were present, intraperitoneal administration resulted in a lower estimated radiation dose to blood as compared with intravenous administration. In this model normalization to equal estimated radiation doses to blood for both routes of administration indicated that a twice as high estimated radiation dose can be guided to solid intraperitoneal tumour deposits following intraperitoneal administration. Evacuation of ascitic tumour cells prior to monoclonal antibody injection further increased the estimated radiation dose to solid intraperitoneal tumour deposits following intraperitoneal delivery. Following simultaneous intravenous and intraperitoneal injection of the monoclonal antibody, tissue uptake showed no relevant differences in the subcutaneous tumour model. Overall, the intraperitoneal route of administration was found to be the best choice for therapeutic delivery of iodine-131 labelled monoclonal antibodies. PMID- 7859770 TI - Somatostatin receptor scintigraphy in forty-eight patients with the Zollinger Ellison syndrome. GRESZE: Groupe d'Etude du Syndrome de Zollinger-Ellison. AB - In patients with the Zollinger-Ellison syndrome, which is either sporadic or integrated into multiple endocrine neoplasia type 1, accurate localization of all the tumours is difficult and may have therapeutic implications. In an attempt to improve this localization, somatostatin receptor scintigraphy using [111In-DTPA-D Phe1]-octreotide was performed prospectively in 48 consecutive patients with the Zollinger-Ellison syndrome. Thirty of them had the sporadic type of this disease. Scintigraphic data were compared with data obtained by conventional imaging methods, and also, in 32 selected patients, with those obtained by endoscopic ultrasonography. Somatostatin receptor scintigraphy showed abnormal tracer uptake in 39 patients (81%), in whom it correctly identified 50 of the 60 tumoral sites (83%) previously localized by the other imaging methods. In 17 patients (35%) somatostatin receptor scintigraphy disclosed abnormal tracer uptake at 18 different tumoral sites: 14 were located in the abdomen, including four in the liver and eight in the duodenopancreatic area, and four outside the abdomen, including two in the mediastinum. Six of the ten tumoral sites which were not correctly identified by somatostatin receptor scintigraphy were located in the duodenopancreatic area. However, in the 20 patients for whom conventional techniques failed to visualize any tumour in the duodenopancreatic area, somatostatin receptor scintigraphy was positive in ten (50%) whereas endoscopic ultrasonography was only positive in five (25%). In our patients with the Zollinger-Ellison syndrome, somatostatin receptor scintigraphy appeared to be a useful new addition to the battery of tests used for tumour detection. PMID- 7859771 TI - The value of thallium and three-phase bone scans in the evaluation of bone and soft tissue sarcomas. AB - Thirty-seven patients with newly diagnosed or treated sarcomas had 47 sets of sequential thallium scans (TS) followed by three-phase bone scan (TPBS) on the same day. The diagnosis in all patients was verified by biopsy (n = 40) or long term follow-up studies (n = 7). The sensitivity, specificity, and accuracy of TS and TPBS in detecting sarcomatous lesions was calculated: TS sensitivity was 88%, specificity 69%, and accuracy 83%; blood flow (BF) and blood pool (BP) sensitivity was 91%, specificity 54%, and accuracy 81%; delayed bone scan (DB) sensitivity was 88%, specificity 38%, and accuracy 74%. In 17 studies the flow and blood pool parts of the TPBS and TS demonstrated the soft tissue component of sarcomas, which would have been missed if only the delayed bone scan had been performed. The TS lesion to normal tissue ratio alone was not very helpful in differentiating sarcomas from benign conditions because some benign lesions are highly cellular and vascular while some malignant lesions, such as chondrosarcoma, have poor vascularity and a less cellular chondroid matrix. However, when the thallium ratio was correlated with similar ratios calculated from the BP image, it was found that if the TS lesion to normal tissue ratio exceeded the BP lesion to normal tissue ratio (12 patients), the specificity for detecting sarcomatous lesions was 100%. Nevertheless, the reverse was not true. The positive predictive value of this observation was 100% and the negative predictive value was 37%. PMID- 7859772 TI - A semi-automated method for edge detection in the evaluation of left ventricular function using ECG-gated single-photon emission tomography. AB - Thallium-201 gated single-photon emission tomography (GSPET) of myocardium was performed at rest in 18 patients. Images were reconstructed to obtain end diastolic (ED) and end-systolic (ES) images. The endocardial and epicardial edges of the left ventricle (LV) for the ED and ES images were defined for the mid ventricular images of the short-axis slices, using a semi-automated method. LV wall thickness was measured for ED and ES images at 10 degrees intervals. Mean LV thickness was derived as the mean of the LV thickness for the three mid ventricular slices. The systolic thickening (ST) was derived as: mean LV thickness (ES)--mean LV thickness (ED). The systolic thickening ratio (STR) was defined as: ST/mean LV thickness (ED). LV cavity area was measured. The dilation ratio (DR) was defined as: [mean cavity area (ED)--mean cavity area (ES)]/mean cavity area (ED). LV ejection fraction (LVEF) was estimated using technetium-99m gated blood pool study. There was a linear correlation between LVEF and ST (r = 0.85), LVEF and STR (r = 0.77) and LVEF and DR (r = 0.81). There was a strong correlation (r = 0.85) between regional STR and regional percent count increase in 52 segments which did not have perfusion defects. As well as for the evaluation of myocardial perfusion, GSPET images can be of use for the assessment of LV function using an appropriate method for LV edge detection. PMID- 7859773 TI - Twenty-four-hour quantitative thallium imaging for predicting beneficial revascularization. AB - To determine the utility of 24-h thallium single-photon emission tomographic imaging for the assessment of myocardial viability, 40 patients with persistently decreased uptake on 3-h delayed imaging after exercise were studied before and after bypass surgery (n = 34) or coronary angioplasty (n = 6). Wall motion improvement after revascularization was also analysed in 23 patients with respect to the segments with and without 24-h redistribution. Of a total of 113 segments without redistribution at 3-h imaging after exercise, 62 (55%) demonstrated redistribution at 24 h. After revascularization 57 (92%) of these 62 segments revealed improvement of thallium uptake. On the other hand 40 (78%) of the 51 segments with persistently decreased thallium uptake until 24 h did not show improvement of uptake after revascularization. Of the 15 segments with > 50% relative thallium uptake and without redistribution on 24-h images, ten showed improvement of thallium uptake after revascularization. Hence higher uptake even without 24-h redistribution may indicate viability. Regional wall motion improved in 22 of 23 segments with redistribution on 24-h images, and did not improve after revascularization in 19 of 22 segments without redistribution at 24 h. These data suggest that 24-h late imaging with quantitative analysis may provide reliable information about reversible myocardial ischaemia in segments that demonstrate a fixed perfusion abnormality on conventional 3-h delayed imaging. PMID- 7859774 TI - Different kinetics of lung clearance of technetium-99m labelled diethylene triamine penta-acetic acid in patients with sarcoidosis and smokers. AB - The rate of clearance from the lungs of inhaled technetium-99m labelled diethylene triamine penta-acetic acid (99mTc-DTPA) is often increased in interstitial lung disease as well as in smoking. In smokers a bi-exponential clearance course of 99mTc-DTPA when measured over 3 h has previously been shown. This study was performed to compare the kinetics of clearance of 99mTc-DTPA, measured for 3 h, in sarcoid patients and healthy smokers. Forty-one never smoking patients with sarcoidosis and radiological signs of intrathoracic disease were studied. The results were compared with those of 16 healthy current smokers and of 14 healthy never-smokers reported previously. A mono-exponential clearance equation described the clearance in 22 of the sarcoid patients and all normal never-smokers, but with a shorter average tracer half-life in the patients (P < 0.05). In 19 patients and all smokers a bi-exponential equation gave a significantly better curve fit. The rate of clearance of the slow component was higher in patients with sarcoidosis than in smokers (P < 0.05). The fraction of the tracer cleared by the fast clearance component was smaller in patients with sarcoidosis than in smokers (P < 0.01). Differences in kinetics of clearance of 99mTc-DTPA in sarcoidosis and smoking could thus be demonstrated, suggesting that the abnormal clearance is caused by diverging pathophysiological mechanisms. PMID- 7859775 TI - Radiation doses to those accompanying nuclear medicine department patients: a waiting room survey. EANM Task Group Explaining Risks. European Association of Nuclear Medicine. AB - In a multi-centre European trial we have assessed the radiation dose to those accompanying patients undergoing nuclear medicine investigations. Dosemeters were first calibrated against each other and then used to measure the radiation dose to the nurse or relative while they were in the waiting room. In departments where there was one waiting room the median radiation dose was 13 microSv, and the corresponding figures for where there were two waiting rooms and where the patients were allowed to leave the department with their nurse or relative were 12 and 11 microSv, respectively. These figures are not significantly different. However, we found that the median radiation dose to relatives was 13 microSv while that to nurses was 3 microSv (P < 0.01), although the waiting times were not significantly different. The reasons for these differences are discussed. Our data do not support the need for a second waiting room for injected patients in a nuclear medicine department. PMID- 7859776 TI - Evaluation of pancreatic lipase activity by simple urine analysis after oral administration of a new iodine-131-labeled triglyceride. AB - A new iodine-131-labeled triglyceride analogue called "MIPAG" [1,2-dipalmitoyl-3 [(15-p-iodophenyl) pentadecan-1-oyl]rac-glycerol] has been prepared in which 15 (p-iodophenyl)pentadecanoic acid (IPPA) is attached to position-3. MIPAG has been developed for the evaluation of pancreatic exocrine function by simple urine analysis and has been evaluated in rats and humans. After oral administration, IPPA is released from the triglyceride by the action of pancreatic lipases followed by intestinal absorption and the principal IPPA metabolite (p iodobenzoic acid, IBA) is primarily excreted in the urine. Excretion in the urine and feces was evaluated in rats, as well as the biodistribution in various organs over 21 days. Twenty patients without pancreatic disease (normals) and four patients without pancreatic insufficiency were also investigated. Following oral administration of 30 microCi of MIPAG, urine was collected for two successive 24 h periods. Blood samples were drawn and thin-layer chromatographic (TLC) analysis was performed on the serum lipid extracts. Urine from normals contained 44.9% +/- 7.7% and 61.8% +/- 8.4% of the administered activity after 24 and 48 h, respectively. The patients with pancreatic insufficiency excreted 13.1 +/- 5.6% and 18.9% +/- 6.2%, respectively, which was significantly decreased (P < 0.001) compared with normals. The TLC profiles showed an increasing proportion of IBA with time. Urine analysis after oral administration of MIPAG thus appears to be an attractive new techniques for the evaluation of pancreatic lipase activity by a simple urine analysis. PMID- 7859777 TI - Experimental biodistribution studies of 99mTc-recombinant human serum albumin (rHSA): a new generation of radiopharmaceutical. AB - Recombinant human serum albumin (rHSA) produced by cultured fermentation has been prepared in the form of microcapsules nominally 3-5 microns in diameter and radiolabelled with technetium-99m following reduction with stannous chloride. Radiochemical purity was assessed by chromatography on instant thin-layer chromatography and found to be greater than 90%. No evidence of aggregation was seen by microscopic examination. Imaging biodistribution studies in New Zealand white rabbits demonstrated targeting to the liver or lung, respectively, depending upon the size and surfactant properties of the microcapsules. This communication is the first to show scintigraphic studies using 99mTc-labelled rHSA with the potential for lung, liver and cardiovascular imaging and demonstrates that recombinant DNA technology offers an important new source of materials suitable for use as radiopharmaceuticals without the need for pooled human blood products. PMID- 7859778 TI - Radiopharmaceuticals and the gastrointestinal tract. AB - A review is presented of the design of radiolabelled test meals for the evaluation of gastrointestinal function, including oesophageal transit, gastro oesophageal reflux, gastric emptying, enterogastric reflux and transit through the whole bowel. Descriptions of different systems are presented, together with validations of the procedures used. Published methods for assessment of oesophageal transit show a marked degree of consistency, whereas gastric emptying studies employ a wide range of both liquid and solid test meals. Recommendations are made concerning the optimal system for investigation of each part of the gastrointestinal tract, but whichever system is adopted, it is important to employ some validation procedures, and to establish normal ranges in the population under study. PMID- 7859779 TI - Brain single-photon emission tomography using technetium-99m bicisate (ECD) in a case of complex partial seizure. AB - The clinical application of technetium-99m bicisate (ethyl cysteinate dimer, ECD) for ictal and interictal studies of regional cerebral blood flow (rCBF) in a patient suffering from medically intractable simple and complex partial seizures is reported. The interictal study was performed 60 min p.i. and the ictal studies were performed at 60 min p.i. using an annular crystal single photon emission tomography (SPET) system dedicated for high-resolution brain SPET imaging. Visual evaluation of the studies was carried out, as well as semiquantitative measurement of regional tracer uptake. Magnetic resonance imaging (MRI) scans revealed atrophy of almost the complete left frontal lobe and the ventral parts of the left temporal lobe, including in part the temporomesial structures. The left parietal and occipital structures and the right hemisphere were normal. The interictal study showed a large perfusion defect involving the whole left frontal lobe as well as the left temporal lobe with remaining small areas of normal cortical tracer uptake. The ictal studies detected circumscribed hyperperfusion within the left mesial temporal lobe (ventral part of the hippocampus). Additionally an increase in perfusion could be seen within the entire remaining left temporal lobe. Semiquantitative evaluation of tracer uptake comparing both studies detected markedly increased uptake within the focus compared to the remaining left temporal lobe. On this basis the newly available tracer for studies of rCBF, 99mTc-bicisate, seems to be of value for the detection of epileptogenic foci. Additionally, the value of ictal rCBF studies in the presurgical evaluation of those patients presenting severe morphological alterations on MRI is clearly underlined by this case. PMID- 7859780 TI - Does technetium-99m bicisate image local brain metabolism in late ictal temporal lobe epilepsy? AB - Ictal increase in regional cerebral blood flow as judged by single-photon emission tomography (SPET) is a common phenomenon during focal epileptic seizures. Up to 2 min postictally, regional hyperperfusion is a consistent finding with technetium-99m hexamethylpropylene amine oxime (HMPAO) in temporal lobe epilepsy. A new 99mTc-labelled lipophilic cerebral blood flow imaging agent, bicisate, has considerably longer radiochemical stability and yields better image quality than 99mTc-HMPAO. In this report, we present the case of a 21-year-old female patient with temporal lobe complex partial seizures. Magnetic resonance imaging revealed right hippocampal sclerosis. A dose of 550 MBq of 99mTc-bicisate was injected 35 s after the onset of a seizure during intracranial EEG videotelemetry. At the moment of injection, subdural EEG demonstrated the beginning of late ictal discharges and postictal suppression in the right temporomesial areas. Late ictal SPET images showed marked right fronto-temporo parietal hypoactivity. The interictal SPET study clearly showed right frontotemporal hypoactivity. These preliminary data suggest that 99mTc-bicisate shows late ictal/early postictal hypoactivity which might represent the primary change in neuronal metabolism rather than the secondary change in cerebral blood flow. PMID- 7859782 TI - Bone scintigraphy versus human immunoglobulin scintigraphy in the clinical investigation of psoriatic arthropathy. PMID- 7859781 TI - Reduced bone marrow uptake of indium-111 labelled monoclonal antibody after radiotherapy. AB - Uptake of indium-111 in bone marrow is seen in patients who have received 111In labelled antibody. We report a case in which 111In uptake was not seen in the area of previous irradiation whereas fairly high uptake was noted in other bone marrow areas. 111In-labelled monoclonal antibody, which reacts with mucin, was injected into a patient with cancer of the sigmoid colon who had received radiotherapy for uterine cervical cancer 5 years previously. Marked accumulation of the antibody was observed in the tumour. Uptake of 111In in bone marrow was also seen except in the previously irradiated pelvic region. This phenomenon supports the idea that bone marrow uptake of 111In is the result of transchelation of 111In from antibody to transferrin. PMID- 7859783 TI - Exaggerated role of prone technique in breast cancer imaging with technetium-99m methoxyisobutylisonitrile. PMID- 7859784 TI - Do we really care about absorbed radiation dose. PMID- 7859785 TI - Progress and direction of gastrointestinal nuclear medicine. PMID- 7859786 TI - The pioneers of pediatric medicine. Allan Macy Butler (1894-1986). PMID- 7859787 TI - Acute alcohol intoxication among children and adolescents. AB - Severe toxicity from ethanol, manifested as coma, occurs at lower blood alcohol concentrations in young teenagers than in adults. Coma, vomiting and hypothermia are the commonest symptoms in young teenagers intoxicated by alcohol. The biochemical disturbances in children 11-16 years of age with alcohol intoxication resemble those of adults. Mild acidosis of a respiratory and metabolic origin and mild hypokalaemia are common findings in young teenagers. Young teenagers eliminate ethanol at the same rate as adults, whereas preschool age children are reported to eliminate ethanol twice as fast. The effect of ethanol on the state of consciousness is directly proportional to the blood alcohol concentration. Among small children the risk of hypoglycaemia is increased. Data on family history, social status, drinking habits, and children's motives for getting drunk are also of clinical importance. Fluid replacement with glucose-containing fluids and follow up are generally the only treatments needed for complete recovery. When children and adolescents are healthy, well-nourished and have not fasted, no severe complications are expected. PMID- 7859788 TI - Endoscopic ethanol injection for treatment of bleeding peptic ulcer. AB - We treated three children aged 10, 11 and 13 years with actively bleeding ulcers using local endoscopic injection of pure ethanol. Ethanol was injected into several sites around a visible vessel with or without bleeding. Haemostasis following ethanol injection therapy was confirmed by endoscopy performed the day after treatment. No rebleeding was observed. There were no complications related to the procedure. Injection therapy is technically simple and inexpensive. Conclusion Our results suggest that endoscopic ethanol injection is safe and may be the treatment of choice for control of bleeding from peptic ulcers in children. PMID- 7859789 TI - Weight/height2.88 as a screening test for obesity or thinness in schoolage children. AB - We wished to determine a weight for height measure for use as a simple screening test throughout the schoolage years for obesity or thinness similar to the body mass index in adults but not correlated with either height or age. Single measurements of height, weight, pubertal stage and two site skinfold thickness were collected on 979 healthy London schoolchildren (559 male) aged 4.6-18.8 years from 11 schools by one anthropometrist. Weight/height2.88 was uncorrelated with height or age in either sex. The median (95% confidence interval of the median) value for boys (12.74, 12.58-12.90) did not vary within this age group, height or pubertal stage. In girls the median value 12.46 (12.20-12.61) was valid for all girls less than breast stage 4 but rose sharply to 13.64 (13.21-14.06) thereafter. Percentile charts and nomograms are provided. Conclusion Weight/height2.88 may be a simple screening test for obesity or thinness throughout the schooling years and that its independence of age and height greatly simplifies longitudinal assessment. PMID- 7859791 TI - Association of antiphospholipid antibodies with systemic lupus erythematosus in a child presenting with chorea: a case report. AB - A 16-year-old girl, diagnosed 1 year previously as having Sydenham chorea, was found to have systemic lupus erythematosus according to the American Rheumatism Association criteria. She now presented with pulmonary emboli and renal involvement and responded to immunosuppressive and anticoagulant therapy. The high levels of anticardiolipin antibodies returned to normal along with the clinical symptoms. CONCLUSION: We suggest that anticardiolipin antibodies are relevant to the development of chorea and thrombo-embolic complications and that these auto-antibodies should be sought for in similar cases. PMID- 7859790 TI - Association of increased numbers of peripheral blood double-negative T lymphocytes with elevated serum IgG levels in severely handicapped children. AB - CD3+4-8- double negative cells in peripheral blood lymphocytes were examined in 21 severely handicapped children divided into two groups according to serum IgG level. All children were bedridden and were taking multiple anticonvulsants and there were no apparent clinical differences between these two groups. Serum levels of IgG correlated well with percentages of CD3+4-8- double negative lymphocytes in patients of both groups. In comparisons between the two groups, the high IgG group had higher counts of CD3+4-8- double negative lymphocytes in peripheral blood than the normal IgG group. Two distinct types of double negative cells were identified in the patients with high IgG: one had T-cell antigen receptors of gamma delta heterodimers, the other had receptors of alpha beta chains on their surface. As double negative T-cells are reported to have an important role in defence against bacterial infections, the increased numbers of CD3+4-8- T-cells of both phenotypes in the high IgG patients may reflect exposure to repetitive bacterial stimuli or persistent subclinical infection which in many cases, may be undetectable clinically. Moreover, the hyperimmune states shown by the high serum IgG of these patients may result from the appearance of these unique lymphocytes because they are reported to have a helper function for IgG synthesis in vitro. Taken together, the increased numbers of double negative cells in patients with high IgG may reflect activated defence mechanisms and the development of hyperimmune status. PMID- 7859792 TI - CD3-negative lymphoproliferative disease of granular lymphocytes in a girl with an unusual pattern of anti-Epstein-Barr virus antibodies. AB - We describe an 11-year-old girl who initially had mild hepatosplenomegaly and then presented with abnormal expansion of CD3-negative granular lymphocytes in peripheral blood and Epstein-Barr virus (EBV) genome in the DNA obtained from the peripheral blood mononuclear cells (PBMNC). After approximately 3 years, she developed oedema, ascites, marked hepatosplenomegaly, and pancytopenia, and showed both a profile of anti-EBV antibodies of reactivated infection and a high titre of anti-cytomegalovirus antibody. Although she was treated with antibiotics, ganciclovir, and prednisolone, she died of hepatic failure. CONCLUSION: Careful clinical observation, periodic examination of anti-EBV antibodies, and the analysis of EBV genome from PBMNC are needed in young patients with CD3-negative lymphoproliferative disease of granular lymphocytes. PMID- 7859793 TI - Acute childhood neuroborreliosis with a selective immune response to a low molecular weight protein expressed by Borrelia garinii. AB - In patients with Lyme borreliosis the early immune response to Borrelia burgdorferi is usually directed against the flagellin (41 kD) antigen. However, the sera of 4 out of 12 children with typical early neuroborreliosis contained antibodies to two low molecular weight proteins of 19 and 23 kD. These antibodies were demonstrated in serological tests using Borrelia garinii as antigen source. B. garinii is the species of B. burgdorferi sensu lato associated with neuroborreliosis. In contrast serological tests using B. burgdorferi sensu stricto, associated with arthritis, or using VS461 strains (B. afzelii), associated with chronic skin disease, were false-negative. Monospecific rabbit sera raised against the 23 kD protein of B. garinii strain W1 detected the 23 kD epitope in B. garinii isolates only. Results of serological tests for Lyme borreliosis may depend on the infecting strain and on the choice of the strain used as antigen source for diagnostic tests. The attending physician should interpret serological test results with care and rely on astute clinical judgement. PMID- 7859794 TI - Pulmonary effects of closure of patent ductus arteriosus in premature infants with severe respiratory distress syndrome. AB - The pulmonary effects of closure of a patent ductus arteriosus (PDA) were investigated in 11 premature infants with severe respiratory distress syndrome. Successful closure of a PDA did not improve the short-term severity of pulmonary disease (24 and 48 h after treatment) as judged by the arterial/alveolar oxygen tension ratio or the amount of ventilatory support. Also, pulmonary mechanics measured 24 h before, 24 and 48 h after treatment, were not statistically different. CONCLUSION: Infants with severe respiratory disease requiring high ventilation pressure and high oxygen concentration, where structural changes in the lungs are already established, will rarely show short-term improvement in pulmonary disease as a result of closure of a PDA. The overall clinical condition may, however, improve as a result of reduced cardiovascular strain. Earlier treatment of a PDA could reduce the ventilation period and the possible risk of developing chronic lung disease. PMID- 7859795 TI - Dicarboxylic aciduria, significance and prognostic indications. PMID- 7859796 TI - No white matter abnormalities in untreated patients with persistent hyperphenylalaninaemia: findings in magnetic resonance imaging. German PKU Collaborative Study. PMID- 7859797 TI - Growth hormone treatment in Turner syndrome. PMID- 7859798 TI - Communicating a drug alert. A case study on acitretin in The Netherlands. AB - In October 1990, a recall procedure was initiated for the teratogenic drug acitretin, and the recommended post-therapy contraception period after acitretin therapy was extended from 2 months to 2 years due to the possibility of its conversion to the lipophilic compound etretinate. The aim of the present study was to evaluate the communication procedures and their effects as a drug alert from the health authorities, the pharmaceutical company and professional associations of health professionals to the population at risk. A model was used to evaluate communication between three hierarchical levels. Data were obtained via semi-structured interviews and structured questionnaires. Communication procedures were evaluated according to channel characteristics and by analysis of their contents. The effect was measured as whether the drug dispensers identified acitretin users, contacted physicians, and whether physicians communicated in person with the population at risk. The penetration of direct mail from the health authorities and from the pharmaceutical company ranged from 97-98% and 65 94% at Level 2 (health professionals). The population at risk was informed via personal communication with health professionals, and/or the mass media. Of the women at risk, 19% were contacted by a dermatologist, 30% by their GP, and 39% by the pharmacist. 35% was never informed by any health professional. The Dutch health care system is adequately equipped for effective communication between health authorities, pharmaceutical industry and health professionals.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859799 TI - Safety and efficacy of lifibrol upon four-week administration to patients with primary hypercholesterolaemia. AB - The efficacy and safety of lifibrol, a novel cholesterol-lowering drug, was investigated in a double-blind clinical study in 168 patients with primary hypercholesterolaemia. Placebo and four lifibrol dose groups (150, 300, 450 and 600 mg/day) were tested over a period of 4 weeks. The mean LDL-cholesterol changes were 5.7%, -11.1%, -27.7%, -34.5% and -35.0%, respectively, after 4 weeks of treatment. No major changes in HDL-cholesterol were seen after this period. With the present study design, a decrease in triglycerides (-28%) was significant in the highest dosage group only. Additionally, it was shown that further independent risk factors for coronary heart disease were favourably influenced. Fibrinogen decreased in all dosage groups with a maximal mean value of 18% and a tendency toward reduction in lipoprotein (a) was observed in patients with high baseline levels (> 30 mg.dl-1). Lifibrol was generally well tolerated in all dosage groups and no serious adverse events were reported. Laboratory parameters did not show any clinically relevant alterations. PMID- 7859800 TI - Suppression of respiratory burst of polymorphonuclear leukocytes by azelastine hydrochloride (Azeptin). AB - The inhibitory action of azelastine hydrochloride (Azeptin) on the respiratory burst in peripheral polymorphonuclear leukocytes (PMN) and pulmonary alveolar macrophages (PAM) has been studied. Azeptin in vitro suppressed chemiluminescence and superoxide (O2-) generation by human PMN in a dose- and time-dependent manner. Phorbol myristyl acetate (PMA) and formyl-methionyl-leucyl-phenylalanine (FMLP)-induced O2- generation were strongly suppressed by 10(-6) M and 10(-5) M Azeptin, respectively. PMN and PAM from rabbits injected with Azeptin 0.2 mg.kg-1 for 5 days showed lower chemiluminescence and O2- generation than cells from untreated rabbits. Nitroblue tetrazolium reduction activity in human PMN was suppressed by treatment of PMN with 10(-6) M Azeptin for 6 h. Inositol trisphosphate, intracellular free calcium, and protein kinase C activity were decreased by 10(-6) M to 10(-5) M Azeptin. The tyrosine phosphorylation of many proteins, especially a 115 kDa protein, was suppressed by 10(-5) M Azeptin. However, superoxide dismutase activity in PMN, PAM, and lung tissue samples was only slightly decreased, even when the rabbits were treated with 1.0 mg.kg-1 Azeptin for 5 days. The results suggest that Azeptin suppresses multiple signal transduction steps in the respiratory burst of PMN. This suppressive action should be very useful in the prevention and treatment of reactive oxygen associated disorders. PMID- 7859801 TI - Angiotensin converting enzyme inhibition does not affect response to exogenous angiotensin II in the forearm of mild-moderate hypertensive patients. AB - It has been proposed that the suppression of endogenous levels of angiotensin II by angiotensin converting enzyme inhibition, may result in up-regulation of vascular AT1 receptors. This study evaluated the effects of orally administered enalapril on angiotensin II induced vasoconstriction in the human forearm of patients with mild-moderate hypertension. Patients received in random order, enalapril (20 mg) or matched placebo daily for 2 weeks. Forearm blood flow response to increasing doses of angiotensin II was measured using venous occlusion plethysmography at the beginning of the study and at the end of each 2 week treatment period. Treatment with enalapril significantly reduced plasma angiotensin II levels and supine blood pressure compared to placebo. The percentage reductions in forearm blood flow in the infused arm, in response to the maximum dose of angiotensin II (50 pmol.min-1) were 53.2% at baseline, 51.4% on placebo and 59.5% on enalapril. The differences were not significantly different. This study demonstrates that suppression of plasma angiotensin II does not enhance the response to exogenous intra-arterial angiotensin II in the human forearm of mild-moderately hypertensive patients. PMID- 7859802 TI - Characteristics of plasma protein binding of tacrine hydrochloride: a new drug for Alzheimer's disease. AB - The aim of this study was to characterise the plasma protein binding of tacrine hydrochloride (THA) in vitro. Binding was assessed in the plasma of 11 healthy individuals aged 20 to 27 years using ultrafiltration followed by HPLC assay. At THA concentrations from 10 to 100 ng/ml protein binding ranged from 78.6 to 71.0%. Binding to commercially available human albumin ranged from 41.7 to 38.3% and to human alpha 1-acid glycoprotein from 23.1 to 12.4% over the THA concentrations from 25 to 100 ng/ml. THA binding and total plasma protein, plasma albumin and alpha 1-acid glycoprotein were measured in healthy young subjects (n = 13), healthy elderly individuals (n = 12) and patients hospitalised with acute illnesses (n = 8). There were significant differences between the groups in total plasma protein, plasma albumin and in alpha 1-acid glycoprotein but no differences in the protein binding of THA which remained constant at about 75%. There was no correlation between THA binding and any plasma protein concentration. The THA binding was not high enough to be of major significance clinically or to reduce the validity of total plasma THA measurement in therapeutic monitoring. PMID- 7859803 TI - Pharmacokinetics of torasemide and its metabolites in end-stage renal disease. AB - The pharmacokinetics of torasemide, a new loop diuretic, as well as its active metabolites M1 and M3, and its inactive main metabolite, M5, were studied in 12 patients with end-stage renal failure during single i.v. (n = 6) or single oral (n = 6) dosing of 200 mg torasemide, and during chronic oral treatment for 9 days (n = 12). The elimination half-life (t1/2) of torasemide was unchanged in renal failure, whereas t1/2 of the torasemide metabolites M1, M3, and M5 were markedly prolonged. However t1/2 as well as the area under the plasma level time curve of torasemide and its metabolites were unchanged during chronic compared to acute administration. The results of this study suggest that despite the increased half life of torasemide metabolites M1, M3 and M5 in end-stage renal failure patients, no accumulation of the parent drug torasemide and its metabolites during chronic dosing is demonstrable. PMID- 7859804 TI - The effect of renal impairment on the pharmacokinetics of oxcarbazepine and its metabolites. AB - We have studied the effect of renal impairment on the pharmacokinetics of oxcarbazepine, its active monohydroxy-metabolite (which predominates in plasma), their glucuronides, and the inactive dihydroxy-metabolite after a single oral dose of oxcarbazepine (300 mg). Six subjects with normal renal function and 20 patients with various degrees of renal impairment participated. The mean areas under the plasma concentration-time curves of oxcarbazepine and its monohydroxy metabolite were 2-2.5-times higher in patients with severe renal impairment (CLCR < 10 ml.min-1) than in healthy subjects. The apparent elimination half-life of the monohydroxy-metabolite [19 (SD 3) h] in these patients was about twice that in healthy subjects. The effect of renal impairment on the plasma concentrations of glucuronides was more marked. The renal clearances of the unconjugated monohydroxy-metabolite and its glucuronides (the main compounds recovered in urine) correlated well with creatinine clearance. The maximum target dose in patients with slight renal impairment (CLCR > 30 ml.min-1) should not be changed. In patients with moderate renal impairment (CLCR 10-30 ml.min-1) it should be reduced by 50%. In patients with severe renal impairment (CLCR < 10 ml.min-1), the glucuronides of oxcarbazepine and its monohydroxy-metabolite are likely to accumulate during repeated administration, and dosage adjustment of oxcarbazepine in these patients could not be proposed from this single administration study. PMID- 7859806 TI - Comparative pharmacokinetics of bismuth from ranitidine bismuth citrate (GR122311X), a novel anti-ulcerant and tripotassium dicitrato bismuthate (TDB). AB - GR122311X (ranitidine bismuth citrate, Glaxo Group Research Ltd.) is a salt of ranitidine with a complex of bismuth and citric acid which is being developed for the treatment of peptic ulceration. In this study, 4 groups of 12 healthy male subjects were dosed for 10 days with either GR122311X 500 mg bid (301 mg bismuth per day), GR122311X 1.0 g bid (602 mg bismuth per day), tripotassium dicitrato bismuthate (TDB, DeNoltab, Gist Brocades Ltd., Weybridge, England) 240 mg bid (431 mg bismuth per day) or placebo. After the last dose the geometric mean for Cmax for 500 mg bid of GR122311X was 5 ng.g-1, for 1.0 g bid GR122311X it was 12 ng.g-1 and it was 21 ng.g-1 for 240 mg TDB bid. The corresponding trough plasma levels were 2 ng.g-1, 4 ng.g-1 and 4 ng.g-1, respectively. The AUC over a dosing interval after the last dose (AUC tau) were 34 ng.h.g-1, 71 ng.h.g-1 and 79 ng.h.g-1, respectively. The bismuth urinary recoveries over the last dosing interval (Ae tau) were 97 micrograms, 227 micrograms and 309 micrograms, respectively, which is less than 1% of the administered doses. The renal clearance of bismuth was less than the glomerular filtration rate. After adjustment for bismuth dose, the Cmax for GR122311X 500 mg was 35% that of TDB, while for GR122311X 1.0 g the Cmax was 42% that of TDB. Similar differences were observed for Ae tau. In conclusion bismuth pharmacokinetics after oral administration of GR1223311X exhibited lower Ae tau and Cmax, with a much narrower Cmax range than those observed for TDB. PMID- 7859807 TI - Pharmacokinetics of intravenous omeprazole in children. AB - This study was undertaken to define the pharmacokinetics of omeprazole in children and included 13 patients, heterogeneous in terms of age (0.3 to 19 years), underlying disease and biological constants, indication of omeprazole administration and associated therapy. The dose administered ranged from 36.9 to 139 mg.1.73 m-2. The pharmacokinetic parameters of omeprazole were: systemic clearance, 0.23 l.kg-1.h-1; volume of distribution, 0.45 l.kg-1; elimination half life 0.86 h; but were highly variable between individuals. Dosage, differences in hepatic and renal function and associated therapy may contribute to inter individual variability. Within the range of doses administered, the pharmacokinetic parameters were similar to those reported in adults. The drug has been well tolerated in all children. PMID- 7859805 TI - Cholesterol malabsorption caused by sitostanol ester feeding and neomycin in pravastatin-treated hypercholesterolaemic patients. AB - Serum cholesterol values were insufficiently reduced by pravastatin in two different patient populations. Therefore, we studied whether further cholesterol reduction could be achieved by inhibiting both cholesterol synthesis (by pravastatin) and absorption (by neomycin or sitostanol ester). Thus, we measured serum cholesterol, cholesterol precursors (reflecting cholesterol synthesis), cholestanol and plant sterols (reflecting cholesterol absorption and biliary secretion) for up to 6 weeks in pravastatin-treated patients with familial hypercholesterolaemia (FH, n = 13) and with and without ileal bypass during addition of neomycin (1.5 g per day) and in another patient population of non-FH (n = 14) subjects during addition of sitostanol ester (1.5 g per day). Addition of neomycin lowered serum total, LDL and HDL cholesterol by a further 20%, and increased the pravastatin-lowered precursor:cholesterol ratios by 20% (irrespective of ileal bypass). It also reduced by 20% the plant sterol:cholesterol ratio (irrespective of ileal bypass) which was markedly increased by pravastatin alone. Pravastatin and neomycin in combination lowered total, LDL and HDL cholesterol by 45%, 53% and 17%, respectively. This combined regimen reduced the serum lathosterol:cholesterol ratio to about half of the reduction caused by pravastatin, while the elevation of the plant sterols:cholesterol ratio was less with the combination than with pravastatin alone. Changes in serum cholesterol precursor:cholesterol and plant sterol:cholesterol ratios during the combined treatment were smaller in the subgroup with ileal bypass. Addition of sitostanol ester did not lower serum total or LDL cholesterol nor the precursor:cholesterol ratios significantly, while the reduction observed in the plant sterols:cholesterol ratios was similar to that achieved with neomycin addition.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859808 TI - Pharmacokinetic analysis of sparse in vivo NMR spectroscopy data using relative parameters and the population approach. AB - NMR spectroscopy in vivo when applied to studying drugs and their metabolites usually measures relative concentration in a tissue over time. Only ratios of clearance and volume parameters can be estimated from these data. Low drug dosages (relative to the sensitivity of in vivo NMR) or rapid drug elimination create the additional problem of data sparsity where a pharmacokinetic model cannot be fitted individually. We have investigated whether relative and absolute pharmacokinetic parameters can be estimated from such data by applying a population model. The data analysed were relative concentrations of 5 fluorouracil (FU) and of the sum of its catabolites alpha-fluoro-beta-ureido propanoic acid (FUPA) and alpha-fluoro-beta-alanine (FBAL) in the liver, as monitored in 16 cancer patients by [19F]-NMR spectroscopy during and after a 10 min intravenous infusion of 650 mg FU.m-2. The "structural" part of the population model was a non-linear, two-compartment model featuring one FU compartment with volume VFU, a saturable clearance of FU by conversion into the catabolites where CL = vmax/(kM+CFU), a catabolite compartment with volume Vcat, and a concentration-independent clearance of the catabolites, CLcat. The parameters actually fitted were: gamma, vmax, kM.VFU, Vcat/VFU, and CLcat/Vcat where gamma is a proportionality factor relating the NMR signal intensity of FU to the amount of FU in the body and, therefore, has no purely pharmacokinetic interpretation. All parameters were checked for random interindividual variation: gamma and vmax were also tested for inter-occasion variation. The program system NONMEM was used for model fitting.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859810 TI - Cost evaluation of a new iv device in an Israeli hospital. AB - A new device for IV admixtures has been developed in Israel, the Vialink minibag. It consists of a partly filled minibag, attached by rubber tubing to a sterile receptable into which various types of vials containing drugs can be firmly inserted. Time and motion studies were conducted to determine the time and cost associated with the preparation, dispensing and administration of reconstituted parenteral antibiotics via CIVAS (within minibags or Vialink bags) and preparation by nurses in wards in minibags. CIVAS with minibags was least expensive, followed by Vialink minibags. Self preparation on the ward by nurses was found to be the most expensive system. Only 55% of all IV admixtures can be prepared by the Vialink system. As only one hospital in Israel has CIVAS, the study provides a solid justification for implementing pharmacy intravenous admixture services in all Israeli hospitals. The advantages and disadvantages of each method are discussed. CIVAS (minibags and Vialink) permits the individualised preparation of sterile admixtures for each patient and provides advantages in terms of efficiency, economy and prevention of errors. PMID- 7859809 TI - Using ofloxacin as a time marker in hair analysis for monitoring the dosage history of haloperidol. AB - Hair samples were obtained 1-5 months after ingestion of the antimicrobial ofloxacin, which had been given for 1 or 3 days at the commencement of haloperidol administration, or when its dosage was reduced. The axial distribution of ofloxacin, haloperidol and its active metabolite, reduced haloperidol, was analysed in segments from single strands of hair. Ofloxacin was detected where the content of haloperidol and reduced haloperidol along the hair shaft showed a sharp change, corresponding to the change in dose. When we matched the time scale of the dosage history to the growth rate, which was estimated using ofloxacin as the time marker, the distribution of the haloperidol and reduced haloperidol precisely coincided with the rise and fall in the dose of haloperidol. These findings demonstrate that ofloxacin can serve as a time marker when drug distribution along the hair shaft is used to obtain the drug exposure history of an individual. PMID- 7859811 TI - Glucuronidation clearance of 8-hydroxyclomipramine in relation to sparteine and mephenytoin phenotype. PMID- 7859812 TI - Identification of phosphoinositide-specific phospholipase C-beta 1 and GTP binding protein, Gq alpha, in bovine iris sphincter membranes: characteristics of the phospholipase and its coupling to cholinergic muscarinic receptors. AB - Previously, we have established that treatment of iris sphincter smooth muscle with carbachol (CCh) results in increased phospholipase C (PLC)-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) into 1,2 diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) and in muscle contraction. To throw more light on the mechanism of muscarinic stimulation of PLC in this tissue we have investigated the properties of this enzyme and its regulation by GTP analogs and protein phosphorylation in bovine iris sphincter membranes. The data obtained can be summarized as follows: (1) the presence of PLC-beta 1 and a GTP-binding protein, Gq alpha, was detected in the microsomal (membrane) fraction by anti-PLC beta 1 and anti-Gq alpha antibodies, respectively. The membrane PLC hydrolysed exogenously added PIP2 and this hydrolysis was increased dose-dependently by Ca2+ (1-10 microM) but the enzyme activity was inhibited by Mg2+. (2) Addition of guanosine 5'-O-thiotriphosphate (GTP gamma S, 0.1 microM) to the membrane fraction increased PIP2 hydrolysis by 30%, whereas addition of CCh (10 microM) was without effect. However, when added together, CCh and GTP gamma S increased PIP2 hydrolysis by 46%. This effect was significantly inhibited by atropine and by the anti-PLC-beta 1 and anti-Gq alpha antibodies. (3) Removal of PLC-beta 1 from the membranes with 2 M KCl resulted in a significant reduction of the CCh-induced PIP2 hydrolysis, and this effect of the muscarinic agonist was restored when the membrane fraction was supplemented with PLC-beta 1 purified from bovine brain.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859813 TI - Paracrine role of keratinocyte growth factor in rabbit corneal epithelial cell growth. AB - Keratinocyte growth factor (KGF), a member of the fibroblast growth factor (FGF) family, is expressed in stromal fibroblasts and acts specifically on cells of epithelial origin as a paracrine mediator. In this study, we examined KGF and KGF receptor (KGF-R) mRNA expression in rabbit corneal epithelial cells and keratocytes, using a reverse transcription polymerase chain reaction (RT-PCR) method. We also examined the effects of KGF on the proliferation of rabbit corneal cells in vitro. mRNA from cultured rabbit skin fibroblasts, conjunctival fibroblasts, corneal epithelial cells and keratocytes was first reverse transcribed, and then amplified by PCR using primers specific for KGF and KGF-R. KGF mRNA was expressed in skin fibroblasts, conjunctival fibroblasts and keratocytes, but not in corneal epithelial cells. In contrast, KGF receptor mRNA was expressed in corneal epithelial cells, but not in skin fibroblasts, conjunctival fibroblasts or keratocytes. The results of Southern hybridization experiments of PCR products also showed that KGF mRNA was expressed in skin fibroblasts, conjunctival fibroblasts and keratocytes, whereas KGF receptor mRNA was expressed in corneal epithelial cells. Nucleotide sequencing of the PCR products revealed that their sequences were identical to the expected nucleotide sequences. Using the methylene blue method, we found that KGF enhanced the growth of cultured rabbit corneal epithelial cells, but not keratocytes, at a concentration of 0.01 to 100 ng ml-1. Furthermore, KGF also augmented 3H thymidine incorporation into the corneal epithelial cells. These results suggest that KGF is a paracrine mediator of the proliferation of corneal epithelial cells as well as of keratinocytes in the skin. PMID- 7859814 TI - Combined elastic and Raman light scattering of human eye lenses. AB - The distribution of the scattering coefficient (as defined in the appendix) at a wavelength of 647.1 nm along the visual axis of human eye lenses was investigated using a specially designed set-up for spatially resolved measurements of the intensity of the scattered light. For the same lenses, the distribution of the protein content was measured using confocal Raman microspectroscopy. Data collected by both methods were processed in terms of a recently developed theory of short-range, liquid-like order of crystallin proteins that accounts for eye lens transparency. Seven fresh intact human lenses of varying age have been investigated. In addition, elastic and Raman scattering measurements have been performed on fixed lenses. The main results and conclusions are: (1) Fixation significantly affects the light scattering properties of the eye lens. The average level of scattering increases and a change in the distribution of scattered light intensity along the visual axis occurs. Protein content and average distribution were not altered by fixation. (2) There are significant differences between the distribution of the scattering coefficient for lenses of different ages. For young lenses (18 and 20 years) regions with a low protein content (anterior and posterior cortex) show a higher level of elastic light scattering, while for older lenses (42-78 years old) there is no obvious correlation between the scattering level and protein content. (3) Changes in the level of light scattering along the visual axis of the lens cannot be explained by protein concentration effects.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859815 TI - Altered proportions of RCS-rat eyes. AB - The growth pattern of RCS-rat eyes with hereditary retinal degeneration was analysed morphometrically, evaluating midsagittal sections of the entire globe and sections of the chamber angle region. No changes of the axial diameter of RCS rat eyes were found if compared with eyes of age-matched controls. There were, however, characteristic proportional changes in the anterior eye segment of RCS rats. The distance between the peripheral end of Descemet's membrane (DM) and both the posterior end of Schlemm's canal and the ora serrata were significantly elongated indicating that this region might be most susceptible to growth factors. The length of the posterior globe up to the level of the ora serrata was shorter in RCS rats than in control rats. In addition, in RCS-rat eyes the pars plana was significantly elongated and the pars plicata shortened. Ultrastructural changes of ciliary epithelium were not seen before 7 months of age in RCS rats. They were only present in those parts of the circumference in which the stromal capillaries also revealed structural changes. The ciliary epithelial alterations were therefore considered secondary to narrowing or rarefication in the adjacent blood vessels. PMID- 7859817 TI - Role of neutrophils in breakdown of the blood-retinal barrier following intravitreal injection of platelet-activating factor. AB - Breakdown of the blood-retinal barrier occurs in inflammatory conditions and in ischemic retinal diseases such as diabetic retinopathy. Platelet-activating factor (PAF) is a potent inflammatory mediator which increases vascular permeability. The purpose of this study was to determine if intravitreally injected PAF would cause breakdown of the blood-retinal barrier and, if so, by what mechanism. Fluorescein angiography was performed before and at 0.5, 1, 2, 3 and 4 hr after PAF injection into the vitreous cavity of rabbit eyes and the eyes were enucleated immediately for light and electron microscopy. Slow flowing thrombi were observed in all PAF-injected eyes. Complete vascular occlusion was observed in 10 of 16 eyes after 3 and 4 hr. There was no fluorescein leakage in any of eyes before or at 0.5 or 1 hr after PAF injection. Fourteen of 20 eyes had fluorescein leakage at 2, 3 and 4 hr after PAF injection. The extent of fluorescein leakage correlated with the degree of polymorphonuclear leukocyte (PMN) margination, disruption of the endothelial cell layer, infiltration into vascular walls and migration into the vitreous cavity. PMNs appeared to migrate by both intercellular and transcellular routes across the endothelium. Pretreatment of rabbits with a PAF inhibitor, BN52021, prevented most of the abnormal findings. PMID- 7859816 TI - Drusen-like deposits in the outer retina of Japanese quail. AB - Histological examination of the outer retina of Japanese quail (Coturnix coturnix Japonica) ranging in age from 4-48 months revealed the presence of drusen-like deposits which closely resemble those described in primate and human retinas. At both light and electron microscopic levels, these deposits were characterized by randomly distributed, granular and heterogenous materials. Larger deposits with pleomorphic inclusions, often globular in shape, occurred more frequently in older quail, particularly in males. An increase in the incidence and size of drusenoid deposits occurred with increasing age, with a greater rate of accumulation in males than in females. Previously, we have shown that retinal pigment epithelial lipofuscin increases more rapidly with age in female quail and that cumulative light damage is associated with increased lipofuscin in females but not in males. In the present study, no increase in drusen-like deposits was observed in single light-damaged or double light-damaged retinas of either sex. Thus, lipofuscin and the frequency and size of drusenoid deposits do not appear to be directly linked, although both increase with age in both sexes. PMID- 7859818 TI - Microdialysis measurement of catecholamines in rabbit vitreous after retinal laser photocoagulation. AB - A method of intravitreous microdialysis in vivo is used to measure the vitreal concentration of catecholamines and their metabolites after laser panphotocoagulation of rabbit retina. Noradrenaline, dopamine and dihydroxyphenylacetic acid could be measured. No significant immediate effects of laser coagulation on their concentration could be demonstrated. After 4 days an increase in dihydroxyphenylacetic acid was observed, which subsided after 7 days. At that moment a slight increase of vitreous dopamine was noted. PMID- 7859819 TI - Transferrin, one of the major vitreous proteins, is produced within the eye. AB - Transferrin occurs in the vitreous at a higher relative concentration than found in the plasma or in the aqueous humor. This has been related to a possible local synthesis of transferrin by some component of the eye, although convincing evidence for this has not been available. Recently, the intraocular synthesis of several vitreous glycoproteins, possibly by the ciliary body, was demonstrated by our group. This paper reports experiments that characterize vitreous transferrin as one of these glycoproteins. Vitreous of rabbits injected intravitreally either with 3H-fucose or 3H-tyrosine and killed 40 hr after the injection was processed for 1D and 2D-electrophoresis, followed by immunoblot techniques or fluorography. It was possible to detect a labeled polypeptide with the same molecular weight and pI of rabbit plasma transferrin. Furthermore, this labeled polypeptide could be specifically eluted from columns of Sepharose conjugated with antibody against rabbit plasma transferrin. Thus, these results demonstrate that at least part of the transferrin of the vitreous is synthesized within the eye. PMID- 7859820 TI - Recoverin: a potent uveitogen for the induction of photoreceptor degeneration in Lewis rats. AB - Recoverin is a calcium-binding protein identified as an autoantigen in a paraneoplastic degenerative disease of the human retina known as cancer associated retinopathy (CAR). In this study we investigated whether recoverin could elicit an immune response leading to the degeneration of photoreceptor cells in a rodent retina, and whether an animal model of CAR could be developed. Injection of Lewis rats with recoverin caused degeneration of the photoreceptor cells. Several features of uveoretinitis were observed, including vitreous cells, perivasculitis, retinal lesions and complete loss of the photoreceptor cell layer. The first clinical signs of retinal inflammation were observed 10-14 days after immunization. The earliest histological changes in the retina also were observed 14 days after immunization. Infiltration of the photoreceptor cell layer and inner layers of the retina with lymphocytic and some polymorphonuclear cells was frequently observed. Photoreceptors were damaged and later fully degenerated. This sequence of events was associated with high antibody titers against recoverin in all animals tested. Cellular responses to recoverin assayed between days 7 and 28 after immunization showed strong in vitro proliferative activities to recoverin. In addition, all aspects of the degenerative events could be reproduced in naive animals by the adoptive transfer of stimulated lymphocytes obtained from animals previously immunized with recoverin. This study demonstrates the successful induction of photoreceptor degeneration using recoverin as an immunogen. We demonstrate that recoverin is both a potent antigen and uveitogen. These observations may be relevant to our understanding of CARs in humans. PMID- 7859821 TI - The oxygen distribution in the prelaminar optic nerve head of the cat. AB - Oxygen-sensitive microelectrodes were used to measure oxygen profiles from the prelaminar region of the cat optic nerve head. From the profiles, the oxygen distribution of this tissue was determined. Changes in oxygen levels in response to flicker stimulation were obtained. Also, the regulatory ability of this tissue was assessed by acutely increasing IOP and by presenting the cat with periods of hyperoxia. The cells in the optic nerve head were found to exist in the same oxygen environment as cells of the inner retina. Oxygen tensions usually varied between 0 and 40 mmHg, with the mean being between 10 and 20 mmHg. There was no difference in oxygen levels between central and peripheral parts of the optic nerve head, nor was there a difference as a function of depth. Different levels of light adaptation of the retina had no effect on oxygen levels in the optic nerve head, but flicker stimulation of the retina resulted in decreases in tissue oxygen tension. A small number of experiments in which the intraocular pressure was raised showed that oxygen levels in the optic nerve head were not drastically altered during acute decreases in perfusion pressure. Based on the size of changes in tissue oxygen tensions during hyperoxia, it appeared that blood vessels in the optic nerve head constricted in response to systemic hyperoxia. PMID- 7859822 TI - Protein alterations in age-related cataract associated with a persistent hyaloid vascular system in senescence-accelerated mouse (SAM). AB - The occurrence of age-related cataract associated with a persistent hyaloid vascular system is the most prominent feature in SAMP9, an inbred strain of Senescence-accelerated Mouse. To examine the cataractogenesis, we analysed protein changes in the process of cataract formation in the lens. The cataractous lenses showed a striking decrease in water-soluble protein content, in contrast to increases in the amount of water insoluble protein. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and Western blots of water-soluble protein in the cataractous lenses showed additional high molecular weight beta crystallin proteins of about 43 kDa, concomitant with decreased amounts of 29-kDa and 31-kDa beta-crystallins and 21-kDa gamma-crystallin, as compared with findings in normal lenses. Although there was no apparent difference between the patterns of SDS-PAGE of urea-soluble and urea-insoluble proteins isolated from cataractous and normal lenses, slightly increased reactivity of bands around 43 kDa against anti-beta-crystallin antibody was observed in cataractous lenses. The calcium content was elevated and activity of transglutaminase was increased in the cataractous lenses. While the molecular weight of beta-crystallin polymers cross-linked in vitro by exogenous transglutaminase was not completely compatible with those of high molecular weight beta-crystallins observed in the cataractous lenses, these findings do suggest the contribution of this enzyme to production of high molecular weight beta-crystallins and to insolubilization of these proteins in the cataractous lenses in SAMP9. PMID- 7859823 TI - Prevention of collagen crosslinking increases form-deprivation myopia in tree shrew. AB - To examine whether collagen crosslinking is important for the regulation of refractive development, tree shrews were treated with agents that block collagen crosslinking [beta-aminoproprionitrile (beta-APN), or D-penicillamine (DPA)] and underwent monocular deprivation (MD) of form vision by eyelid closure to induce myopia. MD began on the first day of visual exposure and continued for 75 days. After 15-20 days of visual exposure, daily intraperitoneal injections of beta-APN (beta-APN MD animals, n = 5) or DPA (DPA MD animals, n = 5) were administered for 17-21 days. beta-APN open animals (n = 5) received the same injection schedule, but both eyes remained open. Saline MD animals (n = 5) received i.p. saline and MD. At 75 days of visual exposure, the MD eyes of beta-APN treated tree shrews were highly myopic (-23.6 +/- 3.3 D) in comparison to their open control eyes. This was markedly greater than the difference in saline MD animals (-11.0 +/- 0.8 D). DPA MD animals showed a relative myopia of -14.3 +/- 2.2 D. The structural correlate of the myopia, elongation of the vitreous chamber in the deprived eyes relative to the control eyes, was significantly greater in the beta-APN MD animals 0.53 +/- 0.03 mm, which was not significantly different from the saline MD group. Thinning of the posterior sclera, but not the cornea, was observed in the deprived eyes of beta-APN treated tree shrews, along with a tessellated appearance to the fundus. The eyes of the beta-APN open animals showed no significant differences from normal. Beta-APN MD and DPA MD treated chickens did not develop greater myopia or vitreous chamber elongation than standard MD chickens. The selective effect of the lathyritic agents on the deprived eyes in tree shrew suggests that collagen crosslinking interacts, in the mammalian sclera, with a retinally-derived signal to regulate the elongation of the eye in myopia. PMID- 7859824 TI - Blood-to-lens transport of reduced glutathione in an in situ perfused guinea-pig eye. AB - Transport mechanisms of reduced glutathione (GSH) in intact eye are poorly understood. In this study, an in situ vascular eye perfusion (VEP) model was used to characterize the transport kinetics of circulating GSH into the aqueous humor and lens in guinea pigs. Radiolabeled [35S]GSH or [3H]GSH and [14C]sucrose (an extracellular space marker) were exposed to the blood-aqueous barrier up to 10 min, and uptake of tracers by the aqueous humor and lens was determined in the presence of different concentrations of unlabeled peptide as GSH, a gamma glutamyl compound as a derivative of GSH (GSH monoethyl ester), and an inhibitor of gamma-glutamyl transpeptidase (GGT) activity. Plasma-aqueous and aqueous-lens compartmental unidirectional transport constant, K(in), and the initial rapid volume of distribution, Vi, were estimated by multiple-time-point graphic analysis. Our results indicated that both labeled GSH and sucrose entered the aqueous humor slowly at comparable rates with respective blood-aqueous K(in) values of 1.34 +/- 0.12 and 1.25 +/- 0.08 min-1 x 10(3). In contrast to blood aqueous transport, GSH uptake by the lens was rapid, and the respective aqueous lens K(in) values for labeled GSH and sucrose were 79.3 +/- 4.1 and 3.5 +/- 0.7 min-1 x 10(3). Over 94% of plasma-derived GSH remained in its original molecular form of GSH in the lens, during the 10 min perfusion both with and without the GGT inhibitor, serine borate. The amount of [35S]GSH in lens anterior epithelium (dpm mg-1) was more than three times that of aqueous humor (dpm microliter-1) within only 10 min of VEP. There was also significant accumulation of [35S]GSH in the interior cortex, as indicated by 10-min cortex/aqueous ratio of 0.65. A specific GGT independent GSH transport system was demonstrated in the lens in situ, with a Km of 26 +/- 3 microM, and Vmax of 34 +/- 3 pmol min-1 g-1 of whole lens tissue water. The lenticular influx of GSH was inhibited by GSH monoethyl ester with an affinity that was half that for GSH. It is concluded that: (a) uptake of plasma-derived GSH into the aqueous humor is by simple diffusion, and (b) cellular uptake of GSH by the lens is carrier-mediated via mechanism that is separate from the transpeptidation metabolic pathway. PMID- 7859825 TI - Methylglyoxal concentration and glyoxalase activities in the human lens. AB - The activities of glyoxalase I and glyoxalase II and the concentration of methylglyoxal were determined in 26 human lenses. The activity of glyoxalase I (mean +/- S.D.) was 15.62 +/- 3.90 U (g wet weight)-1 and the activity of glyoxalase II was 0.189 +/- 0.087 U (g wet weight)-1 (n = 26). The concentration of methylglyoxal of the human lenses was 1.78 +/- 0.84 nmol (g wet weight)-1 (n = 26). There was a significant negative correlation of both the activity of glyoxalase I and the activity of glyoxalase II with subject age but no correlation of methylglyoxal concentration with subject age. The concentration of methylglyoxal in the lenses was approximately 20-fold higher than in blood samples from normal human subjects. Given the previously reported decrease in the concentration of reduced glutathione in the human lens with age, there is expected to be a marked decrease in in situ activity of glyoxalase I and concomitant susceptibility of human lens proteins to modification by methylglyoxal with age. The metabolism of methylglyoxal and the formation of methylglyoxal-modified proteins may be linked to the development of senile and diabetic cataract. PMID- 7859826 TI - Buthionine sulfoximine induced cataracts in mice contain insolubilized crystallins with calpain II cleavage sites. PMID- 7859827 TI - GM-CSF and M-CSF expression is associated with macrophage proliferation in progressing and regressing rabbit atheromatous lesions. AB - Recent studies have documented that macrophages are a significant cell component of atherosclerotic lesions and may play a significant role in the pathogenesis of these lesions. It has also been documented that markers of cell proliferation (e.g., the proliferating cell nuclear antigen) can be expressed by macrophage subpopulations in atherosclerotic lesions, and there is great interest in identifying cell mediated factors which might be instrumental in macrophage proliferation in this context, perhaps accounting for the persistence of macrophages within this context. Important candidates for this function include granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony stimulating factor (M-CSF); the latter has been previously demonstrated to be expressed in human and rabbit atherosclerotic lesions. We have extended these studies by studying immunocytochemical localization of GM-CSF and M-CSF in progressing and regressing lesions of cholesterol-fed rabbits, documenting expression of these factors predominantly in macrophages, but also in some smooth muscle-cells and endothelial cells. The simultaneous documentation of macrophage subpopulations expressing the proliferating cell nuclear antigen in the same lesions provides evidence to support the hypothesis that macrophage GM-CSF and M CSF production represents a factor underlying macrophage proliferation and accumulation in atherosclerotic lesions. PMID- 7859828 TI - Comparison of the testicular effects of 2-methoxyethanol (ME) in rats and guinea pigs. AB - Glycol ethers produce both hemato- and testicular toxicity in animals, which is dependent on both the alkyl chain length and animal species used. Ethylene glycol monobutyl ether (2-butoxyethanol, BE) causes hemolytic anemia in rats but not in guinea pigs, and red blood cells from both guinea pigs and humans are minimally affected in vitro by the active metabolite 2-butoxyacetic acid. This demonstrates the importance of animal species selection for assessing human risk to BE exposure. 2-Methoxyethanol (ME) produces testicular lesions in rats characterized primarily by the degeneration of spermatocytes undergoing meiotic division with minimal or no hemolytic changes. Because of the differential hemolytic response to BE between rats and guinea pigs, the present study addressed whether the testicular response to ME was similarly dichotomous. Adult rats or guinea pigs were given a single dose of either 200 or 300 mg ME/kg by gavage, and testicular and hemolytic changes were assessed 24 hr after treatment. Testis histology in rats showed dose-dependent degeneration of dividing spermatocytes in stage XIV tubules as expected, with only minimal hemolytic changes, also as expected. In contrast, no testicular or hemolytic effects were observed in guinea pigs 24 hr after either single ME dose. In a subsequent study, a single dose or multiple (3 daily) doses of 200 mg ME/kg were given, and animals were examined at 4 days after the start of treatment. Testes from rats given both single and multiple ME doses showed, as expected, tubules depleted of spermatocytes and early spermatids. In guinea pigs, spermatocyte degeneration was observed in stage III/IV tubules for both dosing schemes, but was much less severe and widespread and differed from rats in morphological characteristics, specifically in the appearance of nuclear chromatin degeneration. In the rat, degenerating spermatocytes showed uniformly condensed and dispersed chromatin, while in the guinea pig they showed marked chromatin condensation at the nuclear periphery. No hemolytic changes were observed in either species or dosing scheme. In summary, although ME-associated testicular lesions were observed in both species, they differed significantly in onset, characteristics, and severity. Both the nature of the differential testicular response to ME and a comparison to the in vitro human testicular response to the active metabolite 2-methoxyacetic acid are subjects of future study. PMID- 7859830 TI - Effects of cis-diamminedichloroplatinum II (cisplatin) on the splenic tissue of rats: a histoquantitative study. AB - Histoquantitative methods were applied to study the changes of splenic structure and proportions of splenic tissue compartments in cisplatin-treated (6 mg/kg body wt) male Wistar rats. Six days after treatment the significant reduction of volume density of white pulp was observed, which was due to the very prominent decrease of volume density of follicles. The volume density of periarteriolar lymphatic sheaths did not change substantially. Volume density of the marginal zone was also significantly reduced. A significant increase of volume density of connective tissue was observed. Morphometrical parameters of the follicles were also markedly altered: the number of follicles per mm2 of spleen section area, the numerical density of the follicles in the spleen, and the total number of the follicles were significantly reduced. PMID- 7859829 TI - Further studies on physicochemical properties of mitochondrial membranes during the formation process of megamitochondria in the rat liver by hydrazine. AB - Physicochemical properties of lipids extracted from hepatic mitochondria of rats fed with 1% hydrazine diet for 3 days (3H-mitochondria) and 7 days (7H mitochondria) were studied using differential scanning calorimetry and the fluorescence polarization measurements. Results obtained from lipids extracted from 3H-mitochondria were as follows: (1) Thermotropic phase transition temperatures (Tm) were elevated with a distinct increase in transition enthalpy (delta H) compared to those of the control due to increases in relative amounts of phosphatidylethanolamine (PE) and phosphatidylserine (PS) in phospholipid species. (2) Tm in lipids and phospholipids extracted from 3H-mitochondria was elevated with decreases in delta H after the addition of Ca2+, whereas delta H of the control was increased after the addition of Ca2+. (3) Phosphatidylcholine (PC) liposomes containing PE or PS at concentrations corresponding to PE/PC or PS/PC ratio in 3H-mitochondria showed elevations of transition temperatures with decreases in delta H values after the addition of Ca2+, whereas those containing PE or PS ratio at concentrations corresponding to PE/PC or PS/PC in the control mitochondria showed increases in delta H values after the addition of Ca2+. (4) There were essentially no changes in membrane fluidity between lipids extracted from 3H-mitochondria and those extracted from the control mitochondria. Addition of Ca2+ to lipids extracted from 3H-mitochondria, however, caused elevation of membrane fluidity while those extracted from the control mitochondria showed no changes in membrane fluidity after the addition of Ca2+. (5) Increases in the ratio of unsaturated fatty acids to saturated fatty acids (U/S ratio) in phospholipids extracted from 3H-mitochondria were found to be mainly due to those in PS. These data may suggest that hydrazine modifies the membrane of mitochondria favorable for the membrane fusion via enhanced acidic phospholipid Ca2+ interactions. PMID- 7859831 TI - Characterization of single-stranded DNA binding proteins in rat glial-enriched nuclei. AB - Single-stranded DNA binding proteins (SSBs) are those proteins which preferentially bind single-stranded DNA as opposed to double-stranded DNA and are known to be involved in recombination, amplification, and repair of DNA. To characterize single-stranded DNA binding proteins of glial cells and to examine their potential involvement in induction of neurogenic tumors in rats, nuclei were isolated from target glia and non-target liver of carcinogenically sensitive Sprague-Dawley (SD) and resistant Berlin-Druckrey-IV (BD-IV) rats of various ages and rapidly proliferating glioma cells. Nuclei were fractionated into chromatin, a preribosomal RNA protein complex, heterogeneous nuclear ribonucleoprotein complex (hnRNP), and nucleoplasm. SSBs were isolated, quantitated, and characterized by electrophoresis. A comparison of the contents of SSBs relative to RNA and their electrophoretic profiles between chromatin and hnRNP revealed that SSBs of liver chromatin were mainly associated with RNA. However, it was found that glial chromatin, particularly that of juvenile rats, was enriched with a heterogeneous series of SSBs which were not found in liver chromatin and presumably associated with chromosomal DNA. Some of these SSBs were enriched in glial chromatin of sensitive SD rats compared with that of resistant BD-IV rats. High mobility group proteins (HMG) 1 and 2 constituted major SSB components in the nucleoplasm and a greater amount of these HMGs were found in juvenile glia, compared to adult glia and juvenile and adult liver. Fractionation of glial SSBs and determination of their biological functions may contribute to the further understanding of the role these proteins may play in the processes of carcinogenesis. PMID- 7859832 TI - Analysis of cell surface antigens using anti-rat hepatocyte monoclonal antibodies, particularly HAM 1. AB - The expression of antigens on rat hepatocytes was examined by immunoelectron microscopy using monoclonal antibody HAM 1. The antigen recognized by HAM 1 was expressed mainly on both sinusoidal and bile-canalicular faces and only sparsely on the contiguous face. All rat hepatoma cell lines examined were intensely labeled with HAM 1, but poorly labeled with HAM 3, HAM 4, and HAM 5, as revealed by flow cytofluorometry and radioimmunoassay. Expression levels of HAM 1 antigen on the AH 44 hepatoma cell line similar to the degree seen in normal liver were demonstrated by radioimmunoassay. HAM 1 antigen was also expressed weakly on lymphocytes, thymocytes, and some bone marrow cells, but not on red blood cells, and differed from the MHC class I antigen recognized by HAM 2 and OX 18. Significant amounts of cell surface antigens recognized by all the monoclonal antibodies (HAM 1-HAM 5) were confirmed by radioimmunoassay on the cell surface of primary cultured hepatocytes. These results suggest that the rat hepatoma cell lines employed are different from normal hepatocytes, that primary cultured hepatocytes are more similar to normal hepatocytes in the degree of expression of their cell surface antigens, and that HAM 1 antigen appears to be a significant antigen on both normal and transformed hepatocytes. PMID- 7859833 TI - Molecular subtypes of env sequences around V3 region of human immunodeficiency virus type 1 in Taiwan. AB - Samples of peripheral blood mononuclear cells (PBMC) were collected during 1990 91 from seropositive healthy, male HIV-1 carriers visiting Taipei Venereal Disease Control Center, and a male AIDS patient admitted to a general hospital. The V3 and its flanking nucleotide (nt) sequences in their DNA were amplified by polymerase chain reaction (PCR) and compared with those of known HIV-1 prototypes. The nt sequences obtained from 21 individuals (e.g., TW92) clustered as Group A, which were highly homologous (95.6-99.5%) to that of HXB2 virus while those from 6 individuals (TW90, TW91, TW97, TW99, TW102 and TW104) were classified as Group B showing low similarities (73.2-84.2%) to those of HXB2 and moderate similarities (80.7-90.0%) to those of SC and Bangkok (BK) viruses. By comparison of their deduced amino acid sequences with those of consensus sequences for subtypes A-F as defined by Myers et al. (1993), both Groups A and B viruses (except TW102) together with those of HXB2, SC and BK viruses could be identified as members or variants of subtype B, and the TW102 virus as a member of subtype E viruses. Individuals with the Group A viruses included 4 homosexual and 17 heterosexual Taiwanese males, 2 of the latter having a history of i.v. drug abuse. Among individuals with Group B viruses, those with TW97, TW99, TW104 and TW91, who was an AIDS patient, were heterosexual Taiwanese males, whereas both TW90 and TW102 viruses were from individuals who were overseas heterosexual Chinese from Thailand, the former with a history of i.v. drug abuse and the latter without. PMID- 7859835 TI - Risk factors for histologically confirmed benign breast tumors. AB - A case-control study of 156 cases of various types of benign breast disease (BBD) and 156 population controls was conducted to investigate the role of various behavioral, reproductive, and hormonal factors in the etiology of these breast disorders. Our results indicate that the distinct histological groups of BBD differ from each other in respect to possible risk factors. Small sample size poses severe restrictions on the conclusiveness of the results and thus they should be considered as preliminary and suggestive. Our results do not support the notion that BBD could be considered as a uniform entity with common risk factors. PMID- 7859834 TI - A strong negative association between alcohol consumption and the risk of hepatocellular carcinoma in cirrhotic patients. A case-control study. AB - We carried out a hospital-based, case-control study to assess the association of both the Hepatitis B Virus (HBV) infection and the lifetime daily alcohol intake with the risk of developing hepatocellular carcinoma (HCC) in patients with liver cirrhosis (LC). Cases were 62 consecutive inpatients of a Gastroenterology Division in whom a first diagnosis of HCC superimposed on LC was made. Two control groups were used: 310 patients without liver disease, matched 1:5 with cases and randomly selected from inpatients of the same hospital, and 97 consecutive asymptomatic inpatients in whom the first diagnosis of LC was made. Alcohol intake was quantified in all subjects by a standardized questionnaire. HBV infection was associated with HCC development in cirrhotics (odds ratio = 6.8; 95% confidence interval = 1.4-32.3), whereas we observed a trend towards a decreased HCC risk at increased alcohol intake values (odds ratio from 1 for lifetime abstainers to 0.2 for drinkers of 175 g/day or more). Our results suggest that alcohol intake is not a direct determinant of HCC, but its role is mediated by LC. Cirrhotics with high alcohol intake do not usually survive long enough to develop HCC. PMID- 7859836 TI - Long-term persistence of anti-diphtheria toxin antibodies among adults in Israel. Implications for vaccine policy. AB - Vaccination against diphtheria has essentially led to the disappearance of the disease in Israel. However, in other countries with high immunization coverage, isolated cases and small outbreaks have occurred in adults. Immunity following vaccination or natural exposure to toxigenic strains of C. diphtheriae is conferred by serum antibodies to diphtheria toxin. Since booster doses of diphtheria toxoid are recommended every ten years in adults, this raises the question of persistence of protective levels of anti-diphtheria toxin antibodies. In this study we assessed a possible age-related decline in anti-diphtheria toxin antibodies among adults in Israel. The study population comprised random samples in three age groups: 263 male recruits aged 18-19 years, 116 male reserve soldiers aged 25-35 years and 153 aged 41-51 years. Anti-diphtheria toxin antibody levels were measured by means of ELISA. Results indicate that 64.3% (95% CI = 58.5-70.1%) of those aged 18-19 had anti-diphtheria toxin levels in excess of 0.1 IU ml-1, whereas the corresponding figures for ages 25-35 and 41-51 were 32.8% (95% CI = 24.2-41.3%) and 15% (95% CI = 9.4-20.7%). However, even in the oldest age group, 95.4% (95% CI = 90.8-98.1%) had antibodies above the presumed protective level of 0.01 IU ml-1. Although these results indicate a significant age-related decline in anti-diphtheria toxin antibodies in vaccinated subjects, most had apparently protective levels. The absence of cases suggests that vaccine induced immunity is long-lasting. However the immune status of the population should be carefully monitored. PMID- 7859837 TI - Prevalence of asthma among Emirates school children. AB - The aim of this study was to determine the prevalence of asthma among United Arab Emirates school children aged 6-14 years. A cross-sectional study of 850 school children living in both urban and rural areas (average age 9.36 +/- 2.11 years, 46.8% boys and 53.2% girls) was conducted using self-administered questionnaires between October 1992 and May 1993. The population sample had a high prevalence rate of diagnosed asthma (13.6%), breathlessness or tightness in chest (9.7%), allergic rhinitis (22.9%), and nocturnal cough (8.9%). Allergic rhinitis was the most frequently seen respiratory illness when compared to other respiratory symptoms. The frequency of asthma, allergic rhinitis and eczema among parents reflected the same pattern as that seen in the children. Prevalence rate of asthma was not significantly higher in fathers (5.9%) than in mothers (5.3%). The differences between the sexes were not significant in any of the age group studied for any of the allergic conditions, except for diagnosed asthma in which the prevalence rate in males was significantly higher than that in females. On the whole, the prevalence rate of all the conditions increased with age. But the frequency of allergic rhinitis symptoms was significantly higher in mothers (16%) than in fathers (10.8%). These results are consistent with those obtained in neighbouring gulf countries and are higher than those of some developed countries, but the differences are not statistically significant. PMID- 7859838 TI - HCV, HIV, HBV and HDV infections in intravenous drug addicts. AB - Hepatitis viruses and the acquired immunodeficiency viruses often infect intravenous drug addicts (IVDAs). Our study includes 255 IVDAs (26 females and 229 males, aged 20-35 years) from Cagliari. Of 255 subjects examined, 207 (81.1%) were positive for anti-HCV and 84 (32.9%) for anti-HIV. Nineteen (7.4%) subjects were HBsAg carriers, and 12 of these (63%) had an HDV superinfection. Markers of previous HBV infections were tested in 223 cases and 137 (61.4%) were found positive; of these 14 (10.2%) also had HDV infection. Of the 223 drug addicts examined for all infection markers, 18 (8%) were negative to all markers, 46 (20.6%) were positive to only one, 89 (39.9%) were positive to two, 64 (28.7%) to three and 6 (2.6%) were positive to all. Subjects with a single infection were significantly fewer than those with multiple infections. The correlations studied among the various markers did not point out any statistically significant associations. Even so, a previous HBV infection was more common while active HBV/HDV infections were less common among subjects with anti-HCV; HDV infection was more common among HIV-positive subjects. In HBsAg carriers neither HBV-DNA nor HCV-RNA was detected; HCV-RNA was found more frequently in anti-HIV positive subjects than in subjects with the anti-HCV isolate. PMID- 7859839 TI - HIV epidemiology and risk behavior promoting HIV transmission in Austrian prisons. AB - In 1989, 1990 and 1992, 19%, 15% and 10%, respectively, of all prisoners newly admitted to prisons and penitentiary institutions in Austria underwent HIV antibody tests. Based on the HIV test outcome in prisons in which more than 80% of the newly admitted inmates were tested, annual HIV prevalences among prison inmates in Austria were determined. These were 0.5% (11/2,223), 1.3% (19/1,466) and 0.9% (14/1,509) in 1989, 1990 and 1992, respectively. The prevalence rates among prison inmates in Austria are thus 5 times higher than those in the general Austrian population. About 5% of all inmates belong to the high-risk group of intravenous drug users. Inquiries into HIV risk behavior among prison inmates showed that, in Austrian prisons just like in those of many other countries, intravenous drug use and sexual contacts are common practices. As disposable needles and condoms are not available to prison inmates, these practices carry a particularly high risk of HIV transmission. The data collected can be taken as a basis for developing strategies which are designed to reduce the risk of HIV transmission in prisons and which have a major bearing on the development of the HIV pandemic. PMID- 7859840 TI - The evolution of pulmonary tuberculosis in coal miners in Asturias, northern Spain. An attempt to reduce the rate over a 15-year period, 1971-1985. AB - A prospective study of 53,753 coal miners was undertaken at the Instituto Nacional de Silicosis (INS) in Asturias, Spain, during the period 1971 to 1985. This included a complete medical history, physical examination, pulmonary function tests, and intensive search for pulmonary tuberculosis. A total of 1,136 new cases of active pulmonary tuberculosis were found, all of which were confirmed by bacteriology. The average incidence was 150 +/- 31 cases per 100,000 miners year-1. Annual analysis revealed that this figure remained fairly stable during the period of study. Only a reduction of the prevalence in the subgroup of miners with massive pulmonary fibrosis was seen in later years. The risk of tuberculosis among miners was three times greater than that for the general population of the same area. Our inability to reduce the incidence of pulmonary tuberculosis in a large group of coal miners, in spite of the fact that the treatments given were effective and that in the last eight years chemoprophylaxis was given to close contacts, should be emphasized. PMID- 7859841 TI - Helicobacter pylori seroepidemiology in risk groups. AB - Helicobacter pylori is associated with peptic ulcer and chronic active gastritis. The response to infection can be determined by measuring serum titers of anti-H. pylori antibodies. We compared antibody titers in 612 serum samples from 570 individuals considered at risk for H. pylori infection, 170 of them are control sera from 110 adults and 60 children with no gastric alterations. The study groups were 93 institutionalized mentally handicapped children, 40 heterosexual couples, 101 HIV-sero-positive patients, 86 patients with chronic renal failure and 40 individuals (20 adults and 20 children) with symptoms associated with gastritis or gastroduodenal ulcer disease. In the adult and child control groups, 33.5% and 11.6% of the individuals had circulating anti-H. pylori antibodies. Significantly more adults (80%) and children (75%) with gastric symptoms had detectable circulating antibody titers. Elevated titers were also found in institutionalized children and in adults with renal failure. PMID- 7859842 TI - Comparison of risk factors for coronary heart disease in Dresden and Munster. Results of the DRECAN (Dresden Cardiovascular Risk and Nutrition) study and the PROCAM (Prospective Cardiovascular Munster) Study. AB - Trend analyses based on WHO statistics for average life expectancy, age standardized cardiovascular (CVD) morbidity and mortality show significant differences between the former German Democratic Republic (GDR) and the former Federal Republic of Germany (FRG). To investigate whether this is due to a different prevalence of cardiovascular risk factors, the Dresden Cardiovascular Risk and Nutrition (DRECAN) study was conducted using the complete methodology of the Prospective Cardiovascular Munster (PROCAM) study, i.e., the same methods and strict quality controls, with an exchange of specimens between both laboratories. The results were compared with those of an adjusted subpopulation of the PROCAM study. Even before unification there were only small differences in lipoprotein profiles between West and East Germany, 10 months after unification these differences were minimal. The survey does not sufficiently explain the differences in CHD morbidity and mortality between Western and Eastern Germany. Further analyses of the nutritional aspects will show whether the change, in available foodstuffs after unification has led to substantially changed nutritional habits, and whether this might explain some of the results. PMID- 7859843 TI - 766 cases of oral cleft in Italy. Data from Emilia Romagna (IMER) and northeast Italy (NEI) registers. AB - Epidemiological and genetic variables for oral clefts were analysed for the years 1981-1989 in a case-control study of congenital malformations in the Emilia Romagna, Veneto, and Friuli regions, and in the Trento and Bolzano hospitals. Birth prevalence for all cases of cleft lip with or without cleft palate (CL(P)) was 8.2 per 10,000 births, and that for cleft palate only (CP) was 6.1 per 10,000. Coexisting abnormalities were found in 23% of CL(P) cases and in 43% of CP. No clusters in time or space were detected. For isolated clefts, a predominance of males among CL(P) and of females among CP was found; epilepsy was the only maternal risk factor correlated with clefts, and an association between clefting and consanguinity was found. Empirical recurrence risks were calculated in both isolated CL(P) and CP. PMID- 7859844 TI - Molecular epidemiology for local outbreaks of methicillin resistant Staphylococcus aureus (MRSA). The need for several methods. AB - Subtyping isolates may be useful for epidemiological studies of methicillin resistant-Staphylococcus aureus (MRSA) outbreaks. Among subtyping methods, DNA based techniques have been applied very effectively for this purpose. An outbreak of MRSA infections took place in one hospital in Barcelona early during 1991. From the beginning of the outbreak to December 92, 70 MRSA isolates from different patients and sources were collected. All strains were evaluated by restriction endonuclease analysis of plasmid DNA (REAP) and macrorestriction endonuclease analysis of genomic DNA using Sma I and pulsed-field-gel electrophoresis (PFGE). Plasmid screening and REAP using Hind III demonstrated two plasmid subtypes: subtype A showing a large plasmid, and subtype B showing the same large plasmid plus a smaller one. Subtypes A and B corresponded to the more recent and older isolates, respectively, suggesting the loss of the small plasmid during the epidemic. PFGE using Sma I displayed two closely related profiles (PFGE subtype A and A'; CS = 0.90). These subtypes were different from those subtypes exhibited from 4 methicillin-susceptible-Staphylococcus aureus (MSSA) isolates from the same hospital and from 2 epidemiologically unrelated MRSA isolates. Almost all isolates showing PFGE subtype A preceded those isolates showing PFGE subtype A'. This fact and the similarity between both subtypes suggested minor chromosomal DNA rearrangement during the outbreak from a unique strain. While PFGE using Sma I is a useful tool in evaluation of clonal dissemination, our data suggest epidemic or local outbreaks may need several methods to best delineate the source and spread of MRSA strains. The reproducibility and discriminatory power of REAP makes it a useful adjunct in this context. PMID- 7859845 TI - The HIV prevalence among pregnant women in the Amsterdam region (1988-1991). AB - The objective of the study was to monitor the HIV prevalence in the years 1988 1991 among pregnant women in the Amsterdam region, visitors to an abortion clinic and 3 outpatient infertility clinics. All women attending these clinics were asked to participate in the study on a voluntary basis and were tested with informed consent. The women were questioned about risk-bearing behaviour of themselves and their sexual partner(s). In the period 1988-1991, of the 23,827 eligible pregnant women, 22,165 women participated (93.0%). Twenty-seven women were found to be positive for HIV antibodies (0.12%, 95% CI: 0.08%-0.17%), of whom twenty belonged to a known HIV risk group or had a partner who belonged to one of these groups and 7 women had no known HIV risk. Seventeen of the 27 women had a foreign nationality. The annual HIV prevalence among pregnant women was: 1988: 0.28%; 1989: 0.10%; 1990: 0.10%; 1991: 0.11%. In the years 1990 and 1991, of the 1,128 eligible women visiting the abortion clinic 953 (84.5%) were tested. Eleven women were HIV-seropositive (1.15%, 95% CI: 0.6%-2.0%), of whom 9 were from an AIDS endemic region, 1 woman had a partner from this region and 1 woman had no known HIV risk. Four African women had HIV-2 antibodies. At the 3 outpatient infertility clinics 1 woman was found to be HIV-positive (0.13%; 95% CI: 0.02-0.9). She had no other risk than a partner from an AIDS endemic area. In the Amsterdam region there was a steady and low HIV prevalence (0.1%) among pregnant women through the years 1988-1991. The prevalence in the abortion clinic was ten times higher. The program was able to detect possible high risk groups within the population. Migration and travelling can play an important role in the spread of HIV in the general heterosexual population. PMID- 7859846 TI - Premature mortality in former Yugoslavia. AB - To evaluate the level of health attained before the war started, premature mortality from all causes in the former Yugoslavia was analyzed by republics and provinces in two respective periods. Premature mortality, measured by the crude rate of years of potential life lost, fell from 12,762.6 in 1970 to 6,320.1 per 100,000 population aged 0-64 in 1990 (50% decrease). Age-adjusted rates of republics/provinces declined during the same period to various degrees (30% to 70%). PMID- 7859847 TI - Tick-borne encephalitis in Austria: incidence 1990 and 1991. AB - In Austria 85 patients (1.10/100,000) were hospitalized with a tick-borne encephalitis (TBE) in 1990, 77 patients (0.98/100,000) in 1991. A relatively low incidence is seen in the younger age groups. The regional distribution follows the distribution of infested areas, with the highest rates in the two provinces Karnten and Steiermark provinces. PMID- 7859848 TI - In vitro activity of eight antibiotics against Salmonella and Shigella species. AB - The minimum inhibitory concentrations (MICs) of ampicillin, chloramphenicol, trimetoprimsulfamethoxazole (TMP-SMX), ofloxacin, ciprofloxacin, pefloxacin, enoxacin and fleroxacin for Salmonella spp. (n = 72) and Shigella spp. (n = 52) were established. S. typhi isolates were all susceptible to all of the antibiotics tested. In non-typhi salmonellae and Shigella spp., resistance to ampicillin, chloramphenicol and TMP-SMX with various rates were encountered, but all isolates were susceptible to fluoroquinolones. PMID- 7859850 TI - Paradoxical urinary iodine concentration in an endemic goitre area of Tunisia. PMID- 7859851 TI - Extended-spectrum beta-lactamases from Klebsiella pneumoniae strains isolated at an Italian hospital. AB - Eighteen strains of Klebsiella pneumoniae recently isolated from hospitalized patients were resistant or moderately resistant to oxyimino-cephalosporins (ceftazidime and/or cefotaxime), aztreonam, cefoxitin and all but one were susceptible to imipenem. Analysis of enzymes produced by these clinical isolates revealed a wide pattern of extended-spectrum beta-lactamases. All isolates produced one or more beta-lactamases that were characterized preliminarily by their isoelectric point. Strains isolated early were from patients in the Intensive Care Unit and produced an ES beta-lactamase with an apparent pI of 7.6, whereas the later isolates were from surgical and medical wards of the same hospital and produced ES beta-lactamases with apparent pI of 8.2 and 8.4, respectively. This suggests the emergence of SHV-5 and MIR-1 beta-lactamases in our hospital. Agarose gel electrophoresis of plasmid DNA revealed the presence of a similar plasmid of approximate size 60 Kb in all isolates. PMID- 7859849 TI - Risk of infections transmitted by arthropods and rodents in forestry workers. AB - One hundred and fifty-one forestry workers and 151 matched office clerks were compared as to the presence of antibodies against Borelia burgdorferi, tick-borne encephalitis virus, Puumalavirus and lymphocytic choriomeningitis virus. Their occupational risks of being infected by Borrelia was fourfold and significant, by Puumalavirus and lymphocytic choriomeningitis virus was increased but not significant. No seropositivity has been established against tick-borne encephalitis virus. PMID- 7859853 TI - Environmental and personal monitoring of exposure to urban noise and community response. AB - Noise exposure of a population sample living in a city in northern Italy (Genoa) was assessed by measuring the noise in the area as well as with personal sound detectors. Sampling was conducted during a standard day and covered a period of time spent out-of-doors, at work (service sector) and at home. Ambient noise at home and at work was assessed with sound-level meters, personal exposure levels were assessed with personal sound-level/dosimeters. Information regarding each environment was obtained with an interview including also a subjective judgement on traffic intensity and noise levels. The mean individual equivalent continuous sound level (Leq) of recorded noise was 74.5 dB(A) for 24 h and 63.9 dB(A) at night. A further distinction was made between noise exposure at home (Leq 74.4), work (Leq 74.0) and during city transfers (Leq 79.3). Leq values for individual hours, Leq daytime (Leq, d), Leq nighttime (Leq,n) and Leq day-night (Ldn) indices calculated in the different environments, i.e. at work, home and out-of doors, are reported here. Individual noise levels have then been compared with environmental data and with subjective noise exposure judgement. PMID- 7859852 TI - Vaccination against hepatitis B: results of the analysis of 2000 population members in Croatia. AB - The results of the analysis of vaccination against hepatitis B performed in 2,000 persons of high-risk groups in Croatia are described. All susceptible non immunocompromised persons (HBsAg, anti-HBs, and anti-HBc negative) received either plasma-derived vaccine (HB-Vax MSD, 20 micrograms per dose) or recombinant HB vaccine (ENGERIX-B, SKB, 20 micrograms per dose) according to a 0.1 and 6 month schedule. Hemodialysis patients received four doses of HB vaccine (40 micrograms per dose). Seroconversion occurred in 98% of health care workers, 98.5% of family members of HBsAg chronic carriers, 98% of infants born to HBsAg carrier-mothers and 92% of hemodialysis patients. The percentage of poor responders (titer of anti-BHs = 1-10 mIU/ml) for the groups was 2, 2, 8 and 20%, respectively, while low-responders (titer of anti-BHs = 10.1-100 mIU/ml) were 5, 4.5, 12 and 26%, respectively. A significant prevalence of non-responders, poor responders and low-responders among male health care workers was noticed (p = 0.01, 0.026 and 0.002, respectively). Females significantly prevailed among excellent-responders (p = 0.0039). In hemodialysis patients, there were 8% non responders, 19.5% poor-responders, and 26% low-responders. A significant difference between the percentage of good-responders (titer of anti-HBs = 101 1,000 mIU/ml) and excellent-responders (titer of anti-HBs over 1,000 mIU/ml) among health care workers and hemodialysis patients was documented (91% versus 46.5%, p < 0.0001). The combined passive-active immunization (hyperimmune hepatitis B globulin + hepatitis B vaccine) was effective in 98% of infants born to HBsAg carrier-mothers, and only one boy developed subclinical HBV infection (HBsAg and anti-HBc positive findings with normal ALT-values).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859854 TI - Aspergillus flavus and aflatoxin B1 in flour production. AB - This paper discusses the results of investigations of contamination with aflatoxin-producing fungi and aflatoxin B1 affecting 545 samples of wheat grains, 475 samples of intermediate products of wheat grain being milled to flour (like middlings) and 238 samples of flour. A significant contamination with moulds was detected in analyzed samples. Although Aspergillus (34.87%) and Penicillium (32.37%) dominated, other types were also present, e.g., Cladosporium, Fusarium, Mucor, Alternaria, Rhizopus, Absidia and Trichoderma (listed in order of frequency). The presence of Aspergillus flavus, the known aflatoxin producer, was detected in 9.94% of analyzed samples. Isolates of A. Flavus were capable of producing aflatoxin B1 under favourable conditions. Aflatoxin B1 was found in 76.8% of samples contaminated with A. flavus. The highest contamination with aflatoxin B1 was detected in wheat grain samples (mean value of 16.3 micrograms/kg) and in intermediate products of wheat grain being milled to flour (mean value of 11.13 micrograms/kg). Contamination was lower in flour samples (mean value of 4.13 micrograms/kg). With regard to proposed standards given by the FAO and WHO, under which the content of aflatoxin should not exceed 30 micrograms/kg in food products, only two of 96 samples did not meet these criteria. PMID- 7859856 TI - A multicentre study: Staphylococcus and Enterococcus susceptibility to antibiotics. AB - A multicentre study to evaluate the susceptibility of Gram-positive cocci isolated from clinical samples, was performed by six centres working in different areas of Italy. We examined 4,544 strains of Staphylococcus aureus, 4,381 strains of coagulase-negative staphylococci and 2,478 strains of enterococci. The following antibiotics were tested: penicillin G, ampicillin, amoxicillin, piperacillin, imipenem, oxacillin, ofloxacin, pefloxacin, ciprofloxacin, gentamicin, tobramycin, amikacin, netilmicin, rifampicin, clindamycin, tetracycline, cotrimoxazole, erythromycin, chloramphenicol, vancomycin and teicoplanin. Oxacillin-susceptible staphylococci confirmed their susceptibility to many other antimicrobial agents while oxacillin-resistant strains confirmed their multiple and frequent resistance to antibiotics. Resistance to oxacillin, cotrimoxazole and chloramphenicol was more frequent in coagulase-negative staphylococci than in Staphylococcus aureus. Aminoglycosides, rifampicin and quinolones were more active against coagulase-negative staphylococci than against Staphylococcus aureus. Enterococci were susceptible to penicillins and imipenem, and moderately susceptible to ciprofloxacin. Susceptibility of 70-79% was observed with high levels of aminoglycosides. Excellent results against staphylococci and enterococci were observed with vancomycin and teicoplanin. PMID- 7859855 TI - Epidemiology of abdominal symptoms in a random population: prevalence, incidence, and natural history. AB - The study presents results from a five-year follow-up on abdominal symptoms in an age and sex stratified random sample of 4,581 Danes. Abdominal pain occurred significantly more often among women (prevalence: 49%, incidence: 21%) compared to mean (prevalence: 38%, incidence: 15%). Five years later the pain had disappeared in 43% of the men and 31% of the women (p = 0.003). Distension, borborygmi, and altering consistency of stools occurred with a prevalence of approximately 50% and an incidence of approximately 30%, significantly more often among women compared to men. Five years later these symptoms had disappeared in about 20%. Prevalence of both heartburn and acid regurgitation were significantly higher among men (38%) than women (30%), whereas no sex difference was observed regarding incidence of these symptoms (16%). Approximately 30% of subjects who had experienced heartburn or acid regurgitation did not do so five years later. In conclusion, abdominal symptoms occur frequently and recurrently in the general population. This information is of importance to doctors when they evaluate patients with abdominal complaints, but no obvious organic etiology. PMID- 7859857 TI - Nosocomial infection in a neonatal intensive care unit and its prevention with selective intestinal decolonization. A multivariant evaluation of infection reduction. AB - A prospective cohort study in a neonatal intensive care unit (ICU) was carried out to evaluate whether the incidence of infection in neonates receiving intestinal decolonization was reduced in comparison to those who did not. This study was performed after controling possible confounding infection risk factors. A total of 536 babies were screened in our ICU during the 27-month study period. Neonates were admitted to the ICU for different reasons: low weight, respiratory distress syndrome, acute fetal suffering, surgery, etc. The doctor in charge decided whether the baby should be decolonized or not, so this experimental study was non-random. Thus more of the babies with a greater risk of infection were decolonized more often than the other babies who were not so much at risk. In this study, babies were classified by type of decolonization given: a well performed Selective Intestinal Decolonization (SID) was done (early and with three oral drugs: E polymyxin, tobramycin and nystatin): 10.8% of the babies; Incorrect SID (was begun late and/or less than three drugs were used): 16.7% of the babies; and Without SID (72.9%). Total nosocomial infection (NI) was 11.2%, catheter-associated sepsis was 42% of the total NI. When the NI incidence was directly compared among groups, it was lower in the group without SID, but infants with decolonization initially had more infection risk factor than the first group. For this reason, multiple logistic regression was used in order to stratify factors by infection probability, and correcting the existing bias.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859858 TI - An outbreak of Campylobacter infection associated with the consumption of unpasteurised milk at a large festival in England. AB - Seventy-two laboratory confirmed cases of Campylobacter infection were identified in people who attended a large festival in England. A case-control study was undertaken to identify the vehicle of infection. Potential risk factors included the water supply to the site, and food, bottled spring water and unpasteurised milk sold at the event. Only the consumption of unpasteurised milk showed a statistical association with having a Campylobacter infection, strongly suggesting that this was the vehicle of infection. PMID- 7859859 TI - Alcohol and mortality. Results from the EPOZ (Epidemiologic Study of Cardiovascular Risk Indicators) follow-up study. AB - To investigate the association of alcohol intake with mortality from all causes, cardiovascular disease (CVD), cancer and other causes (e.g., accidents, violence, suicide), we performed an analysis of data obtained in a prospective follow-up study conducted in the Netherlands since 1977. Causes of death were defined for a cohort of 1,620 persons (760 men and 860 women) examined in 1977. During the 10 year follow-up period, 123 (7.6%) of the participants died. Frequency of alcohol consumption was obtained separately for wine, beer and liquor by means of a questionnaire. Although no significant association could be established between alcohol consumption and all-cause mortality, all-cause mortality tended to be lower in alcohol consumers compared to abstainers. The age- and sex-adjusted risk estimates of death from CVD were 0.29 (0.11-0.74), 0.46 (0.21-0.96) and 0.32 (0.13-0.77) for subjects with occasional, frequent and daily alcohol use, respectively, compared with those who did not drink at baseline. The mortality risks of never-drinkers and ex-drinkers were similar. A J- or U-shaped relation between alcohol consumption and CVD mortality could not be confirmed in our data but the available information on the amount of alcohol consumed was limited. No significant influence on the risk estimates of death from cancer or other causes was found. However, mortality tended to be higher for those who consumed more alcohol. The protective effect of alcohol intake on CVD mortality found in our data persisted after excluding subjects with cardiovascular or other major diseases at baseline from the analysis. PMID- 7859860 TI - Patterns of smoking in Spain. Results from a regional general population survey. AB - Smoking patterns were examined in 2500 individuals, aged 14-70 years living in Castille and Leon (Spain) in the fall of 1992. Of these, 39.6% were regular smokers, 7.2% were occasional smokers, 14.8% were former smokers, and 30.4% were non-smokers. Sex differences were striking: there was a higher prevalence of regular smokers among males than females, males smoked much more, and were more frequently French-type cigarette smokers. A comparison of the present figures with data from an earlier survey carried out in 1989 suggests that smoking is decreasing in Spain. PMID- 7859861 TI - Bladder cancer and black tobacco cigarette smoking. Some results from a French case-control study. AB - A retrospective study was planned in the Herault (Mediterranean) region of France where bladder cancer mortality and incidence rates are high. In the present paper, variations in bladder cancer risk according to various smoking-related variables, in particular time of exposure and type of tobacco, are examined. This case-control study with 219 male incident cases and 794 male population controls randomized from electoral rolls was carried out in 1987-89. Trained interviewers obtained information on demographics, dietary habits (coffee, alcohol, artificial sweeteners, vegetables, spices, etc.), occupational exposures and detailed history of tobacco smoking (average number of cigarettes per day, number of years of smoking, age at which they began and/or quitted smoking, use of filter-tip and type of tobacco). The odds ratio (OR) for cigarette smokers versus non-smokers was greater than 5. Results for number of cigarettes daily, duration of smoking and lifetime smoking showed a highly significant dose-response relationship, which was confirmed when these variables were treated as continuous in a logistic regression model. Eighty-eight percent of the smokers used black tobacco. Quitting smoking did not result in a significant reduction in bladder cancer risk. Higher risks were associated with starting to smoke at an early age (OR before age 13 versus after age 21 = 3.42; 95% CI 1.07-10.9) and with black tobacco smoking (OR black versus blond = 1.63; 95% CI 0.73-3.64). Results suggest that black tobacco may be more harmful than blond tobacco and may have an early non-reversible role in bladder carcinogenesis. PMID- 7859862 TI - Sperm-induced urolithiasis in the rat. AB - Experiments are described demonstrating that experimental insemination with autologous or homologous sperm into the ventral prostate or bladder neck of outbred Zbar male rats induces intravesical precipitation or stones. These observations suggest that clinical conditions resulting in intravesical sperm may be contributory to bladder lithiasis in man and may have relevance to its prevalence in men vs. women. PMID- 7859863 TI - Risk factors for high blood pressure among workers in French poultry slaughterhouses and canneries. AB - The aim of the present study is to examine the relationship between the working conditions of employees in the food industry and blood pressure. An epidemiological survey was conducted between 1987 and 1988 in 17 poultry slaughterhouses and 6 canneries in the French regions of 'Bretagne' and 'Pays de Loire'. One thousand, four hundred and seventy-four workers were included in the study. Data was collected in the course of the medical visit organized annually for employees. Mean diastolic (DBP) and systolic blood pressure (SBP) were analyzed separately for male and female workers. The results indicate a significant relationship between blood pressure, and age and obesity. Amongst the various features of working condition studies, loud noise and the number of work breaks were found to be associated with heightened mean values of DBP or SBP in men only. Type and size of the factory was found to be associated with blood pressure readings for both sexes. A number of working conditions giving rise to heightened mental strain were found to be related to a lowering in mean blood pressure: for example, irregular work finishing times for men and production-line work for women. A discussion of these results reveals the complexity of the relationships which exist between physical and environmental factors in this type of setting and blood pressure of employees. PMID- 7859864 TI - Prevalence of antimicrobial resistance of Streptococcus pneumoniae in southwest Germany as determined by the E test. AB - We have studied the prevalence of anti-microbial resistance of Streptococcus pneumoniae in Southwest Germany. One hundred seventy-four clinical isolates of pneumococci collected from hospitalized patients between October 1992 and April 1994 were used for MIC determinations. MICs for penicillin, ceftriaxone, erythromycin, and rifampicin were assessed by the E test. Eleven of the 174 strains (6.3%) were intermediately resistant to penicillin (MIC between 0.1 and 1.0 microgram/ml) and four of the 174 strains (2.3%) were intermediately resistant to ceftriaxone (MIC between 0.1 and 1.0 microgram/ml). All four isolates with a reduced susceptibility to ceftriaxone also demonstrated intermediate resistance to penicillin. Six of the 174 strains (3.5%) were highly resistant (MIC > or = 8 micrograms/ml) to erythromycin. Resistance to rifampicin was not observed. Our results demonstrate that pneumococcal resistance to penicillin and erythromycin has increased markedly in Germany over the last decade. Our findings underline the need for continuous surveillance of antimicrobial resistance of Streptococcus pneumoniae. PMID- 7859865 TI - Relationship between severity, costs and claims of hospitalized patients using the Severity of Illness Index. AB - The results of the prospective application of Horn's 'Severity of Illness Index' in a teaching hospital during 1987, 1989, and 1990 constitute the basis of the present report. The average overall severity of illness scores for the three years were 1.42 in 1987, 1.65 in 1989, and 1.46 in 1990. Most of the processes evaluated in the three periods showed an overall distribution among severity levels 1 and 2, both overall and when the seven dimensions of the severity of illness index were analyzed. A statistically significant correlation between the overall severity of illness and average length of stay was found for patients in 1989 and 1990. The length of stay differed significantly in the different severity levels. When the four levels of the seven dimensions of the severity of illness index for 1987, 1989, and 1990 were compared, it was observed that figures were not uniformly distributed. There was a statistically significant association between severity of illness for hospital service and pharmacy charges per hospital stay for both 1989 and 1990, as well as a statistically significant inverse relationship between severity of illness and the number of claims per hospital service in both periods of time. Case-mix methods that account for the severity of patients constitute a useful indicator of quality for the management of different hospital services and of the hospital as a whole. PMID- 7859866 TI - Decline in anti-HAV prevalence in the Milan area between 1958 and 1992. AB - We have compared the prevalence of antibody to HAV in sera collected from healthy individuals of Milan in 1958, 1977 and 1992 respectively. The results show a dramatic reduction of HAV circulation likely due to the considerable improvement of socioeconomic and hygienic living conditions which have occurred in Italy during the last decades. PMID- 7859867 TI - Analysing the sequence diversity of the 5' NC-region of HCV-isolates found in southern Germany. AB - In this study we compared the nucleotide sequence of the 5' NC-region of the HCV genome isolated from seven patients and two blood donors from Southern Germany. We could identify two very distinct groups of isolates: the first very similar to the HCV prototype sequence (HCV1) with homology ranging from 99.5% to 98.7%; the second showing 91.7% homology to the HCV1. Group 1 isolates could be found in five patients and the two blood donors. Group 2 isolates could be found in the two other patients. Finally, we could observe neither nucleotide insertion nor deletion in the isolates described here. PMID- 7859868 TI - Nosocomial septicaemias in a cardiologic ward. A case-control study. AB - Nosocomial septicaemias were studied in a cardiologic ward at the University Hospital of Antwerp, Belgium. The incidence of nosocomial infections was found to be 2.7 per 1,000 admissions per year. A case-control study suggested that in contrast with coronarography and pacemaker implantation, percutaneous transluminal coronary angioplasty may be a risk factor for nosocomial septicaemia (OR 4.5, 95% confidence interval 0.7-33.4). PMID- 7859869 TI - Salmonella enteritidis phage types in Germany. AB - In order to monitor the epidemiological situation of S. enteritidis in Germany, in 1990-91 1138 isolates from more than 180 locations in West Germany were phage typed. 1124 strains (98.8%) from all sources were typeable, belonging to 21 different phage types (PT). PT4 strains were isolated most frequently (70.8%). In addition, PT7, 25, 34 and 8 were of epidemiological relevance with incidences of 7.2 to 4.5%. The comparison of data shows that in Germany, like in other parts of Europe, PT4 predominates. This phage type is, however, infrequent in North America, where PT8 has the highest incidence. PMID- 7859870 TI - Soluble receptors for tumour necrosis factor in clinical laboratory diagnosis. AB - Soluble tumour necrosis factor receptors (sTNF-Rs) play a role as modulators of the biological function of tumour necrosis factor-alpha (TNF-alpha) in an agonist/antagonist pattern. In various pathologic states the production and release of sTNF-Rs may mediate host response and determine the course and outcome of disease by interacting with TNF-alpha and competing with cell surface receptors. The determination of sTNF-Rs in body fluids such as plasma or serum is a new tool to gain information about immune processes and provides valuable insight into a variety of pathological conditions. Regarding its immediate clinical use, sTNF-Rs levels show high accuracy in the follow-up and prognosis of various diseases. In HIV infection and sepsis, sTNF-Rs concentrations strongly correlate with the clinical stage and the progression of disease and can be of predictive value. Determination of sTNF-Rs also gives useful information for monitoring cancer and autoimmune diseases. The information provided is often even superior to that obtained with classical disease markers, probably due to the direct involvement of the "TNF system" in the pathogenetic mechanisms in these patients. The available data imply that the measurement of sTNF-Rs, especially of the sTNF-R 75kD type, is a useful adjunct for quantification of the Th1-type immune response, similar to other immune activation markers such as neopterin and beta 2-microglobulin. Endogenous sTNF-Rs concentrations appear to reflect the activation state of the TNF-alpha/TNF receptor system. PMID- 7859871 TI - Outpatient supportive therapy after induction to remission therapy in adult acute myelogenous leukaemia (AML) is feasible: a multicentre study. AB - Twenty-four adult patients with AML were treated with standard "7 + 3" chemotherapy. After administering the myeloablative drugs in the hospital, patients were instructed to continue their supportive treatment on an outpatient basis; they received ciprofloxacin, cotrimoxasole and itraconazole vo until the absolute granulocyte count rose above 1 x 10(9)/l. Platelet concentrates were given every other day until the platelet count rose above 20 x 10(9)/l. Complete remission (CR) was obtained in 87%. Fever developed in 29% and 2 cases were complicated by indwelling-catheter-related Pseudomona aeruginosa septicaemia, 1 Entamoeba hystolytica enteritis and 1 Pneumocystis carinii pneumonia; these patients were hospitalized to treat these infections specifically. In no case was the infection fatal. The median disease free-survival (DFS) was 17 months, 12 month DFS was 66%, and 30-month DFS was 17%. Our calculations have shown that 1700 USD/patient were saved by avoiding prolonged hospitalization; this may provide not only economical, but also psychological advantages to patients. PMID- 7859872 TI - Survival and risk of leukaemia in polycythaemia vera and essential thrombocythaemia treated with oral radiophosphorus: are safer drugs available? AB - For 366 patients with polycythaemia vera (PV) or essential thrombocythaemia (ET) diagnosed 1971-1990, oral administration of 32-P was used as myelosuppressive treatment. Retreatment was not restricted to any defined interval and the number of treatments or the total dose were not limited. For 107 patients, follow-up was > 10 years. 15 of these presented with life-threatening occlusive vascular symptoms and their survival was short. For the remaining 92 patients 5-yr survival was not significantly worse than for a Swedish population matched for age and sex. Survival at 10 yr was lower, 51% versus 66% expected. Acute myeloid leukaemia (AML) was diagnosed in 11 of the 107 patients (10.3%). In the whole material of 366 patients, 17 have developed AML with a median time of 8.5 yr from start of treatment. There was a maximum incidence of 4% per yr after 8-12 yr. Later, the incidence decreased. The median annual dose of 32-P for the AML patients was 100 MBq and was not significantly larger than for a matched control group surviving without AML, 96 MBq. The results are compared with reports on PV or ET patients treated with busulphan (Bu) or hydroxyurea (HU). With comparable periods of follow-up there are no indications that an adequate myelosuppression with oral 32-P will be associated with shorter survival or higher incidence of AML than treatment with Bu or HU. It is concluded that, for the time being, oral administration of 32-P is an acceptable standard treatment in PV and ET. PMID- 7859873 TI - Disseminated intravascular coagulation (DIC) in adult patients with acute leukaemia. AB - In 71 patients with acute leukaemia admitted for remission induction, disseminated intravascular coagulation (DIC) was looked for in 50 patients and diagnosed in 10 (20%). Of 10 patients with acute lymphoblastic leukaemia, 3 had DIC, and of 40 patients with acute myeloblastic leukaemia, 7 had DIC. The presence of DIC was related to bleeding manifestations within the first 2 weeks. A haemorrhagic diathesis was present in all DIC patients: 4 had minor and 6 had major bleeding, i.e. WHO grade > or = 2. In addition to blood product support, most DIC patients were treated with low doses of heparin and tranexamic acid. In all DIC patients the haemorrhagic symptoms preceded the heparin administration. Among 40 screened patients without DIC, 17 patients had minor and 3 had major haemorrhagic manifestations. Thus, the proportion of patients with major bleeding was significantly greater among the DIC patients (6/10 vs 3/40, p < 0.001). In conclusion, DIC at presentation was associated with a significantly increased risk for severe haemorrhagic complications and should be looked for in adults with acute leukaemia. PMID- 7859875 TI - Three-year results of MIM salvage treatment for refractory/relapsed intermediate grade NHL. PMID- 7859874 TI - Sequential administration of recombinant human granulocyte-macrophage colony stimulating factor and human erythropoietin for treatment of myelodysplastic syndromes. AB - Treatment of myelodysplastic syndromes (MDS) with recombinant human erythropoietin (Epo) is successful in only 10% to 25% of patients. We performed a pilot study in 10 anaemic patients with MDS to examine whether sequentially applied recombinant human granulocyte-macrophage colony-stimulating factor (GM CSF) and Epo improves haemoglobin levels and/or reduces red blood cell transfusion requirements. Morphological diagnoses of patients were refractory anaemia (RA) in 3 cases, RA with ring sideroblasts in 3 cases and RA with excess blasts in 4 cases. GM-CSF was given subcutaneously at a dose of 150 micrograms/m2/d during the initial 10 days. From day 11, Epo was administered by subcutaneous injections for 8 weeks at a dose of 100 U/kg/d and subsequently at an escalated dose of 200 U/kg/d in 3 patients. Changes in reticulocyte counts, haemoglobin levels, RBC support and ferrokinetic parameters were compared with pretreatment values. Two out of 8 evaluable patients showed a rise in haemoglobin levels at week 8 and 10, respectively, and lost their transfusion dependency for a period of 13 and 27 weeks. In 1 patient, haemoglobin level increased only after dose escalation of Epo (200 U/kg/d). Leukocyte counts remained uneffected by treatment with Epo, while 1 patient showed a 4-fold increase in platelet numbers. Toxicity was mild. Two patients died of pneumonia and global heart failure, respectively, unrelated to growth factor therapy. Based on this pilot study, we conclude that sequential treatment with GM-CSF and Epo does not increase erythroid responses in anaemic patients with MDS. Because of the delayed increase in haemoglobin in both responders, we surmise that the beneficial effects were induced by Epo alone. PMID- 7859876 TI - Mild thrombocytopenia induced by phagocytosis of marrow pseudo-Gaucher cells in a patient with chronic myelogenous leukaemia. PMID- 7859877 TI - Red blood cell volume (MCV) as a new prognostic factor of multiple myeloma. PMID- 7859878 TI - Low molecular weight heparin in the prophylaxis and treatment of disseminated intravascular coagulation in acute promyelocytic leukemia. PMID- 7859879 TI - High fluorescence reticulocytes are an indicator of bone marrow recovery after chemotherapy. PMID- 7859880 TI - High TORCH seroprevalence rate in multiply transfused beta thalassemic children in India. PMID- 7859881 TI - Treatment of refractory idiopathic thrombocytopenic purpura (ITP) PMID- 7859882 TI - Pure red cell aplasia caused by parvovirus B19 infection in a renal transplant recipient. PMID- 7859883 TI - Clinical implications of cytokine and soluble receptor measurements in patients with newly-diagnosed aggressive non-Hodgkin's lymphoma. AB - Serum levels of 13 different cytokines and receptors were measured serially in 78 patients with aggressive non-Hodgkin's lymphoma (NHL) treated by 4 cycles of an intensive multi-agent chemotherapy regimen. Recombinant human granulocyte macrophage colony-stimulating factor (GM-CSF) was administered subcutaneously in 36 of these patients from day + 5 to day + 18 after each chemotherapy. Statistically significantly higher pretreatment levels of interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10), the soluble IL-2 receptor (sIL-2r), the soluble transferrin receptor (sTf-r), and neopterin, were observed in NHL patients as compared to controls (p < 0.001 for all molecules). sIL-2r and sTf-r levels correlated with tumor burden (p < 0.001 and p = 0.003, respectively) whereas IL-6 was higher in patients presenting B symptoms (p < 0.001). Cytokine levels progressively declined to normal ranges in responding patients, while they remained elevated in non-responders. Relapsed patients also presented increased concentrations of several molecules. During the administration of GM-CSF, we observed the drastic increase of sIL-2r, while lower elevations were recorded for a number of cytokines, including IL-8, tumor necrosis factor-alpha, interleukin-1 beta, IL-6, and IL-2. However, upon completion of the induction treatment, cytokine/receptor levels were comparable among individuals with the same type of response, whether or not they had received GM-CSF. No single parameter was found to be of prognostic significance, but the combination of elevated IL-10 and of sIL-2r greater than 3000 U/ml selected a subgroup of 7 patients who failed induction treatment (p = 0.002). These results demonstrate that cytokine and soluble receptor measurements can provide valuable informations for a better management of NHL, in terms both of markers to monitor disease activity and of prognostic indicators. PMID- 7859884 TI - [The regulation of testicular function by paracrine mechanism]. AB - It is well accepted that testicular function is controlled by gonadotropins. Androgen secretion is regulated by LH, whereas spermatogenesis is controlled by FSH and locally produced androgens. However, evidence has accumulated to indicate that this extratesticular control system is modulated by equally important intratesticular cell-cell interactions. The study of this local control system has received major impetus from the development techniques which have allowed isolation and culture of purified testicular cells and has revealed that testicular cells respond to previously unexpected variable humoral factors which are produced by testicular cells themselves, namely testicular paracrinology. Numerous reviews with regard to cell-cell interactions have been published. In this paper, we attempted to summarize recent topics of para and autocrinology of testicular androgen biosynthesis and spermatogenesis. PMID- 7859885 TI - [A case of primary thyroid T-cell lymphoma with infiltration of lymphoma cells in peripheral blood: diagnosed by DNA analysis]. AB - A 57-year-old woman came to our hospital with complaints of neck swelling and headache in 1991. She was diagnosed as having chronic thyroiditis in euthyroidism because she had a diffuse goiter with both antithyroglobulin antibody (TGHA) and antimicrosomal antibody (MCHA). In 1992, she complained of the rapid growth of her thyroid gland and a swallowing disturbance. Atypical lymphocytes were observed in 16.5% of leukocytes in peripheral blood and similar atypical cells were found in bone marrow. Although an ultrasound scan of the thyroid gland revealed a symmetrical enlargement without a pseudocystic appearance, cytological study with fine needle aspiration biopsy of the thyroid gland demonstrated an abundance of atypical lymphoid cells. A whole body scintigram with 67gallium citrate showed no significant accumulation except in the thyroid gland. With a diagnosis of suspected primary thyroid lymphoma, total thyroidectomy was performed. However the diagnosis of malignant lymphoma was not confirmed histologically. A study of lymphocytes subset with two-color flow cytometry, which was performed for both lymphocytes in peripheral blood and infiltrating lymphocytes in the resected thyroid gland, revealed abnormal increased CD4 positive T cells and decreased HLA-DR expression. Additionally, southern blot DNA analysis for abnormal lymphocytes using restriction enzymes, EcoRI and BamHI, demonstrated rearrangement of the T-cell antigen receptor, which indicates a monoclonal proliferation of lymphocytes. After total thyroidectomy, atypical lymphocytes in peripheral blood decreased, and circulating autoantibodies including TGHA and MCHA disappeared. From these data, this patient was finally diagnosed as having a primary T-cell lymphoma of the thyroid gland, which is a very rare type of thyroid lymphoma.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859886 TI - [Serum levels of intact molecular osteocalcin in children with growth hormone (GH) deficiency during GH therapy: an early predictor of GH therapy]. AB - Recently we developed a sandwich enzyme immunoassay (EIA) specific for intact molecular osteocalcin (I-OC), produced only by osteoblast cell and partially released into blood circulation, to establish a specific biochemical marker of bone formation. In order to confirm whether serum I-OC levels constitute a specific marker for bone formation and to assess the relationship between serum I OC levels and growth response to growth hormone (GH) therapy, we measured the serum I-OC in serial serum samples using this EIA from 61 children with GH deficiency who showed significant bone growth during GH therapy. The serum I-OC levels in children with GH deficiency before GH therapy were slightly lower than those in normal children (Kanzaki S. et al., J. Clin Endocrinol Metab. 1992;75:1104-9), and had a wide distribution overlapped with the normal range. These levels were apparently increased during GH treatment; that is, in contrast to the levels of 22.9 +/- 1.5 ng/ml (mean +/- SE) before GH treatment, the levels after 1 and 2 months of GH treatment were 29.1 +/- 1.6 ng/ml and 32.5 +/- 1.8 ng/ml, respectively. However, they decreased slightly at 3 months and then they gradually rose to 37.5 +/- 2.8 ng/ml after 12 months, I-OC ratios, represented by the I-OC level at each month of GH therapy in relation to pretreatment level, correlated well with the growth response (growth velocity, growth velocity SD score and delta growth velocity SD score) after 12 months of GH treatment. Correlation coefficients of the growth velocity versus I-OC ratio at 1 and 6 months of GH treatment were 0.677 (p < 0.001, N = 58) and 0.752 (p < 0.001, N = 55), respectively. However, both IGF-I and ALP ratios represented in the same way as the I-OC ratio, correlated poorly as compared with the I-OC ratio. These results demonstrate that the change of serum I-OC levels indicates a direct and sensitive reflection of bone formation, because serum I-OC levels significantly increased with the growth response to GH therapy. The measurement of serum I-OC levels after 1 month of GH treatment may be a useful tool in predicting improved growth velocity during long-term GH therapy. PMID- 7859887 TI - [A case of familial Mediterranean fever with obvious family history]. AB - A 26-year-old female was admitted to our hospital on December 4, 1992, because of recurrent fever. She had experienced recurrent fever of over 38 degrees C, occurring at irregular intervals 4-6 times a year with chest or abdominal pain, since the age of 19. After delivery of a baby at the age of 25, her symptoms had increased to once a week. In the febrile phase, leukocytosis, an increased erythrocyte sedimentation rate and positive CRP were recognized. These symptoms and laboratory findings spontaneously disappeared within a few days. Despite systemic and careful examinations, no evidence of infectious diseases, collagen diseases or malignant diseases were found. There were no significant differences of serum and urine catecholamines, and urine etiocholanolone between the febrile phase and the afebrile phase. An intravenous infusion of metaraminol induced symptoms similar to a spontaneous attack, and the metaraminol rechallenge test became negative after she was treated with oral colchicine. Based on these findings, she was diagnosed as having familial Mediterranean fever. Since she was treated with colchicine, the febrile attacks have decreased. Significantly, her elder brother has had similar recurrent fever with abdominal pain. He was diagnosed as having familial Mediterranean fever due to a positive metaraminol provocative test, and his febrile attacks have also been suppressed by colchicine. This is the first case of familial Mediterranean fever with obvious family history in Japan. PMID- 7859888 TI - [Clinical significance of the measurement of the urinary concentration of iodine in differentiating silent thyroiditis from Graves' disease]. AB - In order to differentiate silent thyroiditis (SLT) from Graves' disease, the usefulness of the measurement of the urinary concentration of iodine was evaluated in this study. The subjects employed were 39 patients with SLT and 40 patients with Graves' disease. Patients were advised to avoid any iodine containing food or medication for a week before the examination. The urinary concentration of iodine (UI) and the serum concentration of thyroid hormones were determined. UI was calculated from the amount of iodine in the spot urine by multiplying it by the ratio of iodine to creatinine. Since the UI value thus obtained was significantly well correlated with the UI value for 24 hour urine, the former value was used instead of the latter value thereafter. Mean UI value in the patients with SLT was 482.4 +/- 296.4 mu g/day and that in the patients with Graves' disease was 169.8 +/- 75.2 mu g/day, the former value being significantly higher than the latter (p < 0.0001). A strong and significant correlation between UI and the serum concentration of FT4 or T3 (TT3) was found in the patients with SLT (r = 0.76, p < 0.0001 and r = 0.54, p < 0.02), but not in those with Graves' disease (r = 0.34, p = 0.07 and r = 0.24, p = 0.14) Mean UI/FT4 ratio and mean UI/TT3 ratio was significantly higher in patients with SLT than those with Graves' disease and the overlaps in the ratios between these two groups were very slight. These results indicate that both the ratios of UI/FT4 and UI/TT3 were useful parameters to differentiate SLT from Graves' disease. The higher UI value observed in the patients with SLT was thought to be due to the increase in the amount of inorganic iodine which was liberated from the iodinated material leaked from the damaged thyroid tissue by the deiodinating mechanism in the peripheral tissues. PMID- 7859889 TI - [The variation of Japanese urinary excretion of iodine in different decades of age]. AB - In order to evaluate whether or not iodine intake in Japanese is variable among different aged subjects and also whether this variation is concordant with the age distribution in patients with chronic thyroiditis, we tried to examine the urinary iodine excretion of euthyroid people in various decades of age. One hundred and twenty outpatients without thyroid disorders, aged 22 to 77 y.o., were selected at random and were divided into 6 groups according to age. Mean total urinary iodine excretion (UIT) and concentration (UIC) were 336.1 micrograms/day and 31.4 micrograms/dl/cr, respectively, and they were in good correlation (r = +0.82, p < 0.001). A straight line on log normal probability was recognized between the ratio of cumulative frequency and values of UIT. UIT and UIC were significantly correlated with serum nonhormonal iodine, respectively (r = +0.21, p < 0.01; r = +0.28, p < 0.01). These indicators in the 3rd decade were lower than those in the 6th decade (p < 0.01, p < 0.05). UIT increased with age up to the 6th decade and then decreased gradually to the 8th decade. Therefore, UIT in all the subjects formed a bell-shaped distribution with a significant peak in the 6th decade (H = 12.1, p < 0.05). Rates of renal iodine clearance (UIC/SNI) in the 6th decade increased significantly more than those in the 4th decade (p < 0.01), and the distribution of those rates in the 6 groups were similar to that of UIT.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859890 TI - [The effect of occult hyperprolactinemia (OHP) on gonadotropin secretion system]. AB - The present study was conducted to investigate the effects of the transient increase of serum prolactin levels on the gonadotropin secretion system in patients with occult hyperprolactinemia (OHP). 216 cases of normoprolactinemic hypothalamic anovulatious were selected by LH-RH and TRH loading tests, and 5mg/day of bromocriptine was administered for more than 8 weeks. The effectiveness of the bromocriptine administration was estimated by the ultrasonic examination of the follicular development. The endocrinological backgrounds were compared between bromocriptine effective (154 cases, group A) and non-effective (62 cases, group B) patients. Serum prolactin levels 30min. after LH-RH and TRH loading (PRL30 in group A were significantly higher than those of group B (74.1 +/- 36.5 vs. 38.0 +/- 18.2ng/ml, p < 0.01). From this result, it was thought that many of the OHP patients were selected in group A. Serum LH levels 30min. after loading test (LH30) in group A also increased compared to those of group B (65.0 +/- 66.5 vs. 43.1 +/- 34.3mIU/ml, p < 0.02). The LH/FSH ratio before loading was also higher in group A (1.3 +/- 0.6) than that of group B (1.0 +/- 0.5, p < 0.02). This fact showed that group A also contained patients with hyper-LH hypothalamic anovulation, which is known as the endocrinological PCOD. There were also significant inverse correlations between serum levels of prolactin and FSH in group A (before loading values: r = 0.272, 30min. after loading: r = 0.224, p < 0.01). By the administration of bromocriptine, serum prolactin levels decreased both in group A and B, and the elevated serum LH/FSH ratio (1.0 +/- 0.4, p < = 0.02), LH30 (46.1 +/- 37.0mIU/ml, p < 0.005) also decreased significantly. Serum levels of FSH in group A increased significantly with treatment (before loading: 5.4 +/- 2.6-->6.2 +/- 2.0, 30min. after loading: 10.6 +/- 6.0-->14.6 +/- 9.9mIU/ml, p < 0.005). From these facts, it was concluded that FSH secretion was suppressed even by a slight increase of serum prolactin levels which was usually seen in the OHP, and bromocriptine administration was effective not only for the suppression of serum prolactin and LH levels, but also for the improvement of FSH secretion in the OHP patients. PMID- 7859891 TI - Medical hypothesis: cardiovascular complications of diabetes mellitus-from glucose to insulin and back. AB - Vascular complications such as atheroma, hypertension and macroangiopathy are the leading causes of morbidity and mortality in diabetic patients. Epidemiological and clinical data linking hyperinsulinaemia to both hypertension and atherosclerosis are inconsistent. Hyperglycaemia is the distinguishing feature of diabetes and it seems a likely candidate for the poor cardiovascular outlook of diabetic patients. High blood glucose levels cause selective impairment of endothelium-dependent relaxation and delay cell replication time of cultured human endothelial cells. These effects of hyperglycaemia are reversed by a number of antioxidants, including superoxide dismutase, catalase and glutathione. Impaired endothelium-dependent vasodilation has been reported both in Type 1 and Type 2 diabetic patient. The evidence for a role of oxygen-derived free radicals in the pathogenesis of vascular diabetic complications can be summarized as follows: 1) glucose can auto-oxidize generating oxygen derived free radicals; 2) elevated levels of oxygen derived free radicals are found in red blood cells, plasma and retina of diabetic animals and patients, and correlate with metabolic control; 3) endogenous antioxidants are all decreased in diabetic tissues and blood; and 4) treatment with different antioxidants may improve many of the metabolic abnormalities reported to occur in diabetic patients. The use of antioxidants to reduce the risk of coronary heart disease in diabetes should await the results of randomized trials with these drugs in the primary and secondary prevention of coronary disease. PMID- 7859892 TI - Lipoprotein (a) and other risk factors in children with insulin-dependent diabetes mellitus and children without diabetes. AB - AIMS: To study serum Lp (a) levels and other metabolic cardiovascular risk factors in children with type 1 diabetes mellitus (DM) as compared to sex and age matched nondiabetic children. The correlation of Lp (a) serum levels and other lipid parameters with HbA1c concentration in diabetic children was investigated. DESIGN: Transversal observational study. TARGET POPULATION: 36 C-peptide negative Type 1 diabetic children without microalbuminuria and no macromicrovascular nor neurological complications, aged 8 to 15 years; 17 boys, 19 girls. Mean duration of Type 1 diabetes was 4.99 +/- 3.04 years, daily insulin needs 32.79 +/- 12.64 Units. 41 healthy children with no family history of diabetes mellitus, aged 8 to 15 years, 26 boys, 15 girls, were studied in parallel as the control group. METHODS: Serum total cholesterol and triglycerides were assayed by enzymatic methods, High-density lipoprotein (HDL) cholesterol by enzymatic method after precipitation of very-low-density (VLDL) and low-density lipoprotein (LDL) fractions. The LDL fraction was estimated after serum precipitation as the difference between total cholesterol and supernatant cholesterol concentrations. Apo-AI, apoA-II and apo-B were measured by radial immunodiffusion assays. Serum Lp(a) was measured by a monoclonal anti-Lp(a) antibody (ELISA) method and whole blood glycosylated hemoglobin A1c (HbA1c) by high resolution liquid chromatography. RESULTS: HbA1c concentration in diabetic children was 7.51 +/- 1.54% vs 4.16 +/- 0.35% in nondiabetic children. Lp(a) serum levels did not significantly differ among both groups (25 +/- 22 mg/dl in diabetics; 22 +/- 22 mg/dl in controls). Significant correlation was found between HbA1c levels and each of TC, LDL and TG serum concentrations in the diabetic group. Lp (a) levels were only correlated with glycated hemoglobin in the two patients showing the highest levels of HbA1c; in the diabetic group: HbA1c 10.9 and 11.5%. CONCLUSIONS: In 36 children aged 8-15 years with uncomplicated Type 1 diabetes for less than 15 years duration, Lp (a) serum levels were positively correlated with HbA1c only in two of them showing the poorest metabolic control. PMID- 7859893 TI - Management of type 2 diabetes mellitus in France: attitudes and practices among a representative sample of general practitioners. AB - PURPOSE: Medical knowledge regarding chronic illness has increased in recent years. Critical gaps in our understanding of the educational factors necessary to change the clinical aspects of most diseases remain. The role of the general practitioner, the primary care provider, in the delivery of educational interventions has not been clearly defined. METHODS: For the first phase in the educational diagnosis of Type 2 diabetic patients treated by general practitioners in France, a stratified random sample of 8% of general practitioners was drawn; 70% agreed to be interviewed. RESULTS: Demographic characteristics of physicians were comparable with previous studies. Physicians accepted the seriousness of the disease. 75.9% devoted at least as much time to the psychological as to the somatic aspects of the disease. 74.7% reported using a co-active approach with patients, permitting the use of more innovative educational strategies. Logistic regression analysis indicated that the ages of the physicians and patients, inclusion of the family, the number of patients seen, and the perception of patients as compliant were predictive of the co active approach. CONCLUSIONS: The overwhelming proportion of physicians who use the co-active approach was the single most important factor in the development of an educational intervention where the general practitioner serves as the primary, continuous reinforcer for long-term behavior change. This program is currently being tested in a randomized clinical trial among general practitioners in France. PMID- 7859894 TI - [Quality of life of patients during treatment of type I diabetes. Importance of a questionnaire focused on the subjective quality of life]. AB - The aims of this study were 1) to study the quality of life in diabetic patients receiving one of two different forms of insulin delivery and 2) to check in this disease, the reliability and responsiveness of a questionnaire (SQLP: subjective quality of life profile) which we have previously used and validated in other pathological states. A total of 743 Type 1 diabetic subjects, receiving two different forms of insulin injection completed this questionnaire twice, at a monthly interval. These patients stressed a certain number of somatic manifestations as well as their difficulty to move around or perform every-day life activities. The results from this trial show that the questionnaire was capable of demonstrating that the easiest mode of insulin injection was selectively and significantly related to a higher satisfaction with being able to move around. PMID- 7859895 TI - Abnormalities suggestive of cardiomyopathy in patients with type 2 diabetes of relatively short duration. AB - OBJECTIVE: The aim was to assess the presence of cardiomyopathic features in asymptomatic patients with Type 1 and Type 2 diabetes mellitus. RESEARCH DESIGN AND METHODS: Fifty-two (27 Type 1; mean duration: 10.2 +/- 7.4 yr; 25 Type 2, mean duration: 6.5 +/- 4.4 yr) diabetic patients with no signs of ischaemic heart disease or high blood pressure were studied by noninvasive techniques: Holter ECG; Filtered-Amplified ECG (FAECG); Exercise ECG; Echocardiography (BD, TM) and Doppler evaluation of diastolic parameters. Twenty-four healthy subjects matched for age were studied as controls. RESULTS: Holter ECG did not detect rhythm disturbances or features of silent ischaemia in either group of patients. With FAECG, at least one criterion of late ventricular potentials was found in 28% of Type 2 patients, vs 11% of Type 1 patients and 8.3% of control subjects. With exercise ECG, maximum oxygen uptake, anaerobic threshold, and workload performance were all significantly lower in Type 2 patients compared to control subjects. Echocardiography depicted a greater end diastolic interventricular septum thickness in Type 2 patients than in control subjects, with a trend toward left ventricular hypertrophy in 28% of Type 2 and 7.4% of Type 1 patients. Doppler echocardiography revealed a significant decrease in early diastolic peak filling rates (E) in diabetic patients as a whole group (Type 1 + Type 2) compared to controls. Late diastolic peak filling rates (A) were significantly higher in Type 2 patients than in their controls. The E/A ratio was significantly lower in diabetic patients (as a whole group) than in control subjects; this was accounted for mainly by a significant decrease of E/A in Type 2 patients compared to their controls. CONCLUSIONS: Our major finding rests on the disclosure of abnormalities suggestive of cardiomyopathy in Type 2 diabetic patients with a relatively short duration of the known disease, while these alterations appeared in our study less prominent in Type 1 patients despite a longer duration of the disease. Among the various noninvasive techniques, FAECG and Doppler echocardiography used to detect late ventricular potentials and to assess left ventricular diastolic dysfunction, respectively, appear to be suitable tools. PMID- 7859896 TI - [Effect of arterial pressure level evaluated using ambulatory measurement on the two year course of microalbuminuria of type 1 diabetic subjects]. AB - The aim of the present study is the evaluation two years apart of the effect of initial blood pressure values on ambulatory blood pressure determinations on the rise of microalbuminuria in 77 Type 1 diabetic patients. At the beginning of the study, subjects with incipient nephropathy have a whole day systolic and diastolic blood pressure greater than those whose microalbuminuria is below than 30 mg/24 h (127.7 +/- 15.1 mmHg versus 115 +/- 14.3 mmHg, p < 0.001; 76.6 +/- 8.1 mmHg versus 72.5 +/- 7.3 mmHg, p < 0.05). Among patients whose initial microalbuminuria was lower than 30 mg/24 h, incipient nephropathy will not be dependent on initial blood pressure values but conditioned by patients' age and duration diabetes of mellitus. On the other hand, blood pressure increases the microalbuminuria of the patients who had incipient nephropathy at the beginning of the study. In patients with diabetes mellitus, ambulatory blood pressure monitoring appreciates the impact of the pressure rise on the kidney, retina and heart. PMID- 7859898 TI - Type 1 diabetes mellitus and homocyst(e)ine. AB - High Homocyst(e)ine levels (H) have been recently recognized as a risk factor for atherosclerosis. Patients with Diabetes Mellitus (DM) are prone to atherosclerosis. Therefore, this study was designed to search for the effect of DM on H and their relationship. Forty-one Type 1 diabetic subjects (DS, age 34.8 +/- 12 yr, DM duration: 10.7 +/- 11.1 yr) were compared to 40 age-matched control subject (CS, age 34.2 +/- 9.1 yr). H (measured by ion-exchange chromatography, units: mumol/l) and several parameters (creatininemia; triglycerides; total, HDL, LDL cholesterol; Lp(a); HbA1c; vitamins B9 and B12) were determined after an overnight fast. H were significantly (p = 0.0001) lower in DS (6.8 +/- 2.2) than in CS (9.5 +/- 2.9). This difference was still apparent in male and female subgroups compared to matched CS (p = 0.003 for each). No correlation was found between H and: lipids, vitamins, renal or retinal status. But H seemed to increase with age, especially in women (p = 0.03; r = 0.32). While there is, at this time, no explanation for the lower H observed in DS, it appears that H cannot directly account for accelerated atherosclerosis in DM. Nevertheless, it remains to be established if high, or even normal, H could identify a subgroup of DS at higher risk of precocious and severe atherosclerosis. PMID- 7859897 TI - Effects of captopril on ambulatory blood pressure, renal and cardiac function in microalbuminuric type 1 diabetic patients. AB - OBJECTIVE: To study the effect of Captopril on ambulatory blood pressure, renal and cardiac function and extracellular volume in microalbuminuric Type 1 diabetic patients. DESIGN: Randomized, double blind placebo controlled study of two years duration. SETTING: University clinic. PATIENTS: Twenty-two patients without hypertension. INTERVENTION: Patients received 50 mg Captopril or placebo twice a day. MEASUREMENTS: Ambulatory blood pressure, renal function, extracellular volume, and echocardiographic indices of cardiac function and dimensions were assessed annually. Clinic blood pressure and urinary albumin excretion were measured every 3 months. RESULTS: Twenty-four hour mean arterial blood pressure was unchanged in the Captopril group (mean +/- SD) (baseline 93 +/- 4 and follow up 91 +/- 8 mmHg) and in the placebo group (96 +/- 7 and 97 +/- 10 mmHg, NS). Night/day ratio of blood pressure was unaffected. Glomerular filtration rate was unchanged and renal plasma flow increased in the Captopril (557 +/- 97 and 600 +/ 112 ml min-1) versus the placebo group (574 +/- 85 and 535 ml min-1, p = 0.05). Filtration fraction was reduced in the Captopril versus the placebo group (p < 0.05). Extracellular volume and echocardiographically derived parameters were unaffected. The relative change in day time mean arterial blood pressure in the Captopril group correlated with changes in urinary albumin excretion (Spearmans r = 0.85, p < 0.05) unlike clinic mean arterial blood pressure (r = 0.33, p = 0.35). CONCLUSION: Diurnal rhythm of blood pressure was unaffected by long term administration of Captopril. Renal plasma flow was increased and filtration fraction reduced. A significant association between changes in urinary albumin excretion and blood pressure after Captopril was revealed only by the implementation of ambulatory blood pressure measurements. PMID- 7859899 TI - [Should we prescribe regular physical activity for patients presenting with type 2 diabetes?]. PMID- 7859900 TI - Absence of microalbuminuria in insulin resistant patients with angina pectoris and normal coronary arteries (syndrome X) PMID- 7859901 TI - The menopausal transition: a dynamic approach to the pathogenesis of neurovegetative complaints. AB - In our cross-sectional study we investigated the separate influence of three main factors, namely menopausal and estrogen status, and chronological age, on ten neurovegetative climacteric complaints reported in the scale of Kupperman et al. A multivariate statistical analysis was performed by a multivariate statistical approach on 1161 untreated women seen at the Menopause Center of the Ferrara University Hospital. Ninety women (age range, 41-54 years) were premenopausal; 492 women (age range, 38-55 years) were perimenopausal with irregular periods or amenorrhea for less than 12 months; 468 women (age range, 41-69 years) had a spontaneous menopause (age range, 37-66 years); 111 had had hysterectomy with bilateral ovariectomy while still regularly menstruating. Serum estrone was used as the indicator of the patients' estrogen status. A clear positive trend was demonstrated between menopausal status and the prevalence of depression, hot flushes, insomnia and joint pain. However, only the prevalence of hot flushes amongst these four symptoms was significantly related with the climacteric estrogen decline (beta = -0.006, P = 0.001). Moreover, menopausal status appeared to influence the intensity of fatigue, hot flushes, insomnia and paresthesia. Age was found to significantly (P = 0.053) co-vary only with the intensity of the hot flushes, with a positive relation (beta = 0.092, r = 0.104, P = 0.003), whereas estrone values did not significantly co-vary with any symptom. Furthermore, while neurovegetative symptoms are largely present also in the absence of hot flushes, when these latter are present, they exacerbate both the intensity and the prevalence of all the other symptoms.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859902 TI - Vascular resistance in uterine and ovarian arteries: its association with infertility and the prognosis of infertility. AB - In this study we investigated the blood flow in uterine (u.a.) and ovarian arteries (o.a.) in healthy women and infertility patients and the relationship of vascular resistance to the etiology and the prognosis of infertility. A total of 101 consecutive infertility patients referred to hospital for investigations were studied by Doppler ultrasound. Couples with male infertility were excluded. The control group comprised 19 healthy women having regular menstrual cycle and no history of infertility. The pulsatility index (PI) in o.a. and u.a. was measured in pre- and post-ovulatory phase of the menstrual cycle. The PI values of the controls were compared with those of the patients with various infertility etiologies. The PI values of the infertility patients who subsequently delivered were compared with those of the patients failing to deliver. Infertility patients had high PI in o.a. and u.a. in the luteal phase more often than controls. High vascular resistance in u.a. and o.a. in the luteal phase reduce the take-baby home rate. PMID- 7859903 TI - Amino acids, glucose and lactate concentrations in umbilical cord blood in relation to umbilical artery flow patterns. AB - OBJECTIVE: To study possible relationships between abnormal placental perfusion, hypoxemia and impaired fetal nutrient supply. STUDY DESIGN: Umbilical artery flow velocity waveforms were assessed in high risk pregnancies and compared with controls. Three groups were studied. In group I (n = 13) the pulsatility index (PI) was within normal limits, in group II (n = 9) PI was > 2 S.D. in the presence of positive end diastolic velocities and in group III (n = 13) end diastolic velocities were absent. pH and PO2 levels and concentrations of amino acids, glucose and lactate were measured in umbilical blood obtained at cesarean section (n = 35). RESULTS: An inverse correlation was found between concentrations of essential amino acids concentrations and the pulsatility index in the umbilical artery (P = 0.03). No correlation with hypoxemia was found (P = 0.32). The glycine/valine ratio was significantly increased in the groups with abnormal Doppler velocity indices (P = 0.02). Glucose concentrations were significantly reduced in the case of absent end diastolic velocities (P = 0.001). No significant differences were found between the three groups concerning lactate concentrations and acid-base balance parameters. CONCLUSIONS: These findings, especially the increased glycine/valine ratio, which is characteristic for kwashiorkor, indicate that abnormal placental perfusion is associated with impaired fetal nutrient supply, in the presence of a normal fetal oxygenation. PMID- 7859905 TI - Placenta percreta with bladder invasion: surgical strategy to avoid massive blood loss. AB - Placenta percreta with bladder invasion is a rare complication of pregnancy, causing life-threatening hemorrhage. We report two further cases. In the second case we opted for a specific surgical guideline based on immediate ligature of both the hypogastric arteries before hysterectomy. This approach resulted in considerably less blood loss than is usually reported. PMID- 7859904 TI - Relaxin (hRLX-2)-induced weakening of human fetal membranes in vitro. AB - We examined the effect of human relaxin (hRLX-2) on the biomechanical properties of human fetal membranes in vitro. Intact chorioamniotic membranes were obtained from twelve elective cesarean sections before the onset of labor. Membrane strips with a fixed width were biomechanically tested after incubation for 20 h with hRLX-2 in concentrations of 10(-7) mol/l and 10(-9) mol/l. Incubation with hRLX-2 (10(-9) mol/l) changed the load-strain values as the membrane stiffness was decreased by 19% when compared with controls: median 2.45 N (range, 0.81-4.31) versus 3.03 N (1.28-5.46), P = 0.02 (Mann-Whitney test). For description of the membrane material as such, the stress-strain values were calculated by dividing the load-strain values with the cross sectional area of the membranes. Incubation with hRLX-2 (10(-9) mol/l) decreased the tensile strength of the membranes by 30% 0.817 N/mm2 (0.282-1.139) vs. 0.575 N/mm2 (0.101-1.150), P = 0.03--and reduced the elastic modulus by 31%--2.26 N/mm2 (0.82-5.08) versus 1.57 N/mm2 (0.51-3.71), P = 0.002. Less pronounced effects were found after incubation with hRLX (10(-7) mol/l). No quantitative or qualitative changes of the membrane collagen were found after relaxin incubation. Although the mechanism for rupture of the fetal membranes remains unknown, the present results suggest that relaxin might be involved in the process leading to rupture of the membranes. PMID- 7859906 TI - Family planning investing in the future. PMID- 7859907 TI - Prolonged intravenous ritodrine therapy: a comparison between multiple and singleton pregnancies. AB - To compare multiple and singleton pregnancies in the treatment of threatened preterm delivery with prolonged intravenous ritodrine, 32 women with multiple pregnancy (26 twins, 6 triplets, 70 fetuses, 30.3 +/- 3.5 weeks) and 51 women with singleton pregnancy (31.3 +/- 2.6 weeks) admitted for threatened preterm delivery without rupture of the membranes were the subjects of a retrospective study of obstetric data, perinatal outcome and maternal adverse effects. Significance was assessed by chi 2 test and Student's t test. Multiple pregnancies were associated with a marked increase in the duration of tocolysis (17.2 +/- 17.3 vs. 7.6 +/- 8.1 days, P < 0.01), incidence of delivery before 37 weeks (87.5 vs. 35.3%, P < 0.01) and incidence of maternal cardiovascular complications (34.4 vs. 4.0%, P < 0.01), including three cases of pulmonary edema. The incidences of delivery before 32 weeks (12.5 vs. 7.8%) and of neonatal death (2.9 vs. 0%) were not significantly different in the two groups. Multiple pregnancies dramatically increased the incidence of maternal adverse effects of prolonged intravenous ritodrine therapy. Neonatal benefit is questionable and was difficult to establish since it was not a randomized study. PMID- 7859908 TI - Fetal pulse oximetry: correlation between changes in oxygen saturation and neonatal outcome. Preliminary report on 39 cases. AB - Arterial oxygen saturation of the fetus during labour (SPO2) measured with a fetal pulse oximeter was compared to the neonatal condition measured by umbilical vein pH and Apgar score. Changes in oxygen saturation (index of desaturation) during the second stage of labour were also compared to neonatal outcome. Fifty five patients with abnormal fetal heart rate pattern during labour had a continuous monitoring of fetal oxygen saturation using the Nellcor N-400 pulse oximeter. SPO2 measurement during the last 10 min of labour was significantly correlated to umbilical vein pH and to 1-min Apgar score (P = 0.022 and P = 0.025, respectively). A much higher correlation was found between the index of desaturation and umbilical vein pH at birth and with 1-min Apgar score (P = 0.002 and P < 0.001, respectively). When considering the lower value of umbilical vein pH at birth to be 7.20, and the normal value of SPO2 during labour to be > or = 40% (negative test), we observed a 100% negative predictive value of oximetry. If these results are confirmed in a larger series of patients, analysis of the changes in fetal arterial oxygen saturation during labour (index of desaturation) could be a good indicator of the condition of the newborn. A normal SPO2 value during labour could be reassuring in case of abnormal fetal heart rate. PMID- 7859909 TI - The impact of timing and frequency of prenatal visits on the outcome of pregnancy in the perinatal registry of Bavaria 1987-1988. AB - A retrospective analysis was made on the singleton births included in the Bavarian statewide perinatal registry (Bayerische Perinatalerhebung, BPE; 99,252 births from BPE 1987 and 79,661 births from BPE 1988) with respect to the timing of the first prenatal consultation and the frequency of visits during pregnancy. If the first prenatal visit was scheduled after 21 weeks, the rates of infants transferred to pediatric units relative risk (RR = 1.34, P < 0.0001, chi 2-test), of low birth weight (RR = 1.41, P < 0.0001) and of stillbirths (RR = 1.70, P < 0.025) were higher than if the first visit was at 9-12 weeks. Similarly, after < 4 prenatal visits, the rates of infants transferred (RR = 3.91), of low birth weight (RR = 9.18), of stillbirths (RR = 7.65) and of neonatal deaths (RR = 29.5) were significantly (P < 0.0001) higher than after > 10 visits. Prenatal care was defined as 'standard' if the initial consultation was scheduled at or before 12 weeks and whether 10-12 visits were completed during a normal duration of pregnancy. 'Below standard' prenatal care was associated with a higher rate of infants transferred (P < 0.01) and of stillbirths (P < 0.0005). Prenatal care was more frequently (P < 0.0001) classified as 'below standard' in mothers older than 39 years (40.45%, RR = 2.45) and in adolescent mothers (58.67%, RR = 5.12) than in those 25-29 years of age (21.71%), in fourth and subsequent (48.22%, RR = 3.44) than in first pregnancies (21.32%) and in foreign (39.65%, RR = 2.18) than in German mothers (23.19%).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859910 TI - Laparoscopic study on the microbiology and severity of acute pelvic inflammatory disease. AB - OBJECTIVE: To study the microbiologic findings in relation to the severity of acute pelvic inflammatory disease (PID). STUDY DESIGN: Of 72 women with acute PID verified and graded by laparoscopy and endometrial histopathology, 37 had mild PID and 35 had severe PID. Cervical, endometrial and tubal cultures were obtained for Chlamydia trachomatis, Neisseria gonorrhoeae, genital mycoplasmas, facultative and anaerobic bacteria and herpes simplex virus. RESULTS: C. trachomatis was the primary pathogenic agent in 44% of patients with acute PID. C. trachomatis and N. gonorrhoea were as common in both severity groups, although C. trachomatis was isolated significantly more frequently from the fallopian tubes among cases with severe PID. Where aerobic or facultative bacteria other than C. trachomatis or N. gonorrhoeae were concerned, Escherichia coli and Haemophilus influenzae were the most important aerobic bacteria isolated from the fallopian tubes. Anaerobic bacteria were recovered from the fallopian tubes significantly more frequently in cases with severe PID than in those with mild PID, whereas their presence in the endometrium was not related to the severity of PID. CONCLUSIONS: The role of C. trachomatis as the leading cause of PID was confirmed in both laparoscopically mild and severe PID. Severe PID with abscess is invariably a polymicrobial infection with anaerobic bacteria involved, whereas their role in affecting the outcome of mild PID as well as the need of antianaerobic antimicrobial therapy in mild PID remains questionable. PMID- 7859911 TI - Tubal histopathology in ectopic pregnancies. AB - A histopathologic study in eighty six patients with ectopic pregnancy and in eighty six control patients was undertaken to evaluate the association between ectopic pregnancy and tubal pathology in our population. Fifty six (65%) and nine (10.4%) cases with chronic salpingitis (CS) were diagnosed in the study group and in the control group, respectively. This difference was statistically significant (p < 0.001). Twelve of 56 cases with chronic salpingitis were salpingitis isthmica nodosa (SIN) and no patient with SIN was observed in the control group. SIN was always concomittant with chronic salpingitis in our study. Based on these findings, we concluded that chronic salpingitis and SIN have an important role in the etiology of ectopic pregnancy in our population and SIN is significantly associated with chronic salpingitis. PMID- 7859912 TI - The view of women aged 45-65 and their partners on aspects of the climacteric phase of life. AB - OBJECTIVE: to make an inventory of the opinions and attitudes of the Dutch female population (aged 45-65) and their partners on the climacteric period. DESIGN: Data were collected as part of a weekly computer assisted questionnaire filled in by a representative panel composed of 234 women aged 45-65 and their partners. SETTING: A random sample of the population of The Netherlands. RESULTS: 12% of the women were current users of hormone replacement therapy (HRT), 21% had been hysterectomized, 32% were smokers. Although the prevalence of climacteric symptoms was as expected, only 1 out of 3 peri- and post-menopausal women were really troubled by the symptoms and had consulted a physician. The attitude towards HRT was neutral. Most women preferred a natural approach as a solution to the problems. Information on the climacteric was mostly obtained via the media, but in general the self-assessed level of knowledge was regarded by the panel as very low, even in current HRT users. Women on HRT were more positive toward treatment, and less confident about the spontaneous disappearance of the problems. Nearly all women, including current HRT users, regarded the absence of menstruation as a relief. Partners of climacteric women had the same opinion as their wives on all items. CONCLUSION: There is a lack of information on the climacteric and on the use of HRT. The Dutch female population tends to a natural approach of the climacteric without medication, but the general attitude can be regarded as neutral. PMID- 7859913 TI - Receptor-mediated effects of angiotensin II on neurons. AB - Aside from its well-known and numerous actions at peripheral tissues, the octapeptide angiotensin II (ANG II) elicits specific receptor-mediated effects within the central nervous system. In this review we focus on the receptor mediated actions of ANG II on neurons. The distribution of ANG II receptors in the brain and physiological, electrophysiological, and cellular effects mediated by these receptors are discussed. This is extended to a review of the characteristics of ANG II receptor subtypes on cultured neurons and the cellular and genomic actions mediated by these receptors. Finally, we develop this information into speculative models for the cellular effects mediated by each ANG II receptor subtype in neurons. PMID- 7859914 TI - Osmoreceptors, osmoreception, and osmoregulation. AB - Mammals have evolved sophisticated behavioral and physiological responses to oppose changes in the osmolality of their extracellular fluid. The behavioral approach consists of regulating the intake of salt and water through changes in sodium appetite and thirst. The physiological approach comprises adjustments of renal excretion of water and sodium which are achieved through changes in the release of antidiuretic and natriuretic hormones. Individually, these osmoregulatory responses are controlled by "osmoreceptors": groups of specialized nerve cells capable of transducing changes in external osmotic pressure into meaningful electrical signals. Some of these sensors are located in the region of the hepatic portal vein, a strategic site allowing early detection of the osmotic impact of ingested foods and fluids. Changes in systemic osmolality, however, are detected centrally, within regions that include the medial preoptic area, the median preoptic nucleus, the organum vasculosum lamina terminalis (OVLT), the subfornical organ, and the supraoptic nucleus (SON). While studies have indicated that these central and peripheral osmoreceptors participate in the control of osmoregulatory responses, little is known of the mechanisms by which this is achieved. One notable exception, however, consists of the osmotic control of electrical activity in SON neurons which, in the rat, contributes to the regulation of natriuresis and diuresis through effects on the secretion of oxytocin and vasopressin. Previous studies have shown that these cells are respectively excited and inhibited by hypertonic and hypotonic conditions. Experiments in vitro indicate that these responses result from both the endogenous osmosensitivity of these cells and changes in synaptic drive. Patch clamp analysis has revealed that SON neurons are respectively depolarized and hyperpolarized by increases and decreases in external osmolality and that these intrinsic responses result from changes in the activity of mechanosensitive cationic channels. Moreover, intracellular recordings in hypothalamic explants have shown that changes in electrical activity are associated with proportional changes in the frequency of glutamatergic excitatory postsynaptic potentials derived from osmosensitive OVLT neurons. Both of these mechanisms, therefore, may participate in the osmotic regulation of neurohypophysial hormone release in situ. PMID- 7859915 TI - Probing the brain and spinal cord with neuropeptides in pathways related to pain and other functions. AB - The principles involved in the fabrication and use in vivo of antibody microprobes are described. These devices have shown that immunoreactive (ir) substance P and ir-neurokinin A are released in the region of the substantia gelatinosa of the spinal cord when impulses arrive in nociceptors. Particularly with ir-neurokinin A, rapid inactivation does not appear to occur, resulting in the released neuropeptides accessing sites relatively remote from sites of release. Microprobes have also provided evidence that the sites accessed by ir substance P are controlled by spinal cord peptidases and that peptidase inhibition by the endogenous neuropeptide calcitonin gene-related peptide expands the distribution of sites reached. Inflammatory joint disease results in a relatively massive central release of ir-substance P when the damaged joints are flexed or compressed. Antibody microprobe studies of the spinal release of ir galanin have favored release from intrinsic spinal neurons rather than from primary afferent terminals following peripheral noxious stimuli. Immunoreactive somatostatin was found to be released following noxious thermal but not noxious mechanical peripheral stimuli but it is uncertain whether this results from release predominantly from primary afferents or intrinsic spinal neurons. Studies using antibody microprobes inserted into the brain have detected the release of ir-substance P in the ventral region of the striatum following administration of amphetamine. Microprobes have also followed peptide release from striatal terminals in substantia nigra and have provided evidence of a basal presence of ir-neurokinin A but not of substance P. Depletion of the dopamine input to the striatum, or blockade of dopamine receptors, caused considerable reduction of ir neurokinin A released within the substantia nigra. PMID- 7859916 TI - Cloning and tissue distribution of the human 11 beta-hydroxysteroid dehydrogenase type 2 enzyme. AB - The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta HSD) is thought to protect the non-selective mineralocorticoid receptor from occupation by glucocorticoids, and to modulate access of glucocorticoids to glucocorticoid receptors resulting in protection of the fetus and gonads. A ubiquitous low affinity NADP+ dependent enzyme (11 beta HSD1) and a tissue specific, high affinity NAD+ dependent form (11 beta HSD2) of 11 beta HSD exist. We now report the isolation of a cDNA coding for human 11 beta HSD2. The new isoform is NAD+ dependent, exclusively dehydrogenase in directionality, inhibited by glycyrrhetinic acid and metabolizes the synthetic glucocorticoid dexamethasone; it displays Km values for corticosterone and cortisol of 5.1 nM and 47 nM, respectively. Sequence alignment shows that 11 beta HSD2 shares 35% identity with 17 beta HSD2, but is only 14% identical with 11 beta HSD1. The 11 beta HSD2 gene is highly expressed in kidney, colon, pancreas and placenta and the message is also present in the ovary, prostate and testis. These data suggest that 11 beta HSD2 plays an important role in modulating mineralocorticoid and glucocorticoid receptor occupancy by glucocorticoids. PMID- 7859917 TI - The mature form of interleukin-1 alpha is constitutively expressed in immature male germ cells from rat. AB - In the present study we show that immature germ cells from rat testis contain both interleukin-1 alpha (IL-1 alpha) mRNA and immunoreactive proteins. In contrast, in primary cultures of Sertoli cells and peritubular cells. IL-1 alpha mRNA and immunoreactive protein were below the levels of detection. Immunoblots of lysates from these germ cells showed the presence of strong 17 kDa bands (mature forms of IL-1 alpha) and a much weaker 33 kDa band (precursor form). The finding of cell-associated mature forms of IL-1 alpha in germ cells indicates that immature male germ cells are able to process IL-1 alpha independent of its secretion. Data from isolated cell fractions, as well as from whole testis tissue from rats of various ages, indicate that IL-1 alpha expression takes place in late pachytene spermatocytes and early round spermatids. Whether IL-1 alpha plays a role intracellularly in germ cells or exerts its effects on neighboring Sertoli cells remains to be shown. PMID- 7859918 TI - Cytochrome P-450scc activity and substrate supply in human placental trophoblasts. AB - The degree of saturation of cytochrome P-450scc with cholesterol and the substrate turnover number of the cytochrome in cultured trophoblasts and mitochondria from the human placenta were investigated. Cholesterol sulfate was found to be a suitable substrate for probing the degree of saturation of cytochrome P-450scc with substrate during culture and in isolated mitochondria, since it enabled the maximum velocity of the cholesterol side-chain cleavage reaction to be estimated. In contrast, 25-hydroxycholesterol and low density lipoprotein supported trophoblast progesterone production at lower rates than that measured with saturating cholesterol sulfate. In the absence of exogenous substrate, the highest rate of progesterone synthesis by trophoblasts was observed at the beginning of the culture. With cholesterol sulfate as substrate, the turnover number of cytochrome P-450scc in cultured cells was 2.8 min-1 and was not significantly different to the turnover number of the cytochrome for placental mitochondria, where cholesterol is known to be saturating. Results indicate that cholesterol is limiting for progesterone synthesis in cultured trophoblasts even in the presence of lipoprotein rich medium and 8-bromo-cAMP. The concentration of cytochrome P-450scc in trophoblasts was only 20% of that measured for placental homogenate suggesting an induction of the cytochrome occurs when the trophoblasts fuse in vivo to form syncytiotrophoblasts. PMID- 7859919 TI - Relative quantitative analysis of glucagon receptor mRNA in rat tissues. AB - Total RNA prepared from nine rat tissues were analyzed for their content in glucagon receptor mRNA by two independent hybridization approaches: (1) simple dot blot analysis using labelled oligodeoxynucleotide; (2) highly specific RNase protection assay using labelled antisense RNA. Hybridization signal was quantified by laser densitometric scanning of autoradiographies. Results were expressed for each method relative to the liver content (100%) for either a constant amount of total RNA or for a constant amount of beta-actin mRNA. We obtained similar relative values of glucagon receptor mRNA per constant amount of total RNA by the two hybridization methods: in liver (100 and 100), in kidney (38 and 34), and in heart (12 and 11). The glucagon receptor mRNA was overestimated by the less specific dot assays, in adrenal glands (21 versus 10) and in adipose tissues (24 versus 5). In the stomach, brain, duodenum and lung, the signal was equal to or below the reliable quantification limit. Reverse transcription and polymerase chain reaction (RT-PCR) of glucagon receptor mRNA with limited cycle number were performed using two sets of primers: the first set amplified a single band at the 3' coding end, and the second, 3-6 bands at the 5' coding end, revealing tissue-specific polymorphism. RT-PCR data confirmed the presence of glucagon receptor mRNA in liver, kidney, heart, adrenal glands and adipose tissue, and allowed the detection of a very low amount of glucagon receptor mRNA in the stomach, the duodenum and brain but not in the lung.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859920 TI - Regulation of heat-shock protein (hsp70) gene expression by hGH and IL2 in rat Nb2 lymphoma cells. AB - A comparative study of hGH and IL2 post-signaling effects, as examined by RNA expression (Nb29) and protein levels of the heat-shock protein hsp70, was performed in a hormone-dependent rat lymphoma cell line, Nb2-11C. Optimal doses of hGH or IL2 increased Nb29 expression in a dose-dependent manner. Addition of both mitogens to cell cultures affected Nb29 expression and mitogenesis synergystically, indicating a possible interaction between the post-receptoral mechanisms of these mitogens. Pretreatment of the cells with cholera toxin (CT) inhibited Nb29 expression, protein levels and mitogenesis of hGH- or IL2-induced cells up to 50%, indicating the involvement of Gs-proteins in the post-signaling processes of both hGH and IL2. Incubation of cell cultures with low concentrations of pertussis toxin (IAP) (0.01 ng/ml) markedly increased Nb29 expression in hGH but not in IL2-induced cells, suggesting specific involvement of the Gi-protein in post-signaling processes of hGH-induced cells. Addition of the PKC activator 12-O-tetra-decanoyl phorbol ester (TPA) to control cell cultures markedly increased the expression of Nb29 RNA levels but not mitogenesis, indicating that induction of these proteins in the cells is not sufficient for cell proliferation. Furthermore, incubation of hGH- or IL2-induced cells with the potent PKC inhibitor staurosporin (ST) decreased the levels of Nb29 in both hGH- and IL2-induced cells, although the effect of the mitogens differed significantly in their inhibition slopes. These results indicate that activation of PKC is one of the signaling pathways differentially involved in hGH and IL2 stimulation of cells.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859921 TI - Targeted pituitary tumorigenesis using the human thyrotropin beta-subunit chain promoter in transgenic mice. AB - We have generated transgenic mice that express the simian virus 40 (SV40) large T antigen under the control of a 1109 bp 5'-flanking sequence of the human thyrotropin beta-subunit (TSH beta) gene. The hybrid gene, termed TTP-1, was microinjected into fertilized mouse eggs and 11 transgenic mice were obtained. One of the transgenic mice, a female, a phenotypical dwarf, developed a pituitary tumor and wasted away from 7 to 9 weeks after birth. To establish the transgenic mouse line, her ovaries were transferred to a normal female, whose ovaries were removed beforehand. To examine the tissue specificity of transgene expression, mRNA of SV40 large T antigen was monitored in various tissues from the transgenic mice by the reverse transcriptase-polymerase chain reaction analysis, and was detected only in the pituitary. Histological and immunohistochemical analyses showed that the pituitary tumors of the transgenic mice were composed of poorly differentiated pituitary cells expressing SV40 large T antigen. These results indicated that the 1109 bp sequence of the human TSH beta 5'-flanking region is essential for pituitary-specific expression of SV40 large T antigen in transgenic mice, which exhibited a dwarf phenotype and developed pituitary tumors. The tumors were composed of undifferentiated cells and did not produce thyrotropin. These transgenic mice should provide a valuable animal model for studying the pathogenesis of anterior pituitary tumors. PMID- 7859922 TI - Nuclear retinoic acid receptor characterization in cultured human trophoblast cells: effect of retinoic acid on epidermal growth factor receptor expression. AB - Vitamin A is an important factor during gestation and its metabolite, retinoic acid (RA), is a potent teratogen. However, RA action on the placenta is still poorly understood. In this study we analysed the presence of RARs and RXRs in human trophoblastic cells. We determined that RAR alpha was the more expressed form in term placenta, and that RAR beta was induced by RA treatment. Then we analysed RA effects on endocrine activities and on epidermal growth factor (EGF) receptor expression. We found that RA decreased 125I-labeled EGF binding and EGF dependent phosphorylation. Furthermore, RA treatment led to a concentration dependent decrease in the amount of EGFR protein expression. This treatment also decreased EGF receptor mRNA levels, suggesting transcriptional regulation of the EGF receptor. Thus we demonstrated that RA could interact with feto-placental development by modulating trophoblast EGF receptors expression, probably via its nuclear receptors. PMID- 7859923 TI - 9-cis-retinoic acid represses estrogen-induced expression of the very low density apolipoprotein II gene. AB - The chicken very low density apolipoprotein II (apoVLDLII) gene is estrogen inducible and specifically expressed in liver. We examined the possible involvement of the retinoid X receptor (RXR) and its ligand 9-cis-retinoic acid (9-cis-RA) in the activation of the apoVLDLII promoter. We first concentrated on a potential RXR recognition site, which deviates at only one position from a perfect direct A/GGGTCA repeat spaced by one nucleotide (DR-1) and was earlier identified as a common HNF-4/COUP-TF recognition site. However, band shift analysis revealed that this imperfect DR-1 motif does not interact with RXR alpha homodimers. In accordance with this observation we found that this regulatory element does not mediate transactivation through RXR alpha in the presence of 9 cis-RA. However, our experiments revealed another, unexpected, effect of 9-cis RA. Instead of stimulating, 9-cis-RA attenuated estrogen-induced expression of transfected estrogen-responsive VLDL-CAT reporter plasmids. This repression appeared to take place through the main estrogen response element (ERE) of the gene. Importantly, 9-cis-RA also strongly repressed the estrogen-induced expression of the endogenous apoVLDLII gene in cultured chicken hepatoma cells. PMID- 7859924 TI - Serotonergic involvement in the regulation of prolactin and vasoactive intestinal peptide mRNA expression in the rat anterior pituitary. AB - These studies examined the contribution of serotonin (5-HT) to the control of prolactin (PRL) and vasoactive intestinal peptide (VIP) messenger RNA expression in rat anterior pituitary. Daily injection of rats with the biosynthetic precursor to serotonin, 5-hydroxytryptophan (5-HTP; 25 mg/kg, q.i.d.), resulted on day 5 in a 50% increase in the expression of PRL mRNA in the pituitary while at the same time reducing the levels of both the 1.0 and 1.7 kb VIP mRNA transcripts. Co-treatment of rats with 5-HTP plus the catecholamine biosynthesis inhibitor, alpha-methyl-tyrosine (alpha-MT; 150 mg/kg, q.d. x 2 days), or the dopamine receptor antagonist haloperidol (1.25 mg/kg, b.i.d. x 5 days), resulted in increases in pituitary PRL message levels that were greater than those observed with either anti-dopaminergic agent alone. In contrast, 5-HTP was unable to reverse the inhibition of PRL mRNA expression caused by treatment with the dopamine receptor agonist bromocriptine (2.5 mg/kg, b.i.d. x 5 days). Neither alpha-MT, haloperidol nor bromocriptine had a significant effect on pituitary VIP mRNA expression. Administration of the direct-acting 5-HT receptor agonist quipazine (5 mg/kg, b.i.d.) for 14 consecutive days caused a significant increase in pituitary PRL mRNA levels on day 1 and reached a plateau of 90% above control levels on days 7 and 14. VIP mRNA levels rose significantly on day 1 of quipazine treatment but thereafter fell to a minimum of 22% (1.0 kb) and 52% (1.7 kb) of control by day 14.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859925 TI - Effect of endothelin-1 on phospholipase D activity in osteoblast-like cells. AB - We examined the effect of endothelin-1 (ET-1) on phosphatidylcholine-hydrolyzing phospholipase D activity in osteoblast-like MC3T3-E1 cells. ET-1 stimulated the formation of choline (EC50 10 nM) as well as that of inositol phosphates (EC50 1.2 nM). The effects of ET-1 and 12-O-tetradecanoylphorbol-13-acetate, a protein kinase C-activating phorbol ester, were additive. Staurosporine enhanced the ET-1 induced formation of choline. NaF or pertussis toxin were ineffective. The results indicate that ET-1 activates phospholipase D independent of protein kinase C in osteoblast-like cells. PMID- 7859926 TI - Estrogen receptor-mediated direct stimulation of colon cancer cell growth in vitro. AB - In vivo and epidemiological data suggest a mitogenic role for estrogens (E) in colon cancer. The presence of estrogen receptor (ER) and ER mRNA in colonic epithelium and colon cancer cells, make it necessary to explore the possible direct effects of E on colon cancer growth. In this study, a 15-mer oligodoxynucleotide (oligo) antisense to the region of the translation start codon of estrogen receptor mRNA inhibited ER expression in a mouse colon cancer cell line (MC-26), as determined by receptor binding assay. Antisense oligo also decreased ER mRNA levels in MC-26 cells. The growth-stimulatory effect of E was abolished by antisense oligo treatment, demonstrating that the ER is directly involved in the regulation of colon cancer cell growth. PMID- 7859927 TI - Isolation and identification of midkine and pleiotrophin in bovine follicular fluid. AB - Ovarian factors that promote growth of vascular smooth muscle cells were investigated. Two distinct heparin-binding polypeptides were isolated from bovine follicular fluid by successive chromatographies. N-Terminal and tryptic peptide fragment analysis of these polypeptides revealed that they are identical to midkine (MK) and pleiotrophin (PTN), respectively, which form a new family of heparin-binding growth/differentiation factors. Two N-terminally distinct forms of midkine were also identified in the bovine follicular fluid. The concentrations of MK and PTN in the bovine follicular fluid were estimated to be 125 micrograms/l and 400 micrograms/l, respectively. The present findings that MK and PTN are quite rich in the follicular fluid will provide a new insight into so far unclarified functions of MK and PTN, especially their roles in the maturation of ovarian follicles. PMID- 7859928 TI - Characterization of the stimulatory actions of thymic factor(s) on basal and gonadotropin-induced steroidogenesis in cultured rat granulosa cells. AB - Recently, there have been numerous reports that demonstrate the importance of the thymus gland in reproductive physiology. Previously, we have reported that thymic factors (TFs) which are present in thymic cell culture-conditioned medium (TCM) could stimulate basal progesterone and estradiol production from cultured rat granulosa cells. The current study attempts to characterize the stimulatory actions of TFs on both basal and FSH induced steroidogenesis. Thymic epithelial cells from immature female rats were isolated and used for production of TCM. Granulosa cells were obtained from immature diethylstilbestrol (DES)-treated rats. TFs stimulated both basal and FSH-induced progesterone secretions 80 and 17 times, respectively, as compared to the control media. The effects of TFs on basal and FSH-induced 20 alpha-hydroxyprogesterone secretion were comparable to those on progesterone production (40x and 10x, respectively). In addition, TCM stimulated basal and FSH-induced estradiol secretion approximately 4 and 2.5 times, respectively, compared to control. Stimulation of aromatase enzyme activity followed a similar trend as estradiol secretion, and TCM stimulated basal and FSH-stimulated aromatase enzyme activity approximately 15 and 3 times, respectively compared to control. Thus, these results indicate that the observed increases in progesterone and estradiol secretions in TCM-treated rat granulosa cells are likely to be due to elevated activities of specific steroidogenic enzymes. Measurements of total cell protein and DNA synthesis indicate that enhanced steroidogenesis in TCM-treated cells is not due to increased cell growth and/or proliferation. Rather, the enhanced steroidogenesis is probably due to an increased steroid biosynthetic capability of the cells.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859929 TI - Arginine vasopressin (AVP) causes the reversible phosphorylation of the myristoylated alanine-rich C kinase substrate (MARCKS) protein in the ovine anterior pituitary: evidence that MARCKS phosphorylation is associated with adrenocorticotropin (ACTH) secretion. AB - We have recently shown that AVP causes a protein kinase C (PKC)-dependent increase in ACTH release and biosynthesis in ovine anterior pituitary cells. In these cells, AVP also causes the translocation of PKC from the cytosol to the cell membrane which is maximal at 5 min, but the intracellular events distal to protein kinase C activation that underlie ACTH secretion have not been well characterized to date. Since the MARCKS protein has been implicated in neurosecretion and is phosphorylated by PKC in synaptosomes, studies were carried out to determine whether AVP might cause MARCKS phosphorylation in the ovine anterior pituitary, and to determine whether this phenomenon might be temporally correlated with PKC translocation and the release of ACTH. When cytosolic fractions of rat brain, ovine anterior pituitary, and cultured ovine anterior pituitary cells were incubated with purified PKC, several proteins were phosphorylated including those in the region of 83-85 kDa. After precipitation of the proteins with 40% acetic acid, the 83-85 kDa phosphoproteins were selectively recovered in the acid soluble phase. Phosphopeptide maps of either the 83 or 85 kDa proteins were generated with Staphylococcus aureus V8 protease and revealed 13 and 9 kDa phosphopeptides, which are characteristic of the authentic MARCKS protein. An identical phosphopeptide map was also obtained when the MARCKS protein was selectively extracted from intact 32P-labeled anterior pituitary cells. MARCKS phosphorylation was markedly increased when ovine anterior pituitary cells were exposed to 1 microM phorbol 12-myristate 13-acetate (PMA). When the cells were exposed to 1 microM AVP, MARCKS phosphorylation increased at 15 s and reached the maximal plateau value at 30 s. MARCKS phosphorylation then started to diminish at 2 min, and baseline levels were attained by 10 min. In the same cells, AVP stimulated ACTH release in a biphasic manner-during the first 30 s, there resulted a rapid burst of ACTH secretion that was followed by a slower, but sustained rate of secretion. We conclude that: (1) AVP causes a rapid, and reversible, phosphorylation of the MARCKS protein in the ovine anterior pituitary; (2) since the AVP-induced increase in MARCKS phosphorylation occurs much earlier in these cells than does PKC trans-location, MARCKS phosphorylation may provide a more sensitive index of the onset of PKC activation than the translocation assay; (3) the close temporal association between MARCKS phosphorylation and the rapid early release of ACTH suggests that MARCKS phosphorylation may be involved in the initial intracellular events that underly exocytosis of the hormone. PMID- 7859930 TI - Positional cloning works! Identification of genes that cause IDDM. AB - The strategy of positional cloning has been highly successful in identifying a number of single gene disorders that exhibit clear Mendelian patterns of inheritance. Positional cloning of insulin-dependent diabetes mellitus (IDDM) has been assisted by the expansion of molecular genetic tools and highly informative markers, so that new IDDM susceptibility genes are being uncovered. The ultimate characterization of IDDM susceptibility, including the manner in which the individual genes interact to determine the genetic component of susceptibility, may be hindered by the complexity of the disease itself. Recent developments in analytic and experimental genetics have renewed enthusiasm in the use of identity by descent (state) methods that use affected relatives (sib pairs) rather than pedigrees as a fundamental tool of gene mapping. Given the relative position of IDDM susceptibility genes, major hurdles in understanding the roles of the identified genes in defining genetic susceptibility as well as their function lie ahead. PMID- 7859931 TI - Does intra-abdominal adipose tissue in black men determine whether NIDDM is insulin-resistant or insulin-sensitive? AB - Insulin resistance in black Americans with non-insulin-dependent diabetes mellitus (NIDDM) is found in only 60% of those with a body mass index (BMI) of < 30 kg/m2, suggesting that NIDDM can occur independent of peripheral insulin resistance. When insulin resistance is present, it is not necessarily correlated with obesity. Numerous studies have shown that increased amounts of intra abdominal adipose tissue are associated with various metabolic abnormalities. We therefore investigated whether the occurrence of insulin resistance in black NIDDM men could be explained by the pattern of body adipose tissue distribution rather than total adiposity. Twenty-two near-normoglycemic black men (fasting plasma glucose [mean +/- SD] = 104 +/- 10 mg/dl, HbA1c = 4.6 +/- 0.78%, age 48.9 +/- 9.2 years, and BMI 26.5 +/- 2.4 kg/m2) were studied. The euglycemic insulin clamp with 1 mU.kg-1.min-1 insulin infusion and D-[3-3H]glucose was used to measure insulin action. Whole-body computed tomography with 22 scans was used to determine body composition. Total body adipose tissue was 19.6 +/- 7.51, and the percentage of body fat was 27 +/- 7. Glucose disposal ranged from 2.5 to 8.1 mg.kg-1.min-1 (10 men were insulin-sensitive and 12 were insulin-resistant). There was a strong inverse correlation between glucose disposal and the proportion of total adipose tissue in the intra-abdominal region (r = -0.78, P < 0.001), while there was no correlation between glucose disposal and total muscle volume, BMI, total adipose tissue volume, or total subcutaneous adipose tissue volume.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859932 TI - Effect of intracerebroventricular insulin infusion on diabetic hyperphagia and hypothalamic neuropeptide gene expression. AB - To test the hypothesis that diabetic hyperphagia results from insulin deficiency in the brain, diabetic rats (streptozotocin-induced) were given an intracerebroventricular (ICV) infusion of saline or insulin (at a dose that did not affect plasma glucose levels) for 6 days. Food and water intake were significantly increased in diabetic rats, but only food intake was affected by ICV insulin. Diabetic hyperphagia was reduced 58% by ICV insulin compared with ICV saline (P < 0.05) and was accompanied by a 69% increase in diabetes-induced weight loss (P < 0.05). To evaluate whether central nervous system (CNS) insulin deficiency affects expression of neuropeptides involved in food intake, in situ hybridization was done for neuropeptide Y (NPY), which stimulates feeding, in the hypothalamic arcuate nucleus and for cholecystokinin (CCK) and corticotropin releasing hormone (CRH), which inhibit feeding, in the hypothalamic paraventricular nucleus. In diabetic rats, NPY mRNA hybridization increased 280% (P < 0.05), an effect reduced 40% by ICV insulin (P < 0.05). CCK mRNA hybridization increased 50% in diabetic rats (P < 0.05), a response reduced slightly by ICV insulin (P < 0.05), whereas CRH mRNA hybridization decreased 33% in diabetic rats (P < 0.05) and was unchanged by ICV insulin. The results demonstrate that CNS infusion of insulin to diabetic rats reduces both hyperphagia and overexpression of hypothalamic NPY mRNA. This observation supports the hypothesis that a deficiency of insulin in the brain is an important cause of diabetic hyperphagia and that increased hypothalamic NPY gene expression contributes to this phenomenon. PMID- 7859933 TI - The pharmacokinetics of nicotinamide in humans and rodents. AB - Nicotinamide, a derivative of the B vitamin niacin, is currently under trial for the prevention of insulin-dependent diabetes mellitus after success in the NOD mouse. However, the dose, route of administration, and formulation of nicotinamide given to humans is quite different from those used successfully in animals, and the aim of this study was to investigate the plasma pharmacokinetics of oral nicotinamide in humans in two doses and in two different formulations (standard and the long-acting Enduramide). There were no significant differences in the kinetics of the low dose of standard nicotinamide (2.5 mg/kg) and low-dose Enduramide (6.7 mg/kg) in young adult men. Nonlinear kinetics were found with both formulations at higher doses, e.g., a 10-fold increase in the dose of the standard nicotinamide produced a 62-fold increase in the area under the plasma concentration-time curve (AUC). The high dose of standard nicotinamide (25 mg/kg body wt) produced a mean peak plasma concentration 75% higher than that achieved with the sustained release nicotinamide preparation given in a dose similar to that currently used in prevention trials (2 g identical to 26.6 mg/kg body wt for a 75-kg subject). The AUC was also significantly greater with the standard formulation, indicating a higher bioavailability. Long-term plasma levels for high doses of both formulations were modeled from the single-dose kinetics by computer program. The AUC for standard nicotinamide was 1.7 times higher than that for Enduramide.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859934 TI - Kinin, a mediator of diabetes-induced glomerular hyperfiltration. AB - Renal kallikrein is increased in diabetic patients and streptozotocin (STZ) induced diabetic rats with hyperfiltration. Chronic inhibition of renal kallikrein reduces glomerular filtration rate (GFR) and renal plasma flow (RPF) in hyperfiltering STZ-induced diabetic rats. To investigate whether these actions of kallikrein and its inhibition are kinin-mediated, we used a B2-kinin receptor antagonist (BKA). In STZ-induced diabetic rats with hyperfiltration, renal kallikrein excretion rate was significantly increased (P < or = 0.01), and kinin excretion rate was increased 57%, as compared with control rats. Left kidney GFR and RPF were measured before and during a 40-min infusion of BKA (0.5 micrograms.kg-1.min-1) or vehicle. Infusion of the kinin receptor antagonist reduced the GFR and RPF significantly. GFR was reduced by 18%, from an average baseline value of 2.07 +/- 0.11 to 1.70 +/- 0.06 ml/min, P < or = 0.001 (means +/ SE). RPF was reduced by 25%, from 6.74 +/- 0.38 to 5.06 +/- 0.17 ml/min, P < or = 0.001. Total renal vascular resistance was significantly increased during BKA infusion, P < or = 0.001. Vehicle infusion for the same period had no significant effect on GFR, RPF, or renal vascular resistance. These findings further support the hypothesis that increased renal production of kinins contributes to the renal vasodilation of diabetes. PMID- 7859935 TI - Does insulin-like growth factor I predict incidence and progression of diabetic retinopathy? AB - We evaluated the relationship of insulin-like growth factor (IGF)-I to incidence and progression of diabetic retinopathy over a 6-year interval in a large population-based study of diabetes in southern Wisconsin. Participants included people with younger-onset diabetes (n = 66 adolescents, n = 661 adults > or = 18 years of age) and older-onset diabetes (n = 285 for those using insulin, n = 248 for those not using insulin). Fundus photographs were graded in a masked fashion using standardized protocols to determine the severity of retinopathy in each eye. Serum IGF-I levels were measured during 1984-1986 using a double-antibody radioimmunoassay. Mean IGF-I was highest in adolescents (499.1 micrograms/l), lower in younger-onset adult (280.1 micrograms/l), and lowest in the older-onset group (205.7 and 221.2 micrograms/l for older-onset group using insulin and not using insulin, respectively). The incidence of retinopathy was not significantly higher in people with higher IGF-I levels in any group. The odds of developing diabetic retinopathy in 6 years for each 10 micrograms/l increase in IGF-I after controlling for age, glycosylated hemoglobin, and duration of diabetes at baseline was 1.21 (95% confidence interval [CI] 0.95-1.54) for adolescents; 1.00 (95% CI 0.93-1.08) for younger-onset adults; 0.93 (95% CI 0.85-1.02) for the older-onset group using insulin; and 0.99 (95% CI 0.95-1.04) for the older-onset group not using insulin. In summary, IGF-I was not associated with 6-year incidence or progression of diabetic retinopathy in any of the groups. PMID- 7859936 TI - Bedtime insulin/daytime glipizide. Effective therapy for sulfonylurea failures in NIDDM. AB - Bedtime insulin (BI)/daytime sulfonylurea (DSU) therapy was studied double-blind in 30 non-insulin-dependent diabetes mellitus subjects in whom sulfonylurea (SU) therapy had failed. Subjects were switched to glipizide for 2 months (phase I) to confirm failure (fasting plasma glucose [FPG] 12.0 +/- 0.4 mmol/l) and then randomly assigned into three groups: BI-DSU; BI-no DSU; and DSU-no BI. During phase II (3 months), the BI dose was fixed (20 U/1.73 m2, low-dose). In phase III (3 months), BI was titrated up (high-dose) to achieve good control or until hypoglycemic symptoms prevented further dose increases. In phase IV (6 months), 25 of the 30 original subjects received open-labeled, high-dose BI-DSU. Low-dose BI-DSU markedly reduced FPG (13.6 +/- 0.8 to 8.0 +/- 0.6 mmol/l, P < 0.001), mean 24-h glucose (P < 0.001), HbA1c (8.9 +/- 0.7 to 7.6 +/- 0.3%, P = 0.07), and basal hepatic glucose production (HGP) (P < 0.005). A positive correlation (r = 0.69, P < 0.05) between the declines in FPG and HGP was observed. Neither low dose BI alone nor DSU alone reduced FPG, mean 24-h glucose, HbA1c, or basal HGP. High-dose (40 +/- 5 U/day) BI plus DSU further reduced the FPG (6.3 +/- 0.6 mmol/l), HbA1c (7.1 +/- 0.3%), mean 24-h plasma glucose, and basal HGP (all P < 0.05 vs. phase II).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859937 TI - Proinsulin as a marker for the development of NIDDM in Japanese-American men. AB - Disproportionate hyperproinsulinemia is one manifestation of the B-cell dysfunction observed in non-insulin-dependent diabetes mellitus (NIDDM), but it is unclear when this abnormality develops and whether it predicts the development of NIDDM. At baseline, measurements of proinsulin (PI) and immunoreactive insulin (IRI) levels were made in 87 second-generation Japanese-American men, a population at high risk for the subsequent development of NIDDM, and, by using World Health Organization criteria, subjects were categorized as having normal glucose tolerance (NGT; n = 49) or impaired glucose tolerance (IGT; n = 38). After a 5-year follow-up period, they were recategorized as NGT, IGT, or NIDDM using the same criteria. After 5 years, 16 subjects had developed NIDDM, while 71 had NGT or IGT. Individuals who developed NIDDM were more obese at baseline, measured as intra-abdominal fat (IAF) area on computed tomography (P = 0.046) but did not differ in age from those who continued to have NGT or IGT. At baseline, subjects who subsequently developed NIDDM had higher fasting glucose (P = 0.0042), 2-h glucose (P = 0.0002), fasting C-peptide (P = 0.0011), and fasting PI levels (P = 0.0033) and disproportionate hyperproinsulinemia (P = 0.056) than those who continued to have NGT or IGT after 5 years of follow-up. NIDDM incidence was positively correlated with the absolute fasting PI level (relative odds = 2.35; P = 0.0025), even after adjustment for fasting IRI, IAF, and body mass index (relative odds = 2.17; P = 0.013).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859939 TI - Contribution of hepatic glycogenolysis to glucose production in humans in response to a physiological increase in plasma glucagon concentration. AB - The contribution of net hepatic glycogenolysis to overall glucose production during a physiological increment in the plasma glucagon concentration was measured in six healthy subjects (18-24 years, 68-105 kg) after an overnight fast. Glucagon (approximately 3 ng.kg-1.min-1), somatostatin (0.1 microgram.kg 1.min-1), and insulin (0.9 pmol.kg-1.min-1) were infused for 3 h. Liver glycogen concentration was measured at 15-min intervals during this period using 13C labeled nuclear magnetic resonance spectroscopy, and liver volume was assessed from magnetic resonance images. The rate of net hepatic glycogenolysis was calculated from the decrease in liver glycogen concentration over time, multiplied by the liver volume. The rate of glucose appearance (Ra) was calculated from [3-3H]glucose turnover data using a two-compartment model of glucose kinetics. Plasma glucagon concentration rose from 136 +/- 18 to 304 +/- 57 ng/l and plasma glucose concentration rose from 5.6 +/- 0.1 to 10.4 +/- 0.9 mmol/l on initiation of the infusions. Mean baseline Ra was 11.8 +/- 0.4 mumol.kg 1.min-1, increased rapidly after the beginning of the infusions, reaching its highest value after 20-40 min, and returned to baseline by 140 min. Liver glycogen concentration decreased almost linearly (from 300 +/- 19 mmol/l liver at baseline to 192 +/- 20 mmol/l liver at t = 124 min) during 2 h after the beginning of the infusions, and the calculated mean rate of net hepatic glycogenolysis was 21.7 +/- 3.6 mumol.kg-1.min-1. Mean Ra during the same time period was 22.8 +/- 2.3 mumol.kg-1.min-1. Thus, net hepatic glycogenolysis accounted for 93 +/- 9% of Ra.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859938 TI - Local ventromedial hypothalamus glucopenia triggers counterregulatory hormone release. AB - To test the hypothesis that nuclei of the ventromedial hypothalamus (VMH) play a key role in the detection of counterregulatory responses to hypoglycemia, we delivered the glucopenic agent 2-deoxyglucose via bilaterally placed microdialysis probes into the VMH of conscious, chronically catheterized rats. The goal was to produce cellular glucopenia localized to the VMH. The volume of brain tissue exposed to 2-deoxyglucose was determined by adding [3H]2 deoxyglucose to the dialysate; its distribution in cerebral tissue was almost exclusively limited to the VMH. Rats with microdialysis probes placed into the frontal lobes served as a control group. Local perfusion of 2-deoxyglucose (but not glucose) into the VMH caused a prompt twofold increase in plasma glucose in association with a striking elevation of plasma glucagon (3.5-fold), epinephrine (30-fold), and norepinephrine (3.5-fold). No effect was seen when 2-deoxyglucose was delivered into the frontal lobes. We conclude that glucopenia localized to the VMH triggers the release of counterregulatory hormones that defend against hypoglycemia. Thus, the neurons that sense glucopenia may be situated in the VMH. PMID- 7859941 TI - Mechanisms of intracellular pH regulation during postischemic reperfusion of diabetic rat hearts. AB - A marked decrease in the activity of the amiloride-sensitive Na+/H+ exchanger has been demonstrated in hearts from streptozotocin (STZ)-induced diabetic rats. The aim of this study was to investigate the contribution of other specific sarcolemmal transport mechanisms to intracellular pH (pHi) recovery upon reperfusion in STZ-induced diabetic rat hearts and their relation to recovery of ventricular function. Isovolumic rat hearts were submitted to a zero-flow ischemic period of 28 min at 37 degrees C and then reperfused for 28 min. The time course of pHi decline during ischemia and of recovery on reperfusion was followed by means of 31P-labeled NMR. The perfusion buffers used were either HEPES or CO2/HCO3-. An HCO3(-)-dependent (amiloride-insensitive) mechanism contributed to pHi recovery after ischemia in the diabetic rat hearts. Even when the Na+/H+ exchanger was blocked by amiloride in nominally HCO3(-)-free solution, a rapid rise in pHi occurred during the first 3 min of reperfusion. The early rise in pHi was reduced by external lactate and inhibited by alpha-cyano-4 hydroxycinnamate. This suggested that a coupled H(+)-lactate efflux may be a major mechanism for acid extrusion in the initial stage of reperfusion. The observation of a higher functional recovery on reperfusion in diabetic hearts is in accordance with previous studies using HCO3- buffer. However, this study shows that a good recovery of function occurred even more rapidly in diabetic hearts receiving HEPES-buffered solution than in those receiving HCO3(-)-buffered solution. This suggests that the HCO3(-)-dependent mechanism of regulation may be depressed in diabetic rat hearts. PMID- 7859940 TI - Effects of acute, subacute, and chronic diabetes on carbohydrate and energy metabolism in rat sciatic nerve. Relation to mechanisms of peripheral neuropathy. AB - To address the problem of the pathogenesis of diabetic neuropathy, rats were made diabetic by alloxan administration, and sciatic nerves were sampled for electrolyte and water content and levels of selected carbohydrates and intermediates in energy metabolism at 3, 6, and 26 weeks. Significant increases were seen in the nerve content of glucose, sorbitol, and fructose. Decreases of myo-inositol were not statistically significant. Glucose-6-phosphate was increased at all times; fructose-1,6-bisphosphate was elevated at 6 and 26 weeks. Nerve ATP and phosphocreatine levels were both increased concomitantly, as was the energy charge. Nerve lactate levels increased only at 26 weeks when plasma lactate levels were also high. Plasma ketone bodies were elevated throughout the 26-week experimental interval. It is postulated that ketone bodies were being used as alternative metabolic fuels in diabetic nerve, thereby causing inhibition of pyruvate oxidation and increased aerobic production of lactate. Increased plasma ketone body levels could also inhibit hepatic lactate uptake. There was no other evidence for hypoxia/ischemia. Lactate:pyruvate ratios did not differ from control values at any time in these ketotic hypoinsulinemic animals. Five major hypotheses have been proposed to explain the pathogenesis of diabetic neuropathy: 1) hypoxia/ischemia, 2) hyperglycemic pseudohypoxia, 3) myo-inositol deficiency, 4) fructose and polyol accumulation and osmotic disequilibrium, and 5) nonenzymatic glycation of macromolecules by fructose and glucose. The data obtained in this study seem to fit best with hypotheses 4 and perhaps 5. PMID- 7859942 TI - Regulation of postprandial whole-body proteolysis in insulin-deprived IDDM. AB - Suppression of tissue proteolysis is an important mechanism of postprandial protein anabolism, and it may be mediated by insulin, hyperaminoacidemia, or both. To evaluate whether insulin is essential in the regulation of this process, we have investigated the effect of mixed-meal ingestion on whole-body protein breakdown in insulin-deprived insulin-dependent diabetes mellitus (IDDM) patients and normal control subjects. Endogenous phenylalanine and leucine rate of appearance (Ra) from proteolysis were measured at steady-state conditions using a multiple stable isotope technique before and after the constant administration of a synthetic mixed meal. In the postabsorptive state, the IDDM patients exhibited accelerated intracellular leucine Ra (IDDM, 2.64 +/- 0.19 mumol.min-1.kg-1; control, 2.02 +/- 0.08 mumol.min-1.kg-1; P < 0.05) and plasma phenylalanine Ra (IDDM, 0.73 +/- 0.03 mumol.min-1.kg-1; control, 0.61 +/- 0.04 mumol.min-1.kg-1; P < 0.05). During meal ingestion, endogenous phenylalanine and leucine Ra values were suppressed in both the insulin-deficient IDDM (P < 0.05) and control subjects (P < 0.05). Although postmeal endogenous leucine and phenylalanine Ra values remained greater (P < 0.05) in IDDM, the delta changes from the basal endogenous leucine Ra (IDDM, -0.56 +/- 0.11 mumol.min-1.kg-1; control, -0.56 +/- 0.09 mumol.min-1.kg-1) and phenylalanine Ra (IDDM, -0.13 +/- 0.01 mumol.min-1.kg 1; control, -0.14 +/- 0.02 mumol.min-1.kg-1) were similar in both groups. In the IDDM patients, the postmeal increases from the basal leucine concentration were onefold greater (P < 0.05) than in the control-subjects.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859943 TI - Important role of insulin and flow in stimulating glucose uptake in contracting skeletal muscle. AB - The relative role of contractions, insulin, and increased supply of glucose and insulin, via an increase in blood flow, in stimulating glucose uptake in skeletal muscle during contractions was studied in isolated perfused rat hindlimbs. Hindlimbs were perfused with a standard perfusate medium containing 6 mmol/l glucose and four different insulin concentrations (0, 100, 500, and 20,000 microU/ml). Contractions were induced by supramaximal intermittent electrical stimulation of the sciatic nerve. Three different perfusion protocols were used: 1) muscles were stimulated to contract without concomitantly increasing perfusate flow; 2) flow was increased in the absence of electrical stimulation; and 3) muscles were stimulated to contract together with a flow increase. Both contractions and increased flow of perfusate, applied as separate stimuli, increased (P < 0.05) glucose uptake in the absence of insulin. Yet when submaximal insulin concentrations were added to the perfusate, the stimulatory action of both contractions and increased blood flow on muscle glucose uptake was augmented. The higher the submaximal insulin concentration, the greater the increment (P < 0.05). This effect, however, faded at supramaximal insulin concentration. Electrical stimulation associated with an increase in perfusion flow rate produced a greater (P < 0.05) rise in glucose uptake than did contractions alone. In fact, stimulation of muscle glucose uptake by contractions and increased flow proved to be additive at any insulin concentration. We conclude that contractions and increased blood flow act as additional stimuli to muscle glucose uptake at any insulin concentration.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859944 TI - Normal effect of insulin to stimulate leg blood flow in NIDDM. AB - In patients with non-insulin-dependent diabetes mellitus (NIDDM), a decreased effect of insulin in stimulating leg blood flow (LBF) has been reported. We reinvestigated the effect of insulin on LBF and validated our data by use of other measures. Eight healthy men (control group) and seven men with NIDDM were studied (age 59 +/- 1 and 58 +/- 3 years, weight 83 +/- 3 and 86 +/- 6 kg, fat free mass 66 +/- 1 and 64 +/- 3 kg, respectively [mean +/- SE, all P > 0.05]; body mass index 26 +/- 1 and 29 +/- 1 kg/m2, fasting plasma insulin 72 +/- 7 and 187 +/- 22 pmol/l, fasting plasma glucose 5.8 +/- 0.2 and 10.2 +/- 1.7 mmol/l [all P < 0.05]). A three-step hyperinsulinemic glucose clamp (ambient glucose level) was performed, combined with catheterization of an artery and both femoral veins. Expiratory air was collected, LBF was measured by thermodilution, and blood was sampled and analyzed for oxygen content. Insulin concentration was increased to 416 +/- 22 and 509 +/- 43 (step I), 1,170 +/- 79 and 1,299 +/- 122 (step II), and 15,936 +/- 1,126 and 16,524 +/- 1,916 (step III) pmol/l in control and NIDDM subjects, respectively (P > 0.05). LBF increased similarly (P > 0.05) in the two groups (from 287 +/- 23 and 302 +/- 12 [basal] to 308 +/- 31 and 362 +/- 9 [I], 371 +/- 29 and 409 +/- 17 [II], and 434 +/- 32 and 472 +/- 29 [III] ml.min-1.leg-1 in control and NIDDM subjects, respectively).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859945 TI - Different roles of class I and class II Clostridium histolyticum collagenase in rat pancreatic islet isolation. AB - Crude Clostridium histolyticum collagenase was purified by gel filtration and fractionated by anion exchange chromatography into class I with high collagen digestion activity (CDA) and low FALGPA (2-furanacryloyl-L-leucylglycyl-L-prolyl L-alanine) hydrolysis activity (FHA), class II with low CDA and high FHA, and a fraction called class I/II with intermediate activities. The roles of these collagenase classes in rat pancreatic islet isolation were investigated. Dissociations were carried out with 360 mg of pancreatic tissue in 10 ml of buffer containing 10% (wt/vol) albumin to suppress endogenous proteolytic activity, 100 U of C. histolyticum neutral protease, and one or two purified collagenase(s). For purified nonfractionated (PNF) collagenase, 2.6 mg of enzyme containing 2.4 U CDA and 38.0 U FHA was used, and for the separate classes, comparable amounts of activity were added. PNF collagenase dissociated the tissue completely in 32 min and yielded 5.0 +/- 0.4 microliters islet tissue/g pancreas. Class I collagenase alone dissociated pancreatic tissue extremely slowly and incompletely; only a few islets were released (0.7 +/- 0.2 microliters/g pancreas). Class II collagenase alone dissociated the tissue adequately in 50 min, and a high islet yield of 5.7 +/- 0.6 microliters/g was obtained. With class I/II, a similar dissociation time (47 min) and islet yield (5.5 +/- 0.3 microliters/g) were obtained. Combining class I and class II collagenase resulted in a more rapid dissociation (32 min) and a higher islet yield (7.1 +/- 0.8 microliters/g) than that obtained with PNF collagenase (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859946 TI - Inhibition of sorbitol dehydrogenase. Effects on vascular and neural dysfunction in streptozocin-induced diabetic rats. AB - These experiments were undertaken to assess the role of sorbitol dehydrogenase in mediating sorbitol pathway-linked neural and vascular dysfunction in rats with streptozocin-induced diabetes. 2-methyl-4-[N,N-dimethylsulfamoyl-piperazino] pyrimidine (S-0773), a putative inhibitor of sorbitol dehydrogenase, was given in the drinking water to control and diabetic rats. After 5 weeks of diabetes, glycosylated hemoglobin levels were increased twofold and were unaffected by S 0773. Sorbitol levels in diabetic rats were increased 11- to 14-fold in ocular tissues and sciatic nerve; S-0773 increased sorbitol levels another 4-fold or more in these same tissues but had much smaller effects in other tissues. Diabetes-associated increases in fructose levels and lactate:pyruvate ratios in retina and in sciatic nerve were markedly attenuated by S-0773. S-0773 also attenuated, but did not completely normalize, impaired caudal nerve conduction and vascular dysfunction in ocular tissues, sciatic nerve, and aorta in diabetic rats. These observations, together with other evidence, suggest that sorbitol pathway-linked vascular dysfunction (in ocular tissues, peripheral nerve, and aorta) and electrophysiological dysfunction (in peripheral nerve) induced by diabetes are more closely linked to increased oxidation of sorbitol to fructose than to putative osmotic effects of elevated sorbitol levels or redox and metabolic imbalances associated with reduction of glucose to sorbitol by aldose reductase. PMID- 7859948 TI - Scanner information timely for medical educators. PMID- 7859947 TI - Trinucleotide repeats at the rad locus. Allele distributions in NIDDM and mapping to a 3-cM region on chromosome 16q. AB - A 10-allele polymorphism was identified in rad (ras associated with diabetes), a gene that is overexpressed in non-insulin-dependent diabetes mellitus (NIDDM) muscle. The polymorphism, designated RAD1, consists of a variable number of trinucleotide repeats (GTT and ATT) located in the poly(A) region of an intronic Alu sequence. Based on the number of GTT and ATT repetitions, the alleles can be grouped into four classes (I-IV). RAD1 allele frequencies were determined in 210 NIDDM patients and 133 nondiabetic control subjects, all Caucasians. One allele (number 8, class III) accounted for > 80% of the chromosomes in both groups. However, an excess of minor alleles, all belonging to class I, II, or IV, was observed among NIDDM chromosomes (P < 0.025), suggesting a possible association between RAD1 and NIDDM predisposition. To promote further studies to test the hypothesis that genetic variability at the rad locus contributes to NIDDM, we mapped rad on the human genome. Using the fluorescence in situ chromosomal hybridization technique, rad was unequivocally assigned to chromosomal band 16q22. In families that were informative for RAD1, the rad locus was mapped within a 3-cM region defined by the markers D16S265, D16S186, and D16S397 (logarithm of odds scores = 10.08, 10.9, and 10.84 at recombination fractions of 0.024, 0.001, and 0.03, respectively). The high degree of heterozygosity of these markers will allow large-scale family studies to be performed to test the presence of linkage between rad and NIDDM. PMID- 7859949 TI - An elderly population's medical values and advance health care directives. PMID- 7859950 TI - Minority faculty--recruiting, retaining, and sustaining. PMID- 7859951 TI - Resident attrition from family practice residencies: United States versus international medical graduates. AB - BACKGROUND: Attrition of residents from family practice residency programs may cause significant problems for faculty, residents, and patients. The objective of this study was to determine international medical graduates' attrition rate from family practice residencies, compared with US medical school graduates. METHODS: Surveys were sent to all family practice residency program directors asking them to calculate their attrition rate for a 10-year period. RESULTS: The overall response rate was 56.6%, but interpretable responses were received from 45% of all civilian, continental US family practice residencies. Responding programs did not differ from all family practice programs with respect to program overall. Of those residents leaving, 63% did so to enter other specialties. The attrition rate was 18.5% for international graduates, compared with 7.8% for US graduates (P < .0001). International graduates enrolled outside of the National Resident Matching Program (NRMP) were most likely to leave programs before completion. CONCLUSIONS: Attrition rates from family practice residency programs are higher for international medical graduates than for US graduates. International graduates enrolled outside of the NRMP were most likely to leave a program. PMID- 7859952 TI - Cultures engaging cultures: international medical graduates training in the United States. AB - International medical graduates (IMGs) represent an increasing proportion of residents in all US residency training programs. Family practice residencies have experienced significant increases in IMG enrollment in the last 3 years. Residency programs in family practice need to make curricular adjustments to enhance the transition for IMGs. Adjusting the psychosocial curriculum, through changes in orientation, behavioral conferences, and family consultations, contributes to a culture-centered approach to teaching both IMGs and US medical graduates. Faculty need to identify both personal loss and cultural issues for IMGs in various stages of the resident's life cycle. Lifestyle changes and loss of self-esteem, country, and accessibility to family can be demoralizing for IMGs coping with the demands of internship. Specific stages of the family life cycle can exert additional stresses for IMGs and their families. Understanding the specific challenges for IMGs during each life cycle stage can be instructive and helpful. Faculty can introduce initiatives that encourage cultural pride and respect. Support groups, international meals, cultural retreats, adjusted advising systems, and ongoing faculty reflection on treatment of IMGs demonstrates residency appreciation of diversity and leads to a healthier, culturally rich learning environment for all involved in residency education. PMID- 7859953 TI - Evidence of discrimination against international medical graduates applying to family practice residency programs. AB - BACKGROUND AND OBJECTIVES: The purpose of the study was to test the hypothesis that discrimination exists against international medical graduates (IMGs) applying to US family practice residency programs. METHODS: Two sets of letters were sent to 146 family practice residency programs randomly selected from the Directory of Graduate Medical Education Programs. The letters requested information and an application. All letters were identical except that the author of the first set was described as "a foreign medical graduate." The author of the second set was described as "a fourth-year medical student at the University of Nebraska Medical Center." Replies were monitored for 6 weeks after the second mailing. Response rates to each "candidate" were measured. In addition, responses were evaluated for the presence of a brochure describing the residency program, an application, cover letter, invitation for interview, eligibility criteria, and other material. RESULTS: A total of 113 programs (79%) responded. Of these, 102 responded to the fourth-year medical student and 57 responded to the IMG. Of the 46 programs replying to both candidates, only 20 provided identical mailings. Nine of the 46 programs required IMGs to meet standards that exceeded requirements set by the Educational Commission for Foreign Medical Graduates for residency training in the United States. CONCLUSIONS: A pattern of dissimilarity exists in the way family practice residency programs respond to requests for application materials, and the differences appear to depend on whether the candidate is a US medical graduate or an IMG. These results raise questions about the fairness of current methods of resident selection. PMID- 7859954 TI - Of pride and prejudice. PMID- 7859955 TI - Rural community health agencies as primary care clerkship sites for medical students. AB - BACKGROUND AND OBJECTIVES: This study describes a student-centered third-year clerkship involving student choice and on-site investigation of rural community health care agencies. The objective of the clerkship was student understanding of how to explore and use community agencies to enhance the care of patients. METHODS: The course was evaluated through pre- and postcourse surveys of attitudes about primary care, care of the socially disadvantaged, knowledge of social agencies, and specialty orientation. Also analyzed were student clerkship evaluation forms, student performance evaluations, and review by external consultants. RESULTS: Students reported statistically significant increases in knowledge about social agencies (P = .0001). Attitudes of social responsibility for health care and greater concern about patients' social well-being were reported but were not statistically significant. While students agreed with the philosophy of the experience, they felt the course would have been more valuable later in their training. Student performance exceeded faculty expectations in all cases. External evaluators felt the community agency contacts were crucial experiences for future caregivers. CONCLUSIONS: A student-centered clerkship using community-based agencies can provide a valid educational experience, even in remote rural areas. Students develop facility in contacting and using community resources. Participation can give new perspectives on patient care not achievable in other sites. The long-term benefits of this early community exposure remain to be investigated. PMID- 7859956 TI - An elective primary care track in the preclinical years. AB - BACKGROUND AND OBJECTIVES: Early exposure to primary care is hypothesized as a means of reducing attrition in primary care specialty preference over the course of medical school. This study evaluated an elective preclinical primary care track that featured generalist instructors as role models and a community office based experience in the second year of medical school. METHODS: A total of 386 students from the University of Southern California graduating classes of 1991 1993 (both primary care track participants and nonparticipants) completed questionnaires on attitudes about primary care before and after the primary care track experiences. These pre- and post-second year data were linked with data for the same students from the Association of American Medical Colleges matriculation questionnaire and data on their specialty choices at graduation. RESULTS: The primary care track, instituted during a period of declining interest in primary care among incoming students at our medical school, was not found to be associated with pre- and post-second year declines in participants' specialty preferences or attitudes toward primary care. Enrollment in the track and preclinical interest in primary care specialties were related to exogenous student characteristics (especially females). Enrollment was strongly predictive of primary care specialty choice at graduation but were not found to be related to students' anticipated debt levels for their medical education. CONCLUSION: Use of a primary care track in the preclinical years may help stem the decline in interest in primary care known to occur over the course of medical school. Coupled with a primary care specialty choice, participation in the track is clearly related to choice of a primary care specialty at graduation. PMID- 7859957 TI - A curriculum for teaching faculty budgeting and financial management skills. AB - BACKGROUND: As funding sources diminish, it is critical for faculty members in primary care residency programs to better utilize available resources. The curriculum presented here, a practice management course for academicians, can provide fellows and new faculty with some of the budgeting and financial management skills necessary to perform in an academic environment. METHODS: The curriculum described is a 6-hour seminar series that relates essential budgeting and financial management concepts with academic practice. RESULTS: Pre- and postassessments displayed a statistically significant increase in the learner's fund of knowledge. One year after instruction, six of seven participants had used an aspect of the curriculum. All seven recommended its continuation. CONCLUSION: This curriculum should be considered for implementation in all fellowship programs that train future faculty. PMID- 7859958 TI - Pap smear screening in family physicians' offices in a rural area with a high cervical cancer rate. AB - BACKGROUND AND OBJECTIVES: Cervical cancer, when detected early by methods like the Pap test, is usually curable. Unfortunately, Pap smear screening is not universal, and mortality from cervical cancer still occurs. The objective of this study was to identify the extent to which female patients were not receiving annual Pap tests in nine family physicians' offices in the lower Rio Grande Valley region of Texas. METHODS: Patients age 18 or older were asked the date of their last Pap test. The answer was recorded on a chart sticker to help the physician identify patients in need of a Pap test. RESULTS: Of 5,526 women seen in the nine physicians' offices over a 3-month time period, 42% had not had a Pap smear within the previous 2 years. When offered a Pap test during this study, only 18% of patients refused. CONCLUSION: There appears to be a need for education of physicians and patients about the importance of Pap smear testing and a change in office routines that encourages incorporation of Pap testing into primary physicians' office practices. PMID- 7859959 TI - Levels of family involvement in patient visits by family medicine faculty. AB - BACKGROUND: This study investigates levels of family involvement (LFI) in patient visits by family medicine faculty, extends validity testing of the LFI model, and provides data for comparison with a previous study of LFI in patient visits by family practice residents. METHODS: Twenty visits were taped for each of five physician faculty and were rated according to whether family involvement was indicated and if it occurred. RESULTS: Of the 100 visits, 47 showed minimal or no family involvement. Of the 29 visits when faculty provided medical information and advice to a family, 66% involved children. Family issues were discussed in only 18% of visits if only adult patients were considered. Overall, however, family involvement occurred in 80% of the visits in which it was indicated. The results of this study, which involved faculty, showed slightly higher family involvement levels than found for residents in a previous study, but the difference was not statistically significant. CONCLUSION: The similarity between faculty LFI in this study and LFI exhibited by residents in a previous study may mean that both groups are currently exhibiting appropriate LFI. However, the unexpected findings may be a function of the research tools' inadequate sensitivity. Methodology changes are recommended to increase sensitivity in measuring family orientation, particularly for individual adult patients. PMID- 7859960 TI - Selective sedation for colonoscopy. AB - A study of selective sedation for colonoscopy was conducted in two parts. All procedures were performed by one experienced colonoscopist. In the first phase, 41 patients received intravenous sedation before colonoscopy and were then prospectively randomized to either a "not-reversed" group, which did not receive flumazenil before withdrawal of the colonoscope, or to a "reversed" group, which received flumazenil before colonoscope withdrawal. None of the 20 patients reversed and 1 of the 21 patients not reversed experienced pain during the withdrawal phase of colonoscopy. Sixty percent of patients in the reversed group and 10% in the not-reversed group remembered the colonoscopic findings being explained during the procedure. Ninety percent and 81% of patients in the reversed and not-reversed groups, respectively, expressed a preference to be awake to watch the withdrawal of the colonoscope. In the second phase of this study, 40 patients underwent colonoscopy without prior intravenous sedation. Sedation was given only if pain was experienced during the procedure. Thirty percent had no pain at all, 55% minimal pain, 8% moderate pain, and 3% severe pain. Twenty-three percent required intravenous sedation, whereas 78% did not receive any sedation. Ninety-three percent were willing to undergo another colonoscopy without prior sedation. Only 8% preferred prior intravenous sedation before any future colonoscopy. PMID- 7859962 TI - Prospective, randomized comparison of disposable and reusable biopsy forceps in gastrointestinal endoscopy. AB - We prospectively compared biopsy specimens obtained with reusable and disposable stainless steel biopsy forceps of varying sizes and configurations. Six types of forceps were used: (1) jumbo reusable forceps, (2) jumbo disposable forceps with a Teflon sheath, (3) regular reusable forceps, (4) regular disposable forceps with a Teflon sheath, (5) regular long-jaw disposable forceps, and 6) regular long-jaw disposable forceps with a Teflon sheath. "Jumbo" forceps were those requiring an endoscopic biopsy channel of at least 3.3 mm. "Regular" forceps were those requiring only a 2.8-mm channel. Two biopsy specimens were obtained with each of the six forceps from normal-appearing stomach, duodenum, and sigmoid colon (25 sets at each location). Mixed and coded specimens were scored by a single pathologist for volume (height, width, and length) and histologic depth. Reusable and disposable jumbo forceps yielded biopsy specimens of similar volumes (30 +/- 1 mm3 and 33 +/- 1 mm3, respectively) and histologic depth (grades of 3.3 +/- 0.1 and 3.5 +/- 0.1, respectively). In comparison, the regular-sized biopsy forceps gave specimens with half the volume of those obtained by the jumbo forceps (reusable, 13 +/- 1 mm3; disposable with Teflon sheath, 15 +/- 1 mm3; long-jaw, 16 +/- 1 mm2; and long-jaw with Teflon sheath, 17 +/- 1 mm3). However, the histologic depths of specimens obtained with the regular disposable forceps were the same as those of specimens obtained with the jumbo forceps. Regular reusable biopsy forceps yielded specimens with the smallest overall volume and histologic depth. We conclude that disposable forceps are equivalent to reusable forceps and that the two types can be used interchangeably in gastrointestinal endoscopy. We recommend the use of jumbo forceps whenever possible because they provide biopsy specimens that are double the size of those obtained with regular forceps. PMID- 7859961 TI - Effect of supplemental oxygen on cardiopulmonary changes during gastrointestinal endoscopy. AB - This prospective study evaluated supplemental oxygen as an effective means of preventing hypoxemia and electrocardiographic changes in sedated patients undergoing endoscopic procedures. Ninety-five patients with documented ischemic heart disease and 106 patients without heart or lung disease were studied. Patients within each group received either supplemental oxygen (2 L/minute) via nasal cannula or room air. Hypoxemia (oxygen saturation below 90%) and ST-segment deviations occurred in cardiac and control groups. The combination of midazolam and meperidine significantly increased the risk for hypoxemia as compared to midazolam alone (44% versus 8%). Supplemental oxygen significantly decreased, but did not entirely prevent, hypoxemia in cardiac and control groups. The incidence of ST-segment deviation in cardiac patients who were hypoxic was significantly lower in the group receiving oxygen (p = .0015). Supplemental oxygen did not affect the incidence of arrhythmias. Prophylactic supplemental oxygen should be administered to patients with ischemic heart disease who undergo conscious sedation for upper and lower gastrointestinal endoscopic procedures. PMID- 7859963 TI - A comparison of the incidence of transient bacteremia and infectious sequelae after sclerotherapy and rubber band ligation of bleeding esophageal varices. AB - A comparison of the incidence of transient bacteremia and infectious sequelae in patients undergoing sclerotherapy and those undergoing variceal ligation has not yet been reported. Fifty patients admitted with acute esophageal variceal bleeding were treated with sclerotherapy between July 1990 and July 1991. Fifty five patients were treated with banding ligation between July 1991 and July 1992. Blood cultures were taken before and 5 minutes, 30 minutes, and 24 hours after treatment to compare the incidence of transient bacteremia in each group. The incidence of infectious sequelae during hospitalization was also compared. Transient bacteremia occurred in 17.2% of the sclerotherapy group and in 3.3% of the ligation group (p < 0.03). Infectious sequelae occurred in 18% of the sclerotherapy group and 1.8% of the ligation group (p < 0.01). Apart from bacteremia, the most frequently encountered infectious sequela was spontaneous bacterial peritonitis. Both transient bacteremia and infectious sequelae are more likely to develop when liver disease is severe. Two patients in the sclerotherapy group but none in the ligation group died of infectious sequelae. The incidence of transient bacteremia and infectious complications after sclerotherapy for acute variceal bleeding is about 5 to 10 times greater than that after variceal ligation. Inasmuch as it is equally effective and entails fewer infectious complications, variceal ligation is preferable to sclerotherapy for patients with acute variceal bleeding. Further randomized trials are needed. PMID- 7859964 TI - Bacteremia and bacterascites after endoscopic sclerotherapy for bleeding esophageal varices and prevention by intravenous cefotaxime: a randomized trial. AB - Thirty-one patients were randomized during 39 episodes of bleeding to receive either 1 g of intravenous cefotaxime (19 patients) or no antibiotic (20 patients) immediately before emergency endoscopic sclerotherapy. Blood was obtained for culture before and at 5 minutes, 4 hours, and 24 hours after the procedure. Specimens for culture were taken from the endoscope tip and channel, water bottle, and injection needle after sclerotherapy. When ascites was present (5 patients in the antibiotic group, 7 in the control group), fluid was obtained by paracentesis before endoscopy and at 4 and 24 hours. Bacteremia occurred in 1 of 19 patients in the antibiotic group (5.3%), compared with 6 of 19 in the control group (31.6%; p = .04). The cultured organisms were oral flora and usually also contaminated the endoscope and needle. No bacteria were cultured from ascitic fluid in any patient nor was the ascitic fluid white cell count elevated. Clinical infection attributable to sclerotherapy did not develop in any patient. In conclusion, the frequency of bacteremia after endoscopic sclerotherapy for bleeding esophageal varices can be reduced by prophylactic administration of intravenous cefotaxime. However, this may not be clinically relevant, given the absence of bacterascites and infection in this study. These findings do not support the routine use of antibiotics before sclerotherapy. PMID- 7859965 TI - Perendoscopic manometry of the distal ileum and ileocecal junction: technique, normal patterns, and comparison with transileostomy manometry. AB - The technique of perendoscopic manometry was used to study the motor patterns of the ileocecal junction and distal ileum. An expert endoscopist cannulated the distal ileum of 20 unsedated subjects in 260 +/- 252 (mean +/- SD) seconds, causing no discomfort beyond that of an ordinary colonoscopic examination. No sphincter-like motor activity was detected at the ileocecal junction, and four distinct motility patterns were identified in the distal ileum: (1) tone variations, (2) slow phasic contractions, (3) regular rapid phasic contractions, and (4) prolonged rapid phasic contractions. Previous appendectomy and insertion of the colonoscope into the distal ileum to position the manometric catheter did not affect the manometric recordings. Perendoscopic manometry of the distal ileum was compared with transileostomy manometry in 9 subjects. Perendoscopic and transileostomy manometric recordings showed the same motor patterns except for a longer occurrence of tone variations with perendoscopic manometry. In conclusion, this study shows that perendoscopic manometry of the distal ileum and ileocecal junction is feasible; recorded motor patterns are not affected. PMID- 7859966 TI - Early feeding after percutaneous endoscopic gastrostomy is safe in children. AB - Most patients are fasted for at least 12 to 24 hours following percutaneous endoscopic gastrostomy. In order to decrease the period of fasting, inadequate nutritional support, and hospitalization time, we began enteral feedings in 24 of 28 consecutive children, aged 4 weeks to 20 years, who were referred for PEG, 6 hours following the procedure. All patients received their full volume of feedings within 24 hours. Twelve of 13 outpatients were discharged in less than 24 hours. There were no complications related to early feeding and no complications that required discontinuation of feedings. Early feeding following PEG insertion is safe in children. PMID- 7859968 TI - Endosonography-guided real-time fine-needle aspiration biopsy. AB - Twenty-six patients were prospectively evaluated with endosonography-guided real time fine-needle-aspiration biopsy. This cohort comprised 14 patients with a pancreatic mass revealed by CT or a stricture of the main pancreatic duct seen at ERCP, 7 patients with mediastinal lymphadenopathy, 3 patients with extrapancreatic abdominal masses, and 2 patients with subepithelial or infiltrative lesions. Endosonography-guided real-time fine-needle-aspiration biopsy was diagnostic in 18 of 20 patients in whom surgical confirmation was available or in whom malignancy was found and confirmed by clinical follow-up (accuracy of 90%). In the subgroup of patients with pancreatic lesions, 3 had previously undergone nondiagnostic CT-guided fine-needle-aspiration biopsy and 2 did not have evidence of a mass by CT. Real-time fine-needle-aspiration biopsy was diagnostic for malignancy in 4 of these individuals. In the 7 patients with mediastinal lymph nodes, 2 had nondiagnostic transbronchial biopsy and 2 had no evidence of mediastinal lymphadenopathy by CT scan. Endosonography-guided real time fine-needle-aspiration biopsy diagnosed malignancy in both individuals with nondiagnostic transbronchial studies and was able to identify mediastinal lymphadenopathy in the 2 patients with negative CT scans (malignancy confirmed with real-time fine-needle-aspiration biopsy in 1). Overall, in 9 of 10 lesions in which visualization by CT was not possible (5), CT-guided fine-needle aspiration was unsuccessful (3), or prior nonsurgical biopsy techniques were unsuccessful (2), real-time fine-needle-aspiration biopsy was diagnostic.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859967 TI - Endoscopic ultrasound-guided fine-needle aspiration. AB - Thirty-eight consecutive patients underwent endoscopic ultrasound-guided fine needle aspiration. Of 46 lesions, 34 were extraluminal (12 pancreatic masses, 8 periesophageal nodes, 6 celiac nodes, 2 pericolonic masses, 1 mediastinal mass, 1 perigastric mass, 1 liver, 1 periduodenal node, 1 perirectal mass, 1 perirectal node) and 12 were submucosal (8 gastric, 3 duodenal, 1 esophageal). One hundred sixty-three passes were made, with an average of 3.5 passes per lesion and 4.3 passes per patient (range, 1 to 8). Adequate specimens were obtained from 91% of targeted lesions. The overall diagnostic accuracy was 87%. In patients with malignant lesions, sensitivity was 91% and specificity 100%. Celiac nodes were successfully sampled and diagnostic in 5 of 6 (83%) patients. No complications occurred. Using this technique, an initial tissue diagnosis of malignancy was made in 66% of cancer patients without a previous diagnosis and the preoperative stage was changed in 44% of cancer patients. The additional information gained by this modality directly influenced the decision not to perform surgery in 26% of patients with a primary malignancy. Endoscopic ultrasound-guided fine-needle aspiration is feasible and can be safely used to evaluate submucosal and extraluminal lesions in both the upper and lower gastrointestinal tract with a high degree of diagnostic accuracy. PMID- 7859969 TI - Endoscopic lithotripsy of bile duct stones using a new laser with automatic stone recognition. AB - Biliary stones can be removed in 85% to 90% of patients using endoscopic sphincterotomy; in the rest alternative methods are required. Thirty-eight consecutive patients in whom conventional methods had failed underwent laser lithotripsy with a new laser system. A flashlamp-pumped pulsed laser with rhodamine 6G as dye (594 nm) has a tissue-stone recognition system that can identify bile duct stones by analyzing backscattered light and interrupt the pulse in case of tissue contact (Lithognost, Telemit, Munich, Germany). Access of the 0.25- or 0.30-mm-diameter laser fiber to the stones was achieved perorally in 18 patients. In 13 of these cases, eccentrically located stones in the middle or proximal common bile duct were targeted with a 3.4-mm miniscope introduced through a standard duodenoscope. Fluoroscopically guided peroral lithotripsy was performed in 5 patients with stones in the distal common bile duct that could be approached with a standard ERCP catheter. Percutaneous cholangioscopic laser lithotripsy was carried out in 20 patients with stones not amenable to retrograde techniques. The mean number of bile duct stones per patient was 3.6, and the average diameter of the largest stone of each patient was 25 mm (range, 8 to 52 mm). The bile ducts were cleared in all but 1 patient in a mean number of 1.3 sessions lasting 15 to 115 minutes (mean, 60). No laser-related complications were observed. The Lithognost laser was successfully used in 37 of 38 patients referred for the removal of difficult bile duct stones.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7859970 TI - Antibiotics, biliary sepsis, and bile duct stones. AB - Bacteriologic studies of bile and blood cultures of 579 patients with ductal stones and infected bile revealed that 121 patients (21%) had associated bacteremia. Analysis of bile and stone cultures showed that Escherichia coli, Klebsiella sp, Enterobacter sp, Enterococcus sp, and Streptococcus sp were the most commonly isolated bacteria. Two-thirds of the patients with bacteremia had similar organisms isolated from blood and bile. Pharmacokinetic studies of the hepatic/biliary excretion profiles of ceftazidime, cefoperazone, imipenem, netilmicin, and ciprofloxacin were performed by ERCP and nasobiliary catheter drainage. The bile samples obtained immediately after cannulation from patients with complete biliary obstruction contained low or undetectable levels of the antibiotics administered--the exception being ciprofloxacin, which was present at a concentration of 20% of the serum level. In vitro determination of minimum inhibitory concentration of the aforementioned antibiotics against 199 isolates of biliary pathogens revealed imipenem and ciprofloxacin to have the highest antimicrobial activity. Based on pharmacokinetic studies and in vitro susceptibility findings, we conclude that ciprofloxacin is superior to the other tested antibiotics in prophylaxis and treatment of biliary sepsis. PMID- 7859971 TI - Knot tying at flexible endoscopy. AB - Four new knotting techniques were developed for use at flexible endoscopy: (1) half hitches tied with knot-pusher, (2) thread-locking device, (3) self tightening slip-knot, and (4) externally releasable knot. Remoteness from site of action, access through small-diameter orifice, and difficulty in applying lateral traction to tighten knots are problems met in knot tying at endoscopy. All four knotting techniques were studied in experiments on postmortem human stomachs and used for radio-telemetry studies and anti-reflux operations in survival studies in dogs using endoscopic sewing techniques. Half hitches tied at endoscopy with a knot-pusher were also used in human studies to treat esophageal reflux and secure pH radio-telemetry capsules for long-term measurements. Externally releasable knots were used to secure nasogastric tubes to the stomach of five patients for long-term nutrition. Knot tying is feasible at flexible endoscopy by a variety of new techniques. Endoscopically tied knots can be as secure as surgically hand tied knots and have been used successfully in man. PMID- 7859972 TI - An endoscopically deliverable tissue-transfixing device for securing biosensors in the gastrointestinal tract. PMID- 7859973 TI - Endoscopic esophagogastric balloon tamponade. PMID- 7859974 TI - A reliable method for the endoscopic placement of a nasoenteric feeding tube. PMID- 7859976 TI - Combined magnification endoscopy with chromoendoscopy for the evaluation of Barrett's esophagus. PMID- 7859975 TI - First-generation video enteroscope: fourth-generation push-type small bowel enteroscopy utilizing an overtube. PMID- 7859977 TI - Endoscopic and histologic diagnosis of submucosal tumors of the gastrointestinal tract using combined strip biopsy and bite biopsy. PMID- 7859978 TI - Hepatobiliary fibropolycystic disease in a patient with autosomal dominant polycystic kidney disease. PMID- 7859979 TI - Right-sided monolobar Caroli's disease with intrahepatic stones: nonsurgical management with ERCP. PMID- 7859980 TI - Patency of endoscopic cystoduodenostomy maintained by a Z stent. PMID- 7859981 TI - Comfort and quality in colonoscopy. PMID- 7859982 TI - Comparative studies for endoscopic devices. PMID- 7859983 TI - Sigmoidoscopic appearances in bone marrow transplant recipients. PMID- 7859984 TI - Endoscopic treatment of a colonic anastomotic mucosal bridge. PMID- 7859985 TI - Intravenous erythromycin to clear the stomach of obstructing clot. PMID- 7859986 TI - An improved safety maneuver for placing overtubes during endoscopic variceal ligation. PMID- 7859987 TI - Bile cast formation after cholecystectomy. PMID- 7859988 TI - Hyperplastic polyps and risk of proximal colonic neoplasms. PMID- 7859989 TI - Deflating replacement gastrostomy [correction of gastroscopy] tubes. PMID- 7859990 TI - Sclerotherapy catheter malfunction and successful needle retrieval. PMID- 7859991 TI - Transmaxillary, percutaneous endoscopic gastrostomy. PMID- 7859992 TI - Perforation after catheter-guided endoscopic intubation. PMID- 7859993 TI - Federal classification of rapid urease test for H. pylori. PMID- 7859994 TI - Imaging of the common bile duct in patients undergoing laparoscopic cholecystectomy. PMID- 7859995 TI - Geriatric care: a nursing specialty in changing times. PMID- 7859996 TI - Alzheimer's disease caregivers: the focused program. A communication skills training program helps nursing assistants to give better care to patients with disease. PMID- 7859997 TI - Learning to use a medical technology. New technologies must be approached with a healthy skepticism, and a great deal of planning. PMID- 7859998 TI - Nursing interventions for chronically confused nursing home residents. PMID- 7859999 TI - Managing mealtime in the independent group dining room: an educational program for nurse's aides. PMID- 7860000 TI - Elder care: results of a one-day educational program for VA nursing assistants. PMID- 7860001 TI - Emerging Veterans Health Administration geriatric and extended care initiatives. PMID- 7860002 TI - Medications that may cause cognitive impairment in older adults. PMID- 7860004 TI - Physician's rights & responsibilities/medical ethics. PMID- 7860003 TI - Simulated presence therapy: using selected memories to manage problem behaviors in Alzheimer's disease patients. PMID- 7860005 TI - Comparisons in good and bad: criminality in Japan and Germany. AB - In the field of criminological comparison, Japan and Germany are very suitable subjects. A nearly identical penal law and a social structure of highly developed industrial societies after a complete destruction at the end of World War War II give a good match. At first sight, Japan's crime rate is less than 1/4 of that in Germany. The impact of organised crime on the reduction of general crime is discussed. PMID- 7860006 TI - Concepts and diagnosis of brain death. AB - The different concepts of brain death are subject to controversial debate. It is outlined that only the whole-brain concept, that is the irreversible loss of all functions of the entire brain, is consistent with the death of man. Cortical death or brain-stem death should not be considered in this respect. The operational procedure for determining brain death is outlined with special regard to those cases in which a definite diagnosis cannot be made clinically. It is shown that apnea testing must be accompanied by blood-gas analysis, as it may take 15 min for the PaCO2 to achieve the desired level of 8 kPa. The problem with CNS-depressing drugs and their metabolites interfering with the clinical diagnosis--e.g. sedatives, barbiturates, opioids--is described, and it is stressed that, in these cases, the cerebral panangiography (digital subtraction angiography with catheter tip in the aortic arch) is the gold standard for the final and definite proof of brain death. PMID- 7860007 TI - Brain death: neuropathological findings and forensic implications. AB - 'Brain death' is defined pathophysiologically as intracranial circulatory arrest. The morphological features of brain death include cerebral edema, absence of reactive changes, and--after an interval of 15-36 h--the morphological hallmarks of respirator brain: edema, global softening of the brain, dusky discoloration of the gray matter, and often necrotic and sloughing tonsillar herniations. The following implications of brain death for forensic medicine are discussed: discriminating between respirator and autolytic brain, declaration of death, determining the time of brain death versus the time of the traumatic event leading to brain death, and neuropathological control of the clinical diagnosis of brain death. These issues are elucidated and their bearing on forensic practice is illustrated by several real-life situations. Thus, neuropathological examination in the case of clinically diagnosed brain death is--without doubt- necessary in order to answer several questions often or regularly expected. PMID- 7860008 TI - Importance of supravitality in forensic medicine. AB - Based on physiological investigations on latency period, survival period and resuscitation period under complete temporary ischemia, supravitality can be defined as even longer survival period of tissues (compared to the resuscitation period) after complete irreversible ischemia. Supravitality is mostly defined by functional parameters (sensitivity to excitation). Parameters of supravital metabolism (substrates and metabolites of anaerobic glycolysis) as a basis for supravital reactions (sensitivity to excitation) are discussed. Particular supravital reaction patterns in comparison to physiological conditions are mentioned (Cannon-Rosenbluth's law of denervation, supersensitivity to pharmacological excitation, local contraction instead of propagated excitation). Lastly, morphological alterations which can be induced during the early supravital period (latency period, survival period) as well as their destination from local vital reactions will be briefly mentioned. PMID- 7860009 TI - Brain-death and pregnancy. AB - This paper examines the case of a pregnant woman killed by a traffic accident (brain-death), but under intensive care and discusses legal and ethical aspects. Ceasing intensive care was, legally, neither necessary nor forbidden. Ethically, the right to life in a defensive meaning is unlimited, however, in the sense of a right to participate, it is dependent of the circumstances, which include economy as well as the chances of the child. PMID- 7860010 TI - Brain-death as an anthropological or as a biological concept. AB - In 1968, when the Harvard Committee defined brain-death to characterize irreversible coma, the question of when a doctor might stop resuscitation remained unresolved: brain-death is a safe, but not a sufficient criterion. Furthermore, the committee defined brain-death to be the death of man without any more than pragmatic reasons. Philosophers tried to give anthropological reasons, as important human functions are located in the brain. But this is misleading, for instance to concepts of partial brain-death. Biologically, however, the death of the whole brain disintegrates the organism and can therefore be accepted as the criterion for death of man. PMID- 7860011 TI - The present state of heart transplantation. AB - After more than 25 years, including long periods of scepticism, heart transplantation, with the introduction of several fundamental innovations, has become a routine clinical procedure for treating life-threatening end-stage heart failure. Annually, 3000-4000 transplantations are performed worldwide. Heart transplantation has been performed successfully in patients of almost all ages, from newborn babies with untreatable heart defects to 70-year-olds. Transplant organs are explanted from deceased donors who have suffered brain death. The circulation is kept stable for several hours during which time a well-functioning heart can be excised. In Europe, as a rule, donor organs are matched to recipients by national or multinational organ-sharing organisations. 'Eurotransplant', for example, serves medical institutions in Germany, Austria, and the Benelux states. This enables 500-600 hearts to be transplanted in Germany each year. Since 1986, 650 heart transplantations have been performed at the German Heart Institute Berlin (GHIB) and more than 100 are performed per year. In recent years, heart-lung, single-, and double-lung transplantations have been added to the GHIB's surgical program, accounting for more than 40 operations since the institute's inception. Patients at the GHIB have ranged in age from 8 days to 68 years, including 48 patients under the age of 16 years. Approximately two-thirds of the patients suffered from dilated cardiomyopathy and one-third from coronary artery disease. Smaller groups of patients suffered from valvular or congenital heart disease. Patients were selected for heart transplantation when heart failure was untreatable by other means and when their life expectancy was estimated to be 6 months or less.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7860012 TI - Xenotransplantation and its future. AB - Today at the beginning of the era of xenotransplantation, only simple and single observations about comparative physiology, biochemistry and anatomy are known. In addition, very few data exist which inform about the mechanisms after successful xenotransplantation. Nothing is known about the phenomena following successfully suppressed hyperacute xenogeneic rejection (HXR). Neither the elimination of a single factor nor the mitigation of whole systems has led to clinically relevant survival times (SVT). Pig organs transplanted into non-human primates survived a maximum of 22 days. The hope that transgenic manipulation and modification would be useful in prolonging the SVT of xenogeneic grafts still awaits supporting evidence. But within a short time, xenotransplantation could enable patients to receive a life saving animal organ as an alternative to an allograft. Xenotransplantation would, as a new dimension in medicine, shorten if not eliminate waiting lists. Therefore, scientists must vigorously develop xenografting as a viable alternative to allotransplantation. Xenotransplantation would not be the terrible danger that some individuals proclaim, and would also not simply be the extension of transplantation but would rather be a victory in medical research. PMID- 7860013 TI - The role of law in the patient-physician relationship. AB - Free or bound decision, individual responsibility or professional ethical control, conduct according to conscience or to legal directives: these buzzword dyads indicate just a few of the issues with which a physician sees himself confronted in his decision-making. And indeed not only in cases of extraordinary procedures, such as reanimation and transplantation, sterilization and fertilization, abortion and perinatology, psychosurgery and sex-change operations, experiments on human subjects and gene manipulation; but also in the day-to-day routine of patient referral or non-referral, or of continuation or termination of treatment, a physician faces the dilemma of whether or not he may take advantage of opportunities that present themselves. These problems could be summed up under the rubric of the justifications and limits of 'medical discretion'. This, however, is certainly wide open to misunderstandings because, in this way, the doctor appears to usurp an exemption for himself which ethicists and legal experts do not believe they can grant him unconditionally. In order to elucidate this problem, two issues are subject to closer analysis. First, the widespread prejudice that medical conduct is determined largely by impartial medical facts for which the establishment of norms is fundamentally elusive: this issue will be disputed on the basis of problems determining the concept and criteria of death and the appropriate termination of treatment.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7860014 TI - Theological theses on the ethics of organ transplantation and on a law concerning the transplantation. AB - The message of the resurrection from the dead is relevant to human beings living and dying in the unity of body and soul. The personality of man is inseparable connected with this unit--even beyond death. Brain death only marks a (decisive) point during the process of dying, and it cannot be defined as the death of a human being (in general). Theological ethics object to this definition and to a new dualism of brain and body as well as of body and personality (i.e. soul), because this dualism socialises the organs of individuals and denies the personal dignity of disappearing life. Therefore, the explantation of organs must depend on a personal declaration of consent given by the adult sponsor himself. Each information given on organ transplants must clarify that the explanation of organs means an interruption of dying. PMID- 7860015 TI - The hippocratic oath and ethics in medicine. AB - For the last number of years, when ethical problems were discussed in Germany in public, the hippocratic oath was quoted as the valid norm for medical ethics. Although no physician swears this oath in Germany, it is necessary to know its contents, its origin and its role in the history of medicine. And it is necessary to ask some questions: What are the ethical claims of the hippocratic oath? Does it really originate from Hippocrates? How and why did the hippocratic oath become the 'Magna Carta' of behaviour for physicians? Do specific medical ethics exist over time? Do specific medical ethics exist in general? And if it exists, can it be normative ethics? A short survey of the multiple dependences of medical situations shows that ethics in medicine must undertake a new beginning. It cannot be normative ethics, it cannot be situation ethics, it must be differential ethics. It has to respect rules and declarations, but it has also to compare the benefits and risks. In the center of such ethics stands the responsibility of the physician. To assume this responsibility, the physician needs knowledge, the ability to make decisions and a conscience. PMID- 7860017 TI - Function and duties of an ethics committee at a university faculty of medicine: 13 years of personal experience. AB - The sad history of experimentation with human subjects by physicians in this century demonstrates the need for an international code of medical ethics which must be recognised by all physicians performing research on human subjects. In order to realise this goal, ethics committees, i.e. committees for the protection of human subjects, are absolutely necessary. Regulations are also needed which make obligatory the submission of every research protocol involving human subjects to an ethics committee. The educational impact of such regulations upon medical students and physicians, and the advantage for patients and volunteers is immense and outweighs the time and workload involved. PMID- 7860018 TI - Reproductive medicine--a field of contradictory legislation in Germany. AB - A brief survey is given on the German legislation concerning reproductive medicine which is contradictory both in juridical and ethical terms. Being under strong ideologic and/or populistic pressure, it favours negative family planning measures such as all kinds of birth control including induced abortion, and handicaps, on the other hand, the more sophisticated procedures of assisted fertilization to overcome infertility. Thus, legal restrictions in this country halt the scientific progress and set back the clinical standard in comparison to our neighbouring countries, all of which are more liberal in their respective legislation. PMID- 7860019 TI - Medical law and ethics in abortion--results of a comparative study in Japan and Germany. AB - Based on interviews with 180 women in Ube, Japan, and 200 woman in Mainz, Germany, the authors report on different opinions on reproductive medicine, with particular reference to abortion. In the light of the historical German-Japanese legal relationship, the latest ruling of the Bundesverfassungsgericht on abortion is discussed, with some remarks from J. Reiter on its social ethics. PMID- 7860016 TI - Ethical, legal and medical problems on the borderline between life and death. AB - 'Brain death' appears to be almost a closed chapter in medical history. But it remains fascinating, particularly regarding future developments, how medical discoveries, moral dilemmas, ethics and law have merged and lead to a common consent on the principal medical, ethical and juristic positions. After a consideration of these questions, topical problems concerning the extent and the limits of medical responsibilities, especially with regard to euthanasia and the problems of a broad interpretation of brain death are discussed. PMID- 7860020 TI - Ethical and medico-legal problems concerning so-called hunger strikers. AB - In the Middle European medico-legal climate, the moral rule 'salus aegroti suprema lex' has been accepted for a long time. In the last few years, under the pressure of fear of accusation of a paternalistic attitude, this postulate has been changed to 'voluntas aegroti suprema lex'. The question stands: Is this valid in each case and in all the situations? For example, it is possible to use compulsory treatment with those who have not given their informed consent. Even the charter of basic human rights and freedom states in its article 6 that everyone has a right of life. The law specifies in which cases an individual can be accepted or can be held in a health care institution without his/her consent. In cases of so-called 'hunger strikers', the strikers refuse food and expose themselves to extreme starvation in order to reach some political goals or to express their views. If, in such situations, the patient endangers his/her life, the physician who is facing this problem is, according to Czech law and similarly to some other Central European laws, and according to the Ethical Code of the Czech Medical Chamber, bound to act to protect and restore the life and the health of that person. The Health Care Act No. 540/1991 of the Czech Republic states the obligation to provide emergency care to anyone whose life or health is threatened. Compulsory treatment is possible, for example, if an individual shows signs of mental disease or if an intoxication threatens him or his neighbourhood.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7860021 TI - Experiences with committees dealing with the issues of ethics. AB - Ethics committees have been active in Germany for 15 years now. Since 1983, such committees, which were established under public law with medical schools, medical associations and representatives of the Federal Health Office among their members, have established a working group with a growing membership of currently some 45 committees. The group's functions include the exchange of experience, the discussion of relevant ethical issues as well as the harmonization and standardization of their internal procedures. In addition, it serves as a point of contact for members of Parliament. Government and journalists. Since 1990, the group has published four yearbooks under the title of 'Medizin-Ethik' [1]. Germany's ethics committees are bodies serving no other purpose than that of biomedical research on human beings (scientific experiments, diagnostic and therapeutic methods, clinical trials involving drugs). They are intended to protect test persons and patients against acts which must not be permitted for ethical and/or legal reasons. Ethics committees fulfil the task of counselling the medically responsible researcher and of examining in advance whether relevant scientific, legal, medical and ethical standards will be met by the biomedical project envisaging scientific research on human beings and whether such a project will not violate accepted values. The ethical and legal standards to be adhered to in this connection have been laid down in the declaration issued by the World Medical Association in Helsinki/Tokyo/Venice/Hong Kong, they have been codified in human rights declarations and in a great number of national legal provisions and have been included in scientific standards.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7860022 TI - Interlaboratory comparison of quantitative determinations of drug in hair samples. AB - Testing human hair for drugs of abuse is a relatively new technique which requires control before being fully accepted in Justice applications. A consensus procedure was recently proposed to the four French Laboratories performing hair analysis for opiates and cocaine. Results of two independent controls have shown that the laboratories have performed very well quantitatively, using the recommended method. In order to compare these results with those obtained by other procedures, one sample was sent to 15 laboratories concerned with the analysis of human hair for drugs of abuse in Germany, Italy, Spain, and United States. Results from this study have indicated that the French recommended method is in accordance with the general procedures. PMID- 7860023 TI - Analytical procedures for determination of opiates in hair: a review. AB - This article reviews the analysis of opiates in hair. Hair matrix pretreatment, hydrolysis, extraction and detection procedures are presented amongst a study of over 70 bibliographic data. In addition, a new method for the extraction of opiates from hair, in which a powdered sample of hair is extracted directly by subcritical fluid, is presented. PMID- 7860024 TI - The detection of 6-monoacetylmorphine in urine, serum and hair by GC/MS and RIA. AB - 6-Monoacetylmorphine (6-MAM) is a good indicator for the intake of heroin and can be detected in blood, urine and hair of heroin users. A new radioimmunoassay (RIA) designed specifically for 6-monoacetylmorphine (6-MAM) was tested for its usefulness for the quantitation of the drug in urine, serum and hair. Its cross reactivity with heroin and its metabolites, and related compounds was also determined. Eighty-nine hair, six serum and 25 urine samples where 6-MAM had been previously identified by GC/MS were analysed for 6-MAM with the new RIA kit. A good correlation existed between the GC/MS and RIA results for the hair samples. However, the amount of 6-MAM found in serum and urine differed considerably between the two methods. This difference could be explained by the cross reactivity of the antibody with morphine and morphine-6-glucuronide, which are present in much larger amounts in serum and urine, than in hair. To evaluate a new rationalisation procedure, some hair samples were split into two portions after incubation. One part was analyzed for 6-MAM by RIA, and the other portion by GC/MS. PMID- 7860025 TI - Decontamination procedures for drugs of abuse in hair: are they sufficient? AB - This paper reviews the methods for decontaminating hair exposed to external solutions of drugs of abuse. Exposure of hair to cocaine at 1 microgram/ml for 5 min is sufficient to contaminate hair, yet decontamination is a very slow process. Using externally contaminated hair, a number of decontamination procedures were attempted, and none removed all the contamination. The percentage of external contamination removed depended on the hair type, with thick black hair being the most resistant to decontamination. Hair treated by dying incorporated externally applied drugs differently, depending on the hair type. Thick black hair became more absorbent whereas thin brown hair became less absorbent. Kinetic wash criteria are evaluated for their ability/inability to determine if hair has been contaminated from external sources. A theoretical framework for the incorporation and removal of drugs from hair is discussed, and the hypothesis that inaccessible domains exist in hair which trap drugs is critically examined. The results presented in this paper strongly suggest that much more information on the decontamination of hair and the differentiation of exogenously and endogenously incorporated drugs is needed before hair analysis can be employed in most forensic applications. We propose that the radioactive tracer methods discussed herein are well suited for evaluating any new decontamination or extraction technique. PMID- 7860026 TI - Detection and diagnostic interpretation of amphetamines in hair. AB - A review with 22 references on detection and incorporation of amphetamines in hair is presented. This review deals with the detection, incorporation into hair, behavior in the hair shaft, confirmation of past drug use and diagnosis of dependence mainly regarding amphetamine and methamphetamine, along with methoxyphenamine, methylenedioxymethamphetamine, bromomethamphetamine, deprenyl, benzphetamine, fenproporex and mefenorex. First, pretreatment, extraction and analytical methods for amphetamines in hair using immunoassay, HPLC and GC/MS are discussed. This is followed by sections describing the animal experiments, incorporation rates of amphetamines from blood to hair and relationship between drug history and drug distribution in hair. Finally, the diagnosis of amphetamine dependence and confirmation of methamphetamine baby by hair analysis is discussed. The paper concludes with a brief outlook. PMID- 7860027 TI - The determination of cocaine in hair: a review. AB - The explosion of literature related to the analysis of hair for cocaine and its products is reviewed. In the commonly accepted applications of hair testing for cocaine, those related to criminal or civil investigations and pharmacotoxicologic studies occupy most of the relevant published work. This review uses detailed, 'binary' (yes/no) tables to demonstrate trends in the literature, and allows researchers and caseworkers quick access to the literature most important for answering a variety of questions. PMID- 7860028 TI - Simultaneous quantification of opiates, cocaine and cannabinoids in hair. AB - The present paper describes a sensitive method developed in our laboratory for the simultaneous analysis of opiates (morphine, codeine and monoacetylmorphine), cocainis (cocaine and benzoylecgonine) and cannabinoids (delta 9 tetrahydrocannabinol and 11-nor-delta 9-tetrahydrocannabinol-9-carboxylic acid) in hair samples. After decontaminating the sample with dichloromethane, two consecutive hydrolyses were performed in order to achieve the best conditions for extracting the three kinds of drugs from the protein matrix. First the opiate and cocainic compounds were extracted by means of a soft acidic hydrolysis with 0.1 N HCl at 50 degrees C overnight and organic solvent extraction at pH 9.2. The cannabinoids need a stronger basic hydrolysis with 11.8 N KOH for 10 min at laboratory temperature. After adding maleic acid, the cannabinoids were extracted with an organic solvent. The derivatization was carried out with heptafluorobutyric anhydride and hexafluoropropanol. Calibration curves were linear between 0.5-100 ng/mg of hair. Recovery and reproducibility were assured. The quantification limits ranged between 0.04-0.26 ng/mg of hair. Seventy hair samples from known drug abusers were cut into 1-cm segments and analyzed by this method. The ranges of measured concentrations (ng/mg) were 0.31-89 for cocaine, 0.1-5.76 for benzoylecgonine, 0.34-45.79 for morphine, 0.45-39.59 for codeine, 0.09-48.18 for monoacetylmorphine, 0.06-7.63 for THC and 0.06-3.87 for THC-COOH. The results of sectional analyses agreed with the self reported drug histories. The usefulness of this method is in assessing earlier drug consumption, and also at the same time obtaining a chronological profile of the consumption of these three types of drugs. PMID- 7860029 TI - Testing human hair for cannabis. AB - To validate information on cannabis use, we investigated human hair and pubic hair for cannabinoids (THC and THC-COOH) by gas chromatography/mass spectrometry. Samples (100 mg approximately) were decontaminated with methylene chloride, then pulverized and dissolved in 1 ml 1 N NaOH for 10 min at 95 degrees C in the presence of 200 ng of deuterated standards. After cooling, samples were extracted by n-hexane/ethyl acetate after acidification with acetic acid. After derivatization of the dry extract by PFPA/PFP-OH, the drugs were separated on a 30-m capillary column and detected using selected-ion monitoring (m/z 377 and 459 for THC and THC-COOH, respectively). Forty-three hair samples were obtained from fatal heroin overdose cases. Among them, 35% tested positive for cannabinoids. Hair concentrations ranged from 0.26 to 2.17 ng/mg (mean, 0.74 ng/mg) and 0.07 to 0.33 ng/mg (mean, 0.16 ng/mg) of THC and THC-COOH, respectively. As is generally the case for other drugs detected in hair, metabolite concentration was always lower when compared to the parent drug concentration. In public hair, THC concentrations ranged from 0.34 to 3.91 ng/mg (mean, 1.35 ng/mg) and THC-COOH concentrations from 0.07 to 0.83 ng/mg (mean, 0.28 ng/mg). In most cases, the highest cannabinoid concentration was found in pubic hair, suggesting that this sample may be the more suitable for cannabis testing. PMID- 7860030 TI - Hair analysis: a worthless tool for therapeutic compliance monitoring. AB - Hair analysis has been presented by some authors as a possible tool of investigation for estimating patients' compliance to long-term therapies. This paper summarises the different publications that have been devoted to this topic and highlights the available statistically data presented to support this proposition. Qualitative results of such determinations may be of some interest but due to the enormous interindividual variations of quantitative data, the idea of using hair analysis to ascertain whether a patient has taken his treatment exactly as prescribed, clearly appears to be inapplicable. PMID- 7860031 TI - Phenobarbital in hair and drug monitoring. AB - Phenobarbital analysis was performed in vertex hair of patients by gas chromatography mass spectrometry (GC/MS). After washing with dichloromethane, about 250 mg were ground to dust in a ball mill. A 50-mg sample was stirred mechanically for 10 min with 3 ml of NH4Cl/HCl buffer (pH 2.0) containing phenobarbital D5. A solid phase extraction was performed (extrelut Merck) and elution was achieved with chloroform/isopropanol/n-heptane (50:17:33; v/v). A full scan (40-240 uma) acquisition was realized by GC/MS with an ion trap (ITD 700 Finnigan) using a DB5-MS chromatographic column. Quantification was achieved by integrating dominants ions (phenobarbital, 204; phenobarbital D5, 209). Compared to serum, hair concentrates phenobarbital during anti-epileptic therapy (average value 36.4 ng/mg, n = 40 vs. 18.7 mg/l, n = 23). A group correlation exists between phenobarbital in hair and phenobarbital in serum, and between phenobarbital in hair and clinic observation in some typical cases. Phenobarbital in hair yields good information over a long period, especially when blood collection has not been made, when clinical disorders are observed on long-term therapeutic observance. PMID- 7860033 TI - Segmental hair analysis for cocaine and heroin abuse determination. AB - Segmental hair analysis was performed to obtain information about the history of drug abuse of subjects in a rehabilitation programme. The analytical data from hair samples were correlated, when possible, with urine analysis and to toxicological anamnesis. Toxicological analysis of hair seems to be a valid tool in this specific field. PMID- 7860032 TI - Hair and urine analysis: relative distribution of drugs and their metabolites. AB - This work studies the distribution of cocaine and heroin metabolites in hair and urine of living polidrug abusers. Cocaine, benzoylecgonine (BEG), ecgonine methyl ester (EME), morphine, codeine and 6-monoacetylmorphine (6-MAM) were simultaneously extracted and analyzed by GC/MS in SIM mode. The results obtained show a different distribution of heroin and cocaine metabolites in urine and hair. In urine, we generally find BEG and EME for cocaine abuse, and morphine for heroin abuse. In hair, we detect cocaine and MAM as major metabolites for cocaine and heroin abuse, respectively. PMID- 7860034 TI - What constitutes a positive result in hair analysis: proposal for the establishment of cut-off values. AB - Hair is still a seldom used specimen in most laboratories but its analysis has the potential of making a valuable contribution. Despite the many worthwhile reports, the scientific community at large still has reservations about the validity of hair analysis. Some of this is due to a lack of consensus among the active investigators on how to interpret the results from an analysis of hair. In USA, passive exposure seems to be a major problem, which can only be eliminated with difficulty. On the other hand, in Europe, scientists are performing standard decontamination procedures. It would be very helpful if a group of active researchers on hair analysis, representative of academic, government and private laboratories could define what are the areas of agreement and what are the issues that require further efforts to get a consensus. We propose the following guidelines: (1) a complete decontamination procedure, including the analysis of the wash solution; (2) two distinct analytical methods (immunoassay and GC/MS, or two different GC/MS methods); (3) the establishment of cut-off values (using 30 mg hair samples), 0.5 ng/mg of 6-MAM in the case of heroin abuse, and 1 ng/mg of cocaine in the case of cocaine abuse, which can be decreased to 0.5 ng/mg when use is supported by other evidence of drug intake. PMID- 7860035 TI - Testing human hair for drugs of abuse. IV. Environmental cocaine contamination and washing effects. AB - Active cocaine use results in sequestration of parent drug in hair. In addition, hair has unique physicochemical properties that permit absorption of cocaine from the environment. When hair is tested for evidence of cocaine, it is important to consider whether the positive test resulted from active drug use or environmental contamination. In a series of laboratory experiments, it was found that exposure of 'cut' hair to cocaine vapor ('crack' smoke) and to aqueous solutions of cocaine hydrochloride resulted in significant contamination of hair samples. Similar results were obtained with two subjects who were exposed to cocaine vapor in an unventilated room. The amount of contamination adsorbed by hair depended upon both time and extent of exposure. Washing the hair samples with methanol removed > 70% of the cocaine contaminant after cocaine vapor exposure, but was less effective (< 50%) following contamination with aqueous cocaine. Shampoo treatment cycles (overnight soaking) progressively removed increasing amounts of cocaine from the contaminated hair, but residual cocaine remained after 10 cycles. Studies were also performed to determine the usefulness of benzoylecgonine as a marker of active cocaine administration. Small amounts of benzoylecgonine (ca. 1 ng/mg) were formed in hair as a result of environmental contamination with cocaine. Also, it was found that benzoylecgonine could be adsorbed from illicit cocaine contaminated with benzoylecgonine. It was concluded that positive hair test results should be interpreted cautiously due to the possibility of environmental contamination from cocaine and related constituents. PMID- 7860036 TI - Theoretical limits of the evaluation of drug concentrations in hair due to irregular hair growth. AB - When examining concentration relationships of doses it must be taken into account that hair growth is irregular. Hair growing from the shaved skin after a single dose of a certain drug cannot possibly contain the same concentration as hair after the same dose that has not been cut over a long period. Concentrations can even change during the hair growth in cases where the hair had been cut a couple of months before the hair sample was taken. The variations in the expected concentrations can exceed 20%. On the other hand, the evaluation of a hair tuft which has grown after the last drug consumption may be important in forensic cases where the hair which has grown earlier is not available. This may lead to misinterpretations at low concentrations. Expected concentrations are calculated assuming a telogen part of 10%. PMID- 7860037 TI - Drug testing by urine and hair analysis: complementary features and scientific issues. AB - Hair analysis and urinalysis are complementary tests for establishing drug use. Hair analysis provides long-term information, from months to years, concerning both the severity and pattern of drug use. In contrast to this, urinalysis can indicate only drug use, and then generally only that which has occurred within the last 2-3 days. Field studies have demonstrated that hair analysis is considerably more effective than urinalysis at identifying drug users. This difference is due to the wider surveillance window of hair analysis and to the susceptibility of urinalysis to evasive maneuvers. The main concerns with urinalysis are endogenous evidentiary false positives caused by passive drug exposure, e.g., ingestion of poppy seed. This problem arises from the hypersensitivity of the urine test, i.e. the need to use low cut-off levels in order to compensate for the temporary recording of drug use. This problem does not occur with hair analysis since its wide window of detection and permanent record of drug use ensure that the detection efficiency of the test is not compromised by the use of more effective cut-off levels guarding against passive endogenous drug exposure. On the other hand, exogenous evidentiary false positives due to external contamination of hair by drugs present in the environment (e.g., smoke) are the main concern of hair analysis. This problem, however, can be effectively avoided by washing the hair specimen, by kinetic analyses of the wash data, and by measurement of metabolites. The possibility of bias due to race and/or hair color is avoided by the exclusion of melanin from the analysis of hair. The safety and effectiveness of hair testing has been established by extensive field studies with over 400,000 specimens. PMID- 7860038 TI - Measurement of drugs in neonatal hair; a window to fetal exposure. AB - Because the hair neonates are born with grows during the last 3 months of pregnancy, the presence of drugs (e.g. cocaine) or environmental toxins (e.g. nicotine) reflects fetal exposure to such compounds. In the case of cocaine, hair measurement are several fold more sensitive than maternal history or urine measurements. Measurements of cotinine in neonatal hair are capable of distinguishing between fetal exposure to passive versus active smoking. Because most cocaine users also smoke cigarettes, neonatal measurements of both cocaine and cotinine will allow cumulative quantification of fetal risk. PMID- 7860039 TI - A research note: the outcome of GC/MS/MS confirmation of hair assays on 93 cannabinoid (+) cases. AB - This article reports the outcome of gas chromatography/tandem mass spectrometry confirmations for THC and carboxy-THC on 93 hair samples screened by RIA for cannabinoids. The samples were taken from probationers in Pinellas County, FL, who voluntarily provided the research staff with six hair and six urine specimens, collected at 1-month intervals. There were 40 samples that were RIA (+), urinalysis (-). Samples were selected which had cannabinoid (+) outcomes for hair, urine, or both. The THC and/or the carboxy-THC was (+) on confirmation. Of these 40 samples, 22 were (+) for both THC and carboxy-THC, 15 were (+) for THC but not carboxy-THC, and three were carboxy THC (+), but THC (-). Only one sample had a (+) RIA, but was (-) for both THC and carboxy-THC on confirmation. RIA detection of cannabinoids was confirmed in nearly all cases. Most cases that were RIA (-) but urine (+) were cannabinoid (+) when analyzed by GC/MS/MS. PMID- 7860040 TI - Capillary electrophoresis: a new tool in forensic toxicology. Applications and prospects in hair analysis for illicit drugs. AB - Capillary electrophoresis, the modern approach to instrumental electrophoresis, is probably the most rapidly expanding analytical technique that has appeared in recent years. In the hands of forensic toxicologists, capillary electrophoresis (CE) represents a powerful new analytical tool, which has proved suitable for the investigation of illicit drugs in seized preparations and also in complex biological matrices, among which is hair. CE can be applied according to different separation mechanisms, and among those that are toxicologically relevant are capillary zone electrophoresis and micellar electrokinetic capillary chromatography, which display different selectivities. For the investigation of hair for drugs of abuse, capillary electrophoresis proved effective, providing simultaneous determinations of different drugs without derivatization, with acceptable sensitivity (typically better than 1 ng of drug per mg of hair). The possibility of carrying out determinations of the same analytes, based on different separation mechanisms (capillary zone electrophoresis and micellar electrokinetic chromatography) with the same instrumentation, simply changing the buffer composition, provides an interesting possibility of 'internal' confirmation of the results. PMID- 7860041 TI - Does the evaluation of proliferative activity predict malignancy of prognosis in endocrine tumors? PMID- 7860042 TI - Proliferative activity in parathyroid tumors as detected by Ki-67 immunostaining. AB - Clear morphological criteria for differentiating benign from malignant parathyroid tumors are not yet available and unfavorable prognosis cannot be predicted by histopathological parameters alone. A retrospective study of a series of parathyroid lesions was designed to evaluate the diagnostic role of the cell cycle-associated Ki-67 antigen detected by MIB-1 monoclonal immunocytochemistry. The mean tumor proliferative fraction (TPF), expressed as the number of Ki-67-positive nuclei per 1,000 cells, was 0.8 in normal parathyroid glands (nine specimens), 26.0 in hyperplasias (11 specimens), 32.8 in adenomas (11 specimens), and 60.5 in a group of tumors with histological features consistent with carcinoma (12 specimens). The difference between the latter two values was statistically significant (P < .05). When the five most clinically aggressive tumors were considered, the difference was even more remarkable (TPF, 78.6; P < .001). Oncocytic and pleomorphic cell components were found to proliferate with a labeling pattern similar to that of the chief cells. We conclude that proliferative activity is an additional useful parameter for evaluating parathyroid tumors diagnostically. Aggressive behavior may be expected in those tumors with a TPF greater than 6%. PMID- 7860043 TI - Growth activity in hyperplastic and neoplastic human thyroid determined by an immunohistochemical staining procedure using monoclonal antibody MIB-1. AB - To increase our understanding of the basic biological mechanisms of thyroid diseases, growth activity (GA) in 232 thyroid lesions was determined by immunohistochemistry using monoclonal antibody MIB-1. The GA tended to be higher in hyperplastic lesions, adenomatous goiter (MIB-1-positive cell rate, 0.73%), and Graves' disease (1.68%) than in normal tissue (0.19%). The GA for differentiated thyroid carcinomas (2.00%) was much lower than for adenocarcinomas of other organs, such as breast, lung, stomach and colon (44.67%). Of the thyroid carcinomas, the highest GA was observed in undifferentiated carcinomas (32.67%), and follicular carcinomas (3.18%) showed a higher GA than papillary carcinomas (1.83%). There was no significant difference between the GA of follicular carcinomas and solid/trabecular adenomas, although widely invasive follicular carcinomas showed a higher GA than minimally invasive carcinomas. No significant correlations between GA and patient age, sex, and tumor diameter, metastasis, or histological features were observed in papillary carcinomas. Familial medullary carcinomas showed a higher GA than sporadic tumors. All latent papillary carcinomas had a very low GA. Our findings suggest that immunohistochemical investigation using the antibody MIB-1 contributes to the understanding of growth characteristics and biological activities in thyroid diseases. PMID- 7860044 TI - Vulvar intraepithelial neoplasia: age, morphological phenotype, papillomavirus DNA, and coexisting invasive carcinoma. AB - Recent studies suggest that subsets of vulvar intraepithelial neoplasia (VIN) may be distinguished based on morphological presentation, the presence or absence of human papillomavirus (HPV) nucleic acids, and patient age. We analyzed 65 VIN lesions, including 15 with associated squamous cell carcinoma, to determine the relationship between pathological parameters associated with common types of VIN (multinucleation, koilocytosis, verruco-papillary morphology, diffuse atypia), rarer variants (differentiation, basal atypia), patient age, and papillomavirus nucleic acids. For all lesions higher mean ages were observed in patients with lesions that were associated with cancer and with well differentiated VIN variants with basal atypia only. A strong negative correlation with HPV nucleic acids was observed for differentiated variants with basal atypia (P = .002). In the common or "classic" VIN group patients with lesions with koilocytotic atypia, multinucleation, and verruco-papillary morphology were generally younger. However, no parameter or group of parameters defined a subset of patients with a significantly lower mean age or lesions with a higher index of HPV nucleic acids. Three of six lesions of lichen sclerosus (LS)-associated VIN, including one involving invasive carcinoma in elderly women, contained HPV nucleic acids; all three lesions exhibited the features of classic VIN. The finding of HPV across a broad age range suggests that this virus may play a role in vulvar neoplasia at any point in life. The direct demonstration of HPV nucleic acids within three LS associated VINs is intriguing because it links two distinct risk factors to the same neoplasm. PMID- 7860045 TI - p53 accumulation in benign breast biopsy specimens. AB - Several studies of benign breast lesions using methacran-fixed, paraffin-embedded tissues and cytological preparations have suggested that p53 accumulation in these lesions as detected by immunohistochemical (IHC) staining is rare to absent. As a result, several different investigators have suggested that p53 immunoreactivity in breast specimens infers a diagnosis of malignancy or may identify premalignant lesions. We immunostained 271 breast biopsy specimens from 271 patients with the monoclonal anti-p53 antibody BP-53-12 and found positive nuclear staining in seven of 23 malignant lesions (30%) and 39 of 248 benign biopsy specimens (16%). Of the benign lesions, 30% of fibroadenomas, nonpremalignant breast lesions, were positive. Long-term follow-up information was available on 48 patients with benign biopsy specimens and showed that 12% of those positive and 7% of those negative for p53 developed breast carcinoma. This difference was not significant (P > .2). We conclude that (1) p53 immunoreactivity in breast lesions should not be used as exclusive evidence of malignancy and (2) p53 immunoreactivity in benign breast lesions may not identify a subset of patients at increased risk for breast carcinoma. PMID- 7860046 TI - p53 quantitative immunocytochemical analysis in breast carcinomas. AB - A series of 200 breast carcinomas was investigated on frozen sections using PAb 1801 p53 monoclonal antibody and streptavidin biotin peroxidase complex. Densitometric analysis of the immunoprecipitates was assessed by processing digitized microscopic images. p53 was observed in the nucleus of 48% of the tumors. Some tumors (14 of 91) tested in parallel on paraffin sections were negative, although positive on frozen sections. Image analysis showed that the surfaces positive with anti-p53 and the staining intensity were decreased (P < .01) on paraffin sections. The p53 tumor expression was independent of patient age, tumor size, axillary lymph node status, HER-2/neu and cathepsin D expression, and nuclear morphometric parameters. However, p53 correlated with high histological grade (P < .01), lack of estrogen receptor (ER) (P = .0015) and progesterone (PR) (P = .0065) antigenic sites, pS2 detection (P = .03), high Ki 67 immunoreactivity (P = .018), large silver-stained nucleolar organizer region (AgNOR) nuclear surface ratio (P < .02), and degree of hyperploidy (P < .03), and was more often observed in the comedocarcinomas. The results suggest that p53 expression in breast carcinomas is not a totally independent prognostic indicator and that the clinical relevance and prognostic significance of p53 expression in breast carcinomas can be reliably assessed provided that the procedures are standardized, particularly with regard to the use of frozen sections and image analysis processing of the immunodetection. PMID- 7860047 TI - Nevoid melanoma: a clinicopathological study of seven cases of malignant melanoma mimicking spindle and epithelioid cell nevus and verrucous dermal nevus. AB - We report seven cases of a distinctive type of malignant melanoma characterized by a deceptively benign histological appearance with an architecture resembling that of benign melanocytic nevi on scanning magnification. Two predominant architectural patterns were observed: a dome-shaped pattern (two specimens) and a verrucoid pattern (five specimens). The specimens with a dome-shaped pattern of growth were characterized by a smooth epidermal surface and a proliferation of epithelioid melanoma cells with an inconspicuous intraepidermal component resembling spindle and epithelioid cell nevi (Spitz nevi). Gradual diminution in the size of dermal nests toward the bases of the lesions simulating the maturation phenomenon of benign nevi was observed; however, the dermal organization in cords and strands of melanoma cells and the persistence of cellular atypia extending to the bases of the tumors allowed their recognition as malignant melanomas. On the other hand, the specimens with a verrucoid growth pattern consisted of broad, exophytic tumors with a verrucous epidermal surface resembling that of papillomatous dermal nevi but distinguished from them by the presence of a continuous proliferation of melanocytes along the dermal-epidermal junction and by confluent sheets of melanoma cells in the dermis without evidence of true maturation. Clinical follow-up showed local recurrence in three patients after intervals ranging from 5 months to 5 years and regional metastasis in one patient after 2 years. The lesions described here may constitute a serious pitfall for diagnosis because of their innocent silhouette on scanning magnification and their superficial resemblance to spindle and/or epithelioid cell nevi and benign verrucous melanocytic nevi. Proper attention to cytological detail and subtle architectural features will aid in recognizing this unusual variant of malignant melanoma. PMID- 7860048 TI - Distribution pattern of the basement membrane components is one of the significant prognostic correlates in peripheral lung adenocarcinomas. AB - Clinicopathological variables that might have an effect on prognosis were analyzed in 98 samples of resectable peripheral lung adenocarcinoma. Pathological stage (stage I v stage II, III, or IV; P < .001), degree of central fibrosis (grade 1 or 2 v grade 3 or 4; P < .01), and histological grade (well differentiated v moderately or poorly differentiated; P < .05) were shown to be prognostic factors, whereas any other variable, including patient age at diagnosis, sex, cigarette smoking habits, and tumor histological subtype and cytological type, showed no meaningful correlation with patient length of survival. The distribution pattern of the basement membranes (BMs) was significantly associated with pathological stage (intact v disrupted or absent; P < .001). It was noteworthy that in stage I samples a significant relationship between the distribution pattern of the BMs and patient length of survival was found (intact v disrupted or absent; P < .001), although such a relationship could not be detected when analyzed in samples from the other pathological stages. The distribution pattern of the BMs also was correlated with the presence or absence of lymph node metastasis but not with its extension. There were no meaningful relationships between the distribution pattern of the BMs and any other clinicopathological variables, including degree of central fibrosis, histological grade, etc. The distribution pattern of the BMs in peripheral lung adenocarcinomas might be useful for postoperative therapeutic strategy and could serve as an important prognostic indicator for stage I lesions. PMID- 7860049 TI - Pressure (decubitus) ulcer: variation in histopathology--a light and electron microscope study. AB - The histopathology of pressure (decubitus) ulcers from 20 patients was examined by light and electron microscopy. Surgical biopsy specimens from the ulcer edge, ulcer margin, and adjacent normal, nonulcerated skin showed four general types of ulcer histopathology. Morphological features common to all ulcer groups were a dense fibrin matrix, occluded blood vessels, numerous inflammatory cells, and a range of cellular viability from functionally normal appearing cells to cells in all stages of necrosis. These data present structural reference points for comparing pressure ulcer pathology and evaluating the effects of growth factors on wound healing. PMID- 7860050 TI - Fetoplacental histology as a predictor of karyotype: a controlled study of spontaneous first trimester abortions. AB - It has been suggested that inferences about fetal karyotype can be made from examination of placental and decidual histology in early, spontaneous abortions (SABs). We assessed the reproducibility and predictive value of histologic features in 75 karyotyped, first trimester SABs; 32% (24 of 75) had normal male karyotypes (46,XY) and 68% (51 of 75) were cytogenetically abnormal (29 trisomy, 12 triploidy, eight monosomy X, and two tetraploidy). Three pathologists independently assessed 17 fetal, placental, and decidual histological findings and made predictions about the karyotype (normal, abnormal, or uncertain). Good to excellent interobserver and intraobserver reproducibility (kappa > 0.58) was achieved for the identification of five histological features: villous cavitation, anucleate fetal erythrocytes, amnion, umbilical cord, and fetal tissue. When histology and karyotype were compared using Fisher's exact test, no histological feature was associated with "any abnormal karyotype," two features (anucleate, fetal erythrocytes and umbilical cord) were associated with a normal karyotype, two features (villous dysmorphism and cisterns) were associated with triploidy, and four features (villous hydrops, no umbilical cord, no fetal tissue, and no anucleate erythrocytes) were associated with trisomy. Despite these significant histological-cytogenetic associations, the positive predictive values of each of these histological features with their corresponding karyotypes were low, ranging from 0.41 to 0.73 (mean, 0.53). Our data suggest that certain histological features in first trimester SABs are associated with the SAB's karyotype and are reproducible; however, such histological features did not perform as well as diagnostic tests for predicting the likelihood of normal versus abnormal karyotype. PMID- 7860051 TI - Breast cancer heterogeneity: evaluation of clonality in primary and metastatic lesions. AB - Breast cancers often contain different clones of tumor cells. Attention to the cellular properties of breast cancer metastases may identify characteristics in primary tumors that are associated with metastasis. Such characteristics could include DNA content, cell proliferation, abnormal oncogene expression, or relative cell population (clonal dominance). We examined DNA ploidy (image analysis), proliferation index (proliferating cell nuclear antigen-1 immunostaining), and expression of Her-2/neu oncoprotein in 17 invasive breast cancer samples (36 primary tumor samples) and 82 corresponding regional metastases. In all samples the primary tumor was multiclonal (usually biclonal) by DNA ploidy analysis. In approximately 90% of metastatic DNA clones (30 of 34) the corresponding clone was identified in a primary tumor sample representing 25% or more of the tumor cell population (significant clone). A majority DNA clone (> or = of tumor cell population) existed in 60% (21 of 36) of primary tumor samples and in 70% (60 of 82) of metastases (30% diploid v 70% nondiploid in both groups). In approximately 50% of metastases (37 of 82) an unexpected majority clone was identified (not a majority in any primary tumor sample) and the ratio of diploid to nondiploid clones also was 30% to 70%. However, in 80% of majority metastatic clones (46 of 60) that clone was a significant primary tumor clone. Proliferation index was quite variable in primary tumor samples and in corresponding metastases. Overexpression of Her-2/neu oncoprotein in the primary tumor of seven of 10 patients also was identified in all corresponding metastases in five of seven patients and in some metastases in two of seven patients. The metastases in three Her-2/neu-negative patients were all negative. We conclude that (1) DNA clones are stable after metastasis, (2) clonal majorities in metastases reflect clones identified in primary tumors, (3) different metastatic clones from an individual tumor can establish clonal majorities, (4) neither diploid nor aneuploid cells have a metastatic advantage in breast cancer, (5) proliferation indices are heterogeneous, and (6) overexpression of Her-2/neu is usually consistent between primary tumors and corresponding metastases. PMID- 7860052 TI - Metallothionein expression in duct carcinoma in situ of the breast. AB - In a previous study immunocytochemically detectable metallothionein (MT) expression in tumor cells of invasive duct carcinoma of the breast was shown to be associated with a more aggressive behavior and these findings have been subsequently confirmed by others. The aim of this study was to examine the prevalence and significance of MT positivity in preinvasive duct carcinoma in situ (DCIS). Fifty-five specimens of pure screen-detected DCIS were stained immunocytochemically for MT using the antibody E9. The intensity and distribution of MT staining were assessed using a semiquantitative method resulting in intensity distribution (ID) scores allowing duct by duct analysis in relation to architectural and cytological features of the DCIS. In general, myoepithelial cells around benign and malignant structures stained uniformly strongly for MT. Staining in DCIS was analyzed by architecture irrespective of cytology and by nuclear grade irrespective of architecture. The results showed that MT staining was significantly greater in comedo (ducts with necrosis) DCIS (ID = 97) compared with noncomedo (ducts without necrosis) DCIS (ID = 56) (P = .05 by Mann Whitney U statistic) and that low cytological grade (ID = 50) was associated with less MT staining than was high cytological grade (ID = 92) (P = .05 by Mann Whitney U statistic). These observations thus are consistent with the previously observed association between MT positivity and more aggressive behavior in invasive duct carcinoma of the breast. PMID- 7860053 TI - Diagnostic criteria of limited adenocarcinoma of the prostate on needle biopsy. AB - Over a period of 25 weeks 434 needle biopsy specimens of the prostate were sent to the author for consultation because of diagnostic concerns. The final diagnoses were cancer (69%), benign (13%), atypical but not diagnostic (10%), high grade prostatic intraepithelial neoplasia (PIN) (5%), and miscellaneous (3%). The most common benign entities mimicking cancer were atrophy (29 specimens) and adenosis (19 specimens). The 300 cancer specimens were analyzed further. Architecturally, the presence of small glands between larger benign glands was the most common pattern seen in 80% of carcinomas; haphazard growth patterns, single cells, and cribriform glands were seen less frequently. The following diagnostic features were helpful: nuclear enlargement (77% of specimens); prominent nucleoli (76%); pink acellular intraluminal secretions (53%); amphophilic cytoplasm (39%); blue-tinged mucinous secretions (34%); crystalloids (25%); PIN (13%); mitotic figures (11%); and perineural invasion (3%). The mean and median numbers of malignant glands in this series were 31 and 20, respectively (range, two to 300). Tumors with a Gleason score lower than 6 caused greater diagnostic problems for referring physicians because these tumors had a greater number of malignant glands, yet were still sent in for consultation (P = .0018). Gleason score was positively correlated with prominent nucleoli and amphophilic cytoplasm and inversely correlated with the presence of crystalloids. Prominent nucleoli, which often are quoted as being essential for the diagnosis of prostate cancer, were not seen in 24% of the specimens and seen only rarely in another 25%. The diagnosis of prostate cancer is based on a constellation of features. Even in this series with a limited number of malignant glands, 85% of specimens contained three or more of the above-listed diagnostic features in addition to architectural atypia. PMID- 7860054 TI - Human acute tubular necrosis: a lectin and immunohistochemical study. AB - To determine the nephron segment distribution of tubular epithelial damage and regeneration and the proliferative activity of various nephron segments in human acute tubular necrosis (ATN) with an antibody to proliferating cell nuclear antigen (PCNA) and to compare the findings in native kidneys with ATN with those in transplant kidneys with ATN, archival tissues from 12 native and 21 transplant kidney biopsy specimens and nine transplant nephrectomy specimens were collected that all showed obvious morphological signs of ATN. Nineteen patients with transplant kidneys with ATN were immunosuppressed with cyclosporine and 11 were immunosuppressed with prednisone and azathioprine. There was a predominance of "regenerating" tubules (tubules with thin epithelium) in the distal nephron in native kidneys with ATN; in the transplant kidneys this was less conspicuous. The number of Tamm-Horsfall protein (THP)-positive tubules was decreased in all kidneys with ATN compared with normal human kidneys. In contrast, the number of THP-positive casts was much higher in all kidneys with ATN than in the normal kidneys. In transplant kidneys with ATN the number of THP-positive casts was substantially lower than in native kidneys with ATN. The macula densa appears to maintain its morphological integrity in kidneys with ATN. Both regenerating and normal appearing tubules expressed vimentin and HLA-DR. The proliferation index (PI; ie, percentage of PCNA-positive nuclei) of the renal tubular epithelium in normal control kidneys varied between 0.22 and 0.33, depending on the tubule segment. The highest PI was noted in the transplant kidneys with ATN not treated with cyclosporine (8.0), followed by the native kidneys with ATN (4.4) and the transplant kidneys with ATN treated with cyclosporine (4.3). We did not find any significant difference in the PI between the regenerating (5.0) and normal appearing (5.6) tubules. Proximal tubules (8.7) showed significantly higher PI values than distal tubules (3.5) in transplant kidneys with ATN. Our results show substantial differences between native kidneys and transplant kidneys with ATN. Tubular epithelial cell proliferation in human ATN is prominent and appears to correlate with the severity of ATN. Light microscopically normal appearing tubules and regenerating tubules participate equally in the regeneration of injured tubules. Cyclosporine may have an inhibitory effect on cell regeneration (proliferation) in human transplant kidneys with ATN. PMID- 7860055 TI - Congenital vascular malformation of the uterus in a stillborn: a case report. AB - A case of a rare condition of uterine vascular malformation is reported in a stillborn fetus. No other vascular lesion was identified in the fetus during autopsy. The finding of a uterine vascular malformation in a stillborn fetus confirms the congenital nature of some uterine vascular lesions. Congenital uterine vascular malformations warrant clinical and pathomorphological differentiation from acquired arteriovenous fistulas of the uterus. PMID- 7860056 TI - Eosinophilic temporal and systemic arteritis. AB - We describe a 39-year-old patient with an unusual type of bilateral temporal arteritis characterized histologically by inflammation, diffuse eosinophilic infiltration, destruction of elastic tissue, and fibrosis. In addition, the patient had a history of systemic vasculitis, peripheral eosinophilia, eosinophilic lymphadenitis, and membranous glomerulonephritis. The patient has been followed up for 14 years and is well controlled on moderate doses of steroids. We propose that this patient suffers from an immune reaction to an unknown, possibly infectious, antigen. PMID- 7860057 TI - On the origin of lymphoid neoplasms in rheumatoid arthritis. PMID- 7860058 TI - Actin-binding protein expression in melanocytic proliferations. PMID- 7860059 TI - The genetic contribution to the phenotype. AB - The phenotype is the result of ontogenetic development. This holds true also at the molecular level, because molecular biological processes take place within the organism. In ontogenesis, genetic and nongenetic factors interact in producing successive states, each of which is the prerequisite, and determines the conditions, for the next one to follow. In this interplay, genes are a necessary, but not sufficient, component. The structures already present, gradients, threshold values, positional relationships, and conditions of the internal milieu, are equally essential. Thus, even monofactorial traits can be considered to be of multifactorial causation, and the varying borderline conditions that arise during development add to the complexity. From this standpoint, it is not to be expected that a mutation has a consistent phenotypic outcome, and the genotype-phenotype relationship may be irregular. In the present review, genotypic heterogeneity versus phenotypic heterogeneity is discussed with the help of some selected examples of hereditary diseases. Conditions and mechanisms contributing to this heterogeneity are addressed. It is concluded that the genotype-phenotype relationship is neither unidimensional, programmatical nor hierarchical in a strict sense. Nevertheless, in particular cases, ontogenetic modification appears to be of minor significance, so that the phenotype of a mutation can be predicted with considerable accuracy. This is no surprise if, depending on the nature of the mutation and the physiological function of the gene affected, the genotype-phenotype relationship is direct. However, this relationship may also be consistent in more complex conditions. It is assumed that the total of the non-genetic influences (epigenetic, environmental) are usually so similar or are compensated by the organism to such an extent that the respective mutation acts as the major variable during ontogenetic development. PMID- 7860060 TI - Trisomy 7 in non-neoplastic tubular epithelial cells of the kidney. AB - The cellular origin of trisomy 7 in non-neoplastic kidney tissue specimens from 10 patients, seven with malignant tumors and three with non-neoplastic kidney diseases, was studied by the MAC (morphology antibody chromosomes) technique, which allows analysis of cellular morphology/histology, immunophenotype, and chromosomal aneuploidy by conventional cytogenetics, and/or fluorescent in situ hybridization in both interphase and mitotic cells. In primary cultures, trisomy 7 was detected primarily in cytokeratin-positive cells. Among freshly isolated renal cells, the trisomy was mainly observed in proximal tubular cells positive to brush-border antigen, and, to a lesser extent, in distal tubular cells positive to Tamm-Horsfall glycoprotein. The frequency of trisomy 7 in lymphocytes expressing CD3 or CD22 antigens isolated from non-neoplastic and tumor tissues was substantially lower than in the epithelial cells and was not increased compared with that in control lymphocytes from peripheral blood. The results thus demonstrate that the non-neoplastic kidney cells with trisomy 7 are mainly normal epithelial cells, preferentially those of the proximal tubule. PMID- 7860061 TI - Genetic homogeneity of cartilage-hair hypoplasia. AB - Cartilage-hair hypoplasia (CHH) is an autosomal recessive metaphyseal chondrodysplasia characterized by short stature and hypoplasia of the hair. Associated pleiotropic features include deficient erythrogenesis, impaired T-cell mediated immunity, Hirschsprung's disease, and an increased risk of malignancies. CHH is most prevalent among the Old Order Amish in the United States and among the Finns, but sporadic families have been described among many other populations. We have previously mapped the gene for CHH to the short arm of chromosome 9 in Finnish and Amish families. The CHH locus resides close to D9S163 within an interval of 1.5 cM flanked by D9S165 and D9S50. In order to investigate the genetic homogeneity of CHH in various populations, we studied nine families with no genealogical connections to either Amish or Finns. No recombinants were detected between the CHH gene and any of the three closest marker loci studied, suggesting that CHH in these families results from mutation(s) at the same locus as in the Amish and Finnish families. PMID- 7860062 TI - The PKU mutation S349P causes complete loss of catalytic activity in the recombinant phenylalanine hydroxylase enzyme. AB - The mutation S349P in exon 10 of the phenylalanine hydroxylase (PAH) gene was identified in one Norwegian and one Polish phenylketonuria (PKU) allele on a haplotype 1.7 background. This missense mutation in PAH codon 349 is a T to C transition in cDNA position 1267. This mutation has been reported both on haplotype 1 and 4, suggesting recurrent mutation. In two different expression systems, the pET and the pMAL systems of Escherichia coli, it was shown that the S349P mutation, introduced by site directed mutagenesis, results in complete loss of enzymatic activity. Thus, protein instability alone does not seem to be the direct cause of the lack of activity of this PKU mutation as previously reported. PMID- 7860064 TI - Demonstration of the spf-ash mutation in Spanish patients with ornithine transcarbamylase deficiency of moderate severity. AB - We have found in patients with ornithine transcarbamylase (OTC) deficiency from two Spanish families (A and B), replacement by A of G at the 3'-end of exon 4 of the OTC gene. The same mutation is found in the spf-ash mouse, a rodent model of mild OTC deficiency, causing a neutral R129H mutation and inefficient splicing at the 5' donor site of the exon 4-intron 4 junction, with resultant 4%-7% residual OTC activity. The mutation, detected in our patients using polymerase chain reaction (PCR) amplification of the ten OTC exons, single strand conformation polymorphism (SSCP) analysis and direct sequencing of PCR-amplified exon 4, results in the loss of a unique MspI restriction site which can be used for rapid diagnosis. The mutation was transmitted by the mother in family A and arose de novo in the patient in family B. Residual OTC activity, determined in a male and a female patient, was 1.3% and 3.5% of normal, respectively. Despite this low activity, the surviving patients have developed normally. PMID- 7860063 TI - Two mutant alleles of the insulin receptor gene in a family with a genetic form of insulin resistance: a 10 base pair deletion in exon 1 and a mutation substituting serine for asparagine-462. AB - Mutations in the insulin receptor gene cause several genetic syndromes associated with extreme insulin resistance. We have studied three insulin resistant siblings with acanthosis nigricans, dental abnormalities, and acral hypertrophy. The female patient also had primary amenorrhea due to hyperandrogenism. All three patients were compound heterozygotes with two mutant alleles of the insulin receptor gene. One allele had a 10-bp deletion in the region of exon 1 encoding the hydrophobic signal peptide; this leads to a frameshift and premature chain termination at codon 61. The deletion occurs at the site of a direct repeat of a hexanucleotide sequence interrupted by a tetranucleotide sequence; the deletion may have resulted from recombination between the upstream and downstream hexanucleotide repeats. In the other mutant allele, there is a missense mutation substituting serine for Asn462-a mutation identified previously in one allele of the insulin receptor gene in a patient with type-A insulin resistance. The Ser462 mutation impaired the ability of acidic pH to dissociate insulin from the receptor. Thus, Thus, like the previously described Glu460 mutation, the Ser462 mutation may retard dissociation of insulin from the receptor in the acidic compartment of the endosome and may, as a result, accelerate the rate of receptor degradation. PMID- 7860065 TI - Germline mutations of the RET proto-oncogene in eight Japanese patients with multiple endocrine neoplasia type 2A (MEN2A). AB - Multiple endocrine neoplasia type 2A (MEN2A) is a dominantly inherited cancer syndrome characterized by medullary thyroid carcinoma, pheochromocytoma, and parathyroid hyperplasia. The gene responsible for MEN2A was localized by linkage analysis to chromosome 10q11.2 in 1987, and recently mutations in RET, a proto oncogene in the candidate region, were discovered in patients with MEN. The majority of mutations found so far in MEN2A patients have been located in nucleotide sequences encoding cysteine residues in the extracellular domain of RET. To characterize MEN2A germline alterations in the Japanese population, we screened DNA from eight unrelated patients for mutations in exons 10 and 11 of the RET proto-oncogene and found mutations in all eight patients, at codons 618, 620, or 634; each of these sites encodes a cysteine residue in the extracellular domain of RET. The mutations were confirmed in other affected individuals in the respective families by digestion of polymerase chain reaction (PCR) products containing the mutated codons with restriction enzymes (Rs alpha I, CfoI, or AluI) for which cleavage sites had been generated by the specific genetic alteration. These PCR-restriction enzyme systems will be useful for genetic diagnosis in members of families carrying these mutations. PMID- 7860066 TI - Ornithine transcarbamylase deficiency: new sites with increased probability of mutation. AB - Ornithine transcarbamylase (OTC) deficiency, the most common inborn error of the urea cycle, shows an X-linked inheritance with frequent new mutations. Investigations of patients with OTC deficiency have indicated an overproportionate share of mutations at CpG dinucleotides. These statistics may, however, be biased because of the easy detection of CpG mutations by screening for TaqI and MspI restriction sites. In the present study, we investigated 30 patients, with diagnosed OTC deficiency, for new sites with an increased probability of mutation by complete DNA sequence analysis of all ten exons of the OTC gene. In six patients, two codons in exons 2 and 5, respectively, contained novel recurrent mutations, all of them affecting CpG dinucleotides. They included C to T and G to A transitions in codon 40, changing an arginine to cysteine and histidine, respectively, and a C to T transition in codon 178 causing the substitution of threonine by methionine. The first two mutations were characterized by a mild clinical course with high risk of sudden death in late childhood or early adulthood, whereas the third mutation showed a more severe phenotypic expression. In addition to these novel mutations, we identified four patients with the known R277W mutation, making it the most common point mutation of the OTC gene. PMID- 7860067 TI - Localization of the gene for a novel human adenylyl cyclase (ADCY7) to chromosome 16. AB - A novel form of human adenylyl cyclase (ADCY7) has been discovered in the human erythroleukemia cell line (HEL). This cell line has been widely used as a model for studies of the characteristics of human platelets. Data from HEL cells suggests that ADCY7 may be the major AC form in human platelets. In the current study polymerase chain reaction (PCR) techniques coupled with use of human/rodent somatic hybrid panels and a yeast artificial chromosome (YAC) library were used to determine the chromosomal localization of the gene (adcy7) for ADCY7 enzyme. A 251-bp product from the 3' untranslated region of human adcy7 was amplified for PCR mapping and the results localize the adcy7 gene to region 16q12-16q13 of the human genome. The AC enzyme family is characterized by the presence of 12 membrane-spanning domains in its sequences, and this chromosomal region is known to contain other genes coding for proteins characterized by 12 membrane-spanning domains. PMID- 7860068 TI - A missense mutation P136L in the arylsulfatase A gene causes instability and loss of activity of the mutant enzyme. AB - Metachromatic leukodystrophy is a lysosomal storage disease caused by deficiency of arylsulfatase A. Sequencing of the arylsulfatase A genes of an Ashkenazi Jewish patient suffering from the severe late infantile form of the disease revealed a point mutation in exon 2 causing proline 136 to be substituted by leucine. The patient was homozygous for this mutation. Studies on Ltk- cells stably expressing the mutant enzyme show that the mutation causes complete loss of enzyme activity and rapid degradation in an early biosynthetic compartment. PMID- 7860069 TI - Factor XKetchikan: a variant molecule in which Gly replaces a Gla residue at position 14 in the light chain. AB - To seek the possible molecular defect in a patient with deficient factor X plasma procoagulant activity, factor X gene exosn and splice junctions were subjected to heteroduplex analyses and sequencing. A mutation in exon 2 was confirmed as substitution of A by G at nucleotide position 206, coding for Gly instead of a Glu which is a normal precursor for gamma-carboxylated glutamic acid (Gla) at amino acid position 14. An abolished TaqI restriction site was used to indicate homozygosity of the defect, but occurrence of a gene deletion with attendant heterozygosity could not be excluded. The deletion of a Gla residue could affect the Ca(2+)-binding properties of factor X or confer a flexibility interfering with the interactive properties of the light chain. The defect could explain the decreased functional activity of circulating factor X and the mild bleeding tendency of the propositus. PMID- 7860071 TI - A recombination event excludes the ROM1 locus from the Best's vitelliform macular dystrophy region. AB - Best's vitelliform macular degeneration has been genetically linked to chromosome 11. Subsequently, the disease locus has been refined to an interval between D11S903 and PYGM and, more recently, between D11S986 and D11S480. The gene encoding ROM1, a photoreceptor-specific membrane protein, has been independently mapped within the Best's disease region and has thus become a strong candidate for the Best's disease gene. In this study, we have mapped ROM1 relative to Best's disease and the loci D11S986, UGB (uteroglobin), and PYGM (human muscle glycogen phosphorylase) in recombinant Best's disease chromosomes. We demonstrate that UGB is localized proximal to ROM1 and that both UGB and ROM1 recombine with the disease phenotype. Thus, this analysis excluded ROM1 as the Best's disease gene. PMID- 7860070 TI - A Gly238Ser substitution in the alpha 2 chain of type I collagen results in osteogenesis imperfecta type III. AB - In general, osteogenesis imperfecta (brittle bone disease) is caused by heterozygous mutations in the genes encoding the alpha 1 or alpha 2 chains of type I collagen (COL1A1 and COL1A2, respectively). In this study we screened these genes in a proband presenting with the severe form (type III) of osteogenesis imperfecta for mutations which might result in the phenotype. Single strand conformation polymorphism mapping analysis was used to identify a region suspected of harbouring the mutation and subsequent sequence analysis revealed a heterozygous G to A transition in the alpha 2(I) gene of type I collagen in the individual. The resulting substitution of the glycine at position 238 of the alpha chain by serine is the most N-terminal yet reported for this chain. PMID- 7860072 TI - Regional localization of the human EGF-like growth factor CRIPTO gene (TDGF-1) to chromosome 3p21. AB - The CRIPTO gene encodes a novel human growth factor structurally related to epidermal growth factor. We localized the CRIPTO gene to chromosome 3p21 by fluorescence in situ hybridization with a cosmid clone containing 40 kb of the CRIPTO genomic region (TDGF-1). To suppress hybridization to CRIPTO-related sequences, present in multiple copies in the human genome, hybridization was carried out in the presence of unlabeled CRIPTO cDNA in excess over the probe. Our finding confirms the provisional mapping of the CRIPTO gene to chromosome 3, and assigns it precisely to a chromosomal region involved in several rearrangements occurring in malignancy. PMID- 7860073 TI - Confidence intervals for predicted age of onset, given the size of (CAG)n repeat, in Huntington's disease. PMID- 7860074 TI - Assignment of a human autoimmune antigen, p80-coilin gene to chromosome 17q21-q23 and of its possible pseudogene to chromosome 14. AB - In order to determine the chromosomal locations of an autoimmune antigen, the coilin gene and its pseudogene, we amplified the segments of the two genes by the polymerase chain reaction (PCR) and screened a panel of somatic cell hybrids for the presence of the gene products. The results indicate that the human coilin gene and its pseudogene can be assigned to chromosome 17 and chromosome 14, respectively. Further analysis of cell hybrids bearing chromosome 17 with various deletions localized the coilin gene to the region q21-q23. PMID- 7860075 TI - De novo missense mutation Y174S in exon 1 of the adrenoleukodystrophy (ALD) gene. AB - Adrenoleukodystrophy (ALD) is an X-linked disease, characterised by an alteration of the peroxisomal beta-oxidation of the very long chain fatty acids. The ALD gene has been identified and mutations have been detected in ALD patients. We report here a new missense mutation in the ALD gene of a male patient, predicting a tyrosine to serine substitution at codon 174 (mutation Y174S). The mother of the ALD patient does not have the Y174S mutation in her leukocyte DNA, indicating that Y174S arose de novo in the patient. Y174S is the first reported de novo mutation in the ALD gene. PMID- 7860076 TI - Premature termination codon at the sterol 27-hydroxylase gene causes cerebrotendinous xanthomatosis in a French family. AB - Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive lipid-storage disease caused by mutations in the sterol 27-hydroxylase gene (CYP27). So far several mutations causing CTX have been identified and characterized. A new mutation creating an insertion of cytosine at position 6 in the cDNA, which is expected to result in a frameshift and a premature termination codon at codon 179, has been identified in a French family. The mutation creates a new site for the restriction endonuclease HaeIII. PMID- 7860077 TI - A novel RsaI polymorphism within intron 39 of the neurofibromatosis type 1 (NF1) gene. PMID- 7860078 TI - Polymerase chain reaction detection of two novel human N-acetylgalactosamine-6 sulfate sulfatase gene polymorphisms by single-strand conformation polymorphism analysis or by StyI and StuI cleavages. AB - We describe two common single-base polymorphisms of the N-acetylgalactosamine-6 sulfate sulfatase gene after StyI or StuI restriction sites. These polymorphisms were readily detected by single-strand conformation polymorphism (SSCP), using the polymerase chain reaction (PCR). PMID- 7860079 TI - Detection of a HindIII restriction fragment length polymorphism in the human phenol sulfotransferase (STP) locus. AB - The gene encoding human phenol-preferring phenol sulfotransferase (STP) has been cloned and mapped to chromosome 16p. A HindIII RFLP in this gene is described. PMID- 7860080 TI - Detection of a Tsp509I polymorphism in the 3' UTR of the human tyrosinase related protein-1 (TYRP) gene. AB - We have identified a Tsp509I polymorphism in the 3' UTR of the human tyrosinase related protein-1 gene (TYRP). TYRP is one of several genes involved in melanin pigment production. PMID- 7860081 TI - A common Ser/Thr polymorphism in the perforin-homologous region of human complement component C7. AB - Complement component C7 plays an important role in the formation of the membrane attack complex of the complement system. Here we describe a novel polymorphism of human C7, namely a nucleotide sequence polymorphism changing codon 367 from AGT (encoding Ser) to ACT (encoding Thr). Using the polymerase chain reaction, the polymorphism is easily detectable either as a MaeIII restriction fragment length polymorphism or by single-strand conformation analysis. The two alleles are both very common, probably in all major races. PMID- 7860082 TI - Genetic analysis combining path analysis with regressive models: the TAU model of multifactorial transmission. AB - We have extended regressive models by incorporating a simple path model (the TAU model). This was achieved for both class A and class D regressive models by expressing the residual correlations in the regressive models in terms of parameters of the path model. We have presented explicit solutions for path coefficients in terms of the residual correlations. These methods were applied to a French-Canadian family study on body mass index. It was found that the estimate of pseudopolygenic heritability was robust under class A (t2 = 0.28) and class D (t2 = 0.26) models. PMID- 7860083 TI - RsaI and BclI polymorphism of the transferrin receptor gene. AB - Polymorphism of the transferrin receptor gene has previously not been observed. Here we report two new restriction fragment length polymorphisms (RFLPs) of the transferrin receptor gene. Digestion with RsaI revealed three variable fragments at 1.15, 1.05 and 0.85 kb. After cleavage with BclI, two polymorphic 2.8- and 2.3 kb fragments were found. There was strong linkage disequilibrium between the two RFLPs, and Saamis showed a highly significant difference from Finns and Swedes with respect to allele frequencies. The new polymorphisms of the transferrin receptor gene may be useful markers in population and linkage studies and in studies of associations with body iron stores and susceptibility to genotoxic damage and cancer. PMID- 7860084 TI - Genetic differentiation of Jordanian Moslems and Christians. AB - Two samples representing the Moslem and Christian communities of Jordan were examined for the polymorphic serum proteins AHSG, BF, FXIIIB, GC, HP, PI, PLG, and TF. The results revealed similar allele distributions, and low interpopulation differentiation (GST = 0.0004) between the two communities. The low HP*1S (< 0.12) allele frequencies and the comparatively high PLG*B (> 0.40) and BF*S.07 (approximately equal to 0.05) frequencies are characteristic of the populations of this region. PMID- 7860085 TI - Sickle cell disease in a Brazilian population from Sao Paulo: a study of the beta s haplotypes. AB - In this study we have determined the frequency of beta S haplotypes in a Brazilian sickle cell disease population from Sao Paulo, Brazil, by analyzing sequence variations in the immediate 5' flanking and second intervening sequence (IVSII) regions of the gamma globin genes. This association between sequence differences and beta s haplotype backgrounds was determined by screening genomic DNA samples using dot blot analysis of polymerase chain reaction products. We studied 148 beta s chromosomes, and found that haplotype 20 (CAR or Bantu) significantly predominated in this population. This is in agreement with the findings of the historical Portuguese Atlantic slave trade from Africa to South America. PMID- 7860086 TI - An association study between schizophrenia and the dopamine receptor genes DRD3 and DRD4 using haplotype relative risk. AB - Our work investigates the relationship between genetic factors and schizophrenia, seeking to identify a gene or genes associated with the clinical form of the disease in a group of Italian patients. In pursuit of the 'dopaminergic hypothesis' of schizophrenia, we explored a possible etiologic role of two dopamine receptor genes, DRD3 and DRD4, that have been repeatedly suggested as factors in the pathophysiology of the disease. We typed DNA polymorphisms in each of the genes that code for variation in the amino acid sequence of the receptor protein. An innovative design using parental chromosomes as controls--the 'haplotype relative risk' strategy--represents a significant improvement over previous association studies in psychiatric genetics. Our results suggest that, at least in our well-defined population, the candidate genes DRD3 and DRD4 do not appear to play a major role in the genetic etiology of schizophrenia. PMID- 7860088 TI - Genetic diversity in the Lithuanian rural population as illustrated by variation in the ABO and Rh(D) blood groups. AB - Regional and temporal variations in the ABO and Rh blood group gene frequencies were studied in the rural population of Lithuania. The total material, comprising blood group data for about 37,000 individuals, was subdivided according to place of residence into 401 parishes, 44 administrative districts and 6 ethnolinguistic regions. A significant regional heterogeneity was found. Gene diversity figures were higher than those observed in some other countries when studied at similar hierarchical levels. The gene frequency variation at the district level was compared to expected effects of genetic drift and migration and it was estimated that a migration rate of 5-10% would counter genetic drift in the rural population of Lithuania. PMID- 7860089 TI - Adverse outcomes of pregnancy and blood groups: a relationship with no importance? AB - Seeking a relationship between blood groups and successful pregnancy, Linn's group carried out an analysis using the medical records of 11,659 women. They found a significantly higher frequency of bleeding during pregnancy among Rh(+) women, when compared with Rh(-) women. However, they concluded that this relationship is not important because it is due to confounding variables and not to the mother's phenotype. It should be noticed that although we cannot say that there is a causal relationship, there is definitely a relationship between Rh phenotype and bleeding during pregnancy in the study published by Linn and co workers. This relationship is important from an evolutionary standpoint and it suggests that the natural selection could be working more intensely against Rh(+) than against Rh(-) mothers. PMID- 7860087 TI - Estimating the frequency of nonpaternity in Switzerland. AB - In linkage analysis and gene mapping in general, typing error and/or errors in specifying pedigree relationships between individuals typically lead to an upwards bias in recombination fraction estimates and to a loss of power for detecting linkage. [Ott J: Analysis of Human Genetic Linkage. Baltimore, Johns Hopkins University Press, 1991]. The presence of nonpaternity is the most common source of error of misspecification of pedigree relationships between individuals that can have a negative impact on pedigree analysis. We have developed estimates of underlying nonpaternity probabilities based on observed Mendelian inconsistencies. The methods were applied to a sample of 1,607 children and their parents. Genetic marker data were investigated to test for exclusions due to nonpaternity. Among the 1,607 children, 11 or 0.68% exclusions were found. When a constant nonpaternity rate was assumed for each child, its maximum likelihood estimate turned out to be 0.78% with asymptotic 95% confidence limits of 0.41% and 1.35%. When varying nonpaternity rates were assumed, its mean was estimated as 0.83% with asymptotic 95% confidence limits of 0.32% and 1.33%. PMID- 7860090 TI - Inhibition of interleukin 2 production and alteration of interleukin 2 mRNA processing by human T-T cell hybridoma-derived suppressor factors. AB - We investigated the mechanisms by which two human T-T cell hybridoma-derived suppressor factors (SFs) (designated 160 and 169) (Platsoucas et al., Hybridoma 1987;6:589; Kunicka et al., Hybridoma 1989;8:127) inhibit the proliferative response to mitogens by human peripheral blood mononuclear cells (PBMCs). Interleukin 2 (IL-2) production by human PBMCs cultured with concanavalin A or OKT3 monoclonal antibody for 12 or 36 hr in the presence of 160 or 169 SF was found to be inhibited > 80% when compared to control PBMC cultures stimulated with mitogen in the absence of SFs. This suppression of IL-2 production was not due to the SFs interfering with IL-2-induced proliferation of the IL-2-dependent murine cell clone used to determine the levels of IL-2. The proliferative responses of SF-treated PBMCs could not be restored by addition of exogenous recombinant human IL-2 (rIL-2) (1-100 U/ml). Furthermore, inhibition of the proliferative responses by the SFs could not be reversed by addition of exogenous rIL-1, rIL-2, or rIL-4 alone or in paired combinations. The expression of IL-2 receptors (TAC Ag) on concanavalin A-activated cultures at 12- or 36-hr time points was not affected by treatment with the SFs. Both the 160 and 169 hybridoma derived SFs were found to cause the accumulation of an mRNA of 2.8 kb that hybridized with an IL-2-specific oligonucleotide probe. This 2.8-kb transcript was in addition to the expected 1.0-kb, transiently expressed IL-2 message, and it could be superinduced in the presence of cycloheximide. These results suggest that these SFs may be influencing RNA splicing pathways. These SFs appear to be useful molecules for probing the regulatory controls of lymphocyte proliferation and may constitute important physiological regulators of the immune response. In addition, they may have clinical activity for the treatment of patients that received transplants, patients with autoimmune diseases, and others. PMID- 7860091 TI - A novel marker of murine bone marrow hematopoietic stem cells that is expressed on peripheral T cells and is associated with a functionally important molecule on activated cytotoxic T lymphocytes. AB - A MAb (R2/60) has been isolated that defines a novel lymphocyte marker of murine T cells. The determinant recognized by MAb R2/60 is present on a subset of bone marrow (BM) hematopoietic stem cells, on adult thymocytes, on peripheral T cells (both resting and activated), and on murine T cell tumor lines, although it is not expressed on mature B cells. In immunoprecipitation studies using radiolabeled membrane lysates from adult thymocytes, MAb R2/60 precipitated a 44 kDa membrane-bound dimer. Functionally, MAb R2/60 mediated antigen-independent cell lysis by activated CTLs, and by CTL clones, when bridged to Fc receptor bearing target cells; however, binding of MAb R2/60 to effector cells prior to cytotoxic assays did not inhibit target cell lysis by CTLs, suggesting that the R2/60 determinant is involved in transmembrane signaling to already activated CTLs, but that it is not involved in target cell adhesion or antigen recognition. Moreover, direct stimulation of T cells by MAb R2/60 in the absence of additional stimuli did not induce cell proliferation, further implying that the R2/60 determinant is functionally involved in the effector rather than the inductive phase of the T cell response. PMID- 7860092 TI - Construction and expression of chimeric antibodies by a simple replacement of heavy and light chain V genes into a single cassette vector. AB - A novel vector pMH-gpt, which is proved useful for cloning mouse immunoglobulin heavy and light chain V genes and for expressing mouse-human chimeric antibody, was constructed. The vector contains human genomic C gamma 1 and C kappa genes, cloning sites for immunoglobulin V region genes, murine Ig promoters, a human Ig heavy chain enhancer, and the selection marker gene Eco-gpt. Because VH and V kappa genes can be cloned into a single vector, a chimeric antibody gene is easily constructed by this simple insertion procedure. The usefulness of the vector was confirmed by construction of two mouse-human chimeric antibodies. Mouse monoclonal antibody (MAb) 196-14 recognizes the ovarian cancer-associated antigen (CA125), and MoAb 2-18 reacts with carcinoembryonic antigen (CEA). Mouse human chimeric 196-14 and 2-18 antibodies were readily constructed and efficiently produced in a mouse myeloma cell line by utilizing the vector. Both chimeric antibodies retained binding activity to their respective antigens. In biodistribution and immunoscintigraphy studies, specificity of radiolabeled chimeric 196-14 antibody was identical to that of its murine counterpart and significant accumulation at the tumor site was observed. The pMH-gpt vector is useful for constructing and producing mouse-human chimeric antibodies. PMID- 7860093 TI - Detection of a 45-kilodalton antigen overexpressed in a cisplatin-resistant human ovarian carcinoma cell line. AB - To characterize the membrane changes associated with cisplatin resistance, we raised monoclonal antibodies (MAbs) against a cisplatin-resistant subline (OV1/DDP) derived from a human ovarian carcinoma cell line (OV1/p). An MAb, designated OCP02, was selected for its particularly high affinity for the resistant cell line. It bound 3.1-fold higher to OV1/DDP cells than to OV1/p cells and recognized an M(r) 45K antigen. This antigen appeared to be present in several normal and tumorous tissues. Its distribution in normal tissues was mainly detected in tissues involved in secretory processes, suggesting that this antigen could be related to a transport mechanism in normal cells as well as in drug-resistant cells. PMID- 7860094 TI - Monoclonal antibody specifically reacting against 73-kilodalton heat shock cognate protein: possible expression on mammalian cell surface. AB - The heat shock proteins (hsp) are regarded as being immunogenic to the animal hosts. Although certain hsp are suggested to be expressed on the cell surface, further evidence for the cell surface expression of these proteins has been required. In this article we report the development of a MAb NT22. This antibody reacted with ATP-binding proteins (which contain a large amount of 70-kDa hsp family) of HeLa cells, and with purified bovine 70-kDa hsp. It did not react with the E. coli lysate, but clearly reacted with the recombinant rat hsc73. However, NT22 failed to react with hsp72. Furthermore, stress treatment of cells also indicated that considerable amounts of NT22-defined antigen translocated into the nucleus from the cell cytoplasm. These results suggest that NT22 is a novel MAb that reacts specifically to the mammalian hsc73. Moreover, this antibody could detect the constitutive and stress-induced cell surface expression of its relevant antigen. It is expressed preferentially on EBV-transformed B cell and certain epithelial cancer cell lines. However, resting B cells did not express this antigen on the cell surface. These data indicate that hsc73 could be expressed on the cell surface of certain cells, and suggest that hsc73 may interact with the host immune system. PMID- 7860095 TI - Monoclonal antibodies against a synthetic peptide from human immunodeficiency virus type 1 Nef protein. AB - Monoclonal antibodies against a synthetic peptide (aa 138-152) from HIV-1 Nef protein were produced and characterized. Three hybridoma lines producing monoclonal antibodies (MAbs) against the synthetic peptide were generated by fusion between P3-X63 Ag8.653 myeloma cells and BALB/c splenocytes from mice immunized with the synthetic peptide coupled to keyhole limpet hemocyanin (KLH). The hybridomas were screened and selected by ELISA with the peptide coupled to bovine serum albumin (BSA) immobilized to the polystyrene surface and specificity for the peptide was confirmed by competitive ELISA with the peptide free in solution. The reactions of the MAbs with a 5-aa motif (WCYKL) included in the sequence were examined with synthetic peptides and two of the MAbs reacted with the motif. The recognitions of recombinant full-length Nef protein were also tested. One MAb reacted with the protein in both ELISA and dot blot, and one only in dot blot, whereas the last MAb did not recognize the recombinant full-length Nef protein. PMID- 7860097 TI - Identification and characterization of a monoclonal antibody that neutralizes ricin toxicity in vitro and in vivo. AB - We wanted to identify and characterize MAbs with specificity for the toxic lectin ricin, which could serve as detection reagents in elucidating mechanisms and tissue distribution. Neutralizing MAbs could be developed into immunotherapeutics to reverse clinical intoxications from immunotoxin or to counteract the use of ricin as a terrorist or biological warfare weapon. Two hybridomas, UNIVAX 70 and 138, producing MAbs against ricin were identified by Western blot strip analysis. The antibodies were IgG1 and were specific for the ricin A chain with no ricin B chain cross-reactivity. The MAbs neutralized ricin in vitro in an EL-4 mouse leukemia cell assay and in an in vivo mouse model. The two antibodies recognized the same epitope or overlapping epitopes, based on a competition with one another. All further characterization proceeded on the assumption that they were the same. The MAb UNIVAX 70/138 was characterized in vivo by titrating it against an 18 micrograms/kg (> six LD50) i.v. challenge and by titrating the i.v. toxin challenge against a constant dose of 100 micrograms of passive antibody per mouse. A 4:1 molar ratio of MAb to ricin led to neutralization of > or = 90% of the toxin in vitro. The MAb recognized ricin toxoid prepared by formaldehyde treatment and after conjugation of low molecular weight haptens (based on ELISA) equally as well as it recognized ricin and ricin A chain. The affinity and specificity of UNIVAX 70/138 give it excellent reagent potential, and the toxin neutralizing capacity makes it at least a log and a half better than the next best candidate immunotherapeutic. PMID- 7860096 TI - Development of human monoclonal antibodies to rabies. AB - A total of nine human monoclonal antibodies (MAbs) to rabies virus were generated from peripheral B lymphocytes of subjects immunized with human diploid cell rabies vaccine by somatic cell hybridization. The MAbs were analyzed for their antigen-binding specificities using ELISA, Western blot, and immunoprecipitation assays. The different assays made it possible to identify MAbs directed to the surface glycoprotein, nucleoprotein, nominal phosphoprotein, and matrix protein. One of the MAbs that recognized the surface glycoprotein neutralized rabies virus. PMID- 7860098 TI - A kringle-specific monoclonal antibody. AB - Kringle domains are found in several plasma proteins of blood coagulation and fibrinolysis. A murine monoclonal antibody, designated alpha HII-5, was produced against a synthetic peptide representing residues 216-231 of human prothrombin kringle 2. The sequence of the hexadecapeptide (Glu-Asn-Phe-Cys-Arg-Asn-Pro-Asp Gly-Asp-Glu-Glu-Gly-Val-Gly-Cys) is conserved in several kringle-containing proteins, represents a predicted region of high local hydrophilicity in prothrombin kringle 2, and contains the anionic (Asp-223 and Asp-225) residues that contribute to lysine binding by plasminogen kringle 4. In a solution-phase immunoassay, antibody alpha HII-5 bound prothrombin and the kringle 5 light chain fragment of plasminogen (miniplasminogen), but not plasminogen or plasmin. In contrast, using a solid-phase assay with antigen immobilized onto a surface (polystyrene microtiter plates, glass, or nitrocellulose) antibody alpha HII-5 specifically bound prothrombin, plasminogen, recombinant tissue plasminogen activator (tPA), and the apo(a) subunit of lipoprotein(a). By immunoblotting analysis antibody alpha HII-5 bound determinants on prothrombin fragment 2 and plasminogen kringle 5. These observations suggest that a subset of kringle domains on plasma proteins, including prothrombin kringle 2 and plasminogen kringle 5, contains a homologous antigenic determinant in the region of the kringle lysine-binding site. In contrast to prothrombin kringle 2, the homologous peptide site on plasminogen is not available for antibody binding except when plasminogen is adsorbed to a nonphysiological surface, or when kringles 1-4 are removed. PMID- 7860099 TI - Affinity membrane identification of immunoglobulin subclass in hybridoma screening. AB - Monoclonal hybridomas secrete immunoglobulins with a single antigen specificity and distinct class/subclass structure. Hybridoma management has commonly incorporated tests of antigen specificity into early screening procedures, but has not typically utilized assays of immunoglobulin structure. In this article, we describe a technique of class/subclass typing using polyvinylidene difluoride affinity membranes and a colorigenic enzymatic amplification system. The typing of monoclonal antibody structure was sufficiently sensitive to permit its routine use within several weeks of hybridoma fusion. The information obtained from early and routine class/subclass determinations included a semiquantitative assessment of monoclonal antibody concentration. In addition, the detection of a single immunoglobulin class/subclass in a microtiter well supernatant supported the possibility that the colony was monotypic. The application of class/subclass typing and Poisson statistics to hybridoma fusions provided a numerical estimate of the probability of colony monotypia. PMID- 7860101 TI - The NCLEX experience. PMID- 7860100 TI - Effects of interleukin 4 on production of IgE monoclonal antibodies directed against glucose oxidase. AB - Interleukin 4 is a cytokine that promotes the growth of B cells and the synthesis of IgE subclass antibody. Here we report the results of our study that was designed to determine if recombinant murine interleukin 4 (rmIL-4) can increase the yield of hybridomas secreting IgE subclass monoclonal antibodies directed against glucose oxidase. Three BALB/c mice (test group) were primed i.p. with 50 micrograms of glucose oxidase and then boosted i.v. 2 weeks later with 5 micrograms of glucose oxidase plus 200 ng of rmIL-4. A standard hybridoma fusion was performed 3 days later, and the fusion products were then cultured in the presence of 20 ng of rmIL-4 per milliliter. Another group of three mice underwent an identical immunization and fusion procedure, except that the rmIL-4 was omitted (control group). At 21 days after fusion, the test group had a significantly greater frequency of wells with hybridomas (average frequency = 191 per 1000 wells in test group versus 58 in control group; chi 2 = 1803; p = 0.0001) and wells containing IgG anti-glucose oxidase (mean of 23 per 1000 wells in test group versus 3 in control group; chi 2 = 506, p = 0.0001). Moreover, the IL-4-treated group had a significantly higher frequency of wells containing IgE antibodies (mean of 44 versus 11 in control group; chi 2 = 288, p = 0.0001) and IgE antibodies directed against glucose oxidase (mean of 5 per 1000 wells versus 2 in control group; chi 2 = 21, p = 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7860102 TI - Everything you always wanted to know about graduate nursing education. PMID- 7860104 TI - Having confidence in work relationships. PMID- 7860103 TI - Job hunting in the world of nursing. PMID- 7860105 TI - NSNA/Johnson & Johnson consumer products essay contest--3rd place winner "my most memorable patient". PMID- 7860106 TI - RNs: competition tightest for new grads. PMID- 7860107 TI - Taking the NCLEX: information every candidate should know. National Council of State Boards of Nursing. PMID- 7860108 TI - Intra-abdominal abscess--a challenge for abdominal surgeons. PMID- 7860109 TI - Endoscopic cystogastrostomy: preliminary experience. AB - OBJECTIVE: To study the usefulness of endoscopic drainage in the management of pancreatic pseudocyst. METHODS: Five patients with pancreatic pseudocyst were subjected to endoscopic cystogastrostomy. In addition 7 french stent was placed between the cyst and stomach in three patients. RESULTS: The three patients with a cystogastrostomy and stent had complete resolution of the pseudocyst in 2-6 weeks without any complications after a mean follow up of 3.5 months. One patient with rapidly enlarging post-traumatic pancreatic pseudocyst, who was treated with only cystogastrostomy had a significant decrease in cyst size. Another patient with post-traumatic pseudocyst had bleeding during cyst puncture; the procedure was abandoned and surgical drainage was done. CONCLUSIONS: Endoscopic cystogastrostomy is an effective method of treatment for suitably situated pancreatic pseudocysts and obviates the need for radiological help. PMID- 7860110 TI - Assessment of optimal dose of lactose for lactose hydrogen breath test in Indian adults. AB - To evaluate the possibility of using a 12.5 g or 25 g oral dose of lactose for hydrogen breath test for diagnosis of lactose intolerance instead of the usual 50 g dose. 35 patients with non-ulcer dyspepsia and an abnormal 50 g lactose breath hydrogen of more than 20 ppm over the base line were retested using 12.5 g and 25 g lactose. 32 (91.4%) and 15 (42.8%) of these 35 patients had an abnormal hydrogen breath test using 25 g (p = ns compared to 50 g dose) and 12.5 g (p < 0.001) lactose doses respectively. This study reveals that it may be possible to use a 25 g lactose dose instead of a 50 g dose for the lactose hydrogen breath test. PMID- 7860111 TI - Medical treatment of peptic ulcer--a critical analysis. PMID- 7860112 TI - Pneumatic dilatation of achalasia cardia with indigenous pneumatic dilator. AB - Fifteen patients with achalasia cardia underwent pneumatic dilatation using an indigenous pneumatic dilator. The dilator was prepared using a Levin's tube, latex condoms and silk cloth and was introduced under vision with the help of an endoscope. Clinical improvement was seen in all the patients whereas radiological improvement occurred in 11 patients. There were no procedure-related complications. PMID- 7860113 TI - Abdominal cocoon--the cauliflower sign on barium small bowel series. AB - We report a case of abdominal cocoon encasing the small bowel diagnosed pre peratively on radiology. Barium small bowel series showed the ileal loops clumped together as within a sac, giving a cauliflower-like appearance on sequential films. At surgery, the membrane enclosing the loops was thin and flimsy. PMID- 7860114 TI - Hepatic injury in sulfone syndrome: hepatitis or cholestasis? PMID- 7860115 TI - Tuberculous abscess of the liver associated with HIV infection. AB - Tuberculosis is an AIDS-defining illness in HIV-seropositive patients. Though disseminated tuberculosis is common in HIV-seropositive patients, hepatic involvement in the form of abscess formation is rare. We report such a patient. PMID- 7860116 TI - Fibrosing necrotic nodule of the liver. AB - A fibrosing necrotic nodule of the liver is described in a 35 year old man suffering from malaria. This non-tumorous lesion is considered to be an entity of diverse pathogenesis. PMID- 7860117 TI - Isolated esophageal tuberculosis. AB - Isolated esophageal tuberculosis is very rare. We report a patient who presented with history of retrosternal pain and dysphagia and on investigation was found to have a smooth esophageal mass. Endoscopic biopsy showed epitheloid cell granuloma with necrosis suggestive of tuberculosis. CT scan of the thorax showed no involvement of adjacent structures. The patient responded to antitubercular therapy. PMID- 7860118 TI - Omental rhabdomyosarcoma presenting with pyrexia. AB - A 45-year-old man was admitted with pyrexia and intermittently palpable lump in the left lumbar region. Laparotomy revealed a primary omental tumor which on histological examination showed alveolar rhabdomyosarcoma of the omentum. Following surgery the fever subsided. Presentation of omental rhabdomyosarcoma with fever has not been reported earlier. PMID- 7860119 TI - Spontaneous esophageal perforation: atypical presentation. AB - A case of spontaneous esophageal perforation occurring in a healthy esophagus without any predisposing factor is reported. The problem of delayed diagnosis has been discussed. PMID- 7860120 TI - Intraperitoneal abscesses: diagnostic dilemmas and therapeutic options. AB - BACKGROUND: The diagnosis of intraperitoneal abscesses is difficult, resulting in delay in treatment and poor prognosis. Although recent advances in the management have led to significant improvement in prognosis, the choice of therapeutic modality is unclear. AIMS: The role of clinical features and investigations in the diagnosis of intraperitoneal abscesses was studied. The relation of prognosis to delay in diagnosis was also analyzed. Also assessed was the efficacy of various therapeutic modalities. METHODS: Thirty consecutive patients diagnosed to have intraperitoneal abscesses were analyzed. Abscesses were analyzed. Abscesses were divided on the basis of ultrasonography findings into simple and complex (with or without fecal fistula). The following points were evaluated: clinical features, and hematological, biochemical and microbiological reports, imaging findings and the role of therapeutic modalities like percutaneous aspiration (single or multiple), catheter drainage and operative drainage (transperitoneal, extraperitoneal and percutaneous). RESULTS: Clinical features and hematological investigations, though sensitive, were non-specific in diagnosis. Klebsiella was the commonest organism cultured, followed by Proteus, E coli and Pseudomonas. Blood culture was positive in only 6 percent of cases. Real-time ultrasonography had an accuracy of 84%. Contrast X-rays were required in 43% of cases. All the deaths (4 of 30) occurred when the diagnosis and treatment were delayed by more than 4 days. USG-guided aspiration (single and multiple) and USG-guided catheter drainage were effective in simple abscesses but failed in complex abscesses. Transperitoneal operative drainage was successful in 15 of 18 cases (6 of 8 simple abscesses and 9 of 10 complex abscesses). The mortality in patients with simple and complex abscesses was 2 of 17 and 2 of 13 respectively. CONCLUSIONS: Early detection with consequent early treatment is vital for good prognosis of intraperitoneal abscesses. Early diagnosis requires a high degree of clinical suspicion and appropriate use of imaging modalities. USG-guided percutaneous drainage is effective for simple abscesses whereas complex abscesses require operative drainage, sometimes in combination with initial USG-guided drainage. PMID- 7860121 TI - Angiosarcoma of cecum: unusual presentation with intussusception. AB - We report a 55-year-old man with angiosarcoma of the cecum who presented with generalized colicky abdominal pain with a mass in the periumbilical region. The lesion at surgery was a colo-colic intussusception extending to the midtransverse colon. A radical right hemicolectomy was done. Metastases to regional lymph nodes were noted in the specimen. PMID- 7860122 TI - Congenital abnormalities in a case with extrahepatic portal venous obstruction. PMID- 7860123 TI - Leiomyosarcoma of the duodenum. AB - Leiomyosarcoma of the duodenum is a rare tumor. These tumors manifest with unexplained melena, anemia and sometimes partial duodenal obstruction. Diagnosis is difficult on account of inaccessibility for biopsy. Treatment involves excision of the duodenum with reconstruction, a difficult task with high morbidity and mortality. However, if the tumor is successfully treated, its prognosis is usually good because of its non-aggressive nature. PMID- 7860124 TI - Effect of cigarette smoking on gastric bicarbonate secretion. PMID- 7860125 TI - Broken guide wire after Savary-Gillard dilation. PMID- 7860126 TI - Bifid pancreas. PMID- 7860127 TI - Perforated acute duodenal ulcer can be treated conservatively. PMID- 7860128 TI - Use of indigenous and economical substitutes for variceal band ligation accessories. PMID- 7860129 TI - Prognosis in intra-abdominal sepsis. AB - Peritonitis is a common surgical problem with a high mortality rate. Recent advances have not brought down the mortality rate. Eighty six patients with intra abdominal sepsis were studied for factors affecting prognosis. The factors which significantly affected prognosis were: duration of illness, source of infection and APACHE-II score. Further, among the factors contributing to APACHE II score, statistical analysis using logistic regression identified some factors which individually affect outcome. Our results indicate that mortality rate is high in patients with long duration of illness, postoperative peritonitis and organ system insufficiency. PMID- 7860130 TI - Working group report on schistosomes, liver flukes and Helicobacter pylori. PMID- 7860131 TI - UICC Study Group on basic and clinical cancer research: apoptosis in normal and tumor cells. PMID- 7860132 TI - Survival in breast cancer: a population-based study in Bangalore, India. AB - Survival from cancer reflects the aggressiveness of the disease, the effectiveness of treatment and host factors such as age. While hospital-based survival rates are typically used to evaluate the care provided in a particular hospital, population-based survival reflects the effectiveness of the overall cancer control strategy in the region. Here, we report the survival experience of 1514 breast cancer patients registered by the Bangalore population-based registry during 1982-1989. There have been very few reports on survival from cancer in India, mainly because of poor patient follow-up and inadequate system of registration of death. This has been largely overcome in this study by means of active follow-up through visits of homes of patients. Scrutiny of medical records and matching with death certificates, was also carried out in a small proportion (12%) of cases. Thus, information on vital status (whether dead or alive) as on January 1, 1993 was available for 1334 (88%) subjects and partial follow up data were available for a further 34 (2%). The observed 5 year survival was 42.3% and the corresponding relative survival was 46.8%. The observed survival was 57.4% for localized disease, 45.8% for direct extension, 37% for those with regional node involvement, 14.2% for distant metastasis and 38.3% for those with unstaged disease. The clinical extent of disease and the educational status were independent predictors of survival. PMID- 7860134 TI - Diet, alcohol, smoking and cancer of the upper aerodigestive tract: a prospective study among Hawaii Japanese men. AB - A cohort study of upper aerodigestive tract cancer was conducted among 7,995 Japanese-American men who were interviewed and examined from 1965 to 1968. Information was collected about smoking history and alcohol and dietary intake. After 24 years, 92 incident cases with histological confirmation of diagnosis were identified. Current cigarette smokers at time of examination had a 3-fold risk for upper aerodigestive tract cancer compared with never-smokers. A dose response relationship was present with increasing amount and duration of cigarette use. Consumption of beer, wine, spirits and total alcohol was strongly associated with increased risk. Of 23 food and beverage categories, only candy/jelly/soda pop consumption had a statistically significant inverse trend. Frequent consumption of fruit was also inversely associated with this cancer. In contrast, the risk tended to be positively associated with consumption of rice, seaweed, tofu or tsukudani (a mixed dish of fish, sugar, soy sauce and seaweed), but the dose-response relationship was not statistically significant. For nutrient intake, increased calcium and fat intake decreased the risk for this cancer. PMID- 7860133 TI - 67-kDa laminin-receptor expression adds prognostic information to intra-tumoral microvessel density in node-negative breast cancer. AB - Experimental studies have shown that the 67-kDa laminin receptor (LRec) is an important molecule for the interaction of tumour cells with the extracellular matrix, and that it plays a role in the early steps of angiogenesis and in tumour invasion and metastasis. We performed a multi-parametric study in 171 node negative breast cancers, followed for a median time of 6 years, to verify whether determination of the LRec provides prognostic information in addition to intra tumoral microvessel density (IMD), a measure of tumour angiogenesis, and to other biological and conventional indicators. A positive association between LRec expression and high neovascularization was found, although it did not reach significance. LRec was not associated either with other biological markers (oestrogen receptor, progesterone receptor and p53 expression) or to the conventional prognostic features [menopausal status, tumour size, histological types, grading and peri-tumoral lymphatic vessel invasion (PLVI)]. In univariate analysis, IMD, p53, PgR, PLVI, grading and tumour size were significant prognostic indicators of relapse-free survival (RFS). LRec expression approached significance when considered as a dichotomous variable, after having selected the optimum cutoff of 10% to distinguish high-risk from low-risk patients. For overall survival (OS), tumour size and IMD (continuous variable) were significant prognostic factors, and p53 approached significance. In multivariate analysis for RFS, the joint variable LRec and vascularization was the strongest independent prognostic factor, followed by PgR, PLVI and p53. For OS, tumour size was the only independent prognostic indicator in this series. PMID- 7860135 TI - Risk of ocular melanoma in relation to cutaneous and iris naevi. AB - A case-control study was set up to assess the risk of eye melanoma in relation to the number and type of cutaneous melanocytic naevi and pigmented lesions of the iris. Cases comprised 211 unselected ocular melanoma patients attending the Ocular Oncology Clinic at Moorfields Eye Hospital, London, during November 1990 to October 1991 and diagnosed after August 1986. Hospital and general practice controls (416) were recruited in the North East Thames Region of the UK. Cutaneous naevi greater than or equal to 2 mm in diameter were counted on the skin. Clinically atypical and congenital naevi were recorded separately. Pigmented lesions of the iris were counted. The relative risk for ocular melanoma increased with numbers of atypical naevi and numbers of common naevi. Ten percent of cases but 3% of controls had at least 100 naevi of 2 mm or greater diameter. Seven percent of cases and 0.4% of controls had 4 or more atypical naevi. Pigmented lesions of the iris were significantly more common in cases than controls. Nine percent of cases had the Atypical Mole syndrome (AMS) phenotype compared with 1% of controls. Six cases had concurrent cutaneous melanoma primaries. We conclude that atypical and iris naevi are important risk factors for eye melanoma and that patients with eye melanoma are at increased risk of cutaneous melanoma. Dermatological examination for the AMS phenotype and cutaneous melanoma should be recommended in eye melanoma patients with large numbers of pigmented lesions of the skin or family history of melanoma. PMID- 7860136 TI - A case-control study of hepatitis B and C virus infections in the etiology of hepatocellular carcinoma. AB - During a 16-month period in 1991-1992, blood samples and questionnaire data were obtained from 65 incident cases of hepatocellular carcinoma (HCC) as well as from 2 control groups of hospitalized patients matched on gender and age, which included 65 metastatic liver cancer (MLC) patients and 65 patients hospitalized for eye, ear, nose or throat conditions. Coded sera were tested for hepatitis B surface antigen (HBsAg), antibody to hepatitis B core antigen, antibody to HBsAg and antibody to hepatitis C virus (anti-HCV) by enzyme immunoassay. The odds ratios (with 95% confidence intervals) in logistic regression modeling comparing the HCC cases to the combined control series were 18.8 (8.2-43.2) for the presence of HBsAg and 7.7 (1.7-35.1) for anti-HCV. In the present hospital-based case-control study anti-HCV testing was conducted on recently collected sera, using a second-generation enzyme immunoassay with confirmation by immunoblot assay. Comparisons with previous work in a similar population demonstrated that, when second-generation anti-HCV assays are applied to sera stored for 7-15 years, confirmatory assays or a higher diagnostic cut-off point may be necessary to ensure that the testing is specific. PMID- 7860137 TI - Karyotypic features of malignant tumors of the nasal cavity and paranasal sinuses. AB - Cytogenetic analysis of short-term cultures from 6 tumors of the nasal cavity and paranasal sinuses--one esthesioneuroblastoma, 2 adenocarcinomas and 3 squamous cell carcinomas (SCC)--revealed clonal chromosome aberrations in all cases. The esthesioneuroblastoma had a complex hyperdiploid karyotype. None of the aberrations was similar to those previously described in short-term cultures or established cell lines from esthesioneuroblastomas. The 2 adenocarcinomas had complex karyotypic changes, which in both cases included rearrangements of bands 9p22 and 14q11. One SCC had 5 unrelated pseudodiploid clones, 1 displayed a highly complex karyotype, including rearrangement of band 11q13, and 1 had simple karyotypic changes with loss of 6q material and gain of 3q. These findings are similar to those described in head-and-neck SCC at other sites. PMID- 7860138 TI - Elevated antibody titers to Epstein-Barr virus prior to the diagnosis of Epstein Barr-virus-associated gastric adenocarcinoma. AB - Epstein-Barr virus (EBV) has recently been identified in the tumor cells of patients with gastric carcinoma. We tested pre-morbid serum samples from a carefully monitored cohort of Japanese men in order to investigate the possibility that patients with EBV-associated gastric cancer represent a sub-set of individuals with long-standing difficulties in appropriately managing EBV infection. From a serum bank, we obtained 108 samples derived from 54 patients destined to develop gastric adenocarcinoma and 54 controls. Samples were tested under code for antibodies to EBV-capsid antigen, early antigen and nuclear antigen. Individuals who were positive for IgA antibodies against EBV viral capsid antigen (VCA) and IgG antibodies against the R component of EBV early antigen were at a 3.9-fold and 1.9-fold excess risk of disease, respectively. Antibody titers to EBV VCA were significantly higher in those destined to get EBV associated gastric cancer than those subsequently developing non-EBV-associated gastric cancer or age-and-gender-matched controls. These findings suggest that the inability to control EBV infection on a long-term basis exists many years prior to the development of EBV-associated gastric cancer, and that EBV may play an etiologic role in this sub-set of malignancies. PMID- 7860139 TI - Expression of transforming growth factor alpha and its receptor in human neuroendocrine tumours. AB - Transforming growth-factor-alpha (TGF-alpha) is a 50-amino-acid polypeptide that binds to the epidermal growth factor (EGF) receptor and stimulates cell growth. It has been suggested that enhanced production of TGF-alpha and EGF receptors by tumour cells promote tumour-cell growth by autocrine mechanisms. In the present study we have investigated the expression of TGF-alpha and EGF receptors in human neuroendocrine tumours, including midgut carcinoid tumours, phaeochromocytomas and medullary thyroid carcinomas. TGF-alpha expression was demonstrated in biopsies of all tumours examined (n = 30) and EGF receptors in a majority of tumours by Northern analysis and/or immunocytochemistry. Expression of TGF-alpha and EGF receptors was also demonstrated in primary cultures of tumour cells. Carcinoid tumours and phaeochromocytomas in culture secreted detectable amounts of TGF-alpha into the culture medium (400-700 pM). The amount of secreted TGF alpha could be suppressed by octreotide treatment in individual tumours. Administration of exogenous TGF-alpha stimulated carcinoid tumour growth in vitro as determined by the DNA contents of cell cultures. The growth-stimulatory effect of TGF-alpha could be partially blocked by the use of neutralizing anti-EGF receptor monoclonal antibodies (MAbs). In conclusion, several human neuroendocrine tumours express both TGF-alpha and EGF receptors in in vivo and in vitro, suggesting that TGF-alpha may regulate tumour-cell growth by autocrine mechanisms. PMID- 7860140 TI - Role of mature leukemic cells in the amplification of leukemic stem cells in a murine model. AB - The recently described PGM-2 leukemia displays a hierarchical structure with bipotential stem cells, B-lymphocyte and macrophage progenitor cells, and post mitotic end cells. Because the different cell types can easily be identified in vitro by clonal culture assays and simple staining procedures, this leukemia is a useful model for the study of the interactions between different cell compartments in a leukemic clone. Our analysis of the impact of mature leukemic macrophages on the proliferation of stem cells was facilitated by the establishment of long-term cultures producing new stem cells over prolonged periods of time. A prerequisite was the development of an adherent layer of fibroblasts and leukemic macrophages. Enumeration of adherent cells revealed a good correlation between the number of macrophages and the number of stem cells generated, and expansion of the macrophage population by treatment with interleukin 3 (IL-3) resulted in a significant improvement of the culture conditions. Leukemic macrophages were also able to induce the formation of stem cell colonies in agar culture, suggesting a role for humoral mediators. Antibody neutralization experiments and bioassays identified IL-7 and IL-6 as factors cooperating in the stimulation of stem-cell self-renewal. Feed-back stimulation of leukemic stem cells by mature leukemic cells may also be relevant to human leukemias and have implications for differentiation therapy. PMID- 7860141 TI - Decreased macrophage-mediated cytotoxicity in mammary-tumor-bearing mice is related to alteration of nitric-oxide production and/or release. AB - Peritoneal-exudate macrophages (PEM) from mammary-tumor-bearing mice have impaired cytotoxic activity against syngeneic and allogeneic tumor targets. The ability of PEM from normal and tumor-bearing mice to bind tumor targets was found to be similar in the presence or the absence of surrogate receptors, which enhanced the binding but not the killing of tumor targets by PEM from tumor bearing mice, suggesting that other mechanisms are involved in their impaired cytolytic activity. Soluble and membrane-bound TNF-alpha, as well as H2O2, were found in higher amounts in PEM from tumor bearers upon stimulation with LPS, as compared with PEM from normal mice. However, tumor-bearers' macrophages displayed decreased capacity to produce and/or release nitric oxide, which could be reversed by the addition of increasing levels of IFN-gamma. These results indicate that the lack of macrophage cytotoxicity in mammary-tumor-bearing mice is related to impaired production and/or release of NO by these effector cells, possibly aggravated by the insufficient IFN-gamma production previously reported in these animals. Moreover, mammary-tumor progression results in dis-regulation of synthesis of macrophage-mediators, with over-production of molecules to which mammary-tumor cells are insensitive and deficient production of NO, the crucial molecule to which these cells appear to be highly sensitive. PMID- 7860143 TI - Treatment of Philadelphia-chromosome-positive human leukemia in SCID mouse model with herbimycin A, bcr-abl tyrosine kinase activity inhibitor. AB - The molecular basis of the Philadelphia chromosome (Ph1) is a structurally altered c-abl (bcr-abl) gene which encodes an abnormally large protein with protein tyrosine kinase activity. Herbimycin a, which effectively reduced intracellular phosphorylation by bcr-abl tyrosine kinase, preferentially inhibited the growth of Ph1-positive leukemia cell lines. Injection of Ph1 positive and -negative leukemia cell lines into mice with severe combined immunodeficiency (SCID) resulted in the death of all mice due to leukemia, although the severity of illness varied according to the cell lines used. Administration of herbimycin A significantly enhanced the survival of mice inoculated with the Ph1-positive leukemia cell lines tested but barely affected the survival of mice inoculated with the Ph1-negative leukemia cell lines tested. These results suggest that herbimycin A and related compounds may be useful for the treatment of Ph1-positive leukemia. The disease that developed using the Ph1 positive leukemia cell line NALM-20 resembled human Ph1-positive acute lymphoid leukemia. There was an inverse relationship between the survival time of mice and the number of cells inoculated. The SCID mouse-NALM-20 human leukemia chimera would be a good experimental model for screening tyrosine kinase inhibitors as therapeutic agents against Ph1-positive leukemia. PMID- 7860142 TI - Mechanisms of MRP over-expression in four human lung-cancer cell lines and analysis of the MRP amplicon. AB - Some multidrug resistant cell lines over-express the gene encoding the multidrug resistance-associated protein (MRP). In all cell lines reported thus far, over expression is associated with gene amplification. We have studied the predominant mechanisms of MRP over-expression in 4 human lung-cancer cell lines that cover a range of drug-resistance levels, and we have analyzed the MRP amplicon. In the SW 1573-derived, weakly resistant cell line 30.3M, MRP mRNA is elevated 3-fold in the absence of gene amplification. Run-on analysis shows that the increased MRP gene expression in this cell line is due to transcriptional activation. In the highly resistant GLC4/ADR and COR-L23/R cells, MRP gene amplification predominates, whereas in the moderately resistant MOR/R cells, gene amplification is combined with a mechanism resulting in an additional increase in the level of MRP mRNA. Fluorescence in situ hybridization shows that, in the GLC4/ADR cells, amplified MRP sequences are present both in double minute chromosomes (DM) and in homogeneously staining regions (HSR). By pulsed-field gel electrophoresis we show that the MRP-containing DM are 1 Mb in length. Chromosome-16-specific repetitive sequences adjacent to the MRP gene are also present in the DM and HSR, compatible with the involvement of these sequences in recombination events underlying MRP gene amplification. Our results show that low levels of drug resistance may arise by transcriptional activation of the MRP gene, whereas at high levels of drug resistance amplification of the MRP gene predominates, possibly facilitated by the presence of recombination-prone sequences. PMID- 7860144 TI - Over-expression of hsp70 confers tumorigenicity to mouse fibrosarcoma cells. AB - Over-expression of the major heat-shock protein hsp70 in WEHI-S tumor cells renders them resistant to the cytotoxic effects of tumor necrosis factor (TNF). To study the significance of this resistance in vivo, the tumorigenic potential of WEHI-S cells transfected with human hsp70 in sense and anti-sense orientation was investigated in athymic and in normal syngenic mice. A striking correlation was observed between the level of hsp70 expression and tumorigenicity in athymic mice. Hsp70 expression rendered WEHI cells tumorigenic also in normal mice, but higher numbers of cells were required for tumor formation than in athymic mice. Over-expression of hsp70 in WEHI-S cells did not enhance their anchorage dependent growth in vitro or their ability to form colonies in soft agar. The hsp70-transfected cells exhibited greatly increased resistance against killing by murine natural cytotoxic cells and macrophages in vitro. A similar tumorigenic phenotype could also be induced independently of hsp70 by prolonged culture of WEHI-S cells with TNF. These results suggest that over-expression of hsp70 increases the tumorigenic potential of WEHI-S cells in mice, by allowing these cells to escape from the early TNF-mediated anti-tumor immune surveillance. PMID- 7860145 TI - Somatostatin analog RC-160 inhibits growth of CFPAC-1 human pancreatic cancer cells in vitro and intracellular production of cyclic adenosine monophosphate. AB - The effect of somatostatin analog RC-160 on the growth of CFPAC-1 human pancreatic cancer cells in vitro was investigated. RC-160 effectively inhibited the proliferation of CFPAC-1 cells in culture, inducing a time- and dose dependent decrease in the number of treated cells. A significant suppression of cell growth was observed after 48 and 72 hr of the exposure to (1 microM) RC-160, the cell number being decreased by 38% and 46%, respectively. RC-160 was more potent than SS-14 or SMS201-995 in inhibiting the growth of CFPAC-1 cells, and after 48-hr treatment the cell number decreased by 49% for RC-160 compared with 12% for SS-14 and 27% for SMS201-995. Binding experiments demonstrated that specific receptors for somatostatin were present on CFPAC-1 cells. SS-14 showed a high binding affinity for [125I]-Tyr11-SS-14 receptors on CFPAC-1 cells. Scatchard analysis indicated the presence of 2 classes of somatostatin binding sites on the cells, one with high binding affinity and low capacity and the other with low binding affinity and high capacity. RC-160 could bind to somatostatin receptors on these cells with an affinity similar to SS-14 but significantly higher than that of SMS201-995. Radioimmunoassay of intracellular cAMP showed that RC-160 could powerfully inhibit forskolin-stimulated cAMP production in CFPAC-1 cells. Addition of forskolin to the cultures increased cAMP concentrations in the cellular lysate of treated cells. RC-160 attenuated or nullified in a dose-dependent manner the cAMP production stimulated by forskolin. Our observations indicate that somatostatin analog RC-160 inhibits the proliferation of CFPAC-1 human pancreatic cancer cells in vitro and that this effect may involve the intracellular cAMP pathway. PMID- 7860146 TI - Nucleotide sequence analysis of a full-length human T-cell leukemia virus type I from adult T-cell leukemia cells: a prematurely terminated PX open reading frame II. AB - Human T-cell leukemia virus type 1 (HTLV-1) is etiologically associated with adult T-cell leukemia/lymphoma (ATL). The prototypic HTLV-1, ATK, is the only full-length provirus cloned from uncultured leukemic cells and completely sequenced prior to this study. We have determined the complete nucleotide sequence of another full-length HTLV-1 provirus cloned directly from leukemic cells. A premature termination codon was found in the second open reading frame (orf II) of the pX region. Our finding indicates that open reading frame II of the HTLV-1 pX region is not required for outgrowth of ATL leukemic clones in vivo. PMID- 7860148 TI - Kinetics of cisplatin-induced apoptosis in murine mammary and ovarian adenocarcinomas. AB - There is mounting evidence to indicate that the mode of cell death known as apoptosis plays an important role in cancer therapy. Most supporting observations have come from experiments conducted in vitro, and it is important to extend such studies to in vivo systems. We have therefore evaluated the magnitude and kinetics of apoptosis induction in tumors from mice treated with cisplatin (CP). Two transplantable murine tumors were studied: a mammary adenocarcinoma, MCa-4, and an ovarian adenocarcinoma, OCa-1. Tumor-bearing mice were injected with various doses of CP, and specimens were obtained over several days. Apoptosis was scored by morphometric analysis of histological sections of the tumors using the features characteristic of cells undergoing this mode of cell death. The results showed a significant apoptotic response in both tumors within a few hours after injection of the drug. The kinetics were very broad, with apoptotic cells present over essentially the entire time course studied. Dose-response relationships for CP-induced apoptosis were compared to the tumor response measured in terms of tumor growth delay. PMID- 7860147 TI - The effect of E1A transfection on MMP-9 expression and metastatic potential. AB - The expression of MMP-9 in rat embryo fibroblasts (REF) transformed with Ha-ras or with Ha-ras and v-myc is associated with metastatic behavior. In contrast, REF transformed with Ha-ras and the adenovirus E1A genes (E1A) are tumorigenic, do not release MMP-9 and are rarely metastatic. In this report, we establish that E1A expression results in decreased levels of MMP-9 mRNA in an Ha-ras and v-myc transformed cell line and examine which of the functional domains of E1A participate in the inhibition of MMP-9 expression and which contribute to the suppression of metastasis. The metastatic 2.10 REF line, derived by co transfection with v-myc and Ha-ras, constitutively expresses high levels of MMP-9 (92 kDa gelatinase). Transfection of E1A wild-type plasmids into this cell line eliminates detectable MMP-9 mRNA expression and greatly reduces MMP-9 activity. Transfection of 2.10 with E1A plasmids encoding mutations in conserved region 2 (CR2) retained inhibition of MMP-9 similar to the inhibition seen with wild-type E1A. Transfection with E1A containing mutations in CRI or the amino terminal region diminished, but did not fully inhibit, MMP-9 expression. In contrast, inhibition of MMP-9 was lost in with E1A mutations in CR3. Cells transfected with E1A mutants in CR1, the amino terminal region or CR3 retained metastatic behavior. Our findings delineate the regions of E1A responsible for MMP-9 inhibition and further define the domains of E1A responsible for inhibition of metastasis. PMID- 7860149 TI - Targeted inhibition of tumor-cell growth by recombinant heregulin-toxin fusion proteins. AB - Fusion of functional domains of proteins by in vitro recombination of gene fragments can be used to generate novel anti-tumor agents. The combination of tumor-cell-recognition functions and toxic functions results in cytotoxic molecules with a high specificity for tumor cells. Human adenocarcinomas are frequently characterized by over-expression of members of the epidermal-growth factor (EGF) receptor family (ErbB-1, 2, 3 and 4), when compared with normal cells. These tumors are particularly suited to treatment with recombinant toxins. The human heregulins (HRG) and their rat counterparts (neu differentiation factor, NDF) have been identified as ligands for these receptors. Two chimeric heregulin-toxin fusions consisting of the EGF-like receptor recognition domain of the heregulin isoforms HRG alpha and HRG beta I, and the domains II, Ib and III of the Pseudomonas exotoxin A (ETA) were constructed. HRG beta I-ETA is highly cytotoxic for the mammary carcinoma cell lines SK-BR-3 and MDA-MB-453. HRG alpha ETA was less active than HRG beta I-ETA. The killing activity of the recombinant toxins correlated with the expression levels of ErbB-3 and/or ErbB-4 in the cell lines studied. High expression of ErbB-2 is not sufficient to confer sensitivity towards the HRG-ETA. Treatment of mice with 0.4 mg/kg/day of HRG beta I-ETA caused growth retardation of transplanted human breast tumor cells. Higher levels of HRG beta I-ETA administration resulted in acute hemorrhagic necrosis of the liver. PMID- 7860151 TI - Maternal recall of birthweights of adult children: validation by hospital and well baby clinic records. AB - BACKGROUND: Several studies have suggested that maternal recall of offspring birthweight compares well to data from birth certificates or medical records. However, these studies describe relatively short recall periods and pertain to populations where hospitalized childbirth is the norm. Accuracy of maternal recall has not been confirmed after long recall periods or in populations where non-hospitalized childbirth is common. METHODS: Accuracy of recalled birthweights is assessed among 626 women interviewed at an average age of 43.3 years (standard deviation [SD] 1 year), at which time the average age of their 1297 offspring was 17.9 years (range 1-29 years, SD 4.8 years). One-third of these infants were delivered at home. Recalled birthweight was compared to hospital or Well Baby clinic records, available for 66% (861/1297) of all births. RESULTS: Record availability was not related to birthweight. For the 861 infants for whom both sources were available mean recorded birthweight was 3342 g (SD 586 g) and mean recalled birthweight 3340 g (SD 675 g). Recalled weights overestimated recorded weights by 109 g (95% Cl: 68-151) among infants weighing > 3750 g and underestimated recorded weights by 83 g (95% Cl: 54-111) among infants weighing < or = 3250 g. CONCLUSIONS: As an outcome variable recalled birthweights were unbiased, but less precise than recorded birthweights. Use of recalled birthweight does not sacrifice study power however and may increase generalizability provided recalled weights are available for 30% more infants than recorded weights. For individual birthweight assessment and for use as an independent variable recalled weights are biased and may have to be adjusted using recorded data as available. PMID- 7860150 TI - Intrauterine device use and risk of tubal pregnancy: an Indonesian case-control study. AB - BACKGROUND: We assessed the risk of tubal pregnancy among women who (1) were currently using an intrauterine device (IUD) and (2) had discontinued IUD use while still sexually active and at risk of pregnancy using data from a multicentre case-control study of married women conducted in Indonesia. METHODS: Cases were 560 women diagnosed with histologically confirmed ectopic pregnancy from April 1989 to August 1990 at any one of 11 participating hospitals. Controls were 1120 non-pregnant women similar in age and place of residence to the cases. In-person interviews were conducted to collect information regarding current and past contraceptive use as well as other demographic and personal characteristics. RESULTS: Women currently using an IUD were considerably less likely than women not currently using contraception, but more likely than users of hormonal or surgical means of contraception, to develop a tubal pregnancy. Women who had discontinued using an IUD had a 70% subsequent increase in risk of tubal pregnancy (adjusted RR = 1.7, 95% Cl: 1.1-2.5) relative to women who had never used an IUD. This increase in risk was most pronounced in women who reported multiple episodes of IUD use and, to a lesser extent, in women with a long (> 3 year) duration of IUD use. CONCLUSIONS: The associations we observed are similar to those previously reported in studies conducted in developed countries. The results are of particular interest because this study was conducted in a location in which the Dalkon Shield IUD was never available, and among a population of married, gravid women for whom IUD use is generally considered most appropriate. PMID- 7860152 TI - Factors influencing admission to hospital during terminal childhood illnesses in Kenya. AB - BACKGROUND: Access to essential clinical services offered by district hospitals or health centres forms an important component of primary health care activities in the developing world. Utilization of hospital facilities during life threatening childhood illnesses will affect survivorship. METHODS: We have examined clinical, geographical, social, economic and demographic features of families of 49 children who consulted a hospital facility during a terminal illness and 88 who did not during a 1-year prospective demographic and hospital based surveillance of a rural community on the Kenyan Coast. RESULTS: Of children who died without admission, 15% had symptoms which lasted only 1 day compared to no children who were admitted (P = 0.004). Furthermore, those who died without admission tended to live further away from the nearest bus stage (P = 0.01) and had made greater use of traditional healers (P = 0.08). Mothers' education or household socioeconomic status did not influence admission to hospital. CONCLUSION: Health education is required to improve early recognition of clinical signs warranting hospital care and traditional healers should be included in any community-based education programmes. PMID- 7860153 TI - Prevalence of migraine headache in Canada: a population-based survey. AB - BACKGROUND: The aim of the present study was to estimate the prevalence of migraine headache among Canadian adults (aged > or = 18 years) and analyse variation by age, gender, household income and province of residence. METHODS: A population-based survey was undertaken using telephone interviews with 2922 adults who were randomly selected from households across Canada by stratified regional sampling. The questionnaire asked about frequency and characteristics of headaches experienced and other symptoms. The diagnostic criteria of the International Headache Society were used to classify people as migraineurs (with or without aura), headachers or non-headachers. RESULTS: Of 8921 random calls to households, 4235 were eligible and 2922 interviews were successfully completed (response rate 66%). The prevalence of migraineurs, headachers and non-headachers among males was 7.8%, 76.1%, 16.1% and among females was 24.9%, 65.6%, 9.4%. For females prevalence appears to increase with age, peaking at 40-44 years and declining thereafter. Sex-specific prevalence for males and females, controlling for age, was significantly lower in the province of Quebec compared to other provinces. We found no association between migraine prevalence and household income. Of 500 people classified by IHS criteria as migraineurs only 232 (46%) reported any migraine diagnosis by a physician. CONCLUSION: We estimate that 2.6 million adult females and 0.8 million adult males in Canada are migraineurs, but only half are likely to have been diagnosed by a physician. Contrary to a recent US survey, people from lower income households in Canada are not at greater risk of migraine. The lower prevalence of migraine in Quebec was unexpected and remains unexplained, but it may be influenced by language/translation problems. PMID- 7860154 TI - An age and period reconstruction of the HIV epidemic in Italy. AB - BACKGROUND: The majority of AIDS cases in Italy are among intravenous drug users (68%) and homosexual men. An age, period and cohort (APC) model is presented and used to reconstruct the HIV epidemics in Italy. Projections of AIDS-related conditions (ARC) and AIDS cases are attempted based on a hypothesis of minima and an endemic hypothesis. METHODS: The model is a generalization of the usual back calculation method which considers age, competitive mortality, susceptible population and therapy effects. Estimates of the HIV epidemic in Italy are obtained using Italian AIDS counts (corrected for delay in reporting), and an incubation time distribution (estimated from data of an Italian cohort), which was found to be dependent on the age at infection. The impact of AZT therapy, introduced in Italy in mid1987, is evaluated using a modification of the incubation time distribution dependent on period of infection. RESULTS: The estimated number of new infections in Italy declined after 1987, although the number of new AIDS cases has continued to rise, albeit less steeply in recent years. When delay in the progression to AIDS due to therapy is taken into account, the estimated number of people infected in mid1990 increases from 52,000 to 67,000, with approximately 12% of subjects already in the ARC stage. The age at maximum risk of infection is 25 years in males and 23 years in females. CONCLUSIONS: Using a hypothesis of no more HIV infections after 1990, AIDS counts would be still rising in Italy up to 1993 as a result of past infections and of the long incubation period. PMID- 7860155 TI - Methodological approaches in a baseline study of diarrhoeal morbidity in weaning age children in rural Zaire. AB - A community-based prospective study of diarrhoeal morbidity of weaning-age children in 18 geographically separate village clusters was conducted as the baseline phase of a controlled trial of a hygiene education intervention to reduce diarrhoeal diseases in rural Zaire. For 12 weeks trained interviewers collected information at weekly home visits about the diarrhoeal morbidity of 2082 children aged 3-35 months. Included in the analyses were 1914 children (92%) with 9 or more complete weeks of data. Mothers' reporting of the existence or otherwise of episodes appeared reliable, and more than 70% of children had at least one episode of diarrhoea during the 12-week study period, the mean number of episodes being 1.9 per child. Reporting of the start and termination of diarrhoeal episodes was, however, irregularly distributed among the 7 days between successive home interviews, with 36% of all episodes reported as starting on interview days, and 29% reported as ending the day before an interview: in each case, only 14% would have been expected. After adjusting for these reporting biases, 61% of the episodes lasted 2-4 days, but a number of very long duration were also reported, and the mean duration of the episodes was 4.8 days. Children, had, on average, 9.2 days of diarrhoea during the study period. Contrasts with previous characterizations of reporting error in diarrhoeal studies are noted. PMID- 7860156 TI - Community-based hygiene education to reduce diarrhoeal disease in rural Zaire: impact of the intervention on diarrhoeal morbidity. AB - BACKGROUND: Diarrhoeal disease is a leading cause of morbidity in young children in rural Zaire. Few diarrhoea prevention programmes have been implemented in Bandundu Province, where available data suggest an annual prevalence rate of 10%. The urgent need to reduce diarrhoeal morbidity in Zaire, together with the potential effectiveness and feasibility of hygiene education as a diarrhoea prevention strategy, led to the development of the present research project. METHODS: A randomized, controlled trial of an education intervention to reduce diarrhoea through improved personal and domestic hygiene behaviours was conducted in 18 geographically separate village clusters (sites) in rural Zaire. For 12 weeks baseline information on the diarrhoeal morbidity of 2082 children aged 3-35 months was collected at weekly home visits, and structured observations of hygiene practices related to diarrhoea were made on a subset of 300 families. Intervention messages addressed disposal of animal faeces from the yard, handwashing after defecation and before meal preparation and eating, and disposal of children's faeces. Three months after the start of the intervention and exactly 1 year after the baseline studies, a second diarrhoeal morbidity study and a second observational study were conducted in order to evaluate the intervention. RESULTS: Children in intervention communities experienced an 11% reduction in the risk of reporting diarrhoea during the peak diarrhoeal season, compared to controls (P < 0.025). The largest differences were seen among children aged 24-35 months, with those from intervention communities reporting significantly fewer episodes, shorter mean durations and hence fewer days of diarrhoea. There was some evidence that greater reductions in diarrhoea occurred in sites where the quality of the intervention, a scored measure of volunteer efficacy and community participation, was highest. CONCLUSIONS: The results of this study suggest that hygiene education may be an effective approach to reduce the incidence and duration of diarrhoeal episodes in rural Zaire. Children aged 2 years appear to benefit the most. A Hawthorne effect of the education may contribute to diarrhoeal reductions. PMID- 7860157 TI - Chest illness in infancy and chronic respiratory disease in later life: an analysis by month of birth. AB - BACKGROUND: Cohorts born at different times of year differ in their risk of exposure to seasonal respiratory infections in early life, but are likely to have similar socioeconomic status and lifestyle thereafter. METHODS: We investigated the long-term consequences of acute chest illness in infancy for later development of chronic respiratory disease by analysing variations by month of birth in hospital admissions for respiratory illness (total n = 49,866), chronic respiratory symptoms and ventilatory function among British school children (n = 11,482) and middle-aged adults (total n = 55,829). RESULTS: Admission for bronchiolitis in the first year of life was three times more common for infants born September to November (autumn) than those born March to May, yet people born in the autumn experienced fewer respiratory symptoms and had better ventilatory function. In two surveys of middle-aged men, forced expiratory volume in one second/forced ventilatory capacity (FEV1/FVC) was significantly (P = 0.025) higher among autumn births. Hospital admissions for chronic bronchitis/emphysema and pneumonia varied little with season of birth. Admissions for asthma were significantly (P < 0.05) more common among children and young adults born in the autumn. CONCLUSIONS: These findings do not support the hypothesis of a causal link between chest illness in infancy and the later development of chronic bronchitis and emphysema. The variation in asthma admissions with month of birth deserves further investigation. PMID- 7860158 TI - Immunization of 6 and 9 month old infants with AIK-C, Edmonston-Zagreb, Leningrad 16 and Schwarz strains of measles vaccine. AB - BACKGROUND: Measles kills more than 1 million infants per year and is particularly lethal in infants < 1 year old in developing countries. Recent reports have suggested that measles vaccines of different strains and titre differ in their immunogenicity in young infants. We sought to identify strains and titres of measles vaccines which would be effective in 6 and 9 month old infants. METHODS: We conducted a randomized trial of AIK-C, Edmonston-Zagreb (EZ), Leningrad-16 and Schwarz strains of measles vaccine at different titres in 1202 6 month old and 1250 9 month old infants. Antibody levels were measured by haemagglutination inhibition assay. Seroconversion was defined as a change from seronegative to seropositive or a fourfold rise in titre above the expected level after antibody decay (assumed antibody half-life = 6 weeks). Chi-square tests were used to compare seroconversion rates and rates of adverse reactions among the groups. Comparison of geometric mean titres (GMT) was done by the Student's t test. RESULTS: No severe or unusual adverse reactions occurred during the 6 weeks after vaccination. All strains induced high seroconversion rates in 9 month old infants. In 6 month olds, medium- and standard-titre AIK-C induced the highest rates of seroconversion. Antibody titres at 6 weeks after vaccination were highest in recipients of Schwartz vaccine and lowest for EZ vaccine recipients. CONCLUSIONS: Standard-titre AIK-C may be more effective than other measles vaccine strains for early measles immunization and should be evaluated further for efficacy, long-term immunogenicity, and long-term safety. PMID- 7860159 TI - Sex differences in the humoral antibody response to live measles vaccine in young adults. AB - BACKGROUND: Following vaccination of children using high-titre live measles vaccine, excess non-specific mortality was reported, particularly among females. Since vaccination with live measles virus results in a temporary depression of the immune response to other antigens, the female predominance in subsequent non measles mortality may be due to sex differences in response to live measles vaccines. METHODS: In this study, the immunogenicity of standard titre live Schwarz strain measles vaccine was examined 2 and 4 weeks post-vaccination in 223 males and 66 female aged 18-20 years in Israel in 1991. RESULTS: Females had higher post-vaccination geometric mean titre (GMT) at all levels of pre vaccination titres at both 2 and 4 weeks. Furthermore, after controlling for differences in pre-vaccination titres, overall the post-vaccination GMT for females was about 50% higher than for males (P < 0.001). CONCLUSIONS: These findings indicate that females exhibit a stronger humoral immune response to measles vaccine. Possible sex differences in immunosuppression following measles vaccination should be explored. PMID- 7860160 TI - The epidemiology of melioidosis in Ubon Ratchatani, northeast Thailand. AB - BACKGROUND: Melioidosis, or infection with Pseudomonas pseudomallei is an important cause of morbidity and mortality in South East Asia and Northern Australia. The epidemiology of melioidosis in Ubon Ratchatani, Northeast Thailand was studied over a 5-year period from 1987 to 1991. METHODS: Rates and, when possible, the risks of developing melioidosis were calculated. The numerator was the number of culture-proven cases of melioidosis seen in the 1000-bed referral hospital of the province. The denominators were obtained from the population census, a survey of Health, Welfare and Use of Traditional Medicine, and the North Eastern Meterological Centre, Thailand. RESULTS: The average incidence of human melioidosis was 4.4 (95% confidence interval [CI]: 3.8-5.0) per 100,000. The disease affected all ages with the highest incidence in 40-60 years olds. Melioidosis was 1.4 (95% CI: 0.4-5.3) times more common in males than females. The disease showed a significant seasonal variation in incidence, and a strong linear correlation with rainfall (r = 0.7, 95% CI: 0.5-0.9) Adults exposed to soil and water in their work (most were rice farmers) had an increased risk of melioidosis (in the 40-59 year age group, relative risk = 4.1, 95% CI: 2.4-6.9). Most adult patients had an underlying disease (mainly diabetes mellitus) predisposing them to this infection. CONCLUSION: Melioidosis may result from either acute exposure to the organism in the soil and water, or 're-activation' of an asymptomatic childhood infection (by an unidentified possibly infective seasonal cofactor). The results from this analysis are consistent with both hypotheses. Further epidemiological studies are needed to identify risk factors so that optimal strategies for control of melioidosis may be developed. PMID- 7860161 TI - Outmigrant ascertainment for bias assessment in environmental epidemiology. AB - BACKGROUND: In the summer of 1985, the McGill Epidemiology Rapid Response Unit undertook a study comparing two areas exposed to emissions of 'sour gas' refineries to an unexposed area. One operational objective of the project was the identification and survey of all the people who had lived in the study area but had since moved (outmigrants). METHODS: We estimated the number of outmigrants (people who had ever lived in the area during the period 1957 to 1985) to be 3363 by using information obtained from our cross-sectional survey and from population statistics for the area of interest. Ten different methods combined lead to the identification of approximately 87% of all the outmigrants who left the study area during that period. We used vital statistics to identify the outmigrants who had died and mailed questionnaires to obtain the necessary information from the others. RESULTS: We confirmed the vital status of approximately 46% of them (1532/3363). The results from the outmigrant survey showed that they were younger than area residents, that they experienced lower rates of heart disease and hypertension and that they had moved for health reasons in only 1.3% of the cases. These findings were similar across comparison areas. CONCLUSION: We concluded that there was no effect due to migration bias on the cross-sectional study results. This evidence considerably strengthened the conclusions regarding the effects of exposure, a benefit that largely justified the cost of identifying and surveying the outmigrants. PMID- 7860162 TI - Cigarette smoking and cervical cancer. PMID- 7860163 TI - Cigarette smoking and cervical cancer. PMID- 7860164 TI - Number of sexual partners and smoking behaviour as risk factors for cervical dysplasia: comments on the evaluation of interaction. PMID- 7860165 TI - A distinction between cumulative incidence and risk as measures of disease occurrence. PMID- 7860166 TI - Stratospheric ozone and health. AB - BACKGROUND: Stratospheric ozone is being depleted and ambient ultraviolet (UV) irradiance is probably increasing. While remedial steps have been taken through the Montreal protocols, at best it will take some 90 years for stratospheric ozone concentrations to return to the levels existing in the 1970s. METHODS: The evidence that these changes may have harmful effects on health has been reviewed. RESULTS: The direct harmful effects are skin cancer, ocular damage and, possibly, immune suppression with an increase in infectious disease. Indirect, harmful effects resulting from climate change, changes in atmospheric chemistry, and changes in food supply may also occur. Beneficial effects are also possible but have largely escaped attention. Quantification of these effects is either uncertain or impossible at present and the outcomes for health in 50 years time can only be guessed at. CONCLUSIONS: To understand better the health consequence of stratospheric ozone depletion, we need to know the quantitative relationship between ambient UV radiation and skin cancer, whether or not UV radiation really causes cataract and other ocular effects and what the quantitative relationships are, whether effects of UV radiation on immune function produce detectable health consequences, whether there are important beneficial effects of increasing UV radiation and, ultimately, what the balance of all these effects might be on health on a global scale. PMID- 7860167 TI - Maternal role in type 2 diabetes mellitus: indirect evidence for a mitochondrial inheritance. AB - BACKGROUND: The role of mitochondrial inheritance in type 2 diabetes mellitus has received much attention recently. In this study, three existing datasets in Taiwan are analysed to examine this theory. METHODS: Two of the datasets were community surveys and one a hospital case series. Subjects who had information regarding their paternal or maternal diabetic status were selected for the present study. In the first dataset, 745 subjects had information about paternal diabetic status and 765 had information about maternal diabetic status. In the second dataset, 255 and 267 subjects had the paternal and maternal information, respectively. In the third, a total of 3625 subjects had information about both their paternal and maternal diabetic status. Diabetic status of the study subjects was determined by fasting plasma glucose levels and/or oral glucose tolerance test; their parental diabetic status was collected by interview. RESULTS: The three datasets consistently demonstrated a significantly elevated odds ratio (OR) for reporting maternal diabetes (OR = 2.64, 95% confidence interval: 1.12-5.71) in diabetic patients as compared to non-diabetic subjects. The reporting of paternal diabetes, however, was not significantly different between diabetics and non-diabetics. In addition, the OR for reporting paternal diabetes were not significantly different between groups of different age-at onset. With respect to maternal history, the OR increased significantly when age at-onset was younger (test-for-trend P < 0.001). CONCLUSIONS: Our findings support mitochondrial inheritance of type 2 diabetes mellitus in the human population. The age-modifying effect was also in accordance with the mitochondrial oxidative phosphorylation paradigm for degenerative diseases. PMID- 7860168 TI - Cancer morbidity among employees in a Danish pharmaceutical plant. AB - BACKGROUND: Workers in the pharmaceutical industry may be exposed to many potential carcinogens. We investigated cancer morbidity in a Danish plant where enzymes, insulin, antibiotics and sex hormones were produced in substantial quantities. METHODS: Altogether 10,889 people ever employed (1964-1988) at the pharmaceutical plant were retrieved from the files of a compulsory pension fund, and followed-up in the nationwide Danish Cancer Registry (1964-1989). Site specific standardized incidence ratios (SIR) were estimated, based on cancer rates for the national population. Information on risk factors for breast cancer, e.g. number of children, age at menarche and first delivery, obesity, and non occupational use of sex hormones was obtained from samples of the female employees, and compared to equivalent variables from the general population. RESULTS: The overall SIR for women was significantly elevated (n = 5554; SIR = 1.2). Excess risk was particularly seen for breast cancer (n = 97; SIR = 1.5), especially in a subgroup who had started work at the factory aged 30-39 and had continued to work for 1-9 years (SIR = 2.8). The SIR was near unity for men (n = 5335); however, three men with breast cancer versus 0.4 expected were found. Lifestyle components explained only about one-quarter of the excess female breast cancers. Proxy measures of intensity of occupational exposure to sex hormones or insulin showed no association with the risk for breast cancer. CONCLUSIONS: It seems unlikely that either a single occupational factor or an unusual reproductive pattern can explain the elevated breast cancer risk. Therefore, the finding requires further study. PMID- 7860169 TI - Socioeconomic status and breast cancer incidence: a prospective cohort study. AB - BACKGROUND: To gain more insight into the relation between socioeconomic status (SES) and breast cancer risk, we have studied that association, before and after adjustment for traditional risk factors for breast cancer, in a prospective cohort study on lifestyle and cancer that started in 1986 in the Netherlands amongst 62,573 women aged 55-69 years. METHODS: At baseline, data on SES, diet, reproductive factors and other covariates were collected by means of a self administered questionnaire. For data-analysis a case-cohort approach was used. After 3.3 years of follow-up, 471 incident cases were available for analysis. RESULTS: We did not find a higher age-adjusted risk of breast cancer for those with a higher level of education (RR highest/lowest level of education = 0.94, 95% confidence interval [CI]: 0.63-1.39, trend-P = 0.15). Although upper white collar workers had a slightly higher breast cancer risk than blue-collar workers (RR = 1.16, 95% CI: 0.83-1.62, trend-P = 0.34), women with a profession of higher social standing did not have a higher risk (RR highest/lowest social standing = 0.73, 95% CI: 0.24-2.23, trend-P = 0.86). Additional adjustment for traditional risk factors did not alter the association between SES and breast cancer risk. CONCLUSIONS: We did not find an association between SES and breast cancer risk. This is not in agreement with studies conducted in other European countries and North America. PMID- 7860170 TI - Risk factors for invasive cervical cancer in Kenyan women. AB - BACKGROUND: Few epidemiological investigations of invasive cervical cancer have been conducted in Sub-Saharan African populations. METHODS: Using information collected as part of the hospital-based World Health Organization (WHO) Collaborative Study of Neoplasia and Steroid Contraceptives, we examined potential risk factors for invasive cervical cancer among Kenyan women. In all 112 women with histologically confirmed invasive cervical cancer diagnosed at the Kenyatta National Hospital, Nairobi, Kenya, between June 1981 and September 1988 and 749 control subjects were included in the present analyses. All women were interviewed regarding their medical and reproductive history, methods of birth control, and history of sexual relationships and sexually transmitted infections. Multiple logistic regression procedures were used to derive maximum likelihood estimates of adjusted odds ratios (OR) and 95% confidence intervals (CI). RESULTS: After adjusting for age, several factors were found to be associated with invasive cervical cancer. These include multiple sexual partners, early age at first sexual intercourse (OR = 1.9 and 2.6 for women reporting first intercourse at age 16-17 years and < 15 years, respectively, compared to women with first intercourse > or = 18 years), history of abnormal vaginal discharge (OR = 13.8, 95% CI: 8.3-23.0), and history of gonorrhoeal infection (OR = 3.2, 95% CI: 1.6-6.2). Low educational attainment and multiparity were also associated with the risk of invasive cervical cancer. Although the Papanicolaou smear has been extensively used as a screening method for cervical cancer in many countries, only three cases and four controls reported ever having a Papanicolaou smear (2.6% cases and 0.5% of controls). CONCLUSIONS: As has been observed in other parts of the world, cervical neoplasia in Kenya appears to be a late consequence of venereally transmitted carcinogenic agents. PMID- 7860171 TI - Contraceptive and reproductive risks for cervical dysplasia in southwestern Hispanic and non-Hispanic white women. AB - BACKGROUND: Various contraceptive practices and reproductive factors have been associated with cervical neoplasia in case-control studies worldwide. METHODS: To investigate contraceptive and reproductive risk factors associated with high grade cervical dysplasia in southwestern Hispanic and non-Hispanic white women, we carried out a clinic-based case-control study among university-affiliated clinic attendees. RESULTS: Oral contraceptive use ever (odds ratio [OR] = 0.4, 95% confidence interval [CI]: 0.2-0.9) and past diaphragm use (OR = 0.3, 95% CI: 0.1-0.8) were protective for dysplasia in analyses adjusted for age, ethnicity, sexual behaviour, and for cervical papillomavirus (HPV) infection. After further adjustment for Pap smear screening interval, oral contraceptive use ever remained protective for dysplasia. Vaginal deliveries were strongly associated with dysplasia with > 2 vaginal deliveries associated with a 3.9-fold increase in risk after adjustment for age, ethnicity, sexual behaviour, and HPV infection. Using logistic regression models to simultaneously control for effects of multiple factors as potentially related to cervical dysplasia, we found low educational attainment, cervical HPV infection, cigarette smoking, history of any sexually transmitted disease, and having one or more vaginal deliveries to be associated with dysplasia; oral contraceptive use and past diaphragm use also remained protective for high-grade cervical dysplasia in these regression analyses. CONCLUSIONS: The data suggest that use of oral contraceptives (ever) and past diaphragm use are protective for high-grade cervical dysplasia among Hispanic and non-Hispanic white women in New Mexico. The clinic-based perspective of this research (versus population-based studies) may help explain some of these findings. PMID- 7860172 TI - Risk factors for renal cell carcinoma in Denmark: role of medication and medical history. AB - BACKGROUND: Several recent studies of risk factors for renal cell carcinoma have indicated that use of diuretics may increase risk of this cancer. It has also been suggested that use of weak analgesics, which are known to increase risk of cancer of the renal pelvis and ureter, may also be associated with an increased risk of renal cell carcinoma--the most frequent type of kidney cancer. METHODS: A population-based case-control study was undertaken to investigate the role of diuretics, other anti-hypertensive drugs, analgesics, and medical history in the aetiology of renal cell carcinoma. The study base was the total Danish population, and 368 histologically verified cases and 396 sex- and age-matched controls who were interviewed from February 1989 to May 1992. RESULTS: Response rates were 76% among cases and 79% among controls. We found no general increase in risk among users of diuretics or analgesics, although women taking loop diuretics and heavy users of acetyl salicylic acid had slightly increased risks. The use of nondiuretic anti-hypertensive medications was associated with decreased risk in women. We found non-significantly increased risks for history of hypertension and other cardiovascular disorders. We also observed elevated risks for urological disorders in both sexes which may be a result of recall bias. CONCLUSION: This study provides only limited support for the suggested association between risk of renal cell carcinoma and use of diuretics and analgesics. The coexistence of renal cell carcinoma and cardiovascular diseases could be caused by risk factors that are common to these conditions. PMID- 7860173 TI - Lifestyle and the risk of acute myocardial infarction in a Gulf Arab population. AB - BACKGROUND: Recent statistics indicate that acute myocardial infarction (AMI) is becoming very common in the State of Bahrain. A population-based case-control study was carried out to explore the importance of lifestyle in the occurrence of AMI in Bahrain among those aged 30-79 years. METHODS: Seventy consecutive cases with a first episode of AMI were identified from a register, which included all hospital admissions, during the period 1 February 1992 to 31 July 1992, and compared with 516 subjects obtained from a random sample of the same community. Multiple logistic regression was used to control for demographic variables as well as for the mutual confounding effects of the investigated risk factors. RESULTS: Of the patients with first-time AMI, 64% did not walk regularly for exercise compared with 34% of community controls (adjusted odds ratio [OR] = 3.06, 95% confidence interval [CI]: 1.24-5.15). In all, 12% of community controls has a history of hypertension and 9% had diabetes. The comparative figures for AMI patients were 44% for hypertension (adjusted OR = 5.04, 95% CI: 2.82-9.00) and 22% for diabetes (adjusted OR = 3.28, CI: 1.73-6.20). Cigarette smoking and infrequent consumption of fruits and vegetables also appeared to be associated with an increased risk of AMI. CONCLUSION: There is scope for lifestyle change in reducing AMI risk, by changes in physical activity, smoking and dietary habits. In addition, measures to control hypertension and diabetes should be given a high priority in any national health policy to prevent AMI. PMID- 7860174 TI - Alcohol intake and serum lipids in a Japanese population. AB - BACKGROUND: Previous epidemiological and clinical studies have shown that alcohol, which increases high density lipoprotein (HDL) cholesterol levels, has an anti-atherogenic effect. But data on the effects of alcohol on low density lipoprotein (LDL) cholesterol are scarce. In this paper a cross-sectional study on the associations of alcohol in graded doses with serum lipids in a Japanese population is presented. METHODS: The daily alcohol intake of 832 Japanese men aged 35-59 was determined and the subjects were divided into five categories according to their daily alcohol consumption. The associations of alcohol intake and the kind of alcoholic beverage with serum lipids were determined by multiple regression analyses taking into consideration the differences of other confounding factors, i.e. age, body mass index (BMI) and smoking. RESULTS: Serum triglycerides and HDL-cholesterol were higher (P < 0.001) with higher alcohol intake while LDL-cholesterol was lower (P < 0.01). In multiple regression analysis, after adjusting for age, BMI and number of cigarettes smoked per day, HDL-cholesterol and the ratio of HDL-cholesterol to LDL-cholesterol were found to have a significant positive relationship with daily alcohol consumption (P < 0.001) and LDL-cholesterol to have a significant negative relationship (P < 0.001). The kind of alcoholic beverage had no significant relationship with serum HDL-cholesterol and LDL-cholesterol; however, serum triglycerides were found to be significantly lower in those who drank beer (P < 0.05). CONCLUSIONS: Alcohol drinkers have a higher HDL-cholesterol level and lower LDL-cholesterol level than non-drinkers. This anti-atherogenic lipid profile in alcohol drinkers may be explained by the effect of alcohol on serum lipids independent of age, BMI and smoking. PMID- 7860175 TI - Total and HDL-cholesterol in The Netherlands: 1987-1992. Levels and changes over time in relation to age, gender and educational level. AB - BACKGROUND: To gain insight into the prevalence of and trends in plasma cholesterol levels in the general population of the Netherlands, a monitoring project was carried out from 1987 to 1992. METHODS: Each year a random sample of men and women aged 20-59 years in three towns in the Netherlands was invited to participate in the study. The overall response rate was 50% for men and 57% for women and a total of almost 42,000 men and women participated. Total (TC) and high density lipoprotein cholesterol (HDL-C) was measured and the non-HDL-C/HDL-C ratio was computed. Data were age-standardized to the Dutch population distribution aged 20-59 years. RESULTS: The prevalence of hypercholesterolaemia (TC > or = 6.5 mmol/l) in men ranged from 5% in the youngest (20-29 years) to 29% in the oldest age group (50-59 years), and from 4% to 38% in women. Low HDL-C levels (< or = 0.9 mmol/l) in men ranged from 15% in the youngest to 26% in the oldest age group, and in women from 4% in the youngest to 7% in the oldest age group. The lipid profile of those with a higher educational level was more favourable than that of the less educated. From 1987 to 1992, in men, TC decreased by 0.12 mmol/l, HDL-C decreased by 0.07 mmol/l and the non-HDL-C/HDL-C ratio increased by 0.22. In women no statistically significant changes were observed. Changes over time did not differ according to age and educational level. CONCLUSION: The prevalence of hypercholesterolaemia is still high in the Netherlands. During the period 1987-1992 the lipid profile worsened in men and remained stable in women. PMID- 7860176 TI - Short-term effects of air pollution on daily mortality in Athens: a time-series analysis. AB - BACKGROUND: Athens has a serious air pollution problem which became evident in the early 1970s. Studies for the years 1975-1982 have indicated a positive association of sulphur dioxide (SO2) with total daily mortality. Since 1983 the pollution profile in Athens has gradually changed but the levels of smoke, SO2 and carbon monoxide (CO) remain relatively high. METHODS: The association of air pollution with daily all-cause mortality in Athens for the years 1984-1988 was investigated using daily values of SO2, smoke and CO. Autoregressive models with log-transformed daily mortality as the dependent variable, were used to adjust for temperature and relative humidity (both lagged by 1 day), year, season and day of week, as well as for serial correlations in mortality. RESULTS: Graphic analysis revealed non-linear monotonically increasing relationships between total mortality and SO2, smoke and CO, with steeper exposure-response slopes at lower air pollution levels. Air pollution data lagged by 1 day had the strongest association with daily mortality. In three separate autoregression models for log(SO2), log(smoke) and log(CO) the regression coefficients for each were highly statistically significant (P < 0.001). Further multiple regression modelling showed that SO2 and smoke are both independent predictors of daily mortality, though to a lesser extent than temperature and relative humidity. The inclusion of CO in the model did not further improve the prediction of daily mortality. The magnitude of association is small, for instance, a 10% reduction in smoke is estimated to decrease daily mortality by 0.75% (95% confidence interval [CI]: 0.51-0.99). However, it cannot be accounted for by climatic and seasonal effects, so that a causal influence of air pollution on daily mortality seems plausible. CONCLUSIONS: These findings suggest that current air pollution levels in Athens (and many other industrialized cities) may be responsible for substantial numbers of premature deaths, and hence remain an important public health issue. PMID- 7860177 TI - Deaths due to flash floods in Puerto Rico, January 1992: implications for prevention. AB - BACKGROUND: In January 1992, the Commonwealth of Puerto Rico sustained unusually heavy rainfall, which caused flash floods and deaths. METHODS: We conducted a descriptive study and a case-control study to determine the circumstances of these deaths and to identify mortality-prevention strategies. We describe the time, place, and circumstances of each death, and compare this information with water-level and rainfall data and the timing of warnings. Using controls selected from the affected population, we estimated the risk of death by age, sex, and vehicle occupancy during the flood. RESULTS: Within 7 hours, 23 people died in 17 incidents; 20 of the decedents (87%) were occupants of motor vehicles. The estimated risk of mortality was significantly elevated for motorists (odds ratio = 16, 95% confidence interval: 3.5-144). Being in a vehicle to evacuate a flash flood area was protective; however, being in a vehicle during the flood for other reasons further increased the risk of mortality. Deaths occurred early during the rapid rise of water and before official warnings were issued. CONCLUSION: We recommend improving the sensitivity of the warning system and its ability to disseminate appropriate information rapidly. We also recommend educating officials and the public about the risks of driving on flooded roads and in potential flash flood conditions; and about the unique flash flood risks associated with specific topographical features in their region. PMID- 7860178 TI - Lifetime prevalence estimates of pathological gambling in New Zealand. AB - BACKGROUND: Legalized gambling has proliferated recently in many countries and is a public health issue because of the association between gambling participation and the prevalence of pathological gambling. Relatively little is known about the epidemiology of this disorder or the characteristics of pathological gamblers living in the community. This paper summarizes the major findings of a national prevalence survey of pathological gambling conducted in New Zealand; the first national survey to have been conducted to date, and compares them with the results of studies undertaken in the US and Canada. METHODS: A national adult sample of 4053 people was interviewed by telephone to determine involvement in gambling activities. The interview included the South Oaks Gambling Screen (SOGS) for pathological gambling. RESULTS: Of the sample, 2.7% (+/- 0.5%) scored as probable pathological gamblers and a further 4.2% (+/- 0.6%) scored as problem gamblers. These prevalence rates are higher than those reported in previous studies using the SOGS. Ethnicity, age, gender, employment status, having a parent who had gambling problems and regular participation in continuous forms of gambling were major risk factors. CONCLUSIONS: In New Zealand pathological gambling appears to have a lifetime prevalence approximately half that of drug abuse/dependence. The findings suggest that prevalence has increased in recent years and provide a baseline for further study. The risk factors identified give a focus for future research into aetiology, prevention and treatment. PMID- 7860179 TI - Comparison of dietary habits, physical activity and body size among Chinese in North America and China. AB - BACKGROUND: Chinese in North America have higher rates of many chronic diseases than do Chinese in Asia. However, there is a lack of data among comparisons of the environmental and lifestyle factors for Chinese in China and Chinese residing in North America. METHODS: We examined self-reported dietary nutrient intakes, physical activity patterns and body mass index of 2488 healthy Chinese men and women residing in North America (US and Canada) and in the People's Republic of China. RESULTS: On average, Chinese in China consumed more calories (males 2904 kcal in China, versus 2201 kcal in North America; females 2317 Kcal in China, versus 1795 Kcal in North America and more carbohydrate, but less fat (males 72.2 g in China versus 84.5 g in North America, females 56.6 g in China versus 70.8 g in North America), protein, vitamin A, beta-carotene and vitamin C than did Chinese in North America. Per cent calories from fat was 35% for Chinese in North America and 22% for Chinese in China. In contrast, the per cent of calories from carbohydrates was 62-68% in China and 48% in North America. Chinese in China reported spending more time in vigorous activity, sleeping and walking but less hours in sitting than Chinese in North America. Chinese in China weighted less and were leaner than North American Chinese. CONCLUSIONS: These differences in nutrient intakes, physical activity and body size of Chinese living on two different continents suggest possible explanations for observed differences in chronic disease rates in the two populations. PMID- 7860180 TI - Reproducibility and validity of a self-administered physical activity questionnaire. AB - BACKGROUND: The reproducibility and validity of self-administered questionnaires on physical activity and inactivity were examined in a random (representative) sample of the Nurses' Health Study II cohort and a random sample of African American women in that cohort. METHODS: Repeat questionnaires were administered 2 years apart. Past-week activity recalls and 7-day activity diaries were the referent methods; these instruments were sent to participants four times over a 1 year period. RESULTS: The 2-year test-retest correlation for activity was 0.59 for the representative sample (n = 147) and 0.39 for the African-American sample (n = 84). Correlations between activity reported on recalls and that reported on questionnaire were 0.79 and 0.83 for the representative and African-American samples, respectively. Correlations between activity reported in diaries and that reported on questionnaire were 0.62 and 0.59, respectively. Test-retest coefficients for inactivity were 0.52 and 0.55, respectively. Correlations between inactivity reported in diaries and that reported on questionnaire were 0.41 and 0.44, respectively. CONCLUSION: The simple, short questionnaires on activity and inactivity used in the Nurses' Health Study II are reasonably valid measures for epidemiological research. PMID- 7860181 TI - [Effectiveness (accessibility and compliance) of a program of early diagnosis of pulmonary tuberculosis in a penitentiary population]. AB - The aim of the study was to determine the effectiveness of a pulmonary tuberculosis detection Program in a Spanish prison (280-320 inmates) with a high turn-over rate (500 entries annually). 754 prisoners without antituberculous chemotherapic or chemoprophylaxis were included. 642 (85.1%) had access to the Program; the highest percentage of access was obtained when tuberculin test was performed at the entrance (96.4%) versus 80.5% when it was differed (P < 0.000001). The compliance observed was 82.2%, with no evidence that a greater accessibility was influential al all. The effectiveness was 70%, greater when tuberculin test was performed at the entrance in prison (76.7%) versus 66.8% when it was differed (P < 0.000001). We conclude that since pulmonary tuberculosis rates in prisons are so high and since it is possible to obtain a high effectiveness in detection programs, if were generalize these programs in concurrence with an adequate treatment of tuberculosis cases we shall obtain high efficiency rates. PMID- 7860182 TI - [Evolution of cesarean section rates in Spain: 1984-1988]. AB - The objective of this work is to describe the evolution of cesarean section rates in Spain from 1984 through 1988. National rates increased from 9.92% to 19.99%. Trend is significantly rising nationwide and in all Communities. Overall differences have decreased (CSV from 1.73 to 11.72) because there are two groups of regions: one with high rates, the other one with low rates. Rates are significantly higher in private hospitals (14.53%). These differences could show the controversy and uncertainty in the indications and the influence of organizational factors. Although new sources of information to obtain population rates and outcomes studies adjusted by women clinic and sociodemographic characteristics are due to be developed, these differences lead to suspect that there is a gap between the theoretic quality medical science could provide and the actual quality medical practice is providing, explained just by reasons out from clinical factors. PMID- 7860183 TI - [Survival of women with breast cancer in a hospital-based registry (1979-1991)]. AB - We analyzed the survival of 268 women diagnosed with breast cancer between 1979 and 1991, registered at the Tumour Registry of the Hospital S. Jaume i Sta. Magdalena, Mataro (Barcelona). Relative survival rates at two, five and ten years were 0.84, 0.69 and 0.49, respectively. The largest difference in survival was observed in relation to the stage at the time of diagnosis. The survival was worse in women aged between 30 and 39 years and between 80 and 89 years. No significant differences were observed in survival in relation to the interval from first symptoms to diagnosis. The survival at 5 years shows some trend towards improvement during the period between 1979 and 1986. PMID- 7860184 TI - [Geographical analysis of cancer incidence in the Autonomous Community of the Basque Country]. AB - With the aim of improving knowledge about the geographical distribution of malignant tumors in the Autonomous Community of the Basque Country, incidence rates standardized by age of the 13 most frequent cancer types in each sex were analyzed, in relation to the 27 geographical regions the Community was divided into. In order to carry out this population based descriptive study correspondence analysis was used. By retaining the first two factors 42% of the variance was explained in the case of men, and 40% in the case of women. The main finding in the male sex was the marked inequality between Rural Alava and the Mining Area of Bizkaia. The latter was characterized by lymphomas and neoplasms of larynx, and the former by neoplasms of pancreas and prostate and leukaemias. It was also found a geographical pattern distinguished by the difference among regions located in the coast and those located in the inner. This last pattern was the most relevant result in the female sex, cancer of oral cavity, malignant melanoma of skin and leukaemias being responsible for the coast pattern, and neoplasms of gallbladder, lung and stomach for the inner pattern. The findings of this study confirm the interest of Correspondence Analysis as an exploratory method and may encourage other investigators to use it much more frequently. PMID- 7860185 TI - [Formation of a cohort of opiate addicts through linkage of confidential records]. AB - The need to combine several files in order to create a cohort of opiate addicts, sufficiently large for the analysis of its mortality, requires use of the probabilistic method of record linkage. This study is a preliminary phase in which two sub-files of the Hospital del Mar (Barcelona) Register of toxicological emergencies are linked. This phase served to adapt probabilistic record linkage to our files, develop computer programs, define agreement criteria, and evaluate the validity and performance of the method. In order to safeguard confidentiality, identification variables were limited to sex, birth date and three initial letters from each surname. The automated probabilistic linkage was seen to be feasible, valid and efficient; in contrast to deterministic approaches, sensitivities and specificities above 95% were obtained with visual reviewing of under 5% of the records. Difficulties encountered during the process are discussed. PMID- 7860186 TI - [Simulation of a hospital emergency department and its potential use in management]. AB - We developed a computer simulation model of Emergency Department Operations of the Hospital Ntra. Sra. del Pino as a queue system. We designed and analyzed alternative functional structures of the Department and their implications on resources organization and reallocation. We programmed the operations, relations and flows between the components of the system with the simulation language SIMSCRIPT II.5. We have designed alternative configurations to assess how technical efficiency could be improved through the reallocation of human resources; how the system react would to interarrival time of patients changes; and what decisions must be taken about resources allocation in order to improve efficiency. Triage, Emergency Laboratory and radiology have the maximum average waiting times (11, 31 and 12 minutes, respectively). Some alternative organization patterns may improve this problem. Their social cost is also quantified in this work. PMID- 7860187 TI - [Health crisis or crisis of medicine?]. AB - The paper compares the existence of a crisis of medicine (characterised by a lack of assessment mechanisms of the medical treatment outcomes and their health alternatives) with a health crisis (characterised by the existence of health's determinants outside the health service area and the increase in the health demand) and the need to search for adequate solutions in order to solve them. We approach the problem from different standpoints. First, we search for ideas in the free market. Second, we propose several considerations on the "Health Maintenance Organisation" (HMOs) in the USA as well as on their limitations. Third, we study the radical proposals of change in Spain, Holland and the United Kingdom with the problems that competition can bring about, emphasizing the current difficulties in the British reforms and the lessons to consider from the Spanish case. Finally, the author concludes by pointing out the need for a more efficient use of resources and a better choice of priorities in Health. PMID- 7860188 TI - Herpes simplex virus hepatitis and related problems. PMID- 7860189 TI - The management and biological behavior of Wilms tumor. PMID- 7860190 TI - Perspectives on the endoplasmic reticulum as an "architectural editor" with special reference to human chondrocytes and osteoblasts. PMID- 7860191 TI - Regulation of intracellular protein degradation with special reference to lysosomes: role in cell physiology and pathology. PMID- 7860192 TI - Brown tumour as a complication of secondary hyperparathyroidism in uraemia: a case report. AB - A 15-year-old girl who developed "brown tumour" as a complication of secondary hyperparathyroidism while on maintenance haemodialysis therapy is described. Parathyroidectomy with implantation of a portion of one parathyroid gland was performed. Recovery of the lesion was noted 6 months after surgery and a ratio of about 1/12 was found when the systemic parathormone level was compared to that obtained from the vein draining the implanted parathyroid tissue. We would like to emphasize that signs and symptoms of secondary hyperparathyroidism should be sought for before complications develop; and if medical therapy is unsuccessful, this type of surgery is a justified option. PMID- 7860193 TI - The characteristics of urolithiasis in east Thrace: a statistical review. AB - During a 6-year period 390 patients with urinary tract calculus were studied: 293 had upper and 38 had lower urinary tract calculi. Of these, 59 passed their stones spontaneously on conservative therapy, 294 were treated surgically and 37 stones were removed by endoscopic means. Of the patients 10.54% had a history of urolithiasis, 5.34% reported family history. In contrast to the common belief, the highest admission rate was in winter. The male to female ratio was found to be 2.2:1, whereas it was equal (1:1) in childhood. The peak incidence was between the ages 30 and 39. Urinary tract infection and obstruction of varying severity were the common coexisting abnormalities. Calcium was the main component of both the upper and lower tract stones. Calcium oxalate+phosphate and calcium oxalate+struvite were the most common mixed stones. Blood typing did not reveal any specificity for urinary calculous disease. On the other hand, occupational groups leading a sedentary life were more prone to this malady. PMID- 7860194 TI - Carcinoma presenting as intrarenal haematoma, either spontaneously or after minor trauma. AB - When minor injury results in renal haematoma, evaluation must exclude an underlying malignant condition. Three cases and their diagnostic problems are presented. The value and limitations of ultrasonography, arteriography, percutaneous fine needle aspiration biopsy and CT-scan are discussed. PMID- 7860195 TI - Renal pelvic tumour diagnosed incidentally after traumatic rupture of hydronephrotic kidney. AB - A 27-year-old man was found to have a low grade transitional cell tumour of the renal pelvis at pathological examination of his traumatically ruptured kidney. The kidney was also hydronephrotic due to urolithiasis of long duration. The medicolegal aspects of the case are evaluated. PMID- 7860196 TI - Urolithiasis and phytotherapy. AB - The effects of seven plants with suspected application to prevent and treat stone kidney formation (Verbena officinalis, Lithospermum officinale, Taraxacum officinale, Equisetum arvense, Arctostaphylos uva-ursi, Arctium lappa and Silene saxifraga) have been studied using female Wistar rats. Variations of the main urolithiasis risk factors (citraturia, calciuria, phosphaturia, pH and diuresis) have been evaluated. It can be concluded that beneficial effects caused by these herb infusions on urolithiasis can be attributed to some disinfectant action, and tentatively to the presence of saponins. Specifically, some solvent action can be postulated with respect to uric stones or heterogeneous uric nucleus, due to the basifying capacity of some herb infusions. Nevertheless, for all the mentioned beneficial effects, more effective and equally innocuous substances are well known. PMID- 7860197 TI - Endoscopic transvaginal bladder neck suspension for stress urinary incontinence. AB - We report the short-term results in 23 women who underwent endoscopic transvaginal bladder neck suspension for stress urinary incontinence. During follow-up for 3-14 months (mean 6 months) complete dryness was achieved in 15 (79%) of the 19 patients. Significant improvement with only minor occasional leaks after surgery was observed in 2 patients (10.5%) and the remaining 2 cases (10.5%) were failures. Four patients were lost to follow-up. No serious complication was noted. This relatively easy operation with acceptable success and morbidity rates has been found to be comparable with the other surgical techniques being used. PMID- 7860198 TI - Adherence of Candida albicans to epithelial cells from normal and cancerous urinary bladders. AB - Patients with malignancies are at high risk to develop infections by Candida albicans. We have compared the adherence of C. albicans isolated from urine cultures to bladder epithelial cells obtained from healthy volunteers and patients with cancer of the bladder. The mean number of C. albicans adhering per epithelial cell from areas infiltrated from cancer was significantly higher as compared to cells obtained from intact areas of cancerous bladders and from normal bladders. The increased adherence of C. albicans to cancerous epithelial cells suggests that malignancies are associated with alterations of the epithelial cell surface which render the cells more susceptible to colonization by C. albicans. The increased colonization may predispose these patients to C. albicans infections. PMID- 7860199 TI - Selection of patients for intravesical therapy for superficial bladder cancer. AB - In a nonrandomized retrospective study, 133 patients with superficial transitional cell carcinoma of the bladder were evaluated to identify any clinical prognostic features which indicate the necessity of intravesical therapy (IVT). The risk factors taken into account were stage, grade and multiplicity of the tumour. All patients were treated initially by complete transurethral resection (TUR); 27 patients received no further treatment after resection of the tumour, 106 patients received adjuvant IVT over a period of 6 weeks. The mean follow-up was 23 and 18.8 months in the TUR-only group and TUR+IVT group, respectively. In the TUR-only group 7 and in the TUR+IVT group 29 recurrences were encountered. Patient group with no risk factors (Ta, GI, solitary tumour) or with only one risk factor revealed no statistical difference in terms of the recurrence rate from the identical control group. So it does not seem worthwhile to give additional therapy in the low-risk group. Another notable outcome of this study was that the higher the potential risk factors, the higher the likelihood of recurrence. The results suggest that T1 tumours, multifocal tumours, and high grade tumours have poor prognosis, making additional treatment necessary. PMID- 7860200 TI - A solitary and synchronous metastasis of renal cell carcinoma to the bladder. AB - We report a case of renal cell carcinoma with solitary metastasis to the bladder which occurred and was treated synchronously. The mode of spread and possible treatment modalities are discussed with relevant information from the literature. PMID- 7860201 TI - Cytomegalovirus prostatitis. Case report and review of the literature. AB - We report the case of a patient undergoing chemotherapy for multiple myeloma discovered to have cytomegalovirus prostatitis. The findings of a hypoechoic prostatic lesion on ultrasound and a slightly elevated prostatic specific antigen of 4.6 ng/ml prompted a prostate biopsy. Cytopathologic examination and immunohistochemical staining demonstrated cytomegalovirus within the prostate. This virus is a common pathogen in the immunosuppressed patient, but its presence in the male genital tract is relatively rare. No previous reports of biopsy proven cytomegalovirus prostatitis appear in the literature. The relationship of cytomegalovirus to the prostate is discussed in detail. PMID- 7860202 TI - The value of prognostic factors in prostatic cancer. AB - Several prognostic parameters of prostatic carcinoma needed to help guide treatment in individual patients are discussed. Tumour volume, nodal and bone metastases, grading, prostate-specific antigen and DNA ploidy have been correlated with prognosis. Recent studies have analysed tumour volume in detail. However, currently there is no single prognostic factor which can predict tumour aggressiveness on an individual patient basis to rationalize decisions. Multivariate analyses are therefore in progress to determine independent prognostic variables. PMID- 7860204 TI - Posterior urethral valves in an adult male. A case report. AB - A rare case is presented of an adult male with congenital posterior urethral valves with retained ejaculation. The development, diagnosis, and treatment of posterior urethral valves are discussed. PMID- 7860203 TI - Burned-out tumour of the testis presenting as retroperitoneal choriocarcinoma. AB - A case of "burned-out" tumour of the testis in a 20-year-old man is reported. The tumour presented as widespread retroperitoneal metastases. Orchiectomy displayed a subalbugineal fibrous scar close to the rete testis. Diagnostic biopsy of the unresectable retroperitoneal tumour showed a choriocarcinoma. Although appropriate chemotherapy was promptly started, the patient died 7 months after the initial complaints. PMID- 7860205 TI - Fracture of corpus cavernosum following penile venous surgery. A case report. AB - A rare complication of fracture of the corpus cavernosum following penile venous surgery is described here. Problems of diagnosis and management are briefly outlined. PMID- 7860206 TI - Unusual, benign asymptomatic scrotal masses in children: case reports and review of the literature. AB - Asymptomatic scrotal masses (ASM) in children constitute an entity of pathologies, ranging from congenital anomalies to neoplasms. Testicular ultrasound is the imaging modality of choice in the evaluation of ASM, although there is extensive overlap between benign and malignant lesions. Five children with ASM of benign origin are presented: 2 boys had extratesticular mass (one paratesticular lipoma and one voluminous sebaceous scrotal cyst); the remaining 3 patients had testicular mass (one supernumerary testis, one intratesticular cyst and one unilateral testicular hypertrophy). Basing on the ultrasonographic appearance, a certain diagnosis of benign lesion was made only in the last 2 cases; the remaining patients underwent explorative inguinotomy in order to rule out any malignancy. Some guidelines for proper diagnosis of ASM in childhood are proposed by the authors. However, at least in children, testicular preservation should not be based only on the sonographic findings, and surgical exploration is mandatory whenever the nature of the lesion remains unclear. PMID- 7860207 TI - Squamous cell carcinoma of the scrotum. AB - A patient complained of scrotal mass which was found to be a squamous cell carcinoma. There was no occupational exposure and nodal spread was not obtained. We present this rare case. PMID- 7860208 TI - Cytokine secretion by peripheral blood monocytes from patients with acute poststreptococcal glomerulonephritis. AB - We have measured the release of interleukin-1 beta (IL-1) and tumour necrosis factor-alpha (TNF) by unstimulated monocytes and monocytes stimulated with lipopolysaccharide (LPS) isolated from the peripheral blood of two patients with acute poststreptococcal glomerulonephritis (AGN) and 16 healthy controls. We have demonstrated that spontaneous and LPS-induced cytokine release correlated with disease activity in the AGN patients. We speculate that in vivo streptococcal infection itself may alter peripheral blood monocyte cytokine secretion. PMID- 7860209 TI - A case of severe anti-neutrophil cytoplasmic antibody (ANCA)-positive crescentic glomerulonephritis and asymptomatic gastric cancer. AB - A 64-year-old man presented with symptoms of systemic immune disease dominated by rapidly progressive glomerular injury with highly positive ANCA of cytoplasmic distribution. The clinical course was characterized by dependence upon the intensity of immunosuppression, which has finally led to development of fungal septicaemia and death. The post mortem examination revealed occult gastric cancer with regional lymphatic involvement and crescentic glomerulonephritis, while failing to substantiate clinical findings of systemic vasculitis. This is, to our knowledge, the first case of ANCA-positive glomerulonephritis accompanying visceral malignancy and as such raises the question of whether it results from a simple coincidence or a causal relationship. PMID- 7860210 TI - Cytomegalovirus infections in renal transplant patients. AB - The incidence of cytomegalovirus infection in Chinese patients was reviewed in a retrospective study of 99 renal transplant recipients. CMV infection occurred in 18 patients (18.2%). In 4 the infection was considered primary and in 14 it was thought to be reactivation. Of the infections 88.9% occurred within the first 6 months after transplantation, 44.4% were asymptomatic, while the rest had protean manifestations with the commonest combinations of fever, hepatic dysfunction and haematological abnormalities. One patient succumbed to the infection. Significant difference was seen in the incidence of CMV infections among patients who had received different antirejection therapy, being the highest (37%) among those who had received either Atgam or OKT3. Among the various secretions, urine gave the best yield of virus cultures. PMID- 7860211 TI - Serum immunosuppressive acidic protein in haemodialysis patients with and without acquired cystic disease of the kidney. AB - Serum levels of immunosuppressive acidic protein (IAP) were measured in 20 haemodialysis patients with acquired cystic disease of the kidney (ACDK) and in 44 without it. Serum IAP levels in haemodialysis patients with and without ACDK were significantly elevated compared to that in controls. However, there was no considerable difference between haemodialysis patients with and without ACDK. A significant reduction in this marker was not found after dialysis treatment. This indicates that elevation of IAP may be related to an increased incidence of renal cell carcinoma in haemodialysis patients. PMID- 7860212 TI - Phylogeny and ontogeny of chemical signaling: origin and development of hormone receptors. PMID- 7860213 TI - Cell and molecular biology of flagellar dyneins. PMID- 7860214 TI - Morphological and functional reorganization of human carcinomas in vitro. PMID- 7860215 TI - Growth factor-induced cell migration: biology and methods of analysis. PMID- 7860216 TI - Cellular and molecular effects of thymic epithelial cells on thymocytes during differentiation and maturation. PMID- 7860217 TI - Actin-binding proteins in cell motility. PMID- 7860218 TI - The cell biology of nematocysts. PMID- 7860219 TI - Impact of altered gravity on aspects of cell biology. PMID- 7860220 TI - Cellular resistance to cancer chemotherapy. PMID- 7860221 TI - Increased urokinase receptor levels in human gastrointestinal neoplasia and related liver metastases. AB - Human carcinomas of the oesophagus, stomach, colorectum, and their liver metastases were previously shown to have increased levels of the urokinase-type plasminogen activator (u-PA). The proteolytic activity of u-PA on the surface of tumour cells is thought to play a key role in invasion and metastasis of malignancies. Therefore, in this study we quantitatively determined the presence of specific u-PA receptors in human gastrointestinal carcinomas, premalignant colonic adenomas, liver metastases, and adjacent normal tissues. All carcinomas showed a 2- to 13-fold higher level of u-PA receptor than their corresponding normal tissues at both the antigen level (ELISA) and the mRNA level (Northern blotting). Colonic adenomas also showed enhanced levels of the u-PA receptor protein. The state of occupancy of the u-PA receptors was determined using a specific ligand-binding assay in which free u-PA receptors were cross-linked with 125I-u-PA and visualized by autoradiography. Colonic carcinomas and liver metastases contained higher levels of free u-PA receptor compared to their corresponding normal tissues. Acid treatment of the receptors prior to cross linking did not enhance the u-PA/u-PA receptor complex formation. The free u-PA receptor levels in colonic adenomas and in oesophageal and stomach carcinomas showed less difference compared with their normal reference tissues. The increased presence of specific receptors for u-PA in gastrointestinal carcinomas, particularly primary colonic carcinomas and their metastatic lesions in the liver, emphasizes the involvement of the urokinase pathway of plasminogen activation in gastrointestinal carcinogenesis and renders it a putative target for clinical intervention. PMID- 7860222 TI - Stimulation of the 92-kD type IV collagenase promoter and enzyme expression in human melanoma cells. AB - The 92-kD type IV collagenase is a member of the metalloproteinase family which degrades type IV collagen, a major component of basement membrane and is involved in tumor invasion and metastasis. The promoter and adjacent regulatory sequences of the 92-kD type IV collagenase have been identified previously and three cis acting elements homologous to the binding sites for AP-1, NF-KB and SP-1 proteins contributed to induction of the promoter activity by 12-O-tetradecanoylphorbol 13 acetate (TPA) and tumor necrosis factor (TNF-alpha) in HT1080 cells. To date, no direct correlation between promoter activity and expression of the 92-kD type IV collagenase has been reported in normal or cancer cells. In this study, the effects of the transcriptional stimulation of the 92-kD type IV collagenase gene on the expression of the enzyme in human A2058 melanoma cells was analyzed by zymography experiments. Quantitative immunoblots using a monoclonal antibody that recognized specifically and exclusively the 92-kD type IV collagenase, confirmed that the 92-kD gelatinase was 92-kD type IV collagenase. Stimulation of the promoter activity resulted in increased gelatinase activity in the culture medium of A2058 cells. A direct correlation between TPA- and TNF-alpha-mediated promoter stimulation of the 92-kD type IV collagenase gene and its expression was also demonstrated in the human fibrosarcoma HT1080 cells. Interleukin-1 alpha failed to induce 92-kD gene promoter activity and type IV collagenase expression in melanoma and fibrosarcoma cell lines. Our data demonstrated that TPA- and TNF alpha-induced 92-kD type IV collagenase promoter stimulation leads to a proportional increase of enzyme expression and secretion and thus could contribute to the activation of the invasive phenotype. PMID- 7860223 TI - Characterization of cysteine proteases and their endogenous inhibitors in MCF-7 and adriamycin-resistant MCF-7 human breast cancer cells. AB - The expression of three lysosomal cysteine proteases was examined in a lowly metastatic, MCF-7 human breast cancer cell line and its highly metastatic, Adriamycin-resistant variant, MCF-7/AdrR. While levels of cathepsin H activity were similar in all cell lines at each stage of growth, intracellular cathepsin B and L activities were highest in MCF-7/AdrR. These high levels were accompanied by growth-related increases in acid/pepsin-activatable cathepsin activity in the culture medium. Analyses of endogenous cathepsin B inhibitor activity in control and heat-treated cell homogenates after fractionation by fast protein liquid chromatography suggested that alterations in cystatin-like, cysteine protease inhibitor activities contribute to increased levels of cathepsin activities in metastatic MCF-7/AdrR cells. PMID- 7860224 TI - Metastasis of B16F10 mouse melanoma inhibited by lovastatin, an inhibitor of cholesterol biosynthesis. AB - Lovastatin (LST) is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) reductase, a rate-limiting enzyme that regulates the biosynthesis of cholesterol. This drug is used clinically to treat patients with hypercholesterolemia. Numerous studies have also suggested an important, if not essential, role of the cholesterol biosynthetic pathway to cell growth and proliferation. In fact, recent studies demonstrating the inhibitory effects of LST on various tumor cells have drawn much attention. We now describe a novel action of LST that inhibited experimental lung metastasis of the highly metastatic B16F10 mouse melanoma in nude mice. Further, when used in in vitro studies, LST pretreatment of B16F10 cells resulted in inhibition of attachment, motility, and invasion, which are key steps in the dynamic sequence of events that comprise the metastatic cascade. Our studies also suggested that the antimetastatic effect of LST on B16F10 cells is probably not mediated by a growth inhibitory action. We submit that these observations identify an antimetastatic agent with potentially useful clinical application. PMID- 7860225 TI - Prostate tumor cell invasion: a comparison of orthotopic and ectopic models. AB - Interest in orthotopic models has been generated by recent reports of increased invasive and metastatic potential demonstrated by tumor cell lines following injection into their tissue of origin rather than subcutaneously. We have previously demonstrated that transfection of the tumorigenic human prostate cell line, Du-145, with the metalloproteinase matrilysin increased its ability to invade the diaphragm following an intraperitoneal injection. In this study we compare the invasive and metastatic behavior of transfected Du-145 cell lines injected into the dorsal lateral lobe of the prostate to that observed when they are injected intraperitoneally. Immunohistochemistry was used to examine 37 orthotopically injected severe combined immunodeficient mice for local invasion and metastatic lesions. In addition, the effect of injection site on the level of expression of four genes thought to influence the invasiveness of tumor cells (matrilysin, stromelysin, TIMP-1, and TIMP-2), was determined by northern analysis of orthotopic and subcutaneous tumor tissue. The results demonstrate that the level of mRNA expression of the genes examined was similar at the two sites of injection and that the invasive properties of Du-145 cells following orthotopic implantation were comparable to that observed on the diaphragm following intraperitoneal injection. The advantages of the diaphragm invasion model are: less procedure-related mortality, ease of cell delivery, and provision of an easily orientated structure in which the earliest penetration of a basal lamina can be observed. PMID- 7860226 TI - Phase I and pharmacologic study of liposomal daunorubicin (DaunoXome). AB - We have completed a phase I and pharmacology study of liposomally-encapsulated daunorubicin (DaunoXome). Of 32 patients entered, 30 were evaluable. No toxicity was encountered at the initial dose-escalation steps from 10 to 60 mg/m2. At 80 mg/m2, two patients manifested grade 2 neutropenia. At least grade 3 neutropenia occurred in all patients receiving 120 mg/m2. Alopecia and subjective intolerance were mild. Cardiotoxicity was not observed except for an episode of arrhythmia in a patient with lung cancer and prior radiation. Only one minor objective response was observed in this population of refractory solid tumors. Pharmacokinetics differed from those of the free drug with no detection of daunorubicinol. We recommend future phase II studies with a dose of 100 mg/m2 in previously treated and 120 mg/m2 of DaunoXome in previously untreated patients with solid tumors. PMID- 7860227 TI - Weekly gemcitabine in advanced or metastatic solid tumors. A clinical phase I study. AB - Gemcitabine (GEM) is a novel deoxycytidine analogue which has shown promising antitumor activity in solid tumor models and a broad range of schedule-dependent MTDs (12-4560 mg/m2) in preliminary clinical studies. The present phase I trial evaluated escalating doses of weekly GEM using a 30-min infusion at a starting dose-level of 300 mg/m2/wk x 3 every 28 days. At least 3 patients entered each dose-level step and 3 more cases were treated when significant toxicity was seen. A total of 39 patients with various advanced solid tumors and prior chemotherapy entered this study. Six escalation steps (102 courses) were tested to define the MTD at 1,370 mg/m2/wk. No definite dose-effect relationships were observed for myelosuppression up to 1,095 mg/m2/wk. However, increased severity of leucopenia (dose-limiting) and greater non-hematologic toxicity as well as a higher number of toxic treatment delays, requiring subsequent dose attenuation in 6 out of 12 patients, were observed at 1,370 mg/m2/wk. In all, 6 out of 11 patients experiencing WHO grade > or = 3 toxicity (11/21 events recorded in 11/18 courses) were treated at the MTD. Clinically significant toxicity included (patients with WHO grade 2-3): leucopenia (44%), thrombocytopenia (26%), anemia (23%), fever (69%), emesis (38%) and AST/ALT rise (26%). Mild proteinuria, ankle edema, skin rash, hair loss and mucositis were seen in < or = 5%.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7860229 TI - Phase II evaluation of mitoxantrone plus cis-platinum in patients with advanced breast cancer. A Southwest Oncology Group study. AB - The Southwest Oncology Group studied the response rate and toxicity of mitoxantrone (7.5 or 10 mg/m2 to 12.0 mg/m2) and cis-platinum (100 mg/m2) in 30 patients with advanced breast cancer as second-line therapy. There were 2 partial responses in 29 eligible patients. Toxicity was considerable, with 27 patients having grade 3 or 4 toxicity. Grade 3-4 toxicity included vomiting, thrombocytopenia, granulocytopenia, leukopenia and anemia. The combination of mitoxantrone plus cis-platinum has minimal activity as second-line therapy in metastatic breast cancer. PMID- 7860228 TI - Efficacy of prednisone in refractory multiple myeloma and measurement of glucocorticoid receptors. A Southwest Oncology Group study. AB - BACKGROUND: Prednisone is an active drug in the treatment of multiple myeloma. The optimal dose, frequency, and role of glucocorticoid receptors (GR) in response to prednisone is unknown. PURPOSE: The purposes of this study were (1) to estimate the response rate of alternate-day high dose prednisone in patients with relapsing and refractory multiple myeloma; (2) to measure the rate of GR levels; and (3) to correlate the response of prednisone with GR status. PATIENTS AND METHODS: Between 8/86 and 1/90, 127 patients were entered onto the study with 121 evaluable for response. The number of GR sites/cell was determined on mononuclear cells isolated from pretreatment bone marrow aspirates using a one point GR binding assay. Patients received prednisone 100 mg po qod x 2 weeks, followed by 50 mg po qod x 10 weeks. RESULTS: The overall response rate was 10% (95% CI: 5-15%) with a median survival of 11.8 months. The GR sites/cell ranged from 0-53,212 with a mean of 8,371 sites/cells. Stratification of GR sites into 0 2,500, 2,501-6,000 and > 6,000 sites/cells was associated with a response rate of 6%, 27% and 4% respectively (p = 0.009). The median survival of patients in these categories was 8.1, 14.9 and 10.6 months respectively. This was not significant by the logrank test (p = 0.11). Although myeloma patients with intermediate levels of GR sites/cell initially responded more favorably to prednisone, their long-term survival was not significantly improved. CONCLUSIONS: Alternate-day high-dose prednisone was well tolerated and may provide palliative benefit for a subset of patients with relapsing and refractory multiple myeloma. The survival of patients on this study was comparable to that reported with other but more toxic doses of glucocorticoids. PMID- 7860231 TI - A phase II study of vinblastine in combination with acrivastine in patients with advanced renal cell carcinoma. AB - Renal cell carcinoma exhibits chemoresistance attributable in part to the P glycoprotein drug efflux mechanism. Acrivastine is a hydrophylic antihistamine that has been shown in vitro to reverse this form of resistance. After five patients were treated on a dose-finding study, seventeen patients with metastatic or unresectable renal cell carcinoma were entered into a phase II study of vinblastine in combination with acrivastine. Patients received oral acrivastine at doses of 400 mg every 4 hours for 6 days and a 96-hour continuous infusion of vinblastine at a dose of 1.6 mg/m2/24 h. Of 15 evaluable patients, no tumor responses were seen. The regimen was well-tolerated with the majority of toxicities being gastrointestinal and hematologic. Serum levels of acrivastine, its principal metabolite (270C81) and vinblastine were measured during the study. Based on in vitro data, the plasma levels of acrivastine were within a range adequate to block P-glycoprotein activity. High doses of acrivastine were well tolerated clinically, however, the combination of acrivastine and vinblastine was not active against renal cell carcinoma. PMID- 7860230 TI - Phase II trial of intravenous melphalan in advanced colorectal carcinoma. AB - BACKGROUND: Relatively few studies have examined the activity of alkylating agents in the treatment of advanced colorectal adenocarcinoma. Recent reports have suggested possible therapeutic activity for high-dose intravenous melphalan administered with autologous bone marrow transplantation (BMT) support. We conducted a phase II study to determine the efficacy of administering intravenous melphalan at doses that do not require BMT support in patients with advanced colorectal adenocarcinoma. PATIENTS AND METHODS: Fifteen patients with histologically proven, bidimensionally measurable disease were treated. The starting dose of melphalan was 30 mg/m2, with dose escalation permitted. RESULTS: No objective responses were observed. Toxic effects were primarily reversible granulocytopenia and thrombocytopenia. There were no treatment-associated deaths. CONCLUSION: Melphalan's lack of efficacy at the doses administered does not disprove the steep chemotherapy dose-response relationship postulated for many solid tumors. However, we feel that it is unlikely that repetitive courses of high dose melphalan with autologous BMT support will be a practical approach to the management of advanced colorectal adenocarcinoma. PMID- 7860232 TI - Phase II trial of topotecan in patients with advanced renal cell carcinoma. AB - Fifteen patients with advanced renal cell carcinoma were treated on a phase II trial with topotecan. None of the fourteen evaluable patients achieved a complete or partial response. Myelosuppression was the most common toxicity. Eighty percent (12 of 15) of patients experienced grade III or IV neutropenia and/or anemia. Topotecan is not efficacious in the treatment of advanced renal cell carcinoma. PMID- 7860233 TI - Phase II evaluation of merbarone in renal cell carcinoma. AB - The Southwest Oncology Group (SWOG) studied the response rate and toxicity of merbarone (1,000 mg/m2 IV continuous infusion days 1-5, q 21 days) in patients with advanced metastatic renal cell carcinoma. Among 36 eligible patients, there was one partial response for a response rate of 3% (95% C.I. 0.1-15%). There were no mixed responses. There were no treatment related deaths or adverse drug reactions. Significant anemia, diarrhea, and hypercalcemia were observed. Mild to moderate degrees of malaise/fatigue/lethargy, dizziness/vertigo, hyperglycemia, creatinine increase, nausea, vomiting, weight loss, pedal edema, dyspnea, and granulocytopenia were noted. Merbarone does not have significant activity as a single agent in advanced renal cell carcinoma. PMID- 7860234 TI - Phase II study of echinomycin in the treatment of renal cell carcinoma ECOG study E2885. AB - Seventeen patients were treated with echinomycin for metastatic renal cell carcinoma. Echinomycin is a bifunctional DNA intercalating agent with broad preclinical antitumor activity. It was given at 1200 mg/m2 by intravenous infusion over 30-60 min weekly for 4 weeks. The treatment was repeated every 6 weeks. There were no responses observed in the study. No life threatening or lethal toxicity was documented in 13 eligible patients. The median survival of these patients was 13.7 months. We conclude that echinomycin is not active against metastatic renal cell carcinoma at the dose and schedule tested. PMID- 7860235 TI - Phase II trial of trimetrexate in untreated advanced gastric carcinoma. A Southwest Oncology Group study. AB - Twenty-three evaluable patients with advanced gastric adenocarcinoma were treated with trimetrexate at doses of 8-12 mg/m2 intravenously daily for five days, with cycles repeated every 21 days. One complete response was seen for an overall response rate of 4% (95% confidence interval 0-22%). Hematologic toxicities of grade > or = 3 were seen in 10/23 patients, and overall any grade 3 or greater toxicity was seen in 14/23 patients. Trimetrexate has minimal activity against gastric adenocarcinoma in this study, and no further investigation of this agent at this dose and schedule is recommended in this disease. PMID- 7860236 TI - Phase II trial of piroxantrone in gastric carcinoma. A Southwest Oncology Group study. AB - Twenty-one evaluable patients with advanced gastric adenocarcinoma were treated with piroxantrone at a dose of 150 mg/m2 intravenously every 21 days. One objective response was seen for an overall response rate of 5% (95% confidence interval 0-24%). Toxicities of grade > or = 3 were primarily hematologic and seen in 13/21 patients. Piroxantrone has minimal activity against gastric adenocarcinoma and no further investigation of this agent on this schedule in this disease is recommended. PMID- 7860237 TI - Growth-inhibitory properties of novel anthracyclines in human leukemic cell lines expressing either Pgp-MDR or at-MDR. AB - The objective of the experiments reported in this paper was the identification of promising anthracycline analogs on the basis of lack of cross-resistance against tumor cells presenting either P-glycoprotein multidrug resistance (Pgp-MDR) or the altered topoisomerase multidrug resistant (at-MDR) phenotype. Differently modified anthracycline analogs known to be active against MDR cells were assayed in vitro against CEM human leukemic cells, and the sublines CEM/VLB100 and CEM/VM 1 exhibiting respectively the Pgp-MDR and the at-MDR phenotype. Two classes of molecules, in which the -NH2 group in C-3' position is substituted with a morpholino, methoxymorpholino (morpholinyl-anthracycline), or an alkylating moiety, present equivalent efficacy in the drug-sensitive and the two drug resistant sublines. These results indicate that such molecules may exert their cytotoxic effect through a mode of action different from that of "classical" anthracyclines and is not mediated through topoisomerase II inhibition. Both molecules represent novel concepts in the field of new anthracyclines derivatives. PMID- 7860240 TI - Break the silence, begin the cure. PMID- 7860239 TI - A mass media reality check. PMID- 7860238 TI - Evaluation of the methemoglobinemia associated with sulofenur. AB - A new class of antineoplastic agents, the diarylsulfonylureas entered clinical trials with the testing of Sulofenur (LY186641). Phase I trials and preclinical studies showed the dose limiting toxicity to be methemoglobinemia. We studied the incidence of methemoglobinemia, sulfhemoglobinemia and cytochrome b5 reductase deficiency in nine consecutive patients enrolled in a phase II trials using Sulofenur. The specific Malloy method as well as clinically standard co-oximeter measurements were used to determine methemoglobin levels and marked discrepancies were noted. One patient with symptomatic methemoglobinemia had enzyme levels and family history consistent with a heterozygous state for a cytochrome b5 reductase deficiency. We conclude that the clinical incidence of methemoglobinemia will be overestimated by co-oximeter measurements but that Sulofenur does produce clinically significant methemoglobinemia in cytochrome b5 reductase deficient patients. PMID- 7860241 TI - Finding the right words. PMID- 7860242 TI - Why do they stay? PMID- 7860243 TI - A survivor's story. PMID- 7860244 TI - Who are the batterers? PMID- 7860246 TI - Understanding domestic violence. PMID- 7860245 TI - A child's perspective on abuse of a parent, by a parent. PMID- 7860247 TI - A world of violence. PMID- 7860248 TI - Healing diversions. PMID- 7860249 TI - Watch for red flags. PMID- 7860250 TI - Prospects for achieving the national target on smoking prevalence by the year 2000. PMID- 7860251 TI - Women and arthritis. PMID- 7860252 TI - Management of acute exacerbations of rheumatoid arthritis. PMID- 7860253 TI - The role of a female urodynamics clinic. PMID- 7860255 TI - Hormone replacement therapy and breast cancer--current controversies. PMID- 7860254 TI - Guidelines in choosing a contraceptive pill. PMID- 7860257 TI - HIV and psychiatry. PMID- 7860256 TI - Conservative management of osteoarthritis of the hip. PMID- 7860258 TI - Alcohol related problems in elderly people--a prospective study. AB - Alcohol related problems in elderly people are often difficult to diagnose because of denial and non specific presentation in this age group. This study examines the factors related to alcohol abuse in elderly people referred to a psychiatry of old age service over a six month period. Patients were specifically screened for alcohol related psychiatric, physical and social problems. Of the 150 patients referred, 23 (15%) had alcohol related problems, with 12 (52%) denying any history of alcohol abuse/dependence. The majority were female (15/23, 65%), of which 10 were late-onset drinkers. Loneliness was found to be a contributory factor in 10 (43%) patients. A large proportion of patients had physical, psychiatric and social problems related to alcohol. Twenty one patients (91%) required psychiatric follow-up. In conclusion, this study confirms elderly peoples vulnerability to the destructive effects of alcohol. PMID- 7860259 TI - "Cead Mile Failte"--an assessment of the screening of 178 Bosnian refugees to Ireland. AB - The number of refugees in Western Europe has risen dramatically. Such an increase poses unique challenges for all health personnel. This paper describes how the Republic of Ireland, a country with little experience of refugees, initially coped with 178 Bosnian refugees. An open-access general practitioner service was combined with a general screening protocol. Patients with significant problems tended to visit GP's, for appropriate treatment, soon after arrival. Of a total of 92 problems diagnosed at screening, general medical (14%), psychiatric (14%) and gynaecological (11%) were the most frequently encountered. Of the 30 problems referred, 80% were referred by a GP. Deficiencies in immunisation and drug history are highlighted. We make recommendations to improve the quality of future initial refugee assessment procedures. PMID- 7860260 TI - Small area analysis of low birth weight. AB - Birthweight is a broad indicator of health and socio-economic development in a population. This study was designed to examine small area patterns in the incidence of low birthweight in Dublin for the years 1986-89 and to explore the relationship between low birthweight and socio-economic factors. A number of district electoral divisions with a significantly raised incidence of low birthweight were identified. These were mainly in areas with a high proportion of local authority housing. There was significant positive correlation between the incidence of low birthweight and male unemployment, percentage of population in social classes 5 & 6 and proportion of population covered by medical cards, and a significant negative correlation with percentage of population in social classes 1 & 2 and number of cars per house. Forward stepwise multiple regression showed that the proportion of population covered by medical cards was the best predictor of low birthweight, but it only explained 22% of the total variance. These findings are consistent with previous work published in the international literature and provide evidence of an association between socioeconomic disadvantage and poor health in Dublin. PMID- 7860261 TI - A review of vascular rings 1980-1992. AB - Over a period of 13 years 21 patients between the ages of three weeks and 13 years presenting to this centre had a vascular ring. A double aortic arch was present in 11 cases, a right aortic arch with a retroesophageal left subclavian artery in five cases, a right aortic arch with a normal left innominate artery, a Kommerell's diverticulum and a left ligamentum arteriosum encircling the trachea and oesophagus occurred in two cases and an aberrant left pulmonary artery arising from the right pulmonary artery occurred in three cases. The majority (19/21) presented with a history of chronic stridor, although other significant associated symptoms included: recurrent respiratory infection, wheeze, cyanotic episodes and difficulty or pain on swallowing. The barium swallow was the most useful method of investigation and was diagnostic in all of the 95% of cases in which it was performed. Nineteen patients underwent surgery uneventfully although stridor often remained a problem for some time following repair. Six patients (28%) had associated congenital heart disease. Three (14%) patients who did not have surgery died. PMID- 7860262 TI - Oropharyngeal dysphagia--the need for effective management. AB - Increasing international recognition of the high incidence of oropharyngeal dysphagia has incited Speech and Language Therapists to establish a service for the management of this life-threatening disorder. This study evaluates the first such Irish service instigated in St. James's Hospital four years ago. Retrospective analysis of Speech and Language Therapy departmental records for a twelve month period examined incidence of referral for dysphagia, subsequent clinical and objective assessment findings and management recommendations. A referral rate of 52% emerged with a mean of 74 years. CVA was found to be the commonest etiology. Therapeutic intervention was implemented with 68% of dysphagic subjects considered suitable candidates and improvement evidenced in 78% of treated cases. These results highlight the prevalence of oropharyngeal dysphagia in a neurologically impaired Irish adult population and the efficacy of a dysphagia service in its management, while categorically stating the need for such service provision nationwide. PMID- 7860263 TI - The capacity of dogs to serve as reservoirs for gastrointestinal disease in children. AB - A total of 40 Canine faecal specimens were collected from 10 different halting sites in the Dublin area. Specimens were taken from the site surface. The sites were determined by laboratory confirmed gastroenteritis infections reported in children. Each stool specimen was primarily examined for Giardia and Cryptosporidium but was also analysed for the presence of bacterial enteropathogens. The occurrence of canine zoonoses was not established, however the 40% prevalence of Giardia coupled with the 30% prevalence of bacterial enteropathogens on these sites support the supposition that dogs are a potential source of gastroenteritis infections in children within the travelling community. The potential dangers of zoonotic transmission as demonstrated by this survey must be acknowledged. PMID- 7860264 TI - Antenatal intraventricular haemorrhage. AB - Germinal matrix-intraventricular haemorrhage (IVH) is a well described complication of premature birth. We present two infants with severe IVH in the absence of other serious neonatal illness. These lesions probably occurred antenatally and prior to the onset of labour. Unrecognised intrauterine stresses may cause intraventricular haemorrhagic or ischaemic lesions in the immature brain. Timing of these lesions is important for both clinical and indeed medico legal reasons. PMID- 7860265 TI - Factors associated with delay to treatment for acute myocardial infarction in Ireland. AB - Irish data from the ISIS-2 multi-centre study of thrombolytic therapy has indicated longer delays to treatment for acute myocardial infarction (AMI) than in other countries (7.9 vs 6.9 hours, p < 0.001). Further examination of this database (n = 831 patients) found no influence of age and sex of patient on delay times. Distance from hospital was not associated with delay while previous experience of MI was marginally associated with decreased delay (previous MI: 7.1 vs no previous MI: 8 hours, p = 0.06). These relatively lengthy Irish delays require further investigation to inform management strategies aimed at reducing delay. PMID- 7860266 TI - Superovulation treatment for in-vitro fertilization. PMID- 7860267 TI - Pulmonary echinococcal disease. PMID- 7860268 TI - Advance care planning. Priorities for ethical and empirical research. PMID- 7860270 TI - Increasing the prevalence of advance care planning. PMID- 7860269 TI - Recognizing good decisionmaking for incapacitated patients. PMID- 7860271 TI - Families' roles in advance directives. PMID- 7860272 TI - Preferences and other moral sources. PMID- 7860273 TI - Advance directives. Implications for policy. PMID- 7860274 TI - Following advance directives. PMID- 7860276 TI - What makes a directive valid? PMID- 7860277 TI - The green eggs and ham phenomena. PMID- 7860275 TI - Are we asking the right questions? PMID- 7860278 TI - Advance care planning. Priorities for ethical and empirical research. PMID- 7860279 TI - Individual preferences and advance directives. PMID- 7860280 TI - Good decisionmaking for incompetent patients. PMID- 7860281 TI - The ethics of excess. PMID- 7860282 TI - When is birth unfair to the child? PMID- 7860283 TI - Docs on the box. Or, how we learned to stop worrying and love the tube. PMID- 7860284 TI - Cancer and maybe a baby? PMID- 7860285 TI - Ethics: public and private. PMID- 7860286 TI - The ethical life of health care organizations. PMID- 7860287 TI - Tight budgets and doctors' duties. PMID- 7860288 TI - Tight budgets and doctors' duties. PMID- 7860289 TI - Tight budgets and doctors' duties. PMID- 7860290 TI - Praxis less than perfect. PMID- 7860291 TI - Determining "medical necessity" in mental health practice. PMID- 7860292 TI - Diabetes mellitus and heart disease risk factors in Hawaiians. The Native Hawaiian Health Research Project, RCMI Program. PMID- 7860293 TI - Non-traditional and traditional treatment of Hawaiian and non-Hawaiian adolescents. PMID- 7860294 TI - Native Hawaiian traditional healing. PMID- 7860295 TI - Mamane: scientific therapy for asthma? AB - Mortality from asthma in Hawaii continues to increase and chronic problems of medication compliance, side effects, and cost persist. The advisability of adding alternative (traditional) medication for its anti-inflammatory and anti-allergic function was examined. One of the herbs for asthma in the Hawaiian narrative tradition is mamane, or in scientific terminology, Sophora chrysophylla. The scientific literature on S. chrysophylla and of the closely related species Sophora flavescens ait were reviewed in this context and the findings support further investigation. PMID- 7860296 TI - Health care aboard the Hokulea--energy requirement study. AB - The Hokulea was designed and built as an archaeological experiment to test the theory of "intentional exploration and colonization of Polynesia as opposed to the theory of accidental settlement." It is a 60-foot replica of an early Polynesian voyaging canoe. First launched in the spring of 1975, the Hokulea has made multiple voyages between Hawaii and Tahiti navigated without the use of instruments of any kind. The Polynesian Voyaging Society is the no-for-profit corporation that built and operates the Hokulea and the Hawaii Loa, a larger double-hulled sailing vessel scheduled for its maiden voyage in 1995. PMID- 7860297 TI - The Hawaiian diet at Maui Memorial Hospital. PMID- 7860298 TI - Hawaiian medicine. PMID- 7860299 TI - Project Sapphire. PMID- 7860300 TI - A review of the risks of leukemia in relation to parental pre-conception exposure to radiation. AB - The apparent risk of childhood leukemia resulting from paternal pre-conception radiation exposure found among children of the Sellafield (West Cumbria, UK) workforce is compared with the apparent risk in a number of other epidemiological studies. In particular, the extent of the incompatibility of the leukemia pre conception exposure risks in the offspring of the Sellafield workforce born in the village of Seascale with the risks for those born in the rest of west Cumbria, and with the risks in the offspring of the Japanese bomb survivors, the Ontario radiation workers, and the Scottish radiation workers is discussed. A variety of animal data relating to the possibility of leukemia arising as a result of parental pre-conception exposure is also considered. It is concluded that the extent of the inconsistency of the leukemia risks in the Seascale data with this body of epidemiological and experimental data makes it highly unlikely that the association observed in the West Cumbria dataset represents a causal relationship. PMID- 7860301 TI - Plutonium concentrations in lichens of Rocky Flats environs. AB - Xanthoparmelia spp. lichens were used to study the spatial distribution of plutonium concentrations in nonvascular plants surrounding the Rocky Flats nuclear weapons facility with respect to distance, direction, age, and washing. Plutonium concentrations in lichens were inversely related to distance from the initial contamination site with a directional component which corroborated wind borne transport as the primary means of dispersion. Ultrasonic washing and the relative age of the lichen proved to be significant only at p = 0.21 and p = 0.96, respectively. Isotopic ratios of 239,240Pu to 238Pu were highly variable at low activities but remained consistent at 62.6 for samples with high total plutonium activity. Correlation of Xanthoparmelia spp. lichen 239,240Pu concentrations to surface soil concentrations showed a direct relationship (r = 0.767; p < 0.001). The correlation was supported by soil retention studies which revealed a lichen soil content ranging from 11 to 18% on a dry mass basis with a possible particle size selectivity in the different concentration ratios adjacent to and away from the initial contamination site. Results suggest that further study into the in situ biomonitoring of surface soil by Xanthoparmelia spp. lichens is promising. PMID- 7860302 TI - The variability in fallout content of soils and plants and the design of optimum field sampling strategies. AB - Sampling was carried out at an upland peat site in Ireland to assess the variability in 137Cs deposition to soils and activity concentration in individual vegetation species. A 3,600 m2 quadrat was laid out, and a soil core was extracted within each of sixteen 20 x 20 cm soil monoliths. The coefficient of variation values for 137Cs deposition and activity in individual soil horizons were in all cases greater than 30%, and the relative variability between corresponding horizons tended to increase with depth. Samples of Calluna vulgaris and Juncus squarrosus were taken at each soil sampling location and coefficients of variation for 137Cs activity in these species were 12 and 20%, respectively. The data was used to examine the relationship between the number of samples analyzed in a survey, the variability within those samples, and the way those two factors affect our ability to detect between-site differences in 137Cs contamination levels. A methodology is developed for detection of between-site differences in 137Cs contamination under different experimental criteria. The data show that, of the sample types examined, between-site differences could be detected most efficiently with C. vulgaris. Because of the variability associated with the 137Cs content of each sample type, between-site differences could be detected with fewer plant samples than soil samples. Plant-soil concentration ratios, transfer factors, and plant-plant ratios were calculated from the data, and the variability associated with each parameter was assessed. The variation among values for plant-plant ratios was less than among concentration ratios, and the greatest spread of values was associated with plant-soil transfer factors. PMID- 7860304 TI - A theoretical model for 222Rn adsorption on activated charcoal canisters in humid air based on Polanyi's potential theory. AB - Water vapor interferes with the adsorption of 222Rn gas by passive activated charcoal devices used to estimate indoor air concentrations. The 222Rn adsorption coefficient is the fundamental parameter characterizing charcoal's ability to adsorb 222Rn. The Dubinin-Radushkevich equation, based on Polanyi's potential theory, was modified to include two terms quantifying the effect of both water vapor and sampling time on the 222Rn adsorption coefficient of passive charcoal devices. A single equation was derived that quantifies the 222Rn adsorption coefficients at any temperature, humidity and exposure time using six experimentally determined physical constants that are unique for a particular passive charcoal device. The theoretical model was verified with published experimental data, and it showed a good correlation between theory and experiment. The model proved to be consistent with experimental data, provided that the amount of water vapor adsorbed by the charcoal device during sampling remains below a critical level, termed the breakpoint. PMID- 7860303 TI - Distribution of uranium in human organs of an urban Indian population and its relationship with clearance half-lives. AB - This organ burdens of uranium were estimated for an urban Indian (Bombay) population living in a normal background environment, using the technique of neutron activation analysis, in combination with post-irradiation chemical separation. The total organ burdens were: skeleton > muscle > soft tissue > lungs > kidney > liver > heart. A comparison was made between the observed organ burdens of uranium for skeleton, kidney, and muscle with those obtained by applying the metabolic model of uranium as recommended by International Commission on Radiological Protection (ICRP) to its daily intake by urban population. The observed organ burdens for kidney and muscle were found to be 4 and 70 times higher than the derived burden values; however, the two estimates were similar in the case of skeleton. This observation indicated that the clearance half-lives for uranium present in kidney and muscle tissue are likely to be longer than those reported by ICRP. For skeleton, however, the clearance half-life reported by the ICRP appeared to be reasonable. PMID- 7860305 TI - Sensitivity of a mixed field dosimetry algorithm to uncertainties in thermoluminescent element readings. AB - An error analysis of the effects of the algorithms used to resolve the deep and shallow dose components for mixed fields from multi-element thermoluminescent (TLD) badge systems was undertaken for a commonly used system. Errors were introduced independently into each of the four element readings for a badge, and the effects on the calculated dose equivalents were observed. A normal random number generator was then utilized to introduce simultaneous variations in the element readings for different uncertainties. The Department of Energy Laboratory Accreditation Program radiation fields were investigated. Problems arising from the discontinuous nature of the algorithm were encountered for a number of radiation sources for which the algorithm misidentified the radiation field. Mixed fields of low energy photons and betas were found to present particular difficulties for the algorithm. The study demonstrates the importance of small fluctuations in the TLD element's response in a multi-element approach. PMID- 7860306 TI - An intercomparison study of 237Np determination in artificial urine samples. AB - An intercomparison study of low-level 237Np determination in artificial urine samples has been carried out. The purpose of this study was to find the "optimal" method presently available for use in a routine in-vitro radiobioassay program for occupationally exposed workers. Four synthetic urine samples with differing 237Np concentrations were prepared: (1) 3 mBq kg-1 of 237Np; (2) 3 mBq kg-1 of 237Np with natural uranium, 239Pu and 241Am as interferences; (3) 50 mBq kg-1 of 237Np; and (4) a matrix blank. The solutions were submitted to 10 alpha-particle and 10 inductively coupled plasma-mass spectrometry (ICP-MS) laboratories of which six and four laboratories, respectively, returned results. Two laboratories performed assays using both techniques. The radiochemical method of choice used 239Np as the tracer, which utilized a combination of coprecipitation and anion exchange separation. The best results obtained by ICP-MS were comparable with but not better than the most accurate results obtained by alpha-particle spectrometry. Alpha-particle spectrometry measurements overall gave consistently better agreement with known values. PMID- 7860307 TI - Application of a canine 238Pu biokinetics/dosimetry model to human bioassay data. AB - Associated with the use of 238Pu in thermoelectric power sources for space probes is the potential for human exposure, primarily by inhalation and most likely as 238PuO2. Several models have been developed for assessing the level of intake and predicting the resulting radiation dose following human exposure to 239Pu. However, there are indications that existing models do not adequately describe the disposition and dosimetry of 238Pu following human exposure. In this study, a canine model that accounts for these differences has been adapted for use with human excretion data. The model is based on existing knowledge about organ retention of plutonium. An analysis of the sensitivity of the model to changes in aerosol-associated properties indicated that predictions of urinary excretion are most sensitive to changes in particle solubility and diameter and in the ratio of fragment:particle surface area. Application of the model to urinary excretion data from seven workers exposed to a 238Pu ceramic aerosol gave estimated intakes of 390-8,200 Bq and associated initial pulmonary burdens of 80-1,700 Bq. The resulting 50-y dose commitments to critical organs per Bq of 238Pu intake were estimated to be 0.5 mSv for the thoracic region, 0.2 mSv for the liver, and 1 mSv for the bone surfaces. PMID- 7860308 TI - Deposition patterns of molecular phase radon progeny (218Po) in lung bifurcations. AB - Indoor air contamination by radon and its decay products is currently the focus of considerable attention and is considered by many to be the greatest potential cause of lung cancer in the human environment next to smoking. The bifurcations of the human respiratory tract are regions in which enhanced local deposition of particles (hot spots) can occur. These hot spots are important in estimating the risk from radon exposure but existing mathematical models do not characterize them accurately. In this study, radon progeny in the molecular size range were sampled through an aluminium model of a lung bifurcation. The parent and secondary tube diameters used correspond to the third and fourth generations in Weibel's lung model. Steady state, nominally laminar flows were used in the study. Deposition was measured along the inside, outside, top, and bottom walls of the secondary tubes. Experimental results indicate that the deposition along the inside wall is noticeably higher than that along the other walls. The results also show that along the inside, top, and bottom walls the deposition has its overall maximum at the carina. Other maxima are also observed along the secondary tubes downstream from the carina. PMID- 7860309 TI - Gas bremsstrahlung evaluations for a phi-factory. AB - Gas bremsstrahlung from the phi-Factory presently under construction at the INFN Frascati National Laboratories (Italy) has been studied using the Monte Carlo FLUKA code. Photon spectrum and quantitative estimates of fluence rates and tissue absorbed dose rates are given. On the basis of the obtained results the precautions to be taken are discussed. PMID- 7860310 TI - Mutant frequencies in workers at the Sellafield installation. AB - The frequency of hypoxanthine-guanine phosphoribosyltransferase (hprt) mutations has been determined in the peripheral T-lymphocytes of 18 workers at the Sellafield nuclear reprocessing installation with cumulative recorded radiation doses of about 500 mSv or more in comparison with a matched control group of 18 workers with doses less than 50 mSv. The mean dose of the exposed group was 663 mSv (range 449.3-880.8), and of the unexposed group 10.9 mSv (range 0-46.5). During the most recent 6 y the mean doses were 40.1 mSv (range 1.9-93.9) and 2.3 mSv (range 0-8.7), respectively. The logarithmic mean mutant frequency of the exposed group (9.3 x 10(-6)) was lower than that of the unexposed group (12.4 x 10(-6)). The apparent inverse association of mutant frequency and exposure varied in statistical significance tests from borderline to p < 0.01 depending on how the analysis was performed and whether recent or total exposure was considered. PMID- 7860311 TI - Alpha pulse height distributions with ZnS(Ag) scintillator. AB - A flask coated with ZnS(Ag) scintillator is one of the most accurate detectors available for measuring 222Rn. To maintain this accuracy, the counting system consisting of a photomultiplier tube and associated electronics must be checked on a regular basis. A combination of an alpha source and a ZnS(Ag) scintillator is commonly used for these purposes. This paper compares the pulse height distributions of 4 alpha sources with the pulse height distribution from a 100 cm3 scintillation flask containing 222Rn. The source that most closely reproduced the distribution from an actual 222Rn sample in a 100 cm3 scintillation flask consisted of a sealed flask, of the same type, which contains a small piece of uranium-ore. PMID- 7860312 TI - A simple formula to predict approximate initial contamination of lake water following a pulse deposition of radionuclide. AB - The objective of this note is to suggest a simple approximate mathematical formula to predict the initial contamination of lakes following a single pulse of radionuclide deposition on the lake water surface. To estimate the initial concentration of 137Cs in lake water averaged over a period of few weeks, the following expression was suggested: Cw = D/(h+h delta), where D is the radionuclide deposition, h is the average depth of the lake and hD is a parameter depending on the sediment characteristics. Using a generic value of h delta = 6 m, the above formula was successfully applied to some European lakes contaminated following the Chernobyl accident. PMID- 7860313 TI - Skin dose calculations for uranium fuel particles below 500 microns in diameter. AB - Two different methods for skin dose calculations, VARSKIN Mod 2 and PSS are compared for a spherical uranium fuel particle (diameter 1-500 microns) deposited on the skin. Nuclide-specific beta dose rate at different skin depths for a particle of unit activity is determined as a function of particle size. Both methods show that the effects of self-shielding must be included in the dose calculations for low and medium energy beta emitters. Skin dose rate is drastically overestimated when point source approximation is used. For high energy beta emitters (e.g., 90Y, 106Rh, and 144Pr) the volume source can be approximated as a point source. The difference in doses is then below 20% for particles up to 100 microns in diameter. The models give equal results deep in the skin (in terms of range of the beta particles). The reason is that the correction due to the diminished backscattering in air-tissue interface is insignificant at large distances. For three-dimensional sources the backscattering correction should be introduced in the VARSKIN Mod 2. PMID- 7860314 TI - A radiological characterization of remediated tank battery sites. AB - Tank battery sites have historically been used for the initial processing of crude oil which separates water and sediment from the produced oil. Typically, one or more producing wells is connected to a tank battery site consisting of storage and separation tanks. Historical operating practices also included a production holding pit for increased separation of oil, water, and sediment. The sediment remaining in the pit is composed of an oily, viscous material called sludge. Under certain circumstances, this sludge may contain naturally occurring radioactive material. The methodology required for reclamation of the production holding pits consisted of removal of soil and sludge from the pits with controlled land-spreading to achieve biodegradation of the hydrocarbons. The purpose of this study was to perform a radiological characterization on representative tank battery sites that had been reclaimed in the above fashion. The average gamma radiation exposure rates encountered ranged from 2.1-7.2 pC kg 1 s-1. The average concentration of 226Ra for the tank battery sites ranged from 0.5-2.3, 0.5-2.8, and 0.3-3.2 Bq g-1 for soil depths of 0-15, 15-30, and 30-51 cm, respectively. Average radon flux measurements ranged from 29.7-211.8 mBq m-2 s-1. Measurements of the radon emanation coefficient of NORM ranged from 3-7%. PMID- 7860315 TI - Installation of 60Co 100 cm source-to-axis distance teletherapy units in vaults designed for 80-cm units. AB - 60Co teletherapy units featuring 100 cm source-to-axis distances and with nominal source activities of 481 TBq (13,000 Ci) are available as replacements for older model 80 cm source-to-axis teletherapy units that generally have source activities of less than 370 TBq (10,000 Ci). We have redesigned and renovated two vaults--one of which required supplemental shielding--designed for older 80 cm source-to-axis units with 333 TBq (9,000 Ci) sources and installed modern 100 cm source-to-axis units with 481 TBq (13,000 Ci) sources. Renovation costs (in 1991 U.S. dollars) were about $40,000 and $160,000; the latter, including shielding costs, was about two-thirds of projected costs for installation of a 6 MV electron beam linear accelerator (linac). We have designed the treatment heads of these 100 cm 60Co units to accept the secondary field shaping blocks used on 100 cm source-to-axis linacs, allowing the 60Co units to be used as emergency back-up units for linacs when they are inoperable. PMID- 7860316 TI - Unavoidable radioactivity in medical waste. PMID- 7860317 TI - The geographical accessibility of hospitals to the aged: a geographic information systems analysis within Illinois. AB - OBJECTIVE: This article uses geographic information systems and their related tools to empirically measure and display the geographic accessibility of the aged population to hospital facilities within Illinois. DATA SOURCES AND STUDY SETTING: Geographic accessibility of Illinois' aged population is measured from each of the state's 10,796 census block groups to the state's 214 hospital facilities. Block group demographic compositions and centroids are obtained from 1990 census files. Hospital coordinates are obtained by the authors. STUDY DESIGN: Of five alternative measures of accessibility considered, empirical estimates are obtained for two: choice set and minimum distance. Access to both general hospitals and the subset having specialized geriatric facilities is measured with special attention to differences in accessibility between the aged within metropolitan statistical areas (MSAs) and those outside MSAs. Cumulative accessibility distributions and their summary statistics provide a basis of comparison among subgroups. DATA COLLECTION AND EXTRACTION: Geographic information systems (GIS) and their related tools are used as a means of efficiently capturing, organizing, storing, and retrieving the required data. Hospitals and census block groups are geocoded to specific locations in the database, and aspatial attributes are assigned to the hospitals and block groups. The GIS database is queried to produce shaded isarithm and point distribution maps that show the location of hospitals relative to surrounding aged populations. CONCLUSION: The vast majority of Illinois' aged population is within close proximity to hospital facilities. Eighty percent (1,147,504 persons) of the aged in Illinois are within 4.8 miles (7.7 km) of a hospital and 11.6 miles (18.7 km) of two hospitals. However, geographic accessibility differences between the aged living in MSAs and those living outside MSAs to hospitals offering geriatric services are substantial; but there is no evidence that the aged's geographical accessibility to hospitals is less favorable than that of the general population. Detailed accessibility measures permitted by geographic information system technology call into question the continued use of crude empirical accessibility measures. PMID- 7860318 TI - Understanding the factors behind the decision to purchase varying coverage amounts of long-term care insurance. AB - OBJECTIVE: This article examines the factors related to an individual's decision to purchase a given amount of long-term care insurance coverage. DATA SOURCE AND STUDY SETTING: Primary data analyses were conducted on an estimation sample of 6,545 individuals who had purchased long-term care (LTC) insurance policies in late 1990 and early 1991, and 1,248 individuals who had been approached by agents but chose not to buy such insurance. Companies contributing the two samples represented 45 percent of total sales during the study year. STUDY DESIGN: A two stage logit-OLS (ordinary least squares) choice-based sampling model was used to examine the relationship between the expected value of purchased coverage and explanatory variables that included: demographic traits, attitudes, risk premium, nursing home bed supply, and Medicaid program configurations. DATA COLLECTION: Mail surveys were used to collect information about individuals' reasons for purchase, attitudes about long-term care, and demographic characteristics. Through an identification code, information on the policy designs chosen by these individuals was linked to each of the returned mail surveys. The response rate to the survey was about 60 percent. PRINCIPAL FINDINGS: The model explains about 47 percent of the variance in the dependent variable-expected value of policy coverage. Important variables negatively associated with the dependent variable include advancing age, being married, and having less than a college education. Variables positively related include being male, having more income, and having increasing expected LTC costs. Medicaid program configuration also influences the level of benefits purchased: state reimbursement rates and the presence of comprehensive estate recovery programs are both positively related to the expected value of purchased benefits. Finally, as the difference between the premium charged and the actuarially fair premium increases, individuals buy less coverage. CONCLUSIONS: An important finding with implications for policymakers is that changes in Medicaid policy affect the decisions of consumers regarding the acquisition of private LTC policies as well as the level of protection chosen. This is particularly important to states interested in pursuing public-private partnerships in long-term care financing. PMID- 7860319 TI - Measuring hospital mortality rates: are 30-day data enough? Ischemic Heart Disease Patient Outcomes Research Team. AB - OBJECTIVE: We compare 30-day and 180-day postadmission hospital mortality rates for all Medicare patients and those in three categories of cardiac care: coronary artery bypass graft surgery, acute myocardial infarction, and congestive heart failure. DATA SOURCES/COLLECTION: Health Care Financing Administration (HCFA) hospital mortality data for FY 1989. STUDY DESIGN: Using hospital level public use files of actual and predicted mortality at 30 and 180 days, we constructed residual mortality measures for each hospital. We ranked hospitals and used receiver operating characteristic (ROC) curves to compare 0-30, 31-180, and 0-180 day postadmission mortality. PRINCIPAL FINDINGS: For the admissions we studied, we found a broad range of hospital performance when we ranked hospitals using the 30-day data; some hospitals had much lower than predicted 30-day mortality rates, while others had much higher than predicted mortality rates. Data from the time period 31-180 days postadmission yield results that corroborate the 0-30 day postadmission data. Moreover, we found evidence that hospital performance on one condition is related to performance on the other conditions, but that the correlation is much weaker in the 31-180-day interval than in the 0-30-day period. Using ROC curves, we found that the 30-day data discriminated the top and bottom fifths of the 180-day data extremely well, especially for AMI outcomes. CONCLUSIONS: Using data on cumulative hospital mortality from 180 days postadmission does not yield a different perspective from using data from 30 days postadmission for the conditions we studied. PMID- 7860320 TI - Determining VA physician requirements through empirically based models. AB - OBJECTIVE: As part of a project to estimate physician requirements for the Department of Veterans Affairs, the Institute of Medicine (IOM) developed and tested empirically based models of physician staffing, by specialty, that could be applied to each VA facility. DATA SOURCE/STUDY SETTING: These analyses used selected data on all patient encounters and all facilities in VA's management information systems for FY 1989. STUDY DESIGN: Production functions (PFs), with patient workload dependent on physicians, other providers, and nonpersonnel factors, were estimated for each of 14 patient care areas in a VA medical center. Inverse production functions (IPFs), with physician staffing levels dependent on workload and other factors, were estimated for each of 11 specialty groupings. These models provide complementary approaches to deriving VA physician requirements for patient care and medical education. DATA COLLECTION/EXTRACTION METHODS: All data were assembled by VA and put in analyzable SAS data sets containing FY 1989 workload and staffing variables used in the PFs and IPFs. All statistical analyses reported here were conducted by the IOM. PRINCIPAL FINDINGS: Existing VA data can be used to develop statistically strong, clinically plausible, empirically based models for calculating physician requirements, by specialty. These models can (1) compare current physician staffing in a given setting with systemwide norms and (2) yield estimates of future staffing requirements conditional on future workload. CONCLUSIONS: Empirically based models can play an important role in determining VA physician staffing requirements. VA should test, evaluate, and revise these models on an ongoing basis. PMID- 7860321 TI - Predictors of young physicians practicing specialties without prior graduate medical education. AB - OBJECTIVE: This study identifies predictors of young physicians practicing specialties for which they did not report having graduate medical education. DATA SOURCE: A secondary analysis was conducted using a nationally representative survey of young physicians, Practice Patterns of Young Physicians, 1987 (United States). Physicians were under 40 years of age and in uninterrupted practice more than one but fewer than six complete years. STUDY DESIGN: Young physicians who practiced specialties without prior graduate medical education (GME) in these specialties were compared to young physicians who practiced only the specialties for which they reported GME. Comparisons were made on sociodemographic characteristics, international medical graduate status, number and types of GME specialties, year completed GME, and preference for a practice position that was not offered. DATA EXTRACTION METHODS: Sample size was 4,440, including 345 (7.8 percent) physicians who practiced specialties without prior GME. Logistic regression analysis was used to identify predictors of young physicians practicing specialties without prior GME. PRINCIPAL FINDINGS: Physicians who practiced specialties without prior GME more likely were younger, members of minorities other than Black, and with a physician father, high medical school educational debt, and GME in the more generalist specialties. Interaction effects occurred among sex, marital status, and having had GME in internal medicine. Goodness-of-fit analyses indicated that the predictors were useful, but classification table results indicated that at best two out of three cases could be correctly classified. CONCLUSIONS: Practicing specialties without prior graduate medical education in those specialties was related to sociodemographic characteristics and type of specialty training, but a fuller understanding of the circumstances affecting physician specialty changes will require querying physicians directly about their practice choices. PMID- 7860324 TI - Needlestick injury during disposal of blood-collection needle. PMID- 7860322 TI - Estimating annual charges for ambulatory care from limited utilization data. AB - OBJECTIVE: This study explores the types of utilization information needed to produce a reasonable estimate of annual charges for ambulatory care that could be used in the absence of charge or cost data as an aggregate utilization measure. DATA SOURCE: Charge and utilization data from the RAND Health Insurance Experiment were used. STUDY DESIGN: Services provided to enrollees in the Health Insurance Experiment at each of the six sites for a one-year period were grouped into categories according to California Relative Value Studies (CRVS) codes. Using annual charges as the dependent variable, we evaluated linear regression models for their predictive accuracy, as indicated by adjusted R2-values. Categories of services were combined on the basis of clinical meaningfulness (e.g., all provider visits into one group), and predictive accuracy of models with these groupings of services examined. We examined model validity by applying the derived models to each of the 30 remaining site-years of data from the Health Insurance Experiment. PRINCIPAL FINDINGS: We were able to explain 84 percent of the variance in charges with a model containing counts of provider visits exclusive of mental health visits, mental health provider visits, days drugs were prescribed, days radiologic procedures were performed, procedural visits subdivided according to whether they were performed by a surgical or medical provider, days laboratory and/or pathology tests were performed, days a grouping of miscellaneous tests were performed, and days supplies were purchased. When applied to the validation data, this model predicted a mean of 77 percent of the variance and mean charges 102 +/- 9 percent of actual mean charges. A model with only the first four of the listed categories explained 77 percent of the variance in charges. CONCLUSIONS: Models using only counts of several broad categories of services perform rather well in predicting annual charges for ambulatory care. PMID- 7860325 TI - Patient burn caused by excessive illumination during surgical microscopy. PMID- 7860323 TI - Needlestick-prevention devices. PMID- 7860326 TI - Risk of electrosurgical burns at needle electrode sites. PMID- 7860328 TI - Legal issues in health education revisited: focus on diabetes. PMID- 7860327 TI - Difficulty synchronizing with Zoll PD 1200 defibrillator/monitor/pacemakers. PMID- 7860329 TI - Diabetes update. AB - This article is a brief overview of the incidence, classification, and diagnosis of diabetes mellitus. Current concepts of diabetes management, including nutrition, exercise, and medication, are introduced. PMID- 7860330 TI - Critical paths: implications for improving practice. AB - A critical path has been defined as a "written plan that functions as a map and timetable for efficient and precise delivery of health care." Critical paths are seen as a method of maintaining quality care while controlling costs through coordination of services. Many benefits have been realized through the use of critical paths in acute care settings. Despite their effectiveness in acute care settings, critical paths have received minimal attention in home healthcare. The purposes of this paper are to (1) illustrate the ways that home care can benefit from the use of critical paths; and (2) describe a process that home care providers can use to develop critical paths. PMID- 7860331 TI - Humor and elderly caregivers. AB - Elderly caregivers of the homebound chronically ill experience many burdens. This article describes the use of humor by elderly caregivers as a method to ease the burden of their work. Home care nurses can incorporate humor as an intervention to help these elderly caregivers. PMID- 7860332 TI - A quality improvement approach to blood glucose monitoring. AB - Blood glucose monitoring is a valuable tool to the home care nurse. A quality assurance study was conducted to validate blood glucose meter results. Individual education then was provided to nurses that greatly increased precision and accuracy of meter readings. PMID- 7860333 TI - Marketing for community health nurses. AB - Marketing has become an important function of the nursing management process. The community health nurse executive must incorporate marketing in his or her administrative role. An effective marketing plan will benefit the organization, the nurse executive, and, ultimately, the consumer. PMID- 7860334 TI - The determinants of community health nursing in Taiwan: past, present, and future aspects. AB - There are many determinants that influence the development of community health nursing in Taiwan. Political reality and policy, economic development, social changes, universality of education, systematization of healthcare, and disease changes are among the main factors. The author individually describes these influences in reference to past and current situations. Then, the author discusses the future prospects of these influences on community health nursing in Taiwan. PMID- 7860335 TI - Rehabilitation's three Rs. PMID- 7860337 TI - Reform is dead: long live reform. Interview by Joan E Caserta. PMID- 7860336 TI - We'll plant tomatoes in the spring. PMID- 7860338 TI - The effects of home visits on anxiety levels of the client with a coronary artery bypass graft and of the family. AB - This study compared the anxiety scores of 30 clients and their spouses who had received home visits from the nurse with 30 clients and spouses who did not receive home visits. All clients had undergone coronary artery bypass graft surgery. Anxiety was measured by the State Trait Anxiety Inventory, Form Y-1, and the Affect Adjective Check List, Today Form. Analysis of variance investigated differences between anxiety scores of clients and six demographic variables. Type A behavior pattern was assessed by the Jenkins Activity Survey and a tool based on the Framingham Type A Scale. A t-test showed that clients and families who received home visits had significantly lower anxiety levels than those who did not receive visits (P < 0.05). A t-test also showed that Type A clients and families had the same or even lower anxiety scores than Type B clients and families, but was not significant (P < 0.05). Results of the study indicate the value of home visits to the client with a coronary artery bypass graft and to the family by the nurse as a method of decreasing anxiety and preventing costly rehospitalization. PMID- 7860339 TI - Medical-device user instructions: the patient's need, the nurse's role. AB - This article discusses the provision of adequate education to lay users of medical devices in the home. It specifically focuses on the written instructions that are part of the labeling for these devices, advising nurses on what to look for in determining the effectiveness of instructions for lay users; how to use that information to advise patients and physicians; and how to influence the quality of the instruction manuals developed by the manufacturers of the devices. PMID- 7860340 TI - Monitoring diabetes therapy. AB - This article discusses methods for monitoring diabetes therapy. Emphasis is placed on client assessment and selection of appropriate products to ensure accurate results. PMID- 7860341 TI - Blood glucose monitoring systems. AB - Blood glucose monitoring has evolved from a helpful test to an essential part of diabetes treatment. The equipment used for testing also has been changing rapidly, so that today there are numerous monitoring systems on the market representing a wide range of features and prices. The variety makes it confusing for professionals and clients alike to select an appropriate product. The home healthcare nurse is invited to read the companion article, "Monitoring Diabetes Therapy," which is published in this issue, for a discussion of points to consider when choosing a meter. The following chart (Table 1) is designed to assist the home healthcare nurse to identify various meters and to compare features. PMID- 7860342 TI - Pittsburgh plague--1918: an oral history. AB - This article is an oral history that highlights the influenza epidemic of 1918 as it affected 26 people. General history depicts the broad sweep of the pandemic. The hope is to give a human face to the poignancy of individual experience. Significant progress has been made in nursing science in the treatment and prevention of influenza. The task of nursing practice remains to integrate new knowledge and to adapt it to the care of each person placed in one's care. PMID- 7860344 TI - A lifestyle: at what price?. Interview by Joan E Caserta. PMID- 7860343 TI - AIDS and malnutrition: dual assaults on the body. AB - The immune system is impaired by either malnutrition or human immunodeficiency virus infection. When these occur together, their compounding effects promote altered metabolism, inadequate intake, and malabsorption, which further impair immune function and contribute to human immunodeficiency virus wasting. Careful dietary management can help meet nutritional needs without further compromising the immune status of the person living with acquired immune deficiency syndrome. PMID- 7860345 TI - Using therapeutic silence in home healthcare nursing. AB - This article examines the role of silence in the practice of home healthcare nursing. The literature is limited regarding the use of silence in therapeutic relationships in home healthcare nursing. Silence is often uncomfortable for the home healthcare nurse and the client, but when silence is used purposefully by the nurse, effective communication can be a successful intervention. PMID- 7860347 TI - Caring. PMID- 7860346 TI - Activities of daily living and the cardiac client who is homebound. PMID- 7860348 TI - Home mechanical ventilator management. PMID- 7860349 TI - Understanding dissociative identity disorder: in my mirror. PMID- 7860350 TI - Current research findings related to individuals with diabetes mellitus. PMID- 7860351 TI - A tribute to home care (the art of home care). PMID- 7860353 TI - Leukocyte differentiation antigens. How to keep up with the litany of CD antigens. PMID- 7860352 TI - High-tech home care for nurses: questioning technologies. AB - To build a common ground for questioning, this paper describes and defines technology, inappropriate technology, technology assessment, and technological regimes that community health nurses confront. Then, control of technology and effects on individual, family, and community are explored. In conclusion, two decision-making guides are proposed to help the home health nurse assess the human effects of technology and to support family decisions about whether technology is appropriate. PMID- 7860354 TI - The molecular basis of allorecognition. Assessment of the involvement of peptide. PMID- 7860355 TI - Structural and functional analysis of HLA-DR beta-promoter polymorphism and isomorphism. AB - Evolutionary relatedness among the highly polymorphic DR beta genes has been established based on shared nucleotide sequences and structural organization of DR beta loci. The evolution of promoter regions of the B1*0701, B1*0101, B1*1501, B5*0101 genes was analyzed by cloning and sequencing. This shows that the polymorphism and isomorphism of HLA DR beta genes extend into the 5' flanking promoter region of the genes and that evolutionary relatedness also exists among the DR beta gene promoters. This suggests that DR beta gene promoters and coding regions coevolved. The effect of the naturally occurring nucleotide substitutions in the polymorphic and isomorphic DR beta promoters on transcriptional activity has been determined in a transient expression system. The transcriptional activity of two polymorphic DR beta promoters, B1*1501 and B1*0701, and two isomorphic DR2 promoters, B1*1501 and B5*0101, is the same for these promoters. Together these data suggest that naturally occurring substitutions do not significantly affect the transcriptional activity of these promoters. PMID- 7860356 TI - A simple method of HLA-DRB typing using enzymatically amplified DNA and immobilized probes on microtiter plate. AB - We have developed a simple and economical method for HLA-DNA typing, called microtiter plate hybridization (PCR-MPH), which could replace standard PCR-SSO. This method is similar to that of an ELISA. Briefly, the PCR products labeled at the 5' termini with biotin were hybridized with probes immobilized on a microtiter well, and the bound PCR products were detected by streptavidin conjugated enzymes followed by color development. A system for HLA-DRB1 "generic" typing (e.g., DR1, DR2), using microtiter wells coated with 12 different SSOs has been established. The HLA-DRB types classified using this method agreed well with those obtained by conventional serologic typing. The advantages of this microtiter plate-hybridization method for routine HLA-DNA typing are a short assay time, easy processing of large numbers of samples, and the potential for automation. PMID- 7860357 TI - Molecular analysis of HLA-B27 haplotypes in Caucasoids. Frequencies of B27-Cw in Jewish and Spanish populations. AB - PCR in combination with SSO probes was used to analyze the polymorphism in exons 2 and 3 of HLA-B27 subtypes and HLA-C-related alleles in two genetically distant Caucasian groups: Spanish and Jewish populations. AS patients and healthy B27 donors from both populations were analyzed in order to ascertain B27-Cw haplotypes. Three different ancestral haplotypes were found to be represented in both populations: B*2705/Cw*0102, B*2705/Cw*02022, and B*2702/Cw*02022. The B*2705 (92.5%) was the most frequent allele found in the Spanish population, carried by B*2705/Cw*0102 (60.9%) and B2705/Cw*02022 (30.4%) haplotypes. In contrast, B*2702 (59.4%) was the most prevalent allele found in the Jewish population and was carried by the B*2702/Cw*02022 (63.3%) haplotype. No different allelic and haplotypic distributions were among healthy and AS patients in either Spanish or Jewish populations. The differences found in the distribution of B27 haplotypes among Spanish and Jewish Caucasian populations are consistent with the genetic distance of these ethnic groups. When the Jewish population was subdivided into Ashkenazi (A) and non-Ashkenazi (NA) groups, no significant differences were observed in the distribution of B*2702/Cw*02022 haplotype. Minor differences were observed in the underrepresented B*2705 haplotypes. The present results reflect the ancestral affinities of A and NA Jewish populations. A possible HLA-B27 evolutive pathway in Caucasians is proposed according to the data available for the B27/Cw ancestral haplotypes in Spanish and Jewish groups. PMID- 7860358 TI - Major histocompatibility complex class II and III in Addison's disease. MHC alleles do not predict autoantibody specificity and 21-hydroxylase gene polymorphism has no independent role in disease susceptibility. AB - The major autoantigens in Addison's disease have recently been shown to be members of the adrenal steroidogenic enzymes, such as 21OH. The genes encoding the 21OH enzyme are located in the class III segment of the MHC complex. Therefore, its identification as an autoantigen provides a novel link between MHC and susceptibility to this autoimmune disease. We have determined the MHC class II (DRB1, DQA1, DQB1, DPB1) and class III (TNF, HSP70, C4, 21OH) gene polymorphism in patients with Addison's disease. Also, we tested whether presence of autoantibodies against 21OH is associated with specific alleles in MHC. Our results show that patients with Addison's disease in association with APS2 or Addison's disease as an isolated form share highly similar MHC class II and class III alleles. A very strong association with HLA DRB1*0301, DQA1*0501, DQB1*0201, and DPB1*0101, as well as with the C4A + 21OHA gene deletion and TNFB*1 allele was observed. However, identical gene markers were observed also in controls matched for DRB1*0301, thus suggesting that the patient group did not carry MHC gene segments specific for Addison's disease. The presence of autoantibodies against 21OH was not found to be directly determined by the MHC alleles; rather it was associated with the clinical form of the disease. PMID- 7860359 TI - Susceptibility to alloimmunization to platelet HPA-1a antigen involves TAP1 polymorphism. AB - The alloimmunization against platelet HPA-1a antigen in mothers of thrombocytopenic neonates is strongly associated with HLA class II structures (DR3 and DR13) and especially with HLA-DR52a antigen (98% of the cases reported here). Because new genes have recently been mapped within the MHC class II region, we typed TAP1 and TAP2 gene polymorphisms by ARMS-PCR in order to characterize more effectively MHC genes involved in this alloimmunization. Our results showed that TAP1*0102 allele was significantly associated with NAIT only in the population of HLA-DR 13-DR52a-immunized women (50%) versus HLA-DR 13-DR52a controls (20%) (p < 0.05), and not in HLA-DR3-DR52a-immunized women versus HLA DR3-DR52a controls. There is no linkage disequilibrium between TAP1*0102 and DRB1*13 alleles (delta = -0.0063) that could account for this result. The higher frequency of TAP1*0102 allele among HLA-DR 13-DR52a-immunized women suggests that HPA-1a antigen presentation and recognition may be influenced by nonclassic HLA class II gene polymorphisms, or that other linked but yet unknown genes could interfere. PMID- 7860360 TI - Chronic active autoimmune hepatitis in children. Strong association with a particular HLA-DR6 (DRB1*1301) haplotype. AB - The association of HLA antigens and type I or "lupoid" CAH-C was investigated in a population of 52 Argentinian Caucasoid patients. When compared with a population of normal individuals of the same ethnic group (n = 197), a significant increase of HLA-DR6 was observed (68.6% in patients vs 17.3% in controls; RR = 12.3, chi 2 = 52.4, pc = 0.00001). DNA typing showed that the HLA DRB1*1301 allele was present in 32 out of 33 HLA-DR6 patients (66.6% of all the C CAH patients vs 10.5% in controls; RR = 16.2, chi 2 = 111.3, pc = 0.00001). Analysis of HLA-DQB1 alleles also showed a significant increase of DQB1*0603 (RR = 15.4, chi 2 = 106.5, pc = 0.00001), an allele found in strong linkage disequilibrium with DRB1*1301. The association of CAH-C with this particular HLA DR6 haplotype has not been previously described for the adult onset CAH. This different HLA predisposition, together with the fact that extrahepatic autoimmune diseases occur frequently only in the adult form of the disease, suggest that the immunopathogenic mechanisms involved in the development of these diseases may be different. PMID- 7860361 TI - Serologic and nucleotide sequencing analyses of a novel DR52-associated DRB1 allele with the DR 'NJ25' specificity, designated DRB1*1307. AB - A novel DR52-associated DRB1* allele, designated DRB1*1307, was encountered in the course of our HLA-DRB1 genotyping study in a Japanese population by PCR-RFLP. Comparison of the nucleotide sequence of its second exon with those of the other known DRB1 alleles revealed that DRB1*1307 was most similar to DRB1*1101, differing by two amino acid substitutions. From a family study, DRB1*1307 was found to segregate with a haplotype of DRB3*0202-DQA1*0501-DQB1*0301, which was also observed with DRB1*1101 in a Japanese population. DRB1*1307 was recognized in three of 652 healthy Japanese controls (gene frequency: 0.24%) with the same DR-DQ haplotype, indicating that DRB1*1307 arose from DRB1*1101 by a gene conversionlike event(s) and/or point mutations. Further, it was also observed that this allele had a strong linkage disequilibrium with HLA-B70 (p < 0.001). This new DRB1*1307 allele was serologically defined as DR 'NJ25,' and it gave an almost identical serologic pattern to DRB1*1406. On sequence comparison, however, no unique amino acid residues conserved in DRB1*1406 and DRB1*1307 but absent in all the other DRB1 alleles could be found, indicating that two amino acid changes at positions 47 and 58 abolished the reactivity against the DR11 antisera. PMID- 7860362 TI - Significance of the six peptide-binding pockets of HLA-A2.1 in influenza A matrix peptide-specific cytotoxic T-lymphocyte reactivity. AB - To evaluate the roles of the six peptide-binding pockets of HLA-A2.1 in FMP specific CTL recognition, we have constructed an extensive library of HMy2.C1R cell lines expressing mutant HLA-A2.1 molecules with different amino acid substitutions in each of the six pockets. These cell lines were tested for their ability to present synthetic FMP 58-66 to FMP-specific, HLA-A2.1-restricted human CTL lines. Six of 12 mutants with amino acid changes in pocket B significantly affect the FMP-specific CTL recognition, suggesting that pocket B plays a critical role in FMP-specific CTL recognition. Surprisingly, mutations in all other pockets, except for pocket F, also have significant effects on the CTL recognition. These results suggest that even the shallow pockets, which are likely to be less critical for peptide binding than the deep pockets, play a crucial role in FMP-specific CTL recognition. PMID- 7860363 TI - Molecular characterization of a novel, serologically detectable, HLA-C allele: Cw*1602. AB - Cw*1602, a novel HLA-C allele belonging to the newly assigned Cw*16 group, has been cloned and sequenced from a Spanish Caucasoid cell expressing a "Cw6.2" phenotype. Some of the polymorphic substitutions of the new allele, and linkage disequilibrium to B51, had been predicted on the basis of previously published studies. The primary structure of Cw*1602 is in agreement with its serologic reactivity and, in comparison with that of Cw*1601, underlines the dimorphism of HLA-C molecules at residues 77 and 80 of the alpha 1-domain alpha helix. PMID- 7860364 TI - Susceptibility alleles at HLA-DRB1, -DQA1, and -DQB1 loci in Ethiopian childhood insulin-dependent diabetes mellitus. PMID- 7860365 TI - Sorting through the complexities of ovarian cancer. PMID- 7860366 TI - Laparoscopy-assisted vaginal hysterectomy: cost analysis and review of initial experience in a community hospital. AB - During the past 2 years, an increasing number of gynecologic surgeons have performed laparoscopy-assisted vaginal hysterectomy (LAVH) and laparoscopic hysterectomy (LH). Although these procedures have become more common, they are still considered controversial. Many gynecologists question their cost, safety, efficacy, and indications. We reviewed and analyzed the perioperative and postoperative course of ten patients as well as the total cost. The patients who underwent these procedures were compared with ten matched patients who underwent abdominal hysterectomy for similar indications. Compared with control subjects, patients in the laparoscopic group had a shorter hospitalization stay (2.2 days vs 4.2 days), shorter recovery (2 weeks vs 5 weeks), and 28% fewer complications. Although the LAVH took significantly longer than TAH (3.28 hours vs 1.75 hours), the total hospital costs and charges for both procedures were similar. As technology advances and techniques are modified, the laparoscopic approach should reduce hospital costs and charges significantly. The current results suggest that LAVH may eventually be preferred to the TAH approach by physicians and their patients. PMID- 7860367 TI - Planning a medical relief mission. AB - Surveillance of drug consumption and disease incidence from medical relief missions in two locations--southeast Asia and eastern Africa--revealed close similarities. Analgesics, antibiotics, antimalarials, antihistamine or decongestant preparations (or both), bronchodilators, and scabicides were the 10 most commonly used drugs. Orthopedic, respiratory, gastrointestinal, dermatologic, and ophthalmic conditions, malaria, sexually transmitted diseases, and parasitic infestations were encountered most frequently. Recognition and early treatment of xerophthalmia, trachoma, and onchocerciasis, which are rare in more developed countries but common at tropical latitudes, can prevent the blindness that results from untreated disease progression. Pulse-temperature relationships and fever patterns may offer diagnostic clues to physicians deprived of laboratory support. Important logistic considerations, disease incidences, and selected topics and idiosyncrasies of humanitarian aid missions to tropical communities are discussed in hopes of aiding providers who are planning future relief missions. PMID- 7860368 TI - Unstable angina: clinical practice guidelines for diagnosis and management. Agency for Health Care Policy and Research. AB - Unstable angina is one of the most common reasons for hospital admission in the United States and causes substantial morbidity and mortality. Diagnosis of unstable angina is complicated by the dynamic range of presentations, which can vary between atypical chest pain and acute myocardial infarction. Overcautious management can result in unnecessary hospital admission, whereas inappropriate conservative strategies can cause cardiac injury and death. To define treatment strategies for these patients, the US Agency for Health Care Policy and Research in March 1994 published guidelines on the diagnosis and management of unstable angina. The emphasis is on diagnosis or exclusion of coronary artery disease, establishment of the patient's risk for adverse outcome, and triage to the most appropriate treatment regimen. The guidelines emphasize the use of aspirin, heparin sodium, nitroglycerin, and beta-blockers as the core therapy. Appropriate strategies are reviewed, starting with intensive medical management and ending with patient care after discharge. Many physicians will probably modify their approach to the diagnosis and treatment of unstable angina on the basis of these new guidelines. PMID- 7860369 TI - Bicarbonate therapy in the treatment of lactic acidosis: medicine or toxin? AB - The metabolic acidosis resulting from poor tissue perfusion is considered to have several significant hemodynamic effects. Correction of the acidosis with sodium bicarbonate seems to be a rational approach to this problem. However, the current medical literature shows little clinical benefit to this tactic. In fact, indiscriminate bicarbonate administration may, itself, have deleterious effects. Concurring with the absence of a consistent therapeutic advantage to the use of sodium bicarbonate in the treatment of lactic acidosis due to inadequate tissue perfusion, the American Heart Association removed the routine use of sodium bicarbonate from the treatment of cardiac arrest in the algorithms of the Advanced Cardiac Life Support course. Although the debate continues, a detailed review of the medical literature does not support the use of sodium bicarbonate in this setting. PMID- 7860370 TI - Ewings sarcoma as an etiology for persistent back pain in a 17-year-old girl after trauma to the back. AB - Back pain--a common complaint familiar to all physicians--can be either a manifestation of musculoskeletal dysfunction or a symptom of a more serious underlying disease. Unfortunately, the diagnosis can be difficult, and back pain that is not resolved by conservative treatment requires aggressive investigation. The author presents the case history of a 17-year-old patient whose back pain had been extensively evaluated by a series of specialists to no avail until further workup revealed the problem to be Ewing's sarcoma. The steps required to diagnose elusive back pain are presented, together with a brief discussion of cauda equina syndrome and conus medullaris syndrome, components of both of which were found in this patient. PMID- 7860371 TI - Irradiation alone or combined with surgery in carcinoma of the cervix: when will we know the answer? PMID- 7860372 TI - Surgical staging, extended field radiation, and enteric morbidity in the treatment of cervix cancer. PMID- 7860373 TI - Width of the therapeutic window: what is the optimal dose-per-fraction for high dose rate cervix cancer brachytherapy? PMID- 7860374 TI - An assessment of treatment options for breast conservation in the elderly woman with early stage breast cancer. PMID- 7860375 TI - What have we accomplished in the management of patients with small cell anaplastic carcinoma of the lung? PMID- 7860376 TI - Interstitial brachytherapy in velo-tonsillar tumors: the ultimate boost. PMID- 7860377 TI - Letter to the editor regarding editorial by Bosset et al. IJROBP 29:205-208; 1994. PMID- 7860378 TI - In response to McLean and Duncan. PMID- 7860379 TI - Letter to the editor regarding Wand and Efird IJROBP 25:657-660; 1994. PMID- 7860380 TI - One step forward and two steps back. PMID- 7860381 TI - Irradiation alone or combined with surgery in stage IB, IIA, and IIB carcinoma of uterine cervix: update of a nonrandomized comparison. AB - PURPOSE: Definitive radiation therapy alone or combined with surgery in carcinoma of the uterine cervix yields comparable tumor control and survival in Stages I and IIA when patients are adequately treated with either modality. Our 30-year institutional experience is described. METHODS AND MATERIALS: This is a nonrandomized comparison of treatment results of 415 patients with Stage IB, 137 with Stage IIA, and 340 with Stage IIB carcinoma of the uterine cervix treated with irradiation alone and 197 with Stage IB, 44 with Stage IIA, and 65 with limited Stage IIB treated with pre- or postoperative irradiation and surgery. Irradiation alone consisted of a combination of external beam therapy and intracavitary insertions to deliver doses of 70 to 85 Gy to point A for patients with Stages IB and IIA disease and 80 to 90 Gy for patients with bulky or Stage IIB tumors. For patients treated with irradiation and surgery, various combinations of external beam and intracavitary therapy were used to deliver 60 to 75 Gy to point A. Surgical procedures consisted of radical hysterectomy with or without lymph node dissection in 130 patients with Stage IB, 28 patients with Stage IIA, and 10 patients with limited Stage IIB. Fifty-seven patients had total abdominal or conservative hysterectomy with or without lymph node dissection, and 3 had vaginal hysterectomy. In addition, 51 patients with Stage IIB tumors underwent pelvic lymphadenectomy after definitive irradiation. RESULTS: The 5 year cause-specific survival (CSS) rates for patients with Stage IB nonbulky tumors treated with irradiation alone or irradiation combined with surgery were 90 and 85%, respectively, and the 10-year survival rate was 84% with either modality. In patients with bulky tumors (> 5 cm), the 5-year CSS rates were 61% with irradiation alone and 63% with irradiation plus surgery; at 10 years the rates were 61 and 68%, respectively (p = 0.5). For those with Stage IIA nonbulky tumors, the 5-year CSS rates were 75% with irradiation alone and 83% with combined irradiation and surgery, and 10-year CSS rates were 66 and 71%, respectively. In patients with Stage IIA bulky tumors, the 5-year CSS rates were 69% with irradiation alone and 60% with irradiation plus surgery, and at 10 years, 69 and 44%, respectively (p = 0.05). In patients with Stage IIB nonbulky tumors treated with irradiation alone or combined with surgery, the 5- and 10 year CCS rates were 72 and 65%, respectively; the corresponding survival rates with bulky tumors or bilateral parametrial involvement were 56 and 50%. Incidence of pelvic failures, alone or with distant metastasis, for Stage IB was 10% (43 out of 415) with irradiation alone and 14% (28 of 197) with irradiation plus surgery; for Stage IIA, 17% (23 out of 137) with irradiation alone and 20% (9 our of 44) with irradiation plus surgery; and for Stage IIB, 23% (88 out of 391) with irradiation alone and 29% (4 out of 14) with irradiation plus surgery. Grade 3 sequelae were comparable in both groups (irradiation alone, 5% to 11%; irradiation combined with surgery, 8% to 12%); the differences are not statistically significant. The most frequent major sequelae in 892 patients receiving irradiation only were rectovaginal fistula (13 cases, 1.5%), proctitis (10, 1.1%), small bowel obstruction (16, 1.8%), ureteral stricture (16, 1.8%), and vesicovaginal fistula (8, 0.9%). In 306 patients treated with irradiation plus surgery, the most commonly recorded major sequelae were small bowel obstruction/perforation (13 cases, 4.2%), ureteral stricture (8, 2.6%), vesicovaginal fistula (5, 1.6%), and rectovaginal fistula (4, 1.3%). CONCLUSION: Irradiation alone or combined with surgery yields comparable pelvic tumor control, survival, and morbidity in patients with Stage IB, IIA, and limited IIB carcinoma of the uterine cervix. PMID- 7860382 TI - Severe radiation morbidity in carcinoma of the cervix: impact of pretherapy surgical staging and previous surgery. AB - PURPOSE: The purpose of this study is to delineate the factors which (a) contribute to an increase in the severe, radiation induced complication rate and (b) have a significant effect on survival in patients with International Federation of Gynecologists and Obstetricians (FIGO) Stage I-IVA cervical cancer undergoing pretherapy surgical staging. METHODS AND MATERIALS: From 1971-1991, 189 patients underwent pretherapy surgical staging via a retroperitoneal approach (67) or transperitoneal approach (122). Seventy-nine patients had previously experienced a laparotomy. Patients subsequently received a median of 85 Gy to point A. In patients receiving paraaortic radiation, a median of 45 Gy was administered. One hundred and thirty-two (69.8%) patients received hydroxyurea as a radiation sensitizer. RESULTS: Pretherapy surgical evaluation revealed that 21 of 89 (23.6%) Stage II patients and 32 of 85 (37.6%) Stage III patients had paraaortic lymph node metastases. Multivariate logistic regression analysis detailed the significant factors favorably influencing the radiation-induced complication rate to be a retroperitoneal approach of pretherapy surgical staging and no previous laparotomy. Survival was significantly prolonged in patients receiving hydroxyurea, evaluated via a retroperitoneal incision, with negative paraaortic lymph nodes, and with an early stage of disease. CONCLUSION: A retroperitoneal approach to pretherapy surgical staging and absence of previous surgery reduced the incidence of subsequent radiation-induced complications. Despite improvements in the detection of occult disease, prolonged survival is impaired when the therapeutic measures currently available are used. PMID- 7860383 TI - Late rectal complication following high dose rate intracavitary brachytherapy in cancer of the cervix. AB - PURPOSE: To examine the incidence of radiation-induced late rectal complications using a rectal reference point in patients with cancer of the uterine cervix. METHODS AND MATERIALS: The subjects were 253 patients with cancer of the cervix who underwent high dose rate intracavitary brachytherapy (HDR-ICR). The rectal point (RP) was defined according to the criteria recommended in the ICRU Report 38. The time-dose factor (TDF) and the biologically effective dose (BED) were calculated as components of the cumulative reference rectal dose using the rectal reference point dose in intracavitary brachytherapy combined with the external whole pelvis dose. RESULTS: Statistical comparison of factors affecting the incidence of late rectal complication was conducted using data for 161 patients. The incidence of late rectal complications in the 161 patients was 9 patients (5.6%) for grade 1, 51 patients (31.7%) for grade 2, 11 patients (6.8%) for grade 3, and 13 patients (8.1%) for grade 4. The TDF and BED values were significantly correlated with the incidence of late rectal complication, and also showed strong correlation (r = 0.976) with each other. Grade 4 rectal complication was not observed in any patients with TDF below 130 or BED below 147. The calculated incidence of complications ranged from 5 to 10% at TDF values from 104 to 124 and at BED values from 119 to 146. CONCLUSION: These data regarding the incidence of rectal complication may be useful in reducing the incidence of late rectal complications arising after HDR-ICR treatment of cervical uterine cancer by adjusting the dose per fraction and number of fractions of HDR-ICR in individual patients and by improving the technique of inserting the intracavitary radiation apparatus. PMID- 7860384 TI - High dose rate brachytherapy for carcinoma of the uterine cervix: comparison of two different fractionation regimens. AB - PURPOSE: There is no consensus as to the best dose-fractionation regimen in high dose rate (HDR) brachytherapy for cervix cancer. Since 1983, two fractionation regimens have been used in different time periods at National Cancer Center Hospital, and their treatment results have been compared in terms of 5-year survival, local control, and complication rate to find the better therapeutic regimen. METHODS AND MATERIALS: From November 1983 to October 1990, 130 patients with uterine cervix carcinoma were treated with HDR intracavitary brachytherapy using a remote afterloading system. There were 21 Stage Ib patients, 5 Stage IIa, 29 Stage IIb, 2 Stage IIIa, 68 Stage IIIb, and 5 Stage IVa. The median age was 64 years. The median follow-up time was 50 months. Radiotherapy consisted of external beam irradiation to the pelvis (mean dose of 50 Gy), combined with HDR brachytherapy (mean dose of 20 Gy to point A) given 5 Gy per session twice weekly (group A: 54 patients) or 6 Gy once weekly (group B: 76 patients). RESULTS: The overall 5-year survival was 52% in group A and 72% in group B. Local recurrence rate was 11%, and distant failure rate was 21%, with no difference between the two groups. The complication rate was significantly lower in group B (37%) than in group A (55%). Multivariate analysis has shown that factors affecting survival were stage, brachytherapy dose, and local control status. No factor was predictive of local control, but the external beam radiation dose significantly influenced the risk of complications. CONCLUSION: The once-weekly HDR intracavitary applications combined with properly adjusted external beam pelvic irradiation is a safe and effective treatment for patients with uterine cervix cancer. PMID- 7860385 TI - Heuristically derived tumor burden score as a prognostic factor for stage IIIB carcinoma of the cervix. AB - PURPOSE: A retrospective analysis of radiotherapeutic management of locally advanced carcinoma of the uterine cervix was performed to evaluate the effect of various treatment parameters and disease extent upon treat outcome. METHODS AND MATERIALS: Between 1976 and 1989, 89 patients with Stage IIIB disease were treated with external beam radiotherapy and brachytherapy. Treatment outcomes were evaluated by dose to Point A, the proportion of Point A dose delivered by brachytherapy, clinical response at 3 months, and a newly developed tumor burden scoring system that quantifies the anatomical extent of disease. Kaplan-Meier estimates of tumor control and survival parameters were determined. RESULTS: Loco regional control (LRC), disease-free survival (DFS), and overall survival (OVS) at 5 years were 52.9%, 45.5%, and 50.3%, respectively. Clinical response at 3 months was highly predictive of local and distant tumor control. There was no correlation between proportion of brachytherapy dose and treatment outcome. The tumor burden scoring system demonstrates that FIGO Stage IIIB disease can be clinically divided into two prognostic groups of low and high tumor burden. Five year LRC was 62.9% and 40.2% for the low and high tumor burden groups, respectively (p = 0.024). Within the high tumor burden group the LRC was 53.0% and 22.5% when the point A dose given was > 78 Gy and < or = 78 Gy, respectively (p = 0.047). This correlated with improved DFS and OVS. CONCLUSION: The tumor burden scoring system subdivides FIGO Stage IIIB cervical carcinoma into two prognostic groups, predicting for overall survival and demonstrating a dose response in the high tumor burden group. This system may serve to improve future comparison of treatment outcome and to guide selection of patients who may benefit from a more aggressive treatment approach. PMID- 7860386 TI - Factors influencing cosmetic results after conservation therapy for breast cancer. AB - PURPOSE: Host, tumor, and treatment-related factors influencing cosmetic outcome are analyzed for patients receiving breast conservation treatment. METHODS AND MATERIALS: Four-hundred and fifty-eight patients with evaluable records for cosmesis evaluation, a subset of 701 patients treated for invasive breast cancer with conservation technique between 1969 and 1990, were prospectively analyzed. In 243 patients, cosmetic evaluation was not adequately recorded. Cosmesis evaluation was carried out from 3.7 months to 22.3 years, median of 4.4 years. By pathologic stage, tumors were 62% T1N0, 14% T1N1, 15%, T2N0, and 9% T2N1. The majority of patients were treated with 4-6 MV photons. Cosmetic evaluation was rated by both patient and physician every 4-6 months. A logistic regression analysis was completed using a stepwise logistic regression. P-values of 0.05 or less were considered significant. Excellent cosmetic scores were used in all statistical analyses unless otherwise specified. RESULTS: At most recent follow up, 87% of patients and 81% of physicians scored their cosmetic outcome as excellent or good. Eighty-two percent of physician and patient evaluations agreed with excellent-good vs. fair-poor rating categories. Analysis demonstrated a lower proportion of excellent cosmetic scores when related to patient age > 60 years (p = 0.001), postmenopausal status (p = 0.02), black race (p = 0.0034), and T2 tumor size (p = 0.05). Surgical factors of importance were: volume of resection > 100 cm3 (p = 0.0001), scar orientation compliance with the National Surgical Adjuvant Breast Project (NSABP) guidelines (p = 0.0034), and > 20 cm2 skin resected (p = 0.0452). Extent of axillary surgery did not significantly affect breast cosmesis. Radiation factors affecting cosmesis included treatment volume (tangential breast fields only vs. three or more fields) (p = 0.034), whole breast dose in excess of 50 Gy (p = 0.0243), and total dose to tumor site > 65 Gy (p = 0.06), as well as optimum dose distribution with compensating filters (p = 0.002). Daily fraction size of 1.8 Gy vs. 2.0 Gy, boost vs. no boost, type of boost (brachytherapy vs. electrons), total radiation dose, and use of bolus were not significant factors. Use of concomitant chemotherapy with irradiation impaired excellent cosmetic outcome (p = 0.02). Use of sequential chemotherapy or adjuvant tamoxifen did not appear to diminish excellent cosmetic outcomes (p = 0.31). Logistic regression for excellent cosmetic outcome analysis was completed for age, tumor size, menopausal status, race, type of surgery, volume of breast tissue resected, scar orientations, whole breast radiation dose, total radiation dose, number of radiation fields treated, and use of adjuvant chemotherapy. Significant independent factors for excellent cosmetic outcome were: volume of tissue resected (p = 0.0001), type of surgery (p = 0.0001), breast radiation dose (p = 0.005), race (p = 0.002), and age (p = 0.007). CONCLUSIONS: Satisfactory cosmesis was recorded in 81% of patients. Impaired cosmetic results are more likely with improper orientation of tylectomy and axillary incisions, larger volume of breast resection, radiation dose to the entire breast in excess of 50.0 Gy, and concurrent administration of chemotherapy. Careful selection of treatment procedures for specific patients/tumors and refinement in surgical/irradiation techniques will enhance the cosmetic results in breast conservation therapy. PMID- 7860387 TI - Breast conservation treatment of early stage breast cancer: patterns of failure. AB - PURPOSE: This study retrospectively assesses the patterns of failure in conservatively treated early stage breast cancer patients by correlating various clinical, pathologic, and treated-related factors with local, axillary, and distant relapse. METHODS AND MATERIALS: Between 1973 and 1990, 796 patients (817 breasts) received breast conservation surgery followed by radiotherapy. Local recurrences were counted as events even if they occurred simultaneously or after the appearance of axillary or distant metastases. RESULTS: The 10-year actuarial relative disease-free survival (DFS) rate for T1N0, T2N0, and T1-2N1 was 82%, 71%, and 54%, respectively. Stage N0 patients had a significant DFS advantage over N1 patients (p = 0.02). The 15-year actuarial local recurrence-free rate for T1 and T2 tumors was 82% and 87%, respectively (p = nonsignificant). Univariate analysis identified three significant risk factors for local relapse: (a) 48 breasts with tumors showing an extensive intraductal component had a crude local recurrence rate of 23% compared to 8% for 769 breasts without intraductal component (p = 0.0016); (b) the actuarial 10-year local recurrence-free rate for patients under age 40 years was 64% compared to 88% for patients over 40 years (p < 0.0001); (c) the 10-year actuarial local recurrence-free rate for 416 postmenopausal women without adjuvant tamoxifen was 83% compared to 97% for 107 postmenopausal women with tamoxifen (p = 0.0479). Salvage therapy for operable local recurrent patients resulted in a 8-year actuarial DFS rate of 47%, significantly lower than that obtained with primary treatment. The incidence of axillary relapse as the first sign of recurrence was 2%, and could be correlated with the lack of axillary dissection (p < 0.0000005) and primary tumor size (p = 0.03). Radiotherapy to the axilla did not influence axillary relapse. Actuarial 5 year DFS rate after treatment of isolated axillary recurrence was 27%. Axillary failure was a marker for distant failure. Contralateral breast cancer occurred in 8% of patients and did not have a detrimental effect on survival. Adjuvant tamoxifen decreased the 9-year actuarial incidence of contralateral breast cancer from 10% to 4% (p = 0.053). CONCLUSIONS: Tumors with extensive intraductal component, age under 40 years, and the omission of adjuvant tamoxifen in postmenopausal women increased local recurrence rate. Stage T2 and the lack of axillary dissection increased axillary recurrence rate. Stage N+ and local or axillary relapse increased distant failure rate. Axillary irradiation did not influence locoregional control nor survival. Improved therapy is needed for relapsing patients. PMID- 7860388 TI - Tamoxifen with and without radiation after partial mastectomy in patients with involved nodes. AB - PURPOSE: To determine the effect of tamoxifen on local control after partial mastectomy with and without adjuvant breast irradiation. METHODS AND MATERIALS: A retrospective study of 97 node positive patients identified from the records of the London Regional Cancer Center included 44 patients who received tamoxifen and breast irradiation (40 or 50 Gy plus booster dose) after partial mastectomy, and 53 patients who received tamoxifen only after partial mastectomy. Base line characteristics of the two groups were similar. RESULTS: At 39 months actuarial follow-up there was a breast tumor recurrence (BTR) in 5% vs. 21% of patients when radiation was omitted (p = 0.0388), but there was no difference in the cause specific mortality of the two treatment groups. Cox Regression analysis (on only 10 BTR) showed age and adjuvant radiation as significant predictors of BTR. In patients not receiving radiation, no BTR was seen in 22 patients > or = 70 years of age at diagnosis vs. 8 BTR in 31 patients < 70 years (p = 0.0130). All BTR occurred while patients were receiving tamoxifen. CONCLUSIONS: Tamoxifen alone with omission of radiation after partial mastectomy provides inferior breast tumor control in node positive patients. This is especially true for patients under 70 years of age. Patients aged 70 years or older at the time of diagnosis of breast cancer who receive tamoxifen have a low rate of breast tumor recurrence when radiation is omitted. These patients represent a group for whom radiation might not be necessary. PMID- 7860389 TI - Breast cancer in elderly women: a retrospective analysis of combined treatment with tamoxifen and once-weekly irradiation. AB - PURPOSE: To evaluate retrospectively the efficacy of combined modality treatment (hormone therapy and hypofractionated radiotherapy) in a population of very elderly women with breast cancer. METHODS AND MATERIALS: Records on 70 patients of median age 81 years, treated between January 1988 and February 1994, whose median follow-up is now 36 months, have been evaluated. Information obtained included clinical stage at diagnosis, histology, tumor grading, hormone receptor levels, details of treatment, type of failure, survival data, and status at last follow-up examination. Treatment consisted of Tamoxifen 20 mg daily and a hypofractionated course of high dose-per-fraction once-weekly radiotherapy. In the majority of cases this consisted of seven exposures of 6.5 Gy (five to the involved breast, and two to the tumor bed) given over 6 weeks, on a 60Co unit. Nodes were treated when clinically involved, to a dose of 27.5-30 Gy in five to six fractions. RESULTS: At median follow-up of 36 months, the overall survival rate is 87% [confidence interval (CI) 78-95%], the disease specific survival rate is 88% (CI 80-96%), and 72% (CI 60-84%) of patients are free of disease. The local control rate at 36 months is 86% (CI 76-95%). When analyzed by T stage, 81% of T1 patients, 96% of T2 patients, 60% of T3 patients and, paradoxically 100% of T4 patients were in local control at 36 months, although at that point there were just four such patients available for consideration in the T4 group. Initial response to hormone therapy does not appear to be a predictive indicator for ultimate loco-regional control. There is a trend towards greater probability of loco-regional failure if total dose delivered to the breast is less than 35 Gy. CONCLUSIONS: Women of elderly age are often denied combined modality therapy, because of coexistant disease or fears held by the responsible physicians that elderly patients are unable to tolerate surgery or protracted courses of radiotherapy. Consequently, many are treated by tamoxifen alone with poor results. This study demonstrates that very high rates of loco-regional control are achievable using hormonal treatment combined with high dose-per-fraction once weekly radiotherapy. PMID- 7860390 TI - Outcome and prognostic factors for local recurrence in mammographically detected ductal carcinoma in situ of the breast treated with conservative surgery and radiation therapy. AB - PURPOSE: We have retrospectively reviewed our institution's experience treating a predominantly mammographically detected population of ductal carcinoma in situ (DCIS) patients with conservative surgery and radiation therapy (CSRT) to determine outcome and prognostic factors for local recurrence. METHODS AND MATERIALS: Between January 1, 1982 and December 31, 1988, 52 consecutive cases of DCIS of the breast were treated with CSRT at William Beaumont Hospital. Forty-six (88%) were mammographically detected nonpalpable lesions. All patients underwent at least an excisional biopsy and 28 (54%) were reexcised. The axilla was surgically staged in 41 (79%) and all were N0. The entire breast was irradiated to 45-50 Gy over 5-6 weeks. The tumor bed was boosted in 49 (94%) so that the minimum dose was 60 Gy. The three patients not boosted received a minimum dose of 50 Gy to the entire breast. Pathologic materials were reviewed by one of the authors. RESULTS: The predominant DCIS pattern was comedo in 40%, cribriform in 28%, solid in 17%, and micropapillary in 15%. The predominant nuclear grade was Grade I in 51%, Grade II in 49%, and Grade III in 0%. The median follow-up is 68 months. There have been three recurrences in the treated breast at a median time to failure of 30 months. The 5- and 8-year actuarial local recurrence rate is 6%. One patient recurred with invasive ductal cancer at 28 months, and the other two recurrences were DCIS at 30 and 50 months. All three patients were treated with salvage mastectomy. The patient who recurred locally with an invasive cancer developed metastasis and died at 64 months. The 5- and 8-year actuarial cause specific survival rates are 100% and 97%, respectively. The following pathologic factors were analyzed for an association with local recurrence: predominant DCIS histology, predominant nuclear grade, and highest nuclear grade. Of these, the predominant nuclear grade was the best predictor of local recurrence (p = 0.070). No clinical or treatment related factor analyzed was associated with local recurrence. CONCLUSION: Our results indicate that excellent local control (94%) at 8 years is obtainable after CSRT in a mammographically detected population of patients with DCIS. The predominant nuclear grade was the only factor found that may be associated with local recurrence. PMID- 7860391 TI - A phase II trial evaluating selective use of altered radiation dose and fractionation in patients with unresectable rhabdomyosarcoma. AB - PURPOSE: Between 1987 and 1991, 25 children with advanced rhabdomyosarcoma (20 with IRS Group 3 disease and 5 with Group 4 disease) were entered on a prospective study evaluating selective use of hyperfractionated irradiation (HFI) and reduced-dose conventionally fractionated irradiation (CFI), based on disease status following induction chemotherapy (ifosfamide or melphalan, followed by vincristine, adriamycin, and cyclophosphamide combination) with or without delayed surgery. METHODS AND MATERIALS: Patients with gross disease following induction chemotherapy with or without delayed surgery, and whose primary tumor sites did not involve the central nervous system, received HFI (n = 12) at 1.1 Gy twice-a-day to 59.4-63.8 Gy total. Patients with parameningeal primaries and intracranial disease extension received HFI with initiation of therapy (n = 2). Those with microscopic disease following induction chemotherapy with or without delayed surgery (n = 11) received reduced-dose CFI to 40 Gy. Active follow-up ranges from 28-75 months (median = 43 months) with no patient lost to follow-up. RESULTS: Eighteen patients (72%) are alive and without evidence of disease, including 8 of the children with gross residual disease postinduction therapy. The absolute 2-year continuous local tumor control rate is 86% for all patients. Among the 14 who received HFI, the absolute 2-year continuous local tumor control rate is 75% at 33 to 67 months (median = 38 months) postirradiation. Hyperfractionated irradiation was associated with expected enhancement of acute reactions, which all resolved with conservative medical management. Grade 4 or 5 acute toxicities were not seen. Significant late radiation morbidity has, thus far, been minimal and limited to Grade 1 and 2 events. Among the 11 who received reduced-dose CFI, the absolute 2-year continuous local tumor control rate is 100% at 25 to 70 months (median = 40 months) postirradiation. CONCLUSION: This limited experience suggests that HFI to a dose level of 60 Gy can be used selectively in children with advanced rhabdomyosarcoma left with gross disease following induction chemotherapy, with or without delayed surgery, with an apparent improvement in local control, and minimization of potential late radiation toxicity. Concurrently, those left with microscopic disease following induction therapy can be selectively treated with reduced-dose CFI with excellent local control. PMID- 7860392 TI - Interdigitating versus concurrent chemotherapy and radiotherapy for limited small cell lung cancer. AB - PURPOSE: Sequencing and timing of chemotherapy and radiotherapy for limited small cell lung cancer (LSCLC) was studied in two consecutive trials. METHODS AND MATERIALS: In the interdigitating (IDG) trial, three cycles of COPE (cyclophosphamide 750 mg/M2 i.v. Day 1, vincristine 2 mg i.v. Day 8, cisplatin [DDP] 20 mg/M2 Days 1-3, etoposide 100 mg/M2 i.v. Days 1-3), were followed by thoracic radiation therapy (1.5 Gy bid 5-6 h apart, repeated twice at 3-week intervals) to give 45 Gy in 9 weeks; COPE was given during the intervals and for two more cycles. Operable patients had thoracotomy followed by IDG. Prophylactic cranial irradiation (PCI), 2.0 Gy x 15 fractions with a total dose of 30 Gy in 3 weeks, was given to the complete responders (CR) after completion of chemotherapy. In the concurrent (CON) trial, patients received DDP 60 mg/M2 i.v. Day 1, and etoposide 120 mg/M2 i.v. Days 1-3 for four cycles, every 3 weeks, and concurrent thoracic radiation therapy to 45 Gy with either 1.8 Gy daily, for 5 weeks or 1.5 Gy bid for 3 weeks. Prophylactic cranial irradiation (PCI) was given to the complete responders, 2.5 Gy daily for 2 weeks (25 Gy) (approximately 3 months after the initiation of treatment). RESULTS: The IDG group had 28 evaluable patients with median follow-up of 17.5 months. The CON group had 33 evaluable patients with median follow-up of 21 months. Overall survival rates for IDG patients were 79% at 1 year, 39% at 2 years, 30% at 3 years, and 27% at 4 years compared to 93%, 70%, 51%, and 46%, respectively, for the patients treated with CON (p = 0.01). Loco-regional recurrence (44%) and distant metastasis (48%) was more frequent as the first site of failure in the IDG group compared to the CON group (30% and 30%, respectively). Brain metastases constituted 30% of first metastases with IDG compared to none with CON. Esophagitis was significantly greater with CON. Hematologic and pulmonary toxicity were similar with IDG and CON. One death due to infection was seen in each treatment group. CONCLUSION: Concurrent chemoradiotherapy appears to be more effective than IDG. Earlier administration of PCI with concurrent chemotherapy and thoracic irradiation may reduce the risk of brain metastasis. PMID- 7860393 TI - Mitomycin, cisplatin, and vindesine followed by radiotherapy combined with cisplatin in stage III nonsmall cell lung cancer: long-term results. AB - PURPOSE: To assess the tolerance, response rate, pattern of failure, and long term survival of patients with unresectable nonsmall cell lung cancer treated with one cycle of induction chemotherapy followed by concurrent cisplatin and radiotherapy. METHODS AND MATERIALS: From 1986 to 1988, 45 patients with histologically proven nonsmall cell lung cancer clinical Stage III (29 IIIA and 16 IIIB) were included in this study. Patients received one cycle of Mitomycin C 10 mg/m2 day 1, Cisplatin 120 mg/m2 day 1, and Vindesine 3 mg/m2 days 1, 8, 15, and 22, by i.v. bolus injection. Radiotherapy was started within 4-6 weeks after completion of chemotherapy, with a total tumor dose of 60 Gy, at 2 Gy/day. Cisplatin, 20 mg/m2/day by i.v. continuous infusion was administered for days 1-5 of radiation treatment. RESULTS: The main toxic acute effects were nausea vomiting grade 1-3 in 38 patients (85%). Ten patients (22%) developed esophagitis grade 3. Leukopenia grade 1-2 was observed in 18 patients (40%), grade 3 in 12 (27%), and grade 4 in 4 (9%). Three patients (6.6%) died by granulocytopenia and sepsis. A bronchoscopic proven complete response was achieved in 9 patients (21.5%) and partial response in 28 patients (67%). With a minimum follow-up of 65 months, overall median survival was 13 months, 2-year survival was 21%, and 5 year survival was 7%, with no statistical difference between Stage IIIA and IIIB. Median survival of patients with complete response was 23.2 months, and 5-year survival was 33%. CONCLUSION: This treatment scheme produced a severe toxicity and in spite of a high response rate, long-term survival is poor, similar to previous studies with radiotherapy alone. PMID- 7860394 TI - Phase I/II study of treatment of locally advanced (T3/T4) non-oat cell lung cancer with concomitant boost radiotherapy by the Radiation Therapy Oncology Group (RTOG 83-12): long-term results. AB - PURPOSE: This pilot study was undertaken to evaluate the effect of high dose-per fraction radiotherapy given to the tumor primary concurrently with conventional fractionated radiotherapy to the electively irradiated regional lymph nodes (concomitant boost). This article reports the late results of toxicity and survival. METHODS AND MATERIALS: Fifty-nine patients with histologically proven clinical Stage T3-T4, N1-3 nonsmall cell lung cancer were prospectively enrolled in this study. Fifty-six were evaluable for late effects. The treatment delivered 2.68 Gy daily to the primary tumor, 5 days a week, to a total dose of 75 Gy in 28 fractions in 5.5 weeks. At the same treatment sessions, the electively irradiated nodal areas received 1.8 Gy daily, 5 days per week, to a total dose of 50.4 Gy. All doses were calculated with heterogeneity corrections for lung density. RESULTS: Presently, one patient remains alive at 7.7 years. Median survival was 10.0 months with 1-, 2-, 3-, and 5-year survival rates of 41%, 25%, 18%, and 4%, respectively. Three patients developed severe late complications, including pulmonary fibrosis and osteonecrosis. The remainder of the patients, however, developed only grade 1 or 2 pulmonary fibrosis and/or pneumonitis. CONCLUSION: We conclude that concomitant boost radiotherapy in the manner reported resulted in acceptable late toxicity. The 2- and 3-year survivals compared favorably with the best-reported results in the literature with either hyperfractionated or chemoradiotherapy treatment. Studies that deliver higher radiotherapy doses to the gross tumor combined with chemotherapy are in order. PMID- 7860396 TI - The decreased influence of overall treatment time on the response of human breast tumor xenografts following prolongation of the potential doubling time (Tpot). AB - PURPOSE: Repopulation during fractionated radiotherapy has been postulated to result in a significant loss in local control in rapidly proliferating tumors. Clinical data suggest that accelerated fractionation schedules can overcome the influence of repopulation by limiting the overall treatment time. Unfortunately, accelerated therapy frequently leads to increased acute reactions, which may become dose limiting. An alternative to accelerated fractionation would be to decrease the rate of repopulation during therapy. To test the potential efficacy of this alternative, we examined the effect of reducing tumor proliferation rate on the response of MCF-7 human breast carcinoma xenografts treated with a short vs. a long course of fractionated therapy. To reduce the proliferation rate, we deprived nude mice transplanted with MCF-7 xenografts of the growth-stimulating hormone estradiol (E2). We have previously reported that E2 deprivation increases the potential doubling time (Tpot) for MCF-7 xenografts from a mean of 2.6 days to 5.3 days (p < 0.001). METHODS AND MATERIALS: E2-stimulated and E2-deprived MCF 7 breast carcinoma xenografts were clamped hypoxically and irradiated with four fractions of 5 Gy each, using either a short (3-day) or long (9-day) treatment course. E2 stimulation was restored in all animals at the completion of irradiation. Radiation response was determined by regrowth time and regrowth delay of the irradiated tumors as compared to unirradiated controls. RESULTS: Prolongation of therapy in rapidly proliferating, E2-stimulated tumors (Tpot approximately 2.6 days) resulted in a significant decrease in regrowth time in two identical experiments. With results pooled for analysis, the regrowth times for the short and long treatments were 62 and 32 days, respectively (combined p < 0.001). The shorter regrowth times suggest that there was less overall tumor damage with the longer fractionated radiotherapy course. No significant difference in regrowth time was observed in the more slowly proliferating, E2 deprived tumors (Tpot approximately 5.3 days) treated with either the short or long regimen. Median regrowth times were 48 and 54.5 days for the short and long treatments, respectively (combined p = 0.14). Similar changes were observed in regrowth delay. CONCLUSIONS: Reduction in the rate of cell proliferation, induced by E2 deprivation in MCF-7 human breast xenografts during fractionated radiotherapy, resulted in a significantly decreased dependence on overall treatment time in comparison to the more rapidly proliferating E2-stimulated tumors. This model suggests that pharmacologically induced reduction in the rate of tumor cell proliferation during a course of fractionated radiotherapy may be a viable alternative to accelerated fractionation for the treatment of rapidly proliferating tumors. PMID- 7860397 TI - The intrinsic radiosensitivity of cervical carcinoma: correlations with clinical data. AB - PURPOSE: The aims of the work were to study the intrinsic radiosensitivity of tumor biopsies from patients with cervical carcinoma and to correlate the data with information on patient age, disease stage, differentiation status, tumor volume, and tumor ploidy. METHODS AND MATERIALS: Radiosensitivity was assessed for 145 tumors in vitro as surviving fraction at 2 Gy (SF2) using a clonogenic assay. RESULTS: Although the clonogens in tumors classified as Stage I or II tended to be more radiosensitive than in Stage III or IV disease, the difference was not statistically significant (p > 0.15). There was also no significant difference in the intrinsic radiosensitivity of well, moderately, or poorly differentiated tumors or between squamous cell carcinoma and adenocarcinoma (p > 0.53). There was no correlation between patient age and tumor radiosensitivity (p = 0.49). Large volume (> or = 4 cm) disease was more radioresistant than small volume (< 4 cm) disease, but the difference was not significant (p = 0.08). Finally, diploid tumors tended to be more radioresistant than aneuploid tumors (p = 0.07). CONCLUSION: The intrinsic radiosensitivity of cervix tumors is independent of disease stage, tumor grade, and patient age. Weak trends, however, were observed of increased tumor radioresistance for large volume disease and diploid tumors, suggesting that tumor SF2 may not be a completely independent parameter. PMID- 7860395 TI - Pilot study of human recombinant interferon gamma and accelerated hyperfractionated thoracic radiation therapy in patients with unresectable stage IIIA/B nonsmall cell lung cancer. AB - PURPOSE: Gamma interferon has a wide range of properties, including the ability to sensitize solid tumor cells to the effects of ionizing radiation. The North Central Cancer Treatment Group has previously completed pilot studies of accelerated hyperfractionated thoracic radiation therapy (AHTRT) in patients with unresectable Stage IIIA/B nonsmall cell lung cancer (NSCLC). This Phase I study was designed to assess the toxicity of concomitant gamma interferon and AHTRT in a similar patient population. METHODS AND MATERIALS: Between December 1991 and May 1992, 18 patients with unresectable Stage IIIA/B NSCLC were treated with daily gamma interferon (0.2 mg subcutaneously) concomitant with AHTRT (60 Gy given in 1.5 Gy twice daily fractions). All patients had an Eastern Cooperative Oncology Group performance status of 0 or 1 with weight loss < 5%. Eight patients had Stage IIIA and 10 had Stage IIIB disease. RESULTS: Nine patients (50%) experienced severe, life-threatening, or fatal toxicities. Eight of the patients (44%) developed significant radiation pneumonitis, which was severe in six patients and fatal in two patients (11% treatment-related mortality). Two patients (11%) developed severe radiation esophagitis. With follow-up of 15-21 months, 2 patients are alive, and 16 have died. The median survival time and 1 year survival rate is 7.8 months and 38%, respectively. CONCLUSION: Gamma interferon appeared to sensitize normal lung tissue to the effects of radiation, as demonstrated by the high incidence of severe or fatal radiation pneumonitis. We do not recommend pursuing gamma interferon as a radiosensitizer in this setting. PMID- 7860398 TI - Repopulation kinetics during fractionated irradiation and the relationship to the potential doubling time, Tpot. AB - PURPOSE: Therapeutic outcome may be adversely affected by repopulation in solid tumors during fractionated irradiation. It has been proposed that the repopulation rate of the surviving cells may be reflected by the pretreatment potential doubling time (Tpot). This concept has been examined by comparing pretreatment Tpot measurements to repopulation monitored in five transplantable murine tumors during fractionated radiation treatment. METHODS AND MATERIALS: Up to nine fractions of 2 Gy were given to clamped tumors on a 6 h schedule, which allowed adequate time for repair, or on a 24 h schedule, which incorporated more time for repopulation. Tumors were removed from treatment at various times and tumor cell survival was analyzed using an excision assay. The ratio of the cell survival in tumors treated with the same total dose on the two different fractionation schedules (24 h/6 h) was used to calculate an effective doubling time for repopulation during the treatment (Teff). Potential doubling time was assessed in untreated tumors by giving the tumor-bearing animals 5 bromodeoxyuridine (BrdUrd) and, at various times later, removing the tumors for flow cytometric analysis. Tpot values were calculated by two different widely used methods. RESULTS: For four tumors (RIF-1, KHT-C, KHT-LP1, and B16-F1), the Teff was greater than Tpot indicating that repopulation was not as rapid as suggested by Tpot. For SCC-VII, the only carcinoma tested, Teff was smaller than Tpot indicating that repopulation was more rapid than predicted by Tpot. Individual estimates of Tpot made from single tumor samples taken at different times after BrdUrd administration varied by factors of 2 to 7 for the different tumors. CONCLUSION: These findings indicate a need for caution in applying measurements of Tpot for prediction of regrowth rates in individual patients' tumors. PMID- 7860399 TI - The effects of clamping and reoxygenation on repopulation during fractionated irradiation. AB - PURPOSE: Clamping of solid tumors is often used during radiobiological experiments to eliminate reoxygenation and hypoxia as confounding variables. The appropriateness of this procedure has been questioned recently. METHODS AND MATERIALS: This article describes experiments designed to examine the tumor surviving fraction (TSF) during fractionated treatment (up to 9 x 2 Gy, every 6 h or 24 h) given under normal, unclamped conditions (aerobic), and to compare it to TSF values for treatment given under clamped conditions (anoxic). The dose per fraction for the clamped procedure was 5.5 Gy, approximately equivalent to the unclamped doses of 2 Gy (based on an assumed OER of 2.75). RESULTS: Overall, the survival in the unclamped experiments was greater than in the clamped experiments. When the contribution of repopulation to this phenomenon was analyzed, no significant difference was found for four (KHT-C, KHT-LP1, RIF-1, B16F1) of five transplantable murine tumor cell lines used. However, for the SCC VII squamous cell carcinoma, following small numbers of fractions there appeared to be more repopulation during the aerobic treatment schedule. Reoxygenation during the treatment was also analyzed, and the results indicate that, even with 24 h between doses, reoxygenation was insufficient to prevent an increasing hypoxic fraction during the treatment, which can explain the enhanced survival seen for the aerobic vs. the anoxic irradiation conditions. CONCLUSION: With the fractionation schedules used in this study, there was no evidence for a difference in repopulation kinetics when the treatment was given to clamped (anoxic) or unclamped (aerobic) tumors. In all five tumors studied, reoxygenation between the 2 Gy fractions was insufficient to prevent hypoxia from affecting the response of the tumors to the treatment. PMID- 7860400 TI - Radiation nephropathy in the rhesus monkey: morphometric analysis of glomerular and tubular alterations. AB - PURPOSE: The morphologic responses of the monkey kidney glomeruli and tubules to fractionated irradiation were assessed. METHODS AND MATERIALS: Both kidneys of adult female rhesus monkeys were irradiated with doses of gamma-rays ranging from 24 Gy in 12 fractions up to 36 Gy in 18 fractions. Serial renal biopsies were taken between 1 and 12 weeks after irradiation. The kidneys were removed at necropsy 16-23 weeks after irradiation. Glomeruli were assessed for the presence of pathologic features, including intercapillary eosinophilic material, ectatic capillaries, thrombi, hemorrhage, adhesions, and sclerosis. The relative proportion of renal cortex occupied by glomeruli, interstitium, or tubules was determined using a Chalkley point grid. Tubules were further scored as being either normal or abnormal in appearance. RESULTS: Examination of the renal biopsies revealed that progressive glomerular lesions were evident within 4-12 weeks after irradiation. Tubular changes were mild and focal. Morphometric analysis of whole kidneys removed at necropsy demonstrated that numbers of glomeruli with ectatic capillaries, thrombi, and hemorrhage were significantly different from controls at 16-23 weeks after irradiation by all of the doses in the range of 24 to 36 Gy. A significant (p < 0.05) increase in the relative proportion of renal cortex occupied by glomeruli and interstitium was indicative of tubule loss. Further analysis of these tubular changes revealed a highly significant (p < 0.001) dose-dependent increase in the proportion of abnormal to normal tubules. Thus following a dose of 24 Gy in 12 fractions, the ratio of abnormal: normal tubules was approximately 1:2; after 36 Gy in 18 fractions the ratio was 3:1. CONCLUSIONS: Glomeruli appeared to be very radiosensitive because after the clinically relevant dose of 24 Gy in 12 fractions essentially all glomeruli were altered in the irradiated kidneys as compared to controls. Thus, efforts aimed at increasing the threshold dose for development of radiation nephropathy should be directed primarily at preventing the glomerular lesions. PMID- 7860401 TI - Clinical evaluation of an interstitial remote afterloading device for multichannel intracavitary irradiation. AB - PURPOSE: The purpose of this report is to describe the clinical implementation and evaluation of an interstitial remote afterloading device for multichannel intracavitary brachytherapy. METHODS AND MATERIALS: Two 15-channel low dose rate devices were adapted for use with Fletcher-Suit tandem and ovoids and Simon Heyman capsules. The technical records for 103 intracavitary brachytherapy procedures performed from February 1989 through February 1991 were reviewed. RESULTS: Isodose distributions from fixed source trains for Microselectron low dose rate gynecologic applicators closely approximate standard manual afterloading sources and applicators. Device malfunctions occurred in 51% (53 out of 103) of the procedures. Malfunctions by applicator type were 70% (51 out of 73) for tandem, ovoids, and capsules, 12% (2 out of 17) for tandem and ovoids, and none (0 out of 13) for ovoids only. The most common malfunction occurred during source transfer. Total implant time was prolonged 0 to 4% by malfunction and 10% by patient care interruptions, depending on applicator type. CONCLUSION: The adaptation of the Microselectron device for multichannel gynecologic intracavitary brachytherapy results in similar dose distributions as standard manual after loading sources and a decreased radiation exposure to nursing personnel. The system has a high rate of malfunctions but a low overall prolongation of implant time due to malfunction. PMID- 7860402 TI - Analysis of clinical complication data for radiation hepatitis using a parallel architecture model. AB - PURPOSE: The detailed knowledge of dose volume distributions available from the three-dimensional (3D) conformal radiation treatment of tumors in the liver (reported elsewhere) offers new opportunities to quantify the effect of volume on the probability of producing radiation hepatitis. We aim to test a new parallel architecture model of normal tissue complication probability (NTCP) with these data. METHODS AND MATERIALS: Complication data and dose volume histograms from a total of 93 patients with normal liver function, treated on a prospective protocol with 3D conformal radiation therapy and intraarterial hepatic fluorodeoxyuridine, were analyzed with a new parallel architecture model. Patient treatment fell into six categories differing in doses delivered and volumes irradiated. By modeling the radiosensitivity of liver subunits, we are able to use dose volume histograms to calculate the fraction of the liver damaged in each patient. A complication results if this fraction exceeds the patient's functional reserve. To determine the patient distribution of functional reserves and the subunit radiosensitivity, the maximum likelihood method was used to fit the observed complication data. RESULTS: The parallel model fit the complication data well, although uncertainties on the functional reserve distribution and subunit radiosensitivity are highly correlated. CONCLUSION: The observed radiation hepatitis complications show a threshold effect that can be described well with a parallel architecture model. However, additional independent studies are required to better determine the parameters defining the functional reserve distribution and subunit radiosensitivity. PMID- 7860403 TI - Simultaneous delivery of electron beam therapy and ultrasound hyperthermia using scanning reflectors: a feasibility study. AB - PURPOSE: The feasibility of simultaneously delivering external electron beam radiation and superficial hyperthermia using a scanning ultrasound reflector array system (SURAS) was experimentally investigated and demonstrated. METHODS AND MATERIALS: A new system uses a scanning reflector to distribute the acoustic energy from a planar ultrasound array over the surface of the target volume. External photon/electron beams can be concurrently delivered with hyperthermia by irradiating through the scanning reflectors. That is, this system enables the acoustic waves and the radiation beams to enter the target volume from the same direction. Reflectors were constructed of air-equivalent materials for maximum acoustic reflection and minimum radiation attenuation. Acoustically, the air reflectors were compared to brass reflectors (assumed ideal) for reflectivity and specular quality using several single transducers ranging in frequency from 0.68 to 4.8 MHz. The relative reflectivity was determined from acoustic power measurements using a force-balance technique. The specular quality was assessed by comparing the acoustic pressure fields reflected by air reflectors with those reflected by brass reflectors. Also, acoustic pressure fields generated by a SURAS prototype for two different arrays (2.24 and 4.5 MHz) were measured to investigate field distribution variations as a function of the distance separating the array and the scanning reflector. All pressure fields were measured with a hydrophone in a degassed water tank. Finally, to determine the effect of the air reflectors on electron dose distributions, these were measured using film in a water-equivalent solid phantom after passage of a 20 MeV electron beam through the SURAS. These measurements were performed with the reflector scanning continuously across the electron beam and at rest within the electron beam. RESULTS: The measurements performed using single ultrasound transducers showed that the air reflectors had power reflectivities of 87-96% that of brass, and that for smooth surfaces the reflections from air reflectors were as specular as those from brass reflectors. Acoustic pressure fields measurements of the SURAS for two different arrays showed that the 50% pressure amplitude contours were well-distributed across the projected surface area of the array for different distances separating the array and the reflector. Finally, film dosimetry showed that the electron dose distribution was not affected by the air reflector of the SURAS either for the scanning case or the stationary case. This indicates that the reflectors as made are basically water-equivalent in terms of high energy ionizing radiation. The measured isodoses also indicate that the constructed SURAS prototype would allow the delivery of adequate radiation (90% isodose) to a depth of 2.0 cm. CONCLUSIONS: The results presented show that the SURAS design has the potential to deliver hyperthermia to large superficial tumors, while allowing simultaneous irradiation with 20 MeV electron beams without adverse effects on the radiation dose delivery. PMID- 7860404 TI - Thermal response and hyperthermic radiosensitization of scid mouse bone marrow CFU-C. AB - PURPOSE: Scid mice are severely immunodeficient as a result of a defective recombinase system. Mice with the scid mutation have been shown to have an increased sensitivity to ionizing radiation, presumably as a result of an inability to repair DNA damage. Little is known of the impact of this mutation on the thermal response and on hyperthermic radiosensitization. This investigation established the thermal response (42-44 degrees C), patterns of thermotolerance development, and the impact of hyperthermia (60 min at 40 degrees C or 42 degrees C) on the radiation response of bone marrow colony forming unit-culture cells (CFU-C) in scid mice. METHODS AND MATERIALS: Anesthetized scid mice (pentobarbital, 90 mg/kg) were killed by cervical dislocation and the nucleated marrow obtained from both tibia and femora by passing 2 ml of cold McCoy's 5A medium supplemented with 15% fetal bovine serum through each bone. Single cell suspensions of nucleated marrow were heated in 12 x 75 mm sterile tissue culture tubes at a concentration of approximately 5 x 10(6) cells/ml. Radiation, when used, was delivered immediately prior to hyperthermia by a 137Cs irradiator (dose rate of 1.20 Gy/min). Colony forming unit-culture were cultured in semisolid agar in the presence of colony stimulating factor (conditioned medium from L929 cells) for 7 days. RESULTS: The slope of the radiation dose-response curve for CFU-C in scid mice was biphasic, the Dos (+/- SE) were 0.29 +/- 0.03 Gy and 1.09 +/- 0.20 Gy, respectively. The Dos of the radiation dose-response curve for wild type marrow from CB-17 and Balb/c mice were 1.28 +/- 0.05 Gy and 1.47 +/- 0.15 Gy, respectively. The Dos of the hyperthermia dose-response curves for scid mice were 75 +/- 5, 10 +/- 1.4, and 4 +/- 0.2 min, respectively, for temperatures of 42 degrees, 43 degrees, and 44 degrees C. Thermotolerance development at 37 degrees C increased to a maximum at approximately 240 min after acute hyperthermia (15 min at 44 degrees C) and thereafter, decreased to control levels within 15 h. Thermotolerance did not develop in scid CFU-C during chronic hyperthermia at temperatures < 42.5 degrees C. Hyperthermia (60 min at 40 degrees or 42 degrees C) immediately after ionizing radiation did not significantly alter the terminal slope of the radiation dose-response curve of scid CFU-C (Do = 1.28 +/- 0.08 Gy). By contrast, hyperthermia following radiation of wild type CFU-C resulted in a decrease in the Do from 1.47 +/- 0.05 Gy (Balb/c, rad only) to 1.31 +/- 0.08 or 1.06 +/- 0.18 Gy for 60 min at 40 degrees or 42 degrees C, respectively. CONCLUSION: These results show that the thermal response and the pattern of thermotolerance development of scid CFU-C were similar to that of wild type Balb/c CFU-C, but that hyperthermia given immediately after ionizing radiation did not alter the radiation response of scid CFU-C. The scid mutation does not increase hyperthermic sensitivity or change the pattern of thermotolerance development of scid mouse CFU-C, implying that the scid mutation is not involved with thermal response, but does render the already radiation-sensitive scid cells incapable of thermal radiosensitization. PMID- 7860405 TI - Follow-up of cognitive functioning in patients with small cell lung cancer. AB - PURPOSE: Study of the course of possible treatment-related cognitive impairment in patients with small cell lung cancer. METHODS AND MATERIALS: Thirty-two consecutive patients with small cell lung cancer underwent successive neurologic and neuropsychologic examinations until 5 months after prophylactic cranial irradiation, and in their pretherapeutic condition were compared to matched controls. Patients with brain metastases were excluded from this study. RESULTS: Neurologic examination revealed central nervous system (CNS) abnormalities only in the 14 patients with brain metastases. In the remaining patients, neuropsychologic tests showed clear differences between the pretherapeutic performance of patients and that of matched controls (p < 0.001), but no significant deterioration either during or after therapy (0.1 < p < 0.8). CONCLUSION: The difference between the pretherapeutic performance of patients and that of matched controls may indicate disease-related cognitive impairment. Within the observation period, no adverse effects of the used therapy were found. Our observations underline the importance of a pretherapeutic assessment in neurotoxicity research. PMID- 7860406 TI - The effect of irradiation on lung function and perfusion in patients with lung cancer. AB - PURPOSE: To prospectively study the changes in lung function in patients with lung carcinoma treated with relatively high doses of irradiation. METHODS AND MATERIALS: Lung function was assessed prior to and at 6 and 12 months following radiation therapy by a clinical dyspnea score, formal pulmonary function tests (lung volume spirometry and diffusion capacity) as well as an ipsilateral hemithorax lung perfusion scan. Changes in dyspnea score were evaluated by the chi-square and the Fishers exact test. Changes in formal lung function tests were compared with the t-test for dependent data and correlations with the t-test for independent data. Fifty-one patients were entered into the study. There were 42 evaluable patients at 6 months after irradiation and 22 evaluable patients at 12 months after irradiation. RESULTS: A worsening of dyspnea score from 1 to 2, which is clinically acceptable, occurred in 50% or more of patients. However, a dyspnea score of 3, which is a serious complication, developed in only 5% of patients. The diffusion capacity (DLCO) decreased by 14% at 6 months and 12% at 12 months) (p < 0.0001). The forced vital capacity and total lung capacity decreased between 6% and 8% at 6 months and 12 months, which was statistically significant. The forced expiratory volume in 1 s decreased between 2 and 3% at 6 month and 12 months, which was not statistically significant. The ipsilateral hemithorax perfusion decreased by 17 and 20% at 6 and 12 months (p < 0.0001). There was no correlation between the initial hemithorax perfusion, or its decrease at follow up and the decrease in DLCO. CONCLUSION: Lung irradiation results in some loss of lung function in patients with lung cancer with a projected survival of 6 months or more. The pretreatment DLCO assessment should be useful in predicting clinical tolerance to irradiation. PMID- 7860407 TI - Concurrent radiotherapy and chemotherapy with protracted continuous infusion of 5 fluorouracil in inoperable esophageal squamous cell carcinoma. AB - PURPOSE: The feasibility of a concurrent chemoradiotherapeutic protocol for patients with inoperable esophageal squamous cell carcinoma was tested. METHODS AND MATERIALS: Concurrent chemoradiotherapy using protracted low-dose continuous infusions of five-fluorouracil (5-FU; 250-300 mg/m2/24 h) and standard external beam irradiation was given to 28 patients with inoperable esophageal squamous cell carcinoma between November 1991 and June 1993. RESULTS: For 25 patients receiving a total dose of > or = 60 Gy and concurrent 5-FU infusion for more than 5 weeks, the complete response rate was 52%. Local progression-free rate in this chemoradiotherapy group was significantly higher than the historical controls treated by radiotherapy alone (p < 0.05). A multivariate analysis revealed the treatment scheme (concomitant chemoradiotherapy vs. radiotherapy alone) to be a significant factor in local control (p < 0.01). Swallowing pain (39%), anorexia (39%), and nausea (32%) were the most frequent early reactions. Serious late radiation complications have not been observed. CONCLUSION: The concurrent chemoradiotherapy using protracted low-dose continuous infusion of 5-FU and standard radiotherapy is an effective and safe method to obtain a local control in inoperable esophageal squamous cell carcinoma. PMID- 7860408 TI - Radiation therapy for primary orbital lymphoma. AB - PURPOSE: The influence of tumor size, grade, thoroughness of staging workup, and radiation dose on disease control, radiation-related complications, and incidence of systemic progression of primary orbital lymphoma is analyzed. METHODS AND MATERIALS: Twenty patients with Stage I primary orbital lymphoma were treated from August 1976 through August 1991 at Mallinckrodt Institute of Radiology. Staging workups included physical examination, chest x-ray, complete blood count (CBC), liver function test, and computerized tomography (CT) scan of the orbit, abdomen, and pelvis. Nineteen patients had bone marrow biopsy. The histological types based on the National Cancer Institute working formulation were 9 low-grade and 11 intermediate-grade, including five lymphocytic lymphomas of intermediate differentiation. The extension of disease and the volume of tumor were evaluated by CT scan of the orbit. The most commonly used radiation therapy technique was single anterior direct field with 4 MV or 6 MV photons. Lens was shielded or not treated in eight patients. Dose ranged from 20 to 43.2 Gy. Thirteen of 20 patients received 30 Gy. Minimum follow-up was 24 months (median, 4 years). RESULTS: Local control was achieved in all 20 patients. One patient with lymphocytic lymphoma with intermediate differentiation developed disseminated disease. Actuarial disease-free survival (DFS) was 100% and 90% at 2 and 5 years, respectively. No retinopathy was observed. Cataracts were noted in seven patients at 1 to 10 years following irradiation (median, 2 years). Three patients developed lacrimal function disorder; however, no corneal ulceration occurred. CONCLUSIONS: Thirty Gy in 15 fractions appears to be a sufficient dose for local control with acceptable morbidity, especially for low-grade, as well as certain types of intermediate-grade lymphomas, such as diffuse small cleaved cell and lymphocytic lymphoma of intermediate differentiation. Systemic dissemination is minimal, provided local control is achieved and initial staging workups are adequate. PMID- 7860409 TI - The use of digitally reconstructed radiographs for three-dimensional treatment planning and CT-simulation. AB - PURPOSE: Recent interest in computed tomography-simulation (CT-simulation) suggests the possibility of a shift to digital images for field verification. This article examines the quality of Digitally Reconstructed Radiographs (DRRs) to determine if they can reasonably be substituted for conventional simulator films, and suggests techniques to improve these images. METHODS AND MATERIALS: Special developmental software and computer hardware allowed extremely rapid reformatting of CT data to produce images geometrically equivalent to treatment unit portal films. The technique uses a trilinear interpolation algorithm and gives a 512 x 512 DRR for any arbitrary beam direction. Resolution in line pairs/cm (lp/cm) for both simulator radiographs and DRRs was measured with a special test phantom. Patient data was reformatted to illustrate methods for improving the quality of the DRR. RESULTS: The equipment used for this study reformats 50 512 x 512 CT scans in 8 s. The resolution for a DRR is limited by the voxel size of the CT scans. For typical voxel dimensions, the resolution was found to be 7 lp/cm transverse and 1.0 lp/cm longitudinal compared to 21.0 lp/cm for a simulator radiograph. Patient movement during the scan procedure further degrades the DRR. The reduced quality of this image makes it more difficult to discern structures, and it may not always be possible to perform essential tasks such as counting vertebral bodies. However, viewing the treatment field superimposed on a DRR displayed with a step function to include only bone aided in the identification of relevant landmarks. Switching between soft tissue, bone, or air windows takes less than 10 s on the equipment used for this study, and the use of different display techniques improved the viewer's ability to evaluate field positioning. CONCLUSIONS: A DRR cannot match the spatial resolution of a radiograph taken with a short exposure and small focal spot, but the ability to change the display mode for the DRR increases the usefulness of these images. Fast reformatting is particularly important when evaluation of field position requires the comparison of each portal image to a series of DRRs. PMID- 7860410 TI - A new model for "accept or reject" strategies in off-line and on-line megavoltage treatment evaluation. AB - PURPOSE: With megavoltage on-line imaging, a temporal record of the treatment setup variation is made available during the course of radiotherapy. This work describes the theoretical framework where the imaging data is incorporated as feedback for deriving off-line and on-line "accept or reject" decisions to improve the quality of radiotherapy on an individual patient basis. METHODS AND MATERIALS: A dynamic model of treatment setup variation is developed to describe: (a) the variations of multifraction treatment position and (b) the variation of measurement. Based on this model, a confidence region of subsequent treatment position is estimated from measurements of previous treatment position. The confidence region is compared with an allowance region of the treatment position, representing the acceptable margin of setup variation. The difference of the two regions are then evaluated to derive off-line and on-line "accept or reject" treatment decisions. RESULTS: The model was simulated retrospectively using sequential daily images from different treatment sites. "Accept or reject" decisions were produced for on-line and off-line applications. The results also demonstrate the ability of the model to include the effects of setup variation that drifted during the course of treatment. CONCLUSION: The preliminary result demonstrates that "accept or reject" treatment decisions can be derived quantitatively from on-line imaging data. The model shows potential to guide the physician and therapist in implementing efficient and accurate treatment adjustments. Further work is required to test the model in the clinical setting. PMID- 7860411 TI - Quantitative bremsstrahlung single photon emission computed tomographic imaging: use for volume, activity, and absorbed dose calculations. AB - PURPOSE: To perform bremsstrahlung single photon emission computed tomographic (SPECT) imaging using 32P chronic phosphate for volume and activity quantitation to calculate absorbed dose estimates. METHODS AND MATERIALS: Seven cancer patients enrolled in clinical Phase I therapeutic protocols were injected with 2.5 million particles of macroaggregated albumin, followed by colloidal 32P chromic phosphate by direct interstitial injection into the tumor-bearing region under computed tomographic (CT) guidance. SPECT images were obtained in these patients. The patient body contour was defined through the use of two externally placed Compton backscatter 99mTc sources. A computer algorithm was written to facilitate region-of-interest volume and activity determination on the reconstructed SPECT slices based on a fixed threshold method. Three sequential SPECT studies were acquired in two of these patients, to determine the accuracy of activity quantitation for bremsstrahlung SPECT studies using Chang's postprocessing method of attenuation compensation with a computer-generated body contour based on the Compton backscatter sources, and an experimentally measured effective linear attenuation coefficient for 32P. The serial data in these two patients were used to calculate absorbed dose estimates. RESULTS: The 99mTc backscatter sources enabled the patient body outline to be clearly visualized in all the transaxial reconstructed slices and did not contribute significant counts to the patient 32P counts. The calculated activities from the SPECT studies were within 7.8% of the administered 32P activity. The two calculated patient absorbed doses were 4.2 x 10(3) Gy and 5.9 x 10(3) Gy for injected activities of 736 MBq and 920 MBq, respectively. CONCLUSION: We conclude that accurate quantitative bremsstrahlung SPECT imaging, for the case of high contrast well-localized activity distributions, with a commercially available postprocessing attenuation correction algorithm, can be performed in a clinical setting. Entirely SPECT based measurements can be used to generate absorbed dose estimates. PMID- 7860412 TI - Method of localization and implantation of the lumpectomy site for high dose rate brachytherapy after conservative surgery for T1 and T2 breast cancer. AB - PURPOSE: This article describes our technique of localization and implantation of the lumpectomy site of patients with T1 and T2 breast cancer. Our method was developed as part of our Phase I/II pilot study of high dose rate (HDR) brachytherapy alone after conservative surgery for early breast cancer. METHODS AND MATERIALS: In March 1992, we started a pilot study of HDR brachytherapy to the lumpectomy site as the sole radiotherapy after conservative surgery for clinical T1 or T2 invasive breast cancer. Initially, the protocol required intraoperative placement of the interstitial needles at the time of definitive surgery to the breast. The protocol was then generalized to allow the implantation of the lumpectomy site after definitive surgery to the breast, either at the time of subsequent axillary nodal dissection or postoperatively. To date, five patients have been implanted intraoperatively at the time of definitive breast surgery. Twelve patients were implanted after definitive breast surgery, with 7 patients being done at the time of axillary nodal dissection and 5 patients postoperatively. We devised a method of accurately localizing and implanting the lumpectomy site after definitive breast surgery. The method relies on the previous placement of surgical clips by the referring surgeon to mark the lumpectomy site. For each patient, a breast mold is made with radio-opaque angiocatheters taped onto the mold in the supero-inferior direction. A planning CT scan is then obtained through the lumpectomy site. The volume of the lumpectomy site, the number of implant planes necessary, and the orientation of the implants are then determined from the CT scan. The angiocatheters provide a reference grid on the CT films to locate the entry and exit points of the interstitial needles on the plastic mold. The entry and exit points for reference needles are then transferred onto the patient's skin enabling implantation of the lumpectomy site. Needle positions with respect to the lumpectomy site are then verified using simulator radiographs. RESULTS: Eight double plane implants and four single plane implants have been done using this method. Five implants were done using direct visualization. It has not been necessary to reorient the implant in any of the patients. If not for the presence of surgical clips, the size of the lumpectomy site cannot be separated from the surrounding normal breast tissue. CONCLUSION: This technique is an accurate way to localize the lumpectomy site for HDR brachytherapy. PMID- 7860413 TI - High dose-rate microselectron molds in the treatment of skin tumors. AB - PURPOSE: The feasibility of high dose rate iridium afterloaded molds in the treatment of skin tumors. METHODS AND MATERIALS: Expanded silicone rubber and bronchial applicator tubes were used in the construction of various molds. The number of tubes used and the separation between them depends on the size and area to be treated. Source dwell position and time are set to follow Paterson-Parker rules. Single plane expanded silicone rubber molds between 15 X 15 mm and 60 X 70 mm were used in 120 different sites, and of the others, seven were perspex double molds, two were cylindrical applicators, and one was a partially shielded intranasal applicator. One hundred and thirty lesions of various site and histology were treated in all. After exclusion of treatments that were combined with either external beam or chemotherapy, 106 lesions (76 patients) were evaluated. RESULTS: Full response was obtained in all but four basal cell carcinomas. The acute reaction ranged from moist desquamation (27 sites) to erythema only. Follow-up at 5 or more months revealed no changes whatever in 47 sites; 53 showed an excellent cosmetic outcome, although slight changes in pigmentation or minimal atrophy was demonstrable and 6 sites became noticeably atrophic with patchy pigmentation. For 9.6 months of average follow-up time, no recurrences have been observed. CONCLUSION: The high-dose-rate iridium-loaded skin applicators offer the possibility of improved therapeutic ratio in the treatment of superficial skin tumors. With the availability of a high-dose-rate afterloader this technique is simple and straightforward. PMID- 7860414 TI - Long-term results of treatment of cervical carcinoma in the United States in 1973, 1978, and 1983: Patterns of Care Study (PCS). AB - PURPOSE: To extend the observations of patients with carcinoma of the cervix treated in 1973 for over 15 years, in 1978 for over 10 years, and in 1983 for over 5 years for survival and local control to compare treatment times and outcome. METHODS AND MATERIALS: A nationwide survey of the patterns of practice in radiation therapy for patients with squamous carcinoma of the cervix collected pretreatment and treatment data using external surveyors who reviewed patients' records. Outcome information was updated for the three separate databases by mail survey. Overall survival, no evidence of disease (NED) survival, and local control curves by stage were plotted using the estimates derived by the Kaplan Meier method. RESULTS: Total number of patients surveyed was 1686: 937 patients in 1973, 565 patients in 1978, and 184 patients in 1983. These are the results from changes in treatment policy, particularly the increasing use of brachytherapy. Of Stage III patients, the percentage receiving brachytherapy was 60.5% in 1973, 76.5% in 1978, and 87.9% in 1983 (p < 0.001 by linear trend test). Also, there was an increased proportion in use of higher energy for external pelvic irradiation during the more recent time period, e.g., 28% in the 1973 study, 60% in the 1978 study, and 87% in the 1983 study compared to the usage of cobalt-60 equipment. Comparison of results including overall survival, local control, and NED survival for the three different time periods showed improvement in outcome for Stage III in 1983, but not Stages I and II. The 5-year survival for Stage III increased from 25% in the 1973 survey to 47% in the 1983 survey, a linear trend that is statistically significant (p = 0.02). CONCLUSION: The long term results of radiotherapy for patients with carcinoma of the cervix show improved outcome for Stage III patients, which probably results from improved treatment, including higher energy for pelvic irradiation and increase in use of brachytherapy contributing better local control and fewer complications. PMID- 7860415 TI - Neuropsychological effects of cranial radiation: current knowledge and future directions. AB - Radiation is an invaluable therapeutic tool in the treatment of cancer, with well established palliative and curative efficacy. As patient survival has improved, attention has focused on long-range treatment side effects. One such adverse effect, neuropsychological impairment, is incompletely understood. Much of the extant research has been directed at childhood leukemia survivors treated with low-dose whole-brain radiation. Less is known about the effects of high-dose focal or whole-brain radiation used in the treatment of brain lesions. This article reviews the scientific literature in this area, with greatest emphasis on methodologically rigorous studies. Research design considerations are discussed. Review findings suggest that low-dose whole-brain radiation (18 to 24 Gy) in children is associated with mild delayed IQ decline, with more substantial deficits occurring in children treated at a young age. A high incidence of learning disabilities and academic failure is observed in this population and may be caused by poor attention and memory rather than low intellectual level. Children who receive higher dose radiation for treatment of brain tumors experience more pronounced cognitive decline. At higher doses, whole-brain radiation, in particular, is linked to deleterious cognitive outcomes. Remarkably little is known about cognitive outcomes in irradiated adults. Preliminary findings indicate that certain cognitive functions, including memory, may be more vulnerable to decline than others. Suggestions for future research are proposed. PMID- 7860416 TI - The effects of health care reform on academic medical centers: 1994 Gold Medal Address. PMID- 7860417 TI - The testicular iron shuttle: a "nurse" function of the Sertoli cells. AB - The techniques of cell culture and molecular biology first revealed that Sertoli cells synthesize transferrin. Accumulated biological information led to a plausible model for the role of testicular transferrin in an iron shuttle system designed to transport ferric ions around the cellular tight junctions to the germ cells inside the blood-testis barrier. Experiments done in culture and in vivo have supported many aspects of this model. A mutant mouse model that lacks the ability to synthesize transferrin is defective in spermatogenesis and may help to delineate the nature of the iron requirement by germ cells. The levels of seminal transferrin, possibly of Sertoli cell origin, are proportional to sperm production in humans and cattle and may be an effective indicator of Sertoli cell function. The testicular iron shuttle thus represents an important "nurse cell" function of the Sertoli cells. PMID- 7860418 TI - Follicle-stimulating hormone (FSH) escape during chronic gonadotropin-releasing hormone (GnRH) agonist and testosterone treatment. AB - Observations that serum follicle-stimulating hormone (FSH) levels begin to rise after initial suppression during chronic gonadotropin-releasing hormone (GnRH) agonist treatment of men with prostate cancer had led to speculation that FSH escape might in part account for the failure of GnRH agonist analogs to completely suppress spermatogenesis in normal eugonadal men. However, previous studies in healthy young men failed to report FSH escape during GnRH agonist treatment for up to 16 weeks. We considered the possibility that this may have been due to the insensitivity of the FSH assays. Accordingly, using highly sensitive and specific two-site directed fluorometric assays and a sustained release GnRH agonist formulation, we reexamined the issue of whether serum FSH levels rise after initial suppression during chronic GnRH agonist treatment. Two groups of healthy normal men, 19-50 years of age, received 7.5 mg of a long acting GnRH agonist microcapsule formulation (Lupron Depot; TAP Pharmaceutical Company, North Chicago, Illinois) on days 1 and 30. In addition, the subjects received either 4 or 8 mg/day testosterone replacement by means of a testosterone microcapsule injected intramuscularly on day 1. Serum luteinizing hormone (LH) and FSH levels were measured by sensitive and specific two-site directed fluorometric assays on multiple occasions during the 3-week control period and the 9-week treatment period. Serum LH levels declined to a nadir between 2 and 4 weeks and stayed suppressed throughout the remainder of the treatment period in both the 4- and 8-mg testosterone groups.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7860419 TI - The effect of vasoactive intestinal polypeptide (VIP) on rabbit cavernosal smooth muscle contractility. AB - Vasoactive intestinal polypeptide (VIP) has emerged as a possible candidate for a nonadrenergic, noncholinergic inhibitory neurotransmitter in penile erection. In this study, the effect of VIP and its relationship to the adrenergic and cholinergic mechanisms were examined using isolated corpus cavernosal strips from the rabbit penis. The mechanism of action of VIP on corporal relaxation was investigated with respect to the activation of cyclic GMP and the mobilization of calcium and potassium ions. VIP caused a dose-dependent relaxation of the cavernosal strip. Pretreatment with VIP had no effect on the contraction induced by norepinephrine, phenylephrine, and clonidine. VIP had no synergistic effect on the relaxation produced by acetylcholine or isoproterenol. Neither atropine nor propranolol had any blocking effect on the VIP-induced relaxation. Methylene blue decreased the VIP-induced relaxation of the cavernosal strip. VIP had no effect on the contraction induced by KCl at either 20 or 80 mM. In calcium-free high potassium physiologic salt solution, VIP inhibited the calcium-induced contraction. These results suggests that the mechanism of action of VIP is not mediated through classical adrenergic and cholinergic neurotransmission on rabbit cavernosal strips, but that VIP may exert its action by the activation of cyclic GMP, which may be associated, in part, with the inhibition of calcium influx. PMID- 7860420 TI - Growth factors (EGF, IGF-I) modulate the morphological differentiation of adult marmoset (Callithrix jacchus) Sertoli cells in vitro. AB - The effects of epidermal growth factor (EGF) and insulin-like growth factor I (IGF-I) on mature marmoset (Callithrix jacchus) Sertoli cells in vitro were investigated using light and electron microscopic and histochemical means. The morphological data were substantiated by morphometric analysis at the electron microscopic level. In a bicameral chamber system, cultured Sertoli cells displayed a high degree of ultrastructural differentiation and exhibited a polarized appearance. Basally located tight junctions joined adjacent cells. Germ cells of early stages of development were regularly seen. Under the influence of IGF-I, cells developed extensive cell-cell contacts. The surface density of smooth endoplasmic reticulum was increased. In contrast, the volume density of lipid inclusions was decreased. The morphological integrity of enclosed germ cells was maintained for a longer period. With EGF, cells were arranged in loose aggregates. Intercellular spaces were widened. The volume density of lipid inclusions was increased. Germ cells exhibited profound signs of degeneration early in culture, paralleled by increased development of phagolysosomes and high acid-beta-galactosidase activity. Under the influence of either growth factor, mitochondria displayed a shift from the crista to the tubulo-vesicular type. Mitochondrial dimensions and the volume density of mitochondrial compartment were increased. In comparison with control cultures all documented changes were statistically significant. Our findings indicate that marmoset Sertoli cells are target cells for EGF and IGF-I. Moreover, the dynamics of intercellular contacts, germ cell survival, and morphological indices of lipid and/or steroid metabolism seem to be differentially modulated. PMID- 7860421 TI - Immunoreactive parathyroid hormone-related protein is present in human seminal plasma and is of prostate origin. AB - Parathyroid hormone-related protein (PTHrP) is a regulatory peptide that has been associated with normal fetal growth and differentiation as well as the regulation of fetal calcium. We recently demonstrated the expression of PTHrP in neuroendocrine cells of human prostatic glands. The present study was undertaken to determine if semen contained PTHrP and to determine if there were any differences in seminal PTHrP between normal and vasectomized men. Radioimmunoassay was used to examine whether immunoreactive PTHrP in seminal fluid is secreted by the prostate. Significant quantities of immunoreactive PTHrP were detected in all seminal samples from normal men of ages 24-34 years (mean +/ SD, 12.94 +/- 8.2 ng/ml). Vasectomy did not decrease the semen levels of PTHrP (25.53 +/- 12.14 ng/ml). In addition, immunohistochemical evaluation with a monoclonal antibody used in our previous study did not show PTHrP immunostaining in the seminal vesicles. These findings indicate that seminal PTHrP is predominantly of prostatic origin. Moreover, the significant correlations between PTHrP and calcium levels in human seminal plasma from both normal (P < 0.001) and vasectomized (P < 0.02) patients suggest that PTHrP may serve as a regulatory factor of calcium secretion in the prostate. PMID- 7860422 TI - Immunocytochemical localization of glutathione S-transferase Yo subunit in the rat testis and epididymis. AB - The glutathione S-transferases (GSTs) are a family of isozymes that catalyze the conjugation of glutathione with electrophiles. These proteins exist as homo- or heterodimers and are separated into five classes (alpha, mu, pi, theta, and sigma). In the present study, the distribution of the GST Yo subunit, a member of the mu family, was examined immunocytochemically in the adult rat testis and epididymis using both light microscopy (LM) and electron microscopy (EM). In the testis, an intense immunoperoxidase reaction was observed over Leydig cells but not macrophages. Within the seminiferous epithelium, only weak reactivity was noted over Sertoli cells, spermatogonia, spermatocytes, and step 1-15 spermatids. There was, however, a progressive and dramatic increase in the intensity of staining in the cytoplasmic lobes of spermatids between steps 16 and 19. Residual bodies, representing the detached cytoplasmic lobes of the late step 19 spermatids, were also intensely stained. Initially seen near the lumen of the tubule, they eventually appeared at different levels of the tubule at stages IX XI; none were present at stage XII. Cytoplasmic droplets of step 19 spermatids were also intensely reactive. After spermiation, the cytoplasmic droplets of spermatozoa within the proximal region of the epididymis remained intensely stained. A noticeable decrease in staining was observed in the cauda epididymidis in those droplets that were still there. Quantitation of the labeling density (number of gold particles representing anti-Yo antigenic sites/microns 2) paralleled the LM results; for example, between step 15 and 19 spermatids, a greater than sevenfold increase in labeling density was noted. In the epididymis, a progressive increase in immunoreactivity was observed over epithelial principal cells from the initial segment to the cauda region of this tissue. There was little reactivity over basal, halo, or clear cells. In all reactive cells, gold particles were distributed randomly throughout the cytoplasmic matrix and nucleus. The present work thus demonstrates that, at the end of spermiogenesis, the GST Yo subunit is expressed at high levels in late spermatids. Furthermore, the presence of this protein in late spermatids and cytoplasmic droplets of spermatozoa suggests that this conjugating enzyme may play a role in protecting these cells from electrophilic attack. Also interesting is the correlation between the loss of reactivity in cytoplasmic droplets of spermatozoa of the distal region of the epididymis and the concomitant increase of reactivity in principal cells of this region. PMID- 7860423 TI - A new approach to study the architectural arrangement of spermatogenic stages revealed little evidence of a partial wave along the length of human seminiferous tubules. AB - Although evidence of the spermatogenic wave in humans has been reported, little is known about the architectural arrangement of stages along the length of tubules in men with varied rates of sperm production. To conduct these studies, methodology is needed to stage relatively long lengths of straight portions of tubules in several men. Testes obtained at autopsy were glutaraldehyde perfused. Six men representing a range of daily sperm production were selected for this study. Wedges composed of groups of seminiferous tubules attached to the rete testis and separated by testicular septa were teased apart from the remaining testicular tissue, fixed in osmium, and oriented during Epon embedding. This orientation allowed for sections to be cut perpendicular to the length of the group of tubules, beginning at the end near where the tubules had been attached to the rete testis. Also, a tubule isolated away from the rete testis was oriented for perpendicular sectioning for one of the men. Several serial sections were cut at a setting of 22 microns, and each was optically sectioned approximately at 7 microns and photographed using Nomarski optics. Because many cytoplasmic and nuclear features of spermatogonia, spermatocytes, and spermatids were distinguished in photomicrographs produced by Nomarski optics, this optical system facilitated the identification of stages of the spermatogenic cycle in human seminiferous tubules.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7860424 TI - Alterations of testicular function after induced autoimmune orchitis in rats. AB - The endocrinological profile of animals with experimental autoimmune orchitis (EAO) has not been sufficiently explored. With this purpose orchitis was induced in adult rats by active immunization with testicular homogenate (TH) and adjuvants. Animals were sacrificed 50 or 80 days after the first immunization. Forty-three percent of rats immunized with TH developed orchitis. Different degrees of cell sloughing and atrophy of the seminiferous tubules and numerous macrophages and lymphocytes in close association with Leydig cells were seen. A significant increase in the number of Leydig cells was observed in rats with orchitis killed at 50 and 80 days. An enhanced number of interstitial non-Leydig cells was also detected in rats with testicular damage killed at 80 days. Levels of serum follicle-stimulating hormone (FSH) were two- to threefold higher in rats with EAO compared to concentrations detected in other groups. Moreover, rats with orchitis had significantly increased testicular testosterone. Serum luteinizing hormone (LH) did not change in animals of any group. In vitro studies showed an increase in the basal and human chorionic gonadotropin (hCG)-stimulated testosterone production in rats with EAO. The increase in testicular steroidogenesis without a concomitant enhancement in serum LH levels detected in rats with autoimmune orchitis suggests the existence of local control mechanisms. PMID- 7860425 TI - Changes in the endocrinological milieu after clomiphene citrate treatment for oligozoospermia: the clinical significance of the estradiol/testosterone ratio as a prognostic value. AB - We have already reported that the rate of increase in the estradiol/testosterone ratio (E2/T ratio) following human chorionic gonadotropin (hCG) injection has prognostic value in the treatment of oligozoospermia. It was found that the rate of increase in the E2/T ratio was statistically greater in the therapeutically ineffective cases compared to the therapeutically effective cases. The present study was planned in order to elucidate the relationship between the changes in the endocrinological milieu, especially the change in the E2/T ratio, and the therapeutic efficacy when clomiphene citrate was administered. Thirty-eight oligozoospermic patients were administered 25 mg of clomiphene citrate daily for 3 months. Sixteen of the 38 (42.1%) cases showed improvement of more than 10 x 10(6)/ml in sperm concentration. The rate of increase in the E2/T ratio of the effective cases (0.90 +/- 0.43) during the administration of clomiphene citrate was statistically (P = 0.02) lower than that of the ineffective cases (1.44 +/- 0.80). The rate of increase in the E2/T ratio during clomiphene citrate treatment showed a statistically positive correlation (r = 0.542) with the rate of increase following hCG injection performed before clomiphene citrate treatment. The rate of increase in follicle-stimulating hormone (FSH) in the ineffective cases (2.16 +/- 1.01) was statistically higher than in the effective cases (1.50 +/- 0.43).(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7860426 TI - In vivo model for chronic direct intratesticular drug administration. AB - The efficacy and toxicity of a new method for chronic direct intratesticular drug infusion were assessed in a rat model. To this end, luteinizing hormone (LH) or buffer was infused via miniosmotic pumps for 14 days directly into the parenchyma of Copenhagen rat testes. The surgical manipulation and direct infusion of buffer did not have any apparent adverse effect upon either spermatogenesis or steroidogenesis as measured by testis weight, homogenization-resistant spermatid count, and in vitro response of the testes to a maximally stimulating concentration of LH. Histologic studies revealed only a localized inflammatory response in the testis around the Silastic tubing leading from the mini-osmotic pump to the testis. The biologic efficacy of direct infusion into the testis was assessed by determining the ability of mini-osmotic pump-infused LH to maintain steroidogenesis for 14 days in animals whose pituitary function was suppressed by simultaneous subcutaneous placement of testosterone/estradiol capsules. Steroidogenesis was found to be maintained quantitatively in testes infused with an appropriate dose of LH. At a given LH dose, the directly infused testes were found to produce fivefold more testosterone than contralateral testes and 10-fold more testosterone than testes from rats receiving systemic administration of the same dose of LH. We conclude that the miniosmotic pump system is a useful means to chronically administer a high concentration of LH, and presumably other agents, to the testis without any significant adverse effects. PMID- 7860427 TI - Nanovid microscopy for assessing sperm membrane changes induced by in vitro capacitating and acrosomal reacting procedures. AB - This study was to verify the usefulness of Nanovid microscopy techniques for evaluating induced modifications in bovine spermatozoal membranes. Frozen thawed bovine sperm were labeled with 20-nm colloidal gold particles bound to concanavalin A (ConA) or heparin ligands. Sperm membrane changes were induced in vitro by capacitating and acrosome-reacting procedures. Capacitation was induced by incubation with 10 micrograms/ml of heparin for 4 hours at 37 degrees C, 5% CO2, and high humidity. Membrane changes associated with the acrosome reaction were induced by addition of lysophosphatidylcholine (100 micrograms/ml) and incubation for 15 minutes at 37 degrees C, 5% CO2, and high humidity. Gray intensity (black = 0; white = 255) of sperm (ONCELL) and background (OFFCELL) were evaluated with computer-enhanced videomicroscopy with either differential interference contrast (DIC) or Nanovid optics. A high gold concentration on a membrane region produced blacker video pictures with Nanovid microscopy. Gray intensity of video pictures of a region with little or no gold would have a gray intensity equal to or greater than that of the background, that is, toward white. Weighted least squares methods were used to analyze ONCELL data using OFFCELL as a covariate. In experiment 1, ONCELL intensities of cells labeled with ConA-gold complex were lower than those labeled with heparin-gold at the same treatment level. In experiment 2, ONCELL intensity decreased as the concentration of heparin-gold increased from 0 to 0.041 microgram/microliter heparin. ONCELL intensity significantly decreased after sperm were treated with the highest heparin-gold level and acrosome reacted.(ABSTRACT TRUNCATED AT 250 WORDS) PMID- 7860428 TI - Effect of bovine oviductal estrus-associated protein on the ability of sperm to capacitate and fertilize oocytes. AB - At estrus, an oviduct-specific, estrus-associated glycoprotein (EAP) of molecular weight 85-95,000, is secreted by the oviductal epithelium and found in cannula derived bovine oviductal fluid (ODF). The objectives of these studies were to determine if bovine sperm were capacitated by EAP in vitro, whether this effect differed for EAP derived from ODF versus conditioned medium from oviduct ampullar explants, and to determine if sperm capacitated in vitro with EAP-fertilized bovine eggs. Sperm were incubated for up to 6 hours with partially purified EAP derived from ODF and assessed for capacitation by their ability to undergo the acrosome reaction following exposure to lysophosphatidylcholine. At 4 hours of incubation, the number of capacitated sperm in treatments containing 50% ODF or EAP plus bovine serum albumin (BSA) was similar, and it was significantly greater than the number of capacitated sperm in treatments containing antibodies to EAP. Using purified EAP derived from ampullar explant-conditioned medium, twice the number of sperm were capacitated after 4 hours with EAP from conditioned medium or with ODF than with treatments containing anti-EAP. The fertilizing ability of sperm incubated with EAP was significantly greater than that for sperm incubated without EAP or with anti-EAP. We conclude that bovine EAP, derived from both ODF and in vitro cultures, promotes sperm fertilizing ability. PMID- 7860429 TI - A new method to generate canine seminal emission and its application to men: direct electrical stimulation of the vas deferens. AB - Seminal emission from the ejaculatory duct (SEED) by direct electrical stimulation of the vas deferens was investigated in the dog, and the technique was applied to men. The stimulus parameters used were 2 msec, 10 Hz, and 8 V for dogs or 15-20 V for humans. In vitro studies using tetrodotoxin demonstrated that the major portion of the muscle contraction under the above stimulation was neurogenic. The stimulation of the pars epididymica, the middle vas, or the ampulla of the vas caused SEED in all dogs having intact hypogastric nerves (HNs) and receiving transection of bilateral HNs 1, 6, and 12 months before electrical stimulation. The dye instilled into the canine cauda epididymis was transported to the ampulla and emitted into the posterior urethra by electrical stimulation of the vas regardless of the site stimulated. The electrical stimulation of eight vasa deferentia (pars epididymica) of five prostatic carcinoma patients generated emission from the severed proximal end of all vasa examined at orchidectomy. All of the stimulations of 13 middle vasa of seven patients with emission loss caused SEED. The above results indicate that direct electrical stimulation of the canine and human vas deferens causes SEED regardless of the site stimulated or the absence of HNs, which are the major pathway of the efferent signal for SEED. PMID- 7860430 TI - Phosphatidylcholine enhances the acrosomal responsiveness of human sperm. AB - Supplementing bovine serum albumin-containing medium with phosphatidylcholine (PC) accelerated the in vitro development of human sperm acrosomal responsiveness. Responsiveness was assessed by exposing the sperm to progesterone. The maximum effect was produced by incubation with 100 micrograms PC/ml, which resulted in 40% (23-56%) (mean, 95% confidence limits) of the sperm becoming responsive to progesterone at 24 hours, compared to 23% (10-40%) of control sperm. Enhancement was apparent after as little as 6 hours of incubation in vitro, and the number of responsive sperm was still increasing at the last time point tested (30 hours). PC had no apparent ill effects; it did not alter the percentage of motile sperm or the percentage of sperm stained with the supravital stain, Hoechst 33258. Enhanced responsiveness required prolonged incubation in PC, because PC was not effective when it was only applied at the same time as progesterone. Lysophosphatidylcholine did not enhance acrosomal responsiveness when used at concentrations from 10 ng/ml to 100 micrograms/ml, indicating that the effect of PC was not due to trace amounts of lysophosphatidylcholine. PC also increased the response of sperm to the Ca2+/H(+) exchanging ionophore, ionomycin, suggesting that PC modifies an event that is coincident with or subsequent to the rise in intracellular free Ca2+ that is triggered by progesterone. PMID- 7860431 TI - Post-thaw bovine spermatozoal quality estimated from fresh samples. AB - Comparisons were made among flow cytometrically quantified populations of fresh and cryopreserved bovine spermatozoa, tri-stained with fluorophores rhodamine 123 (R123), 5- (and 6-) carboxy-4',5'-dimethylfluorescein diacetate (CMFDA), and propidium iodide (PI), and analyzed by dual parameter flow cytometry. The purpose was to find parameters in fresh semen samples that were potentially predictive of frozen sample parameters so that bulls with marginal cryopreservation capacity could be identified. Fresh and cryopreserved aliquots of semen from two sets of six bulls were semen processed in either milk (bulls 1-6) or egg yolk citrate (bulls 11-16). Membrane-damaged red (PI) and intact green (CMFDA + R123) populations were evaluated as percentages of 10,000-cell samples or numbers per straw. In milk, gated central subsets of membrane-damaged sperm cells in fresh samples and moribund cells in post-thaw samples were significantly correlated for sample percentages (r = 0.90, P = 0.014) and cell numbers per straw (r = 0.94, P = 0.006). In egg yolk citrate, fresh and frozen membrane-damaged populations were correlated (percentages: r = 0.81, P = 0.048; numbers: r = 0.88, P = 0.019). Additionally, post-thaw motility estimated by a photographic method was correlated with the number of sperm cells per straw in the intact central green subset (r = 0.98, P = 0.0006). These findings suggest that partitioning red and gree populations into smaller, central subset populations reveals significant relationships between fresh and cryopreserved bull ejaculates. The proportion of membrane-damaged spermatozoa in fresh semen seems to be predictive of the proportion of post-thaw membrane-damaged or moribund spermatozoa. The data consistently showed ejaculates of bulls 1 and 12 as having the greatest cryopreservation potentials, and bulls 4 and 16 the least. Thus, flow cytometric evaluation of fresh semen may be useful for identifying young sires with relatively poor fertilizing potential. PMID- 7860432 TI - Large-cell anaplastic lymphoma of the gastrointestinal tract: an immuno- and genotypic study on archival material. AB - Primary large-cell anaplastic lymphomas (LCAL) presenting in the gastrointestinal tract are rare and sometimes difficult to distinguish from nonlymphoid tumors. Because recognition of these tumors as lymphoma has clinical and prognostic implications for the patient, the diagnostic contribution of genotyping by polymerase chain reaction (PCR) and of immunophenotyping was evaluated in 16 routinely processed samples of gastric and small-intestinal LCALs. Gene rearrangement analysis was done with primers for the immunoglobulin heavy (IgH) and T-cell receptor gamma(TCR gamma) chain. Nine of the 16 cases were assigned to T- or B-lymphoid lineage immunophenotypically. Twelve of the 16 samples had a predominant T- or B-cell clone by PCR. Combination of both methods resulted in lineage assignment of 14 cases (9 T-LCAL, 5 B-LCAL). Two LCAL samples were EBV positive by PCR, one also by immunophenotyping. High expression levels of p53 did not correlate with the presence of EBV or cell lineage. Thus, gene rearrangement studies on routinely processed biopsy specimens by PCR are practical and add to the diagnostic repertoire in cases of gastrointestinal large-cell tumors of immunophenotypically undefined lineage. PMID- 7860433 TI - Growth of sensitive and drug-resistant human myeloid leukemia cells in SCID mice. AB - Drug resistance is a critical problem in the therapy of hematologic malignancies. Recent advances in the transplantation of human normal and transformed hematopoietic cells into severe combined immunodeficient (SCID) mice provide an opportunity to study the biologic and molecular events that mediate resistance. We studied the engraftment of several human myelogenous leukemia cell lines sensitive and resistant to amsacrine (mAMSA), vincristine, hycamptamine, methotrexate, or doxorubicine (KBM3/AMSA, K562/Vcr, HL60/Hy10, K562/MTX, HL60/Dox). The distribution and growth potential of these cells was evaluated using molecular and histologic techniques. Inoculation of 2 x 10(7) leukemic cells led to manifestation of disease, and subsequent tissue analysis showed evidence of leukemia. The survival of mice varied from 21 to 135 days. Terminally, the animals showed symptoms of wasting, development of local tumors, or both. Massive leukemic dissemination with infiltration of bone marrow and various organs including lungs, spleen, liver, ovaries, and brain was detected in most cases. No differences were observed in the tissue distribution of sensitive as compared to resistant leukemia cells. These findings demonstrated that human leukemic cells retain, in SCID mice, the clinico-pathologic picture of the original disease in humans. The development of numerous drug-resistant phenotypes in vitro does not alter the subsequent behavior of resistant cells in vivo when compared with sensitive counterparts. The levels of resistance are not modified by passage through SCID mice. This model offers an opportunity for developing new preclinical in vivo systems for modulation of drug resistance, and the combination of this in vivo model with gene transfer methods will also provide an important system for testing the molecular alterations involved in drug resistance and leukemic progression. PMID- 7860434 TI - Characteristics and outcome of patients with acute lymphocytic leukemia and myeloperoxidase-positive blasts by electron microscopy. AB - The purpose of the study was to analyze the clinical and laboratory characteristics of patients with acute lymphocytic leukemia (ALL) who exhibited myeloperoxidase-positive blasts by electron microscopy (EM-MPO-positive), and assess their response to therapy and their prognosis. Since 1988, 21 adults with newly-diagnosed ALL and EM-MPO-positive blasts were referred to our service. In addition to documentation of their clinical and hematopathologic characteristics, patients underwent cytogenetic, immunophenotypic, molecular, and electron microscopic evaluations. Twenty patients were treated with the vincristine Adriamycin-dexamethasone (VAD) regimen, and one patient was induced with amsacrine and high-dose cytosine arabinoside (ara-C). The 21 patients were among 141 patients with ALL (15%) seen during the same period. Their median age was 46 years (range 15 to 77 years). The immunophenotype was T-cell ALL in 12 patients (57%). Karyotypic studies did not demonstrate specific recurrent abnormalities. The median percentage of EM-MPO-positive blasts was 15% (range 3% to 45%). Eighteen patients (85%) had high-risk ALL. With induction chemotherapy 15 of 20 (75%) receiving VAD therapy achieved a complete remission (CR). However, the median CR duration was 18 months, and the median survival was 18 months with a 3 year disease-free survival rate of 25%. There were eight relapses and one lineage switch to acute myelogenous leukemia (AML). Patients with ALL and EM-MPO-positive disease are a unique subgroup with long-term poor prognosis on conventional anti ALL therapy, and may benefit from intensification treatments with agents effective against AML. PMID- 7860435 TI - Establishment of a human thymic stromal cell line (R-3-4) and its adhesive capacity with T cells in vitro. AB - T cells are considered to be activated in the thymus, and it has been emphasized recently that the thymic stromal cells play an important role in the process of T cell maturation. To clarify how the stromal cells interact with T cells a cloned stromal cell line from human thymus was established and its adhesive capacity with T cells was studied. A recombinant plasmid, pSV3gpt containing SV40 large T antigen was introduced to human thymic stroma by the calcium phosphate co precipitation method, and the thymic stromal cell line R-3-4 was obtained. Immunohistochemical examination showed that R-3-4 possessed with HLA-class 1 antigen, laminin, fibronectin, and keratin. To determine if the R-3-4 interacts with T cells, the binding activity of R-3-4 with T cells examined by using rosette formation technique. The R-3-4 formed rosette only with the T cells, but both B cells and myeloid cells did not bind to the R-3-4. This rosette formation between R-3-4 and T cells was inhibited when T cells were pretreated with anti CD2 antibodies, suggesting that some mechanism involving CD2 participates in this binding. Our novel established thymic stromal cell line might be useful for studying the interactions between thymic stroma and T cells in vitro. PMID- 7860436 TI - Red cell transfusion therapy in chronic anemia. AB - This article discusses anemia, the evaluation of symptoms, and the compensatory mechanisms that are brought into play by chronic anemia. The oxygen dissociation curve is described as is the effect of 2,3-DPG on hemoglobin-oxygen binding. Human tolerance to anemia is discussed and the article concludes with proposed transfusion strategies in chronic anemia. PMID- 7860437 TI - Transfusion therapy in congenital hemolytic anemias. AB - Transfusion with red blood cells is a mainstay in the prevention or treatment of complications associated with the more serious congenital hemolytic anemias. These disorders include hemoglobinopathies, red cell enzyme deficiency disorders, and abnormalities of the red cell membrane. Particular emphasis is devoted to the relatively common hemoglobin disorders, including sickle cell disease and thalassemia syndromes. PMID- 7860439 TI - Transfusion therapy in the patient undergoing hematopoietic stem cell transplantation. AB - Optimal transfusion therapy for the patient undergoing stem cell transplantation will vary, depending on a variety of independent factors. These factors include the source of hematopoietic progenitor cells, The relationship between donor and recipient, and the timing of the transfusion relative to the transplant. Stem cell transplantation also changes the traditional views of blood groups: a patient may have more than one of the traditional blood groups at different stages of transplantation. PMID- 7860440 TI - Transfusion therapy in solid organ transplantation. AB - Numerous transfusion issues arise in the support of solid organ transplantation. ABO and HLA can cause graft rejection immunity or problems in transfusion support. Blood usage has been reduced by the use of erythropoietin in renal failure and aprotinin during liver transplants. Multifactorial coagulopathy during liver transplant surgery continues to be a challenge requiring close monitoring, however. The beneficial effect of transfusions on graft survival has lessened in recent years, but remains an area of active research. PMID- 7860441 TI - Therapeutic support of the patient with thrombocytopenia. AB - This article provides an update on the methods of collection, preservation, storage, and administration of platelet concentrates. The current indications for platelet transfusions are reviewed, and current knowledge concerning alloimmunization and its prevention is summarized. In addition, the ongoing controversies related to prophylactic administration of platelets versus therapeutic administration are reviewed. PMID- 7860438 TI - Transfusion therapy in autoimmune hemolytic anemia. AB - Autoimmune hemolytic anemias include warm and cold reactive autoimmune hemolytic anemias (WAIHA and CAD), paroxysmal cold hemoglobinuria (PCH), and drug-induced hemolytic anemias. If autoimmune hemolytic anemia is suspected, the clinical history should be communicated to the transfusion service, because specific tests to confirm these diagnoses are not routinely performed. This includes evaluation of the patient's RBCs for bound IgG and complement (direct antiglobulin test) and evaluation of the patient's serum for antibodies with RBC specificity. For warm or cold autoimmune hemolytic anemia, special procedures including autoabsorption may be necessary to identify underlying RBC alloantibodies prior to transfusion. Transfused RBCs may not have normal survival in patients with RBC autoantibodies. The decision to transfuse should consider the patient's need for oxygen-carrying capacity, the risk of withholding transfusion, and the potential benefit of alternative therapy. PMID- 7860442 TI - Granulocyte transfusion therapy. AB - Although the efficacy of therapeutic granulocyte transfusions as treatment for progressive infections in severely neutropenic patients is supported by the medical literature, this form of therapy is not widely accepted because it has been extremely difficult to transfuse an adequate dose of compatible granulocytes. Recently, the possibility has been raised to greatly increase the number of granulocytes collected by stimulating normal donors with recombinant granulocyte colony-stimulating factor. Accordingly, it is reasonable to reassess the possible role for granulocyte transfusions as therapy for progressive bacterial, yeast, and fungal infections. PMID- 7860443 TI - Transfusion therapy in congenital coagulopathies. AB - Transfusion therapy for the congenital coagulopathies has changed considerably in recent years. Improved donor screening, purification, and virucidal methodologies have resulted in much safer plasma-derived clotting factor concentrates. Additionally, synthetic products such as rF VIII and DDAVP are licensed and available. For persons with hemophilia B, nonthrombogenic coagulation F IX concentrates are available. Treatment recommendations for each of the congenital coagulopathies are discussed. PMID- 7860444 TI - Transfusion therapy in acquired coagulopathies. AB - Acquired coagulopathies, such as are observed in patients with liver disease, uremia, and acute disseminated intravascular coagulation, are complex disorders usually involving a combination of deficiency of multiple coagulation factors, platelet dysfunction, and thrombocytopenia. Transfusion of specific blood products, such as fresh-frozen plasma, platelets, and cryoprecipitate, may be effective in the treatment and prevention of hemorrhage in patients with these disorders; however, the optimal regimens continue to be defined. Because the risks of virus transmission along with hemolytic and allergic reactions continue to accompany blood product transfusions, nontransfusional forms of treatment of acquired coagulopathies, such as desmopressin acetate, antifibrinolytic agents, and aprotinin, have assumed greater roles in the treatment of these hemostatic disorders. Much work remains to define better the most effective and safest approach to the treatment of the acquired coagulopathies. PMID- 7860445 TI - Mononuclear cell adoptive immunotherapy. AB - In contrast with red cells, platelets, and granulocytes, hemotherapy using lymphocytes and monocytes is only beginning to be explored. Blood banks and transfusion services, the traditional sources of expertise in sterile cell processing, storage, and transfusion, have played an integral role in the early technical development of mononuclear cell adoptive immunotherapy, and are logical partners in its future. This article reviews the clinical experience with this novel transfusion therapy. PMID- 7860446 TI - Issues in transfusion therapy in the patient with malignancy. AB - Transfusion medicine has emerged in the wake of therapeutic successes in almost every branch of medicine to optimize blood product support and minimize consequent complications. The role of transfusion therapy has become increasingly more critical as improved therapeutic regimens augment the survival of the patient with malignancy. Perhaps more so than in any other field, recognition of long-term sequelae of transfusion in oncology depends upon short-term success. Every day, blood products are collected, selected, modified, and created with specific clinical intentions in mind. The practitioner in hematology/oncology needs to understand both the benefits and consequences of transfusion therapy, with an increased emphasis on the long-term implications and complications. PMID- 7860448 TI - Prescribing practices in Britain. PMID- 7860447 TI - Prescribing practices in Britain. PMID- 7860449 TI - Prevalence and risk factors of psychopathology in Ethiopian children. AB - OBJECTIVE: To determine the prevalence and risk factors associated with psychopathology in Ethiopian children aged 6 to 11 years living in Jimma town. METHOD: The mothers of 611 randomly selected children (317 boys and 294 girls) were interviewed to determine the presence of 64 child problem behaviors. Scores on the Child Behavior Problem Questionnaire were normed and reduced to eight subscales using responses to a second scale developed by the World Health Organization (the Reporting Questionnaire for Children). Measures of maternal psychopathology, family stress, and child disability were included. RESULTS: Separate analyses conducted for boys and girls yielded prevalence rates of 21.45% for boys and 25.17% for girls. Principal-components analyses identified common syndromes such as aggressive, anxious, delinquent, depressed, hyperactive, uncommunicative, and immature. Two additional syndromes, hostile/withdrawn and insecure, were particularly prevalent. Children whose mothers reported more psychiatric symptoms for themselves tended to score higher on at least one of the pathology subscales. CONCLUSIONS: On a measure developed for Ethiopian children, the prevalence and risk factors were similar to those found in other countries. Several differences in syndromes indicate the need for culture-specific analyses of psychopathology in children. PMID- 7860450 TI - Combined pharmacotherapy: an emerging trend in pediatric psychopharmacology. PMID- 7860451 TI - Demographic and clinical features of obsessive-compulsive disorder in children and adolescents. AB - OBJECTIVE: To describe the demography, symptomatology, and comorbidity of 31 clinically referred children and adolescents with obsessive-compulsive disorder. METHOD: The patients were assessed in an outpatient clinic for lifetime psychopathology with the Diagnostic Interview for Children and Adolescents. The child and adolescent version of the Yale-Brown Obsessive Compulsive Scale (CY BOCS) was used to group obsessive-compulsive symptoms and rate symptom severity. Demographic, medical, developmental, academic, and behavioral information was recorded by the parents in the Yale Children's Inventory and the Child Behavior Checklist. RESULTS: The male-female ratio was approximately 3:2. Most patients had had multiple obsessions and compulsions that had changed over time. The CY BOCS correlated highly with another measure of obsessive-compulsive behavior, but not with any of the Child Behavior Checklist scales. Symptom severity was influenced by an interaction between gender and age at onset of the illness. More than 80% of the subjects had other lifetime psychiatric diagnoses. CONCLUSIONS: The results provide further evidence that obsessive-compulsive disorder is a chronic, severe illness in children and adolescents that is often associated with other forms of psychopathology. The data support the concurrent and discriminant validity of the CY-BOCS. PMID- 7860452 TI - Disulfiram in adolescence? PMID- 7860453 TI - Whole blood serotonin and disruptive behaviors in juvenile obsessive-compulsive disorder. AB - OBJECTIVE: The study was conducted with children and adolescents with obsessive compulsive disorder (OCD) to assess the relationship of whole blood serotonin (5 HT) content to a concurrent diagnosis of a disruptive behavior disorder (DBD) and to severity ratings of aggressive behavior. METHOD: Eighteen children and adolescents who met DSM-III-R criteria for OCD were evaluated with a structured interview, clinician rating scales, and the Child Behavior Checklist (CBCL). Blood 5-HT concentration was assayed with a fluorometric procedure. Relationships among categorical diagnoses, dimensional ratings, and blood 5-HT content were analyzed with bivariate and multivariate techniques. RESULTS: OCD subjects with a DBD (n = 6) had significantly higher scores than those without a DBD (n = 12) on the Total Problem scale, the Externalizing Problem scale, and several of the behavioral syndrome scales of the CBCL. Blood 5-HT concentrations were significantly lower in those with a DBD than in those without a DBD, and blood 5 HT concentrations had significant negative correlations with the Total score, the Externalizing score, and the Aggressive Behavior score of the CBCL. CONCLUSIONS: The results provide further evidence of a significant relationship between aggressive behavior and serotonergic functioning. PMID- 7860454 TI - Similarities in response to fluoxetine in the treatment of children and adolescents with obsessive-compulsive disorder. AB - OBJECTIVE: Obsessive-compulsive disorder (OCD) is a relatively common disorder that frequently has its onset in childhood and is associated with substantial morbidity and dysfunction despite availability of new treatments. However, antiobsessional agents have not been systematically evaluated in young children and their effectiveness beyond the short term has not been well studied. The purpose of this study was to evaluate the usefulness of fluoxetine in the long term treatment of both children and adolescents with OCD. METHOD: All pediatric patients with a DSM-III-R diagnosis of OCD who were treated with fluoxetine were ascertained from retrospective chart reviews of a pediatric psychopharmacology clinic. Response to treatment was evaluated by experienced clinicians using the Clinical Global Impression Scale. RESULTS: Of 38 identified patients, 28 (74%) showed moderate to marked improvement of OCD symptoms on doses averaging 50 mg/day (1.0 mg/kg per day) over an average follow-up period of 19 months. Similar effects were observed in children and adolescents. CONCLUSION: Although limited by their retrospective nature, these findings indicate that fluoxetine may be effective in prepubertal children and that the effect can be sustained over time. PMID- 7860455 TI - Case study: obsessive-compulsive disorder after severe traumatic brain injury in an adolescent. AB - The neurological underpinnings of obsessive-compulsive disorder (OCD) are still largely undetermined. We report a prospective case study of a young subject who developed OCD and impulsive aggression after traumatic brain injury. The implications are that frontal and temporal lobe lesions may be sufficient to precipitate OCD in the absence of clear striatal injury and that compulsivity and impulsivity may represent different psychophysiological states. PMID- 7860456 TI - An open trial of guanfacine in the treatment of attention-deficit hyperactivity disorder. AB - OBJECTIVE: Medications such as clonidine have been shown to facilitate calming, to enhance frustration tolerance, and to reduce aggression in hyperactive children. The use of guanfacine (Tenex), an alpha 2 noradrenergic agonist similar to clonidine, was studied as an alternative because of its longer excretion half life, decreased sedative side effects, and more selective binding profile. METHOD: Thirteen psychiatric outpatients diagnosed with ADHD were rated at baseline and while taking guanfacine to determine its efficacy as a treatment for ADHD. Comparisons of Conners parent ratings within subject were used to measure behavioral changes in the subjects. RESULTS: During guanfacine treatment, patients' mean scores improved significantly overall (1.27 off, 0.85 on, t = 2.55, p < .015) and in Conners Hyperactivity (1.63 off, 0.94 on, t = 3.69, p < .01), Inattention (1.92 off, 1.21 on, t = 3.32, p < .01), and Immaturity (1.81 off, 0.92 on, t = 3.77, p < .01) factors. CONCLUSIONS: This preliminary study indicates that guanfacine is a beneficial and useful treatment of ADHD, reducing hyperactive behaviors and enabling greater attentional ability with minimal side effects. We are currently collecting data in a double-blind study measuring guanfacine's efficacy with and in comparison to methylphenidate. PMID- 7860457 TI - Case study: maternal residual attention deficit disorder associated with failure to thrive in a two-month-old infant. AB - A male infant was admitted twice during his second month of life for failure to thrive. An extensive organic workup was unremarkable. During the second admission, the pediatric inpatient psychiatry team was consulted. Evaluation led to the diagnosis of residual attention deficit disorder in the mother. Inattention and impulsivity hampered mother's ability to feed the child. Successful treatment of mother's residual attention deficit disorder with methylphenidate led to significant improvement in the infant's feeding, subsequent weight gain, and observed maternal-child interaction. PMID- 7860458 TI - Father involvement and cognitive/behavioral outcomes of preterm infants. AB - OBJECTIVE: To assess the independent effect of father involvement on intellectual and behavioral outcome of 985 low birth weight preterm infants followed longitudinally from birth to age 3 years as part of the Infant Health and Development Program. METHOD: The sample for this study is drawn from eight urban sites, composed largely of ethnically diverse and relatively disadvantaged families. On the basis of a combined score for father's stable presence in the home and amount of play with the infant, we defined extreme groups of high involvement fathers (33%, n = 305) and low-involvement fathers (16%, n = 148), with the remainder as a middle group (51%). RESULTS: Most fathers played a meaningful role as play partner with their high-risk infants. Approximately 75% of fathers were reported to play with the baby every day at 12 (peak), 24, and 36 months. Fathers who were black, younger, had teenage mothers as companions, or were from low-income families were less involved with their infants. For black fathers, low family income was significantly associated with low father involvement. Within the black ethnic subgroup only, higher father involvement was associated with improved cognitive outcome. Mean IQ for the high-involvement subgroup was 6.00 points higher than for the low-involvement group even after adjusting for family income, neonatal health, treatment group status, and paternal age. CONCLUSION: Father involvement enhances cognitive outcome in black families and may have implications for intervention. PMID- 7860459 TI - The public discussion of homosexuality. PMID- 7860460 TI - Influence of race on diagnosis in adolescent psychiatric inpatients. AB - OBJECTIVE: To examine racial differences in 352 psychiatric inpatients, aged 12 to 18 years, at a state hospital facility that accepted admissions from throughout South Carolina. These were all the adolescent admissions during an entire calendar year (1988). There were 101 African-American and 251 white subjects. METHOD: The data were abstracted from patients' hospital medical records and nursing incident reports. DSM-III-R discharge diagnoses were assigned to five non-mutually exclusive groupings (organic/psychotic, mood/anxiety, disruptive, personality, substance abuse). Racial differences were analyzed using chi 2, logistic regression, and T statistics. RESULTS: African-Americans were more likely to be involuntarily committed at the time of admission (p = .010). Organic/psychotic diagnoses were much more frequent in African-Americans (odds ratio = 3.15, p < .003). Whites (p = .0347) were almost two times more likely to receive mood/anxiety diagnoses even when controlling for gender, type of admission, and comorbid diagnoses. Substance abuse was more often diagnosed in whites (odds ratio = 5.46, p < .0001). CONCLUSIONS: This study identifies significant racial differences in the discharge diagnoses of psychiatrically hospitalized adolescents. African-Americans have fewer mood/anxiety and substance abuse diagnoses but significantly more organic/psychotic diagnoses. Some of these differences may reflect ethnocentric clinician bias in the diagnostic assessment of youth from differing cultural/racial backgrounds. PMID- 7860461 TI - Cognitive-behavioral psychotherapy for children and adolescents with OCD: a review and recommendations for treatment. AB - OBJECTIVE: To critically review the published literature on cognitive-behavioral psychotherapy for obsessive-compulsive disorder (OCD) in children and adolescents. METHOD: The psychiatric and psychological literature was systematically searched for "studies" applying cognitive-behavioral principles to children and adolescents with OCD. RESULTS: Thirty-two investigations, most of them single case reports, were identified. Despite manifold differences in terminology and theoretical framework, all but one showed some benefit for cognitive-behavioral interventions. Graded exposure and response prevention form the core of treatment; anxiety management training and OCD-specific family interventions may play an adjunctive role. Poor compliance, inadequately documented and inconsistently applied treatment, and lack of exportability were recurrent problems. CONCLUSIONS: Abundant clinical and emerging empirical evidence suggest that cognitive-behavioral psychotherapy, alone or in combination with pharmacotherapy, is an effective treatment for OCD in children and adolescents. Future research in this area will need to focus on comparisons of cognitive-behavioral psychotherapy to other treatments, on component analyses, and on the application of exportable protocol-driven treatments to divergent patient populations. PMID- 7860462 TI - Sexual, assaultive, and suicidal behaviors among urban minority junior high school students. AB - OBJECTIVE: A greater understanding of minority adolescents' involvement in sex and violence is an essential precursor to the development of effective prevention programs targeted at inner-city youths. METHOD: To estimate the prevalence of involvement in sexual, assaultive, and suicidal behaviors and to quantify the relative importance of demographic, psychosocial, and behavioral risk factors for those behaviors, a survey was administered in the spring of 1992 to a sample of 3,738 predominantly Hispanic and African-American students attending four junior high schools in an economically disadvantaged, medically underserved New York City school district. The mean age of participants was 13.5 years; 73.7% were Dominican, 6.9% were other Hispanic, and 10.4% were black. RESULTS: Thirty-one percent of males and 7% of females reported involvement in sexual intercourse, 27% of males and 8% of females reported involvement in assaultive behavior and 10% of males and 19% of females reported suicide intentions/attempts. The primary risk factor for sexual intercourse was a belief that involvement in intercourse was common and acceptable among peers. The primary risk factor for assaultive behavior was adverse social circumstances. The primary risk factor for suicide intentions/attempts was symptoms of depression. The risk for involvement in each of the three investigated risk behaviors was substantially increased by involvement in the other two behaviors. CONCLUSIONS: These findings underscore the urgent need for comprehensive sex and violence prevention programs targeted at urban minority junior high school students and suggest factors that may identify students at highest risk. PMID- 7860463 TI - Depressive symptoms and suicidal ideation among Mexican-origin and Anglo adolescents. AB - OBJECTIVE: To examine the prevalence of depressive symptoms and suicidal ideation, their comorbidity, and associated risk factors in adolescence. METHOD: A self-administered questionnaire was completed in class by students in three middle schools (grades 6 through 8) enrolling more than 3,200 students. Usable questionnaires were obtained from 2,614 (81.5%), of which 924 were Anglo and 1,354 were of Mexican origin Depression was measured using the 20-item Center for Epidemiologic Studies Depression Scale and suicidal ideation using four items on thoughts of death and suicide. RESULTS: The minority adolescents reported significantly higher crude prevalence rates of symptoms of depression and thoughts of suicide than their Anglo counterparts. Prevalence rates were highest for females of Mexican origin. There was a strong association between depression and suicidal ideation in both ethnic groups. Multivariate logistic regression analyses indicated significant correlates of depressive symptoms were suicidal ideation (adjusted odds ratio = 10.9), loneliness, and use of English, in that order. Significant correlates of suicidal ideation were depression (adjusted odds ratio = 10.6), loneliness, two-parent household, use of English, and being of Mexican origin. More than 80% of those with high ratings on suicidal ideation scored as depressed in both ethnic groups. CONCLUSIONS: Results are consistent with other studies suggesting rates of suicidal ideation among adolescents are in the 10% to 20% range, while rates of depressive symptoms are in the 35% to 50% range using standard caseness scores. Mexican-American youths appear to be at higher risk than Anglo youths, particularly for suicidal ideation. In addition, it appears that youths who are lonely are more likely to report higher rates of both depression and suicidal ideation. The data also indicate that youths who spoke only or mostly English reported lower rates of depression and suicidal ideation, suggesting that acculturation may play a role as well. PMID- 7860464 TI - Prevalence of psychiatric symptoms and their relation to adjustment among Chinese American youth. AB - OBJECTIVE: The primary purpose of this investigation is to assess psychiatric symptoms of Chinese-American children using Achenbach's Child Behavior Checklist (CBCL) and to determine the impact of acculturation on these symptoms. METHOD: One hundred eighty-one forms of a Chinese CBCL and a 10-item questionnaire on adjustment and ethnic patterns of socialization were completed by a parent or guardian of Chinese-American children attending a Chinese school in New York City. RESULTS: The sample's total problem, internalizing, externalizing, total competence, activities, and social scores were significantly lower than Achenbach's American norms by age and sex. Favorable adjustment was correlated significantly with lower total problem and internalizing scores. Recent immigrants did not have higher symptom scores. CONCLUSION: Lower scores of the Chinese-American children may be due to temperamental differences, underreporting by the respondent, or cultural intolerance of misbehavior. PMID- 7860465 TI - Falciparum malaria complicating cholestatic jaundice and acute renal failure. AB - Nine patients of acute falciparum malaria with severe hyperbilirubinemia developed acute renal failure (ARF). All of them had evidence of intrahepatic cholestasis and needed hemodialysis for several weeks; 7 survived and 2 died, one due to cerebral malaria, the other multiple organ failure. Interestingly, referal diagnosis did not include malaria as a cause of ARF in 8 out of 9 patients. PMID- 7860466 TI - Pregnancy with idiopathic thrombocytopenic purpura. AB - The management of ITP in pregnancy remains controversial, particularly with reference to labour management. Thirteen pregnancies in 9 women with ITP are analysed with respect to maternal and neonatal outcome. One pregnancy culminated in spontaneous abortion. Ten infants were born by vaginal delivery and two by Caesarean section. There were no maternal or perinatal deaths. Maternal morbidity was not increased significantly due to ITP and none of the infants had purpuric manifestations even with low platelet counts. It is concluded that the obstetric management of these patients should be individualised and should not be based on platelet count alone. PMID- 7860467 TI - Serum & tissue magnesium content in patients of aluminium phosphide poisoning and critical evaluation of high dose magnesium sulphate therapy in reducing mortality. AB - Role of high dose magnesium sulphate therapy was evaluated in 50 patients of Aluminium Phosphide (AIP) poisoning. Simultaneously serum and RBC magnesium levels were studied in these patients at six different points within first 24 hours. In non-survivors magnesium content of various tissues (brain, stomach, kidneys, liver, lungs and heart) was also estimated. Magnesium estimation (tissue as well as serum) was done using atomic absorption spectrophotometer. No significant difference was found in dose related mortality rates in patients treated with and without magnesium sulphate. The immediate causes of death in these patients included intractable shock, shock coupled with arrhythmias and adult respiratory distress syndrome (ARDS). Serum as well as RBC magnesium content was within normal range at all the six points (0, 1, 3, 6, 12 and 24 hours after arrival in hospital). Tissue magnesium content of various organs (in non-survivors) was more (p < 0.01) compared to that of corresponding organs in controls (accidental deaths). No significant alterations were seen in other serum electrolytes (Na, K, Ca, PO4). The data confirmed that neither there was any evidence of hypomagnesemia in these patients nor magnesium sulphate therapy improved survival. Survival can be improved (to some extent) with continuous cardiac monitoring and use of appropriate anti-arrhythmic agents. However, imposition of stringent restrictions on the free supply of AIP and caging of tablets in plastic packs with holes and spikes may yield better results in preventing AIP poisoning rather than treating these patients. PMID- 7860468 TI - Changes in 6 keto PGF1 alpha and TXB2 in patients with myocardial infarction. AB - A study was carried out on the plasma levels of 6 Keto PGF1 alpha and Thromboxane B2 (TXB2) in patients with acute myocardial infarction. Our results showed a generalized increase in the levels after acute myocardial infarction. The 6 Keto PGF1 alpha levels increased twice as compared to control values while the TXB2 levels increased nine times as compared to control values. The prostaglandin levels were found to increase from day 1 to day 3 and further from day 3 to day 7. In most of the patients with uncomplicated myocardial infarction the 6 Keto PGF1 alpha levels were higher than the TXB2 levels. In patients with myocardial infarction accompanied by arrhythmias the TXB2 levels dominated over the 6 Keto PGF1 alpha levels. PMID- 7860469 TI - Albendazole therapy for neurocysticercosis. AB - Based on clinical evaluation and computed tomography (CT) of the brain, 30 cases of neurocysticercosis were diagnosed. Diagnosis was supported by presence of histopathologically proven subcutaneous cysticerci in 12 cases. Three primary neurological syndromes were established i.e. epilepsy in 22 cases, increased intracranial tension in 6 cases and meningoencephalitis in 2 cases. Albendazole was administered orally in a dose of 15 mg/kg bodyweight/day for 30 days without prophylactic steroids. Follow up CT study at 3 months and 12 months revealed complete regression of all lesions in 2 cases, partial regressions in 14 cases and change in morphology in 4 cases. Transient appearence of fresh subcutaneous cysticerci as a side effect of therapy was noted in 4 cases. Albendazole, though acting slow, is considered a suitable alternative to praziquantel in medical management of parenchymal neurocysticercosis. PMID- 7860470 TI - Immunoglobulins in viral hepatitis. AB - Serum immunoglobulin G, M and A levels were studied in 4 patients of type A, 23 patients of type B and 23 cases of non A-non B hepatitis. Sixteen age and sex matched healthy individuals were stydied as controls. IgM levels were found to be significantly raised in all the 3 types of hepatitis patients as compared to those in controls, while IgG and IgA levels were not significantly altered in any type of hepatitis. There was no statistically significant difference between the increased levels of IgM in various types of hepatitis. No immunoglobulin response was found to be characteristic of any particular type of hepatitis. PMID- 7860471 TI - Ramipril vs captopril in mild to moderate hypertension. AB - Ramipril 5 mg once daily was compared to Captopril 50 mg twice daily in a randomised, double-blind, parallel group study in 60 patients with a diastolic blood pressure between 95 to 120 mmHg over a period of 2 months. Both drugs in the dose regimen used in this study exerted a similar anti-hypertensive effect at the end of 2 months of treatment resulting in a fall of supine diastolic blood pressure with Ramipril = 19.27 +/- 3.34 mmHg and Captopril = 19.15 +/- 2.63, in patients receiving the drugs without the diuretic. The mean fall in supine diastolic blood pressure 4 hours after the first dose of Ramipril was 6.5 mmHg and Captopril 8 mmHg. None of the patients developed first dose hypotension or orthostatic hypotension and there was no significant alteration of the heart rate in either group. The serum K+ levels remained unchanged in both groups of patients. Both drugs were well tolerated and there were no adverse effects observed on the liver, kidney, blood sugar or haemopoietic system. Based on the results of this study, it can be concluded that the antihypertensive efficacy of 5 mg ramipril in a once daily dose is equivalent to 50 mg captopril given twice daily. However an appreciably greater number of patients reported improvement in the "quality of life' parameters with ramipril as compared to captopril. Thus for the routine treatment of mild to moderate arterial hypertension, ramipril offers reliable antihypertensive efficacy in a once daily dose, thereby helping to improve patient compliance and making the treatment more economical. PMID- 7860473 TI - Drug resistance of S. typhi in Shimla. PMID- 7860472 TI - Choice of antibiotics for empiric treatment of serious infections. AB - We have compared the in vitro activity of commonly used aminoglycosides- Gentamicin and Amikacin with Ciprofloxacin to determine whether the latter has any role in the empiric treatment of serious bacterial infections. Our results indicate that ciproloxacin was comparable or had a better activity than gentamicin or Amikacin against clinical isolates. As it can be administered orally, hospitalization can be avoided in a large number of patients. PMID- 7860474 TI - Non-responsiveness to antimicrobial therapy. AB - During the course of treating patients the clinician is faced with the problem of non-response to drugs. The expected therapeutic benefit is not observed. The cause may lie in the diagnosis, sub-type of disease, in the resistance of invading micro-organism or the drug itself. The drug dose, frequency, duration, mode of administration, compliance may be inadequate, inappropriate; the patient's pharmacokinetic profile may be unexpected, unusual; there may be alteration in the receptor, population, type, compensatory mechanism of the body etc. The relative importance of the host, parasite and drug related factors varies with disease, type of patient and drug under consideration. In the second section of the Clinical Pharmacology series, the causes of non-responsiveness to drugs will be discussed with reference to a few common diseases. The principles are applicable to may others.